PMID- 30455681 TI - Role of Downregulation and Phosphorylation of Cofilin in Polarized Growth, MpkA Activation and Stress Response of Aspergillus fumigatus. AB - Aspergillus fumigatus causes most of aspergillosis in clinic and comprehensive function analysis of its key protein would promote anti-aspergillosis. In a previous study, we speculated actin depolymerizing factor cofilin might be essential for A. fumigatus viability and found its overexpression upregulated oxidative response and cell wall polysaccharide synthesis of this pathogen. Here, we constructed a conditional cofilin mutant to determine the essential role of cofilin. And the role of cofilin downregulation and phosphorylation in A. fumigatus was further analyzed. Cofilin was required for the polarized growth and heat sensitivity of A. fumigatus. Downregulation of cofilin caused hyphal cytoplasmic leakage, increased the sensitivity of A. fumigatus to sodium dodecyl sulfonate but not to calcofluor white and Congo Red and farnesol, and enhanced the basal phosphorylation level of MpkA, suggesting that cofilin affected the cell wall integrity (CWI) signaling. Downregulation of cofilin also increased the sensitivity of A. fumigatus to alkaline pH and H2O2. Repressing cofilin expression in A. fumigatus lead to attenuated virulence, which manifested as lower adherence and internalization rates, weaker host inflammatory response and shorter survival rate in a Galleria mellonella model. Expression of non phosphorylated cofilin with a mutation of S5A had little impacts on A. fumigatus, whereas expression of a mimic-phosphorylated cofilin with a mutation of S5E resulted in inhibited growth, increased phospho-MpkA level, and decreased pathogenicity. In conclusion, cofilin is crucial to modulating the polarized growth, stress response, CWI and virulence of A. fumigatus. PMID- 30455682 TI - Corrigendum: Collection and Curation of Transcriptional Regulatory Interactions in Aspergillus nidulans and Neurospora crassa Reveal Structural and Evolutionary Features of the Regulatory Networks. AB - [This corrects the article DOI: 10.3389/fmicb.2018.00027.]. PMID- 30455680 TI - Swine Enteric Colibacillosis in Spain: Pathogenic Potential of mcr-1 ST10 and ST131 E. coli Isolates. AB - This is a wide epidemiological study of 499 E. coli isolates recovered from 179 outbreaks of enteric colibacillosis from pig production farms in Spain during a period of 10 years. Most samples were of diarrheagenic cases occurred during the post-wean period (PWD) which showed to be significantly associated with ETEC (67%) followed by aEPEC (21.7%). On the contrary, aEPEC was more prevalent (60.3%) among diarrheas of suckling piglets, followed by ETEC (38.8%). STEC/ETEC or STEC were recovered in 11.3 and 0.9% of PWD and neonatal diarrhea, respectively. Detection of the F4 colonization factor was not significantly different between isolates recovered from neonatal pigs and those recovered post wean (40.5 versus 27.7%) while F18 was only present among PWD isolates (51.5% of ETEC, STEC, and STEC/ETEC isolates). We also found a high prevalence of resistance to colistin related to the presence of the mcr-1 gene (25.6% of the diarreagenic isolates). The characterization of 65 representative mcr-1 isolates showed that all were phenotypically resistant to colistin (>2 MUg/ml), and most (61 of 65) multidrug-resistant (MDR). Six ETEC and one STEC mcr-1 isolates were also carriers of ESBL genes. In addition, other seven mcr-1 isolates harbored mcr 4 (three ETEC) and mcr-5 (two ETEC and two aEPEC) genes. In the phylogenetic analysis of the 65 mcr-1 diarrheagenic isolates we found that more than 50% (38 out of 65) belonged to A-ST10 Cplx and from those, 29 isolates showed the clonotype CH11-24. In this study, we also recovered 18 ST131 isolates including seven mcr-1 carriers. To the best of our knowledge, this would be the first report of ST131 mcr-1 isolation in pigs. Worryingly, the swine mcr-1 ST131 carriers also showed MDR, including to trimethoprim-sulfamethoxazole, tobramycin, gentamicin and ciprofloxacin. In the PFGE-macrorestriction comparison of clinical swine and human ST131, we found high similarities (>=85%) between two pig and two human ST131 isolates of virotype D5. Acquisition of mcr-1 by this specific clone means an increased risk due to its special feature of congregating virulence and resistance traits, together with its spread capability. Here we show a potential zoonotic swine source of ST131. PMID- 30455684 TI - Enhanced Interferon-beta Response Contributes to Eosinophilic Chronic Rhinosinusitis. AB - Type I interferon (IFN-I, including IFN-alpha and IFN-beta) response has been implicated in eosinophilic inflammation, in addition to antiviral function. This study aimed to investigate the role of IFN-I in the pathogenesis of eosinophilic chronic rhinosinusitis (ECRS). IFN-alpha, IFN-beta, cytokine expression, and IFN beta cellular localization in the sinonasal tissue from control subjects and ECRS patients with nasal polyps (NP) were determined using real time-PCR, ELISA, and immunohistochemistry. ECRS was induced in wild-type (WT) and IFNAR1 knockout (Ifnar1 -/-) mice by intranasal challenge with Aspergillus protease and ovalbumin. Stromal cells cultured from NP tissue were stimulated by exogenous IFN beta, and their CCL11 production and IRF3, IRF7, STAT1, STAT2, and IRF9 gene and/or protein expression were measured. IFN-beta, IL-5, IL-13, and CCL11 expression was higher in the NP tissue from ECRS patients, compared to the control group. IFN-beta was highly colocalized with the CD11c+ cells in NP. IFN beta levels positively correlated with IL-5, IL-13, and CCL11 levels as well as the number of eosinophils in the NP tissue and CT score. The histological severity of ECRS, levels of IL-4, IL-5, IL-13, and CCL11 in the nasal lavage fluid, and total serum IgE levels were less in Ifnar1 -/- mice than in WT mice. CCL11 production, and STAT1 and STAT2 mRNA and STAT1, phospho-STAT1, and phospho STAT2 protein expression were significantly increased by exogenous IFN-beta in NP stromal cells. Our data suggest that IFN-beta response was upregulated in ECRS and may play role in ECRS development. IFN-beta may contribute to ECRS by enhancing CCL11 production. Thus, increased IFN-beta response in the sinonasal mucosa may underlie ECRS pathogenesis. PMID- 30455683 TI - A Distinct Esophageal mRNA Pattern Identifies Eosinophilic Esophagitis Patients With Food Impactions. AB - Eosinophilic esophagitis (EoE), a Th2-type allergic immune disorder characterized by an eosinophil-rich esophageal immune infiltrate, is often associated with food impaction (FI) in pediatric patients but the molecular mechanisms underlying the development of this complication are not well understood. We aim to identify molecular pathways involved in the development of FI. Due to large variations in disease presentation, our analysis was further geared to find markers capable of distinguishing EoE patients that are prone to develop food impactions and thus expand an established medical algorithm for EoE by developing a secondary analysis that allows for the identification of patients with food impactions as a distinct patient population. To this end, mRNA patterns from esophageal biopsies of pediatric EoE patients presenting with and without food impactions were compared and machine learning techniques were employed to establish a diagnostic probability score to identify patients with food impactions (EoE+FI). Our analysis showed that EoE patients with food impaction were indistinguishable from other EoE patients based on their tissue eosinophil count, serum IgE levels, or the mRNA transcriptome-based p(EoE). Irrespectively, an additional analysis loop of the medical algorithm was able to separate EoE+FI patients and a composite FI score was established that identified such patients with a sensitivity of 93% and a specificity of 100%. The esophageal mRNA pattern of EoE+FI patients was typified by lower expression levels of mast cell markers and Th2 associated transcripts, such as FCERIB, CPA3, CCL2, IL4, and IL5. Furthermore, lower expression levels of regulators of esophageal motility (NOS2 and HIF1A) were detected in EoE+FI. The EoE+FI -specific mRNA pattern indicates that impaired motility may be one underlying factor for the development of food impactions in pediatric patients. The availability of improved diagnostic tools such as a medical algorithm for EoE subpopulations will have a direct impact on clinical practice because such strategies can identify molecular inflammatory characteristics of individual EoE patients, which, in turn, will facilitate the development of individualized therapeutic approaches that target the relevant pathways affected in each patient. PMID- 30455685 TI - The Vacuolar Pathway in Macrophages Plays a Major Role in Antigen Cross Presentation Induced by the Pore-Forming Protein Sticholysin II Encapsulated Into Liposomes. AB - Cross-presentation is an important mechanism for the differentiation of effector cytotoxic T lymphocytes (CTL) from naive CD8+ T-cells, a key response for the clearance of intracellular pathogens and tumors. The liposomal co-encapsulation of the pore-forming protein sticholysin II (StII) with ovalbumin (OVA) (Lp/OVA/StII) induces a powerful OVA-specific CTL activation and an anti-tumor response in vivo. However, the pathway through which the StII contained in this preparation is able to induce antigen cross-presentation and the type of professional antigen presenting cells (APCs) involved have not been elucidated. Here, the ability of mouse bone marrow-derived dendritic cells (BM-DCs) and macrophages (BM-MPhis) stimulated with Lp/OVA/StII to activate SIINFEKL-specific B3Z CD8+ T cells was evaluated in the presence of selected inhibitors. BM-MPhis, but not BM-DCs were able to induce SIINFEKL-specific B3Z CD8+ T cell activation upon stimulation with Lp/OVA/StII. The cross-presentation of OVA was markedly decreased by the lysosome protease inhibitors, leupeptin and cathepsin general inhibitor, while it was unaffected by the proteasome inhibitor epoxomicin. This process was also significantly reduced by phagocytosis and Golgi apparatus function inhibitors, cytochalasin D and brefeldin A, respectively. These results are consistent with the concept that BM-MPhis internalize these liposomes through a phagocytic mechanism resulting in the cross-presentation of the encapsulated OVA by the vacuolar pathway. The contribution of macrophages to the CTL response induced by Lp/OVA/StII in vivo was determined by depleting macrophages with clodronate-containing liposomes. CTL induction was almost completely abrogated in mice depleted of macrophages, demonstrating the relevance of these APCs in the antigen cross-presentation induced by this formulation. PMID- 30455686 TI - CD9 Controls Integrin alpha5beta1-Mediated Cell Adhesion by Modulating Its Association With the Metalloproteinase ADAM17. AB - Integrin alpha5beta1 is a crucial adhesion molecule that mediates the adherence of many cell types to the extracellular matrix through recognition of its classic ligand fibronectin as well as to other cells through binding to an alternative counter-receptor, the metalloproteinase ADAM17/TACE. Interactions between integrin alpha5beta1 and ADAM17 may take place both in trans (between molecules expressed on different cells) or in cis (between molecules expressed on the same cell) configurations. It has been recently reported that the cis association between alpha5beta1 and ADAM17 keeps both molecules inactive, whereas their dissociation results in activation of their adhesive and metalloproteinase activities. Here we show that the tetraspanin CD9 negatively regulates integrin alpha5beta1-mediated cell adhesion by enhancing the cis interaction of this integrin with ADAM17 on the cell surface. Additionally we show that, similarly to CD9, the monoclonal antibody 2A10 directed to the disintegrin domain of ADAM17 specifically inhibits integrin alpha5beta1-mediated cell adhesion to its ligands fibronectin and ADAM17. PMID- 30455687 TI - Tumor-Derived Microvesicles Enhance Cross-Processing Ability of Clinical Grade Dendritic Cells. AB - Tumor cells release extracellular microvesicles (MVs) in the microenvironment to deliver biological signals to neighboring cells as well as to cells in distant tissues. Tumor-derived MVs appear to play contradictory role promoting both immunosuppression and tumor growth and both evoking tumor specific immune response. Recent evidences indicate that tumor-derived MVs can positively impact Dendritic Cells (DCs) immunogenicity by reprogramming DC antigen processing machinery and intracellular signaling pathways, thus promoting anti-tumor response. DCs are considered pivot cells of the immune system due to their exclusive ability to coordinate the innate and acquired immune responses, cross present exogenous antigens, and prime naive T cells. DCs are required for the induction and maintenance of long-lasting anti-tumor immunity and their exploitation has been extensively investigated for the design of anti-tumor vaccines. However, the clinical grade culture conditions that are required to generate DCs for therapeutic use can strongly affect their functions. Here, we investigated the immunomodulatory impact of MVs carrying the MUC1 tumor glycoantigen (MVsMUC1) as immunogen formulation on clinical grade DCs grown in X VIVO 15 (X-DCs). Results indicated that X-DCs displayed reduced performance of the antigen processing machinery in term of diminished phagocytosis and acidification of the phagosomal compartment suggesting an altered immunogenicity of clinical grade DCs. Pulsing DCs with MVsMUC1 restored phagosomal alkalinization, triggering ROS increase. This was not observed when a soluble MUC1 protein was employed (rMUC1). Concurrently, MVsMUC1 internalization by X-DCs allowed MUC1 cross-processing. Most importantly, MVsMUC1 pulsed DCs activated IFNgamma response mediated by MUC1 specific CD8+ T cells. These results strongly support the employment of tumor-derived MVs as immunogen platforms for the implementation of DC-based vaccines. PMID- 30455689 TI - miRNA miR-21 Is Largely Dispensable for Intrathymic T-Cell Development. AB - Development of T cells in the thymus is tightly controlled to continually produce functional, but not autoreactive, T cells. miRNAs provide a layer of post transcriptional gene regulation to this process, but the role of many individual miRNAs in T-cell development remains unclear. miR-21 is prominently expressed in immature thymocytes followed by a steep decline in more mature cells. We hypothesized that such a dynamic expression was indicative of a regulatory function in intrathymic T-cell development. To test this hypothesis, we analyzed T-cell development in miR-21-deficient mice at steady state and under competitive conditions in mixed bone-marrow chimeras. We complemented analysis of knock-out animals by employing over-expression in vivo. Finally, we assessed miR-21 function in negative selection in vivo as well as differentiation in co-cultures. Together, these experiments revealed that miR-21 is largely dispensable for physiologic T-cell development. Given that miR-21 has been implicated in regulation of cellular stress responses, we assessed a potential role of miR-21 in endogenous regeneration of the thymus after sublethal irradiation. Again, miR 21 was completely dispensable in this process. We concluded that, despite prominent and highly dynamic expression in thymocytes, miR-21 expression was not required for physiologic T-cell development or endogenous regeneration. PMID- 30455688 TI - Human Dendritic Cell Subsets Undergo Distinct Metabolic Reprogramming for Immune Response. AB - Toll-like receptor (TLR) agonists induce metabolic reprogramming, which is required for immune activation. We have investigated mechanisms that regulate metabolic adaptation upon TLR-stimulation in human blood DC subsets, CD1c+ myeloid DCs (mDCs) and plasmacytoid DCs (pDCs). We show that TLR-stimulation changes expression of genes regulating oxidative phosphorylation (OXPHOS) and glutamine metabolism in pDC. TLR-stimulation increases mitochondrial content and intracellular glutamine in an autophagy-dependent manner in pDC. TLR-induced glutaminolysis fuels OXPHOS in pDCs. Notably, inhibition of glutaminolysis and OXPHOS prevents pDC activation. Conversely, TLR-stimulation reduces mitochondrial content, OXPHOS activity and induces glycolysis in CD1c+ mDC. Inhibition of mitochondrial fragmentation or promotion of mitochondrial fusion impairs TLR stimulation induced glycolysis and activation of CD1c+ mDCs. TLR-stimulation triggers BNIP3-dependent mitophagy, which regulates transcriptional activity of AMPKalpha1. BNIP3-dependent mitophagy is required for induction of glycolysis and activation of CD1c+ mDCs. Our findings reveal that TLR stimulation differentially regulates mitochondrial dynamics in distinct human DC subsets, which contributes to their activation. PMID- 30455691 TI - Overview of the Germline and Expressed Repertoires of the TRB Genes in Sus scrofa. AB - The alpha/beta T cell receptor (TR) is a complex heterodimer that recognizes antigenic peptides and binds to major histocompatibility complex (MH) molecules. Both alpha and beta chains are encoded by different genes localized on two distinct chromosomal loci: TRA and TRB. The present study employed the recent release of the swine genome assembly to define the genomic organization of the TRB locus. According to the sequencing data, the pig TRB locus spans approximately 400 kb of genomic DNA and consists of 38 TRBV genes belonging to 24 subgroups located upstream of three in tandem TRBD-J-C clusters, which are followed by a TRBV gene in an inverted transcriptional orientation. Comparative analysis confirms that the general organization of the TRB locus is similar among mammalian species, but the number of germline TRBV genes varies greatly even between species belonging to the same order, determining the diversity and specificity of the immune response. However, sequence analysis of the TRB locus also suggests the presence of blocks of conserved homology in the genomic region across mammals. Furthermore, by analysing a public cDNA collection, we identified the usage pattern of the TRBV, TRBD, and TRBJ genes in the adult pig TRB repertoire, and we noted that the expressed TRBV repertoire seems to be broader and more diverse than the germline repertoire, in line with the presence of a high level of TRBV gene polymorphisms. Because the nucleotide differences seems to be principally concentrated in the CDR2 region, it is reasonable to presume that most T cell beta-chain diversity can be related to polymorphisms in pig MH molecules. Domestic pigs represent a valuable animal model as they are even more anatomically, genetically and physiologically similar to humans than are mice. Therefore, present knowledge on the genomic organization of the pig TRB locus allows the collection of increased information on the basic aspects of the porcine immune system and contributes to filling the gaps left by rodent models. PMID- 30455690 TI - ATF3 Sustains IL-22-Induced STAT3 Phosphorylation to Maintain Mucosal Immunity Through Inhibiting Phosphatases. AB - In gut epithelium, IL-22 transmits signals through STAT3 phosphorylation (pSTAT3) which provides intestinal immunity. Many components in the IL-22-pSTAT3 pathway have been identified as risk factors for inflammatory bowel disease (IBD) and some of them are considered as promising therapeutic targets. However, new perspectives are still needed to understand IL-22-pSTAT3 signaling for effective clinical interventions in IBD patients. Here, we revealed activating transcription factor 3 (ATF3), recently identified to be upregulated in patients with active IBD, as a crucial player in the epithelial IL-22-pSTAT3 signaling cascade. We found ATF3 is central to intestinal homeostasis and provides protection during colitis. Loss of ATF3 led to decreased crypt numbers, more shortened colon length, impaired ileal fucosylation at the steady state, and lethal disease activity during DSS-induced colitis which can be effectively ameliorated by rectal transplantation of wild-type colonic organoids. Epithelial stem cells and Paneth cells form a niche to orchestrate epithelial regeneration and host-microbe interactions, and IL-22-pSTAT3 signaling is a key guardian for this niche. We found ATF3 is critical for niche maintenance as ATF3 deficiency caused compromised stem cell growth and regeneration, as well as Paneth cell degeneration and loss of anti-microbial peptide (AMP)-producing granules, indicative of malfunction of Paneth/stem cell network. Mechanistically, we found IL-22 upregulates ATF3, which is required to relay IL-22 signaling leading to STAT3 phosphorylation and subsequent AMP induction. Intriguingly, ATF3 itself does not act on STAT3 directly, instead ATF3 regulates pSTAT3 by negatively targeting protein tyrosine phosphatases (PTPs) including SHP2 and PTP-Meg2. Furthermore, we identified ATF3 is also involved in IL-6-mediated STAT3 activation in T cells and loss of ATF3 leads to reduced capacity of Th17 cells to produce their signature cytokine IL-22 and IL-17A. Collectively, our results suggest that via IL-22-pSTAT3 signaling in the epithelium and IL-6-pSTAT3 signaling in Th17 cells, ATF3 mediates a cross-regulation in the barrier to maintain mucosal homeostasis and immunity. PMID- 30455692 TI - Polydatin Prevents Lipopolysaccharide (LPS)-Induced Parkinson's Disease via Regulation of the AKT/GSK3beta-Nrf2/NF-kappaB Signaling Axis. AB - Parkinson's disease (PD) is a common neurodegenerative disease characterized by selective loss of dopaminergic neurons in the substantia nigra (SN). Neuroinflammation induced by over-activation of microglia leads to the death of dopaminergic neurons in the pathogenesis of PD. Therefore, downregulation of microglial activation may aid in the treatment of PD. Polydatin (PLD) has been reported to pass through the blood-brain barrier and protect against motor degeneration in the SN. However, the molecular mechanisms underlying the effects of PLD in the treatment of PD remain unclear. The present study aimed to determine whether PLD protects against dopaminergic neurodegeneration by inhibiting the activation of microglia in a rat model of lipopolysaccharide (LPS) induced PD. Our findings indicated that PLD treatment protected dopaminergic neurons and ameliorated motor dysfunction by inhibiting microglial activation and the release of pro-inflammatory mediators. Furthermore, PLD treatment significantly increased levels of p-AKT, p-GSK-3betaSer9, and Nrf2, and suppressed the activation of NF-kappaB in the SN of rats with LPS-induced PD. To further explore the neuroprotective mechanism of PLD, we investigated the effect of PLD on activated microglial BV-2 cells. Our findings indicated that PLD inhibited the production of pro-inflammatory mediators and the activation of NF kappaB pathways in LPS-induced BV-2 cells. Moreover, our results indicated that PLD enhanced levels of p-AKT, p-GSK-3betaSer9, and Nrf2 in BV-2 cells. After BV-2 cells were pretreated with MK2206 (an inhibitor of AKT), NP-12 (an inhibitor of GSK-3beta), or Brusatol (BT; an inhibitor of Nrf2), treatment with PLD suppressed the activation of NF-kappaB signaling pathways and the release of pro inflammatory mediators in activated BV-2 cells via activation of the AKT/GSK3beta Nrf2 signaling axis. Taken together, our results are the first to demonstrate that PLD prevents dopaminergic neurodegeneration due to microglial activation via regulation of the AKT/GSK3beta-Nrf2/NF-kappaB signaling axis. PMID- 30455694 TI - Molecular Markers Distinguishing T Cell Subtypes With TSDR Strand-Bias Methylation. AB - Human regulatory CD4+CD25+FOXP3+ T cells (Treg) play important roles in the maintenance of self-tolerance and immune homeostasis in various disease settings and are also involved in the suppression of effective immune responses. These cells are heterogeneous in phenotype and function, and the ability to reliably distinguish between various FOXP3-expressing subpopulations can affect the development of successful therapies. This study demonstrates that hypomethylated CpG sites, present in four regions of the FOXP3 locus, CAMTA1 and FUT7 gene regions, can be used to distinguish several subsets of Treg from conventional CD4+ T lymphocytes (Tcon) in donors of both genders. We describe a previously unreported strand-bias hemimethylation pattern in FOXP3 promoter and TSDR in donors of both genders, with the coding strand being demethylated within promoter and methylated within TSDR in all CD4+ lymphocyte subtypes, whereas the template strand follows the previously described pattern of methylation with both regions being more demethylated in Treg subtypes and mostly methylated in Tcon. This strand-specific approach within the TSDR may prove to be instrumental in correctly defining Treg subsets in health and in disease. PMID- 30455695 TI - Gastric Cancer Is the Leading Cause of Death in Italian Adult Patients With Common Variable Immunodeficiency. AB - An increased prevalence of malignant lymphoma and of gastric cancer has been observed in large cohorts of patients with common variable immunodeficiency (CVID), the most frequently symptomatic primary immunodeficiency. Surveillance strategies for cancers in CVID should be defined based on epidemiological data. Risks and mortality for cancers among 455 Italian patients with CVID were compared to cancer incidence data from the Italian Cancer Registry database. CVID patients showed an increased cancer incidence for all sites combined (Obs = 133, SIR = 2.4; 95%CI = 1.7-3.5), due to an excess of non-Hodgkin lymphoma (Obs = 33, SIR = 14.3; 95%CI = 8.4-22.6) and of gastric cancer (Obs = 25; SIR = 6.4; 95%CI = 3.2-12.5). CVID patients with gastric cancer and lymphoma had a worse survival in comparison to cancer-free CVID (HR: 4.8, 95%CI: 4.2-44.4 and HR: 4.2, 95%CI: 2.8 44.4). Similar to what observed in other series, CVID-associated lymphomas were more likely to be of B cell origin and often occurred at extra-nodal sites. We collected the largest case-series of gastric cancers in CVID subjects. In contrast to other reports, gastric cancer was the leading cause of death in CVID. Standardized mortality ratio indicated a 10.1-fold excess mortality among CVID patients with gastric cancer. CVID developed gastric cancer 15 years earlier than the normative population, but they had a similar overall survival. Only CVID diagnosed at early stage gastric cancer survived >24 months. Stomach histology from upper endoscopy performed before cancer onset showed areas of atrophic gastritis, intestinal metaplasia or dysplasia. CVID patients might progress rapidly to an advanced cancer stage as shown by patients developing a III-IV stage gastric cancer within 1 year from an endoscopy without signs of dysplasia. Based on high rate of mortality due to gastric cancer in Italian CVID patients, we hereby suggest a strategy aimed at early diagnosis, based on regular upper endoscopy and on Helicobacter pylori infection treatment, recommending an implementation of national guidelines. PMID- 30455696 TI - Clinical T Cell Receptor Repertoire Deep Sequencing and Analysis: An Application to Monitor Immune Reconstitution Following Cord Blood Transplantation. AB - Spectratyping assays are well recognized as the clinical gold standard for assessing the T cell receptor (TCR) repertoire in haematopoietic stem cell transplant (HSCT) recipients. These assays use length distributions of the hyper variable complementarity-determining region 3 (CDR3) to characterize a patient's T cell immune reconstitution post-transplant. However, whilst useful, TCR spectratyping is notably limited by its resolution, with the technique unable to provide data on the individual clonotypes present in a sample. High-resolution clonotype data are necessary to provide quantitative clinical TCR assessments and to better understand clonotype dynamics during clinically relevant events such as viral infections or GvHD. In this study we developed and applied a CDR3 Next Generation Sequencing (NGS) methodology to assess the TCR repertoire in cord blood transplant (CBT) recipients. Using this, we obtained comprehensive TCR data from 16 CBT patients and 5 control cord samples at Great Ormond Street Hospital (GOSH). These were analyzed to provide a quantitative measurement of the TCR repertoire and its constituents in patients post-CBT. We were able to both recreate and quantify inferences typically drawn from spectratyping data. Additionally, we demonstrate that an NGS approach to TCR assessment can provide novel insights into the recovery of the immune system in these patients. We show that NGS can be used to accurately quantify TCR repertoire diversity and to provide valuable inference on clonotypes detected in a sample. We serially assessed the progress of T cell immune reconstitution demonstrating that there is dramatic variation in TCR diversity immediately following transplantation and that the dynamics of T cell immune reconstitution is perturbed by the presence of GvHD. These findings provide a proof of concept for the adoption of NGS TCR sequencing in clinical practice. PMID- 30455698 TI - Mechanisms of NK Cell Activation and Clinical Activity of the Therapeutic SLAMF7 Antibody, Elotuzumab in Multiple Myeloma. AB - Multiple myeloma (MM) is a bone marrow plasma cell neoplasm and is the second most-common hematologic malignancy. Despite advances in therapy, MM remains largely incurable. Elotuzumab is a humanized IgG1 monoclonal antibody targeting SLAMF7, which is highly expressed on myeloma cells, and the antibody is approved for the treatment of relapsed and/or refractory (RR) MM in combination with lenalidomide and dexamethasone. Elotuzumab can stimulate robust antibody dependent cellular cytotoxicity (ADCC) through engaging with FcgammaRIIIA (CD16) on NK cells and antibody-dependent cellular phagocytosis (ADCP) by macrophages. Interestingly, SLAMF7 is also expressed on cytolytic NK cells, which also express the requisite adaptor protein, EAT-2, to mediate activation signaling. Accumulating evidence indicates that antibody crosslinking of SLAMF7 on human and mouse NK cells can stimulate EAT-2-dependent activation of PLCgamma, ERK, and intracellular calcium mobilization. The binding of SLAMF7 by elotuzumab can directly induce signal transduction in human NK cells, including co-stimulation of the calcium signaling triggered through other surface receptors, such as NKp46 and NKG2D. In RRMM patients, elotuzumab monotherapy did not produce objective responses, but did enhance the activity of approved standard of care therapies, including lenalidomide or bortezomib, which are known to enhance anti-tumor responses by NK cells. Taken together, these preclinical results and accumulating experience in the clinic provide compelling evidence that the mechanism of action of elotuzumab in MM patients involves the activation of NK cells through both CD16-mediated ADCC and direct co-stimulation via engagement with SLAMF7, as well as promoting ADCP by macrophages. We review the current understanding of how elotuzumab utilizes multiple mechanisms to facilitate immune-mediated attack of myeloma cells, as well as outline goals for future research. PMID- 30455697 TI - T cell Allorecognition Pathways in Solid Organ Transplantation. AB - Transplantation is unusual in that T cells can recognize alloantigen by at least two distinct pathways: as intact MHC alloantigen on the surface of donor cells via the direct pathway; and as self-restricted processed alloantigen via the indirect pathway. Direct pathway responses are viewed as strong but short-lived and hence responsible for acute rejection, whereas indirect pathway responses are typically thought to be much longer lasting and mediate the progression of chronic rejection. However, this is based on surprisingly scant experimental evidence, and the recent demonstration that MHC alloantigen can be re-presented intact on recipient dendritic cells-the semi-direct pathway-suggests that the conventional view may be an oversimplification. We review recent advances in our understanding of how the different T cell allorecognition pathways are triggered, consider how this generates effector alloantibody and cytotoxic CD8 T cell alloresponses and assess how these responses contribute to early and late allograft rejection. We further discuss how this knowledge may inform development of cellular and pharmacological therapies that aim to improve transplant outcomes, with focus on the use of induced regulatory T cells with indirect allospecificity and on the development of immunometabolic strategies. KEY POINTS Acute allograft rejection is likely mediated by indirect and direct pathway CD4 T cell alloresponses.Chronic allograft rejection is largely mediated by indirect pathway CD4 T cell responses. Direct pathway recognition of cross-dressed endothelial derived MHC class II alloantigen may also contribute to chronic rejection, but the extent of this contribution is unknown.Late indirect pathway CD4 T cell responses will be composed of heterogeneous populations of allopeptide specific T helper cell subsets that recognize different alloantigens and are at various stages of effector and memory differentiation.Knowledge of the precise indirect pathway CD4 T cell responses active at late time points in a particular individual will likely inform the development of alloantigen-specific cellular therapies and will guide immunometabolic modulation. PMID- 30455699 TI - In vitro Evidence That Combination Therapy With CD16-Bearing NK-92 Cells and FDA Approved Alefacept Can Selectively Target the Latent HIV Reservoir in CD4+ CD2hi Memory T Cells. AB - Elimination of the latent HIV reservoir remains the biggest hurdle to achieve HIV cure. In order to specifically eliminate HIV infected cells they must be distinguishable from uninfected cells. CD2 was recently identified as a potential marker enriched in the HIV-1 reservoir on CD4+ T cells, the largest, longest lived and best-characterized constituent of the HIV reservoir. We previously proposed to repurpose FDA-approved alefacept, a humanized alpha-CD2 fusion protein, to reduce the HIV reservoir in CD2hi CD4+ memory T cells. Here, we show the first evidence that alefacept can specifically target and reduce CD2hi HIV infected cells in vitro. We explore a variety of natural killer (NK) cells as mediators of antibody-dependent cell-mediated cytotoxicity (ADCC) including primary NK cells, expanded NK cells as well as the CD16 transduced NK-92 cell line which is currently under study in clinical trials as a treatment for cancer. We demonstrate that CD16.NK-92 has a natural preference to kill CD2hi CD45RA- memory T cells, specifically CD45RA- CD27+ central memory/transitional memory (TCM/TM) subset in both healthy and HIV+ patient samples as well as to reduce HIV DNA from HIV+ samples from donors well controlled on antiretroviral therapy. Lastly, alefacept can combine with CD16.NK-92 to decrease HIV DNA in some patient samples and thus may yield value as part of a strategy toward sustained HIV remission. PMID- 30455693 TI - The Interplay Between Immune Response and Bacterial Infection in COPD: Focus Upon Non-typeable Haemophilus influenzae. AB - Chronic obstructive pulmonary disease (COPD) is a debilitating respiratory disease and one of the leading causes of morbidity and mortality worldwide. It is characterized by persistent respiratory symptoms and airflow limitation due to abnormalities in the lower airway following consistent exposure to noxious particles or gases. Acute exacerbations of COPD (AECOPD) are characterized by increased cough, purulent sputum production, and dyspnea. The AECOPD is mostly associated with infection caused by common cold viruses or bacteria, or co infections. Chronic and persistent infection by non-typeable Haemophilus influenzae (NTHi), a Gram-negative coccobacillus, contributes to almost half of the infective exacerbations caused by bacteria. This is supported by reports that NTHi is commonly isolated in the sputum from COPD patients during exacerbations. Persistent colonization of NTHi in the lower airway requires a plethora of phenotypic adaptation and virulent mechanisms that are developed over time to cope with changing environmental pressures in the airway such as host immuno inflammatory response. Chronic inhalation of noxious irritants in COPD causes a changed balance in the lung microbiome, abnormal inflammatory response, and an impaired airway immune system. These conditions significantly provide an opportunistic platform for NTHi colonization and infection resulting in a "vicious circle." Episodes of large inflammation as the consequences of multiple interactions between airway immune cells and NTHi, accumulatively contribute to COPD exacerbations and may result in worsening of the clinical status. In this review, we discuss in detail the interplay and crosstalk between airway immune residents and NTHi, and their effect in AECOPD for better understanding of NTHi pathogenesis in COPD patients. PMID- 30455700 TI - Limited Foxp3+ Regulatory T Cells Response During Acute Trypanosoma cruzi Infection Is Required to Allow the Emergence of Robust Parasite-Specific CD8+ T Cell Immunity. AB - While it is now acknowledged that CD4+ T cells expressing CD25 and Foxp3 (Treg cells) regulate immune responses and, consequently, influence the pathogenesis of infectious diseases, the regulatory response mediated by Treg cells upon infection by Trypanosoma cruzi was still poorly characterized. In order to understand the role of Treg cells during infection by this protozoan parasite, we determined in time and space the magnitude of the regulatory response and the phenotypic, functional and transcriptional features of the Treg cell population in infected mice. Contrary to the accumulation of Treg cells reported in most chronic infections in mice and humans, experimental T. cruzi infection was characterized by sustained numbers but decreased relative frequency of Treg cells. The reduction in Treg cell frequency resulted from a massive accumulation of effector immune cells, and inversely correlated with the magnitude of the effector immune response as well as with emergence of acute immunopathology. In order to understand the causes underlying the marked reduction in Treg cell frequency, we evaluated the dynamics of the Treg cell population and found a low proliferation rate and limited accrual of peripheral Treg cells during infection. We also observed that Treg cells became activated and acquired a phenotypic and transcriptional profile consistent with suppression of type 1 inflammatory responses. To assess the biological relevance of the relative reduction in Treg cells frequency observed during T. cruzi infection, we transferred in vitro differentiated Treg cells at early moments, when the deregulation of the ratio between regulatory and conventional T cells becomes significant. Intravenous injection of Treg cells dampened parasite-specific CD8+ T cell immunity and affected parasite control in blood and tissues. Altogether, our results show that limited Treg cell response during the acute phase of T. cruzi infection enables the emergence of protective anti-parasite CD8+ T cell immunity and critically influences host resistance. PMID- 30455701 TI - Innate Lymphocytes in Adipose Tissue Homeostasis and Their Alterations in Obesity and Colorectal Cancer. AB - Colorectal cancer (CRC) is the third most common cancer worldwide and a leading cause of death, with burden expected to increase in the coming years. Enhanced adiposity, particularly visceral fat, is associated with increased cancer incidence representing an important indicator of survival, prognosis, recurrence rates, and response to therapy for several tumors including CRC. Compelling evidence has been achieved that the low-grade chronic inflammation characterizing obesity represents a main factor that can favor carcinogenesis. Adipocytes and adipose tissue (AT) infiltrating immune cells contribute to obesity-related inflammation by releasing soluble factors affecting, both locally and systemically, the function of several cell types, including immune and cancer cells. The unbalanced production of immune mediators as well as the profound changes in the repertoire and activation state of immune cells in AT of obese subjects represent key events in the processes that set the basis for a pro tumorigenic microenvironment. AT harbors a unique profile of immune cells of different origin that play an important role in tissue homeostasis. Among these, tissue-resident innate lymphocytes are emerging as important AT components whose depletion/aberrant activation occurring in obesity could have an impact on inflammation and immune-surveillance against tumors. However, a direct link between obesity-induced dysfunction and cancer development has not been demonstrated yet. In this review, we provide an overview of human obesity- and CRC-induced alterations of blood and adipose tissue-associated innate lymphocytes, and discuss how the adipose tissue microenvironment in obesity might influence the development of CRC. PMID- 30455702 TI - Toll-Like Receptor Stimulation by MicroRNAs in Acute Graft-vs.-Host Disease. AB - Acute graft-vs.-host disease (aGVHD) is a frequent complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), accounting for substantial morbidity and mortality associated with this treatment modality. The pathogenesis of aGVHD involves a complex cascade of humoral and cellular interactions in which donor T cells target HLA mismatched host tissues, causing tissue injury through secretion of pro-inflammatory cytokines and induction of direct cytotoxicity. Toll-like receptors (TLRs) are key components of the innate immune system that recognize endogenous danger-associated molecular patterns (DAMPs) and exogenous pathogen-associated molecular patterns (PAMPs). Patients receiving conditioning chemotherapy and/or whole-body irradiation prior to all-HSCT are prone to gastrointestinal damage and translocation of microbiota across compromised intestinal epithelium, resulting in release of PAMPs and DAMPs. These "danger signals" play critical roles in disease pathogenesis by both initiating and propagating aGVHD through dendritic cell maturation and alloreactive T cell responses. There are 10-15 TLRs identified in mammalian species, a subset of which recognize single-stranded RNA (ssRNA) and serve as a key component of viral immunity. Recently, ssRNAs other than those of viral origin have been investigated as potential ligands of TLRs. MicroRNAs (miRs) are short (19-24 nt) non-coding RNAs that play critical roles in a variety of diseases. While traditionally miRs post-translationally modulate gene expression, non-canonical functions such as regulating TLR stimulation by acting as TLR ligands have been described. Here, we review the role of TLRs in aGVHD pathogenesis, the function of miRs in TLR stimulation, and the recent literature describing miRs as TLR ligands in aGVHD. PMID- 30455704 TI - The Role of NLRP3 and IL-1beta in the Pathogenesis of Inflammatory Bowel Disease. AB - It is logical to assume that a major pro-inflammatory mechanism, i.e., the NLRP3 inflammasome would play a prominent role in the pathogenesis of the Inflammatory Bowel Disease (IBD) in humans. However, while both studies of murine models of gut disease and patients provide data that the main cytokine product generated by this inflammasome, IL-1beta, does in fact contribute to inflammation in IBD, there is no evidence that IL-1beta plays a decisive or prominent role in "ordinary" patients with IBD (Crohn's disease). On the other hand, there are several definable point mutations that result in over-active NLRP3 inflammasome activity and in these cases, the gut inflammation is driven by IL-1beta and is treatable by biologic agents that block the effects of this cytokine. PMID- 30455705 TI - Encephalitis Associated to Metabotropic Glutamate Receptor 5 (mGluR5) Antibodies in Cerebrospinal Fluid. AB - A 68-years-old Hispanic man, complained of night sweats, low grade fewer, unexplained weight loss, and memory problems over 3 months. Abdominal tomography showed multiple intra-abdominal adenopathy and biopsy confirmed classic Hodgkin's lymphoma. He commenced treatment with chemotherapy. Three months later, he had acute onset of inattention, auditory hallucinations and alterations of anterograde memory. The patient developed psychomotor agitation, unresponsive to a combination of neuroleptics and benzodiazepines. Brain MRI showed a small established cerebellar infarction. Electroencephalogram was normal. Tests for toxic metabolic encephalopathy were negative. One oligoclonal IgG bands was found in the Cerebrospinal fluid (CSF), which was not observed in corresponding serum, but cell count and protein were normal. Extensive testing for infectious encephalitis was unremarkable. CSF testing for commercially available neural and non-neural autoantibodies was negative. The patient fulfilled the Gultekin diagnostic criteria for paraneoplastic limbic encephalitis and methylprednisolone IV 1g/d for 5 days was given. He recovered rapidly, with progressive improvement in memory and psychomotor agitation. After treatment commenced, results for antibodies to mGluR5 in CSF taken prior to treatment were returned as positive. mGluR5 is found on post-synaptic terminals of neurons and microglia and is expressed primarily in the hippocampus and amygdala. This case highlights the difficulties in diagnosing this type of encephalitis: the CSF did not show pleocytosis, the MRI showed only chronic change and the electroencephalogram was normal. The dramatic recovery after methylprednisolone help to better characterized the clinical spectrum of auto-immune encephalitis. Diagnosing anti mGlutR5 encephalitis may lead to potentially highly effective treatment option and may anticipate the diagnostic of a cancer. A high index of suspicion is needed to avoid missed diagnosis. In patients with unexplained encephalitis, testing for antibodies to mGluR5 in CSF and serum should be considered. When there is a reasonable index of suspicion of auto-immune encephalitis, treatment should not be delayed for the antibody results. PMID- 30455706 TI - Fibrosis Development in HOCl-Induced Systemic Sclerosis: A Multistage Process Hampered by Mesenchymal Stem Cells. AB - Objectives: Skin fibrosis is the hallmark of systemic sclerosis (SSc) a rare intractable disease with unmet medical need. We previously reported the anti fibrotic potential of mesenchymal stem cells (MSCs) in a murine model of SSc. This model, based on daily intra-dermal injections of hypochlorite (HOCl) during 6 weeks, is an inducible model of the disease. Herein, we aimed at characterizing the development of skin fibrosis in HOCl-induced SSc (HOCl-SSc), and evaluating the impact of MSC infusion during the fibrogenesis process. Methods: After HOCl SSc induction in BALB/c mice, clinical, histological and biological parameters were measured after 3 weeks (d21) and 6 weeks (d42) of HOCl challenge, and 3 weeks after HOCl discontinuation (d63). Treated-mice received infusions of 2.5 * 105 MSCs 3 weeks before sacrifice (d0, d21, d42). Results: HOCl injections induced a two-step process of fibrosis development: first, an 'early inflammatory phase', characterized at d21 by highly proliferative infiltrates of myofibroblasts, T-lymphocytes and macrophages. Second, a phase of 'established matrix fibrosis', characterized at d42 by less inflammation, but strong collagen deposition and followed by a third phase of 'spontaneous tissue remodeling' after HOCl discontinuation. This phase was characterized by partial fibrosis receding, due to enhanced MMP1/TIMP1 balance. MSC treatment reduced skin thickness in the three phases of fibrogenesis, exerting more specialized mechanisms: immunosuppression, abrogation of myofibroblast activation, or further enhancing tissue remodeling, depending on the injection time-point. Conclusion: HOCl-SSc mimics three fibrotic phenotypes of scleroderma, all positively impacted by MSC therapy, demonstrating the great plasticity of MSC, a promising cure for SSc. PMID- 30455703 TI - Myeloid Cell Hypoxia-Inducible Factors Promote Resolution of Inflammation in Experimental Colitis. AB - Colonic tissues in Inflammatory Bowel Disease (IBD) patients exhibit oxygen deprivation and activation of hypoxia-inducible factor 1alpha and 2alpha (HIF 1alpha and HIF-2alpha), which mediate cellular adaptation to hypoxic stress. Notably, macrophages and neutrophils accumulate preferentially in hypoxic regions of the inflamed colon, suggesting that myeloid cell functions in colitis are HIF dependent. By depleting ARNT (the obligate heterodimeric binding partner for both HIFalpha subunits) in a murine model, we demonstrate here that myeloid HIF signaling promotes the resolution of acute colitis. Specifically, myeloid pan-HIF deficiency exacerbates infiltration of pro-inflammatory neutrophils and Ly6C+ monocytic cells into diseased tissue. Myeloid HIF ablation also hinders macrophage functional conversion to a protective, pro-resolving phenotype, and elevates gut serum amyloid A levels during the resolution phase of colitis. Therefore, myeloid cell HIF signaling is required for efficient resolution of inflammatory damage in colitis, implicating serum amyloid A in this process. PMID- 30455707 TI - Phenotypic Selection in Ornamental Breeding: It's Better to Have the BLUPs Than to Have the BLUEs. AB - Plant breeders always face the challenge to select the best individuals. Selection methods are required that maximize selection gain based on available data. When several crosses have been made, the BLUP procedure achieves this by combining phenotypic data with information on pedigree relationships via an index, known as family-index selection. The index, estimated based on the intra class correlation coefficient, exploits the relationship among individuals within a family relative to other families in the population. An intra-class correlation coefficient of one indicates that the individual performance can be fully explained based on the family background, whereas an intra-class correlation coefficient of zero indicates the performance of individuals is independent of the family background. In the case the intra-class correlation coefficient is one, family-index selection is considered. In the case the intra-class correlation coefficient is zero, individual selection is considered. The main difference between individual and family-index selection lies in the adjustment in estimating the individual's effect depending on the intra-class correlation coefficient afforded by the latter. Two examples serve to illustrate the application of the BLUP method. The efficiency of individual and family-index selection was evaluated in terms of the heritability obtained from linear mixed models implementing the selection methods by suitably defining the treatment factor as the sum of individual and family effect. Family-index selection was found to be at least as efficient as individual selection in Dianthus caryophyllus L., except for flower size in standard carnation and vase life in mini carnation for which traits family-index selection outperformed individual selection. Family-index selection was superior to individual selection in Pelargonium zonale in cases when the heritability was low. Hence, the pedigree based BLUP procedure can enhance selection efficiency in production-related traits in P. zonale or shelf-life related in D. caryophyllus L. PMID- 30455708 TI - RNA Catabolites Contribute to the Nitrogen Pool and Support Growth Recovery of Wheat. AB - Turn-over of RNA and catabolism of nucleotides releases one to four ammonia molecules; the released nutrients being reassimilated into primary metabolism. Preliminary evidence indicates that monocots store high levels of free nucleotides and nucleosides but their potential as a source of internal organic nitrogen for use and remobilization is uncharted. Early tillering wheat plants were therefore starved of N over a 5-day time-course with examination of nucleic acid yields in whole shoots, young and old leaves and roots. Nucleic acids constituted ~4% of the total N pool of N starved wheat plants, which was comparable with the N available from nitrate (NO3 -) and greater than that available from the sum of 20 proteinogenic amino acids. Methods were optimized to detect nucleotide (purine and pyrimidine) metabolites, and wheat orthologs of RNA degradation (TaRNS), nucleoside transport (TaENT1, TaENT3) and salvage (TaADK) were identified. It was found that N starved wheat roots actively catabolised RNA and specific purines but accumulated pyrimidines. Reduced levels of RNA corresponded with induction of TaRNS2, TaENT1, TaENT3, and TaADK in the roots. Reduced levels of GMP, guanine, xanthine, allantoin, allantoate and glyoxylate in N starved roots correlated with accumulation of allantoate and glyoxylate in the oldest leaf, suggesting translocation of allantoin. Furthermore, N starved wheat plants exogenously supplied with N in the form of purine catabolites grew and photosynthesized as well as those plants re-supplied with NO3 -. These results support the hypothesis that the nitrogen and carbon recovered from purine metabolism can support wheat growth. PMID- 30455709 TI - Mechanical Effects of Cellulose, Xyloglucan, and Pectins on Stomatal Guard Cells of Arabidopsis thaliana. AB - Stomata function as osmotically tunable pores that facilitate gas exchange at the surface of plants. Stomatal opening and closure are regulated by turgor changes in guard cells that result in mechanically regulated deformations of guard cell walls. However, how the molecular, architectural, and mechanical heterogeneities that exist in guard cell walls affect stomatal dynamics is unclear. In this work, stomata of wild type Arabidopsis thaliana plants or of mutants lacking normal cellulose, hemicellulose, or pectins were experimentally induced to close or open. Three-dimensional images of these stomatal complexes were collected using confocal microscopy, images were landmarked, and three-dimensional finite element models (FEMs) were constructed for each complex. Stomatal opening was simulated with a 5 MPa turgor increase. By comparing experimentally measured and computationally modeled changes in stomatal geometry across genotypes, anisotropic mechanical properties of guard cell walls were determined and mapped to cell wall components. Deficiencies in cellulose or hemicellulose were both predicted to stiffen guard cell walls, but differentially affected stomatal pore area and the degree of stomatal opening. Additionally, reducing pectin molecular mass altered the anisotropy of calculated shear moduli in guard cell walls and enhanced stomatal opening. Based on the unique architecture of guard cell walls and our modeled changes in their mechanical properties in cell wall mutants, we discuss how each polysaccharide class contributes to wall architecture and mechanics in guard cells. This study provides new insights into how the walls of guard cells are constructed to meet the mechanical requirements of stomatal dynamics. PMID- 30455710 TI - Nuclear Import of Arabidopsis Poly(ADP-Ribose) Polymerase 2 Is Mediated by Importin-alpha and a Nuclear Localization Sequence Located Between the Predicted SAP Domains. AB - Proteins of the Poly(ADP-Ribose) Polymerase (PARP) family modify target proteins by covalent attachment of ADP-ribose moieties onto amino acid side chains. In Arabidopsis, PARP proteins contribute to repair of DNA lesions and modulate plant responses to various abiotic and biotic stressors. Arabidopsis PARP1 and PARP2 are nuclear proteins and given that their molecular weights exceed the diffusion limit of nuclear pore complexes, an active import mechanism into the nucleus is likely. Here we use confocal microscopy of fluorescent protein-tagged Arabidopsis PARP2 and PARP2 deletion constructs in combination with site-directed mutagenesis to identify a nuclear localization sequence in PARP2 that is required for nuclear import. We report that in co-immunoprecipitation assays PARP2 interacts with several isoforms of the importin-alpha group of nuclear transport adapters and that PARP2 binding to IMPORTIN-alpha2 is mediated by the identified nuclear localization sequence. Our results demonstrate that PARP2 is a cargo protein of the canonical importin-alpha/beta nuclear import pathway. PMID- 30455712 TI - DNA-Free Genome Editing of Brassica oleracea and B. rapa Protoplasts Using CRISPR Cas9 Ribonucleoprotein Complexes. AB - The CRISPR/Cas9 genome editing system has already proved its efficiency, versatility and simplicity in numerous applications in human, animal, microbe and plant cells. Together with the vast amount of genome and transcriptome databases available, it represents an enormous potential for plant breeding and research. Although most changes produced with CRISPR/Cas9 do not differ from naturally occurring mutations, the use of transgenesis during varietal development can still trigger GMO legislation in countries that rely on process-based regulation. Moreover, stable integration of DNA coding for genome-editing tools into plant genomes can result in insertional mutagenesis, while its prolonged expression can cause mutations in off-target sites. These pitfalls can be avoided with the delivery of preassembled ribonucleoprotein complexes (RNPs) composed of purified recombinant enzyme Cas9 and in vitro-transcribed or synthesized sgRNA. We therefore aimed to develop a DNA-free protocol for site-directed mutagenesis of three species of the genus Brassica (B. oleracea, B. napus, and B. rapa) with the use of RNPs. We chose cabbage, rapeseed and Chinese cabbage as species representatives and introduced RNPs into their protoplasts with PEG 4000. Four sgRNAs targeting two endogenous genes (the FRI and PDS genes, two sgRNAs per gene) were introduced into all three species. No mutations were detected after transfection of rapeseed protoplasts, while we obtained mutation frequencies of 0.09 to 2.25% and 1.15 to 24.51% in cabbage and Chinese cabbage, respectively. In both species, a positive correlation was displayed between the amount (7.5, 15, 30, and 60 MUg) of Cas9 enzyme and sgRNA introduced and mutation frequency. Nucleotide changes (insertions and deletions) were detected 24 h after transfection and did not differ 72 h after transfection. They were species-, gene and locus-dependent. In summary, we demonstrated the suitability of RNP transfection into B. oleracea and B. rapa protoplasts for high-efficiency indel induction of two endogenous genes. Due to the relatively high mutation frequencies detected (up to 24.51%), this study paves the way for regeneration of precisely mutated Brassica plants without the use of transgenesis. PMID- 30455713 TI - Drought and Phytophthora Are Associated With the Decline of Oak Species in Southern Italy. AB - Forest decline induced by climate change is a global phenomenon that affects many tree species, mainly in drought-prone areas as the Mediterranean region. In southern Italy, several oak species have shown decline symptoms and elevated mortality since the 2000s due to drought stress. However, it remains to be answered whether decline occurred alone or whether a pathogen was also involved. To this aim, we compared two coexisting oak species in a forest located in southern Italy which are assumed to be less (Quercus cerris) and more tolerant to drought (Quercus pubescens). We sampled fifteen couples of neighboring declining (D) and non-declining (ND) trees of both species. Wood cores were taken from all trees to perform dendrochronological analyses to detect the decline onset and link it to potential climatic drivers. Carbon isotope ratios (d13C) were analyzed in wood of the two vigor classes to compare their water-use efficiency. Phytophthora presence was also assessed in soil samples from ten D-ND couples of trees per species. The oak species most affected by drought-induced decline in terms of leaf shedding and mortality was Q. cerris, i.e., the least tolerant to drought. In both species, the D trees showed a reduced growth rate compared with ND trees from 2000 onward when drought and warming intensified. Q. pubescens showed higher growth sensitivity to precipitation, temperature and drought than Q. cerris. This sensitivity to climate was magnified in D trees whose growth decreased in response to warm and dry conditions during the prior winter and the late summer. The Q. pubescens D trees were more efficient in their water use than ND trees before the growth divergence between D and ND trees amplified. In the studied area, Phytophthora quercina was isolated from 40% of the sampled trees, and tended to be more frequent amongst ND than amongst D trees. Our data suggests that droughts and warm summer conditions triggered oak decline. The high prevalence of P. quercina in the studied area warrants further study as a potential predisposing factor. PMID- 30455714 TI - Influence of Differ P Enrichment Frequency on Plant Growth and Plant C:N:P in a P Limited Subtropical Lake Wetland, China. AB - Phosphorus (P) enrichment as a result of anthropogenic activities can potentially alter plant C:N:P stoichiometry. However, the influence of different P enrichment frequencies on plant C:N:P stoichiometry in P-limited ecosystems is still unclear. In this study, we conducted a P-addition experiment to elucidate the effect of various P enrichment frequencies on the plant C:N:P stoichiometry of Carex brevicuspis in a freshwater wetland at Dongting Lake, China. We used four P enrichment frequencies (treatment A: no P addition; treatment B: three 0.1 g kg-1 additions at 10-day intervals; treatment C: two 0.15 g kg-1 additions at 15-day intervals; and treatment D: one 0.3 g kg-1 addition during the experimental period) in a factorial design with an experimental duration of 30 days. Biomass accumulation was lowest in the treatment A and highest in the treatment C, and increased with decreasing P addition frequency. The shoot:root ratio did not differ significantly between the four treatments. Both foliar and root C concentrations were not significantly different between the treatments. Foliar N concentration was significantly lower in the treatment D than in the other three treatments, while root N concentration did not differ significantly between the treatments. Both foliar and root P concentrations, and foliar C:N were much higher in the treatment B than in the treatment A. However, root C:N did not differ significantly between treatments. Both foliar and root C:P and N:P of C. brevicuspis were lower in the treatment B than in the treatment A. These results indicated that different frequencies of P addition significantly influenced plant growth. Moreover, P enrichment, rather than frequency, significantly influenced plant C:N:P stoichiometry. Our results improve our understanding of the influence of different P enrichment frequencies on plant C:N:P stoichiometry and nutrient cycling in freshwater wetlands. PMID- 30455711 TI - Haplotype Loci Under Selection in Canadian Durum Wheat Germplasm Over 60 Years of Breeding: Association With Grain Yield, Quality Traits, Protein Loss, and Plant Height. AB - Durum wheat was introduced in the southern prairies of western Canada in the late nineteenth century. Breeding efforts have mainly focused on improving quality traits to meet the pasta industry demands. For this study, 192 durum wheat lines were genotyped using the Illumina 90K Infinium iSelect assay, and resulted in a total of 14,324 polymorphic SNPs. Genetic diversity changed over time, declining during the first 20 years of breeding in Canada, then increased in the late 1980s and early 1990s. We scanned the genome for signatures of selection, using the total variance Fst-based outlier detection method (Lositan), the hierarchical island model (Arlequin) and the Bayesian genome scan method (BayeScan). A total of 407 outliers were identified and clustered into 84 LD-based haplotype loci, spanning all 14 chromosomes of the durum wheat genome. The association analysis detected 54 haplotype loci, of which 39% contained markers with a complete reversal of allelic state. This tendency to fixation of favorable alleles corroborates the success of the Canadian durum wheat breeding programs over time. Twenty-one haplotype loci were associated with multiple traits. In particular, hap_4B_1 explained 20.6, 17.9 and 16.6% of the phenotypic variance of pigment loss, pasta b* and dough extensibility, respectively. The locus hap_2B_9 explained 15.9 and 17.8% of the variation of protein content and protein loss, respectively. All these pleiotropic haplotype loci offer breeders the unique opportunity for further improving multiple traits, facilitating marker-assisted selection in durum wheat, and could help in identifying genes as functional annotations of the wheat genome become available. PMID- 30455715 TI - Transcriptome Analysis of Cinnamomum chago: A Revelation of Candidate Genes for Abiotic Stress Response and Terpenoid and Fatty Acid Biosyntheses. AB - Cinnamomum chago, an endangered species endemic to Yunnan province, possesses large economic and phylogenetic values in Lauraceae. However, the genomic information of this species remains relatively unexplored. In this study, we used RNAseq technology to characterize and annotate the C. chago transcriptome and identify candidate genes involved in special metabolic pathways and gene associated simple sequence repeats (SSRs) and single-nucleotide polymorphism (SNP). A total of 129,097 unigenes, with a mean length of 667 bp and an N50 length of 1,062 bp, were assembled. Among these genes, 56,887 (44.07%) unigenes were successfully annotated using at least one database. Furthermore, 47 and 46 candidate genes were identified in terpenoid biosynthesis and fatty acid biosynthesis, respectively. A total of 22 candidate genes participated in at least one abiotic stress response of C. chago. Additionally, a total of 25,654 SSRs and 640 SNPs were also identified. Based on these potential loci, 55 novel expressed sequence tag (EST)-SSR primers were successfully developed. This work provides comprehensive transcriptomic data that can be used to establish a valuable information platform for gene prediction, signaling pathway investigation, and molecular marker development for C. chago and other related species. Such a platform can facilitate further studies on germplasm conservation and utilization of Lauraceae species. PMID- 30455718 TI - Component resolved analysis of ash pollen allergy in Bavaria. AB - Background: Sensitization to ash pollen is underestimated in various regions. The prevalence in Germany is about 10%. However, allergy to ash pollen is widely overlooked by allergists, since the pollination period of ash and birch in central Europe closely overlap and rhinoconjunctival symptoms during April/May are often assigned to birch pollen. Component resolved analysis of the different ash allergens is not routinely available. Therefore, we would like to question the usefulness of component resolved diagnostic via olive components, as ash and olive are both part of the Oleaceae family. Methods: 113 patients with nasal provocation and skin prick test to ash were retrospectively compared regarding their specific immunoglobulin E antibody profiles with response to native ash extract, rOle e 1, nOle e 7 and rOle e 9. Results: In nasal provocation testing 58% of 113 patients sensitized to ash were allergic, 42% were only sensitized without showing symptoms. Skin prick testing and serology against native ash extract detected most patients sensitized to ash pollen, whereas rOle e 1 was less sensitive. However, the value of measurements of skin prick test, serology to native ash extract and rOle e 1 did not allow a differentiation between an allergy and clinically silent sensitization. Specific antibodies to nOle e 7 and rOle e 9 were only seen in individual patients and were all positive for native ash extract and rOle e 1. Conclusion: Skin prick testing and serology to native extract of ash pollen are the most reliable tools to diagnose a sensitization to ash pollen for patients living in Germany. Component resolved diagnostic to the major allergen rOle e 1 as representative of the Oleaceae family is possible but was less sensitive. Diagnostic of nOle e 7 and rOle e 9 did not show any additional benefit. Regarding differentiation between allergy and clinically silent sensitization to ash pollen, provocation is the leading diagnostic tool. Concluding, in routine clinical practice the standard methods-skin prick test, serology to native ash extract and provocation testing-remain crucial in the diagnosis and differentiation of ash sensitization and allergy. PMID- 30455717 TI - Sweet syndrome: a rare feature of ANCA-associated vasculitis or unusual consequence of azathioprine-induced treatment. AB - Background: Sweet syndrome is a rare skin condition characterised by fever, neutrophilia, and tender erythematous skin lesions and has been reported to occur in association with anti-neutrophil cytoplasmic antibodies (ANCA) as well as complicate treatment with azathioprine therapy. Azathioprine, a relatively safe immunosuppressive, is frequently used to maintain disease remission in the treatment of ANCA-associated vasculitis. The occurrence of Sweet syndrome in a patient with ANCA-positive vasculitis and following treatment with azathioprine prompted us to present this clinical case and share this unusually rare occurrence. In doing so, we also wish to discuss current understanding of the disease and plausible associations. Case presentation: Herein, we discuss the case of a 54-year old white male, who presented with features of ANCA vasculitis with haemoptysis, arthralgia, abnormal kidney function with active urine sediment and a positive p-ANCA titre. Standard immunosuppressive treatment with corticosteroids and intravenous rituximab resulted in disease remission. Due to significant steroid side effects, his steroid treatment was gradually tapered and switched to azathioprine over a 6-month period. Two weeks following initiation of azathioprine, he developed a painful maculo-papular erythematous skin rash and fever. A skin biopsy confirmed classical features consistent with Sweet syndrome. Withdrawal of azathioprine and treatment with oral corticosteroids and colchicine therapy resulted in complete resolution of the rash, although he continued to have high titres of MPO positive ANCA. Conclusion: Sweet syndrome is a rare adverse reaction to azathioprine but has also been reported to occur in association with ANCA vasculitis. The temporal association with azathioprine in our case and the relatively rapid resolution of the skin vasculitis upon its withdrawal suggested a primarily drug-induced reaction rather than an associated feature of ANCA vasculitis. PMID- 30455716 TI - The Impact of Post-transcriptional Control: Better Living Through RNA Regulons. AB - Traditionally, cancer is viewed as a disease driven by genetic mutations and/or epigenetic and transcriptional dysregulation. While these are undoubtedly important drivers, many recent studies highlight the disconnect between the proteome and the genome or transcriptome. At least in part, this disconnect arises as a result of dysregulated RNA metabolism which underpins the altered proteomic landscape observed. Thus, it is important to understand the basic mechanisms governing post-transcriptional control and how these processes can be co-opted to drive cancer cell phenotypes. In some cases, groups of mRNAs that encode protein involved in specific oncogenic processes can be co-regulated at multiple processing levels in order to turn on entire biochemical pathways. Indeed, the RNA regulon model was postulated as a means to understand how cells coordinately regulate transcripts encoding proteins in the same biochemical pathways. In this review, we describe some of the basic mRNA processes that are dysregulated in cancer and the biological impact this has on the cell. This dysregulation can affect networks of RNAs simultaneously thereby underpinning the oncogenic phenotypes observed. PMID- 30455720 TI - Aetiology of anaphylaxis in patients referred to an immunology clinic in Colombo, Sri Lanka. AB - Background: The aetiology of anaphylaxis differs according to types of foods consumed, fauna and foliage and cultural practices. Although the aetiology of anaphylaxis in Western countries are well known, the causes in South Asian countries have not been reported. We sought to determine the causes of anaphylaxis in patients referred to an immunology clinic in Colombo, Sri Lanka. Methods: 238 episodes of anaphylaxis were reviewed in 188 patients who were referred and skin prick tests and in vitro tests (ImmunoCap) were carried out to assess the presence of allergen specific IgE. Clinical features and severity of anaphylaxis was also recorded along with treatment received. Results: Anaphylaxis to food either following direct exposure 90/238 (37.5%) or after exercise in the form of food dependent exercise induced anaphylaxis 29/238 (12.2%) was the predominant cause of anaphylaxis. Allergy to cow's milk and red meat, after immediate exposure, accounted for 66/238 (27.7%) of instances of all episodes of anaphylaxis and 66/90 (73.33%) of anaphylaxis due to food. Vaccines accounted for 28/238 (11.8%) of instances of anaphylaxis, especially among children. Of those who developed anaphylaxis to the MMR (n = 14), 71.4% of them had specific IgE to cow's milk and 35.7% of them had specific IgE to beef. Of those who developed anaphylaxis to insect stings, 27/42 of these episodes occurred following stings of ants (family Formicidae). The predominant cause of anaphylaxis changed with the age, with food allergy being the most frequent trigger of anaphylaxis in childhood, while drug allergy and idiopathic anaphylaxis being more frequent after 30 years of age. Conclusions: In this cohort, anaphylaxis to red meat appears to be the predominant cause of food induced anaphylaxis and presence of beef specific IgE and cow's milk, appears to be a predisposing factor for vaccine induced anaphylaxis. PMID- 30455721 TI - A comprehensive characterization of aggravated aging-related changes in T lymphocytes and monocytes in end-stage renal disease: the iESRD study. AB - Background: Patients with end-stage renal disease (ESRD) exhibit a premature aging phenotype of the immune system. Nevertheless, the etiology and impact of these changes in ESRD patients remain unknown. Results: Compared to healthy individuals, ESRD patients exhibit accelerated immunosenescence in both T cell and monocyte compartments, characterized by a dramatic reduction in naive CD4+ and CD8+ T cell numbers but increase in CD8+ TEMRA cell and proinflammatory monocyte numbers. Notably, within ESRD patients, aging-related immune changes positively correlated not only with increasing age but also with longer dialysis vintage. In multivariable-adjusted logistic regression models, the combination of high terminally differentiated CD8+ T cell level and high intermediate monocyte level, as a composite predictive immunophenotype, was independently associated with prevalent coronary artery disease as well as cardiovascular disease, after adjustment for age, sex, systemic inflammation and presence of diabetes. Levels of terminally differentiated CD8+ T cells also positively correlated with the level of uremic toxin p-cresyl sulfate. Conclusions: Aging-associated adaptive and innate immune changes are aggravated in ESRD and are associated with cardiovascular diseases. For the first time, our study demonstrates the potential link between immunosenescence in ESRD and duration of exposure to the uremic milieu. PMID- 30455719 TI - Unraveling the enigma: elucidating the relationship between the physicochemical properties of aluminium-based adjuvants and their immunological mechanisms of action. AB - Aluminium salts are by far the most commonly used adjuvants in vaccines. There are only two aluminium salts which are used in clinically-approved vaccines, Alhydrogel(r) and AdjuPhos(r), while the novel aluminium adjuvant used in Gardasil(r) is a sulphated version of the latter. We have investigated the physicochemical properties of these two aluminium adjuvants and specifically in milieus approximating to both vaccine vehicles and the composition of injection sites. Additionally we have used a monocytic cell line to establish the relationship between their physicochemical properties and their internalisation and cytotoxicity. We emphasise that aluminium adjuvants used in clinically approved vaccines are chemically and biologically dissimilar with concomitantly potentially distinct roles in vaccine-related adverse events. PMID- 30455722 TI - Healthy elderly Singaporeans show no age-related humoral hyporesponsiveness nor diminished plasmablast generation in response to influenza vaccine. AB - Abstract: Improving influenza vaccine efficacy is a priority to reduce the burden of influenza-associated morbidity and mortality. By careful selection of individuals based on health we show sustained response to influenza vaccination in older adults. Sustaining health in aging could be an important player in maintaining immune responses to influenza vaccination. Trial registration: NCT03266237. Registered 30 August 2017, https://clinicaltrials.gov/ct2/show/NCT03266237. PMID- 30455723 TI - Association of sex hormone-binding globulin with nonalcoholic fatty liver disease in Chinese adults. AB - Background: Sex hormone-binding globulin (SHBG), a glycoprotein synthesized by hepatocytes, has been linked to insulin resistance and hepatic lipid metabolism and is suggested to be associated with nonalcoholic fatty liver disease (NAFLD). This study aimed to investigate the association of SHBG with NAFLD in Chinese adults. Methods: We conducted a community-based, cross-sectional study in China involving 2912 participants aged 40-75 years old. All participants underwent detection for hepatic fat infiltration by ultrasound in addition to providing complete medical history and undergoing physical and blood biochemical examinations. The association of serum SHBG with the presence of NAFLD was reported by adjusted odds ratio after applying logistic regression models. To further explore the relationship between SHBG and NAFLD, mRNA expression of SHBG and hepatocyte nuclear factor 4-alpha (HNF4alpha), as well as intrahepatic triglycerides, were determined from the liver tissues of 32 subjects with different degrees of steatosis. Results: Serum SHBG levels in patients with NAFLD (median, 43.8 nmol/L; interquartile range, 33.4-56.8 nmol/L) were significantly lower than those in non-NAFLD subjects (median, 63.4 nmol/L; interquartile range, 47.6-83.1 nmol/L). Serum SHBG levels were inversely correlated with WHR, trunk fat percentage, glucose, HOMA-IR, TG, UA and DHEAS, and were positively correlated with HDL-C levels (all p < 0.001). Logistic regression analysis indicated that serum SHBG levels were negatively associated with the presence of NAFLD in all subjects, as well as the subgroups stratified by sex, BMI and HOMA IR (all p < 0.05). In human liver tissues, SHBG and HNF4alpha mRNA expression decreased along with the elevated grade of hepatic steatosis. Both SHBG and HNF4alpha mRNA expression levels were negatively correlated with intrahepatic triglycerides. Conclusions: These results demonstrate that SHBG levels were negatively associated with the presence of NAFLD in middle-aged and elderly Chinese adults. PMID- 30455724 TI - Investigating the microstructure of plant leaves in 3D with lab-based X-ray computed tomography. AB - Background: Leaf cellular architecture plays an important role in setting limits for carbon assimilation and, thus, photosynthetic performance. However, the low density, fine structure, and sensitivity to desiccation of plant tissue has presented challenges to its quantification. Classical methods of tissue fixation and embedding prior to 2D microscopy of sections is both laborious and susceptible to artefacts that can skew the values obtained. Here we report an image analysis pipeline that provides quantitative descriptors of plant leaf intercellular airspace using lab-based X-ray computed tomography (microCT). We demonstrate successful visualisation and quantification of differences in leaf intercellular airspace in 3D for a range of species (including both dicots and monocots) and provide a comparison with a standard 2D analysis of leaf sections. Results: We used the microCT image pipeline to obtain estimates of leaf porosity and mesophyll exposed surface area (Smes) for three dicot species (Arabidopsis, tomato and pea) and three monocot grasses (barley, oat and rice). The imaging pipeline consisted of (1) a masking operation to remove the background airspace surrounding the leaf, (2) segmentation by an automated threshold in ImageJ and then (3) quantification of the extracted pores using the ImageJ 'Analyze Particles' tool. Arabidopsis had the highest porosity and lowest Smes for the dicot species whereas barley had the highest porosity and the highest Smes for the grass species. Comparison of porosity and Smes estimates from 3D microCT analysis and 2D analysis of sections indicates that both methods provide a comparable estimate of porosity but the 2D method may underestimate Smes by almost 50%. A deeper study of porosity revealed similarities and differences in the asymmetric distribution of airspace between the species analysed. Conclusions: Our results demonstrate the utility of high resolution imaging of leaf intercellular airspace networks by lab-based microCT and provide quantitative data on descriptors of leaf cellular architecture. They indicate there is a range of porosity and Smes values in different species and that there is not a simple relationship between these parameters, suggesting the importance of cell size, shape and packing in the determination of cellular parameters proposed to influence leaf photosynthetic performance. PMID- 30455725 TI - Triple A patient cells suffering from mitotic defects fail to localize PGRMC1 to mitotic kinetochore fibers. AB - Background: Membrane-associated progesterone receptors are restricted to the endoplasmic reticulum and are shown to regulate the activity of cytochrome P450 enzymes which are involved in steroidogenesis or drug detoxification. PGRMC1 and PGRMC2 belong to the membrane-associated progesterone receptor family and are of interest due to their suspected role during cell cycle. PGRMC1 and PGRMC2 are thought to bind to each other; thereby suppressing entry into mitosis. We could previously report that PGRMC2 interacts with the nucleoporin ALADIN which when mutated results in the autosomal recessive disorder triple A syndrome. ALADIN is a novel regulator of mitotic controller Aurora kinase A and depletion of this nucleoporin leads to microtubule instability. Results: In the current study, we present that proliferation is decreased when ALADIN, PGRMC1 or PGRMC2 are over expressed. Furthermore, we find that depletion of ALADIN results in mislocalization of Aurora kinase A and PGRMC1 in metaphase cells. Additionally, PGRMC2 is over-expressed in triple A patient fibroblasts. Conclusion: Our results emphasize the possibility that loss of the regulatory association between ALADIN and PGRMC2 gives rise to a depletion of PGRMC1 at kinetochore fibers. This observation may explain part of the symptoms seen in triple A syndrome patients. PMID- 30455726 TI - Human papillomavirus E5 protein, the undercover culprit of tumorigenesis. AB - Human papillomavirus (HPV) is the most common viral infection of the reproductive tract worldwide. It has been well documented that the HPV oncoproteins E6 and E7 play important roles in cancer progression and maintenance. However, the high risk HPV E5 protein is also demonstrated to affect some cellular pathway and signaling in human cell lines. In this letter we argue for the need of further investigation and suggest that the HPV E5 protein should be acknowledged as an oncoprotein of HPV. PMID- 30455727 TI - Human papillomavirus (HPV) and Epstein-Barr virus (EBV) in keratinizing versus non- keratinizing squamous cell carcinoma of the oropharynx. AB - Background: Oral and oropharyngeal squamous cell carcinomas (OSCC and OPSCC) represent the majority of head and neck squamous cell carcinomas (HNSCC). Human papillomavirus (HPV) is an important etiologic factor together with Epstein-Barr virus (EBV). Little is known on the prevalence of major herpesviruses [EBV, cytomegalovirus (CMV) and HHV-6, - 7 and - 8] in HNSCCs. Methods: Fifty-one formalin-fixed paraffin-embedded (FFPE) tissue samples taken at surgery (40 oropharyngeal, 11 oral) were analyzed for 40 HPV genotypes (20 high-risk types), EBV, CMV, HHV-6, - 7 and - 8 by quantitative PCR. Expression of the HPV-induced p16INK4A protein was also investigated by immunohistochemistry (IHC). Results: In SCC, the prevalence of EBV was significantly higher compared to that of HPV (EBV 51% vs. HPV 19.5%; P = 0.005). HPV infection was found in 25% of OPSCC and in none of the OSCC; conversely, higher prevalence of EBV was found in OSCC (72.7%). HPV and EBV co-infection was detected only in 4 (10%) OPSCC. CMV was detected in only two cases, whereas HHV-6, - 7 and - 8 resulted negative. The prevalence of HPV but no EBV was associated with the non-keratinizing SCC type (NKSCC) compared to the keratinizing SCC type (KSCC)(HPV-DNA P < 0.005; EBV = 0.054). Conclusions: Single HPV or EBV positivity was higher in OSCC than in OPSCC. Other potentially oncogenic herpesvirus types were minimally or not represented. PMID- 30455729 TI - Increasing access to psychological treatments for adults by improving uptake and equity: rationale and lessons from the UK. AB - Objectives: Access to psychological treatments has been defined by Gulliford as comprising supply, effectiveness, equity and uptake. In the UK, a recent national programme "Improving Access to Psychological Treatments" has significantly increased supply and assessed effectiveness, but paid less attention to uptake and equity. The model developed by Gask et al. delineating processes relevant to improving access for 'hard-to-engage' groups in the UK, including black and minority groups seems relevant. This paper presents studies of a large-scale 'community workshop' intervention model developed by Brown to improve access for adults in the UK, designed to improve uptake and equity. We describe two 'community workshop' interventions for common mental health problems to which people have been able to self-refer and where uptake and equity have been high. Key components of this model are a 'group-sensitive engagement' ethos which includes self-referral, non-diagnostic titles of the intervention, a non-mental health setting, face-to-face presentation as well as a brief intervention and an acceptable format. Conclusion: The model of community workshops with its 'group sensitive engagement' ethos to which adults can self-refer may be very relevant in providing access for people with mental health needs in national and international settings.Trial registration Classic ISRCTN26634837. PMID- 30455728 TI - Endemic Kaposi sarcoma in HIV-negative children and adolescents: an evaluation of overlapping and distinct clinical features in comparison with HIV-related disease. AB - Background: Endemic Kaposi sarcoma (KS) was first described in African children over fifty years ago, but has recently been overshadowed by HIV-related disease. We aimed to evaluate the similarities and differences between endemic HIV negative and epidemic HIV-positive pediatric KS in a KS-associated herpesvirus endemic region of Africa. Methods: We describe clinical characteristics of 20 HIV negative children with endemic KS over a six-year period and compare findings with a historical control-an HIV-related pediatric KS cohort from Lilongwe, Malawi. Results: The HIV-negative endemic KS cohort was 70% male with a median age of 9.3 years. Lymph node involvement was present in 50%, hyperpigmented skin lesions in 45%, and woody edema in 40%. One patient (5%) presented with oral KS involvement and no patients presented initially with visceral KS. Significant anemia (hemoglobin < 8 g/dL) and thrombocytopenia (platelet count < 100 * 109/L) were found at time of original KS diagnosis in 45 and 40% respectively. In both HIV-negative and HIV-positive cohorts, lymphadenopathy was the most common presentation, prototypical skin lesions were often absent, severe cytopenias were a common clinical feature, and treatment outcomes were similar. Patients with endemic KS demonstrated less frequent oral involvement (5% versus 29%, P = 0.03) and a lower proportion of patients with visceral involvement (0% versus 16%, P = 0.06). Conclusions: These data suggest clinical overlap between epidemiological variants. Treatment protocols for pediatric KS in sub-Saharan Africa should be devised to include both endemic HIV-negative and epidemic HIV-related disease to better define the clinical and biological comparison. PMID- 30455730 TI - Characteristics of perinatal depression in rural central, India: a cross sectional study. AB - Background: Perinatal depression is associated with negative effects on child behavioural, cognitive and emotional development, birth outcomes, and physical growth. In India, increased priority accorded to mental health programs mean it is now possible to reduce the population-level burden of perinatal depression. In this secondary analysis of two studies, we aimed to describe the epidemiological features of depression among community- and facility-based samples of perinatal women from rural central India, and to describe the help-seeking behaviours from those women who screened positive for depression. Methods: The Community Study was a multi-round population-based cross-sectional survey (n = 6087). The Facility Study was a multi-round facility-based cross-sectional survey (n = 1577). Both studies were conducted in Sehore District, Madhya Pradesh between 2013 and 2017. Field workers conducted structured interviews with perinatal women. The questionnaire had sections relating to sociodemographic characteristics, depression screening using the Patient's Health Questionnaire (PHQ9), treatment seeking for depression-related symptoms, and disability. Using data pooled from both studies, we tested each characteristic for association with the total screening score and with screening positive for depression. Results: We identified 224 perinatal women from the Community Study and 130 perinatal women from the Facility Study, of whom 8.8% and 18.5% screened positive for depression, respectively. For the continuous PHQ9 score, there was evidence of a "U" shaped association with age, and positive associations with pregnancy, disability score, suicidality and being a health facility attendee. For the binary PHQ9 score, there was evidence of positive associations with pregnancy, disability score, suicidality and being a health facility attendee. Conclusions: This study highlights where the largest population-level variations in perinatal depression symptoms are present in this Indian sample, for which mental health service provision should be made a priority. Epidemiological evidence generated by this study, as well as new evidence on peer-delivered interventions for perinatal depression, must be utilized by policy-makers to prioritize mental health services for mothers along with maternal and child health services. PMID- 30455731 TI - Dye-decolorizing peroxidases in Irpex lacteus combining the catalytic properties of heme peroxidases and laccase play important roles in ligninolytic system. AB - Background: The white rot fungus Irpex lacteus exhibits a great potential in biopretreatment of lignocellulose as well as in biodegradation of xenobiotic compounds by extracellular ligninolytic enzymes. Among these enzymes, the possible involvement of dye-decolorizing peroxidase (DyP) in lignin degradation is not clear yet. Results: Based on the extracellular enzyme activities and secretome analysis, I. lacteus CD2 produced DyPs as the main ligninolytic enzymes when grown in Kirk's medium supplemented with lignin. Further transcriptome analysis revealed that induced transcription of genes encoding DyPs was accompanied by the increased expression of transcripts for H2O2-generating enzymes such as alcohol oxidase, pyranose 2-oxidase, and glyoxal oxidases. Meanwhile, accumulation of transcripts for glycoside hydrolase and protease was observed, in agreement with abundant proteins. Moreover, the biochemical analysis of IlDyP2 and IlDyP1 confirmed that DyPs were able to catalyze the oxidation of typical peroxidases substrates ABTS, phenolic lignin compounds DMP, and guaiacol as well as non-phenolic lignin compound, veratryl alcohol. More importantly, IlDyP1 enhanced catalytic activity for veratryl alcohol oxidation in the presence of mediator 1-hydroxybenzotriazole, which was similar to the laccase/1 hydroxybenzotriazole system. Conclusions: The results proved for the first time that DyPs depolymerized lignin individually, combining catalytic features of different peroxidases on the functional level. Therefore, DyPs may be considered an important part of ligninolytic system in wood-decaying fungi. PMID- 30455733 TI - Fractionation and characterization of lignin streams from unique high-lignin content endocarp feedstocks. AB - Background: Lignin is a promising source of building blocks for upgrading to valuable aromatic chemicals and materials. Endocarp biomass represents a non edible crop residue in an existing agricultural setting which cannot be used as animal feed nor soil amendment. With significantly higher lignin content and bulk energy density, endocarps have significant advantages to be converted into both biofuel and bioproducts as compared to other biomass resources. Deep eutectic solvent (DES) is highly effective in fractionating lignin from a variety of biomass feedstocks with high yield and purity while at lower cost comparing to certain ionic liquids. Results: In the present study, the structural and compositional features of peach and walnut endocarp cells were characterized. Compared to typical woody and herbaceous biomass, endocarp biomass exhibits significantly higher bulk density and hardness due to its high cellular density. The sugar yields of DES (1:2 choline chloride: lactic acid) pretreated peach pit (Prunus persica) and walnut shell (Juglans nigra) were determined and the impacts of DES pretreatment on the physical and chemical properties of extracted lignin were characterized. Enzymatic saccharification of DES pretreated walnut and peach endocarps gave high glucose yields (over 90%); meanwhile, compared with dilute acid and alkaline pretreatment, DES pretreatment led to significantly higher lignin removal (64.3% and 70.2% for walnut and peach endocarps, respectively). The molecular weights of the extracted lignin from DES pretreated endocarp biomass were significantly reduced. 1H-13C HSQC NMR results demonstrate that the native endocarp lignins were SGH type lignins with dominant G-unit (86.7% and 80.5% for walnut and peach endocarps lignins, respectively). DES pretreatment decreased the S and H-unit while led to an increase in condensed G-units, which may contribute to a higher thermal stability of the isolated lignin. Nearly all beta-O-4' and a large portion of beta-5' linkages were removed during DES pretreatment. Conclusions: The high lignin content endocarps have unique cell wall characteristics when compared to the other lignocellulosic biomass feedstocks. DES pretreatment was highly effective in fractionating high lignin content endocarps to produce both sugar and lignin streams while the DES extracted lignins underwent significant changes in SGH ratio, interunit linkages, and molecular sizes. PMID- 30455732 TI - Cloning, purification, and characterization of an organic solvent-tolerant chitinase, MtCh509, from Microbulbifer thermotolerans DAU221. AB - Background: The ability to use organic solvents in enzyme reactions offers a number of industrially useful advantages. However, most enzymes are almost completely inactive in the presence of organic solvents. Thus, organic solvent tolerant enzymes have potential applications in industrial processes. Results: A chitinase gene from Microbulbifer thermotolerans DAU221 (mtch509) was cloned and expressed in Escherichia coli BL21 (DE3). The molecular weight of the expressed MtCh509 protein was approximately 60 kDa, and it was purified by His-tag affinity chromatography. Enzymatic assays showed that the optimum temperature for MtCh509 chitinase activity was 55 degrees C, and the enzyme was stable for 2 h at up to 50 degrees C. The optimum pH for MtCh509 activity was in the sub-acidic range, at pH 4.6 and 5.0. The activity of MtCh509 was maintained in presence of 1 M salt, gradually decreasing at higher concentrations, with residual activity (20%) detected after incubation in 5 M salt. Some organic solvents (benzene, DMSO, hexane, isoamyl alcohol, isopropyl alcohol, and toluene; 10-20%, v/v) increased the reactivity of MtCh509 relative to the aqueous system. When using NAG3, as a substrate, MtCh509 produced NAG2 as the major product, as well as NAG4, demonstrating that MtCh509 has transglycosylation activity. The K m and V max values for MtCh509 using colloidal chitin as a substrate were 9.275 mg/mL and 20.4 U/mg, respectively. Thus, MtCh509 could be used in extreme industrial conditions. Conclusion: The results of the hydrolysate analysis and the observed increase in enzyme activity in the presence of organic solvents show that MtCh509 has industrially attractive advantages. This is the first report on an organic solvent-tolerant and transglycosylating chitinase from Microbulbifer species. PMID- 30455734 TI - Genome mining of 2-phenylethanol biosynthetic genes from Enterobacter sp. CGMCC 5087 and heterologous overproduction in Escherichia coli. AB - Background: 2-Phenylethanol (2-PE) is a higher aromatic alcohol that is widely used in the perfumery, cosmetics, and food industries and is also a potentially valuable next-generation biofuel. In our previous study, a new strain Enterobacter sp. CGMCC 5087 was isolated to produce 2-PE from glucose through the phenylpyruvate pathway. Results: In this study, candidate genes for 2-PE biosynthesis were identified from Enterobacter sp. CGMCC 5087 by draft whole genome sequence, metabolic engineering, and shake flask fermentation. Subsequently, the identified genes encoding the 2-keto acid decarboxylase (Kdc) and alcohol dehydrogenase (Adh) enzymes from Enterobacter sp. CGMCC 5087 were introduced into E. coli BL21(DE3) to construct a high-efficiency microbial cell factory for 2-PE production using the prokaryotic phenylpyruvate pathway. The enzymes Kdc4427 and Adh4428 from Enterobacter sp. CGMCC 5087 showed higher performances than did the corresponding enzymes ARO10 and ADH2 from Saccharomyces cerevisiae, respectively. The E. coli cell factory was further improved by overexpressing two upstream shikimate pathway genes, aroF/aroG/aroH and pheA, to enhance the metabolic flux of the phenylpyruvate pathway, which resulted in 2-PE production of 260 mg/L. The combined overexpression of tktA and ppsA increased the precursor supply of erythrose-4-phosphate and phosphoenolpyruvate, which resulted in 2-PE production of 320 mg/L, with a productivity of 13.3 mg/L/h. Conclusions: The present study achieved the highest titer of de novo 2-PE production of in a recombinant E. coli system. This study describes a new, efficient 2-PE producer that lays foundation for the industrial-scale production of 2-PE and its derivatives in the future. PMID- 30455735 TI - Rewiring glycerol metabolism for enhanced production of poly-gamma-glutamic acid in Bacillus licheniformis. AB - Background: Poly-gamma-glutamic acid (gamma-PGA) is a natural polymer with great potential applications in areas of agriculture, industry, and pharmaceutical. The biodiesel-derived glycerol can be used as an attractive feedstock for gamma-PGA production due to its availability and low price; however, insufficient production of gamma-PGA from glycerol is limitation. Results: The metabolic pathway of Bacillus licheniformis WX-02 was rewired to improve the efficiency of glycerol assimilation and the supply of NADPH for gamma-PGA synthesis. GlpK, GlpX, Zwf, and Tkt1 were found to be the key enzymes for gamma-PGA synthesis using glycerol as a feedstock. Through combinational expression of these key enzymes, the gamma-PGA titer increased to 19.20 +/- 1.57 g/L, which was 1.50-fold of that of the wild-type strain. Then, we studied the flux distributions, gene expression, and intracellular metabolites in WX-02 and the recombinant strain BC4 (over-expression of the above quadruple enzymes). Our results indicated that over expression of the quadruple enzymes redistributed metabolic flux to gamma-PGA synthesis. Furthermore, using crude glycerol as carbon source, the BC4 strain showed a high productivity of 0.38 g/L/h, and produced 18.41 g/L gamma-PGA, with a high yield of 0.46 g gamma-PGA/g glycerol. Conclusions: The approach to rewiring of metabolic pathways enables B. licheniformis to efficiently synthesize gamma-PGA from glycerol. The gamma-PGA productivity reported in this work is the highest obtained in glutamate-free medium. The present study demonstrates that the recombinant B. licheniformis strain shows significant potential to produce valuable compounds from crude glycerol. PMID- 30455737 TI - Draft genome sequence and detailed characterization of biofuel production by oleaginous microalga Scenedesmus quadricauda LWG002611. AB - Background: Due to scarcity of fossil fuel, the importance of alternative energy sources is ever increasing. The oleaginous microalgae have demonstrated their potential as an alternative source of energy, but have not achieved commercialization owing to some biological and technical inefficiency. Modern methods of recombinant strain development for improved efficacy are suffering due to inadequate knowledge of genome and limited molecular tools available for their manipulation. Results: In the present study, microalga Scenedesmus quadricauda LWG002611 was selected as the preferred organism for lipid production as it contained high biomass (0.37 g L-1 day-1) and lipid (102 mg L-1 day-1), compared to other oleaginous algae examined in the present study as well as earlier reports. It possessed suitable biodiesel properties as per the range defined by the European biodiesel standard EN14214 and petro-diesel standard EN590:2013. To investigate the potential of S. quadricauda LWG002611 in details, the genome of the organism was assembled and annotated. This was the first genome sequencing and assembly of S. quadricauda, which predicted a genome size of 65.35 Mb with 13,514 genes identified by de novo and 16,739 genes identified by reference guided annotation. Comparative genomics revealed that it belongs to class Chlorophyceae and order Sphaeropleales. Further, small subunit ribosomal RNA gene (18S rRNA) sequencing was carried out to confirm its molecular identification. S. quadricauda LWG002611 exhibited higher number of genes related to major activities compared to other potential algae reported earlier with a total of 283 genes identified in lipid metabolism. Metabolic pathways were reconstructed and multiple gene homologs responsible for carbon fixation and triacylglycerol (TAG) biosynthesis pathway were identified to further improve this potential algal strain for biofuel production by metabolic engineering approaches. Conclusion: Here we present the first draft genome sequence, genetic characterization and comparative evaluation of S. quadricauda LWG002611 which exhibit high biomass as well as high lipid productivity. The knowledge of genome sequence, reconstructed metabolic pathways and identification of rate-limiting steps in TAG biosynthesis pathway will strengthen the development of molecular tools towards further improving this potentially one of the major algal strains for biofuel production. PMID- 30455736 TI - Improved xylose tolerance and 2,3-butanediol production of Klebsiella pneumoniae by directed evolution of rpoD and the mechanisms revealed by transcriptomics. AB - Background: The biological production of 2,3-butanediol from xylose-rich raw materials from Klebsiella pneumoniae is a low-cost process. RpoD, an encoding gene of the sigma factor, is the key element in global transcription machinery engineering and has been successfully used to improve the fermentation with Escherichia coli. However, whether it can regulate the tolerance in K. pneumoniae remains unclear. Results: In this study, the kpC mutant strain was constructed by altering the expression quantity and genotype of the rpoD gene, and this exhibited high xylose tolerance and 2,3-butanediol production. The xylose tolerance of kpC strain was increased from 75 to 125 g/L, and the yield of 2,3 butanediol increased by 228.5% compared with the parent strain kpG, reaching 38.6 g/L at 62 h. The RNA sequencing results showed an upregulated expression level of 500 genes and downregulated expression level of 174 genes in the kpC mutant strain. The pathway analysis further showed that the differentially expressed genes were mainly related to signal transduction, membrane transport, carbohydrate metabolism, and energy metabolism. The nine most-promising genes were selected based on transcriptome sequencing, and were evaluated for their effects on xylose tolerance. The overexpression of the tktA encoding transketolase, pntA encoding NAD(P) transhydrogenase subunit alpha, and nuoF encoding NADH dehydrogenase subunit F conferred increased xylose consumption and increased 2,3-butanediol production to K. pneumoniae. Conclusions: These results suggest that the xylose tolerance and 2,3-butanediol production of K. pneumoniae can be greatly improved by the directed evolution of rpoD. By applying transcriptomic analysis, the upregulation of tktA, pntA, and nuoF that were coded are essential for the xylose consumption and 2,3-butanediol production. This study will provide reference for further research on improving the fermentation abilities by means of other organisms. PMID- 30455738 TI - Enhancing enzymatic saccharification of sugarcane bagasse by combinatorial pretreatment and Tween 80. AB - Background: The recalcitrant structure of lignocellulosic biomass made it challenging for their bioconversion into biofuels and biochemicals. Pretreatment was required to deconstruct the intact structure by the removal of hemicellulose/lignin, improving the cellulose accessibility of enzyme. Combinatorial pretreatments with liquid hot water/H2SO4 and ethanol/NaOH of sugarcane bagasse were developed to improve enzymatic hydrolysis under mild conditions. Results: After one-step 60% ethanol containing 0.5% NaOH pretreatment with solid to liquid ratio of 1/10, the glucose yield after hydrolysis for 72 h with enzyme dosage of 20 FPU/g substrate was enhanced by 41% and 205% compared to that of NaOH or 60% ethanol pretreated solids, respectively. This improvement was correlated with the removal of hemicellulose and lignin. However, using combinatorial pretreatments with 1% H2SO4 followed by 60% ethanol containing 0.5% NaOH, the highest glucose yield with Tween 80 reached 76%, representing 84.5% of theoretical glucose in pretreated substrate. While retaining similar glucose yield, the addition of Tween 80 capacitated either a reduction of enzyme loading by 50% or shortening hydrolysis time to 24 h. However, the enhancement with the addition of Tween 80 decreased as hydrolysis time was extended. Conclusions: This study demonstrated that a combinatorial pretreatment with 1% H2SO4 followed by 60% ethanol containing 0.5% NaOH had significant effects on improving the enzymatic hydrolysis of sugarcane bagasse. The addition of Tween 80 enabled reducing the enzyme loading or shortening the hydrolysis time. This study provided an economically feasible and mild process for the generation of glucose, which will be subsequently converted to bioethanol and biochemicals. PMID- 30455739 TI - Development of a promising microbial platform for the production of dicarboxylic acids from biorenewable resources. AB - Background: As a sustainable industrial process, the production of dicarboxylic acids (DCAs), used as precursors of polyamides, polyesters, perfumes, plasticizers, lubricants, and adhesives, from vegetable oil has continuously garnered interest. Although the yeast Candida tropicalis has been used as a host for DCA production, additional strains are continually investigated to meet productivity thresholds and industrial needs. In this regard, the yeast Wickerhamiella sorbophila, a potential candidate strain, has been screened. However, the lack of genetic and physiological information for this uncommon strain is an obstacle that merits further research. To overcome this limitation, we attempted to develop a method to facilitate genetic recombination in this strain and produce high amounts of DCAs from methyl laurate using engineered W. sorbophila. Results: In the current study, we first developed efficient genetic engineering tools for the industrial application of W. sorbophila. To increase homologous recombination (HR) efficiency during transformation, the cell cycle of the yeast was synchronized to the S/G2 phase using hydroxyurea. The HR efficiency at POX1 and POX2 loci increased from 56.3% and 41.7%, respectively, to 97.9% in both cases. The original HR efficiency at URA3 and ADE2 loci was nearly 0% during the early stationary and logarithmic phases of growth, and increased to 4.8% and 25.6%, respectively. We used the developed tools to construct W. sorbophila UHP4, in which beta-oxidation was completely blocked. The strain produced 92.5 g/l of dodecanedioic acid (DDDA) from methyl laurate over 126 h in 5-l fed-batch fermentation, with a productivity of 0.83 g/l/h. Conclusions: Wickerhamiella sorbophila UHP4 produced more DDDA methyl laurate than C. tropicalis. Hence, we demonstrated that W. sorbophila is a powerful microbial platform for vegetable oil-based DCA production. In addition, by using the developed genetic engineering tools, this emerging yeast could be used for the production of a variety of fatty acid derivatives, such as fatty alcohols, fatty aldehydes, and omega-hydroxy fatty acids. PMID- 30455740 TI - Effects of pH on steam explosion extraction of acetylated galactoglucomannan from Norway spruce. AB - Background: Acetylated galactoglucomannan (AcGGM) is a complex hemicellulose found in softwoods such as Norway spruce (Picea abies). AcGGM has a large potential as a biorefinery feedstock and source of oligosaccharides for high value industrial applications. Steam explosion is an effective method for extraction of carbohydrates from plant biomass. Increasing the reaction pH reduces the combined severity ( Results: Reducing the severity of steam explosion resulted in lower yields, although the extracted oligosaccharides had a higher degree of polymerization. Higher buffering pH also resulted in a higher fraction of xylan in the extracted oligos. Oligosaccharides extracted in buffers of pH > 5.0 were deacetylated. Buffering leads to a removal of acetylations from both the extracted oligosaccharides and the hemicellulose in the residual biomass. Treatment of the residual biomass with a GH5 family mannanase from Aspergillus nidulans was not able to improve the AcGGM yields. No hydroxymethylfurfural formation, a decomposition product from hexoses, was observed in samples soaked with buffers at pH higher than 4.0. Conclusions: Buffering the steam explosion reactions proved to be an effective way to reduce the combined severity ( PMID- 30455741 TI - Enhanced triacylglycerol production in the diatom Phaeodactylum tricornutum by inactivation of a Hotdog-fold thioesterase gene using TALEN-based targeted mutagenesis. AB - Background: In photosynthetic oleaginous microalgae, acyl-CoA molecules are used as substrates for the biosynthesis of membrane glycerolipids, triacylglycerol (TAG) and other acylated molecules. Acyl-CoA can also be directed to beta oxidative catabolism. They can be utilized by a number of lipid metabolic enzymes including endogenous thioesterases, which catalyze their hydrolysis to release free fatty acids. Acyl-CoA availability thus plays fundamental roles in determining the quantity and composition of membrane lipids and storage lipids. Results: Here, we have engineered the model diatom Phaeodactylum tricornutum to produce significantly increased TAGs by disruption of the gene encoding a Hotdog fold thioesterase involved in acyl-CoA hydrolysis (ptTES1). This plastidial thioesterase can hydrolyze both medium- and long-chain fatty acyl-CoAs, but has the highest activity toward long-chain saturated and monounsaturated fatty acyl CoAs. The maximum rate was found with oleoyl-CoA, which is hydrolyzed at 50 nmol/min/mg protein. The stable and targeted interruption of acyl-CoA thioesterase gene was achieved using a genome editing technique, transcription activator-like effector nucleases (TALENs). Disruption of native ptTES1 gene resulted in a 1.7-fold increase in TAG content when algal strains were grown in nitrogen-replete media for 8 days, whereas the content of other lipid classes, including phosphoglycerolipids and galactoglycerolipids, remained almost unchanged. The engineered algal strain also exhibited a marked change in fatty acid profile, including a remarkable increase in 16:0 and 16:1 and a decrease in 20:5. Nitrogen deprivation for 72 h further increased TAG content and titer of the engineered strain, reaching 478 MUg/109 cells and 4.8 mg/L, respectively. Quantitative determination of in vivo acyl-CoAs showed that the total acyl-CoA pool size was significantly higher in the engineered algal strain than that in the wild type. Conclusions: This study supports the role of ptTES1 in free fatty acid homeostasis in the plastid of Phaeodactylum and demonstrates the potential of TALEN-based genome editing technique to generate an enhanced lipid-producing algal strain through blocking acyl-CoA catabolism. PMID- 30455742 TI - New drug developments in metastatic gastric cancer. AB - Metastatic gastric cancer is associated with a poor prognosis and novel treatment options are desperately needed. The development of targeted therapies heralded a new era for the management of metastatic gastric cancer, however results from clinical trials of numerous targeted agents have been mixed. The advent of immune checkpoint inhibitors has yielded similar promise and results from early trials are encouraging. This review provides an overview of the systemic treatment options evaluated in metastatic gastric cancer, with a focus on recent evidence from clinical trials for targeted therapies and immune checkpoint inhibitors. The failure to identify appropriate predictive biomarkers has hampered the success of many targeted therapies in gastric cancer, and a deeper understanding of specific molecular subtypes and genomic alterations may allow for more precision in the application of novel therapies. Identifying appropriate biomarkers for patient selection is essential for future clinical trials, for the most effective use of novel agents and in combination approaches to account for growing complexity of treatment options. PMID- 30455743 TI - The effect of pre-admission immunosuppression on colectomy rates in acute severe ulcerative colitis. AB - Background: Patients on immunosuppression at the time of acute severe ulcerative colitis have been suggested to be at a higher risk of colectomy than those who are treatment-naive. The aim of this study was to examine the effect of immunosuppressive therapy on the risk of colectomy. Method: We conducted a retrospective observational cohort study using prospective data examining the 30 day and 1 year colectomy rates of 200 consecutive patients with an index episode of acute severe ulcerative colitis as defined by the Truelove and Witts criteria. Results: Immunosuppression on admission was shown not to increase colectomy rate at 30 days post-admission (immunomodulator: p = 0.422, oral steroids: p = 0.555). A total of 24 patients underwent colectomy between 30 days and 1 year. A three fold higher risk of colectomy at 1 year was seen in those requiring an immunomodulator prior to the index admission compared with those started de novo during the index admission [41% versus 14% odds ratio (OR): 2.93 (1.19-7.24 p = 0.016)]. Factors most predictive of colectomy at 30 days were abdominal radiographic colonic dilation ?5.5 cm, first presentation of ulcerative colitis, C-reactive protein ? 45 mg/l on day 3 of therapy and bowel frequency ?8 on day 3. Conclusion: The need for an immunomodulator prior to admission with acute severe ulcerative colitis increases the medium-term colectomy rate by three-fold at 1 year. Prospective studies are needed to confirm these findings and develop strategies to reduce the high risk in this subgroup of patients. PMID- 30455744 TI - Physical and mechanical therapies for lower limb symptoms in children with Hypermobility Spectrum Disorder and Hypermobile Ehlers-Danlos Syndrome: a systematic review. AB - Background: Hypermobility Spectrum Disorder and Hypermobile Ehlers Danlos Syndrome are two common heritable genetic disorders of connective tissue. Both conditions are characterised by excessive joint range of motion and the presence of musculoskeletal symptoms, and are associated with joint instability, motion incoordination, decreased joint position sense, and musculoskeletal pain. Hypermobility Spectrum Disorder is the new classification for what was previously known as Joint Hypermobility Syndrome. This systematic review evaluates the evidence for physical and mechanical treatments for lower limb problems in children with Hypermobility Spectrum Disorder and Hypermobile Ehlers Danlos Syndrome. Methods: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, PUBMED and CINAHL were searched to October 2017 for randomised controlled trials (RCT) and quasi-RCTs evaluating physical and mechanical interventions for lower limb problems in children with hypermobility. Two authors independently screened studies for eligibility for inclusion and three review authors independently assessed risk of bias of included studies. One author extracted and analysed statistical data, which were checked by a second author. Results: Two RCTs including a total of 86 participants were eligible for inclusion. Trials evaluated differences between generalised versus targeted physiotherapy programs and between performing knee extension exercises to the neutral versus hypermobile range. There was no clear benefit of any of the physical therapies evaluated. Conclusion: There is very limited evidence to guide the use of physical and mechanical therapies for lower limb problems in children with Hypermobility Spectrum Disorder and Hypermobile Ehlers Danlos Syndrome. Mechanical therapies have not been evaluated in RCTs and results of the two RCTs of physical therapies do not definitively guide physical therapy prescriptions. Current studies are limited by small sample sizes and high attrition rates. No physical therapy has been compared to a sham intervention no intervention or no intervention, so overall effectiveness is unknown. PMID- 30455745 TI - Comparative effects of vitamin D and vitamin C supplementations with and without endurance physical activity on metabolic syndrome patients: a randomized controlled trial. AB - Objective: Vitamin D and C levels have inverse relation with the metabolic syndrome components and they are used as antioxidant supplements during enduring metabolic activities. In the present study, we hypothesized that the intake of vitamin D and/or C with endurance physical activity might reduce the risk of metabolic syndrome. Methods: A randomized control study recruited 180 participants of both genders, aged between 30 and 50 years. The participants were assigned into six groups receiving different doses of vitamin D or vitamin C with or without physical activities. Data were collected over a period of 3 months, and the results were analyzed using SPSS version 20. Results: Variations in the effect of the supplements on various body variables including: Fasting plasma glucose, total cholesterol, low-density lipoprotein cholesterol and blood pressure, showed that vitamin D has more influence compared to vitamin C. However, vitamin D and C supplements do not have any effect on weight when consumers are undergoing endurance physical exercise. But vitamin C consumer group has more effect in waist circumference, triglyceride, and high-density lipoprotein, as compared to vitamin D consumer group. Conclusion: We conclude that, consumption of vitamin D or vitamin C supplements may improves the life of metabolic syndrome patients. However, the combination of physical activities and vitamin supplements maximize the effect, and this combination should be recommended.Trial registration WHO-ICTRP IRCT20161110030823N2. Registered 01 February 2018. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=IRCT20161110030823N2. PMID- 30455747 TI - Can-SINE dynamics in the giant panda and three other Caniformia genomes. AB - Background: Although repeat sequences constitute about 37% of carnivore genomes, the characteristics and distribution of repeat sequences among carnivore genomes have not been fully investigated. Based on the updated Repbase library, we re annotated transposable elements (TEs) in four Caniformia genomes (giant panda, polar bear, domestic dog, and domestic ferret) and performed a systematic, genome wide comparison focusing on the Carnivora-specific SINE family, Can-SINEs. Results: We found the majority of young recently integrated transposable elements are LINEs and SINEs in carnivore genomes. In particular, SINEC1_AMe, SINEC1B_AMe and SINEC_C1 are the top three most abundant Can-SINE subfamilies in the panda and polar bear genomes. Transposition in transposition analysis indicates that SINEC1_AMe and SINEC1B_AMe are the most active subfamilies in the panda and the polar bear genomes. SINEC2A1_CF and SINEC1A_CF subfamilies show a higher retrotransposition activity in the dog genome, and MVB2 subfamily is the most active Can-SINE in the ferret genome. As the giant panda is an endangered icon species, we then focused on the identification of panda specific Can-SINEs. With the panda-associated two-way genome alignments, we identified 250 putative panda specific (PPS) elements (139 SINEC1_AMes and 111 SINEC1B_AMes) that inserted in the panda genome but were absent at the orthologous regions of the other three genomes. Further investigation of these PPS elements allowed us to identify a new Can-SINE subfamily, the SINEC1_AMe2, which was distinguishable from the current SINEC1_AMe consensus by four non-CpG sites. SINEC1_AMe2 has a high copy number (> 100,000) in the panda and polar bear genomes and the vast majority (> 96%) of the SINEC1_AMe2 elements have divergence rates less than 10% in both genomes. Conclusions: Our results suggest that Can-SINEs show lineage-specific retransposition activity in the four genomes and have an important impact on the genomic landscape of different Caniformia lineages. Combining these observations with results from the COSEG, Network, and target site duplication analysis, we suggest that SINEC1_AMe2 is a young mobile element subfamily and currently active in both the panda and polar bear genomes. PMID- 30455748 TI - The Role of TNF-alpha induced MSCs on Suppressive Inflammation by Increasing TGF beta and IL-10. AB - BACKGROUND: Mesenchymal stem cells (MSCs) may serve as immunoregulators by producing various anti-inflammatory molecules. Under sufficient level of TNF alpha, MSCs become activated and adopt immune-suppressive phenotype (MSCs type-2) by releasing various anti-inflammatory molecule including TGF-beta and IL-10. However, the ability of MSC itself to produce IL-10 under TNF-alpha stimulation and the correlation of TGF-beta production of MSCs to IL-10 level remains to be elucidated. AIM: In this study, MSCs were activated with various TNF-alpha doses to determine the increase of IL-10 and TGF-beta level as well as its correlation. MATERIAL AND METHODS: This study used post-test only control group design, by using 3 study groups, consist of 1 control (C) and 2 treatments (T) (TNF-alpha = 5 and 10 ng/mL) with triplicate induced in MSC for 24 hours, then the levels of IL-10 and TGF-beta were measured by using ELISA assay. RESULTS: The results of this study showed a significant increase of TGF-beta and IL-10 levels (p < 0.05) at TNF-alpha 5 and 10 ng/mL dose of TNF-alpha. Moreover, there was a significant negative correlation between TGF-beta and IL-10 level on 5 and 10 ng/mL dose TNF alpha treatment. CONCLUSION: Based on our study, we conclude that the 5 ng/mL dose of TNF-alpha is a sufficient dose for MSCs to suppress the inflammatory milieu. The higher increase of TGF beta is due to the controlled inflammation by IL-10. PMID- 30455746 TI - Cochlear dysfunction and microvascular complications in patients with type 1 diabetes mellitus. AB - Sensorineural hearing impairment has been associated with DM, and it is probably linked to the same pathophysiological mechanisms as well-established in microvascular diabetes complications. The study of otoacoustic emissions (OAEs) is useful to identify subclinical cochlear dysfunction. Therefore, the aim of this study was to evaluate the association between abnormal OAEs responses, diabetic kidney disease (DKD) and diabetic cardiac autonomic neuropathy (CAN). We performed a cross-sectional study with 37 type 1 DM patients without auditory symptoms, submitted to the study of Distortion Product Otoacoustic Emissions (DPOAEs) and screened for DKD and CAN. The otoacoustic emissions responses were considered abnormal in 27/37 (73%) patients. A correlation was found between abnormal OAEs responses and presence of DKD (r = 0.36, p < 0.05), and 14/16 (88%) patients with a lower amplitude of OAEs in 8 kHz frequency band presented DKD. Abnormal OAEs responses in the 6 kHz frequency band were correlated with the presence (r = 0.41, p = 0.01) and severity of CAN (r = 0.44, p < 0.001). Additionally, 7/9 (78%) patients with abnormal OAE responses in this frequency also presented abnormal CAN scores. Our results suggest that abnormal otoacoustic emissions responses in high frequency bands are associated with diabetes microvascular complications and could be a risk marker for DKD and CAN, presenting low sensitivity and high specificity. Therefore, assuming that hearing impairment is a pre-clinical stage of hearing loss, performing distortion product otoacoustic emissions in T1DM patients with microvascular complications could be useful to identify those who would be benefit with regular audiologic follow up and tighter diabetes control. PMID- 30455749 TI - Vascular Endothelial Growth Factor 936 C/T Gene Polymorphism in Indonesian Subjects with Diabetic Polyneuropathy. AB - AIM: This study aimed to confirm the role of f VEGF gene 936 C/T polymorphism and Diabetic Polyneuropathy (DPN) in the Indonesian population as well as to investigate its relationship with VEGF-A level and the role of vascular risk factors. MATERIAL AND METHODS: This was a cross-sectional study involving 152 subjects. Clinical symptoms and signs of DPN were examined using DNE and DNS scoring followed by nerve conduction study. All subjects underwent anthropometric, clinical examination and laboratory procedures to obtain body mass index, HbA1C level, lipid profile, Polymorphism of +936 C/T VEGF gene (PCR RFLP technique), and VEGF-A plasma level (ELISA). Statistical analysis using a t test or Mann-Whitney was performed to assess continuous data and Chi-square for categorical data. Multivariate logistic regressions were also performed to determine the relationship between independent variables and DPN. RESULTS: Sixty nine (45.4%) fulfilled the diagnostic criteria of DPN. There was a significant association between CT + TT genotype and DPN (OR 0.35 95%CI 0.16-0.79 p = 0.01). Multivariate logistic regression showed that plasma VEGF-A level (OR = 1.003; 95% CI = 1.000-1.007; p = 0.03), diabetes duration (OR = 1.108; 95% CI = 1.045-1.175; p = 0.001), and CT+TT genotype (OR = 0.347; 95%CI = 0.148-0.817; p = 0.013) were associated with DPN. Sub-group analysis on subjects with HbA1C level >=7% showed that VEGF-A (OR = 1.011; 95%CI = (1.004-1.017; p = 0.03), diabetes duration (OR = 1.245; 95% CI = 1.117-1.388; p < 0.001), CT + TT genotype (OR = 0.259; 95%CI = 0.074-0.911p = 0.035), with an adition of HDL (OR = 0.916; 95% CI = 0.857-0.978; p = 0.009) were significant predictors of DPN while LDL (OR = 1.017; 95% CI = 1.000-1.035; p = 0.053) acted as modifying factor. CONCLUSION: It appeared that CT + TT genotype of VEGF +936 gene might act as a protecting factor for DPN while VEGF-A, diabetes duration, HDL, and LDL acted as risk factors especially on subjects with HbA1C level >= 7. PMID- 30455750 TI - Correlation between 25-Hydroxyvitamin D and Lipid Profile among Children with Beta Thalassemia Major. AB - BACKGROUND: Beta thalassemia major is associated with lipid profile abnormalities, presented as a lower level of total cholesterol (TC), low-density lipoproteins (LDL), high-density lipoprotein (HDL), and higher triglyceride level; increasing risk for cardiovascular complications. The previous studies indicated that Vitamin D give a positive impact on the lipid profile in healthy children population. However, its role needs to be determined in a high-risk group of children with beta-thalassemia major. AIM: To determine the correlation between vitamin D (25-OHD) and lipid profile among children with beta-thalassemia major. METHODS: A cross-sectional study was conducted in a general tertiary hospital in Medan, Sumatera Utara, Indonesia from January to March 2018. Subjects were children aged below 18-year-old with beta-thalassemia major. The measurement of vitamin D (25-OHD) level and 10-12 hour overnight fasting serum lipid profile including total cholesterol, triglyceride, HDL, and LDL were performed. The analysis was done using Pearson's correlation and Fisher test. P value < 0.05 was considered significant. RESULTS: Forty-five subjects were enrolled in this study, with serum ferritin level ranged from 1017 to 13372 ng/mL. The prevalence of vitamin D deficiency (a 25-OHD level less than 20 ng/mL) in this study was 40%, with mean value at 20.6 (SD 5.3) ng/mL. The markers for cardiovascular risk were observed to be elevated, both in Atherogenic Index Plasma (0.32 +/- 0.25) and TC: HDL ratio (4.2 +/- 1.5). Statistical analysis revealed that Vitamin D had positive correlation with total cholesterol (r = 0.302, p = 0.044) and HDL (r = 0.297, p = 0.048). There was no significant correlation between both vitamin D and triglyceride (p = 0.305), or vitamin D and LDL (p = 0.727). CONCLUSION: Vitamin D correlated positively with total cholesterol and HDL in children with beta-thalassemia major. Positive correlation to HDL indicated a beneficial effect of vitamin D to reduce the risk of cardiovascular complication. PMID- 30455751 TI - Overview of MDM2 and B-RAF Expression in Gastric Lesions. AB - BACKGROUND: Globally, gastric cancer (GC) it is the fourth most common cancer and the third cause of cancer-related deaths. Overexpression of MDM2 and B-RAF appeared to be increased in malignancy and associated with poor prognosis in several human tumours, but their role in gastric cancer remains controversial. AIM: We had investigated the immunohistochemical expression of MDM2 and B-RAF in 136 gastric lesions with/without H. pylori association. MATERIAL AND METHODS: Studied specimens include chronic gastritis (32), intestinal type GC (70), diffuse GC (22) and gastrointestinal stromal tumours (GIST) (12). RESULTS: MDM2 expression increased significantly in intestinal GC compared to other groups (p < 0.001), while B-RAF expression increased significantly in GIST compared to other groups (p < 0.001). H. pylori increased expression of MDM2 in intestinal GC cases but did not affect B-RAF expression. MDM2 expression correlated with high grade of tumor differentiation (p < 0.001), deep invasion (p < 0.05), nodal metastases (p < 0.05) and distant metastases (p < 0.1) in intestinal GC, while B-RAF expression did not correlate with TNM stage (p < 0.1). CONCLUSION: MDM2 up regulation was more frequent in intestinal GC, while B-RAF up-regulation was more frequent in GIST compared to other groups; MDM2 expression in intestinal GC was correlated with H. pylori association, high grade of differentiation, deep invasion, nodal and distant metastases, meanwhile, B-RAF expression was correlated with high-grade intestinal GC but did not correlate with H. pylori or TNM stage. The possible role of both MDM2 and B-RAF in predicting progression of gastric tumours and prognosis deserves further investigations. PMID- 30455752 TI - The Effect of Treadmill Treatment on Oxidative Stress Markers and Endogenous Antioxidant Status in Obesity Mice. AB - AIM: This study aimed to determine the effect of treadmill treatment on oxidative stress markers and endogenous antioxidant status seen from MDA, GSH, MnSOD enzyme specific activity and blood catalase of obese mice. MATERIALS AND METHODS: This research is experimental laboratory research using post-test control design group only. The study lasted for 28 days and was divided into 4 groups of study, i.e., group K (normal control), KP (obesity control), P1 (obesity mice with 1 x 10 minute treadmill treatment a day), and P2 (obesity mice with 2 x 10-minute treadmill treatment a day). RESULTS: The treadmill treatment had an effect on the improvement of the oxidative status of mice with a decrease of MDA level of obesity mice blood (p <= 0.05) compared to KP control. An elevated endogenous antioxidant status of obesity mice was seen from elevated GSH levels, MnSOD specific activity and blood catalase of obesity mice (p <= 0.05) compared with KP controls. Treatment of 1 x 10-minute treadmill per day decreased blood MDA level, increased GSH enzyme and increased specific activity of MnSOD enzyme and blood catalase of obese mice. CONCLUSIONS: The 2 x 10-minute daily treadmill did not differ significantly in improving the oxidative status and endogenous antioxidant status compared with the treadmill 1 x 10 minutes a day (p >= 0.05). PMID- 30455753 TI - Assessment of Expression of Ki-67 in Benign and Malignant Prostatic Lesions among Sudanese Patients. AB - BACKGROUND: Prostatic cancer is one of the most common cancers of males in a Sudanese population. The early detection is very important, as it is only curable at an early stage. AIM: The objective of this study was to investigate the expression pattern of Ki-67 in benign and malignant prostatic lesions to improve the diagnosis that may help in better management and prevention of disease. MATERIAL AND METHODS: Fifty-eight formalin fixed paraffin blocks from diagnosed cases of prostatic tumours with different grade, and stages were included in this study. Ki-67 expression was examined immunohistochemically by using monoclonal mouse anti-human Ki67 IS626. The results were correlated with Gleason score and tumour differentiation and stage. RESULTS: The frequency of histological types was as follow: 11 cases of benign prostate, atic hyperplasia (19%) and 47 cases of prostatic cancer (81%). Our results stated that prostatic adenocarcinoma among Sudanese patients was of low grade which means tumours are less aggressive. Furthermore, the findings demonstrate that Ki-67 expression in prostatic carcinoma smears was correlated significantly with the degree of Gleason score (P < 0.05). CONCLUSIONS: We found that the prostatic adenocarcinoma among Sudanese patients was less aggressive. Furthermore, Ki-67 expression was proportional to the grade of a tumour and it was a useful prognostic and diagnostic biomarker. PMID- 30455754 TI - Impact of Maternal Obesity and Mobile Phone Use on Fetal Cardiotocography Pattern. AB - BACKGROUND: The fetal heart rate (FHR) is a good marker of fetal well-being during labour. Cardiotocography is used to record the FHR and uterine contractions and can detect possible fetal hypoxia. Mobile phones use, and obesity is suggested to influence the FHR and cardiovascular development. AIM: The present study aimed to study the differences in FHR pattern between fetuses of obese vs non-obese groups when using a mobile phone. METHODS: We conducted a clinical trial to test the impact of mobile phone use on FHR using a single mobile phone with Specific Absorption Rate rating of 0.99 W/kg for 10 minutes. Data from this clinical trial were analysed to compare the FHR pattern between fetuses of obese women (exposed group) vs those of non-obese women (control group). The two study groups (obese vs non-obese) were compared regarding four. FHR patterns: baseline FHR, variability, acceleration and deceleration scores. Data were analysed by SPSS software version 23.0 using the independent-samples t tests. RESULTS: Sixty-nine women were included in the final analysis (obese group: n = 22 and non-obese group: n = 47). Fetuses of the obese women had significantly higher baseline FHR and less FHR variability scores when compared with fetuses of the non-obese women (mean difference 2.9 and 3.18, respectively). CONCLUSION: Fetuses of obese women had abnormal FHR pattern compared with fetuses of non-obese women. The use of mobile phone slightly influenced the FHR variability score. These results highlight the importance of proper management of obesity in women within the childbearing period. PMID- 30455755 TI - Determinants of Exclusive Breastfeeding in a Sample of Egyptian Infants. AB - BACKGROUND: Breastfeeding is an optimum, healthy, and economical mode of feeding an infant. However, many preventable obstacles hinder exclusive breastfeeding in the first six months of life. AIM: We aimed to assess the social-, maternal- and infant-related factors disturbing exclusive breastfeeding in the first six months of life. METHODS: It is a retrospective study included 827 dyads of mothers and infants older than 6 months (411 exclusively breastfed, 311 artificially-fed and 105 mixed feds). Mothers were interviewed to obtain sociodemographic information, maternal medical history and perinatal history and a detailed history of infant feeding. RSULTS: Many factors were found to support the decision for artificial feeding rather than exclusive breastfeeding, including maternal age < 25 years (OR = 2.252), child birth order > 3rd (OR = 2.436), being a primi-para (OR = 1.878), single marital status (OR = 2.762), preterm infant (OR = 3.287) and complicated labor (OR = 1.841). Factors in favor of mixed feeding included cesarean section (OR = 2.004) and admission to the Neonatal Intensive Care Unit (OR = 1.925). CONCLUSIONS: Although it isn't a community-based study and its results can't be generalised, plans to improve health and development of children are preferable to include the following: health education and awareness programs about the importance of exclusive breastfeeding should be directed for young and first-time mothers. Improved antenatal care to reduce perinatal and neonatal problems; and training, monitoring, and supervising community health care workers to recognise labour complications and provide support and knowledge to lactating mothers. PMID- 30455756 TI - Tertiary Lymphoid Structures in Colorectal Cancers and Their Prognostic Value. AB - BACKGROUND: Tumor-infiltrating lymphocytes (TIL) in tumour stroma are considered to be involved in the elimination of malignant cells and prevention of metastasis formation. TIL consist of T lymphocytes including cytotoxic lymphocytes that are a constituent part of the effector mechanism of anti-tumour immunity and B lymphocytes that can form tertiary lymphoid structures (TLS). TLS has been described in several solid tumours and colorectal carcinoma (CRC), and the influence on the local and systemic anti-cancer response. AIM: This study aimed to quantify the presence of TLS in CRC patients and to determine their role in tumour progression. PATIENTS AND METHODS: The study included 103 patients with CRC who underwent surgery at the University Clinic of Digestive Surgery in Skopje, whose operative material was analysed at the Institute of Pathology, Medical Faculty in Skopje. The density of TLS was determined and correlated with the neoplasm status of local growth (T), positive lymph nodes, lymphatic invasion, and stage of the disease and tumour grade. RESULTS: The density of TLS was significantly higher in patients with higher stage, lower T status, and negative lymph nodes, in patients with no lymphatic invasion and with better differentiated tumours. CONCLUSION: The density of TLS plays an important role in controlling the tumour growth, and it can be a parameter for neoplasm progression in CRC patients. The density of TLS influences the control of tumour progression. PMID- 30455757 TI - EBV Positive Gastric Carcinomas and Their Clinicopathological Characteristics. AB - BACKGROUND: The understanding of the etiopathogenesis of gastric carcinoma (GC) can be a base for development of new therapeutic methods to reduce mortality and to increase survival in patients with GC. The percentage of Epstein - Barr virus (EBV) positive gastric carcinomas is uncertain, and the etiologic importance of EBV in the pathogenesis of GC has still not been elucidated. AIM: This study aimed to determine the percentage of EBV associated GC as well as to determine their clinicopathological characteristics. MATERIAL AND METHODS: The study included 80 patients with GC who were analysed for ethnicity, local growth of a tumour (T status), the presence of nodal metastases (N), the presence of distant metastases (M), stage of the disease and degree of carcinoma differentiation. For detection of EBV, immunostainings were performed on tumour tissue and the peripheral non-tumour gastric mucosa. RESULTS: Positive immunostaining with an antibody against EBV was found in 19 (23.75%) of the 80 patients with gastric carcinomas. EBV immunostainings were significantly different in patients with or without metastasis and between patients of Macedonian and Albanian ethnicity (p < 0.0001, p < 0.009, respectively). EBV immunoexpression was significantly associated with the presence of distant metastases and with patients of Albanian ethnicity. CONCLUSION: Association of EBV immunostainings with distant metastasis in patients with GC suggests the influence of EBV infection on the progression of gastric carcinoma. Due to scarce and doubtful literature data on EBV associated GC, further studies are necessary to determine the role of EBV regarding aetiology, treatment and prognosis in patients with EBV associated gastric carcinoma. PMID- 30455758 TI - A Comparison of Metoclopramide and Ondansetron Efficacy for the Prevention of Nausea and Vomiting In Patients Suffered From Renal Colic. AB - BACKGROUND: Renal stones are the third common disease of the urinary system after infections and diseases of the prostate. One of the most common manifestations of this disease after acute pain is nausea and vomiting. AIM: To compare the efficacy of metoclopramide and ondansetron in improving nausea and vomiting in patients referred to the emergency department with a chief complaint of nausea and vomiting. METHODS: This randomised double-blind clinical trial was conducted on patients referred to the emergency department of Vali-e Asr Hospital. Mg5 intravenous morphine and ketorolac ampoule were injected to control renal colic. Then, patients were randomly divided into two groups. Group 1 consisted of 90 subjects receiving 10 mg intravenous metoclopramide and group 2 including 90 subjects receiving 4 mg intravenous ondansetron. Vital signs were also measured and recorded. RESULTS: The mean and standard deviation of nausea in 0, 15, 30, 45, 60 and 120 minutes showed no significant difference between the two groups. Mean and standard deviation of vomiting at 0 minutes showed no significant difference between the two groups, but the remaining minutes, 15, 30, 45, 60 and 120, exhibited significant difference as a comparison of two groups, indicating that vomiting in the metoclopramide group was higher than ondansetron group. CONCLUSION: Our findings indicated that ondansetron was more effective than metoclopramide in preventing and improving vomiting in patients referred to emergency renal colic, where can be used with more efficacy and more acceptable side effects to improve nausea and vomiting. PMID- 30455759 TI - Tolerability of Omalizumab in Asthma as a Major Compliance Factor: 10-Year Follow Up. AB - BACKGROUND: There is a lack of data related to real life, long-term safety, tolerability and compliance of omalizumab treatment in asthma patients beyond 6 years. AIM: Study aimed to assess safety, tolerability, compliance and all reasons for treatment discontinuation during 10 years on omalizumab. SUBJECT AND METHODS: This is a retrospective, observational study of uncontrolled asthma patients receiving omalizumab for the last 10 years. All data were collected from patients' files (demographics, adverse events, comorbidities, compliance index, reasons for discontinuation of omalizumab). Reactions to omalizumab were classified as local and systemic, and their severity as mild, moderate or severe. Reactions were either immediate (minutes to hours after drug administration) or delayed (after days). Compliance to omalizumab, defined as Compliance index (CI), was calculated by comparing milligrams of given to milligrams of prescribed dose/ per year. RESULTS: Out of 35 patients receiving omalizumab, 15 drop out at different time points mostly due to treatment efficacy or appearance of new comorbidities. Patients who continue for the next ten years had mild to moderate adverse events related to omalizumab. There was no increased risk of severe adverse events during 10 years on omalizumab. Patient's treatment tolerability, despite mild to moderate adverse events, is in favour of compliance. CONCLUSION: Compliance with omalizumab mildly decreased over 10 years but was not affected by severe adverse events of treatment or new comorbidities. Although, omalizumab is safe medicine appearance of new comorbidities has to be closely followed up. PMID- 30455760 TI - Probiotics Improve Urogenital Health in Women. AB - BACKGROUND: Urogenital recurrent infections represent a global medical issue in the world, affecting millions of women because of dramatic shifts in bacterial composition and concentrations in response to numerous endogenous and exogenous factors. Urogenital microbiota forms a mutually beneficial relationship with their host and has a major impact on health and disease. AIM: This study aimed to compare probiotic therapy versus placebo in Oxidative Stress Values (OSVs) and histological features in urogenital infections in female patients. METHODS: Forty (n = 40) patients diagnosed with recurrent urogenital infections were recruited to be treated as test group (n = 20), receiving Probiotics, and a control group (n = 20), receiving looking similar placebo, both for 90 days. Both the groups were assessed for total oxidant capacity (d-ROMs test) and biological antioxidant potential as iron-reducing activity (BAP test) at baseline, after 1 and 3 months. Histological changes on inner vaginal mucosa were also investigated, during the entire study. RESULTS: d-ROM assay clearly showed that the values of the test group were significantly different, thus leading the general health conditions from a state of high oxidative stress to low oxidative stress levels. Increasing of BAP values were more significant, and clinically relevant, in probiotic test group over time. CONCLUSION: Our pilot study gave interesting and promising elements to confirm the safety and effectiveness of oral probiotics in preventing/reducing the recurrent urogenital infections by an overall modification of inner vaginal microbiota. PMID- 30455761 TI - The Impact of Pursed-lips Breathing Maneuver on Cardiac, Respiratory, and Oxygenation Parameters in COPD Patients. AB - BACKGROUND: Respiratory system, together with the cardiovascular and central nervous system, is responsible for all processes related to oxygenation and hemodynamics and the defect in the functioning of each of these systems, along with ageing, can have mutual effects on their performance and physiological symptoms. The use of Pursed-lips Breathing (PLB) training is an essential part of the treatment of patients with the obstructive pulmonary disease, PLB stimulates the autonomic nervous system and causes relaxation and improvement of physiological parameters. AIM: This study was conducted to evaluate the effect of PLB on cardiac, pulmonary and oxygenation level in patients with Chronic Obstructive Pulmonary Disease (COPD). METHODS: A three-group clinical trial study with experimental and control which was purposefully conducted with the participation of patients with COPD and healthy individuals referring to Madani hospital Khoy, in 2017. The sample size was selected to be 60 subjects. The patients were randomly allocated to two groups of intervention and control with 20 patients, and 20 healthy subjects were assigned to the healthy intervention group. The demographic, anthropometric information form and checklist recording changes in levels of oxygenation, respiration, temperature, heart rate and blood pressure with cardiopulmonary follow up in three stages before, during and after PLB were used for data collection. Data were analysed using descriptive statistics, repeated measure test, ANOVA, and Chi-square. RESULTS: On evaluation within the COPD patient intervention group in Saturation of Peripheral Oxygen (SPO2) index with the mean difference of 2.05 percent, Respiratory Rate(RR)-0.65 minute and Pulse Rate(PR)-1.6 bpm was significant (p <= 0.05), and systolic blood pressure index in healthy subjects was increased (3.35 mmHg). CONCLUSION: The results of this study indicated that using effective PLB as an easy, inexpensive, non- invasive and non-pharmacological method is considered as an important factor in improving the status of oxygenation and physiological indicators in patients with COPD and should be considered as an important part of rehabilitation programs for these patients. PMID- 30455763 TI - Comparison of Dexmedetomidine and Fentanyl as an Adjuvant to Lidocaine 5% for Spinal Anesthesia in Women Candidate for Elective Caesarean. AB - AIM: This study aimed to compare the effect of Dexmedetomidine and fentanyl as an adjuvant to lidocaine 5% in spinal anaesthesia to increase post-operative analgesia among women candidates for elective caesarean. METHODS: Eighty-four pregnant women candidates for caesarian were randomly divided into fentanyl and Dexmedetomidine groups. In the first group, 25 MUg fentanyl was added to lidocaine 5% while in the second group, 0.5 MUg per kilogram Dexmedetomidine was added to lidocaine 5%. After the operation, a pain score of the patients in recovery and within 4, 12 and 24 hours after the operation, the average length of analgesia and the average amount of the analgesics taken within 24 hours and after the operation were recorded. RESULTS: The average length of postoperative anaesthesia and the average amount of the drug taken within the first 24 hours after the operation in fentanyl group was more than the Dexmedetomidine group (P = 0.01). Shivering in Dexmedetomidine group was more common than what was observed in the fentanyl group (P = 0.001). Higher rates of nausea-vomiting were observed in the fentanyl group (P = 0.001). CONCLUSIONS: Fentanyl results in a longer period of postoperative analgesia and less consumption of drugs after the operation. Fentanyl is recommended in caesarian. PMID- 30455762 TI - Comparison of the Effects of Omega 3 and Vitamin E on Palcitaxel-Induced Peripheral Neuropathy. AB - BACKGROUND: Paclitaxel-induced peripheral neuropathy is the most important side effect limiting the use of this medication. AIM: This study aimed to compare the effects of omega-3 and vitamin E on the incidence of peripheral neuropathy in patients receiving Taxol. METHODS: In this clinical trial, 63 patients who were a candidate for receiving taxol, were enrolled based on inclusion and exclusion criteria. In group O, patients received 640 mg omega-3 three times a day, and group E, received 300 mg vitamin E two times a day. Patients took the supplements up to three months after the onset of Taxol. Group P received placebo for a similar period. All patients referred to a neurologist for electrophysiological evaluation before the onset of chemotherapy and at months 1 and 3. The presence of neuropathy and its progression was recorded by the neurologist. RESULTS: Neurological examination in this study indicated that 6 patients (28.6%) in Group O, 7 patients (33.3%) in group E, and 15 patients (71.4%) in placebo group started peripheral neuropathy. There was a significant difference between intervention groups and the placebo group (p = 0.0001) and no significant difference between intervention groups (p = 0.751). CONCLUSION: Our data suggested that vitamin E and omega-3 may significantly reduce the incidence of Paclitaxel-induced peripheral neuropathy. Routine administration of such supplements that have no special side effect for patients under chemotherapy may greatly enhance their quality of life. PMID- 30455764 TI - Giant Mushroom-Like Cutaneous Cylindroma of the Head. AB - BACKGROUND: Dermal cylindroma is a rare benign skin tumour. CASE REPORT: We report a giant stalked, mush-room-like cylindroma of the head-and-neck region in a 73-year-old female patient. A tumour was surgically removed, and the defect could be closed by a cheek transposition flap. CONCLUSION: The mushroom-like growth pattern has yet not been described for cylindroma. PMID- 30455765 TI - Behcet's Disease - Case Presentation and Review Literature. AB - BACKGROUND: Behcet's syndrome is associated with inflammation of various areas of the body. Sy. Behcet is a rare, chronic, recurrent disease characterised by changes in the: Arteries that supply blood to the body's tissues, veins that take the blood back to the lungs, the back of the eye's retina, brain, joints, skin and bowels. There is a close correlation between the geographical distribution of HLA-B51 and its prevalence. In the etiopathogenesis, there are indications of genetic susceptibility associated with environmental influence. Although aetiology is not yet known, it is thought of viral or autoimmune genes but is not yet confirmed by relevant analysis. CASE REPORT: This was a case of a 29 years old young female presenting with recurrent oral and genital ulcers. Eye lesions usually start in one eye and then pass to the other eye. They are like iridocyclitis extending very quickly to another eye. Three months later, a few shifts were introduced in the form of small initial ulcers, which for 4-5 days have been enlarged and then epithelized by leaving the catapult in the genital mucus. In the skin of the lower extremities, papules appear to be as large as corn grain. CONCLUSION: Diagnosis of Behcet's syndrome is determined based on eye changes, oral mucous and genital mucosa. Treatment of Behcet's syndrome depends on the severity and the location of its manifestations. PMID- 30455766 TI - Lipoma of the Neck. AB - BACKGROUND: Lipomas are benign formations with the mesenchymal origin, which are found in the head and neck region in a very small percentage of cases. In these cases, they usually occur in the posterior neck and usually grow very slowly without causing complaints. However, when they cover the front of the neck, it is necessary to confirm the adipose origin of a tumour and to exclude the connection with the thyroid gland. Although in principle, lipomas are benign, there are three more unfavourable possibilities of 1) malignancy of lipomas, 2) the occurrence of de novo liposarcomas or 3) the association of lipomas with other tumours, such as retinoblastoma. CASE REPORT: We present a 74-year-old woman with a painless subcutaneous formation in the neck. A Fine Needle Aspiration Biopsy (FNA) was performed, with the conclusion of the cytological result for lipoma. Surgical removal was planned under general anaesthesia. CONCLUSION: Usually, lipomas do not require surgery, but when they engage muscles they become indicative of surgical treatment. PMID- 30455767 TI - The Contribution of Indian Endodontists in Rotary Endodontics to Pubmed Database, from 2000-2017. AB - AIM: This study aimed at assessing the trends of publications of Indian Endodontists in the field of rotary Endodontics in the PubMed database from 2000 2017. METHODS: The date of publication was set from 1st January 2000 to 31st December 2017, wherein keywords entered in the advanced search were "Indian" AND "Dental" AND "Rotary Endodontics". From the collected articles the following criteria were noted: year of publication, the name of the journal, status of the journal, name of the first author, state of origin and the rotary Endodontic file system used. RESULTS: All data was subjected for statistical analysis by SPSS software version 16. The data were subjected to chi-square test, and a statistically significant difference (p < 0.001) was obtained in the inter-6 yearly interval starting from 2000-2017; in the status of the journal; the state of origin and in the generation of rotary files which were published during the study period. CONCLUSION: The plethora of publications by Indian Conservative Dentists and Endodontists is on the rise, and with the advent of better technology a greater interest in the mechanics and properties of these rotary file systems has invoked greater research work. PMID- 30455768 TI - Management of Maxillary Impacted Teeth and Complex Odontome: A Review of Literature and Case Report. AB - BACKGROUND: Teeth impaction has become a common problem faced by orthodontic clinicians with the greatest incidence reported among third molars and maxillary canines. The great challenge lies in successfully treating these cases without deleteriously affecting the impacted as well as adjacent teeth while achieving acceptable functional and esthetic results. Several etiological factors have been associated with impactions including the presence of an odontome which is an asymptomatic odontogenic hamartomatous lesion. CASE REPORT: This article presents a detailed orthodontic assessment and treatment of a 16 years old female having impacted right maxillary lateral incisor and canine caused by complex odontome. CONCLUSION: Successful orthodontic treatment of multiple impactions can be achieved with minimal side effects even when odontomes are associated, through 3D radiographic examination, detailed evaluation as well as proper biomechanical control. PMID- 30455769 TI - Sugar Substitutes: Mechanism, Availability, Current Use and Safety Concerns-An Update. AB - BACKGROUND: Dental caries has continued to be the major oral disease in the past, as well as the present scenario. Cariogenic sugars in the presence of specific bacteria Streptococcus mutans over a period have been attributed as the major etiologic agent for dental caries. The association between sugar consumption and dental caries has been well documented. AIM: Hence, the dental profession shares an interest in the search for safe, palatable sugar substitutes. METHODS: Therefore, the use of a suitable sugar substitute can help in combating dental caries. RESULTS: Out of the various sugar substitutes available, xylitol is the most widely used. It is available in various forms. It decreases the plaque formation, bacterial adherence and inhibits the growth of Mutans Streptococci. CONCLUSION: This article provides a comprehensive review of the sugar substitutes, present-day availability, role in the prevention of dental caries and their safety concerns. PMID- 30455770 TI - A Qualitative Study on the Importance and Value of Doctor-Patient Relationship in Iran: Physicians' Views. AB - BACKGROUND: Doctor-patient relationship [DPR] refers to verbal and non-verbal communication between doctor and patient, which is of great importance in consultation sessions. AIM: Therefore, the present study attempts to explore the importance and value of DPR in Iran. MATERIAL AND METHODS: The method used in the study was conventional content analysis. The data were collected from 21 faculty members (FMs) of Shiraz University of Medical Sciences (SUMS), Shiraz, Iran, who participated in three focus group discussions (FGDs). Transcribed data were analysed using Conventional Content Analysis (CCA) which identified condensed meaning units, subthemes, and themes. RESULTS: Four themes were extracted from 198 meaning units, 87 condensed meaning units, and 17 subthemes. These included gateway [the role of DPR]; nonlinearity [the nature of DPR]; distortion (quality of DPR in the context); and dysfunctional system (weakness in health system). Generally, results showed DPR to be the gateway to consultations based on non verbal communication and doctor empathy. The study showed distorted DPR which was due to the dysfunctionality of the health care system. CONCLUSION: As indicated DPR plays an important role in medical contexts, but if distorted it leads to an unsuccessful outcome. Therefore, to promote DPR, it is necessary to reinforce its structure. Thus, the infrastructure has to be modified and developed at all levels. PMID- 30455771 TI - A Dermatological Questionnaire for General Practitioners with a Focus on Hidradenitis Suppurativa. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a skin chronic inflammatory disease typically located in several areas such as perianal, inguinal and axillary regions. In 40% to 70% of cases, general practitioners (GPs) are the first health care professionals consulted by patients suffering from HS. The role of GPs in HS management could be more substantial than it has been in the past. AIM: We developed a questionnaire to assess the knowledge of HS by GPs and to evaluate if in their perception the dermatologist is the reference medical doctor for pathology above. METHODS: The data were processed by a univariate descriptive statistical analysis. RESULTS: Our study showed GPs could recognise patients affected by HS. They have proven to know the main features of HS. Nevertheless, the second part of the questionnaire has highlighted the considerable confusion of GPs about who the reference figure is. CONCLUSION: The data registered regarding therapy and follow up too, only show a mild preponderance of dermatologist compared to other professional figures, such as a surgeon, GPs and plastic surgeon. PMID- 30455772 TI - Sexual Desire and Related Factors in Middle-Aged and Elderly Married Women: A Cross-Sectional Study in Iran. AB - BACKGROUND: The sexual desire in the middle-aged and senior women is one of the factors affecting their quality of life and psychological well-being. AIM: The present study was aimed to assess the sexual desire and related factors among married women aged 50-70 years. MATERIALS AND METHODS: In this descriptive analytical study, 210 married menopausal women aged 50-70 years were selected by cluster sampling method. Data were collected using a demographic profile questionnaire and Sexual Desire Inventory (SDI), and analysed by SPSS version 22 software using descriptive statistics and independent t-test, ANOVA and Pearson correlation coefficient tests. RESULTS: The mean age of women was 59.40 +/- 5.93 years, and the mean sexual desire score was 22.66 +/- 17.78 (out of 112). There was a significant relationship between sexual desire score and age, educational level, occupation of women and spouses, age of menopause, marital history, number of pregnancies and children, individual health and pain level (P < 0.001). The sexual desire score had a significant association with diabetes, hypertension, heart disease, high cholesterol, chronic pain, gastrointestinal problems, chronic ulcers, bladder and intestinal problems, joint and bone disorders, taking cardiac medications, antihypertensive, anticoagulant, insulin, cholesterol-lowering drugs (P < 0.001). CONCLUSION: The low sexual desire score and its reduction with age and the presence of various diseases and factors affecting sexual desire highlight the importance of diagnostic screening, family related educational planning and the role of health care providers in the health status of the older adults. PMID- 30455773 TI - Do Personality Characteristics Constitute the Profile of Burnout-Prone Correctional Officers? AB - AIM: This study examined the relationship between personality characteristics and burnout syndrome among Bulgarian correctional officers. METHODS: The cross sectional study took place through individual, voluntary and anonymous interviewing of 307 employees from three district prisons. Maslach burnout inventory, Eysenck personality questionnaire and demographic characteristics were administered. RESULTS: The personality predictors of emotional exhaustion were low emotional stability and low level of dimension extraversion. The predictors of depersonalization were high levels of neuroticism and psychoticism and low level of extraversion. CONCLUSION: This research helps to identify employees who are at risk for developing burnout as a result of their personalities. In Bulgaria, there is still no official information about studies in this area. PMID- 30455774 TI - The Quality of EBM Sources Perceived By Belgian Family Physicians. AB - BACKGROUND: Belgian family physicians use several local and international sources for evidence-based medicine (EBM). AIM: This study aims to investigate the quality of these EBM sources according to the Belgian family physicians. METHODS: A sample of Belgian family physicians completed a digital survey on the quality of EBM sources. RESULTS: Respondents evaluated the quality of the information for the major part of the local and international EBM sources good to excellent. More than 50% of the respondents found in the major part of the sources an answer to the question. More than half of the respondents found the necessary information in less than 5 minutes in most of the sources. Younger participants self evaluated their search skills better than older participants. CONCLUSION: The quality of most frequently used EBM sources in Belgium is evaluated as good and client-friendly. More than half of the respondents found an answer to their questions in most of the sources and this within 5 minutes. PMID- 30455775 TI - Falsification of Type at Work: Assessment of Prevalence and Investigation of Predictors. AB - BACKGROUND: Occupational-stress, job-satisfaction and poor health outcomes are closely related and strongly pertain to individuals' mental health and physiological well-being. Falsification of Type is a growing term in the field of organisational psychology that measures occupational stress when working in a job that does not match one's, natural leader. AIM: The present work aims at determining the prevalence of falsification of type and associated socio demographic and work-related factors. METHODS: The study sample consists of 150 researchers working at the National Research Centre of Egypt. Participants were asked to complete a self-report Falsification of Type Questionnaire, Andrews and Withey scale for Job Satisfaction, in addition to socio-demographic and work related variables. Statistics included descriptive and comparative analyses. A regression model was built with falsification of the type as the dependent variable. RESULTS: Facilities showed the highest rate of dissatisfaction in the Job Satisfaction Questionnaire. The most prominent manifestations of falsification were fatigue and irritability, and its predictors were the position, interpersonal relationships, facilities and sex according to the regression model. Falsification of type could seriously contribute to occupational stress. Job satisfaction is highly about falsification. CONCLUSION: More research on the Falsification of Type at work is recommended with the greater attention of employers to the importance of the concept of person-job fit. PMID- 30455776 TI - Knowledge and Concerns of Parents Regarding Childhood Fever at a Public Health Clinic in Kuching, East Malaysia. AB - BACKGROUND: Parental anxiety regarding fever may be unwarranted as most cases are owing to self-limiting causes. AIM: To assess the level of knowledge and concerns regarding childhood fever among parents with young children in a public health clinic in Kuching, East Malaysia. METHODS: This cross-sectional study was conducted among parents recruited from a maternal and child health clinic, with children aged 6 months to 6 years. The participants completed a self-administered questionnaire regarding their knowledge and concerns about childhood fever. Descriptive statistical analyses were performed, and associations between dependent and independent variables were determined. RESULTS: Only 26.1% of participants were found to have good knowledge. Knowledge regarding childhood fever was significantly associated with parent's ethnicity, education level, and household income. About 72% of parents were always worried about their child's illness. Three major reasons for their concerns were persistently rising temperature; discomfort caused by the fever, and feared complications of fever. CONCLUSION: Excessive parental anxiety due to poor knowledge and misconceptions about fever may lead to poor quality of life and inappropriate management of fever. Healthcare providers may help by educating parents about fever and serious signs that indicate the need to seek healthcare advice. PMID- 30455777 TI - Advances in the Diagnosis of GERD Using the Esophageal pH Monitoring, Gastro Esophageal Impedance-pH Monitoring, And Pitfalls. AB - PH monitoring is not capable of detecting all types of reflux, especially when the amount of acid is very low or not at all in the refluxate. Multichannel intraluminal impedance-pH monitoring (MII-pH) is used as a new method to assess bolus transport. The types of reflexes including acid, weak acid and weak alkaline MII-pH is capable of distinguishing more reflux episodes based upon use of physical and chemical parameters of the refluxate, leads to a diagnosis of normal acid reflux from abnormal nonacidic reflux. 24-h oesophagal pH monitoring can be effectively used to assess the potential relationship between symptoms and refluxes. MII-pH is capable of distinguishing more reflux episodes based upon use of physical and chemical parameters of the refluxate, leads to a diagnosis of normal acid reflux from abnormal nonacidic reflux. It can be used to confirm gastro-oesophagal reflux episodes, where has a sensitivity and specificity for diagnosing GERD in comparison with endoscopy or pH-metry. PMID- 30455779 TI - Intensification of Basal Insulin Therapy with Lixisenatide in Patients with Type 2 Diabetes in a Real-World Setting: The BASAL-LIXI Study. AB - Background: Basal insulin reduces fasting blood glucose levels, but postprandial blood glucose levels may remain higher. Traditional strategies with rapid insulin intensification can cause hypoglycemic episodes and weight gain. Glucagon-like peptide-1 receptor agonists, such as the short-acting lixisenatide, are able to control postprandial excursions, without weight gain, and with a low risk of hypoglycemic events. Objective: Due to the limited data on the combination of lixisenatide with basal insulin (with or without oral antidiabetes drugs) in clinical practice, this study evaluated changes in parameters associated with glycemic control and anthropometric data after 24 weeks of this therapy intensification. Methods: This was a multicenter, retrospective observational study of 129 patients with type 2 diabetes that was uncontrolled by basal insulin. Their treatment was intensified by the addition of lixisenatide at least 24 weeks before being included in the study. Data were retrospectively collected to determine changes in glycated hemoglobin (HbA1c) levels, blood glucose levels, weight, and body mass index. Adverse reactions and hypoglycemic events were also recorded. Results: After 24 weeks of therapy intensification with lixisenatide, a significant reduction in HbA1c levels was observed (-1.1%; P < 0.001). An HbA1c <7% was achieved in 30.2% of patients, and 17.1% reached an HbA1c <6.5%. There was a reduction in fasting blood glucose (31.8 [60.3] mg/dL; P < 0.001) and postprandial blood glucose (55.0 [49] mg/dL; P < 0.001) levels, as well as body weight (4.0 [5.4] kg; P < 0.001) and body mass index (1.5 [1.9]; P < 0.001). The most commonly observed adverse reactions were nausea (n = 9), in line with previous studies. Hypoglycemia events were rare; only reported in 2 patients. Conclusions: Intensification strategy based on lixisenatide added to basal insulin (with or without oral antidiabetes drugs) can be an effective treatment option in patients with uncontrolled type 2 diabetes. In this small, selected population, glycemic control was significantly improved in terms of HbA1, fasting blood glucose levels, and postprandial glucose levels, with a reduction of body weight and low risk of hypoglycemic events. (Curr Ther Res Clin Exp. 2018; 79:XXX XXX). PMID- 30455778 TI - Barriers and facilitators to adherence to group exercise in institutionalized older people living with dementia: a systematic review. AB - Objectives: Research suggests targeted exercise is important for people living with dementia, especially those living in residential care. The aim of this review was to collect and synthesize evidence on the known barriers and facilitators to adherence to group exercise of institutionalized older people living with dementia. Methods: We searched all available electronic databases. Additionally, we searched trial registries (clinicaltrial.gov, and WHO ICTRP) for ongoing studies. We searched for and included papers from January 1990 until September 2017 in any language. We included randomized, non-randomized trials. Studies were not eligible if participants were either healthy older people or people suffering from dementia but not living in an institution. Studies were also excluded if they were not focused on barriers and facilitators to adherence to group exercise. Results: Using narrative analysis, we identified the following themes for barriers: bio-medical reasons and mental wellbeing and physical ability, relationships dynamics, and socioeconomic reasons. The facilitators were grouped under the following thematic frames: bio-medical benefits and benefits related to physical ability, feelings and emotions and confidence improvements, therapist and group relationships dynamics and activity related reasons. Conclusions: We conclude that institutionalized older people living with dementia, even those who are physically frail, incontinent and/or have mild dementia can demonstrate certain level of exercise adherence, and therefore can respond positively to exercise programs. Tailored, individually-adjusted and supported physical activity, led by a knowledgeable, engaging and well communicating therapist/facilitator improves the adherence to group exercise interventions of institutionalized older people living with dementia. PMID- 30455780 TI - Functional Subunit Reconstruction of Giant Facial Congenital Melanocytic Nevi in Children With the Use of Matriderm and Skin Graft: Surgical Experience and Literature Review. AB - Introduction: Facial giant congenital melanocytic nevus represents a major cosmetic deformity for the child and parents and is a challenge for the plastic surgeons to achieve best cosmetic results. Herein, we present a case of single stage surgical reconstruction using partial-thickness scalp skin graft aided with Matriderm dermal substitute for a facial giant congenital melanocytic nevus. Methods: An 8-year-old boy presented with a facial giant congenital melanocytic nevus without leptomeningeal involvement. A single-stage complete excision of the nevus was performed. A split-thickness skin graft, 12/1000-inch thick, was then harvested from the anterior scalp region for reconstruction. A 1-mm Matriderm dermal substitute was first applied, on which functional subunit skin graft was then secured to cover the defect. Eyelid reconstruction was reconstructed separately using full-thickness postauricular skin grafts. Results: Histopathology of the excised specimen confirmed the diagnosis of congenital melanocytic nevus, with no evidence of melanoma. The donor area healed with a favorable scar and no donor site morbidity or complications such as alopecia or hypertrophic scar. The postoperative result was satisfactory with minimal residual nevus around the eye, and the patient was fully satisfied with the cosmetic and functional results. Discussion and Conclusions: Resection of facial congenital melanocytic nevi, followed by single-stage reconstruction using Matriderm and skin graft from the scalp, is an excellent and fast reconstructive method with promising aesthetic outcomes and greater improvement in physiological outcome, especially in the pediatric population. PMID- 30455781 TI - Extrapleural Superficial Solitary Fibrous Tumor on the Posterior Shoulder: A Case Report and Review of the Literature. AB - Objective: Mesenchymal in origin, solitary fibrous tumors are primarily seen within the pleura of the lung or in serosal-lined body cavities. Constituting 1% to 2% of all soft-tissue tumors, solitary fibrous tumors are rare entities, especially when found in extrapleural and in superficial locations. A review of PubMed MEDLINE literature for superficial solitary fibrous tumors revealed 71 reports in case reports and small case series. Methods: In this report, we describe a 74-year-old man with an extrapleural superficial solitary fibrous tumor, as well as present a review of the current published literature to date. Results: We present the clinical course, surgical procedure, histopathological features, and treatment options, as well as present a compilation of the published data on superficial solitary fibrous tumors. Conclusions: Based on the current literature, solitary fibrous tumors are more common in middle-aged women and in the head and neck region. Diagnosis of solitary fibrous tumors requires tissue sampling and staining for immunohistochemical markers. Management of these tumors is based on wide local excision with histologically negative margins. If negative margins cannot be surgically achieved, adjuvant therapies including radiation have been described. With extrapleural manifestations of solitary fibrous tumors seldom reported in the literature, it is our hope that reporting these unusual instances will raise awareness of such disease manifestations and allow for earlier diagnosis and treatment. PMID- 30455782 TI - Partial Resection of a Reconstruction Plate After Mandibular Reconstruction Using a Free Fibula Osteocutaneous Flap: Another Approach to Keep It Simple. PMID- 30455783 TI - Utilizing the Retrograde Descending Internal Mammary Vein in DIEP Flap Anastomosis. PMID- 30455784 TI - Hepatitis B virus infection among sexually active individuals in Nigeria: a cross sectional study. AB - Introduction: Hepatitis B virus (HBV) infection is a major health challenge in sub-Saharan African countries. Chronic HBV infection is a risk factor for severe disease progression. Perinatal and sexual transmissions of Hepatitis B virus are the main routes of infection in HBV endemic countries like Nigeria. However, there is paucity of data as regards the major contributory route of transmission to chronic HBV infection in this region. Also, in Nigeria, not everyone at high risk of the infection has been identified. Therefore our study investigated the prevalence of HBV infection among sexually active individuals in Nigeria. Methods: Blood samples collected from 463 participants (360 sexually active individuals and 103 teenagers) recruited from health institutions across the country were tested for the presence of HBsAg, and HBV nucleic acid related antigen (HBVNRAg) by ELISA. Positive samples were further tested for the presence of HBeAg and antiHBe by ELISA. Data were analyzed using Chi-square and binary logistic regression at p = 0.05. Results: HBsAg and HBVNRAg were detected in 10.4% and 7.6% of the participants respectively. STI clinic attendees had the highest prevalence for HBsAg (17%; p = 0.002). Teenagers had the lowest HBsAg (1.9; p = 0.002) and HBVNRAg (2.9%; p = 0.0001) prevalence rates. Male gender (p = 0.01) and reproductive age group (p=0.009) were the major predictors of chronic HBV infection. Conclusion: Sexual transmission was identified as the major contributor to chronic HBV infection. Sexually active individuals especially those with STIs are high risk groups for chronic HBV infection. Interventions targeted at this group is therefore recommended. PMID- 30455786 TI - Application of the Canadian C-Spine rule and nexus low criteria and results of cervical spine radiography in emergency condition. AB - Introduction: The Canadian C Spine Rule (CCR) and the National Emergency X Radiography Utilization Study (Nexus) low criteria are well accepted as guide to help physician in case of cervical blunt trauma. Methods: We aimed to evaluate retrospectively the application of these recommendations in our emergency department. Secondly we analyzed the quality of cervical spine radiography (CSR) in an emergency setting. Results: 281 patients with cervical blunt trauma were analyzed retrospectively. The CCR and the NEXUS rules were respected in 91.2% and 96.8% of cases respectively. No lesions were found in 96.4% of patient. A lesion was present in 1.1% of patient and suspected in 2.5% of patient. The quality of CSR was adequate in only 37.7% of patient. The poor quality of CSR was due either to the lack of C7 vertebrae visualization in 64.6% or other lower vertebrae in 28%. Other causes included the absence of open mouth view (8%), the absence C1 vertebrae visualization (3.4%), artifact in 2.3% and the absence of lateral view in 0.6% of patient. Conclusion: CCR and NEXUS are widely used in our emergency department. The high rate of inadequate CSR reinforces the debate about it's utility in emergency condition. PMID- 30455785 TI - [Characteristics of work-related injuries and the fate of the victims: about 133 cases reported to the Social Security Fund in Dakar, Senegal]. AB - Introduction: Work-related injuries have an impact on social security system of the country, on the victims as well as on their relatives. The objective is the aim of our study was to describe the different characteristics of work-related injuries reported to the Social Security Fund (CSS) in Dakar as well as the socioprofessional course of the victims. Methods: We conducted a retrospective cross-sectional study over a period of 5 years, from 2002 to 2006. Data were collected from 133 cases out of 9 308 reported to the CSS. Various parameters were studied: the socioprofessional characteristics of victims and the lesional features of the injuries. The victims were interviewed to gather informations about their socioprofessional history and their professional situation. Results: The average age of patients was 37,55 years, with a male predominance (99,22 %). BPW (22.6%) and fishing (15%) sectors were most affected. Almost two thirds of injuries happened in the workplace (77.4%). These injuries resulted in fractures in 51.7% of cases and affected the hand in 30.1% of cases. Nearly two thirds of injured subjects (60.9%) had resumed their profession. Thirty one subjects were fired and 12 were redeployed. The average period of temporary total incapacity was 236.7 days. The median annual pension was 1 640 329 CFA Francs (2 504,31 Euros). Conclusion: In Senegal, work-related injuries don't have specific characteristics, as described elsewhere. The low resources allocated to the victims and the lack of supporting social-policy measures explain the different types of suffering of the victims and their families. PMID- 30455787 TI - Pathology of lymph node tuberculosis in Yaounde: diagnostic agreement based on the Kappa coefficient. AB - Introduction: Lymph node tuberculosis remains widespread in Cameroon. Our goal was to compare the diagnostic agreement between the hematein-eosin coloration technique and the Ziehl-Neelsen technique. Methods: This study is a retrospective and comparative study realized in the Yaounde University Teaching Hospital over a period of 5 years. We needed to specify the diagnostic agreement for tuberculosis, first inter observer and secondly between the standard and special colorations. The data we collected allowed us to determine the agreement rates observed and the kappa (k) coefficients with linear weighting. Results: The 186 samples of the 1726 cases of tuberculosis of all locations represented a proportion of 10.78%. There were more male patients (65.05%) with a sex ratio (M:F) of 1.30. The average age was 24.21 +/- 15.5 with the extremes from 5 to 68 years. The most represented age group was from 10 to 39 years. The two observers agreed in 93 cases using hematein eosin coloration (P0 = 83.87 %; k = 0.8109) and on 73 samples using the Ziehl-Neelsen coloration (P0 = 89.78 %; k = 0.7734). The two coloration techniques presented an agreement on 104 samples (P0 = 88.17 %; k = 0.8783). Conclusion: The routine choice of the hematein eosin coloration technique not paired with the coloration technique of Ziehl-Neelsen can effectively alleviate the program for fighting tuberculosis in an environment of limited resources. PMID- 30455788 TI - [Epidemiological and pathological profile of colorectal cancer: about 36 cases]. AB - Colorectal cancer is classified among the most common cancers in the world (after breast cancer and prostate cancer) and it is the second digestive tract cancer in Morocco after stomach cancer. However, its incidence in our country is lower than that of western countries (2.5 to 3.3 / 100 000 ha) but it coincides with that of Maghreb countries where this cancer affects young subjects in 27% of cases. Colorectal cancer (CRC) is one of the best examples of multistep carcinogenesis. Knowing the anatomopathological characteristics of CRC will certainly affect our therapeutic approaches. We conducted a retrospective epidemiological and anatomopathological study in the Department of Visceral Surgery at the Military Hospital Moulay Ismail, Meknes over a period of 5 years from January 2012 to December 2016. The study involved 36 patients: 14 women and 22 men. The aim of this study was to analyze the epidemiological profile and the anatomopathological features of colorectal cancers. The analysis of our results shows a specific epidemiological profile which is characteristic of a type of colorectal cancer affecting younger subjects, mainly male patients. Sporadic carcers are largely predominant, occurring mainly in the rectosigmoid region. A low degree of differentiation of adenocarcinomas with mucinous features is correlated with advanced TNM and Aster Coller staging and with lymph node status with poor prognosis. This multidisciplinary approach will be a novelty at national level, thus making our structure of clinical practice and research one of the centres for multidisciplinary management of colorectal cancer in Morocco. PMID- 30455790 TI - A chronic myeloid leukemia case with a variant translocation t(11;22) (q23;q11.2): masked Philadelphia or simple variant translocation? AB - Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome (Ph), usually due to a reciprocal translocation, t(9;22)(q34;q11.2). The remaining cases (2-10%) have variant translocation, and more rarely (~1%) a cryptic rearrangement is present which can be detected by fluorescence in situ hybridization analysis in a CML patient with a Ph-negative karyotype (Masked Ph). We present a masked/variant BCL-ABL-positive CML patient showing a t(11;22)(q23;q11.2) which was detected using a combined approach of conventional cytogenetics and reverse transcription polymerase chain reaction. In February 2013, the patient was diagnosed as having CML. Imatinib mesylate (400 mg/day), was then started. Under imatinib therapy a complete hematologic and cytogenetic response was attained. In December 2013, an increment in BCR-ABL/ABL transcript levels according to the International Scale (from 0.0471% to 1.4034%), indicating imatinib failure, was documented. Administration of nilotinib (400 mg twice daily) resulted in durable molecular response after 3 months. The patient is still on nilotinib treatment throughout the observation period with no sign of recurrence and adverse events. PMID- 30455789 TI - Caregiver delay in seeking healthcare during the acute phase of pediatric illness, Kigali, Rwanda. AB - Introduction: Delay in seeking healthcare contributes significantly to under-five mortality. Multiple socioeconomic and demographic factors have been reported as predictors of such delay. There is no published research in this area in Rwanda. Our aim was to describe the caregivers' delay in seeking healthcare during the acute phase of a childhood illness among under-five children admitted in a tertiary hospital, Rwanda. Methods: This was an analytical, descriptive cross sectional study conducted at University Teaching Hospital of Kigali. Bivariate analysis and logistic multivariate regression were used to analyze factors associated with delayed care-seeking behavior, defined as seeking care after the first 48 hours of illness onset. Results: Among 275 admitted children under age five, care-seeking delay occurred in 35% (97/275) of cases. The most significant predictors of delay in seeking care were use of traditional healers (AOR = 14.87, 95% CI: 3.94-56.12), the recognition of illness as mild (AOR = 8.20, 95% CI: 4.08 16.47), use of un-prescribed medicine at home (AOR = 2.00, 95% CI: 1.01-3.91), use of special prayers provided by ministers of God before seeking healthcare (AOR = 6.42, 95% CI: 2.50, 16.48), and first consultation at public institutions (AOR = 4.00, 95% CI:1.54-10.39). Conclusion: Even though Rwanda has made tremendous achievements in strengthening the community-based health systems, delayed care-seeking is a reality. Health education and behavior change communication interventions are needed at the community level to address the factors that lead to delay in seeking healthcare. PMID- 30455791 TI - Knowledge and experience with cochrane and evidence based medicine among health professionals in Debreberhan Referral Hospital in Ethiopia: a cross-sectional survey. AB - Introduction: Cochrane generates and disseminates high-quality systematic reviews through the cochrane library. We surveyed Ethiopian health professionals' knowledge and experience with cochrane, the cochrane library and Evidence Based Medicine (EBM). Methods: A cross-sectional survey was conducted using a convenient sample of health professionals in DebreBerhan Referral hospital in Ethiopia. Participants completed a pre-tested self-administered survey before EBM training. Data were analyzed using Fisher's exact or Chi-Squared test with Yates' correction. The strength of association between variables was quantified using odds ratios with 95% confidence intervals. Results: The response rate was 71.4% (35/49). Over half (54.3%) of the sample were males; 68.6% aged <= 30 years; 54.3% were physicians and 37.1% were nurses. Up to 65.7% had heard about Cochrane and only two knew cochrane South Africa as their reference centre. Nearly 48.6% were aware of the cochrane library, of whom 46% accessed it however; none used it for lacking awareness, search skills, access to internet and time constraints. Majority had a positive attitude towards EBM; 45.7% had heard of EBM; 74.3% rated their EBM knowledge as low; 74.3% lacked EBM training; and 88.6% were keen to attend EBM course. Adequate EBM knowledge was correlated with prior training (OR = 3.7, 95% CI 1.9-6.9, P<0.001], high self-assessment of EBM knowledge (OR = 0.27, 95% CI 0.14-0.51, P<0.001), male gender (P = 0.04), a positive attitude towards EBM (P = 0.001) and awareness of Cochrane (P = 0.004). Conclusion: Ethiopian health professionals have unmet training needs and want support through professional development workshops and an improved education system to provide high-quality evidence-based healthcare. PMID- 30455792 TI - [Post-traumatic carpo-metacarpal arthrosis of the fifth finger treated with stabilized arthroplasty: about two cases and literature review]. AB - Old fractures and dislocations of the base of the fifth metacarpal may result in post-traumatic arthrosis which is troublesome from a functional point of view and characterized by a difficult management. Stabilized arthroplasty is based on arthroplastic resection of the base of the fifth metacarpal associated with lateral diaphysometaphyseal arthrodesis between the fourth and the fifth metacarpal. This study involving two patients aimed to describe the advantages and the peculiarities of stabilized arthroplasty compared to other techniques in the treatment of the sequelae of fractures and dislocations of the base of the fifth metacarpal. PMID- 30455793 TI - [Non-type b Haemophilus influenzae: a rare cause of meningitis in an infant with a guarded prognosis]. AB - Non-Type b Haemophilus is a rare cause of invasive secondary localization in young children. We here report the case of a child aged 11 months old who had Meningitis due to Non-Type b Haemophilus, a gram -negative bacilli of polymorphous appearance still exceptionally described in the literature, whose origin was undetermined and whose evolution was fatal. Clinicians and microbiologists should suspect the presence of these infrequent serotypes, especially on a particular case. PMID- 30455794 TI - Corrigendum: Schwannome benin du nerf grand sciatique, a propos de 2 cas. AB - [This corrects the article DOI: 10.11604/pamj.2014.18.252.4684.]. PMID- 30455795 TI - Socio-economic and demographic determinants of tobacco use in Kenya: findings from the Kenya Demographic and Health Survey 2014. AB - Introduction: Every year, more than 6,000 Kenyans die of tobacco related diseases (79 men and 37 women die per week), while more than 220,000 children and more than 2,737,000 adults continue to use tobacco each day. Some suggest that these numbers will rise without concerted efforts to strengthen the implementation of tobacco control measures. To date, there remains much to be learned about what contributes to tobacco consumption in Kenya. This study analyses the socio economic and demographic determinants of tobacco use in Kenya. Methods: To analyze the determinants of tobacco use in Kenya, this study uses the 2014 Kenya Demographic and Health Survey. A logistic regression is used to estimate the probability of an individual smoking, given a set of socio-economic and demographic characteristics. Results: Results suggest that the overall smoking and smokeless prevalence rate is 17.3% and 3.10% respectively among men. Women have low rates with smoking and smokeless prevalence standing at 0.18% and 0.93% respectively. However, for both genders, tobacco use is influenced by age, marital status, residence, region, educational status and gender. Conclusion: Socio-economic, demographic and geographic disparities on tobacco use should be explored in order to ensure prudent allocation of resources used for tobacco control initiatives. Allocation of resources for tobacco control including monitoring advertisements, sales to underage persons and general distribution of human resource for tobacco control should be based on socio-economic and demographic dynamics. PMID- 30455796 TI - Non-clinical isolates as potential reservoirs of antibiotic resistance in Port Harcourt, Nigeria. AB - Introduction: Multidrug resistance (MDR) is a growing problem worldwide. This type resistance often arises due to the sequential acquisition of drug resistance determinants and subsequent clonal spread. It is therefore important to determine possible reservoirs of these MDR gene to help set out control strategies. This study was aimed at analysing susceptibility patterns of various non-clinical Gram negative bacterial strains to determine their potential as reservoirs of MDR. Methods: Thirty-five non-clinical Gram negative bacteria were identified and susceptibility profile determined using standard methodologies. Results: Findings showed a preponderance of Pseudomonas aeruginosa and Escherichia Coli. Resistance rates of above 80% were noted in 50% of antibiotics, though none of the isolates were resistant to Ofloxacin. Majority of isolates (68.6%) had a multiple antibiotic resistance (MAR) index greater than 0.5, but only 20% of Escherichia Eoli. were found in this category. A high level of MDR was noted in this study (71.4%), but again only 20% of these were Escherichia Coli. Conclusion: Gram negative bacteria are the most common group of bacteria frequently encountered in clinical microbiology. In more recent years, infections with these organisms have been further complicated by the phenomenon of drug resistance. Non-clinical isolates have been postulated as possible reservoirs. Findings from this study of widespread multidrug resistance support this idea. This study however highlights the lack of MDR in Escherichia Coli, which is promising. More extensive studies will need to be carried out to properly assess the role of non-clinical isolates as reservoirs of MDR determinants. PMID- 30455797 TI - [Pneumothorax catamenial: results of 18 cases operas]. AB - This study aims to propose a therapeutic approach for catamenial pneumothorax based on outcomes reported in 18 cases. We conducted a retrospective study of 18 female elderly patients with an average age of 32.2 years who had undergone surgery for right (16 cases) and bilateral catamenial pneumothorax (2 cases) from January 1994 to December 2016. The patients were divided into 3 groups on the basis of the evolution of our surgical capability over time: group 1(G1) from January 1994 to June 2006, group 2 (G2) from July 2006 to February 2008, group 3(G3) from March 2008 to December 2016, these groups were composed of 5, 2 and 11 patients respectively. All these patients were nulliparous who had suffered from dysmenorrhoea associated, in 11 cases, to catamenial chest pain since puberty. Standard radiographic evaluation of the chest was sistematically performed and complemented, in 8 cases, by chest CT scan that showed apical bubbles in addition to pneumothorax (5 cases). Exploration through posterolateral mini-thoracotomy (16 cases) and through videothoracoscopy (2 case of G3) showed diaphragmatic fenestrations (18 cases) and bubbles (5 cases). Biopsy of lesions as well as resection of the bubbles were sistematically performed . Surgical treatment of diaphragmatic fenestrations was based, in group 1, on resection-suture with pleural abrasion, in group 2, on Gore-tex patches coverage with pleural abrasion and, in group 3, on patch coverage with pleural talcage. Each patient underwent hormone therapy (triptoreline) for 6 months during postoperative period, in order to suspend menstruations. Surgical outcomes were evaluated on the basis of the recurrence or non-recurrence of a pneumothorax after resumption of menstruations. Mortality was zero. Postoperative hospital length of stay was 9.32 days. Anatomo pathological examinations confirmed thoracic endometriosis in 9 cases. After a mean follow-up period of 5.3 years, outcomes were good in 12 patients (3/5 in G1, 1/2 in G2 and 8/11 in G3); 3 patients in G3 continued to have minimal episodes of dyspnoea at the beginning of some menstrual cycles without radiological evidence of recidivism, 3 patients (2 in G1 and 1 in G2) had recurrences requiring reoperation. We recommend phrenoplasty using patches associated with pleural talcage and complementary concomitant hormone therapy for 6 months in patients suffering from catamenial pneumothorax with diaphragmatic fenestrations. PMID- 30455798 TI - [Electrocardiographic and echocardiographic abnormalities in patients with cirrhosis due to viral hepatitis B: about 60 cases reported in the Hepatogastroenterologic Department at the Aristide Le Dantec Hospital in Dakar (HALD)]. AB - This study aimed to evaluate the electrocardiographic abnormalities in patients with cirrhosis due to viral hepatitis B and to identify their determinants. We conducted a prospective study in the Hepatogastroenterologic Department and in the Department of Cardiology at the Aristide Le Dantec Hospital in Dakar over a period of 8 months. All patients with cirrhosis due to viral hepatitis B and without a history of heart disease were included in the study. We collected and analyzed the epidemiological, clinical, echographic, endoscopic, electrocardiographic, echocardiographic (2D and Doppler) data and laboratory data from all patients. Sixty patients were enrolled. The prevalence of cirrhosis due to viral hepatitis B was 3.4%. The average age was 41 years and the sex-ratio was 1.6 (37 men). Cirrhosis was classified as Child-Pugh B in 29 patients (49%), Child-Pugh C and Child Pugh A in 20 patients (33%) and 11 patients (18%) respectively. The most common electrocardiographic abnormalities included left ventricular hypertrophy and QTc interval prolongation detected in 27 patients (45%) and 24 patients (40%) respectively. Statistical analysis showed an association between prolonged QTc interval and the severity of cirrhosis (p = 0.01, RR = 2, CI = 0.24 - 0.341). Echocardiographic abnormalities were dominated by left ventricle dilatation (58.3%) and cardiac hyperoutput (43.3%), with an average output of 6.05 l/ min. Statistical analysis revealed a significant association between cirrhosis severity and cardiac hyperoutput (p = 0.003; CI: 95%, 2,883-38,58; RR = 2). A total of 14 patients (23.3%) had latent cirrhotic cardiomyopathy. Cirrhosis due to viral hepatitis B can cause a wide range of different cardiac abnormalities. These include morphological and/or electrophysiological abnormalities whose severity appears to be correlated with cirrhosis severity. PMID- 30455799 TI - Factors associated with postpartum depression among adolescents in Uganda. AB - Postpartum depression (PPD) is a common and disabling public health complication of the postpartum period in women. It is believed to occur three times more commonly in developing countries than in the developed world and is more prevalent among women in the first six weeks after birth. Research suggests that postpartum depression is more commonly diagnosed among adolescents and may be a risk factor for poor growth and development in children born to these mothers. Therefore, adolescents are a special age group that requires specific health care maternal interventions in order to detect and treat post-partum depression. PMID- 30455800 TI - Marfan syndrome: a case report and pictorial essay. AB - We report a case of Marfan syndrome (MFS) in a South African patient, which is extraordinary because of the large constellation of clinical, radiological and vascular anomalies in a single patient. A literature search from 1950 to date did not show a similar report of such extensive clinical characteristics of MFS. PMID- 30455801 TI - Autosomal recessive polycystic kidney disease (ARPKD) in a Nigerian newborn: a case report. AB - Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder but even rarer in Africans and it is one of the causes of nephropathies in childhood. Although isolated cases of adult PKD have been reported in Nigerians; to the best of our knowledge, this case is the first to be reported in the paediatric age group in Nigeria. A case of autosomal recessive polycystic kidney disease presenting with severe perinatal asphyxia and severe respiratory distressis here by presented. Fetal ultrasonography during the pregnancy missed the diagnosis. The difficulty in making diagnosis and management is discussed. Autopsy helped to unravel the diagnosis in this case report. PMID- 30455802 TI - Africa is on the verge of a major health crisis and the need for nutrition and health surveys is imperative. AB - The African region may be reaching a tipping point for a major health crisis. Over the last few decades for example, there has been a significant increase in the prevalence of obesity and associated comorbidities. This alarming trend is attributed to the rapid urbanization, increase in income, and unhealthy lifestyles among many others. Most importantly, managing and treating non communicable diseases (NCDs) is expensive and proving to be beyond the reach of ordinary Africans. Interestingly, Africa has not fully eradicated undernutrition particularly micronutrient malnutrition especially among women and children. Additionally, HIV/AIDs, malaria, diarrheal diseases and other preventable infectious diseases continue to pose serious threat to the health of the populace. The management of NCDs is challenging and costly as most healthcare systems on the continent are largely built for the provision of curative care for communicable diseases. This article proposes the institution of nutrition and health surveys in individual countries to monitor trends. We believe this approach, in addition to addressing lifestyle and behavioral factors, may be effective in curbing the rising phenomenon of obesity and NCDs. PMID- 30455804 TI - Physical activity profile of Nigeria: implications for research, surveillance and policy. AB - Appraising the status of physical activity surveillance, research and policy in Nigeria is relevant to national and regional public health actions on physical activity promotion and non-communicable disease control. This study aimed to 1) evaluate the physical activity profile of Nigeria and 2) propose strategies for improving physical activity in the country. The Global Observatory for Physical Activity-GoPA! with inputs from local experts systematically collected sociodemographic and physical activity surveillance, national policy and research indicators data for Nigeria in 2014. The Nigerian Country Card highlighting the status of these indicators was developed in 2015 and launched in 2016. Prevalence of physical activity among Nigerian adults was 78% (female=76%, male=79%). There was no physical activity surveillance system and national plan, and no empirical data on the proportion of all deaths directly due to physical inactivity in Nigeria. Few (n=7) articles related to physical activity and public health were published in 2013 and the country occupied the 38th position in the global research ranking, contributing about 0.24% to physical activity research worldwide. Implementing national physical activity plans and multi-sectorial collaborations between government and non-governmental partners are needed to improve physical activity surveillance, research and policy in Nigeria and other African countries with similar physical activity gaps. PMID- 30455803 TI - [Spontaneous rupture of hydatid cyst of liver in the peritoneal cavity with intact proligerous membrane: about a case and literature review]. AB - Rupture of hydatid cyst of liver with intact proligerous membrane is rare. We report the case of a 63 year-old female patient presenting with right hypocondrium pain without fever or jaundice. Diagnostic imaging examination showed hydatid cyst in segment IV of liver associated with pelvic cystic lesion measuring 12 cm x 06 cm. Surgical exploration revealed ruptured unilocular hydatid cyst of the liver with intact proligerous membrane and free in the peritoneal cavity. This study aims to report a new case of intraperitoneal rupture of hydatid cyst of liver with intact proligerous membrane and to highlight the diagnostic and therapeutic difficulties due to this complication. PMID- 30455805 TI - [Connective tissue diseases in the hospital setting in Lome: a retrospective study of 231 cases]. AB - This study aimed to highlight the epidemiological , clinical, therapeutic and evolutionary profile of connective tissue diseases in the hospitals setting in Lome. We conducted a retrospective and descriptive study from January 1, 1993 to December 30, 2012. We focused on the medical records of patients with connective tissue diseases hospitalized in five Departments of Dermatology and Rheumatology at the Hospitals in Lome. During the study period, we identified 231 cases of connective tissue diseases in the five study centers, corresponding to a frequency of 0.19% of consultations. The average age of patients was 36,96+/-15 years, the sex-ratio was 0,2. Major connective tissue diseases included lupus disease (50.22%), sclerodermas (21,64%) and rheumatoid polyarthritis (20.35%). Clinically, the main clinical manifestations of connective tissue diseases included discoid lupus lesions (87.50%) and photosensitivity (82.50%) in patients with systemic lupus erythematosus, skin sclerosis (90.48%) in patients with systemic scleroderma and distal joint involvement (100%) in patients with rheumatoid arthritis. Treatment in patients with systemic lupus erythematosus (92.5%) and rheumatoid arthritis (73.47%) was based on systemic corticosteroids. Connective tissue diseases are rare in people living in Lome, with a predominance of lupus disease. They are more frequent in young women. Treatment is based on systemic corticosteroids. PMID- 30455806 TI - Magnitude, causes and characteristics of trauma victims visiting Emergency and Surgical Units of Dilchora Hospital, Eastern Ethiopia. AB - Introduction: In developing countries, approximately sixteen hundred people die every day from all types of injuries, making injury the third most common cause of all mortalities in the region. The objective of this study was to examine the magnitude, causes and types of traumatic injuries in patients visiting Dilchora Hospital in Dire Dawa Administration of Eastern Ethiopia. Methods: We conducted a cross-sectional study which was supplemented with qualitative data. Descriptive and thematic analyses were used to characterize the trauma in terms of victims, causes and types. Results: A total of 382 patients were identified within a two month period of data collection. The most common causes of traumatic injuries identified were conflict (42.67%), road traffic accidents (35.07%), falls (13.35%) and burn injuries (8.90%). Soft tissue injuries (57.6%), abrasion (29.3%) and fractures (22.3%) were the three most common types of injuries experienced. Most of the victims were males, those people in the productive age bracket and those living in urban areas. Poor road structure, poor adherence to traffic rules and the use of old and poorly maintained vehicles were the main reasons for the road traffic accidents. Substance use behaviors in urban areas and farmland boundary issues in rural areas were the common causes of conflicts, and females were the most common victims of burn injuries. Conclusion: A high magnitude of injuries was observed such that, on average, six trauma victims visited the hospital each day. Conflict and road traffic accidents were the two most common causes of traumatic injuries. Poor vehicular conditions and poor road design were the main reasons identified for road traffic accident related trauma, which requires multilevel interventions. PMID- 30455807 TI - Predictors of loss to follow up among HIV-exposed children within the prevention of mother to child transmission cascade, Kericho County, Kenya, 2016. AB - Introduction: HIV-exposed infants (HEI) lost-to-follow-up (LTFU) remains a problem in sub Saharan Africa (SSA). In 2015, SSA accounted >90% of the 150,000 new infant HIV infections, with an estimated 13,000 reported in Kenya. Despite proven and effective HIV interventions, many HEI fail to benefit because of LTFU. LTFU leads to delays or no initiation of interventions, thereby contributing to significant child morbidity and mortality. Kenya did not achieve the <5% mother to-child HIV transmission target by 2015 because of problems such as LTFU. We sought to investigate factors associated with LTFU of HEI in Kericho County, Kenya. Methods: A case-control study was conducted in June 2016 employing 1:2 frequency matching by age and hospital of birth. We recruited HEI from HEI birth cohort registers from hospitals for the months of September 2014 through February 2016. Cases were infant-mother pairs that missed their 3-month clinic appointments while controls were those that adhered to their 3-month follow-up visits. Consent was obtained from caregivers and a structured questionnaire was administered. We used chi-square and Fisher's Exact tests to compare groups, calculated odds ratios (OR) and 95% confidence intervals (CI), and performed logistic regression to identify independent risk factors. Results: We enrolled 44 cases and 88 controls aged >=3 to 18 months: Cases ranged from 7.3-17.8 months old and controls from 6.8-17.2 months old. LTFU cases' caregivers were more likely than controls' caregivers to fear knowing HEI status (aOR= 12.71 [CI 3.21 50.23]), lack knowledge that HEI are followed for 18 months (aOR= 12.01 [CI 2.92 48.83]), avoid partners knowing their HEI status(OR= 11.32 [CI 2.92-44.04]), and use traditional medicine (aOR= 6.42 [CI 1.81-22.91]).Factors that were protective of LTFU included mothers knowing their pre-pregnancy HIV status (aOR= 0.23 [CI 0.05-0.71]) and having household health insurance (aOR= 0.11 [CI 0.01-0.76]). Conclusion: Caregivers' intrinsic, interpersonal, community and health system factors remain crucial towards reducing HEI LTFU. Early HIV testing among mothers, disclosure support, health education, and partner involvement is advocated. Encouraging households to enroll in health insurance could be beneficial. Further studies on the magnitude and the reasons for use of home treatments among caregiver are recommended. PMID- 30455808 TI - Testing a proof of concept model for group couples counseling in family planning in Northern Uganda. AB - Introduction: The post-conflict Acholi sub-region of Uganda is undergoing a period of transition that is influencing access, acceptability and use of family planning (FP). Low FP use and high unmet need for FP in Uganda's northern region provides a unique opportunity to test a community-based group counseling approach to reduce unintended pregnancies among young couples. We share findings from a proof of concept testing model in delivering fertility awareness methods (FAM) to groups of couples by trained non-health community youth agents. Methods: The group counseling model was developed for couples interested in two FAM-standard days method (SDM) and TwoDay Method-within rural communities in Northern Uganda. WALAN was tested in a three-month proof of concept phase, employing 24 direct observations of group counseling sessions; quantitative interviews with 9 couples using either SDM or TwoDay Method; 2 focus group discussions with youth facilitators, and; 9 key informant interviews with providers and leaders. Results: The proof of concept results suggest model feasibility and acceptability among participating communities. Couples learned how to use FAM correctly. All 9 interviewed female users reported 100% correct knowledge of method use. Couples also reported high levels of satisfaction for both methods. SDM and TwoDay Method participants reported comfort and satisfaction in learning about FAM in small groups with other couples. Conclusion: The proof of concept phase confirmed intervention feasibility, albeit with some model adjustments. The results were used to inform the pilot intervention, launched in April 2016 within 15 other villages in the same region. PMID- 30455810 TI - [Foreign body in the iris]. AB - We report the case of a 28-year old man victim of left ocular trauma. Ophthalmologic examination showed visual acuity 8/10 (without correction), cloudy patch at 7 o'clock (A) with foreign body in the iris at the level of cloudy patch (B). PMID- 30455809 TI - [Impact of HIV status on the overall prevalence of chronic hepatitis B infection in Parakou, Benin]. AB - Introduction: The prevalence of hepatitis B is very variable across geographic areas and seems to be influenced by HIV infection. This study aims to evaluate the impact of serologic HIV status on the overall prevalence of hepatitis B in a Hospital in Parakou, Benin. Methods: We conducted a cross-sectional study of adults aged 18 years old and over hospitalized in the Departmental University Hospital Center in Parakou between May 2011 and June 2012. The diagnosis of hepatitis B was made on the basis of rapid HBsAg tests while the diagnosis of HIV was made on the basis of rapid HIV tests using venous blood samples. Data were analyzed using EpiInfo software. Multivariate logistic regression model was implemented to investigate factors associated with hepatitis B. Results: Out of 1516 subjects included, 744 were HIV seropositive. The average age was 31.3 + 11.1 years and 65.1% were women. The prevalence rate of hepatitis B in the whole sample was 13.9% [CI95:12.2%-15.7%]. This prevalence was higher in HIV seropositive subjects (16.9% vs 10.9%; p < 0.0006), however there was not a more significant difference in multivariate analysis, except for the group of subjects from Borgou/Alibori (p < 0.02). A consistent association was observed between age group 24-44 years (p < 0.03), male sex (p < 0.01), primary school education (p < 0.02) and a high prevalence of hepatitis B. Conclusion: The prevalence of hepatitis B was higher in HIV seropositive subjects. This was influenced by age, sex, education level and geographical origin. PMID- 30455811 TI - [Tuberculous bursitis of the shoulder in a patient with chronic renal insufficiency: about a case]. AB - Tuberculosis of the shoulder is rare. It encompasses all articular and periarticular tuberculouses of the shoulder. Its insidious evolution, mimicking inflammatory and degenerative diseases, reflects the frequency of its diagnostic delay. We report a rare case of tuberculous bursitis of the shoulder in a woman living in rural areas, with renal insufficiency and treated for peritoneal TB and psoas. The anamnesis revealed signs of tuberculous impregnation. Clinical examination showed painful swelling of the shoulder associated with stiffness. MRI of the shoulder objectified infectious bursal disease. Its tuberculous origin was confirmed by the histological examination of ultrasound-guided synovial biopsy. The patient underwent TB treatment with good outcome. At 9-year follow up, the patient had satisfactory articular function with no recurrence of infectious disease. PMID- 30455812 TI - [Difficulties in managing Graves' disease in children: about a case]. AB - Adequate management of Graves' disease in children is an area of controversy in pediatric endocrinology, while optimal duration of medical treatment inducing remission in disease as well as indications for therapeutic alternatives still needs to be determined. We report the case of a 11-year old female child with no particular past medical history., presenting with progressive weight loss associated with diarrhea. Her parents brought the child to hospital because neighbours noticed anterior cervical swelling on her. Clinical and paraclinical data helped to retain the diagnosis of Graves' disease. The patient underwent medical treatment with carbimazole. Patient's evolution was marked by the occurrence of thrombocytopenia, suggesting prudent administration of medical treatment. Iratherapy was indicated due to the absence of remission after 4 years of treatment. Although rare, Graves' disease is the first cause of hyperthyroidism in children. Positive diagnosis is easy but its management may pose enormous problems. Medical treatment is based on synthetic antithyroid drugs, but they are not always innocuous, as in the case of our patient. Then subtotal thyroidectomy or radioactive iodine treatment are two therapeutic alternatives. Graves' disease is a rare and severe disease in children posing considerable management difficulties. PMID- 30455813 TI - [Splenic infarction revealing infectious endocarditis in a pregnant woman: about a case and brief literature review]. AB - The diagnosis of splenic infarction is rarely reported in pregnant women. Current incidence of splenic infarction, especially during infectious endocardites as well as diagnostic methods used are poorly specified in the literature. We here report the case of a 26-year old woman with no particular previous history or cardiovascular risk factor who, at the end 14 weeks of amenorrhea, presented to the Emergency Department with febrile syndrome evolving over 10 days and abdominal pain of recent onset at the level of the left hypochondre. Clinical examination showed febrile patient with a temperature of 39.5 degrees C, tenderness of the left hypochondre and panaritium at the level of the palm of the left hand and of the sole of the foot. Gynecological examination was strictly normal. Given this clinical picture, abdominal ultrasound showed mediosplenic anechoic area with hilar apex and with peripheral edges, suggesting splenic infarct. Etiological assessment included echocardiography showing thickened and remodeled oslerian graft on the mitral valve with large valve vegetation and MI grade II. Blood cultures were performed during the febrile peaks and were positive for golden staph. Patient's evolution was marked by the occurrence of large ischemic stroke and worsening of neurological condition, leading to death after several systemic emboli. Splenic infarction in a pregnant woman is very rare. However, clinical and radiological examination of the spleen must be performed in patients with acute abdominal pain of the left hypochondre. In the present case, pain of the left hypochondre associated with fever and Osler's false whitlow was found to be splenic infarction associated with infectious endocarditis. Probabilistic antibiotic therapy as first-line therapy is justified during infective endocarditis and should be secondarily adapted to the bacteriological results. Although rare, splenic infarction can have severe consequences such as abscesses or rupture, which must encourage vigilance. PMID- 30455814 TI - A double jeopardy: transection of the aero-digestive tract after penetrating neck trauma. PMID- 30455815 TI - [Corrigendum: Ethnobotanical study of plants used in the treatment of diabetes in the traditional medicine of Maritime Region, Togo]. AB - [This corrects the article DOI: 10.11604/pamj.2015.20.437.5660.][This corrects the article DOI: 10.11604/pamj.2015.20.437.5660.]. PMID- 30455816 TI - [Fonsecaea pedrosoi-induced chromoblastomycosis: about a case]. AB - We report the case of a 13-year old female patient from rural areas presenting with papulonodular lesion of 4/3cm in the lower third of the right leg, evolving over the last two years. Skin biopsy showed papillomatous hyperplasia with neutrophilic microabscess and spores. Direct mycological examination showed fumagoid bodies and Fonsecaea pedrosoi was isolated from culture. The patient underwent medico-surgical treatment (terbinafine 250mg/day for 6 months + resection and then skin graft) with good evolution and a follow-up period of 2 years without recurrences. Chromoblastomycosis is a chronic fungal skin infection, common in tropical and subtropical areas and rare in North Africa. In Morocco, only seven cases have been reported in the literature until June 2014. It is contracted from inoculation of germ after contact with the soil or organic matters. Responsible officers are pigmented fungi belonging to the dematiated group. Given its rarity, it can mimic other dermatoses such as leishmaniasis or tuberculosis. Despite the rarity of this infection, clinicians should suspect it in patients with chronic skin lesions (verrucous, vegetative, nodular and grouped in patches), especially if they occur in areas exposed to potential plant injuries, such as the lower limbs. Mycological examination is necessary to confirm the diagnosis. Surgery or the association between surgery and systemic antifungal drugs are the treatments of choice because antifungal drugs alone may result in resistances or recurrences. PMID- 30455817 TI - Large cell neuroendocrine carcinoma of the nasal cavity: an extremely rare and new distinct entity. AB - Large cell neuroendocrine carcinoma (LCNEC) is a rare but distinct entity of nasal cavity carcinomas. Only a very few cases have been reported in the nasal cavity. Its treatment is not well established. We report the case of a LCNEC in a 70 years old patient who presented with right nasal obstruction and epistaxis since 2 months. Diagnosis was confirmed by histological and immunohistochemical study. The patient underwent complete endoscopic removal of the tumor combined to adjuvant chemoradiotherapy. After 6 month follow-up, the patient was in complete clinical and radiological remission. We will discuss in this paper the various epidemiology, clinical features, pathological findings, differential diagnosis, and evolution of treatment of this uncommon malignancy in the light of current knowledge. Optimal treatment strategies are yet to be determined for this rare malignancy with poor prognosis including surgery and chemoradiotherapy. PMID- 30455819 TI - Particular dental erosion. PMID- 30455818 TI - Complications of traditional bone setters (TBS) treatment of musculoskeletal injuries: experience in a private setting in Warri, South-South Nigeria. AB - Introduction: Complications arising from the practice of traditional bone setting is a major contributor to the challenges the orthodox orthopaedic practitioner in Nigeria faces. We share our experience at a multi-specialist private health facility in Warri, South-south, Nigeria. Methods: Case notes of patients with musculoskeletal injuries who had prior treatment by traditional bone setters with resulting complications before presenting at our health facility for treatment were reviewed and relevant information extracted and entered in an already prepared proforma. Data were analysed using SPSS version 17 and results presented in form of means, percentages, ratios and tables. Results: 43 cases were reviewed in a period of 8 years. There were 21 males and 22 females. The average age of patients was 44.8 +/- 20.3 years. The most frequent age group affected was that of 40-49 years. 45.8% of the initial injuries were due to road traffic accidents while 39.5% resulted from falls. Femoral fractures and humeral fractures formed 20.4% and 14.8% of cases respectively. 40.8% of traditional bone setters complications observed were non-union of fractures of various bones followed by mal-union in 24.5% of cases. Conclusion: The observed complications of traditional bone setters practice in this study were similar to those previously reported in the literature. These complications constitute a significant challenge to the orthopaedic practitioner in Africa with associated negative socioeconomic impact on our society. Government and other relevant stakeholders need to unite and take decisive actions to mitigate this problem. PMID- 30455820 TI - [Evaluation of surgical antibiotic prophylaxis in a Tunisian University Hospital]. AB - Antibiotic prophylaxis (ATBP) is one of the specific measures for the prevention of surgical site infections, whose impact has been quantified in clean or clean contaminated surgery. Our study aims to evaluate the conformity of ATBP practices and the adherence to the prescribing protocols adopted in our Hospital. We conducted a clinical audit retrospective observational study, evaluating antibiotic prophylaxis practices in our Hospital in the month of March 2015. The primary study endpoint was the overall compliance of the observed practices with the 5 major criteria defined by the French National Authority for Health (FNAH). We followed the guidelines of the French Society of Anesthesia and Intensive Care published in 2010. The study included 150 patients who had undergone surgery in the Department of General Surgery, Orthopaedics and Urology. The overall compliance rate was 33.3%. The compliance with each of the 5 major criteria defined by the FNAH was 74% for the indication; 84% for the time between injection and incision; 60% for the choice of ATB; 89.3% for the dose of the first injection and 72% for the duration of ATBP. The compliance was variable depending on the Department; better compliance was reported in the Department of Urology, in scheduled surgery and when the prescriber was an anesthetist resuscitator. A global strategy including organization, education and restriction, could lead to a real improvement in the rate of compliance with ATBP practices. Successive audits should be carried out regularly in order to evaluate the impact of the undertaken actions. PMID- 30455821 TI - [Emergency treatment of sickle cell diseases in the Blood Diseases Department at the Koutoukou Maga National Teaching Hospital, Cotonou, Benin]. AB - Introduction: Evolution of sickle cell disease is marked by the occurrence of acute complications, some of which are real emergencies that can give rise to life-threatening or functional cosequences. This study aims to evaluate the frequency and the evolution of emergency treatment of sickle cell disease in the Blood Diseases Department at the Koutoukou Maga National Teaching Hospital, Cotonou. Methods: We conducted a retrospective and descriptive study of all patients hospitalized for emergency treatment of sickle cell disease from January 2014 to December 2015. We excluded patients hospitalized for chronic sickle cell disease complications. Results: Out of 813 hospitalizations, two hundred and four (204) emergency treatments of sickle cell disease were registered (prevalence 25%). The average age of our patients was 24.2 years. The most represented age group was 20-30 years (45.6%). Male sex predominated (60.8%). Pupils/students was the most represented group (55.9%). Acute pain was the primary reason for hospitalization to 63.7%. Normal homozygous individuals (SS) were mostly represented (72.1%). Osteoarticular vaso-occlusive complications predominated (70.1%). Documented infectious complications were dominated by malaria (27.5%). Decompensated anemia accounted for 30.4%. Therapeutic approach was based on hydration (85.3%). The average length of stay in hospital was 5.4 days. Outcome was favorable in 96,5% of cases. Mortality accounted for 2.5%. Conclusion: Emergency treatments of sickle cell disease are frequent. Early diagnosis as well as early and effective management are necessary. Ongoing training programs in emergency treatments of sickle cell disease are necessary to reduce mortality. PMID- 30455822 TI - [Assessment of virological quality of transfused blood in the town of Bukavu, South Kivu, Democratic Republic of Congo]. AB - Introduction: In Bukavu, transfused blood is selected using rapid diagnostic tests (RDTs). These tests are easily performed without specialized equipments. This study aims to evaluate the virological quality of transfused blood assessed using rapid diagnostic tests. Methods: A blood sample was drawn from a blood bag and collected in a 4ml dry tube in 5 Health Care Facilities over a month. Counter analysis was performed on each sample using rapid tests and ELISA. Intrinsic and extrinsic values were calculated. Cohen's kappa coefficient was used to evaluate the reliability of RDT compared with ELISA. Results: Three hundred and twelve samples were collected; 5 samples were positive for one or the other virologic marker while 307 samples were negative in all the tests. However Elisa showed, out of the 307 samples which were RDT test negative, 15 other positive samples including 3 samples positive for HIV, 3 for HCV and 9 for HBV. In addition, ELISA validated some RDT-positive samples and contradicted other results. Sensitivity and positive predictive value from rapid diagnostic tests were very low. The reliability of these tests was satisfactory, medium or low. Conclusion: Blood assessed using RDTs poses a non negligible risk of viral infections. This study highlights the need for more reliable and efficient tests in our Health Care Facilities. PMID- 30455823 TI - Comparative in vitro activity of ciprofloxacin and levofloxacin against isolated uropathogens in Ghana: a pilot study. AB - Introduction: Studies on urinary tract infections (UTIs) in West Africa from 1990 to 2012 have showed moderate to high antimicrobial resistance to commonly prescribed antibiotics. Fluoroquinolones have been the main stay in the management of UTIs, but recent reports show emergence of resistance. Levofloxacin and ciprofloxacin still remain the commonest fluoroquinolones prescribed for UTIs in many settings. objective: this study sought to compare activity of ciprofloxacin and levofloxacin against clinical isolates obtained from patients with suspected UTI at the Ghana Police Hospital. Methods: Midstream urine samples from 153 suspected UTI patients who visited the Ghana Police Hospital from July 2016 to March 2017 were examined. Urine samples were cultured and isolates identified by standard biochemical and serological methods. The Kirby-Bauer disc diffusion method was used to determine susceptibility of isolates to ciprofloxacin and levofloxacin. Results: UTI prevalence was significantly (p < 0.05) higher among female patients (74.5%) than male patients (25.5%). Clinical uropathogens isolated from urine samples were Escherichia coli (28.1%), Coliform spp (43.2%), Klebsiella spp (26.1%) and Staphylococcus aureus (2.6%). Overall sensitivity of the uropathogens to ciprofloxacin and levofloxacin were 77.1% and 62.8%, respectively. Staphylococcus aureusshowed greater resistance to levofloxacin (75%) compared to ciprofloxacin (25%). All Gram-negative isolates showed a higher sensitivity to ciprofloxacin compared to levofloxacin: Escherichia coli; 69.8% vrs 62.8%, Coliform spp; 80.3% vrs 65.2%, and Klebsiella spp; 80% vrs 62.5%. Conclusion: This study revealed emergence of resistance of uropathogens to quinolones. The isolates showed higher sensitivity to ciprofloxacin compared to levofloxacin. Rational prescribing and use of these fluoroquinolones following local susceptibility data is thus recommended. PMID- 30455824 TI - Infertility in the Moroccan population: major risk factors encountered in the reproductive health centre in Rabat. AB - Infertility is responsible for a major cost burden for patients and health care systems. Therefore identifying preventable risk factors for infertility may contribute to the development of more cost-effective approaches to solving the infertility problem. However, such investigations have never been conducted in Morocco. Thereby, the objective of the present study was to determine the occurrence and distribution of these factors among Moroccan infertile couples. This retrospective study included 1265 infertile couples who attended the Assisted Reproductive Technology Unit of the Reproductive Health Centre of the University Hospital Ibn Sina in Rabat. All couples had been infertile for at least 1 year and both partners were fully investigated. Couples had primary and secondary infertility in 77.2% and 22.8% of cases, respectively. Women were overweight in 47.9% of cases and obese in 25.8% of cases while men were overweight in 44.6% of cases and obese in 14.7% of cases. 18.9% of women and 17.5% of men had a previous abdominopelvic or urogenital surgery. A history of sexually transmitted infection was reported by 7% of men and 5.8% of women. A history of tuberculosis was found 9.3% of women and 4.8% of men. In addition, 31.7% of men were cigarette smokers and 8.4% consumed alcohol. The study showed that preventable risk factors of infertility are common among Moroccan infertile couples. However, additional studies are required to investigate each factor and its relation to infertility in the Moroccan population. PMID- 30455825 TI - A man with facial disfigurement. PMID- 30455826 TI - [Collection in the thigh revealing bladder fistula after radiotherapy for prostate cancer]. AB - Urinary fistulas are a rare late complication after radiotherapy for prostate cancer. We here report the case of a 76-year old patient who had undergone radical prostatectomy 4 years before followed by external beam radiotherapy for prostate cancer. The patient presented with recurrent thigh swelling . Clinical examination showed renitent and painless mass at the level of the medial compartment of the right thigh. Ultrasound followed by CT scan showed big homogeneous fluid collection in the inner thigh exercising a slight compression on femoral vessels. Surgical drainage was performed removing 900 ml cloudy liquid whose bacteriological examination was negative. Post operative suites were marked by a sharp reduction of diuresis. However significant quantity of clear liquid continued to be drained. Given the patient's clinical picture, methylene blue test followed by retrograde cystography were performed confirming the diagnosis of fistula originating from the ureterovesical junction. The drainage of the collection was obtained through the insertion of a local probe for several weeks. PMID- 30455827 TI - Chemotherapy-induced liver injury in metastatic colorectal cancer: about 48 cases. AB - Neoadjuvant chemotherapy of colorectal liver metastases can induce hepatotoxicity in noncancerous liver. The aim of the present study was to describe the chemotherapy-induced major changes in the hepatic parenchyma and their prognostic impact. We undertook a retrospective study of 48 cases of colorectal liver metastases treated with neoadjuvant therapy followed by liver resection. These cases were collected at the Pathology Department of Mongi Slim Hospital over a 2 year period (July 2015-February 2018). Our series consisted of 27 men and 21 women with a sex-ratio (M/F = 1.28). The average age of our patients was 57.68 years old with extremes ranging from 30 to 75 years old. All patients received chemotherapy with FOLFOX. From a total of 48 operative specimens examined, we found 24 cases (50%) of non-systematized steatosis, grade 1 sinusoidal obstruction syndrome (n = 12) and grade 2 sinusoidal obstruction syndrome (n = 12), regenerative nodular hyperplasia (n = 3), portal and/or lobular inflammatory infiltrate (n = 6). In three cases, no abnormalities were reported in the liver parenchyma. Surgical margins were < 1 mm in seven cases and were invaded in four cases. Preoperative chemotherapy is associated with regimen-specific liver injury. The presence of such an injury may have a negative impact on the functional reserve of the liver, thereby increasing the risk of surgical morbidity and mortality. PMID- 30455828 TI - Two Year, Single Center Clinical Outcome After Catheter Ablation For Paroxysmal Atrial Fibrillation Guided by Lesion Index. AB - Background: This study describes the use of lesion index (LSI) as a direct measure to assess the adequacy of ablation lesion formation with force-sensing catheters in ablation of paroxysmal atrial fibrillation (PAF). LSI is calculated by the formula:LSI = CF (g) *Current (mA) *Time (sec). Methods: Fifty consecutive patients with PAF underwent pulmonary vein (PV) isolation using a catheter dragging technique and targeting different LSI values in different anatomical areas.A force-sensing ablation catheter was used to continuously measure contact force (CF) and guide radiofrequency ablation (RF) lesion formation. Ablation lesions were delivered to achieve an LSI value of 5.0 in posterior locations, 5.5 in anterior locations and 6.0 in the regionbetween the left atrial appendage and left superiorpulmonary vein ridge. Force-time Integral (FTI) was not used to evaluate lesion formation. Results: A single center, retrospective analysis was performed with 196/198 (99%) PVs acutely isolated. The mean procedure time was 134 +/- 34 mins and the mean fluoroscopy time was 7.8 +/- 3.2 mins. At a mean follow up of two years, 43/50 (86%) of patients were in normal sinus rhythm with no documented recurrences of atrial fibrillation. Conclusion: LSI can be used to guide the placement of durable lesion formation with RF ablation using CF catheters in patients with PAF. PMID- 30455829 TI - Incidence of Atrial Fibrosis in Non-Valvular Atrial Fibrillation Patients and its Impact on Recurrence after Pulmonary Vein Antral Isolation. AB - Background: Atrial fibrillation (AF) is the most common sustained arrhythmia; it affects 1%-2% of the general population [1]. Many studies demonstrated an association between atrial fibrosis and AF [2]. There is increasing evidence that even in patients with lone AF; the AF is an arrhythmic manifestation of a structural atrial disease which has been described as fibrotic atrial cardiomyopathy [3]. It is unknown whether the presence of atrial fibrosis has any impact on post pulmonary vein antrum isolation outcome. Purpose of the study: This study aims to determine the incidence of atrial fibrosis in patients with non-valvular AF and its impact on recurrence after pulmonary vein antrum isolation. Patients and Methods: This study included twenty eight consecutive patients referred for first-time pulmonary vein antrum isolation for the treatment of symptomatic recurrent non-valvular AF not responding to medical treatment, Isolation of the pulmonary veins antra was performed using three dimensional electroanatomical mapping, detailed voltage map was done in the right and left atrium, before ablation and Low-voltage zones were identified. Follow up of the patients was done for 6 months after the procedure to detect recurrence of AF. Results: Left atrium fibrosis was present in 6 (21.4%) cases, right atrium fibrosis was present only in 1 (3.6%) case and recurrence of atrial fibrillation after 6 months occurred in 12 (42.9%) cases. AF burden was significantly higher in the recurrence group [50.33 +/-19.7 (48) (hour/month)] as compared to no recurrence group [29.5 +/- 6.99 (32) (hour/month)] with P-value 0.002 and the incidence of left atrium fibrosis was significantly higher in the recurrence group as compared to no recurrence group with P-value 0.024. The only significant predictors of recurrence were the presence of left atrium fibrosis (OR 10.71, 95% CI 1.05 to 109.78; P=0.046) and AF burden (OR 1.14, 95% CI 1.02 to 1.27; P=0.023). The only significant predictor of the presence of left atrium fibrosis was AF burden (OR 1.06, 95% CI 1.01 to 1.13; P=0.031). Conclusions: The presence of the atrial fibrosis in the left atrium is an independent predictor of atrial fibrillation recurrence after pulmonary vein antrum isolation after 6 months without left atium substrate modification. PMID- 30455830 TI - LARIAT Trial Updates. AB - The thrombus formed within the LAA is responsible for the vast (about 90%) majority of strokes. Anticoagulation, although effective therapy for stroke prevention is not feasible in a significant minority of patients due to various reasons. Two percutaenous LAA exclusion techniques have been developed in an effort to decrease risk for stroke: endocardial closure/plugging of the LAA (Watchman, Amplatzer devices) and epicardial LAA ligation (LARIAT). The aim of this study is to review the trial data to date for the LARIAT device. The LARIAT suture has been used in more than 4500 patients with high success of LAA complete closure (92-100%), mostly in the patients unable to take anticoagulation and in a small minority as antiarrhythmic option. The LARIAT technique has evolved with a change in pericardial access method that resulted in dramatic improvement of safety. LAA closure performance with LARIAT system seems to be similar to Watchman device, with small leaks during follow-up in 6-24% of the cases, which do not to correlate with thrombo-embolic events. LAA has been proven to play an important triggering role in patients with persistent atrial fibrillation. Small studies had shown that LAA ligation with LARIAT could terminate persistent atrial fibrillation and possible improve ablation success. Ongoing aMAZE randomized trial is studying if LAA ligaiton using LARIAT suture leads to improved atrial fibrillation ablation success. Available data suggests that LAA closure using LARIAT epicardial suture is a good alternative for stroke risk reduction in patients who are unable to be on anticoagulation therapy. LARIAT system might improve success of AF ablation for patients with persistent and long persistent AF, pending the results of the ongoing aMAZE trial. PMID- 30455831 TI - Coronary Sinus Electrograms May Predict New-onset Atrial Fibrillation After Typical Atrial Flutter Radiofrequency Ablation (CSE-AF). AB - Background: Complex fractionated electrograms (EGMs) of the coronary sinus electrograms (CSEs) are employed as a target during radiofrequency ablations (RFA) of atrial fibrillation (AF). Anatomically, CSEs includes both of left atrium (LA), coronary sinus musculature and right atrium (RA) electrograms. Aim: To determine the significance of fractionated CSE and delayed potentials as a predictor of new-onset AF after radiofrequency ablation (RFA) of isolated atrial flutter (AFL). Methods: Consecutive patients underwent AFL ablation. Fractionated and/or continuous discrete activities were recorded from coronary sinus electrograms during sinus rhythm and during pacing. Earliest CSE to the S nadir or peak R in milliseconds was recorded and considered as propagation delay for EGMs. Results: Forty patients were included during a mean follow-up period of 55.1+/- 15.8 months. Twenty patients (50 %) developed AF while the remaining 20 patients maintained sinus rhythm(SR) during the follow-up period. Proximal and mid CSEs were significantly fractionated in AF group compared to group with no AF development (65 % and 60% Vs. 35 % and 30 %, p = 0.03, respectively). However, during pacing from distal duo-decapolar catheter (pole 1-2), distal CSEs alone were significantly fractionated (p < 0.05) compared to SR group. Significant delayed propagation of proximal CSE during pacing and in sinus rhythm were observed in AF group (12.3 +/- 9.2 ms vs 7.1 +/- 3.6 ms, p = 0.03) and (7.2 +/- 2.9 ms Vs 8.1 +/- 4.6 ms, p= 0.02) in the same order. Conclusion: Incidence of AF is associated with fractionated proximal and mid CSE in sinus rhythm and distal CSE during paced rhythm after isolated AFL ablation. Delayed proximal CSE propagation is correlated with AF incidence. PMID- 30455832 TI - Management and Disposition of Atrial Fibrillation in the Emergency Department: A Systematic Review. AB - Introduction: Management of atrial fibrillation (AF) and atrial flutter (AFL) in the emergency department (ED) varies greatly, and there are currently no United States guidelines to guide management with regard to patient disposition after ED treatment. The aim of this systematic review was to evaluate the literature for decision aids to guide disposition of patients with AF/AFLin the ED, and assess potential outcomes associated with different management strategies in the ED. Methods and Results: A systematic review was done using PubMed (MEDLINE), Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE, combining the search terms "Atrial Fibrillation", "Atrial Flutter", "Emergency Medicine", "Emergency Service", and "Emergency Treatment". After removal of duplicates, 754 articles were identified. After initial screening of titles and abstracts, 69full text articles were carefully reviewed and 34 articles were ultimately included in the study based on inclusion and exclusion criteria. The articles were grouped into four main categories: decision aids and outcome predictors, electrical cardioversion-based protocols, antiarrhythmic-based protocols, and general management protocols. Conclusion: This systematic review is the first study to our knowledge to evaluate the optimal management of symptomatic AF/AFLin the ED with a direct impact on ED disposition. There are several viable management strategies that can result in safe discharge from the ED in the right patient population, and decision aids can be utilized to guide selection of appropriate patients for discharge. PMID- 30455834 TI - Prognostic Value of Atrial Fibrillation Inducibility in Patients Without History of Clinical Atrial Fibrillation. AB - Purpose: During invasive electrophysiological studies (EPS), atrial fibrillation (AF) can be induced in patients without a history of AF. However, the prognostic value is not well evaluated in this population. Our aim was to investigate whether AF inducibility in those patients is associated with future clinical episodes of AF; whether non-inducibility is predictive of freedom from new-onset AF and finally, to examine clinical factors associated with inducibility. Methods: Medical records from patients undergoing EPS between the years 2011 and 2014 were analysed retrospectively with 62 patients matching our inclusion criteria. Patients were divided into subgroups according to their inducibility status and underwent follow-up. Patients were assessed by a structured telephone interview, data from the further treating physicians and ECG recordings. Results: AF was inducible in 19 patients ("induction group") and not inducible in the remaining 43 ("control group"). Inducibility was associated with a higher age (p=0.002), lower GFR (p=0.002), higher CHAD2S2-VASc score (p=0.004) and diagnosis of mitral (p=0.014), tricuspid (p=0.017) and pulmonary (p=0.026) valve insufficiency. Three months after EPS, 89.5% of all inducible patients were free of diagnosed AF, in contrast to 100% of those without inducibility (p=0.031). At three years, no significant difference was left (p=0.162). Conclusion: AF inducibility was found more often in an older population with cardiac comorbidities. While inducibility was associated with an increased rate of diagnosed new-onset clinical AF in the months after testing, non-inducibility seemed to be associated with freedom from AF at least in the short to medium term. However, there was no significant difference in the long term follow-up. PMID- 30455833 TI - Atrioventricular Nodal Catheter Ablation in Atrial Fibrillation Complicating Congestive Heart Failure. AB - The development of atrial fibrillation (AF) during the course of the evolution of heart failure (HF) worsens the clinical outcomes and the prognosis accounting for an enormous economic burden on healthcare. AF is considered to be an independent predictor of morbidity and mortality increasing the risk of death and hospitalization in 76% in HF patients. Despite the good clinical results obtained with conventional pharmacological agents and different new drugs, the optimal medical treatment can fail in the intention to improve symptoms and quality of life of HF patients with severe left ventricular dysfunction and AF with uncontrolled ventricular rate. Therefore, the necessity to utilize cardiac devices to perform cardiac resynchronization therapy (CRT), or the need to use catheter ablation, or both, emerges facing the failure of optimal medical treatment in order to achieve hemodynamic improvement. Some of these AF patients will require atrio-ventricular nodal (AVN) catheter ablation in order to restore 100% CRT functionality and improvements in clinical outcomes. It is hard to imagine that the deliberate destruction of a natural and normally functional specialized tissue of the main conduction system of the heart would do any good. However, in the presence of AF with rapid ventricular response due to normal conduction through the AV node in HF patients, the fast ventricular rate can cause deleterious consequences in the clinical outcome. Moreover, there are interesting published data which will be analyzed in this manuscript documenting significant acute and long-term improvement in left ventricular function, symptoms, exercise tolerance, clinical outcomes, and quality of life in selected HF patients with paroxysmal and persistent drug-refractory AF who have undergone AVN ablation and permanent pacemaker implantation. PMID- 30455835 TI - Clinical Utility of Intravenous Nifekalant Injection during Radiofrequency catheter Ablation for Persistent Atrial Fibrillation. AB - Background: Radiofrequency catheter ablation (RFCA) for persistent atrial fibrillation (AF) is still challenging even in RFCA-era for AF. The aim of this study was to assess the clinical utility of nifekalant, a pure potassium channel blocker,during RFCA for persistent AF. Methods and results: We retrospectively enrolled 157 consecutive persistentAF patientsundergoing first RFCA procedure withcomplex fractionated atrial electrogram (CFAE)ablation after pulmonary veins isolation and compared outcomes between patientswith (NFK group: N=79) and without (No-NFK group: N=78)additional CFAE ablation using intravenous nifekalant (0.3mg/kg). Primary endpoint was 24-month atrial arrhythmia-free survival post ablation.The prevalence of AF terminationwas significantly higher in NFK group than No-NFK group (64.6% versus 7.7%, P<0.001). Arrhythmia-free survival, however, was not significantly different between 2 groups (61.5% versus 54.1%, P=0.63).There was no significant difference between 2 groups in the prevalence of recurrent atrial tachycardia(25.0% versus 23.5%, P=0.89). Arrhythmia-free survivalin patients with AF termination during procedure was significantly higher thanthose without (73.0% versus 41.0%, P=0.002; adjusted hazard ratio 0.48, 95% confidence interval 0.17-0.84, P=0.02) amongNFK group,but not amongNo-NFK group (66.7% versus 53.2%, P=0.53). Conclusions: Intravenous nifekalant injection during additional CFAE ablation did not improve sinus maintenancerate after RFCA procedure for AF, but AF termination by nifekalant injection could be a clinical predictor of better success rates after procedure. PMID- 30455836 TI - Ineffective ICD Shocks for Ventricular Fibrillation in a Patient with a Left Ventricular Assist Device: Continuous Flow During the Electrical Storm. AB - Ventricular arrhythmias are life-threatening and can serve as a precursor to sudden death. They are a common presentation in patients with severely reduced left ventricular (LV) function. The use of an implantable cardioverter defibrillator (ICD) is seen as an acceptable therapy against malignant ventricular arrhythmias. In patients with LV heart failure, a left ventricular assist device (LVAD) can provide pulsatile flow to mimic the cardiac systolic and diastolic function. We report a case of a 38-year-old male with a LVAD who presented to the emergency department due to syncope and frequent ICD discharges. There were documented episodes of ventricular fibrillation and a failed defibrillator threshold test. PMID- 30455837 TI - Subxiphoid Hybrid Approach for Epicardial/Endocardial Ablation and LAA Exclusion in Patients with Persistent and Longstanding Atrial Fibrillation. AB - Two patients with long-standing atrial fibrillation (AF) refractory to medical management and with prior pulmonary vein isolation underwent a new hybrid epicardial/endocardial subxyphoid approach for AF ablation and left atrial appendage (LAA) ligation. Pulmonary vein and LA posterior wall isolation, as well as LAA exclusion were achieved in both patients. There were no procedural complications. Both patients remain in sinus rhythm. Both patients are off antiarrhythmic medications. PMID- 30455839 TI - Risk Stratification of an Accessory Pathway Using Isoproterenol after Cardiac Arrest. AB - A 43-year-old man presented after ventricular fibrillation cardiac arrest with evidence of pre-excited atrial fibrillation. Electrophysiology study with guideline-directed testing demonstrated a low risk accessory pathway effective refractory period, which became high-risk with isoproterenol infusion. This case represents a challenging scenario wherein a high-risk pathway may be misclassified using the currently indicated methods of risk stratification. PMID- 30455838 TI - California Study of Ablation for Atrial Fibrillation:Re-hospitalization for Cardiac Events (CAABL-CE). AB - Background: Catheter ablation (ABL) for non-valvular (NV) atrial fibrillation (AF) improves rhythm control. Our aim was to compare re-hospitalization for heart failure (HF), acute coronary syndrome (ACS), or recurrent AF among patients with NVAF who underwent ABL versus controls. Methods: From the Office of Statewide Planning and Development (OSHPD) database, we identified all patients who had at least one hospitalization for AF between 2005-2013. Patients who subsequently underwent ABL were compared to controls (up to fivematched controls by age, sex and duration of AF between diagnosis and time of ABL). Cases with valve disease, open maze, other arrhythmias, or implanted cardiac devices were excluded. Pre specified clinical outcomes including readmission for HF, ACS, severe or simple AF (severe = with HF or ACS; simple= without HF or ACS)were assessed using a weighted proportional hazard model adjusting for number of hospital admissions with AF before the ABL, calendar year of ABL, and presence of chronic comorbidities. Results: The study population constituted 8338 cases and controls, with mean 3.5+ 1 patient-year follow up. In the ABL cohort, there was lower risk of re-hospitalizations for HF, HR=0.55(95%CI: 0.43-0.69,); ACS,HR=0.5(95%CI: 0.35 0.72,); severe AF [HR=0.86 (CI:0.74-0.99), and higher for simple AF, HR=1.25 (CI:1.18-1.33). Conclusions: In patients with NVAF,although ABL is associated with increased risk of re-hospitalization for simple AF, ABL was associated with a significant reduction in the risk of re-hospitalization for HF, ACS and severe AF. These findingsrequireconfirmation in a prospective clinical trial. PMID- 30455840 TI - Cryoballoon-to-Pulmonary Vein Occlusion Assessment via Capnography Technique: Where Does Occlusion Testing by End-Tidal CO2 Measurement "Fit" as a Predictor of Long-Term Efficacy? AB - Introduction: Parameters used to gauge the effectiveness of a cryoballoon lesion have been described that monitor the ablation at the time of balloon-to-pulmonary vein (PV) occlusion, during the cryoablation freeze, and at the thaw phase of the cryoablation. This study examines the balloon-to-PV occlusion step and monitors the completeness of occlusion using capnography to measure end-tidal CO2 (ETCO2). Specifically, the main objective was to determine if ETCO2 measurements can be used to quantify the amount of balloon-to-PV occlusion and to determine if acute ETCO2 parameters could predict long-term freedom from atrial fibrillation (AF). Methods and Results: In a prospective study, 30 subjects were cryoballoon ablated for drug refractory symptomatic paroxysmal AF by pulmonary vein isolation method. During the balloon-to-PV occlusion and throughout the cryoablation, ETCO2 measurements were recorded. The subjects were followed for a 12-month period to monitor their freedom from AF. Five subjects had a recurrence of AF outside of a 90-day blanking period but before the 12-month endpoint. Between the 25 subjects that maintained normal sinus rhythm (NSR) and the 5 subjects that had recurrent AF (rAF), there were no statistical differences in procedural parameters, including: the number of cryoablations per PV, duration of each cryoablation, balloon nadir temperature, or balloon thaw time. Additionally, there were no statistical differences in baseline ETCO2 and in nadir ETCO2 between the two cohorts; however, when examining Delta ETCO2, the subjects in the NSR cohort had a significantly larger change compared to the rAF cohort (P<0.001). The largest change in ETCO2 during balloon-to-PV occlusion was observed during the cryoballoon ablation of the superior PVs; however, Delta ETCO2 did not solely predict long-term freedom from AF for the individual subject. Conclusion: Delta ETCO2 did tend to be larger in the NSR cohort compared to the rAF cohort; however, ETCO2 monitoring was more responsive in the superior PVs and less useful in the inferior PVs. Moreover, ETCO2 monitoring could not be used as a sole indicator of long-term efficacy. Suggesting that monitoring balloon-to-PV occlusion is a necessary first in cryoballoon ablation, but other parameters must be incorporated and observed as surrogates of a circumferential and transmural lesion formation with long-term durability. PMID- 30455841 TI - Complete genome sequence of Planococcus sp. PAMC21323 isolated from Antarctica and its metabolic potential to detoxify pollutants. AB - The Planococcus sp. PAMC21323 is a yellow pigment-producing bacterium isolated from King George Island in Antarctica; it has a broad growth temperature range of 5-40 degrees C. Herein, we describe the complete genome sequence information of the genus Planococcus with its annotated sequence, genetic features for bioremediation, and oxidative stress capacity. The Planococcus sp. PAMC21323 possesses chromosomal DNA (3,196,500-bp) with plasmid DNA (3364-bp). The complete 3,199,864-bp of the genome consists of 3171 genes including 60 transfer RNAs and 24 ribosomal RNAs. Strain PAMC21323 encodes various genes associated with detoxification of heavy metal ions and aromatic hydrocarbons. Moreover, it is equipped with diverse stress response systems, which can be used to sense the internal and oxidative stresses caused by detoxification. This is the first report highlighting the genetic potential of Planococcus sp. PAMC21323 in bioremediation, suggesting application of this psychrotrophic strain in bioremediation in harsh environments. PMID- 30455842 TI - Sleep Disordered Breathing challenges: From diagnosis to treatment. PMID- 30455843 TI - Effects of hormonal contraceptives on sleep - A possible treatment for insomnia in premenopausal women. AB - Due to the changes that took place since the 1970s, women have achieved important socioeconomic positions. Many tasks, including domestic and familiar ones, continue to be under women's responsibility, which leads to an overload work. Additionally, the female organism has its peculiarities due to hormonal changes. Adding all these factors up, women seem to be more vulnerable to stressing factors and consequently, might be prone to present several health problems. Within this scenario, one can point out insomnia as a highly prevalent disease among women, directly affecting performance and quality of life. Progesterone has an important effect over sleep, acting both as a hypnogenic and as a respiratory stimulant. Hormonal contraceptives are largely recognized among the modern society women; however, little is known about the effects of these drugs on sleep. This proposal hypothesizes that the use of hormonal contraceptives, mainly those based on progestagens could be a new therapeutic element for the treatment of insomnia and one more tool to be used to improve women's sleep pattern and quality of life. PMID- 30455844 TI - Peripheral body temperature impairment in individuals with type 1 diabetes mellitus. AB - Objective: The aim of the present study was to evaluate the peripheral temperature rhythmicity and control in individuals with type 1 diabetes mellitus. Methods: Twelve non-obese adults (20-40 years old) with type 1 diabetes mellitus (T1D) and eight control individuals, matched for age and BMI, wore a wrist temperature recorder for 10 consecutive days. Recorded data were aggregated to calculate M10 (ten hours of highest temperature) and L5 (five hours of lowest temperature) of wrist temperature values for both groups. Results: Mean wrist temperature and M10 were not different when comparing the groups. The wrist temperature amplitude was reduced in the T1D group (p=0.039), due to a higher L5 (p=0.038). Discussion: While the higher L5 observed in T1D could be explained by less efficient heat dissipation, the amplitude flattening coincides with that observed in elderly. PMID- 30455845 TI - Comparison of sleep quality assessed by actigraphy and questionnaires to healthy subjects. AB - Sleep quality analysis is crucial for human health and it is related to duration, rhythm and quality. The goal of this study is to analyze objective assessment of the sleep-wake cycles with actigraphy, subjective questionnaires and their relationship with sleep quality indices. A wearable actigraph registered the sleep habits of 41 healthy subjects for 9 days. Afterwards, the subjects filled two questionnaires about sleep quality (Pittsburgh Sleep Quality Index) and sleepiness (Epworth Sleepiness Scale). The subjects were divided into two groups based on cut-off scores and the actigraphy parameters were compared between groups. Group 1 in ESS and PSQI categorization had less diurnal sleepiness and better sleep quality, respectively, than Group 2. Measurements of regularity (IS), fragmentation (IV), active phase amplitude (M10), rest amplitude (L5), and relative amplitude (RA) were compared between groups. Group 2 had higher L5 values. Parameter L5 (lowest of 5 consecutive hours of activity) was concluded to be relevant to identify the sleep conditions of the subjects. PMID- 30455846 TI - Severe sleep apnea, Cheyne-Stokes respiration and desaturation in patients with decompensated heart failure at high altitude. AB - Objectives: To determine the sleep-disordered breathing in patients with decompensated HF (DHF) at an altitude of 2640m. Methods: Polysomnogram during the first 48 hours of admission in patients hospitalized for DHF. Sleep apnea (SA) was defined as an apnea hypopnea index (AHI) > 5/hour and central sleep apnea (CSA) as central apnea index (CAI) >= 50% of the AHI. Results: Sixteen participants, LVEF 24.2+/-9.9%. All patients had SA, severe in 12 (75%), CSA in 8 (50%) and 7 (43.8%) presented Cheyne-Stokes respiration (CSR). Out of the eight patients with obstructive SA, five had a central component (CAI >= 5/h). The SpO2 decreased during sleep to 80.6+/-5.5% and in patients with CSR to 77.6+/-6.9%. Conclusions: At an altitude of 2640m all patients with DHF presented sleep apnea, most were severe, with CSA and a significant percentage of CSR that was associated with higher oxygen desaturation. PMID- 30455847 TI - Executive functioning is preserved in healthy young adults under acute sleep restriction. AB - Objectives: This study aimed to evaluate if a partial morning or evening sleep restriction protocol could affect executive functioning in healthy young adults. Methods: Participants were assigned to one of three groups: control (n=18), in which participants maintained their habitual sleep/wake cycle; morning restriction (n=17), in which volunteers terminated sleep approximately three hours earlier than the usual on the experimental night, and evening restriction (n=13), in which volunteers initiated sleep approximately three hours later than the usual on the experimental night. On the day of the experiment, they performed the Stroop Test, the Go-NoGo Test and the Iowa Gambling Task (IGT). Results: When compared to the control group, neither morning nor evening sleep-restricted individuals displayed any significant deficits in: a) selective attention as assessed by the interference index (H=3.38; p=0.18) and time to performed the interference card (H=2.61; p=0.27) on the Stroop test; b) motor response inhibition as assessed by number of false alarms (H=0.8; p=0.67) on the Go-NoGo Test; and c) in decision-making as assessed by total won (H=2.64; p=0.26) and number of selected advantageous cards (H=4.43; p=0.11) on the IGT. Conclusion: These findings suggest that the ability to pay attention, inhibit a motor response and make decisions is preserved following approximately 3 hours of sleep restriction, regardless of its timing (in the morning or in the evening). PMID- 30455848 TI - Simulated intention-to-treat analysis based on clinical parameters of patients at high risk for sleep apnea derivated to respiratory polygraphy. AB - Purpose: Obstructive Sleep Apnea-Hypopnea Syndrome (OSAS) is a public health problem. We designed a pilot study to validate empiric indication of CPAP therapy in a population with moderate-to-high pre-test probabilities who underwent self administered home-based respiratory polygraphy (RP). Methods: A cross-sectional simulation study was performed. CPAP therapy could be indicated by two independent blind observers. Observer 1's decision was based on the results of STOP-BANG (SBQ) and Epworth Sleepiness Scale (ESS) and Observer 2 used all objective data provided by RP + SBQ + ESS. Results: We evaluated 1763 patients; 1060 men and 703 women (39.2%) with a mean age of 53.6+/-13.8 and a body mass index (BMI) of 32.8+/-7.5 kg/m2. We found evidence of mild (34.1%), moderate (26.6%), and severe (18.3%) There were Apnea-Hypopnea Index (AHI) relationship between > 5 or < 5 SBQ and RP AHI (p<0.05). BMI > 25 kg/m2 + snoring (S) + observed apnea (O) + 1 of the following: ESS > 11, hypertension (HT) or > 5 SBQ components showed sensitivity of 40% (CI95%: 37.3-43) and specificity of 95.1% (CI93.4-96.4). The performance of 5 SBQ components with regard to gender and empirical CPAP therapy was; (women vs. men): AUC-ROC 0.625 (CI95%: 0.599-0.651) vs. 0.70 (CI95%: 0.68-0.72), p<0.01, respectively. Conclusions: STOP-BANG and ESS made it possible to indicate CPAP reliably (low rate of false-positive results) in 20-40% of patients who needed such therapy according to clinical history and RP results. These clinical criteria performed better in male. PMID- 30455849 TI - Generalized Anxiety disorder but not depression is associated with insomnia: a population based study. AB - Background: Insomnia is a common problem, however, its prevalence has never been examined in Indian population. Moreover, a number of psychiatric disorders have been found to be associated with insomnia in clinical population, but this association has scarcely been examined in general population. Methods: This epidemiological study was done in an urban and a rural population. Subjects were selected using Kish method. After obtaining informed consent, psychiatric disorders were diagnosed using Hindi version of Mini International Neuropsychiatric Interview. Hindi version of Insomnia Severity Index was used to diagnose insomnia. Results: 1700 subjects were included in this study. In this study, prevalence of insomnia was 10.3%. Its prevalence increased with increasing years of education (p=0.009). Insomnia was more frequent in subjects living in joint families (p<0.001), having higher education (p=0.009), those who were separated (p<0.001), among subjects belonging to middle socio-economic status (p<0.001) and in urban population compared to semi-urban and rural population (p<0.001). Insomnia was also more frequent among subjects with major depressive disorder, generalized anxiety disorder, alcohol dependence, cannabis dependence and tobacco use. However, binary logistic regression analysis showed that only higher education, unemployment, generalized anxiety disorder and tobacco use were associated with insomnia. Conclusion: Insomnia in general population is associated with higher education, unemployment, generalized anxiety disorders and tobacco use. PMID- 30455850 TI - Access to CPAP treatment in patients with moderate to severe sleep apnea in a Latin American City. AB - Introduction: The most effective treatment for moderate to severe obstructive sleep apnea (OSA) is continuous positive airway pressure (CPAP) but adherence may be a limiting factor. Most compliance studies often only include patients under CPAP treatment, neglecting the importance of access to treatment. The aim of this study was to evaluate CPAP access and compliance in OSA patients, after CPAP indication and titration. Methods: We included moderate to severe OSA patients, diagnosed by in-lab polysomnography (PSG), with CPAP indication and effective pressure titration. Between 12 to 18 months after treatment was indicated a telephone questionnaire was administered including questions about access to CPAP, reasons of no access, reported adherence and symptoms improvement. Results: A total of 213 patients responded to the survey (171 males, mean age 53.4+/-13.5 and BMI 34.02+/-8.8 kg/m2). Almost a third of the patients (28.2%) did not initiate CPAP treatment. Out of 213, 153 patients (71.8%) started treatment with CPAP and 120 (56.3%) reported still being under treatment a year after indication, additionally, 85.8% reported that they were using it =4hs/night. Those who accessed to CPAP were on average, older age, had full coverage of treatment by their medical insurance, required lower effective pressure and experienced more severe sleepiness compared to those individuals who did not accessed to CPAP. Discussion: A significant proportion of OSA patients with CPAP indication did not initiate and/or eventually abandoned CPAP. Approximately only 50% of the patients were still under treatment, with acceptable self-reported adherence rate and clinical response, one year after the initial treatment indication. Additional measures are necessary to increase access to CPAP and improve long-term compliance. PMID- 30455851 TI - Scientific production of Brazilian speech language pathologists in sleep medicine. AB - Introduction: Previous diagnosis and intervention in patients with sleep disordered breathing involves several health professionals. Speech-Language and Hearing Sciences (SLHS) performance has been solidified through scientific production. Objective: To describe the inclusion of Brazilian Speech-Language Pathologists (SLP) in the field of sleep disorders, through the description of studies, scientific publications and participation in scientific events. Data Synthesis: A search and an analysis of the Brazilian SLP publications in the field of sleep disorders were carried out, including articles, monographs, dissertations, thesis and abstracts published in annals of events. The databases Lilacs, SciELO, Pubmed, Google Scholar tool and Lattes platform were accessed, with final search in January 2018. The analysis consisted of a description of the year of publication, type of publication, area of the SLHS, place of publication and/or event. 40 articles were found in national and international journals, from 1999 to 2017. In relation to publications in books, one book about the subject was published in 2009 and eight chapters of books were published. In the monograph format, 21 studies were carried out, there are 13 dissertations and eight thesis. A total of 151 abstracts were published in annals of scientific events, from 2001 to 2017 and 63 lectures were conducted by SLP. Conclusion: The inclusion of Brazilian SLP in the area of sleep disorders has been supported by scientific publications in the format of articles in national and international journals, monographs, thesis, dissertations, books and publications in event annals. PMID- 30455852 TI - How do men with severe sexual and physical childhood traumatization experience trauma-stabilizing group treatment? A qualitative study. AB - Background: Exposure to potentially traumatizing events, defined as events involving actual or threatened death or serious injury, is associated with an elevated risk of developing enduring physical, psychological and social problems. Complex post-traumatic stress disorder (PTSD) is a disorder that can occur after prolonged and repeated trauma. At least 30% of the sexually abused population is male, but in spite of this fact, treatment research focusing on male victims is virtually non-existent in comparison to research on female victims. Objective: Trauma-stabilizing group treatment is an increasingly used treatment method for patients with complex PTSD. The aim of the present study was to explore how men participating in a gender-specific trauma-stabilizing intervention experience this treatment approach. Methods: Five men who participated in a trauma stabilizing group treatment were interviewed with a semi-structured qualitative interview. The data were analysed using interpretative phenomenological analysis. Results: The analysis revealed five main themes. The themes highlight the experiences of the participants and describe positive and negative experiences: (1) Group atmosphere, comprising safety, community, emotional openness, anxiety and pressure; (2) Learning, categorized into knowledge and self-understanding; (3) Motivation, which describes both inner and outer motivation; (4) Structure, comprising structure of the meetings, group size and duration of the meetings; and (5) Gender, defined as the experiences of being in an all-male group with female group leaders. Conclusions: There seem to be a lot of advantages to inviting men to attend gender-specific groups for trauma-stabilizing treatment. The men emphasized the support they received and that participating in a mixed gender group would have been more difficult. In the future, it may be important to arrange all-male stabilization groups with more focus on male-specific topics. PMID- 30455853 TI - Trauma-related altered states of consciousness in post-traumatic stress disorder patients with or without comorbid dissociative disorders. AB - Background: The four-dimensional ('4-D') model has been proposed as a theoretical framework to understand and delineate trauma-related dissociative experiences, categorizing symptoms into trauma-related altered states of consciousness (TRASC) and normal waking consciousness (NWC), which occur along four dimensions: time, thought, body and emotion. Objective: The main aim of the present study was to evaluate the validity of this model in patients with post-traumatic stress disorder (PTSD), with and without comorbid dissociative disorders. Method: The predictions of the 4-D model were tested in 142 patients with PTSD, with (N = 46) and without (N = 96) comorbid dissociative disorders. Results: As predicted by the 4-D model, experiences of TRASC were less frequent and more specifically related to other measures of dissociation, dissociative disorder comorbidity and a history of childhood sexual abuse compared to experiences of NWC. The predicted lower intercorrelation of TRASC was not supported. Conclusion: The 4-D model represents a promising framework for understanding dissociation across trauma related disorders. PMID- 30455854 TI - Copper Chaperone Atox1 Interacts with Cell Cycle Proteins. AB - The anaphase-promoting complex (APC) is involved in several processes in the cell cycle, most prominently it facilitates the separation of the sister chromatids during mitosis, before cell division. Because of the key role in the cell cycle, APC is suggested as a putative target for anticancer agents. We here show that the copper chaperone Atox1, known for shuttling copper in the cytoplasm from Ctr1 to ATP7A/B in the secretory pathway, interacts with several APC subunits. Atox1 interactions with APC subunits were discovered by mass spectrometry of co immunoprecipitated samples and further confirmed using proximity ligation assays in HEK293T cells. Upon comparing wild-type cells with those in which the Atox1 gene had been knocked out, we found that in the absence of Atox1 protein, cells have prolonged G2/M phases and a slower proliferation rate. Thus, in addition to copper transport for loading of copper-dependent enzymes, Atox1 may modulate the cell cycle by interacting with APC subunits. PMID- 30455855 TI - Pharmacoinformatic Approach to Explore the Antidote Potential of Phytochemicals on Bungarotoxin from Indian Krait, Bungarus caeruleus. AB - Venomous reptiles especially serpents are well known for their adverse effects after accidental conflicts with humans. Upon biting humans these serpents transmit arrays of detrimental toxins with diverse physiological activities that may either lead to minor symptoms such as dermatitis and allergic response or highly severe symptoms such as blood coagulation, disseminated intravascular coagulation, tissue injury, and hemorrhage. Other complications like respiratory arrest and necrosis may also occur. Bungarotoxins are a group of closely related neurotoxic proteins derived from the venom of kraits (Bungarus caeruleus) one of the six most poisonous snakes in India whose bite causes respiratory paralysis and mortality without showing any local symptoms. In the current study, by employing various pharmacoinformatic approaches, we have explored the antidote properties of 849 bioactive phytochemicals from 82 medicinal plants which have already shown antidote properties against various venomous toxins. These herbal compounds were taken and pharmacoinformatic approaches such as ADMET, docking and molecular dynamics were employed. The three-dimensional modelling approach provides structural insights on the interaction between bungarotoxin and phytochemicals. In silico simulations proved to be an effective analytical tools to investigate the toxin-ligand interaction, correlating with the affinity of binding. By analyzing the results from the present study, we proposed nine bioactive phytochemical compounds which are, 2-dodecanol, 7-hydroxycadalene, indole-3-(4'-oxo)butyric acid, nerolidol-2, trans-nerolidol, eugenol, benzene propanoic acid, 2-methyl-1-undecanol, germacren-4-ol can be used as antidotes for bungarotoxin. PMID- 30455856 TI - Discovery of novel quinazoline derivatives bearing semicarbazone moiety as potent EGFR kinase inhibitors. AB - Aimed at discovering effective EGFR inhibitors, six series of quinazoline derivatives bearing a semicarbazone moiety were designed, synthesized and evaluated in different cancer cell lines (A549, HepG2, MCF-7 and PC-3). Most of the selected compounds showed remarkable cytotoxicity with IC50 values reaching the nanomole range. Further, the inhibition efficacy of 11 compounds against EGFR kinases was tested, which demonstrated excellent IC50 values in nanomolar level. Importantly, 2 compounds exhibited IC50 values of 0.05 nM and 0.1 nM against wild type EGFR respectively, suggesting more potent activities than that of the positive control, Afatinib (4.0 nM). Excitingly, 2 compounds showed excellent enzyme inhibitory activity with 8.6 nM and 5.6 nM for double T790 M/L858R mutant EGFRs, which is almost the same as Afatinib (3.8 nM). Structure-activity relationships (SARs) analysis indicated that the type of small molecule amine in pyrrole moiety or the chain length of pyrrolamine moiety had no obvious impact on the inhibition efficacy of our synthesized compounds against cancer cells. In addition, results of cell cycle analysis indicated that the G2/M phase of A549 cells was efficiently arrested by the selected compounds. These preliminary results demonstrate that 2 compounds may be promising lead compound-targeting EGFR. PMID- 30455857 TI - Hyperglycemia aggravates microenvironment hypoxia and promotes the metastatic ability of pancreatic cancer. AB - Background: Diabetes mellitus and pancreatic cancer are intimately related. Our previous studies showed that high levels of blood glucose promote epithelial mesenchymal transition of pancreatic cancer. In this study, we evaluated the relationship between hyperglycemia and hypoxic tumor microenvironments. Methods: HIF-1alpha expression was evaluated by immunohistochemistry in clinical pancreatic cancer tissues with or without diabetes mellitus. Statistcal analysis was performed to explore the relationship between HIF-1alpha expression and pathological features of patients with pancreatic cancer. In vivo and in vitro models was established to detect whether a hyperglycemia environment could cause hypoxia in the pancreatic parenchyma and promote pancreatic cancer. In addition, we also tested the effect of HIF-1alpha siRNA on the high glucose-induced invasive and migratory abilities of BxPC-3 cells in culture. Result: Our data showed that pancreatic cancer patients with diabetes had a higher level of HIF 1alpha expression as well as biliary duct invasion and larger tumor volumes than individuals in the euglycemic group. Diabetic nude mice treated with streptozotocin (STZ) exhibited larger tumors and were more likely to develop liver metastasis than control mice. Acinar cells of the pancreas in diabetic mice showed an obvious expansion of the endoplasmic reticulum and increased nuclear gaps as well as chromatin close to the cellular membrane in some acinar cells. The expression area for Hypoxyprobe-1 and HIF-1alpha in the diabetic orthotopic xenograft group was larger than that in the control group. The expression level of HIF-1alpha in the BxPC-3 cancer cell line increased in response to high glucose and CoCl2 concentrations. The high glucose-induced invasive ability, migratory capacity and MMP-9 expression were counter-balanced by siRNA specific to HIF-1alpha. Conclusion: Our results demonstrate that the association between hyperglycemia and poor prognosis can be attributed to microenvironment hypoxia in pancreatic cancer. PMID- 30455860 TI - Flood tolerance in two tree species that inhabit both the Amazonian floodplain and the dry Cerrado savanna of Brazil. AB - Comparing plants of the same species thriving in flooded and non-flooded ecosystems helps to clarify the interplay between natural selection, phenotypic plasticity and stress adaptation. We focussed on responses of seeds and seedlings of Genipa americana and Guazuma ulmifolia to substrate waterlogging or total submergence. Both species are commonly found in floodplain forests of Central Amazonia and in seasonally dry savannas of Central Brazil (Cerrado). Although seeds of Amazonian and Cerrado G. americana were similar in size, the germination percentage of Cerrado seeds was decreased by submergence (3 cm water) and increased in Amazonian seeds. The seeds of Amazonian G. ulmifolia were heavier than Cerrado seeds, but germination of both types was unaffected by submergence. Three-month-old Amazonian and Cerrado seedlings of both species survived 30 days of waterlogging or submersion despite suffering significant inhibition in biomass especially if submerged. Shoot elongation was also arrested. Submersion triggered chlorosis and leaf abscission in Amazonian and Cerrado G. ulmifolia while waterlogging did so only in Cerrado seedlings. During 30 days of re-exposure to non-flooded conditions, G. ulmifolia plants that lost their leaves produced a replacement flush. However, they attained only half the plant dry mass of non flooded plants. Both submerged and waterlogged G. americana retained their leaves. Consequently, plant dry mass after 30 days recovery was less depressed by these stresses than in G. ulmifolia. Small amounts of cortical aerenchyma were found in roots 2 cm from the tip of well-drained plants. The amount was increased by flooding. Waterlogging but not submergence promoted hypertrophy of lenticels at the stem base of both species and adventitious rooting in G. ulmifolia. Despite some loss of performance in dryland plants, flood tolerance traits were present in wetland and dryland populations of both species. They are part of an overall stress-response potential that permits flexible acclimation to locally flooded conditions. PMID- 30455859 TI - More than just exosomes: distinct Leishmania infantum extracellular products potentiate the establishment of infection. AB - The use of secretion pathways for effector molecule delivery by microorganisms is a trademark of pathogenesis. Leishmania extracellular vesicles (EVs) were shown to have significant immunomodulatory potential. Still, they will act in conjunction with other released parasite-derived products that might modify the EVs effects. Notwithstanding, the immunomodulatory properties of these non vesicular components and their influence in the infectious process remains unknown. To address this, we explored both in vitro and in vivo the immunomodulatory potential of promastigotes extracellular material (EXO), obtained as a whole or separated in two different fractions: EVs or vesicle depleted EXO (VDE). Using an air pouch model, we observed that EVs and VDE induced a dose-dependent cell recruitment profile different from the one obtained with parasites, attracting significantly fewer neutrophils and more dendritic cells (DCs). Additionally, when we co-inoculated parasites with extracellular products a drop in cell recruitment was observed. Moreover, in vitro, while VDE (but not EVs) downregulated the expression of DCs and macrophages activation markers, both products were able to diminish the responsiveness of these cells to LPS. Finally, the presence of Leishmania infantum extracellular products in the inoculum promoted a dose-dependent infection potentiation in vivo, highlighting their relevance for the infectious process. In conclusion, our data demonstrate that EVs are not the only relevant players among the parasite exogenous products. This, together with the dose-dependency observed, opens new avenues to the comprehension of Leishmania infectious process. The approach presented here should be exploited to revisit existing data and considered for future studies in other infection models. PMID- 30455858 TI - Hydrogel-assisted neuroregeneration approaches towards brain injury therapy: A state-of-the-art review. AB - Recent years have witnessed the development of an enormous variety of hydrogel based systems for neuroregeneration. Formed from hydrophilic polymers and comprised of up to 90% of water, these three-dimensional networks are promising tools for brain tissue regeneration. They can assist structural and functional restoration of damaged tissues by providing mechanical support and navigating cell fate. Hydrogels also show the potential for brain injury therapy due to their broadly tunable physical, chemical, and biological properties. Hydrogel polymers, which have been extensively implemented in recent brain injury repair studies, include hyaluronic acid, collagen type I, alginate, chitosan, methylcellulose, Matrigel, fibrin, gellan gum, self-assembling peptides and proteins, poly(ethylene glycol), methacrylates, and methacrylamides. When viewed as tools for neuroregeneration, hydrogels can be divided into: (1) hydrogels suitable for brain injury therapy, (2) hydrogels that do not meet basic therapeutic requirements and (3) promising hydrogels which meet the criteria for further investigations. Our analysis shows that fibrin, collagen I and self assembling peptide-based hydrogels display very attractive properties for neuroregeneration. PMID- 30455863 TI - Elective cholecystectomy as a rare presentation of metastatic breast cancer. AB - Cholecystectomy leads, occasionally, to the diagnosis of subclinical primary carcinomas and rarely metastatic tumors. The authors report the diagnosis of gallbladder metastasis after an elective cholecystectomy for symptomatic cholelithiasis. Histological examination disclosed a metastasis from a lobular breast carcinoma. Authors found no more than 25 case reports of breast cancer metastasis in English literature. Of those, only one reports first diagnosis after elective cholecystectomy with no radiological or macroscopic signs of malignancy. Rare clinical presentations, as in this case, should always be kept in mind specially in high volume centers. These rare presentations lack good quality evidence and challenge the best standard treatment regimen available. Multidisciplinary assessment is the key to maximize the risk/benefit of different treatment modalities. In this case report, although curative surgery was attempted, progression disease was typical of an advance staged disease. PMID- 30455862 TI - A two-level model for the role of complex and young genes in the formation of organism complexity and new insights into the relationship between evolution and development. AB - Background: How genome complexity affects organismal phenotypic complexity is a fundamental question in evolutionary developmental biology. Previous studies proposed various contributing factors of genome complexity and tried to find the connection between genomic complexity and organism complexity. However, a general model to answer this question is lacking. Here, we introduce a 'two-level' model for the realization of genome complexity at phenotypic level. Results: Five representative species across Protostomia and Deuterostomia were involved in this study. The intrinsic gene properties contributing to genome complexity were classified into two generalized groups: the complexity and age degree of both protein-coding and noncoding genes. We found that young genes tend to be simpler; however, the mid-age genes, rather than the oldest genes, show the highest proportion of high complexity. Complex genes tend to be utilized preferentially in each stage of embryonic development, with maximum representation during the late stage of organogenesis. This trend is mainly attributed to mid-age complex genes. In contrast, young genes tend to be expressed in specific spatiotemporal states. An obvious correlation between the time point of the change in over- and under-representation and the order of gene age was observed, which supports the funnel-like model of the conservation pattern of development. In addition, we found some probable causes for the seemingly contradictory 'funnel-like' or 'hourglass' model. Conclusions: These results indicate that complex and young genes contribute to organismal complexity at two different levels: Complex genes contribute to the complexity of individual proteomes in certain states, whereas young genes contribute to the diversity of proteomes in different spatiotemporal states. This conclusion is valid across the five species investigated, indicating it is a conserved model across Protostomia and Deuterostomia. The results in this study also support 'funnel-like model' from a new viewpoint and explain why there are different evo-devo relation models. PMID- 30455864 TI - Transient femoral nerve neuropathy secondary to haematoma after medial thigh lift. AB - We report an unusual and rare complication of transient femoral nerve neuropathy secondary to a large haematoma after medial thigh lift surgery. This has never been previously reported in the literature in association with this procedure. It is prudent to raise awareness that such a significant complication, although rare, can occur even with such a benign procedure, and that it is readily reversible with prompt recognition and early treatment. PMID- 30455865 TI - Identification of Pen m 4 as a potential cause of occupational asthma to Gammarus shrimp. AB - We present the case of a 34-year-old male patient employed for 8 years in a company manufacturing and packaging animal feed. The patient developed occupational asthma to dry Gammarus powder. The diagnosis was confirmed by specific bronchial provocation test. The determination of specific IgE antibodies was positive for Pen m 4, a sarcoplasmic calcium binding protein, with a level of 6.7 ISU-E. The sensitization to Pen m 4 described here may identify a new allergen causing occupational asthma in these workers. PMID- 30455866 TI - A prospective case series evaluating use of an in-line air detection and purging system to reduce air burden during major surgery. AB - Background: Intravascular air embolism (AE) is a preventable but potentially catastrophic complication caused by intravenous tubing, trauma, and diagnostic and surgical procedures. The potentially fatal risks of arterial AE are well known, and emerging evidence demonstrates impact of venous AEs on inflammatory response and coagulation factors. A novel FDA-approved in-line air detection and purging system was used to detect and remove air caused by administering a rapid fluid bolus during surgery. Methods: A prospective, randomized, case series was conducted. Subjects were observed using standard monitors, including transesophageal echocardiography (TEE) in the operating room. After general anesthesia was induced, an introducer and pulmonary artery catheter was inserted in the right internal jugular to administer fluids and monitor cardiac pressures. Six patients undergoing cardiac surgery were studied. Each patient received four randomized fluid boluses: two with the in-line air purging device, two without. For each bolus, a bulb infuser was squeezed three times (10-15 mL) over 5 s. The TEE was positioned in the mid-esophageal right atrium (RA) to quantify peak air clearance, and images were video recorded throughout each bolus. Air was quantified using optical densitometry (OD) from images demonstrating maximal air in the RA. Results: All subjects demonstrated significantly lower air burden when the air reduction device was used (p = 0.004), and the average time to clear 90% of air was also lower, 3.7 +/- 1.2 s vs. 5.3 +/- 1.3 s (p < 0.001). Conclusion: An air purging system reduced air burden from bolus administration and could consequently reduce the risk of harmful or fatal AEs during surgery. PMID- 30455861 TI - Genome-wide transcriptome profiling and spatial expression analyses identify signals and switches of development in tapeworms. AB - Background: Tapeworms are agents of neglected tropical diseases responsible for significant health problems and economic loss. They also exhibit adaptations to a parasitic lifestyle that confound comparisons of their development with other animals. Identifying the genetic factors regulating their complex ontogeny is essential to understanding unique aspects of their biology and for advancing novel therapeutics. Here we use RNA sequencing to identify up-regulated signalling components, transcription factors and post transcriptional/translational regulators (genes of interest, GOI) in the transcriptomes of Larvae and different regions of segmented worms in the tapeworm Hymenolepis microstoma and combine this with spatial gene expression analyses of a selection of genes. Results: RNA-seq reads collectively mapped to 90% of the > 12,000 gene models in the H. microstoma v.2 genome assembly, demonstrating that the transcriptome profiles captured a high percentage of predicted genes. Contrasts made between the transcriptomes of Larvae and whole, adult worms, and between the Scolex-Neck, mature strobila and gravid strobila, resulted in 4.5-30% of the genes determined to be differentially expressed. Among these, we identified 190 unique GOI up-regulated in one or more contrasts, including a large range of zinc finger, homeobox and other transcription factors, components of Wnt, Notch, Hedgehog and TGF-beta/BMP signalling, and post-transcriptional regulators (e.g. Boule, Pumilio). Heatmap clusterings based on overall expression and on select groups of genes representing 'signals' and 'switches' showed that expression in the Scolex-Neck region is more similar to that of Larvae than to the mature or gravid regions of the adult worm, which was further reflected in large overlap of up-regulated GOI. Conclusions: Spatial expression analyses in Larvae and adult worms corroborated inferences made from quantitative RNA-seq data and in most cases indicated consistency with canonical roles of the genes in other animals, including free-living flatworms. Recapitulation of developmental factors up-regulated during larval metamorphosis suggests that strobilar growth involves many of the same underlying gene regulatory networks despite the significant disparity in developmental outcomes. The majority of genes identified were investigated in tapeworms for the first time, setting the stage for advancing our understanding of developmental genetics in an important group of flatworm parasites. PMID- 30455868 TI - Correction to: Candidemia in a major regional tertiary referral hospital - epidemiology, practice patterns and outcomes. AB - [This corrects the article DOI: 10.1186/s13756-017-0184-1.]. PMID- 30455867 TI - Healthcare-associated infections in intensive care units in Taiwan, South Korea, and Japan: recent trends based on national surveillance reports. AB - Background: Sustainable systematic interventions are important for infection prevention and control (IPC). Data from surveillance of healthcare-associated infections (HAI) provides feedback for implementation of IPC programs. To address the paucity of such data in Asia, we searched for national HAI surveillance and IPC programs in this region. Methods: Data were analysed from open access national surveillance reports of three Asian countries: Taiwan, South Korea and Japan from 2008 to 2015. National IPC programs were identified. Results: There were differences among the countries in surveillance protocols, hospital coverage rates, and national IPC policies and programs. Nevertheless, there was a 53.0% reduction in overall HAI over the 8-year period. This consisted of a decrease from 9.34 to 5.03 infections per 1000 patient-days in Taiwan, from 7.56 to 2.76 in Korea, and from 4.41 to 2.74 in Japan (Poisson regression, all p < 0.05). Across the three countries, Escherichia coli and Candida albicans were the major pathogens for urinary tract infection. Staphylococcus aureus, Acinetobacter baumannii and Enterococcus faecium were common bloodstream pathogens. For pneumonia, S. aureus, A. baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae were the predominant pathogens, with considerable country differences. There was a 64.6% decrease in the number of isolates of methicillin-resistant S. aureus, 38.4% decrease in carbapenem-resistant P. aeruginosa and 49.2% decrease in carbapenem-resistant A. baumannii (CRAB) in Taiwan (all p < 0.05), and similarly in Korea with the exception of CRAB (30.5 and 50.4% reduction, respectively, both p < 0.05). Conclusion: We found a significant decrease in HAI across the three countries in association with sequential multifaceted interventions such as hand hygiene, care bundles, and antimicrobial stewardships. Further regional collaboration could be forged to develop joint strategies to prevent HAI. PMID- 30455870 TI - Doped, conductive SiO 2 nanoparticles for large microwave absorption. AB - Although many materials have been studied for the purpose of microwave absorption, SiO2 has never been reported as a good candidate. In this study, we present for the first time that doped, microwave conductive SiO2 nanoparticles can possess an excellent microwave absorbing performance. A large microwave reflection loss (RL) of -55.09 dB can be obtained. The large microwave absorption originates mainly from electrical relaxation rather than the magnetic relaxation of the incoming microwave field. The electrical relaxation is attributed to a large electrical conductivity that is enabled by the incorporation of heterogeneous (N, C and Cl) atoms. The removal of the magnetic susceptibility only results in a negligible influence of the microwave absorption. In contrast, the removal of the heterogeneous atoms leads to a large decrease in the electrical conductivity and microwave absorption performance. Meanwhile, the microwave absorption characteristics can be largely adjusted with a change of the thickness, which provides large flexibility for various microwave absorption applications. PMID- 30455869 TI - Should antibiotic prophylaxis before orthopedic implant surgery depend on the duration of pre-surgical hospital stay? AB - Background: Prolonged hospital stay before surgery is a risk for colonization with antibiotic-resistant microorganisms and possible antibiotic-resistant surgical site infections (SSI), which lacks acknowledgement in international guidelines for perioperative antibiotic prophylaxis. Method: Retrospective cohort study focusing on prophylaxis-resistant SSI in adult orthopedic implant patients; with emphasis on length of hospital stay prior to the index surgery. Results: We enrolled 611 cases of SSI (median age, 65 years; 241 females and 161 immune suppressed) in four large implant groups: arthroplasties (n = 309), plates (n = 127), spondylodeses (n = 31), and nails (n = 46). The causative pathogen was resistant to the perioperative antibiotic prophylaxis regimen in 307 cases (307/611; 50%), but the length of pre-surgical hospitalization did not influence the incidences of prophylaxis-resistant SSIs. These incidences were (107/211;51%) for the admission day, (170/345;49%) within 10 days of delay, (19/35;54%) between 10 and 20 days, and (11/20; 55%) beyond 20 days of hospital stay before surgery. The corresponding incidences of methicillin-resistant staphylococci were 13%, 14%, 17%, and 5%, respectively. In adjusted group comparisons, the length of prior hospital stay was equally unrelated to future prophylaxis-resistant SSI (odds ratio 1.0, 95% confidence interval 0.99-1.01). Conclusions: In our retrospective cohort of orthopedic implant SSI, the length of pre-surgical hospital stay was unrelated to the incidence of prophylaxis-resistant pathogens. PMID- 30455872 TI - "Perspective" - A new approach to serve our Light community. PMID- 30455871 TI - X-ray-activated long persistent phosphors featuring strong UVC afterglow emissions. AB - Phosphors emitting visible and near-infrared persistent luminescence have been explored extensively owing to their unusual properties and commercial interest in their applications such as glow-in-the-dark paints, optical information storage, and in vivo bioimaging. However, no persistent phosphor that features emissions in the ultraviolet C range (200-280 nm) has been known to exist so far. Here, we demonstrate a strategy for creating a new generation of persistent phosphor that exhibits strong ultraviolet C emission with an initial power density over 10 milliwatts per square meter and an afterglow of more than 2 h. Experimental characterizations coupled with first-principles calculations have revealed that structural defects associated with oxygen introduction-induced anion vacancies in fluoride elpasolite can function as electron traps, which capture and store a large number of electrons triggered by X-ray irradiation. Notably, we show that the ultraviolet C afterglow intensity of the yielded phosphor is sufficiently strong for sterilization. Our discovery of this ultraviolet C afterglow opens up new avenues for research on persistent phosphors, and it offers new perspectives on their applications in terms of sterilization, disinfection, drug release, cancer treatment, anti-counterfeiting, and beyond. PMID- 30455873 TI - Inflammatory pseudotumour: A rare tumor of lung. AB - Inflammatory pseudotumours of the lungs have rarely been reported. These have been described as a benign entity of unknown origin and are often locally invasive requiring extensive pulmonary resection. Complete resection is the key to prevent recurrence and the prognosis is excellent following surgery. We describe a patient with inflammatory pseudotumour of the lung. He was a middle aged man who presented with haemotysis and the chest X-ray and computerized tomography were indicative of a nonbenign lesion in the right upper lobe. Excision biopsy confirmed the diagnosis of inflammatory myofibroblastic pseudotumour of the lung. This is a rare inflammatory nonneoplastic condition commonly affecting children and young adults. PMID- 30455874 TI - Laparoscopic transabdominal preperitoneal repair of strangulated femoral hernia: Superiority of an unusual emergency surgical approach due to a case. AB - Introduction: Inguinal hernia repair is one of the most common operations of general surgery. In order to avoid complicated and urgent cases, performing such operations electively is generally accepted. Otherwise, unforeseen emergency surgical situations accompanied by incarceration and strangulation may occur. Case presentation: In this article, we present a 45-year-old female patient with strangulated femoral hernia repair that we performed using the laparoscopic transabdominal preperitoneal method, unlike other conventional methods. Discussion: Early diagnosis and elective surgical treatment have an important role in hernia surgery, especially due to increased morbidity and mortality. Laparoscopic inguinal hernia repair has developed in the recent years as a prominent method and nowadays it is performed much easier than the open method even in urgent and challenging cases. Conclusion: The transabdominal preperitoneal method has superiority over the conventional method in terms of ensuring that intestinal loop is visible during the strangulated femoral hernia repair and that the feeding of the intestine is intact. PMID- 30455875 TI - Malignant phyllodes tumor with metastases to lung, adrenal and brain: A rare case report. AB - Background: Phyllodes tumors are spectrum of tumors ranging from benign to malignant. Malignant spectrum pose a management challenge for clinicians due to high risks of recurrence and metastasis. Malignant phyllodes tumor with brain, lung and adrenal metastases at the same time is rare. Case presentation: A 37 years-old unmarried female presented with an ulcerated huge lump in left breast with severe bleeding. Trucut biopsy showed necrosis with spindle cell proliferation with atypia for which she underwent modified radical mastectomy with final diagnosis of malignant phyllodes tumor. Three months after surgery, patient presented with headache, which on further evaluation showed masses in lung, right adrenal and brain. Conclusion: We presented a rare case of malignant phyllodes tumor with clinical, imaging and histological findings with metastases to multiple sites early in course and poor outcome of the patient despite margin negative resection. PMID- 30455876 TI - Effect of HLA on development of asthma. AB - Background: Asthma is a disease characterized by a chronic inflammation of the airways caused by the interaction of genetic susceptibility with environmental factors. Inflammation and remodeling are critical components of asthma. It is shown that many genes are involved in the pathogenesis of asthma. Aim of study: To identify/compare the association between HLA-DRB1 alleles and development of asthma in a sample of Iraqi Arab Muslims. Patients and methods: A case-control study (forty patients and forty healthy control) was carried out in Medical city Teaching Hospital, Baghdad-Iraq. The study participants were patients with asthma consulted the hospital from September - 2013 to January - 2015. HLA DRB1genotyping was done using a panel of sequence-specific oligonucleotide probes (SSOP) using HLA-DRB1amplification and hybridization kits (SSO HLA type DRB1 plus and Mastermix for HLA type DRB1 Amp plus kits -Innogenetics-Belgium) using automated method by AutoLipa - 48Innogenetics-Belgum. Results: There was an increased frequency of HLADRB1*03:01:01 in control group compared with patients group (P = 0.009, Odds ratio = 0.1228, 95% CI: 0.0254-0.5930). Other allele like HLA-DRB1* 070101was significantly increased in asthmatic patients in compares with control group (P = 0.005, Odds ratio = 6.641, 95% CI: 1.7319-25.4657). Conclusions: HLA alleles have an effect on development asthma in patients with HLA-DRB1*070101 while HLADRB1* 030101 may have a protective effect in Iraqi Arab Muslims individuals against development of asthma. PMID- 30455877 TI - Evaluation of BCL2 and TNFalpha as mRNA biomarkers for monitoring the immune response in critically ill children. AB - Background: Hospital acquired infection (HAI) and multiple organ dysfunctions (MODS) remain a leading cause of death in pediatric intensive care unit (PICU) despite the great efforts to control it. Objective: Our objective was to assess the mRNA of TNFalpha and BCL2 for prediction of HAI and/or MODS in our community. Patients and methods: Fifty children, admitted to PICU, were included in the study after exclusion of cases of end-stage renal failure, end-stage liver failure and congenital immune deficiency. Serial Blood samples were collected for complete blood count (CBC) and other routine investigations. Gene expression of (TNFalpha and BCL2) was quantified using quantitative real time PCR (qRT-PCR). Centers of disease control (CDC) criteria were used to detect HAI, and organ failure index (OFI). Pediatric logistic organ dysfunction (PELOD) and pediatric risk of mortality (PRISM) scores were used for follow up. The results were compared between the group who acquired HAI and who didn't. Gene expression was tested with a ROC curve to detect its ability to predict HAI. Main results: The overall complication (HAI and/or MODS) rate was 52%, Complicated cases had a significantly longer duration of stay in PICU (0.002) and in overall hospital stay (p = 0.013) and a higher death rate (p = 0.000). On day1; TNFalpha, BCL2 and lymphocytic count were lower in patients who developed complications (p = 0.02, p = 0.000 and p = 0.04, respectively), all had the ability to predict the complications with AUC (0.7, 0.8 and 0.67 respectively). On day 4: TNFalpha and BCL2 returned to normal levels while the lymphocytic count still lower in complicated cases, p = 0.001 and AUC = 0.73. Conclusions: TNFalpha and BCL2 on admission can predict HAI and MODS (AUC = 0.7 and AUC = 0.8), but were of no use in the follow-up, however, the lymphocytic count is a rapid, easy and cheap test to assess the immune state with a good predictive and follow up values. PMID- 30455878 TI - Anesthetic and obstetric outcomes in pregnant women undergoing cesarean delivery according to body mass index: Retrospective analysis of a single-center experience. AB - Aim: To evaluate maternal, neonatal and anesthetic outcomes according to BMI in women undergoing cesarean section. Background: Increased incidence rates of obesity and morbid obesity have been reported in the United States. Pregnant obese patients are at increased risk of maternal and fetal complications, and obstetric and anesthetic management of these patients is especially challenging. Methods: A retrospective chart review of patients who underwent cesarean section in a single center between 2015 and 2016 was conducted. Anesthetic, obstetric and neonatal outcomes were analyzed in relation to levels of BMI. Results: Seven hundred and seventy one patients underwent cesarean section during the study period. The number of patients with normal BMI, obesity and morbid obesity was 213 (27.6%), 365 (47.3%) and 193 (25%), respectively. Sixty-one percent of the patients in morbidly obese group had at least one comorbidity (p < 0.01). We found no significant differences with respect to perioperative obstetric complications. Intraoperative blood loss was significantly higher in the morbidly obese group. Conclusion: Increasing BMI is associated with comorbidities such as hypertension and diabetes mellitus, and with increased intraoperative blood loss. We were unable to detect differences in other obstetric, anesthetic and neonatal outcomes. PMID- 30455879 TI - Effect of dietary arginine to lysine ratios on productive performance, meat quality, plasma and muscle metabolomics profile in fast-growing broiler chickens. AB - Background: Due to the important functions of arginine in poultry, it should be questioned whether the currently adopted dietary Arg:Lys ratios are sufficient to meet the modern broiler requirement in arginine. The present study aimed, therefore, to evaluate the effects of the dietary supplementation of L-arginine in a commercial broiler diet on productive performance, breast meat quality attributes, incidence and severity of breast muscle myopathies and foot pad dermatitis (FPD), and plasma and muscle metabolomics profile in fast-growing broilers. Results: A total of 1,170 1-day-old Ross 308 male chicks was divided into two experimental groups of 9 replicates each fed either a commercial basal diet (CON, digestible Arg:Lys ratio of 1.05, 1.05, 1.06 and 1.07 in each feeding phase, respectively) or the same basal diet supplemented on-top with crystalline L-arginine (ARG, digestible Arg:Lys ratio of 1.15, 1.15, 1.16 and 1.17, respectively). Productive parameters were determined at the end of each feeding phase (12, 22, 33, 43 d). At slaughter (43 d), incidence and severity of FPD and breast myopathies were assessed, while plasma and breast muscle samples were collected and analyzed by proton nuclear magnetic resonance-spectroscopy. The dietary supplementation of arginine significantly reduced cumulative feed conversion ratio compared to the control diet at 12 d (1.352 vs. 1.401, P < 0.05), 22 d (1.398 vs. 1.420; P < 0.01) and 33 d (1.494 vs. 1.524; P < 0.05), and also tended to improve it in the overall period of trial (1.646 vs. 1.675; P = 0.09). Body weight was significantly increased in ARG compared to CON group at 33 d (1,884 vs. 1,829 g; P < 0.05). No significant effect was observed on meat quality attributes, breast myopathies and FPD occurrence. ARG birds showed significantly higher plasma concentration of arginine and leucine, and lower of acetoacetate, glutamate, adenosine and proline. Arginine and acetate concentrations were higher, whereas acetone and inosine levels were lower in the breast of ARG birds (P < 0.05). Conclusions: Taken together, these data showed that increased digestible Arg:Lys ratio had positive effects on feed efficiency in broiler chickens probably via modulation of metabolites that play key roles in energy and protein metabolism. PMID- 30455880 TI - Dual-energy X-ray absorptiometry scans accurately predict differing body fat content in live sheep. AB - Background: There is considerable interest in implementing mobile scanning technology for on-farm body composition analysis on live animals. These experiments evaluated the use of dual energy X-ray absorptiometry (DXA) as an accurate method of total body fat measurement in live sheep. Results: In Exp. 1, visceral and whole body fat analysis was undertaken in sheep with body condition scores (BCS) in the range 2 to 3.25 (scale 1: thin to 5: fat). The relationship of BCS was moderately correlated with visceral fat depot mass (r = 0.59, P < 0.01, n = 24) and whole body fat (r = 0.70, P < 0.001, n = 24). In Exp. 2, sheep with BCS in the range 2.25 to 3.75 were blood sampled to analyse circulating leptin concentrations, and were DXA scanned immediately post mortem for total body fat. Plasma leptin concentrations had low correlations with BCS (r = 0.50, P < 0.05, n = 17) and DXA body fat (r = 0.42, P < 0.05, n = 17), and no correlation with chemical body fat (r = 0.17, P > 0.05, n = 9). There was a moderate correlation between DXA body fat and BCS (r = 0.70, P < 0.01, n = 17), and DXA body fat was highly correlated with chemical body fat (r = 0.81, P < 0.001, n = 9). In Exp. 3, a series of five DXA scans, at 8-week intervals, was performed on growing sheep over a 32-week period. The average BCS ranged from 2.39 +/- 0.07 (S.E.M.) to 3.05 +/- 0.11 and the DXA body fat (%) ranged from 16.8 +/- 0.8 to 24.2 +/- 1.2. There was a moderate correlation between DXA body fat and BCS over the 32 weeks (r = 0.61, P < 0.001, n = 24). Conclusions: Overall, these experiments indicated that there was good agreement between BCS, DXA and chemical analysis for measuring total body fat in sheep, and that DXA scanning is a valid method for longitudinal measurement of total body fat in live sheep. PMID- 30455881 TI - Investigating self-reported health by occupational group after a 10-year lag: results from the total Belgian workforce. AB - Background: Belgium lacks a systematic overview of health differences by occupation. This is the first study to examine self-reported health among 27 occupational groups in Belgium with a lag time of 10 years. Methods: Individual data are derived from an anonymous linkage between the 1991 and 2001 Belgian census. The total working population (25-55 years) is selected from the 1991 Belgian census. Self-reported health (1 = fair or (very) bad health; 0 = (very) good health) was obtained from the 2001 census. Logistic regression analysis was used to analyse the health of 1.5 million men and 1.0 million women by occupational group in 1991. The active sex-specific population in 1991 and 2001 was the reference group. Controls include age, activity status and housing status at the time of 2001 census. Results: Both male and female workers in physically demanding occupations were more likely to report poor health. The three occupations with the highest age-adjusted Odds Ratios (OR) were extraction and building trade workers (ORmale 2.08 95% Confidence Interval (CI) 2.05-2.10; ORfemale 2.15 CI 1.93-2.40); services elementary workers (ORmale 2.06 CI 2.03 2.10; ORfemale 2.37 CI 2.34-2.41); and labourers in construction, manufacturing and transport (ORmale 1.90 CI 1.86-1.93; ORfemale 2.21 CI 2.12-2.29). Men and women in teaching, scientific, health-related and managerial positions had the lowest age-adjusted ORs for poor self-reported health. The pattern in occupational health differences remained the same after controlling for activity status and socio-economic position. Conclusions: Occupational health inequalities are apparent after a lag time of 10 years. The identification of types of workers in poor health provide valuable insights to future health promotion strategies in the Belgian workforce. PMID- 30455882 TI - Assessment of knowledge and practices of healthcare workers towards infection prevention and associated factors in healthcare facilities of West Arsi District, Southeast Ethiopia: a facility-based cross-sectional study. AB - Background: The prevention of healthcare associated infections is central to the provision of safe, high quality healthcare. Infections acquired in healthcare facilities are a major public health concern, contributing to increased morbidity, mortality, and cost in both developed and developing countries. Although most of these infections can be prevented with relatively inexpensive infection prevention and control measures in many developing countries, in sub Saharan African healthcare facilities have no effective infection prevention programs. Additionally, there is limited information on healthcare worker infection prevention knowledge and practice in countries such as Ethiopia. The aim of this study was to assess the knowledge and practices of healthcare workers with respect to infection prevention and associated factors in healthcare facilities in southeast Ethiopia. Methods: A facility-based cross-sectional study design was used to study healthcare workers in the southeast, Ethiopia. Multi stage sampling was employed to select 680 healthcare workers from 30 randomly selected healthcare facilities. Data was collected using a self-administered structured questionnaire. Descriptive statistics were computed. Multivariable logistic regression was performed to identify factors associated with healthcare workers infection prevention knowledge and practice. Results: A total of 648 healthcare workers participated in this study, for a response rate of 95.3%. Of these, 53.7% (95% CI: 49.8, 57.4%) and 36.3% (95% CI: 32.4, 40.1%) of the respondents were assessed as knowledgeable and reported safe infection prevention practices respectively. The likelihood of self-reporting safe infection prevention practice significantly increased if healthcare workers had received training (AOR = 5.31; 95% CI: 2.42,11.63) and had infection prevention guidelines available (AOR = 3.34; 95% CI: 1.65, 6.76). Healthcare workers were more likely to have infection prevention knowledge if they worked longer ten years or more (AOR = 3.41; 95% CI: 1.22, 9.55); worked in facilities with infection prevention committees (AOR = 1.78; 95% CI: 1.01, 3.13), had infection prevention guidelines available (AOR = 2.44; 95% CI: 1.45, 4.12); had training (AOR = 5.02; 95% CI: 1.45, 8.59). Conclusions: Inadequate infection prevention knowledge and unsafe practices were frequent among study participants, reflecting a potentially common problem at public healthcare facilities in southeast Ethiopia. Healthcare workers have better knowledge and safer practices if they had received infection prevention training and had infection prevention guidelines in their workplace. Interventions should be designed to consider these identified factors. PMID- 30455884 TI - Efficacy of fecal microbiota transplantation in a patient with chronic intractable constipation. AB - We have presented the first case report of FMT therapy for a patient with chronic intractable constipation. This therapy resulted in good, medium-term outcomes. Follow-up analysis of the intestinal flora suggested that transplanted microbes from the donor, particularly Bifidobacterium and Clostridium cluster IX, may have been incorporated into the recipient. PMID- 30455883 TI - Implementing TB control in a rural, resource-limited setting: the stop-TB Italia project in Senegal. AB - Background: Since 2013 StopTB Italia Onlus supports the Senegalese National Tuberculosis Programme by improving diagnostic capability with technological interventions, ameliorating educational programs for health care personnel, rising awareness among civil society and providing economical support for patients during treatment. The purpose of our study was to assess the preliminary results of an interventional cooperation project in a peripheral health care facility in Senegal. Methods: An observational, retrospective, pre-post study was conducted to compare Tuberculosis (TB) retention in care and outcome between a one-year period before and a four-year period after. Results: Overall, 239 patients with active TB were included, 196 (82%) of whom after the starting of the collaboration project. At diagnosis 35/43(81.4%) vs 151/196 (77%) patients were smear sputum positive before and after the beginning of the project, respectively.At 2 months follow up 23/35 (65.7%) patients in 2012 vs. 139/151 (92%) patients in 2013-2016 had negative control AFB stain (p = 0.249), 4/35 (11.4%) vs 12/151 (8%) patients remained AFB stain positive (p = 0.17), 7/35 (20%) vs 0/151 died before the 2 months follow up (p < 0.0001). TB treatment outcome was more frequently favourable after the beginning of cooperation 29/43 (67.4%) vs. 176/196 (89.8%) patients, (p < 0.0001). Patients' mortality during treatment decreased from 8/43 (18.6%) in 2012 to 11/196 (5.6%) patients in the following years (p = 0.009). Conclusion: The implementation of diagnostic procedures, if integrated in a socio-economical intervention, impacts favourably on TB retention in care and treatment outcomes. PMID- 30455885 TI - A novel report of a primary Merkel cell carcinoma lesion in the nasal vestibule. AB - Merkel cell carcinoma (MCC) accounts for less than 1% of cutaneous malignancies. As the lesion may mimic benign entities, clinicians' differential should include rare entities to improve outcomes by early intervention. We present a case of primary MCC in the nasal vestibule requiring partial rhinectomy, suprahyoid lymphadenectomy, and radiation therapy. PMID- 30455886 TI - DNM1 Mutation in a child associated with progressive bilateral mesial temporal sclerosis. AB - This case represents a novel association of a DNM1 gene mutation with status epilepticus and progressive bilateral mesial temporal sclerosis. This could have future implications for treatment in patients with DNM1 mutation and refractory epilepsy as the mesial temporal sclerosis may become bilateral, making the patient a poor surgical candidate. PMID- 30455887 TI - Modified ex utero intrapartum treatment procedure in a bicornuate uterus breech presentation Pierre Robin fetus with severe micrognathia and cleft palate. AB - Thorough prenatal evaluation allows for identification of fetuses with compromised airway. The ex utero intrapartum treatment procedure enables maintaining uteroplacental circulation during cesarean section while securing a potentially obstructed fetal airway, converting a potentially catastrophic situation into a controlled one. An expert multidisciplinary team is the key to success. PMID- 30455888 TI - Systemic lupus erythematosus with refractory ulcerated livedoid vasculopathy: Successful treatment with intravenous immunoglobulin and warfarin. AB - We reported a patient with systemic lupus erythematosus complicated by livedoid vasculopathy (LV), who responded well to intravenous immunoglobulin and warfarin. Cutaneous lesions of LV resemble those of cutaneous vasculitis. LV should be included in the differential diagnosis of leg ulcerations even in the presence of autoimmune disorders. PMID- 30455889 TI - Successful management of critical iliac artery aneurysm which is unexpectedly accompanied by acute aortic dissection type B: A case report. AB - Acute aortic dissection with concurrent large aortic aneurysm is a catastrophic condition. Clinicians may be faced with the dilemma of how to manage these patients. This case reports a successful management crisis in a patient with a type B aortic dissection and a large left common iliac artery aneurysm. PMID- 30455890 TI - Congenital Zika syndrome phenotype in a child born in Brazil in December 2011. AB - We report a case of a Brazilian child born in 2011 with congenital Zika syndrome phenotype. Zika virus (ZIKV) may have been circulating in Brazil more than 4 years before the outbreak. ZIKV infection might be considered in children with this phenotype even without known circulation of ZIKV. PMID- 30455891 TI - BCR-ABL exon 7 deletion and novel point mutation in patient with chronic myelogenous leukemia and TKI resistance. AB - I report a novel BCR-ABL point mutation c.844G>C p.E282Q and a case of combination of two BCR-ABL point mutations (p.E282Q and p.L298R) and exon 7 deletion (del. c.1086-1270) in TKI-resistant patient. These point mutations were present only in a truncated transcript and were absent in "wild-type" BCR-ABL transcript. PMID- 30455892 TI - ReGeneraTing Agents (RGTA(r)) are a new option to improve amputation outcomes in the recovery of severe hand injuries. AB - CACIPLIQ20(r) was used to accelerate the healing process and stimulate the viability of flaps and skin grafts, thereby improving amputation outcomes. An excellent range of motion was achieved with hardly any contracture or scarring. Pain relief and reduced sensitivity was noted, while healing of bone and tendon also improved, resulting in functional recovery. PMID- 30455893 TI - Youngest presenting patient with dystonia 24 and review of the literature. AB - Dystonia 24 was first reported in 2000 as an autosomal dominant cause of dystonia caused by variants in the ANO3 gene. Although many adults have been described with dystonia 24, since 2014, an increasing number of children have also been reported. Dystonia 24 should also be considered in the differential of a child with unexplained dystonia. PMID- 30455894 TI - First detection and molecular characterization of a DENV-1/DENV-4 co-infection during an epidemic in Rio de Janeiro, Brazil. AB - In the 80s, dengue viruses type 1 and 4 (DENV-1 and 4) were isolated in North region of Brazil. However, it was only after the DENV-1 introduction in the state of Rio de Janeiro (RJ) in mid-1980s, that dengue became a nationwide public health problem. In 2009, this serotype re-emerged causing an explosive epidemic in the country. DENV-4 was first detected in RJ in 2011 and in 2012, and DENV-1 and 4 were co-circulating and responsible for a high number of cases notifications. Here, we describe the detection and molecular characterization of a DENV-1/4 co-infection in sample of 2012 in RJ. PMID- 30455895 TI - Splinting and mechanical disruption of the mitral valve apparatus by an endocardial left ventricular lead while delivering cardiac resynchronization therapy. AB - Splinting and mechanical disruption of the mitral valve apparatus is an important limitation of an endocardial left ventricular (LV) pacing lead. Further, long term data are required before this approach is more widely adopted. PMID- 30455896 TI - Malignant transformation of a spiradenoma with blaschkoid pattern. AB - Eccrine spiradenoma is a benign and rare adnexal tumor originating from cutaneous eccrine sweat glands. It usually presents as a solitary lesion. It can have different presentations, including a blaschkoid arrangement which is rare. Malignant transformation is possible and usually occurs after a long period of latency in multifocal types. PMID- 30455897 TI - A serious case of primary Raynaud's phenomenon in an infant. AB - We present a case of severe Raynaud phenomenon (RP) in an infant. The current strategy of RP treatment is incomplete; excluding secondary Raynaud phenomenon is vital as well. This case aims to help those with similar symptoms in the future by gathering data on cases. PMID- 30455898 TI - A case for expanding carrier testing to include actionable X-linked disorders. AB - A research study utilizing whole-genome sequence analysis for preconception carrier screening provided a genome-first detection of a severe de novo Factor VIII mutation in a woman with implications for pregnancy management and life saving interventions of her newborn son, and a challenge to the existing paradigm regarding carrier testing. PMID- 30455899 TI - Dentoalveolar fracture: A complication of extraction of upper left first molar. AB - The current trend of managing maxillary tuberosity fractures is traumatic and results in the loss of bone and teeth. Treatment options that chose to retain the fractured segments and teeth have been perceived to be unfavorable. This case report shows that maxillary tuberosity fractures can be treated conservatively. PMID- 30455900 TI - 54-cm enteric duplication cyst in a 13-year-old female. AB - Enteric duplication cyst is a very rare condition, the affected individual may be asymptomatic. It has serious complications, on top of which is a malignant transformation tendency. To avoid these complications, resection of the duplication seems to be mandatory, even if it is an incidental finding. PMID- 30455901 TI - Goltz syndrome in males: A clinical report of a male patient carrying a novel PORCN variant and a review of the literature. AB - Here, we report a novel mosaic mutation in the PORCN gene in a male Goltz syndrome patient. We also compare the phenotypes of all reported males with a confirmed molecular diagnosis. This report serves to further clarify the phenotype of Goltz syndrome and suggests that expression in males varies. PMID- 30455902 TI - Diagnostic pitfalls for GJB2-related hearing loss: A novel deletion detected by Array-CGH analysis in a Japanese patient with congenital profound hearing loss. AB - Here, we report a novel deletion (copy number variation: CNV) in the GJB2 gene observed in a Japanese hearing loss patient. The deleted segment started in the middle of the GJB2 gene, but the GJB6 gene remained intact. This partial deletion in the GJB2 gene highlights the need for further improvements in GJB2 screening. PMID- 30455903 TI - Unexpected discovery of hemoglobinopathy C/beta degrees thalassemia. AB - High performance liquid chromatography (HPLC) is the current method of choice for the detection of hemoglobinopathies and the quantification of A2 and fetal hemoglobin. We are describing a case where a double heterozygosity C/beta thalassemia was fortuitously identified, during assaying HBA1c, by HPLC. PMID- 30455904 TI - Can pulmonary sarcoidosis trigger a progressive multifocal leukoencephalopathy? Considerations from a case series and a review of literature. AB - Progressive multifocal leukoencephalopathy (PML) is a severe infectious brain disease with lethal outcome mainly seen in immunocompromised subjects. Herein, we describe a new form of PML with different outcome which was observed in patients suffering from systemic sarcoidosis. Thus, we raise the question whether preexisting sarcoidosis might predispose for or even trigger PML. PMID- 30455905 TI - Dosimetric advantages of stereotactic radiosurgery as a boost to adjuvant conventional radiotherapy in the setting of adenoid cystic carcinoma of the parotid with skull base invasion. AB - This study highlights gamma knife stereotactic radiosurgery (GK-SRS) as boost therapy in a patient with adenoid cystic carcinoma of the parotid involving the skull base and invasion of the facial nerve. Using GK-SRS, dose to the brainstem and temporal lobe were reduced when compared to less conformal radiotherapy techniques. PMID- 30455906 TI - Accuracy of mucosa supported guided dental implant surgery. AB - Implant deviation at platform and apex was comparable to that seen in similar studies, showing that Mucosa Supported Guided Dental Implant Surgery can be a safe implant placement technique. Implant diameter and length, bone density and density deviations showed moderate strong correlation with apical deviation. PMID- 30455907 TI - A case of rabies in a Kano brown doe. AB - This manuscript aims at creating awareness especially to livestock farmers and veterinarians/clinicians that rabies occurs in livestock species. Furthermore, clinicians should note that the viral load in dog bite cases by rabid dog can be reduced by vigorous washing and disinfection which may ultimately delay the clinical manifestation of rabies. PMID- 30455908 TI - Single incision VATS decortication for 3rd stage empyema. AB - The use of U-VATS should be preferred to conventional three-port VATS if skills are mastered as it causes less and single intercostal trauma. Moreover, it minimizes infection spread to the chest wall. We advocate the use of U-VATS as a routine approach in patient with empyema stage III for positive outcome. PMID- 30455909 TI - Successful treatment of heparin-induced thrombocytopenia with apixaban in a patient with chronic kidney disease requiring hemodialysis. AB - Heparin-induced thrombocytopenia (HIT) is a prothrombotic state that can affect patients with chronic kidney disease (CKD) on hemodialysis (HD). This case highlights the potential usefulness of apixaban therapy for patients with HIT and CKD on HD. PMID- 30455910 TI - Interdisciplinary recognizing and managing of drug-induced tardive oromandibular dystonia: two case reports. AB - Tardive dystonia is a risk factor in medical antipsychotic treatment. It often begins with repetitive involuntary jaw and tongue movements resulting in impaired chewing and detrimental effect on the dentition. The orofacial dysfunction may go unrecognized in a neurological setting. The diagnosis may be difficult so we suggest interdisciplinary collaboration. PMID- 30455911 TI - When occam's razor can fail- active mycobacteria infection and lung cancer: A case of neuroendocrine lung cancer diagnosed in the setting of refractory mycobacterium avium-intracellulare. AB - The link between Myobacterium avium-intracellulare and lung cancer remains underemphasized in literature. Our objective is to increase awareness of Myobacterium avium-intracellulare and coexisting lung cancer and to emphasize the need in establishing prevalence and specific testing guidelines in this patient population. PMID- 30455912 TI - Tuberculous colon perforation mimicking acute appendicitis: A case report and review of the literature. AB - Acute appendicitis is the most common surgical condition encountered in the pediatric age group but the clinical presentation could be misleading. This highlights the importance of exploratory laparotomy even in the absence of systemic manifestations in order not to miss a serious underlying pathology such as intestinal tuberculosis. PMID- 30455913 TI - Nonsurgical management of a large necrotic nasal tip wound using a viable cryopreserved placental membrane. AB - A large necrotic nasal wound with interdomal subcutaneous tissue loss and the exposed greater alar cartilage was managed conservatively with a placental allograft. This approach is an alternative to the complex staged surgical reconstructive procedures for poor surgical candidates, patients unwilling to undergo facial surgeries, or autologous nasal graft failures. PMID- 30455914 TI - Right-sided infective endocarditis in patients with uncorrected ventricular septal defect and patent ductus arteriosus: Two case reports. AB - Uncorrected left-to-right shunt congenital heart defect is a predisposing factor for infective endocarditis (IE), especially right-sided IE which has different clinical manifestations and complications from left-sided IE. Prompt diagnosis by means of transthoracic echocardiography and timely antibiotics management for IE are encouraged to prevent multiorgan failure and fatal pulmonary embolism. PMID- 30455915 TI - Anorectal melanoma treated with abdominoperineal resection. AB - The diagnosis of primary malignant melanoma of the anorectum is extremely rare and carries a very poor prognosis. While it is the third most common site of a primary melanoma, it accounts for <1% of anorectal malignancies. We present cases of anorectal melanoma treated with abdominoperineal resection. PMID- 30455916 TI - Induction of remission in autoimmune polyglandular syndrome type three (APS III): An old drug with new perspectives. AB - The autoimmune polyglandular syndrome is a sequential chain of autoimmune events. Whenever diagnosed, the clinician's target should be induction of remission and if possible hindering its progression especially if associated with refractory vitiligo, resistant Grave's, or unexplained hyperglycemia in T1DM. Azathioprine could be used for induction of remission in autoimmune polyglandular syndrome type three especially with vitiligo and autoimmune thyroiditis. PMID- 30455917 TI - Nivolumab-induced severe acute kidney injury with a long latent phase in a patient with non-small-cell lung cancer: A case report. AB - In the treatment of immunotherapy with immune checkpoint inhibitors, we often experience immune-related adverse event which manifest most frequently as a skin disorder, and very rarely as a renal disorder. In our manuscript, we report the case of a 71-year-old man with nivolumab-induced severe acute kidney injury (AKI) in which the time from treatment initiation to the onset of AKI was the longest among the previously reported cases (377 days). Prolonged follow-up is therefore warranted to detect late-onset AKI. PMID- 30455918 TI - Missense variants in TMEM67 in a patient with Joubert syndrome. AB - We present a patient with a clinical diagnosis of Joubert syndrome with COACH phenotype who carries two TMEM67 variants of uncertain significance (VUS). One VUS can be reclassified as "likely pathogenic" by adding clinical data. As genetic testing becomes more accessible, more VUS will require clinical correlation for accurate classification. PMID- 30455919 TI - Ablation of recurrent malignant idiopathic ventricular tachycardia: When proper diagnosis and success is a matter of contact. AB - Effective and stable contact between the catheter tip and the tissue is crucial for both mapping and lesion formation during cardiac ablation procedures. Contact force catheter may be not only a therapeutic approach to arrhythmias, but also a tool for achieving accurate characterization of the arrhythmic substrate. PMID- 30455920 TI - Membranous or membranous-like GN: A case report of massive proteinuria, positive serum with negative PLA2R on biopsy. AB - This case report represents primary membranous glomerulonephritis (MGN) with positive serum anti-PLA2R antibodies, 2+ positivity for IgG4 on immunofluorescence with routine fresh-frozen sections and negative PLA2R stain on biopsy. He was treated as primary MGN based on positive serum PLA2R and the absence of clinical symptoms or signs suggestive of any secondary MGN. PMID- 30455921 TI - A case of a tumor-like condition in the optic nerve head of a pig. AB - A tumor-like condition of the optic nerve head of unknown etiology was found in a domestic pig. Clinical and histological manifestations suggest that the unusual tumor-like condition is probably a variant of proliferative optic neuropathy caused by unknown nonspecific damage (perhaps trauma), which was received earlier. PMID- 30455922 TI - Cystic neutrophilic granulomatous mastitis with corynebacterium and staphylococcus mimicking breast carcinoma. AB - Cystic neutrophilic granulomatous mastitis (CNGM) is an increasingly recognized entity in the differential diagnosis of granulomatous inflammation involving the breast. We present the first case report of CNGM mimicking carcinoma of the breast with two mixed bacterial species as the causative pathogens (Corynebacterium and Staphylococcus spp.). PMID- 30455923 TI - Actinic comedonal plaque in skin of color: A case report. AB - Actinic comedonal plaque is a variant of Favre-Racouchot syndrome which is a complication of solar degeneration of the skin. It is common in skin types 1-4 and unknown to rare in skin of color. This case report should create an awareness of this disease so not to be missed. PMID- 30455924 TI - Arteriovenous malformation after punch biopsy clinically mimicking a basal cell carcinoma: Case report and review of literature. AB - Arteriovenous malformations (AVM's) of the skin can be acquired post blunt or penetrating trauma. They may clinically mimic basal cell carcinomas and other lesions with overlying telangiectasia. Specific clinical, dermoscopic, and histological clues differentiate these conditions. AVM's may progress to destructive lesions and early surgical intervention is key. PMID- 30455925 TI - Early experience of seven hepatocellular carcinoma cases treated with regorafenib. AB - Regorafenib became second-line treatment for the patients with sorafenib refractory. In our study, two patients could not continue regorafenib for its adverse effects. It was suggested that appropriate use criteria of regorafenib should be observed and manage adverse effects earlier. PMID- 30455926 TI - Extending the critical regions for mutations in the non-coding gene RNU4ATAC in another patient with Roifman Syndrome. AB - Compound heterozygosity of a previously described pathogenic variant and a second novel nucleotide substitution (NR_023343.1:n.116A>C) affecting a highly conserved nucleotide in the noncoding RNU4ATAC gene could be identified in a patient with overlapping features of Roifman Syndrome. These data extend the spectrum of pathogenic variants in RNU4ATAC. PMID- 30455927 TI - GATA4 variant identified by whole-exome sequencing in a Japanese family with atrial septal defect: Implications for male sex development. AB - We identified a heterozygous p.(R284H) variant of GATA4 in a Japanese family with atrial septal defect, including boys with apparently normal male sex development. The findings, together with the previous data, imply that GATA4 variants primarily cause congenital heart disease and rarely result in 46,XY disorder of sex development. PMID- 30455928 TI - Lithium improved behavioral and epileptic symptoms in an adolescent with ring chromosome 20 and bipolar disorder not otherwise specified. AB - We present a case of ring chromosome 20 syndrome in a twelve-year-old girl, with resistant epileptic disease and severe behavioral impairment that both drastically improved after a lithium challenge. If replicated, this could support the use of lithium as a safe treatment in the management of this severe phenotype. PMID- 30455929 TI - Severe cholestatic jaundice associated with Graves' disease. AB - We describe a rare case of Graves' disease presenting with atrial fibrillation and severe cholestasis. An extensive evaluation for hepatobiliary causes of cholestasis, including hepatic biopsy, was entirely negative. He was successfully treated with methimazole and eventual thyroidectomy. With caution, thionamides can be utilized successfully for such patients. PMID- 30455930 TI - B-cell lymphoblastic lymphoma of the nictitating membrane as the first presenting sign in a 2-year-old Springer Spaniel. AB - B-cell lymphoblastic lymphoma is an aggressive malignant disease. Necropsy and microscopical examination revealed widespread disease with a high proliferation index. This is the first reported case of B-cell lymphoblastic lymphoma presenting in the ocular region and only the second reported lymphoma of the nictitating membrane. PMID- 30455931 TI - Two unrelated patients with autosomal dominant omodysplasia and FRIZZLED2 mutations. AB - Presented are two patients with autosomal dominant omodysplasia and mutations in the FZD2 gene. The mutations identified have been recently reported, suggesting the possibility of recurrent mutations. The phenotypes of these patients overlap with what has been previously reported, though intellectual disability as seen in our patient is not typical. PMID- 30455932 TI - Identification of a de novo case of COL5A1-related Ehlers-Danlos syndrome in an infant in the West Indies leading to improved targeted clinical care. AB - A 1-year-old girl from an underserved community presented with irritability, pain, and delayed motor skills. Our genetics outreach program facilitated the diagnosis of Ehlers-Danlos syndrome masquerading as developmental delay after noting hyperextensible skin. Diagnosis for this family allows for state-of-the art cardiac monitoring and appropriate symptomatic treatment for this rare disease. PMID- 30455933 TI - Transcatheter aortic valve implantation in an orthotopic heart transplant recipient with bicuspid aortic valve. AB - Increasing longevity of heart transplantation recipients and aging donor population accompanied by the older age at transplantation led to an increase in the prevalence of degenerative valvular disease in particular aortic stenosis. TAVI is considered a safe and feasible alternative compared to conventional SAVR in this high-risk population. PMID- 30455934 TI - Successful institutional care for behavioral and psychological symptoms of dementia in a repopulated area after the 2011 Fukushima disaster: A case report. AB - Caregiving in a long-term facility played a key role in improvements of this patient's behavioral and psychological symptoms of dementia, which also led to a reduced caregiver burden on her family members. Considering the global population aging trend, the lesson from this case may apply to other settings beyond disasters. PMID- 30455935 TI - Seizure manifesting as a reaching/grasping movement in a patient with post traumatic epilepsy. AB - Electrical stimulation (ES) of the pre-supplementary or cingulate motor area can cause reaching/grasping (R/G) movements with the hand contralateral to the side of the brain receiving the ES. We report this phenomenon occurring in a 23-year old right-handed man during spontaneous epileptic seizure, which developed after traumatic brain injury. PMID- 30455936 TI - Gastroduodenal intussusception due to gastrointestinal stromal tumor. AB - Gastric GIST should be kept in mind in patients with gastric outlet obstruction. PMID- 30455937 TI - Clinical presentation and management of atraumatic splenic rupture. AB - Atraumatic splenic rupture is a rare, but well-documented and life-threatening clinical entity that is often misdiagnosed. Clinicians should include this entity in their differential diagnosis using clinical judgement even in the absence of a history of trauma. PMID- 30455938 TI - An evident asymmetrical uterus during cesarean delivery. AB - If an obstetrician determines the presence of an asymmetrical uterus during cesarean delivery, the likelihood of an interstitial pregnancy complicated by placenta accreta should be considered. The figures in this article should help advance the current knowledge about a rare type of full-term interstitial pregnancy complicated by placenta accreta. PMID- 30455939 TI - Papillary atrophy of the tongue. AB - Do not forget to give cobalamin supplementation after gastrectomy. Patients at risk of vitamin B12 deficiency should have their vitamin B12 level monitored routinely. PMID- 30455940 TI - Not all inflammation in a renal allograft is rejection. AB - High index of suspicion for adenovirus infection is required in renal graft dysfunction, especially in the setting of hematuria. Histology can mimic acute rejection, which creates a diagnostic dilemma. Tissue adenovirus immunostains, though usually reliable, may not be always positive like in our case. PMID- 30455941 TI - Idiopathic membranoproliferative glomerulonephritis treated with mycophenolate mofetil. AB - "Idiopathic" membranoproliferative glomerulonephritis (MPGN) is rare compared to secondary forms and usually a progressive disease. Studies evaluating the role of steroids were primarily done in children, and the data are sparse in adults. Mycophenolate mofetil is effective and can be used as a steroid-sparing agent in the treatment of idiopathicMPGN. PMID- 30455942 TI - 33-year-old HIV-positive patient presenting with primary effusion lymphoma. AB - Our patient presenting with symptoms of shortness of breath and fever, noncompliant with antiretroviral therapy was found to have a rare HIV-associated non-Hodgkin's lymphoma that carries a dismal prognosis. Early recognition of this condition with prompt treatment may provide a marginal benefit to the patient's overall life expectancy. PMID- 30455943 TI - Splenic mass in a case of CALR-mutated essential thrombocythemia. AB - We report here an intrasplenic large mass in an elderly case of essential thrombocythemia (ET)-myelofibrosis. Laparoscopic splenectomy revealed extramedullary hematopoiesis (EMH) and a type 1 CALR gene mutation (CALR c.1092_1143del52) in the splenic mass. It remains to be determined if CALR mutated ET has an increased tendency to develop mass-forming EMH. PMID- 30455944 TI - Sacral insufficiency fracture after stereotactic body radiation therapy for sacral metastasis. AB - Stereotactic body radiation therapy (SBRT) allows the targeting of high doses of radiation with steep dose gradients. Vertebral fracture is increasingly recognized as an adverse event after SBRT; however, no sacral fractures have been observed after SBRT. We report an extremely rare case of sacral insufficiency fracture after SBRT. PMID- 30455945 TI - Immunology beliefs as a factor in vaccine opposition among complementary and alternative medical providers. AB - Objectives: Parental pediatric vaccine decisions are influenced by parents' health provider networks. Complementary and alternative medical providers may be key influences in the networks of those parents who do not vaccinate their children. Methods: From March to July 2013, we conducted semi-structured interviews of Oregon complementary and alternative medical providers (N = 36) in five disciplines likely to treat parents or children, or both, and whose practitioners are known to express opinions about vaccines and vaccination. We interviewed them concerning their immunology beliefs, vaccine positions, and what these providers recommend to their patients concerning vaccines. We conducted face-to-face interviews and analyzed the interview data using thematic analysis methodology. Results: This article identifies the range and type of immunological beliefs of complementary and alternative medical providers concerning pediatric vaccine recommendations. From repeated readings of the data, we identified three areas of alternative immunological beliefs among complementary and alternative medical providers (i.e. "natural is best," "innate intelligence," and "the fragile immune system"). In addition, complementary and alternative medical providers who embraced mainstream medicine were likely to be vaccine accepters and to mention vaccines as a positive health measure to their patients-these themes were "vaccines prevent illness" and "herd immunity." Conclusion: Complementary and alternative medical providers influence their patients' vaccination decisions, particularly urging caution or complete vaccine avoidance, and may be a major influence in states like Oregon with high non-medical exemption rates. Complementary and alternative medical providers come to their anti-vaccine positions largely through post-graduation continuing education courses and seminars. In Oregon, such courses are unregulated and not vetted. PMID- 30455946 TI - End-user involvement in developing and field testing an online contraceptive decision aid. AB - Objectives: Decision aids in the field of healthcare contribute to informed decision making. To increase the usefulness and effectiveness of decision aids, it is important to involve end-users in the development of these tools. This article reports on the development of an online contraceptive decision aid. Methods: An exploratory, qualitative study was conducted in the Netherlands between 2014 and 2016. The development process of the decision aid consisted of six steps and included a needs assessment and field test. Interviews were conducted with 17 female students. Results: The needs assessment provided information on the preferred content and structure of a contraceptive decision aid and guided the development of the online contraceptive decision aid prototype. Participants had an overall positive impression of the decision aid prototype during the field test. Minor revisions were made based on participants' feedback. Participants expected that the decision aid would positively contribute to decision making by increasing knowledge and awareness regarding the available contraceptive methods and their features and attributes, and by opening up to other options than the known methods. Conclusion: The developed contraceptive decision aid can contribute to better informed decision making and consultation preparation. Involving end-users in development seems valuable to adapt decision aids to specific needs and to identify in what way a decision aid influences decision making. PMID- 30455948 TI - Use of immunohistochemical analysis of CK5/6, CK14, and CK34betaE12 in the differential diagnosis of solid papillary carcinoma in situ from intraductal papilloma with usual ductal hyperplasia of the breast. AB - Objectives: The aim of this study was to use immunohistochemistry to differentiate solid papillary carcinoma in situ from intraductal papilloma with usual ductal hyperplasia (IPUDH). Three types of high-molecular-weight cytokeratins (CKs) - CK5/6, CK14, and CK34betaE12 - were targeted. Methods: We studied 17 patients with solid papillary carcinoma in situ and 18 patients with IPUDH diagnosed by at least two pathologists. Immunohistochemical analyses used antibodies to CK5/6, CK14, and CK34betaE12 to make the differential diagnosis of solid papillary carcinoma in situ versus IPUDH. Immunohistochemical staining was scored as 0-5 using Allred score. Results: Immunohistochemistry with CK5/6 and CK14 antibodies produced scores of 0-3 in all patients with solid papillary carcinoma in situ and 2-5 in all patients with IPUDH. Immunohistochemical staining with CK34betaE12 antibody produced scores of 1-3 in all patients with solid papillary carcinoma and 3-5 in all patients with IPUDH. In tissues from patients with IPUDH, significantly more cells were stained with CK34betaE12 than CK5/6 (p < 0.05) or CK14 (p < 0.05). Conclusion: The immunoreactivity of CK5/6, CK14, and CK34betaE12 antibodies was useful to differentiate solid papillary carcinoma in situ from IPUDH. CK34betaE12 is especially useful for distinguishing solid papillary carcinoma from IPUDH. PMID- 30455947 TI - Anti-proliferative and anti-inflammatory activities of the sea cucumber Holothuria polii aqueous extract. AB - Objective: Sea cucumbers are considered among the most important functional foods. Following bioassay guided fractionation, we assessed the anti proliferative and anti-inflammatory activities of Holothuria polii (H. polii) extracts. Methods: Sea cucumber ethanolic extract and the partially purified aqueous fractions were assessed for their anti-proliferative activities. These latter bioactivities were evaluated in the highly invasive MDA-MB-231 human breast cancer cells in two-dimensional and three-dimensional cultures using trypan blue exclusion assay. The tumor-suppressive effects of sea cucumber ethanolic extract and aqueous fractions were assayed by measuring the trans-well invasion of MDA-MB-231 cells and the expression of some epithelial mesenchymal transition markers using quantitative reverse-transcription polymerase chain reaction and western blot analysis. The anti-inflammatory activity of the aqueous fraction was tested by measuring the secreted levels of interleukin-6, nitric oxide, and matrix metalloproteinase 9 in endotoxin-induced mammary epithelial SCp2 cells and interleukin-1beta in phorbol-12-myristate-13-acetate-activated human monocytic THP-1 cells. Results: Sea cucumber ethanolic extract and the aqueous fraction significantly decreased the proliferation of MDA-MB-231 cells by more than 50% at similar and noncytotoxic concentrations and caused an arrest in the S-phase of the cell cycle of treated cells. In contrast, petroleum ether, chloroform, ethyl acetate, and n-butanol organic fractions did not show any significant activity. Furthermore, sea cucumber ethanolic extract and aqueous fraction reduced the proliferation of MDA-MB-231 cells in three-dimensional cultures by more than 60% at noncytotoxic concentrations. In addition, treatment with these concentrations resulted in the loss of stellate outgrowths in favor of spherical aggregates and a 30% decrease in invasive properties. Both sea cucumber ethanolic extract and aqueous decreased the transcription of vimentin and the protein expression levels of vimentin and N-cadherin in three-dimensional cultures. The aqueous fraction decreased the levels of inflammatory markers interleukin-6, nitric oxide, and matrix metalloproteinase 9 in the mouse mammary SCp2 cells, and the level of interleukin-1beta produced by phorbol-12-myristate 13-acetate-activated THP-1 human monocytic cells. Conclusion: The data reveal for the first time promising anti-proliferative and anti-inflammatory activities in H. polii water extract in two-dimensional and three-dimensional culture models. PMID- 30455949 TI - Assessment of histopathology of wounds based on protein distribution detected by wound blotting. AB - Background: Shortening the duration of healing based on an accurate assessment is important in pressure ulcer management. This study focused on the peroxidase and alkaline phosphatase activity detected by wound blotting, a non-invasive method of collecting wound exudate, to establish a non-invasive and point-of-care assessment method for analyzing the histopathology of wounds using an animal model. Methods: Wounds were created on the dorsal skin of rats. Peroxidase and alkaline phosphatase activities in the wound exudate were detected by wound blotting on post-wounding days 1, 4, 7, and 10. Wound tissue was collected on the same sampling days. Peroxidase and alkaline phosphatase activity within the tissue and myeloperoxidase were visualized. Two types of peroxidase activities were detected by wound blotting: ring and non-ring signals. The histopathological features were compared between wounds with ring and non-ring signals. Results: The wounds with ring signals showed a high level of peroxidase activity, and histological analysis demonstrated that the secreted or deviated peroxidase activity originated from myeloperoxidase, indicating a strong inflammation reaction within the tissue. The histopathology of wounds related to the alkaline phosphatase signals was not identified. Conclusion: The results suggested that ring signals indicated a strong inflammatory reaction and that they could be used to assess non-visible inflammation. PMID- 30455950 TI - Probing the evolutionary robustness of two repurposed drugs targeting iron uptake in Pseudomonas aeruginosa. AB - Lay Summary: We probed the evolutionary robustness of two antivirulence drugs, gallium and flucytosine, targeting the iron-scavenging pyoverdine in the opportunistic pathogen Pseudomonas aeruginosa. Using an experimental evolution approach in human serum, we showed that antivirulence treatments are not evolutionarily robust per se, but vary in their propensity to select for resistance. Background and objectives: Treatments that inhibit the expression or functioning of bacterial virulence factors hold great promise to be both effective and exert weaker selection for resistance than conventional antibiotics. However, the evolutionary robustness argument, based on the idea that antivirulence treatments disarm rather than kill pathogens, is controversial. Here, we probe the evolutionary robustness of two repurposed drugs, gallium and flucytosine, targeting the iron-scavenging pyoverdine of the opportunistic human pathogen Pseudomonas aeruginosa. Methodology: We subjected replicated cultures of bacteria to two concentrations of each drug for 20 consecutive days in human serum as an ex vivo infection model. We screened evolved populations and clones for resistance phenotypes, including the restoration of growth and pyoverdine production, and the evolution of iron uptake by-passing mechanisms. We whole-genome sequenced evolved clones to identify the genetic basis of resistance. Results: We found that mutants resistant against antivirulence treatments readily arose, but their selective spreading varied between treatments. Flucytosine resistance quickly spread in all populations due to disruptive mutations in upp, a gene encoding an enzyme required for flucytosine activation. Conversely, resistance against gallium arose only sporadically, and was based on mutations in transcriptional regulators, upregulating pyocyanin production, a redox-active molecule promoting siderophore independent iron acquisition. The spread of gallium resistance was presumably hampered because pyocyanin-mediated iron delivery benefits resistant and susceptible cells alike. Conclusions and implications: Our work highlights that antivirulence treatments are not evolutionarily robust per se. Instead, evolutionary robustness is a relative measure, with specific treatments occupying different positions on a continuous scale. PMID- 30455951 TI - Influenza, evolution, and the next pandemic. AB - Mortality rates in influenza appear to have been shaped by evolution. During the 1918 pandemic, mortality rates were lower in children compared with adults. This mortality difference occurs in a wide variety of infectious diseases. It has been replicated in mice and might be due to greater tolerance of infection, not greater resistance. Importantly, combination treatment with inexpensive and widely available generic drugs (e.g. statins and angiotensin receptor blockers) might change the damaging host response in adults to a more tolerant response in children. These drugs might work by modifying endothelial dysfunction, mitochondrial biogenesis and immunometabolism. Treating the host response might be the only practical way to reduce global mortality during the next influenza pandemic. It might also help reduce mortality due to seasonal influenza and other forms of acute critical illness. To realize these benefits, we need laboratory and clinical studies of host response treatment before and after puberty. PMID- 30455952 TI - Promoting Endothelial Cell Affinity and Antithrombogenicity of Polytetrafluoroethylene (PTFE) by Mussel-Inspired Modification and RGD/Heparin Grafting. AB - When used as small-diameter vascular grafts (SDVGs), synthetic biomedical materials like polytetrafluoroethylene (PTFE) may induce thrombosis and intimal hyperplasia due to the lack of an endothelial cell layer. Modification of the PTFE in an aqueous solution is difficult because of its hydrophobicity. Herein, aiming to simultaneously promote endothelial cell affinity and antithrombogenicity, a mussel-inspired modification approach was employed to enable the grafting of various bioactive molecules like RGD and heparin. This approach involves a series of pragmatic steps including oxygen plasma treatment, dopamine (DA) coating, polyethylenimine (PEI) grafting, and RGD or RGD/heparin immobilization. Successful modification in each step was verified via Fourier transform infrared (FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS). Plasma treatment increased the hydrophilicity of PTFE, thereby allowing it to be efficiently coated with dopamine. Grafting of dopamine, RGD, and heparin led to an increase in surface roughness and a decrease in water contact angle due to increased surface energy. Platelet adhesion increased after dopamine and RGD modification, but it dramatically decreased when heparin was introduced. All of these modifications, especially the incorporation of RGD, showed favorable effects on endothelial cell attachment, viability, and proliferation. Due to strong cell-substrate interactions between endothelial cells and RGD, the RGD/heparin-grafted PTFE demonstrated high endothelial cell affinity. This facile modification method is highly suitable for all hydrophobic surfaces and provides a promising technique for SDVG modification to stimulate fast endothelialization and effective antithrombosis. PMID- 30455954 TI - Transbronchial lung cryobiopsy: a novel confirmatory tool to diagnose asbestos related pulmonary fibrosis. AB - Asbestosis is diagnosed with a combination of historical, clinical and radiological findings in the absence of another cause. Histology is required when uncertainty exists, with lung biopsy via VATs being gold standard. Transbronchial cryobiopsy is becoming increasingly popular for diagnosing interstitial lung disease and may provide sufficient lung sample to demonstrate asbestosis. A 73 year old man presented with dyspnoea on a background of rheumatoid arthritis, previous methotrexate use and asbestos exposure. Examination revealed fine crackles in the mid and lower zones bilaterally without signs of pulmonary hypertension. The presence of pleural plaques and basal interstitial reticulation on HRCT was suggestive of asbestosis but histology was required to differentiate this from rheumatoid or methotrexate associated ILD. Samples of lung tissue were obtained via transbronchial cryobiopsy, demonstrating fibrosis and asbestos fibres consistent with asbestosis. Transbronchial cryobiopsy appears effective in obtaining sufficient parenchymal lung samples to diagnose asbestosis when clinical uncertainty exists. PMID- 30455955 TI - Gastric perforation related to concurrent use of nintedanib and ramucirumab. AB - The prevalence of lung cancer in idiopathic pulmonary fibrosis (IPF) patients ranges from 9.8 to 38%. Nintedanib, a small molecule receptor tyrosine kinase inhibitor (TKI) of platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and vascular endothelial growth factor receptor (VEGFR), has been approved for IPF after phase III INPULSIS trials in 2014. Ramucirumab, a monoclonal antibody for VEGFR-2, combined with docetaxcel, has been approved for advanced non-small cell lung cancer (NSCLC) after the phase III REVEL trail in 2014. Physicians will have more IPF patients being treated with nintedanib, who subsequently develop NSCLC, and therefore will likely be treated with ramucirumab plus docetaxel. We report the first case of 70-year-old man taking nintedanib for his IPF and treated with ramucirumab plus docetaxel as a seventh-line therapy for his pulmonary adenocarcinoma. On day 15 of his chemotherapy treatment cycle 2, after taking nintedanib for nine days, he developed gastric perforation. PMID- 30455953 TI - Molecular landscape and targeted therapy of acute myeloid leukemia. AB - For decades, genetic aberrations including chromosome and molecular abnormalities are important diagnostic and prognostic factors in acute myeloid leukemia (AML). ATRA and imatinib have been successfully used in AML and chronic myelogenous leukemia, which proved that targeted therapy by identifying molecular lesions could improve leukemia outcomes. Recent advances in next generation sequencing have revealed molecular landscape of AML, presenting us with many molecular abnormalities. The individual prognostic information derived from a specific mutation could be modified by other molecular lesions. Therefore, the genomic complexity in AML poses a huge challenge to successful translation into more accurate risk stratification and targeted therapy. Herein, a summary of these mutations and targeted therapies are described. We focus on the prognostic information of recent identified molecular lesions and emerging targeted therapy. PMID- 30455956 TI - Reactive oxygen species generation is likely a driver of copper based nanomaterial toxicity. AB - Determining the specific nanomaterial features that elicit adverse biological responses is important to inform risk assessments, develop targeted applications, and rationally design future nanomaterials. Embryonic zebrafish are often employed to study nanomaterial-biological interactions, but few studies address the role of the chorion in nanomaterial exposure and toxicity. Here, we used chorion-intact (CI) or dechorionated (DC) embryonic zebrafish to investigate the influence of the chorion on copper-based nanoparticle toxicity. We found that despite higher dissolution and uptake, CuO NPs were less toxic than Cu NPs regardless of chorion status and did not cause 100 % mortality at even the highest exposure concentration. The presence of the chorion inhibited Cu toxicity: DC exposures to Cu NPs had an LC50 of 2.5 +/- 0.3 mg/L compared to a CI LC50 of 13.7 +/- 0.8 mg/L. This highlights the importance of considering zebrafish chorion status during nanotoxicological investigations, as embryo sensitivity increased by one order of magnitude or more when chorions were removed. Agglomerate size, zeta potential, and dissolved Cu did not sufficiently explain the differences in toxicity between Cu NPs and CuO NPs; however, reactive oxygen species (ROS) generation did. Cu NPs generated ROS in a concentration dependent manner, while CuO did not and generated less than Cu NPs. We believe that the differences between the toxicities of Cu NPs and CuO NPs are due in part to their ability to generate ROS which could and should be a hazard consideration for risk assessments. PMID- 30455957 TI - Acute glycemic control in diabetics. How sweet is oprimal? Pro: Sweeter is better in diabetes. AB - Background: The optimal level of glycemic control in ICU patients has been the subject of intense investigation over the last 20 years. A pivotal study (the NICE-SUGAR study) involving more than 6,000 patients has established a target between 8 and 10 mmol/l (144 to 180 mg/dl) as the current standard of care. However, this study did not address whether patients with diabetes should be treated differently and, in particular, whether in such patients a higher glucose target should be used. Main concepts: The last decade has seen multiple studies aiming to describe the association between glycemia in mortality according to whether patients have or do not have diabetes and whether, if they have diabetes, pre-ICU admission glucose control (assessed by glycated hemoglobin A1c (HbA1c) levels) affects the relationship between acute glycemia and outcome. All such studies (now involving thousands and thousands of patients) have consistently shown that diabetic patients have a different relationship between acute glycemia and mortality. In particular, in diabetic patients, increasing glucose levels up to 15 mmol/l (270 mg/dl) or more are not associated with increased risk of death. In patients with a high HbA1c (> 7%) prior to ICU admission, targeting a glucose level below 10 mmol/l (180 mg/dl) is associated with increased risk compared with permissive hyperglycemia. Finally, a recent controlled study comparing a glucose target between 10 and 14 mmol/l (180 to 252 mg/dl) to a glucose target between 6 and 10 mmol/l (180 mg/dl) in diabetic patients found no advantage from tighter glycemia control. A randomized controlled study called LUCID is now underway to test the hypothesis that permissive hyperglycemia might be safer in diabetic patients admitted to the ICU. Conclusions: Until the results of the LUCID trial are available, the burden of evidence is in favour with targeting a more relaxed level of glycemia in diabetic patients (10-14 mmol/l; 180-252 mg/dl), especially in those with poor pre-admission glycemic control. PMID- 30455958 TI - Natural language processing-based assessment of consistency in summaries of product characteristics of generic antimicrobials. AB - To investigate consistency in summaries of product characteristics (SmPCs) of generic antimicrobials, we used natural language processing (NLP) to analyze and compare large amounts of text quantifying consistency between original and generic SmPCs. We manually compared each section of generic and original SmPCs for antimicrobials listed in the electronic Medicines Compendium in the United Kingdom, focusing on omissions and additions of clinically significant information (CSI). Independently, we quantified differences between the original and generic SmPCs using Kachako, a fully automatic NLP platform. Among the 137 antimicrobials listed in the electronic Medicines Compendium, we identified 193 pairs of original and generic antimicrobial SmPCs for the 48 antimicrobials for which generic SmPCs existed. Of these 193 pairs, 157 (81%) were consistent and 36 were inconsistent with the original SmPC. When the cut-off value of RATE (the index of similarity between two SmPCs) was set at 0.860, our NLP system effectively discriminated consistent generic SmPCs with a specificity of 100% and a sensitivity of 61%. We observed CSI omissions but not additions in the SmPC subsection related to pharmacokinetic properties. CSI additions but not omissions were found in the subsections dealing with therapeutic indications and fertility, pregnancy and lactation. Despite regulatory guidance, we observed substantial inconsistencies in the information in the United Kingdom SmPCs for antimicrobials. NLP technology proved to be a useful tool for checking large numbers of SmPCs for consistency. PMID- 30455959 TI - Oral administration of the selective GPR120/FFA4 agonist compound A is not effective in alleviating tissue inflammation in mouse models of prototypical autoimmune diseases. AB - omega3-polyunsaturated free fatty acids (omega3-PUFAs), particularly docosahexaenoic (DHA) and eicosapentaenoic acid (EPA), are thought to exert health promoting effects in metabolic and in inflammatory diseases. The molecular mechanisms of these beneficial effects are only partially understood. DHA and EPA activate Free Fatty Acid receptor 4 (GPR120/FFA4). Recently, the first orally available, synthetic ligand of FFA4, 3-[2-chloro-5-(trifluoromethoxy)phenyl]-3 azaspiro[5.5]undecane-9-acetic acid ("compound A"; cpd A) has been developed. Cpd A exhibits distinctly higher potency, efficiency, and selectivity at FFA4 than omega3-PUFAs and ameliorates insulin resistance and adipose tissue inflammation in the mouse. With GPR120/FFA4 activation believed to also attenuate tissue inflammation in autoimmune diseases, cpd A may also have a beneficial effect in these diseases. We have therefore addressed the therapeutic potential of cpd A in mouse models of three prototypical autoimmune diseases, specifically psoriasis, rheumatoid arthritis, and bullous pemphigoid. The effect of cpd A on the course of AldaraTM-induced psoriasis-like dermatitis, K/BxN serum transfer arthritis, and antibody transfer pemphigoid disease-like dermatitis was scrutinized. Cpd A did not alter the course of Aldara-induced psoriasis-like dermatitis, K/BxN serum transfer arthritis, or antibody transfer pemphigoid disease-like dermatitis. Our results suggest that therapeutic regimens solely relying on FFA4 activation do not bear the potential to treat inflammatory diseases. With cpd A distinctly more potent in activating GPR120/FFA4 than omega3-PUFAs, this also suggests that GPR120/FFA4 activation by omega3-PUFAs does not significantly contribute to the health-promoting effects of omega3-PUFAs in autoimmune diseases. PMID- 30455962 TI - Improving patient safety in developing countries - moving towards an integrated approach. AB - Patient safety is a major public health issue. It has also been recognised as an area for improvement. The purpose of this article is to discuss the need for developing an integrated approach to patient safety improvement in developing countries. Relevant literature to identify the common themes and patterns associated with patient safety improvement was conducted through a search of the online databases (MEDLINE, EMBASE, PUBMED and Google Scholar) for the years 2000 to 2017. Lessons and interventions from developed countries have been taken into consideration to identify the themes needed for patient safety improvement in developing countries. This review provides an integrated approach based on best practice which can be used to guide the development of a national strategy for improving patient safety. Policy makers need to focus on developing a holistic and comprehensive approach to patient safety improvement that takes into account the themes discussed in this article. PMID- 30455961 TI - Prevalence, types and determinants of anemia among pregnant women in Sudan: a systematic review and meta-analysis. AB - Background: Anemia during pregnancy is a public health problem especially in developing countries and it is associated with maternal and perinatal adverse outcomes. There is no meta-analysis on anemia during pregnancy in Sudan. The current systemic review and meta-analysis was conducted to assess the prevalence, types and determinant of anemia during pregnancy in Sudan. Methods: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed. The databases (PubMed, Cochrane Library, Google Scholar, CINAHL, and African Journals Online) were searched using; anemia, pregnancy related anemia and Sudan. Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) and Modified Newcastle - Ottawa quality assessment scale were used for critical appraisal of studies. The pooled Meta logistic regression was computed using OpenMeta Analyst software. Results: Sixteen cross-sectional studies included a total of 15, 688 pregnant women were analyzed. The pooled prevalence of anemia among pregnant women in Sudan was 53.0% (95%, CI = 45.9-60.1). The meta-analysis showed no statistical significant between the age (mean difference = 0.143, 95 CI = - 0.033 - 0.319, P = 0.112), parity (mean difference = 0.021, 95% CI = - 0.035 - 0.077, P = 0.465) between the anemic and no anemic women. Malaria was investigated in six studies. Pregnant women who had malaria infection during pregnancy were 1.94 times more likely to develop anemia than women who had no malaria infection (OR = 1.94, 95% CI =1.33 2.82). Six (37.5%) studies investigated type of anemia. The pooled prevalence of iron deficiency anemia (IDA) among pregnant women in Sudan was 13.6% (95% CI = 8.9-18.2). Conclusion: There is a high prevalence of anemia among pregnant in the different region of Sudan. While age and parity have no association with anemia, malaria infection was associated with anemia. Interventions to promote the strengthening of antenatal care, and access and adherence to nutrition, and malaria preventive measures are needed to reduce the high level of anemia among pregnant women in Sudan. PMID- 30455960 TI - Cellular density-dependent increases in HIF-1alpha compete with c-Myc to down regulate human EP4 receptor promoter activity through Sp-1-binding region. AB - The up-regulated expression of E-type prostanoid (EP) 4 receptors has been implicated in carcinogenesis; however, the expression of EP4 receptors has also been reported to be weaker in tumor tissues than in normal tissues. Indeed, EP4 receptors have been suggested to play a role in the maintenance of colorectal homeostasis. This study aimed to examine the underlying mechanisms/reasons for why inconsistent findings have been reported regarding EP4 receptor expression levels in homeostasis and carcinogenesis by focusing on cellular densities. Thus, the human colon cancer HCA-7 cells, which retain some functional features of normal epithelia, and luciferase reporter genes containing wild-type or mutated EP4 receptor promoters were used for elucidating the cellular density-dependent mechanisms about the regulation of EP4 receptor expression. In silico analysis was also utilized for confirming the relevance of the findings with respect to colon cancer development. We here demonstrated that the expression of EP4 receptors was up-regulated by c-Myc by binding to Sp-1 under low cellular density conditions, but was down-regulated under high cellular density conditions via the increase in the expression levels of HIF-1alpha protein, which may pull out c-Myc and Sp-1 from DNA-binding. The tightly regulated EP4 receptor expression mechanism may be a critical system for maintaining homeostasis in normal colorectal epithelial cells. Therefore, once the system is altered, possibly due to the transient overexpression of EP4 receptors, it may result in aberrant cellular proliferation and transformation to cancerous phenotypes. However, at the point, EP4 receptors themselves and their mediated homeostasis would be no longer required. PMID- 30455963 TI - A delayed diagnosis of Pallister-Hall syndrome in an adult male following the incidental detection of a hypothalamic hamartoma. AB - Pallister-Hall syndrome is a rare autosomal dominant condition that is associated with polydactyly and hypothalamic hamartoma and is caused predominantly by frameshift or nonsense pathogenic variants in the GLI3 gene. The majority of cases are identified during childhood; however, rare reports of diagnoses during adulthood exist. Here, we describe the identification of a novel nonsense GLI3 pathogenic variant in an adult male following the incidental detection of a hypothalamic hamartoma. PMID- 30455965 TI - Gender-informed psycho-educational programme to promote respectful relationships and reduce postpartum common mental disorders among primiparous women: long-term follow-up of participants in a community-based cluster randomised controlled trial. AB - Background: What Were We Thinking (WWWT) is a gender-informed, psychoeducational programme to promote respectful relationships and skilled management of unsettled infant behaviours and thereby reduce postpartum common mental disorders. It comprises a highly structured seminar for couples and babies, usual primary care from a WWWT-trained nurse and take-home print materials. The aim was to assess long-term outcomes after a cluster randomised controlled trial of WWWT. Method: Trial participants who consented completed a computer-assisted telephone interview 18 months postpartum. Depressive symptoms were assessed with the Patient Health Questionnaire (PHQ-9) and anxiety symptoms with the Generalised Anxiety Disorder Scale (GAD-7). Impacts of baseline characteristics and trial arm on changes in scores from baseline to follow-up were calculated using Conditional Latent Growth Curve Models adjusting for prognostic indicators and controlling for clustering effects. Results: Overall, 314/400 (78.5%) women contributed data at baseline (6 weeks postpartum), trial endline (26 weeks postpartum) and follow up (12 months after trial endline). In intention-to-treat analyses, there was a significantly greater improvement in adjusted GAD-7 scores [regression coefficient (RC) -0.55; 95% confidence interval (CI) -0.94 to -0.17] and non significant improvement (RC -0.27; 95% CI -0.63 to 0.08) in PHQ-9 scores from baseline to follow-up in the intervention than the control arm. In a per-protocol analysis, the proportion with GAD-7 scores ?4 (asymptomatic) improved 24.1% (55.7% baseline to 79.8% follow-up, p = 0.043) among women who received the full WWWT programme, which included the seminar, compared with 2.4% (77.1-79.5%, p = 0.706) among those who received the partial intervention (usual care from WWWT trained nurse and print materials). Conclusions: The WWWT programme has a significant sustained beneficial impact on postnatal generalised anxiety among primiparous women compared with usual care. The in-person seminar is the most influential component of the intervention. Psycho-educational programmes integrated into primary care appear promising as a strategy to reduce postpartum common mental disorders. PMID- 30455964 TI - Does mhGAP training of primary health care providers improve the identification of child- and adolescent mental, neurological or substance use disorders? Results from a randomized controlled trial in Uganda. AB - Background: Integrating child and adolescent mental health (CAMH) into primary health care (PHC) using the WHO mental health gap action program (mhGAP) is recommended for closing a mental health treatment gap in low- and middle-income countries, but PHC providers have limited ability to detect CAMH disorders. We aimed to evaluate the effect of PHC provider mhGAP training on CAMH disorder identification in Eastern Uganda. Methods: Thirty-six PHC clinics participated in a randomized controlled trial which compared the proportion of intervention (n = 18) to control (n = 18) clinics with a non-epilepsy CAMH diagnosis over 3 consecutive months following mhGAP-oriented CAMH training. Fisher's exact test and logistic regression based on intention to treat principles were applied. (clinicaltrials.gov registration NCT02552056). Results: Nearly two thirds (63.8%, 23/36) of all clinics identified and recorded at least one non-epilepsy CAMH diagnosis from 40 692 clinic visits of patients aged 1-18 recorded over 4 months. The proportion of clinics with a non-epilepsy CAMH diagnosis prior to training was 27.7% (10/36, similar between study arms). Training did not significantly improve intervention clinics' non-epilepsy CAMH diagnosis (13/18, 72.2%) relative to the control (7/18, 38.9%) arm, p = 0.092. The odds of identifying and recording a non-epilepsy CAMH diagnosis were 2.5 times higher in the intervention than control arms at the end of 3 months of follow-up [adj.OR 2.48; 95% CI (1.31 4.68); p = 0.005]. Conclusion: In this setting, mhGAP CAMH training of PHC providers increases PHC clinics' identification and reporting of non-epilepsy CAMH cases but this increase did not reach statistical significance. PMID- 30455966 TI - Burden of depressive symptoms and non-alcohol substance abuse; and their association with alcohol use and partner violence: a cross-sectional study in four sub-Saharan Africa countries. AB - In sub-Saharan Africa, there are limited data on burden of non-alcohol substance abuse (NAS) and depressive symptoms (DS), yet potential risk factors such as alcohol and intimate partner violence (IPV) are common and NAS abuse may be the rise. The aim of this study was to measure the burden of DS and NAS abuse, and determine whether alcohol use and IPV are associated with DS and/or NAS abuse. We conducted a cross-sectional study at five sites in four countries: Nigeria (nurses), South Africa (teachers), Tanzania (teachers) and two sites in Uganda (rural and peri-urban residents). Participants were selected by simple random sampling from a sampling frame at each of the study sites. We used a standardized tool to collect data on demographics, alcohol use and NAS use, IPV and DS and calculated prevalence ratios (PR). We enrolled 1415 respondents and of these 34.6% were male. DS occurred among 383 (32.3%) and NAS use among 52 (4.3%). In the multivariable analysis, being female (PR = 1.49, p = 0.008), NAS abuse (PR = 2.06, p = 0.02) and IPV (PR = 2.93, p < 0.001) were significantly associated with DS. Older age [odds ratio (OR) = 0.31, p < 0.001)], female (OR = 0.48, p = 0.036) were protective of NAS but current smokers (OR = 2.98, p < 0.001) and those reporting IPV (OR = 2.16, p = 0.024) were more likely to use NAS. Longitudinal studies should be done to establish temporal relationships with these risk factors to provide basis for interventions. PMID- 30455967 TI - Parents' use of harsh punishment and young children's behaviour and achievement: a longitudinal study of Jamaican children with conduct problems. AB - Introduction: Harsh punishment by parents is common in low- and middle-income countries (LMIC), yet there is limited evidence from LMIC of the effects of harsh punishment on child outcomes. Methods: A longitudinal, prospective study was conducted with children with conduct problems to examine the associations between parents' use of harsh punishment during the preschool years on child behaviour and school achievement in grade one of primary school. As part of an efficacy trial in 24 preschools, 225 children with the highest level of teacher-reported conduct problems were evaluated and their parents reported on how often they used harsh punishment. Outcome measures in grade one included child conduct problems by independent observation, teacher and parent report, child social skills by teacher and parent report, direct tests of children's academic achievement and language skills, and tester ratings of child attention and impulse control. Results: Children had a mean age of 6.92 years and 61% were boys. All parents reported using harsh punishment. After controlling for child age and sex, socio economic status, parents' involvement with child and maternal education, frequency of harsh punishment was associated with growth in child conduct problems by independent classroom observations (p = 0.037), parent (p = 0.018) and teacher (p = 0.044) report, a reduction in child social skills by teacher (p = 0.024) and parent (p = 0.014) report and poorer attention during the test session (p = 0.049). Conclusion: The associations between frequency of parents' use of harsh punishment with their preschoolers with conduct problems and later child behaviour indicate a need to train parents in non-violent behaviour management. PMID- 30455969 TI - Building global mental health research capacity: the collaborative hubs for international research on mental health. PMID- 30455968 TI - Correlates of expected eMental Health intervention uptake among Filipino domestic workers in China. AB - Background: Transnational migrant populations face critical barriers to mental health service utilization that perpetuate mental health disparities globally. Overseas Filipino workers (OFWs) number over 2 million globally and 25% are female domestic workers. Structural barriers prevent equitable access to mental health services for this population. Electronic mental health (eMental Health) intervention is a scalable alternative to face-to-face treatment. The current study sought to identify key correlates of intention to use eMental Health within a community of female Filipino domestic workers living and working in Macao (SAR), China. Methods: Respondent-driven sampling implemented at a community field site was used to reach a sample of 1364 female domestic workers. A multivariable adjusted partial proportional-odds (PPO) model was used to assess relevant correlates of intent to use eMental Health. Results: The majority (62.8%) reported being likely to utilize eMental Health. The adjusted PPO model showed that younger age (18-25, 26-35, 36-45 v. over 55), longer time as an OFW, being likely (v. neutral and unlikely) to seek professional services, willingness to pay for services (v. not), belief that mental health services are a priority (v. low priority), having access to Wi-Fi outside the employer's home (v. not), and higher levels of social support were associated with increased odds of intent to use eMental Health. Conclusions: eMental Health is a promising intervention with high potential for uptake among OFWs. The majority of the study population owned a smartphone and were able to connect to the Internet or Wi-Fi. Future work will rigorously evaluate eMental Health programs for use among OFWs. PMID- 30455970 TI - The Cedar Project: exploring determinants of psychological distress among young Indigenous people who use drugs in three Canadian cities. AB - Background: Mental health and wellbeing, including addressing impacts of historical trauma and substance use among young people, has been identified as a key priority by Indigenous communities and leaders across Canada and globally. Yet, research to understand mental health among young Indigenous people who have used drugs is limited. Aims: To examine longitudinal risk and strengths-based factors associated with psychological distress among young Indigenous people who use drugs. Method: The Cedar Project is an ongoing cohort study involving young Indigenous people who use drugs in Vancouver, Prince George, and Chase, British Columbia, Canada. This study included participants who completed the Symptom Checklist-90-Revised, returned for follow-up between 2010 and 2012, and completed the Childhood Trauma Questionnaire. Adjusted linear mixed-effects models estimated effects of study variables on changes in area T-scores of psychological distress. Results: Of 202 eligible participants, 53% were women and the mean age was 28 years. Among men, childhood maltreatment (emotional abuse, physical abuse, sexual abuse, physical neglect), any drug use, blackouts from drinking, and sex work were associated with increased distress. Among women, childhood maltreatment (emotional abuse, physical abuse, physical neglect), blackouts from drinking, and sexual assault were associated with increased distress, while having attempted to quit using drugs was associated with reduced distress. Marginal associations were observed between speaking their traditional language and living by traditional culture with lower distress among men. Conclusion: Culturally safe mental wellness interventions are urgently needed to address childhood trauma and harmful coping strategies that exacerbate distress among young Indigenous people who use drugs. PMID- 30455971 TI - Culture and mental health in Nepal: an interdisciplinary scoping review. AB - Efforts to address global mental health disparities have given new urgency to longstanding debates on the relevance of cultural variations in the experience and expression of distress for the design and delivery of effective services. This scoping review examines available information on culture and mental health in Nepal, a low-income country with a four-decade history of humanitarian mental health intervention. Structured searches were performed using PsycINFO, Web of Science, Medline, and Proquest Dissertation for relevant book chapters, doctoral theses, and journal articles published up to May 2017. A total of 38 publications met inclusion criteria (nine published since 2015). Publications represented a range of disciplines, including anthropology, sociology, cultural psychiatry, and psychology and explored culture in relation to mental health in four broad areas: (1) cultural determinants of mental illness; (2) beliefs and values that shape illness experience, including symptom experience and expression and help-seeking; (3) cultural knowledge of mental health and healing practices; and (4) culturally informed mental health research and service design. The review identified divergent approaches to understanding and addressing mental health problems. Results can inform the development of mental health systems and services in Nepal as well as international efforts to integrate attention to culture in global mental health. PMID- 30455972 TI - In vitro rumen fermentation kinetics, metabolite production, methane and substrate degradability of polyphenol rich plant leaves and their component complete feed blocks. AB - Background: This experiment aimed at assessing polyphenol-rich plant biomass to use in complete feed making for the feeding of ruminants. Methods: An in vitro ruminal evaluation of complete blocks (CFB) with (Acacia nilotica, Ziziphus nummularia leaves) and without (Vigna sinensis hay) polyphenol rich plant leaves was conducted by applying Menke's in vitro gas production (IVGP) technique. A total of six substrates, viz. three forages and three CFBs were subjected to in vitro ruminal fermentation in glass syringes to assess gas and methane production, substrate degradability, and rumen fermentation metabolites. Results: Total polyphenol content (g/Kg) was 163 in A. nilotica compared to 52.5 in Z. nummularia with a contrasting difference in tannin fractions, higher hydrolysable tannins (HT) in the former (140.1 vs 2.8) and higher condensed (CT) tannins in the later (28.3 vs 7.9). The potential gas production was lower with a higher lag phase (L) in CT containing Z. nummularia and the component feed block. A. nilotica alone and as a constituent of CFB produced higher total gas but with lower methane while the partitioning factor (PF) was higher in Z. nummularia and its CFB. Substrate digestibility (both DM and OM) was lower (P < 0.001) in Z. nummularia compared to other forages and CFBs. The fermentation metabolites showed a different pattern for forages and their CFBs. The forages showed higher TCA precipitable N and lower acetate: propionate ratio in Z. nummularia while the related trend was found in CFB with V. sinensis. Total volatile fatty acid concentration was higher (P < 0.001) in A. nilotica leaves than V. sinensis hay and Z. nummularia leaves. It has implication on widening the forage resources and providing opportunity to use forage biomass rich in polyphenolic constituents in judicious proportion for reducing methane and enhancing green livestock production. Conclusion: Above all, higher substrate degradability, propionate production, lower methanogenesis in CFB with A. nilotica leaves may be considered useful. Nevertheless, CFB with Z. nummularia also proved its usefulness with higher TCA precipitable N and PF. It has implication on widening the forage resources and providing opportunity to use polyphenol-rich forage biomass for reducing methane and enhancing green livestock production. PMID- 30455973 TI - In vitro evaluation of nano zinc oxide (nZnO) on mitigation of gaseous emissions. AB - Background: Enteric methane (CH4) accounts for about 70% of total CH4 emissions from the ruminant animals. Researchers are exploring ways to mitigate enteric CH4 emissions from ruminants. Recently, nano zinc oxide (nZnO) has shown potential in reducing CH4 and hydrogen sulfide (H2S) production from the liquid manure under anaerobic storage conditions. Four different levels of nZnO and two types of feed were mixed with rumen fluid to investigate the efficacy of nZnO in mitigating gaseous production. Methods: All experiments with four replicates were conducted in batches in 250 mL glass bottles paired with the ANKOMRF wireless gas production monitoring system. Gas production was monitored continuously for 72 h at a constant temperature of 39 +/- 1 degrees C in a water bath. Headspace gas samples were collected using gas-tight syringes from the Tedlar bags connected to the glass bottles and analyzed for greenhouse gases (CH4 and carbon dioxide-CO2) and H2S concentrations. CH4 and CO2 gas concentrations were analyzed using an SRI 8610 Gas Chromatograph and H2S concentrations were measured using a Jerome 631X meter. At the same time, substrate (i.e. mixed rumen fluid+ NP treatment+ feed composite) samples were collected from the glass bottles at the beginning and at the end of an experiment for bacterial counts, and volatile fatty acids (VFAs) analysis. Results: Compared to the control treatment the H2S and GHGs concentration reduction after 72 h of the tested nZnO levels varied between 4.89 to 53.65%. Additionally, 0.47 to 22.21% microbial population reduction was observed from the applied nZnO treatments. Application of nZnO at a rate of 1000 MUg g- 1 have exhibited the highest amount of concentration reductions for all three gases and microbial population. Conclusion: Results suggest that both 500 and 1000 MUg g- 1 nZnO application levels have the potential to reduce GHG and H2S concentrations. PMID- 30455975 TI - Lactobacillus elicits a 'Marmite effect' on the chicken cecal microbiome. AB - The poultry industry has traditionally relied on the use of antibiotic growth promoters (AGPs) to improve production efficiency and minimize infection. With the recent drive to eliminate the use of AGPs, novel alternatives are urgently required. Recently attention has turned to the use of synthetic communities that may be used to 'seed' the developing microbiome. The current challenge is identifying keystone taxa whose influences in the gut can be leveraged for probiotic development. To help define such taxa we present a meta-analysis of 16S rRNA surveys of 1572 cecal microbiomes generated from 19 studies. Accounting for experimental biases, consistent with previous studies, we find that AGP exposure can result in reduced microbiome diversity. Network community analysis defines groups of taxa that form stable clusters and further reveals Lactobacillus to elicit a polarizing effect on the cecal microbiome, exhibiting relatively equal numbers of positive and negative interactions with other taxa. Our identification of stable taxonomic associations provides a valuable framework for developing effective microbial consortia as alternatives to AGPs. PMID- 30455974 TI - A review of antibiotic prophylaxis for traveler's diarrhea: past to present. AB - As there is rapid increase in international travel to tropical and subtropical countries, there will likely be more people exposed to diarrheal pathogens in these moderate to high risk areas and subsequent increased concern for traveler's diarrhea. The disease may appear as a mild clinical syndrome, yet a more debilitating presentation can lead to itinerary changes and hospitalization. As bacterial etiologies are the most common causative agents of TD, the use of antibiotic prophylaxis to prevent TD has been reported among travelers for several years. The most common type of antibiotic used for TD has changed over 50 years, depending on many influencing factors. The use of antibiotic prophylaxis for TD prevention in travelers is still controversial, mainly because of difficulties balancing the risks and benefits. Many factors, such as emerging drug resistance, side effects, cost and risk behavior need to be considered. This article aims to review antibiotic prophylaxis from the 1950s to 2000s, to describe the trend and reasons for different antibiotic use in each decade. We conclude that prophylactic antibiotics should be restricted to some high-risk travelers or short-term critical trips. PMID- 30455977 TI - Mitochondria-targeting theranostics. AB - Background: Interest in subcellular organelle-targeting theranostics is substantially increasing due to the significance of subcellular organelle targeting drug delivery for maximizing therapeutic effects and minimizing side effects, as well as the significance of theranostics for delivering therapeutics at the correct locations and doses for diseases throughout diagnosis. Among organelles, mitochondria have received substantial attention due to their significant controlling functions in cells. Main body: With the necessity of subcellular organelle-targeting drug delivery and theranostics, examples of mitochondria-targeting moieties and types of mitochondria-targeting theranostics were introduced. In addition, the current studies of mitochondria-targeting theranostic chemicals, chemical conjugates, and nanosystems were summarized. Conclusion: With the current issues of mitochondria-targeting theranostic chemicals, chemical conjugates, and nanosystems, their potentials and alternatives are discussed. PMID- 30455976 TI - Is it feasible to deliver a complex intervention to improve the outcome of falls in people with dementia? A protocol for the DIFRID feasibility study. AB - Background: People with dementia (PWD) experience ten times as many incident falls as people without dementia. Little is known about how best to deliver services to people with dementia following a fall. We used an integrated, mixed methods approach to develop a new intervention which combines theory generated via a realist synthesis and data on current provision and pathways, gathered through a prospective observational study as well as qualitative interviews, focus groups and ethnographic observation. This intervention is to be tested in a feasibility study in the UK National Health Service. Methods: People living with dementia in one of three geographical areas will be eligible for the study if they experience a fall requiring healthcare attention and have an informal carer. Potential participants will be identified by community services (primary care, paramedics, telecare), secondary care (ED, facilitated discharge services, rehabilitation outreach teams) and research case registers. Participants will receive a complex multidisciplinary intervention focused on their goals and interests for up to 12 weeks. The intervention will be delivered by occupational therapists, physiotherapists and rehabilitation support workers. Feasibility outcomes will include recruitment and retention, suitability and acceptability of outcome measures and acceptability, feasibility and fidelity of intervention components. PWD outcome measures will include number of falls, Montreal Cognitive Assessment (MOCA), European Quality of Life Instrument (EQ-5D-5L), Quality of Life-Alzheimer's Disease Scale (QOL-AD), Modified Falls Efficacy Scale (MFES) and Goal Attainment Scaling (GAS). PWD outcome measures completed by an informal carer will include Disability Assessment for Dementia (DAD), EQ-5D-5L Proxy, QoL AD Proxy and a Health Utilisation Questionnaire (HUQ). The carer outcome measure will be the Zarit Burden Interview (ZBI). An embedded process evaluation will explore barriers and facilitators to recruitment and intervention delivery. Discussion: The study results will inform whether and how a larger multicentre RCT should be undertaken. A full RCT would have the potential to show how outcomes can be improved for people with dementia who have fallen. Ethics and dissemination: The National Research Ethics Service Committee Newcastle and North Tyneside 2 approved the feasibility study. Trial registration: International Standard Randomised Controlled Trial Registry. Registration number: ISRCTN41760734. Date of registration: 16/11/2015. PMID- 30455978 TI - Ongoing barriers to immediate postpartum long-acting reversible contraception: a physician survey. AB - Background: Postpartum women are at risk for unintended pregnancy. Access to immediate long-acting reversible contraception (LARC) may help decrease this risk, but it is unclear how many providers in the United States routinely offer this to their patients and what obstacles they face. Our primary objective was to determine the proportion of United States obstetric providers that offer immediate postpartum LARC to their obstetric patients. Methods: We surveyed practicing Fellows and Junior Fellows of the American College of Obstetricians and Gynecologists (ACOG) about their use of immediate postpartum LARC. These members are demographically representative of ACOG members as a whole and represent all of the ACOG districts. Half of these Fellows were also part of the Collaborative Ambulatory Research Network (CARN), a group of ACOG members who voluntarily participate in research. We asked about their experience with and barriers to immediate placement of intrauterine devices and contraceptive implants after delivery. Results: There were a total of 108 out of 600 responses (18%). Participants practiced in a total of 36 states and/or US territories and their median age was 52 years. Only 26.9% of providers surveyed offered their patients immediate postpartum LARC, and of these providers, 60.7% work in a university-based practice. There was a statistically significant association between offering immediate postpartum LARC and practice type, with the majority of providers working at a university-based practice (p < 0.001). Multiple obstacles were identified, including cost or reimbursement, device availability, and provider training on device placement in the immediate postpartum period. Conclusion: The majority of obstetricians surveyed do not offer immediate postpartum long-acting reversible contraception to patients in the United States. This is secondary to multiple obstacles faced by providers. PMID- 30455979 TI - Morphological development of the dorsal hindbrain in an elasmobranch fish (Leucoraja erinacea). AB - The developmental anatomy of the dorsal hindbrain in an elasmobranch fish, Leucoraja erinacea, is described. We focus on the cerebellum, which is a synapomorphy for gnathostomes. Cerebellar development in L. erinacea, a representative of the most basal gnathostome lineage, may be a proxy for the ancestral state of cerebellar development. We also focus on sensory processing regions termed 'cerebellum-like' structures due to common anatomical and physiological features with the cerebellum. These structures may be considered generatively homologous if they share common developmental features. To test this hypothesis, the morphological development of the cerebellum and cerebellum-like structures must first be described. Of particular importance is the development of common features, such as the molecular layer, which is the defining characteristic of these structures. The molecular layers of the cerebellum and cerebellum-like structures are supplied with parallel fiber axons from distinct granule cell populations. These are the lateral granule mass, the dorsal granular ridge, the medial granule mass, and the granular eminences of the cerebellum. Cerebellar and cerebellar-like development in L. erinacea is similar to development in other elasmobranchs. The temporal order in which these granule cell populations develop suggests an evolutionary history of duplication or expansion of an existing developmental event. PMID- 30455980 TI - ISGF3 with reduced phosphorylation is associated with constitutive expression of interferon-induced genes in aging cells. AB - During cellular aging, many changes in cellular functions occur. A hallmark of aged cells is secretion of inflammatory mediators, which collectively is referred to as the senescence-associated secretory phenotype (SASP). However, the mechanisms underlying such changes are unclear. Canonically, the expression of interferon (IFN)-stimulated genes (ISGs) is induced by IFNs through the formation of the tripartite transcriptional factor ISGF3, which is composed of IRF9 and the phosphorylated forms of STAT1 and STAT2. However, in this study, the constitutive expression of ISGs in human-derived senescent fibroblasts and in fibroblasts from a patient with Werner syndrome, which leads to premature aging, was mediated mainly by the unphosphorylated forms of STATs in the absence of INF production. Under homeostatic conditions, STAT1, STAT2, and IRF9 were localized to the nucleus of aged cells. Although knockdown of JAK1, a key kinase of STAT1 and STAT2, did not affect ISG expression or IFN-stimulated response element (ISRE) mediated promoter activities in these senescent cells, knockdown of STAT1 or STAT2 decreased ISG expression and ISRE activities. These results suggest that the ISGF3 complex without clear phosphorylation is required for IFN-independent constitutive ISG transcription in senescent cells. PMID- 30455981 TI - Tetratricopeptide repeat domain 7A is a nuclear factor that modulates transcription and chromatin structure. AB - A loss-of-function mutation in tetratricopeptide repeat domain 7A (TTC7A) is a recently identified cause of human intestinal and immune disorders. However, clues to related underlying molecular dysfunctions remain elusive. It is now shown based on the study of TTC7A-deficient and wild-type cells that TTC7A is an essential nuclear protein. It binds to chromatin, preferentially at actively transcribed regions. Its depletion results in broad range of epigenomic changes at proximal and distal transcriptional regulatory elements and in altered control of the transcriptional program. Loss of WT_TTC7A induces general decrease in chromatin compaction, unbalanced cellular distribution of histones, higher nucleosome accessibility to nuclease digestion along with genome instability, and reduced cell viability. Our observations characterize for the first time unreported functions for TTC7A in the nucleus that exert a critical role in chromatin organization and gene regulation to safeguard healthy immune and intestinal status. PMID- 30455982 TI - Clinical relevance of screening checklists for detecting cancer predisposition syndromes in Asian childhood tumours. AB - Assessment of cancer predisposition syndromes (CPS) in childhood tumours is challenging to paediatric oncologists due to inconsistent recognizable clinical phenotypes and family histories, especially in cohorts with unknown prevalence of germline mutations. Screening checklists were developed to facilitate CPS detection in paediatric patients; however, their clinical value have yet been validated. Our study aims to assess the utility of clinical screening checklists validated by genetic sequencing in an Asian cohort of childhood tumours. We evaluated 102 patients under age 18 years recruited over a period of 31 months. Patient records were reviewed against two published checklists and germline mutations in 100 cancer-associated genes were profiled through a combination of whole-exome sequencing and multiplex ligation-dependent probe amplification on blood-derived genomic DNA. Pathogenic germline mutations were identified in ten (10%) patients across six known cancer predisposition genes: TP53, DICER1, NF1, FH, SDHD and VHL. Fifty-four (53%) patients screened positive on both checklists, including all ten pathogenic germline carriers. TP53 was most frequently mutated, affecting five children with adrenocortical carcinoma, sarcomas and diffuse astrocytoma. Disparity in prevalence of germline mutations across tumour types suggested variable genetic susceptibility and implied potential contribution of novel susceptibility genes. Only five (50%) children with pathogenic germline mutations had a family history of cancer. We conclude that CPS screening checklists are adequately sensitive to detect at-risk children and are relevant for clinical application. In addition, our study showed that 10% of Asian paediatric solid tumours have a heritable component, consistent with other populations. PMID- 30455983 TI - In Vivo Open- and Closed-chest Measurements of Left-Ventricular Myocardial Viscoelasticity using Lamb wave Dispersion Ultrasound Vibrometry (LDUV): A Feasibility Study. AB - Diastolic dysfunction causes close to half of congestive heart failures and is associated with increased stiffness in left-ventricular myocardium. A clinical tool capable of measuring viscoelasticity of the myocardium could be beneficial in clinical settings. We used Lamb wave Dispersion Ultrasound Vibrometry (LDUV) for assessing the feasibility of making in vivo non-invasive measurements of myocardial elasticity and viscosity in pigs. In vivo open-chest measurements of myocardial elasticity and viscosity obtained using a Fourier space based analysis of Lamb wave dispersion are reported. The approach was used to perform ECG-gated transthoracic in vivo measurements of group velocity, elasticity and viscosity throughout a single heart cycle. Group velocity, elasticity and viscosity in the frequency range 50-500 Hz increased from diastole to systole, consistent with contraction and relaxation of the myocardium. Systolic group velocity, elasticity and viscosity were 5.0 m/s, 19.1 kPa, 6.8 Pa.s, respectively. In diastole, the measured group velocity, elasticity and viscosity were 1.5 m/s, 5.1 kPa and 3.2 Pa.s, respectively. PMID- 30455985 TI - Endovascular rescue of vertebro-basilar thrombosis in cervical spine injury. AB - Introduction: Vertebro-basilar thrombosis is often lethal. We report a post traumatic case in which logistical issues were overcome to secure prompt endovascular intervention resulting in a favourable outcome. Case presentation: We report this case to highlight (i) the need, across the United Kingdom, for rapid access to 24/7 neurointerventional services and (ii) the fact that vertebral artery injury during C-spine trauma, while not uncommon, can rarely have catastrophic complications. Discussion: Vertebral artery injuries during C spine trauma can rarely present as a neurovascular emergency requiring neurointerventional rescue. It is our opinion that patients with neurovascular emergencies merit 24/7 neurointerventional services, akin to those provided for acute coronary syndromes. PMID- 30455984 TI - Permanent wettability of a novel, nanoengineered, clinically available, hyaluronan-coated dental implant. AB - The objectives of this study are to evaluate long-term wettability of novel surface-engineered, clinically available dental implants, featuring a surface nanolayer of covalently linked hyaluronan, and to confirm the relationships between wetting properties and surface nanostructure and microstructure. Wettability measurements were performed on clinically available hyaluronan-coated Grade 4 titanium implants, packaged and sterile, that is, in the "on the shelf" condition, after 1 year from production. Wetting properties were measured by the Wilhelmy plate method. Analysis of the surface structure and chemistry was perfomed by X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and energy-dispersive X-ray (EDX) analysis, atomic force microscopy (AFM), and zeta-potential measurement, either on implants or disks or plates subjected to the same surface-engineering process. Results show that hydrophilicity and ensuing capillary rise of the hyaluronan-coated implant surface is unaffected by aging and dry storage. Chemical analysis of the implant surface by XPS and evaluation of the zeta potential indicate that hyaluronan chemistry and not that of titanium dictates interfacial properties. Comparison between XPS versus EDX and SEM versus AFM data confirm that the thickness of the hyaluronan surface layer is within the nanometer range. Data show that nanoengineering of the implant surface by linking of the hydrophilic hyaluronan molecule endows tested titanium implants by permanent wettability, without need of wet storage as presently performed to keep long-term hydrophilic implant surfaces. From an analytical point of view, the introduction in routine clinical practice of nanoengineered implant surfaces requires upgrading of analytical methods to the nanoscale. PMID- 30455986 TI - Penetrating spine injury bisecting thoracic spinal canal with no significant neurological deficits-The midline cord syndrome. AB - Introduction: In India, the incidence of penetrating spine injury (PSI) is increasing because of the increased use of advanced ballistics (missile PSI) among military personnel and sophisticated tools and construction instruments like nail-guns or drills (non-missile PSI) among civilians. These injuries are associated with a risk of neurological damage, central nervous system infections, vascular injury, dural tear followed by CSF leakage, and spinal instability. Case presentation: A 35-year-old male presented with a non-missile PSI with retained iron nail bisecting his dorsal spinal cord, without any motor deficits. Patient presented with only left lower limb proprioceptive loss and L1-L3 paresthesia. Nail removal was done on emergent basis without any further neurological damage. Discussion: To the best of our knowledge, this presentation of a non-missile PSI and has not been previously reported. The specific clinical presentation of this distinct type of injury to the midline structures of the spinal cord is hence named "midline cord syndrome". PMID- 30455987 TI - Generalised muscle weakness after bladder wall injection of Abobotulinum Toxin A: experience of a woman with tetraplegia who required increased caregiver support: importance of doctor-patient communication: duty of candour for spinal cord physician and responsibilities of a patient. AB - Introduction: Generalised muscle weakness can occur after bladder wall injection of Abobotulinum toxin and the patient may require additional caregiver support. Case presentation: A woman with C-8 AIS A tetraplegia received bladder wall injection of Abobotulinum toxin A 1000 units for detrusor over-activity. After 2.5 weeks, she developed weakness of arms; could not lift herself for pressure relief; could not transfer using sliding board; she regained the original muscle strength in 6 weeks. After 13 months, Abobotulinum toxin A 1000 units were injected into detrusor. Ten days after the second Abobotulinum toxin A injection, she developed generalised muscle weakness. She had not regained full function in her arms and hands 8 months later.Prior to bladder wall injection of Abobotulinum toxin A, this patient was not aware that she could develop muscle weakness albeit very rarely. Therefore, the patient made no association of the muscle weakness, which occurred after the first injection, to Abobotulinum toxin A. For this reason, she did not inform the clinicians that she developed weakness of upper limbs following Abobotulinum toxin A injection. As she was not informed of this side effect before the second bladder wall injection of Abobotulinum toxin A, she consented to undergo the repeat procedure and developed generalised muscle weakness. Discussion: Patients should inform doctors the adverse effects of medical therapy so that future treatment is amended to ensure patient safety. Professional duty of candour states that doctors should discuss risks which occur often, those that are serious even if very unlikely, and those that are important to the patient. PMID- 30455988 TI - Knockdown of KIAA1199 attenuates growth and metastasis of hepatocellular carcinoma. AB - Accumulating evidence indicates that KIAA1199 plays a vital role in tumor progression. However, the role of KIAA1199 in hepatocellular carcinoma (HCC) still remains unknown. In this study, we found that KIAA1199 was upregulated in human HCC tissues and in highly metastatic HCC cell lines. Furthermore, the expression of KIAA1199 was significantly correlated with tumor size and metastasis in HCC. Knockdown of KIAA1199 inhibited cell proliferation and migration in vitro, and suppressed tumorigenicity and lung metastasis in vivo. In addition, silencing of KIAA1199 induced G1 phase arrest by reducing cyclinD1 expression. Moreover, KIAA1199 knockdown induced apoptosis by activating endoplasmic reticulum (ER) stress, which was based on the upregulation of ER stress markers, activating transcription factor 4 (ATF4) and CAAT/enhancer binding protein homologous protein (CHOP). In conclusion, our data demonstrated that KIAA1199 knockdown inhibited the growth and metastasis of HCC. PMID- 30455989 TI - Isatin-Schiff base-copper (II) complex induces cell death in p53-positive tumors. AB - Medicinal bioinorganic chemistry is a thriving field of drug research for cancer treatment. Transition metal complexes coordinated to essential biological scaffolds represent a highly promising class of compounds for design of novel target-specific therapeutics. We report here the biological evaluation of a novel Isatin-Schiff base derivative and its Cu(II) complex in several tumor cell lines by assessing their effects on cellular metabolism, real-time cell proliferation and induction of apoptosis. Further, the impact of compounds on the p53 protein and expression of its target genes, including MDM2, p21/CDKN1A, and PUMA was evaluated. Results obtained in this study provide further evidence in support of our prior data suggesting the p53-mediated mechanism of action for Isatin-Schiff base derivatives and their complexes and also shed light on potential use of these compounds for stimulation of apoptosis in breast cancer cells via activation of the pro-apoptotic PUMA gene. PMID- 30455990 TI - Polyamine flux suppresses histone lysine demethylases and enhances ID1 expression in cancer stem cells. AB - Cancer stem cells (CSCs) exhibit tumorigenic potential and can generate resistance to chemotherapy and radiotherapy. A labeled ornithine decarboxylase (ODC, a rate-limiting enzyme involved in polyamine [PA] biosynthesis) degradation motif (degron) system allows visualization of a fraction of CSC-like cells in heterogeneous tumor populations. A labeled ODC degradation motif system allowed visualization of a fraction of CSC-like cells in heterogeneous tumor populations. Using this system, analysis of polyamine flux indicated that polyamine metabolism is active in CSCs. The results showed that intracellular polyamines inhibited the activity of histone lysine 4 demethylase enzymes, including lysine-specific demethylase-1 (LSD1). Chromatin immunoprecipitation with Pol II antibody followed by massively parallel DNA sequencing, revealed the global enrichment of Pol II in transcription start sites in CSCs. Increase of polyamines within cells resulted in an enhancement of ID1 gene expression. The results of this study reveal details of metabolic pathways that drive epigenetic control of cancer cell stemness and determine effective therapeutic targets in CSCs. PMID- 30455991 TI - Is that realistic? The development of a realism assessment questionnaire and its application in appraising three simulators for a gynaecology procedure. AB - Introduction: There is no standard approach to determining the realism of a simulator, valuable information when planning simulation training. The aim of this research was to design a generic simulator realism questionnaire and investigate the contributions of different elements of simulator design to a user's impression of simulator realism and performance. Methods: A questionnaire was designed with procedure-specific and non-procedure-specific (global) questions, grouped in subscales related to simulator structure and function. Three intrauterine contraceptive device (IUCD) simulators were selected for comparison. Participants were doctors of varying experience, who performed an IUCD insertion on each of the three models and used the questionnaire to rate the realism and importance of each aspect of the simulators. The questionnaire was evaluated by correlation between procedure-specific and global items and the correlation of these items to overall realism scores. Realism scores for each simulator were compared by Kruskal-Wallis and subsequent between-simulator comparison by Dunn's test. Results: Global question scores were highly related to procedure-specific scores. Comparison revealed global item subscale scores were significantly different across models on each of the nine subscales (P < 0.001). Function items were rated of higher importance than structure items (mean function item importance 5.36 versus mean structure item importance 5.02; P = 0.009). Conclusions: The designed questionnaire was able to discriminate between the models for perceived simulator realism. Findings from this study may assist simulator design and inform future development of a generic questionnaire for assessing user perceptions of simulator realism. PMID- 30455993 TI - What Does the TOVITO Programme Tell Us about How We Can Manage COPD? AB - Chronic obstructive pulmonary disease (COPD) patients suffer from a significant burden of disease which impairs their quality of life, exercise capacity and lung function. They also suffer from acute worsening of disease, called exacerbations. The role of drug treatment in the management of COPD is aimed at improving lung function, quality of life and reducing the risk of exacerbations. Bronchodilator drugs are the mainstay of therapy and the tow classes, long acting beta2 agonists and long acting anti-muscarinics, are being combined together. The TOVITO programme of clinical research is a comprehensive and consistent set of studies investigating the role of Tiotropium and Olodaterol (Spiolto) on lung function, quality of life, exercise capacity and exacerbation frequency. The programme has included over 16 000 patients who have received the benefits of these two compounds when given together in a suitable inhaler. Safety data was collected with a focus on cardiovascular morbidity and mortality. The use of tiotropium/olodaterol combination resulted in significant gains in lung function, quality of life and exercise endurance. There was no difference between the arms in the Dynagito study which was designed to compare tiotropium/olodaterol combination with its constituent compounds. In all studies no safety concerns were raised. Tiotropium/Olodaterol (Spiolto) is an effective treatment for COPD with benefits to lung function, quality of life and exercise tolerance. PMID- 30455995 TI - Reliability and Validity of the Turkish Translation of the Beliefs about Medicines Questionnaire (BMQ-T) in Patients with Behcet's Disease. PMID- 30455992 TI - NUMB maintains bone mass by promoting degradation of PTEN and GLI1 via ubiquitination in osteoblasts. AB - The adaptor protein NUMB is involved in asymmetric division and cell fate determination and recognized as an antagonist of Notch. Previous studies have proved that Notch activation in osteoblasts contributes to a high bone mass. In this study, however, an osteopenic phenotype was found in 9-week-old mice using osteoblastic specific Col1a1-2.3-Cre to ablate both Numb and its homologue Numbl . The trabecular bone mass decreased dramatically while the cortical bone mass was unaffected. Here, the Notch signal was not activated, while the tensin homologue deleted on human chromosome 10 (PTEN), which dephosphorylates phosphatidylinositide 3-kinases, was elevated, attenuating protein kinase B (Akt). The ubiquitination assay revealed that NUMB may physiologically promote PTEN ubiquitination in the presence of neural precursor cell-expressed developmentally downregulated protein 4-1. In addition, the deficiency of Numb/Numbl also activated the Hedgehog pathway through GLI1. This process was found to improve the ratio of the receptor activator of nuclear factor-kB ligand to osteoprotegerin, which enhanced the differentiation of osteoclasts and bone resorption . In conclusion, this study provides an insight into new functons of NUMB and NUMBL on bone homeostasis. PMID- 30455997 TI - Behcet's Disease and Hemoptysis. PMID- 30455996 TI - Author's Reply. PMID- 30455994 TI - Biologic Agents in the Treatment of Multicentric Castleman Disease. AB - Multicentric Castleman disease (MCD) causes an extensive range of systematic symptoms and can be life-threatening if not treated promptly and appropriately. The pathophysiology of the disease remains unclear; however, interleukin 6 (IL-6) pathway and human herpesvirus 8 infection appear to play an important role. As a result, the treatment of MCD remains complex and often insufficient, although a plethora of therapeutic approaches have been used. Between these, biological agents in the form of monoclonal antibodies against specific pathogenic processes of the disease have improved survival rates significantly. In the present study, we review the clinical results of rituximab, which targets B lymphocytes, siltuximab and tocilizumab, which target the IL-6 pathway, bortezomib, which is a selective proteasome inhibitor, and anakinra, which is an interleukin 1 receptor antagonist. The introduction of these biological agents in the treatment of MCD appears to be promising in the first studies performed. However, more clinical trials are required to assess the efficacy and safety of each agent and to form therapeutic strategies that will be widely accepted. PMID- 30455998 TI - Reporting Adverse Drug Reactions in a Tertiary Care Hospital in Istanbul. PMID- 30456000 TI - Robust and Accurate Capture of Human Joint Pose Using an Inertial Sensor. AB - Wearable inertial measurement units (IMU) measuring acceleration, earth magnetic field, and gyroscopic measurements can be considered for capturing human skeletal postures in real time. Number of movement disorders require accurate and robust estimation of the human joint pose. Though these movements are inherently slow, the accuracy of estimation is vital as many subtle moment patterns, such as tremor are useful to capture under many assessments scenarios. Also, as the end user is a patient with movement disabilities, the practical wearability aspects impose stringent requirements such as the use of minimal number of sensors as well as positioning them in conformable areas of the human body; particularly for longer term monitoring. Estimating skeletal and limb orientations to describe human posture dynamically via model-based approaches poses numerous challenges. In this paper, we convey that the use of measurement conversion ideas-a representation signifying a linear characterization of an inherently non linear estimation problem, pragmatically improves the overall estimation of the limb orientation. A quaternion, as opposed to the Euler angle-based approach is adopted to avoid Gimbal lock scenarios. We also lay a systematic basis for quaternion normalization, typically performed in the pre-filtering stage, by introducing an optimization-based mathematical justification. A robust version of the extended Kalman filter is configured to amalgamate the underlying ideas in enhancing the overall system performance while providing a structured and a comprehensive approach to IMU-based real time human pose estimation problem, particularly in a movement disability capture context. PMID- 30455999 TI - Enantioselective Synthesis of Biaryl Atropisomers via the Addition of Thiophenols into Aryl-Naphthoquinones. AB - We report a cinchona alkaloid catalyzed addition of thiophenol into rapidly interconverting aryl-naphthoquinones, resulting in stable biaryl atropisomers upon reductive methylation. An array of thiophenols and naphthoquinone substrates were evaluated, and we observed selectivities up to 98.5:1.5 e.r. Control of the quinone redox properties allowed us to study the stereochemical stabilities of each oxidation state of the substrates. The resulting enantioenriched products can also be moved on via an SNAr-like reaction sequence to arrive at stable derivatives with excellent enantioretention. PMID- 30456001 TI - Kinect-Based In-Home Exercise System for Lymphatic Health and Lymphedema Intervention. AB - Using Kinect sensors to monitor and provide feedback to patients performing intervention or rehabilitation exercises is an upcoming trend in healthcare. However, the joint positions measured by the Kinect sensor are often unreliable, especially for joints that are occluded by other parts of the body. Also, users' motion sequences differ significantly even when doing the same exercise and are not temporally aligned, making the evaluation of the correctness of their movement challenging. This paper aims to develop a Kinect-based intervention system, which can guide the users to perform the exercises more effectively. To circumvent the unreliability of the Kinect measurements, we developed a denoising algorithm using a Gaussian Process regression model. We simultaneously capture the joint positions using both a Kinect sensor and a motion capture (MOCAP) system during a training stage and train a Gaussian process regression model to map the noisy Kinect measurements to the more accurate MOCAP measurements. For the sequences alignment issue, we develop a gradient-weighted dynamic time warping approach that can automatically recognize the endpoints of different subsequences from the original user's motion sequence, and furthermore temporally align the subsequences from multiple actors. During a live exercise session, the system applies the same alignment algorithm to a live-captured Kinect sequence to divide it into subsequences, and furthermore compare each subsequence with its corresponding reference subsequence, and generates feedback to the user based on the comparison results. Our results show that the denoised Kinect measurements by the proposed denoising algorithm are more accurate than several benchmark methods and the proposed temporal alignment approach can precisely detect the end of each subsequence in an exercise with very small amount of delay. These methods have been integrated into a prototype system for guiding patients with risks for breast-cancer related lymphedema to perform a set of lymphatic exercises. The system can provide relevant feedback to the patient performing an exercise in real time. PMID- 30456002 TI - Utilizing Stereotactic Spine Navigation for Posterior Partial Vertebrectomy in an En Bloc Resection of a Superior Pulmonary Sulcus Tumor Invading the Thoracic Vertebrae: A Technical Note. AB - Prior to the development of en bloc techniques, vertebral invasion by non-small cell lung cancer (NSCLC) had been considered a relative contraindication to surgical intervention. However, reports in the literature have demonstrated increased progression-free survival with the use of neoadjuvant chemotherapy followed by anterior en bloc resection of the residual tumor. Stereotactic spine navigation has been shown to improve accuracy during complex vertebral osteotomies, improving patient outcomes. We report a 53-year-old woman with an NSCLC in the left upper lobe, a periosteum attachment of the second and third thoracic vertebrae (T2 and T3, respectively), and an infiltration of the corresponding nerve roots. We describe a surgical approach for the resection of NSCLC with vertebral infiltration utilizing stereotactic spine navigation and intraoperative computed tomography (CT) (O-Arm, Medtronic, Minneapolis, Minnesota, US) for a posterior approach laminectomy, osteotomy, and partial vertebrectomy, followed by trans-thoracic en bloc resection of a superior pulmonary sulcus tumor with nerve root infiltration. Posterior approach vertebral osteotomy and en bloc resection for superior sulcus NSCLC infiltrating the vertebrae utilizing stereotactic spine navigation and intraoperative CT (O-Arm) is a viable alternative to the traditional anterior approach. PMID- 30456003 TI - Public Awareness of the Emergency Medical Services in Maharashtra, India: A Questionnaire-based Survey. AB - Background and objectives The most widely used emergency medical services (EMS) model in India is the '108' emergency service which primarily functions as an emergency response system to attend patients in need of critical care, trauma and accident victims. This is an observational cross-sectional study which was conducted using a questionnaire that asks the participants about their awareness and opinion of the current EMS system. The results of this study will enable us to ascertain the level of awareness of EMS among the population and address any misconceptions if they exist. Materials and methods All participants had to complete a 24-item self-administered questionnaire consisting of eight socio demographic questions and 16 questions based on the EMS system. Questions regarding the development of the '112' unified emergency service were also included. The convenient sampling method was used for data collection. The distribution of responses was examined using frequencies and percentages. Further analysis was done using the Chi-square test to compare responses between various subgroups based on the age, gender, profession, and level of education. Results A total of 1220 people from the state of Maharashtra responded to the survey and the maximum responses were from Mumbai. Majority of the respondents (59.2%) were from the age group of 15 to 30 years and, most of our responders had received education at the graduate level or above (78.2%). Only 17.5% of the respondents said that they will try to check for responsiveness if they saw a person lying unconscious by the side of the road with the scene being free of any danger. Interestingly, 78.9% of the healthcare professionals who participated in this survey would not check for responsiveness. Only 76.2% of the respondents knew that '108' is the number to dial in case of a medical emergency and about a quarter of them was not aware of it. It may seem that a good number of people are aware of the number. However, with the high number of fatalities occurring every day due to lack of medical facilities and a high current annual death toll on the roads, 100% of the population should know the emergency number. Only 20.2% of the respondents had called the EMS and asked for an ambulance. 68.5% of the respondents would immediately move out of the way and 27.5% of them would move out of their way if the ambulance's lights and sirens were on. About two-thirds of the respondents were unaware of the development of a unified emergency number (112). However, a large majority (82.9%) were in favor of having a unified emergency number instead of a different number for each emergency. Only 43.8% of the respondents were of the opinion that the current EMS coverage was inadequate. 24.9% of the participants rated the current EMS as good, whereas 53.5% rated the EMS average and 16.9% rated it poor. Conclusions An effort should be made to make 100% of the population aware of this service. The first step for increasing awareness would be starting various advertisement campaigns. The next step would be to implement the unified emergency number (112) to address all kinds of distress calls such as police, fire, and ambulance. A very small proportion of the population is trained in first-aid or basic trauma life support. Awareness campaigns and training sessions for the general public should be conducted for the same. It is also necessary to spread awareness and help the populace know about the Good Samaritan law. PMID- 30456004 TI - Expression analysis of two SOMATIC EMBRYOGENESIS RECEPTOR KINASE (SERK) genes during in vitro morphogenesis in Spanish cedar (Cedrela odorata L.). AB - Somatic embryogenesis (SE) is one of the most important steps during regeneration, but the molecular mechanism of SE remains unclear for Cedrela odorata. SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE (SERK) is one of the genes associated with induction of SE and is considered a marker of cells competent to form somatic embryos. Our objective was to clone and characterize the SERK1 and SERK2 gene homologues and analyze their expression patterns during in vitro morphogenesis in Spanish cedar. CoSERK1 and CoSERK2 were isolated from cedar, both share domains characteristic of the SERK family, including leucine-rich repeats, a proline-rich motif, a transmembrane domain, and kinase domains. Embryogenic cultures were established from callus cultures induced on medium supplemented with 1 mg/L dicamba. Histological sections were studied to determine the embryogenic nature of the samples. The CoSERK1 gene was highly expressed during the acquisition of embryogenic competence. The expression level of SERK1 was lower in non-embryogenic tissues and organs than in embryogenic calli, and it was higher in 3-week old embryogenic calli. CoSERK2 gene was highly expressed in leaves and shoots but no difference in expression was obtained between somatic and embryogenic tissues. These results suggest that the expression of CoSERK1 is associated with somatic embryogenesis induction and could be used as a potential marker to monitor the transition from competent to embryogenic cells and tissues in Spanish cedar. PMID- 30456005 TI - A simple and efficient agroinfiltration method in coffee leaves (Coffea arabica L.): assessment of factors affecting transgene expression. AB - The establishment of a simple, rapid and efficient transient expression system is a necessary tool for the functional validation of candidate genes in coffee biotechnology. The effects of Agrobacterium strain, age of the donor plant, infiltration method, and infiltration medium on transgene expression in detached coffee leaves were evaluated. Regarding the effect of Agrobacterium strain, the expression of uidA was higher in GV3101-treated coffee disks than in LBA4404 and ATHV-treated samples. On the other hand, transient expression of uidA was significantly higher in leaf disks from young plants (6-weeks-old) (13.1 +/- 1.4%) than in mature tissue (12-weeks-old) (1.6 +/- 1.2%). Transient uidA expression was higher in detached coffee leaf disks from young plants infiltrated with one injection of 15 uL of Agrobacterium strain GV3101::1303 suspended in MS salts supplemented with 30 g/L sucrose, 1.9 g/L MES and 200 uM AS with subsequent sanding of the abaxial epidermis. Using the optimized protocol, expression of the uidA gene was observed 6, 24 and 48 h and 5 weeks after bacterial injection. DNA was extracted from coffee disks with positive GUS expression and specific mgfp5 and uidA fragments were amplified 5 weeks post-agroinfiltration. On the other hand, using the optimized protocol, a specific cry10Aa (500 bp) fragment was amplified in the agro-infiltrated coffee leaf disks 5 weeks post-agroinfiltration with the plasmid pB427-35S-cry10Aa. Moreover, the expression of the gene cry10Aa in two infiltrated coffee leaf disks was verified by RT-PCR and an expected 500 bp fragment was amplified. PMID- 30456006 TI - Impacts of horizontal gene transfer on the compact genome of the clavulanic acid producing Streptomyces strain F613-1. AB - Mobile genetic elements involved in mediating horizontal transfer events contribute to bacterial evolution, and bacterial genomic plasticity and instability result in variation in functional genetic information in Streptomyces secondary metabolism. In a previous study, we reported the complete genome sequence of the industrial Streptomyces strain F613-1, which produces high yields of clavulanic acid. In this study, we used comparative genomics and bioinformatics to investigate the unique genomic features of this strain. Taken together, comparative genomics were used to systematically investigate secondary metabolism capabilities and indicated that frequent exchange of genetic materials between Streptomyces replicons may shape the remarkable diversities in their secondary metabolite repertoires. Moreover, a 136.9-kb giant region of plasticity (RGP) was found in the F613-1 chromosome, and the chromosome and plasmid pSCL4 are densely packed with an exceptionally large variety of potential secondary metabolic gene clusters, involving several determinants putatively accounting for antibiotic production. In addition, the differences in the architecture and size of plasmid pSCL4 between F613-1 and ATCC 27064 suggest that the pSCL4 plasmid could evolve from pSCL4-like and pSCL2-like extrachromosomal replicons. Furthermore, the genomic analyses revealed that strain F613-1 has developed specific genomic architectures and genetic patterns that are well suited to meet the requirements of industrial innovation processes. PMID- 30456007 TI - Orthogonal test design for optimization of the extraction of essential oil from Asarum heterotropoides var. Mandshuricum and evaluation of its antibacterial activity against periodontal pathogens. AB - The optimum extraction conditions of essential oil from Asarum heterotropoides var. Mandshuricum applied by an orthogonal L9(33) test were a water-to-raw material ratio of 17, a particle size of D 95 <= 3.8 mm and an extraction time of 2 h. In ingredient analysis, gas chromatography/mass spectrometry analysis identified the main components of essential oil as methyl eugenol (45.95%), safrole (17.48%) and 3,5-dimethoxytoluene (10.30%) orderly. In vitro, the minimum inhibitory concentration and minimum bactericidal concentration of essential oil were 0.01 and 0.02% against F. nucleatum, 0.04 and 0.08% against P. intermedia, and 0.005 and 0.005% against P. gingivalis. In vivo, administration of essential oil significantly suppressed alveolar bone resorption induced by F. nucleatum, with bone levels remaining comparable to non-infected mice. These results of antibacterial activity of essential oil in vitro and in vivo show the inhibition of periodontal pathogens and therapy of alveolar bone resorption in mice, suggesting that its essential oil could be a potential natural therapeutic agent for treatment of periodontitis in human beings. PMID- 30456008 TI - Characterization of a thermo-adapted strain of Zymomonas mobilis for ethanol production at high temperature. AB - A thermo-adapted strain of Zymomonas mobilis designated ZM AD41 that capable of growth and ethanol production at high temperature was obtained using the thermal stress adaptation technique. This thermo-adapted strain exhibited approximately 1.8- and 27-fold higher growth rate than the wild-type at 39 degrees C and 41 degrees C, respectively. It was more resistant to stress induced by acetic acid at 200 mM and hydrogen peroxide (H2O2) at 0.4 mM and produced approximately 1.8- and 38.6-fold higher ethanol concentrations than the wild-type at 39 degrees C and 41 degrees C, respectively. Moreover, it had better sedimentation performance during ethanol fermentation at high temperature than the wild-type. Based on the growth performance, heat, acetic acid and H2O2 stress treatments, sedimentation characteristics, and ethanol fermentation capability, Z. mobilis ZM AD41 was a good candidate for ethanol production at high temperature. PMID- 30456009 TI - Lipopolysaccharide-induced priming enhances NO-mediated activation of defense responses in pearl millet challenged with Sclerospora graminicola. AB - Lipopolysaccharide (LPS) elicitors isolated from Pseudomonas fluorescens UOM SAR 14 effectively induced systemic and durable resistance against pearl millet downy mildew disease caused by the oomycete Sclerospora graminicola. Rapid and increased callose deposition and H2O2 accumulation were evidenced in downy mildew susceptible seeds pre-treated with LPS (SLPS) in comparison with the control seedlings, which also correlated with expression of various other defense responses. Biochemical analysis of enzymes and quantitative real-time polymerase chain reaction data suggested that LPS protects pearl millet against downy mildew through the activation of plant defense mechanisms such as generation of nitric oxide (NO), increased expression, and activities of defense enzymes and proteins. Elevation of NO concentrations was shown to be essential for LPS-mediated defense manifestation in pearl millet and had an impact on the other downstream defense responses like enhanced activation of enzymes and pathogen-related (PR) proteins. Temporal expression analysis of defense enzymes and PR-proteins in SLPS seedlings challenged with the downy mildew pathogen revealed that the activity and expression of peroxidase, phenylalanine ammonia lyase, and the PR-proteins (PR-1 and PR-5) were significantly enhanced compared to untreated control. Higher gene expression and protein activities of hydroxyproline-rich glycoproteins (HRGPs) were observed in SLPS seedlings which were similar to that of the resistant check. Collectively, our results suggest that, in pearl millet-downy mildew interaction, LPS pre-treatment affects defense signaling through the central regulator NO which triggers the activities of PAL, POX, PR-1, PR-5, and HRGPs. PMID- 30456010 TI - Transcriptional activation of anthocyanin structural genes in Torenia 'Kauai Rose' via overexpression of anthocyanin regulatory transcription factors. AB - This study was conducted to examine the role of the transcription factors (TFs), RsMYB1 and mPAP1 together with B-Peru (mPAP1 + B-Peru), in regulating anthocyanin biosynthesis in the ornamental torenia (Torenia fournieri) cultivar Kauai Rose using Agrobacterium-mediated transformation. Expression levels of RsMYB1 were the highest in the lines RS5 and RS3, followed by RS4, RS2, and RS1, while transcript levels of mPAP1 + B-Peru increased in the order of PB-6 > PB-5 > PB-7 > PB-8 > PB 2. Moreover, transcript levels of the anthocyanin structural genes in transgenic lines were significantly higher than those in wild-type (WT) plants. Anthocyanin structural gene expression was specifically altered by TF overexpression: the highest expression of anthocyanidin synthase (ANS) was observed in transgenic lines with RsMYB1, while expression of dihydroflavonol-4-reductase (DFR) was the highest in lines with mPAP1 + B-Peru. We expect that enhanced expression of these anthocyanin structural genes will improve anthocyanin content in the flowers of transgenic torenia. Moreover, these results indicate that RsMYB1 and mPAP1 + B Peru can be exploited as anthocyanin regulatory TFs to enhance anthocyanin content in other horticultural plants. PMID- 30456011 TI - Metabolite profiling and molecular responses in a drought-tolerant savory, Satureja rechingeri exposed to water deficit. AB - This study aimed to determine the response of Satureja rechingeri to water deficit by quantifying the expression of three targeted genes and four traditional reference genes using quantitative real-time PCR analysis (RT-qPCR). Drought stress was imposed by withholding water 4 months after planting. Profiling of volatile and non-volatile compounds using gas chromatography/mass spectrometry (GC/MS) and high-performance thin layer chromatography (HPTLC) showed an increasing-decreasing trend of major phenolic and terpenoid compounds such as rosmarinic and caffeic acids, carvacrole, thymol and p-Cymene. Drought stress also lead to significant increases in oil yield, soluble sugars and proline as well as significant reductions in leaf water potential (LWP), relative water content (RWC), and pigments. Metabolite profiling revealed the strategies savory employed to generate different biochemical phenotypes. RT-qPCR analysis showed that up-regulation of the three genes [1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), 3-hydroxy-3-methylglutaryl-coenzyme. A reductase (HMGR) and rosmarinic acid synthase: 4-coumaroyl-CoA (RAS)] selected from the phenylpropanoid and terpenoid biosynthesis pathways were markedly enhanced at the transcript levels of the regulatory steps and directly increased the production of secondary metabolites, including phenolic and terpenoid compounds. Actin protein (ACT), elongation factor 1-alpha (EF1alpha), glyceraldehyde-3-phosphate dehydrogenase cytosolic (GAPC) and ubiquitin-conjugating enzyme (UBC) were used as traditional reference genes. UBC's suitability as the reference genes were verified in S. rechingeri. The study's results provide the foundation for gene expression analysis of savory and other species of Lamiaceae. Thus, the effective application of drought stress before harvesting can increase the quantity and quality of raw material. PMID- 30456012 TI - Prickly pear cactus cladodes powder of Opuntia ficus indica as a cost effective biosorbent for dyes removal from aqueous solutions. AB - The textiles manufacturing is one of the core industries that release a huge amount of dyes during the dyeing process. As a result, the growing demand of an efficient and low-cost treatment has given rise to alternative adsorbents. In the present study, prickly pear cactus cladodes powder (PPCP) of Opuntia ficus indica was investigated as an ecofriendly and low-cost biosorbent of Acid orange 51 (AO51) and Reactive Red 75 (RR75) dyes commonly used in dyeing. The FTIR spectroscopic characterization of PPCP showed the heterogeneity in surface structure and functional groups which confers to the biosorbent its capability to interact with acidic (AO51) and reactive (RR75) dyes molecules. Effects of pH, temperature, initial dye concentration and adsorbent dose on adsorption yield were investigated. The dyes uptake process was closely fitted to the pseudo second order kinetic for both dyes. Experimental data were analyzed by applying the Langmuir, Freundlich, Dubinin-Raduskevich, Temkin, Redlich-Peterson, and BET isotherms equations. The models of BET and Langmuir were considered as the best isotherms models fitting experimental data, respectively, of RR75 and AO51. The maximum Langmuir monolayer biosorption capacities were of 198.9 and 45 mg g-1, respectively for RR75 and AO51. PMID- 30456013 TI - Documentation of virulence and races of Xanthomonas citri pv. malvacearum in India and its correlation with genetic diversity revealed by repetitive elements (REP, ERIC, and BOX) and ISSR markers. AB - Thirty-four Xanthomonas citri pv. malvacearum (Xcm) isolates collected from three cotton-growing zones of India were subjected for virulence and race documentation and further correlated with genetic diversity as revealed by repetitive elements [repetitive extragenic palindromic (REP), enterobacterial repetitive intergenic consensus (ERIC) and BOX elements] and intersimple sequence repeat (ISSR)-PCR analyses. Among the 34 isolates tested for virulence on susceptible cultivar LRA 5166, 7 were recorded as highly virulent (HV), 16 were moderately virulent (MV) and 11 were less virulent (LV). Eight different races were recorded by using ten cotton host differentials. Twenty-two isolates (65%) belonged to race 18. Twelve isolates (35%) pertained to races 3, 5, 6, 7, 8, 11 and 13. REP, ERIC, BOX, combined repetitive elements, and ISSR analyses revealed the presence of 7, 10, 9, 11, and 8 clusters, respectively, at similarity coefficient of 0.70 in dendrograms. Principal coordinate analysis (PCoA) exhibited 76.4% and 77.5% cumulative variability for combined repetitive elements and ISSR analyses. ERIC produced the highest polymorphic information content (PIC) value (0.928). A lot of intra-pathovar variability was observed in virulence and genomic fingerprinting among Xcm isolates. Many of the isolates grouped based on geographical origin irrespective of virulence or race. The spread of the pathogen races in India might be due to the transport of germplasm lines and seed materials from one place to others. PMID- 30456014 TI - Label-free quantitative proteomic analysis revealed a positive effect of ectopic over-expression of PeaT1 from Alternaria tenuissima on rice (Oryza sativa) response to drought. AB - The protein elicitor PeaT1 was found in Alternaria tenuissima and exerted broad spectrum resistance in wheat, cotton, and rice. Recently, we found that overexpressing PeaT1 rice (OE) could enhance plant drought tolerance. Elucidating some elevated drought stress-related proteins and associated mechanisms is inevitable for improving drought tolerance in rice. In this study, combining a label-free quantitative proteomic method, multiple proteins were differentially accumulated in OE plants. Among these, a total of 57 significant changed proteins (including 32 up-regulated and 25 down-regulated) were mainly involved in metabolic, cellular, biological progress, and stress response. Using the RT-qPCR assay, 18 proteins' relative abundance was detected mostly consistent with the proteins abundance in proteomic data. Specially, proteins involved in abiotic stress, such as OsSKIPa and OsPP2C, which were significantly induced in early after dehydration treatment in transgenic rice, and the other stress response genes (prohibitin protein, PsbP protein, msrB Protein) also changed in PeaT1 OE lines. Taken together, these results suggested that these differential proteins would be helpful for understanding the functional molecular mechanism of PeaT1 in rice. PMID- 30456016 TI - Designing and experimental evaluation of gene-specific primers of pea (Pisum sativum) defense proteins. AB - Real-time gene expression analysis by semi-quantitative and quantitative RT-PCR requires a set of gene-specific primers which should have the ability to amplify the gene of interest specifically. In the present study, we have standardized certain parameters for primer design using the freely available Primer3 software. We have designed the primers for defense genes such as ICS (isochorismate synthase), CCoAOMT (caffeoyl CoA O-methyltransferase), C4H (cinnamate 4 hydroxylase), and G-alpha in pea. We have also discussed, the way of sequence retrieval, when the sequence is not reported in the organism of interest. We have evaluated the designed primers using cDNA prepared from mRNA isolated from the pea leaves. By analyzing the results, we have found that primers are perfectly binding with the target and giving single sharp band on a DNA electrophoresis gel. It can be concluded that the parameters used for primer designing by Primer3 play a critical role in the experimental results and parameters defined in the present study resulting in a very good amplification during PCR. PMID- 30456015 TI - Treatment of olive mill wastewater through employing sequencing batch reactor: performance and microbial diversity assessment. AB - This work describes the performance of a sequencing batch reactor (SBR) and the involvement of a novel reconstituted bacterial consortium in olive mill wastewater (OMW) treatment. The organic loading rate applied to the SBR was serially increased in terms of initial COD from 10 to 75 g L-1 to allow gradual acclimatization of activated sludge to high concentrations of toxic compounds in OMW. After the acclimatization period, up to 60% of the total COD content were effectively biodegraded from OMW at 75 g L-1 COD within 30 day hydraulic retention time. The diversity and community composition of cultivable bacteria participating in the aerobic process of treating OMW were further assessed. A total of 91 bacterial strains were isolated from the reactor and analyzed by amplification of the 16S-23S rRNA internal transcribed spacer (ITS) region and by 16S rRNA gene sequencing. The most abundant phylum was Firmicutes (57.1%) followed by Proteobacteria (35.2%) and Actinobacteria (7.7%). The use of the Biolog(r) Phenotype Microarray system to evaluate the ability of isolated strains to utilize OMW phenolic compounds is reported in this work for the first time. Interestingly, results showed that all species tested were able to utilize phenolics as sole carbon and energy sources. The removals of COD and phenolics from undiluted OMW by the reconstituted bacterial consortium were almost similar to those obtained by the acclimatized activated sludge, which suggest that cultivable bacteria play the major role in OMW biodegradation. Phytotoxicity assays using tomato seeds showed a significant improvement of seed germination values for treated OMW. Our overall results suggest that the novel developed bacterial consortium could be considered as a good prospect for phenolics-rich wastewaters bioremediation applications. PMID- 30456017 TI - Genotype frequency contributions of Mx1 gene in eight chicken breeds under different selection pressures. AB - Chicken Mx1 gene, as a positive antiviral gene, has been reported to provide resistance to several viruses especially avian influenza virus. In present research, the genotype frequency contributions of chicken Mx1 polymorphisms were characterized in five lowly selected as well as one moderately selected Sichuan native chicken populations and two highly selected commercial chicken breeds. Together with two newly-identified mutation sites (r.8A > G and r.1257T > C), a total of 13 single nucleotide polymorphisms (SNPs), including seven nonsynonymous mutation and six synonymous mutation, were found in the coding region of chicken Mx1 gene. Local Chinese chicken populations exhibited higher nucleotide diversity than commercial populations. Moreover, amino acid substitution sites as well as positive selection sites were located only in the domain not determined and GTPase domain, implying that amino acids mutations were likely needed in the modulatory and structural regions to better adapt the environment. Collectively, our results suggest that different selection pressures greatly influenced the genotype frequency contributions of chicken Mx1 gene. Understanding the interaction between genetic diversity and artificial selection may help us to better select and breed superior domestic chickens. PMID- 30456018 TI - Outcomes of Craniofacial Open Surgery in Octogenarians. AB - Introduction The steady increase in average life expectancy has led to a rise in the number of referrals of elderly patients for major operations. It is not clear whether age itself is a risk factor for morbidity and mortality after skull base operations. We investigated a possible link among a cohort of patients older than 80 years of age who underwent those surgeries in our department. Methods We conducted a retrospective analysis of all patients who underwent skull base surgery at the TASMC (Tel Aviv Sourasky Medical Center) between 2000 and 2016. Results A total of 369 patients underwent open skull base surgeries in our institution, and 13 were patients older than 80 years. The median age of the octogenarians was 83.4 (range 80-89), and the male-to-female ratio was 7:6. Twelve patients had major systemic comorbidities. Four patients had major complications associated with surgery: three had early wound complications, and one each had early central nervous system complications, early and late systemic complications, and late orbital complications. This complication rate is comparable to that of our younger group of 356 patients. The overall survival rate was measured for 30 days, 1 year, and 3 years, and it was not significantly different between the octogenarians and that of the younger patients. Further comparison of the elderly group with 13 matched younger patients revealed no difference of morbidity and mortality between the two groups. Conclusions Despite their systemic comorbidities, the morbidity and mortality rates associated with skull base surgery in octogenarians appear to be comparable to that of younger patients undergoing the same procedures. PMID- 30456019 TI - Costs in Pituitary Surgery: Racial, Socioeconomic, and Hospital Factors. AB - Objective To investigate the influence of patient demographic factors and hospital factors on cost and length of stay in patients undergoing pituitary surgery. Design/Setting A retrospective cross-sectional study of the 2008 to 2012 Nationwide/National Inpatient Sample. Participants Patient demographics and hospital characteristics for patients undergoing pituitary surgery were compared between white, black, and Hispanic patients. Main Outcome Measures Variables associated with increased cost and increased length of hospital stay were ascertained and compared against each racial and ethnic group via multiple linear regression analysis. Results Of 8,812 patients who underwent pituitary surgery, 5,924 (67.2%) patients were white, 1,590 (18.0%) were black, and 1,296 (14.7%) were Hispanic. Patient variables found to be significantly different between racial groups via univariate analysis were age, chronic conditions, gender, income, and primary payer. Hospital variables found to be significantly different were location/teaching status, region, and ownership. Hospitalization cost was significantly lower for whites (-$3,082, 95% confidence interval [CI] -$3,961 to $2,202) and significantly higher for both blacks ($1,889, 95% CI $842-$2,937) and Hispanics ($2,997, 95% CI $1,842-$4,152). Length of hospital stay was also significantly lower in whites (-1.01, 95% CI -1.31 to -0.72) and significantly higher for both blacks (0.65, 95% CI 0.30 to 1.00) and Hispanics (0.96, 95% CI 0.57-1.35). Conclusions Racial and ethnic factors contribute to differences in hospital utilization and cost for patients undergoing pituitary surgery. Further investigations are necessary to uncover the sources of these disparities in an effort to provide safer and more affordable care to all patients. PMID- 30456021 TI - Morbidity and Volumetric Progression in Juvenile Nasopharyngeal Angiofibroma in a Long-Term Follow-Up. AB - Objective We compare the open and transnasal approaches for the excision of juvenile nasopharyngeal angiofibromas regarding the rate of morbidity, and residual tumor and its symptomatic recurrence over time. In addition, we present volumetric measurements of juvenile nasopharyngeal angiofibromas over time. Methods All surgically treated patients of our institution were reviewed back to 1969 for type of surgery, residual tumor by magnetic resonance imaging (MRI) based volumetry, recurrence, and morbidity. We performed a prospective clinical and radiological follow-up on reachable patients. Results In total, 40 patients were retrievable from our records. We were able to follow up on 13 patients after a mean of 15.7 years since surgery (range: 1-47 years). Patients operated by the open approach had a higher rate of postoperative complications and thus a higher morbidity than endoscopic patients (4/4 vs 3/9; p = 0.007), although tumor sizes were equal among groups ( p = 0.12). Persisting tumor was noted in 3/4 and 4/9 ( p = 0.56) patients, respectively. The corresponding mean volumes of residual tumors were 16.2 +/- 14.4 cm 3 and 10.8 +/- 6.6 cm 3 ( p = 0.27). No progression could be noted in endoscopically treated patients ( p = 0.24, mean time between scans 2 years). Conclusions Our analysis shows that the endoscopic approach results in less morbidity. The open approach does not guarantee freedom from persisting tumor tissue. Age seems to be a most important risk factor for the conversion of an asymptomatic persistence into a symptomatic recurrence. PMID- 30456020 TI - Revision Surgery for Vestibular Schwannomas. AB - Objectives To describe clinical outcomes of patients undergoing revision surgery for vestibular schwannomas. Design Retrospective case series. Setting Tertiary private neurotologic practice. Participants Patients who underwent revision surgeries for recurrent/residual vestibular schwannomas between 1985 and 2015. Main Outcome Measures Degree of resection, facial nerve function, cerebrospinal fluid (CSF) leak. Results A total of 234 patients underwent 250 revision surgeries for recurrent/residual vestibular schwannomas. Of these, 86 carried a diagnosis of neurofibromatosis type 2 (NF2). The mean number of prior surgeries was 1.26, and 197 (85%) prior surgeries had been performed elsewhere. The average age at surgery was 43. The most common approach employed at the time of revision surgery was translabyrinthine (87%), followed by transcochlear (6%), middle fossa (5%), and retrosigmoid (2%). Gross total resection was achieved in 212 revision surgeries (85%). Preoperative House-Brackmann facial nerve function was similar in non-NF2 and NF2 groups (mean: 2.7). Mean postoperative facial nerve function at last follow-up was 3.8 in the non-NF2 group and 3.9 in the NF2 group. History of radiation and the extent of resection were not associated with differences in facial nerve function preoperatively or postoperatively. CSF leaks occurred after 21 surgeries (8%), and six (2%) patients required reoperation. Conclusions This is the largest series of revision surgery for vestibular schwannomas to date. Our preferred approach is the translabyrinthine craniotomy, which can be readily modified to include the transcochlear approach for improved access. CSF leak rate slightly exceeds that of primary surgery, and gross total resection is achievable in the vast majority of patients. PMID- 30456022 TI - Volumetry in the Assessment of Pituitary Adenoma Resection: Endoscopy versus Microscopy. AB - Background Assessment of the extent of resection after surgical resection of pituitary adenomas is most commonly reported in terms of the presence or absence of residual tumor. A quantitative comparison of volumetric resection between endonasal endoscopy (EE) and microsurgery (MS) has rarely been done. Methods A retrospective analysis was performed on a consecutive series of 154 patients with pituitary adenomas treated by the same surgeon at a single institution. We employed volumetric analysis pre- and postoperatively on two cohorts of pituitary adenoma patients treated through MS ( n = 37) versus EE approach ( n = 117). Results Volumetric analysis revealed a higher incidence of complete resection (64.4 vs. 56.8%) and mean volume reduction in the EE cohort (92.7 vs. 88.4%), although not significant. Recurrence rates were significantly lower in the EE group (7.7% vs 24.3%, p = 0.015). Subgroup analysis identified that patients with preoperative tumor volumes >1 mL were less likely to recur through EE (7.8 vs. MS: 29.6%; p = 0.0063). A higher incidence of complete resection was also noted in patients with favorable Knosp grades (0-1) (EE: 87.8 vs. MS: 63.2%; p = 0.036). Postoperative complication rates were not significantly different between both techniques. Conclusion Both microscopy and endoscopy are well-tolerated, effective approaches in the treatment of pituitary adenomas. Our series demonstrated that EE may be superior to MS in preventing tumor recurrence and achieving a complete resection in certain subsets of patients. EE provides a slight advantage in tumor control outcomes that may justify the paradigm shift to pure endoscopy at our center. PMID- 30456023 TI - Clinical Use of Navigation in Lateral Skull Base Surgery: Results of a Multispecialty National Survey among Skull Base Surgeons in Germany. AB - Objective To analyze the current clinical use of navigation at the lateral skull base among skull base surgeons in Germany. Methods A web-based questionnaire was provided to surgeons being head of the department and member of one of the following scientific societies: German Society of Head and Neck Surgery, Maxillo Facial Surgery, Neurosurgery, and German Skull Base Society. Replies were recorded anonymously. The questionnaire included the estimated case load per year and percent of surgery performed with navigation (middle and posterior fossa), type of navigation, estimates of intraoperative inaccuracy, and reasons for not using navigation. Results Eighty nine out of 99 replies met requirements for final analysis. Overall, 37% of skull base surgeons use navigation on a regular basis (15% use no navigation). Optical tracking is more frequently used than magnetic tracking (71 vs 19). At the middle fossa, ENT surgeons split into routine users ( n = 10/36) and rare users ( n = 16/36), the latter stating navigation inaccuracy as a major reason for neglecting navigation. Neurosurgeons use navigation at the middle fossa significantly more often and criticize navigation inaccuracy less. At the posterior fossa, navigation is used less frequently by both ENT and neurosurgeons with similar rates of estimated inaccuracy. Conclusions A moderate use of navigation at the lateral skull base was demonstrated. Insufficient accuracy causes ENT surgeons to frequently omit navigation at the middle fossa (not neurosurgeons) and posterior fossa (also neurosurgeons). Higher intraoperative navigation accuracy is needed to enhance the use of navigation at the lateral skull base. PMID- 30456024 TI - Lumbar Puncture for the Injection of Intrathecal Fluorescein: Should It Be Avoided in a Subset of Patients Undergoing Endoscopic Endonasal Resection of Sellar and Parasellar Lesions? AB - Objectives The use of intrathecal fluorescein (ITF) has become an increasingly adopted practice for the identification of cerebrospinal fluid (CSF) leaks during endoscopic skull base surgery for pituitary adenomas. Administration through lumbar puncture can result in postoperative positional headaches, increasing morbidity, cost, and length of stay. We sought to identify the incidence of and variables associated with postoperative headaches to determine if there was a subgroup of patients in whom this procedure should be avoided. Methods We conducted a retrospective single-institution review of 148 patients who underwent endoscopic resection with ITF for pituitary adenoma between December 2003 and February 2016. We excluded patients who had lumbar drains and with intraoperative CSF leak, as these patients may have other headache etiologies. Patient demographics, comorbidities, tumor features, surgical approach, surgical closure, and histology were recorded. Primary outcomes included the presence of postoperative and positional headaches. Results We identified 62 patients with postoperative headaches (41.9%) and 10 with positional headaches (6.8%), of whom 6 underwent blood patch with complete resolution. Following univariate analysis, there was a significant positive association with prolactin-secreting tumors ( p = 0.008). There was a negative association with a history of hypertension ( p = 0.0001) and age ( p = 0.01). Following multivariate modeling, the significance for hypertension ( p = 0.01) was preserved. Conclusions Positional headaches in patients who receive ITF are uncommon and should not limit its use in the preparations for endoscopic resection of pituitary adenomas. Avoiding ITF in younger patients without hypertension with prolactinomas might decrease the risk of post-ITF positional headaches. PMID- 30456025 TI - Incidence of Prolonged Systemic Steroid Treatment after Surgery for Acoustic Neuroma and Its Implications. AB - Objectives To determine the incidence of prolonged postoperative systemic corticosteroid therapy after surgery for acoustic neuroma as well as the indications and associated risk factors that could lead to prolonged steroid administration, and the incidence of steroid-related adverse effects. Study Designs Retrospective chart review. Methods Retrospective chart review of patients undergoing resection of acoustic neuroma between 2010 and 2017 at two tertiary care medical centers. Patient and tumor characteristics, operative approach, hospital length of stay, initial postoperative taper length, number of discrete postoperative steroid courses, and postoperative complications were analyzed. Results There were 220 patients (99 male, 121 female) with an average age of 49.4 (range 16-78). There were 124 left-sided tumors and 96 right-sided tumors. Within the group, 191 tumors were operated through a retrosigmoid approach, 25 tumors through a translabyrinthine approach, and 4 tumors with a combined retrosigmoid-translabyrinthine approach under the same anesthetic. In total, 35 (15.9%) patients received an extended initial course of postoperative systemic steroids, defined as a taper longer than 18 days. Twenty six (11.8%) patients received additional courses of systemic steroids after the initial postoperative taper. There were 5 (2.3%) patients who required an extended initial taper as well as additional courses of steroids. Aseptic meningitis, often manifested as headache, was the most common indication for additional steroids (14 cases of prolonged taper and 17 cases of additional courses). None of the patient or tumor factors including age, gender, side, size, and approach were statistically significantly associated with either a prolonged initial steroid taper or additional courses of steroids. An extended hospital length of stay was associated with a prolonged initial steroid taper ( p = 0.03), though the initial taper length was not predictive of additional courses of steroids. The cumulative number of days on steroids was associated with need for additional procedures ( p < 0.01) as well as steroid-related side effects ( p = 0.05). The administration of steroids was not found to significantly improve outcomes in postoperative facial paresis. Steroid-related complications were uncommon, seen in 9.26% of patients receiving steroids, with the most common being psychiatric side effects such as agitation, anxiety, and mood lability. Conclusions Systemic corticosteroids are routinely administered postoperatively for patients undergoing craniotomy for the resection of acoustic neuromas. In a review of 220 patients operated by a single neurotologist, no patient or tumor factors were predictive of requiring prolonged initial steroid taper or additional courses of steroids. The cumulative number of days on systemic steroids was associated with undergoing additional procedures and steroid-related side effects. The most common indications for prolonged or additional steroids were aseptic meningitis, cerebrospinal fluid leak, and facial paresis. Additional steroids for postoperative facial paresis did not significantly improve outcomes. Patient reported steroid-related complications were infrequent and were most commonly psychiatric including agitation, anxiety, and mood lability. PMID- 30456026 TI - Is Septoplasty Necessary When Using the Endoscopic Endonasal Transsphenoidal Approach for a Deviated Nasal Septum? AB - Objective This article describes the role played by endoscopic endonasal transsphenoidal approach (EETSA) to the sphenoidal process of the septal cartilage of a deviated nasal septum. Design Case series with chart review. Setting Tertiary referral center. Participants Between 2009 and 2016, 177 patients with skull base tumors who underwent EETSA were included. Main Outcome Measures In 8 cases, the conventional two nostrils-four hands technique was employed (group A). In 16 cases, we placed a right-side conventional nasoseptal flap and a left-side modified nasoseptal rescue flap (group B), and in 153 cases, bilateral modified nasoseptal rescue flaps (group C). The number of septoplasty required cases and the change of nasal cavity area differences reflecting septal deviation were measured. Results Septoplasty during EETSA was performed in two cases: one from group B and one from group C. There was no significant difference in the ratio of septoplasty-required cases among the three groups ( p = 0.127). Between pre- and postoperative nasal cavity, the cross-sectional area difference at the anterior end of the middle turbinate level significantly decreased ( p = 0.045). Also, the angle of deviation at the level of ostiomeatal unit significantly decreased after EETSA ( p < 0.001). Conclusion Separation of a deviated complex surrounding the sphenoidal process of the septal cartilage is the key to relieving a deviated nasal septum. EETSA combined with the two nostrils-four hands technique allows posterior septectomy (including removal of this deviated complex) to be performed. Thus, EETSA may commence without preceding septoplasty even in cases with severe nasal septum deviations. PMID- 30456027 TI - Pediatric Endoscopic Endonasal Approaches for Skull Base Lesions in the Very Young: Is It Safe and Effective? AB - Introduction The fully endoscopic expanded endonasal approach (EEA) has been shown to be safe and efficacious in pediatric patients. However, in the very young patient (ages six and under), the anatomical challenge of working through a small nasal corridor is problematic. The ability to repair the skull base and use a nasoseptal flap (NSF) has also been called into question. Here, we review skull base resections using EEA in patients aged 6 years and younger. Methods A retrospective chart review was conducted on pediatric patients age 6 years and younger who underwent EEA skull base resections over a 3-year period (June 2014 through June 2017). Results Eight children aged 6 and under with seven tumor pathologies underwent an EEA for the resection of their skull base tumors, with a mean follow-up of 1.45 years. Only chordoma cases required multiple-staged resections. There are no tumor recurrences to date. A high-flow intraoperative cerebrospinal fluid (CSF) leak was encountered in three cases, and there were no postoperative CSF leaks. CSF leaks were effectively repaired with NSFs. One patient suffered from postoperative hypopituitarism, one patient experienced recurrent epistaxis secondary to turbinate destruction by the tumor, and one patient expired 8 months postresection secondary to metastatic disease. Conclusion In our case series, EEA for skull base tumors in children aged 6 and under was a safe and effective surgical approach. Skull base defects are able to be effectively addressed with typical repairs including NSFs. Larger studies are warranted to further investigate this technique in this pediatric population. PMID- 30456028 TI - Toxicity of Gamma Knife Radiosurgery May Be Greater in Patients with Lower Cranial Nerve Schwannomas. AB - Objective Gamma Knife stereotactic radiosurgery (GK-SRS) is a preferred treatment option for tumors of the jugular foramen. We hypothesized that GK-SRS toxicity is higher for lower cranial nerve schwannomas than for glomus jugulare tumors despite anatomically similar locations. Methods We performed a retrospective review of all patients who received GK-SRS for glomus jugulare tumors and lower cranial nerve schwannomas at our institution between 2006 and 2014. Because of small sample sizes, Fisher's exact tests and logistic regression techniques were employed using SPSS. Result We identified 20 glomus jugulare tumors and 6 lower cranial nerve schwannoma patients with a median follow-up of 17 months. Median marginal dose was 16 Gy (range 13-18 Gy) and 12.5 Gy (range 12 14 Gy), respectively. All except one patient had tumor control at last follow-up visit. No worsening of pre-existing neurological deficits was observed. There were seven patients who developed any new neurological deficit after GK-SRS, four from the glomus group, and three from the schwannoma group (20 and 50% of each group, respectively). Only two of seven patients had permanent new neurological deficits. Both of them were in the schwannoma group. Univariate analysis showed that only a diagnosis of schwannoma had a greater risk of permanent new cranial nerve complication after GK-SRS compared with diagnosis of glomus jugulare ( p = 0.046). Conclusion Although the marginal dose for glomus jugulare is greater, our study suggests that the risk of a new permanent neurological deficit after GK SRS was higher in the schwannoma group compared with the glomus group. PMID- 30456029 TI - Natural History, Multimodal Management, and Quality of Life Outcomes of Trigeminal Schwannomas. AB - Background Trigeminal schwannomas are the second most common among intracranial schwannomas. These can arise from anywhere between the root and the distal extracranial branches of the trigeminal nerve. Clinical presentation depends on location and size, including but not limited to facial hypesthesia or pain, headaches, dizziness, ataxia, and diplopia. Literature is strikingly scant discussing the natural history of these lesions, while the treatment goals are heavily dependent on tumor presentation. Management decisions must be individualized to each tumor and each patient, while attempting to maximize the quality of life. We present the natural history of these lesions as well as their management by surgical resection or radiation therapy, and report long-term quality of life outcomes. Methods Between 2001 and 2015, 24 patients (66.7% female) with trigeminal schwannomas were diagnosed and managed at Vancouver General Hospital. We analyzed the clinical presentation, surgical results, resection rates, patient quality of life, and complications. To complete the evaluation, we prospectively collected 36-Item Short Form Health Survey (SF-36) quality of life assessments for comparison. Results We identified 12 patients treated with a craniotomy and surgical resection, 4 were treated with radiation therapy, while 8 patients were followed by observation. Mean age of study cohort was 49.2 years (range, 23-79 years), and most patients presented with facial hypesthesia (54.2%) and headaches (37.5%), while 37.5% were incidental findings. There were no major differences in patient demographics between the three groups. Patients offered surgery had larger lesions (mean diameter, 3.4 +/- 1.1 cm) when compared with those that were irradiated or observed, and were more likely to have extracranial extension. Overall patient quality of life improved following treatment (DeltaSF-36 + 12.9) at 3.9 years. Conclusions The treatment goals of trigeminal schwannomas focus on improvement in neurologic symptoms, relief of mass effect, and preservation of cranial nerve function. We demonstrate that smaller lesions found incidentally with minimal symptoms can be followed safely with serial imaging, with 1 of 9 (11.1%) progressing to require treatment over the course of 7.1 years. Management of trigeminal schwannomas should be individualized with an involvement of a multidisciplinary skull base team. PMID- 30456030 TI - Comparison of Constructive Interference in Steady-State and T1-Weighted MRI Sequence at Detecting Pituitary Adenomas in Cushing's Disease Patients. AB - Background T1-weighted magnetic resonance imaging (MRI) remains the standard pituitary imaging sequence. However, up to 50% of pituitary adenomas are missed with standard imaging in Cushing's disease (CD) patients. Utility of other imaging sequences needs be explored. Objective To compare a T2-gradient echo sequence, constructive interference in steady state (CISS), with a contrast enhanced (CE) T1-weighted sequence, volume-interpolated breath-hold examination (VIBE), in the detection of pituitary adenomas in CD patients. Design Retrospective analysis of CD patients who underwent endoscopic transsphenoidal pituitary adenomectomy at our institution. Patients and Measurement Twelve patients were included in the study. Two neuroradiologists, who were blinded to the patients' clinical and surgical findings, independently reviewed the CE-VIBE and CISS images. Localization of pituitary adenoma from imaging was compared with intraoperative localization. Results The averaged sensitivity of detecting pituitary adenoma in CD patients was not significantly different between CE-VIBE sequence (63%) and CISS sequence (54%). The positive predictive value was 75% (Observer A) and 100% (Observer B) with CE-VIBE sequence, and 64% (Observer A) and 100% (Observer B) with CISS sequence. In two patients, pituitary adenoma was easily localized with CISS sequence but hard to detect with CE-VIBE sequence. In two other patients, the adenoma was much better delineated on CE-VIBE sequence. Conclusion In our series, the addition of CISS sequence to T1-weighted MRI imaging protocols improved the detection of pituitary adenomas in CD patients. CISS sequence may be a useful adjunct to T1-weighted pituitary MRI protocols and an appropriate alternative for patients with gadolinium contraindications. PMID- 30456031 TI - Red Blood Cell Transfusions Following Resection of Skull Base Meningiomas: Risk Factors and Clinical Outcomes. AB - Objective This article identifies risk factors for and investigates clinical outcomes of postoperative red blood cell transfusion in patients with skull base meningiomas. Design Retrospective cohort study. Setting Single academic medical center. Participants The transfusion group included patients who had skull base meningiomas and who received packed red blood cell (RBC) transfusion within 7 days of surgery. The no transfusion group included patients who had skull base meningiomas but who did not have RBCs transfused within 7 days of surgery. Main Outcome Measures In-hospital complication rate, length of stay (LOS), and discharge disposition. Results One hundred and ninety-six patients had a craniotomy for resection of a meningioma at our institution from March 2013 to January 2017. Seven patients had skull base meningiomas and received RBC transfusion within 7 days of surgery (the transfusion group). The skull base was an independent risk factor for transfusion after we controlled for the effect of meningioma size (OR 3.89, 95% CI 1.34, 11.25). Operative time greater than 10 hours was an independent risk factor for prolonged hospital stay (OR 8.84, 95% CI 1.08, 72.10) once we controlled for the effect of transfusion. In contrast, transfusion did not independently impact LOS or discharge disposition once we controlled for the effect of operative time. Conclusions The skull base is an independent predictor of RBC transfusion. However, RBC transfusion alone cannot predict LOS or discharge disposition in patients who undergo surgical resection of a skull base meningioma. PMID- 30456034 TI - Microsurgical Gross Total Resection of a Large Residual/Recurrent Vestibular Schwannoma via Translabyrinthine Approach. AB - Although, gross total resection in large vestibular schwannomas is an ideal goal, subtotal resection is frequently performed due to lack of expertise, concerns for facial palsy, or overuse of stereotactic radiation. In this video, we present a 31-year-old man with a 7-year history of tinnitus, dizziness, and hearing loss. The patient had a subtotal resection of a 2.5 cm right-sided vestibular schwannoma via retrosigmoid craniotomy at an outside hospital. He was referred for further surgical resection due to the increased size of the tumor on surveillance magnetic resonance imagings (MRIs) and worsening symptoms. MRI showed a residual/recurrent large schwannoma with extension to the full length of the internal acoustic canal and brain stem compression. He underwent microsurgical gross total resection via a translabyrinthine approach. The facial nerve was preserved and stimulated with 0.15 mA at the brainstem entry zone. He awoke with House-Brackmann grade III facial function, with an otherwise uneventful postoperative course. In this video, microsurgical techniques and important resection steps for this residual/recurrent vestibular schwannoma are demonstrated, and nuances for microsurgical technique are discussed. The link to the video can be found at: https://youtu.be/a0ZxE41Tqzw . PMID- 30456032 TI - Swallowing Dysfunction in Adult Patients with Chiari I Malformation. AB - Background Swallowing difficulties have been reported in patients with Chiari I malformation (CMI) with a prevalence of 4 to 47%, but existing evidence is based only on case reports. We aimed to prospectively study swallowing function in adult patients with CMI before and 3 months after surgical decompression. Methods We included all adult patients diagnosed with CMI from September 2015 to October 2017 who underwent a planned surgery at Sahlgrenska University Hospital, Sweden. The patients were offered the opportunity to participate in and undergo an assessment consisting of the "Watson Dysphagia Scale (WDS)" and "EORTC QLQ-OG25" written questionnaires in addition to videofluoroscopic examination of swallowing (VFS) before and 3 months after surgery. Demographic data and comorbidities were recorded. Results Eleven patients were included, nine of which underwent both pre- and postoperative evaluations. Four patients (36%) reported varying degrees of swallowing complaints (mean WDS score, 16). In two of these, there was substantial penetration of contrast material into the laryngeal vestibule on VFS, and in the other two patients, minor swallowing disturbances were observed. Borderline deviations from normal VFS findings were also found in three asymptomatic patients. Although not all VFS deviations completely disappeared after surgery, the patients reported no remaining symptoms. Conclusion Symptoms of dysphagia and objective abnormalities on VFS are not uncommon in CMI patients. Surgery has the potential to remedy underlying causes of dysphagia, thereby relieving its symptoms. PMID- 30456033 TI - Skull Base Dural Thickness and Relationship to Demographic Features: A Postmortem Study and Literature Review. AB - Dural membrane is an important anatomic structure that surrounds and protects the entire central nervous system. Physical properties of the dura have many pathophysiological and therapeutic implications in cranial surgery, especially skull base disorders. The aim of this study is to investigate variation in skull base dural thickness and correlation with different demographic parameters. At the time of autopsy, the petrous apex dura with the underlying bone of 20 cadavers was harvested. Dural thickness was independently measured by two pathologists at the thinnest and thickest segments in the specimen. Correlational analyses were then performed to compare dural thickness with gender, age, neck circumference, height, weight, and body mass index (BMI). Mean, minimum, and maximum skull base dural thickness in our study was 0.36, 0.27, and 0.46 mm, respectively. Age demonstrated a negative correlation with dural thickness with significantly thinner dura in the older subjects, p = 0.01. There was a trend toward thinner dura in females that approached statistical significance, p = 0.06. No strong correlation could be found with body weight, height, neck circumference, or BMI. Our findings show a considerable intersubject and intrasubject variability in skull base dural thickness. Some demographic parameters also seem to impact dural thickness. Additional histological studies are needed for better understanding of the pathophysiological mechanisms pertaining to the tensile properties of the dural membrane. PMID- 30456035 TI - Trigeminal Nerve Schwannoma of the Cerebellopontine Angle. AB - Introduction Large and even moderate sized, extra-axial cerebellopontine angle (CPA) tumors may fill this restricted space and distort the regional anatomy. It may be difficult to determine even with high resolution magnetic resonance imaging (MRI) if the tumor is dural-based, or what the nerve of origin is if a schwannoma. While clinical history and exam are helpful, they are not unequivocal, particularly since many patients present with a myriad of symptoms, or conversely an incidental finding. We present an atypical appearing, asymptomatic CPA tumor, ultimately identified at surgery to be a trigeminal schwannoma. Case History A 40-year-old man presented with new-onset seizure. MRI identified an incidental heterogeneously contrast-enhancing CPA lesion ( Fig. 1A D ). The tumor was centered on the internal auditory canal (IAC) with no tumor extension into Meckel's cave, IAC or jugular foramen. Audiometry demonstrated 10db of relative left-sided hearing loss with 100% word recognition. Physical examination was negative for focal neurologic deficits. A retrosigmoid craniotomy was performed and an extra-axial, yellow-hued mass was encountered and resected, which was ultimately confirmed to originate from the trigeminal nerve ( Video 1 ). Gross total resection was achieved, and the patient recovered from surgery with partial ipsilateral trigeminal sensory loss and no other new neurologic deficits. Conclusion Pure CPA trigeminal schwannomas are rare, but should be considered in the differential for enhancing CPA lesions. Although, Meckel's cave involvement is frequently observed, it is not universal, and pure CPA schwannomas of all cranial nerves IV-XII have been reported in the literature. The link to the video can be found at: https://youtu.be/AlodYCu70F8 . PMID- 30456036 TI - Presigmoid Approach to Dumbbell Trigeminal Schwannoma. AB - This case is a 15-year-old male, presenting with headaches, right face, and arm numbness, and ataxia. MRI (magnetic resonance imaging) revealed a large right sided dumbbell shaped lesion, extending into the middle and posterior fossa with compression of the brainstem consistent with a trigeminal schwannoma. Treatment options here would be a retrosigmoid suprameatal approach or a lateral presigmoid approach. Given the tumor extension into multiple compartments, a presigmoid craniotomy, combining a middle fossa approach with anterior petrosectomy, and retrolabyrinthine approach with posterior petrosectomy were used to maximize the direct access corridor for resection. The petrous apex was already expanded and remodeled by the tumor. Nerve fascicles preservation technique is paramount to the functional preservation of the trigeminal nerve. The extent of resection should be weighed against the anatomical functional integrity of the nerve. Near total resection is considered if that means more nerve preservation. Postoperatively, the patient had a slight (House-Brackman grade II) facial droop, which resolved over days and developed right trigeminal hypesthesia at several weeks. This case is presented to demonstrate a combined petrosectomy technique for resection of lesions extending into both the middle and posterior cranial fossa with near total resection and trigeminal nerve preservation. The link to the video can be found at: https://youtu.be/kA9GyFhL1dg . PMID- 30456037 TI - Retrosigmoid Approach to the Posterior Fossa Trigeminal Schwannoma. AB - We present a case of a posterior fossa trigeminal schwannoma in a 31-year-old gentleman. Preoperative symptomatology included headaches and dizziness of 6 months in duration. Trigeminal schwannomas isolated to the posterior fossa, not extending into Meckel's Cave, may be adequately resected via a retrosigmoid approach. Thus, a tailored retrosigmoid approach was planned with navigation assistance. A key point to highlight is the difficult identification and preservation of trigeminal nerve fascicles within the tumor mass. In this operative video we show a nerve preservation technique. By identifying the nerve at the anticipated anatomical location and utilizing sharp dissection, we create a dissection plane from the nerve fascicles. The surgical strategy of near total resection and leaving minimal tumor tissue on the nerve should be pursued in return for anatomical preservation of the nerve. Postoperative course was significant for facial hypoesthesia, abducens partial palsy, and gradual improvement of headaches. The link to the video can be found at: https://youtu.be/JsE1-Eonr0k . PMID- 30456038 TI - Resection of a Petroclival Meningioma via the Endoscope-Assisted Retrosigmoid Approach: 2-D Operative Video. AB - We present a case of a petroclival meningioma that was resected through an endoscope-assisted retrosigmoid approach via corridors above and below the facial vestibulocochlear nerve complex. The patient is a 61-year-old female with complaints of left-sided hypesthesia and neuralgia of the infraorbital and zygomatic region, intermittent periorbital myokymia, and a slight facial palsy (HB II). This 2D video demonstrates the operative technique, anatomical and surgical nuances of the skull base approach and microdissection of the tumor from the critical neurovascular structures. A gross total resection was achieved. The patient's facial and trigeminal symptoms resolved completely within a few weeks. At 2 year follow up there was no indication of residual or recurrence. In summary, the retrosigmoid approach with endoscopic assistance is an important and powerful tool in the armamentarium for the microsurgical management of meningiomas of the lateroventral skullbase of the posterior fossa. The link to the video can be found at: https://youtu.be/Px4XIRDoALc . PMID- 30456039 TI - Suboccipital Lateral Approach for Resection of Cerebellopontine Angle Meningioma: Operative Video and Technical Nuances. AB - We present the case of a 34-year-old woman, who presented to our department with a 4 months history of dizziness, hearing loss, and tinnitus on the right side. MRI (magnetic resonance imaging) scan demonstrated a large extra-axial lesion, suggestive of a meningioma, with dural attachments to the petrosal bone surface and tentorium, closely related with the trigeminal, abducens, facial, vestibulocochlear, and lower cranial nerves in the right side. Treatment options were discussed with the patient, and surgical resection was selected to remove the lesion, and decompress the cranial nerves and brainstem. The surgery was performed with a patient in a semi-seated position with head placed in a flexed, nonrotated position. A right lateral suboccipital approach was performed, exposing the right transverse and sigmoid sinuses. After dura opening, microsurgical dissection was used to open the cisterna magna, and obtain cerebellum relaxation. That was followed by identification of cranial nerves VII XII and then identification of the tumor itself. Tumor debulking was then performed with use of suction and ultrasonic aspirator. After extensive resection, the tumor margins were dissected away from brainstem, cerebellum, and cranial nerves. Finally, the tumor attachment to the tentorium was coagulated and cut and the tumor was completely removed. Postoperative MRI confirmed complete resection of the tumor. The patient was discharged on the 1st week after surgery, with no additional postoperative deficits or complications. The link to the video can be found at: https://youtu.be/aZ3jhZTAeAA . PMID- 30456040 TI - Gross Total Resection of Large Cerebellopontine Angle Meningioma with a Supratentorial Extension via Retrosigmoid Approach with Suprameatal Drilling and Tentorial Sectioning. AB - Meningiomas are the second most common neoplasm in the cerebellopontine angle (CPA), and are challenging lesions to treat surgically. With significant refinements in surgical techniques, operative morbidity, and mortality have been substantially reduced. Total or near-total surgical resection can be accomplished in the majority of cases via appropriately selected approaches, and with acceptable morbidity. In this video, we present a 51-year-old woman, who had a 2 year history of vertigo with symptoms that progressed over time. She presented with blurry vision, sensorineural hearing loss, tinnitus, left-sided facial numbness, and double vision. Magnetic resonance imaging (MRI) showed a left-sided homogeneously enhancing mass at CPA with a supratentorial extension. MRI appearance was consistent with a CPA meningioma with supratentorial extension. The patient underwent surgical resection via a retrosigmoid approach. Suprameatal drilling and tentorial sectioning were necessary to achieve gross total resection. The surgery and postoperative course were uneventful. The histopathology was a WHO (world health organization) grade I meningioma. MRI showed gross total resection of the tumor. After a 1.5-year follow-up, the patient is continuing to do well with no residual or recurrent disease. In this video, microsurgical techniques and important steps for the resection of this challenging meningioma of the cerebellopontine angle are demonstrated. The link to the video can be found at: https://youtu.be/CDto52GxrG4 . PMID- 30456041 TI - Combined Presigmoid and Retrosigmoid Approach to Petroclival Meningiomas. AB - Introduction The management of petroclival meningiomas is among the most intimidating in neurosurgery, due to its difficult accessibility and close relationship with vital structures; therefore, an appropriate exposure is mandatory. We present a surgical video demonstrating a presigmoid transtentorial approach, associated with the opening of the retrosigmoid dura to a petroclival meningioma, performed by the senior surgeon (L.A.B.B.), along with its indications and pitfalls. Approach Decision The patient's clinical history is summed to the tumor's radiological features as its extension, vascularization, and venous drainage, when selecting the appropriate approach. The presigmoid transtentorial approach offers a wide exposure of the petroclival area along with the tumor's attachment. Its association with the retrosigmoid route allows the surgeon to freely work through multiple paths, and parallel to the skull base, reducing the traction in the temporal lobe. Clinical Case This is a 39-year-old female presenting with trigeminal neuralgia. Imaging depicted a petroclival meningioma, extending from the posterior aspect of the cavernous sinus to the cerebellopontine angle, extending inferiorly to the jugular bulb. A Simpson II resection was achieved through a combined presigmoid and retrosigmoid approach, and the patient was discharged with no complications or new deficits. Conclusion Petroclival meningiomas are a formidable and surgically treatable disease. The appropriate approach is design to each patient and should not be the limiting factor for total tumor removal, which is truly given by the absence of a dissection plane between the tumor and the brainstem, nerves and vascular structures of the skull base. The link to the video can be found at: https://youtu.be/MFjqZvElBSo . PMID- 30456042 TI - Trochlear Nerve Repair during Retrosigmoid Suprameatal Approach for Petrotentorial Meningioma: Operative Video. AB - When operating on difficult skull base lesions, it is essential to be able to handle unexpected intraoperative findings or troubles, while achieving maximal lesion removal and minimal functional deficit. This video demonstrates a case of trochlear nerve repair that was performed during the retrosigmoid suprameatal approach for treatment of a petrotentorial meningioma, extending into the Meckel's cave. The patient is a 47-year-old woman with a right petrotentorial meningioma, extending into the Meckel's cave. The retrosigmoid suprameatal approach was performed with preservation of the superior petrosal vein. However, a divided trochlear nerve was incidentally found during tumor resection. We hence carefully dissected both nerve ends from the tumor without shortening their lengths, and repaired them by end-to-end anastomosis, using fibrin glue without any graft materials. The tumor was removed completely and the patient's preoperative facial sensory impairment disappeared after the surgery. The patient's facial sensory impairment disappeared completely, but she had transient diplopia after the surgery. However, the newly developed diplopia resolved completely, and she had no neurological deficits or tumor recurrence during the follow-up period of 1-year. The link to the video can be found at: https://youtu.be/g-B-w_zDudg . PMID- 30456043 TI - Retrosigmoid Approach for Resection of Cerebellopontine Angle Meningioma. AB - This video depicts the case of an 81-year-old man who presented with a 3-month history of left-sided facial numbness and gait imbalance. On examination, he had gait ataxia and decreased left facial sensation in the V2 and V3 distribution. Magnetic resonance imaging (MRI) revealed a large homogenously enhancing lesion arising from the inferior surface of the tentorium toward the left cerebellopontine angle causing significant brainstem compression ( Fig. 1A and 1B ). The differential diagnoses for this lesion included meningioma and trigeminal nerve schwannoma. Given the patient's symptoms, the size of the lesion, and the severity of brainstem compression, surgical resection was recommended. The patient underwent a left retrosigmoid craniotomy for resection of the mass ( Fig. 2 ). The patient tolerated the procedure well with no new postoperative neurological deficit. Histopathological examination of the lesion revealed a World Health Organization (WHO) grade I meningioma. Postoperative MRI was consistent with gross total resection of the tumor ( Fig. 1C and 1D ). The patient was discharged home on postoperative day 4. At his last follow-up appointment, 1 month after surgery, the patient reported complete resolution of his imbalance and left-sided facial numbness. The patient gave consent for publication. The link to the video can be found at: https://youtu.be/xoHmhv7bme4 . PMID- 30456044 TI - Endoscope-Assisted Retrosigmoid Approach for Cerebellopontine Angle Epidermoid Tumor. AB - Objectives Surgical resection is the only effective treatment modality for epidermoid tumors. Complete resection with preservation of neurological function must be pursued whenever possible, because it offers a cure for patients. However, the inability to identify hidden remnants, interdigitating around cranial nerves, especially in larger tumors, may be a contributing factor for incomplete resection. This operative video demonstrates the technical nuances in achieving complete resection of a cerebellopontine angle epidermoid tumor via an endoscope-assisted retrosigmoid approach. Design and Setting Operative video of an endoscope-assisted retrosigmoid, approach for complete resection of a cerebellopontine angle epidermoid tumor. The patient was a 16-year-old female, who presented with 1-year history of worsening headaches and imbalance. Her neurological exam was normal, including normal cranial nerve function, and hearing. Radiological evaluation revealed an epidermoid tumor in the right cerebellopontine angle, extending to the interpeduncular cistern. Surgical resection was recommended. Given extension of the tumor across the midline, an endoscope-assisted procedure was planned to increase the odds of complete resection. Results The video demonstrates the surgical technique applied for tumor resection. The patient's clinical symptoms resolved completely after surgery and she remained neurologically intact. Postoperative magnetic resonance imaging (MRI) confirmed complete tumor resection. There were no postoperative complications. Conclusions The use of endoscopic techniques for resection of cerebellopontine angle epidermoid tumor is safe and effective and may increase the odds of complete resection, especially in larger tumors spreading across the midline, by enabling the surgeon clear visualization of deep-seated and contralateral relevant neurovascular structures, not readily accessible by the surgical microscope. The link to the video can be found at: https://youtu.be/X6YP_7OeQQE . PMID- 30456045 TI - Retrosigmoid Craniotomy for Resection of an Epidermoid Cyst of the Posterior Fossa. AB - This video illustrates the case of a 51-year-old woman who presented with sudden onset headache, vertigo, and nausea. Imaging revealed an epidermoid cyst of the posterior fossa with mass effect upon the brainstem and displacement of the basilar artery. This lesion was approached using a left-sided keyhole retrosigmoid craniotomy with monitoring of the cranial nerves. This video illustrates the technique of internal debulking of the cyst contents with minimal manipulation of the cyst capsule, which is often densely adherent to the brainstem, cranial nerves, and vessels in the posterior fossa. Resection of the capsule is often associated with a higher rate of cranial nerve deficits. The tumor was removed completely, but the cyst capsule was left in place. The patient had House-Brackmann grade II facial paralysis postoperatively and complained of some diminished hearing in the left ear. Epidermoid cysts are benign tumors, but the patient may experience much morbidity from their overly aggressive resection, especially when the capsule is densely adhering to critical structures. An alternate strategy is to decompress the contents of the epidermoid cyst, thereby decompressing the brainstem and converting this disease process into a chronic disease that may require reoperation in the long term. Given the tight confines of the posterior fossa, aggressive internal decompression of tumors and mobilization from the brainstem and adjacent nerves are key to avoiding injury to the brainstem and cranial neuropathies. In patients with benign tumors, the goal of the operation should be decompression of the brainstem and preservation of cranial nerve function. The link to the video can be found at: https://youtu.be/nk8-VztB0OI . PMID- 30456046 TI - Endoscopic Assisted Retrosigmoid Approach for Cerebellopontine Angle Epidermoid Tumor. AB - This case is a 20-year-old male, who presented with 1 month of right facial weakness (HB4) and complaints of ipsilateral eye dryness. He was initially treated for Bell's palsy with steroids and antiviral agents, but subsequently developed diplopia with right lateral gaze and underwent an MRI (magnetic resonance imaging). MRI demonstrated a 4.5 cm irregular lesion in the right cerebellopontine angle consistent with an epidermoid cyst. Because the tumor had grown with the development of the central nervous system, it has extended into different compartments, including the tentorial incisura and pineal region. A predefined surgical corridor created by the tumor facilitated access to the majority of the tumor through a retrosigmoid approach. Angled endoscopes (30 degree up and down) provided further visualization of tumor away from the line of sight of the microscope, thus allowing for gross total resection of the lesion. This video also demonstrates a sharp dissection technique necessary for safe removal of adherent tumor from critical neurovascular structures, including the basilar artery and several cranial nerves. The ipsilateral auditory evoked responses (ABRs) showed slight improvement from baseline toward the end of the case. A gross total resection was achieved, as shown by the MRI. The patient remained at his baseline cranial nerve (CN) V, VII, and VIII deficits during the immediate postoperative period. The link to the video can be found at: https://youtu.be/vCq5juJh8hk . PMID- 30456047 TI - Extreme Lateral Supracerebellar Infratentorial Approach to the Lateral Midbrain. AB - This video illustrates the case of a 52-year-old man with a history of multiple bleeds from a lateral midbrain cerebral cavernous malformation, who presented with sudden-onset headache, gait instability, and left-sided motor and sensory disturbances. This lesion was eccentric to the right side and was located in the dorsolateral brainstem. Therefore, the lesion was approached via a right-sided extreme lateral supracerebellar infratentorial (exSCIT) craniotomy with monitoring of the cranial nerves. This video demonstrates the utility of the exSCIT for resection of dorsolateral brainstem lesions and how this approach gives the surgeon ready access to the supracerebellar space, and cerebellopontine angle cistern. The lateral mesencephalic safe entry zone can be accessed from this approach; it is identified by the intersection of branches of the superior cerebellar artery and the fourth cranial nerve with the vein of the lateral mesencephalic sulcus. The technique of piecemeal resection of the lesion from the brainstem is presented. Careful patient selection and respect for normal anatomy are of paramount importance in obtaining excellent outcomes in operations within or adjacent to the brainstem. The link to the video can be found at: https://youtu.be/aIw-O2Ryleg . PMID- 30456048 TI - Extended Retrosigmoid Approach for the Resection of a Pontomedullary Junction Cavernous Malformation. AB - Objectives To describe an extended retrosigmoid approach for the resection of a cavernoma involving the ponto-medullary junction, with emphasis on the microsurgical anatomy and technique. Design A retrosigmoid craniotomy is performed in the lateral decubitus position and the sigmoid sinus exposed. After opening the dura, sutures are placed medial to the sinus to allow its gentle mobilization. Cerebrospinal fluid (CSF) is drained from the cisterna magna, and cerebellopontine cistern, and dynamic retraction is used over the cerebellum. Subarachnoid dissection of the cerebellopontine angle gives access to cranial nerves IX/X, VII/VIII, and VI. Inspection of the pontomedullary junction medial to the facial nerve reveals hemosiderin staining in that region. A small pial opening is made, exposing the hemorrhagic cavity. The cavernous malformation is then identified, dissected circumferentially, and resected. Photographs of the region are borrowed from Dr Rhoton's laboratory to illustrate the microsurgical anatomy. Participants The senior author performed the surgery. The video was edited by Drs. J.B. and V.N. Outcome Measures Outcome was assessed with extent of resection and postoperative neurological function. Results A gross total resection of the lesion was achieved. The patient did not develop any postoperative deficits. Conclusion Understanding the microsurgical anatomy of the cerebellopontine angle and meticulous microneurosurgical technique are necessary to achieve a complete resection of a brainstem cavernoma. The extended retrosigmoid approach provides an adequate corridor to the pontomedullary junction. The link to the video can be found at: https://youtu.be/FIKixWJT75w . PMID- 30456049 TI - Retrosigmoid Approach for Resection of Cerebellar Peduncle Cavernoma. AB - The case described in this video involved a 38-year-old man, who presented with a 4-week history of worsening acute-onset headache, nausea, double vision, and vertigo. On examination, he had impaired tandem gait and diplopia on right horizontal gaze. A computed tomography (CT) scan revealed a hyperdense lesion of the right cerebellopontine angle. Magnetic resonance imaging (MRI) revealed a nonenhancing middle cerebellar peduncle lesion that was isointense on T2-weighed imaging and hypointense on FLAIR imaging ( Fig. 1A - B ). The differential diagnoses for this lesion included cavernous malformation, thrombosed aneurysm, and neurocysticercosis. CT angiography was done preoperatively to rule out cerebral aneurysm. Surgical resection of the lesion was recommended to relieve his symptoms, to prevent further deterioration/bleeding, and to obtain a pathological diagnosis. The patient underwent a right retrosigmoid craniotomy for resection of the right middle cerebellar peduncle cavernoma ( Fig. 2 ). The patient tolerated the procedure well with no new postoperative neurological deficit. Postoperative MRI depicted gross total resection of the lesion and expected residual blood in the resection cavity ( Fig. 1C - D ). The patient was discharged home on postoperative day 4. At his last follow-up appointment, 1 month after surgery, he reported complete resolution of his preoperative symptoms, including diplopia. The patient gave consent for publication. The link to the video can be found at: https://youtu.be/TRieS9DXbV4 . PMID- 30456050 TI - A Rare Complication of Endovascular Embolization: Extruded Onyx on Trigeminal Nerve. AB - Objectives To demonstrate a rare complication of endovascular tumor embolization with onyx. Design Operative video. Setting Department of neurological surgery in a university hospital. Participants A 39-year-old male who was diagnosed with a right sided hemangioblastoma. Main Outcome Measures Surgical resection of the tumor, preservation of the cranial nerves and extruded embolization material on trigeminal nerve. Results The tumor was embolized with onyx the day before surgery. Patient woke up with no sensation in the right side of his face. Diffusion magnetic resonance imaging (MRI) showed a small restricted diffusion area within the right superior cerebellar vermis. Microsurgical resection of the tumor was uneventful and complete resection was achieved (Fig. 1). After the resection was completed, the trigeminal nerve was identified. Some of the capillaries overlying the nerve as well as the cerebellum and brain stem had extruded onyx-embolic material (Fig. 2). Some of the onyx over the cerebellum was removed; however, the ones on the trigeminal nerve and brain stem were not removed due to the risk of injury to the nerve. Postoperative MRI confirmed total resection. Patient made excellent recovery except he continued to have no sensation in the right side of his face. Conclusion Preoperative embolization is an important adjunct to resection of large hemangioblastomas in selected cases because it may facilitate circumferential dissection and debulking of the tumor. Although extrusion of the embolization material is relatively common, immediate extrusion of onyx and its transfixion on a cranial nerve has not been reported before. Judicial selection of preoperative embolization is required in hemangioblastomas. The link to the Video can be found at: https://youtu.be/s0DjD26Xkas . PMID- 30456051 TI - Gross Total Resection of a Jugular Foramen Thyroid Medullary Metastasis via a Transjugular Transsigmoid Approach. AB - Surgical resection of jugular foramen tumors poses a significant challenge to skull base surgeons with the selection of an appropriate surgical approach, a matter of some debate. Jugular foramen metastatic tumors may mimic paragangliomas, and in some selected cases surgical resection is needed. In this video, we demonstrate the microsurgical gross total resection of a jugular foramen tumor via a postauricular trans-jugular trans-sigmoid approach. The patient is a 61-year-old man with a 7-year history of medullary thyroid cancer, who underwent three neck operations and radiation to the neck. He developed lower cranial nerve palsies (IX, X, and XI) with preoperative aspiration deficits, dysphonia, status post phonosurgery for vocal cord paralysis, profound sensorineural hearing loss, and muscle atrophy of the left shoulder. He initially received stereotactic radiation of the jugular foramen tumor at an outside hospital without histopathological diagnosis. Follow-up magnetic resonance images (MRIs) showed progressive enlargement of the tumor over the postradiation year. The decision was made to resect this tumor to enable histopathological diagnosis, and to provide local tumor control, since his primary disease has been stable. He underwent microsurgical gross total resection via a transjugular transsigmoid approach. After skeletonizing the sigmoid sinus and jugular bulb, the sigmoid sinus was ligated and rolled toward the jugular bulb, where the major part of the tumor was. Then, using the transjugular route, the tumor was removed en bloc. The surgery and postoperative course were uneventful. The histopathology was a thyroid medullary cancer metastasis. He was followed with serial MRIs, and there was no recurrent tumor at 2 years follow-up. In this video, microsurgical techniques and important steps for the resection of a jugular foramen metastatic tumor are demonstrated. The link to the video can be found at: https://youtu.be/oXC6fX2CC84 . PMID- 30456052 TI - Effects of a physical activity intervention on schoolchildren's health-related quality of life: The active smarter kids (ASK) cluster-randomized controlled trial. AB - We investigated whether a seven-month (November 2014 to June 2015), school-based cluster-randomized controlled physical activity intervention improved health related quality of life (HRQoL) in 10-year old children. The participants (N = 1229) from 57 elementary schools in Sogn og Fjordane County, Norway, were cluster randomized by school either to the intervention (I) or control (C) group. The planned intervention in the 28 I-schools was 300 min of physical activity per week, compared to 135 min in the 29C-schools. HRQoL was assessed by self-report, using the Kidscreen-27 questionnaire. Objectively measured physical activity did not differ between the I-schools and C-schools during the intervention. No effect of the intervention was found for HRQoL: Physical well-being (P = 0.789), Psychological well-being (P = 0.682), Autonomy & parents (P = 0.662), Social support & peers (P = 0.828) and School environment (P = 0.074). In conclusion, the ASK school-based physical activity intervention showed no significant effect on HRQoL. PMID- 30456053 TI - Meeting fruit and vegetable consumption and physical activity recommendations among adolescents intending to lose weight. AB - Two-thirds of adolescents who are overweight or have obesity report weight loss intentions. Most report using weight loss strategies consistent with expert recommendations for obesity prevention; however whether they meet recommended fruit and vegetable (F&V) intake and physical activity (PA) recommendations is unknown. We investigated whether weight loss attempts, and weight loss strategies were associated with meeting F&V and PA recommendations. Data were from the 2010 National Youth Physical Activity and Nutrition Study, which surveyed a cross sectional, nationally representative sample of U.S. high school students. Analyses were restricted to overweight/obese students (n = 2841). Adjusted logistic regression models assessed the odds of meeting daily F&V and weekly PA recommendations after adjusting for grade, sex, race/ethnicity and perceived weight status. Compared to students who were overweight and were not currently intending to lose weight, students who were overweight and intending to lose weight were not more likely to meet F&V or PA. Among students with obesity, those who intended to lose weight were more likely than students who were not currently intending to lose weight to meet F&V recommendations (OR: 3.62, 95% CI: 1.70 7.73). Students who were overweight/obese and used F&V or PA for weight loss were significantly more likely to meet the corresponding recommendation than students intending to lose weight without specific strategies. Weight loss attempts alone do not affect the likelihood of meeting most expert recommendations. Public health efforts emphasizing recommended strategies for healthy eating and active living still need to be encouraged for overweight/obese youth. PMID- 30456054 TI - Interventions to prevent Lyme disease in humans: A systematic review. AB - Lyme disease (LD) is an infection transferred to humans through bites from infected ticks. Surveillance indicates that the number of LD cases is increasing in the UK, therefore, improved knowledge about reducing transmission from ticks to humans is needed. Eighteen electronic databases were searched and additional web-based searching was conducted, to locate empirical research, published from 2002 onwards. Sixteen studies that evaluated five types of prevention intervention were included: personal protection (n = 4), domestic strategies (landscape modification and chemical pest control) (n = 3), education (n = 6), vaccination (n = 3), and deer-reduction programmes (n = 2). In general the quality of evidence was low. Results suggest that personal protection strategies, including the use of tick repellents and wearing of protective clothes, can prevent tick bites and reduce the incidence of LD among adults. Educational interventions were generally successful for improving adults' knowledge, behavioural beliefs (e.g., self-efficacy for performing tick checks) and preventative behaviour, but for children, the findings were mixed. For adults and children, knowledge changes did not typically translate into a lower incidence of LD. Whilst evidence on vaccination against LD is promising, too few studies were available to reach robust conclusions. There was no evidence of effectiveness for deer culling, and the evidence was inconclusive for applying acaricide (tick poison) to deer's ears and heads. Low-quality evidence suggests that personal protective strategies, that limit exposure to ticks, should continue to be recommended, as should education to encourage the adoption of personal protective strategies; further investigation of education interventions for children, vaccination and deer programmes is needed. PMID- 30456056 TI - The Sendai Framework and emergency care. PMID- 30456055 TI - Differences in physical activity time-use composition associated with cardiometabolic risks. AB - This study investigates the association between the overall physical activity composition of the day (sedentary behavior (SB), light intensity physical activity (LIPA) and moderate-to-vigorous physical activity (MVPA)) and cardiometabolic health, and examines whether improved health can be associated with replacing SB with LIPA. A cross-sectional analysis of the Health Survey for England 2008 on N = 1411 adults was undertaken using a compositional analysis approach to examine the relationship between cardiometabolic risk biomarkers and physical activity accounting for co-dependency between relative amounts of time spent in different behavior. Daily time spent in SB, LIPA and MVPA was determined from waist-mounted accelerometry data (Actigraph GT1M) and modelled against BMI, waist circumference, waist-to-hip ratio, blood pressure, total and HDL cholesterol, HbA1c, and VO2 maximum. The composition of time spent in SB, LIPA and MVPA was statistically significantly associated with BMI, waist circumference, waist-to-hips ratio, HDL cholesterol and VO2 maximum (p < 0.001), but not HbA1c, systolic and diastolic blood pressure, or total cholesterol. Increase of relative time spent in MVPA was beneficially associated with obesity markers, HDL cholesterol, and VO2 maximum, and SB with poorer outcomes. The association of changes in LIPA depended on whether it displaced MVPA or SB. Increasing the proportion of MVPA alone may have the strongest potential association with adiposity outcomes and HDL cholesterol but similar outcomes could also be associated with a lower quantity of MVPA provided a greater quantity of SB is replaced overall with LIPA (around 10.5 min of LIPA is equivalent to 1 min of MVPA). PMID- 30456057 TI - The clinical practice of emergency medicine in Mahajanga, Madagascar. AB - Introduction: Little is documented concerning the clinical practice of emergency care in low- and middle-income countries. The lack of structural models presents serious obstacles to the development of effective emergency care services. This study provides such a model by describing the clinical practice at the emergency centre of the Centre Hopitalier Universitaire de Mahajanga in Madagascar. Methods: This was a retrospective chart review of all adult patients presenting to the emergency centre from September to November 2012. Archived chart data were extracted into a computer database. Data included: age, sex, date, diagnostic investigations, procedures, medications, and diagnosis. Results: 727 charts were reviewed, averaging eight patients per day. The three most frequent pathologies observed were trauma, gastrointestinal, and infectious disease. A total of 392 received diagnostic investigations. These were chiefly complete blood counts (n = 218), blood glucose (n = 155) and ECG (n = 92). Chest X-rays (n = 83), extremity X-rays (n = 55) and skull/face X-rays (n = 44) comprised the most common imaging. Ultrasounds were primarily abdominal (n = 9), renal/genitourinary (n = 6), and obstetric (n = 2). Therapeutic interventions were performed in 564 patients, most commonly intravenous access (n = 452) and wound/orthopaedic care (n = 185). Medications were administered to 568 patients, mostly anti inflammatory/analgesics (n = 463) and antibiotics (n = 287). Conclusion: This is the first descriptive study of the clinical practice of emergency medicine in Mahajanga, Madagascar. It provides both the Malagasy and international medical communities with an objective analysis of the practice of emergency care in Madagascar from both diagnostic and therapeutic standpoints. Emergency care here focuses on the management of traumatic injury and infectious disease. The diagnostic imaging, pharmacologic and procedural therapeutic interventions reflect the burdens placed upon this institution by these diseases. We hope this study will provide guidance for the further development of Malagasy-specific emergency care systems. PMID- 30456058 TI - Free Open Access Medical Education resource knowledge and utilisation amongst Emergency Medicine trainees: A survey in four countries. AB - Introduction Free Open Access Medical Education encompasses a broad array of free online resources and discussion fora. The aim of this paper was to describe whether Emergency Medicine trainees in different contexts know about Free Open Access Medical Education, whether or not they know about its different platforms, which ones they use, and what the major barriers to regular usage are. Methods A convenience sample was surveyed on awareness and use of Free Open Access Medical Education blogs, podcasts, websites and Twitter at three institutions (in Australia, Botswana and Papua New Guinea) and one deanery (United Kingdom) between June 2013 and June 2014 using an online survey tool or via hand distributed survey. Results 44 trainees responded: four from Botswana, seven from Papua New Guinea, ten from the United Kingdom and 23 from Australia. 82% were aware of blogs, 80% of websites, 75% of podcasts and 61% of Twitter as resources in Emergency Medicine. Awareness and use of specific resources were lower in Botswana and Papua New Guinea. For blogs, podcasts and websites, trainees who had looked at a resource at least once were neutral or agreed that it was relevant. For Twitter, some trainees found it difficult to navigate or not relevant. Lack of awareness of resources rather than lack of internet access was the main barrier to use. Conclusion The Emergency Medicine trainees in both developed and low resource settings studied were aware that Free Open Access Medical Education resources exist, but trainees in lower income settings were generally less aware of specific resources. Lack of internet and device access was not a barrier to use in this group. PMID- 30456059 TI - Agar ultrasound phantoms for low-cost training without refrigeration. AB - Introduction: Ultrasound is a technique that can be utilised to augment procedures to increase their safety and efficacy, but requires that health professionals be trained to use this imaging modality before it can be implemented. With the extremely high cost of manufactured phantoms, homemade alternatives are popular substitutes. Gelatine is commonly used as a matrix to suspend analogues and mimic tissue, but other substrates like ground meat can also be used. Both of these substrates require refrigeration and are subject to spoiling. Our research was designed to evaluate whether agar models would be superior to traditional Gelatine models in their sustainability and whether they would produce ultrasound images adequate for training. Methods: Agar models of varying formulas (percent agar by weight with certain additives varied) were tested for acceptable fidelity to real tissue, ultrasound image quality, and durability compared to gelatine models and human tissue. Results: A five percent by-mass agar model augmented with small amounts of suspended wheat flour presented as a model that could generate an ultrasound image that remarkably resembled that of real tissue. This agar model does not require refrigeration, is resistant to spoiling and desiccation, mimics tissue texture well, is durable enough to withstand high-volume training, and can be recycled to make new models. Conclusion: Agar phantoms are easy to make, do not require refrigeration, and have multiple distinct advantages over gelatine models for ultrasound training in austere conditions. PMID- 30456060 TI - Endotracheal tube cuff pressures and tube position in critically injured patients on arrival at a referral centre: Avoidable harm? AB - Introduction: The consequences of excessive endotracheal tube (ETT) cuff pressure are known and have long-term effects; however less attention is placed upon cuff pressure and tube position pre-hospital and in emergency centre. The aim of this study was to evaluate the ETT cuff pressure and tube position on arrival of all patients admitted to the Trauma Unit at Inkosi Albert Luthuli Central Hospital, both from scene and inter-hospital transfers to determine the median cuff pressure and if there were differences between the two groups. Methods: Data from Trauma Unit patients are entered into a prospective; UKZN approved (BE207-09) Trauma Database. Data on 65 admissions between April and December 2014 were reviewed to determine the arrival cuff pressure and tube position. Data captured included patient age, cuff pressure, where and who intubated the patient, and time since intubation to cuff pressure check. Data were analysed by descriptive statistics and Student's t-test for continuous data. Results: Most patients had sustained motor vehicle related trauma, with a male predominance. Equal numbers were intubated pre-hospital versus the in-hospital group. Eighty percent of ETT's were placed in the correct anatomical location, however only 23% of cuff pressures were found to be within the safe pressure limits. ETT cuff pressures were excessive in the pre-hospital ALS group more often than the facility intubation group (p = 0.042). There were fatal complications related to supra glottic intubations resulting in aspiration pneumonia, highlighting the need for X-ray confirmation of tube position. Conclusion: Most patients, whether intubated on-scene or at hospital have ETT cuff pressures that are excessive, with the potential for ischaemic necrosis of the tracheal mucosa. ETT cuff manometry should be standard of care for all prehospital and in-hospital intubations where the tube will remain in situ for any prolonged period of time. Before inter facility transfer ETT position should be confirmed radiologically. PMID- 30456061 TI - Availability of resources for emergency care at a second-level hospital in Ghana: A mixed methods assessment. AB - Introduction: Emergency care is an essential component of health systems, particularly in low- and middle-income countries. We sought to assess the availability of resources to provide emergency care at a second-level hospital in Ghana. By doing so, deficits that could guide development of targeted intervention strategies to improve emergency care could be identified. Methods: A qualitative and quantitative assessment of capacity for care of emergency patients was performed at the Emergency Centre of the Police Hospital, a second level hospital in Accra, Ghana. Direct inspection and job-specific survey of clinical, orderly, administrative and ambulance staff was performed. Responses to quantitative questions were described. Qualitative responses were examined by content analysis. Results: Assessment revealed marked deficiencies in many essential items and services. However, several successes were identified, such as laboratory capacity. Among the unavailable essential items, some were of low cost, such as basic airway supplies, chest tubes and several emergency medications. Themes from staff responses when asked how to improve emergency care included: provide periodic training, increase bed numbers in the emergency unit, ensure availability of essential items and make personal protective equipment available for all staff caring for patients. Conclusion: This study identified opportunities to improve the care of patients with emergency conditions at the Police Hospital in Ghana. Low-cost improvements in training, organization and planning could improve item and service availability, such as: developing a continuing education curriculum for staff in all areas of the emergency centre; holding in-service training on existing protocols for triage and emergency care; adding checklists to guide appropriate triage and safe transfer of patients; and perform a root cause analysis of item non-availability to develop targeted interventions. PMID- 30456062 TI - Electronic Medical Records in low to middle income countries: The case of Khayelitsha Hospital, South Africa. AB - Introduction: Electronic Medical Records (EMRs) have shown benefit for clinical, organisational, and societal outcomes. In low-to-middle-income countries, the desire for EMRs will continue to rise as increasing trauma and infectious disease rates necessitate adequate record keeping for effective follow-up. 114 nations are currently working on national EMRs, with some using both a full EMR (Clinicom) and a paper-based system scanned to an online Enterprise Content Management (ECM) database. Methods: The authors sought to evaluate the ability and completeness of the EMR at Khayelitsha Hospital (KH) to capture all Emergency Centre (EC) encounters classified as trauma. Based on the high trauma rates in the Khayelitsha area and equally high referral rates from KH to higher-level trauma centres, an assumption was made that its rates would mirror nationwide estimates of 40% of EC visits. Records from July 2012 to June 2013 were examined. Results: 3488 patients visited the EC in the month of July 2012. 10% were noted as trauma on Clinicom and within their records were multiple sections with missing information. The remaining months of Aug 2012-June 2013 had an average trauma load of 8%. On further investigation, stacks of un-scanned patient folders were identified in the records department, contributing to the unavailability of records from January 2013 to the time of study (June 2013) on ECM. Conclusion: The results highlight difficulties with implementing a dual record system, as neither the full EMR nor ECM was able to accurately capture the estimated trauma load. Hospitals looking to employ such a system should ensure that sufficient funds are in place for adequate support, from supervision and training of staff to investment in infrastructure for efficient transfer of information. In the long run, efforts should be made to convert to a complete EMR to avoid the many pitfalls associated with handling paper records. PMID- 30456063 TI - Typhoid intestinal perforation: Point-of-care ultrasound as a diagnostic tool in a rural Ugandan Hospital. AB - Introduction: Point-of-care ultrasound (POCUS) in resource-limited areas has demonstrated utility in the hands of physicians and may be useful for non physician providers to learn as well. Case Report: An 11 year old male presented with abdominal pain and diffuse abdominal tenderness to a remote Emergency Centre (EC). An Emergency Care Practitioner, a non-physician emergency care provider with limited ultrasound training, used bedside ultrasonography and alerted the on call surgeon of complex intraperitoneal fluid representing perforated typhoid, which expedited the patient's care. Discussion: There is scant literature involving cases of non-physician use of POCUS, particularly in the emergency care setting. This case demonstrates the potential benefits of training these providers in POCUS. PMID- 30456064 TI - Uchunguzi (Journal Watch/Montre de Journal). PMID- 30456065 TI - Ujuzi (Practical Pearl/Perle Pratique). PMID- 30456066 TI - Time to standardise levels of care amongst Out-of-Hospital Emergency Care providers in Africa. AB - The African Federation for Emergency Medicine's Out-of-Hospital Emergency Care (OHEC) Committee convened 15 experts from various OHEC systems in Africa to participate in a consensus process to define levels of care within which providers in African OHEC systems should safely and effectively function. The expert panel concluded that four provider levels were relevant for African OHEC systems: (i) first aid, (ii) basic life support, (iii) intermediate life support, and (iv) advanced life support. Definitions for each provider level were also created to aid standardisation of providers across Africa and to help advance the practice of OHEC. PMID- 30456067 TI - Sub-Saharan African hospitals have a unique opportunity to address intentional injury to children. PMID- 30456068 TI - Pre-hospital clinical practice guidelines - Where are we now? PMID- 30456069 TI - A promising poison information centre model for Africa. AB - Introduction: The burden of poisoning exposures in Africa is a significant public health concern, yet only ten African countries have poisons information centres. The establishment of poisons centres was subsequently identified as a priority. This article focuses on workshop discussions with international multi-sector stakeholders in Eastern Africa regarding the possibility of a sub-regional poisons centre serving multiple countries. Methods: The project was led by an independent consultant under the guidance of an international steering group. Steering group members provided input at international multi-stakeholder meetings and during monthly teleconferences. Results: Participants of the stakeholder meetings agreed that the establishment of a sub-regional poisons centre in Eastern Africa was necessary and feasible. Virtual collaboration is possible due to recent technological developments, and the overall suggestion was for countries to establish their own poisons centres and to network and coordinate these centres through a network hub. Conclusion: A number of benefits might result from such a poisons centre network hub, including: (1) Improved cooperation between countries on poisoning problems; (2) Harmonisation and strengthening of research and surveillance; (3) Common standards and best practices e.g. regulating chemicals, data management, and staff training; and (4) Greater bargaining power to secure resources. Further investigation is needed to identify the most suitable location for the network hub, the activities it should fulfil, and the availability of specialists in poisons information who could become members of the hub. PMID- 30456070 TI - Tapping into a vital resource: Understanding the motivators and barriers to blood donation in Sub-Saharan Africa. AB - Introduction: Sub-Saharan Africa (SSA) has a need for blood and blood products that exceeds current availability. This unmet demand is evidenced by persistently high mortality rates associated with potentially reversible conditions such as haemorrhage and anaemia. This study reviews current literature on blood donation in SSA to identify common local motivators and deterrents to blood donation and highlights specific interventions that have successfully increased the number of blood donors in this region. Methods: The authors searched the health literature to identify original studies conducted in SSA that addressed blood donation motivators and deterrents. Data were then extracted from each study to determine how often each study identified specific motivators and deterrents. Results: Pro social motivation, such as altruism and the desire to have a positive effect on the community, is the most frequently noted reason for people in SSA countries to donate blood. Negative attitudes and misconceptions towards blood donation, in addition to perceived negative health effects caused by donation, are the two most frequently mentioned reasons that dissuade individuals from donating blood. Conclusion: Due to paucity of research on this topic, our understanding of blood donor behaviour in SSA is limited. Local traditions and cultures intimately shape individuals' proclivity towards the donation process. In order to change the attitudes and behaviours of many potential donors in SSA it is important to address the deterrents to blood donation, as many represent misconceptions or culture-specific beliefs that may be the ultimate driving force dictating donor behaviour. PMID- 30456071 TI - Economic development and road traffic fatalities in two neighbouring African nations. AB - Introduction: The rapid growth of Botswana's economy since independence in 1966 has brought more tarred roads and vehicles, accompanied by an escalating road crash fatality rate. We tested the hypothesis that motor vehicle crash fatality increases resulted from, rather than just corresponded with, annual gross domestic product (GDP) increases. Data from Zambia, adjacent to Botswana, were used for comparison. Methods: Annual social and economic indicators and motor vehicle crash fatality rates in Botswana and Zambia were accessed from 1960 to 2012 and analysed using vector autoregressive analysis and Granger causality tests. Results: In Botswana, annual changes in per capita GDP predicted annual changes in motor vehicle crash fatality rates (p = 0.042). The opposite was not observed; annual changes in motor vehicle crash fatality rates did not predict annual GDP changes. These findings suggest that GDP growth in a given year caused additional road traffic fatalities in Botswana and that, on average, every billion dollar increase in GDP produced an increase in the rate of road traffic fatalities. In Zambia, annual GDP changes predicted annual fatality rate changes three years later (p = 0.029), but annual changes in road crash fatality rates also predicted annual increases in per capita GDP (p = 0.026) three years later, suggesting a correlation between trends, but not a causal effect of GDP. Conclusion: Road crash fatalities increased in recent decades in both Zambia and Botswana. But the rapid economic development in Botswana over this time period appears to have driven proportionate road traffic fatality increases. There are opportunities for newly emerging economies such as Zambia, Angola, and others to learn from the Botswana experience. Evidence-based investments in road safety interventions should be concomitant with economic development. PMID- 30456073 TI - Professional needs of young Emergency Medicine specialists in Africa: Results of a South Africa, Ethiopia, Tanzania, and Ghana survey. AB - Introduction: Emergency Medicine (EM) residency programmes are new to Africa and exist in only a handful of countries. There has been no follow up on faculty development needs nor training of these graduates since they completed their programmes. The African Federation for Emergency Medicine (AFEM) aims to explore the needs of recent EM graduates with respect to the need for resources, mentorship, and teaching in order to develop a focused African faculty development intervention. Methods: As part of the AFEM annual survey, all those who have graduated since 2012 from a Sub-Saharan African EM residency programme were approached. These included Muhimbili University of Health and Allied Sciences (MUHAS) in Tanzania, Addis Ababa University (AAU) in Ethiopia, Komfo Anokye Teaching Hospital (KATH) in Ghana, the University of Cape Town (UCT) in South Africa, the University of Pretoria (UP) in South Africa, the University of Witswatersrand (Wits) in South Africa, and the University of KwaZulu-Natal (UKZN) in South Africa. Results: The 47 respondents rated themselves as most confident medical experts in knowledge, procedural skills, and communication. Overall graduates felt least equipped as scholars and managers, and requested more educational materials. They reported that the best way for AFEM to support them is through emergency care advocacy and support for their advocacy activities and that their most critical development need is for leadership development, including providing training materials. Conclusion: Recent graduates report that the best ways for AFEM to help new EM graduates is to continue advocacy programmes and the development of leadership and mentorship programmes. However, there is also a demand from these graduates for educational materials, especially online. PMID- 30456074 TI - Uchunguzi (Journal Watch/Montre de Journal). PMID- 30456072 TI - Injury patterns and health outcomes among pregnant women seeking emergency medical care in Kumasi, Ghana: Challenges and opportunities to improve care. AB - Introduction: In high-income countries, injury is the most common cause of non obstetric death among pregnant women. However, the injury risk during pregnancy has not been well characterized for many developing countries including Ghana. Our study described maternal and fetal outcomes after injury at the Komfo Anokye Teaching Hospital (KATH) in Kumasi, Ghana, and identified associations between the prevalence of poor outcomes and maternal risk factors. Methods: We conducted a cross-sectional study to identify pregnant women treated for injury over a 12 month period at KATH in Kumasi, Ghana. Descriptive statistics were used to characterize the population. We identified the association between poor outcomes and maternal risk factors using multivariable Poisson regression. Results: There were 134 women with documented pregnancy who sought emergency care for injury (1.1% of all injured women). The leading injury mechanisms were motor vehicle collision (23%), poisoning (21%), and fall (19%). Assault was implicated in 3% of the injuries. Eleven women (8%) died from their injuries. The prevalence of poor fetal outcomes: fetal death, distress or premature birth, was high (61.9%). One in four infants was delivered prematurely following maternal injury. After adjusting for maternal and injury characteristics, poor fetal outcomes were associated with pedestrian injury (adjusted prevalence ratio (aPR) 2.5, 95% CI 1.5-4.6), and injury to the thoraco-abdominal region (aPR 2.1, 95% CI 1.4-3.3). Conclusions: Injury is an important cause of maternal morbidity and poor fetal outcomes. Poisoning, often in an attempt to terminate pregnancy, was a common occurrence among pregnant women treated for injury in Kumasi. Future work should address modifiable risk factors related to traffic safety, prevention of intimate partner violence, and prevention of unintended pregnancies. PMID- 30456075 TI - Ujuzi (Practical Pearl/Perle Pratique). PMID- 30456076 TI - South African pre-hospital guidelines: Report on progress and way forward. PMID- 30456077 TI - Developing metrics for emergency care research in low- and middle-income countries. AB - Introduction: There is little research on emergency care delivery in low- and middle-income countries (LMICs). To facilitate future research, we aimed to assess the set of key metrics currently used by researchers in these settings and to propose a set of standard metrics to facilitate future research. Methods: Systematic literature review of 43,109 published reports on general emergency care from 139 LMICs. Studies describing care for subsets of emergency conditions, subsets of populations, and data aggregated across multiple facilities were excluded. All facility- and patient-level statistics reported in these studies were recorded and the most commonly used metrics were identified. Results: We identified 195 studies on emergency care delivery in LMICs. There was little uniformity in either patient- or facility-level metrics reported. Patient demographics were inconsistently reported: only 33% noted average age and 63% the gender breakdown. The upper age boundary used for paediatric data varied widely, from 5 to 20 years of age. Emergency centre capacity was reported using a variety of metrics including annual patient volume (n = 175, 90%); bed count (n = 60, 31%), number of rooms (n = 48, 25%); frequently none of these metrics were reported (n = 16, 8%). Many characteristics essential to describe capabilities and performance of emergency care were not reported, including use and type of triage; level of provider training; admission rate; time to evaluation; and length of EC stay. Conclusion: We found considerable heterogeneity in reporting practices for studies of emergency care in LMICs. Standardised metrics could facilitate future analysis and interpretation of such studies, and expand the ability to generalise and compare findings across emergency care settings. PMID- 30456078 TI - Bedside ultrasound training at Muhimbili National Hospital in Dar es Salaam, Tanzania and Hospital San Carlos in Chiapas, Mexico. AB - Introduction: In resource-rich settings, bedside ultrasound has rapidly evolved to be a crucial part of emergency centre practice and a growing part of critical care practice. This portable and affordable technology may be even more valuable in resource-limited environments where other imaging modalities are inaccessible, but the optimal amount of training required to achieve competency in bedside ultrasound is largely unknown. We sought to evaluate the feasibility of implementation of a mixed-modality bedside ultrasound training course for emergency and generalist acute care physicians in limited resource settings, and to provide a description of our core course components, including specific performance goals, to facilitate implementation of similar initiatives. Methods: We conducted a standardised training course at two distinct sites-one large, urban tertiary hospital in Tanzania with a dedicated Emergency Centre, and one small, rural, hospital in southern Mexico with a general, acute intake area. We report on pre-training ultrasound use at both sites, as well as pre- and post training views on most useful indications. Results: Overall, participants were very satisfied with the course, although approximately one-third of the providers at both sites would have preferred more hands-on training. All participants passed a standardised exam requiring image acquisition and interpretation. Discussion: Introducing bedside ultrasound training in two distinct resource limited settings was feasible and well-received. After a brief intensive period of training, participants successfully passed a comprehensive examination, including demonstration of standardised image acquisition and accurate interpretation of normal and abnormal studies. PMID- 30456079 TI - A pilot training program for point-of-care ultrasound in Kenya. AB - Introduction: Ultrasound is an effective and affordable clinical diagnostic tool highly attractive for use in low and middle income countries (LMICs), but access to training programs in these countries is limited. The objective of our study was to develop and pilot a program for healthcare providers in Kenya in the use of point-of-care ultrasound. Methods: Trainees were recruited in district hospitals for participation in three all-day workshops held every 3-5 months from September 2013 through November 2014. Prior to the initial workshop, trainees were asked to study a training manual, and a knowledge test was administered. Ultrasound-credentialed emergency physicians provided brief didactic lessons then hands-on training for eFAST and obstetric training. This was followed by an observed assessment of scanning image quality (IM) and diagnostic interpretation (IN). Results: Eighty-one trainees enrolled in four initial training sessions and 30 attended at least one refresher session. Among those trainees who attended refresher sessions, there was an increase in the proportion passing both the knowledge and practical tests at the follow-up, as compared to the initial session. Overall, mean practical skill scores also trended toward an increase over time, with a significantly higher mean score in November 2014 (2.64 + 0.38, p = 0.02) as compared to March 2014 (2.26 + 0.54), p < 0.05. Pre-workshop preparation evolved over time with the goal of maximizing trainee readiness for the hands-on course. A strong correlation was observed between knowledge and practical skill scores illustrating the importance of pre-workshop training. Conclusions: Our pilot workshop showed promise in promoting knowledge and practical skills among participants, as well as increasing use in patient care. Results also suggest that refresher training may provide additional benefits for some participants. These findings provide a strong rationale for expanding the training program and for measuring its clinical impact. PMID- 30456080 TI - Added value of graded compression ultrasound to the Alvarado score in cases of right iliac fossa pain. AB - Introduction: Acute appendicitis is one of the most common emergencies treated by the general surgeon. Simple appendicitis can progress to perforation, which is associated with a much higher morbidity and mortality, and surgeons have therefore been inclined to operate when the diagnosis is probable rather than wait until it is certain. The aim of this study was to evaluate the sensitivity and specificity of the Alvarado score combined with ultrasounds of the abdomen and pelvis in cases of right iliac fossa pain with suspected acute appendicitis. Methods: 100 patients admitted to the Department of Surgery at Alexandria Main University Hospital in 2013 complaining of right iliac fossa pain with suspected acute appendicitis were studied prospectively. The demographic information, histopathology, physical examination, laboratory data, Alvarado score, sonography report and histopathological reports of these patients were gathered. The treating surgeon made decisions for surgery or conservative management without any intervention from the research team. Results: A combination of methods showed that Alvarado alone was 100% sensitive in excluding appendicitis at scores below five and was highly specific at scores above eight (91.9%) with no added value when combining it with ultrasound in those scores. On the other hand, ultrasound was beneficial only in patients with Alvarado scores between five and eight for detecting appendicitis and not excluding it (increasing specificity to 100% and not affecting sensitivity). Conclusion: Ultrasound is a good adjuvant examination in cases with Alvarado scores between five and eight in order to diagnose appendicitis. Negative ultrasound results do not exclude appendicitis and further assessment by other modalities should be performed. PMID- 30456081 TI - Conservative management of gunshot oesophageal injuries: A report of two consecutive exceptional cases. AB - Introduction: Oesophageal trauma carries high mortality and morbidity. For penetrating intrathoracic oesophageal injury, surgical repair has been the standard for decades to avoid its devastating consequences. Case report: Both patients presented with a thoracoabdominal gunshot wound and retained intraabdominal missile. Although there were no visible signs of perforation on oesophagoscopy or contrast swallow, the presence of an intraluminal bullet highly suggested a thoracic oesophageal injury. Discussion: Non-operative management of intrathoracic oesophageal perforation is controversial. Small perforations or contained leaks diagnosed within 24-48 h in a stable patient with no mediastinitis or empyema can be managed non-operatively with antibiotics and nasogastric feeds. These two case reports support the notion of selective non operative management of asymptomatic patients with penetrating injury to the oesophagus. PMID- 30456082 TI - Message in a bottle. The use of chest radiography for diagnosis of pericardial effusion. AB - Introduction: The diagnosis of pericardial effusion may be elusive, and only diagnosed with echocardiography. Case reports: Here we report the cases of two patients who presented to the emergency centre (EC) with dyspnoea, and their chest X-rays (CXR) revealed the "water bottle sign", which is the typical appearance of the cardiac silhouette that is present when there is a large pericardial effusion. Discussion: This clinched the diagnosis of pericardial effusion, where the diagnosis may have otherwise been delayed. We discuss these cases, and the relevant literature and discuss the benefits of standard chest radiography in aiding in the diagnosis of pericardial effusion. PMID- 30456083 TI - Uchunguzi (Journal Watch/Montre de Journal). PMID- 30456084 TI - Ujuzi (Practical Pearl/Perle Pratique). PMID- 30456085 TI - Access to out-of-hospital emergency care in Africa: Consensus conference recommendations. AB - Out-of-hospital emergency care (OHEC) should be accessible to all who require it. However, available data suggests that there are a number of barriers to such access in Africa, mainly centred around challenges in public knowledge, perception and appropriate utilisation of OHEC. Having reached consensus in 2013 on a two-tier system of African OHEC, the African Federation for Emergency Medicine (AFEM) OHEC Group sought to gain further consensus on the narrower subject of access to OHEC in Africa. The objective of this paper is to report the outputs and statements arising from the AFEM OHEC access consensus meeting held in Cape Town, South Africa in April 2015. The discussion was structured around six dimensions of access to care (i.e. awareness, availability, accessibility, accommodation, affordability and acceptability) and tackled both Tier-1 (community first responder) and Tier-2 (formal prehospital services and Emergency Medical Services) OHEC systems. In Tier-1 systems, the role of community involvement and support was emphasised, along with the importance of a first responder system acceptable to the community in which it is embedded in order to optimise access. In Tier-2 systems, the consensus group highlighted the primacy of a single toll-free emergency number, matching of Emergency Medical Services resource demand and availability through appropriate planning and the cost-free nature of Tier-2 emergency care, amongst other factors that impact accessibility. Much work is still needed in prioritising the steps and clarifying the tools and metrics that would enable the ideal of optimal access to OHEC in Africa. PMID- 30456087 TI - A brave African discussion on emergency medicine. PMID- 30456086 TI - Bedside ultrasound as a simple non-invasive method of assessing intracranial pressure in a limited resource setting. AB - Introduction: Increased intracranial pressure is usually measured with invasive methods that are not practical in resource-limited countries. However, bedside ultrasound, a non-invasive method, measures the optic nerve sheath diameter and could be a safe and accurate alternative to measure intracranial pressure, even in children. Case report: We report a case of a 15-year old patient who presented with severe headache, projectile vomiting, and neck pain for two months. The bedside ultrasound showed a 10 mm optic nerve sheath diameter and a Computed Tomography scan of her brain revealed obstructive hydrocephalus secondary to a mass in the fourth ventricle. After intervening, we were able to monitor the decrease in her optic nerve sheath diameter with ultrasound. Conclusion: Performing invasive procedures continues to be a challenge in the resource limited setting. However, bedside ultrasound can be a useful tool in emergency centres for early detection and monitoring of intracranial pressure. PMID- 30456088 TI - Emergency care conference in the land of a thousand hills. PMID- 30456089 TI - The first Tanzanian Conference on Emergency Medicine. PMID- 30456090 TI - The role of wilderness medicine training in resource-limited settings. PMID- 30456091 TI - Seeking health care from a general hospital in Uganda following a fracture or a dislocation. AB - Introduction: Selecting a treatment approach and a facility to get treated from, poses a challenge in musculoskeletal injuries in Africa. The study aimed at determining demographic and injury characteristics of patients with musculoskeletal injuries and how these impact the time and reason for presenting to a general hospital in Uganda. Methods: An observational study was carried out at Entebbe general hospital on patients presenting with musculoskeletal injuries between 1 November 2014 and 28 February 2015. The patient demographics, injury characteristics, duration of injury to presentation for treatment and reason for seeking treatment from this hospital were noted. Results: A total of 101 patients were recruited. Of these, 95 had fractures while six had dislocations. Patients took an average of 96 h before presenting for care, females taking significantly longer than males (191.2 and 58.6 h respectively, p = 0.005). The fractured segment of bone significantly influenced the patients' choice for care at this hospital (p = 0.02). Discussion: Entebbe General Hospital serves a young and unemployed population for musculoskeletal injuries. These patients present late for care, especially females. Patients base their choice for care from this hospital on the character of the injury. PMID- 30456092 TI - The clinical profile and acute care of patients with traumatic spinal cord injury at a tertiary care emergency centre in Addis Ababa, Ethiopia. AB - Introduction: Traumatic spinal cord injuries can have catastrophic physical, psychological, and social consequences, particularly in low resource settings. Since many of these injuries result in irreversible damages, it is essential to understand risk factors for them and focus on primary prevention strategies. The objectives of this study are to describe the demographics, injury characteristics, and management of traumatic spinal cord injury victims presenting to the Adult Emergency Centre of Tikur Anbessa Specialised Hospital in Addis Ababa, the tertiary referral centre for emergency care in Ethiopia. Methods: A prospective cross sectional survey was conducted from October 2013 to March 2014 in the Adult Emergency Centre of Tikur Anbessa Specialised Hospital. Patients were identified at triage and followed through admission to discharge from the emergency centre. Results: Eighty-four patients with traumatic spinal cord injuries were identified. The mean age was 33 years and 86% were male. The most common mechanisms of injury were motor vehicle collisions (37%), falls (31%), and farming injuries (11%). The cervical spine (48%) was the most commonly injured region and 41% were complete spinal cord injuries. Most patients (77%) did not receive any prehospital care or medical care at other facilities prior to arrival in the Emergency Centre. Conclusion: In our context, traumatic spinal cord injuries predominantly affect young men, and the majority of victims suffer severe injuries with little chance of recovery. Attention to occupational and road traffic safety is essential to mitigate the personal and societal burdens of traumatic spinal cord injuries. It is also imperative to focus on improving prehospital care and rehabilitation services for traumatic spinal cord injury victims. PMID- 30456093 TI - Development of a trauma and emergency database in Kigali, Rwanda. AB - Introduction: Injuries account for 10% of the global burden of disease, resulting in approximately 5.8 million deaths annually. Trauma registries are an important tool in the development of a trauma system; however, limited resources in low- and middle-income countries (LMIC) make the development of high-quality trauma registries challenging. We describe the development of a LMIC trauma registry based on a robust retrospective chart review, which included data derived from prehospital, emergency centre and inpatient records. Methods: This paper outlines our methods for identifying and locating patients and their medical records using pragmatic and locally appropriate record linkage techniques. A prehospital database was queried to identify patients transported to University Teaching Hospital - Kigali, Rwanda from December 2012 through February 2015. Demographic information was recorded and used to create a five-factor identification index, which was then used to search OpenClinic GA, an online open source hospital information system. The medical record number and archive number obtained from OpenClinic GA were then used to locate the physical medical record for data extraction. Results: A total of 1668 trauma patients were transported during the study period. 66.7% were successfully linked to their medical record numbers and archive codes. 94% of these patients were successfully linked to their medical record numbers and archive codes were linked by four or five of the five pre-set identifiers. 945 charts were successfully located and extracted for inclusion in the trauma registry. Record linkage and chart extraction took approximately 1256 h. Conclusion: The process of record linkage and chart extraction was a resource intensive process; however, our unique methodology resulted in a high linkage rate. This study suggests that it is feasible to create a retrospective trauma registry in LMICs using pragmatic and locally appropriate record linkage techniques. PMID- 30456096 TI - Uchunguzi (Journal Watch/Montre de Journal). PMID- 30456094 TI - Epidemiology of injuries and outcomes among trauma patients receiving prehospital care at a tertiary teaching hospital in Kigali, Rwanda. AB - Introduction: Injury accounts for 9.6% of the global mortality burden, disproportionately affecting those living in low- and middle-income countries. In an effort to improve trauma care in Rwanda, the Ministry of Health developed a prehospital service, Service d'Aide Medicale Urgente (SAMU), and established an emergency medicine training program. However, little is known about patients receiving prehospital and emergency trauma care or their outcomes. The objective was to develop a linked prehospital-hospital database to evaluate patient characteristics, mechanisms of injury, prehospital and hospital resource use, and outcomes among injured patients receiving acute care in Kigali, Rwanda. Methods: A retrospective cohort study was conducted at University Teaching Hospital - Kigali, the primary trauma centre in Rwanda. Data was included on all injured patients transported by SAMU from December 2012 to February 2015. SAMU's prehospital database was linked to hospital records and data were collected using standardised protocols by trained abstractors. Demographic information, injury characteristics, acute care, hospital course and outcomes were included. Results: 1668 patients were transported for traumatic injury during the study period. The majority (77.7%) of patients were male. The median age was 30 years. Motor vehicle collisions accounted for 75.0% of encounters of which 61.4% involved motorcycles. 48.8% of patients sustained injuries in two or more anatomical regions. 40.1% of patients were admitted to the hospital and 78.1% required surgery. The overall mortality rate was 5.5% with nearly half of hospital deaths occurring in the emergency centre. Conclusion: A linked prehospital and hospital database provided critical epidemiological information describing trauma patients in a low-resource setting. Blunt trauma from motor vehicle collisions involving young males constituted the majority of traumatic injury. Among this cohort, hospital resource utilisation was high as was mortality. This data can help guide the implementation of interventions to improve trauma care in the Rwandan setting. PMID- 30456095 TI - Focused assessment with sonography for HIV-associated tuberculosis (FASH) case series from a Rwandan district hospital. AB - Introduction: The majority of HIV-TB co-infection worldwide is reported in Africa. The risk of developing extra-pulmonary tuberculosis (EPTB) increases as immune deficiency progresses but is difficult to diagnose. Point-of-care ultrasonography (POCUS) can be an effective adjunct to identify and treat EPTB associated findings using the focused assessment with sonography for HIV associated TB (FASH) protocol. Case report: Three HIV-infected patients without known history of EPTB presented to a Rwandan district hospital with fever and unclear infection. Initial testing did not reveal a source. Each patient was then evaluated with the FASH protocol by a Rwandan emergency physician with POCUS training. All patients had findings suggestive of EPTB by ultrasound. Anti-TB treatment was initiated, and all subsequently demonstrated symptom improvement. Discussion: This case series demonstrates the additional clinical information obtained. It describes how management was changed using POCUS and the FASH in a resource-limited setting in Rwanda and calls for further FASH protocol validation studies. PMID- 30456097 TI - Ujuzi (Practical Pearl/Perle Pratique). PMID- 30456098 TI - Mawasiliano (Correspondence/Correspondance). PMID- 30456099 TI - Cervical collars and immobilisation: A South African best practice recommendation. AB - Introduction: The consequences of spinal injury as a result of trauma can be devastating. Spinal immobilisation using hard trauma boards and rigid cervical collars has traditionally been the standard response to suspected spinal injury patients even though the risk may be extremely low. Recently, adverse events due to the method of immobilisation have challenged the need for motion restriction in all trauma patients. International guidelines have been published for protection of the spine during transport and this article brings those guidelines into the South African context. Recommendations: Trauma patients need to be properly assessed using both an approved list of high and low risk factors, as well as a thorough examination. They should then be managed accordingly. Internationally validated assessment strategies have been developed, and should be used as part of the patient assessment. The method of motion restriction should be selected to suit the situation. The use of a vacuum mattress is the preferable technique, with the use of a trauma board being the least desirable. Conclusion: The need for motion restriction in suspected spinal injury should be properly evaluated and appropriate action taken. Not all trauma patients require spinal motion restriction. PMID- 30456100 TI - African emergency care providers' attitudes and practices towards research. AB - Introduction: Emergency care research in Africa is not on par with other world regions. The study aimed to assess the perceptions and practices towards research among current emergency care providers in Africa. Methods: A survey was sent to all individual members of the African Federation of Emergency Medicine. The survey was available in English and French. Results: One hundred and sixty-eight responses were analysed (invited n = 540, responded n = 188, 34.8%, excluded n = 20). Responders' mean age was 36.3 years (SD = 9.1); 122 (72.6%) were male, 104 (61.9%) were doctors, and 127 (75.6%) were African trained. Thirty-seven (22%) have never been involved in research; 33 (19.6%) have been involved in ?5 research projects. African related projects were mostly relevant to African audiences (n = 106, 63.1%). Ninety-four (56%) participants have never published. Forty-one (24.4%) were not willing to publish in open access journals requesting a publication fee; 65 (38.7%) will consider open access journals if fees are sponsored. Eighty responders (47.6%) frequently experienced access block to original articles due to subscription charges. Lack of research funding (n = 108, 64.3%), lack of research training (n = 86, 51.2%), and lack of allocated research time (n = 76, 45.2%) were the main barriers to research involvement. Improvement of research skills (n = 118, 70.2%) and having research published (n = 117, 69.6%) were the top motivational factors selected. Responders agreed that research promotes critical thinking (n = 137, 81.5%) and serve as an important educational tool (n = 134, 80.4%). However, 134 (79.8%) feel that emergency care workers need to be shown how to use research to improve clinical practice. Most agreed that insufficient emergency care research is being conducted in Africa (n = 113, 67.3%). Discussion: There is scope to increase research involvement in emergency care in Africa, but solutions need to be find to address lack of research-related funding, training and time. PMID- 30456101 TI - Emergency care capabilities in the Kingdom of Swaziland, Africa. AB - Introduction: Emergency care is available in many forms in Swaziland, and to our knowledge there has never been a systematic study of emergency centres (ECs) in the country. The purpose of this study was to describe the characteristics, resources and capacity of emergency centres in the Kingdom. Methods: The National Emergency Department Inventory (NEDI)-International survey instrument (www.emnet nedi.org) was used to survey all Swaziland ECs accessible to the general public 24/7. EC staff were asked about calendar year 2014. Data were entered directly into Lime Survey, a free, web-based, open-source survey application. Responses were analysed using descriptive statistics, including proportions and medians with interquartile ranges (IQR). Results: Sixteen of 17 ECs participated (94% response rate). Participating ECs were either in hospitals (69%) or health centres (31%). ECs had a median of 53,399 visits per year (IQR 15,000-97,895). Fourteen (88%) ECs had a contiguous layout, and the other two (12%) were non contiguous. Overall, eight (53%) had access to cardiac monitors and 11 (69%) had a 24/7 clinical laboratory available. Only 1 (6%) EC had a dedicated CT scanner, while 2 (13%) others had limited access through their hospital. The typical EC length-of-stay was between 1 and 6 h (44%). The most commonly available specialists were general surgeons, with 9 (56%) ECs having them available for in person consultation. No ECs had a plastic surgeon or psychiatrist available. Overall, 75% of ECs reported running at overcapacity. Discussion: Swaziland ECs were predominantly contiguous and running at overcapacity, with high patient volumes and limited resources. The limited access to technology and specialists are major challenges. We believe that these data support greater resource allocation by the Swaziland government to the emergency care sector. PMID- 30456102 TI - A description of pharmacological analgesia administration by public sector advanced life support paramedics in the City of Cape Town. AB - Introduction: Emergency Medical Services are ideally placed to provide relief of acute pain and discomfort. The objectives of this study were to describe pre hospital pain management practices by Emergency Medical Services in the Western Cape, South Africa. Methods: A retrospective, descriptive survey was undertaken of analgesic drug administration by advanced life support paramedics. Patient care records generated in the City of Cape Town during an 11-month period containing administrations of morphine, ketamine, nitrates and 50% nitrous oxide/oxygen were randomly sampled. Variables studied were drug dose, dose frequency, and route of administration, patient age, gender, disorder and call type as well as qualification and experience level of the provider. Results: A total of 530 patient care records were included (n = 530). Morphine was administered in 371 (70%, 95% CI 66-74) cases, nitrates in 197 (37%, 95% CI 33 41) and ketamine in 9 (1.7%, 95% CI 1-3) cases. A total of 5 mg or less of morphine was administered in 278 (75%, 95% CI 70-79) cases, with the median dose being 4 mg (IQR 3-6). Single doses were administered to 268 (72.2%, 95% CI 67-77) morphine administrations, five (56%, 95% CI 21-86) ketamine administrations and 161 (82%, 95% CI 76-87) of nitrate administrations. Chest pain was the reason for pain management in 226 (43%) cases. Advanced Life Support Providers had a median experience level of two years (IQR 2-4). Discussion: Pre-hospital acute pain management in the Western Cape does not appear to conform to best practice as Advanced Life Support providers in the Western Cape use low doses of morphine. Chest pain is an important reason for drug administration in acute pre-hospital pain. Multimodal analgesia is not a feature of care in this pre-hospital service. The development of a Clinical Practice Guideline for and training in pre-hospital pain should be viewed as imperative. PMID- 30456104 TI - Uchunguzi (Journal Watch/ Montre de Journal). PMID- 30456105 TI - Ujuzi (Practical Pearl/Perle Pratique). PMID- 30456106 TI - Mawasiliano (Correspondence/Correspondance). PMID- 30456107 TI - Libyan healthcare system during the armed conflict: Challenges and restoration. PMID- 30456103 TI - A systematic review of burn injuries in low- and middle-income countries: Epidemiology in the WHO-defined African Region. AB - Introduction: According to the World Health Organization (WHO), burns result in the loss of approximately 18 million disability adjusted life years (DALYs) and more than 250,000 deaths each year, more than 90% of which are in low- and middle income countries (LMICs). The epidemiology of these injuries, especially in the WHO-defined African Region, has yet to be adequately defined. Methods: We performed a systematic review of the literature regarding the epidemiology of thermal, chemical, and electrical burns in the WHO-defined African Region. All articles indexed in PubMed, EMBASE, Web of Science, Global Health, and the Cochrane Library databases as of October 2015 were included. Results: The search resulted in 12,568 potential abstracts. Through multiple rounds of screening using criteria determined a priori, 81 manuscripts with hospital-based epidemiology as well as eleven manuscripts that included population-based epidemiology were identified. Although the studies varied in methodology, several trends were noted: young children appear to be at most risk; most individuals were burned at home; and hot liquids and flame are the most common aetiologies. Discussion: While more population-based research is essential to identifying specific risk factors for targeted prevention strategies, our review identifies consistent trends for initial efforts at eliminating these often devastating and avoidable injuries. PMID- 30456108 TI - An assessment of nurse-led triage at Connaught Hospital, Sierra Leone in the immediate post-Ebola period. AB - Introduction: Nurse-led triage, using the South African Triage Scale, was introduced to the emergency centre of the tertiary referral hospital in Freetown, Sierra Leone in early 2014 prior to the Ebola epidemic. The aim of this study was to measure the effectiveness of the process now that the country has been declared free of Ebola. Methods: The study was conducted over a five-day consecutive period in the adult emergency centre of the main government teaching hospital in December 2015. The times from arrival to triage and medical assessment were recorded and compared for each triage category. We also assessed the inter-rater reliability of the process. Results: 111 patients were included during the study period. In terms of acuity, 6% were categorised as red, 27% were orange, 20% yellow and 47% green. Triage Early Warning Score was correctly calculated in 90% of cases and there was inter-rater agreement of colour code and triage category on 92% of occasions (k = 0.877, p < 0.001). Median time from triage to assessment was 15 min for red patients, 20 min for orange, 40 min for yellow and 72 min for green. Discussion: The triage process is functioning effectively in the emergency centre after the Ebola epidemic and provides a reliable assessment of undifferentiated patients presenting to the hospital to ensure that they are seen in a timely manner based on acuity. PMID- 30456109 TI - Student paramedic rapid sequence intubation in Johannesburg, South Africa: A case series. AB - Introduction: Pre-hospital rapid sequence intubation was introduced within paramedic scope of practice in South Africa seven years ago. Since then, little data has been published on this high-risk intervention as practiced operationally or by students learning rapid sequence intubation in the pre-hospital environment. The objective of this study was to describe a series of pre-hospital rapid sequence intubation cases, including those that South African University paramedic students had participated in. Methods: A University clinical learning database was searched for all endotracheal intubation cases involving the use of neuromuscular blockers between 1 January 2011 and 31 December 2015. Data from selected cases were extracted and analysed descriptively. Results: Data indicated that most patients were young adult trauma victims with a dominant injury mechanism of vehicle-related accidents. The majority of cases utilised ketamine and suxamethonium, with a low rate of additional paralytic medication administration. 63% and 72% of patients received post-intubation sedation and analgesia, respectively. The overall intubation success rate from complete records was 99.6%, with a first pass success rate of 87.9%. Students were successful in 92.4% of attempts with a first-pass success rate of 85.2%. Five percent of patients experienced cardiac arrest between rapid sequence intubation and hospital arrival. Discussion: Students demonstrated a good intubation success and first pass-success rate. However, newly qualified paramedics require strict protocols, clinical governance, and support to gain experience and perform pre hospital rapid sequence intubation at an acceptable level in operational practice. More research is needed to understand the low rate of post-intubation paralysis, along with non-uniform administration of post-intubation sedation and analgesia, and the 5% prevalence of cardiac arrest. PMID- 30456110 TI - Poor adherence to Tranexamic acid guidelines for adult, injured patients presenting to a district, public, South African hospital. AB - Introduction: In South Africa's high injury prevalent setting, it is imperative that injury mortality is kept to a minimum. The CRASH-2 trial showed that Tranexamic acid (TXA) in severe injury reduces mortality. Implementation of this into injury protocols has been slow despite the evidence. The 2013 Western Cape Emergency Medicine Guidelines adopted the use of TXA. This study aims to describe compliance. Methods: A retrospective study of TXA use in adult injury patients presenting to Khayelitsha Hospital was done. A sample of 301 patients was randomly selected from Khayelitsha's resuscitation database and data were supplemented through chart review. The primary endpoint was compliance with local guidance: systolic blood pressure <90 or heart rate >110 or a significant risk of haemorrhage. Injury Severity Score (ISS) was used as a proxy for the latter. ISS >16 was interpreted as high risk of haemorrhage and ISS <8 as low risk. Linear regression and Fischer's Exact test were used to explore assumptions. Results: Overall compliance was 58% (172 of 295). For those without an indication, this was 96% (172 of 180). Of the 115 patients who had an indication, only eight (18%) received the first dose of TXA and none received a follow-up infusion. Compliance with the protocol was significantly better if an indication for TXA did not exist, compared to when one did (p < 0.001). Increased TXA use was associated only with ISS >15 (p < 0.001). Discussion: TXA is not used in accordance with local guidelines. It was as likely not to be used when indicated than when not indicated. Reasons for this are multifactorial and likely include stock levels, lack of administration equipment, time to reach definitive care, poor documentation and hesitancy to use. Further investigation is needed to understand the barriers to administration. PMID- 30456111 TI - Describing the categories of people that contribute to an Emergency Centre crowd at Khayelitsha hospital, Western Cape, South Africa. AB - Introduction: Emergency Centre (EC) crowding has globally been recognised to adversely affect patients, staff and visitors. Anecdotally, local ECs are perceived to be fairly crowded, however, not much is known about the size of this crowd and what constitutes it. Although more reliable, resource restrictions render more detailed flow studies less achievable. This study describes the EC crowd at Khayelitsha hospital in Cape Town, South Africa as the number and different categories of people, at predefined times during the day over a four week period. Methods: A prospective, cross-sectional design was used. Headcounts were made by predefined groups at 09h00, 14h00, and 21h00 every day for four weeks. Predefined groups included doctors, nurses, visitors, patients, and other allied health staff. Summary statistics were used to describe the data. Precision was described using the 95% confidence interval. Results: A total of 16,353 people were counted during the study period. On average, 6370 (39%) of the groups were staff, 5231 (32%) were patients and 4752 (29%) were visitors. Of the staff, 586 (3.6%) were EC doctors, 733 (4.4%) were non-EC doctors, 1488 (9%) were EC nurses, and 445 (3%) were non-EC nurses. Although patient numbers in the EC remained constant, visitors and non-EC staff varied significantly with visitors peaking in the afternoon and non-EC staff drastically reducing in the evening. The EC was consistently crowded - average occupancy: 130%. Conclusion: Staff levels fluctuated predictably, reducing at night and over weekends, while patient levels remained constant. Non-EC doctors more than doubled during the day on week shifts, in significantly more numbers than EC doctors, suggesting that many of the patients in the EC were likely to be admissions boarding in the EC. Visitor numbers were substantial during visiting hours and further aggravated crowding. Resource-light studies involving flow are important to explore crowding in low- and middle income settings. PMID- 30456112 TI - Poisoning cases and their management in emergency centres of government hospitals in northwest Ethiopia. AB - Introduction: With the widespread availability of a vast number of chemicals and drugs, acute poisoning is a common medical emergency worldwide. In spite of the success of interventions to prevent toxic ingestions, acute poisoning continues to be an important public health problem. Because of weak regulations and limited health care services in developing countries, adverse outcomes from poisoning are more prevalent than in the developed world. Due to the limited Ethiopian literature on this topic, the primary objective of this study was to evaluate and report poisoning cases, their management and outcome in northwest Ethiopia. Methods: This is a retrospective study of all poisoning cases admitted and managed in the emergency centres of Gondar Teaching Referral Hospital and Metema and Debark district hospitals, from September 2010 to December 2014. Data was collected through retrospective chart review of patients who were admitted due to poisoning. Results: There were 543 registered poisoning cases listed in the registry during the study period, of which 344 cases (63.4%) had complete data and were included in the final analysis. There were 48,619 emergency centre visits during the study period, with poisoning cases accounting for 1.1%. Females (60%) were predominant among intentional as well as unintentional poisoning cases. Patients between 15 and 24 years of age accounted for 55% of the cases. Patients poisoned with organophosphate and bleaching agents accounted for 35% and 25%, respectively. Among the poisoning patients, 74% were treated with decontamination, while those exposed to organophosphate were treated with atropine 45.5% (55/121) of the time. Discussion: Young females comprise a group at increased risk for suicidal poisonings. As a developing nation, pesticide and bleaching agents remain a significant cause of acute poisonings in Ethiopia. Intentional poisoning remains the most significant identified cause of poisoning overall. PMID- 30456113 TI - A survey of emergency medicine and orthopaedic physicians' knowledge, attitude, and practice towards the use of peripheral nerve blocks. AB - Introduction: Peripheral nerve blocks (also known as regional anaesthesia) are currently used by many anaesthesiologists and emergency physicians for perioperative and procedural pain management. Methods: This is a cross sectional descriptive study conducted to evaluate knowledge, attitudes, and current practice towards use of peripheral nerve blocks for lower extremity injuries at Black Lion Hospital, a tertiary trauma centre in Addis Ababa. Results: A standardised survey was conducted with 64 participants working in emergency medicine [30/64 (46.9%)] and orthopaedics [34/64 (53.1%)]. Twenty-three of 64 (35.9%) respondents had received formal training. Knowledge was acquired from didactic/workshop format for 15/23 (65.2%), followed by peer training 6/23 (39.1%). The majority, 62/64 (96.9%), believed that knowledge of general anatomy and nerve blocks are very important. Thirty-one of 64 (48%) of the respondents did not routinely perform peripheral nerve blocks. A majority, 27/31 (87.1%) stated they lacked the required skills. Ultrasound guidance of the femoral nerve 16/33 (48.5%) was the most commonly performed peripheral nerve block, followed by ankle block using anatomic landmarks 15/33 (45.5%). Almost all (15/16) ultrasound guided nerve blocks were done by emergency medicine providers, while all anatomic land mark guided blocks were done by orthopaedic teams. A majority of the respondents (93.8%) (n = 60) were optimistic that their practice on peripheral nerve blocks would increase in future. A highly significant association was found between previous training on peripheral nerve blocks and the number of peripheral nerve blocks performed in a month; p value - 0.006. Discussion: This study indicates peripheral nerve blocks are likely underutilised due to lack of training. There was a positive attitude towards peripheral nerve blocks but gaps on knowledge and practice. PMID- 30456114 TI - Traumatic chylothorax in a young child: Case report and management. AB - Introduction: A chylothorax is an uncommon feature of paediatric chest trauma. Case report: We report a case of traumatic chylothorax following blunt chest trauma in an eight year-old girl with polytrauma after being hit by a motor vehicle. She was initially found to have a bilateral frontal skull fracture extending into the left parietal area, pulmonary contusions, left posterior rib fractures, left clavicular fracture and a degloving injury of her left foot. On the fifth day of her admission she developed progressive dyspnoea with signs of a pleural effusion, which was confirmed radiologically and drained by tube thoracostomy. Biochemical analysis confirmed chylothorax, which was managed conservatively with a fat free diet. The chest tube was removed after it stopped draining over 20 mL per 12 hours and she made a full recovery. Discussion: Initial management of chylothorax is conservative with tube thoracostomy drainage and fat free diet. Traumatic chylothroax is a rare complication following chest trauma and can take days to develop and to become clinically apparent. It is therefore important to be vigilant for potential late complications in blunt chest trauma in children, especially if there are extensive rib fractures, a sign of major transmission of force to the thorax. PMID- 30456115 TI - Uchunguzi (Journal Watch/ Montre de Journal). PMID- 30456116 TI - Ujuzi (Practical Pearl/Perle Pratique). PMID- 30456117 TI - A hands-on guide to doing content analysis. AB - There is a growing recognition for the important role played by qualitative research and its usefulness in many fields, including the emergency care context in Africa. Novice qualitative researchers are often daunted by the prospect of qualitative data analysis and thus may experience much difficulty in the data analysis process. Our objective with this manuscript is to provide a practical hands-on example of qualitative content analysis to aid novice qualitative researchers in their task. PMID- 30456118 TI - What intracranial pathologies are most likely to receive intervention? A preliminary study on referrals from an emergency centre with no on-site neurosurgical capabilities. AB - Introduction: Access to neurosurgical facilities remains limited in resource restricted medical environments worldwide, including Africa. Many hospitals refer patients to off-site facilities if they require intervention. Unnecessary referrals, however, can be detrimental to the patient and/or costly to the healthcare system itself. The aim of this study was to determine the frequency and associated intracranial pathology of patients who did and did not receive active neurosurgical intervention after having presented to an academic emergency centre at a hospital without on-site neurosurgical capabilities. Methods: A one year, retrospective record review of all patients who presented with potential neurosurgical pathology to a tertiary academic emergency centre in Johannesburg, South Africa was conducted. Results: A total of 983 patients received a computed tomography brain scan for suspected neurosurgical pathology. There were 395 positive scans; 67.8% with traumatic brain injury (TBI) and 32.3% non-traumatic brain injury (non-TBI). Only 14.4% of patients received neurosurgical intervention, mostly non-TBI-related. The main intervention was a craniotomy for both TBI and non-TBI patients. The main TBI haemorrhages that received an intervention were subdural (SDH) (16.5%) and extradural (10.4%) haemorrhages. More than half the patients with non-TBI SDHs as well as those with aneurysms and subarachnoid haemorrhages received an intervention. Discussion: Based on this study's findings, in a resource-restricted setting, the patients who should receive preference for neurosurgical referral and intervention are (1) those with intracranial haemorrhages (2) those with non-traumatic SDH more than traumatic SDH and (3) those patients with non-traumatic subarachnoid haemorrhages caused by aneurysms. PMID- 30456119 TI - Percutaneous coronary intervention still not accessible for many South Africans. AB - Introduction: The incidence of myocardial infarction is rising in Sub-Saharan Africa. In order to reduce mortality, timely reperfusion by percutaneous coronary intervention (PCI) or thrombolysis followed by PCI is required. South Africa has historically been characterised by inequities in healthcare access based on geographic and socioeconomic status. We aimed to determine the coverage of PCI facilities in South Africa and relate this to access based on population and socio-economic status. Methods: This cross-sectional study obtained data from literature, directories, organisational databases and correspondence with Departments of Health and hospital groups. Data was analysed descriptively while Spearman's Rho sought correlations between PCI-facility resources, population, poverty and medical insurance status. Results: South Africa has 62 PCI facilities. Gauteng has the most PCI-facilities (n = 28) while the Northern Cape has none. Most PCI-facilities (n = 48; 77%) are owned by the private sector. A disparity exists between the number of private and state-owned PCI-facilities when compared to the poverty (r = 0.01; p = 0.17) and insurance status of individuals (r = -0.4; p = 0.27). Conclusion: For many South Africans, access to PCI-facilities and primary PCI is still impossible given their socio-economic status or geographical locale. Research is needed to determine the specific PCI facility needs based on geographic and epidemiological aspects, and to develop a contextualised solution for South Africans suffering a myocardial infarction. PMID- 30456120 TI - Attitude of interns towards implementation and contribution of undergraduate Emergency Medicine training: Experience of an Ethiopian Medical School. AB - Introduction: Emergency Medicine is a medical specialty based on knowledge and skills required for the prevention, diagnosis and management of the acute and urgent aspects of illness and injury affecting patients of all age groups with a full spectrum of undifferentiated physical and behavioural disorders. Addis Ababa University School of Medicine started its Emergency Medicine Residency in 2010 and Emergency Medicine training for fourth-year medical students started in 2013. This study aims to assess attitudes of fifth year medical students towards Emergency Medicine training and its contribution to their final year of medical school training. Methods: Two hundred fifth year medical students participated in the study by convenience sampling. Self-administered questionnaires and Likert scales were used for data collection. Descriptive frequencies and chi-square analysis were done for categorical data. Ethical oversight was provided by the Institutional Review Board of the Addis Ababa University College of Health Sciences. Results: Of the 200 participants, 150 were male and 50 were female. 80% agreed its relevance for undergraduates. Relevance was significantly associated with recommendation to other medical schools (chi 2 = 8.34, Pr = 0.004). 72% of respondents agreed lectures are appropriate teaching methods, 70% agreed group activity, 68.5% skill sessions, 67.5% morning discussions, 64% diagnostic session, 60% duty exposures and 45% seminars. Difficulties faced during internship are primarily attributed to lack of facilities, ranging from the setup of the emergency centre to instruments and emergency drugs. 60% of respondents agreed that Emergency Medicine training is important to future careers. 65% agreed recommending training to other medical schools. Conclusion: An Emergency Medicine rotation during the final year of medical school provides opportunities to learn about undifferentiated medical emergencies and it should be included for other medical schools in the country. Participants suggest that leadership aspects of Emergency Medicine need more emphasis as the curriculum is further developed in the future. PMID- 30456121 TI - Quality improvement in emergency service delivery: Assessment of knowledge and skills amongst emergency nurses at Connaught Hospital, Sierra Leone. AB - Introduction: The ability to deliver quality emergency care services is reliant on a well-trained workforce. Since Sierra Leone was declared Ebola free in December 2015, the country has now moved into the post-Ebola reconstructive phase focusing on specialty training of healthcare workers. This development aligns well to the growing momentum for improved emergency medicine as a speciality in other regions of Sub-Saharan Africa. The first stage in assessing how to develop an emergency nursing speciality in Sierra Leone is to conduct an assessment of what is needed in terms of educational interventions. Concurrently enhancing emergency nursing capacity requires a comprehensive understanding of the role, function and emergency nurse educational requirements. This study was conducted to fully understand the current context, elucidate current nursing functions and gain knowledge of the educational desires and needs of nurses in the emergency centre at Connaught Hospital, the largest referral hospital in Sierra Leone. Methods: This mixed-methods study comprised self-assessment, one multiple-choice questionnaire, focus group interviews and observational methods. Results: Emergency nurses scored relatively low on the multiple-choice questionnaire, indicating through the self-assessment that they aspired to learn more about several topics within emergency care, and identified several themes which were considered to be barriers to delivery of care through focus group discussions and observations in the emergency centre. Conclusion: This study has identified key aspects of emergency nursing speciality training to be developed through theoretical and skill-based education provided by the nursing schools and hospital clinical facilities in Sierra Leone. PMID- 30456122 TI - Evaluation of a point-of-care ultrasound scan list in a resource-limited emergency centre in Addis Ababa Ethiopia. AB - Introduction: Emergency centres (EC) in low- and middle-income countries often have limited diagnostic imaging capabilities. Point-of-care ultrasound (POCUS) is used in high-income countries to diagnose and guide treatment of life-threatening conditions. This study aims to identify high impact POCUS scans most relevant to practice in an Ethiopian EC. Methods: A prospective observational study where patients presenting to Tikur Anbessa Specialized Hospital EC in Addis Ababa were eligible for inclusion. Physicians referred patients with a clinical indication for POCUS from a pre-determined 15-scan list. Scans were performed and interpreted, at the bedside, by qualified emergency physicians with POCUS training. Results: A convenience sample of 118 patients with clinical indications for POCUS was enrolled. The mean age was 35 years and 42% were female. In total, 338 scans were performed for 145 indications in 118 patients. The most common scans performed were pericardial (n = 78; 23%), abdominal free fluid (n = 73; 22%), pleural effusion/haemothorax (n = 51; 15%), inferior vena cava (n = 43; 13%), pneumothorax (n = 38; 11%), and global cardiac activity (n = 25; 7%). One hundred and twelve (95%) POCUS scans provided clinically useful information. In 53 (45%) patients, ultrasound findings changed patient management plans by altering the working diagnosis (n = 32; 27%), resulting in a new treatment intervention (n = 28; 24%), resulting in a procedure/surgical intervention (n = 17; 14%) leading to consultation with a specialist (n = 16; 14%), and/or changing a disposition decision (n = 9; 8%). Discussion: In this urban, low-resource, academic EC in Ethiopia, POCUS provided clinically relevant information for patient management, particularly for polytrauma, undifferentiated shock and undifferentiated dyspnea. Results have subsequently been used to develop a locally relevant emergency department ultrasound curriculum for Ethiopia's first emergency medicine residency program. PMID- 30456123 TI - Characterising emergency centre encounters in Mbour, Senegal as emergent emergency care, emergent-primary care or non-emergent. AB - Introduction: Emergency medicine is a relatively new specialty in Africa, with the first emergency medicine training programme only started in South Africa in 2004. Continued emergency centre development and preparedness relies on a better understanding of the quantity and category of emergency centre encounters within the various African regions. Methods: This study was conducted over four, consecutive months in 2014 using a retrospective chart review, aimed to examine the types of visits made to one emergency centre at the Grande Mbour Hospital in Mbour, Senegal. The New York University Emergency Department Algorithm was used to classify emergency centre encounters. Each diagnosis included in this study was classified per the algorithm as non-emergent; emergent but primary care treatable; emergent with emergency centre care needed but avoidable/preventable; and emergent with emergency centre care needed and not avoidable/preventable. The algorithm also categorised diagnoses of injury, mental health problems, alcohol, or substance abuse. Results: This study included 1268 diagnoses from the emergency centre. The most common presentations in Mbour, Senegal were injuries, with 302 cases (33%), and from the category: emergent but primary care treatable, with 303 cases (33%). In total, 174 cases (19%) were classified as: non-emergent. While only 93 cases (10%) were considered: emergency care needed/preventable or avoidable, a substantial number (n = 218, 24%) were categorised as: emergent with emergency centre care needed and not avoidable/preventable. Conclusion: This study provides the first description of patients presenting for care in the emergency centre of Mbour's hospital and demonstrates the wide range of illnesses and types of trauma that the emergency centre must accommodate while contending with the limited resources available in the area. Understanding the burden of disease will help prioritise resources appropriately. PMID- 30456124 TI - Epidemiology, clinical characteristics and outcomes of head injured patients in an Ethiopian emergency centre. AB - Introduction: Head injury is a leading cause of mortality in Africa. We characterise the epidemiology and outcomes of head injury at an Ethiopian emergency centre. Methods: We conducted a prospective cohort study of all head injured patients presenting to the Emergency Centre of Tikur Anbessa Specialised Hospital, Addis Ababa. Data was collected via a standardised form from the patient's chart, radiology reports and operative reports. Patients were followed until discharge, facility transfer, death, or 7 days in hospital. Consent was obtained from the patient or substitute decision maker. Results: Among 204 head injured patients enrolled, the majority were <30 years old (51.0%) and male (86.8%). Forty-one percent of injuries occurred from road traffic accidents (RTAs). A significant number of patients had at least one indicator of severe injury on presentation: 51 (25.0%) had a GCS < 9, 53 (26.0%) had multi-system trauma, 95 (46.6%) had >=1 abnormal vital sign and of the 133 patients with data available, 37 (27.8%) had a Revised Trauma Score (RTS) < 6. Patients injured by RTA were more likely to have indicators of severe injury than other mechanisms, including multi-system trauma (OR 3.2, 95% CI 1.7-6.2, p = 0.00), GCS < 9 (OR 3.7, 95% CI 1.8-7.4, p = 0.00), >=1 abnormal vital sign (OR 2.5, 95% CI 1.4-4.6, p = 0.00) or an RTS score < 6 (OR 3.6, 95% CI 1.6-8.1, p = 0.00). Overall, 149 (73.0%) patients were discharged from hospital, 34 (16.7%) were transferred to another hospital, and 21 patients died (10.3%). In multivariable analysis, death was significantly associated with age over 60 years (aOR 68.8, 95% CI 2.0-2329.0, p = 0.02), GCS < 9 (aOR 14.8, 95% CI 2.2-99.5, p = 0.01), fixed bilateral pupils (aOR 39.1, 95% CI 4.2-362.8, p < 0.01) and hypoxia (oxygen saturation <90%; aOR 14.2%, 95% CI 2.6-123.9, p = 0.01). Conclusion: Head injury represents a significant risk for morbidity and mortality in Ethiopia, of which RTA's increase injury severity. Targeted approaches to improving care of the injured may improve outcomes. PMID- 30456125 TI - Idiopathic pulmonary vein thrombosis: An unexpected cause of respiratory distress and acute heart failure. A case report and review of the literature. AB - Introduction: Pulmonary vein thrombosis is a potentially fatal disease. The association between pulmonary vein thrombosis and chronic heart failure has not been described in the literature. Case report: Herein, we report a case involving a 73-year-old woman, with a medical history of ischemic congestive heart failure, who was hospitalised for acute decompensated heart failure with respiratory distress. A computed tomography pulmonary angiography was performed to rule out the possibility of pulmonary embolism, and it showed evidence of pulmonary vein thrombosis. No cause was determined for the pulmonary vein thrombosis; hence, it was considered idiopathic and anticoagulation therapy was initiated for the patient. However, the patient died a few days after admission to the intensive care unit. Conclusion: This case of pulmonary vein thrombosis is presented to promote awareness of this disease entity. We also want to emphasize the importance of maintaining a high index of clinical suspicion for this diagnosis, particularly in patients with acute decompensated heart failure who are refractory to standard therapy. PMID- 30456127 TI - Scientific abstracts from the 2017 Rwanda Emergency Care Association conference. PMID- 30456126 TI - Ujuzi (Practical Pearl/Perle Pratique). PMID- 30456128 TI - Accidental similarity. PMID- 30456129 TI - Developing an emergency nursing short course in Tanzania. AB - Nurses are the largest group of healthcare workers in Africa. By adequately equipping nurses to identify, intervene and care for emergency conditions, emergency healthcare systems can be strengthened. To address this need, a nursing working group was formed within the African Federation for Emergency Medicine (AFEM). The aim of this international emergency nursing group was to develop a guiding document to help improve emergency nursing skills within Africa. Using this guiding document, a group of Tanzanian clinical nurse trainers was selected to develop a context specific short course. They used this guiding document as a foundation to improve skill development. The pilot course was well received and has since expanded to training in five regions within the United Republic of Tanzania. The clinical nurse trainers leading the course, are supported by a mentorship programme with competent educators within a global emergency nursing infrastructure. This course, a combination of local knowledge, formal mentorship programs, and international nursing support, demonstrates that investing in the improvement of emergency nursing skills can have high impact results with low cost. This will ultimately improve emergency care on the continent. PMID- 30456130 TI - Competence in performing emergency skills: How good do doctors really think they are? AB - Introduction: Despite the differences in exposure and experience in dealing with medical emergencies, all doctors should nevertheless be competent to assist a patient in need of resuscitation. The objective of this study was to describe the level of self-assessed emergency skill competence that specialist trainees in various disciplines possessed as well as to identify factors that may have contributed to their level of self-perceived competence. Methods: A prospective, cross-sectional, questionnaire study of various specialist trainees' self perceived levels of competence in emergency skills was conducted across three academic hospitals in Johannesburg, South Africa. Trainees from General Surgery and Internal Medicine (Clinical) and Psychiatry and Radiology (Non-Clinical) rated their self-perceived level of competence in a list of basic, intermediate and advanced emergency skills according to a five-point Likert ranking scale. Results: Ninety-four specialist trainees participated in the study - a response rate of 36%. The overall median competence rating for cardiac arrest resuscitation was 3.0 [IQR 3.0, 4.0] (i.e. intermediate). The median competence rating for cardiac arrest resuscitation in the clinical group (4.0) [IQR 3.0, 4.0] was higher than in the non-clinical group (3.0) [IQR 2.0, 3.0] (p < 0.001). Current or expired certification in Paediatric Advanced Life Support (PALS) or Advanced Paediatric Life Support (APLS) courses increased perceived competence and delays in starting specialisation resulted in a decrease in overall competence composite scores for each year of delay after internship. Discussion: General Surgery and Internal Medicine trainees had a higher level of self perceived competence in various emergency skills than their non- clinical counterparts. Current certification in advanced life support courses had a positive impact on trainees' self- perceived levels of competence in emergency skills. Specialist trainees who had less delay before starting their specialist training also demonstrated higher levels of perceived competence. PMID- 30456131 TI - Emergency medical services (EMS) training in Kenya: Findings and recommendations from an educational assessment. AB - Background: Over the past twenty years, Kenya has been developing many important components of a prehospital emergency medical services (EMS) system. This is due to the ever-increasing demand for emergency medical care across the country. To better inform the next phase of this development, we undertook an assessment of the current state of EMS training in Kenya. Methods: A group of international and Kenyan experts with relevant EMS and educational expertise conducted an observational qualitative assessment of Kenyan EMS training institutions in 2016. Three assessment techniques were utilised: semi-structured interviews, document review, and structured observations. Recommendations were reached through a consensus process amongst the assessment team. Results: Key findings include: (i) No national or state-level policy exists that establishes levels of EMS providers or expected fund of knowledge and skills; (ii) Training institutions have independently created their own individual training standards; (iii) Training materials are not adapted for the local context; (iv) The foundation of basic anatomy and physiology education is weak; (v) Training does not focus on symptom- or syndrome-based complaints; (vi) Students had difficulty applying foundational classroom knowledge in simulations and clinical encounters; (vii) There is limited emphasis on complex critical thinking. Discussion: Standardisation of training is needed in Kenya, including clearly defined levels of providers and expected learning outcomes. A nationally standardised EMS provider scope of practice may also help focus EMS education. Instructors must reinforce basic anatomy and physiology amongst all trainees to establish a robust foundation, then layer on field experience before trainees receive advanced training. Training graduates should be EMS providers who approach patient care with high order symptom- or syndrome-based critical thinking. While these recommendations are specific to the Kenyan EMS environment, they may have wider applicability to other developing EMS systems in resource-limited settings. PMID- 30456132 TI - A quality improvement study of the emergency centre triage in a tertiary teaching hospital in northern Ethiopia. AB - Introduction: An effective emergency triage system should prioritize both trauma and non-trauma patients according to level of acuity, while also addressing local disease burden and resource availability. In March 2012, an adapted version of the South African Triage Scale was introduced in the emergency centre (EC) of Ayder Comprehensive Specialized Hospital in northern Ethiopia. Methods: This quality improvement study was conducted to evaluate the implementation of nurse led emergency triage in a large Ethiopian teaching hospital using the Donabedian model. A 45% random sample was selected from all adult emergency patients during the study period, May 10th to May 25th 2015. Patient charts were collected and retrospectively reviewed. Presence and proper completion of the triage form were appraised. Triage level was abstracted and compared with patient outcome (dichotomized as "admitted to hospital or died" and "discharged alive from emergency centre") to quantify over- and under-triage triage. Results: From 251 randomly selected patients, 107 (42.6%) charts were retrieved. From these, only 45/107 (42.1%) contained the triage form filled within the chart. None of the triage forms were filled out completely. From 13 (28.9%) admitted or deceased patients, the under-triage rate was 30.7% and from 32 (71.1%) patients discharged alive from the EC the over-triage rate was 21.9%. Discussion: The under-triage rate observed in this study exceeds the recommended threshold of 5% and is a serious patient safety concern. However, under-triage may have been magnified by irregularities in the hospital admission process. Haphazard medical record handling, poor documentation, erroneous triage decisions, and poor rapport between nurses and physicians were the main process-related challenges that must be addressed through intensive training and improved human resource management approaches to enhance the quality of triage in the emergency centre. PMID- 30456133 TI - Assessing the impact of an emergency trauma course for senior medical students in Kenya. AB - Introduction: Ninety percent of all injury-related deaths occur in low- and middle-income countries. The WHO recommends short, resource-specific trauma courses for healthcare providers. Studies show that teaching trauma courses to medical students in developed countries leads to significant increases in knowledge and skill. High costs hinder widespread and sustained teaching of these courses in low-income countries. Methods: A two-day trauma course was designed for students at Moi College of Health Sciences in Eldoret, Kenya. Participants underwent pre- and post-course written and simulation testing and rated their confidence in 21 clinical scenarios and 15 procedures pre- and post-course using a five point Likert scale. A subset of the students was re-evaluated nine months post-course. Using the paired t-test, mean written, simulation and confidence scores were compared pre-course, immediately post-course and nine months post course. Results: Twenty-two students were enrolled. Written test score means were 61.5% pre-course and 76.9% post-course, mean difference 15.5% (p < 0.001). Simulation test score means were 36.7% pre-course and 82.2% post-course, mean difference 45.5% (p < 0.001). Aggregate confidence scores were 3.21 pre-course and 4.72 post-course (scale 1-5). Ten out of 22 (45.5%) students were re evaluated nine months post-course. Results showed written test score mean of 75%, simulation score mean of 61.7%, and aggregate confidence score of 4.59 (scale 1 5). Mean differences between immediate post- and nine months post-course were 1.6% (p = 0.75) and 8.7% (p = 0.10) for the written and simulation tests, respectively. Conclusion: Senior Kenyan medical students demonstrated statistically significant increases in knowledge, skills and confidence after participating in a novel student trauma course. Nine months post-course, improvements in knowledge skills and confidence were sustained. PMID- 30456134 TI - Preventative measures taken against hypothermia in selected Durban hospitals' emergency centres and operating theatres. AB - Introduction: Hypothermia is common in emergency general surgical patients. It is known to be associated with major complications in multiple organ systems. It is also easily preventable with the use of safe and cost-effective equipment. However, by observation, it appears that this equipment is used too infrequently thus resulting in unnecessary harm to patients. Methods: This descriptive, observational, cross-sectional study was conducted in two arms to evaluate both emergency centres and operating theatres in the major state hospitals in Durban. It was conducted as an audit as well as a questionnaire-based study, to ascertain the availability of equipment used to prevent hypothermia and also how appropriately the equipment was being used. Results: There was good availability of equipment in both the operating theatres and the emergency centres. However it was being used very poorly, particularly in emergency centres (41% of responses deemed not beneficial to patients versus 29% from operating theatres; 39% of answers beneficial versus 54% from operating theatres). Institutions with hypothermia-prevention protocols scored significantly better than those without a protocol (59% versus 25% beneficial; p = 0.01). Conclusion: In the field of hypothermia prevention, there was sufficient equipment to result in optimal patient care. However there appears to be a lack of knowledge amongst health care providers, resulting in suboptimal use of this equipment. Protocolised management may provide a solution to this problem and improve patient outcomes. PMID- 30456135 TI - Barriers and facilitators to Electronic Medical Records usage in the Emergency Centre at Komfo Anokye Teaching Hospital, Kumasi-Ghana. AB - Introduction: The use of paper for record keeping (or a manual system) has been the order of the day in almost all health care facilities in resource poor countries. This system has presented numerous challenges, which the use of Electronic Medical Records (EMR) seeks to address. The objectives of the study were to identify the facilitators and barriers to EMR implementation in Komfo Anokye Teaching Hospital's (KATH) Emergency Centre (EC) and to identify lessons learned. These will help in implementation of EMR in ECs in similar settings. Methods: This was a non-interventional, descriptive cross-sectional and purely qualitative study using a semi-structured interview guide for a study population of 24. The interviews were manually recorded and analysed thematically. EMR implementation was piloted in the EC. Some of the EC staff doubled as EMR personnel. An open source EMR was freely downloaded and customised to meet the needs of the EC. The EMR database created was a hybrid one comprising of digital bio-data of patients and scanned copies of their paper EC records. Results: The facilitators for utilising the system included providing training to staff, the availability of some logistics, and the commitment of staff. The project barriers were funding, full-time information technology expertise, and automatic data and power backups. It was observed that with the provision of adequate human and financial resources, the challenges were overcome and the adoption of the EMR improved. Discussion: The EMR has been a partial success. The facilitators identified in this study, namely training, provision of logistics, and staff commitment represent foundations to work from. The barriers identified could be addressed with additional funding, provision of information technology expertise, and data and power back up. It is acknowledged that lack of funding could substantially limit EMR implementation. PMID- 30456136 TI - A comparison of direct laryngoscopy to video laryngoscopy by paramedic students in manikin-simulated airway management scenarios. AB - Introduction: We compare the effectiveness of direct laryngoscopy (DL) to video laryngoscopy (VL) in simulated, difficult airway scenarios in a cohort of novice, prehospital, emergency care providers. Methods: Forty-five (45) students were randomised to DL or VL groups and then tasked to perform intubation on a manikin in three simulated airway scenarios. The scenarios included an uncomplicated intubation, intubation with manual in-line neck stabilisation (MILNS), and a simulated motor vehicle entrapment, with C-Spine held from behind, using a face to-face intubation technique. The primary outcome was time taken to intubate, with secondary outcomes including first pass success rate, number of intubation attempts, Cormack-Lehane (CL) view grade obtained, adverse event rate, and self reported laryngoscopist comfort. Results: Twenty-seven participants (VL n = 15, DL n = 12) completed the study. Mean time to intubate was not statistically different between VL and DL groups in any scenario. VL was associated with an increased frequency of intubation attempts (p = 0.043) and failed intubations (RR 6.4, 95% CI 0.92-44.33, p = 0.0175) in the face-to-face intubation scenario, VL was associated with a reduced incidence of poor CL view (RR 0.06, 95% CI 0.004 0.997, p = 0.0497) in the face-to-face intubation scenario, and a reduction in the frequency of dental damage (RR 0.13, 95% CI 0.02-0.96, p = 0.0165) in the supine MILNS scenario. Discussion: In our small sample, we found DL to be superior to VL in relation to a reduced risk of failed intubation and frequency of intubation attempts despite VL being superior in obtaining a good view of the vocal cords in a face-to-face intubation scenario. We found no statistically significant difference in the time taken to intubate in any scenarios. A larger study is required to inform practice and education around prehospital use of VL. PMID- 30456137 TI - Views of emergency care providers about factors that extend on-scene time intervals. AB - Introduction: Rapid response, patient care and transportation remain recognised goals of the Emergency Medical Services (EMS). Spending more time on-scene may delay the initiation of definitive care interventions. This study focused on describing the perceptions of a sample of emergency care providers regarding the impact of environmental, clinical and systemic factors with respect to their on scene time intervals. Method: The study was descriptive and prospective in nature making use of a self-designed questionnaire. Basic descriptive methods were used during the analysis of the participants' responses to 16 close-ended questions. A further review of the limited narrative elicited by two open-ended questions allowed for the reporting of additional views and opinions. Results: Thirty-three (92%) participants agreed that extended time on-scene may negatively affect patient outcome. Twenty-three (64%) agreed that spending longer than 20 min on scene may be considered excessive for medical emergencies and 28 (77%) felt the same for trauma cases. Respondents felt that many of the environmental, clinical and systemic factors mentioned in the questionnaire do have the potential to extend on-scene time intervals. The factors that were seen to have the greatest effect included waiting for fire, rescue and police services, patient acuity, the use of an air ambulance, patient extrication and multi-casualty incidents. Discussion: There are a number of environmental, clinical and systemic factors that emergency care providers indicate have the potential to extend on-scene time intervals. Acknowledging and attempting to address these factors is important for EMS as limiting the time spent on-scene is not only clinically desirable but may also lead to improved efficiency and availability of resources. PMID- 30456138 TI - Cardiopulmonary resuscitation by Emergency Medical Services in South Africa: Barriers to achieving high quality performance. AB - Introduction: Survival rates from out-of-hospital cardiac arrest significantly improve when high-quality cardiopulmonary resuscitation (CPR) is performed. Despite sudden cardiac arrest being a leading cause of death in many parts of the world, no studies have determined the quality of CPR delivery by Emergency Medical Services (EMS) personnel in South Africa. The aim of this study was to determine the quality of CPR provision by EMS staff in a simulated setting. Methods: A descriptive study design was used to determine competency of CPR among intermediate-qualified EMS personnel. Theoretical knowledge was determined using a multiple-choice questionnaire, and psychomotor skills were video-recorded then assessed by independent reviewers. Correlational and regression analysis were used to determine the effect of demographic information on knowledge and skills. Results: Overall competency of CPR among participants (n = 114) was poor: median knowledge was 50%; median skill 33%. Only 25% of the items tested showed that participants applied relevant knowledge to the equivalent skill, and the nature and strength of knowledge influencing skills was small. Demographic factors that significantly influenced both knowledge and skill were the sector of employment, the guidelines EMS personnel were trained to, age, experience, and the location of training. Conclusion: Overall knowledge and skill performance was below standard. This study suggests that theoretical knowledge has a small but notable role to play on some components of skill performance. Demographic variables that affected both knowledge and skill may be used to improve training and the overall quality of Basic Life Support CPR delivery by EMS personnel. PMID- 30456139 TI - A one year audit of patients with venous thromboembolism presenting to a tertiary hospital in Johannesburg, South Africa. AB - Introduction: Given the growing burden of venous thromboembolism (VTE) worldwide and the paucity of data from the developing world, the aim of this study was to audit the characteristics, risk factors and length of hospital stay of patients with VTE presenting to a tertiary hospital emergency centre in Johannesburg, South Africa. Methods: The study was a retrospective record review of all patients who presented with VTE to a tertiary academic emergency centre in Johannesburg, South Africa from 1 April 2012 to 30 March 2013. Results: Venous thromboembolism was identified in 74 patients; 56 (75.7%) with isolated deep vein thrombosis, 13 (17.6%) with pulmonary embolism and five (6.8%) who had a concurrent deep vein thrombosis with pulmonary embolism. The median age of the patients was 40 years old (range 19-90). The female to male ratio was 2:1. HIV infection, tuberculosis and history of immobilisation were the most common risk factors. The median duration of hospital stay was 14 days (range 4-36). A therapeutic International Normalised Ratio at discharge was only reached in 36.5% of patients. Conclusion: Venous thromboembolism presentation to the emergency centre is not common, but the risks associated with the morbidity and mortality related to it makes it important despite its relative scarcity. The prevalence of HIV infection amongst patients with VTE is concerning - not only related to the frequency of the pathology but also due to HIV not being factored into the common VTE risk stratification scores. PMID- 30456140 TI - Qualitative inquiry into Registered General Nurses' experiences in the emergency centre. AB - Introduction: Though nurses are frontline workers in emergency care, their experiences in emergency centres are seldom researched. This study explored lived experiences of Registered General Nurses working in emergency centres. Methods: This study employed an exploratory qualitative design. Purposive sampling was used in selecting hospitals and participants for study. Data were collected through semi-structured interviews with 20 Registered General Nurses who worked in emergency centres. Data analysis was performed through content analysis. Results: Demographic results revealed that only one respondent used knowledge of critical care nursing to practice emergency care in an emergency centre. Four thematic categories emerged after qualitative data analysis: a) Emergency centre as a place of learning and increased confidence for nurses; b) Feelings of joy in emergency centres; c) Social and physical consequences of emergency centres on lives of emergency centre nurses; d) Clients receiving low quality care in emergency centres. Discussion: Employment of specialist trained emergency staff and formal education of Registered General Nurses in the advanced role of emergency care nursing may be necessary to improve quality of care rendered to clients in emergency centres. PMID- 30456141 TI - Prospective assessment of patients with stroke in Tikur Anbessa Specialised Hospital, Addis Ababa, Ethiopia. AB - Introduction: The burden of stroke is increasing in many low- and middle-income countries. In Ethiopia, stroke has become a major cause of morbidity, long-term disability, and mortality. Time from stroke onset to hospital presentation is a critical factor in acute stroke care. This study aimed to describe risk factors for stroke and clinical presentation of patients presenting to the emergency centre with stroke. Methods: We conducted a cross sectional study conducted from August 2015 to January 2016 in an urban tertiary care centre in Addis Ababa, Ethiopia. Descriptive statistics and multivariable logistic regression models were used to evaluate associations between stroke types and stroke risk factors, and delayed presentation and clinical indicators. P-values less than .05 were considered statistically significant. Results: A total of 104 patients were included. The mean age was 53 years, and 56% were male. Only 30% of patients arrived using an ambulance service. The most common presenting symptoms were altered mental status (48%), hemiparesis (47%), facial palsy (45%), hemiplegia (29%), and aphasia (25%). Hypertension was the most common risk factor (49%), followed by cardiovascular disease (20.2%) and diabetes mellitus (11%). The majority of strokes were haemorrhagic in aetiology (56%). The median arrival time to the emergency centre was 24 h after symptoms onset; only 15% presented within three hours. Patients with hypertension, or presented with loss of consciousness were significantly more likely to have haemorrhagic stroke (p < .001 and p = .01 respectively). The only risk factor robustly associated with ischaemic stroke was cardiac illness (odds ratio 3.99, p = .01). Discussion: Our study identified hypertension to be the most common risk factor for stroke. The predominant aetiology type in this cohort is haemorrhagic stroke. Lastly, the median arrival time to an emergency centre was 24 h after symptom onset. PMID- 30456142 TI - A pilot study on the management and outcomes of self-poisoning in a rural Ugandan Emergency Centre. AB - Introduction: The Global Emergency Care Collaborative and Nyakibale Hospital in Rukungiri opened the first functional emergency centre in rural Uganda. We investigated decontamination, management and outcomes of poisoned patients in the emergency centre. Methods: An electronic database started recording charts from 24 March 2012. A search for diagnoses concerning self-poisoning was performed from 24 March 2012 to 30 December 2013 and 192 charts were found and de identified. Data collection included: age, sex, poison and duration, intent, vital signs, physical examination, decontamination, antidote use and follow-up status. Results: From 24 March 2012 to 30 December 2013 poisoning accounted for 96 patient encounters. Of these, 33 were associated with alpha-2 agonists and 16 were associated with organophosphorous or carbamate pesticides. The post decontamination fatality rate was 5.7%. The fatality rate of those without decontamination was 8.3%. Of those who were given atropine, 38.8% had no known indication. Of the 96 patient encounters, there were seven deaths; six were due to pesticides. Discussion: In resource-limited settings where antidotes and resuscitative capabilities are scarce, decontamination needs to be studied further. Repeat atropine use without indication may lead to depletion of an essential antidote. Future directions include a public health education programme and an algorithm to help guide clinical decisions. PMID- 30456143 TI - An unusual cause of recurrent laryngospasm: A case report. AB - Introduction: Laryngospasm is a partial or complete closure of the vocal cords, causing stridor and then complete airway obstruction. We present an unusual case of recurrent laryngospasm following cervical spine trauma. Case report: A 41-year old pedestrian was hit by a car sustaining several spine fractures including a comminuted fracture of C1. These were initially unrecognised, and his cervical spine was not immobilised. During this time the patient experienced three episodes of laryngospasm requiring intubation. On day 11 his fractures were identified, and a Philadelphia collar was placed. He made a full recovery without any neurological sequelae. Discussion: Laryngospasm is a recognised complication of anaesthesia and intubation. This case illustrates that this life-threatening complication can also follow cervical fractures, and reinforces the need for prompt and careful review of imaging to identify such fractures in trauma patients, especially those with stridor. PMID- 30456144 TI - Emergency centre diagnosis and treatment of purulent pericarditis: A case report from Tanzania. AB - Introduction: Purulent pericarditis poses diagnostic and therapeutic challenges, especially in resource-limited settings due to the unavailability of diagnostic tools, equipment, and expertise. Case report: A three-year-old female presented to the emergency centre at Muhimbili National Hospital in Dar es Salaam, Tanzania with altered mental status, lethargy, intermittent fevers, worsening difficulty in breathing, and progressive lower extremity swelling over two months. The child was in shock upon arrival. Point-of-care ultrasound demonstrated cardiac tamponade secondary to purulent pericarditis. An ultrasound guided pericardiocentesis and lavage was successfully done in the emergency centre and antibiotics were started. Though definitive management (pericardiectomy) was delayed, the child survived to hospital discharge. Conclusion: Pericardiocentesis, pericardial lavage, and the initiation of broad spectrum antibiotics are the mainstay of early treatment of purulent pericarditis. This treatment can be done safely in an emergency centre with little specialised equipment aside from point-of-care ultrasound. PMID- 30456145 TI - Freely Accessible Medical Education (FAME) for Africa. PMID- 30456146 TI - The accuracy of paediatric weight estimation during simulated emergencies: The effects of patient position, patient cooperation, and human errors. AB - Introduction: The effect of patient position and patient cooperation on the accuracy of emergency weight estimation systems has not been evaluated previously. The objective of this study was to evaluate weight estimation accuracy of the Broselow tape, the PAWPER XL tape, the Mercy method, and a custom designed mobile phone App in a variety of realistic simulated paediatric emergencies. Methods: This was a prospective study in which 32 emergency medicine volunteers participated in eight simulations of common paediatric emergency conditions, using children models. The participants used each of the four methods to estimate the children's weight. The accuracy of and time taken for the weight estimations were evaluated for each method. A regression analysis determined the effects of patient position and cooperation on weight estimation accuracy. Evaluation of subgroups of best-performers and worst-performers among the participants provided information on the effects of human user-error on weight estimation accuracy. Results: The Broselow tape, Mercy method, App and the PAWPER XL tape achieved percentages of weight estimation within 10% of actual weight in 47.7, 57.3, 68.1, and 73.0% of estimations, respectively. Patient position and cooperation strongly impacted the accuracy of the Broselow tape, had a minimal effect on the Mercy method and the App, and had no effect on the PAWPER XL tape. The best performing participants achieved very high accuracy with all methods except the Broselow tape. Discussion: The Mercy method, the App, and the PAWPER XL tape achieved exceptionally high accuracy even in uncooperative and sub optimally positioned children when used by the best-performing participants. Human error, from inexperience and inadequate training, had the most significant impact on accuracy. The Mercy method was the most subject to human error, and the PAWPER XL tape, the least. Adequate training in using weight estimation systems is essential for paediatric patient safety. PMID- 30456147 TI - Paediatric weight estimation practices of advanced life support providers in Johannesburg, South Africa. AB - Introduction: The choice of weight estimation method to use during prehospital paediatric emergency care is important because it needs to be both accurate and easy to use. Accuracy is important to ensure optimum drug dosing while ease-of use is important to minimise user errors and the cognitive load experienced by healthcare providers. Little is known about which weight estimation systems are used in the prehospital environment anywhere in the world. This knowledge is important because if the use of inappropriate weight estimation practices is identified, it could be remedied through education and institutional policies. Methods: This was a prospective questionnaire study conducted in Johannesburg, South Africa, which obtained information on the knowledge, attitude and practice of weight estimation amongst advanced life support (ALS) paramedics. Results: Forty participants were enrolled, from both the public and private sectors. The participants' preferred method of weight estimation was visual estimation (7/40; 18%), age-based formulas (16/40; 40%), parental estimation (3/40; 8%), the Broselow tape (2/40; 5%) and the PAWPER tape (11/40; 28%). No participant was familiar with or used the Mercy method. All participants were very confident in the accuracy of their selected system. Discussion: The knowledge and understanding of weight estimation systems by many advanced life support paramedics was poor and the use of inappropriate weight estimation systems was common. Further education and intervention is needed in order to change the sub optimal weight estimation practices of ALS paramedics in Johannesburg. PMID- 30456148 TI - Estimating children's weight in a Rwandan emergency centre. AB - Introduction: Most drugs, fluids and ventilator settings depend on the weight of a paediatric patient. However, knowledge of the weight is often unavailable as the urgency of the situation may impede measurement. The most common methods for paediatric weight estimation are based on height or age. This study aimed to compare the accuracy of various weight estimation methods and to derive a dedicated age-based tool within a Rwandan setting. Methods: This was a retrospective study using age, weight and height data from randomly selected charts of Rwandan children, aged between one and ten years, who attended the paediatric emergency centre, Centre Hospitalier Universitaire de Kigali, Rwanda. Weights were estimated using four versions of the Broselow Tape and several age based formulae. Linear regression was used to derive a new age-based weight estimation formula, the Rwanda Rule. Weight estimations were then compared with actual weight using Bland-Altman analysis, and the proportions of estimates within 10 and 20% of actual weight. Results: There were 327 children included in the study. The derived Rwanda Rule was: weight (kg) = [1.7 * age (years)] + 8. This formula and the original Advanced Paediatric Life Support formula (weight = [2 * age] + 8) performed similarly. Both were better than other age-based formulae (69% of estimates within 20% of actual weight). All editions of the Broselow Tape performed better than age-based rules. The 1998 version performed best with 84.8% of estimates within 20% of actual weight. Discussion: This study is the first to compare paediatric weight estimation methods in Rwanda. Locally, and until we have evidence from further research that other methods are superior, we would advise use of the 1998 Broselow Tape in children aged one to ten years old. Where the Broselow Tape is not available, the original Advanced Paediatric Life Support formula should be used. PMID- 30456149 TI - A cross-sectional survey of child abuse management knowledge among emergency medicine personnel in Cape Town, South Africa. AB - Introduction: Child abuse is a common condition in the emergency centres of South Africa. It is critical for both prehospital emergency care practitioners and emergency centre-based emergency medicine registrars to be competent in screening, diagnosing, treating, and documenting child abuse. Our goal was to assess the knowledge of child abuse management in a sample of prehospital emergency care practitioners and emergency medicine registrars in Cape Town, South Africa. Methods: A mixed-methods approach of quantitative and qualitative data was used to survey a sample of 120 participants (30 emergency medicine registrars and 90 prehospital emergency care practitioners: 30 Basic Life Support, 30 Intermediate Life Support, and 30 Advanced Life Support). An expert panel created the survey to ensure content validity and survey questions were designed to assess the perceived and actual knowledge of participants. We hypothesised that there would be significantly higher levels of perceived and actual knowledge in emergency medicine registrars compared to emergency care practitioners. An open-ended question on how participants felt dealing with child abuse was qualitatively analysed using thematic analysis. Results: There were significant differences in the levels of perceived knowledge (58% of emergency medicine registrars agreed that they felt adequately trained overall, versus 39% of emergency care practitioners; -19% difference, 95% CI -26% to -12%) and actual knowledge (83% of emergency medicine registrars with correct answers, versus 62% of emergency care practitioners; -21% difference, 95% CI -26% to -16%) among participants. Themes that emerged from qualitative analysis included personal distress, retaliation, frustration, medical system frustration, and personal competence concerns. Discussion: Significant perceived and actual knowledge deficits of child abuse management exist among both emergency care practitioners and emergency medicine registrars in this setting. Future interventions should address the need for guidelines and increased training opportunities to ensure the health and safety of abused children. PMID- 30456150 TI - A qualitative study exploring nurses' attitudes, confidence, and perceived barriers to implementing a traumatic brain injury nursing chart in Uganda. AB - Introduction: In Africa, traumatic brain injuries frequently result from road traffic injuries and assaults. Despite limited resources and the high costs of life-saving neurosurgical interventions, secondary brain injury prevention has the potential for improving outcomes. However, nurses and other medical personnel infrequently monitor vital signs, blood sugar, and pulse oximetry and only sporadically re-assess neurological status. Methods: In one-on-one, semi structured interviews, 27 nurses from Mulago Hospital's emergency centre, a tertiary care trauma hospital in Kampala, Uganda, provided feedback regarding a traumatic brain injury-focused education session and use of a nursing chart for detecting secondary brain injury. The interviews explored the nurses' confidence and perceived barriers to long-term chart implementation and traumatic brain injury care, as well as their ideas for improving this intervention. Interviews were audio recorded, transcribed, and coded using ATLAS.ti: Qualitative Data Analysis and Research Software (Cleverbridge, Inc., Chicago, USA) and Microsoft Word and Excel (Microsoft Office, Redmond, USA) for thematic content analysis. Results: Key findings identified in the interviews included the nurses' attitudes toward the chart and their feelings of increased confidence in assessing and caring for these patients. The main barriers to continuous implementation included inadequate staffing and resources. Conclusion: Nurses were receptive to the education session and nursing chart, and felt that it increased their confidence and improved their ability to care for traumatic brain injured patients. However, lack of supplies, overwhelming numbers of patients, and inadequate staffing interfered with consistent monitoring of patients. The nurses offered various suggestions for improving traumatic brain injury care that should be further investigated. More research is needed to assess the applicability of a standardised traumatic brain injury nursing education and chart in a broader context. PMID- 30456151 TI - Estimated injury-associated blood loss versus availability of emergency blood products at a district-level public hospital in Cape Town, South Africa. AB - Introduction: International guidance suggests that injury-associated haemorrhagic shock should be resuscitated using blood products. However, in low- and middle income countries resuscitation emphasises the use of crystalloids - mainly due to poor access to blood products. This study aimed to estimate the amount of blood loss from serious injury in relation to available emergency blood products at a secondary-level, public Cape Town hospital. Methods: This retrospective, cross sectional study included all injured patients cared for in the resuscitation area of Khayelitsha Hospital's emergency centre over a fourteen-week period. Injuries were coded using the Abbreviated Injury Scale, which was then used to estimate blood loss for each patient using an algorithm from the Trauma Audit Research Network. Descriptive statistics were used to describe blood volume lost and blood units required to replace losses greater than 15% circulating blood volume. Four units of emergency blood are stored in a dedicated blood fridge in the emergency centre. Platelets and fresh plasma are not available. Results: A total of 389 injury events were enrolled of which 93 were excluded due to absent clinic data. The mean age was 29 (+/-10) years. We estimated a median of one unit of blood requirement per week or weekend, up to a maximum of eight or six units, respectively. Most patients (n = 275, 94%) did not have sufficient injury to warrant transfusion. Overall, one person would require a transfusion for every 15 persons with a moderate to serious injury. Conclusion: The volume of available emergency blood appears inadequate for injury care, and doesn't consider the need for other causes of acute haemorrhage (e.g. gastric, gynaecological, etc.). Furthermore, lack of other blood components (i.e. plasma and platelets) presents a challenge in this low-resourced setting. Further research is required to determine the appropriate management of injury-associated haemorrhage from a resource and budget perspective. PMID- 30456152 TI - Major incident simulation in Rwanda: A report of two exercises. AB - Introduction: Healthcare systems must be equipped to handle major incidents. Few have been described in the African setting, including in Rwanda. The purpose of this case report was to describe and discuss two major incident simulations in Rwanda with different challenges. Case report: We report two recent major incident exercises conducted in Rwanda, in 2017. The exercises exemplify two different types of multiple casualty incidents requiring the deployment of extra ordinary resources, one due to the location of the incident (off-shore), and the other due to the large volume of casualties. Both exercises required extensive multi-agency planning and training beforehand, as part of an increasing awareness of the need for preparedness for these types of incidents. Conclusion: The exercises demonstrated the need for a standardised, physiological method of triage based on clinical needs; this is in order to maximise the number of lives saved. Triage training should be an integral part of further major incident exercises, which should be conducted regularly. PMID- 30456153 TI - The burden of intentional self-poisoning on a district-level public Hospital in Cape Town, South Africa. AB - Introduction: Intentional self-poisoning is a significant part of the toxicological burden experienced by emergency centres. The aim of this study was to describe all adults presenting with intentional self-poisoning over a six month period to the resuscitation unit of Khayelitsha Hospital, Cape Town. Methods: Adult patients with a diagnosis of intentional self-poisoning between 1 November 2014 and 30 April 2015 were retrospectively analysed after eligible patients were obtained from the Khayelitsha Hospital Emergency Centre database. Missing data and variables not initially captured in the database were retrospectively collected by means of a chart review. Summary statistics were used to describe all variables. Results: A total of 192 patients were included in the analysis. The mean age was 27.3 years with the majority being female (n = 132, 68.8%). HIV-infection was a comorbidity in 39 (20.3%) patients, while 13 (6.8%) previously attempted suicide. Presentations per day of the week were almost equally distributed while most patients presented after conventional office hours (n = 152, 79.2%), were transported from home (n = 124, 64.6%) and arrived by ambulance (n = 126, 65.6%). Patients spend a median time of 3h37m in the resuscitation unit (interquartile range 1 h 45 m-7 h 00 m; maximum 65 h 49 m). Patient acuity on admission was mostly low according to both the Triage Early Warning Score (non-urgent n = 100, 52.1%) and the Poison Severity Score (minor severity n = 107, 55.7%). Pharmaceuticals were the most common type of toxin ingested (261/343, 76.1%), with paracetamol the most frequently ingested toxin (n = 48, 25.0%). Eleven patients (5.7%) were intubated, 27 (14.1%) received N acetylcysteine, and 18 (9.4%) received benzodiazepines. Fourteen (7.3%) patients were transferred to a higher level of care and four deaths (2%) were reported. Discussion: Intentional self-poisoning patients place a significant burden on emergency centres. The high percentage of low-grade acuity patients managed in a high-acuity area is of concern and should be investigated further. PMID- 30456154 TI - A description of the self-perceived educational needs of emergency nurses in Durban, KwaZulu-Natal, South Africa. AB - Introduction: Emergency nurses are usually the first to interact with critically ill patients and victims of violence and injuries, and require advanced skills and knowledge to manage such patients. Inadequate training prevents nurses from providing optimal emergency care, and it is important to investigate if there are any skills and competencies lacking in these emergency nurses. We sought to describe the self-perceived educational needs of emergency nurses in Durban, South Africa. Methods: A descriptive quantitative survey was conducted with nurses working in four emergency centres (two state, and two privately funded hospitals) in Durban, South Africa. Results: The survey questionnaire was distributed with a response rate of 79% (n = 128). Almost half the respondents (48%, n = 61) scored less than the mean score of 29, thus indicating lower competency levels. The majority of respondents (67%, n = 85) perceived themselves as highly competent in basic skills (e.g. assess breathing, administer oxygen, assess circulation). Less than half the respondents (45%, n = 57) perceived themselves as highly competent in the intermediate skills (e.g. control haemorrhage, assist with endotracheal intubation, manage shock). A large number of respondents (46%, n = 59) perceived themselves as least competent in advanced skills (e.g. defibrillation/cardioversion, interpreting an echocardiogram [ECG]). The mean score obtained for educational need was 100, thus reflecting a high educational need, and more than half the respondents (62%, n = 79) scored higher than the mean score of 100 for educational needs. The lowest score was 41. Thirty percent (n = 38) of the respondents scored 117, indicating educational needs for all the competencies listed. Overall, 72% (n = 92) agreed that emergency education was a need. Discussion: The study emphasises the need for support systems for educational development of emergency nurses. Further training in specific skills and competencies may enhance emergency care provided. There is a growing need for ongoing educational development of emergency nurses in South Africa. PMID- 30456155 TI - The association between hospital arrival time, transport method, prehospital time intervals, and in-hospital mortality in trauma patients presenting to Khayelitsha Hospital, Cape Town. AB - Introduction: Trauma is a leading cause of unnatural death and disability in South Africa. The aim of the study was to determine whether method of transport, hospital arrival time or prehospital transport time intervals were associated with in-hospital mortality among trauma patients presenting to Khayelitsha Hospital, a district-level hospital on the outskirts of Cape Town, South Africa. Methods: The Khayelitsha Hospital Emergency Centre database was retrospectively analysed for trauma-related patients presenting to the resuscitation area between 1 November 2014 and 30 April 2015. Missing data and additional variables were collected by means of a chart review. Eligible patients' folders were scrutinised for hospital arrival time, transport time intervals, transport method and in hospital mortality. Descriptive statistics were presented for all variables. Categorical data were analysed using the Fisher's Exact test and Chi-square, continuous data by logistic regression and the Mann Whitney test. A confidence interval of 95% was used to describe variance and a p-value of <0.05 was deemed significant. Results: The majority of patients were 19-44 year old males (n = 427, 80.3%) and penetrating trauma the most frequent mechanism of injury (n = 343, 64.5%). In total, 258 (48.5%) patients arrived with their own transport, 254 (47.7%) by ambulance and 20 (3.8%) by the police service. The arrival of trauma patients peaked during the weekend, and was especially noticeable between midnight and six a.m. In-hospital mortality (n = 18, 3.4%) was not significantly affected by transport method (p = 0.26), hospital arrival time (p = 0.22) or prehospital transport time intervals (all p-values >0.09). Discussion: Method of transport, hospital arrival time and prehospital transport time intervals did not have a substantially measurable effect on in-hospital mortality. More studies with larger samples are suggested due to the small event rate. PMID- 30456156 TI - A cross-sectional survey of burnout amongst doctors in a cohort of public sector emergency centres in Gauteng, South Africa. AB - Introduction: Working in emergency care is commonly regarded as highly stressful. This is also true in the African setting characterised by high patient loads and limited resources. As in other similarly demanding occupations, burnout can be anticipated. The aim of this study was to examine the level of burnout amongst doctors in a cohort of public sector emergency centres in Gauteng, South Africa. Methods: An observational, cross-sectional design was employed, using the Maslach Burnout Inventory-Human Services Survey (which has been tested and validated in similar settings elsewhere). The study included a cohort of doctors working in the emergency centres of public sector hospitals in Gauteng, South Africa. Results: One hundred participants completed the questionnaire out of a possible 124 doctors working at the five centres. Ninety-three met the inclusion criteria and was further analysed. Seven respondents were specialist emergency physicians (7.5%), 36 were emergency medicine registrars (38.7%) and 50 were medical officers (53.8%). Fifty one respondents were female (55.0%). Analysis of burnout component scores showed a mean emotional exhaustion score of 31.69 (standard deviation, SD = 10.32), with 62 respondents (66.7%) in the high-risk group - from 86 (92.5%) at moderate to high risk. The mean de-personalisation score was 13.39 (SD = 6.21), with 50 respondents (53.8%) in the high-risk group - from 75 (80.7%) at moderate to high risk of burnout. The mean personal accomplishment score was 34.87 (SD = 6.54), with 21 respondents (22.6%) in the high-risk group - from 65 (69.9%) at moderate to high risk of burnout. Discussion: The results indicate that a large proportion of the doctors who work in these emergency centres are at moderate to high risk of burnout. Based on our findings we recommend that interventions be introduced at the work place to reduce burnout in doctors and improve their mental well-being. This will ensure better service delivery to patients with emergencies. Further research into the causes of occupational burnout should be explored. PMID- 30456157 TI - Head injury burden in a major referral hospital emergency centre in Botswana. AB - Introduction: This study describes the demographics, aetiology, emergency centre diagnosis and severity indicators of patients with head injuries presenting to the largest referral hospital emergency centre in Botswana. Methods: Cross sectional retrospective data was collected from July 2015 to September 2015 for all emergency centre head injury presentations at Princess Marina Hospital. Information was extracted from emergency centre records regarding patient demographics, mechanism of injury, clinical observations, diagnosis, and treatment. Results: Three-hundred and sixty head injury patients presented to the emergency centre in the three months, averaging four per day. 80% were less than 40 years of age and males accounted for 69% of all presentations. 58% of injuries were listed as being accidental, 39% recorded from assaults and 38% from road traffic accidents. The most common emergency centre clinical diagnosis was concussion and the most common radiological diagnosis skull fracture. The median Glasgow Coma Scale was 15 with a range from 3 to 15; and, among patients for whom Revised Trauma Score could be calculated, 79% scored the lowest probability of death in the Revised Trauma Score. Discussion: Head injury disproportionately overburdened males in this study, and head injury aetiology and demographic picture was similar to regional data. Severity scoring using the Glasgow Coma Scale was only available among 66% of patients and Revised Trauma Score calculable in half of presentations. Only 55% of head injury patients were discharged from the emergency centre, despite the preponderance of low severity scores. Head CTs appear to have been over-utilised and implementation of a Traumatic Head CT guideline for our setting is proposed. This study improves understanding of the burden of head injury in Botswana and advocates for national referral guidelines for patients with head injury in Botswana. PMID- 30456159 TI - Essential medicines for emergency care in Africa. AB - Objectives: Essential medicines lists (EMLs) are efficient means to ensure access to safe and effective medications. The WHO has led this initiative, generating a biannual EML since 1977. Nearly all countries have implemented national EMLs based on the WHO EML. Although EMLs have given careful consideration to many public health priorities, they have yet to comprehensively address the importance of medicines for treating acute illness and injury. Methods: We undertook a multi step consensus process to establish an EML for emergency care in Africa. After a review of existing literature and international EMLs, we generated a candidate list for emergency care. This list was reviewed by expert clinicians who ranked the medicines for overall inclusion and strength of recommendation. These medications and recommendations were then evaluated by an expert group. Medications that reached consensus in both the online survey and expert review were included in a draft emergency care EML, which underwent a final in-person consensus process. Results: The final emergency care EML included 213 medicines, 25 of which are not in the 2017 WHO EML but were deemed essential for clinical practice by regional emergency providers. The final EML has associated recommendations of desirable or essential, and is subdivided by facility level. Thirty-nine medicines were recommended for basic facilities, an additional 96 for intermediate facilities (e.g. district hospitals), and an additional 78 for advanced facilities (e.g. tertiary centres). Conclusion: The 25 novel medications not currently on the WHO EML should be considered by planners when making rational formularies for developing emergency care systems. It is our hope that these resource-stratified lists will allow for easier implementation, and will be a useful tool for practical expansion of emergency care delivery in Africa. PMID- 30456158 TI - Is there an association between central venous pressure measurement and ultrasound assessment of the inferior vena cava? AB - Introduction: Early assessment of volume status is paramount in critically ill patients. Central venous pressure (CVP) measurement and ultrasound assessment of the inferior vena cava (IVC) are both used for volume assessment in the emergency centre. Recent data is conflicting over whether there is a correlation between CVP and ultrasound assessment of the IVC. Methods: This was a retrospective review of an audit previously performed in the Emergency Unit of Ngwelezane Hospital in Kwazulu-Natal. The audit involved measuring inferior vena cava collapsibility index (IVC-CI) within 5 min of CVP measurement. In this retrospective study, audit data were analysed to determine if an association exists. Results: Twenty-four patients were included. The median age of participants was 36 (IQR 42) years (95% CI 33-56). The median time to ultrasound was 18.6 (52.5) h (95% CI 7.5-36.2). The mean CVP was 13.7 +/- 7.7 cm H2O and mean IVC-CI was 39.4 +/- 17.8%. Based on a Pearson correlation test, there was a weak negative correlation between CVP and IVC-CI, which was not statistically significant (r = -0.05, n = 24, p = 0.81, 95% CI -0.5 to 0.4) for all participants. However, among females there was a moderate negative correlation between CVP and IVC-CI, which was not statistically significant (r = -0.43, n = 7, p = 0.34, 95% CI -0.9 to 0.5), while among males there was a weak positive correlation, which was not statistically significant (r = 0.16, n = 17, p = 0.53, 95% CI -0.3 to 0.6). Discussion: There is no significant correlation between CVP and IVC-CI. Further validation research is required to support our preliminary findings of no significant correlation between CVP measurement and ultrasound assessment of the IVC. CVP and IVC ultrasound should be used as clinical adjuncts, and not as stand-alone measures of volume assessment. PMID- 30456160 TI - A low fidelity eye model for lateral canthotomy training. AB - We introduce a low-fidelity, low-cost, reusable training model for the lateral canthotomy procedure. We believe that this trainer has the potential to improve clinicians' knowledge and skill of the procedure, especially when cost or access to higher-fidelity trainers is prohibitive. PMID- 30456161 TI - Long term survival of a dog with disseminated Aspergillus deflectus infection without definitive treatment. AB - Canine disseminated fungal infection by Aspergillus species carries a guarded to grave prognosis as they often rapidly progress and are refractory to treatment with many euthanased soon after diagnosis. This case report describes a 2.5 year old female spayed German Shepherd Dog diagnosed with disseminated Aspergillus deflectus infection for which definitive treatment was declined by the owners. With only palliative management the dog survived three years and two months before succumbing to chronic kidney disease. PMID- 30456162 TI - Disseminated cryptococcosis in a HIV-negative patient: Case report of a newly diagnosed hypertensive adult presenting with hemiparesis. AB - We report a case of disseminated cryptococcosis in a 42-year old immunocompetent female. Prior to admission at Bugando Medical Center, the patient was attended at three hospitals for hypertension and clinically diagnosed malaria. Following diagnosis of disseminated Cryptococcus at our center, she was successfully treated with fluconazole but remained with visual loss. Blood cultures should be considered in the management of any adult presenting with fever to enable early detection of the least expected differentials like in this case. PMID- 30456163 TI - Triadelphia pulvinata: A rare invasive fungal infection in a diabetic patient. AB - Invasive fungal infections are a leading cause of morbidity and mortality in the immunocompromised patients. We report a case of Triadelphia pulvinata, a rare dematiaceous fungi causing invasive fungal infection in a 68 year old diabetic Iraqi female. The diagnosis was made by combining the phenotypic findings and genome sequencing. There are only 4 case reports in literature and this is probably the first from India which was treated by Liposomal Amphotericin B. PMID- 30456164 TI - Efficacy of Chitosan in promoting wound healing in extraction socket: A prospective study. AB - Purpose: Chitosan has been shown to promote wound healing and induce bone formation. The aim of this split-mouth study was to evaluate the effectiveness of chitosan based dressing in wound healing after lower third molar extraction. Method: Asymptomatic symmetrical mandibular third molars were extracted simultaneously in 27 patients and Chitosan dressing was placed into the extraction socket in the test side. Pain scores were recorded on VAS using a 0 to 10 pain score. Wound healing was compared between right and left side. Radiographic findings were evaluated by observing lamina dura and density of extraction socket. Results: Test group had more pain than control at all time intervals and unerupted tooth sites showed mean pain score significantly more than erupted tooth sites. Test group was superior to control in event of wound healing. Healing was significantly better in erupted tooth than unerupted tooth. At second week 12 sites showed better radiographic findings in chitosan treated group compared to 3 sites in the control group. At third month, 14 sites showed improved bone formation in chitosan treated group compared to 4 in control group. None of the unerupted teeth group showed better radiographic finding in test side at 2 week and 3 month compared to erupted teeth group. Conclusion: Chitosan is effective in promoting wound healing and early osteogenesis in erupted tooth socket after extraction. We recommend that chitosan dressing should be used in the sockets of erupted tooth after extraction but should be avoided in unerupted or impacted teeth cases. PMID- 30456165 TI - Bilateral pulmonary nodules and intravascular pulmonary histiocytosis: A rare presentation of hemophagocytic lymphohistiocytosis secondary to Epstein-Barr Virus infection. AB - A 61-year-old male presented with worsening dyspnoea and constitutional symptoms for few weeks followed by bloody diarrhoea and loss and fever. Physical exam revealed tachycardia, respiratory distress, and splenomegaly without lymphadenopathy. Work up showed pancytopenia, hypofibrinogenemia, acute kidney injury requiring haemodialysis, high ferritin level, positive IgG and IgM for EBV and positive soluble CD25. Chest CT scan showed bilateral pulmonary nodules. Lung biopsy showed intravascular pulmonary histiocytosis while bone marrow biopsy was negative for hemophagocytes. A diagnosis of hemophagocytic lymphohistiocytosis (HLH) was made based on fulfilling the diagnostic criteria and systemic steroids were initiated, which improved the patient's condition gradually with resolution of dyspnoea, AKI and pancytopenia. Repeat chest CT scan showed resolution of bilateral pulmonary nodules. The patient was transferred to a tertiary centre to receive HLH-specific therapy. We present a rare presentation of HLH with steroid responsive bilateral pulmonary nodules and a rare histopathologic finding of pulmonary intravascular histiocytosis, which has never been described in HLH or the lung tree. PMID- 30456166 TI - Unilateral pulmonary artery agenesis manifested by hemoptysis in pregnancy. AB - Unilateral pulmonary artery agenesis (UPAA) is a rare congenital anomaly which can be symptomatic or even asymptomatic. Most of patients with isolated UPAA have mild symptoms and it is difficult to be diagnosed, especially when abnormal findings of chest radiograph are the first presentation. It is often misdiagnosed and is not considered during differential diagnosis. To make a diagnosis of UPAA, various imaging modalities including chest radiograph, computed tomography (CT), and angiography are used. We report a 33-year-old woman in pregnancy presented recurrent hemoptysis whose CT was postponed due to her pregnancy. Although CT is a useful diagnostic tool, chest radiograph could be used instead in pregnancy suggesting UPAA with a lot of information. PMID- 30456167 TI - Anti PD-1 immunotherapy related interstitial lung disease presenting as respiratory failure - A review with case series. AB - Introduction: Lung cancer is one of the most common cancers in the world and it is the leading cause of cancer-related deaths, among men and women, in the United States. In advanced non-small cell lung cancers, immune checkpoint inhibitors such as programmed cell death protein-1 inhibitors (PD-1 inhibitors) have become second-line therapy and have revolutionized the management in selective cases conferring better overall response rates and progression free survival. Methods: We present a case series and review of literature emphasizing this immune-related adverse events (irAEs) in patients with metastatic non-small cell lung cancer and esophageal cancer who were treated with Nivolumab as a second line therapeutic option. Results: PD-1 inhibitors such as, Nivolumab and Pembrolizumab, have shown a stable regression of various malignancies, such as metastatic melanoma, renal cell carcinoma and metastatic non-small cell lung cancer. We describe 2 cases of such immune related adverse effects associated with immune check point inhibitors with recovery in one of the patients. Steroid therapy has been the cornerstone for treatment for such immune related adverse effects. Importance has also been laid on the typical radiographic patterns of pneumonitis and interstitial lung disease associated with immunotherapy. Conclusions: We attempt to raise awareness, discuss early management strategies and hypothesize an association between the incidence and development of these adverse events in cancer patients treated with anti-PD-1 immunotherapeutic agents. PMID- 30456168 TI - Flare of eosinophilic granulomatosis with polyangiitis related to pregnancy: Case report and review of the literature. AB - Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by excessive eosinophil accumulation in the peripheral blood and affected tissues with development of granulomatous vasculitic organ damage. It is strongly associated with asthma and ear-nose-throat disease. It often affects patients between the ages of 40 and 60 years. It is unknown whether pregnancy impacts the disease activity of EGPA, including initial diagnosis or relapse. Because of its rarity and age of susceptibility, there are few reported cases describing pregnancy in women with quiescent or active EGPA. Here, we describe a young woman who experienced EGPA relapse during pregnancy and subsequently underwent an elective caesarean section for non-reassuring fetal status at 37 weeks without complication. PMID- 30456169 TI - Benign pulmonary nodular lymphoid hyperplasia (NLH) in an HIV infected patient; A diagnostic dilemma. PMID- 30456170 TI - Epileptic spasms as the presenting seizure type in a patient with a new "O" of TORCH, congenital Zika virus infection. AB - Congenital TORCH infections are a significant cause of epileptic spasms, an infantile epileptic encephalopathy, through disruptions to several pathways in neurodevelopment. Congenital Zika virus has a similar neurotropism to other TORCH agents, and leads to microcephaly, severe neurodevelopmental impairment, and high rates of early onset seizures. Here we report a child with confirmed congenital Zika virus who developed extensor epileptic spasms and hypsarrhythmia associated with a loss of early developmental milestones. Early treatment led to resolution of epileptic spasms and improved developmental trajectory, though the child continues to have ongoing focal seizures and prominent developmental impairment. Congenital Zika virus infection requires close monitoring as early identification of epileptic spasms is likely important in long term developmental outcome. PMID- 30456171 TI - Heterotopia or overlaying cortex: What about in-between? AB - We describe a patient with unilateral periventricular nodular heterotopia (PNH) and drug-resistant epilepsy, whose SEEG revealed that seizures were arising from the PNH, with the almost simultaneous involvement of heterotopic neurons ("micronodules") scattered within the white matter, and subsequently the overlying cortex. Laser ablation of heterotopic nodules and the adjacent white matter rendered the patient seizure free. This case elucidates that "micronodules" scattered in white matter between heterotopic nodules and overlying cortex might be another contributor in complex epileptogenicity of heterotopia. Detecting patient-specific targets in the epileptic network of heterotopia creates the possibility to disrupt the pathological circuit by minimally invasive procedures. PMID- 30456173 TI - Letter to the Editor: Metal hypersensitivity reactions in the context of EssureTM. AB - *Allergic systemic contact dermatitis has been reported with the use of EssureTM.*Hypersensitivity may be considered upon exclusion of common pelvic disease etiologies.*Asymptomatic, functioning implanted devices do not warrant patch testing or removal. PMID- 30456172 TI - Alteration in thiols homeostasis, protein and lipid peroxidation in renal tissue following subacute oral exposure of imidacloprid and arsenic in Wistar rats. AB - The aim of present study was to assess whether No Observed Effect Level (NOEL) of imidacloprid (IMI) potentiates the arsenic induced renal toxicity at its maximum contaminant level in drinking water in Wistar rats. Significant elevation of lipid and protein oxidation with reduced level of total thiols and antioxidant enzymes (catalase, superoxide dismutase, glutathione reductase, glutathione peroxidase and glutathione-s-transferase) in renal tissue may have contributed to increased renal plasma biomarkers (creatinine and blood urea nitrogen) following repeated exposure of IMI and arsenic alone and in-combination. The altered renal biomarkers in co-exposed groups corroborated with histopathological alterations in renal tissue. The observations indicated that altered thiol homeostasis in renal tissue may be associated with increased lipid and protein oxidation in IMI and arsenic administered rats. It is concluded that administration of IMI potentiate the arsenic induced renal damage in Wistar rats. PMID- 30456174 TI - Quantitative imaging of membrane micropolarity in living cells and tissues by spectral phasors analysis. AB - Intracellular micropolarity is essential in several metabolic processes, as it controls membrane permeability, regulating the fluxes of molecules and energy. Here we describe a method for the determination of the micropolarity in living cells using spectral confocal microscopy. The method is based on a phasor analysis of spectrally resolved images of live cells, labelled with the solvatochromic probe Nile Red. An application is provided to extract a polarity profile from the acquired Spectral datasets, which represent the contribution of hyperpolar, polar and non-polar lipids, and to generate a micropolarity map at submicrometric spatial resolution. A metabolic parameter, representing a quantitative index of the fatty acid-triacylglycerol turnover, is also furnished. This method allows a functional profiling of cells and tissues and the detection of metabolic imbalances between lipid storage and usage. *Use of spectral resolved confocal microscopy of Nile Red labelled cells for pixel resolved determination of the membranes micropolarity.*Spectral acquisition increases the specificity and sensitivity of the detection to provide a polarity profile and a metabolic index for fatty acid-TG turnover.*Use of spectral resolved confocal microscopy of Nile Red labelled cells for pixel resolved determination of the membranes micropolarity. PMID- 30456175 TI - Removal of phosphate from River water using a new baffle plates electrochemical reactor. AB - During the last 50 years, the human activities have significantly altered the natural cycle of phosphate in this planet, causing phosphate to accumulate in the freshwater ecosystems of some countries to at least 75% greater than preindustrial levels, which indicates an urgent need to develop efficient phosphate treatment methods. Therefore, the current study investigates the removal of phosphate from river water using a new electrochemical cell (PBPR). This new cell utilises perforated baffle plates as a water mixer rather than magnetic stirrers that require power to work. This study investigates the influence of key operational parameters such as initial pH (ipH), current density (J), inter-electrode distance (ID), detention time (t) and initial phosphate concentration (IC) on the removal efficiency, and influence of the electrocoagulation process on the morphology of the surface of electrodes. Overall, the results showed that the new reactor was efficient enough to reduce the concentration of phosphate to the permissible limits. Additionally, SEM images showed that the Al anode became rough and nonuniform due to the production of aluminium hydroxides. The main advantages of the electrocoagulation technique are: *The EC method does not produce secondary pollutants as it does not required chemical additives, while other traditional treatment methods required either chemical or biological additives [[1], [2], [3], [4]].*It has a large treatment capacity and a relatively short treatment time in comparison with other treatment methods, such as the biological methods [1,[5], [6], [7]].*The EC method produces less sludge than traditional treatment traditional chemical and biological treatment methods [8,9]. EC technology, like any other treatment method, has some drawbacks that could limit its performance. For instance, it still has a clear deficiency in the variety of reactor design, and the electrodes should be periodically replaced as they dissolve into the solution due to the oxidation process [2,10]. PMID- 30456177 TI - Naegleria species population found in pond water of parks in Mashhad city, Can the physicochemical factors affect it? AB - Naegleria species are the ubiquitous free-living amoebas that are found worldwide in soil and water. Among Naegleria spp., N. fowleri can cause primary amebic meningoencephalitis (PAM). Ninety water samples were collected from the pond of parks. Also, the water quality parameters were measured at the sampling site (such as temperature, pH, total dissolved solids (TDS), electrical conductivity (EC) and Turbidity). After filtering, the samples were cultured on Bacto-agar enriched with Escherichia coli. A PCR assay was conducted on the culture-positive samples in the ITS1, 5.8SrDNA and ITS2 regions, and then the PCR products were sequenced. The pond water of parks was contaminated with some Naegleria spp. (except N. fowleri) and a Vahlkampfia avara. There was no significant relationship between water quality parameters and the presence of Naegleria (p > 0.05). Our protocol investigates to detect Naegleria spp. from ponds water of parks in Mashhad city and the relations between the water quality parameters and its presence. PMID- 30456176 TI - Radionuclides proportion and radiological risk assessment of soil samples collected in Covenant University, Ota, Ogun State Nigeria. AB - The activity levels of 238U, 232Th and 40K in soil surrounding major office complexes in Covenant University were analyzed for radiological hazards to determine the safety of the residents in such environment. Sixteen (16) soil samples were collected, prepared and sent to Acme laboratory in Canada for analysis with the use of high purity germanium detector. The mean activity concentrations of 238U, 232Th and 40K were found to be 45 +/- 10, 135 +/- 8 and 195 +/- 20 respectively. The concentrations of 238U and 232Th were found to be higher than the world recommended standard of 35 and 30, while the result for 40K was noted to be lower than the world safe limit. The average values of Raeq, D, AED, Iyr, Hex and ELCR in this study were estimated to be 252.33 Bq/kg, 110.15 nGy/h, 0.13 mSv/y, 1.78, 0.68 and 0.47 * 10-3 respectively. It was noticed that none of the measured parameters was higher than the internationally recommended safe limits. 232Th was found to be the major contributor to the environmental radionuclides in the area of study. Therefore, the inhabitants of the office complexes whose environment was assessed are considered not be exposed to any radiological hazards. PMID- 30456178 TI - A direct and non-invasive method for kidney delivery of therapeutics in mice. AB - Kidney is a vital organ that maintains the homeostasis in terms of acid-balance, toxin filtration and blood pressure control. Kidney malfunction can be fatal and the renal research administers testing pharmaceutical agents or stem cells in rodents to study their therapeutic efficacy. However, targeted delivery of agents into mice kidney is strenuous and may require laparotomy. Here we present a direct delivery method for cell transplantation or drug injection into the mice kidney. The method is simple and can be performed non-invasively with avoidance of surgical intervention on the animals. Nevertheless, this method serves as an efficient method for in vivo drug delivery or engraftment studies for renal research. *Direct delivery into the kidney.*Non-invasive method. PMID- 30456179 TI - Detection of lymph node metastases in genitourinary cancers. PMID- 30456180 TI - Assessing lymph node status in patients with kidney cancer. AB - Accurate detection of lymph node involvement on pre-operative imaging in patients diagnosed with renal cell carcinoma (RCC) is critical for determination of disease stage, one of the most significant prognostic factors in RCC. The presence of lymph node involvement in RCC doubles a patient's risk of distant metastasis and significantly reduces their 5-year survival. Currently, lymph node involvement in patients with RCC is evaluated with numerous modalities, with rapid advancements occurring across these modalities. The purpose of this study was to evaluate the advantages and disadvantages of each modality and utilize sensitivities and specificities to determine the highest performing modalities for accurate lymph node involvement in renal cancer. A comprehensive computer based literature search of full-length original research English language studies of human subjects with biopsy-proven RCC was performed to evaluate publications on the diagnostic performance of color Doppler sonography (CDS), magnetic resonance imaging (MRI), lymphotrophic nanoparticle enhanced MRI (LNMRI), multidetector-row computed tomography (MDCT), F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET), and PET/CT for evaluation of lymph node status in kidney cancers in articles that were published prior to May 2018. Limited studies were available for evaluating CDS performance for determination of lymph node involvement in renal cancer. While CT is the most common modality for nodal staging, due to its availability and relatively low expense, it did not demonstrate the highest performance of the modalities examined for determination of lymph node status in patients with RCC. Of the modalities examined, MRI demonstrated the highest sensitivity (92-95.7%) for detection of lymph node involvement in RCC. Studies of lymph node involvement in RCC using both MRI and CT indicated that using the current diameter criteria (greater than 1 cm) for determination of positive lymph nodes should be re-evaluated as micro-metastases are frequently overlooked. Studies evaluating lymph node involvement with FDG-PET had the highest specificity (100%), indicating FDG-PET is the preferred modality for confirming lymph node involvement and extent of involvement. However, due to the low sensitivity of FDG-PET, clinicians should be skeptical of negative reports of lymph node involvement in RCC patients. Further studies examining determination of lymph node involvement in renal cancer across modalities are greatly needed, current literature suggests utilizing a combination of MRI and FDG-PET may offer the highest accuracy. PMID- 30456181 TI - Lymph node imaging of pediatric renal and suprarenal malignancies. AB - Pediatric renal and suprarenal cancers are relatively rare malignancies, but are not without significant consequence to both the patient and caretakers. These tumors are often found incidentally and present as large abdominal masses. Standard of care management involves surgical excision of the mass, but contemporary treatment guidelines advocate for use of neoadjuvant or adjuvant chemotherapy for advanced stage disease, such as those cases with lymph node involvement (LNI). However, LNI detection is based primarily on surgical pathology and performing extended lymph node dissection can add significant morbidity to a surgical case. In this review, we focus on the use and performance of imaging modalities to detect LNI in Wilms' tumor (WT), neuroblastoma, and pediatric renal cell carcinoma (RCC). We report on how imaging impacts management of these cases and the clinical implications of LNI. A literature search was conducted for studies published on imaging-based detection of LNI in pediatric renal and suprarenal cancers. Further review focused on surgical and medical management of those cases with suspected LNI. Current imaging protocols assisting in diagnosis and staging of pediatric renal and suprarenal cancers are generally limited to abdominal ultrasound and cross-sectional imaging, mainly computed tomography (CT). Recent research has investigated the role of more advance modalities, such as magnetic resonance imaging (MRI) and positron emission tomography (PET), in the management of these malignancies. Special consideration must be made for pediatric patients who are more vulnerable to ionizing radiation and have characteristic imaging features different from adult controls. Management of pediatric renal and suprarenal cancers is influenced by LNI, but the rarity of these conditions has limited the volume of clinical research regarding imaging-based staging. As such, standardized criteria for LNI on imaging are lacking. Nevertheless, advanced imaging modalities are being investigated and potentially represent more accurate and safer options. PMID- 30456183 TI - A pictorial review of bladder cancer nodal metastases. AB - Lymph node involvement in bladder cancer is common and has prognostic implications. Early and accurate identification of metastatic lymph nodes is, therefore, important in ensuring appropriate patient triage and management. The purpose of this review is to provide a pictorial and educational overview of the staging and imaging appearance of metastatic lymph nodes in bladder cancer. Additionally, a secondary aim of this manuscript is to provide a review of the diagnostic accuracy of common imaging modalities available for detecting metastatic lymph nodes in affected patients. PMID- 30456182 TI - Evaluation of lymph node status in patients with urothelial carcinoma-still in search of the perfect imaging modality: a systematic review. AB - While accurate lymph node status evaluation in urothelial carcinoma patients is essential for the correct disease staging and, hence, establishing the most beneficial treatment strategy, the diagnostic performance of routine imaging in regards to this issue is not satisfactory. For the purpose of this article, we systematically reviewed the contemporary literature on the sensitivity and specificity of particular imaging modalities which have been studied for detecting lymph node metastases in patients diagnosed with urothelial carcinoma. The evidence reviewed shows that computed tomography (CT), although recognized as the imaging modality of choice, is associated with marked limitations, resulting in its low sensitivity for lymph node involvement detection in urothelial carcinoma patients, with no study reporting a value higher than 46% using standard cut-off values. Markedly higher sensitivity rates may be achieved with magnetic resonance imaging (MRI), especially when using ultrasmall superparamagnetic iron oxide as the contrast agent, however, no uniform protocol has been systematically studied up to date. The vast majority of recent evidence concerns positron emission tomography (PET), which is being reported to improve the diagnostic performance of CT alone, as has been demonstrated in multiple articles, which investigated the accuracy of PET/CT at primary or post-treatment staging of urothelial carcinoma patients. However, there has been substantial heterogeneity in terms of methodology and results between those studies, making it premature to draw any definitive conclusions. The results of this review lead to a conclusion, that while CT, despite being not fully satisfactory, still remains the gold-standard method of imaging for staging purposes in urothelial carcinoma, other imaging modalities are under investigation, with promising results. PMID- 30456185 TI - Fluciclovine positron emission tomography in the setting of biochemical recurrence following local therapy of prostate cancer. AB - Approximately one in five men will demonstrate biochemical recurrence (BCR) following local therapy for prostate cancer (PCa). Advanced imaging modalities including positron emission tomography (PET) imaging of various radiotracers have become more commonplace to visualize foci of disease recurrence. We performed a systematic review of the literature to describe current evidence in support of 18F-fluciclovine (Axumin) PET imaging in this clinical setting. An English literature search was conducted on PubMed/Medline for original investigations on 18F-fluciclovine PET for PCa. Boolean criteria included the terms: prostate, fluciclovine, FACBC and Axumin. Published articles meeting these criteria and their respective bibliographies and diagnostic modalities were included after review, when appropriate. Our literature review identified 93 articles. Among these, 18 met our inclusion criteria. Evidence suggests 18F-fluciclovine PET imaging is safe, well-tolerated and offers acceptable sensitivity and specificity for the detection of localized intraglandular and extraprostatic PCa foci in the setting of persistence or recurrence after primary treatment. Compared to other available PET radiotracers available, evidence suggests that 18F-fluciclovine may outperform ProstaScint and 11C-choline in this clinical setting. Furthermore, 18F fluciclovine PET may aid guiding decision-making in regards to salvage therapy planning. Further investigation is warranted to validate these early findings and to further compare this agent to other available radiotracers in this setting. PMID- 30456184 TI - Diffusion-weighted imaging (DWI) in lymph node staging for prostate cancer. AB - In patients with prostate cancer, the presence of lymph node (LN) metastases is a critical prognostic factor and is essential for treatment planning. Conventional cross-sectional imaging performs poorly for nodal staging as both computed tomography (CT) and magnetic resonance imaging (MRI) are mainly dependent on size and basic morphological criteria. Therefore, extended pelvic LN dissection (ePLND) remains the gold standard for LN staging, however, it is an invasive procedure with its own drawbacks, thus creating a need for accurate preoperative imaging test. Incorporating functional MRI by using diffusion-weighted MRI has proven superior to conventional MRI protocol by means of both qualitative and quantitative assessment. Currently, the increased diagnostic performance remains insufficient to replace ePLND and the future role of DWI may be through combination with MR lymphangiography or with novel positron emission tomography (PET) tracers. In this article, the current state of data supporting DWI in LN staging of patients with prostate cancer is discussed. PMID- 30456186 TI - Keeping up with the prostate-specific membrane antigens (PSMAs): an introduction to a new class of positron emission tomography (PET) imaging agents. AB - Prostate-specific membrane antigen (PSMA) targeted positron emission tomography (PET) is an emerging prostate cancer imaging method, which has been reported to have a higher sensitivity and specificity than the currently approved PET imaging agents. Multiple PSMA ligands are being investigated around the world and applications range from primary tumor characterization, to local staging, biochemical recurrence, metastasis, and image-guided interventions. The most investigated PET tracers are labelled with 68-Gallium or 18-Fluoride and are discussed in this review. Additionally, 99mTc labeled PSMA agents for single photon emission computed tomography (SPECT) imaging are elucidated as an alternative method of PSMA image acquisition. PMID- 30456188 TI - Hyperpolarized 13C magnetic resonance imaging, using metabolic imaging to improve the detection and management of prostate, bladder, and kidney urologic malignancies. AB - Approximately 25% of the 2 million new cancer diagnoses in the United States in 2018 were comprised of malignancies of the urogenital system. Of these cancers, 75% occurred in the kidney/renal pelvis, prostate, and urinary bladder. Early diagnosis is beneficial to long-term survival. Currently, urologists rely heavily on computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), and positron emission tomography (PET) to both diagnose and offer prognoses, but these techniques are limited in their resolution and are more effective when cancers have reached macroscopic size in later stages. Recent developments in cancer metabolomics have revealed that cancerous cells preferentially upregulate specific metabolic pathways as a means of conserving their resources and maximizing their growth potential. This has opened a new avenue for early diagnosis with much higher resolution, reliability, and accuracy through 13C hyperpolarized MRI. Preferential cancer pathways can be elucidated through this technique using 13C-labeled molecules utilized for energy generation and tumor growth. As these pathways are identified, targeted therapies are being designed to inhibit these pathways to allow for treatment that is cytotoxic to malignant cells but preserves native cells. In this paper, we review the current understanding of urologic cancer metabolomics, specifically in the kidney, prostate, and bladder. We will review the basic physics of MRI and demonstrate how hyperpolarized 13C MRI offers an innovative solution to early diagnosis as well as creates novel avenues for more targeted therapy. PMID- 30456187 TI - Clinical implications of PET/CT in prostate cancer management. AB - Several imaging modalities exist for the investigation of prostate cancer (PCa). From ultrasound to computed tomography (CT) and magnetic resonance imaging (MRI), the role of imaging in detecting lesion foci, staging, and localizing disease after biochemical recurrence (BCR) is expanding. However, many of the conventional imaging modalities are suboptimal, particularly in the detection of metastasis. Positron emission tomography (PET) has recently emerged as a promising tool in PCa management. The ability to develop radiolabeled tracers for functional imaging based on characteristics of PCa cells can potentially provide more insight into management by utilizing key features of those cells, such as metabolic activity, increased proliferation, and receptor expression. 18 flurodeoxyglucose (FDG) is one of the earliest tracers used in PET imaging that takes advantage of increased metabolism of glucose. Its role in PCa has been somewhat limited due to poor resolution and confounders including noise resulting from the proximity of the prostate to the bladder. Choline, a precursor molecule for a major component of the cell membrane, phosphatidylcholine, shows increased uptake in cells with rapid proliferation. When compared to metabolic based imaging techniques with FDG, choline PET/CT was superior. Nevertheless, choline PET/CT was not equivocal to MRI in detection of local disease, but was superior to conventional imaging in localizing metastasis and lymph node metastasis (LNM). Fluciclovine is another novel marker that utilizes the increased proliferation seen in tumor cells. Studies have shown it to be superior to choline PET/CT in PCa management, particularly in patients with BCR. As with choline PET/CT, studies that have assessed the impact of fluciclovine on clinical practice have highlighted the impact of these new tracers on clinical decision making. Most recently, the newest molecular probe targeting prostate specific membrane antigen (PSMA) was developed. It offers higher detection rates compared to choline PET/CT and conventional imaging modalities and has shown promise in LNM and BCR. With the wide range of available PET tracers, this review aims to highlight the role of each in lesion foci detection, primary staging, disease recurrence and explore the potential clinical impact. PMID- 30456190 TI - The use of F-FDG PET/CT in testicular cancer. AB - Testicular germ cell tumors are one of the most common neoplasms in young men. After inguinal orchiectomy is performed, treatment options range from active surveillance to chemotherapy, radiation therapy or retroperitoneal lymphadenectomy. For the accurate use of the different treatment options, precise imaging techniques are necessary to reduce side effects of the aggressive therapies but also to avoid undertreatment exposing the patient to the risk of recurrence. F-FDG PET/CT is already recommended in the European guidelines for the follow up of seminomas under certain conditions but conventional primary staging or restaging is still performed with CT or MRI. Recently, the importance of F-FDG PET/CT in this context has become an interesting topic of academic discussion and subject of various clinical trials which are reviewed in the following. PMID- 30456189 TI - Lymph node imaging in testicular cancer. AB - Testicular cancer is a rare malignancy mainly affecting young men. Survival for testicular cancer remains high due to the effectiveness of multimodal treatment options. Accurate imaging is imperative to both treatment and follow-up. Both computed tomography (CT) and magnetic resonance imaging (MRI) suffer from size cut-offs as the only distinguishing characteristic of benign vs. malignant lymph nodes and may miss up to 30% of micro-metastatic disease. While functional [positron emission tomography (PET)] imaging may rule out disease in patients with seminoma who have undergone chemotherapy, there is insufficient evidence to recommend its use in other settings. This review highlights the uses and pitfalls of conventional imaging during staging, active surveillance, and post-treatment phases of both seminomatous and non-seminomatous germ cell tumors (NSGCT). PMID- 30456191 TI - Detection of lymph node metastases in penile cancer. AB - Penile cancer (PC) is a relatively rare malignancy in the United States (US) but a greater concern in developing nations. Lymph node imaging remains critical to the staging and treatment of this disease as metastases develop in a predictable, anatomic fashion. Early surgical intervention remains a mainstay in treatment and imaging often aids in decision making. This review highlights the indications for imaging in both low-stage and advanced disease. Furthermore, we discuss the benefits and limitations of currently available imaging for staging of inguinal and pelvic lymph nodes in PC and novel modalities in development. PMID- 30456193 TI - James D. Brooks: prostate cancer screening awaits optimization to reduce inappropriate treatment. PMID- 30456194 TI - Smooth muscle relaxant activity of Crocus sativus (saffron) and its constituents: possible mechanisms. PMID- 30456192 TI - Sentinel lymph node imaging in urologic oncology. AB - Lymph node (LN) metastases in urological malignancies correlate with poor oncological outcomes. Accurate LN staging is of great importance since patients can benefit from an optimal staging, accordingly aligned therapy and more radical treatments. Current conventional cross-sectional imaging modalities [e.g., computed tomography (CT) and magnetic resonance imaging (MRI)] are not accurate enough to reliably detect early LN metastases as they rely on size criteria. Radical lymphadenectomy, the surgical removal of regional LNs, is the gold standard of invasive LN staging. The LN dissection is guided by anatomic considerations of lymphatic drainage pathways of the primary tumor. Selection of patients for lymphadenectomy heavily relies on preoperative risk stratification and nomograms and, as a result a considerable number of patients unnecessarily undergo invasive staging with associated morbidity. On the other hand, due to individual variability in lymphatic drainage, LN metastases can occur outside of standard lymphadenectomy templates leading to potential understaging and undertreatment. In theory, metastases from the primary tumor need to pass through the chain of LNs, where the initial node is defined as the sentinel LN. In theory, identifying and removing this LN could lead to accurate assessment of metastatic status. Radiotracers and more recently fluorescent dyes and superparamagnetic iron oxide nanoparticles (SPION) are injected into the primary tumor or peritumoral and the sentinel LNs are identified intraoperatively by a gamma probe, fluorescent camera or a handheld magnetometer. Preoperative imaging [e.g., single-photon emission computed tomography (SPECT)/CT or MRI] after tracer injection can further improve preoperative planning of LN dissection. While sentinel LN biopsy is an accepted and widely used approach in melanoma and breast cancer staging, its use in urological malignancies is still limited. Most data published so far is in penile cancer staging since this cancer has a typical echelon-based lymphatic metastasizing pattern. More recent data is encouraging with low false-negative rates, but its use is limited to centers with high expertise. Current guidelines recommend sentinel LN biopsy as an accepted alternative to modified inguinal lymphadenectomy in patients with pT1G2 disease and non-palpable inguinal LNs. In prostate cancer, a high diagnostic accuracy could be demonstrated for the sentinel approach. Nevertheless, due to lack of data or high false-negative rates in other urological malignancies, sentinel LN biopsy is still considered experimental in other urological malignancies. More high-level evidence and longitudinal data is needed to determine its final value in those malignancies. In this manuscript, we will review sentinel node imaging for urologic malignancies. PMID- 30456195 TI - Toxicological profile of the aqueous-fermented extract of Musa paradisiaca in rats. AB - Objective: This study was conducted to assess the toxicity profile of the aqueous fermented extract of Musa paradisiaca in rats. Materials and Methods: In acute toxicity test, the rats of different groups were orally administered with a single dose of 500, 1000, 2000 and 5000 mg/kg of fermented extract of M. paradisiaca. The rats were monitored for behavioral changes, toxicity signs and mortality. In sub-acute test, the rats were orally administered with fermented M. paradisiaca extract (200, 400 and 800 mg/kg/day) for 14 days. Haematological and serum biochemical parameters were evaluated and histopathological studies of the liver and kidney were done. The study was performed from June to July 2017. Results: Concerning the acute toxicity, no toxicity signs or death were recorded and an LD50 value of >5 g/kg for fermented extract of M. paradisiaca was observed. Regarding the sub-acute toxicity, ingestion of the fermented extract of M. paradisiaca caused no significant effects (p<0.05) in terms of relative organ weight, body weight percentage, haemoglobin, red blood cells count, electrolytes levels, lymphocytes count, basophils count, and aspartate aminotransferase (AST) and alkaline phosphatase (ALP) levels. However, significant differences (p<0.05) were observed in white blood cells, eosinophils, platelets, neutrophils and monocytes counts, and urea, creatinine, alanine aminotransferase (ALT) and high density lipoprotein (HDL) levels. The histological assessments of the liver and kidney showed normal results. Conclusion: The findings of this study has suggested that daily administration of fermented extract of M. paradisiaca at doses up to 800 mg/kg for 14 days, is not toxic and may be considered safe for therapeutic uses. PMID- 30456196 TI - Protective effect of Rheum turkestanicum root against mercuric chloride-induced hepatorenal toxicity in rats. AB - Objective: The present study was designed to investigate the protective effects of hydroalcoholic extract of Rheum turkestanicum against HgCl2 hepatorenal toxicity in rats. Materials and Methods: Animals were randomly divided into five groups (n= 6 in each group) and received HgCl2 and plant's extract, intraperitoneally. Group1 received saline (1 mL/kg/day), group 2 received extract (200 mg/kg/day), group 3 was treated with HgCl2 (5 mg/kg/day,) and groups 4 and 5 received the extract (100 and 200 mg/kg/day, respectively), 1 hr before HgCl2 administration. All injections last for 3 days. Blood samples and specimens of the liver and kidney were collected 24 hr after the last injection. Results: Data showed that HgCl2 significantly increases liver malondialdehyde (MDA) level, reduces total sulfhydryl content and increases serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, compared to control group. The histopathological changes such as inflammatory cells infiltration was observed in HgCl2-treated group while plant's extract partially improved histological changes. The extract (100 and 200 mg/kg/day) improved the liver functions as reflected by significant reductions in AST and ALT levels in serum, MDA decreased and the content of total sulfhydryl elevated. Also, the extract improved necrosis and atrophy of the kidney induced byHgCl2. Pretreatment with the extract reduced creatinine and urea in serum, and glucose and protein concentrations in urine, compared to HgCl2- treated group (group III). The extract significantly reversed HgCl2-induced depletion in thiol content and elevation in MDA content. Conclusion: Therefore, oxidative stress may play an important role in HgCl2-induced hepatorenal injury and R. turkestanicum extract may be regarded as a useful to protect the kidney and liver against HgCl2-induced oxidative damage. PMID- 30456197 TI - Efficacy of Nigella sativa seeds oil in patients with Behcet's disease: a double blind randomized controlled trial. AB - Objective: Nigella sativa (NS) is a herbal medicine with anti-inflammatory and anti-oxidant functions. This study was designed to evaluate the effect of oral administration of NS seeds oil on the treatment of Behcet's disease (BD). Materials and methods: In this double-blind randomized controlled study, 130 patients with BD were screened and 71 patients with BD were randomly allocated to the treatment (n=37) and control (n=34) groups. Finally, 32 and 30 patients in the treatment and control groups, respectively, completed the study. The study protocol was registered in the Iranian Registry of Clinical Trials (IRCT) with registration No. IRCT201511086975N5. Treatment and control groups received soft gels containing 1000 mg NS oil or 1000 mg placebo per day for 12 months, respectively. Disease activity using the Iranian Behcet's disease dynamic activity measure (IBDDAM), total inflammatory activity index (TIAI) and Behcet's disease current activity form (BDCAF) were evaluated in all patients before initiation of the trial and every 2 months, for 12 months. Results: Disease activity decreased in the study groups; difference between the two groups was not significant. No serious adverse events were seen in the treatment and control groups. Conclusion: NS oil at the dose of 1000 mg/day is not effective in controlling BD activity. PMID- 30456198 TI - Evolvulus alsinoides methanolic extract triggers apoptosis in HepG2 cells. AB - Objective: The objective of the present study was to evaluate the cytotoxic potentials of Evolvulus alsinoides in human hepatoma HepG2 cells. Materials and Methods: HepG2 cells were treated with methanolic extract of E. alsinoides at 20, 40 and 80 ug/ml for 24 hr and cytotoxic effect was analyzed by MTT assay. The apoptosis rate was investigated by Hoechst 33342 and annexin V/propidium iodide staining. Mitochondrial membrane potential was evaluated by rhodamine staining. Also, the expression of catenin - beta 1 protein was analyzed by western blotting. Results: E. alsinoides methanolic extract treatment caused significant cytotoxicity in HepG2 cells in a concentration-dependent manner. Dual staining assay confirmed the presence of early and late apoptotic cells only in extract treated groups. Plant extract treatment also caused nuclear fragmentation and chromatin condensation in HepG2 cells. Mitochondrial membrane potential also reduced upon E. alsinoides treatments. This treatment also modulated the catenin beta 1 protein expression. Conclusion: In this study, we demonstrated the proapoptotic potential E. alsinoides in HepG2 cells; thus, this plant may be beneficial in the treatment of liver cancer. PMID- 30456199 TI - Saffron (Crocus sativus) versus duloxetine for treatment of patients with fibromyalgia: A randomized double-blind clinical trial. AB - Objective: Saffron was found efficient and safe in treatment of neuropsychiatric disorders, in particular depression. We compared the efficacy of saffron with duloxetine in treatment of patients with fibromyalgia. Materials and Methods: In this double-blind parallel-group clinical trial, outpatients with fibromyalgia were randomized to receive either saffron 15 mg or duloxetine 30 mg starting with 1 capsule per day in the first week followed by 2 capsules per day from week 2 until the end of week 8. Participants were men and women aged 18-60 years diagnosed with fibromyalgia based on the American College of Rheumatology 2010 criteria who also had a pain score>=40 based on visual analogue scale. Participants were excluded in case they had rheumatologic diseases, inflammatory/infectious/autoimmune arthritis, comorbid neuropsychiatric disorders except depressive disorders, pain due to traumatic injuries, drug history of duloxetine or saffron use, current use of psychoactive medications, recent use of muscle relaxants, steroids, opioid analgesics, benzodiazepines, anti-epileptics, or injective analgesics. Primary outcomes included differences in mean score changes from baseline to endpoint between the treatment arms for Hamilton Rating Scale for Depression, Fibromyalgia Impact Questionnaire, and Brief Pain Inventory. Results: Socio-demographic characteristics and baseline scores were similarly distributed between the two treatment arms (2n=46). No significant difference was detected for any of the scales neither in terms of score changes from baseline to endpoint between the two treatment arms (Mean score changes: 4.26 to 2.37; p-values: 0.182-0.900) nor in terms of timetreatment interactions (p-values: 0.209-0.964). Conclusions: Saffron and duloxetine demonstrated comparable efficacy in treatment of fibromyalgia symptoms. PMID- 30456200 TI - Evaluation of leishmanicidal effect of Euphorbia petiolata extract by in vivo anti-leishmanial assay using promastigotes of Leishmania major. AB - Objective: The extract of different species of Euphorbia has been successfully used as a remedy for treatment of cutaneous leishmaniasis. The aim of this study was to assess the in vitro leishmanicidal effect of Euphorbia petiolata (E. petiolata) extract. Materials and Methods: Ethanolic percolated and methanolic Soxhlet extract of E. petiolata on promastigotes of L. major at different concentrations of extracts, one positive control group and one negative control group as well as 1 solvent control were prepared and placed in 24-well plates that contained 40,000 parasites/well. Afterwards, plates were incubated at 25 C for six days and number of parasites in each well were determined on days 2, 4 and 6 of the experiment. Results: Both percolated and Soxhlet extracts in methanol and DMSO solvents had significant effects (equal to that of amphotericin B) on promastigote form of parasite at the concentration of 1 mg/ml. At lower concentrations, the extracts of E. petiolata had favorable leishmanicidal activity and killed L. major promastigotes dose-dependently. Conclusion: Our results support the possibility of E. petiolata extracts application as an anti leishmanial agent with similar effects to amphotericin B. PMID- 30456201 TI - Arbutin attenuates behavioral impairment and oxidative stress in an animal model of Parkinson's disease. AB - Objective: Arbutin has been shown to have antioxidant and free-radical scavenging properties. The aim of this study was to investigate the effects of arbutin administration on behavioral impairment, and oxidative and nitrosative stress in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animal model of Parkinson's disease (PD). Materials and Methods: PD model was developed by 4 intraperitoneal (i.p.) injections of MPTP (20 mg/kg) with 2 h intervals in mice. Experimental groups received once daily injection of saline as vehicle (control group) or arbutin (50 mg/kg, i.p.) one week before MPTP injections and this protocol was continued seven days post lesion. Behavioral deficits were evaluated using locomotion test, hanging wire test and forepaw stride length. Parameters indicating the oxidation levels including lipid peroxidation marker (TBARS), nitrite, protein carbonyl levels and antioxidant activity including ferric reducing antioxidant power (FRAP) were assessed in serum and midbrain samples. Results: Treatment with arbutin improved motor functions in an MPTP-induced PD model compared to control group (p<0.001). Mice treated with MPTP showed reduced levels of FRAP (p<0.001) and increased levels of TBARS (p<0.001), nitrite (p<0.001) and protein carbonyl (p<0.01), compared to the control group. In contrast to the MPTP group, arbutin treatment decreased the levels of TBARS (p<0.05), nitrite (p<0.05), protein carbonyl (p<0.05), and increased FRAP levels (p<0.05) in mice with PD. Conclusion: These findings suggest that arbutin attenuates the behavioral impairment and oxidative stress in a PD animal model. PMID- 30456203 TI - Clinical Significance of Elevated S100A8 Expression in Breast Cancer Patients. AB - Breast cancer is the leading cause of female cancer-related death; however, novel biomarkers for predicting cancer recurrence still need to be explored. Aberrant expression of S100A8 has been reported to be related to tumor progression in various cancer types. This study aims to evaluate the clinical significance of S100A8 expression in breast cancer patients. In this study, data from 140 breast cancer patients were retrospectively collected to examine the association between S100A8 expression and clinical prognosis. Increased S100A8 expression was detected in breast cancer patients with relapse. The patients with increased S100A8 levels had significantly shorter disease-free survival (DFS) and overall survival (OS). In a multivariate survival analysis, a high histological grade and an elevated S100A8 level were independent factors associated with poor DFS and OS. Moreover, S100A8 expression was correlated with clinical subtype in breast cancer patients. The results showed that ER-negative and triple-negative breast cancer (TNBC) patients had significantly higher expression of S100A8 than patients with other subtypes. In conclusion, this study identified S100A8 as a potential biomarker for relapse in breast cancer patients. PMID- 30456202 TI - Topical application of Cassia fistula L. fruit gel in management of cutaneous lesions of pemphigus vulgaris: A double-blind, placebo-controlled clinical trial. AB - Objective: Cassia fistula L. fruit extract has been traditionally used in the treatment of pemphigus vulgaris (PV) lesions in Iran. The aim of this study was to determine the efficacy of C. fistula fruit gel on healing time of PV lesions in a clinical setting. Materials and Methods: This was a randomized, double-blind placebo-controlled clinical trial that was performed in dermatology ward at Saadi hospital, affiliated to Shiraz University of Medical Sciences, Shiraz, Iran. Right- or left- sided lesions of PV patients on standard systemic treatment were randomized for treatment with either C. fistula fruit gel or placebo prescribed twice daily. The largest diameter of each lesion was measured at the baseline (day 0) and on days 10 and 20. Epithelialization Index (EI), as outcome measure was calculated and compared between the two groups. Results: The present study comprised 20 patients, with overall 82 cutaneous lesions including 41 lesions in the C. fistula fruit gel group and 41 lesions in the placebo group. The EI in the C. fistula fruit gel group was significantly higher than that of the placebo group both on day 10 (65+/-28vs 30+/-34; p=0.001) and at the end of the study (91+/-22 vs 69+/-49; p=0.003). Conclusion: Topical application of C. fistula fruit gel can be considered as an effective adjuvant therapy in treatment of PV. PMID- 30456205 TI - Evaluation of Knowledge, Perception, and Risk Awareness About Breast Cancer and Its Treatment Outcome Among University of Gondar Students, Northwest Ethiopia. AB - Background: Breast cancer is among the most common life-threatening public health problems of global concern including Ethiopia. Knowledge and awareness about the disease will help to reduce the number of cases who present at late stages of the disease. The objective of this survey was to assess the knowledge, perception and risk awareness about breast cancer among female medical and health science students of University of Gondar, Ethiopia. Methods: A cross sectional survey was conducted from May 03 to June 01, 2017 at University of Gondar, Ethiopia. Three hundred students were proportionally selected from nine departments using simple random sampling method. Using a structured questionnaire data on risk factors, symptoms and perception about breast cancer and its management approach was collected. Data were entered to and analyzed using SPSS version 21. Results: A total of 300 students had fully completed the survey making the response rate 95.24. The participants' mean age was 21.4 years with the standard deviation (SD) of 2.13 years. The overall level of knowledge on breast cancer was low. Majority of the participants were unaware for complex risk factors such as first child after the age of 30 years (51%), early onset of menses (55.3%), and menopause after the age of 55 years (47.7%) are liked with breast cancer even though they acknowledged old age, family history, and smoking as possible risk factors for breast cancer. Pain in the breast region, change in the shape of the breast, and nipple discharge were the most frequently correctly identified symptoms of breast cancer. Majority of the study participants had also correct beliefs about breast cancer management and its outcomes. however, they had negative perception of breast cancer treatment by considering it to be a long-term and painful process. In binary logistic regression analysis department (p = 0.000) and year of study (p = 0.008) were found to be an independent predicting factors for knowledge among the study participants. Conclusions: The overall level of knowledge on breast cancer and clinical breast examination guidelines was found to be low even though majority had positive perception toward the treatment and its outcomes. Hence, intensive breast health awareness campaign, which should also stress on the importance of early detection and reporting, is necessary to improve the knowledge about breast cancer. PMID- 30456204 TI - The Influence of Metabolism on Drug Response in Cancer. AB - Resistance to therapeutic agents, either intrinsic or acquired, is currently a major problem in the treatment of cancers and occurs in virtually every type of anti-cancer therapy. Therefore, understanding how resistance can be prevented, targeted and predicted becomes increasingly important to improve cancer therapy. In the last decade, it has become apparent that alterations in cellular metabolism are a hallmark of cancer cells and that a rewired metabolism is essential for rapid tumor growth and proliferation. Recently, metabolic alterations have been shown to play a role in the sensitivity of cancer cells to widely-used first-line chemotherapeutics. This suggests that metabolic pathways are important mediators of resistance toward anticancer agents. In this review, we highlight the metabolic alterations associated with resistance toward different anticancer agents and discuss how metabolism may be exploited to overcome drug resistance to classical chemotherapy. PMID- 30456207 TI - IL-1R and Inflammasomes Mediate Early Pulmonary Protective Mechanisms in Respiratory Brucella Abortus Infection. AB - Brucella spp. infection is frequently acquired through contaminated aerosols. The role of interleukin-1 beta (IL-1beta) in the early pulmonary response to respiratory Brucella infection is unknown. As shown here, IL-1beta levels in lung homogenates and bronchoalveolar lavage fluid (BALF) of mice intratracheally inoculated with B. abortus were increased at 3 and 7 days p.i. At 7 days p.i., pulmonary CFU numbers were higher in IL-1 receptor (IL-1R) knockout (KO) mice than in wild type (WT) mice. At different times p.i. CFU in lungs and BALF were higher in mice lacking some inflammasome components (caspase-1, AIM2, NLRP3) than in WT mice. At 2 days p.i. pulmonary levels of IL-1beta and CXCL1 (neutrophils chemoattractant) were lower in caspase-1/11 KO mice. At day 3 p.i., neutrophils counts in BALF were lower in caspase-1/11 KO mice than in WT mice. During in vitro infections, IL-1beta secretion was lower in alveolar macrophages from caspase-1/11, NLRP3 or AIM2 KO mice than in WT controls. Similarly, IL-1beta production by B. abortus-infected alveolar epithelial cells was reduced by pretreatment with a specific caspase-1 inhibitor. This study shows that IL-1R, probably through IL-1beta action, and the NLRP3 and AIM2 inflammasomes are involved in pulmonary innate immune protective mechanisms against respiratory B. abortus infection. PMID- 30456206 TI - Cellular Phenotype Plasticity in Cancer Dormancy and Metastasis. AB - Cancer dormancy is a period of cancer progression in which residual tumor cells exist, but clinically remain asymptomatic for a long time, as well as resistant to conventional chemo- and radiotherapies. Cellular phenotype plasticity represents that cellular phenotype could convert between epithelial cells and cells with mesenchymal traits. Recently, this process has been shown to closely associate with tumor cell proliferation, cancer dormancy and metastasis. In this review, we have described different scenarios of how the transition from epithelial to mesenchymal morphology (EMT) and backwards (MET) are connected with the initiation of dormancy and reactivation of proliferation. These processes are fundamental for cancer cells to invade tissues and metastasize. Recognizing the mechanisms underlying the cellular phenotype plasticity as well as dormancy and targeting them is likely to increase the efficiency of traditional tumor treatment inhibiting tumor metastasis. PMID- 30456209 TI - Tetralogy of Fallot With Right Aortic Arch and Retro-Aortic Innominate Vein. AB - Right aortic arch (RAA) and retro-aortic innominate vein are rare vascular anomalies. Diagnosis of these anatomical variations can be achieved using fetal echocardiography, post-natal echocardiography, and computed tomography scan. RAA can form a vascular ring when associated with other vascular anomalies which may compress the trachea and/or esophagus. On the other hand, the existence of retro aortic innominate vein can influence the clinical decision-making and surgical strategy. We report a rare occurrence of both RAA and retro-aortic innominate vein in a 3 months old girl with a prenatal diagnosis of tetralogy of Fallot and include details of her presentation and successful management. PMID- 30456208 TI - A glance at imaging bladder cancer. AB - Purpose: Early and accurate diagnosis of Bladder cancer (BCa) will contribute extensively to the management of the disease. The purpose of this review was to briefly describe the conventional imaging methods and other novel imaging modalities used for early detection of BCa and outline their pros and cons. Methods: Literature search was performed on Pubmed, PMC, and Google scholar for the period of January 2014 to February 2018 and using such words as "bladder cancer, bladder tumor, bladder cancer detection, diagnosis and imaging". Results: A total of 81 published papers were retrieved and are included in the review. For patients with hematuria and suspected of BCa, cystoscopy and CT are most commonly recommended. Ultrasonography, MRI, PET/CT using 18F-FDG or 11C-choline and recently PET/MRI using 18F-FDG also play a prominent role in detection of BCa. Conclusion: For initial diagnosis of BCa, cystoscopy is generally performed. However, cystoscopy can not accurately detect carcinoma insitu (CIS) and can not distinguish benign masses from malignant lesions. CT is used in two modes, CT and computed tomographic urography (CTU), both for dignosis and staging of BCa. However, they cannot differentiate T1 and T2 BCa. MRI is performed to diagnose invasive BCa and can differentiate muscle invasive bladder carcinoma (MIBC) from non-muscle invasive bladder carcinoma (NMIBC). However, CT and MRI have low sensitivity for nodal staging. For nodal staging PET/CT is preferred. PET/MRI provides better differentiation of normal and pathologic structures as compared with PET/CT. Nonetheless none of the approaches can address all issues related for the management of BCa. Novel imaging methods that target specific biomarkers, image BCa early and accurately, and stage the disease are warranted. PMID- 30456210 TI - A Scoping Review of the Evidence on Health Promotion Interventions for Reducing Waterpipe Smoking: Implications for Practice. AB - Background: Waterpipe tobacco smoking is a traditional method of tobacco use, especially in the Eastern Mediterranean Region (EMR), but its prevalence is growing worldwide, especially among young people. Although often perceived as less harmful than other methods of tobacco use because the smoke passes through water, accumulating evidence shows harmful effects and that some smokers become addicted. Interventions that deglamourise and denormalise use have been recommended but little is known about the range and impact of different health prevention and promotion interventions. Methods: A scoping review of literature was undertaken to explore the breadth of literature and assess the range and impact of community based health promotion interventions for waterpipe smoking. Searches were conducted in Medline, Embase, CINAHL, Psychinfo, and the Cochrane database of systematic reviews. Interventions were classified using a health promotion framework and data extracted on the aspects of prevention/promotion addressed; key strategies employed, evidence of effectiveness or impact on behavior change as well as barriers to implementation and perceived success factors. Results: Ten studies were included in the review. They include brief interventions to increase quit rates; community campaigns to raise awareness and increase knowledge; web based health education and skill development to increase perceived risks and intention to quit; as well as studies that evaluated product labeling and opportunities for policy interventions to create healthy environments. Conclusions: The evidence base is small but growing. Brief interventions for waterpipe users, community campaigns, and web based tailored information can modify perceptions of addiction and increase intentions to quit. Product labeling may be an effective policy tool to curb waterpipe smoking. A range of policy interventions have been identified but not evaluated. PMID- 30456212 TI - Quantification of Lipoteichoic Acid in Hemodialysis Patients With Central Venous Catheters. AB - Hemodialysis patients with central venous catheters (CVCs) have chronic systemic inflammation, the source of which may be related to intraluminal bacterial biofilm. There is currently no non-invasive method to adequately evaluate intraluminal biofilm. Lipoteichoic acid (LTA) is a Gram-positive bacterial cell wall component that is spontaneously shed. The purpose of this study was to determine whether LTA could be quantified in biological samples and to evaluate potential relationships to markers of inflammation. Heparin-locked catheter aspirate was drawn from both the arterial and venous ports of each CVC prior to dialysis initiation. Venous blood from the dialysis circuit was collected 30 min after dialysis initiation. LTA was quantified in aspirate and plasma. Key markers of inflammation (interleukin-6, and hepcidin) and endothelial dysfunction (soluble vascular endothelial cadherin) were also determined in plasma samples. Catheter aspirate and systemic blood samples were obtained from 40 hemodialysis patients. The median (range) duration of catheter use was 130 (20-1635) days. Unexpectedly, median (range) plasma LTA concentrations (ng/mL) were significantly higher than catheter aspirate LTA concentrations [3.93 (0.25-15) vs. 2.38 (0.1 8.1), respectively, p = 0.01] in the majority (70%) of patients. Area under the receiver operator characteristic (ROC) curve showed good potential prognostic value of catheter aspirate LTA predicting systemic LTA concentrations with an area under the curve of 0.815 (95% CI, 0.68-0.95). A significant correlation was found between LTA and serum ferritin (r = 0.32, p = 0.04), however, there were no significant correlations between LTA and the other inflammation biomarkers assessed. LTA is quantifiable in aspirate and plasma of hemodialysis patients with CVCs and warrants further investigation to determine potential clinical application to intraluminal biofilm evaluation. PMID- 30456211 TI - A New Mixed-Valence Mn(II)Mn(III) Compound With Catalase and Superoxide Dismutase Activities. AB - The synthesis, X-ray molecular structure, physico-chemical characterization and dual antioxidant activity (catalase and superoxide dismutase) of a new polymeric mixed valence Mn(III)Mn(II) complex, containing the ligand H2BPClNOL (N-(2 hydroxybenzyl)-N-(2-pyridylmethyl)[(3-chloro)(2-hydroxy)] propylamine) is described. The monomeric unit is composed of a dinuclear Mn(II)Mn(III) moiety, [Mn(III)(MU-HBPClNOL)(MU-BPClNOL)Mn(II)(Cl)](ClO4).2H2O, 1, in which the Mn ions are connected by two different bridging groups provided by two molecules of the ligand H2BPClNOL, a phenoxide and an alkoxide group. In the solid state, this mixed valence dinuclear unit is connected to its neighbors through chloro bridges. Magnetic measurements indicated the presence of ferromagnetic [J = +0.076(13) cm-1] and antiferromagnetic [J = -5.224(13) cm-1] interactions. The compound promotes O 2*- dismutation in aqueous solution (IC50 = 0.370 MUmol dm-3, k cat = 3.6x106 M-1 s-1). EPR studies revealed that a high-valent Mn(III)-O Mn(IV) species is involved in the superoxide dismutation catalytic cycle. Complex 1 shows catalase activity only in the presence of a base, e.g., piperazine or triethylamine. Kinetic studies were carried out in the presence of piperazine and employing two different methods, resulting in k cat values of 0.58 +/- 0.03 s-1 (detection of O2 production employing a Clark electrode) and 2.59 +/- 0.12 s-1 (H2O2 consuption recorded via UV-Vis). EPR and ESI-(+)-MS studies indicate that piperazine induces the oxidation of 1, resulting in the formation of the catalytically active Mn(III)-O-Mn(IV) species. PMID- 30456213 TI - Protein Supplementation Throughout 10 Weeks of Progressive Run Training Is Not Beneficial for Time Trial Improvement. AB - Introduction: Protein supplementation is proposed to promote recovery and adaptation following endurance exercise. While prior literature demonstrates improved performance when supplementing protein during or following endurance exercise, chronic supplementation research is limited. Methods: Runners (VO2peak = 53.6 +/- 8.9 ml/kg/min) were counter-balanced into a placebo group (PLA; n = 8) or protein group (PRO; n = 9) based on sex and VO2peak, and underwent 10 weeks of progressive endurance training. Prior to training, body composition, blood cell differentials, non-invasive mitochondrial capacity using near-infrared spectroscopy, and a 5 km treadmill time trial (TT) were evaluated. Progressive training then commenced (5-10% increase in weekly volume with a recovery week following 3 weeks of training) whereby PRO supplemented with 25 g of whey protein following workouts and prior to sleep (additional 50 g daily). PLA supplemented similarly with a < 1 g sugar pill per day. Following training, participants were reanalyzed for the aforementioned tests. Results: VO2peak and initial 5 km TT were not significantly different between groups. PRO consumed significantly more dietary protein throughout the training period (PRO = 132 g/d or 2.1 g/kg/day; PLA = 84 g/d or 1.2 g/kg/day). Running volume increased significantly over time, but was not significantly different between groups throughout training. Blood measures were unaltered with training or supplementation. Mitochondrial capacity trended toward improving over time (time p = 0.063) with no difference between groups. PLA increased lean mass 0.7 kg (p < 0.05) while PRO experienced infinitesimal change (-0.1 kg, interaction p = 0.049). PLA improved 5 km TT performance 6.4% (1 min 31 s), while PRO improved only 2.7% (40 s) (interaction p = 0.080). Conclusion: This is the first evidence to suggest long-term protein supplementation during progressive run training is not beneficial for runners. PMID- 30456214 TI - Conceptualizing a Sustainable Food System in an Automated World: Toward a "Eudaimonian" Future. AB - The industrialized world has entered a new era of widespread automation, and although this may create long-term gains in economic productivity and wealth accumulation, many professions are expected to disappear during the ensuing shift, leading to potentially significant disruptions in labor markets and associated socioeconomic difficulties. Food production, like many other industrial sectors, has also undergone a century of mechanization, having moved toward increasingly large-scale monoculture production-especially in developed economies-with higher yields but detrimental environmental impacts on a global scale. Certain characteristics of the food sector and its products cast doubts on whether future automation will influence it in the same ways as in other sectors. We conceptualize a model of future food production within the socioeconomic conditions created by widespread automation. We ideate that despite immediate shocks to the economy, in the long run higher productivity can free up human activity to be channeled toward more interactive, skill-intensive food production systems, where communal efforts can reduce industrial reliance, diversify farming, and reconnect people to the biosphere-a realization of human well-being that resembles the classical philosophical ideal of Eudaimonia. We explore food production concepts, such as communal gardens and polyculture, and the economic conditions and institutions needed to underwrite them [e.g., a universal basic income (UBI)]. However, arguments can be raised as to why social-ecological systems would benefit from more labor-intensive food production. In this paper we: (1) discuss the current state of the food system and the need to reform it in light of its environmental and social impacts; (2) present automation as a lever that could move society toward more sustainable food production; (3) highlight the beneficial attributes of a Eudaimonian model; and (4) discuss the potential challenges to its implementation. Our purpose is to highlight a possible outcome that future research will need to refine and expand based on evidence and successful case studies. The ultimate aim is to promote a food system that can provide food security while staying within the safe operating space of planetary boundaries, produce more nutritious diets, enhance social capital, and reconnect communities with the biosphere. PMID- 30456215 TI - Transcriptional Profiling of Hypoxia-Regulated Non-coding RNAs in Human Primary Endothelial Cells. AB - Hypoxia occurs in human atherosclerotic lesions and has multiple adverse effects on endothelial cell metabolism. Recently, key roles of long non-coding RNAs (lncRNAs) in the development of atherosclerosis have begun to emerge. In this study, we investigate the lncRNA profiles of human umbilical vein endothelial cells subjected to hypoxia using global run-on sequencing (GRO-Seq). We demonstrate that hypoxia regulates the nascent transcription of ~1800 lncRNAs. Interestingly, we uncover evidence that promoter-associated lncRNAs are more likely to be induced by hypoxia compared to enhancer-associated lncRNAs, which exhibit an equal distribution of up- and downregulated transcripts. We also demonstrate that hypoxia leads to a significant induction in the activity of super-enhancers next to transcription factors and other genes implicated in angiogenesis, cell survival and adhesion, whereas super-enhancers near several negative regulators of angiogenesis were repressed. Despite the majority of lncRNAs exhibiting low detection in RNA-Seq, a subset of lncRNAs were expressed at comparable levels to mRNAs. Among these, MALAT1, HYMAI, LOC730101, KIAA1656, and LOC339803 were found differentially expressed in human atherosclerotic lesions, compared to normal vascular tissue, and may thus serve as potential biomarkers for lesion hypoxia. PMID- 30456216 TI - Functional Gains in Children With Spastic Hemiplegia Following a Tendon Achilles Lengthening Using Computerized Adaptive Testing-A Pilot Study. AB - Purpose: This pilot study evaluated the outcomes of tendon Achilles lengthening in 12 children (mean age: 11.2 years) with spastic hemiplegia. Methods: Cerebral Palsy Computer Adaptive Tests, the timed up-and-go, the Gross Motor Function Measure, the Gillette Functional Assessment Questionnaire, and the Pediatric Outcomes Data Collection Instrument were administered at baseline and at 6, 12, and 24 months postsurgery. Results: Significant improvement at the latest follow up (12-24 months following surgery) was seen in all domains of the Cerebral Palsy Computer Adaptive Test: activity (P = .017), lower extremity (P = .005), global (P = .005), pain (P = .005), and fatigue (P = .028), as well as in the Gross Motor Function Measure-D domain (P = .02) and the mobility domain of the Pediatric Outcomes Data Collection Instrument (P = .04). Conclusion: These findings indicate that the tendon Achilles lengthening improved functional outcome in these children as measured by tests of physical function, walking speed, and activity performance. PMID- 30456217 TI - Challenges in Advanced Therapy Medicinal Product Development: A Survey among Companies in Europe. AB - Advanced therapy medicinal products (ATMPs) hold promise as treatments for previously untreatable and high-burden diseases. Expectations are high and active company pipelines are observed, yet only 10 market authorizations were approved in Europe. Our aim was to identify challenges experienced in European ATMP clinical development by companies. A survey-based cohort study was conducted among commercial ATMP developers. Respondents shared challenges experienced during various development phases, as well as developer and product characteristics. Descriptions of challenges were grouped in domains (clinical, financial, human resource management, regulatory, scientific, technical, other) and further categorized using thematic content analysis. A descriptive analysis was performed. We invited 271 commercial ATMP developers, of which 68 responded providing 243 challenges. Of products in development, 72% were in early clinical development and 40% were gene therapies. Most developers were small- or medium sized enterprises (65%). The most often mentioned challenges were related to country-specific requirements (16%), manufacturing (15%), and clinical trial design (8%). The European ATMP field is still in its early stages, and developers experience challenges on many levels. Challenges are multifactorial and a mix of ATMP-specific and generic development aspects, such as new and orphan indications, novel technologies, and inexperience, adding complexity to development efforts. PMID- 30456218 TI - Review of diffuse cortical injury on diffusion-weighted imaging in acutely encephalopathic patients with an acronym: "CRUMPLED". AB - Purpose: Acute encephalopathic syndromes can present a diagnostic challenge due to the wide range of possible etiologies, which also can have vastly different outcomes. The presence of diffuse cortical injury (DCI) on diffusion-weighted imaging (DWI) can help narrow the differential diagnosis. The aim of this review is to categorize the range of possible etiologies of DCI into a useful acronym, "CRUMPLED". Methods: A review of the PACS system was completed to find a characteristic example of patients with DCI on DWI from different etiologies. The diagnosis was confirmed for each example via a subsequent review of the electronic medical record used to assess for data such as biopsy results, laboratory values, and clinical correlation. The electronic exhibit intends to demonstrate several sample cases of each letter within the acronym, and to demonstrate which types of DCI are potentially reversible or irreversible. Findings/Discussion: The possible etiologies of DCI on DWI can be organized using the acronym "CRUMPLED": 'C' = Creutzfeldt-jakob disease, 'R' = reversible cerebral vasoconstriction syndrome; 'U' = urea cycle disorders (hyperammonemia) and Uremia; 'M' = mitochondrial (cytopathy/encephalopathy); 'P' = prolonged seizure and posterior reversible encephalopathy (PRES); 'L' = laminar necrosis (hypoxic-ischemic encephalopathy) and liver disease (acute hepatic encephalopathy); 'E' = encephalitis (infectious meningoencephalitis); 'D' = diabetes mellitus (hypoglycemia). Other secondary imaging findings (outside of DWI) can be used to help differentiate between the aforementioned etiologies, such as the use of ADC maps, FLAIR imaging, intravenous contrast. Conclusion: "CRUMPLED" is proposed as a convenient acronym for the categorization of a diverse range of acute etiologies associated with DCI on DWI, arising from varying degrees of cytotoxic edema. These etiologies can range from being potentially reversible (e.g. hyperammonemia or prolonged seizures) to irreversible (e.g. hypoxic-ischemic injury). PMID- 30456220 TI - Data on the 14C date obtained from the charcoal figure "Black fox" in Shulgan Tash (Kapova) cave, Southern Ural, Russia. AB - Shulgan-Tash (Kapova) cave in southern Ural, Russia, is the easternmost European site hosting Late Paleolithic cave art. Most of the 195+ drawings catalogued in the cave are made with red natural pigment (ochre), and only a handful of drawings are made with charcoal, see "Catalogue of images" [4], "Hohlenmalerei im Ural: Kapova und Ignatievka; die altsteinzeitlichen Bilderhohlen im sudlichen Ural," [5]. "Constraining the ages of the Late Palaeolithic cave paintings in the Shulgan-Tash cave, Southern Urals, Russia" [6]. None of the charcoal drawings were directly dated by 14C method so far. Black lines delineating a figure similar to the outline of a fox are known in the cave. Here we present data on the 14C AMS date of charcoal with which the lines were drawn. Calibration of the data was performed using the Bomb13NH1 dataset, see "Atmospheric radiocarbon for the period 1950-2010" [7] and the IntCal13 dataset, see "IntCal13 and Marine13 radiocarbon age calibration curves 0-50,000 years cal BP" [8]. The calibrated age distribution has maximum probability density (65.3%) between 1877 and 1918. PMID- 30456219 TI - Chest pain CT in the emergency department: Watch out for the myocardium. AB - Rationale and Objectives: To evaluate the frequency and relevance of hypodense myocardium (HM) encountered in patients undergoing chest-pain CT in the emergency department (ED). Material and Methods: In this IRB-approved retrospective study, ECG-gated chest-pain CT examinations of 300 consecutive patients (mean age 60 +/- 17 years) presenting with acute chest-pain to our ED were evaluated. Once ST segment elevation infarction was excluded, chest-pain CT including the coronary arteries (rule-out acute coronary syndrome (ACS), pulmonary embolism (PE) and acute aortic syndrome (AAS): chest-pain CTcoronary, n = 121) or not including the coronary arteries was performed (rule-out PE and AAS: chest-pain CTw/o coronary, n = 179). Each myocardial segment was assessed for the presence of HM; attenuation was measured and compared to normal myocardium. Results: HM was identified in 27/300 patients (9%): 12/179 in chest-pain CTw/o coronary (7%) and 15/121 in chest-pain CTcoronary (12%). Mean attenuation of HM (40 +/- 17 HU) was significantly lower than that of healthy myocardium (103 +/- 18 HU, p < 0.001), with a mean difference of 61 +/- 19 HU. In 15/27 patients (55.6%) with HM, the final diagnosis was acute MI, and in the remaining 12/27 patients (44.4%) previous MI was found in the patients' history. Chest-pain CTw/o coronary identified HM in 10/15 patients (66.6%) with a final diagnosis of acute MI. Conclusion: HM indicating acute MI are often encountered in chest pain CT in the ED, also in chest-pain CTw/o coronary when MI is not suspected. This indicates that the myocardium should always be analyzed for hypodense regions even when MI not suspected. PMID- 30456221 TI - Binding energies and the entry route of palmitic acid and palmitoylcarnitine into myoglobin. AB - The interaction of lipids (entry mechanism) with respect to both oxy- and deoxy myoglobin was explored using unrestrained Molecular Dynamics simulations. The results indicated a spontaneous entry of both palmitic and palmitoylcarnitine molecules into the oxy-Mb structure at the main binding site, whereas in deoxy Mb, both the lipid ligands move away from the protein surface. For the alternative binding locations, entry of the ligands was independent of the oxygenation state. Presented here are the tables with the myoglobin binding energies for palmitic acid and palmitoylcarnitine estimated using Alchemical Free Energy Perturbation approach for the key structures obtained in unrestrained Molecular Dynamics simulations. These data are referenced in the original article "Exploring the entry route of palmitic acid and palmitoylcarnitine into myoglobin", reference number YABBI7787. PMID- 30456222 TI - Particle bombardment-mediated co-transformation of the Cht-2 gene in wheat and the associated changes in defense mechanisms in transgenic plants infected with Fusarium graminearum. AB - Fusarium graminearum is a major global pathogen of cereals and is considered the main causal agent of Fusarium head blight disease in wheat. Infection with Fusarium graminearum causes a significant reduction in crop yield and quality; therefore, it is very important to improve wheat pathogen resistance. In the present study, the plasmid pAHCht-2 harboring the rice chitinase (Cht-2) gene for pathogen resistance and the plasmid pAB6 containing the gus reporter and bar selectable marker genes were used for genetic transformation of immature embryo derived calli of the Egyptian wheat cultivar Giza 164 using particle bombardment. Associated changes in defense mechanisms in the transgenic plants were investigated. The transgenic plants had significantly decreased total protein content, phenolic compounds and antioxidant enzyme activities (peroxidase and catalase), and significantly increased phenylalanine ammonia lyase and chitinase activities compared with non-transgenic plants under biotic stress conditions caused by F. graminearum infection. Our results show that activating a specific program of gene expression related to environmental stress conditions can reduce the cost of the stress on plant metabolism. PMID- 30456223 TI - Data on spatio-temporal representation of mineral N fertilization and manure N application as well as ammonia volatilization in French regions for the crop year 2005/06. AB - The data presented in this article are related to the research article entitled "A new framework to estimate spatio-temporal ammonia emissions due to Nitrogen fertilization in France" (Ramanantenasoa et al., 2018) but are given with more details at a regional scale (NUTS2) in the objective to get them available for other research or applied studies. They concerns (i) the data implemented in the CADASTRE_NH3 framework and (ii) the data obtained using it, for crop year 2005/06. For the source data, the article focusses on the N fertilization practice management description, as this dataset is the most difficult to collect and to analyze in the objective of realistically representing the spatial and temporal variabilities needed in the framework. PMID- 30456224 TI - Proteomics data for characterizing Microbacterium oleivorans A9, an uranium tolerant actinobacterium isolated near the Chernobyl nuclear power plant. AB - Microbacterium oleivorans A9 cells were exposed or not to 10 uM uranyl nitrate as resting cells in sodium chloride solution. Bacteria exposed to U(VI) and controls were harvested after 0.5, 4, and 24 h of toxicant exposure. Bacteria were subjected to high-throughput proteomics analysis using a Q-Exactive HF high resolution tandem mass spectrometer incorporating an ultra-high-field orbitrap analyzer. MS/MS spectra were assigned with a protein sequence database derived from a draft genome obtained by Illumina sequencing and systematic six-reading frame translation of all the contigs. Proteins identified in bacteria exposed to U(VI) and controls at the three time points allow defining the proteome dynamics upon uranium stress. The data reported here are related to a published study regarding the proteome dynamics of M. oleivorans A9 upon uranium stress by Gallois et al. (in press) entitled "Proteogenomic insights into uranium tolerance of a Chernobyl's Microbacterium bacterial isolate". The data accompanying the manuscript describing the database searches and comparative analysis have been deposited to the ProteomeXchange with identifier PXD005794. PMID- 30456225 TI - Effect of the reaction medium on the characteristics of silanized titanium dioxide particles: Differences obtained in the Zeta potential data and infrared spectra. AB - In this document we present the differences in the Zeta potential and in the Infrared spectra data obtained from the characterization of silanized titanium dioxide particles, using two different solvents as reaction media: ethanol and toluene. Also, we provide micrographs of transmission electron microscopy in order to show morphological differences between the analyzed samples. PMID- 30456226 TI - Input and benchmarking data for flow simulations in discrete fracture networks. AB - This article reports and describes the data related to the paper "Conforming, non conforming and non-matching discretization couplings in discrete fracture network simulations" (Fumagalli et al., 2019). The data provided include a set of geometrical input data of Discrete Fracture Networks (DFNs) and a set of simulation results. The geometrical data describe the geometry of fracture networks of increasing complexity. These data also include the geometry of a DFN extruded from a real fracture outcrop in Western Norway. Simulation results are obtained using several different numerical schemes and provide convergence history, plots over line and upscaled output quantities related to the various considered geometries. PMID- 30456227 TI - Dataset regarding baseline and follow-up characteristics of out-of-hospital cardiac arrest patients focused on neurological outcomes. AB - This data article contains the data related to the research article entitled "Long-term neurological outcomes in out-of-hospital cardiac arrest patients treated with targeted-temperature management" (Caro-Codon et al., 2018). In this dataset, we report details regarding the flow chart of the included patients and the specific exclusion criteria. We also include information on the difference between the patients who attended the structured personal interview (and therefore were finally included in the study) and those who did not attend. Neuropsychiatric and functional data before and after cardiac arrest are also reported. Finally, we list all the "de novo" focal neurological deficits identified after cardiac arrest in the related population. PMID- 30456228 TI - Dataset of (+/-)-NBI-74330 (CXCR3 antagonist) influence on chemokines under neuropathic pain. AB - Our data give evidence that CXCR3 ligands exhibit pronociceptive properties and play an important role in the initiation, development and maintenance of neuropathic pain. Moreover, intrathecal administration of each CXCR3 ligand induced hypersensitivity reactions in naive mice and of its neutralizing antibodies diminished neuropathic pain syndrome in CCI-exposed mice. Furthermore, our results indicate that selective CXCR3 antagonist (+/-)-NBI-74330 reduced the neuropathic pain-related behaviour and also enhanced morphine analgesic potency in CCI-exposed rats. Interestingly, our data show that (+/-)-NBI-74330 administration diminished the spinal IBA1 and, in parallel, downregulated CXCL4, CXCL9 and CXCL10. In addition, CXCR3 antagonist increased the spinal GFAP, what correlates with upregulation of CXCR3 and CXCL11. Moreover, in DRG (+/-)-NBI 74330 did not change IBA1 and GFAP positive cells activation, however downregulated also CXCL9. CXCR3 and CXCL10 were co-localized predominantly with neuronal marker in the spinal cord. Summing up, chronic (+/-)-NBI-74330 intrathecal injection promotes beneficial analgesic effects in rat neuropathic pain model, as described in details in "Pharmacological blockade of CXCR3 by (+/ )-NBI-74330 reduces neuropathic pain and enhances opioid effectiveness - evidence from in vivo and in vitro studies" (Piotrowska et al., 2018). PMID- 30456229 TI - Morphological dataset of aboveground macrofungal communities within different forest conversion stages in the Eifel National Park in Germany. AB - This dataset includes 235 aboveground macrofungal species observed at 15 sampling sites, which are associated with five different forest conversion stages. We used a space-for-time substitution approach to represent a forest conversion from Norway spruce (Picea abies) to European beech (Fagus sylvatica) through three different, widely used management practices. In addition to the results of 75 macrofungal field surveys, this data article includes information about site characteristics, vegetation structure, and observation frequencies. A multivariate statistic and myco-ecological interpretation of the macrofungal dataset is presented in an associated research article entitled "Forest conversion from Norway spruce to European beech increases species richness and functional structure of aboveground macrofungal communities" (Heine et al., 2019) [1]. PMID- 30456230 TI - Dataset on the development of palladium nanoparticle decorated colloidal porous organic polymer for photocatalytic Suzuki coupling. AB - Herein, we report the synthesis and characterization data of visible-light-active colloidal azobenzene-based porous organic polymer (Azo-POP) and its Pd nanoparticle loaded analog (Pd-Azo-POP). The setup for photocatalytic Suzuki reactions triggered by Pd-Azo-POP under conventional batch reaction mode as well as in a prototypal continuous flow system has also been provided in addition to the detailed catalytic data including 1H and 13C NMR spectra of the obtained products. For further discussions on the materials, their effect on overall catalysis and mechanistic insight, please refer to the associated article "Pd nanoparticle decorated azobenzene-based colloidal porous organic polymer for visible and natural sunlight-induced Mott-Schottky junction mediated instantaneous Suzuki coupling" (Chakraborty et al., 2019). PMID- 30456231 TI - Digital templates and brain atlas dataset for the mouse lemur primate. AB - We present a dataset made of 3D digital brain templates and of an atlas of the gray mouse lemur (Microcebus murinus), a small prosimian primate of growing interest for studies of primate biology and evolution. A template image was constructed from in vivo magnetic resonance imaging (MRI) data of 34 animals. This template was then manually segmented into 40 cortical, 74 subcortical and 6 cerebro-spinal fluid (CSF) regions. Additionally, the dataset contains probability maps of gray matter, white matter and CSF. The template, manual segmentation and probability maps can be downloaded in NIfTI-1 format at https://www.nitrc.org/projects/mouselemuratlas. Further construction and validation details are given in "A 3D population-based brain atlas of the mouse lemur primate with examples of applications in aging studies and comparative anatomy" (Nadkarni et al., 2018) [1], which also presents applications of the atlas such as automatic assessment of regional age-associated cerebral atrophy and comparative neuroanatomy studies. PMID- 30456232 TI - Data exploration on diet, and composition, energy value and functional division of prey items ingested by White Storks Ciconia ciconia in south-western Poland: Dietary variation due to land cover, reproductive output and colonial breeding. AB - The dataset presented in this data paper supports "Linking land cover satellite data with dietary variation and reproductive output in an opportunistic forager: Arable land use can boost an ontogenetic trophic bottleneck in the White Stork Ciconia ciconia" (Orlowski et al. 2019) [1]. Analysis of data on diet and prey composition based on an investigation of 165 pellets of White Storks Ciconia ciconia sampled from 52 nests showed that their diet was based primarily on 'eurytopic prey' (embracing taxa from grassland and a variety of non-cropped habitats), the biomass contribution of which in the diet was disproportionately (3-4-fold) higher than the percentage of available corresponding habitats. Similarly, prey items from water/wetland sites prevailed over the availability of corresponding habitats. The opposite pattern characterized prey taxa from arable habitats and forests, the contribution of which was lower than the availability of the corresponding habitats. The total energy content per pellet (calculated by summing the energy content of all individual prey items across one specific prey group) was the most strongly correlated with the biomass of Orthoptera, thereafter with that of mammals, other vertebrates, earthworms and other invertebrates, but not with the biomass of Coleoptera. White Storks from nests of low productivity pairs (i.e. with 1-2 fledglings) consumed a significantly (up to two-fold) higher biomass of Coleoptera, Orthoptera and all invertebrates, which also translated into a higher total biomass and a higher total energy content compared to the diet of high-productivity pairs (i.e. with 3-4 fledglings). Our data, in particular those relating to energy content in a variety of invertebrate taxa, and their body mass and functional division in terms of habitat preferences should be useful for other researchers to calculate energy budgets of predatory animals living in agricultural landscapes in Europe. PMID- 30456233 TI - Data supporting the life cycle impact assessment and cost evaluation of technical alternatives for providing water and heating services to a suburban development in Gallivare Sweden. AB - The article presents input data that were used in Pericault et al. (2018) for life cycle impact assessment and total cost assessment of five technical alternatives for heat and water services provision in a suburban development in Sweden. The data consists of a list of environmental impacts (cumulative exergy demand of energy carriers - CExDe, global warming potential - GWP, abiotic depletion potential of elements - ADPE), costs, amortisation periods, lifetimes and output flows of the system processes composing the alternatives. The data was derived from values collected in lifecycle databases, environmental product declarations, scientific publications and personal communications with companies. PMID- 30456234 TI - Road mortality locations of small and medium-sized mammals along a partly-fenced highway in Quebec, Canada, 2012-2015. AB - The data presented here consist of the locations of 839 roadkill points from four years (2012-2015) of roadkill surveys for small and medium-sized mammals (under 30 kg) from a four-lane highway in Quebec (Highway 175) during the months of May to October. Seventeen species or species groups were identified, all local to the area, and none of which were identified as species at risk, threatened, or endangered. The GPS coordinates of each roadkill event are given, along with the date, time of day (morning or evening), location (northbound or southbound lanes) and species (where possible). Within the surveyed road, 18 wildlife passages with 100 m fencing on each side of the passage entrances were built for small and medium-sized mammals. The GPS coordinates of the 18 passages and the end of each corresponding fence are also provided. PMID- 30456235 TI - Data on the prevalence of addiction to the Internet among individuals with a history of drug abuse. AB - The purpose of this data article is to present the prevalence of Internet addiction in people with a history of substance abuse disorder in Kerman during 2016-2017. For this purpose, 223 people with the history of substance abuse disorder in three cities of Kerman province completed the demographic form and Young's Internet addiction questionnaire. Demographic characteristics of participants was analyzed and presented here. Young's Addiction Commitment Questionnaire contains 20 questions, each with a score of 1 to 5. The history of participants about the drug abuse was investigated. In addition, the prevalence of Internet addiction among the participants was evaluated. The internet addiction is more common in people with a history of drug abuse which may be a behavioral substitute for drug addiction. PMID- 30456236 TI - Data on collagen structures in leather with varying moisture contents from small angle X-ray scattering and three point bend testing. AB - The data presented in this article are related to the research article entitled "Effect of collagen packing and moisture content on leather stiffness" (Kelly et al., 2018). This article describes how moisture content affects collagen packing and leather stiffness. Structural changes were experimentally introduced into ovine leather through biaxial strain during tanning ('stretch tanning'). Leather samples produced normally without strain ('non-stretch tanned') and those produced by stretch tanning, were conditioned in a range of relative humidity environments and then analysed by small angle X-ray scattering and three point bend testing. The collagen D-spacing, lateral intermolecular spacing and flexural properties were measured under these varying moisture contents. PMID- 30456237 TI - USDA-ARS Colorado maize growth and development, yield and water-use under strategic timing of irrigation, 2012-2013. AB - This data set was collected over two years, 2012-2013, on maize under 12 irrigation treatments with varying levels of deficit during late-vegetative and grain-filling growth stages in semi-arid Northern Colorado supplied with surface drip irrigation. The data set, which can be found online at the USDA National Agricultural Library data repository (doi: 10.15482/USDA.ADC/1439968), includes hourly weather data; plant growth and canopy development over the season; final biomass, yield and harvest index; and daily water balance data including irrigation, precipitation, soil water content, and estimates of crop evapotranspiration. Soil parameters for the site, as well as data from a previous experiment on maize with different treatments can also be found online (doi: 10.15482/USDA.ADC/1254006). Here, we describe the synthesis of data collected from 2012 to 2013. These data can be used for modeling the relationship between maize yield and field-level water use under season water availability. PMID- 30456238 TI - Data on microcirculatory perfusion dips in the resting nail bed. AB - This article contains the raw data from the article entitled: "The presence of synchronized perfusion dips in the microcirculation of the resting nail bed" Mirdell et al. (in press). A laser speckle contrast imager (LSCI) was used to make a total of 21 recordings of the perfusion in the resting nail bed of 10 healthy test subjects. The first 10 recordings were acquired after 5 min of acclimatization. An additional 10 recordings were acquired in the same test subjects, after 20 min of acclimatization. In the last recording, a digital nerve block was applied to the left dig III. The data show the presence of highly irregular perfusion variations, a phenomenon we like to call perfusion dips. The data also show how the perfusion dips can be abolished through a digital nerve block. An algorithm for the quantification of the perfusion dips is included in the data. PMID- 30456239 TI - Dataset on the comparative proteomic profiling of mouse saliva and serum from wild type versus the dystrophic mdx-4cv mouse model of dystrophinopathy. AB - The comparative proteomic data presented in this article provide supporting information to the related research article "Proteomic identification of elevated saliva kallikrein levels in the mdx-4cv mouse model of Duchenne muscular dystrophy " (Murphy et al., 2018). Here we provide additional datasets on the comparative proteomic analysis of saliva and serum proteins and the mass spectrometric identification of kallikrein isoform Klk-1 in wild type versus mdx 4cv saliva specimens. The data article presents the systematic identification of the assessable saliva proteome and the differential presence of proteins in saliva versus serum samples. Representative mass spectrometric scans of unique peptides that were employed to identify the kallikrein isoform Klk-1 in wild type versus mdx-4cv saliva specimens are provided. The dataset contains typical saliva associated marker proteins, including alpha-amylase and albumin, as well as distinct isoforms of cystatin, serpin, kallikrein, cathepsin, glutathione transferase, carbonic anhydrase, mucin, pyruvate kinase, and aldolase. PMID- 30456240 TI - Experimental tests on real-scale EBF structures with horizontal and vertical links. AB - The paper presents data achieved during an experimental test campaign executed on real-scale one storey/one bay EBF steel structures with vertical and horizontal links. Experimental tests were executed in displacement control by applying cyclic loading histories following ECCS45 protocol and constant amplitude-imposed displacements. Data provide indications concerning the energy dissipated by each prototype during tests, the corresponding shear force - angular distortion curves of the dissipative link and, besides, the force-displacement behavior of the steel prototypes until failure. PMID- 30456241 TI - Data on the determination of human epidermis integrity in skin permeation experiments by electrical resistance. AB - The data presented in this article are related to the research article entitled "Design of in vitro skin permeation studies according to the EMA Guideline on quality of transdermal patches" (https://doi.org/10.1016/j.ejps.2018.09.014) (Cilurzo et al., 2018) [1]. In vitro permeation studies are generally carried out by Franz's diffusion cell method using human epidermis as a membrane (Franz, 1975) [2]. The evaluation of membrane integrity is mandatory to assure the quality of the experiments. However, the methods used for this determination are different and the results are strictly dependent on the operative conditions. The article reports the electrical resistance values of human epidermis samples and in vitro skin permeability data of caffeine and benzoic acid. The data are used to establish a cut-off suitable for checking the skin integrity. This information may be useful to enable critical or extended analyses in order to contribute to the development of a compendial method. PMID- 30456242 TI - Gender specific click and tone burst evoked ABR datasets from mice lacking the Cav2.3 R-type voltage-gated calcium channel. AB - This data article provides raw auditory evoked brainstem responses (ABRs) from controls and Cav2.3 transgenics, i.e. heterozygous Cav2.3+/- and Cav2.3-/- null mutants. Gender specific ABR recordings were performed in age-matched animals under ketamine/xylazine narcosis. Data presented here include ABRs upon both click and tone burst presentation in the increasing SPL mode using a commercially available ABR setup from Tucker Davis Technologies Inc. (TDT, USA). Detailed information is provided for the sound attenuating cubicle, electrical shielding, electrode parameters, stimulus characteristics and architecture, sampling rate, filtering processes and ABR protocol application during the course of data acquisition and recording. The later are important for subsequent analysis of click and tone burst related hearing thresholds, amplitude growth function and peak latencies. Raw data are available at MENDELEY DATA, DIO: , URL: ). PMID- 30456243 TI - Data on combination of parabolic solar system with CH4 cycle and power tower solar system with Cu-Cl cycle for hydrogen production in the city of Ghardaia (Algeria). AB - This data show the combination of parabolic through solar system with CH4 cycle and power tower solar system with Cu-Cl cycle for hydrogen production capacity in the city of Gharadaia which is located in the south of Algeria. A proper measurement of meteorological factors such as temperature, humidity, and solar irradiation has been done in the city of Ghardaia due to the solar concentration in this city. In the meantime thermo-chemical systems (Cu-Cl, CH4 cycles) have been integrated with the thermal solar systems through. PMID- 30456244 TI - Data for praying mantis mitochondrial genomes and phylogenetic constructions within Mantodea. AB - In this data article, we provide five datasets of mantis mitochondrial genomes: (1) PCG123: nucleotide sequences of 13 protein-coding genes including all codon positions; (2) PCG123R: nucleotide sequences of two rRNAs and 13 protein-coding genes including all codon positions; (3) PCG12: nucleotide sequences of 13 protein-coding genes without third codon positions; (4) PCG12R: nucleotide sequences of two rRNAs and 13 protein-coding genes without third codon positions, and (5) PCGAA: amino acid sequences of 13 protein-coding genes. These were used to construct phylogenetic relationships within Mantodea and the phylogenetic trees inferred from Bayesian analysis using two data sets (PCG12R, PCGAA) and Maximum Likelihood analysis using four data sets (PCG123, PCG12, PCG12R and PCGAA). We also provide initiation codon, termination codon, amino acid length and nucleotide diversity (Pi) of protein-coding genes among 27 mantises. The whole mitochondrial genomes of 27 praying mantises were submitted to GenBank with the accession numbers KY689112-KY689138. PMID- 30456245 TI - Dataset on analysis of quality of health and social insurance subscription in different socio-economic class of workers in selected areas in southwest Nigeria. AB - National social health insurance scheme aims to improve the health of citizens and provide equal access to health care across different income classes. This empirical datasets describes quality of health, insurance subscription, awareness, health care coverage and benefits in different socio-economic class of workers in Ota and Lagos, Nigeria. The perception of individual's state of health and level of satisfaction of accessed health care are reported and opinions on ways to meet the health needs of workers in a developing country such as Nigeria. PMID- 30456246 TI - Global household air pollution database: Kitchen concentrations and personal exposures of particulate matter and carbon monoxide. AB - The Global Household Air Pollution (HAP) Measurements database, commissioned by the World Health Organization, provides an organized summary of data reported in the literature describing HAP microenvironments, methods and measurements. As of June 2018, the database contains measurements from 43 countries obtained from 196 studies published through 2016. The database includes information useful for understanding the range of household and personal air pollution measurements that have been collected in a country, as well as characteristics of the cooking environment, including primary cooking fuel type, stove type, heating fuel type and kitchen location. Quantitative particulate matter (PM) of various size fractions and/or carbon monoxide (CO) exposure measurements included in the database can be aggregated and analyzed to generate summary statistics (e.g. average sub-national, national, regional and global HAP exposures) to assess temporal and spatial relationships. The quantitative PM exposure measurements in the database have been used in global predictive modeling of HAP-PM2.5 exposures ("Global Estimation of Exposure to Fine Particulate Matter (PM2.5) from Household Air Pollution" (Shupler et al., 2018) [1]). PMID- 30456247 TI - Data describing the eco-physiological responses of twenty-four sunflower genotypes to water deficit. AB - This article presents experimental data describing the physiology and morphology of sunflower plants subjected to water deficit. Twenty-four sunflower genotypes were selected to represent genetic diversity within cultivated sunflower and included both inbred lines and their hybrids. Drought stress was applied to plants in pots at the vegetative stage using the high-throughput phenotyping platform Heliaphen at INRA Toulouse (France). Here, we provide data including specific leaf area, osmotic potential and adjustment, carbon isotope discrimination, leaf transpiration, plant architecture: plant height, leaf number, stem diameter. We also provide leaf areas of individual organs through time and growth rate during the stress period, environmental data such as temperatures, wind and radiation during the experiment. These data differentiate both treatment and the different genotypes and constitute a valuable resource to the community to study adaptation of crops to drought and the physiological basis of heterosis. It is available on the following repository: https://doi.org/10.25794/phenotype/er6lPW7V. PMID- 30456248 TI - Redox-proteomes of human NOS1-transduced versus MOCK SH-SY5Y neuroblastoma cells under full nutrition, serum-free starvation, and rapamycin treatment. AB - Upregulations of neuronal nitric oxide synthase (nNOS/NOS1) in the mouse brain upon aging and stress suggest a role of NO-dependent redox protein modifications for age-associated protein imbalances or dysfunctions. We generated a cell model, in which constitutive expression of nNOS in SH-SY5Y cells at a level comparable with mouse brain replicates the aging phenotype, that is, slowing of cell proliferation, cell enlargement, and expression of senescence markers. nNOS+ and MOCK cells were exposed to proteostasis stress by the treatment with rapamycin or serum-free starvation versus control conditions. To analyze NO-mediated S nitrosylations (SNO) and other reversible protein modifications including disulfides and sulfoxides, we used complimentary proteomic approaches encompassing 2D-SNO-DIGE (differential gel electrophoresis), SNO-site identification (SNOSID), SNO Super-SILAC, SNO BIAM-Switch, and Redox-BIAM switch. The redox proteomes were analyzed using hybrid liquid chromatography/mass spectrometry (LC/MS). Full scan MS-data were acquired using Xcalibur, and raw mass spectra were analyzed using the proteomics software MaxQuant. The human reference proteome sets from uniprot were used as templates to identify peptides and proteins and quantify protein expression. The DiB data file contains MaxQuant output tables of the redox-modified proteins.The tables include peptide and protein identification, accession numbers, protein, and gene names, sequence coverage and quantification values of each sample. Differences in protein redox modifications in MOCK versus nNOS+ SH-SY5Y cells and interpretation of results are presented in (Valek et al., 2018). PMID- 30456249 TI - Deep proteome of human nNOS/NOS1-positive versus MOCK SH-SY5Y neuroblastoma cells under full nutrition, serum free starvation and rapamycin treatment. AB - Upregulations of neuronal nitric oxide synthase (nNOS/NOS1) in the mouse brain upon aging suggest a role in age-associated changes of protein homeostasis. We generated a cell model, in which constitutive expression of nNOS in SH-SY5Y cells at a level comparable to mouse brain replicates the aging phenotype i.e. slowing of cell proliferation, cell enlargement and expression of senescence markers. nNOS+ and MOCK cells were exposed to proteostasis stress by treatment with rapamycin or serum-free starvation. The proteomes were analyzed per SILAC or label-free using hybrid liquid chromatography/mass spectrometry (LC/MS). Full scan MS-data were acquired using Xcalibur, and raw mass spectra were analyzed using the proteomics software MaxQuant. The human reference proteome from uniprot was used as template to identify peptides and proteins and quantify protein expression. The DiB data file contains essential MaxQuant output tables and includes peptide and protein identification, accession numbers, protein and gene names, sequence coverage and quantification values of each sample. Differences in protein expression in MOCK versus nNOS+ SH-SY5Y cells and interpretation of results are presented in Valek et al. (2018). Raw mass spectra and MaxQuant output files have been deposited to the ProteomeXchange Consortium (Vizcaino et al., 2014) via the PRIDE partner repository with the dataset identifier PRIDE: PXD010538. PMID- 30456250 TI - Clinical data and risk factors for diabetic nephropathy in Brazilian central population. AB - This article describes data set of the profile of patients diagnosed with Diabetic Nephropathy (DN) undergoing hemodialysis and followed-up by Hemodialysis Service in medical centers in Goiania, Go, Brazil. These data describe specifically the demographic, clinical, and lifestyle variables of 101 patients. In addition, these data provide detailed clinical associations about the profile of patients diagnosed with DN and which are made publicly available to enable critical or extended analyzes. For further interpretation of the data presented in this article, see the research article: Do GST polymorphisms influence in the pathogenesis of diabetic nephropathy? (Lima et al., 2018). PMID- 30456251 TI - Data on bioassay of toxicity reduction of treated textile wastewater by using nanophotocatalytic process by Daphnia magna. AB - Practicability and possibility of photocatalytic degradation of Ro16 textile dye and the actual wastewater of textile were studied on pilot scale. The amount of reduction in solution toxicity was studied and assessed by the application of a bioassay using Daphnia magna. The solution toxicity at the beginning of the process has an increasing procedure and this is caused by the intermediate products that are produced during the photocatalytic process from the mother compounds, and are more toxic compared to them, and their toxicity declines at the end of the process with the completion of mineralization. The procedure of toxicity increase and its decrease in the course of photocatalytic process has a direct relation with the amount of mineralization. PMID- 30456252 TI - Data on the knowledge, attitude, and performance of Ph.D. students attending an educational course (Tehran, Iran). AB - The Department of Medical Education of Iran University of Medical Sciences organized a workshop on empowerment and familiarity with the teaching and learning principles. The data presented here is based on the effectiveness of this workshop. This data was acquired from 29 postgraduates who take part in a two-day educational course and instructional design workshop. The samples were selected by convenience sampling. Data collection tool was a questionnaire that consisted of 5 questions for demographic variables, 20 question about attitude and satisfaction, 30 questions on knowledge as pretest and posttest, and 3 questions about behavior and performance. The descriptive statistics of data were analyzed using SPSS-14. The mean score of pre-test and post-test in case of knowledge, attitude, and performance in teaching and instructional design were calculated. In addition, the viewpoints of educational departments on the third level of Kirkpatrick's model i.e. the students' post-workshop behavior change (transferring learning to the workplace) were obtained. PMID- 30456253 TI - Carbon (CI) and energy intensity (EI) dataset for retail stores. AB - This data article presents data collected from the 250 highest revenue retailers around the world, assessed according to publicly available data from the fiscal year 2016, in order to determine retailer's overall carbon intensity (CI) and energy intensity (EI). Data collection included additional variables such as retailers' revenue rank, operational typology, number of stores, store sales area and number of workers. Based on this dataset, CI and EI benchmarks were calculated for food and non-food retailers, applying the statistic function first quartile (Q1) for the best practice, second (Q2) and third (Q3) quartiles for conventional practice and fourth quartile (Q4) for worst practice and correlations were tested between the variables "EI", "CI" and "retailer revenue", applying the statistic function CORREL (Ferreira et al., In press) [1]. Finally, a cluster analysis was performed for food and non-food retailers, to identify possible segmentation patterns between the variables "EI", "CI" and "retailer revenue". The information provided in this data article is useful for furthering research developments on the influence of isolated variables on retail EI and CI and in assisting retailers, architects, engineers, and policy makers in establishing optimal energy performance goals for the design and operation of retail stores. For further data interpretation and discussion, see the article "Combined carbon and energy intensity benchmarks for sustainable retail stores" (Ferreira et al., In press), of the same authors. PMID- 30456254 TI - Characterisation of patients with familial chylomicronaemia syndrome (FCS) and multifactorial chylomicronaemia syndrome (MCS): Establishment of an FCS clinical diagnostic score. AB - Data presented in this article are supplementary material to our article entitled "Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS): expert panel recommendations and proposal of an "FCS Score" (Moulin et al., 2018, in press). The data describe the genotypes of patients with familial chylomicronaemia syndrome (FCS) and multifactorial chylomicronaemia syndrome (MCS), from the validation and replication cohorts. PMID- 30456255 TI - Electric vehicle sound stimuli data and enhancements. AB - Data for six electric vehicle WOT interior sound measurements and eight enhanced sound signatures are presented. The measurement of electric vehicle interior sound signature data and the enhancement of these stimuli are documented in this data article. The procedures and equipment that were used to record the data, as well as the transposition, harmony and order addition, frequency filtering and modulation enhancement techniques that were applied to these stimuli are explained in detail. The transient frequency content of the 12 sound stimuli is presented in acoustic spectrograms along with the audio files in.mp3 format. PMID- 30456257 TI - Data on hamster LD50 from Leptospira and its impact on Title 9, Codified Federal Regulations Sections 113.102-113.103 test validity. AB - These data and analyses support the research article "Re-evaluating the LD50 requirements in the codified potency testing of veterinary vaccines containing Leptospira serogroups Icterohaemorrhagiae and Canicola in the United States" (Walker et al., 2018). Validity and disposition requirements submitted to the Center for Veterinary Biologics (CVB) are provided for serials (numbered lots) of commercial product potency tested for serogroups Canicola and Icterohaemorrhagiae in support of the Virus-Serum-Toxin Act (VSTA). Time course data for hamster loss after challenge with various concentrations of Leptospira during codified potency testing are also presented. The dose of Leptospira lethal to 50% of hamsters (LD50) was calculated by the Dragstedt-Behrens method for the in vivo data collected, and the equation is described here. PMID- 30456256 TI - Dataset on schistosomiasis control using potassium usnate against Biomphalaria glabrata at different developmental stage and Schistosoma mansoni cercariae. AB - This text presents complementary data corresponding to schistosomiasis mansoni's vector control and toxicity on Schistosoma mansoni cercariae using potassium usnate. This information support our research article "Potassium Usnate Toxicity Against Embryonic Stages of the Snail Biomphalaria glabrata and Schistosoma mansoni Cercariae" [1], and focuses on the analysis of the detailed data regarding the different concentrations of potassium usnate and their efficiency to B. glabrata mortality and non-viability and S. mansoni cercariae mortality etiologic agent of the disease. PMID- 30456258 TI - LC-HRMS data as a result of untargeted metabolomic profiling of human cerebrospinal fluid. AB - Cerebrospinal fluid (CSF) is a key body fluid that maintains the homeostasis in central nervous system (CNS). As a biofluid whose content reflects the brain metabolic activity, the CSF is analyzed in the context of neurological diseases and is rarely collected from healthy subjects. For this reason, the metabolite variation associated with general phenotypic characteristics such as gender and age have hardly ever been studied. Here we present the hydrophilic interaction liquid chromatography-high resolution mass spectrometry (HILIC-HRMS) data as a result of untargeted metabolomics analysis of a cohort of elderly cognitively healthy volunteers (n = 32). 146 unambiguously identified water soluble metabolites (using accurate mass, retention time and MS/MS matching against spectral libraries) were measured and their abundances across all the subjects depending on their gender are provided in this article. Data tables are available at https://data.mendeley.com/datasets/c73xtsd4s5/1. it's published on mendeley, the DOI is DOI:10.17632/c73xtsd4s5.1. The data presented in this article are related to the research article entitled "A global HILIC-MS approach to measure polar human cerebrospinal fluid metabolome: Exploring gender-associated variation in a cohort of elderly cognitively healthy subjects" (Gallart-Ayala et al., 2018, In press). PMID- 30456259 TI - The dataset about the deformations under axial compression of concrete and cement sand mortar impregnated with oil. AB - This article contains data of longitudinal and transverse deformations of concrete and cement-sand prisms impregnated with mineral I-30A, corn and olive oil, under axial compression up to loads that do not create destructive stresses. The stress level, as the ratio of the compressive stress sigma to the design compressive strength R b , varied from 0.054 sigma/R b to 0.845 sigma/R b . The values of deformation for various axial compression loads are presented for control samples and for samples impregnated with mineral oil I-30A with a viscosity of 15 degrees E, corn oil with a viscosity of 9 degrees E, and olive oil with a viscosity of 11 degrees E on Engler scale. The data are associated with the research article "Influence of viscosity of vegetable and mineral oil on deformation properties of concrete and cement-sand mortar" (Alexander et al., 2018). PMID- 30456260 TI - Data on motivations of food choices obtained by two techniques: Online survey and in-depth one-on-one interview. AB - This data article provides the data related to the research article entitled "Motivations for meal and snack times: Three approaches reveal similar constructs" (Phan et al., 2018). The data consists of two datasets collected from two research techniques: online survey questionnaire and one-on-one interview. The data include details of the food and beverage items the participants consumed at specific eating occasions together with the motivations associated with consumption of those foods. The data also provides the food groups to which the food items belong, to facilitate different levels of data analysis to explore the relationship between food, eating occasions and people's motivations. PMID- 30456261 TI - Anisotropy and directional elastic behavior data obtained from the second-order elastic constants of portlandite Ca(OH)2 and brucite Mg(OH)2. AB - This article reports data on the anisotropy and directional elastic behavior, namely Young's modulus E, linear compressibility beta, shear modulus MU, Poisson's ratio nu and wave velocities Vs1, Vs2 and Vp, of brucite (magnesium hydroxide, Mg(OH)2) and portlandite (calcium hydroxide, Ca(OH)2), calculated from their second order elastic constants at different hydrostatic compressions (Ulian and Valdre, in press). The dataset has been obtained by ab initio quantum mechanical means, by employing density functional theory methods, in particular the B3LYP hybrid functional, all-electron Gaussian-type orbitals basis sets and a correction to take into account the effects of dispersive forces. PMID- 30456262 TI - Data supporting assessment for nitrous oxide emissions from soils under traditional cropland and apple orchard in the Loess Plateau of China. AB - The data presented in this article relates to the research article entitled "Nitrous oxide emissions from soils under traditional cropland and apple orchard in the semi-arid Loess Plateau of China" (https://doi.org/10.1016/j.dib.2016.08.027) (Pang et al., 2019). The dataset includes soil N2O emissions for two land use types (wheat field and apple orchard) in the semi-arid Loess Plateau and related environmental factors, such as soil temperature and soil moisture. In addition, the estimated annual average and seasonal cumulative emissions of N2O are presented here. Nitrous oxide emissions were measured by static, closed chamber methods. The data provides evidence for the difference in N2O emissions among two dominant land uses on the Loess Plateau of China. PMID- 30456263 TI - Characterisation, electrochemical and oxidative addition data of organophosphorus containing rhodium(I) complexes. AB - This data article contains the 1H Nuclear Magnetic Resonance (NMR), ultraviolet and visible (UV-vis) and Attenuated Total Reflectance Fourier Transformed Infra red (ATR FTIR) characterization of a series of organophosphorus-containing rhodium(I) complexes. The electrochemical data acquired by means of cyclic voltammetry of the three organophosphorus-containing ligands (with the structure C6H5XPPh2, where X = O, S and NH) and their acetylacetonato (monocarbonyl) organophosphorus rhodium(I) compounds, [Rh(acac)CO(C6H5XPPh2)] are reported. Additionally, the kinetic data of the oxidative addition of methyl iodide to the rhodium(I) complexes, are also presented. PMID- 30456264 TI - Fecal metabolomic dataset of American ginseng-treated DSS mice: Correlation between ginseng enteric inflammation inhibition and its biological signatures. AB - Although anti-inflammatory effects of American ginseng metabolites have been investigated at systemic and cellular levels, the biological signatures of ginseng microbial metabolite-induced bioactivities are still unknown. To fill this knowledge gap and to support the findings published in the companion research article entitled "American ginseng microbial metabolites attenuated DSS induced colitis and abdominal pain" (Wang et al., 2018), we are here to provide datasets of enteric microbiome biotransformation and fecal metabolomics. For the microbiome biotransformation study, data were obtained from C57BL6 mice treated with a broad-spectrum antibiotic metronidazole. After oral administration of ginseng extract, we observed that compound K (CK) was undetectable in metronidazole-treated mouse stools but was detected in stools from vehicle treated mice, suggesting biotransformation of CK is gut microbial dependent. In the fecal metabolomic study, three small molecules which were associated with gut inflammation were identified. In the DSS mice, the levels of lactate, linoleic acid, and malic acid increased significantly in the model group. After ginseng treatment, the expressions of these metabolites reduced significantly. Thus, the selective fecal endogenous metabolites could be used as biological signatures reflecting severity of enteric inflammation and ginseng treatment outcomes. Our results showed the enteric microbiome plays a key role for CK conversion, and the effects of CK on enteric inflammation can be demonstrated by the metabolomics data. PMID- 30456265 TI - Phytoremediation of heavy metals (Ni, Cd, Pb) by Azolla filiculoides from aqueous solution: A dataset. AB - In this article, the data of heavy metals phytoremediation efficiency were provided. The Azolla was collected from the lake around the Rasht city and washed in tap water, then weighed (0.2, 0.4 and 0.8 g), and kept for 15 days in the 100 ml disposable container in the presence 5, 10 and 25 mg/L of lead, nickel and cadmium ions. The samples were stored in polyethylene containers for analysis of the metal concentration with ICP-OES. According to the results, removal efficiency was increased from 40% to 70% at 10 days along with the increasing of the biomass from 2.0 to 8.0 g. The removal efficiency of Ni (II), Cd (II), and Pb (II) were increased by increasing the contact time up to 10 days. The removal efficiency decreased by increasing of the metals concentration from 5 to 25 mg/L. The highest removal efficiency was observed at heavy metals concentrations of 5 mg/L and contact time of 10 days. Results showed that Azolla had a high potential for the removal of heavy metals from water resources and it can be used in phytoremediation of heavy metals in environmental refinement projects. PMID- 30456266 TI - Local data of heat flux, wall temperature and the void phase along the boiling curve during vertical subcooled flow boiling of refrigerant Novec 649 at a copper wall. AB - This data set contains local experimental data of heat flux, wall temperature and void data profiles for vertical subcooled flow boiling of refrigerant Novec 649 at a copper wall. This data article presents average boiling curves from single phase convection to fully developed film boiling for six combinations of mass flux and subcooling. Void profiles are provided for void fraction, void detection frequency, void velocity and void ligament size for three characteristic states along each boiling curve. Thermocouples were used to measure heat flux and temperature. Optical single fiber and double fiber micro probes were used for obtaining void data profiles. A traversing mechanism was used to position the optical fiber micro probes relative to the heater surface. PMID- 30456267 TI - Data on the stem cells paracrine effects on apoptosis and cytokine milieu in an experimental model of cardiorenal syndrome type II. AB - The data reported in this article are related to the paper entitle "Stem cells transplantation positively modulates the heart-kidney cross talk in Cardiorenal Syndrome Type II" (Vescovo et al., 2019), which analyzed the impact of stem cells injection in cardiorenal syndrome type II. The dataset contains detailed information on apoptosis and cytokines milieu modification after injection of c Kit-selected human amniotic fluid stem cells (hAFS) or rats vascular progenitor cells (rSVC-GFP group) in an experimental model of CRSII. The data can be useful for clarifying the paracrine effects exerted by the injected cells. PMID- 30456268 TI - Supporting plots and tables on vapour-liquid equilibrium prediction for synthesis gas conversion using artificial neural networks. AB - This article contains data on vapor-liquid equilibrium modeling of 1533 gas liquid solubilities divided over sixty binary systems viz. carbon monoxide, carbon dioxide, hydrogen, water, ethane, propane, pentane, hexane, methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, and 1-hexanol in the solvents phenanthrene, 1-hexadecanol, octacosane, hexadecane and tetraethylene glycol at pressures up to 5.5 MPa and temperatures from 293 to 553 K using literature data. The solvents are considered to be potentially significant in the conversion of synthesis gas through gas-slurry processes. Artificial neural networks limited to one hidden layer and up to five neurons in the hidden layer were used to predict the binary plots. PMID- 30456269 TI - Data on chromatographic isolation of cysteine mixed-disulfide conjugates of Allium thiosulfinates and their role in cellular thiol redox modulation. AB - This data article contains experimental data on the preparation and semi preparative isolation of S-Alk(en)ylmercaptocysteine (CySSRs, R = allyl, "A", 1 propenyl, "Pe" or methyl, "Me") generated through conjugation reactions between allyl and 1-propenyl enriched thiosulfinates (TS) and cysteine. The data presented are related to the research article "S-Alk(en)ylmercaptocysteine suppresses LPS-induced pro-inflammatory responses in murine macrophages through inhibition of NF-kappaB pathway and modulation of thiol redox status" (Tocmo and Parkin, in press). In this data article, we included a detailed procedure for CySSR preparation, their purification through semi-preparative chromatography and their toxicity profiles in RAW 264.7 macrophages. Data included also highlight, the ability of CySSRs to modulate intracellular thiol redox status. PMID- 30456270 TI - Acoustic recordings data from an echoic environment and a toolkit for its analysis. AB - The primary data are the impulse responses that were recorded in an echoic environment, using a set of twelve loudspeakers and a microphone. They were used as a part of an acoustic calibration process of large environments, as presented by Kazakov and Nelken (DOI: 10.1016/j.jneumeth.2018.08.025; Kazakov and Nelken, 2018). The impulse responses can be also used to localize the microphone in 3D (multi-lateration). The required audio files and the MATLAB code allows a complete reproduction of the experiment. PMID- 30456271 TI - DFT and CV data of 4-phenyl-substituted dichloro(bis{2-[1-(phenyl)-1H-1,2,3 triazol-4-yl-kappaN3]pyridine-kappaN})iron(II) coordination compounds. AB - The data presented in this paper are related to the research article entitled "Synthesis, characterisation and electrochemistry of eight Fe coordination compounds containing substituted 2-(1-(4-R-phenyl-1H-1,2,3-triazol-4-yl)pyridine ligands, R=CH3, OCH3, COOH, F, Cl, CN, H and CF3." (Conradie et al., 2019) [1]. This paper presents electrochemical and density functional theory data of 4 phenyl-substituted dichloro(bis{2-[1-(4-R-phenyl)-1H-1,2,3-triazol-4-yl kappaN3]pyridine-kappaN})iron(II) compounds, containing differently substituted 2 (1-(4-R-phenyl)-1H-1,2,3-triazol-1-yl)pyridine ligands (L2 - L9) (Tawfiq et al., 2014) [2]. Density functional theory calculated data of five different structural isomers for each compound, consistently show that the title compounds are octahedral and that the isomer with the chloride atoms, the pyridine nitrogens and the triazol nitrogens trans to each other, has the lowest energy. Natural bonding orbital (NBO) data and quantum theory of atoms in molecules (QTAIM) data of dichloro(bis{2-[1-(phenyl)-1H-1,2,3-triazol-4-yl-kappaN3]pyridine kappaN})iron(II) show origin for the preference of the trans isomer. PMID- 30456272 TI - A proteomic dataset of secreted proteins by three Staphylococcus saprophyticus strains. AB - This article presents a proteomic dataset generated from a comparative analysis of the exoproteome of Staphylococcus saprophyticus, ATCC 15305, 7108 and 9325 strains. The extract of secreted proteins were obtained after incubation of stationary phase cells in BHI medium. All samples were submitted to nano-ESI-UPLC MSE, and the spectrum obtained was processed and analyzed by ProteinLynx Global Server (PLGS), Uniprot and Pedant databases, for identification, annotation and functional classification of proteins. Fold changes and protein relative abundances were properly reported. This report is related to the research article entitled "The exoproteome profiles of three Staphylococcus saprophyticus strains reveal diversity in protein secretion contents" (Oliveira et al., 2018). The proteomic data generated have been deposited to the ProteomeXchange Consortium, via the PRIDE partner repository, with a project number PXD008643, https://www.ebi.ac.uk/pride/archive/projects/PXD008643. PMID- 30456273 TI - Proteomic profiling data of HEK293 proteins bound to human recombinant renalases 1 and -2. AB - Renalase (RNLS) is a recently discovered protein involved in blood pressure regulation. It exists both as an intracellular catalytically active flavoprotein (EC 1.6.3.5 dihydro-NAD(P):oxygen oxidoreductase) and an extracellular protein that demonstrates various cell protecting effects. Using a twenty-membered peptide corresponding to the residues 220-239 of the renalase sequence (RP-220) and the HK-2 cell line Wang et al. identified a renalase-binding protein, which was considered as a receptor for extracellular renalase crucial for MAPK signaling (Wang et al., 2015) [1]. In this study we have investigated profiles of renalase binding proteins in HEK293 cells by using affinity based proteomic profiling with full-length recombinant human RNLS-1 and human RNLS-2 as affinity ligands followed by analysis of bound proteins by liquid chromatography-mass spectrometry. Both renalases (RNLS-1 and RNLS-2) contain the RP-220 sequence (residues 220-239) but differ in their C-terminal region (residues 293-342 and 293-325, respectively). Profiling of HEK293 proteins resulted in identification of two different sets of proteins specifically bound to RNLS-1 and RNLS-2, respectively. We thus demonstrate that the C-terminal region is crucial for specific binding of renalase to its targets and/or receptors. PMID- 30456274 TI - Not lost to follow-up: A rare case of CHILD syndrome in a boy reappears. PMID- 30456276 TI - Intermittent plaque on the neck. PMID- 30456275 TI - Introduction to reflectance confocal microscopy and its use in clinical practice. AB - Reflectance confocal microscopy (RCM) is a novel technology that provides noninvasive, in vivo imaging of the skin at nearly histologic resolution. In 2016, the US Centers for Medicare and Medicaid Services (CMS) established reimbursement codes for RCM image acquisition and for the reading and interpretation of images. The combination of RCM imaging with dermoscopy has improved the accuracy of skin cancer diagnosis while reducing the number of biopsies of benign skin lesions. With that, we are starting to see more dermatologists and dermatopathologists using RCM in clinical practice. This editorial is to serve as an introduction on RCM imaging with a focus on its usefulness in both the diagnosis and management of skin cancers. We end by briefly describing the characteristic RCM features of normal skin to serve as a building block for later cases that will explore both the benefits and drawbacks of incorporating RCM imaging for benign and malignant lesions. PMID- 30456277 TI - Two cases of maggot debridement therapy in pyoderma gangrenosum. PMID- 30456278 TI - Ustekinumab-associated disseminated verrucae. PMID- 30456279 TI - Halo formations around senile hemangiomas in diffuse plane normolipemic xanthomatosis associated with monoclonal gammopathy. PMID- 30456280 TI - Kava-induced acute cutaneous toxicity: An increasingly recognized characteristic clinicohistologic pattern. PMID- 30456281 TI - Eruption of solitary reticulohistiocytoma after intense pulsed light burn. PMID- 30456282 TI - Vitiligo in a patient undergoing nivolumab treatment for non-small cell lung cancer. PMID- 30456283 TI - Intercalated low doses of antimonials for disseminated cutaneous leishmaniasis caused by Leishmania guyanensis: A successful approach in Amazonas, Brazil. PMID- 30456284 TI - Wong-type dermatomyositis during anti-PD-1 therapy. PMID- 30456285 TI - Eruptive melanocytic nevi associated with ponatinib. PMID- 30456286 TI - Association between diabetes mellitus and progression free survival in women with ovarian granulosa cell tumors. AB - *Diabetes mellitus confers worse survival in women with granulosa cell tumors.*Routine lymphadenectomy does not improve survival in women with granulosa cell tumors.*Women in this cohort had a high prevalence of concurrent breast cancer.*Further studies are needed to see if glycemic control improves survival outcomes. PMID- 30456287 TI - Primary mediastinal choriocarcinoma in a female patient: Case report and review of the literature. AB - *Primary mediastinal choriocarcinoma is rare, especially in female patients.*Genomic losses predominated our case, which has not been previously reported.*This tumor lacked human chorionic gonadotropin and required histologic diagnosis. PMID- 30456288 TI - Neuropsychological comparison of incident MCI and prevalent MCI. AB - Introduction: Little empirical work has been done to examine differences between mild cognitive impairment (MCI) diagnosed in research settings with longitudinal data (incident MCI) and MCI diagnosed in clinical settings (prevalent MCI). Because Alzheimer's disease progresses over a clinicopathological continuum, we examined the cognitive differences between these two different sources of MCI patients. Methods: We compared 52 consecutively identified patients with prevalent amnestic MCI with 53 incident amnestic MCI participants from the Arizona APOE study. Neuropsychological data from common tests were compared encompassing four cognitive domains and one global indicator. Results: Prevalent MCI cases performed significantly worse than incident MCI cases on global as well as domain-specific measures. Discussion: By the time patients seek evaluation for memory loss, they have more severe single domain, amnestic MCI than research subjects with incident MCI. Studies of MCI should distinguish incident and prevalent not just single- and multiple-domain MCI. PMID- 30456289 TI - What do we know about strategies to manage dementia-related wandering? A scoping review. AB - Three of five persons with dementia will wander, raising concern as to how it can be managed effectively. Wander-management strategies comprise a range of interventions for different environments. Although technological interventions may help in the management of wandering, no review has exhaustively searched what types of high- and low-technological solutions are being used to reduce the risks of wandering. In this article, we perform a review of gray and scholarly literature that examines the range and extent of high- and low-tech strategies used to manage wandering behavior in persons with dementia. We conclude that although effectiveness of 49 interventions and usability of 13 interventions were clinically tested, most were evaluated in institutional or laboratory settings, few addressed ethical issues, and the overall level of scientific evidence from these outcomes was low. Based on this review, we provide guidelines and recommendations for future research in this field. PMID- 30456290 TI - Characterizing heterogeneity in the progression of Alzheimer's disease using longitudinal clinical and neuroimaging biomarkers. AB - Introduction: Models characterizing intermediate disease stages of Alzheimer's disease (AD) are needed to inform clinical care and prognosis. Current models, however, use only a small subset of available biomarkers, capturing only coarse changes along the complete spectrum of disease progression. We propose the use of machine learning techniques and clinical, biochemical, and neuroimaging biomarkers to characterize progression to AD. Methods: We used a large multimodal longitudinal data set of biomarkers and demographic and genotype information from 1624 participants from the Alzheimer's Disease Neuroimaging Initiative. Using hidden Markov models, we characterized intermediate disease stages. We validated inferred disease trajectories by comparing time to first clinical AD diagnosis. We trained an L2-regularized logistic regression model to predict disease trajectory and evaluated its discriminative performance on a test set. Results: We identified 12 distinct disease states. Progression to AD occurred most often through one of two possible paths through these states. Paths differed in terms of rate of disease progression (by 5.44 years on average), amyloid and total-tau (t-tau) burden (by 10% and 69%, respectively), and hippocampal neurodegeneration (P < .001). On the test set, the predictive model achieved an area under the receiver operating characteristic curve of 0.85. Discussion: Progression to AD, in terms of biomarker trajectories, can be predicted based on participant specific factors. Such disease staging tools could help in targeting high-risk patients for therapeutic intervention trials. As longitudinal data with richer features are collected, such models will help increase our understanding of the factors that drive the different trajectories of AD. PMID- 30456291 TI - A computerized, self-administered test of verbal episodic memory in elderly patients with mild cognitive impairment and healthy participants: A randomized, crossover, validation study. AB - Introduction: Performance of "Revere", a novel iPad-administered word-list recall (WLR) test, in quantifying deficits in verbal episodic memory, was evaluated versus examiner-administered Rey Auditory Verbal Learning Test (RAVLT) in patients with mild cognitive impairment and cognitively normal participants. Methods: Elderly patients with clinically diagnosed mild cognitive impairment (Montreal Cognitive Assessment score 24-27) and cognitively normal (Montreal Cognitive Assessment score >=28) were administered RAVLT or Revere in a randomized crossover design. Results: A total of 153/161 participants (Revere/RAVLT n = 75; RAVLT/Revere n = 78) were randomized; 148 (97%) completed study; 121 patients (mean [standard deviation] age: 70.4 [7.84] years) were included for analysis. Word-list recall scores (8 trials) were comparable between Revere and RAVLT (Pearson's correlation coefficients: 0.12-0.70; least square mean difference [Revere-RAVLT]: -0.84 [90% CI, -1.15; -0.54]). Model factor estimates indicated trial (P < .001), period (P < .001) and evaluation sequence (P = .038) as significant factors. Learning over trials index and serial position effects were comparable. Discussion: Participants' verbal recall performance on Revere and RAVLT were equivalent. PMID- 30456292 TI - Bayesian latent time joint mixed-effects model of progression in the Alzheimer's Disease Neuroimaging Initiative. AB - Introduction: We characterize long-term disease dynamics from cognitively healthy to dementia using data from the Alzheimer's Disease Neuroimaging Initiative. Methods: We apply a latent time joint mixed-effects model to 16 cognitive, functional, biomarker, and imaging outcomes in Alzheimer's Disease Neuroimaging Initiative. Markov chain Monte Carlo methods are used for estimation and inference. Results: We find good concordance between latent time and diagnosis. Change in amyloid positron emission tomography shows a moderate correlation with change in cerebrospinal fluid tau (rho = 0.310) and phosphorylated tau (rho = 0.294) and weaker correlation with amyloid-beta 42 (rho = 0.176). In comparison to amyloid positron emission tomography, change in volumetric magnetic resonance imaging summaries is more strongly correlated with cognitive measures (e.g., rho = 0.731 for ventricles and Alzheimer's Disease Assessment Scale). The average disease trends are consistent with the amyloid cascade hypothesis. Discussion: The latent time joint mixed-effects model can (1) uncover long-term disease trends; (2) estimate the sequence of pathological abnormalities; and (3) provide subject-specific prognostic estimates of the time until onset of symptoms. PMID- 30456295 TI - Due Process in Medical Education: Legal Considerations. AB - Throughout the medical education continuum, some students encounter difficulty in meeting academic or professional standards that leads to remediation or dismissal. Termination of a student without due process may lead to litigation by deprivation of a student's property or liberty interest. This article outlines the concept of procedural and substantive due process as applied to litigated student dismissal cases in undergraduate and graduate medical education. Determination of the amount of due process owed is based on whether the dismissal is academic or nonacademic. The decision to dismiss a student where the entire student record has been reviewed, due process provided, and the institution complied with its own policies is usually upheld by the courts in litigation. PMID- 30456294 TI - Inhibitory Projections from the Inferior Colliculus to the Medial Geniculate body Originate from Four Subtypes of GABAergic Cells. AB - GABAergic cells constitute 20-40% of the cells that project from the inferior colliculus [(IC) a midbrain auditory hub] to the medial geniculate body [(MG) the main auditory nucleus of the thalamus]. Four subtypes of GABAergic IC cells have been identified based on their association with perineuronal nets (PNs) and dense rings of axosomatic terminals expressing vesicular glutamate transporter 2 (VGLUT2 rings). These subtypes differ in their soma size and distribution within the IC. Based on previous work emphasizing large GABAergic cells as the origin of GABAergic IC-MG projections, we hypothesized that GABAergic IC cells surrounded by PNs and VGLUT2 rings, which tend to have larger somas, were more likely to project to the MG than smaller cells lacking these extracellular markers. Here, we injected retrograde tract tracers into the MG of guinea pigs of either sex and analyzed retrogradely labeled GABAergic cells in the ipsilateral IC for soma size and association with PNs and/or VGLUT2 rings. We found a range of GABAergic soma sizes present within the IC-MG pathway, which were reflective of the full range of GABAergic soma sizes present within the IC. Further, we found that all four subtypes of GABAergic IC cells participate in the IC-MG pathway, and that GABAergic cells lacking PNs and VGLUT2 rings were more prevalent within the pathway than would be expected based on their overall prevalence in the IC. These results may provide an anatomical substrate for the multiple roles of inhibition in the IC-MG pathway, which have emerged in electrophysiological studies. PMID- 30456293 TI - nNOS-Expressing Neurons in the Ventral Tegmental Area and Substantia Nigra Pars Compacta. AB - GABA neurons in the VTA and SNc play key roles in reward and aversion through their local inhibitory control of dopamine neuron activity and through long-range projections to several target regions including the nucleus accumbens. It is not clear whether some of these GABA neurons are dedicated local interneurons or if they all collateralize and send projections externally as well as making local synaptic connections. Testing between these possibilities has been challenging in the absence of interneuron-specific molecular markers. We hypothesized that one potential candidate might be neuronal nitric oxide synthase (nNOS), a common interneuronal marker in other brain regions. To test this, we used a combination of immunolabelling (including antibodies for nNOS that we validated in tissue from nNOS-deficient mice) and cell type-specific virus-based anterograde tracing in mice. We found that nNOS-expressing neurons, in the parabrachial pigmented (PBP) part of the VTA and the SNc were GABAergic and did not make detectable projections, suggesting they may be interneurons. In contrast, nNOS-expressing neurons in the rostral linear nucleus (RLi) were mostly glutamatergic and projected to a number of regions, including the lateral hypothalamus (LH), the ventral pallidum (VP), and the median raphe (MnR) nucleus. Taken together, these findings indicate that nNOS is expressed by neurochemically- and anatomically distinct neuronal sub-groups in a sub-region-specific manner in the VTA and SNc. PMID- 30456296 TI - The Legal Aspects of Diversity in Academic Pathology. AB - Diversity and inclusion in academic pathology center on building a diverse, inclusive pathology faculty. Understanding the basics of federal law, and the US Supreme Court cases that interpret those laws, allows one to consider good practices in diversity hire recruitment and retention that protects the pathology chair, the pathology department, and the institution. Consideration of inclusion and unconscious bias are helpful in building and sustaining robust, valuable academic pathology faculty diversity. PMID- 30456297 TI - The Johns Hopkins Department of Pathology Novel Organizational Model: A 25-Year Old Ongoing Experiment. AB - In 1993, the present Department of Pathology at Johns Hopkins was established with the leadership of a new chair (ie, referred to as department director at Hopkins) and upon the integration of 3 separate and independent departments at the Johns Hopkins School of Medicine (Pathology) and the Johns Hopkins Hospital (Pathology, Laboratory Medicine). This new department was organized into 17 divisions, each of which was expected to develop and maintain significant clinical, educational, and research programs of excellence. To facilitate performance and alignment across missions and parent organizations, a novel professional and administrative structure was created. Professionally, vice chairs (ie, deputy directors) for research, teaching, and patient care were appointed to oversee and coordinate these activities across all units of the department. Likewise, to focus and enhance expertise, individual administrators were appointed for academic, clinical, and business affairs. A departmental executive committee was created consisting of the vice-chairs and administrators, which was presided over by the chair. Simultaneously, substantial effort was put into measuring and improving the organizational culture using evidence-based methods. Significant improvements were documented by the year 2000 in departmental performance in research, education, clinical service, culture, and finances. Under 2 successive leaders, the department has maintained its eminence across missions and financial performance. This 25-year experience supports the tenet that innovative and strategic organizational structures and functional alignments can provide sustainable competitive advantages in performance. PMID- 30456298 TI - mTORC1 is a key mediator of RON-dependent breast cancer metastasis with therapeutic potential. AB - Metastasis is the biggest challenge in treating breast cancer, and it kills >40,000 breast cancer patients annually in the US. Aberrant expression of the RON receptor tyrosine kinase in breast tumors correlates with poor prognosis and has been shown to promote metastasis. However, the molecular mechanisms that govern how RON promotes metastasis, and how to block it, are still largely unknown. We sought to determine critical effectors of RON using a combination of mutational and pharmacologic strategies. High-throughput proteomic analysis of breast cancer cells upon activation of RON showed robust phosphorylation of ribosomal protein S6. Further analysis revealed that RON strongly signals through mTORC1/p70S6K, which is mediated predominantly by the PI3K pathway. A targeted mutation approach to modulate RON signaling validated the importance of PI3K/mTORC1 pathway for spontaneous metastasis in vivo. Finally, inhibition of mTORC1 with an FDA approved drug, everolimus, resulted in transient shrinkage of established RON dependent metastases, and combined blockade of mTORC1 and RON delayed progression. These studies have identified a key downstream mediator of RON dependent metastasis in breast cancer cells and revealed that inhibition of mTORC1, or combined inhibition of mTORC1 and RON, may be effective for treatment of metastatic breast cancers with elevated expression of RON. PMID- 30456299 TI - 21-Gene assay as predictor of chemotherapy benefit in HER2-negative breast cancer. AB - The NSABP B-20 prospective-retrospective study of the 21-gene Oncotype DX Breast Cancer Recurrence Score(r) test predicted benefit from addition of chemotherapy to tamoxifen in node-negative, estrogen-receptor positive breast cancer when recurrence score (RS) was >=31. HER2 is a component of the RS algorithm with a positive coefficient and contributes to higher RS values. Accrual to B-20 occurred prior to routine testing for HER2, so questions have arisen regarding assay performance if HER2-positive patients were identified and excluded. We report an exploratory reanalysis of the B-20, 21-gene study following exclusion of such patients. Patients were considered HER2 positive if quantitative RT-PCR for HER2 was >=11.5 units, and excluded from re-analyses performed using the original cutoffs: <18, 18-30, >=31, and the TAILORx cutoffs: <11, 11-25, >25. The endpoint remained distant recurrence-free interval (DRFI) as in the original study. Distribution was estimated via the Kaplan-Meier method and compared via log-rank test. Multivariate Cox proportional hazards models estimated chemotherapy benefit in each group. In the RS < 18 and 18-30 groups, 1.7 and 6.7% were HER2 positive. In the RS >= 31 group, 41% were HER2 positive. Exclusion resulted in fewer events, with loss of significance for benefit from chemotherapy in the overall HER2-negative cohort (log-rank P = 0.06), but substantial benefit from chemotherapy remained in the RS >= 31 cohort (HR = 0.18; 95% CI: 0.07-0.47) and the RS > 25 cohort (HR = 0.28; 95% CI: 0.12-0.64). No benefit from chemotherapy was evident in the other RS groups. Following exclusion of HER2 positive patients based on RT-PCR expression, substantial benefit of chemotherapy remained for RS >= 31 as originally employed, and with RS > 25 employed in TAILORx. PMID- 30456300 TI - The origin and stability of nanostructural hierarchy in crystalline solids. AB - The structural hierarchy exhibited by materials on more than one length scale can play a major part in determining bulk material properties. Understanding the hierarchical structure can lead to new materials with physical properties tailored for specific applications. We have used a combined experimental and phase-field modeling approach to explore such a hierarchical structure at nanoscale for enhanced coarsening resistance of ordered gamma' precipitates in an experimental, multicomponent, high-refractory nickel-base superalloy. The hierarchical microstructure formed experimentally in this alloy is composed of a gamma matrix with gamma' precipitates that contain embedded, spherical gamma precipitates, which do not directionally coarsen during high-temperature annealing but do delay coarsening of the larger gamma' precipitates. Chemical mapping via atom probe tomography suggests that the supersaturation of Co, Ru, and Re in the gamma' phase is the driving force for the phase separation, leading to the formation of this hierarchical microstructure. Representative phase-field modeling highlights the importance of larger gamma' precipitates to promote stability of the embedded gamma phase and to delay coarsening of the encompassing gamma' precipitates. Our results suggest that the hierarchical material design has the potential to influence the high-temperature stability of precipitate strengthened metallic materials. PMID- 30456301 TI - Label-free imaging of amyloid plaques in Alzheimer's disease with stimulated Raman scattering microscopy. AB - One of the key pathological features of Alzheimer's disease (AD) is the existence of extracellular deposition of amyloid plaques formed with misfolded amyloid-beta (Abeta). The conformational change of proteins leads to enriched contents of beta sheets, resulting in remarkable changes of vibrational spectra, especially the spectral shifts of the amide I mode. Here, we applied stimulated Raman scattering (SRS) microscopy to image amyloid plaques in the brain tissue of an AD mouse model. We have demonstrated the capability of SRS microscopy as a rapid, label free imaging modality to differentiate misfolded from normal proteins based on the blue shift (~10 cm-1) of amide I SRS spectra. Furthermore, SRS imaging of Abeta plaques was verified by antibody staining of frozen thin sections and fluorescence imaging of fresh tissues. Our method may provide a new approach for studies of AD pathology, as well as other neurodegenerative diseases associated with protein misfolding. PMID- 30456302 TI - Multiple-q noncollinear magnetism in an itinerant hexagonal magnet. AB - Multiple-q spin order, i.e., a spin texture characterized by a multiple number of coexisting magnetic modulation vectors q, has recently attracted attention as a source of nontrivial magnetic topology and associated emergent phenomena. One typical example is the triple-q skyrmion lattice state stabilized by Dzyaloshinskii-Moriya interactions in noncentrosymmetric magnets, while the emergence of various multiple-q states of different origins is expected according to the latest theories. Here, we investigated the magnetic structure of the itinerant polar hexagonal magnet Y3Co8Sn4, in which several distinctive mechanisms favoring multiple-q states are allowed to become active. Small-angle neutron-scattering experiments suggest the formation of incommensurate triple-q magnetic order with an in-plane vortex-like spin texture, which can be most consistently explained in terms of the novel four-spin interaction mechanism inherent to itinerant magnets. The present results suggest a new route to realizing exotic multiple-q orders and that itinerant hexagonal magnets, including the R 3 M 8Sn4 family with wide chemical tunability, can be a unique material platform to explore their rich phase diagrams. PMID- 30456303 TI - Minimizing friction, wear, and energy losses by eliminating contact charging. AB - One-fourth of the global energy losses result from friction and wear. Although friction and tribocharging were presented to be mutually related, reduction of friction and wear by eliminating tribocharges on common polymers, and decrease of power losses in devices with polymer parts were not shown to date. Here, we demonstrate that for common polymers, friction-which is strongly related to surface charge density-can be notably reduced by various methods of tribocharge mitigation, namely, corona discharging, solvent treatment, or placing a grounded conductor on the backside of one of the shearing materials. In our simple demonstrations, we found that by preventing tribocharge accumulation, a remarkable two-thirds of power loss during operation of simple mechanical devices with common polymers and plastic parts can be saved and wear can be reduced by a factor of 10. These demonstrations indicate important practical ramifications in mechanical systems with insulating parts. PMID- 30456304 TI - Realization of flat band with possible nontrivial topology in electronic Kagome lattice. AB - The energy dispersion of fermions or bosons vanishes in momentum space if destructive quantum interference occurs in a frustrated Kagome lattice with only nearest-neighbor hopping. A discrete flat band (FB) without any dispersion is consequently formed, promising the emergence of fractional quantum Hall states at high temperatures. Here, we report the experimental realization of an FB with possible nontrivial topology in an electronic Kagome lattice on twisted multilayer silicene. Because of the unique low-buckled two-dimensional structure of silicene, a robust electronic Kagome lattice has been successfully induced by moire patterns after twisting the silicene multilayers. The electrons are localized in the Kagome lattice because of quantum destructive interference, and thus, their kinetic energy is quenched, which gives rise to an FB peak in the density of states. A robust and pronounced one-dimensional edge state has been revealed at the Kagome edge, which resides at higher energy than the FB. Our observations of the FB and the exotic edge state in electronic Kagome lattice open up the possibility that fractional Chern insulators could be realized in two dimensional materials. PMID- 30456305 TI - Practice analysis of junior doctors in Ethiopia: implications for strengthening medical education, practice and regulation. AB - Background: A high performing physician workforce is critical to attain nationally set health sector goals. Ethiopia has expanded training of medical doctors. However, little is known about junior doctors' performance. Understanding medical practice is essential to inform medical education and practice, establish licensure examination and guide workforce management decisions. We conducted a practice analysis study to identify gaps in Ethiopian medical education and practice, and to determine composition of subjects in national licensing examination. Methods: We conducted a cross-sectional study with national representative sample of junior doctors. After calculating a sample size of 198, we used a two-stage stratified cluster sampling method to select study participants. We collected data using a structured questionnaire comprising 222 tasks. Study participants reported in interviews on frequency of, competence at, and importance of doing each task for improved health outcome. We developed proportions, averages, graphs and tables. Using the results of practice analysis and experts' ratings, relative weights of subjects in the national licensing examination for medical undergraduates were determined. Results: A total of 191 junior doctors participated. Most were males (74.6%) and had less than 2 years of experience (69.8%). Junior doctors frequently performed tasks of internal medicine and pediatrics. Their participation in obstetrics and gynecology, ophthalmology, psychiatry and dentistry services was infrequent. Junior doctors had competency gaps to conduct clinical procedures, research and health programming tasks. Practice analysis results and expert ratings generated comparable recommendations for composition of a national licensing examination, with more than three-quarters of the items focusing on internal medicine, pediatrics, surgery, obstetrics and gynecology, and public health. Conclusion: Junior doctors in Ethiopia rarely managed psychiatry, ophthalmology and dental patients. They had competence gaps in clinical procedures, research and health programming skills. The findings have implications for establishing licensing examination, and reviewing curriculum, continuing professional development, placement and rotation policy, and distribution of responsibilities. PMID- 30456306 TI - Acute pancreatitis after major spine surgery: a case report and literature review. AB - Background: Acute pancreatitis has been described as potential complication of both abdominal and non-abdominal surgeries. The pathogenetic mechanism underlying acute pancreatitis in spine surgery may include intraoperative hemodynamic instability causing prolonged splanchnic hypoperfusion, as well as mechanical compression of the pancreas due to scoliosis correction, with a higher risk in cases of more extended fusions, especially in young adults with lower body mass index (BMI). Case presentation: We report here a case of postoperative acute pancreatitis with benign evolution in a young female patient after the first and second surgery of a two-stage correction of right thoracic idiopathic scoliosis.In December 2017, the patient underwent first-stage T4-L3 posterior arthrodesis with T7-T12 osteotomies and temporary magnetic bar. Intraoperative blood loss required massive transfusion. In the immediate postoperative period, the patient started reporting nausea/vomiting, abdominal pain at pressure, moderate meteorism, abdominal distension, hypoactive bowel sounds, and fever. Laboratory tests indicated a progressive increase in aspartate aminotransferase, alanine aminotransferase, serum amylase, lipase, phospho-creatine kinase, and reactive C-protein. A CT scan showed free abundant abdominal fluid in the hepatic, renal, pancreatic, and pelvic regions. After the diagnosis, a hypolipidic diet was initiated, and good hydration per os was maintained. After gastroenterologic consultation, somatostatin, rifaximin, and ursodehoxycholic acid were initiated and maintained for 8 days. In the following days, laboratory tests showed a slow but consistent decrease in liver and pancreatic enzymes until normalization. In January 2018, the patient underwent second-stage surgery with removal of magnetic bar, definitive posterior fusion, and instrumentation T4-L3. Laboratory tests showed a second, even more significant, increase in the amylase and lipase level and a moderate increase in the reactive C-protein. Therapy was maintained until complete normalization of amylase and lipase levels. Conclusions: Early recognition of symptoms plays a key role in preventing severe morbidity after scoliosis surgery. When symptoms suggest abdominal complication, pancreatic and liver enzymes are to be evaluated for posing prompt diagnosis. Gastroenterologic consultation and eventual imaging are further steps in differential diagnosis and treatment of this rare complication. PMID- 30456307 TI - Retraction Note: Brace classification study group (BCSG): part one - definitions and atlas. AB - [This retracts the article DOI: 10.1186/s13013-016-0102-y.]. PMID- 30456309 TI - Spotlight on early-career researchers: an interview with Jelena Baranovic. AB - Jelena Baranovic began her independent career at University of Edinburgh in September 2018. In this short Q&A she tells us about her experience as an early career researcher, the advice she would give to her younger self, and the lessons learned from studying ion channel physiology, for both biology and career development. PMID- 30456308 TI - Transcriptomic analysis of hepatocellular carcinoma reveals molecular features of disease progression and tumor immune biology. AB - Hepatocellular carcinoma (HCC) develops in the context of chronic inflammatory liver disease and has an extremely poor prognosis. An immunosuppressive tumor microenvironment may contribute to therapeutic failure in metastatic HCC. Here, we identified unique molecular signatures pertaining to HCC disease progression and tumor immunity by analyzing genome-wide RNA-Seq data derived from HCC patient tumors and non-tumor cirrhotic tissues. Unsupervised clustering of gene expression data revealed a gradual suppression of local tumor immunity that coincided with disease progression, indicating an increasingly immunosuppressive tumor environment during HCC disease advancement. IHC examination of the spatial distribution of CD8+ T cells in tumors revealed distinct intra- and peri-tumoral subsets. Differential gene expression analysis revealed an 85-gene signature that was significantly upregulated in the peri-tumoral CD8+ T cell-excluded tumors. Notably, this signature was highly enriched with components of underlying extracellular matrix, fibrosis, and epithelial-mesenchymal transition (EMT). Further analysis condensed this signature to a core set of 23 genes that are associated with CD8+ T cell localization, and were prospectively validated in an independent cohort of HCC specimens. These findings suggest a potential association between elevated fibrosis, possibly modulated by TGF-beta, PDGFR, SHH or Notch pathway, and the T cell-excluded immune phenotype. Indeed, targeting fibrosis using a TGF-beta neutralizing antibody in the STAMTM model of murine HCC, we found that ameliorating the fibrotic environment could facilitate redistribution of CD8+ lymphocytes into tumors. Our results provide a strong rationale for utilizing immunotherapies in HCC earlier during treatment, potentially in combination with anti-fibrotic therapies. PMID- 30456310 TI - Combining multimodal adaptive optics imaging and angiography improves visualization of human eyes with cellular-level resolution. AB - Visualizing the cellular manifestation of disease has recently been aided by an increasing number of adaptive optics (AO)-based imaging modalities developed for the living human eye. However, simultaneous visualization of multiple, interacting cell types within a complete neural-epithelial-vascular complex has proven challenging. By incorporating AO with indocyanine green angiography, we demonstrate the possibility of imaging photoreceptors, retinal pigment epithelial cells, and choriocapillaris in the living human eye. Unexpectedly, we found that there was uptake of indocyanine green dye into the retinal pigment epithelial cells in the earliest phases of imaging, which formed the basis for devising a strategy to visualize the choriocapillaris. Our results expand the range of applications for an existing, FDA-approved, systemically injected fluorescent dye. The combined multimodal approach can be used to evaluate the complete outer retinal complex at the cellular level, a transformative step toward revealing the in vivo cellular status of neurodegenerative conditions and blinding diseases. PMID- 30456311 TI - Adult Antarctic krill proves resilient in a simulated high CO2 ocean. AB - Antarctic krill (Euphausia superba) have a keystone role in the Southern Ocean, as the primary prey of Antarctic predators. Decreases in krill abundance could result in a major ecological regime shift, but there is limited information on how climate change may affect krill. Increasing anthropogenic carbon dioxide (CO2) emissions are causing ocean acidification, as absorption of atmospheric CO2 in seawater alters ocean chemistry. Ocean acidification increases mortality and negatively affects physiological functioning in some marine invertebrates, and is predicted to occur most rapidly at high latitudes. Here we show that, in the laboratory, adult krill are able to survive, grow, store fat, mature, and maintain respiration rates when exposed to near-future ocean acidification (1000 2000 MUatm pCO2) for one year. Despite differences in seawater pCO2 incubation conditions, adult krill are able to actively maintain the acid-base balance of their body fluids in near-future pCO2, which enhances their resilience to ocean acidification. PMID- 30456312 TI - IFNL4-DeltaG is associated with prostate cancer among men at increased risk of sexually transmitted infections. AB - Sexually transmitted infections can reach the prostate gland where their harmful effects are mediated by innate immunity, including interferons. Humans are polymorphic for the germline dinucleotide variant, rs368234815-TT/DeltaG, in the IFNL4 gene encoding interferon lambda4. Since the IFNL4-DeltaG allele has been linked to impaired viral clearance, we hypothesized that potential exposure to sexually transmitted pathogens, as assessed by the number of lifetime sexual partners, may increase prostate cancer risk in an IFNL4-DeltaG-dependent manner. Accordingly, we find that men with 10 or more sexual partners and at least one copy of IFNL4-DeltaG have a significantly increased risk of prostate cancer while those with the same number of partners but lacking IFNL4-DeltaG do not. Moreover, a test for effect modification shows a positive interaction between the number of lifetime partners and IFNL4-DeltaG in the development of aggressive prostate cancer. Based on these findings, we conclude that a gene-environment interaction between IFNL4-DeltaG and sexual activity may increase the risk of prostate cancer. PMID- 30456313 TI - Trapping intermediates in metal transfer reactions of the CusCBAF export pump of Escherichia coli. AB - Escherichia coli CusCBAF represents an important class of bacterial efflux pump exhibiting selectivity towards Cu(I) and Ag(I). The complex is comprised of three proteins: the CusA transmembrane pump, the CusB soluble adaptor protein, and the CusC outer-membrane pore, and additionally requires the periplasmic metallochaperone CusF. Here we used spectroscopic and kinetic tools to probe the mechanism of copper transfer between CusF and CusB using selenomethionine labeling of the metal-binding Met residues coupled to RFQ-XAS at the Se and Cu edges. The results indicate fast formation of a protein-protein complex followed by slower intra-complex metal transfer. An intermediate coordinated by ligands from each protein forms in 100 ms. Stopped-flow fluorescence of the capping CusF W44 tryptophan that is quenched by metal transfer also supports this mechanism. The rate constants validate a process in which shared-ligand complex formation assists protein association, providing a driving force that raises the rate into the diffusion-limited regime. PMID- 30456314 TI - RanBP2 regulates the anti-retroviral activity of TRIM5alpha by SUMOylation at a predicted phosphorylated SUMOylation motif. AB - TRIM5alpha is a cytoplasmic restriction factor that blocks post-entry retroviral infection. Evidence suggests that its antiviral activity can be regulated by SUMO, but how this is achieved remains unknown. Here, we show that TRIM5alpha forms a complex with RanGAP1, Ubc9, and RanBP2 at the nuclear pore, and that RanBP2 E3 SUMO ligase promotes the SUMOylation of endogenous TRIM5alpha in the cytoplasm. Loss of RanBP2 blocked SUMOylation of TRIM5alpha, altered its localization in primary cells, and suppressed the antiviral activity of both rhesus and human orthologs. In cells, human TRIM5alpha is modified on K84 within a predicted phosphorylated SUMOylation motif (pSUM) and not on K10 as found in vitro. Non-modified TRIM5alpha lacked antiviral activity, indicating that only SUMOylated TRIM5alpha acts as a restriction factor. This work illustrates the importance of the nuclear pore in intrinsic antiviral immunity, acting as a hub where virus, SUMO machinery, and restriction factors can meet. PMID- 30456316 TI - Effects of repetitive transcranial magnetic stimulation on ER stress-related genes and glutamate, gamma-aminobutyric acid and glycine transporter genes in mouse brain. AB - Repetitive transcranial magnetic stimulation (rTMS) is an emerging therapy for the treatment of psychiatric disorders. However, the mechanisms underlying the therapeutic effects of rTMS are still unclear, limiting its optimisation. Lasting effects suggest changes in disease-related genes, so we conducted gene chip and qRT-PCR analyses of genes associated with psychiatric diseases in the mouse brain at various times following 1, 20, 30 or 40 days of rTMS. Many genes were differentially expressed in the rTMS-treated mouse brain compared to sham controls, including genes encoding neurotransmitter transporters (upregulation of EAAT4, GLAST, GLT-1, GAT2, GAT4, GLYT1 and GLYT2), and endoplasmic reticulum (ER) stress proteins (downregulation of IRE1alpha, IRE1beta, and XBP1, upregulation of ATF6 and GRP78/Bip). Expression changes in many of these genes were also observed 10 days after the last rTMS treatment. In PC12 cells, rTMS upregulated GRP78/Bip mRNA and enhanced resistance against H2O2 stress. These results suggest that rTMS differentially modulates multiple genes associated with psychiatric and neurodegenerative disorders. Sustained changes in the expression of these genes may underlie the therapeutic efficacy of chronic rTMS. PMID- 30456318 TI - Paraneoplastic PRES from lymphoma induced hypercalcemia: Case report and review of the literature. AB - Hypercalcemia from tumors has been associated with Posterior Reversible Encephalopathy Syndrome (PRES) but the mechanism remains unclear. In this article, we describe a case of PRES caused by hypercalcemia from lymphoma. We summarize the available scientific evidence linking hypercalcemia to failure of cerebral autoregulation and potentially PRES. A major link is the hypomagnesemia induced by hypercalcemia. While this concept requires further clinical testing and validation, it is clinically significant for the management of PRES, even when not directly caused by hypercalcemia. PMID- 30456317 TI - Ano-rectal wall dose-surface maps localize the dosimetric benefit of hydrogel rectum spacers in prostate cancer radiotherapy. AB - Background and purpose: To evaluate spatial differences in dose distributions of the ano-rectal wall (ARW) using dose-surface maps (DSMs) between prostate cancer patients receiving intensity-modulated radiation therapy with and without implantable rectum spacer (IMRT+IRS; IMRT-IRS, respectively), and to correlate this with late gastro-intestinal (GI) toxicities using validated spatial and non spatial normal-tissue complication probability (NTCP) models. Materials and methods: For 26 patients DSMs of the ARW were generated. From the DSMs various shape-based dose measures were calculated at different dose levels: lateral extent, longitudinal extent, and eccentricity. The contiguity of the ARW dose distribution was assessed by the contiguous-DSH (cDSH). Predicted complication rates between IMRT+IRS and IMRT-IRS plans were assessed using a spatial NTCP model and compared against a non-spatial NTCP model. Results: Dose surface maps are generated for prostate radiotherapy using an IRS. Lateral extent, longitudinal extent and cDSH were significantly lower in IMRT+IRS than for IMRT IRS at high-dose levels. Largest significant differences were observed for cDSH at dose levels >50 Gy, followed by lateral extent at doses >57 Gy, and longitudinal extent in anterior and superior-inferior directions. Significant decreases (p = 0.01) in median rectal and anal NTCPs (respectively, Gr 2 late rectal bleeding and subjective sphincter control) were predicted when using an IRS. Conclusions: Local-dose effects are predicted to be significantly reduced by an IRS. The spatial NTCP model predicts a significant decrease in Gr 2 late rectal bleeding and subjective sphincter control. Dose constraints can be improved for current clinical treatment planning. PMID- 30456315 TI - Improved reference genome for the domestic horse increases assembly contiguity and composition. AB - Recent advances in genomic sequencing technology and computational assembly methods have allowed scientists to improve reference genome assemblies in terms of contiguity and composition. EquCab2, a reference genome for the domestic horse, was released in 2007. Although of equal or better quality compared to other first-generation Sanger assemblies, it had many of the shortcomings common to them. In 2014, the equine genomics research community began a project to improve the reference sequence for the horse, building upon the solid foundation of EquCab2 and incorporating new short-read data, long-read data, and proximity ligation data. Here, we present EquCab3. The count of non-N bases in the incorporated chromosomes is improved from 2.33 Gb in EquCab2 to 2.41 Gb in EquCab3. Contiguity has also been improved nearly 40-fold with a contig N50 of 4.5 Mb and scaffold contiguity enhanced to where all but one of the 32 chromosomes is comprised of a single scaffold. PMID- 30456319 TI - A historical argument for regulatory failure in the case of Primodos and other hormone pregnancy tests. AB - The drug Primodos and other hormone pregnancy tests (HPTs) remained on the British market for about a decade after they were first implicated, in 1967, as a possible cause of birth defects. In November 2017, an expert working group (EWG) set up by the Medicines and Healthcare Products Regulatory Agency (MHRA) concluded against such an association. However, it was explicitly 'not within the remit of the EWG to make formal conclusions or recommendations on the historical system or regulatory failures', a situation that has left many stakeholders dissatisfied. Placing the question of a teratogenicity to one side, this article takes a more contextual and comparative approach than was possible under the auspices of MHRA. It asks why an unnecessary and possibly even harmful drug was allowed to remain on the British market when a reliable and perfectly safe alternative existed: urine tests for pregnancy. Based on archival research in several countries, this article builds a historical argument for regulatory failure in the case of HPTs. It concludes that the independent review which campaigners are calling for would have the potential to not only bring them a form of closure, but would also shed light on pressing issues of more general significance regarding risk, regulation and communication between policy makers, medical experts and patients. PMID- 30456320 TI - Production of hollow-type spherical bacterial cellulose as a controlled release device by newly designed floating cultivation. AB - We developed a novel cultivating system for hollow-type spherical bacterial cellulose (HSBC) gel production without any molds or template. It consisted of floating aqueous medium droplet containing Gluconacetobacter xylinus (G. xylinus) at the boundary of two non-mixed silicone oil layers. The fibrils of bacterial cellulose (BC) were produced at the interface of water and oil phases. Fibril layers effectively thickened layer-by-layer and eventually formed a shell structure. The size of the HSBC gel can be controlled by the volume of dropped cell suspension. For cell suspensions of 50 MUL and 10 MUL, HSBC gels of approximately 4.0 mm and 2.5 mm were obtained, respectively. The shell of the HSBC gel is the gelatinous membrane formed by well-organized fibril networks; they comprised type-I crystal structure of cellulose. Additionally, we studied release profile of the fluorescein isothiocyanate-dextran (FITC-Dex) and observed that it released rapidly from the HSBC gels compared to from the BC gels obtained by the static culture method. The release behavior from HSBC gel agreed satisfactorily with Higuchi model. Therefore, the shell of HSBC gel is surely a thin gelatinous membrane of BC, and would be useful as a drug release device. PMID- 30456322 TI - Second law analysis for nonlinear convective flow of a reactive couple stress fluid through a vertical channel. AB - The present article investigates the entropy generation rate in the nonlinear convective flow of a reactive couple stress liquid through a channel filled with saturated materials and subjected to convective cooling. Analytical solutions of the coupled nonlinear boundary-value problems arising from the mathematical formulation are obtained by using the Homotopy Analysis Method (HAM). The analytical solutions are further validated numerically with the fourth order Runge-Kutta (RK4) to establish the accuracy of the method. Velocity, temperature, entropy generation, and heat irreversibility ratio profiles are presented and discussed extensively. The result of the computation shows that entropy generation increases significantly with increasing buoyancy parameter. PMID- 30456321 TI - Acute benzo[a]pyrene treatment causes different antioxidant response and DNA damage in liver, lung, brain, stomach and kidney. AB - Acute effects of oxidative damage induced by benzo[a]pyrene (B[a]P) on various organs are still not clear. In this study, we investigated oxidative stress and DNA damage in liver, lung, stomach, brain and kidney of ICR male mice induced by acute B[a]P treatment. B[a]P treatment led to a significant decrease at the different doses in body weight. For the variations of superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), glutathione (GSH) and GSH/GSSG, significant increases were observed at 24 h, then decreased till 72 h after B[a]P injection. The increase percent indicated in a dose- dependent decrease manner. However, glutathione peroxidase (GPx), GSSG and MDA were significantly increased in a time- and dose-dependent increase manner. DNA damage showed the significant and top levels at 24 h, and increased in proportion to the doses of B[a]P treatment. The total induction could be indicated by the variation of MDA at 24 h after B[a]P injection and showed the following order of predominance: lung > liver > kidney = stomach > brain. This was further certificated by histopathological changes in the examined organs. Additionally, the levels of serum glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), and blood urea nitrogen (UN), creatinine were also significantly increased at 24 h after B[a]P injection. These findings suggested the disturbance of antioxidant responses and aggravation of DNA damages, and the different responses on various organs induced by acute B[a]P treatment in organism. PMID- 30456324 TI - Temporomandibular Joint Internal Derangement Score (TIDS): novel magnetic resonance imaging assessment score and its relation to invasive treatment in patients with clinical temporomandibular joint pathology. AB - Purpose: A new magnetic resonance imaging (MRI) based scoring system for temporomandibular joint (TMJ) internal derangement was developed to predict disease severity and the likelihood of invasive treatment. Patients and methods: Reports and images from bilateral TMJ MRI studies of 100 consecutive patients with TMJ pain were retrospectively reviewed. A Temporomandibular Joint Internal Derangement Score (TIDS) score was composed of 6 MRI characteristics: joint effusion, disc displacement, disc nonrecapture, disc degenerative changes, abnormal condyle translation, and condyle arthritis. The primary endpoint was whether disease severity merited invasive treatment (arthrocentesis, arthroscopy, arthroplasty, or discectomy). Primary analyses were conducted as univariate regression, with the level of significance set at p < .05. Multivariate regression was also used to assess the impacts of each variable upon the need for invasive treatment. Results: Invasive treatment was performed in 29 patients and planned in an additional 9 patients. Patients with clinical bilateral pathology were no more likely to undergo invasive treatment than those with unilateral clinical pathology. Statistically significant correlations were found between bilateral invasive treatment and the presence of bilateral joint effusions (p = 0.0037) and disc displacement (p = 0.014), as well as with increasing values of right TIDS (p = 0.0015) and bilateral TIDS (p = 0.0090). Bilateral TIDS of greater than 6 was correlated with both bilateral invasive treatment (p = 0.0033) and with invasive treatment of any kind (p = 0.041). In each instance of TIDS > 6, the patient demonstrated multiple signs of bilateral TMJ pathology. On multivariate regression, only disc recapture failed to trend towards statistical significance in both the six and twelve component regressions, which trended towards significance only in the twelve component analysis. Conclusion: A TIDS score was developed to serve as an adjunct to the clinical assessment of TMJ pathology. Bilateral TIDS score greater than 6 was statistically significantly correlated with the severity of TMJ pathology. PMID- 30456325 TI - Assessing land use and land cover changes and agricultural farmland expansions in Gambella Region, Ethiopia, using Landsat 5 and Sentinel 2a multispectral data. AB - The pace of change in land use and cover in Ethiopia depends on three main factors that cause pressure on agriculture land: resettlement programmes, population growth and increasing agricultural investments. Gambella is one of the regions of Ethiopia that attracts large-scale agricultural investments that extensively drive land use and cover changes in the region. The aim of this study is to examine the rate, extent and distribution of various land use and cover changes in Gambella Regional State, Ethiopia, from 1987 to 2017. The analysis is mainly based on Landsat 5 and Sentinel 2A satellite images and fieldwork. Two Landsat Thematic Mapper and a Sentinel 2A image were used for determining the maximum likelihood of land use/cover classification. The results show that farmland decreased by 26 km2 from 1987 to 2000; however, during the last two decades, agricultural land area increased by 599 km2, mainly at the cost of tropical grasslands and forests. We found that areas cultivated by smallholder farmers increased by 9.17% from 1987 to 2000. However, small-scale farm activities decreased by 7% from 2000 to 2017. Areas cultivated by large-scale state farms totalled 202 km2 in 1987; but by 2000, this large-scale state farming had been completely abandoned by the state, and as a result, its land use has decreased to zero. Despite this, in 2017 large-scale farming increased to 746 km2. In addition, Gambella National Park, which is the nation's largest national park and ecosystem, was also largely affected by Land Use and Land Cover changes. The conversion of savannah/tropical grasslands to agricultural farmland has caused varied and extensive environmental degradation to the park. The Land Use and Land Cover changes in the Gambella region are discussed on the basis of underlying socioeconomic factors. PMID- 30456323 TI - Recent advancements in compact layer development for perovskite solar cells. AB - Herein, we will present recent progress in the compact layer (CL) or hole blocking layer (HBL) which is known as an important layer and not as an essential layer for perovskite solar cells (PSCs). The CL involves an effective role to enhance efficiency in PSCs. Thus, any change, modification, and replacement in this layer will have a profound effect on the performance and improvement of some characteristics such as photo-stability, durability and hysteresis effect. These changes can improve the applications of PSCs in the flexible cell, industrial mass production, high-scale manufacturing. In this review, we will present recent studies on CLs. PMID- 30456326 TI - A novel approach to the application of hexagonal mesoporous silica in solid-phase extraction of drugs. AB - Mesoporous silica with hexagonal type structure containing amine functional group was introduced. Firstly, aminopropyl hexagonal mesoporous silica was synthetized in a co-condensation process, via templating route of n-dodecylamine. Then synthesized mesoporous material were characterized, and FT-IR spectrum confirmed the presence of amine group and CHN analysis determined the amount of organic layer. The high surface area (750 m2/g) was determined by applying nitrogen adsorption-desorption technique. The morphology was examined by scanning electron microscopy which proved hexagonal structure. The crystallinity of mesoporous material was observed in XRD pattern of this material. According to previous background of such material in adsorbing drug, herein, the efficiency of this material in adsorbing of 5-fluorouracil was evaluated through solid phase extraction method in aqueous and plasma media with high performance liquid chromatography. The extraction efficiency was evaluated for drug concentrations of 500-2000 ng/ml by means of 5-20 mg/ml hexagonal mesoporous silica in both media. The results showed good to excellent recovery rate of in both aqueous and plasma medium which confirmed that the aminopropyl functionalized hexagonal mesoporous silica could be considered as promising device for drug bioanalysis. PMID- 30456327 TI - Lessons learned from two interventions designed to increase adherence to LTBI treatment in Latino youth. AB - : Effort is required to meet the Healthy People 2020 goal of tuberculosis (TB) disease reduction to 1 new case per 100,000 in the United States (US) and reduce burden among those disparately affected. Preventing new cases by reducing conversion from latent TB infection (LTBI) to infectious disease is one approach to reducing disease burden. This paper describes the outcome of a trial designed to determine if LTBI-positive youth prescribed daily Isoniazid with peer counseling would achieve higher adherence than attention control participants. The paper also compares adherence to a previous trial. 263 students age 15.9 years (SD = 1.2), 51.7% female, 96.2% Latino, 43.7% foreign-born were randomly assigned to condition. Adherence was measured by self-report validated by metabolite analysis. Outcome analyses used number of pills taken and proportion of youth consuming 80% of medication. There was no significant difference by condition for either analysis. Thirty-seven percent of adherence participants completed treatment versus 40% of controls. Without a usual-care control group we were unable to determine whether conditions were equally effective or ineffective. The study's inability to pay for treatment resulted in the intervention being tested in the context of compromised access to care. Still to be determined is whether same-age peers can influence adherence among Latino adolescents. Trial registration: ClinicalTrials.gov Identifier NCT00233168. PMID- 30456330 TI - Refueling the Failing Heart: A Case for Sodium-Glucose Cotransporter 2 Inhibition in Cardiac Energy Homeostasis. PMID- 30456329 TI - Empagliflozin Increases Cardiac Energy Production in Diabetes: Novel Translational Insights Into the Heart Failure Benefits of SGLT2 Inhibitors. AB - SGLT2 inhibitors have profound benefits on reducing heart failure and cardiovascular mortality in individuals with type 2 diabetes, although the mechanism(s) of this benefit remain poorly understood. Because changes in cardiac bioenergetics play a critical role in the pathophysiology of heart failure, the authors evaluated cardiac energy production and substrate use in diabetic mice treated with the SGTL2 inhibitor, empagliflozin. Empagliflozin treatment of diabetic db/db mice prevented the development of cardiac failure. Glycolysis, and the oxidation of glucose, fatty acids and ketones were measured in the isolated working heart perfused with 5 mmol/l glucose, 0.8 mmol/l palmitate, 0.5 mmol/l beta-hydroxybutyrate (betaOHB), and 500 MUU/ml insulin. In vehicle-treated db/db mice, cardiac glucose oxidation rates were decreased by 61%, compared with control mice, but only by 43% in empagliflozin-treated diabetic mice. Interestingly, cardiac ketone oxidation rates in db/db mice decreased to 45% of the rates seen in control mice, whereas a similar decrease (43%) was seen in empagliflozin-treated db/db mice. Overall cardiac adenosine triphosphate (ATP) production rates decreased by 36% in db/db vehicle-treated hearts compared with control mice, with fatty acid oxidation providing 42%, glucose oxidation 26%, ketone oxidation 10%, and glycolysis 22% of ATP production in db/db mouse hearts. In empagliflozin-treated db/db mice, cardiac ATP production rates increased by 31% compared with db/db vehicle-treated mice, primarily due to a 61% increase in the contribution of glucose oxidation to energy production. Cardiac efficiency (cardiac work/O2 consumed) decreased by 28% in db/db vehicle-treated hearts, compared with control hearts, and empagliflozin did not increase cardiac efficiency per se. Because ketone oxidation was impaired in db/db mouse hearts, the authors determined whether this contributed to the decrease in cardiac efficiency seen in the db/db mouse hearts. Addition of 600 MUmol/l betaOHB to db/db mouse hearts perfused with 5 mmol/l glucose, 0.8 mmol/l palmitate, and 100 MUU/ml insulin increased ketone oxidation rates, but did not decrease either glucose oxidation or fatty acid oxidation rates. The presence of ketones did not increase cardiac efficiency, but did increase ATP production rates, due to the additional contribution of ketone oxidation to energy production. The authors conclude that empagliflozin treatment is associated with an increase in ATP production, resulting in an enhanced energy status of the heart. PMID- 30456328 TI - Phase II Randomised Controlled Trial of a patient decision-aid website to improve treatment decision-making for young adults with bipolar II disorder: A feasibility study protocol. AB - Background/aims: This paper describes the protocol for a feasibility study for a parallel Phase II randomised control trial (RCT) aiming to evaluate a novel decision-aid website (e-DA) to support young adults with bipolar II disorder (BPII), and their families. Material and methods: The e-DA was developed according to the International Patient Decision-Aid Standards (IPDAS). Participants will be 40 young adults (18-30 years) referred to a specialist outpatient clinical facility, who have a confirmed clinical diagnosis of BPII. Participants will be randomised (1:1) to receive access to the clinic's online factsheets/website with (Intervention) or without (Control) the e-DA. A series of validated and purpose-designed questionnaires will be administered at baseline (T0), immediately post-decision (T1), and 3 months post-decision (T2). Questionnaires assess key decision-making constructs related to decision-making quality, including: decisional conflict, subjective and objective treatment knowledge, values-based informed choice, concordance between preferred/actual decision-making involvement, preparation for decision-making, and decisional regret. Self-report symptom severity and anxiety will ascertain the safety of e DA use. The focus of analyses will be to assess effect sizes, in order to guide a future RCT. Discussion: This feasibility study will evaluate a world first, evidence-based online decision-support resource, a DA website, for young adults with BPII and their families who are deciding on treatment options for relapse prevention. Findings will determine the e-DA's feasibility in RCT procedures (i.e., outpatient clinical setting) and provide estimates of effect sizes on outcomes related to improving treatment decision-making and patient outcomes in a sample of potential end-users, compared to usual care. Trial registration: This trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR) - ACTRN12617000840381. PMID- 30456332 TI - Asynchronous Shortening of Telomere Length and Cardiovascular Outcomes. PMID- 30456331 TI - Cardiac-Referenced Leukocyte Telomere Length and Outcomes After Cardiovascular Surgery. AB - Leukocyte telomere shortening reflects stress burdens and has been associated with cardiac events. However, the patient-specific clinical value of telomere assessment remains unknown. Moreover, telomere shortening cannot be inferred from a single telomere length assessment. The authors investigated and developed a novel strategy for gauging leukocyte telomere shortening using autologous cardiac atrial referencing. Using multitissue assessments from 163 patients who underwent cardiovascular surgery, we determined that the cardiac atrium-leukocyte telomere length difference predicted post-operative complexity. This constituted the first evidence that a single-time assessment of telomere dynamics might be salient to acute cardiac care. PMID- 30456334 TI - Intravenous Infusion of the Novel HNO Donor BMS-986231 Is Associated With Beneficial Inotropic, Lusitropic, and Vasodilatory Properties in 2 Canine Models of Heart Failure. AB - The effects of the nitroxyl donor BMS-986231 on hemodynamics, left ventricular (LV) function, and pro-arrhythmic potential were assessed using canine heart failure models. BMS-986231 significantly (p < 0.05) increased LV end-systolic elastance, pre-load-recruitable stroke work, ejection fraction, stroke volume, cardiac output, ratio of early-to-late filling time integrals, and early mitral valve inflow velocity deceleration time. BMS-986231 significantly decreased LV filling pressures, end-diastolic stiffness, the time-constant of relaxation, end diastolic wall stress, systemic vascular resistance, and myocardial oxygen consumption. BMS-986231 had little effect on heart rate and did not induce de novo arrhythmias. Thus, BMS-986231 has beneficial inotropic, lusitropic, and vasodilatory effects. PMID- 30456333 TI - Hypermethylation of the Micro-RNA 145 Promoter Is the Key Regulator for NLRP3 Inflammasome-Induced Activation and Plaque Formation. AB - Two major issues are involved in clinical atherosclerosis treatment. First, there are no significant clinical markers for early diagnosis of atherosclerosis. Second, the plaque will not regress once it initiates even if the risk factors are removed. In this paper, the research shows that the hypermethylation level of the microRNA 145 (miR-145) promoter is related to a DNMT1 and TET2 dynamic imbalance. The reduction of miR-145 causes NLRP3 (nucleotide-binding oligomerization domain-like receptor protein 3) inflammasome activation through CD137/NFATc1 signaling. These findings could be a potential target for plaque regression in the future. PMID- 30456336 TI - Drugging the Hippo (Pathway): A Strategy to Stimulate Cardiac Regeneration? PMID- 30456335 TI - Discovery of a Small Molecule to Increase Cardiomyocytes and Protect the Heart After Ischemic Injury. AB - Accumulating data suggest that new cardiomyocytes in adults are generated from existing cardiomyocytes throughout life. To enhance the endogenous cardiac regeneration, we performed chemical screenings to identify compounds that activate pro-proliferative YES-associated protein and transcriptional enhancer factor domain activities in cardiomyocytes. We synthesized a novel fluorine containing TT-10 (C11H10FN3OS2) from the biologically hit compound. TT-10 promoted cardiomyocyte proliferation and simultaneously exerted antioxidant and antiapoptotic effects in vitro. TT-10 treatment in mice ameliorated myocardial infarction-induced cardiac dysfunction at least in part via enhancing clonal expansion of existing cardiomyocytes with nuclear YES-associated protein expression. Stimulating cardiomyocyte proliferation and/or protection with TT-10 might complement current therapies for myocardial infarction. PMID- 30456337 TI - Electrical Vagal Nerve Stimulation Ameliorates Pulmonary Vascular Remodeling and Improves Survival in Rats With Severe Pulmonary Arterial Hypertension. AB - This study aimed to elucidate the therapeutic effects of electrical vagal nerve stimulation (VNS) on severe pulmonary arterial hypertension in a rat model. In a pathophysiological study, VNS significantly restored autonomic balance, decreased mean pulmonary arterial pressure, attenuated pulmonary vascular remodeling, and preserved right ventricular function. In a survival study, VNS significantly improved the survival rate in both the prevention (VNS from 0 to 5 weeks after a SU5416 injection) and treatment (VNS from 5 to 10 weeks) protocols. Thus, VNS may serve as a novel therapeutic strategy for pulmonary arterial hypertension. PMID- 30456338 TI - Vagal Nerve Stimulation for Pulmonary Hypertension: Some Promise, Some Skepticism. PMID- 30456339 TI - Novel Mechanistic Roles for Ankyrin-G in Cardiac Remodeling and Heart Failure. AB - Ankyrin polypeptides are intracellular proteins responsible for targeting cardiac membrane proteins. Here, the authors demonstrate that ankyrin-G plays an unexpected role in normal compensatory physiological remodeling in response to myocardial stress and aging; the authors implicate disruption of ankyrin-G in human heart failure. Mechanistically, the authors illustrate that ankyrin-G serves as a key nodal protein required for cardiac myofilament integration with the intercalated disc. Their data define novel in vivo mechanistic roles for ankyrin-G, implicate ankyrin-G as necessary for compensatory cardiac physiological remodeling under stress, and implicate disruption of ankyrin-G in the development and progression of human heart failure. PMID- 30456342 TI - Are Synthetic Data Derivatives the Future of Translational Medicine? PMID- 30456340 TI - Mendelian Randomization Studies Promise to Shorten the Journey to FDA Approval. AB - There has been a dearth of new drugs approved for cardiovascular disorders. The cost is prohibitive, averaging to $2.5 billion, and requiring 12.5 years. This is in large part due to the high failure rate, with only 5% approval by the Food and Drug Administration. Despite preclinical studies showing potential safety and efficacy, most fail when they go to clinical trials phase I to III. One cause for failure is the drug target, often discovered to be a biomarker rather than causative for the disease. Mendelian randomization (MR) studies would determine whether the drug target is causative and could save millions of dollars and time, and prevent unnecessary exposure to adverse drug effects. This was demonstrated in 3 clinical trials that were negative with 2 drugs, veraspladib and darapladib. MR studies during the trials showed the targets of secretory and lipoprotein associated phospholipids A2 are not causative for coronary artery disease and predicted negative results. The requirement for MR studies is a genetic risk variant with altered function, randomized at conception that remains fixed throughout one's lifetime. It is not confounded by dietary, lifestyle, or socioeconomic factors. It is more sensitive than randomized controlled trials because exposure to the risk factor is fixed for a lifetime. MR studies showed plasma high-density lipoprotein cholesterol is not a causative target of coronary artery disease, and neither is uric acid, C-reactive protein, and others. MR studies are highly sensitive in determining whether drug targets are causative, and are relatively easy, inexpensive, and not time consuming. It is recommended that drug targets undergo MR studies before proceeding to randomized controlled trials. PMID- 30456343 TI - MRI analysis to map interstitial flow in the brain tumor microenvironment. AB - Glioblastoma (GBM), a highly aggressive form of brain tumor, is a disease marked by extensive invasion into the surrounding brain. Interstitial fluid flow (IFF), or the movement of fluid within the spaces between cells, has been linked to increased invasion of GBM cells. Better characterization of IFF could elucidate underlying mechanisms driving this invasion in vivo. Here, we develop a technique to noninvasively measure interstitial flow velocities in the glioma microenvironment of mice using dynamic contrast-enhanced magnetic resonance imaging (MRI), a common clinical technique. Using our in vitro model as a phantom "tumor" system and in silico models of velocity vector fields, we show we can measure average velocities and accurately reconstruct velocity directions. With our combined MR and analysis method, we show that velocity magnitudes are similar across four human GBM cell line xenograft models and the direction of fluid flow is heterogeneous within and around the tumors, and not always in the outward direction. These values were not linked to the tumor size. Finally, we compare our flow velocity magnitudes and the direction of flow to a classical marker of vessel leakage and bulk fluid drainage, Evans blue. With these data, we validate its use as a marker of high and low IFF rates and IFF in the outward direction from the tumor border in implanted glioma models. These methods show, for the first time, the nature of interstitial fluid flow in models of glioma using a technique that is translatable to clinical and preclinical models currently using contrast-enhanced MRI. PMID- 30456341 TI - Epigenetics in Cardiac Fibrosis: Emphasis on Inflammation and Fibroblast Activation. AB - Chemical modifications to nucleosomal DNA and histone tails greatly influence transcription of adjacent and distant genes, a mode of gene regulation referred to as epigenetic control. Here, the authors summarize recent findings that have illustrated crucial roles for epigenetic regulatory enzymes and reader proteins in the control of cardiac fibrosis. Particular emphasis is placed on epigenetic regulation of stress-induced inflammation and fibroblast activation in the heart. The potential of developing innovative small molecule "epigenetic therapies" to combat cardiac fibrosis is highlighted. PMID- 30456344 TI - The ER morphology-regulating lunapark protein induces the formation of stacked bilayer discs. AB - Lunapark (Lnp) is a conserved membrane protein that localizes to and stabilizes three-way junctions of the tubular ER network. In higher eukaryotes, phosphorylation of Lnp may contribute to the conversion of the ER from tubules to sheets during mitosis. Here, we report on the reconstitution of purified Lnp with phospholipids. Surprisingly, Lnp induces the formation of stacked membrane discs. Each disc is a bicelle, with Lnp sitting in the bilayer facing both directions. The interaction between bicelles is mediated by the cytosolic domains of Lnp, resulting in a constant distance between the discs. A phosphomimetic Lnp mutant shows reduced bicelle stacking. Based on these results, we propose that Lnp tethers ER membranes in vivo in a cell cycle-dependent manner. Lnp appears to be the first membrane protein that induces the formation of stacked bicelles. PMID- 30456345 TI - CHRAC/ACF contribute to the repressive ground state of chromatin. AB - The chromatin remodeling complexes chromatin accessibility complex and ATP utilizing chromatin assembly and remodeling factor (ACF) combine the ATPase ISWI with the signature subunit ACF1. These enzymes catalyze well-studied nucleosome sliding reactions in vitro, but how their actions affect physiological gene expression remains unclear. Here, we explored the influence of Drosophila melanogaster chromatin accessibility complex/ACF on transcription by using complementary gain- and loss-of-function approaches. Targeting ACF1 to multiple reporter genes inserted at many different genomic locations revealed a context dependent inactivation of poorly transcribed reporters in repressive chromatin. Accordingly, single-embryo transcriptome analysis of an Acf knock-out allele showed that only lowly expressed genes are derepressed in the absence of ACF1. Finally, the nucleosome arrays in Acf-deficient chromatin show loss of physiological regularity, particularly in transcriptionally inactive domains. Taken together, our results highlight that ACF1-containing remodeling factors contribute to the establishment of an inactive ground state of the genome through chromatin organization. PMID- 30456346 TI - BACE2 distribution in major brain cell types and identification of novel substrates. AB - beta-Site APP-cleaving enzyme 1 (BACE1) inhibition is considered one of the most promising therapeutic strategies for Alzheimer's disease, but current BACE1 inhibitors also block BACE2. As the localization and function of BACE2 in the brain remain unknown, it is difficult to predict whether relevant side effects can be caused by off-target inhibition of BACE2 and whether it is important to generate BACE1-specific inhibitors. Here, we show that BACE2 is expressed in discrete subsets of neurons and glia throughout the adult mouse brain. We uncover four new substrates processed by BACE2 in cultured glia: vascular cell adhesion molecule 1, delta and notch-like epidermal growth factor-related receptor, fibroblast growth factor receptor 1, and plexin domain containing 2. Although these substrates were not prominently cleaved by BACE2 in healthy adult mice, proinflammatory TNF induced a drastic increase in BACE2-mediated shedding of vascular cell adhesion molecule 1 in CSF. Thus, although under steady-state conditions the effect of BACE2 cross-inhibition by BACE1-directed inhibitors is rather subtle, it is important to consider that side effects might become apparent under physiopathological conditions that induce TNF expression. PMID- 30456347 TI - Serine catabolism is essential to maintain mitochondrial respiration in mammalian cells. AB - Breakdown of serine by the enzyme serine hydroxymethyltransferase (SHMT) produces glycine and one-carbon (1C) units. These serine catabolites provide important metabolic intermediates for the synthesis of nucleotides, as well as methyl groups for biosynthetic and regulatory methylation reactions. Recently, it has been shown that serine catabolism is required for efficient cellular respiration. Using CRISPR-Cas9 gene editing, we demonstrate that the mitochondrial SHMT enzyme, SHMT2, is essential to maintain cellular respiration, the main process through which mammalian cells acquire energy. We show that SHMT2 is required for the assembly of Complex I of the respiratory chain. Furthermore, supplementation of formate, a bona fide 1C donor, restores Complex I assembly in the absence of SHMT2. Thus, provision of 1C units by mitochondrial serine catabolism is critical for cellular respiration, at least in part by influencing the assembly of the respiratory apparatus. PMID- 30456348 TI - The Arabidopsis homolog of human G3BP1 is a key regulator of stomatal and apoplastic immunity. AB - Mammalian Ras-GTPase-activating protein SH3-domain-binding proteins (G3BPs) are a highly conserved family of RNA-binding proteins that link kinase receptor mediated signaling to RNA metabolism. Mammalian G3BP1 is a multifunctional protein that functions in viral immunity. Here, we show that the Arabidopsis thaliana homolog of human G3BP1 negatively regulates plant immunity. Arabidopsis g3bp1 mutants showed enhanced resistance to the virulent bacterial pathogen Pseudomonas syringae pv. tomato. Pathogen resistance was mediated in Atg3bp1 mutants by altered stomatal and apoplastic immunity. Atg3bp1 mutants restricted pathogen entry into stomates showing insensitivity to bacterial coronatine mediated stomatal reopening. AtG3BP1 was identified as a negative regulator of defense responses, which correlated with moderate up-regulation of salicylic acid biosynthesis and signaling without growth penalty. PMID- 30456349 TI - Pervasive allele-specific regulation on RNA decay in hybrid mice. AB - Cellular RNA abundance is determined by both RNA transcription and decay. Therefore, change in RNA abundance, which can drive phenotypic diversity between different species, could arise from genetic variants affecting either process. However, previous studies in the evolution of RNA expression have been largely focused on transcription. Here, to globally investigate the effects of cis regulatory divergence on RNA decay in mammals for the first time, we quantified allele-specific differences in RNA decay rates (ASD) in an F1 hybrid mouse. Out of 8,815 genes with sufficient data, we identified 621 genes exhibiting significant cis-divergence. Systematic analysis of these genes revealed that the genetic variants affecting microRNA binding and RNA secondary structures contribute to the observed divergences. Finally, we demonstrated that although the divergences in RNA abundance were predominantly determined by allelic differences in RNA transcription, most genes with significant ASD did not exhibit significant difference in RNA abundance. For these genes, the apparently compensatory effect between the allelic differences in RNA transcription and ASD suggests that changes in RNA decay could serve as important means to stabilize RNA abundances during mammalian evolution. PMID- 30456350 TI - Proteomics and C9orf72 neuropathology identify ribosomes as poly-GR/PR interactors driving toxicity. AB - Frontotemporal dementia and amyotrophic lateral sclerosis patients with C9orf72 mutation show cytoplasmic poly-GR and poly-PR aggregates. Short poly-(Gly-Arg) and poly-(Pro-Arg) (poly-GR/PR) repeats localizing to the nucleolus are toxic in various model systems, but no interactors have been validated in patients. Here, the neuronal interactomes of cytoplasmic GFP-(GR)149 and nucleolar (PR)175-GFP revealed overlapping RNA-binding proteins, including components of stress granules, nucleoli, and ribosomes. Overexpressing the poly-GR/PR interactors STAU1/2 and YBX1 caused cytoplasmic aggregation of poly-GR/PR in large stress granule-like structures, whereas NPM1 recruited poly-GR into the nucleolus. Poly PR expression reduced ribosome levels and translation consistent with reduction of synaptic proteins detected by proteomics. Surprisingly, truncated GFP-(GR)53, but not GFP-(GR)149, localized to the nucleolus and reduced ribosome levels and translation similar to poly-PR, suggesting that impaired ribosome biogenesis may be driving the acute toxicity observed in vitro. In patients, only ribosomes and STAU2 co-aggregated with poly-GR/PR. Partial sequestration of ribosomes may chronically impair protein synthesis even in the absence of nucleolar localization and contribute to pathogenesis. PMID- 30456351 TI - Somatic role of SYCE2: an insulator that dissociates HP1alpha from H3K9me3 and potentiates DNA repair. AB - The synaptonemal complex is a proteinaceous structure essential for meiotic recombination, and its components have been assumed to play a role exclusively in the germ line. However, SYCE2, a component constituting the synaptonemal complex, is expressed at varying levels in somatic cells. Considering its potent protein binding activities, it may be possible that SYCE2 plays a somatic role by affecting nuclear functions. Here, we show that SYCE2 constitutively insulates HP1alpha from trimethylated histone H3 lysine 9 (H3K9me3) to promote DNA double strand break repair. Unlike other HP1alpha-binding proteins, which use the canonical PXVXL motifs for their bindings, SYCE2 interacts with the chromoshadow domain of HP1alpha through its N-terminal hydrophobic sequence. SYCE2 reduces HP1alpha-H3K9me3 binding without affecting H3K9me3 levels and potentiates ataxia telangiectasia mutated-mediated double-strand break repair activity even in the absence of exogenous DNA damage. Such a somatic role of SYCE2 is ubiquitously observed even if its expression levels are low. These findings suggest that SYCE2 plays a somatic role in the link between the nuclear microenvironment and the DNA damage response potentials as a scaffold of HP1alpha localization. PMID- 30456353 TI - Neuronal Abeta42 is enriched in small vesicles at the presynaptic side of synapses. AB - The amyloid beta-peptide (Abeta) is a physiological ubiquitously expressed peptide suggested to be involved in synaptic function, long-term potentiation, and memory function. The 42 amino acid-long variant (Abeta42) forms neurotoxic oligomers and amyloid plaques and plays a key role in the loss of synapses and other pathogenic events of Alzheimer disease. Still, the exact localization of Abeta42 in neurons and at synapses has not been reported. Here, we used super resolution microscopy and show that Abeta42 was present in small vesicles in presynaptic compartments, but not in postsynaptic compartments, in the neurites of hippocampal neurons. Some of these vesicles appeared to lack synaptophysin, indicating that they differ from the synaptic vesicles responsible for neurotransmitter release. The Abeta42-containing vesicles existed in presynapses connected to stubby spines and mushroom spines, and were also present in immature presynapses. These vesicles were scarce in other parts of the neurites, where Abeta42 was instead present in large, around 200-600 nm, vesicular structures. Three-dimensional super-resolution microscopy confirmed that Abeta42 was present in the presynapse and absent in the postsynapse. PMID- 30456352 TI - Discovery of a cofactor-independent inhibitor of Mycobacterium tuberculosis InhA. AB - New antitubercular agents are needed to combat the spread of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis. The frontline antitubercular drug isoniazid (INH) targets the mycobacterial enoyl-ACP reductase, InhA. Resistance to INH is predominantly through mutations affecting the prodrug-activating enzyme KatG. Here, we report the identification of the diazaborines as a new class of direct InhA inhibitors. The lead compound, AN12855, exhibited in vitro bactericidal activity against replicating bacteria and was active against several drug-resistant clinical isolates. Biophysical and structural investigations revealed that AN12855 binds to and inhibits the substrate-binding site of InhA in a cofactor-independent manner. AN12855 showed good drug exposure after i.v. and oral delivery, with 53% oral bioavailability. Delivered orally, AN12855 exhibited dose-dependent efficacy in both an acute and chronic murine model of tuberculosis infection that was comparable with INH. Combined, AN12855 is a promising candidate for the development of new antitubercular agents. PMID- 30456355 TI - ERalpha activity depends on interaction and target site corecruitment with phosphorylated CREB1. AB - The two transcription factors estrogen receptor alpha (ERalpha) and cyclic adenosine monophosphate (cAMP)-responsive element binding protein 1 (CREB1) mediate different signals, bind different response elements, and control different transcriptional programs. And yet, results obtained with transfected reporter genes suggested that their activities may intersect. We demonstrate here that CREB1 stimulates and is necessary for ERalpha activity on a transfected reporter gene and several endogenous targets both in response to its cognate ligand estrogen and to ligand-independent activation by cAMP. The stimulatory activity of CREB1 requires its DNA binding and activation by phosphorylation, and affects the chromatin recruitment of ERalpha. CREB1 and ERalpha are biochemically associated and share hundreds to thousands of chromatin binding sites upon stimulation by estrogen and cAMP, respectively. These shared regulatory activities may underlie the anti-apoptotic effects of estrogen and cAMP signaling in ERalpha-positive breast cancer cells. Moreover, high levels of CREB1 are associated with good prognosis in ERalpha-positive breast cancer patients, which may be because of its ability to promote ERalpha functions, thereby maintaining it as a successful therapeutic target. PMID- 30456354 TI - Chronic platelet-derived growth factor receptor signaling exerts control over initiation of protein translation in glioma. AB - Activation of the platelet-derived growth factor receptors (PDGFRs) gives rise to some of the most important signaling pathways that regulate mammalian cellular growth, survival, proliferation, and differentiation and their misregulation is common in a variety of diseases. Herein, we present a comprehensive and detailed map of PDGFR signaling pathways assembled from literature and integrate this map in a bioinformatics protocol designed to extract meaningful information from large-scale quantitative proteomics mass spectrometry data. We demonstrate the usefulness of this approach using a new genetically engineered mouse model of PDGFRalpha-driven glioma. We discovered that acute PDGFRalpha stimulation differs considerably from chronic receptor activation in the regulation of protein translation initiation. Transient stimulation activates several key components of the translation initiation machinery, whereas the clinically relevant chronic activity of PDGFRalpha is associated with a significant shutdown of translational members. Our work defines a step-by-step approach to extract biologically relevant insights from global unbiased phospho-protein datasets to uncover targets for therapeutic assessment. PMID- 30456356 TI - Co-existing feedback loops generate tissue-specific circadian rhythms. AB - Gene regulatory feedback loops generate autonomous circadian rhythms in mammalian tissues. The well-studied core clock network contains many negative and positive regulations. Multiple feedback loops have been discussed as primary rhythm generators but the design principles of the core clock and differences between tissues are still under debate. Here we use global optimization techniques to fit mathematical models to circadian gene expression profiles for different mammalian tissues. It turns out that for every investigated tissue multiple model parameter sets reproduce the experimental data. We extract for all model versions the most essential feedback loops and find auto-inhibitions of period and cryptochrome genes, Bmal1-Rev-erb-alpha loops, and repressilator motifs as possible rhythm generators. Interestingly, the essential feedback loops differ between tissues, pointing to specific design principles within the hierarchy of mammalian tissue clocks. Self-inhibitions of Per and Cry genes are characteristic for models of suprachiasmatic nucleus clocks, whereas in liver models many loops act in synergy and are connected by a repressilator motif. Tissue-specific use of a network of co-existing synergistic feedback loops could account for functional differences between organs. PMID- 30456357 TI - Transcriptional repression by FACT is linked to regulation of chromatin accessibility at the promoter of ES cells. AB - The conserved and essential histone chaperone, facilitates chromatin transcription (FACT), reorganizes nucleosomes during DNA transcription, replication, and repair and ensures both efficient elongation of RNA Pol II and nucleosome integrity. In mammalian cells, FACT is a heterodimer, consisting of SSRP1 and SUPT16. Here, we show that in contrast to yeast, FACT accumulates at the transcription start site of genes reminiscent of RNA polymerase II profile. Depletion of FACT in mouse embryonic stem cells leads to deregulation of developmental and pro-proliferative genes concomitant with hyper-proliferation of mES cells. Using MNase-seq, Assay for Transposase-Accessible Chromatin sequencing, and nascent elongating transcript sequencing, we show that up regulation of genes coincides with loss of nucleosomes upstream of the transcription start site and concomitant increase in antisense transcription, indicating that FACT impacts the promoter architecture to regulate the expression of these genes. Finally, we demonstrate a role for FACT in cell fate determination and show that FACT depletion primes embryonic stem cells for the neuronal lineage. PMID- 30456358 TI - Molecular analysis of human Ero1 reveals novel regulatory mechanisms for oxidative protein folding. AB - Oxidative protein folding in the ER is driven mainly by oxidases of the endoplasmic reticulum oxidoreductin 1 (Ero1) family. Their action is regulated to avoid cell stress, including hyperoxidation. Previously published regulatory mechanisms are based on the rearrangement of active site and regulatory disulfides. In this study, we identify two novel regulatory mechanisms. First, both human Ero1 isoforms exist in a dynamic mixed disulfide complex with protein disulfide isomerase, which involves cysteines (Cys166 in Ero1alpha and Cys165 in Ero1beta) that have previously been regarded as being nonfunctional. Second, our kinetic studies reveal that Ero1 not only has a high affinity for molecular oxygen as the terminal acceptor of electrons but also that there is a high cooperativity of binding (Hill coefficient >3). This allows Ero1 to maintain high activity under hypoxic conditions, without compromising cellular viability under hyper-hypoxic conditions. These data, together with novel mechanistic details of differences in activation between the two human Ero1 isoforms, provide important new insights into the catalytic cycle of human Ero1 and how they have been fine tuned to operate at low oxygen concentrations. PMID- 30456360 TI - Pericytes promote skin regeneration by inducing epidermal cell polarity and planar cell divisions. AB - The cellular and molecular microenvironment of epithelial stem/progenitor cells is critical for their long-term self-renewal. We demonstrate that mesenchymal stem cell-like dermal microvascular pericytes are a critical element of the skin's microenvironment influencing human skin regeneration using organotypic models. Specifically, pericytes were capable of promoting homeostatic skin tissue renewal by conferring more planar cell divisions generating two basal cells within the proliferative compartment of the human epidermis, while ensuring complete maturation of the tissue both spatially and temporally. Moreover, we provide evidence supporting the notion that BMP-2, a secreted protein preferentially expressed by pericytes in human skin, confers cell polarity and planar divisions on epidermal cells in organotypic cultures. Our data suggest that human skin regeneration is regulated by highly conserved mechanisms at play in other rapidly renewing tissues such as the bone marrow and in lower organisms such as Drosophila. Our work also provides the means to significantly improve ex vivo skin tissue regeneration for autologous transplantation. PMID- 30456359 TI - Recruitment of ubiquitin-activating enzyme UBA1 to DNA by poly(ADP-ribose) promotes ATR signalling. AB - The DNA damage response (DDR) ensures cellular adaptation to genotoxic insults. In the crowded environment of the nucleus, the assembly of productive DDR complexes requires multiple protein modifications. How the apical E1 ubiquitin activation enzyme UBA1 integrates spatially and temporally in the DDR remains elusive. Using a human cell-free system, we show that poly(ADP-ribose) polymerase 1 promotes the recruitment of UBA1 to DNA. We find that the association of UBA1 with poly(ADP-ribosyl)ated protein-DNA complexes is necessary for the phosphorylation replication protein A and checkpoint kinase 1 by the serine/threonine protein kinase ataxia-telangiectasia and RAD3-related, a prototypal response to DNA damage. UBA1 interacts directly with poly(ADP-ribose) via a solvent-accessible and positively charged patch conserved in the Animalia kingdom but not in Fungi. Thus, ubiquitin activation can anchor to poly(ADP ribose)-seeded protein assemblies, ensuring the formation of functional ataxia telangiectasia mutated and RAD3-related-signalling complexes. PMID- 30456361 TI - Chromatin-mediated translational control is essential for neural cell fate specification. AB - Neural cell fate specification is a multistep process in which stem cells undergo sequential changes in states, giving rise to particular lineages such as neurons and astrocytes. This process is accompanied by dynamic changes of chromatin and in transcription, thereby orchestrating lineage-specific gene expression programs. A pressing question is how these events are interconnected to sculpt cell fate. We show that altered chromatin due to loss of the chromatin remodeler Chd5 causes neural stem cell activation to occur ahead of time. This premature activation is accompanied by transcriptional derepression of ribosomal subunits, enhanced ribosome biogenesis, and increased translation. These untimely events deregulate cell fate decisions, culminating in the generation of excessive numbers of astrocytes at the expense of neurons. By monitoring the proneural factor Mash1, we further show that translational control is crucial for appropriate execution of cell fate specification, thereby providing new insight into the interplay between transcription and translation at the initial stages of neurogenesis. PMID- 30456362 TI - Proteins of generalist and specialist pathogens differ in their amino acid composition. AB - Pathogens differ in their host specificities, with species infecting a unique host (specialist pathogens) and others having a wide host range (generalists). Molecular determinants of pathogen's host range remain poorly understood. Secreted proteins of generalist pathogens are expected to have a broader range of intermolecular interactions (i.e., higher promiscuity) compared with their specialist counterparts. We hypothesize that this increased promiscuity of generalist secretomes may be based on an elevated content of primitive amino acids and intrinsically disordered regions, as these features are known to increase protein flexibility and interactivity. Here, we measure the proportion of primitive amino acids and percentage of intrinsically disordered residues in secreted, membrane, and cytoplasmic proteins from pathogens with different host specificity. Supporting our prediction, there is a significant general enrichment for primitive amino acids and intrinsically disordered regions in proteins from generalists compared to specialists, particularly among secreted proteins in prokaryotes. Our findings support our hypothesis that secreted proteins' amino acid composition and disordered content influence the pathogens' host range. PMID- 30456363 TI - Beetle luciferases with naturally red- and blue-shifted emission. AB - The different colors of light emitted by bioluminescent beetles that use an identical substrate and chemiexcitation reaction sequence to generate light remain a challenging and controversial mechanistic conundrum. The crystal structures of two beetle luciferases with red- and blue-shifted light relative to the green yellow light of the common firefly species provide direct insight into the molecular origin of the bioluminescence color. The structure of a blue shifted green-emitting luciferase from the firefly Amydetes vivianii is monomeric with a structural fold similar to the previously reported firefly luciferases. The only known naturally red-emitting luciferase from the glow-worm Phrixothrix hirtus exists as tetramers and octamers. Structural and computational analyses reveal varying aperture between the two domains enclosing the active site. Mutagenesis analysis identified two conserved loops that contribute to the color of the emitted light. These results are expected to advance comparative computational studies into the conformational landscape of the luciferase reaction sequence. PMID- 30456364 TI - Vnn1 pantetheinase limits the Warburg effect and sarcoma growth by rescuing mitochondrial activity. AB - Like other tumors, aggressive soft tissue sarcomas (STS) use glycolysis rather than mitochondrial oxidative phosphorylation (OXPHOS) for growth. Given the importance of the cofactor coenzyme A (CoA) in energy metabolism, we investigated the impact of Vnn1 pantetheinase-an enzyme that degrades pantetheine into pantothenate (vitamin B5, the CoA biosynthetic precursor) and cysyteamine-on tumor growth. Using two models, we show that Vnn1+ STS remain differentiated and grow slowly, and that in patients a detectable level of VNN1 expression in STS is associated with an improved prognosis. Increasing pantetheinase activity in aggressive tumors limits their growth. Using combined approaches, we demonstrate that Vnn1 permits restoration of CoA pools, thereby maintaining OXPHOS. The simultaneous production of cysteamine limits glycolysis and release of lactate, resulting in a partial inhibition of STS growth in vitro and in vivo. We propose that the Warburg effect observed in aggressive STS is reversed by induction of Vnn1 pantetheinase and the rewiring of cellular energy metabolism by its products. PMID- 30456365 TI - Immunoediting is not a primary transformation event in a murine model of MLL-ENL AML. AB - Although it is firmly established that endogenous immunity can prevent cancer outgrowth, with a range of immunomodulatory strategies reaching clinical use, most studies on the topic have been restricted to solid cancers. This applies in particular to cancer initiation, where model constraints have precluded investigations of immunosurveillance and immunoediting during the multistep progression into acute myeloid leukemia (AML). Here, we used a mouse model where the chimeric transcription factor MLL-ENL can be conditionally activated in vivo as a leukemic "first-hit," which is followed by spontaneous transformation into AML. We observed similar disease kinetics regardless of whether AML developed in WT or immunocompromised hosts, despite more permissive preleukemic environments in the latter. When assessing transformed AML cells from either primary immunocompetent or immunocompromised hosts, AML cells from all sources could be targets of endogenous immunity. Our data argue against immunoediting in response to selective pressure from endogenous immunity as a universal primary transformation event in AML. PMID- 30456366 TI - RNase E cleavage shapes the transcriptome of Rhodobacter sphaeroides and strongly impacts phototrophic growth. AB - Bacteria adapt to changing environmental conditions by rapid changes in their transcriptome. This is achieved not only by adjusting rates of transcription but also by processing and degradation of RNAs. We applied TIER-Seq (transiently inactivating an endoribonuclease followed by RNA-Seq) for the transcriptome-wide identification of RNase E cleavage sites and of 5' RNA ends, which are enriched when RNase E activity is reduced in Rhodobacter sphaeroides. These results reveal the importance of RNase E for the maturation and turnover of mRNAs, rRNAs, and sRNAs in this guanine-cytosine-rich alpha-proteobacterium, some of the latter have well-described functions in the oxidative stress response. In agreement with this, a role of RNase E in the oxidative stress response is demonstrated. A remarkably strong phenotype of a mutant with reduced RNase E activity was observed regarding the formation of photosynthetic complexes and phototrophic growth, whereas there was no effect on chemotrophic growth. PMID- 30456367 TI - Role of Cnot6l in maternal mRNA turnover. AB - Removal of poly(A) tail is an important mechanism controlling eukaryotic mRNA turnover. The major eukaryotic deadenylase complex CCR4-NOT contains two deadenylase components, CCR4 and CAF1, for which mammalian CCR4 is encoded by Cnot6 or Cnot6l paralogs. We show that Cnot6l apparently supplies the majority of CCR4 in the maternal CCR4-NOT in mouse, hamster, and bovine oocytes. Deletion of Cnot6l yielded viable mice, but Cnot6l -/- females exhibited ~40% smaller litter size. The main onset of the phenotype was post-zygotic: fertilized Cnot6l -/- eggs developed slower and arrested more frequently than Cnot6l +/- eggs, suggesting that maternal CNOT6L is necessary for accurate oocyte-to-embryo transition. Transcriptome analysis revealed major transcriptome changes in Cnot6l -/- ovulated eggs and one-cell zygotes. In contrast, minimal transcriptome changes in preovulatory Cnot6l -/- oocytes were consistent with reported Cnot6l mRNA dormancy. A minimal overlap between transcripts sensitive to decapping inhibition and Cnot6l loss suggests that decapping and CNOT6L-mediated deadenylation selectively target distinct subsets of mRNAs during oocyte-to embryo transition in mouse. PMID- 30456368 TI - JIP2 haploinsufficiency contributes to neurodevelopmental abnormalities in human pluripotent stem cell-derived neural progenitors and cortical neurons. AB - Phelan-McDermid syndrome (also known as 22q13.3 deletion syndrome) is a syndromic form of autism spectrum disorder and currently thought to be caused by heterozygous loss of SHANK3. However, patients most frequently present with large chromosomal deletions affecting several additional genes. We used human pluripotent stem cell technology and genome editing to further dissect molecular and cellular mechanisms. We found that loss of JIP2 (MAPK8IP2) may contribute to a distinct neurodevelopmental phenotype in neural progenitor cells (NPCs) affecting neuronal maturation. This is most likely due to a simultaneous down regulation of c-Jun N-terminal kinase (JNK) proteins, leading to impaired generation of mature neurons. Furthermore, semaphorin signaling appears to be impaired in patient NPCs and neurons. Pharmacological activation of neuropilin receptor 1 (NRP1) rescued impaired semaphorin pathway activity and JNK expression in patient neurons. Our results suggest a novel disease-specific mechanism involving the JIP/JNK complex and identify NRP1 as a potential new therapeutic target. PMID- 30456369 TI - Neuron-specific inactivation of Wt1 alters locomotion in mice and changes interneuron composition in the spinal cord. AB - Locomotion is coordinated by neuronal circuits of the spinal cord. Recently, dI6 neurons were shown to participate in the control of locomotion. A subpopulation of dI6 neurons expresses the Wilms tumor suppressor gene Wt1. However, the function of Wt1 in these cells is not understood. Here, we aimed to identify behavioral changes and cellular alterations in the spinal cord associated with Wt1 deletion. Locomotion analyses of mice with neuron-specific Wt1 deletion revealed a slower walk with a decreased stride frequency and an increased stride length. These mice showed changes in their fore-/hindlimb coordination, which were accompanied by a loss of contralateral projections in the spinal cord. Neonates with Wt1 deletion displayed an increase in uncoordinated hindlimb movements and their motor neuron output was arrhythmic with a decreased frequency. The population size of dI6, V0, and V2a neurons in the developing spinal cord of conditional Wt1 mutants was significantly altered. These results show that the development of particular dI6 neurons depends on Wt1 expression and that loss of Wt1 is associated with alterations in locomotion. PMID- 30456370 TI - The histone chaperone FACT modulates nucleosome structure by tethering its components. AB - Human FAcilitates Chromatin Transcription (hFACT) is a conserved histone chaperone that was originally described as a transcription elongation factor with potential nucleosome assembly functions. Here, we show that FACT has moderate tetrasome assembly activity but facilitates H2A-H2B deposition to form hexasomes and nucleosomes. In the process, FACT tethers components of the nucleosome through interactions with H2A-H2B, resulting in a defined intermediate complex comprising FACT, a histone hexamer, and DNA. Free DNA extending from the tetrasome then competes FACT off H2A-H2B, thereby promoting hexasome and nucleosome formation. Our studies provide mechanistic insight into how FACT may stabilize partial nucleosome structures during transcription or nucleosome assembly, seemingly facilitating both nucleosome disassembly and nucleosome assembly. PMID- 30456371 TI - Dynamic m6A methylation facilitates mRNA triaging to stress granules. AB - Reversible post-transcriptional modifications on messenger RNA emerge as prevalent phenomena in RNA metabolism. The most abundant among them is N6 methyladenosine (m6A) which is pivotal for RNA metabolism and function; its role in stress response remains elusive. We have discovered that in response to oxidative stress, transcripts are additionally m6A modified in their 5' vicinity. Distinct from that of the translationally active mRNAs, this methylation pattern provides a selective mechanism for triaging mRNAs from the translatable pool to stress-induced stress granules. These stress-induced newly methylated sites are selectively recognized by the YTH domain family 3 (YTHDF3) "reader" protein, thereby revealing a new role for YTHDF3 in shaping the selectivity of stress response. Our findings describe a previously unappreciated function for RNA m6A modification in oxidative-stress response and expand the breadth of physiological roles of m6A. PMID- 30456373 TI - Distinctive features of lincRNA gene expression suggest widespread RNA independent functions. AB - Eukaryotic genomes produce RNAs lacking protein-coding potential, with enigmatic roles. We integrated three approaches to study large intervening noncoding RNA (lincRNA) gene functions. First, we profiled mouse embryonic stem cells and neural precursor cells at single-cell resolution, revealing lincRNAs expressed in specific cell types, cell subpopulations, or cell cycle stages. Second, we assembled a transcriptome-wide atlas of nuclear lincRNA degradation by identifying targets of the exosome cofactor Mtr4. Third, we developed a reversible depletion system to separate the role of a lincRNA gene from that of its RNA. Our approach distinguished lincRNA loci functioning in trans from those modulating local gene expression. Some genes express stable and/or abundant lincRNAs in single cells, but many prematurely terminate transcription and produce lincRNAs rapidly degraded by the nuclear exosome. This suggests that besides RNA-dependent functions, lincRNA loci act as DNA elements or through transcription. Our integrative approach helps distinguish these mechanisms. PMID- 30456374 TI - Atomic force microscopy reveals structural variability amongst nuclear pore complexes. AB - The nuclear pore complex (NPC) is a proteinaceous assembly that regulates macromolecular transport into and out of the nucleus. Although the structure of its scaffold is being revealed in increasing detail, its transport functionality depends upon an assembly of intrinsically disordered proteins (called FG-Nups) anchored inside the pore's central channel, which have hitherto eluded structural characterization. Here, using high-resolution atomic force microscopy, we provide a structural and nanomechanical analysis of individual NPCs. Our data highlight the structural diversity and complexity at the nuclear envelope, showing the interplay between the lamina network, actin filaments, and the NPCs. It reveals the dynamic behaviour of NPC scaffolds and displays pores of varying sizes. Of functional importance, the NPC central channel shows large structural diversity, supporting the notion that FG-Nup cohesiveness is in a range that facilitates collective rearrangements at little energetic cost. Finally, different nuclear transport receptors are shown to interact in qualitatively different ways with the FG-Nups, with particularly strong binding of importin-beta. PMID- 30456372 TI - Transformation-induced stress at telomeres is counteracted through changes in the telomeric proteome including SAMHD1. AB - Telomeres play crucial roles during tumorigenesis, inducing cellular senescence upon telomere shortening and extensive chromosome instability during telomere crisis. However, it has not been investigated if and how cellular transformation and oncogenic stress alter telomeric chromatin composition and function. Here, we transform human fibroblasts by consecutive transduction with vectors expressing hTERT, the SV40 early region, and activated H-RasV12. Pairwise comparisons of the telomeric proteome during different stages of transformation reveal up-regulation of proteins involved in chromatin remodeling, DNA repair, and replication at chromosome ends. Depletion of several of these proteins induces telomere fragility, indicating their roles in replication of telomeric DNA. Depletion of SAMHD1, which has reported roles in DNA resection and homology-directed repair, leads to telomere breakage events in cells deprived of the shelterin component TRF1. Thus, our analysis identifies factors, which accumulate at telomeres during cellular transformation to promote telomere replication and repair, resisting oncogene-borne telomere replication stress. PMID- 30456376 TI - Loss of HDAC11 ameliorates clinical symptoms in a multiple sclerosis mouse model. AB - Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease of the central nervous system (CNS). There is no known cure for MS, and currently available drugs for managing this disease are only effective early on and have many adverse side effects. Results from recent studies suggest that histone deacetylase (HDAC) inhibitors may be useful for the treatment of autoimmune and inflammatory diseases such as MS. However, the underlying mechanisms by which HDACs influence immune-mediated diseases such as MS are unclear. More importantly, the question of which specific HDAC(s) are suitable drug targets for the potential treatment of MS remains unanswered. Here, we investigate the functional role of HDAC11 in experimental autoimmune encephalomyelitis, a mouse model for MS. Our results indicate that the loss of HDAC11 in KO mice significantly reduces clinical severity and demyelination of the spinal cord in the post-acute phase of experimental autoimmune encephalomyelitis. The absence of HDAC11 leads to reduced immune cell infiltration into the CNS and decreased monocytes and myeloid DCs in the chronic progressive phase of the disease. Mechanistically, HDAC11 controls the expression of the pro-inflammatory chemokine C-C motif ligand 2 (CCL2) gene by enabling the binding of PU.1 transcription factor to the CCL2 promoter. Our results reveal a novel pathophysiological function for HDAC11 in CNS demyelinating diseases, and warrant further investigations into the potential use of HDAC11-specific inhibitors for the treatment of chronic progressive MS. PMID- 30456375 TI - Small RNA-Seq reveals novel miRNAs shaping the transcriptomic identity of rat brain structures. AB - In the central nervous system (CNS), miRNAs are involved in key functions, such as neurogenesis and synaptic plasticity. Moreover, they are essential to define specific transcriptomes in tissues and cells. However, few studies were performed to determine the miRNome of the different structures of the rat CNS, although a major model in neuroscience. Here, we determined by small RNA-Seq, the miRNome of the olfactory bulb, the hippocampus, the cortex, the striatum, and the spinal cord and showed the expression of 365 known miRNAs and 90 novel miRNAs. Differential expression analysis showed that several miRNAs were specifically enriched/depleted in these CNS structures. Transcriptome analysis by mRNA-Seq and correlation based on miRNA target predictions suggest that the specifically enriched/depleted miRNAs have a strong impact on the transcriptomic identity of the CNS structures. Altogether, these results suggest the critical role played by these enriched/depleted miRNAs, in particular the novel miRNAs, in the functional identities of CNS structures. PMID- 30456378 TI - Laminin gamma1 C-terminal Glu to Gln mutation induces early postimplantation lethality. AB - Laminin-integrin interactions regulate various adhesion-dependent cellular processes. gamma1C-Glu, the Glu residue in the laminin gamma1 chain C-terminal tail, is crucial for the binding of gamma1-laminins to several integrin isoforms. Here, we investigated the impact of gamma1C Glu to Gln mutation on gamma1-laminin binding to all possible integrin partners in vitro, and found that the mutation specifically ablated binding to alpha3, alpha6, and alpha7 integrins. To examine the physiological significance of gamma1C-Glu, we generated a knock-in allele, Lamc1 EQ , in which the gamma1C Glu to Gln mutation was introduced. Although Lamc1 EQ/EQ homozygotes developed into blastocysts and deposited laminins in their basement membranes, they died just after implantation because of disordered extraembryonic development. Given the impact of the Lamc1 EQ allele on embryonic development, we developed a knock-in mouse strain enabling on-demand introduction of the gamma1C Glu to Gln mutation by the Cre-loxP system. The present study has revealed a crucial role of gamma1C-Glu-mediated integrin binding in postimplantation development and provides useful animal models for investigating the physiological roles of laminin-integrin interactions in vivo. PMID- 30456379 TI - S-phase transcriptional buffering quantified on two different promoters. AB - Imaging of transcription by quantitative fluorescence-based techniques allows the examination of gene expression kinetics in single cells. Using a cell system for the in vivo visualization of mammalian mRNA transcriptional kinetics at single gene resolution during the cell cycle, we previously demonstrated a reduction in transcription levels after replication. This phenomenon has been described as a homeostasis mechanism that buffers mRNA transcription levels with respect to the cell cycle stage and the number of transcribing alleles. Here, we examined how transcriptional buffering enforced during S phase affects two different promoters, the cytomegalovirus promoter versus the cyclin D1 promoter, that drive the same gene body. We found that global modulation of histone modifications could completely revert the transcription down-regulation imposed during replication. Furthermore, measuring these levels of transcriptional activity in fixed and living cells showed that the transcriptional potential of the genes was significantly higher than actual transcription levels, suggesting that promoters might normally be limited from reaching their full transcriptional potential. PMID- 30456377 TI - Dynamic reorganisation of intermediate filaments coordinates early B-cell activation. AB - During B-cell activation, the dynamic reorganisation of the cytoskeleton is crucial for multiple cellular responses, such as receptor signalling, cell spreading, antigen internalisation, intracellular trafficking, and antigen presentation. However, the role of intermediate filaments (IFs), which represent a major component of the mammalian cytoskeleton, is not well defined. Here, by using multiple super-resolution microscopy techniques, including direct stochastic optical reconstruction microscopy, we show that IFs in B cells undergo drastic reorganisation immediately upon antigen stimulation and that this reorganisation requires actin and microtubules. Although the loss of vimentin in B cells did not impair B-cell development, receptor signalling, and differentiation, vimentin-deficient B cells exhibit altered positioning of antigen-containing and lysosomal associated membrane protein 1 (LAMP1+) compartments, implying that vimentin may play a role in the fine-tuning of intracellular trafficking. Indeed, vimentin-deficient B cells exhibit impaired antigen presentation and delayed antibody responses in vivo. Thus, our study presents a new perspective on the role of IFs in B-cell activation. PMID- 30456380 TI - Identification of Plasmodium GAPDH epitopes for generation of antibodies that inhibit malaria infection. AB - Plasmodium sporozoite liver infection is an essential step for parasite development in its mammalian host. Previously, we used a phage display library to identify mimotope peptides that bind to Kupffer cells and competitively inhibit sporozoite-Kupffer cell interaction. These peptides led to the identification of a Kupffer cell receptor-CD68-and a Plasmodium sporozoite ligand-GAPDH-that are required for sporozoite traversal of Kupffer cells and subsequent infection of hepatocytes. Here, we report that the C-terminal end of Plasmodium GAPDH interacts with the Kupffer CD68 receptor, and identify two epitopes within this region as candidate antigens for the development of antibodies that inhibit Plasmodium infection. PMID- 30456382 TI - Secretory granule protein chromogranin B (CHGB) forms an anion channel in membranes. AB - Regulated secretion is an intracellular pathway that is highly conserved from protists to humans. Granin family proteins were proposed to participate in the biogenesis, maturation and release of secretory granules in this pathway. However, the exact molecular mechanisms underlying the intracellular functions of the granin family proteins remain unclear. Here, we show that chromogranin B (CHGB), a secretory granule protein, inserts itself into membrane and forms a chloride-conducting channel. CHGB interacts strongly with phospholipid membranes through two amphipathic alpha helices. At a high local concentration, CHGB insertion in membrane causes significant bilayer remodeling, producing protein coated nanoparticles and nanotubules. Fast kinetics and high cooperativity for anion efflux from CHGB vesicles suggest that CHGB tetramerizes to form a functional channel with a single-channel conductance of ~125 pS (150/150 mM Cl-). The CHGB channel is sensitive to an anion channel blocker and exhibits higher anion selectivity than the other six known families of Cl- channels. Our data suggest that the CHGB subfamily of granin proteins forms a new family of organelle chloride channels. PMID- 30456381 TI - CARM1 methylates MED12 to regulate its RNA-binding ability. AB - The coactivator-associated arginine methyltransferase (CARM1) functions as a regulator of transcription by methylating a diverse array of substrates. To broaden our understanding of CARM1's mechanistic actions, we sought to identify additional substrates for this enzyme. To do this, we generated CARM1 substrate motif antibodies, and used immunoprecipitation coupled with mass spectrometry to identify cellular targets of CARM1, including mediator complex subunit 12 (MED12) and the lysine methyltransferase KMT2D. Both of these proteins are implicated in enhancer function. We identified the major CARM1-mediated MED12 methylation site as arginine 1899 (R1899), which interacts with the Tudor domain-containing effector molecule, TDRD3. Chromatin immunoprecipitation-seq studies revealed that CARM1 and the methyl mark it deposits are tightly associated with ERalpha specific enhancers and positively modulate transcription of estrogen-regulated genes. In addition, we showed that the methylation of MED12, at the R1899 site, and the recruitment of TDRD3 by this methylated motif are critical for the ability of MED12 to interact with activating noncoding RNAs. PMID- 30456384 TI - MBNL1 alternative splicing isoforms play opposing roles in cancer. AB - The extent of and the oncogenic role played by alternative splicing (AS) in cancer are well documented. Nonetheless, only few studies have attempted to dissect individual gene function at an isoform level. Here, we focus on the AS of splicing factors during prostate cancer progression, as these factors are known to undergo extensive AS and have the potential to affect hundreds of downstream genes. We identified exon 7 (ex7) in the MBNL1 (Muscleblind-like 1) transcript as being the most differentially included exon in cancer, both in cell lines and in patients' samples. In contrast, MBNL1 overall expression was down-regulated, consistently with its described role as a tumor suppressor. This observation holds true in the majority of cancer types analyzed. We first identified components associated to the U2 splicing complex (SF3B1, SF3A1, and PHF5A) as required for efficient ex7 inclusion and we confirmed that this exon is fundamental for MBNL1 protein homodimerization. We next used splice-switching antisense oligonucleotides (AONs) or siRNAs to compare the effect of MBNL1 splicing isoform switching with knockdown. We report that whereas the absence of MBNL1 is tolerated in cancer cells, the expression of isoforms lacking ex7 (MBNL1 Deltaex7) induces DNA damage and inhibits cell viability and migration, acting as dominant negative proteins. Our data demonstrate the importance of studying gene function at the level of alternative spliced isoforms and support our conclusion that MBNL1 Deltaex7 proteins are antisurvival factors with a defined tumor suppressive role that cancer cells tend to down-regulate in favor of MBNL +ex7 isoforms. PMID- 30456383 TI - Ribosomal stalling landscapes revealed by high-throughput inverse toeprinting of mRNA libraries. AB - Although it is known that the amino acid sequence of a nascent polypeptide can impact its rate of translation, dedicated tools to systematically investigate this process are lacking. Here, we present high-throughput inverse toeprinting, a method to identify peptide-encoding transcripts that induce ribosomal stalling in vitro. Unlike ribosome profiling, inverse toeprinting protects the entire coding region upstream of a stalled ribosome, making it possible to work with random or focused transcript libraries that efficiently sample the sequence space. We used inverse toeprinting to characterize the stalling landscapes of free and drug bound Escherichia coli ribosomes, obtaining a comprehensive list of arrest motifs that were validated in vivo, along with a quantitative measure of their pause strength. Thanks to the modest sequencing depth and small amounts of material required, inverse toeprinting provides a highly scalable and versatile tool to study sequence-dependent translational processes. PMID- 30456385 TI - Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N terminus of USP1. AB - The Fanconi anemia pathway for DNA interstrand crosslink repair and the translesion synthesis pathway for DNA damage tolerance both require cycles of monoubiquitination and deubiquitination. The ubiquitin-specific protease-1 (USP1), in complex with USP1-associated factor 1, regulates multiple DNA repair pathways by deubiquitinating monoubiquitinated Fanconi anemia group D2 protein (FANCD2), Fanconi anemia group I protein (FANCI), and proliferating cell nuclear antigen (PCNA). Loss of USP1 activity gives rise to chromosomal instability. Whereas many USPs hydrolyse ubiquitin-ubiquitin linkages, USP1 targets ubiquitin substrate conjugates at specific sites. The molecular basis of USP1's specificity for multiple substrates is poorly understood. Here, we reconstitute deubiquitination of purified monoubiquitinated FANCD2, FANCI, and PCNA and show that molecular determinants for substrate deubiquitination by USP1 reside within the highly conserved and extended N-terminus. We found that the N-terminus of USP1 harbours a FANCD2-specific binding sequence required for deubiquitination of K561 on FANCD2. In contrast, the N-terminus is not required for direct PCNA or FANCI deubiquitination. Furthermore, we show that the N-terminus of USP1 is sufficient to engineer specificity in a more promiscuous USP. PMID- 30456386 TI - LATS1 and LATS2 suppress breast cancer progression by maintaining cell identity and metabolic state. AB - Deregulated activity of LArge Tumor Suppressor (LATS) tumor suppressors has broad implications on cellular and tissue homeostasis. We examined the consequences of down-regulation of either LATS1 or LATS2 in breast cancer. Consistent with their proposed tumor suppressive roles, expression of both paralogs was significantly down-regulated in human breast cancer, and loss of either paralog accelerated mammary tumorigenesis in mice. However, each paralog had a distinct impact on breast cancer. Thus, LATS2 depletion in luminal B tumors resulted in metabolic rewiring, with increased glycolysis and reduced peroxisome proliferator-activated receptor gamma (PPARgamma) signaling. Furthermore, pharmacological activation of PPARgamma elicited LATS2-dependent death in luminal B-derived cells. In contrast, LATS1 depletion augmented cancer cell plasticity, skewing luminal B tumors towards increased expression of basal-like features, in association with increased resistance to hormone therapy. Hence, these two closely related paralogs play distinct roles in protection against breast cancer; tumors with reduced expression of either LATS1 or LATS2 may rewire signaling networks differently and thus respond differently to anticancer treatments. PMID- 30456388 TI - Transposon silencing in the Drosophila female germline is essential for genome stability in progeny embryos. AB - The Piwi-interacting RNA pathway functions in transposon control in the germline of metazoans. The conserved RNA helicase Vasa is an essential Piwi-interacting RNA pathway component, but has additional important developmental functions. Here, we address the importance of Vasa-dependent transposon control in the Drosophila female germline and early embryos. We find that transient loss of vasa expression during early oogenesis leads to transposon up-regulation in supporting nurse cells of the fly egg-chamber. We show that elevated transposon levels have dramatic consequences, as de-repressed transposons accumulate in the oocyte where they cause DNA damage. We find that suppression of Chk2-mediated DNA damage signaling in vasa mutant females restores oogenesis and egg production. Damaged DNA and up-regulated transposons are transmitted from the mother to the embryos, which sustain severe nuclear defects and arrest development. Our findings reveal that the Vasa-dependent protection against selfish genetic elements in the nuage of nurse cell is essential to prevent DNA damage-induced arrest of embryonic development. PMID- 30456387 TI - Interaction modulation through arrays of clustered methyl-arginine protein modifications. AB - Systematic analysis of human arginine methylation identifies two distinct signaling modes; either isolated modifications akin to canonical post translational modification regulation, or clustered arrays within disordered protein sequence. Hundreds of proteins contain these methyl-arginine arrays and are more prone to accumulate mutations and more tightly expression-regulated than dispersed methylation targets. Arginines within an array in the highly methylated RNA-binding protein synaptotagmin binding cytoplasmic RNA interacting protein (SYNCRIP) were experimentally shown to function in concert, providing a tunable protein interaction interface. Quantitative immunoprecipitation assays defined two distinct cumulative binding mechanisms operating across 18 proximal arginine glycine (RG) motifs in SYNCRIP. Functional binding to the methyltransferase PRMT1 was promoted by continual arginine stretches, whereas interaction with the methyl binding protein SMN1 was arginine content-dependent irrespective of linear position within the unstructured region. This study highlights how highly repetitive modifiable amino acid arrays in low structural complexity regions can provide regulatory platforms, with SYNCRIP as an extreme example how arginine methylation leverages these disordered sequences to mediate cellular interactions. PMID- 30456391 TI - Phosphorylation of Arp2 is not essential for Arp2/3 complex activity in fission yeast. AB - LeClaire et al presented evidence that phosphorylation of three sites on the Arp2 subunit activates the Arp2/3 complex to nucleate actin filaments. We mutated the homologous residues of Arp2 (Y198, T233, and T234) in the fission yeast genome to amino acids that preclude or mimic phosphorylation. Arp2/3 complex is essential for the viability of fission yeast, yet strains unable to phosphorylate these sites grew normally. Y198F/T233A/T234A Arp2 was only nonfunctional if GFP-tagged, as observed by LeClaire et al in Drosophila cells. Replacing both T233 and T234 with aspartic acid was lethal, suggesting that phosphorylation might be inhibitory. Nevertheless, blocking phosphorylation at these sites had the same effect as mimicking it: slowing assembly of endocytic actin patches. Mass spectrometry revealed phosphorylation at a fourth conserved Arp2 residue, Y218, but both blocking and mimicking phosphorylation of Y218 only slowed actin patch assembly slightly. Therefore, phosphorylation of Y198, T233, T234, and Y218 is not required for the activity of fission yeast Arp2/3 complex. PMID- 30456389 TI - The crystal structure of Staufen1 in complex with a physiological RNA sheds light on substrate selectivity. AB - During mRNA localization, RNA-binding proteins interact with specific structured mRNA localization motifs. Although several such motifs have been identified, we have limited structural information on how these interact with RNA-binding proteins. Staufen proteins bind structured mRNA motifs through dsRNA-binding domains (dsRBD) and are involved in mRNA localization in Drosophila and mammals. We solved the structure of two dsRBDs of human Staufen1 in complex with a physiological dsRNA sequence. We identified interactions between the dsRBDs and the RNA sugar-phosphate backbone and direct contacts of conserved Staufen residues to RNA bases. Mutating residues mediating nonspecific backbone interactions only affected Staufen function in Drosophila when in vitro binding was severely reduced. Conversely, residues involved in base-directed interactions were required in vivo even when they minimally affected in vitro binding. Our work revealed that Staufen can read sequence features in the minor groove of dsRNA and suggests that these influence target selection in vivo. PMID- 30456392 TI - Substrate fluxes in brown adipocytes upon adrenergic stimulation and uncoupling protein 1 ablation. AB - Brown adipocytes are highly specialized cells with the unique metabolic ability to dissipate chemical energy in the form of heat. We determined and inferred the flux of a number of key catabolic metabolites, their changes in response to adrenergic stimulation, and the dependency on the presence of the thermogenic uncoupling protein 1 and/or oxidative phosphorylation. This study provides reference values to approximate flux rates from a limited set of measured parameters in the future and thereby allows to evaluate the plausibility of claims about the capacity of metabolic adaptations or manipulations. From the resulting model, we delineate that in brown adipocytes (1) free fatty acids are a significant contributor to extracellular acidification, (2) glycogen is the dominant glycolytic substrate source in the acute response to an adrenergic stimulus, and (3) the futile cycling of free fatty acids between lipolysis and re esterification into triglyceride provides a mechanism for uncoupling protein 1 independent, non-shivering thermogenesis in brown adipocytes. PMID- 30456390 TI - Disruption of stromal hedgehog signaling initiates RNF5-mediated proteasomal degradation of PTEN and accelerates pancreatic tumor growth. AB - The contribution of the tumor microenvironment to pancreatic ductal adenocarcinoma (PDAC) development is currently unclear. We therefore examined the consequences of disrupting paracrine Hedgehog (HH) signaling in PDAC stroma. Herein, we show that ablation of the key HH signaling gene Smoothened (Smo) in stromal fibroblasts led to increased proliferation of pancreatic tumor cells. Furthermore, Smo deletion resulted in proteasomal degradation of the tumor suppressor PTEN and activation of oncogenic protein kinase B (AKT) in fibroblasts. An unbiased proteomic screen identified RNF5 as a novel E3 ubiquitin ligase responsible for degradation of phosphatase and tensin homolog (PTEN) in Smo-null fibroblasts. Ring Finger Protein 5 (Rnf5) knockdown or pharmacological inhibition of glycogen synthase kinase 3beta (GSKbeta), the kinase that marks PTEN for ubiquitination, rescued PTEN levels and reversed the oncogenic phenotype, identifying a new node of PTEN regulation. In PDAC patients, low stromal PTEN correlated with reduced overall survival. Mechanistically, PTEN loss decreased hydraulic permeability of the extracellular matrix, which was reversed by hyaluronidase treatment. These results define non-cell autonomous tumor promoting mechanisms activated by disruption of the HH/PTEN axis and identifies new targets for restoring stromal tumor-suppressive functions. PMID- 30456394 TI - Effect of traditional and modern culinary processing, bioaccessibility, biosafety and bioavailability of eritadenine, a hypocholesterolemic compound from edible mushrooms. AB - Eritadenine is a hypocholesterolemic compound that is found in several mushroom species such as Lentinula edodes, Marasmius oreades, and Amanita caesarea (1.4, 0.7 and 0.6 mg per g dry weight, respectively). It was synthesized during all developmental stages, being present in higher concentrations in the skin of shiitake fruiting bodies. When subjected to traditional cooking, grilling followed by frying were more adequate methodologies than boiling or microwaving to maintain its levels. Modern culinary processes such as texturization (with agar-agar) and spherification (with alginate) also interfered with its release. Grilling and gelling using gelatin enhanced eritadenine's bioaccessibility in an in vitro digestion model. An animal model (where male and female rats were administered 21 and 10 mg per kg animal per day of eritadenine) indicated that intake of the compound was safe under these concentrations; it reached the liver and reduced the atherogenic index (TC/HDL) in rat sera. Thus, it might be used to design a functional food. PMID- 30456395 TI - Metal-free difunctionalization of alkynes leading to alkenyl dithiocyanates and alkenyl diselenocyanates at room temperature. AB - A simple and practical method for the synthesis of alkenyl dithiocyanates and alkenyl diselenocyanates has been developed via stereoselective difunctionalization of alkynes with NaSCN or KSeCN at room temperature. Through this methodology, a series of alkenyl dithiocyanates and alkenyl diselenocyanates could be efficiently and conveniently obtained in moderate to good yields under mild and metal-free conditions by the simple use of oxone and PhI(OAc)2 as the oxidants. PMID- 30456396 TI - Confinement of aqueous mixtures of ionic liquids between amorphous TiO2 slit nanopores: electrostatic field induction. AB - Electrostatic potential in the vicinity of the surface is induced when aqueous mixtures of hydrophobic and hydrophilic ionic liquids (ILs) are confined between a slit nanopore of amorphous but not crystalline TiO2 semiconductors. According to our molecular dynamics (MD) simulations, the extent of ion-pairing lifetime under such nanoscale confinement is substantially lower than its value in the bulk. It becomes still lower when aqueous mixtures of ionic liquid electrolytes are used. Ion-ion correlation is broken completely in the confined dilute aqueous electrolyte systems. The anions and cations of the ILs migrate and accumulate at the opposite amorphous TiO2 electrodes that are separated by 10 nm to arrange a nanosize pore. In contrast, we have shown that the electrostatic interactions between the IL ions are dominant when the electrolyte is confined between anatase (101) TiO2. A similar trend is observed for the inorganic electrolyte system. These findings shed light on the design of new cells for electrochemical applications. PMID- 30456393 TI - Plk1 regulates spindle orientation by phosphorylating NuMA in human cells. AB - Proper orientation of the mitotic spindle defines the correct division plane and is essential for accurate cell division and development. In metazoans, an evolutionarily conserved complex comprising of NuMA/LGN/Galphai regulates proper orientation of the mitotic spindle by orchestrating cortical dynein levels during metaphase. However, the molecular mechanisms that modulate the spatiotemporal dynamics of this complex during mitosis remain elusive. Here, we report that acute inactivation of Polo-like kinase 1 (Plk1) during metaphase enriches cortical levels of dynein/NuMA/LGN and thus influences spindle orientation. We establish that this impact of Plk1 on cortical levels of dynein/NuMA/LGN is through NuMA, but not via dynein/LGN. Moreover, we reveal that Plk1 inhibition alters the dynamic behavior of NuMA at the cell cortex. We further show that Plk1 directly interacts and phosphorylates NuMA. Notably, NuMA-phosphorylation by Plk1 impacts its cortical localization, and this is needed for precise spindle orientation during metaphase. Overall, our finding connects spindle-pole pool of Plk1 with cortical NuMA and answers a long-standing puzzle about how spindle-pole Plk1 gradient dictates proper spindle orientation for error-free mitosis. PMID- 30456397 TI - Mechanism of nitrones and allenoates cascade reactions for the synthesis of dihydro[1,2-a]indoles. AB - Quantum mechanical calculations (DLPNO-CCSD(T) and dispersion-corrected DFT) are employed to gain insights into the mechanism and selectivity in the catalytic synthesis of dihydropyrido[1,2-a]indoles from the cascade reaction between nitrones and allenes. Implications for controlling diverging pathways is discussed. PMID- 30456398 TI - Selective nitrogen doping of graphene oxide by laser irradiation for enhanced hydrogen evolution activity. AB - Selective nitrogen-doping of graphene oxide with a high pyridinic N ratio (51%; L GO) was achieved by laser irradiation of graphene oxide with ammonia. The resulting L-GO exhibited enhanced electrocatalytic properties; specifically, the overpotential of the hydrogen evolution reaction (HER) was improved by over 400 mV at 10 mA cm-2 compared to the pristine graphene oxide. PMID- 30456399 TI - Spin state engineered ZnxCo3-xO4 as an efficient oxygen evolution electrocatalyst. AB - Oxygen evolution is the key step in the oxidation of water in electrolyzers and photoelectrochemical cells for the production of hydrogen. Developing a non precious metal oxide catalyst with good electrocatalytic activity for the oxygen evolution reaction (OER) is very challenging. In this work, nanostructured ZnxCo3 xO4 has been shown as an efficient catalyst with a low overpotential for the OER in 0.1 M KOH solution. Substitution of Co2+ in the spinel oxide Co3O4 with Zn2+ creates a higher number of high-spin Co3+, which is found to be directly correlated with the OER activity of ZnxCo3-xO4. Zn0.8Co2.2O4 (x = 0.8) with the optimum amount of Co2+/Co3+ and high-spin Co3+ content showed a very low overpotential of ~250 mV, at 10 mA cm-2, with a turnover frequency of ~3 * 10-3 s 1 for the OER. The high Faradaic efficiency along with the stability of Zn0.8Co2.2O4 and electrocatalytic activity comparable with that of precious metal oxides indicate that this composition is a promising catalyst for water oxidation. PMID- 30456400 TI - Phase transition and superconductivity in ReS2, ReSe2 and ReTe2. AB - Transition metal dichalcogenides have attracted significant attention due to both fundamental interest and their potential applications. Here, we have systematically explored the crystal structures of ReX2 (X = S, Se, and Te) over the pressure range of 0-300 GPa, employing swarm-intelligence-based structure prediction methodology. Several new structures are found to be stable at high pressures. The calculated enthalpy of formation suggested that all predicted high pressure structures are stable against decomposition into elemental end-members. Moreover, we found that the simulated X-ray diffraction patterns of ReSe2 are in good agreement with experimental data. Pressure-induced metallization of ReX2 has been revealed from the analysis of its electronic structure. Our electron-phonon coupling calculations indicate ReSe2 and ReTe2 are superconducting phases at high pressures. PMID- 30456401 TI - Cationic abnormal N-heterocyclic carbene ruthenium complexes as suitable precursors for the synthesis of heterobimetallic compounds. AB - The cationic abnormal N-heterocyclic carbene complex [Ru(OAc)(dppe)(PC)]Br (2b) (PC = bidentate phosphine-carbene ligand) has been obtained by treatment of the neutral derivative RuBr(OAc)(PPh3)(PC) (2a) with dppe in THF. Reaction of 2b with Ag2O afforded the heterobimetallic complex Ru(OAc)(dppe)(PC)AgBr (2c) which can be easily transmetallated with [Ir(cod)Cl]2 giving Ru(OAc)(dppe)(PC)IrCl(cod) (2d). Similarly, [{Ru(OAc)(PC)(PC')}2Ag][AgBr2] (1b) reacts with [Ir(cod)Cl]2 with formation of Ru(OAc)(PC)(PC')IrCl(cod) (1e). All complexes were characterized by NMR in solution and by single crystal X-ray diffraction studies in solid state. For the cationic complexes the 1H NMR resonance of the carbene proton is considerably down-field shifted (delta > 9 ppm) with respect to that of the neutral derivatives. Cyclic voltammetry and differential pulse voltammetry studies show that the Ru-centered redox process occurs at lower potential (DeltaE > 100 mV) after transmetallation with iridium, suggesting an interaction of the two metals along the pi-system of the heterocycle ligand. These complexes display catalytic activity in transfer hydrogenation of acetophenone in 2-propanol with a significant influence of Ir and Ag centers on the Ru moiety. The synthesis of the imidazolyl-based N-heterocyclic dicarbene Ru-Ir complexes, which entails the easy metallation of the reactive cationic abnormal N-heterocyclic carbene Ru complexes with Ag2O, represents a suitable pathway for the preparation of heterometallic ruthenium complexes. PMID- 30456402 TI - Copper based coordination polymers based on metalloligands: utilization as heterogeneous oxidation catalysts. AB - This work presents the synthesis and characterization of two Cu(ii)-based coordination polymers prepared by utilizing two different Co(iii)-based metalloligands offering appended arylcarboxylic acid groups. Both coordination polymers are three-dimensional in nature and present pores and channels filled with water molecules. Both coordination polymers function as heterogeneous catalysts for the epoxidation of various olefins using O2 while employing isobutyraldehyde as the coreductor and for peroxide-mediated oxidation of assorted benzyl alcohols. The catalytic results illustrate efficient oxidation reactions, whereas the hot-fltration test and leaching experiments indicate the true heterogeneous nature of the catalysis. PMID- 30456403 TI - Azide-tagged sphingolipids for the proteome-wide identification of C16-ceramide binding proteins. AB - Ceramide plays key roles in autophagy, inflammation and apoptosis. However, little is known about the molecular mechanisms regulating its function and only a handful of cellular effectors are known for this lipid. Here we show that azide tagged sphingolipids are powerful tools to identify ceramide targets. The combination of a protein array analysis and a mass spectrometry-based proteomic profiling successfully detects known ceramide-binding proteins and identifies others not yet reported, several of which we validated using a variety of techniques. PMID- 30456404 TI - Phase transformation in two-dimensional covalent organic frameworks under compressive loading. AB - As a new class of two-dimensional (2D) materials, 2D covalent organic frameworks (COFs) are proven to possess remarkable electronic and magnetic properties. However, their mechanical behaviours remain almost unexplored. In this work, taking the recently synthesised dimethylmethylene-bridged triphenylamine (DTPA) sheet as an example, we investigate the mechanical behaviours of 2D COFs based on molecular dynamics simulations together with density functional theory calculations. A novel phase transformation is observed in DTPA sheets when a relatively large in-plane compressive strain is applied to them. Specifically, the crystal structures of the transformed phases are topographically different when the compressive loading is applied in different directions. The compression induced phase transformation in DTPA sheets is attributed to the buckling of their kagome lattice structures and is found to have significant impacts on their material properties. After the phase transformation, Young's modulus, band gap and thermal conductivity of DTPA sheets are greatly reduced and become strongly anisotropic. Moreover, a large in-plane negative Poisson's ratio is found in the transformed phases of DTPA sheets. It is expected that the results of the compression-induced phase transformation and its influence on the material properties observed in the present DTPA sheets can be further extended to other 2D COFs, since most 2D COFs are found to possess a similar kagome lattice structure. PMID- 30456405 TI - Influence of hydrocolloids (galactomannan and xanthan gum) on the physicochemical and sensory characteristics of gluten-free cakes based on fava beans (Phaseolus lunatus). AB - Most gluten-free bakery formulations have starch sources of low nutritional value. The objective of this work was to use fava beans (Phaseolus lunatus) for the production of gluten-free sponge cakes, in addition to evaluating the effects of the partial substitution of fava bean flour by galactomannan and xanthan gum, isolated or mixed at 0.5 and 1.0% proportions, compared with a commercial reference. The properties such as viscosity, specific gravity and microscopy of the air bubbles were evaluated in the raw cakes, while the cooked cakes were analyzed according to physicochemical (chemical composition, specific volume, texture and color) and sensorial properties. Hydrocolloids increased the viscosity, specific gravity, and incorporation of air into the batters. Xanthan gum increased the cakes' firmness after cooking; in what concerns color parameters, hydrocolloids did not interfere. Cakes based on fava beans had better sensory acceptance with or without the presence of hydrocolloids and presented higher levels of moisture, proteins, lipids and ashes when compared to the commercial reference, proving to be an excellent food option without gluten and high nutritional value. PMID- 30456406 TI - Above room temperature spin crossover in thioamide-functionalised 2,6-bis(pyrazol 1-yl)pyridine iron(ii) complexes. AB - This work describes the synthesis of two novel functionalised 2,6-bis(pyrazol-1 yl)pyridine (bpp) ligands, namely 2,6-bis(pyrazol-1-yl)pyridine-4-carbothioamide (bppCSNH2) and N-methyl-2,6-bis(pyrazol-1-yl)pyridine-4-carbothioamide (bppCSNHMe). The corresponding solvated or non-solvated Fe(ii) salts, [Fe(bppCSNH2)2]X2 and [Fe(bppCSNHMe)2]X2 (X = BF4- or ClO4-) were synthesised and their properties measured by SQUID magnetometry, Evans NMR, differential scanning calorimetry and single crystal X-ray diffraction. In the solid state [Fe(bppCSNH2)2]2+ salts persist in the low spin state below 350 K. The structure of [Fe(bppCSNH2)2](BF4)2.2MeNO2 shows a network of intermolecular interactions responsible for the low spin state stabilisation, relative to the prototypical [Fe(bpp)2]2+ spin crossover (SCO) salts. By contrast the complexes of bppCSNHMe both display abrupt SCO above 300 K. [Fe(bppCSNHMe)2](BF4)2.MeNO2 requires solvent loss before SCO can be observed centred at 332 K. The non-solvated [Fe(bppCSNHMe)2](ClO4)2 shows SCO centred at 325 K. Analysis of solvated and non solvated crystal structures suggests that cooperativity is facilitated by thioamide-group interactions with neighbouring pyrazolyl and pyridyl moieties. PMID- 30456407 TI - Diffusiophoretic design of self-spinning microgears from colloidal microswimmers. AB - The development of strategies to assemble microscopic machines from dissipative building blocks are essential on the route to novel active materials. We recently demonstrated the hierarchical self-assembly of phoretic microswimmers into self spinning microgears and their synchronization by diffusiophoretic interactions [Aubret et al., Nat. Phys., 2018]. In this paper, we adopt a pedagogical approach and expose our strategy to control self-assembly and build machines using phoretic phenomena. We notably introduce Highly Inclined Laminated Optical sheets microscopy (HILO) to image and characterize anisotropic and dynamic diffusiophoretic interactions, which cannot be performed by conventional fluorescence microscopy. The dynamics of a (haematite) photocatalytic material immersed in (hydrogen peroxide) fuel under various illumination patterns is first described and quantitatively rationalized by a model of diffusiophoresis, the migration of a colloidal particle in a concentration gradient. It is further exploited to design phototactic microswimmers that direct towards the high intensity of light, as a result of the reorientation of the haematite in a light gradient. We finally show the assembly of self-spinning microgears from colloidal microswimmers and carefully characterize the interactions using HILO techniques. The results are compared with analytical and numerical predictions and agree quantitatively, stressing the important role played by concentration gradients induced by chemical activity to control and design interactions. Because the approach described hereby is generic, this works paves the way for the rational design of machines by controlling phoretic phenomena. PMID- 30456408 TI - Hemiaminal ether linkages provide a selective release of payloads from polymer conjugates. AB - We introduce here hemiaminal ether linkages, synthesized by coupling a vinyl ether and a 1,2,3-triazole, as responsive groups in polymers to allow the selective release of a functional molecule. The release kinetics of benzotriazole from polymer nanoparticles shows a fast release at low pH values and a prolonged or even no release under mildly acidic conditions and at neutral pH. PMID- 30456409 TI - Bare versus protected tetrairidium clusters by density functional theory. AB - The tetrairidium (Ir4) clusters are subnanometric systems vastly applied in catalysis, especially, because of the higher activity than mononuclear Ir complexes, intrinsic and controllable stability in relation to supports, and non coalescence properties. The main catalytic properties of nanoclusters (activity and selectivity) are directly associated with their size, shape, and interactions with the environment, whose understanding requires study at the atomistic level. Here, the Ir4 clusters are studied considering the energetic stability for different chemical environments, bare versus protected, using density functional theory calculations within the generalized gradient approximation with van der Waals corrections and spin-orbit coupling, employing the all-electron projected augmented wave method. The square planar isomer is confirmed for the bare case as the lowest energy configuration considering semilocal and non-local exchange correlation functionals, however, for different chemical environments (Ir4 protected by CO, O2, PH3, and SH2 ligands) the energy stability scenario is different; for CO, O2, and PH3 ligands the tetrahedron is the most stable isomer, in agreement with experimental insights, while for SH2 ligands the square motif is the most stable isomer. To improve the understanding of these systems, structural and electronic analysis were performed, in addition to energy decomposition analysis, to explore the bonding situation in Ir4 compounds. Our results showed an important relationship between the geometrical behavior and the nature and magnitude of Ir2Ir2 interactions, showing how the chemical environment affects the Ir4 nanoclusters. In general, the compounds with tetrahedron motifs showed a weakening of the sigma and pi bonds in relation to the square ones. PMID- 30456410 TI - Compositional effect of two-dimensional monodisperse AuPd bimetallic nanoparticle arrays fabricated by block copolymer nanopatterning on catalytic activity of CO oxidation. AB - We present a straightforward approach for fabricating AuPd nanocatalysts based on self-assembled block copolymer nanopatterning. CO oxidation was carried out on AuPd alloy nanoparticles and the activity increased with increasing Pd content; this synergistic activity can be precisely tuned by varying the chemical composition. Theoretical calculations suggest that Pd clusters are required to bind and dissociate O2 for oxidation of coadsorbed CO molecules. Our results suggest that the geometric configuration of the Pd atoms on the surface are a key factor in the catalytic activity. PMID- 30456411 TI - Photo-selective chain end transformation of polyacrylate-iodide using cysteamine and its application to facile single-step preparation of patterned polymer brushes. AB - Cysteamine, which is an inexpensive and non-toxic aminothiol, was successfully employed as a photo-selective chain end transformation agent of iodo-terminated polymer chains (polymer-I). Polymer-I was selectively transformed to hydrogen terminated (polymer-H) and thiol-terminated (polymer-SH) polymers with and without UV irradiation, respectively. This method is applicable to acrylate polymers. This photo-selective reaction offered a single-step preparation of patterned polymer brushes with SH and H chain end functionalities as a unique application. PMID- 30456412 TI - Non-animal models in dermatological research. AB - Despite widely used for basic and preclinical studies in dermatology, available animal models only partly recapitulate human skin features often leading to disappointing outputs when preclinical results are translated to the clinic. Therefore, the need to develop alternative, non-animal models is widely recognized to more closely recapitulate human skin pathophysiology and to address the pressing ethical demand of reducing the number of animals used for research purposes, following the globally accepted 3Rs principle (Replacement, Reduction and Refinement). Skin is the outermost organ of the body, and, as such, easily accessible. Different skin cell types can be propagated in vitro and skin can be reconstructed for therapeutic transplantation as well as for in vitro modeling of physiopathological conditions. Bioengineered skin substitutes have been developed and evolved from elementary to complex systems, more and more closely resembling complete skin architecture and biological responses. In silico analyses take advantage from the huge amount of data already available from human studies for identifying and modeling molecular pathways involved in skin pathophysiology without further animal testing. The present review recapitulates the available non-animal models for dermatological research and sheds lights on their prospective technological evolution. PMID- 30456413 TI - The current status of alternative methods for cosmetics safety assessment in China. PMID- 30456414 TI - PCNL in the prone position VS PCNL in the modified supine Double-S position: is there a better position? A prospective randomized trial. AB - The study was performed to evaluate the efficacy of our modified supine position (called "Double-S") in percutaneous nephrolithotripsy (PCNL) and to make a contribution to the question: "Is there a better position in PCNL?". The superiority of one position is still under debate in the scientific community. In our study, we described and compared our position with the standard prone one to evaluate the possible benefits. This is a prospective randomized clinical trial conducted for 17 months. It consisted of two sub-studies: trial A (patients with stones approachable with a single anterograde access) and trial B (patients with stones approachable with a single anterograde access combined with a retrograde access). A 1:1 randomization was performed in both trials to compare the supine Double-S position with the prone one. We found that the Double-S position presents the same safety and efficacy outcomes as the standard prone one. Moreover, we proved that this particular position can reduce the patient positioning time and effort sustained by professional nurses if compared to the prone one. The same outcomes were found in trial A and in trial B. Trial B confirms the efficacy of our position also when a combined access is needed. We proved that the Double-S position is safe and effective both in anterograde treatments and in combined anterograde-retrograde procedures with benefits in the positioning time and effort level. PMID- 30456415 TI - Population pharmacokinetics of oxcarbazepine active metabolite in Chinese paediatric epilepsy patients and its application in individualised dosage regimens. AB - PURPOSE: Oxcarbazepine (OXC) is an antiepileptic drug metabolised to active 10 monohydroxy derivative (MHD) following oral administration. There are no MHD population pharmacokinetic (PPK) models that describe the influence of genetic factors on MHD pharmacokinetics (PK). We developed a PPK model of MHD to investigate gene polymorphism of enzymes associated with MHD PK in Chinese paediatric epilepsy patients and evaluated its utility for dose individualisation. METHODS: Data were prospectively collected from 141 paediatric epilepsy patients (aged <= 14 years) who received OXC therapy at the First Affiliated Hospital of Fujian Medical University. The trough concentrations at steady state were determined by enzyme-multiplied immunoassay. Patients were genotyped for four single nucleotide polymorphisms (UGT2B7 802T>C, UGT1A9 I399C>T, ABCB1 3435C>T, and ABCB2 1249G>A). Patient gender, age, body weight (BW), hepatorenal function, and co-administrations were recorded. The PPK model was developed using nonlinear mixed-effects modelling software. The clinical performance of the final model was evaluated by including additional paediatric patients (n = 20) in the validation group. RESULTS: Oral clearance of MHD was significantly influenced by BW. The MHD PK was unrelated to the other covariates, such as the four single nucleotide polymorphisms and co-administration with new generation antiepileptic drugs. The final BW-dependent exponent model showed the best fit with our data and predicted the trough concentrations in the validation group more accurately than the basic model. A new dosing strategy combining the dosage guideline and Bayesian method is proposed to individualise OXC regimens. CONCLUSION: A PPK model was established to estimate individual MHD clearance in paediatric patients taking OXC to develop individualised OXC dosing regimens for Chinese paediatric epilepsy patients. PMID- 30456416 TI - Validity of the Korean Triage and Acuity Scale for predicting 30-day mortality due to severe trauma: a retrospective single-center study. AB - PURPOSE: Since January 2016, emergency medical centers in South Korea have used the Korean Triage and Acuity Scale (KTAS) as the initial triage tool for all patients, including trauma patients, who visited the emergency department (ED). This present study aimed to assess the validity of the KTAS for predicting 30-day mortality due to severe trauma. METHODS: This retrospective study included patients with severe trauma (injury severity score >= 16) from January 2016 to December 2017. Using KTAS, all patients were triaged as levels 1, 2, 3, and 4 by triage nurses. The primary outcome was 30-day mortality, and the secondary outcome was disposition at the ED. Disposition at the ED included admission to the general ward, intensive care unit, or operation room or death in the ED. RESULTS: Of the 827 included patients, 30-day mortality was observed in 14.9% (n = 123) of patients. Mortality was observed in 52.5% (n = 42), 15.5% (n = 69), 4.1% (n = 12), and 0.0% (n = 0) of patients in levels 1, 2, 3, and 4, respectively. The Cox proportional hazard regression analysis showed that compared to level 3, level 1 [hazard ratio (HR) 4.868; 95% confidence interval (CI) 2.341-10.119] and level 2 (HR 2.070; 95% CI 1.083-3.956) were independently associated with 30-day mortality. Patients with lower KTAS levels were more likely to be admitted to the operation room and were more likely to die in the ED. CONCLUSION: Lower KTAS levels were associated with higher 30-day mortality due to severe trauma. KTAS shows adequate validity for predicting 30-day mortality from severe trauma. PMID- 30456417 TI - Penetrating trauma and invasive management of thorax trauma. PMID- 30456418 TI - Outer retinal layers as predictors of visual acuity in retinitis pigmentosa: a cross-sectional study. AB - PURPOSE: To evaluate the integrity of the outer retinal layers-outer nuclear layer (ONL), external limiting membrane (ELM), ellipsoid (EZ), and interdigitation band (IZ)-using spectral-domain optical coherence tomography and estimate their effect on visual acuity in retinitis pigmentosa (RP). METHODS: A cross-sectional study was performed in the Ophthalmology Department of Hospital de Braga, Portugal. Patients with RP followed in the Hospital de Braga during January to August 2017 were included. Exclusion criteria were lack of data, macular edema due to RP, and concomitant retinal, optic nerve, or corneal disease that could interfere with visual acuity. Age, sex, time from diagnosis, phakic status, ONL thickness, and presence or absence of foveal ELM, EZ, and IZ were correlated to the best-corrected visual acuity (BCVA). RESULTS: Forty-eight eyes were analyzed. There was a strong and positive correlation in BCVA between both eyes (p < .001*). ONL thickness was decreased in 95.8%. The EZ was the most absent layer (79.2%), followed by IZ (70.8%) and ELM (45.8%). A positive family history (p = .04*) and increased time from diagnosis (p = .037*) correlated with worse BCVA. A thicker ONL (p = .001*) and the presence of subfoveal ELM (p < .001*), EZ (p < .001*), and IZ (p = .02*) are correlated with better BCVA. There was a strong and positive correlation between the number of layers affected and a lower BCVA (p < .001). The presence of EZ was a significant predictor of BCVA (p = .02*). CONCLUSIONS: The status of the outer retinal layers seems to influence BCVA. The status of the EZ was the most important predictor of BCVA but the ONL, ELM, and IZ may have a cumulative effect in the progression of visual loss. PMID- 30456419 TI - RKI-1447, a Rho kinase inhibitor, causes ocular hypotension, actin stress fiber disruption, and increased phagocytosis. AB - PURPOSE: This study investigated the hypotensive effect of RKI-1447, a Rho kinase inhibitor, in a porcine ex vivo pigmentary glaucoma model. METHODS: Twenty-eight porcine anterior chambers were perfused with medium supplemented with 1.67 * 107 pigment particles/ml for 48 h before treatment with RKI-1447 (n = 16) or vehicle control (n = 12). Intraocular pressure (IOP) was recorded and outflow facility was calculated. Primary trabecular meshwork cells were exposed to RKI-1447 or vehicle control; effects on the cytoskeleton, motility, and phagocytosis were evaluated. RESULT: Compared to baseline, the perfusion of pigment caused a significant increase in IOP in the RKI-1447 group (P = 0.003) at 48 h. Subsequent treatment with RKI-1447 significantly reduced IOP from 20.14 +/- 2.59 to 13.38 +/ 0.91 mmHg (P = 0.02). Pigment perfusion reduced the outflow facility from 0.27 +/- 0.03 at baseline to 0.18 +/- 0.02 at 48 h (P < 0.001). This was partially reversed with RKI-1447. RKI-1447 caused no apparent histological changes in the micro- or macroscopic TM appearance. RKI-1447-treated primary TM cells showed significant disruption of the actin cytoskeleton both in the presence and absence of pigment (P < 0.001) but no effect on TM migration was observed. Pigment treated TM cells exhibited a reduction in TM phagocytosis, which RKI-1447 reversed. CONCLUSION: RKI-1447 significantly reduces IOP by disrupting TM stress fibers and increasing TM phagocytosis. These features may make it useful for the treatment of secondary glaucomas with an increased phagocytic load. PMID- 30456420 TI - Pupil fields in a patient with early-onset postgeniculate lesion. PMID- 30456421 TI - Utility of allogeneic hematopoietic stem cell transplantation using international donors in a homogenous ethnic population: question in the era of various alternative donors. AB - The advent of various alternative donors in allogeneic hematopoietic stem cell transplantation (HSCT) raises the question of using international donors, especially in ethnically homogenous populations. We analyzed the clinical outcome and medical expense of human leukocyte antigen (HLA)-matched HSCT using domestic and international donors. We analyzed the patients who received allogeneic HSCT at five medical centers in Korea in the last 10 years. Using propensity-score matching, we compared overall survival (OS), relapse-free survival (RFS), and transplantation-related complications. Medical expense was analyzed based on National Health Insurance Service (NHIS) data. A total of 269 patients were analyzed after 3:1 (domestic/international) matching. There was no difference in OS (p = 0.395) and RFS (p = 0.604) between the domestic and international donor groups (5-year OS rate 42.9 and 37.8%, 5-year RFS rate 37.6 and 33.5% for domestic and international groups, respectively). No difference in chronic graft versus-host disease (GVHD) incidence was observed (34.2% in domestic and 35.9% in international group, p = 0.804). Early infection was more frequent in the domestic group (55.0 vs. 35.8%, p = 0.007), whereas infection after 30 days was more frequent in the international group (28.7 vs. 49.3%, p = 0.001). Mean medical expense was far higher in the international group, by US $51,944 in the entire follow-up period (p < 0.001). We would expect similar outcomes for international and domestic donors in terms of survival and treatment-related complications with HLA-matched HSCT in other ethnically homogenous populations. These findings should be considered together with the high cost of using international donors in the era of various alternative donors. PMID- 30456422 TI - Diffuse large B cell lymphoma and schistosomiasis: a rare simultaneous occurrence. PMID- 30456424 TI - Effect of Age, Sex, Bolus Volume, and Bolus Consistency on Whiteout Duration in Healthy Subjects During FEES. AB - One of the major limitations of the fiberoptic endoscopic evaluation of swallowing (FEES) is related to the challenging application of temporal measures. Among them, Whiteout (WO) is due to pharyngeal and tongue base contraction and might be used as an estimation of the pharyngeal phase duration. The aims of this study were to evaluate the inter- and intrarater reliability of WO duration and to appraise the effects of age, sex, volume, and texture of the boluses on this temporal measurement. A total of 30 healthy volunteers were recruited. According to their age, the subjects were grouped into three different age groups. Each of them underwent FEES examination with different textures (liquid, semisolid, and solid) and volumes. FEES examinations were video recorded, processed with the software Daisy Viewer 2.0, which allowed the acquisition of 25 frames per second (s) and analyzed by three different raters in order to collect data on WO duration. A total of 863 swallowing acts were video recorded. Intra- and interrater reliability of WO duration were excellent. Both volume and bolus's texture significantly affected WO duration. In particular, WO duration was significantly shorter for the liquid texture than for the semisolid and solids ones. In addition, male subjects scored significantly higher values of WO duration. Finally, WO duration was significantly higher in seniors. WO duration seems to be a reliable temporal measure during FEES examination. WO duration seems to be affected by several factors such as age, sex, volume, and consistency. PMID- 30456423 TI - Immobilization of a Ce(IV)-substituted polyoxometalate on ethylenediamine functionalized graphene oxide for selective extraction of phosphoproteins. AB - A sorbent for selective extraction of phosphoproteins was obtained by immobilization of a Ce(IV)-substituted polyoxometalate on ethylenediamine functionalized graphene oxide (CeEGO). The resulting composites exhibit an adsorption capacity of 981 mg g-1 for beta-casein due to the synergistic effect of metal-affinity interaction between Ce(IV) and phosphate groups and pi-stacking interaction between the polyoxometalate framework and the phosphate groups. The results of LC-MS and SDS-PAGE analysis show that the CeEGO composites can be applied to the extraction of phosphoproteins from protein mixture, and as little as 50 MUg mL-1 of the phosphoprotein beta-casein can be detected by SDS-PAGE. It was also applied to the extraction of beta-casein from spiked biological samples such as drinking milk, whole blood and swine heart tissue extract. Graphical abstract An efficient sorbent is obtained by immobilization of a Ce(IV) substituted polyoxometalate on ethylenediamine-functionalized graphene oxide (CeEGO). The resulting composites exhibit highly selective capture capacity towards phosphoproteins due to the synergistic effect of metal-affinity interaction between Ce(IV) and phosphate groups and pi-stacking interaction between the polyoxometalate framework and the phosphate groups. PMID- 30456425 TI - A survey of traditional and faith healers providing mental health care in three sub-Saharan African countries. AB - BACKGROUND: Traditional and faith healers constitute an important group of complementary and alternative mental health service providers (CAPs) in sub Sahara Africa. Governments in the region commonly express a desire to integrate them into the public health system. The aim of the study was to describe the profile, practices and distribution of traditional and faith healers in three sub Saharan African countries in great need for major improvements in their mental health systems namely Ghana, Kenya and Nigeria. MATERIALS AND METHODS: A mapping exercise of CAPs who provide mental health care was conducted in selected catchment areas in the three countries through a combination of desk review of existing registers, engagement activities with community leaders and a snowballing technique. Information was collected on the type of practice, the methods of diagnosis and the forms of treatment using a specially designed proforma. RESULTS: We identified 205 CAPs in Ghana, 406 in Kenya and 82 in Nigeria. Most (> 70%) of the CAPs treat both physical and mental illnesses. CAPs receive training through long years of apprenticeship. They use a combination of herbs, various forms of divination and rituals in the treatment of mental disorders. The use of physical restraints by CAPs to manage patients was relatively uncommon in Kenya (4%) compared to Nigeria (63.4%) and Ghana (21%). CAPs often have between 2- to 10-fold capacity for patient admission compared to conventional mental health facilities. The profile of CAPs in Kenya stands out from those of Ghana and Nigeria in many respects. CONCLUSION: CAPs are an important group of providers of mental health care in sub-Saharan Africa, but attempts to integrate them into the public health system must address the common use of harmful treatment practices. PMID- 30456426 TI - Effect of the Brazilian cash transfer programme on suicide rates: a longitudinal analysis of the Brazilian municipalities. AB - PURPOSE: There is a growing awareness of the economic and contextual factors that may play a role in the aetiology of suicide. The Programa Bolsa Familia (PBF) the Brazilian conditional cash transfer programme, established in 2004, aims to attenuate the effects of poverty of Brazilians. Our study aims to evaluate the effect of Bolsa Familia Programme (BFP) coverage on suicide rates in Brazilian municipalities. METHODS: We conducted an ecological study using 2004-2012 panel data for 5507 Brazilian municipalities. We calculated age-standardized suicide rates for each municipality and year. BFP coverage was categorized according to three levels (< 30%, >= 30% and < 70% and >= 70%) and duration (coverage <= 70% for all years, >= 70% for 1 year, >= 70% for 2 years, >= 70% for 3 or more years). We used negative binomial regression models with fixed effects, adjusting for socio-economic, demographic and social welfare co-variables. RESULTS: An increase in BFP coverage was associated with a reduction in suicide rates. The strongest effect was observed when in addition to greater municipal coverage (RR 0.942, 95% CI 0.936-0.947), the duration of the high coverage was maintained for 3 years or more (RR 0.952 95% CI 0.950-0.954). CONCLUSIONS: The results provide evidence that the conditional cash transfer programme may reduce suicide in Brazilian municipalities, mitigating the effect of poverty on suicide incidence. PMID- 30456427 TI - Prediction of water erosion sensitive areas in Mediterranean watershed, a case study of Wadi El Maleh in north-west of Algeria. AB - Water erosion phenomenon has significant effects on productivity and environment in Algeria. This contribution presents interesting study on soil erosion risk of Wadi El Maleh watershed using RUSLE model based on original data. The erosion process results from effects of several factors, including rainfall erosivity, soil erodibility, land slope length, land use, and conservation practices. Soil erosion map in the entire watershed area is obtained by the superposition of the generated maps of each previous factor. The obtained results showed that the mean soil loss rate is about 9 t/ha/year in the whole watershed area. These results are comparable to those reported in watersheds having the same hydrologic characteristic. Based on 2017 couples of (Q-C) recorded over 17 years (from 1981 to 1998), we have estimated the suspended sediment transport of Wadi El Maleh to be annually about 2.94 t/ha/year which represents just 32.6% of the eroded rate, i.e., two thirds of the eroded sediment are deposited, especially in the plains. This high values of deposited sediments is mainly due to relatively moderate slopes and dense vegetation. PMID- 30456428 TI - Historical aspects of the foundation of the Latin American Society of Pediatric Neurosurgery. PMID- 30456429 TI - Dynamic magnetic resonance imaging parameters for objective assessment of the magnitude of tethered cord syndrome in patients with spinal dysraphism. AB - BACKGROUND: Dynamic magnetic resonance imaging (MRI)-based criteria for diagnosing magnitude of tethered cord syndrome (TCS) in occult spinal dysraphism are proposed. METHODS: In this prospective, case-control design study, MRI lumbosacral spine was performed in 51 subjects [pilot group (n = 10) without TCS (for defining radiological parameters), control group (n = 10) without TCS (for baseline assessment), and study group (n = 31) with spinal dysraphism (thick filum terminale [n = 12], lumbar/lumbosacral meningomyelocoele [n = 6], and lipomyelomeningocoele [n = 13])]. The parameters compared in control and study groups included oscillatory frequency (OF), difference in ratio, in supine/prone position, of distance between posterior margin of vertebral body and anterior margin of spinal cord (oscillatory distance [OD]), with canal diameter, at the level of conus as well as superior border of contiguous two vertebrae above that level; delta bending angle (DeltaBA), difference, in supine/prone position, of angle between longitudinal axis of conus and that of lower spinal cord; and sagittal and axial root angles, subtended between exiting ventral nerve roots and longitudinal axis of cord. An outcome assessment at follow-up was also done. RESULTS: In the study group (cord tethered), significantly less movement at the level of conus (OF0, p = 0.013) and one level above (OF1, p = 0.03) and significant difference in DeltaBA (p = 0.0) were observed in supine and prone positions, compared to controls. Ventral nerve root stretching resulted in sagittal/axial root angle changes. Median OF (0.04) in the lipomyelomeningocoele group was significantly less than that in control group (0.23). Median OF was also lesser in patients with thick filum terminale or meningomyelocele. Difference in median sagittal and axial root angles among the study and control groups was statistically significant (p = 0.00). CONCLUSION: New dynamic MRI based parameters to establish the presence and magnitude of TCS have been defined. OF measured the extent of loss of translational cord displacement in supine and prone positions; DeltaBA defined the relative angulation of conus with lower spinal cord, and sagittal and axial root angles represented ventral nerve root stretching. The difference in OF or DeltaBA was minimum in the group with thick filum terminale and progressively increased in the groups with lipomyelomeningocele and meningomyelocele. PMID- 30456430 TI - The consistency of care for older patients with a hip fracture: are the results of the integrated orthogeriatric treatment model of the Centre of Geriatric Traumatology consistent 10 years after implementation? AB - : In the past 10 years after implementation, the orthogeriatric treatment model led in general to consistent outcomes for 1555 older adults in terms of most of the complications and mortality. Surgery was more often delayed to 24-48 h after arrival at the hospital, while the length of hospital stay shortened. INTRODUCTION: Since 1 April 2008, patients aged >= 70 years presenting themselves with a hip fracture at Ziekenhuisgroep Twente (ZGT) have been treated according to the orthogeriatric treatment model. The aim of this study was to investigate if outcomes of the orthogeriatric treatment model are consistent over the first 10 years after implementation. METHODS: Between 1 April 2008 and 31 December 2016, patients aged >= 70 years who were surgically treated at ZGT for a hip fracture were included and divided into three periods equally distributed in time. Patient characteristics, in-hospital logistics, complications, and mortality data were compared between the three periods. RESULTS: A total of 1555 patients were included. There was a shift in the surgical treatment for the fractured neck of femur from dynamic hip screw/cannulated screws to hemiarthroplasty (p < 0.001). Surgery within 24 h after arrival to the hospital decreased (p < 0.001), while surgery within 48 h stayed the same (p = 0.085). Length of hospital stay significantly decreased over time (p < 0.001). Complication rates were consistent except for the number of postoperative anemia, delirium, and urinary tract infections. Mortality rates did not change over the years. CONCLUSIONS: The orthogeriatric treatment model leads in general to consistent outcomes concerning mortality and most of the complications, except for postoperative anemia, delirium, and urinary tract infections. Inconsistent complication rates were influenced by altered diagnosis and treatment protocols. Length of hospital stay reduced, while time to surgery was more often delayed to 24-48 h. Monitoring clinical outcomes of the orthogeriatric treatment model over time is recommended in order to optimize and maintain the quality of care for this frail patient population. PMID- 30456431 TI - Changes in cardiac autonomic activity during intracranial pressure plateau waves in patients with traumatic brain injury. PMID- 30456432 TI - Autonomic aspects of sudden unexpected death in epilepsy (SUDEP). AB - Sudden unexpected death in epilepsy (SUDEP) is a major cause of epilepsy-related mortality. SUDEP is highly linked to seizures, with most deaths occurring after convulsive seizures in sleep. In most cases of SUDEP, convulsive seizures appear to directly trigger catastrophic cardiorespiratory dysfunction leading to death. In the last few decades, many pathophysiological mechanisms have been proposed to explain the sequence of events leading to death. Patients with epilepsy often have underlying autonomic dysfunction, as measured by heart rate variability and other testing modalities. Additionally, seizures often trigger acute cardiac and respiratory dysfunction. While sinus tachycardia is the most common cardiac finding during seizures, asystole and malignant tachyarrhythmias may also occur. Seizures can also lead to respiratory dysfunction, including central ictal and obstructive apnea related to laryngospasm. Available data suggest that there could be underlying autonomic dysfunction, potentially related to genetic, medication, and other factors that might predispose individuals to sudden catastrophic cardio-respiratory dysfunction in the setting of a seizure, resulting in SUDEP. Further exploration of this possible link is needed. Patients with medically refractory epilepsy are at the highest risk, and adequate management via medical therapy to control convulsive seizures, or surgical intervention may decrease the SUDEP risk. Recently, many automated seizure detection systems have been developed to detect convulsive seizures, which may enable caregivers to more closely monitor individuals with epilepsy. Improved identification of seizures may be important for patients with refractory epilepsy as close supervision and timely intervention after a seizure could potentially reduce the risk of SUDEP. PMID- 30456434 TI - Physicians' awareness of gadolinium retention and MRI timing practices in the longitudinal management of pituitary tumors: a "Pituitary Society" survey. AB - PURPOSE: In view of mounting attention related to possible brain retention of gadolinium-based contrast agents (GBCAs) in patients with normal renal function, our purpose was to detail results from a survey of pituitary experts to assess: 1) the timing interval and frequency of pituitary magnetic resonance imaging (MRI) following surgical and/or medical and/or radiation therapy of pituitary tumors, 2) awareness of the types of GBCAs used and their possible safety issues. METHODS: The Pituitary Society Education Committee composed a survey with 12 multiple choice questions, 8 of which specifically addressed the time interval and frequency of MRI in the longitudinal management of pituitary tumors. The survey was distributed at two meetings; the International Pituitary Neurosurgeons Society conference in San Diego, CA, on February 18th, 2018, and the Pituitary Society Membership and Career Development Forum, Chicago, IL on March 18th, 2018. RESULTS: There is consensus among pituitary endocrinologists and neurosurgeons that long-term repeated imaging is recommended in most pituitary tumors, although the precise strategy of timing varied depending on the specialist group and the specific clinical context of the adenoma. The data also suggest that International Pituitary Neurosurgeons Society neurosurgeons, as well as Pituitary Society neuroendocrinologists, are sometimes unaware of which contrast agents are used by their institution, and many are also unaware that evidence of long-term brain retention has been reported with the use of GBCAs in patients with normal function. CONCLUSIONS: International pituitary endocrinologists and pituitary neurosurgeons experts suggest ongoing MRIs for the management of pituitary tumors; strategies vary based on clinical context, but also on individual experience and practice. PMID- 30456435 TI - Clinical spectrum of Lyme disease. AB - Lyme disease (borreliosis) is one of the most common vector-borne diseases worldwide. Its incidence and geographic expansion has been steadily increasing in the last decades. Lyme disease is caused by Borrelia burgdorferi sensu lato, a heterogeneous group of which three genospecies have been systematically associated to Lyme disease: B. burgdorferi sensu stricto Borrelia afzelii and Borrelia garinii. Geographical distribution and clinical manifestations vary according to the species involved. Lyme disease clinical manifestations may be divided into three stages. Early localized stage is characterized by erythema migrans in the tick bite site. Early disseminated stage may present multiple erythema migrans lesions, borrelial lymphocytoma, lyme neuroborreliosis, carditis, or arthritis. The late disseminated stage manifests with acordermatitis chronica atrophicans, lyme arthritis, and neurological symptoms. Diagnosis is challenging due to the varied clinical manifestations it may present and usually involves a two-step serological approach. In the current review, we present a thorough revision of the clinical manifestations Lyme disease may present. Additionally, history, microbiology, diagnosis, post-treatment Lyme disease syndrome, treatment, and prognosis are discussed. PMID- 30456436 TI - Non-Typhi, non-Paratyphi Salmonella-related hospitalisations in Spain: trends, clinical aspects, risk factors for worse prognosis and hospital costs. AB - This study reviews non-typhoid Salmonella (NTS)-related hospitalisations at National level in Spain between 2010 and 2015. NTS hospitalisations were obtained from the National Registry of Hospitalisations. A descriptive analysis of the hospitalisations was performed, including hospitalisation rates (HR) and case fatality rates (CFR%) calculation. For those with NTS as Main Diagnosis logistic regression were used to estimate the relationship between the different factors and death outcome. 21,660 registered NTS-related hospitalisations were described (88.8% with Salmonella coded as Main Diagnosis). Average HR2010-2015 was 7.7 (range, 7.3 to 8.1) hospitalisations/100,000 population. Those with NTS infections as Secondary Diagnosis were on average (p < 0.001) older (47.9 vs. 36.5 years), presented worse Charlson Comorbidity Index (2.1 vs. 1.2), higher CFR% (4.8% vs. 0.7%), spent more days hospitalised (15.1 vs. 5.8 days), and generated more costs (6173 vs. 4272 euros/per hospitalisation) than those with NTS as Main Diagnosis. For those with NTS as Main Diagnosis increased risk of death was related to being > 64 years old (OR = 20.99; p < 0.001); presenting septicaemia (OR = 15.82; p < 0.001) or localised infections (OR = 3.98; p = 0.061); Charlson Comorbidity Index > 3 (OR = 4.57; p < 0.001); a non-HIV co infection (OR = 1.80; p = 0.013); other risk factors (OR = 5.70; p < 0.001); bowel perforation (OR = 70.30; p < 0.001); or acute renal failure (OR = 1.95; p = 0.001). In those with Salmonella as Main Diagnosis, among all complications, bowel perforation presented the strongest association with death outcome. Clinical practice guidelines can help to identify patients at risk of bowel perforation to reduce the fatality of the disease. PMID- 30456437 TI - Identification, clinical-pathological characteristics and treatment outcomes of patients with metastatic breast cancer and somatic human epidermal growth factor receptor 2 (ERBB2) mutations. AB - PURPOSE: The human epidermal growth factor receptor 2 (ERBB2) may harbour somatic mutations that drive breast tumorigenesis. Here, we study prevalence, tumour characteristics and disease outcome of ERBB2 mutations in a large unselected cohort of metastatic breast cancer (mBC) patients. METHODS: We retrospectively included all mBC patients with sufficient primary breast tumour, diagnosed between 2000 and 2015 (n = 775). Genomic DNA was subjected to a targeted resequencing assay to identify hotspot mutations in exon 8, 17, 19, 20, and 21 of ERBB2. We studied demographics, tumour characteristics, median distant disease free survival (DDFS), using a time-to-event analysis and time to progression (TTP) and overall survival (OS) upon metastasis, using Kaplan-Meier and log-rank statistics to assess differences between ERBB2-mutation statuses. RESULTS: ERBB2 mutations were observed in 1.8% of the samples (13/721). Patient and tumour characteristics were independent of ERBB2 mutations. Luminal ERBB2-mutated (ERBB2mut+) cases (n = 5) had a shorter DDFS than ERBB2mut- cases (median DDFS 0.8 vs. > 4.0 years, p = 0.02). ER-positive ERBB2mut+ patients who received an aromatase inhibitor (AI) as first-line treatment (stage IV disease) had a worse TTP vs. ERBB2mut- patients (n = 3 vs. 156; median TTP 103 vs. 311 days, p = 0.04). OS for all subtypes was lower for ERBB2mut+ vs. ERBB2mut- cases (n = 11 vs. 669; median OS 1.1 vs. 2.3 years, p = 0.46). CONCLUSION: ERBB2mut+ are rare in patients in whom mBC developed and no evidence was found for an association with specific types of BC or patient characteristics, although outcomes of ERBB2mut+ carriers might be worse. The latter, however, needs to be validated in larger populations. PMID- 30456438 TI - Milk intake and mammographic density in premenopausal women. AB - PURPOSE: Mammographic density is a strong risk factor for breast cancer. Although diet is associated with breast cancer risk, there are limited studies linking adult diet, including milk intake, with mammographic density. Here, we investigate the association of milk intake with mammographic density in premenopausal women. METHODS: We analyzed data from 375 cancer-free premenopausal women who had routine screening mammography at Washington University School of Medicine, St. Louis, Missouri in 2016. We used Volpara to measure volumetric percent density, dense volume, and non-dense volume. We collected information on recent milk intake (past 12 months), and categorized skim milk and low/reduced fat milk intake into 4 groups: < 1/week, 1/week, 2-6 times/week, >= 1/day, while whole and soy milk intake were categorized into 2 groups: < 1/week, >= 1/week. We used multivariable linear regression model to evaluate the associations of milk intake and log-transformed volumetric percent density, dense volume, and non dense volume. RESULTS: In multivariable analyses, volumetric percent density was 20% (p-value = 0.003) lower in the 1/week group, 14% (p-value = 0.047) lower in the 2-6/week group, and 12% (p-value = 0.144) lower in the >= 1/day group (p trend = 0.011) compared with women who consumed low/reduced-fat milk < 1/week. Attenuated and non-significant associations were observed for low/reduced-fat milk intake and dense volume. There were no associations of whole, skim, and soy milk intake with volumetric percent density and dense volume. CONCLUSIONS: Recent low/reduced-fat milk intake was inversely associated with volumetric percent density in premenopausal women. Studies on childhood and adolescent milk intake and adult mammographic density in premenopausal women are needed. PMID- 30456439 TI - A Developmental Study of the Narrative Components and Patterns of Chinese Children Aged 3-6 Years. AB - To investigate the narrative development of Chinese-speaking children aged 3-6 years, 80 children were prompted to tell personal stories. High point analysis was used and both narrative components and overall narrative patterns were analyzed. In terms of narrative components, Chinese children were more skillful in using complicating action, orientation and evaluation than they were in resolution, direct and reported speech. With age, their narratives were longer and richer in content. No gender differences were found in any of the seven narrative components. For narrative patterns, the most frequent was the two-event pattern at age 3 and the chronological pattern from age 4 to age 6. However, the chronological pattern at age 5 and 6 differed from the chronological pattern at age 4. The proportion of leap-frog, two-event and one-event patterns decreased with age, but most Chinese children at age 6 have yet to develop the ability to tell a classic narrative that includes resolution. These findings provided evidence for a developmental pattern of the narrative development in preschool Chinese children and suggested more attention should be paid to improve children's ability to resolve a story, telling listeners how everything worked out in the end. PMID- 30456441 TI - Genomic Signatures Among Acanthamoeba polyphaga Entoorganisms Unveil Evidence of Coevolution. AB - The definition of a genomic signature (GS) is "the total net response to selective pressure". Recent isolation and sequencing of naturally occurring organisms, hereby named entoorganisms, within Acanthamoeba polyphaga, raised the hypothesis of a common genomic signature despite their diverse and unrelated evolutionary origin. Widely accepted and implemented tests for GS detection are oligonucleotide relative frequencies (OnRF) and relative codon usage (RCU) surveys. A common pattern and strong correlations were unveiled from OnRFs among A. polyphaga's Mimivirus and virophage Sputnik. RCU showed a common A-T bias at third codon position. We expanded tests to the amoebal mitochondrial genome and amoeba-resistant bacteria, achieving strikingly coherent results to the aforementioned viral analyses. The GSs in these entoorganisms of diverse evolutionary origin are coevolutionarily conserved within an intracellular environment that provides sanctuary for species of ecological and biomedical relevance. PMID- 30456440 TI - Folding, Assembly, and Persistence: The Essential Nature and Origins of Biopolymers. AB - Life as we know it requires three basic types of polymers: polypeptide, polynucleotide, and polysaccharide. Here we evaluate both universal and idiosyncratic characteristics of these biopolymers. We incorporate this information into a model that explains much about their origins, selection, and early evolution. We observe that all three biopolymer types are pre-organized, conditionally self-complementary, chemically unstable in aqueous media yet persistent because of kinetic trapping, with chiral monomers and directional chains. All three biopolymers are synthesized by dehydration reactions that are catalyzed by molecular motors driven by hydrolysis of phosphorylated nucleosides. All three biopolymers can access specific states that protect against hydrolysis. These protected states are folded, using self-complementary interactions among recurrent folding elements within a given biopolymer, or assembled, in associations between the same or different biopolymer types. Self-association in a hydrolytic environment achieves self-preservation. Heterogeneous association achieves partner-preservation. These universal properties support a model in which life's polymers emerged simultaneously and co-evolved in a common hydrolytic milieu where molecular persistence depended on folding and assembly. We believe that an understanding of the structure, function, and origins of any given type of biopolymer requires the context of other biopolymers. PMID- 30456443 TI - Mechanisms of Blood-Brain Barrier Disruption in Herpes Simplex Encephalitis. AB - Herpes simplex encephalitis (HSE) is often caused by infection with herpes simplex virus 1 (HSV-1), a neurotropic double-stranded DNA virus. HSE infection always impacts the temporal and frontal lobes or limbic system, leading to edema, hemorrhage, and necrotic changes in the brain parenchyma. Additionally, patients often exhibit severe complications following antiviral treatment, including dementia and epilepsy. HSE is further associated with disruptions to the blood brain barrier (BBB), which consists of microvascular endothelial cells, tight junctions, astrocytes, pericytes, and basement membranes. Following an HSV-1 infection, changes in BBB integrity and permeability can result in increased movement of viruses, immune cells, and/or cytokines into the brain parenchyma. This leads to an enhanced inflammatory response in the central nervous system and further damage to the brain. Thus, it is important to protect the BBB from pathogens to reduce brain damage from HSE. Here, we discuss HSE and the normal structure and function of the BBB. We also discuss growing evidence indicating an association between BBB breakdown and the pathogenesis of HSE, as well as future research directions and potential new therapeutic targets. Graphical Abstract During herpes simplex encephalitis, the functions and structures of each composition of BBB have been altered by different factors, thus the permeability and integrity of BBB have been broken. The review aim to explore the potential mechanisms and factors in the process, probe the next research targets and new therapeutic targets. PMID- 30456442 TI - Genes Encoding Mammalian Oviductal Proteins Involved in Fertilization are Subjected to Gene Death and Positive Selection. AB - Oviductal proteins play an important role in mammalian fertilization, as proteins from seminal fluid. However, in contrast with the latter, their phylogenetic evolution has been poorly studied. Our objective was to study in 16 mammals the evolution of 16 genes that encode oviductal proteins involved in at least one of the following steps: (1) sperm-oviduct interaction, (2) acrosome reaction, and/or (3) sperm-zona pellucida interaction. Most genes were present in all studied mammals. However, some genes were lost along the evolution of mammals and found as pseudogenes: annexin A5 (ANXA5) and deleted in malignant brain tumor 1 (DMBT1) in tarsier; oviductin (OVGP1) in megabat; and probably progestagen-associated endometrial protein (PAEP) in tarsier, mouse, rat, rabbit, dolphin, and megabat; prostaglandin D2 synthase (PTGDS) in microbat; and plasminogen (PLG) in megabat. Four genes [ANXA1, ANXA4, ANXA5, and heat shock 70 kDa protein 5 (HSPA5)] showed branch-site positive selection, whereas for seven genes [ANXA2, lactotransferrin (LTF), OVGP1, PLG, S100 calcium-binding protein A11 (S100A11), Sperm adhesion molecule 1 (SPAM1), and osteopontin (SPP1)] branch-site model and model-site positive selection were observed. These results strongly suggest that genes encoding oviductal proteins that are known to be important for gamete fertilization are subjected to positive selection during evolution, as numerous genes encoding proteins from mammalian seminal fluid. This suggests that such a rapid evolution may have as a consequence that two isolated populations become separate species more rapidly. PMID- 30456444 TI - Allelic imbalance and haploinsufficiency in MYBPC3-linked hypertrophic cardiomyopathy. AB - Mutations in cardiac myosin binding protein C (MYBPC3) represent the most frequent cause of familial hypertrophic cardiomyopathy (HCM), making up approximately 50% of identified HCM mutations. MYBPC3 is distinct among other sarcomere genes associated with HCM in that truncating mutations make up the vast majority, whereas nontruncating mutations predominant in other sarcomere genes. Several studies using myocardial tissue from HCM patients have found reduced abundance of wild-type MYBPC3 compared to control hearts, suggesting haploinsufficiency of full-length MYBPC3. Further, decreased mutant versus wild type mRNA and lack of truncated mutant MYBPC3 protein has been demonstrated, highlighting the presence of allelic imbalance. In this review, we will begin by introducing allelic imbalance and haploinsufficiency, highlighting the broad role each plays within the spectrum of human disease. We will subsequently focus on the roles allelic imbalance and haploinsufficiency play within MYBPC3-linked HCM. Finally, we will explore the implications of these findings on future directions of HCM research. An improved understanding of allelic imbalance and haploinsufficiency may help us better understand genotype-phenotype relationships in HCM and develop novel targeted therapies, providing exciting future research opportunities. PMID- 30456445 TI - A Novel Flexible Full-Cell Lithium Ion Battery Based on Electrospun Carbon Nanofibers Through a Simple Plastic Package. AB - The paper reports a novel flexible full-cell lithium ion battery (LIB) through a simple plastic package method. Carbon nanofibers (CNFs) are synthesized by electrospinning technology and the subsequent carbonation process. The CNFs with three-dimensional interconnected fibrous nanostructure exhibit a stable reversible capacity of 412 mAh g-1 after 100 cycles in the half-cell testing. A full cell is assembled by using CNF anode and commercial LiCoO2 cathode, and it displays good flexibility and lighting LED ability. The aggregate thickness of the constructed full-cell LIB is approximately 500 MUm, consisting of a CNFs/Cu film, a separator, a LiCoO2/Al film, electrolyte, and two polyvinyl chloride (PVC) films. The structure, morphology, and the electrochemical performances of electrospun CNFs and LiCoO2 electrodes are analyzed in details. PMID- 30456447 TI - Cemiplimab: First Global Approval. AB - Cemiplimab (LIBTAYO(r); cemiplimab-rwlc), a human programmed death receptor-1 (PD 1) monoclonal antibody that binds to PD-1 and blocks its interaction with programmed death ligands 1 (PD-L1) and 2 (PD-L2), is being developed by Regeneron Pharmaceuticals and Sanofi Genzyme. The drug is being investigated as a treatment for various cancers and in September 2018 received approval in the USA for the treatment of patients with metastatic cutaneous squamous cell carcinoma or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation. This article summarizes the milestones in the development of cemiplimab leading to this first global approval for the treatment of advanced cutaneous squamous cell carcinoma. PMID- 30456446 TI - Burden of Herpes Zoster in the Japanese Population with Immunocompromised/Chronic Disease Conditions: Results from a Cohort Study Claims Database from 2005-2014. AB - INTRODUCTION: The aim of this study is to describe the disease burden and costs of herpes zoster (HZ) in the general adult Japanese population or patients with immunocompromised (IC) conditions or chronic disorders. METHODS: A retrospective cohort study of individuals aged 18-74 years was conducted using January 2005 to December 2014 records from the Japan Medical Data Center claims database. Twenty eight IC conditions and chronic disorders were defined by diagnosis codes and/or procedures/treatments. HZ and its related complications were identified. Incidence rates (IR), frequency of HZ-related complications, healthcare resource utilization (HRU), and direct medical costs were estimated. HRU and costs were estimated on a subcohort of HZ cases occurring April 2012-January 2014. RESULTS: The overall IR of HZ in the total cohort of 2,778,476 adults was 4.92/1000 person years (PY) [95% confidence interval (CI): 4.86-4.98] and increased with age. The IR in the IC cohort (51,818 subjects) was 8.87/1000 PY (95% CI: 8.29-9.48), ranging from 5.55/1000 PY (95% CI: 4.26-7.09) in psoriasis to 151.68/1000 PY (95% CI: 111.45-201.71) in hematopoietic stem cell transplant recipients; most IRs were in the range 6-10/1000 PY. The IRs in individuals with chronic disorders were also relatively high, in the range 5.40-12.90/1000 PY. The frequency of postherpetic neuralgia was 4.01% (95% CI: 3.72-4.33) in the total cohort and 11.73% (95% CI: 9.01-14.93) in the IC cohort. The mean [standard deviation (SD)] number of outpatient visits was 3.4 (4.9) and 5.0 (5.7), respectively, and the proportion of HZ patients hospitalized was 2.20% and 6.70%, respectively. The mean (SD) direct medical cost per HZ episode was Y34,664 (Y54,433) and Y55,201 (Y92,642) in the total and IC cohort, respectively. CONCLUSIONS: The elevated burden of HZ in Japanese individuals harboring IC conditions and chronic disorders documented in our study underlines the need for prevention of HZ in people with these conditions. FUNDING: GlaxoSmithKline Biologicals SA. PMID- 30456448 TI - Electrohydraulic Lithotripsy for Pancreatic Duct Stones Under Digital Single Operator Pancreatoscopy (with Video). AB - BACKGROUND: Recently, a digital single-operator cholangiopancreatoscope (DSOC) has become available. This system allows the performance of electrohydraulic lithotripsy (EHL) even within the main pancreatic duct (MPD). However, there are only few reports of EHL for MPD stones using SPY-DS. AIMS: The aim of this study was to evaluate the technical feasibility and efficacy of EHL for MPD stones under DSOC guidance. METHODS: Between October 2016 and August 2017, patients with MPD stones were retrospectively enrolled in this study. The presence of MPD stones was diagnosed by endoscopic ultrasound and MRCP. The patients' baseline characteristics and those of the stones, including their size, number, and site in the MPD, number of EHL procedures, and adverse events, were reviewed. RESULTS: A total of 21 patients were retrospectively enrolled. The etiologies of chronic pancreatitis were idiopathic (n = 4) and alcohol induced (n = 17). The pancreatic stone was variously located in the head (n = 6), body (n = 11), tail (n = 1), head and body (n = 2), and body and tail (n = 1) of the pancreas. Median pancreatic stone size was 12 mm, and the mean number of ERCP sessions was 1.29 (range 1-3). EHL was successfully performed in 15 patients (85.7%, 18/21), and the rate of complete stone clearance was 88.2% (18/21). Severe adverse events were not seen in any of the patients, although one patient developed mild acute pancreatitis. CONCLUSIONS: In conclusion, although additional case reports and prospective studies are needed, EHL under DSOC may be an option to treat MPD stones. PMID- 30456449 TI - Valproic acid exerts specific cellular and molecular anti-inflammatory effects in post-operative conjunctiva. AB - Valproic acid (VPA) is a histone deacetylase inhibitor used clinically for neurological disorders. It is also potentially useful as anti-fibrotic therapy as it reduced collagen deposition in the post-operative conjunctiva. In this study, we further evaluated the effects of VPA on post-operative inflammation using the mouse model of conjunctival scarring. VPA, injected into the subconjunctiva immediately after surgery, did not cause any adverse tissue response when examined by live microscopy and produced an apparent reduction of proinflammatory and proangiogenic markers in immunohistological examinations. In-depth analyses of the treated operated tissues revealed that VPA selectively inhibited the CD45highF4/80low macrophage subset as well as the production of specific proinflammatory cytokines/ chemokines, including CXCL1, IL-5, IL-6, and IL-10 which were reduced by >= 2.0-fold. VPA also specifically reduced tissue NF-kB2 p100 protein by mean 3.87-fold. On conjunctival fibroblasts, VPA treatment resulted in decreased secretion of specific cytokines, including CCL2, VEGF-A, and IL-15. In the presence of TNF-alpha, VPA inhibited the induction of specific cytokines/chemokines, notably CCL5 and VEGF-A, as well as NF-kB2 p100. In corroboration, VPA suppressed TNF-alpha stimulation of NF-kB reporter transcription by 1.51-fold. These data indicate that VPA can modulate both proinflammatory cellular and molecular targets in a selective manner and may therefore attenuate surgery-induced conjunctival inflammation. These and previous findings suggest that, by suppressing key mediators of both inflammation and fibrosis, VPA is a useful therapeutic for improving surgical outcome involving the conjunctiva. KEY MESSAGES: VPA inhibited recruitment of a CD45highF4/80low macrophage subset. VPA reduced chemokine and cytokine levels in treated tissues. VPA selectively suppressed tissue NF-kB2 p100 levels. VPA suppressed TNF-alpha induction of chemokines, cytokines and NF-kB2 p100 expression. VPA suppressed TNF alpha stimulation of NF-kB reporter. PMID- 30456450 TI - Dichotomal functions of phosphorylated and unphosphorylated STAT1 in hepatocellular carcinoma. AB - Interferons (IFNs) with antiviral and immune-stimulatory functions have been widely used in prevention and treatment of hepatocellular carcinoma (HCC). Signal transducer and activator of transcription 1 (STAT1) is a key element of the IFN signaling, and the function of STAT1 is critically determined by its phosphorylation state. This study aims to understand the functions of phosphorylated (p-) and unphosphorylated (u-) STAT1 in HCC. We found that u-STAT1 is significantly elevated in patient HCC tumor tissues and predominantly expressed in cytoplasm; while p-STAT1 is absent. Loss of u-STAT1 potently arrested cell cycle and inhibited cell growth in HCC cells. Induction of p-STAT1 by IFN-alpha treatment effectively triggers the expression of interferon stimulated genes (ISGs), but has moderate effect on HCC cell growth. Interestingly, both u-STAT1 and p-STAT1 are induced by IFN-alpha, through with distinct time-dependent process. Furthermore, the ISG induction patterns mediated by p-STAT1 and u-STAT1 are also distinct. Importantly, artificial blocking of the induction of u-STAT1, but not p-STAT1, sensitizes HCC cells to treatment of IFNs. Therefore, p-STAT1 and u-STAT1 exert dichotomal functions and coordinately regulate the responsiveness to IFN treatment in HCC. KEY MESSAGES: STAT1 is upregulated and predominantly presented as u-STAT1 in HCC, while p-STAT1 is absent. U-STAT1 sustains but p-STAT1 inhibits HCC growth. The dynamic change of phosphorylation state of STAT1 control the responsiveness to IFN treatment. PMID- 30456451 TI - Robotically assisted long bone biopsy under MRI: cadaver study results. AB - RATIONALE AND OBJECTIVES: We have designed and constructed an MR-safe robot made entirely of nonmetallic components with pneumatic actuators and optical encoders. The robot was developed to enable bone biopsies to be performed under magnetic resonance imaging (MRI) guidance in pediatric patients. The purpose of this study was to show the feasibility of using the robot for biopsy of the femur and tibia in a cadaver leg. Our long-term goal is to eliminate radiation exposure during bone biopsy procedures and provide more timely and accurate diagnosis for children with bone cancers and bone infections. METHODS: The MR-safe robot was mounted on the MRI table. A cadaver leg was procured from an anatomy supply house and placed on the MRI table. All required hospital precautions for infection control were taken. A total of 10 biopsy targets were sampled using MRI guidance: five from the femur and five from the tibia. A handheld, commercially available battery-powered bone drill was used to facilitate drilling through the cortex. After the study, the leg was scanned with CT to better visualize and document the bone biopsy sites. Both the MRI and CT images were used to analyze the results. RESULTS: All of the targets were successfully reached with an average targeting accuracy of 1.43 mm. A workflow analysis showed the average time for the first biopsy was 41 min including robot setup time and 22 min for each additional biopsy including the time for the repeat MRI scan used to confirm accurate targeting. The robot was shown to be MRI transparent, as no image quality degradation due to the use of the robot was detected. CONCLUSION: The results showed the feasibility of using an MR-safe robotic system to assist the interventional radiologist in performing precision bone biopsy under MRI guidance. Future work will include developing an MR-safe drill, improving the mounting of the robot and fixation of the leg, and moving toward first in child clinical trials. PMID- 30456452 TI - Is right-sided ligamentum teres hepatis always accompanied by left-sided gallbladder? Case reports and literature review. AB - Right-sided ligamentum teres (RSLT) hepatis is a rare anatomical variant in which the fetal umbilical vein is connected to the right paramedian trunk of the portal vein. Despite its rarity, it is crucial for surgeons and intervention specialists because of its frequent association with intrahepatic vascular and biliary anomalies. Inattention to these anomalies before intervention, especially living donor liver transplantation, can have life-threatening consequences. The relationship between gallbladder location and RSLT is still controversial, with RSLT regarded as one of the critical features of left-sided gallbladder in most studies. According to these hypotheses, once RSLT is present, left-sided gallbladder must be found as well. Here, we report three cases in which RSLT was associated with intrahepatic portal vein anomalies. In one case, the gallbladder was left-sided, but in the other two cases, it had a normal cholecystic axis to the right of the umbilical fissure. Therefore, the relationship between RSLT and gallbladder location may require redefinition, and surgeons should be aware of vascular anomalies once RSLT has been detected, even in the absence of left-sided gallbladder or biliary anomalies. TEACHING POINTS: * Right-sided ligamentum teres (RSLT) hepatis is a rare anatomical variant, which is frequently associated with intrahepatic vascular and biliary anomalies. Previous studies had discussed the vascular anomalies in livers with RSLT. * However, no predictable correlation exists between portal vein anomalies and anomalous biliary confluences in patients with RSLT. Moreover, we found that RSLT does not always coexist with left-sided gallbladder. * Unawareness of these vascular and biliary anomalies in liver with RSLT before intervention can have life-threatening consequences. * Thus, the vascular and biliary variations should be surveyed in multimodality imaging studies such as dynamic CT, 3D magnetic resonance cholangiopancreatography, or digital subtraction angiography once the RSLT is detected before intervention. PMID- 30456453 TI - Controllable Fabrication of Au-Coated AFM Probes via a Wet-Chemistry Procedure. AB - Tip-enhanced Raman spectroscopy (TERS), which offers a spatial resolution far beyond the limitations of the optical diffraction and detection sensitivity down to a single molecular level, has become one of the powerful techniques applied in current nanoscience and technology. However, the excellent performance of a TERS system is very much dependent on the quality of metallized probes used in TERS characterization. Thus, how to prepare higher-quality probes plays a vital role in the development and application of TERS technique. In this work, one simple wet-chemistry procedure was designed to fabricate atomic force microscopy-based TERS (AFM-TERS) probes. Through the controlled growth of a gold film on a commercial silicon AFM probe, TERS probes with different apex diameters were prepared successfully. A series of TERS results indicated that the probes with the apex size of 50~60 nm had the maximum TERS enhancement, and the Raman enhancement factor was in the range of 106 to 107. Compared with those prepared by other fabrication methods, our TERS probes fabricated by this wet-chemistry method have the virtues of good stability, high reproducibility, and strong enhancement effect. PMID- 30456454 TI - Toxicity and in vivo release profile of sirolimus from implants into the vitreous of rabbits' eyes. AB - PURPOSE: To assess the in vivo release profile and the retinal toxicity of a poly (lactic-co-glycolic acid) (PLGA) sustained-release sirolimus (SRL) intravitreal implant in normal rabbit eyes. METHODS: PLGA intravitreal implants containing or not SRL were prepared, and the viability of ARPE-19 and hES-RPE human retinal cell lines was examined after 24 and 72 h of exposure to implants. New Zealand rabbits were randomly divided into two groups that received intravitreal implants containing or not SRL. At each time point (1-8 weeks), four animals from the SRL group were euthanized, the vitreous was collected, and drug concentration was calculated. Clinical evaluation of the eyes was performed weekly for 8 weeks after administration. Electroretinography (ERG) was recorded in other eight animals, four for each group, at baseline and at 24 h, 1, 4, 6, and 8 weeks after the injection. ERG was carried out using scotopic and photopic protocols. The safety of the implants was assessed using statistical analysis of the ERG parameters (a and b waves, a and b implicit time, B/A ratio, oscillatory potential, and Naka-Rushton analysis) comparing the functional integrity of the retina between the PLGA and SRL-PLGA groups. After the last electrophysiological assessment, the rabbits were euthanized and retinal histopathology was realized. RESULTS: After 24 and 72 h of incubation with PLGA or SRL-PLGA implants, ARPE-19 and hES-RPE cells showed viability over 70%. The maximum concentration of SRL (199.8 ng/mL) released from the device occurred within 4 weeks. No toxic effects of the implants or increase in the intraocular pressure was observed through clinical evaluation of the eye. ERG responses showed no significant difference between the eyes that received PLGA or SRL-PLGA implants at baseline and throughout the 8 weeks of follow-up. No remarkable difference in retinal histopathology was detected in rabbit eyes treated with PLGA or SRL-PLGA implants. CONCLUSIONS: Intravitreal PLGA or SRL-PLGA implants caused no significant reduction in cell viability and showed no evident toxic effect on the function or structure of the retina of the animals. SRL was released from PLGA implant after application in the vitreous of rabbits during 8 weeks. PMID- 30456455 TI - Role of miR-9-5p in preventing peripheral neuropathy in patients with rheumatoid arthritis by targeting REST/miR-132 pathway. AB - MicroRNAs (miRNAs) are found to play a key role in neural cell differentiation, peripheral nerve injury, and rheumatoid arthritis (RA). However, no study has yet been conducted highlighting their role in RA-induced peripheral neuropathy. Here, we investigated the role of miRNAs in RA-induced peripheral neuropathy. Levels of six miRNAs were detected in serum collected from 15 patients with RA and peripheral neuropathy and 16 patients with RA. In vitro, Schwann cells were treated with 0.1 ng/mL IL-6 and 20 ng/mL TNF-alpha. The expression level of miR-9 5p and its association with the repressor element-1 silencing transcription factor (REST) were investigated. The roles of miR-9-5p and REST in Schwann cell injury were examined after transfection of miR-9-5p mimics or REST siRNA. In patients with RA and peripheral neuropathy, serum miR-9-5p was significantly downregulated when compared with RA. In IL-6- and TNF-alpha-stimulated Schwann cells, apoptosis was induced, while the cell viability and level of miR-9-5p were inhibited. A significantly negative correlation was observed between miR-9-5p and REST. Transfection of miR-9-5p mimics and REST siRNA significantly reversed the inhibition of cell viability and induction of apoptosis caused by IL-6 and TNF alpha. In addition, overexpression of miR-9-5p upregulated the expression of miR 132, miRNA targeting E1A binding protein EP300 (EEP300), phosphatase and tensin homolog (PTEN) and forkhead box O3 (FOXO3). These results showed that Schwann cells were protected by miR-9-5p from inflammatory damage by targeting REST/miR 132 pathway, which could provide new targets for treatment of RA-induced peripheral neuropathy. PMID- 30456456 TI - Butyric acid induces spontaneous adipocytic differentiation of porcine bone marrow-derived mesenchymal stem cells. AB - Butyric acid (BA) affects the differentiation of mesenchymal stem cells (MSC) through the activation of different transcriptional pathways. The aim of this study was to determine the effects of BA on proliferation and spontaneous differentiation of porcine bone marrow-derived MSC. Second passage MSC (n = 6) were cultured in either a basal medium (BM, DMEM + 10% FBS), or BM + 2.5 mmol/L BA (BA-2.5) or BM + 5 mmol/L BA (BA-5). Cell proliferation was significantly decreased by both BA-2.5 and BA-5 after 48 h and 72 h (- 55% and - 63%, respectively). To assess the impact of BA on spontaneous differentiation, MSC were cultured for 27 d, with complete media changes every 3 d. At day 27, cells were stained for osteocytic, chondrocytic, and adipocytic differentiation. No terminal differentiation was detected in control MSC, while accumulated small drops of lipids were stained by Oil-Red-O in BA-treated cells. The phenotypic changes were associated with changes in gene expression, determined by qPCR. Treatment with BA modulated the expression of adipocytic differentiation markers: peroxisome proliferator-activated receptor gamma and CCAAT/enhancer binding protein alpha were significantly increased by both BA-2.5 and BA-5 throughout the study, while lipoprotein lipase and fatty acid-binding protein 4 were increased by BA-5 at day 3, and decreased by both BA-5 and BA-2.5 later throughout the study. Osteocalcin and aggrecan mRNA was reduced throughout the experiment by both doses of BA (P < 0.05). In conclusion, our data support that BA promotes the spontaneous differentiation of porcine bone marrow-derived MSC toward an adipocytic lineage in the absence of inducing cocktail media. PMID- 30456458 TI - Associations of hemodynamics, morphology, and patient characteristics with aneurysm rupture stratified by aneurysm location. AB - PURPOSE: The mechanisms of cerebral aneurysm rupture are not fully understood. We analyzed the associations of hemodynamics, morphology, and patient age and gender with aneurysm rupture stratifying by location. METHODS: Using image-based models, 20 hemodynamic and 17 morphological parameters were compared in 1931 ruptured and unruptured aneurysms with univariate logistic regression. Rupture rates were compared between males and females as well as younger and older patients and bifurcation versus sidewall aneurysms for different aneurysm locations. Subsequently, associations between hemodynamics and morphology and patient as well as aneurysm characteristics were analyzed for aneurysms at five locations. RESULTS: Compared to unruptured aneurysms, ruptured aneurysms were characterized by a more irregular shape and were exposed to a more adverse hemodynamic environment described by faster flow, higher wall shear stress, more oscillatory shear, and more unstable and complex flows. These associations with rupture status were consistent for different aneurysm locations. Rupture rates were significantly higher in males at the internal carotid artery (ICA) bifurcation, ophthalmic ICA, and the middle cerebral artery (MCA) bifurcation. At the anterior communicating artery (ACOM) and MCA bifurcation, they were significantly higher for younger patients. Bifurcation aneurysms had significantly larger rupture rates at the MCA and posterior communicating artery (PCOM). In these groups with higher rupture rates, aneurysms were characterized by adverse hemodynamics and more complex shapes. CONCLUSION: Hemodynamic and morphological differences between ruptured and unruptured aneurysms are consistent across locations. Adverse morphology and hemodynamics are related to rupture as well as younger age, male gender, and bifurcation aneurysms. PMID- 30456457 TI - Global challenges for seagrass conservation. AB - Seagrasses, flowering marine plants that form underwater meadows, play a significant global role in supporting food security, mitigating climate change and supporting biodiversity. Although progress is being made to conserve seagrass meadows in select areas, most meadows remain under significant pressure resulting in a decline in meadow condition and loss of function. Effective management strategies need to be implemented to reverse seagrass loss and enhance their fundamental role in coastal ocean habitats. Here we propose that seagrass meadows globally face a series of significant common challenges that must be addressed from a multifaceted and interdisciplinary perspective in order to achieve global conservation of seagrass meadows. The six main global challenges to seagrass conservation are (1) a lack of awareness of what seagrasses are and a limited societal recognition of the importance of seagrasses in coastal systems; (2) the status of many seagrass meadows are unknown, and up-to-date information on status and condition is essential; (3) understanding threatening activities at local scales is required to target management actions accordingly; (4) expanding our understanding of interactions between the socio-economic and ecological elements of seagrass systems is essential to balance the needs of people and the planet; (5) seagrass research should be expanded to generate scientific inquiries that support conservation actions; (6) increased understanding of the linkages between seagrass and climate change is required to adapt conservation accordingly. We also explicitly outline a series of proposed policy actions that will enable the scientific and conservation community to rise to these challenges. We urge the seagrass conservation community to engage stakeholders from local resource users to international policy-makers to address the challenges outlined here, in order to secure the future of the world's seagrass ecosystems and maintain the vital services which they supply. PMID- 30456459 TI - The joint association of musculoskeletal pain and domains of physical activity with sleep problems: cross-sectional data from the DPhacto study, Denmark. AB - PURPOSE: To investigate if occupational physical activity (OPA) and leisure-time physical activity (LTPA) influence the association between musculoskeletal pain and sleep problems. METHODS: Cross-sectional study includes 678 workers in the Danish PHysical ACTivity cohort with Objective measurements (DPhacto). Musculoskeletal pain was assessed by questionnaires, while OPA and LTPA were measured with accelerometers for up to 6 consecutive days. We used logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for self-reported insomnia symptoms and non-restorative sleep. RESULTS: Analyses of the joint association of musculoskeletal pain and OPA showed that workers with high pain and high OPA had ORs of 5.80 (95% CI 2.64-12.67) for insomnia symptoms and 2.50 (95% CI 1.37-4.57) for non-restorative sleep, compared to those with low pain and low OPA, whereas workers with high pain and low OPA had ORs of 4.67 (95% CI 2.17-10.07) for insomnia symptoms, and 2.67 (95% CI 1.46-4.89) for non restorative sleep, respectively. Furthermore, workers with high pain and high LTPA had ORs of 4.23 (95% CI 2.16-8.32) for insomnia symptoms and 1.95 (95% CI 1.09-3.48) for non-restorative sleep, compared to those with low pain and low LTPA, whereas workers with high pain and low LTPA had ORs of 3.34 (95% CI 1.66 6.70) for insomnia symptoms and 2.14 (95% CI 1.21-3.80) for non-restorative sleep, respectively. CONCLUSIONS: Workers with high musculoskeletal pain who also conducted high levels of OPA or LTPA reported higher prevalence of insomnia symptoms. PMID- 30456460 TI - Coronary computed tomography angiography (CCTA) in patients with suspected stable coronary artery disease (CAD): diagnostic impact and clinical consequences in the German Cardiac CT Registry depending on stress test results. AB - To evaluate diagnostic impact of clinical use of coronary computed tomography angiography (CCTA) in patients with suspected stable coronary artery disease (CAD) and its consequences in daily practice for patient management, depending on stress test results in daily practice. Between 2009 and 2014 of a total population of 1352 patients of the German Cardiac Computed Tomography (CT) Registry who had previously undergone stress tests, CCTA visualizations were carried out on the coronary arteries with suspected stable CAD. Patients were divided into three groups according to stress test results: Group 1 with inconclusive (n = 178, 13.2%), Group 2 with ischemia in stress test (n = 372, 27.5%) and Group 3 without ischemia in stress test (n = 802, 59.3%). The test of preference was the stress electrocardiogram (ECG), which was performed more frequently in patients without ischemia in stress test as compared to those with ischemia (96.3% vs. 93.0%, p = 0.015). The incidence of detected obstructive CAD was lower in patients with suggested ischemia in stress test as compared to patients with inconclusive results (14.1% vs. 21.1%, p = 0.037). There was no difference in the incidence of an obstructive CAD in patients with and without ischemia in stress test (14.1% vs. 15.8%, p = 0.440). CCTA is a reliable, non invasive option for ruling-out obstructive CAD irrespective of the stress test result. PMID- 30456461 TI - Olaparib Tablet: A Review in Ovarian Cancer Maintenance Therapy. AB - Olaparib (Lynparza(r)), a first-in-class poly (ADP-ribose) polymerase (PARP) inhibitor, has recently been approved in a new tablet formulation as maintenance treatment for recurrent high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in complete or partial response to platinum based chemotherapy. Relative to an earlier capsule formulation, the tablet formulation of olaparib has improved bioavailability, thereby reducing pill burden and offering a more convenient dosage regimen. In the phase III SOLO2 study, maintenance treatment with olaparib tablets significantly prolonged median PFS (primary endpoint) relative to placebo in patients with platinum-sensitive, recurrent, ovarian cancer bearing gBRCA mutations. Results from an earlier phase II study (Study 19) assessing the capsule formulation supported these findings, with a significant PFS benefit (primary endpoint) observed with olaparib relative to placebo as maintenance therapy in patients with platinum-sensitive, recurrent, ovarian cancer, with or without BRCA mutations. Olaparib tablet had a manageable tolerability profile, with most adverse events of mild or moderate severity. Given its efficacy and manageable tolerability profile, olaparib tablets provide a useful maintenance treatment option for recurrent, platinum-sensitive ovarian cancer, regardless of BRCA mutation status, with the tablet formulation providing a more convenient dosing option. PMID- 30456462 TI - Analysis of key genes and micro-RNA-mRNA regulatory networks in women with ulcerative interstitial cystitis/pain bladder syndrome. AB - INTRODUCTION AND HYPOTHESIS: This aim of this study was to better understand ulcerative interstitial cystitis/painful bladder syndrome (IC/PBS) at the molecular level and provide new clues related to diagnosis and treatment. METHODS: The microarray data set GSE11783, including the mRNA and miRNA profiles of bladder tissue obtained at cystoscopic biopsy from patients with ulcerative IC/PBS (presence of at least one Hunner's ulcer) and normal controls, was downloaded from the GEO (Gene Expression Omnibus) database (National Center for Biotechnology Information). These were evaluated using Greenspring GX and Ingenuity Pathway Analysis (IPA) software. The differentially expressed genes (DEGs) and miRNAs (DEMs) in these two groups were identified. Subsequently, the DEGs were subjected to functional analysis, and a protein-protein interaction (PPI) network was constructed. Finally, the miRNA-mRNA regulatory network was visualized using Cystoscope software. RESULTS: Four DEMs and 1521 DEGs were identified between the ulcerative IC/PBS and control groups. The PPI network of the DEGs was constructed by STRING, which was composed of 393 nodes and 1039 edges, including 221 upregulated genes and 172 downregulated genes. Moreover, 27 genes in the PPI network were identified as hub genes in the IC/PBS group, e.g., PNOC, SSTR1, FPR3, GPR18 and APLNR. Subsequently, 27 clusters were selected from the PPI network using MCODE. It was shown that the most significant cluster consisted of 22 nodes and 231 edges. Moreover, miR-21 was the most significantly upregulated miRNA and was predicted to target one upregulated gene (RASGRP1) and two downregulated genes (KLF5 and SC5D). CONCLUSIONS: The results of this data mining and integration provide further information on the possible molecular basis of IC/PBS pathogenesis as well as potential biomarkers and therapeutic targets for ulcerative IC/PBS diagnosis and treatment. PMID- 30456463 TI - Incidence and impact of prosthesis-patient mismatch following transcatheter aortic valve implantation. AB - INTRODUCTION: The implications of prosthesis-patient mismatch (PPM) in the context of transcatheter aortic valve implantation (TAVI) are still controversial. The objective of our study was thus to investigate the incidence and prognostic impact of PPM after TAVI. METHODS: Our analysis included 613 TAVI patients in whom the indexed effective orifice area (iEOA) after TAVI was obtained in vivo using echocardiography. Prosthesis sizing was guided by pre procedural ECG-gated computed tomography. Based on VARC-2 established criteria for significant PPM (iEOA <= 0.85 cm2/m2 in the setting of BMI < 30 kg/m2 and iEOA <= 0.7 cm2/m2 in the context of BMI >= 30 kg/m2), patients were attributed to a "No PPM" or a "PPM" group. RESULTS: We observed PPM after TAVI in 192 patients (31.3%) with moderate PPM being present in 150 subjects (24.5%) and severe PPM in 42 patients (6.9%). EuroSCORE, impaired LV function, and male gender were associated with PPM status. The "No PPM" group was characterized by higher rates of self-expandable valves (40.4% vs. 25.5%, p < 0.001). In a multivariate analysis age > 81.2 years, chronic obstructive pulmonary disease, peripheral artery disease, impaired LV function, acute kidney failure stage 3 as well as periprocedural myocardial infarction emerged as independent risk predictors for all-cause mortality after TAVI. After a median follow-up of 12.2 months PPM failed to show a significant association with overall survival (79.2% vs. 79.3%, p = 0.692). CONCLUSIONS: The incidence of PPM after TAVI seems to be substantially lower than after SAVR. PPM was less common using self-expandable valves. In our analysis, patients with PPM following TAVI did not have higher rates of all-cause mortality. PMID- 30456464 TI - Me, the transplant and the ICU: a patient's story. PMID- 30456465 TI - "What's new?" : Immunostimulating strategies in the ICU. PMID- 30456466 TI - Host-pathogen interactions and prognosis of critically ill immunocompetent patients with pneumococcal pneumonia: the nationwide prospective observational STREPTOGENE study. AB - PURPOSE: To assess the relative importance of host and bacterial factors associated with hospital mortality in patients admitted to the intensive care unit (ICU) for pneumococcal community-acquired pneumonia (PCAP). METHODS: Immunocompetent Caucasian ICU patients with PCAP documented by cultures and/or pneumococcal urinary antigen (UAg Sp) test were included in this multicenter prospective study between 2008 and 2012. All pneumococcal strains were serotyped. Logistic regression analyses were performed to identify risk factors for hospital mortality. RESULTS: Of the 614 patients, 278 (45%) had septic shock, 270 (44%) had bacteremia, 307 (50%) required mechanical ventilation at admission, and 161 (26%) had a diagnosis based only on the UAg Sp test. No strains were penicillin resistant, but 23% had decreased susceptibility. Of the 36 serotypes identified, 7 accounted for 72% of the isolates, with different distributions according to age. Although antibiotics were consistently appropriate and were started within 6 h after admission in 454 (74%) patients, 116 (18.9%) patients died. Independent predictors of hospital mortality in the adjusted analysis were platelets <= 100 * 109/L (OR, 7.7; 95% CI, 2.8-21.1), McCabe score >= 2 (4.58; 1.61-13), age > 65 years (2.92; 1.49-5.74), lactates > 4 mmol/L (2.41; 1.27-4.56), male gender and septic shock (2.23; 1.30-3.83 for each), invasive mechanical ventilation (1.78; 1 3.19), and bilateral pneumonia (1.59; 1.02-2.47). Women with platelets <= 100 * 109/L had the highest mortality risk (adjusted OR, 7.7; 2.8-21). CONCLUSIONS: In critically ill patients with PCAP, age, gender, and organ failures at ICU admission were more strongly associated with hospital mortality than were comorbidities. Neither pneumococcal serotype nor antibiotic regimen was associated with hospital mortality. PMID- 30456468 TI - Negative feelings about the timing of first sexual intercourse: findings from the Health Behaviour in School-aged Children study. AB - OBJECTIVES: This study investigates the association between negative feelings about the first intercourse timing and sociodemographic and contextual factors. We hypothesized that girls and adolescents with an older first sexual partner will be more likely to report negative feelings and that prevalence of those feelings will vary across countries. METHODS: Adolescents (N = 6073, mean age = 15.6 +/- 0.34), from Bulgaria, France, Ireland, and Scotland, taking part in the 2013/2014 HBSC study, were asked about sexual initiation, their age and partner's age at first intercourse, and their feeling about the timing of first intercourse. RESULTS: One-fifth of the 1321 adolescents who had had sexual intercourse reported negative feelings about the first intercourse timing. Girls, adolescents from low affluent families, and those with an older first partner were more likely to report negative feelings. However, after adjustment for covariates, only girls and those from less affluent families had significantly higher odds of reporting negative feelings. CONCLUSIONS: Sexual education programmes need to explicitly address decision-making around timing of first intercourse in order to reduce negative feelings, with a special attention to gender and social inequalities. PMID- 30456467 TI - Fluid administration for acute circulatory dysfunction using basic monitoring: narrative review and expert panel recommendations from an ESICM task force. AB - An international team of experts in the field of fluid resuscitation was invited by the ESICM to form a task force to systematically review the evidence concerning fluid administration using basic monitoring. The work included a particular emphasis on pre-ICU hospital settings and resource-limited settings. The work focused on four main questions: (1) What is the role of clinical assessment to guide fluid resuscitation in shock? (2) What basic monitoring is required to perform and interpret a fluid challenge? (3) What defines a fluid challenge in terms of fluid type, ranges of volume, and rate of administration? (4) What are the safety endpoints during a fluid challenge? The expert panel found insufficient evidence to provide recommendations according to the GRADE system, and was only able to make recommendations for basic interventions, based on the available evidence and expert opinion. The panel identified significant gaps in the scientific evidence on fluid administration outside the ICU (excluding the operating theater). Globally, scientific communities and health care systems should address these critical gaps in evidence through research on how basic fluid administration in resource-rich and resource-limited settings can be improved for the benefit of patients and societies worldwide. PMID- 30456469 TI - Interpreting the Athlete's ECG: Current State and Future Perspectives. AB - Sudden cardiac death (SCD) is the leading cause of death in athletes. A large proportion of these deaths are associated with undiagnosed cardiovascular disease. Screening for high-risk individuals enables early detection of pathology, as well as permitting lifestyle modification or therapeutic intervention.ECG changes in athletes occur as a result of electrical and structural adaptations secondary to repeated bouts of exercise. Such changes are common and may overlap with patterns suggestive of underlying cardiovascular disease. Correct interpretation is therefore essential, in order to differentiate physiology from pathology. Erroneous interpretation may result in false reassurance or expensive investigations for further evaluation and unnecessary disqualification from competitive sports.Interpretation of the athlete's ECG has evolved over the past 12 years, beginning with the 2005 European Society of Cardiology (ESC) consensus, progressing to the ESC recommendations (2010), Seattle Criteria (2013) and the 'refined' criteria (2014). This evolution culminated in the recently published international recommendations for ECG interpretation in athletes (2017), which has led to a significant reduction in false positives and screening-associated costs. This review aims to describe the evolution of the current knowledge on ECG interpretation as well as future directions. PMID- 30456470 TI - [Geriatric rehabilitation medicine: state of the art]. PMID- 30456471 TI - [Pain in old age]. AB - The prevalence of chronic pain increases with increasing age. Multimorbidity increases the risk of disease-related pain. Addressing the problem of pain in higher age is concerned with an increasing problem of care. The multimorbidity and the resulting multimedication are important for the medical care of pain. The therefore necessary physician-patient verbal communication can hardly be remunerated and carried out in the current care landscape. Existing resources must be bundled. The quality of life of older people and not the absence of pain, must be emphasized. Particularly problematic is the recognition and treatment of pain in patients with dementia. Pain in dementia patients is more rarely detected. In addition to questioning relatives and caregivers, a structured pain interview is necessary. The pharmacology of chronic pain is concerned above all with the prevention of iatrogenic risks through interactions and pharmacological complications. The patient-related treatment priorities must be checked and adjusted during the course of treatment. To be considered are age-related altered metabolic pathways. A sensible therapy option is the training of physical activity with a positive effect on the entire pain experience. Behavioral medical treatment procedures are other important building blocks in pain therapy. In addition to the multimodal therapeutic approaches, a stronger interdisciplinary collaboration of special pain medicine and geriatrics is necessary. PMID- 30456472 TI - Consequences of interrupted employment careers on early retirement and pension entitlements. AB - BACKGROUND: Reduced earning capacity pensions are an important welfare state benefit for those who are no longer able to work due to chronic illness. However, the low average pension entitlements are a cause for concern. OBJECTIVE: Early retirement results in lower overall pensions due to obligatory deductions, often combined with less stable working careers and longer periods of unemployment. The following analysis investigates the consequences of career characteristics for pension entitlements in 2014. MATERIALS AND METHODS: Longitudinal data from the German Pension Insurance records, the "Completed Insurance Biographies 2014" (SUF VVL 2014), are used to study differences between pensioners who had retired early due to ill health and regular old age pensioners in terms of working career stability and the resulting monthly pension payments. Linear regression is used to explore reasons for overall lower pensions for persons with reduced earning capacity. RESULTS: On average, more old age pensioners had had uninterrupted working careers and they had experienced less unemployment before retirement. These differences explain the major part of the difference between the two kinds of pension entitlements. However, early retirees also often experienced income decline compared to old age pensioners with a similar working career. CONCLUSION: Lower reduced earning capacity pension entitlements are a result of income inequality on the labor market and the increasing long-term unemployment. PMID- 30456473 TI - [Change of retirement transition in the political paradigm shift in Europe : Late career and retirement transitions in Germany, Austria, Sweden and Estonia]. AB - BACKGROUND: In the last two decades labor market participation for older employees has undergone a gradual political paradigm shift in many European countries from a policy of early retirement to one of extending working lives and active aging. OBJECTIVE: This study investigated if this political paradigm shift is causing new social inequalities in retirement transition due to restricted financial possibilities for early retirement. MATERIAL AND METHODS: Data were derived from the European Union Labor Force Survey from the years 2006 and 2012 and selected European countries (Germany, Austria, Sweden and Estonia) were analyzed. RESULTS: Associations between the specific implementation of the policy of active aging, the freedom of choice in retirement timing and retirement transition were found. It seems that voluntary retirement transitions are highest in those countries where the labor market and social policies are most coherent and aimed at supporting older workers' employability. CONCLUSION: The reduction of early retirement incentives should be supported by active labor market policies and a policy of extensive age-independent further training measures in order to minimize social inequalities. PMID- 30456474 TI - Engagement: what is it good for? The role of learner engagement in healthcare simulation contexts. AB - Learner engagement matters, particularly in simulation-based education. Indeed, it has been argued that instructional design only matters in the service of engaging learners in a simulation encounter. Yet despite its purported importance, our understanding of what engagement is, how to define it, how to measure it, and how to assess it is limited. The current study presents the results of a critical narrative review of literature outside of health sciences education, with the aim of summarizing existing knowledge in these areas and providing a research agenda to guide future scholarship on learner engagement in healthcare simulation. Building on this existing knowledge base, we provide a working definition for engagement and provide an outline for future research programs that will help us better understand how health professions' learners experience engagement in the simulated setting. With this in hand, additional research questions can be addressed including: how do simulation instructional design features (fidelity, range of task difficulty, feedback, etc.) affect engagement? What is the relationship between engagement and simulation learning outcomes? And how is engagement related to or distinct from related variables like cognitive load, motivation, and self-regulated learning? PMID- 30456475 TI - 18F-labeled anti-human CD20 cys-diabody for same-day immunoPET in a model of aggressive B cell lymphoma in human CD20 transgenic mice. AB - PURPOSE: Metabolic imaging using [18F]FDG is the current standard for clinical PET; however, some malignancies (e.g., indolent lymphomas) show low avidity for FDG. The majority of B cell lymphomas express CD20, making it a valuable target both for antibody-based therapy and imaging. We previously developed PET tracers based on the humanised anti-CD20 antibody obinutuzumab (GA101). Preclinical studies showed that the smallest bivalent fragment, the cys-diabody (GAcDb, 54.5 kDa) with a peak uptake at 1-2 h post-injection and a biological half-life of 2-5 h, is compatible with short-lived positron emitters such as fluorine-18 (18F, t1/2 110 min), enabling same-day imaging. METHODS: GAcDb was radiolabeled using amine-reactive N-succinimidyl 4-[18F]-fluorobenzoate ([18F]SFB), or thiol reactive N-[2-(4-[18F]-fluorobenzamido)ethyl]maleimide ([18F]FBEM) for site specific conjugation to C-terminal cysteine residues. Both tracers were used for immunoPET imaging of the B cell compartment in human CD20 transgenic mice (hCD20TM). [18F]FB-GAcDb immunoPET was further evaluated in a disseminated lymphoma (A20-hCD20) syngeneic for hCD20TM and compared to [18F]FDG PET. Tracer uptake was confirmed by ex vivo biodistribution. RESULTS: The GAcDb was successfully 18F-radiolabeled using two different conjugation methods resulting in similar specific activities and without impairing immunoreactivity. Both tracers ([18F]FB-GAcDb and [18F]FBEM-GAcDb) specifically target human CD20 expressing B cells in transgenic mice. Fast blood clearance results in high contrast PET images as early as 1 h post injection enabling same-day imaging. [18F]FB-GAcDb immunoPET detects disseminated lymphoma disease in the context of normal tissue expression of hCD20, with comparable sensitivity as [18F]FDG PET but with added specificity for the therapeutic target. CONCLUSIONS: [18F]FB-GAcDb and [18F]FBEM-GAcDb could monitor normal B cells and B cell malignancies non invasively and quantitatively in vivo. In contrast to [18F]FDG PET, immunoPET provides not only information about the extent of disease but also about presence and localisation of the therapeutic target. PMID- 30456476 TI - The interplay between copper(II), human serum albumin, fatty acids, and carbonylating agent interferes with Cys 34 thiol reactivity and copper binding. AB - Cys34 thiol group of human serum albumin (HSA) represents major plasma antioxidant. Its reactivity is influenced by multiple factors. The influence of fatty acids (FA; saturated, mono, and poly unsaturated acids from fish oil) binding to HSA, on copper(II) binding affinity and Cys34 thiol group accessibility/reactivity, in the presence of carbonylation agent (methylglyoxal, MG) was examined. HSA-copper(II) content, thiol group reactivity, and HSA carbonylation level were monitored spectrophotometrically. Changes in HSA were followed by fluorescence spectroscopy and native PAG electrophoresis. FA/HSA molar ratio was screened by GC. Together, binding of copper(II) ions and FA to HSA increase the reactivity of Cys34 thiol group (depending on the type of FA), with constant contribution of copper(II) ions of one-third. Carbonylation of FA HSA-Cu(II) complexes caused a decrease in the Cys34 thiol group content, accompanied by a decrease in the content of HSA-bound copper. The carbonylation level of guanidine groups was not affected by FAs and copper(II) binding. Fluorescent emission spectra of FA-HSA-Cu(II)-MG complexes showed conformational changes in HSA molecule. Although binding of fatty acids and copper ions caused a significant increase in the thiol group reactivity, Cys34 thiol from FA-HSA Cu(II) complexes reacted with MG in smaller extent than expected, probably as a consequence of conformational changes introduced by carbonylation. Increase in the percentage of reacted-free thiol groups with MG (due to FA and copper binding) may not seem to be very significant, but it is very important in complex biological systems, where catalytic metal is present. PMID- 30456477 TI - The increasing prevalence of chronic lymphocytic thyroiditis in papillary microcarcinoma. AB - Although the incidence of some malignancy has decreased over the recent years, this is not the case of papillary thyroid microcarcinoma (PTMC), whose incidence has increased worldwide. Most PTMC are found incidentally after histological examination of specimens from surgery for benign thyroid disease. Hashimoto's thyroiditis, whose incidence has also increased, coexists in about one in three PTMC patients. Three different mechanisms have been proposed to clarify the association between chronic lymphocytic thyroiditis and PTMC, namely tumor development/growth by: (i) TSH stimulation, (ii) expression of certain proto oncogenes, (iii) chemokines and other molecules produced by the lymphocytic infiltrate. Whether Hashimoto's thyroiditis protects against lymph node metastasis is debated. Overall, autommune thyroiditis seems to contribute to the favorable prognosis of PTMC. Major limitations of the studies so far performed include: (i) retrospective design, (ii) limited statistical power, (iii) high risk of selection bias, (iv) and predominant Asian ethnicity of patients. Full genetic profiling of both diseases and identification of environmental factors capable to trigger them, as well as well-powered prospective studies on different ethnical groups, may help understand their causal association and why their frequencies are continuing raising. PMID- 30456478 TI - [Self-help support, self-help groups and self-help friendliness in Switzerland between subsidiary structure and national development needs]. AB - The Swiss welfare state is marked by strong federalism and subsidiarity, e. g. when it comes to social and health policies. This contribution presents findings of the first national study on self-help in Switzerland.This contribution is based on three sub-projects: 1. an oral and an online survey of the management personnel of the national organization Self-help Switzerland (Selbsthilfe Schweiz) and all regional self-help centers; 2. a quantitative-descriptive evaluation of the Self-help Switzerland's database with over 2500 self-help groups; and 3. twelve semi-structured interviews with experts from the social and health system.Little support is given at the national level to the self-help system. While Self-help Switzerland deals with topics of national importance, promotion of self-help has so far primarily been the domain of the regional self help centers. This led to large regional differences in the dissemination and the development of self-help groups. There are also regional disparities in the cooperation between self-help groups and centers with the professionals and institutions from the social and health system.Self-help is discussed as characteristic for the federalist and subsidiary culture of the Swiss welfare state. The current self-help landscape is regionally based and locally financed. There is a substantial need for development on the national level: a legal base is required as well as stronger funding for self-help support and initiatives for self-help friendliness. PMID- 30456480 TI - Population pharmacokinetics and exposure-response assessment of veliparib co administered with temozolomide in patients with myeloid leukemias. AB - PURPOSE: Veliparib is an oral inhibitor of poly(ADP-ribose) polymerase enzyme. Combination of veliparib and temozolomide was well-tolerated and demonstrated clinical activity in older patients with relapsed or refractory acute myeloid leukemia (AML) or AML arising from pre-existing myeloid malignancies. We aimed to perform quantitative assessments of pharmacokinetics, efficacy, and safety of veliparib in this patient population to inform future trial design. METHODS: Population pharmacokinetic analysis was performed using Phoenix(r) NLME with pharmacokinetic data obtained from 37 subjects after oral administration of veliparib in a Phase I study with and without temozolomide. Effect of covariates (age, sex, BMI, creatinine clearance (CLCR), and co-administration of temozolomide) on the pharmacokinetics of veliparib were evaluated, as well as impact of veliparib exposure on mucositis (dose-limiting toxicity), objective response rate (ORR), and overall survival. RESULTS: A two-compartment model with first-order elimination and a first-order absorption with lag-time adequately described veliparib pharmacokinetics. CLCR and body weight were clinically significant covariates for veliparib disposition. The proportion of subjects with all grade mucositis increased with veliparib exposure (AUC). However, no trend in ORR and overall survival was observed with increasing exposure. CONCLUSIONS: Veliparib with temozolomide presents a promising combination for older patients with myeloid leukemias. An exposure-safety relationship was established for this combination. Further clinical investigations aimed at elucidating the veliparib exposure-efficacy/safety relationship and optimizing dosing recommendations for maximizing benefit-risk in patients with advanced myeloid malignancies should study veliparib doses ranging up to 120 mg in combination with temozolomide. PMID- 30456481 TI - Correction to: The Met Needs for Pediatric Surgical Conditions in Sierra Leone: Estimating the Gap. AB - In the original article, Johan von Schreeb's last name was spelled incorrectly. It is correct as reflected here. PMID- 30456482 TI - Enhanced REVENUE After Surgery? A Cost-Standardized Enhanced Recovery Pathway for Mastectomy Decreases Length of Stay. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) protocols have been shown to improve surgical, anesthetic, and economic outcomes in intermediate-to-high-risk surgeries. Its influence on length of stay and cost of low-risk surgeries has yet to be robustly studied. As value-based patient care comes to the forefront of anesthesiology research, the focus shifts to strategies that maintain quality while effectively containing cost. METHODS: In July 2016, we implemented an ERAS for mastectomy protocol consisting of limiting fasting state, preoperative multimodal analgesia, and pectoralis I and II blocks. After 1 year, patient records were retrospectively reviewed for length of stay, opioid consumption, pain scores, and hospital charges. RESULTS: Implementation of an ERAS protocol for mastectomies led to a decrease in opioid consumption, and statistically significant decrease in length of stay (1.19 vs. 1.44, p = 0.01). No significant change in hospital charges was observed ($25,787 vs. $25,863, p = 0.97); however, the variance of charges was significantly decreased (6.8 * 107 vs. 1.5 * 108, p = 0.002). The decrease in length of stay translated to an extra 100 hospital bed days which can provide up to an additional $2,100,000 in gross patient service revenue from additional mastectomy volume. CONCLUSION: ERAS protocols for mastectomies may prove beneficial by allowing growing hospitals to increase bed capacity and consequently surgical volume. Despite no change in hospital charges, we predict a potential increase in gross patient service revenue of $2.1 million due to saved hospital bed days. PMID- 30456483 TI - Decision-Making in the Emergency Laparotomy: A Mixed Methodology Study. AB - INTRODUCTION: More than 30,000 emergency laparotomies take place annually in England and Wales (Symons et al. in Br J Surg 100(10):1318-1325, 2013; Shapter et al. in Anaesthesia 67(5):474-478, 2012). They are associated with high morbidity and an average inpatient 30-day mortality rate of 11%. Inextricably linked to outcomes is the decision-making process of whether or not to operate (NELA Project Team First patient report of the National Emergency Laparotomy Audit. RCoA, London, 2015; Crebbin et al. in Aust N Z J Surg 83(6):422-428, 2013). A mixed-methods study was undertaken to investigate decision-making in the emergency laparotomy and influencing factors. METHODS: Semi-structured interviews were undertaken amongst general surgeons, exploring the decision-making process. Results helped guide design of an online survey, consisting of vignettes and subsequent questions. Respondents were asked to decide whether or not they would perform a laparotomy for each vignette and the results compared to grade, risk attitudes and reflective practice. Responses were analysed for effect of previous positive and negative experiences and for consistency. RESULTS: Interviews revealed multiple important factors when considering whether or not to perform an emergency laparotomy, broadly categorised into patient-related, surgeon-related and external factors. A total of 116 general surgeons completed the survey: 12 SHOs, 79 registrars and 25 consultants. Non-consultants were 10.4% (95% CI +/ 9.7%) more likely to perform an emergency laparotomy than consultants (p = 0.036) on multivariate analysis. No association was observed between operative practices and risk attitudes (p = 0.22), reflective practice (p = 0.7) or previous positive or negative experiences in univariate (p = 0.67) or multivariate analysis. Surgeons were not proven to be either consistent nor inconsistent in their decision-making. CONCLUSION: The decision to operate or not in an emergency laparotomy directly effects patient outcome. This study demonstrates a difference in decision-making and risk attitudes between consultants and their juniors. To address this, formal teaching of models of decision-making, influencing factors and vignette-based consultant-led discussions should be introduced into surgical training. PMID- 30456479 TI - Advancing Health Policy and Program Research in Diabetes: Findings from the Natural Experiments for Translation in Diabetes (NEXT-D) Network. AB - PURPOSE OF REVIEW: To advance our understanding of the impacts of policies and programs aimed at improving detection, engagement, prevention, and clinical diabetes management in the USA, we synthesized findings from a network of studies that used natural experiments to evaluate diabetes health policies and programs. FINDINGS: Studies from the Natural EXperiments for Translation in Diabetes (NEXT D) network used rigorous longitudinal quasi-experimental study designs (e.g., interrupted time series) and analytical methods (e.g., difference-in-differences) to augment causal inference. Investigators partnered with health system stakeholders to evaluate whether glucose testing rates changed from before-to after clinic interventions (e.g., integrating electronic screening decision prompts in New York City) or employer programs (e.g., targeted messaging and waiving copayments for at-risk employees). Other studies examined participation and behavior change in low- (e.g., wellness coaching) or high-intensity lifestyle modification programs (e.g., diabetes prevention program-like interventions) offered by payers or employers. Lastly, studies assessed how employer health insurance benefits impacted healthcare utilization, adherence, and outcomes among people with diabetes. NEXT-D demonstrated that low-intensity interventions to facilitate glucose testing and enhance engagement in lifestyle modification were associated with small improvements in weight but large improvements in screening and testing when supported by electronic health record-based decision-support. Regarding high-intensity diabetes prevention program-like lifestyle programs offered by payers or employers, enrollment was modest and led to weight loss and marginally lower short-term health expenditures. Health plans that incentivize patient behaviors were associated with increases in medication adherence. Meanwhile, shifting patients to high-deductible health plans was associated with no change in medication use and preventive screenings, but patients with diabetes delayed accessing healthcare for acute complications (e.g., cellulitis). Findings were more pronounced among lower-income patients, who experienced increased rates and acuity of emergency department visits for diabetes complications and other high-severity conditions. Findings from NEXT-D studies provide informative data that can guide programs and policies to facilitate detection, prevention, and treatment of diabetes in practice. PMID- 30456484 TI - Use of ultrasonography to evaluate the dynamics of the infrapatellar fat pad after anterior cruciate ligament reconstruction: a feasibility study. AB - PURPOSE: There has been no specific study on the quantitative morphological changes that occur in the infrapatellar fat pad (IPFP) after anterior cruciate ligament (ACL) reconstruction. We used ultrasonography to evaluate the dynamics of the IPFP in knees after ACL reconstruction using the contralateral knees as controls. METHODS: We enrolled 31 patients 3 months after they underwent ACL reconstruction. The thickness of the superficial part of the IPFP was measured using longitudinally oriented ultrasound images of the anterior part of both knees at 90 degrees and 10 degrees flexion. We then used these data to calculate the ratio of the change in thickness. RESULTS: At 90 degrees knee flexion, the superficial part of the IPFP was significantly thinner in the reconstructed knees (9.3 +/- 3.4 mm) than in the contralateral knees (11.8 +/- 4.6 mm). The thickness change ratio was significantly smaller in the reconstructed knees (188.6 +/- 64.7%) than in the contralateral knees (249.7 +/- 73.8%). CONCLUSION: When assessed 3 months after ACL reconstruction, the thickness of the superficial part of the IPFP at 90 degrees knee flexion and the thickness change ratio of the IPFP were both significantly lower in the reconstructed knees than in the contralateral knees. PMID- 30456485 TI - Comment on: Perinatal exposure to a glyphosate-based herbicide impairs female reproductive outcomes and induces second-generation adverse effects in Wistar rats. PMID- 30456486 TI - A systematic analysis of Nrf2 pathway activation dynamics during repeated xenobiotic exposure. AB - Oxidative stress leads to the activation of the Nuclear factor-erythroid-2 related factor 2 (Nrf2) pathway. While most studies have focused on the activation of the Nrf2 pathway after single chemical treatment, little is known about the dynamic regulation of the Nrf2 pathway in the context of repeated exposure scenarios. Here we employed single cell live imaging to quantitatively monitor the dynamics of the Nrf2 pathway during repeated exposure, making advantage of two HepG2 fluorescent protein reporter cell lines, expressing GFP tagged Nrf2 or sulfiredoxin 1 (Srxn1), a direct downstream target of Nrf2. High throughput live confocal imaging was used to measure the temporal dynamics of these two components of the Nrf2 pathway after repeated exposure to an extensive concentration range of diethyl maleate (DEM) and tert-butylhydroquinone (tBHQ). Single treatment with DEM or tBHQ induced Nrf2 and Srxn1 over time in a concentration-dependent manner. The Nrf2 response to a second treatment was lower than the response to the first exposure with the same concentration, indicating that the response is adaptive. Moreover, a limited fraction of individual cells committed themselves into the Nrf2 response during the second treatment. Despite the suppression of the Nrf2 pathway, the second treatment resulted in a three fold higher Srxn1-GFP response compared to the first treatment, with all cells participating in the response. While after the first treatment Srxn1-GFP response was linearly related to Nrf2-GFP nuclear translocation, such a linear relationship was less clear for the second exposure. siRNA-mediated knockdown demonstrated that the second response is dependent on the activity of Nrf2. Several other, clinically relevant, compounds (i.e., sulphorophane, nitrofurantoin and CDDO-Me) also enhanced the induction of Srxn1-GFP upon two consecutive repeated exposure. Together the data indicate that adaptation towards pro-oxidants lowers the Nrf2 activation capacity, but simultaneously primes cells for the enhancement of an antioxidant response which depends on factors other than just Nrf2. These data provide further insight in the overall dynamics of stress pathway activation after repeated exposure and underscore the complexity of responses that may govern repeated dose toxicity. PMID- 30456487 TI - Evidence of intraspecific prey switching: stage-structured predation of polar bears on ringed seals. AB - Prey switching is a phenomenon in which a predator disproportionately consumes the most abundant prey type, and switches to preferentially consume another prey type if the first becomes relatively rare. This concept may be expanded outside of its usual usage describing switching between prey species (interspecific), to describe switching between prey stages within a given species (intraspecific). Polar bears (Ursus maritimus) are thought to seek out naive ringed seal (Pusa hispida) pups in the spring, but how that may change in years with low seal productivity is unknown. We addressed two main questions: If polar bears typically select for ringed seals' pups, how does this change in years with reduced ringed-seal productivity? How does polar bear predation during years with low ringed-seal productivity impact the ringed seal population? We created a matrix population model for ringed seals to get an estimate of each stage's availability to polar bears in the spring. These estimates of availability were combined with existing studies on the ages of seals consumed by polar bears in years of both high and low ringed seal productivity. Our results suggest that polar bears typically strongly select for ringed seal pups, but switch to disproportionately select older ringed seals in years with low pup availability. The effects of this on ringed seal population growth appear negligible. Non intuitive results on the effect of prey switching on the prey population emphasize the importance of considering environmental sequences rather than individual years. PMID- 30456488 TI - Changes in the photosynthesis properties and photoprotection capacity in rice (Oryza sativa) grown under red, blue, or white light. AB - Non-photochemical quenching (NPQ) of the excited state of chlorophyll a is a major photoprotective mechanism plants utilize to survive under high light. Here, we report the impact of long-term light quality treatment on photosynthetic properties, especially NPQ in rice. We used three LED-based light regimes, i.e., red (648-672 nm), blue (438-460 nm), and "warm" white light (529-624 nm), with the incident photon flux density of 300 umol photons m-2 s-1, the difference in the absorbed photon flux densities by leaves grown under different light quality being less than 7%. Our results show that blue light, as compared to white light, induced a significant decrease in Fv/Fm, a decreased rate of reduction of P700+ after P700 was completely oxidized; furthermore, blue light also induced higher NPQ with an increased initial speed of NPQ induction, which corresponds to the qE component of NPQ, and a lower maximum quantum yield of PSII, i.e., Y(II). In contrast, rice grown under long-term red light showed decreased Y(II) and increased NPQ, but with no change in Fv/Fm. Furthermore, we found that rice grown under either blue or red light showed decreased transcript abundance of both catalase and ascorbate peroxidase, together with an increased H2O2 content, as compared to rice grown under white light. All these data suggest that even under a moderate incident light level, rice grown under blue or red light led to compromised antioxidant system, which contributed to decreased quantum yield of photosystem II and increased NPQ. PMID- 30456489 TI - Seminal plasma (SP) induces a rapid transforming growth factor beta 1 (TGFbeta1) independent up-regulation of epithelial-mesenchymal transdifferentiation (EMT) and myofibroblastic metaplasia-markers in endometriotic (EM) and endometrial cells. AB - PURPOSE: To study if short-term exposure (2 h and 6 h) of endometrial/endometriotic tissues and cells to 10% seminal plasma (SP) can induce EMT/metaplasia. METHODS: Basic research experimental study was carried out in a University hospital-based fertility center. Semen samples, peritoneal fluid (PF) from endometriosis patients, endometrial biopsy from premenopausal women, immortalized endometriotic epithelial cell line (12Z), and immortalized endometrial stromal cell line (St-T1b) were studied. Rapid stain identification test (RSID), TGFbeta1 immunofluorescence of washed sperms, TGFbeta1-ELISA of SP and PF, in vitro study (2 h and 6 h incubation) and real-time PCR of endometrial tissue and cell lines to analyze gene expression of EMT/metaplasia markers and mediators were done. RESULTS: SP is still detectable in washed semen. TGFbeta1 was expressed on the plasma membrane of the sperms and was significantly more concentrated in SP (88.17 ng/ml) than PF. 10% SP induced an up-regulation of alpha smooth muscle actin expression in endometrial tissue (p = 0.008) and in 12Z cells (p = 0.05), mostly TGFbeta1-independent. TWIST expression was persistently significantly down-regulated while Snail1 and 2 were up-regulated, though insignificant. CONCLUSION: Our results provide novel evidence to support that even in semen washed twice, SP is still detectable. The changes in EMT/metaplasia markers and mediators give a new insight into a possible effect of SP on the pathogenesis of endometriosis. PMID- 30456490 TI - Myiasis in humans-a global case report evaluation and literature analysis. AB - Myiasis refers to the infestation of living humans and vertebrates with fly larvae that feed on necrotic or vital tissue of the host. Since the invasion of new fly species in Europe is currently being observed, which live obligatorily parasitically or are close relatives of such species, the aim of this study is to obtain a global overview of the distribution of myiasis-causing fly species in times of climate change and to assess the possible consequences for Western Europe. A systematic literature search was conducted using Pubmed/Medline for the years 1997 to 2017 and a total of 464 international case reports from 79 countries were evaluated. The described cases were caused by 41 different species. In 99.4% of the cases, it was a colonization by just one species, a maximum of three species were detected in a human. Casuistics from Western Europe mostly describe myiasis as a "holiday souvenir" from tropical regions. Reports of autochthonous cases are rare in comparison to other regions. With regard to rising temperatures and the invasion of new fly species, a noticeable increase in the number of cases in Western Europe is to be assumed, which could be an increasing problem in the clinical area and in care, which is why thorough monitoring for professional identification and treatment seems important in the future. PMID- 30456491 TI - Endocrine and immune responses of larval amphibians to trematode exposure. AB - In nature, multiple waves of exposure to the same parasite are likely, making it important to understand how initial exposure or infection affects subsequent host infections, including the underlying physiological pathways involved. We tested whether experimental exposure to trematodes (Echinostoma trivolvis or Ribeiroia ondatrae) affected the stress hormone corticosterone (known to influence immunocompetence) in larvae representing five anuran species. We also examined the leukocyte profiles of seven host species after single exposure to R. ondatrae (including four species at multiple time points) and determined if parasite success differed between individuals given one or two challenges. We found strong interspecific variation among anuran species in their corticosterone levels and leukocyte profiles, and fewer R. ondatrae established in tadpoles previously challenged, consistent with defense "priming." However, exposure to either trematode had only weak effects on our measured responses. Tadpoles exposed to E. trivolvis had decreased corticosterone levels relative to controls, whereas those exposed to R. ondatrae exhibited no change. Similarly, R. ondatrae exposure did not lead to appreciable changes in host leukocyte profiles, even after multiple challenges. Prior exposure thus influenced host susceptibility to trematodes, but was not obviously associated with shifts in leukocyte counts or corticosterone, in contrast to work with microparasites. PMID- 30456492 TI - Pathological and molecular characterization of avian malaria in captive Magellanic penguins (Spheniscus magellanicus) in South America. AB - Avian malaria is a mosquito-borne disease that affects multiple avian species and is caused by protozoans of the genus Plasmodium. An avian malaria infection caused by Plasmodium sp. in Magellanic penguins (Spheniscus magellanicus) with high mortality is described in a zoo in Southern Brazil. Clinically, three birds presented signs of inappetence, anorexia, pale mucosa, dyspnea, and opisthotonus, with death in a clinical course of 5-8 h. At the necropsy, all birds exhibited pale mucosa, marked splenomegaly and hepatomegaly, in addition to moderate leptomeningeal blood vessels ingurgitation in the brain. Microscopically, multiple exoerythrocytic meronts were observed in the cytoplasm of endothelial cells in the spleen, liver, heart, lungs, brain, kidneys, and pancreas. The spleen had a multifocal perivascular inflammatory infiltrate of lymphocytes, plasma cells, and macrophages, which also exhibited hemosiderosis and erythrophagocytosis. The liver had a multifocal periportal inflammatory infiltrate of lymphocytes, macrophages, and plasma cells, in addition to marked hemosiderosis in the hepatic sinusoids. Fragments of spleen, liver, brain, skeletal muscle, and lung were tested by the polymerase chain reaction technique for the detection of a fragment of the cytochrome B gene from haemosporidians, which resulted positive for Plasmodium spp. After sequencing, the samples were phylogenetically associated to Plasmodium sp. detected in Turdus albicollis (KU562808) in Brazil and matched to the lineage TURALB01 previously detected in T. albicollis. Avian malaria infections caused by Plasmodium sp. of lineage TURALB01 may occur in S. magellanicus with high mortality, and, thus, it is essential to detect and characterize the agent involved to obtain the differential diagnosis of the condition. PMID- 30456493 TI - Bioaccumulation of metal(loid)s in Cardisoma crassum and pollution assessment in a mangrove protected area in Mexico. AB - The bioaccumulation of several elements in "mouthless crabs" (Cardisoma crassum) and their concentrations in environmental samples were assessed in a mangrove forest within a natural protected area located in the middle of Puerto Vallarta, Mexico. The concentrations of Al, As, Ba, Cd, Cr, Cu, Fe, Ni, Pb, Sr, Si, V, and Zn in sediments, mangrove litterfall, and pore water and their bioaccumulations in the muscle and shell tissue of C. crassum were determined during rainy and dry seasons. Two different sampling sites were compared, selected according to the influence of the tide. The samples were analyzed by ICP-OES. In pore water, half of the elements of interest were below the limits of detection. Pb and Cd concentrations were only detected in the sedimentary phase. Al and Fe presented the highest concentrations at both sampling sites in the sediments and mangrove litterfall. There were no significant differences between sampling seasons in water samples (P > 0.05). Only Cu presented significant differences between sampling seasons in the mangrove litterfall samples and V in the sediment samples (P < 0.05). The sediment quality guidelines indicated that only Cd was above the threshold effect limit. As, Cd, Cr, Ni, and Pb remained below the limits of detection in muscle tissue and shell samples. The biota-sediment accumulation factors (BSAFs) determined for Cu and Zn were above 1.0, indicating the accumulation of these elements in the muscle tissue of C. crassum, while the BSAF values in the shell were above the threshold for Ba, Si, and Sr. PMID- 30456494 TI - Effect of placement conditions for active monitoring of trace element with the epiphytic moss. AB - In this work, problems arising by use of active biomonitoring are discussed. Biomonitoring technique using positioned vertically frameworks and epiphytic moss Pylaisia polyantha is proposed. The influence of tree species on which the bark of the frameworks is fixed, altitude, and orientation is researched. For this purpose, frameworks were placed at two sampling sites of Tomsk on different trees (poplar, birch), at altitudes of 0.5 and 1.5 and with different orientations in May; the exposure time was 20 weeks. The concentrations of As, Ba, Br, Ca, Ce, Co, Cr, Cs, Eu, Fe, Hf, K, La, Lu, Mo, Rb, Sb, Sc, Sm, Tb, Th, U, Yb, and Zn were determined by neutron activation analysis at the research reactor of Tomsk Polytechnic University. Increasing concentrations of half of the chemical elements was revealed during the exposure. The high-capacity frameworks used to accumulate certain elements-Cs, Eu, Hf, K, Lu, Sb, Yb-were revealed. PMID- 30456495 TI - Quantitative blood flow evaluation of vasodilation-stress compared with dobutamine-stress in patients with end-stage liver disease using 82Rb PET/CT. AB - BACKGROUND: Our aim was to determine if end-stage liver disease (ESLD) is associated with an attenuated response to vasodilator-stress or dobutamine-stress using 82Rb-PET MPI with blood flow quantification. METHODS AND RESULTS: Pre-liver transplant patients who had a normal dipyridamole-stress (n = 27) or dobutamine stress (n = 26) 82Rb PET/CT MPI study with no identifiable coronary artery calcium were identified retrospectively and compared to a prospectively identified low-risk of liver disease dipyridamole-stress control group (n = 20). The dipyridamole-stress liver disease group had a lower myocardial flow reserve (MFR) (1.89 +/- 0.79) than the control group (2.79 +/- 0.96, P < .05). The dobutamine-stress group had a higher MFR than both other groups (3.69 +/- 1.49, P < .05). A moderate negative correlation between MELD score and MFR was demonstrated for the dipyridamole-stress liver disease group (r = - 0.473, P < .05). This correlation was not observed for the dobutamine-stress liver disease group (r = - 0.253, P = .21). The liver failure group as a whole (n = 53) had a higher resting myocardial blood flow (0.97 +/- 0.33 mL/min/g) than the control group (0.82 +/- 0.26, P < .05). CONCLUSION: Dipyridamole demonstrates an attenuated vasodilatory response in ESLD patients compared to a non-ESLD control group related to higher resting blood flow and comparatively reduced stress blood flow. Dobutamine does not demonstrate this effect implying it may be the preferred pharmacologic MPI stress agent for ESLD patients. PMID- 30456496 TI - PET imaging of sympathetic innervation with [18F]Flurobenguan vs [11C]mHED in a patient with ischemic cardiomyopathy. PMID- 30456497 TI - Hypertrophic cardiomyopathy with apical aneurysm: Unraveling contribution and usefulness of gating to myocardial perfusion SPECT and a multi-modality investigation. PMID- 30456498 TI - Higher incidence of vasodilator-induced left ventricular cavity dilation by PET when compared to treadmill exercise-ECHO in hypertrophic cardiomyopathy. AB - BACKGROUND: Vasodilator-induced transient left ventricular cavity dilation (LVCD) by positron emission tomography (PET) is associated with microvascular dysfunction in hypertrophic cardiomyopathy (HCM). Here we assessed whether HCM patients who develop LVCD by PET during vasodilator stress also develop LV cavity dilation by echocardiography (ECHO-LVCD) following exercise stress. METHODS: A retrospective analysis of cardiac function and myocardial blood flow (MBF) was conducted in 108 HCM patients who underwent perfusion-PET and exercise-ECHO as part of their clinical evaluation. We performed a head-to-head comparison of LV volumes and ejection fraction (LVEF) at rest and stress (during vasodilator stress, post-exercise), in 108 HCM patients. A ratio > 1.13 of stress to rest LV volumes was used to define PET-LVCD, and a ratio > 1.17 of stress to rest LVESV was used to define ECHO-LVCD. Patients were divided into 2 groups based on the presence/absence of PET-LVCD. MBF and myocardial flow reserve were quantified by PET, and global longitudinal strain (GLS) was assessed by ECHO at rest/stress in the two groups. RESULTS: PET-LVCD was observed in 51% (n = 55) of HCM patients, but only one patient had evidence of ECHO-LVCD (ratio = 1.36)-this patient also had evidence of PET-LVCD (ratio = 1.20). The PET-LVCD group had lower PET-LVEF during vasodilator stress, but ECHO-LVEF increased in both groups post-exercise. The PET-LVCD group demonstrated higher LV mass, worse GLS at rest/stress, and lower myocardial flow reserve. Incidence of ischemic ST-T changes was higher in the PET-LVCD group during vasodilator stress (42 vs 17%), but similar (30%) in the two groups during exercise. CONCLUSION: PET-LVCD reflects greater degree of myopathy and microvascular dysfunction in HCM. Differences in the cardiac effects of exercise and vasodilators and timing of stress-image acquisition could underlie discordance in ischemic EKG changes and LVCD by ECHO and PET, in HCM. PMID- 30456499 TI - Myocardial blood flow measures using cardiac positron emission tomography: Software comparisons. PMID- 30456500 TI - The breathless swimmer: could this be swimming-induced pulmonary edema? AB - Swimming-induced pulmonary edema is an infrequently encountered cause of acute respiratory distress in open-water swimmers. The condition can be challenging, with athletes often wanting answers to three main questions regarding (i) a definitive and robust diagnosis, (ii) the risk of recurrence, and (iii) what can be done to avoid recurrence. This commentary provides an overview of the best available evidence, in light of a recently published systematic review. PMID- 30456501 TI - Cardiac biomarkers improve prediction performance of the combination of American Society of Anesthesiologists physical status classification and Americal College of Surgeons National Surgical Quality Improvement Program calculator for postoperative mortality in elderly patients: a pilot study. AB - BACKGROUND: Our previous research has shown American Society of Anaesthesiologists physical status classification (ASA) score and Americal College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) calculator to have the most accuracy in the prediction of postoperative mortality. AIMS: The aim of our research was to define the most reliable combination of cardiac biomarkers with ASA and ACS NSQIP. METHODS: We have included a total of 78 patients. ASA score has been determined in standard fashion, while we used the available interactive calculator for the ACS NSQIP score. Biomarkers BIRC5, H-FABP, and hsCRP have been measured in specialized laboratories. RESULTS: All of the deceased patients had survivin (BIRC5) > 4.00 pg/ml, higher values of H-FABP and hsCRP and higher estimated levels of ASA and ACS NSQIP (P = 0.0001). ASA and ACS NSQIP alone had AUC of, respectively, 0.669 and 0.813. The combination of ASA and ACS NSQIP had AUC = 0.841. Combination of hsCRP with the two risk scores had AUC = 0.926 (95% CI 0.853-1.000, P < 0.0001). If we add three cardiac biomarkers to this model, we get AUC as high as 0.941 (95% CI 0.876-1.000, P < 0.0001). The correction of statistical models with comorbidities (CIRS-G score) did not change the accuracy of prediction models that we have provided. DISCUSSION: Addition of ACS NSQIP and biomarkers adds to the accuracy of ASA score, which has already been proved by other authors. CONCLUSION: Cardiac biomarker hsCRP can be used as the most reliable cardiac biomarker; however, the "multimarker approach" adds the most to the accuracy of the combination of clinical risk scores. PMID- 30456502 TI - Long-term oncologic after robotic versus laparoscopic right colectomy: a prospective randomized study. AB - OBJECTIVE: The aim of this study was to compare the long-term outcomes of robot assisted right colectomy (RAC) with those for conventional laparoscopy-assisted right surgery (LAC) for treating right-sided colon cancer. BACKGROUND: The enthusiasm for the robotic techniques has gained increasing interest in colorectal malignancies. However, the role of robotic surgery in the oncologic safety has not yet been defined. METHODS: From September 2009 to July 2011, 71 patients with right-sided colonic cancer were randomized in the study. Adjuvant therapy and postoperative follow-up were similar in both groups. The primary and secondary endpoints of the study were hospital stay and survival, respectively. Data were analyzed by intention-to-treat principle. RESULTS: The RAC and LAC groups did not differ significantly in terms of baseline clinical characteristics. Compared with the LAC group, RAC was associated with longer operation times (195 min vs. 129 min, P < 0.001) and higher cost ($12,235 vs. $10,319, P = 0.013). The median follow-up was 49.23 months (interquartile range 40.63-56.20). The combined 5-year disease-free rate for all tumor stages was 77.4% (95% confidence interval [CI], 60.6-92.1%) in the RAC group and 83.6% (95% CI 72.1-0.97.0%) in the LAC group (P = 0.442). The combined 5-year overall survival rates for all stages were 91.1% (95% CI 78.8-100%) in the RAC group and 91.0% (95% CI 81.3-100%) in the LAC group (P = 0.678). Using multivariate analysis, RAC was not a predictor of recurrence. CONCLUSIONS: RAC appears to similar long-term survival as compared with LAC. However, we did not observe any clinical benefits of RAC which could translate to a decrease in expenditures. TRIAL REGISTRY: http://www.ClinicalTrials.gov , number NCT00470951. PMID- 30456503 TI - Clinical prediction model for tumor progression in Barrett's esophagus. AB - BACKGROUND: Individuals with Barrett's esophagus (BE) are at increased risk of high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC), but the cost effectiveness of general surveillance of BE is low. This study aimed to identify a risk prediction model for tumor progression in individuals with BE based on age, sex, and risk factors found at upper endoscopy, enabling tailored surveillance. METHODS: This nested case-control study originated from a cohort of 8171 adults diagnosed with BE in 2006-2013 in the Swedish Patient Registry. Cases had EAC/HGD (n = 279) as identified from the Swedish Cancer Registry, whereas controls had no EAC/HGD (n = 1089). Findings from endoscopy and histopathology reports were extracted from medical records at 71 Swedish hospitals and from the Swedish Patient Registry. Multivariable logistic regression provided odds ratios (OR) with 95% confidence intervals (CIs). RESULTS: Older age (OR 1.02 [95% CI 1.01-1.03] per year), male sex (OR 2.8 [95% CI 1.9-4.1]), and increasing maximum BE length (OR 2.3 [95% CI 1.4-3.9] for segments 3-8 cm and OR 4.3 [95% CI 2.5 7.2] for segments >= 8 cm) increased the risk of EAC/HGD, while the circumferential extent of the BE, hiatal hernia or reflux esophagitis did not. A model based on age, sex, and maximum BE length predicted 71% of all EAC/HGD cases. CONCLUSIONS: A simple combination of the variables age, sex and maximum BE length showed fairly good accuracy for predicting tumor progression in BE. This clinical risk prediction model may help to tailor future surveillance programs. PMID- 30456504 TI - Predictors of hernia recurrence after Rives-Stoppa repair in the treatment of incisional hernias: a retrospective cohort. AB - BACKGROUND: Rives-Stoppa retromuscular repair (RSR) has been traditionally used to provide adequate coverage for large abdominal wall defects and appears to be more advantageous compared to other surgical techniques concerning complications and recurrence rates. The aim of this study was to identify the independent predictors associated to hernia recurrence after RSR in the treatment of incisional hernias. METHODS: This is a retrospective observational study of 213 patients who underwent RSR between June 2007 and January 2014 at a tertiary centre. Main inclusion criteria were adults with midline hernia classified as M1, M2, M3, M4, or M5, according to EHS classification. All the cases presented a transverse hernia defect measurement greater than 5 cm (grades W2 and W3). Recurrence rate was determined by clinical examination plus confirmation by abdominal CT scan. RESULTS: At a median of 57.6 months (range 46-75 months) of postoperative follow-up, we reported 15 cases of recurrence (7.1%). Recurrences occurred after a mean period of 19.4 months (range 2-49 months). On multivariate analysis, steroid or immunosuppressive drugs use (OR 2.02; CI 1.16-3.95, p = 0.004), the development of postoperative hematoma (OR 2.9; CI 1.55-4.10, p = 0.001), and needing surgery for the hematoma (OR 2.1; CI 1.21-3.29, p = 0.004) were predictors of recurrence after RSR. There was no significant difference in recurrence rate among obesity, smoking, urgent repair, type of mesh fixation, operative time, type of prosthesis, or concomitant procedures. CONCLUSIONS: In our current study, using immunosuppressive drugs, the development of postoperative hematoma and needing surgery for the hematoma were associated with increased risk of hernia recurrence after RSR. PMID- 30456505 TI - Is laparoscopic left adrenalectomy with the anterior submesocolic approach for Conn's or Cushing's syndrome equally safe and effective as the lateral and anterior ones? AB - BACKGROUND: The aim of the present study is to report and to compare the results of three different laparoscopic transperitoneal surgical approaches [lateral transperitoneal (LT), anterior transperitoneal (AT) and anterior transperitoneal submesocolic (ATS)] for the treatment of Conn's and Cushing's syndrome from left adrenal disease. METHODS: This study is a retrospective analysis of prospectively collected data. From 1994 to 2017, 535 laparoscopic adrenalectomies (LA) were performed. One hundred and sixty-four patients with Conn's or Cushing's syndrome underwent left LA. Patients were divided in three groups based on the approach: LT (Group A), AT (Group B) and ATS (Group C). RESULTS: The diagnosis was Conn's and Cushing's syndrome in 99 and 65 patients, respectively. LT was used in 13 cases, AT in 55 and ATS in 96. No significant differences in patient's gender, age and BMI were observed. Mean operative time was 117.6 +/- 33.7, 107.6 +/- 40.3 and 96.2 +/- 47.5 min for Groups A, B and C, respectively. Conversion to open surgery was observed in 4 Group C patients (4.1%). Morbidity occurred in 2 Group B (2%) and in 5 Group C patients (5.2%). CONCLUSIONS: In case of Conn's or Cushing's syndrome, left LA with ATS approach is equally safe and effective as compared to the LT and AT approaches. Early control of the adrenal vein with minimal gland manipulation and limited surgical dissection are the major advantages of the submesocolic approach. Even if statistically significant differences are not observed, postoperative results are the same as those reported in the literature with other approaches. PMID- 30456506 TI - Right hemicolectomy: a network meta-analysis comparing open, laparoscopic assisted, total laparoscopic, and robotic approach. AB - BACKGROUND: There are a variety of surgical approaches for the management of right-sided colonic neoplasms. To date, no method has been shown superior in terms of surgical and perioperative outcomes. This meta-analysis compared open (ORH), laparoscopic-assisted (LRH), total laparoscopic (TLRH), and robotic right hemicolectomy (RRH) to assess surgical outcomes and perioperative morbidity and mortality. STUDY DESIGN: We conducted an electronic systematic search using PubMed, EMBASE, and Web of Science that compared RRH, TLRH, LRH, and ORH. Forty eight studies met the inclusion criteria: 5 randomized controlled trials, 25 retrospective, and 18 prospective studies totalling 5652 patients were included. RESULTS: The overall complication rate was similar between RRH and TLRH (RR 1.0; Crl 0.66-1.5). The anastomotic leak rate was higher in LRH and ORH compared to RRH (RR 1.9; Crl 0.99-3.6 and RR 1.2; Crl 0.55-2.6, respectively), whereas it was lower in TLRH compared to RRH (RR 0.88 Crl 0.41-1.9). The risk of reoperation was significantly higher in ORH compared to TLRH (RR 3.3; Crl 1.3-8.0). Operative time was similar in RRH compared to LRH (RR - 27.0; Crl - 61.0 to 5.9), and to TLRH (RR - 24.0; Crl - 70.0 to 21.0). The hospital stay was significantly longer in LRH compared to RRH (RR 3.7; Crl 0.7-6.7). CONCLUSION: The surgical management of right-sided colonic disease is evolving. This network meta-analysis observed that short-term outcomes following RRH and TLRH were superior to standard LRH and ORH. The adoption of more advanced minimally invasive techniques can be costly and have associated learning phases, but will ultimately improve patient outcomes. PMID- 30456507 TI - Barriers and facilitators to deliberate practice using take-home laparoscopic simulators. AB - BACKGROUND: Several regions in the UK and Ireland have delivered home-based laparoscopic simulation programmes in an attempt to progress surgical trainees' skills through deliberate practice. However, engagement with these programmes has been poor. This study aims to uncover the barriers to engagement with home-based simulation, with a view to developing an improved programme. METHODS: This was a qualitative study using focus groups with key stakeholders including junior surgical trainees, consultants/attendings and simulation faculty. Data were collected across four regions in three countries. Data were audio-recorded, transcribed and a thematic analysis was performed using NVivo software. RESULTS: Sixty-three individuals were interviewed in 12 focus groups (43 trainees, 20 trainers). Trainees cited competing commitments as a barrier to engaging with home-based simulation. They tended to focus on scoring 'points' towards career progression rather than viewing tasks as interesting, or associated with personal development. Their view was that this approach is perpetuated by the training system, which rewards trainees for publications and exams, but not for operative skill. Trainees were unsatisfied with metric feedback and wanted individual feedback from consultants (attendings). Trainees perceived consultants as lacking interest in the programmes and training in general. However, some consultants were unaware of the programmes being delivered and others felt lacking in confidence to deliver the necessary training. CONCLUSIONS: Scheduled simulation sessions which provide trainees with the opportunity for consultant feedback may improve engagement. Tackling the 'point-scoring' culture is more challenging. This could be addressed by modified assessment structures, greater recognition and accountability for trainers, and recognition and funding of simulation strategies including in-house skills sessions. PMID- 30456508 TI - Modular laser-based endoluminal ablation of the gastrointestinal tract: in vivo dose-effect evaluation and predictive numerical model. AB - BACKGROUND: Endoscopic submucosal dissection allows for "en bloc" removal of early gastrointestinal neoplasms. However, it is technically demanding and time consuming. Alternatives could rely on energy-based techniques. We aimed to evaluate a predictive numerical model of thermal damage to preoperatively define optimal laser settings allowing for a controlled ablation down to the submucosa, and the ability of confocal endomicroscopy to provide damage information. MATERIALS AND METHODS: A Nd:YAG laser was applied onto the gastric mucosa of 21 Wistar rats on 10 spots (total 210). Power settings ranging from 0.5 to 2.5W were applied during 1-12 s, with a consequent energy delivery varying from 0.5 to 30 J. Out of the 210 samples, a total of 1050 hematoxilin-eosin stained slides were obtained. To evaluate thermal injury, the ratio between the damage depth (DD) over the mucosa and the submucosa thickness (T) was calculated. Effective and safe ablation was considered for a DD/T ratio <= 1 (only mucosal and submucosal damage). Confocal endomicroscopy was performed before and after ablation. A numerical model, using human physical properties, was developed to predict thermal damage. RESULTS: No full-thickness perforations were detected. On histology, the DD/T ratio at 0.5 J was 0.57 +/- 0.21, significantly lower when compared to energies ranging from 15 J (a DD/T ratio = 1.2 +/- 0.3; p < 0.001) until 30 J (a DD/T ratio = 1.33 +/- 0.31; p < 0.001). Safe mucosal and submucosal ablations were achieved applying energy between 4 and 12 J, never impairing the muscularis propria. Confocal endomicroscopy showed a distorted gland architecture. The predicted damage depth demonstrated a significant positive linear correlation with the experimental data (Pearson's r 0.85; 95% CI 0.66 0.94). CONCLUSIONS: Low-power settings achieved effective and safe mucosal and submucosal ablation. The numerical model allowed for an accurate prediction of the ablated layers. Confocal endomicroscopy provided real-time thermal damage visualization. Further studies on larger animal models are required. PMID- 30456509 TI - Laparoscopic duodenum-preserving total pancreatic head resection: a novel surgical approach for benign or low-grade malignant tumors. AB - BACKGROUND: Duodenum-preserving total pancreatic head resection (DPPHRt) is an accepted alternative surgical procedure for benign or low-grade malignant tumors of the pancreatic head by preserving the duodenum with its intact blood supply from the pancreatic duodenal arterial arcade. This study describes our experience in laparoscopic DPPHRt (LDPPHRt). To our knowledge, this is the first description of this novel minimally invasive operation. METHODS: From August 2016 to May 2017, all consecutive patients who underwent LDPPHRt for pancreatic head lesions at the HPB Surgery Department, Sun Yat-Sen Memorial Hospital in Guangzhou, China were enrolled into this retrospective study. RESULTS: There were ten women and two men. The average age was 37.3 years (range 8-61 years). The average diameter of the pancreatic head lesions on pre-operative CT/MR was 3.7 cm (range 2-4.8 cm). All the LDPPHRt procedures were performed successfully. There was no peri operative death. The average operative time was 272.5 min (range 210-320 min). The average blood loss was 215 ml (range 50-450 ml). Post-operative complications included pancreatic fistula grade B (two patients, or 16.7%) and biliary fistula (two patients, or 16.7%). All the complications responded well to conservative treatment. The mean post-operative hospital stay was 11.5 days (range 6-25 days). CONCLUSIONS: LDPPHRt provided a minimally invasive approach with good organ preservation for benign or low-grade malignant tumors of the pancreatic head. The long-term oncological outcomes, and the exocrine and endocrine pancreatic functions after this operation require further studies. PMID- 30456510 TI - Operating hurts: a study of EAES surgeons. AB - BACKGROUND: Work-related pain and discomfort experienced by surgeons is widely reported in the literature. A survey was, therefore, conducted to explore this issue among members of the European Association for Endoscopic Surgery (EAES). METHODS: The survey was emailed to 2980 EAES members in 2017 enquiring about their working practice, musculoskeletal (MSK) pain and burnout. RESULTS: A total of 569 (19%) surgeons responded, of whom 556 were practicing surgeons; 86% were consultants, 84% were male, and 94% were right-handed. Respondents operated on average 3.3 days/week with 27% of their procedures lasting longer than 3 h. The 386 endoscopists surveyed reported performing an average of 5.3 procedures/day with 83% performing endoscopy at least once per week. Over half of practicing surgeons (62%) reported their worst pain score was 3 or higher (10-point scale) in the past 7 working days, encompassing 71% of their open, 72% laparoscopic, 48% robot-assisted cases and 52% of their endoscopies. Of the 120 surgeons who had ever sought medical help for aches, pain or discomfort, 38% were currently in pain and 16% had considered leaving surgery due to their MSK pain, 26% had reported work-related pain to their employer, 26% had been on short-term disability during their career and 4% long-term disability due to MSK disorders. A significant proportion of the respondents (49%) felt their physical discomfort would influence the ability to perform or assist with surgical procedures in the future. These surgeons reported significantly lower satisfaction from their work (p = 0.024), higher burnout (p = 0.005) and significantly higher callousness toward people (p < 0.001) than those not fearing loss of career longevity. CONCLUSION: The results show that MSK pain is prevalent amongst EAES members. Nearly half the respondents had career longevity fears from pain/discomfort which, in turn, correlated with more prevalent feelings of burnout. More emphasis should be placed on the aetiology, prevention and management of musculoskeletal pain in the surgical workforce. PMID- 30456511 TI - Results of a two-phased clinical study evaluating a new multiband mucosectomy device for early Barrett's neoplasia: a randomized pre-esophagectomy trial and a pilot therapeutic pilot study. AB - BACKGROUND: Multiband mucosectomy (MBM) is the preferred technique for piecemeal resection of early neoplastic lesions in Barrett's esophagus (BE). The currently most widely used device for MBM is the Duette device. Recently, the Captivator EMR device has come available which might have practical advantages over the Duette device. METHODS: Phase I was a randomized pre-esophagectomy trial with a non-inferiority design aiming to compare EMR specimens obtained with the Captivator and the Duette device. PRIMARY OUTCOME: max diameter of the EMR specimens, secondary outcomes: min diameter, max thickness of the EMR specimens and resected submucosal stroma. Phase II were clinical pilot cases aiming to evaluate the feasibility of EMR using the Captivator device. Primary outcome was the successful EMR rate and secondary outcomes included procedure time and adverse events. RESULTS: Phase I: 24 EMR specimens (12 pairs) were obtained from six patients. The median max diameter of EMR specimens obtained with the Captivator device was 16 mm [IQR 12-21] versus 18 mm [IQR 13-23] for the Duette device. Non-inferiority of the max diameter of the Captivator specimens could not be demonstrated (median difference 1 mm, 95% CI - 3.26 to + 5.26). However, when using paired analysis, no significant difference was found (p 0.573). In addition, no statistically significant differences were found in the min diameter, max thickness of EMR specimens, and max thickness of resected submucosal stroma. Phase II: 5 BE patients with early neoplastic lesions were included. Successful EMR was achieved in 100%. Median procedure time was 33 min (IQR 25-39). One patient developed transient dysphagia, without signs of stenosis on endoscopy. CONCLUSIONS: EMR of early Barrett's neoplasia using the Captivator device is comparable to Duette EMR when looking at size of resected specimens. In the first patients, EMR using the Captivator was feasible, resulting in successful resection without acute adverse events. PMID- 30456513 TI - Author Index to Volume 30: 2018. PMID- 30456512 TI - Usefulness of the thread-traction method in endoscopic full-thickness resection for gastric submucosal tumor: a comparative study. AB - BACKGROUND: Endoscopic full-thickness resection (EFTR) has shown great prospects in treating gastric submucosal tumors (SMTs) from the muscularis propria. However, it is very difficult sometimes to ideally expose the tumor and gain adequate visualization for the dissection site. In the present study, we applied the thread-traction (TT) method to assist EFTR in treating gastric SMTs and investigated the feasibility and effectiveness of this strategy. METHODS: A total of 28 patients were involved in the study. 13 patients were treated by TT assisted EFTR (TT group) and the others by non-assisted EFTR (NA group). Data on clinical characteristics and therapeutic outcomes were collected for analysis. RESULTS: The average tumor size was 1.6 +/- 0.4 cm. En bloc resection rate was 92.9%. Histopathological evaluation indicated that 22 tumors were gastrointestinal stromal tumors (78.6%), all at low- or very low-risk, and 6 tumors were leiomyomas (21.4%). The total complication rate was 32.1%. All complications were managed intra-operatively or conservatively. Both the total procedure time and the perforation time were significantly shorter in patients of TT group than those of NA group (71.9 +/- 30.5 vs. 107.5 +/- 35.8 min, P = 0.010; 38.3 +/- 22.0 vs. 68.6 +/- 24.2 min, P = 0.002). The pain score evaluated by visual analogue system after operation was significantly lower in patients of TT group than those of NA group (4.5 +/- 1.1 vs. 5.8 +/- 1.4, P = 0.014). Although complication rate was lower in patients of TT group than those of NA group, the difference was not statistically significant (15.4% vs. 46.7%, P = 0.114). No residual or recurrent tumors were observed during a mean follow-up period of 17.9 +/- 4.4 months. CONCLUSIONS: The TT method could effectively assist EFTR to shorten operation time and decrease the risk of complications. PMID- 30456514 TI - Factors limiting physical activity after acute type A aortic dissection. AB - BACKGROUND: Acute type A aortic dissection (AAD) leads to high hospital mortality rates in the first 48 h after the onset of symptoms. Survivors, however, have good long-term perspectives and enhanced survival especially if regaining moderate amounts of physical activity. METHODS: This study analyzed 131 survivors (from 180 consecutive patients, aged 60 years (rande 30-84 years, 71% male) of acute AAD after a median time of 44 months (range 1-147 months). The hospital mortality was 13.5%. The group of physically active patients was compared with those with a sedentary life style. The qualitative and quantitative data on physical activity were correlated with data from an aortic registry. RESULTS: Overall 87% of patients reported 1 or more types of physical activities after hospital discharge. The most common types were walking (51%), biking (29%), hiking (15%) and gymnastics (14%). Patients with a sedentary life style underwent longer hypothermic circulatory arrest times (39 min, range 8-167 min vs. 47 min, range 27-79 min, p = 0.009), had a longer intensive care unit (ICU) stay (Pearsons r = -0.226 [between length of ICU stay and hours of physical activity after hospital discharge], p = 0.033) and suffered more frequently from postoperative paresis (33.3% vs. 3.8%, p < 0.001) compared with physically active patients. Binary logistic regression analysis showed female gender (p = 0.026) and higher body mass index (p = 0.019) to be independently associated with a reduced amount of physical activity. CONCLUSIONS: This study demonstrate that the majority of survivors of acute aortic dissection type A regain a physically active life including the practice of a variety of sports. Factors predictive of a sedentary life style can be identified. Female patients deserve special attention. PMID- 30456515 TI - Consent documentation for elective orthopaedic surgery. AB - OBJECTIVES: Currently in Ireland, there is a lack of uniformity regarding the method in which the consent process is routinely documented. The purpose of this study was to evaluate the standard consent forms used in elective orthopaedic hospitals in Ireland. In addition, this paper explores the relevant guidelines from the UK and Ireland relating to consent documentation. METHODS: Standard consent forms used in the 24 public hospitals that perform elective orthopaedic surgery were analysed and compared, based on the inclusion or exclusion of 22 unique consent-related items or statements selected by the authors. In addition, each form was analysed for format, word count, and readability. RESULTS: Within 24 hospitals with elective orthopaedic surgery, there were 21 unique consent forms being used. There was a mean inclusion of 9.5 of the 22 unique items per form with a standard deviation of 5.1 (range 2-18), indicating a wide discrepancy. For each unique consent-related item in the analysis, the mean rate of inclusion was 43.4% (SD 26.7%). The mean Flesch Reading Ease Score was 43.3. The format varied from 1 to 4 pages, with a word count of 109 to 1041 (mean 414.7). CONCLUSION: The findings demonstrate a lack of uniformity of both format and content amongst the consent forms currently being used in elective orthopaedic hospitals in Ireland. This paper supports the use of a nationally standardised consent documentation method in order to improve the efficiency of the consent process and ensure greater protection against litigation. PMID- 30456516 TI - Validation of a virtual reality laparoscopic appendicectomy simulator: a novel process using cognitive task analysis. AB - BACKGROUND: Virtual reality (VR) simulation is a vital component of surgical training with demonstrated improvements in surgical quality and clinical outcome. AIMS: To validate the LAP Mentor (SimbionixTM) laparoscopic appendicectomy (LA) VR simulator with inclusion of a novel tool, Cognitive Task Analysis (CTA). METHODS: Thirty-two novices and nine experienced surgeons performed two simulated LAs. An expert-consensus questionnaire guided face validity assessment. Content validity was assessed using CTA-derived questions encompassing eight operative steps and four decision points. Construct validity was evaluated using dexterity metrics, masked assessment of surgical quality using the OSATS global rating scale, and mental workload from two validated tools: the NASA-TLX and SMEQ. Ten novices performed eight further LAs for learning curve assessment. RESULTS: Face validity was demonstrated across all domains. Considering content validity, the essential technical and non-technical steps were evident. The experienced group performed the procedure quicker (median time 361 vs. 538 s, P = 0.0039) with fewer total movements (426 vs. 641, P < 0.0001) and shorter idle time (131 vs. 199 s, P = 0.0006). This correlated with higher OSATS scores (median 33.5 vs. 22.2, P < 0.0001) and lower mental demand (NASA-TLX: 9.0 vs. 13.75, P = 0.012; SMEQ: 60 vs. 80, P = 0.0025), indicating construct validity. Learning curve data showed statistically significant improvements after the 7th session for procedure time, total movements and idle time, which correlated with reduction in mental demand. CONCLUSIONS: The LAP Mentor demonstrates face, content and construct validity for LA; thus, it can be used as an effective tool in surgical training. Task repetition leads to achievement of expert benchmarks. PMID- 30456517 TI - Assessment of potential changes in soil erosion using remote sensing and GIS: a case study of Dacaozi Watershed, China. AB - Soil erosion is a major global environmental problem. Therefore, a method of calculating potential soil erosion is necessary for soil and water resource management, as well as for assessing the risk of soil erosion. This study aimed to develop a simple method for calculating potential soil erosion change (PSEC) by combining the Universal Soil Loss Equation (USLE) and a Geographic Information System (GIS). The USLE model includes a rainfall erosivity factor (R), soil erodibility factor (K), cover management factor (C), slope gradient factor (S), length factor (L), and the supporting practice factor (P). Using a measured patch of soil and water conservation as the experimental unit, weather and soil data were combined to calculate R and K. Remote sensing images were used to extract vegetation cover (VC) and calculate C, while digital elevation models were used to extract and calculate S and L; land use maps were used to determine the P of each patch. The PSEC of each patch was then calculated according to the results of the above mentioned six factors. Finally, the PSEC of the entire study area was calculated on the basis of a patch area weighting method, which was validated in the Dacaozi Watershed in China, where a 1-year soil and water conservation project was implemented, beginning in November of 2013. In this study, the PSEC of the Dacaozi Watershed in May of 2017 was calculated, accounting for approximately 3 years of project implementation. The results showed that the average VC increased by 21.6% after 3 years of project implementation, whereas C decreased by 46.4%. The value of P did not change significantly from before to after project implementation. The average S decreased from 22.6 +/- 12.1 degrees to 21.3 +/- 10.6 degrees , and S decreased by 6.8%. In contrast, L increased by 33.3%. On the whole, the PSEC in the Dacaozi Watershed was 0.3925 and the potential soil erosion decreased by 60.75% after 3 years of conservation. PMID- 30456519 TI - Earlier Versus Later Augmentation with an Antipsychotic Medication in Patients with Major Depressive Disorder Demonstrating Inadequate Efficacy in Response to Antidepressants: A Retrospective Analysis of US Claims Data. AB - INTRODUCTION: There is little evidence regarding the most effective timing of augmentation of antidepressants (AD) with antipsychotics (AP) in patients with major depressive disorder (MDD) who inadequately respond to first-line AD (inadequate responders). The study's objective was to understand the association between timing of augmentation of AD with AP and overall healthcare costs in inadequate responders. METHODS: Using the Truven Health MarketScan(r) Medicaid, Commercial, and Medicare Supplemental databases (7/1/09-12/31/16), we identified adult inadequate responders if they had one of the following indicating incomplete response to initial AD: psychiatric hospitalization or emergency department (ED) visit, initiating psychotherapy, or switching to or adding on a different AD. Two mutually exclusive cohorts were identified on the basis of time from first qualifying event date to first date of augmentation with an AP (index date): 0-6 months (early add-on) and 7-12 months (late add-on). Patients were further required to be continuously enrolled 1 year before (baseline) and 1 year after (follow-up) index date. Patients with schizophrenia or bipolar disorder diagnoses were excluded. General linear regression was used to estimate adjusted healthcare costs in the early versus late add-on cohort, controlling for baseline demographic and clinical characteristics, insurance type, medications, and ED visits or hospitalizations. RESULTS: Of the 6935 identified inadequate responders, 68.7% started an AP early and 31.3% late. At baseline, before AP augmentation, patients in the early add-on cohort had higher psychiatric comorbid disease burden (47.3% vs. 42.5%; p < 0.001) and higher inpatient utilization [mean (SD) 0.41 (0.72) vs. 0.27 (0.67); p < 0.001] than in late add-on cohort. During follow-up, the adjusted total all-cause healthcare cost was significantly lower in the early vs. late add-on cohort ($18,864 vs. $20,452; p = 0.046). CONCLUSION: Findings of this real-world study suggest that, in patients with MDD who inadequately responded to first-line AD treatment, adding an AP earlier reduces overall healthcare costs. FUNDING: Otsuka Pharmaceutical Development and Commercialization, Inc. and Lundbeck. PMID- 30456520 TI - An Economic Evaluation of Iron Isomaltoside 1000 Versus Ferric Carboxymaltose in Patients with Inflammatory Bowel Disease and Iron Deficiency Anemia in Denmark. AB - INTRODUCTION: The incidence of inflammatory bowel disease (IBD) in Denmark is among the highest in the world, with Crohn's disease and ulcerative colitis occurring at rates of 9.1 and 18.6 per 100,000 person-years respectively in 2010 2013. Anemia is the most prevalent extraintestinal complication of IBD, most commonly caused by iron deficiency. In treating IBD-associated iron deficiency anemia (IDA), intravenous iron is more effective and better tolerated and shows a faster response than oral iron. The present study evaluated resource use and costs associated with using iron isomaltoside (Monofer; IIM) versus ferric carboxymaltose (Ferinject; FCM) in patients with IDA and IBD in Denmark. METHODS: A budget impact model was developed to evaluate the cost of IIM compared with FCM from a Danish healthcare payer perspective. Iron deficits were modeled using dosing tables and a joint distribution of bodyweight [mean 75.4 kg, standard deviation (SD) 17.4 kg] and hemoglobin (mean 10.8 g/dL, SD 1.4 g/dl) based on observational data from patients with IBD. Retreatment frequency was modeled using a pooled retrospective analysis of randomized trial data, and costs were modeled using diagnosis-related groups with an outpatient infusion cost of DKK 2855. RESULTS: Using IIM required 1.2 infusions (per treatment) to correct the mean iron deficit compared with 1.6 with FCM. Treating 2.54 patients with IIM would therefore avoid one infusion compared with FCM. Patients using IIM required multiple infusions in 25.0% of cases compared with 64.3% with FCM. Over 5 years, total estimated costs were DKK 21,406 per patient with IIM compared with DKK 28,137 with FCM, corresponding to savings of DKK 6731 with IIM. CONCLUSION: Using IIM in place of FCM markedly reduced the number of iron infusions required in patients with IBD and IDA in Denmark. The reduction in infusions was accompanied by reductions in cost compared with FCM. FUNDING: Pharmacosmos A/S. PMID- 30456518 TI - Medically important biofilms and non-thermal plasma. AB - In recent decades, the non-thermal plasma, i.e. partially or completely ionized gas produced by electric discharges at ambient temperature, has become of interest for its microbiocidal properties with potential of use in the food industry or medicine. Recently, this interest focuses not only on the planktonic forms of microorganisms but also on their biofilms. The works in this interdisciplinary field are summarized in this review. The wide range of biofilm plasma interactions is divided into studies of general plasma action on bacteria, on biofilm and on its oral and dental application; a short overview of plasma instrumentation is also included. In addition, not only biofilm combating but also an important area of biofilm prevention is discussed. Various DC discharges of the point-to-plane type. Author's photograph, published in Khun et al. (Plasma Sources Sci Technol 27:065002, 2018). PMID- 30456521 TI - The structural and functional roles of CTCF in the regulation of cell type specific and human disease-associated super-enhancers. AB - BACKGROUND: Super-enhancers play critical roles in cell-type specific gene controls and human disease progression. CCCTC-binding factor (CTCF), a transcriptional repressor that insulates the expression of neighboring genes and is involved in chromatin interactions, is frequently present in the boundary regions of or within super-enhancers. However, the structural and functional roles of CTCF in regulating super-enhancers remain elusive. OBJECTIVE: To provide a comprehensive review describing the distinct chromatin features and functional roles of CTCF within super-enhancers. METHODS: This review compares the various tools used to study the three-dimensional (3D) chromatin architecture of super enhancers; summarizes the chromatin features of CTCF within cell-type specific super-enhancers and their in vivo biological activities, as determined by CRISPR/Cas9 genome editing; and describes the structural and functional activities of CTCF within human disease-associated super-enhancers. CONCLUSION: This review provides fundamental insights into the regulatory mechanisms of super enhancers and facilitates studies of tissue-specific developmental processes and human disease progression. PMID- 30456522 TI - Identifying natural genotypes of grain number per panicle in rice (Oryza sativa L.) by association mapping. AB - INTRODUCTION: As one of the main yield components, grain number per panicle (GNP) played critical role in the rice yield improvement. The identification of natural advantageous variations under different situations will promote the sustainable genetic improvement in rice yield. OBJECTIVES: This study was designed to identify natural genotypes in a rice mini-core collection, to examine the genotypic effects across the indica and japonica genetic background in different environments, and excavating the superior genotypes that had drove the modern genetic improvement. METHODS: The association mapping of GNP was carried out using a mini-core collection including 154 indica and 119 japonica accessions in seven different environments. Genotypic effects of each genotype for each QTL were calculated and genotype frequency distortion between the commercial rice cultivars and landraces was screened by chi2-test. RESULTS: In total, 74 QTLs containing stable and sensitive QTLs in various environments were detected. Within them, 20 positive and 24 negative genotypes in indica, and 24 positive and 16 negative genotypes in japonica were identified. When checking the accumulation of positive genotypes identified in indica across cultivars in each of the two subspecies, it indicated that increased number of positive genotypes identified in indica results in the substantially increased GNP in both indica and japonica across all of the environments, while this trend was not obvious for the positive genotypes identified in japonica especially in short day environments. Moreover, the positive and negative genotype frequency distortion between the landraces and commercial rice cultivars indicated that both positive selection of positive genotypes and negative selection of negative genotypes had driven the genetic improvement on GNP. CONCLUSION: Our findings suggested that the accumulation of positive genotypes and purifying negative genotypes played equivalently important roles in the improvement of rice yield, but the efficient use for some QTLs or genotypes depends on the comprehensive evaluation of their effect under diverse genetic backgrounds and environments. PMID- 30456523 TI - Characterization of chloroplast genomes of Alnus rubra and Betula cordifolia, and their use in phylogenetic analyses in Betulaceae. AB - OBJECTIVE: Betulaceae is a relatively small birch family that comprises about 160 deciduous trees and shrubs. Chloroplast (cp) genome sequencing of Alnus rubra and Betula cordifolia was carried out to elucidate their molecular features and phylogenetic relationship among species in Betulaceae family. METHODS: Chloroplast genome sequencing was carried out using next generation sequencing method. Molecular and genomic features of the two cp genomes were characterized with other cp genomes in Betulaceae. Also, molecular phylogenetic analysis was performed using the whole cp genome sequences. RESULTS: The average cp genome length was 160,136 bp among the Betulaceae species. Base compositions of the cp genomes were skewed toward a high AT ratio, with an average of 63.4%. We identified 117 different genes 83 with protein coding, 4 with ribosomal RNA, and 30 with tRNA. Eighteen genes contained introns which were conserved among the cp genomes of all Betulaceae. We mined 82 SSRs from the cp genomes of A. rubra, A. cordifolia, and A. nana. The SSRs were variable in motif repeat numbers and presence/absence among the cp genomes. CONCLUSION: Chloroplast genome-wide sequence comparison from 11 Betulaceae species and one cp genome of evergreen oak revealed that the patterns of sequence variations were congruent with two subfamily classification Betuloideae (Alnus and Betula) and Corylaceae (Corylus, Ostrya, and Carpinus). Subsequent phylogenetic analysis also supports the sub classifications of these species. PMID- 30456524 TI - TaF: a web platform for taxonomic profile-based fungal gene prediction. AB - INTRODUCTION: The accurate prediction and annotation of gene structures from the genome sequence of an organism enable genome-wide functional analyses to obtain insight into the biological properties of an organism. OBJECTIVES: We recently developed a highly accurate filamentous fungal gene prediction pipeline and web platform called TaF. TaF is a homology-based gene predictor employing large-scale taxonomic profiling to search for close relatives in genome queries. METHODS: TaF pipeline consists of four processing steps; (1) taxonomic profiling to search for close relatives to query, (2) generation of hints for determining exon-intron boundaries from orthologous protein sequence data of the profiled species, (3) gene prediction by combination of ab inito and evidence-based prediction methods, and (4) homology search for gene models. RESULTS: TaF generates extrinsic evidence that suggests possible exon-intron boundaries based on orthologous protein sequence data, thus reducing false-positive predictions of gene structure based on distantly related orthologs data. In particular, the gene prediction method using taxonomic profiling shows very high accuracy, including high sensitivity and specificity for gene models, suggesting a new approach for homology-based gene prediction from newly sequenced or uncharacterized fungal genomes, with the potential to improve the quality of gene prediction. CONCLUSION: TaF will be a useful tool for fungal genome-wide analyses, including the identification of targeted genes associated with a trait, transcriptome profiling, comparative genomics, and evolutionary analysis. PMID- 30456525 TI - Genome-wide identification of the HKT genes in five Rosaceae species and expression analysis of HKT genes in response to salt-stress in Fragaria vesca. AB - INTRODUCTION: The high-affinity potassium transporter (HKT) gene family is implicated in the regulation of response to salt stress in different plants. Yet, knowledge remains very limited for them in the Rosaceae species. The whole genome sequences of the five Rosaceae species, including Fragaria vesca (woodland strawberry), Malus domestica (apple), Pyrus communis (pear), Prunus mume (mei) and Prunus persica (peach), give the opportunity to uncover the evolutionary pattern of the HKT genes among Rosaceae genomes. OBJECTIVES: The primary objective of this study was to identify the HKT genes in five Rosaceae species and understand the potential biological functions of the HKT genes in response to salt stress in Fragaria vesca. METHODS: In this study, the HKT genes in five Rosaceae species were identified by bioinformatics. The phylogenetic tree was constructed and Ka and Ks values were calculated by MEGA 5.0. Genetic mapping of these genes were processed by MapInspect software. In addition, the physico chemical properties, the cis-acting elements, the intron/exon structures, and the conserved domain motifs of these genes were analyzed and predicted by the websites of ProtParam, Pfam, PlantCARE, GSDS, MEME, and Motif Scan. RESULTS: In the present study, a total of 12 HKT genes were identified from five Rosaceae species. In the phylogenetic tree, orthologous genes were clustering together rather than paralogous genes and PcHKTs underwent two species-specific duplications before the divergence of pear and apple.. Furthermore, various expression levels of FvHKT genes revealed that woodland strawberry HKT genes are associated in responding to the salt stress. The activities of ROS-scavenging enzymes, superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) were also measured in different treatments of salt-stressed woodland strawberry leaves, which suggested that the three enzymes may also take part in response to salt stress. CONCLUSION: The Ka/Ks ratio demonstrated that purifying selection played a major role in the evolutionary processes of HKT genes among the Rosaceae species, and FvHKT genes are involved in response to salt stress. PMID- 30456526 TI - Prediction of Y haplogroup by polymerase chain reaction-reverse blot hybridization assay. AB - BACKGROUND: The analysis of Y-SNPs from crime scene samples is helpful for investigators in narrowing down suspects by predicting biogeographical ancestry. OBJECTIVE: In this study, a PCR-reverse blot hybridization assay (REBA) for predicting Y-chromosome haplogroups was employed to determine the major haplogroups worldwide, including AB, DE, C, C3, F, K, NO, O, O2, and O3 and evaluated. METHODS: The REBA detects nine biallelic Y chromosome markers (M9, M89, M122, M145, M175, M214, M217, P31, and RPS4Y711) simultaneously using multiple probes. RESULTS: The REBA for Y-single nucleotide polymorphisms (SNP) genotyping was performed using 40 DNA samples from Asians-14 Koreans, 10 Indonesians, six Chineses, six Thais, and four Mongolians. 40 Asian samples were identified as haplogroup O2 (40%), O3 (32.5%), C3 (17.5%), O (7.5%) and K (2.5%). These cases were confirmed by DNA sequence analysis (kappa = 1.00; P < 0.001). CONCLUSION: PCR-REBA is a rapid and reliable method that complements other SNP detection methods. Therefore, implementing REBA for Y-SNP testing may be a useful tool in predicting Y-chromosome haplogroups. PMID- 30456527 TI - The potential role of Ets-1 and miR-326 in CD19+B cells in the pathogenesis of patients with systemic lupus erythematosus. AB - OBJECTIVES: The aim of this study was to investigate the B cell-associated transcription factors, Ets-1 and microRNA, miR-326 in systemic lupus erythematosus (SLE) patients, and their correlation with the pathogenesis of SLE. METHOD: A total of 44 SLE patients and 20 healthy controls were enrolled in this research, all patients fulfilled the American College of Rheumatology classification criteria for SLE. The mRNA expression of Ets-1 and miR-326 in CD19+B cells from SLE patients were examined by qRT-PCR. The percentages of CD19+CD138+plasma cells were analyzed by Flow cytometry. RESULTS: We found decreased expression of Ets-1 mRNA in SLE patients compared with the healthy controls ([0.228 (0.145, 0.507)] vs [0.583 (0.452, 0.763)], p = 0.001),while increased expression of miR-326 mRNA in CD19+B cells SLE patients compared with the healthy controls([1.092 (0.457, 2.855)] vs [0.685 (0.274, 0.819)], p = 0.008). The percentage of CD19+CD138+plasma cells in SLE patients was higher than that of healthy controls (0.55 +/- 0.21% vs 0.36 +/- 0.21%, p = 0.002). Moreover, a negative correlation between expression of Ets-1 mRNA and miR-326 mRNA in CD19+B cells was detected (r = - 0.334, p = 0.027). A significant association between the occurrences of CD19+CD138+plasma cells and the levels of Ets-1 mRNA and miR-326 mRNA was observed (r = - 0.417, p = 0.005 and r = 0.482, p = 0.001, respectively). CONCLUSIONS: Our results suggest that miR-326 might promote B cells differentiation by targeting Ets-1, a negative regulator of B cells differentiation and therefore participate in the pathogenesis of SLE. PMID- 30456528 TI - Severe necrotizing myositis associated with long term anti-neoplastic efficacy following nivolumab plus ipilimumab combination therapy. AB - Immune-related adverse events (irAEs), have been reported under immune checkpoint inhibitors. Nivolumab plus ipilimumab (N + I) demonstrated meaningful improvements in key patient-reported outcomes, in patients with pretreated microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). We report a case of severe necrotizing myositis which occurred in a patient treated with N + I combination for mCRC MSI-H. A 61-year-old woman was diagnosed with mCRC MSI-H and BRAFV600E mutated with synchronous liver, pleural, and lymph nodes metastases. After she failed to respond to standard chemotherapy (two lines with 5-fluorouracil, oxaliplatin, and irinotecan + bevacizumab), she received in a clinical trial (CheckMate 142), nivolumab 3 mg/kg, and ipilumumab 1 mg/kg every 3 weeks [4]. One week after the second infusion, she developed rapidly extending proximal muscles weakness associated with diffuse erythematous rash with grade 2/5 strength on abdominal, dorsal, and proximal limb muscles and impressive muscular edema. The creatine kinase level was at 14827 U/L (0-160 U/L), without any detectable autoantibodies. The electromyogram showed a severe myogenic syndrome, and muscular histological analysis demonstrated extensive muscular necrosis, with scarce lymphocytic infiltrates and pathological expression of class I HLA and C5b9 complement deposits with severe endomysial edema. N-I therapy was discontinued. Intravenous methylprednisolone was initiated for 3 days followed by 1 mg/kg/day orally, combined with intravenous immunoglobulins (2 g/kg/day for 2 days). At 3 years of first infusion of N + I, patient is without any new progressive disease, in partial response on the liver, pleural, and nodes metastasis, with only persistent minor psoas weakness. PMID- 30456529 TI - Correction to: Aging and apolipoprotein E in HIV infection. AB - The row describing the clinical study of Mukerji et al. (2016) was inadvertently deleted during the compilation of Table 3. As a result, the citation for Mukerji et al. (2016) was not included in the "References" section of the manuscript. PMID- 30456530 TI - Author's reply to the letter to the editor regarding "Use of early postoperative serum creatinine changes to predict acute kidney injury after cardiothoracic surgery". PMID- 30456532 TI - Symbiont-Driven Male Mating Success in the Neotropical Drosophila paulistorum Superspecies. AB - Microbial symbionts are ubiquitous associates of living organisms but their role in mediating reproductive isolation (RI) remains controversial. We addressed this knowledge gap by employing the Drosophila paulistorum-Wolbachia model system. Semispecies in the D. paulistorum species complex exhibit strong RI between each other and knockdown of obligate mutualistic Wolbachia bacteria in female D. paulistorum flies triggers loss of assortative mating behavior against males carrying incompatible Wolbachia strains. Here we set out to determine whether de novo RI can be introduced by Wolbachia-knockdown in D. paulistorum males. We show that Wolbachia-knockdown D. paulistorum males (i) are rejected as mates by wild type females, (ii) express altered sexual pheromone profiles, and (iii) are devoid of the endosymbiont in pheromone producing cells. Our findings suggest that changes in Wolbachia titer and tissue tropism can induce de novo premating isolation by directly or indirectly modulating sexual behavior of their native D. paulistorum hosts. PMID- 30456533 TI - CIZ1 Expression Is Upregulated in Hemangioma of the Tongue. AB - Hemangioma is a vascular neoplasm and one of the most common benign tumors. The pathogenesis of hemangioma has not been fully understood. CIZ1 (Cip1-interacting zinc finger protein 1) is a nuclear protein and the binding partner of p21. Dysregulation of CIZ1 expression has been reported in various types of cancerous tissues. In this study, we examined CIZ1 expression in hemangioma of the tongue and explored its function in vascular endothelial cells, the proliferative cell type in hemangioma. Immunohistochemistry showed that CIZ1 was highly expressed in hemangioma of the tongue while its expression is minimal in the normal tongue tissues. In vitro, knockdown of CIZ1 expression by shRNA transfection significantly reduced the proliferation and migration of human umbilical vein endothelium cells (HUVECs), suggesting a positive role of CIZ1 in endothelial cell proliferation and migration. Therefore, CIZ1 might involve in pathogenesis of hemangioma of the tongue by regulation of endothelial cell functions. PMID- 30456534 TI - Cold water immersion or LED therapy after training sessions: effects on exercise induced muscle damage and performance in rats. AB - Cryotherapy and phototherapy have been suggested as recovery methods due to their anti-inflammatory effects. They may also induce mitochondrial biogenesis, thus favoring endurance training adaptation. The aim of this study was to evaluate the anti-inflammatory and ergogenic effects of phototherapy or cold water immersion (CWI) applied daily after exercise in rats. Thirty-five rats were divided into five groups: control (CO), non-exercised (CE), passive recovery (PR), cold water immersion (CWI), and LED therapy (LED). The CO and CE groups were not submitted to training; however, the CE were submitted to an exhaustion test after the training period. Low-intensity swimming training (21 sessions, 45 min) was performed followed by passive recovery (PR), CWI (10 degrees C, 5 min), or infrared irradiation (940 nm, 4 J/cm2). Forty-eight hours after the final training session, the CE, PR, CWI, and LED animals were submitted to an exhaustion test. The animals were euthanized 24 h later and submitted to hematological, creatine kinase (CK), and C-reactive protein (PCR) analysis. Gastrocnemius and soleus muscles were submitted to histological analysis. No differences in blood cell counts, CK, and PCR were detected between groups. The CE group presented an increased number of areas with necrosis in the gastrocnemius and soleus muscles. The PR group presented the highest frequency of areas with edema and inflammation followed by CWI and LED groups. None of the recovery methods improved the performance in the exhaustion test. Successive applications of recovery methods do not improve exercise performance, but downmodulate the inflammation and prevent muscle necrosis. PMID- 30456535 TI - Low-level laser irradiation modulates the proliferation and the osteogenic differentiation of bone marrow mesenchymal stem cells under healthy and inflammatory condition. AB - The aim of this in vitro study was to evaluate the effects of low-level laser therapy (LLLT) at different energy intensities on proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) under healthy and inflammatory microenvironments. Human BMSCs and BMSCs from inflammatory conditions (i-BMSCs, BMSCs treated with tumor necrosis factor alpha; TNF-alpha) were subject to LLLT (Nd:YAG;1064 nm) at different intensities. We designed one control group (without irradiation) and four testing groups (irradiation at 2, 4, 8, and 16 J/cm2) for both BMSCs and i-BMSCs. Cell proliferation was measured using colony-forming unit fibroblast assay and 3-(4,5-dimethylthiazol-2yl)-2,5 diphenyltetrazolium bromide assay. Osteogenic capacity of cells was determined by alkaline phosphatase (ALP) staining, ALP activity assay, Alizarin Red S staining and the mRNA transcript levels of genes runt-related transcription factor 2 (Runx2), ALP, and osteocalcin. Moreover, the effects of LLLT on secretion of TNF alpha in BMSCs and i-BMSCs were measured by enzyme-linked immunosorbent assay. Our results demonstrated LLLT could significantly promote BMSC proliferation and osteogenesis at densities of 2 and 4 J/cm2. LLLT at density of 8 J/cm2 could promote the proliferation and osteogenesis of i-BMSCs. However, LLLT at 16 J/cm2 significantly suppressed the proliferation and osteogenesis of BMSCs both in healthy and in inflammatory microenvironment. Moreover, we also found that the expression of TNF-alpha was obviously inhibited by LLLT at 4, 8, and 16 J/cm2, in an inflammatory microenvironment. Considering these findings, LLLT could improve current in vitro methods of differentiating BMSCs under healthy and inflammatory microenvironments prior to transplantation. PMID- 30456536 TI - The effect of low-level laser irradiation on hyperglycemia-induced inflammation in human gingival fibroblasts. AB - Hyperglycemia-induced inflammation can greatly increase the risk of periodontal disease in people with diabetes. Low-level laser irradiation (LLLI) has been used for wound healing and anti-inflammation in many cases, and LLLI is known to inhibit the lipopolysaccharide (LPS)-stimulated inflammatory response. However, the therapeutic effect of LLLI in diabetes patients with periodontitis remains unknown. In this study, we cultured human gingival fibroblasts (HGFs) in high glucose medium (35 mM) to mimic a hyperglycemic environment, and then measured the anti-inflammatory effect of LLLI by assessing the expression of pro inflammatory genes including tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, and IL-8 by quantitative real-time polymerase chain reaction. The results demonstrated no significant inflammatory response in HGFs cultured in mannitol medium and in those treated only with LLLI. However, HGFs cultured only in high-glucose medium showed significantly higher expression of pro-inflammatory cytokine than in those treated together with LLLI. We then observed that LLLI reduced the expression of pro-inflammatory cytokines in HGFs cultured in high glucose medium by modulating cAMP signaling. We also investigated whether antioxidant (vitamin C) treatment reduced the inflammatory effect of oxidative stress in HGFs cultured in high-glucose medium but found no additive effect upon co-treatment with LLLI, suggesting that LLLI may activate cAMP signaling, but not reactive oxygen species (ROS) signaling, to reduce the high glucose-induced inflammation. In conclusion, LLLI may have an anti-inflammatory effect on HGFs in a high glucose environment and may benefit the treatment of periodontal disease in diabetes patients. PMID- 30456537 TI - A Practical Guide to Curing Onychomycosis: How to Maximize Cure at the Patient, Organism, Treatment, and Environmental Level. AB - Onychomycosis is a fungal nail infection caused by dermatophytes, non dermatophyte molds, and yeasts. Treatment of this infection can be difficult, with relapse likely to occur within 2.5 years of cure. The objective of this article is to review factors that can impact cure and to suggest practical techniques that physicians can use to maximize cure rates. Co-morbidities, as well as disease severity and duration, are among the many patient factors that could influence the efficacy of antifungal therapies. Furthermore, organism, treatment, and environmental factors that may hinder cure include point mutations, biofilms, affinity for non-target enzymes, and exposure to fungal reservoirs. To address patient-related factors, physicians are encouraged to conduct confirmatory testing and treat co-morbidities such as tinea pedis early and completely. To combat organism-focused factors, it is recommended that disruption of biofilms is considered, and drugs with multiple routes of delivery and unique mechanisms of action are prescribed when traditional agents are not effective. Extending follow-up periods, using combination treatments, and considering pulse regimens may also be of benefit. Through these practical techniques, physicians can maximize cure and limit the risk of relapse and re infection. PMID- 30456538 TI - Elevated IL-16 expression is associated with development of immune dysfunction in children with autism. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in communication skills and social behaviors. Several studies have suggested that neuroimmune dysfunction plays a significant role in the pathogenesis of ASD; however, its exact etiology is unknown. Interleukin-16 (IL 16), a chemoattractant, is associated with various inflammatory processes. However, its role in children with ASD is unclear. This study aimed to investigate whether IL-16 expression is associated with immune dysfunction in children with ASD. We examined IL-16 expression in CD4+, CD8+, CD14+, CCR3+, and CXCR7+ cells in typically developing (TD) controls and children with ASD using flow cytometry in peripheral blood mononuclear cells (PBMCs). We also investigated the expression of IL-1beta+IL-16+, IL-6+IL-16+, and TNF-alpha+IL-16+ in TD controls and children with ASD. We further explored IL-16 mRNA and protein expression using RT-PCR and western blotting. CD4+IL-16+, CD8+IL-16+, CD14+IL 16+, CCR3+IL-16+, and CXCR7+IL-16+ cells increased significantly in children with ASD compared with TD controls. We also showed that expression of IL-1beta+IL-16+, IL-6+IL-16+, and TNF-alpha+IL-16+ was elevated in children with ASD compared with TD controls. Moreover, IL-16 mRNA and protein expression was significantly induced in children with ASD compared with TD controls. These results suggest that IL-16 expression could play an essential role in immune alteration in children with ASD. PMID- 30456539 TI - The relationship between delay discounting and alcohol dependence in individuals with and without comorbid psychopathology. AB - RATIONALE: Alcohol use disorder (AUD) has been associated with greater discounting of delayed monetary rewards, but it is unclear whether this association is primarily related to alcohol consumption or is secondary to the presence of psychiatric comorbidities. It is also unclear if steeper rates of discounting are associated with greater AUD severity. OBJECTIVE: We sought to determine whether the presence of comorbid psychiatric disorders affected the relationship between AUD and delay discounting. We also examined whether more severe AUD was associated with greater delay discounting. METHODS: In this cross sectional study, 793 adults completed a delay discounting task. Subjects were divided into four groups based on diagnosis: current AUD with psychiatric comorbidities (N = 226), current AUD without psychiatric comorbidities (N = 203), past AUD (N = 69), and healthy controls (N = 295). In those with AUD, we investigated the relationship between delay discounting and alcohol dependence symptom count and recent drinking history. We also compared individuals seeking treatment to non-treatment seeking individuals. Psychiatric comorbidities examined included mood disorders, anxiety disorders, and substance use disorders. RESULTS: After adjusting for age, sex, income, and education, individuals with current AUD showed significantly higher rates of delay discounting than healthy controls and individuals with a past diagnosis of AUD. The presence of comorbid psychiatric diagnoses was not associated with steeper discounting. Among those with AUD, there was no evidence for a continuous relationship between delay discounting and AUD severity or alcohol consumption. Finally, non-treatment seekers with AUD had steeper delay discounting than treatment seekers. CONCLUSIONS: Individuals with AUD show steeper delay discounting than healthy adults, but the effect is small and there is no added effect from comorbid psychopathology or increased AUD severity. This suggests that steeper delay discounting may have a more limited effect on human alcohol use than previously supposed. PMID- 30456540 TI - Sex difference in the association of body mass index and BDNF levels in Chinese patients with chronic schizophrenia. AB - RATIONALE AND OBJECTIVE: Schizophrenia displays sex differences in many aspects. Decreased brain-derived neurotrophic factor (BDNF) levels have been reported to be associated with high body weight or obesity as well as other psychopathological aspects in schizophrenia patients. This study aimed to explore sex differences in the relationship between serum BDNF levels and obesity in patients with chronic schizophrenia. METHODS: We recruited 132 Chinese patients with chronic schizophrenia (98 males and 34 females) and compared sex differences in the body mass index (BMI), obesity, serum BDNF levels, and their associations. Psychopathology symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). A regression model with various demographic and clinical variables was applied to predict the serum levels of BDNF. RESULTS: Female patients had a higher rate of obesity and higher BMI, but lower BDNF levels than male schizophrenia patients. A significantly negative correlation was observed between BMI and BDNF levels only in female patients but not in male patients. The multiple regression model with demographic and clinical variables significantly predicted BDNF levels only in female patients, with a medium size effect. And only in female patients, BMI made a significant contribution to this prediction. CONCLUSION: Our results indicate significant sex differences in the obesity, BMI, BDNF levels, and their association in chronic patients with schizophrenia, showing a significant inverse correlation between BMI and BDNF levels only in female patients. Thus, sex needs to be considered when assessing the relationship between BDNF and metabolic syndromes in schizophrenia. PMID- 30456542 TI - Robotic versus conventional primary total knee arthroplasty: clinical and radiological long-term results with a minimum follow-up of ten years. AB - PURPOSE: The aim of this study was (1) to compare the clinical and radiological outcomes of robotic and conventional total knee arthroplasty with a minimum follow-up of ten years, (2) to evaluate the survival rate, (3) and to estimate the accuracy of the two techniques by analyzing the outliers of the total knee arthroplasty (TKA) patients. METHODS: We evaluated 351 patients (390 knees), 155 patients undergoing robotic TKA, and 196 patients treated with conventional TKA with a mean follow-up of 11.0 years. HSS, KSS, WOMAC, and SF-12 questionnaires were used for clinical evaluation. Mechanical alignment, implant radiological measurements, and outliers were analyzed for radiological results. Kaplan-Meier survival analysis was performed for survival rate. RESULTS: All clinical assessments showed excellent improvements in both groups (all p < 0.05), without any significant difference between the groups (p > 0.05). The conventional TKA group showed a significantly higher number of outliers compared with the robotic TKA group (0 < 0.05). The cumulative survival rate was 98.8% in the robotic TKA group and 98.5% in the conventional TKA group with excellent survival (p = 0.563). CONCLUSION: Our study showed excellent survival with both robotic and conventional TKA and similar clinical outcomes at long-term follow-up. And, in terms of radiological outcome, robotic TKA showed better accuracy and consistency with fewer outliers compared with conventional TKA. With longer follow-up and larger cohort, the accuracy and effectiveness of robotic TKA on implant survival rate can be elucidated in the future. PMID- 30456541 TI - Olfactory dysfunction: properties of the Sniffin' Sticks Screening 12 test and associations with quality of life. AB - PURPOSE: The Sniffin' Sticks Screening 12 test is a test of olfactory performance based on pen-like odor dispensing devices. The aims of this study were to analyze the performance of this test in a general population sample and to explore associations between olfactory dysfunction and quality of life. METHODS: A large community sample (n = 7267) completed the Sniffin' Sticks Screening 12 test and several questionnaires measuring quality of life, anxiety, dispositional optimism, social support, and satisfaction with life. RESULTS: According to the criteria recommended by the test manufacturer, 5.1% of the participants were anosmic (score <= 6), 52.4% were dysosmic (7 <= score <= 10), and 42.5% were normosmic (score >= 11). While frequencies of correct identification differed between the 12 sticks, all sticks contributed positively to the test results. The associations between olfactory functioning and quality of life variables were negligible. In the multivariate analyses, none of the associations reached the 1% significance level. CONCLUSIONS: While studies with patients in otorhinolaryngological clinics often report substantial detriments to their quality of life in relation to olfactory dysfunction, the present epidemiological study cannot confirm this association for the general population. PMID- 30456543 TI - Antibody-initiated beneficial and harmful immune responses. AB - A critical function of the immune system is to maintain tolerance to self by corrective immune responses throughout life, including preventing or correcting changes that may interfere with organ function and architectural integrity. These changes have two broad categories, namely (1) exogenous antigen-induced mishaps (e.g., due to bacterial, viral or fungal infections) and (2) endogenous antigen caused ailments initiated by modified self-antigens derived from damaged organs following exposure to smoke, certain drugs, chemicals, infectious agents, radiation, etc., resulting in autoimmune diseases or cancer. In some cases, cells of the immune system are unable to respond with a corrective antibody response. For example, presentation of a modified self-antigen can initiate a pathogenic IgG immune response, thereby causing an autoimmune disease. Furthermore, if cancer-associated antigens are not appropriately presented to the cells of the immune system, there is failure to mount a specific pathogenic lytic IgG autoantibody response for recognition and elimination of cancer-associated antigens, and as a consequence, the cancer continues to proliferate.The third vaccination technique that we have developed and designated a modified vaccination technique (MVT) is able to correct these immunological mishaps. The premise of the MVT is that it can prevent both exogenous (infectious and contagious diseases) and endogenous (autoimmune diseases and cancer) antigen caused diseases, as well as terminate established diseases. Therefore, by exploiting the immune system's natural abilities to make corrective responses, it has both prophylactic and therapeutic actions, with minimal side effects. PMID- 30456544 TI - Vitamin D deficiency, endothelial function and bone biomarkers in post-kidney transplantation patients from North India. AB - PURPOSE: CKD patients after kidney transplantation continue to suffer from elevated CV events which may be related to low vitamin D and its adverse impact on vascular function. The prevalence of vitamin D deficiency in North Indian kidney transplantation patients and its impact on vascular and bone biomarkers is unknown which this study investigated. METHODS: Non-diabetic, stable, > 6 months post-kidney transplantation patients, not on vitamin D supplementation, were recruited after informed consent. Data on demographics, anthropometrics and treatment were collected. Blood samples were stored at - 80 degrees C until analysis for bone and endothelial cell biomarkers using standard ELISA techniques. RESULTS: The clinical characteristics were: age 37.4 +/- 9.9 years, 80% men, 27% ex-smokers, BP 125.5 +/- 15.7/78.6 +/- 9.7 mmHg, cholesterol 172.0 +/- 47.8 mg/dL, hemoglobin 12.6 +/- 2.3 g/dL, calcium 9.5 +/- 0.6 mg/d and iPTH 58.4 +/- 32.9 ng/mL and vitamin D 36.5 +/- 39.8 nmol/L. Patients with vitamin D < 37.5 nmol/L (66%) had similar age, serum creatinine, serum phosphate, iPTH, blood pressure but lower calcium (9.3 +/- 0.7 vs. 9.6 +/- 0.5 mg/dL; p = 0.024), lower FGF23 (median 18.8 vs. 80.0 pg/mL; p = 0.013) and higher E-selectin (15.8 +/- 7.9 vs. 13.0 +/- 5.5 ng/mL; p = 0.047). On Univariate analysis, E-selectin (r = - 0.292; p = 0.005), FGF23 (r = 0.217; p = 0.036) and calcium (r = 0.238; p = 0.022) were significantly correlated with vitamin D levels. On stepwise multiple regression analysis, only E-selectin was associated with vitamin D levels (beta = - 0.324; p = 0.002). CONCLUSION: Vitamin D deficiency was common in kidney transplant recipients in North India, associated with low FGF23 and high E selectin. These findings suggest further investigations to assess the role of vitamin D deficiency-associated endothelial dysfunction, its implications and reversibility in kidney transplantation recipients. PMID- 30456545 TI - Management of anxiety and depression in haemodialysis patients: the role of non pharmacological methods. AB - Anxiety and depression in patients undergoing haemodialysis can be reduced by a variety of treatment methods, including pharmacological therapy, cognitive behavioural therapy, regular exercise and relaxation techniques, such as Benson's relaxation method and acupressure treatment. Additionally, intradialytic exercise training programmes have a positive effect on patients' physical and psychological functioning. Moreover, social support from family and social environment, spirituality and religiosity, tele- nursing programmes and participation in network support groups frequently lead to a reduction of anxiety and depressive symptoms in these people. Finally, the provision of education and information to dialysis patients by renal professionals and a systematic psychiatric evaluation of these individuals can lead to early diagnosis and treatment of depressive symptoms. PMID- 30456546 TI - Protective effect of astaxanthin against contrast-induced acute kidney injury via SIRT1-p53 pathway in rats. AB - PURPOSE: The present study was designed to further investigate the protective effect of astaxanthin (AST) on contrast-induced acute kidney injury (CI-AKI) in rats and the relationship between SIRT1-p53 pathway and astaxanthin. METHODS: 40 adult male Sprague Dawley (SD) rats were randomly divided into five groups (n = 8/group): control (CON), normal rats treated with AST (AST), CM-treated (CM), CM rats treated with isoform of nitric oxide synthase (iNOS) inhibitor (iNOS + CM), and CM rats treated with AST (AST + CM). Serum creatinine (Scr) and blood urea nitrogen (BUN) values were measured at 72 h following the procedure. Hematoxylin and eosin (H-E) staining was used to observe the pathologic changes of kidney. Tunel staining was used to test apoptosis of kidney tubules. Oxidative stress, SIRT1 activity, nitric oxide (NO), and 3-nitrotyrosine (3-NT) content were individually measured with the commercial available kits. RESULTS: Compared with the CON group, Scr and BUN levels significantly increased in the CM group (P < 0.05), and the values in two pre-treatment groups (iNOS + CM and AST + CM) had significantly decreased (P < 0.05). H-E and Tunel staining had shown that renal tubular injury was severe in CM group. The renal injury score and apoptosis index in the two pre-treatment groups also decreased (P < 0.05). The present study showed that in CM group the levels of oxidative stress indicators significantly increased, and the activities of antioxidant stress indicators significantly decreased. These indicators in two pre-treatment groups significantly improved (P < 0.05). In the CM group the expression levels of SITR1 significantly increased, and the ac-p53/p53 significantly increased (P < 0.05). Compared with the CM group, in AST + CM group the expression levels of SIRT1 increased, the expression levels of p53 and ac-p53/p53 decreased (P < 0.05).The levels of NO and 3-NT in CM group significantly increased (P < 0.05). Compared the CM group, the levels in the two pre-treatment groups significantly decreased (P < 0.05). CONCLUSIONS: Astaxanthin has a protective effect on CI-AKI, the mechanism may be related to the SIRT1-p53 pathway. Astaxanthin can reduce the content of NO and 3-NT in renal tissue of CI-AKI, and alleviate the renal injury induced by contrast agents. PMID- 30456547 TI - Prevalence of pulmonary hypertension in peritoneal dialysis patients: a meta analysis. AB - PURPOSE: Recent epidemiological evidence indicates an association between peritoneal dialysis (PD) patients and pulmonary hypertension (PH). However, the true prevalence of PH associated with PD has not been well described. So we conducted a meta-analysis to summarize the point prevalence of PH in adults with PD. METHODS: PubMed, EMBASE, the Cochrane Collaboration, and the reference lists of relevant articles were searched to identify eligible studies. We used a random effect meta-analysis model to estimate the prevalence of PH. We also performed sensitivity analyses and assessments of publishing bias. RESULTS: Fourteen observational studies (n = 1483 participants) were included in this meta analysis. The result of analysis in random-effect model showed that the pooled prevalence was 21% (95% CI 16-28), with significant heterogeneity between these studies (I2 = 84%, p < 0.01). Sensitivity analysis further demonstrated the results to be robust. Besides, the Egger's test (p = 0.287) showed no significant publication bias. CONCLUSIONS: PH is highly prevalent in patients with PD. Further studies are encouraged to definitively clarify the relationship between PH and PD. PMID- 30456549 TI - Mineralogical and geochemical characterization of mining wastes: remining potential and environmental implications, Muteh Gold Deposit, Iran. AB - Muteh Gold Deposit is the biggest active gold district in Iran consisting of two mines, Senjedeh and Chah-Khatoun, and seven mineral occurrences. Senjedeh has been mined about 20 years ago and was recently closed because of the depletion of the reserves. Chah-Khatoun went into operation few years ago. During the previous decades, more than 22 Mt of low-grade wastes has been produced from both mines. The wastes are assumed to be a possible source of gold, especially with recent increase in the world gold prices. In this research, 62 surface and subsurface samples were taken from four waste dumps in Senjedeh and two dumps in Chah Khatoun mines. The optical mineralogy, XRD, ICP-MS analysis, SEM, and electron probe microanalysis (EPMA) studies were carried out to investigate the mineralogical and geochemical characteristics of the waste rocks. In addition to identification of major and minor primary and secondary phases, the mode of occurrence of minerals and also the content of precious and economic elements have been studied. The main opaque mineral was found to be pyrite. Among the economic elements, Au was recognized in the pyrite lattice as well as electrum. The Au grades are higher than 0.5 mg/kg in some waste piles. Zinc and Cu revealed concentrations above 5000 and about 1400 mg/kg, respectively. It is for the first time that electrum is reported in Muteh. Therefore, regarding the economically recoverable content of Au, the studied waste rocks may be considered as potential ores of coming years. Among the environmentally significant elements, As showed concentrations of up to 25 mg/kg which may be of pollution concerns. PMID- 30456548 TI - [Thyroid medicine for ENT physicians]. AB - Diseases of the thyroid gland are frequent incidental findings during ultrasound examination of the neck. They affect nearly one third of the normal population. Treatment is not always indicated; however, laboratory diagnostic measures must be initiated to specify the disease. The primary indications for consulting a thyroid specialist are thyroid nodules, goiters, autonomy of the thyroid gland, autoimmune diseases, Graves' disease, and Hashimoto thyroiditis. The aim of this review is to provide an overview of the most important thyroid diseases and their treatment options. PMID- 30456550 TI - Comparison between single photon emission computed tomography with computed tomography and planar scintigraphy in sentinel node biopsy in breast cancer patients. AB - OBJECTIVE: Radio-guided sentinel node (SN) biopsy is a standard method used in the treatment of early breast cancer. Single photon emission computed tomography with computed tomography (SPECT/CT) has been commonly used for SN detection. SPECT/CT adds precise anatomical information of SN sites, and it is reported that more SNs may be detectable on SPECT/CT than on planar imaging. We here investigate which breast cancer patients have benefited from SPECT/CT over planar imaging. METHODS: A total of 273 breast cancer patients including 80 with ipsilateral breast tumor relapse (IBTR) underwent both multiple-view planar imaging and SPECT/CT for SN detection. The number of SNs, the patients who had benefitted from SPECT/CT, and the SN procedure failure rate were compared between SPECT/CT and planar imaging. Factors influencing the visualization of para sternal and ipsilateral level II, III nodes, and contralateral axillary nodes were also analyzed using logistic regression analysis. RESULTS: The number of hot spots did not differ between SPECT/CT and multiple-view planar imaging. Eight contaminated patients and 52 patients with visualized extra-level I axillary nodes benefited from identifying precise anatomical sites. Even though radioactive nodes could be harvested in most (192/193) of the non-IBTR patients (7/8 in non-SN visible patients), no radioactive nodes could be found during surgery in 11 of 80 IBTR patients. Axillary surgery (dissection) increased the visualization of para-sternal and level II, III axillary nodes, and previous irradiation increased the visualization of contralateral axillary nodes. CONCLUSION: Multiple-view planar imaging was equivalent to SPECT/CT for depicting hot nodes for radio-guided SN detection in breast cancer. SPECT/CT was useful when precise anatomical information was necessary, especially regarding sentinel lymph nodes other than ipsilateral axilla. Logistic regression analysis revealed that axillary surgery (dissection) increased the visualization of para-sternal and level II, III axillary nodes, and the only relevant factor influencing visualization of contralateral axillary SNs was previous radiation to the breast. PMID- 30456551 TI - Hybrid robotic-assisted transversus abdominis release versus open transversus abdominis release: a comparison of short-term outcomes. AB - BACKGROUND: Although the open transversus abdominis release (oTAR) is an effective operation for large ventral hernias, it is historically associated with a relatively long length of stay. Robotic retromuscular transversus abdominis release (rTAR) allows minimally invasive repair of complex ventral hernias with shorter length of stay (LOS) compared to open repairs (TAR), but hybrid robotic TAR (hrTAR), partial open intervention via incision through the overlying hernia sac for fascial closure, may be required to accomplish effective repair of large defects. We compare LOS and short-term outcomes of a cohort of our hrTAR patients to our historical oTAR patients. METHODS: All hrTAR performed in our institution between November 2015 and July 2017 contained in a prospectively maintained robotic database and/or in the Americas Hernia Society Quality Collaborative (AHSQC) database were analyzed. Additionally, open TAR patients maintained in a prospective personal database and/or in the AHSQC from September 2013 to August 2016 were similarly analyzed and compared with hrTAR patients. RESULTS: 134 TAR patients and 49 hrTAR patients were analyzed. Age, gender, BMI, HTN, DM, and proportion of recurrent hernia were not significantly different. Hernia width (14.3 cm vs 14.0 cm, p = 0.80) and length (21.9 vs 20.0 cm, p = 0.10) were similar between groups. Mean operative times did not differ significantly between groups (274 min vs 304 min p = 0.06). Thirty day wound events including SSI and SSOPI were not significantly different between groups. LOS was significantly shorter in the hrTAR group (3 vs 7 days, p <= 0.001). CONCLUSION: Hybrid robotic transversus abdominis release (hrTAR) may be performed with significantly lower LOS, similar wound morbidity and complication profile compared to open TAR. This novel surgical technique provides a minimally invasive option for a challenging subset of large ventral hernias which cannot be treated effectively with a purely robotic approach and would traditionally require and open operation. PMID- 30456552 TI - The lateral joint space width can be measured reliably with Telos valgus stress radiography in medial knee osteoarthritis. AB - OBJECTIVE: To examine the reproducibility of valgus stress radiographs with the Telos stress device for assessment of lateral compartment degenerative changes in patients with medial osteoarthritis of the knee. MATERIALS AND METHODS: A prospective reliability study was performed. Seventy-nine patients (80 knees) were included, and standardized valgus stress radiographs were obtained using the Telos stress device. Osteophytes and joint space narrowing (JSN) were graded using the OARSI (Osteoarthritis Research Society International) classification, and the joint space width (JSW) was measured in millimeters. Reproducibility was determined as intra-and inter-rater reliability and test-retest reliability. Weighted kappa was used to determine the reliability of osteophyte and JSN grading, and the intra-class correlation coefficient for JSW. RESULTS: Grading of osteophytes had an intra- and inter-rater reliability ranging from 0.40 to 0.83 on the medial side and ranging from 0.39 to 0.87 on the lateral side. Grading of medial JSN had an intra- and inter-rater reliability ranging from 0.62 to 0.84, and grading of lateral JSN had an intra- and inter-rater reliability ranging from 0.32 to 0.65. Intra- and inter-rater reliability of JSW ranged from 0.84 to 0.98 on the medial side, and from 0.59 to 0.89 on the lateral side. Test-retest reliability of JSW of the medial and lateral side ranged from 0.69 to 0.92. CONCLUSIONS: Standardized valgus stress radiographs taken with the Telos stress device are a reliable supplement in the assessment of medial OA of the knee. Evaluation of the lateral compartment on valgus stress radiographs is most reliable with measurement of the lateral JSW. PMID- 30456553 TI - Incorporating musculoskeletal ultrasound into your radiology practice: patients, patience, and why your department cannot do without it. PMID- 30456554 TI - Selective rickets from localized advanced maturation-a case report. AB - An unusual cause of rickets is illustrated by a patient with infantile multisystem inflammatory disease who, by age 2 years and 4 months, developed striking radiographic and clinical rickets restricted to those joints involved by the inflammatory process. The locally increased vascularity from his inflammation led to increased maturation at those sites so rapid as to override the usual enchondral calcification, thus causing a rickets pattern. Other sites, such as the proximal humeri, lacking any inflammation, showed no increased maturation rate and did not manifest local rickets. Rapid local bone maturation may cause localized rickets. PMID- 30456555 TI - Basic Calcium Phosphate Crystals Induce Osteoarthritis-Associated Changes in Phenotype Markers in Primary Human Chondrocytes by a Calcium/Calmodulin Kinase 2 Dependent Mechanism. AB - Chondrocytes in osteoarthritis undergo a phenotype shift leading to increased production of cartilage-degrading enzymes. There are similarities between the phenotype of osteoarthritic chondrocytes and those of growth plate chondrocytes. Hydroxyapatite can promote chondrocyte differentiation in the growth plate. Basic calcium phosphate (BCP) crystals (which consist of hydroxyapatite, octacalcium apatite and tricalcium phosphate) are frequently found in osteoarthritic joints. The objective of this study was to determine whether BCP crystals induce disease associated changes in phenotypic marker expression in chondrocytes. Primary human chondrocytes isolated from macroscopically normal cartilage were treated with BCP for up to 48 h. Expression of indian hedgehog (IHH), matrix metalloproteinase 13 (MMP13), interleukin-6 (IL-6) and type X collagen (COLX) were higher, and expression of sry-box 9 (SOX9) lower, in BCP-treated chondrocytes (50 ug/mL) compared to untreated controls. COLX protein was also present in BCP-treated chondrocytes. Intracellular calcium and levels of phosphorylated and total calcium/calmodulin kinase 2 (CaMK2) were elevated following BCP treatment due to BCP-induced release of calcium from intracellular stores. CaMK2 inhibition or knockdown ameliorated the BCP-induced changes in SOX9, IHH, COLX, IL-6 and MMP13 expression. BCP crystals induce osteoarthritis-associated changes in phenotypic marker expression in chondrocytes by calcium-mediated activation of CaMK2. The presence of BCP crystals in osteoarthritic joints may contribute to disease progression. PMID- 30456556 TI - Chronic Non-bacterial Osteomyelitis: A Review. AB - Chronic non-bacterial osteomyelitis (CNO) is a rare auto-inflammatory bone disorder, with a prevalence of around one in a million patients. In the more severe form, it is referred to as chronic recurrent multifocal osteomyelitis (CRMO). We present the current knowledge on epidemiology, pathophysiology as well as diagnostic options and treatment regimens. CNO/CRMO most commonly affects children and lesions are often seen in the metaphyseal plates of the long bones, but cases have been described affecting all age groups as well as lesions in almost every bone. It is, therefore, a disease that clinicians can encounter in many different settings. Diagnosis is mainly a matter of exclusion from differential diagnoses such as bacterial osteomyelitis and cancer. Magnetic resonance imaging is the best radiological method for diagnosis coupled with a low-grade inflammation and a history of recurring episodes. Treatment is based on case reports and consists of alleviating symptoms with non-steroidal anti inflammatory drugs since the disease is often self-limiting. Recently, more active treatments using either bisphosphonates or biological treatment are becoming more common, to prevent long term bone damage. In general, due to its rarity, much remains unclear regarding CNO/CRMO. We review the known literature on CNO/CRMO and propose areas of interest as well as possible ways to make current diagnostic criteria more detailed. We also find unifocal cases of the jaw to be a possible sub-type that may need its own set of criteria. PMID- 30456557 TI - Adrenal crisis presented as acute onset of hypercalcemia and hyponatremia triggered by acute pyelonephritis in a patient with partial hypopituitarism and pre-dialysis chronic kidney disease. AB - A 57-year-old woman with pre-dialysis chronic kidney disease (CKD) was hospitalized because of fever and fatigue. On admission, increased inflammatory response and pyuria with bacteriuria were observed. Pyelonephritis was successfully treated with antibiotics, whereas her fatigue continued and she developed progressive hypercalcemia and hyponatremia; serum sodium level, 116 mEq/L and corrected serum calcium level, 13.4 mg/dL. Plasma concentrations of adrenocorticotropic hormone and cortisol and serum luteinizing hormone were under the detection level. Although the reaction of other anterior pituitary hormones and the serum antidiuretic hormone (ADH) was preserved, the response of serum luteinizing hormone to administration of luteinizing hormone releasing hormone was impaired. Magnetic resonance imaging showed no structural abnormality in the thalamus, hypothalamus, and pituitary gland. She was diagnosed with adrenal insufficiency caused by partial hypopituitarism in concomitant with pyelonephritis. After starting hydrocortisone replacement, serum levels of sodium and calcium were rapidly normalized. This case highlights the importance of adrenal insufficiency as a differential diagnosis of hypercalcemia in patients with pre-dialysis CKD, especially when hyponatremia was concomitantly observed. Besides, infection should be considered as an important trigger for the development of latent adrenal insufficiency since it could increase the physiological demand of corticosteroid in the body. Also, CKD may enhance the magnitude of hypercalcemia since CKD patients have decreased capacity to increase urinary calcium excretion. PMID- 30456558 TI - Wax Ester Composition of Songbird Preen Oil Varies Seasonally and Differs between Sexes, Ages, and Populations. AB - Chemical signaling has been well studied in invertebrates and mammals but less so in birds, due to the longstanding misconception that olfaction is unimportant or even non-existent in this taxon. However, recent findings suggest that olfaction plays an important role in avian mate choice and reproductive behavior, similar to other taxa. The leading candidate source for compounds involved in avian chemical communication is preen oil, a complex mixture secreted from the uropygial gland. Preen oil contains volatile compounds and their potential wax ester precursors, and may act as a reproductive chemosignal. Reproductive signals are generally sexually dimorphic, age-specific, seasonally variable, and may also vary geographically. We tested whether preen oil meets these expectations by using gas chromatography to examine the wax ester composition of preen oil in song sparrows (Melospiza melodia). We found that the wax ester composition of preen oil was significantly different between sexes, age classes, seasons, and populations. Collectively, our results suggest that song sparrow preen oil meets the criteria of a chemical cue that may influence mate choice and reproduction. Our findings in song sparrows, which are sexually monomorphic in plumage, also parallel patterns described for dark-eyed juncos (Junco hyemalis), a closely related songbird with sexually dimorphic plumage. Behavioral tests are needed to confirm that song sparrows attend to the cues present in preen oil, but our findings support the increasingly accepted idea that chemical communication is common and widespread in birds as it is in other taxa. PMID- 30456559 TI - Hyper-diversity of CRH interneurons in mouse hippocampus. AB - Hippocampal inhibitory interneurons comprise an anatomically, neurochemically and electrophysiologically diverse population of cells that are essential for the generation of the oscillatory activity underlying hippocampal spatial and episodic memory processes. Here, we aimed to characterize a population of interneurons that express the stress-related neuropeptide corticotropin-releasing hormone (CRH) within existing interneuronal categories through the use of combined electrophysiological and immunocytochemical approaches. Focusing on CA1 strata pyramidale and radiatum of mouse hippocampus, CRH interneurons were found to exhibit a heterogeneous neurochemical phenotype with parvalbumin, cholecystokinin and calretinin co-expression observed to varying degrees. In contrast, CRH and somatostatin were never co-expressed. Electrophysiological categorization identified heterogeneous firing pattern of CRH neurons, with two distinct subtypes within stratum pyramidale and stratum radiatum. Together, these findings indicate that CRH-expressing interneurons do not segregate into any single distinct subtype of interneuron using conventional criteria. Rather our findings suggest that CRH is likely co-expressed in subpopulations of previously described hippocampal interneurons. In addition, the observed heterogeneity suggests that distinct CRH interneuron subtypes may have specific functional roles in the both physiological and pathophysiological hippocampal processes. PMID- 30456560 TI - Temporarily increased TGFbeta following radon spa correlates with reduced pain while serum IL-18 is a general predictive marker for pain sensitivity. AB - Sustained pain relief following radon spa therapy in patients suffering from chronic painful diseases has been well described. But still, the underlying mechanisms are not fully understood. We conducted the prospective and explorative RAD-ON01 study which included 103 patients who suffered from chronic painful musculoskeletal disorders of the spine and/or joints and present here the data of the examination of pro- and anti-inflammatory cytokines in the serum of the patients before and at weeks 6, 12 and 30 after therapy. While TNFalpha, IL 1beta, IFNgamma, IL-1Ra and IL-10 were not altered, TGFbeta was temporarily significantly (p = 0.013) elevated 6 weeks after therapy. Importantly, this elevation positively correlated with lowered pain sensitivity (r = 0.41). Further, the amount of IL-18 in the serum positively correlated with lowered pain sensitivity. Therefore, IL-18 can be considered as predictive marker for pain sensitivity of radon spa patients. We conclude that alterations in TGFbeta and general IL-18 levels in serum have prognostic and predictive value in situations of lowered pain by exposure of patients to very low-doses of radiation as it is the case in radon spa. PMID- 30456561 TI - MRI morphologic and clinicopathologic characteristics for predicting outcomes in patients with locally advanced rectal cancer. AB - PURPOSE: The aim of this study was to investigate the value of MRI morphologic and clinicopathologic factors for predicting 3-year disease-free survival (DFS) in patients with locally advanced rectal cancer (LARC). METHOD: In this retrospective study, pre- and post-neoadjuvant chemoradiotherapy (nCRT) MRI morphologic (e.g., pre-nCRT MRI-detected extramural venous invasion) and clinicopathologic variabilities (e.g., pathological complete response) were evaluated in all patients. Three-year DFS was estimated using Kaplan-Meier product-limit method, and Cox proportional hazards models were used to determine associations between morphologic or clinicopathologic variabilities and survival outcomes. RESULTS: A total of 115 patients (39 females and 76 males; median age, 54 years; age range, 28-82 years) with LARC treated with nCRT were enrolled. With a median follow-up of 48.0 months, the 3-year DFS was 79.0% for all patients. During follow-up, 18 patients died, 28 patients experienced relapse (26 distant, one local, and one both), and 69 patients were censored. MRI-detected extramural venous invasion (mrEMVI) was the only significantly independent factor of long term survival, while HR was 2.308 (95% CI 1.151-4.629, P = 0.018) on univariate and 2.495 (95% CI 1.243-5.012, P = 0.010) on multivariate analysis. The 3-year cumulative survival rate in patients with mrEMVI negativity compared with positivity were 86.6% versus 65.0% (P = 0.015), respectively. CONCLUSION: In conclusion, pre-nCRT mrEMVI status was the independent significant risk factor for long-term outcomes in LARC patients treated with nCRT, while the other morphologic and clinicopathologic characteristics were not related to the patient survival. PMID- 30456562 TI - Increased Iron Availability Aggravates the Infection of Escherichia coli O157:H7 in Mice. AB - Iron plays an important role both in bacterial pathogenicity and in host defense mechanisms, which has frequently been underestimated. The primary purpose of this study was to investigate the influence of iron supplementation on the progression of bacterial infection. We used mice as an experimental model to supplement iron after Escherichia coli (E. coli) O157:H7 infection and found that iron supplementation exacerbated clinical symptoms of bacterial infection by increasing mortality and reducing body weight. Iron supplementation promoted the colonization of bacteria and enhanced inflammatory responses by increasing C reaction protein level and the phagocytic capacity of PBMCs, as well as upregulating the expression of TNF-alpha and IL-1beta in E. coli O157:H7 challenged mice. In vitro cell experiment confirmed that an excess of iron would enhance the growth of E. coli O157:H7 and worsen the outcome of bacterial infection. Therefore, it is certainly plausible that iron supplementation in bacterial infection may worsen rather than improve host outcome. PMID- 30456563 TI - Complications in children with percutaneous endoscopic gastrostomy (PEG) placement. AB - INTRODUCTION: The aim of this study was to analyze the complication rates and mortality in association with different operative techniques of percutaneous endoscopic gastrostomy (PEG), age, underlying diseases and other risk factors. Moreover, analysis of the indications of PEG insertion and the underlying comorbidities was also performed. METHODS: This study performs a literature analysis of PEG-related complications in children. Literature was searched on PubMed(r) (1994-2017) using terms "percutaneous endoscopic gastrostomy", "complications", "mortality" and "children". RESULTS: Eighteen articles with 4631 patients were analyzed. The mean age was 3 years (0-26 years). Operative techniques were: pull technique in 3507 (75.7%), 1 stage PEG insertion in 449 (9.7%), introducer technique in 435 (9.4%), image-guided technique in 195 (4.2%) and laparoscopic-assisted PEG in 45 (1.6%). Most frequent indications for PEG insertion were dysphagia (n = 859, 32.6%), failure to thrive (n = 723, 27.5%) and feeding difficulties (n = 459,17.4%). Minor complications developed in n1518 patients (33%), including granulation (n = 478, 10.3%), local infection (n = 384, 8.3%) and leakage (n = 279, 6%). In 464 (10%) patients, major complications occurred; the most common were systemic infection (n = 163, 3.5%) and cellulitis (n = 47, 1%). Severe complication like perforation occurred in less than 0.3%. Patients with lethal outcomes (n = 7, 0.15%) had severe comorbidities; and the cause of mortality was sepsis in all cases. Prematurity or young age did not affect complication rate. Patients with ventriculoperitoneal (VP) shunt had higher risk of major complications. In high-risk patients, laparoscopic-assisted PEG insertion had less major and severe complication than traditional pull technique. CONCLUSIONS: PEG is a safe operative technique; although minor complications are relatively common and occur in up to 1/3 of patients, there is a fairly low rate of severe complications. Two-thirds of PEG patients have at least one comorbidity. Patients with VP shunt have higher risk of major complications. In high-risk patients, laparoscopic-assisted PEG is recommended. PMID- 30456564 TI - Effect of vitamin D treatment in children with attention-deficit hyperactivity disorder. AB - BACKGROUND: In this research the symptom improvement of attention-deficit hyperactivity disorder (ADHD) of children was assessed by oral vitamin D administration in Tabriz, Iran. METHODS: In this double-blind, randomized clinical trials, 96 children (2-18 years) were enrolled to placebo and vitamin D groups. Children took vitamin D pearl (50,000 IU/week) or placebo for 6 weeks. Children, who had the change in methylphenidate dosage and received any anticonvulsants and corticosteroids were excluded from the research. ADHD symptoms were diagnosed by Conners parent rating scale (CPRS) test at baseline and after intervention. ADHD Conners divided into inattention (IA), hyperactivity/impulsivity (H/I) and combination type (C) subscales. Vitamin D serum level was assessed at baseline and after 8 weeks in both groups. RESULTS: The differences between CPRS and its subscales were not significant at baseline (P > 0.05). The Conners IA score was decreased in vitamin D group (P < 0.05; adjusted with age and baseline values). ADHD Conners and all subscale scores reduced remarkably after intervention in patients with insufficient level of vitamin D compared to placebo (P < 0.05). CONCLUSIONS: Oral vitamin D improved ADHD symptoms with a particular effect on inattention symptoms. In addition, symptoms related to all subscales were improved remarkably in patients with insufficient level of vitamin D. Vitamin D treatment in children with ADHD could be considered due to the expand benefit of vitamin D in body. PMID- 30456565 TI - Increased lipid accumulation but not reduced metabolism explains improved starvation tolerance in cold-acclimated arthropod predators. AB - Predatory arthropods are used for biological control in greenhouses, but there is increasing interest to extend their use to the outdoor environment where temperatures are typically lower. Acclimation at low temperature increases the ability of ectotherms to cope with subsequent more extreme cold, but may involve costs or benefits to other performance traits. A recent study in mesostigmatid mites (Gaeolaelaps aculeifer) showed that starvation tolerance was improved following a period of cold exposure. However, the physiological mechanisms that underlie improved starvation tolerance following cold exposure were not investigated. To examine whether cold acclimation would also improve starvation tolerance in an insect, we repeated the starvation study in another arthropod predator, the pirate bug Orius majusculus, as well as in G. aculeifer. Before tests, the two species were acclimated at 10, 15, or 20 degrees C for 7 (G. aculeifer) or 16 (O. majusculus) days. We then analyzed the effects of thermal exposure on body composition, consumption, and basal metabolic rate in both species. Our results confirmed that exposure to low temperature improves starvation tolerance in these arthropod predators. Body composition analyses revealed that both species had accumulated larger lipid stores during exposure to colder temperature, which at least in part can explain the larger starvation tolerance following cold exposure. In contrast, consumption and basal metabolic rate were not changed by thermal acclimation. Our study indicates that predatory arthropods exposed to cold increase their physiological robustness and ability to endure environmental challenges, including low temperature and low prey availability. PMID- 30456566 TI - Modeling and prediction of future ecotourism conditions applying system dynamics. AB - The ecotourism industry is one of the largest industries and has an important role in the economic social and cultural development of societies, especially in developing countries. Policymaking and planning procedures in this industry require the application of the methods that can appropriately model mutual and complex interactions and contacts. System dynamics is an accurate modeling method to simulate complex systems in a structured way and to design more effective policies by using these complex systems. In this study, the interactions and dynamics of the main components of ecotourism (effective variables) in the Taleghan area are modeled using system dynamics. To formulate and model simulations in the period between 2005 and 2015 was considered, and then extending the period of investigation, the model simulation was performed till the year 2025. Among the most important results of this study is the effect of the environment on the demand for ecotourism. Environmental degradation and the degradation of the quality of the environment lead to a reduced demand for ecotourism. This study predicts the future of ecotourism by this dynamic and designs a group of policies for the sustainable and comprehensive development of ecotourism on the basis of the behavior of the model variables in order to prevent the degradation of environment and simultaneously ensure that ecotourism demand is not negatively affected. Finally, the best policy "depending construction to the state of the area environment" was selected among them. PMID- 30456567 TI - Correction to: Identification and functional validation of a unique set of drought induced genes preferentially expressed in response to gradual water stress in peanut. AB - The original version of this article contains the following duplicate figures, namely blots showing expression data of clones. PMID- 30456568 TI - Bone autografting in medial open wedge high tibial osteotomy results in improved osseous gap healing on computed tomography, but no functional advantage: a prospective, randomised, controlled trial. AB - PURPOSE: Medial open wedge high tibial osteotomy (owHTO) is a valuable surgical technique used to manage medial degeneration in varus knees. Iliac crest autograft is considered the gold standard gap-filler. It was hypothesised that iliac crest autograft promotes gap healing and improves functional outcome in owHTO. METHODS: Between 2005 and 2009, patients scheduled to undergo owHTO stabilised by a medial locking compression plate were randomised to undergo owHTO either with iliac crest autograft (group A) or without bone void filler (group B). Pre- and postoperative leg axes were recorded. At 3 and 12 months postoperatively, the healing of the osteotomy gap was measured as a percentage on CT images, and functional scores were recorded. RESULTS: There were 15 patients in group A, and 25 in group B. The groups were similar in age, sex ratio, knee varus deformity, body mass index, and smoking status. Group A and B had similar preoperative varus (6.9 degrees vs. 7.6 degrees ) and postoperative valgus (2.2 degrees vs. 3.0 degrees ). Compared with the control group, group A had a significantly greater degree of osseous gap healing after 3 months (40.1% vs. 10.8%, p = 0.045) and 12 months (91.5% vs. 59.1%, p <= 0.001). Multiple linear regression analysis found that bone grafting was an independent promoting factor for gap healing, while increased preoperative varus was an independent retardant factor at 3 months (p = 0.004 and p = 0.002, respectively) and 12 months (p <= 0.001 and p = 0.003, respectively). Younger age was a promoting factor for gap healing on CT at 3 months (p <= 0.001), but not at 12 months. No correlations were found between bone healing and functional outcome, body mass index, or smoking status. CONCLUSIONS: Iliac crest autograft significantly increases healing of the osteotomy gap after owHTO. Increased preoperative varus and older patient age are independent factors that delay early healing of the osteotomy. However, no functional advantage was found at 3 or 12 months postoperatively. Therefore, routine use of iliac crest autograft cannot be recommended. LEVEL OF EVIDENCE: II. PMID- 30456569 TI - Alignment factors affecting the medial meniscus extrusion increases the risk of osteoarthritis development. AB - PURPOSE: Varus alignment is known as one of the major causes of medial compartment osteoarthritis (OA). Medial meniscus extrusion also plays a critical role in the in the development of OA. However, studies on the exact relationship between alignment parameters and medial meniscus extrusion are limited. Therefore, this study aimed to investigate this relationship in patients with knee OA. METHODS: Based on a retrospective analysis of the outpatient magnetic resonance imaging (MRI) database, 190 knees were identified to be examined using weight-bearing, whole-leg radiographs and MRIs within 3 months from the first consultation. Subsequently, various parameters of lower leg alignment were measured, which affected the knee varus in radiographs. Finally, a statistical analysis was performed to assess the relationships between the OA grade, distance of medial meniscus extrusion (MME), and alignment parameters; hip-knee-ankle angle (HKAA), percentage of mechanical axis (% MA), medial proximal tibial angle (MPTA), and joint line convergence angle (JLCA). The subjects were divided according to the presence or absence of MME (Group A: MME distance below 3 mm, Group B: MME distance 3 mm and above) to assess the differences in each alignment parameter correlated with MME distance between the groups. RESULTS: MME distance significantly increased with OA grade progression. HKAA, % MA, MPTA, and JLCA significantly correlated with medial meniscus extrusion distance (r = - 0.21, - 0.23, - 0.16, 0.3, respectively). Multiple regression analysis of each significant alignment combined with age, sex, and body mass index revealed that HKAA, % MA, MPTA, and JLCA were significant independent factors of MME distance (P = 0.008, 0.0026, 0.011, 0.0001, respectively). These significant findings were reinforced in group B. In contrast, the correlation between alignment parameters and medial meniscus extrusion distance was not significant in group A. CONCLUSION: Varus alignment factors are related to MME distance especially in extruded meniscus knees, as the OA grade progressed. Therefore, the coexistence of varus alignment and MME can be the risk factors for OA progression. As the low MPTA was an independent alignment factor for generating varus alignment, patients with osteoarthritis of the knee with both, low MPTA and MME could be the appropriate candidates for early intervention by high tibial osteotomy. LEVEL OF EVIDENCE: III. PMID- 30456570 TI - Good clinical and radiological results of total knee arthroplasty using varus valgus constrained or rotating hinge implants in ligamentous laxity. AB - PURPOSE: The optimal degree of constraint of a total knee arthroplasty for treatment of knee osteoarthritis with ligamentous laxity is under debate. While varus valgus constrained knees require a minimum level of ligamentous stability, rotating hinge knees can even be implanted if the collateral ligaments have been lost completely. It seems plausible that joint kinematics are determined by implant design in rotating hinge knees, whereas varus valgus constrained knees may be influenced by remaining stabilizers. This may result in more predictable clinical results of hinge knees. The hypothesis of the present study, therefore, was that stability and clinical outcome are better after total knee arthroplasty using rotating hinge knees than after using varus valgus constrained knees. METHODS: All patients who were treated using a mobile-bearing varus valgus constrained knee or a rotating hinge knee for treatment of end-stage osteoarthritis and ligamentous laxity were included. At follow-up, clinical scores were determined (WOMAC, VAS, KSS, FJS, Lysholm). Furthermore, body mass index, operating time, and postoperative complications were documented. Whole leg radiographs as well as patella axial radiographs were analyzed for implant alignment and patella tracking. RESULTS: Eighty-five patients were included in this retrospective study. Both groups showed an average range of motion of 113 degrees . No significant difference between the two groups was observed for any of the scores recorded. In the rotating hinge knee group, a more precise tibia positioning in relation to the mechanical axis but also a significant lateralisation and tilting of the patella were seen, compared with the varus valgus constrained knee group. CONCLUSIONS: Rotating hinge knees did not perform better than mobile-bearing varus valgus constrained knees clinically. Both prosthesis types showed equally good clinical outcomes with regard to stability, mobility, satisfaction, pain and operating time. LEVEL OF EVIDENCE: Retrospective case series, Level IV. PMID- 30456571 TI - Risk of subsequent fracture after prior fracture among older women. AB - : Among 377,561 female Medicare beneficiaries who sustained a fracture, 10% had another fracture within 1 year, 18% within 2 years, and 31% within 5 years. Timely management to reduce risk of subsequent fracture is warranted following all nontraumatic fractures, including nonhip nonvertebral fractures, in older women. INTRODUCTION: Prior fracture is a strong predictor of subsequent fracture; however, postfracture treatment rates are low. Quantifying imminent (12-24 month) risk of subsequent fracture in older women may clarify the need for early postfracture management. METHODS: This retrospective cohort study used Medicare administrative claims data. Women >= 65 years who sustained a clinical fracture (clinical vertebral and nonvertebral fracture; index date) and were continuously enrolled for 1-year pre-index and >= 1-year (>= 2 or >= 5 years for outcomes at those time points) post-index were included. Cumulative incidence of subsequent fracture was calculated from 30 days post-index to 1, 2, and 5 years post-index. For appendicular fractures, only those requiring hospitalization or surgical repair were counted. Death was considered a competing risk. RESULTS: Among 377,561 women (210,621 and 10,969 for 2- and 5-year outcomes), cumulative risk of subsequent fracture was 10%, 18%, and 31% at 1, 2, and 5 years post-index, respectively. Among women age 65-74 years with initial clinical vertebral, hip, pelvis, femur, or clavicle fractures and all women >= 75 years regardless of initial fracture site (except ankle and tibia/fibula), 7-14% fractured again within 1 year depending on initial fracture site; risk rose to 15-26% within 2 years and 28-42% within 5 years. Risk of subsequent hip fracture exceeded 3% within 5 years in all women studied, except those < 75 years with an initial tibia/fibula or ankle fracture. CONCLUSIONS: We observed a high and early risk of subsequent fracture following a broad array of initial fractures. Timely management with consideration of pharmacotherapy is warranted in older women following all fracture types evaluated. PMID- 30456572 TI - Utility of four sarcopenia criteria for the prediction of falls-related hospitalization in older Australian women. AB - : Numerous sarcopenia definitions are not associated with increased falls-related hospitalization risk over 5 years to 9.5 years in older community-dwelling Australian women. Measures of muscle strength and physical function, but not appendicular lean mass (measured by dual-energy X-ray absorptiometry) may help discriminate the risk of falls-related hospitalization. INTRODUCTION: The aim of this prospective, population-based cohort study of 903 Caucasian-Australian women (mean age 79.9 +/- 2.6 years) was to compare the clinical utility of four sarcopenia definitions for the prediction of falls-related hospitalization over 9.5 years. METHODS: The four definitions were the United States Foundation for the National Institutes of Health (FNIH), the European Working Group on Sarcopenia in Older People (EWGSOP), and modified FNIH (AUS-POPF) and EWGSOP (AUS POPE) definitions using Australian population-specific cut points (< 2 SD below the mean of young healthy Australian women). Components of sarcopenia including muscle strength, physical function, and appendicular lean mass (ALM) were quantified using hand grip strength, timed-up-and-go (TUG), and dual-energy X-ray absorptiometry (DXA), respectively. Incident 9.5-year falls-related hospitalization were captured by linked data. RESULTS: Baseline prevalence of sarcopenia according to FNIH (9.4%), EWGSOP (24.1%), AUS-POPF (12.0%), and AUS POPE (10.7%) differed substantially. Sarcopenia did not increase the relative hazard ratio (HR) for falls-related hospitalization before or after adjustment for age (aHR): FNIH aHR 1.00 95%CI (0.69-1.47), EWGSOP aHR 1.20 95%CI (0.93 1.54), AUS-POPF aHR 0.96 95%CI (0.68-1.35), and AUS-POPE aHR 1.33 95%CI (0.94 1.88). When examining individual components of sarcopenia, only muscle strength and physical function but not ALM (adjusted for height2 or BMI) were associated with falls-related hospitalization. CONCLUSION: Current definitions of sarcopenia were not associated with falls-related hospitalization risk in this cohort of community-dwelling older Australian women. Finally, measures of muscle strength and physical function, but not ALM (measured by DXA) may help discriminate the risk of falls-related hospitalization. PMID- 30456573 TI - Association between malnutrition-inflammation score and risk of subsequent self reported bone fractures in prevalent kidney transplant recipients. AB - : Chronic inflammation and protein energy wasting (PEW) syndrome are common in kidney transplant recipients (KTR). The presence of inflammation and PEW syndrome can directly affect bone resorption and bone formation, leading to bone loss and fractures. We showed PEW is independently associated with new clinically detected bone fractures in prevalent KTR. INTRODUCTION: Kidney transplant recipients (KTR) have a 4-fold higher risk of fracture compared to the general population. Chronic inflammation and PEW syndrome are common in KTR and are associated with poor outcomes. We hypothesized that the Malnutrition-Inflammation Score (MIS), a validated measure of PEW, is associated with higher risk of bone fractures in KTR. METHODS: This prospective cohort study included 839 prevalent KTR from a Central European academic center. MIS, a semiquantitative instrument of PEW, was calculated at the study entry. Self-reported history of fractures was recorded during the 2-year follow-up period. The association between MIS and bone fractures was examined in logistic regression analyses with adjustment for age, gender, eGFR, smoking habits, history of pre-transplant bone fractures, and acute rejection. RESULTS: Mean age was 51 +/- 13 years, and 56% of patients were males with median (interquartile range) transplant vintage 69 (38-112) months, estimated glomerular filtration rate 55 +/- 21 ml/min/1.73 m2, and calculated MIS 3 (2-4) at enrollment. Fifty-five (7%) patients experienced self-reported bone fractures during the 2-year follow-up period. Higher MIS score showed linear association with increased risk of fracture. Each one-point higher MIS was associated with 23% higher risk of bone fractures (odds ratio (OR) and 95% CI 1.23, 1.12-1.34), which remained significant after multivariable adjustments (OR 1.17, 95% CI 1.06-1.29). CONCLUSION: The MIS is independently associated with new clinically detected bone fractures in prevalent KTR. PMID- 30456574 TI - CCR5 blockage by maraviroc: a potential therapeutic option for metastatic breast cancer. AB - PURPOSE: Bone metastasis is observed in up to 70% of breast cancer patients. The currently available treatment options are palliative in nature. Chemokine receptor 5 (CCR5) has gained attention as therapeutic target in various malignancies. Here, we investigated the effects of targeting CCR5 by its antagonist maraviroc in metastatic breast cancer cells. METHODS: In response to maraviroc exposure, cytotoxicity was assessed using an MTT proliferation assay, whereas the effects on colony formation and migration were assessed using colony formation, transwell chamber migration and scratch wound healing assays, respectively. Apoptosis-related activities were investigated using nuclear staining, annexin-V FITC staining and Western blotting. Cell cycle changes were analysed using flow cytometry and qRT-PCR for cell cycle relevant genes. A nude rat model for breast cancer bone metastasis was used to evaluate the in vivo efficacy of CCR5 targeting by maraviroc. Circulatory levels of the three cognate ligands for CCR5 (CCL3, CCL4, CCL5) were analysed in sera of breast cancer patients using ELISA. RESULTS: We found that blockade of CCR5 attenuated the proliferation, colony formation and migration of metastatic breast cancer cells, and induced apoptosis and arrest in the G1 phase of the cell cycle. Expression profiling highlighted the involvement of cell cycle related signalling cascades. We also found that treatment with maraviroc significantly inhibited bone metastasis in nude rats implanted with MDA-MB-231 breast cancer cells. Finally, we found that the circulatory levels of three cognate ligands for the CCR5 receptor varied between breast cancer patients and healthy controls. CONCLUSION: Our findings indicate that targeting CCR5 may be an effective strategy to combat breast cancer bone metastasis. PMID- 30456575 TI - Laparoscopic repair of an incarcerated diaphragmatic hernia after right hepatectomy for hepatic injury: a case report. AB - BACKGROUND: Diaphragmatic hernias (DH) are generally classified as either congenital or acquired. Acquired DH are generally of traumatic cause, being a rare complication after hepatectomy. Although repair of a DH can be performed via laparotomy, laparoscopy, or thoracoscopy, the use of laparoscopy is rare after hepatectomy owing to the formation of scar tissue. In this case, we describe our successful attempt at laparoscopic repair of a recurrent DH after hepatectomy. CASE PRESENTATION: A 30-year-old man underwent right hepatectomy for trauma and thoracotomy via the eighth intercostal space, with direct closure of the diaphragm by suturing. The patient subsequently developed a right DH, with strangulation ileus of the small intestine. He underwent laparotomy 3 months after the initial surgery. The defect was observed to be clearly separate from the previously sutured area of the diaphragm. Five years after treatment, the patient developed abdominal pain and vomiting due to incarceration of the transverse colon in the right intrathoracic space (detected via abdominal computed tomography and radiography). The patient was again diagnosed with DH and underwent laparoscopic repair of the hernia with direct closure. The patient was discharged 11 days after surgery without further complication. CONCLUSIONS: A laparoscopic approach was feasibly and safely used to repair a recurrent DH after hepatectomy. The surgical approach will need to be decided in a patient-specific manner. PMID- 30456576 TI - Ethambutol targets the glutamate racemase of Mycobacterium tuberculosis-an enzyme involved in peptidoglycan biosynthesis. AB - Increasing drug resistance in pathogens including Mycobacterium tuberculosis (MTB) has been ascribed to mutations in the known target genes. However, many of these drugs have multiple targets; some of which have not been identified so far. Understanding the mechanism of action of these drugs holds a great promise in better management of disease especially by drug-resistant strains. In this study, we report glutamate racemase (MurI), a crucial enzyme of phase I peptidoglycan (PG) biosynthesis pathway of MTB, as an additional target of ethambutol (EMB). The effect on EMB on the MurI protein at structural and functional level was studied using different spectroscopic, biochemical, and insilico approaches. Spectroscopic analysis revealed that EMB-modified protein undergoes conformational alterations. Furthermore, in vitro racemization studies of the MurI protein suggest that EMB decreases its functional activity. Docking studies revealed that EMB interacts with most of the active residues at the binding site and blocks the binding pocket. Overall, data suggests that EMB, a primary drug used for the treatment of tuberculosis (TB), acts as a competitive inhibitor of substrate for binding to mycobacterial MurI protein. The study also points out to our lacunae in understanding the site and mechanism of action of existing drugs. Furthermore, glutamate racemase is a conserved protein of the bacterial kingdom; therefore, ethambutol could be a promising candidate as a broad-spectrum antibiotic for many other bacterial diseases. PMID- 30456577 TI - Biosurfactants produced by Serratia species: Classification, biosynthesis, production and application. AB - Biosurfactants are surface-active molecules that are synthesised non-ribosomally by a wide range of microorganisms including bacteria, yeast and filamentous fungi. The bacterial genus Serratia is gaining international interest, as biosurfactants produced by this genus have emerged as a promising source of antimicrobial, antifouling and antitumour compounds that possess emulsification and surface activity. Various species of Serratia have been identified as biosurfactant producers, including Serratia marcescens, Serratia rubidaea and Serratia surfactantfaciens. Members of the Serratia genus have been reported to principally produce two classes of biosurfactants, namely lipopeptides and glycolipids. Lipopeptides produced by Serratia species include serrawettins and stephensiolides, while identified glycolipids include rubiwettins and rhamnolipids. This review will primarily focus on the classification of biosurfactants produced by Serratia species and the genes and mechanisms involved in the biosynthesis of these biosurfactant compounds. Thereafter, an indication of the primary growth conditions and nutrient composition required for the optimum production of biosurfactants by this genus will be outlined. An overview of the latest advances and potential applications of the biosurfactants produced by Serratia in the medical, pharmaceutical, agricultural and petroleum industries is also provided. PMID- 30456578 TI - Disparities in Statin Use in New York City: Implications for Health Reform. AB - Heart disease is the leading cause of death in the USA, and there is an extensive literature describing disparities in the treatment of the disease. Cholesterol lowering medications are an effective strategy for reducing the risk of cardiovascular diseases for many patients, but some who are prescribed these medications fail to take them. We examine data from the 2014 New York City Community Health Survey to investigate the factors that influence why patients are not compliant in following the prescribed regimen. We focus on adults age 45 and older who report that they are diagnosed with elevated cholesterol levels and were told by a health professional they needed to take cholesterol-lowering medication. We find that evident disparities: individuals with low incomes, those who rely on emergency departments for their healthcare, have not received medical care within the past year, are depressed, and identify as black non-Hispanic and Hispanic are less likely to adhere to a cholesterol-lowering medication program. Although Medicare beneficiaries are less likely to take cholesterol-lowering medication than those with private insurance, those who were on Medicaid or were uninsured did not report lower rates of adherence. PMID- 30456580 TI - [MicraTM leadless pacemaker : Clinical experience and perspectives]. AB - Leadless pacemakers have the potential to fundamentally change the field of device therapy. As leads and generator pockets are no longer needed with this technology, many potentially dangerous complications of conventional pacemaker systems like lead fractures, lead endocarditis or pocket infections can be effectively avoided. At present, MicraTM (Medtronic Inc., Minneapolis, MN, USA) is the only commercially available leadless pacemaker. Since its first-in-human implantation in 2013, thousands of these devices have been implanted worldwide. This article presents an overview of the present clinical evidence and future perspectives of this promising new technology. PMID- 30456581 TI - Long-term stability of RNA isolated from muscle of red seabream (Pagrus major) during ice storage. AB - Recovering high-quality intact RNA from postmortem tissue is of major concern for gene expression studies. However, it is difficult to perform RNA extraction from aquacultured fish immediately after death, as rapid and accurate skills are needed for the procedure. The objective of this study was to quantitatively assess the integrity of total RNA extracted from muscle, liver, and digestive tract tissues of red seabream stored in ice as whole bodies, at a range of time points up to 10 days postmortem, using RNA integrity number (RIN) and quantitative PCR (qPCR). The RIN of total RNA in muscle remained over 8.0 for 5 days postmortem. The RINs in the liver and digestive tract were under 5.0 at 2 days postmortem. The mRNA levels of tissue inhibitor metalloproteinase 2 (TIMP-2) and beta-actin, measured using qPCR in muscle, decreased to 87.8% at 1 day postmortem and to 45.5% at 2 days postmortem, from that at 0 days postmortem. In the liver and digestive tract, the mRNA levels were not significantly changed until 1 day postmortem. These results indicate that RNA, especially from fish muscle, can be maintained at high quality for several days postmortem solely by storing the fish body in ice. PMID- 30456579 TI - Evaluation of the status and the relationship between essential and toxic elements in the hair of occupationally exposed workers. AB - Lead poisoning is a common disease in lead-acid battery manufacturing industries. Workers can be also exposed to various toxic elements present as contaminants or used as catalysts to enhance batteries' performances. In the present study, levels of essential and toxic elements and their relationship were assessed by analyzing scalp hair samples of 52 workers in a Pb battery manufacturing plant. The impact of some confounding factors on hair mineral contents was also investigated. For comparative purposes, nonoccupationally exposed subjects were selected as controls. All elements were determined by triple quadrupole ICP-MS. The results indicated significantly higher levels of Pb, Sb, As, and Cd in the hair of workers when compared to controls (p < 0.01). The Spearman correlation test revealed significant correlations between Pb/Cr, Pb/Mn, Pb/Ni, Pb/As, Pb/Se, Pb/Sb, Hg/As, Hg/Sn, Hg/Sb, Sb/Cr, Sb/As, Sb/Se, Sb/Cd, Sb/Sn, Sn/Cr, Sn/As, Sn/Cd, Cd/As, Se/Ni, As/Cr, Ni/Cr, Ni/Mn, and Mn/Cr in the hair of workers and Pb/Cr, Pb/Mn, Pb/Ni, Pb/Cd, Mn/Ni, Mn/Cd, Cd/Ni, As/Ni, Sn/Ni, Sb/Sn, and Hg/Sn in the hair of controls. Multiple linear regression analysis revealed linear dependence including Cr = f(Pb, Ni, Sb), Mn = f(Ni, Sb), Ni = f(Mn, Cr, -Cd) (Cd was negatively correlated, beta < 0), As = f(Sn, Sb, Hg), Se = f(Ni); Sn = f(As), Sb = f(As, Mn, -Hg, Sn, Se, -Ni) (Hg and Ni were negatively correlated), Hg = f(As, -Sb, Sn) (Sb was negatively correlated), and Pb = f(Cr). The result of this study can be very useful to explain the interactions between elements or for comparison studies when establishing reference ranges or monitoring elements in workplaces. PMID- 30456582 TI - Clinicopathologic analysis and subclassification of benign lipomatous lesions of the colon. AB - Benign lipomatous lesions of the colon are generally asymptomatic. A few histologic subtypes are appreciable, but this is poorly studied. We categorized 404 benign colonic lipomatous lesions as vascular lipoma, fibrolipoma, mucosal lipoma, or lipoma not otherwise specified (NOS). We compared patient age and sex, tumor site and size, symptoms, whether the lesion was flat or pedunculated, and whether an overlying epithelial lesion was present. Symptomatic cases (4%) were larger on average than non-symptomatic ones (mean 3.70 cm vs. 1.30 cm, P < 0.0001). Lipoma NOS was commonly right-sided (P < 0.001) and commonly had an associated epithelial proliferation (P = 0.0004). Vascular lipomas were larger (mean 1.93 cm, P < 0.0001) than other types; they were the most commonly symptomatic, though this was not statistically significant. Mucosal lipomas were smallest on average (mean 0.48 cm) and were not associated with any clinical syndromes. Some colonic lipomas are non-incidental. Vascular lipomas are more often large, while lipomas NOS more often have an associated epithelial proliferation. Colonic lipomas are generally sporadic. PMID- 30456583 TI - Correction to: Three-dimensional black-blood contrast-enhanced MRI improves detection of intraluminal thrombi in patients with acute ischaemic stroke. AB - The original version of this article, published on 19 March 2018, unfortunately contained a mistake. In the section "MR examination," the contrast medium Gadoterate meglumine was incorrectly named Gadodiamide. PMID- 30456584 TI - CT reconstruction algorithms affect histogram and texture analysis: evidence for liver parenchyma, focal solid liver lesions, and renal cysts. AB - PURPOSE: To determine the effects of different reconstruction algorithms on histogram and texture features in different targets. MATERIALS AND METHODS: Among 3620 patients, 480 had normal liver parenchyma, 494 had focal solid liver lesions (metastases = 259; hepatocellular carcinoma = 99; hemangioma = 78; abscess = 32; and cholangiocarcinoma = 26), and 488 had renal cysts. CT images were reconstructed with filtered back-projection (FBP), hybrid iterative reconstruction (HIR), and iterative model reconstruction (IMR) algorithms. Computerized histogram and texture analyses were performed by extracting 11 features. RESULTS: Different reconstruction algorithms had distinct, significant effects. IMR had a greater effect than HIR. For instance, IMR had a significant effect on five features of liver parenchyma, nine features of focal liver lesions, and four features of renal cysts on portal-phase scans and four, eight, and four features, respectively, on precontrast scans (p < 0.05). Meanwhile, different algorithms had a greater effect on focal liver lesions (six in HIR and nine in IMR on portal-phase, three in HIR, and eight in IMR on precontrast scans) than on liver parenchyma or cysts. The mean attenuation and standard deviation were not affected by the reconstruction algorithm (p > .05). Most parameters showed good or excellent intra- and interobserver agreement, with intraclass correlation coefficients ranging from 0.634 to 0.972. CONCLUSIONS: Different reconstruction algorithms affect histogram and texture features. Reconstruction algorithms showed stronger effects in focal liver lesions than in liver parenchyma or renal cysts. KEY POINTS: * Imaging heterogeneities influenced the quantification of image features. * Different reconstruction algorithms had a significant effect on histogram and texture features. * Solid liver lesions were more affected than liver parenchyma or cysts. PMID- 30456585 TI - Multi-parametric MRI zone-specific diagnostic model performance compared with experienced radiologists for detection of prostate cancer. AB - OBJECTIVES: Compare the performance of zone-specific multi-parametric-MRI (mp MRI) diagnostic models in prostate cancer detection with experienced radiologists. METHODS: A single-centre, IRB approved, prospective STARD compliant 3 T MRI test dataset of 203 patients was generated to test validity and generalisability of previously reported 1.5 T mp-MRI diagnostic models. All patients included within the test dataset underwent 3 T mp-MRI, comprising T2, diffusion-weighted and dynamic contrast-enhanced imaging followed by transperineal template +/- targeted index lesion biopsy. Separate diagnostic models (transition zone (TZ) and peripheral zone (PZ)) were applied to respective zones. Sensitivity/specificity and the area under the receiver operating characteristic curve (ROC-AUC) were calculated for the two zone-specific models. Two radiologists (A and B) independently Likert scored test 3 T mp-MRI dataset, allowing ROC analysis for each radiologist for each prostate zone. RESULTS: Diagnostic models applied to the test dataset demonstrated a ROC-AUC = 0.74 (95% CI 0.67-0.81) in the PZ and 0.68 (95% CI 0.61-0.75) in the TZ. Radiologist A/B had a ROC-AUC = 0.78/0.74 in the PZ and 0.69/0.69 in the TZ. Radiologists A and B each scored 51 patients in the PZ and 41 and 45 patients respectively in the TZ as Likert 3. The PZ model demonstrated a ROC-AUC = 0.65/0.67 for the patients Likert scored as indeterminate by radiologist A/B respectively, whereas the TZ model demonstrated a ROC-AUC = 0.74/0.69. CONCLUSION: Zone-specific mp-MRI diagnostic models demonstrate generalisability between 1.5 and 3 T mp-MRI protocols and show similar classification performance to experienced radiologists for prostate cancer detection. Results also indicate the ability of diagnostic models to classify cases with an indeterminate radiologist score. KEY POINTS: * MRI diagnostic models had similar performance to experienced radiologists for classification of prostate cancer. * MRI diagnostic models may help radiologists classify tumour in patients with indeterminate Likert 3 scores. PMID- 30456586 TI - Risk assessment of copper-containing contraceptives: the impact for women with implanted intrauterine devices during clinical MRI and CT examinations. AB - OBJECTIVES: To assess the risks for implant users with copper-containing intrauterine devices (IUDs) during MR and CT examinations. METHODS: A tissue mimicking phantom suitable for all experiments within this study was developed. Seven different types of copper IUDs were evaluated. Heating and dislocation of each IUD were investigated at two clinically relevant positions in 1.5 T and 3 T MR scanners. Artifacts in the field of view caused by each tested IUD were determined for clinical MR and CT imaging. RESULTS: No significant heating of any tested IUD was detected during MR measurements. The temperature increase was less than 0.6 K for all IUDs. Neither angular deflection nor translation of any IUD was detected. Artifacts in MR images were limited to the very vicinity of the IUDs except for one IUD containing a steel-visualizing element. Streaking artifacts in CT were severe (up to 75.5%) in the slices including the IUD. CONCLUSION: No significant risk possibly harming the patient was determined during this phantom study, deeming MR examinations safe for women with an implanted copper IUD. Image quality was more impaired for CT than for MR imaging and needs careful consideration during diagnosis. KEY POINTS: * Risk assessment of copper-containing IUDs with regard to heating, dislocation, and artifacts during MR and CT imaging. * Neither significant heating nor dislocation was determined in MR; image quality was more impaired for CT than for MR imaging and needs careful consideration during diagnosis. * The tested IUDs pose no additional risks for implant users during MR and CT examinations. PMID- 30456587 TI - What Do We Know About Youth Softball Pitching and Injury? AB - Participation rates in fastpitch softball are continually on the rise, especially in youth. With the increased participation also comes the increased injury susceptibility. Unfortunately, the common misconception about the dynamic 360 degrees windmill softball pitch, that it is a natural motion and thus does not cause stress on the shoulder, deterred investigation into pitching mechanics until recently. As pitching injuries in softball are on the rise, more attention is needed into the mechanics of the windmill softball pitch and injury implications. Therefore, it was the purpose of this current opinion paper to shed light on what is known about youth softball pitching and injury susceptibility. PMID- 30456588 TI - Correction to: Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease. AB - Due to a typesetting error the wrong Table 2 was used. The correct Table 2 is shown here. PMID- 30456590 TI - Epigallocatechin gallate suppresses premature senescence of preadipocytes by inhibition of PI3K/Akt/mTOR pathway and induces senescent cell death by regulation of Bax/Bcl-2 pathway. AB - The phytochemical epigallocatechin gallate (EGCG) has been reported to alleviate age-associated immune disorders and organ dysfunction. However, information regarding the mechanistic role of EGCG in the suppression of cellular senescence is limited. The present study thus assessed the effects and underlying mechanisms of EGCG in the inhibition of senescence as well as its potential to selectively eliminate senescent cells (senolytics) using 3T3-L1 preadipocytes. Premature senescence was established in cells by repeated exposure of H2O2 at a sub-lethal concentration (150 MUM). H2O2 treated cells showed characteristic senescence associated features including increased cell size, senescence-associated beta galactosidase activity (SA-beta-gal), development of senescence-associated secretory phenotype (SASP), activation of reactive oxygen species (ROS) and pathways, DNA damage as well as induction of cell cycle inhibitors (p53/p21WAF1/p16INK4a). In addition, a robust activation of PI3K/Akt/mTOR and AMPK pathways was also observed in H2O2 treated cells. Presence of EGCG (50 and 100 MUM) showed significant downregulation of PI3K/Akt/mTOR and AMPK signaling along with the suppression of ROS, iNOS, Cox-2, NF-kappaB, SASP and p53 mediated cell cycle inhibition in preadipocytes. In addition, EGCG treatment also suppressed the accumulation of anti-apoptotic protein Bcl-2 in senescent cells thereby promoting apoptosis mediated cell death. Our results collectively show that EGCG acts as an mTOR inhibitor, SASP modulator as well as a potential senolytic agent thereby indicating its multi-faceted attributes that could be useful for developing anti-aging or age-delaying therapies. PMID- 30456589 TI - Larval crowding results in hormesis-like effects on longevity in Drosophila: timing of eclosion as a model. AB - There is increasing evidence that stress during development can affect adult-life health status and longevity. In the present study, we examined life span (LS), fly weight, fecundity and expression levels of longevity-associated genes (Hsp70, InR, dSir2, dTOR and dFOXO) in adult Drosophila melanogaster flies reared in normal [low density (LD), ~ 300-400 eggs per jar] or crowded [high density (HD), more than 3000 eggs per jar] conditions by using the order (day) of emergence as an index of the developmental duration (HD1-5 groups). Developmental time showed a significant trend to increase while weight showed a significant trend to decrease with increasing the timing of emergence. In both males and females eclosed during first 2 days in HD conditions (HD1 and HD2 groups), both mean and maximum LSs were significantly increased in comparison to LD group. In males, mean LS was increased by 24.0% and 23.5% in HD1 and HD2 groups, respectively. In females, corresponding increments in mean LS were 23.8% (HD1 group) and 29.3% (HD2 group). In HD groups, a strong negative association with developmental time has been found for both male and female mean and male maximum LSs; no association with growth rate was observed for female maximum LS. The female reproductive activity (fecundity) tended to decrease with subsequent days of eclosion. In HD groups, the levels of expression of all studied longevity-associated genes tended to increase with the timing of eclosion in males; no differences were observed in females. On the basis of findings obtained, it can be assumed that the development in conditions of larval overpopulation (if not too extended) could trigger hormetic response thereby extending the longevity. Further studies are, however, needed to confirm this assumption. PMID- 30456591 TI - Acute medical management of aortic dissection. AB - Acute aortic dissection is a life-threatening disease. Current therapeutic guidelines recommend medical therapy with aggressive blood pressure lowering for patients with acute aortic dissection, when they are not indicated for emergency surgery. In particular, patients with aortic dissection without ascending aorta involvement (Stanford type B) are treated medically, unless they have fatal complications. Patients with type B aortic dissection who have critical complications have higher early mortality than that in patients without complications. However, recent advances in thoracic endovascular aortic repair can improve the clinical outcomes in such patients. Accordingly, current guidelines recommend thoracic endovascular aortic repair for patients with complicated type B aortic dissection. However, patients with visceral ischemia still have a poor prognosis, even when they are treated with thoracic endovascular aortic repair; an early diagnosis and intervention is crucial to prevent mortality. Understanding the pathophysiological anatomy that can induce organ malperfusion might be important for an early diagnosis and intervention. This review summarizes the current state of acute medical management in patients with acute aortic dissection, based on current evidence and expert consensus, focusing on patients with type B aortic dissection. PMID- 30456592 TI - Atrial fibrillation in hypertrophic cardiomyopathy: prevalence, clinical impact, and management. AB - Hypertrophic cardiomyopathy (HCM) is the most common hereditary cardiomyopathy characterized by left ventricular hypertrophy and spectrum of clinical manifestation. Atrial fibrillation (AF) is a common sustained arrhythmia in HCM patients and is primarily related to left atrial dilatation and remodeling. There are several clinical, electrocardiographic (ECG), and echocardiographic (ECHO) features that have been associated with development of AF in HCM patients; strongest predictors are left atrial size, age, and heart failure class. AF can lead to progressive functional decline, worsening heart failure and increased risk for systemic thromboembolism. The management of AF in HCM patient focuses on symptom alleviation (managed with rate and/or rhythm control methods) and prevention of complications such as thromboembolism (prevented with anticoagulation). Finally, recent evidence suggests that early rhythm control strategy may result in more favorable short- and long-term outcomes. PMID- 30456593 TI - Apparent Diffusion Coefficient Histogram Analysis for Assessing Tumor Staging and Detection of Lymph Node Metastasis in Epithelial Ovarian Cancer: Correlation with p53 and Ki-67 Expression. AB - PURPOSE: To investigate the potential of apparent diffusion coefficient (ADC) histogram parameters in epithelial ovarian cancer (EOC) for distinguishing different tumor stages and determining lymph node status and correlations between ADC values and p53 and Ki-67 expression. PROCEDURES: Forty-nine EOC patients underwent preoperative magnetic resonance imaging. Staging and lymph node status were determined postoperatively. ADC values were measured using histogram analysis and compared between groups. Relationships between ADCs and Ki-67 and p53 expression were explored. RESULTS: DC parameters differed significantly between stage I vs II, I vs III, and I vs IV. The parameters were significantly lower in the lymph node-positive group than in the lymph node-negative group, were significantly negatively correlated with Ki-67 labeling index, and were all significantly lower in the mutation-type p53 group than in the wild-type p53 group. CONCLUSIONS: ADC histogram analysis can help discriminate stage I from advanced-stage EOC and predict lymph node metastasis. ADC parameters were correlated with Ki-67 labeling index; the parameters may help indicate p53 expression. PMID- 30456594 TI - The role of osteopontin in kidney diseases. AB - BACKGROUND: Osteopontin (OPN) is a pleiotropic glycoprotein expressed in various cell types in animals and in humans, including bone, immune, smooth muscle, epithelial and endothelial cells. Moreover, OPN is found in kidneys (in the thick ascending limbs of the loop of Henle and in distal nephrons) and urine. The protein plays an important role in mineralization and bone resorption. In addition, OPN is involved in the regulation of immunity and inflammation, angiogenesis and apoptosis. It was demonstrated that OPN and some OPN gene polymorphic variants are associated with the pathogenesis and progression of multiple disorders, such as cancer, autoimmune, neurodegenerative and cardiovascular diseases. Moreover, recent studies suggested that OPN is associated with the pathogenesis of renal failure. METHODS: In this review, I briefly discussed the role of OPN and its gene polymorphisms in kidney physiology, as well as in various kidney diseases. FINDINGS AND CONCLUSION: Most studies reported that OPN expression is elevated in urolithiasis, and also in acute and chronic kidney diseases, and in renal allograft dysfunction. Moreover, it was demonstrated that polymorphic variants of the OPN gene may be associated with renal failure. However, some reports suggested that OPN is essential for tubulogenesis, and that it inhibits calcium oxalate crystal formation and retention, nitric oxide synthesis, cell apoptosis and promotes cell regeneration. Thus, further studies are required to fully understand the role of OPN in kidney physiology and pathology. Eventually, these studies may result in the identification of OPN as a valuable marker for renal dysfunction prognosis and treatment. PMID- 30456595 TI - Hans Selye and his studies on the role of mast cells in calciphylaxis and calcergy. AB - Hans Selye was an endocrinologist, a pioneer of research on biological stress in human individuals and groups. His most important scientific contributions include in 1936 the evidence that the pituitary-adrenal-thymus axis was activated by various nocuous stimuli, which led to the involution of the thymus and of the lymphoid organs; in 1946, the theory of general adaptation syndrome (GAS), pointing out that this is a general reaction that leads to resistance of the organism to various insults. This review article is focused on the general interest of Selye on the important role played by mast cells in different pathological conditions and in particular in calciphylaxis and calcergy, summarized in a classic book, which is a lasting contribution on the subject. PMID- 30456596 TI - MALDI MS Imaging at Acquisition Rates Exceeding 100 Pixels per Second. AB - The practicality of matrix-assisted laser desorption/ionization (MALDI) time-of flight (TOF) mass spectrometry (MS) applied to molecular imaging of biological tissues is limited by the analysis speed. Typically, a relatively low speed of stop-and-go micromotion of XY stages is considered as a factor substantially reducing the rate with which fresh sample material can be supplied to the laser spot. The sample scan rate in our laboratory-built high-throughput imaging TOF mass spectrometer was significantly improved through the use of a galvanometer based optical scanner performing fast laser spot repositioning on a target plate. The optical system incorporated into the ion source of our MALDI TOF mass spectrometer allowed focusing the laser beam via a modified grid into a 10-MUm round spot. This permitted the acquisition of high-resolution MS images with a well-defined pixel size at acquisition rates exceeding 100 pixel/s. The influence of selected parameters on the total MS imaging time is discussed. The new scanning technique was employed to display the distribution of an antitumor agent in 3D colorectal adenocarcinoma cell aggregates; a single MS image comprising 100 * 100 pixels with 10-MUm lateral resolution was recorded in approximately 70 s. Graphical Abstract. PMID- 30456597 TI - Routine Absorption Mode FTMS Data Display with an Ethoxylated Anionic Detergent as a Dual-Role (Mass and Phase) Calibrant. AB - Absorption mode display of Fourier transform mass spectrometry (FTMS) data is known to improve both peak shape and resolution. Most FTMS data, however, are shown in magnitude mode due to the lack of a routine for determining the phase of ions that are necessary for absorption mode display. Despite the recent development of phase calibration methods, the use of absorption mode processing as a routine has been inhibited by the lack of a good phase calibration standard, particularly a standard that can be used as both a mass and a phase calibrant. A dual-role calibrant will enable the consolidation of mass and phase calibration into a single step making phase calibration as accessible as mass calibration without any incremental increase in complexity in the calibration procedure. We tested a series of detergents and found Triton QS-15, an anionic detergent, suitable as a dual-role calibrant. Additionally, Triton QS-15 produces both positive and negative ion series and thus can be used as a calibrant in both ionization modes. The establishment of a phase calibration routine helps to enable the application of FTMS in areas that require extreme mass resolution. One of the areas is the separation of the fine isotopic peaks of molecules with a large molecular mass (e.g., > 500 u). For data acquired using an ion cyclotron resonance instrument with a small magnet (e.g., 7 Tesla), there may not be adequate mass resolution to establish a useful isotopic fine structure if the data is displayed in the historical magnitude mode. A mere switch to the absorption mode display makes the isotopic fine structure (IFS) readily available for molecular formula determination. Graphical Abstract ? x. PMID- 30456598 TI - Rice UCL8, a plantacyanin gene targeted by miR408, regulates fertility by controlling pollen tube germination and growth. AB - BACKGROUND: Pollen tube formation and growth are crucial steps that lead to seed production. Despite the importance of pollen tube growth, the molecular mechanisms implicated in its spatial and temporal control are not fully known. In this study, we found an uclacyanin gene, OsUCL8, that regulates pollen intine deposition and pollen tube growth. FINDINGS: The overexpression of OsUCL8 led to a striking irregularity in pollen tube growth and pollination and thus affected the seed setting rate in rice; many pollen tubes appeared to lose the ability to grow directly into the style. Conversely, plants with OsUCL8 knocked out and plants overexpressing miR408, a negative regulator of OsUCL8, had vigorous pollens with a higher germination rate. We further demonstrated that OsUCL8 mainly affects pollen intine formation. The addition of Vitamin B1 (VB1) significantly contributed to the germination of OXUCL8 pollen grains, suggesting that OsUCL8 could be associated with VB1 production. Using a yeast two-hybrid system, we revealed that OsUCL8 interacts with the protein OsPKIWI, a homolog of the Arabidopsis FNRL protein. We thus hypothesized that OsUCL8 might regulate the production of VB components by interacting with OsPKIWI. This study revealed a novel molecular mechanism of pollen tube growth regulation. CONCLUSIONS: The rice plantacyanin family member OsUCL8 plays an important role in pollen tube formation and growth and, in turn, regulates fertility and the seed setting rate. PMID- 30456599 TI - GPTMS-Modified Bredigite/PHBV Nanofibrous Bone Scaffolds with Enhanced Mechanical and Biological Properties. AB - Bioceramic nanoparticles with high specific surface area often tend to agglomerate in the polymer matrix, which results in undesirable mechanical properties of the composites and poor cell spreading and attachment. In the present work, bredigite (BR) nanoparticles were modified with an organosilane coupling agent, 3-glycidoxypropyltrimethoxysilane (GPTMS), to enhance its dispersibility in the polymer matrix. The polyhydroxybutyrate-co-hydroxyvaletare (PHBV) nanofibrous scaffolds containing either bredigite or GPTMS-modified bredigite (G-BR) nanoparticles were fabricated using electrospinning technique and characterized using scanning electron microscopy, transmission electron microscopy, and tensile strength. Results demonstrated that modification of bredigite was effective in enhancing nanoparticle dispersion in the PHBV matrix. PHBV/G-BR scaffold showed improved mechanical properties compared to PHBV and PHBV/BR, especially at the higher concentration of nanoparticles. In vitro bioactivity assay performed in the simulated body fluid (SBF) indicated that composite PHBV scaffolds were able to induce the formation of apatite deposits after incubation in SBF. From the results of in vitro biological assay, it is concluded that the synergetic effect of BR and GPTMS provided an enhanced hFob cells attachment and proliferation. The developed PHBV/G-BR nanofibrous scaffolds may be considered for application in bone tissue engineering. PMID- 30456600 TI - BAR domain proteins-a linkage between cellular membranes, signaling pathways, and the actin cytoskeleton. AB - Actin filament assembly typically occurs in association with cellular membranes. A large number of proteins sit at the interface between actin networks and membranes, playing diverse roles such as initiation of actin polymerization, modulation of membrane curvature, and signaling. Bin/Amphiphysin/Rvs (BAR) domain proteins have been implicated in all of these functions. The BAR domain family of proteins comprises a diverse group of multi-functional effectors, characterized by their modular architecture. In addition to the membrane-curvature sensing/inducing BAR domain module, which also mediates antiparallel dimerization, most contain auxiliary domains implicated in protein-protein and/or protein-membrane interactions, including SH3, PX, PH, RhoGEF, and RhoGAP domains. The shape of the BAR domain itself varies, resulting in three major subfamilies: the classical crescent-shaped BAR, the more extended and less curved F-BAR, and the inverse curvature I-BAR subfamilies. Most members of this family have been implicated in cellular functions that require dynamic remodeling of the actin cytoskeleton, such as endocytosis, organelle trafficking, cell motility, and T tubule biogenesis in muscle cells. Here, we review the structure and function of mammalian BAR domain proteins and the many ways in which they are interconnected with the actin cytoskeleton. PMID- 30456601 TI - Mechanisms of contractile ring tension production and constriction. AB - The contractile ring is a remarkable tension-generating cellular machine that constricts and divides cells into two during cytokinesis, the final stage of the cell cycle. Since the ring's discovery, the parallels with muscle have been emphasized. Both are contractile actomyosin machineries, and long ago, a muscle like sliding filament mechanism was proposed for the ring. This review focuses on the mechanisms that generate ring tension and constrict contractile rings. The emphasis is on fission yeast, whose contractile ring is sufficiently well characterized that realistic mathematical models are feasible, and possible lessons from fission yeast that may apply to animal cells are discussed. Recent discoveries relevant to the organization in fission yeast rings suggest a stochastic steady-state version of the classic sliding filament mechanism for tension. The importance of different modes of anchoring for tension production and for organizational stability of constricting rings is discussed. Possible mechanisms are discussed that set the constriction rate and enable the contractile ring to meet the technical challenge of maintaining structural integrity and tension-generating capacity while continuously disassembling throughout constriction. PMID- 30456602 TI - [Personalized medicine in the field of inflammatory skin diseases]. AB - BACKGROUND: For sufficient treatment of patients with chronic inflammatory skin diseases, new concepts need to be established and biomarkers must be identified. OBJECTIVE: Presentation of new markers, their quality and implications for the clinical daily routine. MATERIAL AND METHODS: This article presents a discussion of basic research and a review of current achievements of personalized medicine in the area of chronic inflammatory skin diseases. RESULTS: Promising biomarker for the various entities of chronic inflammatory skin diseases have been proposed; however, they need to be prospectively validated and translated into affordable and feasible tests. CONCLUSION: There is still a long way to go to establish personalized medicine in the field of chronic inflammatory skin diseases and its success is dependent on multicenter collaboration to validate and implement novel biomarkers. PMID- 30456603 TI - The novel PI3K inhibitor S1 synergizes with sorafenib in non-small cell lung cancer cells involving the Akt-S6 signaling. AB - Non-small cell lung cancer (NSCLC) has been the major cause of cancer-related deaths worldwide. Targeted therapy has been available as an additive strategy for NSCLC patients, but the inevitable resistance to mono-targeted agents has largely hampered its usage in the clinic. We have previously designed and synthesized a novel small molecule compound S1, 2-methoxy-3-phenylsulfonamino-5-(quinazolin-6 yl) benzamides and demonstrated its inhibition of PI3K and mTOR as well as the anti-tumor potential. In the present study, we have identified that S1 alone or combined with the multi-kinase inhibitor sorafenib can inhibit the in vitro cell proliferation of NSCLC cells (A549, NCI-H157 and 95D cells) and tumor growth in the A549 xenograft model. S1 alone produced inhibitory effects on the colony formation, cell migration and invasion and angiogenesis, with more pronounced inhibition when used with sorafenib. We further revealed that S1 mainly inhibited the Akt/S6 phosphorylation while sorafenib mostly decreased the phosphorylation of ERK. Together, the novel PI3K/mTOR inhibitor S1 per se exhibits strong anti tumor effects in NSCLC cells and A549 xenograft, effects possibly via its inhibition of cell proliferation, invasion and migration and angiogenesis. The combination of S1 and sorafenib exerts potentiated anti-tumor effects, in which the underlying mechanisms may involve their differential modulation of the phosphorylation of Akt and S6 in the PI3K/Akt/mTOR cascades and ERK phosphorylation in the Raf/MEK/ERK pathways. The combination of S1 and sorafenib could be used as an additive approach in treating NSCLC in the clinic. PMID- 30456604 TI - Complementarity of molecular and elemental mass spectrometric imaging of GadovistTM in mouse tissues. AB - Drug biodistribution analyses can be considered a key issue in pharmaceutical discovery and development. Here, mass spectrometric imaging can be employed as a powerful tool to investigate distributions of drug compounds in biologically and medically relevant tissue sections. Both matrix-assisted laser desorption ionization-mass spectrometric imaging as molecular method and laser ablation inductively coupled plasma-mass spectrometric imaging as elemental detection method were applied to determine drug distributions in tissue thin sections. Several mouse organs including the heart, kidney, liver, and brain were analyzed with regard to distribution of GadovistTM, a gadolinium-based contrast agent already approved for clinical investigation. This work demonstrated the successful detection and localization of GadovistTM in several organs. Furthermore, the results gave evidence that gadolinium-based contrast agents in general can be well analyzed by mass spectrometric imaging methods. In conclusion, the combined application of molecular and elemental mass spectrometry could complement each other and thus confirm analytical results or provide additional information. PMID- 30456605 TI - Improving deep proteome and PTMome coverage using tandem HILIC-HPRP peptide fractionation strategy. AB - Despite being orthogonal to reverse-phase separation and valuable for posttranslational modification (PTM) pre-enrichment, hydrophilic interaction liquid chromatography (HILIC) has not been widely adopted for large-scale proteomic applications. Here, we first evaluated the performance of HILIC in comparison with the popular high-pH reverse-phase (HPRP) separation, as the first dimension for tryptic peptide fractionation in a shotgun workflow to characterize the complex 293T cell proteome. The data indicated that the complementary nature of HILIC and HPRP for peptide separation was mainly due to different hydrophobicity preferences. Realizing that uncaptured components from one mode can be resolved in the other mode, we then designed and compared two multidimensional separation schemes using HILIC and HPRP in tandem for peptide prefractionation, in terms of identification efficiency and coverage at peptide, protein, and PTM levels. A total of 22,604 and 23,566 peptides corresponding to 4481 and 4436 proteins from 293T cell lysate were detected using HILIC-HPRP- and HPRP-HILIC-based shotgun proteomics workflow, respectively. In addition, without assistance of enrichment techniques, the tandem fractionation methods aided to identify 46 different PTMs from over 10,000 of spectra using blind modification search algorithm. We concluded that HILIC is a valuable alternative option for peptide prefractionation in a large-scale proteomic study, but can be further augmented with the use of a secondary HPRP separation. PMID- 30456607 TI - Characterization of air contaminants emitted during laser cutting of carbon fiber reinforced composite materials. AB - The emission of ultrafine carbonaceous particles during the laser cutting of fiber-reinforced polymer (CFRP) composite materials was investigated. The study was based on characterization of air contaminants emitted during laser cutting of an epoxy-based CFRP material with respect to particle size distribution, particle morphology, and chemical composition. Results indicate that about 90% of the total particulate mass is present as fine particulate matter with an aerodynamic cut-off diameter of 0.25 MUm, and considerable amounts of ultrafine carbonaceous particulate matter dominated by organic carbon are emitted during high-power laser cutting of CFRP. PMID- 30456606 TI - Liquid chromatography-tandem mass spectrometry analysis of 17-hydroxyprogesterone in dried blood spots revealed matrix effect on immunoassay. AB - Immunoassays for measuring 17-hydroxyprogesterone (17-OHP) produce high rates of false positives that impact the identification of congenital adrenal hyperplasia (CAH) in neonates. A confirmatory test with high analytical specificity employing liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology is needed in newborn screening for CAH. 17-OHP and cortisol were extracted from dried blood spot (DBS) samples, resolved on a C18 column, and measured using tandem mass spectrometry. The results were compared with those determined using the AutoDELFIA immunoassay. The LC-MS/MS method had a limit of quantitation of 10.0 and 5.0 ng/mL for 17-OHP and cortisol, respectively. The method characteristics showed coefficient variation (%CV) <= 11.9% for both 17-OHP and cortisol, recoveries ranging from 83.1 to 101.5% for 17-OHP and from 95.1 to 102.8% for cortisol, and linearity with R2 = 0.9994 for 17-OHP and R2 = 0.9996 for cortisol, clinical sensitivity of 100.0% and a specificity of 96.4% as obtained by receiver operating characteristic analysis on 45 patient samples when 17-OHP > 39.1 ng/mL was selected as the cutoff value. Comparison between the LC-MS/MS and the AutoDELFIA immunoassay methods revealed a poor correlation for patient DBS samples (R2 = 0.6784); however, an excellent correlation was obtained for QC and proficiency test (PT) DBS samples (R2 = 0.9797). The LC-MS/MS method produced reliable results for 17-OHP and cortisol for the diagnosis of CAH. The AutoDELFIA immunoassay appears to be subject to matrix effects in the analysis for 17-OHP in DBS patient samples. The DBS samples of non-patient origin may not be suitable for assessing analytical accuracy of immunoassays. PMID- 30456608 TI - Impact of financial development and economic growth on environmental quality: an empirical analysis from Belt and Road Initiative (BRI) countries. AB - This study aims to analyze the impact of financial development, foreign direct investment, economic growth, electricity consumption, and trade openness on environmental quality for a panel of 59 Belt and Road Initiative (BRI) countries, over the period of 1980-2016. The presence of the environmental Kuznets curve (EKC) hypothesis is investigated. The cross-sectional augmented Dickey-Fuller (CADF) and cross-sectional Im, Pesaran, and Shin panel unit root test; the Westerlund cointegration test, the dynamic seemingly unrelated regression (DSUR) approach; and the Dumitrescu and Hurlin (Econ Model 29:1450-1460, 2012) panel causality approach are employed. It is found that the analyzed variables are stationary at first differences and are cointegrated. It is also found that an increase in financial development, foreign direct investment, and trade openness enhance environmental quality, while the increase in economic growth and electricity consumption degrade environmental quality. The presence of the EKC hypothesis for the selected panel countries is validated. Furthermore, the Dumitrescu-Hurlin (DH) panel causality test result confirmed the presence of bidirectional causality among economic growth, foreign direct investment, financial development, electricity consumption, and trade openness with environmental quality. PMID- 30456609 TI - The effect of biochars application on reducing the toxic effects of nickel and growth indices of spinach (Spinacia oleracea L.) in a calcareous soil. AB - Nowadays, production of biochar from agricultural wastes and its use for the amelioration of contaminated soils with heavy metals is increasing to reduce their negative effects on the growth of various plants. A factorial greenhouse experiment as a completely randomized design with three replications was performed to study the effect of different biochars on the spinach growth in a calcareous soil with different levels of nickel (Ni). The first factor consisted of biochars (control (CL), licorice root pulp (LRB), and rice husk (RHB) prepared at two pyrolysis temperatures (350 degrees C and 550 degrees C), each at 2.5% (w/w)), and the second factor included Ni application levels (0 (N0), 150 (N1), and 300 (N2) mg kg-1 soil). Shoot dry weight (15.0%), photosynthetic pigments (chlorophyll a (46.5%), b (39.5%), carotenoids (52.0%)), and micronutrients uptake (iron (51.8%), manganese (66.4%), copper (62.9%), and zinc (47.1%)) were decreased by increasing the Ni levels from N0 to N2. The activity of antioxidant enzymes (catalase (36.3%) and guaiacol peroxidase (29.3%)) and Ni uptake were increased by the Ni application levels. The biochar treatments (RHB350, RHB550, and LRB550) increased shoot dry weight of spinach through the reduction of Ni uptake, activity of antioxidant enzymes and enhancement of the micronutrients absorption. In general, the effect of the biochars produced at 550 degrees C on the reduction of Ni uptake and the increase in plant growth were better than the biochars produced at 350 degrees C. Finally, it could be concluded that the RHB550 is more suitable for reducing the Ni toxicity and improving the growth indices of the spinach. PMID- 30456610 TI - Towards the effective E-waste management in Bangladesh: a review. AB - Nowadays, the electrical and electronic products are a crucial commodity for different purposes of daily life and they are multiplying five times faster than human like mobile phones, which has reached zero to 7.2 billion in only three decades. A 5-10% yearly increase in the amount of used electrical and electronic equipment that are disposed of prudently can cause environmental hazards that have an aversive effect on human health, marine life, contamination of groundwater, and reduces soil's fertility. Management of this enormous influx of electrical and electronic waste is a challenge for developing countries like Bangladesh with barebones solid waste management infrastructure. Inadequacy of public awareness, policies and poor budget in the field of waste management are few of the key factors behind this delineating scenario. In this study, the picture electrical and electronic waste productions in Bangladesh along with the recent E-waste management systems have been presented comprehensively. Based on the study, it was concluded that most of the adapted E-waste management methods are conversational and detached from current technological capability. A set of sustainable E-waste management system has been suggested along with the challenges, which might appear during the implementation of these strategies. Successful implementation of these suggested systems would advance the quality of E-waste management in Bangladesh increasing the current 35% overall E-waste recycling rate and offer enormous energy from the waste. PMID- 30456611 TI - High-rate activated sludge processes for municipal wastewater treatment: the effect of food waste addition and hydraulic limits of the system. AB - Conventional activated sludge (CAS) process is one of the most commonly applied processes for municipal wastewater treatment. However, it requires a high energy input and does not promote energy recovery. Currently, high-rate activated sludge (HRAS) process is gaining importance as a good option to reduce the energy demand of wastewater treatment and to capture organic matter for valorizing through anaerobic digestion (AD). Besides, food waste addition to wastewater can help to increase the organic matter content of wastewater and thus, energy recovery in AD. The objective of this study is to evaluate the applicability of co-treatment of municipal wastewater and food waste in a pilot-scale HRAS system as well as to test the minimal hydraulic retention times (HRTs) such as 60 and 30 min. Food waste addition to the wastewater resulted in a 10% increase in chemical oxygen demand (COD) concentration of influent. In the following stages of the study, the pilot-scale system was operated with wastewater solely under the HRTs of 60 and 30 min. With the decrease of HRT, particulate COD removal increased; however, soluble COD removal decreased. The results demonstrated that if the settling process is optimized, more particulate matter can be diverted to sludge stream. PMID- 30456612 TI - Scanning electron microscopy for analysing maturity of compost/vermicompost from crop residue spiked with cattle dung, Azolla pinnata and Aspergillus terreus. AB - Rice straw and wheat straw were mixed with cattle dung (C), Azolla pinnata (A) and Aspergillus terreus (F) and subjected to aerobic composting and vermicomposting. Eight different mixtures were made as R, RC, RA, RF, RCF, RCA, RFA and RCFA and W, WC, WF, WA, WCA, WCF, WFA and WCFA. Ratio of straw and cattle dung was kept as 2:1, and weight of cattle dung was reduced proportionally when Azolla (20 g) or fungus (20 ml) was added in a mixture. Surface structural morphology of the initial and final mixtures was analysed with SEM. Initial samples showed larger particle size with a coarse surface, less compaction and arrangement of biomass as a dense meshwork of lingo-cellulosic fibres. Final samples showed smaller particle size, compaction and several pores per unit area. Electron micrographs clearly show enhancement of degradation and better texture with the addition of fungus, Azolla or cattle dung to the straw. Azolla and cattle dung when added separately, enhanced degradation and compaction, but the mixtures with fungus showed degradation with no compaction. Maximum homogeneity and smallest particle size of RCFA and WCFA indicated that addition of Azolla and fungus along with cattle dungenhanced degradation of straw and enhancement was remarkably more when the mixtures were subjected to vermicomposting. This is a first report highlighting vermicomposting of the straw mixed with Azolla and fungus along with cattle dung for obtaining a better quality product suitable for agricultural use. Parallel variation in C/N ratio and nutrient profile of the mixtures show that SEM helps in determining maturity index of composts. PMID- 30456613 TI - Overall plant responses to Cd and Pb metal stress in maize: Growth pattern, ultrastructure, and photosynthetic activity. AB - This study provides a full description of the responses of the crop energy plant Zea mays to stress induced by Cd and Pb, in view of a possible extensive use in phytoattenuation of metal-polluted soils. In this perspective, (i) the uptake capability in root and shoot, (ii) the changes in growth pattern and cytological traits, and (iii) the photosynthetic efficiency based on photochemistry and the level of key proteins were investigated in hydroponic cultures. Both metals were uptaken by maize, with a translocation factor higher for Cd than Pb, but only Cd treated plants showed a reduced growth compared to control (i.e., a lower leaf number and a reduced plant height), with a biomass loss up to 40%, at the highest concentration of metal (10-3 M). The observation of cytological traits highlighted ultrastructural damages in the chloroplasts of Cd-treated plants. A decline of Rubisco and D1 was observed in plants under Cd stress, while a relevant increase of the same proteins was found in Pb-treated plants, along with an increase of chlorophyll content. Fluorescent emission measurements indicated that both metals induced an increase of NPQ, but only Cd at the highest concentration determined a significant decline of Fv/Fm. These results indicate a different response of Z. mays to individual metals, with Pb triggering a compensative response and Cd inducing severe morpho-physiological alterations at all investigated levels. Therefore, Z. mays could be successfully exploited in phytoattenuation of Pb-polluted soil, but only at very low concentrations of Cd to avoid severe plant damages and biomass loss. PMID- 30456614 TI - Dynamics of nitrogen, phosphorus, and organic pollutant losses from a small watershed in the drinking-water source protection area in Guiyang City of Southern China. AB - Nutrients in runoff degrade water quality. The development of schemes to mitigate such degradation requires a characterization of the underlying dynamic processes of nutrient loss. The drinking-water source protection area in the Lake Hongfeng watershed of Guiyang City, the capital of Guizhou Province, China, has been delimited for effective conservation. However, no systematic observations have provided data on nutrient losses from these areas that could support optimal management. We selected one typical watershed in the area. Automatic gauges were installed to record the water levels and calculate runoff rates during 2010 and 2011. A total of 1523 runoff samples were collected at an interval of 3 h during a day; total nitrogen (TN), total phosphorus (TP), and chemical oxygen demand (COD) were tested. The results indicated that surface runoff rates were primarily less than 15 L/s but rapidly increased 1-30 times 15 L/s when it rained. TN, TP, and COD concentrations primarily fluctuated between 0.06 and 18.79 mg/L, between 0.01 and 1.57 mg/L, and between 0.01 and 160 mg/L, respectively. TN and COD concentrations in 98.98% and 52.04% of the runoff samples, respectively, exceeded the upper limit required by the Environmental Quality Standards for Surface Water (EQSSW) in China. Conversely, 94.29% of the runoff samples had lower concentrations than the upper limit of TP concentration. Surface runoff has been seriously polluted by nitrogen and organic pollutants. The occurrence frequency of different runoff rates and TP and COD concentrations showed different distributions, but TN concentrations had a normal distribution. There was a significant relationship between runoff rates and TP concentration and TN, TP, or COD loss. TN, TP, and COD loss primarily occurred on vegetable lands, rice fields, and residential sites. Effectively controlling nitrogen fertilizer that is applied on vegetable lands and paddy fields and managing wastewater and solid waste are urgent. The results reported here will also provide references for many other regions facing similar problems. PMID- 30456616 TI - Dispersant-modified iron nanoparticles for mobility enhancement and TCE degradation: a comparison study. AB - Dispersants including Tween 20, Tween 40, Tween 60, and polyacrylic acid (PAA) were used to modify nanoscale zero-valent iron (nZVI). All dispersants dispersed nZVI effectively. PAA-modified nZVI was more stable than nZVI that was modified with Tween surfactant. Iron nanoparticles that were prepared using 0.5-5.0% (vol%) of PAA remained in suspension for more than 2 h. nZVI that was modified using Tween surfactant remained in suspension for 30-60 min, and there was complete sedimentation of bare iron in 10 min. When 2.0-5.0% (vol%) of Tween surfactant was used, the stability of the nZVI that was modified using Tween 20 was much better than that for nZVI that was modified using Tween 40 or Tween 60. The results for the transportation test show that nZVI that was prepared using 2% (vol%) of Tween 20 exhibited the best mobility in porous media. Approximately 83 90% of TCE was degraded by bare, PAA-modified, and Tween 20-modified nZVI, and about 63-67% of TCE was removed by nZVI that was modified using Tween 40 and Tween 60 during 20 days of reaction. The production of cis-dichloroethene (DCE) and 1,1-DCE demonstrates that TCE is removed via reductive dechlorination. The results of this study show that PAA- and Tween 20-modified nZVI are more practical for in situ remediation because they exhibit good mobility and degrade TCE effectively. PMID- 30456615 TI - Effects of CO2 application and endophytic bacterial inoculation on morphological properties, photosynthetic characteristics and cadmium uptake of two ecotypes of Sedum alfredii Hance. AB - Plant uptake of cadmium (Cd) is affected by soil and environmental conditions. In this study, hydroponic experiments were conducted to investigate the effects of elevated CO2 coupled with inoculated endophytic bacteria M002 on morphological properties, gas exchange, photosynthetic pigments, chlorophyll fluorescence, and Cd uptake of S. alfredii. The results showed that bio-fortification processes (elevated CO2 and/or inoculated with endophytic bacteria) significantly (p < 0.05) promoted growth patterns, improved photosynthetic characteristics and increased Cd tolerance of both ecotypes of S. alfredii, as compared to normal conditions. Net photosynthetic rate (Pn) in intact leaves of hyperaccumulating ecotype (HE) and non-hyperaccumulating ecotype (NHE) were increased by 73.93 and 32.90%, respectively at the low Cd (2 MUM), 84.41 and 57.65%, respectively at the high Cd level (10 MUM). Superposition treatment increased Cd concentration in shoots and roots of HE, by 50.87 and 82.12%, respectively at the low Cd and 46.75 and 88.92%, respectively at the high Cd level. Besides, superposition treatment declined Cd transfer factor of NHE, by 0.85% at non-Cd rate, 17.22% at the low Cd and 22.26% at the high Cd level. These results indicate that elevated CO2 coupled with endophytic bacterial inoculation may effectively improve phytoremediation efficiency of Cd-contaminated soils by hyperaccumulator, and alleviate Cd toxicity to non-hyperaccumulator ecotype of Sedum alfredii. PMID- 30456617 TI - Evaluation of the bias and precision of regression techniques and machine learning approaches in total dissolved solids modeling of an urban aquifer. AB - TDS is modeled for an aquifer near an unlined landfill in Canada. Canadian Drinking Water Guidelines and other indices are used to evaluate TDS concentrations in 27 monitoring wells surrounding the landfill. This study aims to predict TDS concentrations using three different modeling approaches: dual step multiple linear regression (MLR), hybrid principal component regression (PCR), and backpropagation neural networks (BPNN). An analysis of the bias and precision of each models follows, using performance evaluation metrics and statistical indices. TDS is one of the most important parameters in assessing suitability of water for irrigation, and for overall groundwater quality assessment. Good agreement was observed between the MLR1 model and field data, although multicollinearity issues exist. Percentage errors of hybrid PCR were comparable to the dual-step MLR method. Percentage error for hybrid PCR was found to be inversely proportional to TDS concentrations, which was not observed for dual-step MLR. Larger errors were obtained from the BPNN models, and higher percentage errors were observed in monitoring wells with lower TDS concentrations. All models in this study adequately describe the data in testing stage (R2 > 0.86). Generally, the dual-step MLR and hybrid PCR models fared better (R2avg = 0.981 and 0.974, respectively), while BPNN models performed worse (R2avg = 0.904). For this dataset, both regression and machine learning models are more suited to predict mid-range data compared to extreme values. Advanced regression methods (hybrid PCR and dual-step MLR) are more advantageous compared to BPNN. PMID- 30456618 TI - Pure ultra-fine carbon particles do not exert pro-coagulation and inflammatory effects on microvascular endothelial cells. AB - Pro-thrombotic and inflammatory changes play an important role in cardiovascular morbidity and mortality, resulting from short-term exposure to fine particulate air-pollution. Part of those effects has been attributed to the ultra-fine particles (UFPs) that pass through the lung and directly contact blood-exposed and circulating cells. Despite UFP-induced platelet activation, it is unclear whether the penetrated particles exert any direct effect on endothelial cells. While exposure levels are boosting as a result of world-wide increases in economic development and desertification, which create more air-polluted regions, as well as increase in demands for synthetic UFPs in medicine and various industries, further studies on the health effects of these particles are required. In this study, human pulmonary and cardiac microvascular endothelial cells (MECs) have been exposed to 0.1, 1, 10, and 100 MUg/ml suspensions of either a natural (carbon black) or a synthetic (multi-walled carbon nano-tubes) type of UFPs, in vitro. As a result, no changes in the levels of coagulation factor VIII, Von Willebrand factor, Interleukin 8, and P-selectin measured in the cells' supernatant were observed prior to and 6, 12, and 24 h after exposure. In parallel, the spatio-temporal effect of UFPs on cardiac MECs was evaluated by Transmission Electron Microscopy. Despite phagocytic uptake of pure UFPs observed on cellular sections of the treated cells, Weibel-Palade bodies remained intact in shape and similar in number when compared with the untreated cells. Our work shows that carbon itself is a non-toxic carrier for endothelial cells. PMID- 30456619 TI - Fishing lines and fish hooks as neglected marine litter: first data on chemical composition, densities, and biological entrapment from a Mediterranean beach. AB - We reported first data on the densities and chemical composition of fishing lines and fish hooks deposited on a Mediterranean beach. On a sampling area of 1.5 ha, we removed a total of 185,028 cm of fishing lines (density 12.34 cm/m2) and 33 hooks (density 22 units/ha). Totally, 637.62 g (42.5 mg/m2) of fishing lines were collected. We sampled 120 items entangled belongings to 7 animal taxa (density 6.49 items/100 m of fishing lines). We also observed a not quantifiable number of egagropiles (Posidonia oceanica spheroids), Rhodophyceae (Halymenia sp.) and segments of reeds of Phragmites communis, trapped in the fishing lines. Fourier transform infrared (FTIR) spectroscopy was used in order to identify the chemical composition of the fishing lines: 92% was made of nylon while 8.0% was determined as fluorocarbon based polymers (polyvinylidene fluoride). Because of their subtlety and reduced size, sandy beach cleaning operations should include at least two consecutive removal samplings: indeed, a part of this litter (12.14%) is not removed in the first sampling. The unexpected high density of fishing lines suggests specific management actions aimed to periodically remove this neglected anthropogenic litter. PMID- 30456620 TI - Raman microspectroscopic identification of microplastic particles in freshwater bivalves (Unio pictorum) exposed to sewage treatment plant effluents under different exposure scenarios. AB - We investigated the uptake of microplastic (MP, <5 mm) particles by using freshwater bivalves (Unio pictorum) as biological samplers in the environment. They were exposed either directly to the biologically purified sewage of a North Bavarian sewage treatment plant (STP) or placed in a small river up- and downstream of the wastewater discharge for 28 days and 6 months, respectively. A control group was maintained in a pond. After acid digestion, the soft tissue was analyzed for MP particles by means of Raman microspectroscopy (RM, over 3000 particles individually measured), which allows for identification and quantification of particles down to 1 MUm. Only in the bivalve collective exposed to STP effluents MP was found, however a very small amount (maximum of nine MP particles in the bivalve sample exposed for 6 months). In the bivalves up- and downstream of the wastewater discharge and in control organisms from a pond, no microplastic was identified. The amount of microplastic particles was small in absolute terms and small in relative terms (ca. 1:100 (6 months) and below 1:1000 (28 days)) as hundreds of particles per sample were analyzed which turned out to be non-plastic. Including the results for the river, this indicates a rather low MP contamination level for organisms in close vicinity to a sewage treatment plant. PMID- 30456621 TI - Degradation of crude oil by mixed cultures of bacteria isolated from the Qinghai Tibet plateau and comparative analysis of metabolic mechanisms. AB - This study investigates the biodegradation of crude oil by a mixed culture of bacteria isolated from the Qinghai-Tibet plateau using gas chromatography-mass spectrometer (GC-MS) and the gravimetric method. The results showed that a mixed culture has a stronger ability to degrade hydrocarbon than pure cultures. Once both Nocardia soli Y48 and Rhodococcus erythropolis YF28-1 (8) were present in a culture, the culture demonstrated the highest crude oil removal efficiency of almost 100% after 10 days of incubation at 20 degrees C. Moreover, further analysis of the degradation mechanisms used by the above strains, which revealed utilization of different n-alkane substrates, indicated the diversity of evolution and variations in different strains, as well as the importance of multiple metabolic mechanisms for alkane degradation. Therefore, it is concluded that a mixed culture of Y48 and YF28-1 (8) strains can provide a more effective method for bioremediation of hydrocarbon-contaminated soil in permafrost regions. PMID- 30456622 TI - Prediction of cadmium concentration in brown rice before harvest by hyperspectral remote sensing. AB - Cadmium (Cd) contaminated rice has become a global food security issue. Hyperspectral remote sensing can do rapid and nondestructive monitoring of environmental stress in plant. To realize the nondestructive detection of Cd in brown rice before harvest, the leaf spectral reflectance of rice exposed to six different levels of Cd stress was measured during the whole life stages. In addition, the dry weight of rice grain and Cd concentrations in brown rice were measured after harvest. The impact of Cd stress on the quantity and the quality of rice grain and on the leaf reflectance of rice was analyzed, and hyperspectral estimation models for predicting the Cd content in brown rice during three growth stages were established. The results showed that rice plants can impact the quality of the brown rice seriously, even if the impact on the quantity was not significant. All the established models had the capability to estimate Cd concentrations in brown rice (R2 > 0.598), and the best performance model, with the R2 value of 0.873, was use first derivative spectrum of booting stage as variable. It was concluded that the hyperspectral of rice leaves provides a new insight to predict Cd concentration in brown rice before harvest. PMID- 30456623 TI - Consensus statement on the use of HRT in postmenopausal women in the management of osteoporosis by SIE, SIOMMMS and SIGO. PMID- 30456624 TI - Physical activity in women with subclinical hypothyroidism. AB - PURPOSE: Physical activity is associated with many health-related benefits. However, there is a shift towards inactive lifestyles around the world. Subclinical hypothyroidism (SCH) may have adverse effects similar to hypothyroidism. The presence of symptoms and reduced physical performance in SCH may contribute to an inactive lifestyle. Therefore, the present study aimed to compare physical activity levels (PALs) between women with subclinical hypothyroidism and healthy controls. METHODS: Thirty-two women with newly diagnosed SCH and 28 healthy women were enrolled in this cross-sectional study. Arterial stiffness was evaluated by pulse wave velocity (PWV). Neuromuscular symptoms were questioned. Participants wore a physical activity monitor (SenseWear(r) Armband) for 4 consecutive days. Handgrip and quadriceps muscle strength were assessed by dynamometer. Functional exercise capacity was assessed by 6-minute walk test (6MWT). RESULTS: There was no significant difference in sociodemographic variables between the groups. PWV was significantly higher in the SCH group (P = 0.006). Physical activity duration and number of steps were significantly lower in the SCH group (P < 0.05). There was significant difference in neuromuscular symptoms, handgrip and quadriceps muscle strength, and 6MWT distance between the groups (P < 0.05). CONCLUSIONS: This study demonstrates that women with SCH had lower PALs compared to healthy controls. Women with SCH should participate in exercise programs to increase physical activity and muscle strength to achieve adequate PALs. PMID- 30456625 TI - Correction to: Are there any differential responses to concussive injury in civilian versus athletic populations: a neuroimaging study. AB - The original version of this article contained mistakes in the article title, and the authors would like to correct them. The article title should be "Are there any differential responses to concussive injury in civilian versus athletic populations: a neuroimaging study". PMID- 30456626 TI - In reply: a call for feedback on postoperative care: do we need an automated tool? PMID- 30456627 TI - Focus on Peer Review: An Online Peer Review Course by Nature Masterclasses : Nature Publishing Group. URL: https://masterclasses.nature.com/courses/205. PMID- 30456628 TI - A call for feedback on postoperative care: Do we need an automated tool? PMID- 30456629 TI - [The 4 R of the ESC guidelines 2018: relevance, redundancy, reality, and relativization]. PMID- 30456630 TI - [ESC/EACTS guidelines on myocardial revascularization 2018 : The most important innovations]. AB - The guidelines on myocardial revascularization published in 2018 are a joint initiative of the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery. To establish indications for myocardial revascularization by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), evidence of the functional relevance of coronary artery stenoses is needed either by non-invasive imaging function tests or intravascular hemodynamic measurements. The prognostic and symptomatic benefits of myocardial revascularization depend on whether complete revascularization can be achieved. This needs to be considered when choosing the most appropriate revascularization strategy. In addition, the individual operative risk, the technical feasibility, the presence of diabetes mellitus and the anatomical complexity of coronary artery disease, as assessed by the SYNTAX score, are key criteria when choosing the optimal method of revascularization. For PCI radial artery access and the general use of drug-eluting stents are recommended. For CABG multiple arterial grafts should be strived for including the radial artery for treatment of high grade coronary stenosis. PMID- 30456631 TI - [Update of the ESC guidelines 2018 on cardiovascular diseases during pregnancy : Most important facts]. AB - Heart diseases are the most common cause of maternal death during pregnancy in Western countries. The current ESC guidelines 2018 for the management of cardiovascular diseases during pregnancy is a guide for any physician facing the challenge of caring for pregnant women with cardiovascular diseases. Among the new concepts compared to 2011, are recommendations to classify maternal risk due to the modified World Health Organization (mWHO) classification, introduction of the pregnancy heart team, guidance on assisted reproductive therapy, specific recommendations on anticoagulation for low-dose and high-dose requirements of vitamin K antagonists and the potential use of bromocriptine in peripartum cardiomyopathy. The Food and Drug Administration (FDA) categories A-D and X should no longer be used. Therefore, the table of drugs was completed with detailed information from animal and human studies on maternal and fetal risks. The new findings on specific heart diseases are presented in detail in the respective chapters. PMID- 30456632 TI - Alternative Views on the Role of Sex Steroid Hormones on the Emergence of Phenotypic Diversity in Female Sexual Orientation. PMID- 30456633 TI - ATMT transformation efficiencies with native promoters in Botryosphaeria kuwatsukai causing ring rot disease in pear. AB - Botryosphaeria kuwatsukai is an important fungal pathogen affecting pear fruits. However, infection processes of this fungus are still unclear. This study seeks to develop the fungal transformation of B. kuwatsukai by Agrobacterium tumefaciens-mediated transformation (ATMT), assess the reliability of appropriate vectors and examine the infection processes in vitro using a GFP labeled strain of B. kuwatsukai. To establish a highly effective transformation system in B. kuwatsukai, binary vectors containing various lengths of H3 promoters and TEF promoters fused with GFP and hygromycin B resistance gene cassettes were constructed. These cassettes were integrated into the genomic DNA of B. kuwatsukai with high transformation frequency by the ATMT method. Transformants showed strong expression of GFP and hygromycin B resistance genes in cells. Furthermore, we investigated if native promoters are more suitable to govern marker genes than other general promoters used in other filamentous fungi. The results obtained herein demonstrate that the vectors constructed in this study can be utilized with high transformation rate. Microscopic examinations also reveal that fungal hyphae undergo morphological changes during the infection process resulting in biotrophic stage of infected host cells. Our results provide genetic insights to further explore the infection processes of B. kuwatsukai. PMID- 30456635 TI - Ticagrelor Versus Prasugrel for the Treatment of Patients with Type 2 Diabetes Mellitus Following Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis. AB - INTRODUCTION: Antiplatelet therapy is very important following percutaneous coronary intervention (PCI). New generation P2Y12 inhibitors (ticagrelor and prasugrel) might potentially replace clopidogrel for the treatment of post interventional acute coronary syndrome (ACS). In this analysis, we aimed to systematically compare the post-interventional clinical outcomes and bleeding events observed with ticagrelor versus prasugrel in patients with type 2 diabetes mellitus (T2DM). METHODS: EMBASE, MEDLINE, the Cochrane Central Register of Controlled Trials, and www.ClinicalTrials.gov were carefully searched for publications comparing the post-coronary interventional outcomes following ticagrelor versus prasugrel use in patients with T2DM. Adverse clinical outcomes and bleeding events were considered as the endpoints. Statistical analysis was carried out by the Revman software (version 5.3). Odds ratios (OR) and 95% confidence intervals (CI) were used to represent the data during subgroup analysis. RESULTS: A total of 2004 participants with T2DM were included in this analysis. Following PCI, mortality (OR 1.00, 95% CI 0.57-1.76; P = 0.99, I2 = 19%), myocardial infarction (OR 0.86, 95% CI 0.42-1.75; P = 0.67, I2 = 0%), major adverse cardiac events (OR 0.73, 95% CI 0.42-1.27; P = 0.27, I2 = 0%), and stroke (OR 0.72, 95% CI 0.20-2.59; P = 0.61, I2 = 0%) were not significantly different between ticagrelor and prasugrel. In addition, total bleeding events (OR 0.87, 95% CI 0.55-1.40; P = 0.58, I2 = 6%), Thrombolysis in Myocardial Infarction (TIMI) defined minor bleeding (OR 2.39, 95% CI 0.58-9.91; P = 0.23, I2 = 0%), TIMI defined major bleeding (OR 1.42, 95% CI 0.27-7.45; P = 0.68, I2 = 0%), bleeding defined according to the Bleeding Academic Research Consortium (BARC) major bleeding (OR 0.55, 95% CI 0.22-1.36; P = 0.20, I2 = 0%), BARC minor bleeding (OR 1.44, 95% CI 0.52-3.99; P = 0.48, I2 = 0%), and total minimal bleeding (OR 3.12, 95% CI 0.55-17.59; P = 0.20, I2 = 0%) were also not significantly different. CONCLUSION: Ticagrelor and prasugrel were not associated with significantly different adverse clinical outcomes and bleeding events in these patients with T2DM. Therefore, both antiplatelet agents might safely be used in patients with T2DM following coronary intervention. However, this head-to head comparison still remains a major challenge which should be resolved in larger clinical trials. PMID- 30456634 TI - Treatment of Rectal Cancer in Older Adults. AB - PURPOSE OF REVIEW: Rectal cancer is predominantly a disease of older adults but current guidelines do not incorporate the associated specific challenges leading to wide variation in the delivery of cancer care to this subset of population. Here, we will review the current data available regarding the management of rectal cancer in older adults. RECENT FINDINGS: The greatest challenge arises in the management of stage II/III disease as it involves tri-modality treatment that can be harder to tolerate by frail older patients. Response to neoadjuvant treatment is being used as a new marker to tailor further therapy and possibly avoid surgery. Oxaliplatin can be omitted from the adjuvant treatment without compromising outcomes. Physicians should perform geriatric assessment utilizing many validated tools available to help predict treatment tolerability and outcomes in older adults that can help personalize subsequent management. Most older adults can undergo standard therapy for stages I, II, or III rectal cancer with curative intent. Increasing evidence suggests that patients with a clinical complete response to neoadjuvant treatment may be observed closely with the possibility of avoiding surgery. Studies are evaluating alternate systemic treatments for advanced metastatic disease with the hope of maintaining quality of life without compromising cancer outcomes. PMID- 30456636 TI - Correction to: Insulin Injection Technique in China Compared with the Rest of the World. AB - The original article can be found online. PMID- 30456637 TI - Correction of Tear Trough Deformity Using Autologous Fibroblast Combined with Keratin: New Soft Tissue Filler. AB - OBJECTIVE: To evaluate the effectiveness and safety of autologous fibroblasts combined with keratin gel for tear trough deformity rectification as injectable soft tissue filler. MATERIALS AND METHODS: The new injectable soft tissue filler was derived from autologous fibroblasts and keratin gel. A total of 35 patients received treatment of this filler injection for tear trough deformity rectification. All the patients were followed up, and the clinical features including photographs and satisfaction were collected and assessed at 1, 3, 6, 12 and 24 months after injection. The efficacy of each patient was evaluated independently by blinded evaluators at different time points. All patients consented to publish identifiable photographs in this study. RESULTS: Tear trough deformity was improved even at 18-24 months post-injection. No severe adverse effects were observed resulting from the filler injection. CONCLUSION: Combination of autologous fibroblasts and keratin is efficient and safe for correction of the tear trough deformity with long-term satisfaction and desirable result. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 30456638 TI - Corrective Strategies for a Complex Deformity Caused by "European-Style Double Eyelid" Blepharoplasty in Asians. AB - BACKGROUND: "European-style double eyelid" blepharoplasty often leads to a complex deformity, which includes one or more of the following features: a high fold, upper eyelid depression, multiple folds, an obvious scar, blepharoptosis, and lower flap tumidness. However, there is still a lack of comprehensive research on evaluation and treatment strategies for this complex deformity. METHODS: During a 6-year period, 65 patients (106 eyes) with a high fold and upper eyelid depression underwent corrective blepharoplasty. The authors classified this complex deformity as mild, moderate, or severe based on the extent of adhesion and tissue insufficiency, and we performed preaponeurotic fat flap transfer in 47 eyes (44.3%), free fat graft in 35 eyes (33%), and free dermis-fat graft in 24 eyes (22.6%), respectively. RESULTS: The outcomes in 87 eyelids were judged as excellent; and the grading was excellent in 41 eyes (87.2%) that underwent preaponeurotic fat flap transfer, 30 eyes (85.7%) that received a free fat graft, and 16 eyes (66.7%) that received a free dermis-fat graft. The outcomes in only 3 eyes (2.8%) were evaluated as unsatisfactory. CONCLUSIONS: The fundamental reasons behind this deformity were adhesion and tissue insufficiency above the supratarsal crease. The purpose of correction was to reconstruct the gliding system and restore the volume. The authors performed preaponeurotic fat flap transfer, free fat graft, and free dermis-fat graft and achieved satisfactory results. Great improvement in ptosis was achieved by releasing the adhesion and lowering the fold in patients with normal levator muscle function. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 30456639 TI - Galactocele After Aesthetic Breast Augmentation with Silicone Implants: An Uncommon Presentation. AB - BACKGROUND: Breast augmentation is one of the most frequently performed esthetic operations. Galactorrhea and galactocele formation are both very rare complications. The real cause still remains unknown, but various risk factors have been well reported in the literature. This report concerns a case of postoperative galactocele following bilateral breast augmentation via the inframammary approach with dual-plane insertion of implants, which is usually considered a protective approach in terms of risk factors for induction of postoperative galactorrhea. METHODS: The patient had no significant surgical, gynecological or medical history, including galactorrhea or hyperprolactinemia, and did not present any chest wall abnormalities. There has been no use of oral contraceptives or any other drugs. After the surgical procedure, the patient presented with infection-like symptoms, for which galactorrhea or galactocele was initially not considered, mainly for the absence of specific risk factors. RESULTS: After antibiotic and bromocriptine therapy, her breast returned to normal, with no pain, inflammation, enlargement or esthetic alterations. After 6 months of follow-up, the patient did not present any abnormality and she was satisfied with the result. CONCLUSION: With our report, we want to underline that galactorrhea and galactocele cannot be ruled out, even in patients with no risk factors and with procedures considered as "protective." With a fast diagnosis and a specific therapy, implants and final result can be rescued. Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 30456640 TI - The Collagenase of the Bacterium Clostridium histolyticum in the Treatment of Irradiation-Induced Capsular Contracture. AB - BACKGROUND: Irradiation therapy is an important pillar in the treatment of breast cancer. However, it can trigger capsular fibrosis, the most significant complication of implant-based breast reconstruction. As collagen is the main component of fibrotic capsules, the collagenase of the bacterium Clostridium histolyticum poses a potential treatment option for this pathological condition. METHODS: Thirty-six rats received miniature silicone implants on their backs. On day 1, the implant sites of two groups were irradiated with 10 Gy. On day 120, one irradiated group received collagenase injections into the implant pockets (n = 12). Non-irradiated (n = 12) and irradiated capsules (n = 12) were injected with plain solvent solution serving as controls. Data were analyzed by means of in vivo imaging, histology, immunohistochemistry and gene expression analysis. RESULTS: Compared with both controls, the injection of collagenase led to significantly thinner capsules. This was verified by in vivo imaging and histology. Although irradiation provoked alterations in capsule collagen structure and vessel wall thickness, the application of collagenase resulted in a significant reduction of collagen density. This was accompanied by an up regulation of VEGF-A gene expression. Of note, hematoma formation inside the implant pocket occurred in two cases after collagenase injection. CONCLUSIONS: The collagenase of the bacterium Clostridium histolyticum is effective in degrading irradiation-induced capsular fibrosis around silicone implants. Hematoma formation occurred most likely because of irradiation-induced alterations in vessel wall architecture and capsule vascularization. Further studies need to be performed to address the clinical safety of this novel treatment option. PMID- 30456641 TI - Unmet Needs and Pro-health Behavior in Patients with Chronic Respiratory Diseases. AB - Coordinated healthcare paradigm addressing the biopsychosocial spheres of patients seems advantageous for the management of chronic diseases. The purpose of the study was to determine the influence of unmet needs on pro-health behavior in chronic respiratory diseases and to recognize the factors that help identify the unmet needs. The patients were asked to complete the Camberwell Assessment of Needs Inventory and the Health Behavior Inventory. The study group consisted of 171 adult patients with chronic respiratory diseases. The study participants were recruited from among the patients of 130 general practitioners between July 2011 and March 2016. The findings of this study indicate that any prevention program should focus on increasing the level of satisfied needs in patients with chronic respiratory diseases. For the most effective treatment, fragmented and disease focused processes should be replaced by integrated health and social care. We conclude that the treatment process that involves interdisciplinary clinical approach, which, aside from the physical treatment, could recognize and address the psychological aspects of unmet needs would be conducive to undertake pro health behavior by pulmonary patients. PMID- 30456642 TI - Photoresponsive Hydrogels with Photoswitchable Stiffness: Emerging Platforms to Study Temporal Aspects of Mesenchymal Stem Cell Responses to Extracellular Stiffness Regulation. AB - An extensive number of cell-matrix interaction studies have identified matrix stiffness as a potent regulator of cellular properties and behaviours. Perhaps most notably, matrix stiffness has been demonstrated to regulate mesenchymal stem cell (MSC) phenotype and lineage commitment. Given the therapeutic potential for MSCs in regenerative medicine, significant efforts have been made to understand the molecular mechanisms involved in stiffness regulation. These efforts have predominantly focused on using stiffness-defined polyacrylamide (PA) hydrogels to culture cells in 2D and have enabled elucidation of a number of mechano-sensitive signalling pathways. However, despite proving to be a valuable tool, these stiffness-defined hydrogels do not reflect the dynamic nature of living tissues, which are subject to continuous remodelling during processes such as development, ageing, disease and regeneration. Therefore, in order to study temporal aspects of stiffness regulation, researchers have developed and exploited novel hydrogel substrates with in situ tuneable stiffness. In particular, photoresponsive hydrogels with photoswitchable stiffness are emerging as exciting platforms to study MSC stiffness regulation. This chapter provides an introduction to the use of PA hydrogel substrates, the molecular mechanisms of mechanotransduction currently under investigation and the development of these emerging photoresponsive hydrogel platforms. PMID- 30456643 TI - Technique of air-leak testing of ileocolic anastomosis. PMID- 30456644 TI - Endoscopic negative pressure therapy of the upper gastrointestinal tract. AB - Endoscopic negative pressure therapy (ENPT) has been adapted for upper gastrointestinal tract applications. More than 400 patients have already been treated with ENPT due to transmural defects in the upper gastrointestinal tract, with a success rate of 87%. The greatest experience exists for the treatment of anastomotic leakages and perforations of the esophagus. The ENPT is also used in the duodenum, pancreas and for complications after bariatric surgery. There are new indications that go beyond treatment in complication management. Innovative drainage types and endoscopic techniques have been developed that broaden the spectrum of applications. The aim of this article is to give an overview of the current status of ENPT in the upper gastrointestinal tract. PMID- 30456645 TI - [Incidental finding of mucinous neoplasia of the appendix : Treatment strategies]. AB - Tumors of the appendix are not a uniform group but differ significantly in terms of their origin/histology and metastatic behavior. Furthermore, tumors of the appendix are often diagnosed as incidental findings after appendectomy for acute appendicitis. A subgroup of these neoplasms are low-grade appendiceal mucinous neoplasms (LAMN). These are mucus-forming tumors of the appendiceal lumen, which can lead to rupture of the appendix and seeding into the abdominal cavity. Therefore LAMN are considered precursors of pseudomyxoma peritonei (PMP). It is essential to clearly differentiate the subgroups of LAMN as well as the resection status. According to this it is determined whether (radical) appendectomy is a sufficient therapy or further treatment, such as ileocecal resection with hyperthermic intraperitoneal chemotherapy (HIPEC) or cytoreductive surgery (CRS) is necessary. There is no standardized concept regarding the follow-up after resection of LAMN. Generally, it is recommended to perform a computed tomography (CT) scan of the abdomen and determination of tumor markers 6 months postoperatively and then once a year. A recommendation regarding the duration of follow-up is difficult as there are case reports in which PMP has occurred more than 15 years after removal of LAMN. PMID- 30456646 TI - Myths, reality and future of mesenchymal stem cell therapy. AB - Mesenchymal stem cell (MSC) therapy represents an alternative approach for tissue regeneration and inflammation control. In spite of a huge amount of preclinical data that has been accumulated on the therapeutic properties of MSCs, there are many conflicting results, possibly due to differences in the properties of MSCs obtained from different sources or underestimated mechanisms of MSC in vivo behavior. This review consolidates the in vivo effects of MSC therapy, discusses the fate of MSCs after intravascular and local delivery and proposes possible trends in MSC therapy. PMID- 30456647 TI - ChECing out Rif1 action in freely cycling cells. AB - In buddying yeast, like all eukaryotes examined so far, DNA replication is under temporal control, such that some origins fire early and some late during S phase. This replication timing program is established in G1 phase, where chromatin states are thought to prevent binding of key-limiting initiation factors at late firing origins. Although many factors are involved in replication initiation, a new player, Rif1, has recently entered the scene, with a spate of papers revealing a global role for the protein in the control of replication initiation timing from yeasts to humans. Since budding yeast Rif1 was known to bind only to telomeric and silent mating loci regions, it remained controversial whether Rif1 acts directly at replication origins or instead influences origin activity indirectly. In this perspective, we discuss our recent finding that Rif1 binds directly to the replication origins that it controls. In this study, we also found that Rif1's regulatory activity at origins is best revealed by an assay (sort-seq) that measures replication in unperturbed, freely cycling cultures, as opposed to commonly used protocols in which cells are first blocked in the G1 phase of the cell cycle by mating pheromone, then released into a synchronous S phase. Finally, we discuss how the sequestration of Rif1 at telomeres, through an interaction with the arrays of Rap1 molecules bound there, plays an important role in limiting Rif1's action primarily to telomere-proximal replication origins. PMID- 30456649 TI - Berberine ameliorates lipopolysaccharide-induced learning and memory deficit in the rat: insights into underlying molecular mechanisms. AB - Systemic lipopolysaccharide (LPS) triggers neuroinflammation with consequent development of behavioral and cognitive deficits. Neuroinflammation plays a crucial role in the pathogenesis of neurodegenerative disorders including Alzheimer's disease (AD). Berberine is an isoquinoline alkaloid in Berberis genus with antioxidant and anti-inflammatory property and protective effects in neurodegenerative disorders. In this research, beneficial effect of this alkaloid against LPS-induced cognitive decline was assessed in the adult male rats. LPS was intraperitoneally administered at a dose of 1 mg/kg to induce neuroinflammation and berberine was given via gavage at doses of 10 or 50 mg/kg, one h after LPS, for 7 days. Treatment of LPS group with berberine at a dose of 50 mg/kg (but not at a dose of 10 mg/kg) improved spatial recognition memory in Y maze, performance in novel object recognition task (NORT), and prevented learning and memory dysfunction in passive avoidance tasks. Furthermore, berberine lowered hippocampal activity of acetylcholinesterase (AChE), malondialdehyde (MDA), protein carbonyl, activity of caspase 3, and DNA fragmentation and improved antioxidant capacity through enhancing glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase, and glutathione (GSH). Besides, berberine attenuated inflammation-related indices, as was evident by lower levels of nuclear factor kappa B (NF-kappaB), toll-like receptor 4 (TLR4), tumor necrosis factor alpha (TNFalpha), and interleukin 6 (IL-6). Berberine also appropriately restored hippocampal 3-nitrotyrosine (3-NT), cyclooxygenase 2 (Cox 2), glial fibrillary acidic protein (GFAP), sirtuin 1, and mitogen-activated protein kinase (p38 MAPK) with no significant alteration of brain-derived neurotrophic factor (BDNF). In summary, berberine could partially ameliorate LPS-induced cognitive deficits via partial suppression of apoptotic cascade, neuroinflammation, oxido-nitrosative stress, AChE, MAPK, and restoration of sirtuin 1. PMID- 30456648 TI - Genome sequence of the opportunistic human pathogen Magnusiomyces capitatus. AB - The yeast Magnusiomyces capitatus is an opportunistic human pathogen causing rare yet severe infections, especially in patients with hematological malignancies. Here, we report the 20.2 megabase genome sequence of an environmental strain of this species as well as the genome sequences of eight additional isolates from human and animal sources providing an insight into intraspecies variation. The distribution of single-nucleotide variants is indicative of genetic recombination events, supporting evidence for sexual reproduction in this heterothallic yeast. Using RNAseq-aided annotation, we identified genes for 6518 proteins including several expanded families such as kexin proteases and Hsp70 molecular chaperones. Several of these families are potentially associated with the ability of M. capitatus to infect and colonize humans. For the purpose of comparative analysis, we also determined the genome sequence of a closely related yeast, Magnusiomyces ingens. The genome sequences of M. capitatus and M. ingens exhibit many distinct features and represent a basis for further comparative and functional studies. PMID- 30456651 TI - Eigensolutions and spectral analysis of a model for vertical gene transfer of plasmids. AB - Plasmids are autonomously replicating genetic elements in bacteria. At cell division, plasmids are distributed among the two daughter cells. This gene transfer from one generation to the next is called vertical gene transfer. We study the dynamics of a bacterial population carrying plasmids and are in particular interested in the long-time distribution of plasmids. Starting with a model for a bacterial population structured by the discrete number of plasmids, we proceed to the continuum limit in order to derive a continuous model. The model incorporates plasmid reproduction, division and death of bacteria, and distribution of plasmids at cell division. It is a hyperbolic integro differential equation and a so-called growth-fragmentation-death model. As we are interested in the long-time distribution of plasmids we study the associated eigenproblem and show existence of eigensolutions. The stability of this solution is studied by analyzing the spectrum of the integro-differential operator given by the eigenproblem. By relating the spectrum with the spectrum of an integral operator we find a simple real dominating eigenvalue with a non-negative corresponding eigenfunction. Moreover, we describe an iterative method for the numerical construction of the eigenfunction. PMID- 30456650 TI - Triclosan in over the counter medicines of South China. AB - Triclosan (TCS) is an endocrine disruptor which may affect endocrine function, antibiotic resistance, and thyroid hormone homeostasis. As a broad-spectrum antimicrobial agent used in medical and personal care products, TCS was frequently detected in human urine, indicating widespread human exposure to this chemical. Over-the-counter medicines (OTCs) may be a potential source of human exposure to TCS. In this study, 84 OTCs were collected from Guangzhou, South China, including medicines intended for both children and adults. We determined the concentration of TCS in OTCs and the estimated daily intakes (EDIs) of TCS by evaluating OTCs for different age groups of the Chinese population. Our results indicated over half of the evaluated medicines contained TCS and the highest concentration reached 7.825 ng/g, with a median value of 0.017 ng/g. TCS was frequently found in adult medicines (detected in 85% of samples), and the concentrations were significantly higher than those in children's medicines. TCS in OTCs may come from packaging materials, cultivated soils, or production process (Chinese patent medicines). The EDIs of TCS (estimated with 95th concentration in OTC medicines) were 0.305, 0.191, 0.287, 0.331, and 0.135 and 0.110 ng/kg-bw/day for infants, toddlers, children, teenagers, and adult females and males, respectively. Compared to other potential sources, human exposure to TCS from OTCs was limited in China-much less than TCS exposure through personal care products or indoor dust. PMID- 30456652 TI - An incremental deformation model of arterial dissection. AB - We develop a mathematical model for a small axisymmetric tear in a residually stressed and axially pre-stretched cylindrical tube. The residual stress is modelled by an opening angle when the load-free tube is sliced along a generator. This has application to the study of an aortic dissection, in which a tear develops in the wall of the artery. The artery is idealised as a single-layer thick-walled axisymmetric hyperelastic tube with collagen fibres using a Holzapfel-Gasser-Ogden strain-energy function, and the tear is treated as an incremental deformation of this tube. The lumen of the cylinder and the interior of the dissection are subject to the same constant (blood) pressure. The equilibrium equations for the incremental deformation are derived from the strain energy function. We develop numerical methods to study the opening of the tear for a range of material parameters and boundary conditions. We find that decreasing the fibre angle, decreasing the axial pre-stretch and increasing the opening angle all tend to widen the dissection, as does an incremental increase in lumen and dissection pressure. PMID- 30456653 TI - High biodiversity silvopastoral system as an alternative to improve the thermal environment in the dairy farms. AB - The aim of this work was to evaluate the influence of high biodiversity silvopastoral system (SPSnuclei) on microclimate and thermal comfort index thru a parallel with treeless pasture (TLP) during the four seasons of the year. Three conditions were determined for this study: shadowing area in SPSnuclei, sunny area in SPSnuclei, and sunny area in TLP. During two consecutive days in each season, the following microclimatic variables were collected: air temperature ( degrees C), relative humidity (%), illuminance (lux), wind speed (m/s), and soil surface temperature ( degrees C). The temperature and humidity index (THI) was calculated for each condition as indicative of thermal comfort. An influence analysis was carried out by generalized linear models to evaluate the system effects on the microclimatic variables. A confirmatory analysis was done with Wilcoxon-Mann-Whitney. Systems (SPSnuclei x TLP) influenced the microclimatic variables and THI (p < 0.05). The lowest means of air temperature, illuminance, wind speed, and soil surface temperature were found in SPSnuclei. As expected, autumn and winter presented a comfortable environment even on treeless pastureland. Only the SPSnuclei showed a comfortable environment for dairy production during spring. During summer, the TLP had a microclimate and thermal comfort index not suitable for dairy production already in the first hours of the day (THI between 79 and 85). We concluded that SPSnuclei provided better environment for pasture-based dairy production when compared to TLP. The high THI measured in TLP during summer could be a limiting factor on animal production. PMID- 30456654 TI - Bioaccumulation of Cr, Ni, Cd and Pb in the Economically Important Freshwater Fish Schizothorax plagiostomus from Three Rivers of Malakand Division, Pakistan: Risk Assessment for Human Health. AB - Contamination of freshwater ecosystems such as rivers with hazardous heavy metals is an environmental problem of public health concern. Accumulation of potentially toxic heavy metals in freshwater fish causes a potential health threat to their consumers including humans. The present research aimed to (1) investigate the accumulation of four potentially toxic heavy metals viz. Cr, Ni, Cd and Pb in muscle tissue of the commercially important freshwater fish Schizothorax plagiostomus at different sites of River Swat, River Panjkora and River Barandu in northern Pakistan (2) to compare gross metal accumulation in the fish samples by calculating metal pollution index (MPI) and (3) to assess potential risk to the health of the fish consumers. Samples were analyzed for the heavy metals by flame atomic absorption spectrophotometry (FAAS). Risk analysis showed that Ni risk was higher at River Panjkora and River Barandu, Pb risk was higher at River Swat and River Panjkora while Cd risk was quite low at all the three rivers. PMID- 30456655 TI - Potentially Toxic Metals in Soil and Dominant Plants from Tonglushan Cu-Fe Deposit, Central China. AB - Twenty-one soil samples and two dominant plant species (Elsholtzia splendens and Imperata cylindrical) were collected in Tonglushan Cu-Fe deposit, central China. Chemical analysis results showed that the soil contained low-level nutrients and high concentrations of potentially toxic metals. The geoaccumulation index results indicated that the study area was polluted by Cu-Zn-Cd-Pb. The levels of Cu in plant species were highest, followed by Zn, Pb, and Cd. The highest levels of Zn (261 mg kg-1), Cd (6.33 mg kg-1) and Pb (12.6 mg kg-1) were found in the leaf of Elsholtzia splendens and the highest concentration of Cu (1158 mg kg-1) was found in the root of Imperata cylindrica. Potentially toxic metals uptake and accumulation abilities were investigated by the bioconcentration factor and translocation factor, respectively. The results suggested that the Elsholtzia splendens may be a suitable candidate for Cd clean up using phytoextraction. PMID- 30456656 TI - Arsenic Removal of Contaminated Soils by Phytoremediation of Vetiver Grass, Chara Algae and Water Hyacinth. AB - This research has been carried out for assessing phytoremediation of contaminated soils with 4 concentrations of arsenic by three plants, namely Vetiver grass (Vetiveria zizanioides), Chara algae (Chara vulgaris) and Water hyacinth (Hyacintus orientalis). The experimental results showed that at least two sampling times were significantly different. In addition, at least two plants were also significantly different in terms of percentages of total arsenic that were removed from the soil of the pots, as well as significant interactions between plant and arsenic concentrations. The results obtained from the thermodynamic studies show that, obtained by zero Gibbs free-energy, the process reached an equilibrium on the 60th day of the experiment, and, in fact, the adsorption of arsenic after the 60th day would be negligible. PMID- 30456657 TI - Flu DRiPs in MHC Class I Immunosurveillance. AB - Since the publication of the DRiP (defective ribosomal product) hypothesis in 1996, numerous studies have addressed the contribution of DRiPs to generating viral antigenic peptides for CD8+ T cell immunosurveillance. Here, we review studies characterizing the generation of antigenic peptides from influenza A virus encoded DRiPs, discuss the many remaining mysteries regarding the nature of their co-translational generation, and speculate on where the future might lead. PMID- 30456658 TI - Reverse Genetics for Peste des Petits Ruminants Virus: Current Status and Lessons to Learn from Other Non-segmented Negative-Sense RNA Viruses. AB - Peste des petits ruminants (PPR) is a highly contagious transboundary animal disease with a severe socio-economic impact on the livestock industry, particularly in poor countries where it is endemic. Full understanding of PPR virus (PPRV) pathobiology and molecular biology is critical for effective control and eradication of the disease. To achieve these goals, establishment of stable reverse genetics systems for PPRV would play a key role. Unfortunately, this powerful technology remains less accessible and poorly documented for PPRV. In this review, we discussed the current status of PPRV reverse genetics as well as the recent innovations and advances in the reverse genetics of other non segmented negative-sense RNA viruses that could be applicable to PPRV. These strategies may contribute to the improvement of existing techniques and/or the development of new reverse genetics systems for PPRV. PMID- 30456659 TI - MicroRNA-135a Modulates Hepatitis C Virus Genome Replication through Downregulation of Host Antiviral Factors. AB - Cellular microRNAs (miRNAs) have been shown to modulate HCV infection via directly acting on the viral genome or indirectly through targeting the virus associated host factors. Recently we generated a comprehensive map of HCV-miRNA interactions through genome-wide miRNA functional screens and transcriptomics analyses. Many previously unappreciated cellular miRNAs were identified to be involved in HCV infection, including miR-135a, a human cancer-related miRNA. In the present study, we investigated the role of miR-135a in regulating HCV life cycle and showed that it preferentially enhances viral genome replication. Bioinformatics-based integrative analyses and subsequent functional assays revealed three antiviral host factors, including receptor interacting serine/threonine kinase 2 (RIPK2), myeloid differentiation primary response 88 (MYD88), and C-X-C motif chemokine ligand 12 (CXCL12), as bona fide targets of miR-135a. These genes have been shown to inhibit HCV infection at the RNA replication stage. Our data demonstrated that repression of key host restriction factors mediated the proviral effect of miR-135a on HCV propagation. In addition, miR-135a hepatic abundance is upregulated by HCV infection in both cultured hepatocytes and human liver, likely mediating a more favorable environment for viral replication and possibly contributing to HCV-induced liver malignancy. These results provide novel insights into HCV-host interactions and unveil molecular pathways linking miRNA biology to HCV pathogenesis. PMID- 30456660 TI - Glucose control using a closed-loop device decreases inflammation after cardiovascular surgery without increasing hypoglycemia risk. AB - Although tight glucose control might reduce inflammation after cardiac surgery, it remains unclear whether inflammation can be controlled by maintaining glucose levels within 110-180 mg/dL. We hypothesized that a glucose target range of 110 180 mg/dL decreases inflammation after cardiovascular surgery. This retrospective study included 72 cardiovascular surgery patients divided into two groups according to the glucose control approach. Patients allocated to the closed-loop group received closed-loop glucose control (target glucose levels at 110-180 mg/dL) from admission to the intensive care unit until 9 a.m. on postoperative day (POD) 1. Patients allocated to the conventional group received conventional glucose control using a sliding scale method to maintain blood glucose levels < 200 mg/dL. Primary outcomes were C-reactive protein (CRP) levels on PODs 1, 2, and 7. Data were reported as mean +/- standard deviation. Comparisons were performed using the chi-squared test and unpaired t test, with p < 0.05 indicating statistical significance. The closed-loop group had significantly lower average glucose levels (169 +/- 24 vs. 201 +/- 36 mg/dL, p < 0.001) and standard deviation of glucose levels (22 +/- 13 vs. 44 +/- 20 mg/dL; p < 0.001). The CRP levels on PODs 2 and 7 were significantly lower in the closed-loop group than in the conventional group (10.8 +/- 5.6 vs. 14.1 +/- 5.7 mg/dL, p = 0.02; 4.6 +/- 2.5 vs. 7.3 +/- 4.0 mg/dL, p < 0.001; respectively). Our findings suggest that glucose control using a closed-loop device might decrease inflammation after cardiovascular surgery without increasing hypoglycemia risk. PMID- 30456661 TI - Mechanical properties of a new thermally deformable mitral valve annuloplasty ring and its effects on the mitral valve. AB - Ideally, an annuloplasty ring's shape should be changed intraoperatively if mitral valve repair is unsuccessful because of a short coaptation length or systolic anterior motion. Several post-implantation adjustable rings have been developed, but they are not freely deformable and are unsuitable for asymmetric repair of the valvular annulus. We developed a novel thermally deformable mitral annuloplasty ring to address these problems and assessed the ring's mechanical properties and its effect on the mitral valve anatomy. This ring was made of polycaprolactone. Tensile and bending tests were performed to evaluate the ring's mechanical properties. The ratio of the transverse and septal-lateral length was determined as 4:3. Using 10 pig hearts, we measured the post-deformation coaptation length and minimum distance from the coaptation to the ventricular septum, which is a factor of abnormal systolic anterior motion of the mitral valve. In the mechanical tests, the ring's yield point was greater than the deformation force of the annulus in humans. In pigs with deformation from "4:3" to "4:2", the coaptation length was significantly increased in each mitral valve part. In pigs with deformation from "4:3" to "4:4", the minimum distance from the coaptation to the ventricular septum was significantly increased. Asymmetrical ring deformation increased the coaptation length only at the deformed area. In conclusion, this new thermally deformable mitral annuloplasty ring could be "order-made" to effectively change the coaptation length in all parts of the mitral valve and the distance from the coaptation to septum post-deformation via intraoperative heating. PMID- 30456662 TI - Impaired renal function and fever of unknown origin in a patient with pediatric granulomatous arthritis: Questions. PMID- 30456663 TI - A rare cause of AA amyloidosis and end-stage kidney failure: Questions. PMID- 30456664 TI - A rare cause of AA amyloidosis and end-stage kidney failure: Answers. PMID- 30456665 TI - Impaired renal function and fever of unknown origin in a patient with pediatric granulomatous arthritis: Answers. PMID- 30456666 TI - Renal aspects of metabolic acid-base disorders in neonates. AB - Acid-base homeostasis is one of the most tightly regulated systems in the body. Maintaining the acid-base balance is particularly challenging for preterm infants and growing neonates. The kidney, which represents the crucial ultimate line of defense against disturbances of acid-base balance, undergoes a complex maturation process during the transition from a fetal to an extra-uterine environment. This review article summarizes the physiology of acid-base regulation by the immature human kidney and discusses disorders of acid-base balance, such as metabolic acidosis, respiratory acidosis, metabolic alkalosis, and respiratory alkalosis. In conditions of metabolic acidosis, the serum anion gap and the urinary anion gap can be useful tools to define the nature of the acidosis. Metabolic acidosis can reflect a decrease in glomerular filtration rate, or be the consequence of selective disorders of proximal or distal tubular function. Most tubulopathies associated with metabolic acidosis observed in neonates are primary, hereditary, isolated tubulopathies. Proximal renal tubular acidosis is characterized by bicarbonate wasting, while the distal types of renal tubular acidosis are secondary to distal acidification defects. All tubulopathies are associated with hypokalemia, with the exception of type 4 hyperkalemic distal renal tubular acidosis. The transporter defects in the various acid-base tubulopathies are now well defined. Treatment of the acidosis varies according to the site and mechanism of the defect. Chronic renal tubular acidosis or alkalosis severely impair growth and calcium metabolism. Early rational therapeutic intervention can prevent some of the consequences of the disorders and improves the prognosis. PMID- 30456667 TI - [Labral pathologies of the hip joint]. AB - Magnetic resonance imaging (MRI) of the hip joint is performed for the diagnostics of many clinical pathologies. For clarification of pathologies of the hip joint conventional MRI and MR arthrography are used. The use of MRI either with or without the intravenous administration of contrast material is performed to diagnose bone marrow lesions, necrosis of the femoral head, inflammatory and tumorous lesions affecting the hip joint and its components. After the intra articular administration of a diluted solution of contrast material, which results in distension of the joint, MR arthrography is performed for the diagnosis of intra-articular pathologies, such as lesions of the labrum acetabulare, chondral lesions and free intra-articular bodies. In recent times, MR arthrography is carried out with continuous traction of the limb to be examined because this leads to a distension of the joint and its components and in this way particularly lesions of the labrum with involvement of cartilage can be visualized even better. This article gives an overview of MRI and the accuracy of detecting lesions of the labrum acetabulare and the influence on the therapeutic approach. PMID- 30456668 TI - Deep Semantic Segmentation of Kidney and Space-Occupying Lesion Area Based on SCNN and ResNet Models Combined with SIFT-Flow Algorithm. AB - Renal segmentation is one of the most fundamental and challenging task in computer aided diagnosis systems. In order to overcome the shortcomings of automatic kidney segmentation based on deep network for abdominal CT images, a two-stage semantic segmentation of kidney and space-occupying lesion area based on SCNN and ResNet models combined with SIFT-flow transformation is proposed in paper, which is divided into two stages: image retrieval and semantic segmentation. To facilitate the image retrieval, a metric learning-based approach is firstly adopted to construct a deep convolutional neural network structure using SCNN and ResNet network to extract image features and minimize the impact of interference factors on features, so as to obtain the ability to represent the abdominal CT scan image with the same angle under different imaging conditions. And then, SIFT Flow transformation is introduced, which adopts MRF to fuse label information, priori spatial information and smoothing information to establish the dense matching relationship of pixels so that the semantics can be transferred from the known image to the target image so as to obtain the semantic segmentation result of kidney and space-occupying lesion area. In order to validate effectiveness and efficiency of our proposed method, we conduct experiments on self-establish CT dataset, focus on kidney organ and most of which have tumors inside of the kidney, and abnormal deformed shape of kidney. The experimental results qualitatively and quantitatively show that the accuracy of kidney segmentation is greatly improved, and the key information of the proportioned tumor occupying a small area of the image are exhibited a good segmentation results. In addition, our algorithm has also achieved ideal results in the clinical verification, which is suitable for intelligent medicine equipment applications. PMID- 30456669 TI - ASO Author Reflections: Distal Pancreatectomy with Celiac Axis Resection for Locally Advanced Pancreatic Cancer-Patient Selection and Surgical Experience are Key. PMID- 30456670 TI - ASO Author Reflections: Redefining the Ki-67 Index Stratification for Low-Grade Pancreatic Neuroendocrine Tumors. PMID- 30456671 TI - ASO Author Reflections: Preoperative Venous Thromboembolism in Asymptomatic Patients Undergoing Major Oncologic Surgery. PMID- 30456672 TI - Morbidity and Mortality Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Data from the DGAV StuDoQ Registry with 2149 Consecutive Patients. AB - BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are performed for well-selected patients with peritoneal surface malignancies. This combined treatment is potentially associated with an increased rate of complications. OBJECTIVE: The aim of this paper was to analyze the morbidity and mortality of CRS and HIPEC in the German national registry. METHODS: We present a retrospective analysis of 2149 consecutive patients from 52 hospitals. The data were prospectively documented in the DGAV StuDoQ Registry between February 2011 and December 2016. RESULTS: Almost two-thirds of all patients had a colorectal malignancy; therefore, the most frequently performed resections were colectomies (54%) and rectal resections (30%). Only 36.2% of all patients had no anastomosis, and fewer than 20% of all patients were older than 70 years of age (16.4%). Enteric fistula and anastomotic leaks occurred in 10.5% of all cases. The reoperation rate was 14.6% (95% confidence interval [CI] 11.51 18.1). Major grade 3 and 4 complications (Clavien-Dindo classification) occurred in 19.3% of all patients, half of which were due to surgical complications. The overall 30-day postoperative hospital mortality was 2.3% (95% CI 1.02-3.85). Multivariate analysis showed an increased risk for morbidity associated with pancreatic resections (odds ratio [OR] 2.4), rectal resection (OR 1.5), or at least one anastomosis (OR 1.35), and mortality with reoperation (OR 8.7) or age > 70 years (OR 3.35). CONCLUSIONS: CRS and HIPEC are associated with acceptable morbidity and low mortality. These results show that CRS and HIPEC can be safely performed nationwide when close mentoring by experienced centers is provided. PMID- 30456673 TI - Long-Term Prognostic Impact of Severe Postoperative Complications After Lung Cancer Surgery. AB - BACKGROUND: Postoperative complications are reportedly related to poor prognosis following lung cancer surgery; however, the difference in the prognostic impact according to immune-nutritional status is unknown. METHODS: In 411 patients with completely resected non-small cell lung cancer, the relationship between severe postoperative complications (SPCs; Clavien-Dindo grade III or higher) and survival was retrospectively analyzed, with special reference to preoperative immune-nutritional status based on the prognostic nutritional index (PNI), which was calculated using serum albumin level and total lymphocyte count. RESULTS: A total of 52 (12.7%) patients had SPCs. The most common SPC was air leak (n = 39), atelectasis/sputum (n = 4), pneumonia (n = 2), pyothorax (n = 2), and bleeding (n = 2). The 5-year overall survival (OS) rates in patients with and without SPCs were 63.8% and 80.1%, respectively (p = 0.007). A multivariate Cox proportional hazard model revealed SPCs had a negative prognostic impact on patients with preserved immune-nutritional status (PNI >= 48.3; first to third quartile), but not on those with poor immune-nutritional status (PNI < 48.3; fourth quartile), with statistically significant interaction. Further analysis focused on 309 patients with preserved immune-nutritional status. The OS and relapse-free survival (RFS) rates were significantly worse in patients with SPCs than in those without (p < 0.001). After controlling for potential confounders, SPCs remained significantly associated with worse OS (adjusted hazard ratio [HR] 2.49, 95% confidence interval [CI] 1.21-4.83; p = 0.015) and RFS (adjusted HR 2.02, 95% CI 1.10-3.53; p = 0.025). CONCLUSION: Severe complications following lung cancer surgery could negatively impact prognosis, particularly in patients with preserved immune-nutritional status. PMID- 30456674 TI - ASO Author Reflections: Endoscopic Ultrasonography for Determining Clinical T Classification for Esophageal Squamous Cell Carcinoma. PMID- 30456675 TI - Multicentric Ipsilateral Invasive Breast Carcinomas Might have Higher 21-Gene Recurrence Score Compared with Multifocal Ipsilateral Invasive Breast Carcinomas. PMID- 30456677 TI - Hepatic Angiosarcoma: A Multi-institutional, International Experience with 44 Cases. AB - BACKGROUND: Hepatic angiosarcoma is a rare primary liver tumor. The aim of this current study was to evaluate the presentation and treatment outcomes in a modern cohort. METHODS: This was a retrospective, multi-institutional, observational study of patients with histopathologic diagnoses of primary hepatic angiosarcoma from four institutions. Clinicopathologic characteristics, treatments, and patient outcomes were examined. RESULTS: Forty-four patients with hepatic angiosarcoma were identified. Patients were predominantly Caucasian and presented at a median age of 63.7 years; 81.4% of patients had bilobar disease and 37.2% had metastatic disease at the time of presentation. Only 10 patients underwent surgical resection. Median overall survival for the entire cohort was 5.8 months (interquartile range 1.9-16.4), and 1-, 3-, and 5-year actual survival was 30.0%, 8.1%, and 5.6%, respectively. There were only two 5-year survivors, both of whom presented with localized disease and underwent curative resection. CONCLUSION: The prognosis for hepatic angiosarcoma remains quite poor. Surgical resection for localized disease results in the best outcomes. Unfortunately, current imaging modalities are often non- diagnostic, and most patients are unresectable at the time of presentation. PMID- 30456676 TI - The Differences in Clinicopathologic and Prognostic Characteristics Between Surgically Resected Peripheral and Central Lung Squamous Cell Carcinoma. AB - BACKGROUND: Pulmonary peripheral-type squamous cell carcinoma (p-SqCC) has been increasing in incidence. However, little is known about the clinicopathologic features of p-SqCC. This study aimed to investigate the clinicopathologic characteristics and clinical outcomes of p-SqCC compared with central-type SqCC (c-SqCC) in a large cohort of surgically resected lung SqCC patients with long term follow-up results. METHODS: The study included 268 patients with SqCC who underwent surgical resection at the authors' institute from January 1990 to September 2013. The mean follow-up period was 67.1 months. The clinicopathologic and genetic characteristics were investigated in relation to their association with progression-free survival (PFS) and overall survival (OS) based on tumor location. RESULTS: The study cohort included 120 patients with p-SqCC and 148 patients with c-SqCC. Compared with c-SqCC, p-SqCC was correlated with older age (p = 0.002), female sex (p = 0.033), better performance status (p < 0.001), smaller tumor (p = 0.004), less lymph node metastasis (p < 0.001), and an earlier pathologic stage (p < 0.001). Despite the clinicopathologic differences, tumor location was not significantly correlated with clinical outcomes. For the p-SqCC patients, the multivariate analysis showed a significant correlation of lymphovascular invasion (PFS, p < 0.001; OS, p < 0.001) and lymph node metastasis (p = 0.007; OS, p = 0.022) with poor PFS and OS, but a significant correlation of incomplete tumor resection (PFS, p = 0.009) only with poor PFS. CONCLUSIONS: The clinicopathologic features differed between the p-SqCC and c-SqCC patients. Lymphovascular invasion and lymph node metastasis were independent prognostic factors of p-SqCC. These prognostic factors may be potentially used as indicators for adjuvant therapies to be used with patients who have p-SqCC. PMID- 30456678 TI - Survival Outcomes of Two Phase 2 Studies of Adjuvant Chemotherapy with S-1 Plus Oxaliplatin or Capecitabine Plus Oxaliplatin for Patients with Gastric Cancer After D2 Gastrectomy. AB - BACKGROUND: Two phase 2 trials of oxaliplatin-containing adjuvant therapy for patients with gastric cancer (GC) after D2 gastrectomy were conducted in Japan. The SOXaGC trial evaluated the tolerability and safety of adjuvant therapy with S 1 plus oxaliplatin (SOX), whereas the J-CLASSIC trial evaluated the feasibility of adjuvant therapy with capecitabine plus oxaliplatin (CAPOX). Because both were studies that did not evaluate survival results as study end points, the authors evaluated the survival outcomes for the patients in the two trials. METHODS: All 62 and 100 patients in the full analysis set of the SOXaGC and J-CLASSIC trials, respectively, were included in the current study. Their information about survival outcome was collected. The primary end point was relapse-free survival (RFS), and the secondary end point was overall survival (OS). RESULTS: For the pathologic stage (pStage 2) patients treated with CAPOX, the 3-year RFS rate was 87.8% and the 3-year OS rate was 92.7%. For the pStage 3 patients treated with SOX and CAPOX, the 3-year RFS rates were respectively 70.9% and 67.8% (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.50-1.72), whereas the 3-year OS rates were respectively 75.7% and 79.3% (HR, 1.10; 95% CI, 0.54-2.26). Subgroup analysis showed significant interactions between the treatment (SOX vs. CAPOX) and both sex (male vs. female; P = 0.024) and histologic type (diffuse vs. other, P = 0.069). CONCLUSIONS: This exploratory analysis demonstrated that SOX and CAPOX are suggested to have similar efficacy for pStage 3 GC patients after D2 gastrectomy. Differences in the treatment effect according to sex and histologic type warrant further evaluation. PMID- 30456679 TI - ASO Author Reflections: Metastatic Biopsy of Osteosarcoma with Circulating RNA. PMID- 30456680 TI - The Prognostic Significance of the Oncotype DX Recurrence Score in T1-2N1M0 Estrogen Receptor-Positive HER2-Negative Breast Cancer Based on the Prognostic Stage in the Updated AJCC 8th Edition. AB - BACKGROUND: This study aimed to evaluate the prognostic significance of the Oncotype DX recurrence score (RS) in T1-2N1M0 estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer based on the prognostic stage in the updated American Joint Commission on Cancer, 8th edition. METHODS: The Surveillance, Epidemiology, and End Results database was searched to identify ER-positive invasive ductal breast cancer in T1-2N1M0 with RS results diagnosed between 2004 and 2012. Patients with RS were categorized into low-risk (RS < 11), intermediate-risk (RS 11-25), and high-risk (RS > 25) groups. The distributions of clinical-pathological characteristics were compared among the RS risk groups using Pearson's Chi square. Breast cancer-specific survival (BCSS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared across RS groups using the log-rank statistic. Cox models were fitted to assess the factors independently associated with survival. RESULTS: The study enrolled 4059 cases categorized into prognostic stages IA to IIB. The RS risk groups were positively correlated with pathological prognostic stages (P < 0.001). The RS risk groups differed significantly in terms of BCSS and OS (P < 0.001). According to the multivariate analysis, RS risk group was an independent prognostic factor for BCSS and OS together with the pathological prognostic stage. The subgroup analysis showed similar survival rates across pathological prognostic stages in the RS low-risk group but significant differences in survival rates among pathological prognostic stages in the RS intermediate-risk group. The survival rates among the RS risk groups also differed significantly in pathological prognostic stage IA. CONCLUSIONS: Oncotype DX RS provided independent prognostic significance to complement the prognostic staging system. PMID- 30456682 TI - Long-Term Implications of Unplanned Conversion During Laparoscopic Liver Resection for Hepatocellular Carcinoma. AB - BACKGROUND: Laparoscopic liver resection (LLR) is increasingly utilized for patients with hepatocellular carcinoma (HCC). However, long-term outcomes for patients requiring conversion to an open procedure during LLR have not been examined. METHODS: Patients undergoing attempted LLR for HCC were identified within the National Cancer Database. Patients undergoing successful LLR were compared with those who required unplanned conversion with regard to perioperative outcomes and overall survival (OS). Those experiencing conversion were further compared with patients who underwent planned open resection after propensity score matching. RESULTS: Unplanned conversion occurred in 228 (18.0%) of 1270 patients undergoing LLR. Compared with successful LLR, conversion was associated with greater length of stay (6 vs. 4 days, p < 0.001), higher readmission rates (7.8% vs. 2.6%, p = 0.001), and reduced OS (55.1 vs. 67.6 months, p = 0.074). Unplanned conversion during major hepatectomy was associated with significantly worse OS (median 35.7 months) compared with successful major and minor LLR (median not reached and 67.6 months, respectively, p = 0.004). Compared with planned open resection, similar results were noted as conversion during major LLR was associated with worse OS (median 27.3 months) compared with open major hepatectomy (median not reached; p = 0.002). Unplanned conversion was independently associated with increased mortality (hazard ratio 1.38) after adjustment in a multivariable model. Tumor size was the strongest predictor of conversion on logistic regression analysis. CONCLUSIONS: Unplanned conversion during LLR for HCC is associated with inferior OS. This difference is most pronounced for major hepatectomy. LLR should be considered cautiously in patients with larger, more advanced tumors likely to require major resection. PMID- 30456681 TI - Validation of a Nomogram for Non-sentinel Node Positivity in Melanoma Patients, and Its Clinical Implications: A Brazilian-Dutch Study. AB - BACKGROUND: Non-sentinel node (NSN) positivity impacts the prognosis of melanoma patients; however, the benefits of completion lymph node dissection in patients with positive sentinel nodes (SNs) are limited. OBJECTIVE: We aimed to present a predictive nomogram for NSN positivity in melanoma patients with a positive SN biopsy. METHODS: This retrospective analysis from patients who underwent SN biopsy in a Brazilian institution from 2000 to 2015 was used for the construction and internal validation of the nomogram. This nomogram was then externally validated in a cohort of Dutch patients. RESULTS: The Brazilian cohort comprised 1213 patients, with a mean follow-up of 5.11 years. Breslow thickness (odds ratio [OR] 1.170, 95% confidence interval [CI] 1.043-1.314]; p = 0.008), number of positive SNs (OR 1.092, 95% CI 1.034-1.153; p = 0.001), and largest diameter of the metastatic deposit (OR 3.217, 95% CI 1.551-6.674; p = 0.002) were statistically significant for NSN positivity. Internal validation was performed using a bootstrapping technique. A good performance was observed (Brier score 0.097) and an excellent power of discrimination was achieved (area under the curve [AUC] 0.822). The nomogram was then applied to the Dutch cohort, and its overall performance (Brier score 0.085), calibration (Hosmer-Lemeshow goodness-of fit test; p = 0.198), and discriminatory power (AUC 0.752, 95% CI 0.615-0.890) were all adequate. CONCLUSIONS: We presented a nomogram for assessing NSN probability that should not only be used for surgical considerations but also for risk stratification and clinical decisions. Internal validation has shown that this is an adequate model, while external validation increases the model's reliability and suggests that it can be globally incorporated. PMID- 30456683 TI - Reply to "Multicentric Ipsilateral Invasive Breast Carcinomas Might Have Higher 21-Gene Recurrence Score Compared with Multifocal Ipsilateral Invasive Breast Carcinomas". PMID- 30456684 TI - Synthesis and Spectral Characteristics of BODIPY Dyes with Two or Three Dipyrrin Domains. AB - Several boron-dipyrrin (BODIPY) based fluorophores with two and three dipyrrin cores were synthesized and investigated in solvents under the concentration variation. Comparative analysis of spectral and photophysical changes under increasing the number of the cores in the dye molecule was made. Mutual influence of dipyrrin cores was detected leading to the increasing of the compounds rigidity and, thus, the absence of fluorescent molecular rotor effects under the viscosity variation. Aggregation induced quenching, which was observed for many mono-domain BODIPY dyes is reduced in case of investigated poly-domain compounds. PMID- 30456685 TI - Correction to: A retrospective analysis of weight changes in HIV-positive patients switching from a tenofovir disoproxil fumarate (TDF)- to a tenofovir alafenamide fumarate (TAF)-containing treatment regimen in one German university hospital in 2015-2017. AB - The original version of this article unfortunately contained mistakes. PMID- 30456686 TI - Venous thromboembolism risk factors in a pediatric trauma population. AB - PURPOSE: New guidelines have been proposed for venous thromboembolism (VTE) prophylaxis in pediatric trauma patients. This paper seeks to evaluate risk factors associated with VTE that might further guide patient selection for prophylaxis. METHODS: Review of a tertiary children's academic hospital's trauma database for VTE events and associated risk factors from 2005 to 2016. RESULTS: 15,306 pediatric trauma patients were identified and reviewed. During this time period there were 6191 admissions (40.4%), of which 20 developed a VTE (0.3%) including two pulmonary emboli. Primary outcome was comparison of risk factors for developing a VTE that were identified in the literature. Age stratification revealed the highest incidence of VTE in children under the age of 2 (0.7%), which increased with CVC placement when compared to children aged 2-12 and 13-15 (0.036 Fisher's exact test). CONCLUSIONS: VTE after pediatric trauma is rare, and may be more uncommon than previously reported. CVC placement was the strongest predictor of VTE, particularly in infant and toddler patients which can explain their higher overall incidence compared to other pediatric age groups. Identifying high-risk patients is important to optimize screening and prophylaxis of VTE in pediatric trauma patients while minimizing risks of anticoagulation. PMID- 30456687 TI - Acquired isolated hypoganglionosis as a distinct entity: results from a nationwide survey. AB - PURPOSE: Acquired isolated hypoganglionosis (A-IH) is a late-onset intestinal pseudo-obstruction disorder and shows different pathophysiological findings from congenital isolated hypoganglionosis (C-IH). In this study, we retrospectively examined five cases of A-IH and investigated the features of A-IH. METHODS: Five cases of A-IH were extracted from a nationwide retrospective cohort study in 10 years, from which totally 355 cases of Allied Disorders of Hirschsprung's Disease (ADHD) were collected. RESULTS: Ages of onset were between 13 and 17 years in three cases, and 4 years and 4 months in ones. Initial symptoms were abdominal distension and/or chronic constipation in 4 cases, whereas one exhibited intestinal perforation. Affected lesions varied from case to case, extending various length of intestinal tracts. All cases underwent multiple operations (average: 4.6 times), such as enterostomy, resection of dilated intestines, and/or pull-through. Pathological findings showed the decreased numbers of ganglion cells and degeneration of ganglion cells, whereas the size of the plexus was normal. Currently, all cases were alive and almost all eat regular food without requiring parenteral feeding. CONCLUSION: A-IH is rare, but distinct entity characterized by different clinical courses and pathological findings from those of C-IH. The outcome is considered to be favorable after a resection of affected intestine. PMID- 30456688 TI - Blood Sugar Level Indication Through Chewing and Swallowing from Acoustic MEMS Sensor and Deep Learning Algorithm for Diabetic Management. AB - Diabetes, a metabolic disorder due to high blood glycemic index in the human body. The glycemic index varies in the human of improper diet and eating pattern such as junk foods, variation in the quantity of food, swallowing of food without chewing and stress. However, the diagnose of increase or decrease in the glycemic index is a challenging task. Similarly, the regulation of glycemic index without regular exercise is a major problem in day to day life. In this paper, we propose a novel SCS method to regulate glycemic index without exercise through changing the eating method. The proposed SCS eating method consists of Size of the food, Chewing style and Swallow time (SCS) of the food to regulate glycemic index. Furthermore, the proposed SCS method evaluate and validate through the acoustic signal acquired and processed with deep learning algorithm to analyze the chewing pattern of food to formulate a standard procedure for eating style and to reduce the glycemic level. The validation of diabetes done by measurement of blood glycemic through AccuChek Instant S Glucometer. Furthermore, the SCS method of eating style from 50 diabetes persons reduces the blood glucose level drastically by 85% after following the proposed method of eating style. PMID- 30456689 TI - Implications of low fiber levels in finishing lambs on performance, health, rumen, and carcass parameters. AB - The objective of this study was to evaluate the effects of different levels of NDF in high-concentrate diets on performance and aspects ruminal, blood, and carcass parameters of finishing lambs. Twenty-four lambs, with initial BW of 24 +/- 3 kg, were randomly divided into individual pens, in a completely randomized design, comprising three treatments with eight repetitions each. The treatments consisted of dietary levels of 15%, 20%, and 25% of NDF, based on DM. The diets were composed of corn, soybean meal, minerals, and corn silage and were offered twice a day, with daily control of what was offered and refused, to determine dry matter intake (DMI). The animals were weighed weekly and slaughtered after 50 days of confinement. Performance evaluations, blood parameters, carcass, and ruminal parameters were evaluated. Lambs fed with lower dietary fiber had better carcass yield (P < 0.005). Blood count, blood biochemical parameters, rumen short chain fatty acid production and protozoan population were not affected by the dietary NDF level. It was concluded that in high-concentrate diets with 15% NDF resulting in better weight gain of the animals in the confinement, good carcass yields without the animal having altered health and ruminal parameters. PMID- 30456691 TI - Estimation of daily nutrient allowances for pigs fed with alternative feed resources in smallholder enterprises in Kenya. AB - This study estimated the daily nutrient allowances from conventional commercially compounded feed and alternative feeds resources in smallholder pig enterprises in Busia, Nakuru, and Kiambu counties in Kenya. Feeding data from 144 pig enterprises was used to compute the daily dry matter (DM), crude protein (CP), and metabolisable energy (ME) supplied to pigs per kilogram bodyweight. Analysis of variance of the mean values was computed using SPSS statistical software and SAS(r) systems with Tukey's test to separate the means. Results showed that the daily nutrient allowance provided by some alternative feed resources was generally very low; however, home-made feed formulations supplied reasonably sufficient dietary energy and CP. Swill was the most popular feed resource in Busia County; however, the amount of energy supplied from swill was very low (ME = 19.98 kcal/kg body weight). The daily CP allowance for pigs fed on swill, farm residue, and market waste was very low ranging between 1.1 and 3.6 g/kg body weight. The findings of this study indicate that there is need for capacity development for farmers with respect to feeding practices that have no capacity to supply sufficient nutrient allowances. Research should focus more improving supply of nutrients from viable alternative feed resources through use of technology. PMID- 30456690 TI - Impact of on-farm feeding practices on the reproductive indices of pigs reared under educated smallholder system in Imo State, Nigeria. AB - The aim of this study was to determine the impact of on-site feeding practices on the reproductive indices of pigs reared under educated smallholder system in Imo State, southeastern Nigeria. The smallholder pig farms (S1, S2, M, L1, and L2) visited were divided into small-, medium-, and large-size farms, with small farms stocking 70-80, medium 120-130, and larger 230-270 pigs. In each farm, six weaner pigs comprising Large White, Landrace, and Duroc breeds were selected and their ages and initial body weights determined. The feeds offered to the weaner pigs were physically characterized for their ingredient components. Thereafter, representative samples of the feeds were subjected to proximate biochemical analysis on the 1st, 7th, and 13th weeks of the study using standard methods. Results showed that all the farms utilized palm kernel cake as their major energy feedstuffs, in addition to soybean, common salt, local fish meal, and vitamins premix. Data generated were analyzed using analysis of variance and descriptive statistics (mean and percentages). The mean crude protein values of the feed samples collected from these farms were of similar range (13.49-14.20%), while crude fiber and ether extract values were very high. Data on calculated metabolizable energy values were also relatively low for growing pigs. There was significant (p < 0.05) differences in the final body weights of the grower pigs after 14 weeks of feeding across the farms. There were significant (p > 0.05) changes in weight gain, with farms S1, S2, M, L1, and L2 returning 24.50, 10.00, 67.50, 11 00, and 7.50 kg mean weights, respectively. There is a slight increment in birth weight of piglets in farms S1, S2, M, and L2 when compared with those in farm L1. Direct observations revealed that farms S1, L1, and L2 practiced flushing techniques which invariably resulted in higher litter size recorded in these farms. The dams in farms S1, L1, and L2 were observed to gain more weight during gestation and shed little during lactation. PMID- 30456692 TI - Prevalence of bovine viral diarrhea virus in dairy cattle herds in eastern China. AB - Bovine viral diarrhea virus (BVDV) is a worldwide spreading pestivirus affecting cattle and other ruminants; however, there have been few reports on epidemiologic investigation of BVDV in eastern China. In this study, bulk tank milk from 36 herds of dairy cattle in eastern China was submitted to serological investigations, 77.8% of herds was BVDV antibody positive. Individual animal status in two herds was further investigated collecting blood samples, the positive ratio was 49.74% and 24.64%, and the average positive ratio of calves, heifers, and lactating cows was 15.94%, 40.16%, and 41.7%, respectively. Moreover, clinical survey was carried out among 8170 dairy cattle from 36 herds, for diarrhea syndrome, respiratory problems and reproductive failure, and pathogens of all clinical cattle were further investigated. The results showed that BVDV was one of the main pathogen, which infected animals combining with various other viruses. Then, nine BVDV strains were isolated; phylogenetic analysis showed that BVDV subtypes currently circulating in eastern China were BVDV 1a and BVDV 1c. In addition, out of 377 cows tested, the 1.86% detected positive to the BVDV antigen. This study provided the foundation of further study on vaccination and control strategies of BVDV in eastern China. PMID- 30456693 TI - Detection of the presence of Coxiella burnetii in a case of goat abortion: a first report from India. AB - Abortion is a major cause of economic loss to the goat industry. Coxiella burnetii the causative agent of Q fever is an important zoonotic agent known to be prevalent worldwide. In the present investigation, we detected the presence of Coxiella burnetii by the modified Ziehl Neelsen method of staining and its DNA by trans-PCR assay in the placenta obtained from the aborted goat. We also ruled out other common causes of abortion in this case. Based on a literature survey, this is the first report on the direct detection of Coxiella burnetii from an aborted goat to be reported from India. PMID- 30456694 TI - Central contributions to torque depression: an antagonist perspective. AB - Torque depression (TD) is the reduction in steady-state isometric torque following active muscle shortening when compared to an isometric reference contraction at the same muscle length and activation level. Central nervous system excitability differs in the TD state. While torque production about a joint is influenced by both agonist and antagonist muscle activation, investigations of corticospinal excitability have focused on agonist muscle groups. Hence, it is unknown how the TD state affects spinal and supraspinal excitability of an antagonist muscle. Eight participants (~ 24y, three female) performed 14 submaximal dorsiflexion contractions at the intensity needed to maintain a level of integrated electromyographic activity in the soleus equivalent to 15% of that recorded during a maximum plantar flexion contraction. The seven contractions of the TD protocol included a 2 s isometric phase at an ankle angle of 140 degrees , a 1 s shortening phase at 40 degrees /s, and a 7 s isometric phase at an angle of 100 degrees . The seven isometric reference contractions were performed at an ankle angle of 100 degrees for 10 s. Motor evoked potentials (MEPs), cervicomedullary motor evoked potentials (CMEPs), and maximal M-waves (Mmax) were recorded from the soleus in both conditions. In the TD compared to isometric reference state, a 13% reduction in dorsiflexor torque was accompanied by 10% lower spinal excitability (normalized CMEP amplitude; CMEP/Mmax), and 17% greater supraspinal excitability (normalized MEP amplitude; MEP/CMEP) for the soleus muscle. These findings demonstrate a neuromechanical coupling following active muscle shortening and indicate that the underlying mechanisms of TD influence antagonist activation during voluntary force production. PMID- 30456695 TI - Production, Gene Cloning, and Overexpression of a Laccase in the Marine-Derived Yeast Aureobasidium melanogenum Strain 11-1 and Characterization of the Recombinant Laccase. AB - Aureobasidium melanogenum strain 11-1 with a high laccase activity was isolated from a mangrove ecosystem. Under the optimal conditions, the 11-1 strain yielded the highest laccase activity up to 3120.0 +/- 170 mU/ml (1.2 U/mg protein) within 5 days. A laccase gene (LAC1) of the yeast strain 11-1 contained two introns and encoded a protein with 570 amino acids and four conserved copper-binding domains typical of the fungal laccase. Expression of the LAC1 gene in the yeast strain 11 1 made a recombinant yeast strain produce the laccase activity of 6005 +/- 140 mU/ml. The molecular weight of the recombinant laccase after removing the sugar was about 62.5 kDa. The optimal temperature and pH of the recombinant laccase were 40 degrees C and 3.2, respectively, and it was stable at a temperature less than 25 degrees C. The laccase was inhibited in the presence of sodium dodecyl sulfate (SDS), ethylenediaminetetraacetic acid (EDTA), phenylmethanesulfonyl fluoride (PMSF), and DL-dithiothreitol (DTT). The Km and Vmax values of the laccase for 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) was 6.3 * 10-2 mM and 177.4 M/min, respectively. Many synthetic dyes were greatly decolored by the laccase. PMID- 30456696 TI - Production of Lipids and Proteome Variation in a Chilean Thraustochytrium striatum Strain Cultured under Different Growth Conditions. AB - Total lipids and docosahexaenoic acid (DHA) production by a Chilean isolated thraustochytrid were evaluated under different growth conditions in shake flasks. The analyzed strain was identified as Thraustochytrium striatum according to an 18S rRNA gene sequence analysis. The strain (T. striatum AL16) showed negligible growth in media prepared with artificial seawater at concentrations lower than 50% v/v and pH lower than 5. Maltose and starch were better carbon sources for growth than glucose. DHA content of the biomass grown with maltose (60 g L-1) was doubled by increasing the agitation rate from 150 to 250 rpm. The DHA (0.8-6%) and eicosapentaenoic acid (0.2-21%) content in the total lipids varied depending on culture conditions and culture age. Lipid and DHA concentration increased (up to 5 g L-1 and 66 mg L-1, respectively) by regularly feeding the culture with a concentrated starch solution. Carotenoid accumulation was detected in cells grown with maltose or starch. Contrasting conditions of starch and glucose cultures were selected for comparative proteomics. Total protein extracts were separated by two-dimensional gel electrophoresis; 25 spots were identified using ESI-MS/MS. A protein database (143,006 entries) for proteomic interrogation was generated using de novo assembling of Thraustochytrium sp. LLF1b - MMETSP0199_2 transcriptome; 18 proteins differentially expressed were identified. Three ATP synthases were differentially accumulated in cultures with glucose, whereas malate dehydrogenase was more abundant in cells cultured with starch. PMID- 30456697 TI - Neuroendocrine Liver Metastasis-a Specific Set of Markers to Detect Primary Tumor Sites. AB - The diagnosis of neuroendocrine neoplasia (NEN) is often made at an advanced stage of disease, including hepatic metastasis. At this point, the primary may still be unknown and sometimes cannot even be detected by functional imaging, especially in very small tumors of the pancreas (pan) and small intestinal (si) entities. The site of the primary may be based on biopsy specimens of the liver applying a specific set of markers. Specimens of liver metastases from 87 patients with NENs were studied. In retrospect, 50 patients had si and 37 pan NENs. Tissue samples were evaluated by immunohistochemistry. The markers applied were insulin gene enhancer protein Islet-1 (ISL-1), homeobox protein CDX-2 (CDX2), thyroid transcription factor 1 (TTF-1), and serotonin. Positive stains for CDX2 were documented in 43 (86%) and for serotonin in 45 (90%) of 50 siNENs. Three panNENs were positive for CDX2 and one for serotonin, respectively. ISL-1 was negative throughout in siNENs and also negative in 8 of 50 panNENs (21.6%). TTF-1 was negative in more than 90% of the specimens of either entity. Immunohistochemical markers in liver metastasis can lead the way to the site of the primary NEN. They should always be used in combined clusters. PMID- 30456698 TI - Role of Ca2+ as protectant under heat stress by regulation of photosynthesis and membrane saturation in Anabaena PCC 7120. AB - The present study was aimed at understanding the effects of heat stress on selected physiological and biochemical parameters of a model cyanobacterium, Anabaena PCC 7120 in addition to amelioration strategy using exogenous Ca2+. A comparison of the cells exposed to heat stress (0-24 h) in the presence or absence of Ca2+ clearly showed reduction in colony-forming ability and increase in reactive oxygen species (ROS) leading to loss in the viability of cells of Ca2+-deficient cultures. There was higher level of saturation in membrane lipids of the cells supplemented with Ca2+ along with higher accumulation of proline. Similarly, higher quantum yield (7.8-fold) in Ca2+-supplemented cultures indicated role of Ca2+ in regulation of photosynthesis. Relative electron transport rate (rETR) decreased in both the sets with the difference in the rate of decrease (slow) in Ca2+-supplemented cultures. The Ca2+-supplemented sets also maintained high levels of open reaction centers of PS II in comparison to Ca2+ deprived cells. Increase in transcripts of both subunits ((rbcL and rbcS) of RubisCO from Ca2+-supplemented Anabaena cultures pointed out the role of Ca2+ in sustenance of photosynthesis of cells via CO2 fixation, thus, playing an important role in maintaining metabolic status of the heat-stressed cyanobacterium. PMID- 30456699 TI - [Healthy life expectancy of older migrants and non-migrants in three European countries over time]. AB - We analysed differences in healthy life expectancy at age 50 (HLE50) between migrants and non-migrants in Belgium, the Netherlands, and England and Wales, and their trends over time between 2001 and 2011 in the latter two countries. Population, mortality and health data were derived from registers, census or surveys. HLE50 was calculated for non-migrants, western and non-western migrants by sex. We applied decomposition techniques to determine whether differences in HLE50 between origin groups and changes in HLE50 over time were attributable to either differences in mortality or health. The results show that in all three countries and among both sexes, older migrants, in particular those from non western origin, could expect to live fewer years in good health than older non migrants, mainly because of differences in self-rated health. Differences in HLE50 between migrants and non-migrants diminished over time in the Netherlands, but they increased in England and Wales. Improvements in HLE50 over time were mainly attributable to mortality decline. Interventions aimed at reducing the health and mortality inequalities between older migrants and non-migrants should focus on prevention, and target especially non-western migrants. PMID- 30456700 TI - Enhancement of nutrient removal performance of activated sludge with a novel hybrid biofilm process. AB - The aim of this study was to investigate the efficacy of a hybrid biofilm pilot scale treatment plant, designed with a novel configuration by the integration of a fixed-film system, to improve nitrogen removal. The pilot-scale system was established at a wastewater treatment plant in Istanbul and operated based on stream separation following a process consisting of Bio-P and primary sedimentation units in which carbonaceous compounds were entrapped/incorporated in settled biomass. The ammonia-rich supernatant was directed to a moving bed biofilm (MBBR) nitrification tank to obtain an efficient nitrification with the reduced organic loading after the primary sedimentation. The conventional activated sludge process, for which the net specific growth rate ([Formula: see text]) was measured to be 0.26 day-1 at 15 degrees C, exhibited a low nitrification capacity. However, the pilot-scale hybrid biofilm system secured nitrification performance up to 1.8 gN/m2/day ammonia loading, providing a competitive advantage over the conventional single sludge systems. The proposed hybrid configuration enables removal efficiencies of 80% and 85% for total nitrogen and phosphorus. It was possible to entrap organic matter by mixing 30% of return activated sludge (RAS) with raw wastewater. Simulation-based design study showed that the use of the hybrid biofilm system reduces the environmental footprint and aeration requirement of the nutrient removal by about 50% and 19%, respectively. Economic analyses highlighting the benefit of hybrid biofilm over conventional BNR system are illustrated. PMID- 30456701 TI - Helicobacter pylori Infection Does Not Impact on Lung Transplant Outcome. AB - BACKGROUND: Helicobacter pylori (HP) is a spiral, gram-negative, microaerophilic bacterium that colonises the human gastric mucosa and is associated with gastrointestinal and extragastrointestinal disorders. Since no data are yet available on HP infection in lung transplant patients, we evaluated the prevalence and impact of HP infection in a population of such patients. METHODS: Sixty-seven lung transplant patients were enrolled in the study (35 females and 32 males, age 48.4 +/- 13.3 years), 54 underwent bilateral and 13 single lung transplant. Serum antibodies against HP and CagA were assayed in all subjects. RESULTS: The prevalence of HP infection in lung transplant patients was similar to that in the general population (49.25% vs. 51.4%), whereas HP-positive patients showed lower CagA positivity (9% vs. 50.2%, p < 0.0001). There was a higher prevalence of HP infection in patients who underwent lung transplant because of pulmonary fibrosis (p = 0.049), and a lower prevalence in COPD patients (p = 0.011). No correlation was found between HP infection in lung transplant patients and graft outcome. No differences in primary graft dysfunction, acute rejection or bronchiolitis obliterans syndrome-free survival were found. However, more patients who required three or more post-transplant re hospitalisations were observed among HP-positive patients. CONCLUSIONS: The prevalence of HP infection in lung transplant patients was comparable to that of the general population and to that reported in heart and kidney transplant recipients. It did not seem to impact short-, mid- or long-term lung allograft outcome. H. pylori infection did not prove to be clinically relevant in lung transplant patients. PMID- 30456702 TI - Sirtuin 1 inhibits TNF-alpha-mediated osteoclastogenesis of bone marrow-derived macrophages through both ROS generation and TRPV1 activation. AB - Sirtuin 1 (SIRT1), also known as NAD-dependent deacetylase, has been reported to increase in vivo osteoclast-mediated bone resorption. However, its effects on osteoclastogenesis or bone loss in vitro have not been widely examined. Therefore, the effects and underlying mechanism of SIRT1 on osteoclast differentiation in mice in vitro were studied. During RANKL-induced osteoclastogenesis in differentiated bone marrow-derived macrophages (BMMs), SIRT1 downregulation was observed. The use of resveratrol (SIRT1 activator) and SIRT1 overexpression was found to inhibit osteoclastogenesis, which was confirmed by TRAP staining and activity loss, reduced expression of osteoclast markers and related genes, and a decrease in the number of multinuclear cells. In contrast, treatment with EX-527 (SIRT1 inhibitor) as well as SIRT1 silencing promoted osteoclastogenesis. Furthermore, the tumor necrosis factor (TNF)-alpha level was reduced by resveratrol treatment and SIRT1 overexpression but increased following EX-527 incubation and SIRT1 depletion. TNF-alpha silencing blocked the osteoclastogenesis of BMMs promoted by SIRT1 depletion. Moreover, transient receptor potential vanilloid 1 (TRPV1) channel activation and reactive oxygen species (ROS) production, which are associated with osteoclastogenesis, were impaired by TNF-alpha silencing. These data demonstrate that SIRT1 directly inhibits osteoclastogenesis by inhibiting ROS generation and TRPV1 channel activation under mediation of TNF-alpha. PMID- 30456703 TI - Processing without noticing in inattentional blindness: A replication of Moore and Egeth (1997) and Mack and Rock (1998). AB - Surreptitious online measures can reveal the processing of stimuli that people do not report noticing or cannot describe. People seem to glean everything from low level Gestalt grouping information to semantic meaning from unattended and unreported stimuli, and this information seems capable of influencing performance and of priming semantic judgments. Moore and Egeth (Journal of Experimental Psychology: Human Perception and Performance, 23, 339-352, 1997) provided evidence that judgments about the lengths of two lines were influenced by the grouping of background dots, even when subjects did not notice the pattern the dots formed. Mack and Rock (1998) reported that subjects could be primed to complete a stem with a word to which they were inattentionally blind. In this registered report, we replicated these two classic findings using large online samples (Ns = 260 and 448), finding support for the influence of grouping despite inattentional blindness, but not for word-stem priming. PMID- 30456704 TI - The Future of Maternal and Child Health. AB - INTRODUCTION: The purpose of this commentary is to start a national conversation about the future of maternal and child health (MCH). In the coming decades, we will have unprecedented opportunities to improve MCH, but will also face unprecedented threats. METHODS: This paper examines emerging opportunities and threats to MCH, and discusses strategies for leading the future of MCH. RESULTS: Scientific advancements will continue to drive improvements in MCH, but to unleash its full potential for improving population health future MCH research must become more transdisciplinary, translational, and precise. Technological innovations could dramatically transform our work in MCH while big data could enhance predictive analytics and precision health; our challenge will be to assure equitable access. The greatest gains in MCH will continue to come from improving social conditions, which will require advancing MCH in all policies. Climate change, infectious outbreaks and antimicrobial resistance pose increasing threats to MCH, which can be averted by reducing global warming, implementing global early warning systems, and instituting responsible antimicrobial stewardship. The growing burden of chronic diseases in children and adults need to be addressed from an ecological and life course perspective. The water crisis in Flint shined a spotlight on the growing health threats from America's decaying infrastructure. DISCUSSION: We can lead the future of MCH by starting a national conversation, improving MCH research, and preparing future MCH workforce, but the future of MCH will depend on our effectiveness in bringing about social and political change in the coming decades. PMID- 30456706 TI - Moonlighting by Psychiatry Residents: a Survey of Residents and Training Directors. AB - OBJECTIVE: This study sought to assess the prevalence of moonlighting among psychiatry residents; the perceived effects of moonlighting on resident recruitment, education, and liability; and policies and practices governing oversight. METHODS: In 2013, surveys were emailed to all general psychiatry residency programs that were accredited by the Accreditation Council for Graduate Medical Education and had available contact information (n = 183). Resident surveys were emailed to program coordinators with a request to forward the survey link to their residents. RESULTS: Responses were received from 63 program directors (34% response rate) and 238 residents (about 5% of total general psychiatry residents). Most psychiatry program directors (95%) indicated that their programs permit moonlighting. Moonlighting participation increased with each year of training, culminating with 67% of fourth year residents. Most residents and faculty (87%) agreed that moonlighting enhanced resident education. Thirty-seven percent of program directors reported having no oversight procedures in place to monitor moonlighting activities. Thirty-nine percent of resident survey responders reported having no supervision for at least one of their moonlighting activities and only 9% reported always having access to on-site supervision. CONCLUSION: Though limited by a low response rate, this study found that moonlighting seems to remain prevalent among psychiatry residents and widely accepted by psychiatry residency training programs. There appears to be relatively limited program oversight for moonlighting activities, many of which seem to lack close supervision. PMID- 30456705 TI - Genetics of Obesity in Diverse Populations. AB - PURPOSE OF REVIEW: The prevalence of obesity continues to rise, fueling a global public health crisis characterized by dramatic increases in type 2 diabetes, cardiovascular disease, and many cancers. In the USA, several minority populations, who bear much of the obesity burden (47% in African Americans and Hispanic/Latinos, compared to 38% in European descent groups), are particularly at risk of downstream chronic disease. Compounding these disparities, most genome wide association studies (GWAS)-including those of obesity-have largely been conducted in populations of European or East Asian ancestry. In fact, analysis of the GWAS Catalog found that while the proportion of participants of non-European or non-Asian descent had risen from 4% in 2009 to 19% in 2016, African-ancestry participants are still just 3% of GWAS, Hispanic/Latinos are < 0.5%, and other ancestries are < 0.3% or not represented at all. This review summarizes recent developments in obesity genomics in US minority populations, with the goal of reducing obesity health disparities and improving public health programs and access to precision medicine. RECENT FINDINGS: GWAS of populations with the highest burden of obesity are essential to narrow candidate variants for functional follow-up, to identify additional ancestry-specific variants that contribute to individual genetic susceptibility, and to advance both public health and precision medicine approaches to obesity. Given the global public health burden posed by obesity and downstream chronic conditions which disproportionately affect non-European populations, GWAS of obesity-related traits in diverse populations is essential to (1) locate causal variants in GWAS identified regions through fine mapping, (2) identify variants which influence obesity across ancestries through generalization, and (3) discover novel ancestry specific variants which may be low frequency in European populations but common in other groups. Recent efforts to expand obesity genomic studies to understudied and underserved populations, including AAAGC, PAGE, and HISLA, are working to reduce obesity health disparities, improve public health, and bring the promise of precision medicine to all. PMID- 30456707 TI - Spatial gradient and quantitative attribution of karst soil erosion in Southwest China. AB - Soil erosion estimation has attracted considerable attention from the scientific community and governments because of its importance to sustainable regional development. In karst areas, the heterogeneous environment and rocky desertification create difficulties in determining the influencing factors and spatial patterns of soil erosion. A quantitative analysis of karst soil erosion distribution was conducted by applying the revised soil loss equation model and the geographical detector method of attribution identification, which was based on spatial variance analysis. The results show that soil erosion was most severe in areas with an elevation of 1200-1800 m and intense anthropogenic activity. When the vegetation coverage was below 0.5-0.6, soil erosion showed characteristics of a source-limited regime and increased with the increasing vegetation coverage. When the vegetation coverage was higher than 0.5-0.6, soil erosion followed a transport-limited regime and decreased with the increasing vegetation coverage. The factor detector showed land use to be the dominant factor, explaining 51% of soil erosion distribution. Among various land use types, dry land had the greatest vulnerability to soil erosion. Slope served as a controlling factor at large scales, especially when combined with annual precipitation exceeding 1500 mm, and in dry and grassland areas. From the attribution analysis of multiple factors, the combination of land use and slope was the controlling interaction factor explaining 68% of soil erosion distribution. The methods and results of this research could serve as scientific references for decision makers and researchers exploring the characteristics of soil erosion to develop effective measures for its control. PMID- 30456708 TI - Application of a pixel-shifted linear interpolation technique for reducing the projection number in tomosynthesis imaging. AB - Tomosynthesis images are reconstructed from several projections. However, the number of projections is proportional to the exposure dose, and a reduction in the number of projections would result in a reduction of radiation dose to the patient but also degradation of image quality. The purpose of this study was to propose a new computerized method to supply interpolation images instead of real projection images for maintaining the number of projection images and image quality of reconstructed tomosynthesis images. A set of images comprising one half the number of projection images [37 projections (Half set)], selected from the original full set of projection images [73 projections (Full set)], was used at an interval of one by one. In this study, the authors used a new linear interpolation technique (Shift-Linear method), which takes into account shifted distances between two corresponding pixels on two projection images. The image quality of tomosynthesis images reconstructed from the full set and the quasi full projection images, which were produced from the Half set using the Shift Linear method, was compared. Image quality was assessed in terms of modulation transfer function, noise power spectrum, contrast-to-noise ratio, and the detective quantum efficiency. Using this proposed method, the image quality of reconstructed tomosynthesis images could be maintained with the reduction of approximately 50% exposure dose. PMID- 30456709 TI - Treatment of the primary tumor in metastatic prostate cancer. AB - The cornerstone of treatment for metastatic prostate cancer patients has been conventional androgen deprivation therapy, with additional systemic therapy initiated only after castration resistance, and local therapy reserved for palliation. Compelling results from modern trials challenge this paradigm, arguing for initiating escalated hormone therapy and/or chemotherapy during the castration-sensitive disease state for many patients. Furthermore, modern radiotherapy techniques allow for local control of disease with low risk of toxicity. Finally, new PET probes with enhanced sensitivity and accuracy are likely to become a part of routine staging and will lead to an increased incidence of patients with metastatic disease at presentation, with a shift toward identification of patients with limited metastatic disease. As such, the landscape is primed for investigations aimed to explore the role of primary tumor therapy for patients with metastatic prostate cancer. We review the existing data evaluating primary tumor therapy for patients with metastatic prostate cancer and describe ongoing clinical trials testing the hypothesis that primary tumor therapy may benefit patients with metastatic prostate cancer. PMID- 30456710 TI - Visceral obesity in Asian living kidney donors significantly impacts early renal function after donor nephrectomy. AB - INTRODUCTION: Obesity may be a risk factor for kidney donors to develop reduced renal function. The Framingham heart study suggested that visceral adipose tissue (VAT) confers a more adverse metabolic profile compared with subcutaneous adipose tissue (SAT). Asians tend to have a higher VAT composition and it is unclear if their kidney function is affected differently. We hypothesized that Asian living kidney donors who have visceral obesity are at a higher risk of renal function deterioration 1 year after donation. METHODS: Between 2011 and 2014, we retrospectively evaluated data from 73 consecutive patients (52% male; mean age 44.9 +/- 11.7 years) before they underwent donor nephrectomy and at their 1 year routine follow-up. VAT and SAT were measured at the level of the umbilicus on pre operative computerized tomography (CT). Visceral obesity (VO) was defined as a VAT > 100 cm [2] and patients were then further divided and compared in two subgroups: VAT > 100 and < 100 cm [2]. Estimated glomerular filtration rate (eGFR, mL/min per 1.73 m [2]) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation pre-operatively and 1 year post operatively. RESULTS: Both subgroups had similar baseline kidney function (P = NS) pre-operatively. At the 1 year follow-up, patients with VO experienced a more significant decline of renal function (109 +/- 9 to 89 +/- 8 mL/min per 1.73 m2), compared to those without VO (111 +/- 12 to 96 +/- 11 mL/min per 1.73 m2, P = 0.013). VO was associated with a body mass index (BMI) > 25 kg/m2 (P < 0.001), male gender (P < 0.001) and older age at the time of donor nephrectomy (48.0 vs 39.5 years, P = 0.01). The presence of hypertension or hyperlipidaemia pre operatively, choice of surgical approach, and post-operative complication rates, did not differ significantly between the subgroups. CONCLUSIONS: Visceral obesity as defined by VAT > 100 cm2 at the level of the umbilicus on cross-sectional imaging, may have a significant impact on early renal function after donor nephrectomy. Adiposity markers, as measured by cross-sectional CT imaging, may be incorporated into routine pre-operative kidney donor workup. PMID- 30456711 TI - Female urethroplasty: contemporary thinking. AB - PURPOSE: Female urethral stricture disease is a rare entity. To date, its diagnosis and treatment have been poorly studied, with small numbers, and variable definitions of success. With growing interest in this area of reconstructive urology, there is an increased number of surgical techniques. In this article, we review current trends, definitions, etiologies and surgical techniques available for management of FUSD. METHOD: We completed a review of publications in: English; Pubmed, and Google scholar. Key words identified for review were, female urethra stricture, female urethroplasty and female urethral dilation, female pelvic fracture, and female urethral reconstruction. Papers were reviewed, and references of relevant papers reviewed. RESULTS: Iatrogenic injury is the most common cause of female urethral stricture disease. Assessment requires a thorough patient history, examination and either flexible cystoscopy and/or fluoroscopic urodynamics to determine the most appropriate surgical approach for stricture repair. Multiple open urethroplasty techniques are described with various grafts and flaps, with good medium-term success. Minimally invasive techniques remain well-employed but have poor long-term success, with increased failure with multiple attempts at treatment. CONCLUSION: Female urethral stricture disease is a complex clinical entity that requires a measured and thorough evaluation. Individualized approach should be undertaken reviewing the patient's symptoms, the stricture's etiology, surrounding vaginal tissue health and stricture location. Promising medium-term success rates with vaginal flaps and buccal mucosal graft urethroplasty have been reported, with disappointing long-term results from repeated urethral dilation. Further research comparing techniques and defining successful long-term outcomes is required. PMID- 30456712 TI - Neuronopathic Gaucher disease presenting with microcytic hypochromic anemia. AB - Gaucher disease (GD) is caused by a hereditary deficiency of glucocerebrosidase, resulting in accumulation of glucosylceramide and potentially manifesting as hepatosplenomegaly. We report the case of a 15-month-old boy with chronic neuronopathic GD. The patient had prolonged anemia despite continued iron supplementation for 3 months. White blood count (WBC), hemoglobin (Hb), platelet count, and corrected reticulocyte count were 3,300 /uL, 8.7 g/dL, 90,000 /uL, and 0.55, respectively. The patient had microcytic hypochromic anemia with mildly elevated ferritin. Physical examination revealed hepatosplenomegaly. Bone-marrow aspiration showed sheets of Gaucher cells. Glucocerebrosidase activity in monocytes was significantly lower than normal. Genetic analysis revealed a homozygous L444P mutation of GBA, and he was diagnosed with type 1 GD. Enzyme replacement treatment (ERT) consisting of imiglucerase was initiated and was effective; WBC, Hb, and platelet count gradually normalized and the hepatosplenomegaly improved. However, when the patient entered elementary school, he showed mild impaired cognitive function, and supranuclear gaze palsy occurred the same year. He was ultimately diagnosed with type 3 GD and continued ERT. Pediatric hemato-oncologists should be aware of GD, especially when patients exhibit anemia refractory to iron therapy, radiologic bone deformity, neurologic signs or symptoms, and growth retardation. PMID- 30456713 TI - Appraisal of patient-reported outcome measures in analogous diseases and recommendations for use in phase II and III clinical trials of pyruvate kinase deficiency. AB - PURPOSE: Pyruvate kinase deficiency (PKD) is a rare disease and understanding of its epidemiology and associated burden remains limited. With no current curative therapy, clinical manifestations can be life threatening, clinically managed by maintaining adequate hemoglobin levels through transfusion and subsequent support, but with frequent complications. Treatment goals are to maintain/improve the patient's quality of life. With new therapies, reliable, valid, and relevant patient-reported outcome (PRO) tools are required for use in clinical trials. METHODS: Systematic literature search identified no current PRO tools for capturing/measuring the impact of PKD and treatments in clinical trials. Therefore, the search strategy was revised to consider conditions analogous to PKD in terms of symptoms and impacts that might serve as parallels to the experience in PKD; this included sickle cell anemia, thalassemia, and hemolytic anemia. Psychometric properties, strengths, and weakness of selected appropriate PRO instruments were compared, and recommendations made for choice of PRO tools. RESULTS: In adult populations, EORTC QLQ C30 and SF-36v2 are recommended, the former being a basic minimum, covering generic HRQoL, and core symptoms such as fatigue. In pediatric populations, PedsQL Generic Core Scale to measure HRQoL and PedsQL MFS scale to measure fatigue are recommended. CONCLUSIONS: Some symptoms/life impacts may be unique to PKD and not observable in analogous conditions. A 'Physico-Psychosocial Model' derived from the 'Medical Model' is proposed to form the basis for a hypothesized conceptual framework to address the development of PKD-specific PRO instruments. PMID- 30456714 TI - Interpretation and use of patient-reported outcome measures through a philosophical lens. AB - PURPOSE: As patient-reported outcome measures (PROMs) increasingly become key outcome indicators in health care, there has been growing concern about the potential negative consequences that could result when interpretations are being made to inform clinical and policy decisions. Therefore, we explored theoretical issues, assumptions, and consequences of using PROMs from a philosophical point of view. METHODS: Our analysis of the literature was informed by Gadamerian hermeneutics, which emphasizes the dialectical processes that occur during interpretation, to provide insights as to how different users interpret and use standardized questions about health and quality of life. RESULTS: We structured our consideration according to three tenets of using PROMs: (1) the use of PROMs involves the interpretation of contextual elements; (2) interpretation of PROMs is an ongoing dialectical interaction; and (3) the use of PROMs involves openness and reflexivity. These findings suggest that hermeneutics provides a useful approach to examining the complexities of measuring patient-reported outcomes by attending to the perspectives of different users (e.g., patients, clinicians, administrators, and policy-makers) at the micro-, meso-, and macro-levels and the broader socio-historical and economic situation. CONCLUSION: Because PROMs can have different meanings and are used for different purposes, we propose that hermeneutics be used as a lens to ask reflexive questions about the problems of measurement and open a pluralistic dialogue with respect to the way we use PROMs and the interpretations we make of the findings that derive from our studies. PMID- 30456715 TI - Rasch validation of the Danish version of the shoulder pain and disability index (SPADI) in patients with rotator cuff-related disorders. AB - PURPOSE: The psychometric properties of the shoulder pain and disability index (SPADI) have been extensively evaluated using classical test theory, but very few studies have applied Rasch analysis. The purpose of this study was to validate the Danish version using Rasch analysis. METHODS: Responses to the SPADI from 229 patients (48% female, mean age 54.5) were included in the Rasch analysis. Overall fit, individual item fit, local response dependence, dimensionality, targeting, reliability, and differential item functioning (DIF) were examined. RESULTS: After iterative analyses, good fit to the Rasch model was observed, with acceptable targeting and uni-dimensionality. SPADI should be reported as two separate subscales: Pain and Functional Disability. The pain subscale initially demonstrated misfit due to local dependence and DIF, but a log linear Rasch model showed good fit to the Rasch model with acceptable targeting and uni dimensionality. A six-item version of the disability subscale exhibited adequate fit in the Danish version. The same items were also found to fit the Rasch model in the English version. CONCLUSIONS: The measurement properties of the Danish SPADI are similar to those of the English version. SPADI should be reported as two separate subscales. For the pain subscale, DIF with respect to age was disclosed, but the impact was small. The eight-item disability subscale did not fit the Rasch model. A six-item version of the disability subscale exhibited adequate fit in the Danish version. The same items were also found to fit the Rasch model in the English version. PMID- 30456716 TI - How depressed is "depressed"? A systematic review and diagnostic meta-analysis of optimal cut points for the Beck Depression Inventory revised (BDI-II). AB - INTRODUCTION: The Beck Depression Inventory revised (BDI-II) is widely used tool to screen for depression. The aim of the present study was to systematically review and synthesize studies that determined optimal cut points for the BDI-II. METHOD: We identified 27 studies that tried to identify optimal cut points for the BDI-II. Study quality was assessed using QUADAS criteria. Cut points and their variability were analyzed descriptively, via simulation and synthesized with a diagnostic meta-analysis. Analysis was performed on all studies and subgroups based on the setting (psychiatric, somatic, healthy). RESULTS: Cut points identified as optimal ranged from 10 to 25 across all studies. Simulation based estimations of the variability inherent in studies show that much of the between-study differences may be attributed to random fluctuations. Diagnostic meta-analysis across all studies revealed that a cut point of 14.5 (95% CI 12.75 16.44) is optimal, yielding a sensitivity of 0.86 and a specificity of 0.78. Analyses within the different settings suggest using sample-specific cut points, specifically 18.18 in psychiatric settings, and 12.9 in primary care settings and healthy populations. CONCLUSION: Most studies aimed at determining optimal cut points fail to acknowledge that reported results are only estimates and subject to random fluctuations resulting in conflicting recommendations for practitioners. Taking into account these fluctuations, we find that practitioners should use different cut points to screen for depression in primary care and healthy populations (a score of 13 and higher indicates depression) and psychiatric settings (a score of 19 and higher indicates depression). Methods to describe this variability and meta-analysis to synthesize findings across studies should be used more widely. PMID- 30456717 TI - Loci and candidate genes in soybean that confer resistance to Fusarium graminearum. AB - KEY MESSAGE: Association analysis techniques were used to identify and verify twelve single nucleotide polymorphisms (SNPs) associated with Fusarium graminearum resistance. Two novel candidate genes were obtained. Fusarium graminearum causes seed and root rot and seedling damping-off of soybean, leading to severe yield loss. Presently, the genetic basis of resistance to F. graminearum is elucidated in only four soybean accessions, which is not sufficient for resistance improvement. The objective of the present study was to identify the genome-wide genetic architecture of resistance to F. graminearum in landraces and cultivated soybeans based on a growth room evaluation. The resistance levels of 314 diverse accessions were tested, and 22,888 single nucleotide polymorphisms (SNPs) with a minor allele frequency of > 0.05 were developed using the specific-locus amplified fragment sequencing (SLAF-seq) approach. Twelve SNPs were identified as associated with F. graminearum resistance, and these SNPs were located at 12 genomic regions on eight chromosomes (Chr.) and could explain 5.53-14.71% of the observed phenotypic variation. One SNP, rs9479021, located on Chr.6, overlapped with qRfg_Gm06, the known QTL for resistance to F. graminearum. The other SNPs were novel and associated with resistance to F. graminearum. Nine novel candidate genes were predicted to contribute to resistance to F. graminearum according to the haplotype and transcript abundance analysis of the candidate genes. The identified markers and resistant cultivars are valuable for the improvement of resistance to F. graminearum. PMID- 30456718 TI - Dissecting the genetics underlying the relationship between protein content and grain yield in a large hybrid wheat population. AB - KEY MESSAGE: Additive and dominance effect QTL for grain yield and protein content display antagonistic pleiotropic effects, making genomic selection based on the index grain protein deviation a promising method to alleviate the negative correlation between these traits in wheat breeding. Grain yield and quality related traits such as protein content and sedimentation volume are key traits in wheat breeding. In this study, we used a large population of 1604 hybrids and their 135 parental components to investigate the genetics and metabolomics underlying the negative relationship of grain yield and quality, and evaluated approaches for their joint improvement. We identified a total of nine trait associated metabolites and show that prediction using genomic data alone resulted in the highest prediction ability for all traits. We dissected the genetic architecture of grain yield and quality-determining traits and show results of the first mapping of the derived trait grain protein deviation. Further, we provide a genetic analysis of the antagonistic relation of grain yield and protein content and dissect the mode of gene action (pleiotropy vs linkage) of identified QTL. Lastly, we demonstrate that the composition of the training set for genomic prediction is crucial when considering different quality classes in wheat breeding. PMID- 30456719 TI - Palliative care after stroke. AB - Stroke is the leading cause of disability and one of the most common reasons of death around the world. Information is not sufficient on the palliative care (PC) needs of stroke patients and factors affecting their prognosis. In this study, we have investigated the demographics and comorbidities of stroke patients followed up in a PC center (PCC), and the factors efficient on their prognosis. Medical records of 132 patients followed-up in PCC with stroke diagnosis between years 2016 and 2017 were reviewed retrospectively. Patients diagnosed with stroke were grouped as ischemic stroke, intracerebral hematoma (ICH) and subarachnoid hemorrhage (SAH). Age, gender, PCC hospitalization period (LOS), Glasgow Coma Scale, comorbidities such as percutaneous endoscopic gastrostomy, tracheostomy, pressure ulcer (PU), and discharge status (home, intensive care unit, exitus) have been compared for the patients included in the study. While average age was 72.41 +/- 16.03 and hospitalization period was 35.47 +/- 36.13 days, 92 patients (69.7%) were diagnosed with ischemic stroke, 20 patients (15.2%) with ICH, and 20 patients (15.2%) were diagnosed with SAH. The rate of exitus in patients diagnosed with ischemic stroke was significantly higher than patients diagnosed with ICH and SAH (p = 0.02), and hypertension rate was higher in patients with ischemic stroke than patients diagnosed with SAH (p = 0.007). The age of patients with exitus were found to be significantly higher (p = 0.001). Length of stay (LOS) in PC was determined to be significantly higher in patients with tracheostomy and patients diagnosed with ICH compared to patients with SAH. Furthermore, PU rate was significantly higher in patients diagnosed with ICH than patients with SAH (p = 0.007). Patients who experienced stroke and their families need comprehensive palliative care for psychosocial support, determination of patient-focused care objectives, and symptom management. There is a need for studies on larger populations to eliminate prognostic uncertainties and provide successful symptom management in patients following stroke. PMID- 30456720 TI - Prevalence of shoulder morbidity after treatment for breast Cancer in South Africa. AB - PURPOSE: Breast cancer is the most frequently diagnosed cancer and leading cause of cancer death among women, representing a considerable public health burden in South Africa and other low-middle income countries. Short- and long-term complications of these treatments include shoulder morbidities such as pain, decreased range of motion, tightness, weakness, pain, numbness and lymphoedema and may be present for up to 6 years post-treatment. An understanding of baseline demographic and clinical risk factors can guide rehabilitation and management strategies for high-risk patients. The aims of this study were to quantify the burden of shoulder pain and disability in a tertiary academic hospital in Cape Town, South Africa, and identify potential risk factors for the development of shoulder morbidity. METHODS: This study was a cross-sectional analysis of the prevalence of shoulder pain and dysfunction in women attending their post treatment annual follow-up visit for unilateral breast carcinoma. RESULTS: Three in four patients reported a presence of any pain or disability while only 9% experienced severe pain and disability. Multivariable ordinal logistic regression analysis identified race, side, axillary surgery, chemotherapy and age as significant predictors of pain and chemotherapy a significant predictor of disability. CONCLUSION: The substantial burden of shoulder morbidity in this population represents a significant public health burden. The use of identified clinical and demographic characteristics may guide in the development of survivorship programmes incorporating surveillance and management of these high risk patients. PMID- 30456721 TI - Association of SHMT1, MAZ, ERG, and L3MBTL3 Gene Polymorphisms with Susceptibility to Multiple Sclerosis. AB - Multiple sclerosis (MS) is the most common inflammatory and chronic disease of the central nervous system (CNS). A complex interaction between genetic, environmental, and epigenetic factors is involved in the pathogenesis of MS. With the advancement of GWAS, various variants associated with MS have been identified. This study aimed to evaluate the association of single-nucleotide polymorphisms (SNPs) rs4925166 and rs1979277 in the SHMT1, MAZ rs34286592, ERG rs2836425, and L3MBTL3 rs4364506 with MS. In this case-control study, the association of five SNPs in SHMT1, MAZ, ERG, and L3MBTL3 genes with relapsing remitting MS (RR-MS) was investigated in 190 patients and 200 healthy individuals. Four SNPs including SHMT1 rs4925166, SHMT1 rs1979277, MAZ rs34286592, and L3MBTL3 rs4364506 were genotyped using PCR-RFLP and genotyping of ERG rs2836425 was performed by tetra-primer ARMS PCR. Our findings showed a significant difference in the allelic frequencies for the four SNPs of SHMT1 rs4925166, SHMT1 rs1979277, MAZ rs34286592, and ERG rs2836425, while there were no differences in the allele and genotype frequencies for L3MBTL3 rs4364506. These significant associations were observed for the following genotypes: TT and GG genotypes of SHMT1 rs4925166 (OR 0.47 and 1.90, respectively) genotype GG of SHMT1 rs1979277 (OR 0.63), genotype GG of MAZ rs34286592 (OR 0.61), TC and CC genotypes of ERG rs2836425 (OR 1.89 and 0.50, respectively). Our study highlighted that people who are carrying genotypes including GG (SHMT1 rs4925166) and TC (ERG rs2836425) have the highest susceptibility chance for MS, respectively. However, genotypes TT (SHMT1 rs4925166), CC (ERG rs2836425), GG (MAZ rs34286592), and GG (SHMT1 rs1979277) had the highest negative association (protective effect) with MS, respectively. L3MBTL3 rs4364506 was found neither as a predisposing nor a protective variant. PMID- 30456722 TI - Tetrastischus howardi density and dispersal toward augmentation biological control of sugarcane borer. AB - The number of Tetrastischus howardi (Olliff) females to be released and their dispersion should be known, that way, used D. saccharalis pupae as sentinel host to measure parasitism as function of the release density of the parasitoid and its location in the field. Two sets of trials were run aiming first to define the number of parasitoids to be released and the dispersal of the parasitoid using plots in sugarcane commercial fields, respectively. Pieces of sugarcane stalk holding sentinel pupae were taken to the field and exposed to parasitism in both trials. The parasitoid was released at the rate of 20, 40, 80, and 160 females per sentinel pupa, except for the control plot without releasing. The parasitism rate was calculated based on the recovered pupae after 96 h of exposure time from releasing the parasitoids. The models estimated the best parasitism rate by releasing 102 parasitoids per pupa. In the second trial, sentinel pupae were arranged in five subsequent circles corresponding 4, 8, 12, 16, and 20 m around the central parasitoid releasing point at rate of 4, 8, 12, 16, and 18 pupae per circle. The mean estimated dispersal distance was 7.64 m, with a covering area of 80.07 m2. Based on these findings, release of T. howardi is recommended in 125 points per hectare of sugarcane at rate of 102 females per pupa of the pest aiming to achieve homogeneous distribution and parasitism. PMID- 30456723 TI - A case of gossypiboma diagnosed with transanal double-balloon enteroscopy. AB - Gossypiboma is an iatrogenic granuloma caused by retained surgical gauze. A 48 year-old woman with a history of cesarean section was incidentally found to have a pelvic mass on preoperative computed tomography examination for pectus excavatum. Abdominal enhanced computed tomography showed a 40-mm mass containing air in the pelvis. The mass was suspected to be continuous with the ileum. Transanal double-balloon enteroscopy showed a small fistula that was likely caused by penetration of the ileum dozens of centimeters from the ileocecal valve. A yellow-brown, movable, and fibrous body was found in the fistula. A part of the fibrous body was extracted with forceps. Pathological examination revealed that it was gauze. This is the first reported case of an asymptomatic gossypiboma penetrating the ileum that was diagnosed with double-balloon enteroscopy. Our results suggest that double-balloon enteroscopy is useful for early diagnosis of pelvic mass penetrating intestine, including gossypiboma. PMID- 30456724 TI - Comparison between novel and standard high-density 3D electro-anatomical mapping systems for ablation of atrial tachycardia. AB - Ultra-high-density mapping allows very accurate characterization of circuits/mechanisms in atrial tachycardia (AT). Whether these advantages will translate into a better procedural or long-term clinical outcome is unknown. Sixty consecutive AT ablation procedures using ultra-high-density mapping (RhythmiaTM, group 1) were retrospectively compared to 60 consecutive procedures using standard high-density mapping (Carto/NavXTM, group 2) (total 209 AT, 79% left AT). A higher number of maps were performed in group 1 (4.8 +/- 2.5 vs 3.2 +/- 1.7, p = 0.0001) with similar acquisition duration (12 +/- 5 vs 13 +/- 6 min per map, p = ns), although with a greater number of activation points (10,543 +/- 5854 vs 689 +/- 1827 per map, p < 0.0001). AT location remained undetermined in 5 AT in group 1 vs 10 (p = 0.1). Mechanism remained undetermined in 5 AT from group 1 vs 11 (p = 0.06). Acute complete success was achieved in 77%, in both groups. At 1-year follow-up, AT recurred in 37% in group 1 vs 50% in group 2 (p = 0.046). There are less long-term recurrences after AT ablation using ultra-high-density mapping system compared to standard high-density 3D mapping, possibly because of a better comprehensive approach of AT mechanisms. PMID- 30456725 TI - Acculturation and Postpartum Depression Among Immigrant Women of Arabic Descent. AB - Acculturation has been related to risk of postpartum depression (PPD) among immigrant women globally. The purpose of this study was to examine the relationship between acculturation and PPD symptoms among U.S. immigrant women of Arabic descent. A cross-sectional study was conducted with 115 postpartum immigrant women of Arabic descent. Women completed questionnaires including measures of acculturation [attraction to Arabic culture (AArC), attraction to American culture (AAmC), marginalization] and PPD symptoms (Edinburgh Postnatal Depression Scale-EPDS) between 1 and 12 months postpartum. Twenty-five percent of women (n = 29) had EPDS scores >= 10 that represent PPD symptoms. Women with higher marginalization reported more PPD symptoms (r = .25, p = .008). None of the acculturation factors correlated with PPD symptoms after adjustment for maternal sociodemographic and health characteristics. Higher education (p = .001), lower gestational age at birth (p < .05), and antenatal anxiety (p < .05) were correlated with PPD symptoms in multivariate analyses. Health care providers should identify and assess immigrant women of Arabic descent for antenatal anxiety as this may identify women at risk for development of PPD symptoms. Future studies need to examine acculturation in relation to mental health among immigrant women of Arabic descent. PMID- 30456726 TI - FRAX(r) based intervention thresholds for management of osteoporosis in Singaporean women. AB - : Potential FRAX(r)-based major osteoporotic fracture (MOF) and hip fracture (HF) intervention thresholds (ITs) for postmenopausal Singaporean women were explored. Age-dependent ethnic-specific and weighted mean ITs progressively increased with increasing age. Fixed ITs were derived via discriminatory value analysis. MOF and HF ITs with highest the Youden index were chosen as optimal. INTRODUCTION: We aimed to explore FRAX(r)-based intervention thresholds (ITs) to potentially guide osteoporosis treatment in Singapore, a multi-ethnic nation. METHOD: One thousand and one Singaporean postmenopausal community-dwelling women belonging to Chinese, Malay and Indian ethnicities underwent clinical risk factor (CRF) and BMD assessment. FRAX(r) major osteoporotic fracture (MOF) and hip fracture (HF) probabilities were calculated using ethnic-specific models. We employed the translational logic adopted by NOGG (UK), whereby osteoporosis treatment is recommended to any postmenopausal woman whose fracture probability based on other CRFs is similar to or exceeds that of an age-matched woman with a fracture. Using the same logic, ethnic-specific and mean weighted age-dependent ITs were computed. Employing these age-dependent ITs as a reference, the performance of fixed (age-independent) ITs were examined using ROC curves and discriminatory analysis, with the highest Youden index (YI) (sensitivity + specificity - 1) used to identify the optimal MOF and HF ITs. RESULTS: The mean age was 58.9 (6.9) years. Seven hundred and eighty-nine (79%) women were Chinese, 136 (13.5%) Indian and 76 (7.5%) Malay. Age-dependent MOF ITs ranged from 3.1 to 33%, 2.5 to 17% and 2.5 to 16% whilst HF ITs ranged from 0.7 to 17%, 0.4 to 6% and 0.4 to 6.3% in Chinese, Malay and Indian women, respectively, between the ages of 50 and 90 years. The weighted age-dependent MOF and HF ITs ranged from 2.9% and 0.6%, respectively, at the age of 50, to 28% and 14% at 90 years of age. Fixed MOF/HF ITs of 5.5%/1%, 2.5%/1% and 2.5%/0.25% were identified as the most optimal by the highest YI in Chinese, Malay and Indian women, respectively. Fixed MOFP and HF ITs of 4% and 1%, respectively, were found to be most optimal on the weighted means analysis. CONCLUSION: The ITs for osteoporosis treatment in Singapore show marked variations across ethnicities. Weighted mean thresholds may overcome the dilemma of intervening at different thresholds for different ethnicities. Choosing fixed ITs may have to involve trade-offs between sensitivity and specificity. FRAX(r)-based age-dependent or the fixed intervention thresholds suggested as an alternative to be considered for use in Singapore though further studies on the societal and health economic impacts of choosing these thresholds in Singapore are needed. PMID- 30456727 TI - The Contribution of Poliomyelitis to President Roosevelt's Heart Failure. A Lesson on the Importance of Vaccinations for Cardiovascular Prevention. PMID- 30456728 TI - Cardiovascular and mortality events in type 2 diabetes cardiovascular outcomes trials: a systematic review with trend analysis. AB - AIMS: To investigate cardiovascular disease and mortality trends in control arm participants of diabetes cardiovascular outcome trials (CVOTs). METHODS: We electronically searched CVOTs published before October 2017. Data on all-cause mortality, cardiovascular mortality and events, and baseline characteristics were collected, along with study calendar years. Trends were estimated using negative binomial regressions and reported as rate ratio (RR) per 5-year intervals. RESULTS: 26 CVOTs, conducted from 1961 to 2015, included 86788 participants with 6543 all-cause deaths, 3265 cardiovascular deaths, and 7657 3-point major adverse cardiovascular events (3-P MACE; combined endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke). In unadjusted analysis, there was an increasing trend for 3-P MACE rates over time (5-year RR 1.57; 95% CI 1.34, 1.84); a small increasing trend for cardiovascular disease mortality rates (1.13; 1.01, 1.26); and stable rates for all-cause death. Adjusting for age, sex, previous myocardial infarction, and diabetes duration, there was no evidence of trends for 3-P MACE or cardiovascular disease mortality rates, while reducing rates were observed for nonfatal myocardial infarction (5-year RR: 0.72; 0.54, 0.96), total stroke (0.76; 0.66, 0.88), and nonfatal stroke (0.60; 0.43, 0.82). CONCLUSIONS: In contrast to real-world data, there was no evidence of an improvement in all-cause and cardiovascular mortality in type 2 diabetes participants included in control arms of randomised clinical trials across 5 decades. Further studies should investigate whether and how dissimilarities in populations, procedures, and assessments of exposures and outcomes explain the differences between real-world setting and clinical trials. PMID- 30456729 TI - Time-Compressed Speech Identification Is Predicted by Auditory Neural Processing, Perceptuomotor Speed, and Executive Functioning in Younger and Older Listeners. AB - Older adults typically have difficulty identifying speech that is temporally distorted, such as reverberant, accented, time-compressed, or interrupted speech. These difficulties occur even when hearing thresholds fall within a normal range. Auditory neural processing speed, which we have previously found to predict auditory temporal processing (auditory gap detection), may interfere with the ability to recognize phonetic features as they rapidly unfold over time in spoken speech. Further, declines in perceptuomotor processing speed and executive functioning may interfere with the ability to track, access, and process information. The current investigation examined the extent to which age-related differences in time-compressed speech identification were predicted by auditory neural processing speed, perceptuomotor processing speed, and executive functioning. Groups of normal-hearing (up to 3000 Hz) younger and older adults identified 40, 50, and 60 % time-compressed sentences. Auditory neural processing speed was defined as the P1 and N1 latencies of click-induced auditory-evoked potentials. Perceptuomotor processing speed and executive functioning were measured behaviorally using the Connections Test. Compared to younger adults, older adults exhibited poorer time-compressed speech identification and slower perceptuomotor processing. Executive functioning, P1 latency, and N1 latency did not differ between age groups. Time-compressed speech identification was independently predicted by P1 latency, perceptuomotor processing speed, and executive functioning in younger and older listeners. Results of model testing suggested that declines in perceptuomotor processing speed mediated age-group differences in time-compressed speech identification. The current investigation joins a growing body of literature suggesting that the processing of temporally distorted speech is impacted by lower-level auditory neural processing and higher level perceptuomotor and executive processes. PMID- 30456730 TI - Speech Perception with Spectrally Non-overlapping Maskers as Measure of Spectral Resolution in Cochlear Implant Users. AB - Poor spectral resolution contributes to the difficulties experienced by cochlear implant (CI) users when listening to speech in noise. However, correlations between measures of spectral resolution and speech perception in noise have not always been found to be robust. It may be that the relationship between spectral resolution and speech perception in noise becomes clearer in conditions where the speech and noise are not spectrally matched, so that improved spectral resolution can assist in separating the speech from the masker. To test this prediction, speech intelligibility was measured with noise or tone maskers that were presented either in the same spectral channels as the speech or in interleaved spectral channels. Spectral resolution was estimated via a spectral ripple discrimination task. Results from vocoder simulations in normal-hearing listeners showed increasing differences in speech intelligibility between spectrally overlapped and interleaved maskers as well as improved spectral ripple discrimination with increasing spectral resolution. However, no clear differences were observed in CI users between performance with spectrally interleaved and overlapped maskers, or between tone and noise maskers. The results suggest that spectral resolution in current CIs is too poor to take advantage of the spectral separation produced by spectrally interleaved speech and maskers. Overall, the spectrally interleaved and tonal maskers produce a much larger difference in performance between normal-hearing listeners and CI users than do traditional speech-in-noise measures, and thus provide a more sensitive test of speech perception abilities for current and future implantable devices. PMID- 30456731 TI - Hydrogen Sulfide Protects Hippocampal Neurons Against Methamphetamine Neurotoxicity Via Inhibition of Apoptosis and Neuroinflammation. AB - Methamphetamine (METH) known as a highly neurotoxic compound associated with irreversible brain cell damage that results in neurological and psychiatric abnormalities. The mechanisms of METH intoxication mainly involve intraneuronal events including oxidative stress, excitotoxicity, and dopamine oxidation. Based on recent studies, H2S can protect neurons through anti-inflammatory, antioxidant, and antiapoptotic mechanisms. Therefore, we aimed to study the effects of protection of H2S against METH neurotoxicity. The 72 male Wistar rats were randomly allocated into six groups: control (n, 12), H2S (n, 12), METH (n, 12), METH + H2S 1 mg/kg (n, 12), METH + H2S 5 mg/kg (n, 12), and METH + H2S 10 mg/kg (n, 12) groups, (NaHS as a H2S donor; 1, 5, 10 mg/kg). METH neurotoxicity was induced by 40 mg/kg of METH in four intraperitoneal (IP) injections (e.g., 4 * 10 mg/kg q. 2 h, IP). NaHS was administered at 30 min, 24 h, and 48 h after the final injection of METH. Seven days after METH injection, the brains were removed for biochemical assessments, glial fibrillary acidic protein (GFAP), and caspase 3 immunohistochemistry staining. H2S treatment could significantly increase both superoxide dismutase and glutathione (P < 0.01), and a reduction was observed in malondialdehyde (P < 0.05) and TNF-alpha (P < 0.01) versus the METH group. Moreover, H2S could significantly decrease caspase-3 and GFAP-positive cells in the CA1 region of the hippocampus (P < 0.01) compared to the METH group. According to the findings, H2S makes significant neuroprotective impacts on METH neurotoxicity due to its antioxidant and anti-inflammatory activities. PMID- 30456732 TI - Revised reference curves of bone mineral density according to age and sex for Iranian children and adolescents. AB - : Bone health evaluation in children requires an appropriate reference database. We have shown higher curves for spine aBMD in Iranian subjects than Americans, but lower curves for femoral neck and total body. These results can be used as reference values to assist Iranian clinicians in interpreting and monitoring bone densitometry results. PURPOSE: Bone health evaluation requires an appropriate reference database that can identify the bone deficit according to age, sex, puberty, and race. The aim of this study was to determine bone mineral density Z scores in Iranian children and adolescents and their comparability with other reference data. METHODS: A sample of 476 healthy children and adolescents, aged 9 18 years, from Kawar (an urban community, 50 km east of Shiraz, Iran) was selected and bone mineral measurements of the lumbar spine, femoral neck, and total body (less head) were done. Sex-specific height-for-age, weight-for-age, and BMI-for-age Z-scores, as well as bone mineral density Z-scores, were calculated. RESULTS: Extended reference curves for bone mineral content (BMC) and areal bone mineral density (aBMD) of the total body less head, lumbar spine, and femoral neck, for ages 9-18 years were constructed relative to sex and age. We found that median, - 2SD, and + 2SD curves for the lumbar spine aBMD were higher in Iranian subjects than in the American participants, but the curves of the femoral neck and total body were lower. Also, we showed that subjects with a lower height-for-age Z-score had a lower BMC and aBMD Z-score in the lumbar spine, femoral neck, and total body (p < 0.001). CONCLUSIONS: Relevant differences in bone mineral density and its curves exist between Iranian children and adolescents and other databases, revealing a significant potential for misdiagnosis. However, our results can be used to provide reference databases to assist clinicians in interpreting, assessing, and monitoring bone densitometry. PMID- 30456733 TI - Parental Origins, Mixed Unions, and the Labor Supply of Second-Generation Women in the United States. AB - This study examines the joint impact of parental origins and partner choice on the employment behavior of second-generation women in the United States. We find that endogamy (choosing a first- or second-generation partner from the same national-origin group) is associated with lower labor supply among second generation women, net of the effects of parental origin culture as proxied using the epidemiological approach to cultural transmission. Parental origin effects are mediated by education, but endogamy curtails economic activity regardless of educational attainment. The findings are robust for married women. Findings for women in cohabiting unions are more heterogeneous, however: cohabitation appears to mute some of the relationship between parental origin culture and women's economic behavior. In particular, the negative relationship between endogamy and women's labor supply does not hold for women in cohabiting unions. PMID- 30456734 TI - A non-ideal authenticity-based conceptualization of personal autonomy. AB - Respect for autonomy is a central moral principle in bioethics. The concept of autonomy can be construed in various ways. Under the non-ideal conceptualization proposed by Beauchamp and Childress, everyday choices of generally competent persons are autonomous to the extent that they are intentional and are made with understanding and without controlling influences. It is sometimes suggested that authenticity is important to personal autonomy, so that inauthenticity prevents otherwise autonomous persons from making autonomous decisions. Building from Beauchamp and Childress's theory, this article develops a non-ideal authenticity based conceptualization of personal autonomy. Factors that indicate inauthentic decision-making are explicated, and the full concept is defended from three expected objections. The theory is then tested on a paradigm case which has concerned theorists and practitioners for some time, namely the possible inauthenticity of anorexia nervosa patients' decision-making. It is concluded that the theory seems to be fruitful in analyses of the degree of autonomy of patients' decision-making, and that it succeeds in providing reliable action guidance in practical contexts. PMID- 30456735 TI - Pollination features and floral volatiles of Gymnospermium scipetarum (Berberidaceae). AB - The discovery of few isolated populations of Gymnospermium scipetarum (since now considered as an amphi-Adriatic endemic) in the S-Apennines prompted to investigate, also for conservation purposes, some aspects of its reproductive biology. We aim: (1) to determine if insects play an important role in pollination; (2) to describe the pollinator community; (3) to detect floral scent composition. Experiments of insect exclusion were carried out in the field using 24 flowering individuals: one raceme was capped whereas the nearest one was used as control to ascertain differences in seed set. Pollinator community was detected during the blooming phase of two consecutive flowering seasons by visual observation; insect identification was made at the highest possible taxonomic resolution with the help of digital photographs. In order to determine the chemical composition of the volatiles, we used SPME sampling of cultivated plants. Mann-Whitney U test reveals significant differences for treatment in mean seed set with very low values for capped flowers, thus clearly indicating as insects are crucial for successful pollination. During the 42 h of observations we detected 326 visitors belonging to only three guilds: 79% were Diptera, 20% Hymenoptera and 1% Coleoptera. We identified overall 36 floral organic compounds with only two compounds common to the other studied Berberidaceae. Ambrox was never identified before in the floral scents of any angiosperm. The presence in the scent of several aldehydes and one ketone (benzophenone) could be related to the detected dominance of muscoid flies as pollinators. Floral morphology and composition of the pollinators community indicate a generalist pollination behaviour probably related to its phenology and habitat preference. The possibility of being pollinated also by muscoid flies can be considered an advantage for the reproductive fitness of the species, since these Diptera are abundant in the mountain pastures surrounding the forest habitat of Gymnospermium. PMID- 30456736 TI - Cardiac Progenitor Cell-Derived Extracellular Vesicles Reduce Infarct Size and Associate with Increased Cardiovascular Cell Proliferation. AB - Cell transplantation studies have shown that injection of progenitor cells can improve cardiac function after myocardial infarction (MI). Transplantation of human cardiac progenitor cells (hCPCs) results in an increased ejection fraction, but survival and integration are low. Therefore, paracrine factors including extracellular vesicles (EVs) are likely to contribute to the beneficial effects. We investigated the contribution of EVs by transplanting hCPCs with reduced EV secretion. Interestingly, these hCPCs were unable to reduce infarct size post-MI. Moreover, injection of hCPC-EVs did significantly reduce infarct size. Analysis of EV uptake showed cardiomyocytes and endothelial cells primarily positive and a higher Ki67 expression in these cell types. Yes-associated protein (YAP), a proliferation marker associated with Ki67, was also increased in the entire infarcted area. In summary, our data suggest that EV secretion is the driving force behind the short-term beneficial effect of hCPC transplantation on cardiac recovery after MI. PMID- 30456737 TI - Splanchnic Circulation and Intraabdominal Metabolism in Two Porcine Models of Low Cardiac Output. AB - The impact of acute cardiac dysfunction on the gastrointestinal tract was investigated in anesthetized and instrumented pigs by sequential reductions of cardiac output (CO). Using a cardiac tamponade (n = 6) or partial inferior caval vein balloon inflation (n = 6), CO was controllably reduced for 1 h each to 75% (CO75%), 50% (CO50%), and 35% (CO35%) of the baseline value. Cardiac output in controls (n = 6) was not manipulated and maintained. Mean arterial pressure, superior mesenteric arterial blood flow, and intestinal mucosal perfusion started to decrease at CO50% in the intervention groups. The decrease in superior mesenteric arterial blood flow was non-linear and exaggerated at CO35%. Systemic, venous mesenteric, and intraperitoneal lactate concentrations increased in the intervention groups from CO50%. Global and mesenteric oxygen uptake decreased at CO35%. In conclusion, gastrointestinal metabolism became increasingly anaerobic when CO was reduced by 50%. Anaerobic gastrointestinal metabolism in low CO can be detected using intraperitoneal microdialysis. PMID- 30456738 TI - Lack of associations between thyroid function and obstructive sleep apnea severity in adults with prediabetes and diabetes mellitus. AB - PURPOSE: Hypothyroidism is associated with a high frequency of obstructive sleep apnea (OSA). However, the prevalence of OSA in hypothyroid patients is not different from the general population in many reports. The importance of thyroid function screening in sleep-disordered breathing is still controversial. This study aimed to explore the association between thyroid dysfunction and OSA in the adults with prediabetes or diabetes mellitus type 2, who have very high prevalence of OSA. METHODS: OSA was assessed using an in-home monitoring device, WatchPAT200. OSA severity was measured using apnea-hypopnea index (AHI), oxygen desaturation index (ODI), minimum oxygen saturation (minO2), and time spent under oxygen saturation < 90% (T90). Patients with pre-existing thyroid dysfunction were excluded. RESULTS: Participants included 70 men and 118 women with mean age 52.8 +/- 10.9 years and body mass index 28.2 +/- 4.9 kg/m2. One hundred forty participants (75%) had OSA, with a median AHI of 10.1 (interquartile range 4.8, 18.3). The percentage of positive thyroid autoantibody (thyroperoxidase and thyroglobulin antibody) was similar among the subjects with and without OSA. There was no correlation between the levels of thyroid function (TSH, FT3, FT4, TSH/FT3, and TSH/FT4 ratio) and the severity indices of OSA (AHI, ODI, minO2, and T90). CONCLUSIONS: These data do not support universal screening for thyroid dysfunction in OSA patients with diabetes or prediabetes. PMID- 30456739 TI - Postural and vestibular changes related to CPAP treatment in moderate-to-severe OSA patients: a 12-month longitudinal study. AB - PURPOSE: To assess whether vestibulo-ocular reflex (VOR) gain, posturography parameters and related clinical outcomes can improve in OSA patients after 12 months of CPAP treatment, taking into consideration that a certain degree of vestibular dysfunction has been identified in these subjects. METHODS: Vestibular, postural, clinical, and polygraphic parameters were assessed in 32 OSA patients before and after beneficial CPAP treatment by means of video head impulse test (vHIT), static posturography (SP), Dizziness Handicap Inventory (DHI), Epworth Sleepiness Scale (ESS), and Apnea-Hypopnea Index (AHI), respectively, and were compared by means of a "within-subject" ANOVA model and Spearman's rank correlation. RESULTS: After the 12-month period of treatment, OSA patients demonstrated a significant reduction in AHI values, in both opened and closed eyes conditions of surface and length as well as in power spectra recorded in low, middle, and high frequency interval. Although a significant improvement was also recorded among DHI and ESS scores, VOR gain increase did not survive to post-hoc corrections. Finally, positive correlations between the differences between pre- and post-treatment AHI, ESS, and PS values were found. CONCLUSIONS: The present work highlighted that postural instability and dizziness-related conditions due to OSA may improve after 12 months of CPAP treatment. Although VOR gain did not demonstrate significant improvement, this study might open future perspectives directed to assessing VOR gain changes after longer periods of CPAP treatment. PMID- 30456740 TI - Complete mitochondrial genome of northern Indian red muntjac (Muntiacus vaginalis) and its phylogenetic analysis. AB - We report complete mitochondrial genome of Northern Indian red muntjac, Muntiacus vaginalis, and its phylogenetic inferences. Mitogenome composition was 16,352 bp in length and its overall base composition in the circular genome was A = 33.2%, T = 29.0%, C = 24.50% and G = 13.30%. It exhibited a typical mitogenome structure, including 22 transfer RNA genes, 13 protein-coding genes, two ribosomal RNA genes and a major non-coding control region (D-loop region). All the genes except ND6 and eight tRNA's were encoded on the heavy strand. Phylogenetic analyses showed that M. vaginalis is closely related to M. muntjak and formed a sister relationship with Elaphodus cephalophus. In view of the unclear distribution range and escalating habitat loss, it is important to identify its population genetic status. The complete mitogenome described in this study can be used in further phylogenetics, identification of extant maternal lineage, evolutionary significance unit and its genetic conservation. PMID- 30456741 TI - A composite 3D printed model of the midcarpal joint. AB - Three-dimensional (3D) printing has recently been developed as a resource for teaching human anatomy through the accurate reproduction of anatomical specimens. Using a composite 3D printed model with the incorporation of metal and magnets, we were able to demonstrate and analyse movements at the midcarpal joint during the 'dart thrower's motion', which is an important motion in daily activities involving the use of the hand. The hand component with the distal row of carpal bones was subjected to flexion and extension at the midcarpal joint and observed for simultaneous abduction/adduction. Notable adduction was observed in the flexed position as compared to the extended position. Moreover, while the primary movements at the midcarpal joint were taking place in the medial part of the joint, the lateral part of the joint (which is ellipsoid) served to accommodate the arc of movement. We suggest that such composite 3D printed models are useful teaching tools for enhancing the understanding of complex joint movements. PMID- 30456742 TI - Correction to: Anti-inflammatory activity of caffeic acid derivatives isolated from the roots of Salvia miltiorrhiza Bunge. AB - The author would like to include conflict of interest statement of the online published article. The correct conflict of interest statement should read as: Conflict of interest The authors declare no conflict of interest. PMID- 30456743 TI - Radon, an invisible killer in Canadian homes: perceptions of Ottawa-Gatineau residents. AB - OBJECTIVES: Canadians have reason to care about indoor air quality as they spend over 90% of the time indoors. Although indoor radon causes more deaths than any other environmental hazard, only 55% of Canadians have heard of it, and of these, 6% have taken action. The gap between residents' risk awareness and adoption of actual protective behaviour presents a challenge to public health practitioners. Residents' perception of the risk should inform health communication that targets motivation for action. In Canada, research about the public perception of radon health risk is lacking. The aim of this study was to describe residents' perceptions of radon health risks and, applying a theoretical lens, evaluate how perceptions correlate with protection behaviours. METHODS: We conducted a mixed online and face-to-face survey (N = 557) with both homeowners and tenants in Ottawa-Gatineau census metropolitan area. Descriptive, correlation, and regression analyses addressed the research questions. RESULTS: Compared to the gravity of the risk, public perception remained low. While 32% of residents expressed some concern about radon health risk, 12% of them tested and only 3% mitigated their homes for radon. Residents' perceptions of the probability and severity of the risk, social influence, care for children, and smoking in home correlated significantly with their intention to test; these factors also predicted their behaviours for testing and mitigation. CONCLUSION: Health risk communication programs need to consider the affective aspects of risk perception in addition to rational cognition to improve protection behaviours. A qualitative study can explore the reasons behind the gap between testing and mitigation. PMID- 30456744 TI - A mixed methods evaluation of capturing and sharing practitioner experience for improving local tobacco control strategies. AB - OBJECTIVE: Practitioner experience is one type of evidence that is used in public health planning and action. Yet, methods for capturing and sharing experience are under-developed. We evaluated the reach, uptake and use of an example of capturing and sharing practitioner experience from tobacco control known as documentation of practice (DoP) reports. METHODS: The participatory, mixed methods approach included the following: a document review to capture data related to the extent and how DoP reports reached the target population; an online survey to assess awareness, use and perceptions about DoP reports; and semi-structured interviews to identify and explore examples of instrumental, conceptual and symbolic use of DoP reports. The samples for the survey and interviews included tobacco control practitioners from public health units in Ontario, Canada. RESULTS: Seventy-three individuals participated in the survey and 10 were interviewed. Awareness of at least one DoP report was high. The most common way of learning about DoP reports was email. DoP reports focused on policy issues had highest use; these reports were used in conceptual (helped raise awareness), instrumental (directly informed local policy development) and symbolic (confirmed a choice already made) ways. DoP reports may be improved with key messages, shorter development timelines, more relevant topic selection and dissemination to audiences beyond public health. CONCLUSION: DoP reports are useful to public health practitioners working in tobacco control within Ontario; refinements to development and dissemination processes will enhance use. Future studies and adaptations of DoP reports could help improve use of practitioner experience as one source of evidence informing public health practice. PMID- 30456745 TI - Effects of Clozapine on the Gut: Cross-Sectional Study of Delayed Gastric Emptying and Small and Large Intestinal Dysmotility. AB - BACKGROUND: Gastrointestinal hypomotility in people taking clozapine is common, poorly understood and potentially dangerous. It causes distress and sometimes sudden death, with greater associated morbidity than the better known adverse effect of clozapine, agranulocytosis. Neither the mechanism nor prevalence of clozapine-induced gastrointestinal hypomotility is well understood. Previous studies show clozapine impedes colon transit, likely owing to anticholinergic and anti-serotonergic properties. However, regional gastrointestinal transit times (including gastric and small bowel emptying) have not been quantified. METHODS: We used wireless motility capsules to measure gastric emptying and small and large bowel transit times in clozapine-treated individuals. We tested 17 clozapine-treated patients without any known gastrointestinal dysfunction, and compared data with matched normative transit times. RESULTS: Clozapine-treated participants had significant 'slow gut', with dysmotility in at least one region of the gastrointestinal tract evident in 82%, with 59% experiencing multi regional dysmotility. Delayed gastric emptying was diagnosed in 41%, delayed small bowel transit in 71% and delayed colon transit in 50%. Only 18% of participants had normal studies. Hypomotility was not correlated with ethnicity, sex or duration of treatment. Subjective reporting of constipation had low sensitivity in predicting dysmotility. Delayed gastric emptying had been unrecognised clinically for all participants. CONCLUSION: Clozapine is associated with significant multi-regional gastrointestinal dysfunction. This is relevant when considering the relationship between clozapine use and conditions such as gastroparesis, choking, aspiration pneumonia, constipation, ileus and intestinal pseudo-obstruction. While the constipating properties of clozapine are now well recognised, this study shows a high degree of vigilance is required for both lower and upper gastrointestinal dysmotility in people taking this antipsychotic. PMID- 30456746 TI - Impact of Antidepressant Use on the Trajectory of Alzheimer's Disease: Evidence, Mechanisms, and Therapeutic Implications. AB - The relationship between antidepressants and Alzheimer's disease (AD) is very complex, and the literature is mixed regarding the effect of these medications on the trajectory of the disease. This paper reviews findings from relevant clinical studies that have assessed the impact of antidepressants on AD onset and disease progression. To date, these medications seem to attenuate the risk of developing the disease without affecting the rate of progression. However, most evidence stems from observational studies that are subject to methodological bias. Serotonergic antidepressants are thought to affect AD pathophysiology by reducing beta-amyloid (Abeta) plaque formation and promoting hippocampal neurogenesis. However, the mechanisms underlying their effect need to be examined further, especially in humans. Moreover, more robust clinical studies in terms of design (randomized controlled trials) and longer duration of follow-up are needed. Variables, including depression timeline/onset and its clinical course, apolipoprotein E4 (APOE4) genotype status, sex, dose/duration of antidepressant treatment, and AD biomarkers need to be incorporated in future trials to better elucidate the effect of antidepressants on AD risk. PMID- 30456747 TI - Joint Maximum Likelihood Estimation for High-Dimensional Exploratory Item Factor Analysis. AB - Joint maximum likelihood (JML) estimation is one of the earliest approaches to fitting item response theory (IRT) models. This procedure treats both the item and person parameters as unknown but fixed model parameters and estimates them simultaneously by solving an optimization problem. However, the JML estimator is known to be asymptotically inconsistent for many IRT models, when the sample size goes to infinity and the number of items keeps fixed. Consequently, in the psychometrics literature, this estimator is less preferred to the marginal maximum likelihood (MML) estimator. In this paper, we re-investigate the JML estimator for high-dimensional exploratory item factor analysis, from both statistical and computational perspectives. In particular, we establish a notion of statistical consistency for a constrained JML estimator, under an asymptotic setting that both the numbers of items and people grow to infinity and that many responses may be missing. A parallel computing algorithm is proposed for this estimator that can scale to very large datasets. Via simulation studies, we show that when the dimensionality is high, the proposed estimator yields similar or even better results than those from the MML estimator, but can be obtained computationally much more efficiently. An illustrative real data example is provided based on the revised version of Eysenck's Personality Questionnaire (EPQ R). PMID- 30456748 TI - Estimating the Cognitive Diagnosis [Formula: see text] Matrix with Expert Knowledge: Application to the Fraction-Subtraction Dataset. AB - Cognitive diagnosis models (CDMs) are an important psychometric framework for classifying students in terms of attribute and/or skill mastery. The [Formula: see text] matrix, which specifies the required attributes for each item, is central to implementing CDMs. The general unavailability of [Formula: see text] for most content areas and datasets poses a barrier to widespread applications of CDMs, and recent research accordingly developed fully exploratory methods to estimate Q. However, current methods do not always offer clear interpretations of the uncovered skills and existing exploratory methods do not use expert knowledge to estimate Q. We consider Bayesian estimation of [Formula: see text] using a prior based upon expert knowledge using a fully Bayesian formulation for a general diagnostic model. The developed method can be used to validate which of the underlying attributes are predicted by experts and to identify residual attributes that remain unexplained by expert knowledge. We report Monte Carlo evidence about the accuracy of selecting active expert-predictors and present an application using Tatsuoka's fraction-subtraction dataset. PMID- 30456749 TI - Effect of Lyophilized, Encapsulated Lactobacillus fermentum and Lactulose Feeding on Growth Performance, Heavy Metals, and Trace Element Residues in Rainbow Trout (Oncorhynchus mykiss) Tissues. AB - Heavy metals naturally occur in the environment and are causing great concern all around the world. Accumulation of heavy metals in fish tissues can lead to serious adverse effects in humans when consumed in the amounts exceeding the safe consumption levels. In this study, Lactobacillus fermentum 1744 (ATCC 14931) and lactulose were used in the fish diet in order to investigate their effects on growth performance, intestinal villous morphology, and heavy metals residues. Fishes were randomly allocated into three replicates of five different treatments. The control group received the basal diet, while the experimental groups were fed on the basal diet supplemented with encapsulated and lyophillized probiotic, lactulose (prebiotic) and L. fermentum, and lactulose as synbiotic. All the groups were fed three times daily for a period of 56 days. At the end of growth period, 10 fish per replicate were randomly collected in order to take the samples of the fillet, gills, and liver. Results showed that the encapsulated L. fermentum plus lactulose improve growth performance and exclude absorption and accumulation of heavy metals in rainbow trout liver and gills. The villous height were increased in all the samples except the group 2 fed on the lactulose (p < 0.05). PMID- 30456750 TI - Adiponectin and vitamin D-binding protein concentrations are independently associated in apparently healthy women but not men: a validation cohort. PMID- 30456751 TI - An update on adrenal endocrinology: significant discoveries in the last 10 years and where the field is heading in the next decade. AB - The last 10 years have produced an amazing number of significant discoveries in the field of adrenal endocrinology. The development of the adrenal gland was linked to specific molecules. Cortisol-producing lesions were associated mostly with defects of the cyclic AMP (cAMP) signaling pathway, whereas aldosterone producing lesions were found to be the result of defects in aldosterone biosynthesis or the potassium channel KCNJ5 and related molecules. Macronodular adrenal hyperplasia was linked to ARMC5 defects and new genes were found to be involved in adrenocortical cancer (ACC). The succinate dehydrogenase (SDH) enzyme was proven to be the most important molecular pathway involved in pheochromocytomas, along with several other genes. Adrenomedullary tumors are now largely molecularly elucidated. Unfortunately, most of these important discoveries have yet to produce new therapeutic tools for our patients with adrenal diseases: ACC in its advanced stages remains largely an untreatable disorder and malignant pheochromocytomas are equally hard to treat. Thus, the challenge for the next 10 years is to translate the important discoveries of the previous decade into substantial advances in the treatment of adrenal disorders and tumors. PMID- 30456752 TI - Flavisolibacter aluminii sp. nov., a novel member of the genus Flavisolibacter isolated from an automotive air conditioning system. AB - A Gram-stain-negative, aerobic, non-motile, rod-shaped, and yellow-pigmented bacterium, designated strain ID1709T, was isolated from an automotive air conditioning system collected in Korea. Analysis of 16S rRNA gene sequence similarity showed that strain ID1709T had 92.2-94.3% similarities with the type strains of members of the genus Flavisolibacter. The major cellular fatty acids were iso-C15:0, iso-C15:1 G, iso-C17:0 3-OH, and summed feature 3 (C16:1omega7c and/or C16:1omega6c). The predominant respiratory quinone was MK-7. The polar lipids comprised phosphatidylethanolamine, aminoglycophospholipid, two unidentified aminolipids, and three unidentified lipids. The DNA G + C content of the strain was 35.6 mol%. Based on phenotypic, chemotaxonomic, and genotypic data, strain ID1709T represents a novel species in the genus Flavisolibacter, for which the name Flavisolibacter aluminii sp. nov. (= KACC 19451T = KCTC 52778T = NBRC 112870T), is proposed. PMID- 30456753 TI - Increased susceptibility against Cryptococcus neoformans of lupus mouse models (pristane-induction and FcGRIIb deficiency) is associated with activated macrophage, regardless of genetic background. AB - The severity of cryptococcosis in lupus from varying geneticbackgrounds might be different due to the heterogeneity of lupus-pathogenesis. This study explored cryptococcosis in lupus mouse models of pristane-induction (normal geneticbackground) and FcGRIIb deficiency (genetic defect). Because the severity of lupus nephritis, as determined by proteinuria and serum creatinine, between pristane and FcGRIIb-/- mice were similar at 6-month-old, Cryptococcus neoformans was intravenously administered in 6-month-old mice and were age-matched with wild type. Indeed, the cryptococcosis disease severity, as evaluated by mortality rate, internal-organ fungal burdens and serum cytokines, between pristane and FcGRIIb-/- mice was not different. However, the severity of cryptococcosis in wild-type was less severe than the lupus mice. On the other hand, phagocytosis activity of peritoneal macrophages from lupus mice (pristane and FcGRIIb-/-) was more predominant than the wild-type without the difference in macrophage killing activity among these groups. In addition, the number of active T helper cells (Th cell) in the spleen, including Th-cells with intracellular IFN-gamma, from lupus mice (pristane and FcGRIIb-/-) was higher than wildtype. Moreover, these active Th-cells were even higher after 2 weeks of cryptococcal infection. These data support enhanced macrophage activation through prominent Th-cells in both lupus models. In conclusion, an increased susceptibility of cryptococcosis in both lupus models was independent to genetic background. This might due to Th-cell enhanced macrophage phagocytosis with the interference of macrophage killing activity from Cryptococcal immune-evasion properties. PMID- 30456754 TI - Gramella fulva sp. nov., isolated from a dry surface of tidal flat. AB - A novel Gram-stain-negative, aerobic, motile by means of gliding, and short rod shaped bacterium, designated strain SH35T, was isolated from the dry surface of a tidal flat in Hwasung-si, South Korea. Growth occurred at 10-40 degrees C (optimum 30 degrees C), at pH 6.0-8.0 (optimum pH 7.0), in 1-12% NaCl (optimum 2%), and was inhibited in the absence of NaCl and Ca2+ ions. Phylogenetic analysis based on the 16S rRNA gene sequences showed that strain SH35T belonged to the genus Gramella and was a member of the family Flavobacteriaceae with highest sequence similarity to Gramella flava JLT2011T (96.1%), followed by Gramella oceani CCAMSZ-TT (95.6%), and 93.0-94.9% to other recognized Gramella species. The major cellular fatty acids (> 5% of the total) of strain SH35T were iso-C15:0, Iso-C16:0, anteiso-C15:0, iso-C17:0 3-OH and summed feature 9 (C16:0 10-methyl and/or C17:1 iso omega9s). The major polar lipids were phosphatidylethanolamine, two unidentified aminolipids and nine unidentified polar lipids. The major respiratory quinone and the predominant polyamine were menaquinone-6 (MK-6) and symhomospermidine, respectively. The DNA G + C content was 40.5 mol% (39.7% based on total genome calculations). Based on phylogenetic analysis and physiological and biochemical characterization, strain SH35T represents a novel species of the genus Gramella, for which the name Gramella fulva sp. nov. is proposed. The type strain is SH35T (= KACC 19447T = JCM 32369T). PMID- 30456755 TI - Anti-varicella-zoster virus activity of cephalotaxine esters in vitro. AB - Harringtonine (HT) and homoharringtonine (HHT), alkaloid esters isolated from the genus Cephalotaxus, exhibit antitumor activity. A semisynthetic HHT has been approved for treatment of chronic myelogenous leukemia. In addition to antileukemic activity, HT and HHT are reported to possess potent antiviral activity. In this study, we investigated the effects of HT and HHT on replication of varicella-zoster virus (VZV) in vitro. HT and HHT, but not their biologically inactive parental alkaloid cephalotaxine (CET), significantly inhibited replication of recombinant VZV-pOka luciferase. Furthermore, HT and HHT, but not CET, strongly induced down-regulation of VZV lytic genes and exerted potent antiviral effects against a VZV clinical isolate. The collective data support the utility of HT and HHT as effective antiviral candidates for treatment of VZV associated diseases. PMID- 30456756 TI - Paraburkholderia dokdonella sp. nov., isolated from a plant from the genus Campanula. AB - The novel Gram-stain-negative, rod-shaped, aerobic bacterial strain DCR-13T was isolated from a native plant belonging to the genus Campanula on Dokdo, an island in the Republic of Korea. Comparative analysis of the 16S rRNA gene sequence indicated that this strain is closely related to Paraburkholderia peleae PP52-1T (98.43% 16S rRNA gene sequence similarity), Paraburkholderia oxyphila NBRC 105797T (98.42%), Paraburkholderia sacchari IPT 101T (98.28%), Paraburkholderia mimosarum NBRC 106338T (97.80%), Paraburkholderia denitrificans KIS30-44T (97.46%), and Paraburkholderia paradise WAT (97.45%). This analysis of the 16S rRNA gene sequence also suggested that DCR-13T and the six closely related strains formed a clade within the genus Paraburkholderia, but that DCR-13T was clearly separated from the established species. DCR-13T had ubiquinone 8 as its predominant respiratory quinone, and its genomic DNA G + C content was 63.9 mol%. The isolated strain grew at a pH of 6.0-8.0 (with an optimal pH of 6.5), 0-4% w/v NaCl (with an optimal level of 0%), and a temperature of 18-42 degrees C (with an optimal temperature of 30 degrees C). The predominant fatty acids were C16:0, summed feature 8 (C18:1omega7c/C18:1omega6c), C17:0 cyclo, C19:0 cyclo omega8c, summed feature 3 (C16:1omega6c/C16:1omega7c) and summed feature 2 (C12:0 aldehyde), and the major polar lipids were phosphatidylglycerol and phosphatidylethanolamine. On the basis of polyphasic evidence, it is proposed that strain DCR-13T (= KCTC 62811T = LMG 30889T) represents the type strain of a novel species, Paraburkholderia dokdonella sp. nov. PMID- 30456757 TI - Rotavirus-mediated alteration of gut microbiota and its correlation with physiological characteristics in neonatal calves. AB - Diarrhea is a fatal disease to neonatal calves, and rotavirus is the main pathogen associated with neonatal calf diarrhea. Although previous studies have reported that the gut microbiota is changed in calves during diarrhea, less is known about whether rotavirus infection alters the structure of the gut microbiota. Here, we characterized fecal microbial communities and identified possible relationships between the gut microbiota profiles and physiological parameters. Five fecal specimens of rotavirus-infected calves from 1 to 30 days after birth and five fecal specimens of age-matched healthy calves were used for the microbial community analysis using the Illumina MiSeq sequencer. Rotavirus infection was associated with reduced rotavirus infection significantly reduced the richness and diversity of the bacterial community. Weighted unique fraction metric analysis exhibited significant differences in community membership and structure between healthy and rotavirus-infected calves. Based on relative abundance analysis and linear discriminant analysis effect size, we found that the representative genera from Lactobacillus, Subdoligranulum, Blautia, and Bacteroides were closely related to healthy calves, while the genera Escherichia and Clostridium were closely affiliated to rotavirus-infected calves. Furthermore, canonical correlation analysis and Pearson correlation coefficient results revealed that the increased relative abundances of Lactobacillus, Subdoligranulum, and Bacteroides were correlated with normal levels of physiological characteristics such as white blood cells, blood urea nitrogen, serum amyloid protein A, and glucose concentration in serum. These results suggest that rotavirus infection alters the structure of the gut microbiota, correlating changes in physiological parameters. This study provides new information on the relationship between gut microbiota and the physiological parameters of rotavirus-mediated diarrheic calves. PMID- 30456758 TI - Oral suplatast tosilate for the treatment of urticaria pigmentosa, skin lesion in mastocytosis. PMID- 30456759 TI - Integrative Multi-View Regression: Bridging Group-Sparse and Low-Rank Models. AB - Multi-view data have been routinely collected in various _elds of science and engineering. A general problem is to study the predictive association between multivariate responses and multi-view predictor sets, all of which can be of high dimensionality. It is likely that only a few views are relevant to prediction, and the predictors within each relevant view contribute to the prediction collectively rather than sparsely. We cast this new problem under the familiar multivariate regression framework and propose an integrative reduced-rank regression (iRRR), where each view has its own low-rank coefficient matrix. As such, latent features are extracted from each view in a supervised fashion. For model estimation, we develop a convex composite nuclear norm penalization approach, which admits an efficient algorithm via alternating direction method of multipliers. Extensions to non-Gaussian and incomplete data are discussed. Theoretically, we derive non-asymptotic oracle bounds of iRRR under a restricted eigenvalue condition. Our results recover oracle bounds of several special cases of iRRR including Lasso, group Lasso and nuclear norm penalized regression. Therefore, iRRR seamlessly bridges group-sparse and low-rank methods and can achieve substantially faster convergence rate under realistic settings of multi view learning. Simulation studies and an application in the Longitudinal Studies of Aging further showcase the efficacy of the proposed methods. This article is protected by copyright. All rights reserved. PMID- 30456761 TI - Outcomes and risk factors of transfusion-associated circulatory overload: a case control study. AB - BACKGROUND: Transfusion-associated circulatory overload (TACO) is a growing concern in clinical practice. STUDY DESIGN AND METHODS: A case control study was performed at the Nimes University Hospital, France. TACO cases occurring after RBC transfusion reported from January 1, 2014, to May 31, 2017, were included as cases. Four controls by case were randomly selected among the other RBC recipients on the same day. RESULTS: During the study period, 60 TACO diagnoses were reported for 37,029 transfused RBCs to a total of 8787 patients; 240 controls were included. The average rate of TACO was one case every 616 RBCs transfused. One in 146 transfused patients experienced TACO. TACO was associated with a higher 28-day mortality (22% vs. 11%; p = 0.003), and a longer hospital stay compared with controls (23.5 +/- 19.6 days vs. 15.9 +/- 20.1 days; p < 0.001). Four risk factors were independently associated with TACO in multivariable analysis: chronic use of loop diuretics (odds ratio [OR], 6.5, 95% confidence interval [CI], 3.3-12.9), hemorrhagic shock (OR, 12; 95% CI, 2.9-50), body weight <46 kg (OR, 7.9; 95% CI, 2.3-26.8) and chronic hypertension (OR, 4.1; 95% CI, 2-8.5). CONCLUSION: TACO was frequent and associated with poor outcome. Four independent risk factors were identified: hemorrhagic shock, low body weight, chronic use of diuretics, and chronic hypertension. PMID- 30456760 TI - Inflammatory molecules produced by meniscus and synovium in early and end-stage osteoarthritis: a coculture study. AB - The aim of this study was to identify the molecules and pathways involved in the cross-talk between meniscus and synovium that may play a critical role in osteoarthritis (OA) pathophysiology. Samples of synovium and meniscus were collected from patients with early and end-stage OA and cultured alone or cocultured. Cytokines, chemokines, metalloproteases, and their inhibitors were evaluated at the gene and protein levels. The extracellular matrix (ECM) changes were also investigated. In early OA cultures, higher levels of interleukin-6 (IL 6) and IL-8 messenger RNA were expressed by synovium and meniscus in coculture compared with meniscus cultured alone. RANTES release was significantly increased when the two tissues were cocultured compared with meniscus cultured alone. Increased levels of matrix metalloproteinase-3 (MMP-3) and MMP-10 proteins, as well as increased release of glycosaminoglycans and aggrecan CS846 epitope, were observed when synovium was cocultured with meniscus. In end-stage OA cultures, increased levels of IL-8 and monocyte chemoattractant protein-1 (MCP-1) proteins were released in cocultures compared with cultures of meniscus alone. Chemokine (C-C motif) ligand 21 (CCL21) protein release was higher in meniscus cultured alone and in coculture compared with synovium cultured alone. Increased levels of MMP-3 and 10 proteins were observed when tissues were cocultured compared with meniscus cultured alone. Aggrecan CS846 epitope release was increased in cocultures compared with cultures of either tissue cultured alone. Our study showed the production of inflammatory molecules by synovium and meniscus which could trigger inflammatory signals in early OA patients, and induce ECM loss in the progressive and final stages of OA pathology. PMID- 30456762 TI - Airway anomalies in patients with craniosynostosis. AB - OBJECTIVES: 1) Characterize the spectrum of airway anomalies in patients with craniosynostosis, and 2) identify clinical characteristics of these patients that may be associated with the development of airway anomalies. METHODS: This study is a retrospective case series assessing the type and frequency of airway anomalies in all patients with craniosynostosis seen at a tertiary-care children's hospital between 2000 and 2016. Cohort analyses were then performed to identify differences in airway anomalies dependent on syndromic associations, multisutural fusion, and location of suture fusion. Clinical characteristics examined included demographics and additional neurologic and craniofacial abnormalities. RESULTS: Four hundred and ninety-six patients with craniosynostosis (83.5% white, 64.5% male; 33.9% sagittal, 28.8% metopic, 11.5% coronal, 1.2% lambdoid, and 24.6% multisutural) were included. Notable airway anomalies included the following: 13.3% adenotonsillar hypertrophy, 8.9% laryngomalacia, 7.3% tracheomalacia, 7.1% subglottic stenosis, 4.0% bronchomalacia, 3.8% laryngeal cleft, and 1.2% vocal fold paresis. Multisutural craniosynostosis patients (n = 122) were more likely to have obstructive sleep apnea (P = 0.005), adenotonsillar hypertrophy (P = 0.014), tracheomalacia (P = 0.011), subglottic stenosis (P < 0.001), and epiglottic/base of tongue collapse (P = 0.003) and require tracheostomy (P = 0.001) and mechanical ventilation (P = 0.017) compared with single suture craniosynostosis. Syndromic craniosynostosis patients (n = 33) were more likely to have obstructive sleep apnea (P < 0.001), laryngomalacia (P = 0.047), and subglottic stenosis (P = 0.009) compared with nonsyndromic patients. CONCLUSION: Airway anomalies are prevalent in patients with craniosynostosis; patients with multisutural or syndromic types have an increased risk of developing certain abnormalities. There should be a lower threshold for referral for airway evaluation in these populations. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018. PMID- 30456763 TI - Microsponge: An emerging drug delivery strategy. AB - Hit, Lead & Candidate Discovery Microsponges are the spherical particles ranging from 5 to 300 MUm in size. These are further made up of clusters of smaller spheres. They are designed for delivering the drug efficiently at a comparatively lesser dose and enhancing the stability, modifying the drug release profile and minimizing the side effects. Microsponge drug delivery system decrease transdermal invasion of the active ingredient into the skin while increasing the time the drug remains on the skin surface or within the epidermis. Preparation of the microsponges includes two techniques: Liquid-liquid suspension polymerization and Quasi-emulsion solvent diffusion method. Their characterization and evaluation can be done in many ways like particle-size measurement and porosity, morphology, true density determination, analyzing the rheological properties, and dissolution studies. Present work focuses on the detailed study of the microsponge drug delivery system. This will help the reader to get all the information regarding the microsponge delivery systems. PMID- 30456764 TI - Ex vivo radiocontrast description of the caudal epigastric arteries in horses. AB - OBJECTIVE: To determine the location of the deep and superficial caudal epigastric arteries in relation to 3 midline positions and the relationship between the location of these arteries, body circumference, and body condition score. STUDY DESIGN: Descriptive anatomical study. SAMPLE POPULATION: Nine horses, aged 1-28 years (mean 10.61 +/- 8.89 SD). METHODS: Body condition score and body circumference were measured prior to euthanasia. Angiographic studies of the deep and superficial caudal epigastric arteries were performed on resected abdominal walls. The distances between the deep and the superficial caudal epigastric arteries and 3 midline positions were measured. Correlations among these distances, body circumference, and body condition score were analyzed. RESULTS: The location of the deep caudal epigastric artery correlated with body circumference and body condition score at the umbilicus (r = 0.53 and 0.68, respectively), midpoint landmark (r = 0.79 and 0.83, respectively), and prepubic tendon attachment (r = 0.69 and 0.78, respectively). The course of this artery could be estimated by multiplying body circumference by 0.04 +/- 0.02 at the umbilicus, 0.07 +/- 0.01 at the midpoint landmark, and 0.03 +/- 0.015 at the prepubic tendon attachment. The course of the superficial caudal epigastric artery did not correlate with anatomic landmarks. CONCLUSION: The course of the deep caudal epigastric artery could be estimated at 3 midline landmarks on the basis of body circumference and body condition score in equine cadavers. CLINICAL SIGNIFICANCE: Predicting the course of the caudal epigastric arteries in the equine abdomen based on correlation among location, body circumference, and body condition score may prevent iatrogenic damage during creation of laparoscopic portals. PMID- 30456765 TI - Water channel activity of putative aquaporin-6 present in Aedes aegypti. AB - Aquaporins (AQPs) are integral membrane channels that facilitate the bidirectional transport of water and sometimes other small solutes across biological membranes. AQPs are important in mediating environmental adaptations in mosquitoes and are considered as a novel target for the development of effective insecticides against mosquitoes. Here, we expressed Aedes aegypti AQP6 ( AaAQP6) in human embryonic kidney (HEK) 293 cells and analyzed the water permeability by a conventional swelling assay, that is, a real-time change in cell size corresponding to the cell swelling induced by hyposmotic solution. The swelling assay revealed that AaAQP6 is a mercury-sensitive water channel. Gene expression studies showed that AaAQP6 is highly expressed in the pupae than other developmental stages. Heterologous expression of AaAQP6 in HEK cell was mainly observed intracellularly suggesting AaAQP6 possibly could be a subcellular water channel and may play an osmoregulatory function in the pupae of A. aegypti. PMID- 30456767 TI - Transient corneal depression after open heart surgery with cardiopulmonary bypass. PMID- 30456766 TI - Multidisciplinary care results in similar maternal and perinatal mortality rates for women with and without SCD in a low-resource setting. AB - In Africa, the maternal mortality rate in sickle cell disease (SCD) is ~10%. Our team previously demonstrated an 89% decrease in mortality rate in a before-and after feasibility study among women with SCD living in low-resource setting in Ghana. In the same cohort including additional participants with and without SCD, we used a prospective cohort design to test the hypothesis that implementing a multidisciplinary care team for pregnant women with SCD in low-resource setting will result in similar maternal and perinatal mortality rates compared to women without SCD. We prospectively enrolled pregnant women with and without SCD or trait and followed them up for 6-week postpartum. We tested the newborns of mothers with SCD for SCD. We recruited age and parity matched pregnant women without SCD or trait as the comparison group. Maternal and perinatal mortality rates were the primary outcomes. A total of 149 pregnant women with SCD (HbSS, 54; HbSC, 95) and 117 pregnant women without SCD or trait were included in the analysis. Post-intervention, maternal mortality rates were 1.3% and 0.9% in women with and without SCD, respectively (P = 1.00); the perinatal mortality rates were 7.4% and 3.4% for women with and without SCD, respectively (P = 0.164). Among the mothers with SCD, ~15% of newborns had SCD. Multidisciplinary care of pregnant women with SCD may reduce maternal and perinatal mortality rates to similar levels in pregnant women without SCD in low-resource settings. Newborns of mothers with SCD have a high rate of SCD. PMID- 30456768 TI - Psychometric properties of the Group Climate Instrument (GCI) in individuals with mild intellectual disability or borderline intellectual functioning. AB - BACKGROUND: This study examined the psychometric properties of the Group Climate Instrument (GCI) in a sample of N = 189 adults (79% men) with mild intellectual disability or borderline intellectual functioning who were residents of a treatment facility in the Netherlands. METHOD: Construct validity of the GCI was examined by means of confirmatory factor analysis. Also, reliability and convergent validity of the GCI were examined. We also examined the variability in perception of the living group climate between and within living groups by computing intraclass correlation coefficients. RESULTS: The model contained four first-order factors (support, growth, group atmosphere and repression) and a second-order factor overall climate, providing preliminary support for construct validity of the GCI. Reliability coefficients were good for all factors. Preliminary evidence for convergent validity was found in significant moderate associations between subscales and single item ratings for the factors of group climate. The intraclass correlation coefficients indicated that a considerate proportion of variance can be attributed to between-group differences. CONCLUSIONS: The GCI might be used to assess perception of the living group climate for individuals with mild intellectual disability or borderline intellectual functioning in psychiatric and forensic care settings, although further development of the GCI and replication of our findings seem necessary. PMID- 30456769 TI - Four priorities for new links between conservation science and accounting research. AB - Article impact statement: New collaborations with accounting research can improve conservation impact of ecosystem-based information systems. PMID- 30456770 TI - The impact of atrial fibrillation on transcatheter mitral valve repair outcomes: A propensity-matched analysis. AB - BACKGROUND: The concomitant presence of atrial fibrillation (AF) in the setting of Transcatheter Mitral Valve Repair (TMVR) represents a clinical challenge. Despite the high AF burden in patients presenting for the TMVR procedure, there are no studies that evaluate the impact of AF on in-hospital outcomes of TMVR in a nationally representative United States sample reflecting real practice. Therefore, we sought to study the outcomes of AF patients undergoing TMVR. METHODS AND RESULTS: The study included 1026 patients from the National Inpatient Sample (NIS) registry. Patients (age >=18 years) who had undergone TAVR as a primary procedure from 2011 to 2014 were included, using the ICD-9-CM diagnostic codes. We examined patient characteristics and in-hospital outcomes. To account for patient and hospital-level baseline differences, we performed propensity score-matched analysis. The prevalence of AF was approximately 56%. After adjusting for patient-level and hospital-level characteristics, there was no statistical difference regarding in-hospital mortality (odds ratio [OR] 0.72, 95%CI 0.29-1.80, P = 0.487), post-TMVR complications, length of stay (OR 1.15, 95%CI 0.97-1.38, P = 0.111), and cost of hospitalization (OR 1.04, 95%CI 0.94 1.14, P = 0.475) between the group with AF versus without AF. However, patients with AF were more likely to have non-routine hospital discharge (42.94% vs 35.48% P = 0.02). CONCLUSION: AF is a frequently encountered arrhythmia among patients undergoing TMVR with MitraClip. However, TMVR can be performed safely in the vast majority of patients, irrespective of their baseline rhythm. PMID- 30456771 TI - The effect of cancer diagnosis on switching health insurance in medicare. AB - Because health insurance is intended to protect patients in the event of a health shock, it is important to evaluate health insurance policy in the context of patients who experience health shocks. I measure the effect of cancer diagnosis on health insurance switching in order to compare cancer patient's preferences among private and publicly administered Medicare. I estimate that a cancer diagnosis increases the probability a patient will leave a private Medicare plan, for the public plan, by 0.8% points (41%). Similarly, a cancer diagnosis decreases the probability a patient will leave the public Medicare plan, for a private plan, by 0.5% points (16%). The implication is that private Medicare plans are relatively less attractive to cancer patients than they are to noncancer patients. PMID- 30456772 TI - Environmental and physiochemical controls on coral calcification along a latitudinal temperature gradient in Western Australia. AB - The processes that occur at the micro-scale site of calcification are fundamental to understanding the response of coral growth in a changing world. However, our mechanistic understanding of chemical processes driving calcification is still evolving. Here, we report the results of a long-term in situ study of coral calcification rates, photo-physiology, and calcifying fluid (cf) carbonate chemistry (using boron isotopes, elemental systematics, and Raman spectroscopy) for seven species (four genera) of symbiotic corals growing in their natural environments at tropical, subtropical, and temperate locations in Western Australia (latitudinal range of ~11 degrees ). We find that changes in net coral calcification rates are primarily driven by pHcf and carbonate ion concentration [ CO32- ]cf in conjunction with temperature and DICcf . Coral pHcf varies with latitudinal and seasonal changes in temperature and works together with the seasonally varying DICcf to optimize [ CO32- ]cf at species-dependent levels. Our results indicate that corals shift their pHcf to adapt and/or acclimatize to their localized thermal regimes. This biological response is likely to have critical implications for predicting the future of coral reefs under CO2 -driven warming and acidification. PMID- 30456773 TI - Reinterpreting homoeopathy in the light of placebo effects to manage patients who seek homoeopathic care: A systematic review. AB - Homoeopathy is widespread, and users claim to benefit from it. However, clear evidence of its efficacy over placebo is not available to date. As a consequence, a social separation between homoeopathy users and mainstream medicine exists, exposing these patients to many risks. Our primary objective is to assess homoeopathy efficacy by systematically reviewing existing systematic reviews and meta-analyses and to systematically review trials on open-label placebo (OLP) treatments. A secondary objective is to understand if homoeopathy as a whole may be considered as a placebo treatment. PubMed/Medline, Embase, Google Scholar, and Cochrane Library were systematically searched for systematic reviews and meta analyses on homoeopathy efficacy, and 61 studies were included. Same databases plus Journal of Interdisciplinary Placebo Studies (JIPS) were also systematically searched for randomised controlled trials (RCTs) on OLP treatments, and 10 studies were included. Databases were searched up to 24 February 2018. Two authors independently screened all retrieved articles and selected studies eligible for inclusion. The quality of reviews of included studies was evaluated with a dedicated NIH tool in the first review, whereas the risk of bias of trials of included studies was assessed with the specific Cochrane tool in the second review. Qualitative syntheses show that homoeopathy efficacy can be considered comparable to placebo, and that OLP treatments may be effective in some health conditions. Placebo effects like placebo itself, treatment context, physician patient relationship, and other nonspecific factors can define the idea of placebo treatments, which may be effective in some conditions. If homoeopathy efficacy is comparable to placebo, and if placebo treatments can be effective in some conditions, then homoeopathy as a whole may be considered as a placebo treatment. Reinterpreting homoeopathy as a placebo treatment would define limits and possibilities of this practice. This perspective shift suggests a strategy to manage patients who seek homoeopathic care and to reconcile them with mainstream medicine in a sustainable way. PMID- 30456775 TI - Prevention of early-onset GBS disease: A pinch of probability is worth a pound of perhaps. AB - An effective screening program identifies risk factors that increase disease likelihood, and reduces disease development through risk modification or intervention strategies tailored to the population. No screening program exemplifies this more than the prevention of newborn early-onset group B streptococcal (EOGBS) disease. From the 1990s, guidelines advocated either a risk based or a screening approach for intrapartum antibiotic prophylaxis. Unfortunately, no randomized trials have evaluated risk factor based intrapartum antibiotic prophylaxis versus universal screening approaches for the prevention of perinatal group B streptococcal infection. This article is protected by copyright. All rights reserved. PMID- 30456774 TI - Using a tablet application about nutrition in home care-Experiences and perspectives of healthcare professionals. AB - Undernutrition is an extensive problem among patients in community care services. The literature identifies several barriers that hinder health professionals in identifying nutritional problems and providing nutrition interventions. We developed Appetitus, a tablet application (app) focused on nutrition for older adults. Patients used the app, advised by healthcare professionals. In this study with qualitative design, we explored experiences and perspectives of healthcare professionals who used Appetitus when providing home care. We interviewed 24 healthcare professionals individually and in focus groups. We subjected the data to qualitative content analysis. Healthcare professionals used Appetitus as a mediator in dialogues with patients about nutrition. Giving the older adults an active role in nutrition assessment afforded opportunities to strengthen their involvement in care. Registrations of food and drink consumption gave the healthcare professionals insight into patients' situations and revealed problems of which the healthcare professionals had not been aware. Based on their experience with Appetitus, healthcare professionals suggested using electronic tools to assess and document the nutritional situation of a larger patient group in home care. In future use of Appetitus, healthcare professionals' levels of knowledge and confidence when advising patients about nutrition must be emphasised and addressed. Barriers such as time constraints and limited continuity of care are also areas that require attention when new nutrition practices are implemented. PMID- 30456776 TI - Electronic medical record documentation of tobacco cessation support at eight community safety-net clinics with a high prevalence of tobacco use. AB - OBJECTIVES: The high prevalence of tobacco use at primary care safety-net clinics represents an opportunity to offer assistance with cessation. Documentation of smoking status, offering advice and medications, and referral to cessation services are important steps in supporting cessation attempts and are required elements by payors and accrediting agencies to demonstrate care quality. This study examines tobacco cessation support rates and patient characteristics using electronic medical record (EMR) data. METHODS: This cross-sectional study engaged eight community health centers affiliated with a county hospital system in NE Ohio where adult tobacco use rates exceed 30%. EMR data from June 2014 through May 2016 were analysed to assess rates of tobacco cessation counselling, order of cessation medications, or both. The association of tobacco cessation support with patient characteristics and quit attempts was assessed using multivariable logistic regression models. RESULTS: Among 21 702 current tobacco users, 74% had no intervention documented; 15.4% had counselling documented, 6.4% were prescribed tobacco cessation medication, and 4.2% had both documented. Males, those aged 18 to 34, and African Americans were more likely to have no documented intervention. Of current tobacco users with at least two visits, 5.6% had a quit attempt. Medication alone was associated with a greater likelihood of a quit attempt (AOR: 1.72 [95% CI: 1.36-2.17]) as well as counselling and medication combined (AOR: 1.95 [95% CI: 1.48-2.56]). CONCLUSIONS: Tobacco cessation support was lacking for 74% of current smokers and was less likely in subgroups including males, younger adults, and African Americans. Ordering tobacco cessation medication combined with counselling nearly doubled the likelihood of a quit attempt. PMID- 30456777 TI - Tuning of hydrogel stiffness using a two-component peptide system for mammalian cell culture. AB - Self-assembling peptide hydrogels (SAPHs) represent emerging cell cultures systems in several biomedical applications. The advantages of SAPHs are mainly ascribed to the absence of toxic chemical cross-linkers, the presence of ECM-like fibrillar structures and the possibility to produce hydrogels with a large range of different mechanical properties. We will present a two-component peptide system with tuneable mechanical properties, consisting of a small pentapeptide (SFFSF-NH2 , SA5N) that acts as a gelator and a larger 21-mer peptide (SFFSF GVPGVGVPGVG-SFFSF, SA21) designed as a physical cross-linker. The hydrogels formed by different mixtures of the two peptides are made up mainly of antiparallel beta-sheet nanofibers entangling in an intricate network. The effect of the addition of SA21 on the morphology of the hydrogels was investigated by atomic force microscopy and transmission electron microscopy and correlated to the mechanical properties of the hydrogel. Finally, the biocompatibility of the hydrogels using 2D cell cultures was tested. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 00A: 000-000, 2018. PMID- 30456778 TI - Safety and acceptability of medical abortion by telemedicine above nine gestational weeks: a population-based cohort study. AB - OBJECTIVE: To assess the safety and acceptability of abortion through telemedicine > 9 (9+0) gestational weeks (gw). DESIGN: Cohort study. SETTING: Poland. POPULATION: 615 women who requested and performed abortion through telemedicine June 1st- December 31st 2016. METHODS: Risks of adverse outcomes were calculated as adjusted odds ratios (OR) with 95% confidence intervals (CI) by unconditional logistic regression according to gestational age at abortion <= or > 9 gw. MAIN OUTCOME MEASURES: Self-reported hospital visits for concerns related to the abortion within 0-1 days of the abortion, heavy bleeding, pain and bleeding more than expected and low satisfaction. RESULTS: Among women <= 9gw and >9gw, 3.3% vs 11.7% went to hospital for concerns within 0-1 days of the abortion (AOR 3.82, 95% CI 1.90-7.69). Among women 11w+1d-14w+2d the rate was 22.5% (AOR 9.20, 95% CI 3.58-23.60). Among women <= 9gwand > 9 gw, the rate of heavy bleeding was 6.8% vs 10.1% (AOR 1.65, 95% CI 0.90-3.04), the rate of low satisfaction was 2.4% vs 1.6% (AOR 0.69, 95% CI 0.14-3.36), the rate of bleeding more than expected was 45.6% vs 57.8% (AOR 1.26, 95% CI 0.78-2.02), and the rate of pain more than expected was 35.6% vs 38.8% (AOR 1.11, 95% CI 0.71-1.71). CONCLUSIONS: Medical abortion through telemedicine >9 gw is associated with a higher risk of same-day or day-after hospital visits for concerns related to the procedure and this risk increases with gestational age. Self-reported rates of heavy bleeding, low satisfaction or unmet expectations with medical abortion do not increase with gestational age. This article is protected by copyright. All rights reserved. PMID- 30456779 TI - Analysis of implant loss risk factors especially in maxillary molar location: A retrospective study of 6977 implants in Chinese individuals. AB - BACKGROUND: The knowledge of the potential risk factors associated with implant loss is crucial for dental clinicians, but the opinions about the risk factors are still diverse and controversial. PURPOSE: This retrospective study assessed the risk factors associated with implant loss, especially that in the maxillary molar location. MATERIALS AND METHODS: From January 2015 to March 2017, 4338 Chinese patients received 6977 implants at Nanjing Stomatological Hospital. Information on patient age, gender, bone grafting procedure, implant location, length and diameter, and the records of lost implants were obtained. The Kaplan Meier method and log-rank test were used to conduct a survival function analysis. Chi-square test and multivariate Cox regression analysis were used to identify risk factors related to implant loss. RESULTS: The cumulative survival rate (CSR) after 0-32 months of observation period for all implants was 97.76%, and the CSR for maxillary molar implants was 97.00%. Maxillary molar implants showed a significantly lower CSR than the other implants (P < .05). Male sex, short implants (<10 mm) were considered as risk factors for implant loss. However, male sex and bone grafting procedure were regarded as risk factors for maxillary molar implant loss, which was slightly different from the result of all implants. CONCLUSIONS: Male sex, short implants (<10 mm) and maxillary molar location were considered as potential risk factors for implant loss, whereas male sex and bone grafting procedure were significantly associated with implant loss in maxillary molar location. PMID- 30456781 TI - How thyroid hormones and their inhibitors affect cartilage growth and shape in the frog Xenopus laevis. AB - Understanding how skeleton changes shape in ontogeny is fundamental to understanding how its shape diversifies in phylogeny. Amphibians pose a special case because their jaw and throat skeleton consists of cartilages that are dramatically reshaped midway through life to support new feeding and breathing styles. Although amphibian metamorphosis is commonly studied by immersing larvae in thyroid hormones (TH), how individual cartilages respond to TH is poorly understood. This study documents the effects of larval stage and TH type (T4 vs. T3), dose and deprivation on the size, shape and morphogenesis of the lower jaw and ceratohyal cartilages in the frog Xenopus laevis. It uses thyroid inhibitors to isolate the effects of each hormone at specific concentrations. It also deconstructs the TH responses into the effects on individual dimensions, and uses measures of percent change to eliminate the effects of body size and growth rate variation. As stage increases, T4 and T3 responses become increasingly similar to each other and to natural remodeling; the differences at low and intermediate stages result largely from abnormal responses to T3. Most notably, the beak-like lower jaw commonly observed at the lowest stage in other studies results largely from arrested growth of cartilage. TH responses are superimposed upon the growth typical for each stage so that cartilages can attain postmetamorphic shapes through dimensional changes that exceed those of natural metamorphosis. Using thyroid inhibitors alters the outcome of TH-induced remodeling, and T4 has almost the same capacity to induce metamorphic shape changes as T3. The results have implications for understanding how the starting shapes of larval elements affect morphogenesis, how chondrocytes behave to change cartilage shape, and how intracellular processing of TH might contribute to interspecific differences in shape change. Also, the data on animal mortality and which stages and doses most closely replicate natural remodeling have practical value for researchers who treat Xenopus tadpoles with TH. PMID- 30456780 TI - Effects of a topical lotion containing aminophylline, caffeine, yohimbe, l carnitine, and gotu kola on thigh circumference, skinfold thickness, and fat mass in sedentary females. AB - BACKGROUND AND OBJECTIVE: Topical aminophylline, caffeine, yohimbe, l-carnitine, and gotu kola (Centella asiatica) may aid in reducing body fat. LipoxydermTM contains these ingredients and was used to test if fat loss of the thigh, in conjunction with a low intensity exercise program and restricted calorie intake, was enhanced via the topical application of this lotion. METHODS: This was a double-blind, placebo-controlled, within-group study that investigated the effects of LipoxydermTM on thigh fat mass, circumference, and skinfold thickness. Seven participants underwent pre/post-exercise testing for weight, bilateral thigh circumference/skinfold thickness, and body composition/thigh fat mass assessment via dual-energy X-ray absorptiometry. Participants followed a hypocaloric diet, walked 150 minutes/wk, and were randomly assigned to apply a placebo to one leg and LipoxydermTM to their other leg for 28 days. Separate two way mixed factorial repeated measures ANOVAs were used to compare the effects of LipoxydermTM to the placebo on thigh circumference, skinfold thickness, and fat mass. RESULTS: A significant time x group interaction was found for thigh circumference (F1,6 = 18.2, P = 0.005), skinfold thickness (F1,6 = 14.6, P = 0.009), and fat mass (F1,6 = 37.1, P = 0.001). CONCLUSIONS: A twice-daily topical application of LipoxydermTM for 28 days compared to a placebo combined with a walking program and a restricted caloric intake is more effective at reducing thigh circumference (1.2 vs 0.8 cm), thigh skinfold thickness (3.7 vs 2.0 mm), and thigh fat mass (100.0 g vs 57.3 g). PMID- 30456782 TI - Whole- and partial-body cryotherapy in aesthetic dermatology: Evaluating a trendy treatment. AB - This manuscript addresses the use of whole- and partial-body cryotherapy in aesthetic dermatology. Over the past several years, these have become trendy treatments that have been marketed for many purported benefits in overall skin appearance and skin health. With increased access through cryotherapy facilities and medical spas, whole- and partial-body cryotherapy have grown in popularity. Unfortunately, many of the advertised claims have little, if any, scientific evidence behind them. Here, we summarize the data available in the literature. As trends evolve, clinicians should continue to be knowledgeable about them and their evidence in order to properly counsel patients appropriately. PMID- 30456783 TI - The human circadian clock from health to economics. AB - In the course of evolution, health is prioritized for human well-being and economies. Epidemiological and experimental studies suggest that modern life habits, including eating habits, and living and working conditions, can deteriorate health through circadian misalignment. This has been most commonly observed with urban societies and working classes of non-standard working schedules (NSWSs), such as shift work, night work, and overtime work. Poor health conditions with NSWSs generate economic burden for the modern society. Therefore, we attempt to provide a systematic approach to understanding the relations among the circadian clock, health, and economics. To understand these connections, we review the mechanisms of the human circadian clock and how modern living conditions can misalign the circadian system and associated health consequences. We also emphasize the importance of health for the modern economy and the economic costs of health disorders associated with circadian disruption and NSWSs. PMID- 30456784 TI - Contact dermatitis caused by ballpoint pen ink: A problem for a schoolchild. PMID- 30456785 TI - LY294002, a PI3K pathway inhibitor, prevents leptin-induced adverse effects on spermatozoa in Sprague-Dawley rats. AB - This study examined the effects of PI3K and AMPK signalling pathway inhibitors on leptin-induced adverse effects on rat spermatozoa. Sprague-Dawley rats, aged 14 16 weeks, were randomised into control, leptin-, leptin + dorsomorphin (AMPK inhibitor)-, and leptin+LY294002 (PI3K inhibitor)-treated groups with six rats per group. Leptin was given once daily for 14 days via the intraperitoneal (i.p.) route at a dose of 60 ug kg-1 body weight. Rats in the leptin and inhibitor treated groups received concurrently either dorsomorphin (5 mg kg-1 day-1 ) or LY294002 (1.2 mg kg-1 day-1 ) i.p. for 14 days. Controls received 0.1 ml of normal saline. Upon completion, sperm count, sperm morphology, seminiferous tubular epithelial height (STEH), seminiferous tubular diameter (STD), 8-hydroxy 2-deoxyguanosine (8-OHdG) and phospho-Akt/total Akt ratio were estimated. Data were analysed using ANOVA. Sperm count, STEH and STD were significantly lower, while the percentage of spermatozoa with abnormal morphology and the level of 8 OHdG were significantly higher in rats treated with leptin and leptin + dorsomorphin when compared to those in controls and LY294002-treated rats. Testicular phospho-Akt/total Akt ratio was significantly higher in leptin and leptin + LY294002-treated rats. In conclusion, LY294002 prevents leptin-induced changes in rat sperm parameters, suggesting the potential role of the PI3K signalling pathway in the adverse effects of leptin on sperm parameters. PMID- 30456786 TI - Nonparametric Group Sequential Methods for Evaluating Survival Benefit from Multiple Short-Term Follow-up Windows. AB - This manuscript takes a fresh look at group sequential methods applied to two sample tests of censored survival data and proposes an alternative method of defining and evaluating treatment benefit. Our method re-purposes traditional censored event time data into a sequence of short-term outcomes taken from (potentially overlapping) follow-up windows. A new two-sample restricted means test based on this restructured follow-up data is proposed along with group sequential methods for its use in the clinical trial setting. This method compares favorably with existing methods for group sequential monitoring of time to-event outcomes, including methods for monitoring the restricted means test and the logrank test. Our method performs particularly well in cases where there is a delayed treatment effect and/or a subset of cured patients. As part of developing group sequential methods for these analyses, we consider asymmetric error spending approaches that differentially limit the chances of stopping incorrectly for perceived efficacy versus perceived harm attributed to the investigational arm of the trial. Recommendations for how to choose proper group sequential stopping boundaries are given, with supporting simulations and an example from the AIDS Clinical Trial Group. This article is protected by copyright. All rights reserved. PMID- 30456787 TI - Clinical Endpoint Bioequivalence Studies Are Not Sensitive: A Perspective From Generic Drugs. PMID- 30456788 TI - In this December issue. PMID- 30456789 TI - Cultural competence in the emergency department: Clinicians as cultural learners. PMID- 30456791 TI - Equity for Indigenous peoples in the emergency department: A Maori perspective. PMID- 30456792 TI - When guidelines guide us to harm. PMID- 30456793 TI - Repeated blast model of mild traumatic brain injury alters oxycodone self administration and drug seeking. AB - Each year, traumatic brain injuries (TBI) affect millions worldwide. Mild TBIs (mTBI) are the most prevalent and can lead to a range of neurobehavioral problems, including substance abuse. A single blast exposure, inducing mTBI alters the medial prefrontal cortex, an area implicated in addiction, for at least 30 days post injury in rats. Repeated blast exposures result in greater physiological and behavioral dysfunction than single exposure, however, the impact of repeated mTBI on addiction is unknown. In this study, the effect of mTBI on various stages of oxycodone use was examined. Male Sprague Dawley rats were exposed to a blast model of mTBI once per day for three days. Rats were trained to self-administer oxycodone during short (2 hour) and long (6 hour) access sessions. Following abstinence, rats underwent extinction and two, cued reinstatement sessions. Sham and rbTBI rats had similar oxycodone intake, extinction responding, and cued reinstatement of drug seeking. A second group of rats were trained to self-administer oxycodone with varying reinforcement schedules (fixed ratio (FR)-2 and FR-4). Under an FR-2 schedule, rbTBI-exposed rats earned fewer reinforcers than sham-exposed rats. During 10 extinction sessions, the rbTBI-exposed rats exhibited significantly more seeking for oxycodone than the sham-injured rats. There was a positive correlation between total oxycodone intake and day 1 extinction drug seeking in sham, but not rbTBI exposed rats. Together, this suggests that rbTBI-exposed rats are more sensitive to oxycodone-associated cues during reinstatement than sham-exposed rats and that rbTBI may disrupt the relationship between oxycodone intake and seeking. This article is protected by copyright. All rights reserved. PMID- 30456794 TI - Icariside II prevents hypertensive heart disease by alleviating endoplasmic reticulum stress via the PERK/ATF-4/CHOP signalling pathway in spontaneously hypertensive rats. AB - OBJECTIVES: Reducing endoplasmic reticulum stress (ERS)-induced cardiomyocyte apoptosis is a key strategy for preventing hypertensive heart disease. In our previous study, Icariside II can improve left ventricular remodelling in spontaneously hypertensive rats (SHRs). This study aims to determine whether Icariside II can exert its effect by inhibiting ERS-induced cardiomyocyte apoptosis via the PERK/ATF-4/CHOP signalling pathway. METHODS: Spontaneously hypertensive rats were randomly divided into model group and Icariside II groups. The rats in the Icariside II groups were intragastrically administrated with Icariside II 4, 8 and 16 mg/kg from 14 to 26 week-age, respectively. The left ventricular function was measured at the 18, 22 and 26 week-age by small animal ultrasound. At the end of the 26th week, cardiomyocyte apoptosis was analysed and the levels of GRP78, PERK, ATF-4 and CHOP gene and protein were detected. KEY FINDINGS: The function of left ventricular became declined with age in SHRs, but improved in Icariside II groups. Myocardial apoptosis was aggravated in SHRs, but alleviated in Icariside II groups. Icariside II could reduce the levels of GRP78, PERK, ATF-4, CHOP gene and protein that increased in SHRs. CONCLUSIONS: Icariside II prevents hypertensive heart disease by alleviating ERS-induced cardiomyocyte apoptosis, and its mechanism is related to the impediment of the PERK/ATF-4/CHOP signalling pathway. PMID- 30456795 TI - Burst SCS Microdosing Is as Efficacious as Standard Burst SCS in Treating Chronic Back and Leg Pain: Results From a Randomized Controlled Trial. AB - INTRODUCTION: The burst waveform, a recent innovation in spinal cord stimulation (SCS), can achieve better outcomes than conventional tonic SCS, both for de novo implants and as a salvage therapy. Burst stimulation delivers more energy per second than tonic stimulation, which is a consideration for battery consumption. The clinical effectiveness of an energy-conserving strategy was investigated. METHODS: Subjects were experienced users of BurstDR SCS for back and leg pain. Three 2-week stimulation paradigms were presented in blinded random order: standard (continuously delivered) BurstDR, microdosing A: 5 sec of BurstDR alternating with 5 sec of no stimulation, and microdosing B: 5 sec of BurstDR alternating with 10 sec of no stimulation. The primary outcome for each paradigm was change in pain ratings, and secondary outcomes included changes in scores for quality of life, satisfaction, and preference. RESULTS: Twenty-five subjects assessed all three stimulation paradigms. There were no significant differences in pain (visual analog scale) or quality of life (EQ-5D) when comparing standard burst outcomes with those of microdosing A and, separately, microdosing B. Microdosing paradigms were graded with slightly higher level of satisfaction and were generally preferred above standard burst stimulation. DISCUSSION: These results suggest that the use of energy-efficient burst microdosing stimulation paradigms with alternating stimulation-on and stimulation-off periods can provide clinically equivalent results to standard burst stimulation. This is important for extending SCS battery life. Further research is needed to comprehensively characterize the clinical utility of this approach and the neurophysiological mechanisms for the maintenance of pain relief during stimulation-off periods. PMID- 30456796 TI - Glycaemic Efficacy and Safety of Linagliptin compared to Basal-Bolus Insulin Regimen in Patients with Type 2 Diabetes Undergoing Non-Cardiac Surgery: A Multicenter Randomized Clinical Trial. AB - AIMS: The use of incretin-based therapy instead of or complementary to insulin therapy is an active area of research in hospitalized patients with type 2 diabetes (T2D). We determined glycaemic efficacy and safety of linagliptin compared to basal-bolus insulin regimen in hospitalized surgical patients with T2D. MATERIALS AND METHODS: This prospective open-label multicenter study randomized T2D patients undergoing non-cardiac surgery with admission blood glucose(BG) 7.8-22.2 mmol/L treated with diet, oral agents or total insulin dose(TDD) <=0.5 units/kg/day to linagliptin(n=128) daily or basal-bolus(n=122) with glargine once daily and rapid-acting insulin before meals. Both groups received supplemental insulin for BG>7.8 mmol/L. The primary endpoint was difference in mean daily BG between groups. RESULTS: Mean daily BG was inferior in linagliptin compared to basal-bolus group (9.5+/-2.6 vs. 8.8+/-2.3 mmol/L/dL, p=0.03) with mean daily BG difference of 0.6mmol/L (95% confidence interval 0.04, 1.2). In patients with randomization BG<11.1 mmol/L (63% of cohort), mean daily BG was similar in linagliptin vs basal-bolus (8.9+/-2.3 vs. 8.7+/-2.3 mmol/L, p=0.43); however, patients with BG>=11.1 mmol/L treated with linagliptin had higher BG compared to basal-bolus (10.9+/-2.6 vs. 9.2+/-2.2 mmol/L, p<0.001). Linagliptin resulted in fewer hypoglycaemic events (1.6% vs. 11%, p=0.001, 86% relative risk reduction), similar supplemental insulin (and lower number of daily insulin injections (2.0+/-3.3 vs 3.1+/-3.3, p<0.001) compared to basal-bolus. CONCLUSIONS: In patients with T2D undergoing non-cardiac surgery presenting with mild to moderate hyperglycaemia (BG <11.1 mmol/L), daily linagliptin is a safe and effective alternative to multi-dose insulin therapy resulting in similar glucose control with lower hypoglycaemia. This article is protected by copyright. All rights reserved. PMID- 30456797 TI - Microglial modulation through colony-stimulating factor-1 receptor inhibition attenuates demyelination. AB - Multiple sclerosis (MS) is one of the most common causes of progressive disability affecting young people with very few therapeutic options available for its progressive forms. Its pathophysiology involves demyelination and neurodegeneration apparently driven by microglial activation, which is physiologically dependent on colony-stimulating factor-1 receptor (CSF-1R) signaling. In the present work, we used microglial modulation through oral administration of brain-penetrant CSF-1R inhibitor BLZ945 in acute and chronic cuprizone (CPZ)-induced demyelination to evaluate preventive and therapeutic effects on de/remyelination and neurodegeneration. Our results show that BLZ945 induced a significant reduction in the number of microglia. Preventive BLZ945 treatment attenuated demyelination in the acute CPZ model, mainly in cortex and external capsule. In contrast, BLZ945 treatment in the acute CPZ model failed to protect myelin or foster remyelination in myelin-rich areas, which may respond to a loss in microglial phagocytic capacity and the consequent impairment in oligodendroglial differentiation. Preventive and therapeutic BLZ945 treatment promoted remyelination and neuroprotection in the chronic model. These results could be potentially transferred to the treatment of progressive forms of MS. PMID- 30456798 TI - The Effects of Depressive Symptom Management Interventions on Low-Income Mothers: A Systematic Review and Meta-Analysis. AB - AIM: To evaluate the effects of depressive symptom management interventions for low-income mothers. BACKGROUND: Depressive symptoms and depression are common complications following childbirth. Depressive symptoms experienced by low-income mothers negatively affect infant-toddler development. DESIGN: A systematic review and meta-analysis was conducted to provide a synthesized and critical appraisal of the included studies. DATA SOURCES: We conducted a systematic search of randomized controlled trials in the following electronic databases through November 2017: PubMed, EMBASE, CINAHL, PsycInfo and Cochrane Library CENTRAL. REVIEW METHODS: Ten studies were found in the systematic review of depressive symptom management interventions in terms of content, mode of delivery, session and provider. We then conducted a meta-analysis of nine randomized controlled trials with 798 participants, comparing low-income mothers with and without depressive symptom management interventions. RESULTS: A significant effect was noted for depressive symptom management interventions in improving depressive symptoms in low-income mothers with young children and for interventions lasting eight weeks or less. CONCLUSION: The meta-analysis suggested that depressive symptom management interventions for low-income mothers can be effective; however, the effectiveness varies by intervention type, intervention duration and whether the mothers had other children. IMPACT: The findings of this study will contribute to the development of effective depressive symptom management interventions by providing scientific evidence for the development of such programs for low-income mothers, especially with respect to target population and intervention duration. This article is protected by copyright. All rights reserved. PMID- 30456800 TI - The red cell phenotype and compatibility calculators: Two web-based tools. PMID- 30456799 TI - Exercise during transition from compensated left ventricular hypertrophy to heart failure in aortic stenosis rats. AB - We evaluated the influence of aerobic exercise on cardiac remodelling during the transition from compensated left ventricular (LV) hypertrophy to clinical heart failure in aortic stenosis (AS) rats. Eighteen weeks after AS induction, rats were assigned into sedentary (AS) and exercised (AS-Ex) groups. Results were compared to Sham rats. Exercise was performed on treadmill for 8 weeks. Exercise improved functional capacity. Echocardiogram showed no differences between AS-Ex and AS groups. After exercise, fractional shortening and ejection fraction were lower in AS-Ex than Sham. Myocyte diameter and interstitial collagen fraction were higher in AS and AS-Ex than Sham; however, myocyte diameter was higher in AS Ex than AS. Myocardial oxidative stress, evaluated by lipid hydroperoxide concentration, was higher in AS than Sham and was normalized by exercise. Gene expression of the NADPH oxidase subunits NOX2 and NOX4, which participate in ROS generation, did not differ between groups. Activity of the antioxidant enzyme superoxide dismutase was lower in AS and AS-Ex than Sham and glutathione peroxidase was lower in AS-Ex than Sham. Total and reduced myocardial glutathione, which is involved in cellular defence against oxidative stress, was lower in AS than Sham and total glutathione was higher in AS-Ex than AS. The MAPK JNK was higher in AS-Ex than Sham and AS groups. Phosphorylated P38 was lower in AS-Ex than AS. Despite improving functional capacity, aerobic exercise does not change LV function in AS rats. Exercise restores myocardial glutathione, reduces oxidative stress, impairs JNK signalling and further induces myocyte hypertrophy. PMID- 30456801 TI - Cerebral blood flow modulations during antisaccade preparation in chronic hypotension. AB - In addition to symptoms including fatigue, dizziness, reduced drive, or mood disturbance, individuals with chronic low blood pressure (hypotension) frequently report cognitive complaints. While attentional deficits have been empirically confirmed, it is still unknown whether the impairments also encompass executive functions. This study investigated cerebral blood flow modulations in hypotension during a precued antisaccade/prosaccade task requiring the executive function of proactive inhibition in addition to preparatory attention. Using functional transcranial Doppler sonography, bilateral blood flow velocities in the middle cerebral arteries (MCA) were recorded in 39 hypotensive and 40 normotensive participants. In the task, a stimulus appeared left or right of a fixation point 5 s after a cuing stimulus; subjects had to move their gaze to the mirror image position of the stimulus (antisaccade) or toward it (prosaccade control condition). Video-based eye tracking was used for ocular recording. A right dominant MCA blood flow increase arose during task preparation, which was smaller in hypotensive than normotensive participants. In addition, hypotensive participants exhibited lower peak velocity of the saccadic response. The extent of the reductions in blood flow and task performance in hypotension did not differ between antisaccade and prosaccade conditions. The smaller MCA flow increase may reflect reduced activity in the dorsolateral prefrontal and inferior parietal cortices during proactive inhibition and preparatory attention in hypotension. Given that group differences in blood flow and performance arose independent of task complexity and executive function load, hypotension may be characterized by basic attentional impairments rather than particular executive function deficits. PMID- 30456802 TI - HMGB1-RAGE signaling facilitates Ras-dependent Yap1 expression to drive colorectal cancer stemness and development. AB - HMGB1-RAGE signaling plays an integral role in inflammation-driven carcinogenesis. In the present study, we showed that RAGE has direct association with K-Ras following HMGB1 exposure in colorectal cancer (CRC) cells. Immunofluorescence analysis revealed a significant co-localization between RAGE and K-Ras in HMGB1-exposed CRC cells. Moreover, we uncovered that HMGB1-mediated RAGE activation led to Yap1 accumulation in a Ras-dependent mechanism in CRC cells. HMGB1 activated the expression of Yap1 downstream stemness marker proteins CD44 and Sox2 in RAGE- and Ras-dependent manners. Furthermore, HMGB1 exposure led to the proliferation of CRC cells and the expansion of CRC stem cells. RAGE, Yap1 and CD44 were overexpressed in CRC specimens. Linear regression analysis revealed that the expression of RAGE was positively correlated with Yap1 in clinical CRC specimens. Both of RAGE and Yap1 expression were correlated with advanced histological grades, lymph node metastasis and TNM stages. Finally, we revealed that both of RAGE and Yap1 expression could predicted unfavorable prognosis in CRC patients. These findings implicated that HMGB1-RAGE signaling may promote Yap1 activation and CRC progression, shedding new light on the mechanisms underlying inflammation-driven CRC development. This article is protected by copyright. All rights reserved. PMID- 30456803 TI - Validation of Current Good Manufacturing Practice Compliant Human Pluripotent Stem Cell-Derived Hepatocytes for Cell-Based Therapy. AB - Recent advancements in the production of hepatocytes from human pluripotent stem cells (hPSC-Heps) afford tremendous possibilities for treatment of patients with liver disease. Validated current good manufacturing practice (cGMP) lines are an essential prerequisite for such applications but have only recently been established. Whether such cGMP lines are capable of hepatic differentiation is not known. To address this knowledge gap, we examined the proficiency of three recently derived cGMP lines (two hiPSC and one hESC) to differentiate into hepatocytes and their suitability for therapy. hPSC-Heps generated using a chemically defined four-step hepatic differentiation protocol uniformly demonstrated highly reproducible phenotypes and functionality. Seeding into a 3D poly(ethylene glycol)-diacrylate fabricated inverted colloid crystal scaffold converted these immature progenitors into more advanced hepatic tissue structures. Hepatic constructs could also be successfully encapsulated into the immune-privileged material alginate and remained viable as well as functional upon transplantation into immune competent mice. This is the first report we are aware of demonstrating cGMP-compliant hPSCs can generate cells with advanced hepatic function potentially suitable for future therapeutic applications. Stem Cells Translational Medicine 2018. PMID- 30456804 TI - An open-label, single-site study to evaluate the tolerability, safety, and efficacy of using a novel facial moisturizer for preparation and accelerated healing pre and post a single full-face radiofrequency microneedling treatment. AB - BACKGROUND: Skincare cosmeceutical products have been shown to address intrinsic and extrinsic skin aging. Radiofrequency (RF) with microneedling is effective and safe in improving skin laxity and texture. Pairing skincare cosmeceutical products pre- and post-procedure is beneficial as it enhances patient results, patient results, patient experience, and reduces patient downtime. OBJECTIVE: To evaluate the tolerability, safety, and efficacy of a multi-ingredient anti-aging facial moisturizer when applied pre- and post-procedure consisting of a single RF microneedling treatment. METHOD: Fifteen female patients, aged 37-60, Fitzpatrick skin types I-IV, with mild-to-moderate wrinkles were included in the study. Patients applied a multi-ingredient anti-aging facial moisturizer twice a day (morning and night) two weeks prior to RF microneedling and four weeks post-RF microneedling (twice a day). At each time point, investigator objective assessment, self-assessments, and clinical photography were taken. RESULT: There were no adverse events as evaluated by the investigator. For this combined treatment and procedure patient scored comfort as the highest for satisfaction. Tolerability parameters erythema and edema were reported after RF microneedling treatment and were significant compared to the pre-procedure timepoint. Eighty percent of patients showed an improvement in Glogau Wrinkle Scale, but improvement was not statistically significant between baseline and end of study. Improvements in all skin attributes (radiance, tone, smoothness, texture, redness, dryness, and overall appearance) were statistically significant at the end of the study. Self-perceived skin attribute improvements included overall improvement, brightness, texture, pigmentation, redness, and tightness. The combination of the anti-aging facial moisturizer and RF microneedling was recommended by the patients in this study. CONCLUSION: This clinical study positively supports the hypothesis that combining the multi-ingredient anti-aging facial moisturizer pre- and post-RF microneedling was safe and tolerable for the patients. PMID- 30456805 TI - LncRNA FOXD2-AS1 accelerates the papillary thyroid cancer progression through regulating the miR-485-5p/KLK7 axis. AB - It has been proved that long noncoding RNAs (lncRNAs) are important modulators in the tumorigenesis and progression of various malignant tumors. Recently, lncRNA FOXD2-AS1 has been reported to be an oncogene in several kinds of human cancers. However, the function of FOXD2-AS1 in papillary thyroid cancer (PTC) has not been well investigated. This study aims to explore the biological role and mechanism of FOXD2-AS1 in PTC. At first, the expression of FOXD2-AS1 was examined in PTC tissues and cell lines with quantitative reverse transcription-polymerase chain reaction (qRT-PCR). FOXD2-AS1 was found to observably upregulated in PTC tissues and cell lines. Kaplan-Meier survival analysis revealed that high expression of FOXD2-AS1 was closely correlated with the unfavorable prognosis of patients with PTC. Based on the TCGA data set, KLK7 was overexpressed in PTC tumor samples. Our experimental data further validated the upregulation of KLK7 in PTC tissues and cell lines. Similarly, high level of KLKF was associated with poor prognosis of patients with PTC. The positive expression association between FOXD2-AS1 and KLK7 was analyzed with Pearson correlation coefficient. Loss-of-function assays revealed that knockdown of FOXD2-AS1 or KLK7 greatly inhibited PTC cell proliferation and migration, while induced cell apoptosis. Results of mechanism experiments suggested that FOXD2-AS1 functioned as a competing endogenous RNA (ceRNA) to enhance the expression of KLK7 by sponging miR-485-5p in PTC. Rescue assays were conducted to verify the function of FOXD2-AS1/miR-485-5p/KLK7 axis in PTC progression. PMID- 30456806 TI - Repeating a year of UK medical school. PMID- 30456807 TI - Tetrahydroxy stilbene glucoside protected against diabetes-induced osteoporosis in mice with streptozotocin-induced hyperglycemia. AB - Tetrahydroxy stilbene glucoside (TSG), an active component from medicinal herb Polygonum multiflorum Thunb, could block the activity of the tissue renin angiotensin system (RAS), which plays a critical role in development of diabetic osteoporosis. This study aimed to determine if TSG therapy could alleviate bone deteriorations in diabetic mouse model induced by streptozotocin. The diabetic mice showed the loss of trabecular bone mass and the changes of trabecular bone microarchitectural parameters as well as the increase in amount of tartrate resistant acid phosphatase (TRAP)-positive osteoclasts at the distal metaphysis of femur when compared with those of nondiabetic mice. Treatment with TSG significantly elevated calcium content in serum and bone and improved biological parameters of trabecular bone, accompanied by increasing messenger RNA (mRNA) expression of RUNX-2, COL-I, and OCN and protein expression of beta-catenin as well as down-regulating protein expression of RAS components including renin and AT1R. In addition, TSG repressed diabetes-induced decrease in ratio of OPG/RANKL expression and increase in sclerostin expression in bone. The similar effects of TSG on osteoblasts-specific genes were found in MC3T3-E1 cells. Taken together, the present study demonstrated the osteopreserve effects of TSG in diabetic mice, and the underlying mechanism might be attributed to its regulation on osteogenesis and osteoclastogenesis. PMID- 30456808 TI - New insights on the role of DNA methylation in cardiovascular disease. AB - We read with interest the research article by Lind et al. recently published in the European Journal of Clinical Investigation (ESCI) [1], in which the authors investigated the potential association between DNA methylation-based estimation of biological age and cardiovascular disease. We would congratulate the authors since among other outstanding papers [2-6] this article was awarded by the ESCI Council as the Best Clinical Research Article published in the European Journal of Clinical Investigation from November 2017 to October 2018. The study by Lind and coworkers is a prospective cohort analysis enrolling 832 participants followed-up over a period of 10 years. This article is protected by copyright. All rights reserved. PMID- 30456809 TI - Metal-Containing Polymers and Metallopolymers: A Special Issue Dedicated to Prof. George R. Newkome. PMID- 30456810 TI - Using word clouds to Re-envision letters of recommendation for residency applicants. AB - OBJECTIVES/HYPOTHESIS: To develop a "word cloud"-based visual letter of recommendation (VLOR) and to evaluate its efficiency in discerning applicant quality compared to narrative letters of recommendation (NLORs). STUDY DESIGN: Cross-sectional cohort study. METHODS: NLORs for 48 otolaryngology residency applicants interviewed from the 2016 application cycle were identified and mined for descriptive terms to generate a word cloud, referred to as a VLOR. Eight individuals reviewed and rated a total of 187 blinded NLORs and 48 VLORs on a four-point scale (negative to exceptional). Median VLOR and NLOR scores and the time to review for each candidate were compared using the Wilcoxon signed rank test. RESULTS: It took significantly more time to review the NLORs in comparison to the VLORs (67 seconds, interquartile range [IQR]: 41-98 seconds vs. 17 seconds, IQR: 11-26 seconds, P < .001). There was no significant difference between median scores for VLORs and NLORs (P = .136). Review time and score correlated positively for VLORs and was statistically significant (rho = 0.459, P = .001), indicating that more time spent reviewing equates to higher scores. The same relationship appeared with NLORs, but was not statistically significant (rho = 0.276, P = .058). CONCLUSIONS: VLORs are a novel and efficient additive tool for screening candidates for otolaryngology residency interview slots. Their scores do not significantly vary from NLOR scores and are significantly faster to evaluate. LEVEL OF EVIDENCE: 2b Laryngoscope, 2018. PMID- 30456811 TI - Using Bayes model averaging to leverage both gene main effects and G * E interactions to identify genomic regions in genome-wide association studies. AB - Genome-wide association studies typically search for marginal associations between a single-nucleotide polymorphism (SNP) and a disease trait while gene environment (G * E) interactions remain generally unexplored. More powerful methods beyond the simple case-control (CC) approach leverage either marginal effects or CC ascertainment to increase power. However, these potential gains depend on assumptions whose aptness is often unclear a priori. Here, we review G * E methods and use simulations to highlight performance as a function of main and interaction effects and the association of the two factors in the source population. Substantial variation in performance between methods leads to uncertainty as to which approach is most appropriate for any given analysis. We present a framework that (a) balances the robustness of a CC approach with the power of the case-only (CO) approach; (b) incorporates main SNP effects; (c) allows for incorporation of prior information; and (d) allows the data to determine the most appropriate model. Our framework is based on Bayes model averaging, which provides a principled statistical method for incorporating model uncertainty. We average over inclusion of parameters corresponding to the main and G * E interaction effects and the G-E association in controls. The resulting method exploits the joint evidence for main and interaction effects while gaining power from a CO equivalent analysis. Through simulations, we demonstrate that our approach detects SNPs within a wide range of scenarios with increased power over current methods. We illustrate the approach on a gene-environment scan in the USC Children's Health Study. PMID- 30456812 TI - Response of localized, resistant, tingling vitiligo to pregabalin: A case report. AB - Vitiligo is a common depigmenting disease with complex pathogenesis. One of the proposed pathogenesis is the neural hypothesis, which suggests an altered reaction to neuropeptides, catecholamines, and their metabolites affecting melanocytes. Here, we report a case of 26-year-old female patient, whose vitiligo patches were associated with unusual crawling and tingling sensation and responded to a clinical trial of pregabalin. PMID- 30456813 TI - Cyclosporine-induced toxic leukoencephalopathy in toxic epidermal necrolysis. PMID- 30456815 TI - Blaschkoid blue vitiligo. PMID- 30456816 TI - Novel approach using transoral robotic surgery for resection of cervical spine chordoma. AB - Chordomas are rare, infiltrative neoplasms of notochordal origin that present along the spinal canal; en bloc surgical resection is paramount to successful treatment. Limited visualization and complex anatomy are major challenges to resection of upper cervical spine chordomas and often require invasive surgery. A 27-year-old male presented with an incidentally discovered chordoma of the midline second cervical vertebra of the spine. To obtain en bloc resection of the lesion while both overcoming limitations due to access and without introducing morbidity from traditional anterior approaches, we elected using transoral robotic surgery for resection. Due to complete resection, the patient remains disease-free and was spared adjuvant radiation. Laryngoscope, 2018. PMID- 30456814 TI - Increasing intentions to use mental health services among university students. Results of a pilot randomized controlled trial within the World Health Organization's World Mental Health International College Student Initiative. AB - BACKGROUND: The majority of university students with mental health problems are untreated. Only a small empirical literature exists on strategies to increase mental health service use. AIMS: To investigate the effects and moderators of a brief acceptance-facilitating intervention on intention to use mental health services among university students. METHOD: Within the German site of the World Health Organization's World Mental Health International College Student (WMH-ICS) initiative, 1,374 university students were randomized to an intervention condition (IC; n = 664) or a control condition (CC; n = 710) that was implemented in the survey itself. Both conditions received the questions assessing mental disorders and suicidality that were included in other WMH-ICS surveys. The IC group then additionally received: Internet-based personalized feedback based on subject symptom severity in the domains of depression, anxiety, substance use, suicidal thoughts and behaviors, and nonsuicidal self-injury; psychoeducation tailored to the personal symptom profile; and information about available university and community mental health services. The primary outcome was reported intention to use psychological interventions in the next semester, which was the last question in the survey. A broad range of potential moderating factors was explored. RESULTS: There was a significant main effect of the intervention with students randomized to IC, reporting significantly higher intentions to seek help in the next semester than students in the CC condition (d = 0.12, 95% CI: 0.02 to 0.23). Moderator analyses indicated that the intervention was more effective among students that fulfilled the criteria for lifetime (d = 0.34; 95% CI: -0.08 to 0.7) and 12-month panic-disorder (d = 0.32; 95% CI: -0.10 to 0.74) compared with those without lifetime (d = 0.11; 95% CI: 0.00 to 0.22) or 12-month panic disorder (d = 0.11; 95% CI: 0.00 to 0.22), students with lower (d = 0.37; 95% CI: -0.77 to 1.51) than higher (d = -0.01; 95% CI: -0.36 to 0.34) self-reported physical health, and students with nonheterosexual (d = 0.38; 95% CI: 0.08 to 0.67) compared with heterosexual (d = 0.06; 95% CI: -0.06 to 0.17) sexual orientation. The intervention had no effects among students who reported that they recognized that they had an emotional problem and "are already working actively to change it" (Stage 4 "stages of change"). CONCLUSIONS: A simple acceptance-facilitating intervention can increase intention to use mental health services, although effects, are on average, small. Future studies should investigate more personalized approaches with interventions tailored to barriers and clinical characteristics of students. In order to optimize intervention effects, the development and evaluation should be realized in designs that are powered to allow incremental value of different intervention components and tailoring strategies to be evaluated, such as in multiphase optimization designs. PMID- 30456817 TI - Brain-derived neurotrophic factor promotes proliferation and progesterone synthesis in bovine granulosa cells. AB - Brain-derived neurotrophic factor (BDNF) is involved in regulating the growth of ovarian follicles, maturation of the oocyte, and development of the early embryo through its receptor, tyrosine kinase receptor B (TrkB). However, it is still unclear as to how BDNF influences proliferation and steroidogenesis of bovine granulosa cells (GCs). In this paper, we confirmed that BDNF and TrkB were expressed in bovine GCs, and that proliferation and steroidogenesis by bovine GCs were reduced by knockdown of BDNF or inhibition of TrkB. With respect to GC proliferation, BDNF enhanced cellular viability and the percentage of cells in the S phase. BDNF also activated both protein kinase B (PKB, also known as AKT) and the extracellular signal-regulated protein kinase 1/2 (ERK1/2)-signaling pathway. Through the AKT-signaling pathway, BDNF increased the expression of proliferation-related genes, including cyclin A1 (CCNA1), cyclin E2 (CCNE2), cyclin D1 (CCND1), and cyclin-dependent kinase 1 (CDK1). However, through the ERK1/2 signaling pathway, BDNF only increased the expression of CCNA1 and CCNE2. Regarding steroidogenesis by bovine GCs, BDNF promoted progesterone (P 4 ) synthesis, but had no effect on estradiol; it also activated the AKT-signaling pathway and increased the expression of steroidogenesis-related genes, including steroidogenic acute regulatory protein (STAR) and hydroxy-delta-5-steroid dehydrogenase, 3beta- and steroid delta-isomerase 1 (HSD3B1). In summary, our data are the first to show that BDNF promotes the proliferation of bovine GCs through TrkB-AKT and ERK1/2 signaling pathways and increases P4 synthesis by bovine GCs through the TrkB-AKT signaling pathway. PMID- 30456818 TI - Reconciling nutritional geometry with classical dietary restriction: Effects of nutrient intake, not calories, on survival and reproduction. AB - Dietary restriction (DR) is one of the main experimental paradigms to investigate the mechanisms that determine lifespan and aging. Yet, the exact nutritional parameters responsible for DR remain unclear. Recently, the advent of the geometric framework of nutrition (GF) has refocussed interest from calories to dietary macronutrients. However, GF experiments focus on invertebrates, with the importance of macronutrients in vertebrates still widely debated. This has led to the suggestion of a fundamental difference in the mode of action of DR between vertebrates and invertebrates, questioning the suggestion of an evolutionarily conserved mechanism. The use of dietary dilution rather than restriction in GF studies makes comparison with traditional DR studies difficult. Here, using a novel nonmodel vertebrate system (the stickleback fish, Gasterosteus aculeatus), we test the effect of macronutrient versus calorie intake on key fitness-related traits, both using the GF and avoiding dietary dilution. We find that the intake of macronutrients rather than calories determines both mortality risk and reproduction. Male mortality risk was lowest on intermediate lipid intakes, and female risk was generally reduced by low protein intakes. The effect of macronutrient intake on reproduction was similar between the sexes, with high protein intakes maximizing reproduction. Our results provide, to our knowledge, the first evidence that macronutrient, not caloric, intake predicts changes in mortality and reproduction in the absence of dietary dilution. This supports the suggestion of evolutionary conservation in the effect of diet on lifespan, but via variation in macronutrient intake rather than calories. PMID- 30456819 TI - Equus caballus papillomavirus 8 (EcPV8) associated with multiple viral plaques, viral papillomas, and squamous cell carcinoma in a horse. AB - BACKGROUND: Equus caballus papillomavirus 8, a recently discovered virus, has been reported to cause generalised papillomavirus in horses OBJECTIVES: To describe a case in which multiple viral plaques, viral papillomas, squamous cell carcinoma (SCC) in situ and invasive squamous cell carcinoma (ISCC) were associated with EcPV8 in a horse. STUDY DESIGN: Case report. METHODS: A 16-year old mixed breed horse presented with dozens of raised crusted papular to nodular lesions over the course of 4 years. Masses have been surgically excised four times and cisplatin beads and emulsion were implanted on three different occasions, however new masses continue to develop in sites of previous masses as well as new sites. RESULTS: Multiple viral plaques, viral papillomas, SCC in situ and ISCC, localised to the inguinal region, were diagnosed via histopathology. EcPV8 DNA was detected via PCR. MAIN LIMITATIONS: Because so few cases have been reported, we do not know the incidence of EcPV8 nor how often it may be associated with SCC in situ or ISCC without further study. CONCLUSIONS: This is the fourth reported case of viral papillomatosis in the context of an EcPV8 infection in a horse. This is the first case in which SCC has been associated with EcPV8. This article is protected by copyright. All rights reserved. PMID- 30456820 TI - Exceptionally Long C-C Single Bonds in Diamino-o-carboranes as Induced by Negative Hyperconjugation. AB - The synthesis of a series of 1,2-diamino-o-carboranes (1 - 4) is reported. The molecular structures of these diamino-o-carboranes are remarkable as the inner cluster C-C bonds are all ultra-long (162.7 - 193.1 pm) and vary substantially with small variations of the substituents. The results of quantum mechanical investigations suggests that the origin of the bond elongation is significant in plane negative hyperconjugation of lone pairs of the nitrogen substituents with the sigma* orbitals of C-C in o-carboranes. PMID- 30456821 TI - Effectiveness of metacognitive interventions for mental disorders in adults - a systematic review and meta-analysis (METACOG). AB - We evaluated the effectiveness and acceptability of metacognitive interventions for mental disorders. We searched electronic databases and included randomized and non-randomized controlled trials comparing metacognitive interventions with other treatments in adults with mental disorders. Primary effectiveness and acceptability outcomes were symptom severity and dropout, respectively. We performed random-effects meta-analyses. We identified Metacognitive Training (MCTrain), Metacognitive Therapy (MCTherap) and Metacognition Reflection and Insight Therapy (MERIT). We included 49 trials with 2,609 patients. In patients with schizophrenia, MCTrain was more effective than a psychological treatment (cognitive remediation, SMD=-0.39). It bordered significance when compared to standard or other psychological treatments. In a post hoc analysis, across all studies, the pooled effect was significant (SMD=-0.31). MCTrain was more effective than standard treatment in patients with obsessive-compulsive disorder (SMD=-0.40). MCTherap was more effective than a waitlist in patients with depression (SMD=-2.80), posttraumatic stress disorder (SMD=-2.36) and psychological treatments (cognitive behavioral) in patients with anxiety (SMD= 0.46). In patients with depression MCTherap was not superior to psychological treatment (cognitive behavioral). For MERIT, the database was too small to allow solid conclusions. Acceptability of metacognitive interventions among patients was high on average. Methodological quality was mostly unclear or moderate. Metacognitive interventions are likely to be effective in alleviating symptom severity in mental disorders. While their add-on value against existing psychological interventions awaits to be established, potential advantages are their low threshold and economy. PMID- 30456822 TI - Association of common type 1 and type 2 diabetes gene variants (PTPN22, INS, and TCF7L2) with Latent Autoimmune Diabetes in Adults (LADA): a meta-analysis. AB - OBJECTIVE: The meta-analysis was aimed to determine the association of common type 1 diabetes (T1D) and type 2 diabetes (T2D) gene variants (PTPN22 rs2476601C/T, INS rs689A/T and TCF7L2 rs7903146C/T) with Latent Autoimmune Diabetes in Adults (LADA). METHOD: A systematic search of electronic databases was carried out to pool data from 16 independent case-control studies for three gene variants until 2017. The pooled allele and genotype frequencies for each T1D and T2D gene variants were used to calculate odds ratio with 95% confidence interval to assess the strength of the association. Heterogeneity test and evaluation of publication bias for all the selected studies were performed. RESULTS: A total of 8869 cases and 20829 controls pooled from 16 case-control studies were included. For rs2476601, a significant association was found in the homozygote TT (OR 2.67; 95% CI 1.92 - 3.70; P<.0001), heterozygote CT (OR 1.61; 95% CI 1.44 - 1.79; P<0.0001) and T allele (OR 1.62; 95% CI 1.48 - 1.78; P<0.0001). Overall, a significant inverse association was observed for rs689 in TT genotype (OR 0.43 [95%CI 0.30-0.64; P<0.0001], AT genotype (OR 0.53[95%CI 0.45 0.62; P<0.0001], and T allele (OR 0.61[95% CI 0.52- 0.71; P<0.0001]). In the rs7903146 polymorphism, T allele (OR 1.19; 95% CI 1.00 - 1.40, P=0.04) may be associated with the risk of LADA. CONCLUSION: rs2476601C/T, rs689A/T and rs7903146C/T polymorphisms were found to be associated with risk of LADA, thereby indicating that genetically it could be an admixture of both T1D and T2D. PMID- 30456823 TI - Post-cataract surgery endophthalmitis: the role of prophylactic antibiotic eye drops. PMID- 30456824 TI - Idiopathic neutropenia of infancy: data from the Italian Neutropenia Registry. AB - Autoimmune neutropenia of infancy (AIN) is characterized by low risk of severe infection, tendency to spontaneously resolve and typically onset at < 4-5 years of age; it is due to auto-antibodies whose detection is often difficult. In case of negativity of 4 anti-neutrophils autoantibody tests, after having excluded ethnic, post infection, drug induced or congenital neutropenia, according to the Italian guidelines the patients will be defined as affected by "idiopathic neutropenia" (IN). We describe the characteristics of 85 IN patients enrolled in the Italian neutropenia registry: they were compared to 336 children affected by AIN. The two groups were clinically very similar and the main differences were detection age (later in IN), length of disease (longer in IN) and, among recovered patients, age of spontaneous recovery: the median age at resolution was 2.13 years in AINs and 3.03 years in INs (p = 0.00002). At bivariate analysis among AIN patients earlier detection age (p = 0.00013), male sex (p = 0.000748), absence of leucopenia (p = 0.0045), and absence of monocytosis (p = 0.0419) were significantly associated with earlier recovery; in the IN group only detection age (p = 0.013) and absence of monocytosis (p = 0.0333) were significant. At multivariate analysis detection age and absence of monocytosis were independently significant (p = 6.7e-05 and p = 4.4e-03 respectively) in the AIN group, whereas in the IN group only detection age stayed significant (p = 0.013). This article is protected by copyright. All rights reserved. PMID- 30456825 TI - 18 F-FDG PET/CT for locoregional surveillance following definitive treatment of head and neck cancer: A meta-analysis of reported studies. AB - PURPOSE: To evaluate the performance of 18 F-fluorodeoxy-d-glucose positron emission tomography-computed tomography (18 F-FDG PET/CT) in identifying local failure and regional failure following curative radiotherapy or surgery for head and neck squamous cell carcinoma. METHODS: A comprehensive literature search identified studies published between January 2010 and August 2016. Diagnostic performance of 18 F-FDG PET/CT was evaluated for local failure/regional failure stratified by treatment-to-scan time interval of <=3 versus >3 months. RESULTS: Twenty-four studies (2627 patients) were included. Compared to <=3 months, 18 F FDG PET/CT performed >3 months showed significantly improved sensitivity (87% vs 60%, P = 0.020) and specificity (93% vs 84%, P < 0.001) for local failure. There was no significant difference in sensitivity (79% vs 56%, P = 0.100) or specificity (95% vs 97%, P = 0.35) for regional failure >3 versus <=3 months. CONCLUSIONS: This meta-analysis confirms high specificity but modest sensitivity of posttreatment 18 F-FDG PET/CT for local failure and regional failure. Sensitivity and specificity are significantly improved when 18 F-FDG PET/CT is performed >3 months for local failure. PMID- 30456826 TI - Bilingual children with autism spectrum disorders: The impact of amount of language exposure on vocabulary and morphological skills at school age. AB - Studies of bilingual children with Autism Spectrum Disorders (ASD) have focused on early language development using parent report measures. However, the effect of bilingual exposure on more complex linguistic abilities is unknown. In the current study, we examined the impact of amount of language exposure on vocabulary and morphological skills in school-aged children with ASD who did not have intellectual disability. Forty-seven typically developing children and 30 children with ASD with varying exposure to French participated in the study. We investigated the impact of amount of language exposure, nonverbal IQ, age, and working memory on language abilities via regression analyses. Current amount of language exposure was the strongest predictor of both vocabulary skills (accounting for 62% of the variance) and morphological skills (accounting for 49% of the variance), for both typically-developing children and children with ASD. These findings highlight the central role amount of language exposure plays in vocabulary and morphological development for children with ASD, as it does for typically-developing children. In addition, they provide further evidence that, when provided with adequate language exposure, many children with ASD are capable of acquiring two languages. Autism Research 2018, 11: 1667-1678. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We studied typically developing children and children with ASD living in a bilingual society who had varying exposure to French (ranging from bilinguals to monolinguals). We investigated the impact of amount of language exposure, nonverbal IQ, age, and working memory on their vocabulary and morphological skills. Current amount of language exposure was the strongest predictor of language skills in both groups of children. Findings indicate that when provided with adequate language exposure, many children with ASD are capable of acquiring two languages. PMID- 30456827 TI - Prevalence of objectively-measured sedentary behaviour in early years: systematic review and meta-analysis. AB - BACKGROUND: The early years have been identified as a critical period during which sedentary habits may be established, as this behaviour appears to track throughout life. OBJECTIVE: The purpose of this systematic review and meta analysis is to summarise the current literature on the prevalence of sedentary behaviour in children aged 1 to 5.99 years, reporting differences between boys and girls, weekdays and weekend days, childcare hours and non-childcare hours, and between time spent indoors and outdoors while children attended childcare. METHODS: Five databases were searched until 26.10.2017 and meta-analyses were conducted to estimate prevalence and calculate mean differences in prevalence between groups. RESULTS: Fifty studies representing 14,598 children (2 to 5.99 yr) were included. Children spent 51.4% of their waking time in sedentary behaviours. Boys spent less time being sedentary than girls (estimate difference= 1.4%;95%CI=-2.0:-0.7;p<0.001). No significant differences were found between weekdays/weekend days (estimate difference=-0.4;95%CI=-2.0:1.2;p=0.61) nor between childcare hours/non-childcare hours (estimate difference=%;95%CI= 0.9:6.6;p=0.136). While attending childcare centres, children were more sedentary indoors than outdoors (estimate difference=14.4%;95%CI=11.8:16.9;p<0.001). CONCLUSIONS: Our results suggest that young children spend a significant portion of their waking hours in sedentary behaviours. While at childcare, young children accumulated more sedentary behaviour indoors than outdoors. Girls were more likely to be more sedentary than boys. No significant differences were found between weekdays and weekends, or between childcare and non-childcare hours. There is a need for higher-quality studies with strong designs, using age and device appropriate cut-off points, to improve evidence-base and to better establish prevalence of sedentary behaviour in young children. This article is protected by copyright. All rights reserved. PMID- 30456829 TI - Genetics meets dna methylation in rare diseases. AB - Alterations in epigenetic landscapes are hallmarks of many complex human diseases, yet, it is often challenging to assess the underlying mechanisms and causal link with clinical manifestations. In this regard, monogenic diseases that affect actors of the epigenetic machinery are of considerable interest to learn more about the etiology of complex traits. Spectacular breakthroughs in medical genetics are largely the result of advances in genome-wide approaches to identify genomic and epigenomic alterations in patients. These approaches have enabled the identification of an ever-increasing number of hereditary disorders caused by defects in the establishment of epigenetic marks early during development or in the perpetuation of such marks at later stages. We focus our review on particular cases where DNA methylation landscapes are altered at the genome scale, whether it is a direct consequence of mutations in DNA methyltransferases (DNMT) or that it reflects initial alterations of chromatin states or guiding factors caused by mutations in chromatin modifiers or transcription factors. Collectively, increased knowledge of these rare diseases will add to our understanding of the genetic determinants of DNA methylation in humans. Moreover, investigating how perturbations to these determinants affect genome function has far-reaching potential to understand various complex human diseases. This article is protected by copyright. All rights reserved. PMID- 30456828 TI - Sex differences in the genetic architecture of obsessive-compulsive disorder. AB - Obsessive-compulsive disorder (OCD) is a highly heritable complex phenotype that demonstrates sex differences in age of onset and clinical presentation, suggesting a possible sex difference in underlying genetic architecture. We present the first genome-wide characterization of the sex-specific genetic architecture of OCD, utilizing the largest set of OCD cases and controls available from the Psychiatric Genomics Consortium. We assessed evidence for several mechanisms that may contribute to sex differences including a sex dependent liability threshold, the presence of individual sex-specific risk variants on the autosomes and the X chromosome, and sex-specific pleiotropic effects. Furthermore, we tested the hypothesis that genetic heterogeneity between the sexes may obscure associations in a sex-combined genome-wide association study. We observed a strong genetic correlation between male and female OCD and no evidence for a sex-dependent liability threshold model, suggesting that sex combined analysis does not suffer from widespread loss of power because of genetic heterogeneity between the sexes. While we did not detect any significant sex-specific genome-wide single nucleotide polymorphisms (SNP) associations, we did identify two significant gene-based associations in females: GRID2 and GRP135, which showed no association in males. We observed that the SNPs with sexually differentiated effects showed an enrichment of regulatory variants influencing expression of genes in brain and immune tissues. These findings suggest that future studies with larger sample sizes hold great promise for the identification of sex-specific genetic risk factors for OCD. PMID- 30456830 TI - Non-reassuring results in agreement trial comparing glass and plastic capillary tubes for neonatal blood gas sampling. AB - AIM: To determine agreement between neonatal capillary blood gases taken with plastic and glass tubes. METHODS: An agreement study was carried out in a regional tertiary neonatal unit. Inpatient babies >= 1 Kg were recruited to the study when parents gave consent. After taking the routine glass capillary tube sample, a plastic tube sample was taken and run if the heel continued to bleed. Successful sample pairs were recorded and analysed against pre-defined acceptable differences. Assessment was also made of differences in failure rates between tube types for each parameter. RESULTS: Twenty-eight babies provided 135 blood gas pairs, of which five pairs were excluded. Successful pairing of results was achieved for pH in 105 valid samples. There were more failed plastic samples than glass, reaching significance for almost all parameters. pH, pO2 and pCO2 showed poor agreement (<80%) between glass and plastic tubes. On limited analysis of one successful blood gas pair per neonate to minimise bias, results remained non reassuring. CONCLUSION: The findings of this study do not advocate switching from glass to plastic capillary tubes in our Newborn Intensive Care Unit. Further studies are required to assess agreement of glass and plastic capillary tubes for neonatal blood gas sampling. This article is protected by copyright. All rights reserved. PMID- 30456831 TI - Visualizing Phase Segregation in Mixed-Halide Perovskite Single Crystals. AB - Mixed organolead halide perovskites (MOHPs), CH3NH3Pb(BrxI1-x)3, have been shown to undergo phase segregation into I-rich domains under illumination, presenting a major challenge to their development in photovoltaic and light-emitting devices. Recent work suggests phase segregated domains are localized at crystal boundaries, driving investigations into the role of edge structure and the growth of larger crystals with reduced surface area. Herein, a method for growing large (30*30*1 um) monocrystalline MAPb(BrxI1-x)3 single crystals is presented. The direct visualization of the growth of nanocluster-like I-rich domains throughout the entire crystal revealed grain boundaries are not required for this transformation. Narrowband fluorescence imaging and time-resolved spectroscopy provided new insight into the nature of phase segregated domains and the collective impact on optoelectronic properties. PMID- 30456832 TI - Caring for adults with congenital heart disease in a regional setting. AB - OBJECTIVE: The number of adults with congenital heart disease has increased with improvements in surgical and medical management, posing a challenge for regional and rural settings, which might have difficulties accessing specialised professionals with congenital heart disease services. This study aims to ascertain the demographics and management of adults with congenital heart disease seen by a cardiology practice in regional Australia to better understand the needs of regional adults with congenital heart disease. DESIGN: A descriptive study using data from clinical notes collected between April 2013 and April 2016. SETTING: A private cardiology practice in Coffs Harbour, New South Wales. The practice has a treating cardiologist, senior sonographer, visiting cardiothoracic surgeon and visiting paediatric cardiologist. PARTICIPANTS: One-hundred-and-one adults with congenital heart disease (age: 16-88 years; 55 women). MAIN OUTCOME MEASURES: Congenital heart disease defect, lesion severity, referral reason, past surgery, pulmonary hypertension, cardiac surgery during the study, mortality, adherence with follow-up plans and specialist referral. RESULTS: Sixty-six patients had simple congenital heart disease, 24 had congenital heart disease of moderate complexity and 11 had congenital heart disease of great complexity. Most were referred for surveillance, seven were referred due to pregnancy and eight were new diagnoses. Six patients died, nine had cardiac operations and five were treated for pulmonary arterial hypertension. Overall adherence to the treating cardiologist's follow-up plans was 84%. All patients with congenital heart disease of great complexity were referred to congenital heart disease specialists. CONCLUSION: A substantial number of patients had complex pathology, new diagnoses or required surgery, highlighting the importance of developing integrated services with the close support of outside specialists in managing adults with congenital heart disease in regional settings. PMID- 30456833 TI - Standardized extract of Erythrina velutina Willd. attenuates schizophrenia-Like behaviours and oxidative parameters in experimental animal models. AB - OBJECTIVES: To study the effects of the standardized extract from the leaves of Erythrina velutina in behavioural and oxidative parameters in the ketamine induced schizophrenia model. METHODS: Mice received ketamine (KET) or saline for 7 days. From 8th to 14th day, the animals received Erythrine (Eryt) (100, 200 or 400 mg/kg) or olanzapine (Olanz), 1 h after KET administration. At 14th day, 30 min after the last administration of KET, the open-field and pre-pulse inhibition (PPI) tests were performed. Then, the animals were sacrificed and the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) were dissected for the oxidative tests. KEY FINDINGS: Ketamine increased spontaneous locomotor activity and grooming. KET decreased the PPI, which was reversed by combining it with Eryt or olanzapine. KET decreased GSH concentration in PFC and ST this was reversed by Eryt. KET increased MDA concentration in PFC and HC this was reversed by Eryt. Eryt and Olanzapine reduced MDA concentration in ST when compared to KET group. Nitrite concentration was reduced by administration of KET in the PFC. CONCLUSIONS: These results demonstrate that the standardized extract of E. velutina can prevent behavioural symptoms and oxidative stress induced by repeated doses of KET. PMID- 30456834 TI - A possible association of HLA-C*07:18:01:01 and HLA-B*58:01. AB - HLA-C*07:18:01:01 is possibly in association on the same haplotype as HLA B*58:01. PMID- 30456835 TI - Ghrelin receptor deletion reduces binge-like alcohol drinking in rats. AB - Ghrelin is a gastric hormone that has been implicated in the neurobiology of alcohol drinking. We have recently developed a ghrelin receptor (GHSR) knockout (KO) rat model, which exhibits reduced food consumption and body weight. In addition, recent preliminary work suggests that the gut-microbiome, which appears to interact with the ghrelin system, may modulate alcohol drinking. Here, we investigated the effects of GHSR deletion on alcohol consumption utilizing GHSR KO and wild type (WT) rats in three separate alcohol consumption paradigms: 1. operant self-administration (30 min sessions); 2. drinking in the dark (DID; 4 h sessions); 3. intermittent access (24 h sessions). These paradigms model varying degrees of alcohol consumption. Furthermore, we sought to investigate the gut microbiome composition of GHSR KO and WT rats before and after alcohol exposure. We found that the GHSR KO rats self-administered significantly less alcohol compared with WT rats in the operant paradigm, and consumed less alcohol than WT in the initial stages of the DID paradigm. No genotype differences were found in the intermittent access test. In addition, we found a significant decrease in gut microbial diversity after alcohol exposure in both genotypes. Thus, the present results indicate that the ghrelin system may be involved in drinking patterns that result in presumably increased alcohol exposure levels and that GHSR may constitute a potential pharmacological target for the reduction of binge-alcohol consumption. The potential functional role of the gut-microbiome in alcohol drinking, and interaction with the ghrelin system, is an interesting topic for further investigation. This article is protected by copyright. All rights reserved. PMID- 30456837 TI - Issue Highlights: November 2018. PMID- 30456836 TI - The prognostic role of the cardio-ankle vascular index. PMID- 30456838 TI - New insights into the roles and regulation of SphK2 as a therapeutic target in cancer chemoresistance. AB - Chemoresistance is a complicated process developed by most cancers and accounts for the majority of relapse and metastasis in cancer. The main mechanisms of chemoresistance phenotype include increased expression and/or activated drug efflux pumps, altered DNA repair, altered metabolism of therapeutics as well as impaired apoptotic signaling pathways. Aberrant sphingolipid signaling has also recently received considerable attention in chemoresistance. Sphingolipid metabolites regulate main biological processes such as apoptosis, cell survival, proliferation, and differentiation. Two sphingosine kinases, SphK1 and SphK2, convert sphingosine to sphingosine-1-phosphate, an antiapoptotic bioactive lipid mediator. Numerous evidence has revealed the involvement of activated SphK1 in tumorigenesis and resistance, however, contradictory results have been found for the role of SphK2 in these functions. In some studies, overexpression of SphK2 suppressed cell growth and induced apoptosis. In contrast, some others have shown cell proliferation and tumor promotion effect for SphK2. Our understanding of the role of SphK2 in cancer does not have a sufficient integrity. The main focus of this review will be on the re-evaluation of the role of SphK2 in cell death and chemoresistance in light of our new understanding of molecular targeted therapy. We will also highlight the connections between SphK2 and the DNA damage response. Finally, we will provide our insight into the regulatory mechanisms of SphKs by two main categories, micro and long, noncoding RNAs as the novel players of cancer chemoresistance. PMID- 30456839 TI - Advancing the social psychology of rapid societal change. AB - In this introduction to the special section on rapid societal change, we highlight the challenges posed by rapid societal changes for social psychology and introduce the seven papers brought together in this special section. Rapid societal changes are qualitative transformations within a society that alter the prevailing societal state. Recent such changes include the election of right-wing populist governments, the Arab Spring revolutions, and devastating civil wars in the Middle East. Conceptually, such events require consideration of how societal level events relate to more proximal psychological processes to bring about the often abrupt, non-linear (as opposed to incremental and linear) nature of rapid societal change. They also require empirical approaches that allow such qualitative transformations to be captured and studied. This is true both in terms of directly addressing rapidly unfolding societal events in research, and in terms of how rapid, discontinuous change can be analysed. The papers in the special section help to address these issues through introducing novel theoretical and methodological approaches to studying rapid societal change, offering multiple perspectives on how macro-level changes can both create, and be created by, micro-level social psychological phenomena. PMID- 30456840 TI - Recent progress in follicular lymphoma in Japan and characteristics of the duodenal type. AB - The incidence of lymphoma has rapidly increased over the last 40 years in Japan, following a trend that is very similar to that of breast cancer. In particular, the relative frequency of follicular lymphoma (FL) has reached that in Western countries. Given its indolence, a "watch-and-wait" approach is often applied to FL patients. We have shown that FL is often detected in the second portion of the duodenum and has a distinct follicular dendritic cell distribution and heavy chain variable usage similar to mucosa-associated lymphoid tissue (MALT) lymphoma. Although the t(14;18)(q32;q21) frequency is the same as in the nodal subtype of FL, there are also ongoing mutations, immunopositivity for cluster of differentiation 10 and B-cell lymphoma (BCL)6, and overexpression of BCL2. Gene expression profiling has shown that it is more similar to gastric MALT lymphoma than to nodal FL. Duodenal-type FL lacks the activation-induced cytidine deaminase (AID) expression observed in nodal ones, although this may be compensated for by BTB domain and CNC homolog 2. Based on these findings, duodenal-type FL has been included in the Revised 4th edition of the World Health Organization classification published in late 2017. PMID- 30456841 TI - The relationship between workplace characteristics and work ability in residential aged care: What is the role of work-life interaction? AB - AIMS: To examine whether the work-life interface (through work-family conflict and overall work-life balance) moderates the relationship between work ability and workplace demands and resources. DESIGN: This study used a cross-sectional survey design to collect data from 426 employees working in residential aged care. METHODS: A paper-based questionnaire was distributed to all permanent and casual employers at eight aged care facilities in Melbourne, Australia, between June - September 2013. Moderation analyses were conducted using PROCESS v. 2.13 in SPSS v. 22. RESULTS/FINDINGS: As expected, workplace demands and resources directly influenced workers' work ability. In addition, moderate-to-high levels of work-family conflict and low-to-moderate levels of satisfaction with work-life balanced combined interactively with particular workplace demands and resources (relationships with management, physical demands and safety climate) to reduce work ability. CONCLUSIONS: This study advances understanding of how work-life balance and work-life conflict can influence work ability levels and shows that addressing the work-life interface may be a legitimate means to improve work ability, potentially leading to continued workforce participation. IMPACT: Staff retention in the residential aged care sector needs to be addressed. One possible means of achieving this is through improving work ability. The present study expanded knowledge of how the work-life interface may influence work ability. The research demonstrated that releationships between work ability and particular workplace demands and resources were moderated by the work-life interface. This finding has implications for how human resources managers of residential aged care facilities may improve workforce retention-through facilitating employees to manage the work-life interface better. This article is protected by copyright. All rights reserved. PMID- 30456842 TI - When Safety Climate is not Enough: Examining the Moderating Effects of Psychosocial Hazards on Nurse Safety Performance. AB - AIM: To examine the association between components of safety climate and psychosocial hazards with safe work behaviors as well as test the moderating effects of psychosocial hazards on the safety climate-safety performance relationships. BACKGROUND: The effects of a strong safety climate on safety performance are well cited, however, the conditions that have an impact on this relationship warrant attention (Zohar, 2010). While the psychosocial hazards commonly reported by nurses are predictors of well-being and job attitudes, evidence suggests that these may also place boundaries on the effects of safety climate on safe work practices. DESIGN: This study used a cross-sectional design to collect data from 146 nurses. METHODS: Participants were recruited through convenience sampling and snowball sampling methods in 2017. Nurses completed an online questionnaire and received a $5 e-gift card as compensation. SPSS v.23 and PROCESS v3.0 were used to analyze the data. RESULTS/FINDINGS: A strong safety climate was positively associated with nurses' safety performance. While psychosocial hazards did not predict safety performance, they did moderate the safety climate-performance relationship. High levels of perceived stressors weakened the association between promoting two-way safety communication, the use and implementation of procedures to promote safe work practices and management's endorsement of health and safety with safe work performance. CONCLUSION: The positive effects of safety climate on nurses' safety performance are contingent on the levels of psychosocial hazards nurses experience. When aiming to improve safety performance among nurses, it is important for efforts to also focus on the psychosocial conditions of the work environment. This article is protected by copyright. All rights reserved. PMID- 30456843 TI - The Impact of Metformin Use on the Cardiovascular Effects of DPP-4 Inhibitors: an Analysis of Medicare Claims Data 2007-2015. AB - AIMS: Metformin may moderate cardiovascular outcomes with dipeptidyl peptidase-4 inhibitors (DPP-4i). We examined outcomes of DPP-4i initiation with and without concurrent metformin. MATERIALS AND METHODS: We identified Medicare enrollees initiating DPP-4i, sulfonylurea, or thiazolidinedione. Using propensity score weighted Poisson models, we evaluated one-year cardiovascular outcome incidence among initiators of DPP-4i versus comparators in subgroups with and without concurrent metformin use, and assessed the interaction between initiation drug and metformin. Outcomes included mortality, non-fatal myocardial infarction (MI), stroke, and a composite. RESULTS: For the DPP-4i (n=13,391) versus sulfonylurea (n=33,206) comparison, rate differences in composite outcome incidence favored DPP-4i: -2.0/100 person-years among metformin users (95%CI: -2.7,-1.3) and -1.0 ( 1.8,-0.2) among metformin non-users. Similar rate difference trends among metformin users and non-users were seen for mortality (-1.5 (-2.1,-0.9) and -0.7 (-1.4,0.0)) and non-fatal MI (-0.5 (-0.8,-0.3) and 0.1 (-0.2,0.4)). The interaction between DPP-4i initiation and metformin was statistically significant for non-fatal MI (p=0.008). For the DPP-4i (n=22,210) versus thiazolidinedione (n=9,517) comparison, rate differences in composite outcome incidence for DPP-4i initiation were -0.6/100 person-years (-1.5,0.2) among metformin users and 1.0 (0.0,2.0) among metformin non-users. Similar rate difference trends among metformin users and non-users were seen for mortality (-0.5 (-1.3,0.1) and 0.8 ( 0.0,1.7)) and non-fatal MI (-0.1 (-0.4,0.2) and 0.2 (-0.1,0.6)). The interaction between DPP-4i initiation and metformin was statistically significant for the composite (p=0.024) and mortality (p=0.023). CONCLUSIONS: Incidence rate differences in multiple cardiovascular outcomes appeared more favorable when DPP 4i initiation occurred in the presence of metformin, suggesting a possible interaction between DPP-4i and metformin. This article is protected by copyright. All rights reserved. PMID- 30456844 TI - Downregulation of long noncoding RNA LOC101928134 inhibits the synovial hyperplasia and cartilage destruction of osteoarthritis rats through the activation of the Janus kinase/signal transducers and activators of transcription signaling pathway by upregulating IFNA1. AB - Osteoarthritis (OA) is the most common disease of arthritis, a chronic joint disease that is always correlated with massive destruction such as cartilage destruction, inflammation of the synovial membrane, and so on. This study aims to explore the role of long noncoding RNA (lncRNA) LOC101928134 in the synovial hyperplasia and cartilage destruction, more specifically, in the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway in an OA rat model. Microarray-based gene expression analysis was conducted to screen out the lncRNA differentially expressed in OA and predict the target gene of the lncRNA with the involvement of the signaling pathway through Kyoto encyclopedia of genes and genomes (KEGG) analysis. A model of OA was established and treated with the small interfering RNA LOC101928134/inhibitor of JAK/STAT signaling pathway to investigate the relationship among LOC101928134, IFNA1, and the JAK/STAT signaling pathway in OA. The effect of LOC101928134 on the serum levels of IFNA1, interleukin-1beta, and tumor necrosis factor-alpha, and the apoptosis of synovial and cartilage cells was evaluated. LOC101928134, which was found to be highly expressed in knee joint synovial tissues of OA rats, regulated the expression of IFNA1 gene and inhibited JAK/STAT signaling pathway. Downregulation of LOC101928134 resulted in reduced knee joint synovitis, relived inflammatory damage, and knee joint cartilage damage of OA rats. Besides, synovial cell apoptosis was enhanced upon LOC101928134 downregulation, while cartilage cell apoptosis of OA rats was suppressed. These results demonstrate that downregulation of LOC101928134 suppresses the synovial hyperplasia and cartilage destruction of OA rats via activation of JAK/STAT signaling pathway by upregulating IFNA1, providing a new candidate for the treatment of OA. PMID- 30456845 TI - NRP-1 INTERACTS WITH GIPC1 and SYX TO ACTIVATE p38 MAPK SIGNALING AND CANCER STEM CELL SURVIVAL. AB - Epidermal cancer stem cells (ECS cells) comprise a limited population of cells that form aggressive, rapidly growing and highly vascularized tumors. VEGF-A/NRP 1 signaling is a key driver of the ECS cell phenotype and aggressive tumor formation. However, relatively less is known regarding the downstream events following VEGF-A/NRP-1 interaction. In the present study, we show that VEGF-A/NRP 1, GIPC1 and Syx interact to increase RhoA-dependent p38 MAPK activity to enhance ECS cell spheroid formation, invasion, migration and angiogenic potential. Inhibition or knockdown of NRP-1, GIPC1 or Syx attenuates RhoA and p38 activity to reduce the ECS cell phenotype, and NRP-1 knockout, or pharmacologic inhibition of VEGF-A/NRP-1 interaction or RhoA activity, reduces p38 MAPK activity and tumor growth. Moreover, expression of wild-type or constitutively-active RhoA, or p38, in NRP1-knockout cells, restores p38 activity and the ECS cell phenotype. These findings suggest that NRP-1 forms a complex with GIPC1 and Syx to activate RhoA/ROCK-dependent p38 activity to enhance the ECS cell phenotype and tumor formation. This article is protected by copyright. All rights reserved. PMID- 30456846 TI - Anomalous interaction of tri-acyl ester derivatives of uridine nucleoside with a l-alpha-dimyristoylphosphatidylcholine biomembrane model: a differential scanning calorimetry study. AB - OBJECTIVES: Uridine was conjugated with fatty acids to improve the drug lipophilicity and the interaction with phospholipid bilayers. METHODS: The esterification reaction using carbodiimides compounds as coupling agents and a nucleophilic catalyst allowed us to synthesize tri-acyl ester derivatives of uridine with fatty acids. Analysis of molecular interactions between these tri acyl ester derivatives and l-alpha-dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLV) - as a mammalian cell membrane model - have been performed by differential scanning calorimetry (DSC). KEY FINDINGS: The DSC thermograms suggest that nucleoside and uridine triacetate softly interact with phospholipidic multilamellar vesicles which are predominantly located between the polar phase, whereas the tri-acyl ester derivatives with fatty acids (myristic and stearic acids) present a strongly interaction with the DMPC bilayer due to the nucleoside and aliphatic chains parts which are oriented towards the polar and lipophilic phases of the phospholipidic bilayer, respectively. However, the effects caused by the tri-myristoyl uridine and tri-stearoyl uridine are different. CONCLUSIONS: We show how the structural changes of uridine modulate the calorimetric behaviour of DMPC shedding light on their affinity with the phospholipidic biomembrane model. PMID- 30456847 TI - Automated Synthesis Protocol of Sequence-Defined Oligo-Urethane-Amides Using Thiolactone Chemistry. AB - An automated, iterative protocol for the synthesis of multifunctional, sequence defined oligo-urethane-amides using thiolactone chemistry is reported. Here, sequenced functionalization of the backbone is easily introduced using commercially available primary amines. The chemistry is carried out on solid phase using different supports for better optimization of the synthetic protocol and in order to demonstrate the versatility of the approach. This technique is very effective for iterative synthesis and solid-phase chemistry and enables the exploration of full automation of this approach using a robotic peptide synthesizer. As a result, this automated protocol allows for the synthesis of a sequence-defined nonamer of high purity. PMID- 30456848 TI - Clinical Endpoint Bioequivalence Studies Are Needed: A Perspective From Brand Drugs. PMID- 30456849 TI - Arsenic enhances cell death and DNA damage induced by ultraviolet B exposure in mouse epidermal cells through the production of reactive oxygen species. AB - BACKGROUND: Ultraviolet (UV)B radiation has long been considered a carcinogen in both epidemiological surveys and experimental studies. However, recent work has suggested that different dosages of UVB exert different influences on cells. There are also co-carcinogenesis factors such as arsenic that affect the role of UVB. AIM: To explore the co-carcinogenesis effect of UVB and arsenic on the mouse epidermal cell line JB6 and the mechanism underlying it. METHODS: Growth of JB6 cells was measured by MTT assay. We carried out a comet assay to determine the DNA damage caused by UVB and arsenic, and tested the expression of DNA repair protein by western blotting. Reactive oxygen species (ROS) were measured using DCF and DHE staining, and changes in antioxidant enzymes were assessed using western blotting. RESULTS: Viability assays showed that arsenic increased the UVB induced death rate. Arsenic enhanced DNA damage caused by UVB both directly by injury to double-stranded DNA and indirectly by reducing the capability of DNA repair in JB6 cells. All of these effects are the results of increased ROS generation and reduced expression of the antioxidant enzyme superoxide dismutase (SOD)1. CONCLUSION: Arsenic was found to enhance UVB-induced production of ROS and to downregulate SOD1 expression, leading to DNA damage and apoptosis in mouse skin cells. The combination of arsenic and UVB exposure was found to differentially regulate the expression of SOD1 and SOD2. PMID- 30456850 TI - Malperfusion following repair of a type I aortic dissection. PMID- 30456851 TI - Therapists' and non-therapists' constructions of heterosex: A qualitative story completion study. AB - OBJECTIVES: Little research has examined the discourses that shape therapists' sense-making around heterosex. This paper explores the discourses of sexuality and gender underpinning therapists' and non-therapists' responses to a sexual experimentation scenario in a heterosexual relationship. It also considers the value of the novel technique of story completion (SC), in which participants are asked to write a story in response to a hypothetical scenario, for qualitative psychology and psychotherapy research. DESIGN: This research used a comparative SC design (Kitzinger & Powell, ). Participants were sequentially presented with and invited to complete two story stems: one in which a male character suggested 'trying something new' to his female partner and one in which the female character made the suggestion. The stems were otherwise identical. METHODS: A total of 100 SCs were written by 49 (28 female; 21 male) therapists and 51 (29 female; 22 male) non-therapists. Participants were recruited mainly via UK-based email lists and Facebook groups, and therapeutic training organizations, and the data were analysed using a feminist post-structuralist thematic analysis (Braun & Clarke, ). RESULTS: Both groups of participants drew on heteronormative discourses of sexuality and gender to make sense of the stem. Engaging in sexual experimentation was often depicted as a demonstration of being normal. In some stories written by women, sex was framed as a site for negotiating 'equality' and reciprocity in relationships. Therapists were more likely than non-therapists to frame 'difficulties' within relationships as opportunities for personal growth and increased emotional depth, and their stories included greater emotional complexity. CONCLUSION: These findings raise questions about practitioner training and whether it results in therapists drawing on narrow and restrictive discourses of heterosex in clinical practice. PRACTITIONER POINTS: Training on sexual issues is largely absent from non-specialist practitioner training courses, which potentially means therapists are ill-equipped to respond to clients' anxiety about sexual issues. Evidence from this and other research indicates that therapists' sense-making around heterosexual sexual relationships is underpinned by narrow and restrictive discourses that entrench traditional gender relations and limit sexual agency. Psychologists are increasingly taking up positions of clinical leadership and are looked to for models of best practice. Drawing on theorizations of sexual difficulties, and of anxieties about sexual practice, that challenge traditional gender and heteronorms, and the commodification and medicalization of sex, is important for effective psychological leadership relating to the treatment of sexual issues and the furthering of social justice agendas. PMID- 30456852 TI - Right ventricle apex pacing identifies the presence of ventricular premature depolarizations-induced cardiomyopathy. AB - BACKGROUND: A high burden of ventricular premature depolarizations (VPDs) has been associated with potentially reversible left ventricular (LV) dysfunction, termed as VPD-induced cardiomyopathy (CMP). However, many patients maintain normal LV function despite a high VPD burden. The purpose of this study was to identify CMP by right ventricle apex (RVa) pacing method in patients with high VPD burden. METHODS: A total of 62 patients (28 male; mean age = 50 +/- 15 years) with idiopathic VPDs undergoing ablation were enrolled. RVa pacing was recorded in all patients during the procedure. The paced QRS duration (QRSd) during RV pacing was measured from the pacing spike to the latest QRS deflection on any surface electrocardiogram lead. Patients were divided into two groups: reversible VPD-induced CMP (Group R; n = 15, 14 males, mean age = 54 +/- 14 years) and normal LV function (Group N; n = 47, 23 males, mean age = 54 +/- 15 years). RESULTS: The LV ejection fraction (%) was significantly lower in Group R as compared with Group N (Group R, Group N = 36 +/- 6, 58 +/- 4; P < 0.001); however, LV end-diastolic dimension mm was not significantly different between the two study groups (Group R, Group N = 54 +/- 5, 50 +/- 6; P = 0.06). Similarly, sinus QRS width (P = 0.10), VPD-burden (P = 0.36), and body surface area (P = 0.75) were not significantly different between Group R and Group N. The QRSd was significantly longer in Group R compared with Group N (177 +/- 8 vs 150 +/- 14; P < 0.001). Using a QRSd cut-off value of 170.1 ms, VPD-induced CMP was identified with a sensitivity of 73% and a specificity of 97%. CONCLUSION: RVa pacing with transmyocardial conduction time assessment was a useful method for identifying idiopathic VPD-induced CMP. Using a QRSd cut-off value of 170.1 ms, VPD-induced CMP was identified with a sensitivity of 73% and a specificity of 97%. PMID- 30456853 TI - Temporal pattern of neuronal insulin release during Caenorhabditis elegans aging: Role of redox homeostasis. AB - The insulin-IGF-1/DAF-2 pathway has a central role in the determination of aging and longevity in Caenorhabditis elegans and other organisms. In this paper, we measured neuronal insulin secretion (using INS-22::Venus) during C. elegans lifespan and monitored how this secretion is modified by redox homeostasis. We showed that INS-22::Venus secretion fluctuates during the organism lifetime reaching maximum levels in the active reproductive stage. We also demonstrate that long-lived daf-2 insulin receptor mutants show remarkable low levels of INS 22::Venus secretion. In contrast, we found that short-lived mutant worms that lack the oxidation repair enzyme MSRA-1 show increased levels of INS-22::Venus secretion, specifically during the reproductive stage. MSRA-1 is a target of the insulin-IGF-1/DAF-2 pathway, and the expression of this antioxidant enzyme exclusively in the nervous system rescues the mutant insulin release phenotype and longevity. The msra-1 mutant phenotype can also be reverted by antioxidant treatment during the active reproductive stage. We showed for the first time that there is a pattern of neuronal insulin release with a noticeable increment during the peak of reproduction. Our results suggest that redox homeostasis can modulate longevity through the regulation of insulin secretion, and that the insulin-IGF 1/DAF-2 pathway could be regulated, at least in part, by a feedback loop. These findings highlight the importance of timing for therapeutic interventions aimed at improving health span. PMID- 30456854 TI - Access and closure management of large bore femoral arterial access. AB - Femoral and radial artery access continue to be the standard of care for percutaneous coronary interventions. Cardiac catheterization has progressed to encompass a wide range of diagnostic and interventional procedures including coronary, peripheral, endovascular, and structural heart disease interventions. Despite advanced technology to make these procedures safe, bleeding, and vascular complications continue to be a substantial source of morbidity, especially in patients undergoing large-bore access procedures. New variations of percutaneous devices have reduced complications associated with these procedures. However, safe vascular access with effective hemostasis requires special techniques which have not been well described in the literature. Large-bore femoral artery access is feasible, safe, and associated with low complication rates when a protocol is implemented. Wayne State University, Detroit Medical Center Heart Hospital is a tertiary care, high-volume center for endovascular, structural heart and complex high risk indicated procedures with more 150 procedures involving mechanical circulatory support (MCS) devices per year. In this manuscript, we describe our approach to femoral artery large-bore sheath insertion and management. Our protocol includes proper identification of the puncture site, device selection, insertion, assessment of limb perfusion while on prolong MCS support, and hemostasis techniques after sheath removal. PMID- 30456855 TI - Perception of biological motions is preserved in people with autism spectrum disorder: electrophysiological and behavioural evidences. AB - BACKGROUND: There have been some controversies over the ability of individuals with autism spectrum disorder (ASD) to perceive biological motion. In this study, we used electroencephalography and behavioural measures (recognition test) to examine whether or not children with ASD can correctly identify biological motion. METHOD: Twenty participants with ASD (mean = 11.3, SD = 2.1 years) and 20 typically developed (TD) participants (mean = 11.4, SD = 2.8 years) participated in the study. They watched videos and point light displays of actions, and their EEG was recorded. Then they answered action recognition test, and their accuracy and response times were recorded. RESULTS: Our findings showed that children with ASD had the same mu suppression as a TD age-matched control group in both point light display and video presentations. Furthermore, the results showed that while TD and ASD groups did not differ in accuracy, ASD participants had a slower reaction time. CONCLUSION: Taken together, our results indicate that the perception of non-emotional BMs is preserved in children with ASD. PMID- 30456856 TI - The Role of Psychological Distress in the Relationship between the Severity of Pressure Injury and Pain Intensity in Hospitalized Adults. AB - AIMS: To examine the effect of psychological distress in mediating the relationship between the severity of pressure injury and pain intensity in hospitalized adults. BACKGROUND: Despite the prevalence of pressure injury (previously known as pressure ulcers) in hospitalized adults, the current knowledge of pain associated with pressure injury is limited and findings are inconsistent. There is also a lack of understanding of the relationship between psychological distress and pain from pressure injury. DESIGN: Retrospective cross sectional secondary analysis of data from electronic health records. METHODS: The data were retrieved from the third day of admission in the period between 2013 - 2016 through the Integrated Data Repository. Electronic health records were reviewed to collect data as needed. The mediation effect was tested by using path analysis implemented through Mplus. RESULTS: Path analysis revealed that the severity of pressure injuries and psychological distress have significant direct effects on pain intensity in hospitalized adults. However, the relationship between the severity of pressure injury and pain intensity was not significantly mediated by psychological distress. CONCLUSIONS: Hospitalized adults who have more severe pressure injury and more treatments for psychological distress experienced greater pain intensity. Healthcare providers must pay attention to treating psychological distress among hospitalized adults to manage pain. Further study is needed to validate these findings and it should incorporate more appropriate measures of psychological distress. The lack of standardized nursing documentation in electronic health records severely limits the usefulness of data from electronic health records for nursing research. This article is protected by copyright. All rights reserved. PMID- 30456857 TI - Identification and functional analysis of proteins in response to light intensity, temperature, and water potential in Brassica rapa hypocotyl. AB - Hypocotyl elongation is an early event in plant growth and development and is sensitive to fluctuations in light, temperature, water potential, nutrients, etc. Most research on hypocotyl elongation has focused on the regulatory mechanism of a single environment factor. However, information about combined effects of multi environment factors remains unavailable, and overlapping sites of the signaling pathways of environment factors in the regulation hypocotyl elongation remain unclear. To identify how cross-talks among light intensity, temperature and water potential to regulate hypocotyl elongation in Brassica rapa L. ssp. chinesis, a comprehensive isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic approach was adopted. In total, 7259 proteins were quantified, and 378 differentially expressed proteins (DEPs) were responsive to all three environment factors. The DEPs were involved in a variety of biochemical processes, including signal transduction, cytoskeletal organization, carbohydrate metabolism, cell wall organization, protein modification, and transport. The DEPs did not function in isolation, but acted in a large and complex interaction network to affect hypocotyl elongation. Among the DEPs, phyB was outstanding for its significant fold change in quantity and complex interaction networks with other proteins. In addition, changes of sensitivity to environment factors in phyB-9 suggested a key role in the regulation of hypocotyl elongation. Overall, the data presented in this study show a profile of proteins interaction network in response to light intensity, temperature and water potential and provides molecular basis of hypocotyl elongation in B. rapa. This article is protected by copyright. All rights reserved. PMID- 30456858 TI - Judicial precedents associated with periungual warts in South Korea. PMID- 30456859 TI - A novel KRT71 variant in curly-coated dogs. AB - Curly fur is a common phenotype in many dog breeds, known to result from a missense variant (c.451C>T) in exon 2 of the keratin 71 (KRT71) gene. During screening for this variant across various breeds, we found that Curly Coated Retrievers (CCRs) fixed with the trait did not carry the known variant. By analysis of whole-genome sequencing data of one CCR we identified a novel genetic cause for curly fur. We found a novel structural variant in exon 7 of the KRT71 gene (c.1266_1273delinsACA) that was predicted to result in a frameshift and stop loss, therefore significantly affecting the structure of the protein, if translated. The variant was also found at lower frequencies in five other breeds, including Lagotto Romagnolo, Bichon Frise, Spanish Water Dog, Chesapeake Bay Retriever and Irish Terrier. One curly-coated Lagotto carried neither of the two KRT71 variants. These results identify a second variant for curly coat in KRT71 and suggest the existence of additional alleles. This study enables the development of an additional KRT71 gene test for breeders to understand and manage coat types. PMID- 30456860 TI - PINK1/Parkin-mediated mitophagy promotes apelin-13-induced vascular smooth muscle cell proliferation by AMPKalpha and exacerbates atherosclerotic lesions. AB - Aberrant proliferation of vascular smooth muscle cells (VSMC) is a critical contributor to the pathogenesis of atherosclerosis (AS). Our previous studies have demonstrated that apelin-13/APJ confers a proliferative response in VSMC, however, its underlying mechanism remains elusive. In this study, we aimed to investigate the role of mitophagy in apelin-13-induced VSMC proliferation and atherosclerotic lesions in apolipoprotein E knockout (ApoE-/-) mice. Apelin-13 enhances human aortic VSMC proliferation and proliferative regulator proliferating cell nuclear antigen expression in dose and time-dependent manner, while is abolished by APJ antagonist F13A. We observe the engulfment of damage mitochondria by autophagosomes (mitophagy) of human aortic VSMC in apelin-13 stimulation. Mechanistically, apelin-13 increases p-AMPKalpha and promotes mitophagic activity such as the LC3I to LC3II ratio, the increase of Beclin-1 level and the decrease of p62 level. Importantly, the expressions of PINK1, Parkin, VDAC1, and Tom20 are induced by apelin-13. Conversely, blockade of APJ by F13A abolishes these stimulatory effects. Human aortic VSMC transfected with AMPKalpha, PINK1, or Parkin and subjected to apelin-13 impairs mitophagy and prevents proliferation. Additional, apelin-13 not only increases the expression of Drp1 but also reduces the expressions of Mfn1, Mfn2, and OPA1. Remarkably, the mitochondrial division inhibitor-1(Mdivi-1), the pharmacological inhibition of Drp1, attenuates human aortic VSMC proliferation. Treatment of ApoE-/- mice with apelin-13 accelerates atherosclerotic lesions, increases p-AMPKalpha and mitophagy in aortic wall in vivo. Finally, PINK1-/- mutant mice with apelin-13 attenuates atherosclerotic lesions along with defective in mitophagy. PINK1/Parkin-mediated mitophagy promotes apelin-13-evoked human aortic VSMC proliferation by activating p-AMPKalpha and exacerbates the progression of atherosclerotic lesions. PMID- 30456861 TI - Dexmedetomidine alleviates cerebral ischemia-reperfusion injury in rats via inhibition of hypoxia-inducible factor-1alpha. AB - Dexmedetomidine (Dex) was reported to reduce ischemia-reperfusion (I/R) injury in kidney and brain tissues. Thus, we aimed to study the role and mechanism of Dex in cerebral I/R injury by inhibiting hypoxia-inducible factor-1alpha (HIF-1alpha) and apoptosis. First, I/R injury models were established. Six groups were assigned after different treatments: sham, I/R, I/R+Dex, I/R+2-methoxyestradiol (2ME2) (HIF-1alpha inhibitor), I/R+CoCl 2 (HIF-1alpha activator), and I/R+Dex+CoCl 2 groups. Neurological function, cerebral infarction volume, survival, and apoptosis of brain cells were then analyzed. Besides, immunohistochemistry and Western blot analysis were used to detect the expression of HIF-1alpha, BCL-2[B-cell leukemia/lymphoma 2] adenovirus E1B interacting protein 3 (BNIP3), B-cell leukemia/lymphoma 2 (BCL2), BCL2[B-cell leukemia/lymphoma 2] associated X (Bax), and cleaved-caspase3 proteins in brain tissues. I/R rats showed cerebral infarction, increased neurological function score, number of terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL)-positive cells and HIF-1alpha-positive cells as well as decreased neurons. Inhibition of HIF-1alpha can reduce the apoptosis induced by I/R, and overexpression of HIF-1alpha can aggravate apoptosis in brain tissue of I/R rats. Furthermore, activation of HIF-1alpha expression blocks the inhibitory effect of Dex on neuronal apoptosis in I/R rats. Dex may inhibit the neuronal apoptosis of I/R rats by inhibiting the HIF-1alpha pathway and then improve the cerebral I/R injury in rats. PMID- 30456862 TI - SIG-1273 protects skin against urban air pollution and when formulated in AgeIQTM Night Cream anti-aging benefits clinically demonstrated. AB - BACKGROUND: SIG-1273 is a novel cosmetic active that provides a broad spectrum of benefits to the skin. Considering the chronic skin exposure to pollution in urban areas, we sought to determine if SIG-1273 could provide additional protection against skin aging by inhibiting pollutant-induced cytotoxicity and inflammation. OBJECTIVE: Determine if SIG-1273 possesses antipollution properties in vitro and evaluate the potential anti-aging benefits of Age IQTM Night Cream clinically in human subjects. METHODS: In vitro studies utilizing normal human epidermal keratinocytes (NHEKs), were co-treated with urban dust (SRM 1649b) and SIG-1273 (toxicity protection measured by MTS assay). A water-soluble fraction of urban dust (UD-WS) induces pro-inflammatory cytokine release (IL-8) from NHEKs (measured via ELISA). An 8-week, 37-subject clinical trial was performed with 0.05% SIG-1273 formulated in Age IQTM Night Cream and applied topically to assess its potential to reduce the appearance of aging. RESULTS: In vitro studies using NHEKs demonstrate SIG-1273 protects against urban dust-induced cell toxicity, reducing cell death by 66% and concentration dependently inhibits UD-WS-induced IL-8 production (IC50 = 20 nmol/L), outperforming niacinamide, ascorbic acid, and alpha-tocopherol, commonly used actives in antipollution skin-care products. Clinical assessment of Age IQTM Night Cream shows it is effective in improving the appearance of facial skin aging including fine lines and wrinkles, skin texture, skin clarity/brightness, and firmness/elasticity. CONCLUSIONS: SIG-1273, is demonstrated here for the first time to possess antipollution properties. Included as a key active ingredient in Age IQTM Night Cream, this novel topical formulation provides benefits to individuals with aging skin. PMID- 30456863 TI - Meta-analysis of risk and protective factors for gastrointestinal bleeding after percutaneous coronary intervention. AB - AIM: To quantitatively analyse factors related to gastrointestinal bleeding after percutaneous coronary intervention and provide evidence for the prevention of gastrointestinal bleeding. DATA SOURCES AND REVIEW METHODS: Cochrane Library, Pubmed, Embase, and Ovid databases were searched from inception to 31 May 2018; case-control and cohort studies published in English were included. The methodological quality of each study was assessed by two independent reviewers using the Newcastle-Ottawa Scale. Meta-analysis was performed using Revman version 5.3. RESULTS: A total of 16 publications yielded data about risk factors. It was found that age older than 70 years, age (per 10-year increase), female sex, baseline anaemia, history of smoking, history of using alcohol, history of peptic ulcer disease, chronic renal failure, previous bleeding, shock, congestive heart failure, acute myocardial infarction, prior use of inotropic medications, and prior use of antithrombotic medications were positively associated with gastrointestinal bleeding. Four articles yielded data about protective factors. It was found that proton-pump inhibitor and bivalirudin therapy were negatively associated with gastrointestinal bleeding after percutaneous coronary intervention. CONCLUSION: This research found risk and protective factors which can assist in effective management of this potentially fatal complication. PMID- 30456864 TI - Prevalence and clinicians' awareness of psychiatric comorbidities among first episode schizophrenia. AB - BACKGROUND: To explore the prevalence and clinicians' awareness of psychiatric comorbidities, and to identify factors associated with current psychiatric comorbidities in first-episode schizophrenia (FES) patients. METHOD: In this cross-sectional study, 128 patients with FES, who were in symptomatic remission, were consecutively recruited from a local early intervention clinic. All patients were interviewed using the Chinese bilingual version of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Axis I Disorders, Positive and Negative Syndrome Scales, Scale to Assess Unawareness of Mental Disorder, Social and Occupational Functioning Assessment Scale, Simpson-Angus Scale, Barnes Akathisia Rating Scale and Abnormal Involuntary Movement Scale. Bivariate and multivariate analyses were performed to investigate factors associated with psychiatric comorbidities in FES patients. RESULTS: The lifetime and point prevalence of psychiatric comorbidities among FES patients were 47.7% and 27.3%, respectively. Current psychiatric comorbidities were documented on the medical records of 39.3% of the patients. The FES patients with current psychiatric comorbidities had a lower level of functioning. Depression in FES was also associated with akathisia. CONCLUSION: Psychiatric comorbidities are prevalent among community FES patients. In addition to achieving symptomatic remission in schizophrenia, both treating psychiatric comorbidities and minimizing the side-effects of treatment, particularly akathisia, are fundamental for supporting FES patients in their journey to recovery. PMID- 30456865 TI - The impact of pycnogenol supplementation on plasma lipids in humans: A systematic review and meta-analysis of clinical trials. AB - The effects of pycnogenol on plasma lipids are controversial. A systematic review and meta-analysis of clinical trials were conducted to obtain a conclusive result in humans. PubMed, Scopus, and Google Scholar were systematically searched until March 2018, to explore the clinical trials that examined the effect of pycnogenol supplementation on lipid parameters among adult human. Methodological quality of the eligible studies was evaluated using the Cochrane Collaboration's tool. To estimate the effect size, changes in blood lipids were implemented. Results were pooled using a random effects model. Potential sources of heterogeneity were explored by subgroup analysis. A systematic review and meta-analysis of 14 clinical trials with 1,065 participants suggested a significant increase in plasma concentration of high density lipoprotein cholesterol (HDL-C; 3.27 mg/dL; 95% CI [0.19, 6.36]; p = 0.038). In contrast, plasma levels of total cholesterol (TC; -4.45 mg/dL, 95% CI [-11.24, 2.34]; p = 0.199), triacylglycerol (TAG; -3.64 mg/dL; 95% CI [-17.89, 10.61]; p = 0.616), and low density lipoprotein cholesterol (LDL-C; -3.61 mg/dl; 95% CI [-8.76, 1.55]; p = 0.171) were not altered. Adjustment for confounding variables was poor in included studies. Also, these studies did not assess dietary lipid intake. The results indicate that pycnogenol supplementation improves levels of HDL-C; however, the changes in TC, TAG, and LDL-C were not clinically relevant. Since there are few phytochemicals that have a significant increasing effect on HDL-C levels, pycnogenol may have important role in prevention of cardiovascular diseases. PMID- 30456866 TI - Liraglutide pharmacotherapy reduces body weight and improves glycemic control in juvenile obese / hyperglycemic male and female rats. AB - AIMS: Maternal and early-postnatal consumption of high-fat/high-sucrose diet (HFSD) dramatically alters the offspring phenotype, predisposing the progeny to have reduced sensitivity to satiation signals, increased body weight, and blood glucose impairments. Recent therapeutics for treating adult obesity have focused on targeting the glucagon-like-peptide-1 (GLP-1) system. Here, we examine whether the GLP-1 receptor agonist liraglutide could be used in juvenile male and female rats as an anti-obesity/diabetic pharmaceutical to prevent not only adolescent obesity/ hyperglycemia, but also prevent early-adult onset obesity. MATERIAL AND METHODS: Pregnant dams were fed either standard chow or HFSD from gestational day 2, throughout pregnancy and lactation. Offspring were weaned on to the respective maternal diet. Juveniles received daily subcutaneous injection of liraglutide (50 MUg/kg, from postnatal day [PND]30-PND40 and 200 MUg/kg from PND40-PND60) or vehicle. Food intake, body weight and glycemic levels were evaluated across the experimental period. RESULTS: Chronic liraglutide administration in juveniles prevented body weight gain in males and retained a normo-glycemic profile in both male and female rats. CONCLUSION: These preclinical data suggest that maternal and early-life consumption of HFSD increases caloric intake, body weight gain and hyperglycemia, a collective set of unwanted metabolic effects that appear to be treatable in juveniles with liraglutide pharmacotherapy intervention. This article is protected by copyright. All rights reserved. PMID- 30456867 TI - Comparing two short versions of the 32-item Hypomania Checklist (HCL-32) for patients with bipolar disorder. AB - PURPOSE: To compare the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) between Hypomania Checklist-20 (HCL 20) and HCL-16. DESIGN AND METHODS: Altogether, 350 subjects with bipolar disorders (BD) or major depressive disorders (MDD) were included. The sensitivity, specificity, PPV, NPV, and area under the curve between the HCL-20 and the HCL-16 for BD and its subtypes were compared. FINDINGS: The HCL-16 demonstrated superior performance in terms of sensitivity + specificity than HCL 20. For discriminating BD and BD-I patients from MDD patients, HCL-16 showed better sensitivity than HCL-20, while HCL-20 showed better specificity than HCL 16. PRACTICE IMPLICATIONS: Our results showed that both HCL-20 and HCL-16 have a fair screening ability, but HCL-16 showed a relatively superior performance considering its length. PMID- 30456868 TI - Autotaxin and vascular endothelial growth factor receptor-2 and -3 are related to vascular development during the progression of chronic viral hepatitis C. AB - Vascular endothelial growth factor (VEGF) and autotaxin (ATX) play important roles in embryonic vasculogenesis and cancer progression. This study examines whether these two angiogenic factors cooperate in the mechanism that regulates vascular development during the progression of chronic viral hepatitis C (CVH-C) (Inuyama classification, F1-F4). First, surgical wedge biopsy specimens and needle biopsy specimens were obtained. Immunohistochemical staining for ATX and vascular endothelial growth factor receptor was assessed in serial sections. Immunoelectron microscopy was conducted with a perfusion-fixation method. In normal control liver tissue specimens, ATX was expressed at low levels within the branches of the hepatic artery and hepatic sinusoids. In F1 CVH-C liver tissue specimens, ATX was expressed within the branches of the hepatic artery. Additionally, VEGFR-2 was expressed within the branches of the hepatic artery and capillaries. In F3-F4 CVH-C liver tissue specimens, positive staining for ATX and VEGFR-2 or VEGFR-3 was detected in the branches of the hepatic artery or microlymphatic vessels. ATX-1 reaction products were specifically expressed on the plasma membrane of some microvascular endothelial cells (ECs) in the proliferative capillary artery. VEGFR-2 was expressed on caveolae in ECs and vascular smooth muscle cells. VEGFR-3 immunogold particles were also observed in lymphatic ECs. These results suggest functional interactions among ATX, VEGFR-2, and VEGFR-3 in the modulation of hemovascular and lymphovascular cell activation during vascular development. PMID- 30456869 TI - The importance of early diagnosis of Mycobacterium abscessus complex in patients with cystic fibrosis. AB - Mycobacterium abscessus complex can cause severe lung infections and has proven to be a serious threat to patients with cystic fibrosis and a challenge for clinicians due to difficulties in timely diagnosis and complex multidrug treatment regimes. Mycobacterial culture is the gold standard for diagnosis, but in most cystic fibrosis centers it is performed less frequently than culture for other pathogens. Consensus today recommends just one annual mycobacterial culture for asymptomatic patients with cystic fibrosis, a strategy likely to lead to diagnostic delays. Postponement of diagnosis might be the deciding factor in whether an early colonization turns into chronic infection. This review highlights the latest developments in knowledge about the pathogenicity and clinical consequences of M. abscessus complex pulmonary disease, addressing the central theme of why pulmonary infection requires early identification and aggressive antibiotic treatment. The window of opportunity, before M. abscessus complex transforms from a mucosal colonizer to a chronic biofilm infection, is where microbial eradication is most likely to be successful, making early diagnosis essential for improved outcomes. PMID- 30456871 TI - Voriconazole-induced QTc prolongation in a pediatric population. AB - AIM: To evaluate Corrected QT (QTc) interval prolongation (QTcP) in pediatric patients treated with voriconazole and identify its associated risk factors in this setting. METHODS: Clinical, voriconazole-related, and corrected QT interval (QTc) data were collected retrospectively from the electronic medical records of voriconazole-treated pediatric patients attending a large tertiary medical center in 2011-2016 who underwent electrocardiography before and during therapy. Paired comparison of QTc intervals before and during voriconazole treatment was performed, adjusted for concurrent medications, electrolyte disturbances, and co morbidities. RESULTS: Fifty-five patients (mean age 10.1+/-5.4 years) met the inclusion criteria; 34 had an oncologic or hemato-oncologic diagnosis. Mean QTc interval was 402.8+/-27.9 milliseconds (msec) before voriconazole treatment and 440.0+/-45.3 msec on treatment (p <0.001). During treatment, 38 patients (61.8%) had QTcP >=30 msec and 17 (30.9%), QTcP >=60 msec; 10 patients (18.2%) had QTc >=500 msec of whom one acquired torsades de pointes. On multivariate analysis, older age (p=0.025), lower potassium level (p=0.025), and longer baseline QTc (0.032) were associated QTcP >=60 msec, but not daily or cumulative dose of voriconazole. CONCLUSION: This study demonstrated a high rate of clinically significant QTcP in voriconazole-treated children. Proper QTc monitoring, together with laboratory monitoring and electrolyte imbalance correction, is important to prevent cardiac arrhythmias in this patient population. This article is protected by copyright. All rights reserved. PMID- 30456870 TI - WHO laboratory validation of Xpert(r) CT/NG and Xpert(r) TV on the GeneXpert system verifies high performances. AB - Effective tests for diagnosis of sexually transmitted infections (STIs), used point of care to inform treatment and management decisions, are urgently needed. We evaluated the analytical sensitivity and specificity of the Xpert(r) CT/NG and Xpert(r) TV tests, examining 339 samples spiked with phenotypically and/or genetically diverse strains of Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis, and other related species that may cross-react. The APTIMA Combo 2 test and APTIMA TV test were used as reference tests. The analytical sensitivity for all three agents in the Xpert(r) CT/NG and Xpert(r) TV tests was <=102 genome equivalents/reaction. The analytical specificity of both tests was high. False-positive results were identified in the Xpert(r) TV test when challenging with high concentrations of Trichomonas tenax, Trichomonas gallinae, Trichomonas stableri, and Trichomonas aotus. However, the clinical relevance of these cross-reactions can likely be neglected, because these species have not been identified in urogenital samples from humans. In conclusion, the analytical sensitivity and specificity of the user-friendly Xpert(r) CT/NG and Xpert(r) TV tests on the GeneXpert system were high. The results support the use of specimens from also extra-genital sites, for example, pharynx and rectum. However, appropriate clinical validations are additionally required. PMID- 30456872 TI - From Supramolecular Vesicles to Micelles: Controllable Construction of Tumor Targeting Nanocarriers Based on Host-Guest Interaction between a Pillar[5]arene Based Prodrug and a RGD-Sulfonate Guest. AB - The targeting ability, drug-loading capacity, and size of the drug nanocarriers are crucial for enhancing the therapeutic index for cancer therapy. Herein, the morphology and size-controllable fabrication of supramolecular tumor-targeting nanocarriers based on host-guest recognition between a novel pillar[5]arene-based prodrug WP5-DOX and a Arg-Gly-Asp (RGD)-modified sulfonate guest RGD-SG is reported. The amphiphilic WP5-DOX?RGD-SG complex with a molar ratio of 5:1 self assembles into vesicles, whereas smaller-sized micelles can be obtained by changing the molar ratio to 1:3. This represents a novel strategy of controllable construction of supramolecular nanovehicles with different sizes and morphologies based on the same host-guest interactions by using different host-guest ratios. Furthermore, in vitro and in vivo studies reveal that both these prodrug nanocarriers could selectively deliver doxorubicin to RGD receptor-overexpressing cancer cells, leading to longer blood retention time, enhanced antitumor efficacy, and reduced systematic toxicity in murine tumor model, suggesting their potential application for targeted drug delivery. PMID- 30456873 TI - Self-Assembly of Polymer-Coated Plasmonic Nanocrystals: From Synthetic Approaches to Practical Applications. AB - Self-assembly of plasmonic nanocrystals (PNCs) and polymers provides access to a variety of functionalized metallic-polymer building blocks and higher-order hybrid plasmonic assemblies, and thus is of considerable fundamental and practical interest. The hybrid assemblies often not only inherit individual characteristics of polymers and PNCs but also exhibit distinct photophysical and catalytic properties compared to that of a single PNC building block. The tailorable plasmonic coupling between PNCs within assemblies enables the precise control over localized surface plasmon resonance, which subsequently affords a series of light-driven or photo-activated applications, such as surface-enhanced Raman scattering detection, photoacoustic imaging, photothermal therapy, and photodynamic therapy. In this review, the synthetic strategies of a library of PNC-polymer hybrid building blocks and corresponding assemblies are summarized along with the mechanisms of polymer-assisted self-assembly of PNCs and the concepts for bridging the intrinsic properties of PNC-polymer assemblies to widespread practical applications. PMID- 30456874 TI - Topoisomerase 1B poisons: Over a half-century of drug leads, clinical candidates, and serendipitous discoveries. AB - Topoisomerases are DNA processing enzymes that relieve supercoiling (torsional strain) in DNA, are necessary for normal cellular division, and act by nicking (and then religating) DNA strands. Type 1B topoisomerase (Top1) is overexpressed in certain tumors, and the enzyme has been extensively investigated as a target for cancer chemotherapy. Various chemical agents can act as "poisons" of the enzyme's religation step, leading to Top1-DNA lesions, DNA breakage, and eventual cellular death. In this review, agents that poison Top1 (and have thus been investigated for their anticancer properties) are surveyed, including natural products (such as camptothecins and indolocarbazoles), semisynthetic camptothecin and luotonin derivatives, and synthetic compounds (such as benzonaphthyridines, aromathecins, and indenoisoquinolines), as well as targeted therapies and conjugates. Top1 has also been investigated as a therapeutic target in certain viral and parasitic infections, as well as autoimmune, inflammatory, and neurological disorders, and a summary of literature describing alternative indications is also provided. This review should provide both a reference for the medicinal chemist and potentially offer clues to aid in the development of new Top1 poisons. PMID- 30456875 TI - Decarboxylative ipso-Amination of Activated Benzoic Acids. AB - In the presence of a bimetallic Pd/Cu-system with 1,10-phenanthroline as the ligand and air or NMO as oxidants, electron-deficient benzoic acids undergo oxidative decarboxylative coupling with unprotected amines. This operationally simple aniline synthesis is widely applicable with regard to the amine and gives good yields even on multi-gram scale. The orthogonality of this reaction to other Pd-catalyzed cross-couplings allows the concise synthesis of multi-substituted arenes via sequential C-C, C-Cl and C-N functionalizations. Mechanistic investigations suggest the intermediacy of hypervalent Pd species. PMID- 30456876 TI - Echo-tracking evaluation of changes in common carotid artery Wall elasticity after smoking cessation. AB - The aim of this study was to explore changes in the common carotid arterial wall elasticity after smoking cessation. Carotid artery ultrasonographic examination was performed in 136 patients, then 1 or 2 years after smoking cessation. We used echo-tracking (ET) to measure stiffness index (beta), pressure-strain elasticity modulus (Ep), arterial compliance (AC), augmentation index (AI), and local pulse wave velocity (PWVbeta). Patients were divided into four groups based on whether or not they successfully stopped smoking (groups M and N, respectively) and whether (groups M2 and N2, respectively) or not (groups M1 and N1, respectively) they showed comorbidities. In group M1, beta, Ep and PWVbeta were lower at 1 year than before smoking cessation, while AC and AI did not change. At 2 years, beta, Ep, PWVbeta, and AC, but not AI, improved further. In group M2, beta, Ep, and PWVbeta decreased at 2 years, whereas AC and AI did not change. In groups N1 and N2, none of the variables changed significantly. ET can be used quantitatively to evaluate the impact of smoking cessation on the elasticity of the common carotid artery wall. PMID- 30456878 TI - Cryosurgical management of basal cell carcinoma: in vivo follow-up using reflectance confocal microscopy. PMID- 30456877 TI - Interactions between monoamine oxidase A rs1137070 and smoking on brain structure and function in male smokers. AB - The monoamine oxidase A (MAOA) enzyme metabolizes monoamine neurotransmitters such as dopamine, serotonin and norepinephrine, and its genetic polymorphism (rs1137070) influences its activity level and is associated with smoking behaviors. However, the underlying neural mechanisms of the gene * environment interactions remain largely unknown. In this study, we aimed to explore the interactive effects of the rs1137070 and cigarette smoking on gray matter volume (GMV) and functional connectivity strength (FCS). A total of 81 smokers and 42 nonsmokers were enrolled in the present study. Voxel-based morphometry analysis showed a significant rs1137070 genotype * smoking effect on the GMV of the left orbitofrontal cortex (OFC), such that individuals with risk allele had greater GMV among nonsmokers but not smokers. Meanwhile, rs1137070 variant and nicotine dependence interactively altered the FCS of the right hippocampus, the left inferior parietal lobule (IPL), the left dorsolateral prefrontal cortex and bilateral OFC. In addition, the FCS in the left IPL was correlated with smoking initiation and smoking years in smokers with the risk allele. These findings suggest that MAOA rs1137070 contributes to the susceptibility to nicotine dependence through its influence on brain circuits involved in reward and attention, and interacts with smoking in the progression. This article is protected by copyright. All rights reserved. PMID- 30456879 TI - TMEM106A inhibits cell proliferation, migration, and induces apoptosis of lung cancer cells. AB - Transmembrane protein 106A (TMEM106A) has been found to function as tumor suppressor in gastric and renal cancer. However, the role of TMEM106A in nonsmall cell lung carcinoma (NSCLC) has not been investigated. In this study, we evaluated the expression profile of TMEM106A in NSCLC tissues and cell line, and explored the roles of TMEM106A in NSCLC cell lines. Our results showed that TMEM106A expression was significantly decreased in human NSCLC tissues. In vitro assays showed that TMEM106A expression in NSCLC cell lines was much lower than that in the bronchial epithelial cell line. Besides, overexpression of TMEM106A reduced cell proliferation, migration, and invasion, while induced cell apoptosis in NSCLC cells. TMEM106A overexpression repressed epithelial-mesenchymal transition (EMT), which was illustrated by increased E-cadherin expression and decreased the expressions of N-cadherin, and vimentin. In addition, TMEM106A overexpression suppressed the activation of phosphoinositide 3-kinase/protein kinase B/nuclear factor-kappaB (PI3K/Akt/NF-kappaB) signaling pathway in NSCLC cells. Our results indicated that TMEM106A acted as a tumor suppressor in NSCLC, and could be a therapeutic target for the management of NSCLC. PMID- 30456880 TI - Oxymatrine ameliorates diabetes-induced aortic endothelial dysfunction via the regulation of eNOS and NOX4. AB - AIM: Oxymatrine (OMT) is the major quinolizidine alkaloid extracted from the root of Sophora flavescens Ait (the Chinese herb Kushen) and exhibits diverse pharmacological actions. In this study, we investigated the effects of OMT on diabetes-associated aortic endothelial dysfunction in a rat model of diabetes and its mechanisms. METHODS: Male Sprague-Dawley rats were randomly divided into five groups: control, diabetic rats, diabetic rats treated with OMT (60, 120 mg/kg per day, by gavage), and diabetic rats treated with metformin (20 mg/kg per day, by gavage). The serum fasting blood glucose, insulin, total cholesterol, triglyceride, and nitric oxide (NO) levels were determined with commercial kits. Biochemical indices reflecting oxidative stress, such as malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) were analyzed with commercial kits. Mitochondrial reactive oxygen species 2',7' dichlorofluorescein diacetate (DCFH-DA) was measured by fluorescence microscopy. Histological analyses were conducted to observe morphological changes. Western blot analysis was applied to detect the expression levels of eNOS and NOX4. Reverse transcription polymerase chain reaction was used to detect the expressions of eNOS and NOX4 messenger RNA (mRNA). RESULTS: The diabetic rats exhibited markedly reduced body weight and increased plasma glucose levels. Moreover, the diabetic rats showed oxidative stress (significantly increased MDA and decreased SOD, CAT, GSH-Px, and serum NO levels). Hyperglycemia caused significant endothelial injury and dysfunction, including vasodilative and histologic changes in the diabetic rats. The expressions of phospho-eNOS protein and mRNA were significantly decreased, while the NOX4 protein expression was increased in the aortas of the diabetic rats. All of these diabetes-induced effects were reversed by OMT in the diabetic rats. CONCLUSION: The OMT treatment ameliorates diabetic endothelial dysfunction through enhanced NO bioavailability by upregulating eNOS expression and downregulating expression of NOX4. PMID- 30456881 TI - How does studying rurally affect peer networks and resilience? A social network analysis of rural- and urban-based students. AB - OBJECTIVE: To examine differences in peer networks between urban-based students and rural-stream students in an Australian medical school and to examine how characteristics of networks relate to resilience. DESIGN: Cross-sectional survey asking students to signify social, academic and support relationships with students in the same year and to complete a survey on their resilience. SETTING AND PARTICIPANTS: All second-, third- and fourth-year students at the Australian National University Medical School. MAIN OUTCOME MEASURES: Social network analysis comparing peer networks, t-test comparing mean resilience of urban and rural students. RESULTS: A visual analysis of the peer networks of year 2, 3 and 4 medical students suggests greater integration of rural-stream students within the year 2 and 4 urban cohorts. Resilience is similar between year 2 and 3 students in both urban and rural streams, but is significantly higher in year 4 rural-stream students, compared to their urban-based peers. Networks of rural stream students suggest key differences between their period spent rurally and on their return and integration within the larger student cohort. Furthermore, rural students, once reintegrated, had larger and stronger social networks than their urban counterparts. CONCLUSION: The results of the study suggest that the rural experience can instruct support systems in urban settings. However, whether the rural placement creates a more resilient student or resilient students are selected for rural placement is unclear. PMID- 30456882 TI - Chewing function, general health and the dentition of older Australian men: The Concord Health and Ageing in Men Project. AB - OBJECTIVES: To describe the associations between chewing function with oral health and certain general health characteristics, in a population of community dwelling older Australian men. METHODS: Analysis of data obtained from a cross sectional analysis of the 4th wave of the Concord Health and Ageing in Men Project cohort of 614 participants, 524 whom were dentate, aged 78 years and over. Their chewing capacity was assessed using three main indicators: capacity to chew eleven food items ranging from boiled eggs through to fresh carrots and nuts; discomfort when eating; and interruption of meals. Associations with chewing were tested for dentate vs edentate participants, numbers of teeth present, active dental disease and key general health conditions such as disabilities, comorbidities and cognitive status. Log binomial regression models adjusted for age, country of birth, income, education and marital status. Prevalence ratios and 95% confidence intervals were estimated. RESULTS: Twenty one per cent of participants could not eat hard foods, while 23.1% reported discomfort when eating, and 8.8% reported interrupted meals when eating. There was a threefold difference in the capacity of dentate men to chew firm meat over that of edentulous men (95% CI, 2.0-4.9); a 2.5 times greater likelihood of edentate men reporting discomfort when eating (95% CI: 1.5-4.3); and 1.9 times greater likelihood of edentate participants reporting having meals interrupted (95% CI: 1.4-2.6). Chewing/eating difficulties were associated with both dental status (number of teeth, active dental caries) and self-rated dental health. Fewer than 20 teeth and the presence of active coronal or root decay were associated with more discomfort when eating. General health conditions associated with chewing function included disability, physical activity, comorbidities, cognitive status and depression. Older men's self-rated oral health and general health perceptions were also associated with aspects of chewing function. Poorer self-reported oral health was associated with inability to eat hard foods (95% CI: 1.3-2.7) and with discomfort when eating (95% CI: 2.6-5.1), while poorer self reported general health was associated with discomfort when eating (95% CI: 1.2 2.2). CONCLUSIONS: Falling rates of edentulism may lead to improved chewing and eating function in older men. Maintaining 20 or more natural teeth, and preventing active coronal and root caries should enhance chewing function and promote self-reported health and oral health. Lower capacity to chew hard foods and a higher reporting of discomfort when eating is associated with co-morbidity in older Australian men. PMID- 30456883 TI - International comparison of trends in patients commencing renal replacement therapy by primary renal disease. AB - AIM: To examine international time trends in the incidence of renal replacement therapy (RRT) for end-stage renal disease (ESRD) by primary renal disease (PRD). METHODS: Renal registries reporting on patients starting RRT per million population for ESRD by PRD from 2005 to 2014, were identified by internet search and literature review. The average annual percentage change (AAPC) with a 95% confidence interval (CI) of the time trends was computed using Joinpoint regression. RESULTS: There was a significant decrease in the incidence of RRT for ESRD due to diabetes mellitus (DM) in Europe (AAPC=-0.9; 95%CI-1.3;-0.5) and to hypertension/renal vascular disease (HT/RVD) in Australia (AAPC=-1.8; 95%CI-3.3; 0.3), Canada (AAPC=-2.9; 95%CI-4.4;-1.5) and Europe (AAPC=-1.1; 95%CI-2.1;-0.0). A decrease or stabilization was observed for glomerulonephritis in all regions and for autosomal dominant polycystic kidney disease (ADPKD) in all regions except for Malaysia and the Republic of Korea. An increase of 5.2% to 16.3% was observed for DM, HT/RVD and ADPKD in Malaysia and the Republic of Korea. CONCLUSION: Large international differences exist in the trends in incidence of RRT by primary renal disease. Mapping of these international trends is the first step in defining the causes and successful preventative measures of CKD. This article is protected by copyright. All rights reserved. PMID- 30456884 TI - LncRNAs regulating stemness in aging. AB - One of the most outstanding observations from next-generation sequencing approaches was that only 1.5% of our genes code for proteins. The biggest part is transcribed but give rise to different families of RNAs without coding potential. The functional relevance of these abundant transcripts remains far from elucidated. Among them are the long non-coding RNAs (lncRNAs), a relatively large and heterogeneous group of RNAs shown to be highly tissue-specific, indicating a prominent role in processes controlling cellular identity. In particular, lncRNAs have been linked to both stemness properties and detrimental pathways regulating the aging process, being novel players in the intricate network guiding tissue homeostasis. Here, we summarize the up-to-date information on the role of lncRNAs that affect stemness and hence impact upon aging, highlighting the likelihood that lncRNAs may represent an unexploited reservoir of potential therapeutic targets for reprogramming applications and aging-related diseases. PMID- 30456885 TI - Antinociceptive properties of 25-methoxy hispidol A, a triterpinoid isolated from Poncirus trifoliata (Rutaceae) through inhibition of NF-kappaB signalling in mice. AB - The 25-methoxy hispidol A (25-MHA) is a triterpenoid, isolated from the immature fruit of Poncirus trifoliata (Rutaceae). The pretreatment with 25-MHA markedly (p < 0.001) attenuated the formalin-induced biphasic responses as well as acetic acid-induced writhing responses. The intraperitoneal administration of 25-MHA significantly attenuated the mechanical hyperalgesia (p < 0.001) and allodynia (p < 0.05). Similarly, 25-MHA also significantly attenuated (p < 0.001) complete Freund's adjuvant (CFA)-induced paw edema in mice. The 25-MHA treatment significantly attenuated the production of nuclear kappa B (NF-kappaB) (p65 nuclear subunit). The cytokines are the important mediators of inflammation and pain; however, treatment with 25-MHA exhibited significant inhibition (p < 0.001) on the mRNA expression levels of various inflammatory mediators. The 25-MHA administration also significantly enhanced antioxidant enzymes (p < 0.001) and inhibited the oxidative stress markers. The current study indicates that 25-MHA significantly (p < 0.001) inhibited the nitric oxide (NO) in mice plasma. Similarly, the haematoxylin and eosin (H&E) staining shows that 25-MHA administration significantly inhibited the inflammatory process in the mice paw tissue compared with the CFA-treated group. The 25-MHA treatment did not exhibited any toxicity on the liver, kidney, muscles strength, and motor co ordination in mice. The 25-MHA was coadministered with the various drugs such as tramadol, piroxicam, and gabapentin to observe the synergistic effect. PMID- 30456886 TI - Progression of hearing loss in neurofibromatosis type 2 according to genetic severity. AB - OBJECTIVES/HYPOTHESIS: This study set out to describe the progression of hearing loss in patients with neurofibromatosis type 2 (NF2), treated in a quaternary multidisciplinary clinic. It also aimed to compare hearing loss across patients grouped according to a known genetic severity score to explore its utility for prognostication. STUDY DESIGN: Retrospective cohort study. METHODS: We conducted a study of 147 patients with confirmed NF2 diagnosis for a mean observational period of 10 years. Pure-tone average (PTA), optimum discriminations scores (ODS), and genotype data were collected. Patients were classified according to hearing class (American Academy of Otolaryngology), their candidacy for auditory implantation (UK National NF2 consensus) and grouped by genetic severity as: 1 = tissue mosaic, 2A = mild classic, 2B = moderate classic, and 3 = severe. Survival analysis investigated the effect of genetic severity on the age of loss of serviceable hearing. RESULTS: Genetic severity was a significant predictor of hearing outcomes such as ODS, hearing classification, and maximum annual PTA deterioration. Although the overall median age of loss of serviceable hearing was 78 years, there was significant variation according to the genetic severity; the median for severe patients was 32 years compared to a median of 80 for tissue mosaic patients. CONCLUSIONS: This is the first description of long-term hearing outcomes in a clinical setting across a large heterogeneous cohort of patients with NF2. The results highlight the potential importance and benefit of considering the genetic severity score of patients when undertaking treatment decisions, as well as planning future natural history studies. LEVEL OF EVIDENCE: 2c Laryngoscope, 2018. PMID- 30456887 TI - Comparison of the HAT study, the largest global hypoglycaemia study to date, with similar large real-world studies. AB - AIMS: Optimal diabetes care requires clear understanding of the incidence of hypoglycaemia in real-world clinical practice. Current data on hypoglycaemia are generally limited to those reported from randomised controlled clinical trials. The Hypoglycaemia Assessment Tool (HAT) study, a non-interventional real-world study of hypoglycaemia, assessed hypoglycaemia in 27,585 people across 24 countries. The present study compared the incidence of hypoglycaemia from the HAT study with other similarly designed, large, real-world studies. MATERIALS AND METHODS: A literature search of PubMed (1995-2017) for population-based studies of insulin-treated patients with type 1 or type 2 diabetes (T1D, T2D), excluding clinical trials and reviews, identified comparable population-based studies reporting the incidence of hypoglycaemia. RESULTS: The 24 comparative studies, including >24,000 participants with T1D and >160,000 participants with T2D, varied in design, size, inclusion criteria, definitions of hypoglycaemia and method for recording hypoglycaemia. Reported rates (events/per patient-year [PPY]) of hypoglycaemia were higher in patients with T1D than in those with T2D (overall T1D 21.8-73.3, T2D 1.3-37.7; mild/non-severe T1D 29.0-126.7, T2D 1.3 41.5; severe T1D 0.7-5.8, T2D 0.0-2.5; nocturnal T1D 2.6-11.3, T2D 0.38-9.7), and were similar to the ranges found in the HAT study. CONCLUSIONS: The HAT data on hypoglycaemia incidence were comparable with those from other real-world studies and indicate a high incidence of hypoglycaemia among insulin-treated patients. Differences in rates between studies are mostly explained by differences in patient populations and study methodology. The goal of reducing hypoglycaemia should be a target for continued educational and evidence-based pharmacological interventions. This article is protected by copyright. All rights reserved. PMID- 30456888 TI - Gamma Knife radiosurgery for glomus tumors: Long-term results in a series of 30 patients. AB - BACKGROUND: Glomus tumors are rare and benign hypervascular tumors. Surgery represented the mainstay of their treatment, even if it has been associated with high morbidity and mortality rates. Recently, the treatment shifted to a multimodal approach and Gamma Knife radiosurgery represents one of the treatment options. METHODS: Authors retrospectively analyzed the clinical and radiological outcome of a series of patients who underwent Gamma Knife radiosurgery for glomus tumors. RESULTS: Thirty patients underwent Gamma Knife radiosurgery. Mean tumor volume was 7.69 cc (range 0.36-24.6). Mean tumor margin dose was 16 Gy (range 13 18). Median follow-up was of 91 months (mean 90; range 11-172). Overall clinical control rate was 100%; overall volumetric tumor control rate was 96.6%. Patients' and tumors' characteristics, treatment data, and outcome have been analyzed. CONCLUSION: Gamma Knife radiosurgery represents a safe and effective treatment for glomus tumors. Longer follow-up and larger cohort studies are needed to definitively outline the role of Gamma Knife radiosurgery for glomus tumors. PMID- 30456889 TI - Complex robotic compared to manual coronary interventions: 6- and 12-month outcomes. AB - OBJECTIVES: To assess the long-term safety and efficacy of robotic percutaneous coronary revascularization for use in complex coronary lesions. BACKGROUND: Robotically assisted percutaneous coronary intervention (PCI) is safe and feasible in simple coronary lesions and has excellent short-term procedural and clinical outcomes for complex lesions; however, long-term safety and efficacy outcomes are unknown. METHODS: A total of 103 consecutive patients underwent a total of 108 robotic (R)-PCI procedures (age 68.1; 78.3% male) over 18 months, and 210 patients underwent a total of 226 manual (M)-PCI procedures (age 67.5; 78.1% male) during the same period. Patients were subsequently followed and both 6-month and 12-month major adverse cardiovascular events (MACE), comprised of any death, stroke, myocardial infarction, or target vessel revascularization, are reported and compared. RESULTS: There was no difference between the two groups with regard to overall MACE at 6 months (R-PCI 5.8% vs. M-PCI 3.3%, P = 0.51) or at 12 months (R-PCI 7.8% vs. M-PCI 8.1%, P = 0.92). There was no difference between the individual components of the primary combined endpoint at either time point. No access site complications occurred in either cohort that met BARC III or higher criteria. CONCLUSIONS: At the 6- and 12-month time points following R PCI, no difference in clinical outcomes or safety measures was observed as compared to M-PCI. PMID- 30456890 TI - Cortactin expression: Association with disease progression and survival in oral squamous cell carcinoma. AB - BACKGROUND: Cortactin (CTTN) is located on chromosome 11q13 and is associated with invasiveness in various cancer entities. CTTN protein expression could be a prognosticator of oral squamous cell carcinoma (OSCC) in terms of recurrence and survival. METHODS: CTTN-dependent invasion was performed using migration assay in human papillomavirus-negative head and neck squamous cell carcinoma (HNSCC) cells. Cortactin protein analysis in tissue microarrays was used for correlation with clinical parameters, as well as for survival analysis. Gene expression profiling in HNSCC cells was performed to unreveal CTTN signaling. RESULTS: Knockdown of CTTN in HNSCC cells showed less invasion in vitro. Gene expression profiling showed various deregulated genes known to be involved in progression. We confirmed the link between CTTN overexpression and progression in a large clinical cohort. High expression was associated with worse overall and progression-free survival. CONCLUSIONS: We propose CTTN for managing OSCC in terms of adjuvant therapy and aftercare. Furthermore, our study reveals new potential targets in CTTN signaling for individualized OSCC therapy. PMID- 30456891 TI - Autocrine VEGF signalling on M2 macrophages regulates PD-L1 expression for immunomodulation of T cells. AB - M2-polarized macrophages, on one hand, can promote tumour vascularization by producing proangiogenic factors, such as vascular endothelial growth factor (VEGF). On the other hand, the expression of VEGF receptors (VEGFR) in this cell lineage was also reported. Although the function of VEGF/VEGFR axis plays a pivotal role in macrophages infiltration and angiogenesis, however, there is still lack of the direct evidence to show the role of VEGF as an autocrine operating in M2 macrophages, particularly for immunomodulation. In our study, we surprisingly discovered that M2 macrophages polarized by baicalin can simultaneously express VEGF and its receptors. Taking advantage of this unique culture system, we were able to investigate the biological activity of M2 macrophages in response to the autocrine VEGF milieu. Our results showed that the expression of programmed death-ligand 1 (PD-L1) on M2 macrophages was significantly up-regulated in autocrine VEGF milieu. Through the blockade of autocrine VEGF signalling, PD-L1 expression on M2 macrophages was dramatically down-regulated. Furthermore, transplantation of PD-L1+ M2 macrophage stimulated by autocrine VEGF into allogeneic mice significantly suppressed host CD4+ /CD8+ T cells in the peripheral blood and increased CD4+ CD25+ regulatory T cells in the bone marrow. In conclusion, our findings provide a novel biological basis to support the current successful strategy using combined VEGF/PD-1 signalling blockade in cancer therapy. PMID- 30456892 TI - Architecture and organization of mouse posterior parietal cortex relative to extrastriate areas. AB - The posterior parietal cortex (PPC) is a multifaceted region of cortex, contributing to several cognitive processes including sensorimotor integration and spatial navigation. Although recent years have seen a considerable rise in the use of rodents, particularly mice, to investigate PPC and related networks, a coherent anatomical definition of PPC in the mouse is still lacking. To address this, we delineated the mouse PPC using cyto- and chemoarchitectural markers from Nissl-, parvalbumin- and muscarinic acetylcholine receptor M2-staining. Additionally, we performed bilateral triple anterograde tracer injections in primary visual cortex (V1) and prepared flattened tangential sections from one hemisphere and coronal sections from the other, allowing us to co-register the cytoarchitectural features of PPC with V1 projections. This revealed that extrastriate area A was largely contained within lateral PPC, that medial PPC overlapped with the anterior portion of area AM, and that anterior RL overlapped partially with area PtP. Furthermore, triple anterograde tracer injections in PPC showed strong projections to associative thalamic nuclei as well as higher visual areas, orbitofrontal, cingulate and secondary motor cortices. Retrograde circuit mapping with rabies virus further showed that all cortical connections were reciprocal. These combined approaches provide a coherent definition of mouse PPC that incorporates laminar architecture, extrastriate projections, thalamic, and cortico-cortical connections. This article is protected by copyright. All rights reserved. PMID- 30456893 TI - Hexapole [9]Helicene. AB - This work presents the first hexapole [9]helicene (H9H). Co-catalyzed [2+2+2] cyclotrimerization of a dinaphthopyrene (DNP) functionalized alkyne provides the hexaaryl benzene precursor 2, which is transformed into H9H via a dehydrocyclization reaction. Formation of each embedded [9]helicene involves forging of a new C-C bond, which stitches together two [4]helicene subunits of the neighboring DNP blades, reminiscent of the initial method Martin developed for the preparation of [9]helicene in the 1960s. Single crystal X-ray analysis of both 2 and H9H discloses their extremely distorted and crowded structural features. Chiral resolution, optical and electronic properties of H9H are also included. PMID- 30456894 TI - Inhibitory effect of MSH6 gene silencing in combination with cisplatin on cell proliferation of human osteosarcoma cell line MG63. AB - Osteosarcoma (OS) is one of the most common primary bone malignancies, with the survival rate of patients with OS remaining low. Therefore, we conducted this study to identify the potential role combination of both MSH6 gene silencing and cisplatin (DDP) plays in OS cell proliferation and apoptosis. Microarray-based gene expression profiling was used to identify the differentially expressed genes (DEGs) in patients with OS, as well as microRNAs (miRNAs) that regulate the candidate gene. OS tissues from 67 patients with OS along with normal tissues from 24 amputee patients were collected for detection of the positive expression of mutS homolog 6 (MSH6) protein, mRNA, and protein expressions of c-myc, cyclin D1, l-2, B-cell lymphoma 2 (Bcl-2), Stathmin, proliferating cell nuclear antigen (PCNA), and Bcl-2-associated X (Bax). Moreover, after MSH6 silencing and DDP were treated on the selected human OS cell line MG63 with the highest expression of MSH6, cell viability, cell cycle distribution, and apoptosis were detected. The microarray analysis showed that MSH6 was upregulated in OS chip data. Furthermore, silencing MSH6 combined with DDP reduced expressions of c-myc, cyclin D1, Bcl-2, Stathmin, and PCNA, and elevated Bax expression, whereas inhibiting OS cell viability, impeding cell cycle distribution, and inducing apoptosis. In conclusion, our preliminary results indicated that the combination of MSH6 gene silencing coupled with DDP may have a better effect on the inhibition of OS cell proliferation and promote apoptosis, potentially providing targets for the OS treatment. PMID- 30456895 TI - Chiral Sulfide Catalysis for Desymmetrizing Enantioselective Chlorination. AB - Unprecendented chiral sulfide-catalyzed desymmetrizing enantioselective chlorination is disclosed. Various aryl-tethered diolefins and diaryl-tethered olefins afforded teralins or tricyclic hexahydrophenalene derivatives bearing multiple stereogenic centers in high yields with excellent enantio- and diastereoselectivities. In contrast, tertiary amine catalyst (DHQD)2PHAL led to a diastereomer product. The products could be transformed to diverse compounds such as spiro N-heterocycles. PMID- 30456896 TI - Hematopoietic stem cell transplantation for adult patients with isolated NPM1 mutated acute myeloid leukemia in first remission. AB - Acute myeloid leukemia (AML) in first remission (CR1) with isolated NPM1 mutation (iNPM1m) is considered a good prognosis genotype, although up to one third relapse. To evaluate the best transplant strategy, we retrospectively compared autologous stem cell transplantation (auto-SCT), related (MSD) and fully matched unrelated (MUD) allogeneic stem cell transplantation (allo-SCT). We identified 256 adult patients including 125 auto-SCT, 72 MSD and 59 MUD. The 2-year leukemia free survival (LFS) was 62% in auto-SCT, 69% in MUD and 81% in MSD (p=0.02 for MSD versus others). The 2-year overall survival (OS) was not different among auto SCT, MUD and MSD, reaching 83% (p=0.88). The 2-year non-relapse mortality (NRM) was 2.5% in auto-SCT and 7.5% in allo-SCT (p=0.04). The 2-year cumulative incidence of relapse (RI) was higher after auto-SCT (30%) than after MUD (22%) and MSD (12%, p=0.01). In multivariate analysis, MSD versus auto-SCT but not MUD versus auto-SCT was associated with lower RI (p<0.01 and p=0.13, respectively) and better LFS (p=0.01 and p=0.31, respectively). Age correlated with higher NRM (p<0.01). Allo-SCT using MSD appears as a reasonable transplant option for young patients with iNPM1m AML in CR1. Auto-SCT was followed by worse RI and LFS, but similar OS to both allo-SCT modalities. This article is protected by copyright. All rights reserved. PMID- 30456897 TI - Integrated Hydrological Modeling of Climate Change Impacts in a Snow-Influenced Catchment. AB - The potential impact of climate change on water resources has been intensively studied for different regions and climates across the world. In regions where winter processes such as snowfall and melting play a significant role, anticipated changes in temperature might significantly affect hydrological systems. To address this impact, modifications have been made to the fully integrated surface-subsurface flow model HydroGeoSphere (HGS) to allow the simulation of snow accumulation and melting. The modified HGS model was used to assess the potential impact of climate change on surface and subsurface flow in the Saint-Charles River catchment, Quebec (Canada) for the period 2070-2100. The model was first developed and calibrated to reproduce observed streamflow and hydraulic heads for current climate conditions. The calibrated model was then used with three different climate scenarios to simulate surface flow and groundwater dynamics of the 2070-2100 period. Winter stream discharges are predicted to increase by about 80%, 120%, and 150% for the three scenarios due to warmer winters, leading to more liquid precipitation and more snowmelt. Conversely, the summer stream discharges are predicted to fall by about 10%, 15%, and 20% due to an increase in evapotranspiration. However, the annual mean stream discharge should remain stable (+/- 0.1 m3 /s). The predicted increase in hydraulic heads in winter may reach 15 m, and the maximum decrease in summer may reach 3 m. Simulations show that winter processes play a key role in the seasonal modifications anticipated for surface and subsurface flow dynamics. PMID- 30456898 TI - Intracranial artery stenosis magnetic resonance imaging aetiology and progression study: Rationale and design. AB - BACKGROUND: It has been shown that intracranial artery stenosis (ICAS) plays a key role in Chinese ischemic stroke or transient ischemic attack (TIA) patients. Many vascular diseases can lead to ICAS, such as atherosclerosis, dissection, vasculitis, moyamoya disease, and reversible cerebral vasoconstriction syndrome (RCVS). In addition, progression of intracranial atherosclerotic disease (ICAD) will increase the risk of ischemic cerebrovascular events. The ICASMAP study primarily aims to determine the etiology and disease distribution of ICAS using noninvasive magnetic resonance (MR) imaging and evaluate the rate for progression of ICAD in symptomatic population. METHODS: The ICASMAP study is a prospective, observational, and multicenter study by recruiting 300 subjects (18-80 years old) with recent stroke or TIA (within 2 weeks after onset of symptoms) in China. All the subjects will undergo MR imaging examination including brain and intracranial artery MR imaging at baseline. In addition, the clinical risk factors will be collected and blood biomarkers will be tested. A subgroup of more than 200 subjects who were diagnosed with ICAD according to baseline MR imaging will be followed up for 2 years. During the follow-up study, MR imaging examination will be performed at 12 and 24 months. The primary end point is presence of progression of intracranial artery atherosclerotic plaques. CONCLUSIONS: The ICASMAP study investigates the etiology of ICAS and progression of ICAD in Chinese stroke patients and may help to improve the precise diagnosis and intervention of ICAS and stroke prevention. PMID- 30456900 TI - Bacillus subtilis exopolysaccharide prevents allergic eosinophilia. PMID- 30456899 TI - IqYmune(r) is an effective maintenance treatment for multifocal motor neuropathy: a randomised, double-blind, multicenter cross-over non-inferiority study versus Kiovig(r) - The LIME Study. AB - Intravenous immunoglobulin (IVIg) is the gold-standard for maintenance treatment of multifocal motor neuropathy (MMN). This phase III, randomised, double-blind, multicentre, active-control, crossover study, aimed to evaluate the non inferiority of IqYmune(r) relative to Kiovig(r), primarily based on efficacy criteria. Twenty-two adult MMN patients, treated with any brand of IVIg (except Kiovig(r) or IqYmune(r)) at a stable maintenance dose within the range of 1 to 2 g/kg every 4 to 8 weeks, were randomised to receive either Kiovig followed by IqYmune, or IqYmune followed by Kiovig. Each product was administered for 24 weeks. The primary endpoint was the difference between IqYmune(r) and Kiovig(r) in mean assessments of modified Medical Research Council (MMRC) 10 sum score (strength of five upper-limb and five lower-limb muscle groups, on both sides, giving a score from 0 to 100) during the evaluation period (non-inferiority margin of Delta = 2). A linear mixed model analysis demonstrated the non inferiority of IqYmune relative to Kiovig, independently of the covariates (value at baseline, treatment period and treatment sequence). The estimated 'IqYmune - Kiovig' difference was -0.01, with a 95% CI -0.51 to 0.48. The number of adverse reactions (ARs) and the percentage of patients affected were similar for the two products: 39 ARs in 10 patients with IqYmune(r) versus 32 ARs in 11 patients with Kiovig(r). No thromboembolic events nor hemolysis nor renal impairment were observed. In this first clinical trial comparing two IVIg brands for maintenance treatment of MMN, efficacy and tolerability of both brands were similar. PMID- 30456901 TI - Chronic dialysis in patients with end-stage renal disease: Relevance to kidney xenotransplantation. AB - Renal allotransplantation clearly offers better survival and quality of life for end-stage renal disease (ESRD) patients than chronic dialysis. The median waiting time for a deceased donor kidney in a suitable ESRD patient is 3.9 years. The initial candidates for pig kidney xenotransplantation will be those with ESRD unlikely to receive an allograft within a reasonable period of time. It is thus reasonable to ascertain whether clinical trials of xenotransplantation might likewise offer superior outcomes. Chronic dialysis in patients with ESRD is associated with poor quality of life, significant morbidity, and relatively high mortality, with only 56% surviving 3 years and 42% at 5 years. However, a significant number of these patients, because of comorbidities, frailty, etc, would not be considered for renal allotransplantation and likely not for xenotransplantation. As genetically engineered pig kidneys have satisfactorily supported life in immunosuppressed nonhuman primates for many months or even more than a year, consideration in carefully selected patients could be given to pig kidney xenotransplantation. We suggest that, in order to give a patient the best possible outcome, the pig kidney could be transplanted pre-emptively (before dialysis is initiated). If it fails at any stage, the patient would then begin chronic dialysis and continue to await an allograft. The present (limited) evidence is that failure of a pig graft would not be detrimental to a subsequent allograft. PMID- 30456902 TI - Freezing of dendritic cells with trehalose as an additive in the conventional freezing medium results in improved recovery after cryopreservation. AB - BACKGROUND: Dendritic cell (DC) vaccination involves administration of multiple doses. Cryopreservation of tumor antigen-pulsed DCs can provide a ready to use vaccine source and eliminate the need of frequent withdrawal of the patient's blood for vaccine preparation. The aim of this study was to assess the effect of addition of trehalose in the freezing medium on the recovery of DCs after cryopreservation. STUDY DESIGN AND METHODS: DCs were generated from mononuclear cells from apheresis samples of healthy donors. For long-term storage of 6 months, cells were frozen with a rate-controlled programmable freezer and stored in liquid nitrogen. For short-term storage of 1 month, cells were frozen and stored at -80 degrees C. DCs frozen with Iscove's Modified Dulbecco's Medium + 10% dimethyl sulfoxide + 20% fetal bovine serum served as the control group, while the test group was additionally supplemented with 50 MUg/mL of trehalose. After revival of control and test DCs, they were assessed for viability, morphology, phenotype, and functions. RESULTS: The addition of trehalose to the conventional freezing medium helped to preserve the viability and functionality of DCs better than dimethyl sulfoxide alone in both long- and short-term cryopreservation. Trehalose also protected the mitochondrial membrane potential and cytoskeleton integrity of DCs, which are necessary for their functionality. Mediators of the intrinsic apoptotic pathway like Caspase-9 and Bim-1 were found to be low in the test. CONCLUSION: Supplementation of conventional freezing medium with trehalose results in better quality of DCs revived after cryopreservation. This finding could help improve DC vaccine preparation for cancer immunotherapy. PMID- 30456903 TI - Cardio-ankle vascular index and cardiovascular disease: Systematic review and meta-analysis of prospective and cross-sectional studies. AB - The cardio-ankle vascular index (CAVI) is a new measure of arterial stiffness that reflects the stiffness from the ascending aorta to the ankle arteries, and demonstrates little dependence on blood pressure during the evaluation. However, a comprehensive assessment of the association of CAVI with cardiovascular disease (CVD) has not been reported. We performed a systematic review to assess the association between CAVI and CVD. We searched for both prospective and cross sectional studies using MEDLINE, Embase, and Cochrane from inception until April 11, 2017. We pooled the results using random-effects models. Among 1519 records, we identified nine prospective studies (n = 5214) and 17 cross-sectional eligible studies (n = 7309), with most enrolling high CVD risk populations in Asia. All nine prospective studies investigated composite CVD events as an outcome (498 cases including coronary events and stroke) but modeled CAVI inconsistently. The pooled adjusted hazard ratio for CVD events per 1 standard deviation increment of CAVI in four studies was 1.20 (95% CI: 1.05-1.36, P = 0.006). Of the 17 cross sectional studies, 13 studies compared CAVI values between patients with and without CVD and all reported significantly higher values in those with CVD (pooled mean difference in CAVI values 1.28 [0.86-1.70], P < 0.001). This systematic review suggests a modest association between CAVI and incident CVD risk, and highlights the need for studies assessing CAVI as a predictor of CVD in the general population and non-Asian countries. PMID- 30456905 TI - The Portuguese version of the Personality Inventory for the DSM-5 in a community and a clinical sample. AB - The Personality Inventory for DSM-5 (PID-5) measures the maladaptive traits of the model for personality and its disorders, as proposed in section III of the DSM-5. The current study aimed to examine whether the Portuguese PID-5 distinguished non-clinical participants (N = 1223, Mage = 36.73, standard deviation = 15.72) from clinical participants (N = 202, Mage = 43.82, standard deviation = 11.33) with respect to dysfunctional personality traits and to explore the PID-5 factor structure in both samples. The PID-5 scale medians were higher in the clinical sample than in the community sample. All analyses were statistically significant (p <= 0.001) with medium size effects. In the community sample, a five-factor structure emerged, and the factors resembled the PID-5 domains. However, in the clinical sample, a four-factor structure was retained, in which the Psychoticism domain did not clearly emerge. The composition of the clinical sample along with its small size may account for these unexpected results. Overall, the results provide evidence of the PID-5's ability to distinguish between psychiatric and community individuals and of the model's structural similarity in community samples, across studies and nationalities. More research is required to understand the Portuguese PID-5 structure in clinical samples. (c) 2018 John Wiley & Sons, Ltd. PMID- 30456904 TI - Urinary glucose excretion after dapagliflozin treatment: an exposure-response modeling comparison between Japanese and non-Japanese patients diagnosed with Type 1 Diabetes Mellitus. AB - AIMS: Assess dapagliflozin exposure-response relationship in Japanese and non Japanese patients with Type 1 diabetes mellitus (T1DM) and investigate if a dose adjustment is required in Japanese patients. MATERIALS AND METHODS: Data from two clinical studies were used to develop a non-linear mixed effects model describing the relationship between dapagliflozin exposure (area under the concentration curve) and response (24h urinary glucose excretion [UGE]) in Japanese and non Japanese patients with T1DM. The effects of patient-level characteristics (covariates; identified using a stepwise procedure) on response was also assessed. Simulations were performed using median-normalized covariate values. RESULTS: Data from 84 patients were included. Average self-monitored blood glucose (SMBG) at Day 7, change from baseline in total insulin dose at Day 7, and baseline estimated glomerular filtration rate (eGFR) all had a significant effect on 24h UGE, with SMBG being the most influential. Dapagliflozin systemic exposure for matching doses and baseline eGFR was similar between Japanese and non Japanese patients; however, higher SMBG and a greater reduction in total insulin dose was observed in the Japanese population. When the significant covariates were included, the model fit the data well for both populations, and accurately predicted exposure-response in the Japanese and non-Japanese populations, in agreement with the observed data. CONCLUSIONS: There was no difference in dapagliflozin exposure-response in Japanese and non-Japanese patients with T1DM once differences in renal function, glycemic control and insulin dose reductions between studies were considered. Therefore, no dose adjustment is recommended in Japanese patients with T1DM. This article is protected by copyright. All rights reserved. PMID- 30456906 TI - Pharmacokinetics of TAK-875 and its toxic metabolite TAK-875- acylglucuronide in rat plasma by liquid chromatography tandem mass spectrometry. AB - TAK-875 is a selective partial agonist of hGPR40 receptor, which was unexpectedly terminated at phase III clinical trials due to its severe hepatotoxicity. The purpose of this study was to investigate the pharmacokinetics of TAK-875 and its toxic metabolite TAK-875-acylglucuronide in rat plasma by liquid chromatography tandem mass spectrometry (LC-MS/MS). Plasma samples were extracted with ethyl acetate and chromatographic separations were achieved on a C18 column with water and acetonitrile containing 0.05% ammonium hydroxide as mobile phase. The sample was detected in selected reaction monitoring (SRM) mode with precursor-to-product ion transitions being m/z 523.2->148.1, m/z 699.3->113.1 and m/z 425.2->113.1 for TAK-875, TAK-875-acylglucuronide and IS, respectively. The assay showed good linearity over the tested concentration ranges (r > 0.9993), with the LLOQ being 0.5 ng/mL for both analytes. The extraction recovery was more than 78.45% and no obvious matrix effect was detected. The highly sensitive LC-MS/MS method has been further applied for the pharmacokinetic study of TAK-875 and its toxic metabolite TAK-875-acylglucuronide in rat plasma. Pharmacokinetics results revealed that oral bioavailability of TAK-875 was 86.85%. The in vivo exposures of TAK-875 acylglucuronide in terms of AUC0-t were 17.54% and 22.29% of that of TAK-875 after intravenous and oral administration, respectively. PMID- 30456907 TI - Development and evaluation of a transfusion medicine genome wide genotyping array. AB - BACKGROUND: Many aspects of transfusion medicine are affected by genetics. Current single-nucleotide polymorphism (SNP) arrays are limited in the number of targets that can be interrogated and cannot detect all variation of interest. We designed a transfusion medicine array (TM-Array) for study of both common and rare transfusion-relevant variations in genetically diverse donor and recipient populations. STUDY DESIGN AND METHODS: The array was designed by conducting extensive bioinformatics mining and consulting experts to identify genes and genetic variation related to a wide range of transfusion medicine clinical relevant and research-related topics. Copy number polymorphisms were added in the alpha globin, beta globin, and Rh gene clusters. RESULTS: The final array contains approximately 879,000 SNP and copy number polymorphism markers. Over 99% of SNPs were called reliably. Technical replication showed the array to be robust and reproducible, with an error rate less than 0.03%. The array also had a very low Mendelian error rate (average parent-child trio accuracy of 0.9997). Blood group results were in concordance with serology testing results, and the array accurately identifies rare variants (minor allele frequency of 0.5%). The array achieved high genome-wide imputation coverage for African-American (97.5%), Hispanic (96.1%), East Asian (94.6%), and white (96.1%) genomes at a minor allele frequency of 5%. CONCLUSIONS: A custom array for transfusion medicine research has been designed and evaluated. It gives wide coverage and accurate identification of rare SNPs in diverse populations. The TM-Array will be useful for future genetic studies in the diverse fields of transfusion medicine research. PMID- 30456908 TI - Tongguan capsule-derived herb reduces susceptibility to atrial fibrillation by inhibiting left atrial fibrosis via modulating cardiac fibroblasts. AB - Tongguan capsule is a compound Chinese medicine used to treat ischaemic heart diseases. This study aimed to investigate whether Tongguan capsule-derived herb (TGD) has a preventive effect on atrial fibrillation (AF) in post-myocardial infarction (MI) rats and to determine the underlying mechanisms. MI was induced by ligation of the left anterior descending coronary artery. TGD was administered to the post-MI rats over a 4-week period. The TGD-treated rats had lower rates of AF inducibility and shorter AF durations than the MI rats. TGD improved the left atrial (LA) conduction velocity and homogeneity. It reduced the fibrosis-positive areas and the protein levels of collagen types I and III in the left atrium. In vitro, it inhibited the expression of collagen types I and III by inhibiting the proliferation, migration, differentiation and cytokine secretion of cardiac fibroblasts (CFs). In conclusion, the current study demonstrated that TGD reduces susceptibility to AF and improves LA conduction function in rats with post-MI by inhibiting left atrial fibrosis and modulating CFs. Targeting the CF population may be a novel antiarrhythmic therapeutic approach. PMID- 30456909 TI - Medially-Stabilized Total Knee Arthroplasty Does Not Alter Knee Laxity and Balance in Cadaveric Knees. AB - Instability after total knee arthroplasty (TKA) can lead to suboptimal outcomes and revision surgery. Medially-stabilized implants aim to more closely replicate normal knee motion than other implants following TKA, but no study has investigated knee laxity (motion under applied loads) and balance (i.e., difference in varus/valgus motion under load) following medially-stabilized TKA. The primary purposes of this study were to investigate how medially-stabilized implants change knee laxity in non-arthritic, cadaveric knees and if it produces a balanced knee after TKA. Force-displacement data were collected on 18 non arthritic cadaveric knees before and after arthroplasty using medially-stabilized implants. Varus-valgus and anterior-posterior laxity and varus-valgus balance were compared between native and medially-stabilized knees at 0 degrees , 20 degrees , 60 degrees , and 90 degrees under three different loading conditions. Varus-valgus and anterior-posterior laxities were not different between native and medially-stabilized knees under most testing conditions (p > 0.068), but differences of approximately 2 degrees less varus-valgus laxity at 20 degrees of flexion and 4mm more anterior-posterior laxity at 90 degrees were present from native laxities (p < 0.017) Medially-stabilized implant balance had <=1.5 degrees varus bias at all flexion angles. Future studies should confirm if the consistent laxity afforded by the medially-stabilized implant is associated with better and more predictable post-operative outcomes. This article is protected by copyright. All rights reserved. PMID- 30456910 TI - A New Derivatization Method for the Determination of Valproic Acid in Serum Using Tetramethylammonium Hydroxide as a Catalyst. AB - Valproic acid (VPA) pharmacokinetics is highly variable, and monitoring of its blood levels is necessary to determine its appropriate dosage. This study aimed to establish and validate a novel derivatization method for the determination of VPA. The method was based on the catalytic effect of tetramethylammonium hydroxide (TMAH) using 2, 4'-dibromoacetophenone (pBPB) as a derivatization reagent. After derivatization, samples were injected into the HPLC system for analysis. The method showed a good linearity in the range of 1.0-200.7 MUg.mL-1 , and the limit of quantification (LOQ) was 1 MUg.mL-1 . All values of the accuracy and relative standard deviations (RSD) were acceptable for the analyses of biological samples. The recoveries were in the range from 91.6% to 97.4% for VPA with RSD less than 3.9%. A novel and high conversion-rate derivatization method has been developed and validated for the determination of VPA in human serum. It can be applied to the analysis of VPA in clinic serum samples. PMID- 30456911 TI - Annexin A3 gene silencing promotes myocardial cell repair through activation of the PI3K/Akt signaling pathway in rats with acute myocardial infarction. AB - Acute myocardial infarction (AMI), as a severe consequence of coronary atherosclerotic heart disease, always contributes to the loss of myocardial cells. Mounting evidence shows that annexin protects the myocardium from ischemic injury. In this study, we examine the inhibition of annexin A3 (ANXA3) on AMI through the phosphatidylinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. We selected rats to build an AMI model which was then assigned into different groups. The hemodynamic parameters after transfection were detected by using enzyme-linked immunosorbent assay. The effect of silencing of ANXA3 on inflammatory reaction and the PI3K/Akt signaling pathway was assessed. Rats transfected with ANXA3-short hairpin RNA had alleviated hemodynamics, inflammatory reaction, decreased infarct size, alpha-smooth muscle actin, Collagen I, and Collagen III as well as an increased vascular endothelial growth factor. Silencing ANAX3 would promote repair and healing of myocardial tissue by activation of the PI3K/Akt signaling pathway. Collectively, our study provides evidence that the downregulation of ANXA3 promotes the repair and healing of myocardial tissues by activating the PI3K/Akt signaling pathway. PMID- 30456912 TI - Zooming in on Cryopreservation of hiPSCs and Neural Derivatives: A Dual-Center Study Using Adherent Vitrification. AB - Human induced pluripotent stem cells (hiPSCs) are an important tool for research and regenerative medicine, but their efficient cryopreservation remains a major challenge. The current gold standard is slow-rate freezing of dissociated colonies in suspension, but low recovery rates limit immediate post-thawing applicability. We tested whether ultrafast cooling by adherent vitrification improves post-thawing survival in a selection of hiPSCs and small molecule neural precursor cells (smNPCs) from Parkinson's disease and controls. In a dual-center study, we compared the results by immunocytochemistry (ICC), fluorescence activated cell sorting analysis, and RNA-sequencing (RNA-seq). Adherent vitrification was achieved in the so-called TWIST substrate, a device combining cultivation, vitrification, storage, and post-thawing cultivation. Adherent vitrification resulted in preserved confluency and significantly higher cell numbers, and viability at day 1 after thawing, while results were not significantly different at day 4 after thawing. RNA-seq and ICC of hiPSCs revealed no change in gene expression and pluripotency markers, indicating that physical damage of slow-rate freezing disrupts cellular membranes. Scanning electron microscopy showed preserved colony integrity by adherent vitrification. Experiments using smNPCs demonstrated that adherent vitrification is also applicable to neural derivatives of hiPSCs. Our data suggest that, compared to the state-of-the-art slow-rate freezing in suspension, adherent vitrification is an improved cryopreservation technique for hiPSCs and derivatives. Stem Cells Translational Medicine 2018. PMID- 30456913 TI - Contemporary transradial access practices: Results of the second international survey. AB - OBJECTIVES: To gain insight into current practice of transradial angiography and intervention in the United States and around the world. BACKGROUND: Transradial access (TRA) has grown worldwide. In a prior survey, there was significant practice variation and there was minimal US participation which limited the generalizability to US operators. METHODS: We used an internet-based survey software program to solicit input from practicing interventional cardiologists from the United States and around the world. US operators were compared with outside the United States (OUS) operators and respondent-level comparisons were made with the prior survey to assess for temporal changes in practice. RESULTS: Between August 2016 and January 1, 2017, 125 interventional cardiologists completed the survey representing 91 countries with the United States having 449 (39.9%) respondents. Preprocedure, noninvasive testing for collateral circulation is used more commonly in the United States (54.1%) than around the world (26.6%) but its use has decreased since 2010. In the US, 48.8% of operators never use ultrasound and 92.6% of OUS operators never use it; only 4.4% overall use ultrasound in >50% of cases. Use of bivalirudin has decreased in the US and OUS. Nearly, 30% of operators do not assess for radial artery patency following hemostasis. US respondents used TRA less commonly for primary PCI for STEMI than their global counterparts. CONCLUSIONS: There is wide variation in how TRA procedures are performed including relatively low rates of adherence to practices that are known to improve outcomes. Further education aimed at increasing use of best practices will impact patient outcomes. PMID- 30456914 TI - Evidence for protein kinase involvement in the 5-HT- [Ca2+ ]i - pannexin-1 signalling pathway in type II glial cells of the rat carotid body. AB - NEW FINDINGS: What is the central question of this study? The mammalian carotid body (CB) is a peripheral chemoreceptor organ involved in O2 and CO2 /H+ homeostasis. Recent studies suggest that 5-HT, released from CB receptor cells, can stimulate adjacent glial-like type II cells, leading to a rise in intracellular Ca2+ ([DeltaCa2+ i ]) and activation of ATP-permeable pannexin-1 (Panx-1) channels. The aim of this study was to elucidate the role of protein kinases in the 5-HT-[Ca2+ ]i -Panx-1 signalling pathway. What is the main finding and its importance? Src family kinase (SKF) and PKA, acting downstream from [DeltaCa2+ i ], played central roles in 5-HT-mediated Panx-1 channel activation. This provides new insight into mechanisms regulating CB excitation, especially in pathophysiological conditions. ABSTRACT: Chemoreceptor (type I) cells of the rodent carotid body (CB) synthesize and release several neurotransmitters/neuromodulators including 5-hydroxytryptamine (5-HT), implicated in enhanced CB excitation following exposure to chronic intermittent hypoxia, e.g. sleep apnea. However, recent studies suggest that 5-HT can robustly stimulate adjacent glial-like type II cells via ketanserin-sensitive 5-HT2 receptors, leading to intracellular Ca2+ elevation [DeltaCa2+ i ] and activation of ATP-permeable pannexin-1 (Panx-1) channels. Using dissociated rat CB cultures, we investigated the role of protein kinases in the intracellular signalling pathways in type II cells. In isolated type II cells, 5-HT activated a Panx-1 like inward current (I5-HT ) that was reversibly inhibited by the Src family kinase (SFK) inhibitor PP2 (1 MUM), but not by its inactive analog PP3 (1 MUM). Moreover, I5-HT was reversibly inhibited (> 90%) by H-89 (1 MUM), a PKA blocker, whereas the PKC blocker GF109203X (2 MUM) was largely ineffective. By contrast, the P2Y2R agonist UTP (100 MUM) activated Panx-1-like currents that were reversibly inhibited (~60%) by either H-89 or GF109203X. Using fura-2 spectrofluorimetry, the 5-HT-induced [DeltaCa2+ i ] was unaffected by PP2, H-89, and GF109293X, suggesting the kinases acted downstream of the Ca2+ rise. Because intracellular Ca2+ chelation was previously shown to block receptor-mediated, Panx-1 current activation in type II cells, these data suggest that CB neuromodulators use overlapping, but not necessarily identical, signalling pathways to activate Panx-1 channels and release of ATP, a CB excitatory neurotransmitter. In conclusion, these studies provide new mechanistic insight into 5-HT signalling in the CB that has pathophysiological relevance. This article is protected by copyright. All rights reserved. PMID- 30456915 TI - Identification of symptom clusters and their synergistic effects on quality of life in rheumatoid arthritis patients. AB - AIMS: To examine the presence of symptom clusters and synergistic effects of symptom clusters on quality of life in rheumatoid arthritis patients. BACKGROUND: Rheumatoid arthritis patients frequently experience multiple concurrent symptoms of pain, fatigue, and depression. DESIGN: A nonexperimental, cross-sectional correlation design. METHODS: The study participants were 179 rheumatoid arthritis patients. Data were collected between August and December 2016. A hypothetical model was developed based on the Theory of Unpleasant Symptoms Model: physiological antecedents included disease activity and obesity; symptoms of pain, fatigue, and depression were hypothesized as being clustered, and quality of life was taken as the outcome variable. RESULTS: Disease activity had significant direct effects on pain, fatigue, and depression and indirect effects on fatigue and depression, whereas obesity had a significant direct effect on fatigue alone. Three symptom clusters, namely, pain fatigue, fatigue depression, and pain-fatigue depression were identified and found to have significant synergistic effects on quality of life. CONCLUSIONS: Our findings support the importance of managing clusters of symptoms simultaneously, that is, collective symptom management. Inter-cluster dynamics between symptoms should be considered when nurses develop symptom management strategies or self-management programs to improve the quality of life of rheumatoid arthritis patients. PMID- 30456916 TI - Statin use and survival in patients with gastric cancer in two independent population-based cohorts. AB - PURPOSE: Preclinical studies show statins inhibit pathways involved in gastric cancer progression, with observational studies demonstrating reduced gastric cancer risk in statin users. However, few studies have investigated statin use and survival in gastric cancer. We investigated statin use and survival in two large population-based gastric cancer cohorts. METHODS: Patients diagnosed with gastric cancer from 1998 to 2012 were identified from English and Scottish cancer registries. Statin prescriptions were identified from linkages to the UK Clinical Practice Research Datalink in England and the Prescribing Information System in Scotland, and deaths identified from national mortality records. Time-dependent Cox regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CIs) for cancer-specific mortality by statin use in multivariate analysis. Meta-analysis techniques pooled results across the cohorts. RESULTS: The combined cohorts contained 3833 patients with gastric cancer and 2392 cancer-specific deaths. Statin use after diagnosis was associated with reduced cancer-specific mortality (adjusted HR 0.83; 95% CI, 0.74-0.92). HRs for less than 1 year and over 1 year of statin use were similar (adjusted HR 0.83; 95% CI, 0.73-0.94 and adjusted HR 0.83; 95% CI, 0.64-1.01, respectively). Statin use prior to diagnosis was also associated with reduced cancer-specific mortality (adjusted HR 0.91; 95% CI, 0.84-0.98). CONCLUSIONS: In two independent UK cohorts, there was some evidence that statin use was associated with reduced cancer-specific mortality. However, these associations were weak in magnitude and did not follow a clear dose response, and we cannot rule out confounding by stage. PMID- 30456917 TI - Application of in vivo MR methods in the study of breast cancer metabolism. AB - In the last two decades, various in vivo MR methodologies have been evaluated for their potential in the study of cancer metabolism. During malignant transformation, metabolic alterations occur, leading to morphological and functional changes. Among various MR methods, in vivo MRS has been extensively used in breast cancer to study the metabolism of cells, tissues or whole organs. It provides biochemical information at the metabolite level. Altered choline, phospholipid and energy metabolism has been documented using proton (1 H), phosphorus (31 P) and carbon (13 C) isotopes. Increased levels of choline containing compounds, phosphomonoesters and phosphodiesters in breast cancer, which are indicative of altered choline and phospholipid metabolism, have been reported using in vivo, in vitro and ex vivo NMR studies. These changes are reversed on successful therapy, which depends on the treatment regimen given. Monitoring the various tumor intermediary metabolic pathways using nuclear spin hyperpolarization of 13 C-labeled substrates by dynamic nuclear polarization has also been recently reported. Furthermore, the utility of various methods such as diffusion, dynamic contrast and perfusion MRI have also been evaluated to study breast tumor metabolism. Parameters such as tumor volume, apparent diffusion coefficient, volume transfer coefficient and extracellular volume ratio are estimated. These parameters provide information on the changes in tumor microstructure, microenvironment, abnormal vasculature, permeability and grade of the tumor. Such changes seen during cancer progression are due to alterations in the tumor metabolism, leading to changes in cell architecture. Due to architectural changes, the tissue mechanical properties are altered; this can be studied using magnetic resonance elastography, which measures the elastic properties of tissues. Moreover, these structural MRI methods can be used to investigate the effect of therapy-induced changes in tumor characteristics. This review discusses the potential of various in vivo MR methodologies in the study of breast cancer metabolism. PMID- 30456918 TI - Of mice and men: is there a future for metformin in the treatment of hepatic steatosis? AB - Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver diseases, of which the first stage is steatosis. It is one of the most common liver diseases in developed countries and there is a clear association between type 2 diabetes (T2DM) and NAFLD. It is estimated that 70% of people with T2DM have NAFLD and yet there is currently no licenced pharmacological agent to treat NAFLD. Whilst lifestyle modification may ameliorate liver fat, it is often difficult to achieve or sustain, thus there is great interest in pharmacological treatments for NAFLD. Metformin is the first line medication in the management of T2DM and evidence from animal and human studies has suggested that it may be useful in reducing liver fat via inhibition of lipogenesis and increased fatty acid oxidation. Findings from the majority of studies undertaken in rodent models clearly suggest that metformin may be a powerful therapeutic agent to specifically reduce liver fat accumulation; data from human studies is less convincing. In this review we discuss the evidence for the specific effects of metformin treatment on liver fat accumulation in animal and human studies and the underlying proposed mechanisms to try and understand and reconcile the difference in findings from rodent and human work. This article is protected by copyright. All rights reserved. PMID- 30456919 TI - Leukoderma induced by Rhododendrol is different from leukoderma of vitiligo in pathogenesis: a novel comparative morphological study. AB - BACKGROUND: Rhododendrol (Rhododenol(r)), an inhibitor of tyrosinase activity, is used as a skin-whitening component. Many cases of leukoderma after the application have been reported, termed Rhododenol-induced leukoderma (RIL). The aim of this study was to clarify the pathogenesis of RIL morphologically through comparison with vitiligo. METHODS: We examined 14 cases of RIL and 15 cases of vitiligo using routine histopathology and immunohistochemistry. Thirteen cases of RIL, 6 cases of vitiligo and specimens of the RIL mouse model were evaluated by electron microscopy. RESULTS: There were common findings in RIL and vitiligo at the light-microscopic level: a) vacuolar changes in the dermoepidermal junction, b) melanophages in the papillary dermis, c) perifollicular lymphocyte infiltration, d) loss or decrease of basal melanin pigment and e) decrease of melanocytes in the lesions. The ultrastructural observations demonstrated specific findings of RIL: 1) remaining melanocytes in depigmented lesions, 2) inhomogeneous melanization in melanocytes and 3) degenerated melanosomes in melanocytes. Some of the findings were observed in a RIL mouse model. Furthermore, it is notable that cell organelles of melanocytes were intact in our RIL cases. CONCLUSIONS: Morphological changes of RIL targeting melanosomes in melanocytes without degeneration of organelles reflect the reversible clinical course of most cases. This article is protected by copyright. All rights reserved. PMID- 30456920 TI - Synthesis of Porous Covalent Quinazoline Networks (CQNs) and Their Gas Sorption Properties. AB - The development of different classes of porous polymers by linking organic molecules using new chemistries still remains a great challenge. Here we introduce for the first time the synthesis of covalent quinazoline networks (CQNs) using an ionothermal synthesis protocol. Zinc chloride (ZnCl2) was used as the solvent and catalyst for the condensation of aromatic ortho-aminonitriles to produce tricycloquinazoline linkages. The resulting CQNs show a high porosity with a surface area up to 1870 m2 g-1. Varying the temperature and the amount of catalyst enables us to control the surface area as well as the pore size distribution of the CQNs. Furthermore, their high nitrogen content and significant microporosity make them a promising CO2 adsorbent with a CO2 uptake capacity of 7.16 mmol g-1 (31.5 wt %) at 273 K and 1 bar. Because of their exceptional CO2 sorption properties, they are promising candidates as an adsorbent for the selective capture of CO2 from flue gas. PMID- 30456921 TI - Sequential processing in the classic oddball task: ERP components, probability, and behavior. AB - This study compared the ERP components and behavior associated with the auditory equiprobable and classic oddball tasks, to relate the cognitive processing stages in those paradigms and continue the development of the sequential processing schema. Target and nontarget ERP data were acquired from 66 healthy young adults (Mage = 20.1, SD = 2.4 years, 14 male) who completed both equiprobable (target p = 0.5) and oddball tasks (target p = 0.3). Separate temporal PCAs were used to decompose the ERP data in each task and condition, and the similarity of the components identified in each condition was examined between tasks. Probability effects on component amplitudes and behavior were also analyzed to identify task differences in cognitive demands. A highly similar series of components was identified in each task, closely matching the schema: targets elicited N1-3, N1 1, PN, N2c, P3b, SW1, SW2; whereas nontargets elicited N1-3, N1-1, PN, N2b, P3a, SW1, SW2. N1-1 and PN amplitudes increased as stimulus probability decreased, irrespective of the condition. N2b, P3b, SW1, and SW2 amplitudes also varied between tasks, illustrating task-specific demands on those processing stages. These findings complemented the behavioral outcomes, which demonstrated greater accuracy and control in the classic oddball task. Overall, this study demonstrated comparable processing in the auditory equiprobable and classic oddball tasks, extending the generalizability of the schema and enabling further integration of the ERP theory associated with these tasks. This study also clarifies stimulus probability effects on the schema, providing important insight into the functionality of common ERP components. PMID- 30456922 TI - Noble-Metal-Free Electrocatalysts for Oxygen Evolution. AB - Oxygen evolution reaction (OER) plays a vital role in many energy conversion and storage processes including electrochemical water splitting for the production of hydrogen and carbon dioxide reduction to value-added chemicals. IrO2 and RuO2 , known as the state-of-the-art OER electrocatalysts, are severely limited by the high cost and low earth abundance of these noble metals. Developing noble-metal free OER electrocatalysts with high performance has been in great demand. In this review, recent advances in the design and synthesis of noble-metal-free OER electrocatalysts including Ni, Co, Fe, Mn-based hydroxides/oxyhydroxides, oxides, chalcogenides, nitrides, phosphides, and metal-free compounds in alkaline, neutral as well as acidic electrolytes are summarized. Perspectives are also provided on the fabrication, evaluation of OER electrocatalysts and correlations between the structures of the electrocatalysts and their OER activities. PMID- 30456923 TI - Differences in biocompatibility of microneedles from cyclic olefin polymers with human endothelial and epithelial skin cells. AB - Microneedles are promising devices for transdermal delivery and diagnostic applications, due to their minimally invasive and painless nature of application. However, so far, applications are limited to small scale research projects. Material selection and production for larger projects remain a challenge. In vitro testing using human cell culture could bridge the gap between cost effective screening of suitable materials and concerns for safety and ethics. In this study, materials were tested for effects on viability and morphology of human endothelial cells and keratinocytes. In addition, materials were assessed for their potential to influence cellular differentiation and barrier formation. Elution-based testing of inflammatory markers revealed no negative effects in all applied tests, whereas the assessment of differentiation markers on cells in direct contact with the material showed differences and allowed the selection of candidate materials for future medical device applications. This study illustrates that elution-based biocompatibility testing can paint an incomplete picture. Advanced staining techniques and cell types specific for the application of the medical device improve material selection to reduce and replace animal testing at an early stage in the development process. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 00A: 000-000, 2018. PMID- 30456924 TI - Pd-Catalyzed Enantioselective Ring-Opening/Cross-Coupling and Cyclopropanation of Cyclobutanones. AB - A palladium-catalyzed enantioselective sequential ring-opening/cross-coupling of cyclobutanones is disclosed, providing chiral indanones bearing C3-quaternary stereocenters. The reaction process involves palladium-catalyzed nucleophilic addition of cyclobutanones and aryl halides, enantioselective beta-carbon elimination and intermolecular trapping of a transient sigma-alkylpalladium complex with boronic acids. Alternatively, an intramolecular cyclopropanation is realized via C-H bond functionalization in the absence of external coupling reagents, affording chiral cyclopropane-fused-indanones in good yields and enantioselectivity. PMID- 30456925 TI - Systemic alterations induced by phospholipase A2 , BmooTX-I, isolated from Bothrops moojeni snake venom. AB - Ophidic accidents are among the problems of public health in Brazil. The components from bothropic venom are responsible for many systemic clinical complications resulting from envenomation. The present work aimed to analyse the systemic changes induced in mice after intraperitoneal administration of BmooTX I, a myotoxic acidic phospholipase A2 isolated from Bothrops moojeni venom. Urinalysis was performed and the following plasma biochemical markers were documented: urea, creatinine and uric acid (renal function); glucose and amylase (pancreatic function); alanine aminotransferase, alkaline phosphatase and gamma GT (intra- and extrahepatic function); creatine kinase and enzymatic lactate (muscle function). Our results showed that after the intraperitoneal injection of BmooTX-I the urine of these animals showed glycosuria, proteinuria, haematuria, bacteriuria, bilirubinuria, polyuria and nitrite. The plasma biochemical analysis showed alterations in levels of urea, creatinine and uric acid. Amylase concentration was not altered significantly, but the plasma glucose increased significantly compared to controls. The plasma levels of alanine aminotransferase and alkaline phosphatase decreased and increased, respectively, in these same animals. On the other hand, the plasma gammaGT concentration did not undergo significant modification compared to the control group. The plasma concentration of CK increased, while the enzymatic lactate concentration decreased after the injection of the BmooTX-I. Therefore, in mice BmooTX-I is capable of causing systemic alterations which manifest as renal, muscular, hepatic and pancreatic impairment. PMID- 30456926 TI - Natural killer cells induce neutrophil extracellular trap formation in venous thrombosis. AB - BACKGROUND: Neutrophils contribute to venous thrombosis through the release of neutrophil extracellular traps (NETs) but the mechanism triggering their formation remains unclear. In vitro data show that interferon gamma (IFNgamma) induces the formation of NETs. OBJECTIVES: We hypothesize that IFNgamma and the transcription factor Tbet promote venous thrombosis through neutrophil activation. METHODS: Venous thrombosis was induced by flow restriction in the inferior vena cava in IFNgamma deficient (-/-), Tbet-/- or wild type (WT) mice. After 48h, thrombus size was measured using high-frequency ultrasound. NET formation was determined by immunofluorescence. RESULTS AND CONCLUSIONS: Thrombus formation was reduced in Tbet-/- and IFNgamma-/- mice, suggesting that Tbet/IFNgamma expressing cells are required for venous thrombosis. The number of NETs formed during thrombosis was significantly lower in Tbet-/- and IFNgamma-/- mice. NET formation was also decreased in WT mice treated with an IFNgamma blocking antibody. Injection of recombinant IFNgamma in IFNgamma-/- mice rescued the phenotype. Natural killer (NK) cells were specifically depleted prior to venous thrombosis induction. NK cell depletion results in decreased NET formation and smaller thrombi suggesting that NK cells are required for thrombus development. In depleted mice, adoptive transfer of WT NK cells induced similar thrombosis burden as in WT mice. In contrast, adoptive transfer of IFNgamma -/- NK cells results in thrombus similar in size to depleted mice. In vitro, we show that WT neutrophils release fewer NETs when co-cultured with IFNgamma-/- NK cells. This study demonstrates that NK cell-dependent IFNgamma production is crucial for thrombus development by promoting the formation of NETs by neutrophils. This article is protected by copyright. All rights reserved. PMID- 30456927 TI - Immunomodulatory effect of gamma-irradiated Astragalus polysaccharides on immunosuppressed broilers. AB - In this study, we irradiated Astragalus polysaccharides (APS) using 25 kGy 60 Co gamma ray to obtain gamma-irradiated Astragalus polysaccharides (IAPS) and then investigated the effects of IAPS on growth performance and immune function of cyclophosphamide (CPM)-treated broilers. The physicochemical properties of APS and IAPS (molecular weight, water solubility, viscosity, morphological and structural properties) were evaluated. Then, 384 one-day-old Arbor Acres broiler chicks with similar initial weight were randomly assigned into 6 groups: the non treated group (control), and CPM-treated groups were fed either a basal diet or the diets containing 900 mg/kg APS, or 900, 600, 300 mg/kg IAPS, respectively. On days 16, 18, and 20, all broilers except for the control group were intramuscularly injected with 0.5 ml CPM (40 mg/kg.BW). Broilers in the control group were intramuscularly injected with 0.5 ml sterilized saline (0.75%, wt/vol). This trial lasted for 21 days. The physicochemical treatment showed that gamma irradiation could decrease the molecular weight and viscosity, and increase the water solubility of APS (p < 0.05), whereas the structural properties of APS was not affected. In the animal trial, 900 mg/kg APS or 900, 600 mg/kg IAPS relieved the decreased growth performance, thymus index, T lymphocytes proliferation, serum IgG concentration, NOS activity and the increased blood heterophil:lymphocyte ratio in CPM-treated broilers (p < 0.05). CPM-induced decreases in B lymphocytes proliferation and serum IgM concentration were only increased by IAPS at 900 mg/kg (p < 0.05). Overall, both APS and IAPS alleviated CPM-induced immunosuppression. Especially, IAPS possessed better immunomodulatory effect than APS, indicating that gamma irradiation could be used as an effective method to enhance the immunomodulatory activity of APS. PMID- 30456928 TI - Chromatin imaging and new technologies for imaging the nucleome. AB - Synergistic developments in advanced fluorescent imaging and labeling techniques enable direct visualization of the chromatin structure and dynamics at the nanoscale level and in live cells. Super-resolution imaging encompasses a class of constantly evolving techniques that break the diffraction limit of fluorescence microscopy. Structured illumination microscopy provides a twofold resolution improvement and can readily achieve live multicolor imaging using conventional fluorophores. Single-molecule localization microscopy increases the spatial resolution by approximately 10-fold at the expense of slower acquisition speed. Stimulated emission-depletion microscopy generates a roughly fivefold resolution improvement with an imaging speed proportional to the scanning area. In parallel, advanced labeling strategies have been developed to "light up" global and sequence-specific DNA regions. DNA binding dyes have been exploited to achieve high labeling densities in single-molecule localization microscopy and enhance contrast in correlated light and electron microscopy. New-generation Oligopaint utilizes bioinformatics analyses to optimize the design of fluorescence in situ hybridization probes. Through sequential and combinatorial labeling, direct characterization of the DNA domain volume and length as well as the spatial organization of distinct topologically associated domains has been reported. In live cells, locus-specific labeling has been achieved by either inserting artificial loci next to the gene of interest, such as the repressor operator array systems, or utilizing genome editing tools, including zinc finer proteins, transcription activator-like effectors, and the clustered regularly interspaced short palindromic repeats systems. Combined with single-molecule tracking, these labeling techniques enable direct visualization of intra- and inter-chromatin interactions. This article is categorized under: Laboratory Methods and Technologies > Imaging. PMID- 30456929 TI - Corrigendum. PMID- 30456930 TI - Single Incision Robotic Surgery plus One for left-sided Colon Cancer-a video vignette. AB - Single-incision laparoscopic surgery (SILS) for left-sided colon cancer is a challenging procedure and remains the ultimate aim of colorectal surgeons worldwide. This is due to the difficulties of instrument manipulation and applying the endo-staplers to the pelvic cavity. Despite the introduction of the novel Da Vinci Single-Site(r) platform, designed to overcome the shortcomings of SILS, it has not been routinely adopted in left-sided colon cancer surgery due to the limited range of motion, lack of dexterity, and most importantly the lack of second traction that is required for colorectal surgery [1-3]. This article is protected by copyright. All rights reserved. PMID- 30456931 TI - An optimal kernel-based U-statistic method for quantitative gene-set association analysis. AB - Single-variant-based genome-wide association studies have successfully detected many genetic variants that are associated with a number of complex traits. However, their power is limited due to weak marginal signals and ignoring potential complex interactions among genetic variants. The set-based strategy was proposed to provide a remedy where multiple genetic variants in a given set (e.g., gene or pathway) are jointly evaluated, so that the systematic effect of the set is considered. Among many, the kernel-based testing (KBT) framework is one of the most popular and powerful methods in set-based association studies. Given a set of candidate kernels, the method has been proposed to choose the one with the smallest p-value. Such a method, however, can yield inflated Type 1 error, especially when the number of variants in a set is large. Alternatively one can get p values by permutations which, however, could be very time consuming. In this study, we proposed an efficient testing procedure that cannot only control Type 1 error rate but also have power close to the one obtained under the optimal kernel in the candidate kernel set, for quantitative trait association studies. Our method, a maximum kernel-based U-statistic method, is built upon the KBT framework and is based on asymptotic results under a high dimensional setting. Hence it can efficiently deal with the case where the number of variants in a set is much larger than the sample size. Both simulation and real data analysis demonstrate the advantages of the method compared with its counterparts. PMID- 30456932 TI - Assessing ecological and physiological costs of melanism in North American Papilio glaucus females: Two decades of dark morph frequency declines. AB - Polymorphisms for melanic form of insects may provide various selective advantages. However, melanic alleles may have significant/subtle pleiotrophic "costs". Several potential pleiotrophic effects of the W (=Y) - linked melanism gene in Papilio glaucus L.(Lepidoptera) showed no costs for melanic versus yellow in adult size, oviposition preferences, fecundity, egg viability, larval survival/growth rates, cold stress tolerance, or post-diapause emergence times. Sexual selection (males choosing yellow rather than mimetic dark females had been suggested to provide a balanced polymorphism in P. glaucus, but spermatophore counts in wild females and direct field tethering studies of size-matched pairs of virgin females (dark and yellow), show that male preferences are random or frequency-dependent from Florida to Michigan, providing no yellow counter advantages. Recent frequency declines of dark (melanic/mimetic) females in P. glaucus populations are shown in several major populations from Florida (27.3 degrees N latitude) to Ohio (38.5 degrees N). Summer temperatures have increased significantly at all these locations during this time (1999-2018), but whether dark morphs may be more vulnerable (in any stage) to such climate warming remains to be determined. Additional potential reasons for the frequency declines in mimetic females are discussed: 1) genetic introgression of Z-linked melanism suppressor genes from P. canadensis (R & J) and the hybrid species, P. appalachiensis (Pavulaan & Wright), 2) differential developmental incompatibilities, or Haldane effects, known to occur in hybrids, 3) selection against intermediately melanic ("dusty") females (with the W-linked melanic gene, b+) which higher temperatures can cause. This article is protected by copyright. All rights reserved. PMID- 30456933 TI - Novel prognostic markers within the CD44-stromal ligand network in pancreatic cancer. AB - The dense stroma in pancreatic cancer tumours is rich in secreted extracellular matrix proteins and proteoglycans. Secreted hyaluronan, osteopontin and type IV collagen sustain oncogenic signalling by interactions with CD44s and its variant isoform CD44v6 on cancer cell membranes. Although well established in animal and in vitro models, this oncogenic CD44-stromal ligand network is less explored in human cancer. Here, we use a pancreatic cancer tissue microarray from 69 primary tumours and 37 metastatic lymph nodes and demonstrate that high tumour cell expression of CD44s and, surprisingly, low stromal deposition of osteopontin correlate with poor survival independent of established prognostic factors for pancreatic cancer. High stromal expression of hyaluronan was a universal trait of both primary tumours and metastatic lymph nodes. However, hyaluronan species of different molecular mass are known to function differently in pancreatic cancer biology and immunohistochemistry cannot distinguish between them. By gas-phase electrophoretic molecular mobility analysis we uncover a shift towards high molecular mass hyaluronan in pancreatic cancer tissue compared to normal pancreas. And at a transcriptional level, we find that hyaluronan synthesising HAS2 correlates positively with CD44. The resulting prediction that high molecular mass hyaluronan would then correlate with poor survival in pancreatic cancer was confirmed in serum samples, where we demonstrate that hyaluronan >27 kDa measured before surgery is an independent predictor of postoperative survival. Our findings confirm the prognostic value of CD44 tissue expression and highlight osteopontin tissue expression and serum high molecular mass hyaluronan as novel prognostic markers in pancreatic cancer. This article is protected by copyright. All rights reserved. PMID- 30456934 TI - Recovery of layered tissue optical properties from spatial frequency-domain spectroscopy and a deterministic radiative transport solver. AB - We present a method to recover absorption and reduced scattering spectra for each layer of a two-layer turbid media from spatial frequency-domain spectroscopy data. We focus on systems in which the thickness of the top layer is less than the transport mean free path ( 0.1 - 0.8l * ) . We utilize an analytic forward solver, based upon the N'th-order spherical harmonic expansion with Fourier decomposition ( SHEFN ) method in conjunction with a multistage inverse solver. We test our method with data obtained using spatial frequency domain spectroscopy with 32 evenly spaced wavelengths within lambda = 450 to 1000 nm on six-layered tissue phantoms with distinct optical properties. We demonstrate that this approach can recover absorption and reduced scattering coefficient spectra for both layers with accuracy comparable with current Monte Carlo methods but with lower computational cost and potential flexibility to easily handle variations in parameters such as the scattering phase function or material refractive index. To our knowledge, this approach utilizes the most accurate deterministic forward solver used in such problems and can successfully recover properties from a two-layer media with superficial layer thicknesses. PMID- 30456935 TI - Segmentation of yeast cell's bright-field image with an edge-tracing algorithm. AB - Phenotype analysis of yeast cell requires high-throughput imaging and automatic analysis of abundant image data. At first, each cell needs to be segmented and labeled in the bright-field images. However, the ambiguous boundary of bright field yeast cell images leads to the failure of traditional segmentation algorithms. We propose a segmentation algorithm based on the morphological characteristics of yeast cells. Seed points are first identified along the cell contour and then connected by an edge tracing approach. In this way, "ill detected" noise points are removed so that edges of yeast cells can be successfully extracted in bright-field images with sparsely distributed cells. In densely packed images, yeast cells with normal morphology can also be correctly segmented and labeled. PMID- 30456936 TI - A step-by-step approach to developing scales for survey research. AB - BACKGROUND: While questionnaires and scales are some of the simplest methods of collecting data, their development requires a rigorous process. In recent years, several new questionnaires and scales have been developed. Although various papers have outlined how to develop questionnaires, their use in survey research, as well as how to ensure their validity and reliability, the actual development of scales - including the generation of items, scaling, the testing of validity and reliability, and refinement of the scale - is missing in the literature. AIM: To outline a systematic and rigorous process for developing scales for survey research and to differentiate between three interchangeably used terms: scale, questionnaire and inventory. DISCUSSION: Developing a valid and reliable scale is daunting because of the challenges associated with the conceptualisation, contextualisation and operationalisation of the phenomenon of interest. Researchers should use multiple approaches at each step of development to tackle these challenges. CONCLUSION: This paper provides a step-by-step approach to developing scales by providing explicit instructions and practical examples. This six-step process can enable nurse researchers to develop a scale applicable to their study's intended population, which is also valid and reliable for measuring the phenomenon of interest. IMPLICATIONS FOR PRACTICE: Rigorous nursing research demands that instruments be valid and reliable measures. Systematic development of scales is key to ensuring that nurse researchers accurately measure abstract concepts when conducting surveys with a given population. This paper is a first step in addressing the gap in the methodological literature and will contribute to greater rigour in research. PMID- 30456937 TI - Income-Related Monthly Adjustment Amounts for Medicare Part B and Prescription Drug Coverage Premiums. Final rule. AB - The Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) changed the modified adjusted gross income (MAGI) ranges associated with Medicare Part B and Medicare prescription drug coverage premiums for years beginning in 2018. The Bipartisan Budget Act of 2018 (BBA 2018) revised the MAGI ranges again for years beginning with 2019. We consider a beneficiary's MAGI and tax filing status to determine: The percentage of the unsubsidized Medicare Part B premium that the beneficiary must pay; and the percentage of the cost of basic Medicare prescription drug coverage the beneficiary must pay. This final rule makes our regulations consistent with the MAGI ranges specified by MACRA and BBA 2018. PMID- 30456938 TI - Setting Up Surface-Enhanced Raman Scattering Database for Artificial Intelligence Based Label-Free Discrimination of Tumor Suppressor Genes. AB - The quality of input data in deep learning is tightly associated with the ultimate performance of machine learner. Taking advantages of unique merits of surface-enhanced Raman scattering (SERS) methodology in the collection and construction of database (e.g., abundant intrinsic fingerprint information, noninvasive data acquisition process, strong anti-interfering ability, etc.), herein we set up SERS-based database of deoxyribonucleic acid (DNA), suitable for artificial intelligence (AI)-based sensing applications. The database is collected and analyzed by silver nanoparticles (Ag NPs)-decorated silicon wafer (Ag NPs@Si) SERS chip, followed by training with a deep neural network (DNN). As proof-of-concept applications, three kinds of representative tumor suppressor genes, i.e., p16, p21 and p53 fragments, are readily discriminated in label-free manners. Prominent and reproducible SERS spectra of these DNA molecules are collected and employed as input data for DNN learning and training, which enables selective discrimination of DNA target(s). The accuracy rate for the recognition of specific DNA target reaches 90.28%. PMID- 30456939 TI - Natural Sugar Assisted Chemically Reinforced Highly Durable Piezo-Organic Nanogenerator with Superior Power Density for Self-Powered Wearable Electronics. AB - Natural piezoelectric material is of increasing interest particularly for applications in biocompatible, implantable, and flexible electronic devices. In this paper we introduce a cost effective, easily available natural piezoelectric material, i.e., sugar in the field of wearable piezoelectric nanogenerator (PNG) where low electrical output, biocompatibility and performance durability are still critical issues. We report on a high performance piezo-organic nanogenerator (PONG) based on the hybridization of sugar encapsulated polyvinylidene fluoride (PVDF) nanofiber webs (SGNFW). We explore the crucial role of single crystal sugar having fascinating structure along with the synergistic enhancement of piezoelectricity during nano-confinement of sugar interfaced macromolecular PVDF chains. As a consequence, the SGNFW based PONG exhibits outstanding electricity generation capability (for example ~100V under 10 kPa human finger impact and maximum power density of 33 mW/m2) in combination with sensitivity to abundantly available different mechanical sources (such as wind flow, vibration, personal electronics and acoustic vibration). Consequently, it opens up suitability in multifunctional self-powered wearable sensor designs for realistic implementation. In addition, commercially available capacitors are charged up effectively by the PONG due to its rapid energy storage capability. The high performance or the PONG not only offers the "battery free" energy generation (several portable units of LEDs and a LCD screen are powered up without using external storage) but also promises its use in wireless signal transmitting systems that widens the potential in personal health care monitoring. Furthermore, owing to the geometrical stress confinement effect, the PONG is proven to be a highly durable power generating device validated by stability test over 10 weeks. Therefore, the organic nanogenerator would be a convenient solution for portable personal electronic devices that are expected to operate in a self-powered manner. PMID- 30456940 TI - Design of Novel Self-Healing Thermoplastic Vulcanizates Utilizing Thermal/Magnetic/Light-Triggered Shape Memory Effects. AB - We designed novel self-healing thermoplastic vulcanizates (TPVs), achieving excellent thermal/magnetic/light-triggered shape memory assisted self-healing behavior. Damage on polylactide (PLA)/epoxidized natural rubber (ENR)/Fe3O4 TPVs could be healed via three events synergistically: the shape memory effect of TPVs resulted in the physical contact of damaged surfaces; the desorption-absorption of ENR/Fe3O4-bound rubber promoted interdiffusion of ENR chains, leading to the self-healing of ENR phase; ENR was grafted onto PLA segments to assist PLA rearranging and entangling again to achieve the repair of TPVs. This self-healing TPV is reported for the first time and paves the way to design next-generation self-healing materials. PMID- 30456941 TI - Antimicrobial Imidazolium Ionic Liquids for the Development of Minimal Invasive Calcium Phosphate-Based Bionanocomposites. AB - Biofilm formation is one of the main obstacles that occur during in vivo implantation, which compromises the implant functionality and patients' health. This is the inspiration for the development of novel implant materials that contain broad-spectrum antimicrobial activity, including antibacterial and antifungal, and enable the local release of antimicrobial agents. Here, multifunctional calcium phosphate-ionic liquid (IL) materials, possessing antimicrobial and repair/regeneration features plus injectability, are proposed as implants in minimally invasive surgery. This approach was based on the loading of 1-alkyl-3-alkylimidazolium chloride ionic liquids (ILs) (C nMImCl ( n = 4, 10, 16) and (C10)2MImCl) during the in situ sol-gel synthesis of calcium phosphates (CaP) and study of their effects on CaP crystallization and biological properties. Physical, morphological, and biological investigations were performed to evaluate the bionanocomposites' properties. The IL N-alkyl chain length influenced the crystallization of CaP and, consequently, the biological properties, which afforded bionanocomposites (when loaded with C16MImCl or (C10)2MImCl) that, (i) inhibit both in vitro bacterial and fungal growth; (ii) reduce the in vitro inflammatory response; (iii) induce osteogenic differentiation in the basal medium of human mesenchymal stem cells; and (iv) are injectable. This will enable the design of multifunctional injectable implants with antimicrobial, anti-inflammatory, and regenerative properties to be used in minimally invasive surgery of bone and maxillofacial defects. PMID- 30456942 TI - Synthesizing Living Tissues with Microfluidics. AB - In native tissues, various cell types organize and spatiotemporally function and communicate with neighboring or remote cells in a highly regulated way. How can we replicate these amazing functional structures in vitro? From the view of a chemist, the heterogeneous cells and extracellular matrix (ECM) could be regarded as various chemical substrate materials for "synthetic" reactions during tissue engineering. But how can we accelerate these reactions? Microfluidics provides ideal solutions. Microfluidics could be metaphorically regarded as a miniature "biofactory", whereas the on-chip critical chemical cues such as biomolecule gradients and physical cues such as geometrical confinement, topological guidance, and mechanical stimulations, along with the external stimulations such as light, electricity, acoustics, and magnetics, could be regarded as "catalytic cues" which can accelerate the "synthetic reactions" by precisely and effectively manipulating a series of cell behaviors including cell adhesion, migration, growth, proliferation, differentiation, cell-cell interaction, and cell-matrix interaction to reduce activation energy of the "synthetic reactions". Thus, on the microfluidics platform, the "biofactory", various "synthetic" reactions take place to change the substrate materials (cells and ECM) into products (tissues) in a nonlinear way, which is a typical feature of a biological process. By precisely organizing the substrate materials and spatiotemporally controlling the activity of the products, as a "biofactory", the microfluidics system can not only "synthesize" living tissues but also recreate physiological or pathophysiological processes such as immune responses, angiogenesis, wound healing, and tumor metastasis in vitro to bring insights into the mechanisms underlying these processes taking place in vivo. In this Account, we borrow the concept of chemical "synthesis" to describe how to "synthesize" artificial tissues using microfluidics from a chemist's view. Accelerated by the built-in physiochemical cues on microfluidics and external stimulations, various tissues could be "synthesized" on a microfluidics platform. We summarize that there are "step-by-step synthesis" and "one-step synthesis" on microfluidics for creating desired tissues with unprecedented precision, accuracy, and speed. In recent years, researchers developed various microfluidic techniques including creating adhesive domains for mediating reverse and precise adhesion, chemical gradients for directing cell growth, geometrical confinements and topological cues for manipulating cell migration, and mechanics for stimulating cell differentiation. By employing and orchestrating these on-chip tissue "synthetic" conditions, "step by-step synthesis" could be realized on chips to develop multilayered tissues such as blood vessels. "One-step synthesis" on chips could develop functional three-dimensional tissue structures such as neural networks or nephron-like structures. Based on these on-chip studies, many critical physiological and pathophysiological processes such as wound healing, tumor metastasis, and atherosclerosis could be deeply investigated, and the drugs or therapeutic approaches could also be evaluated or screened conveniently. The "synthetic tissues on microfluidics" system would pave an avenue for precise creation of artificial tissues for not only fundamental research but also biomedical applications such as tissue engineering. PMID- 30456943 TI - Dual-Function Electrochromic Supercapacitors Displaying Real-Time Capacity in Color. AB - Dual-function electrochromic supercapacitors (ECSs) indicating their real-time charge capacity in color are fabricated using tungsten trioxide (WO3) and Li doped ion gels containing hydroquinone (HQ). The ECSs in this work can simultaneously serve as either electrochromic devices (ECDs) or supercapacitors, so the coloration/bleaching and charging/discharging characteristics are investigated between 0 and -1.5 V. At the optimal HQ concentration, a large transmittance contrast (~91 %), high coloration efficiency (~61.9 cm2/C), high areal capacitance (~13.6 mF/cm2), and good charging/discharging cyclic stability are achieved. By exploiting the elastic characteristics of the gel electrolytes, flexible ECSs are also fabricated on plastic substrates and exhibit good bending durability. Moreover, the practical feasibility is evaluated by demonstrating the use of the ECSs as an energy storage device and a power source. PMID- 30456944 TI - Antifouling Ion-Exchange Resins. AB - Large quantities of organic ion-exchange resins are used worldwide for water decontamination and polishing. Fouling by microorganisms and decomposition products of natural organic matter severely limits the lifetime of these resins. Much research has thus been invested in polymer-based antifouling coatings. In the present study, poly(4-styrenesulfonate) (PSS) and a co-polymer of PSS and a zwitterionic group were used to spontaneously coat commercial Dowex 1X8 anion exchange resin. UV-visible spectroscopy provided a precise measure of the kinetics and amount of PSS sorbed onto or into resin beads. When challenged with Chlamydomonas reinhardtii algae, uncoated resin was rapidly fouled by algae. Coating the resin with either the homopolymer of PSS or the co-polymer with zwitterion eliminated fouling. Using narrow- and wide-molecular-weight distribution PSS, a cutoff molecular weight of about 240 repeat units was found, above which PSS was unable to diffuse into the resin. Thus, only one monolayer of added PSS was sufficient to confer a highly desirable antifouling property on this resin while consuming less than 0.1% of the exchanger capacity. Radioactive sulfate ions were used to probe the kinetics of (self)exchange, which were virtually unaffected by the PSS coating. This resin treatment is a fast, ultra low-cost step for potentially enhancing the lifetime of ion exchangers. PMID- 30456945 TI - Molybdenum-Incorporated Mesoporous Silica: Surface Engineering toward Enhanced Metal-Support Interactions and Efficient Hydrogenation. AB - In heterogeneous catalysis, strong metal-support interactions are highly desired to improve catalytic turnover on metal catalysts. Herein, molybdenum is uniformly incorporated into mesoporous silica (KIT-6) to accomplish strong interactions with iridium catalysts, and consequently, active and selective hydrogenation of carbonyl compounds. Mo-incorporated KIT-6 (Mo-KIT-6) affords electronic interactions to improve the proportion of metallic Ir0 species, avoiding the easy surface oxidation of ultrafine metals in silica mesocavities. Owing to the effective H2 activation and subsequent hydrogenation on metallic Ir0 sites, optimal Ir/Mo-KIT-6 with a high Ir0/Irdelta+ ratio delivers prominent performance in the hydrogenation of amides to amines and alpha,beta-unsaturated aldehydes to unsaturated alcohols. As for N-acetylmorpholine hydrogenation, the Ir/Mo-KIT-6 catalyst achieves efficient turnover toward N-ethylmorpholine with high selectivity (>99%) and exhibits activity that relies on the engineered chemical state of Ir sites. Such promotion is further proved to be universal in cinnamaldehyde hydrogenation. This work will provide new opportunities for catalyst design through surface/interface engineering. PMID- 30456946 TI - Fluorescence-based high throughput screening technologies for natural chloride ion channel blockers. AB - Chloride channels represent a group of potential drug targets, their blockers showed significant protecting effect on impaired cells by modulating apoptosis, autophagy and other cell signals. However, clinical drugs with chloride channel inhibitory properties have not yet been developed. Natural product extract becomes an underlying candidate satisfied the clinical requirements for its low toxicity, low cost and abundant sources. Here, a fluorescence-based EYFP H148Q/I153L-HeLa cell line model was constructed by molecular cloning and verified by Real-time PCR and Western Blotting assay. By using this chloride channel blocker screening model, 7 hit compounds chosen from 6988 natural compounds showed the channel blocking activity. Then the hit compounds were further validated by electrophysiological patch-clamp analysis. Our study preliminarily identified PC-4 as a new chloride channel inhibitors and demonstrated the reliability and sensitivity of fluorescence-based high throughput screening technologies for discovery of biologically active compounds from natural herbal compounds. PMID- 30456947 TI - An Enzyme-Free MicroRNA Assay Based-on Fluorescence Counting of Click Chemical Ligation-Illuminated Magnetic Nanoparticles with Total Internal Reflection Fluorescence Microscopy. AB - MicroRNAs (miRNAs) have been considered as promising cancer biomarkers. However, the simple but sensitive detection of low levels of miRNAs in biological samples still remains challenging. Herein, we wish to report an entirely enzyme-free, simple and highly sensitive miRNA assay based on the counting of cycling click chemical ligation (3CL)-illuminated fluorescent magnetic nanoparticles (MNPs) with a total internal reflection fluorescence microscopy (TIRFM). In this strategy, each miRNA molecule can trigger many cycles of click chemical ligation reactions to produce plentiful ligated oligonucleotides (ODNs) with both 5' biotin and 3'-fluorophore, resulting in efficient signal amplification. It is worth noting that only the li-gated ODNs can bring fluorophores onto streptavidin functionalized MNPs (STV-MNPs). Notably, merely 10 fluorescent molecules on each 50 nm MNP can make it bright enough to be clearly visualized by the TIRFM, which can significantly improve the detection sensitivity for miRNA. Through fluorescence counting of individual MNPs and integrating their fluorescence intensities, the amount of target miRNA can be quantitatively determined. This miRNA assay can be accomplished in a mix-and-read manner just by simply mixing the enzyme-free 3CL reaction system with the MNPs before TIRFM imaging, which avoids tedious immobilization, washing and purification steps. Despite the extremely simple operation, this strategy exhibits high sensitivity with a quite low detection limit of 50 fM target miRNA as well as high specificity to well discriminate miRNA sequences with a single-base variation. Furthermore, the applicability of this method in real biological samples is also verified through the accurate detection of miRNA target in cancer cells. PMID- 30456948 TI - PbS Quantum Dots/2D Non-layered CdSxSe1-x Nanosheets Hybrid Nanostructure for High-Performance Broadband Photodetectors. AB - Two-dimensional (2D) non-layered nanomaterials have attracted extensive attention for electronic and optoelectronic applications recently due to their distinct properties. In this work, we firstly employed a facile one-step method to synthesize 2D non-layered cadmium sulfide selenide (CdSxSe1-x, x=0.33) nanosheets with highly crystalline structure and then we introduced a generic spin-coating approach to fabricate PbS quantum dots (QDs)/2D CdSxSe1-x nanosheets hybrid nanostructure and demonstrate their potential for high-performance broadband photodetectors. Compared with pure 2D CdSxSe1-x nanosheets photodetectors, the photoelectric performance of the PbS/CdSxSe1-x hybrid nanostructure is enhanced by three orders of magnitude under near infra (NIR) light illumination and maintain its performance in visible (Vis) range. The photodetector exhibits a broadband response range from Vis to NIR with ultrahigh Ilight/Idark ratio (3.45*106), a high spectra responsivity (1.45*103 A/W) and high detectivity (1.05*1015 Jones), respectively. The proposed QDs/2D non-layered hybrid nanostructure based photodetector paves a promising way for the next-generation high performance broadband optoelectronic devices. PMID- 30456949 TI - Revisiting Conversion Reaction Mechanisms in Lithium Batteries: Lithiation-Driven Topotactic Transformation in FeF2. AB - Intercalation-type electrodes have now been commonly employed in today's batteries due to their capability of storing and releasing lithium reversibly via topotactic transformation, conducive to small structural change, but they have limited interstitial sites to hold Li. In contrast, conversion electrodes feature high Li-storage capacity, but often undergo large structural change during (de)lithiation, resulting in cycling instability. One exception is iron fluoride (FeF2), a conversion-type cathode that exhibits both high capacity and high cycling stability. Herein, we report a lithiation-driven topotactic transformation in a single crystal of FeF2, unveiled by in situ visualization of the spatial and crystallographic correlation between the parent and converted phas-es. Specifically, conversion in FeF2 resembles the intercalation process but involves transport of both Li+ and Fe2+ ions within the F-anion array, leading to formation of Fe preferentially along specific crystallographic ori-entations of FeF2. Throughout the process, the F-anion framework is retained, creating a checkerboard-like structure, within which the volume change is largely compensated, thereby enabling the high cyclability in FeF2. Findings from this study, with unique insights into conversion reaction mechanisms, may help to pave the way for designing conversion-type electrodes for the next-generation lithium batteries. PMID- 30456950 TI - Calcium-induced lipid nanocluster structures: sculpturing of the plasma membrane. AB - The plasma membrane of the cell is a complex, tightly-regulated, heterogeneous environment shaped by proteins, lipids, and small molecules. Ca2+ ions are important cellular messengers, spatially separated from anionic lipids. Upon cell injury, disease, or apoptotic events, anionic lipids are externalized to the outer leaflet of the plasma membrane and encounter Ca2+, resulting in dramatic changes in the plasma membrane structure and initiation of signaling cascades. Despite high chemical and biological significance, the structures of lipid-Ca2+ nanoclusters are still not known. Previously, we demonstrated by solid-state NMR spectroscopy that upon binding to Ca2+, individual phosphatidylserine lipids populate two distinct yet-to-be-characterized structural environments. Here, we concurrently employ extensive all-atom MD simulations with our accelerated membrane mimetic and detailed NMR measurements to identify lipid-Ca2+ nanocluster conformations. We find that major structural characteristics of these nanoclusters, including inter-lipid pair distances and chemical shifts, agree with observable NMR parameters. Simulations reveal that lipid-ion nanoclusters are shaped by two characteristic, long-lived lipid structures induced by divalent Ca2+. Using ab initio quantum mechanical calculations of chemical shifts on MD captured lipid-ion complexes, we show that computationally observed conformations are validated by experimental NMR data. Both NMR measurements on diluted specifically-labeled lipids and MD simulations reveal that the basic structural unit that reshapes the membrane is a Ca2+-coordinated phosphatidylserine tetramer. Our combined computational and experimental approach presented here can be applied to other complex systems where charged membrane-active molecular agents leave structural signatures on lipids. PMID- 30456951 TI - Red phosphorus: an elementary semiconductor for room-temperature NO2 gas sensing. AB - Black and blue phosphorus (both allotropes of elementary phosphorus) have recently been widely explored as an active material of electronic devices, and their potential in gas sensing applications has been demonstrated. On the other hand, amorphous red phosphorus (a-RP), a much cheaper and readily available phosphorus allotrope, has seldom been investigated as an electronic material, and their gas sensing properties have never been studied. In this work we investigated these properties of a-RP by combining experimental characterizations with theoretical calculations. We found that a-RP exhibited an amphoteric character for detecting both commonly regarded reducing and oxidizing gas molecules, featuring a negative correlation between the electrical resistance of a-RP and the gas concentration. Interestingly, the a-RP based sensors appear to be particularly suitable for room-temperature NO2 detection, exhibiting excellent sensitivity and selectivity as well as fast temporal response and recovery. A unique sensing feature of a-RP toward NO2 was identified, which was associated with the expansion of P-P bonds upon NO2 chemisorption. Based on density functional theory calculations we proposed a physiochemical model to elaborate the synergistic effects of the P-P bond expansion and Langmuir isotherm adsorption on the electronic properties and gas sensing processes of a-RP. PMID- 30456952 TI - Synthesis and Evaluation of 1,5-Dithia-D-laminaribiose, Triose and Tetraose as Truncated beta-(1->3)-Glucan Mimetics. AB - The preparation and characterization of a series of di-, tri- and tetrasaccharide analogs of beta-(1->3)-glucans is described in which each pyranoside ring is replaced by a 5-thiopyranosyl ring and each glycosidic oxygen by a thioether. These oligomeric 1,5-dithio-D-glucopyranose derivatives were shown to inhibit the staining of human neutrophils and of mouse macrophages by fluorescent anti-CR3 and anti-dectin-1 antibodies, respectively. The compounds were also demonstrated to stimulate phagocytosis and pinocytosis indicative of binding to the carbohydrate binding domains of complement receptor 3 (CR3) and dectin-1. Activity in all three assays was optimium at the level of the trisaccharide mimic suggesting that while the replacement of ethereal oxygens by thioethers results in greater affinity for the aromatic-lined hydrophobic binding pockets, the presence of multiple longer C-S bonds eventually results in a mismatch and a loss of affinity. PMID- 30456953 TI - Porphyrins as Photoredox Catalysts in Csp2-H Arylations: Batch and Continuous Flow Approaches. AB - We have investigated both batch and continuous flow photoarylations of enol acetates to yield different alpha-arylated aldehyde and ketone building blocks by using diazonium salts as the aryl-radical source. Different porphyrins were used as SET photocatalysts, and photophysical as well as electrochemical studies were performed to rationalize the photoredox properties and suggest mechanistic insights. Notably, the most electron-deficient porphyrin (meso tetra(pentafluorophenyl)porphyrin) shows the best photoactivity as an electron donor in the triplet excited-state, which was rationalized by the redox potentials of excited states and the turnover of the porphyrins in the photocatalytic cycle. Scope, a two-step continuous protocol and multigram-scale reactions are also presented revealing a robust, cost-competitive and easy methodology, highlighting the significant potential of porphyrins as SET photocatalysts. PMID- 30456954 TI - Strengthened and Thermally Resistant Poly(lactic acid) Based Composite Nanofibers Prepared via Easy Stereocomplexation with Antibacterial Effects. AB - Strengthened PLA based materials with improved mechanical performances and improved thermal resistance, notably, are prepared by introducing stereocomplex crystallite (SC), an ideal filler, into the materials. Owning to the intermolecular hydrogen bond among the stereoisomer chains, the melting point of the special crystallite is up to 200 oC, which is 50 oC higher than the isostactic crystallite. The modulus of the PLA based materials can be enhanced to several hundred MPa due to the integrated polymer chain arrangement. In this study, we electrospun hybrid nanofibers consisted of PLA stereoisomers and induced the stereocomplex crystallization under a mild condition (65 oC for 1 hour). The mild warming is favorable for the protection of chlorogenic acid (CA) that was selected as antibacterial agent. Both of Gram-positive and Gram-negative bacteria were efficiently cleared away using the warmed nanofibers that released CA rapidly within just a few hours. Used as filters, the SC electrospinning membrane also presented potent filtering effect leaving no bacteria retained in the filtrates. Attributing to SC, the PLA based nanofibers showed extremely increased melting temperature over 200 oC and improved Young's modulus up to 270.0 MPa. The durable nanofibers prepared in present study are meaningful for enlarging the application of PLA based materials, for example, as filters, masks and packages. PMID- 30456955 TI - The veA gene acts as a positive regulator of conidia production, ochratoxin A biosynthesis, and oxidative stress tolerance in Aspergillus niger. AB - The veA gene is a key regulator governing morphogenetic development and secondary metabolism in many fungi. Here, we characterized and disrupted a veA ortholog in an ochratoxigenic Aspergillus niger strain. Morphological development, ochratoxin A (OTA) biosynthesis and oxidative stress tolerance in the wild-type and veA disruption strains were further analyzed. Accordingly, the link between the veA gene and development of specific gene brlA, OTA biosynthesis key gene pks, and the oxidative stress tolerance related gene cat was explored. Results demonstrated that the veA gene acts as a positive regulator of conidia production, OTA biosynthesis, and oxidative stress tolerance in A. niger regardless of light conditions. Darkness promoted conidial production and OTA biosynthesis in A. niger wild-type strain. Our results contribute to a better understanding of the veA regulatory mechanism and suggest the veA gene as a potential target for developing control strategies for A. niger infection and OTA biosynthesis. PMID- 30456956 TI - Highly Stereoselective Assembly of alpha-Carbolinone Skeletons via N-Heterocyclic Carbene-Catalyzed [4 + 2] Annulations. AB - A series of iminoindoline-derived alkenes was found to be a new class of excellent aza-diene electrophiles in NHC-catalyzed asymmetric [4 + 2] cyclizations. This transformation is mainly characterized by excellent compatibility, which allows aza-diene substrates to incorporate various substituents and functionalities, including (hetero)aryl, (linear or branched)alkyl, alkenyl, alkynyl, and ester groups. Forty examples of the desired tetrahydro-alpha-carbolinones were facilely synthesized using this method, with up to 99% yield and >99% ee. PMID- 30456958 TI - Recipe for Dirac Phonon States with a Quantized Valley Berry Phase in Two Dimensional Hexagonal Lattices. AB - The topological quantum states in two-dimensional (2D) materials are fascinating subjects of research, which usually highlight electron-related systems. In this work, we present a recipe that leads to Dirac phonon states with a quantized valley Berry phase in 2D hexagonal lattices by first-principles calculations. We show that candidates possessing the 3-fold rotational symmetry at the corners of the hexagonal Brillouin zone host valley Dirac phonons, which are guaranteed to remain intact with respect to perturbations. We identify that such special topological features populated by Dirac phonons can be realized in various 2D materials. In particular, the monolayer CrI3, an attractive 2D magnetic semiconductor with exotic applications in spintronics, is an ideal platform to investigate nontrivial phonons in experiments. We further confirm that the phonon Berry phase is quantized to +/- pi at two inequivalent valleys. The phonon edge states terminated at the projection of phonon Dirac cones are clearly visible. This work demonstrates that 2D hexagonal lattices with attractive valley Dirac phonons will extend the knowledge of valley physics, providing wide applications of topological phonons. PMID- 30456957 TI - Seongsanamides A-D: Antiallergic Bicyclic Peptides from Bacillus safensis KCTC 12796BP. AB - Six seongsanamides were isolated from the culture broth of Bacillus safensis KCTC 12796BP, and their structures were elucidated by spectroscopic data analysis combined with Marfey's method, electronic circular dichroism calculations, and biosynthetic gene cluster analysis. Compounds 1-4 were bicyclic peptides with isodityrosine residues; 5 and 6 were monocyclic peptides. Only the bicyclic seongsanamides inhibited degranulation and LTC4/PGD2 generation in IgE/Ag stimulated bone marrow-derived mast cells. Oral administration of 1 suppressed mast cell-dependent passive cutaneous anaphylaxis reaction. PMID- 30456959 TI - Asymmetric Ionic Conditions Generate Large Membrane Curvatures. AB - Biological membranes possess intrinsic asymmetry. This asymmetry is associated not only with leaflet composition in terms of membrane species but also with differences in the cytosolic and periplasmic solutions containing macromolecules and ions. There has been a long quest for understanding the effect of ions on the physical and morphological properties of membranes. Here, we elucidate the changes in the mechanical properties of membranes exposed to asymmetric buffer conditions and the associated curvature generation. As a model system, we used giant unilamellar vesicles (GUVs) with asymmetric salt and sugar solutions on the two sides of the membrane. We aspirated the GUVs into micropipettes and attached small beads to their membranes. An optical tweezer was used to exert a local force on a bead, thereby pulling out a membrane tube from the vesicle. The assay allowed us to measure the spontaneous curvature and the bending rigidity of the bilayer in the presence of different ions and sugar. At low sugar/salt (inside/out) concentrations, the membrane spontaneous curvature generated by NaCl and KCl is close to zero, but negative in the presence of LiCl. In the latter case, the membrane bulges away from the salt solution. At high sugar/salt conditions, the membranes were observed to become more flexible and the spontaneous curvature was enhanced to even more negative values, comparable to those generated by some proteins. Our findings reveal the reshaping role of alkali chlorides on biomembranes. PMID- 30456960 TI - Amphistome infections in domestic and wild ruminants in East and Southern Africa: A review. AB - In this article, the main amphistome species infecting domestic and wild ruminants in East and Southern Africa, their snail intermediate hosts and epidemiological features are reviewed and discussed. Twenty-six amphistome species belonging to nine genera from three families occur in domestic and wild ruminants in the region under review and over 70% of them belong to the genera Calicophoron, Carmyerius and Cotylophoron. Of the amphistome species, 76.9% are shared between domestic and wild ruminant hosts - an important observation when considering the different options for control. Seven freshwater snail species belonging to four genera from two families act as intermediate hosts of the identified amphistome species, with the genus Bulinus contributing 57% of the snail species. Some of the snails are intermediate hosts of amphistome species belonging to the same genus or to different genera; a phenomenon not yet fully elucidated as some snails are reported to be naturally infected with amphistome cercariae of unidentified species. Only nine (34.6%, 9/26) of the amphistome species have known snail intermediate hosts, while most (65.4%, 17/26) have unknown hosts. Species of intermediate hosts and the potential of the flukes to infect these hosts, the biological potential of the snail hosts, the definitive hosts management systems and their grazing habits are considered to be the main factors influencing the epidemiology of amphistomosis. Based on the epidemiological features of amphistome infections, various practical control options are discussed. Further research is necessary to determine amphistome snail associations, develop diagnostic tests that can detect prepatent infections in the definitive host, determine the burden and economic importance of amphistomosis in domestic and wild ruminants and the efficacy of different anthelmintics in the treatment of patent infections. PMID- 30456961 TI - Molecular analysis of Shiga toxin-producing Escherichia coli O157:H7 and non-O157 strains isolated from calves. AB - Shiga toxin-producing Escherichia coli (STEC) O157 and non-O157 are food-borne pathogens and contaminants of foods of animal origin. This study was conducted to investigate the presence of virulence and integrase genes in STEC isolates from diarrhoeic calves in Fars Province, Iran. Five hundred and forty diarrheic neonatal calves were randomly selected for sampling. Rectal swabs were collected and cultured for isolation and identification of E. coli following standard methods. The isolates were analysed for the presence of class 1 integrons and bacterial virulence factors using polymerase chain reaction (PCR). Antimicrobial susceptibility testing was performed using the Kirby-Bauer disc diffusion method. Out of 540 diarrhoeic faecal samples, 312 (57.7%) harboured E. coli and 71 (22.7%) of them were identified as STEC: 41(69.5%) carried the stx2 gene, 21 (35.6%) carried the stx1 gene and 3 (5%) carried both. Twenty-six (44%) of the isolates showed the eaegene. Among the STEC isolates examined for susceptibility to eight antimicrobial agents, erythromycin and penicillin (96.8%) resistance were most commonly observed, followed by resistances to ampicillin (71.8%), tetracycline (62.5%) and trimethoprim/sulfamethoxazole (39%). Integrons were detected by PCR in 36% of the STEC tested isolates, 57 (89%) of which showed resistance to at least three antimicrobial agents. Our findings should raise awareness about antibiotic resistance in diarrhoeic calves in Fars Province, Iran. Class 1 integrons facilitate the emergence and dissemination of multidrug resistance (MDR) among STEC strains recovered from food animals. PMID- 30456962 TI - Audiological follow-up in a risk-based newborn hearing screening programme: An exploratory study of the influencing factors. AB - BACKGROUND: Follow-up return rate in Early Hearing Detection and Intervention (EHDI) programmes is of specific importance as it ensures that benchmarks are met and that no child with suspected hearing loss is left unidentified. OBJECTIVES: The aim of this study was to determine the factors influencing audiological follow-up of high-risk infants in a risk-based newborn hearing screening programme. METHOD: A non-experimental, exploratory, qualitative research design was employed. Purposive sampling was used. The study was conducted at a secondary level hospital in the public health care sector in South Africa. Participants comprised 10 caregivers (age range 26-40 years) of infants who had been enrolled in a risk-based newborn hearing screening programme, and returned for follow-up appointments. Data were collected using semi-structured interviews. Responses were recorded by the researcher and a colleague to ensure rigour and trustworthiness of findings. Data were analysed using thematic analysis for open ended questions and descriptive statistics for the closed-ended questions. RESULTS: The most common positive contributors that facilitated participants' attendance at follow-up appointments were: having friendly audiologists; a clear line of communication between caregiver and audiologist and a reminder of the appointment. The most significant perceived challenge that participants described in returning for the follow-up appointment was living in far proximity from the hospital. CONCLUSION: Findings of the study revealed that influencing factors on follow-up return rate are demographic, socio-economic, and interpersonal in nature and further suggested the need for an all-inclusive appointment day. It may be of importance to not only look at what is being done to improve the follow up return rate but also how it should be done in terms of professional-to-patient communication and interactions. PMID- 30456963 TI - Electronic health record system in the public health care sector of South Africa: A systematic literature review. AB - BACKGROUND: South Africa is planning to implement the National Health Insurance (NHI) scheme in the near future. The NHI is intended to improve the accessibility of quality health care services for all South African citizens. For the NHI to achieve this objective, an electronic health record (EHR) system to register and track patients who visit different health care providers will have to be developed. AIM: To identify critical success factors for the implementation of EHRs in South Africa's public health care sector. SETTING: This study reviewed studies on EHR implementation in African countries published between 2006 and 2017. METHODS: The study made use of a systematic literature review to identify barriers to the implementation of EHRs in the public health care sector. RESULTS: Fifteen articles were included in the study. The study identified technical, social and environmental barriers to the implementation of EHRs. The barriers could further be broken down into lack of supporting infrastructure; user training and commitment; political influence or strategy; legislation and regulations; and the lack of a framework for implementation and management of EHRs. The study suggests six main recommendations for the successful implementation of EHRs in South Africa's public health care sector. CONCLUSION: The study recommended investing in alternative infrastructure facilities, incentivising the health informatics field to attract and retain information and communication technology professionals and to encourage the participation of all stakeholders in the development process to develop context-relevant e-health implementation strategies, legislation and frameworks. Government should also allocate separate budgets for e-health projects. PMID- 30456964 TI - Effect of diabetes self-management education on glycaemic control among type 2 diabetic patients at a family medicine clinic in Kenya: A randomised controlled trial. AB - BACKGROUND: Diabetes self-management education (DSME) is a key component of diabetes care aimed at delaying complications. Unlike usual care, DSME is a more structured educational approach provided by trained, certified diabetes educators (CDE). In Kenya, many diabetic patients are yet to receive this integral component of care. At the family medicine clinic of the Aga Khan University Hospital (AKUH), Nairobi, the case is no different; most patients lack education by CDE. AIM: This study sought to assess effects of DSME in comparison to usual diabetes care by family physicians. SETTING: Family Medicine Clinic, AKUH, Nairobi. METHODS: Non-blinded randomised clinical trial among sub-optimally controlled (glycated haemoglobin (HbA1c) >= 8%) type 2 diabetes patients. The intervention was DSME by CDE plus usual care versus usual care from family physicians. Primary outcome was mean difference in HbA1c after six months of follow-up. Secondary outcomes included blood pressure and body mass index. RESULTS: A total of 220 diabetes patients were screened out of which 140 met the eligibility criteria and were randomised. Around 96 patients (69%) completed the study; 55 (79%) in the DSME group and 41 (59%) in the usual care group. The baseline mean age and HbA1c of all patients were 48.8 (standard deviation [SD]: 9.8) years and 9.9% (SD: 1.76%), respectively. After a 6-month follow-up, no significant difference was noted in the primary outcome (HbA1c) between the two groups, with a mean difference of 0.37 (95% confidence interval: -0.45 to 1.19; p = 0.37). DSME also made no remarkable change in any of the secondary outcome measures. CONCLUSION: From this study, short-term biomedical benefits of a structured educational approach seemed to be limited. This suggested that offering a short, intensified education programme might have limited additional benefit above and beyond the family physicians' comprehensive approach in managing chronic conditions like diabetes. PMID- 30456965 TI - Experiences of school health nurses regarding the provision of the school health service delivery in the Tshwane district. AB - BACKGROUND: Irrespective of the provision of an integrated school health policy, the school health nurses continue to experience multiple challenges regarding the provisioning of school health service delivery. AIM: The aim of this paper was to explore and describe the experiences of school health nurses regarding school health service delivery in the Tshwane district. SETTING: Schools in the Tshwane district in Pretoria were used in the study. METHODS: A qualitative and descriptive phenomenological design was used to conduct the study. Purposive sampling techniques were used to select a sample from the population of school health nurses employed in the Tshwane district and conduct the enquiry because of their knowledge and experience of school health services. The researchers collected data by means of unstructured, one-on-one in-depth interviews. The Tesch data analysis method was used by the researcher and co-coder. The researcher identified categories, subcategories and themes and these were reduced into grouping topics that were related to one another. RESULTS: Positive and negative experiences of school health nurses emerged. It was evident from the findings of the study that the factors affecting the quality of the integrated school health programme (ISHP) provided were interrelated. Most of these factors negatively affected service delivery. CONCLUSION: It was recommended that the partnership between the National Department of Health and National Department of Basic Education as the main role players should be sustained at all times to ensure the successful implementation of the ISHP. PMID- 30456966 TI - Stakeholders' experiences in implementation of rapid changes to the South African prevention of mother-to-child transmission programme. AB - BACKGROUND: South Africa's prevention of mother-to-child transmission (PMTCT) of the human immunodeficiency virus (HIV) programme has undergone rapid changes in the last two decades. Initially, the provision of single antiretroviral therapy was based on eligibility criteria in the year 2001, which later changed to combination therapy. This was aimed at preventing mother-to-child transmission of HIV. Since 2015, all pregnant women were eligible for antiretroviral treatment regardless of their CD4 count. Although significant strides were made to reduce mother-to-child transmission of HIV, increased efforts are required to meet UNAIDS targets, World Health Organization (WHO) elimination framework goals and sustainable development goals to eliminate new HIV infections in children and ending the HIV epidemic by 2030. AIM: The aim of the study was to explore healthcare workers' experiences and patient perceptions of the implementation of rapid changes to the PMTCT programme in four public healthcare facilities. SETTING: The study was conducted in the four public healthcare facilities within the two highly HIV-burdened districts of iLembe and eThekwini in KwaZulu-Natal province, South Africa. METHODS: This study used a qualitative, exploratory, descriptive study design using interviews and focus group discussions. Participants were selected using purposive sampling. Following verbatim transcription of the data, thematic data analysis was used through data reduction and data display and the emergence of four themes. RESULTS: A total of 61 stakeholders were interviewed. Four major themes emerged: (1) impact of poor health system design, (2) impact of poor communication of changes, (3) contextual factors affecting innovation in healthcare and (4) skill deficit in change management and forward planning. CONCLUSION: A healthcare system more responsive to the experiences of healthcare workers and pregnant women is required to effectively implement changes in priority programmes. PMID- 30456967 TI - A mortality review of tuberculosis and HIV co-infected patients in Mahalapye, Botswana: Does cotrimoxazole preventive therapy and/or antiretroviral therapy protect against death? AB - BACKGROUND: The World Health Organization aims to reduce tuberculosis (TB) mortality rate from 15% in 2015 to 6.5% by 2025. AIM: This study determined the profile of TB and human immunodeficiency virus (HIV) co-infected patients who died in Mahalapye District, Botswana, while on anti-TB medication and the factors that contributed to such outcome. SETTING: The study was conducted in the Mahalapye Health District in Botswana. METHODS: This was a cross-sectional study that reviewed patient records from the Mahalapye District Health Management Team Electronic Tuberculosis Register from January 2013 to December 2015. RESULTS: The majority of the TB and HIV co-infected patients were on antiretroviral therapy (ART) (486 [81.63%]) or were initiated cotrimoxazole preventive therapy (CPT) (518 [87.2%]) while taking anti-TB treatment. Seventy-three (13.6%) TB and HIV co-infected patients died before completing anti-TB treatment. Three-quarters (54 [74.4%]) of patients who died before completing anti-TB treatment were on ART, among them two patients who were on ART at least 3 months prior to commencing anti-TB. Also, the majority (64 [87.7%]) of TB and HIV co-infected patients were commenced on CPT prior to death. There was a bimodal density curve of death occurrence in those who did not commence ART and in those who did not commence CPT. CONCLUSION: This study established that TB and HIV co-infected patients had a TB mortality of 13.6%. A high mortality rate was observed during the first 3 months in those who did not take ART and during the second and the fifth month in those who did not commence CPT. Further study is needed to clarify this matter. PMID- 30456968 TI - The pattern and characteristics of sexual assault perpetrators and survivors managed at a sexual assault referral centre in Lagos. AB - BACKGROUND: There has presumably been an increase in cases of sexual assault in Nigeria; however, accurate data on the characteristics of the survivors and perpetrators are not readily available in most cases. AIM: To report the pattern and characteristics of sexual assault perpetrators and survivors managed at the Mirabel Centre, Lagos State University Teaching Hospital (LASUTH), Ikeja - a three-year review. METHODS: A retrospective audit carried out in the sexual assault referral centre (SARC) - Mirabel Centre, LASUTH, Lagos State, Nigeria. A total of 2160 case files from July 2013 to January 2017 were assessed for age group of survivors and gender, among others. RESULTS: A total of 2160 cases were analysed. The mean age of survivors was 13.9 (+/- 4.4) years with the 11-20 years age group having the highest number of survivors (48.4%) and the 0-10 years age group having 35.9% of survivors. Majority of the survivors (97.7%) were female. The majority of the perpetrators were known to the survivors with 10.3% being family members. Defilement (71.6%) was the most reported type of assault at the centre with rape (20.3%) being the second most common. The majority of the referrals to the centre were from the police (76.7%), while self-referrals made up 8% of referrals. CONCLUSION: Minors and adolescents formed the majority of the survivors. Defilement was the most reported form of sexual violence. There needs to be special intervention for better monitoring and protection of minors and youths against sexual assault. The establishment of more sexual assault referral centres in Nigeria will increase reportage and treatment of survivors. PMID- 30456969 TI - The role of gender in the spread of HIV and AIDS among farmworkers in South Africa. AB - BACKGROUND: Gender inequality and men's perceived sexual and economic superiority over women are central to human immunodeficiency virus (HIV) infection. The farming community in which the participants in the study live operates along such patriarchal lines, with the men making the important decisions for their families. AIM: To explore and describe the role of gender in the spread of HIV and acquired immunodeficiency syndrome (AIDS) among farmworkers in South Africa. SETTING: The study was conducted in the Levubu farms, Vhembe district, Limpopo Province, South Africa. METHODS: The researchers adopted a qualitative, explorative and descriptive research design with in-depth semi structured interviews. Purposive and convenience sampling methods were used to select participants who met the inclusion criteria. Data collected were thematically analysed using Creswell's data analysis method. Lincoln and Guba's model to ensure trustworthiness and ethical standards were applied. RESULTS: The findings of the study clearly indicated that powerlessness and lack of decision making by female farmworkers was common as female farmworkers were dependent on their male partners to make decisions in the workplace as well as decisions regarding sexual matters in a relationship. CONCLUSION: The main conclusion drawn from the findings were that farmworkers are continuously exposed to exploitation and disempowerment in a variety of ways with very little support from their supervisors, which makes them vulnerable to contracting HIV. PMID- 30456970 TI - Knowledge and practices of parents about child eye health care in the public sector in Swaziland. AB - BACKGROUND: Swaziland, like many other developing countries, lacks appropriate eye health services, particularly for children. AIM: To determine the knowledge and practices of parents about child eye health care in the public sector in Swaziland. SETTING: The setting for this study was Swaziland. METHODS: A descriptive study involving cross-sectional sampling methodology and quantitative analysis was employed with 173 randomly selected parents whose children attended public schools in Swaziland. RESULTS: Out of 173 participants, 104 (60.1%) parents reported that they have never taken their children for an eye test and 69 (31.7%) felt that their children's vision was fine. Ninety-seven (53.1%) parents indicated having no knowledge about child eye conditions and no significant association was found between level of education and knowledge of eye conditions affecting children (p = 0.112). Having an immediate family member who wore spectacles increased the likelihood of a child being taken for eye testing (p = 0.001), but decreased the likelihood of being well informed about eye health (p = 0.218). Of those parents who reported taking their children for eye tests, 34 (49.3%) reported that they were given eye drops and 31 (44.9%) stated that their children were prescribed spectacles. Eighty-seven (50.3%) parents accepted the idea of their children wearing spectacles. CONCLUSION: The findings of the study suggest the need for parents to be informed about basic child eye health care and the importance of their children having regular eye examinations. PMID- 30456971 TI - ? AB - Contexte: L'epidemie du virus de l'immunodeficience humaine au Mozambique est un probleme grave de sante publique et le Ministere de la Sante a etendu le traitement antiretroviral a tous les districts du pays. Cependant, on constate un nombre eleve d'abandon du traitement encore insuffisamment evalue. L'Organisation Mondiale de la Sante recommande que les tradipraticiens de sante collaborent avec les systemes nationaux de sante dans les pays en developpement, pour combattre cette epidemie, mais il existe peu d'actions dans ce domaine a ce jour.Objectif: Evaluer la connaissance des tradipraticiens sur l'infection et leur disponibilite a cooperer avec les services de sante dans la Province de Nampula au Mozambique, pour ameliorer les resultats du traitement antiretroviral.Lieux: Cinq centres de sante des districts de la Province de Nampula, au Nord du Mozambique, avec des taux eleves d'incidence du virus d'immunodeficience humaine et d'abandon du traitement.Methodes: Une etude mixte transversale, utilisant des interviews cibles et des discussions de groupes focaux. Les donnees quantitatives etaient traitees par frequence et les donnees qualitatives par analyse de discours et ethnographie locale.Resultats: Nous avons interviewe 79 tradipraticiens de sante. La perte de poids etait souvent consideree comme le signal principal de suspicion d'infection par le virus d'immunodeficience humaine et certains tradipraticiens ne pas les signes de la maladie ; la majorite pensait que les antiretroviraux ameliorent la qualite de vie des patients, ne pretendait pas traiter l'infection, savait qu'elle n'est pas curable, avait une idee sur le concept de bonne adhesion au traitement et referait les cas compliques au centre de sante. En ce qui concerne l'alimentation, la moitie considerait exclusivement les cereales comme l'aliment principal ; les fruits etaient importants pour un quart ; l'eau potable est ignoree. La majorite etait prete a collaborer avec le systeme de sante et avait des propositions de cooperation pratique : la qualification et la reconnaissance individuelle et la formation integree avec les professionnels de sante.Conclusion: Les tradipraticiens connaissaient l'infection par le virus d'immunodeficience humaine et les facteurs associes, mais il y a des lacunes. Ils ont signale qu'ils utilisaient principalement les plantes medicinales, ce qui peut contribuer au traitement des infections opportunistes et la majorite referait deja des patients au centre de sante ; mais la collaboration necessite une procedure educative et une articulation structuree. Les lacunes de connaissance empechent une cooperation efficace dans le combat contre l'epidemie. Le groupe est disponible pour cooperer avec le systeme de sante pour ameliorer les resultats du traitement antiretroviral, mais pour ca il est necessaire d'informer et former les tradipraticiens dans un processus integre de collaboration avec les professionnels de sante conventionnels. PMID- 30456972 TI - An audit of the management of ectopic pregnancies in a district hospital, Gauteng, South Africa. AB - BACKGROUND: Ectopic pregnancy (EP) is a life-threatening condition; at Odi Hospital, approximately 7-10 EPs are managed weekly. Our study is the first to assess the management of this life-threatening condition at Odi Hospital. AIM: This study aimed to determine the incidence of EP and to assess the profile of women who presented with EP at Odi District Hospital from 01 January 2010 to 31 December 2014. SETTING: The study was conducted at Odi District Hospital, located in Mabopane, a township in Gauteng province, 45 km north of Tshwane, South Africa (SA). METHODS: This was a cross-sectional study. RESULTS: We analysed 263 completed patient records. The incidence rate was 22 per 1000 live births. The mean age was 28.9 years (SD +/- 6.09), 57% were within the age group of 25-34 years, 90.9% were single and 85.2% were unemployed. Abdominal pain was the most common presenting complaint (81.1%). Ninety-nine (37.8%) were in a state of haemorrhagic shock. Possible risk factors were not documented in the patient files for 95%. A third (34.2%) were operated on within 4 hours of consultation. Early management was associated with poor record-keeping (p = 0.02). There was a delay in confirming the diagnosis in 48.7%. It was associated with gestational age (p = 0.0017), previous abdominal surgery (p = 0.0026), normal haemoglobin level at the time of consultation (p = 0.0024), considerable haemoperitoneum at operation (p < 0.00001) and per vaginal bleeding (p = 0.003). CONCLUSION: The study highlighted the need to emphasise the importance of good record-keeping and documentation in patients, as well as the urgent need for ultrasound skills training among clinicians to implement the Essential Steps in Managing Obstetric Emergencies programme at this hospital to improve the management of EP and other obstetric emergencies. PMID- 30456973 TI - How clinicians experience a simulated antiretroviral therapy adherence exercise: A qualitative study. AB - BACKGROUND: With the shift of paediatric antiretroviral therapy (ART) from tertiary to primary health care, there has been a need to train clinicians working in primary health care facilities to support adherence to treatment. An adherence simulation exercise was included in a course on paediatric human immunodeficiency virus (HIV) and tuberculosis (TB) to stimulate health care providers' awareness and generate empathy of complex paediatric adherence practices. AIM: The aim of this study was to describe the experience of clinicians completing the simulation exercise and to assess whether enhancing their empathy with patients and treatment supporters would improve their perceived clinical and counselling skills. SETTING: The study was conducted at the Faculty of Medicine and Health Sciences, Stellenbosch University, and a guesthouse in Cape Town. METHODS: The adherence module used blended learning methodology consisting of face-to-face contact sessions and distance learning. A qualitative thematic approach was used to understand the participant experiences through focus-group discussions and semi-structured interviews. RESULTS: Three thematic clusters emerged, namely, experiences of the simulated exercise, patient provider relationships and adherence strategies. Their experiences were both positive and challenging, especially when a 'caregiver and/or treatment supporter' scenario encouraged participants to reflect on their own relationships with their patients. Clinicians had also considered how empathy fits into their scope of responsibilities. Text messaging and adherence counselling strategies were identified. CONCLUSION: Simulated learning activities have the potential to create awareness of relationships between clinicians and their patients and generate ideas and discussion that could lead to improvements in clinical practice, and adherence promotion strategies. PMID- 30456974 TI - Outbreak of scurvy in Tana River County, Kenya: A case report. AB - Over a five-month period, clinicians in Tana River County Kenya observed an increasing number of patients presenting to health facilities with a common collection of symptoms including fevers, joint pains and gum hypertrophy. After initial investigative and management strategies failed to reveal a diagnosis, patients were empirically commenced on ascorbic acid for presumed scurvy. This strategy resulted in the rapid resolution of symptoms in 65 patients within two weeks. PMID- 30456975 TI - Building consensus for the development of child eye care services in South Darfur State of Sudan using the Delphi technique. AB - BACKGROUND: Global estimates suggest there are almost 19 million visually impaired children worldwide, most of whom reside in poor countries, with the major cause being treatable. AIM: To determine the barriers to accessing childhood eye care services and to develop an eye care plan for children in South Darfur State, Sudan. SETTING: The study took place in South Darfur State, Sudan. METHODS: The classical Delphi technique was used to build consensus on a list of statements, which were generated based on the themes established by the experts, as well as on an extensive literature review. RESULTS: Response rates ranged from 90% in the first round (n = 18), 100% in the second round (n = 18) to 89% in the third and final round (n = 16). The total number of statements recommended by the Delphi panellists for development of the paediatric eye care plan, was 60 based on a consensus level of 80% agreement or more. The expert's consensus on the following key elements for promotion and improvement of child eye care: The main barriers to accessing child eye care were high poverty rate, unavailability of child eye services and a lack of community awareness. The challenges facing visually impaired children were an absence of paediatric ophthalmologists, low vision and orthoptic services. CONCLUSION: The main barriers to accessing child eye care services were financial, clinical access and lack of knowledge. There should be greater collaboration between the Ministries of Health, Education and non-governmental organisations (NGOs), to work together in addressing these barriers. PMID- 30456976 TI - Perceptions about family-centred care among adult patients with chronic diseases at a general outpatient clinic in Nigeria. AB - BACKGROUND: Few studies in Africa have described patients' perceptions about family-centred care (FCC). AIM: The aim of this study was to explore perceptions of FCC among patients with chronic diseases. SETTING: The study was conducted at a general outpatient clinic (GOPC) in Jos, north-central Nigeria. METHODS: We used a mixed-methods phenomenological study design and conducted structured and semi-structured interviews with 21 adult patients with chronic diseases at a general outpatient clinic in north-central Nigeria. RESULTS: Patients described FCC using progressive levels of family engagement including the doctor inquiring about history of similar disease in the family, information sharing with family members and fostering of family ties. They described current family involvement in their care as either inquiring about their health, accompanying them to the clinic or offering material or social support and health advice. Also, patients considered the value of FCC based on how it meets information needs of the family, influences individual health behaviour and addresses family dynamics. Those who were literate and older than 50 years of age favoured FCC during history taking. Those who were literate, aged lesser than 50 years and had poor disease control showed preference for FCC during treatment decision-making. CONCLUSION: The acceptability of FCC is a complex synthesis of age, socio economic status, literacy and disease outcomes. Patients older than 50 years, with good treatment outcomes, and those without formal education may need further education and counselling on this approach to care. PMID- 30456977 TI - Distribution of cervical abnormalities detected by visual inspection with acetic acid in Swaziland, 2011-2014: A retrospective study. AB - BACKGROUND: Cervical cancer is the fourth most common cancer worldwide among women, with the number of new cases increasing from 493 243 in 2002 to 527 000 in 2012. These numbers are likely to be underestimated because given the lack of registration resources, cervical cancer deaths are usually under-reported in low income countries. AIM: To describe the distribution of and trends in visual inspection with acetic acid (VIA) to detected cervical abnormalities in Swaziland by reviewing records of VIA examinations performed at two main hospitals in Swaziland between 2011 and 2014. SETTING: Mbabane Government Hospital and Realign Fitkin Memorial (RFM). METHODS: Records of cervical screening using VIA at the Mbabane government hospital and RFM hospital between 2011 and 2014 were retrieved. Positivity rates (PRs) of VIA with 95% confidence intervals (95% CI) were calculated and used as proxies of cervical abnormalities. Odds ratios of the association between VIA-detected cervical abnormalities and human immunodeficiency virus (HIV) status were estimated using logistic regressions. RESULTS: VIA was positive in 1828 of 12 151 VIA records used for analysis (15%, 95% CI: 14.4-15.7). VIA was positive in 9% (36 of 403) women under the age of 20, in 15.5% (1714 of 11 046) of women aged 20-49 years and in 11.1% (78 of 624) of women aged 50-64 years. A decreasing trend of VIA positivity was observed over time at both screening centres (p for trend < 0.001). Of 2697 records with Papanicolaou results, 20% (67 of 331) VIA-positives and only 5% (114 of 2366) VIA negatives had high-grade squamous intraepithelial lesion. Among 4578 women with reported HIV status, 1702 were HIV-positive (37.2%, 95% CI: 35.8-38.6). The prevalence of HIV in VIA-positive women was 62.5% (95% CI: 58.7-66.2), almost double that among VIA-negative women (33.0%, 95% CI: 31.6-34.5) and that among all women screened (p < 0.001). HIV-positive women were 3.4 times more likely to have cervical abnormalities on VIA than HIV-negative women (OR: 3.4, 95% CI: 2.8 4.0, p < 0.01). CONCLUSION: The high VIA PRs observed over four years in this study may reflect the prevalence of cervical abnormalities, in particular, in HIV positive women. VIA is not a robust screening test, but it can play a major role in strengthening and expanding cervical cancer screening prevention programmes in resource-limited countries. PMID- 30456978 TI - Detection of Salmonella from animal sources in South Africa between 2007 and 2014. AB - Retrospective laboratory-based surveillance was conducted on Salmonella serotypes isolated from various animal species from 2007 to 2014 at the Agricultural Research Council, Onderstepoort Veterinary Research Institute, South Africa. During the surveillance period, 1229 salmonellae isolations were recorded. Around 108 different serotypes were recovered from nine different food and non-food animal host species. The three most common serotypes were Salmonella entericasubspecies enterica serotype Heidelberg (n = 200), Salmonella enterica subspecies enterica serotype Enteritidis (n = 170) and Salmonella enterica subspecies enterica serotype Typhimurium (n = 146). These were followed by Salmonella enterica subspecies enterica serotype Anatum (n = 62) and Salmonella entericasubspecies enterica serotype Infantis (n = 57). Salmonella enterica subspecies enterica serotype Schwarzengrund and Salmonella enterica subspecies entericaserotype Muenchen were recovered in 50 and 48 cases, respectively. Of the total number of isolations recorded during the period under review, 871 (70.8%) occurred in poultry and other birds, 162 (13.2%) in horses, 116 (9.4%) in cattle, 26 (2.1%) in sheep and goats, 22 (1.8%) in rhinoceroses, 16 (1.3%) in pigs, 8 (0.6%) in crocodiles, 6 (0.5%) in cats and 6 (0.5%) in leopards. Food animals accounted for 83.5% of the total isolations, with cattle and poultry representing approximately 72.7%. Forty-two (3.4 %) isolates were found from non-food animals that include rhinoceroses (n = 22), crocodiles (n = 8), leopards (n = 6) and cats (n = 6). Salmonella Heidelberg was the most frequently isolated serotype, whereas S. Typhimurium had the widest zoological distribution. Clinical laboratory isolation of different Salmonella serotypes from various hosts may aid in recognising the threat to livestock, public and environmental health. Moreover, it may also highlight the potential zoonotic and food safety risk implications of the detected Salmonella serotypes. PMID- 30456979 TI - Laparoscopic repositioning of chronic gastric volvulus in a dog. AB - A 12-year-old spayed Newfoundland bitch was presented with chronic non-productive vomiting, regurgitation and coughing of six weeks' duration. On clinical examination, the dog was depressed with no other significant findings. Haematology and biochemistry investigations detected no abnormalities. Thoracic and abdominal radiographs revealed a megaoesophagus and an abnormally positioned pylorus. A thoracic and abdominal computed tomography scan confirmed the abnormal position of the stomach, together with moderate aspiration pneumonia. Laparoscopic examination of the peritoneal cavity revealed the greater omentum wrapped over the stomach, with a fold visualised between the abnormally positioned pyloric antrum and the gastric corpus. A 180-degree clockwise gastric rotation was laparoscopically diagnosed and corrected. The normal position of the stomach was confirmed before a laparoscopic-assisted incisional gastropexy was performed. Post-operatively the vomiting and regurgitation resolved and the patient was discharged. Twenty-four hours after discharge, the dog was presented with deteriorating clinical signs of aspiration pneumonia. The owner declined treatment, additional diagnostics as well as a necropsy and requested euthanasia. Chronic gastric volvulus should be considered as a rare differential diagnosis in dogs with non-specific, chronic gastrointestinal signs. Radiography, computed tomography and laparoscopy are valuable diagnostic aids in making this diagnosis. Chronic gastric volvulus can be successfully reduced laparoscopically as reported here for the first time. PMID- 30456980 TI - Use of butorphanol and diprenorphine to counter respiratory impairment in the immobilised white rhinoceros (Ceratotherium simum). AB - Opioid-induced immobilisation results in severe respiratory impairment in the white rhinoceros. It has therefore been attempted in the field to reverse this impairment with the use of opioid agonist-antagonists, such as nalorphine, nalbuphine, butorphanol and diprenorphine; however, the efficacy of some of these treatments has yet to be determined. The efficacy of butorphanol, either alone or in combination with diprenorphine both with and without oxygen insufflation, in alleviating opioid-induced respiratory impairment was evaluated. The study was performed in two parts: a boma trial and a field trial. Rhinoceroses were immobilised specifically for the study, according to a strict protocol to minimise confounding variables. A two-way analysis of variance was used to compare the physiological responses of the rhinoceroses to the different treatments and their effects over time. The intravenous administration of butorphanol (at 3.3 mg per mg etorphine) plus diprenorphine (at 0.4 mg per mg etorphine) did not offer any advantage over butorphanol (at 15 mg per mg etorphine) alone with regard to improving PaO2, PaCO2 and respiratory rates in etorphine-immobilised white rhinoceroses. Both butorphanol + diprenorphine + oxygen and butorphanol + oxygen, at the doses used, significantly improved the etorphine-induced hypoxaemia in both boma- and field-immobilised white rhinoceroses. Clinically acceptable oxygenation in field-immobilised white rhinoceroses can be achieved by using either treatment regimen, provided that it is combined with oxygen insufflation. PMID- 30456981 TI - The knowledge, perceptions and relationship behaviour of rugby and football players towards HIV infection at the University of Limpopo. AB - BACKGROUND: Sport has the capability to unite a country. To achieve winning teams, athletes have to rely on each other and often have close physical contact. Disclosure of a positive human immunodeficiency virus (HIV) status may be problematic for athletes in contact sports as they may suffer discrimination and stigmatisation which may impact their relationship behaviours. This may impact frontline nursing and medical staff dealing with on-field 'blood' injuries. OBJECTIVES: The purpose of this study was to determine if individuals who participate in football and rugby are aware of the risk of HIV infection in contact sports and their perceptions and reported behaviour towards HIV-positive athletes. METHOD: A cross-sectional survey design with a qualitative element. Quantitative data were analysed using descriptive statistics, while thematic content analysis was used to analyse qualitative data.Non-proportional quota sampling was used for male rugby (n = 23) and football (30) players registered at the University of Limpopo (Turfloop campus). RESULTS: The results supported previous research in that there are gaps in HIV knowledge. For instance, not knowing that anal sex may cause HIV infection and believing that saliva can transmit HIV and that blood transfusions are unsafe. CONCLUSION: Problematic findings were that a portion of the sample believed that having sex with a virgin could cure HIV and the majority of the sample believed that being 'bewitched' could cause HIV and acquired immunodeficiency syndrome (AIDS). PMID- 30456982 TI - Undergraduate nursing students' experience of clinical supervision. AB - BACKGROUND: Clinical supervision plays a major role in the undergraduate nursing programme. There have been some local studies addressing clinical supervision; however, there still remains a lack of knowledge and understanding how to improve quality supervision of undergraduate nursing students. This article is based on the authors' original thesis. OBJECTIVES: The objective of the study was to explore the experiences of undergraduate nursing students on clinical supervision. METHOD: A descriptive design with a qualitative approach using focus group interviews was used to explore the experiences of undergraduate nursing students regarding clinical supervision. Purposive sampling was used for selection of 36 participants. The participants needed to be enrolled at the institution under study, at the time of the study, as undergraduate nursing students in order to meet the inclusion criteria. The participants also needed to have worked at clinical facilities where they received clinical supervision. Nine (n = 9) students were purposively selected from each year level to participate in focus group interviews. The interviews were analysed using content analysis. RESULTS: The findings indicated both positive and negative experiences regarding clinical supervision. The results were tabulated in which the positive experiences were grouped together and were separated from the negative experiences of the undergraduate students. Positive experiences included the support that was received from supervisors. These were, however, overshadowed by many comments on negative experiences concerning the behaviour and competencies of the supervisors. The findings also confirmed that the students experienced differences in the clinical procedures demonstrated by various supervisors. Negative experiences that relate to abusive behaviour such as misuse of power were also found, as well the incongruence amongst clinical supervisors regarding clinical procedures. Recommendations were proposed to enhance clinical supervision and the learning experiences of student nurses. CONCLUSION: The study findings suggest a need for continuous professional development for clinical supervisors by means of in-service training as well as to maintain congruence by clinical supervisors when demonstrating clinical procedures. PMID- 30456983 TI - Stigma and chronic illness: A comparative study of people living with HIV and/or AIDS and people living with hypertension in Limpopo Province, South Africa. AB - BACKGROUND: Stigma among people with chronic illnesses exists, preventing many sufferers from presenting for treatment especially in South Africa. OBJECTIVES: This study compared stigma experiences of people living with human immunodeficiency virus and/or acquired immunodeficiency syndrome (HIV and/or AIDS) (PLWHA) and people living with hypertension (PLWHPT) in Limpopo Province of South Africa. METHOD: Using a cross-sectional design, 600 participants (300 PLWHA with mean age of 31 years, standard deviation of 8.2; and 300 PLWHPT with age of 55 years, standard deviation of 8.1) were purposefully sampled at HIV and/or AIDS and hypertension outpatient clinics. The perceived stigma of AIDS scale was used to assess stigma in the HIV and/or AIDS sample while the adapted version was used to assess stigma in PLWHPT. Data were analysed using independent t-test. RESULTS: Results indicated that PLWHA experienced significantly higher enacted stigma (t(598) = -11.79, p < 0.001) as compared to PLWHPT. However, PLWHPT experienced significantly higher internalised stigma (t(598) = 37.56, p < 0.001) and perceived stigma (t(598) = 41.71, p < 0.001) than PLWHA. CONCLUSION: Stigma among people with chronic illnesses is existent. The stigma type is, however, dependent on the nature of the illness. Stigma reduction interventions among these populations are indicated. PMID- 30456984 TI - Long term survival after early unloading with Impella CP(r) in acute myocardial infarction complicated by cardiogenic shock. AB - BACKGROUND:: The use of percutaneous left ventricular assist devices in patients with acute myocardial infarction complicated by cardiogenic shock (AMICS) is evolving. The aim of the study was to assess the long-term outcome of patients with AMICS depending on early initiation of Impella CP(r) support prior to a percutaneous coronary intervention (PCI). METHODS:: We retrospectively reviewed all patients who underwent PCI and Impella CP(r) support between 2014 and 2016 for AMICS at our institution. We compared survival to discharge between those with support initiation before (pre-PCI) and after (post-PCI) PCI. RESULTS:: A total of 73 consecutive patients (69+/-12 years old, 27.4% female) were supported with Impella CP(r) and underwent PCI for AMICS (34 pre-PCI vs. 39 post-PCI). All patients were admitted with cardiogenic shock, and 58.9% sustained cardiac arrest. Survival at discharge was 35.6%. Compared with the post-PCI group, patients in the pre-PCI group had more lesions treated ( p=0.03), a higher device weaning rate ( p=0.005) and higher survival to discharge as well as to 30 and 90 days after device implantation, respectively (50.0% vs. 23.1%, 48.5% vs. 23.1%, 46.9 vs. 20.5%, p < 0.05). Kaplan-Meier analysis showed a higher survival at one year (31.3% vs. 17.6%, log-rank p-value=0.03) in the pre-PCI group. Impella support initiation before PCI was an independent predictor of survival up to 180 days after device implantation. CONCLUSIONS:: In this small, single-centre, non randomized study Impella CP(r) initiation prior to PCI was associated with higher survival rates at discharge and up to one year in AMICS patients presenting with high risk for in-hospital mortality. PMID- 30456985 TI - Myeloperoxidase activity and acute coronary syndrome survival: long-term evaluation in the ERICO study. AB - AIM: We aimed to analyze the influence of myeloperoxidase (MPO) activity on mortality in the Acute Coronary Syndrome Registry Strategy (ERICO) study. METHODS: MPO activity levels were evaluated in 342 patients. We performed survival analyses using Kaplan-Meier curves and Cox regression with respective hazard ratios, 95% CI, according to MPO tertiles distribution up to 7 years of follow-up. RESULTS: Higher MPO activity levels were seen in men, smokers, diabetics and those who were taking aspirin. MPO activity levels were neither significant in relation to mortality nor to survival rates up to seven years. CONCLUSION: We found no relationship between elevated levels of MPO activity post acute coronary syndrome and mortality up to 7-years of follow-up in the ERICO study. PMID- 30456986 TI - Epigenetic meta-analysis across three civilian cohorts identifies NRG1 and HGS as blood-based biomarkers for post-traumatic stress disorder. AB - AIM: Trauma exposure is a necessary, but not deterministic, contributor to post traumatic stress disorder (PTSD). Epigenetic factors may distinguish between trauma-exposed individuals with versus without PTSD. MATERIALS & METHODS: We conducted a meta-analysis of PTSD epigenome-wide association studies in trauma exposed cohorts drawn from civilian contexts. Whole blood-derived DNA methylation levels were analyzed in 545 study participants, drawn from the three civilian cohorts participating in the PTSD working group of the Psychiatric Genomics Consortium. RESULTS: Two CpG sites significantly associated with current PTSD in NRG1 (cg23637605) and in HGS (cg19577098). CONCLUSION: PTSD is associated with differential methylation, measured in blood, within HGS and NRG1 across three civilian cohorts. PMID- 30456987 TI - Effectiveness of video-based modelling to facilitate conversational turn taking of adolescents with autism spectrum disorder who use AAC. AB - This study evaluated and compared the effectiveness of packaged video modelling (VM) and video self-modelling (VSM) interventions to develop conversational behaviors with four adolescents with autism spectrum disorder (ASD) who used augmentative and alternative communication (AAC). The study was conducted using an alternating treatments design nested within a multiple baseline design. The intervention effect was measured using Robust-Improvement Rate Difference (R IRD). The results demonstrated that, overall, video-based modelling used in conjunction with a system of least prompts was effective in promoting conversation skills in adolescents with ASD who used AAC. Without the systematic instruction, R-IRD indicated that these techniques yielded only small to moderate intervention effects. The findings demonstrated the necessity of systematic instruction for this group of participants. This investigation provides preliminary evidence to support the use of packaged video-based modelling interventions to develop conversation skills in adolescents with ASD who use AAC systems. PMID- 30456988 TI - Characterization and toxicology evaluation of zirconium oxide nanoparticles on the embryonic development of zebrafish, Danio rerio. AB - Zirconia oxide nanoparticles (ZrO2NPs) are known to be one of the neutral bioceramic metal compounds that has been widely used for their beneficial applications in many biomedical areas, in dental implants, bone joint replacements, drug delivery vehicles, and in various industrial applications. To study the effects of ZrO2NPs on zebrafish model, we used early life stages of the zebrafish (Danio rerio) to examine such effects on embryonic development in this species. ZrO2NPs were synthesized by the sol-gel method, size about 15-20 nm and characterized by SEM, EDX, XRD, FTIR, UV-Vis Spectra. In this study, zebrafish embryos were treated with ZrO2NPs 0.5, 1, 2, 3, 4, or 5 MUg of nanoparticles/ml during 24-96 hour post fertilization (hpf). The results showed that >=0.5-1 MUg/ml of ZrO2NPs instigated developmental acute toxicity in these embryos, causing mortality, hatching delay, and malformation. ZrO2NPs exposure induced axis bent, tail bent, spinal cord curvature, yolk-sac, and pericardial edema. A typical phenotype was observed as an unhatched dead embryo at >=1 MUg/ml of ZrO2NPs exposure. This study is one of the first reports on developmental toxicity of zebrafish embryos caused by zirconium oxide nanoparticles in aquatic environments. Our results show that exposure of zirconium oxide nanoparticles is more toxic to embryonic zebrafish at lower concentrations. The results will contribute to the current understanding of the potential biomedical toxicological effects of nanoparticles and support the safety evaluation and synthesis of Zirconia oxide nanoparticles. PMID- 30456989 TI - Design, synthesis and cholinesterase inhibitory activity of alpha-mangostin derivatives. AB - alpha-mangostin, a polyphenol xanthone derivative, was mainly isolated from pericarps of the mangosteen fruit (Garcinia mangostana L.). In present investigation, a series of derivatives were designed, synthesised and evaluated in vitro for their inhibitory activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among the synthesised xanthones, compounds 1, 9, 13 and 16 showed AChE selective inhibitory activity, 15 was a BuChE selective inhibitor while 2, 3, 5, 6, 7, 12 and 14 were dual inhibitors. The most potent inhibitor of AChE was 16 while 5 was the most potent inhibitor of BuChE with IC50 values of 5.26 MUM and 7.55 MUM respectively. PMID- 30456991 TI - Avascular necrosis post unstable slipped capital femoral epiphysis: a treatment algorithm with staged hinged hip distraction: mid-term results. AB - BACKGROUND:: Management of avascular necrosis (AVN) of the femoral head in slipped capital femoral epiphysis (SCFE) is difficult. We proposed to ascertain if staged hip distraction could prevent collapse and recover the femoral head. METHODS:: A retrospective review of the hip database retrieved 16 children with unstable SCFE and AVN. All underwent capital realignment by surgical dislocation followed by 2nd-stage hinged hip distraction. Patient demographics and radiographic parameters of deformity, AVN and arthritis were collected. The patients scored their hip function both before and after intervention and at follow-up using the modified Harris Hip Score and Nonarthritic Hip score. RESULTS:: 7 boys and 9 girls formed the study group ( n = 16). The average age at surgery was 12.7 years (9-16 years). 8 rights hips and 8 left hips were involved. The average follow-up was 45 months (33-66 months). Group A ( n = 7) had hip distraction only if the follow-up radiographs showed AVN changes and collapse. Based on the observations in Group A, the protocol was changed for Group B. Group B ( n = 9) underwent hip distraction at 6 weeks of capital realignment for avascularity of the femoral head. In Group A, all patients had further collapse and advanced arthritis at follow-up. In Group B all patients had hip joint space restored and good hip function without pain at follow-up. CONCLUSIONS:: Pre emptive application of hip distractor for those children with proven lack of blood flow to the femoral head is a potential option to stall the progression of AVN and to help recover useful hip function. PMID- 30456990 TI - Chemical composition and antifungal activity of essential oils from Senecio nutans, Senecio viridis, Tagetes terniflora and Aloysia gratissima against toxigenic Aspergillus and Fusarium species. AB - Essential oils from aerial parts of Senecio nutans, Senecio viridis, Tagetes terniflora and Aloysia gratissima were analysed by GC-MS and their antifungal activities were assayed on toxigenic Fusarium and Aspergillus species. Sabinene (27.6 +/- 0.1%), alpha-phellandrene (15.7 +/- 0.3%), o-cymene (9.6 +/- 0.2%) and beta-pinene (6.1 +/- 0.2%) in S. nutans, 9,10-dehydrofukinone (92.7 +/- 0.2%) in S. viridis, beta-thujone (36.1 +/- 0.1%), alpha-thujone (32.2 +/- 0.2%), 1,8 cineol (10.7 +/- 0.1%) and sabinene (6.2 +/- 0.2%) in A. gratissima, and cis tagetone (33.6 +/- 0.2%), cis-beta-ocimene (17.1 +/- 0.2%), trans-tagetone (17.0 +/- 0.1%), cis-ocimenone (8.0 +/- 0.2%) and trans-ocimenone (8.2 +/- 0.1%) in T. terniflora. The oils showed moderate antifungal activity (1.2 mg/mL > MIC >0.6 mg/mL) on the Fusarium species and a weak effect on Aspergillus species. The antifungal activity was associated on F. verticillioides to the high content of cis-tagetone, trans-tagetone, cis-beta-ocimene, cis-ocimenone, trans-ocimenone and on F. graminearum due to the total content of oxygenated sesquiterpenes and 9,10- dehydrofukinone. The oil of S. viridis synergized the effect of fungicides and food preservatives on F. verticillioides. PMID- 30456992 TI - Dynamic Regulation Responding to an External Stimulus: A Differential Equation Model. AB - This study examines the dynamic regulation process responding to an external stimulus. The damped oscillator model has been used to describe this process. However, the model does not allow a nonzero steady state, even though the oscillations may continue and do not necessarily damp toward zero. This study introduces the driven damped oscillator model which has an additional parameter to identify different patterns of the steady state. Three methods, generalized local linear approximation, continuous time structural equation modeling, and analytic solutions of differential equations are provided to estimate model parameters. A simulation study indicates that parameters in the driven damped oscillator model are well recovered. The model is then illustrated using a data set on the daily reports of sales after a sale promotion. Potential applications and possible expansions of this model are also discussed. PMID- 30456994 TI - Theme 14 Palliative care and decision making. PMID- 30456993 TI - The level of evidence of medical marijuana use for treating disabilities: a scoping review. AB - PURPOSE: Twenty-nine states have bypassed federal regulations by legalizing marijuana (MJ) either medicinally, recreationally or both. The FDA states that there is no empirical evidence that MJ is effective to treat these disorders. With over a billion individuals living with a disability across the globe, it is crucial to fully research the efficaciousness and safety of medical MJ to treat this population. The purpose to present the results of a scoping review of studies focused on the levels of evidence currently available on medical MJ's efficacy in treatment across a large range of disabilities. METHODS: Databases were searched for research articles on the current level of evidence to support medical MJ use among people with disabilities. RESULTS: Forty-one peer reviewed articles met the inclusion criteria. Articles focused on attention deficit hyperactivity disorder, post-traumatic stress disorder, depression, schizophrenia, spinal cord injury, multiple sclerosis/movement disorders, fibromyalgia, epilepsy, with some that focused on multiple disabilities. CONCLUSIONS: The level of evidence for the use of medical MJ among people with disabilities varies greatly, and has a clear lack of methodologically sound studies. Overall, medical MJ does not improve the level of functioning, but it may improve the overall quality of life for people with disabilities. Implications for Rehabilitation Epilepsy can be a disabling chronic disorder which not only impacts physically but can restricts quality of life. Quality of life is diminished even more with treatment resistant epilepsy. Chronic pain is the leading cause of disability and is the most common cause of long-term disability. There is sufficient evidence that medical marijuana is effective in treating epileptic seizures and chronic pain. Medical marijuana may improve the level of functioning and quality of life for individuals with certain disabilities. PMID- 30456995 TI - Theme 1 Genetics and genomics. PMID- 30456996 TI - Theme 6 Tissue biomarkers. PMID- 30456997 TI - Theme 13 Clinical management and support. PMID- 30456998 TI - Theme 5 Epidemiology and informatics. PMID- 30456999 TI - Theme 12 Respiratory and nutritional management. PMID- 30457000 TI - Theme 4 Human cell biology and pathology. PMID- 30457001 TI - Theme 11 Cognitive and psychological assessment and support. PMID- 30457002 TI - Theme 3 In vivo experimental models. PMID- 30457003 TI - Theme 10 Disease stratification and phenotyping. PMID- 30457005 TI - Theme 2 In vitro experimental models. PMID- 30457004 TI - Poster Author Index. PMID- 30457006 TI - Poster Contents Page. PMID- 30457007 TI - Oral Sessions. PMID- 30457008 TI - Theme 9 Clinical trials and trial design. PMID- 30457009 TI - Theme 8 Clinical imaging and electrophysiology. PMID- 30457011 TI - Theme 7 Pre-clinical therapeutic strategies. PMID- 30457010 TI - Poster Subject Index. PMID- 30457012 TI - Session Subject Index. PMID- 30457013 TI - Session Author Index. PMID- 30457014 TI - Coffee, Green Tea, and Caffeine Intake and Liver Cancer Risk: A Prospective Cohort Study. AB - We aimed to investigate whether coffee, green tea, and caffeine intake are associated with liver cancer risk, using data of a prospective cohort study. This study included 30,824 participants (14,240 men and 16,584 women) aged 35 years or older in the Takayama study, which was launched on September 1, 1992. The consumption frequencies of coffee and green tea were assessed using a self administered questionnaire. Caffeine intake was estimated from the consumption frequencies of caffeine-containing beverages and foods and their caffeine content per serving. The incidence of liver cancer was confirmed using regional population-based cancer registries. During the follow-up period of 16 years, a total of 172 participants developed liver cancer. The adjusted hazard ratios and 95% confidence intervals (CIs) in relation to coffee consumption were 0.65 (95% CI: 0.46-0.93) for less than once per day, 0.63 (95% CI: 0.39-1.02) for once per day, and 0.40 (95% CI: 0.20-0.79) for twice per day or more, compared with nondrinkers. No associations with green tea, black tea and caffeine intake were observed. The present study confirmed that coffee consumption significantly reduces liver cancer risk and raises the possibility that caffeine intake might not account for the association. PMID- 30457015 TI - A Ciliary Motility Index for Activity Measurement in Cell Cultures With Respiratory Syncytial Virus. AB - BACKGROUND: The respiratory epithelium is frequently infected by the respiratory syncytial virus, resulting in inflammation, a reduction in cilia activity and an increase in the production of mucus. METHODS: In this study, an automatic method has been proposed to characterize the ciliary motility from cell cultures by means of a motility index using a dense optical flow algorithm. This method allows us to determine the ciliary beat frequency (CBF) together with a ciliary motility index of the cells in the cultures. The object of this analysis is to automatically distinguish between normal and infected cells in a culture. RESULTS: The method was applied in 2 stages. It was concluded from the first stage that the CBF is not a good enough indicator to discriminate between the control and infected cultures. However, the ciliary motility index does succeed in discriminating between the control and infected cultures using the t test with a value t = 6.46 and P < .001. In the second stage, it has been shown that the ciliary motility index did not differ significantly between patients, and the analysis of variance test gives alpha = 0.05, F = 1.61, P = .20. A threshold for this index has been determined using a receiver operating characteristics analysis that gives an area under the curve of 0.93. CONCLUSIONS: We have obtained a ciliary motility index that is able to discriminate between control and infected cultures after the eighth postinfection day. After infection, there is a rapid cilia loss of the cells and the measured CBF corresponds to the remaining noninfected cells. This is why the CBF does not discriminate between the control and the infected cells. PMID- 30457016 TI - Inter-professional communication and interaction in the neurological rehabilitation team: a literature review. AB - BACKGROUND: Neurological early rehabilitation aims at regaining cooperativity and acquiring rehabilitation capability with brain-injured patients, most of whom are transferred from Intensive Care Units, most of whom still require intensive care and suffer from disorders of consciousness. In neurological early rehabilitation, therapeutic nursing is an integral part of the therapeutic team. Other than the specialized therapists, nurses are present on the ward 24/7, which gives them a closer perspective on the patient. The research question was how do nurses, physiotherapists, occupational therapists and speech therapists communicate and interact as teams in neurological rehabilitation wards. A literature review was conducted aiming at inter-professional communication and interaction with special regard to the role of these four professionals being the core team members in these settings. METHODS: A literature search was conducted in the period from August to October 2016 within the following electronic Databases: Medline, CINAHL, PSYNDEX, SpeechBITE, PEDro und OTseeker. Further searches were undertaken in the reference lists of obtained studies to locate other relevant material. The aim was to gather and evaluate the evidence about inter-professional teamwork in neurological early rehabilitation. The main inclusion criterion was the presence of the following professionals as participants in the study: Nurses, physiotherapists, occupational therapists and speech therapists. Twenty-seven studies were found relevant, of which 17 (12 qualitative and five quantitative) bore empirical results that related to the research questions. These 17 studies were qualitatively analysed for the grade of evidence, methods and the relevance for the conditions and processes in rehabilitation units. Out of 17 studies, four were performed in neurological rehabilitation settings, five in stroke units, six in general rehabilitation, one in short-term care rehabilitation and one in geriatric rehabilitation. Due to the scarcity of material, all these studies were analysed under the perspective of relevance for neurological early rehabilitation. RESULTS: The results of this exploratory literature review indicate that the efficiency and quality of cooperation in rehabilitation teams could be improved through a better patient-oriented inter-professional communication. This is achieved through cross-professional team organization, team supervision and by including team communication in vocational and on-the-job training. Profession-specific terminologies and differences in understanding of roles could be barriers for collaboration in teams. CONCLUSIONS: According to this literature review, successful inter-professional patient-orientated care is promoted by being informed about the various functions of team members from different disciplines, about the role each member plays within the team and communication styles. Means of improving communication are being outlined. Implications for Rehabilitation Inter-professional communication is promoted by cross-professional team organization. Inter-professional communication should be included in vocational and on-the-job-training and supervision. Barriers for communication in teams are different terminologies and differences in role perception. PMID- 30457017 TI - Bridging the intention-behavior gap for cardiac rehabilitation participation: the role of perceived barriers. AB - PURPOSE: Patients referred to cardiac rehabilitation after an acute coronary syndrome event commonly report strong intention to attend, but at least one-third do not participate. This study explored whether well-documented cardiac rehabilitation barriers (e.g., comorbidities, logistical/time constraints, and low social support) moderate the association between intention to participate and actual program enrollment and attendance. METHOD: Following referral but prior to commencing a 12-week outpatient cardiac rehabilitation program, 100 patients with acute coronary syndrome completed measures of intention to attend cardiac rehabilitation, perceived cardiac rehabilitation barriers, and social support. Program enrollment and attendance were determined by chart review. RESULTS: Despite high reported intention to attend (M = 6.08/7.00, SD = 1.80), nearly one in-five did not enroll. Weaker intention to attend (b = 0.46, SE = 0.16, p = 0.004) and greater cardiac rehabilitation barriers (b= -1.67, SE = 0.70, p = 0.017) corresponded to lower program enrollment. Similarly, weaker intention (b = 2.29, SE = 0.50, p < 0.001) and greater barriers (b =-6.19, SE = 1.55, p < 0.001) predicted poorer attendance. Barriers moderated the association between intention to participate and cardiac rehabilitation enrollment (b=-0.60, SE = 0.29, p = 0.037) and attendance (b = -3.12, SE = 1.02, p = 0.003). CONCLUSIONS: Perceived cardiac rehabilitation barriers influence whether patients successfully translate their intention to attend into actual program participation. Enhancing self efficacy to overcome barriers may represent an important intervention target among prospective cardiac rehabilitation patients. Implications for Rehabilitation Patients with acute coronary syndrome report strong intention to attend cardiac rehabilitation upon referral, yet cardiac rehabilitation programs remain underutilized. Assessing and addressing perceived barriers during the transition to cardiac rehabilitation, even when patients present as highly motivated to attend, may be critical to promoting program uptake. Rehabilitation professionals should ask patients about specific barriers to attending cardiac rehabilitation (e.g., financial constraints, transportation problems) and provide individualized solutions (e.g., fee subsidization, home- or web-based programs) to increase participation. PMID- 30457018 TI - Comparative pharmacokinetic evaluation of extended release itopride HCl pellets with once daily tablet formulation in healthy human subjects: a two treatment, four period crossover study in fasted and fed condition. AB - OBJECTIVE: In this study, pharmacokinetics (PKs) and bioavailability of newly developed extended release (ER) Itopride HCl 150 mg encapsulated ER pellets (test) and 150 mg Ganaton ER once-daily (OD) tablets (reference) were compared and evaluated under fasted and fed conditions. METHODS: Twelve healthy human subjects were enrolled in a single dose, randomized; two treatments, two sequences, four period crossover study. A modified and validated liquid chromatographic method was used for the estimation of Itopride HCl in plasma samples. The data were analyzed through non-compartmental model using PK software Phoenix Winnonlin version 7. The outcome was measured on logarithmically transformed data, where p > 0.05 was considered as non-significant with 90% CI limit of 0.8-1.25. RESULTS: The Cmax, AUC0-t, and AUC0-infinity values of Itopride HCl 150 mg ER pellets versus that of OD 150 mg tablets, in fed and fasted states, were within the limits specified by FDA to establish bioequivalence. The relative bioavailability of Itopride HCl 150 mg ER pellets were 1.019 (fed) and 1.081(fasted). The 90% CIs of AUC values for Itopride HCl 150 mg ER pellets and OD 150 mg tablets in fed versus fast were significantly greater and were not within 80-125% limit. CONCLUSION: The test and reference formulations had similar pharmacokinetic parameters in each condition studied. However, an increase in the amount of drug was observed in the fed state. PMID- 30457019 TI - Complete polypectomy and early detection and management of residual disease to reduce the risk of interval colorectal cancers. AB - Advances in colorectal polyp detection and resection methods aim to reduce interval cancer rates. Complete polypectomy is essential to reduce the risk of early recurrence and the development of interval cancers. To achieve this, polyps must first be correctly identified and then completely excised. This article reviews current adenoma detection methods in use and the management of residual disease. PMID- 30457020 TI - The SHA2PE score: a new score for lower gastrointestinal bleeding that predicts low-risk of hospital-based intervention. AB - OBJECTIVES: Lower gastrointestinal bleeding (LGIB) risk scores have mainly focused on identifying high-risk patients. A risk score aimed at predicting which patients will not require hospital-based intervention may reduce unnecessary hospital admissions. The aim of the current study was to develop such a risk score. MATERIAL AND METHODS: A retrospective, population-based study that included patients presenting to the emergency room (ER) with LGIB from 2010 to 2013. Hospital-based intervention was defined as blood transfusion, endoscopic hemostasis, arterial embolization or surgery. The study cohort was split into train (70%) and test (30%) data. Train data were used to produce a multiple logistic regression model and a risk score that was validated on the test data. RESULTS: Overall, 581 patients presented 625 times to the ER, mean age 61 (+/ 22), males 49%. Of train data patients, 72% did not require hospital-based intervention. Independent predictors of low-risk patients (did not require hospital-based intervention) were systolic pressure >=100mmHg (Odds ratio [OR] 4.9), hemoglobin >12g/dL (OR 103), hemoglobin 10.5-12.0g/dL (OR 19), no antiplatelets (OR 3.7), no anticoagulants (OR 2.2), pulse <=100 (OR 2.9), and visible bleeding in the ER (OR 3.8). When validating the score on the test data, only 2% were wrongly predicted to be low-risk, the negative predictive value was 96% and the area under curve was 0.83. CONCLUSIONS: A new risk score has been developed for LGIB that may help identify low-risk patients in the ER that can be managed in an outpatient setting, thereby lowering unnecessary hospital admissions. PMID- 30457021 TI - PDK2 induces Cisplatin-resistance in lung adenocarcinoma via transcriptional regulation of CNNM3. AB - Recurrence of lung adenocarcinoma has become one of the most frequent causes of major cancer incidence and mortality worldwide according to its frequently gained resistance to chemotherapies. In this study, we identified a poorly-studied kinase pyruvate dehydrogenase kinase isoform 2 (PDK2) as the most up-regulated kinase encoding gene in Cisplatin resistant lung adenocarcinoma. Additionally, PDK2-dependent Cisplatin-resistance promotes tumor growth of lung adenocarcinoma both in vitro and in vivo. Clinically, PDK2 expression was up-regulated in lung adenocarcinoma and was correlated to the poor prognosis of lung cancer patients. Mechanically, PDK2 promoted cell growth and Cisplatin-resistance of lung adenocarcinoma via transcriptional regulation of cyclin and CBS domain divalent metal cation transport mediator 3 (CNNM3), indicating that PDK2-CNNM3 signaling axis could be a potential therapeutic target for Cisplatin-resistant lung adenocarcinoma. PMID- 30457022 TI - A novel sex difference in Drosophila contact chemosensory neurons unveiled using single cell labeling. AB - Among the sensory modalities involved in controlling mating behavior in Drosophila melanogaster, contact sex pheromones play a primary role. The key receptor neurons for contact sex pheromones are located on the forelegs, which are activated in males upon touching the female abdomen during tapping events in courtship actions. A fruitless (fru)-positive (fru [+]) male-pheromone sensing cell (M-cell) and a fru [+] female-pheromone sensing cell (F-cell) are paired in a sensory bristle on the legs, and some fru [+] chemoreceptor axons project across the midline in the thoracic neuromere in males but not in females. However, the receptor cells that form sexually dimorphic axon terminals in the thoracic ganglia remain unknown. By generating labeled single-cell clones, we show that only a specific subset of fru [+] chemosensory neurons have axons that cross the midline in males. We further demonstrate that there exist two male specific bristles, each harboring two chemosensory neurons; neither of which exhibits midline crossing, a masculine characteristic. This study reveals hitherto unrecognized sex differences in chemosensory neurons, imposing us to reinvestigate the pheromone input pathways that impinge on the central courtship circuit. PMID- 30457023 TI - Psoriasis and cardiovascular disease: the elusive link. AB - Psoriasis, an autoimmune inflammatory disease, with its most common coexisting condition, psoriatic arthritis, seem to be more than just a local skin or joint disease, as evidence has accumulated over the years that it is associated with cardiovascular disease (CVD), which may confer an increased cardiovascular event and death rate. The data come mostly from observational studies and meta-analyses and indicate a potential pathogenetic link between these two systemic diseases, however definite proof of this detrimental relationship awaits further prospective studies. Newer anti-psoriatic biologic therapies seem to confer a cardiovascular benefit, but this needs future randomized controlled studies to confirm. All these intricate issues of a potential link between psoriasis and CVD are discussed and elaborated in this overview, in an attempt to shed further light on pivotal aspects of the association between psoriasis and CVD. PMID- 30457025 TI - How habit affects continuous use: evidence from Jordan's national health information system. AB - Implementing a health information system (HIS) to enhance healthcare services and patients' experience has become a growing trend in developing countries. Yet little is known about acquainted users' attitudes on continuing the use of an HIS after adoption. Healthcare professionals (physicians and nurses in particular) are reluctant to use HISs because they perceive them as an interruption of their interaction with patients, thus negatively influencing their efficiency. In this study, we extend the technology acceptance model (TAM) by integrating habit as an exogenous variable that affects HISs' perceived ease of use (PEOU) and perceived usefulness (PU) to investigate experienced healthcare professionals' attitudes in continuing to use an HIS. The setting of this study is a developing country (Jordan) that implemented a nationwide HIS named Hakeem. The findings show that in the context of healthcare, attitude is the major determinant to continue using HISs. Findings also show that habit significantly increases healthcare professionals' perception of PU and PEOU, which improves their attitudes toward continuing to use HISs. These findings have implications for both research and practice. PMID- 30457024 TI - Gastrointestinal Behcet's-like disease with myelodysplastic neoplasms with trisomy 8: a French case series and literature review. AB - We report the 11 cases of +8-MDS/MPN associated with Behcet's-like syndrome and compare them with Behcet's disease and Crohn's disease, pool with literature cases for analysis. Data for patients with +8-MDS/MPN and Behcet's-like syndrome were collected from MINHEMON. Eleven patients had Behcet's-like syndrome and +8 MDS/MPN (median age 75 years [IQR 65-87]; M/F ratio 0.8). MDS and Behcet's-like syndrome were diagnosed at the same time (7/11, 64%). By comparison with 63 patients with idiopathic Behcet's disease without associated MDS, those with Behcet's-like syndrome and +8-MDS/MPN were older (median 75 vs 48 years; p = .0003) and had less pseudofolliculitis (11% vs 62%; p = .0045) and ocular impairment (0% vs 52%; p = .0008), but more frequent gastrointestinal involvement (60% vs 13%; p = .0005). By comparison with Crohn's disease, 39 patients with Behcet's-like syndrome and +8-MDS/MPN were significantly older (median 72 [53-78] vs 36 [27-45] years; p = .0002) and more frequently had oral aphtosis (97% vs 5%, p < .0001), skin features (50% vs 10%, p = .0005) and arthralgia (63% vs 20%, p = .03). Median survival did not differ between patients with Behcet's-like syndrome and +8-MDS/MPN and those with +8-MDS/MPN (n = 103) (47 vs 34 months, p = .61). AML-free survival did not differ between patients with MDS/MPN with and without Behcet's-like syndrome (p = .29). MDS/MPN with trisomy 8 can be associated with particular phenotype of ulcerative digestive disease resembling Behcet's or Crohn's disease and should be considered a single disease. PMID- 30457026 TI - Donor-specific anti-HLA antibodies by solid phase immunoassays: advantages and technical concerns. AB - The detection of donor-specific antibodies (DSAs) is a cornerstone in the immunological risk assessment prior to organ transplantation. The detection methods have developed rapidly during the last decade, and the evidence for clinical interpretation of results obtained by solid phase immunoassays (SPI) is slowly accumulating. Nevertheless, technical limitations and theoretical concerns still mean that "expert opinions" govern clinical decision-making when results of bead-based arrays are applied in immunological risk assessment prior to transplantation. This article underlines the prognostic value of SPI in the immunized recipient of an organ transplant while cautioning uncritical clinical interpretation of mean fluorescence intensity (MFI) as a quantitative parameter in organ transplantation based on documented as well as theoretical shortcomings of the method. The role of SPI-based detection of anti-HLA antibodies in clinical transplantation diagnostics is summarized and put into perspective of the Sensitization in Transplantation: Assessment of Risk (STAR) working group report 2017. PMID- 30457027 TI - The impact of community-based mental health service provision on stigma and attitudes towards professional help-seeking. AB - BACKGROUND: Stigma of mental ill-health and attitudes towards help-seeking are recognized barriers to seeking professional help, and have previously been linked to the type of support services available. AIMS: This study examined if the introduction of community-based mental health services to an area impacts mental health stigma and attitudes towards professional help-seeking amongst local residents. METHOD: A repeated cross-sectional study comprising of community surveys in two localities was carried out before and after community-based mental health services were introduced (N = 1074). Measures including perceived public and self-stigma of mental ill-health, and attitudes towards seeking professional help were compared across the two time points. RESULTS: Both public and self stigma were significantly lower, and attitudes towards seeking professional help significantly more positive, after community-based mental health services had been introduced in each locality. CONCLUSIONS: The presence of local, accessible mental health services can positively impact help-seeking behaviour by reducing stigma and changing norms and attitudes around professional help-seeking. PMID- 30457028 TI - Assessing the impact of sexual function on perceptions of masculinity among prostate cancer survivors in the United States: findings from the prostate cancer registry. AB - BACKGROUND: Prostate cancer carries emasculating symptoms and treatment effects. These symptoms and treatment effects impact a man's sexual function; a central theme to masculinity. This study seeks to assess the impact of sexual function on perceptions of masculinity. METHODS: A voluntary-sample of men self-selected into the registry. Data were based on a series of questions related to Health-Related Quality of Life and functional status. RESULTS: Based on the analysis, 50.2% of men did not feel less masculine, 33.2% of men were still interested in sex, 40.2% of men still engaged in sex "a little bit," and 34.8% of men still found sex "quite a bit" enjoyable. Additionally, 31.1% of identified issues with erectile dysfunction and 45.5% of men showed no discomfort with being sexually active. CONCLUSION: Sexual function has an impact on perceptions of masculinity but additional underlying issues outside of sexual function may contribute to perceptions of masculinity. PMID- 30457029 TI - Pocket-sized ultrasound device for internal jugular puncture: A randomized study of performance on a simulation model. AB - INTRODUCTION:: The aims of our study were to compare the performance of experienced emergency physicians for internal jugular vein puncture using a conventional ultrasound device versus a pocket-sized ultrasound in a training model. METHODS:: In this single-center, prospective, randomized study, emergency physicians performed one puncture with each device in a randomized order. No emergency physicians used a pocket-sized ultrasound for central vascular catheter insertion in clinical practice. A medium-fidelity training model was used. Each image was judged based on an image quality scale from 0 to 5. RESULTS:: Twenty emergency physicians were included: nine females (45%), median experience 2.5 years [2.0;4.3]. The median time to achieve a puncture with the conventional ultrasound device was 22 s [17;26] versus 28 s [13;43] with the pocket-sized ultrasound ( p = 0.43). Eighteen (90%) emergency physician punctures were successful with the conventional ultrasound device versus 18 (90%) with the pocket-sized ultrasound ( p = 1). The image quality was 4 [3;5] in the conventional ultrasound device group versus 4 [3;5] in the pocket-sized ultrasound group ( p = 0.32). CONCLUSION:: Pocket-sized ultrasound and conventional ultrasound device performances are not statistically different for internal jugular vein-guided ultrasonography in a training model. These results must be confirmed in a clinical study. PMID- 30457030 TI - Quantum chemical simulations revealed the toxicokinetic mechanisms of organic phosphorus flame retardants catalyzed by P450 enzymes. AB - The metabolic fate and toxicokinetics of organic phosphorus flame retardants catalyzed by cytochrome P450 enzymes (CYPs) are here investigated by in silico simulations, leveraging an active center model to mimic the CYPs, triphenyl phosphate (TPHP), tris(2-butoxyethyl) phosphate and tris(1,3-dichloro-2-propyl) phosphate as substrates. Our calculations elucidated key main pathways and predicted products, which were corroborated by current in vitro data. Results showed that alkyl OPFRs are eliminated faster than aryl and halogenated alkyl substituted OPFRs. In addition, we discovered a proton shuttle pathway for aryl hydroxylation of TPHP and P = O bond-assisted H-transfer mechanisms (rather than nonenzymatic hydrolysis) that lead to O-dealkylation/dearylation of phosphotriesters. PMID- 30457031 TI - Depression and economic status: evidence for non-linear patterns in women from Mexico. AB - BACKGROUND: While social determinants of health perspective might lead to the hypothesis that higher economic achievements should be associated with better mental health, the evidence for adults is mixed and inconclusive. AIM: We test the role of wealth as a predictor of depressive symptoms controlling for a number of socio-demographic covariates, with a specific interest in gender-specific patterns. METHODS: Using a nationally representative survey from Mexico (N = 44,618), we carry out multivariate regression analysis where we jointly model linear and quadratic measures of wealth to detect non-linear relations between depression and wealth. RESULTS: The paper reports clear evidence of an inverted-U relationship between depressive symptoms and wealth for females, whereas the relationship for males tends to be linear and decreasing with wealth as expected (though weak and significant only in the upper part of the wealth distribution). Our findings are robust to alternative empirical strategies and we discuss potential explanations for this novel finding. CONCLUSION: The paper confirms that the association between standards of living and depression is complex, due to the mediating role of socio-demographic characteristics and the existence of non-linearities not fully explored in the literature. PMID- 30457032 TI - Percutaneous treatment of right-sided subclavian stenosis using radial approach. PMID- 30457033 TI - Increased prevalence of androgen deficiency in endurance-trained male runners across the life span. PMID- 30457034 TI - Nanoparticles induce apoptosis via mediating diverse cellular pathways. AB - With a special size and structure, nanoparticles (NPs) have excellent application prospects in various fields and are widely used in the biomedicine, cosmetics and chemical industries nowadays. However, there have been some reports on the biosafety of this new type of material, pointing out its cytotoxicity in inducing apoptosis. With different physicochemical properties in size, shape, surface charge, and ligand, NPs exhibit different biocompatibilities when interacting with different cells. Therefore, a comprehensive and deep study into the proapoptotic mechanism of NPs is necessary. In the present review, we summarize the NP-triggered apoptotic signal pathways in detail and highlight some important functional molecules involved. We hope our findings and perspectives provide a new direction for the sound development of nanotechnology in the future. PMID- 30457035 TI - Brachioplasty a superficialization procedure of brachial arteriovenous access for hemodialysis after weight loss: A novel approach. PMID- 30457037 TI - A review of Military Psychology: Clinical and Operational Applications. PMID- 30457036 TI - Ruthenium complex delivery using liposomes to improve bioactivity against HeLa cells via the mitochondrial pathway. AB - AIM: The aim of this study was to encapsulate a ruthenium complex [Ru(ttbpy)2PIP](ClO4)2 (Ru) in liposomes to enhance their antitumor effect on human cervical cancer. METHODS: The Ru-loaded PEGylated liposomes (Ru-Lip) were prepared using thin-film hydration method. The mechanism of action was studied. RESULTS: A novel Ru was successfully synthesized. Ru-Lip showed stronger cytotoxic activity against HeLa cells than Ru. Ru-Lip demonstrated a more significant increase in apoptosis, reactive oxygen species production and apoptosis-associated processes (intracellular calcium concentration, cytochrome c release and activation of Bax and caspase-3) than Ru. Ru-Lip exhibited greater blockade efficacy in the cell cycle G1 phase and greater DNA damage than Ru. CONCLUSION: Ru-Lip significantly elevates the anticancer effect via reactive oxygen species-mediated mitochondrial dysfunctional pathway. PMID- 30457038 TI - Does the spatial-numerical association of response codes effect depend on digits' relative or absolute magnitude? Evidence from a perceptual orientation judgment task. AB - Many previous studies have demonstrated the SNARC effect-i.e., participants are faster to respond with their left/right hand to small/large numbers. However, there is a debate on whether it is based on working or long-term memory (i.e., relative or absolute magnitude). Here, we examined the flexibility of the spatial numerical associations using orientation judgment tasks. Participants were asked to judge the orientation of a rotated frame surrounding an Arabic digit under numerical ranges 1-6, 4-9 (Experiment 1), and 1-9 (Experiment 2). The task difficulty was manipulated by rotating stimuli. We observed a significant SNARC effect for range 1-6 and a reversed SNARC effect for 4-9, regardless of the total numerical range presented in the task. Furthermore, the SNARC effect became more salient with increasing task difficulty. Our results suggest that the SNARC effect is based on the absolute magnitude of digits, supporting the long-term memory explanation. PMID- 30457039 TI - Effects of scripted activities on false feelings of having previously visited a location. AB - False memories of one's past are often created by unconscious influences of previous experiences. This study examined whether action sequences, scripts that are frequent in everyday life, might induce false beliefs of having visited a location. Participants were shown photos of places they had not previously visited. Next, they rated how strongly they felt that they had visited the locations in the target scenes. Results indicated that when typical actions were presented in canonical order before the target scene, the feeling of having previously visited the location increased, relative to a condition with a random ordering of typical actions or to one with no presented actions. This study suggests that activation of script knowledge and misattribution of the source of feelings of familiarity elicit false beliefs of having visited a specific location, even if one understands that one has never previously visited the location. PMID- 30457040 TI - Social Worker Integrated Care Competencies Scale (SWICCS): Assessing social worker clinical competencies for health care settings. AB - Integrating physical and behavioral health services has the potential to reduce health disparities and service inequities among persons most at risk. However, clinical social workers in integrated health settings must possess relevant knowledge and skills to provide quality care to diverse populations. The Social Worker Integrated Care Competency Scale (SWICCS), developed to complement the Integrated and Culturally Relevant Care (ICRC) field education curriculum, measures students' self-perceptions of knowledge and skills associated with providing behavioral health care. Three student cohorts (n = 38) completed the SWICCS three times during an integrated care field practicum. Results indicated a statistically significant increase in student knowledge and skills at each time point, with a large effect size (r = -.87). The SWICCS demonstrated utility in measuring and tracking social work student acquisition of knowledge and skills required for practice in integrated care environments. PMID- 30457041 TI - Life Sciences Discovery and Technology Highlights. PMID- 30457042 TI - Multi-functional chimeric peptides: The more the merrier. AB - Peptides are recognized as highly specific and efficacious molecules, and thus have gained recognition as therapeutics in the recent years. In contrast to the monotherapy, multi-target combination therapy that includes two or more drugs with the complementary mechanism of action are proven to be efficacious in complex pathophysiological conditions. However, combining various drugs lead to complex pharmacokinetic and pharmacodynamic profile and pose safety risks. Herein, we reviewed the therapeutic potential of multifunctional chimeric peptides with examples from the field of metabolic, cardiovascular and neuropathic pain disease. PMID- 30457043 TI - Synthetic Cross-linking of Peptides: Molecular Linchpins for Peptide Cyclization. AB - Peptide-derived drugs constitute a significant fraction of therapeutic agents. In 2013, The global market of peptide therapeutics was ca. $19 billion; this value does not include revenue from insulin derivatives of $28 million. The combined sales of insulin and non-insulin peptide drugs is estimated to exceed $70 billion by 2019. A significant fraction of peptide-derived drugs is composed of an amino acid sequence and additional chemical functionalities that improve biological and pharmacological properties of the drug. In this review, we focus on synthetic cross-linkers that we refer to as "linchpins", which are commonly used to constrain the secondary structure of peptides and equip them with added benefits such as resistance to proteolytic degradation and conformational stability. The latter property leads to an increase in binding potency and increased bioavailability due to increased permeation through biological membranes. Some linchpins can even introduce properties not found in natural peptides such as light-responsiveness. Peptides cyclized by linchpins, can be viewed as a sub class of a larger family of peptide-derived drugs with desired pharmacological performance in vivo. To understand how chemical modifications by linchpins improve drug discovery, this review also briefly summarizes canonical examples of chemical modification used in modern peptide therapeutics. PMID- 30457044 TI - Molecular Basis of Memory: A Grand Orchestra of Pattern Formation by Hydrogen Bonds? PMID- 30457045 TI - Tuberculosis - present medication and therapeutic prospects. AB - BACKGROUND: Tuberculosis (TB) has been present in the history of human civilization since time immemorial and has caused more deaths than any other infectious disease. It is still considered one of the ten most common epidemiologic causes of death in the world. As a transmissible disease, it is initiated by rod-shaped (bacillus) mycobacteria. The management of tuberculosis became possible owing to several discoveries beginning in 1882 with the isolation of the TB bacillus by Robert Koch. The diagnosis of TB was enabled by finding a staining method for TB bacteria identification (1883). It was soon realized that a large-scale policy for the treatment and prevention of tuberculosis was necessary, which resulted in the foundation of International Union against Tuberculosis and Lung Diseases (1902). An antituberculotic vaccine was developed in 1921 and has been in therapeutic use since then. TB treatment regimens have changed over the decades and the latest recommendations are known as Directly Observed Treatment Short-course (DOTS, WHO 1993). METHODS: A search of bibliographic databases was performed for peer-reviewed research literature. A focused review question and inclusion criteria were applied. Standard tools were used to assess the quality of retrieved papers. RESULTS: A total of 112 papers were included comprising original publications and reviews. The paper overviews anti-TB drugs according to their mechanism of action. The chemical structure, metabolism and unwanted effects of such drugs have been discussed. The most recent treatment regimens and new drugs, including those in clinical trials, are also presented. CONCLUSION: Despite a 22% decrease in the tuberculosis fatality rate observed between 2000 and 2015, the disease remains one of the ten prime causes of death worldwide. Increasing bacterial resistance and expensive, prolonged therapies are the main reasons for efforts to find effective drugs or antituberculotic regimens, especially to cure multidrug resistant tuberculosis. PMID- 30457046 TI - Sulfated Non-Saccharide Glycosaminoglycan Mimetics as Novel Drug Discovery Platform for Various Pathologies. AB - Glycosaminoglycans (GAGs) are very complex, natural anionic polysaccharides. They are polymers of repeating disaccharide units of uronic acid and hexosamine residues. Owing to their template-free, spatiotemporally controlled, and enzyme mediated biosyntheses, GAGs possess enormous polydispersity, heterogeneity, and structural diversity which often translate into multiple biological roles. It is well documented that GAGs contribute to physiological and pathological processes by binding to proteins including serine proteases, serpins, chemokines, growth factors, and microbial proteins. Despite advances in the GAG field, the GAG protein interface remains largely unexploited by drug discovery programs. Thus, non-saccharide glycosaminoglycan mimetics (NSGMs) have been rationally developed as a novel class of sulfated molecules that modulate GAG-protein interface to promote various biological outcomes of substantial benefit to human health. In this review, we describe the chemical, biochemical, and pharmacological aspects of recently reported NSGMs and highlight their therapeutic potentials as structurally and mechanistically novel anti-coagulants, anti-cancer agents, anti emphysema agents, and anti-viral agents. We also describe the challenges that complicate their advancement and describe ongoing efforts to overcome these challenges with the aim of advancing the novel platform of NSGMs to clinical use. PMID- 30457047 TI - Biological Activities and Pharmacological Applications of Cyclodextrins Complexed with Essential Oils and Their Volatile Components: a Systematic Review. AB - BACKGROUND: Essential oils (EOs) and their volatile components (VCs) have varied biological and pharmacological activities, but the low solubility and bioavailability hamper their applications, so that the inclusion in cyclodextrins (CDs) is likely to improve their physicochemical properties and pharmacological effects. OBJECTIVE: The authors conducted a systematic review to evaluate the biological activities and pharmacological applications of essential oils and their volatile components complexed with cyclodextrins. METHODS: The search terms 'Cyxlodextrin', 'Inclusion Complex', 'Volatile oils', 'Essential oil' and 'Volatile components' were used to retrieve articles from the PUBMED, MEDLINE and SCOPUS databases. RESULTS: A total of 38 articles were identified. In in vitro and preclinical studies, a greater efficacy of EOs and their VCs complexed with different CDs types was found when compared to free forms in the various biological activities and animal models of the pharmacological tests evaluated. CONCLUSION: This review of selected studies showed that the use of CDs promotes greater solubility, bioavailability and efficacy of EOs and their VCs indicating an interesting alternative for the biotechnological development of new therapeutic formulations. PMID- 30457048 TI - Synaptic Plasticity in PTSD and Associated Comorbidities: The Function and Mechanism for Diagnostics and Therapy. AB - The studying of synaptic plasticity, the ability of synaptic connections between neurons to be weakened or strengthened and specifically long-term potentiation (LTP) and long-term depression (LTD), is one of the most active areas of research in neuroscience. The process of synaptic connections playing a crucial role in improving cognitive processes is important to the processing of information in brain. In general, the dysfunction of synaptic plasticity was involved in a wide spectrum of central nervous system (CNS) disorders, including some neurodegenerative disorders. Thus, synaptic plasticity which is dysfunction reported in neurodegenerative disorders may be also involved in posttraumatic stress disorder (PTSD), an anxiety and/or memory disorder developed after experiencing natural disasters, domestic violence or combat-related trauma. In this review, we mainly focus on discussing the biological function and mechanism for diagnostics and therapy of synaptic plasticity in PTSD and associated comorbidities, such as schizophrenia, depression, sleep disturbances and alcohol dependence, and further study the molecular mechanisms of PTSD with a particular focus on the LTP/LTD, glutamatergic ligand-receptor systems, voltage-gated calcium channels (VGCCs) and brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB). The summarized function and mechanism of synaptic plasticity in PTSD and its comorbidities may help us further understand PTSD and provide insight to novel neuroplasticity modifying for diagnostics and treatment for PTSD. PMID- 30457049 TI - The Potential of Receptor for Advanced Glycation End Products (RAGE) as a Therapeutic Target for Lung Associated Diseases. AB - The receptor for advanced glycation end products (RAGE) is a multi-ligand pattern recognition receptor that is highly expressed in lung epithelial cells. It helps alveolar epithelial cells to maintain their morphology and specific architecture. However, in various pathophysiological conditions, pulmonary tissues express supraphysiological level of RAGE and its ligands including advanced glycation end products, high mobility group box 1 proteins and S100 proteins. These ligands on interaction with RAGE stimulate various downstream signaling pathways that generate inflammation and oxidative stress leading to asthma, chronic obstructive pulmonary disease, lung cancers, idiopathic pulmonary fibrosis, acute lung injury, pneumonia, bronchopulmonary dysplasia, cystic fibrosis and sepsis. Thus, pharmacological agents that can either suppress the production of RAGE or block its biological activity would offer promising therapeutic value against pathogenesis of the aforementioned lung associated diseases. This review presents a comprehensive overview of the recent progress made in defining the functions of RAGE in pulmonary diseases. PMID- 30457050 TI - Editorial: ADVANCEMENT IN MICROBIAL CHEMINFORMATICS. PMID- 30457051 TI - MicroRNAs as therapeutic agents: The future of the battle against cancer. AB - Since their discovery in the 1990's, the study of a class of non-coding, single stranded RNAs, christened the microRNAs has opened up new vistas in the field of cancer biology. MicroRNAs bind to their target mRNAs to act as either oncogenes or tumour suppressors. With the near-complete elucidation of the biogenesis pathway, and the advent of rapid sequencing technologies, microRNAs have slowly cemented their place as essential biomarkers for delineating the progression, metastasis, relapse or drug resistance of cancer. Being crucial players in the cancer pathway, there has been considerable urgency in designing molecules - both at the nucleotide and non-nucleotide level to counter the effects of their binding. A number of different approaches have yielded quite a body of compounds which have been found to be effective in the treatment of various tumours across many different organs. In this study, the focus is on the review of the timeline of discovery and characterization of microRNAs, underline their importance in different cancers, shed light on the discovery of anti-microRNA compounds and illustrate their uses in deriving new strategies to combat cancer. PMID- 30457052 TI - Design, synthesis and anxiolytic activity evaluation of N-acyl-tryptophanyl containing dipeptides, potential TSPO ligands. AB - BACKGROUND: The 18 kDa translocator protein (TSPO), previously known as the peripheral-type benzodiazepine receptor, plays a key role for synthesis of neurosteroids by promoting transport of cholesterol from the outer to the inner mitochondrial membrane, which is the rate-limiting step in neurosteroid biosynthesis. Neurosteroids interact with non benzodiazepine site of GABAa receptor causing an anxiolytic effect without the side effects. METHODS: Using the original peptide drug-based design strategy, the first putative dipeptide ligand of the TSPO N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide (GD-23) was obtained. Molecular docking of GD-23 in the active pocket of the TSPO receptor using Glide software was carried out. The lead compound GD-23 and its analogues were synthesized using activated succinimide esters coupling method. The anxiolytic activity of GD-23 and its analogues was investigated in vivo, using two validated behavioral tests, illuminated open field and elevated plus-maze. RESULTS: The in vivo studies revealed that the following parameters are necessary for the manifestation of anxiolytic activity of new compounds: the L configuration of tryptophan, the presence of an amide group at the C-terminus, the specific size of the N-acyl substituent at the N-terminus. Compound GD-23 (N carbobenzoxy-L-tryptophanyl-L-isoleucine amide) demonstrated a high anxiolytic like effect in the doses of 0.05-1.0 mg/kg i.p. comparable with that of diazepam. Compound GD-23 was also active in the open field test when was administered orally in the doses of 0.1-5.0 mg/kg. The involvement of TSPO receptor in the mechanism of anxiolytic-like activity of new compounds was proved by the antagonism of compound GD-23 with TSPO selective inhibitor PK11195 as well as with inhibitors of enzymes which are involved in the biosynthesis of neurosteroids, trilostane and finasteride. CONCLUSIONS: A series of N-acyl tryptophanyl-containing dipeptides were designed and synthesized as 18 kDa translocator protein (TSPO) ligands. Using a drug-based peptide design method a series of the first dipeptide TSPO ligands have been designed and synthesized and their anxiolytic activity has been evaluated. In general, some of compounds displayed high level of anxiolytic efficacy comparable with that of diazepam. The involvement of TSPO receptor in the mechanism of anxiolytic activity of new compounds was proved using two methods. On this basis, the N-acyl-L-tryptophanyl isoleucine amides could potentially be a novel class of TSPO ligands with anxiolytic activity. PMID- 30457053 TI - Rabbit as an Animal Model for Pharmacokinetics Studies of Enteric Capsule Contains Recombinant Human Keratinocyte Growth Factor-Loaded Chitosan Nanoparticles. AB - BACKGROUND: Recombinant human keratinocyte growth factor (rHuKGF) has gained considerable attention by researchers as epithelial cells proliferating agent. Moreover, intravenous truncated rHuKGF (palifermin) has been approved by Food and Drug Administration (FDA) to treat and prevent chemotherapy-induced oral mucositis and small intestine ulceration. The labile structure and short circulation time of rHuKGF in-vivo are the main obstacles that reduce the oral bioactivity and dosage of such proteins at the target site. OBJECTIVE: Formulation of methacrylic acid-methyl methacrylate copolymer-coated capsules filled with chitosan nanoparticles loaded with rHuKGF for oral delivery. METHODS: We report on chitosan nanoparticles (CNPs) with diameter < 200 nm, prepared by ionic gelation, loaded with rHuKGF and filled in methacrylic acid-methyl methacrylate copolymer-coated capsules for oral delivery. The pharmacokinetic parameters were determined based on the serum levels of rHuKGF, following a single intravenous (IV) or oral dosages using rabbit model. Furthermore, fluorescent microscope imaging was conducted to investigate the cellular uptake of the rhodamine-labelled rHuKGF-loaded nanoparticles. The proliferation effect of the formulation on FHs 74 Int cells was studied as well by MTT assay. RESULTS: The mucoadhesive and absorption enhancement properties of chitosan and the protective effect of methacrylic acid-methyl methacrylate copolymer against rHuKGF release at the stomach, low pH, were combined to promote and ensure rHuKGF intestinal delivery and increase serum levels of rHuKGF. In addition, in-vitro studies revealed the protein bioactivity since rHuKGF-loaded CNPs significantly increased the proliferation of FHs 74 Int cells. CONCLUSION: The study revealed that oral administration of rHuKGF-loaded CNPs in methacrylic acid-methyl methacrylate copolymer-coated capsules is practically alternative to the IV administration since the absolute bioavailability of the orally administered rHuKGF-loaded CNPs, using rabbit as animal model, was 69%. Fluorescent microscope imaging revealed that rhodamine-labelled rHuKGF-loaded CNPs were taken up by FHs 74 Int cells, after 6 hours' incubation time, followed by increase in the proliferation rate. PMID- 30457054 TI - Association Between Pulmonary Hypertension and Transcatheter Aortic Valve Replacement: Analysis of A Nationwide Inpatient Sample Database. AB - INTRODUCTION: This study was done to review the association of pulmonary hypertension (PH) with Transcatheter Aortic Valve Replacement (TAVR) procedures done in the US for years 2010 to 2012. METHODS: We used Nationwide Inpatient Sample (NIS) data to extract data for patients who were hospitalized with a primary/secondary diagnosis of TAVR as specified by International Classification of Disease (ICD-9) codes 35.05 and 35.06. PH was identified with ICD-9 codes 416.0 and 416.8. Logistic regression models were used to analyze the association between PH and clinical outcomes of TAVR. RESULTS: A total of 8,824 weighted discharges were identified with primary/secondary diagnosis of TAVR of which 1,976 (22.4%) also had PH. Mean age of patients undergoing TAVR with and without PH was 81.4 and 81.1 years, respectively. More females had a diagnosis of PH with TAVR when compared to males, (56.9% vs. 43.1). When controlling for demographics, diabetes and hypertension; the association between PH and TAVR was statistically significant (p<.0001). Estimated odds of TAVR with PH was 5.46 (95% CI: 4.63, 6.41) times greater than for TAVR without PH. Similarly, the estimated odds for a length of stay greater than 1 week for TAVR with PH was 1.43 (95% CI: 1.12, 1.82; p=.0034) times greater than odds for TAVR without PH. PH was not statistically significant for in-hospital mortality in patients receiving TAVR (p=0.7067). CONCLUSION: This study suggests underlying PH does not influence the immediate mortality of patients underlying TAVR. Further studies are needed to delve into the bearing of PH on TAVR. PMID- 30457055 TI - Hair Loss Prevention by a Scalp Cooling Device in Early Breast Cancer Patients: the Poliambulanza Preliminary Experience. AB - BACKGROUND: The most effective agents in the treatment of breast cancer have as common side effect the hair loss. Some studies reported a reduction of hair loss with the use of the scalp cooling device. Indeed, it decreases the drug accumulation in the hair follicles. We report our preliminary experience with a scalp cooling device in reducing chemotherapy-induced alopecia and related distress in breast cancer patients undergoing adjuvant chemotherapy. METHODS: Hair loss grading and treatment tolerability were evaluated during chemotherapy every 21 days and 3 weeks after the last cycle of chemotherapy via Dean's scale by patients and operators and a comfort analogic scale by patients. We administered the Hospital Anxiety and Depression Scale questionnaire at the baseline and at the end of treatment to assess the distress related to chemotherapy-induced alopecia. RESULTS: Among the 46 patients identified, 27 accepted the device. The eligible chemotherapy regimens included docetaxel + cyclophosphamide (TC), doxorubicin + cyclophosphamide (AC) and paclitaxel (P) weekly + trastuzumab (T). 24 pts (89%) completed the treatment; 3 pts (11%) treated with AC prematurely interrupted use of the scalp-cooling device due to inefficacy. After the last cycle of chemotherapy, the number of patient who perceived a HL < grade 2 was 16 (59%). The hair retention reported by operators has been higher (78%). 81.5% of patients well tolerated the treatment. CONCLUSION: In our study, the scalp-cooling device reduced chemotherapy-induced alopecia in taxane-based chemotherapy. Furthermore, it suggests a discordance in hair loss perception between patients and operators. PMID- 30457056 TI - Anti-Arthritic Effect of Garcinol Enriched Fraction Against Adjuvant Induced Arthritis. AB - BACKGROUND: Garcinia indica also known as kokum is used in traditional system of medicine for relieving inflammation and rheumatic pain. Garcinol, a benzophenone obtained from its fruit rind is reported to have anti-inflammatory effect via modulating arachidonic acid metabolism, suppressing iNOS expression, NF-kappaB activation and COX-2 expression. It has also been studied for antioxidant and anticancer activity. Apart from these, few patents claim that Garcinol also has anti-obesity and hepatoprotective effect and has a potential to be used for treatment of renal disorders, endometriosis and cardiac dysfunction. OBJECTIVE: Garcinol Enriched Fraction (GEF) from the fruit rind of Garcinia indica should be effective in treatment of arthritis, one of the chronic inflammatory disorder owing to its anti-inflammatory property as indicated by earlier experiments. METHODS: GEF was prepared from the fruit rind of Garcinia indica and quantified using LC-MS/MS. It was found to contain 89.4%w/w of garcinol. GEF was evaluated at the dose of 10mg/kg for its efficacy against Complete Freund's Adjuvant (CFA) induced arthritis in Wistar albino rats. Paw volumes of both sides were measured by Plethysmometer and body weight was recorded on 0, 1, 5, 12 and 21st day. The hyperalgesic response was also measured by motility test and stair climbing test. RESULTS: GEF showed a significant reduction in paw swelling (p < 0.0001) and arthritis index (p < 0.0001) exhibiting anti-inflammatory potential. It also improves the motility and stair climbing ability of experimental animals (p < 0.05), thus reducing hyperalgesia. CONCLUSION: Garcinol enriched fraction shows anti-arthritic activity in experimental animals. PMID- 30457057 TI - Effect of smoking methods and natural spices on quality and consumer acceptance of smoked Silver catfish (Chrysichthys nigrodigitatus). AB - AIMS AND BACKGROUND: Fish serves as a good source of dietary protein which is very inexpensive in relation to other animal protein foods. Fish is a cheap source of animal protein and it is an excellent component of human diet. This study assessed the effects of smoking methods and natural spices on studied parameters and consumer acceptance of smoked silver catfish (Chrysichthys nigrodigitatus). METHODS: One hundred samples of silver catfish were obtained by purposive sampling method. The fresh fish samples were smoked in two batches, the first batch was smoked with drum smoker and the second batch with oven smoker while the control was smoked without the natural spices. Rancidity indices (TVB N, TMA-N, TBA and pH), microbiological analysis and sensory evaluation were carried out on smoked fish samples. The recent patents on edible fat blends (US20020031595A1), long chain fatty acids (WO2008085840A2) and esters of polyunsaturated fatty acids (US20090023808A1) helped in selecting the analytical methods. RESULTS: The results showed that there was statistical significant difference (P<=0.05) between total volatile base-nitrogen, trimethylamine values and pH of the smoked silver catfish samples treated with different concentrations of clove, ginger and garlic paste and those samples which were not treated with clove, ginger and garlic. This study showed that smoking methods has effects on quality indices, microbial quality and consumer acceptance of smoked silver catfish. Clove, ginger and garlic have some anti-oxidative effects on rancidity indices of smoked silver catfish as there was inverse relationship between clove, ginger and garlic and values of peroxide, free fatty acid and thiobarbituric acid. This was also observed for the microbial quality of the smoked silver catfish. There was also inverse relationship between clove, ginger and garlic and all the sensory parameters except for texture and as the concentrations of the natural spices increase the values of the sensory parameters decreases. CONCLUSION: In conclusion, this study showed that smoking methods affects the studied parameters, microbial quality and consumer acceptance of smoked silver catfish. Addition of clove, ginger and garlic had anti-microbial and anti oxidative effects on quality parameters of smoked silver catfish. There was also a negative correlation between clove, ginger and garlic and all the sensory parameters except for texture. PMID- 30457058 TI - Patents for the Physiological Quality in Seeds of Peach Rootstock Classified by Weight and Stored for Different Periods. AB - BACKGROUND: - Among stone fruit, the peach (Prunus persica (L) Batsch) is one of the most widely grown species in Brazil, in both area cultivated and in production. OBJECTIVE: the aim of this study was to evaluate the physiological quality of heavy and light seeds of four cultivars of Prunus persica for two storage periods, from tests of electrical conductivity, germination, and an analysis of initial plantlets growth. METHODS: The electrical conductivity test (EC) was conducted in a completely randomised design (CRD), in a 4 x 2 x 5 factorial scheme with five replications. The germination test was carried out in CRD, in a 4 x 2 factorial scheme with eight replications. The physiological quality of the seeds was determined at zero and twelve month's storage. For the growth analysis, the experimental design was in CRD, in a 4 x 2 factorial scheme with four replications. RESULTS: Under the conditions of the present study, it was found that the tests of germination and electrical conductivity were complementary in evaluating physiological quality in seeds of Prunus persica rootstock, suggesting that independent of the weight of the seeds, in 'Capdeboscq', 'Aldrighi', 'Okinawa' and 'Okinawa Roxo', there is a loss of quality and viability when the seeds are stored for a period of 12 months. CONCLUSION: Under the experimental conditions of the present study, it was concluded that storage for a period of 12 months in Recent patents is not rather recommendable for maintaining quality and viability in seeds of Prunus persica of the Capdeboscq, Aldrighi, Okinawa and Okinawa Roxo cultivars. PMID- 30457059 TI - New insight into the diagnostic cut-off value of serum anti-Toxocara IgG for ocular toxocariasis in uveitis patients. AB - Uveitis is one of the commonest causes of vision loss worldwide and its exact etiology is still not clarified in most patients. The current study is a trial to assess the efficacy of serum anti-Toxocara immunoglobulin G (IgG) by enzyme linked immunosorbent assay (ELISA) as a diagnostic tool for ocular toxocariasis (OT) and to detect OT prevalence and the associated ocular manifestations in sera of patients with uveitis. One hundred and twelve patients (62 females and 50 males) with uveitis were diagnosed by ophthalmologists, radiologists and rheumatologists according to ocular manifestations, laboratory and radiological investigations. Serum anti-Toxocara IgG titers were determined by ELISA in sera of all patients. Our results revealed that OT is highly associated with intermediate and posterior uveitis. Children and young adult females, especially those residing in rural areas, complained mainly of diminution of vision in the left eye, with strabismus and leukocoria. At a cut-off value of 0.258, the sensitivity and specificity of IgG ELISA were 93.3% and 100%, respectively. In conclusion, at a novel cut-off value of 0.258 the serum anti-Toxocara IgG ELISA is predicted to be a diagnostic tool for OT regarding sensitivity and specificity. Also, it has potential importance in the interpretation and differential diagnosis of OT. Thus, serum anti-Toxocara IgG ELISA should be a routine test for screening of suspected cases. PMID- 30457060 TI - Evidence for oestrogen sensitivity in perinatal depression: pharmacological sex hormone manipulation study. AB - BACKGROUND: Enhanced sensitivity to oestrogen signalling may drive increased risk for depressive symptoms when exposed to peripartum sex-steroid hormone fluctuations.AimTesting if 116 pre-identified sex steroid-responsive transcripts that predicted perinatal depression (PND) translates to a pharmacological model of hormone-induced mood changes. METHOD: We generated longitudinal, genome-wide gene-expression and DNA-methylation data from 60 women exposed to a gonadotrophin releasing hormone agonist (GnRHa) or placebo. We used linear mixed-effect models to assess differences between baseline and follow-up for gene expression and DNA methylation in the biphasic ovarian response to GnRHa. RESULTS: Of the 116 PND predictive transcripts, a significant (19%) overlap was observed with those differentially expressed post-GnRHa at both early and later follow-up, indicating sustained effects. Similarly, 49% of tested genes were differentially methylated post-GnRHa at the late follow-up. Within the GnRHa group, a large proportion of PND genes were significantly associated (gene expression; DNA methylation) with changes in depressive symptoms (28%; 66%), oestradiol levels (49%; 66%) and neocortex serotonin transporter binding (8%; 45%) between baseline and follow-up. CONCLUSIONS: Our data bridge clinical PND biomarkers with a pharmacological model of sex hormone-induced mood changes and directly relate oestrogen-induced biological changes with depressive symptoms and associated serotonin-signalling changes. Our data highlight that individual variations in molecular sensitivity to oestrogen associate with susceptibility to hormone-induced mood changes and hold promise for candidate biomarkers.Declaration of interestV.G.F. received honorarium for being a speaker for H. Lundbeck A/S. E.B.B. receives research funding from Bohringer Ingelheim to investigate FKBP5 as a potential drug target for depression. PMID- 30457061 TI - Density-dependent distribution of parasitism risk among underground hosts. AB - Variation in parasitism risk among hosts can arise from between-patch and within patch factors, but considerably less information is known about the latter. This study investigated how distributions of the oriental fruit fly Bactrocera dorsalis influenced its parasitism by the pupal parasitoid Dirhinus giffardii in the laboratory. Because B. dorsalis larvae pupate underground, pupation depth was considered as an important factor that affects the risk of parasitism. When the density of B. dorsalis larvae was varied (1, 10, and 100 larvae per arena), average pupation depth increased with the density. When the depth of pupae was manipulated, the rate of parasitism differed by depths. Parasitism at 0 cm differed from the random parasitoid model expectation, but parasitism at 1 cm was not different from the model expectation. Few pupae at 2 cm were parasitized. In another experiment, when pupae were simultaneously presented at 0 cm and 1 cm depths, parasitism at 1 cm was weakened by the presence of puape at 0 cm. These results imply that the density of the host influences pupation depth as well as the distribution of parasitism and plays an important role in host-parasitoid dynamics. PMID- 30457062 TI - Where and when? How phenological patterns of armyworm moths (Lepidoptera: Noctuidae) change along a latitudinal gradient in Brazil. AB - The phenological patterns exhibited by different organisms are known as adaptive responses to the cyclical environmental conditions. However, only a limited number of researches explore which factors are responsible for these phenological patterns in pest species. In the current study, abundance patterns were studied in the phenology of three Spodoptera Guenee, 1852 species, along the 29 degrees latitudinal gradient in South America. The goal was to test whether widely distributed and abundant crop pest species would exhibit different phenological responses to seasonal meteorological variables and host plant availability. To test this, 13 light traps were set up in Brazil to collect adult Spodoptera samples at the time of the new moon, every month, from June 2015 to May 2016. The time of occurrence and intensity of the phenology were determined for each species, employing circular statistics. Both metrics revealed significant variations among the different species, as well as the factors associated with them. Latitude was found to affect the period of occurrence in Spodoptera cosmioides (Walker, 1858) and Spodoptera albula (Walker, 1857), whereas in Spodoptera frugiperda (J. E. Smith, 1797) its effect was evident only in the intensity of its phenology. Further, both meteorological variables and host plant availability in the sampling sites produced predictive models to account for the phenological patterns expressed. These findings suggest that different species of Spodoptera exhibit different adaptive strategies in their life cycles in response to environmental conditions, thus necessitating specific management practices regarding their seasonal population fluctuation. PMID- 30457063 TI - Hearing loss and psychiatric disorders: a review. AB - Hearing loss is one of the most common yet unrecognized impairments experienced by adults, especially as they age. Mental health investigators and practitioners require better understanding of hearing loss, its association with psychiatric disorders, and the treatment of these disorders in the presence of hearing loss as well as the treatment of hearing loss itself. In this review, the authors briefly explore the global burden of hearing loss. Next we provide an overview of the extant literature on hearing loss associated with cognitive impairment, depression, anxiety disorders, psychoses, and quality of life with attention focused on the strength of the association, possible mechanisms explaining the association, data on treatment options specific to these disorders, and future research opportunities for these disorders. Current approaches to the treatment of hearing loss are presented, including hearing aids, rehabilitation including psychotherapies, surgical procedures (specifically cochlear implants), and induction loops connected to telecoils. Finally, cutting edge research into the pathophysiology and potential biological treatments of hearing loss is described. PMID- 30457064 TI - Molecular and comparative morphological analysis of central European parasitic flatworms of the superfamily Brachylaimoidea Allison, 1943 (Trematoda: Plagiorchiida) - CORRIGENDUM. PMID- 30457065 TI - Role of hypothalamic tanycytes in nutrient sensing and energy balance. AB - Animal models are valuable for the study of complex behaviours and physiology such as the control of appetite because genetic, pharmacological and surgical approaches allow the investigation of underlying mechanisms. However, the majority of such studies are carried out in just two species, laboratory mice and rats. These conventional laboratory species have been intensely selected for high growth rate and fecundity, and have a high metabolic rate and short lifespan. These aspects limit their translational relevance for human appetite control. This review will consider the value of studies carried out in a seasonal species, the Siberian hamster, which shows natural photoperiod-regulated annual cycles in appetite, growth and fattening. Such studies reveal that this long-term control is not simply an adjustment of the known hypothalamic neuronal systems that control hunger and satiety in the short term. Long-term cyclicity is probably driven by hypothalamic tanycytes, glial cells that line the ventricular walls of the hypothalamus. These unique cells sense nutrients and metabolic hormones, integrate seasonal signals and effect plasticity of surrounding neural circuits through their function as a stem cell niche in the adult. Studies of glial cell function in the hypothalamus offer new potential for identifying central targets for appetite and body weight control amenable to dietary or pharmacological manipulation. PMID- 30457066 TI - Epistaxis and mortality. AB - BACKGROUND: Epistaxis is a common emergency presentation to ENT. The 'Epistaxis 2016: national audit of management' collected prospective data over a 30-day audit window in 113 centres. A 30-day all-cause mortality rate of 3.4 per cent was identified. This study examines in more detail the subgroup of patients who died during the audit period. METHODS: There were 985 eligible patients identified. Of these, 33 patients died within the audit period. World Health Organization bleeding score, Modified Early Warning System score, haemostasis time, source of referral, co-morbidities and cause of death were investigated from the dataset. RESULTS: Patients who died were more likely to come from a ward environment, have co-existing cardiovascular disease, diabetes or a bleeding diathesis, be on antithrombotic medication, or have received a blood transfusion. Patients did not die from exsanguination. CONCLUSION: Epistaxis may be seen as a general marker of poor health and a poor prognostic sign. PMID- 30457067 TI - Hepatic fatty acid synthesis and partitioning: the effect of metabolic and nutritional state. AB - When we consume dietary fat, a series of complex metabolic processes ensures that fatty acids are absorbed, transported around the body and used/stored appropriately. The liver is a central metabolic organ within the human body and has a major role in regulating fat and carbohydrate metabolism. Studying hepatic metabolism in human subjects is challenging; the use of stable isotope tracers and measurement of particles or molecules secreted by the liver such as VLDL-TAG and 3-hydroxybutyrate offers the best insight into postprandial hepatic fatty acid metabolism in human subjects. Diet derived fatty acids are taken up by the liver and mix with fatty acids coming from the lipolysis of adipose tissue, and those already present in the liver (cytosolic TAG) and fatty acids synthesised de novo within the liver from non-lipid precursors (known as de novo lipogenesis). Fatty acids are removed from the liver by secretion as VLDL-TAG and oxidation. Perturbations in these processes have the potential to impact on metabolic health. Whether fatty acids are partitioned towards oxidation or esterification pathways appears to be dependent on a number of metabolic factors; not least ambient insulin concentrations. Moreover, along with the phenotype and lifestyle factors (e.g. habitual diet) of an individual, it is becoming apparent that the composition of the diet (macronutrient and fatty acid composition) may play pivotal roles in determining if intra-hepatic fat accumulates, although what remains to be elucidated is the influence these nutrients have on intra-hepatic fatty acid synthesis and partitioning. PMID- 30457068 TI - Weight change increases the odds of psychological distress in middle age: bidirectional analyses from the Whitehall II Study. AB - BACKGROUND: Mood disorders and adiposity are major public health challenges. Few studies have investigated the bidirectional association of weight and waist circumference (WC) change with psychological distress in middle age, while taking into account the potential U-shape of the association. The aim of this study was to examine the bidirectional association between psychological distress and categorical change in objectively measured weight and WC. METHODS: We analysed repeated measures (up to 17 522 person-observations in adjusted analyses) of psychological distress, weight and WC from the Whitehall II cohort. Participants were recruited at age 35-55 and 67% male. Psychological distress was assessed using the General Health Questionnaire. We used random-effects regressions to model the association between weight and WC changes and psychological distress, with and without a 5-year lag period. RESULTS: Psychological distress was associated with weight and WC gain over the subsequent 5 years but not the second 5-year period. Weight gain and loss were associated with increased odds for incident psychological distress in models with and without time-lag [odds ratio (OR) for incident psychological distress after 5-year time-lag: loss 1.20, 95% confidence interval (CI) 1.00-1.43; gain>5% 1.20, 95% CI 1.02-1.40]. WC changes were only associated with psychological distress in models without time-lag (OR for incident psychological distress: loss 1.29, 95% CI 1.02-1.64; gain>5% 1.33, 95% CI 1.11-1.58). CONCLUSIONS: Weight gain and loss increase the odds for psychological distress compared with stable weight over subsequent 10 years. In contrast, the association between psychological distress and subsequent weight and WC changes was limited to the first 5 years of follow-up. PMID- 30457069 TI - Profiles of visuospatial memory dysfunction in opioid-exposed and dependent populations. AB - BACKGROUND: Chronic opioid exposure is common world-wide, but behavioural performance remains under-investigated. This study aimed to investigate visuospatial memory performance in opioid-exposed and dependent clinical populations and its associations with measures of intelligence and cognitive impulsivity. METHODS: We recruited 109 participants: (i) patients with a history of opioid dependence due to chronic heroin use (n = 24), (ii) heroin users stabilised on methadone maintenance treatment (n = 29), (iii) participants with a history of chronic pain and prescribed tramadol and codeine (n = 28) and (iv) healthy controls (n = 28). The neuropsychological tasks from the Cambridge Neuropsychological Test Automated Battery included the Delayed Matching to Sample (DMS), Pattern Recognition Memory, Spatial Recognition Memory, Paired Associate Learning, Spatial Span Task, Spatial Working Memory and Cambridge Gambling Task. Pre-morbid general intelligence was assessed using the National Adult Reading Test. RESULTS: As hypothesised, this study identified the differential effects of chronic heroin and methadone exposures on neuropsychological measures of visuospatial memory (p < 0.01) that were independent of injecting behaviour and dependence status. The study also identified an improvement in DMS performance (specifically at longer delays) when the methadone group was compared with the heroin group and also when the heroin group was stabilised onto methadone. Results identified differential effects of chronic heroin and methadone exposures on various neuropsychological measures of visuospatial memory independently from addiction severity measures, such as injecting behaviour and dependence status. PMID- 30457070 TI - Treatment of anorexia nervosa: is it lacking power? PMID- 30457071 TI - Progressive Supranuclear Palsy-like Syndrome from Possible Cerebral Amyloid Angiopathy. PMID- 30457072 TI - Gongylonema infection of wild mammals in Japan and Sardinia (Italy). AB - The gullet worms, classical Gongylonema pulchrum and newly differentiated Gongylonema nepalensis, are prevalent in various mammals in Japan and Sardinia, Italy, respectively. The former species is cosmopolitan in distribution, dwelling in the mucosa of the upper digestive tract of a variety of domestic and wild mammals, and also humans. At present, the geographical distribution of G. nepalensis is known in Nepal and Sardinia, with the nematode having been recorded from the oesophagus of water buffaloes (Nepal), cattle, sheep, goats and wild mouflon (Sardinia). To clarify their natural transmission cycles among domestic and wild mammals, the present study analysed the ribosomal RNA gene (rDNA) and mitochondrial cytochrome c oxidase subunit 1 gene (cox1) of worms of various origins: G. pulchrum worms from sika deer, wild boars, Japanese macaques, and feral alien Reeves's muntjacs in Japan, and G. nepalensis worms from a red fox and a wild boar in Sardinia. Although the internal transcribed spacer (ITS) regions of rDNA and partial cox1 nucleotide sequences of G. pulchrum from native wild mammals in Japan were distinct from those of the worms in cattle, the worms from feral alien Reeves's muntjacs showed the cattle-type ITS genotype and cox1 cattle-I and II haplotypes. The rDNA and cox1 nucleotide sequences of G. nepalensis from a red fox in Sardinia were almost identical to those of the worms from domestic and wild ruminants on the island. The ecological interaction between domestic and wild mammals and their susceptibility to different Gongylonema spp. must be considered when trying to elucidate this spirurid's transmission dynamics in nature. PMID- 30457073 TI - Tongue base mucosectomy for carcinoma of unknown primary using endoscopic electrocautery: rationale for wider implementation of an institutionally restricted technique. AB - BACKGROUND: Cervical metastasis from an unknown primary site invariably results in pan-mucosal irradiation if a primary tumour is not identified. Transoral robotic and laser-assisted mucosectomy are valid techniques to increase diagnostic rates, but these remain restricted to certain centres. This paper describes, in detail, a technique in which mucosectomy is performed via endoscopic electrocautery. METHODS: Patients were prospectively recruited between May 2017 and June 2018. Inclusion criteria stipulated biopsy-proven metastatic cervical squamous cell carcinoma, with negative findings on magnetic resonance imaging and positron emission tomography/computed tomography, in addition to examination under anaesthetic, tonsillectomy and 'blind' tongue base biopsies without tumour identification, prior to mucosectomy. RESULTS: Of nine patients, a mucosal primary was identified in four (44.4 per cent), for which ipsilateral intensity-modulated radiotherapy was advocated in three and completion tongue base resection in the fourth. Dysplasia was demonstrated in two further patients, which provided information relevant to radiotherapy fields and post-treatment surveillance. No surgical complications were identified. CONCLUSION: Tongue base mucosectomy using electrocautery and conventional tonsillectomy equipment is a safe, effective technique in the identification of cervical metastasis from an unknown primary site. It expands the potential breadth of use, quickens prolonged diagnostic pathways and obviates the necessity for pan-mucosal irradiation. PMID- 30457074 TI - Rejoinder relating to correspondence by Dr Eleanor Woodward, Professor Robyn Richmond on Brose LS, Simonavicius E, McNeill A (2018). Maintaining abstinence from smoking after a period of enforced abstinence. PMID- 30457075 TI - Augmentation therapies for treatment-resistant depression: systematic review and meta-analysis. AB - BACKGROUND: Depression is considered to have the highest disability burden of all conditions. Although treatment-resistant depression (TRD) is a key contributor to that burden, there is little understanding of the best treatment approaches for it and specifically the effectiveness of available augmentation approaches.AimsWe conducted a systematic review and meta-analysis to search and quantify the evidence of psychological and pharmacological augmentation interventions for TRD. METHOD: Participants with TRD (defined as insufficient response to at least two antidepressants) were randomised to at least one augmentation treatment in the trial. Pre-post analysis assessed treatment effectiveness, providing an effect size (ES) independent of comparator interventions. RESULTS: Of 28 trials, 3 investigated psychological treatments and 25 examined pharmacological interventions. Pre-post analyses demonstrated N-methyl-d-aspartate-targeting drugs to have the highest ES (ES = 1.48, 95% CI 1.25-1.71). Other than aripiprazole (four studies, ES = 1.33, 95% CI 1.23-1.44) and lithium (three studies, ES = 1.00, 95% CI 0.81-1.20), treatments were each investigated in less than three studies. Overall, pharmacological (ES = 1.19, 95% CI 1.80-1.30) and psychological (ES = 1.43, 95% CI 0.50-2.36) therapies yielded higher ESs than pill placebo (ES = 0.78, 95% CI 0.66-0.91) and psychological control (ES = 0.94, 95% CI 0.36-1.52). CONCLUSIONS: Despite being used widely in clinical practice, the evidence for augmentation treatments in TRD is sparse. Although pre-post meta analyses are limited by the absence of direct comparison, this work finds promising evidence across treatment modalities.Declaration of interestIn the past 3 years, A.H.Y. received honoraria for speaking from AstraZeneca, Lundbeck, Eli Lilly and Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion and Janssen; and research grant support from Janssen. In the past 3 years, A.J.C. received honoraria for speaking from AstraZeneca and Lundbeck; honoraria for consulting with Allergan, Janssen, Livanova, Lundbeck and Sandoz; support for conference attendance from Janssen; and research grant support from Lundbeck. B.B. has recently been (soon to be) on the speakers/advisory board for Hexal, Lilly, Lundbeck, Mundipharma, Pfizer, and Servier. No other conflicts of interest. PMID- 30457076 TI - Detecting Clostridium difficile outbreaks with ward-specific cut-off levels based on the Poisson distribution. PMID- 30457077 TI - Prescribing of psychotropic drugs and indicators for use in residential aged care and residents with dementia. AB - : ABSTRACTIntroduction:It is well established that there is a high prescribing rate of psychotropic agents in residential aged care (RAC). The appropriateness of these medications has become controversial, given the limited data on efficacy and growing evidence of associated adverse outcomes. OBJECTIVE: To assess psychotropic prescribing in RAC including identification of potentially inappropriate prescriptions (PIPs) and common psychological and behavioral symptoms indicated for prescribing. These were viewed in context of dementia and different RAC facilities. METHODS: Electronic care plans of 779 RAC residents across 12 facilities were examined to elucidate psychotropic prescribing rates, PIPs, and indications for use. RESULTS: One in two residents (48.1%) were prescribed a psychotropic drug. The primary reasons for prescribing were depression (61.5%), anxiety (26.7%), sleep problems (25.4%), agitation (13.7%), psychosis (11.0%), and other behaviors (7.2%). Residents with dementia (56.6%) were more likely to be prescribed a drug for agitation and psychosis, and had a significantly increased prescription rate for antidepressants (OR = 1.50, 95% CI = 1.08-2.08, p = 0.01) and antipsychotics (OR = 1.88, 95% CI = 1.23-2.88, p < 0.01). Conversely, residents with dementia were less likely to receive medication to combat sleeping difficulties, with significantly lower benzodiazepine prescribing (OR = 0.63, 95% CI = 0.44-0.91, p = 0.01). Over half of all psychotropic prescriptions (54.0%) were potentially inappropriate based on the Beers Criteria. There was high variability of prescribing rates between homes. CONCLUSION: There is a high prescribing rate of potentially inappropriate medications. Residents with dementia are more likely to receive medication for agitation and psychosis, and are less likely to receive medication to combat sleeping difficulties. PMID- 30457078 TI - Course of Cognitive Functioning in Institutionalized Persons With Moderate to Severe Dementia: Evidence From the Severe Impairment Battery Short Version. AB - OBJECTIVES: To adequately monitor the course of cognitive functioning in persons with moderate to severe dementia, relevant cognitive tests for the advanced dementia stages are needed. We examined the ability of a test developed for the advanced dementia stages, the Severe Impairment Battery Short version (SIB-S), to measure cognitive change over time. Second, we examined type of memory impairment measured with the SIB-S in different dementia stages. METHODS: Participants were institutionalized persons with moderate to severe dementia (N = 217). The SIB-S was administered at 6-month intervals during a 2-year period. Dementia severity at baseline was classified according to Global Deterioration Scale criteria. We used mixed models to evaluate the course of SIB-S total and domain scores, and whether dementia stage at baseline affected these courses. RESULTS: SIB-S total scores declined significantly over time, and the course of decline differed significantly between dementia stages at baseline. Persons with moderately severe dementia declined faster in mean SIB-S total scores than persons with moderate or severe dementia. Between persons with moderate and moderately severe dementia, there was only a difference in the rate of decline of semantic items, but not episodic and non-semantic items. CONCLUSIONS: Although modest floor and slight ceiling effects were noted in severe and milder cases, respectively, the SIB-S proved to be one of few available adequate measures of cognitive change in institutionalized persons with moderate to severe dementia. (JINS, 2018, 00, 1 11). PMID- 30457079 TI - Developing a Comprehensive Trauma- and Resiliency- Focused Program After Superstorm Sandy in New York City. AB - ABSTRACTTo contribute to the ongoing discourse about successful programming supporting intermediate behavioral and mental health needs of vulnerable communities affected by disaster, this article presents the Children's Health Fund (CHF) Sandy Recovery and Resiliency Program as a descriptive case study for a multifaceted, community-based approach to building resiliency, coping, and socioemotional skills in an underserved community in New York City that was affected by Superstorm Sandy. The case study involves retrospective review and analysis of qualitative and quantitative data that were collected as part of routine care and program implementation. From the analysis emerged a program consisting of 3 components: (1) delivery of workshops and community events to decrease stigma and build community-wide resilience, (2) delivery of workshops for students and educators in the local school to increase coping skills as well as referrals to clinical mental health care, and (3) provision of mental health care via a mobile mental health clinic. As a result, we found that following periods of excessive trauma, children and families require a broad-based approach to mental health support. Additionally, the use of the mobile clinic abated most common access barriers and served as a proxy of the concern of the organization for the community. (Disaster Med Public Health Preparedness. 2018;page 1 of 5). PMID- 30457080 TI - The effects of immunization against gonadotropin-releasing hormone on growth performance, reproductive activity and carcass traits of heavy weight gilts. AB - Heavy weight gilts commonly show signs of oestrus during the late finishing phase, which results in a period of reduced feed intake and growth rate. Immunization against gonadotropin-releasing hormone (GnRH) (IM, immunocastration) was developed for finishing boars and recently extrapolated to females. Immunocastration acts by suppressing reproductive activity and improving the growth potential. The objective of this study was to evaluate the effects of IM on growth performance, reproductive activity and carcass characteristics of late finishing gilts. Seventy-two gilts (63.49 +/- 0.39 kg) were either injected with saline (Intact) or immunized against GnRH (Immunized). The study consisted of three experimental periods: between the first to second immunization (V1 to V2, 15 to 19 weeks of age), from the second immunization to the beginning of daily boar exposure (DBE) (V2 to DBE, 19 to 21 weeks of age) and from the beginning of DBE to slaughter (S) (DBE to S, 21 to 25 weeks of age). Immunized gilts showed an overall increase (from 15 to 25 weeks) of 3.90 kg (P 0.05). Immunized gilts showed 4.4% increased cold carcass weight (P 0.05). Immunocastration reduced ovarian and uterine weights by 82% (P < 0.001) and 93% (P < 0.001), respectively, and suppressed oestrus manifestation in all gilts in the immunized group (P < 0.001). These results indicate that immunization against GnRH is a promising tool for stimulating growth performance with no detrimental effects on carcass quality of heavy weight finishing gilts, by means of oestrus suppression. PMID- 30457081 TI - Effects of wisdom and religiosity on subjective well-being in old age and young adulthood: exploring the pathways through mastery and purpose in life. AB - : ABSTRACTObjectives:Prior research found that the positive association between wisdom and subjective well-being might at least partially be explained by a greater sense of mastery and purpose in life. This study tested whether religiosity provides an alternative pathway to well-being and whether the associations are moderated by age cohort and nation of residency. DESIGN AND PARTICIPANTS: A quota sample design was used, stratified by age group, sex, and nation of residency, to collect cross-sectional survey data of 111 older adults (age range 62-99 years, M = 77.20, SD = 8.98) and 100 young adults (age range 21 30 years, M = 24.05, SD = 2.69) from Canada and the United States. MEASUREMENTS: Face-to-face interviews were conducted to administer the survey. All measures consisted of validated scales and items. RESULTS: Multi-group path analysis confirmed that mastery and purpose in life partially mediated the association between wisdom and well-being. Religiosity offered an alternative pathway to well being, also partially through a greater sense of mastery and purpose in life. Wisdom was statistically more strongly related to mastery among older adults, whereas the association between mastery and purpose in life was statistically stronger among young adults. The mediated pathways from wisdom and religiosity to well-being did not differ by nation of residency. CONCLUSIONS: These results highlight the importance of internal strengths for subjective well-being among both young and older adults and add confidence to the generalizability of the mediated path model for North America. PMID- 30457082 TI - Effect of bidi smoking on nasal mucociliary clearance: a comparative study. AB - OBJECTIVE: To compare nasal mucociliary clearance in adult non-smokers, cigarette smokers and bidi smokers using the methylene blue dye test. METHODS: The study sample consisted of 20 non-smokers, 20 cigarette smokers and 20 bidi smokers (age range, 20-40 years). A single drop of the methylene blue dye was placed at the anterior end of the inferior turbinate of the participants' nasal cavity. The distance travelled by the methylene blue in 15 minutes inside the nasal cavity was measured. Nasal mucociliary clearance of the three groups was compared using the Kruskal Wallis test. RESULTS: Nasal mucociliary clearance was significantly decreased in bidi smokers as compared to cigarette smokers and non-smokers (p < 0.05). Multivariate analysis revealed a significant association between nasal mucociliary clearance and bidi smoking, number of cigarettes or bidis smoked per day, and pack-years (all p < 0.05). CONCLUSION: Nasal mucociliary clearance measurement is a simple and useful index for assessing the effect of smoking on the mucociliary activity of nasal mucosa. PMID- 30457083 TI - Cellular fraction analysis of pericardial effusion helps the diagnosis of eosinophilic myocarditis. AB - Eosinophilic myocarditis is rare in children, and consequently, it is difficult to diagnose eosinophilic myocarditis rapidly. We report the clinical course of acute eosinophilic myocarditis with pericarditis in two adolescent boys and their associated electrocardiograms. The two patients, 13- and 14-year-old boys, developed cardiomegaly and chest pain with vomiting. On examination by two dimensional echocardiography, thickening of the ventricular septum and a pericardial effusion were detected. The eosinophil count had increased by the pericardial effusion. Acute eosinophilic myocarditis often complicates a moderate to severe pericardial effusion owing to acute pericarditis. A cellular fraction analysis of the pericardial effusion is easy and useful for the diagnosis of eosinophilic myocarditis. Some serial changes in the electrocardiogram occur during each stage of acute eosinophilic myocarditis. They are induced by eosinophilic granules, which are capable of inducing tissue damage and dysfunction, and those changes in the electrocardiogram resemble the changes after an acute myocardial infarction. It is important to know the characteristics of eosinophilic myocarditis in order to prevent lethal complications. PMID- 30457084 TI - Symptoms of problematic feeding in children with CHD compared to healthy peers. AB - Children with CHD often experience difficulty with oral feeding, which contributes to growth faltering in this population. Few studies have explored symptoms of problematic feeding in children with CHD using valid and reliable measures of oral feeding. The purpose of this study was to describe symptoms of problematic feeding in children with CHD compared to healthy children without medical conditions, taking into account variables that may contribute to symptoms of problematic feeding. Oral feeding was measured by the Pediatric Eating Assessment Tool, a parent report assessment of feeding with evidence of validity and reliability. This secondary analysis used data collected from web-based surveys completed by parents of 1093 children between 6 months and 7 years of age who were eating solid foods by mouth. General linear models were used to evaluate the differences between 94 children with CHD and 999 children without medical conditions based on the Pediatric Eating Assessment Tool total score and four subscale scores. Covariates tested in the models included breathing tube duration, type of CHD, gastroesophageal reflux, genetic disorder, difficulty with breast- or bottle-feeding during infancy, cardiac surgery, and current child age. Children with CHD had significantly more symptoms of problematic feeding than healthy children on the Pediatric Eating Assessment Tool total score, more physiologic symptoms, problematic mealtime behaviours, selective/restrictive eating, and oral processing dysfunction (p <0.001 for all), when taking into account relevant covariates. Additional research is needed in children with CHD to improve risk assessment and develop interventions to optimise feeding and growth. PMID- 30457085 TI - Intergenerational associations in physical maltreatment: Examination of mediation by delinquency and substance use, and moderated mediation by anger. AB - Findings as to whether individuals' experiences of physical maltreatment from their parents in childhood predict their own perpetration of physical maltreatment toward their children in adulthood are mixed. Whether the maltreatment experienced is severe versus moderate or mild may relate to the strength of intergenerational associations. Furthermore, understanding of the roles of possible mediators (intervening mechanisms linking these behaviors) and moderators of the intervening mechanisms (factors associated with stronger or weaker mediated associations) is still relatively limited. These issues were examined in the present study. Mediating mechanisms based on a social learning model included antisocial behavior as assessed by criminal behaviors and substance use (alcohol and drug use), and the extent to which parental angry temperament moderated any indirect effects of antisocial behavior was also examined. To address these issues, data were used from Generations 2 and 3 of a prospective three-generational study, which is an extension of the Oregon Youth Study. Findings indicated modest intergenerational associations for severe physical maltreatment. There was a significant association of maltreatment history, particularly severe maltreatment with mothers' and fathers' delinquency. However, neither delinquency nor substance use showed significant mediational effects, and parental anger as a moderator of mediation did not reach significance. PMID- 30457086 TI - The utility of virtual reality surgical simulation in the undergraduate otorhinolaryngology curriculum. AB - OBJECTIVE: To examine the impact of temporal bone virtual reality surgical simulator use in the undergraduate otorhinolaryngology curriculum. METHODS: Medical students attended a workshop involving the use of a temporal bone virtual reality surgical simulator. Students completed a pre-workshop questionnaire on career interests. A post-workshop questionnaire evaluated the perceived usefulness and enjoyment of the virtual reality surgical simulator experience, and assessed changes in their interest in ENT. RESULTS: Thirty-two fifth-year University of Auckland medical students were recruited. The majority of students (53.1 per cent) had already chosen their career path. The simulator experience was useful for: stimulating thoughts around career plans (71.9 per cent), providing hands-on experience (93.8 per cent) and teaching disease processes (93.8 per cent). After the workshop, 53.1 per cent of students were more interested in a career in ENT. CONCLUSION: Virtual reality may be a fun and engaging way of teaching ENT. Furthermore, it could help guide student career planning. PMID- 30457087 TI - New Canadian guideline provides evidence-based approach to non-occupational HIV prophylaxis. AB - The incidence of HIV infections in Canada has increased yearly since 2014. New cases of HIV have resulted almost exclusively from non-occupational exposures, including sexual contact and needle sharing. Appropriate HIV post-exposure prophylaxis is under-prescribed to patients who present to the emergency department after a high-risk exposure. In November of 2017, a Canadian guideline on HIV pre-exposure prophylaxis (PrEP) and non-occupational post-exposure prophylaxis (nPEP) was published. The guideline presents a standardized, evidence based approach to assessing risk for HIV transmission and prescribing HIV prophylaxis. This summary highlights the key points from the guideline that are relevant to the practice of emergency medicine in Canada. PMID- 30457088 TI - Intervention Packages for Early Visceral Leishmaniasis Case Detection and Sandfly Control in Bangladesh: A Comparative Analysis. AB - We compared the efficacy of three intervention packages for active case detection (ACD) of visceral leishmaniasis (VL)/post-kala-azar dermal leishmaniasis (PKDL) combined with sandfly control around an index case. The packages were 1) no kala azar transmission activity involving indoor residual spraying (IRS) with deltamethrin, peri-domestic deployment of larvicide with temephos, and house-to house search for cases; 2) fever camp (FC) plus durable wall lining (DWL) with deltamethrin; and 3) FC plus insecticide (deltamethrin) impregnated bed-nets (ITN) around an index case. Fever camp includes 1-day campaign at the village level to screen and diagnose VL, PKDL, leprosy, malaria, and tuberculosis among residents with chronic fever or skin disease. Efficacy was measured through yield of new cases, vector density reduction, and mortality at 1, 3, 6, 9, and 12 months following intervention. Fever camp + DWL was the most efficacious intervention package with 0.5 case detected per intervention, 79% reduction in vector density (incidence rate ratio [IRR] = 0.21, P = 0.010), and 96% (95% confidence interval: 94.21%, 98.55%) sandfly mortality at 12 months. No kala-azar transmission activity was efficacious for vector control (74% vector reduction, IRR = 0.26, P < 0.0001 at 9 months; and 80% sandfly mortality at 3 months), but not for case detection (0 case per intervention). Fever camp + ITN was efficacious in detection of VL/PKDL cases (0.43 case per intervention), but its efficacy for vector control was inconsistent. We recommend index case-based FC for ACD combined with DWL or IRS plus larvicide for sandfly control during the consolidation and maintenance phases of the VL elimination program of the Indian subcontinent. PMID- 30457089 TI - Evidence of Self-Medication with Chloroquine before Consultation for Malaria in the Southern Pacific Coast Region of Colombia. AB - Self-medication with antimalarial drugs is a major factor in the development of drug resistance, exerting subtherapeutic drug pressure on circulating parasite populations. Data on self-medication with antimalarials from the Southern Pacific coast region of Colombia, where 4-aminoquinolines resistance and political instability prevail, are vital to elimination strategies. We present results of an exploratory study of 254 individuals having malaria symptoms who sought malaria diagnosis in two hospitals in Tumaco, Department of Narino, Colombia. Thirty-two percent (82/254) of participants had positive Saker-Solomons urine tests, indicating self-medication with chloroquine (CQ) before consultation for diagnosis. Notably, among 30 pregnant women participating in the study, 43% were Saker--Solomons positive. Molecular analysis of the K76T position encoded by the pfcrt gene revealed the mutant allele in all four samples that were both positive for Plasmodium falciparum and positive for the Saker-Solomons test, suggesting persistent CQ pressure. The high frequency of self-medication, particularly among pregnant women merits attention by public health authorities and comprehensive investigation. PMID- 30457090 TI - Clustering of Infant Mortality Within Families in Rural Burkina Faso. AB - In this study, we analyze clustering of infant deaths within families living in a rural part of western Burkina Faso. The study included 9,220 infants, born between 1993 and 2009 in Nouna Health and Demographic Surveillance System (HDSS). A clustering of infant deaths in families was explored by calculating observed versus expected number of infant deaths within families for a given family size. In addition, risk ratios were calculated for infant death depending on the vital status of the previous sibling. We observed 470 infant deaths, yielding an overall infant mortality risk of 51/1,000 births. Clustering of infant deaths within families was observed (P = 0.004). In smaller families, the mortality of firstborns was higher than for the following siblings. The infant mortality risk was higher when the preceding sibling died in infancy (P = 0.03). The study supports the hypothesis of infant death clustering existing within rural families in West Africa. Further studies are needed to shed more light on these findings with the goal to develop effective interventions directed toward the families who already lost a child. PMID- 30457091 TI - A Cross-Sectional Population Study of Geographic, Age-Specific, and Household Risk-Factors for Asymptomatic Plasmodium falciparum Malaria Infection in Western Kenya. AB - The burden of Plasmodium falciparum (Pf) malaria in Kenya is decreasing; however, it is still one of the top 10 causes of morbidity, particularly in regions of western Kenya. Between April 2015 and June 2016, we enrolled 965 apparently healthy children aged 0-15 years in former Nyanza and Western provinces in Kenya to characterize the demographic, geographic, and household risk factors of asymptomatic malaria as part of an epidemiologic study to investigate the risk factors for endemic Burkitt lymphoma. The children were sampled using a stratified, multistage cluster sampling survey design. Malaria was assessed by rapid diagnostic test (RDT) and thick-film microscopy (TFM). Primary analyses of Pf malaria prevalence (pfPR) are based on RDT. Associations between weighted pfPR and potential risk factors were evaluated using logistic regression, accounting for the survey design. Plasmodium falciparum malaria prevalence was 36.0% (27.5%, 44.5%) by RDT and 22.3% (16.0%, 28.6%) by TFM. Plasmodium falciparum malaria prevalence was positively associated with living in the lake-endemic area (adjusted odds ratio [aOR] 3.46; 95% confidence interval [95% CI] 1.63, 7.37), paternal occupation as peasant farmer (aOR 1.87; 1.08, 3.26) or manual laborer (aOR 1.83; 1.00, 3.37), and keeping dogs (aOR 1.62; 0.98-2.69) or cows (aOR 1.52; 0.96-2.40) inside or near the household. Plasmodium falciparum malaria prevalence was inversely associated with indoor residual insecticide spraying (IRS) (aOR 0.44; 0.19, 1.01), having a household connected to electricity (aOR 0.47; 0.22, 0.98), and a household with two (aOR 0.45; 0.22, 0.93) or >= three rooms (aOR 0.41; 0.18, 0.93). We report high but geographically heterogeneous pfPR in children in western Kenya and significant associations with IRS and household level socioeconomic factors. PMID- 30457092 TI - Acute Flavivirus and Alphavirus Infections among Children in Two Different Areas of Kenya, 2015. AB - Alphaviruses and flaviviruses are known to be endemic in Eastern Africa, but few data are available to evaluate the prevalence of these infections. This leads to missed opportunities for prevention against future outbreaks. This cohort study investigated the frequency of alphavirus and flavivirus incident infections in two regions of Kenya and identified potential risk factors. Seroconversions for alphavirus and flavivirus infections were identified by IgG ELISA in a cohort of 1,604 acutely ill children over the year 2015. The annual incidence was 0.5% (0.2 1.2%) for alphaviruses and 1.2% (0.7-2.2%) for flaviviruses. Overall, seroprevalence was significantly higher for alphaviruses in western Kenya than on the coast (P = 0.014), whereas flavivirus seroprevalence was higher on the coast (P = 0.044). Poverty indicators did not emerge as risk factors, but reliance on household water storage was associated with increased exposure to both alphaviruses and flaviviruses (odds ratio = 2.3). PMID- 30457093 TI - Serum Procalcitonin Concentration and Its Relationship with Local Manifestations after Snakebites. AB - The local signs and symptoms following snakebites are similar to those of cellulitis caused by bacterial infections. This leads to empirical treatment with antibiotics, which however is not supported by evidence. Procalcitonin (PCT) is a biomarker with good diagnostic accuracy for bacterial infection. We studied serum PCT concentration in 100 patients aged 13 years or more, presenting to the hospital with significant local manifestations (crossing the joint proximal to the bitten wound) within 24 hours after snakebite. The extent and progression of local manifestations were monitored 12 hourly. Baseline PCT measurement was carried out for all patients and measurement was repeated 12 hourly only in those patients with progressive local manifestations. The median interqartile range PCT concentration did not differ significantly by the severity of local manifestation at presentation (Grade 2 = 0.28 [0.26-0.30]; Grade 3 = 0.28 [0.26-0.32]; Grade 4 = 0.27 [0.26-0.32] ng/mL; P = 0.15). Furthermore, we did not observe an increase in PCT concentration on serial estimation in those with progressive local manifestation (0.28, 0.29, and 0.29 ng/mL) over 36 hours. These observations suggest that the local manifestations following snakebites were not caused by bacterial infection. PMID- 30457094 TI - Fatal Snakebite Envenoming and Agricultural Work in Brazil: A Case-Control Study. AB - We investigated the association between fatal snakebite envenoming and agricultural work in Brazil, considering the effects of relevant covariables. A nested case-control study was performed using 1,119 fatal cases of snakebite envenoming among persons aged >= 10 years, notified to the Brazilian official reporting system, from 2004 to 2015. As controls, 4,476 cases were randomly selected from the 115,723 nonfatal cases of snakebite, without missing data, that occurred in the same time period. The main predictor was occupation in the agriculture sector; the main outcome was death by snakebite envenoming. Logistic regression analysis was used to investigate the main association, controlling for the effects of relevant covariables. Fatal cases had a 20% greater chance (odds ratio [OR] = 1.20; 95% confidence interval [CI]: 1.00-1.39) of being among farmers than the controls. However, late (>= 6 hours) time to treatment (OR = 2.00; 95% CI: 1.70-2.36); adequate antivenom with an insufficient (OR = 1.25; 95% CI: 1.04-1.50) or excessive (OR = 4.89; 95% CI: 4.10-6.03) number of vials; inadequate antivenom and insufficient or excessive number of vials (OR = 3.87; 95% CI: 2.40-6.24); no use of antivenom (OR = 2.05; 95% CI: 1.60-2.64); and age >= 60 years (OR = 1.98; 95% CI: 1.61-2.44) were more strongly associated with lethality. Lethality was 1.0% in the period, being 0.47% among those receiving early and adequate treatment. We concluded that in Brazil, fatal snakebite envenoming was associated with agricultural work, controlling for relevant covariates. However, quality of health care provided and greater age were much more strongly associated with lethality. PMID- 30457095 TI - Case Report: Central Nervous System Strongyloidiasis: Two Cases Diagnosed Antemortem. AB - Central nervous system (CNS) strongyloidiasis is a known but rare form of disseminated infection. The diagnosis is often made postmortem, with only five published cases of an antemortem diagnosis. We report two fatal cases of CNS strongyloidiasis diagnosed antemortem, with Strongyloides stercoralis larvae visualized in the CNS sample in one case. Risk factors for disseminated strongyloidiasis common to both cases included origination from the Caribbean, underlying human T-lymphotropic virus-1 infection, and recent prednisone use. Both cases occurred in Canada, where the occurrence of Strongyloides is uncommon, and serve as a reminder to maintain a high index of suspicion in patients with epidemiologic or clinical risk factors for dissemination. PMID- 30457096 TI - Evaluating Urban Taeniasis as a Threat to Cysticercosis Elimination in Northern Peru. AB - Reintroduction of Taenia solium into a region in Peru where it had been eliminated prompted evaluation of the possibility of reintroduction from an urban reservoir of taeniasis. In a cross-sectional study of an adjacent urban area, we found low prevalence of taeniasis (4/1,621; 0.25%), suggesting minimal risk of parasite reintroduction into rural areas through this route. PMID- 30457097 TI - Chloroquine-Primaquine Therapeutic Efficacy, Safety, and Plasma Levels in Patients with Uncomplicated Plasmodium vivax Malaria in a Colombian Pacific Region. AB - In Colombia, published studies for the treatment of uncomplicated Plasmodium vivax malaria with chloroquine-primaquine (CQ-PQ) are scarce. The aim of the study was to evaluate the therapeutic efficacy and safety profile of this combination. A clinical trial was performed in adults with uncomplicated P. vivax malaria using the 28-day World Health Organization validated protocol. Patients received supervised antimalarial treatment and the primary efficacy end point was the clinical and parasitological response. Safety was assessed through adverse events surveillance, and plasma levels of antimalarial drugs were measured. A total of 77 patients were included. Adequate clinical and parasitological response rate diagnosed by thick blood smear examination was achieved in 72 of 73 patients (98.6%) with a complete 28-day follow-up. There were two parasitological therapeutic failures (TFs) (2.9%) on day 28, established by polymerase chain reaction among 68 patients, one of them with a positive film. No adverse events were detected. After completing the antimalarial treatment, all patients reached adequate plasma concentrations of CQ and desethylchloroquine (DECQ), with medians of 302.9 and 104.0 ng/mL, respectively. Uncomplicated P. vivax malaria treatment with CQ-PQ standard treatment was effective and safe in the study population; TFs were not associated with low plasma levels of CQ and DECQ. PMID- 30457098 TI - High Prevalence of Extended-Spectrum Beta-Lactamase CTX-M-Producing Escherichia coli in Small-Scale Poultry Farming in Rural Ecuador. AB - Small-scale farming may have large impacts on the selection and spread of antimicrobial resistance to humans. We conducted an observational study to evaluate antibiotic-resistant Escherichia coli populations from poultry and humans in rural northwestern Esmeraldas, Ecuador. Our study site is a remote region with historically low resistance levels of third-generation antibiotics such cefotaxime (CTX), a clinically relevant antibiotic, in both poultry and humans. Our study revealed 1) high CTX resistance (66.1%) in farmed broiler chickens, 2) an increase in CTX resistance over time in backyard chicken not fed antibiotics (2.3-17.9%), and 3) identical bla CTX-M sequences from human and chicken bacteria, suggesting a spillover event. These findings provide evidence that small-scale meat production operations have direct impacts on the spread and selection of clinically important antibiotics among underdeveloped settings. PMID- 30457099 TI - Severe Disseminated Gonococcal Infection with Polyarticular Gout: Two Cases in Older Travelers. AB - Two male travelers with histories of gout and hazardous alcohol consumption, presented with a triad of severe culture-positive disseminated gonococcal infection, crystal-positive polyarticular gout, and gonococcal soft tissue collections, following unprotected sexual contact in The Philippines. Both men initially attributed symptoms to gout, since their usual joints were affected, but clinical deterioration occurred with self-administration of anti-inflammatory agents alone. The clinical courses were severe and protracted, requiring aggressive management of infection with prolonged intravenous antimicrobials and repeated surgery, and prolonged anti-inflammatory agents for gout. Joint symptom onset in each case occurred within a week of sexual exposure in conjunction with hazardous alcohol ingestion. We speculate that acute dissemination of infection to previously damaged joints triggered polyarticular gout, with progressive infection, exacerbated by unopposed anti-inflammatory agents and delayed antibiotics. Disseminated gonococcal infection can occur with polyarticular gout and delays in recognition and treatment, including while traveling, can lead to severe disease from both. PMID- 30457100 TI - Diagnosis of Cryptosporidiosis in Renal Transplantation in a Low-Prevalence Setting. AB - Cryptosporidiosis is commonly described as a cause of gastroenteritis syndrome in the organ transplant population, mainly in high-prevalence settings, with stool microscopy as the predominant diagnostic modality. Therapeutic options in this group of patients are limited, making their management exceptionally challenging. We describe a case of a renal transplant recipient with cryptosporidiosis confirmed by the stool FilmArray gastrointestinal panel (GIP) nucleic acid-based assay and stool microscopy, describe our institutional experience in diagnosing cryptosporidiosis in a low-prevalence setting, and review the available literature on management of this condition in the organ transplant population. In a low-prevalence setting, the GIP can serve as a rapid screening tool in the diagnosis of cryptosporidiosis. PMID- 30457101 TI - Biliary Taeniasis with Cholecystitis: An Unusual Case of Taenia solium Infection with a Literature Review. AB - Taeniasis is a cosmopolitan helminthic disease caused by Taenia species, which included Taenia solium, Taenia saginata, and Taenia asiatica. These parasites typically infect the small intestine, but cases of aberrant migration have been reported. We treated a 70-year-old man who presented with vomiting and colicky abdominal pain. On physical examination, Murphy's sign was positive, and laboratory findings indicated severe inflammation. Computed tomography and magnetic resonance cholangiopancreatography revealed typical features of cholecystitis. An 82-cm-long, slender and degenerated, parasite-like organism was aspirated through a percutaneous transhepatic gallbladder drainage tube. After extensive washing of the organism, we detected yellowish-brown colored, spherical 37.9 * 33.8-um-sized taenid eggs with thick transverse striations. Hematoxylin eosin-stained worm sections also contained Taeniidae eggs. Polymerase chain reaction amplification of DNA extracted from the worm with species-specific cytochrome c1 primer sets detected a T. solium-specific fragment. Because of sustained high fever combined with inflammatory signs, the patient underwent laparoscopic cholecystectomy and inflamed gallbladder removal. A histopathologic specimen demonstrated chronic reactive cholecystitis. The patient's fever and leukocytosis rapidly resolved after surgery. We experienced an uncommon case of biliary taeniasis representing cholecystitis caused by adult worm of T. solium. PMID- 30457102 TI - Development of a Novel Protocol Based on Blood Clot to Improve the Sensitivity of qPCR Detection of Toxoplasma gondii in Peripheral Blood Specimens. AB - Quantitative polymerase chain reaction (qPCR) for Toxoplasma gondii multicopy genes has emerged as a promising strategy for sensitive detection of parasite DNA. Quantitative polymerase chain reaction can be performed from blood samples, which are minimally invasive to collect. However, there is no consensus about what type of blood specimen yields the best sensitivity in qPCR assays. The development of a novel protocol for qPCR detection of T. gondii using blood clot, involving an appropriate DNA extraction method and the use of an internal amplification control to monitor the reaction is presented in the present study. Quantitative polymerase chain reaction assays directed to the B1 and REP529 genes were performed in spiked specimens of whole blood, guanidine-EDTA blood, and clot. The clot-based qPCR was shown to be more sensitive when compared with other types of specimens, detecting five and 0.05 T. gondii genomes, using B1 and REP529 targets, respectively. Finally, a comparative analysis with samples from HIV patients with clinical suspicion of toxoplasmosis was performed, demonstrating the detection of four positive suspected cases with clots compared with only one using guanidine-EDTA blood. The high analytical sensitivity and the cost-effective advantages offered by clot supports this methodology as a good laboratory tool to monitor parasite burden. PMID- 30457105 TI - Impact of eHealth in Allergic Diseases and Allergic Patients. AB - The emergence of new technology grants allergists and patients the opportunity to compile data and receive feedback regarding key symptoms, risk behaviour and/or management. The term "eHealth" refers to a diverse group of tools that use computerized technologies to improve efficacy and efficiency of the health care industry. eHealth comprises a variety of technologies, such as the use of mobile devices (mHealth) in medical care, including electronic diaries, wearable sensors or adherence monitoring; health informatics (e.g. electronic health records, computerized physician order entry, clinical decision support); telemedicine, which is the use of information and communication technologies for the management of diseases and medical education; social media platforms, and the analysis of information acquired through these platforms using "big data" technologies. In this review, we summarize the evidence surrounding use of eHealth technology and relevance to allergic conditions. PMID- 30457103 TI - A stochastic epigenetic switch controls the dynamics of T-cell lineage commitment. AB - Cell fate decisions occur through the switch-like, irreversible activation of fate-specifying genes. These activation events are often assumed to be tightly coupled to changes in upstream transcription factors, but could also be constrained by cis-epigenetic mechanisms at individual gene loci. Here, we studied the activation of Bcl11b, which controls T-cell fate commitment. To disentangle cis and trans effects, we generated mice where two Bcl11b copies are tagged with distinguishable fluorescent proteins. Quantitative live microscopy of progenitors from these mice revealed that Bcl11b turned on after a stochastic delay averaging multiple days, which varied not only between cells but also between Bcl11b alleles within the same cell. Genetic perturbations, together with mathematical modeling, showed that a distal enhancer controls the rate of epigenetic activation, while a parallel Notch-dependent trans-acting step stimulates expression from activated loci. These results show that developmental fate transitions can be controlled by stochastic cis-acting events on individual loci. PMID- 30457104 TI - The lost world of Cuatro Cienegas Basin, a relictual bacterial niche in a desert oasis. AB - Barriers to microbial migrations can lead adaptive radiations and increased endemism. We propose that extreme unbalanced nutrient stoichiometry of essential nutrients can be a barrier to microbial immigration over geological timescales. At the oasis in the Cuatro Cienegas Basin in Mexico, nutrient stoichiometric proportions are skewed given the low phosphorus availability in the ecosystem. We show that this endangered oasis can be a model for a lost world. The ancient niche of extreme unbalanced nutrient stoichiometry favoured survival of ancestral microorganisms. This extreme nutrient imbalance persisted due to environmental stability and low extinction rates, generating a diverse and unique bacterial community. Several endemic clades of Bacillus invaded the Cuatro Cienegas region in two geological times, the late Precambrian and the Jurassic. Other lineages of Bacillus, Clostridium and Bacteroidetes migrated into the basin in isolated events. Cuatro Cienegas Basin conservation is vital to the understanding of early evolutionary and ecological processes. PMID- 30457106 TI - Immune basis of food allergic reactions. AB - Food allergies are diseases where the normal tolerance response to oral antigens is altered. Recent advances have begun to uncover mechanisms that mediate sensitization to food allergens and maintenance of this disease. Production of alarmins by epithelial cells triggers a cascade that leads to allergen-specific IgE synthesis. A role of IL-9 in mast cell recruitment and amplification of allergic response has also been identified. In recent years, increasing evidence suggests that sensitization to food allergens can be developed by non-oral routes, in particular the skin, which led to the proposal of the 'dual exposure hypothesis'. Environmental factors such as diet or microbiota can shape the immune system to promote tolerance or sensitization to food antigens. While the mechanism of primary tolerance to food antigens is quite clear, the one leading to permanent tolerance in already food-allergic individuals through immunotherapy is still under study. Understanding the mechanisms by which oral tolerance is suppressed and sensitization is developed will help to identify new targets to develop combinatory therapies for the treatment of food allergies. PMID- 30457107 TI - Hemophagocytic Lymphohistiocytosis in Dermatomyositis PMID- 30457108 TI - Bull's Head Sign in a Patient with SAPHO Syndrome PMID- 30457109 TI - The Adipokine Profile and the Cardio-Metabolic Risk in Non-Obese Young Adults. AB - BACKGROUND: Young, non obese adults are considered at low risk for cardio metabolic diseases, although markers of unhealthy metabolic state are not uncommon findings in this population. The dysfunction of the adipose tissue, evaluated by the adipokine profile, significantly influences lipid and glucose metabolism and the low grade systemic inflammation. AIMS: To determine the relation between the adipose tissue dysfunction and already confirmed indicators of the cardio-metabolic risk: the atherogenic index of plasma (AIP), the lipid accumulation product (LAP), the homeostatic model assessment of insulin resistance (HOMA-IR) and the low grade inflammation markers: interleukin 6 and high sensitivity C-reactive protein (hsCRP). STUDY DESIGN: cross-sectional. METHODS: We recruited 93 non obese, healthy young adults. Anthropometric, lipid profile, inflammatory markers and adipokines were measured. An abnormal adipokine profile (high leptin to adiponectin ratio) was considered as marker of a dysfunctional adipose tissue. The correlation between the leptin to adiponectin ratio, on one side, and the anthropometric measurements, the AIP, the LAP, HOMA IR, the interleukin 6 and the hsPrC, on the other side, was determined. RESULTS: We found a direct correlation between the abnormal adipokine profile and the cardio-metabolic risk indicators mentioned above, except for the low grade inflammatory markers. In the regression model derived from our data, leptin to adiponectin ratio was best correlated with the unfavorable plasma lipid profile, as estimated by the AIP (r=0.097, CI=0.015-0.180, p=0.021). Significanly higher leptin to adiponectin ratio was found in the insulin resistant group (p=0.012) and in the highest LAP quartile (p=0.032). CONCLUSION: Our results suggest that high leptin to adiponectin ratio is a suitable candidate for the cardio-vascular and metabolic risk assessment in young, non-obese population. PMID- 30457110 TI - Cystoscopic evaluation and clinical phenotyping in interstitial cystitis / Bladder pain syndrome. AB - Herein, we aimed to review, report and discuss the role of cystoscopy and clinical phenotyping in interstitial cystitis/bladder pain syndrome (IC/BPS). For this purpose; a comprehensive nonsystematic review of the relevant literature was conducted. We reviewed articles published in English and indexed in the PubMed, Embase, and Google Scholar databases. Original manuscripts, review articles, case series, and case reports were taken into consideration. Data regarding the indications for, technique and possible findings of cystoscopy with hydrodistension (HD) and biopsy, as well as clinical implications of cystoscopic information and the concept and utility of clinical phenotyping within the context of IC/BPS were extracted and discussed. IC/BPS is diagnosed based on symptomatic assessment and exclusion of confusable diseases. There is not a universal aggrement upon the evaluation and diagnostic algorithm of IC/BPS. The majority of the guidelines recommend cystoscopy with HD and biopsy as a diagnostic prerequisite. Various different techniques have been described for cystoscopy with HD. General or epidural anesthesia is more commonly preferred and advocated while assessing endoscopic alterations in patients suspected of having IC/BPS. Cystoscopy with HD and biopsy enables more objective exclusion of confusable diseases. It also provides the basis of European Society for the Study of Interstitial Cystitis classification. IC/BPS patients who demonstrate positive cystoscopic (glomerulations and/or Hunner lesion) and histologic findings have a more severe symptomatology and may benefit from lesion-targeted endoscopic treatments. Clinical phenotyping has been implemented for IC/BPS and may be used for individualized assessment and treatment. Keywords: Bladder pain, cystoscopy, hydrodistension, biopsy, phenotyping. PMID- 30457111 TI - Special issue on multiprobe techniques. PMID- 30457112 TI - Avian-inspired energy-harvesting from atmospheric phenomena for small UAVs. AB - Fixed-wing small, unmanned aerial vehicles usually fly in atmospheric boundary layers that are often under the influence of turbulent environments. Inspired by nature's flyers, an application of an energy-harvesting flight strategy for increasing the energy state of the aircraft is presented. This paper provides basic longitudinal flight dynamic model exposing the physics behind the process. It shows significant power savings in flight with a sinusoidal and stochastic wind profile with active control of energy-harvesting. The active control based on optimized proportional gains was implemented for energy extraction from realistic atmospheric conditions, leading to significant energy savings for a 'bird-sized' vehicle. The paper reveals the equipment and necessary preparations for the flight test campaign. Moreover, it describes the design of a custom controller and its calibration in the wind tunnel against roll movements during pitching maneuvers. Finally, it investigates the benefits and potential of the automated process of energy-harvesting with simple proportional control through flight tests in a turbulent environment, validating the concept through the increased energy state of the aircraft. PMID- 30457113 TI - From healing wounds to resorbable electronics, levan can fill bioadhesive roles in scores of markets. AB - Levan is a fructose homopolysaccharide which gained attention recently for its unusual combination of properties distinguishing it from other natural biodegradable polysaccharides like chitosan, cellulose or starch. Among the strongest bioadhesives, film-forming levan is garnering interest for its role in some simple solutions to difficult problems. One of these is illustrated by the elegant research using laser-based techniques to construct levan films for healing wounds and burned tissue. Another is the development of bioresorbable electronic implants. Levan has been found in habitats as diverse as salterns and thermal waters to tropical plants and sugar factories. This review of the low viscosity, levan adhesive describes the mechanisms by which it forms bonds and the reasons behind some of its practical and industrial applications. Here we present descriptions from the literature for feasible approaches ready to transition from the laboratory to those searching for answers in fields as varied as medicine, packaging and furniture assembly. PMID- 30457114 TI - Mirror twin grain boundaries in molybdenum dichalcogenides. AB - Mirror twin grain boundaries (MTBs) exist at the interface between two grains of 60 degrees rotated hexagonal transition metal dichalcogenides (TMDC). These grain boundaries form a regular atomic structure that extends in one dimension and thus may be described as a one-dimensional (1D) lattice embedded in the 2D TMDC. In this review, the different atomic structures and compositions of these MTBs are discussed. The obvious formation of MTBs is by coalescence of two twinned grains. In addition, however, in MoSe2 and MoTe2 a different formation mechanism has been revealed for the formation of Mo-rich MTBs. It has been shown that excess Mo can be incorporated into the TMDC lattices. These excess Mo atoms can then reorganize into closed, triangular MTB-loops that can grow in size by adding more Mo atoms to them. This mechanism allows the formation of dense MTB networks in MoSe2 and MoTe2. Such MTB networks have been observed in samples grown by molecular beam epitaxy (MBE) and consequently their presence needs to be considered in understanding the properties of MBE grown MoSe2 and MoTe2. Density functional theory as well as photoemission spectroscopy of MTB networks have shown that MTBs exhibit dispersing 1D-bands that intersect the Fermi-level, thus suggesting that these are 1D electron systems. Consequently, experimental data have been interpreted to reveal a charge density wave (or Peierls) instability, as well as a Tomonaga-Luttinger liquid behavior for electrons confined in 1D. We discuss these observations and the controversies that remain in the interpretation of some data. The metallic properties of the MTBs and their formation in dense networks also sparked the potential use of such crystal modifications for making metallic contacts to MoTe2 or MoSe2. Moreover, these crystal modifications may also boost the catalytic properties of these materials. PMID- 30457115 TI - Radiative recombination in narrow gap HgTe/CdHgTe quantum well heterostructures for laser applications. AB - Radiative recombination is studied in CdHgTe/HgTe QWs with bandgap in the 40-140 meV range using four-band Kane model. Calculated radiative lifetimes agree well with the photoconductivity kinetics measurements. We show that the side maxima in the valence band hinder the radiative recombination at high carrier concentrations and discuss how to overcome this effect for the development of long-wavelength lasers. PMID- 30457116 TI - Statistical CT reconstruction using region-aware texture preserving regularization learning from prior normal-dose CT image. AB - In some clinical applications, prior normal-dose CT (NdCT) images are available, and the valuable textures and structure features in them may be used to promote follow-up low-dose CT (LdCT) reconstruction. This study aims to learn texture information from the NdCT images and leverage it for follow-up LdCT image reconstruction to preserve textures and structure features. Specifically, the proposed reconstruction method first learns the texture information from those patches with similar structures in NdCT image, and the similar patches can be clustered by searching context features efficiently from the surroundings of the current patch. Then it utilizes redundant texture information from the similar patches as a priori knowledge to describe specific regions in the LdCT image. The advanced region-aware texture preserving prior is termed as 'RATP'. The main advantage of the PATP prior is that it can properly learn the texture features from available NdCT images and adaptively characterize the region-specific structures in the LdCT image. The experiments using patient data were performed to evaluate the performance of the proposed method. The proposed RATP method demonstrated superior performance in LdCT imaging compared to the filtered back projection (FBP) and statistical iterative reconstruction (SIR) methods using Gaussian regularization, Huber regularization and the original texture preserving regularization. PMID- 30457117 TI - A statistically optimized regional thresholding method (SORT) for bone lesion detection in 18F-NaF PET/CT imaging. AB - Identification of individual lesions on 18F-NaF PET bone scans is a time consuming and often subjective process that makes accurate characterization of disease burden challenging. Current automated methods either underestimate disease or struggle with high false positive rates. We developed a statistically optimized regional thresholding (SORT) method that optimizes detection of bone lesions. This study assessed 18F-NaF PET/CT scans of 37 bone metastatic prostate cancer patients. Each PET image was divided into 19 skeletal regions. Areas of disease in each skeletal region were identified by an experienced nuclear medicine physician. A region of interest (ROI) was placed at each disease location and local maxima were extracted for both healthy and diseased ROIs. Secondary physician review was performed after identification of suspicious local maxima. Region-specific SUV thresholds were determined based on receiver operating characteristic (ROC) analysis optimized for detection of malignant disease. The detection performance of the SORT thresholds were compared to commonly used SUV > 10 g ml-1 (SUV10) and SUV > 15 g ml-1 (SUV15) global thresholds. The sensitivity of the SORT thresholds to various factors was evaluated, such as the number of subjects evaluated or image reconstruction settings. 1751 lesions were manually identified by the nuclear medicine physician. SORT identified different thresholds in each skeletal region (SUV range: 3-13 g ml-1). Region-specific SORT thresholding resulted in higher sensitivity (95.8%) than commonly used global thresholds (82.8% for SUV10 and 58.4% for SUV15) while maintaining a high specificity (97.1%, compared to 97.3% for SUV10 and 100.0% for SUV15). Factors, such as reconstruction settings, had minimal impact on threshold optimization, resulting in an average change of 10% (range: 2%-17%) in thresholds for each factor. Region-specific SUV thresholding of NaF PET images for bone lesion detection in metastatic prostate patients was found to be superior to current global thresholding methods. PMID- 30457118 TI - Automated classification of benign and malignant lesions in 18F-NaF PET/CT images using machine learning. AB - PURPOSE: 18F-NaF PET/CT imaging of bone metastases is confounded by tracer uptake in benign diseases, such as osteoarthritis. The goal of this work was to develop an automated bone lesion classification algorithm to classify lesions in NaF PET/CT images. METHODS: A nuclear medicine physician manually identified and classified 1751 bone lesions in NaF PET/CT images from 37 subjects with metastatic castrate-resistant prostate cancer, 14 of which (598 lesions) were analyzed by three additional physicians. Lesions were classified on a five-point scale from definite benign to definite metastatic lesions. Classification agreement between physicians was assessed using Fleiss' kappa. To perform fully automated lesion classification, three different lesion detection methods based on thresholding were assessed: SUV > 10 g ml-1, SUV > 15 g ml-1, and a statistically optimized regional thresholding (SORT) algorithm. For each ROI in the image, 172 different imaging features were extracted, including PET, CT, and spatial probability features. These imaging features were used as inputs into different machine learning algorithms. The impact of different deterministic factors affecting classification performance was assessed. RESULTS: The factors that most impacted classification performance were the machine learning algorithm and the lesion identification method. Random forests (RF) had the highest classification performance. For lesion segmentation, using SORT (AUC = 0.95 [95%CI = 0.94-0.95], sensitivity = 88% [86%-90%], and specificity = 0.89 [0.87-0.90]) resulted in superior classification performance (p < 0.001) compared to SUV > 10 g ml-1 (AUC = 0.87) and SUV > 15 g ml-1 (AUC = 0.86). While there was only moderate agreement between physicians in lesion classification (kappa = 0.53 [95% CI = 0.52-0.53]), classification performance was high using any of the four physicians as ground truth (AUC range: 0.91-0.93). CONCLUSION: We have developed the first whole-body automatic disease classification tool for NaF PET using RF, and demonstrated its ability to replicate different physicians' classification tendencies. This enables fully automated analysis of whole-body NaF PET/CT images. PMID- 30457119 TI - Validation of fast motion-including dose reconstruction for proton scanning therapy in the liver. AB - This study validates a method of fast motion-including dose reconstruction for proton pencil beam scanning in the liver. The method utilizes a commercial treatment planning system (TPS) and calculates the delivered dose for any translational 3D target motion. Data from ten liver patients previously treated with photon radiotherapy with intrafraction tumour motion monitoring were used. The dose reconstruction method utilises an in-house developed program to incorporate beam's-eye-view tumour motion by shifting each spot in the opposite direction of the tumour and in-depth motion as beam energy changes for each spot. The doses are then calculated on a single CT phase in the TPS. Two aspects of the dose reconstruction were assessed: (1) The accuracy of reconstruction, by comparing dose reconstructions created using 4DCT motion with ground truth doses obtained by calculating phase specific doses in all 4DCT phases and summing up these partial doses. (2) The error caused by assuming 4DCT motion, by comparing reconstructions with 4DCT motion and actual tumour motion. The CTV homogeneity index (HI) and the root-mean-square (rms) dose error for all dose points receiving >70%, >80% and >90% of the prescribed dose were calculated. The dose reconstruction resulted in mean (range) absolute CTV HI errors of 1.0% (0.0-3.0)% and rms dose errors of 2.5% (1.0%-5.3%), 2.1% (0.9%-4.5%), and 1.8% (0.7%-3.7%) for >70%, >80% and >90% doses, respectively, when compared with the ground truth. The assumption of 4DCT motion resulted in mean (range) absolute CTV HI errors of 5.9% (0.0-15.0)% and rms dose errors of 6.3% (3.9%-12.6%), 5.9% (3.4% 12.5%), and 5.4% (2.6%-12.1%) for >70%, >80% and >90% doses, respectively. The investigated method allows tumour dose reconstruction with the actual tumour motion and results in significantly smaller dose errors than those caused by assuming that motion at treatment is identical to the 4DCT motion. PMID- 30457120 TI - Nodal-line semimetal superlattices. AB - Spatial modulations, such as superlattices, to realize topological materials have recently been studied in theoretical and experimental works. In this paper, we investigate properties of the superlattices of the nodal-line semimetal and the normal insulator. We consider two types of superlattices, with the stacking direction being perpendicular or parallel to the plane where the nodal line lies. In particular, we show that when the stacking direction is parallel to the plane, the nodal lines remain but they change their shapes because of the folding of the Brillouin zone. We also study the superlattices with magnetization. One can expect that the quantum anomalous Hall (QAH) phase emerges in some cases, depending on the direction of the magnetization. If the magnetization is along the C 2-invariant axis, the superlattice becomes the Weyl semimetal phase if the C 2-invariant axis intersects the nodal lines, and otherwise it becomes the QAH phase. PMID- 30457121 TI - MRI-guidance for motion management in external beam radiotherapy: current status and future challenges. AB - High precision conformal radiotherapy requires sophisticated imaging techniques to aid in target localisation for planning and treatment, particularly when organ motion due to respiration is involved. X-ray based imaging is a well-established standard for radiotherapy treatments. Over the last few years, the ability of magnetic resonance imaging (MRI) to provide radiation-free images with high resolution and superb soft tissue contrast has highlighted the potential of this imaging modality for radiotherapy treatment planning and motion management. In addition, these advantageous properties motivated several recent developments towards combined MRI radiation therapy treatment units, enabling in-room MRI guidance and treatment adaptation. The aim of this review is to provide an overview of the state-of-the-art in MRI-based image guidance for organ motion management in external beam radiotherapy. Methodological aspects of MRI for organ motion management are reviewed and their application in treatment planning, in room guidance and adaptive radiotherapy described. Finally, a roadmap for an optimal use of MRI-guidance is highlighted and future challenges are discussed. PMID- 30457122 TI - Fluorescence protein complementation in microscopy: applications beyond detecting bi-molecular interactions. AB - Conventional fragments of fluorescent proteins used in bimolecular fluorescence complementation technique (BiFC), form light-emitting species only when they are kept in close proximity by interacting proteins of interest. By contrast, certain fluorescent protein fragments complement spontaneously, namely those corresponding to the 1st to 10th beta-strands (GFP1-10) and the 11th beta-strand of superfolder GFP (GFP11). They were designed as folding reporters for high throughput expression and structure biology. Besides, for light microscopy, self associating fluorescent protein fragments constitute a valuable and sometimes unique tool. The GFP11 tag is very advantageous when a full-length fluorescent protein cannot be fused to a protein of interest, namely for live imaging of certain pathogens. Self-associating GFP fragments enable live labelling of specific synapses, visualization of proteins topology and their exposure to particular subcellular compartments. Present review aims to attract attention of scientific community to these tools and to inspire their further development and applications. PMID- 30457123 TI - Effect of dynamically changing the substrate's easy axis on the response time of nematic samples. AB - Recent discoveries of advanced photocontrolled materials have kindled a great deal of interest on their use as command surfaces that switch easy axis under light radiation. One noticeable point when using switchable surfaces on any application is how the dynamical process propagates to the bulk directors. In this paper, we theoretically study the effect of a relaxing easy axis over time on a nematic sample when finite anchoring energy and surface viscosity are included. We first consider the case where just one of the substrates decay over time in an initially distorted director organization. Next, we assume that both substrates can be switched simultaneously. From the calculated director we obtained the optical profile and finally the molecular response time of the material. The response time depends on both the materials and the surfaces properties including its decay time. Our results might be used for understanding and engineering liquid crystal displays and other electro-optical devices with photocontrolled alignment layers. PMID- 30457124 TI - Intramatricial injections for nail psoriasis: An open-label comparative study of triamcinolone, methotrexate, and cyclosporine. PMID- 30457125 TI - The pitfall in diagnosing focal lesions of the liver. PMID- 30457126 TI - Current management of Clostridioides (Clostridium) difficile infection in adults: a summary of recommendations from the 2017 IDSA/SHEA clinical practice guideline. AB - Clostridioides (Clostridium) difficile infection (CDI) is the most common cause of healthcare-associated, infectious diarrhea in the developed world. The Infectious Diseases Society of America (IDSA) and the Society for Hospital Epidemiology of America (SHEA) CDI clinical guidelines were updated in 2017. The update reflects the decline in ribotype 027 and increased incidence of community associated CDI, current challenges in CDI diagnosis, the importance of antibiotic stewardship and contact/isolation precautions in infection prevention/control, and many significant changes in CDI management. This review summarizes and examines these new guidelines, how they compare to other recommendations, and more recent data on CDI management. PMID- 30457127 TI - Small intestinal metastasis from primary lung cancer. PMID- 30457128 TI - Potential contribution of monounsaturated fatty acids to cardiovascular risk in chronic kidney disease. AB - Introduction Patients suffering from chronic kidney disease (CKD) are particularly vulnerable to the development of cardiovascular disease (CVD). Increased endogenous monounsaturated fatty acids (MUFA) synthesis by stearoil-CoA desaturase-1 (SCD1) might predispose to cardiovascular complications. Objectives The aim of this study was to examine the serum MUFA content in patients at successive stages of CKD, and to evaluate associations between MUFA and SCD1 activity, as well as the patients' diet, and their cardiovascular risk. Patients and methods Fatty acid composition was analyzed in sera of 177 patients at successive stages of CKD, and in 30 healthy controls, by gas chromatography - mass spectrometry. Results We found increasing serum MUFA content at successive stages of CKD, as well as significant correlations with various risk factors of CVD. Moreover, there was a concurrent trend of the prevalence of CVD with the progress of the disease. Estimated SCD1 activity was tightly associated with serum MUFA content; whereas no association was found between dietary MUFA intake and their serum levels. Conclusions Our results indicate that the elevation of serum MUFA in CKD patients may contribute to an increased risk of CVD during CKD progress, and it results mainly from increased endogenous synthesis by SCD1. PMID- 30457130 TI - Adrenal angiomyolipoma: a rare localization. PMID- 30457129 TI - An unexpected spherical mass in the left ventricle accidentally found during abdominal ultrasound. PMID- 30457131 TI - Scientometric Analysis of SIRT6 Studies. AB - BACKGROUND SIRT6 is a molecule of significant interest in the field of epigenetics. This review of the literature aimed to explore research hotspots and other bibliometric features of SIRT6 by applying several bibliometric analysis tools and by establishing a comprehensive scientometric analysis model of SIRT6. MATERIAL AND METHODS The research sample included 441 articles related to SIRT6 obtained from the Web of Science core collection. Bicomb software was used to extract high frequency keywords, and then a binary matrix and a co-word matrix were constructed. We used Gcluto for double clustering, EXCEL for strategic coordinate building, Citespace software for co-citation analysis, CitNetExplorer for citation analysis, and Vosviewer for journal and term analysis. RESULTS Research hotspots and the base knowledge of SIRT6 were determined by co-word and co-citation network analysis. The strategic coordinates approach was used to assess the research prospects of each hotspot and the connections between these hotspots. The distribution of disciplines and journals was determined and both a term density map and a dual-map were constructed by application of different tools. CONCLUSIONS SIRT6's regulation of chromatin, lifespan, DNA damage, and metabolism make up the most important SIRT6 intellectual basis from the past 10 years. SIRT6 study has concentrated on the effects of this molecule on tumors and shown promising trends in understanding neural diseases. However, there has been little analysis of how SIRT6 effects are part of more complex systems. Work by Motoslavsky (2006) represents a milestone in SIRT6 research, and the studies by Kawahara 2009 and Kim 2010 are key in the knowledge transmission of SIRT6 research. PMID- 30457133 TI - Effect of in vitro digestion on the functional properties of Psidium cattleianum Sabine (araca), Butia odorata (Barb. Rodr.) Noblick (butia) and Eugenia uniflora L. (pitanga) fruit extracts. AB - Brazilian native fruits are reported to be promising sources of bioactive compounds; however their bioactivity depends on their stability along the digestive process. This study evaluated the alpha-glucosidase inhibition, antioxidant activity and total phenolic content (TPC) stability of araca, butia and pitanga fruit extracts using an in vitro digestion model. Additionally, the individual phenolic compound recovery of the most stable and active extract was evaluated by HPLC-DAD-ESI-MS/MS. Overall, the antioxidant activity of all extracts decreased along the process. Araca fruit extracts, at the end of digestion, showed alpha-glucosidase inhibition values similar to their non digested extracts and the highest TPC recovery (28%). Recovery of individual phenolic compounds of red araca fruit extract revealed a negative impact on the stability of ellagitannins. Araca fruit extract seems to provide phenolic compounds with alpha-glucosidase inhibitory properties after the gastrointestinal digestion, indicating their potential to be used in the control of type II diabetes. PMID- 30457132 TI - Silicon oxides: a promising family of anode materials for lithium-ion batteries. AB - Silicon oxides have been recognized as a promising family of anode materials for high-energy lithium-ion batteries (LIBs) owing to their abundant reserve, low cost, environmental friendliness, easy synthesis, and high theoretical capacity. However, the extended application of silicon oxides is severely hampered by the intrinsically low conductivity, large volume change, and low initial coulombic efficiency. Significant efforts have been dedicated to tackling these challenges towards practical applications. This Review focuses on the recent advances in the synthesis and lithium storage properties of silicon oxide-based anode materials. To present the progress in a systematic manner, this review is categorized as follows: (i) SiO-based anode materials, (ii) SiO2-based anode materials, (iii) non-stoichiometric SiOx-based anode materials, and (iv) Si-O-C-based anode materials. Finally, future outlook and our personal perspectives on silicon oxide based anode materials are presented. PMID- 30457134 TI - Phosphirenium borate betaines from alkynylphosphanes and the halogeno-B(C6F5)2 reagents. AB - A series of phosphanyl substituted alkynes R12P-C[triple bond, length as m-dash]C R2 [R12P: Mes2P or tBu2P; R2: SiMe3, Ph, tBu] reacts with the X-B(C6F5)2 reagents [X: Cl, Br] to give thermally rather stable neutral zwitterionic phosphirenium borate products. Five examples of this class of compounds were characterized by X ray diffraction. PMID- 30457135 TI - Identification and inhibitory activity against alpha-thrombin of a novel anticoagulant peptide derived from oyster (Crassostrea gigas) protein. AB - A newly discovered anticoagulant peptide was isolated, purified and identified from the pepsin hydrolysate of oyster (Crassostrea gigas) which could potently prolong the activated partial thromboplastin time and the thrombin time. The anticoagulant peptide with a 1264.36 Da molecular mass was similar to the amino acid sequence of the C-terminal segment (DFEEIPEEYLQ) of hirudin (a potent thrombin inhibitor). The peptide specifically inhibited a vital blood coagulation factor: thrombin. The molecular docking energy scores of the anticoagulant peptide with the active site, exosite-I and exosite-II of thrombin were 132.355 kcal mol-1, 151.266 kcal mol-1 and 147.317 kcal mol-1, respectively. The anticoagulant peptide interacted with thrombin by competing with fibrinogen for an anion-binding exosite I. In the anticoagulant peptide-thrombin complex, there are seven hydrogen bonds and reciprocity exists between hydrogen atoms and oxygen atoms, and electrostatic and hydrophobic interactions are also involved. Such abundant interactions may be accountable for the high affinity and specificity of the anticoagulant peptide. PMID- 30457136 TI - The effect of particle wettability on the stick-slip motion of the contact line. AB - Contact line dynamics is crucial in determining the deposition patterns of evaporating colloidal droplets. Using high-speed interferometry, we directly observe the stick-slip motion of the contact line in situ and are able to resolve the instantaneous shape of the inkjet-printed, evaporating pico-liter drops containing nanoparticles of varying wettability. Integrated with post-mortem optical profilometry of the deposition patterns, the instantaneous particle volume fraction and hence the particle deposition rate can be determined. The results show that the stick-slip motion of the contact line is a strong function of the particle wettability. While the stick-slip motion is observed for nanoparticles that are less hydrophilic (i.e., particle contact angle theta ~ 74 degrees at the water-air interface), which results in a multiring deposition, a continuous receding of the contact line is observed for more hydrophilic nanoparticles (i.e., theta ~ 34 degrees ), which leaves a single-ring pattern. A model is developed to predict the number of particles required to pin the contact line based on the force balance of the hydrodynamic drag, interparticle interactions, and surface tension acting on the particles near the contact line with varying particle wettability. A three-fold increase in the number of particles required for pinning is predicted when the particle wettability increases from the wetting angle of theta ~ 74 degrees to theta ~ 34 degrees . This finding explains why particles with greater wettability form a single-ring pattern and those with lower wettability form a multi-ring pattern. In addition, the particle deposition rate is found to depend on the particle wettability and vary with time. PMID- 30457137 TI - Disposable silicon-glass microfluidic devices: precise, robust and cheap. AB - Si-glass microfluidics have long provided unprecedented precision, robustness and optical clarity. However, chip fabrication is costly (~500 USD per chip) and in practice, devices are not heavily reused. We present a method to reduce the cost per-chip by two orders of magnitude (~5 USD per chip), rendering Si-glass microfluidics disposable for many applications. The strategy is based on reducing the area of the chip and a whole-chip manifolding strategy that achieves reliable high-pressure high-temperature fluid connectivity. The resulting system was validated at 130 bar and 95 degrees C and demonstrated in both energy and carbon capture applications. We studied heavy oil flooding with brine, polymer, and surfactant polymer solutions and found the surfactant polymer as the most effective solution which recovered ~80% of the oil with the least amount of injection while maintaining a relatively uniform displacement front. In a carbon capture application, we measured the dilation of an emerging ionic liquid analog, choline chloride with urea, in gaseous and supercritical CO2. Previously restricted to niche microfluidic applications, the approach here brings the established benefits of Si-glass microfluidics to a broad range of applications. PMID- 30457138 TI - Interpreting the interfacial and colloidal stability of bulk nanobubbles. AB - This paper elucidates parts of the mystery behind the interfacial and colloidal stability of the novel bubble system of bulk nanobubbles. Stable bulk nanobubble suspensions have been generated in pure water using hydrodynamic cavitation in a high-pressure microfluidic device. The effects of pH adjustment, addition of different types of surfactant molecules and salts on the nanobubble suspensions have been studied. Results show that nanobubble interfaces in pure water are negatively charged, suggesting the formation of an electric double layer around the nanobubbles. It is presumed that the external electrostatic pressure created by the charged nanobubble interface, balances the internal Laplace pressure; therefore, no net diffusion of gas occurs at equilibrium and the nanobubbles are stable. Such stability increases with increasing alkalinity of the suspending medium. The addition of mono- and multi-valent salts leads to the screening of the electric double layer, hence, destabilizing the nanobubbles. Different surfactant molecules (non-ionic, anionic, cationic) affect the stability of bulk nanobubbles in different ways. Calculations based on the DLVO theory predict a stable colloidal system for bulk nanobubbles in pure water and this could be a further reason for their observed longevity. All in all, in pure water, the long term stability of bulk nanobubbles seems to be caused by a combination of ion stabilisation of their interface against dissolution and colloidal stability of the suspension. PMID- 30457139 TI - A needle-like optofluidic probe enables targeted intracellular delivery by confining light-nanoparticle interaction on single cell. AB - Intracellular delivery of molecular cargo is the basis for a plethora of therapeutic applications, including gene therapy and cancer treatment. A very efficient method to perform intracellular delivery is the photo-activation of nanomaterials that have been previously directed to the cell vicinity and bear releasable molecular cargo. However, potential in vivo applications of this method are limited by our ability to deliver nanomaterials and light in tissue. Here, we demonstrate intracelullar delivery using a needle-like optofluidic probe capable of penetrating soft tissue. Firstly, we used the optofluidic probe to confine an intracellular delivery mixture, composed of 100 nm gold nanoparticles (AuNP) and membrane-impermeable calcein, in the vicinity of cancer cells. Secondly, we delivered nanosecond (ns) laser pulses (wavelength: 532 nm; duration: 5 ns) using the same probe and without introducing a AuNP cells incubation step. The AuNP photo-activation caused localized and reversible disruption of the cell membrane, enabling calcein delivery into the cytoplasm. We measured 67% intracellular delivery efficacy and showed that the optofluidic probe can be used to treat cells with single-cell precision. Finally, we demonstrated targeted delivery in tissue (mouse retinal explant) ex vivo. We expect that this method can enable nanomaterial-assisted intracellular delivery applications in soft tissue (e.g. brain, retina) of small animals. PMID- 30457140 TI - The antifungal activity of extracts of Osmundea pinnatifida, an edible seaweed, indicates its usage as a safe environmental fungicide or as a food additive preventing post-harvest fungal food contamination. AB - In the present work, we explored the antifungal activity of the wild edible seaweed Osmundea pinnatifida (Rhodophyta) collected from the Portuguese coast, which is used as a food seasoning in Scotland, Ireland and Portugal. We performed a sequential extraction of the seaweed components with methanol, dichloromethane and n-hexane. These extracts showed an antifungal activity against Alternaria infectoria and Aspergillus fumigatus. The n-hexane fraction of the seaweed inhibited the sporulation of Alternaria infectoria at 30 MUg mL-1 and induced a statistically significant (P < 0.001) decrease in beta-glucan content. Furthermore, liquid cultures of Aspergillus fumigatus supplemented with 10 MUg mL 1 of the n-hexane fraction showed abnormal conidiophores, completely devoid of phialides and conidia associated with a decrease of 18.3% in the chitin content (P < 0.01). The n-hexane fraction analysis by GC-MS revealed that it includes palmitic acid (29.6%), phytol isomer 1 (12.8%), oleic acid (9.6%), stearic acid (6.2%) and d-(-)-tagatofuranose (4.1%), among other compounds present at lower concentrations. The present study reveals Osmundea pinnatifida as a promising source of biologically active compounds inhibiting fungal growth and conidiation, the main dispersal mechanism of filamentous fungi as Aspergillus fumigatus and Alternaria alternata, revealing its utility both as an environmental fungicide against fungal diseases and as a food preservative against fungal post-harvest food contamination. PMID- 30457141 TI - A facile approach to fabricate self-assembled magnetic nanotheranostics for drug delivery and imaging. AB - Superparamagnetic iron oxide (SPIO) nanoparticles have been extensively employed for theranostic applications due to their good biocompatibility and excellent magnetic resonance imaging (MRI) properties. However, these particles typically require surface modification due to their hydrophobic surfaces caused by the oil phase surfactants used in the fabrication and thus, the drug loading on their surface is usually limited. Here, we provided a novel and facile approach to conveniently perform surface modification of SPIO while simultaneously loading a large amount of drug. By synthesizing an amphiphilic irinotecan-based compound with a hydrophobic tail enabling insertion into the SPIO assembly, an excellent SPIO-based theranostic nanomedicine (SPIO@IR) was produced. SPIO@IR not only extensively improved the drug efficacy, but also allowed visualization by MRI in biological systems. PMID- 30457142 TI - On the role of driving force in water transport through nanochannels within graphene oxide laminates. AB - The comprehensive understanding of water transport in GO membranes is of great interest. The water transport mechanism studied by many researchers suggests that capillary pressure is the driving force of water transport in GO membranes at the highest humidity level. Besides the capillary pressure, low-friction flow and surface diffusion also contribute to the fast water transport. This mini review provides an integrated image on the role of driving force in water transport through nanochannels in GO membranes which can be helpful in developing high performance GO-based membranes in future for water, environment and energy related applications. PMID- 30457143 TI - Janus monolayer of WSeTe, a new structural phase transition material driven by electrostatic gating. AB - Phase transition materials are widely exploited in sensors, switches, and information storage devices. However, the dynamic control of structural phase transitions in low-dimensional materials is rarely reported, except for the recent demonstration of semiconductor-semimetal transition in monolayer MoTe2 modulated by electrostatic gating. Here, based on density functional theory calculations we screen in the Janus family of transition metal dichalcogenides, MXY where M = Mo or W, X/Y = S, Se, or Te, for new two-dimensional phase transition materials. We find that the Janus monolayer of WSeTe undergoes reversible phase transitions modulated by electrostatic gating, owing to the small energy difference between H and T' phases, ET' - EH = 48 meV. The gate voltage of 2.0 V (with high dielectric gating the injected charge is ~1013 cm-2) is required to trigger the semiconductor-semimetal transition in WSeTe. The kinetic barrier for both forward and backward phase transitions is ~0.66 eV, which is significantly lower than that in MoTe2, leading to three orders of magnitude increase in the transition rate and much more rapid response of devices. PMID- 30457144 TI - Tuning the collapse transition of weakly charged polymers by ion-specific screening and adsorption. AB - The experimentally observed swelling and collapse response of weakly charged polymers to the addition of specific salts displays quite convoluted behavior that is not easy to categorize. Here we use a minimalistic implicit solvent/explicit-salt simulation model with a focus on ion-specific interactions between ions and a single weakly charged polyelectrolyte to qualitatively explain the observed effects. In particular, we demonstrate ion-specific screening and bridging effects cause collapse at low salt concentrations whereas the same strong ion-specific direct interactions drive re-entrant swelling at high concentrations. Consistently with experiments, a distinct salt concentration at which the salting-out power of anions inverts from the reverse to direct Hofmeister series is observed. At this so called isospheric point, the ion specific effects vanish. Furthermore, with additional simplifying assumptions, an ion-specific mean-field model is developed for the collapse transition which quantitatively agrees with the simulations. Our work demonstrates the sensitivity of the structural behavior of charged polymers to the addition of specific salt beyond simple screening and shall be useful for further guidance of experiments. PMID- 30457145 TI - The Alzheimer's disease amyloid-beta peptide affects the size-dynamics of raft mimicking Lo domains in GM1-containing lipid bilayers. AB - Alzheimer's disease (AD) is characterized by the overproduction of the amyloid beta peptide (Abeta) which forms fibrils under the influence of raft microdomains containing the ganglioside GM1. Raft-mimicking artificial liquid ordered (Lo) domains containing GM1 enhance amyloid-beta polymerization. Other experiments suggest that Abeta binds preferably to the non-raft liquid disordered (Ld) phase rather than to the Lo phase in the presence of GM1. Here, the interaction of Abeta(1-42) with GM1-containing biphasic Lo-Ld giant vesicles was investigated. Fluorescence colocalisation experiments confirm that Abeta(1-42) binds preferentially to the Ld phase. The effect of Abeta(1-42) on the Lo-Ld size dynamics was studied using photoinduced spinodal decomposition which mimics the nanodomain-microdomain raft coalescence. Abeta affects the kinetics of the coarsening phase and the size of the resulting microdomains. The effect depends on which phase is in a majority: when the Lo microdomains are formed inside an Ld phase, their growth rate becomes slower and their final size smaller in the presence of Abeta(1-42), whereas when the Ld microdomains are formed inside an Lo phase, the growth rate becomes faster and the final size larger. Fluorimetric measurements on large vesicles using the probe Laurdan indicate that Abeta(1-42) binding respectively increases or decreases the packing of the Ld phase in the presence or absence of GM1. The differential effects of Abeta on spinodal decomposition are accordingly interpreted as resulting from distinct effects of the peptide on the Lo-Ld line tension modulated by GM1. Such modulating effect of Abeta on domain dynamics could be important for lipid rafts in signaling disorders in AD as well as in Abeta fibrillation. PMID- 30457146 TI - Compatibility between the cysteine-cyclopentenedione reaction and the copper(i) catalyzed azide-alkyne cycloaddition. AB - The cysteine-cyclopentenedione reaction can be combined with the copper(i) catalyzed azide-alkyne cycloaddition provided that the former is carried out first. If not, the azide and the cyclopentenedione undergo a 1,3-dipolar cycloaddition, which furnishes triazole-containing compounds and products resulting from nitrogen loss. Both of these products were fully characterized. Attempts to obtain either of them as the main compound or to drive the reaction nearly to completion were unsuccessful, which points to the azide cyclopentenedione reaction as not being useful for bioconjugation. PMID- 30457147 TI - Onset of vertical bonds in new GaN multilayers: beyond van der Waals solids. AB - A suspended single layer of GaN in a honeycomb structure is stable in a planar geometry. By stacking these GaN layers one can construct bilayers or multilayers, even new three-dimensional (3D) periodic structures. In this study, we clarified how the planar layers are buckled with the onset of vertical Ga-N bonds. Among the four stable phases of bilayer GaN, only one of them maintains the planar geometry, which is bound by weak van der Waals interactions. For the remaining three phases, the layers are buckled with the onset of weak vertical bonds, and attain total energies slightly lower than that of the planar geometry. Structural phase changes, as well as direct-indirect band transitions take place under strain and electrostatic charging. The vertical bonds become shorter in multilayers, and eventually attain the bulk value. Among the stable phases of 3D periodic GaN, only one with a graphite-like structure behaves as a layered, van der Waals solid; whereby others are 3D uniform crystals beyond the van der Waals solid. PMID- 30457148 TI - A carbon foam-supported high sulfur loading composite as a self-supported cathode for flexible lithium-sulfur batteries. AB - A binder-free, self-supported, flexible cathode is explored for application in flexible lithium-sulfur (Li-S) batteries. The cathode is constructed using nitrogen (N)-doped carbon foam/carbon nanotubes (CNTs) as the scaffold and filled with poly(3,4-ethylenedioxythiophene) (PEDOT)-encapsulated sulfur nanoparticles as the active material. The dense CNTs coated on the skeleton of the 3D N-doped foam enhance flexibility, and the highly conductive CNTs are crossed and twined together to create an interconnected skeleton for rapid electron transport. The conductive PEDOT shell of sulfur nanoparticles and the N-doping of the carbon foams restrain the dissolution of polysulfides through the enhanced chemisorption of lithium polysulfides. The best cathode with a sulfur loading of 2.6 mg cm-2 has an eminent capacity of 1395 mA h g-1 during the initial cycle at 0.1 C. Furthermore, freestanding cathodes are assembled into flexible Li-S batteries, which demonstrate significant achievement at various bending angles. The capacity fading rate is 0.16% per cycle at 30 degrees after 120 cycles. Its high sulfur loading, high capacitance, and good flexibility make this cathode material a promising candidate for potential application in flexible electronics. PMID- 30457149 TI - Tailoring porous carbon spheres for supercapacitors. AB - The last decade has witnessed significant breakthroughs in the synthesis of porous carbon spheres (PCSs). This Review provides an updated summarization on the controlled synthesis of PCSs for supercapacitors. The synthetic methodologies can be generally categorized into (i) hard templating, (ii) soft templating, (iii) the modified Stober method, (iv) hydrothermal carbonization (HTC), and (v) aerosol-assisted methods. The obtained PCSs include microporous/mesoporous/macroporous carbon spheres, single-/multi-shelled hollow carbon spheres, and yolk@shell carbon spheres. The structure-electrochemical performance correlation is discussed. Finally, the future research directions on the rational design of PCSs for supercapacitors are predicted. PMID- 30457150 TI - Surface state-controlled C-dot/C-dot based dual-emission fluorescent nanothermometers for intra-cellular thermometry. AB - Fluorescence-based nanothermometers have potential to offer accuracy in the measurement of temperature using non-contact approaches. Herein, a C-dot/C-dot based dual-emission temperature sensing platform is fabricated through the electrostatic self-assembly of two kinds of fluorescent CDs with opposite charges. This dual-emission platform consists of several nearly-spherical CDs with two emission centers in blue (440 nm) and orange (590 nm) regions. The orange fluorescence exhibits discernible response to external temperatures in the range of ~15 to 85 degrees C; on the other hand, the blue fluorescence remains nearly constant. A continuous fluorescence color change in response to temperature from orange to blue can be clearly observed by the naked eye. Thus, the as-prepared C-dot based dual-emission nanospheres can be used for optical thermometry with high reproducibility and sensitivity (0.93%/ degrees C). Detailed characterization shows that temperature (in the 15-85 degrees C window) impacts the surface states of orange emissive CDs, leaving the blue emissive CDs unaffected. A model is proposed to explain the observations. Finally, by taking advantage of the excellent biocompatibility and stability, the CD based fluorescent nanothermometer is successfully used for the visual measurement of intracellular temperature variations. PMID- 30457151 TI - Liquid crystalline droplets in aqueous environments: electrostatic effects. AB - We demonstrate the strong impact of electrostatic properties on radial-bipolar structural transitions in nematic liquid crystal (LC) droplets dispersed in different aqueous environments. In the experimental part of the study, we systematically changed the electrostatic properties of both LC droplets and aqueous solutions. Mixtures of nematics were studied by combining LC materials with negative (azoxybenzene compounds) and strongly positive (cyanobiphenyl) dielectric anisotropy. The aqueous solutions were manipulated by introducing either polyvinyl alcohol, glycerol, electrolyte or amphiphilic anionic surfactant SDS into water. In the supporting theoretical study, we identified the key parameters influencing the dielectric constant and the electric field strength of aqueous solutions. We also estimated the impact of different electrolytes on the Debye length at the LC-aqueous interface. The obtained results are further analysed for chemical and biological sensing applications. PMID- 30457152 TI - Recent progress in transition metal phosphides with enhanced electrocatalysis for hydrogen evolution. AB - Increasing demand for hydrogen energy has boosted the exploration of inexpensive and effective catalysts. Transition metal phosphides (TMPs) have been proven as excellent catalysts for the hydrogen evolution reaction (HER). Very recently, the search for TMP-based catalysts has being mainly directed at enhanced electrocatalytic performance. Hence, a concluded guideline for enhancing HER activity is highly desired. In this mini review, we briefly summarize the most recent and instructive developments in the design of TMP-based catalysts with enhanced electrocatalysis for hydrogen evolution from composition and structure engineering strategies. These strategies and perspectives are also meaningful for designing other inexpensive and high-performance catalysts. PMID- 30457153 TI - Colloidal stability dictates drop breakup under electric fields. AB - Electric fields can deform drops of fluid from their equilibrium shape, and induce breakup at sufficiently large field strengths. In this work, the electric field induced breakup of a squalane drop containing a colloidal suspension of carbon black particles with polyisobutylene succinimide (OLOA 11000) surfactant is studied. The drop is suspended in silicone oil. The breakup mode of a drop containing carbon black depends strongly on the suspension stability. It is observed that a drop of a stable suspension of carbon black has the same breakup mode as a drop with surfactant alone, i.e., without added carbon black. At lower electric fields, these drops break by the formation of lobes at the two ends of the drop; and at higher fields the homogeneous lobes break in a non-axisymmetric manner. However, a drop of an unstable suspension shows a drastically different breakup mode, and undergoes breakup much faster compared to a drop with surfactant alone. These drops elongate and form asymmetric lobes that develop into fingers and eventually disintegrate in an inhomogeneous, three-dimensional fashion. As a basis for comparison, the breakup of a pure squalane drop, and a squalane drop with equivalent surfactant concentrations but no carbon black particles is examined. Axisymmetric boundary integral computations are used to elucidate the mechanism of breakup. Our work demonstrates the impact of colloidal stability on the breakup of drops under an electric field. Colloidal stability on the time scale of drop deformation leads to rich and unexplored breakup phenomena. PMID- 30457154 TI - Hierarchically porous metal-organic frameworks: rapid synthesis and enhanced gas storage. AB - Large pore sizes, high pore volumes, facile synthesis conditions, and high space time yields are recognized as four crucial criteria in the fabrication of metal organic frameworks (MOFs). However, these four objectives are rarely realized together. Herein, we have developed a simple and versatile method that employs 1,4-butanediamine (BTDM) as a template for rapidly fabricating four stable hierarchically porous MOFs (H-MOFs), including HKUST-1, ZIF-8, ZIF-67, and ZIF 90. The synthesis conditions are simple and facile at room temperature and ambient pressure, and the synthesis time can be shortened to 1 min. The resultant H-MOFs exhibit multimodal hierarchically porous structures with meso- and macropores interconnected with micropores, as well as high pore volumes (0.76 cm3 g-1). The maximum space-time yield for the hierarchically porous HKUST-1 reaches 7.4 * 104 kg m-3 d-1, at least one order of magnitude higher than previous reported yields. Notably, the additive BTDM not only facilitates crystal growth but also guides the formation of meso- and macropores. The synthesis route is highly versatile, as analogues (e.g., tetramethyl-1,3-diaminopropane and tetramethyldiaminomethane) can also be employed as templates to prepare diverse H MOFs. Furthermore, the porosities of the H-MOFs are readily tuned by controlling the metal source, template amount and type of template. The as-synthesized H-MOFs act as adsorbents with significantly improved performances relative to those of microporous MOFs used for CH4 and CO2 gas storage. This strategy may aid in the large-scale industrial synthesis of desirable H-MOFs for gas storage. PMID- 30457155 TI - Thrombosis and Haemostasis: Past, present and future. PMID- 30457156 TI - Stroke prevention in atrial fibrillation: Past, present and future. AB - Concepts and our approaches to stroke prevention in atrial fibrillation (AF) have changed markedly over the last decade. There has been an evolution over the approach to stroke and bleeding risk assessment, as well as new treatment options. An increasing awareness of AF has led to calls to improve the detection of and population screening for AF. Stroke and bleeding risk assessment continues to evolve, and the ongoing debate on balance between simplicity and practicality, against precision medicine will continue. In this review article, we provide an overview of past, present and the (likely) future concepts and approaches to stroke prevention in AF. We propose three simple steps (the Birmingham '3-step') that offers a practical management pathway to help streamline and simplify decision-making for stroke prevention in patients with AF.Note: The review process for this paper was fully handled by Christian Weber, Editor in Chief. PMID- 30457157 TI - Microvesicles in vascular homeostasis and diseases. AB - Microvesicles are members of the family of extracellular vesicles shed from the plasma membrane of activated or apoptotic cells. Microvesicles were initially characterised by their pro-coagulant activity and described as "microparticles". There is mounting evidence revealing a role for microvesicles in intercellular communication, with particular relevance to hemostasis and vascular biology. Coupled with this, the potential of microvesicles as meaningful biomarkers is under intense investigation. This Position Paper will summarise the current knowledge on the mechanisms of formation and composition of microvesicles of endothelial, platelet, red blood cell and leukocyte origin. This paper will also review and discuss the different methods used for their analysis and quantification, will underline the potential biological roles of these vesicles with respect to vascular homeostasis and thrombosis and define important themes for future research. PMID- 30457159 TI - Predictors of oral cavity bleeding and clinical outcome after dental procedures in patients on vitamin K antagonists. AB - Patients on vitamin K antagonists (VKA) often undergo invasive dental procedures. International guidelines consider all dental procedures as low-risk procedures, while bleeding risk may differ between standard low-risk (e. g. extraction 1-3 elements) and extensive high-risk (e.g. extraction of >3 elements) procedures. Therefore current guidelines may need refinement. In this cohort study, we identified predictors of oral cavity bleeding (OCB) and evaluated clinical outcome after low-risk and highrisk dental procedures in patients on VKA. Perioperative management strategy, procedure risk, and 30-day outcomes were assessed for each procedure. We identified 1845 patients undergoing 2004 low-risk and 325 high-risk procedures between 2013 and 2015. OCB occurred after 67/2004 (3.3 %) low-risk and 21/325 (6.5 %) high-risk procedures (p=0.006). In low-risk procedures, VKA continuation with tranexamic acid mouthwash was associated with a lower OCB risk compared to continuation without mouthwash [OR=0.41, 95 %CI 0.23 0.73] or interruption with bridging [OR=0.49, 95 %CI 0.24-1.00], and a similar risk as interruption without bridging [OR=1.44, 95 %CI 0.62-3.64]. In high-risk procedures, VKA continuation was associated with an increased OCB risk compared to interruption [OR=3.08, 95 %CI 1.05-9.04]. Multivariate analyses revealed bridging, antiplatelet therapy, and a supratherapeutic or unobjectified INR before the procedure as strongest predictors of OCB. Non-oral cavity bleeding (NOCB) and thromboembolic event (TE) rates were 2.1 % and 0.2 %. Bridging therapy was associated with a two-fold increased risk of NOCB [OR=1.93, 95 %CI 1.03 3.60], but not with lower TE rates. In conclusion, predictors of OCB were mostly related to perioperative management and differed between low-risk and high-risk procedures. Perioperative management should be differentiated accordingly. PMID- 30457158 TI - The management of acute venous thromboembolism in clinical practice. AB - Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in Europe. Data from real-world registries are necessary, as clinical trials do not represent the full spectrum of VTE patients seen in clinical practice. We aimed to document the epidemiology, management and outcomes of VTE using data from a large, observational database. PREFER in VTE was an international, non interventional disease registry conducted between January 2013 and July 2015 in primary and secondary care across seven European countries. Consecutive patients with acute VTE were documented and followed up over 12 months. PREFER in VTE included 3,455 patients with a mean age of 60.8 +/- 17.0 years. Overall, 53.0% were male. The majority of patients were assessed in the hospital setting as inpatients or outpatients (78.5%). The diagnosis was deep-vein thrombosis (DVT) in 59.5% and pulmonary embolism (PE) in 40.5%. The most common comorbidities were the various types of cardiovascular disease (excluding hypertension; 45.5%), hypertension (42.3%) and dyslipidaemia (21.1%). Following the index VTE, a large proportion of patients received initial therapy with heparin (73.2%), almost half received a vitamin K antagonist (48.7%) and nearly a quarter received a DOAC (24.5%). Almost a quarter of all presentations were for recurrent VTE, with >80% of previous episodes having occurred more than 12 months prior to baseline. In conclusion, PREFER in VTE has provided contemporary insights into VTE patients and their real-world management, including their baseline characteristics, risk factors, disease history, symptoms and signs, initial therapy and outcomes. PMID- 30457160 TI - Circulating nociceptin and CGRP in medication-overuse headache. AB - BACKGROUND: Previous studies found low serum levels of nociceptin in migraine patients but high serum levels of calcitonin gene-related peptide (CGRP). CGRP can elicit migraine-like headache. Medication-Overuse Headache (MOH) often has migraine features and can mimic chronic migraine. We therefore hypothesized that as in migraine, serum levels of nociceptin would be lower and CGRP serum levels higher in MOH patients compared with those in healthy volunteers. We hypothesized the serum levels would normalize after detoxification. METHODS: Seventeen MOH patients, hereof 70.6% with chronic migraine and MOH, and 30 sex and age matched headache-free controls were included. MOH patients underwent a 2-month out patient detoxification program and after six months 10 patients and 19 controls were retested. Blood samples were analyzed blinded. RESULTS: We found no differences in the levels of nociceptin and CGRP between MOH patients and controls (p=0.65 and p=0.59). The mean headache frequency reduction was 43% and 70% of patients reverted to episodic headache after 6 months, but the levels of nociceptin and CGRP were unchanged (p=0.71 and p=0.82). CONCLUSION: In contrast to previous findings in migraine patients, we found normal serum levels of nociceptin and CGRP in MOH patients. Thus, we find no evidence that the increased headache frequency of MOH patients could be caused by altered nociceptin and CGRP levels. This underlines the importance of identifying medication overuse in chronic headache and treating the MOH. This article is protected by copyright. All rights reserved. PMID- 30457162 TI - Lack of Emotional Awareness is Associated with Thwarted Belongingness and Acquired Capability for Suicide in a Military Psychiatric Inpatient Sample. AB - OBJECTIVE: To examine potential links between facets of impulsivity and emotion dysregulation to components of the Interpersonal-Psychological Theory of Suicide (thwarted belongingness, perceived burdensomeness, and acquired capability) among U.S. military personnel. METHOD: The current study performed secondary data analysis from a randomized control trial testing the efficacy of a cognitive therapy for 134 service members (71.64% male, 68.66% Caucasian; mean age: 30.14) admitted to a psychiatric inpatient unit for a suicide-related crisis. We utilized the Difficulties in Emotion Regulation Scale, the Barratt Impulsivity Scale, the Acquired Capability for Suicide Scale, and the Interpersonal Needs Questionnaire. RESULTS: All emotion dysregulation dimensions and one impulsivity facet (attentional) were positively correlated with perceived burdensomeness and thwarted belongingness. Lack of emotional awareness was positively associated with acquired capability. After controlling for depression, hopelessness, and demographic covariates, lack of emotional awareness was significantly associated with both thwarted belongingness and acquired capability, but not perceived burdensomeness, and impulsivity dimensions did not link to any variable of interest. CONCLUSIONS: Findings imply that individuals with reduced emotional awareness may have difficulty cultivating interpersonal bonds and be more vulnerable to elevated acquired capability. Lack of emotional awareness may be a potential contributor to both suicidal desire and capability. PMID- 30457161 TI - Lipidomics as a diagnostic tool of the metabolic and physiological state of managed whales: A correlation study of systemic metabolism. AB - Integrating multifactor blood analysis is a key step toward a precise diagnosis of the health status of marine mammals. Variations in the circulating lipid profile reflect changes in the metabolism and physiology of an individual. To demonstrate the practicability of lipid profiling for physiological assessment, the phosphorylcholine-containing lipids in the plasma of long-term managed beluga whales (Delphinapterus leucas) were profiled using a lipidomics methodology. Using a multivariate analysis, the mean corpuscular volume, cholesterol, potassium, and gamma-glutamyltranspeptidase levels were well modeled with the lipid profile of the female whales. In the models, the correlated lipids provided information about blood parameter-related metabolism and physiological regulation, in particular relating to cholesterol and inflammation. In the males, the levels of cholesterol, triglycerides, blood urea nitrogen, creatinine, plasma iron, and segmented neutrophil were well modeled with the lipid profile. In addition to providing information about the related metabolism and regulation, through a cross-linked analysis of the blood parameters, the correlated lipids indicated a parallel regulation involved in the energy metabolism of the male whales. Lipidomics as a method for revealing the context of physiological change shows practical potential for the health care of managed whales. PMID- 30457163 TI - An investigation on the impact of substrate type, temperature, and iodine on moon jellyfish production. AB - Jellyfish are a popular public aquarium species, however, their collection from natural populations is undesirable due to impact on species abundance and bycatch. Thus, a sustainable supply of jellyfish bred in-house would be highly desirable. Here we describe an investigation into developing a sustainable moon jellyfish, Aurelia aurita, breeding program by determining the impact of substrate type on reattachment of polyps and the influence of iodine and temperature on strobilation and ephyra production. To test whether reattachment and growth of moon jellyfish polyps are influenced by substrate type polyps were provided with anthropogenic and natural substrates after being dislodged in experimental aquaria. Polyps selectively re-attached to plastics rather than natural materials. However, polyp growth was similar on all tested substrates. We tested whether cooling and addition of iodine affected strobilation. A period of cooling of around 10 degrees C while also introducing soluble iodine to the polyps enhanced strobilation rate. This method produced ephyra at a reliable rate in captivity negating the need for collection of wild individuals providing a supply of individuals for exhibit and for conservation research within a public aquarium. These results demonstrate that plastics should be adopted as an easier to colonize substrate and the use of cooling with iodine addition can enhance sustainable breeding protocols of moon jellyfish and may be relevant to the production of comparable jellyfish species. PMID- 30457164 TI - DSCAM-AS1 promotes tumor growth of breast cancer by reducing miR-204-5p and up regulating RRM2. AB - Breast cancer (BC) is a common malignancy worldwide. More than 3700 000 women die of BC every year. DSCAM-AS1 was overexpressed several kinds of cancer and miR-204 5p was lowly expressed, which indicated that miR-204-5p had anti-tumor activity and DSCAM-AS1 had pro-tumor activity. We intended to analyze DSCAM-AS1, miR-204 5p and ribonucleotide reductase M2 (RRM2). Microarray analysis and quantitative Real Time fluorescence Polymerase Chain Reaction (qRT-PCR) were employed to determine DSCAM-AS1 and miR-204-5p expression. Luciferase reporter assay was applied to examine the target relationship between DSCAM-AS1, miR-204-5p and RRM2. Cell Counting Kit-8 (CCK-8 assay), transwell assay and flow cytometry were used to detect cell proliferation, invasion and apoptosis. The expression of DSCAM-AS1, miR-204-5p and RRM2 were confirmed by Western blot. We also conducted in vivo assay to verify the effect of DSCAM-AS1. DSCAM-AS1 was up-regulated, while miR-204-5p was down-regulated in BC tissues and cells. DSCAM-AS1 directly targeted miR-204-5p. DSCAM-AS1 promoted the proliferation and invasion of BC cells by reducing miR-204-5p and inhibiting miR-204-5p expression. DSCAM-AS1 expression was related to the expression of RRM2, and miR-204-5p could reverse the function of DSCAM-AS1. RRM2 was up-regulated in BC cells, and miR-204-5p inhibited RRM2 expression by targeting RRM2. Overexpression of RRM2 stimulated proliferation and cell invasion and impeded apoptosis. In vivo experiments showed that knockdown of DSCAM-AS1 decreased the tumorigenesis of BC cells, increased the expression of miR-204-5p. DSCAM-AS1 promoted proliferation and impaired apoptosis of BC cells by reducing miR-204-5p and enhancing RRM2 expression. DSCAM AS1/miR-204-5p/RRM2 may serve as novel therapeutic targets for BC. This article is protected by copyright. All rights reserved. PMID- 30457165 TI - Genetic polymorphisms of diabetes-related genes, their interaction with diabetes status, and breast cancer incidence and mortality: The Long Island Breast Cancer Study Project. AB - PURPOSE: To examine 143 diabetes risk single nucleotide polymorphisms (SNPs), identified from genome-wide association studies, in association with breast cancer (BC) incidence and subsequent mortality. METHODS: A population-based sample of Caucasian women with first primary invasive BC (n = 817) and controls (n = 1,021) were interviewed to assess diabetes status. Using the National Death Index, women with BC were followed for >18 years during which 340 deaths occurred (139 BC deaths). Genotyping was done using DNA extracted from blood samples. We used unconditional logistic regression to estimate age-adjusted odds ratios and 95% confidence intervals (CIs) for BC incidence, and Cox regression to estimate age-adjusted hazard ratios and CIs for all-cause and BC-specific mortality. RESULTS: Twelve SNPs were associated with BC risk in additive genotype models, at alpha = 0.05. The top three significant SNPs included SLC30A8-rs4876369 (P = 0.0034), HHEX-rs11187146 (P = 0.0086), and CDKN2A/CDKN2B-rs1333049 (P = 0.0086). Diabetes status modified the associations between rs4876369 and rs2241745 and BC incidence, on the multiplicative interaction scale. Six SNPs were associated with all-cause (CDKAL1-rs981042, P = 0.0032; HHEX-rs1111875, P = 0.0361; and INSR rs919275, P = 0.0488) or BC-specific (CDKN2A/CDKN2B-rs3218020, P = 0.0225; CDKAL1 rs981042, P = 0.0246; and TCF2/HNF1B-rs3094508, P = 0.0344) mortality in additive genotype models, at alpha = 0.05. CONCLUSIONS: Genetic polymorphisms that increase the risk of developing diabetes may also increase the risk of developing and dying from BC. This article is protected by copyright. All rights reserved. PMID- 30457166 TI - Radiological evaluation of kyphoplasty with an intravertebral expander after osteoporotic vertebral fracture. AB - Spinal deformities due to osteoporotic vertebral compression fractures can be reduced by balloon kyphoplasty, but the correction may be partly lost when the balloon is deflated. The present study aimed to evaluate an intravertebral expander developed to reduce and maintain vertebral body height while cement is injected to correct spinal deformities due to osteoporotic vertebral fractures. The study included 31 osteoporotic vertebral body fractures in 31 patients, classified as A1 according to the AO classification, who underwent kyphoplasty using an intravertebral expander. The kyphosis angle was significantly corrected from 13.4 degrees prior to kyphoplasty to 10.8 degrees (p < 0.01) after surgery, but this correction was lost at 12 months (13.3 degrees). The correction of the kyphosis angle best correlated with the pre-operative mobility of the fracture (r = 0.59, p < 0.01), and the loss of the kyphosis improvement correlated with the amount of correction (r = 0.49, p = 0.01). All patients, except for six with adjacent vertebral fractures, experienced significant pain reduction (VAS 8.7 pre operatively and 2.0 at 12 months; p < 0.01), and the pain was not affected by the correction of the spinal deformity or the loss of correction in the follow-up period. These results suggest that the mobility of the fracture mainly determines the extent of deformity correction rather the device used for reduction, and greater corrections are at increased risk for losing the improvement. This article is protected by copyright. All rights reserved. PMID- 30457167 TI - Impact of Facilitated Behavior Change Strategies on Food Intake Monitoring and Body Weight Measurements in Acute Care: Case Examples From the More-2-Eat Study. AB - BACKGROUND: Assessing and monitoring food intake and body weight of all hospital patients is considered part of "best practice" nutrition care. This study presents case examples describing the impact of behavior change strategies on embedding these 2 monitoring processes in hospitals. METHODS: Four hospital medical units that participated in the More-2-Eat implementation study to improve nutrition care focused on improving food intake and/or weight monitoring practices. The percentage of admitted patients who received these care practices were tracked through chart audits over 18 months. Implementation progress and behavior change strategies were documented through interviews, focus groups, scorecards, and monthly telephone calls. Case examples are explored using mixed methods. RESULTS: Of the 4 units, 3 implemented food intake monitoring. One provided food service workers the opportunity to record food intake, with low intake discussed by an interdisciplinary team during bedside rounds (increased from 0% to 97%). Another went from 0% to 61% of patients monitored by introducing a new form ("environmental restructuring") reminding staff to ask patients about low intake. A third unit increased motivation to improve documentation of low intake and improved from 3% to 95%. Two units focused on regularity of body weight measurement. One unit encouraged a team approach and introduced 2 weigh days/week (improved from 14% to 63%), while another increased opportunity by having all patients weighed on Saturdays (improved from 11% to 49%). CONCLUSION: Difficult-to-change nutrition care practices can be implemented using diverse and ongoing behavior change strategies, staff input, a champion, and an interdisciplinary team. PMID- 30457168 TI - Sex specific actions of drugs in preterm infants. AB - Most neonatologists are aware that outcomes are different for preterm girls and boys. Boys who are born preterm are about 50% more likely to die in hospital than girls and neurodevelopmental impairment is more common in male than female survivors. These differences in outcome have been attributed to biological sex, rather than sociocultural gender. The underlying mechanisms remain largely unknown and have been reported to involve a multitude of immunological, genetic and hormonal differences (1). This article is protected by copyright. All rights reserved. PMID- 30457169 TI - Biphasic pathologic pattern in transformed mycosis fungoides not associated with DUSP22-IRF4 translocation. AB - Large-cell transformation in mycosis fungoides (MF) is usually encountered in tumors and is associated with prognosis worsening. It is defined by the onset of more than 25% of lymphocytes, usually expressing CD30, exceeding 4 times the size of normal lymphocytes, either diffuse or organized in sheets in the dermal infiltrate. Recently, an unusual biphasic pathologic pattern was reported in lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (ALCL) which was constantly associated with DUSP22-IRF4 gene rearrangement(1)(2)(3) . We report a case of transformed mycosis fungoides (TMF) with a biphasic infiltrate not associated with DUSP22 gene rearrangement. This article is protected by copyright. All rights reserved. PMID- 30457170 TI - Evaluating the impact of extended field-of-view CT reconstructions on CT values and dosimetric accuracy for radiation therapy. AB - PURPOSE: Wide bore CT scanners use extended field-of-view (FOV) reconstruction algorithms to attempt to recreate tissue truncated due to large patient habitus. Radiation therapy planning systems rely on accurate CT numbers in order to correctly plan and calculate radiation dose. This study looks at the impact of extended FOV reconstructions on CT numbers and radiation dose calculations in real patient geometries. METHODS: A large modular phantom based on real patient geometries was created to surround a CIRS Model 062M phantom. The modular sections included a smooth patient surface, a skin fold in the patient surface, and the addition of arms for simulation of the patient in arms up or arms down position. This phantom was used to evaluate the accuracy of CT numbers for three extended FOV algorithms implemented on Siemens CT scanners: eFOV, HDFOV, and HDProFOV. Six different configurations of the phantoms were scanned and images were reconstructed for the three different extended FOV algorithms. The CIRS phantom inserts and overall phantom geometry were contoured in each image, and the HU numbers were compared to an image of the phantom within the standard scan FOV (sFOV) without the modular sections. To evaluate the effect on dose calculations, 6 radiotherapy patients previously treated at our institution (3 head and neck & 3 chest/pelvis) whose body circumferences extended past the 50 cm sFOV in the treatment planning CT were used. Images acquired on a Siemens Sensation Open scanner, were reconstructed using sFOV, eFOV and HDFOV algorithms. A physician and dosimetrist identified the radiation target, critical organs, and external patient contour. A benchmark CT was created for each patient, consisting of an average of the 3 CT reconstructions with a density override applied to regions containing truncation artifacts. The benchmark CT was used to create an optimal radiation treatment plan. The plan was copied onto each CT reconstruction without density override and dose was recalculated. RESULTS: Tissue extending past the sFOV impacts the HU numbers for tissues inside and outside the sFOV when using extended FOV reconstructions. On average, the HU for all CIRS density inserts in the arms up (arms down) position varied by 43HU (67HU), 39HU (73HU), and 18HU (51HU) for the eFOV, HDFOV, and HDProFOV scans, respectively. In the patient dose calculations, patients with a smooth patient contour had the least deviation from the benchmark in the HDFOV (0.1-0.5%) compared to eFOV (0.4-1.8%) reconstructions. In cases with large amounts of tissue and irregular skin folds, the eFOV deviated the least from the benchmark (range 0.2-0.6% dose difference) compared to HDFOV (range 1.3-1.8% dose difference). CONCLUSIONS: All reconstruction algorithms demonstrated good CT number accuracy in the center of the image. Larger artifacts are seen near and extending outside the scan FOV, however, dose calculations performed using typical beam arrangements using the extended FOV reconstructions were still mostly within 2.5% of best estimated reference values. This article is protected by copyright. All rights reserved. PMID- 30457171 TI - The price of life: the impact of cost on decision-making for extremely premature neonates in China. PMID- 30457172 TI - Full-Thickness Rotator Cuff Tear In Rat Results In Distinct Temporal Expression Of Multiple Proteases In Tendon, Muscle, And Cartilage. AB - The etiology of joint tissue degeneration following rotator cuff tear remains unclear. Thus, the purpose of this study was to understand the timeline of protease activity in the soft tissues of the shoulder (tendon, muscle, and cartilage) that may lead to down-stream degeneration following rotator cuff tear. A well-established rat model involving suprascapular nerve denervation and supraspinatus/infraspinatus tendon transection was employed. Histological staining and/or micro-computed tomography (uCT) were used to observe structural damage in the supraspinatus tendon and muscle, humeral head cartilage, and subchondral bone. Multiplex gelatin zymography was utilized to assess protease activity in the supraspinatus tendon and muscle, and humeral head cartilage. Zymography analysis demonstrated that cathepsins were upregulated in the first week in all tissues, while MMP-2 maintained prolonged activity in supraspinatus tendon between 1 and 3 weeks and increased only at 3 weeks in supraspinatus muscle. In supraspinatus tendon, increased cathepsin L and MMP-2 activity in the first week was concurrent with matrix disorganization and infiltration of inflammatory cells. In contrast, significant upregulation of cathepsin L and K activity in supraspinatus muscle and humeral head cartilage did not correspond to any visible tissue damage at one week. However, focal defects developed in half of all animals' humeral head cartilage by 12 weeks (volume: 0.12 +/- 0.09 mm3 ). This work provides a more comprehensive understanding of biochemical changes to joint tissue over time following rotator cuff tear. Overall, this provides insight into potential therapeutic targets and will better inform ideal intervention times and treatments for each tissue. This article is protected by copyright. All rights reserved. PMID- 30457173 TI - Extremely Photostable Electron-Deficient Phthalocyanines That Generate High Levels of Singlet Oxygen. AB - A robust lead-mediated synthetic procedure for the generation of phthalocyanines substituted with electron-withdrawing groups has been developed. The free-base phthalocyanine and various metal complexes were prepared without discernible degradation of the peripheral electron-withdrawing substituents. Upon irradiation with red light, some of the thus obtained metal complexes generated high levels of singlet oxygen. Especially a palladium complex exhibited attractive photostability upon exposure to singlet oxygen as a bleaching agent. The photostability of such complexes that may manifest concomitantly to the generation of high levels of singlet oxygen was attributed to the presence of the electron-withdrawing groups, which results in energetically low-lying highest occupied molecular orbitals. PMID- 30457174 TI - PPP3CB contributes to poor prognosis through activating nuclear factor of activated T-cells signaling in neuroblastoma. AB - We previously identified a gain-of-function mutation in PPP3CB in a neuroblastoma (NB) with MYCN amplification. Here we investigated the functional and clinical role of PPP3CB in NB. High PPP3CB expression was an independent indicator predicting poor prognosis of NB. Overexpression of wildtype or mutated PPP3CB (PPP3CBmut) promoted cell growth, but PPP3CB knockdown decreased cell growth in NB cells. Forced expressions of PPP3CB and PPP3CBmut activated NFAT2 and NFAT4 transcription factors and inhibited GSK3beta activity, resulting in the increase in the expressions of c-Myc, MYCN and beta-catenin, which were downregulated in response to PPP3CB knockdown. Treatment with calcineurin inhibitor cyclosporin A (CsA) or FK506 suppressed cell proliferation and induced apoptotic cell death in both MYCN-amplified and MYCN-non-amplified NB cell lines. Expression of PPP3CB protein was decreased in response to two calcineurin inhibitors. c-Myc, MYCN and beta-catenin were downregulated at the mRNA and protein levels in CsA or FK506 treated NB cells. Our data indicate that elevated expression of PPP3CB and the expression of its constitutively active mutant contribute to the aggressive behavior of NB tumors and therefore suggest that inhibition of calcineurin activity might have therapeutic potential for high-risk NB. This article is protected by copyright. All rights reserved. PMID- 30457175 TI - Family Secrecy in Family Therapy Practice: An Explorative Focus Group Study. AB - The aim of this focus group study was to explore the experiences of family therapists working with family secrecy. Our study highlights that family secrets present important and compelling challenges for family therapists. Furthermore, our study reveals that there seem to be some basic strategies family therapists use in dealing with these challenges in therapy sessions. One basic strategy is that family therapists try to guard their position of being a trustworthy therapist for each family member by avoiding becoming stuck in family secrecy. Furthermore, therapists explore ways to guide the family toward the disclosure of the secret in order to alleviate the toxicity of the secrecy. This highlights the importance of the systemic model and how influential this perspective is in family therapy practice. Some participants, however, have in addition a second strategy they sometimes use: talking with the family about secrecy without aiming to disclose the secret. In the discussion section of the article we reflect on the possibility that in the strategic choices family therapists make conceptual issues might be involved. Furthermore, we stress the importance of further research. PMID- 30457176 TI - Neuroticism is associated with higher antenatal care utilization in obstetric low risk women. AB - INTRODUCTION: Elevated neuroticism is associated with higher health care utilization in the general population. This study aimed to investigate the association between neuroticism and the use of publicly financed antenatal care in obstetric low-risk women, also considering predisposing and need factors for health care utilization. MATERIAL AND METHODS: Participants comprised 1052 obstetric low-risk women (no chronic diseases or adverse pregnancy conditions) included in several obstetrics/gynecology studies in Uppsala, Sweden. Neuroticism was self-rated on the Swedish universities Scales of Personality. Medical records of their first subsequent pregnancy were scanned for antenatal care use. Associations between antenatal care use and neuroticism were analyzed with logistic regression (binary outcomes) or negative binomial regression (count outcomes) comparing the 75th vs 25th neuroticism percentiles. Depending on the Akaike information criterion the exposure was modeled as either linear or with restricted cubic splines. Analyses were adjusted for predisposing (sociodemographic and parity) and need factors (body mass index and psychiatric morbidity). RESULTS: After adjustment, women with higher neuroticism had more fetal ultrasounds (incidence rate ratio =1.09, 95% confidence interval (CI); 1.02 to 1.16), more emergency visits to an obstetrician/gynecologist (incidence rate ratio=1.22, 95%CI; 1.03 to 1.45), and were more likely to visit a fear-of childbirth clinic (odds ratio=2.71, 95%CI; 1.71 to 4.29). Moreover, they more often consulted midwives in specialized antenatal care facilities (significant J shaped association). CONCLUSIONS: Neuroticism was associated with higher utilization of publicly financed antenatal care in obstetric low-risk women, even after adjusting for predisposing and need factors. Future studies should address the benefits of interventions as a complement to routine antenatal care programs to reduce subclinical anxiety. This article is protected by copyright. All rights reserved. PMID- 30457177 TI - Pd-Catalyzed Annulation of 1-Halo-8-arylnaphthalenes and Alkynes Leading to Heptagon-Embedded Aromatic Systems. AB - A palladium-catalyzed heptagon-forming annulation reaction between 1-halo-8 arylnaphthalene and diarylacetylene is reported. The reaction is promoted using a catalytic system comprised of Pd(OAc)2, moderately electron-deficient triarylphosphine P(4-ClC6H4)3, and Ag2CO3 to afford benzo[4,5]cyclohepta[1,2,3 de]naphthalene derivatives in moderate to good yields, in preference to fluoranthene as a competing byproduct. Twofold annulation can also be achieved to access a novel heptagon-embedded polycyclic aromatic hydrocarbon compound. PMID- 30457178 TI - Imbalance of tyrosine by modulating TyrA arogenate dehydrogenases impacts growth and development of Arabidopsis thaliana. AB - L-Tyrosine is an essential aromatic amino acid required for synthesis of proteins and a diverse array of plant natural products; however, little is known how the levels of tyrosine are controlled in planta and linked to overall growth and development. Most plants synthesize tyrosine by TyrA arogenate dehydrogenases, which are strongly feedback inhibited by tyrosine and encoded by TyrA1 and TyrA2 genes in Arabidopsis thaliana. While TyrA enzymes have been extensively characterized at biochemical levels, their in planta functions remain uncertain. Here we found that TyrA1 suppression reduces seed yield due to impaired anther dehiscence, whereas TyrA2 knockout leads to slow growth with reticulate leaves. The tyra2 mutant phenotypes were exacerbated by TyrA1 suppression and rescued by expression of TyrA2, TyrA1, or tyrosine feeding. Low light conditions synchronized the tyra2 and wild-type growth and ameliorated the tyra2 leaf reticulation. After shifting to normal light, tyra2 transiently decreased tyrosine and subsequently increased aspartate before the appearance of the leaf phenotypes. Overexpression of deregulated TyrA enzymes led to hyper accumulation of tyrosine, which was also accompanied by elevated aspartate and reticulate leaves. These results revealed that TyrA1 and TyrA2 have distinct and overlapping functions in flower and leaf development, respectively, and that imbalance of tyrosine, caused by altered TyrA activity and regulation, impacts growth and development of Arabidopsis. The findings provide critical bases for improving the production of tyrosine and its derived natural products and further elucidating the coordinated metabolic and physiological processes to maintain tyrosine levels in plants. This article is protected by copyright. All rights reserved. PMID- 30457180 TI - Systematic Review of the Applications of Three-Dimensional Printing in Colorectal Surgery. AB - BACKGROUND: Three-dimensional (3D) printing has been recognized as a revolutionary technological innovation that has benefitted numerous disciplines, including medicine. The present systematic review aimed to demonstrate the current applications of 3D printing in colorectal surgery along with the limitations and potential future applications of this innovation. METHODS: A PRISMA-compliant systematic literature search of studies that applied 3D printing in colorectal surgery in the period January 1990 through to July 2018 was conducted. Electronic databases including PubMed/Medline, Scopus, and Cochrane library were searched. All full-text original articles were eligible for inclusion. RESULTS: Nine studies including 58 patients of a median age of 60.7 years were reviewed. The studies assessed 3D printing in patients with planned stoma construction, colon cancer with liver metastasis, right colon cancer, rectal cancer, intractable constipation and anal fistula. The applications of 3D printing were classified into three categories: patient education, preoperative planning, and evaluation of response of colorectal liver metastasis to chemotherapy. 3D printed models aided in planning resection of colorectal liver metastasis, facilitating D3 lymphadenectomy in complete mesocolic excision, improving the understanding of pelvic anatomy in laparoscopic rectal cancer treatment, guiding electrode implantation in sacral neuromodulation for intractable constipation, and elucidating the morphology of anal fistula tract and anal sphincter muscles. CONCLUSION: Colorectal surgery may benefit from 3D printing in enhancing patient education before stoma construction, preoperative planning, and evaluation of response of liver metastasis to chemotherapy using 3D ultrasonography. This article is protected by copyright. All rights reserved. PMID- 30457179 TI - Evaluation of normal cadaveric Achilles tendon and enthesis with ultrashort echo time (UTE) magnetic resonance imaging and indentation testing. AB - Entheses are regions where tendons and ligaments attach to bone, and are the primary target in seronegative and other diseases of the musculoskeletal (MSK) system. MRI has been widely used for visualizing features of inflammatory and degenerative MSK disease; however, normal tendons and entheses have short transverse relaxation times (T2 ), and show little or no signal with conventional clinical MRI pulse sequences, making it difficult to investigate their MR properties. In this study we examined the normal MR morphology of the cadaveric Achilles tendon and enthesis at 3 T using novel three-dimensional ultrashort echo time (3D UTE) Cones sequences, and at 11.7 T using conventional MRI sequences. We also studied the MR properties of the Achilles tendon and enthesis including T2 *, T1 , and magnetization transfer ratio (MTR). In addition, MT modeling of macromolecular proton fractions was investigated using 3D UTE Cones sequences at 3 T. Indentation testing was performed to investigate the mechanical properties of the tendons and entheses, and this was followed by histological examination. In total five specimens (<50 years) were investigated. On average, tendons and entheses respectively had T2 * values of 0.93 +/- 0.48 ms and 2.77 +/- 0.79 ms, T1 values of 644 +/- 22 ms and 780 +/- 55 ms, MTRs of 0.373 +/- 0.03 and 0.244 +/ 0.009 with an MT power of 1000 degrees and frequency offset of 2 kHz, and macromolecular proton fractions of 18.0 +/- 2.2% and 13.9 +/- 1.9%. Compared with the tendon, the enthesis generally had a longer T2 *, a longer T1 , a lower MTR, and a lower macromolecular proton fraction as well as both a higher Young's modulus and stiffness. Results from this study are likely to provide a useful baseline for identifying deviations from the normal in seronegative arthritis and other disease of the entheses. PMID- 30457181 TI - Disentangling longitudinal relations between youth cannabis use, peer cannabis use, and conduct problems: developmental cascading links to cannabis use disorder. AB - AIMS: To determine whether cannabis use during adolescence can increase risk not only for cannabis use disorder (CUD) but also for conduct problems, potentially mediated by exposure to peers who use cannabis. DESIGN, SETTING, PARTICIPANTS: Longitudinal study analyzing four waves of longitudinal data from 364 racially and socio-economically diverse, urban, US community youth (at baseline: Mage = 13.51 (0.95); 49.1% female). MEASUREMENTS: Self-reports of cannabis use, conduct problems, proportion of peers using cannabis and CUD criteria at the final wave were analyzed using a method sensitive to changes over development, the random intercept cross-lagged panel model. FINDINGS: Change in cannabis use did not predict changes in conduct problems or peer cannabis use over time, controlling for gender, race-ethnicity and socio-economic status. Instead, increases in conduct problems predicted increases in cannabis use and ultimately CUD, with some of the effect mediated by increases in the prevalence of peer cannabis use [beta = 0.12, 95% confidence interval (CI) = 0.07, 0.20]. Additionally, affiliation with peers who used cannabis predicted subsequent CUD via increased personal cannabis use (beta = 0.08, 95% CI = 0.04, 0.14). Significant within person betas for the cross-lagged effects ranged between 0.20 and 0.27. CONCLUSIONS: Cannabis use in adolescence does not appear to lead to greater conduct problems or association with cannabis-using peers apart from pre-existing conduct problems. Instead, adolescents who (1) increasingly affiliate with cannabis-using peers or (2) have increasing levels of conduct problems are more likely to use cannabis, and this cascading chain of events appears to predict cannabis use disorder in emerging adulthood. PMID- 30457182 TI - An invisible patient: Healthcare professionals' perspectives on caring for adolescents and young adults who have a sibling with cancer. AB - The impact of a young person's cancer diagnosis extends to siblings, yet support services to address siblings' needs are limited. This study explores healthcare professionals' (HCPs') perspectives on engaging and supporting adolescent and young adult (AYA, 12-25 years) siblings of young cancer patients in hospital settings. Semi-structured interviews with nine HCPs explored participants' views on models of care, engagement and assessment of siblings, available services, barriers to care, and future directions. Participants understood the impact of cancer and need to support AYA siblings, but were unclear how these responsibilities fit in with existing models of care and clinical roles. Siblings' absence from hospitals complicated processes of engagement, assessment and provision of care, challenging some participants to engage siblings outside the clinical context. In the absence of direct contact, HCPs largely relied on patients and parents to report or refer siblings for care. Service and resource limitations further restricted the provision of support to siblings. Despite HCPs' recognition of the need to support siblings, their "invisibility," lack of standardised assessment and service constraints complicate the provision of care in hospital settings. Integrating hospital-based care with community services may better facilitate the engagement and support of AYA siblings. PMID- 30457183 TI - Fine-needle aspiration cytology vs core-needle biopsy for the diagnosis of extracranial head and neck schwannoma. AB - BACKGROUND: We aimed to investigate the feasibility of diagnosing head and neck schwannomas using core-needle biopsy (CNB), and to compare this technique to fine needle aspiration cytology (FNAC). METHODS: We designed a prospective case series in which 52 FNAC and 29 CNB samples from 48 patients with head and neck schwannoma were analyzed. Patient demographics, pathological results, and complications were also evaluated. RESULTS: Of the 81 total specimens, 24/52 (46.2%) of the FNAC and 0/29 (0.0%) of the CNB samples were unsatisfactory (P < .001). Specific diagnoses of schwannoma, including "suspicious schwannoma" and "consistent with schwannoma," were obtained from 10/52 (19.2%) of the FNAC samples and 28/29 (96.6%) of the CNB samples (P < .001). Major complications such as hematoma or permanent nerve injury did not occur in patients who underwent either method. CONCLUSIONS: CNB can diagnose schwannomas with a higher accuracy than FNAC without increasing the rate of complications. PMID- 30457184 TI - General practitioners' management of cancers in Australian adolescents and young adults. AB - General practitioners (GPs) are often the first point of contact adolescents and young adults (AYAs, aged 10-29) with cancer have with the health system, and they are well-placed to coordinate their complex medical and psychosocial care. This study is the first to report characteristics of patients, GPs and cancers involved in AYA cancer management consultations in Australia, using data from a nationally representative sample of 972,100 patient-GP encounters in 2006-2016. AYA cancers were managed in 212 encounters, equating to approximately 137 per 100,000 AYA consultations. This rate was higher in older AYAs (25-29 years) and those who held a concession card. Approximately 30% of cancers managed were classified as "new", with GPs primarily providing counselling, education, and referrals to specialist care, imaging and pathology. This suggests that GPs are involved in the ongoing care of AYAs with cancer from diagnosis, in conjunction with other healthcare professionals. This is an encouraging indication of the potential for integrated multidisciplinary care extending from active treatment into survivorship; however, further work is needed to explore the changing role of GPs across the cancer trajectory. PMID- 30457185 TI - Patients with extensive regional lymph node involvement (pN2) following potentially curative surgery for colorectal cancer are at an increased risk for developing peritoneal metastases - a retrospective single institution study. AB - OBJECTIVES: The goal was to determine the incidence and clinical behavior of peritoneal metastases (PM) in patients with colorectal cancer undergoing potentially curative surgery, comparing patients with extensive loco-regional lymph node involvement (pN2) with those who have serosal involvement (pT4), a known risk factor for developing PM. METHODS: A retrospective analysis of a prospectively maintained database was performed. All patients with pT4 and pN2 were included in the analysis. The diagnostic criteria were the finding of PM during surgery with biopsy confirmation as well as imaging features suggestive of PM including ovarian metastases and omental deposits. RESULTS: 214 patients treated between May 2010 and October 2015 were included. Of these 110 (51.4%) had pT4 and 131 (61.2%) pN2 tumours. 17.2% patients with pT4 tumours and 20.2% patients with pN2 tumours developed PM (p=0.53). The median time to detection of PM was 16.6 months and 11.8 months for pT4 and pN2 tumours respectively. The PM were isolated in 51.8% of patients with pN2. Non-peritoneal metastases developed in 37.5% with pN2. In pN2 tumours, the incidence of PM was higher in signet ring cell and mucinous tumours (p<0.01), positive surgical margins (p=0.02), colonic versus rectal tumours (p=<0.01) and right colon primary tumours. (p=0.01) CONCLUSIONS: Patients with pN2 tumours are at an increased risk of developing PM, which is similar to the risk in pT4 tumours. pN2 tumours should be included in clinical trials evaluating preventive/proactive strategies. There is a need to identify predictive biomarkers for development of PM versus other sites of metastases. This article is protected by copyright. All rights reserved. PMID- 30457186 TI - Notification of an abnormal Pap smear result: An intervention study. AB - This study aims to assess whether notification of an abnormal Pap smear result via a phone call, delivered by a trained healthcare provider, has an effect on women's HRQoL, coping and awareness of HPV. For this intervention study, women were consecutively recruited from a women's health clinic in Sweden. Women in the intervention group (n = 113) were notified of their Pap smear result via a phone call by a trained healthcare provider, while those in the comparison group (n = 122) were notified via a standard letter. A questionnaire was used to collect data. The results found no significant differences between the groups for HRQoL. However, 42.5% of women in the intervention group versus 48.3% in the comparison group reported anxiety. Women in the intervention group were more satisfied with the manner in which they were notified of their abnormal result than those in the comparison group (92.0% vs. 67.2%; p < 0.001), more aware of HPV (71% vs. 50%; p = 0.001), and called healthcare services less often (10.6% vs. 18.0%; p = 0.113), no significance. In conclusion, notification of an abnormal Pap smear result via a phone call does not increase women's HRQoL or reduce their anxiety. PMID- 30457187 TI - Novel adamantane-substituted acridine donor for blue dual fluorescence and efficient organic light-emitting diodes. AB - Thus far, blue dual fluorescence emission (DFE) has not been realized owing to the limited choice of chemical moieties and severe geometric deformation of the DFE emitters leading to strong intramolecular charge transfer (ICT) with a large Stokes shift in excited states. Herein, an emitter (1'r,5'R,7'S)-10-(4-(4,6 diphenyl-1,3,5-triazin-2-yl)phenyl)-10H-spiro [acridine-9,2'-adamantane] (a-DMAc TRZ) containing a novel adamantine-substituted acridine donor was reported, which exhibits unusual blue DFE. The introduction of the rigid and bulky adamantine moiety not only suppressed the geometry relaxation in excited state and reduced ICT, but also induced the formation of quasi-axial conformer (QAC) and quasi equatorial conformer (QEC) geometries, leading to deep-blue conventional fluorescence and sky-blue thermally activated delayed fluorescence (TADF). Moreover, the lowest triplet excited state (3LE) of QAC was discovered to be higher lying than that of QEC, making Dexter energy transfer (DET) channel from 3LE of QAC to 3CT of QEC possible with short intermolecular distance. Corresponding organic light-emitting diodes (OLEDs) achieved a maximum external quantum efficiency (EQE) of ~29%, which is the highest result among all reported OLEDs based on DFE emitters. PMID- 30457188 TI - Surface Modification Based on Diselenide Dynamic Chemistry: Towards Liquid Motion and Surface Bioconjugation. AB - Surface modification is an important technique in a series of interesting fields, such as self-cleaning, surface patterning, sensing and detection, etc. Diselenide bond was proved to be a dynamic covalent bond that can undergo diselenide metathesis reaction simply under visible light irradiation. Herein we develop the diselenide dynamic chemistry into a versatile surface modification method with fast response and reversibility. Diselenide bond could be modified onto various substrates like PDMS, quartz and ITO conductive film glass, etc. Different functional diselenide molecules could then be immobilized onto the surface via diselenide metathesis reaction. We demonstrated that by using this modification method we could achieve the liquid motion in a capillary tube. We also proved that this approach has the potential to serve as an efficient modification method for surface bioconjugation, which has practical applications in clinical usage. PMID- 30457189 TI - Priming of LTP in amygdala and hippocampus by prior paired pulse facilitation paradigm in mice lacking brain serotonin. AB - This study focuses on analyzing long term potentiation (LTP) changes in the lateral nucleus of the amygdala (LA) and in the CA1 region of the hippocampus in slices derived from mice deficient in tryptophan hydroxylase 2 (TPH2-/- ), the rate-limiting enzyme for 5-HT synthesis in the brain. We found a reduced LTP in both brain structures in TPH2-/- mice. However, we found no changes in the magnitude of LTP in TPH2-/- mice compared to wildtype mice when it was preceded by a paired pulse protocol. Whereas the magnitude of long term depression (LTD) did not differ between wildtype and TPH2-/- mice, priming synapses by LTD induction facilitated subsequent CA1-LTP in wildtype mice to a greater extent than in TPH2-/- mice. In the LA we found no differences between the genotypes in this protocol of metaplasticity. These data show that, unlike exogenous 5-HT application, lack of 5-HT in the brain impairs cellular mechanisms responsible for induction of LTP. It is supposed that suppression of LTP observed in TPH2-/- mice might be compensated by mechanisms of metaplasticity induced by paired pulse stimulation or low frequency stimulation before the induction of LTP. This article is protected by copyright. All rights reserved. PMID- 30457190 TI - 'Punching above their weight': a qualitative examination of local governments' organisational efficacy to improve the social determinants of health. AB - OBJECTIVE: The World Health Organization calls upon local government worldwide to play a greater role in improving public health by improving the social determinants of health. This research aimed to determine how local governments in Victoria, Australia, conceptualised their organisational efficacy to address public health with reference to their statutory obligations. METHODS: Sixteen in depth interviews were conducted with Victorian local government health planners. Thematic analysis was used to determine the importance of state health priorities and the perceived organisational efficacy of local government to address health via social determinants. RESULTS: While there were disparities between state and local priorities for health, local government believes it can make an important contribution to improving health through 'upstream' approaches. CONCLUSIONS: Victorian local government has strongly adopted the socio-ecological model of health and is aware of the important role that its diverse policy and program areas play in creating healthy communities. The Victorian State Government's priorities, which adopted a more 'downstream' approach, were less influential. Implications for public health: State governments' priority settings should be responsive to local governments' unique local knowledge of health priorities. There is value in legislating a social determinants role for local government, provided it is supported by state and national government policies that facilitate public health. PMID- 30457191 TI - Associations between nutrition risk status, body composition and physical performance among community-dwelling older adults. AB - OBJECTIVE: To investigate the associations between nutrition risk status, body composition and physical performance among community-dwelling older New Zealanders. METHODS: This cross-sectional study enrolled 257 community-dwelling older adults (median age 79 years). Assessments included the Mini Nutritional Assessment-Short Form (MNA(r)-SF) for nutrition risk; the Eating Assessment Tool 10 for dysphagia risk; bioimpedance analysis for body composition (free fat mass (FFM) and percentage body fat) and gait speed for physical performance. A multiple logistics regression analysis was conducted, to determine factors associated with lower odds [OR (95% CI)] for nutrition risk. RESULTS: Every yearly increase in age was associated with higher odds 1.09 (1.01-1.17) for nutrition risk. Additionally, nutrition risk was less likely to occur among participants of age <85 years 0.30 (0.11-0.79), with no dysphagia 0.29 (0.09 0.97) and those with a healthy gait speed 0.29 (0.09-0.97). Lower odds for nutrition risk were also found with increasing values of FFM index 0.51 (0.34 0.77), and percentage body fat 0.81 (0.72-0.90). Gait speed was positively correlated with FFM index (r=0.19 p<0.022), percentage body fat (r=0.23, p=0.006) and BMI (r=0.29, p<0.001). CONCLUSION: Among these participants, associations between nutrition risk, body composition and physical performance were found. Implications for public health: Routine screening of nutrition risk and/or physical performance among vulnerable older adults is key towards identifying those in need of assessment and dietary intervention. Alongside strategies to encourage physical activity, this may help to slow losses of FFM and protect physical performance. PMID- 30457192 TI - Punching above their weight: Large release of greenhouse gases from small agricultural dams. AB - Freshwater ecosystems play a major role in global carbon cycling through the breakdown of organic material and release of greenhouse gases (GHGs). Carbon dioxide (CO2 ) and methane (CH4 ) emissions from lakes, wetlands, reservoirs and small natural ponds have been well studied, however, the GHG emissions of highly abundant, small-scale (<0.01 km2 ) agricultural dams (small stream and run-off impoundments) are still unknown. Here, we measured the diffusive CO2 and CH4 flux of 77 small agricultural dams within south-east Australia. The GHG emissions from these waterbodies, which are currently unaccounted for in GHG inventories, amounted to 11.12 +/- 2.59 g CO2 -equivalent m2 /day, a value 3.43 times higher than temperate reservoir emissions. Upscaling these results to the entire state of Victoria, Australia, resulted in a farm dam CO2 -equivalent/day emission rate of 4,853 tons, 3.1 times higher than state-wide reservoir emissions in spite of farm dams covering only 0.94 times the comparative area. We also show that CO2 and CH4 emission rates were both significantly positively correlated with dissolved nitrate concentrations, and significantly higher in livestock rearing farm dams when compared to cropping farm dams. The results from this study demonstrate that small agricultural farm dams can be a major source of greenhouse gas emissions, thereby justifying their inclusion in global carbon budgets. PMID- 30457193 TI - CHRONIC ULCERATIVE STOMATITIS: a comprehensive review and proposal for diagnostic criteria. AB - Chronic ulcerative stomatitis (CUS) is an immune-mediated disorder characterized by oral erosions and ulcers usually refractory to conventional treatments. The disease often involves middle-aged and older women with painful lesions sometimes resembling those of erosive oral lichen planus (OLP). The most affected sites are the buccal mucosa, the gingiva and the tongue, but the skin is involved in 22.5% of cases. Histopathologic features in CUS are non-specific and indistinguishable from those of OLP, with the exception of the presence of a mixed infiltrate composed of lymphocytes and plasma cells. Direct immunofluorescence (DIF) analysis reveals the presence of stratified epithelium-specific antinuclear antibodies (SES-ANA) in the lower third of the epithelium. The IgG antibodies detected on DIF are directed against the ?Np63alpha isoform of p63 expressed in the nuclei of the epithelial basal cells. A distinguishing feature of CUS is the low response to conventional corticosteroid therapy and the good outcome with hydroxychloroquine at the dosage of 200 mg/day or higher dosages. This paper presents a comprehensive review of CUS and is accompanied by a new case report (the 73rd case) and a proposal for updated diagnostic criteria. This article is protected by copyright. All rights reserved. PMID- 30457194 TI - "MICROWAVES IN BODY SCULPTING: A PROSPECTIVE STUDY". PMID- 30457195 TI - Vulnerable, single and living in poverty: Women's challenges to accessing food in the Australian Capital Territory. AB - OBJECTIVE: To explore challenges to food access faced by vulnerable women living in the Australian Capital Territory and surrounds. METHOD: Qualitative study comprising semi-structured interviews supplemented with quantitative demographic data. RESULTS: Forty-one women, mean age of 43 years, living in government and community housing who had an income of <$300 per week participated. A total of 78% of women had completed Year 10 or above and 93% had accessed food from at least one charitable organisation. Women requested greater and reliable access to meat, dairy and quality fruit and vegetables. Primary challenges to accessing food included: limited income, distance to food outlets, lack of nutritious, safe and healthy food, limited knowledge of services and opening hours. CONCLUSION: Access to safe, nutritious and healthy food is difficult for women living in poverty. Acknowledgement of challenges that contribute to women's food insecurity by all stakeholders is essential to address the problem and build sustainable actions and solutions. Implications for public health: Collaboration from all stakeholders within our food system is required to address current inequities to accessing reliable, nutritious and safe food and to reduce individual food insecurity. PMID- 30457196 TI - Polymacrocycles Derived via Ugi Multi-Component Reactions. AB - The synthesis of macrocycles based on the Ugi-4CR has been thoroughly explored by Wessjohann and coworkers, while polymerizations utilizing the Ugi-4CR are already patented by Ugi and recently studied more in detail, developing a new trend in polymer chemistry. Here, the combination of both, that is, the synthesis of polymacrocycles, is demonstrated. As diverse functional groups can be easily introduced in a macrocycle via Ugi-4CR, a straightforward design of polymacrocycles is achieved in a two-step procedure. First, the Ugi-4CR of 10 undecenoic acid, a diamine, a diisocyanide, and an aldehyde results in diversely substituted macrocycles having two terminal double bonds. Subsequently, these macrocycles are polymerized by ADMET (acyclic diene metathesis) or thiol-ene polymerization to generate polymacrocycles with potential application in coordination chemistry as, for example, sensors, filters, or phase-transfer catalysts. Moreover, the setup of the literature-known Ugi macrocyclization is simplified by systematic reaction screening. PMID- 30457198 TI - 'Climate refugees': is it time to legally acknowledge those displaced by climate disruption? PMID- 30457197 TI - Efficacy and safety of switching to dolutegravir plus emtricitabine/tenofovir disoproxil fumarate (TDF) or elvitegravir/cobicistat/emtricitabine/TDF in virologically suppressed HIV-infected patients in clinical practice: results from a multicentre, observational study. AB - OBJECTIVES: The aim of the study was to compare the efficacy and tolerability of switching antiretroviral therapy to dolutegravir + emtricitabine/tenofovir disoproxil fumarate (TDF) with those of switching to elvitegravir/cobicistat/emtricitabine/TDF in clinical practice. METHODS: In a multicentre real-life observational study, we analysed data for HIV-infected patients on antiretroviral treatment with viral load < 50 HIV-1 RNA copies/mL switching to dolutegravir + emtricitabine/TDF (dolutegravir group) or elvitegravir/cobicistat/emtricitabine/TDF (elvitegravir group). Follow-up was censored at 48 weeks. RESULTS: The 48-week estimated proportion maintaining virological efficacy was 96.1% with dolutegravir (n = 123) and 95.4% with elvitegravir (n = 186; P = 0.941). Patients in the dolutegravir group showed more treatment discontinuations, but these were mainly as a result of simplification. The elvitegravir group showed more discontinuations because of renal adverse events (2.7% versus 0% with dolutegravir). Interestingly, no difference was observed between the two regimens in central nervous system toxicity-related discontinuations. Switching to dolutegravir was associated with a better blood lipid profile. CONCLUSIONS: Switching to dolutegravir + emtricitabine/TDF was associated with similar efficacy and tolerability to switching to elvitegravir/cobicistat/emtricitabine/TDF in virologically suppressed patients in clinical practice, although reasons for discontinuation showed differences between regimens. These results should be interpreted with caution, as this is a nonrandomized comparison. PMID- 30457199 TI - Nitrogen-containing bisphosphonate therapy-Part II: Assessment of alveolar bone tissue inflammatory response in rats-A blind randomized controlled trial. AB - This study aimed to evaluate the alveolar bone tissue inflammatory response in rats undergoing zoledronic acid therapy. The study sample was composed of 28 Wistar rats. Animals from the test group GTa received a weekly intraperitoneal dose of 0.2 mg/kg of zoledronic acid for 3 weeks, while test group GTb received the same dose for 8 weeks. A physiological saline dose, equivalent to that of the medication, was administered to the controls in groups GCa and GCb. A defect was created in the dental crown of the lower first molars using a drill to simulate pulp and periapical injury. Data were evaluated regarding image grey levels by cone-beam computed tomography and histologically by assigning scores for the presence of inflammatory infiltrate, type of infiltrate, vascularization, bone necrosis and dental resorption. Grey levels in the 3-week therapy group (GTa) showed more pronounced changes in comparison with those seen in the GCa group (P < 0.05). Evaluation of the scores demonstrated no association between any of the variables amongst the groups (>0.05). However, bone remodelling decreased in the groups receiving the medication. Bone necrosis was present more frequently in group GTb than in the control group GCb. The results suggest that the drug interfered in the reaction capacity of the alveolar bone tissue as test group GTa showed higher grey levels in comparison to the control group GCa. In addition, there was less bone remodelling activity, with the appearance of bone necrosis zones and intense acute inflammatory infiltrate associated with the 8-week therapy group GTb. PMID- 30457200 TI - An evaluation of mainstream type 2 diabetes educational programmes in relation to the needs of people with intellectual disabilities: A systematic review of the literature. AB - BACKGROUND: Risk reduction and self-management programs for type 2 diabetes (T2D) are commonplace. However, little is known about their appropriateness for people with intellectual disabilities (ID). This review evaluates successful components and theoretical basis of interventions and preventions in relation to the needs of people with ID with or at risk of T2D. METHOD: Characteristics of 23 randomised controlled trialled T2D educational programs were systematically assessed alongside the needs of people with ID, and evaluated in terms of study design and theoretical application. RESULTS: Successful components of programs align to the needs of people with ID. Further adaptations are required to ensure accessibility of materials and social support to enable reflection on illness perceptions and self-efficacy, as underpinned by Self-regulation and Social cognitive theories. CONCLUSIONS: Support is provided for further trials of self management and preventative adaptations under development. Impact may be enhanced through preventions aimed at younger groups in educational settings. PMID- 30457201 TI - Interferon-gamma Receptor 1 and GluR1 upregulated in motor neurons of symptomatic hSOD1G93A mice. AB - Motor neurons are markedly vulnerable to excitotoxicity mostly by alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) stimulation and are principal targets in the neurodegenerative disease Amyotrophic Lateral Sclerosis. Interferon-gamma (IFN-gamma), a pro-inflammatory cytokine, can independently cause neuronal dysfunction by triggering calcium influx through a calcium permeable complex of IFN-gamma receptor 1(IFNGR1) subunit and AMPAR subunit GluR1. This receptor complex is formed via a non-canonical neuron-specific IFN gamma pathway that involves Jak1/Stat1 and Protein Kinase A. In this study, we explore the expression of the pathway's participants for the first time in the hSOD1G93A Amyotrophic Lateral Sclerosis mouse model. Elevated IFNGR1 and GluR1 are detected in motor neurons of hSOD1G93A symptomatic mice ex vivo, unlike the downstream targets - Jak1, Stat1, and Protein Kinase A. We, also, determine effects of IFN-gamma alone or in the presence of an excitotoxic agent, kainate, on motor neuron survival in vitro. IFN-gamma induces neuronal damage, but does not influence kainate-mediated excitotoxicity. Increased IFNGR1 can most likely sensitize motor neurons to excitotoxic insults involving GluR1 and/or pathways mediated by IFN-gamma, thus, serving as a potential direct link between neurodegeneration and inflammation in Amyotrophic Lateral Sclerosis. This article is protected by copyright. All rights reserved. PMID- 30457202 TI - A protocol for quantifying cardiogenic oscillations in dynamic 129 Xe gas exchange spectroscopy: The effects of idiopathic pulmonary fibrosis. AB - The spectral parameters of hyperpolarized 129 Xe exchanging between airspaces, interstitial barrier, and red blood cells (RBCs) are sensitive to pulmonary pathophysiology. This study sought to evaluate whether the dynamics of 129 Xe spectroscopy provide additional insight, with particular focus on quantifying cardiogenic oscillations in the RBC resonance. 129 Xe spectra were dynamically acquired in eight healthy volunteers and nine subjects with idiopathic pulmonary fibrosis (IPF). 129 Xe FIDs were collected every 20 ms (TE = 0.932 ms, 512 points, dwell time = 32 MUs, flip angle ~ 20 degrees ) during a 16 s breathing maneuver. The FIDs were pre-processed using the spectral improvement by Fourier thresholding technique (SIFT) and fit in the time domain to determine the airspace, interstitial barrier, and RBC spectral parameters. The RBC and gas resonances were fit to a Lorentzian lineshape, while the barrier was fit to a Voigt lineshape to account for its greater structural heterogeneity. For each complex resonance the amplitude, chemical shift, linewidth(s), and phase were calculated. The time-averaged spectra confirmed that the RBC to barrier amplitude ratio (RBC:barrier ratio) and RBC chemical shift are both reduced in IPF subjects. Their temporal dynamics showed that all three 129 Xe resonances are affected by the breathing maneuver. Most notably, several RBC spectral parameters exhibited prominent oscillations at the cardiac frequency, and their peak-to-peak variation differed between IPF subjects and healthy volunteers. In the IPF cohort, oscillations were more prominent in the RBC amplitude (16.8 +/- 5.2 versus 9.7 +/- 2.9%; P = 0.008), chemical shift (0.43 +/- 0.33 versus 0.083 +/- 0.05 ppm; P < 0.001), and phase (7.7 +/- 5.6 versus 1.4 +/- 0.8 degrees ; P < 0.001). Dynamic 129 Xe spectroscopy is a simple and sensitive tool that probes the temporal variability of gas exchange and may prove useful in discerning the underlying causes of its impairment. PMID- 30457203 TI - Fitting algorithms and baseline correction influence the results of non-invasive in vivo quantitation of 2-hydroxyglutarate with 1 H-MRS. AB - 1 H-MRS enables non-invasive detection of 2-hydroxyglutarate (2-HG), an oncometabolite accumulating in gliomas carrying mutations in the isocitrate dehydrogenase (IDH) genes. Reliable 2-HG quantitation requires reproducible post processing, deployment of fitting algorithms and quantitation methods. We prospectively enrolled 38 patients with suspected or recently diagnosed gliomas (IDH mutated n = 26). The MRI protocol included a 1 H single voxel PRESS sequence with volumes of usually 8 mL or more (20 * 20 * 20 mm3 ) at TE = 97 ms and 180 degrees pulse spacing. Our aim was to evaluate the reliability of 2-HG quantitation comparing two frequently used software tools and their respective options of baseline correction (jMRUI with the time domain methods AQSES and QUEST, and LCModel, which analyzes the frequency domain data). For AQSES, degrees of freedom for baseline correction constrains were varied. For LCModel, baseline correction was obtained with and without correction of the unknown background term (predefined macromolecules, lipids). Tissue concentrations were calculated based on the phantom replacement method. Quantitation of 2-HG levels showed similar mean 2-HG tissue concentrations for IDH mutated tumors (2.65mM, range 3.06-2.20) for all methods. Bland-Altman plots (difference plots) did not reveal a systematic bias (fixed bias) for any of the algorithms tested, and we were able to show a significant correlation regarding 2-HG concentration at the same echo time with few statistical outliers (parametric correlation). However, evaluation of outliers suggested that in vivo quantitation of 2-HG is affected not only by the fitting domain (time or frequency), but also by the baseline correction, which is a major contributing factor to the result of 2-HG fitting. Clinical application of 2-HG quantitation as a prognostic or predictive biomarker, particularly in multicenter trials, requires standardized use of fitting methods and baseline correction procedures. PMID- 30457204 TI - Bandages will not fix a fractured system of chronic kidney disease care: Why the Dialysis PATIENTS Demonstration Act cannot be supported by the transplant community. AB - The Dialysis PATIENTS Demonstration Act (DPDA) (H.R 4143/S.2065) is proposed to improve the value of care for dialysis patients. In this issue of AJT,(1) Becker and Nissensen (who work for Da Vita), write to reassure the transplant community that transplantation remains a priority under the DPDA. They express "hope" that the DPDA will be neutral or have little impact on transplantation, while omitting reference to the competitive advantage Da Vita would enjoy under the DPDA. Large dialysis providers such as Da Vita, could more easily assume the risk of all of dialysis patient costs (over $80,000 per patient per year), as envisioned in the DPDA, compared to smaller and non-profit dialysis providers. This article is protected by copyright. All rights reserved. PMID- 30457205 TI - Inequalities in HIV testing uptake and needs among men who have sex with men living in Ireland: findings from an internet survey. AB - OBJECTIVES: HIV disproportionately affects men who have sex with men (MSM) in Ireland. The aim of this study was to improve understanding of HIV testing among MSM living in Ireland to inform prevention and testing initiatives. METHODS: We used data from the MSM Internet Survey Ireland 2015 (MISI 2015), a cross sectional survey of MSM living in Ireland. We identified factors associated with never having tested for HIV using univariable and multivariable logistic regression. We identified preferred sites for future tests and examined the relationships between unmet HIV testing needs and socio-demographic groups. RESULTS: More than one-third (n = 1006; 36%) of MSM had never tested for HIV. Multivariable logistic regression showed that untested men were more likely to be aged 18-24 years, live outside Dublin, have a lower level of education, be born in Ireland, identify as bisexual, be out to fewer people, and not have had sex with a man in the previous 12 months. The same groups of men also had the least knowledge about HIV and were least confident in accessing an HIV test. Men who had never tested for HIV were more likely to prefer testing by their general practitioner (GP) or using home sampling HIV kits and less likely to prefer testing in a sexual health clinic. CONCLUSIONS: HIV prevention and testing programmes for MSM should be targeted towards younger men, those living outside Dublin and those with lower levels of education. We recommend increased promotion and availability of free HIV testing services in a range of clinical and nonclinical settings (including self-sampling and home testing). PMID- 30457206 TI - Fine-needle aspiration of alveolar soft part sarcoma: Histologic correlation and aberrant CD68 expression. AB - Alveolar soft part sarcoma is a rare highly malignant neoplasm of the soft tissue and usually occurs in the lower extremities of children and young adults. We report two cases of alveolar soft part sarcoma: a 24-year-old Latino man with a 10-cm neck mass and a 56-year-old Latino woman with a recurring thigh mass. Fine needle aspiration and a core biopsy were performed on both, which was followed by tumor resection on the man. The smears displayed numerous loosely cohesive or single large cells with abundant granular cytoplasm, round nuclei, vesicular chromatin, and occasional prominent nucleoli. Periodic and Schiff (PAS)-positive, diastase-resistant rhomboid, or needle-shaped crystals were present. Both tumors had diffuse and strong nuclear TFE3 expression and aberrant cytoplasmic CD68 expression. Fluorescence in situ hybridization analysis was performed in the first case, which detected a characteristic translocation t(X;17)(p11;q25). The diagnosis of alveolar soft part sarcoma was rendered in both cases. Herein, we present the cytology, histology, immunohistochemistry, and molecular findings and discuss the differential diagnosis. PMID- 30457207 TI - Recent developments and applications of capillary and microchip electrophoresis in proteomics and peptidomics (2015-mid 2018). AB - This review summarizes recent developments and applications of capillary and microchip electroseparation methods in proteomic and peptidomic analyses since the year 2015 to ca. mid 2018. Sample preparation procedures for the removal of interfering components or for pre-fractionation and preconcentration of proteins and peptides of interest are discussed. The innovations in coupling of capillary or microchip electroseparation methods with different modes of mass spectrometry detection are covered. In addition, significant recent applications of capillary electromigration methods in both bottom-up and top-down proteomics as well as in determinations of post-translational modifications of proteins are presented. Moreover, several examples of the utilization of capillary electromigration methods coupled with mass spectrometry detection for clinical proteomics and peptidomics are described. PMID- 30457208 TI - Photobleaching of pheomelanin increases its phototoxic potential; physicochemical studies of synthetic pheomelanin subjected to aerobic photolysis. AB - Although melanin is a photoprotective pigment, its elevated photochemical reactivity could lead to various phototoxic processes. Photoreactivity of synthetic pheomelanin, derived from 5-S-cysteinyldopa (5SCD-M) and its photodegradation products obtained by subjecting the melanin to aerobic irradiation with UV-visible light, was examined employing an array of advanced physicochemical methods. Extensive photolysis of 5SCD-M was accompanied by partial bleaching of the melanin, modification of its paramagnetic properties and significant increase in the ability to photogenerate singlet oxygen. The changes correlated with a substantial decrease in the melanin content of benzothiazine (BT) units and increase of modified benzothiazole (BZ) units. Synthetically prepared BZ exhibited higher efficiency to photogenerate singlet oxygen than the synthetic BT, and the free radical form of BZ, unlike that of BT, did not show measurable spin density on nitrogen atom, which was confirmed by quantum chemical calculations. Formation of modified BZ units in the photobleached 5SCD-M is responsible for the paramagnetic and photochemical changes of the melanin and its elevated phototoxic potential. Given a relatively constant pheomelanin-eumelanin ratio, such undesirable changes could occur in individual of all skin types. This article is protected by copyright. All rights reserved. PMID- 30457209 TI - Genetic markers associated with long term cardiovascular outcome in kidney transplant recipients. AB - There is a clear genetic contribution to the risk of cardiovascular diseases, and a composite genetic risk score (GRS) based on 27 single nucleotide polymorphisms (SNPs) was reported to predict risk of cardiovascular events in the general population. We aimed to evaluate this risk score in renal transplant recipients, a population with heightened cardiovascular risk, with a yet unknown genetic contribution. This article is protected by copyright. All rights reserved. PMID- 30457210 TI - Three-dimensional cancer cell culture in high-yield multiscale scaffolds by shear spinning. AB - Polymeric scaffolds comprising two size scales of microfibers and submicron fibers can better support three-dimensional (3D) cell growth in tissue engineering, making them an important class of healthcare material. However, a major manufacturing barrier hampers their translation into wider practical use: scalability. Traditional production of two-scale scaffolds by electrospinning is slow and costly. For day-to-day cell cultures, the scaffolds need to be affordable, made in high yield to drive down cost. Combining expertise from academia and industry from the United Kingdom and United States, this study uses a new series of high-yield, low-cost scaffolds made by shear spinning for tissue engineering. The scaffolds comprise interwoven submicron fibers and microfibers throughout as observed under scanning electron microscopy and demonstrate good capability to support cell culturing for tumor modeling. Three model human cancer cell lines (HEK293, A549 and MCF-7) with stable expression of GFP were cultured in the scaffolds and found to exhibit efficient cell attachment and sustained 3D growth and proliferation for 30 days. Cryosection and multiphoton fluorescence microscopy confirmed the formation of compact 3D cell clusters throughout the scaffolds. In addition, comparative growth curves of 2D and 3D cultures show significant cell-type-dependent differences. This work applies high-yield shear spun scaffolds in mammalian tissue engineering and brings practical, affordable applications of multiscale scaffolds closer to reality. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018. PMID- 30457211 TI - Vermi-trouble: Cytology of an arm swelling. PMID- 30457212 TI - The lncRNA RMEL3 protects immortalized cells from serum withdrawal-induced growth arrest and promotes melanoma cell proliferation and tumor growth. AB - RMEL3 is a recently identified lncRNA associated with BRAFV600E mutation and melanoma cell survival. Here we demonstrate strong and moderate RMEL3 upregulation in BRAF and NRAS mutant melanoma cells, respectively, compared to melanocytes. High expression is also more frequent in cutaneous than in acral/mucosal melanomas, and analysis of an ICGC melanoma dataset showed that mutations in RMEL3 locus are preponderantly C>T substitutions at dipyrimidine sites including CC>TT, typical of UV-signature. RMEL3 mutation does not correlate with RMEL3 levels, but does with poor patient survival, in TCGA melanoma-dataset. Accordingly, RMEL3 lncRNA levels were significantly reduced in BRAFV600E melanoma cells upon treatment with BRAF or MEK inhibitors, supporting the notion that BRAF MEK-ERK pathway plays a role to activate RMEL3 gene transcription. RMEL3 overexpression, in immortalized fibroblasts and melanoma cells, increased proliferation and survival under serum starvation, clonogenic ability, and xenografted melanoma tumor growth. Although future studies will be needed to elucidate the mechanistic activities of RMEL3, our data demonstrate that its overexpression bypasses the need of mitogen activation to sustain proliferation/survival of non-transformed cells and suggest an oncogenic role for RMEL3. This article is protected by copyright. All rights reserved. PMID- 30457213 TI - Prevalence of high-risk human papilloma virus in liquid-based cervical samples from Turkish women with normal and abnormal cytology. AB - BACKGROUND: The aim of this study was to investigate the prevalence of human papilloma virus (HPV) infection from Turkish women with normal and abnormal cytology. METHODS: Our study population consisted of 1252 women with normal and abnormal cytology. In our clinic, cervical cancer screening was performed by liquid-based cytology testing (ThinPrep Pap Test). Reflex high-risk (HR) HPV testing (Cervista HPV HR and HPV 16/18) was performed in cases with abnormal cytology (n = 330). HR HPV testing was performed to 922 cases with normal cytology. RESULTS: HR HPV was detected in 18.7% of negative for intraepithelial lesion or malignancy (NILM) samples, and in 79.7% of abnormal cytology cases. HPV types 16 and/or 18 were found in 18.6% and 35.3% of normal cytology cases and abnormal cytology cases, respectively. Of all 435 HR HPV-positive samples, HPV type 16 and/or 18 prevalence was significantly higher in cases with more severe cytological abnormalities. CONCLUSIONS: The HPV prevalence among Turkish women with normal and abnormal cytology identified in this study largely concurs with those in other studies throughout the world. HPV types 16 and/or 18 were detected significantly in normal cytology cases in our study. We also found that, as has been previously demonstrated, certain HPV genotypes (16/18) are associated with more severe pathologies. However, larger epidemiological studies in different regions of Turkey are needed to evaluate the accurate prevalence of HPV infection throughout the country. PMID- 30457214 TI - Construction of synthetic promoters by assembling the sigma factor binding -35 and -10 boxes. AB - Promoter is one of the key elements in regulating gene expression. Many natural or synthetic promoters have been modulated by their cis- or tans-regulatory elements to confer instant gene expression change in responding to designated stimuli. In addition, bacterial cells also engage different sigma factors to control the gene expression network at different growth phases or in response to the changing environment and external stresses. In this study, we synthesized a set of promoters that assimilate the endogenous regulation of different sigma factors sigma70 , sigma38 , sigma32 , and sigma24 . Promoters were designed to contain two or more kinds of interlocking sigma factor binding sites. The most competitive sigma factors would be automatically selected by the cell to take over the synthetic promoters during the cell growth course. Some of the synthetic promoters exhibited very strong strengths under different conditions, including stationary phase, low temperature, acidic pH, and high osmotic pressure. Comparing to the T7 promoter, synthetic promoter P21285 achieved higher yields of L-asparaginase and acid urease in Escherichia coli. The research not only expands the synthetic biology toolbox but also provide another strategy to design and construct synthetic promoters in prokaryotes. PMID- 30457215 TI - Color Naming Reflects Both Perceptual Structure and Communicative Need. AB - Gibson et al. () argued that color naming is shaped by patterns of communicative need. In support of this claim, they showed that color naming systems across languages support more precise communication about warm colors than cool colors, and that the objects we talk about tend to be warm-colored rather than cool colored. Here, we present new analyses that alter this picture. We show that greater communicative precision for warm than for cool colors, and greater communicative need, may both be explained by perceptual structure. However, using an information-theoretic analysis, we also show that color naming across languages bears signs of communicative need beyond what would be predicted by perceptual structure alone. We conclude that color naming is shaped both by perceptual structure, as has traditionally been argued, and by patterns of communicative need, as argued by Gibson et al. -although for reasons other than those they advanced. PMID- 30457217 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 48/2018. PMID- 30457216 TI - Quantitative analysis of connectivity in populations of a semi-aquatic mammal using kinship categories and network assortativity. AB - Analyzing the impact of anthropogenic and natural river barriers on the dispersal of aquatic and semi-aquatic species may be critical for their conservation. Knowledge of kinship relationships between individuals and reconstructions of pedigrees obtained using genomic data can be extremely useful, not only for studying the social organization of animals, but also inferring contemporary dispersal and quantifying the effect of specific barriers on current connectivity. In this study, we used kinship data to analyze connectivity patterns in a small semi-aquatic mammal, the Pyrenean desman (Galemys pyrenaicus), in an area comprising two river systems with close headwaters and dams of various heights and types. Using a large SNP dataset from 70 specimens, we obtained kinship categories and reconstructed pedigrees. To quantify the barrier effect of specific obstacles, we built kinship networks and devised a method based on the assortativity coefficient, which measures the proportion between observed and expected kinship relationships across a barrier. The estimation of this parameter enabled us to infer that the most important barrier in the area was the watershed divide between the rivers, followed by a dam on one of the rivers. Other barriers did not significantly reduce the expected number of kinship relationships across them. This strategy and the information obtained with it may be crucial in determining the most important connectivity problems in an area and help develop conservation plans aimed at improving genetic exchange between populations of threatened species. This article is protected by copyright. All rights reserved. PMID- 30457218 TI - Corrigendum: Barium as Honorary Transition Metal in Action: Experimental and Theoretical Study of Ba(CO)+ and Ba(CO). PMID- 30457219 TI - Circadian rhythms. PMID- 30457220 TI - An Evolutionary Approach to the Study of Collaborative Remembering? AB - Hope and Gabbert (2008) and Jay and colleagues (in press) show us that collaborative remembering, in certain contexts, may result in incomplete and less accurate memories. Here, I will discuss the evolutionary origins of this behavior, linking it to phenomena such as social contagion, conformity, and social learning, which are highly adaptive and widespread across non-human taxa. PMID- 30457221 TI - Mathematical Modeling of Oxygen Release from Hyperbarically Loaded Polymers. AB - Polymer-based scaffolds are used extensively in the field of regenerative medicine. These biomaterials may induce therapeutic responses through modulating a wound microenvironment with or without the addition of cells. It has long been known that oxygen is a crucial component of the microenvironment that influences cellular and physiological processes such as metabolism, proliferation, differentiation, matrix deposition, phagocytic killing, and wound healing. Consequently, several studies have investigated the potential for using oxygen eluting biomaterials to regulate the oxygen tension within a wound microenvironment and to tune the regenerative response. We recently demonstrated that hyperbarically loaded polymers could be used as oxygen-delivery devices for biomedical uses. To further develop this strategy, it is important to quantitatively characterize the spatiotemporal oxygen diffusion profile from scaffolds. Here, we use analytical and numerical solutions to describe the profiles of oxygen diffusion from hyperbarically loaded polymers as a function of different scaffold geometries, material compositions, and ambient temperatures. This article is protected by copyright. All rights reserved. PMID- 30457222 TI - Three-Dimensional Graphene-based N-doped Carbon Composites as High-Performance Anode Materials for Sodium-ion Batteries. AB - A nitrogen-doped carbon layer coating on a 3D graphene framework (NCL@GF) was produced by the in-situ polymerization of a uniform polyimide layer on the graphene framework surface and a carbonization process. The NCL@GF exhibited a 3D macroporous structure with uniform N-doped porous carbon layers and a high 5.4 at. % nitrogen content, which not only effectively enhanced the active sites but also facilitated fast ion and electron transport in the 3D pathways. Consequently, the NCL@GF as the anode of a sodium-ion battery (SIB) exhibited a discharge capacity of 357 mAh g-1 at 0.1 A g-1 after 200 cycles, a remarkable rate capability with a capacity of 122 mAh g-1 at 8 A g-1 , and a super long cycle life with a capacity retention of 70 % capacity after 2500 cycles at 0.5 A g-1 . Such performance is superior to that of previously reported carbon or graphene-based composites. PMID- 30457224 TI - A need for a paradigm shift in focus: From Kt/Vurea to appropriate removal of sodium (the ignored uremic toxin). AB - Hemodialysis for chronic renal failure was introduced and developed in Seattle, WA, in the 1960s. Using Kiil dialyzers, weekly dialysis time and frequency were established to be about 30 hours on 3 time weekly dialysis. This dialysis time and frequency was associated with 10% yearly mortality in the United States in 1970s. Later in 1970s, newer and more efficient dialyzers were developed and it was felt that dialysis time could be shortened. An additional incentive to shorten dialysis was felt to be lower cost and higher convenience. Additional support for shortening dialysis time was provided by a randomized prospective trial performed by National Cooperative Dialysis Study (NCDS). This study committed a Type II statistical error rejecting the time of dialysis as an important factor in determining the quality of dialysis. This study also provided the basis for the establishment of the Kt/Vurea index as a measure of dialysis adequacy. This index having been established in a sacrosanct randomized controlled trial (RCT), was readily accepted by the HD community, and led to shorter dialysis, and higher mortality in the United States. Kt/Vurea is a poor measure of dialysis quality because it combines three unrelated variables into a single formula. These variables influence the clinical status of the patient independent of each other. It is impossible to compensate short dialysis duration (t) with the increased clearance of urea (K), because the tolerance of ultrafiltration depends on the plasma-refilling rate, which has nothing in common with urea clearance. Later, another RCT (the HEMO study) committed a Type III statistical error by asking the wrong research question, thus not yielding any valuable results. Fortunately, it did not lead to deterioration of dialysis outcomes in the United States. The third RCT in this field ("in-center hemodialysis 6 times per week versus 3 times per week") did not bring forth any valuable results, but at least confirmed what was already known. The fourth such trial ("The effects of frequent nocturnal home hemodialysis") too did not show any positive results primarily due to significant subject recruitment issues leading to inappropriate selection of patients. Comparison of the value of peritoneal dialysis and HD in RCTs could not be completed because of recruitment problems. Randomized controlled trials have therefore failed to yield any meaningful information in the area of dose and or frequency of hemodialysis. PMID- 30457223 TI - Squamous cell carcinoma of the rectum: Practice trends and patient survival. AB - PURPOSE: Leverage the National Cancer Database (NCDB) to evaluate trends in management of nonmetastatic squamous cell cancer (SCC) of the rectum and their effect on survival for this uncommon tumor. METHODS AND MATERIALS: Retrospective data was obtained from the NCDB for patients diagnosed with SCC of the rectum between 2004 and 2014, including cT1-4, cN0-2, cM0 tumors (cohort A, n = 2296). A subgroup analysis was performed on locally advanced tumors (cT1-T2, N+ or cT3, N any, subcohort B, n = 883), treated with chemoradiation (n = 706) or trimodality therapy (n = 177) including chemotherapy, radiation, and surgery. Pathological complete response rate following neoadjuvant therapy was obtained. Univariate and multivariate logistic regression analyses were performed to generate hazard ratios (HR) investigating factors associated with overall survival. Kaplan-Meier (K-M) method was used to estimate overall surviving proportion at 5 and 10 years. RESULTS: The K-M estimated 5 and 10 year overall survival for stage I disease was 71.3% and 57.8%, respectively; stage II disease was 57.0% and 38.9%, respectively; stage III disease was 57.8% and 41.5%, respectively. On multivariate analysis, higher cT category (P < 0.001) resulted in worse survival. For locally advanced tumors (subcohort B), there was no significant difference in survival between chemoradiation alone compared to trimodality therapy (P = 0.909 on multivariate analysis). CONCLUSIONS: Most providers manage locally advanced SCC of the rectum similar to anal cancer, which results in equivalent overall survival and spares patients from the additional morbidity associated with surgical resection. PMID- 30457225 TI - Strategies for humanizing glycosylation pathways and producing recombinant glycoproteins in microbial expression systems. AB - Homogeneously glycosylated proteins are essential for analyzing the structure of N-glycans, studying their consequences inside cells, and developing therapeutic glycoproteins. However, the isolation of glycoproteins with homogeneous glycans from human is difficult since glycoforms slightly differ from each other with respect to molecular weight and charge. Microbial expression systems have numerous benefits in expression technology and have gained great attention, because they are more adaptable to the biotechnology industry. While selecting an expression host, the glycosylation pattern must be taken into account, because glycosylation strongly depends on cellular production system and selected production clone. This review discussed the technological developments in glycoengineering of microbial expression systems for humanizing the glycosylation profile and highlighted the expression potential of Leishmania expression system. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018. PMID- 30457227 TI - [OBSTETRICS, GYNECOLOGY AND INFERTILITY - THE FUTURE IS ALREADY PRESENT]. PMID- 30457226 TI - Advantage of Z-stacking for teleconsultation between the USA and Colombia. AB - INTRODUCTION: There is an emerging need for telecytology in Colombia as the demand for cytopathology has increased. However, due to economic and technological constraints telecytology services are limited. Our aim was to evaluate the diagnostic feasibility of using whole slide imaging with and without Z-stacking for telecytology in Colombia, South America. METHODS: Archival glass slides from 17 fine needle aspiration smears were digitized employing whole slide imaging (WSI) (Nanozoomer 2.0 HT, Hamamatsu) in one Z-plane at 40x, and panoramic digital imaging (Panoptiq system, ViewsIQ) combining low-magnification digital maps with embedded 40x Z-stacks of representative regions of interest. Fourteen Colombian pathologists reviewed both sets of digital images. Diagnostic concordance, time to diagnosis, image quality (scale 1-10), usefulness of Z stacking, and technical difficulties were recorded. RESULTS: Image quality scored by pathologists was on average 8.3 for WSI and 8.7 for panoramic images with Z stacks (P = .03). However, diagnostic concordance was not impacted by image quality ranking. In the majority of cases (72.4%) pathologists deemed Z-stacking to be diagnostically helpful. Technical issues related to Z-stack video performance constituted only a minor proportion of technical problems reported. Slow downloads and crashing of files while viewing were mostly experienced with larger WSI files. CONCLUSION: This study demonstrated that international telecytology for diagnostic purposes is feasible. Panoramic images had to be acquired manually, but were of suitable diagnostic quality and generated smaller image files associated with fewer technical errors. Z-stacking proved to be useful in the majority of cases and is thus recommended for telecytology. PMID- 30457228 TI - [Q FEVER IN PREGNANCY - IS IT MORE ENIGMATIC OR IS IT MORE CONTAGIOUS?] PMID- 30457229 TI - [PROLONGED SECOND STAGE OF LABOR: CAUSES AND OUTCOMES]. AB - INTRODUCTION: Professional bodies have published guidelines defining the length of the second stage of labor and when it is "prolonged", according to parity and epidural anesthesia administration. Recently these guidelines have been extended, aiming to reduce rates of unplanned cesarean deliveries. AIMS: To examine the risk factors and outcomes of a prolonged second stage of labor, in order to understand its causes and implications for mothers and neonates, including the delivery mode. METHODS: A retrospective study based on 26,476 electronic medical records of deliveries to primiparous mothers of a term singleton fetus, at Hadassah Medical Center, between 2003 and 2015. RESULTS: A prolonged second stage of labor was recorded in 3,225 (12.2%) of mothers (i.e. exceeding 2 hours without epidural anesthesia and 3 hours with it). Epidural anesthesia, persistent occiput posterior, and head circumference or birth weight above the 90th percentile, increased the risk of the prolonged second stage. The risk of unplanned cesarean delivery rose significantly before the 2- or 3-hour cut-off defining a prolonged second stage. Risks of maternal and neonatal complications included: grade III-IV perineal tear, maternal hemorrhage, 5-minute Apgar<=7, umbilical artery pH<7.1, neonatal intensive care admission were also increased. CONCLUSIONS: Epidural anesthesia and fetal parameters increased the risk of prolonged second stage; risks of maternal and fetal complications were also increased. The risk of interventional delivery increased significantly well before the defined cut-off. DISCUSSION: Prolongation of the second stage of labor is a common pathway of many obstetric outcomes. Obstetric management should be based on considerations of individual maternal and neonatal well-being, rather than administrative goals. While reducing cesarean rates is an important goal, attempts to achieve this by prolonging the second stage of labor exposes mothers and neonates to excess risk of cesarean and vacuum delivery as well as obstetric and neonatal complications. PMID- 30457231 TI - [COMPARISON OF TWO APPROACHES FOR PLACENTA ACCRETA: UTERINE PRESERVATION VERSUS CESAREAN HYSTERECTOMY]. AB - AIMS: To compare the maternal and newborn outcome between cases that underwent conservative surgery with uterine preservation (Group A) to cesarean hysterectomy (Group B). BACKGROUND: Placenta accreta defines abnormally adherent and invasive placentation into the myometrium and in some cases invades adjacent organs. In recent years the incidence of placenta accreta cases has risen due to the increasing prevalence of cesarean delivery. The clinical manifestation of placenta accreta might be life threatening maternal bleeding during the attempt to detach the placenta following delivery. In cases where removing the placenta and controlling the bleeding is not possible, the last option is to perform cesarean hysterectomy. METHODS: A retrospective cohort study, was conducted between the years 2004-2015, in order to compare the above two groups. The data are based on patients' records, surgeon reports and histopathologic specimens. RESULTS: Data has been obtained from 148 patients, 49 (33%) of them underwent cesarean hysterectomy. For those who underwent cesarean hysterectomy, it has been found that the time of surgery was shorter, 68 minutes comparing to 113 minutes (P=0.000), there was less amount of blood loss, 965 ml versus 1658 ml (P=0.006), and shorter hospitalization, 8 days compared to 15 (P=0.004), in Group B versus A, respectively. In addition, only one patient from Group B developed fever following surgery (2.7%) compared to 22 patients (20.2%) in Group B versus A, respectively (P=0.009). The 1st and 5th min of Apgar scores were higher, 9,8 and 10,9 in the Group B versus Group A, respectively (P=0.027, P=0.000). CONCLUSIONS: For parturient women who have completed their family planning, cesarean hysterectomy without detaching the placenta accreta is the safer treatment option. PMID- 30457230 TI - [SPERM SELECTION TECHNIQUES: VISUAL ASSESSMENT VERSUS THE BINDING POTENTIAL TO HYALURONIC ACID]. AB - BACKGROUND: The human oocyte is surrounded by hyaluronic acid (HA), which acts as a natural selector. Only spermatozoa expressing HA receptors can reach and fertilize the oocyte. This study aims to compare two sperm selection techniques by correlation to fertilization rates and embryo quality. METHODS: Couples undergoing IVF-ICSI treatment due to mild male infertility were enrolled in a prospective study. According to the randomization, the sperm suspensions were put into a polyvinylpyrrolidone (PVP) droplet or an HA-containing medium droplet (Sperm Slow). In the PVP group motile spermatozoa with the best morphology were selected for injection. From the HA-containing medium those sperm demonstrating vigorous tail beating and an absence of progressive motility as well as good morphology, were selected. Primary outcome measures were fertilization rate and embryo quality. RESULTS: Thirty couples were randomized to the PVP group and 24 to the slow sperm group; 353 oocytes were injected. There was no statistical difference in fertilization or cleavage rate. Furthermore, in the PVP group, the mean number of embryos was higher and the average morphology of the best embryo was superior. CONCLUSIONS: Considering that the HA-based sperm selection technique is more expensive and time consuming, the current study does not support using it as a routine method. PMID- 30457232 TI - [TRIPLET PREGNANCY AFTER SINGLE FROZEN-THAWED EMBRYO TRANSFER IN IVF]. PMID- 30457233 TI - [HPV TEST SCREENING FOR THE DETECTION OF PRECANCEROUS CERVICAL LESIONS AND CERVICAL CANCER]. PMID- 30457234 TI - [BAD DESIGN IN THE HUMAN EMBRYO - EVOLUTION IN PRACTICE]. PMID- 30457235 TI - [MENSTRUAL SYNCHRONY, MYTH OR TRUTH?] PMID- 30457236 TI - [LABOR INDUCTION BY ORAL MISOPROSTOL - EFFECTIVE, SAFE, EASY TO ADMINISTRATE AND INEXPENSIVE]. PMID- 30457237 TI - [HYPNOSIS AND SELF-HYPNOSIS IN THE PRACTICE OF GYNECOLOGY, OBSTETRICS AND FERTILITY]. PMID- 30457238 TI - [HOW DID ISRAEL BECOME AN "IVF NATION": 40 YEARS SINCE LOUISE BROWN'S BIRTH, THE FIRST IN VITRO FERTILIZATION BABY]. PMID- 30457240 TI - [FETAL LIFE IN THREE DIMENSIONS]. PMID- 30457239 TI - [IN-VITRO FERTILIZATION (IVF) TREATMENT IN ISRAEL: THE PUBLIC FUNDING POLICY AND ITS IMPLICATIONS]. PMID- 30457241 TI - Pain assessment in paediatric intensive care: the Italian COMFORT behaviour scale. AB - BACKGROUND: Assessment of pain in paediatric intensive care units (PICUs) is crucial to minimise the risks of inadequate sedation. AIM: To translate and validate the Italian version of the COMFORT behaviour scale (CBS) in a PICU in terms of its psychometric, construct, feasibility and reproducibility properties. METHOD: Before and after tracheal suctioning, 71 observations were performed on 35 sedated and mechanically ventilated patients in three PICUs. Pain and distress were assessed using the CBS and the Nurse Interpretation of Sedation Score (NISS). RESULTS: Interrater agreement and interrater reliability were high before the procedure and moderate after (pre: 100%, Cohen's kappa = 1; post: 79%, Cohen's kappa = 0.558). The scale's internal consistency was calculated before and after the procedure (Cronbach's alpha = 0.81 and 0.91). Agreement between the CBS and the NISS was low before and after the procedure (20% and 28%). The agreement between the tools was low because the NISS, a tool based on expert opinion, is not as precise as the CBS and could be affected by cultural biases. CONCLUSION: The Italian version of the CBS proved to be valid and reproducible for the objective measurement of pain and distress in a wide age range of patients admitted to PICUs. PMID- 30457242 TI - History of Urology at the Sestre Milosrdnice University Hospital Center. AB - The history of Croatian urology clearly shows its affiliation to the medical and civilizational circle of the Western world. The Department of Urology at the Sestre milosrdnice University Hospital Center is the oldest urology institution in the Republic of Croatia. The Department was established in 1894, when the new Sestre milosrdnice Hospital was open in Vinogradska cesta in Zagreb. It was then that doctor Dragutin Masek founded the so-called III Department, which, in addition to treating urology patients, also treated patients with conditions of the ear, nose and throat, eye diseases and dermatologic conditions. Dragutin Masek had already realized that medicine would soon be divided into fields and had assigned younger doctors joining the III Department to specific fields. As a result, urology was given to Aleksandar Blaskovic, who founded the first independent department of urology in Croatia in 1926. In 1927, he was appointed Professor of urology at the Zagreb School of Medicine, where he established the first department of urology and was giving lectures and practicals. Under his leadership, the Department of Urology was given the status of a Clinic, a teach ing department, the first of its kind in Croatia. Owing to all his activities in the field of urology, the history remembers him as the "father of modern Croatian urology". Over the course of the following years, department chairs had changed, but luckily for the patients, approach to work had not. Conscientiousness, trust, competence and charity. After all, charity is the idea that the hospital carries even in its name, after the Sisters of Charity who had founded it. In all the decades, the Department of Urology has been following global development paths, objectively legging behind top facilities in the world by only a few years. Overall professional and scientific urology activities culminated in 1998, when the Clinic became the Reference Center of the Ministry of Health of the Republic of Croatia for prostate cancer, and in 2011, when it became the European Board of Urology Certified Center. All that has been achieved could not have been done without wholehearted help and cooperation of the nurses, as well as every other department employee from the beginnings of urology until today. Despite its rich history, the Department does not rest on laurels. Today, it is a modern urology department together with its European role models. PMID- 30457243 TI - 20 Years of the Reference Center for Prostate Tumors of the Ministry Of Health at the Department of Urology in Sestre Milosrdnice University Hospital Center. AB - The Department of Urology at the Sestre milosrdnice University Hospital Center is the oldest urological institution in the Republic of Croatia and this part of Europe. Today, the Department is a modern tertiary healthcare institution, where the most complex methods of urological practice are performed using modern medical devices and highly sophisticated technology. In 2011, our urology specialist education program was certified by the European Board of Urology (EBU) as the only one of its kind in Croatia. The program was recertified in 2017. The Department runs a program for the early detection of prostate cancer and performs more than 240 radical prostatectomies annually, which is the highest number of such interventions in Croatia. The aim of this study is to present the work and the activities of the Reference Center for Prostate Tumors of the Ministry of Health at the Department of Urology in Sestre milosrdnice University Hospital Center over the last 20 years. The database of the Reference Center for Prostate Tumors of the Ministry of Health at the Department of Urology in Sestre milosrdnice University Hospital Center was reviewed. During the twenty-year period, approximately 15,000 prostate interventions were performed due to benign and malignant diseases. Of this, 7,374 transrectal ultrasound guided prostate biopsies, 2,632 radical prostatectomies with open retropubic access, 3,988 transurethral prostate resections and 1,097 open suprapubic adenomectomies were performed. With the achieved scientific and professional results in monitoring, studying and improving the prevention, diagnosis and therapy of prostate tumors, as well as with the professional conditions and personnel, the Department of Urology in Sestre milosrdnice University Hospital Center truly justifies the title of the Reference Center for Prostate Tumors of the Ministry of Health of the Republic of Croatia awarded to it in 1998. PMID- 30457244 TI - Epidemiology of Prostate Cancer in Croatia - Situation and Perspectives. AB - Prostate cancer represents a significant public health burden in Croatia, as well as in other developed countries. The aim of this paper was to present the current epidemiological situation in Croatia in comparison to other similar countries, using basic indicators such as incidence, mortality, prevalence and survival, and to discuss future possibilities in this field. The incidence of prostate cancer in Croatia has been rapidly increasing since the mid-nineties; recent data indicates that the trend is levelling off. Mortality data show constant increase since the 1960s, but mortality trends seem to be stabilizing in the recent period; however, Croatia is still in the top ten countries regarding prostate cancer mortality in Europe. Five-year prevalence in 2012 was estimated at 7,592 cases (426.7/100,000), ranking Croatia in the middle of European countries in the GLOBOCAN 2012 database. According to the CONCORD-2 study, five-year net survival in Croatia in the 2005-2009 period was 75.1%, which is lower than in similar European countries. The epidemiological pattern of prostate cancer in Croatia indicates a relatively low incidence, with significant room for improvement in mortality and survival data. Given the recent discussions regarding prostate cancer screening modalities, a debate is warranted and should be encouraged regarding the role of PSA testing in Croatia. PMID- 30457245 TI - Role of Multiparametric Magnetic Resonance Imaging in Prostate Cancer Assessment. AB - Multiparametric magnetic resonance is assuming an increasingly important role in the diagnosis, initial assessment and monitoring of patients with prostate cancer. This paper offers a more complex insight into the application of magnetic resonance imaging with prostate cancer, with a current literature overview. The focus is on the problem of initial prostate cancer evaluation which strongly affects further decision-making and therapeutic interventions. Clinical suggestions based on the current guidelines are also offered. PMID- 30457246 TI - Diagnostic Value of Cognitive-Registration Multiparametric Magnetic Resonance Guided Biopsy for the Detection of Prostate Cancer after Initial Negative Biopsy. AB - The aim of this prospective clinical study was to determine the detection rate of prostate cancers by multiparametric magnetic resonance and transrectal ultrasound (mpMRI-TRUS) cognitive fusion biopsies in patients with a previously negative TRUS-guided biopsy. Between 1 October 2016 and 1 July 2017, in 101 consecutive patients with elevated antigen (PSA) and/or positive digital rectal examination and after a negative first TRUS biopsy, a second, repeated prostate biopsy was performed. In 24 patients, cognitive fusion mpMRI-TRUS biopsy of the prostate with 8-10 system cores and 1-3 target biopsies was performed, in line with the European Association of Urology guidelines. In 77 patients, only a classic, repeated TRUS guided biopsy was performed. In patients with mpMRI, the detection rate according to PIRADS-v2 reporting system was: PIRADS 1, n = 0; PIRADS 2, n = 0; PIRADS 3, n = 0; PIRADS 4, n = 6/8 (75%); and PIRADS 5, n = 2/3 (67%). In the group of patients with MR-TRUS cognitive fusion biopsy, the prostate cancer detection rate was 8/24 (33%), while in the control group the detection rate was 12/77 (16%), which was statistically significant (t test, p = 0.037, CI 95% is 0.01 to 0.37). Patients with PIRADS <= 3 (54%) could have avoided the biopsy. PMID- 30457247 TI - Cost-Benefit Analysis of the Introduction of Mp-Mri Guided Biopsies in Croatia. AB - The objective of this study was to determine differential expression of TFF1, TFF2 and TFF3 genes and proteins in breast tumor subtypes. In addition, we investigated the correlation between TFF genes within tumor subgroups, and TFF genes with clinical and pathologic characteristics of the tumor. Study group included 122 patients with surgically removed breast tumors. Samples were investigated using qRT-PCR and immunohistochemistry. TFF1 and TFF3 genes and proteins were expressed in breast tumors, while the levels of TFF2 gene and protein expression were very low or undetectable. TFF1 was significantly more expressed in benign tumors, while TFF3 was more expressed in malignant tumors. Gene and protein expression of both TFF1 and TFF3 was greater in lymph node negative tumors, hormone positive tumors, tumors with moderate levels of Ki67 expression, and in grade II tumors. A strong positive correlation was found between TFF1 and TFF3 genes, and the expression of both negatively correlated with Ki67 and the level of tumor histologic differentiation. Our results suggest that TFF1 and TFF3, but not TFF2, may have a role in breast tumor pathogenesis and could be used in the assessment of tumor differentiation and malignancy. PMID- 30457248 TI - Histopathological Outcomes after Radical Prostatectomy for Prostate Cancer Based On a New Grading System. AB - One of the main reasons for the introduction of a new grading system was Gleason sum 7, which differed significantly in the prognosis of the disease depending on the primary Gleason. The aim of this study was to compare grade group 2 and grade group 3, and the impact of cancer percentages in final pathology reports after radical prostatectomy on the occurrence of T3 stage of the disease after radical prostatectomy of clinically localized prostate cancer. The study covered 365 patients with clinically localized prostate cancer who underwent radical retropubic prostatectomy (RRP) over the period of two years. The average percentage of carcinomas found in pathology reports after RRP was 20.1%. With the increase in the grade group, the average percentage of carcinomas in pathology reports increased significantly, p <0.001. With regard to grade groups 2 and 3, irrespective of cancer percentages in pathology reports, more cases of T3 stage were found in grade group 3 when compared to grade group 2, which was statistically significant (p <0.001). However, grade group 2 and grade group 3 patients with <=10% cancer occurrences in final pathology reports after RRP did not show any statistical significance in the occurrence of T3 stage, p=0.96. Prognostic differences in grade group 2 and grade group 3 patients after RRP are significant, but not in all cases, because of their dependence on the percentage of cancer in the final pathology report after RRP of clinically localized prostate cancer. PMID- 30457249 TI - Expression of LMO2 in Prostate Carcinoma and Adjacent Prostatic Parenchyma. AB - LMO2 (LIM domain only) is a member of transcription factor family of proteins characterized by their cysteine-rich, zinc-binding LIM domains. Its expression in prostate cancer cells, as well as in adjacent stroma, is described in a study in a cohort of 83 patients treated with radical prostatectomy for clinically localized prostate adenocarcinoma. Authors found that LMO2 overexpression in prostate cancer was strongly associated with features indicative of worse prognosis (higher preoperative PSA, higher Gleason score, positive surgical margins, and extraprostatic extension of disease). Expression of LMO2 was also associated with biochemical disease progression. We analysed immunohistochemical expression of LMO2 in prostate cancer epithelial and stromal cells, as well as in adjacent parenchyma. Significant negative correlation between glandular expression of LMO2 in carcinoma and stromal expression in BPH (rho = -0.238, P = 0.033) was found, but also be-tween stromal expression in carcinomas and glandular expression in BPH (rho = -0.255, P = 0.021). Positive correlation was found between stromal expression in BPH and stromal expression in carci-nomas (rho = 0.306, P = 0.005). Study results support the potential role of LMO2 in prostatic carcino-genesis and cancer progression. PMID- 30457250 TI - Unfavorable Clinicopathological Features in Radical Prostatectomy Patients Who Were Spared Pelvic Lymphadenectomy. AB - Pelvic lymph node dissection (PLND) during radical prostatectomy (RP) is the most accurate staging modality for lymph node assessment in patients with prostate cancer. It is recommended in all patients with intermediate or high-risk disease undergoing radical prostatectomy. The goal of our study was to assess unfavorable clinicopathological characteristics in patients with omitted lymphadenectomy (PLND) during radical prostatectomy based on the nomogram proposed by Briganti and colleagues. In 2011, 200 patients undertook radical prostatectomy in our institution. Among them 53 patients who fulfilled Briganti criteria and in whom we omitted lymphadenectomy based on current guidelines. Unfavorable clinicopathological features considered were: stage T3, positive surgical margins or biochemical relapse (BCR). We registered biopsy Gleason score 6 in 34 patients, and 19 patients had Gleason score 7. Stage pT2 was seen in 49 patients, and pT3 in 4. Glea-son score after radical prostatectomy was upgraded from GS 6 to GS 7 in 20 patients (37%) and reduced in 1 patient (2%). After a median follow up of 49 (44-56) months, there were 12 (22.6%) patients with BCR. Patients with biopsy Gleason score 6 (n=34) compared to biopsy Gleason 7 (n=19) patients showed no difference regarding positive margins (p=0.0738) and BCR (p=0,736) at 49 months follow-up. Thus, PLND according to current guidelines can be safely omitted in low-risk patients using Brigantinomogram. PMID- 30457251 TI - Prostatic Artery Embolization as a New Option in the Treatment of Lower Urinary Tract Symptoms in Benign Prostatic Hyperplasia - Current Evidence. AB - Prostatic artery embolization is a minimally invasive endovascular treatment that improves lower urinary tract symptoms in men with benign prostatic hyperplasia. Although further randomized studies and long-term evidence is still needed for this method to be fully incorporated into treatment guidelines for benign prostatic hyperplasia, current studies show that this method can be an effective and safe alternative in patients with a significantly enlarged prostate gland who are not good surgical candidates. Therefore, we present the theory, technical details and potential benefits of this method as we review the current evidence on prostatic artery embolization. PMID- 30457252 TI - Incidental Prostate Cancer in Patients Treated for Benign Prostate Hyperplasia in the Period of 21 Years. AB - The aim of this study was to determine the incidence of incidental prostate cancer and its clinical significance among patients who underwent transurethral prostate resection or transvesical adenomectomy for benign prostate hyperplasia at the Department of Urology in Sestre milosrdnice University Hospital Center from January 1997 to December 2017. A total of 277/4,372 (6.34%) patients from our cohort were diagnosed with incidental prostate cancer (mean age 74.5 years). Due to incomplete data, 12 patents were excluded from further analysis. 44.91% (119/265 patents) of our cohort were stage T1a and 55.09% (146/265) were stage T1b. Clinically significant prostate cancer was found in 168/265 patients (63.40%). When divided into two groups, Gleason score <=6 (mean age 73.58 years) and Gleason score >=7 (mean age 75.77 years), the results showed that Gleason score >=7 patients were significantly older (p=0.0104) and that the tumor extent among patients in this group (mean = 34.58%) was higher than that in Gleason score <=6 group (mean = 11.11%) (p=0.0169). More than a half of patients in our cohort had T1b stage prostate cancer. We found that 63.4% of carcinomas were clinically significant, with 52/265 (19,62%) patients affected by ISUP grade 4 and 5 cancers. Based on our research, we cannot give any recommendations regarding incidental prostate cancer treatment due to lacking preoperative (PSA, DRE) and follow-up data. PMID- 30457253 TI - Transobturator Advance(r) Sling Suspension for the Treatment of Postprostatectomy Stress Urinary Incontinence. AB - Stress urinary incontinence (SUI) continues to present a major complication after radical prostatectomy. Suburethral slings represent one of the less invasive options for postprostatectomy SUI, and a more recent addition is a transobturator sling, the AdVance(r). We report our results with the AdVance(r) sling for the management of postoperative SUI. The evaluation was conducted on 47 patients with AdVance(r) implant for SUI in our institution (November 2010 - June 2017). Measurements included age, etiology of SUI, duration of SUI, follow-up and pad use per day (PPD) pre- and postoperatively. Patients were classified as cured if they used no pads or 1 PPD for security reasons, or as improved if 1-2 PPDs were used and if there was a 50% reduction in pad use per day postoperatively. In our series we observed a reduction of mean PPD of 5.1 (2-8) to 1.7 (0-4) postoperatively. After follow-up and according to our criteria, the cure rate was 51.1% (24/47) and the improvement rate 27.5% (13/47). The overall success rate was 78.6% (37/47). No improvement was observed in 21.4% (10/47) of patients. Failure rates after sling placement for patients with addi-tional treatments following prostatectomy were much higher (60% (3/10) for radiation therapy and 66.7% (4/10) for urethral stricture disease). Our results show favourable cure and improvement rates and are comparable to results from larger series. The most appropriate candidates for the AdVance(r) sling are patients with mild to moderate postprostatectomy SUI. The results may be even better in patients without additional treatment following prostatectomy, such as radiation therapy or surgery for stricture disease. PMID- 30457254 TI - Paneth Cell-Like Component in Prostate Cancer - Case Report. AB - Prostate adenocarcinoma with Paneth cell-like neuroendocrine differentiation is a rare entity. Foci of scattered cells and small clusters are found in the majority of described cases, although cases with predominant Paneth cell-like features have also been recorded. These cells contain eosinophilic cytoplasmic inclusions and lack androgen receptors, and are consequently immune to hormone therapy. It is, therefore, important for pathologists to recognize them. According to literature, clinical outcome depends on the standard grading of the conventional prostate cancer component. We report a case of a 54 year-old patient with prostatic adenocarcinoma showing Paneth cell-like neuroendocrine differentiation. PMID- 30457255 TI - Medicare and Medicaid Programs; CY 2019 Home Health Prospective Payment System Rate Update and CY 2020 Case-Mix Adjustment Methodology Refinements; Home Health Value-Based Purchasing Model; Home Health Quality Reporting Requirements; Home Infusion Therapy Requirements; and Training Requirements for Surveyors of National Accrediting Organizations. Final rule with comment period. AB - This final rule with comment period updates the home health prospective payment system (HH PPS) payment rates, including the national, standardized 60-day episode payment rates, the national per- visit rates, and the non-routine medical supply (NRS) conversion factor, effective for home health episodes of care ending on or after January 1, 2019. This rule also: Updates the HH PPS case-mix weights for calendar year (CY) 2019 using the most current, complete data available at the time of rulemaking; discusses our efforts to monitor the potential impacts of the rebasing adjustments that were implemented in CYs 2014 through 2017; finalizes a rebasing of the HH market basket (which includes a decrease in the labor-related share); finalizes the methodology used to determine rural add-on payments for CYs 2019 through 2022, as required by section 50208 of the Bipartisan Budget Act of 2018 (Pub. L. 115-123) hereinafter referred to as the "BBA of 2018"; finalizes regulations text changes regarding certifying and recertifying patient eligibility for Medicare home health services; and finalizes the definition of "remote patient monitoring" and the recognition of the costs associated with it as allowable administrative costs. This rule also summarizes the case-mix methodology refinements for home health services beginning on or after January 1, 2020, which includes the elimination of therapy thresholds for payment and a change in the unit of payment from a 60-day episode to a 30-day period, as mandated by section 51001 of the Bipartisan Budget Act of 2018. This rule also finalizes changes to the Home Health Value-Based Purchasing (HHVBP) Model. In addition, with respect to the Home Health Quality Reporting Program, this rule discusses the Meaningful Measures Initiative; finalizes the removal of seven measures to further the priorities of this initiative; discusses social risk factors and provides an update on implementation efforts for certain provisions of the IMPACT Act; and finalizes a regulatory text change regarding OASIS data. For the home infusion therapy benefit, this rule finalizes health and safety standards that home infusion therapy suppliers must meet; finalizes an approval and oversight process for accrediting organizations (AOs) that accredit home infusion therapy suppliers; finalizes the implementation of temporary transitional payments for home infusion therapy services for CYs 2019 and 2020; and responds to the comments received regarding payment for home infusion therapy services for CY 2021 and subsequent years. Lastly, in this rule, we are finalizing only one of the two new requirements we proposed to implement in the regulations for the oversight of AOs that accredit Medicare-certified providers and suppliers. More specifically, for reasons set out more fully in the section X. of this final rule with comment period, we have decided not to finalize our proposal to require that all surveyors for AOs that accredit Medicare-certified providers and suppliers take the same relevant and program-specific CMS online surveyor training that the State Agency surveyors are required to take. However, we are finalizing our proposal to require that each AO must provide a written statement with their application to CMS, stating that if one of its fully accredited providers or suppliers, in good- standing, provides written notification that they wish to voluntarily withdraw from the AO's CMS-approved accreditation program, the AO must continue the provider or supplier's current accreditation until the effective date of withdrawal identified by the facility or the expiration date of the term of accreditation, whichever comes first. PMID- 30457256 TI - ROLE OF MICRORNA IN PREDICTING OF ADENOCARCINOMA DEVELOPMENT IN BARRETT'S ESOPHAGUS. AB - Barrett's esophagus is considered as a predictor of esophageal adenocarcinoma with multistage neoplastic progression at present time. The research assessed an expression of microRNA-21 in 25 patients with different degree of metaplasia and dysplasia of mucous coat of esophagus. The level of expression of microRNA depended on the presence and degree of expression of neoplastic changes of mucous coat of esophagus. The expression rising of microRNA was noted in patients with columnar-celled metaplasia and intraepithelial neoplasia and in case of esophageal adenocarcinoma. The treatment strategy could be determined by the method of estimation of the level of microRNA expression in biopsy material from mucous coat of esophagus in patients with gastroesophageal reflux disease and using other criteria. PMID- 30457257 TI - LEVEL OF THE GUALITY OF LIFE OF THE PATIENTS AFTER ESOPHAGOPLASTY ON THE BASIS OF GASTROINTESTINAL INDEX ASSESSMENT. AB - The article presents the interview results of 55 patients after esophagoplasty (30 cases - after esophagogastroplasty, 25 cases - after esophagoplasty) using questionnaire GIQLI. The authors came to conclusions about advantages of extirpation of esophagus with esopagogastroplasty compared with subtotal shunt esophagocoloplasty because of high rate of gastrointestinal index of the quality of life and their components in patients after esophagogastroplasty compared with results of patients after esophagoplasty. There was noted an expessed growth in the scales and rise of gastrointestinal index in patients who underwent esophagogastroplasty after 3 years of follow-up. PMID- 30457258 TI - LAPOROSCOPIC SLEEVE GASTRECTOMY. ROLE AND PLACE IN BARIATRIC SURGERY. AB - Laparoscopic sleeve gastrectomy (LSG) was performed in 522 patients at the period from 2007 to 2015. The operation was carried out by different methods. It was stated that "the ideal candidates" for choosing LSG operation were the patients without metabolic syndrome (MS) and body-weight index, which wasn't higher than 48 kg/m2. The operation could be performed on patients younger than 40 years old in order to correct disorders of insulinic and cholesterol metabolism. Patients with MS have limitations for LSG application, because of this reason, the operation is advisable for younger age group without severe accompanying pathology. The operation could be applied in older age group in order to stabilize general condition in case of high risks as the first (sometimes the last) stage of treatment for the patients whom more effective operation couldn't be recommended. PMID- 30457259 TI - SURGICAL TREATMENT FOR PATIENTS OF ELDERLY AND SENILE AGE WITH LOCALLY ADVANCED COLON CANCER. AB - The article analyzed the results of radical operative treatment of 102 patients aged 35-85 years old. It was shown that combined operations on patients of 60 years old and older were associated with high risk of somatic complications in postoperative period. However, these operations provided more higher rate of survival compared with patients younger than 60 years old and improved the quality of life. PMID- 30457262 TI - LOW-INVASIVE TECHNOLOGIES OF INITIAL SURGICAL D-BRIDEMENT IN POLYTRAUMA AT THE FIRST STAGE OF PROGRAMMED MULTISTAGED SURGICAL TREATMENT AB - The authors described the variants of initial surgical d-bridement on the basis of experience of treatment of 183 patients of multistaged treatment program. PMID- 30457263 TI - RECONSTRUCTIVE AND RESTORATIVE OPERATIONS ON EXTRAHEPATIC BILE DUCTS USING MICROSURGICAL TECHNOLOGIES: EXPERIMENTAL SUBSTANTIATION AND CLINICAL EXPERIENCE. AB - The authors proposed the new methods of forming of microsurgical biliary-enteric anastomoses with sphincteric and antireflux properties. Development and anatomico experimental substantiation of the new methods were performed on 68 experimental animals (dogs) and 20 organocomplexes of human cadavers. An experimental approbation of microsurgical biliary-enteric anastomoses showed the possibility, safety and high function of anastomoses. Microsurgical technique and developed methods of biliary-enteric anastomoses were applied on 65 patients with good results. PMID- 30457264 TI - POSSIBILITIES OF MODERN TECHNOLOGIES OF VISUALIZATION AND MODELING IN ORTHOPEDICS AND THEIR ROLE IN DEVELOPMENT OF INDIVIDUAL CONSTRUCTIONS IN HIP ARTHROPLASTY. AB - The article presents the authors' experience. Medical visualization is applied in orthopedics on all stages such as diagnostics, treatment planning and control of the results. Modern approaches in instrumental diagnostics and specialized application-dependent software allowed a new qualitative level of orthopedics and medical care in different areas of medicine. Modern technologies gave a lot of opportunities to doctors in order to improve diagnostics at higher level, make an individual planning of operations and built individual implants, when it wasn't possible to use standard constructions. PMID- 30457265 TI - TREATMENT OF CONGENITAL PSEUDARTHROSIS OF THE TIBIA. AB - The work is based on an analysis of treatment results of 47 patients with congenital pseudarthrosis of the tibia. The Ilizarov technique of unfree osteoplasty was applied on these patients. The authors considered an application of combined variants of exterior and external osteosynthesis as very perspective in rehabilitation of the patients with congenital pseudarthrosis. PMID- 30457266 TI - [Editorial.Towards the XXI Congress of CNAI]. PMID- 30457267 TI - [On the Field of Honor. Historical research in memory of Italian male nurses who died in the First World War]. AB - AIM: Several Italian male nurses employed at the Ospedale Maggiore in Milan were among the dead during First World War. This paper investigates whether and in which way these people are remembered. In addition the authors draw a picture of the nursing profession as it were in the early Twentieth Century in Italy. METHOD: The administrative documentation of 127 male nurses on duty at the Ospedale Maggiore in Milan and called to arms between 1915 and 1918 was examined. The documents were found in the historical archive of the Ospedale Maggiore from July 2015 to March 2016 and analyzed using the method of historical research according to Chabod (2012). RESULTS: Documents that witnessed the death of 5 male nurses during the war were found. These people were praised for their courage, self-sacrifice and commitment in attending the sick and the wounded. The hospital community arranged to devolve a sum of money to their families in sign of gratitude and commemorated them by engraving their names in a marble monument. CONCLUSIONS: Many memories of civilian male nurses in the years 1915-1918 emerged from this investigation, and the professional identity of nurses in the 1920s emerged quite clearly. The participation of male nurses in the First World War, in conjunction with the recurrence of its centenary, could be further deepened. PMID- 30457268 TI - [Acoustic pollution in neonatal and paediatric intensive care units: a literature review]. AB - AIM: The purpose of this review is to describe acoustic pollution in neonatal and paediatric intensive care units, sources and effects of noise on patients and health care professions and interventions to reduce it. METHOD: The literature review was carried out using four main databanks from November 2016 to December 2016 through variously combined keywords and Mesh. 237 papers were detected. Presence of full text and pertinence were selection criteria. OUTCOME: 43 papers and 2 guidelines were selected. The issue of acoustic pollution was more intensely investigated in neonatal intensive care settings since 2008-2009; research was present in quite numerous countries, although the majority of the studies were carried out in the USA. Most studies show acoustic levels above recommended levels. Many researches attempt to identify the source of noise (monitor, incubators, ventilatory circuits, conversations) and the effects of intense noise like stress, loss of hearing, alterations of vital signs. Interventions to address the issue involve some changes in the staff behaviour through education, drawing the attention of the caregivers to the problem, through modifications of the settings and the use of specific materials to limit noise. CONCLUSIONS: A prolonged exposure to noise can cause serious damage to the patients in the short and long term; the contribution of the nursing staff to limit and control acoustic pollution is thus important. PMID- 30457269 TI - [The nursing hospice care: Critical incidents in managing the relationship with patients and their families]. AB - INTRODUCTION: The hospice care requires nurses to set an empathic but also uninvolved relationship with both the dying and their families. This requirement results in a challenging emotional work. AIMS: Detecting relational difficulties in assisting terminal patients, the study presents the results of an analysis focused on the emotional work of nurses in hospice. METHOD: Twenty-seven nurses voluntarily participated in an interview, realized with the Interpretative Phenomenological Analysis and aimed to investigate the conflicting lived regarded as critical incidents. RESULTS: All nurses are subject to continual emotional work to dissolve the dissonance between how intimately experienced and the implicit rules of the professional role, which seems to require their continuous surface acting. CONCLUSIONS: The palliative care model attaches great importance to the management of the emotional dimension in the relationship with the terminally ill patient and his family. Our research shows that this area is particularly critical and requires a constant burden for nurses. We believe that the emotional work is to find specific moments aimed at elaborating the emotional overload, from which compassion fatigue and burnout may depend. PMID- 30457270 TI - [Measuring Nurses' Quality of Life: adjustment of Satisfaction Profile (SAT-P)]. AB - INTRODUCTION: Individuals' quality of life (QoL) is strictly linked with working environment experiences. The peculiarities of nursing profession yield it to be stressful, requiring high emotional engagement. AIM: The main aim of this study was to validate a reliable tool to measure nurses' QoL. METHODS: A panel of experts selected a tool from literature to measure QoL. They also modified it to achieve more specific version for nurses. The developed tool (NQoLs) was tested on 940 nurses. RESULTS: NQoLs was a valid and reliable tool to describe different nuances of QoL. Therefore, four dimensions emerge from psychometrics analysis, which were physical, emotional, social and working QoL. Moreover, the overall nurses' QoL was good but with some significant differences related to the clinical settings of belonging. The working dimension had the major impact on the overall nurses' QoL. CONCLUSION: NQoLs allows to measure QoL amongst nurses, and that is strategic for both research and management, due to NQoLs can help to face with a number of issues coming from an area with many gaps in knowledge. It should also be helpful to assess QoL in relation with organizational wellbeing amongst nurses. PMID- 30457271 TI - [The evaluation of qualitative research published in nursing journals: protocol of a cross-sectional study]. AB - INTRODUCTION: The nature of nursing has prompted researchers nurses to use a large number of qualitative methodology research. The trend showed a substantial increase in its production between 1997 and 2000 to settle back down in the following years although until recently the qualitative methodology was considered a non-scientific research. The growing number of publications with qualitative design is paid concern to verify the rigor and credibility of studies using this method. The use of the quality assessment tools showed that the methodological precision of studies with a qualitative design has grown over time. AIM: Assessing, using the tool Critical Appraisal Skills Programme, the quality of qualitative studies published in the last five years by international nursing journals with higher impact factor. METHOD: We will search the qualitative articles published on the ten most influential nursing journals that will be submitted by two independent researchers at the Critical Appraisal Skills Programme tool in its original version. EXPECTED RESULTS: The results make it possible to observe whether the qualitative research produced in the field of nursing uses a rigorous methodology in the drafting of the report, assuming that the quality has grown in the past five years than in previous years. CONCLUSION: The study will help researchers assess which level reached nurses in the development of qualitative research. PMID- 30457272 TI - Development of a screening tool to assess dehydration in hospitalized older population: a diagnostic, observational study. AB - INTRODUCTION: dehydration is a frequent condition in older people and is associated with an increased risk of negative health outcomes. In order to adopt strategies to prevent complications, an early recognition of this status is of primary importance. For this reason, a comprehensive assessment tool to monitor hydration status in older people could be useful. AIM: to develop a screening tool to detect dehydration in older people in hospital settings. METHODS: this is a diagnostic, observational study. The new tool is a modified version of the Geriatric Dehydration Screening Tool (GDST), integrated with seven questions and two clinical signs based on updated literature. We tested the new tool with people aged 65 or over. We used as reference standard serum osmolarity. Cronbach's alpha was used to measure the tool's reliability and subscales. We calculated the Area Under ROC Curve (AUC) to choose the cut-off that gave the best balance between sensibility and specificity. RESULTS: 127 patients participated in the study. The reliability of the new GDST was acceptable (Cronbach's alpha 0.63). The diagnostic accuracy, measured with AUC analysis, was 0.83 +/- 0.04, p 0.0001 95% CI 0.72-0.87. The best cut-off value was 6 and showed a sensibility of 78%, specificity of 70%. Tongue dryness proved to be the most significant clinical sign associated with poor hydration status (AUC 0.78; p 0.0001, 95% CI 0.69-0.86). CONCLUSION: The new GDST presented an acceptable reliability and diagnostic accuracy that increased with the assessment of some items, such as tongue dryness. This is the first screening tool that presents a promising cut-off value. PMID- 30457273 TI - ANTIREFLUX RESECTION OF MUCOUS MEMBRANE OF ESOPHAGOGASTRIC ANASTOMOSIS IN TREATMENT OF BARRETT'S ESOPHAGUS: INITIAL EXPERIENCE. AB - Antireflux resection of mucous membrane of esophagogastric anastomosis (ARMS) was performed on 6 patients with typical symptoms of gastroesophageal reflux disease (GERD). The patients had a short segment of solumnar-celled metaplasia (1-2 cm) without radiological and endoscopic signs of hiatal hernia. All the patients received medicamentous therapy by antisecretory agents more than 3 years. The operation included the endoscopic resection of2/3 circle of mucous membrane of esophagogastric anastomosis and resection of the area of columnar-celled metaplasia. The results of treatment were assessed during 3-7 months after ARMS. There was noted an absence of clinical manifestations of GERD, regression of inflammatory signs of mucous coat of esophagus in 4 out of 6 patients. Symptoms of GERD remained in 2 patients, although the intensity of signs significantly decreased. PMID- 30457274 TI - APPLICATION OF LAPAROSCOPIC LIFTING SYSTEMS IN PATIENTS WITH HIGH CARDIORESPIRATORY RISK. AB - Intra-abdominal hypertension during laparoscopic operations increased the risk of complications from cardiovascular and respiratory systems. An application of laparolifting systems allowed doctors to avoid changes of pneumoperitoneum, although it was associated with technical difficulties in operation performance. The authors used a test in order to determine cardiorespiratory reserve in preoperative period. The reserve was characterized by decrease of stroke volume of the heart against the background of intra-abdominal hypertension. There was noted a reliable increase of complication rate in these patients in case of application of standard laparoscopic operation compared with operation using lifting systems. PMID- 30457275 TI - DIRECTED CYTOKINE THERAPY IN COMPLEX TREATMENT OF PATIENTS WITH OBSTRUCTIVE JAUNDICE OF CHOLELITHIC GENESIS. AB - The article analyzed the results of surgical treatment of 137 patients with obstructive jaundice of benign genesis. An immune status was studied in serum in dynamics before surgery. The rates of CD3, CD4, CD8, CD19, Ig A, M, G were determined on the first, third, seventh and fourteenth days after operation. The levels of TNFalpha, IFNgamma, IL-2, IL-6, IL-4, IL-10 were investigated in serum and at the same time TNFalpha, IL-4, IL-6 were noted in the bile duct and IL-6 - in urine. Obstructive jaundice of cholelithis genesis is characterized by disbalance of immune and cytokine status. The depth of disbalance depends on the degree of hepatic dysfunction and presence of purulent cholangitis. The directed cytokine therapy by ronkoleykin influenced positively on elimination of disbalance in immune and cytokine status and this therapy improved results of surgery in postoperative period. PMID- 30457276 TI - RESULTS OF TREATMENT OF COLON CANCER WITH EXTENTION ON THE DUODENUM. AB - The article includes the experience of radical surgical treatment of colon cancer with tumor invasion into the duodenum. Patients (7 cases) underwent surgery. Their average age consisted of 72.3 years old. Right-sided hemicolectomy with atypical resection of the duodenum was performed on 6 patients. Pancreoduodenal resection with removal of the right half of the colon was carried out in one patient. The replacement of defect by overlay duodenojejunostomy with initial part of the small intestine was completed in 5 patients and the defect was sutured in one case during the atypical resection of the duodenum. There weren't lethal outcomes after surgery. There was noted 3-year survival without relapse in 5 patients. According to the author, the atypical resection could be possible in limited invasion of the colon cancer in the duodenum with acceptable reliability level. PMID- 30457277 TI - EFFICACY OF FREE AUTOVENOUS TRANSPLANT IN FEMORAL-POPLITEAL BYPASS BELOW THE JOINT SPACE OF THE KNEE. AB - The article presents an analysis of complex examination and treatment of 60 patients with critical ischemia of the lower extremities due to atherosclerotic lesions of femoral-poplitealtibia segment. Typical traditional autovenous bypass of reverse big saphena was performed for the first (control) group of patients. The operation, which used an original technology by free autovenous transplant with collapsed valves without vein reverse, was completed for the second (experimental) group of patients. An application of original treatment technology allowed an increase of blood flow volume in the extremity in 1,5 times, an arterial blood flow - in 1,6 times, rate of microcirculation - in 1,3 times. An early postoperative complications were decreased on 23,4%, the late shunt thrombosis - on 40%. Long-term shunt passability was improved in 2,6 times and physical component of health - on 10,6%, psychological - on 4,3%. The shunt functioned in 36,7% of the first group and in 83,3% patients of the second group after two years since operation. The extremity was saved in 60% of the first group and 90% patients of the second group. PMID- 30457278 TI - Non-classical variant of MEN I syndrome. PMID- 30457279 TI - Diagnostics and treatment of venous mesenteric venous thrombosis. PMID- 30457280 TI - SURGICAL SAFETY CHECKLIST: FROM IDEA TO PRACTICAL APPLICATION. AB - Methods of surgical interventions performing, modifications, instruments used for operation became more developed every year. In spite of this fact, tendency of increase of the rate of iatrogenic errors took place and it was possible to prevent these mistakes by application of Surgical Safety Checklist. The "checklists" are easily available, not very expensive in practice and they are simple to use. An application of such questionnaires could improve the team work and understanding between members of the crew, which could influence directly on operation outcome. The article presents the history of creation of safety list, the analysis of efficacy of "checklist" application in clinical practice in different countries, information about controversial questions in "checklist", perspectives of its application. PMID- 30457281 TI - Diagnostic and treatment problems of brain abscesses. PMID- 30457282 TI - Theoretical and practical aspects in application of hypothermia in thoracic aorta surgery. PMID- 30457283 TI - Modern strategy in treatment of esophageal cancer. PMID- 30457284 TI - Stenting of the colon in surgery of colorectal cancer complicated by intestinal obstruction. PMID- 30457285 TI - The Federal Government Has Changed How Much You Can Charge to Copy Records. PMID- 30457287 TI - Insurance Solutions for the Dental Graduate. PMID- 30457286 TI - HIPAA Audits: Why Dental Organizations Shouldn't Ignore the Audits. PMID- 30457289 TI - Refractory Odontogenic Infection Associated to Candida Albicans: A Case Report. PMID- 30457288 TI - Diagnostic Discussion. PMID- 30457290 TI - Medicare Program; End-Stage Renal Disease Prospective Payment System, Payment for Renal Dialysis Services Furnished to Individuals With Acute Kidney Injury, End Stage Renal Disease Quality Incentive Program, Durable Medical Equipment, Prosthetics, Orthotics and Supplies (DMEPOS) Competitive Bidding Program (CBP) and Fee Schedule Amounts, and Technical Amendments To Correct Existing Regulations Related to the CBP for Certain DMEPOS. Final rule. AB - This final rule updates and makes revisions to the End-Stage Renal Disease (ESRD) Prospective Payment System (PPS) for calendar year (CY) 2019. This rule also updates the payment rate for renal dialysis services furnished by an ESRD facility to individuals with acute kidney injury (AKI). In addition, it updates and rebases the ESRD market basket for CY 2019. This rule also updates requirements for the ESRD Quality Incentive Program (QIP), and makes technical amendments to correct existing regulations related to the Competitive Bidding Program (CBP) for certain Durable Medical Equipment, Prosthetics, Orthotics and Supplies (DMEPOS). Finally, this rule finalizes changes to bidding and pricing methodologies under the DMEPOS competitive bidding program; adjustments to DMEPOS fee schedule amounts using information from competitive bidding for items furnished from January 1, 2019 through December 31, 2020; new payment classes for oxygen and oxygen equipment and a new methodology for ensuring that new payment classes for oxygen and oxygen equipment are budget neutral; payment rules for multi- function ventilators or ventilators that perform functions of other durable medical equipment (DME); and revises the payment methodology for mail order items furnished in the Northern Mariana Islands. This rule also includes a summary of the feedback received for the request for information related to establishing fee schedule amounts for new DMEPOS items and services. PMID- 30457291 TI - Offering Feedback Help your Team and Practice Grow/ PMID- 30457292 TI - Three Reasons Why a Little Stress Can be Health. PMID- 30457293 TI - Stress in the Dental Office. PMID- 30457294 TI - Treating Anxious Patients. PMID- 30457295 TI - Dentistry as an Endurance Sport. PMID- 30457296 TI - How to Keep Your Practice Healthy When You're Not. PMID- 30457297 TI - Dental Manifestations of Methamphetamine Abuse: A Case Report. PMID- 30457298 TI - DIAGNOSTIC DISCUSSION. PMID- 30457299 TI - Chiropractic. PMID- 30457300 TI - Religious Exemptions and Accommodations for Coverage of Certain Preventive Services Under the Affordable Care Act. Final rules. AB - These rules finalize, with changes based on public comments, interim final rules concerning religious exemptions and accommodations regarding coverage of certain preventive services issued in the Federal Register on October 13, 2017. These rules expand exemptions to protect religious beliefs for certain entities and individuals whose health plans are subject to a mandate of contraceptive coverage through guidance issued pursuant to the Patient Protection and Affordable Care Act. These rules do not alter the discretion of the Health Resources and Services Administration, a component of the U.S. Department of Health and Human Services, to maintain the guidelines requiring contraceptive coverage where no regulatorily recognized objection exists. These rules also leave in place an "accommodation" process as an optional process for certain exempt entities that wish to use it voluntarily. These rules do not alter multiple other federal programs that provide free or subsidized contraceptives for women at risk of unintended pregnancy. PMID- 30457301 TI - Three Ironies. PMID- 30457302 TI - How Well Do You Know the Board of Dentistry Discipline Process: Part 2. PMID- 30457303 TI - Florida Medical Marijuana Law Now Effective. PMID- 30457304 TI - What is the regenerative medicine? PMID- 30457305 TI - Dentist Faces a New Economic Climate. PMID- 30457306 TI - Midlevel Dental Provider. PMID- 30457307 TI - The current status and issues of regenerative medicine. PMID- 30457309 TI - New legislation for regenerative medicine and expectations to researchers. PMID- 30457308 TI - Diagnostic Discussion. PMID- 30457310 TI - Regenerative medicine and stem cells. PMID- 30457311 TI - Trends of regenerative medicine industry in the world. PMID- 30457312 TI - iPS cell generation - associated point mutations. PMID- 30457313 TI - Drug-induced Gingival Overgrowth: What You Need to Know! PMID- 30457315 TI - Polymeric Ionic Liquid-Based Fluorescent Amphiphilic Block Copolymer Micelle for Selective and Sensitive Detection of p-Phenylenediamine. AB - A highly sensitive and selective detection of p-phenylenediamine (PPD) is achieved by a fluorescence sensor, which is constructed by encapsulating the hydrophobic fluorescent 1-pyrenecarboxaldehyde (Py-CHO) into a polymeric ionic liquid (PIL)-based amphiphilic block copolymer (BCP) micelle. The amine-aldehyde condensation reaction between PPD and Py-CHO leads to the fluorescence quenching of Py-CHO, giving rise to the basis for the quantitative detection of PPD. The core cavity of the micelle formed by the self-assembly of PIL provides an excellent hydrophobic environment for the accommodation of fluorescent Py-CHO, offering significant improved sensitivity and selectivity for PPD detection. The amount of PIL in fabricating the amphiphilic BCP micelle, the BCP-Py-CHO micelle concentration, and the detection pH condition are investigated to obtain the best performance of this sensor. The accurate detection of PPD is achieved in the range of 0.02-10 MUmol L-1 under optimal conditions, and the detection limit is 0.007 MUmol L-1 (3sigma/ s). The developed sensor is successfully applied to the determination of PPD contents in hair dyes, spiked water, and urine samples. PMID- 30457314 TI - Side-Chain-Promoted Benzodithiophene-based Conjugated Polymers toward Striking Enhancement of Photovoltaic Properties for Polymer Solar Cells. AB - In this work, we have reported a highly efficient photovoltaic material, PBDTTz SBP, by fine-tuning the side chains of the benzodithiophene (BDT) unit. With the replacement of alkoxy chains with alkylthio chains, a large increase in power conversion efficiency (PCE) was realized. Non-fullerene polymer solar cells (PSCs) without any post-treatment generate an optimal PCE of up to 12.09%, with a high VOC of 0.914 V, JSC of 18.52 mA cm-2, and fill factor of 71.43%. Notably, the efficiency of a PBDTTz-SBP-based solar cell was about 1.31-fold of the PCE (9.20%) of its counterpart based on the polymer, PBDTTz-BP, with alkoxy chains, indicating the striking modulation effect of side-chain engineering. Although VOC and JSC were lower than those of non-fullerene devices, the PSCs with PC71BM as the acceptor exhibited a fairly high fill factor of up to 76.69%, affording a moderate PCE. Our work reported a highly efficient polymer solar cell with a PCE of 12.09% and clearly demonstrated the great tuning effect of alkylthio chains on photovoltaic performance. PMID- 30457316 TI - Perovskite/Poly[bis(4-phenyl)(2,4,6-trimethylphenyl)amine] Bulk Heterojunction for High-Efficient Carbon-Based Large-Area Solar Cells by Gradient Engineering. AB - The performance of low-temperature carbon-based perovskite solar cells (C-PSCs) with high commercial potential was hampered by the inferior interface between the absorber and carbon electrode. In this work, poly[bis(4-phenyl)(2,4,6 trimethylphenyl)amine] (PTAA) was dissolved in an antisolvent for spin-coating perovskite (CH3NH3PbI3, MAPI) films, which was applied to modify both the MAPI films and the interface between the MAPI layer and carbon electrode by gradient engineering. Finally, the C-PSCs based on MAPI-PTAA gradient bulk heterojunction films achieved a power conversion efficiency of 13.0% with an active area of 1 cm2, 26% higher than that of pristine MAPI cells, because of the passivated trap states, accelerated hole extraction, and improved crystalline properties in absorber films. PMID- 30457317 TI - Bioinspired DNA-Inorganic Hybrid Nanoflowers Combined with a Personal Glucose Meter for Onsite Detection of miRNA. AB - Biomineralization is an important process in nature, by which living organisms participate in producing organic/inorganic hybrid materials and the resultant materials show sophisticated structures and excellent physical and chemical properties. Inspired by biomineralization, DNA-Cu3(PO4)2 hybrid nanoflowers (HNFs) were prepared, which exhibited high stability, a high surface-to-volume ratio, and good DNA encapsulation ability. A facile thread platform for microRNA (miRNA) detection was fabricated by employing DNA-Cu3(PO4)2 HNFs as captors, and the signal could be easily read out by a personal glucose meter. The fabricated biosensor could detect miRNA-21 quantitatively and a detection limit of 0.41 nM was achieved. Furthermore, miRNA in A549 cell lysate could also be detected without pretreatment. In this work, we achieved a fast, simple, low-cost method based on the bioinspired DNA-inorganic HNFs for the specific and sensitive detection of miRNA in both aqueous solution and biological samples, indicating its great promise in biomedical and clinical applications. PMID- 30457318 TI - Size-Controlled Synthesis of Drug-Loaded Zeolitic Imidazolate Framework in Aqueous Solution and Size Effect on Their Cancer Theranostics in Vivo. AB - Recently, metal-organic frameworks (MOFs) or coordination polymers have shown great potential for drug delivery, yet little has been done to study how particle size affects their tumor targeting and other in vivo features. This plight is probably due to two challenges: (1) the lack of a biocompatible method to precisely control the size of drug-loaded MOFs and (2) the lack of a robust and facile radiolabeling technique to trace particles in vivo. Here, we report a one pot, rapid, and completely aqueous approach that can precisely tune the size of drug-loaded MOF at room temperature. A chelator-free 64Cu-labeled method was developed by taking the advantage of this rapid and aqueous synthesis. Cancer cells were found to take drug-loaded MOFs in a size-dependent manner. The in vivo biodistribution of drug-loaded MOF was analyzed with positron emission tomography imaging, which, as far as we know, was used for the first time to quantitatively evaluate MOF in living animals, unveiling that 60 nm MOF showed longer blood circulation and over 50% higher tumor accumulation than 130 nm MOF. Altogether, this size-controlled method helps to find the optimal size of MOF as a drug carrier and opens new possibilities to construct multifunctional delivery systems for cancer theranostics. PMID- 30457319 TI - Electron Tomography of Plasmonic Au Nanoparticles Dispersed in a TiO2 Dielectric Matrix. AB - Plasmonic Au nanoparticles (AuNPs) embedded into a TiO2 dielectric matrix were analyzed by combining two-dimensional and three-dimensional electron microscopy techniques. The preparation method was reactive magnetron sputtering, followed by thermal annealing treatments at 400 and 600 degrees C. The goal was to assess the nanostructural characteristics and correlate them with the optical properties of the AuNPs, particularly the localized surface plasmon resonance (LSPR) behavior. High-angle annular dark field-scanning transmission electron microscopy results showed the presence of small-sized AuNPs (quantum size regime) in the as deposited Au-TiO2 film, resulting in a negligible LSPR response. The in-vacuum thermal annealing at 400 degrees C induced the formation of intermediate-sized nanoparticles (NPs), in the range of 10-40 nm, which led to the appearance of a well-defined LSPR band, positioned at 636 nm. Electron tomography revealed that most of the NPs are small-sized and are embedded into the TiO2 matrix, whereas the larger NPs are located at the surface. Annealing at 600 degrees C promotes a bimodal size distribution with intermediate-sized NPs embedded in the matrix and big-sized NPs, up to 100 nm, appearing at the surface. The latter are responsible for a broadening and a redshift, to 645 nm, in the LSPR band because of increase of scattering-to-absorption ratio. Beyond differentiating and quantifying the surface and embedded NPs, electron tomography also provided the identification of "hot-spots". The presence of NPs at the surface, individual or in dimers, permits adsorption sites for LSPR sensing and for surface-enhanced spectroscopies, such as surface-enhanced Raman scattering. PMID- 30457320 TI - 3d-Metal Catalyzed N- and C-Alkylation Reactions via Borrowing Hydrogen or Hydrogen Autotransfer. AB - The conservation of our element resources is a fundamental challenge of mankind. The development of alcohol refunctionalization reactions is a possible fossil carbon conservation strategy since alcohols can be obtained from indigestible and abundantly available biomass. The conservation of our rare noble metals, frequently used in key technologies such as catalysis, might be feasible by replacing them with highly abundant metals. The alkylation of amines by alcohols and related C-C coupling reactions are early examples of alcohol refunctionalization reactions. These reactions follow mostly the borrowing hydrogen or hydrogen autotransfer catalysis concept, and many 3d-metal catalysts have been disclosed in recent years. In this review, we summarize the progress made in developing Cu, Ni, Co, Fe, and Mn catalysts for C-N and C-C bond formation reactions with alcohols and amines using the borrowing hydrogen or hydrogen autotransfer concept. We expect that the findings in this field will inspire others to develop new efficient and selective earth-abundant metal catalysts for borrowing hydrogen or hydrogen autotransfer applications or to develop novel alcohol refunctionalization reactions that can be mediated by such metals. PMID- 30457321 TI - Preparation of Highly Porous Polymer Membranes with Hierarchical Porous Structures via Spinodal Decomposition of Mixed Solvents with UCST Phase Behavior. AB - The predominant method to prepare polymer membranes is based on phase-inversion. However, this method always leads to a dense skin with low porosity when normal polymers are used. Using the self-assembly of certain block copolymers, it is possible to prepare uniform pores with high porosity, but the prices of these polymers are too high to be afforded in practical applications. Here, we report a novel strategy to prepare highly porous and asymmetric polymer membranes using the widely used polyvinylidene fluoride (PVDF) as a prototype. The method combines spinodal decomposition with phase-inversion utilizing mixed solvents that have the unique upper critical solution temperature (UCST) phase behavior. The spinodal decomposition generates a thin surface layer containing a high density of relatively uniform pores in the mesoporous range, and the phase inversion generates a thick bulk layer composed of macrovoids; the two types of structures are interconnected, yielding a highly permeable, selective, and mechanically strong porous membrane. The membranes show an order-of-magnitude higher water permeance than commercial membranes and efficient molecular sieving of macromolecules. Notably, our strategy provides a general toolbox to prepare highly porous membranes from normal polymers. By blending PVDF with cellulose acetate (CA), a highly porous PVDF/CA membrane was prepared and showed similarly high separation performance, but the higher hydrophilicity of CA improved the membrane flux in the present of proteins. PMID- 30457322 TI - Engineering SrSnO3 Phases and Electron Mobility at Room Temperature Using Epitaxial Strain. AB - High-speed electronics require epitaxial films with exceptionally high carrier mobility at room temperature. Alkaline-earth stannates with high room-temperature mobility show outstanding prospects for oxide electronics operating at ambient temperatures. However, despite significant progress over the last few years, mobility in stannate films has been limited by dislocations due to the inability to grow fully coherent films. Here, we demonstrate the growth of coherent, strain engineered phases of epitaxial SrSnO3 (SSO) films using a radical-based molecular beam epitaxy approach. Compressive strain stabilized the high-symmetry tetragonal phase of SSO at room temperature (RT), which, in bulk, exists only at temperatures between 1062 K and 1295 K. We achieved a mobility enhancement of over 300% in doped films compared with the low temperature orthorhombic polymorph. Using comprehensive temperature-dependent synchrotron-based X-ray measurements, electronic transport and first principles calculations, crystal and electronic structures of SSO films were investigated as a function of strain. We argue that strain-engineered films of stannate will enable high mobility oxide electronics operating at RT with the added advantage of being optically transparent. PMID- 30457323 TI - Thiazole-Induced Surface Passivation and Recrystallization of CH3NH3PbI3 Films for Perovskite Solar Cells with Ultrahigh Fill Factors. AB - The quality of perovskite films is a crucial factor governing the photovoltaic performance of perovskite solar cells. However, perovskite films fabricated by the conventional one-step spin-coating procedure are far from ideal due to uncontrollable crystal growth. Herein, we report a facile recrystallization procedure using a thiazole additive coupled with vapor annealing to simultaneously modulate the perovskite crystal growth and suppress the surface defects. High quality perovskite films with no pin holes, high crystallinity, large grain size, and low roughness were obtained. Moreover, using the space charge limited current method, we observe that the defect density of the as prepared perovskite films with the thiazole additive was decreased by 40% when compared with the film without thiazole. The lower defect density of these perovskite films enables the achievement of a final power conversion efficiency of 18% and an exceptionally high fill factor of 0.82, which correspond to a 25% enhancement compared with the control device. Our results reveal a novel and facile path to modulate the perovskite crystal growth and simultaneously suppress the film defect density and increasing efficiency in perovskite photovoltaics and related optoelectronic applications. PMID- 30457324 TI - Decoupling mesoscale functional response in PLZT across the ferroelectric - relaxor phase transition with contact Kelvin probe force microscopy and machine learning. AB - Relaxor ferroelectrics exhibit a range of interesting material behavior comprising high electromechanical response, polarization rotations as well as temperature and electric field- driven phase transitions. The origin of this unusual functional behavior is still elusive due to limited knowledge on polarization behavior at the nanoscale. Piezoresponse force microscopy and associated switching spectroscopy provide access to local electromechanical properties on the micro- and nanoscale and help to address some of these gaps in our knowledge. However, these techniques are inevitably prone to artefacts caused by signal contributions emanating from electrostatic interactions between tip and sample. Understanding functional behavior of complex, disordered systems like relaxor materials with unknown electromechanical properties therefore requires a technique that allows to distinguish between electromechanical and electrostatic response. Here, contact Kelvin probe force microscopy (cKPFM) is used to gain insight into evolution of local electromechanical and capacitive properties of a representative relaxor material lead lanthanum zirconate across the phase transition from a ferroelectric to relaxor state. The obtained multidimensional data set was processed using an unsupervised machine learning algorithm to detect variations in functional response across the probed area and temperature range. Further analysis showed formation of two separate cKPFM response bands below 50 degrees C, providing evidence for polarization switching. At higher temperatures only one band is observed, indicating an electrostatic origin of the measured response. In addition, from the cKPFM data qualitatively extracted junction potential difference, becomes independent of the temperature in the relaxor state. The combination of this multidimensional voltage spectroscopy technique and machine learning allows to identify the origin of the measured functional response and to decouple ferroelectric from electrostatic phenomena necessary to understand the functional behavior of complex, disordered systems like relaxor materials. PMID- 30457326 TI - Single-nucleotide resolution analysis of 5-hydroxymethylcytosine in DNA by enzyme mediated deamination in combination with sequencing. AB - The report of the existence of 5-hydroxymethylcytosine (hm5C) in mammalian genomes is a milestone discovery. hm5C is now generally viewed as the sixth base of DNA with important functions on epigenetic regulation. The in-depth investigation of the biological functions of hm5C requires elucidating the distribution patterns of hm5C in genomes, better in single-nucleotide resolution. It was reported that the cytosine deaminases of APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) family are nucleic acid editing enzymes and can deaminate cytosine (C) to form uracil (U). Particularly, a subfamily of APOBEC (APOBEC3A) can efficiently deaminate both C and 5-methylcytosine (m5C). In the current study, we identified that APOBEC3A protein can effectively deaminate C, m5C, and hm5C, but shows no observable deamination activity toward glycosylated hm5C (beta-glucosyl-5-hydroxymethyl-2'-deoxycytidine, ghm5C) by using the restriction enzyme-based assay and liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) analysis. By virtue of the differential deamination activity of APOBEC3A toward C, m5C and ghm5C in conjugation with sequencing, we developed the single-nucleotide resolution analysis of hm5C in DNA. In this analytical strategy, the original C and m5C in DNA will be deaminated by APOBEC3A to form U and thymine (T), both of which will read as T during sequencing. While the ghm5C is resistant to deamination and will read as C during sequencing. Therefore, the remaining C in the sequence context only could come from original hm5C, which offers the single-nucleotide resolution analysis of hm5C in DNA. This APOBEC3A-mediated deamination sequencing (AMD-seq) is straight forward and involves no bisulfite treatment, which avoids the substantial degradation of DNA. Future application of this strategy can be performed for the reliable mapping of hm5C in genome-wide scale at the single nucleotide resolution. PMID- 30457325 TI - Temperature-robust DNAzyme biosensors confirming ultralow background detection. AB - Catalytic DNA/RNA, such as DNAzyme, has been widely adopted to construct biosensors, especially for metal ion analysis. However, traditional DNAzyme biosensors still suffer from fluctuating and relatively high background. Herein, we proposed a temperature-robust DNAzyme, conferring ultralow background in various temperatures, thus leading to highly sensitive and robust detection of metal ions. Instead of labelling substrate to directly output fluorescence signal, our proposed DNAzyme biosensor utilized a cascade detection process with a couple of proximity fluorescent probes, confirming very low background regardless of the conditions of cleavage reaction. This cascade DNAzyme biosensor conferred a signal to background ratio over 20 when the temperature of catalytic reaction ranged from 20 to 41 C. Benefited from its ultralow-background, it could confer a detection limit of 0.22 nM, which ranked one of the highest sensitivity levels among DNAzyme-based fluorescent biosensors. This DNAzyme biosensor was over 6000 times more selective for Pb2+ against the most active interfering metal ions, Zn2+. Further, it has been successfully applied for analyzing lead pollution in tap water and eggs, with total recoveries ranging from 87% to 114%. This facile, simple and effective design strategy would significantly improve the detection performance of DNAzyme biosensors, thus facilitating its practical applications for both food safety analysis and environment monitoring. PMID- 30457327 TI - Phosphopeptide fragmentation and site localization by mass spectrometry; an update. AB - Pioneering work by among others the groups of Hunt and Mann at the start of this century opened up the era of mass spectrometry based phosphoproteomics1-3. Through advances in sample preparation, phosphopeptide enrichment, mass spectrometric detection, peptide sequencing and dedicated database searches this field has matured and it is nowadays possible to monitor thousands of protein phosphorylation events qualitatively and quantitatively4-8. Such phosphoproteomics studies are important as protein phosphorylation is regulating nearly all biological processes and the deregulation of phosphorylation has been associated with the onset of various diseases9-15. Notwithstanding this maturation and broad acceptance of mass spectrometry based phosphoproteomics by the research community, the mass spectrometric (MS) analysis of phosphorylation remains demanding, mainly due to the often severe substoichiometric levels of phosphorylation and the intrinsic lability of the phosphate group, hampering both enrichment and unambiguous sequencing analysis of phosphopeptides. Here we review the increasing knowledge gathered about the mechanisms behind the fragmentation of phosphopeptide ions and describe additionally recent advances made to improve and facilitate the identification and site localization of phosphorylated peptides. Since our earlier related review in 200916 several fragmentation methods have been introduced and successfully applied to phosphopeptides, such as electron capture (ECD), electron transfer induced dissociation(ETD), and hybrid fragmentation techniques such as EThcD (a combination of ETD and HCD) and AI-ETD (a combination of ETD with infrared photo-activation). A plethora of data has been gathered on endogenous Ser, Thr, Tyr phosphorylation, but also on large synthetic phosphopeptide libraries, providing new insight into the mechanisms behind phosphopeptide fragmentation. Moreover, data on phosphopeptides harboring phosphorylated Histidine, Arginine or Lysine have become available, which exhibit some distinct fragmentation behaviors. Through all this acquired knowledge on phosphopeptide fragmentation and site localization mass spectrometry based phosphoproteomics has matured into a respectable tool for the broader life science research community. PMID- 30457329 TI - Hysteresis and Allostery in Human UDP-Glucose Dehydrogenase Require a Flexible Protein Core. AB - Human UDP-glucose dehydrogenase (hUGDH) oxidizes UDP-glucose to UDP-glucuronic acid, an essential substrate in the phase II metabolism of drugs. The activity of hUGDH is regulated by the conformation of a buried allosteric switch (T131 loop/alpha6 helix). Substrate binding induces the allosteric switch to slowly isomerize from an inactive E* conformation to the active E state, which can be observed as enzyme hysteresis. When the feedback inhibitor UDP-xylose binds, the allosteric switch and surrounding residues in the protein core repack, converting the hexamer into an inactive, horseshoe-shaped complex (EOmega). This allosteric transition is facilitated by large cavities and declivities in the protein core that provide the space required to accommodate the alternate packing arrangements. Here, we have used the A104L substitution to fill a cavity in the E state and sterically prevent repacking of the core into the EOmega state. Steady state analysis shows that hUGDHA104L binds UDP-xylose with lower affinity and that the inhibition is no longer cooperative. This means that the allosteric transition to the high-UDP-xylose affinity EOmega state is blocked by the substitution. The crystal structures of hUGDHA104L show that the allosteric switch still adopts the E and E* states, albeit with a more rigid protein core. However, the progress curves of hUGDHA104L do not show hysteresis, which suggests that the E* and E states are now in rapid equilibrium. Our data suggest that hysteresis in native hUGDH originates from the conformational entropy of the E* state protein core. PMID- 30457330 TI - Biocompatible Symmetric Na-Ion Microbatteries with Sphere-in-Network Heteronanomat Electrodes Realizing High Reliability and High Energy Density for Implantable Bioelectronics. AB - The prolonged life expectancy accelerates the development of implantable bioelectronic devices. However, conventional batteries with limited lifetime, rigid architecture, and inferior energy density greatly restrict their applications in patient's body. Herein, a novel flexible symmetric Na-ion microbattery based on the heteronanomat electrode and the biocompatible electrolyte has been developed. The film electrodes with sphere-in-network architecture are synthesized by simultaneously electrospinning and electrospraying followed by carbonization. The combined technologies allow a uniform incorporation of active materials/C spheres into the carbon nanofiber matrix, which results in the heteronanomat electrodes with robust structure, fast electron/ion transport, and compact mass loading. The flexible microbatteries are fabricated based on the interdigitated microelectrodes and the biocompatible electrolytes, which provides a new implantable power source for bioelectronics. As a proof-of-concept study, the symmetric sodium-ion microbatteries are constructed from the heteronanomat bifunctional electrodes (based on Na2VTi(PO4)3) and the biocompatible electrolyte. The high reversibility, fast kinetics, and high energy density of the symmetric system in the biocompatible electrolytes reveal their superior performance in bioenvironments. Moreover, the high capacity retention (over 98%) and the high stability of microbattery implanted in a living SD rat for a month further demonstrate its high reliability for long-term in vivo diagnosis. Therefore, this work not only presents a new sphere-in-net heteronanomat structure for fabricating high-performance electrode but also gives significant contributions to develop high-energy-density and high safety biocompatible power sources of implantable bioelectronics. PMID- 30457328 TI - New Variations on the Theme of Gold(III) C?N?N Cyclometalated Complexes as Anticancer Agents: Synthesis and Biological Characterization. AB - A series of novel (C?N?N) cyclometalated AuIII complexes of general formula [Au(bipydmb-H)X][PF6] (bipydmb-H = C?N?N cyclometalated 6-(1,1-dimethylbenzyl) 2,2'-bipyridine) were prepared with a range of anionic ligands X in the fourth coordination position, featuring C (alkynyl)-, N-, O-, or S-donor atoms. The X ligands are varied in nature and include three coumarins, 4-ethynylaniline, saccharine, and thio-beta-d-glucose tetraacetate, the tripeptide glutathione (GSH), and a coumarin-substituted amide derived from 4-ethynylaniline. The gold(I) complex [Au(C2ArNHCOQ)(PPh3)] (HC2ArNHCOQ = N-(4-ethynylphenyl)-2-oxo-2 H chromene-3-carboxamide) was also prepared for comparison. The new compounds were fully characterized by means of analytical techniques, including NMR, absorption, and emission spectroscopy. The crystal structures of three cyclometalated AuIII complexes and of the AuI derivative were solved by single-crystal X-ray diffraction. The antiproliferative activity of the new AuIII cyclometalated derivatives was evaluated against cancer cells in vitro. According to the obtained results, only complexes 3-PF6 and 5-PF6, featuring coumarins as ancillary ligands and endowed with high redox stability in solution, display antiproliferative effects, with 5-PF6 being the most potent, while all of the others are scarcely active to nonactive in the selected cell lines. In order to study the reactivity of the compounds with biomolecules, the interaction of complexes 3-PF6 and 5-PF6 with the protein cytochrome c and the amino acids cysteine and histidine was analyzed by electrospray ionization mass spectrometry (ESI MS), showing adduct formation only with Cys after at least 1 h incubation. Furthermore, the parent hydroxo complex [Au(bipydmb-H)(OH)][PF6] (1OH-PF6) was investigated in a competitive assay to determine the protein vs oligonucleotide binding preferences by capillary zone electrophoresis (CZE) coupled to ESI-MS. Of note, the compound was found to selectively form adducts with the oligonucleotide over the protein upon ligand exchange with the hydroxido ligand. Adduct formation occurred within the first 10 min of incubation, demonstrating the preference of 1OH-PF6 for nucleotides in this setup. Overall, the obtained results point toward the possibility to selectively target DNA with gold(III) organometallics. PMID- 30457331 TI - High-Performance Image-Based Measurements of Biological Forces and Interactions in a Dual Optical Trap. AB - Optical traps enable the nanoscale manipulation of individual biomolecules while measuring molecular forces and lengths. This ability relies on the sensitive detection of optically trapped particles, typically accomplished using laser based interferometric methods. Recently, image-based particle tracking techniques have garnered increased interest as a potential alternative to laser-based detection; however, successful integration of image-based methods into optical trapping instruments for biophysical applications and force measurements has remained elusive. Here, we develop a camera-based detection platform that enables accurate and precise measurements of biological forces and interactions in a dual optical trap. In demonstration, we stretch and unzip DNA molecules while measuring the relative distances of trapped particles from their trapping centers with sub-nanometer accuracy and precision. We then use the DNA unzipping technique to localize bound proteins with sub-base-pair precision, revealing how thermal DNA "breathing" fluctuations allow an unzipping fork to detect and respond to the presence of a protein bound downstream. This work advances the capabilities of image tracking in optical traps, providing a state-of-the-art detection method that is accessible, highly flexible, and broadly compatible with diverse experimental substrates and other nanometric techniques. PMID- 30457332 TI - Rhodium-Catalyzed Enantioselective [2 + 2 + 1] Cycloaddition of 1,6-Enynes with Cyclopropylideneacetamides. AB - It has been established that a cationic rhodium(I)/( R)-tol-BINAP or ( R)-BINAP complex catalyzes the enantioselective [2 + 2 + 1] cycloaddition of 1,6-enynes, possessing monosubstituted alkene units, with cyclopropylideneacetamides at room temperature through the elimination of ethylene to give bicyclic (cyclopent-2-en 1-ylidene)acetamides with high enantioselectivity. PMID- 30457333 TI - Macrocyclic Trichothecene Mycotoxins from a Deadly Poisonous Mushroom, Podostroma cornu-damae. AB - Three new macrocyclic trichothecenes (1-3) and five known related compounds (4-8) were isolated from the MeOH extract of a plate culture of the fungus Podostroma cornu-damae, a deadly poisonous mushroom. Miophytocen D (1) is a rearranged macrocyclic type D trichothecene, featuring a bicyclo-[6.5]dodecahydrocyclopenta[ b]chromene scaffold, and the structures of new compounds (1-3) were delineated by the combination of 1D and 2D NMR spectroscopic experiments and HRESIMS, modified Mosher's esterification, and quantum chemical ECD calculations. The isolated compounds (1-8) were evaluated for cytotoxicity against four human breast cancer cell lines (Bt549, HCC70, MDA-MB-231, and MDA-MB-468). Compounds 4, 6, and 8 exhibited significant cytotoxic effects against the breast cancer cell lines, with IC50 values in the range of 0.02-80 nM, which is stronger than doxorubicin, the positive control, and a structure-activity relationship was suggested. PMID- 30457334 TI - Structural Properties of Aqueous Solutions at the (100) and (101) Goethite Surfaces by Molecular Dynamics Simulation. AB - Trace metal concentrations in soils and sediments are often controlled by adsorption to iron oxides such as goethite in both natural and contaminated systems. Because of goethite's importance as an adsorbent, its interaction with aqueous solutions has been studied extensively. Nonetheless, despite the use of numerous analytical and computational tools, the properties of goethite-aqueous solution interfaces are not fully understood. In this research, we investigate the interaction of water and aqueous NaCl, MgCl2, and BaCl2 solutions ranging in concentration from 0.1 to 4 M, with two goethite surfaces, (100) and (101), using classical molecular dynamics simulation. In the past, the (100) surface has been studied the most because of its simplicity; however, goethite crystals in the environment exhibit other prominent surfaces like the (101) surface which may exhibit very different adsorption properties than the (100) surface. The (100) surface has three surface sites; one is an under-coordinated Fe3+ which interacts strongly with water affecting the interfacial water structure, another site remains deprotonated and forms a hydrogen bond to the only hydroxylated surface site. The (101) surface is terminated with five hydroxyl groups that do not interact as strongly with water as the under-coordinated Fe3+ ion and that form a more corrugated surface structure. As a result, the (101) goethite-solution interface exhibits less water structure, weaker electric double layer oscillations, and more inner-sphere ion adsorption, especially for Cl- and Ba2+ ions. The fundamental differences in interfacial properties for these surfaces suggest that the adsorption properties of one goethite surface cannot be averaged to represent goethite interfaces present in soils and sediments. PMID- 30457335 TI - Polyheteroaryl Oxazole/Pyridine-based compounds selected in vitro as G-quadruplex ligands inhibit Rock kinase and exhibit antiproliferative activity. AB - Heptaheteroaryl compounds comprised of oxazole and pyridine units (TOxaPy) are quadruplex DNA (G4)-interactive compounds. Herein, we report on the synthesis of parent compounds bearing either amino side chains (TOxaPy-1-5) or featuring an isomeric oxazole-pyridine central connectivity (iso-TOxapy, iso-TOxapy 1-3) or a bipyridine core (iso-TOxabiPy). The new isomeric series showed significant G4 binding activity in vitro and remarkably 3 compounds (iso-TOxaPy, iso-TOxaPy-1, iso-TOxabiPy) exhibited high antiproliferative activity towards a tumor panel of cancer cell lines. However, these compounds do not behave as typical G-quadruplex binders and the kinase profiling assay revealed that the best antiproliferative molecule iso-TOxaPy selectively inhibited Rock-2. The targeting of Rock kinase was confirmed in cells by the dephosphorylation of Rock-2 substrates, the decrease of stress fibers and peripheral focal adhesions, as well as the induction of long neurite-like extensions. Remarkably two of these molecules were able to inhibit the growth of cells organized as spheroids. PMID- 30457336 TI - Metal- and Phenol-Free Synthesis of Biaryl Ethers: Access to Dibenzobistriazolo 1,4,7-oxadiazonines and Vancomycin-Like Glyco-Macrocycles as Antibacterial Agents. AB - An efficient synthesis of biaryl ethers, from electron-deficient aryl halides using NaH/DMSO under metal- and phenol-free conditions, has been achieved to access dibenzo-bistriazolo-1,4,7-oxadiazonines and vancomycin-like glyco macrocycles. A 44-membered glyco-macrocycle showed promising activity against vancomycin-resistant Staphylococcus aureus (VRSA). PMID- 30457337 TI - A [2 + 2] Photocycloaddition-Fragmentation Approach toward the Carbon Skeleton of cis-Fused Lycorine-type Alkaloids. AB - Starting from isoquinolones, the cis-selective annulation of six-membered rings was possible employing cyclobutenes as olefin components in a [2 + 2] photocycloaddition-fragmentation approach (nine examples, 54-80% yield). The developed sequence enables a conceptually new entry to cis-fused lycorine-type alkaloids of the Amaryllidaceae family with the complete carbon skeleton being successfully assembled. A subsequent von Braun-type reaction emphasized the biological relation between lycorine- and homolycorine-type alkaloids providing a synthetic tool to access this class of natural products. PMID- 30457338 TI - Accurate Gap Determination in Monolayer and Bilayer Graphene/ h-BN Moire Superlattices. AB - High mobility single and few-layer graphene sheets are in many ways attractive as nanoelectronic circuit hosts but lack energy gaps, which are essential to the operation of field-effect transistors. One of the methods used to create gaps in the spectrum of graphene systems is to form long period moire patterns by aligning the graphene and hexagonal boron nitride ( h-BN) substrate lattices. Here, we use planar tunneling devices with thin h-BN barriers to obtain direct and accurate tunneling spectroscopy measurements of the energy gaps in single layer and bilayer graphene- h-BN superlattice structures at charge neutrality (first Dirac point) and at integer moire band occupancies (second Dirac point, SDP) as a function of external electric and magnetic fields and the interface twist angle. In single-layer graphene, we find, in agreement with previous work, that gaps are formed at neutrality and at the hole-doped SDP, but not at the electron-doped SDP. Both primary and secondary gaps can be determined accurately by extrapolating Landau fan patterns to a zero magnetic field and are as large as ~17 meV for devices in near-perfect alignment. For bilayer graphene, we find that gaps occur only at charge neutrality where they can be modified by an external electric field. PMID- 30457339 TI - Correction to " Anti-Selective Asymmetric Nitro-Michael Reaction of Furanones: Diastereocontrol by Catalyst". PMID- 30457340 TI - Photooxidation of unilamellar vesicles by a lipophilic pterin: Deciphering biomembrane photodamage. AB - Pterins are natural products that can photosensitize the oxidation of DNA, proteins and phospholipids. Recently, a new series of decyl-chain (i.e., lipophilic) pterins were synthesized and their photophysical properties investigated. These decyl-pterins led to efficient intercalation in large unilamellar vesicles and produce, under UVA irradiation, singlet molecular oxygen, a highly oxidative species that react with polyunsaturated fatty acids (PUFAs) to form hydroperoxides. Here, we demonstrate that the association of 4 (decyloxy)pteridin-2-amine (O-decyl-Ptr) to lipid membranes is key to its ability to trigger phospholipid oxidation in unilamellar vesicles of phosphatidylcholine rich in PUFAs used as model biomembranes. Our results show that O-decyl-Ptr is at least one order of magnitude more efficient photosensitizer of lipids than pterin (Ptr), the unsubstituted derivative of the pterin family, which is more hydrophilic and freely passes across lipid membranes. Lipid peroxidation photosensitized by O-decyl-Ptr was detected by the formation of conjugated dienes and oxidized lipids, such as hydroxy and hydroperoxides derivatives. These primary products undergo a rapid conversion into short-chain secondary products by cleavage of the fatty acid chains some of which are due to subsequent photosensitized reactions. As a consequence, a fast increase in membrane permeability is observed. Therefore, lipid oxidation induced by O-decyl-Ptr could promote cell photodamage due to the biomembrane integrity loss which, in turn, may trigger cell death. PMID- 30457341 TI - 1,3-Dioxa-[3,3]-Sigmatropic Oxo-Rearrangement of Substituted Allylic Carbamates: Scope and Mechanistic Studies. AB - An unexpected 1,3-dioxa[3,3]-sigmatropic oxo-rearrangement during the treatment of aryl- and alkenyl-substituted allylic alcohols with activated isocyanates is reported. The reorganization of bonds is highly dependent on the electron density of the aromatic ring and the nature of isocyanate used. This metal-free tandem reaction from branched allyl alcohols initiated by a carbamoylation reaction and followed by a sigmatropic rearrangement thus offers a new access to (E)-cinnamyl and conjugated (E,E)-diene carbamates such as N-acyl and N-sulfonyl derivatives. A computational study was conducted in order to rationalize this phenomenon as well as a rearrangement progress kinetic analysis was performed. PMID- 30457342 TI - Direct Synthesis of 3-Acylindoles through Rhodium(III)-Catalyzed Annulation of N Phenylamidines with alpha-Cl Ketones. AB - In the present study, a novel synthetic strategy to directly produce versatile 3 acylindoles through Rh(III)-catalyzed C-H activation and annulation cascade of N phenylamidines with alpha-Cl ketones was developed, in which alpha-Cl ketones serve as unusual one-carbon (sp3) synthons. This strategy features high regioselectivity, efficiency, wide substrate tolerance, and mild reaction conditions, which further underscore its synthetic utility in drug molecule synthesis. PMID- 30457343 TI - Narrowband Perovskite Photodetector-Based Image Array for Potential Application in Artificial Vision. AB - Image sensor arrays are widely used in digital cameras, smartphones, and biorobots. However, most commercial image arrays rely on the dichroic prisms or a set of interference filters to distinguish characteristic color spectrum, which significantly increases the cost and fabrication processing complexity. In this work, an ultranarrow response photodetector with full-width at half-maximum being ~12 nm and specific detectivity over 1011 Jones at 545 nm are successfully achieved in CsPbBr3 polycrystalline films using freeze-drying casting method to adjust the surface-charge recombination. To our best knowledge, this is the narrowest spectrum response for perovskite photodetectors in the visible light waveband. More importantly, a series of narrowband photodetectors are developed to enhance diverse selectivity for target signals covering from blue light to red light via bandgap tuning in CsPbX3 by tailoring the halide component. Finally, an integrated sensing array with CsPbX3 (X = Cl, Br, I) narrowband photodetectors acting as color recognition cones is constructed, which presents clear color and shape recognition paving the way for commercialization of perovskite photodetector in artificial vision. PMID- 30457344 TI - Synthesis of Polycyclic Aromatic Hydrocarbons (PAHs) via a Transient Directing Group. AB - In this work, an efficient synthetic route was developed to construct PAHs with diverse shape, width, and edge topology. The precursors of PAHs were obtained by using a direct arylation of arenes via a transient ligand-directed C-H functionalization strategy and the cycloaromatization was readily achieved by using a Bronsted acid catalyst. This novel route provides an opportunity to build up PAHs in a highly efficient manner. PMID- 30457346 TI - EXPRESS: Comparative Investigation of Secondary Cell Wall Development in Cotton Fiber Near Isogenic Lines Using Attenuated Total Reflection Fourier Transform Infrared Spectroscopy (ATR FT-IR). PMID- 30457345 TI - Three-Component Oxyarylation of Alkenes Enables Access to C3-Substituted Dihydrobenzofurans. AB - A practical and modular three-component alkene oxyarylation with benzoquinone and H2O to rapidly access C3-substituted dihydrobenzofurans has been developed. The (NH4)2S2O8-mediated redox-relay process has an excellent regioselectivity and functional group tolerance and exhibits a broad scope of simple alkenes, rapidly furnishing a variety of the substructures that would require multiple steps to prepare with traditional methods. Mechanistic studies revealed a dual role of benzoquinone serving as both the arylation agent and the origin of dihydroquinone for the reductive cyclization step. PMID- 30457347 TI - Meet and eat, an interdisciplinary group intervention for patients with myotonic dystrophy about healthy nutrition, meal preparation, and consumption: a feasibility study. AB - PURPOSE: To develop and evaluate an interdisciplinary group intervention for patients with myotonic dystrophy regarding healthy nutrition, meal preparation, and consumption, called Meet and Eat. MATERIALS AND METHODS: A design-based approach was used, exploring experiences and needs of patients with myotonic dystrophy and their next of kin. This resulted in a 4-week interdisciplinary outpatient group intervention to increase awareness and change behavior. In a mixed-method feasibility study this intervention was evaluated with participants and facilitators. RESULTS: Participants reported on social impact of difficulties with eating and drinking (speaking, swallowing, and social embarrassment) and a variety of complaints affecting meal preparation and consumption. Patients and family members expressed the wish to learn from others. After delivery of the intervention, self-reported outcome measures demonstrated improvement on eating and drinking issues in daily life. The qualitative evaluation showed increased awareness and appreciation of the following design principles: peer support, multidisciplinary approach, active involvement of patient with myotonic dystrophy and their next of kin by using personal goals and motivational interviewing. CONCLUSION: Participation in Meet and Eat seemed to increase insight in patients' condition and ways of management. However, a longer self-management life style program is recommended to change behavior. Implications for rehabilitation Patients with myotonic dystrophy experience physical, cognitive and psychosocial problems to manage healthy nutrition, meal preparation, and consumption; This multidisciplinary group intervention Meet and Eat in patients with myotonic dystrophy appears to be feasible and seems to result in increased insight and management strategies; Peer support, multidisciplinary approach, personal goals, and involvement of family were key factors; To change eating and drinking behavior, a 4-week intervention is too short. PMID- 30457348 TI - Enteral nutrition in esophageal cancer patients treated with radiotherapy: a Chinese expert consensus 2018. AB - Esophageal cancer (EC) patients receiving radiotherapy are at a high risk of malnutrition, which can increase the side effects of radiotherapy, reduce the accuracy and sensitivity of radiotherapy and decrease treatment effect. Therefore, timely and correct nutritional treatment is crucial. To date, however, neither consensus nor guidelines on enteral nutrition (EN) specifically for EC patients receiving radiotherapy exist. Accordingly, an expert consensus conference was held to establish consensus on the use of EN in EC patients receiving radiotherapy. It reflected the opinions of a multidisciplinary group of experts and a review of the current literature, and established common guidelines for nutritional screening and assessment, nutrition counseling, indication for EN, access and formulas of EN, effect evaluation, nutrition plan adjustment, and home enteral nutrition. PMID- 30457350 TI - Understanding the mechanisms underlying the effects of negative age stereotypes and perceived age discrimination on older adults' well-being. AB - OBJECTIVES: Although numerous studies have documented that negative age stereotypes and perceived age discrimination are related to older adults' lower well-being, few studies have investigated the mechanisms underlying these relationships. In this study, we tested whether self-perceptions of aging and subjective age would help to account for the relation between stereotypes and discrimination and self-esteem. According to the internalization hypothesis, we expected that the effects of negative age stereotypes and greater perceived age discrimination would be driven by more negative self-perceptions of aging and older subjective age. METHOD: A total of 151 older adults completed questions assessing their endorsement of negative age stereotypes, perceived age discrimination, self-perceptions of aging, subjective age, and self-esteem. Relationships among these variables were assessed using serial mediation analyses. RESULTS: Consistent with the internalization hypothesis, negative age stereotypes and perceived age discrimination indirectly predicted older subjective age and lower self-esteem through worsening self-perceptions of aging. However, we did not find a direct effect of negative age stereotypes or perceived discrimination on subjective age, nor an indirect effect of negative age stereotypes and perceived age discrimination on self-esteem through subjective age. CONCLUSION: These results support the internalization hypothesis: among older adults, holding more negative age stereotypes and perceiving more age discrimination is associated with feeling older and with lower self-esteem through worsened perceptions of one's own aging. Given the central role of self perceptions of aging, these findings highlight the importance of promoting more positive self-perceptions in order to maintain or increase older adults' well being. PMID- 30457349 TI - Comparative Efficacy of Methylphenidate and Atomoxetine on Emotional and Behavioral Problems in Youths with Attention-Deficit/Hyperactivity Disorder. AB - OBJECTIVE: Methylphenidate and atomoxetine are efficacious in reducing core symptoms of attention-deficit/hyperactivity disorder (ADHD), but little is known about their efficacy in improving emotional/behavioral problems among youths with ADHD. METHODS: One hundred sixty drug-naive youths with DSM-IV-defined ADHD, aged 7-16 years, were recruited and randomly assigned to osmotic-release oral system methylphenidate (OROS-methylphenidate; n = 80) and atomoxetine (n = 80) in a 24 week, open-label, head-to-head clinical trial. The primary efficacy measure was parent-reported Child Behavior Checklist (CBCL), and the secondary efficacy measures included Youth Self Report (YSR) and Strengths and Difficulties Questionnaire (SDQ), which was based on the ratings of parents, teachers, and subjects. RESULTS: For CBCL, both methylphenidate and atomoxetine groups showed significant improvement in all scores at weeks 8 and 24 except Somatic Complaints in the atomoxetine group. For SDQ, both treatment groups showed significant improvements in the Hyperactive and Conduct subscales for parent ratings, and the Externalizing subscale for teacher ratings at week 24. Methylphenidate was associated with greater improvements in Aggressive Behavior and Somatic Complaints of CBCL and in Conduct subscale of self-reported SDQ at week 24 compared with atomoxetine. CONCLUSIONS: Our findings provide evidence to support that both methylphenidate and atomoxetine were effective in improving a wide range of emotional/behavioral problems in youths with ADHD after 24 weeks of treatment, with greater improvement in aggressive behavior, somatic complaints, and conduct problems in the methylphenidate group. PMID- 30457352 TI - Cone-beam evaluation of pharyngeal airway space in adult skeletal Class II patients with different condylar positions. AB - OBJECTIVES:: To test the null hypothesis that there is no significant difference in pharyngeal airway space among adult skeletal Class II patients with different condylar positions using cone-beam computed tomography (CBCT). MATERIALS AND METHODS:: The CBCT records of 60 patients with skeletal Class II malocclusion (ANB angle >= 4 degrees , Wits >= 0) were selected from the CBCT database. According to the condyle position, the patients were divided in three groups: anterior group (CD <= -12%), centric group (-12% <= CD <= +12%), and posterior group (CD >= +12%). Three-dimensional (3D) pharyngeal airway models were reconstructed using InvivoDental software 5.1.3. The volume and area of the pharyngeal airway space were measured in the 3D airway model. RESULTS:: The volume and area of the pharyngeal airway space in the centric group were significantly smaller than those in the posterior group ( P < .01). The volume and area of the pharyngeal airway space were smallest in the anterior group and significantly increased in the centric and posterior groups ( P < .001). CONCLUSIONS:: The null hypothesis was rejected. Significant differences were noted in pharyngeal airway space among adult skeletal Class II patients with different condylar positions. PMID- 30457351 TI - Relationship of WNT4 Gene with the Risk of Epithelial Ovarian Cancer: A Han Chinese Population-Based Association Study. AB - OBJECTIVE: In China, epithelial ovarian cancer (EOC) patients account for the majority of ovarian cancer patients. The pathogenesis of EOC, one of the most lethal gynecological malignancies, remains unclear. Recently, the role of WNT4 in gynecological disease and tumor development was reported, and a suspicious association of WNT4 with EOC was identified in Europeans. However, the contributions of the WNT4 gene to EOC and the underlying molecular mechanisms remains largely unknown. To determine whether the WNT4 gene is associated with EOC, this study investigated polymorphisms of the WNT4 gene in Han Chinese individuals. MATERIALS AND METHODS: We designed a case/control study with 707 EOC patients and 1563 unrelated healthy controls of Han Chinese descent. A total of eight tag single-nucleotide polymorphisms (SNPs) were genotyped successfully, and both single SNP and haplotype analyses were performed to detect the potential association of variations in the WNT4 gene with EOC. RESULTS: The SNP rs56318008 was found to be strongly associated with EOC risk. In the serous EOC subgroup, individuals harboring the T allele of rs56318008 exhibited a higher risk of EOC than individuals harboring the C allele. Moreover, the odds ratios and 95% confidence intervals revealed an increased risk of EOC in individuals with the T allele of the SNP, and haplotypic analyses confirmed the results, showing a similar pattern. CONCLUSION: Our results show that the WNT4 gene is associated with EOC risk, indicating that this gene may be a potential genetic risk factor for developing EOC. PMID- 30457353 TI - Stability of orthodontic treatment outcomes after 1-year treatment with the eruption guidance appliance in the early mixed dentition: A follow-up study. AB - OBJECTIVES:: To investigate occlusal stability from the early mixed to the permanent dentition in children after early treatment with the eruption guidance appliance (EGA). MATERIALS AND METHODS:: Of 46 participants who received 1-year early EGA treatment, 35 attended a follow-up examination at age 12. Group 1 (n = 21) started their EGA treatment at mean age 7.7 years, and group 2 at 9.1 years. Following 1-year treatment, the EGA was used as a retainer. Changes in overjet, overbite, sagittal molar relationship, and anterior crowding were measured on casts obtained before EGA treatment, after EGA treatment, and at follow-up to evaluate occlusal stability. RESULTS:: Mean overjet, overbite, sagittal molar relation, and mandibular crowding improved significantly during the study period. Participants with good compliance during the retention period had significantly smaller overjet and overbite values than those with poor compliance. CONCLUSIONS:: Early correction of increased overjet, overbite, and class II molar relation with the EGA is maintainable and can also be effective in the permanent dentition, provided the EGA is worn regularly as a retainer. PMID- 30457354 TI - Evaluation of a novel palatal suture maturation classification as assessed by cone-beam computed tomography imaging of a pre- and postexpansion treatment cohort. AB - OBJECTIVES:: To test the reliability and usefulness of the midpalatal suture maturation classification and methodology proposed in 2013 by Angelieri et al. for successful prediction of rapid maxillary expansion (RME) treatment results. MATERIALS AND METHODS:: Reliability testing focused on 16 patients aged 9.5-17 years with early mixed to full permanent dentition, representing all proposed palatal maturation stages, from available preexpansion cone-beam computed tomography (CBCT). A retrospective observational longitudinal (cohort) study evaluated 63 preadolescent and adolescent patients aged 11-17 years with full permanent dentition treated with tooth-borne RME appliances who had CBCT records taken at pre- (T1) and postexpansion (T2). CBCT three-dimensional landmarking produced skeletal and dental widths and dental angulations used to evaluate the extent of skeletal and/or dental expansion. A regression model was used to assess the prediction capability of the T1 palatal suture classification of each subject for dental and skeletal changes. RESULTS:: There was almost perfect intraexaminer agreement and slight to poor interexaminer agreement, differing from previously reported reliability, affected by necessary operator calibration and the degree of postacquisition image sharpness and clarity. Further exploration of its scientific basis suggested that the proposed classification was ill-founded. Results from the cohort study were also wholly unsupportive of efficacy of the proposed palatal suture maturation classification in predicting the magnitude of portrayed changes. CONCLUSIONS:: Clinicians should be cautious in applying this classification. Although it has merits, the palatal classification still needs much more research and validation. PMID- 30457356 TI - Citrullinated Vimentin and biglycan protein fingerprints as candidate serological biomarkers for disease activity in systemic sclerosis: A pilot study. AB - PURPOSE: Extracellular matrix (ECM) deposition and remodelling in skin and lungs of systemic sclerosis (SSc) subjects lead to release of metabolites/biomarkers into circulation. We investigated if biomarkers of ECM degradation (biglycan and elastin) and macrophage activation (citrullinated vimentin) could identify diffuse SSc (dSSc) subjects from controls and the biomarkers discriminative power. METHODS: DSSc subjects (n = 40) fulfilling the 2013 EULAR/ACR classification criteria were divided in early (<2years of symptoms) and late (>=10years of symptoms). Early were subdivided into intermediate and rapid skin thickness progression rate (STPR). Twenty controls were included. Citrullinated and matrix metalloproteinase (MMP)-2/8-degraded vimentin (VICM), MMP-9/12 degraded biglycan (BGM) and MMP-7-degraded elastin (ELM-7) were assessed in serum. Analysis between groups was by Kruskal-Wallis and ROC AUC for discriminative power. RESULTS: VICM and BGM levels were increased in early compared to late dSSc (p< =0.023). VICM was increased in rapid and intermediate STPR compared to controls (p< =0.025). No differences in ELM-7 levels were observed. AUC of VICM was 0.71 for early versus late dSSc and BGM had an AUC of 0.79 for dSSc versus controls. CONCLUSION: This pilot study found differences in biomarker levels between early and late dSSc. This study offers new perspectives of ECM metabolites as potential biomarkers of dSSc. PMID- 30457355 TI - Intermittent Exotropia Treatment with Dichoptic Visual Training Using a Unique Virtual Reality Platform. AB - We evaluated the effect of dichoptic visual training based on a unique virtual reality (VR) platform mounted display in patients with intermittent exotropia (IXT). A total of 25 IXT patients (8 men, 17 women) with a mean age of 12.3 years (range, 5-39 year) were recruited. The Hirschberg test, prism and alternate cover testing (with accommodative targets for fixation at 33 cm in all patients), perceptual eye position (PEP), and stereopsis were evaluated after 1, 3, and 6 months of dichoptic visual neuroplasticity training with a computer-controlled perceptual examination evaluation system. Data collected before and after training were evaluated using SPSS software. After 6 months of perceptual training, a new order stereopsis was established, and eye positions were improved in all 25 patients. After training for 1 and 6 months, the horizontal PEP pixels were much lower than those pretraining, respectively (Delta1-0 = -0.53, p = 0.028; Delta6-0 = -0.80, p = 0.018). There was no statistically significant difference between pretraining and 3 months after training in horizontal PEP (Delta3-0 = -0.29, p = 0.370). There was no significant difference between pretraining and post-training in vertical PEP (p > 0.05). There were significant differences between pretraining and post-training in the cornea's optical reflection and prism diopters (p < 0.01). Dichoptic visual neuroplasticity training based on a VR platform is an effective nonsurgical treatment in patients with IXT. With the VR treatment, the degree of strabismus and stereopsis was improved in IXT patients. Perceptual training with VR can remove obstacles in the visual processing channel and repair defects in visual function. The clinical manifestations of improvement were the decrease in the degree of strabismus and the re-establishment of stereopsis. PMID- 30457357 TI - Transport and Delivery of Interferon-alpha Through Epithelial Tight Junctions via pH-Responsive Poly(Methacrylic Acid Grafted Ethylene Glycol) Nanoparticles. AB - Whereas significant advancements have been made in our fundamental understanding of cancer, they have not yet translated into effective clinical cancer treatments. One of the areas that has the potential to improve the efficacy of cancer therapies is the development of novel drug delivery technologies. In particular, the design of pH-sensitive polymeric complexation hydrogels may allow for targeted oral delivery of a wide variety of chemotherapeutic drugs and proteins. In this work, poly(methacrylic acid grafted ethylene glycol) (P(MAA-g EG) hydrogel nanoparticles were synthesized, characterized, and studied as matrix type, diffusion-controlled, pH-responsive carriers to enable the oral delivery of the chemotherapeutic agent Interferon Alpha (IFN-alpha). The biophysical mechanisms controlling the transport of IFN-alpha were investigated using a Caco 2/HT29-MTX co-culture as a gastrointestinal (GI) tract model. The synthesized nanoparticles exhibited pH-responsive swelling behavior and allowed the permeation of IFN-alpha through the tight junctions of the developed cellular gastrointestinal epithelium model. These studies demonstrate the capabilities of these particles to contribute to the improved oral delivery of protein chemotherapeutics. PMID- 30457358 TI - Cost Effectiveness of Implementing ESC Guidelines for Treatment of Iron Deficiency in Heart Failure in the Nordic Countries. AB - OBJECTIVES: Guidelines of the European Society of Cardiology (ESC) recommend that ferritin and transferrin saturation should be tested in chronic heart failure (HF) and state that iron treatment with ferric carboxymaltose should be considered in HF patients with iron deficiency to alleviate symptoms and improve exercise tolerance and quality of life. This study evaluates the cost effectiveness of the implementation of this recommendation in four Nordic countries (Denmark, Finland, Norway, and Sweden). DESIGN: We performed a cost utility analysis comparing ferric carboxymaltose treatment with placebo over a one-year time period in each country. Data on healthcare resource use and health outcomes were taken from the CONFIRM-HF study and combined with country-specific unit costs. Differences in per-patient costs and quality-adjusted life years (QALYs) were calculated. RESULTS: QALYs were higher (increase of 0.050 QALYs per patient) in the iron-treated group compared with placebo. Per-patient costs were lower in all countries (with reductions ranging from ?36 to ?484). Fewer hospitalizations were one key driver of these results. Another important driver was how well the new routines for iron treatment can be integrated into the current healthcare management of HF. A sensitivity analysis confirmed the results to be robust. CONCLUSIONS: Iron deficiency therapy in HF with ferric carboxymaltose compared with placebo is estimated to both improve health-related quality of life and save healthcare costs in all Nordic countries. A well organized healthcare management of HF patients can enable the implementation of ESC-recommended treatment of iron deficiency without need for additional resources. PMID- 30457359 TI - A Global Perinatal Health Indicator Falters in Afghanistan. AB - Through the life of a global health project in a maternity hospital in Kabul, Afghanistan one indicator-intrapartum mortality-was taken to represent the quality of emergency obstetric care and was at the center of a struggle over project management. The indicator was also contested by Afghan clinicians, and so was adapted, in which process the relationship between the indicator and women's lives outside the hospital was made clear. As the indicator faltered, new possibilities for intervention emerged, although these were not fully realized. Global health governance and financing must be flexible enough to respond when indicators falter. PMID- 30457360 TI - Synergistic Antitumor Effect on Bladder Cancer by Rational Combination of Programmed Cell Death 1 Blockade and CRISPR-Cas9-Mediated Long Non-Coding RNA Urothelial Carcinoma Associated 1 Knockout. AB - Targeted therapy produces objective responses in bladder cancer patients, although the responses can be short. Meanwhile, response rates to immune therapy are lower, but the effects are more durable. Based on these findings, it was hypothesized that urothelial carcinoma associated 1 (UCA1)-targeted therapy could synergize with programmed cell death 1 (PD-1) blockade to enhance antitumor activity. To test this hypothesis, the effects of CRISPR-Cas9 targeting of UCA1 and PD-1 were assessed in vitro and in vivo. It was found that gRNA/cas9-targeted UCA1 induced apoptosis of 5637 bladder cancer cells, whereas PD-1 gene knockout could be achieved by electroporation of gRNA/cas9 targeting PD-1, as detected by polymerase chain reaction. In 5637 cell-xenografted humanized SCID mice, stimulation with CRISPR-Cas9 systems, immune phenotypes, and cytokine expression of human dendritic cells (DCs) was detected by flow cytometry, and polymerase chain reaction, respectively. The results of these assays suggested that the gRNA/cas9 treatment upregulated expression of CD80, CD83, and CD86 and significantly increased interleukin (IL)-6, IL-12, and IL-23 and tumor necrosis factor alpha mRNA levels. Co-administration of anti-PD-1 and anti-UCA1 treatment suppressed tumor growth and markedly improved survival of 5637 xenografted mice. Additionally, the combination treatment increased interferon gamma production by T cells that subsequently enhanced the expression of Th1-associated immune stimulating genes to reduce transcription of regulatory/suppressive immune genes and reshape the tumor microenvironment from an immunosuppressive to a stimulatory state. Finally, anti-UCA1 treatment was shown to induce interferon gamma dependent programmed cell death ligand 1 expression within 5637 xenograft tumors in vivo. Together, these results demonstrate potent synergistic effects of a combination therapy using LncRNA UCA1-targeted therapy and immune checkpoint blockade of PD-1, thus supporting the translational potential of this combination strategy for clinical treatment of bladder cancer. PMID- 30457361 TI - "No policy is an island": how the ICF international classification system may support local education planning in England. AB - BACKGROUND: A crucial issue in special educational needs and disability policy and provision is the documentation of children's functioning, for which many countries have a statutory document. In England this is the education health and care plan. Recent research challenges the quality of these plans. PURPOSE: To provide evidence on the usefulness of the international classification of functioning, disability and health as a system with potential to support the development of higher quality plans in England. METHODS: Twenty-five professionals participated in a one-day training session on the international classification of functioning disability and health, with a focus on designing higher quality SMART targets to be included in children's plans. RESULTS: Overall, participants regarded the system as useful. Comparison of targets written before and after the training show improvements in relevance, specificity and on the extent to which they were action-oriented and measurable. CONCLUSIONS: Results are discussed in light of international lessons learned around the potential of the international classification of functioning disability and health to support policy change. A "no policy is an island" approach is proposed, suggesting local policy-makers should open horizons beyond geographical boundaries in evidence-based decision-making for supporting children with disabilities. Implications for rehabilitation The ICF can be regarded as a useful framework for supporting professionals developing targets for children with Education Health and Care (EHC) plans in England. For developing SMART targets with the ICF, professionals can use the taxonomy to look for detailed aspects of functioning, relevant to a certain developmental stage. Using the ICF can support in making more measurable targets in EHC plans if the universal qualifier scale is applied when describing detailed aspects of functioning. Professionals trained on the ICF recognise its usefulness for writing EHC targets. More in-depth training is recommended for supporting the development of more holistic biopsychosocial EHC plans in England. PMID- 30457362 TI - LOX/LOXL in pulmonary fibrosis: potential therapeutic targets. AB - Lysyl oxidase (LOX) and lysyl oxidase-like proteins (LOXL), a family of extracellular matrix (ECM) crosslinking enzymes that have been recognised as playing an important role in fibrogenesis for more than 40 years, are logical targets for antifibrotic treatments. Pulmonary fibrosis, especially idiopathic pulmonary fibrosis (IPF), is a progressive and lethal disease characterised by excessive deposition of ECM in the lung parenchyma. In this review, we discuss the current clinical approaches for IPF and review members of LOX family-LOX, LOXL1, LOXL2, LOXL3 and LOXL4 in IPF patients and in animal models of bleomycin induced pulmonary fibrosis. Although these findings are controversial and require further validation, LOX/LOXL1/LOXL2 as potential therapeutic targets for IPF deserve continued attention. So far to our knowledge, LOXL3 or LOXL4 has not clearly shown specific therapeutic potential. PMID- 30457363 TI - Association of Methylation Signatures at Hepatocellular Carcinoma Pathway Genes with Adiposity and Insulin Resistance Phenotypes. AB - Obesity and type 2 diabetes mellitus are independent risk factors for the onset and progression of hepatocellular carcinoma (HCC). This study aimed to analyze the association of DNA methylation signatures at HCC pathway genes with obesity and related metabolic disturbances. A population of 474 adults within the Methyl Epigenome Network Association (MENA) project was included. DNA methylation levels were measured in white blood cells by microarray. The identification and discrimination of HCC pathway genes were performed using KEGG and PathDIP databases. Anthropometry measurements, the blood metabolic profile, and clinical data were analyzed. The methylation patterns of 20 CpG sites at HCC pathway genes strongly correlated with BMI (FDR <0.0001). These genes encompassed GADD45A, MTOR, FRAT2, E2F3, WNT7B, FRAT1, LRP5, DPF3, GSTA2, APC, MYC, WNT10B, ARID1B, AKT1, GSTA1, WNT5A, CDK4, GAB1, TCF7, which statistically contributed to the regulation of the HCC pathway (P = 2.10e-07). The main biological process where these genes were implicated included uncontrolled cell proliferation, DNA damage, increased survival, and altered oncogenic expression. Interestingly, 9 out of 20 BMI-associated CpGs also correlated with waist circumference and HOMA-IR index. In conclusion, pathway analysis revealed potential associations of DNA methylation signatures at HCC pathway genes with adiposity and insulin resistance phenotypes. PMID- 30457364 TI - Stimulus Characteristics in Picture Story Exercise Cards and Their Effects on the Social Cognition and Object Relations Scale-Global Rating Method. AB - This study examined the effects of stimulus characteristics from the Picture Story Exercise (PSE; Smith, 1992 ) on the quality of social cognition and object relational functions as expressed in narrative responses. A nonclinical sample of 140 adults told stories to five PSE cards. Three trained raters scored the narratives using the Social Cognition and Object Relations Scale-Global Rating Method (SCORS-G; Stein & Slavin-Mulford, 2018 ). Data were then analyzed to determine the extent to which different PSE cards elicited more pathological or more adaptive ratings on the 8 SCORS-G dimensions. Results showed that different cards produced reliable and significant differences in ratings on different SCORS G dimensions. These results extend findings of previous research (Siefert et al., 2016 ; Stein et al., 2014 ) that used the SCORS-G with Thematic Apperception Test (Murray, 1943 ) cards to a unique and previously unexplored stimulus set. The implications of these findings on the use and interpretation of the PSE and SCORS G are discussed. PMID- 30457365 TI - The Power of the Single Story: Surrogacy and Social Media in Israel. AB - Analyzing interviews with 20 Jewish-Israeli gestational surrogates who gave birth in 2014-2016, I examine the common narrative structure of their personal stories and the way that this becomes what Adichie calls a "single story". This idealized, romanticized, utopian story includes: 1. an intimate bond between surrogate and intended parents; 2. an epic birth; 3. a happy ending, told publicly. After illustrating this structure, I present the consequences of this single story for surrogates whose experiences diverged from, yet were constantly compared to, the "perfect journey" narrative. Anthropologists of reproduction must pay careful attention to digital storytelling as a new reproductive technology. PMID- 30457367 TI - Preventing infection in surgical patients. PMID- 30457368 TI - Transforming the landscape. PMID- 30457366 TI - ABM Clinical Protocol #7: Model Maternity Policy Supportive of Breastfeeding. AB - A central goal of The Academy of Breastfeeding Medicine is the development of clinical protocols for managing common medical problems that may impact breastfeeding success. These protocols serve only as guidelines for the care of breastfeeding mothers and infants and do not delineate an exclusive course of treatment or serve as standards of medical care. Variations in treatment may be appropriate according to the needs of an individual patient. PMID- 30457369 TI - Improving end-of-life care. AB - Janet Scammell, Associate Professor (Nursing), Bournemouth University, considers the importance of education in ensuring nurses have the knowledge and skills to deliver person-centred care at the end of life. PMID- 30457371 TI - Regulation is what we need. PMID- 30457370 TI - Transanal irrigation for bowel dysfunction: the role of the nurse. PMID- 30457372 TI - Monitoring a pulse in adults. AB - Jaden Allan, Senior Lecturer in Adult Nursing, Northumbria University ( jaden.allan@northumbria.ac.uk ) and Karen Sheppard, Sister, Critical Care, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, provide a how-to guide on taking a pulse in adult patients. PMID- 30457373 TI - Urinary catheters PART 1. AB - Barry HIll, Senior Lecturer in Adult Nursing at Northumbria University ( barry.hill@northumbria.ac.uk ), and Michelle Mitchell, Graduate Tutor for Adult Nursing at Northumbria University, discuss the reasons for urinary catheterisation, the different types of catheter and the potential problems patients need to be aware of. PMID- 30457374 TI - Self-confidence and attitude of acute care nurses to the presence of family members during resuscitation. AB - AIM:: the present study aimed to assess the relationship between attitude to the presence of family members during cardiopulmonary resuscitation and confidence of acute care nurses in performing cardiopulmonary resuscitation in the presence of family. METHODS:: this descriptive-analytical study was conducted on nurses working in acute care units (intensive care unit, coronary care unit, and emergency department) in Iran in 2017. A total of 150 nurses entered the study by convenience sampling. Data were collected on nurses' attitude towards the presence of family scale and nurses' self-confidence in presence of family scale. RESULTS:: of the 150 participants, 48 (32%) were men and 102 (68%) were women. Total mean score of attitude was 67+/-10.4 (obtained scores by nurses ranged from 32 to 100). Total mean score of self-confidence was 53.86 +/-11.7 (obtained scores by nurses ranged from 23 to 81). Pearson correlation test showed a significant negative relationship between nurses' attitude toward presence of family members during cardiopulmonary resuscitation and their self-confidence (rr=-0.45, p=0.001). CONCLUSION:: the present study showed that nurses with a higher self-confidence have a more positive attitude toward presence of family members during cardiopulmonary resuscitation. Given the importance of the subject, it should be considered by nursing managers and planners. PMID- 30457375 TI - Working with a patient with an autism spectrum condition. AB - Chris Barber, Visiting Lecturer (Learning Disabilities), Birmingham City University ( chris.barber@bcu.ac.uk ), offers tips for nurses working with adults with autism spectrum conditions. PMID- 30457376 TI - The right to aftercare: identifying the responsible bodies. AB - In the second article on the right to aftercare under the Mental Health Act 1983 , section 117, Richard Griffith considers the identification of the body responsible and whether patients can be charged for their aftercare. PMID- 30457377 TI - Causes of hypothermia and the use of patient-rewarming techniques. PMID- 30457378 TI - Literature review of clinical benefits and reasons to prescribe palliative oxygen therapy in non-hypoxaemic patients. AB - AIMS:: to review current guidelines and studies available to health professionals in the UK and explore the literature to identify reasons for the prescription of palliative oxygen therapy in non-hypoxaemic patients. BACKGROUND:: oxygen therapy is often associated with the palliative treatment for breathlessness. Although prescription guidelines are available and the risks of oxygen therapy are known, the therapy is still prescribed for non-hypoxaemic patients. DESIGN:: a literature search was conducted using relevant databases. Cited evidence from published guidelines was also consulted. RESULTS:: the findings suggest that oxygen is no more effective than room air for treating dyspnoea for non hypoxaemic patients, although two small studies of self-reported benefits from patients and carers indicate different perceptions of need. CONCLUSION:: the findings suggest that there is a knowledge gap with regards understanding the reasons for the prescription of oxygen therapy for non-hypoxaemic patients. PMID- 30457379 TI - Solving the 'stranded patient' problem. AB - Sam Foster, Chief Nurse, Oxford University Hospitals, explains the steps being taken to improve collaboration between health and social care in her trust area to ensure patients are sent home promptly and safely. PMID- 30457380 TI - No room for complacency in patient safety in the NHS. AB - John Tingle, Associate Professor (Teaching and Scholarship), Nottingham Trent University, discusses the speech recently given by Health and Social Care Secretary Matt Hancock at The King's Fund. PMID- 30457381 TI - Development of an e-learning programme to improve knowledge of interprofessional education. AB - Evidence has highlighted the importance of interprofessional education in relation to the promotion of collaborative team working and the ultimate reduction in communication errors between health professionals. The establishment of interprofessional education in undergraduate healthcare programmes prepares students for interprofessional collaboration, which is vital to the delivery of safe patient care. Using a logic model approach an interprofessional education e learning programme was developed and made available to healthcare students to undertake during their clinical practice experiences. This article describes how a logic model process was used to develop and implement this interprofessional education e-learning programme for use by undergraduate healthcare students. PMID- 30457382 TI - Best interest versus advance decisions to refuse treatment in advance care planning for neurodegenerative illness. AB - This article describes the role of nurses assisting people with degenerative illness in advance care planning (ACP) for a time when they may lose decision making capacity. It looks at the concept of advance decisions to refuse treatment (ADRT), as defined in the Mental Capacity Act 2005 , exploring the legal, ethical and philosophical ramifications of carrying out, or overriding, formerly expressed wishes of someone who has subsequently lost decision-making capacity. It uses an illustrative composite case study of an individual with Huntington's disease whose prognosis includes future deterioration in swallowing, together with consideration of whether to have or refuse a percutaneous endoscopic gastrostomy. The author, who as part of his role cares for people with neurodegenerative conditions, including Huntington's disease, discusses the difficulties and dilemmas that nurses experience with ADRTs, drawing on personal experience. He suggests that, rather than focusing on ADRTs, ACP may be most effective in preparing people and their surrogates to make real-time decisions, based on a shared understanding of the individual's values. PMID- 30457383 TI - Does listening to music preoperatively reduce anxiety? An evidence-based practice process for novice researchers. AB - This article discusses the development of a clinical research question, the execution of a systematic literature search strategy, and the critical appraisal of a selected article. It demonstrates an evidence-based review process used by nurses to critique and evaluate the evidence used to support their work. This review was conducted by a novice researcher under the supervision of his lecturer. Learning to conduct an evidence-based practice review enables health professionals to understand how to systematically review primary research relating to clinical practice. This learning experience identified the many facets of a research study that need to be considered to ascertain the validity of the results, and their relevance and application to clinical practice. PMID- 30457384 TI - The final NMC standards for the education of nursing associates. AB - Emeritus Professor Alan Glasper, from the University of Southampton, discusses the recently published set of educational standards for the training of nursing associates in England. PMID- 30457385 TI - Thoughtful, focused time 'being' with families is integral to nursing care. PMID- 30457386 TI - Community hospital closures and the impact on older people. PMID- 30457387 TI - An Optimized Multilocus Variable-Number Tandem Repeat Analysis Typing Scheme for Listeria monocytogenes from Three Western Provinces in China. AB - Listeria monocytogenes is a foodborne pathogen worldwide. Multilocus variable number tandem repeat analysis (MLVA) has been used for listeriosis surveillance and outbreak investigations. MLVA typing schemes have been proposed, but their usefulness for typing isolates from the People's Republic of China has not been assessed. To this aim, all L. monocytogenes strains (79) isolated from 1,445 raw meat and abattoir environmental samples of three western provinces in China were characterized with PCR serogrouping, multilocus sequence typing, and MLVA. The isolates were typed into the four PCR serogroups IIb (38.0%), IIc (26.6%), IIa (24.0%), and IVb (11.4%), with a Simpson's index (SI) of 0.7235. With multilocus sequence typing, they were typed into 18 sequence types (STs), including two new STs, ST1029 and ST1011, with an SI of 0.8880. With the 14 MLVA loci from the previous five schemes, the isolates were typed into 39 MLVA genotypes, with an SI of 0.9656. The typing data indicated that MLVA had the highest typing capability among the three methods. A subsequent optimization analysis identified an optimal combination of eight loci (LMV2, LMV9, LMV1, Lm10, Lm11, Lm15, Lm23, and LMTR6) producing the same SI as that of the 14 loci. The present optimized combination shared only six loci with the optimal nine-loci combination proposed in Australia, verifying for the first time that the optimal combinations varied with the isolates' sets. The current optimal typing scheme was ideal for L. monocytogenes isolates from western China. PMID- 30457388 TI - Microbiological Safety of Fresh Tilapia ( Oreochromis niloticus) from Kenyan Fresh Water Fish Value Chains. AB - This study evaluated the microbiological safety of fresh Nile tilapia ( Oreochromis niloticus) from Kenyan fresh water fish value chains. One hundred seventy-six fish samples were analyzed. The microbial counts of hygiene indicators, total viable aerobic count (TVC), total coliforms, and fecal coliforms isolated by using culture techniques were enumerated, and microbial pathogens present in the fish samples were identified and characterized by using molecular methods. The diversity of bacterial isolates was determined by using the Shannon-Weaver diversity index. The mean of TVC in the samples was 4.44 log CFU/g. A comparison with the European Commission and International Commission on Microbiological Specifications for Foods standards showed two fish samples had counts above the 5.00 log CFU/g limit for TVC, and all the fish samples had total coliform and fecal coliform counts above 2.00 and 1.00 log CFU/g, respectively. Pathogenic strains, including Shiga toxin-producing and enteropathogenic Escherichia coli, Listeria monocytogenes, Yersinia enterocolitica, Klebsiella pneumoniae, and Salmonella enterica, were identified in the fish samples. The diversity of 1,608 bacterial isolates was higher in semiregulated chains than unregulated chains. The diversity was also high at the retail stage of the fish value chain. In conclusion, fresh Nile tilapia samples were above some of the set food safety standards and may be a source of foodborne pathogens. Further microbial risk assessment for detected pathogens is recommended to further support public health protection, taking into account growth, inactivation through cooking, processing, survival, and consumption. PMID- 30457389 TI - Molecular Characterization and Antibiotic Resistance of Foodborne Pathogens in Street-Vended Ready-to-Eat Meat Sold in South Africa. AB - The consumption of food contaminated with microbial populations remains a key route of foodborne infection in developing countries and creates a serious public health burden. This study aimed at identifying foodborne pathogens and their antibiotic resistance profiles in ready-to-eat meat sold in public eateries in the Johannesburg area. A total of 115 samples were examined for the incidence of bacteria pathogens and their antibiotic resistance profiles against commonly used antibiotics (ampicillin, tetracycline, chloramphenicol, erythromycin, ciprofloxacin, streptomycin, and sulphonamides) using the molecular and the disc diffusion methods. Fifteen bacteria species were detected in the samples. Staphylococcus aureus had the highest prevalence (25%), and 53.33% of the isolates exhibited multidrug resistance to the antibiotics tested. Among the isolated bacteria, S. aureus was resistant to at least six antimicrobial agents, whereas 100% of S. aureus, Enterococcus faecalis, and Planomicrobium glaciei were resistant to streptomycin, ciprofloxacin, and chloramphenicol, respectively. This study revealed that a wide diversity of bacteria species contaminate meat sold on the street, which indicates that consumers of ready-to-eat meat sold in public eateries are at risk of food poisoning. Hence, strict intervention strategies should be put in place by government agencies to reduce the menace of food poisoning in the country. PMID- 30457390 TI - Effects of Chitosan and Natamycin on Vacuum-Packaged Phyllo: A Pastry Product. AB - The effects of vacuum packaging, chitosan (1.5%, w/v), and natamycin (10 mg/L, w/v) on phyllo pastry quality were studied by monitoring microbiological, chemical, and sensory changes. Five lots were prepared with or without vacuum packaging, chitosan, and natamycin: A, air packaged (control); V, vacuum packaged; VC, vacuum packaged with chitosan; VN, vacuum packaged with natamycin; and VCN, vacuum packaged with both chitosan and natamycin. Based on the sensory acceptability data, a shelf life of 6 (A), 12 (V), 14 (VN), 16 (VC), and 17 (VCN) days was obtained at 4 degrees C. VCN treatment resulted in a shelf life extension of 11 days compared with the shelf life of the control. Microbiological data revealed that the combination of chitosan and natamycin resulted in significant reductions of microbial species (mesophilic total viable counts, yeasts and molds, psychrotrophic bacteria, lactic acid bacteria, Enterobacteriaceae, and enterococci) of 1 to 3 log CFU/g on the final day (day 18) of storage. Results suggest that the combination of chitosan and natamycin, which is an effective antifungal agent, can delay the spoilage of phyllo pastry while maintaining acceptable sensorial characteristics and the original freshness and appearance of the product. PMID- 30457392 TI - Child and parent perspectives of life quality of children with physical impairments compared with non-disabled peers. AB - BACKGROUND: Life quality has become a widely used concept within rehabilitation and occupational therapy practice. AIM: This study explored child and parent perspectives of life quality of children with physical impairments compared with a group of non-disabled children. METHOD: Data were collected with the Icelandic self- and proxy-reported versions of the KIDSCREEN-27. For children with physical impairments, reports from 34 children and 40 parents were included in the analyses, and in control group reports from 429 children and 450 parents were included. RESULTS: Children with physical impairments evaluated their life quality within the average range on four out of five life quality dimensions. The lowest scores were within the physical well-being dimension. Self-reported scores of children with physical impairments were higher than those of their parents on all dimensions except autonomy and parent relations. Thus, the parents considered more environmental and personal factors to negatively influence their child's life quality than children did themselves. CONCLUSION: Children with physical impairments experience their life quality similarly to non-disabled children. SIGNIFICANCE: Focus on life quality can help occupational therapists to identify what circumstances positively or negatively influence client well-being and to focus more on contextual factors that contribute to disablement. PMID- 30457391 TI - Peritoneal microdialysis as a tool for detecting anastomotic leakage in patients after left-side colon and rectal resection. A systematic review. AB - OBJECTIVE: The objective was to evaluate peritoneal microdialysis in the detection of clinical anastomotic leakage after left-sided colon and rectal resection through a systematic review. METHODS: A systematic review (PRISMA guidelines) based on a systematic search through PubMed, Cochrane Library, and EMBASE (1 February 2017) was performed. Methodological index of non-randomised studies score was selected to assess the methodological quality. Patient demographics and raw data for intraperitoneal microdialysis concentrations of glucose, lactate, glycerol and pyruvate for 5 d postoperative were obtained from the respective study groups. RESULTS: Ten studies with a total of 128 patients were included. Thirty (23%) patients developed clinical anastomotic leakage. The area under the curve for intraperitoneal lactate concentration was significant higher in patients with anastomotic leakage (58.2; 95% CI 39.2, 77.2) compared with the no leakage group (41.0; 95% CI 35.2, 46.1; p = .007). Receiver operating characteristic curve analysis of the maximum measured lactate concentration demonstrated 25% sensitivity, 88% specificity and 74% accuracy for AL at a cut off value of 9.8 mmol/L. The odds ratio for a 5 mmol/L increase in lactate in relation to the risk of AL was 2.9 (CI 1.1, 8.0). CONCLUSIONS: Increased intraperitoneal lactate concentration within the first 5 d postoperative was significantly associated with clinical anastomotic leakage, but with low predictive values. The microdialysis method is not yet ready for clinical implication before large prospective studies have defined cut off values for a biologic marker in the setting of a clear definitions of leakage. PMID- 30457393 TI - Current diagnostic strategies for dilated cardiomyopathy: a comparison of imaging techniques. AB - INTRODUCTION: Dilated cardiomyopathy (DCM) is generally thought as a final common pathway of several conditions leading to the same clinical phenotype. Multiple imaging modalities play a fundamental role in recognizing the underlying pathological substrate in DCM. Areas covered: Echocardiography represents the first reliable and easily accessible diagnostic tool, allowing the identification of associated cardiac abnormalities, such as valve disease and highlighting features associated with an adverse prognosis. Recent advances in technology such as strain analysis and 3D-echocardiography have improved the diagnostic and prognostic capabilities of this technique. Cardiac magnetic resonance (CMR) is considered the gold standard for an accurate and reproducible assessment of ventricular volumes and ejection fraction. In addition, CMR allows us to perform tissue characterization that, through new sophisticated sequences, could be obtained even without gadolinium. Nuclear images could be useful to identify specific causes of left ventricular dysfunction, such as cardiac sarcoidosis and amyloidosis. Finally, endomyocardial biopsy is generally performed if acute myocarditis is suspected in high-risk patients. Expert commentary: Strengths and limitations are different for every method, but multiparametric evaluation of patients and family members could progressively improve current understanding of the disease. This is fundamental to specifically target therapy, allowing us to improve patients' prognosis. PMID- 30457395 TI - Vortioxetine: a novel antidepressant for the treatment of major depressive disorder. AB - INTRODUCTION: Vortioxetine is a novel antidepressant drug approved for the treatment of major depressive disorder (MDD) in adults. It is formulated into tablets and has a dose range of 5-20 mg. The recommended starting dose is 10 mg administered orally once daily without the need for food. Areas covered: This review focuses on the preclinical and clinical discovery of vortioxetine. It analyzes the pharmacological, neurochemical, and behavioral mechanisms of the medication and how these contribute to its potential therapeutic advantages as described in published preclinical and clinical studies and product labels. Expert opinion: Vortioxetine displays high affinity for serotonin transporter (SERT), and serotonin 5-HT3, 5HT1A, 5HT7 receptors. Functional studies show that vortioxetine acts as a SERT blocker, a 5-HT3, 5-HT7 receptor antagonist, and a 5 HT1A receptor agonist. The drug is active in animal models predictive of antipsychotic and antidepressant activities and demonstrates procognitive effects in several animal models that assessed memory, cognition, and executive functions. Short- and long-term clinical trials demonstrated the clinical efficacy of vortioxetine in treating depressive symptoms and cognitive deficits in MDD patients. It also displays fairly benign safety and tolerability profiles. Vortioxetine's unique psychopharmacological properties might contribute to an improved clinical outcome in MDD patient populations. PMID- 30457394 TI - Clinical presentation and treatment of catameinal pneumothorax and endometriosis related pneumothorax. AB - INTRODUCTION: Catamenial pneumothorax (CP) is defined as a recurrent spontaneous pneumothorax occurring in females of reproductive age. In the 'perimenstrual period,' it is still considered relatively rare although accounting for 20-35% of spontaneous pneumothoraces occurring in premenopausal women. It is the most frequent manifestation of thoracic endometriosis, which can also cause pneumothorax during the intermenstrual period (TER non-CP). Areas covered: In this article, we review and comment the clinical presentation, etiopathogenesis, diagnostic criteria, and therapeutic management of CP and TER non-CP. We particularly emphasize on the surgical optimal treatment and associated multidisciplinary care and follow-up. Electronic databases, mostly PubMed, were used for searching terms including 'catamenial pneumothorax' and 'thoracic endometriosis.' Expert commentary: Clinical presentation and imaging of CP and TER non-CP are often unspecific except for possible visualization of endometriosis foci or diaphragmatic lesions at computed tomography-scan or magnetic resonance imaging. Thus, we recommend careful interrogatory and intraoperative inspection for appropriate diagnosis and treatment of pneumothorax in women. Despite better awareness of surgical teams, CP and TER-non CP are still associated with high rates of postoperative recurrence (around 30%). We strongly advocate for a multidisciplinary management including early surgical and chemical pleurodesis, resection of all visible endometriosis-related lesions, hormonal blockade, and prolonged follow-up. PMID- 30457396 TI - Evaluation and comparison of different prehospital triage scores of trauma patients on in-hospital mortality. AB - INTRODUCTION: Several prehospital major trauma patient triage scores have been developed, the triage revised trauma score (T-RTS), Vittel criteria, Mechanism/Glasgow Coma Scale/Age/Systolic blood pressure score (MGAP) and the new trauma score (NTS). These scoring schema allow a rapid and accurate prognostic assessment of the severity of potential lesions. The aim of our study was to compare these scores with in-hospital mortality predictions in a cohort of consecutive trauma patients admitted in a Level 1 trauma center. MATERIALS: Between 2013 and 2016, 1,112 patients were admitted to the "major trauma" spinneret of a Level 1 trauma center in the south of France. All prehospital data needed to calculate the T-RTS, Vittel criteria, the MGAP score and the NTS were collected. The main evaluation criterion was in-hospital mortality at 30 days for all causes. The predictive performances of these scores were evaluated and compared with each other using the analysis of the receiver operating curves. RESULTS: A total of 1,001 patients were included in the analysis, 238 (24%) females, aged 43 +/- 19 years with ISS 15 +/- 13. The area under the curve was for each score: T-RTS, AUC =0.84, [0.82-0.87]; Vittel criteria, AUC =0.87 [0.85 0.89]; MGAP score, AUC =0.91 [0.89-0.92] and NTS, AUC =0.90 [0.88-0.92]. By comparing the ROC curves of these scores, the MGAP and NTS scores were statistically higher than the T-RTS. With the current thresholds, the sensitivity, specificity, positive and negative predictive values of these scores were 91%, 35%, 10%, 98% for T-RTS, 100%, 2%, 8%, 100% for Vittel criteria, 91%, 71%, 24%, 99% for MGAP score, 82%, 86%, 33%, 98% for NTS. Only Vittel's criteria allowed undertriage below 5% as recommended by the American College of Surgeons Committee on Trauma (ACSCOT). CONCLUSION: The comparison of these different triage scores concluded with a superiority of the MGAP and NTS scores compared with the T-RTS. Including the calculation of MGAP or NTS scores with the Vittel criteria would reduce the risk of overtriage in the Level 1 trauma centers by further directing patients at low risk of death to a lower-level trauma facility. PMID- 30457397 TI - What medical education can learn from the fashion industry. PMID- 30457398 TI - How to evaluate patients with congenital heart disease-related pulmonary arterial hypertension. AB - INTRODUCTION: Patients with congenital heart disease (CHD), who develop pulmonary arterial hypertension (PAH), live longer and have better quality of life compared to the past due to PAH specific therapy and improved tertiary care. Areas covered: Clinical examination, objective assessment of functional capacity, natriuretic peptide levels, cardiac imaging and haemodynamics all play a pivotal role in the evaluation, general care and management of PAH specific therapy. This review discusses the epidemiology and pathophysiology of PAH-CHD, and provides hints for the optimal evaluation of these patients. Expert commentary: Further research should be performed in the field of PAH-CHD, as there are many of areas lacking evidence that should be addressed in the future. Networking, especially among the tertiary expert centres, could play a key role in this direction. PMID- 30457399 TI - Using virtual reality for drug discovery: a promising new outlet for novel leads. AB - INTRODUCTION: Virtual reality (VR) environments are increasingly being used by researchers in various fields in addition to being increasingly integrated into various areas of human life, ranging from videogames to different industrial uses. VR can be used to create interactive and multimodal sensory stimuli and thus offers unique advantages over other computer-based approaches for scientific research and molecular-level applications. Consequently, VR is starting to be used in novel drug development, such as in drug discovery, and rational drug design. Areas covered: In this review, the authors discuss the basic development of VR technology, including the available hardware and software. The latest advances of VR technology in novel drug development are then detailed, and the VR programs that can be applied in relevant studies are highlighted. Expert opinion: VR will lead to a revolution in pharmaceutical development. However, there are still obstacles to the successful and extensive application of VR to drug development, including the demand for further improvements to the available hardware and software and the various limitations described with regard to accuracy and precision. As technology continues to improve, the barriers to the widespread adoption of VR will diminish and VR technologies will play an increasingly important role in novel drug development. PMID- 30457400 TI - Prognostic impact of melphalan dose and total body irradiation use in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation with reduced-intensity conditioning. AB - To evaluate the prognostic impact of melphalan dose and total body irradiation (TBI) use in acute myeloid leukemia patients undergoing reduced-intensity allogeneic transplantation, we retrospectively compared outcomes of patients receiving a higher-dose (120-140 mg/m2, n = 379) or lower-dose melphalan (80-110 mg/m2, n = 128) with or without TBI of <=4 Gy. At 3 years, overall survival was 48.9% in the higher-dose group versus 40.3% in the lower-dose group (p = .013). This survival benefit was attributed to lower tumor-related mortality (23.9% vs. 31.7%; p = .049). Non-relapse mortality did not differ (24.8% vs. 23.5%, p = .59). The beneficial effect of a higher-dose melphalan was more evident when combined with TBI in younger patients, those not in complete remission, and those with good performance status. Our findings support the use of a higher-dose melphalan in combination with TBI for reduced-intensity conditioning in physically fit patients. PMID- 30457401 TI - Defining sensory modulation: A review of the concept and a contemporary definition for application by occupational therapists. AB - BACKGROUND: Sensory interventions are prevalent amongst adult mental health practitioners and are supported by major stakeholders and policy makers across the world. The term commonly used by occupational therapists applying sensory practices is sensory modulation, however this term has evolved. AIMS: This paper aims to investigate and clarify the definition of 'sensory modulation' for application by occupational therapists. METHOD: A framework guided this concept analysis on sensory modulation. A summative content analysis approach was employed to code results. RESULTS: Six conceptual themes for sensory modulation were identified. 81% of authors defined sensory modulation as consisting of more than one of these themes. 18% of authors defined sensory modulation as both a neurophysiological process and means to regulate behaviour. CONCLUSION: The concept of sensory modulation has evolved in occupational therapy practice. The authors summarise with the following proposed definition of sensory modulation for contemporary occupational therapy practice: 'Sensory modulation is considered a twofold process. It originates in the central nervous system as the neurological ability to regulate and process sensory stimuli; this subsequently offers the individual an opportunity to respond behaviourally to the stimulus'. SIGNIFICANCE: A contemporary definition of 'sensory modulation' has been identified for occupational therapy practice. PMID- 30457402 TI - The Bayesian borderline regression method: Identifying pass marks for small cohorts. PMID- 30457403 TI - Post-translational and transcriptional dynamics - regulating extracellularvesicle biology. AB - INTRODUCTION: Extracellular vesicles (EVs) are secreted into their extracellular environment, contain a specific repertoire of cellular cargo, and represent a novel vehicle for cell-cell communication. Protein post-translational modifications (PTMs) are emerging as major effectors of EV biology and function, and in turn, regulate cellular signaling. Areas covered: Discovery and investigation of PTMs such as methylation, glycosylation, acetylation, phosphorylation, sumoylation, and many others has established fundamental roles for PTMs within EVs and associated EV function. The application of enrichment strategies for modifications, high-resolution quantitative mass spectrometry based proteomics, and improved technological approaches have provided key insights into identification and characterization of EV-based PTMs. Recently, an overwhelming appreciation for the diversity of modifications, including post transcriptional modifications, dynamic roles of these modifications, and their emerging interplay, including protein-protein, protein-lipid, protein-RNA, and variable RNA modifications, is emerging. At a cellular level, such interplay is essential for gene expression/genome organization, protein function and localization, RNA metabolism, cell division, and cell signaling. Expert commentary: The understanding of these modifications and interactions will provide strategies toward how distinct cargo is localized, sorted, and delivered through EVs to mediate intercellular function, with further understanding of such modifications and intermolecular interactions will provide advances in EV-based therapeutic strategies. PMID- 30457404 TI - Sirolimus in Liver Transplant Recipients With Hepatocellular Carcinoma. PMID- 30457406 TI - Perspectives of UK medical students on the introduction of the adaptive curriculum in the USA. PMID- 30457405 TI - Remote and onsite scoring of OSCEs using generalisability theory: A three-year cohort study. AB - INTRODUCTION: Onsite scoring is common in traditional OSCEs although there is the potential for an audience effect facilitating or inhibiting performance. We aim to (1) analyze the reliability between onsite scoring (OS) and remote scoring (RS); and (2) explore the factors that affect the scoring in different locations. METHODS: A total of 154 students and 84 raters were enrolled in a single-site during 2013-2015. We selected six stations randomly from a 12-station national high-stakes OSCE. We applied generalisability theory for the analysis and investigated the perceptions that affected RS scoring. RESULTS: The internal consistency reliability Cronbach's alpha of the checklists was 0.92. The kappa agreement was 0.623 and the G value was 0.93. The major source of variance comes from the students themselves, but some from locations and raters. The three component analysis including Technical Feasibility, Facilitates Wellbeing, and Observational and Attention Deficits explained 73.886% of the total variance in RS scoring. CONCLUSIONS: Our study has demonstrated moderate agreement and good reliability between OS and RS ratings. We validated the factors of facility operation and quality for RS raters. Remote scoring can provide an alternative forum for the raters to overcome the barriers of distance, space, and avoid the audience effect. PMID- 30457407 TI - Meningococcal B vaccine: The journey from research to real world experience. AB - INTRODUCTION: Neisseria meningitidis serogroup B (MenB) is the most common cause of bacterial meningitis in many industrialized countries and occurs at any age. The highest incidence is in infants aged <1 year, followed by children and adolescents. Four-component MenB vaccine (4CMenB, Bexsero) is the only MenB vaccine authorized for use in all age-groups. Experience with 4CMenB is growing as it is implemented in different countries/age-groups encompassing university students, children, adolescents, and infant mass vaccination programs. Areas covered: An update of recently available data describing the mechanism of immunogenicity of 4CMenB and real-world evidence of vaccine effectiveness and disease impact. We discuss the appropriate age for vaccination to maximize population impacts. Expert commentary: Invasive meningococcal disease is uncommon and sufficiently powered efficacy studies were not feasible during 4CMenB development. Additionally, several thousand genetically diverse invasive MenB strains circulate globally, varying widely in surface protein expression. This posed significant challenges in predicting clinical protection with MenB vaccines. Five years of 4CMenB use post-licensure confirm the clinical benefit of vaccination as predicted during development. Preliminary evidence suggests an extended impact on other meningococcal serogroups and N. gonorrhoeae. PMID- 30457408 TI - Current Status of Liver Transplantation Using Marginal Grafts. AB - The use of marginal liver grafts has become an inevitable option because of the continuous increase in the number of patients awaiting liver transplantation and the severe shortage of suitable donors. Recently, several approaches have been adapted to expand the donor pool and improve the outcome of marginal grafts in both deceased and living donor liver transplantation. Accordingly, this review discusses the various types of marginal grafts in both deceased and living donor liver transplantation, their outcome and the up-to-date innovations or strategies to extend the donor pool and improve the patient and graft survival post transplant. PMID- 30457410 TI - Hey, new faculty.... PMID- 30457409 TI - Molecular characterization of Axenfeld-Rieger spectrum and other anterior segment dysgeneses in a sample of Mexican patients. AB - BACKGROUND: Anterior segment dysgenesis (ASD) and Axenfeld-Rieger spectrum (ARS) are mainly due to PITX2 and FOXC1 defects, but it is difficult in some patients to differentiate among PITX2-, FOXC1-, PAX6- and CYP1B1-related disorders. Here, we set out to characterize the pathogenic variants (PV) in PITX2, FOXC1, CYP1B1 and PAX6 in nine unrelated Mexican ARS/ASD patients and in their available affected/unaffected relatives. MATERIALS AND METHODS: Automated Sanger sequencing of PITX2, FOXC1, PAX6 and CYP1B1 was performed; those patients without a PV were subsequently analyzed by Multiplex Ligation-dependent Probe Amplification (MLPA) for PITX2, FOXC1 and PAX6. Missense variants were evaluated with the MutPred, Provean, PMUT, SIFT, PolyPhen-2, CUPSAT and HOPE programs. RESULTS: We identified three novel PV in PITX2 (NM_153427.2:c.217G>A, c.233T>C and c.279del) and two in FOXC1 [NM_001453.2:c.274C>T (novel) and c.454T>A] in five ARS patients. The previously reported FOXC1 c.367C>T or p.(Gln123*) variant was identified in a patient with ASD. The ocular phenotype related to FOXC1 included aniridia, corneal opacity and early onset glaucoma, while an asymmetric ocular phenotype and aniridia were associated with PITX2. No gene rearrangements were documented by MLPA analysis, nor were any PV identified in PAX6 or CYP1B1. CONCLUSIONS: Heterozygous PV in the PITX2 and FOXC1 genes accounted for 66% (6/9) of the ARS/ASD cases. The absence of PAX6 or CYP1B1 abnormalities could reflect our small sample size, although their analysis could be justified in ARS/ASD patients that present with congenital glaucoma or aniridia. PMID- 30457411 TI - Mometasone furoate sinus implant - a new targeted approach to treating recurrent nasal polyp disease. AB - INTRODUCTION: Chronic rhinosinusitis (CRS) is a broad heterogeneous inflammatory disorder of the nose and paranasal sinuses, resulting from the dysfunctional interplay between host immunity, defective epithelial barrier, and environmental factors. CRS with nasal polyps (CRSwNP) is considered a more severe clinical phenotype with greater burden of symptoms and higher relapse rate, especially with comorbid asthma or aspirin sensitivity. Available treatment options after endoscopic sinus surgery (ESS) - systemic corticosteroids or revision surgery - have significant risks and limitations. Areas covered: Bioabsorbable, steroid eluting implants have been studied extensively for the ability to dilate and re establish sinus patency by the localized, controlled delivery of topical corticosteroids to diseased sinonasal lining and nasal polyps. This review provides a comprehensive, up to date analysis of the literature regarding a novel, office-based, mometasone furoate (MF) sinus implant that may treat patients with recurrent CRSwNP after ESS. Expert commentary: Clinical evidence has demonstrated the safety and efficacy of steroid-eluting implant in the reduction of polyp size, symptom burden, and the need for revision sinus surgery. MF sinus implants may play an important role in the management of patients with recurrent polyposis after sinus surgery. PMID- 30457412 TI - YouTube Videos on Oral Systemic Therapies for Psoriasis: A Cross-Sectional Analysis. PMID- 30457413 TI - Tocilizumab for the Management of Corticosteroid-Resistant Mild to Severe Graves' Ophthalmopathy, a Report of Three Cases. AB - PURPOSE: To discuss the use of tocilizumab in mild to severe Graves' ophthalmopathy as corticosteroid-adjunctive therapy. METHODS: Retrospective case reports. RESULTS: Three patients with corticosteroid-resistant or advanced diplopia-associated Graves' ophthalmopathy were subsequently treated with monthly intravenous tocilizumab at a dose of 8 mg/kg. None reported a past or present history of dysthyroidism. The adjunction of interleukin-6-receptor monoclonal antibody treatment was associated with a significant improvement in ocular symptoms, notably diplopia and proptosis, and functional prognosis in all patients, with one relapse approximately two months after the end of the treatment. CONCLUSION: These clinical reports confirm the relative efficacy and tolerability profile of intravenous tocilizumab in severe or corticosteroid resistant Graves' ophthalmopathy. PMID- 30457414 TI - In-vivo anti-tumor activity of a novel poloxamer-based thermosensitive in situ gel for sustained delivery of norcantharidin. AB - In order to develop a novel norcantharidin (NCTD) delivery system with slow drug release and specific targeting characteristics, we have developed a Poloxamer based NCTD thermosensitive in situ gel. The evaluation of the characteristics of this system using both in vitro and in vivo methods was previously reported. However, its anti-tumor activity in vivo is still not confirmed. Thus, the potential anti-tumor activity and relative mechanism were investigated in a murine H22 hepatoma model. Tumor-bearing mice were treated with different dose of NCTD thermosensitive in situ gel (3.3 mg/kg, 6.6 mg/kg, and 9.9 mg/kg, respectively by intra-tumor injection once every three days, totaling 5 injections per group. Control groups included untreated or NCTD injection (2.2 mg/kg, qd) or blank in situ gel. The expression of vascular endothelial growth factor (VEGF) and CD44 in tumor tissue was examined by immunohistochemistry (IHC) staining. Treatment with middle or high dose of NCTD thermosensitive in situ gel significantly induced tumor regression, inhibited VEGF and CD44 expression and improved survival of tumor-bearing mice. The efficacy of NCTD thermosensitive in situ gel is higher than that of free NCTD injection. Therefore, NCTD thermosensitive in situ gel is a novel NCTD delivery approach for chemotherapeutic treatment of cancer. PMID- 30457415 TI - Novel biomarkers of cardiovascular disease: Applications in clinical practice. AB - Measurement of biomarkers has revolutionized the work-up of patients with suspected cardiovascular disease. The most widely used contemporary cardiovascular biomarkers are the natriuretic peptides in the diagnosis and prognosis of heart failure and cardiac troponins in the diagnosis of acute myocardial infarction. Numerous other biomarkers pertaining to diagnosis, prognosis, and risk prediction have been identified, but few have made their way to clinical practice. In this review, we will initially describe the fundamental approach to evaluate a novel biomarker. Before implementation of a biomarker into clinical practice, several stringent criteria related to its clinical utility are required. Essential statistical metrics such as discrimination, calibration, and reclassification are required to properly evaluate prediction models. We will then discuss the biomarkers according to main groups of cardiovascular pathology:1. myocardial injury (cardiac troponins, heart-type fatty acid-binding protein, cardiac myosin binding protein-C);2. myocardial stress (A-type and B type natriuretic peptides, mid-regional pro-adrenomedullin, copeptin); 3. inflammation (C-reactive protein, interleukin 6, growth differentiation factor 15, soluble suppressor of tumorigenicity 2, galectin-3);4. platelet activation (soluble CD40 ligand, P-selectin);5. plaque instability (lipoprotein-associated phospholipase A2, matrix metalloproteinase-9);6. systemic stress (catecholamines, granin proteins);7. calcium homeostasis (secretoneurin). Finally, we will discuss novel applications of cardiovascular biomarkers, more specifically prediction of ventricular arrhythmias, and the use of biomarkers in composite risk prediction models. PMID- 30457416 TI - Monoclonal antibodies for the treatment of non-hematological tumors: a safety review. AB - INTRODUCTION: The introduction of monoclonal antibodies (moAbs) into clinical practice revolutionized the treatment strategies in several solid tumors. These agents differ from cytotoxic chemotherapy for their mechanism of action and toxicity. By targeting specific antigens present on healthy cells and modulating immune system activity, these biological drugs are able to generate a wide spectrum of peculiar adverse events that can negatively impact on patients' quality of life. Areas covered: In this review, the main side effects associated with the use of moAbs have been described to show their incidence and current management strategies, which may drive clinicians in their daily practice. Expert opinion: The majority of these drugs represents an example of successful innovation, since they are able to induce a significant improvement of patients' survival and quality of life without any increase in related side effects as compared to standard cancer treatments. For this reason, they have become new milestones in personalized therapy for different non-hematological malignancies. With the increasing use of moAbs in treatment regimens, it is strongly recommended that clinicians are knowledgeable about the side effects associated with these agents, their management and monitoring, to optimize the clinical treatment of cancer patients. PMID- 30457417 TI - Let's talk about our mistakes. PMID- 30457418 TI - Influence of Protamine Shell on Nanoemulsions as a Carrier for Cyclosporine-a Skin Delivery. AB - Novel protamine based nanosystems have been studied for cyclosporine-A (CsA) skin delivery. Core-shell structure systems have been developed to this end. These vehicles have particles sizes of 200-300 nm, a low polydispersity index and a zeta potential which varies between -16 mV and +35 mV. The resulting four nanosystems efficiently encapsulated CsA in their oily nucleus (60-80%) and released this drug in a controlled manner. These formulations have shown a high stability in aqueous suspension in storage conditions at 4 degrees C (for at least 21 months) and in acetate buffer at a physiological temperature of 37 degrees C (for at least 24 h). Ex vivo transdermal diffusion experiments using Franz diffusion cells and 2-3 day old pig skin as a biological barrier were performed. All nanoformulations designed produced an increase in CsA transdermal delivery and two of these nanosystems presented a marked promoting effect; the more relevant parameters were smaller particle size (200 +/- 7 nm) and negative superficial charge. Finally, the ability of these nanosystems to enhance retention of CsA in the skin was also studied. The protamine disposition in the shell influenced CsA skin retention. Therefore, the incorporation of CsA into the nanosystems studied here makes them suitable vehicles for CsA transdermal administration. PMID- 30457419 TI - APOE genotypes in Lebanon: distribution and association with hypercholesterolemia and Alzheimer's disease. AB - AIM: We first investigated the distribution of APOE genotypes in Lebanese general population and Alzheimer's disease study (ADS) groups, and compared it with 1000 genomes populations. Then, we assessed eventual association between APOE genotypes, hypercholesterolemia and Alzheimer's disease (AD). MATERIALS & METHODS: This cross-sectional study was conducted on 591 individuals. Clinical and biological data were collected, DNA was extracted and genotyped using Kompetitive allele specific PCR (KASPTM) and PCR-restriction fragment length polymorphis (PCR-RFLP). Results: Prevalence of APOE genotypes in Lebanon was similar to that seen in Asian populations. APOE genotypes were not associated with hypercholesterolemia. A significant difference between APOE genotypes in AD cases versus controls and versus Lebanese general population was seen. Moreover, E4 allele was approximately threefold higher in Alzheimer's disease study patients when compared with the remaining individuals. CONCLUSION: We established the distribution of APOE genotypes in the Lebanon and showed that in contrast to lipid profile, E4 correlates with AD. PMID- 30457420 TI - Silk fibroin nanoparticles for enhanced bio-macromolecule delivery to the retina. AB - The aim of this study was to investigate intravitreal injection of silk fibroin nanoparticles (SFNs) encapsulating bio-macromolecules, achieving enhanced drug bioavailability and extended retention in retina. SFNs were prepared with regenerated silk fibroin (RSF) using desolvation method with fluorescein isothiocyanate labeled bovine serum albumin (FITC-BSA) as bio-macromolecular model drug encapsulated. In vitro physicochemical properties and in vitro drug release of FITC-BSA loaded SFNs (FITC-BSA-SFNs) were evaluated. Cytotoxicity, cellular uptake, and retention of FITC-BSA-SFNs were determined in human retinal pigment epithelial cell line (ARPE-19). In addition, in vivo distribution and safety of intravitreally administered FITC-BSA-SFNs were investigated in New Zealand white rabbits. The particle size of FITC-BSA-SFNs was 179.1 +/- 3.7 nm with polydispersity index (PDI) of 0.102 +/- 0.033 and the zeta potential was greater than -25 mV. FITC-BSA-SFNs exhibited excellent biocompatibility with no cytotoxicity observed within 24 h and 48 h in AREP-19 cells. Compared to FITC-BSA solution, FITC-BSA-SFNs showed enhanced cellular uptake and prolonged retention. Furthermore, FITC-BSA-SFNs achieved accumulated distribution and extended retention in retina in vivo following intravitreal injection compared to a single administration of free drug solution. Therefore, this bio-macromolecule delivery platform based on SFNs could have great potential in the treatment of posterior segment disorders. PMID- 30457421 TI - Impact of a vaccination promotion intervention using motivational interview techniques on long-term vaccine coverage: the PromoVac strategy. AB - BACKGROUND: Delayed vaccinations at 2, 4, and 6 months are associated with a higher probability of delayed age-appropriate vaccination during childhood. This study aimed to assess the effectiveness of an information session on immunization during infancy. METHODS: An individual educational information session with motivational interview techniques for immunization of infants was conducted (experimental group) or not conducted (control group) during postpartum stay in a quasi-experimental cohort study. Immunization data were collected from the Eastern Townships Public Health registry at 3, 5, 7, 13, 19, and 24 months of age. Logistic regressions with repeated measures were performed to assess the intervention's impact. Relative risks (RR) were estimated. A multivariate model was obtained adjusted for confounding factors. RESULTS: The experimental and control groups included 1140 and 1249 families, respectively. In per protocol analysis, a significant increase in VC of 3.2, 4.9, 7.3, 6.7, 10.6, and 5.1% was observed at 3, 5, 7, 13, 19, and 24 months. Children from experimental group had 9% more chance at a complete vaccination status between 3 and 24 months compared to children from control group (RR (95% CI): 1.09 (1.05-1.13), p < .001). Children with complete vaccination status at 3 months were more likely to have a complete vaccination status at 24 months (82.3 vs. 48.1%, RR (95% CI): 2.72 (2.28 3.24), p < .001). After adjustment, the estimated RR of the intervention's impact was 1.05 (1.02-1.07), p < .001. CONCLUSIONS: An educational information session about immunization based on motivational interview techniques conducted during postpartum hospitalization could improve immunization during infancy. PMID- 30457423 TI - Pharmacokinetic interaction between shuanghuanglian and azithromycin injection: A nonlinear mixed-effects model analysis in rats. AB - 1. This study aimed to evaluate the pharmacokinetic interaction of shuanghuanglian (SHL) and azithromycin in rats, and to provide experimental support for rational drug use in clinics. 2. HPLC-UV and HPLC-MS/MS approaches were respectively developed to detect the forsythiaside (active component of SHL) and azithromycin concentrations. Both non-compartmental and compartmental analyses were employed to calculate pharmacokinetic parameters. A nonlinear mixed effects modelling method was applied to fit the drug concentration-time data. The influence of drug coadministration on pharmacokinetic parameters was tested using forward inclusion and backward elimination procedures. 3. After drug co administration, areas under the drug concentration-time curve (AUC) and half lives (T1/2) of both azithromycin and forsythiaside increased significantly, meanwhile, the drug clearance (CL) decreased compared to single drug administration. Both forsythiaside and azithromycin exposures increased after coadministration. Two-compartment models were suitable to describe the in vivo behavior of both azithromycin and forsythiaside. The coadministration of SHL could significantly decrease the central volume of azithromycin (VCA), and forsythiaside clearance (CLF) decreased after co-intravenous administration of azithromycin. 4. Co-intravenous administration of forsythiaside and azithromycin could significantly increase drug exposures for both drugs. Lower dose can provide sufficient drug exposure to obtain antibacterial activity. The coadministration may be a potential method to increase therapy efficiency while decrease adverse drug reactions. PMID- 30457422 TI - Increased in vitro leishmanicidal activity of octyl gallate loaded poly(methyl methacrylate) nanoparticles. AB - The current paucity of effective and affordable drugs for the treatment of leishmaniasis renders the search for new therapeutic alternatives a priority. Gallic acid related compounds display anti-parasitic activities and their incorporation into drug carrier systems, such as polymeric nanoparticles may be a viable alternative for leishmaniasis treatment. Therefore, this study focused on the synthesis and characterization of octyl gallate (G8) loaded poly(methyl methacrylate) (PMMA) nanoparticles via miniemulsion polymerization in order to increase the leishmanicidal activity of this compound. G8 laoded PMMA nanoparticles presented a spherical morphology with a mean size of 108 nm, a negatively charged surface (-33 +/- 5mV) and high encapsulation efficiency (83% +/- 5). FTIR and XRD analysis confirmed that G8 was encapsulated in PMMA nanoparticles and presented a biphasic release profile. The G8 loaded PMMA nanoparticles did not present cytotoxic effect on human red blood cells. G8 loaded PMMA nanoparticles displayed a leishmanicidal activity almost three times higher than free G8 while the cytotoxic activity against human THP-1 cells remained unchanged. PMID- 30457424 TI - Commentary: resolving pertussis resurgence and vaccine immunity using mathematical transmission models. PMID- 30457425 TI - Magnetic extraction of toxin binding liposomes; a method to ameliorate drug toxicity? Preliminary in vitro/ in vivo study. AB - AIM: Removal of a toxin from the body once absorbed is usually not possible. We describe the use of magnetite containing pH gradient 'MagnepH' liposomes to overcome limitations preventing removal. METHODS: MagnepH liposomes were added to albumin solution containing amitriptyline and dosed intravenously in rats prior to amitriptyline injection. Albumin solution or drawn blood was exposed to a magnet and sampled. RESULTS: One third of amitriptyline was extracted in vitro. In vivo amitriptyline concentrations were 1830 nmol/l (controls) and 10870 nmol/l (MagnepH; n = 2). Amitriptyline extraction increased from 0.6% (control) to 10.4% (MagnepH; 95% CI for difference 2.0-17.6%). CONCLUSION: MagnepH liposomes sequestered amitriptyline and could then be extracted. This method has potential to ameliorate limitations to extracorporeal removal of toxins in poisoning. PMID- 30457426 TI - Endobronchial ultrasound transbronchial needle aspiration in elderly patients: safety and performance outcomes EBUS-TBNA in elderly. AB - AIM: Complication rates are low and endobronchial ultrasound guided needle aspiration (EBUS-TBNA) is generally regarded as a safe procedure, but there is a very limited number of studies evaluating the efficacy and safety of the procedure in advanced ages. The aim of this study is to assess the safety and performance outcomes of EBUS-TBNA in elderly. METHODS: It was a retrospective observational study; patients who received EBUS-TBNA between September 2016 and January 2018 were evaluated. We analyzed patient's characteristics, doses of midazolam, and lidocaine used, regions of lymph node biopsies, and complications. Also, functionality and general physical status of patients over 65 years of age were evaluated. RESULTS: During study period 132 cases of EBUS-TBNA were evaluated. 39 (29.5%) cases were aged 70 years, and over. There were more comorbidities in older group. Performance status of older group was worse. Furthermore, when evaluated according to American College of Cardiology (ACC)/American Heart Association (AHA) and American Society of Anesthesiologists (ASA), the older group was found to be composed of the riskier patients. When patients aged between 65 and 69, and over 70 compared, older patient's Barthel, EQ 5-D, SGA, and G8 scores were found to be worse. Despite that, there was no difference in the frequency, and types of complications between both groups. Diagnostic performance was not different between age groups. CONCLUSIONS: Independent from comorbidities, general health status, and functionality EBUS TBNA procedure in 70-year-old and over patients is a safe minimally invasive procedure. PMID- 30457427 TI - Prolonged adrenal insufficiency after high-dose glucocorticoid in infants with leukemia. AB - Although outcomes for infant leukemia have improved recently, transient adrenal insufficiency is commonly observed during treatment, especially after glucocorticoid administration. We identified three infants with acute leukemia who suffered from prolonged adrenal insufficiency requiring long-term (from 15 to 66 months) hydrocortisone replacement. All infants showed life-threatening symptoms associated with adrenal crisis after viral infections or other stress. Severe and prolonged damage of hypothalamo-pituitary-adrenal (HPA) axis is likely to occur in early infants with leukemia, therefore routine tolerance testing to evaluate HPA axis and hydrocortisone replacement therapy are recommended for infants with leukemia to avoid life-threatening complications caused by adrenal crisis. PMID- 30457428 TI - Powerful antibacterial activity of graphene/nanoflower-like nickelous hydroxide nanocomposites. AB - AIM: The development of new and efficient antibacterial agents is urgent to overcome emerging antimicrobial resistance. MATERIALS & METHODS: Herein, we have presented a new-type of 3D antibacterial system to prompt bacteria to contact with the any plane of nanocomposites. RESULTS: Comparing the antibacterial activity of graphene oxide, reduced graphene oxide and graphene-loaded nanoflower like nickelous hydroxide (GN/Ni(OH)2) nanocomposites; the GN/Ni(OH)2 showed stronger bactericidal capability toward Gram-negative/-positive bacteria. Moreover, the GN/Ni(OH)2 with low cytotoxicity can promote it as 'green' antimicrobial agents. And, the GN/Ni(OH)2 presented long-term stable antibacterial effectiveness after 2-month storage. The antibacterial mechanisms of GN/Ni(OH)2 were evidenced as the 3D contact and violent damage to the bacterial structure. CONCLUSION: The GN/Ni(OH)2 provides new insights into the antibacterial properties of 3D nanocomposites for effectively fighting pathogen threats in biomedicine and public health. PMID- 30457429 TI - Strontium Alleviates Endoplasmic Reticulum Stress in a Nonalcoholic Fatty Liver Disease Model. AB - The purpose of this study was to explore the effects of strontium on fatty liver, and to clarify the possible mechanisms by which strontium improves nonalcoholic fatty liver disease (NAFLD). We also evaluated how strontium affected the endoplasmic reticulum stress (ERS) pathways. We established an in vitro model of NAFLD using a human hepatocyte cell line (L02) treated with 0.2 mM palmitic acid. The Sprague-Dawley rats were fed with a high-fat diet (HFD) to establish NAFLD model in vivo. After strontium treatment, the total cholesterol (TC), triglyceride (TG), and lipid deposition in L02 cells and liver tissues were determined. Strontium treatment suppressed intracellular TC and TG levels and lipid accumulation in L02 cells, and the effect of high concentrations of strontium were more obvious. Strontium significantly reduced the mRNA and protein expression of glucose-regulated protein 78 (GRP78), activating transcription factor 6 (ATF6), inositol requiring enzyme 1 (IRE1), SREBP cleavage activator protein (SCAP), sterol regulatory element binding protein 1c (SREBP-1c), and SREBP-2 in L02 cells. In HFD-fed rats, strontium treatment reduced serum TC, TG, and low density lipoprotein cholesterol (LDL-C) levels, concurrent with a decrease in hepatic lipid accumulation. Furthermore, strontium treatment reduced the expression of GRP78 and SREBP-2 protein in liver tissues. Overall, strontium alleviated hepatic steatosis by decreasing ERS-related protein expression in vivo and in vitro models. The results indicated that strontium has the potential to become a new therapy for the prevention and treatment of NAFLD. PMID- 30457430 TI - Surgeon Perspectives Regarding Death and Dying. AB - BACKGROUND: Surgical patients most commonly receive palliative care services within 24-48 hours of death, and reasons for this delay are poorly understood. Research with nonsurgeons suggests that physician characteristics and beliefs about death and dying may contribute to late referral. OBJECTIVE: To describe surgeon perspectives related to death and dying, and their relationship with delayed referrals to palliative care. DESIGN: Using a previously validated survey instrument supplemented by open-ended questions, deductive content analysis was used to describe surgeon preferences for end-of-life care. SETTINGS: Participants were all current nonretired members of the American Society of Colon and Rectal Surgeons. MAIN OUTCOME MEASURES: Surgeon descriptions of a "good death" and how personal experiences influence care provided. RESULTS: Among 131 survey respondents (response rate 16.5%), 117 (89.3%) completed all or part of the qualitative portion of the survey. Respondents consistently reported their personal preferences for end-of-life care, and four central themes emerged: (1) pain and symptom management, (2) clear decision making, (3) avoidance of medical care, and (4) completion. Surgeons also reflected on both good and bad experiences with patients and family members dying, and how these experiences impact practice. LIMITATIONS: The small sample size inherent to Internet surveys may limit generalizability and contribute to selection bias. CONCLUSION: This study reveals surgeon preferences for end-of-life care, which may inform initiatives aimed at surgeons who may underuse or delay palliative care services. Future studies are needed to better understand how surgeon preferences may directly impact treatment recommendations for their patients. PMID- 30457431 TI - Identifying lookouts for epidemio-surveillance: application to the emergence of Xylella fastidiosa in France. AB - Recent detections of Xylella fastidiosa in Corsica island, France, has raised concerns on its possible spread to mainland France and the rest of the Mediterranean basin. Early detection of infected plants is paramount to prevent the spread of the bacteria, but little is known about this pathosystem in European environments, hence standard surveillance strategies may be ineffective. We hence present a new methodological approach for the design of risk-based surveillance strategies, adapted to the emerging risk caused by Xylella fastidiosa . Our proposal is based on a combination of machine learning techniques and network analysis that aims at understanding the main abiotic drivers of the infection, produce risk maps and identify lookouts for the design of future surveillance plans. The identified drivers coincide with known results in laboratory studies about the correlation between environmental variables, such as water stress and temperature, and the presence of the bacterium in plants. Furthermore, the produced risk maps overlap nicely with detected foci of infection, while they also highlight other susceptible regions where Xylella fastidiosa has not been found yet. We conclude the paper presenting a list of recommended regions for an optimized risk-based surveillance campaign based on the predicted spread and probability of detection of the disease. PMID- 30457432 TI - Distribution and genetic diversity of Xylella fastidiosa subsp. pauca associated with olive quick syndrome symptoms in Southeastern Brazil. AB - In Brazil, the host expansion of Xylella fastidiosa subsp. pauca was recently demonstrated with the report of diseased olive trees (Olea europaea), whose symptoms were associated with olive quick decline syndrome (OQDS) early describe in Southern Italy. We employed both PCR-based technique and the culture medium isolation to investigate the geographic dispersion of X. fastidiosa, as well as, the genetic signatures of 21 strains isolated from 11 olive orchards in both, Sao Paulo and Minas Gerais States, Brazil. Xylella fastidiosa subsp. pauca was detected in 83% of orchards examined in the region and was positively diagnosed in 43.7% of all samples with typical scorching symptoms. Of the 21 strains characterized by the fast-evolving microsatellite (SSR) markers, 20 different multilocus microsatellite genotypes (MLMGs) were observed with an overall allelic diversity of HNei = 0.38. Principal component analysis (PCoA) using the SSR markers clustered all strains, except for three, in one cluster evidencing a limited range of genetic diversity. Multilocus sequence typing (MLST) analysis shown the prevalence of a sequence type (ST16) in 75% of the samples. Three novel STs (84, 85, and 86) belonging to the X. fastidiosa subsp. pauca were detected. These results denote that genetically diverse strains of X. fastidiosa subsp. pauca are widely present in olive orchards in Southeastern Brazil, which is consistent with the long history of this bacterium in that region. PMID- 30457433 TI - Satisfaction with the Use of eFlow Closed-System Nebulizer in Patients with Moderate-to-Very Severe Chronic Obstructive Pulmonary Disease: Findings from a Long-Term Safety Study. AB - BACKGROUND: Effective delivery of inhaled drugs in chronic obstructive pulmonary disease (COPD) depends on patients' ability to correctly use an inhalation device. Nebulized delivery may be appropriate for COPD patients who cannot coordinate breath with inhalation or generate adequate inhalational force. Until recently, long-acting muscarinic antagonists (LAMAs), used for maintenance treatment of COPD, were available for delivery only via handheld inhalers. LonhalaTM MagnairTM (glycopyrrolate inhalation solution) is a LAMA delivered via the eFlow(r) closed-system (eFlow CS) vibrating membrane nebulizer. We assessed patient-reported ease of use and satisfaction with the eFlow CS nebulizer in the GOLDEN (Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer)-5 study. METHODS: GOLDEN-5, a phase 3, randomized, open-label trial, evaluated the safety and efficacy of glycopyrrolate/eFlow CS 50 MUg twice daily versus tiotropium 18 MUg once daily (administered via HandiHalerTM) in patients with moderate-to-very severe COPD. Only patients in the glycopyrrolate/eFlow CS group completed a study-specific device use questionnaire, evaluating patients' perceptions about ease of use, confidence in drug delivery, and overall device satisfaction at week 48 or end of study. Responses were summarized by counts and percentages. RESULTS: Of 620 patients who received glycopyrrolate/eFlow CS, 454 completed the questionnaire (mean age [standard deviation, SD] 63.3 [8.5] years; mean BMI [SD] 28.45 [6.208] kg/m2). Based on patient-reported perceptions, most patients (83%) were "confident" to "very confident" that the drug was delivered into their lungs with the eFlow CS; >70% rated the eFlow CS as "easy" or "very easy" to assemble, operate, and clean. Most (75%) patients ranked themselves as being "satisfied" or "very satisfied" overall with the eFlow CS nebulizer. CONCLUSIONS: High levels of satisfaction, confidence, and ease of use were reported with the eFlow CS nebulizer in this study. These findings support the use of the eFlow CS for maintenance treatment of COPD with glycopyrrolate inhalation solution. PMID- 30457434 TI - Evaluating Azoxystrobin Seed Coating Against Maize Late Wilt Disease Using a Sensitive qPCR-Based Method. AB - Harpophora maydis, a phytopathogenic fungus, causes late wilt, a severe vascular maize disease characterized by relatively rapid wilting of maize plants near fertilization. The disease is currently controlled using resistant varieties. Here, we evaluated seed coating efficiency with azoxystrobin against H. maydis in a series of in vitro and in vivo trials. A real-time polymerase chain reaction (qPCR)-based method was developed and proved to be a sensitive, accurate tool for monitoring H. maydis DNA inside infected seeds, sprouts, and tissues of mature plants. In the early growth stages, the chemical coating drastically reduced the pathogen DNA prevalence in host tissues and minimized the suppressing effect on the plants' biomass and development. In an infested field, the qPCR assay identified the pathogen 20 days after seeding, up to a month before conventional PCR detection. In the resistant fodder maize cultivar 32D99, which showed only minor disease symptoms, the seed coating blocked fungal progression and increased cob and plant weight by 39 and 60%, respectively. Nevertheless, this treatment was unable to protect a sensitive maize hybrid, cultivar Prelude, at the disease wilting breakout (60 days after sowing). These results encourage further examination of azoxystrobin and other fungicides in the field using the qPCR detection method to evaluate their efficiency. PMID- 30457435 TI - End-of-Life Preferences Should Be Discussed Routinely Before High-Risk Surgery. PMID- 30457436 TI - Pre-marketing immunogenicity and safety of a lyophilized purified human diploid cell rabies vaccine produced from microcarrier cultures: a randomized clinical trial. AB - The large-scale production of a human diploid cell (HDC) vaccine (HDCV) for rabies is limited by several technical challenges. Kanghua Biological Products Co., Ltd., has successfully used microcarrier technology for the large-scale culture of HDCs in bioreactors to develop a lyophilized and purified HDCV. In this blinded, randomized, parallel-group study conducted between July and October 2014 in Mianzhu, Sichuan Province, China, we monitored the safety and immunogenicity of this vaccine in a healthy population vaccinated according to the Essen post-exposure immunization schedule. A hamster kidney cell vaccine was used as the control. Adverse reactions were monitored 0.5, 6, 24, 48, and 72 h post vaccination to assess safety. Neutralizing antibodies in venous blood were measured on day 7, 14, and 72 to evaluate the immunogenicity of the vaccine while follow-up monitoring continued for 1 month. No serious adverse reactions were observed in any volunteer. The incidence rates of systemic and local adverse reactions were, respectively, 10.6% and 2.9% in the test group and 20.0% and 13.6% in the control group. After the third injection, the positive conversion rates of antibodies in the test and control groups were 100% and 98.82%, respectively. In addition, the average antibody titers on day 7, 14, and 42, were respectively, 1.71, 2.72, and 1.29 times higher than those in the control group. These results indicate that HDCV had a better safety profile and higher immunogenicity than the hamster kidney cell rabies vaccine. Trial registration number: 20130602. PMID- 30457437 TI - Effects on sexual function in Japanese patients with benign prostatic hyperplasia upon switching from combination therapy with alpha1 blocker and dutasteride to combination therapy with tadalafil and dutasteride. AB - This study investigated what sort of effects would occur in terms of sexual function in Japanese patients with benign prostatic hyperplasia (BPH), upon switching from combination therapy with an alpha1 blocker (AB) and dutasteride (DUT) to combination therapy with tadalafil (TAD) and DUT. The baseline and the 15-item International Index of Erectile Function (IIEF-15), Erection Hardness Score (EHS), International Prostate Symptom Score (IPSS), and Overactive Bladder Symptom Score (OABSS) 3 months after switching to the daily administration of TAD 5 mg/DUT 0.5 mg combination therapy, along with the age, prostatic volume, body mass index (BMI), and past medical history of 49 patients who were treated with AB/DUT as pretreatment, were retrospectively investigated. TAD/DUT combination therapy significantly improved the total score of IIEF-15 (from 17.8 +/- 11.6 to 21.4 +/- 13.9, p = .0047), erectile function domain (from 5.8 +/- 5.8 to 7.6 +/- 7.1, p = .0186), and EHS (from 1.9 +/- 1.3 to 2.6 +/- 1.2, p < .0001). Although IPSS and QOL index were significantly improved, no significant differences were observed for OABSS. Switching from AB/DUT combination therapy to TAD/DUT combination therapy brought about improvement in erectile function while leaving room to improve urinary status in Japanese patients. PMID- 30457438 TI - Marion Murray, PhD. PMID- 30457439 TI - Gestational Diabetes and Maternal Weight Management During and After Pregnancy. AB - BACKGROUND: Women diagnosed with gestational diabetes mellitus (GDM) substantially modify their diets during pregnancy to control hyperglycemia. These changes could also affect maternal weight management. MATERIALS AND METHODS: From July 2014 to December 2015 we enrolled women with and without GDM in a prospective cohort study to compare their mean rates of (1) weight gain before GDM screening, (2) weight gain after GDM screening, and (3) postpartum weight loss. All GDM-affected women were referred to Medical Nutrition Therapy and asked to self-monitor blood glucose until delivery. Rate comparisons were conducted separately for each interval using weighted t-tests and inverse probability of treatment weighting (IPTW) to account for age and prepregnancy body mass index (BMI). Linear regression models were developed to characterize the association of GDM status and rate of weight change. RESULTS: The study included 40 women with GDM and 49 women without GDM. The IPTW analysis found that (1) women with and without GDM had similar mean rates of gestational weight gain before GDM screening (0.41 +/- 0.26 kg/week vs. 0.45 +/- 0.35 kg/week, respectively, p = 0.86), (2) women with GDM gained weight at a significantly lower mean rate than women without GDM following GDM screening (0.30 +/- 0.28 kg/week vs. 0.53 +/- 0.28 kg/week, respectively, p = 0.001), and (3) women with and without GDM had similar mean rates of postpartum weight loss (-1.37 +/- 0.58 kg/week vs. -1.28 +/ 0.46 kg/week, respectively, p = 0.73). The linear regression model (adjusted for age and prepregnancy BMI) demonstrated that women with GDM gained 0.19 kg/week less than women without GDM (p = 0.004) during pregnancy after GDM screening. CONCLUSIONS: In the postpartum period, women with GDM lose weight at similar rates to women without GDM despite gaining weight at significantly lower rates following GDM screening. Diagnosis and treatment of GDM may improve maternal weight management, but this benefit is limited to late pregnancy. PMID- 30457440 TI - Effects of nicotine and stress exposure across generations in C57BL/6 mice. AB - Chronic administration of nicotine or exposure to stress can produce long-lasting behavioral and physiological changes in humans and animals alike. Further, the impact of nicotine and stress exposure can be inherited by offspring to produce persistent changes in physiology and behavior. To determine if nicotine and stress interact across generations to influence offspring behavior we exposed F0 male mice to nicotine and F1 male and female mice to chronic unpredictable stress during adolescence. We then measured locomotor sensitization to repeated nicotine injections in the subsequent F2 and F3 generations. Stress exposure alone (F1) did not influence locomotor sensitization in any lineage. However, in the F1 male lineage, F0 nicotine exposure abrogated locomotor sensitization in F2 male and transiently enhanced locomotor sensitization in F2 female offspring. These effects were not passed down to the F3 generations or observed in the F1 female lineage. F1 stress exposure modulated the effects of prior F0 nicotine exposure in a sex-dependent manner. Specifically, stress blunted the nicotine-induced enhancement in locomotor sensitization observed in F2 female offspring of F1 males. The effect of F0 nicotine and F1 stress exposure in females appears to have skipped a generation and enhanced nicotine sensitization only in the F3 generation, and only in females. This novel multigenerational exposure paradigm examining the inheritance of two different environmental exposures demonstrates that nicotine responses can be modified by nicotine and stress exposure from previous generations, and these effects are strongly influenced by sex. PMID- 30457441 TI - Collective influences on individual functioning: Multiple group memberships, self regulation, and depression after acquired brain injury. AB - A growing body of research demonstrates the role that social groups play in protecting health and well-being in the context of adjusting to acquired brain injury (ABI). However, the psychological processes that underpin this relationship are less well understood. The present research extends this work by testing a theoretically derived model about the role of multiple social group belonging in contributing to improved self-regulation and depression symptoms. A cross sectional survey was conducted involving 50 adults with ABI (Mage = 45 years, SD = 12.10; range 22-67 years) who completed a series of self-report measures indexing social group membership, self-regulation, and depression. Support for the predicted model was found with mediation analysis showing that multiple group belonging predicted lowered depression symptoms, by providing a basis for enhancing self-regulation. The findings suggest that belonging to multiple groups provides individuals with multiple opportunities for social interaction with which to trial and develop self-regulatory skills, which, in turn, has a positive influence on depression. PMID- 30457442 TI - Narcissism and stress-reactivity: a biobehavioural health perspective. AB - From a perspective broadly informed by Stress and Coping Theory, this review examined whether theoretically distinct and important dimensions of narcissism (grandiosity and vulnerability) associate with health-related stress-reactivity. Literature searches were conducted and articles were included if they contained a validated baseline assessment of narcissism, a stressor, and a within-person assessment of stress-reactivity (i.e., a baseline and post-stress assessment of a health-related psychological, biological, or behavioural process). Additionally, narcissism measures had to be systematically categorised as assessing grandiosity or vulnerability (see Grijalva, E., Newman, D. A., Tay, L., Donnellan, M. B., Harms, P. D., Robins, R. W., & Yan, T. (2015). Gender differences in narcissism: A meta-analytic review. Psychological Bulletin, 141(2), 261-310. doi: 10.1037/a0038231 ), and narcissism dimensions had to be assessed independently of other constructs. Findings were narratively synthesised within three broad dimensions of stress-reactivity (psychological, biological, and behavioural). Overall, there appear to be relatively consistent patterns that grandiosity and vulnerability are related to altered stress-reactivity. Additionally, grandiosity and vulnerability may differentially influence stress-reactivity depending on the type of stressor and/or indicator of stress-reactivity (e.g., under certain conditions, grandiosity may confer some level of resilience). This review highlights important theoretical and empirical gaps in the emerging narcissism and health literature. Furthermore, this review may help inform methodological considerations for future research, and may also point to physical health outcomes that could conceivably be affected by narcissism over time (e.g., overweight/obesity, cardiovascular disease, HIV/AIDS). PMID- 30457443 TI - Welcoming Death: Exploring Pre-Death Grief Experiences of Caregivers of Older Adults with Dementia. AB - The death of an older adult with dementia often has an uncertain dying trajectory and has been referred to as "the long goodbye." Researchers have found both positive and negative outcomes of pre-death grief for caregivers of individuals with chronic illnesses. This qualitative study explored the end-of-life experiences for 36 bereaved family caregivers of older adults with dementia; focusing on understanding their experiences with pre-death grief. These caregivers shared experiences with the phenomenon of "welcoming death" and findings highlighted the primary reasons they anticipated, accepted, or wished for the death of their family member with dementia. With the overarching goal of improving bereavement outcomes and reducing feeling of guilt, inclusion of pre death grief support services throughout the caregiving process are recommended. PMID- 30457444 TI - End-of-Life Resource for African American Caregivers: Reflections on a Field Education Model. PMID- 30457445 TI - The use of non-adapted anaerobic consortium in batch reactors enable to couple polychlorinated biphenyl degradation and community adaptation. AB - The removal of polychlorinated biphenyls (PCBs) and PCB biosorption was investigated in anaerobic batch reactors with non-adapted sludge fed with 1.5 mg L-1 of six PCB congener (PCB 10, 28, 52, 153, 138 and 180), mineral medium and co substrates. PCBs were analyzed by gas chromatography using headspace solid-phase microextraction (HS-SPME). In the methanogenic reactor the methane production, COD (Carbon Organic Demand) removal (90% of initial 2,292.60 mg L-1) and consumption of volatile organic acids were verified. Nevertheless, anaerobic activity was not observed in the reactor with inactivated biomass and biosorption range of 38% to 89% was measured for distinct PCB congeners in this reactor. The PCB removal was calculated from the PCB bioavailable (not biosorbed) and reached 76% of total PCBs. The selection of some representatives of the Thermotogaceae family, Sedimentibacter and Pseudomonas at 101 days of operation in the methanogenic reactor was correlated with PCB degradation. In addition, the various removal rates for each PCB congener indicate that the removal depends on bioavailability. The selection of the former non-adapted microbiota in the methanogenic reactor combined with PCB degradation occurred at 101 days. These results allow to assert that it is possible to simultaneously couple PCB degradation and community selection, without the previous adaptation step, which is a time-consuming stage. PMID- 30457446 TI - The development and initial validation of the Fatigue Sensitivity Questionnaire. AB - Currently, there is poor understanding of fatigue and the possible psychological conditions that may underlie chronic fatigue. Although substantial work has been directed to better clinically address fatigue, no work has explored individual differences in expectations or perceptions of the negative consequences associated with fatigue-related symptoms. The goals of this study were to (a) develop and (b) validate a measure of expectations or perceptions of the negative consequences associated with fatigue-related symptoms (e.g. fatigue sensitivity) across two independent samples (N = 1,827; 73.1% female; Mage = 21.68; SD = 4.54) of young adults. Results supported a 10-item measure of fatigue sensitivity, entitled the Fatigue Sensitivity Questionnaire (FSQ). The FSQ demonstrated unidimensionality, excellent internal consistency, and strong convergent and discriminant validity. Overall, the 10-item scale offers a single score that can be employed to measure fatigue sensitivity. Clinically, the FSQ may be a brief, informative, and easily disseminated measure in better understanding and capturing expectations or perceptions about the negative consequences of fatigue. As a research tool, the use of the FSQ may provide broader understanding of vulnerability factors that may influence fatigue-related health outcomes. Future research is needed to test the validity of the FSQ in other samples. PMID- 30457447 TI - Walking in Two Worlds: Hmong End of Life Beliefs & Rituals. AB - For over 40 years, the Hmong have sought refuge in the United States; however, many Hmong elders continue to honor healthcare and end-of-life beliefs and rituals that they practiced in their home country. With little knowledge by the general public and healthcare systems about these beliefs and rituals, healthcare professionals may struggle to provide the Hmong community with culturally sensitive care. This study sought to address this gap by conducting in-depth face to-face interviews with 12 Animist and 8Christian Hmong elders born in Southeast Asia, who now reside in the United States. Results provided insights regarding the heterogeneity among these Hmong elders concerning their end-of-life beliefs and rituals. Both Animist and Christian respondents believed family should provide care at end of life. Animist Hmong elders reported the importance of Shamanistic rituals such as soul calling or spiritual offering while Christian Hmong elders believed in the power of prayers. Healthcare providers need to assess Hmong elders' preferences for care at end of life, be open to the inclusion of traditional healers in their care and/or decision-making, and understand preferences of family and community members' involvement in care at the end of life. PMID- 30457448 TI - Framing Federal School Nutrition Policy: The Healthy, Hunger-Free Kids Act in the Nation's News. AB - The 2010 Healthy, Hunger-Free Kids Act (HHFKA) represented a major and controversial overhaul of national nutrition standards for foods served in the United States' nearly 100,000 public schools. To unpack how debate over this far reaching policy was presented to the public, we examined 152 national print; network, network affiliate, and cable television; and public radio news stories about the policy, all appearing during the window surrounding its scheduled reauthorization (9/1/14-1/31/16). We found that HHFKA opponents were more likely to argue from a smaller set of frames that comprised a concise, clear narrative they frequently repeated, while proponents drew from a broader range of frames, each used less frequently, to present their position. In addition, key voices expected to be prominent in a debate over child health-children and parents-were relatively deemphasized. Overall, the primary frames on either side of this debate argued past one another, leaving largely unanswered critical charges about the role of government in assuring the public's health. This debate reflects deeper arguments at the root of many public health policy decisions, and as such, is an illustrative case example for those planning how to enter and help shape national debate over public health policy. PMID- 30457449 TI - The Miracle Already Happened. PMID- 30457450 TI - Correction. PMID- 30457451 TI - Anthropometric characteristics of Chilean workers for ergonomic and design purposes. AB - Obtaining an appropriate match between a product and its end-users requires anthropometric data, which are typically outdated and show variations among different countries. Chile had its anthropometric data taken nearly 20 years ago, thus they are probably outdated. The purpose of this paper is to describe some anthropometric characteristics of Chilean workers. An anthropometric survey involving 27 measures and five calculated body dimensions was conducted in 2016. The measurements were based on ISO 7250 and ISO 15535 to ensure the highest standards possible, and a total of 2946 workers, aged from 18 to 76 years old, participated in the survey. The results showed that Chilean workers have smaller dimensions than Dutch and US workers but have larger dimensions than South Koreans. The data presented in this paper constitute the most up-to-date anthropometric dataset describing the dimensions of Chilean workers. Practitioner summary: In Chile, women are smaller and weigh less than men, and both of these populations have high BMIs. In addition, the Chilean population exhibits substantial differences compared with other international adult populations. The data presented in this paper should be used as a reference when designing for Chilean workers. PMID- 30457452 TI - How People Traveling Abroad to Die Came to be Called "Death Tourists", and Why They Shouldn't. PMID- 30457453 TI - Dying in Long-Term Care: Perspectives from Sexual and Gender Minority Older Adults about Their Fears and Hopes for End of Life. AB - As lesbian, gay, bisexual, transgender, and queer (LGBTQ+) communities age, many individuals expect a need to enter the long-term care system toward the end of life. Not unlike most aging Canadians, this anticipation is met with concern and fear. However, previous research suggests that older LGBTQ + individuals have unique fears often related to personal safety and discrimination. This qualitative study examined the hopes and fears of older LGBTQ + adults considering long-term care as they face end of life. Data were collected from three focus groups in Ontario, Canada, and analyzed using inductive thematic analysis. Specific and frequent reference to fear of entering long-term care homes was common across all focus groups, as participants anticipated: social isolation, decreased independence and capacity for decision-making, increased vulnerability to LGBTQ+-related stigma as well as exposure to unsafe social and physical environments. The results from this study, therefore, emphasize the need for palliative care specialists and long-term care home staff to address the unique health needs of older LGBTQ + adults nearing the end of life in order to work toward allaying fears and creating supportive and inclusive long-term care environments. PMID- 30457454 TI - Are college students health literate? AB - OBJECTIVE: To examine the health literacy of college students. PARTICIPANTS: A convenience sample of 245 graduate and undergraduate college students. METHODS: During February-April of 2018 participants completed the Short Test of Functional Health Literacy which assessed literacy on two passages describing a thyroid scan, and basic healthcare insurance information. RESULTS: Most college students displayed adequate health literacy (99.2%). The ANOVA analyses revealed college classification was the most significant predictor, followed by ethnicity, sex, and primary language. Age was significantly related to health literacy, when holding college classification constant. Interestingly, college major, healthcare work experience, or having health care credentials were not predictors of health literacy. CONCLUSION: This group of college students had adequate health literacy skills. However, the results of this study revealed demographic disparities that suggest further study. PMID- 30457455 TI - Design of novel multi-epitope vaccines against Severe Acute respiratory syndrome validated through multistage molecular interaction and dynamics. AB - Severe Acute respiratory syndrome (SARS) is endemic in south China and is continuing to spread worldwide since the 2003 outbreak, affecting human population of 37 countries till present. SARS is caused by the Severe Acute respiratory syndrome Coronavirus (SARS-CoV). In the present study, we have designed two multi-epitope vaccines (MEVs) composed of cytotoxic T lymphocyte (CTL), helper T lymphocyte (HTL) and B cell epitopes overlap, bearing the potential to elicit cellular as well as humoral immune response. We have used truncated (residues 10-153) Onchocerca volvulus activation-associated secreted protein-1, as molecular adjuvants at N terminal of both the MEVs. Selected overlapping epitopes of both the MEVs were further validated for stable molecular interactions with their respective human leukocyte antigen class I and II allele binders. Moreover, CTL epitopes were further studied for their molecular interaction with Transporter associated with antigen processing. Furthermore, after tertiary structure modelling, both the MEVs were validated for their stable molecular interaction with Toll-Like Receptors 2 and 4. Codon-optimized cDNA of both the MEVs were analyzed for their potential high level of expression in the mammalian cell line (Human) needed for their further in-vivo testing. Overall the present study proposes in-silico validated design of two MEVs against SARS composed of specific epitopes with the potential to cause a high level of virus specific cellular as well as humoral immune response. PMID- 30457456 TI - The protective mechanism underlying total flavones of Dracocephalum (TFD) effects on rat cerebral ischemia reperfusion injury. AB - Previously, total flavones of Dracocephalum (TFD), derived from Dracocephalum, were found to exert protective effects in cerebral ischemia reperfusion injury (CIRI) in middle cerebral artery occlusion (MCAO) rat model. However, the mechanisms underlying these observed effects of TFD on MCAO-induced rats still remain to be determined. Therefore, the aim of this study was to examine whether TFD alleviated MCAO through mechanisms involving anti-inflammatory and anti apoptotic using MCAO rats. The following parameters were measured: (1) percentage (%) area of brain infarction; (2) serum levels of inflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) and (3) expression protein levels of caspase-3 and AMP-activated protein kinase (AMPK). Results showed that MCAO significantly increased the % area of brain infarction, while TFD administration in these animals markedly reduced % area of brain infarction. A significant elevation on serum levels of TNF-alpha and IL-6 was noted with MCAO which was markedly reduced by TFD. In addition, MCAO produced a significant rise in protein expression levels of caspase-3 and AMPK. In contrast, TFD markedly lowered protein expression levels of caspase-3 and AMPK. Data suggest that the protective effects of TFD in MCAO model animals may involve inhibition of inflammatory mediator release associated with apoptosis through down regulation of AMPK signaling pathway. PMID- 30457457 TI - The relationship between emotional clarity and suicidal ideation among trauma exposed adolescents in inpatient psychiatric care: does distress tolerance matter? AB - The present investigation examined associations between low emotional clarity (the extent to which individuals are confused about the specific emotions they are experiencing) and suicidal ideation in a diverse sample of trauma-exposed inpatient adolescents, as well as the moderating role of distress tolerance (DT) in this association. Participants (N = 50; 52.0% female; M = 15.1 years, SD = .51; 44% White) completed measures of emotion dysregulation, posttraumatic stress disorder (PTSD), and suicidal ideation/attempts, as well as a behavioral measure of DT. Controlling for age, gender, presence of mood disorder, and past history of attempts, results revealed a significant interaction between DT and low emotional clarity in relation to suicidal ideation. Specifically, lower emotional clarity was related to suicidal ideation at higher, but not lower, levels of DT. Findings suggest that presence of suicidal ideation among traumatized youth with low emotion clarity is most likely when these emotional deficits are coupled with a high tolerance for cognitive/psychological distress. Given that the ability to withstand distress is arguably a key factor in transitioning individuals from ideation to lethal suicidal behavior, attention to the presence of this construct in the context of clinical practice may be warranted. PMID- 30457458 TI - Radiotherapy for early stage diffuse large B-cell lymphoma with or without double or triple hit genetic alterations. AB - We investigated whether adding radiation (RT) to systemic therapy improved outcomes in early stage diffuse large B-cell lymphoma (DLBCL) patients with or without double- or triple-hit lymphoma (DHL/THL) biology. This analysis included 183 patients profiled with fluorescent in situ hybridization (FISH) for alterations in MYC, BLC2, and/or BCL6. A total of 146 (80%) were non-DHL/THL, 27 (15%) were DHL, and 10 (6%) were THL. Systemic therapy without RT resulted in inferior freedom from relapse (FFR) (HR: 2.28; 95% CI, 1.10-4.77; p = .02). The median FFR for non-DHL/THL was not reached and was 33 and 22.3 months for DHL and THL, respectively; p < .001. Low-risk (R-IPI <2) DHL/THL patients treated with rituximab-based therapy had 3-year FFR rates of 11% and 71% for systemic therapy without and with RT, respectively; p = .04. No differences in overall survival were observed between the treatment groups. Treatment intensification with RT may improve early stage DHL/THL outcomes. PMID- 30457460 TI - Opioids and cancer pain. PMID- 30457459 TI - Politics and palliative care: Malawi. AB - Dion Smyth's review of palliative nursing on the internet. PMID- 30457461 TI - The experiences of family caregivers providing palliative cancer care in Thailand. AB - BACKGROUND:: Family caregivers have a significant role in Thai healthcare, taking on responsibilities of health professionals. The purpose of this research was to explore Thai family caregivers' experiences of providing palliative cancer care. METHODS:: This qualitative study took a phenomenological approach. In-depth interviews were conducted with 14 family caregivers aged 33-72 years in a regional hospital in the north of Thailand. The data was analysed using Colaizzi's phenomenological approach. Rigour was established by following Lincoln and Guba's guidelines for qualitative research. FINDINGS:: The experiences of Thai family caregivers providing palliative cancer care could be categorised into four themes: caring as a team; caring as supportive care; taking care to keep patients happy; and caring for the self while looking after a relative. CONCLUSION:: Health professionals can support family caregivers to deliver the best care for cancer patients and to help them decrease their stress. This study discusses ways how this may be done. PMID- 30457462 TI - Listening to the family's voice: evaluation of a tool to improve symptom control and communication. AB - BACKGROUND:: Acute hospitals provide a high proportion of end-of-life care but some families experience poor communication with clinical staff. AIM:: To evaluate the use of the Family's Voice diary communication tool across nine healthcare settings. METHODS:: A mixed method practice development approach was used incorporating: an audit of the usage of Family's Voice; collation and analysis of written comments; and collation of written feedback from the principal investigators at data collection sites. FINDINGS:: There were 112 completed diaries. Families rated pain and vomiting as well controlled, but agitation and breathlessness were difficult to control. Families were positive about care provided to the patients and themselves. Ten themes were identified from analysis of the families' written comments that echoed national concerns. CONCLUSION:: Evidence for the utility of the diary is building. Future work could focus on strategies for embedding the diary into routine care for all end-of-life patients. PMID- 30457463 TI - Addressing emotions in palliative care. PMID- 30457464 TI - Research Roundup. AB - Synopses of a selection of recently published research articles of relevance to palliative care. PMID- 30457465 TI - A qualitative study of nursing staff experiences of delirium in the hospice setting. AB - BACKGROUND:: Delirium is a common condition occurring in 13-42% of people admitted to palliative care units and up to 88% of these patients are at the end of their lives. It is frequently unrecognised and distressing to all those affected-patients, families and health professionals. In addition, there is considerable uncertainty surrounding its trajectory and optimal management, both of which can be inconsistent. AIMS:: This study aims to explore the experience of nursing staff who are caring for patients with delirium in the hospice environment and understand any potential barriers to its management. METHODS:: Semistructured interviews using emotional touchpoints were conducted with 12 nurses and six healthcare assistants in three hospices in North East England. Data was analysed using interpretative phenomenological analysis. FINDINGS:: The results highlighted gaps in knowledge and understanding in the management of delirium. The results demonstrated delirium had significant emotional effects, which were associated with uncertainty in managing the condition and the impact of this uncertainty on the relationship between staff and patients. CONCLUSION:: This study highlights the emotional impact of caring for patients with delirium. Future work is needed to address the areas of uncertainty identified and ascertain how to best support nursing staff in these challenges. PMID- 30457466 TI - An ethnographic study in nursing homes in Iran. AB - BACKGROUND:: The approach of death is an undeniable part of ageing and death is the most important concern for elderly people who live in nursing homes. This study examines describes how care home residents feel when they recognise that they are close to death. AIMS:: The aim of this study was to explore the experiences of elderly residents who are dying in nursing homes as well as their caregivers toward death in an Iranian context. METHODS:: A focused ethnographic research design was chosen. The research sample consisted of 25 nursing home staff-three nurses, 18 healthcare assistants, two administrators, a social worker and a psychologist-and 10 elderly people in two nursing homes in Iran. Data was collected through field notes, observations and semistructured, in-depth interviews. Data was analysed using thematic analysis. FINDINGS:: There were two main themes of: seeking the embrace of a calm death; and waiting for death. Within these, four subthemes were identified. CONCLUSION:: The perceptions of the participants originated from the nursing home culture and their beliefs in eternal life. Training staff about the cultural needs of dying people and end-of life care would be the most effective way to improve the experience of dying for nursing home residents. PMID- 30457467 TI - IMass Time: The Future, in Future! AB - Joseph John Thomson discovered and proved the existence of electrons through a series of experiments. His work earned him a Nobel Prize in 1906 and initiated the era of mass spectrometry (MS). In the intervening time, other researchers have also been awarded the Nobel Prize for significant advances in MS technology. The development of soft ionization techniques was central to the application of MS to large biological molecules and led to an unprecedented interest in the study of biomolecules such as proteins (proteomics), metabolites (metabolomics), carbohydrates (glycomics), and lipids (lipidomics), allowing a better understanding of the molecular underpinnings of health and disease. The interest in large molecules drove improvements in MS resolution and now the challenge is in data deconvolution, intelligent exploitation of heterogeneous data, and interpretation, all of which can be ameliorated with a proposed IMass technology. We define IMass as a combination of MS and artificial intelligence, with each performing a specific role. IMass will offer advantages such as improving speed, sensitivity, and analyses of large data that are presently not possible with MS alone. In this study, we present an overview of the MS considering historical perspectives and applications, challenges, as well as insightful highlights of IMass. PMID- 30457468 TI - What Are the Multi-Omics Mechanisms for Adaptation by Microorganisms to High Alkalinity? A Transcriptomic and Proteomic Study of a Bacillus Strain with Industrial Potential. AB - Alkaliphilic organisms are among an industrially important class of extremophile microorganisms with the ability to thrive at pH 10-11.5. Microorganisms that exhibit alkaliphilic characteristics are sources of alkali-tolerant enzymes such as proteases, starch degrading enzymes, cellulases, and metabolites such as antibiotics, enzyme inhibitors, siderophores, organic acids, and cholic acid derivatives, which have found various applications in industry for human and environmental health. Yet, multi-omics mechanisms governing adaptation to high alkalinity have been poorly studied. We undertook the present work to understand, as a case study, the alkaliphilic adaptation strategy of the novel microorganism, Bacillus marmarensis DSM 21297, to alkaline conditions using a multi-omics approach that employed transcriptomics and proteomics. As alkalinity increased, bacteria remodeled the peptidoglycan layer by changing peptide moieties along with the peptidoglycan constituents and altered the cell membrane to reduce lipid motility and proton leakiness to adjust intracellular pH. Different transporters also contributed to the maintenance of this pH homeostasis. However, unlike in most well-known alkaliphiles, not only sodium ions but also potassium ions were involved in this process. Interestingly, increased pH has triggered the expression of neither general stress proteins nor gene encoding proteins associated with heat, salt, and nutrient stresses. Only an increase in the expression of oxidative stress related genes was evident. Endospore formation, also a phenomenon closely linked to stress, was unclear. This questioned if high pH was a real stress for B. marmarensis. These new findings, corroborated using the multi-omics approach of the present case study, broaden the knowledge on the mechanisms of alkaliphilic adaptation and might also potentially offer useful departure points for further industrial applications with other microorganisms. PMID- 30457469 TI - MicroRNA-Target Interactions Reloaded: Identification of Potentially Functional Sequence Variants Within Validated MicroRNA-Target Interactions. AB - MicroRNAs (miRNAs) serve as critical regulators of gene expression. However, their binding to target genes can be influenced by genetic variability within the miRNA-target interaction (MTI) sites. We performed an in silico sequence reanalysis to identify novel sequence variants within MTIs with potential functional impacts. A literature search of the PubMed and the Web of Science spanning the years 2008 to April 2018 identified 240 articles reporting MTIs in humans. Sequence reanalysis of reported MTI regions was performed using the Ensembl browser. We found 76 sequence variants within 23 MTIs. We present description of MTIs wherein sequence variants are present within both the mature miRNA seed region and the miRNA target, which we termed miR-gene-target-single nucleotide polymorphism (miR-GenTar-SNP). To the best of our knowledge, this is the first report on copresence of sequence variants within both miRNA gene and the target site. In the course our analyses, the need for extension of current terminology emerged and therefore, novel terminology was introduced: miR-indel, miR-double nucleotide polymorphism (DNP), miR-TS-indel, and miR-TS-DNP. Identification of novel MTI sequence variants is a hitherto understudied, but critical dimension in understanding the complexity of interactions and gene deregulation in various complex diseases. Because such variations might profoundly affect miRNA function, they should be taken into consideration in future research that depends on "variability science" such as precision medicine, human genetics, and genomics in the study of complex diseases. The findings presented herein offer a baseline for further systematic reanalysis of all reported MTIs in human and other species. PMID- 30457470 TI - The Next 100 Years. PMID- 30457471 TI - Cerebellum and cognition in multiple sclerosis. AB - Kalron et al. (Kalron A, Allali G, Achiron A. J Neurol 265: 809-816, 2018.) report that people with multiple sclerosis (PwMS) who fall show a decreased cerebellar volume along with decreased overall cognition compared with nonfallers. While their paper focuses on cerebellar and cognitive alterations in PwMS, these findings may also be explained by additional factors such as aging and have the potential for broader impact in additional clinical populations who simultaneously experience cognitive and mobility dysfunction. PMID- 30457472 TI - Antiobesity Effect of Fermented Chokeberry Extract in High-Fat Diet-Induced Obese Mice. AB - Black-fruited chokeberries (Aronia melanocarpa), growing mainly in the Central and Eastern European countries, have health benefits due to the high concentrations of polyphenolic compounds. However, a strong bitter taste of chokeberries limits its usage as functional food. We hypothesized that the fermented A. melanocarpa with a reduced bitter taste would improve insulin sensitivity and/or ameliorate weight gain induced by high-fat diet (HFD) in male C57BL/6J mice. The mice were administered with HFD together with the 100 mg/kg of natural A. melanocarpa (T1) or the fermented A. melanocarpa (T2) for 8 weeks. The treatment with T2 (100 mg/kg body weight, p.o.) markedly attenuated the weight gain and the increase in serum triglyceride level induced by HFD. The T2-treated group had better glucose tolerance and higher insulin sensitivity as measured by oral glucose tolerance test and intraperitoneal insulin tolerance test in comparison to the T1-treated group. Phytochemical analysis revealed that the main constituents of T2 were cyanidin-3-xyloside and 1-(3',4' dihydroxycinnamoyl)cyclopenta-2,3-diol, and the content of cyanidin glycosides (3 glucoside, 3-xyloside) was significantly reduced during the fermentation process. From the above results, we postulated that antiobesity effect of black chokeberry was not closely correlated with the cyanidin content. Fermented chokeberry might be a viable dietary supplement rich in bioactive compounds useful in preventing obesity. PMID- 30457473 TI - Effects of Herbal Formulas Bojungikgi-tang and Palmijihwang-hwan on Inflammation in RAW 264.7 Cells and the Activities of Drug-Metabolizing Enzymes in Human Hepatic Microsomes. AB - In the present study, Bojungikgi-tang (BJIKT: Buzhongyiqi-tang, Hochuekki-to) and Palmijihwang-hwan (PMJHH: Baweidihuang-wan, Hachimijio-gan), traditional herbal formulas, investigated anti-inflammatory efficacies in murine macrophage cell line and the influence on the activities of drug-metabolizing enzymes (DMEs). The anti-inflammatory potentials of the herbal formulas were evaluated to inhibit the production of the inflammatory mediators and cytokines and the protein expression of inducible nitric oxide and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-treated RAW 264.7 cells. The activities of the major human DMEs, cytochrome P450 isozymes (CYP450s) and UDP-glucuronosyltransferase isozymes (UGTs), were measured by in vitro enzyme assay systems. BJIKT and PMJHH significantly suppressed the prostaglandin E2 (PGE2) production (IC50 = 317.3 and 282.2 MUg/mL, respectively) and the protein expression of COX-2 in LPS-treated RAW264.7 cells. On the human microsomal DMEs, BJIKT inhibited the activities of CYP1A2 (IC50 = 535.05 MUg/mL), CYP2B6 (IC50 > 1000 MUg/mL), CYP2C9 (IC50 = 800.78 MUg/mL), CYP2C19 (IC50 = 563.11 MUg/mL), CYP2D6 (IC50 > 1000 MUg/mL), CYP2E1 (IC50 > 1000 MUg/mL), CYP3A4 (IC50 = 879.60 MUg/mL), UGT1A1 (IC50 > 1000 MUg/mL), and UGT1A4 (IC50 > 1000 MUg/mL), but it showed no inhibition of the UGT2B7 activity at doses less than 1000 MUg/mL. PMJHH inhibited the CYP2D6 activity (IC50 = 280.89 MUg/mL), but IC50 values of PMJHH exceeded 1000 MUg/mL on the activities of CYP1A2, CYP2C19, CYP2E1, and CYP3A4. At concentrations less than 1000 MUg/mL, PMJHH did not affect the activities of CYP2B6, CYP2C9, UGT1A1, UGT1A4, and UGT2B7. The results indicate that both BJIKT and PMJHH may be potential candidates to prevent and treat PGE2- and COX-2-mediated inflammatory diseases. In addition, this study will expand current knowledge about herb-drug interactions by BJIKT and PMJHH. PMID- 30457474 TI - Generation of transgene-free porcine intermediate type induced pluripotent stem cells. AB - Physiologically and anatomically, humans and pigs share many similarities, which make porcine induced pluripotent stem cells (piPSCs) very attractive for modeling human cell therapy as well as for testing safety of iPSC based cell replacement therapies. To date, several integrative and non-integrative strategies have been reported to successfully generate piPSCs, but all resulting piPSCs had integration of transgenes. The use of integrative methods has the disadvantage of potential lack of silencing or inappropriate re-activation of these genes during differentiation, as well as uncertainty regarding disruption of important genomic regions caused by integration. In our study, we performed a non-integrative vector based reprogramming approach using porcine fetal fibroblasts. The resulting four piPSC lines were positive for pluripotency marker and when subjected to in vitro and in vivo differentiation assays, all four lines formed embryoid bodies, capable to differentiate into all three germ layers, and three out of the four cell lines formed teratomas. PCR analysis on genomic and plasmid DNA revealed that the episomal vectors were undetectable in six out of eight subclones derived from one of the piPSC lines (piPSC1) above passage 20. These piPSCs could potentially be ideal cell lines for the generation of porcine in vitro and in vivo models. Furthermore, subsequent analyses of our new transgene independent piPSCs could provide novel insights on the genetic and epigenetic necessities to achieve and maintain piPSCs. PMID- 30457475 TI - Are we speaking the same language? An argument for the consistent use of terminology and definitions for childhood vaccination indicators. AB - Vaccination indicators are used to measure the health status of individuals or populations and to evaluate the effectiveness of vaccination programs or policies. Ensuring that vaccination indicators are clearly and consistently defined is important for effective communication of outcomes, accurate program evaluation, and comparison between different populations, times, and contexts. The purpose of this commentary is to describe commonly used vaccination indicators and to highlight inconsistencies in how childhood vaccine researchers use and define these terms. The indicators we describe are vaccine coverage, uptake, and rate; vaccination status, initiation, and completion; and up-to-date, timely, partial, and incomplete, vaccination. We conclude that many vaccination indicators are not explicitly defined within published research studies and/or are used quite differently across studies. We also note that the choice of indicator in a given study is often driven by program or vaccine specific factors, may be constrained by data availability, and should be chosen to best reflect the outcome of interest. We conclude that the use of consistent language and definitions would promote more effective communication of research findings. We also propose some standardized definitions for common indicators, with the goal of provoking discussion and debate on the issue. PMID- 30457476 TI - Strategically Guiding Research through Careful Consideration of the Path to Impact. PMID- 30457477 TI - Dynamic MRI of a Large Fetal Cardiac Mass. PMID- 30457478 TI - Three-dimensional Distribution of Muscle and Adipose Tissue of the Thigh at CT: Association with Acute Hip Fracture. AB - Purpose To evaluate determinants of hip fracture by assessing soft-tissue composition of the upper thigh at CT. Materials and Methods In this retrospective analysis of prospectively collected data, CT studies in 55 female control participants (mean age, 73.1 years +/- 9.3 [standard deviation]) were compared with those in 40 female patients (mean age, 80.2 years +/- 11.0) with acute hip fractures. Eighty-seven descriptors of the soft-tissue composition were determined. A multivariable best subsets analysis was used to extract parameters best associated with hip fracture. Results were adjusted for age, height, and weight. Results of soft-tissue parameters were compared with bone mineral density (BMD) and cortical bone thickness. Areas under the receiver operating characteristic curve (AUCs) adjusted for multiple comparisons were determined to discriminate fracture. Results The hip fracture group was characterized by lower BMD, lower cortical thickness, lower relative adipose tissue volume of the upper thigh, and higher extramyocellular lipid (EML) surface density. The relative volume of adipose tissue combined with EML surface density (model S1) was associated with hip fracture (AUC, 0.85; 95% confidence interval [CI]: 0.78, 0.93), as well as trochanteric trabecular BMD combined with neck cortical thickness (model B2) (AUC, 0.84; 95% CI: 0.75, 0.92). The model including all four parameters provided significantly better (P < .01) discrimination (AUC, 0.92; 95% CI: 0.86, 0.97) than model S1 or B2. Conclusion In addition to bone mineral density and geometry of the proximal femur, the amount of adipose tissue of the upper thigh and the distribution of the adipocytes in the muscles are significantly associated with acute hip fracture at CT. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 30457479 TI - Diagnosis of Knee Meniscal Injuries by Using Three-dimensional MRI: A Systematic Review and Meta-Analysis of Diagnostic Performance. AB - Purpose To investigate the diagnostic performance of three-dimensional (3D) MRI for depicting meniscal injuries of the knee by using surgery as the standard of reference. Materials and Methods A literature search was performed to identify original studies published between 1985 and 2017. Summary receiver operating characteristic curve and sensitivity analyses were performed to compare the diagnostic performance of 3D versus two-dimensional (2D) MRI for the assessment of knee meniscal injuries and to evaluate the impact of relevant covariates on the diagnostic performance for assessment of knee meniscal injuries. Results Of identified records, 31 studies (1743 3D knee MRI examinations) were included (23 studies also reported the results of 2D MRI). All studies before 2008 used gradient-echo (GRE) sequences, whereas all studies after 2011 used fast spin-echo (FSE) sequences. By comparing FSE and GRE sequences with 2D MRI, pooled estimate of sensitivity (90.0%; P = .2 and 90.1%; P = .2 vs 88.5%) and pooled estimate of specificity (91%; P = .3 and 89.8% vs 90.1%; P = .7) were comparable. The 3D FSE sequences demonstrated similar diagnostic performance as 3D GRE sequences, except for slightly improved sensitivity for depicting lateral meniscal injuries (FSE, 84.6%; GRE, 75%; P = .01). The specificity of 3D sequences improved when multiplanar reformatting was performed (P = .02). Conclusion Both three dimensional (3D) fast spin-echo (FSE) and 3D gradient-echo (GRE) sequences had similar diagnostic performance as two-dimensional sequences, with slight superior sensitivity of 3D FSE sequences compared with 3D GRE sequences for depicting lateral meniscal injuries of the knee. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 30457481 TI - Virtual Hepatic Venous Pressure Gradient with CT: Ready for Prime Time? PMID- 30457480 TI - Circumferential Strain Predicts Major Adverse Cardiovascular Events Following an Acute ST-Segment-Elevation Myocardial Infarction. AB - Purpose To investigate the prognostic value of circumferential left ventricular (LV) strain measured by using cardiac MRI for prediction of major adverse cardiac events (MACE) following an acute ST-segment-elevation myocardial infarction (STEMI). Materials and Methods Participants with acute STEMI were prospectively enrolled from May 11, 2011, to November 22, 2012. Cardiac MRI was performed at 1.5 T during the index hospitalization. Displacement encoding with stimulated echoes (DENSE) and feature tracking of cine cardiac MRI was used to assess circumferential LV strain. MACE that occurred after discharge were independently assessed by cardiologists blinded to the baseline observations. Results A total of 259 participants (mean age, 58 years +/- 11 [standard deviation]; 198 men [mean age, 58 years +/- 11] and 61 women [mean age, 58 years +/- 12]) underwent cardiac MRI 2.2 days +/- 1.9 after STEMI. Average infarct size was 18% +/- 13 of LV mass and circumferential strain was -13% +/- 3 (DENSE method) and -24% +/- 7 (feature- tracking method). Fifty-one percent (131 of 259 participants) had presence of microvascular obstruction. During a median follow-up period of 4 years, 8% (21 of 259) experienced MACE. Area under the curve (AUC) for DENSE was different from that of feature tracking (AUC, 0.76 vs 0.62; P = .03). AUC for DENSE was similar to that of initial infarct size (P = .06) and extent of microvascular obstruction (P = .08). DENSE-derived strain provided incremental prognostic benefit over infarct size for prediction of MACE (hazard ratio, 1.3; P < .01). Conclusion Circumferential strain has independent prognostic importance in study participants with acute ST-segment-elevation myocardial infarction. (c) RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Kramer in this issue. PMID- 30457482 TI - Detection of Breast Cancer with Mammography: Effect of an Artificial Intelligence Support System. AB - Purpose To compare breast cancer detection performance of radiologists reading mammographic examinations unaided versus supported by an artificial intelligence (AI) system. Materials and Methods An enriched retrospective, fully crossed, multireader, multicase, HIPAA-compliant study was performed. Screening digital mammographic examinations from 240 women (median age, 62 years; range, 39-89 years) performed between 2013 and 2017 were included. The 240 examinations (100 showing cancers, 40 leading to false-positive recalls, 100 normal) were interpreted by 14 Mammography Quality Standards Act-qualified radiologists, once with and once without AI support. The readers provided a Breast Imaging Reporting and Data System score and probability of malignancy. AI support provided radiologists with interactive decision support (clicking on a breast region yields a local cancer likelihood score), traditional lesion markers for computer detected abnormalities, and an examination-based cancer likelihood score. The area under the receiver operating characteristic curve (AUC), specificity and sensitivity, and reading time were compared between conditions by using mixed models analysis dof variance and generalized linear models for multiple repeated measurements. Results On average, the AUC was higher with AI support than with unaided reading (0.89 vs 0.87, respectively; P = .002). Sensitivity increased with AI support (86% [86 of 100] vs 83% [83 of 100]; P = .046), whereas specificity trended toward improvement (79% [111 of 140]) vs 77% [108 of 140]; P = .06). Reading time per case was similar (unaided, 146 seconds; supported by AI, 149 seconds; P = .15). The AUC with the AI system alone was similar to the average AUC of the radiologists (0.89 vs 0.87). Conclusion Radiologists improved their cancer detection at mammography when using an artificial intelligence system for support, without requiring additional reading time. Published under a CC BY 4.0 license. See also the editorial by Bahl in this issue. PMID- 30457483 TI - Strain Measures Predict Outcome after ST-Segment-Elevation Myocardial Infarction: Now What? PMID- 30457484 TI - Virtual Hepatic Venous Pressure Gradient with CT Angiography (CHESS 1601): A Prospective Multicenter Study for the Noninvasive Diagnosis of Portal Hypertension. AB - Purpose To develop and validate a computational model for estimating hepatic venous pressure gradient (HVPG) based on CT angiographic images, termed virtual HVPG, to enable the noninvasive diagnosis of portal hypertension in patients with cirrhosis. Materials and Methods In this prospective multicenter diagnostic trial (ClinicalTrials.gov identifier: NCT02842697), 102 consecutive eligible participants (mean age, 47 years [range, 21-75 years]; 68 men with a mean age of 44 years [range, 21-73 years] and 34 women with a mean age of 52 years [range, 24 75 years]) were recruited from three high-volume liver centers between August 2016 and April 2017. All participants with cirrhosis of various causes underwent transjugular HVPG measurement, Doppler US, and CT angiography. Virtual HVPG was developed with a three-dimensional reconstructed model and computational fluid dynamics. Results In the training cohort (n = 29), the area under the receiver operating characteristic curve (AUC) of virtual HVPG in the prediction of clinically significant portal hypertension (CSPH) was 0.83 (95% confidence interval [CI]: 0.58, 1.00). The diagnostic performance was prospectively confirmed in the validation cohort (n = 73), with an AUC of 0.89 (95% CI: 0.81, 0.96). Inter- and intraobserver agreement was 0.88 and 0.96, respectively, suggesting the good reproducibility of virtual HVPG measurements. There was good correlation between virtual HVPG and invasive HVPG (R = 0.61, P < .001), with a satisfactory performance to rule out (7.3 mm Hg) and rule in (13.0 mm Hg) CSPH. Conclusion The accuracy of a computational model of virtual hepatic venous pressure gradient (HVPG) shows significant correlation with invasive HVPG. The virtual HVPG also showed a good performance in the noninvasive diagnosis of clinically significant portal hypertension in cirrhosis. (c) RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Malayeri in this issue. PMID- 30457485 TI - Imaging of Cancer Immunotherapy: Current Approaches and Future Directions. AB - Cancer immunotherapy using immune-checkpoint inhibitors has emerged as an effective treatment option for a variety of advanced cancers in the past decade. Because of the distinct mechanisms of immunotherapy that activate the host immunity to treat cancers, unconventional immune-related phenomena are encountered in terms of tumor response and progression, as well as drug toxicity. Imaging plays an important role in objectively characterizing immune-related tumor responses and progression and in detecting and monitoring immune-related adverse events. Moreover, emerging data suggest a promise for molecular imaging that can visualize the specific target molecules involved in immune-checkpoint pathways. In this article, the background and current status of cancer immunotherapy are summarized, and the current methods for imaging evaluations of immune-related responses and toxicities are reviewed along with their limitations and pitfalls. Emerging approaches with molecular imaging are also discussed as a future direction to address unmet needs. PMID- 30457487 TI - Detecting Breast Cancers with Mammography: Will AI Succeed Where Traditional CAD Failed? PMID- 30457486 TI - A Decision Analysis of Follow-up and Treatment Algorithms for Nonsolid Pulmonary Nodules. AB - Purpose To evaluate management strategies and treatment options for patients with ground-glass nodules (GGNs) by using decision-analysis models. Materials and Methods A simulation was developed for 1 000 000 hypothetical patients with GGNs undergoing follow-up per the Lung Imaging Reporting and Data System (Lung-RADS) recommendations. The initial age range was 55-75 years (mean, 64 years). Nodules could grow and develop solid components over time. Clinically significant malignancy rates were calibrated to data from the National Lung Screening Trial. Annual versus 3-year-interval follow-up of Lung-RADS category 2 nodules was compared, and different treatment strategies were tested (stereotactic body radiation therapy, surgery, and no therapy). Results Overall, 2.3% (22 584 of 1 000 000) of nodules were clinically significant malignancies; 6.3% (62 559 of 1 000 000) of nodules were treated. Only 30% (18 668 of 62 559) of Lung-RADS category 4B or 4X nodules were clinically significant malignancies. The risk of clinically significant malignancy for persistent nonsolid nodules after baseline was higher than Lung-RADS estimates for categories 2 and 3 (3% vs <1% and 1%-2%, respectively). Overall survival (OS) at 10 years was 72% (527 827 of 737 306; 95% confidence interval [CI]: 71%, 72%) with annual follow-up and 71% (526 507 of 737 306; 95% CI: 71%, 72%) with 3-year-interval follow-up (P < .01). At 10 years, OS among patients whose nodules progressed to Lung-RADS category 4B or 4X was 80% after radiation therapy (49 945 of 62 559; 95% CI: 80%, 80%), 79% after surgery (49 139 of 62 559; 95% CI: 78%, 79%), and 74% after no therapy (46 512 of 62 559; 95% CI: 74%, 75%) (P < .01). Conclusion Simulation modeling suggests that the follow-up interval for evaluating ground-glass nodules can be increased from 1 year to 3 years with minimal change in outcomes. Stereotactic body radiation therapy demonstrated the best outcomes compared with lobectomy and with no therapy for nonsolid nodules. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 30457488 TI - Hoax Springs Eternal: The Psychology of Cognitive Deception. PMID- 30457489 TI - "It's just part of life": African American daughters caring for parents with dementia. AB - The purpose of this study was to gain a greater understanding of the experiences of African American daughters caring for parents with Alzheimer's disease or a related dementia (ADRD). In this secondary analysis of a subset (N = 12) of the sample from a previous study, daughters averaged 54 years of age and were caring for parents with moderate to severe ADRD. Results revealed two main categories: Caregiver Concerns and Caregiver Coping. Subcategories included challenging behaviors, social aspects, integration, and family culture and values. Findings offer insight into cultural factors relevant to practice along with research recommendations. PMID- 30457490 TI - Practice Concepts and Innovations for Pediatric End-of-Life Care by the Interdisciplinary Care Team. AB - In recent years, clinical approaches to anticipatory grief and inclusivity amongst the medical team and family members have grown. In thinking about the end of-life concerns within the pediatric care setting, practice concepts, and innovations inform how physicians and members of the interdisciplinary care team choose to approach conversations with parents and family members, as well as the particular level of involvement parents should have in decisions regarding the end of their child's life. PMID- 30457491 TI - Noise at sea: Characterization of extended shift noise exposures among U.S. Navy aircraft carrier support personnel. AB - The purpose of this investigation was to characterize 12-hr on-duty, 12-hr off duty, and 24-hr noise exposures among U.S. Navy aircraft carrier support personnel. Noise dosimetry samples were collected for 47 aircraft carrier support personnel while at sea during airwing carrier qualifications. Leq measurements during 12-hr on-duty, 12-hr off-duty, and over 24-hr periods were compared to Threshold Limit Values. Four similar exposure groups (SEGs) were created based upon departmental assignment and similarity of work tasks: (1) Administration/Religious Ministries/Legal/Training, (2) Combat Systems/Operations, (3) Medical/Dental, and (4) Supply. Equivalent sound level (Leq) measurements in decibels "A" weighted (dBA) were compared to determine significant differences between each group according to 12-hr on-duty, 12-hr off duty, and 24-hr periods. Mean 24-hr noise levels ranged from 69-88 dBA with 22% exceeding the 80 dBA Threshold Limit Value. Twelve-hr on-duty noise levels ranged from 71-90 dBA with 17% exceeding the 83 dBA 12-hr on-duty Threshold Limit Value. Twelve-hr off-duty noise exposure ranged from 68-84 dBA with 95% exceeding the 70 dBA American Conference of Governmental Industrial Hygienists threshold classified as effective quiet to allow for temporary threshold shift recovery. Welch Analysis of Variance and Dunnett T3 post hoc tests revealed SEG 2 had significantly higher 24-hr noise exposures than SEG 3 (p = 0.019) and SEG 4 (p = 0.045). SEG 2 had significantly higher 12-hr on-duty noise exposure than SEG 3 (p = 0.030). One Way Analysis of Variance revealed no significant differences between 12-hr off-duty noise exposures according to SEG (p = .096). Some aircraft carrier support personnel had 12-hr on-duty and 24-hr noise exposures exceeding Threshold Limit Values with a large proportion exceeding the 70 dBA effective quiet limit during 12-hr off-duty periods. Results suggest personnel that are typically considered low risk for hazardous noise exposure (<85 dBA) during 8-hr shifts may have a greater risk of noise exposure when considering full 12-hr and 24-hr shifts when working and living in close proximity. PMID- 30457492 TI - Application of the draft NIOSH Occupational Exposure Banding Process to Bisphenol A: A case study. AB - Bisphenol A is a commercially important chemical used to make polycarbonate plastic, epoxy resins and other specialty products. Despite an extensive body of in vitro, animal and human observational studies on the effects of exposure to bisphenol A, no authoritative bodies in the U.S. have adopted or recommended occupational exposure limits for bisphenol A. In 2017, the National Institute for Occupational Safety and Health published a Draft process for assigning health protective occupational exposure bands, i.e. an airborne concentration range, to chemicals lacking an occupational exposure limit. Occupational exposure banding is a systematic process that uses both quantitative and qualitative toxicity information on selected health effect endpoints to assign an occupational exposure band for a chemical. The Draft process proposes three methodological tiers of increasing complexity for assigning an occupational exposure band. We applied Tier 1 (based on the Globally Harmonized System of Classification and Labelling) and Tier 2 (based on authoritative sources/reviews) to assign an occupational exposure band to bisphenol A. Under both Tier 1 and 2, the occupational exposure band for bisphenol A was "E" (<0.01 mg/m3), an assignment based on eye damage. "E" is the lowest exposure concentration range, reserved for chemicals with high potential toxicity. If eye damage was excluded in assigning an air concentration exposure range, then bisphenol A would band as "D" (>0.01 to 0.1 mg/m3) under Tier 1 (based on reproductive toxicity and respiratory/skin sensitization) and under Tier 2 (based on specific target organ toxicity-repeated exposure). In summary, Tiers 1 and 2 gave the same occupational exposure band for bisphenol A when eye damage was included ("E") or excluded ("D") as an endpoint. PMID- 30457493 TI - The outcome of patients with cultured pathogens at time of nonunion surgery. AB - The purpose of this study is to evaluate incidence, preoperative laboratory markers, and outcomes of patients who positively cultured pathogens (PCP) at time of surgery for long bone fracture nonunion. Two-hundred and eighty-eight patients were enrolled in a trauma study on long bone nonunion. Two-hundred and sixteen of those 288 patients were cultured at the time of fracture nonunion surgery. Laboratory data were collected prior to intervention and infectious laboratory markers ordered on patients suspected for infection. Patients were followed for one year. Wound complications, antibiotic use, healing, function, and re admission for further surgery were assessed. Cultures returned positive on 59 patients (representing 20.5% of the 288 patient cohort or 27.3% of the 216 patients cultured in the operative suite). More PCP's (47.5%; 28 of 59) developed wound complications, with greater mean antibiotic duration and more frequent returns to the OR averaging 1.3 procedures per patient. Twelve-month follow-up was obtained on 249 of the 288 (86.5%) and PCPs reported globally worse function. Patients who PCP at the time of operative management for long bone nonunion was a prognostic indicator of poorer long-term functional outcomes. PMID- 30457494 TI - Pulsed electric fields reduce bacterial attachment to stainless steel plates. AB - The purpose of this study was to evaluate the capacity of pulsed bilateral electric fields to control bacterial attachment on stainless steel plates. Previously sterilized circular metal plates of stainless steel were submerged in a liquid medium with a known concentration of Staphylococcus epidermidis and incubated for 1 hour at 36oC while a 200 Hz pulsed electric field of 18 V/cm was applied for 2.5 MUseg and then sonicated for 5 minutes in 10 ml of saline. Three different models were cultured and compared: 1) negatively-charged plate, 2) positively-charged plate, and 3) control plate without electric current. A total of 39 metal plates were processed. The median adherence in the control group and the electric field group was 312 CFU/mm2 and 16,2 CFU/mm2 respectively (p < 0.001, reduction of 95% of bacterial attachment). Bilateral pulsed electric field is able to reduce bacterial attachment on stainless steel plates in in vitro conditions. PMID- 30457495 TI - Diagnostic pitfalls in the differentiation between pyoderma gangrenosum and necrotizing fasciitis. AB - Pyoderma gangrenosum and necrotizing fasciitis are two rare pathologic entities with a similar clinical image, but a who require a very different management. In general physicians, orthopedics, dermatologists, plastic surgeons will hardly ever see it, but when they do it is very important to distinguish between both. In this paper with the focus on the practical approach ,we expose the diagnostic pitfalls in the differential diagnosis, explain how to prevent them and summarize the evidence on therapeutic management. To achieve this we use a case where the diagnosis was rather difficult and utilize reviews where the clinical features, early diagnostic tools and treatment options are explained. PMID- 30457496 TI - Treatment of chronic osteomyelitis with antibiotic-loaded bone void filler systems: an experience with hydroxyapatites calcium-sulfate biomaterials. AB - This is a retrospective study that aims to quantify the problem of chronic osteomyelitis in one of the largest Italian orthopedic centers. Furthermore this study is focused on evaluation of efficacy of bone void filler systems with particular attention to a subgroup of patients treated with PerOssal(r). Ninety seven patients were included in this study between 2008 and 2013 with a minimum follow up of 24 months. A subgroup of 52 patients was treated with curettage plus PerOssal(r), another group was treated with curettage only or curettage with other bone void filler systems. Overall we obtained a cure rate of 80,4%, whereas 19,6% had recurrent infection. Looking at the subgroup treated with PerOssal(r) we found a healing rate of 86,5%, which was significantly higher compared to the other groups. Of the patients with recurrence of infection, those treated with PerOssal(r) recurred 106 days later than the other patients. PMID- 30457497 TI - Comparison of fine needle aspiration and core needle biopsy in the diagnosis of bone tumours. AB - Much literature exists regarding the diagnostic yield and accuracy of core needle biopsy (CNB) and fine needle aspiration (FNA) but none compares both in the same tumour. Ninety-four patients were prospectively studied using a FNA and CNB. With FNA 70 diagnoses were possible (74,5%). Accurate diagnosis rate was 97,1%. In 92 patients (97,9%) a diagnosis was obtained with CNB and 91 (98,9%) were accurate.. The diagnostic yield was 74,5% for FNA and 97,9% for CNB (p < 0.0001). The diagnostic accuracy was 97,1% for FNA and 98,9% for CNB (p = 0.5787). Regarding determining malignancy FNA and CNB had 98,3% and 98,5% sensibility, 100% and 100% specificity, 100% and 100% positive predictive value and 95,2% and 96,2% negative predictive value, respectively. In conclusion FNA is as accurate as CNB on all accounts. Despite the reliability of FNA, the number of inconclusive cases makes it an inferior technique when compared with CNB. PMID- 30457498 TI - Vascularized fibular autograft as salvage technique in failure of allograft intercalary reconstructions after tumor resections. AB - Intercalary allografts after diaphyseal resections for bone tumors represent the most frequent option of reconstruction. Main complications are non-unions, fractures and infections. The purpose of the current study was to report our experience with the use of vascularized fibular autograft as rescue technique in failed previous reconstructions after intercalary bone tumor resection of the extremities. Twenty-eight patients were followed over time. Causes of failure were non-union, allograft fracture and infection. Vascularized fibular autograft was used with mechanical support of massive bone allograft in 13 cases. Functional results were excellent in 19 cases, good in 8 and fair in one patient. Among complications we reported 4 non-unions, 2 allograft fractures, 1 non-union with plate breakage, 1 plate breakage, 1 infection, 1 limb shortening and 1 knee varus deformity. The rationale of vascularized fibular autograft is to provide biologic support. The association with massive bone allograft provides mechanical strength and early stability. PMID- 30457499 TI - Arthroscopic treatment of greater tuberosity fractures : retrospective review of clinical and radiological outcomes. AB - The purpose of this retrospective study was to analyze the clinical and radiological outcomes and discuss the value of arthroscopic suture bridge technique in patients with isolated greater tuberosity fractures. Between October 2009 and July 2014, 37 patients with greater tuberosity fractures were analyzed. Thirteen of these patients were treated with arthroscopic reduction and fixation. Analysis of the clinical outcome was performed by comparing final range of motion, UCLA and Constant score. Radiological outcome was analyzed with time for union. Postoperative results were analyzed by range of motion, UCLA and constant score. Each figure resulted as: UCLA from 27 to 35 (average: 29); range of motion in forward flexion from 160 degrees to 180 degrees (average: 173 degrees ); Constant score from 69 to 100 (average: 73). Using arthroscopic treatment with a suture-bridge technique can be a useful method in terms of clinical and functional outcomes and be considered as a viable alternative to conventional open techniques. PMID- 30457500 TI - Systematic review and Meta-analysis on acromioplasty in arthroscopic repair of full-thickness rotator cuff tears. AB - The purpose of this study was to perform a systematic review and meta-analysis including all available randomized controlled trials to determine the role of acromioplasty in arthroscopic repair of full-thickness rotator cuff tears. A literature search was conducted in PubMed, Embase, Cochrane, and Web of Science. All randomized and quasi-randomized controlled trials evaluating the outcomes of arthroscopic repair of full-thickness rotator cuff tears with or without acromioplasty were included in our meta-analysis. After the studies were selected by two reviewers, data were collected and extracted independently. Data were pooled for American Shoulder and Elbow Surgeons (ASES) score, Constant-Murley (CM) score, University of California-Los Angeles (UCLA) score, visual analog scale (VAS) for pain and reoperation rate. Five prospective randomized studies involving 465 patients were included. The current meta-analysis did not show any significant difference between acromioplasty and nonacromioplasty groups with regard to the outcomes for ASES score, CM score, UCLA score (P = .17, .05, and .13, respectively). There was also no significant difference in VAS for pain and reoperation rate between the two groups (P = .87, and .57, respectively). On the basis of the currently available evidence, there was no statistically significant difference in clinical outcomes for patients undergoing arthroscopic rotator cuff repair with or without acromioplasty at short-term follow-up. PMID- 30457501 TI - Anatomically based classification of medial clavicle fractures. AB - Medial clavicle fractures represent less than 5% of all clavicle injuries. The purpose of this study was to evaluate reliability of a new anatomically based (AB) classification system compared to other classification systems and to evaluate the clinical outcome of nonoperative treated fractures. 55 acute medial clavicle fractures (55 patients) were 3D reconstructed and evaluated using the Edinburgh (ED), Throckmorton (TR) and new AB classification. The AB classification classified the fracture as medial (Type 1) or lateral (Type 2) to the costoclavicular ligament and no or minimal displaced (Type A) or displaced (Type B). Next, a consecutive retrospective clinical evaluation of 38 of these patients was performed using the Oxford Shoulder and Constant Score. An anatomically based classification shows the highest inter- and intra-observer reliability. In case the fracture line originate medial to the costoclavicular ligament and is displaced the Constant and Oxford scores are significantly less. PMID- 30457502 TI - Association between the capitate-triquetrum distance and carpal collapse in static scapholunate instability. AB - Long-standing scapholunate instability frequently leads to progressive deterioration of the adjacent joint cartilages in a consistent repetitive sequence of arthritis. The purpose of this study was to investigate whether the capitate-triquetrum distance is related with the occurrence of carpal collapse in cases of static scapholunate instability. In this retrospective study, 41 patients formed two groups based on the capitate-triquetrum distance; twenty-four with distance of less than 5mm and 17 with distance of 5mm or more. No significant difference was detected with respect to age, sex distribution, dominant hand involvement, initial treatment and time from injury to final x rays. Three patients (3/24, 12.5%) of the C-T < 5mm group and 10 patients (10/17, 58.8%) of the C-T >= 5mm group had no sign of carpal collapse. This difference was statistically significant (p=0.017). Capitate-triquetrum distance could reliably contribute in the decision making process in difficult cases of static scapholunate instability. PMID- 30457503 TI - Spontaneous posterior shoulder dislocation as the first symptom of a Charcot arthropathy. AB - Neuroarthropathy or Charcot disease is a destructive joint pathology. Upper limb involvement is unusual and often due to syringomyelia. We reported a patient with spontaneous posterior right shoulder dislocation. Thereafter, she presented a quick joint destruction evoking a Charcot shoulder disease after excluding infectious and rheumatologic diseases. Explorations of this Charcot disease lead to the discovery and treatment of syringomyelia. A conservative management of her shoulder neuro-arthropathy has been proposed to the patient. Shoulder involvement in Charcot disease is unusual: only 5% of cases. 18 cases have been reported in English literature. Two theories try to explain Charcot disease: neuro-vascular and neuro-traumatic. There is no efficient treatment for Charcot shoulder disease but it can be prevented by surgical treatment of syringomyelia. Charcot shoulder is a rare and morbid disease for which conservative treatment is recommended because of disappointing results of arthroplasty and arthrodesis. PMID- 30457504 TI - Sonography-guided arthroscopic excision is more effective for treating volar wrist ganglion than dorsal wrist ganglion. AB - The purpose of this study was to compare the treatment results of sonography guided arthroscopic excision for volar and dorsal wrist ganglions. A total of 42 patients with wrist ganglions underwent sonography-guided arthroscopic resection. Clinical outcome measures included wrist range of motion, grip strength, patient rated questionnaire Hand20, and numerical pain rating scale. All patients were assessed for recurrence throughout the follow-up period. Ganglions were located at the dorsal wrist in 26 cases and at the volar wrist in 16 cases. The mean Hand20 and pain scores were significantly improved after sonography-guided arthroscopic resection for both volar and dorsal wrist ganglions. Recurrence was seen in six cases (23%) of dorsal wrist ganglion but no cases of volar wrist ganglion (P < .05). The use of sonography-guided arthroscopic ganglion excision is better for treating volar wrist ganglion than dorsal wrist ganglion. PMID- 30457505 TI - Outcomes of primary surgical repair of zone 2 dDigital nerve injury. AB - The objective of our study was to assess the functional and sensory outcomes of the primary repair of 138 digital nerve injuries in 48 consecutive patients between January 2012 and November 2014, and to determine whether there were any relationships between demographics, clinical characteristics, or functional test results and post-operative sensory recovery outcomes. Mean follow-up was 14 (range, 10 to 20) months. Sensory evaluation was performed using the static two point discrimination test, and post-operative sensoryrecovery results were classified according to the Seddon Classification: 69 (50%) injuries were S3+, 3 (2%) were S3, 15 (11%) were S2, 18 (13%) were S1, and 33 (24%) were S0. Sensory recovery was associated with time between surgery and testing and with objective functional recovery. More than half of digits sustaining nerve injuries had good intermediate-term recovery of sensation after early primary surgical repair. Surgeon experience and early primary repair may have a favorable impact on results. PMID- 30457506 TI - Evaluation of Moebius syndrome with hand manifestations. AB - Moebius Syndrome (MS) is characterized by congenital paralysis of the 6th and 7th cranial nerves, sometimes combined with deficits in cranial nerves and with limb anomalies. We reported that identifying common upper extremity orthopedic manifestations of this syndrome would asist physicians who care for affected patients to promtly establish a dignosis and treatment plan. Our internal medical record system was queried and a keyword search for "Mobius/Moebius Syndrome" was conducted. The clinical data collected for each patient consisted of age at diagnosis, date of first and date of final follow-up, treatment type, treatment duration, and complications from treatment. Clinical data collected for hand and upper limb deformities included effected side, diagnosis, surgical procedures, and any post-op complications. All data was collected from radiographic images including X-ray, ultrasound, CT, and MRI imaging, and clinical, physical therapy, orthotics, and operative notes. As regards older reports, it is realized that abnormalities in upper extremity in MS is associated with PS. We wish that this descriptive study will be helpful for those physicians who encounter this rare disease, in terms of identifying and providing timely treatment for associated upper extremity abnormalities and for assisting in counseling patients. PMID- 30457507 TI - Internal fixation with Kirschner wires is as efficient as rigid screw fixation in scaphoid fracture: long-term functional outcome. AB - This study aimed to compare the long-term efficacy of Kirschner wires and Herbert screw internal fixation in scaphoid fracture. A retrospective chart with radiographic review and functional follow-up was conducted for patients with the scaphoid fracture. 65 patients (40 for K-wire fixation and 25 for Herbert screw) were enrolled. The nonunion rate for K-wire fixation and screw method were indifferent comprehensively and for iliac graft subgroup. Less bone necrosis was found with K-wire fixation (2.5% vs 16%, P=0.049). There's no difference between groups in Mayo scores, post-operation pain and grid strength. Patients with K wire fixation have larger range of motion on radial/ulnar deviation (35.25+/ 11.32 vs 28.00+/-8.66, P=0.007). The results support the use of Kirschner wires in the treatment of scaphoid fractures. Advantages such as high union rates and good function recovery of wrist could be expected from minimal invasion, multi axial stable fixation. PMID- 30457508 TI - Vertebroplasty (PVP) is effective in the treatment of painful vertebral hemangiomas. AB - We assessed the results of percutaneous vertebroplasty treatment of painful vertebral hemangiomas in 110 patients, with a three years follow-up. 110 patients with painful vertebral hemangiomas were treated by percutaneous vertebroplasty. The patients were diagnosed by MRI and observed for 3 years after surgery. Visual Analog Scale was used to assess the level of pain. Pain significantly diminished in all patients, 90% were free of pain for three years after augmentation. In 10% some pain appeared after 1 year, but less intensive than before surgery. 3 years after vertebroplasty 90% of patients were free of pain. No complications of PVP were observed. In 3 patients extravertebral leakage was noted with no clinical symptoms. PVP is highly effective in the treatment of painful vertebral hemangiomas. The method is safe, produce minimal complications and eliminates, or highly reduces pain for a long time period. PMID- 30457509 TI - Comparison of two temporary fixation techniques for the treatment of type II odontoid fracture. AB - To evaluate and compare the clinical and radiographic results between temporary C1-C2 pedicle screw fixation and cable-dragged reduction and cantilever beam internal fixation. Between 2010 and 2013, temporary C1-C2 pedicle screw fixation (Group P, 28 patients) and cable-dragged reduction following cantilever beam internal fixation (Group C, 33 patients) were performed on type II odontoid fracture cases. Implants were removed after fracture union. All of the 61 surgeries were performed successfully with no iatrogenic neurological worsen. One patient in Group P detected intra-operative vertebral artery injury. All patients gained fracture union. Among the observed indexes, only blood loss in Group P (128.9 +/- 73.9ml) is statistically higher than in Group C (97.3 +/- 5 4.2ml). Pedicle screw fixation carries the risk of vertebral artery injury, especially in patients with high-riding vertebral artery. Cable-dragged reduction following cantilever beam internal fixation could avoid the potential risk of vertebral injury, but it prolonged the fixed segments. We thought cable-dragged reduction following cantilever beam internal fixation could be an alternative method for treating type II odontoid fracture. PMID- 30457510 TI - Flavobacterium tibetense sp. nov., isolated from a wetland. AB - A novel, Gram-stain-negative, non-motile and rod-shaped bacterium, designated YH5T, was isolated from the YonghuCo wetland on the Tibetan Plateau. The strain was able to grow optimally with 1 % (w/v) NaCl and tolerated up to 3 % NaCl. Growth occurred at pH 6-9 (optimum pH 7) and 10-37 degrees C (optimum 30 degrees C). Vitamins were not required for growth. The major polar lipid of strain YH5T was phosphatidylethanolamine. The predominant respiratory quinone was menaquinone 6 (MK-6). The major fatty acids were iso-C15 : 0, C16 : 0 10-methyl and/or iso-C17 : 1omega9c, iso-C17 : 0 3-OH, iso-C15 : 1 G and iso-C15 : 0 3-OH. Genome sequencing revealed a genome size of 2.74 Mbp and a G+C content of 33.3 mol%. Analysis of 16S rRNA gene sequences showed that strain YH5T belonged to the genus Flavobacterium, with the closest neighbours Flavobacterium luticocti xz20T (96.7 % similarity), Flavobacterium jejuense EC11T (96.4 %), Flavobacterium jumunjinense HME7102T (95.9 %) and Flavobacterium dongtanense LW30T (95.6 %). DNA DNA relatedness between strain YH5T and the closest phylogenetically related strain F. luticocti xz20T was 27.0 %. Strain YH5T was clearly distinguished from the reference type strains based on phylogenetic analysis, DNA-DNA hybridization, fatty acid composition and a range of physiological and biochemical characteristics. Based on its phenotypic and chemotaxonomic characteristics, strain YH5T is classified as a representative of a novel species of the genus Flavobacterium, for which the name Flavobacterium tibetense sp. nov. is proposed. The type strain is YH5T (=CICC 24247T=KCTC 62174T). PMID- 30457511 TI - Listeria thailandensis sp. nov. AB - During a screening of Listeria species in food samples in Thailand, a Listeria like bacterium was recovered from fried chicken and could not be assigned to any known species. Phylogenetic analysis based on the 16S rRNA gene and on 243 Listeria core genes placed the novel taxon within the Listeria aquatica, Listeria floridensis, Listeria fleishmannii and Listeria costaricensis clade (Listeria sensu lato), with highest similarity to L. floridensis (98.9 %) and L. costaricensis (98.8 %). Whole-genome sequence analyses based on the average nucleotide blast identity (ANI<86 %), the pairwise amino acid identity (AAI>64 %) and on the percentage of conserved proteins (POCP>77 %) with currently known Listeria species confirmed that the strain constituted a new taxon within the genus Listeria. At the phenotypical level, it differs from other Listeria species by the production of acid from d-tagatose and inositol. The name Listeria thailandensis sp. nov. is proposed for the novel species, and is represented by the type strain CLIP 2015/00305T (=CIP 111635T=DSM 107638T). PMID- 30457512 TI - Reclassification of Xanthomonas gardneri (ex Sutic 1957) Jones et al. 2006 as a later heterotypic synonym of Xanthomonas cynarae Trebaol et al. 2000 and description of X. cynarae pv. cynarae and X. cynarae pv. gardneri based on whole genome analyses. AB - Multilocus sequence analysis of Xanthomonas species revealed a very close relationship between Xanthomonas cynarae, an artichoke pathogen and Xanthomonas gardneri, a tomato and pepper pathogen. Results of whole genome sequence comparisons using average nucleotide identity between representative strains of X. gardneri and X. cynarae were well above the threshold of 95-96 %. Inoculations of X. gardneri strains in artichoke leaves caused mild disease symptoms, but only weak symptoms were observed in the bracts. Both X. cynarae and X. gardneri grew equally and caused typical bacterial spot symptoms in pepper after artificial inoculation. However, X. cynarae induced a hypersensitive reaction in tomato, while X. gardneri strains were virulent. Pathogenicity-associated gene clusters, including the protein secretion systems, type III effector profiles, and lipopolysaccharide cluster were nearly identical between the two species. Based on our results from whole genome sequence comparison, X. gardneri and X. cynarae belong to the same species. The name X. cynarae has priority and X. gardneri should be considered as a later heterotypic synonym. An emended description of X. cynarae (type strain=CFBP 4188T, =DSM 16794T) is given. However, due to the host specificity in artichoke and tomato, two pathovars, X. cynarae pv. cynarae and X. cynarae pv. gardneri, are proposed. PMID- 30457513 TI - Aliidiomarina celeris sp. nov., isolated from coastal sediment. AB - A Gram-stain-negative, heterotrophic, facultative anaerobic, gliding and motile bacterium, approximately 0.6-0.9 um wide and 1.5-2.6 um long, designated F3105T, was isolated from a marine sediment sample collected along the coast of Rongcheng, China . The growth of strain F3105T occurred on media with 1.0-8.0 % (w/v) NaCl (optimum, 2.0-3.0 %) and a pH of 6.5-9.5 (optimum, pH 7.5) at 4-45 degrees C (optimum, 37 degrees C). The phylogenetic analysis of the 16S rRNA gene and chemotaxonomic data revealed that the isolate belonged to the genus Aliidiomarina, and is closely related to Aliidiomarina shirensis (95.9 % sequence similarity). The sole isoprenoid quinone was Q-8. The major cellular fatty acids of the isolate were iso-C15 : 0, iso-C17 : 1omega9c and iso-C17 : 0, and its polar lipids consisted of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, aminolipid, two unidentified lipids and two unidentified aminophospholipids. The DNA G+C content of strain F3105T was 49.5 mol%. On the basis of phenotypic distinctiveness and phylogenetic divergence, strain F3105T is considered to represent a novel species of the genus Aliidiomarina, for which the name Aliidiomarinaceleris sp. nov. is proposed. The type strain is F3105T (=MCCC 1H00223T=KCTC 52891T). PMID- 30457514 TI - Arenibacillus arenosus gen. nov., sp. nov., a member of the family Rhodobacteraceae isolated from sea sand. AB - A Gram-stain-negative, aerobic, non-motile, non-spore-forming, rod-shaped bacterial strain, designated CAU 1304T, was isolated from sea sand. Strain CAU 1304T grew optimally at pH 8.5 and 30 degrees C and in the presence of 1 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain CAU 1304T belonged to the family Rhodobacteraceae, and was most closely related to Roseicitreum antarcticum ZS2-28T (96.54 % similarity) and Rhodobacter veldkampii ATCC 35703T (96.46 %). The major fatty acid was C18 : 1omega7c and the respiratory quinone was Q-10. The polar lipids were composed of phosphatidylglycerol, phosphatidylcholine and an unidentified aminolipid. The DNA G+C content was 55.9 mol%. On the basis of phenotypic, chemotaxonomic and phylogenetic analysis, it is proposed that strain CAU 1304T represents a novel species of a new genus of the family Rhodobacteraceae, for which the name Arenibacillus arenosus gen. nov., sp. nov. is proposed. The type strain of Arenibacillus arenosus is CAU 1304T (=KCTC 42827T=NBRC 113022T). PMID- 30457515 TI - SrcA is a chaperone for the Salmonella SPI-2 type three secretion system effector SteD. AB - Effector proteins of type three secretion systems (T3SS) often require cytosolic chaperones for their stabilization, to interact with the secretion machinery and to enable effector delivery into host cells. We found that deletion of srcA, previously shown to encode a chaperone for the Salmonella pathogenicity island 2 (SPI-2) T3SS effectors SseL and PipB2, prevented the reduction of mature Major Histocompatibility Complex class II (mMHCII) from the surface of antigen presenting cells during Salmonella infection. This activity was shown previously to be caused by the SPI-2 T3SS effector SteD. Since srcA and steD are located in the same operon on the Salmonella chromosome, this suggested that the srcA phenotype might be due to an indirect effect on SteD. We found that SrcA is not translocated by the SPI-2 T3SS but interacts directly and forms a stable complex with SteD in bacteria with a 2 : 1 stoichiometry. We found that SrcA was not required for SPI-2 T3SS-dependent, neutral pH-induced secretion of either SseL or PipB2 but was essential for secretion of SteD. SrcA therefore functions as a chaperone for SteD, explaining its requirement for the reduction in surface levels of mMHCII. PMID- 30457516 TI - Mesorhizobium carmichaelinearum sp. nov., isolated from Carmichaelineae spp. root nodules. AB - Five strains of Gram-stain-negative, rod-shaped bacteria were isolated from Carmichaelia and Montigena root nodules. Based on 16S rRNA gene phylogeny, they were shown to belong to the genus Mesorhizobium, and to be most closely related to Mesorhizobium jarvisii ATCC 33669T (100-99.6 % sequence similarity), Mesorhizobium huakuii IAM 14158T (99.9-99.6 %), Mesorhizobium japonicum MAFF303099T (99.8-99.6 %) and Mesorhizobium erdmanii USDA 3471T (99.8-99.5 %). Additionally, the strains formed distinct groups based on housekeeping gene analysis and were most closely related to M. jarvisii ATCC 33669T (89.6-89.5 and 97.6-97.3 % sequence similarity for glnII and recA, respectively), M. erdmanii USDA 3471T (94.3-94.0 and 94.9-94.1 %), M. japonicum MAFF303099T (90.0-89.9 and 96.7-96.2 %) and M. huakuii IAM 14158T (89.9-90.0 and 95.4-94.9 %). Chemotaxonomic data supported the assignment of the strains to the genus Mesorhizobium and DNA-DNA hybridizations, average nucleotide identity analysis, matrix-assisted laser desorption ionization time-of-flight MS analysis, physiological and biochemical tests differentiated them genotypically and phenotypically from their nearest neighbouring species. Therefore, these strains are considered to represent a novel species, for which the name Mesorhizobium carmichaelinearum sp. nov. is proposed. The type strain is ICMP 18942T (=MonP1N1T=LMG 28414T). PMID- 30457517 TI - Spread of the emerging equine-like G3P[8] DS-1-like genetic backbone rotavirus strain in Brazil and identification of potential genetic variants. AB - In 2013, the equine-like G3P[8] DS-1-like rotavirus (RVA) strain emerged worldwide. In 2016, this strain was reported in northern Brazil. The aims of the study were to conduct a retrospective genetic investigation to identify the possible entry of these atypical strains in Brazil and to describe their distribution across a representative area of the country. From 2013 to 2017, a total of 4226 faecal samples were screened for RVA by ELISA, PAGE, RT-PCR and sequencing. G3P[8] represented 20.9 % (167/800) of all RVA-positive samples, further subdivided as equine-like G3P[8], DS-1-like (11.0 %; 88/800) and Wa-like G3P[8] (9.9 %; 79/800). Six equine-like G3P[8] DS-1-like samples were selected for whole-genome investigation, confirming the backbone I2-R2-C2-M2-A2-N2-T2-E2 H2. During 2013-2014, Wa-like G3P[8] was predominant and no equine-like G3P[8] DS 1-like was detected. Equine-like G3P[8] DS-1-like was first identified in Parana in March/2015, suggesting that the strain entered Brazil through the Southern region. Equine-like G3P[8] rapidly spread across the area under surveillance and displayed a marked potential to replace Wa-like G3P[8] strains. Brazilian equine like G3P[8] DS-1-like strains clustered with contemporary equine-like G3P[8] DS-1 like detected worldwide, but exhibited a distinct NSP2 genotype (N2) compared to the previously reported Amazon equine-like G3P[8] DS-1-like strain (N1). Two distinct NSP4 E2 genotype lineages were also identified. Taken together, these data suggest that different variants of equine-like G3P[8] DS-1-like strains might have been introduced into the country at distinct time points, and co circulated in the period 2015-2017. The global emergence of equine-like G3P[8] DS 1-like strains, predominantly in countries using the Rotarix vaccine, raises the question of whether vaccines may be inducing selective pressures on zoonotic strains. PMID- 30457518 TI - Restaurant Inspection Letter Grades and Salmonella Infections, New York, New York, USA. AB - Rates of Salmonella infection in the United States have not changed over the past 20 years. Restaurants are frequent settings for Salmonella outbreaks and sporadic infections. Few studies have examined the effect of posting letter grades for restaurant inspections on the incidence of foodborne illness. We compared Salmonella infection rates in New York, New York, USA (NYC), with those in the rest of New York state before and after implementation of a letter grade system for restaurant inspections in NYC. We calculated a segmented regression model for interrupted time series data. After implementation of letter grading, the rate of Salmonella infections decreased 5.3% per year in NYC versus the rest of New York state during 2011-2015, compared with the period before implementation, 2006 2010. Posting restaurant inspection results as letter grades at the point of service was associated with a decline in Salmonella infections in NYC and warrants consideration for broader use. PMID- 30457519 TI - Vaccinia Virus among Domestic Dogs and Wild Coatis, Brazil, 2013-2015. AB - To determine their potential role as a source of human infection, we tested domestic dogs (urban) and wild coatis (wild) in Brazil for vaccinia virus. Our findings of positive neutralizing antibodies and quantitative PCR results for 35/184 dogs and 13/90 coatis highlight a potential public health risk. PMID- 30457520 TI - Capnocytophaga canimorsus Capsular Serovar and Disease Severity, Helsinki Hospital District, Finland, 2000-2017. AB - We assembled a collection of 73 Capnocytophaga canimorsus isolates obtained from blood cultures taken from patients treated at Helsinki University Hospital (Helsinki, Finland) during 2000-2017. We serotyped these isolates by PCR and Western blot and attempted to correlate pathogen serovar with patient characteristics. Our analyses showed, in agreement with previous research, that 3 C. canimorsus serovars (A-C) caused most (91.8%) human infections, despite constituting only 7.6% of isolates found in dogs. The 3 fatalities that occurred in our cohort were equally represented by these serovars. We found 2 untypeable isolates, which we designated serovars J and K. We did not detect an association between serovar and disease severity, immune status, alcohol abuse, or smoking status, but dog bites occurred more frequently among patients infected with non-A C serovars. Future research is needed to confirm serovar virulence and develop strategies to reduce risk for these infections in humans. PMID- 30457521 TI - Crimean-Congo Hemorrhagic Fever Virus, Mongolia, 2013-2014. AB - During 2013-2014, we collected 1,926 serum samples from humans and 4,583 ticks (Hyalomma asiaticum or Dermacentor nuttalli) in select regions of Mongolia to determine the risk for Crimean-Congo hemorrhagic fever virus (CCHFV) infection among humans in this country. Testing of human serum samples by ELISA demonstrated an overall CCHFV antibody prevalence of 1.4%; Bayankhongor Province had the highest prevalence, 2.63%. We pooled and analyzed tick specimens by real time reverse transcription PCR; 1 CCHFV-positive H. asiaticum tick pool from Omnogovi was identified. In phylogenetic analyses, the virus's partial small segment clustered with CCHFV isolates from Central Asia, and the complete medium segment grouped with CCHFV isolates from Africa, Asia, and the Middle East. This study confirms CCHFV endemicity in Mongolia and provides information on risk for CCHFV infection. Further research is needed to better define the risk for CCHFV disease to improve risk mitigation, diagnostics, and surveillance. PMID- 30457522 TI - Spatial Analysis of Wildlife Tuberculosis Based on a Serologic Survey Using Dried Blood Spots, Portugal. AB - We investigated the spatial epidemiology of bovine tuberculosis (TB) in wildlife in a multihost system. We surveyed bovine TB in Portugal by serologic analysis of elutes of dried blood spots obtained from hunted wild boar. We modeled spatial disease risk by using areal generalized linear mixed models with conditional autoregressive priors. Antibodies against Mycobaterium bovis were detected in 2.4% (95% CI 1.5%-3.8%) of 678 wild boar in 2 geographic clusters, and the predicted risk fits well with independent reports of M. bovis culture. Results show that elutes are an almost perfect substitute for serum (Cohen unweighted kappa = 0.818), indicating that serologic tests coupled with dried blood spots are an effective strategy for large-scale bovine TB surveys, using wild boar as sentinel species. Results also show that bovine TB is an emerging wildlife disease and stress the need to prevent further geographic spread and prevalence increase. PMID- 30457523 TI - Neglected Hosts of Small Ruminant Morbillivirus. AB - Eradication of small ruminant morbillivirus (PPRV) is targeted for 2030. PPRV lineage IV is found in much of Asia and Africa. We used PPRV lineage IV strain Kurdistan/2011 in transmission trials to investigate the role of pigs, wild boar, and small ruminants as PPRV reservoirs. Suids were a possible source of infection. PMID- 30457524 TI - Highly Pathogenic Avian Influenza A(H5N6) in Domestic Cats, South Korea. AB - In December 2016, highly pathogenic avian influenza (HPAI) infection with systemic pathologic lesions was found in cats in South Korea. Genetic analyses indicated that the feline isolates were similar to HPAI H5N6 viruses isolated in chicken farms nearby. This finding highlights the need for monitoring of domestic mammals during HPAI outbreaks. PMID- 30457525 TI - Borrelia miyamotoi Infections in Small Mammals, California, USA. AB - Surveillance to investigate the wildlife-vector transmission cycle of the human pathogen Borrelia miyamotoi in California, USA, revealed infections in dusky footed woodrats, brush mice, and California mice. Phylogenetic analyses suggest a single, well-supported clade of B. miyamotoi is circulating in California. PMID- 30457526 TI - Novel Type of Chronic Wasting Disease Detected in Moose (Alces alces), Norway. AB - Chronic wasting disease (CWD) persists in cervid populations of North America and in 2016 was detected for the first time in Europe in a wild reindeer in Norway. We report the detection of CWD in 3 moose (Alces alces) in Norway, identified through a large scale surveillance program. The cases occurred in 13-14-year-old female moose, and we detected an abnormal form of prion protein (PrPSc) in the brain but not in lymphoid tissues. Immunohistochemistry revealed that the moose shared the same neuropathologic phenotype, characterized by mostly intraneuronal deposition of PrPSc. This pattern differed from that observed in reindeer and has not been previously reported in CWD-infected cervids. Moreover, Western blot revealed a PrPSc type distinguishable from previous CWD cases and from known ruminant prion diseases in Europe, with the possible exception of sheep CH1641. These findings suggest that these cases in moose represent a novel type of CWD. PMID- 30457527 TI - Candidatus Cryptoplasma Associated with Green Lizards and Ixodes ricinus Ticks, Slovakia, 2004-2011. AB - During 2004-2011, we collected green lizards and Ixodes ricinus ticks in Slovak Karst National Park in Slovakia; 90% (36/40) of lizards and 37% of ticks removed from lizards were infected with family Anaplasmataceae bacteria. Only Candidatus Cryptoplasma sp. REP (reptile) was identified in these samples. Green lizards transmit this bacterium. PMID- 30457528 TI - Comparison of 2016-17 and Previous Epizootics of Highly Pathogenic Avian Influenza H5 Guangdong Lineage in Europe. AB - We analyzed the highly pathogenic avian influenza (HPAI) H5 epizootic of 2016-17 in Europe by epidemiologic and genetic characteristics and compared it with 2 previous epizootics caused by the same H5 Guangdong lineage. The 2016-17 epizootic was the largest in Europe by number of countries and farms affected and greatest diversity of wild birds infected. We observed significant differences among the 3 epizootics regarding region affected, epidemic curve, seasonality, and outbreak duration, making it difficult to predict future HPAI epizootics. However, we know that in 2005-06 and 2016-17 the initial peak of wild bird detections preceded the peak of poultry outbreaks within Europe. Phylogenetic analysis of 2016-17 viruses indicates 2 main pathways into Europe. Our findings highlight the need for global surveillance of viral changes to inform disease preparedness, detection, and control. PMID- 30457529 TI - Human Exposure to Novel Bartonella Species from Contact with Fruit Bats. AB - Twice a year in southwestern Nigeria, during a traditional bat festival, community participants enter designated caves to capture bats, which are then consumed for food or traded. We investigated the presence of Bartonella species in Egyptian fruit bats (Rousettus aegyptiacus) and bat flies (Eucampsipoda africana) from these caves and assessed whether Bartonella infections had occurred in persons from the surrounding communities. Our results indicate that these bats and flies harbor Bartonella strains, which multilocus sequence typing indicated probably represent a novel Bartonella species, proposed as Bartonella rousetti. In serum from 8 of 204 persons, we detected antibodies to B. rousetti without cross-reactivity to other Bartonella species. This work suggests that bat associated Bartonella strains might be capable of infecting humans. PMID- 30457530 TI - Rat Hepatitis E Virus as Cause of Persistent Hepatitis after Liver Transplant. AB - All hepatitis E virus (HEV) variants reported to infect humans belong to the species Orthohepevirus A (HEV-A). The zoonotic potential of the species Orthohepevirus C (HEV-C), which circulates in rats and is highly divergent from HEV-A, is unknown. We report a liver transplant recipient with hepatitis caused by HEV-C infection. We detected HEV-C RNA in multiple clinical samples and HEV-C antigen in the liver. The complete genome of the HEV-C isolate had 93.7% nt similarity to an HEV-C strain from Vietnam. The patient had preexisting HEV antibodies, which were not protective against HEV-C infection. Ribavirin was an effective treatment, resulting in resolution of hepatitis and clearance of HEV-C viremia. Testing for this zoonotic virus should be performed for immunocompromised and immunocompetent patients with unexplained hepatitis because routine hepatitis E diagnostic tests may miss HEV-C infection. HEV-C is also a potential threat to the blood product supply. PMID- 30457531 TI - Terrestrial Bird Migration and West Nile Virus Circulation, United States. AB - Host migration and emerging pathogens are strongly associated, especially with regard to zoonotic diseases. West Nile virus (WNV), a mosquitoborne pathogen capable of causing severe, sometimes fatal, neuroinvasive disease in humans, is maintained in highly mobile avian hosts. Using phylogeographic approaches, we investigated the relationship between WNV circulation in the United States and the flight paths of terrestrial birds. We demonstrated southward migration of WNV in the eastern flyway and northward migration in the central flyway, which is consistent with the looped flight paths of many terrestrial birds. We also identified 3 optimal locations for targeted WNV surveillance campaigns in the United States-Illinois, New York, and Texas. These results illustrate the value of multidisciplinary approaches to surveillance of infectious diseases, especially zoonotic diseases. PMID- 30457532 TI - Highly Pathogenic Clone of Shiga Toxin-Producing Escherichia coli O157:H7, England and Wales. AB - We used whole-genome sequencing to investigate the evolutionary context of an emerging highly pathogenic strain of Shiga toxin-producing Escherichia coli (STEC) O157:H7 in England and Wales. A timed phylogeny of sublineage IIb revealed that the emerging clone evolved from a STEC O157:H7 stx-negative ancestor ~10 years ago after acquisition of a bacteriophage encoding Shiga toxin (stx) 2a, which in turn had evolved from a stx2c progenitor ~20 years ago. Infection with the stx2a clone was a significant risk factor for bloody diarrhea (OR 4.61, 95% CI 2.24-9.48; p<0.001), compared with infection with other strains within sublineage IIb. Clinical symptoms of cases infected with sublineage IIb stx2c and stx-negative clones were comparable, despite the loss of stx2c. Our analysis highlighted the highly dynamic nature of STEC O157:H7 Stx-encoding bacteriophages and revealed the evolutionary history of a highly pathogenic clone emerging within sublineage IIb, a sublineage not previously associated with severe clinical symptoms. PMID- 30457533 TI - CTX-M-65 Extended-Spectrum beta-Lactamase-Producing Salmonella enterica Serotype Infantis, United States1. AB - Extended-spectrum beta-lactamases (ESBLs) confer resistance to clinically important third-generation cephalosporins, which are often used to treat invasive salmonellosis. In the United States, ESBLs are rarely found in Salmonella. However, in 2014, the US Food and Drug Administration found blaCTX-M-65 ESBL producing Salmonella enterica serotype Infantis in retail chicken meat. The isolate had a rare pulsed-field gel electrophoresis pattern. To clarify the sources and potential effects on human health, we examined isolates with this pattern obtained from human surveillance and associated metadata. Using broth microdilution for antimicrobial susceptibility testing and whole-genome sequencing, we characterized the isolates. Of 34 isolates, 29 carried the blaCTX M-65 gene with <9 additional resistance genes on 1 plasmid. Of 19 patients with travel information available, 12 (63%) reported recent travel to South America. Genetically, isolates from travelers, nontravelers, and retail chicken meat were similar. Expanded surveillance is needed to determine domestic sources and potentially prevent spread of this ESBL-containing plasmid. PMID- 30457534 TI - Rat Lungworm Infection in Rodents across Post-Katrina New Orleans, Louisiana, USA. AB - Rat lungworm (Angiostrongylus cantonensis), a parasitic nematode that can cause eosinophilic meningitis in humans, was first detected in New Orleans, Louisiana, USA, in the mid-1980s and now appears to be widespread in the southeastern United States. We assessed the distribution, prevalence, and intensity of A. cantonensis infection in New Orleans by examining lung biopsy samples of rodents trapped at 96 sites in 9 areas in Orleans Parish and 1 area in neighboring St. Bernard Parish during May 2015 through February 2017. These areas were selected to capture contrasting levels of income, flooding, and pos-disaster landscape management after Hurricane Katrina in 2005. We detected A. cantonensis in all areas and in 3 of the 4 rat species trapped. Overall prevalence was ~38% but varied by area, host species, and host species co-occurrence. Infection intensity also varied by host species. These findings suggest that socioecological analysis of heterogeneity in definitive and intermediate host infection could improve understanding of health risks across the city. PMID- 30457535 TI - Locally Acquired Leptospirosis in Expedition Racer, Manitoba, Canada. AB - Leptospirosis is found worldwide, except in northern regions. We report a case associated with a backcountry adventure race in Manitoba, Canada. Initially, nonspecific symptomatology and diagnostic pitfalls contributed to a delay in identification. Careful attention needs to be paid to exposure to and risk for leptospirosis in northern and temperate climates. PMID- 30457536 TI - Substance Use and Adherence to HIV Preexposure Prophylaxis for Men Who Have Sex with Men1. AB - The effectiveness of oral HIV preexposure prophylaxis (PrEP) strongly depends on maintaining adherence. We investigated the association between substance use and PrEP adherence, as well as incident sexually transmitted infections (STIs) in a high-risk cohort of 394 participants (391 men who have sex with men and 3 transgender women) who were enrolled in a PrEP demonstration project. We assessed baseline and ongoing substance use over a 48-week period for stimulants and nonstimulant substances and for each substance separately. We measured PrEP adherence by using dried blood spots to obtain levels of tenofovir diphosphate. No differences in these levels were found between substance users and nonsubstance users. Baseline stimulant use was strongly associated (odds ratio 3.4; p<0.001) with incident STIs during the study. Thus, PrEP adherence was not decreased by substance use. Because substance users had increased rates of STIs, indicating higher-risk behavior, they might be excellent candidates for PrEP. PMID- 30457538 TI - Using PCR-Based Sequencing to Diagnose Haycocknema perplexum Infection in Human Myositis Case, Australia. AB - We report a case of myositis in a male patient in Australia who had progressive weakness and wasting in his left lower limb. Although clinical, pathologic, and laboratory assessments were inconclusive, a new, nested PCR-coupled sequencing method enabled the unequivocal diagnosis of myositis caused by the enigmatic nematode Haycocknema perplexum. PMID- 30457537 TI - Risk Factors for Acquiring Scrub Typhus among Children in Deoria and Gorakhpur Districts, Uttar Pradesh, India, 2017. AB - Scrub typhus is associated with outbreaks of acute encephalitis syndrome in Uttar Pradesh, India. A case-control study indicated that children residing, playing, or visiting fields; living with firewood stored indoors; handling cattle fodder; and practicing open defecation were at increased risk for scrub typhus. Communication messages should focus on changing these behaviors. PMID- 30457539 TI - Conservation of White Rhinoceroses Threatened by Bovine Tuberculosis, South Africa, 2016-2017. AB - During 2016-2017, when Kruger National Park, South Africa, was under quarantine to limit bovine tuberculosis spread, we examined 35 white and 5 black rhinoceroses for infection. We found 6 infected white rhinoceroses during times of nutritional stress. Further research on Mycobacterium bovis pathogenesis in white rhinoceroses is needed. PMID- 30457540 TI - Strongyloidiasis and Culture-Negative Suppurative Meningitis, Japan, 1993-2015. AB - Community-acquired Enterobacteriaceae infection and culture-negative meningitis are rare and atypical subtypes of meningitis in adults. Of 37 patients who had atypical suppurative meningitis during 1993-2015 in Okinawa, Japan, 54.5% had strongyloidiasis, of which 9.1% cases were hyperinfections and 3.0% dissemination. Strongyloidiasis should be considered an underlying cause of atypical suppurative meningitis. PMID- 30457541 TI - Disseminated Spiroplasma apis Infection in Patient with Agammaglobulinemia, France. AB - We report a disseminated infection caused by Spiroplasma apis, a honeybee pathogen, in a patient in France who had X-linked agammaglobulinemia. Identification was challenging because initial bacterial cultures and direct examination by Gram staining were negative. Unexplained sepsis in patients with agammaglobulinemia warrants specific investigation to identify fastidious bacteria such as Spiroplasma spp. PMID- 30457542 TI - Outbreak of HIV Infection Linked to Nosocomial Transmission, China, 2016-2017. AB - On January 25, 2017, a physician from ZC Hospital in Hangzhou, China, reported to the Zhejiang Provincial Center for Disease Control and Prevention that a potential HIV outbreak might have occurred during lymphocyte immunotherapy (LIT) performed at the hospital on December 30, 2016. We immediately began investigating and identified the index case-patient as an LIT patient's husband who donated lymphocytes for his wife's LIT and later screened HIV-reactive. Subsequent contamination by a technician resulted in the potential exposure of 34 LIT patients. Acute HIV infection was diagnosed in 5 persons. Phylogenetic analysis confirmed that the HIV-1 gag, pol, and env gene sequences from the index and outbreak-related cases had >99.5% similarity. Rapid investigation and implementation of effective control measures successfully controlled the outbreak. This incident provides evidence of a lapse in infection control causing HIV transmission, highlighting the need for stronger measures to protect patients from infectious disease exposure. PMID- 30457543 TI - Chuzan Virus in Yaks, Qinghai-Tibetan Plateau, China. AB - We detected Chuzan virus (CHUV) in domestic yaks from the Qinghai-Tibetan Plateau, western China, indicating CHUV probably has been transmitted to yaks in recent years. Awareness for CHUV surveillance and transmission and livestock health management in these special regions should be raised to avoid outbreaks and animal loss. PMID- 30457544 TI - Genomic Characterization of beta-Glucuronidase-Positive Escherichia coli O157:H7 Producing Stx2a. AB - Among Shiga toxin (Stx)-producing Escherichia coli (STEC) O157:H7 strains, those producing Stx2a cause more severe diseases. Atypical STEC O157:H7 strains showing a beta-glucuronidase-positive phenotype (GP STEC O157:H7) have rarely been isolated from humans, mostly from persons with asymptomatic or mild infections; Stx2a-producing strains have not been reported. We isolated, from a patient with bloody diarrhea, a GP STEC O157:H7 strain (PV15-279) that produces Stx2a in addition to Stx1a and Stx2c. Genomic comparison with other STEC O157 strains revealed that PV15-279 recently emerged from the stx1a/stx2c-positive GP STEC O157:H7 clone circulating in Japan. Major virulence genes are shared between typical (beta-glucuronidase-negative) and GP STEC O157:H7 strains, and the Stx2 producing ability of PV15-279 is comparable to that of typical STEC O157:H7 strains; therefore, PV15-279 presents a virulence potential similar to that of typical STEC O157:H7. This study reveals the importance of GP O157:H7 as a source of highly pathogenic STEC clones. PMID- 30457546 TI - Influences of Community Interventions on Zika Prevention Behaviors of Pregnant Women, Puerto Rico, July 2016-June 20171. AB - We assessed how community education efforts influenced pregnant women's Zika prevention behaviors during the 2016 Centers for Disease Control and Prevention Puerto Rico Department of Health Zika virus response. Efforts included Zika virus training, distribution of Zika prevention kits, a mass media campaign, and free home mosquito spraying. We used telephone interview data from pregnant women participating in Puerto Rico's Women, Infants, and Children Program to test associations between program participation and Zika prevention behaviors. Behavior percentages ranged from 4% (wearing long-sleeved shirt) to 90% (removing standing water). Appropriate mosquito repellent use (28%) and condom use (44%) were common. Receiving a Zika prevention kit was significantly associated with larvicide application (odds ratio [OR] 8.0) and bed net use (OR 3.1), suggesting the kit's importance for lesser-known behaviors. Offer of free residential spraying was associated with spraying home for mosquitoes (OR 13.1), indicating that women supported home spraying when barriers were removed. PMID- 30457547 TI - Mycoplasma ovipneumoniae in Wildlife Species beyond Subfamily Caprinae. AB - Elucidating the emergence of Mycoplasma ovipneumoniae-associated respiratory disease in ruminants requires identification of the pathogen host range. This bacterium was thought to be host restricted to subfamily Caprinae, but we describe its identification in healthy moose, caribou, and mule deer and diseased mule and white-tailed deer, all species in subfamily Capreolinae. PMID- 30457545 TI - Prevalence of Avian Influenza A(H5) and A(H9) Viruses in Live Bird Markets, Bangladesh. AB - We conducted a cross-sectional study in live bird markets (LBMs) in Dhaka and Chittagong, Bangladesh, to estimate the prevalence of avian influenza A(H5) and A(H9) viruses in different types of poultry and environmental areas by using Bayesian hierarchical logistic regression models. We detected these viruses in nearly all LBMs. Prevalence of A(H5) virus was higher in waterfowl than in chickens, whereas prevalence of A(H9) virus was higher in chickens than in waterfowl and, among chicken types, in industrial broilers than in cross-breeds and indigenous breeds. LBMs with >1 wholesaler were more frequently contaminated by A(H5) virus than retail-only LBMs. Prevalence of A(H9) virus in poultry and level of environmental contamination were also higher in LBMs with >1 wholesaler. We found a high level of circulation of both avian influenza viruses in surveyed LBMs. Prevalence was influenced by type of poultry, environmental site, and trading. PMID- 30457548 TI - Isolation of Burkholderia pseudomallei from a Pet Green Iguana, Belgium. AB - We isolated Burkholderia pseudomallei, the causative agent of melioidosis, from liver granulomas of a pet green iguana (Iguana iguana) in Belgium. This case highlights a risk for imported green iguanas acting as a reservoir for introduction of this high-threat, zoonotic pathogen into nonendemic regions. PMID- 30457549 TI - Use of Next-Generation Sequencing for Diagnosis of West Nile Virus Infection in Patient Returning to Belgium from Hungary. AB - An elderly patient in Belgium who became critically ill after returning from Hungary was tested for pathogens using routine diagnostic tests. All results were negative. However, using next-generation sequencing on a cultured respiratory sample, laboratorians detected a complete West Nile virus genome, similar to strains isolated in southeastern Europe. PMID- 30457550 TI - In-Host Adaptation of Salmonella enterica Serotype Dublin during Prosthetic Hip Joint Infection. AB - Genome degradation has been central to the adaptation of Salmonella enterica serotypes to their hosts throughout evolution. We witnessed the patho-adaptation of a strain of Salmonella Dublin (a cattle-adapted serotype) to a human host during the course of a recurrent prosthetic hip joint infection evolving over several years. PMID- 30457551 TI - Emerging Multidrug-Resistant Hybrid Pathotype Shiga Toxin-Producing Escherichia coli O80 and Related Strains of Clonal Complex 165, Europe. AB - Enterohemorrhagic Escherichia coli serogroup O80, involved in hemolytic uremic syndrome associated with extraintestinal infections, has emerged in France. We obtained circularized sequences of the O80 strain RDEx444, responsible for hemolytic uremic syndrome with bacteremia, and noncircularized sequences of 35 O80 E. coli isolated from humans and animals in Europe with or without Shiga toxin genes. RDEx444 harbored a mosaic plasmid, pR444_A, combining extraintestinal virulence determinants and a multidrug resistance-encoding island. All strains belonged to clonal complex 165, which is distantly related to other major enterohemorrhagic E. coli lineages. All stx-positive strains contained eae-xi, ehxA, and genes characteristic of pR444_A. Among stx-negative strains, 1 produced extended-spectrum beta-lactamase, 1 harbored the colistin resistance gene mcr1, and 2 possessed genes characteristic of enteropathogenic and pyelonephritis E. coli. Because O80-clonal complex 165 strains can integrate intestinal and extraintestinal virulence factors in combination with diverse drug resistance genes, they constitute dangerous and versatile multidrug-resistant pathogens. PMID- 30457552 TI - Metazoan parasite communities of two deep-sea elasmobranchs: the southern lanternshark, Etmopterus granulosus, and the largenose catshark, Apristurus nasutus, in the Southeastern Pacific Ocean. AB - Two deep-sea shark species were obtained as by-catch of the local fishery of the Patagonian toothfish, Dissostichus eleginoides, at depths ranging from 1000 to 2200 m off central and northern Chile. A total of 19 parasite taxa were found in 133 specimens of the southern lanternshark, Etmopterus granulosus, (n = 120) and largenose catshark, Apristurus nasutus, (n = 13). Fourteen taxa (four Monogenea, one Digenea, four Cestoda, one Nematoda, two Copepoda, one Annelida and one Thecostraca) were found in E. granulosus, whereas five taxa (one Monogenea, two Cestoda and two Nematoda) were found in A. nasutus. Representatives of Cestoda showed higher values of prevalence and a greater intensity of infection; this pattern is consistent with reports for elasmobranchs, but the monogenean richness was higher than that previously reported for related deep-sea sharks. Regarding E. granulosus, a positive and significant correlation between host length and abundance was found for six (four ectoparasites, one mesoparasite, and one endoparasite) of the 14 taxa recorded, but prevalence was significantly correlated with host length only for the monogenean Asthenocotyle sp. Although the sample size for A. nasutus was limited, we compared richness, abundance, diversity and evenness at the infracommunity and component community levels. All of these variables were higher for E. granulosus, but at the infracommunity level, abundance was higher for A. nasutus. All the parasite taxa (except two) represent new host and geographical records. PMID- 30457554 TI - CryoEM structures of open dimers of gyrase A in complex with DNA illuminate mechanism of strand passage. AB - Gyrase is a unique type IIA topoisomerase that uses ATP hydrolysis to maintain the negatively supercoiled state of bacterial DNA. In order to perform its function, gyrase undergoes a sequence of conformational changes that consist of concerted gate openings, DNA cleavage, and DNA strand passage events. Structures where the transported DNA molecule (T-segment) is trapped by the A subunit have not been observed. Here we present the cryoEM structures of two oligomeric complexes of open gyrase A dimers and DNA. The protein subunits in these complexes were solved to 4 A and 5.2 A resolution. One of the complexes traps a linear DNA molecule, a putative T-segment, which interacts with the open gyrase A dimers in two states, representing steps either prior to or after passage through the DNA-gate. The structures locate the T-segment in important intermediate conformations of the catalytic cycle and provide insights into gyrase-DNA interactions and mechanism. PMID- 30457555 TI - Genome-wide Estrogen Receptor-alpha activation is sustained, not cyclical. AB - Estrogen Receptor-alpha (ER) drives 75% of breast cancers. Stimulation of the ER by estra-2-diol forms a transcriptionally-active chromatin-bound complex. Previous studies reported that ER binding follows a cyclical pattern. However, most studies have been limited to individual ER target genes and without replicates. Thus, the robustness and generality of ER cycling are not well understood. We present a comprehensive genome-wide analysis of the ER after activation, based on 6 replicates at 10 time-points, using our method for precise quantification of binding, Parallel-Factor ChIP-seq. In contrast to previous studies, we identified a sustained increase in affinity, alongside a class of estra-2-diol independent binding sites. Our results are corroborated by quantitative re-analysis of multiple independent studies. Our new model reconciles the conflicting studies into the ER at the TFF1 promoter and provides a detailed understanding in the context of the ER's role as both the driver and therapeutic target of breast cancer. PMID- 30457553 TI - Proteolytically released Lasso/teneurin-2 induces axonal attraction by interacting with latrophilin-1 on axonal growth cones. AB - A presynaptic adhesion G-protein-coupled receptor, latrophilin-1, and a postsynaptic transmembrane protein, Lasso/teneurin-2, are implicated in trans synaptic interaction that contributes to synapse formation. Surprisingly, during neuronal development, a substantial proportion of Lasso is released into the intercellular space by regulated proteolysis, potentially precluding its function in synaptogenesis. We found that released Lasso binds to cell-surface latrophilin 1 on axonal growth cones. Using microfluidic devices to create stable gradients of soluble Lasso, we show that it induces axonal attraction, without increasing neurite outgrowth. Using latrophilin-1 knockout in mice, we demonstrate that latrophilin-1 is required for this effect. After binding latrophilin-1, Lasso causes downstream signaling, which leads to an increase in cytosolic calcium and enhanced exocytosis, processes that are known to mediate growth cone steering. These findings reveal a novel mechanism of axonal pathfinding, whereby latrophilin-1 and Lasso mediate both short-range interaction that supports synaptogenesis, and long-range signaling that induces axonal attraction. PMID- 30457556 TI - Validity and Reliability of the measure yourself medical outcome profile 2 (MYMOP2) questionnaire among Turkish patients having anorectal disorders. AB - BACKGROUND/AIMS: Measure Yourself Medical Outcome Profile 2 (MYMOP2) is a patient generated outcome measure allowing patients to select the problems that are the most important to them and that they want to address, and it measures the effects of the problem from a wide range of health care interventions. This study aimed to translate the questionnaire into Turkish language (Turkish MYMOP-TMYMOP) and add this clinically useful measure to Turkish medical practice by assessing its validity and reliability. MATERIALS AND METHODS: Fifty volunteers with anorectal disorders were prospectively included into the study. Each patient was enrolled into a pelvic floor training biofeedback program, specific to their anorectal symptomatology. The subjects were administered both the Nottingham Health Profile and the TMYMOP2 questionnaires before the treatment session (initial visit) and at the control follow-up visits (the first and second months, via e-mail or telephone calls). RESULTS: The TMYMOP2 questionnaire was shown to be moderately valid (the Pearson correlation coefficient score between the total scores of the subgroups of the two questionnaires were 0.335 and 0.642, respectively, p<0.05) and highly reliable (the Cronbach's alfa coefficient score between the total scores of the subgroups of the two questionnaires were 0.77, 0.82, and 0.88 in the beginning and at the first and second month follow-up visits, respectively). CONCLUSION: The TMYMOP2 was shown to be a low-to-moderately valid and a highly reliable scale. Because it is brief and short to complete, it might be an important and free-to-use tool to measure the diseases, and it can enhance the patient-centered care within the Turkish health care context. PMID- 30457557 TI - Prospective randomized single-blind study of post-operative bleeding after minor oral surgery in patients with cirrhosis. AB - BACKGROUND/AIMS: The management of patients with cirrhosis requiring dental extractions is complicated due to an increased risk of post-operative bleeding. Topical hemostatic agents are usually required to control bleeding in these cases, as an adjunct to systemic measures of hemostasis. The aims of this randomized, prospective, single-blind clinical study are twofold. The primary aim is to compare the hemostatic efficacy of chitosan and surgicel in patients with cirrhosis after a tooth extraction, and the secondary aim is to assess the value of the current setting as a clinical model of post-operative bleeding following minor oral surgery. MATERIAL AND METHODS: Fifty patients with cirrhosis scheduled for a tooth extraction under local anesthesia were prospectively included in the study in a randomized fashion. Patients were blinded to the treatment group they were in. The cirrhosis classification, bleeding time, trauma score, and corrected bleeding time (during post-operative reviews) were recorded. Statistical evaluations were done. RESULTS: Study groups had an equal number of teeth extractions (40 teeth each). There were no statistically significant differences between the groups with respect to patient demographics, cirrhosis classification, trauma score, and bleeding time. No side effects were noted. CONCLUSION: Both Celox and Surgicel are effective for controlling bleeding and are safe after a tooth extraction in patients with cirrhosis. PMID- 30457558 TI - Chanarin-Dorfman syndrome. AB - Chanarin Dorfman syndrome is a multisystem, very rare, autosomal recessive lipid storage disorder, characterized by the accumulation of lipid vacuoles in neutrophils, and was first described by Dorfman in 1974. Due to a mutation in the ABHD5 gene of the short arm of chromosome 3, lipid is stored in the granulocytes at various sites in the human body, such as the muscle, liver, eye, ear, central nervous system, and bone marrow. Clinically, the disease is presented with ichthyosis, hearing loss, hepatomegaly, splenomegaly, cirrhosis, cataract, keratopathy, myopathy, and mental retardation. A 38-year-old male patient was referred to our Internal Medicine Clinic for consultation with laboratory findings as follows: high aspartate aminotransferase (AST; 203 U/L), alanine aminotransferase (ALT; 151 U/L), gamma-glutamyl transferase (GGT; 167 U/L), creatine kinase (CK; 1127 U/L) levels and low platelet levels (108000). After ultrasonography and gastroscopy, the patient was diagnosed with liver cirrhosis. Bilateral mixed-type hearing loss on audial tests and bilateral punctuate keratopathy, ectropion, and cataract in the left eye on ophthalmological tests were found. For the definitive diagnosis of Chanarin Dorfman syndrome, peripheral blood was examined, which revealed lipid accumulation in the neutrophils (Jordan's anomaly). We emphasize that if a patient has unusual findings, such as ichthyosis, hearing loss, hepatomegaly, splenomegaly, cirrhosis, cataract, keratopathy, myopathy, and mental retardation, the possibility of Chanarin Dorfman syndrome should be considered. PMID- 30457559 TI - Role of percutaneous catheter drainage as primary treatment of necrotizing pancreatitis. AB - BACKGROUND/AIMS: Necrotizing pancreatitis has morbidity and mortality rates exceeding most of the other acute medical emergencies despite the best possible medical and surgical care. Early surgical intervention has a high operative risk. MATERIALS AND METHODS: This prospective open-label study was designed to evaluate the role of percutaneous catheter drainage (PCD) of pancreatic necrosis as primary treatment of acute necrotizing pancreatitis. An ultrasound/computed tomography-guided drainage was performed with 10 or 12 Fr catheters using a 0.35 mm guide wire, irrespective of whether necrosis was infected or not. Patients were followed up for organ dysfunction, need for surgical intervention, and survival at week 8. RESULTS: A total of 20 (65% males) patients who had acute necrotizing pancreatitis with varied etiology were enrolled in the present study. Of these patients, 9 (45%) did not need surgery after PCD. The remaining 11 (55%) patients showed significant reversal of organ failure after PCD insertion (p<0.05 for improvement in serum creatinine, need for mechanical ventilation, and decline in C-reactive protein). Survival at week 8 was 95%. PCD was well tolerated with only two catheter-related complications being observed. CONCLUSION: Percutaneous catheter drainage can be a primary treatment option for necrotizing pancreatitis. In addition, it helps to stabilize critically ill patients and delay the surgical procedure to beyond 4 weeks to improve the surgical outcomes. PMID- 30457560 TI - Association between small intestinal bacterial overgrowth and toll-like receptor 4 in patients with pancreatic carcinoma and cholangiocarcinoma. AB - BACKGROUND/AIMS: Multiple factors have been linked to pathogenesis of pancreatic cancer and cholangiocarcinoma. Until now, few studies have investigated the role of small intestinal bacterial overgrowth (SIBO) and toll-like receptor 4 (TLR-4) signaling in these diseases. This study aimed to examine the relationship between the prevalence of SIBO and the TLR-4 expression in patients with pancreatic carcinoma and cholangiocarcinoma. MATERIALS AND METHODS: A total of 90 human subjects suffering from pancreatic carcinoma (n=30), cholangiocarcinoma (n=30), and healthy controls (n=30) were enrolled in the study. A glucose hydrogen breath test (GHBT) was used to evaluate SIBO. The TLR4 protein expression was measured by immunohistochemistry (IHC). RESULTS: The positive rate of SIBO was 63.3% in the pancreatic cancer group and 46.7% in patients with cholangiocarcinoma, which was significantly greater than 13.3% in the healthy control group (p<0.05). An IHC analysis revealed that the TLR-4 protein expression in the SIBO-positive pancreatic carcinoma patients was significantly higher than that in the SIBO negative patients (p<0.05), and the same result was in the cholangiocarcinoma subjects. In addition, a correlation analysis identified the positive relationship between the prevalence of SIBO and the TLR-4 protein expression in pancreatic carcinoma (r=0.489), and the same result was in the cholangiocarcinoma subjects. CONCLUSION: Our findings indicate a high prevalence of SIBO in pancreatic carcinoma and cholangiocarcinoma, and SIBO displays a positive correlation with the TLR-4 expression, suggesting that SIBO could be a risk factor for the pathogenesis of pancreatic carcinoma and cholangiocarcinoma, in which the TLR4 signaling may be involved. PMID- 30457561 TI - IgG4 related autoimmune pancreatitis and sclerosing cholangitis. PMID- 30457562 TI - A typical gallstone ileus: Clinical, radiological and operational findings. PMID- 30457563 TI - Acroangiodermatitis of Mali (Pseudo-Kaposi Sarcoma) Associated with Chronic Venous Insufficiency and Obesity: A Case Report. AB - INTRODUCTION: Acroangiodermatitis, also known as psesudo-Kapsoi sarcoma, is a rare and benign angioproliferative malady. It presents clinically as purple colored plaques, patches, or nodules resembling Kaposi sarcoma and is often related to chronic venous insufficiency, arteriovenous malformation of the legs, paralyzed limbs, and residual limbs. Obesity is a risk factor for venous insufficiency and could be related to acroangiodermatitis. CASE REPORT: The authors report a case of acroangiodermatitis of the bilateral legs that was misdiagnosed for 3 years. The diagnosis was confirmed using histopathological and immunohistochemical examinations such as hematoxylin and eosin staining and CD34 immunostaining. Multiple modalities were utilized to treat the wounds, including serial debridement, compression dressings, and silver antimicrobial dressings. CONCLUSIONS: It should be stressed that chronic, nonhealing wounds should be biopsied to obtain a proper diagnosis. PMID- 30457564 TI - Defect Reconstruction of an Infected Diabetic Foot Using Split- and Full thickness Skin Grafts With Adjuvant Negative Pressure Wound Therapy: A Case Report and Review of the Literature. AB - INTRODUCTION: Any alteration or impairment to normal wound healing can result in the development of chronic wounds, which may lead to serious complications such as infection and loss of body fluid and proteins. Primary closure alone may not be sufficient to fulfill the criteria of successful defect reconstruction. Therefore, additional procedures such as skin grafting must be considered as an option. CASE REPORT: The case of a 43-year-old woman with diabetes who was admitted to the University Hospital Rebro (Zagreb, Croatia) due to an infected, nonhealing wound on her left foot. Skin grafts combined with negative pressure wound therapy (NPWT) before and after graft application improved wound healing in this patient. CONCLUSIONS: In this patient, the combination of skin grafts with NPWT before and after graft application reduced the comorbidities and complications often seen in the diabetic patient population. Herein, the authors utilized a quicker, cost-efficient, and safer technique of wound closure compared with traditional nonsurgical methods. PMID- 30457565 TI - A dataset of clinically generated visual questions and answers about radiology images. AB - Radiology images are an essential part of clinical decision making and population screening, e.g., for cancer. Automated systems could help clinicians cope with large amounts of images by answering questions about the image contents. An emerging area of artificial intelligence, Visual Question Answering (VQA) in the medical domain explores approaches to this form of clinical decision support. Success of such machine learning tools hinges on availability and design of collections composed of medical images augmented with question-answer pairs directed at the content of the image. We introduce VQA-RAD, the first manually constructed dataset where clinicians asked naturally occurring questions about radiology images and provided reference answers. Manual categorization of images and questions provides insight into clinically relevant tasks and the natural language to phrase them. Evaluating with well-known algorithms, we demonstrate the rich quality of this dataset over other automatically constructed ones. We propose VQA-RAD to encourage the community to design VQA tools with the goals of improving patient care. PMID- 30457566 TI - Combined RNA-seq and RAT-seq mapping of long noncoding RNAs in pluripotent reprogramming. AB - Pluripotent stem cells hold great investigative potential for developmental biology and regenerative medicine. Recent studies suggest that long noncoding RNAs (lncRNAs) may function as key regulators of the maintenance and the lineage differentiation of stem cells. However, the underlying mechanisms by which lncRNAs affect the reprogramming process of somatic cells into pluripotent cells remain largely unknown. Using fibroblasts and induced pluripotent stem cells (iPSCs) at different stages of reprogramming, we performed RNA transcriptome sequencing (RNA-Seq) to identify lncRNAs that are differentially-expressed in association with pluripotency. An RNA reverse transcription-associated trap sequencing (RAT-seq) approach was then utilized to generate a database to map the regulatory element network for lncRNA candidates. Integration of these datasets can facilitate the identification of functional lncRNAs that are associated with reprogramming. Identification of lncRNAs that regulate pluripotency may lead to new strategies for enhancing iPSC induction in regenerative medicine. PMID- 30457567 TI - GloPL, a global data base on pollen limitation of plant reproduction. AB - Plant reproduction relies on transfer of pollen from anthers to stigmas, and the majority of flowering plants depend on biotic or abiotic agents for this transfer. A key metric for characterizing if pollen receipt is insufficient for reproduction is pollen limitation, which is assessed by pollen supplementation experiments. In a pollen supplementation experiment, fruit or seed production by flowers exposed to natural pollination is compared to that following hand pollination either by pollen supplementation (i.e. manual outcross pollen addition without bagging) or manual outcrossing of bagged flowers, which excludes natural pollination. The GloPL database brings together data from 2969 unique pollen supplementation experiments reported in 927 publications published from 1981 to 2015, allowing assessment of the strength and variability of pollen limitation in 1265 wild plant species across all biomes and geographic regions globally. The GloPL database will be updated and curated with the aim of enabling the continued study of pollen limitation in natural ecosystems and highlighting significant gaps in our understanding of pollen limitation. PMID- 30457568 TI - Anthropomorphic breast model repository for research and development of microwave breast imaging technologies. AB - A repository of anthropomorphic numerical breast models is made available for the scientific community to support research and development of microwave imaging technologies for diagnostic and therapeutic applications. These models are constructed from magnetic resonance imaging (MRI) scans acquired at our university hospital. Our 3D breast modelling method is used to translate the MRI scans into 3D models representing the geometry and microwave-frequency properties of tissues in the breast. The reconstructed models demonstrate anatomical realism, reconfigurable complexity, and flexibility to adapt to simulations of various microwave imaging techniques and prototype systems. With these models, realistic and rigorous test scenarios can be defined in simulations to support feasibility analysis, performance verification and design improvements of developing microwave imaging techniques, prior to testing on experimental systems. A repository of breast models is created which includes breasts of varying classification - fatty, scattered, heterogeneous, and dense. In addition, the models include brief documentation to facilitate researchers in selecting a model by matching its features with their requirements. PMID- 30457570 TI - Complementary proteomics strategies capture an ataxin-1 interactome in Neuro-2a cells. AB - Ataxin-1 mutation, arising from a polyglutamine (polyQ) tract expansion, is the underlying genetic cause of the late-onset neurodegenerative disease Spinocerebellar ataxia type 1 (SCA1). To identify protein partners of polyQ ataxin-1 in neuronal cells under control or stress conditions, here we report our complementary proteomics strategies of proximity-dependent biotin identification (BioID) and affinity purification (via GFP-Trap pulldown) in Neuro-2a cells expressing epitope-tagged forms of ataxin-1[85Q]. These approaches allowed our enrichment of proximal proteins and interacting partners, respectively, with the subsequent protein identification performed by liquid chromatography-MS/MS. Background proteins, not dependent on the presence of the polyQ-ataxin-1 protein, were additionally defined by their endogenous biotinylation (for the BioID protocol) or by their non-specific interaction with GFP only (in the GFP-Trap protocol). All datasets were generated from biological replicates. Following the removal of the identified background proteins from the acquired protein lists, our experimental design has captured a comprehensive polyQ-ataxin-1 proximal and direct protein partners under normal and stress conditions. Data are available via ProteomeXchange, with identifier PXD010352. PMID- 30457569 TI - A reference set of curated biomedical data and metadata from clinical case reports. AB - Clinical case reports (CCRs) provide an important means of sharing clinical experiences about atypical disease phenotypes and new therapies. However, published case reports contain largely unstructured and heterogeneous clinical data, posing a challenge to mining relevant information. Current indexing approaches generally concern document-level features and have not been specifically designed for CCRs. To address this disparity, we developed a standardized metadata template and identified text corresponding to medical concepts within 3,100 curated CCRs spanning 15 disease groups and more than 750 reports of rare diseases. We also prepared a subset of metadata on reports on selected mitochondrial diseases and assigned ICD-10 diagnostic codes to each. The resulting resource, Metadata Acquired from Clinical Case Reports (MACCRs), contains text associated with high-level clinical concepts, including demographics, disease presentation, treatments, and outcomes for each report. Our template and MACCR set render CCRs more findable, accessible, interoperable, and reusable (FAIR) while serving as valuable resources for key user groups, including researchers, physician investigators, clinicians, data scientists, and those shaping government policies for clinical trials. PMID- 30457572 TI - High-resolution gridded soil moisture and soil temperature datasets for the Indian monsoon region. AB - High-resolution soil moisture/temperature (SM/ST) are critical components of the growing demand for fine-scale products over the Indian monsoon region (IMR) which has diverse land-surface characteristics. This demand is fueled by findings that improved representation of land-state help improve rainfall/flood prediction. Here we report on the development of a high-resolution (4 km and 3 hourly) SM/ST product for 2001-2014 during Indian monsoon seasons (June-September). First, the quality of atmospheric fields from five reanalysis sources was examined to identify realistic forcing to a land data assimilation system (LDAS). The evaluation of developed SM/ST against observations highlighted the importance of quality forcing fields. There is a significant relation between the forcing error and the errors in the SM/ST. A combination of forcing fields was used to develop 14-years of SM/ST data. This dataset captured inter-annual, intra-seasonal, and diurnal variations under different monsoon conditions. When the mesoscale model was initialized using the SM/ST data, improved simulations of heavy rain events was evident, demonstrating the value of the data over IMR. PMID- 30457571 TI - Generation and quality control of lipidomics data for the alzheimer's disease neuroimaging initiative cohort. AB - Alzheimer's disease (AD) is a major public health priority with a large socioeconomic burden and complex etiology. The Alzheimer Disease Metabolomics Consortium (ADMC) and the Alzheimer Disease Neuroimaging Initiative (ADNI) aim to gain new biological insights in the disease etiology. We report here an untargeted lipidomics of serum specimens of 806 subjects within the ADNI1 cohort (188 AD, 392 mild cognitive impairment and 226 cognitively normal subjects) along with 83 quality control samples. Lipids were detected and measured using an ultra high-performance liquid chromatography quadruple/time-of-flight mass spectrometry (UHPLC-QTOF MS) instrument operated in both negative and positive electrospray ionization modes. The dataset includes a total 513 unique lipid species out of which 341 are known lipids. For over 95% of the detected lipids, a relative standard deviation of better than 20% was achieved in the quality control samples, indicating high technical reproducibility. Association modeling of this dataset and available clinical, metabolomics and drug-use data will provide novel insights into the AD etiology. These datasets are available at the ADNI repository at http://adni.loni.usc.edu/. PMID- 30457573 TI - A data citation roadmap for scientific publishers. AB - This article presents a practical roadmap for scholarly publishers to implement data citation in accordance with the Joint Declaration of Data Citation Principles (JDDCP), a synopsis and harmonization of the recommendations of major science policy bodies. It was developed by the Publishers Early Adopters Expert Group as part of the Data Citation Implementation Pilot (DCIP) project, an initiative of FORCE11.org and the NIH BioCADDIE program. The structure of the roadmap presented here follows the "life of a paper" workflow and includes the categories Pre-submission, Submission, Production, and Publication. The roadmap is intended to be publisher-agnostic so that all publishers can use this as a starting point when implementing JDDCP-compliant data citation. Authors reading this roadmap will also better know what to expect from publishers and how to enable their own data citations to gain maximum impact, as well as complying with what will become increasingly common funder mandates on data transparency. PMID- 30457574 TI - Correction: A robust iron catalyst for the selective hydrogenation of substituted (iso)quinolones. AB - [This corrects the article DOI: 10.1039/C8SC02744G.]. PMID- 30457575 TI - C 2-Symmetric chiral bis(oxazoline)-metal complexes in catalytic asymmetric synthesis. PMID- 30457577 TI - [Caries prevention in historical perspective. Social factors]. AB - At the beginning of the twentieth century, children from poor families had less caries than children from affluent families. Later this changed: as the socio economic status of the parents was higher, the children had less dental caries. The same relationship between socio-economic status and caries prevalence was later evident in adults. Throughout the twentieth century, in individuals with a low socio-economic status more teeth were extracted than in individuals with a high socio-economic status. At the end of the twentieth century, oral health in general was much better than at the beginning. That change is partly due to increased prosperity, increasing attention to oral hygiene, the introduction of fluoride toothpaste and the strong increase in the number of professionals in oral care. Increased knowledge of the causes and prevention of caries also played a role, if a less prominent one. PMID- 30457578 TI - [Wish fulfilling medicine and wish fulfilling dentistry: what does this mean?] AB - Wish fulfilling medicine refers to medical procedures applied without a direct medical need. In wish fulfilling medicine, the wish of the patient is dominant, but wish fulfilling medicine is also promoted indirectly by healthcare providers, (pharmaceutical) companies and healthcare insurers. Wish fulfilling medicine often concerns the enhancement of appearance or performance; therefore, wish fulfilling medicine is also referred to as (human) enhancement (therapy). The line between traditional and wish fulfilling medicine is vague: the border between illness and health, normal and abnormal functioning is not sharply defined and is relative to time and place. In the Netherlands, wish fulfilling medicine is not covered in the basic package provided by healthcare insurers and is paid for by the patients themselves. However, 'pay yourself' is not a decisive criterion for wish fulfilling medicine. With new biotechnological developments the domain of wish fulfilling medicine is expanding. Some dental treatments can be considered as wish fulfilling dentistry, for example in the context of cosmetic dentistry, orthodontics, or dental implantology. Although wish fulfilling medical treatments do not cure disease, they can promote health. PMID- 30457576 TI - Immune checkpoint inhibitors as a real hope in advanced urothelial carcinoma. AB - Metastatic urothelial cancer is an aggressive disease associated with a poor prognosis. In the first-line setting, platinum-based chemotherapy is the standard of care but resistance rapidly occurs. After failure of platinum-based therapy and in cisplatin-ineligible patients, therapeutic options are limited. Malignant cells evolve mechanisms to evade immune recognition, including the expression of cell-surface molecules, named immune checkpoints, on tumor and tumor-specific lymphocytes. Immunotherapy, by targeting these checkpoints, represents a new tool to improve the patient outcome in advanced urothelial carcinoma (UC). Recently, the US FDA approved, in a short time, several immune checkpoint inhibitors in metastatic UC, both after failure of platinum-based therapy and in first-line setting in cisplatin-ineligible patients. This article aims to review the place of immunotherapy in advanced UC. PMID- 30457579 TI - [Needle breakage during local anaesthesia]. AB - Two patients were referred to a maxillofacial surgeon in connection with the occurrence of needle breakage during local anaesthesia. In the first case, of a 67-year-old woman, it concerned a needle breakage after giving mandibular block anaesthesia. The needle could be removed quite easily under local anaesthesia. The second case concerned a less cooperative patient of 8 years old with whom needle breakage occurred after infiltration anaesthesia in the mucobuccal fold of the maxilla with the so-called QuickSleeper 5, needle breakage. After exact localisation by means of cone beam computerised tomography, the 9 mm size needle was removed under general anaesthesia with some difficulty. PMID- 30457580 TI - [Medicaments and oral healthcare. Systematic review of the -literature assessing the effect of drugs on the salivary glands]. AB - Evidence-based reviews of drugs causing medication-induced salivary gland dysfunction, such as xerostomia (sensation of oral dryness) and subjective sialorrhea are lacking. To compile a list of medicaments that influence salivary gland function, electronic databases were searched for relevant articles published up to June 2013. A total of 269 papers out of 3,867 records located satisfied the inclusion criteria (relevance, quality of methodology, strength of evidence). A total of 56 active substances with a higher level of evidence and 50 active substances with a moderate level of evidence of causing salivary gland dysfunction are described in this article. While xerostomia was a commonly reported outcome, the objective effect on salivary secretion was rarely measured. Xerostomia was, moreover, mostly reported as a negative side effect instead of the intended effect of that drug. A comprehensive list of medications having documented effects on salivary gland function or symptoms was compiled, which may assist practitioners in assessing patients who complain of dry mouth while taking medications. PMID- 30457581 TI - [A PhD completed. Maxillary overdentures: with a bar attachment system or locators?] AB - An overdenture on implants is the treatment of choice for patients with complaints about their conventional complete dentures. While a lot is known regarding the performance of implant-supported mandibular overdentures, much less is known regarding the performance of implant-retained maxillary overdentures. In this doctoral dissertation, various aspects of overdentures on 4 dental implants in the maxilla are discussed. From a systematic review of the literature, it appeared that an overdenture (maxillary or mandibular) on implants improved chewing efficiency, increased maximum bite force and increased patient satisfaction. Implants placed with a maximum dehiscence of two thirds of the buccal implant surface also appeared to function well after 5 years. An overdenture with a bar attachment system was associated with less marginal bone loss, a better subjective chewing efficiency and greater patient satisfaction than an overdenture retained by locators. The differences were, however, small and from a cost-effectiveness point of view, the use of overdentures retained by locators would not be a bad choice. PMID- 30457582 TI - An electrochemical enzymatic nanoreactor based on dendritic mesoporous silica nanoparticles for living cell H2O2 detection. AB - The selective and quantitative detection of cellular H2O2 is essential for understanding its roles in physiology and pathology. A new electrochemical H2O2 biosensor, fabricated by immobilizing horseradish peroxidase onto dendritic mesoporous silica nanoparticles (HRP/DMSNs), is employed for living cell H2O2 detection. Taking advantage of the large pore volume and highly accessible internal surface areas of DMSNs, HRP/DMSNs display higher enzymatic loading, better stability and bioactivity in comparison with HRP on nonporous silica nanoparticles (NSNs). Therefore, a HRP/DMSN modified GCE (HRP/DMSNs/GCE) shows attractive electrochemical performance for sensitive and selective detection of H2O2 in 0.1 M pH 7.0 PBS, with a low Kappm value of 11.48 MUM and a low detection limit of 0.11 MUM. In addition, HRP/DMSNs/GCE is successfully applied to detect H2O2 released from a PC12 cell triggered by ascorbic acid (AA). The detected H2O2 amount is close to the reported values. The developed biosensor has potential in the dynamic detection of the flux of H2O2 from living cells for further evaluation of oxidative stress in cells. PMID- 30457583 TI - Tin oxide nanoparticles modified by copper as novel catalysts for the luminol H2O2 based chemiluminescence system. AB - In this study, SnO2 nanoparticles modified by copper were found to greatly enhance the chemiluminescence intensity of the luminol-H2O2 system for the first time. The developed approach was applied for the determination of H2O2 as a proof of-concept example. PMID- 30457584 TI - Cerebrospinal fluid levels of alpha-synuclein measured using a poly-glutamic acid modified gold nanoparticle-doped disposable neuro-biosensor system. AB - Alpha-synuclein (SYN) is a prominent key protein in Parkinson-type dementia. Measurement of the amount of this protein found in the cerebrospinal fluid (CSF) using precise techniques may help in the diagnosis and prognosis of the disease. In this study, a gold nanoparticle (AuNP)-polyglutamic acid (PGA)-modified indium tin oxide (ITO)-based disposable neuro-biosensor system was designed for alpha synuclein (alpha-SYN), an important biomarker of Parkinson's disease. Glutamic acid was formed by electropolymerization on the electrode surface. The parameters that can affect the performance of the biosensing probe were optimized. The techniques used in the design of the immobilization steps, the optimization studies, and the evaluation of the analytical performance of the targeted neuro biosensor are electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV) and square wave voltammetry (SWV). Charge transfer resistance (Rct) changes were highly linear and sensitive with the alpha-SYN concentration in the 4-2000 pg mL-1 range and associated with a limit of detection of 0.135 pg mL-1. With the designed disposable neuro-biosensor system, the amount of alpha-SYN found in CSF samples was determined by the standard addition technique and found to be strikingly sensitive to the target analyte. Morphological and chemical changes on the sensing surface were evaluated by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). In addition, it was determined that the PGA-modified, AuNP-doped neuro-biosensor system has great reproducibility potency, long storage stability, and regeneration capacity. We suggest that the AuNP-PGA combination platform is ideal for use as a biosensing probe to detect alpha-SYN. PMID- 30457585 TI - ATR-FTIR spectroscopy shows changes in ovarian cancer cells after incubation with novel organoamidoplatinum(ii) complexes. AB - Attenuated Total Reflection Fourier Transform Infrared (ATR-FT-IR) spectroscopy has been applied to compare the effect of the new organoamidoplatinum(ii) complexes [Pt{NH(p-HC6F4)CH2CH2N(p-HC6F4)}(py)(O2CR)] (R = C6F4 or 2,4,6-Me3C6H2) with cisplatin on cells from one cisplatin-sensitive ovarian cancer cell line (A2780) and one cisplatin-resistant ovarian cancer cell line (A2780R). After incubation of the cells with cisplatin, 1 and 2 for 48 hours, distinct changes were found in the ATR-FT-IR spectra. Comparison of the second derivative spectra suggests that 1 and 2 induce similar chemical changes in both cell lines, A2780 and A2780R, while cisplatin had a slight effect on A2780 and A2780R cells. Furthermore, drugs 1 and 2 result in changes to the phosphodiester and polysaccharide bands in the spectra. This work shows how ATR-FT-IR can be applied to monitor the effects of organoamidoplatinum(ii) complexes on cisplatin sensitive and cisplatin-resistant cell lines providing potential information on how drugs affect the cellular metabolism. PMID- 30457586 TI - Moral Exemptions and Accommodations for Coverage of Certain Preventive Services Under the Affordable Care Act. Final rules. AB - These rules finalize, with changes based on public comments, the interim final rules issued in the Federal Register on October 13, 2017 concerning moral exemptions and accommodations regarding coverage of certain preventive services. These rules finalize expanded exemptions to protect moral beliefs for certain entities and individuals whose health plans are subject to a mandate of contraceptive coverage through guidance issued pursuant to the Patient Protection and Affordable Care Act. These rules do not alter the discretion of the Health Resources and Services Administration, a component of the U.S. Department of Health and Human Services, to maintain the guidelines requiring contraceptive coverage where no regulatorily recognized objection exists. These rules also leave in place an optional "accommodation" process for certain exempt entities that wish to use it voluntarily. These rules do not alter multiple other federal programs that provide free or subsidized contraceptives for women at risk of unintended pregnancy. PMID- 30457600 TI - Synthesis and electrochemical properties of Li1.3Nb0.3Cr0.4O2 as a high-capacity cathode material for rechargeable lithium batteries. AB - A cation-disordered Li-excess cathode material on the binary system xLi3NbO4-(1 - x)LiCrO2 (x = 0.43) has been successfully prepared by mechanical milling, and delivers a high reversible capacity of ~362 mA h g-1, which originates from a highly reversible Cr3+/Cr6+ three-electron redox reaction with electrochemically inactive niobium ions. PMID- 30457602 TI - Fabrication of injectable CuS nanocomposite hydrogels based on UCST-type polysaccharides for NIR-triggered chemo-photothermal therapy. AB - Injectable nanocomposite hydrogels containing small copper sulfide nanoparticles (6-8 nm) with a 54.6% photothermal conversion efficiency have been facilely prepared by applying an upper critical solution temperature (UCST)-type biopolymer gellan. This minimally invasive formulation ablates cancer completely in vivo after NIR-triggered chemo-photothermal therapy. PMID- 30457603 TI - Lewis adduct formation of hydrogen cyanide and nitriles with arsenic and antimony pentafluoride. AB - The reactions of hydrogen cyanide, butyronitrile, cyclopropanecarbonitrile, pivalonitrile and benzonitrile with arsenic pentafluoride and antimony pentafluoride result in the formation of 1 : 1 Lewis adducts, while malononitrile yielded both 1 : 1 and 1 : 2 Lewis adducts. All adducts were isolated and characterized by multinuclear NMR and vibrational spectroscopy, and in most cases by their X-ray crystal structures. PMID- 30457605 TI - Why does 4-biphenyl carbonyl azide have ultra-short lived excited states? An ultrafast UV-vis spectroscopic and computational study. AB - Upon excitation at 308 nm, 4-biphenyl carbonyl azide (4-BpCON3) shows unusually fast decay of transient absorption associated with the first excited singlet state, with time constants of several ps in MeOH, acetonitrile, and CHCl3. In cyclohexane and cyclohexene, the lifetimes are ca. 0.3 ps, which is in stark contrast to the lifetimes of hundreds of ps in the case of 2-naphthoyl azide. Furthermore, photolysis at 266 and 308 nm brought about the same yields of nitrene and isocyanate products. To understand these findings, we also applied ultrafast transient absorption spectroscopy to the structurally related molecule, fluorene-2-carbonyl azide (F2CON3), in which the two phenyl rings are fixed in a plane by a methylene group. Both carbonyl azides (biphenyl and fluorenyl) have very short lived excited states in different solvents, indicating that the twisting of phenyl rings is not the reason for the fast decay. Theoretical studies using time dependent density functional theory (TDDFT), especially with PBE0 and CAM-B3LYP functionals, suggest that excited-state potential energy surface crossings lead to the efficient and fast decomposition of carbonyl azides upon photoexcitation. Especially, the decay of the Franck-Condon state to the S1 state with pi(CON3)-pi*(N3') transition character, where -N3 is in a bent conformation (?NNN = ca. 125 degrees ), is the key step. Finally, a model is presented to explain solvent dependence, different decaying rates, and other experimental findings. PMID- 30457606 TI - Automated calculation of thermal rate coefficients using ring polymer molecular dynamics and machine-learning interatomic potentials with active learning. AB - We propose a methodology for the fully automated calculation of thermal rate coefficients of gas phase chemical reactions, which is based on combining ring polymer molecular dynamics (RPMD) and machine-learning interatomic potentials actively learning on-the-fly. Based on the original computational procedure implemented in the RPMDrate code, our methodology gradually and automatically constructs the potential energy surfaces (PESs) from scratch with the data set points being selected and accumulated during the RPMDrate simulation. Such an approach ensures that our final machine-learning model provides a reliable description of the PES that avoids artifacts during exploration of the phase space by RPMD trajectories. We tested our methodology on two representative thermally activated chemical reactions studied recently by RPMDrate at temperatures within the interval of 300-1000 K. The corresponding PESs were generated by fitting to only a few thousand automatically generated structures (less than 5000) while the RPMD rate coefficients showed deviation from the reference values within the typical convergence error of RPMDrate. In future, we plan to apply our methodology to chemical reactions that proceed via complex formation thus providing a completely general tool for calculating RPMD thermal rate coefficients for any polyatomic gas phase chemical reaction. PMID- 30457608 TI - Atomistic modelling of entropy driven phase transitions between different crystal modifications in polymers: the case of poly(3-alkylthiophenes). AB - Polymorphism and related solid-state phase transitions affect the structure and morphology and hence the properties of materials, but they are not-so-well understood. Atomistic computational methods can provide molecular-level insights, but they have rarely proven successful for transitions between polymorphic forms of crystalline polymers. In this work, we report atomistic molecular dynamics (MD) simulations of poly(3-alkylthiophenes) (P3ATs), widely used organic semiconductors to explore the experimentally observed, entropy-driven transition from form II to more common form I type polymorphs, or, more precisely, to form I mesophases. The transition is followed continuously, also considering X-ray diffraction evidence, for poly(3-hexylthiophene) (P3HT) and poly(3 butylthiophene) (P3BT), evidencing three main steps: (i) loss of side chain interdigitation, (ii) partial disruption of the original stacking order and (iii) reorganization of polymer chains into new, tighter, main-chain stacks and new layers with characteristic form I periodicities, substantially larger than those in the original form II. The described approach, likely applicable to other important transitions in polymers, provides previously inaccessible insight into the structural organization and disorder features of form I structures of P3ATs, not only in their development from form II structures but also from melts or solutions. PMID- 30457609 TI - New transmetalation reagents for the gold-catalyzed visible light-enabled C(sp or sp2)-C(sp2) cross-coupling with aryldiazonium salts in the absence of a photosensitizer. AB - The scope of photosensitizer-free visible light-driven gold-catalyzed cross coupling was evaluated by a wide variety of organoboron and organosilicon species using four equivalents of aryldiazonium salts and (4-CF3-C6H4)3PAuCl in MeOH. In addition, a C(sp or sp2)-C(sp2) cross-coupling of organotrimethylsilanes and aryldiazonium salts was investigated. The reactions can be conducted under very mild reaction conditions, with a reduced amount of aryldiazonium salt (1.2 equiv.) by using a catalytic amount of Ph3PAuNTf2 in MeCN under irradiation with blue LEDs at room temperature. PMID- 30457612 TI - Impact of chirality on peculiar ibuprofen molecular dynamics: hydrogen bonding organization and syn vs. anti carboxylic group conformations. AB - Studies of the impact of chirality on amorphous states are scarce. Here, we present combined dielectric relaxation spectroscopy (DRS) experiments and molecular dynamics (MD) simulation investigations of homochiral and racemic ibuprofen in the liquid, undercooled liquid and glassy states. The influence of chirality is particularly investigated on the syn and anti conformations of the COOH moiety of the ibuprofen molecule and its link to the peculiar Debye-like dynamical process detected in this compound. Most of the studied properties are found to be nearly identical in the homochiral and racemic systems. But the polarity and intensity of the Debye-like process are clearly found to be more intense in the racemic mixture than in the enantiomerically pure ibuprofen. The difference is explained by the higher population of the anti conformation (with the higher dipole moment) and the lower population of hydrogen bonded cyclic dimers that can be transiently formed in the racemic mixture. PMID- 30457613 TI - Impact of nanogold morphology on interactions with human serum. AB - Gold nanoparticles (AuNPs) of differing shapes are of great interest to researchers due to their unique optical properties, making them potentially powerful theranostic tools. The synthesis of AuNPs is performed frequently, however the assessment of biological activity for each nanoparticle is not always commonplace. While it is thought that physicochemical parameters such as shape may play an important role in dictating the outcomes of interactions which take place at the nano-bio interface, a systematic approach to the assessment of nanomaterials has not been widely adopted. In this study, the interaction between human serum albumin (HSA) and four similar sized but different shaped AuNPs (spherical, rod shaped, prismatic and cubic) synthesised using a common chemical surfactant (CTAB), is presented. Using fluorescence spectroscopy it is shown that all AuNPs exhibit static binding with HSA, however the shape affects both the affinity and strength of the binding. Rod shaped nanoparticles were found to have the highest binding strength and affinity. Conversely, shapes with large flat planar surfaces such as prisms and cubes were shown to have reduced accessibility to the site of the fluorophore within the structure of HSA. The differences observed help to provide a better understanding of the effect of shape on AuNP protein interactions - knowledge which may be applied to the development of AuNPs for future biological applications. PMID- 30457614 TI - Stability of small cationic platinum clusters. AB - The relative stability of small cationic platinum clusters is investigated by photofragmentation experiments. Mass spectra show a smooth intensity distribution except for a local intensity minimum at Pt5+, revealing enhanced stability of the platinum tetramer Pt4+. The possibility that radiative cooling competes with statistical fragmentation after photoexcitation is examined and it is shown that clusters in the N = 3-8 size range do not radiate on the time scale of the experiment. In the absence of radiative cooling, the mass spectra of photofragmented clusters can be well explained by dissociation energies computed using density functional theory. The large calculated HOMO-LUMO gap for Pt4+ (~1.2 eV) is attributed to its highly symmetric structure and provides an explanation for the surprisingly low reactivity of this cluster in different gas phase reactions. PMID- 30457615 TI - Reversible redox inter-conversion of biologically active NAD+/NADH derivatives bound to a gold electrode: ToF-SIMS evidence. AB - The realization of the reversible inter-conversion between NADH and NAD+ is a long-term challenge in biological and energy-related chemistry. Here, we achieve the electrochemical reversible redox of NAD+/NADH derivatives by the functionalization of a gold electrode with a specially designed NAD+ derivative, and the electrochemical redox products are characterized by time-of-flight secondary ion mass spectrometry (ToF-SIMS). PMID- 30457616 TI - Computational characterization of the selective inhibition of human norepinephrine and serotonin transporters by an escitalopram scaffold. AB - Human norepinephrine and serotonin transporters (hNET and hSERT) are closely related monoamine transporters (MATs) that regulate neurotransmitter signaling in neurons and are primary targets for a wide range of therapeutic drugs used in the treatment of mood disorders. The subtle modifications of an escitalopram scaffold exhibit distinct selective inhibition profiles of hNET and hSERT. However, the structural details of escitalopram scaffold binding to hSERT and (or) hNET are poorly understood and still remain a great challenge. In this work, on the basis of more recently solved X-ray crystallographic structure of hSERT in complex with escitalopram, 3 MUs long all-atom MD simulations and binding free energy calculations via MM/GB(PB)SA, thermodynamic integration (TI) and MM/3D-RISM methods were performed to reproduce experimental free energies. And both MM/GBSA and TI have a high correlation coefficient (R2 = 0.95 and 0.96, respectively) between the relative binding free energies of the calculated and experimental values. Furthermore, MM/GBSA per-residue energy decomposition, molecular interaction fingerprints and thermodynamics-structure relationship analysis were employed to investigate and characterize the selectivity of the escitalopram scaffold with three modifications (escitalopram, ligand10 and talopram) to hNET and hSERT. As a result, 4 warm spots (A73, Y151, A477 and I481) in hNET and 4 warm spots (A96, A173, T439 and L443) in hSERT were thus discovered to exert a pronounced effect on the selective inhibition of hNET and hSERT by the studied ligands. These simulation results would provide great insight into the design of inhibitors with the desired selectivity to hNET and hSERT, thus further promoting the research of more efficacious antidepressants. PMID- 30457617 TI - Non-parabolic potential dependence of optical second harmonic generation from the Si(111) electrode/electrolyte interface. AB - We performed potential dependent second harmonic generation (SHG) measurements on the Si(111) electrolyte interface at different azimuthal angles and for different polarization combinations. When the external potential was biased from the equilibrium potential to the flatband potential (Efb), the SHG intensity decreased linearly with the potential when the azimuthal angle was oriented at 30 degrees . This linearity extends well beyond the linear region of the Mott Schottky plot as measured traditionally by capacitance measurements. When the external potential was scanned from Efb toward more negative potentials, the response of SHG intensity showed quadratic behavior and can be described by the parabolic model. The non-parabolic potential dependence cannot be explained with the parabolic model proposed from previous literature. Such asymmetric behavior only implied that the interfacial structure of the Si(111) electrode changes from semiconductor to metal with the applied electric potential biased negatively, i.e. with accumulation of electrons in the surface region. The anisotropic contribution from the Si(111) electrode can also significantly affect the SHG response as seen where the minimum of the potential dependent SHG curve shifts away from Efb. PMID- 30457618 TI - The first stages of oxide growth at the low index Al surfaces (100), (110), (111): clusters and stripes vs. homogeneous growth. AB - We performed a density functional theory (DFT) investigation of the mechanisms of oxide growth at Al(100), Al(110) and Al(111) up to 1 monolayer (ML) coverage of O atoms with 0.125 ML increments. We found that the surface binding site preferences of O-atoms are largely affected by the presence of neighboring O atoms. Based on this we constructed two oxide growth models: the formation of clusters that evolve to stripes with increasing coverage and the formation of a more homogeneous distribution of O-atoms. While the former model is characterized by a lower symmetry of distribution of O-atoms at the surfaces, the latter corresponds to higher symmetries. We found that the prevalence of each oxide growth mode depends on the coverage of O-atoms and that this dependency is different for each surface. For Al(100) and Al(110), up to coverages of 1 ML the oxide grows preferably via the formation of clusters that evolve to stripes with increasing coverage, while for Al(111) the stripes and clusters are the preferred growth mode for coverages up to 0.375 ML, beyond which the homogeneous growth mode is energetically favored. The calculated Al-O pair distribution functions show that the formation of clusters and stripes leads to shorter Al-O bond lengths when compared to the homogeneous growth. The oxides formed at Al(100) and Al(110) have Al-O bond lengths and geometries typical of the shorter bonds of alpha-alumina while at Al(111) the bond lengths are typical of gamma-alumina and beta-alumina. These results suggest that for low coverages, the oxides formed at Al(100) and Al(110) are resemblant of defective alpha-alumina while the oxide formed at Al(111) is similar to less disordered gamma-alumina and beta-alumina. For Al(111), the small energy difference between the growth of clusters and stripes and homogeneous growth does not exclude the coexistence of both growth modes; this could lead to the formation of a defective or amorphous oxide. PMID- 30457619 TI - Two-dimensional black phosphorus: its fabrication, functionalization and applications. AB - Phosphorus, one of the most abundant elements in the Earth (~0.1%), has attracted much attention in the last five years since the rediscovery of two-dimensional (2D) black phosphorus (BP) in 2014. The successful scaling down of BP endows this 'old material' with new vitality, resulting from the intriguing semiconducting properties in the atomic scale limit, i.e. layer-dependent bandgap that covers from the visible light to mid-infrared light spectrum as well as hole-dominated ambipolar transport characteristics. Intensive research effort has been devoted to the fabrication, characterization, functionalization and application of BP and other phosphorus allotropes. In this review article, we summarize the fundamental properties and fabrication techniques of BP, with particular emphasis on the recent progress in molecular beam epitaxy growth of 2D phosphorus. Subsequently, we highlight recent progress in BP (opto)electronic device applications achieved via customized manipulation methods, such as interface, defect and bandgap engineering as well as forming Lego-like stacked heterostructures. PMID- 30457620 TI - Multilayered inorganic-organic microdisks as ideal carriers for high magnetothermal actuation: assembling ferrimagnetic nanoparticles devoid of dipolar interactions. AB - The two major limitations for nanoparticle based magnetic hyperthermia in theranostics are the delivery of a sufficient number of magnetic nanoparticles (MNPs) with high heating power to specific target cells and the residence time of the MNPs at the target location. Ferromagnetic or Ferrimagnetic single domain nanoparticles (F-MNPs), with a permanent magnetic dipole, produce larger magnetic and thermal responses than superparamagnetic nanoparticles (SP-MNPs) but also agglomerate more. MNP agglomeration degrades their heating potential due to dipolar interaction effects and interferes with specific targeting. Additionally, MNPs bound to cells are often endocytosed by the cells or, in vivo, cleared out by the immune system via uptake in macrophages. Here, we present a versatile approach to engineer inorganic-polymeric microdisks, loaded with biomolecules, fluorophores and Fe3O4 F-MNPs that solves both challenges. These microdisks deliver the F-MNPs efficiently, while controlling any undesirable agglomeration and dipolar interaction, while also rendering the F-MNPs endocytosis resistant. We show that these micro-devices are suitable carriers to transport a flat assembly of F-MNPs to the cell membrane unchanged, preserving the magnetic response of the MNPs in any biological environment. The F-MNPs concentration per microdisk and degree of MNP interaction are tunable. We demonstrate that the local heat generated in microdisks is proportional to the surface density of F MNPs when attached to the cell membrane. The key innovation in the production of these microdisks is the fabrication of a mushroom-shaped photolithographic template that enables easy assembly of the inorganic film, polymeric multilayers, and MNP cargo while permitting highly efficient lift-off of the completed microdisks. During the harvesting of the flat microdisks, the supporting mushroom shaped templates are sacrificed. These resulting magnetic hybrid microdisks are tunable and efficient devices for magnetothermal actuation and hyperthermia. PMID- 30457624 TI - Tunable interactions between particles in conically rotating electric fields. AB - Tunable interactions between colloidal particles in external conically rotating electric fields are calculated, while the (vertical) axis of the field rotation is normal to the (horizontal) particle motion plane. The comparison of different approaches, including the methods of noninteracting, self-consistent dipoles, and the boundary element method, indicates that the last method is the most suitable for tunable interaction analysis. Thorough analysis, performed for interactions in pairs and clusters of colloidal particles, indicate that two- and three-body interactions make the main contributions in the interaction energy, while the effect of high-order terms is negligible. The tunable interactions are determined by the dielectric properties of the particles and solvent and can be changed in a wide range, providing a rich variety for the experimental "design" of different interactions, including repulsion, attraction, combination of short-range repulsion with long-range attraction, barrier-type interactions with short-range attraction and long-range repulsion, and double-scale repulsive (core-shoulder) interactions. These conclusions can be generalized for magnetically induced tunable interactions. The results indicate that tunable interactions can be widely applied in self-assembly and particle-resolved studies of generic phenomena in fluids and crystals, and, therefore, are of broad interest in the fields of chemical physics, physical chemistry, materials science, and soft matter. PMID- 30457626 TI - Anisotropic ultraviolet-plasmon dispersion in black phosphorus. AB - By means of momentum-resolved electron energy loss spectroscopy (EELS) coupled with scanning transmission electron microscopy, we have studied the dispersion relation of interband plasmonic modes in the ultraviolet in black phosphorus. We find that the dispersion of the interband plasmons is anisotropic. Experimental results are reproduced by density functional theory, by taking into account both the anisotropy of the single-particle response function, arising from the anisotropic band structure, and the damping. Moreover, our theoretical model also indicates the presence of low-energy excitations in the near-infrared that are selectively active in the armchair direction, whose existence has been experimentally validated by high-resolution EELS (HREELS) in reflection mode. PMID- 30457627 TI - Probing the size- and constituent-mediated mechanical properties and deformation behavior in crystalline/amorphous nanolaminates. AB - Two kinds of crystalline/amorphous nanolaminates (C/ANLs), i.e., Ag/Cu-Zr and Mo/Cu-Zr, with a wide range of modulation ratios eta (thickness ratio of the amorphous layer to the crystalline layer) from 0.1 up to 9.0 were, respectively, prepared using magnetron sputtering. The hardness and the strain rate sensitivity m were measured for comparison through nanoindentation testing. The mechanical properties displayed a strong eta-dependence, which was tuned by the crystalline phases. With the increase of eta, the hardness increased in the Ag/Cu-Zr nanolaminates while it decreased in the Mo/Cu-Zr ones. However, the two C/ANLs showed similar variations in m that was reduced gradually from positive values at small eta to negative values at large eta. Microstructural examination demonstrated that the amorphous Cu-Zr layers in both the C/ANLs showed a deformation-induced crystallization (DIC) phenomenon within the nanoindentation deformation zone. The DIC was highly dependent on eta and became more intense in the Mo/Cu-Zr than in the Ag/Cu-Zr C/ANLs. The eta- and constituent-dependent DIC behaviors were rationalized in light of the stress field applied on the amorphous layers that is sensitive to both the amorphous layer thickness and the crystalline constituents. This DIC-induced negative m in amorphous layers competed with the positive m in crystalline layers, leading to a negative-to positive change in m on reducing eta. The underlying deformation mechanism was revealed to be the cooperation between dislocation activities in the crystalline layers and shear transformation zone motions in the amorphous layers. Furthermore, a modified mechanistic model was utilized to quantitatively describe the eta-dependent hardness at different crystalline constituents. PMID- 30457629 TI - pH-Rate profiles establish that polyketide synthase dehydratase domains utilize a single-base mechanism. AB - FosDH1 from module 1 of the fostriecin polyketide synthase (PKS) catalyzes the dehydration of a 3-hydroxybutyryl-SACP to the (E)-3-butenoyl-SACP. The steady state kinetic parameters, kcat and kcat/Km, were determined over the pH range 3.0 to 9.2 for the FosDH1-catalyzed dehydration of the N-acetycsteamine thioester, 3 hydroxybutyryl-SNAC (3), to (E)-3-butenoyl-SNAC (4). The pH rate profiles for both log(kcat) and log(kcat/Km) each corresponded to a single pH-dependent ionization to give an active site general base, with a calculated pKa 6.1 +/- 0.2 for kcat and pKa 5.7 +/- 0.1 for kcat/Km. These results are inconsistent with the commonly suggested "two-base" (base-acid) mechanism for the dehydratases of PKS and fatty acid biosynthesis and support a simple one-base mechanism in which the universally conserved active site His residue acts as the base to deprotonate C-2 of the substrate, then redonates the proton to the C-3 hydroxyl group to promote C-O bond-cleavage and elimination of water. The carboxylate of the paired Asp or Glu residue is thought to bind and orient the hydroxyl group of the substrate in the stereoelectonically favored conformation. PMID- 30457631 TI - Configurable multifunctional integrated circuits based on carbon nanotube dual material gate devices. AB - Nanoelectronic devices with specifically designed structures for performance promotion or function expansion are of great interest, aiming for diversified advanced nanoelectronic systems. In this work, we report a dual-material gate (DMG) carbon nanotube (CNT) device with multiple functions, which can be configured either as a high-performance p-type field-effect transistor (FET) or a diode by changing the input manners of the device. When operating as a FET, the device exhibits a large current on/off ratio of more than 108 and a drain-induced barrier lowering of 97.3 mV V-1. When configured as a diode, the rectification ratio of the device can be greater than 105. We then demonstrate configurable analog and digital integrated circuits that are enabled by utilizing these devices. The configurability enables the realization of transformable functions in a single device or circuits, which gives future electronic systems the flexibility to adapt to the diverse requirements of their applications and/or ever-changing operating environments. PMID- 30457630 TI - Alginate oligosaccharide alleviates enterotoxigenic Escherichia coli-induced intestinal mucosal disruption in weaned pigs. AB - Alginate oligosaccharide (AOS) is a non-toxic, non-immunogenic, non-carcinogenic and biodegradable product generated by depolymerisation of alginate, and exhibits various salutary properties. The present study was designed to evaluate whether AOS supplementation could attenuate enterotoxigenic Escherichia coli (ETEC) induced intestinal mucosal injury in weaned pigs. Twenty-four weaned pigs were randomly assigned to three treatments: (1) non-challenged control; (2) ETEC challenged control; and (3) ETEC challenge + AOS treatment (100 mg kg-1). On day 12, pigs in the non-challenged group were orally infused with sterilised Luria Bertani culture while pigs in other groups were orally infused with ETEC (2.6 * 1011 colony-forming units). At 3 days after the challenge, all pigs were orally administered d-xylose at 0.1 g per kg body weight and then euthanised 1 h later to obtain serum and intestinal mucosa samples. Our results showed that ETEC infection both reduced (P < 0.05) the villus height and proportion of epithelial cells in the S phase and elevated (P < 0.05) the percentage of total apoptotic epithelial cells in the jejunum and ileum; these deleterious effects caused by ETEC were alleviated (P < 0.05) by supplemental AOS. Meanwhile, AOS ingestion attenuated (P < 0.05) not only the up-regulated tumour necrosis factor receptor 1 (TNFR1), cysteinyl aspartate-specific protease-3 (caspase-3), -8 and -9 transcriptions, as well as the enhanced caspase activities (caspase-3, -8 and 9), but also the down-regulated cyclin E1 and cyclin-dependent kinase 2 (CDK2) transcriptions in jejunal and ileal mucosae, caused by the ETEC challenge. In conclusion, it is possible that the protective effects of AOS against ETEC induced intestinal mucosal disruption in weaned pigs are associated with the restrained enterocyte death, by reducing both mitochondria-dependent and TNFR1 dependent apoptosis and the accelerated enterocyte proliferation, via enhancing the cyclin E-CDK2 complex formation. PMID- 30457636 TI - Visible-light activation of TiO2 by dye-sensitization for degradation of pharmaceutical compounds. AB - This work reports the improvement in the photon absorption and degradation of acetaminophen (ACF) and diclofenac (DFC) by photosensitizing TiO2 with two types of dyes Eosin Y (Ey) and Rhodamine B (RhB). Experimental tests were carried out in a solar simulator for three hours for different systems and both pollutants. The influences of the TiO2 concentration (100, 200 and 800 mg L-1) and the catalyst-dye ratio (2%, 5% and 10%) were investigated. The degradation of the compounds was higher in the presence of TiO2-Ey compared to the TiO2-RhB and TiO2 for both pharmaceutical compounds, which was attributed to the anionic nature of Ey. DFC total degradation was achieved using 100 mg L-1 of catalyst loading and 10% of catalyst-dye ratio and the highest ACF degradation (71%) was obtained at 800 mg L-1 of catalyst loading and 5% of catalyst-dye ratio. The photon absorption was studied for both dyes using the six-flux absorption scattering model (SFM) for estimating the LVRPA (local volumetric rate of photon absorption). This was done by modifying the apparent optical thickness equation. It was found that the presence of dye in the photocatalytic systems considerably increases the LVRPA. The rate coefficients for the degradation of pharmaceutical compounds in the presence of the organic dyes were also obtained. PMID- 30457639 TI - Letter to the Editor: Spontaneous Attachment of Rhegmatogenous Retinal Detachment Following Vitrectomy for Stage 4B Retinopathy of Prematurity and Atypical Retinal Changes Post-Resolution. PMID- 30457640 TI - Update on Emerging Steroid-Based Local Treatments for Noninfectious Uveitis. PMID- 30457641 TI - Impact of Time to Anti-Vascular Endothelial Growth Factor Intervention on Visual Outcomes for Patients Diagnosed With Retinal Vein Occlusion. AB - BACKGROUND AND OBJECTIVES: To analyze the impact of time to treatment with anti vascular endothelial growth factor (VEGF) for patients with macular edema (ME) secondary to retinal vein occlusions (RVO) in routine clinical practice. PATIENTS AND METHODS: One hundred fifty-five eyes with ME secondary to RVO were identified. Patients were divided into initiation of anti-VEGF treatment at 28 days or fewer after symptom onset (Group A), between 28 and 84 days (Group B), and 84 days or more (Group C). RESULTS: A significant central subfield thickness (CST) decrease at 12 months was observed in Groups A, B, and C (-184.14 um, 204.55 um, and -170.71 um, respectively; P < .001). At 12 months, Groups A and B showed significant BCVA improvement (19.14 and 21.11, respectively; P <= .001), whereas Group C showed no significant improvement from baseline (4.01; P < .28). CONCLUSIONS: Anatomical response as measured by CST did not differ between groups, whereas delays in treatment resulted in smaller BCVA improvement with anti-VEGF treatment. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:832-837.]. PMID- 30457642 TI - Retrospective Comparison of Visual Prognosis After Vitrectomy for Idiopathic Epiretinal Membranes With and Without an Ectopic Inner Foveal Layer. AB - BACKGROUND AND OBJECTIVE: To compare the surgical outcomes of epiretinal membrane (ERM) treatment between eyes with and without an ectopic inner foveal layer (EIFL). PATIENTS AND METHODS: Seventy-seven ERM eyes of 76 consecutive patients were investigated retrospectively. Optical coherence tomography examinations and best-corrected visual acuity (BCVA) measurements were performed before and at 6 and 12 months after vitrectomy. RESULTS: In both eyes with and without an EIFL, the BCVAs at 6 and 12 months after vitrectomy were significantly better than those before vitrectomy (P < .05), whereas the BCVAs 6 and 12 months after vitrectomy were significantly better in eyes without an EIFL than in those with an EIFL (P = .014 and P = .019, respectively). CONCLUSIONS: Vitrectomy may be effective in improving visual acuity in eyes with ERMs with and without an EIFL. However, ERM surgery may be desirable before EIFL development to obtain a better prognosis. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:838-845.]. PMID- 30457643 TI - Effect of Therapy on Choroidal Thickness in Patients With Obstructive Sleep Apnea Syndrome. AB - BACKGROUND AND OBJECTIVE: To evaluate effect of continuous positive airway pressure (CPAP) therapy on choroidal thickness in patients with obstructive sleep apnea syndrome (OSAS). PATIENTS AND METHODS: Thirty distinct eyes of 30 patients with OSAS were evaluated right before and 12 months after CPAP treatment in this prospective observational study. Choroidal thickness was measured at the fovea and with periodic intervals of 500 um from the foveal center in both temporal and nasal directions using spectral-domain optical coherence tomography in enhanced depth imaging mode. RESULTS: The patients' mean age was 45.33 years +/- 7.74 years, and there were eight females and 22 males. After CPAP therapy, the choroidal thicknesses were increased significantly at the subfoveal, 500 um nasal to the fovea, 500 um temporal to the fovea, and 1,000 um temporal to fovea points (P < .05). However, none of retinal macular parameters were significantly different in statistical terms between the two measurements (P > .05). CONCLUSIONS: CPAP therapy had a significant influence on choroidal thickness in patients with OSAS, providing an increase in choroidal thicknesses after 12 months. The determination of an increase in choroidal thickness may be useful to reveal the effects of CPAP therapy and also may be one of the mechanisms to improve choroidal function. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:846 851.]. PMID- 30457644 TI - Swept-Source OCT Angiography of the Anomalous Foveal Avascular Zone. AB - BACKGROUND AND OBJECTIVE: To gain insight into clinical presentations associated with anomalous foveal avascular zone (FAZ) architecture and foveal pit morphology. PATIENTS AND METHODS: Twenty-two eyes with anomalous (vascularized) FAZs were identified from 14 patients using optical coherence tomography angiography (OCTA). The FAZ was evaluated in three vascular layers of the retina: the superficial capillary plexus (SCP), the deep capillary plexus (DCP), and the degree of foveal pit hypoplasia was graded. RESULTS: The FAZ was absent in 21 out of 22 eyes at the SCP and in eight out of 22 eyes at the DCP. Foveal pit hypoplasia was more severe in patients where the FAZ was fully vascularized in both the SCP and DCP. The absence of the FAZ did not affect visual acuity. CONCLUSION: Anomalies of the FAZ and foveal pit can present with varying degrees of severity in patients with a wide range of ages and diagnoses. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:852-858.]. PMID- 30457645 TI - Correlation of "Panoramic" Optical Coherence Tomography Angiography With Indocyanine Green Angiography Characteristics of Serpiginous-Like Choroiditis. AB - BACKGROUND AND OBJECTIVES: To analyze the panorama optical coherence tomography angiography (P-OCTA) characteristics of serpiginous-like choroiditis (SLC) and to correlate these findings with indocyanine green angiography (ICGA). PATIENTS AND METHODS: Prospective, observational study of 32 eyes of 24 patients. Twenty-seven eyes of 16 patients who met inclusion criteria were included in the final study. Multimodal imaging was performed using P-OCTA, OCT, fundus autofluorescence, fluorescein angiography, and ICGA. Morphologic features at the site of lesions were analyzed using P-OCTA and correlated with ICGA. RESULTS: P-OCTA in active phase revealed areas of large flow void, which correlated with hypofluorescent areas on ICGA. Healing phase revealed appearance of vascular network due unmasking of choriocapillaris that corresponded to reduced hypofluorescence on ICGA. CONCLUSION: P-OCTA as a noninvasive tool provides widefield and high resolution images that can be used as an complementary tool to ICGA for diagnosis of SLC cases. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:859-869.]. PMID- 30457646 TI - Outer Retinal Tubulation and Neovascular Age-Related Macular Degeneration: A Review of the Pathogenesis and Clinical Implications. AB - Outer retinal tubulation (ORT) is a retinal finding that can mimic intraretinal fluid and has been identified with spectral-domain optical coherence tomography in patients with age-related macular degeneration (AMD). The purpose of this review is to summarize the findings related to the pathogenesis of ORT and its clinical implications. Studies reporting the pathogenesis and the clinical implications of ORT in patients with AMD were identified and summarized. A total of 18 studies were included in this review. The body of evidence to date regarding ORT in patients with AMD indicates that ORT is a structure associated with advanced macular diseases that does not require anti-vascular endothelial growth factor treatment. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:870 876.]. PMID- 30457647 TI - Anatomic Localization of Type 1 and Type 2 Macular Neovascularization Using Swept Source OCT Angiography. AB - BACKGROUND AND OBJECTIVE: Swept-source optical coherence tomography angiography (SS-OCTA) and different boundary-specific segmentation strategies were used to distinguish type 1 macular neovascularization (MNV) from type 2 MNV in eyes with exudative age-related macular degeneration (AMD). PATIENTS AND METHODS: Eyes with exudative AMD were enrolled in a prospective study. Segmentation strategies included a slab from the outer retina (OR) to the choriocapillaris (CC) for the entire MNV, a slab from the retinal pigment epithelium (RPE) to the CC for the type 1 MNV, and a slab from the OR to the RPE for the type 2 MNV. RESULTS: In 13 eyes, SS-OCTA B-scans and en face images using different segmentation strategies were able to identify type 1 and type 2 components of the MNV. CONCLUSION: In eyes with exudative AMD, SS-OCTA imaging and commercially available boundary specific segmentation strategies were used to distinguish between type 1 and type 2 MNV. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:878-886.]. PMID- 30457648 TI - Clinical Course of Autosomal Recessive Bestrophinopathy Complicated by Choroidal Neovascularization. AB - The authors report the clinical course of two cases of autosomal recessive bestrophinopathy (ARB) complicated by choroidal neovascularization (CNV). One patient presenting with a novel BEST1 mutation (c.658 C>T, p.Gln220*) underwent anti-vascular endothelial growth factor therapy. Response to treatment was documented on optical coherence tomography angiography (OCTA). Despite initial response to treatment, recurrent CNV exudation with progressive subretinal fibrosis was observed. In the second patient, the CNV was not treated and spontaneous regression was observed. This report indicates that the clinical course of CNV in ARB may vary considerably, ranging from spontaneous regression to progressive subretinal fibrosis despite intervention. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:888-892.]. PMID- 30457649 TI - Bilateral Vitreous Hemorrhage Following Bilateral Intravitreal Injections of Bevacizumab in an Infant With Retinopathy of Prematurity. AB - Since the publication of BEAT-ROP in 2011, intravitreal bevacizumab (IVB) has become increasingly common for the treatment of posterior type 1 retinopathy of prematurity (ROP). However, long-term data on the safety and efficacy of IVB for ROP are lacking. Vitreous hemorrhage following bevacizumab injections have been rarely reported in infants with ROP, and the need for treatment of these hemorrhages remains in question. Here, the authors report a case of bilateral vitreous hemorrhage in a premature infant within 2 weeks of bilateral intravitreal injections of bevacizumab. These hemorrhages resolved without intervention with regression of ROP in both eyes. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:893-896.]. PMID- 30457650 TI - Macular Hole After Poppers (Alkyl Nitrate) Inhalation in a Child. AB - The authors present the first case of macular hole (MH) after a single inhalation of poppers. A 13-year-old girl presented with vision loss in the left eye (OS). Pediatric and neurology exams were normal. Funduscopy revealed bilateral papilledema and yellow foveal spot OS. Optic neuritis was diagnosed and treated. Due to foveal alteration, optical coherence tomography was performed, and MH was diagnosed. Twenty-three-gauge pars plana vitrectomy, peeling of the internal limiting membrane, and SF6 exchange were performed. Postoperatively, vision restoration and MH closure were observed. Although MH mechanism in the poppers context is unknown, the classic surgery is effective. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:897-900.]. PMID- 30457651 TI - Successful Treatment of a Retinal Detachment Secondary to Multiple Eccentric Macular Holes With Autologous Lens Capsular Flap Transplantation. AB - The authors report a case of a retinal detachment secondary to multiple eccentric macular holes (MEMHs) following an uneventful pars plana vitrectomy and epiretinal membrane peel, successfully treated by autologous lens capsule graft. Anatomical and functional changes were also evaluated. Autologous lens capsule graft is a safe and effective treatment for MEMHs that may improve anatomical and functional results. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:901-903.]. PMID- 30457652 TI - Surgical Management of an Externally Protruding, Perforating Intraocular Foreign Body. AB - Ru-ik Chee Felix Y. Chau In this case of a perforating eye injury by a 2-inch long nail that went through the cornea, lens, and posterior eye wall, the authors describe a combined external, anterior, and posterior segment surgical approach that resulted in safe and successful removal of the foreign body. Initial external trimming of the protruding nail facilitated the use of a noncontact viewing system. Combined limbal and pars plana placement of the vitrectomy cannulas optimized access to both anterior and posterior intraocular structures. Most importantly, careful removal of potential sources of foreign body adhesion to intraocular structures prior to extraction likely increased the likelihood for a successful clinical outcome. Care was taken to remove as much of the vitreous as possible and to keep the eye formed. The patient recovered 20/25+2 vision with aphakic correction. PMID- 30457653 TI - Quantitative Comparison Between Optical Coherence Tomography Angiography and Fundus Fluorescein Angiography Images: Effect of Vessel Enhancement. AB - BACKGROUND AND OBJECTIVE: To compare the vascular parameters derived from optical coherence tomography angiography (OCTA) and fundus fluorescein angiography (FFA) images. PATIENTS AND METHODS: Twenty-two eyes of 22 patients were imaged with OCTA and FFA. FFA images were cropped to the same dimension as OCTA images after registration. Vessel enhancement using a Frangi filter and local fractal analysis was applied to the superficial layer of the OCTA and cropped FFA images. Foveal avascular zone (FAZ) area, vessel density, spacing between large vessels, and spacing between small vessels were quantified. RESULTS: FAZ area was similar between original OCTA, Frangi-filtered OCTA, and FFA images (P = .32). Actual OCTA images had significantly higher vessel density (35.2% +/- 1.45%, P < .001) than Frangi-filtered OCTA images (29.8% +/- 0.78%) and Frangi-filtered FFA images (25.5% +/- 2.41%). Spacing between large vessels was significantly lower in original OCTA images (31.9% +/- 1.47%, P < .001) than Frangi-filtered OCTA images (36.8% +/- 1.24%) and Frangi-filtered FFA images (60.1% +/- 2.68%). Further, FFA images had significantly lower spacing between small vessels (14.4% +/- 0.43%, P < .001) than original OCTA images (32.7% +/- 1.03%) and Frangi-filtered OCTA images (33.4% +/- 0.81%). CONCLUSION: FAZ area was similar between OCTA and FFA, independent of vessel enhancement. However, vessel enhancement improved the agreement of vascular parameters between OCTA and FFA images of the same eye. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e175-e181.]. PMID- 30457654 TI - Visualizing Structure and Vascular Interactions: Macular Nonperfusion in Three Capillary Plexuses. AB - BACKGROUND AND OBJECTIVE: To assess the relationship between retinal vascular and structural changes in the superficial, middle, and deep capillary plexuses (SCP, MCP, DCP) using optical coherence tomography angiography (OCTA) and en face OCT. PATIENTS AND METHODS: Patients with diabetic retinopathy were imaged using the Cirrus HD-OCT with AngioPlex. Using manual segmentation of the retinal layers, the authors compared OCTA to en face OCT images to examine corresponding patterns in each of the three capillary plexuses. RESULTS: Areas of decreased perfusion and capillary dropout on OCTA were found to be associated with three corresponding lesions on en face OCT: hyporeflectivity, cystic edema, and hard exudates. Vascular changes in individual capillary plexuses corresponded with structural changes in their respective perfused retinal layers. CONCLUSIONS: Using manual segmentation on OCTA, the authors provide a framework to visualize the relationship between vascular pathology on OCTA and structural changes on en face OCT within specific capillary plexuses. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e182-e190.]. PMID- 30457655 TI - Monthly Versus Treat-and-Extend Ranibizumab for Diabetic Macular Edema: A Prospective, Randomized Trial. AB - BACKGROUND AND OBJECTIVE: Compare fixed monthly dosing of ranibizumab to treat and-extend (T&E) ranibizumab during a period of 24 months for diabetic macular edema (DME) treatment. PATIENTS AND METHODS: Single-center, randomized, prospective pilot study that included 20 eyes of 20 subjects. Patients' best corrected visual acuity (BCVA) was less than or equal to 20/40 and central foveal thickness on spectral-domain optical coherence tomography was greater than 325 um. Intravitreal ranibizumab was dosed monthly or by protocol-specified treat-and extend. Primary outcome was mean change in mean BCVA. Institutional review board approval was obtained. RESULTS: At month 24 (M24), there was a mean 8.3-letter gain in the monthly treatment group and an 8.5-letter gain in the T&E group (P = .082; 90% confidence interval). The average change from baseline BCVA was not statistically significantly different at any timepoint. At M24, the median number of injections in the monthly and T&E groups were 22.5 and 18.5, respectively (P = .287). CONCLUSIONS: Visual acuity with monthly dosing appears equivalent to T&E dosing during the course of 24 months. There was a trend toward a lower injection burden in the T&E arm. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e191 e197.]. PMID- 30457656 TI - Comparison of Zeiss Cirrus and Optovue RTVue OCT Angiography Systems: A Quantitative and Qualitative Approach Examining the Three Capillary Networks in Diabetic Retinopathy. AB - BACKGROUND AND OBJECTIVES: Construct a method for visualizing the middle capillary plexus (MCP) using Zeiss optical coherence tomography angiography (OCTA) and compare to established segmentation methods using the Optovue system. PATIENTS AND METHODS: Twenty eyes with diabetic retinopathy were imaged. Visualization of the MCP, image artifacts, preservation of pathological changes, foveal avascular zone (FAZ) area, and vessel length density (VLD) were compared between devices. RESULTS: The authors successfully segmented the superficial (SCP), MCP, and deep (DCP) capillary plexuses on both devices. More images artifacts were detected on Optovue. Microaneurysms and telangiectatic vessels were better visualized in the MCP on the Optovue. FAZ area showed a strong correlation between the two instruments (r2= 0.666; P < .0001). The SCP had lower VLD compared to the MCP and DCP on both devices. CONCLUSION: The authors provide an objective and consistent method for manual segmentation using Zeiss OCTA to visualize the three retinal capillary plexuses. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e198-e205.]. PMID- 30457657 TI - Navigated Retina Laser Therapy as a Novel Method for Laser Retinopexy of Retinal Tears. AB - BACKGROUND AND OBJECTIVE: To describe the use of a navigated laser system for the treatment of retinal tears. MATERIALS AND METHODS: A planned pattern laser retinopexy was performed using a navigated laser photocoagulator incorporating rapid panretinal photocoagulation technology with an individualized target overlay to produce a 3 * 3 square pattern surrounding a horseshoe tear. Institutional review board approval was not applicable for this case. RESULTS: Successful laser retinopexy 360 degrees around the tear was achieved. CONCLUSION: In select cases, a navigated laser system may be utilized for the treatment of retinal tears. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e206 e209.]. PMID- 30457658 TI - Choroidal Neovascularization in Torpedo Maculopathy Assessed on Optical Coherence Tomography Angiography. AB - Torpedo maculopathy is characterized by a congenital, unilateral, and torpedo shaped chorioretinal lesion with unclear pathogenesis and evolution. Although the optical coherence tomography angiography (OCTA) characteristics have already been defined in literature, the authors describe for the first time the presence of choroidal neovascularization (CNV) on the temporal edge of this lesion in a 36 year-old woman with a history of altered visual field in her left eye. The authors' investigation supports the hypothesis of an aberrant choroidal circulation underlying the pathogenesis of this condition, and proves the advantage conferred by OCTA in CNV detection over the other angiographic techniques. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e210-e213.]. PMID- 30457659 TI - Iatrogenic Posterior Lens Capsule Rupture and Subsequent Complications due to Nd:YAG Laser Vitreolysis for Vitreous Floaters: A Case Report. AB - Nd:YAG laser vitreolysis has been used as a noninvasive approach to treat visually significant vitreous strands and floaters. However, severe vision threatening complications may occur. The authors describe a rare case of a 60 year-old woman who had suffered rupture of the posterior lens capsule with subsequent cataract formation 1 week post-Nd:YAG laser vitreolysis in the right eye. The authors performed phacoemulsification, pars plana vitrectomy, and intraocular lens implantation at the ciliary sulcus. At 1 month post-surgery, the patient's visual acuity had not recovered well and optical coherence tomography showed epiretinal membrane (ERM) formation. Thus, she underwent secondary pars plana vitrectomy for ERM removal. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e214-e217.]. PMID- 30457660 TI - Single Retinal Layer Changes After Subthreshold Micropulse Yellow Laser in Diabetic Macular Edema. AB - A pilot prospective, interventional study has been conducted on 10 patients with diabetic macular edema (DME) treated with subthreshold micropulse laser (SMPL) to evaluate changes of individual retinal layers and to correlate with functional changes. All patients underwent complete ophthalmologic evaluation including spectral-domain optical coherence tomography (OCT) and microperimetry at baseline, 3 months, 6 months, 9 months, and 12 months. Compared with baseline, a significant decrease was found in inner nuclear layer (INL) and outer retinal layer (ORL) thickness in the central 1 mm (P < .05). Increase in best-corrected visual acuity was significantly and inversely correlated to central retinal thickness (CRT) (P = .0027), INL (P = .0167), and outer nuclear layer (ONL) thickness (P = .0107). Increase in retinal sensitivity was significantly and inversely correlated to CRT and ONL thickness (P < .01). Therefore, SMPL showed to improve firstly functional parameters and then morphologic parameters. Functional parameters were inversely correlated to CRT, INL, and ONL thickness. The exact mechanism of reduction of INL thickness induced by SMPL remains to be further evaluated. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e218-e225.]. PMID- 30457661 TI - [Torsion of wandering spleen - unusual cause to acute abdominal pain in pediatric patients]. AB - Wandering spleen is a rare reason for acute abdominal pain in pediatric patients caused by laxity of the splenic ligaments. It can be complicated by torsion of the pedicle, leading to ischemia, a situation that in most cases results in acute abdominal surgery. To prevent ischemia of a mobile spleen caused by a total occlusion of the pedicle, splenopexy can be considered. We present an unusual case where changes in the position of the operating table during diagnostic laparoscopy might have caused a total occlusion of the pedicle. PMID- 30457662 TI - [Gambling disorder - a current issue in Sweden]. AB - Gambling disorder is a serious condition and a current issue in Sweden. The national prevalence of problem gambling is 2 %, including 0.4 % meeting criteria for gambling disorder, but the incidence numbers are substantially higher due to the dynamic pattern of the disorder with people moving into and out of the problem gambling group. Rapid internet games, such as internet casinos and sports betting, cause a predominant share of the gambling problems, and the market has shown an unrestrained growth for years. New public amendments are upcoming and from the 1st of January 2018, healthcare and social services have a pronounced obligation to offer investigations and treatment (mainly CBT) for gambling disorder. The psychiatric comorbidity is high, and the risk of suicide is clearly elevated among people with gambling disorder. There are quick, evidence-based screening tools that can easily be used in clinical work, as initial steps of investigations. The need for implementing effective national strategies and further research in the area is considerable. PMID- 30457663 TI - [Acute coronary occlusion - possible to diagnose in patients with left bundle branch block]. AB - Electrocardiographic diagnosis of acute coronary occlusion can be difficult in the setting of left bundle branch block. If presumably new bundle branch block is considered equivalent to ST-elevation myocardial infarction, unnecessary coronary angiographies will be performed. On the other hand, the diagnosis of an acute coronary occlusion should not be delayed. Presence of concordant ST-segment changes are specific, but not sensitive, findings in the diagnosis of acute coronary occlusion in patients with left bundle branch block. PMID- 30457664 TI - ? PMID- 30457665 TI - [Implications of Gambling disorder in DSM-5 in Sweden]. AB - The Swedish translation of the diagnostic manual DSM-5 has chosen to use the term "hasardspelsyndrom" for Gambling disorder (GD), although the term gambling addiction is still in use. The inclusion of GD in DSM-5 has led to new amendments that the social and healthcare services have obligations to deal with problematic gambling in the same way as substance use disorders. Now, new Swedish gambling rules will enter into force on January 1, 2019. This means an increased access to all kind of games that may open for new excitements but also cause problems. Therefore, as noticed by many researchers, it is important to foresee all kind of outcomes and find relevant strategies to deal with them. PMID- 30457666 TI - Role of adjuvant therapy in resected stage IA subcentimeter (T1a/T1b) pancreatic cancer. AB - BACKGROUND: The standard of care for patients with resected stage I to stage III pancreatic ductal adenocarcinoma (PDAC) is adjuvant gemcitabine-based chemotherapy. The role of adjuvant treatment in patients with subcentimeter, stage IA PDAC is unknown. The current study evaluated the effect of adjuvant treatment on survival outcomes among patients with American Joint Committee on Cancer/International Union Against Cancer stage IA (T1N0) resected PDAC using the National Cancer Data Base (NCDB). METHODS: A retrospective review of the NCDB was conducted for patients diagnosed with T1 (tumor limited to the pancreas and measuring <=2 cm in greatest dimension), lymph node-negative (N0), resected PDAC between 2004 and 2013. Patient demographics, histology, adjuvant treatment, and survival trends were examined. Kaplan-Meier analysis and log-rank tests were performed to determine the unadjusted association between overall survival (OS), tumor size, and treatment. RESULTS: A total of 876 patients met the inclusion criteria. The patients had a mean age of 66.2 years (range, 32-90 years); approximately 83.3% were white (730 patients) and 53.1% were female (465 patients). Approximately 45.9% of the patients had moderately differentiated tumor histology (402 patients); 70.0% (613 patients) had tumors measuring 1 to 2 cm (T1c) and 30.0% (263 patients) had tumors measuring <1 cm (T1a/T1b). Approximately 94.2% of patients had negative surgical margins (815 patients) and 46.9% (410 patients) received adjuvant therapy. The median OS was significantly different for patients who received adjuvant therapy compared with patients who did not (70.7 months vs 46.9 months; P=.0001). For patients with tumors measuring <1 cm, survival was not found to be significantly different between patients who received adjuvant treatment compared with those who did not (not reached vs 85.3 months; P=.54). In the multivariable analysis, none of the covariates (treatment group, Charlson-Deyo Score, age, insurance, and facility status) demonstrated significant differences for patients with tumors measuring <1 cm. CONCLUSIONS: The current study is the first to demonstrate no survival benefit for adjuvant therapy in patients with resected subcentimeter PDAC. PMID- 30457667 TI - Development of A Comprehensive Biological Hazard-Proof Packaging Film with Insect Repellent, Antibacterial, and Antifungal Activities. AB - A multifunctional film with insect-repellent and antimicrobial activities was developed. Star anise (Illicium verum Hook. f.) oil (SO) proved to be effective in repelling Plodia interpunctella (Hubner) (Lepidoptera: Pyralidae) larvae and was selected as an insect-repellent agent. Thymol, a compound that demonstrated strong growth inhibition activities against both Staphylococcus aureus and Penicillium roqueforti, was selected as an antimicrobial agent. Based on the release profile test of SO using various plastic films, polypropylene (30 MUm; PP 30) and low-density polyethylene (20 MUm; LDPE 20) were selected as laminated films for sustainable insect-repellent and strong antimicrobial effects, respectively. Further, polyethylene terephthalate (12 MUm; PET 12) was selected as an intermediate barrier layer. Finally, structure of the multilayer film was designed as PP 30/SO/PET 12/thymol/LDPE 20. The developed film demonstrated insect-repellent activity for >3 weeks, antibacterial activity for >2 weeks, and antifungal activity for 1 week. The results indicated that the developed multilayer film structure possessed strong, sustained insect-repellent and antimicrobial effects, providing a new possibility for the industrial applications to food packaging. PRACTICAL APPLICATION: A multifunctional active packaging film with insect-repellent and antimicrobial activities was developed. Star anise oil and thymol that showed insect-repellent and antimicrobial activities (antibacterial and antifungal activities), respectively, were added in coating layers in the multilayer film structure. The developed multilayer film proved an efficient insect-repellent activity against Plodia interpunctella for >3 weeks. Also, strong antibacterial and antifungal activities of the developed multilayer film were proved against Staphylococcus aureus and Penicillium roqueforti, respectively. The developed film has a potential for the industrial use to the food packaging material. PMID- 30457668 TI - A Randomized, Double-Blind, Placebo-Controlled Trial of Citicoline in Patients with Alcohol Use Disorder. AB - BACKGROUND: Alcohol use disorder is a major societal and individual burden that exacerbates health outcomes, decreases quality of life, and negatively affects U.S. healthcare spending. Although pharmacological treatments are available for alcohol use disorder, many of them are limited by small effect sizes and used infrequently. Citicoline is a widely available over-the-counter supplement with a favorable side effect profile. It acts through cholinergic pathways and phospholipid metabolism. The current report examines the effect of oral citicoline on alcohol use, craving, depressive symptoms and cognitive outcomes in individuals with alcohol use disorder. METHODS: A 12-week, randomized, double blind, parallel-group, placebo-controlled, pilot study of citicoline (titrated to 2000 mg/day) in 62 adults (age 18-75) with alcohol use disorder was conducted. Alcohol use, such as number of drinking days, amount used, and number of heavy drinking days, was assessed using the Timeline Followback method and liver enzymes, while alcohol craving was measured using the Penn Alcohol Craving Scale. A neurocognitive battery (e.g., Rey Auditory Verbal Learning Test - RAVLT) and depressive symptoms scales (e.g., Inventory of Depressive Symptomatology Self Report - IDS-SR) scores were also collected. Data were analyzed using a random regression analysis. RESULTS: The primary outcome analysis was conducted in the intent-to-treat sample and consisted of n=55 participants (78.2% men and 21.8% women, mean age of 46.47 +/- 9.15 years) with a mean of 77% of days accounted for were drinking days. Significant between-group differences were not observed on alcohol use, craving, cognitive or depressive symptom measures. Citicoline was well tolerated. CONCLUSIONS: This proof-of-concept study observed that citicoline was well tolerated, but was not associated with a reduction in alcohol use or other outcomes, as compared to placebo. The favorable effects reported with citicoline for cocaine use, cognitive disorders, and other conditions do not appear to extend to alcohol use disorder. This article is protected by copyright. All rights reserved. PMID- 30457669 TI - GM-CSF therapy inhibits chronic graft-versus-host disease via expansion of regulatory T cells. AB - Regulatory T cells (Tregs) attenuate excessive immune responses, making their expansion beneficial in immune-mediated diseases, including allogeneic bone marrow transplantation associated with graft-versus-host disease (GVHD). In addition to interleukin-2, Tregs require T-cell receptor and costimulatory signals from antigen-presenting cells, such as DCs, for their optimal proliferation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) increases DC number and may promote DC-dependent Treg proliferation. Here, we demonstrate that GM-CSF treatment increases CD4+ CD8- DCs, which are associated with Treg expansion. In a mouse model of chronic GVHD (cGVHD), GM-CSF therapy expanded Tregs, protected against the development of skin GVHD, and regulated both Th1 and Th17 responses in the peripheral lymph nodes, resulting in an attenuation of skin cGVHD. Notably, the expanded Tregs were instrumental to GM CSF-mediated cGVHD inhibition, which was dependent upon an increased ratio of Tregs to conventional T cells rather than augmentation of suppressive function. These data suggest that GM-CSF induces Treg proliferation by expanding CD4+ CD8- DCs, which in turn regulate alloimmune responses in a cGVHD mouse model. Thus, GM CSF could be used as a therapeutic DC modulator to induce Treg expansion and to inhibit excessive alloimmune responses in immune-related diseases. PMID- 30457670 TI - Follow the trail: Using insights from the growth of palliative care to propose a roadmap for cancer rehabilitation. AB - Despite research explicating the benefits of cancer rehabilitation interventions to optimize physical, social, emotional, and vocational functioning, many reports document low rates of referral to and uptake of rehabilitation in oncology. Cancer rehabilitation clinicians, researchers, and policy makers could learn from the multidisciplinary specialty of palliative care, which has benefited from a growth strategy and has garnered national recognition as an important and necessary aspect of oncology care. The purpose of this article is to explore the actions that have increased the uptake and integration of palliative care to yield insights and multimodal strategies for the development and growth of cancer rehabilitation. After examining the history of palliative care and its growth, the authors highlight 5 key strategies that may benefit the field of cancer rehabilitation: 1) stimulating the science in specific gap areas; 2) creating clinical practice guidelines; 3) building clinical capacity; 4) ascertaining and responding to public opinion; and 5) advocating for public policy change. Coordinated and simultaneous advances on these 5 strategies may catalyze the growth, utilization, and effectiveness of patient screening, timely referrals, and delivery of appropriate cancer rehabilitation care that reduces disability and improves quality of life for cancer survivors who need these services. PMID- 30457671 TI - A Model-Based Meta-Analysis of 24 Antihyperglycemic Drugs for Type 2 Diabetes: Comparison of Treatment Effects at Therapeutic Doses. AB - Model-based meta-analysis was used to compare glycemic control, weight changes and hypoglycemia risk across 24 antihyperglycemic drugs used to treat type 2 diabetes. Electronic searches identified 229 randomized controlled studies comprising 121,914 patients. To ensure fair and unbiased treatment comparisons, the analyses adjusted for important differences between studies, including duration of treatment, baseline glycated hemoglobin, and drug dosages. At the approved doses, glycemic control was typically greatest with glucagon-like peptide 1 receptor agonists (GLP-1RAs), and least with dipeptidyl peptidase-4 (DPP-4) inhibitors. Weight loss was highly variable across GLP-1RAs, but was similar across sodium-glucose cotransporter 2 (SGLT2) inhibitors. Large weight increases were observed with sulfonylureas and thiazolidinediones. Hypoglycemia risk was highest with sulfonylureas, although gliclazide was notably lower. Hypoglycemia risk for DPP-4 inhibitors, SGLT2 inhibitors and thiazolidinediones was generally very low, but increased slightly for both GLP-1RAs and metformin. In summary, important differences between and within drug classes were identified. This article is protected by copyright. All rights reserved. PMID- 30457672 TI - FCGR2A/FCGR3A Gene Polymorphisms and Clinical Variables as Predictors of Response to Tocilizumab and Rituximab in Patients With Rheumatoid Arthritis. AB - We evaluated the influence of clinical, biochemical, and genetic factors on response in 142 patients diagnosed with rheumatoid arthritis, of whom 87 patients were treated with tocilizumab (61.26%) and 55 patients were treated with rituximab (38.7%;) according to the variables European League Against Rheumatism (EULAR) response, remission, low disease activity, and improvement in Disease Activity Score, 28 joints (DAS28) at 6, 12, and 18 months. A retrospective prospective cohort study was conducted. Patients carrying the FCGR3A rs396991-TT genotype treated with tocilizumab showed higher EULAR response (OR, 5.075; 95%CI, 1.20-21.33; P = .027) at 12 months, those who were naive for biological disease modifying antirheumatic drugs (bDMARDs) at the beginning of treatment showed satisfactory EULAR response, higher remission, and greater improvement in DAS28 at 6 months. Younger age at start of tocilizumab treatment was associated with satisfactory EULAR response at 18 months and greater remission at 6 and 18 months. Subcutaneous tocilizumab administration was associated with higher remission at 6 months and improved low disease activity rate at 12 months. In patients treated with rituximab, carriers of the FCGR2A rs1801274-TT genotype had higher EULAR response at 6 months (OR, 4.861; 95%CI, 1.11-21.12; P = .035), 12 months (OR, 4.667; p = 0.066, 95%CI, 0.90-24.12; P = .066), and 18 months (OR, 2.487; 95%CI, 0.35-17.31; P = .357), higher remission (OR: 10.625; p = 0.044, CI95% : 1.07, 105.47) at 6 months, and greater improvement in DAS28 at 12 months (B = 0.782; 95%CI, -0.15 to 1.71; P = .098) and 18 months (B = 1.414; 95%CI, 0.19 2.63; P = .025). The FCGR3A rs396991-G allele was associated with improved low disease activity rate (OR, 4.904; 95%CI, 0.84-28.48; P = .077) and greater improvement in DAS28 (B = -1.083; 95%CI, -1.98 to -0.18; P = .021) at 18 months. Patients with a lower number of previous biological therapies had higher remission at 12 months. We suggest that the FCGR3A rs396991-TT genotype, higher baseline value of DAS28, subcutaneous tocilizumab administration, younger age at the beginning of treatment, and being bDMARD naive are associated with better response to tocilizumab. In patients treated with rituximab, we found better response in those patients with the FCGR2A rs1801274-TT genotype, the FCGR3A rs396991-G allele, and lower number of previous biological therapies. PMID- 30457673 TI - Insights into the regeneration of skin from Acomys, the spiny mouse. AB - Members of the Acomys genus, known as spiny mice, are unique among mammals in being perfectly capable of regenerating large areas of skin that have been removed. During this regenerative process hairs, sebaceous glands, erector pili muscles, adipocytes and the panniculus carnosus all regenerate and the dermis does not scar. We review here the processes that the epidermis and the individual components of the dermis undergo in the regeneration process of the spiny mouse, the molecules that have been identified as potentially being important in regeneration and relate this to what has been proposed as playing a role in studies from the lab mouse, Mus musculus. Differences in the immune systems of spiny mice and lab mice are also highlighted as this is suggested to play a part not only in the perfect wound healing that embryos display but also in regeneration in lower vertebrates. This article is protected by copyright. All rights reserved. PMID- 30457674 TI - Estimation in the progressive illness-death model: A nonexhaustive review. AB - Multistate models can be successfully used for describing complex event history data, for example, describing stages in the disease progression of a patient. The so-called "illness-death" model plays a central role in the theory and practice of these models. Many time-to-event datasets from medical studies with multiple end points can be reduced to this generic structure. In these models one important goal is the modeling of transition rates but biomedical researchers are also interested in reporting interpretable results in a simple and summarized manner. These include estimates of predictive probabilities, such as the transition probabilities, occupation probabilities, cumulative incidence functions, and the sojourn time distributions. We will give a review of some of the available methods for estimating such quantities in the progressive illness death model conditionally (or not) on covariate measures. For some of these quantities estimators based on subsampling are employed. Subsampling, also referred to as landmarking, leads to small sample sizes and usually to heavily censored data leading to estimators with higher variability. To overcome this issue estimators based on a preliminary estimation (presmoothing) of the probability of censoring may be used. Among these, the presmoothed estimators for the cumulative incidences are new. We also introduce feasible estimation methods for the cumulative incidence function conditionally on covariate measures. The proposed methods are illustrated using real data. A comparative simulation study of several estimation approaches is performed and existing software in the form of R packages is discussed. PMID- 30457675 TI - IRF5 regulates unique subset of genes in dendritic cells during West Nile virus infection. AB - Pathogen recognition receptor (PRR) signaling is critical for triggering innate immune activation and the expression of immune response genes, including genes that impart restriction against virus replication. RIG-I-like receptors and TLRs are PRRs that signal immune activation and drive the expression of antiviral genes and the production of type I IFN leading to induction of IFN-stimulated genes, in part through the interferon regulatory factor (IRF) family of transcription factors. Previous studies with West Nile virus (WNV) showed that IRF3 and IRF7 regulate IFN expression in fibroblasts and neurons, whereas macrophages and dendritic cells (DCs) retained the ability to induce IFN-beta in the absence of IRF3 and IRF7 in a manner implicating IRF5 in PRR signaling actions. Here we assessed the contribution of IRF5 to immune gene induction in response to WNV infection in DCs. We examined IRF5-dependent gene expression and found that loss of IRF5 in mice resulted in modest and subtle changes in the expression of WNV-regulated genes. Anti-IRF5 chromatin immunoprecipitation with next-generation sequencing of genomic DNA coupled with mRNA analysis revealed unique IRF5 binding motifs within the mouse genome that are distinct from the canonical IRF binding motif and that link with IRF5-target gene expression. Using integrative bioinformatics analyses, we identified new IRF5 primary target genes in DCs in response to virus infection. This study provides novel insights into the distinct and unique innate immune and immune gene regulatory program directed by IRF5. PMID- 30457676 TI - Innate-like B cell subsets during immune responses: Beyond antibody production. AB - B lymphocytes are recognized for their crucial role in the adaptive immunity since they represent the only leukocyte lineage capable of differentiating into Ab-secreting cells. However, it has been demonstrated that these lymphocytes can exert several Ab-independent functions, including engulfing and processing Ags for presentation to T cells, secreting soluble mediators, providing co stimulatory signals, and even participating in lymphoid tissues development. Beyond that, several reports claiming the existence of multiple B cell subsets contributing directly to innate immune responses have appeared. These "innate like" B lymphocytes, whose phenotype, development pathways, tissue distribution, and functions are in most cases notoriously different from those of conventional B cells, are crucial to early protective responses against pathogens by exerting "crossover" defensive strategies that blur the established boundaries of innate and adaptive branches of immunity. Examples of these mechanisms include the rapid secretion of the polyspecific natural Abs, increased susceptibility to innate receptors-mediated activation, cytokine secretion, downstream priming of other innate cells, usage of specific variable immunoglobulin gene-segments, and other features. As these new insights emerge, it is becoming preponderant to redefine the functionality of B cells beyond their classical adaptive-immune tasks. PMID- 30457677 TI - Decreased nematode clearance & anti-phosphorylcholine specific IgM responses in mannose-binding lectin deficient mice. AB - Brugia malayi is a nematode that causes human lymphatic filariasis. Previously, we showed that mannose binding lectin (MBL) -A is necessary for clearance of B. malayi microfilariae in mice and presence of MBL-A is linked with maximal levels of parasite-specific IgM. Common human MBL gene polymorphisms result in low MBL expression and lead to recurring bacterial infections. Furthermore, these low expressing human MBL polymorphisms result in greatly increased susceptibility to lymphatic filarial infection. Indeed, gain of new filarial infections over a 30 year period are 10-fold higher in people with low, compared to high, MBL expression phenotypes. Human MBL closely resembles mouse MBL-C, rather than MBL A, therefore we examined the role of mouse MBL-C in clearance of microfilariae. Absence of MBL-C alone, or both MBL-A and -C, resulted in delayed clearance of microfilariae and reduced parasite-specific IgM in mice. There were few profound changes in B cell sub-populations or in the ability of MBL-deficient mice to respond to T-dependent or T-independent antigens. However, absence of MBL-A and/or MBL-C resulted in reduced IgM to phosphorylcholine, a constituent of filarial and bacterial antigens, suggesting that inability to form proficient antibody responses to this moiety leads to lack of microfilarial clearance and overall susceptibility to filariasis. This article is protected by copyright. All rights reserved. PMID- 30457678 TI - How chemotherapy and radiotherapy damage the tissue: Comparative biology lessons from feather and hair models. AB - Chemotherapy and radiotherapy are common modalities for cancer treatment. While targeting rapidly growing cancer cells, they also damage normal tissues and cause adverse effects. From the initial insult such as DNA double strand break, production of reactive oxygen species (ROS), and a general stress response, there are complex regulatory mechanisms that control the actual tissue damage process. Besides apoptosis, a range of outcomes for the damaged cells are possible including cell cycle arrest, senescence, mitotic catastrophe, and inflammatory responses and fibrosis at the tissue level. Feather and hair are among the most actively proliferating (mini-)organs, and are highly susceptible to both chemotherapy and radiotherapy damage, thus provide excellent, experimentally tractable model systems for dissecting how normal tissues respond to such injuries. Taking a comparative biology approach to investigate this has turned out to be particularly productive. Started in chicken feather and then extended to murine hair follicles, it was revealed that in addition to p53-mediated apoptosis, several other previously overlooked mechanisms are involved. Specifically, Shh, Wnt, mTOR, cytokine signaling, and ROS-mediated degradation of adherens junctions have been implicated in the damage and/or reparative regeneration process. Moreover, we show here that inflammatory responses, which can be prominent upon histological examination of chemo- or radiotherapy-damaged hair follicle, may not be essential for the hair loss phenotype. These studies point to fundamental, evolutionarily conserved mechanisms in controlling tissue responses in vivo, and suggest novel strategies for the prevention and management of adverse effects that arise from chemo- or radiotherapy. This article is protected by copyright. All rights reserved. PMID- 30457680 TI - The use of cytapheresis in the treatment of infectious diseases. PMID- 30457679 TI - Consequences of diabetes mellitus on neuronal connectivity in limbic regions. AB - Diabetes mellitus (DM) is characterized by high levels of blood glucose. In recent years, its prevalence has increased, which was 422 million in the world in 2014. In elderly patients, DM is associated with deficits in memory and learning processes. The cognitive deficits lead to dementia. With the development of animal models in DM, it has been possible to better understand quantitative morphological changes in numerous neuronal structures belonging to the limbic system, such as the prefrontal cortex (PFC), the hippocampus and basolateral amygdala (BLA). These structures are in close relationship with processes of memory and learning. Several reports have demonstrated that chronic hyperglycemia reduces spinogenesis and dendritic arborization in the aforementioned regions along with a decline in memory and learning processes, especially in streptozotocin (STZ)-induced diabetic rats. In the present review, we discuss animal models, the effects of chronic hyperglycemia on dendritic morphology of limbic regions and memory and learning processes, the effect on neural transmission in these regions, the pathologic mechanisms involved, and the relevance of dendritic morphology in diabetes. All of this information can help us to have a better understanding of dementia in diabetes mellitus and propose strategies for its prevention and treatment. PMID- 30457681 TI - Disassembly of 2D Vertical Heterostructures. AB - As one of the most widely discussed fields, the assembly of nanomaterials has always been extensively studied. However, its inverse process, namely disassembly, is still limited in the ambit of biomolecules. Specifically, in the emerging 2D research field, disassembly still remains unexplored. Inspired by the disassembly of DNA molecules via breaking intermolecular hydrogen bonds, the disassembly of 2D vertical heterostructures (2DVHs) is first achieved through the weakening of the interlayer van der Waals interactions. As a demonstration, ReS2 /WS2 VHs is successfully disassembled into individual building blocks. Density functional theory calculations are performed to study the disassembly of the 2DVHs, which simulate that 2DVHs are first activated by the disassembly promoters and then disassembled with weakened interlayer van der Waals interactions. Such a disassembly process demonstrates that it has great potential to be expanded as a general strategy to achieve the disassembly of other 2D superstructures. PMID- 30457682 TI - Effects of intermittent hyperbaric exposure on endurance and interval exercise performance in well-trained mice. AB - NEW FINDINGS: What is the central question of this study? Intermittent hyperbaric exposure (1.3 ATA with 20.9% O2 ) has been shown to facilitate endurance capacity by facilitating oxidative and glycolytic capacities in skeletal muscle. It currently remains unclear whether this strategy enhances endurance performance in well-trained individuals. What is the main finding and its importance? Hyperbaric exposure (1.3 ATA with 20.9% O2 ) with endurance training enhanced oxidative and glycolytic capacities and protein levels of mitochondrial transcription factor A, dynamin-related protein-1, and heat shock protein 70. Hyperbaric exposure with sprint interval training increased the proportion of type I muscle fibres and promoted capillary growth and muscle fibre hypertrophy. These results may lead to a new strategy for enhancing exercise capacity in well-trained mice. ABSTRACT: The present study was designed to clarify the mechanisms by which hyperbaric exposure (1.3 atmospheres absolute with 20.9% O2 ) improves endurance and interval exercise capacities in highly-trained mice. Male mice in the training group were housed in a cage with a wheel activity device for 7 weeks from 5 weeks old. Voluntary running markedly increased maximal endurance capacity by 6.4-fold. Trained mice were then subjected to either endurance treadmill training (20-32.5 m min-1 ) or sprint interval training (5 sec-run/10 sec-rest, 30-42.5 m min-1 ) with (HypET or HypSIT, respectively) and without (ET or SIT, respectively) 1-h hyperbaric exposure for 4 weeks. Maximal endurance capacity was significantly increased by HypET and HypSIT, while maximal interval capacity was significantly enhanced by HypSIT. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression levels were markedly increased after HypET and HypSIT. Activity levels of 3-hydroxyacyl-CoA-dehydrogenase, citrate synthase, and phosphofructokinase in the red gastrocnemius muscle were increased more by HypET than by ET. Protein levels of mitochondrial transcription factor A, dynamin related protein-1, and heat shock protein 70 increased more by HypET than by ET. The proportion of type I fibres in the soleus muscle was remarkably increased by HypSIT. Capillary-to-fibre ratio values in the white gastrocnemius were increased more by HypSIT than by SIT. These results suggest that hyperbaric exposure has beneficial effects for endurance and interval training to improve exercise capacity in highly-trained mice. This article is protected by copyright. All rights reserved. PMID- 30457683 TI - Development of Sulfonic-Acid-Functionalized Mesoporous Materials: Synthesis and Catalytic Applications. AB - Sulfonic acid based mesostructures (SAMs) have been developed in recent years and have important catalytic applications. The primary applications of these materials are in various organic synthesis reactions, such as multicomponent reactions, carbon-carbon bond couplings, protection reactions, and Fries and Beckman rearrangements. This review aims to provide an overview of the recent developments in the field of SAMs with a particular emphasis on the reaction scope and advantages of heterogeneous solid acid catalysts. PMID- 30457684 TI - Polar-Group Activated Isospecific Coordination Polymerization of ortho Methoxystyrene: Effects of Central Metals and Ligands. AB - Stereo-selective polymerization of polar vinyl monomers has always been a long standing challenge because the employed transition-metal catalysts were easily poisoned by polar groups of monomers. In this contribution, a series of beta diketiminato rare-earth metal complexes 1-5 (L1-5Ln(CH2SiMe3)2(THF)n, Ln = Gd~Lu, Y, and Sc) were successfully synthesized. In combination with AliBu3 and [Ph3C][B(C6F5)4], complexes 1c(Tb)-1g(Tm) exhibited high activities and excellent iso-selectivities for the polymerization of ortho-methoxystyrene (oMOS), in which, the polar methoxy group of oMOS didn't poison but activated the polymerization through sigma-pi chelation to the active species together with the vinyl group. Moreover, the large Gd-attached precursor 1b showed a higher activity albeit with a slightly decreased isoselectivity. Whereas, the small Sc attached precursor 1i was completely inert. Meanwhile, the spacial sterics and the coordination mode of beta-diketiminato ligand could obviously affect and even block oMOS polymerization. This work sheds a new light on the coordination polymerization of polar monomers. PMID- 30457685 TI - Employment and Careers of European Chemists (ESEC2). AB - Employment conditions and career opportunities are in the focus of the new Employment Survey for European Chemists (ESEC2). Conditions and opportunities are individually analysed for all countries with a statistically significant number of responses. The results provide important clues for careers in these countries and in Europe as a whole. The importance of employer sectors varies very much between European countries. A chapter of this report is devoted to career planning of students and new graduates. This is the first general evaluation of the survey. It provides many details about the chemistry workforce in Europe and its development. PMID- 30457686 TI - Levels of choline-containing compounds in normal liver and liver metastases of colorectal cancer as recorded by 1 H MRS. AB - PURPOSE: A relatively high signal for choline-containing compounds (total choline, tCho) is commonly found in 1 H MR spectra of malignant tumors, but it is unclear if this also occurs in tumors in the liver. We evaluated the potential of the tCho signal in single voxel 1 H MR spectra of the human liver to assess metastases of colorectal cancers. EXPERIMENT: MR spectra of an 8 cm3 PRESS localized voxel were obtained at 3 T from the livers of 12 healthy volunteers and from metastatic lesions in 20 patients in two different sessions. To correct for motion artifacts, sequentially recorded spectra were individually phased and frequency aligned before averaging. Spectra were analyzed using LCModel and tissue levels estimated by water referencing. Repeatability was assessed with Bland-Altman analyses. To estimate tumor necrosis, diffusion-weighted imaging of the liver was performed. High resolution magic angle spinning (HRMAS) spectra of tumor and normal liver samples were obtained at 11.7 T. RESULTS: With increasing tumor volumes, tCho levels decreased, indicating a partial volume effect. Mean tCho content in tumors larger than the PRESS voxel (>8 cm3 ) was significantly lower (p < 0.01) than for normal liver: 1.6 (range 0.0-3.4) versus 6.9 (range 4.9 11.1) mmol/kg wet weight, while it was comparable for tumors smaller than 8 cm3 : 7.0 (range 3.8-9.3) mmol/kg. The higher 90th percentile apparent diffusion coefficient value in the larger lesions indicates more necrosis. Measurement repeatability was average in normal livers and poor in tumors. HRMAS did not show substantial differences in choline-containing compounds between normal liver and metastasis. CONCLUSION: An increased tCho content was not observed in 1 H MR spectra of liver metastasis of colorectal cancer, compared with normal liver. This may be due to the background of a high tCho signal in spectra of normal liver or to an intrinsic lower tCho content in these tumors, but is most likely the result of necrosis in metastatic tumor tissue. PMID- 30457687 TI - Diverse Reactivity of Dienes with Pentaphenylborole and 1-Phenyl-2,3,4,5 Tetramethylborole Dimer. AB - The reactions of a monomeric borole and a dimeric borole with 2,3-dimethyl-1,3 butadiene and 1,3-cyclohexadiene were investigated. The monomeric borole reacted at ambient temperature whereas heat was required to crack the dimer to form the monomer and induce reactivity. 2,3-Dimethyl-1,3-butadiene reacts to give diverse products resulting from a cycloaddition process with the B-C moiety of the boroles acting as a dienophile, followed by rearrangements to furnish bicyclic species. For 1,3-cyclohexadiene, a [4+2] process is observed in which 1,3 cyclohexadiene serves as the dienophile and the boroles as the diene partner. The experimental results are corroborated with mechanistic theoretical calculations that indicate dienes can serve as either a diene or dienophile in cycloaddition reactions with boroles. PMID- 30457688 TI - Using the magnetoencephalogram to noninvasively measure magnetite in the living human brain. AB - During the past several decades there has been much interest in the existence of magnetite particles in the human brain and their accumulation with age. These particles also appear to play an important role in neurodegenerative diseases of the brain. However, up to now the amount and distribution of these particles has been measured only in post-mortem brain tissue. Although in-vivo MRI measurements do show iron compounds generally, MRI cannot separate them according to their magnetic phases, which are associated with their chemical interactions. In contrast, we here offer a new noninvasive, in-vivo method which is selectively sensitive only to particles which can be strongly magnetized. We magnetize these particles with a strong magnetic field through the head, and then measure the resulting magnetic fields, using the dcMagnetoencephalogram (dcMEG). From these data, the mass and locations of the particles can be estimated, using a distributed inverse solution. To test the method, we measured 11 healthy male subjects (ages 19-89 year). Accumulation of magnetite, in the hippocampal formation or nearby structures, was observed in the older men. These in-vivo findings agree with reports of post-mortem measurements of their locations, and of their accumulation with age. Thus, our findings allow in-vivo measurement of magnetite in the human brain, and possibly open the door for new studies of neurodegenerative diseases of the brain. PMID- 30457690 TI - Catalytic C1-Alkylation with Methanol and Isotope Labelled Methanol. AB - A new metal catalyzed protocol for the C1-methylation has been developed. By employing an air and moisture stable catalyst together with isotopically labelled methanol a series of D-, CD3- and 13C-labelled products were obtained with good yields under mild reaction conditions with water as the only side product. PMID- 30457689 TI - Increased NAD(H) pool promotes colon cancer progression by suppressing ROS level. AB - Nicotinamide adenine dinucleotide (NAD) exists in a reduced form (NADH) and an oxidized form (NAD+). NAD+ plays crucial roles in cancer metabolism, including in cellular signaling, energy production and redox regulation. However, it remains unclear whether NAD(H) pool size (NAD+ and NADH) could be used as biomarker for colon cancer progression. Here, we showed that the NAD(H) pool size and NAD+ /NADH ratio both increased during colorectal cancer (CRC) progression due to activation of the NAD+ salvage pathway mediated by nicotinamide phosphoribosyltransferase (NAMPT). The NAMPT expression was upregulated in adenoma and adenocarcinoma tissues from CRC patients. The NADH fluorescence intensity measured by two-photon excitation fluorescence (TPEF) microscopy was consistently increased in CRC cell lines, azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC tissues and tumor tissues from CRC patients. The increases in the NAD(H) pool inhibited the accumulation of excessive ROS levels and FK866, a specific inhibitor of NAMPT, treatment decreased the CRC nodule size by increasing ROS levels in AOM/DSS mice. Collectively, our results suggest that NAMPT-mediated upregulation of the NAD(H) pool protects cancer cells against detrimental oxidative stress and that detecting NADH fluorescence by TPEF microscopy could be a potential method for monitoring CRC progression. This article is protected by copyright. All rights reserved. PMID- 30457691 TI - Platinum Nanosheets between Graphite Layers. AB - Two-dimensional platinum nanosheets were obtained by the hydrogen reduction of platinum tetrachloride intercalated between graphite layers, the latter was prepared by the treatment of the mixture of platinum tetrachloride and graphite powder under chlorine atmosphere. The size of platinum nanosheets was 1-3 nm in thickness with a width in the range of 5-300 nm. These nanosheets contain a number of hexagonal holes and edges with an angle of 120 degrees . This review discusses the reduction and oxidation behavior of platinum species and structure of platinum nanosheets between graphite layers. The selective hydrogenation catalyzed by these platinum nanosheets entrapped between the graphite layers is also demonstrated. PMID- 30457692 TI - Ranges and drivers of risk associated with sports and recreational activities in people with haemophilia: results of the Activity-Intensity-Risk Consensus Survey of US physical therapists. AB - INTRODUCTION: Limited evidence describes physical activity-associated bleeding risks for people with haemophilia, and risks are usually described only generically. AIM: To assess activity-specific ranges of risk for joint, soft tissue and head bleeds by identifying inherent and modifiable risk factors associated with each activity, based on opinions of expert physical therapists (PTs). METHODS: Physical therapists from US haemophilia treatment centres (HTCs) participated in a survey of 101 physical activities. For each activity, PTs provided minimum/maximum risk scores (low = 1; high = 5), and indicated specific bleeding risks in six joints and three injury types (bruising, muscle bleeding, head injury). Risk drivers were identified from free-text comments and explored at a consensus meeting, where they were categorized as inherent or modifiable and activity-driven or patient-driven. RESULTS: Of 32 invited PTs, 17 participated; median experience was 24 years as a PT and 16 years at an HTC. Only a few activities had a wide range of risk assessments encompassing both lower and upper ends of the response range. Joint injury risks were consistent with position and physical requirements, and head and muscle bleed risks were associated with physical contact. Eight PTs participated in the consensus meeting; key risk drivers identified included progression from seasonal to year-round participation, overtraining and improper body mechanics. Inherent risks included impact with surface/ball/equipment and field/surface condition; modifiable risks included safety equipment and tricks/stunts. CONCLUSIONS: These data provide a framework for discussion with patients/families, recognizing how certain activities may be modified to decrease risk, and identifying activities with nonmodifiable inherent risks. PMID- 30457693 TI - Reactive Dimerization of an N-heterocyclic Plumbylene: CH Activation with PbII. AB - The N-heterocyclic plumbylene [Fe{(eta5-C5H4)NSiMe3}2Pb:] is in equilibrium with an unprecedented dimer in solution, whose formation involves the cleavage of a strong C-H bond and concomitant formation of a Pb-C and an N-H bond. According to a mechanistic DFT assessment, dimer formation does not involve direct PbII insertion into a cyclopentadienyl C-H bond, but is best described as an electrophilic substitution. The bulkier plumbylene [Fe{(eta5 C5H4)NSitBuMe2}2Pb:], in turn, shows no dimerization, but compensates its electrophilicity by formation of an intramolecular Fe-Pb bond. PMID- 30457694 TI - First-line checkpoint inhibitors in PD-L1-positive patients with advanced urothelial carcinoma. AB - More than 50% of all patients with advanced urothelial carcinoma cannot receive highly toxic cisplatin-based chemotherapy as the first-line treatment because of their unsatisfactory performance status and co-morbidities. Replacement of cisplatin with carboplatin does not produce a desired improvement with regard to efficacy. In addition, 20% of patients either are carboplatin-ineligible or discontinue this drug as well. This article is protected by copyright. All rights reserved. PMID- 30457695 TI - Microwave Flow: A Perspective on Reactor and Microwave Configurations and the Emergence of Tunable Single-mode Heating Toward Large-scale Applications. AB - Microwave heating in chemical reactions was first reported in 1986. There have since been many reports employing microwave heating in organic chemistry, where microwave heating has afforded higher yields of products in shorter time periods. However, such reactions are challenging to scale in batch due to the limited penetration depth of microwaves as well as the wave propagation dependence on cavity size. Continuous flow has addressed both these issues, enabling scalability of microwave processes. As such, a host of reports employing microwave flow chemistry have emerged, employing various microwave heating and reactor configurations in the context of either custom-built or commercial apparatus. The focus of this review is to present the benefits of microwave heating in the context of continuous flow and to characterize the different types of microwave flow apparatus by their design (oscillator, cavity type and reactor vessel). We advocate the adoption of tunable, solid-state oscillator single-mode microwave flow reactors which are more versatile heaters, impart better process control and energy efficiency toward laboratory and larger-scale synthetic chemistry applications. PMID- 30457696 TI - Adsorption of Cyclohexane in Pure Silica Zeolites: High-Throughput Computational Screening Validated by Experimental Data. AB - Adsorption of cyclohexane in pure silica zeolites was studied experimentally and by molecular simulations. Based on the adsorption isobars obtained from the quasi equilibrated temperature adsorption and desorption (QE-TPDA) measurements and reported adsorption isotherms for high-silica zeolites Y, ZSM-5, and ZSM-11 we refined Lennard-Jones parameters for guest-host interactions available in the literature. Adsorption of cyclohexane from equimolar mixture of twisted-boat and chair conformations has been screened in 171 pure silica zeolitic structures using grand canonical Monte Carlo simulations. Almost 20 frameworks showing extraordinary preference for adsorption of the chair conformation over the twisted boat one or vice versa were found. This selectivity was attributed to the geometry of channels and cavities present in the pore structures, as all t-boat selective structures possess channels or cavities of 8.3-9.1 A. We also differentiated ways of chair-selectivity depending on the size and shape of the channels or cavities and also on the arrangement of the guest molecules in the pores. PMID- 30457697 TI - Quantitative detection of IKZF1 deletion by digital PCR in patients with acute lymphoblastic leukemia. PMID- 30457698 TI - The influence of treatment expectations on clinical outcomes and cortisol levels in patients with chronic neck pain: an experimental study. AB - BACKGROUND: The role of contextual factors like pre-existing treatment expectations has been established. However, the effect of verbally-delivered treatment expectations in patient-therapist communication has not been considered, nor the role of cortisol changes within the placebo/nocebo response in people with chronic neck pain. OBJECTIVE: To examine the effect of verbally delivered treatment expectations on clinical outcomes in physical therapy practice and to determine if changes in cortisol levels are associated to changes in neck pain and disability. METHODS: Eighty-three patients with chronic neck pain were randomly allocated to three different verbally-delivered expectations (positive, negative, neutral) during physical therapy interventions. MAIN OUTCOME MEASURES: salivary cortisol, pain and disability, and cervical range of motion. RESULTS: Pain significantly improved in the positive (p<.001) and neutral (p<.001) expectations groups. For salivary cortisol levels, a significant increase was observed in response to treatment in the neutral (p=.045) and negative expectations group (p<.001). No significant correlations were found between changes in salivary cortisol levels and the change in pain in the neutral and negative expectations group. CONCLUSIONS: Physical therapists treating people with chronic neck pain should be attentive when communicating the expected treatment effects to their patients. Whereas verbally-delivered positive or neutral expectations may be beneficial for pain-related measures, giving negative expectations may result in a lack of a treatment response on pain. Cortisol levels increased in response to verbally-delivered neutral and negative expectations, in absence of a nocebo effect. This questions the presumed role of cortisol in the nocebo effect. This article is protected by copyright. All rights reserved. PMID- 30457699 TI - Coacervation of Interfacial Adhesive Proteins for Initial Mussel Adhesion to a Wet Surface. AB - Coacervation of mussel adhesive proteins (MAPs) is proposed as a potential strategy that mussels may use during secretion due to their high concentration density, lack of dispersion into seawater, and low interfacial tension. Particularly, coacervations of interfacial MAPs, foot protein type-3 fast variant (fp-3F) and type-5 (fp-5), are important in the initial mussel adhesion process due to the relationship between the easy secretion/surface wetting properties of the coacervate and primer-like surface adhesive role of interfacial MAPs, which directly contact the marine surface. To the best of the authors' knowledge, this is the first report on coacervate formation of major recombinant interfacial MAPs with high charge densities and the highest 3,4-dihydroxyphenylalanine (Dopa) contents. Specifically, salt-induced coacervation of fp-3F is observed at low pH values corresponding to the acidified environment of the distal depression during mussel secretion. In addition, it shows enthalpy driven upper critical solution temperature behavior, possibly relying on bridging interactions between like charged cationic fp-3Fs including salt-bridge and cation-pi/pi-pi interactions in the presence of specific counterions, supported by Raman spectroscopy. It is believed that this study has broadened the scope of the understanding of coacervation of MAPs and may provide new insight for responsive biomaterial design. PMID- 30457700 TI - Piezophototronic Effect Modulated Multilevel Current Amplification from Highly Transparent and Flexible Device Based on Zinc Oxide Thin Film. AB - In this work, a strain modulated highly transparent and flexible ZnO/Ag nanowires/polyethylene terephthalate optoelectronic device is developed. By utilizing the applied external strain-induced piezophototronic effects of a ZnO thin film, a UV-generated photocurrent is tuned in a wide range starting from 0.01 to 85.07 uA and it is presented in a comprehensive map. Particularly, the performance of the device is effectively enhanced 7733 times by compressive strain, as compared to its dark current in a strain-free state. The observed results are explained quantitatively based on the modulation of oxygen desorption/absorption on the ZnO surface under the influence of applied strains. The presented simple optoelectronic device can be easily integrated into existing planar structures, with potential applications in highly transparent smart windows, wearable electronics, smartphones, security communication, and so on. PMID- 30457701 TI - Recent Advances in Cell Membrane-Camouflaged Nanoparticles for Cancer Phototherapy. AB - Phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) employs phototherapeutic agents to generate heat or cytotoxic reactive oxygen species (ROS), and has therefore garnered particular interest for cancer therapy. However, the main challenges faced by conventional phototherapeutic agents include easy recognition by the immune system, rapid clearance from blood circulation, and low accumulation in target sites. Cell-membrane coating has emerged as a potential way to overcome these limitations, owing to the abundant proteins on the surface of cell membranes that can be inherited to the cell membrane-camouflaged nanoparticles. This review summarizes the recent advances in the development of biomimetic cell membrane-camouflaged nanoparticles for cancer phototherapy. Different sources of cell membranes can be used to coat nanoparticles uisng different coating approaches. After cell-membrane coating, the photophysical properties of the original phototherapeutic nanoparticles remain nearly unchanged; however, the coated nanoparticles are equipped with additional physiological features including immune escape, in vivo prolonged circulation time, or homologous targeting, depending on the cell sources. Moreover, the coated cell membrane can be ablated from phototherapeutic nanoparticles under laser irradiation, leading to drug release and thus synergetic therapy. By combining other supplementary agents to normalize tumor microenvironment, cell-membrane coating can further enhance the therapeutic efficacy against cancer. PMID- 30457702 TI - Preparation of Hollow Nitrogen Doped Carbon via Stresses Induced Orientation Contraction. AB - Hollow structured materials are widely applicable in various fields. Although many routes have been explored for getting such materials, a strategy mainly based on physical effect is still deficient. Herein, a "stresses induced orientation contraction" mechanism for preparation of hollow structures is reported. The composites constructed by zeolite imidazolate framework-8 (ZIF8) cores and polymerized dopamine (PDA) shells, upon annealing, form intensive interfacial interactions, which drag the ZIF8 cores outward to restrain their shrinkage. The gradually accumulated stresses in the central position of ZIF8 dodecahedron nanoparticles, then destroy the ZIF8 crystalline cores to form the hollow structures. In this stress-based route for creating hollow interiors with core-shell composites as the starting materials, three critical factors are necessary: 1) an intensive core-shell interfacial interaction; 2) the distinctly higher shrinkage degree of the cores than the shells; and 3) the relatively loose core structures. In oxygen reduction reaction (ORR) tested with three-electrode solution system and Zn-O2 battery, the achieved hollow nitrogen doped carbon (NC) demonstrates ultrahigh catalytic activities. This work gives an absolutely novel strategy for preparation of hollow structures, which may afford the exploration of a wider range of materials system with hollow interiors. PMID- 30457703 TI - A missense mutation in TYRP1 causes the chocolate plumage color in chicken and alters melanosome structure. AB - The chocolate plumage color in chickens is due to a sex-linked recessive mutation, choc, which dilutes eumelanin pigmentation. Because TYRP1 is sex-linked in chickens, and TYRP1 mutations determine brown coat color in mammals, TYRP1 appeared as the obvious candidate gene for the choc mutation. By combining gene mapping with gene capture, a complete association was identified between the chocolate phenotype and a missense mutation leading to a His214Asn change in the ZnA zinc-binding domain of the protein. A diagnostic test confirmed complete association by screening 428 non-chocolate chickens of various origins. This is the first TYRP1 mutation described in the chicken. Electron microscopy analysis showed that melanosomes were more numerous in feather follicles of chocolate chickens but exhibited an abnormal structure characterized by a granular content and an irregular shape. A similar altered morphology was observed on melanosomes of another TYRP1 mutant in birds, the roux mutation of the quail. This article is protected by copyright. All rights reserved. PMID- 30457704 TI - Bioinformatics methods to select prognostic biomarker genes from large scale datasets: a review. AB - With the increased availability of survival datasets, that comprise both molecular information (e.g., gene expression), and clinical information (e.g., patient survival), numerous genes have been proposed as prognostic biomarkers. Despite efforts and money invested, very few of these biomarkers have been clinically validated and are used routinely. A high false discovery rate is assumed to be largely responsible for this, in particular as the number of tested genes is extremely high relative to the number of patients followed. Here, after describing the historical methodologies on which recent developments have often been based, this review describes studies that have been performed in the last few years. The concepts will be illustrated for a renal cancer dataset, and the corresponding scripts are provided (Suppl. File). These new developments belong to three main fields of applications. First, variable selection concerns various improvements to lasso penalization. Second, accurate definition of p-values and control of the false discovery rate have also been the subject of many studies. Third, the incorporation of biological knowledge, often through the form of networks or pathways, can be used as an a priori and/or to reduce dimensionality. These new and promising developments deserve benchmarking by independent groups not involved in their development, with various independent datasets. Further work on the methodologies is also still required. PMID- 30457705 TI - State of the Art of Pharmaceutical Solid Forms from Crystal Property Issues to Nanocrystals Formulation. AB - The solid form screening of active principal ingredients is a challenge for the pharmaceutical drug development since more than 80% of the marketed drugs are formulated in the solid form. A broad and comprehensive study of the various solid forms of the matter is needed to enhance its translation to clinic. Therefore, the most suitable solid form has to be taken into consideration regarding ex- and in-vivo stability, targeting, solubility, dissolution rate, and bioavailability. In this review, techniques of solid form screening are reported, including differences in the solid forms such as polymorphs, solvates, salts, co crystals and amorphous particles. Moreover, solid drug size reduction is also discussed, with an insight into the emergence of drug nanocrystals formulation. An overview of the smallest nanocrystals in the literature and in the market, is reported. Their application and administration routes are also addressed. PMID- 30457706 TI - A biomimetic lipid membrane device reveals the interaction of cancer biomarkers with human serum lipidic moieties. AB - BACKGROUND: A major problem for the detection of cancer biomarkers in plasma or serum is that common clinical practice does not require the patient to be in a fasting state. Considering that lipoproteins are the main population affected by food intake, we hypothesized that biomarkers could be embedded in lipid particles and thereby opens a new avenue for detection. AIM: Using our recently published biomarker, soluble VE-cadherin (sVE), we tested our hypothesis using techniques of biophysics, biochemistry and the tools of nanobiotechnology on serum samples from kidney cancer patients (n = 106). RESULTS: Optical density as well as contact angle measurements of serum revealed heterogeneity in the particle content of the serum samples. Isolation of the lipidic moieties by ultracentrifugation showed that sVE was detected in this compartment. Further, isolation of lipoprotein subclasses by precipitation with sodium phosphotungstate and MgCl2 , showed that HDL carried the majority of sVE. Immunoprecipitation of sVE confirmed that it was associated with Apolipoprotein A1, a major compound of HDL. Using a biomimetic lipid bilayer membrane coupled with impedance spectroscopy we quantified, in real-time, that the sVE adsorbed to the lipid bilayer membrane without altering its structure. CONCLUSION: Taken together, these results show for the first time a direct interaction of a cancer biomarker with lipids. We anticipate these results to prompt fasting for future blood tests for large-scale studies in the biomarkers research field. PMID- 30457707 TI - Gated Materials: Installing Macrocyclic Arenes-Based Supramolecular Nanovalves on Porous Nanomaterials for Controlled Cargo Release. AB - Supramolecular nanovalves are an emerging class of important elements that are functionalized on the surfaces of inorganic or hybrid nanocarriers in the constructions of smart cargo delivery systems. Taking advantage of the pseudorotaxane structure via host-guest complexation and the dynamic nature of supramolecular interactions, macrocyclic arene-based supramolecular nanovalves have shown great promise in the applications of drug delivery and controlled release. Careful selection of diverse external stimuli, such as pH variations, temperature changes, redox, enzymes, light irradiation, and competitive binding, can activate the opening and closing of the nanovalves by altering the supramolecular structure or binding affinities. Meanwhile, the porous solid supports in controlled release systems also play an important role in the functionalities of the nanocarriers, which include, but not limited to, mesoporous silica nanoparticles (MSNs), metal-organic frameworks (MOFs), core shell nanomaterials, and rare-earth porous nanomaterials. The elaborate decoration by macrocyclic arenes-based supramolecular nanovalves on porous nanomaterials has provided intelligent controlled release platforms. In this review, we will focus on the overview of supramolecular nanovalves based on two typical macrocyclic arenes, that is, calixarenes and pillarenes, and their operation manners in the controlled release processes. PMID- 30457708 TI - Low CD4/CD8 Ratio in Classical Swine Fever Postnatal Persistent Infection Generated at three weeks after birth. AB - Classical swine fever virus (CSFV) is one of the most important pathogens affecting swine. After infection with a moderate virulence strain at eight hours after birth, CSFV is able to induce viral persistence. These animals may appear clinically healthy or showed unspecific clinical signs despite the permanent viremia and high viral shedding, in absence of immune response to the virus. Given the role played by this infection in disease control, we aimed to evaluate the capacity of CSFV to induce postnatal persistent infection at three weeks after birth. Nine pigs were CSFV infected and sampled weekly during six weeks and viral, clinical, pathological and immunological tests were carried out. Also, the CD4/CD8 ratio was calculated with the purpose to relate this marker with the CSFV persistent infection. The IFN-alpha response was detected mainly one week after infection, being similar in all the infected animals. However, 44.4% of animals were CSFV persistently infected, 33.3% died and 22.2% developed specific antibody response. Interestingly, in persistently infected pigs, the T-CD8 population was increased, the T-CD4 subset was decreased and lower CD4/CD8 ratios were detected. This is the first report of CSFV capacity to confer postnatal persistent infection in pigs infected at three weeks after birth, an age in which the weaning could be carried out in some swine production systems. This type of infected animals shed high amounts of virus and are difficult to evaluate from the clinical and anatomopathological point of view. Therefore, the detection of this type of infection and its elimination in endemic areas will be relevant for global CSF eradication. Finally, the low CD4/CD8 ratios found in persistently infected animals may be implicated in maintaining high CSFV replication during persistence and further studies will be performed to decipher the role of these cells in CSFV immunopathogenesis. This article is protected by copyright. All rights reserved. PMID- 30457709 TI - Normothermic machine perfusion may prevent regulated cell death following renal ischemia-reperfusion injury. AB - We congratulate DiRito et al (1) on their excellent review, giving an outlook on possible effects of normothermic machine perfusion (NMP) to prevent renal ischemia-reperfusion injury (IRI). Concerning the pathophysiology behind IRI there was not a discussion of the different regulated (nonapoptotic) cell death pathways in this context, which have been very well investigated over the last few years in murine models (2, 3). This article is protected by copyright. All rights reserved. PMID- 30457710 TI - Structure-Activity Relationships of Hexahydrocyclopenta[c]quinoline Derivatives as Allosteric Inhibitors of CDK2 and EGFR. AB - Following the discovery of a type III allosteric modulator of cyclin-dependent kinase 2 (CDK2) characterized by a hexahydrocyclopenta[c]quinolone scaffold, three different series of its derivatives were synthesized and biologically evaluated. Docking of the synthesized compounds into the allosteric pocket of CDK2 allowed the elucidation of structure-activity relationships (SARs). Moreover, the compounds were tested on the wild-type epidermal growth factor receptor (EGFR) kinase domain (KD) and its clinically relevant T790M/L858R mutant form. Herein we describe the first SAR investigation of allosteric ligands that bind to the type III inhibitor pocket of CDK2 and EGFR-KD. Although the activity of the synthesized inhibitors needs to be improved, the obtained results provide clear-cut indications about pharmacophore requirements and selectivity determinants. Remarkably, this study led to the identification of a selective T790M/L858R EGFR allosteric inhibitor that is inactive toward both wild-type EGFR and CDK2. Finally, docking into the T790M/L858R EGFR-KD led us to hypothesize that the compounds bind to the double-mutant EGFR-KD by adopting a binding mode different from that in CDK2, thus rationalizing the observed selectivity profile. PMID- 30457712 TI - A broader perspective of iatrogenesis. PMID- 30457711 TI - Across the Board: J. Henrique Teles. AB - In this series of articles, the board members of ChemSusChem discuss recent research articles that they consider of exceptional quality and importance for sustainability. This entry features Dr. J. Henrique Teles, who highlights the importance of a holistic view of sustainability. This is particularly important when it comes to bringing results from the lab to industrial use. PMID- 30457713 TI - Caffeine use in preterm infants: from magic to uncertainty. PMID- 30457714 TI - Gastroesophageal reflux in preterm infants: Neonatal myths versus evidence-based medicine. PMID- 30457715 TI - Some ethical aspects of medical education research. PMID- 30457716 TI - Results of the National Program for the Prevention of Blindness in Childhood by Retinopathy of Prematurity in Argentina (2004-2016). AB - INTRODUCTION: The ROP Argentina Group was created in 2003 and is responsible for the National Program for the Prevention of Blindness in Childhood by Retinopathy of Prematurity (ROP) in Argentina. OBJETIVES: To describe the program implementation and results achieved in relation to ROP care in terms of effectiveness, access, and quality (2004-2016). POPULATION AND METHODS: Descriptive, retrospective study with a dynamic cohort carried out in facilities that are part of the registry. Eligible population: All preterm newborn infants with risk factors for ROP. RESULTS: Participating health care services increased from 14 to 98 and covered the 23 provinces and the Autonomous City of Buenos Aires. A total of 956 infants were born with < 1500 g in 2004 and 2739, in 2016. Of these, 22.7 % had some degree of ROP and 7.8 % required treatment (severe ROP). Vision screening exceeded 90 %, and treatments at the place of origin increased (57 %-92 %). The incidence of unusual cases is still high (17.3 % of treated cases), and missed opportunities are still recorded. The use of anti angiogenic drugs trebled since 2011, when they started to be used. CONCLUSIONS: Significant achievements were observed in terms of program representativeness, scope, and adherence, and also in relation to screening access and treatment at the place of origin; however, the incidence of ROP is still high. The persistence of unusual cases and missed opportunities evidences deficiencies in the quality of health care and outpatient followup and underlines the need to strengthen the program actions in relation to services. PMID- 30457717 TI - Self-injurious behaviors among adolescents: A qualitative study of characteristics, meanings, and contexts. AB - INTRODUCTION: Self-injurious behaviors, such as cutting, are quickly spread and transmitted among adolescents, although it is not clear how. Our objective was to describe and analyze the social interactions occurring in relation to these behaviors. POPULATION AND METHODS: Descriptive, qualitative, and cross-sectional design. Population: adolescents with self-injuries detected at the Department of Adolescence between June 2015 and May 2016. Sampling was purposive and randomized until reaching information redundancy. Data were collected from audio-recorded, semi-structured interviews. Descriptive categories were developed based on personal relationships regarding self-injuries. RESULTS: Thirty-six adolescents were included (33 girls). Age: 15.2 +/- 1.9 years. Self-injuries occurred in contexts of conflict with the adult world due to tensions in the household and a neglect of the problems affecting adolescents. Skin cutting was done alone, hidden from the family but shared with peers. Among adolescents, cuts functioned as symbols for their suffering and generated strong ties of identification, belonging, and empathy. Wounds became a recognized and shared asset, around which they grouped their discourse, affection, and other representations of the moment they were living. CONCLUSIONS: Self-injuries provide a transient emotional relief; they are usually in opposition to the adult world, and strong ties of belonging and identification are developed among peers in relation to such injuries. This configuration favors concealment of such behavior from the family and its circulation among adolescents. PMID- 30457718 TI - Effectiveness of an educational intervention to improve nurses' knowledge on pediatric nasogastric intubation. AB - OBJETIVE: To establish the effectiveness of an educational intervention to improve nurses' knowledge on pediatric nasogastric intubation. METHODS: Multicenter, quasi-experimental, pre- and post-test study using a theoretical educational intervention based on bibliographic evidence and assessment of its effectiveness after 4 months. RESULTS: Delivered questionnaires: 1019. Valid questionnaires: 557 (54.66 %) pre-test and 246 (24.14 %) post-test. Pre- and post test answers indicated that the implied risk always entailed by the procedure had been perceived by 53.2 % and then increased to 70.7 % (p < 0.001). Nasogastric (NG) tube size was chosen using tables by 4.3 % of participants, and increased to 24.6 % (p < 0.001). The length of NG tube to be inserted as measured by the nose ear-midumbilicus distance (NEMU) method increased from 34.2 % to 81.3 % (p < 0.001). Confirmation of NG tube placement prior to use increased from 73.1 % to 86.5 % (p < 0.001). Confirmation of the five rights (patient, drug, dosage, route, and timing) prior to NG tube use increased from 85.6 % to 91 %. In relation to confirmation methods, the perception that auscultation was unsafe improved from 11.7 % to 31.1 % (p < 0.001), and its use reduced from 95.1 % to 81.6 %. The perception that the measurement of gastric pH was safe increased from 71.3 % to 91.1 % (p < 0.001), and its use rose from 7.6 % to 54.3 % (p < 0.001). CONCLUSIONS: The educational intervention was effective to increase nurses' knowledge on pediatric nasogastric intubation. PMID- 30457719 TI - Endoscopic findings of the digestive tract secondary to caustic ingestion in children seen at the Emergency Department. AB - BACKGROUND: Caustic ingestion in pediatrics is a common cause of visits to the Emergency Department. An indiscriminate use of cleaning chemicals and an easy access to them are determining factors for these injuries. POPULATION AND METHODS: Descriptive, analytical study. Children aged < 16 years hospitalized between January 1998 and December 2017 were included. The ingested caustic substance was identified as acid or alkaline. A gastrointestinal endoscopy was done to establish the burn grade. The grade of the burn was compared to the type of caustic substance using the chi2 test or the Fisher's exact test; a P value < 0.05 was considered significant. RESULTS: A total of 133 children were admitted to the Emergency Department due to caustic ingestion. The caustic agent was acid in 41 % of cases and alkaline, in 59 %. The most common acid caustic substance was muriatic acid (36.8 %) and the most common alkaline caustic agent was caustic soda (41.4 %). An esophageal burn was the most common consequence of caustic soda ingestion compared to other caustic agents (p = 0.001), whereas muriatic acid ingestion was the most statistically significant cause of stomach burn (p = 0.001) and duodenal burn (p = 0.002). The age group that most commonly ingested some caustic agent (93.2 %) corresponded to children younger than 5 years. CONCLUSIONS: The most common type of ingested caustic agent was alkaline, which caused esophageal burn; whereas, the ingestion of an acid caustic substance caused stomach and duodenal burns, as evidenced by endoscopy. PMID- 30457720 TI - Prediction of height and body mass index based on body segments: Use of Gauld's equations in an Argentine sample. AB - INTRODUCTION: When height cannot be measured or does not account for actual bone growth in children, due to their condition, it may be estimated using equations based on body segments. OBJETIVES: 1. To compare observed height (OH) and predicted height (PH) based on body segments using the equations of Gauld et al. 2. To analyze its applicability in the estimation and interpretation of body mass index (BMI). Materials and methods: A sample of children and adolescents without musculoskeletal alterations. Height, arm span, length of the ulna, the forearm, the tibia and the leg, weight, and pubertal development were registered. BMI was estimated. Differences and agreements between OH and PH were analyzed using the Bland-Altman method and an intraclass correlation coefficient. For BMI, the absolute prediction error and agreement were estimated using a Kappa coefficient. RESULTS: Two hundred and twenty children and adolescents aged 6.04-19.1 years were included. The intraclass correlation coefficient between PH and OH was > 0.9 in all equations. In average, PH overestimated OH by less than 2.0 cm, except when using the ulna length (2.6 cm among girls and 3.4 m among boys). The average absolute prediction error for BMI was < 5 %, except for the ulna length, and the Kappa coefficient was > 0.7. CONCLUSIONS: In our sample, the equations of Gauld et al. were adequate to predict height and estimate BMI. The greatest difference between observed height and predicted height was observed when using the ulna length. PMID- 30457721 TI - Changes in the depth of chest compressions during cardiopulmonary resuscitation in a pediatric simulator. AB - INTRODUCTION: High-quality chest compressions (CCs) are the main component of cardiopulmonary resuscitation (CPR). Objectives. T o assess the depth of CCs during CPR using a pediatric patient manikin. A secondary objective was to explore the association between CC depth and sex, level of training, body mass index, and periodic physical training. MATERIAL AND METHODS: Prospective study with experimental observation. Pediatric residents, pediatricians, nurses, and other health care providers trained in CPR and who attended children were included. A software program was used to record the depth of CCs while performing CPR during 2 minutes. Tiredness was defined as a deterioration in the number of adequately deep CCs (> 50 mm) by more than 3 CCs between the first and the last cycles. RESULTS: A total of 137 subjects participated (85.4 % were women). Only 48 participants (35.8 %) showed an adequate performance in terms of depth. Significant differences were observed for men (p < 0.0001) and trained pediatricians compared to the rest (p = 0.038). A worsening was observed in performance in terms of depth after 2 minutes in 36.5 % of participants. No significant differences were observed in relation to body mass index and physical activity. CONCLUSIONS: Depth rate reduced after 2 minutes. No association was observed with the body mass index or regular physical activity of resuscitators but with their sex and level of training. PMID- 30457722 TI - Is there an association between vitamin D level and iron deficiency in children? AB - INTRODUCTION: Vitamin D (VitD) affects the erythropoiesis. The aim of this study was to evaluate the association between maternal/child 25-OH VitD (25-OHD) levels and iron deficiency (ID) and anemia (IDA) in children aged 6 months-5 years. POPULATION AND METHODS: Between September 2014 and January 2016 children who were admitted to outpatient clinic were included to study. We excluded the children with acute or chronic infection, malnutrition, chronic disease and preterm birth history. Complete blood count, serum iron, total iron binding capacity, ferritin, 25-OHD levels were examined from children and their mothers. Iron and VitD supplementation during infancy and pregnancy and breastfeeding history were questioned. RESULTS: The study included totally 117 children. There were 67 children with ID/IDA [Group 1, mean age (years):2.05+/-1.24 (0.5-5)] and 50 normal children [Group 2, mean age (years): 1.87+/-1.12 (0.58-5)]. There were more VitD deficient children and mothers in Group 1 than in Group 2 (respectively, children 49.3 % vs. 20 % p=0.002; mothers 94 % vs.64 %, p=<0.001). There was a positive correlation between hemoglobin levels of children and maternal/child 25-OHD.The independent risk factors for IDA in children were longer exclusively breastfeeding time (odds ratio [OR], 0.35; 95 % confidence interval [CI], 0.1550.789; p=0.011), shorter duration of regular iron supplementation during infancy and pregnancy (infancy: OR,1.69; 95 % CI 1.148 2.508; p=0.008. pregnancy: OR,1.39; 95 % 0,1.070-1.820; p=0.014) and lower maternal 25-OHD level (OR,1.16; 95 % 0,1.034-1.292; p=0.011). CONCLUSIONS: Maternal/child VitD deficiency is associated with ID/IDA in children aged 6 months-5 years. PMID- 30457723 TI - Non-mandatory immunization and its potential impact on pertussis epidemiology. AB - In this study, we performed a quantitative analysis of the potential short-term consequences on pertussis of the draft bill on Informed Consent for Immunization proposed in Argentina in 2017, which considers a non-mandatory immunization schedule for minors. We used a mathematical model of pertussis transmission, which had been previously developed by our group. It is considered that the mere presentation of the project causes a reduction in coverage because it creates suspicion on the benefits of immunization. Assuming a 5 % annual reduction in coverage for 4 years as of 2018, in the next outbreak, severe cases in infants younger than 1 year will increase more than 100 % compared to the latest outbreak, with an estimated 101 deaths. With a 10 % annual reduction in the coverages for 4 years, the next outbreak would result in an increase of number of cases of more than 200 %, with 163 deaths. PMID- 30457724 TI - Endoscopic treatment of acquired subglottic stenosis in children: Predictors of success. AB - Subglottic stenosis is a congenital or acquired disease characterized by the narrowing of the airways, from the vocal cords to the lower border of the cricoid cartilage. It is one of the main causes of stridor and respiratory distress in children. More than 90 % of laryngeal stenoses are acquired due to prolonged endotracheal intubation. The pediatric management of subglottic stenosis is complex and may be affected by different factors that have an impact on the final outcome. Treatment may involve endoscopic procedures and/or open surgeries. Here we describe our experience in 35 patients with acquired subglottic stenosis who underwent endoscopic treatment with rigid dilation and identify the potential predictors of success of this technique. PMID- 30457725 TI - First do no harm: overdiagnosis in Pediatrics. AB - Many errors can be made in diagnosis: underdiagnosis, misdiagnosis, and overdiagnosis. While underdiagnosis and misdiagnosis are clear errors, in overdiagnosis, a true abnormality is discovered, but detection does not benefit the patient. Harm occurs when patients are further evaluated and treated unnecessarily as a result of making a diagnosis that would never have affected the patient if the diagnosis had not been made. Several phenomena point to potential overdiagnosis: when delayed or missed diagnoses do not result in harm; when there is increased detection of a disease, but no change in the outcome; and when randomized trials show no benefit from the diagnosis. Some might say that there is always benefit in knowing, but the adverse effects of overdiagnosis are well documented. We will need to educate ourselves and our colleagues about the potential for harm from overdiagnosis, and learn how to balance the potential benefit of a diagnosis against the risk of overdiagnosis. PMID- 30457726 TI - Peripheral tuberculous lymphadenitis in pediatrics: 16 years of experience in a tertiary care pediatric hospital of Buenos Aires, Argentina. AB - Extrapulmonary tuberculosis accounts for 15-20 % of all clinical presentations of tuberculosis. Peripheral tuberculous lymphadenitis is the second most common presentation of extrapulmonary tuberculosis in children, after pleural tuberculosis, in Argentina. We analyzed 92 patients with peripheral tuberculous lymphadenitis seen at the Department of Tisiology of Hospital de Ninos "Dr. Ricardo Gutierrez" between August 2000 and September 2015. The patients' mean age was 8.7 +/- 5 years. Nodal sites corresponded to single peripheral (31.5 %), multiple peripheral (20.6 %), and peripheral associated with deep nodes (47.8 %). Cervical lymph nodes were the most common site of involvement (80 %). In 80 % of patients previous antibiotic therapy had been administered, without response. The tuberculosis source was known in 56 %; 69 % had a positive tuberculin skin test; and 54 %, a pathological chest X-ray. Tuberculosis treatment was started on all patients based on clinical criteria, exposure and/or positive tuberculin skin test, prior to microbiological or histological confirmation. The clinical course was either healing (81.5 %), referral to a facility near home (8.7 %) or dropout (8.7 %). One patient died. PMID- 30457727 TI - Main genetic entities associated with supernumerary teeth. AB - Supernumerary teeth represent a common human dental anomaly, defined as presence of extra teeth-more than the normal number foreseen in primary or permanent dentition. The prevalence has been reported between 0.2 to 3%, and is more frequent in males than females. The etiology is heterogeneous, highly variable and most of the cases are idiopathic. However, the presence of multiple impacted or erupted supernumerary teeth is rare and associated with some genetic syndromes: cleidocranial displasia, familial adenomatous polyposis, trichorhinophalangeal syndrome type I, Rubinstein-Taybi syndrome, Nance-Horan syndrome, Opitz G/BBB syndrome, oculofaciocardiodental syndrome and Robinow syndrome (autosomal dominant). The supernumerary teeth should be considered in order to possibly diagnose these entities with the aim of offering an interdisciplinary management and treatment, as well as offer adequate family genetic counseling. PMID- 30457728 TI - [Chronic granulomatous disease: multiple infections as clinical presentation. Pediatric case report]. AB - Chronic granulomatous disease is an uncommon primary immunodeficiency due to a defect of the killing activity of phagocytes, caused by mutations in any of the genes encoding subunits of the superoxide-generating phagocyte NADPH oxidase system. The incidence is 1 in 250 000 live births. It can occur from infancy to adulthood, usually in children under 2 years. Bacterial and fungal infections in association with granuloma lesions are the most common manifestations of the disease. Aspergillus species, Staphylococcus aureus, Serratia marcescens, Nocardia species are the most common microorganisms isolated. We describe here a case of a 1-year-old boy with chronic granulomatous disease and invasive pulmonary aspergillosis, Serratia marcescens osteomyelitis and Enterobacter cloacae cervical granuloma. PMID- 30457729 TI - [Hypertrophic cardiomyopathy in preterm newborn with kidney transplanted mother]. AB - Hypertrophic cardiomyopathy in the newborn is a rare entity with heterogeneous etiology. Transient forms have been described in children of mothers with gestational diabetes and in preterm infants exposed both to prenatal and postnatal corticosteroids. We report a case of a preterm infant son of a mother who received renal transplant in whom hypertrophic cardiomyopathy was detected. He had been prenatally exposed to corticosteroids and tacrolimus that received the mother as immunosuppressive therapy. Both drugs cross the placental barrier and, on reaching the fetus, could have favored its development. Hypertrophic cardiomyopathy may be an uncommon side effect of treatment with tacrolimus in adults and children and it is reversible upon withdrawal. To our knowledge, it is the first published case of transient hypertrophic cardiomyopathy after fetal exposure to both corticosteroids and tacrolimus in the son of a renal transplanted mother. PMID- 30457730 TI - [Visceral larva migrans syndrome and hepatic abscess: A case report]. AB - Toxocariasis canis or catis is a zoonotic infection disseminated in humans. Human beings can act as non-natural hosts in which the parasite can survive for long periods of time and they become infected by the ingestion of geohelminth eggs. These can be located on the ground, playgrounds and children's games, and are mostly eliminated by dogs or cats. There are different spectra in the clinical presentation of this infection, which can vary from an asymptomatic host to the production of serious organic lesions; some of them are ocular toxocariasis, visceral larva migrans, covert toxocariasis and neurotoxocariasis. In this case report a patient who presents with a history of respiratory problems, prolonged fever, and hepatomegaly. Laboratory analyses show hypereosinophilia, hypergammaglobulinemia and serodiagnosis is positive for toxocariasis. Preliminary diagnosis: Visceral Larva Migrans Syndrome. PMID- 30457731 TI - Familial hypocalciuric hypercalcemia: A case report. AB - The finding of persistent hypercalcemia suggests doing other medical tests to find the cause. Familial hypocalciuric hypercalcemia is usually benign and it requires no treatment. It is important to do CASR gene sequencing to avoid unnecessary treatments. We report a 12-year-old child, asymptomatic, with calcemia between 11.4 and 12.2 mg/dl. His father and two brothers presented asymptomatic hypercalcemia. The blood test with magnesium, phosphorus, 25(OH)Vit D was normal, remarkable normal parathyroid hormone for the level of hypercalcemia. Urinary calcium/creatinine ratio was 0,11 mg/dl and 24-hour urinary calcium was 1,8 mg/kg per day. Abdominal and parathyroid ecography, long bone radiographs and densitometry were normal. Genetic study showed a mutation, c.1651A>G, in exon 6 of the calciumsensing receptor gene, confirmed in father and brothers, too. PMID- 30457732 TI - [Enoxaparin overdose in a newborn]. AB - Enoxaparin is a low molecular weight heparin used in the neonatal period. It requires less monitoring than standard or unfractionated heparin, although current knowledge about its dose and therapeutic levels in neonates is scarce. In addition, there is very limited information about the management of overdose in this age group. We present the first case published in Spanish of a neonate who accidentally received a dose of enoxaparin ten times higher than the therapeutic one and an isolated dose of protamine to reverse its effect. PMID- 30457733 TI - [Hypertrichosis cubiti in a girl with precocious puberty: Case report]. AB - Hypertrichosis cubiti is a localized increase in hair density, length and thickness. It is an uncommon and benign entity with very few patients described in the medical literature (more or less than half a hundred). Half of the described patients associate other defects or malformations and the other half are purely aesthetic cases. Early pubarche in girls is defined as the onset of pubic hair before 8 years of age. We present a six-year-old patient with the association not previously described of hypertrichosis cubiti and precocious pubarche. PMID- 30457734 TI - [Adenitis-cellulitis syndrome, an infrequent form of presentation of the late onset neonatal septicemia: Report of two cases]. AB - Septicemia is the main cause of neonatal mortality. The early-onset neonatal sepsis is usually related to maternal factor risks including recto-vaginal colonization. In the late-onset neonatal septicemia it is more difficult to establish the etiology because the majority of the cases are nosocomial or community related. The Streptococcus agalactiae (beta-hemolytic Streptococcus) is the most frequent germ associated with neonatal sepsis in developed countries. The late-onset form usually occurs with septic symptoms and meningitis and, in a few cases, with osteoarticular, skin and soft tissue infection. Adenitis cellulitis syndrome is rarely seen, and its main cause is Staphylococcus aureus, followed by Streptococcus agalactiae. We report two cases of group B Streptococcus late-onset neonatal septicemia, both of them with adenitis cellulitis syndrome. Patients recovered uneventfully after an adequate antibiotic therapy. PMID- 30457735 TI - [Sjogren-Larsson syndrome: Pediatric case report]. AB - Sjogren-Larsson syndrome is characterized by congenital ichthyosis, mental retardation and spastic diplegia or quadriplegia. The primary defect in this syndrome is mutation of ALDH3A2 gen that codes for the fatty aldehyde dehydrogenase. Deficiency of this enzyme causes an accumulation of fatty alcohols and fatty aldehydes, leading to altered cell-membrane integrity. Skin, eyes, and the central nervous system are affected latter. The diagnosis is carried out through the cuantification of the enzyme activity. This case report describes the diagnosis of a clinical syndrome with symptoms of Sjogren-Larsson syndrome by the quantification of the enzymatic activity in a culture of fibroblasts. Also, taking into account the genealogy of the patient, the study was conducted in the parents and a brother with signs suggestive of Sjogren-Larsson syndrome. PMID- 30457736 TI - [Minimally invasive treatment of biliary tract injury secondary to closed abdominal trauma: Clinical case]. AB - Hepatic and biliary tract injuries due to traumatic causes are rare in pediatric patients. Of the total number of patients with closed abdominal trauma, less than 9 % have liver injury, and the frequency varies between 2 and 3 % of biliary tract lesions. Currently, the recommended treatment for closed abdominal trauma with liver injury without hemodynamic repercussion is conservative. In case of presenting intra or extrahepatic biliary tract lesion, the preferred approaches are minimally invasive, such as percutaneous or endoscopic surgery, using laparotomy in selected cases. We present the case of a patient with closed abdominal trauma and liver trauma, initially laparotomized on 2 occasions due to hemodynamic instability and hemoperitoneum; presented a subdiaphragmatic and coleperitoneal bilioma; it was performed minimally invasive percutaneous drainage under tomographic control. PMID- 30457737 TI - [Duct ectasia, an infrequent condition in childhood: A case report]. AB - Bloody discharge from the nipple (thelorrhagia) is a rare symptom in childhood and is a cause of great concern due to the association with carcinoma in adults. The most common cause in children is mammary duct ectasia, which is a benign and self-limiting condition. It is characterized by dilatation of the mammary ducts, fibrosis and periductal inflammation. The etiology has not been identified and is multifactorial. Up to date, only isolated case reports have been published. Therefore, we present a review of the literature and we report a case of a fivemonth- old male infant that resolves spontaneously. We aimed to improve physicians' diagnosis accuracy, the knowledge of this condition and to avoid aggressive studies and treatments. PMID- 30457738 TI - [Atypical presentation of Spondylodiscitis by Kingella Kingae: a case report]. AB - Infectious Spondylodiscitis is a rare infection in children. It is more frequent in patients under 6 years of age. We report the case of an 8-year-old patient with lumbar pain for 2 months, without fever. Xrays, computed tomography and magnetic resonance imaging all three showed spondylodiscitis L4-L5. After a 10 day antibiotic treatment with clindamycin with regular response, a bone puncture was performed isolating Kingella kingae (Kk). Ostearticular infections caused by Kk have increased among infants and children. Due to improvement in culture techniques, the usage of automatic systems and assessment molecular techniques, these infections re-emerged in the past few years. Kk is a pathogen that has lately become significant in osteoarticular infections. PMID- 30457739 TI - Anomalous origin of the right coronary artery from the pulmonary artery in an infant with a heart murmur: Case report. AB - The anomalous origin of the right coronary artery from the pulmonary artery (ARCAPA) is a rare entity that has an incidence of 0.002 % and can potentially cause sudden death. Unlike to the anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA), usually presented with myocardial ischemia and heart failure; the diagnosis of ARCAPA is often incidental during evaluation of a heart murmur. We report a case of a 6 months old female patient referred to us with a cardiac murmur and a suspicion of coronary fistula. For a proper diagnostic assessment an echocardiogram, a computed tomography angiography and a cardiac catheterization were requested. A small ostium secundum-type atrial septal defect (ASD) and an ARCAPA were revealed. At 11 months old, the patient was scheduled for corrective cardiovascular surgery. The aim of this report is to describe a low incidence and potentially fatal disease. PMID- 30457741 TI - Feeder - free culture system for human iPS cells. PMID- 30457740 TI - Clinical applications of human embryonic stem cell. PMID- 30457743 TI - Transcription factor network governing pluripotency. PMID- 30457742 TI - Variation of human pluripotent stem cells in differentiation propensities. PMID- 30457744 TI - Reprogramming by somatic - cell nuclear transfer. PMID- 30457745 TI - New strategy of immunoregulation for allogeneic transplantation. PMID- 30457746 TI - Generation of induced - pluripotent stem cells and differentiation into pancreatic PMID- 30457747 TI - Induction of germ cell lineage from pluripotent stem cells. PMID- 30457748 TI - Endoderm differentiation of iPS cells. PMID- 30457750 TI - Direct reprogramming of somatic cells into neural cell lineages. PMID- 30457749 TI - Induction of neural crest cells from iPS cells. PMID- 30457751 TI - Soldier Values for Citizen Dentists. PMID- 30457752 TI - Why Are the Health Insurance Marketplaces Thriving in Some States but Struggling in Others? AB - Issue: In 2017, health insurance marketplaces in some states were thriving, while those in other states were struggling. What explains these differences? Goal: Identify factors that explain differences in issuers' participation levels in state insurance marketplaces. Methods: Analysis of the Robert Wood Johnson Foundation's HIX Compare dataset, and the National Association of Insurance Commissioners' 2010 Supplemental Health Care Exhibit Report. Findings and Conclusions: State policies and insurance regulations were key factors affecting the number of issuers participating in the marketplaces in 2017. Marketplaces run by states had more issuers than states that rely on the federally facilitated marketplace. States with fewer than four issuers tended to have policies in place that could have been destabilizing--for example, permitting the sale of plans not compliant with the Affordable Care Act's requirements regarding essential health benefits or guaranteed issue. Consumers in states that did not take steps to enforce these insurance market reforms still benefited from their protections, however; they were just enforced at the federal level. States with more issuers were also more likely to have expanded Medicaid. States with fewer issuers tended to be rural and have smaller populations, more concentrated hospital markets, and lower physician-to-population ratios. PMID- 30457753 TI - Neural differentiation of iPS cells. PMID- 30457754 TI - How Well Do You Know the Board of Dentistry Disciplinary Process? Part 3. PMID- 30457755 TI - Generation of cerebral cortex - like structure from human pluripotent stem cells. PMID- 30457757 TI - Letter to the Editor Why is Dental Therapy Good for Patients and Dentists? PMID- 30457758 TI - Induction of cardiovascular cells from iPS cells. PMID- 30457760 TI - Direct reprogramming of cardiomyocyte. PMID- 30457759 TI - Silver Linings Playbook: Strategies for Senior Oral Care. PMID- 30457761 TI - Moving Toward High-Value Health Care: Integrating Delivery System Reform into 2020 Policy Proposals. AB - Issue: Delivery system reform has been a focus of regulatory and legislative policy to date, but it is unclear how policymakers will integrate reforms into their plans for 2020 and beyond. Goal: To present and evaluate options for integrating delivery system reform into upcoming legislative proposals. Methods: Literature review. Findings and Conclusions: Policymakers should integrate delivery system reform into their 2020 plans to continue driving value in the health care system. Several options exist for promoting delivery system reform either through a state-based block grant approach or federal public plan approach. We identify three main principles that are critical for success of reform efforts: information sharing and infrastructure, flexibility to innovate, and alignment and stability of efforts. PMID- 30457762 TI - Tray Tooth Bleaching: The Right Thing at the Right Time. PMID- 30457764 TI - What Big Teeth You have Images That Get Your Patient's Attention. PMID- 30457763 TI - Current status of differentiation studies from pluripotent stem cells (ES/iPS cells) to hematopoietic cells. PMID- 30457765 TI - The Digitization of Dental Education. PMID- 30457766 TI - DIAGNOSTIC DISCUSSION PMID- 30457767 TI - Direct conversion of human adult skin fibroblasts into endothelial cells. PMID- 30457768 TI - Direct induction of hepatocyte - like cells from skin fibroblasts. PMID- 30457770 TI - Generation of pancreatic tissue from iPS cells. PMID- 30457769 TI - The demise of drug design litigation: death by federal preemption. AB - For over half a century, courts and commentators have disagreed as to the standards governing liability for drug design cases. In the last several years, the United States Supreme Court decided two cases that will have a profound effect on whether drug design defect cases, in general, are federally preempted. In PLIVA v. Mensing and Mutual Pharmaceutical Co. v. Bartlett, the Court preempted product liability actions for failure to warn and design defect against the manufacturers of generic drugs that met the FDA standard for the brand name drug. In these cases, the Court made wide-ranging statements that are applicable to brand name drugs as well. This Essay finds the Bartlett Court erred in having read New Hampshire law too narrowly. At the same time, the Court's reasoning has opened a debate as to the scope of federal preemption for brand name drugs. This Essay argues that the sweeping language in these two cases leads to the conclusion that common law drug design cases involving brand name drugs will fall prey to federal preemption. PMID- 30457771 TI - iPS cells and kidney diseases. PMID- 30457794 TI - Regeneration of the kidney from pluripotent stem cells. PMID- 30457795 TI - Trends in Hospital System Affiliation, 2007-2016. AB - Purpose: This policy brief updates a RUPRI Center brief published in 20141 and documents the continued growth in system affiliation by both metropolitan and non metropolitan hospitals. Key Findings: (1) From 2007 to 2016, hospital system affiliation continued to increase across all categories of hospital size, metropolitan/non-metropolitan location, and Critical Access Hospital (CAH)status. (2) From 2007 to 2016, hospital system affiliation increased in all census regions except in the West census region among non-metropolitan hospitals. PMID- 30457796 TI - Strategy for application of human iPS cells into clinical regenerative. PMID- 30457797 TI - Cell type conversion to chondrocytes through direct reprogramming or iPS cells. PMID- 30457798 TI - Programming of induced pluripotent stem cells for hair follicle regeneration. PMID- 30457799 TI - Neural crest stem cells: road to regenerative medicine for damaged central nervous system. PMID- 30457800 TI - Molecular mechanism underlying the cytogenesis from neural stem/progenitor cells. PMID- 30457801 TI - Adult neural stem cells. PMID- 30457802 TI - Hematopoietic stem cells. PMID- 30457803 TI - Biokinetics of mesenchymal stem cells. PMID- 30457804 TI - Intestinal stem cells. PMID- 30457805 TI - Skeletal muscle stem cell. PMID- 30457806 TI - Stem cells in the hair follicle. PMID- 30457807 TI - Regenerative medicine approach using stem cell based organ graft package. PMID- 30457808 TI - Application of iPS technology for NKT cell-mediated tumor immunotherapy. PMID- 30457809 TI - Regenerative medicine for ischemic stroke. PMID- 30457810 TI - Cellular transplant therapy for spinal cord injury. PMID- 30457811 TI - Regeneration of the injured spinal cord via activation of endogenous neural stem. PMID- 30457812 TI - Strategy for elucidating the mechanism controlling axonal regeneration and achieving enhanced axonal regeneration and rewiring after spinal cord injury. PMID- 30457813 TI - The development of myocardial regeneration therapy using cell sheet technology and iPS cells. PMID- 30457815 TI - Novel therapy for severe heart failure using iPS - derived cardiomyocytes transplantation. PMID- 30457826 TI - Regenerative medicine for cardiovascular disease using adipose - derived regenerative cells. PMID- 30457827 TI - Atomic-Scale Structure and Stress Release Mechanism in Core-Shell Nanoparticles. AB - Core-shell nanoparticles find applications in catalysts, sensors, and theranostics. The full internal 3D atomic structure, however, cannot be resolved by current imaging and diffraction techniques. We analyzed the atomic positions and stress-release mechanism in a cubic Au-Pd core-shell nanoparticle in approximately 1000 times higher resolution than current experimental techniques using large-scale molecular dynamics simulation to overcome these limitations. The core-shell nanocube of 73 nm size was modeled similarly to solution synthesis by random epitaxial deposition of a 4 nm thick shell of Pd atoms onto a Au core of 65 nm side length using reliable interatomic potentials. The internal structure reveals specific deformations and stress relaxation mechanisms that are caused by the +4.8% lattice mismatch of gold relative to palladium and differential confinement of extended particle facets, edges, and corners by one, two, or three Au-Pd interfaces, respectively. The three-dimensional lattice strain causes long-range, arc-like bending of atomic rows along the faces and edges of the particle, especially near the Au-Pd interface, a bulging deformation of the Pd shell, and stacking faults in the Pd shell at the corners of the particle. The strain pattern and mechanism of stress release were further characterized by profiles of the atomic layer spacing in the principal crystallographic directions. Accordingly, strain in the Pd shell is several times larger in the extended facets than near the edges and corners of the nanoparticle, which likely affects adsorption, optical, and electrochemical properties. The findings are consistent with available experimental data, including 3D reconstructions of the same cubic nanoparticle by coherent diffractive imaging (CDI) and may be verified by more powerful experimental techniques in the future. The stress release mechanisms are representative for cubic core-shell nanoparticles with fcc structure and can be explored for different shapes by the same methods. PMID- 30457828 TI - Rapid Self-Assembly of Au Nanoparticles on Rigid Mesoporous Yeast-Based Microspheres for Sensitive Immunoassay. AB - A simple, rapid, inexpensive, ecofriendly, and high-throughput biological strategy for the preparation of functional microspheres on a yeast-cell platform was introduced. Microspheres prepared through the treatment of yeast cells with formaldehyde and decoating buffer exhibited excellent characteristics, such as superior mechanical strength, high sulfhydryl group content, and mesoporous structure. Au nanoparticles (NPs) easily and rapidly self-assembled onto the surfaces of the yeast-based microspheres within 5 min to form rigid yeast@Au microspheres with high monodispersity and uniformity. The rapid formation of yeast@Au microspheres mainly involved the enhancement of sulfhydryl groups and mesoporosity. The yeast@Au microspheres were successfully used in a flow cytometry immunoassay to detect Pseudorabies viral infection events. Signal-to noise ratio was enhanced by approximately 49.4-fold. The presence of Au NPs on the yeast-based microspheres greatly improved sensitivity by decreasing noise through reducing nonspecific adsorption, highly enhancing the fluorescence signal caused by the surface plasmon resonance effect, and increasing the coupling efficiency of the capture protein. The presented method was used to analyze 81 clinical swine serum specimens. The results obtained by this developed method were compared with those of commercial diagnostic kits. The sensitivity, specificity, and efficiency of the developed method were 92.31%, 88.24%, and 88.89%, respectively. The excellent characteristics of the yeast@Au microspheres illustrate its great potential for high-throughput immunoassay applications in the fields of disease diagnosis, environmental analysis, and food safety. PMID- 30457829 TI - Smart Plasmonic Nanorobot for Real-Time Monitoring Cyt c Release and Cell Acidification in Apoptosis during Electrostimulation. AB - Cytochrome c (Cyt c) release and cellular pH change are two important mediators of apoptosis. Effective methods to regu-late and/or monitor such two events are therefore highly desired for apoptosis research and cancer cell therapy. Herein, we exploited electrostimulation to regulate cellular Cyt c release and apoptosis process, and by designing and preparing a smart and efficient plasmonic nanorobot (with surface-modified Cyt c-specific aptamer and 4-mercaptobenzoic acid) that capa-ble of Cyt c capture and self-sensing, real-time SERS monitoring of dynamic Cyt c release and simultaneous cell acidifica-tion in apoptosis during electrostimulation was achieved. Distinctly different molecular stress responses in the two events for cancerous MCF-7 and HeLa cells and normal L929 cells were identified and revealed. The method and results are valuable and promising for apoptosis and Cyt c-mediated biology studies. PMID- 30457830 TI - Dystrophin As a Molecular Shock Absorber. AB - Dystrophin is the largest protein isoform (427 kDa) expressed from the gene defective in Duchenne muscular dystrophy, a lethal muscle-wasting and genetically inherited disease. Dystrophin, localized within a cytoplasmic lattice termed costameres, connects the intracellular cytoskeleton of a myofiber through the cell membrane (sarcolemma) to the surrounding extracellular matrix. In spite of its mechanical regulation roles in stabilizing the sarcolemma during muscle contraction, the underlying molecular mechanism is still elusive. Here, we systematically investigated the mechanical stability and kinetics of the force bearing central domain of human dystrophin that contains 24 spectrin repeats using magnetic tweezers. We show that the stochastic unfolding and refolding of central domain of dystrophin is able to keep the forces below 25 pN over a significant length change up to ~800 nm in physiological level of pulling speeds. These results suggest that dystrophin may serve as a molecular shock absorber that defines the physiological level of force in the dystrophin-mediated force transmission pathway during muscle contraction/stretch, thereby stabilizing the sarcolemma. PMID- 30457831 TI - Evolution of Structural Biology Through the Lens of Mass Spectrometry. AB - Since its inception in the early 20th century, mass spectrometry (MS) has become a valuable tool for the analysis of molecules. In the century since JJ Thomson's first use of MS in 1913, the application of this analytical technique has expanded to a wide variety of industries including pharmaceutics, biotechnology, forensics, and environmental. Advancements in instrumentation has allowed for diversity in the type of molecules that can be analyzed by MS. The development of electrospray ionization (ESI) and matrix-assisted laser desorption ionization (MALDI) in the 1980s has increased the size of molecules that can be studied allowing for the analysis of proteins to be well in the scope of the technique and has increased the range of MS to biological applications. Although mass spectrometry has been used for many years to analyze proteins, mainly for protein sequencing, it is only through developments within roughly the last two decades that have enabled it to be used as a technique for studying protein structure. PMID- 30457832 TI - Symmetry-Controlled Electron-Phonon Interactions in van der Waals Heterostructures. AB - The light-matter interactions in the van der Waals (vdWs) heterostructures exhibit many fascinating properties, which can be harnessed to realize novel optoelectronic applications and to probe fundamental physics. Moreover, the electron-phonon interaction in the vdWs heterostructures can have a profound impact on the light-matter interaction properties, since light excited electrons can strongly couple with phonons in heterostructures. Here we report novel symmetry-controlled electron-phonon interactions in engineered two-dimensional (2D) material/silicon dioxide (SiO2) vdWs heterostructures. We observe two new Raman modes arising from originally Raman-silent phonon modes in SiO2. The new Raman modes have fixed peak positions regardless of the type of 2D materials in the heterostructures. Interestingly, such emerging Raman emissions exhibit various symmetry properties in heterostructures with 2D materials of different crystalline structures, controlled by their intrinsic electronic band properties. In particular, we reveal chiral Raman emissions with reversed helicity in contrast to that of typical valley polarization in honeycomb 2D materials, due to the phonon-assisted excitonic intervalley scattering process induced by electron hole exchange interaction. The observation of the symmetry-controlled Raman scattering process not only provides new insights regarding the microscopic mechanisms of electron-phonon interactions in vdWs heterostructures, but also may lead to the realization of new phononic devices. PMID- 30457833 TI - Photothermally Assisted Thinning of Silicon Nitride Membranes for Ultrathin Asymmetric Nanopores. AB - Sculpting solid-state materials at the nanoscale is an important step in the manufacturing of numerous types of sensor devices, in particular solid-state nanopore sensors. Here we present mechanistic insight into laser-induced thinning of low-stress silicon nitride (SiN x) membranes and films. In a recent study, we observed that focusing a visible wavelength laser beam on a SiN x membrane results in efficient localized heating, and we used this effect to control temperature at a solid-state nanopore sensor. A side-effect of the observed heating was that the pores expand/degrade under prolonged high-power illumination, prompting us to study the mechanism of this etching process. We find that SiN x can be etched under exposure to light of ~107 W/cm2 average intensity, with etch rates that are influenced by the supporting electrolyte. Combining this controlled etching with dielectric breakdown, an electrokinetic process for making pores, nanopores of arbitrary dimensions as small as 1-2 nm in diameter and thickness can easily be fabricated. Evidence gathered from biomolecule-pore interactions suggests that the pore geometries obtained using this method are more funnel-like, rather than hourglass-shaped. Refined control over pore dimensions can expand the range of applications of solid-state nanopores, for example, biopolymer sequencing and detection of specific biomarkers. PMID- 30457834 TI - Cancer Treatment through Nanoparticle-Facilitated Fenton Reaction. AB - Currently, cancer is the second largest cause of death worldwide and has reached critical levels. In spite of all the efforts, common treatments including chemotherapy, photodynamic therapy, and photothermal therapy suffer from various problems which limit their efficiency and performance. For this reason, different strategies are being explored which improve the efficiency of these traditional therapeutic methods or treat the tumor cells directly. One such strategy utilizing the Fenton reaction has been investigated by many groups for the possible treatment of cancer cells. This approach is based on the knowledge that high levels of hydrogen peroxide exist within cancer cells and can be used to catalyze the Fenton reaction, leading to cancer-killing reactive oxygen species. Analysis of the current literature has shown that, due to the diverse morphologies, different sizes, various chemical properties, and the tunable structure of nanoparticles, nanotechnology offers the most promising method to facilitate the Fenton reaction with cancer therapy. This review aims to highlight the use of the Fenton reaction using different nanoparticles to improve traditional cancer therapies and the emerging Fenton-based therapy, highlighting the obstacles, challenges, and promising developments in each of these areas. PMID- 30457835 TI - Directional Droplet Propulsion on Gradient Boron Nitride Nanosheet Grid Surface Lubricated with a Vapor Film below the Leidenfrost Temperature. AB - Controlled propulsion of liquid droplets on a solid surface offers important applications in various fields, including fog harvesting, heat transfer, microfluidics, and microdevice technologies. The propulsion of the liquid droplet is realized only if the driven force exceeds the resistance force. Sometimes the directional propulsion of droplets only takes place at the Leidenfrost state to achieve enough lubrication for a vapor cushion. The thick vapor cushions levitate liquid droplets to reduce resistance force. However, it is still challenging to reduce the vapor cushion thickness and simultaneously realize the directional droplet's motion, especially below the Leidenfrost temperature. Here, a structurally hydrophobic boron nitride nanosheet (BNNS) grid surface was constructed with a two-direction topographical gradient, i. e., the perpendicular altitude gradient and the horizontal density gradient. The polar nature of the B N bonds results in intrinsic hydrophilicity of the boron nitride layer, which increases the Leidenfrost point and facilitates wetting even at high temperature. Much thinner vapor-lubricating layers are competent in the droplet's directional motion below the Leidenfrost temperature of the BNNS grid surface because the air gap trapped within boron nitride nanosheet grids acts as a part of the lubrication layer. PMID- 30457836 TI - A pH-Controlled Kit for Total and Direct Bilirubin Built on Mimetic Peroxidase CoFe2O4-DOPA-Catalyzed Fluorescence Enhancement. AB - Facile and reliable detection of total bilirubin (Bt, summation of indirect and direct bilirubin) and direct bilirubin (Bd) in human serum is of crucial importance to clinical diagnosis. However, it is still a challenge to explore an ideal recognition system for discriminating Bd and indirect bilirubin (Bi). In this work, a dual-functional sensor for Bt and Bd was first built on pH controlled and mimetic peroxidase-catalyzed fluorescence enhancement. The fluorescence of nitrogen-doped graphene quantum dots (NGQDs) can be effectively quenched by bilirubin through the IFE process. With the catalysis of dopamine derived magnetic ferrite nanoparticles (CoFe2O4-DOPA), both Bd and Bi were oxidized by H2O2 to colorless and fluorescent oxidates at pH 8.0. Interestingly, only Bd was oxidized at pH 3.5. The discriminating principle of Bd and Bi relied on their pH-controlled oxidation potentials. A sensitive sensor for Bt and Bd was developed on the enhanced fluorescence of the NGQDs/CoFe2O4-DOPA/H2O2 sensing system after bilirubin oxidation, which was originated from a combination of the fluorescence recovery of NGQDs and newly spawned fluorescence of bilirubin oxidates. The designed probe well quantifies Bt and Bd with the detection limits of 10 and 50 nM, respectively. Moreover, a portable diagnostic kit was fabricated and successfully used for the detection of Bt and Bd in 60 unrelated human serum samples, and the obtained results were almost consistent with those measured by biochemistry analyzer. The present kit exhibits the superiorities of high sensitivity and stability, interference-resistant, and green reagents, making it a promising candidate for bilirubin detection in the clinical diagnosis of jaundice. PMID- 30457837 TI - Soft Three-Dimensional Microscale Vibratory Platforms for Characterization of Nano-Thin Polymer Films. AB - Vibrational resonances of microelectromechanical systems (MEMS) can serve as means for assessing physical properties of ultrathin coatings in sensors and analytical platforms. Most such technologies exist in largely two-dimensional configurations with a limited total number of accessible vibration modes and modal displacements, thereby placing constraints on design options and operational capabilities. This study presents a set of concepts in three dimensional (3D) microscale platforms with vibrational resonances excited by Lorentz-force actuation for purposes of measuring properties of thin-film coatings. Nanoscale films including photodefinable epoxy, cresol novolak resin, and polymer brush with thicknesses as small as 270 nm serve as the test vehicles for demonstrating the advantages of these 3D MEMS for detection of multiple physical properties, such as modulus and density, within a single polymer sample. The stability and reusability of the structure are demonstrated through multiple measurements of polymer samples using a single platform, and via integration with thermal actuators, the temperature-dependent physical properties of polymer films are assessed. Numerical modeling also suggests the potential for characterization of anisotropic mechanical properties in single or multilayer films. The findings establish unusual opportunities for interrogation of the physical properties of polymers through advanced MEMS design. PMID- 30457838 TI - In Vivo Bioimaging of Silver Nanoparticle Dissolution in the Gut Environment of Zooplankton. AB - Release of silver ions (Ag+) is often regarded as the major cause for silver nanoparticle (AgNP) toxicity toward aquatic organisms. Nevertheless, differentiating AgNPs and Ag+ in a complicated biological matrix and their dissolution remains a bottleneck in our understanding of AgNP behavior in living organisms. Here, we directly visualized and quantified the time-dependent release of Ag+ from different sized AgNPs in an in vivo model zooplankton ( Daphnia magna). A fluorogenic Ag+ sensor was used to selectively detect and localize the released Ag+ in daphnids. We demonstrated that the ingested AgNPs were dissoluted to Ag+, which was heterogeneously distributed in daphnids with much higher concentration in the anterior gut. At dissolution equilibrium, a total of 8.3 9.7% of ingested AgNPs was released as Ag+ for 20 and 60 nm AgNPs. By applying a pH sensor, we further showed that the dissolution of AgNPs was partially related to the heterogeneous distribution of pH in different gut sections of daphnids. Further, Ag+ was found to cross the gills and enter the daphnids, which may be a potential pathway leading to AgNP toxicity. Our findings provided fundamental knowledge about the transformation of AgNPs and distribution of Ag+ in daphnids. PMID- 30457839 TI - Comprehensive Glycoproteomic Analysis of Chinese Hamster Ovary Cells. AB - The Chinese hamster ovary (CHO) cell line is a major expression system for the production of therapeutic proteins, the majority of which are glycoproteins, such as antibodies and erythropoietin (EPO). The characterization of the glycosylation profiles on different sources and effect therapeutic glycoproteins is critical to understand the important role of glycosylation from CHO cells. In this study, a large scale glycoproteomic workflow was established and applied to CHO-K1 cells expressing EPO. The workflow includes enrichment of intact glycopeptides from CHO K1 cell lysate and medium using hydrophilic enrichment, fractionation of the obtained intact glycopeptides (IGPs) by basic reversed phase liquid chromatography (bRPLC), analyzing the glycopeptides using LC-MS/MS, and annotating the results by GPQuest 2.0. A total of 10,338 N-linked glycosite containing IGPs were identified, representing 1,162 unique glycosites in 530 glycoproteins, including 71 unique atypical N-linked IGPs on 18 atypical N glycosylation sequons with an overrepresentation of the N-X-C motifs. Moreover, we compared the glycoproteins from CHO cell lysate with those from medium using the in-depth N-linked glycoproteome data. The obtained large scale glycoproteomic data from intact N-linked glycopeptides in this study is complementary to the genomic, proteomic, and N-linked glycomic data previously reported for CHO cells. Our method has the potential to monitor the production of recombinant therapeutic glycoproteins. PMID- 30457840 TI - On the Cooperativity Effect in Watson and Crick and Wobble Pairs for a Halouracil Series and Its Potential Quantitative Application Studied through Surface Enhanced Raman Spectroscopy. AB - The nature of the cooperativity effect of hydrogen bonds in Watson and Crick and wobble base pairs formed with thymine, uracil, and its 5-halogenated derivatives (5-fluoro, -chloro, and -bromouracil) has been studied through SERS and by using chemometric tools to process data and extract relevant information. Remarkable differences between the two kinds of pairs were clearly observed, and the behavior correlated to the withdrawing character of different substituents at the 5-position of uracil was verified. Multivariate analyses have also unveiled information about the pair's stability, and a stronger cooperativity effect seems to rule the Watson and Crick pairs when compared to wobble pairs. Defined patterns in the behavior of Watson and Crick pairs allowed the design of an indirect methodology for quantifying 5-bromouracil using a partial least squares (PLS) method with variable selection. Limit of detection (LOD) values of 0.037 and 0.112 mmol L-1 in the absence and presence of structurally similar interferences were reached, while its direct surface-enhanced Raman spectroscopy (SERS) quantification is only possible at ~45 mmol L-1. PMID- 30457841 TI - A family divided: Distinct structural and mechanistic features of the SpoU-TrmD (SPOUT) methyltransferase superfamily. AB - The SPOUT family of enzymes makes up the second largest of seven structurally distinct groups of methyltransferases and is named after two evolutionarily related RNA methyltransferases, SpoU and TrmD. A deep trefoil knotted domain in the tertiary structures of member enzymes defines the SPOUT family. For many years, formation of a homodimeric quaternary structure was thought to be a strict requirement for all SPOUT enzymes, critical for substrate binding and formation of the active site. However, recent structural characterization of two SPOUT members, Trm10 and Sfm1, revealed that they function as monomers without the requirement of this critical dimerization. This unusual monomeric form implies that these enzymes must exhibit a non-traditional substrate binding mode and active site architecture and may represent a new division in the SPOUT family with distinct properties removed from the dimeric enzymes. Here we discuss the mechanistic features of SPOUT enzymes with emphasis on the monomeric members and implications of this "novel" monomeric structure on cofactor and substrate binding. PMID- 30457842 TI - Enzymatic Activity in Fractal Networks of Self-assembling Peptides. AB - The tissue environment is exceptionally complex, with well-controlled biochemical communication occurring between similar and dissimilar cells, as well as, between these cells and local extracellular matrices (ECM). In order to build an artificial ECM that can directly affect regional cell populations, a designer system should allow for controlled degradation, molecular release, and reorganization as related to local cellular function. (RADA)4 self-assembling peptide (SAP) hydrogels are excellent candidates for precisely tuned ECMs, or nanoscaffolds, with several beneficial qualities. They are a class of materials with uncomplicated fabrication and potentially allow for a diverse set of release strategies for many types of bioactive ligands. Enzyme-induced degradation and release of peptide sequences, synthesized within the SAP for on-demand cell signalling, could prove impactful to a plethora of human health applications. However, the degradation products and their release kinetics from these nanoscaffolds may greatly affect the overall system. To address this, enzyme kinetics in self-assembled hydrogels were studied by tethering matrix metalloproteinase 2 (MMP-2) cleavable peptide substrates of differing activities to the C-terminus of (RADA)4. High and low activity sequences, GPQG+IASQ (CP1) and GPQG+PAGQ (CP2), were respectively chosen for tunable release. When incubated with 5 nM MMP-2, over 3 days, both CP1 and CP2 sequences showed product formation values of ~32 and ~9% of the original substrate, respectively. On-demand product formation was found to be dependent upon both SAP composition and enzyme concentrations, and could be tuned over the course of several days and weeks. Despite the fact that the self-assembling peptides are not directly cleavable by MMP-2, the CP1 and CP2 nanoscaffold morphology was visibly degraded by the protease. This degradation yielded a lower fractal dimensions for the matrix and suggested clearance of these materials may be possible over time. PMID- 30457843 TI - Understanding and Engineering Distributed Biochemical Pathways in Microbial Communities. AB - Microbiomes impact nearly every environment on Earth by modulating the molecular composition of the environment. Temporally changing environmental stimuli and spatial organization are major variables shaping the structure and function of microbiomes. The web of interactions among members of these communities and between the organisms and the environment dictates microbiome functions. Microbial interactions are major drivers of microbiomes and are modulated by spatiotemporal parameters. A mechanistic and quantitative understanding of ecological, molecular, and environmental forces shaping microbiomes could inform strategies to control microbiome dynamics and functions. Major challenges for harnessing the potential of microbiomes for diverse applications include the development of predictive modeling frameworks and tools for precise manipulation of microbiome behaviors. PMID- 30457844 TI - Uptake, whole-body distribution & depuration of nanoplastics by the scallop Pecten maximus, at environmentally realistic concentrations. AB - Previous studies of uptake and effects of nanoplastics by marine organisms have been conducted at what may be unrealistically high concentrations. This is a consequence of the analytical challenges in tracking plastic particles in organisms at environmentally relevant concentrations and highlights the need for new approaches. Here, we present pulse exposures of 14C-radiolabeled nanopolystyrene to a commercially important mollusk, Pecten maximus, at what have been predicted to be environmentally relevant concentrations (<15 ug L-1). Uptake was rapid and was greater for 24 nm than for 250 nm particles. After 6 h, autoradiography showed accumulation of 250 nm nanoplastics in the intestine, while 24 nm particles were dispersed throughout the whole-body, possibly indicating some translocation across epithelial membranes. However, depuration was also relatively rapid for both sizes; 24 nm particles were no longer detectable after 14 d, although some 250 nm particles were still detectable after 48 d. Particle size thus apparently influenced the biokinetics and suggests a need for chronic exposure studies. Modelling extrapolations indicated that it could take 300 d of continued environmental exposure for uptake to reach equilibrium in scallop body tissues although the concentrations would still below 2.7 mg g-1. Comparison with previous work in which scallops were exposed to non plastic (silver) nanomaterials of similar size (20 nm), suggests that nanoparticle composition may also influence the uptake tissue distributions somewhat. PMID- 30457845 TI - Solvent-Controlled Spatial Distribution of SI AGET ATRP Grafted Polymers in Lignocellulosic Materials. AB - In the current quest for the design of advanced complex materials, the functionalization of biological materials having hierarchical structures has been of high interest. In the case of lignocellulosic materials, various modification techniques have allowed to obtain materials with outstanding properties. However, the control over the spatial distribution of the modification inside the wood scaffold, which is an important parameter to obtain the desired properties, has yet to be understood. In this study, the use of solvents with different wood swelling capabilities is proposed to control the spatial polymer-modification distribution inside the hierarchical wood structure. Wood cubes were functionalized via SI-AGET-ATRP using solvents with different wood-swelling capabilities. Spectroscopic (Raman and FTIR) and electron microscopy techniques showed that a good wood-swelling solvent as reaction media can transport the polymerization initiator molecule into the cell wall, allowing it to react with all the available OH groups in the wood structure. Conversely, the use of a bad wood-swelling solvent limits the reaction to the available -OH groups at the lumen/cell wall interface. The subsequently added polymers grow from the available initiator sites and therefore show similar spatial distribution. This diffusion limitation is visible not only at the microscopic level (cellular structure) but also at the macroscopic level (over the length of the sample). PMID- 30457846 TI - Strategy for the Rapid Dechlorination of Polychlorinated Biphenyls (PCBs) by Dehalococcoides mccartyi Strains. AB - Anaerobic bacteria play critical roles in the environmental bioremediation of polychlorinated biphenyls (PCBs). However, in situ applications of PCB dechlorinating anaerobes have been largely impeded by difficulties in growing PCB dechlorinators to a high cell abundance in short time periods. Here, we report the accelerated onset of PCB dechlorination by pre-cultivating Dehalococcoides mccartyi strains on chloroethenes as alternative electron acceptors. The extensive dechlorination of Aroclor 1260 was achieved within 1 week by D. mccartyi CG4 pregrown on trichloroethene (TCE) or tetrachloroethene (PCE). Compared to control cultures fed solely with Aroclor 1260, the PCB dechlorination rate was up to 30 times greater in cultures pre-cultivated with chloroethenes. However, when CG4 was simultaneously exposed to multiple potential substrates (PCE, TCE, and PCBs), PCB dechlorination was not observed until PCE was completely depleted. The expression of the bifunctional PCE and PCBs reductive dehalogenase (RDase) gene pcbA4 was inhibited by the presence of both substrates. Furthermore, in the presence of >0.3 mM TCE (produced as an intermediate from PCE dechlorination), the PCB dechlorination rate was an order of magnitude lower than in cultures amended with Aroclor 1260 after the complete depletion of TCE. This reduced PCB dechlorination rate corresponded with a sharp decrease in pcbA4 transcripts in the presence of both TCE and PCBs. The utilization of chloroethenes and PCBs as substrates by CG4 was found to be largely sequential rather than concurrent, suggesting that PCE and TCE are preferred substrates for the RDase responsible for PCE, TCE, and PCB dechlorination. PMID- 30457847 TI - Circulating miRNAs associated with arsenic exposure. AB - Arsenic (As) is a toxic metalloid. Inorganic arsenic (iAs) is a form of As commonly found in drinking water and in some foods. Overwhelming evidence suggest that people chronically exposed to iAs are at risk of developing cancer, or cardiovascular, neurological and metabolic diseases. Although the mechanisms underlying iAs-associated illness remain poorly characterized, a growing body of literature raises the possibility that microRNAs (miRNAs), post-transcriptional gene suppressors, may serve as mediators and/or early indicators of the pathologies associated with iAs exposure. To characterize the circulating miRNA profiles of individuals chronically exposed to iAs, samples of plasma were collected from 109 healthy residents of the city of Zimapan and the Lagunera area in Mexico, the regions with historically high exposures to iAs in drinking water. These plasma samples were analyzed for small RNAs using high-throughput sequencing, and for iAs and its methylated metabolites. Associations between plasma levels of arsenic species and miRNAs were evaluated. Six circulating miRNAs (miRs-423-5p, -142-5p -2, -423-5p +1, -320c-1, -320c-2, and -454-5p), two of which have been previously linked to cardiovascular disease and diabetes (miRs 423-5p, -454-5p), were found to be significantly correlated with plasma MAs. No miRNAs were associated with plasma iAs or DMAs after correction for multiple testing. These miRNAs may represent mechanistic links between iAs exposure and disease or serve as markers of disease risks associated with this exposure. PMID- 30457848 TI - Analyte Regeneration Fluorescent Probes for Formaldehyde Enabled by Regiospecific Formaldehyde-Induced Intramolecularity. AB - An important challenge for reaction-based fluorescent probes is that they generally require analyte consumption for fluorescence signal generation, thus creating potential perturbation of native analyte homeostasis or change of local concentrations. Herein, we reported two formaldehyde (FA) regeneration fluorescent probes, NAP-FAP-1 and NAP-FAP-2. An unprecedented regiospecific FA induced intramolecularity strategy is implemented in the probe design, which adopts 3-(benzylamino)-succinimide as the FA-selective reaction group. The probes are able to capture the analyte molecule, induce regiospecific imide bond cleavage, and then release the captured FA molecule with simultaneous fluorescence turn-on response via a unique dual PeT/ICT quenching mechanism. The probes have shown potentials in detection, comparison, and imaging of FA levels intracellularly and inside lysosomes. These features make them useful for the study of FA homeostasis and functions in biological systems with minimal perturbation. PMID- 30457849 TI - Early Formation Pathways of Surfactant Micelle Directed Ultrasmall Silica Ring and Cage Structures. AB - By combining a surfactant, an organic pore expander, a silane, and poly(ethylene glycol) (PEG), we have observed the formation of a previously unknown set of ultrasmall silica structures in aqueous solutions. At appropriate concentrations of reagents, ~2 nm primary silica clusters arrange around surfactant micelles to form ultrasmall silica rings, which can further evolve into cage-like structures. With increasing concentration, these rings line up into segmented worm-like one dimensional (1D) structures, an effect that can be dramatically enhanced by PEG addition. PEG adsorbed 1D striped cylinders further arrange into higher order assemblies in the form of two-dimensional (2D) sheets or three-dimensional (3D) helical structures. Results provide insights into synergies between deformable noncovalent organic molecule assemblies and covalent inorganic network formation as well as early transformation pathways from spherical soft materials into 1D, 2D, and 3D silica solution structures, hallmarks of mesoporous silica materials formation. The ultrasmall silica ring and cage structures may prove useful in nanomedicine and other nanotechnology based applications. PMID- 30457850 TI - Nanoscale patterning of surfaces via DNA directed spider silk assembly. AB - Oligonucleotide-spider silk conjugates can be placed on silicon wafers by complementary DNA strands, which are coupled chemically to the surface. Such specific immobilization of spider silk proteins allows, the nucleation and guided growth of beta-sheet-rich nanofibrils in the presence of phosphate ions on the surface. Adjustment of the concentration of the immobilized conjugate, phosphate concentration and time of the assembly reaction enables control over fibril surface density and length. Furthermore, soft lithography was used to direct the conjugates on pre-determined spots with a sub-micron resolution yielding high contrast surface patterns. This approach, which combines bottom-up and top-down surface structuring, opens up new possibilities in protein fibril based bionanotechnology. PMID- 30457851 TI - Guest-Adaptable Spin Crossover Properties in a Dinuclear Species Underpinned by Supramolecular Interactions. AB - Molecular crystals with guest-adaptable crystalline structures and properties are comparatively rare owing to their inherent reduced structural stability and malleability to support molecular variation. To overcome this intrinsic challenge, here we introduce structural stabilizing supramolecular interactions into a dinuclear material and henceforth demonstrate a dynamic structural and spin crossover property interchange between solvated (A.3MeOH) and desolvated (A.O) products (A = [FeII2( o-NTrz)5(NCS)4]; 4-( o-nitrobenzyl)imino-1,2,4 triazole). Relatively uncommon for molecular species, the guest molecules in A.3MeOH are evolved (A.O) via a single-crystal to single-crystal transformation with affiliated phase transition resulting in a reversible transformation from one- to two-step spin crossover (SCO) transition character. We additionally present the water-saturated product (A.3H2O), which distinctly shows an abrupt one-step SCO character with a 22 K wide thermal hysteresis loop. Detailed structure-property analysis highlights that the substantial structural malleability and guest-adaptable SCO properties of this dinuclear species are afforded by the supportive, yet flexible, supramolecular interaction pathways derived from the ligand functionalization. PMID- 30457852 TI - Denitrifying anaerobic methane oxidation: a previously overlooked methane sink in intertidal zone. AB - The intertidal zone is an open ecosystem rich in organic matter and plays an important role in global geochemical cycle. It was previously considered that methane was mainly removed by sulfate-dependent anaerobic methane oxidation (sulfate-AOM) process in marine ecosystems while other anaerobic methane oxidation processes were ignored. Recent researches have demonstrated that denitrifying anaerobic methane oxidation (DAMO), consisting of nitrite-dependent anaerobic methane oxidation (Nitrite-AOM) and nitrate-dependent anaerobic methane oxidation (Nitrate-AOM), can also oxidize methane. In this work, the community structure, quantity and potential methane oxidizing rate of DAMO archaea and bacteria in the intertidal zone were studied by high-throughput sequencing, qPCR and stable isotope tracing method. The results showed that Nitrate-AOM and Nitrite-AOM were both active in the intertidal zone and showed approximate methane oxidation rates. The copy number of 16S rRNA gene of DAMO archaea and DAMO bacteria were 104 ~ 105 copies g-1 (dry sediment) while NC10 bacteria were slightly higher. The contribution rate of DAMO process to total anaerobic methane removal in the intertidal zone reached 65.6% ~ 100%, which indicates that DAMO process is an important methane sink in intertidal ecosystem. The laboratory mimic incubation also indicated that DAMO archaea were more sensitive to oxygen and preferred a more anoxic environment. The work will help us draw a complete picture of methane and nitrogen cycles in natural habitats. PMID- 30457853 TI - Bacteriophages To Sensitize A Pathogenic New Delhi Metallo beta-lactamase positive Escherichia coli To Solar Disinfection. AB - Bacteriophages active against a New Delhi metallo beta lactamase (NDM)-positive E. coli PI-7 were isolated from municipal wastewater and tested for their lytic effect against the bacterial host. Bacteriophages were highly specific to E. coli PI-7 when tested for host-range. After determining host-specificity, bacteriophages were tested for their ability to sensitize E. coli PI-7 to solar irradiation. Solar irradiation coupled with bacteriophages successfully reduced the length of the lag-phase for E. coli PI-7 from 4.11 +/- 0.78 h to 1.82 +/- 0.60 h in buffer solution. The reduction of lag-phase length was also observed in filtered wastewater effluent and chlorinated effluent. Previously, we found through gene expression analysis that cell wall, oxidative stress and DNA repair functions played a large role in protecting E. coli PI-7 against solar damage. Here, gene expression analysis of bacteriophage-supplemented solar-irradiated E. coli PI-7 revealed downregulation of cell wall functions. Downregulation of functions implicated in scavenging and detoxifying reactive oxygen species, as well as DNA repair genes was also observed in bacteriophage-supplemented solar irradiated E. coli PI-7. Moreover, solar irradiation activates recA which can induce lytic activity of bacteriophages. Overall, the combined treatment led to gene responses that appeared to make E. coli PI-7 more susceptible to solar disinfection and bacteriophage infection. Our findings suggest that bacteriophages show good potential to be used as a biocontrol tool to complement solar irradiation in mitigating the persistence of antibiotic-resistant bacteria in reuse waters. PMID- 30457854 TI - Room-Temperature Chemoselective Reduction of 3-Nitrostyrene to 3-Vinylaniline by Ammonia Borane over Cu Nanoparticles. AB - We report a new strategy of controlling catalytic activity and selectivity of Cu nanoparticles (NPs) for the ammonia borane initiated hydrogenation reaction. Cu NPs are active and selective for chemoselective reduction of nitrostyrene to vinylaniline under ambient conditions. Their activity, selectivity, and more importantly, stability are greatly enhanced by their anchoring on WO2.72 nanorods, providing a room-temperature full conversion of nitrostyrene selectively to vinylaniline (>99% yield). Compared with all other catalysts developed thus far, our new Cu/WO2.72 catalyst shows much enhanced hydrogenation selectivity and stability without the use of pressured hydrogen. The synthetic approach demonstrated here can be extended to prepare various M/WO2.72 catalysts (M = Fe, Co, Ni), with M being stabilized for many chemical reactions. PMID- 30457855 TI - Rationalization of the Membrane Permeability Differences in a Series of Analogue Cyclic Decapeptides. AB - Cyclization and selected backbone N-methylations are found to be often necessary but not sufficient conditions for peptidic drugs to have a good bioavailability. Thus, the design of cyclic peptides with good passive membrane permeability and good solubility remains a challenge. The backbone scaffold of a recently published series of cyclic decapeptides with six selected backbone N-methylations was designed to favor the adoption of a closed conformation with beta-turns and four transannular hydrogen bonds. Although this conformation was indeed adopted by the peptides as determined by NMR measurements, substantial differences in the membrane permeability were observed. In this work, we aim to rationalize the impact of discrete side chain modifications on membrane permeability for six of these cyclic decapeptides. The thermodynamic and kinetic properties were investigated using molecular dynamics simulations and Markov state modeling in water and chloroform. The study highlights the influence that side-chain modifications can have on the backbone conformation. Peptides with a D-proline in the beta-turns were more likely to adopt even in water the closed conformation with transannular hydrogen bonds, which facilitates transition through the membrane. The population of the closed conformation in water was found to correlate positively with PAMPA log Pe. PMID- 30457856 TI - A Cobalt Metallopeptide Electrocatalyst for the Selective Reduction of Nitrite to Ammonium. AB - A cobalt-tripeptide complex (CoGGH) is developed as an electrocatalyst for the selective six-electron, eight-proton reduction of nitrite to ammonium in aqueous buffer near neutral pH. The onset potential for nitrite reduction occurs at -0.65 V vs. Ag/AgCl (1 M KCl). Controlled potential electrolysis at -0.90 V generates ammonium with a faradaic efficiency of 90 +/- 2% and a turnover number of 3,550 +/- 420 over 5.5 hours. CoGGH also catalyzes the reduction of the proposed intermediates nitric oxide and hydroxylamine to ammonium. These results reveal that a simple metallopeptide is an active functional mimic of the complex enzymes cytochrome c nitrite reductase and siroheme-containing nitrite reductase. PMID- 30457857 TI - Enantioselective Synthesis of des-epoxy-Amphidinolide N. AB - des-epoxy-Amphidinolide N has been achieved in 21 longest linear and 30 total steps. Relying on concise fragment preparation and judicious protecting-group design, our convergent synthesis features an atom-economical Ru-catalyzed alkene alkyne coupling as a key stitching strategy. Calculations reveal a hydrogen bonding bridge within amphidinolide N. Comparisons of 13C NMR chemical shift differences using our synthetic des-epoxy-amphidinolide N reveal that am phidinolide N and carbenolide I are likely identical. PMID- 30457858 TI - qFit-ligand reveals widespread conformational heterogeneity of drug-like molecules in X-ray electron density maps. AB - Proteins and ligands sample a conformational ensemble that governs molecular recognition, activity, and dissociation. In structure-based drug design, access to this conformational ensemble is critical to understand the balance between entropy and enthalpy in lead optimization. However, ligand conformational heterogeneity is currently severely underreported in crystal structures in the Protein Data Bank, owing in part to a lack of automated and unbiased procedures to model an ensemble of protein-ligand states into X-ray data. Here, we designed a computational method, qFit-ligand, to automatically resolve conformationally averaged ligand heterogeneity in crystal structures, and applied it to a large set of protein receptor-ligand complexes. In an analysis of the cancer related BRD4 domain, we found that up to 29% of protein crystal structures bound with drug-like molecules present evidence of unmodeled, averaged, relatively iso energetic conformations in ligand-receptor interactions. In many retrospective cases, these alternate conformations were adventitiously exploited to guide compound design, resulting in improved potency or selectivity. Combining qFit ligand with high-throughput screening or multi-temperature crystallography could therefore augment the structure-based drug design toolbox. PMID- 30457859 TI - The Hancock Alkaloids (-)-Cuspareine, (-)-Galipinine, (-)-Galipeine, and (-) Angustureine: Asymmetric Syntheses and Corrected 1H and 13C NMR Data. AB - The asymmetric syntheses of all members of the Hancock alkaloid family based upon a 2-substituted N-methyl-1,2,3,4-tetrahydroquinoline core are delineated. The conjugate addition of enantiopure lithium N-benzyl- N-(alpha-methyl- p methoxybenzyl)amide to 5-( o-bromophenyl)- N-methoxy- N-methylpent-2-enamide is used to generate the requisite C-2 stereogenic center of the targets, while an intramolecular Buchwald-Hartwig coupling is used to form the 1,2,3,4 tetrahydroquinoline ring. Late-stage diversification completes construction of the C-2 side chains. Thus, (-)-cuspareine, (-)-galipinine, (-)-galipeine, and (-) angustureine were prepared in overall yields of 30%, 28%, 15%, and 39%, respectively, in nine steps from commercially available 3-( o bromophenyl)propanoic acid in all cases. Unambiguously corrected 1H and 13C NMR data for the originally isolated samples of (-)-cuspareine, (-)-galipinine, and ( )-angustureine are also reported, representing a valuable reference resource for these popular synthetic targets. PMID- 30457860 TI - A small molecule inhibitor that stabilizes the autoinhibited conformation of the oncogenic tyrosine phosphatase SHP2. AB - Genetic mutations in the phosphatase PTPN11 (SHP2) are associated with childhood leukemias. These mutations cause hyperactivation of SHP2 due to the disruption of the auto-inhibitory conformation. By targeting the activation-associated protein conformational change, we have identified an SHP2 inhibitor (E)-1-(1-(5-(3-(2,4 dichlorophenyl)acryloyl)-2-ethoxy-4-hydroxybenzyl)-1,2,5,6-tetrahydropyridin-3 yl)-1H-benzo[d]imidazol-2(3H)-one (LY6, 1) using computer-aided drug design database screening combined with cell-based assays. This compound inhibited SHP2 with an IC50 value of 9.8 uM, 7-fold more selective for SHP2 than the highly related SHP1. Fluorescence titration, thermal shift, and microscale thermophoresis quantitative binding assays confirmed its direct binding to SHP2. This compound was further verified to effectively inhibit SHP2-mediated cell signaling and proliferation. Furthermore, mouse and patient leukemia cells with PTPN11 activating mutations were more sensitive to this inhibitor than wild-type cells. This small molecule SHP2 inhibitor has a potential to serve as a lead compound for further optimization studies to develop novel anti-SHP2 therapeutic agents. PMID- 30457861 TI - Alkaloids Reactivity: DFT Analysis of Selective Demethylation Reactions. AB - All possible demethylation reactions of a diverse family of quaternary alkaloids by means of DFT calculations are here described. We aim to develop a rational model that allows explanation of the high selectivity observed experimentally and predicts the occurrence of new alkaloid derivatives. To this end, we have performed detailed analysis of the initial reagents and products. In addition, as a proof of concept, experimentally unknown demethylation reaction of coralyne has been carried out, thus verifying the reliability of the theoretical model here presented. PMID- 30457862 TI - QTAIM Assessment of the Intra- and Intermolecular Bonding in a bis(Nitramido Oxadiazolate) Energetic Ionic Salt at 20 K. AB - Accurate experimental determination of the electron density distribution for the energetic ionic salt bis-ammonium 2,2'-dinitramido-5,5'-bis(1-oxa-3,4-diazolate) dihydrate (1) is obtained from multipole modeling of single-crystal X-ray diffraction data collected at 20 K. The intra- and intermolecular bonding is assessed in terms of the Quantum Theory of Atoms in Molecules (QTAIM) with a view to better understanding the physicochemical properties in relation to chemical bonding. Topological analysis reveals stronger bonding for the N-NO2 bond relative to energetic nitramines RDX and HMX and the indication of a trend between this and impact sensitivity of nitro-containing energetic materials is noted. The intermolecular bonding of 1 is dominated by classical H-bonds but includes multiple pi-bonding interactions and interactions between H-bond donor and acceptor atoms where bond paths are deflected by H-atoms. There also exists a weak O...O interaction between end-on nitro groups, as well as an intramolecular ring-forming 1,5-type interaction. An anharmonic description of thermal motion was required to obtain the best fitting model, despite the low temperature of the study. The experimental study was complemented by periodic boundary DFT calculations at the experimental geometry as well as gas phase calculations on the isolated dianion. PMID- 30457863 TI - Stereoselective Synthesis of Functionalized alpha-Amino Acids Isolated by Filtration. AB - Crystallization-induced diastereomer transformation (CIDT) represents a highly appealing and convenient synthetic tool. Despite its numerous advantages, it remains rather rarely used due to its uncertain predictability to occur. Herein, we describe CIDT based on aza-Michael reactions of diversely functionalized ( E) 3-acylacrylic acids. This method provides direct access to a broad variety of alpha-amino acid derivatives in excellent stereochemical purities. PMID- 30457864 TI - Machine Learning-based Cyclic Voltammetry behavior Model for Supercapacitance of Co-doped Ceria/rGO Nanocomposite. AB - This paper deals with the Cobalt-doped Ceria/reduced graphene oxide (Co-CeO2/rGO) nanocomposite as supercapacitor and modeling of its cyclic voltammetry behavior using Artificial Neural Network (ANN) and Random Forest Algorithm (RFA). A good agreement was found between experimental results and the predicted values generated by using ANN and RFA. Simulation results confirmed the accuracy of the models compared to measurements from supercapacitor module power-cycling. A comparison of best performance between ANN and RFA models shows that the ANN models performed better (value of coefficient of determination > 0.95) than the RFA models for all datasets used in this study. The results of the ANN and RFA models could be useful in designing the unique nanocomposites for supercapacitors and other strategies related with energy and environment. PMID- 30457865 TI - Easy-to-Synthesize Spirocyclic Compounds Possess Remarkable In Vivo Activity Against Mycobacterium Tuberculosis. AB - Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the Spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogs. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome. PMID- 30457866 TI - Efficiency of Charge-Transfer Doping in Organic Semiconductors Probed with Quantitative Microwave and Direct-Current Conductance. AB - Although molecular charge-transfer doping is widely used to manipulate carrier density in organic semiconductors, only a small fraction of charge carriers typically escape the Coulomb potential of dopant counterions to contribute to electrical conductivity. Here, we utilize microwave and direct-current (DC) measurements of electrical conductivity to demonstrate that a high percentage of charge carriers in redox-doped semiconducting single-walled carbon nanotube (s SWCNT) networks is delocalized as a free carrier density in the pi-electron system (estimated as >46% at high doping densities). The microwave and four-point probe conductivities of hole-doped s-SWCNT films quantitatively match over almost 4 orders of magnitude in conductance, indicating that both measurements are dominated by the same population of delocalized carriers. We address the relevance of this surprising one-to-one correspondence by discussing the degree to which local environmental parameters (e.g., tube-tube junctions, Coulombic stabilization, and local bonding environment) may impact the relative magnitudes of each transport measurement. PMID- 30457867 TI - Can the Radical Channel Contribute to the Catalytic Cycle of N-Heterocyclic Carbene (NHC) in Benzoin Condensation? AB - NHC can catalyze benzoin condensation via the key Breslow intermediate. EPR spectroscopy recently confirmed the existence of the radical species, but its catalytic role is still unclear. Herein, we use density functional approaches to study the radical-associated pathway in comparison with the non-radical mechanism reported previously. Theoretical investigations show that the non-radical path (DeltaG? = 18.7 kcal/mol) is more kinetically favorable than the radical route (DeltaG? = 27.6 kcal/mol), which is initialized by the hydrogen abstraction between the Breslow intermediate and benzaldehyde, leading to a radical pair. The product formation is thus dominated by the non-radical pathway. In addition, the Breslow intermediate is less stable than its keto form, which blocks the benzoin condensation and the radical species could play an important role to assist the tautomerization and to promote the catalytic reaction. PMID- 30457868 TI - Structural analysis of the active site and DNA binding of human cytidine deaminase APOBEC3B. AB - APOBEC3s proteins (A3s), a family of human cytidine deaminases, protect the host from endogenous retro-elements and exogenous viral infections by introducing hypermutations. However, overexpressed A3s can modify genomic DNA to promote tumorigenesis, especially A3B. Despite overall similarity, A3 proteins have distinct deamination activity. Recently determined A3 structures have revealed the molecular determinants of nucleotide specificity and DNA binding. However, for A3B, the structural basis for regulation of deamination activity and the role of active site loops in coordinating DNA had remained unknown. Using advanced molecular modeling followed by experimental mutational analysis and dynamics simulations, we investigated molecular mechanism of DNA binding by A3B-CTD. We modeled fully native A3B-DNA structure, identified Arg211 in loop 1 as the gatekeeper coordinating DNA and critical residues for nucleotide specificity. We also identified a unique auto-inhibited conformation in A3B-CTD that restricts access and binding of DNA to the active site. Our results reveal the structural basis for DNA binding and relatively lower catalytic activity of A3B and provide opportunities for rational design of specific inhibitors to benefit cancer therapeutics. PMID- 30457869 TI - Selective inhibitors of human neuraminidase 1 (NEU1). AB - Inhibitors of human neuraminidase enzymes (NEU) are recognized as important tools for the study of their biological function and will be potent tools for elucidating their role in regulating the repertoire of cellular glycans. Here we report the discovery of selective inhibitors of the human neuraminidase 1 (NEU1) and neuraminidase 2 (NEU2) enzymes with exceptional potency. A library of modified 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) analogs, with variability in the C5- or C9-positions, were synthesized and evaluated against four human neuraminidase isoenyzmes (NEU1-4). Hydrophobic groups with an amide linker at the C5 and C9 positions were well accommodated by NEU1, and a hexanamido group was found to give the best potency at both positions. While the C5-hexanamido-C9-hexanamido-DANA analog did not show synergistic improvements for combined modification, an extended alkylamide at an individual position combined with a smaller group at the second gave increased potency. The best NEU1 inhibitor identified was a C5-hexanamido-C9-acetamido DANA that had a Ki of 53 +/ 5 nM and 340-fold selectivity over other isoenzymes. Additionally, we demonstrated that C5-modifications combined with a C4-guandino group provided the most potent NEU2 inhibitor reported, with a Ki of 1.3 +/- 0.2 uM and 7-fold selectivity over other NEU isoenzymes. PMID- 30457870 TI - Distinctly Different Electroresponsive Electrorheological Effect in Low-Molecular Weight and Polymerized Ionic Liquids: Rheological and Dielectric Relaxation Studies. AB - Owing to the robust and tunable properties compared to molecular compounds, ionic liquids (ILs) and polymeric ionic liquids (PILs) are very suitable substances to obtain available smart materials with high stability and strong stimulus responsive characteristic. In this paper, electroresponsive smart electrorheological (ER) effects in low-molecular-weight and polymeric ionic liquids, such as poly[[2-(methacryloyloxy)ethyl]trimethylammonium hexafluorophosphate] (P[MTMA][PF6]) are investigated and compared by a combination of rheology and dielectric relaxation spectroscopy. It is found that although P[MTMA][PF6] and [MTMA][PF6] have same constituent ions, their ER effect is distinctly different. Under electric fields, the ER effect of P[MTMA][PF6] exceeds that of the low-molecular-weight monomeric counterpart by 2-fold of magnitude. As the temperature increases, the ER effect of P[MTMA][PF6] remains in a stable level in wide temperature region, whereas that of [MTMA][PF6] shows strong temperature dependence. By dielectric relaxation spectroscopy, it can clarify that the different ER effect is attributed to the different polarization characteristics induced by cation/anion pair in different substance circumstances. Compared to low-molecular-weight crystal [MTMA][PF6], the slow interfacial polarization with a good temperature dependency related to strong ER effect in wide temperature region is easier to occur in P[MTMA][PF6] because its amorphous polymeric matrix circumstance not only provides lower activation energy for the dissociation and diffusion of ions, but also limits the dissolution of ions in carrier liquid. The result not only deepens the understanding about mechanism behind the electroresponsive ER effects of ILs and PILs but also highlights the potential of PILs as high-performance stimuli-responsive ER materials compared to the low-molecular-weight monomeric counterpart. PMID- 30457871 TI - Lentiquinones A, B, and C, Phytotoxic Anthraquinone Derivatives Isolated from Ascochyta lentis, a Pathogen of Lentil. AB - A strain of the pathogenic fungus Ascochyta lentis isolated from lentil ( Lens culinaris) was studied to ascertain its capability to produce bioactive metabolites. From the culture filtrates were found three new anthraquinone derivatives, named lentiquinones A (1), B (2), and C (3), and the known lentisone. From the mycelium, four known analogues were identified, namely pachybasin (in larger amount), omega-hydroxypachybasin, 1,7-dihydroxy-3 methylanthracene-9,10-dione, and phomarin. Lentiquinones A-C were characterized by spectroscopic methods as 3,4,6-trihydroxy-8-methyl-2 H-benzo[ g]chromene-5,10 dione, 2,3,4,5,10-pentahydroxy-7-methyl-3,4,4a,10-tetrahydroanthracen-9(2 H)-one, and its 2-epimer, respectively, and the relative configuration of the two latter compounds was deduced by X-ray diffraction data analysis. The absolute configuration of lentiquinones B and C was determined as (2 R,3 S,4 S,4a S,10 R) and (2 S,3 S,4 S,4a S,10 R), respectively, by electronic circular dichroism (ECD) in solution and solid state, and TDDFT calculations. When tested by using different bioassays, the novel compounds showed interesting activities. In particular, applied to punctured leaves of host and nonhost plants, the three new compounds and lentisone caused severe necrosis, with lentiquinone A being the most active among the new metabolites. On cress ( Lepidium sativum), this latter compound proved to be particularly active in inhibiting root elongation. On Lemna minor all the compounds reduced the content of chlorophyll, with 1,7-dihyroxy-3 methylanthracene-9,10-dione being the most active. The new compounds, together with lentisone, proved to have antibiotic properties. PMID- 30457872 TI - Using Data Mining to Search for Perovskite Materials with Higher Specific Surface Area. AB - The specific surface area (SSA) of ABO3-type perovskite is one of important properties associating with photocatalytic ability. In this work, data mining methods were used to explore the relationship between the SSA (ranged 1-60m2g-1) of perovskite with its features including chemical compositions and technical parameters. The genetic algorithm (GA)-support vector regression (SVR) method was used to screen the main features for modeling. The correlation coefficient (R) between predicted SSA and experimental SSA reached as high as 0.986 for training set and 0.935 for leave-one-out cross validation (LOOCV), respectively. The ABO3 type perovskite with higher SSA can be screened out by using OCPMDM (online computation platform for materials data mining) developed in our laboratory. Further, an online web server has been developed to share the model for the prediction of SSA of ABO3-type perovskite,which is accessible at the web address: http://118.25.4.79/material_api/csk856q0fulhhhwv. PMID- 30457873 TI - Electron-Mediated Aminyl and Iminyl Radicals from C5 Azido-Modified Pyrimidine Nucleosides Augment Radiation Damage to Cancer Cells. AB - Two classes of azido-modified pyrimidine nucleosides were synthesized as potential radiosensitizers; one class is 5-azidomethyl-2'-deoxyuridine (AmdU) and cytidine (AmdC), while the second class is 5-(1-azidovinyl)-2'-deoxyuridine (AvdU) and cytidine (AvdC). The addition of radiation-produced electrons to C5 azido nucleosides leads to the formation of pi-aminyl radicals followed by facile conversion to sigma-iminyl radicals either via a bimolecular reaction involving intermediate alpha-azidoalkyl radicals in AmdU/AmdC or by tautomerization in AvdU/AvdC. AmdU demonstrates effective radiosensitization in EMT6 tumor cells. PMID- 30457874 TI - Direct Measurement of pi Coupling at the Single-Molecule Level using a Carbon Nanotube Force Sensor. AB - We report a carbon nanotube (CNT) force sensor that combines a suspended CNT transistor with dual-trap optical tweezers to explore the interactions between two individual molecules in the near-equilibrium regime with sub-piconewton resolution. The directly measured equilibrium force (1.2 +/- 0.5 pN) is likely related to the binding force between a CNT and a single DNA base, where two aromatic rings spontaneously attract to each other due to the noncovalent forces between them. On the basis of our force measurements, the binding free energy per base is calculated (~0.34 eV), which is in good agreement with theoretical simulations. Moreover, three-dimensional scanning photocurrent microscopy enables us to simultaneously monitor the morphology changes of the CNT, leading to a comprehensive reconstruction of the CNT-DNA binding dynamics. These experimental results shed light on the fundamental understanding of the mechanical coupling between CNTs and DNA molecules and, more importantly, provide a new platform for direct observation of intermolecular interfaces at the single-molecule level. PMID- 30457876 TI - The Brain before Birth: Using fMRI to Explore the Secrets of Fetal Neurodevelopment. PMID- 30457875 TI - Absolute Orientations of Water Molecules at Zwitterionic Polymer Interfaces and Interfacial Dynamics after Salt Exposure. AB - Nonfouling zwitterionic polymers have wide applications ranging from naval industry to biomedical engineering. Strong hydration at polymer surfaces has been proved to be crucial to their nonfouling property, but absolute orientations of water molecules on the polymers and competition between water and salt binding have not been elucidated. In this work, absolute orientations of water molecules on two zwitterionic polymer brushes, poly(carboxybetaine methacrylate) (pCBMA) and poly(sulfobetaine methacrylate) (pSBMA), were measured using regular and phase sensitive sum frequency generation (SFG) vibrational spectroscopy. The pH dependent studies in the pH range from 2 to 12 showed that at pH of 7, the water absolute orientations are different on the pCBMS and pSBMA surfaces. Phase sensitive SFG studies confirmed the results obtained from the pH dependent measurements. Salt effects on the hydration of zwitterionic polymers were examined as a function of time, which indicated that the pCBMA surface and the associated interfacial water exhibit a slow restructuring process after salt binding (likely due to the strong binding of pCBMA with water), whereas the surface of pSBMA and the associated water have a fast change after salt binding. PMID- 30457877 TI - A New Tool to Capture Patients' Perceptions of the Effects of Lung Transplantation. PMID- 30457878 TI - Big Data, Efficient Markets, and the End of Daily Fantasy Sports As We Know It? AB - Fantasy sports are a popular way for individuals to add another layer of enjoyment to their interest in sports. While fantasy sports have been around for many years, access to big data sets and computer power to process them is a relatively new phenomenon, as well as the ability to compete in daily competitions and not just season-long campaigns. We posit that access to new and yet unforeseen data, models, and computing power to manage it, when viewed through the lens of efficient market hypothesis, will cause the daily fantasy sports market to change dramatically. We compare with several other markets to show the effects, when similar technologies become available. PMID- 30457879 TI - Lessons Learned During Three Decades of Operations of Two Prospective Bioresources. AB - Prospective collection is a model through which biospecimens are provided for research. Using this model, biospecimens are collected based on real-time requests from the research community instead of being collected based on the prediction of future requests. We describe the lessons learned by two bioresources that have operated successfully using a prospective model for over three decades. Our goal is to improve other bioresources by increasing utilization of biospecimens that honor consented donors who provide biospecimens to the research community; this provides strong evidence of stewardship of the public trust. The operation of these sites requires flexibility, close communication, and cooperation with the investigator in developing a standard operating procedure (protocol) based on the investigator's needs described in their initial request. If practicable, almost any preparation can be provided, including fresh (nonfrozen) biospecimens and tissue blots. A quality management system includes rigorous quality control of the specific biospecimens provided to an investigator. The informatics approach focuses on the investigator, the investigator's request, and the biospecimens collected for the investigator; the informatics focus of classic biobanks is on the biospecimens collected to match expected future requests. These lessons have been incorporated into our current operations. Standard investigator agreements (e.g., indemnification and no unapproved biospecimen transfers to third parties) replace material transfer agreements. We have operated under the prospective model of the Cooperative Human Tissue Network (CHTN), which has been successful and has provided over 1.2 million biospecimens since it began in 1987. These tissues have supported over 4300 peer-reviewed scientific articles. Since 2012, about 1000 publications have indicated support by CHTN tissues; their average citation rate is 31 with an H factor of 61. Also, during this period, 114 patents cited the CHTN. We also describe disadvantages of prospective bioresources (e.g., inadequate distribution of rare tissues, biospecimens not immediately available, and delayed clinical outcomes). PMID- 30457880 TI - Error in radiology-where are we now? AB - Error is inherent in radiological practice. Our awareness of the extent of this and the reasons behind it has increased in recent times. Our next step must be the development of a shared understanding with our patients of the limitations as well as the huge benefits of medical imaging. PMID- 30457881 TI - Volumetric analysis at abdominal CT: oncologic and non-oncologic applications. AB - Volumetric analysis is an objective three-dimensional assessment of a lesion or organ that may more accurately depict the burden of complex objects compared to traditional linear size measurement. Small changes in linear size are amplified by corresponding changes in volume, which could have significant clinical implications. Though early methods of calculating volumes were time-consuming and laborious, multiple software platforms are now available with varying degrees of user-software interaction ranging from manual to fully automated. For the assessment of primary malignancy and metastatic disease, volumetric measurements have shown utility in the evaluation of disease burden prior to and following therapy in a variety of cancers. Additionally, volume can be useful in treatment planning prior to resection or locoregional therapies, particularly for hepatic tumours. The utility of CT volumetry in a wide spectrum of non-oncologic pathology has also been described. While clear advantages exist in certain applications, some data have shown that volume is not always the superior method of size assessment and the associated labor intensity may not be worthwhile. Further, lack of uniformity among software platforms is a challenge to widespread implementation. This review will discuss CT volumetry and its potential oncologic and non-oncologic applications in abdominal imaging, as well as advantages and limitations to this quantitative technique. PMID- 30457882 TI - Impact of modern radiotherapy techniques on survival outcomes for unselected patients with large volume non-small cell lung cancer. AB - OBJECTIVE:: Intensity modulated radiotherapy (IMRT) is used, where necessary, for bulky or complex-shaped, locally advanced, non-small cell lung cancer (NSCLC). We evaluate our real-world experience with radical radiotherapy including concurrent chemoradiation (CCRT), and analyse the impact of IMRT on survival outcomes in patients with larger volume disease. METHODS:: All patients treated between May 2011 and December 2017 were included. Analyses were conducted for factors affecting survival, including large volume disease that was defined as planning target volume (PTV) > 500 cc. RESULTS:: In 184 patients with large volume disease, the median overall survival was 19.2 months, compared to 22 months seen with the overall cohort of 251 patients who received radical radiotherapy. PTV and using CCRT were significant predictors for survival. IMRT was used in 93 (50.5%) of 184 patients with large PTV. The patients treated using IMRT had significantly larger disease volume (median PTV = 859 vs 716 cc; p-value = 0.009) and more advanced stage (proportion of Stage IIIB: 56 vs 29%; p-value = 0.003) compared to patients treated with three-dimensional conformal radiotherapy. Yet, the outcomes with IMRT were non-inferior to those treated with 3DCRT. CCRT was used in 103 (56%) patients with large volume disease and resulted in a significantly better median survival of 24.9 months. The proportional benefit from CCRT was also greater than in the overall cohort. CONCLUSION:: Despite being used for larger volume and more advanced NSCLC, inverse-planned IMRT resulted in non-inferior survival. ADVANCES IN KNOWLEDGE:: IMRT enables the safe use of curative CCRT for large-volume, locally-advanced NSCLC. PMID- 30457883 TI - Pathologies of MMP-2 underactivity: A perspective on a neglected condition. AB - A member of the matrix metalloproteinase family, matrix metalloproteinase-2 (MMP 2, gelatinase A), has been extensively studied for its role in both normal physiology and pathological processes. Whereas most research efforts in recent years have investigated the pathologies associated with MMP-2 overactivity, the pathological mechanisms elicited by MMP-2 underactivity are less well understood. Here, we distinguish between two states and describe their causes: (i) MMP-2 deficiency (complete loss of MMP-2 activity) and (ii) MMP-2 insufficiency (defined as MMP-2 activity below baseline levels). Further, we review the biology of MMP-2, summarizing the current literature on MMP-2 underactivity in both mice and humans, and describe research being conducted by our lab towards improving our understanding of the pathological mechanisms elicited by MMP-2 deficiency / insufficiency. We think that this research could stimulate the discovery of new therapeutic approaches for managing pathologies associated with MMP-2 underactivity. Moreover, similar concepts could apply to other members of the matrix metalloproteinase family. PMID- 30457884 TI - A Baseline Quantitative Survey of Campylobacter spp. on Retail Chicken Portions and Carcasses in Metropolitan Perth, Western Australia. AB - INTRODUCTION: Limited baseline retail surveys have been published over the past 10 years on Campylobacter in Australian chicken meat. This study generates quantitative baseline data to assist in risk assessment and management strategies. METHODS: Raw poultry products (n = 315) were purchased for a year (2016-2017) from retail supermarkets in metropolitan Perth, Western Australia (WA). Campylobacter concentration was determined by a direct plating method in all samples, whereas in 58.7% (185/315) of the samples, testing was done using enrichment culture in conjunction with direct plating according to standard methods. RESULTS: Using direct plating, Campylobacter were recovered from 23.8% (75/315) of the samples, whereas 53.7% (100/186) of the samples were positive for Campylobacter using enrichment culture (~1 g). Campylobacter counts revealed that 76.2% of the chicken portions and carcasses were contaminated with <1 log10 colony-forming units (CFU)/g, and 18.7% of the samples were contaminated with >=2 log10 CFU/g. The average Campylobacter concentration among 315 tested chicken meat samples was 1.82 log10 CFU/g (+/-standard deviation (SD) 2.26 log10 CFU/g). The likelihood of Campylobacter recovery by direct plating from chicken products with skin on was significantly higher (odds ratio [OR] 4.4; p < 0.0001) than product forms with skin off. The highest counts of Campylobacter were associated with chicken wings (1.94 log10 CFU/g [+/-SD 2.26 log10 CFU/g]). There were some significant variations in Campylobacter counts based on the interaction between product forms and sourcing poultry processing establishment. CONCLUSIONS: This study provides the first published research on Campylobacter status in retail chicken meat in Australia since almost 10 years. Results from this study add to the knowledge on the assessment of microbial safety of the WA poultry chain, and can be used as an input for future development of quantitative risk assessment of Campylobacter. PMID- 30457885 TI - The use of texture-based radiomics CT analysis to predict outcomes in early-stage non-small cell lung cancer treated with stereotactic ablative radiotherapy. AB - OBJECTIVE:: Stereotactic ablative radiotherapy (SABR) is being increasingly used as a non-invasive treatment for early-stage non-small cell lung cancer (NSCLC). A non-invasive method to estimate treatment outcomes in these patients would be valuable, especially since access to tissue specimens is often difficult in these cases. METHODS:: We developed a method to predict survival following SABR in NSCLC patients using analysis of quantitative image features on pre-treatment CT images. We developed a Cox Lasso model based on two-dimensional Riesz wavelet quantitative texture features on CT scans with the goal of separating patients based on survival. RESULTS:: The median log-rank p-value for 1000 cross validations was 0.030. Our model was able to separate patients based upon predicted survival. When we added tumor size into the model, the p-value lost its significance, demonstrating that tumor size is not a key feature in the model but rather decreases significance likely due to the relatively small number of events in the dataset. Furthermore, running the model using Riesz features extracted either from the solid component of the tumor or from the ground glass opacity (GGO) component of the tumor maintained statistical significance. However, the p value improved when combining features from the solid and the GGO components, demonstrating that there are important data that can be extracted from the entire tumor. CONCLUSIONS:: The model predicting patient survival following SABR in NSCLC may be useful in future studies by enabling prediction of survival-based outcomes using radiomics features in CT images. ADVANCES IN KNOWLEDGE:: Quantitative image features from NSCLC nodules on CT images have been found to significantly separate patient populations based on overall survival (p = 0.04). In the long term, a non-invasive method to estimate treatment outcomes in patients undergoing SABR would be valuable, especially since access to tissue specimens is often difficult in these cases. PMID- 30457887 TI - Biobanking of Fresh-Frozen Gastric Cancer Tissues: Impact of Long-Term Storage and Clinicopathological Variables on RNA Quality. AB - BACKGROUND: Molecular research is increasingly dependent on high-quality biobanked biospecimens. Preanalytical variables in tissue processing and preservation may influence the RNA quality and research results. Hence, the effect of long-term storage and clinicopathological parameters on RNA quality needs to be elucidated. METHODS: Ninety gastric cancer tissue samples were collected and fresh-frozen in a -80 degrees C freezer for 12 years (2006-2017). The histology was assessed and RNA integrity number (RIN) was detected by an Agilent 2100 Bioanalyzer. The impact of storage duration on RNA integrity and histomorphology was analyzed. The difference between RIN values and clinical variables was analyzed. Correlations between pathological parameters such as tumor cell percentage, stroma percentage, necrosis extent, cellularity, and RIN were assessed, respectively. RESULTS: Long-term storage at -80 degrees C for 12 years did not adversely affect RNA integrity and histomorphology. RNA integrity was also not influenced by tumor location, estimated blood loss, cold/warm ischemia time, and surgical approach. However, RIN values were significantly correlated with the tumor cell percentage and stroma percentage. Gastric cancer tissues with higher tumor cell percentage or lower stroma percentage had higher RIN values. CONCLUSIONS: RNA quality of fresh-frozen gastric cancer tissues is influenced by clinical and histological parameters. Standard tissue collection procedure and histological quality control remain essential for tissue biobanking. PMID- 30457888 TI - DNA metabarcoding from sample fixative as a quick and voucher-preserving biodiversity assessment method. AB - Metabarcoding is a powerful, increasingly popular tool for biodiversity assessment, but still suffers from some drawbacks (specimen destruction, separation and size sorting). In the present study, we tested a non-destructive protocol that excludes any sample sorting, where the ethanol used for sample preserving is filtered and DNA is extracted from the filter for subsequent DNA metabarcoding. When tested on macroinvertebrate mock communities, the method was widely successful but was unable to reliably detect mollusc taxa. Three different protocols (no treatment, shaking, freezing) were applied to increase DNA release to the fixative. The protocols resulted in similar success in taxa detection (6.8 7 taxa) but differences in read numbers assigned to taxa of interest (33.8 93.7%). In comparison to conventional bulk sample metabarcoding of environmental samples, taxa with pronounced exoskeleton and small-bodied taxa were especially underrepresented in ethanol samples. For EPT (Ephemeroptera, Plecoptera, Trichoptera) taxa, which are important for determining stream ecological statuses, the methods detected 46 OTUs in common, with only 4 unique to the ethanol samples and 10 to the bulk samples. These results indicate that fixative based metabarcoding is a non-destructive, time-saving alternative for biodiversity assessments focussing on taxa used for ecological status determination. However, for a comprehensive assessment on total biodiversity, the method may not be sufficient, and conventional bulk sample metabarcoding should be applied. PMID- 30457889 TI - Extending the Evolvability Model to the Prokaryotic World: Simulations and Results on Real Data. AB - In 2006, Valiant introduced a variation to his celebrated PAC (Probably Approximately Correct) model to biology, by which he wished to explain how, with two simple mechanisms-random variation and natural selection-complex life mechanisms evolved in such a short time. Subsequently, several works extended and specialized the evolvability framework to more specific processes. In this study, we extend the evolvability framework to accommodate horizontal gene transfer, the transfer of genetic material between unrelated organisms. While in a separate work, we focused on the theoretical aspects of this extension and its learnability power; here, the focus is on more practical and biological facets of this new model. Specifically, we focus on the evolutionary process of developing a trait and model it as the conjunction function. We demonstrate the speedup in learning time for a variant of conjunction to which learning algorithms are known. We also confront the new model with the recombination model on real data of Escherichia coli strains under the task of developing pathogenicity and obtain results adhering to current existing knowledge. Apart from the sheer extension to the understudied prokaryotic world, our work offers comparisons of three different models of evolution under the same conditions, which we believe is unique and of a separate interest. PMID- 30457890 TI - Helicobacter Pylori Detection in Shellfish: A Real-Time Quantitative Polymerase Chain Reaction Approach. AB - Shellfish is a highly valuated natural food product that is usually consumed minimally processed. Some foodborne pathogens have been associated to marine products and isolated from aquatic environments. Helicobacter pylori emerges as one of the most concerning human pathogens associated to water and, thereby, it could be present in raw and slightly treated marine food products. The present research work aimed to detect the presence of H. pylori in Spanish commercial samples of shellfish (mussels, clams, and cockles) by means of a quantitative real-time polymerase chain reaction (qPCR) approach based on the vacuolating cytotoxin A (vacA) gene specificity. Putative H. pylori amplicons were confirmed by sequencing. qPCR was positive for 12 out of the 100 samples, being 67% (8/12) from mussels, 25% (3/12) from clams, and only 8% (1/12) from cockles. After sequencing, three of the amplicons showed 97-99% homology with the H. pylori vacA gene. Quantitative results indicate that the levels of contamination remained below 102 log10 colony forming units per mL (CFU/mL). The present research shows for the first time the effectiveness of the optimized qPCR in the identification of potentially H. pylori contaminated shellfish products. Our results confirm the presence of H. pylori in shellfish from the Spanish western seacoast and verify the possible relationship between the presence of H. pylori in seawater and the role of contaminated seafoods as vehicles of H. pylori entrance into the food chain. PMID- 30457891 TI - Safety of osimertinib in egfr-mutated non-small cell lung cancer. AB - INTRODUCTION: Osimertinib is a third-generation EGFR-TKI, specifically designed to inhibit EGFR sensitizing and T790M acquired mutations, minimizing exposure in EGFR-wildtype tissues. Areas covered: Osimertinib use in EGFR-mutated NSCLC patients is described, focusing on safety and tolerability from studies supporting its approval. Expert opinion: Osimertinib demonstrated greater efficacy, including CNS activity, compared to chemotherapy, with a manageable safety profile in pretreated T790M+ EGFR-mutated patients, leading to FDA approval in 2015 within record time in the oncology field. However, the therapeutic strategy in the EGFR-mutated population is changing, following the FLAURA study in untreated EGFR-mutated patients, in which osimertinib improved PFS compared to other TKIs, with a similar toxicity profile but a lower serious adverse event rate. In April 2018, the FDA and EMA approved osimertinib as first line therapy for EGFR-mutated patients. Long-term survival data will ultimately establish the true benefit of upfront versus sequential strategies guided by T790M status. These studies favor osimertinib for tolerability and safety, except for the slightly higher rate of interstitial lung disease, but which was nonetheless manageable. In the coming years, osimertinib will be consolidated as standard therapy in the EGFR population and in naive and pretreated patients, based on mature survival data and the toxicity profile. PMID- 30457892 TI - Randomized Controlled Pilot Study of Dietary Supplementation with Turmeric or Herbal Combination Tablets on Skin Barrier Function in Healthy Subjects. AB - To compare the effects of turmeric tablets and turmeric-containing herbal combination tablets versus placebo on skin barrier function and sebum production by measuring facial sebum and transepidermal water loss (TEWL) in healthy subjects. This study was a prospective, double-blinded, rater-blinded, randomized pilot study. Thirty-three generally healthy participants were recruited from the UC Davis Department of Dermatology clinic and the surrounding community from 2016 to 2017, 30 participants were enrolled, and 28 participants completed the study. Thirty individuals were recruited and randomized to the placebo, turmeric, or herbal combination tablet groups. The participants were instructed to take the intervention tablets by mouth twice daily for 4 weeks. Facial sebum production and TEWL were assessed at baseline and 4 weeks. Twenty-eight participants completed the study and there were no adverse events. There were no significant changes in sebum excretion rate in any group after 4 weeks compared with baseline. In the herbal combination tablet group, there was a significant decrease in TEWL (P = .003). No significant changes in TEWL were detected in the turmeric or placebo groups. Turmeric-containing herbal combination tablets significantly decreased TEWL after 4 weeks of twice-daily supplementation. There were no adverse events in any of the three intervention arms. Overall, our findings spark future interest in determining how oral supplementation with herbal formulations may improve skin barrier function and skin appearance, and potentially offer alternative or complementary treatment options. PMID- 30457893 TI - Dimensions of the Parent-Child Relationship: Effects on Substance Use in Adolescence and Adulthood. AB - BACKGROUND: Several studies have uncovered a relationship between parenting styles and the likelihood that adolescents use tobacco, alcohol or illegal drugs. OBJECTIVES: This paper extends existing research in two ways. First, we consider a longer time-frame, investigating the relationship between parenting in adolescence and substance use in adulthood. Second, we explore the pathways by which this relationship is expressed, in particular the extent to which the relationships in question are mediated by age at first use and depression. METHODS: Our analysis is based on data from the National Longitudinal Study of Adolescent Health (Add Health), N = 2954, and is conducted using structural equation modeling (SEM). We consider warmth and control as distinct dimensions of parenting, as well as a typology of parenting which combines the two dimensions. RESULTS: Warmth is associated with reduced risks of problem substance use in adulthood, via reduced risks of early initiation and a lower risk of depression. Parental control also has a protective effect via reduced risks of early initiation, but this is offset by a detrimental effect on depression, particularly in the case of older adolescents. We also find that indulgent parenting is not associated with extra risk of any kind compared with the authoritative style, whereas authoritarian and neglectful styles are. Conclusions/Importance: The nexus of relationships which we uncover has implications for policy aimed at reducing substance use in the longer term, suggesting that initiatives to promote warm and responsive parenting may be most effective in reducing the risks of later substance use problems. PMID- 30457894 TI - Spiritual and Religious Coping of Medical Decision Makers for Hospitalized Older Adult Patients. AB - BACKGROUND: Critically ill adult patients who face medical decisions often delegate others to make important decisions. Those who are authorized to make such decisions are typically family members, friends, or legally authorized representatives, often referred to as surrogates. Making medical decisions on behalf of others produces emotional distress. Spirituality and/or religion provide significant assistance to cope with this distress. We designed this study to assess the role of surrogates' spirituality and religion (S/R) coping resources during and after making medical decisions on behalf of critically ill patients. The study's aim was to understand the role that S/R resources play in coping with the lived experiences and challenges of being a surrogate. METHODS: Semistructured interviews were conducted with 46 surrogates by trained interviewers. These were audio-recorded and transcribed by research staff. Three investigators conducted a thematic analysis of the transcribed interviews. The codes from inter-rater findings were analyzed, and comparisons were made to ensure consistency. RESULTS: The majority (67%) of surrogates endorsed belief in God and a personal practice of religion. Five themes emerged in this study. Personal prayer was demonstrated as the most important coping resource among surrogates who were religious. Trusting in God to be in charge or to provide guidance was also commonly expressed. Supportive relationships from family, friends, and coworkers emerged as a coping resource for all surrogates. Religious and nonreligious surrogates endorsed coping strategies such as painting, coloring, silent reflection, music, recreation, and reading. Some surrogates also shared personal experiences that were transformative as they cared for their ill patients. CONCLUSION: We conclude that surrogates use several S/R and other resources to cope with stress when making decisions for critically ill adult patients. The coping resources identified in this study may guide professional chaplains and other care providers to design a patient-based and outcome-oriented intervention to reduce surrogate stress, improve communication, increase patient and surrogate satisfaction, and increase surrogate integration in patient care. We recommend ensuring that surrogates have S/R resources actively engaged in making medical decisions. Chaplains should be involved before, during, and after medical decision making to assess and address surrogate stress. An interventional research-design project to assess the effect of spiritual care on surrogate coping before, during, and after medical decision making is also recommended. PMID- 30457895 TI - Pseudomonas species isolated from tobacco seed promote root growth and reduce lead contents in Nicotiana tobacum K326. AB - Endophytic bacteria are generally helpful for plant growth and protection. We isolated three Pseudomonas strains (K03, Y04 and N05) from tobacco seeds, which could produce siderophores, Indole-3-acetic acid (IAA) and 1-aminocyclopropane-1 carboxylate (ACC) deaminase, fix nitrogen, dissolve phosphorus/potassium and tolerate heavy metals. In pot experiments, the three isolated strains significantly promoted root growth and increased the root enzyme activity in Nicotiana tobacum K326. Furthermore, bacterial inoculations increased the proportion of residual lead (Pb) by 8.36-51.63% and decreased the total Pb content by 3.28-6.38% in the contaminated soil during tobacco planting, compared to those without inoculation. An effective decrease in Pb content had also been found in tobacco leaves with bacterial inoculations. K03 inoculation decreased the Pb content in the upper leaf by 49.80% and Y04 inoculation had the best effect on decreasing the Pb content in the middle leaf by 70.12%. Additionally, soil pH and root activity had significant effects on transformation and translocation of Pb. The study suggested that, to respond to Pb pollutions in soil, the reasonable application of endophytes (e.g., Pseudomonas) might be a promising approach in promoting tobacco growth and reducing Pb contents in tobacco, while simultaneously enhancing Pb stabilization in soils. PMID- 30457896 TI - Feasibility of Perioperative Micro-Computed Tomography of Human Lung Cancer Specimens: A Pilot Study. AB - CONTEXT.-: Lesion localization during intraoperative frozen section of lung resection specimens can be challenging. Imaging could aid lesion localization while enabling 3-dimensional specimen analysis. OBJECTIVE.-: To assess the feasibility of integrating micro-computed tomography (micro-CT) into the perioperative evaluation of fresh surgical lung resection specimens. DESIGN.-: Fresh lung specimens from patients with a presumptive diagnosis of lung cancer were imaged with micro-CT prior to routine histopathologic and molecular analysis. Micro-CT images were assessed to determine image quality, lesion size, and distance from lesion to the nearest surgical margin. Micro-CT measurements were compared to pathologic measurements using Bland-Altman analysis. RESULTS.-: A total of 22 specimens from 21 patients were analyzed (mean image acquisition time, 13 +/- 6 minutes). Histologic quality of imaged specimens was indistinguishable from a control group of nonimaged lung specimens. Artifacts, most commonly from specimen deflation (n = 8), obscured fine detail on micro-CT images of 10 specimens. Micro-CT could successfully localize the target lesion in the other 12 specimens. Distance to the nearest surgical margin was determined in 10 specimens. Agreement of micro-CT with final pathology was good, with a mean difference of -2.8% (limits of agreement -14.5% to 20.0%) for lesion size and 0.5 mm (limits of agreement -4.4 to 3.4 mm) for distance to nearest surgical margin. CONCLUSIONS.-: Micro-CT of fresh surgical lung specimens is feasible and has the potential to evaluate the size and location of lesions within resection specimens, as well as distance to the nearest surgical margin, all without compromising specimen integrity. PMID- 30457898 TI - Effects of a surgical sealant on leakage pressure and circumference of fresh canine cadaver small intestinal anastomoses. AB - OBJECTIVE To evaluate the effect of a bovine albumin-derivatized glutaraldehyde (BA-DG) biopolymer sealant on leakage pressures of intestinal anastomoses in jejunal tissue collected from fresh canine cadavers and to evaluate changes in circumference and cross-sectional area of the anastomotic site resulting from sealant application. SAMPLE 24 jejunal anastomoses from 4 fresh canine cadavers. PROCEDURES Jejunal tissue specimens were collected, and adjacent segment anastomoses were created within 12 hours after euthanasia of each dog. The tissue constructs were randomly assigned to 1 of 2 groups in which sealant was or was not applied. The outer circumference of all anastomoses in the sealant group was measured before and after application of the sealant; the cross-sectional area at the anastomotic site was then calculated at each time point. Tissue constructs were pressure tested, and leakage pressure and site were recorded. All testing was completed within 24 hours after tissue collection. RESULTS Compared with preapplication findings, there were no significant changes in outer circumference or cross-sectional area at the anastomotic site after sealant application. Leakage pressures in the sealant group were significantly higher than those in the no-sealant group. CONCLUSIONS AND CLINICAL RELEVANCE The use of surgical sealant on fresh canine cadaver jejunal anastomoses resulted in significantly higher leakage pressure at the anastomotic site; no immediate tissue deformation of the outer circumference or cross-sectional area occurred after sealant application. Future in vivo investigations are warranted to evaluate the effects of this sealant and potential benefits for clinical patients undergoing enterectomy. PMID- 30457897 TI - Analytical Validation and Clinical Utility of an Immunohistochemical Programmed Death Ligand-1 Diagnostic Assay and Combined Tumor and Immune Cell Scoring Algorithm for Durvalumab in Urothelial Carcinoma. AB - CONTEXT.-: Clinical responses to anti-programmed death receptor-1 and anti programmed death ligand-1 (PD-L1) agents are generally improved in patients with high PD-L1 expression compared with those with low/negative expression across several tumor types, including urothelial carcinoma. OBJECTIVE.-: To validate a PD-L1 immunohistochemical diagnostic test in urothelial carcinoma patients treated with the anti-PD-L1 monoclonal antibody durvalumab. DESIGN.-: The Ventana PD-L1 (SP263) assay was validated for intended use in urothelial carcinoma formalin-fixed, paraffin-embedded samples in studies addressing sensitivity, specificity, robustness, and precision, and implemented in study CD-ON-MEDI4736 1108 (NCT01693562). Efficacy was analyzed in patients classified according to prespecified PD-L1 expression cutoffs: PD-L1 high (if >1% of the tumor area contained tumor-associated immune cells, >=25% of tumor cells or >=25% of immune cells stained for PD-L1; if <=1% of the tumor area contained immune cells, >=25% of tumor cells or 100% of immune cells stained for PD-L1) and PD-L1 low/negative (did not meet criteria for PD-L1 high). RESULTS.-: The assay met all predefined acceptance criteria for sensitivity, specificity, and precision. Interreader and intrareader precision overall agreement were 93.0% and 92.4%, respectively. For intraday reproducibility and interday precision, overall agreement was 99.2% and 100%, respectively. Interlaboratory overall agreement was 92.6%. In study CD-ON MEDI4736-1108, durvalumab demonstrated clinical activity and durable responses in both PD-L1-high and PD-L1-low/negative subgroups, although objective response rates tended to be higher in the PD-L1-high subgroup than in the PD-L1 low/negative subgroup. CONCLUSIONS.-: Determination of PD-L1 expression in urothelial carcinoma patients using the Ventana PD-L1 (SP263) assay was precise, highly reproducible, and clinically relevant. PMID- 30457899 TI - Quantitative assessment of intravenous regional limb perfusion of tiludronate as an adjunctive treatment for lameness caused by navicular syndrome in horses. AB - OBJECTIVE To determine effects for 2 IV regional limb perfusion (IVRLP) protocols involving tiludronate on lameness of horses with navicular syndrome. ANIMALS 15 horses with bilateral forelimb navicular syndrome. PROCEDURES Shoeing and anti inflammatory injection into the distal interphalangeal joint (DIPJ) of both forelimbs (day 0) were performed on all horses. On day 14, horses received 1 of 3 IVRLPs consisting of 0.1 mg of tiludronate/kg (low-dose tiludronate [LDT]; n = 5), 0.2 mg of tiludronate/kg (high-dose tiludronate [HDT]; 5), or saline (0.9% NaCl) solution (placebo; 5); treatments were repeated at days 24 and 34. Lameness severity of both forelimbs was evaluated via subjective evaluation and force plate analysis before and after shoeing on day 0 and at days 14, 34, 60, and 120. Mean subjective lameness score and peak vertical ground reaction force (PVGRF) for the more severely lame forelimb (LFL) and both (combined) forelimbs (CFL) were compared over time. RESULTS For all horses, mean PVGRF for the LFL and CFL was increased at 14 days. No difference in mean subjective lameness score or mean PVGRF was detected within groups at any time. Mean PVGRF of the CFL was higher for the HDT group than the LDT and placebo groups only at 120 days. CONCLUSIONS AND CLINICAL RELEVANCE Use of the tiludronate IVRLP protocols described here provided no further improvement in lameness over therapeutic shoeing and anti inflammatory injection of the DIPJ in horses with navicular syndrome. However, HDT-treated horses were objectively less lame than LDT- or placebo-treated horses at 120 days. PMID- 30457900 TI - Assessment of sedation after intranasal administration of midazolam and midazolam butorphanol in cockatiels (Nymphicus hollandicus). AB - OBJECTIVE To compare sedation in cockatiels (Nymphicus hollandicus) after intranasal administration of midazolam and midazolam-butorphanol. ANIMALS 9 healthy adult cockatiels. PROCEDURES A randomized, controlled, blinded, complete crossover study was conducted. Birds were assigned to 3 treatment groups. Midazolam (3 mg/kg), midazolam-butorphanol (3 mg/kg for each drug), or sterile saline (0.9% NaCl) solution (control treatment) was administered intranasally. Sedation quality was assessed at 3 time points by use of eye and body position; response to visual, auditory, and tactile stimulation; and response during manual restraint on the basis of eye position and struggling intensity. To evaluate attenuation of the manual restraint-induced stress response, heart rate, respiratory rate, and cloacal temperature were measured over a 15-minute period. Treatments were repeated after a minimum washout period of 7 days. RESULTS Median onset of first sedation effects was 85 seconds (range, 60 to 120 seconds) for midazolam and 90 seconds (range, 45 to 180 seconds) for midazolam-butorphanol. Midazolam-butorphanol resulted in significantly less vigorous struggling during restraint than did midazolam or the control treatment. Heart rate did not differ significantly among treatments. The stress-induced increase in respiratory rate was significantly attenuated by midazolam and midazolam-butorphanol, whereas the increase in cloacal temperature was not attenuated by midazolam or midazolam butorphanol. CONCLUSIONS AND CLINICAL RELEVANCE Intranasal administration of midazolam and midazolam-butorphanol resulted in a rapid onset of sedation in cockatiels. Midazolam-butorphanol resulted in deeper sedation in both restrained and unrestrained birds than did midazolam alone. Midazolam and midazolam butorphanol both provided safe and effective sedation in cockatiels. PMID- 30457901 TI - Pharmacokinetics and pharmacodynamics of oral pradofloxacin administration in dogs. AB - OBJECTIVE To determine whether target values for pharmacokinetic-pharmacodynamic (PK-PD) indices against selected canine pathogens were achievable for pradofloxacin in various canine fluids and leukocytes. ANIMALS 8 healthy adult hounds (experiments 1 and 2) and 6 healthy adult dogs (experiment 3). PROCEDURES In 3 experiments, pradofloxacin (3, 6, or 12 mg/kg) and enrofloxacin (5 or 10 mg/kg) were orally administered once a day for 5 days, and blood, interstitial fluid (ISF), and other fluid samples were collected at various points. Sample drug concentrations were measured, and noncompartmental pharmacokinetic analysis was performed; then, PK-PD indices (ratios between maximum observed concentration [Cmax] and minimum inhibitory or mutant prevention concentrations) were determined for 7 bacterial species. RESULTS PK-PD values for pradofloxacin at 3 mg/kg were approximately 5 times as high in leukocyte versus plasma and were lowest in CSF, synovial fluid, and aqueous humor. No significant differences were noted between serum and ISF. Value ratios for serum versus other body fluids were numerically higher for pradofloxacin (vs enrofloxacin) for all fluid types except CSF and aqueous humor. Target PK-PD values were exceeded for pradofloxacin against all 7 bacterial species in leukocytes and against all species except Bacteroides spp in serum and ISF. Enrofloxacin achieved the target Cmax-to minimum inhibitory concentration ratio against Pasteurella multocida in serum, ISF, and leukocytes and for Staphylococcus pseudintermedius in serum and leukocytes. A Cmax-to-mutant prevention concentration ratio >= 1 against Eschericha coli was achieved for pradofloxacin at 6 mg/kg. CONCLUSIONS AND CLINICAL RELEVANCE These findings supported once-daily oral administration of pradofloxacin to dogs at the currently recommended dose (7.5 mg/kg). PMID- 30457902 TI - Activation of chicken macrophages during in vitro stimulation and expression of immune genes. AB - OBJECTIVE To characterize activation and expression of immune genes of chicken macrophages after in vitro stimulation with lipopolysaccharide (LPS) and mouse erythrocytes. ANIMALS Five 15-day-old chickens and 2 BALB/c mice. PROCEDURES Macrophages were extracted from chicken bone marrow or peripheral blood and then stimulated with cytokines secreted from cell lines L929 and HD11. Stimulated chicken macrophages were further cocultured with LPS or mouse erythrocytes, and gene transcription of some distinctive cytokines was detected by use of a real time PCR assay. RESULTS Morphological features and phagocytic function of macrophages were characterized. Activated macrophages had an elongated shape with a large cell nucleus, and they had phagocytic function. Distinctive genes encoding the surface marker gene CD11b were identified; high quantities of CD11b were transcribed. Relative transcription of chicken genes BF and BL in mature cells cocultured with both stimuli was lower than for control cells. However, the quantity of genes encoding M1- or M2-distinctive cytokines (interleukin [IL] 1beta, IL-10, IL-12, inducible nitric oxide synthase, tumor necrosis factor alpha, and transforming growth factor-beta) that were transcribed differed significantly between stimulation with LPS and mouse erythrocytes. CONCLUSIONS AND CLINICAL RELEVANCE Chicken macrophages were differentially stimulated by LPS and mouse erythrocytes, which suggested that in vitro stimulation can distinctly influence the transcription and expression of immune genes of chicken macrophages. PMID- 30457903 TI - Evaluation of the thermal antinociceptive effects and pharmacokinetics after intramuscular administration of buprenorphine hydrochloride to cockatiels (Nymphicus hollandicus). AB - OBJECTIVE To evaluate thermal antinociceptive effects and pharmacokinetics of buprenorphine hydrochloride after IM administration to cockatiels (Nymphicus hollandicus). ANIMALS 16 adult (>= 2 years old) cockatiels (8 males and 8 females). PROCEDURES Buprenorphine hydrochloride (0.3 mg/mL) at each of 3 doses (0.6, 1.2, and 1.8 mg/kg) and saline (0.9% NaCl) solution (control treatment) were administered IM to birds in a randomized within-subject complete crossover study. Foot withdrawal response to a thermal stimulus was determined before (baseline) and 0.5, 1.5, 3, and 6 hours after treatment administration. Agitation sedation scores were also determined. For the pharmacokinetic analysis, buprenorphine (0.6 mg/kg) was administered IM to 12 of the birds, and blood samples were collected at 9 time points ranging from 5 minutes to 9 hours after drug administration. Samples were analyzed with liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated with commercial software. RESULTS Buprenorphine at 0.6, 1.2, and 1.8 mg/kg did not significantly change the thermal foot withdrawal response, compared with the response for the control treatment. No significant change in agitation-sedation scores was detected between all doses of buprenorphine and the control treatment. Plasma buprenorphine concentrations were > 1 ng/mL in all 4 birds evaluated at 9 hours. CONCLUSIONS AND CLINICAL RELEVANCE Buprenorphine at the doses evaluated did not significantly change the thermal nociceptive threshold for cockatiels or cause sedative or agitative effects. Additional studies with other pain assessments and drug doses are needed to evaluate the analgesic and adverse effects of buprenorphine in cockatiels and other avian species. PMID- 30457904 TI - Effect of a constant rate infusion of remifentanil hydrochloride on left ventricular systolic and diastolic function in propofol-anesthetized dogs. AB - OBJECTIVE To assess the effects of a constant rate infusion (CRI) of remifentanil hydrochloride on left ventricular systolic and diastolic function in healthy propofol-anesthetized dogs. ANIMALS 6 healthy Beagles. PROCEDURES Each dog underwent 2 experimental treatments separated by a 7-day interval. In 1 treatment, anesthesia was induced with propofol and maintained with a CRI of propofol (0.6 mg/kg/min); dogs also received a CRI of saline (0.9% NaCl) solution. In the other treatment, anesthesia was similarly induced and maintained with propofol; dogs also received a CRI of remifentanil (0.3 MUg/kg/min). Doppler echocardiographic and hemodynamic variables of interest were determined at baseline (before anesthesia) and at 20, 40, and 60 minutes following the simultaneous start of the 2 CRIs of each treatment; all CRIs were administrated for 60 minutes. RESULTS For the 2 treatments, end-diastolic and end-systolic volume indices did not differ from baseline or at any time point. Peak tissue Doppler-derived mitral annulus systolic velocity decreased from baseline with both treatments; however, no differences were found between treatments at any time point. Mean arterial blood pressure decreased similarly with both treatments. Heart rate and Doppler-determined cardiac index decreased significantly with the propofol-remifentanil treatment, compared with findings for the propofol-saline solution treatment. For the propofol-remifentanil treatment, the ratio of peak velocity flow in early diastole to that in late diastole remained > 1.80, whereas the ratio of early to late Doppler-derived mitral annulus velocity had a normal relaxation pattern. CONCLUSIONS AND CLINICAL RELEVANCE Results of this study indicated that a CRI of remifentanil administered along with a CRI of propofol does not impair left ventricular systolic and diastolic function in healthy dogs. PMID- 30457905 TI - Influence of injection protocol and measurement technique on computed tomographic assessment of glomerular filtration rate in healthy Beagles. AB - OBJECTIVE To compare values of CT-derived glomerular filtration rate (GFR) determined by 3 contrast-medium injection protocols and 4 measurement techniques in healthy Beagles. ANIMALS 9 healthy Beagles (mean +/- SD weight, 13.2 +/- 1.6 kg). PROCEDURES Each dog underwent 3 iohexol-injection protocols (700 mg of iodine/kg administered at a constant rate over 20 seconds, 700 mg of iodine/kg administered following an exponentially decelerated injection over 20 seconds, and 350 mg of iodine/kg at a constant rate over 10 seconds) during dynamic, whole renal-volume CT in randomized order with an interval of >= 7 days between experiments. Values of GFR determined from Patlak plots derived by use of 4 measurement techniques (standard transverse section, optimized transverse section, dorsal reconstruction, and volume calculation techniques) were compared. RESULTS The measurement technique influenced the mean +/- SD GFR results (standard transverse section technique, 2.49 +/- 0.54 mL/kg/min; optimized transverse section technique, 2.72 +/- 0.52 mL/kg/min; dorsal reconstruction technique, 3.00 +/- 0.60 mL/kg/min, and volume calculation technique, 2.48 +/- 0.51 mL/kg/min). The lower iodine dose resulted in a significantly higher GFR value (3.00 +/- 0.65 mL/kg/min), compared with that achieved with either higher dose administration (constant rate injection, 2.54 +/- 0.45 mL/kg/min and exponentially decelerated injection, 2.47 +/- 0.48 mL/kg/min). CONCLUSIONS AND CLINICAL RELEVANCE In healthy Beagles, the CT-derived GFR measurements obtained after injection of a full dose of contrast medium were reduced, compared with measurements obtained after injection of a half dose. This finding is important with regard to potential nephrotoxicosis in dogs with impaired renal function and for GFR measurement with CT-contrast medium protocols. PMID- 30457907 TI - In vitro mechanical evaluation of three transfixation pin-cast constructs applied to equine forelimbs. AB - OBJECTIVE To compare strain at the bone-pin and cast-pin interfaces among 3 transfixation pin-cast constructs applied to equine forelimbs. ANIMALS 15 forelimbs from 15 adult horses. PROCEDURES Limbs were randomly assigned to 1 of 3 constructs. Centrally threaded positive-profile pins were used for all constructs, and the most distal pin was placed just proximal to the epicondyles of the third metacarpal bone. Construct 1 consisted of two 6.3-mm-diameter pins spaced 4 cm apart at 30 degrees to each other. Construct 2 was the same as construct 1 except the pins were placed 5 cm apart. Construct 3 consisted of four 4.8-mm-diameter pins spaced 2 cm apart and at 10 degrees to one another. An osteotomy was created in the proximal phalanx. Strain gauges were attached to the cast and bone proximal to the pins and adjacent to the osteotomy. Limbs underwent compressive loading until failure. Simplified finite element models of constructs 1 and 3 were created to further evaluate strain and load transfer between the bone and cast. RESULTS Strain did not differ between constructs 1 and 2. Compared with the 2-pin constructs, construct 3 had less strain at the bone-pin interface and more strain at the cast-pin interface, which indicated a greater amount of load was transferred to the cast of the 4-pin construct than the cast of the 2 pin constructs. Finite element modeling supported those findings. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that the 4-pin construct was more effective in unloading the fractured bone than either 2-pin construct. PMID- 30457908 TI - Evaluation of animal-to-animal and community contact structures determined by a real-time location system for correlation with and prediction of new bovine respiratory disease diagnoses in beef cattle during the first 28 days after feedlot entry. AB - OBJECTIVE To determine whether animal-to-animal and community contact patterns were correlated with and predictive for bovine respiratory disease (BRD) in beef steers during the first 28 days after feedlot entry. ANIMALS 70 weaned beef steers (mean weight, 248.9 kg). PROCEDURES Calves were instrumented with a real time location system transmitter tag and commingled in a single pen. The location of each calf was continuously monitored. Contact between calves was defined as <= 0.5 m between pen coordinates, and the duration that 2 calves were within 0.5 m of each other was calculated daily. Bovine respiratory disease was defined as respiratory tract signs and a rectal temperature > 40 degrees C. Locational data were input into a community detection program to determine daily calf contact and community profiles. The number of BRD cases within each community was determined. A random forest algorithm was then applied to the data to determine whether contact measures were predictive of BRD. RESULTS Probability of BRD was positively correlated with the number of seconds a calf spent in contact with calves presumably shedding BRD pathogens and number of calves with BRD within the community on the day being evaluated and the previous 2 days. Diagnostic performance of the random forest algorithm varied, with the positive and negative predictive values generally < 10% and > 90%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that direct transmission of BRD pathogens likely occurs among feedlot cattle. The relative contribution of animal-to-animal contact to BRD risk remains unknown and warrants further investigation. PMID- 30457909 TI - Effect of pneumoperitoneum with warmed humidified or standard-temperature carbon dioxide during laparoscopy on core body temperature, cardiorespiratory and thromboelastography variables, systemic inflammation, peritoneal response, and signs of postoperative pain in healthy mature dogs. AB - OBJECTIVE To evaluate effects of pneumoperitoneum created with warmed humidified CO2 (WHCO2) during laparoscopy on core body temperature, cardiorespiratory and thromboelastography variables, systemic inflammation, peritoneal response, and signs of postoperative pain in healthy mature dogs. ANIMALS 6 mature purpose-bred dogs. PROCEDURES In a randomized crossover study, each dog was anesthetized twice, and pneumoperitoneum was created with standard-temperature CO2 (STCO2; 22 degrees C and 0% relative humidity) and WHCO2 (37 degrees C and 98% relative humidity). Data were collected during each procedure, including core body temperature, cardiorespiratory and thromboelastography variables, and inflammatory biomarkers. Peritoneal biopsy specimens were collected and evaluated with scanning electron microscopy. Dogs were assessed for signs of postoperative pain. RESULTS Mean core body temperature was significantly lower (35.2 degrees C; 95% confidence interval, 34.5 degrees to 35.8 degrees C) with WHCO2 than with STCO2 (35.9 degrees C; 95% confidence interval, 35.3 degrees to 36.6 degrees C) across all time points. Cardiac index increased during the procedure for both treatments but was not significantly different between treatments. Thromboelastography variables did not differ significantly between treatments as indicated by the coagulation index. Subjective evaluation of peritoneal biopsy specimens revealed mesothelial cell loss with STCO2. There was no significant difference in circulating C-reactive protein or interleukin-6 concentrations. There was a significant increase in the number of postoperative pain scores > 0 for the WHCO2 treatment versus the STCO2 treatment. CONCLUSIONS AND CLINICAL RELEVANCE Analysis of these data suggested that effects on evaluated variables attributable to the use of WHCO2 for creating pneumoperitoneum in healthy mature dogs undergoing laparoscopy did not differ from effects for the use of STCO2. PMID- 30457910 TI - Sedative and cardiopulmonary effects of buccally administered detomidine gel and reversal with atipamezole in dogs. AB - OBJECTIVE To evaluate hemodynamic, respiratory, and sedative effects of buccally administered detomidine gel and reversal with atipamezole in dogs. ANIMALS 8 adult purpose-bred dogs. PROCEDURES Arterial and venous catheters were placed. Baseline heart rate, respiratory rate, cardiac output (determined via lithium dilution with pulse contour analysis), oxygen delivery, systemic vascular resistance, arterial blood gas values, and sedation score were obtained. Detomidine gel (2.0 mg/m2) was administered on the buccal mucosa. Cardiopulmonary data and sedation scores were obtained at predetermined times over 180 minutes. Atipamezole (0.1 mg/kg) was administered IM at 150 minutes. Reversal of sedation was timed and scored. Data were analyzed with an ANOVA. RESULTS Compared with baseline values, heart rate was lower at 45 to 150 minutes, cardiac output and oxygen delivery were lower at 30 to 150 minutes, and systemic vascular resistance was increased at 30 to 150 minutes. There were no significant changes in Paco2, Pao2, or lactate concentration at any time point, compared with baseline values, except for lactate concentration at 180 minutes. All dogs became sedated; maximum sedation was detected 75 minutes after administration of detomidine. Mean +/- SD time to recovery after atipamezole administration was 7.55 +/- 1.89 minutes; sedation was completely reversed in all dogs. No adverse events were detected. CONCLUSIONS AND CLINICAL RELEVANCE Buccally administered detomidine gel was associated with reliable and reversible sedation in dogs, with hemodynamic effects similar to those induced by other alpha2-adrenoceptor agonists. Buccally administered detomidine gel could be an alternative to injectable sedatives in healthy dogs. PMID- 30457911 TI - Acute recovery from disuse atrophy: the role of stretch-activated ion channels in the activation of anabolic signaling in skeletal muscle. AB - The aim of the study was to (i) measure time course alternations in the rate of protein synthesis (PS) and phosphorylation status of the key anabolic markers and (ii) find out the role of stretch-activated ion channels (SAC) in the activation of anabolic signaling in the rat soleus during an acute reloading following disuse atrophy. Wistar rats were subjected to 14-day hindlimb suspension (HS) followed by 6- 12- and 24 h of reloading. In order to examine the role of SAC in the reloading-induced activation of anabolic signaling the rats were treated with gadolinium (Gd3+), a SAC blocker. The content of signaling proteins was determined by WB. c-Myc mRNA expression was assessed by RT-PCR. After 24-h reloading PS rate was elevated by 44% vs. control. Following 6-h reloading the p p70s6k and p-4E-BP1 did not differ from control, however 12-h reloading resulted in an upregulation of both p70s6k and 4E-BP1 phosphorylation vs. control. The phosphorylation of AKT and GSK-3beta was reduced after HS and then completely restored by 12-h reloading. c-Myc was significantly up-regulated during the entire reloading. Gd3+ treatment during reloading (12 h) prevented a full phosphorylation of p70s6k, rpS6, 4E-BP1 as well as PS activation. The results of the study suggest that (i) enhanced PS during the acute recovery from HS may be associated with the activation of ribosome biogenesis as well as mTORC1-dependent signaling pathways; (ii) functional SAC are necessary for complete activation of mTORC1 signaling in rat soleus during acute recovery from HS. PMID- 30457912 TI - Adipose Tissue Transplantation Ameliorates Lipodystrophy-associated Metabolic Disorders in Seipin-deficient Mice. AB - Seipin deficiency is responsible for type 2 congenital generalized lipodystrophy with severe loss of adipose tissue and can lead to hepatic steatosis, insulin resistance (IR) and dyslipidemia in humans. Adipose tissue secretes many adipokines that are central to the regulation of metabolism. In this study, we investigated whether transplantation of normal adipose tissue could ameliorate severe hepatic steatosis, IR and dyslipidemia in lipoatrophic Seipin gene knockout (SKO) mice. Normal adipose tissue from wild-type mice was transplanted into 6-week-old SKO mice. At 4 months after adipose tissue transplantation (AT), the transplanted fat survived with detectable blood vessels, and the reduced levels of plasma leptin, a major adipokine, were dramatically increased. Severe hepatic steatosis, IR and dyslipidemia in SKO mice were ameliorated after AT. In addition, abnormal hepatic lipogenesis and beta-oxidation gene expression in SKO mice were improved after AT. Our results suggest that AT may be an effective treatment to improve lipodystrophy-associated metabolic disorders. PMID- 30457913 TI - Impact of glycosylphosphatidylinositol-specific phospholipase D on hepatic diacylglycerol accumulation,steatosis,and insulin resistance in diet-induced obesity. AB - Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) is an enzyme which specifically cleaves GPI anchors. Previous human studies suggested the relationship of GPI-PLD to insulin resistance, Type 1 and type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD). However, the biological roles of GPI PLD have not been elucidated. Here, we hypothesized that GPI-PLD impacted on lipid and glucose metabolism, especially in liver. GPI-PLD mRNA was most highly expressed in liver, and hepatic mRNA level and circulating concentration of GPI PLD were significantly augmented in diabetic mice. To investigate in vivo functions of GPI-PLD, we generated GPI-PLD knockout (GP-KO) mice. Mice lacking GPI-PLD exhibited the amelioration of glucose intolerance and hepatic steatosis under high-fat and high-sucrose (HF/HS) diet. Furthermore, diacylglycerol (DAG) content was significantly decreased and PKCepsilon activity was suppressed in livers of GP-KO mice. In vitro knockdown and overexpression experiments of GPI PLD using rat primary hepatocytes showed the GPI-PLD-dependent regulation of intracellular DAG content. Finally, serum GPI-PLD levels were strongly and independently associated with serum alanine transaminase (ALT) (R = 0.37, P = 0.0006) and triglyceride (TG) (R = 0.34, P = 0.001) levels in the male subjects with metabolic syndrome. In conclusion, up-regulation of hepatic GPI-PLD in diabetic conditions leads to DAG accumulation in liver by shedding GPI anchors intracellularly, which may play a causal role in impaired hepatic insulin signaling and progression of NAFLD. PMID- 30457914 TI - The effect of PPARgamma inhibition on bone marrow adipose tissue and bone in C3H/HeJ mice. AB - Bone marrow adipose tissue (BMAT) increases after menopause and increased BMAT is associated with osteoporosis and prevalent vertebral fractures. PPARgamma activation promotes adipogenesis and inhibits osteoblastogenesis, therefore PPARgamma is a potential contributor to the postmenopausal increase in BMAT and decrease in bone mass. The aim of this study is to determine if PPARgamma inhibition can prevent ovariectomy induced BMAT increase and bone loss in C3H/HeJ mice. 14-week-old female C3H/HeJ mice (n=40) were allocated to four intervention groups: sham surgery (Sham) or ovariectomy (OVX, isoflurane anesthesia) with either vehicle (Veh) or PPARgamma antagonist administration (GW9662; 1 mg/kg/day, daily intraperitoneal injections) for 3 weeks. We measured BMAT volume, adipocyte size, adipocyte number and bone structural parameters in the proximal metaphysis of the tibia using polyoxometalate-based contrast enhanced-nanoCT. Bone turnover was measured in the contralateral tibia using histomorphometry. The effects of surgery and treatment were analyzed by two-way ANOVA. OVX increased the BMAT volume fraction (Sham+Veh: 2.9+/-2.7% vs OVX+Veh: 8.1+/-5.0%: P < 0.001), average adipocyte diameter (Sham+Veh: 19.3+/-2.6MUm vs OVX+Veh: 23.1+/-3.4MUm: P = 0.001) and adipocyte number (Sham+Veh: 584+/-337cells/MUm3 vs OVX+Veh: 824+/ 113cells/MUm3: p=0.03), while OVX decreased bone volume fraction (Sham+Veh: 15.5+/-2.8% vs OVX+Veh: 7.7+/-1.9%; P < 0.001). GW9662 had no effect on BMAT, bone structural parameters or bone turnover. In conclusion, ovariectomy increased BMAT and decreased bone volume in C3H/HeJ mice. The PPARgamma antagonist GW9662 had no effect on BMAT or bone volume in C3H/HeJ mice, suggesting that BMAT accumulation is regulated independently of PPARgamma in C3H/HeJ mice. PMID- 30457915 TI - Taking Attention out of Context: Frontopolar Transcranial Magnetic Stimulation Abolishes the Formation of New Context Memories in Visual Search. AB - This study investigates the causal contribution of the left frontopolar cortex (FPC) to the processing of violated expectations from learned target-distractor spatial contingencies during visual search. The experiment consisted of two phases: learning and test. Participants searched for targets presented either among repeated or nonrepeated target-distractor configurations. Prior research showed that repeated encounters of identically arranged displays lead to memory about these arrays, which then can come to guide search (=contextual cueing effect). The crucial manipulation was a change of the target location, in a nevertheless constant distractor layout, at the transition from learning to test. In addition to this change, we applied repetitive transcranial magnetic stimulation (rTMS) over the left lateral FPC, over a posterior control site, or no rTMS at all (=baseline; between-group manipulation) to see how FPC rTMS influences the ability of observers to adapt context-based memories acquired in the training phase. The learning phase showed expedited search in repeated relative to nonrepeated displays, with this context-based facilitation being comparable across all experimental groups. For the test phase, the recovery of cueing was critically dependent on the stimulation site: Although there was evidence of context adaptation toward the end of the experiment in the occipital and no-rTMS conditions, observers with FPC rTMS showed no evidence of relearning at all after target location changes. This finding shows that FPC plays an important role in the regulation of prediction errors in statistical context learning, thus contributing to an update of the spatial target-distractor contingencies after target position changes in learned spatial arrays. PMID- 30457916 TI - Disentangling Neural Sources of Problem Size and Interference Effects in Multiplication. AB - Multiplication is thought to be primarily solved via direct retrieval from memory. Two of the main factors known to influence the retrieval of multiplication facts are problem size and interference. Because these factors are often intertwined, we sought to investigate the unique influences of problem size and interference on both performance and neural responses during multiplication fact retrieval in healthy adults. Behavioral results showed that both problem size and interference explained separate unique portions of RT variance, but with significantly stronger contribution from problem size, which contrasts with previous work in children. Whole-brain fMRI results relying on a paradigm that isolated multiplication fact retrieval from response selection showed highly overlapping brain areas parametrically modulated by both problem size and interference in a large network of frontal, parietal, and subcortical brain areas. Subsequent analysis within these regions revealed problem size to be the stronger and more consistent "unique" modulating factor in overlapping regions as well as those that appeared to respond only to problem size or interference at the whole-brain level, thus underscoring the need to look beyond anatomical overlap using arbitrary thresholds. Additional unique contributions of interference (beyond problem size) were identified in right angular gyrus and subcortical regions associated with procedural processing. Together, our results suggest that problem size, relative to interference, tends to be the more dominant factor in driving behavioral and neural responses during multiplication fact retrieval in adults. Nevertheless, unique contributions of both factors demonstrate the importance of considering the overlapping and unique contributions of each in explaining the cognitive and neural bases of mental multiplication. PMID- 30457917 TI - Dissociating Reward- and Attention-driven Biasing of Global Feature-based Selection in Human Visual Cortex. AB - Objects that promise rewards are prioritized for visual selection. The way this prioritization shapes sensory processing in visual cortex, however, is debated. It has been suggested that rewards motivate stronger attentional focusing, resulting in a modulation of sensory selection in early visual cortex. An open question is whether those reward-driven modulations would be independent of similar modulations indexing the selection of attended features that are not associated with reward. Here, we use magnetoencephalography in human observers to investigate whether the modulations indexing global color-based selection in visual cortex are separable for target- and (monetary) reward-defining colors. To assess the underlying global color-based activity modulation, we compare the event-related magnetic field response elicited by a color probe in the unattended hemifield drawn either in the target color, the reward color, both colors, or a neutral task-irrelevant color. To test whether target and reward relevance trigger separable modulations, we manipulate attention demands on target selection while keeping reward-defining experimental parameters constant. Replicating previous observations, we find that reward and target relevance produce almost indistinguishable gain modulations in ventral extratriate cortex contralateral to the unattended color probe. Importantly, increasing attention demands on target discrimination increases the response to the target-defining color, whereas the response to the rewarded color remains largely unchanged. These observations indicate that, although task relevance and reward influence the very same feature-selective area in extrastriate visual cortex, the associated modulations are largely independent. PMID- 30457918 TI - Visual Simultaneity Judgments Activate a Bilateral Frontoparietal Timing System. AB - In everyday life, we often make judgments regarding the sequence of events, for example, deciding whether a baseball runner's foot hit the plate before or after the ball hit the glove. Numerous studies have examined the functional correlates of temporal processing using variations of the temporal order judgment and simultaneity judgment (SJ) tasks. To perform temporal order judgment tasks, observers must bind temporal information with identity and/or spatial information relevant to the task itself. SJs, on the other hand, require observers to detect stimulus asynchrony but not the order of stimulus presentation and represent a purer measure of temporal processing. Some previous studies suggest that these temporal decisions rely primarily on right-hemisphere parietal structures, whereas others provide evidence that temporal perception depends on bilateral TPJ or inferior frontal regions (inferior frontal gyrus). Here, we report brain activity elicited by a visual SJ task. Our methods are unique given our use of two orthogonal control conditions, discrimination of spatial orientation and color, which were used to control for brain activation associated with the classic dorsal ("where/how") and ventral ("what") visual pathways. Our neuroimaging experiment shows that performing the SJ task selectively activated a bilateral network in the parietal (TPJ) and frontal (inferior frontal gyrus) cortices. We argue that SJ tasks are a purer measure of temporal perception because they do not require observers to process either identity or spatial information, both of which may activate separate cognitive networks. PMID- 30457919 TI - Correction to: Functional Connectivity in Adult Brain Tumor Patients: A Systematic Review, by Fox ME and King TZ. Brain Connect 2018;8(7):381-397. DOI: 10.1089/brain.2018.0623. PMID- 30457920 TI - Effect of Pregabalin on Radiotherapy-Related Neuropathic Pain in Patients With Head and Neck Cancer: A Randomized Controlled Trial. AB - PURPOSE: Neuropathic pain is an unavoidable treatment-related adverse event among patients with head and neck cancer who are undergoing radiotherapy. We aimed to test the efficacy and safety of pregabalin versus placebo in the treatment of radiotherapy-related neuropathic pain. PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled trial was conducted in four centers in China. Eligible patients with a mean pain intensity score of 4 or more on an 11-point numeric rating scale were randomly assigned to receive either active treatment with a flexible dose of pregabalin or placebo for 16 weeks. The primary efficacy outcome was pain reduction measured on the numeric rating scale. RESULT: There were 128 patients who received treatment as randomly assigned. Pain intensity reduction was 2.44 in the pregabalin arm and 1.58 in the placebo arm at week 16, yielding an adjusted mean difference of 0.87 (95% CI, 0.30 to 1.44; P = .003). In the pregabalin arm, 38 patients (59.4%) achieved at least 30% pain relief versus 21 (32.8%) in the placebo arm ( P = .006). Nineteen patients (29.7%) in the pregabalin group and five (7.8%) in the placebo group achieved 50% or greater pain relief ( P = .003). Total scores on the Profile of Mood States-Short Form, pain severity and functional interference of Brief Pain Inventory-Short Form, as well as the physiology and psychology domain of the WHO Quality of Life-BREF all were reduced significantly at week 16 in patients who received pregabalin compared with those who received placebo. There was no significant difference ( P = .29) in the incidence of experiencing at least one adverse event in the pregabalin arm (n = 35; 54.7%) versus the placebo arm (n = 29; 45.3%). CONCLUSION: Patients treated with pregabalin with radiotherapy-related neuropathic pain had greater pain alleviation, better mood states, and higher quality of life compared with patients in the placebo group, with a good tolerability. PMID- 30457921 TI - Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion. AB - PURPOSE: An ASCO provisional clinical opinion (PCO) offers timely clinical direction to ASCO's membership and other health care providers. This PCO addresses identification and management of patients and family members with possible predisposition to pancreatic adenocarcinoma. METHODS: ASCO convened an Expert Panel and conducted a systematic review of the literature published from January 1998 to June 2018. Results of the databases searched were supplemented with hand searching of the bibliographies of systematic reviews and selected seminal articles and contributions from Expert Panel members' curated files. PROVISIONAL CLINICAL OPINION: All patients diagnosed with pancreatic adenocarcinoma should undergo assessment of risk for hereditary syndromes known to be associated with an increased risk for pancreatic adenocarcinoma. Assessment of risk should include a comprehensive review of family history of cancer. Individuals with a family history of pancreatic cancer affecting two first-degree relatives meet criteria for familial pancreatic cancer (FPC). Individuals (cancer affected or unaffected) with a family history of pancreatic cancer meeting criteria for FPC, those with three or more diagnoses of pancreatic cancer in same side of the family, and individuals meeting criteria for other genetic syndromes associated with increased risk for pancreatic cancer have an increased risk for pancreatic cancer and are candidates for genetic testing. Germline genetic testing for cancer susceptibility may be discussed with individuals diagnosed with pancreatic cancer, even if family history is unremarkable. Benefits and limitations of pancreatic cancer screening should be discussed with individuals whose family history meets criteria for FPC and/or genetic susceptibility to pancreatic cancer. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines . PMID- 30457922 TI - Role of Stress and Psychosocial Determinants on Women's Cardiovascular Risk and Disease Development. AB - The notion that cardiovascular disease (CVD) primarily occurs in men is slowly disappearing. More women than men die of CVD every year, and when women survive, the burden and consequences are worse than in men. Markers of stress and other psychosocial factors have been associated with poor outcomes. Multiple studies have demonstrated sex-based differences in the vascular and endothelial responses to mental stress. Psychosocial stressors were also found to be independent risk factors for the development and progression of CVD. This review arises from accumulating evidence suggesting that psychological well-being may improve cardiac-related outcomes, independent of cardiac risk factors. Despite the fact that positive physician-patient engagement is likely to play a critical role in promoting positive psychological traits and healthy behaviors, current physician awareness and advocacy are rather suboptimal, despite active awareness campaigns such as the American Heart Association's Go Red for Women(r). There is a need to further study the role and management of stress as a CVD risk factor, especially in women, who are disproportionately affected. PMID- 30457923 TI - Artificial MicroRNA-Mediated Inhibition of Japanese Encephalitis Virus Replication in Neuronal Cells. AB - Artificial microRNA (amiRNA)-mediated inhibition of viral replication has recently gained importance as a strategy for antiviral therapy. In this study, we evaluated the benefit of using the amiRNA vector against Japanese encephalitis virus (JEV). We designed three single amiRNA sequences against the consensus sequence of 3' untranslated region (3'UTR) of JEV and tested their efficacy against cell culture-grown JEV Vellore strain (P20778) in neuronal cells. The binding ability of three amiRNAs on 3'UTR region was tested in vitro in HEK293T cells using a JEV 3'UTR tagged with luciferase reporter vector. Transient transfection of amiRNAs was nontoxic to cells as evident from the MTT assay and caused minimal induction in interferon-stimulated gene expression. Furthermore, our result suggested that transient expression of two amiRNAs (amiRNA #1 and amiRNA #2) significantly reduced intracellular viral RNA and nonstructural 1 (NS1) protein, as well as diminished infectious viral particle release up to 95% in the culture supernatant as evident from viral plaque reduction assay. Overall, our results indicated that RNA interference based on amiRNAs targeting viral conserved regions at 3'UTR was a useful approach for improvements of nucleic acid inhibitors against JEV. PMID- 30457924 TI - A Comparison of Various Cervical Muscle Strength Testing Methods Using a Handheld Dynamometer. AB - BACKGROUND:: Cervical muscle strength, proposed as a modifiable risk factor in concussions, can be assessed using various methods. The purpose of this study was to compare the reliability and force outputs of 3 methods that use handheld dynamometry (HHD) for assessing cervical muscle strength. HYPOTHESIS:: All 3 testing methods are reliable, and force outputs are significantly different between methods. STUDY DESIGN:: Repeated-measures reliability. LEVEL OF EVIDENCE:: Level 5. METHODS:: The study used a convenience sample of 30 participants. HHD "make tests" for cervical extension, flexion, and right and left side bending were performed using lying push tests, sitting push tests, and sitting pull tests. A sole examiner performed all tests. Two testing sessions were conducted 1 week apart. Analysis included intraclass correlation coefficients (ICCs), repeated-measures analyses of variance (alpha = 0.05) with post hoc Bonferroni tests, and minimal detectable change (MDC) calculations. RESULTS:: All testing methods were reliable; the lying push test had the greatest point estimate values (ICC, 0.89-0.95). Significant differences in force were found between the 3 testing methods. The MDC was most sensitive for the lying push method. CONCLUSION:: Of the 3 cervical muscle testing methods investigated, the lying position with a push test had the largest ICC according to the point estimate and the most sensitive MDC. Force values between the 3 methods were significantly different, which suggests that consistent testing methods should be used. CLINICAL RELEVANCE:: Results from this study support the clinical use of an HHD "make test" in a lying position for assessing cervical muscle strength. The test is reliable and more sensitive to change compared with tests in a seated position. PMID- 30457925 TI - Anti-Bovine Podoplanin Monoclonal Antibody PMab-44 Detects Goat Podoplanin in Immunohistochemistry. AB - Podoplanin (PDPN) is expressed in type I alveolar cells, kidney podocytes, and lymphatic endothelial cells. We have characterized the PDPNs of various animal species using specific anti-PDPN monoclonal antibodies (mAbs). In this study, we investigated whether these anti-PDPN mAbs cross-react with goat PDPN (gPDPN). Flow cytometry demonstrated that the anti-bovine PDPN mAb PMab-44 (IgG1, kappa) reacts with gPDPN, which is overexpressed in CHO-K1 cells. Using immunohistochemical analysis, type I alveolar cells of goat lung were strongly detected by PMab-44. These results indicate that PMab-44 is useful for investigating gPDPN. PMID- 30457926 TI - Patterns of Fluoroquinolone Resistance in Enterobacteriaceae Isolated from the Assiut University Hospitals, Egypt: A Comparative Study. AB - BACKGROUND: An increasing pattern of fluoroquinolone resistance (FQR) among bacterial pathogens has been described worldwide. In this study, we compared the patterns of genetic mechanisms that confer FQR for Escherichia coli and Klebsiella pneumoniae isolated from the Assiut University Hospitals in Egypt. METHODS: Eighty-seven clinical E. coli and K. pneumoniae isolates were tested for mutations in gyrA, gyrB, parC, and parE genes by polymerase chain reaction (PCR) amplification and DNA sequencing. The presence of plasmid-mediated quinolone resistance (PMQR) genes qnrA, qnrB, qnrS, aac(6')-Ib, qepA was screened by PCR and characterized by conjugation. Correlations between different FQR mechanisms and ciprofloxacin minimal inhibitory concentration (MIC) levels were determined. RESULTS: A higher number of quinolone resistance-determining region (QRDR) mutations was detected in E. coli, while the number of PMQR determinants was significantly higher in K. pneumoniae. However, K. pneumoniae showed stronger correlations than E. coli between MIC levels and number of mutations in the QRDR per isolate (rs = 0.8, p < 0.0001 and rs = 0.7, p < 0.0001, respectively) as well as between MIC levels and number of plasmids (rs = 0.4, p = 0.005 and rs = 0.3, p = 0.02, respectively). CONCLUSIONS: Although we observed a prevalence of chromosomal mutations for E. coli and the presence of plasmid-encoded genes for K. pneumoniae that resulted in FQR phenotype, high levels of FQR appeared to occur as a result of gradual accumulation of mutations in QRDR for both bacteria. To our best of knowledge, this is the first study to report and compare the correlation between FQ MIC levels and different genetic mechanisms for FQR in Enterobacteriaceae. PMID- 30457927 TI - Comparison of three methods for cell surface proteome extraction of Listeria monocytogenes biofilms. AB - The cell surface proteome of the foodborne pathogen Listeria monocytogenes, the etiological agent of listeriosis, is critical for understanding the physiological processes associated with stress resistance and persistence in the environment. In this context, the most widespread mode of growth for bacterial cells in natural and industrial environments is in biofilms. Cell surface proteins are, however, challenging to characterize because of their low abundance and poor solubility. Moreover, cell surface protein extracts are usually contaminated with cytoplasmic proteins that constitute the main signal in proteomic analysis. This study aimed to compare the efficiency of three methods to extract and explore surface proteins of L. monocytogenes growing in a biofilm: trypsin shaving, biotinylation, and cell fractionation. Peptide separation and identification were performed by shotgun proteomics using high-performance liquid chromatography combined with tandem mass spectrometry (LC-MS/MS). The biotinylation method was the most effective in extracting surface proteins, with the lowest rate of contamination by cytoplasmic proteins. Although presenting a higher contamination rate in cytoplasmic proteins, the other two techniques allowed the identification of additional surface proteins. Seven proteins were commonly retrieved by the three methods. The extracted proteins belong to several functional classes, involved in virulence, transport, or metabolic pathways. Finally, the three extraction methods seemed complementary and their combined use improved the exploration of the bacterial surface proteome. These new findings collectively inform future discovery and translational proteomics for clinical, environmental health, and industrial applications. PMID- 30457928 TI - Characterization of Resistance Genes and Polymerase Chain Reaction-Based Replicon Typing in Carbapenem-Resistant Klebsiella pneumoniae. AB - BACKGROUND: Fifty isolates of Klebsiella pneumoniae isolated from clinical samples between 2012 and 2016 that were found to be resistant to carbapenems were included in this study. MATERIALS AND METHODS: Resistance genes were investigated by performing PCR. Plasmid typing was performed using PCR-based replicon typing. The clonal relationships between the strains were investigated using pulsed-field gel electrophoresis (PFGE). RESULTS: OXA-48-type carbapenemase genes were detected in 86% (n = 43/50) of K. pneumoniae isolates, whereas NDM-type carbapenemase genes were detected in 14% (n = 7/50) of the isolates. blaTEM was detected 60% (n = 30) of the strains, blaSHV in 78% (n = 39), blaCTX-M-1 in 48% (n = 24), and blaCTX-M-2-type beta-lactamase in 10% (n = 5). blaCTX-M-1 and blaSHV were concomitantly distributed in 40% (n = 20) of the strains, blaTEM and blaSHV in 54% (n = 27), blaTEM, blaSHV, and blaCTX-M-1 in 32% (n = 16) and blaCTX M-1 and blaCTX-M-2 in 10% (n = 5). Strain numbers 66, 69, 76, 77, and 78 coproduced carbapenemases, blaCTX-M-1 and blaCTX-M-2 in addition to blaOXA-48 or blaNDM-1 that were described as hybrid strains. IncR-type replicon was found in 50% (n = 25) of 50 isolates with plasmid typing, whereas IncA/C-type replicon was detected in 40% (n = 20) and IncFIIK-type replicon in 18% (n = 9) of the isolates. Outcomes of the transformation experiments showed that the OXA-48 gene was carried to the receiver cell on FII plasmids. No dominant epidemic clone was detected through PFGE. CONCLUSION: OXA-48 carbapenemase was found to be the most prevalent type of enzyme in our hospital, and the presence of NDM-1-type carbapenemase-carrying strain and an increase in their rate were detected. PMID- 30457929 TI - Matryoshka-Inspired Micro-Origami Capsules to Enhance Loading, Encapsulation, and Transport of Drugs. AB - Stimuli-responsive hydrogels are promising candidates for use in the targeted delivery of drugs using microrobotics. These devices enable the delivery and sustained release of quantities of drugs several times greater than their dry weight and are responsive to external stimuli. However, existing systems have two major drawbacks: (1) severe drug leakage before reaching the targeted areas within the body and (2) impeded locomotion through liquids due to the inherent hydrophilicity of hydrogels. This article outlines an approach to the assembly of hydrogel-based microcapsules in which one device is assembled within another to prevent drug leakage during transport. Inspired by the famous Russian stacking dolls (Matryoshka), the proposed scheme not only improves drug-loading efficiency but also facilitates the movement of hydrogel-based microcapsules driven by an external magnetic field. At room temperature, drug leakage from the hydrogel matrix is 90%. However, at body temperature the device folds up and assembles to encapsulate the drug, thereby reducing leakage to a mere 6%. The Matryoshka inspired micro-origami capsule (MIMC) can disassemble autonomously when it arrives at a targeted site, where the temperature is slightly above body temperature. Up to 30% of the encapsulated drug was shown to diffuse from the hydrogel matrix within 1 h when it unfolds and disassembles. The MIMC is also shown to enhance the movement of magnetically driven microcapsules while navigating through media with a low Reynolds number. The translational velocity of the proposed MIMC (four hydrogel-based microcapsules) driven by magnetic gradients is more than three times greater than that of a conventional (single) hydrogel-based microcapsule. PMID- 30457930 TI - Hand Exo-Muscular System for Assisting Astronauts During Extravehicular Activities. AB - Human exploration of the Solar System is one of the most challenging objectives included in the space programs of the most important space agencies in the world. Since the Apollo program, and especially with the construction and operation of the International Space Station, extravehicular activities (EVA) have become an important part of space exploration. This article presents a soft hand exoskeleton designed to address one of the problems that astronauts face during spacewalks: hand fatigue caused by the pressurized EVA gloves. This device will reduce the stiffness of the spacesuit glove by counteracting the force exerted by the pressurized glove. To this end, the system makes use of a set of six flexible actuators, which use a shape memory alloy (SMA) wire as the actuating element. SMAs have been chosen because some of their features, such as low volume and high force-to-weight ratio, make them a suitable choice taking into account the constraints imposed by the use of the device in a spacesuit. Besides describing the different mechanical and electronic subsystems that compose the exoskeleton, this article presents a preliminary assessment of the device; several tests to characterize its nominal operation have been carried out, as well as position and force control tests to study its controllability and evaluate its suitability as a force assistive device. PMID- 30457931 TI - Cardiovascular Health of Mothers in the United States: National Health and Nutrition Examination Survey 2007-2014. AB - BACKGROUND: Pregnancy and childrearing can impact women's health and alter chronic disease trajectories in later life, including cardiovascular disease. The purpose of this study was to assess measures of women's cardiovascular health by time since last live birth. METHODS: Data were from 4,021 nonpregnant U.S. women, 20-44 years of age, participating in the 2007-2014 National Health and Nutrition Examination Survey (NHANES). Cardiovascular health was assessed using physical measures, laboratory measures, self-reported behaviors, medical conditions, and selected psychosocial factors by time since last live birth. RESULTS: Women reported their last live birth within the past 12 months ("mothers of infants"; 7.4%), >12 months, but <3 years ago ("mothers of toddlers"; 10.0%), or >=3 years ago ("mothers of older children"; 45.2%); 37.3% were nulliparous. Compared with nulliparous women, mothers of older children had a higher prevalence of selected cardiovascular risk factors, including unhealthy diet (75.6% vs. 68.8%) and smoking (28.1% vs. 21.9%), after adjustment for sociodemographics (including age). Mothers of toddlers had a higher prevalence of unhealthy diet (78.0% vs. 68.8%). Mothers also had poorer metabolic health as indicated by a higher prevalence of low HDL cholesterol among mothers of toddlers and older children (44.2% and 40.4%, respectively, vs. 33.6%), and a higher prevalence of high waist circumference among mothers of infants (65.6% vs. 53.8%). Some mothers also had a higher prevalence of other cardiovascular risk factors, including low physical activity and poor sleep. CONCLUSION: Prior pregnancy and childrearing may be associated with selected cardiovascular risk factors among nonpregnant reproductive-aged U.S. women. PMID- 30457932 TI - Magnetic Resonance Spectroscopy Thermometry at 3 Tesla: Importance of Calibration Measurements. AB - To demonstrate the importance of calibration measurements in 3 Tesla proton magnetic resonance (MR) spectroscopy (1H-MRS) thermometry for human brain temperature estimation for routine clinical applications. In vitro proton MR spectroscopy to obtain calibration constants of the water-chemical shift was conducted at 3 Tesla with a temperature-controlled phantom, containing a pH buffered aqueous solution of N-acetyl aspartate (NAA), creatine (Cr), methylene protons of Cr (Cr2), dimethyl silapentane sulfonic acid (DSS), and sodium formate (NaFor). Estimations of absolute human brain temperature were performed utilizing the correlation of temperature to the water-chemical shift for the resonances of NAA, Cr, and Cr2. Data for calibration of the metabolites' chemical shift differences and in vivo temperature estimations were acquired with single-voxel point-resolved spectroscopy (PRESS) sequences (repetition time/echo time = 2000/30 ms; voxel size 2 * 2 * 2 cm3). Spectroscopy data were quantified in the time-domain, and a Pearson correlation analysis was performed to estimate the correlation between the chemical shift of metabolites and measured temperatures. The correlation coefficients (r) of our calibration measurements were NAA 0.9975 (+/-0.0609), Cr -0.9979 (+/-0.0621), Cr2 - 0.9973 (+/-0.0577), DSS -0.9976 (+/ 0.0615), and NaFor -0.8132 (+/-2.348). The mean calculated brain temperature was 37.78 +/- 1.447 degrees C, and the mean tympanic temperature was 36.83 +/- 0.2456 degrees C. Calculated temperatures derived from Cr and Cr2 provided significant (p = 0.0241 and p = 0.0210, respectively) correlations with measured temperatures (r = 0.4108 and r = -0.4194, respectively). Calibration measurements are vital for 1H-MRS thermometry. Small numeric differences in measured signal and data preprocessing without any calibration measurements reduce accuracy of temperature calculations, which indicates that calculated temperatures should be interpreted with caution. Application of this method for clinical purposes warrants further investigation and a more practical approach. PMID- 30457933 TI - Resource-Effective Serosurveillance for the Detection of West Nile Virus in Switzerland Using Abattoir Samples of Free-Range Laying Hens. AB - West Nile virus (WNV) is an important zoonotic pathogen maintained in a natural transmission cycle between mosquitoes and birds as reservoir hosts. In dead-end hosts, such as humans, infection may result in fatal neurologic disease translating into disease and death-related suffering and increased health care costs. In humans, WNV may also be transmitted through blood transfusions and organ transplants. WNV is not present in Switzerland yet, but competent vector species (especially Culex pipiens and Aedes japonicus) are prevalent and an introduction of the virus, likely through wild birds, is expected at any time. Therefore, it is important for Switzerland to be prepared and establish a surveillance system for WNV to initiate increased prevention activities, such as the screening of blood and organ donations and public education activities in case virus circulation is detected. The long-term goal of these surveillance measures would be a reduced infection rate in humans resulting in less suffering and reduced health care costs. To provide the basis for a pragmatic and resource effective WNV surveillance program, this study used aliquots of serum samples of free-range laying hens taken at the abattoir and collected in the frame of the ongoing Swiss Avian Influenza and Newcastle Disease monitoring program for a 2 year period. All 961 aliquots were analyzed using a commercial competitive WNV enzyme-linked immunosorbent assay (ELISA). The study allowed to set up sampling and laboratory routines as a basis for future WNV surveillance activities. At this stage there is no evidence for circulation of WNV in Switzerland. PMID- 30457934 TI - Impact of early telephone contact on 3-month follow-up rates following residential drug and alcohol treatment: A randomized controlled trial. AB - BACKGROUND: Routine outcome monitoring (ROM) is an important component of service provision and qualitity assurance procedures. However, a major logistical and financial challenge for organizations is successfully following up participants once they have left residential alcohol and other drug treatment. The aim of the current study was to assess the impact and effectiveness of an "early" follow-up contact and brief interview on subsequent 3-month ROM follow-up success. METHODS: Participants were 800 clients attending specialist residential alcohol and other drug treatment provided by The Salvation Army. As part of routine outcome assessment procedures, all people attending these programs are asked to complete a 3-month follow-up assessment. Participants were randomly allocated either to the early contact condition (i.e., "early" 2-week follow-up contact prior to the 3-month follow-up assessment) or to the control condition (i.e., no "early" 2 week follow-up prior to the 3-month follow-up assessment). The primary outcomes were the proportion of participants who were followed up and surveyed at 3 months. RESULTS: There were significantly higher follow-up rates at 3 months post discharge for participants in the early contact group (55.6%) compared with the control condition (46.1%). Although there were higher rates of 3-month follow-up for participants in the early contact group, rates of successful survey completion were not significantly different between the 2 groups. CONCLUSIONS: Including an early 2-week telephone call prior to the 3-month assessment increased the number of participants we were able to follow up at 3 months post discharge but did not improve the rate of survey participation at 3 months. The additional costs associated with this activity and the modest increase in follow up rates need to be considered prior to organizations investing in these follow up enhancement activities. PMID- 30457935 TI - Vector-Borne Zoonotic Pathogens in Eurasian Moose (Alces alces alces). AB - Climate change, with warmer temperatures and altered precipitation patterns, has affected the distribution of vectors and vector-borne diseases. In the northern hemisphere, vectors are spreading north, and with them, pathogens of zoonotic and animal health impact. Eurasian moose (Alces alces alces) are physiologically and anatomically adapted for cold climate, and are rarely considered ideal hosts of vectors, apart from deer keds (Lipoptena cervi). To investigate the presence of vector-borne pathogens, spleen samples from 615 moose were collected in southern Sweden from 2008 to 2015. The samples were analyzed with a high-throughput PCR method for 24 bacterial, and 12 parasitic pathogens. Anaplasma (82%), Borrelia (3%), Babesia (3%), and Bartonella (1%) DNA was found, showing that moose are exposed to, and can act as hosts of some of these pathogens, which can have an impact of both animal and human health. These results show that Swedish moose are exposed to pathogens that in some instances are more commonly found in regions with warmer climate, and highlights the importance of also considering moose as sentinels of vector-borne pathogens. Further research is needed to understand the effect of these pathogens on the health of individual moose and to elucidate whether climate change and moose population density interact to create the pattern observed. PMID- 30457936 TI - Did Performing Community Health Needs Assessments Increase Community Health Program Spending by North Carolina's Tax-Exempt Hospitals? AB - As of March 23, 2012, the Internal Revenue Service (IRS) requires tax-exempt hospitals to conduct a Community Health Needs Assessment (CHNA) every 3 years. This study assessed whether the IRS CHNA mandate incentivized North Carolina's tax-exempt hospitals to increase investments in community health programs. The authors gathered the 2012-2016 community benefit reports of 53 North Carolina private, nonprofit hospitals from the North Carolina Hospital Association. Community benefit spending data from the year of the first CHNA were compared to that 2 years later using paired t tests among matched subjects. No significant increases were found in hospitals' community health programs spending (P = 0.6920) or in providing patient care financial assistance (charity or discounted care) (P = 0.0934). In fact, aggregate community health programs spending effectively decreased by 4%, from $393.3 million to $377.5 million. Among all community benefit items, only the unreimbursed cost for treating Medicare patients increased significantly (P = 0.0297). The proportion of spending on community health programs relative to patient care financial assistance decreased significantly (P = 0.0338). Performing CHNAs did not incentivize North Carolina's tax-exempt hospitals to progressively invest in community health programs. The hospitals continue to spend heavily on patient care financial assistance and little on disease prevention and community health improvement activities. These findings suggest that tax-exempt hospitals continue to function as a safety net for the poor and the uninsured rather than as active partners in population health management initiatives. At present, performing CHNAs may be more a demonstration of compliance than a tool to improve population health. PMID- 30457938 TI - Therapeutic Hypothermia. PMID- 30457937 TI - Pulp wash: a new source for production of ligninolytic enzymes and biomass and its toxicological evaluation after biological treatment. AB - Pulp wash was used as substrate for the activity of ligninolytic enzymes of the fungus Pleurotus sajor-caju. Activity of laccase (Lac) and manganese peroxidase (MnP) as well as fungal biomass occurred under four conditions: different pulp wash concentrations, pH variation at the optimal pulp wash concentration, different glucose concentrations, and different concentrations of ammonium nitrate. The best enzyme activity and biomass production were obtained with in natura pulp wash and pH corrected to 5.0 (4884 IU/L Lac; 82 IU/L MnP; 25 g/100 mL biomass). However, the addition of glucose and ammonium nitrate to the pulp wash was not necessary for increasing the enzyme activity and biomass production. Efficient removal of pulp wash chemical oxygen demand (99.66%) and biochemical oxygen demand (83.27%) occurred after the mycoremediation with P. sajor-caju in the optimized conditions. Lactuca sativa L. seeds germination bioassay showed a four-fold reduction in the residue toxicity (EC50 28.72%) after the treatment with the fungus. Our findings are consistent with the notion that pulp wash is an excellent substrate for inducing the activity of ligninolytic enzymes and producing fungal biomass, and that the biological treatment is efficient to reduce effluent toxicity. PMID- 30457939 TI - 3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) use and transitions to injection drug use among street-involved youth. AB - BACKGROUND: Despite the popularity of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) among young people across North America and Europe, MDMA is rarely explored in studies of young people at high risk of injecting drugs. We conducted a study among street-involved youth who use illicit drugs in Vancouver, Canada, to understand if use of MDMA is associated with initiation of injection drugs. METHODS: We followed injection-naive participants in the At-Risk Youth Study (ARYS), an ongoing prospective cohort of street-involved youth aged 14-26 who use illicit drugs. Bivariate and multivariate extended Cox models with time-updated variables were used to examine the association between MDMA use and initiation of injection drug use between September 2005 and May 2015. RESULTS: Among 483 youth, 306 (63.4%) had a history of MDMA use and 218 (45.1%) had used MDMA in the previous 6 months at baseline. A total of 105 (21.7%) youth initiated injection drug use over the 10-year period, yielding an incidence density of 8.51 (95% confidence interval [CI]: 6.96-10.30) per 100 person-years. MDMA use was not significantly associated with initiating injection drugs at the bivariate (hazard ratio: 0.93, 95% CI: 0.61-1.42) or multivariate (adjusted hazard ratio: 0.88, 95% CI: 0.57-1.35) level, after adjusting for socio-demographic and substance use confounders. CONCLUSIONS: Amid ongoing frequent use of MDMA among some young people in North America, we did not observe an elevated risk of injection initiation among those who used MDMA in this cohort of street-involved youth. PMID- 30457940 TI - Karyotypic Divergence of Two Co-Occurring Species of Andean Climbing Catfishes (Siluriformes: Loricarioidei: Astroblepidae). AB - The monotypic Astroblepidae fish family includes 81 species distributed along Central and Northern Andes in South America and Panama in Central America; most aspects regarding its biology, taxonomy, and chromosomal features remain largely unknown. This study reports the karyotype of two sympatric Astroblepus species from the Colombian Andes, aiming to provide novel information on karyotype organization and reveal possible chromosomal rearrangements occurred on these species, through mapping of different repetitive DNA classes, including microsatellites and ribosomal DNA multigene families. The results showed differences in the chromosome number and karyotypic formula: Astroblepus grixalvii had 2n = 52 (28m+8sm +12st +4a) with the metacentric pair number 1 as the largest chromosome pair, whereas Astroblepus homodon had 2n = 54 (30m+8sm +8st +8a) and less evident chromosome size differences. Microsatellite probes marked the tips of all chromosomes in both species except the short arms of acrocentric pair numbers 24 and 25 in A. homodon. Each ribosomal probe marked different chromosome pairs in both species. Microsatellite patterns suggest that the 2n increase probably involved a centric fission event that occurred during the evolutionary history of these species. This is the first karyotype description of an Astroblepus species and it contributes to the theoretical framework about the karyoevolutionary trends within Loricarioidei. PMID- 30457941 TI - Phylogeography and Historical Biogeography of the Astyanax bimaculatus Species Complex (Teleostei: Characidae) in Coastal Southeastern South America. AB - Astyanax bimaculatus, a ubiquitous species in many Neotropical basins, is characterized by a complex taxonomy and are currently considered a species complex. The goal of this study was to analyze 31 populations (N = 136) of this species from southeastern Brazil using cytogenetic techniques: conventional staining, nucleolar organizer region (Ag-NOR), C-banding, and 18S and 5S recombinant DNA fluorescent in situ hybridization (FISH) probes; and molecular techniques: S72, RAG2, and COI. All populations were 2n = 50 (6m + 20sm +18st +6a); Ag-NORs were predominantly simple, C-banding revealed high variation levels within and among basins, and the FISH probes 18S and 5S were restricted to chromosome pairs 14 and 7, respectively. The S72 was uninformative for phylogenetic analyses, and RAG2 showed no variation among populations. The COI gene revealed three haplogroups. The most basal was composed of Pandeiros population (Sao Francisco Basin) that diverged in the Middle Miocene. The second was composed of A. altiparanae from the Upper Parana Basin and Espirito Santo Stream (Paraiba do Sul Basin), whereas the third was composed of Astyanax lacustris from Sao Francisco and coastal basins. The second and third haplogroups diverged in the Pleistocene, indicating that diversification of the bimaculatus complex was driven by tectonic activity and sea-level fluctuations. PMID- 30457942 TI - Zebrafish as a Model to Screen the Potential of Fatty Acids in Reproduction. AB - Sperm quality is an important topic in general health, chemotherapy, and gamete preservation technology. Fatty acid (FA) composition of membranes, which is influenced by the diet, plays key roles in sperm biology and quality. Dietary supplementation with natural products can be used as a technique to screen potential agents to protect, modify, and recover sperm quality. In this study, zebrafish (male [?-ZF] and female [?-ZF]) were fed a single cultivar olive oil (OO) bioencapsulated in Artemia. OO-treated ?-ZF had higher (p < 0.05) sperm density and motility compared to the Artemia nauplii (AN). A significant difference was also observed in follicle abundance at different stages of gametogenesis, and a nonsignificant increase in total fecundity between OO treated ?-ZF and the AN, although in OO-treated ?-ZF, mature follicles had a smaller diameter. A higher fertility rate (FR) was observed in OO-treated pairs compared to the other groups. Hatching in the OO-treated fish was accelerated, although no significant differences could be found in terms of hatching rate (HR) and embryo/larval survival rate (SR). These findings in FR, HR, and SR were also confirmed in male and female replacement mating trials. Taken together, this study shows that altering the FA ratios in the diet has a clear impact on several reproductive parameters in the zebrafish, adding new information about the nutritional requirement of this model species. PMID- 30457943 TI - 2018 Reviewer Recognition. PMID- 30457944 TI - Faculty Posting. PMID- 30457946 TI - Cuspal Flexure and Stress in Restored Teeth Caused by Amalgam Expansion. AB - OBJECTIVE:: Cracks in amalgam-filled teeth may be related to amalgam expansion. This study measured cuspal flexure and used finite element analysis to assess associated stress levels in amalgam-filled teeth. METHODS AND MATERIALS:: External surfaces of 18 extracted molars were scanned in three dimensions. Nine molars were restored with mesio-occluso-distal amalgam fillings; the other teeth were left intact as controls. All teeth were stored in saline and scanned after two, four, and eight weeks. Cuspal flexure and restoration expansion were determined by calculating the difference between scanned surfaces. Stresses in a flexed tooth were calculated using finite element analysis. RESULTS:: Cusps of amalgam-filled teeth flexed outward approximately 3 MUm, and restoration surfaces expanded 4 to 8 MUm during storage. Cuspal flexure was significantly higher in the amalgam group (multivariate tests, p<0.05), but storage time had no significant effect (repeated measures, p>0.05). Expansion caused stress concentrations at the cavity line angles. These stress concentrations increased stresses due to mastication 44% to 178%. CONCLUSIONS:: Amalgam expansion pushed cavity walls outward, which created stress concentrations at the cavity line angles. Expansion stresses can raise stresses in amalgam-filled teeth and contribute to incidentally observed cracks. PMID- 30457947 TI - Benefits of Nonthermal Atmospheric Plasma Treatment on Dentin Adhesion. AB - OBJECTIVES:: This study aimed to evaluate the influence of two nonthermal atmospheric plasma (NTAP) application times and two storage times on the microtensile bond strength (MUTBS) to dentin. The influence of NTAP on the mechanical properties of the dentin-resin interface was studied by analyzing nanohardness (NH) and Young's modulus (YM). Water contact angles of pretreated dentin and hydroxyapatite blocks were also measured to assess possible alterations in the surface hydrophilicity upon NTAP. METHODS AND MATERIALS:: Forty-eight human molars were used in a split-tooth design (n=8). Midcoronal exposed dentin was flattened by a 600-grit SiC paper. One-half of each dentin surface received phosphoric acid conditioning, while the other half was covered with a metallic barrier and remained unetched. Afterward, NTAP was applied on the entire dentin surface (etched or not) for 10 or 30 seconds. The control groups did not receive NTAP treatment. Scotchbond Universal (SBU; 3M ESPE) and a resin based composite were applied to dentin following the manufacturer's instructions. After 24 hours of water storage at 37 degrees C, the specimens were sectioned perpendicular to the interface to obtain approximately six specimens or bonded beams (approximately 0.9 mm2 in cross-sectional area) representing the etch-and rinse (ER) approach and another six specimens representing the self-etch (SE) approach. Half of the MUTBS specimens were immediately loaded until failure, while the other half were first stored in deionized water for two years. Three other bonded teeth were selected from each group (n=3) for NH and YM evaluation. Water contact-angle analysis was conducted using a CAM200 (KSV Nima) goniometer. Droplet images of dentin and hydroxyapatite surfaces with or without 10 or 30 seconds of plasma treatment were captured at different water-deposition times (5 to 55 seconds). RESULTS:: Two-way analysis of variance revealed significant differences in MUTBS of SBU to dentin after two years of water storage in the SE approach, without differences among treatments. After two years of water aging, the ER control and ER NTAP 10-second groups showed lower MUTBS means compared with the ER NTAP 30-second treated group. Nonthermal atmospheric plasma resulted in higher NH and YM for the hybrid layer. The influence of plasma treatment in hydrophilicity was more evident in the hydroxyapatite samples. Dentin hydrophilicity increased slightly after 10 seconds of NTAP, but the difference was higher when the plasma was used for 30 seconds. CONCLUSIONS:: Dentin NTAP treatment for 30 seconds contributed to higher MUTBS after two years of water storage in the ER approach, while no difference was observed among treatments in the SE evaluation. This result might be correlated to the increase in nanohardness and Young's modulus of the hybrid layer and to better adhesive infiltration, since dentin hydrophilicity was also improved. Although some effects were observed using NTAP for 10 seconds, the results suggest that 30 seconds is the most indicated treatment time. PMID- 30457948 TI - Comparison of the Efficacy of Different Fluoride Varnishes on Dentin Remineralization During a Critical pH Exposure Using Quantitative X-Ray Microtomography. AB - OBJECTIVES:: The objective of this in vitro study was to quantify the amount of mineral change in demineralized dentin at pH 5.5 after the application of dental varnishes containing fluoride with casein phosphopeptide-amorphous calcium phosphate, fluoride and bioglass, or fluoride alone. METHODS AND MATERIALS:: A total of 12 extracted human sound mandibular premolar root samples were coated with an acid-resistant varnish, leaving a 2 * 3 mm window at the outer root surface. These root specimens were then randomly divided into four groups and separately subjected to the demineralizing cycle at a pH of 4.8 for five days to create artificial caries-like lesions in dentin. Subsequently, each sample was imaged using quantitative x-ray microtomography (XMT) at a 15-MUm voxel size. Each test group then received one of the following treatments: dental varnish containing casein phosphopeptide-amorphous calcium phosphate and fluoride (CPP ACP, MI varnish, GC Europe), bioglass and fluoride (BGA, Experimental, Dentsply Sirona), or fluoride alone (NUPRO, Dentsply Sirona), as well as a control group, which received no treatment. These samples were kept in deionized water for 12 hours. The thin layer of varnish was then removed. All samples including the nonvarnish group were subjected to the second demineralizing cycle at pH 5.5 for five days. The final XMT imaging was then carried out following the second demineralizing cycle. XMT scan was also carried out to varnish samples at 25 MUm voxel size. The change in mineral concentration in the demineralized teeth was assessed using both qualitative and quantitative image analysis. RESULTS:: There was an increase in radiopacity in the subtracted images of all varnish groups; a significant increase in mineral content, 12% for the CPP-ACP and fluoride ( p<=0.05 and p<=0.001), 25% BGA ( p<=0.001), and 104% fluoride alone varnish ( p<=0.001). There was an increase in the size of radiolucency in the lesion area with a significant decrease in mineral content in the nonvarnish group, 10% ( p<=0.05 and p<=0.001). CONCLUSIONS:: There was encouraging evidence of a remineralization effect following the application of dental varnish on dentin and also an observed resistance to demineralization during the acidic challenge in all cases. However, a dental varnish containing fluoride alone appeared to have a much greater effect on dentin remineralization when compared with CPP-ACP with fluoride and bioglass with fluoride. PMID- 30457949 TI - Using Financial Incentives to Improve Rates of Viral Suppression and Engagement in Care of Patients Receiving HIV Care at 3 Health Clinics in Louisiana: The Health Models Program, 2013-2016. AB - OBJECTIVES:: The Care and Prevention in the United States Demonstration Project aimed to reduce HIV/AIDS-related morbidity and mortality among racial/ethnic minority groups in 8 states. We evaluated Health Models, a pay-for-performance program piloted by the Louisiana Department of Health that used financial incentives to improve rates of engagement in HIV medical care and viral suppression among people with HIV. METHODS:: We enrolled 2076 patients of 3 urban HIV specialty clinics in Louisiana in the Health Models pay-for-performance program on a rolling basis from September 2013 through September 2016 and gave patients cash incentives to attend HIV medical appointments, achieve or maintain viral suppression, and link to supportive services. We used laboratory data collected from Louisiana's HIV surveillance database to calculate rates of engagement in care and viral suppression during the first 24 months of enrollment. RESULTS:: Of the 2076 patients who enrolled, 1400 (67.4%) were non Hispanic black, 1480 (71.3%) were male, 1175 (56.6%) were men who have sex with men, and 1371 (66.0%) reported an annual income of <$15 000. At enrollment, 1456 (70.1%) patients were engaged in HIV care, and 1197 (57.7%) patients were virally suppressed. After 12 months of enrollment, 1474 of 1783 (82.7%) patients were virally suppressed. Of enrolled patients with at least 12 or 24 months of follow up data, 1299 of 1317 (98.6%) patients were engaged in care during their first 12 months of enrollment, and 995 of 1033 (96.3%) patients were engaged in care between 12 and 24 months of enrollment. CONCLUSIONS:: During the implementation of Health Models, enrolled patients had increases in rates of viral suppression and achieved rates of engagement in care and viral suppression that were higher than national levels; however, additional supportive services may be needed to further reduce socioeconomic disparities in the rates of viral suppression. PMID- 30457950 TI - Integrating Federal Collaboration in HIV Programming: The CAPUS Demonstration Project, 2012-2016. PMID- 30457951 TI - Use of Social Network Strategy Among Young Black Men Who Have Sex With Men for HIV Testing, Linkage to Care, and Reengagement in Care, Tennessee, 2013-2016. AB - OBJECTIVES:: Tennessee was 1 of 8 states that received funding from the Care and Prevention in the United States Demonstration Project, which aimed to reduce HIV related morbidity and mortality among racial/ethnic and sexual minority populations. The objective of this study was to describe implementation of a social network strategy (SNS) program, which leverages personal connections in social networks, to reach people with undiagnosed HIV infection for HIV testing. We targeted young black men who have sex with men (MSM) at 3 agencies in Memphis and Nashville, Tennessee, during 2013-2016. METHODS:: Specialists at the 3 agencies identified MSM with and without diagnosed HIV infection (ie, recruiters) who could recruit members from their social networks for HIV testing (ie, network associates). Both recruiters and network associates received OraQuick rapid and confirmatory HIV tests. We used chi2 and Fisher exact tests to assess differences in demographic characteristics, HIV testing, and care engagement status by agency. RESULTS:: Of 1752 people who were tested for HIV in the SNS program, 158 (9.0%) tested positive; of these, 80 (50.6%) were newly diagnosed with HIV. Forty seven of the 78 (60.3%) people who were previously diagnosed with HIV were not in care in the previous 12 months; of these, 27 (57.4%) were reengaged in medical care. Of 80 people newly diagnosed with HIV, 44 (55.0%) were linked to care. CONCLUSIONS:: The SNS program ascertained HIV status among a high-risk population in a heavily burdened region. Further program evaluation is needed to understand how to improve linkage to care among people with newly diagnosed HIV. PMID- 30457953 TI - Learning by Doing: Lessons From the Care and Prevention in the United States Demonstration Project. PMID- 30457952 TI - The Care and Prevention in the United States Demonstration Project: A Call for More Focus on the Social Determinants of HIV/AIDS. PMID- 30457954 TI - Enhancing HIV Prevention and Care Through CAPUS and Other Demonstration Projects Aimed at Achieving National HIV/AIDS Strategy Goals, 2010-2018. PMID- 30457955 TI - The "No Wrong Door" Approach to HIV Testing: Results From a Statewide Retail Pharmacy-Based HIV Testing Program in Virginia, 2014-2016. AB - OBJECTIVE:: As part of the Care and Prevention in the United States Demonstration Project (2012-2016), which aimed to reduce HIV-related morbidity and mortality among racial/ethnic minority groups in 8 states, the Virginia Department of Health (VDH) funded Walgreens to provide HIV testing in retail pharmacies in areas with large racial/ethnic minority communities and high rates of poverty. We describe this program and summarize its outcomes. We hypothesized that (1) offering walk-in HIV testing outside of traditional business hours and alongside other point-of-care tests in retail pharmacies would increase rates of first-time testers and (2) using data on social determinants of health associated with higher rates of HIV infection to locate test sites would increase the identification of people who were previously undiagnosed. METHODS:: Using 2010 US Census data and 2007-2011 five-year population estimates from the American Community Survey, VDH selected 32 Walgreens stores located in census tracts where at least 30% of the population was black and/or Hispanic/Latino and/or where at least 20% of the population was living at or below the federal poverty level. Pharmacists administered the INSTI HIV-1/HIV-2 Rapid Antibody Test. Clients with a reactive test result were linked to confirmatory testing and medical care. RESULTS:: Between June 1, 2014, and September 29, 2016, Walgreens pharmacists performed HIV tests on 3630 clients, of whom 1668 (46.0%) had either never been tested or were unsure if they had been tested. Of all clients tested, 30 (0.8%) had a reactive test result. Of 26 clients who also had positive confirmatory testing, 22 (84.6%) were linked to care. The mean cost per person tested was $41.79, and the mean cost per reactive result was $5057. CONCLUSIONS:: Retail pharmacies may be an effective venue for those who have never been tested for HIV to access HIV testing, particularly if the pharmacies are located in priority areas or where community-based organizations are unable to operate. PMID- 30457956 TI - Cross-site Monitoring and Evaluation of the Care and Prevention in the United States Demonstration Project, 2012-2016: Selected Process and Short-term Outcomes. AB - OBJECTIVE:: The Care and Prevention in the United States (CAPUS) Demonstration Project was a 4-year (2012-2016) cross-agency demonstration project that aimed to reduce HIV/AIDS-related morbidity and mortality among racial/ethnic minority groups in 8 states (Georgia, Illinois, Louisiana, Mississippi, Missouri, North Carolina, Tennessee, and Virginia). Its goals were to increase the identification of undiagnosed HIV infections and optimize the linkage to, reengagement with, and retention in care and prevention services for people with HIV (PWH). We present descriptive findings to answer selected cross-site process and short-term outcome monitoring and evaluation questions. METHODS:: We answered a set of monitoring and evaluation questions by using data submitted by grantees. We used a descriptive qualitative method to identify key themes of activities implemented and summarized quantitative data to describe program outputs and outcomes. RESULTS:: Of 155 343 total HIV tests conducted by all grantees, 558 (0.36%) tests identified people with newly diagnosed HIV infection. Of 4952 PWH who were presumptively not in care, 1811 (36.6%) were confirmed as not in care through Data to Care programs. Navigation and other linkage, retention, and reengagement programs reached 10 382 people and linked to or reengaged with care 5425 of 7017 (77.3%) PWH who were never in care or who had dropped out of care. Programs offered capacity-building trainings to providers to improve cultural competency, developed social marketing and social media campaigns to destigmatize HIV testing and care, and expanded access to support services, such as transitional housing and vocational training. CONCLUSIONS:: CAPUS grantees substantially expanded their capacity to deliver HIV-related services and reach racial/ethnic minority groups at risk for or living with HIV infection. Our findings demonstrate the feasibility of implementing novel and integrated programs that address social and structural barriers to HIV care and prevention. PMID- 30457957 TI - The Evolution of the Secretary's Minority AIDS Initiative Fund: The US Department of Health and Human Services Responds to the National HIV/AIDS Strategy. PMID- 30457958 TI - Implementing a Data to Care Strategy to Improve Health Outcomes for People With HIV: A Report From the Care and Prevention in the United States Demonstration Project. AB - OBJECTIVES:: The Care and Prevention in the United States Demonstration Project included implementation of a Data to Care strategy using surveillance and other data to (1) identify people with HIV infection in need of HIV medical care or other services and (2) facilitate linkages to those services to improve health outcomes. We present the experiences of 4 state health departments: Illinois, Louisiana, Tennessee, and Virginia. METHODS:: The 4 state health departments used multiple databases to generate listings of people with diagnosed HIV infection (PWH) who were presumed not to be in HIV medical care or who had difficulty maintaining viral suppression from October 1, 2013, through September 29, 2016. Each health department prioritized the listings (eg, by length of time not in care, by viral load), reviewed them for accuracy, and then disseminated the listings to staff members to link PWH to HIV care and services. RESULTS:: Of 16 391 PWH presumed not to be in HIV medical care, 9852 (60.1%) were selected for follow-up; of those, 4164 (42.3%) were contacted, and of those, 1479 (35.5%) were confirmed to be not in care. Of 794 (53.7%) PWH who accepted services, 694 (87.4%) were linked to HIV medical care. The Louisiana Department of Health also identified 1559 PWH as not virally suppressed, 764 (49.0%) of whom were eligible for follow-up. Of the 764 PWH who were eligible for follow-up, 434 (56.8%) were contacted, of whom 269 (62.0%) had treatment adherence issues. Of 153 PWH who received treatment adherence services, 104 (68.0%) showed substantial improvement in viral suppression. CONCLUSIONS:: The 4 health departments established procedures for using surveillance and other data to improve linkage to HIV medical care and health outcomes for PWH. To be effective, health departments had to enhance coordination among surveillance, care programs, and providers; develop mechanisms to share data; and address limitations in data systems and data quality. PMID- 30457959 TI - Routine HIV Screening as a Standard of Care: Implementing HIV Screening in General Medical Settings, 2013-2015. AB - OBJECTIVE:: We implemented routine HIV screening as part of the 4-year Care and Prevention in the United States Demonstration Project, whose aim was to reduce HIV/AIDS-related morbidity and mortality among racial/ethnic minority groups in the United States. We describe the capacity-building efforts to implement routine HIV screening and provide lessons learned and implications for practice. METHODS:: From January 2013 through September 2015, the Public Health Institute of Metropolitan Chicago (PHIMC) implemented routine HIV screening in 7 health care systems in Illinois by providing capacity-building assistance focused on systems and operational infrastructure, staff member skills and organizational structure, and clinic culture. Each site received funding to integrate routine HIV screening into the existing clinic flow, engage the entire health care team in the process, and transform the system and shift clinic culture to sustain HIV screening. RESULTS:: All 7 systems established policies and procedures to implement routine screening, 5 systems integrated HIV test ordering and documentation into their electronic health records, and 4 systems established a third-party billing and reimbursement process for testing. The 7 systems conducted a total of 49 285 tests and identified 160 people living with HIV. The number of tests increased by more than 40% each year. CONCLUSIONS:: PHIMC identified the following practices for consideration when implementing routine HIV screening in general medical settings: create a culture that supports HIV screening, use champions in clinics, integrate HIV screening into clinic flow and electronic health records, and train clinic staff members on HIV messaging. Incorporating these practices can help other clinical settings build capacity to make routine HIV screening a standard of care. PMID- 30457960 TI - Synthetic cannabinoid use among a sample of individuals enrolled in community based recovery programs: Are synthetic cannabinoids actually preferred to other drugs? AB - BACKGROUND: Over the past decade, availability and use of novel psychoactive substances such as synthetic cannabinoid receptor agonists (SCRA) have proliferated globally. However, the prevalence of SCRAs use remains uncertain, as does the degree to which individuals reporting SCRA use prefer SCRA to other drugs. METHODS: In April 2017, a total of 500 anonymous surveys were completed by clients enrolled in a residential drug recovery program. Chi-square and t tests were used to examine significant differences between those who had ever used SCRA and those who had not. Logistic regression analysis was conducted in order to determine which other substances used within the past 12 months were significantly associated with past-12-month SCRA use. RESULTS: About 69% (68.4%) of clients reported lifetime SCRA use. Those reporting SCRA use were predominantly younger ([Formula: see text] = 32.5 vs. 40.7, P < .001), single (60.3% vs. 48.1%, P = .011), and white (87.1% vs. 77.7%, P = .008) and were more likely to have experienced past-12-month homelessness (6.5% vs. 3.2%, P = .004). This group had higher rates of probation/parole involvement (79.2% vs. 61.8%, P < .001) and incarceration (91.8% vs. 79.6%, P < .001). Individuals reporting SCRA use also showed extensive substance use histories and favored heroin, opioids, and amphetamines compared with SCRA. Only 5.2% of the SCRA-using group stated that SCRA was a preferred substance, and only 11.8% reported that they would try SCRA again. E-cigarettes (adjusted odds ratio [AOR] = 1.88), traditional cannabis (AOR = 3.87), amphetamines (AOR = 2.20), and synthetic cathinones (AOR = 3.51) were significantly associated with past-12-month SCRA use. Motivations for use included circumnavigating drug screens and peer influence. Approximately half of those who tried SCRA reported adverse effects associated with use. CONCLUSIONS: Prevalence of SCRA use among individuals with a history of substance misuse and criminal justice system involvement is high; however, SCRA are not indicated as a preferred drug. PMID- 30457962 TI - Errata corrige Functional Neurology 2018;33:2 Article: Epidemiological and clinical characteristics of 492 patients in a vegetative state in 29 Italian rehabilitation units. What about outcome? PMID- 30457963 TI - Chronic stroke: an oxymoron or a challenge for rehabilitation? PMID- 30457961 TI - Reemergence of St. Louis Encephalitis Virus in the Americas. AB - We summarize and analyze historical and current data regarding the reemergence of St. Louis encephalitis virus (SLEV; genus Flavivirus) in the Americas. Historically, SLEV caused encephalitis outbreaks in the United States; however, it was not considered a public health concern in the rest of the Americas. After the introduction of West Nile virus in 1999, activity of SLEV decreased considerably in the United States. During 2014-2015, SLEV caused a human outbreak in Arizona and caused isolated human cases in California in 2016 and 2017. Phylogenetic analyses indicate that the emerging SLEV in the western United States is related to the epidemic strains isolated during a human encephalitis outbreak in Cordoba, Argentina, in 2005. Ecoepidemiologic studies suggest that the emergence of SLEV in Argentina was caused by the introduction of a more pathogenic strain and increasing populations of the eared dove (amplifying host). PMID- 30457964 TI - Effects of a nutraceutical combination in patients with chronic lumbosacral radicular pain. AB - Drugs used for the treatment of chronic lumbosacral radicular pain (LRP) may have frequent adverse effects leading to medication withdrawal. The use of add-on nutraceuticals, which have no side effects, may therefore play a role in LRP treatment. We performed a six-week, single-center, open label prospective uncontrolled clinical study to evaluate the effect of a nutraceutical combination (Noxiall(r)) used as an add-on therapy in patients with chronic LRP. Fifteen patients were treated with Noxiall(r) twice a day for 10 consecutive days, followed by once-daily administration up to the end of the six-week treatment. The participants were evaluated at two visits (before-after), when primary and secondary outcomes were assessed. We found a significant reduction in pain severity post-treatment, as assessed using a numerical rating scale (p= 0.03), and a significant reduction in painkiller intake (p=0.03). Nutraceuticals could be a complementary therapy for chronic LRP. PMID- 30457965 TI - Effects on balance skills and patient compliance of biofeedback training with inertial measurement units and exergaming in subacute stroke: a pilot randomized controlled trial. AB - Stroke patients have reduced balance and postural control that limits their activities of daily living and participation in social life. Recently, many exergaming systems based on video-biofeedback have been developed for balance training in neurological conditions, however their efficacy remains to be proven. The aim of this study was to investigate the effects on balance skills and patient compliance of biofeedback training based on inertial measurement units and exergaming in subacute stroke. The enrolled subjects were randomized into two groups: subjects allocated to the experimental group performed 10 sessions of biofeedback balance training using inertial sensors, whereas subjects allocated to the control group performed 10 sessions of conventional balance training. All subjects were assessed at T0 (pre-treatment), T1 (posttreatment) and T2 (1-month follow-up). The Berg Balance Scale, Rivermead Mobility Index and modified Barthel Index were used to assess balance, mobility and global disability, respectively. To assess the severity of the stroke and its effects on the patient we used the National Institutes of Health Stroke Scale and the Canadian Neurological Scale. Finally, a static force platform evaluating stabilometric parameters was used to assess balance skills. Fifteen subjects with subacute stroke (4F; age 57.80 +/- 13.7) completed the experimental protocol. The analysis showed a significant improvement in balance skills and in the overall clinical outcomes in the experimental group compared with the control group; the experimental group also showed better compliance with the training. The biofeedback system of the device used in this study probably enhances neuroplasticity mechanisms of postural and balance skills in subacute stroke patients. PMID- 30457966 TI - The required coefficient of friction in Parkinson's disease: people with freezing of gait. AB - The required coefficient of friction (RCOF) is frequently reported in the literature as an indicator of slip propensity, a consequence of the collisional aspect of legged locomotion. Little is known about the RCOF in pathological gait. Therefore, this study aimed to quantify the RCOF in subjects with Parkinson's disease (PD) and freezing of gait (FOG) during the OFF-pharma phase, and to investigate the interplay between RCOF parameters and ankle kinematic and kinetic gait variables. Fourteen subjects with PD and 14 healthy age-matched subjects were instructed to walk barefoot at self-selected speed over a force platform. The RCOF curve was obtained as the ratio between the tangential and vertical ground reaction forces. Then, the following discrete variables were identified: P1COF (the peak at the loading response phase), V1COF (the valley at midstance phase) and P2COF (the peak at push-off phase). Stepwise multiple regressions were applied to observe the influence of the gait speed and ankle kinematic and kinetic gait variables on RCOF variables. In subjects with PD and FOG the gait speed is a predictor of the RCOF in the loading response phase; plantarflexion and the plantarflexion moment are strong predictors of the RCOF in midstance; finally, push-off power is a predictor of RCOF increasing in the push-off phase. These results characterized the biomechanical strategies adopted by subjects with PD and FOG during gait in order to avoid falls. PMID- 30457967 TI - Non-pharmacological interventions for agitation/aggressive behaviour in patients with dementia: a randomized controlled crossover trial. AB - Agitation/aggressive behaviour is a common behavioural and psychological symptom in people with dementia (PwD), occurring with a frequency of between 13-50.4% according to recent studies, and the rate increases as the severity of cognitive decline increases. The burden on caregivers is considerable. This trial is a randomized controlled crossover trial conducted in Greece. The following measures were used: the Mini-Mental State Examination, Addenbrooke's Cognitive Examination Revised, Geriatric Depression Scale, Functional Rating Scale for Symptoms in Dementia and Neuropsychiatric Inventory. According to the results the most effective nonpharmacological intervention for reducing agitation/aggressive behaviour in PwD was music therapy, followed by aromatherapy and massage, and finally physical exercise. PMID- 30457968 TI - Improved antioxidant defense in the ventral tegmental area increases pain tolerance in male rats. AB - The ventral tegmental area (VTA) is a brain region recently shown to interfere with pain perception. According to previous studies, improvement of antioxidant defense mechanisms reduces pain. The aim of this study was to show that lack of social interaction influences oxidative stress in the VTA and that this results in increased pain tolerance. In this study, 21 male Sprague-Dawley rats were randomly divided into 2 groups: paired and socially isolated (SI). After one week of acclimatization, the SI rats were isolated for 14 days and the other rats were paired for the same period. On day 15, pain tolerance was assessed through the tail flick test, and two days later the rats were investigated for anxiety in an elevated plus maze (EPM). Indices of oxidative stress (levels of malondialdehyde, glutathione, nitrite/nitrate and catalase activity in the VTA) were then studied in the animals. Malondialdehyde in the VTA was found to be reduced in the SI rats compared with the paired rats. Furthermore, catalase activity, glutathione and nitrite/nitrate levels in the VTA were increased in SI compared with paired rats. Pain tolerance on the tail flick test was increased in SI rats compared with paired rats, while anxiety, as assessed by EPM, was reduced in the SI rats compared with the paired rats. Improvement of antioxidant defense and reduction of oxidative stress in the VTA increases pain tolerance and reduces anxiety. In this sense, environmental conditions play an important role in pain control. PMID- 30457969 TI - Neurite orientation dispersion and density imaging can detect presymptomatic axonal degeneration in the spinal cord of ALS mice. AB - Neurite orientation dispersion and density imaging (NODDI), a MRI multi-shell diffusion technique, has offered new insights for the study of microstructural changes in neurodegenerative diseases. Mainly, the present study aimed to determine the connection between NODDI-derived parameters and changes in white matter (WM) abnormalities at early stages of amyotrophic lateral sclerosis (ALS). Spinal cords from ALS mice (G93A-SOD1 mice) were scanned in a Bruker Avance III HD 17.6T magnet. Fluorescent axonal-tagged mice (YFP, G93A-SOD1 mice) were used for quantitative histological analysis. NODDI showed a decrease in intra-cellular volume fraction (-24%) and increases in orientation dispersion index (+35%) and isotropic volume fraction (+33%). In addition, histoathological results demonstrated a reductions in axonal area (-11%) and myelin content (-29%). A histological decrease in WM intra-axonal space (-71%) and an increase in the extra-axonal compartment (+22%) were also detected. Our studies demonstrate that NODDI may be a suitable technique for detecting presymptomatic spinal cord WM microstructural degeneration in ALS. PMID- 30457970 TI - An acute neurological complication of Crohn's disease. PMID- 30457971 TI - Shaping a pain-free future for cluster headache patients. The Declaration of Paris. PMID- 30457972 TI - A Mobile Health Wallet for pregnancy-related healthcare in Madagascar: a mixed methods study on opportunities and challenges. AB - BACKGROUND: Mobile savings and payment systems have been widely adopted to store money and to pay for a variety of services, including healthcare. However, the possible implications of these technologies on financing and payment for maternal healthcare services - which commonly require large one-time out-of-pocket payments - have not yet been systematically assessed in low-resource settings. OBJECTIVE: This study aims to determine the structural, contextual, and experiential characteristics of a mobile-phone-based savings and payment platform, the Mobile Health Wallet (MHW), for skilled healthcare during pregnancy among women in Madagascar. METHODS: We used a two-stage cluster random sampling scheme, to select a representative sample of women utilizing either routine antenatal (ANC) or routine postnatal care (PNC) in public-sector health facilities in two of 8 urban and peri-urban districts of Antananarivo, Madagascar (Atsimondrano and Renivohitra districts). In a quantitative structured survey, we identified saving habits, mobile phone use, media consumptions, and perception of a mobile health wallet with both savings and payment functions. To confirm and explain the quantitative results, we used qualitative data from 6 semi-structured focus group discussions (24 participants in total) in the same population. RESULTS: Out of 412 randomly selected women attending ANC or PNC, 59.3% (95% confidence interval (CI) 54.5-64.1%) saved towards the expected costs of delivery and, out of those, 64.4% (95% CI 58.6-70.2%) used household cash savings for this purpose. 80.3% (95% CI 76.5-84.1%) had access to a personal or family phone and 35.7% (95% CI 31.1-40.3%) previously used mobile money services. Access to skilled healthcare during pregnancy was primarily limited due to financial obstacles like saving difficulties or unpredictability of costs. Another barrier was the lack of information about health benefits or availability of services. The general concept of a MHW for saving towards and payment of pregnancy-related care including the restriction of payments was perceived as beneficial and practicable by the majority of participants. In the discussions, several themes pointed to opportunities for ensuring the success of a MHW through design features: (i) intuitive technical ease of use; (ii) clear communication and information about benefits and restrictions; (iii) availability of a personal customer support. CONCLUSIONS: Financial obstacles are a major cause of limited access to skilled maternal healthcare in Madagascar. A MHW for skilled healthcare during pregnancy was perceived as a useful and desirable tool to reduce financial barriers among women in urban Madagascar. The design of this tool and the communication strategy will likely be the key to success. Particularly important dimensions of design include technical user-friendliness and accessible, personal customer service. PMID- 30457973 TI - Droplet digital PCR for the simultaneous analysis of minimal residual disease and hematopoietic chimerism after allogeneic cell transplantation. AB - Background Minimal residual disease (MRD) and hematopoietic chimerism testing influences clinical decision and therapeutic intervention in patients after allogeneic stem cell transplantation (HSCT). However, treatment approaches to induce complete donor chimerism and MRD negativity can lead to complications such as graft-versus-host disease (GvHD) and marrow aplasia. Therefore, there is a need for comprehensive characterization of the molecular remission status after transplantation. Methods We analyzed 764 samples from 70 patients after HSCT for the simultaneous measurement of chimerism and molecular targets used for MRD testing with a digital PCR (dPCR) platform. Results Mixed chimerism (MC) was detected in 219 samples from 37 patients. The mean percentage of host derived DNA in these clinical samples was 4.3%. Molecular relapse with a positive MRD marker and/or increased WT1 expression was observed in 15 patients. In addition to WT1 overexpression, other MRD positive markers were: NPM1 (Type A, B, K), DNMT3A (R882H), MLL-PTD, IDH1 (R132H) and KRAS (G12S). Increasing MC was observed in 15 patients. This group of patients showed either a positive MRD marker, increased WT1 expression or both. Next, we analyzed whether MC or the molecular target for MRD was first detected. MC and MRD marker positivity in this group was first detected in six and two patients, respectively. In the remaining seven patients MC and MRD positivity was detected simultaneously. Conclusions The combination of MRD and chimerism markers in a dPCR platform represents a practical, sensitive and accurate diagnostic tool for the comprehensive assessment of the molecular remission status of patients undergoing HSCT. PMID- 30457974 TI - Do students achieve the desired learning goals using open-book formative assessments? AB - Objectives: The present study aimed to examine whether medical students benefit from an open-book online formative assessment as a preparation for a practical course. Methods: A between-subjects experimental design was used: participants - a whole cohort of second-year medical students (N=232) - were randomly assigned to either a formative assessment that covered the topic of a subsequent practical course (treatment condition) or a formative assessment that did not cover the topic of the subsequent course (control condition). Course-script-knowledge, as well as additional in-depth-knowledge, was assessed. Results: Students in the treatment condition had better course-script knowledge, both at the beginning, t(212) = 4.96, p < .01, d = 0.72., and in the end of the practical course , t(208) = 4.80, p < .01, d = 0.68. Analyses of covariance show that this effect is stronger for those students who understood the feedback that was presented within the formative assessment, F(1, 213)=10.17, p<.01. Additionally, the gain of in depth-knowledge was significantly higher for students in the treatment condition compared to students in the control condition, t(208) = 3.68., p < .05, d = 0.72 (0.51). Conclusions: Students benefit from a formative assessment that is related to and takes place before a subsequent practical course. They have a better understanding of the topic and gain more in-depth-knowledge that goes beyond the content of the script. Moreover, the study points out the importance of feedback pages in formative assessments. PMID- 30457975 TI - Adiabatic and nonadiabatic charge separation dynamics in graphene oxide quantum dots for overall water splitting. AB - Chemical functionalization and heteroatom doping are two effective strategies for improving the conductivity of a graphene lattice. Nitrogen-doped graphene oxide quantum dot (GOQD) has been reported to possess both p- and n-conductivity that is induced by an oxygen functional group and nitrogen doping, respectively, and is suitable for catalyzing hydrogen and oxygen evolution reactions for complete water splitting. The experimental study shows that the hydrogen evolution reaction occurs considerably faster than the oxygen evolution reaction. However, the mechanism of this phenomenon remains unknown, which poses a challenge to the chemical modification of such classes of materials. In the present work, we perform nonadiabatic ab initio molecular dynamics to explore the charge separation dynamics in N-doped GOQD with oxygen functional groups. Our results show that there exists multiple charge decay channels governed by different mechanisms, which complicates the overall charge separation dynamics in N-doped GOQD. The intramolecular electron transfer mainly occurs through the nonadiabatic channel, whereas the intramolecular hole transfer mainly occurs through the adiabatic channel. There is an additional adiabatic decay channel in the p domain, which accelerates electron-hole recombination in the p-domain. We further calculated the decoherence times and found that the decoherence of intramolecular electron transfer occurs considerably faster than that of hole transfer, which slows the quantum transition of intramolecular electron transfer. Finally, we simulated the carrier relaxation times and found that the electron relaxation is approximately one order of magnitude longer than that of the hole relaxation. Our calculation rationalizes the experimentally observed higher catalytic activity towards the hydrogen evolution compared to the oxygen evolution. More importantly, the calculation explains the fundamental roles of nitrogen doping and oxygen functional groups in the adiabatic and nonadiabatic charge decay mechanisms. PMID- 30457976 TI - CMOS-compatible Si metasurface at visible wavelengths prepared by low-temperature green laser annealing. AB - A low-temperature laser crystallization is newly devised for producing polycrystalline silicon (poly-Si) thin films of low-loss, low surface roughness enough for nanoscale patterning, applicable to practical Si metasurface elements on complementary metal-oxide semiconductor (CMOS) electronic architectures in visible lights. The method is based on dielectric encapsulation of an amorphous Si film and subsequent laser-induced local crystallization. Such poly-Si thin film yields order-of-magnitude smaller surface roughness and grain size than those obtained with the conventional laser annealing processes. The mechanism of the formation of small and uniform crystalline grains during solidification is studied to ensure the smooth surfaces enough for nanoscale patterning. By obtaining root mean square of surface roughness <2.49 nm and extinction coefficient <4.8 * 10-2 at 550 nm, visible metasurface color-filter elements are experimentally demonstrated with the resonant transmission-peak efficiency approaching ~85%. This low-loss poly-Si metasurface is favorably compatible with embedded CMOS electronic architectures in contrast to the conventional thermal annealing processes that often cause failure of electrical device functionalities due to delamination and material-property degradation problems. The proposed fabrication in this study provides a practical method for further development of various Si metasurfaces in the visible domain and their integration with CMOS electronic devices as well. PMID- 30457977 TI - Compositional control of homogeneous InGaN nanowires with the In content up to 90. AB - Homogenous InGaN nanowires with a controlled indium composition up to 90% are grown on GaN/c-Al2O3 templates by catalyst-free hydride vapor phase epitaxy using InCl3 and GaCl as group III element precursors. The influence of the partial pressures on the growth rate and composition of InGaN nanowires is investigated. It is shown how the InN mole fraction in nanowires can be finely tuned by changing the vapor phase composition. Thermodynamic calculations are presented that take into account different interconnected reactions in the vapor phase and show a good agreement with the compositional data. Energy dispersive x-ray spectroscopy profiles performed on single nanowires show a homogenous indium composition along the entire nanowire length. X-ray diffraction measurements performed on nanowires arrays confirm these data. High-resolution transmission electron microscopy analysis shows the wurtzite crystal structure with a reduced defect density for InGaN nanowires with the highest indium content. PMID- 30457978 TI - Peptide-based PET quantifies target engagement of PD-L1 therapeutics. AB - Immune checkpoint therapies have shown tremendous promise in cancer therapy. However, tools to assess their target engagement, and hence ability to predict their efficacy, have been lacking. Here, we show that target engagement and tumor residence kinetics of antibody therapeutics targeting the programmed death ligand 1 (PD-L1) can be quantified non-invasively. In computational docking studies, we observed that PD-L1-targeted antibodies (atezolizumab, avelumab, durvalumab) and a high affinity PD-L1 binding peptide, WL12, have common interaction sites on PD L1. Using the peptide radiotracer [64Cu]WL12 in vivo, we employed positron emission tomography (PET) imaging and biodistribution studies, in multiple xenograft models and demonstrated that variable PD-L1 expression and its saturation by atezolizumab, avelumab, and durvalumab can be quantified independent of biophysical properties and pharmacokinetics of antibodies. Next, we used [64Cu]WL12 to evaluate the impact of time and dose on free fraction of tumor PD-L1 levels during treatment. These quantitative measures enabled, by mathematical modeling, prediction of antibody doses needed to achieve therapeutically effective occupancy (defined as >90%). Thus, we show that peptide based PET is a promising tool for optimizing dose and therapeutic regimens employing PD-L1 checkpoint antibodies, and can be used for improving therapeutic efficacy. PMID- 30457980 TI - TNF/TNFR axis promotes pyrin inflammasome activation and distinctly modulates pyrin inflammasomopathy. AB - Pyrin is an inflammasome sensor that promotes caspase-1-mediated pyroptotic cell death and maturation of proinflammatory cytokines IL-1beta and IL-18. Familial Mediterranean fever (FMF), an autoinflammatory disorder, is associated with mutations in the gene encoding pyrin (MEFV). FMF-knockin (FMF-KI) mice that express chimeric pyrin protein with FMF mutation (MefvV726A/V726A) exhibit an autoinflammatory disorder mediated by autoactivation of the pyrin inflammasome. Increase in the levels of TNF are observed in FMF-KI mice, and many features of FMF overlap with the autoinflammatory disorder associated with TNF receptor signaling. In this study, we assessed the contribution of TNF signaling to pyrin inflammasome activation and its consequent role in distinct FMF pathologies. TNF signaling promoted the expression of pyrin in response to multiple stimuli and was required for inflammasome activation in response to canonical pyrin stimuli and in myeloid cells from FMF-KI mice. TNF signaling promoted systemic wasting, anemia, and neutrophilia in the FMF-KI mice. Further, TNF-induced pathology was induced specifically through the TNFR1 receptor, while TNFR2-mediated signaling was distinctly protective in colitis and ankle joint inflammation. Overall, our data show that TNF is a critical modulator of pyrin expression, inflammasome activation, and pyrin-inflammasomopathy. Further, specific blockade of TNFR1 or activation of TNFR2 could provide substantial protection against FMF pathologies. PMID- 30457979 TI - Spec-seq unveils transcriptional subpopulations of antibody-secreting cells following influenza vaccination. AB - Vaccines are among the most effective public health tools for combating certain infectious diseases such as influenza. The role of the humoral immune system in vaccine-induced protection is widely appreciated; however, our understanding of how antibody specificities relate to B cell function remains limited due to the complexity of polyclonal antibody responses. To address this, we developed the Spec-seq framework, which allows for simultaneous monoclonal antibody (mAb) characterization and transcriptional profiling from the same single cell. Here, we present the first application of the Spec-seq framework, which we applied to human plasmablasts after influenza vaccination in order to characterize transcriptional differences governed by B cell receptor (BCR) isotype and vaccine reactivity. Our analysis did not find evidence of long-term transcriptional specialization between plasmablasts of different isotypes. However, we did find enhanced transcriptional similarity between clonally related B cells, as well as distinct transcriptional signatures ascribed by BCR vaccine recognition. These data suggest IgG and IgA vaccine-positive plasmablasts are largely similar, whereas IgA vaccine-negative cells appear to be transcriptionally distinct from conventional, terminally differentiated, antigen-induced peripheral blood plasmablasts. PMID- 30457981 TI - Autologous graft versus myeloma: it's not a myth. AB - Graft-versus-tumor (GVT) effects have been thought to mostly result from allogeneic transplants; however, there is a growing body of research that supports a possible autologous GVT effect. In early clinical studies, a positive correlation between lymphocyte count recovery after autologous transplantation and overall survival has been observed. However, mechanistic studies to identify the mediators of autologous GVT responses have been lacking. In this issue of the JCI, Vuckovic et al. observed a T cell-dependent autologous GVT effect in the Vk*MYC myeloma model. Moreover, the authors showed that CD8+ T cells mediate myeloma control through IFN-gamma secretion, which could be further augmented with a CD137 agonist, suggesting a therapeutic approach for enhancing autologous GVT. PMID- 30457982 TI - PI3K p110delta inactivation antagonizes chronic lymphocytic leukemia and reverses T cell immune suppression. AB - Targeted therapy with small molecules directed at essential survival pathways in leukemia represents a major advance, including the phosphatidylinositol-3'-kinase (PI3K) p110delta inhibitor idelalisib. Here, we found that genetic inactivation of p110delta (p110deltaD910A/D910A) in the EMU-TCL1 murine chronic lymphocytic leukemia (CLL) model impaired B cell receptor signaling and B cell migration, and significantly delayed leukemia pathogenesis. Regardless of TCL1 expression, p110delta inactivation led to rectal prolapse in mice resembling autoimmune colitis in patients receiving idelalisib. Moreover, we showed that p110delta inactivation in the microenvironment protected against CLL and acute myeloid leukemia. After receiving higher numbers of TCL1 leukemia cells, half of p110deltaD910A/D910A mice spontaneously recovered from high disease burden and resisted leukemia rechallenge. Despite disease resistance, p110deltaD910A/D910A mice exhibited compromised CD4+ and CD8+ T cell response, and depletion of CD4+ or CD8+ T cells restored leukemia. Interestingly, p110deltaD910A/D910A mice showed significantly impaired Treg expansion that associated with disease clearance. Reconstitution of p110deltaD910A/D910A mice with p110deltaWT/WT Tregs reversed leukemia resistance. Our findings suggest that p110delta inhibitors may have direct antileukemic and indirect immune-activating effects, further supporting that p110delta blockade may have a broader immune-modulatory role in types of leukemia that are not sensitive to p110delta inhibition. PMID- 30457983 TI - Over-Expression of ATPase II Alleviates Ethanol-Induced Hepatocyte Injury in HL 7702 Cells. AB - BACKGROUND Excessive alcohol consumption can cause hepatocellular injury. ATPase II (ATP8A1) can display an ATP-dependent phospholipid translocase activity. However, the function of ATP8A1 in hepatocyte injury is still unclear. In the present study we explored the effect of ATP8A1 on ethanol-induced hepatocyte injury. MATERIAL AND METHODS A human hepatocyte strain, HL-7702, was pretreated by ethanol with gradient concentration for 2, 4, 8, and 12 h, and were then divided into 6 groups after the cells were transfected. We detected cell viability by use of the Cell Counting Kit-8 (CCK-8) assay. Reactive oxygen species (ROS), apoptosis rate, and mitochondrial membrane potential (MMP) were measured using flow cytometry. We used quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot to measure the mRNA and protein expression, respectively. RESULTS Ethanol inhibited the viability of HL 7702 cells and suppressed the expression of ATP8A1 in dose- and time-dependent manners. Furthermore, over-expression of ATP8A1 reduced the level of ROS and the apoptosis rate and recovered the MMP. Additionally, over-expressed ATP8A1 regulated the protein and mRNA levels of apoptosis-related molecules. Moreover, over-expression of ATP8A1 enhanced the phosphorylation of phosphatidylinositol 3 kinase (PI3K) and protein kinase B (Akt). CONCLUSIONS Over-expression of ATP8A1 alleviated ethanol-induced hepatocyte injury. Moreover, the PI3K/Akt signaling pathway appears to participate in inhibition of ethanol-induced hepatocyte apoptosis and may provide a candidate target for the treatment of alcoholic liver diseases (ALD). PMID- 30457984 TI - Reproducible research practices, transparency, and open access data in the biomedical literature, 2015-2017. AB - Currently, there is a growing interest in ensuring the transparency and reproducibility of the published scientific literature. According to a previous evaluation of 441 biomedical journals articles published in 2000-2014, the biomedical literature largely lacked transparency in important dimensions. Here, we surveyed a random sample of 149 biomedical articles published between 2015 and 2017 and determined the proportion reporting sources of public and/or private funding and conflicts of interests, sharing protocols and raw data, and undergoing rigorous independent replication and reproducibility checks. We also investigated what can be learned about reproducibility and transparency indicators from open access data provided on PubMed. The majority of the 149 studies disclosed some information regarding funding (103, 69.1% [95% confidence interval, 61.0% to 76.3%]) or conflicts of interest (97, 65.1% [56.8% to 72.6%]). Among the 104 articles with empirical data in which protocols or data sharing would be pertinent, 19 (18.3% [11.6% to 27.3%]) discussed publicly available data; only one (1.0% [0.1% to 6.0%]) included a link to a full study protocol. Among the 97 articles in which replication in studies with different data would be pertinent, there were five replication efforts (5.2% [1.9% to 12.2%]). Although clinical trial identification numbers and funding details were often provided on PubMed, only two of the articles without a full text article in PubMed Central that discussed publicly available data at the full text level also contained information related to data sharing on PubMed; none had a conflicts of interest statement on PubMed. Our evaluation suggests that although there have been improvements over the last few years in certain key indicators of reproducibility and transparency, opportunities exist to improve reproducible research practices across the biomedical literature and to make features related to reproducibility more readily visible in PubMed. PMID- 30457985 TI - Evolution of correlated complexity in the radically different courtship signals of birds-of-paradise. AB - Ornaments used in courtship often vary wildly among species, reflecting the evolutionary interplay between mate preference functions and the constraints imposed by natural selection. Consequently, understanding the evolutionary dynamics responsible for ornament diversification has been a longstanding challenge in evolutionary biology. However, comparing radically different ornaments across species, as well as different classes of ornaments within species, is a profound challenge to understanding diversification of sexual signals. Using novel methods and a unique natural history dataset, we explore evolutionary patterns of ornament evolution in a group-the birds-of-paradise exhibiting dramatic phenotypic diversification widely assumed to be driven by sexual selection. Rather than the tradeoff between ornament types originally envisioned by Darwin and Wallace, we found positive correlations among cross modal (visual/acoustic) signals indicating functional integration of ornamental traits into a composite unit-the "courtship phenotype." Furthermore, given the broad theoretical and empirical support for the idea that systemic robustness functional overlap and interdependency-promotes evolutionary innovation, we posit that birds-of-paradise have radiated extensively through ornamental phenotype space as a consequence of the robustness in the courtship phenotype that we document at a phylogenetic scale. We suggest that the degree of robustness in courtship phenotypes among taxa can provide new insights into the relative influence of sexual and natural selection on phenotypic radiations. PMID- 30457986 TI - Modulation of Drosophila post-feeding physiology and behavior by the neuropeptide leucokinin. AB - Behavior and physiology are orchestrated by neuropeptides acting as central neuromodulators and circulating hormones. An outstanding question is how these neuropeptides function to coordinate complex and competing behaviors. In Drosophila, the neuropeptide leucokinin (LK) modulates diverse functions, but mechanisms underlying these complex interactions remain poorly understood. As a first step towards understanding these mechanisms, we delineated LK circuitry that governs various aspects of post-feeding physiology and behavior. We found that impaired LK signaling in Lk and Lk receptor (Lkr) mutants affects diverse but coordinated processes, including regulation of stress, water homeostasis, feeding, locomotor activity, and metabolic rate. Next, we sought to define the populations of LK neurons that contribute to the different aspects of this physiology. We find that the calcium activity in abdominal ganglia LK neurons (ABLKs), but not in the two sets of brain neurons, increases specifically following water consumption, suggesting that ABLKs regulate water homeostasis and its associated physiology. To identify targets of LK peptide, we mapped the distribution of Lkr expression, mined a brain single-cell transcriptome dataset for genes coexpressed with Lkr, and identified synaptic partners of LK neurons. Lkr expression in the brain insulin-producing cells (IPCs), gut, renal tubules and chemosensory cells, correlates well with regulatory roles detected in the Lk and Lkr mutants. Furthermore, these mutants and flies with targeted knockdown of Lkr in IPCs displayed altered expression of insulin-like peptides (DILPs) and transcripts in IPCs and increased starvation resistance. Thus, some effects of LK signaling appear to occur via DILP action. Collectively, our data suggest that the three sets of LK neurons have different targets, but modulate the establishment of post-prandial homeostasis by regulating distinct physiological processes and behaviors such as diuresis, metabolism, organismal activity and insulin signaling. These findings provide a platform for investigating feeding related neuroendocrine regulation of vital behavior and physiology. PMID- 30457987 TI - Evidence for gene-environment correlation in child feeding: Links between common genetic variation for BMI in children and parental feeding practices. AB - The parental feeding practices (PFPs) of excessive restriction of food intake ('restriction') and pressure to increase food consumption ('pressure') have been argued to causally influence child weight in opposite directions (high restriction causing overweight; high pressure causing underweight). However child weight could also 'elicit' PFPs. A novel approach is to investigate gene environment correlation between child genetic influences on BMI and PFPs. Genome wide polygenic scores (GPS) combining BMI-associated variants were created for 10,346 children (including 3,320 DZ twin pairs) from the Twins Early Development Study using results from an independent genome-wide association study meta analysis. Parental 'restriction' and 'pressure' were assessed using the Child Feeding Questionnaire. Child BMI standard deviation scores (BMI-SDS) were calculated from children's height and weight at age 10. Linear regression and fixed family effect models were used to test between- (n = 4,445 individuals) and within-family (n = 2,164 DZ pairs) associations between the GPS and PFPs. In addition, we performed multivariate twin analyses (n = 4,375 twin pairs) to estimate the heritabilities of PFPs and the genetic correlations between BMI-SDS and PFPs. The GPS was correlated with BMI-SDS (beta = 0.20, p = 2.41x10-38). Consistent with the gene-environment correlation hypothesis, child BMI GPS was positively associated with 'restriction' (beta = 0.05, p = 4.19x10-4), and negatively associated with 'pressure' (beta = -0.08, p = 2.70x10-7). These results remained consistent after controlling for parental BMI, and after controlling for overall family contributions (within-family analyses). Heritabilities for 'restriction' (43% [40-47%]) and 'pressure' (54% [50-59%]) were moderate-to-high. Twin-based genetic correlations were moderate and positive between BMI-SDS and 'restriction' (rA = 0.28 [0.23-0.32]), and substantial and negative between BMI-SDS and 'pressure' (rA = -0.48 [-0.52 - -0.44]. Results suggest that the degree to which parents limit or encourage children's food intake is partly influenced by children's genetic predispositions to higher or lower BMI. These findings point to an evocative gene-environment correlation in which heritable characteristics in the child elicit parental feeding behaviour. PMID- 30457988 TI - Deep learning for chest radiograph diagnosis: A retrospective comparison of the CheXNeXt algorithm to practicing radiologists. AB - BACKGROUND: Chest radiograph interpretation is critical for the detection of thoracic diseases, including tuberculosis and lung cancer, which affect millions of people worldwide each year. This time-consuming task typically requires expert radiologists to read the images, leading to fatigue-based diagnostic error and lack of diagnostic expertise in areas of the world where radiologists are not available. Recently, deep learning approaches have been able to achieve expert level performance in medical image interpretation tasks, powered by large network architectures and fueled by the emergence of large labeled datasets. The purpose of this study is to investigate the performance of a deep learning algorithm on the detection of pathologies in chest radiographs compared with practicing radiologists. METHODS AND FINDINGS: We developed CheXNeXt, a convolutional neural network to concurrently detect the presence of 14 different pathologies, including pneumonia, pleural effusion, pulmonary masses, and nodules in frontal view chest radiographs. CheXNeXt was trained and internally validated on the ChestX-ray8 dataset, with a held-out validation set consisting of 420 images, sampled to contain at least 50 cases of each of the original pathology labels. On this validation set, the majority vote of a panel of 3 board-certified cardiothoracic specialist radiologists served as reference standard. We compared CheXNeXt's discriminative performance on the validation set to the performance of 9 radiologists using the area under the receiver operating characteristic curve (AUC). The radiologists included 6 board-certified radiologists (average experience 12 years, range 4-28 years) and 3 senior radiology residents, from 3 academic institutions. We found that CheXNeXt achieved radiologist-level performance on 11 pathologies and did not achieve radiologist-level performance on 3 pathologies. The radiologists achieved statistically significantly higher AUC performance on cardiomegaly, emphysema, and hiatal hernia, with AUCs of 0.888 (95% confidence interval [CI] 0.863-0.910), 0.911 (95% CI 0.866-0.947), and 0.985 (95% CI 0.974-0.991), respectively, whereas CheXNeXt's AUCs were 0.831 (95% CI 0.790-0.870), 0.704 (95% CI 0.567-0.833), and 0.851 (95% CI 0.785-0.909), respectively. CheXNeXt performed better than radiologists in detecting atelectasis, with an AUC of 0.862 (95% CI 0.825-0.895), statistically significantly higher than radiologists' AUC of 0.808 (95% CI 0.777-0.838); there were no statistically significant differences in AUCs for the other 10 pathologies. The average time to interpret the 420 images in the validation set was substantially longer for the radiologists (240 minutes) than for CheXNeXt (1.5 minutes). The main limitations of our study are that neither CheXNeXt nor the radiologists were permitted to use patient history or review prior examinations and that evaluation was limited to a dataset from a single institution. CONCLUSIONS: In this study, we developed and validated a deep learning algorithm that classified clinically important abnormalities in chest radiographs at a performance level comparable to practicing radiologists. Once tested prospectively in clinical settings, the algorithm could have the potential to expand patient access to chest radiograph diagnostics. PMID- 30457990 TI - The use of machine learning to understand the relationship between IgE to specific allergens and asthma. AB - Thomas Platts-Mills and Matthew Perzanowski provide their expert Perspective on a translational study from Custovic and colleagues that identifies pairings of IgE that show value in estimating risk of concurrent asthma. PMID- 30457991 TI - Automated detection of moderate and large pneumothorax on frontal chest X-rays using deep convolutional neural networks: A retrospective study. AB - BACKGROUND: Pneumothorax can precipitate a life-threatening emergency due to lung collapse and respiratory or circulatory distress. Pneumothorax is typically detected on chest X-ray; however, treatment is reliant on timely review of radiographs. Since current imaging volumes may result in long worklists of radiographs awaiting review, an automated method of prioritizing X-rays with pneumothorax may reduce time to treatment. Our objective was to create a large human-annotated dataset of chest X-rays containing pneumothorax and to train deep convolutional networks to screen for potentially emergent moderate or large pneumothorax at the time of image acquisition. METHODS AND FINDINGS: In all, 13,292 frontal chest X-rays (3,107 with pneumothorax) were visually annotated by radiologists. This dataset was used to train and evaluate multiple network architectures. Images showing large- or moderate-sized pneumothorax were considered positive, and those with trace or no pneumothorax were considered negative. Images showing small pneumothorax were excluded from training. Using an internal validation set (n = 1,993), we selected the 2 top-performing models; these models were then evaluated on a held-out internal test set based on area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and positive predictive value (PPV). The final internal test was performed initially on a subset with small pneumothorax excluded (as in training; n = 1,701), then on the full test set (n = 1,990), with small pneumothorax included as positive. External evaluation was performed using the National Institutes of Health (NIH) ChestX-ray14 set, a public dataset labeled for chest pathology based on text reports. All images labeled with pneumothorax were considered positive, because the NIH set does not classify pneumothorax by size. In internal testing, our "high sensitivity model" produced a sensitivity of 0.84 (95% CI 0.78-0.90), specificity of 0.90 (95% CI 0.89-0.92), and AUC of 0.94 for the test subset with small pneumothorax excluded. Our "high specificity model" showed sensitivity of 0.80 (95% CI 0.72-0.86), specificity of 0.97 (95% CI 0.96 0.98), and AUC of 0.96 for this set. PPVs were 0.45 (95% CI 0.39-0.51) and 0.71 (95% CI 0.63-0.77), respectively. Internal testing on the full set showed expected decreased performance (sensitivity 0.55, specificity 0.90, and AUC 0.82 for high sensitivity model and sensitivity 0.45, specificity 0.97, and AUC 0.86 for high specificity model). External testing using the NIH dataset showed some further performance decline (sensitivity 0.28-0.49, specificity 0.85-0.97, and AUC 0.75 for both). Due to labeling differences between internal and external datasets, these findings represent a preliminary step towards external validation. CONCLUSIONS: We trained automated classifiers to detect moderate and large pneumothorax in frontal chest X-rays at high levels of performance on held out test data. These models may provide a high specificity screening solution to detect moderate or large pneumothorax on images collected when human review might be delayed, such as overnight. They are not intended for unsupervised diagnosis of all pneumothoraces, as many small pneumothoraces (and some larger ones) are not detected by the algorithm. Implementation studies are warranted to develop appropriate, effective clinician alerts for the potentially critical finding of pneumothorax, and to assess their impact on reducing time to treatment. PMID- 30457989 TI - Loss of the Mia40a oxidoreductase leads to hepato-pancreatic insufficiency in zebrafish. AB - Development and function of tissues and organs are powered by the activity of mitochondria. In humans, inherited genetic mutations that lead to progressive mitochondrial pathology often manifest during infancy and can lead to death, reflecting the indispensable nature of mitochondrial biogenesis and function. Here, we describe a zebrafish mutant for the gene mia40a (chchd4a), the life essential homologue of the evolutionarily conserved Mia40 oxidoreductase which drives the biogenesis of cysteine-rich mitochondrial proteins. We report that mia40a mutant animals undergo progressive cellular respiration defects and develop enlarged mitochondria in skeletal muscles before their ultimate death at the larval stage. We generated a deep transcriptomic and proteomic resource that allowed us to identify abnormalities in the development and physiology of endodermal organs, in particular the liver and pancreas. We identify the acinar cells of the exocrine pancreas to be severely affected by mutations in the MIA pathway. Our data contribute to a better understanding of the molecular, cellular and organismal effects of mitochondrial deficiency, important for the accurate diagnosis and future treatment strategies of mitochondrial diseases. PMID- 30457992 TI - Healthy volunteers' perceptions of risk in US Phase I clinical trials: A mixed methods study. AB - BACKGROUND: There is limited research on healthy volunteers' perceptions of the risks of Phase I clinical trials. In order to contribute empirically to long standing ethical concerns about healthy volunteers' involvement in drug development, it is crucial to assess how these participants understand trial risks. The objectives of this study were to investigate (1) participants' views of the overall risks of Phase I trials, (2) their views of the risk of personally being harmed in a trial, and (3) how risk perceptions vary across participants' clinical trial history and sociodemographic characteristics. METHODS AND FINDINGS: We qualitatively and quantitatively analyzed semi-structured interviews conducted with 178 healthy volunteers who had participated in a diverse range of Phase I trials in the United States. Participants had collective experience in a reported 1,948 Phase I trials (mean = 10.9; median = 5), and they were interviewed as part of a longitudinal study of healthy volunteers' risk perceptions, their trial enrollment decisions, and their routine health behaviors. Participants' qualitative responses were coded, analyzed, and subsequently quantified in order to assess correlations between their risk perceptions and demographics, such as their race/ethnicity, gender, age, educational attainment, employment status, and household income. We found that healthy volunteers often viewed the overall risks of Phase I trials differently than their own personal risk of harm. The majority of our participants thought that Phase I trials were medium, high, or extremely high risk (118 of 178), but most nonetheless felt that they were personally safe from harm (97 of 178). We also found that healthy volunteers in their first year of clinical trial participation, racial and ethnic minority participants, and Hispanic participants tended to view the overall trial risks as high (respectively, Jonckheere Terpstra, -2.433, p = 0.015; Fisher exact test, p = 0.016; Fisher exact test, p = 0.008), but these groups did not differ in regard to their perceptions of personal risk of harm (respectively, chi-squared, 3.578, p = 0.059; chi-squared, 0.845, p = 0.358; chi-squared, 1.667, p = 0.197). The main limitation of our study comes from quantitatively aggregating data from in-depth interviews, which required the research team to interpret participants' nonstandardized risk narratives. CONCLUSIONS: Our study demonstrates that healthy volunteers are generally aware of and reflective about Phase I trial risks. The discrepancy in healthy volunteers' views of overall and personal risk sheds light on why healthy volunteers might continue to enroll in clinical trials, even when they view trials on the whole as risky. PMID- 30457993 TI - The Ponseti method in children with clubfoot after walking age - Systematic review and metanalysis of observational studies. AB - BACKGROUND: The prevalence of untreated congenital clubfoot among children older than walking age is higher in developing countries due to limited resources for early care after birth. The Ponseti method represents an intervention option for older, untreated children. METHODS: A metanalysis was conducted of observational studies selected through a systematic review of articles included in electronic databases (Medline, Scopus, Embase, Lilacs, and the Cochrane Library) until June 2017. A pooling analysis of proportions with 95% confidence intervals (CIs) and a publication bias assessment were performed as routine. Estimates of success, recurrence, and complication rates were weighted and pooled using the random effects model. RESULTS: Twelve studies, including 654 feet diagnosed with congenital clubfoot in children older than walking age (older than 1 year old), were included for analysis. The rate of satisfactory outcomes found via a cluster metanalysis of proportions using the random effects model was 89% (95% CI = 0.82 0.94, p < 0.01), relative to the total analysed. The recurrence rate was 18% (95% CI = 0.14-0.24, p = 0.015), and the rate of casting complications was 7% (95% CI = 0.03-0.15, p = 0.19). CONCLUSION: Application of the Ponseti method in children with untreated idiopathic clubfoot older than walking age leads to satisfactory outcomes, has a low cost, and avoids surgical procedures likely to cause complications. The results obtained exhibited considerable heterogeneity. PMID- 30457994 TI - Adaptive feature detection from differential processing in parallel retinal pathways. AB - To transmit information efficiently in a changing environment, the retina adapts to visual contrast by adjusting its gain, latency and mean response. Additionally, the temporal frequency selectivity, or bandwidth changes to encode the absolute intensity when the stimulus environment is noisy, and intensity differences when noise is low. We show that the On pathway of On-Off retinal amacrine and ganglion cells is required to change temporal bandwidth but not other adaptive properties. This remarkably specific adaptive mechanism arises from differential effects of contrast on the On and Off pathways. We analyzed a biophysical model fit only to a cell's membrane potential, and verified pharmacologically that it accurately revealed the two pathways. We conclude that changes in bandwidth arise mostly from differences in synaptic threshold in the two pathways, rather than synaptic release dynamics as has previously been proposed to underlie contrast adaptation. Different efficient codes are selected by different thresholds in two independently adapting neural pathways. PMID- 30457995 TI - Reducing chronic disease through changes in food aid: A microsimulation of nutrition and cardiometabolic disease among Palestinian refugees in the Middle East. AB - BACKGROUND: Type 2 diabetes mellitus and cardiovascular disease and have become leading causes of morbidity and mortality among Palestinian refugees in the Middle East, many of whom live in long-term settlements and receive grain-based food aid. The objective of this study was to estimate changes in type 2 diabetes and cardiovascular disease morbidity and mortality attributable to a transition from traditional food aid to either (i) a debit card restricted to food purchases, (ii) cash, or (iii) an alternative food parcel with less grain and more fruits and vegetables, each valued at $30/person/month. METHODS AND FINDINGS: An individual-level microsimulation was created to estimate relationships between food aid delivery method, food consumption, type 2 diabetes, and cardiovascular disease morbidity and mortality using demographic data from the United Nations (UN; 2017) on 5,340,443 registered Palestinian refugees in Syria, Jordan, Lebanon, Gaza, and the West Bank, food consumption data (2011-2017) from households receiving traditional food parcel delivery of food aid (n = 1,507 households) and electronic debit card delivery of food aid (n = 1,047 households), and health data from a random 10% sample of refugees receiving medical care through the UN (2012-2015; n = 516,386). Outcome metrics included incidence per 1,000 person-years of hypertension, type 2 diabetes, atherosclerotic cardiovascular disease events, microvascular events (end-stage renal disease, diabetic neuropathy, and proliferative diabetic retinopathy), and all-cause mortality. The model estimated changes in total calories, sodium and potassium intake, fatty acid intake, and overall dietary quality (Mediterranean Dietary Score [MDS]) as mediators to each outcome metric. We did not observe that a change from food parcel to electronic debit card delivery of food aid or to cash aid led to a meaningful change in consumption, biomarkers, or disease outcomes. By contrast, a shift to an alternative food parcel with less grain and more fruits and vegetables was estimated to produce a 0.08 per 1,000 person-years decrease in the incidence of hypertension (95% confidence interval [CI] 0.05 0.11), 0.18 per 1,000 person-years decrease in the incidence of type 2 diabetes (95% CI 0.14-0.22), 0.18 per 1,000 person-years decrease in the incidence of atherosclerotic cardiovascular disease events (95% CI 0.17-0.19), and 0.02 decrease per 1,000 person-years all-cause mortality (95% CI 0.01 decrease to 0.04 increase) among those receiving aid. The benefits of this shift, however, could be neutralized by a small (2%) increase in compensatory (out-of-pocket) increases in consumption of refined grains, fats and oils, or confectionaries. A larger alternative parcel requiring an increase in total food aid expenditure by 27% would be more likely to have a clinically meaningful improvement on type 2 diabetes and cardiovascular disease incidence. CONCLUSIONS: Contrary to the supposition in the literature, our findings do not robustly support the theory that transitioning from traditional food aid to either debit card or cash delivery alone would necessarily reduce chronic disease outcomes. Rather, an alternative food parcel would be more effective, even after matching current budget ceilings. But compensatory increases in consumption of less healthy foods may neutralize the improvements from an alternative food parcel unless total aid funding were increased substantially. Our analysis is limited by uncertainty in estimates of modeling long-term outcomes from shorter-term trials, focusing on diabetes and cardiovascular outcomes for which validated equations are available instead of all nutrition-associated health outcomes, and using data from food frequency questionnaires in the absence of 24-hour dietary recall data. PMID- 30457996 TI - Two-stage motion artefact reduction algorithm for electrocardiogram using weighted adaptive noise cancelling and recursive Hampel filter. AB - The presence of motion artefacts in ECG signals can cause misleading interpretation of cardiovascular status. Recently, reducing the motion artefact from ECG signal has gained the interest of many researchers. Due to the overlapping nature of the motion artefact with the ECG signal, it is difficult to reduce motion artefact without distorting the original ECG signal. However, the application of an adaptive noise canceler has shown that it is effective in reducing motion artefacts if the appropriate noise reference that is correlated with the noise in the ECG signal is available. Unfortunately, the noise reference is not always correlated with motion artefact. Consequently, filtering with such a noise reference may lead to contaminating the ECG signal. In this paper, a two stage filtering motion artefact reduction algorithm is proposed. In the algorithm, two methods are proposed, each of which works in one stage. The weighted adaptive noise filtering method (WAF) is proposed for the first stage. The acceleration derivative is used as motion artefact reference and the Pearson correlation coefficient between acceleration and ECG signal is used as a weighting factor. In the second stage, a recursive Hampel filter-based estimation method (RHFBE) is proposed for estimating the ECG signal segments, based on the spatial correlation of the ECG segment component that is obtained from successive ECG signals. Real-World dataset is used to evaluate the effectiveness of the proposed methods compared to the conventional adaptive filter. The results show a promising enhancement in terms of reducing motion artefacts from the ECG signals recorded by a cost-effective single lead ECG sensor during several activities of different subjects. PMID- 30457997 TI - Feature selection for the accurate prediction of septic and cardiogenic shock ICU mortality in the acute phase. AB - Circulatory shock is a life-threatening disease that accounts for around one third of all admissions to intensive care units (ICU). It requires immediate treatment, which is why the development of tools for planning therapeutic interventions is required to deal with shock in the critical care environment. In this study, the ShockOmics European project original database is used to extract attributes capable of predicting mortality due to shock in the ICU. Missing data imputation techniques and machine learning models were used, followed by feature selection from different data subsets. Selected features were later used to build Bayesian Networks, revealing causal relationships between features and ICU outcome. The main result is a subset of predictive features that includes well known indicators such as the SOFA and APACHE II scores, but also less commonly considered ones related to cardiovascular function assessed through echocardiograpy or shock treatment with pressors. Importantly, certain selected features are shown to be most predictive at certain time-steps. This means that, as shock progresses, different attributes could be prioritized. Clinical traits obtained at 24h. from ICU admission are shown to accurately predict cardiogenic and septic shock mortality, suggesting that relevant life-saving decisions could be made shortly after ICU admission. PMID- 30457998 TI - Biochemical characterization of extracellular polymeric substances from endodontic biofilms. AB - Apical periodontitis is frequently associated with the presence of bacteria biofilm, which has an indisputable impact on the prognosis of endodontic therapy due to the high resistance to adverse environmental conditions, chemicals, and antibiotic therapy that characterize bacteria within biofilm. The biofilm matrix acts as a protective shield over the encased microorganisms. The aim of this investigation was to identify the main biochemical components of biofilm matrix from endodontic mono- and dual-species biofilms. Enterococcus faecalis and Actinomyces naeslundii were cultured as mono- and dual-species biofilms for 14 days. Crude extracellular polymeric substances (EPSs) from biofilm matrices were extracted using chemical and physical methods. High-performance liquid chromatography, gas chromatography, and mass spectrometry were used to determine the carbohydrate, protein, and fatty acid components. Chemical analysis of the biofilm matrices revealed that they were mainly composed of stachyose, maltose, and mannose carbohydrates. The protein profile in all biofilm samples showed abundant oxidoreductases and chaperone proteins and some virulence- associated proteins mainly located in the membrane surface. High percentages of saturated and monounsaturated fatty acids were identified in all biofilm matrices, with a major prevalence of palmitic, stearic, and oleic acids. Based on the results, it was possible to obtain for the first time a general overview of the biochemical profile of endodontic biofilm matrices. PMID- 30458000 TI - Ambiguity in logic-based models of gene regulatory networks: An integrative multi perturbation analysis. AB - Most studies of gene regulatory network (GRN) inference have focused extensively on identifying the interaction map of the GRNs. However, in order to predict the cellular behavior, modeling the GRN in terms of logic circuits, i.e., Boolean networks, is necessary. The perturbation techniques, e.g., knock-down and over expression, should be utilized for identifying the underlying logic behind the interactions. However, we will show that by using only transcriptomic data obtained by single-perturbation experiments, we cannot observe all regulatory interactions, and this invisibility causes ambiguity in our model. Consequently, we need to employ the data of multiple omics layers (genome, transcriptome, and proteome) as well as multiple perturbation experiments to reduce or eliminate ambiguity in our modeling. In this paper, we introduce a multi-step perturbation experiment to deal with ambiguity. Moreover, we perform a thorough analysis to investigate which types of perturbations and omics layers play the most important role in the unambiguous modeling of the GRNs and how much ambiguity will be eliminated by considering more perturbations and more omics layers. Our analysis shows that performing both knock-down and over-expression is necessary in order to achieve the least ambiguous model. Moreover, the more steps of the perturbation are taken, the more ambiguity is eliminated. In addition, we can even achieve an unambiguous model of the GRN by using multi-step perturbation and integrating transcriptomic, protein-protein interaction, and cis-element data. Finally, we demonstrate the effect of utilizing different types of perturbation experiment and integrating multi-omics data on identifying the logic behind the regulatory interactions in a synthetic GRN. In conclusion, relying on the results of only knock-down experiments and not including as many omics layers as possible in the GRN inference, makes the results ambiguous, unreliable, and less accurate. PMID- 30457999 TI - Augmented concentrations of CX3CL1 are associated with interstitial lung disease in systemic sclerosis. AB - BACKGROUND: Dysregulation of Fractalkine (CX3CL1) and its receptor CX3CR1 has been linked to the pathobiology of chronic inflammatory conditions. We explored CX3CL1 in systemic sclerosis (SSc) related progressive interstitial lung disease (ILD) and pulmonary hypertension (PH) in two different but complementary sources of biomaterial. METHODS: We collected lung tissue at the time of lung transplantation at UCLA from SSc-ILD patients (n = 12) and healthy donors (n = 12); and serum samples from the prospective Oslo University Hospital SSc cohort (n = 292) and healthy donors (n = 100). CX3CL1 was measured by ELISA. Cellular sources of CX3CL1/CX3CR1 in lung tissues were determined by immunohistochemistry and immunofluorescence. ILD progression and new onset PH endpoints were analysed. RESULTS: CX3CL1 concentrations were increased in SSc in lung tissue as well as in sera. In the UCLA cohort, CX3CL1 was highly correlated with DLCO. In the SSc-ILD lungs, CX3CL1 was identified in reactive type II pneumocytes and airway epithelial cells. CX3CR1 stained infiltrating interstitial mononuclear cells, especially plasma cells. In the Oslo cohort, CX3CL1 correlated with anti Topoisomerase-I-antibody and lung fibrosis. CX3CL1 was associated with ILD progression in multivariable regression analysis but not PH. CONCLUSION: CX3CL1 is associated with progressive SSc-ILD but not SSc-PH. The CX3CR1/CX3CL1 biological axis may be involved in recruiting antibody secreting plasma cells to SSc lungs, thereby contributing to the immune-mediated pathobiology of SSc-ILD. PMID- 30458001 TI - Traditional cooking practices and preferences for stove features among women in rural Senegal: Informing improved cookstove design and interventions. AB - Nearly half the world's population burns solid fuel for cooking, heating, and lighting. The incomplete combustion of these fuels is associated with detrimental health and environmental effects. The design and distribution of improved cookstoves that increase combustion efficiency and reduce indoor air pollution are a global priority. However, promoting exclusive and sustainable use of the improved stoves has proved challenging. In 2012, we conducted a survey in a community in rural Senegal to describe stove ownership and preferences for different stove technologies. This report aims to describe local stove and fuel use, to identify household preferences related to stove features and function, and to elicit the community perceptions of cleaner-burning stove alternatives with a focus on liquid propane gas. Similar to many resource-limited settings, biomass fuel use was ubiquitous and multiple stoves were used, even when cleaner burning alternatives were available; less than 1% of households that owned a liquid propane stove used it as the primary cooking device. Despite nearly universal use of the traditional open fire (92% of households), women did not prefer this stove when presented with other options. Propane gas, solar, and improved cookstoves were all viewed as more desirable when compared to the traditional open fire, however first-hand experience and knowledge of these stoves was limited. The stove features of greatest value were, in order: large cooking capacity, minimal smoke production, and rapid heating. Despite the low desirability and smoke emisions from the traditional open fire, its pervasive use, even in the presence of alternative stove options, may be related to its ability to satisfy the practical needs of the surveyed cooks, namely large cooking capacity and rapid, intense heat generation. Our data suggest women in this community want alternative stove options that reduce smoke exposure, however currently available stoves, including liquid propane gas, do not address all of the cooks' preferences. PMID- 30458002 TI - Seasonality modulates the predictive skills of diatom based salinity transfer functions. AB - The value of diatoms as bioindicators in contemporary and palaeolimnological studies through transfer function development has increased in the last decades. While such models represent a tremendous advance in (palaeo) ecology, they leave behind important sources of uncertainties that are often ignored. In the present study we tackle two of the most important sources of uncertainty in the development of diatom salinity inference models: the effect of secondary variables associated to seasonality and the comparison of conventional cross validation methods with a validation based on independent datasets. Samples (diatoms and environmental variables) were taken in spring, summer and autumn in the freshwater and brackish ditches of the province of North Holland in 1993. Different locations of the same province were sampled again in 2008-2010 to validate the models. We found that the abundance of the dominant species significantly changed between the seasons, leading to inconsistent estimates of species optima and tolerances. A model covering intra-annual variability (all seasons combined) provides averages of species optima and tolerances, reduces the effect of secondary variables due to the seasonality effects, thus providing the strongest relationship between salinity and diatom species. In addition, the all season model also reduces the edge effects usually found in all unimodal-based calibration methods. While based on cross-validation all four models seem to perform relatively well, a validation with an independent dataset emphasizes the importance of using models covering intra-annual variability to perform realistic reconstructions. PMID- 30458003 TI - TIMP-1 is a novel serum biomarker for the diagnosis of colorectal cancer: A meta analysis. AB - PURPOSE: Tissue inhibitor of metalloproteinase-1 (TIMP-1) is a glycoprotein involved in cell survival and tumorigenesis. There have been some promising results regarding the diagnostic value of TIMP-1 for patients with colorectal cancer (CRC). The aim of the present study was to assess the diagnostic accuracy and clinical utility of serum TIMP-1 in CRC patients through meta-analysis. METHODS: A systematic search of online databases was performed to collect eligible studies. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), and summary receiver operator characteristic (SROC) curve were generated from accuracy data using the random-effects model. Fagan's nomogram and the likelihood matrix were applied to estimate the clinical utility of TIMP-1. RESULTS: A total of 9 eligible studies with 1886 patients were included. Among the patients, 819 were pathologically diagnosed with CRC, whereas 1067 did not have adenomas or other cancers. The overall sensitivity, specificity, and DOR of TIMP-1 for the diagnosis of CRC were 0.65 (95% confidence interval (CI): 0.57 0.72), 0.87 (95% CI: 0.76-0.94), and 12.73 (95% CI 5.71-28.38), respectively. The area under the SROC was 0.77 (95% CI, 0.73-0.81), suggesting the potential diagnostic value of TIMP-1 in CRC patients. Among patients with a pretest CRC probability of 20%, posttest probabilities were 56% and 9% for positive and negative TIMP-1 results, respectively. CONCLUSIONS: TIMP-1 expression exhibits an upper moderate diagnostic value in CRC, and TIMP-1 assessment may be useful as a noninvasive screening tool for CRC in clinical practice. PMID- 30458005 TI - Deepbinner: Demultiplexing barcoded Oxford Nanopore reads with deep convolutional neural networks. AB - Multiplexing, the simultaneous sequencing of multiple barcoded DNA samples on a single flow cell, has made Oxford Nanopore sequencing cost-effective for small genomes. However, it depends on the ability to sort the resulting sequencing reads by barcode, and current demultiplexing tools fail to classify many reads. Here we present Deepbinner, a tool for Oxford Nanopore demultiplexing that uses a deep neural network to classify reads based on the raw electrical read signal. This 'signal-space' approach allows for greater accuracy than existing 'base space' tools (Albacore and Porechop) for which signals must first be converted to DNA base calls, itself a complex problem that can introduce noise into the barcode sequence. To assess Deepbinner and existing tools, we performed multiplex sequencing on 12 amplicons chosen for their distinguishability. This allowed us to establish a ground truth classification for each read based on internal sequence alone. Deepbinner had the lowest rate of unclassified reads (7.8%) and the highest demultiplexing precision (98.5% of classified reads were correctly assigned). It can be used alone (to maximise the number of classified reads) or in conjunction with other demultiplexers (to maximise precision and minimise false positive classifications). We also found cross-sample chimeric reads (0.3%) and evidence of barcode switching (0.3%) in our dataset, which likely arise during library preparation and may be detrimental for quantitative studies that use multiplexing. Deepbinner is open source (GPLv3) and available at https://github.com/rrwick/Deepbinner. PMID- 30458004 TI - No effect of unacylated ghrelin administration on subcutaneous PC3 xenograft growth or metabolic parameters in a Rag1-/- mouse model of metabolic dysfunction. AB - Ghrelin is a peptide hormone which, when acylated, regulates appetite, energy balance and a range of other biological processes. Ghrelin predominately circulates in its unacylated form (unacylated ghrelin; UAG). UAG has a number of functions independent of acylated ghrelin, including modulation of metabolic parameters and cancer progression. UAG has also been postulated to antagonise some of the metabolic effects of acyl-ghrelin, including its effects on glucose and insulin regulation. In this study, Rag1-/- mice with high-fat diet-induced obesity and hyperinsulinaemia were subcutaneously implanted with PC3 prostate cancer xenografts to investigate the effect of UAG treatment on metabolic parameters and xenograft growth. Daily intraperitoneal injection of 100 MUg/kg UAG had no effect on xenograft tumour growth in mice fed normal rodent chow or 23% high-fat diet. UAG significantly improved glucose tolerance in host Rag1-/- mice on a high-fat diet, but did not significantly improve other metabolic parameters. We propose that UAG is not likely to be an effective treatment for prostate cancer, with or without associated metabolic syndrome. PMID- 30458006 TI - Predicting the risk of emergency admission with machine learning: Development and validation using linked electronic health records. AB - BACKGROUND: Emergency admissions are a major source of healthcare spending. We aimed to derive, validate, and compare conventional and machine learning models for prediction of the first emergency admission. Machine learning methods are capable of capturing complex interactions that are likely to be present when predicting less specific outcomes, such as this one. METHODS AND FINDINGS: We used longitudinal data from linked electronic health records of 4.6 million patients aged 18-100 years from 389 practices across England between 1985 to 2015. The population was divided into a derivation cohort (80%, 3.75 million patients from 300 general practices) and a validation cohort (20%, 0.88 million patients from 89 general practices) from geographically distinct regions with different risk levels. We first replicated a previously reported Cox proportional hazards (CPH) model for prediction of the risk of the first emergency admission up to 24 months after baseline. This reference model was then compared with 2 machine learning models, random forest (RF) and gradient boosting classifier (GBC). The initial set of predictors for all models included 43 variables, including patient demographics, lifestyle factors, laboratory tests, currently prescribed medications, selected morbidities, and previous emergency admissions. We then added 13 more variables (marital status, prior general practice visits, and 11 additional morbidities), and also enriched all variables by incorporating temporal information whenever possible (e.g., time since first diagnosis). We also varied the prediction windows to 12, 36, 48, and 60 months after baseline and compared model performances. For internal validation, we used 5-fold cross validation. When the initial set of variables was used, GBC outperformed RF and CPH, with an area under the receiver operating characteristic curve (AUC) of 0.779 (95% CI 0.777, 0.781), compared to 0.752 (95% CI 0.751, 0.753) and 0.740 (95% CI 0.739, 0.741), respectively. In external validation, we observed an AUC of 0.796, 0.736, and 0.736 for GBC, RF, and CPH, respectively. The addition of temporal information improved AUC across all models. In internal validation, the AUC rose to 0.848 (95% CI 0.847, 0.849), 0.825 (95% CI 0.824, 0.826), and 0.805 (95% CI 0.804, 0.806) for GBC, RF, and CPH, respectively, while the AUC in external validation rose to 0.826, 0.810, and 0.788, respectively. This enhancement also resulted in robust predictions for longer time horizons, with AUC values remaining at similar levels across all models. Overall, compared to the baseline reference CPH model, the final GBC model showed a 10.8% higher AUC (0.848 compared to 0.740) for prediction of risk of emergency admission within 24 months. GBC also showed the best calibration throughout the risk spectrum. Despite the wide range of variables included in models, our study was still limited by the number of variables included; inclusion of more variables could have further improved model performances. CONCLUSIONS: The use of machine learning and addition of temporal information led to substantially improved discrimination and calibration for predicting the risk of emergency admission. Model performance remained stable across a range of prediction time windows and when externally validated. These findings support the potential of incorporating machine learning models into electronic health records to inform care and service planning. PMID- 30458007 TI - De novo protein structure prediction using ultra-fast molecular dynamics simulation. AB - Modern genomics sequencing techniques have provided a massive amount of protein sequences, but experimental endeavor in determining protein structures is largely lagging far behind the vast and unexplored sequences. Apparently, computational biology is playing a more important role in protein structure prediction than ever. Here, we present a system of de novo predictor, termed NiDelta, building on a deep convolutional neural network and statistical potential enabling molecular dynamics simulation for modeling protein tertiary structure. Combining with evolutionary-based residue-contacts, the presented predictor can predict the tertiary structures of a number of target proteins with remarkable accuracy. The proposed approach is demonstrated by calculations on a set of eighteen large proteins from different fold classes. The results show that the ultra-fast molecular dynamics simulation could dramatically reduce the gap between the sequence and its structure at atom level, and it could also present high efficiency in protein structure determination if sparse experimental data is available. PMID- 30458008 TI - Population sequencing reveals clonal diversity and ancestral inbreeding in the grapevine cultivar Chardonnay. AB - Chardonnay is the basis of some of the world's most iconic wines and its success is underpinned by a historic program of clonal selection. There are numerous clones of Chardonnay available that exhibit differences in key viticultural and oenological traits that have arisen from the accumulation of somatic mutations during centuries of asexual propagation. However, the genetic variation that underlies these differences remains largely unknown. To address this knowledge gap, a high-quality, diploid-phased Chardonnay genome assembly was produced from single-molecule real time sequencing, and combined with re-sequencing data from 15 different Chardonnay clones. There were 1620 markers identified that distinguish the 15 clones. These markers were reliably used for clonal identification of independently sourced genomic material, as well as in identifying a potential genetic basis for some clonal phenotypic differences. The predicted parentage of the Chardonnay haplomes was elucidated by mapping sequence data from the predicted parents of Chardonnay (Gouais blanc and Pinot noir) against the Chardonnay reference genome. This enabled the detection of instances of heterosis, with differentially-expanded gene families being inherited from the parents of Chardonnay. Most surprisingly however, the patterns of nucleotide variation present in the Chardonnay genome indicate that Pinot noir and Gouais blanc share an extremely high degree of kinship that has resulted in the Chardonnay genome displaying characteristics that are indicative of inbreeding. PMID- 30458009 TI - Assessing men with erectile dysfunction before and after living donor liver transplantation in real-world practice: Integrating laboratories into clinical settings. AB - OBJECTIVE: To evaluate the predictive role of the Model for End-Stage Liver Disease (MELD) score concerning changes in testosterone levels following living donor liver transplantation (LDLT) and the effects of LDLT on total testosterone and sex hormone-binding globulin (SHBG) levels, the free androgen index (FAI) and erectile function in LDLT recipients. PARTICIPANTS: 41 adult male recipients of LDLT were evaluated before transplantation and six months after LDLT. MAIN OUTCOME MEASURES: We evaluated the effects of LDLT on total testosterone and SHBG levels, the FAI and erectile function in LDLT recipients. In this prospective study, MELD score, serum total testosterone, SHBG levels and FAI were measured in the morning of the operation day and 1 month, 3 months and 6 months after LDLT. The 5-item version of the International Index of Erectile Function (IIEF-5) questionnaire was administered before LDLT and six months after LDLT to evaluate erectile function. RESULTS: The main outcome measure was dynamic parameter changes of total testosterone, SHBG, FAI and erectile dysfunction. The mean FAI value before LDLT was 16.75+/-10.10. The mean FAI was significantly higher 1 month (32.75+/-15.56; p < 0.01), 3 months (25.23+/-10.26; p < 0.01) and 6 months (29.16+/-11.05; p < 0.01) after LDLT. Mean IIEF-5 scores significantly increased after LDLT (from 11.7+/-7.7 before LDLT to 14.7+/-7.5, p< 0.01). CONCLUSIONS: MELD score correlates with severity of hypogonadism in men with end-stage liver disease. LDLT results in a reduction in serum levels of SHBG, an increase in FAI and improvement in erectile function. PMID- 30458010 TI - Relapse to smoking and health-related quality of life: Secondary analysis of data from a study of smoking relapse prevention. AB - BACKGROUND: Previous studies have shown that smoking and smoking cessation may be associated with health-related quality of life (HRQoL). In this study, we compared changes in HRQoL in people who maintained abstinence with people who had relapsed to smoking. METHODS: This was a secondary analysis of data from a trial of a relapse prevention intervention in 1,407 short-term quitters. The European Quality of Life -5 Dimensions (EQ-5D) measured HRQoL at baseline, 3 and 12 months. Smoking outcome was continuous abstinence from 2 to 12 months, and 7-day smoking at 3 and 12 months. We used nonparametric test for differences in EQ-5D utility scores, and chi-square test for dichotomised response to each of the five EQ-5D dimensions. Multivariable regression analyses were conducted to evaluate associations between smoking relapse and HRQoL or anxiety/depression problems. RESULTS: The mean EQ-5D tariff score was 0.8252 at baseline. People who maintained abstinence experienced a statistically non-significant increase in the EQ-5D score (mean change 0.0015, P = 0.88), while returning to smoking was associated with a statistically significant decrease in the EQ-5D score (mean change -0.0270, P = 0.004). After adjusting for multiple baseline characteristics, the utility change during baseline and 12 months was statistically significantly associated with continuous abstinence, with a difference of 0.0288 (95% CI: 0.0006 to 0.0571, P = 0.045) between relapsers and continuous quitters. The only difference in quality of life dimensions between those who relapsed and those who maintained abstinence was in the proportion of participants with anxiety/depression problems at 12 months (30% vs. 22%, P = 0.001). Smoking relapse was associated with a simultaneous increase in anxiety/depression problems. CONCLUSIONS: People who achieve short-term smoking abstinence but subsequently relapse to smoking have a reduced quality of life, which appears mostly due to worsening of symptoms of anxiety and depression. Further research is required to more fully understand the relationship between smoking and health-related quality of life, and to develop cessation interventions by taking into account the impact of anxiety or depression on smoking. PMID- 30458011 TI - The effect of human placental chorionic villi derived mesenchymal stem cell on triple-negative breast cancer hallmarks. AB - Mesenchymal stem cells (MSCs) can influence the tumour microenvironment (TEM) and play a major role in tumourigenesis. Triple-negative [Ostrogen receptor (ER-), Progesterone receptor (PgR-), and HER2/neu receptor (HER2-)] breast cancer (TNBC) is an aggressive class of BC characterized by poor prognosis and lacks the benefit of routinely available targeted therapies. This study aims to investigate the effect of human placental chorionic villi derived MSCs (CVMSCs) on the behavior of TNBC in vitro. This was done by assaying different cancer hallmarks including proliferation, migration and angiogenesis. Cell proliferation rate of TNBC cell line (MDA-MB231) was monitored in real time using the xCELLigence system. Whereas, Boyden chamber migration assay was used to measure MDA-MB231 motility and invasiveness toward CVMSCs. Finally, a three-dimensional (3D) model using a co-culture system of CVMSCs with MDA-MB231 with or without the addition of human umbilical vein endothelial cells (HUVECs) was created to assess tumour angiogenesis in vitro. CVMSCs were able to significantly reduce the proliferative and migratory capacity of MDA-MB231 cells. Co-culturing of MDA-MB231 with CVMSCs, not only inhibited the tube formation ability of HUVECs but also reduced the expression of the BC characteristic cytokines; IL-10, IL-12, CXCL9 and CXCL10 of CVMSCs. These results support the hypothesis that CVMSCs can influence the behavior of TNBC cells and provides a basic for a potential therapeutic approach in a pre-clinical settings. The data from this study also highlight the complexity of the in vitro cancer angiogenesis model settings and regulations. PMID- 30458012 TI - Questioning the long-term stability of the additive model in comorbid CTD+ADHD - The transition from childhood to adulthood. AB - BACKGROUND: A previous study (Roessner et al. 2007) found psychopathological evidence of an additive model of the comorbid group with Chronic Tic Disorders and Attention Deficit Hyperactivity Disorder (CTD+ADHD), which demanded clinical interventions aimed primarily at the factor ADHD. This 14-year follow-up study tested whether this childhood additive model can also be found in young adulthood and whether ADHD remains the most impairing factor. METHODS: 92 patients (22.8% girls) from Roessner et al. (2007) were re-investigated as young adults at the age of 24 years, broken down into four groups: CTD-only (n = 22), CTD+ADHD (n = 23), ADHD-only (n = 24), and controls (n = 23). The Adult Behavior Checklist (ABCL) was used as an equivalent parent-report instrument to the Child Behavior Checklist (CBCL) applied 14 years ago. Statistically, 2x2 factorial design was completed. RESULTS: From the point of view of parents, the factors CTD and ADHD in young adults contributed almost equally to psychopathological problems and showed many interactions, i.e. an interactive model was supported. In addition, the ADHD factor was no longer the leading problem for psychosocial impairment in the adult CTD+ADHD group. CONCLUSION: The additive model of CTD+ADHD seems to exist no longer in young adults, nor may the childhood predominance of the factor ADHD in comorbid CTD+ADHD. Thus, treatment priority should be decided by clinicians on a case-by-case basis depending on the most impairing disorder of each patient. PMID- 30458013 TI - Impact of a custom-made 3D printed ergonomic grip for direct laryngoscopy on novice intubation performance in a simulated easy and difficult airway scenario-A manikin study. AB - Direct laryngoscopy using a Macintosh laryngoscope is the most widely used approach; however, this skill is not easy for novices and trainees. We evaluated the performance of novices using a laryngoscope with a three-dimensional (3D) printed ergonomic grip on an airway manikin. Forty second-year medical students were enrolled. Endotracheal intubation was attempted using a conventional Macintosh laryngoscope with or without a 3D-printed ergonomic support grip. Primary outcomes were intubation time and overall success rate. Secondary outcomes were number of unsuccessful attempts, first-attempt success rate, airway Cormack-Lehane (CL) grade, and difficulty score. In the easy airway scenario, intubation time, and the overall success rate were similar between two group. CL grade and ease-of-use scores were significantly better for those using the ergonomic support grip (P < 0.05). In the difficult airway scenario, intubation time (49.7+/-37.5 vs. 35.5+/-29.2, P = 0.013), the first-attempt success rate (67.5% vs. 90%, P = 0.029), number of attempts (1.4+/-0.6 vs. 1.1+/-0.4, P = 0.006), CL grade (2 [2, 2] vs. 2 [1, 1], P = 0.012), and ease-of-use scores (3.5 [2, 4] vs. 4 [3, 5], P = 0.008) were significantly better for those using the ergonomic support grip. Linear mixed model analysis showed that the ergonomic support grip had a favorable effect on CL grade (P<0.001), ease-of-use scores (P<0.001), intubation time (P = 0.015), and number of intubation attempts (P = 0.029). Our custom 3D-printed ergonomic laryngoscope support grip improved several indicators related to the successful endotracheal intubation in the easy and difficult scenario simulated on an airway manikin. This grip may be useful for intubation training and practice. PMID- 30458014 TI - Touching beliefs: Using touchscreen technology to elicit subjective expectations in survey research. AB - When making decisions under uncertainty, individuals may form subjective expectations about probabilities of events relevant for their choice. Accurate measurement of subjective expectations is critical for high-quality data needed to analyze individual behavior. This paper reports the development and validity of a new method of eliciting point subjective expectations in developing countries. We developed a touchscreen-based application that combines an animated slider along with dynamic images that change relative sizes based on the probability indicated by the respondent. We compare our method to the more traditional approach of using beans as visual aids. First, we find that respondents have a sound understanding of basic concepts of probability. Second, we test for equality of the distributions elicited with the different methods and find them highly comparable. Third, we provide evidence that respondents report a more favorable opinion about the slider method and more willingness to complete long surveys using the slider rather than beans. Our findings suggest that the slider could be a viable elicitation method for empirical researchers who aim to collect data on subjective expectations in developing countries. PMID- 30458015 TI - Establishing company level fishing revenue and profit losses from fisheries: A bottom-up approach. AB - A third of global fish stocks are overexploited and many are economically underperforming, resulting in potential unrealized net economic benefits of USD 51 to 83 billion annually. However, this aggregate view, while useful for global policy discussion, may obscure the view for those actors who engage at a regional level. Therefore, we develop a method to associate large companies with their fishing operations and evaluate the biological sustainability of these operations. We link current fish biomass levels and landings to the revenue streams of the companies under study to compute potentially unrealized fisheries revenues and profits at the level of individual firms. We illustrate our method using two case studies: anchoveta (Engraulis ringens; Engraulidae) in Peru and menhaden in the USA (Brevoortia patronus and B. tyrannus; Clupeidae). We demonstrate that both these fisheries could potentially increase their revenues compared to the current levels of exploitation. We estimate the net but unrealized fishery benefits for the companies under question. This information could be useful to investors and business owners who might want to be aware of the actual fisheries performance options of the companies they invest in. PMID- 30458016 TI - Logical validation and evaluation of practical feasibility for the SCRuM (School Clinical Rugby Measure) test battery developed for young adolescent rugby players in a resource-constrained environment. AB - There is a growing impetus towards usage of test batteries in talent identification (TID) programmes in rugby. Consequently, there are many test batteries in existence profiling anthropometric, physiological characteristics and rugby-specific skills. There is no consensus in the literature on the constituent variables and corresponding tests required to inform TID programs. Following development of a new test battery called the SCRuM (School Clinical Rugby Measure), this study aimed at establishing face, logical validity and practical feasibility of included tests. The test battery, initially comprised of 23 items, had its face and logical validity evaluated by five (5) adolescent rugby coaches and 20 rugby experts, respectively. Logical validation was conducted in two questionnaire-based rounds with Content Validity Index (I-CVI) calculated for each variable. Subsequently, a cross-sectional study targeting 30 local rugby coaches was conducted to determine the perceived practical feasibility of each test item. The results showed excellent I-CVI (>0.78) for 17 variables (speed, weight, height and skin fold measures, repeated high-intensity exercise performance ability, prolonged high-intensity intermittent running ability, change of direction speed, anaerobic capacity, lower-and upper body muscular power and strength, muscular flexibility, reactive agility, passing for accuracy, tackling proficiency, and catching). However, three tests, namely, Reactive Agility, One Repetition Maximum Back Squat and One Repetition Maximum Bench Press had low test-feasibility indices (T-FI< 35) suggesting practicality concerns with implementation in the Zimbabwean context. Thus, these findings suggest the need for substitution or development of new practically feasible tests for upper-and lower body muscular strength and reactive agility. PMID- 30458017 TI - Tumor-based gene expression biomarkers to predict survival following curative intent resection for stage I lung adenocarcinoma. AB - BACKGROUND: Prognostic biomarkers are needed in clinical setting to predict outcome after resection for early-stage lung adenocarcinoma. The goal of this study is to validate tumor-based single-gene expression biomarkers with demonstrated prognostic value in order to move them along the clinical translation pipeline. METHODS: Prognostic genes were selected from the literature and the best candidates measured by quantitative real-time polymerase chain reaction (qPCR) in tumors of 233 patients with stage I adenocarcinoma. Significant prognostic genes were then validated in an independent set of 210 patients matching the first set in terms of histology, stage, and clinical data. RESULTS: Eleven genes with demonstrated prognostic value were selected from the literature. Complementary analyses in public databases and our own microarray dataset led to the investigation of six genes associated with good (BTG2, SELENBP1 and NFIB) or poor outcome (RRM1, EZH2 and FOXM1). In the first set of patients, EZH2 and RRM1 were significantly associated with better survival on top of age, sex and pathological stage (EZH2 p = 3.2e-02, RRM1 p = 5.9e-04). The prognostic values of EZH2 and RRM1 were not replicated in the second set of patients. A trend was observed for both genes in the joint analyses (n = 443) with higher expression associated with worse outcome. CONCLUSION: Adenocarcinoma specific mRNA expression levels of EZH2 and RRM1 are associated with poor post surgical survival in the first set of patients, but not replicated in a clinically and pathologically matched independent validation set. This study highlights challenges associated with clinical translation of prognostic biomarkers. PMID- 30458018 TI - Lysine at position 329 within a C-terminal dilysine motif is crucial for the ER localization of human SLC35B4. AB - SLC35B4 belongs to the solute carrier 35 (SLC35) family whose best-characterized members display a nucleotide sugar transporting activity. Using an experimental model of HepG2 cells and indirect immunofluorescent staining, we verified that SLC35B4 was localized to the endoplasmic reticulum (ER). We demonstrated that dilysine motif, especially lysine at position 329, is crucial for the ER localization of this protein in human cells and therefore one should use protein C-tagging with caution. To verify the importance of the protein in glycoconjugates synthesis, we generated SLC35B4-deficient HepG2 cell line using CRISPR-Cas9 approach. Our data showed that knock-out of the SLC35B4 gene does not affect major UDP-Xyl- and UDP-GlcNAc-dependent glycosylation pathways. PMID- 30458019 TI - Associations between CT-determined visceral fat burden, hepatic steatosis, circulating white blood cell counts and neutrophil-to-lymphocyte ratio. AB - Visceral adiposity is associated with cardiovascular disease, an association that may be mediated in part by inflammation. We hypothesized that regional measures of visceral adiposity would associate with commonly obtained clinical measures of immune status. We consecutively studied 3,291 subjects (mean age, 49.8+/-9.8 years) who underwent an annual cardiovascular risk survey. Peri-cardial (PCF) and thoracic peri-aortic adipose tissue (TAT) volumes were determined by dedicated computed tomography (CT) software (Aquarius 3D Workstation, TeraRecon, San Mateo, CA, USA). Hepatic steatosis was assessed by abdominal ultrasonography. We explored cross-sectional associations between visceral fat measures and high sensitivity C-reactive protein (hs-CRP), leukocyte counts, and the neutrophil-to lymphocyte ration (NLR). Among 3,291 study participants, we observed positive linear associations between PCF and TAT, higher degree of hepatic steatosis and hs-CRP, various leukocyte counts, either total and its differential counts, and NLR (all trend p<0.001). Multi-variate linear and logistic regression models showed independent associations between PCF/TAT (beta-Coef: 0.14/0.16, both p<0.05) and total WBC counts, with only TAT further demonstrated significant relations with neutrophil counts and NLR (both p<0.05) and independently identified abnormally high WBC and NLR (Odds ratio: 1.18 & 1.21, both p<0.05). C statistics showed significant incremental model prediction for abnormally high WBC and NLR (both DeltaAUROC<0.05) when TAT was superimposed on traditional cardiovascular risks and biochemical information. Greater visceral adiposity burden and hepatic steatosis may be associated with higher circulating leukocyte counts and markers for atherosclerosis, with more pronounced influences for peri aortic adiposity. Our data suggested the differential biological impacts for region-specific visceral adiposity. PMID- 30458020 TI - Four model variants within a continuous forensic DNA mixture interpretation framework: Effects on evidential inference and reporting. AB - Continuous mixture interpretation methods that employ probabilistic genotyping to compute the Likelihood Ratio (LR) utilize more information than threshold-based systems. The continuous interpretation schemes described in the literature, however, do not all use the same underlying probabilistic model and standards outlining which probabilistic models may or may not be implemented into casework do not exist; thus, it is the individual forensic laboratory or expert that decides which model and corresponding software program to implement. For countries, such as the United States, with an adversarial legal system, one can envision a scenario where two probabilistic models are used to present the weight of evidence, and two LRs are presented by two experts. Conversely, if no independent review of the evidence is requested, one expert using one model may present one LR as there is no standard or guideline requiring the uncertainty in the LR estimate be presented. The choice of model determines the underlying probability calculation, and changes to it can result in non-negligible differences in the reported LR or corresponding verbal categorization presented to the trier-of-fact. In this paper, we study the impact of model differences on the LR and on the corresponding verbal expression computed using four variants of a continuous mixture interpretation method. The four models were tested five times each on 101, 1-, 2- and 3-person experimental samples with known contributors. For each sample, LRs were computed using the known contributor as the person of interest. In all four models, intra-model variability increased with an increase in the number of contributors and with a decrease in the contributor's template mass. Inter-model variability in the associated verbal expression of the LR was observed in 32 of the 195 LRs used for comparison. Moreover, in 11 of these profiles there was a change from LR > 1 to LR < 1. These results indicate that modifications to existing continuous models do have the potential to significantly impact the final statistic, justifying the continuation of broad-based, large-scale, independent studies to quantify the limits of reliability and variability of existing forensically relevant systems. PMID- 30458021 TI - East-West cultural differences in encoding objects in imagined social contexts. AB - It has been shown in literature that East Asians are more inclined to process context information than individuals in Western cultures. Using a context memory task that requires studying object images in social contexts (i.e., rating objects in an imagined social or experiential scenario), our recent study revealed an age-invariant advantage for Chinese young and older participants compared to their Canadian counterparts in memory for encoding contexts. To examine whether this cultural difference also occurred during encoding, this follow-up report analyzed encoding performance and its relationship to subsequent memory based on the same data from the same task of the same sample. The results revealed that at encoding, Chinese participants provided higher ratings of objects, took longer to rate, and reported more vivid imagery of encoding contexts relative to their Canadian counterparts. Furthermore, only Chinese participants rated objects with recognized context at retrieval higher and slower relative to those with misrecognized context. For Chinese participants, primarily older adults, slower ratings were only related to better context memory but not item memory. Importantly, Chinese participants' context memory advantage disappeared after controlling for encoding differences. Taken together, these results suggest that Chinese participants' memory advantage for social contexts may have its origin in the construction of elaborative and meaningful object context associations at encoding. PMID- 30458022 TI - Epigenetic outlier profiles in depression: A genome-wide DNA methylation analysis of monozygotic twins. AB - Recent discoveries highlight the importance of stochastic epigenetic changes, as indexed by epigenetic outlier DNA methylation signatures, as a valuable tool to understand aberrant cell function and subsequent human pathology. There is evidence of such changes in different complex disorders as diverse as cancer, obesity and, to a lesser extent, depression. The current study was aimed at identifying outlying DNA methylation signatures of depressive psychopathology. Here, genome-wide DNA methylation levels were measured (by means of Illumina Infinium HumanMethylation450 Beadchip) in peripheral blood of thirty-four monozygotic twins informative for depressive psychopathology (lifetime DSM-IV diagnoses). This dataset was explored to identify outlying epigenetic signatures of depression, operationalized as extreme hyper- or hypo-methylation in affected co-twins from discordant pairs that is not observed across the rest of the study sample. After adjusting for blood cell count, there were thirteen CpG sites across which depressed co-twins from the discordant pairs exhibited outlying DNA methylation signatures. None of them exhibited a methylation outlier profile in the concordant and healthy pairs, and some of these loci spanned genes previously associated with neuropsychiatric phenotypes, such as GHSR and KCNQ1. This exploratory study provides preliminary proof-of-concept validation that epigenetic outlier profiles derived from genome-wide DNA methylation data may be related to depression risk. PMID- 30458023 TI - Mutation of a serine near the catalytic site of the choline acetyltransferase a gene almost completely abolishes motility of the zebrafish embryo. AB - In zebrafish, the gene choline acetyltransferase a (chata) encodes one of the two ChAT orthologs responsible for the synthesis of acetylcholine. Acetylcholine (ACh) is essential for neuromuscular transmission and its impaired synthesis by ChAT can lead to neuromuscular junction disorders such as congenital myasthenic syndromes in humans. We have identified a novel mutation in the chata gene of zebrafish, chatatk64, in a collection of uncharacterised ENU-induced mutants. This mutant carries a missense mutation in the codon of a highly conserved serine changing it to an arginine (S102R). This serine is conserved among ChATs from zebrafish, rat, mice and chicken to humans. It resides within the catalytic domain and in the vicinity of the active site of the enzyme. However, it has not been reported so far to be required for enzymatic activity. Modelling of the S102R variant change in the ChAT protein crystal structure suggests that the change affects protein structure and has a direct impact on the catalytic domain of the protein which abolishes embryo motility almost completely. PMID- 30458024 TI - Mixed blessings: A qualitative exploration of mothers' experience of child care and feeding in the rapidly urbanizing city of Addis Ababa, Ethiopia. AB - Many studies have drawn attention to the vital role mothers have in safeguarding the health and nutritional wellbeing of their children. However, little is known about mothers' experiences and the challenges they face in fulfilling this role in rapidly urbanizing cities in Africa. This study aims to explore child care and feeding practices of mothers with children under five years of age in Addis Ababa, Ethiopia. This qualitative study was conducted using a semi-structured interview guide. A total of thirty-six interviews were conducted with purposively selected participants. All interviews were audio recorded, transcribed verbatim and translated for analysis. We used a thematic analysis approach, which was guided by a resilience framework. The findings are presented as three major themes. 1) 'Mixed blessings-balancing motherhood's expectations'. While mothers identified positively with the social recognition and sense of fulfillment of being a 'good mother', they were ambivalent/torn about earning the necessary income from outside work and fulfilling their duties at home. 2) 'Instabilities due to rampant urban sprawl'. While women expressed a keen desire to balance work and motherhood, the disintegrating social capital, due to large in-migration, market fluctuations and abrupt/forced resettlements to new housing units had left mothers without support for childcare, stressed and exhausted. 3) 'Anchored by faith: a source of resilience to cope with adversities'. In the face of the multiple adversities, mothers cited their strong faith as their most reliable foundation for their resilience. In summary, the societal and environmental changes accompanying the rapid urbanization in low income settings makes combining child care and working outside the home very challenging for mothers. As a result they suffer from fatigue and feelings of isolation. Efforts to improve child feeding and care in urban low-income settings need to consider context appropriate strategies that support mothers with small children. PMID- 30458025 TI - Description of grain weight distribution leading to genomic selection for grain filling characteristics in rice. AB - Grain-filling ability is one of the factors that controls grain yield in rice (Oryza sativa L.). We developed a method for describing grain weight distribution, which is the probability density function of single grain weight in a panicle, using 128 Japanese rice varieties. With this method, we quantitively analyzed genotypic differences in grain-filling ability and used the grain weight distribution parameters for genomic prediction subject to genetic improvement in grain yield in rice. The novel description method could represent the observed grain weight distribution with five genotype-specific parameters of a mixture of two gamma distributions. The estimated genotype-specific parameters representing the proportion of filled grains had applicability to explain the grain filling ability of genotypes comparable to that of sink-filling rate and the conventionally measured proportion of filled grains, which suggested the efficiency and flexibility of grain weight distribution parameters to handle several genotypes. We revealed that perfectly filled grains have to be prioritized over partially filled grains for the optimum allocation of the source of yield in a panicle, from the analysis for obtaining an ideal shape of grain weight distribution. We conducted genomic prediction of grain weight distribution considering five genotype-specific parameters of the distribution as phenotypes relating to grain filling ability. The proportion of filled grains, average weight of filled grains, and variance of filled grain weight, which were considered to control grain yield to a certain degree, were predicted with accuracies of 0.30, 0.28, and 0.53, respectively. The proposed description method of grain weight distribution facilitated not only the investigation of the optimum allocation of nutrients in a panicle for realizing high grain-filling ability, but also allowed genomic selection of grain weight distribution. PMID- 30458026 TI - Lifestyle factors and high body mass index are associated with different multimorbidity clusters in the Brazilian population. AB - Multimorbidity patterns of a population can be influenced by socioeconomic and lifestyle-related factors. Some of these factors are preventable when healthy habits are promoted to the population. This study analyzed the main grouping patterns of chronic diseases and the relationship with socioeconomic and lifestyle-related factors of the Brazilian population (over the age of 18), based on a population-based survey (2013 National Health Survey). A total of 60,202 participants were included. Cluster analysis was carried out to identify the combinations of chronic diseases. Bivariate and multivariate analyses were carried out to verify the relationship between disease clusters and independent variables, utilizing Poisson's regression with robust variance, considering a 95% confidence interval. Cluster analysis revealed four disease clusters:cardiometabolic diseases/cancer, mental/occupational diseases, musculoskeletal diseases and respiratory diseases, all significantly associated with the female gender, current/past smoking habits and overweight/obesity in multivariate analyses. These aspects must be considered when planning health services and developing strategies and guidelines for the prevention and treatment of multiple chronic conditions. PMID- 30458027 TI - On the limit value of compactness of some graph classes. AB - In this paper, we study the limit of compactness which is a graph index originally introduced for measuring structural characteristics of hypermedia. Applying compactness to large scale small-world graphs (Mehler, 2008) observed its limit behaviour to be equal 1. The striking question concerning this finding was whether this limit behaviour resulted from the specifics of small-world graphs or was simply an artefact. In this paper, we determine the necessary and sufficient conditions for any sequence of connected graphs resulting in a limit value of CB = 1 which can be generalized with some consideration for the case of disconnected graph classes (Theorem 3). This result can be applied to many well known classes of connected graphs. Here, we illustrate it by considering four examples. In fact, our proof-theoretical approach allows for quickly obtaining the limit value of compactness for many graph classes sparing computational costs. PMID- 30458029 TI - Feature selection and prediction of treatment failure in tuberculosis. AB - BACKGROUND: Tuberculosis is a major cause of morbidity and mortality in the developing world. Drug resistance, which is predicted to rise in many countries worldwide, threatens tuberculosis treatment and control. OBJECTIVE: To identify features associated with treatment failure and to predict which patients are at highest risk of treatment failure. METHODS: On a multi-country dataset managed by the National Institute of Allergy and Infectious Diseases we applied various machine learning techniques to identify factors statistically associated with treatment failure and to predict treatment failure based on baseline demographic and clinical characteristics alone. RESULTS: The complete-case analysis database consisted of 587 patients (68% males) with a median (p25-p75) age of 40 (30-51) years. Treatment failure occurred in approximately one fourth of the patients. The features most associated with treatment failure were patterns of drug sensitivity, imaging findings, findings in the microscopy Ziehl-Nielsen stain, education status, and employment status. The most predictive model was forward stepwise selection (AUC: 0.74), although most models performed at or above AUC 0.7. A sensitivity analysis using the 643 original patients filling the missing values with multiple imputation showed similar predictive features and generally increased predictive performance. CONCLUSION: Machine learning can help to identify patients at higher risk of treatment failure. Closer monitoring of these patients may decrease treatment failure rates and prevent emergence of antibiotic resistance. The use of inexpensive basic demographic and clinical features makes this approach attractive in low and middle-income countries. PMID- 30458028 TI - Diversity across major and candidate genes in European local pig breeds. AB - The aim of this work was to analyse the distribution of causal and candidate mutations associated to relevant productive traits in twenty local European pig breeds. Also, the potential of the SNP panel employed for elucidating the genetic structure and relationships among breeds was evaluated. Most relevant genes and mutations associated with pig morphological, productive, meat quality, reproductive and disease resistance traits were prioritized and analyzed in a maximum of 47 blood samples from each of the breeds (Alentejana, Apulo-Calabrese, Basque, Bisara, Majorcan Black, Black Slavonian (Crna slavonska), Casertana, Cinta Senese, Gascon, Iberian, Krskopolje (Krskopoljski), Lithuanian indigenous wattle, Lithuanian White Old Type, Mora Romagnola, Moravka, Nero Siciliano, Sarda, Schwabisch-Hallisches Schwein (Swabian Hall pig), Swallow-Bellied Mangalitsa and Turopolje). We successfully analyzed allelic variation in 39 polymorphisms, located in 33 candidate genes. Results provide relevant information regarding genetic diversity and segregation of SNPs associated to production and quality traits. Coat color and morphological trait-genes that show low level of segregation, and fixed SNPs may be useful for traceability. On the other hand, we detected SNPs which may be useful for association studies as well as breeding programs. For instance, we observed predominance of alleles that might be unfavorable for disease resistance and boar taint in most breeds and segregation of many alleles involved in meat quality, fatness and growth traits. Overall, these findings provide a detailed catalogue of segregating candidate SNPs in 20 European local pig breeds that may be useful for traceability purposes, for association studies and for breeding schemes. Population genetic analyses based on these candidate genes are able to uncover some clues regarding the hidden genetic substructure of these populations, as the extreme genetic closeness between Iberian and Alentejana breeds and an uneven admixture of the breeds studied. The results are in agreement with available knowledge regarding breed history and management, although largest panels of neutral markers should be employed to get a deeper understanding of the population's structure and relationships. PMID- 30458031 TI - The prevalence of adult-onset isolated dystonia in Finland 2007-2016. AB - BACKGROUND: Dystonia is a group of chronic diseases, causing considerable physical and psychosocial stress to patients and health care expenses. We studied the prevalence of different dystonia types in Finland in the years 2007-2016. METHODS: All patients with an ICD-10 code of dystonia were retrieved from the national care register. Average age-adjusted yearly prevalence was assessed for adult-onset isolated idiopathic or hereditary dystonia types from patient records from the Uusimaa and Pirkanmaa provinces. RESULTS: 1316 patients were confirmed to have adult-onset isolated idiopathic or hereditary dystonia based on hospital records from two provinces. On average, the age-adjusted prevalence for all adult onset dystonia was 405 per million and for cervical dystonia 304 per million. For other dystonia types the prevalence ranged from 1-33 per million. CONCLUSIONS: Adult onset cervical dystonia was the most common type of dystonia with relatively high prevalence in Finland compared with other countries. The prevalence of other types of dystonia was similar compared with other European studies. The higher prevalence of cervical dystonia may be partially explained by the better coverage of patients in public health care, but genetic and exogenous factors might contribute to it. PMID- 30458032 TI - Spectral features of nuclear DNA in human sperm assessed by Raman Microspectroscopy: Effects of UV-irradiation and hydration. AB - Raman Microspectroscopy represents an innovative tool for the assessment of sperm biochemical features otherwise undetectable by routine semen analysis. Previously, it was shown that induced DNA damage can be detected in smeared sperm by this technique. This novel readout may be of value for clinical settings especially if it can be transferred to living cells. Yet, starting with living sperms this study was carried-out using a variety of conditions to disclose the Raman features of sperm nuclei under different hydration conditions and UV exposure. Human sperm were immobilized and Raman spectra were obtained from individual sperm as repeated measurements. To create conditions with controlled DNA damage, sperm samples were exposed to ultraviolet light. Several media were used to evaluate their effect on Raman spectra in aqueous conditions. To substantiate differences between the experimental conditions, the spectra were analyzed by Principal Component Analysis. We observed that spectra of sperm nuclei obtained in different solutions showed a qualitatively unchanged spectral pattern showing the principal signals related to DNA. Evaluating the effect of ultraviolet light generated the finding that spectra representing DNA damage were only observed in dry conditions but not in aqueous medium. Thus, Raman microspectroscopy was successfully applied for sperm analysis in different conditions, among them in live spermatozoa in aqueous solution during the initial measurement, revealing the principle use of this technique. However, implementation of Raman spectroscopy as a technique for clinical sperm analysis and selection may be especially relevant when DNA evaluation can be established using live sperm. PMID- 30458030 TI - The overlap syndrome of urticaria and gastroesophageal reflux disease. AB - BACKGROUND: One-quarter of systemic symptoms associated with chronic spontaneous urticaria (CSU) are related to gastrointestinal complaints (GICs). OBJECTIVES: To investigate the prevalence and features of urticaria-overlapping GICs. METHODS: In this retrospective cross-sectional survey, 1426 consecutive outpatients were observed at our University Department. Only patients suffering from urticaria or GICs with a complete diagnostic work-up including serum total IgE level (Tot IgE), differential blood count and urticaria activity score (UAS), were evaluated. RESULTS: Among different GICs, gastroesophageal reflux disease (GERD) was the most frequent syndrome observed (15.4%; 95%CI: 13.6-17.3). The prevalence of overlap syndrome for urticaria and GERD was 5.9% (95%CI: 4.7-7.2). In urticaria-patients, the prevalence of GERD was four-fold higher than in patients without hives (44% vs. 11%, p<0.001). UAS was significantly higher in urticaria and GERD overlap syndromes vs. isolated urticarias. In patients with GERD or acute/chronic urticaria or overlap syndrome, Tot-IgE and eosinophil blood count (EBC) differed significantly, with a stepwise increase in their values; from the subgroup of patients with GERD only, to that with overlap of CSU to GERD. Prevalence values for urticaria overlapping with GERD were three- and two-fold higher in CSU and in long-duration GERD cases respectively compared to acute urticaria or short-duration GERD cases. Similar to Th2 pathology models, CSU and GERD overlap syndrome was significantly and independently associated with Total IgE >=100IU/ml or EBC >=250/mmc compared to CSU or GERD. Endoscopic/bioptic findings of non-erosive reflux disease (NERD) or Barrett's esophagus (BE) were more frequent in chronic overlap syndrome than in GERD-patients. CONCLUSIONS: GERD was the most frequent GIC in patients with urticaria. Overlap syndrome was more frequent among patients with CSU, where this syndrome was associated with higher values of UAS, Tot-IgE, EBC and frequencies of NERD and BE. These results suggest that overlap syndrome is frequently a chronic syndrome with a Th2-like profile. PMID- 30458033 TI - Incidence risk of various types of digestive cancers in patients with pre dialytic chronic kidney disease: A nationwide population-based cohort study. AB - Although renal dysfunction is associated with a higher incidence of malignancies, there is no research on the incidence of specific types of digestive cancer in pre-dialytic chronic kidney disease (CKD) patients compared to the general population. This study was conducted on newly diagnosed pre-dialytic CKD patients (n = 35,443) between 2003 and 2013 using the National Health Insurance Service National Sample Cohort in Korea. The risk of digestive cancer development in pre dialytic CKD patients was calculated as the standardized incidence ratio (SIR). During a median follow-up of 54.9 months, the risk of digestive cancer in CKD patients was significantly higher than in the cohort population [SIR; 1.54, 95% confidence interval (95% CI); 1.46-1.62], the SIR of pancreatic cancer was 2.21, and the SIRs of hepatoma, colorectal cancer (CRC), bile duct cancer, and gastric cancer were 2.01, 1.60, 1.40, and 1.25, respectively. Moreover, in CKD patients younger than 40 years, the incidence ratios of hepatoma and CRC were remarkably larger compared with the cohort population of the same age (SIR; 5.98 in hepatoma, 4.58 in CRC). However, the incidence of specific types of digestive cancer seemed to be similar, irrespective of sex. In conclusion, digestive cancers were more frequently observed in CKD-diagnosed patients compared with a cohort population in Korea, which suggests that physicians should closely monitor their patients for the incidence of digestive cancer when they are diagnosed with CKD. PMID- 30458034 TI - Application-aware deadline constraint job scheduling mechanism on large-scale computational grid. AB - Recently, computational Grids have proven to be a good solution for processing large-scale, computation intensive problems. However, the heterogeneity, dynamics of resources and diversity of applications requirements have always been important factors affecting their performance. In response to these challenges, this work first builds a Grid job scheduling architecture that can dynamically monitor Grid computing center resources and make corresponding scheduling decisions. Second, a Grid job model is proposed to describe the application requirements. Third, this paper studies the characteristics of commercial interconnection networks used in Grids and forecast job transmission time. Fourth, this paper proposes an application-aware job scheduling mechanism (AJSM) that includes periodic scheduling flow and a heuristic application-aware deadline constraint job scheduling algorithm. The rigorous performance evaluation results clearly demonstrate that the proposed application-aware job scheduling mechanism can successful schedule more Grid jobs than the existing algorithms. For successful scheduled jobs, our proposed AJSM method is the best algorithm for job average processing time and makespan. PMID- 30458035 TI - Association between age-related factors and extubation failure in elderly patients. AB - BACKGROUND: Elderly patients are being increasingly admitted to the intensive care unit (ICU) for mechanical ventilation. Previous studies demonstrated that 20% to 35% of elderly patients were reintubated within 48 to 72 hours after extubation. Given the age-related physiologic changes and multiple comorbidities in elderly patients, the current conventional parameters for predicting extubation outcomes may not be applicable to this population. This study was performed to identify the association between age-related parameters and extubation failure in elderly patients. METHODS: Intubated elderly patients (age of >=60 years) admitted to the medical ICU of a university-based hospital from October 2014 to July 2015 were included. Failed extubation was defined as reintubation within 48 hours after the first extubation. The associations of extubation failure with demographic data, vital signs, cognition and anxiety, and ventilator parameters at the time of intubation and extubation were analyzed. RESULTS: In total, 127 intubated elderly patients were recruited. Extubation failure occurred in 15 patients (11.8%). Patients with failed extubation had a lower body temperature (37.0 degrees C vs. 37.3 degrees C, P < 0.05) but a higher Facial Anxiety Scale (FAS) score than those with successful extubation (3 vs. 2, P < 0.05). Patients with extubation failure had significantly higher levels of blood urea nitrogen (BUN) (39.88 vs. 58.47 g/dL), serum sodium (137.66 vs. 141.47 mmol/L), and serum calcium (9.52 vs. 10.0 g/dL) but a wider anion gap (12.23 vs. 9.97), but no significant differences in respiratory parameters were found between the two groups. Multiple logistic regression revealed no independent factors associated with successful extubation. CONCLUSION: This study revealed no strong predictive factors. However, several physiological parameters (lower body temperature and higher FAS scores) and metabolic parameters (BUN, sodium, calcium, and anion gap) were significantly associated with the rate of extubation failure. PMID- 30458036 TI - Syllable retrieval precedes sub-syllabic encoding in Cantonese spoken word production. AB - Two experiments were conducted to investigate the time course of syllabic and sub syllabic processing in Cantonese spoken word production by using the picture-word interference task. Cantonese-speaking participants were asked to name individually presented pictures aloud and ignore an auditory word distractor. The targets and distractors were either phonologically related (i.e., sharing two identical word-initial phonemes) or unrelated. In Experiment 1, the target syllables were all consonant-vowel (CV)-structured. The phonological distractor was either a CV syllable (i.e., Full Syllable Overlap) or a CVC (consonant-vowel consonant) syllable (i.e., Sub-syllable Overlap). Relative to the unrelated control, Full Syllable Overlap distractors facilitated naming in all stimuli onset asynchronies (SOAs) (-175, 0, or +175 ms) whereas Sub-syllable Overlap distractors exhibited facilitation only at 0-ms and +175-ms SOAs. Experiment 2 adopted a similar design to examine the possible influence of syllabic structure similarity on the results of Experiment 1. The target syllables were all CVC structured. The phonological distractor was either a CVC (i.e., Syllable structure Consistent) or CV (i.e., Syllable-structure Inconsistent) syllable. Comparable priming was observed between the two distractor conditions across the three SOAs. These results indicated that an earlier priming effect was observed with full syllable overlap than sub-syllabic overlap when the degree of segmental overlap was held constant (Experiment 1). The earlier syllable priming observed in Experiment 1 could not be attributed to the effect of syllabic-structure (Experiment 2), thereby suggesting that the syllable unit is important in Cantonese and is retrieved earlier than sub-syllabic components during phonological encoding. PMID- 30458037 TI - Interpersonal justice climate, extra-role performance and work family balance: A multilevel mediation model of employee well-being. AB - The global economic recession is relevant in public administration, especially in terms of the human factor. If we pretend to empower people as a resource, a key aspect is the perception of equity in their relationships. Previous research has shown how a positive shared interpersonal justice climate (IJC) in a work team impacts employee well-being, affecting the level of engagement and burnout. This influence is crucial in achieving positive results in the organization and for employees. The objective was to analyze the relationship between IJC and extra role performance (ERP) and the mediating role of two indicators of well-being (burnout and engagement) in work teams. Furthermore, the study examined the Job Demands and Resources model (JD-R) including the relationship with the work family balance (WFB) of public employees. The sample was composed of 404 technical and administrative staff in a Spanish public university. The results indicated the significant relationships between the perceptions of IJC and burnout, engagement, and the two work outcomes WFB and ERP. When burnout and engagement were introduced in the regression equations, total mediation effects were produced. PMID- 30458038 TI - Effect of behavioral inhibition system and childhood emotional neglect on serotonergic activity, negative affect, and rejection sensitivity in non-clinical adults. AB - INTRODUCTION: Behavioral inhibition system (BIS) has a strong genetic basis, and emotional neglect (EN) in childhood is one of many environmental experiences that can affect individuals. This study aimed to examine the effects and interaction between BIS and EN on central serotonergic activity and other negative affect and cognition. METHODS: A total of 153 non-clinical volunteers (54 men and 99 women; average age, 27.72 years, standard deviation = 6.40) were included in the analyses. The Behavioral Inhibition System scale, Childhood Trauma Questionnaire, and negative affect and cognition (Beck Depression Inventory, State-Trait Anxiety Inventory, and Rejection Sensitivity Questionnaire) were measured. As a biomarker of central serotonergic activity, the loudness dependence of auditory evoked potentials was measured. RESULTS: High EN was associated with higher loudness dependence of auditory evoked potential (LDAEP) levels and low EN was associated with lower LDAEP levels in high BIS people only. People with high EN people showed significantly higher levels of depression and state anxiety than did those with low EN. Moreover, of people with low BIS, those who had more EN experience had higher levels of rejection sensitivity than did those with less EN experience, while people with high BIS did not show different patterns of rejection sensitivity regardless of the difference of EN. CONCLUSIONS: This study revealed different effects on physiological (loudness dependence of auditory evoked potentials), intrapersonal (depression and state anxiety), and interpersonal aspects (rejection sensitivity) based on the interaction of BIS and EN. Our results suggest that the physiological and interpersonal aspects, but not the intrapersonal aspect, are significantly influenced by the interactive effect of BIS and EN. PMID- 30458040 TI - Correction: Quantitative approach for the risk assessment of African swine fever and Classical swine fever introduction into the United States through legal imports of pigs and swine products. AB - [This corrects the article DOI: 10.1371/journal.pone.0182850.]. PMID- 30458041 TI - Correction: What you saw is what you will hear: Two new illusions with audiovisual postdictive effects. AB - [This corrects the article DOI: 10.1371/journal.pone.0204217.]. PMID- 30458039 TI - Robust desynchronization of Parkinson's disease pathological oscillations by frequency modulation of delayed feedback deep brain stimulation. AB - The hyperkinetic symptoms of Parkinson's Disease (PD) are associated with the ensembles of interacting oscillators that cause excess or abnormal synchronous behavior within the Basal Ganglia (BG) circuitry. Delayed feedback stimulation is a closed loop technique shown to suppress this synchronous oscillatory activity. Deep Brain Stimulation (DBS) via delayed feedback is known to destabilize the complex intermittent synchronous states. Computational models of the BG network are often introduced to investigate the effect of delayed feedback high frequency stimulation on partially synchronized dynamics. In this study, we develop a reduced order model of four interacting nuclei of the BG as well as considering the Thalamo-Cortical local effects on the oscillatory dynamics. This model is able to capture the emergence of 34 Hz beta band oscillations seen in the Local Field Potential (LFP) recordings of the PD state. Train of high frequency pulses in a delayed feedback stimulation has shown deficiencies such as strengthening the synchronization in case of highly fluctuating neuronal activities, increasing the energy consumed as well as the incapability of activating all neurons in a large-scale network. To overcome these drawbacks, we propose a new feedback control variable based on the filtered and linearly delayed LFP recordings. The proposed control variable is then used to modulate the frequency of the stimulation signal rather than its amplitude. In strongly coupled networks, oscillations reoccur as soon as the amplitude of the stimulus signal declines. Therefore, we show that maintaining a fixed amplitude and modulating the frequency might ameliorate the desynchronization process, increase the battery lifespan and activate substantial regions of the administered DBS electrode. The charge balanced stimulus pulse itself is embedded with a delay period between its charges to grant robust desynchronization with lower amplitudes needed. The efficiency of the proposed Frequency Adjustment Stimulation (FAS) protocol in a delayed feedback method might contribute to further investigation of DBS modulations aspired to address a wide range of abnormal oscillatory behavior observed in neurological disorders. PMID- 30458042 TI - Effective approach to organic acid production from agricultural kimchi cabbage waste and its potential application. AB - The biotransformation of agricultural waste into valuable chemicals represents a promising approach in the field of biorefining. Herein, a general but highly efficient and robust process is reported for the production of organic acid from kimchi cabbage waste using lactic acid bacteria. The organic acid produced was tested for efficacy as a biological control agent. Lactobacillus sakei WiKim31 and L. curvatus WiKim38 could efficiently produce organic acids including lactic acid (12.1 and 12.7 g/L), fumaric acid (7.4 and 7.1 g/L), and acetic acid (4.5 and 4.6 g/L) from kimchi cabbage waste (3% substrate loading, w/v) by simultaneous saccharification and fermentation processes for 48 h, and the culture filtrate induced complete mortality of J2s Meloidogyne incognita at 2.5% concentration. These results suggested that lactic acid bacteria L. sakei WiKim31 and L. curvatus WiKim38 can efficiently produce organic acids, and the culture filtrate can be applied as a microbial nematicide. PMID- 30458043 TI - The impact of spoken action words on performance in a cross-modal oddball task. AB - In this study a cross-modal oddball task was employed to study the effect that words spoken either non-urgently or urgently would have on a digit categorization task and if women would exhibit greater behavioral inhibitory control. The words were unrelated to the task itself, but related to the action required to complete the task. Forty participants (21 women) conducted a computerized categorization task while exposed to a sinewave tone as a standard stimulus (75% of the trials) or a to-be ignored word (press, stop) spoken either non-urgently or urgently as unexpected auditory deviant stimulus (6.25% trials for each category). Urgent words had sharp intonation and an average fundamental frequency (F0) ranging from 191.9 (stop) to 204.6 (press) Hz. Non-urgent words had low intonation with average F0 ranging from 103.9.9 (stop) to 120.3 (press) Hz. As expected, deviant distraction and longer response times were found by exposure to the word stop, but deviant distraction was not found to be significant with the word press or due to intonation. While the results showed that women had in general longer reaction times, there were no gender differences found related to the deviant distraction caused by word or intonation. The present results do not support the hypothesis that women have greater behavioral inhibitory control, but there was evidence that the meaning of the word could influence response times. PMID- 30458045 TI - Correction: Cataract surgery and age-related cognitive decline: A 13-year follow up of the English Longitudinal Study of Ageing. AB - [This corrects the article DOI: 10.1371/journal.pone.0204833.]. PMID- 30458046 TI - The impact of environmental change on Palaeolithic and Mesolithic plant use and the transition to agriculture at Franchthi Cave, Greece. AB - The multi-period (~38,000-6000 cal BP) site of Franchthi Cave, located in the Argolid peninsula of southern mainland Greece, is unique in the Eastern Mediterranean for preserving a long archaeological sequence extending from the Upper Palaeolithic through to the end of the Neolithic period. In this paper, we present new anthracological (carbonized fuel wood waste) evidence from Franchthi Cave with which we reconstruct the changing ecology of woodland vegetation in its environs during the late Pleistocene and the early-mid Holocene. The integrated archaeobotanical record (charred wood and non-wood macro-remains) demonstrates that in the Lateglacial the now-submerged coastal shelf of the southern Argolid peninsula was covered by steppe grassland vegetation dominated by junipers, almonds, cereals and legumes. The rapid climatic amelioration that marked the start of the Holocene brought about the disappearance of juniper and the expansion of deciduous woodland, cereals and lentils. This woodland-grassland biome bears no analogues in the modern and historical vegetation ecology of the Aegean basin. Instead, it is directly comparable to the steppe woodland biomes exploited by late Pleistocene and early Holocene hunter-gatherers in Southwest Asia, and points to the convergent evolution of late Pleistocene and early Holocene plant exploitation strategies between the two regions. Continuous sea level rise during the early Holocene led to the gradual extinction of this unique palaeohabitat, which acted as the catalyst for the selective introduction of domesticated cereal crops at Franchthi Cave in the early 9th millennium cal BP. Our meta-analysis of the non-wood archaeobotanical data puts into question the concept of the wholesale introduction of a crop "package" by pioneer settler groups arriving from the East. It is proposed instead that selective cereal crop introduction formed part of a complex pattern of sociocultural interactions that brought together indigenous and immigrant groups into new communities. PMID- 30458044 TI - Predicting acute kidney injury at hospital re-entry using high-dimensional electronic health record data. AB - Acute Kidney Injury (AKI), a sudden decline in kidney function, is associated with increased mortality, morbidity, length of stay, and hospital cost. Since AKI is sometimes preventable, there is great interest in prediction. Most existing studies consider all patients and therefore restrict to features available in the first hours of hospitalization. Here, the focus is instead on rehospitalized patients, a cohort in which rich longitudinal features from prior hospitalizations can be analyzed. Our objective is to provide a risk score directly at hospital re-entry. Gradient boosting, penalized logistic regression (with and without stability selection), and a recurrent neural network are trained on two years of adult inpatient EHR data (3,387 attributes for 34,505 patients who generated 90,013 training samples with 5,618 cases and 84,395 controls). Predictions are internally evaluated with 50 iterations of 5-fold grouped cross-validation with special emphasis on calibration, an analysis of which is performed at the patient as well as hospitalization level. Error is assessed with respect to diagnosis, race, age, gender, AKI identification method, and hospital utilization. In an additional experiment, the regularization penalty is severely increased to induce parsimony and interpretability. Predictors identified for rehospitalized patients are also reported with a special analysis of medications that might be modifiable risk factors. Insights from this study might be used to construct a predictive tool for AKI in rehospitalized patients. An accurate estimate of AKI risk at hospital entry might serve as a prior for an admitting provider or another predictive algorithm. PMID- 30458047 TI - Correction: A Health Threat to Bystanders Living in the Homes of Smokers: How Smoke Toxins Deposited on Surfaces Can Cause Insulin Resistance. AB - [This corrects the article DOI: 10.1371/journal.pone.0149510.]. PMID- 30458048 TI - One-year weight management lowers lipopolysaccharide-binding protein and its implication in metainflammation and liver fibrosis. AB - BACKGROUND: Studies showed that the endotoxemia-related biomarker, lipopolysaccharide-binding protein (LBP), is associated with obesity and fatty liver. The level of LBP is reduced after surgical weight loss. This study aimed to verify the change of serum LBP levels after one-year medical weight management in subjects with obesity. METHODS AND FINDINGS: A total of 62 subjects with obesity, 39 subjects with overweight, and 21 subjects with normal body mass index were enrolled for a one-year weight management program. Basic information, body composition analysis, clinical data, serum LBP level, and abdominal ultrasonography findings were collected. At baseline, the serum LBP levels of the obese and overweight subjects were significantly higher than that of the normal group (30.9+/-7.4 and 29.6+/-6.3 versus 23.1+/-5.6 MUg/mL, respectively, p<0.001). Serum LBP in subjects with obesity was significantly reduced to 26.5+/ 7.1 MUg/mL (p-value < 0.001) after one year. In the multivariate analyses, LBP was associated with high sensitive C-reactive protein (hs-CRP) and non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) before weight management in the obese group. Moreover, the change of LBP in response to weight management was significantly related to the changes of hs-CRP, leukocyte count and NFS by multivariate linear regression analysis also in the obese group. CONCLUSION: The serum level of the endotoxemia-related biomarker, LBP, decreases after one-year weight management in the obese subjects. In addition to serving as a metainflammatroy biomarker like hs-CRP, LBP may also be a potential biomarker as a non-invasive biomarker for the evaluation of liver fibrosis in NAFLD. PMID- 30458049 TI - AGMT3-D: A software for 3-D landmarks-based geometric morphometric shape analysis of archaeological artifacts. AB - We present here a newly developed software package named Artifact GeoMorph Toolbox 3-D (AGMT3-D). It is intended to provide archaeologists with a simple and easy-to-use tool for performing 3-D landmarks-based geometric morphometric shape analysis on 3-D digital models of archaeological artifacts. It requires no prior knowledge of programming or proficiency in statistics. AGMT3-D consists of a data acquisition procedure for automatically positioning 3-D models in space and fitting them with grids of 3-D semi-landmarks. It also provides a number of analytical tools and procedures that allow the processing and statistical analysis of the data, including generalized Procrustes analysis, principal component analysis, a warp tool, automatic calculation of shape variabilities and statistical tests. It provides an output of quantitative, objective and reproducible results in numerical, textual and graphic formats. These can be used to answer archaeologically significant questions relating to morphologies and morphological variabilities in artifact assemblages. Following the presentation of the software and its functions, we apply it to a case study addressing the effects of different types of raw material on the morphologies and morphological variabilities present in an experimentally produced Acheulian handaxe assemblage. The results show that there are statistically significant differences between the mean shapes and shape variabilities of handaxes produced on flint and those produced on basalt. With AGMT3-D, users can analyze artifact assemblages and address questions that are deducible from the morphologies and morphological variabilities of material culture assemblages. These questions can relate to issues of, among others, relative chronology, cultural affinities, tool function and production technology. AGMT3-D is aimed at making 3-D landmarks-based geometric morphometric shape analysis more accessible to archaeologists, in the hope that this method will become a tool commonly used by archaeologists. PMID- 30458050 TI - Automated sequential chromogenic IHC double staining with two HRP substrates. AB - Automated IHC double staining using diaminobenzidine and HRP Magenta is illustrated utilizing a new acidic block with sulfuric acid to prevent cross reactivity. Residual cross-reactivity in double staining is determined to arise from chromogenic-bound antibodies and amplification system during the first part of the double staining. PMID- 30458051 TI - SpillOver stimulation: A novel hypertrophy model using co-contraction of the plantar-flexors to load the tibial anterior muscle in rats. AB - The influence of loading on muscular hypertrophy has previously been studied in rodents by removal of synergistic muscles or various weight-lifting regimes. We present a novel model, evoking hypertrophy in the rat's tibialis anterior (TA) muscle by means of an implanted single channel electrical nerve stimulator. The amount of load experienced by the TA was measured in acute experiments in anaesthetized rats with contractions over a range of stimulation frequency and amplitude. A novel electrode configuration allowed us to elicit concentric, isometric and eccentric contractions within the same setup. This was achieved by 'SpillOver' stimulation in which we adjusted the amount of co-activation of the stronger antagonistic plantarflexors by increasing the stimulus above the level that caused full recruitment of the dorsiflexor muscles. The effect of loading on hypertrophy of the TA was tested in 3-4 week stimulation experiments in two groups of freely-moving rats, with a protocol that resembles typical resistance training in humans. One group performed concentric contractions with no antagonistic co-contraction (unloaded, UNL, n = 5). In the other group the TA was loaded by simultaneous co-contraction of the antagonistically acting plantarflexors (SpillOver, n = 5). The wet mass of the stimulated TA increased in both groups; by 5.4 +/- 5.5% for the UNL-group and 13.9 +/- 2.9% for the SpillOver-group, with significantly greater increase in the SpillOver-group (p<0.05). Our results correlate well with values reported in literature, demonstrating that SpillOver-stimulation is a suitable model in which to study muscular hypertrophy. Even higher gains in muscle-mass may be possible by optimizing and adjusting the stimulation parameters according to the principles of progressive resistance training. PMID- 30458052 TI - Shedding light on the polyphyletic behavior of the genus Sterkiella: The importance of ontogenetic and molecular phylogenetic approaches. AB - Present study, investigates a poorly known species of the genus Sterkiella, i.e., S. tricirrata, based on two populations isolated from soil samples collected from the Colfiorito Regional Park, Umbria Region, Italy and from the Silent Valley National Park, India. Both populations showed a highly similar morphology, however different ontogenetic pattern in between. The study confirms the validity of the species S. tricirrata which was considered to be a species within the Sterkiella histriomuscorum complex. The main ontogenetic difference between S. tricirrata and other species of the genus Sterkiella is the different mode of formation of anlagen V and VI of the proter in the former. In the phylogenetic analyses, Sterkiella tricirrata clusters with Sterkiella sinica within the stylonychine oxytrichids, in a clade away from the type species (Sterkiella cavicola) of the genus Sterkiella. The study highlights the importance of ontogenetic as well as molecular data in shedding light on the polyphyletic behavior of the genus Sterkiella. A detailed description of S. tricirrata based on morphology, ontogenesis and molecular phylogenetic methods is presented. Further, the improved diagnosis has been provided for the genus Sterkiella and the poorly known species S. tricirrata. PMID- 30458053 TI - A method for manual and automated multiplex RNAscope in situ hybridization and immunocytochemistry on cytospin samples. AB - In situ analysis of biomarkers is essential for clinical diagnosis and research purposes. The increasing need to understand the molecular signature of pathologies has led to the blooming of ultrasensitive and multiplexable techniques that combine in situ hybridization (ISH) and immunohistochemistry or immunocytochemistry (IHC or ICC). Most protocols are tailored to formalin-fixed paraffin embedded (FFPE) tissue sections. However, methods to perform such assays on non-adherent cell samples, such as patient blood-derived PBMCs, rare tumor samples, effusions or other body fluids, dissociated or sorted cells, are limited. Typically, a laboratory would need to invest a significant amount of time and resources to establish one such assay. Here, we describe a method that combines ultrasensitive RNAscope-ISH with ICC on cytospin cell preparations. This method allows automated, sensitive, multiplex ISH-ICC on small numbers of non adherent cells. We provide guidelines for both chromogenic and fluorescent ISH/ICC combinations that can be performed either in fully automated or in manual settings. By using a CD8+ T cells in vitro stimulation paradigm, we demonstrate that this protocol is sensitive enough to detect subtle differences in gene expression and compares well to commonly used methods such as RT-qPCR and flow cytometry with the added benefit of visualization at the cellular level. PMID- 30458055 TI - Proteasome-associated HECT-type ubiquitin ligase activity is required for plant immunity. AB - Regulated degradation of proteins by the 26S proteasome plays important roles in maintenance and signalling in eukaryotic cells. Proteins are marked for degradation by the action of E3 ligases that site-specifically modify their substrates by adding chains of ubiquitin. Innate immune signalling in plants is deeply reliant on the ubiquitin-26S proteasome system. While progress has been made in understanding substrate ubiquitination during plant immunity, how these substrates are processed upon arrival at the proteasome remains unclear. Here we show that specific members of the HECT domain-containing family of ubiquitin protein ligases (UPL) play important roles in proteasomal substrate processing during plant immunity. Mutations in UPL1, UPL3 and UPL5 significantly diminished immune responses activated by the immune hormone salicylic acid (SA). In depth analyses of upl3 mutants indicated that these plants were impaired in reprogramming of nearly the entire SA-induced transcriptome and failed to establish immunity against a hemi-biotrophic pathogen. UPL3 was found to physically interact with the regulatory particle of the proteasome and with other ubiquitin-26S proteasome pathway components. In agreement, we demonstrate that UPL3 enabled proteasomes to form polyubiquitin chains, thereby regulating total cellular polyubiquitination levels. Taken together, our findings suggest that proteasome-associated ubiquitin ligase activity of UPL3 promotes proteasomal processivity and is indispensable for development of plant immunity. PMID- 30458054 TI - Targeting inhaled aerosol delivery to upper airways in children: Insight from computational fluid dynamics (CFD). AB - Despite the prevalence of inhalation therapy in the treatment of pediatric respiratory disorders, most prominently asthma, the fraction of inhaled drugs reaching the lungs for maximal efficacy remains adversely low. By and large drug delivery devices and their inhalation guidelines are typically derived from adult studies with child dosages adapted according to body weight. While it has long been recognized that physiological (e.g. airway sizes, breathing maneuvers) and physical transport (e.g. aerosol dynamics) characteristics are critical in governing deposition outcomes, such knowledge has yet to be extensively adapted to younger populations. Motivated by such shortcomings, the present work leverages in a first step in silico computational fluid dynamics (CFD) to explore opportunities for augmenting aerosol deposition in children based on respiratory physiological and physical transport determinants. Using an idealized, anatomically-faithful upper airway geometry, airflow and aerosol motion are simulated as a function of age, spanning a five year old to an adult. Breathing conditions mimic realistic age-specific inhalation maneuvers representative of Dry Powder Inhalers (DPI) and nebulizer inhalation. Our findings point to the existence of a single dimensionless curve governing deposition in the conductive airways via the dimensionless Stokes number (Stk). Most significantly, we uncover the existence of a distinct deposition peak irrespective of age. For the DPI simulations, this peak (~ 80%) occurs at Stk ~ 0.06 whereas for nebulizer simulations, the corresponding peak (~ 45%) occurs in the range of Stk between 0.03-0.04. Such dimensionless findings hence translate to an optimal window of micron-sized aerosols that evolves with age and varies with inhalation device. The existence of such deposition optima advocates revisiting design guidelines for optimizing deposition outcomes in pediatric inhalation therapy. PMID- 30458056 TI - Mkx-deficient Mice Exhibit Hedgehog Signaling Dependent Ectopic Ossification in the Achilles Tendons. AB - Heterotopic ossification is the abnormal formation of mineralized bone in skin, muscle, tendon, or other soft tissues. Tendon ossification often occurs from acute tendon injury or chronic tendon degeneration, of which current treatment relies heavily on surgical removal of the ectopic bony tissues. Unfortunately, surgery creates additional trauma, which often causes recurrence of heterotopic ossification. The molecular mechanisms of heterotopic ossification are not well understood. Previous studies demonstrate that Mkx is a transcription factor crucial for postnatal tendon fibril growth. Here we report that Mkx-/- mutant mice exhibit ectopic ossification in the Achilles tendon within one month after birth and the tendon ossification deteriorates with age. Genetic lineage labeling revealed that the tendon ossification in Mkx-/- mice resulted from aberrant differentiation of tendon progenitor cells. Furthermore, tissue-specific inactivation of Mkx in tendon cells postnatally resulted in similar ossification phenotype, indicating that Mkx plays a key role in tendon tissue homeostasis. Moreover, we show that Hedgehog signaling is ectopically activated at early stages of tendon ossification and that tissue-specific inactivation of Smoothened, which encodes the obligatory transducer of Hedgehog signaling, in the tendon cell lineage prevented or dramatically reduced tendon ossification in Mkx /- mice. Together, these studies establish a new genetic mouse model of tendon ossification and provide new insight into its pathogenic mechanisms. This article is protected by copyright. All rights reserved. PMID- 30458057 TI - Reversal of tabun toxicity, enabled by a triazole annulated oxime library reactivators of acetylcholinesterase. AB - Acetylcholinesterase (AChE), an enzyme that degrades the neurotransmitter acetylcholine, when covalently inhibited by organophosphorus compounds (OPs), such as nerve agents and pesticides, can be reactivated by oximes. However, tabun remains among the most dangerous nerve agents due to the low reactivation efficacy of standard pyridinium aldoxime antidotes. Therefore, finding an optimal reactivator for prophylaxis against tabun toxicity and for post-exposure treatment is a continued challenge. In this study, we analyzed the reactivation potency of 111 novel nucleophilic oximes mostly synthesized using the CuAAC triazole ligation between alkyne and azide building blocks. We identified several oximes with significantly improved in vitro reactivating potential for tabun inhibited human AChE, and in vivo antidotal efficacies in tabun-exposed mice. Our findings offer a significantly improved platform for further development of antidotes and scavengers directed against tabun and related phosphoramidate exposures, such as the Novichok compounds. PMID- 30458058 TI - Fecal microbiota transplantation in cancer management: Current status and perspectives. AB - The human gut is home to a large and diverse microbial community, comprising about 1000 bacterial species. The gut microbiota exists in a symbiotic relationship with its host, playing a decisive role in the host's nutrition, immunity, and metabolism. Accumulating studies have revealed the associations between gut dysbiosis or some special bacteria and various cancers. Emerging data suggest that gut microbiota can modulate the effectiveness of cancer therapies, especially immunotherapy. Manipulating the microbial populations with therapeutic intent has become a hot topic of cancer research, and the most dramatic manipulation of gut microbiota refers to fecal microbiota transplantation (FMT) from healthy individuals to patients. FMT has demonstrated remarkable clinical efficacy against Clostridium difficile infection (CDI) and it is highly recommended for the treatment of recurrent or refractory CDI. Lately, interest is growing in the therapeutic potential of FMT for other diseases, including cancers. We briefly reviewed the current researches about gut microbiota and its link to cancer, and then summarized the recent pre-clinical and clinical evidence to indicate the potential of FMT in cancer management as well as cancer-treatment associated complications. We also presented the rationale of FMT for cancer management such as reconstruction of intestinal microbiota, amelioration of bile acid metabolism, and modulation of immunotherapy efficacy. This article would help to better understand this new therapeutic approach for cancer patients by targeting gut microbiota. This article is protected by copyright. All rights reserved. PMID- 30458060 TI - Flood Risk Perceptions and Insurance Choice: Do Decisions in the Floodplain Reflect Overoptimism? AB - In the presence of rare disasters, risk perceptions may not always align with actual risks. These perceptions can nevertheless influence an individual's willingness to mitigate risks through activities such as purchasing flood insurance. In a survey of Maryland floodplain residents, we find that stated risk perceptions predict voluntary flood insurance take-up, while perceptions themselves varied widely among surveyed residents, owing in large part to differences in past flood experience. We use a formal test for overoptimism in risk perceptions and find that, on aggregate, floodplain residents are overly optimistic about flood risks. PMID- 30458059 TI - A Pilot Trial of RNS60 in Amyotrophic Lateral Sclerosis. AB - INTRODUCTION: RNS60 is a novel immune-modulatory agent that has shown neuroprotective effects in ALS pre-clinical models. RNS60 is administered by weekly intravenous infusion and daily nebulization. The objective of this pilot open-label trial was to test the feasibility, safety, and tolerability of long term RNS60 administration in people with ALS. METHODS: The planned treatment duration was 23 weeks and the primary outcomes were safety and tolerability. Secondary outcomes included PBR28 PET imaging and plasma biomarkers of inflammation. RESULTS: Sixteen participants with ALS received RNS60 and 13 (81%) completed 23 weeks of RNS60 treatment. There were no serious adverse events and no participants withdrew from the trial due to drug-related adverse events. There were no significant changes in the biomarkers. DISCUSSION: Long-term RNS60 administration was safe and well-tolerated. A large, multi-center, phase II trial of RNS60 is currently enrolling participants to test the effects of RNS60 on ALS biomarkers and disease progression. This article is protected by copyright. All rights reserved. PMID- 30458061 TI - A heterozygous splice-site mutation in PTHLH causes autosomal dominant shortening of metacarpals and -tarsals. AB - Short metacarpals and/or -tarsals are typically observed in pseudohypoparathyroidism (PHP) type Ia (PHP1A) or pseudo-PHP (PPHP), i.e. disorders caused by inactivating GNAS mutations involving exons encoding the alpha-subunit of the stimulatory G protein (Gsalpha). Skeletal abnormalities similar to those in PHP1A/PPHP were present in several members of an extended Belgian family without evidence for abnormal calcium and phosphate regulation. Direct nucleotide sequencing of genomic DNA from an affected individual (190/III 1) excluded GNAS mutations. Instead, whole exome analysis revealed a novel heterozygous A > G change at nucleotide -3 up-stream of PTHLH exon 3 that encodes the last two amino acids of the pro-sequence and the mature PTHrP. The same nucleotide change was also found in her affected mother and maternal aunt (190/II 2, 190/II-1), and her affected twin sons (190/IV-1, 190/IV-2), but not in her unaffected daughter (190/IV-3) and sister (190/III-2). Complementary DNA derived from immortalized lymphoblastoid cells from 190/IV-2 (affected) and 190/IV-3 (unaffected) was PCR-amplified using forward primers located either in PTHLH exon 1 (non-coding) or exon 2 (pre-sequence and most of the pro-sequence), and reverse primers located in the 3'-non-coding regions of exons 3 or 4. Nucleotide sequence analysis of these amplicons revealed for 190/IV-2, but not for 190/IV-3, a heterozygous insertion of genomic nucleotides -2 and -1 causing a frame-shift after residue 34 of the prepro-sequence and thus 29 novel residues without homology to PTHrP or any other protein. Our findings extend previous reports indicating that PTHrP haploinsufficiency causes skeletal abnormalities similar to those observed with heterozygous GNAS mutations. This article is protected by copyright. All rights reserved. PMID- 30458062 TI - Targeted Synthesis of Complex Spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-ones by a Novel Intramolecular Cyclization of Azomethine Ylides as Highly Potent MDM2-p53 Inhibitors. AB - MDM2 is a main and direct inhibitor of the crucial tumor suppressor p53. Reports from first clinical trials showed that blocking this interaction with a small molecule inhibitor can have great value in the treatment of cancer for patients with p53 wild-type tumors but also revealed dose-limiting hematological toxicities and drug-induced resistance as main issues. To overcome the former an inhibitor with superior potency and PK properties to ultimately achieve full efficacy with less-frequent dosing schedules is required. Towards this aim we optimized our recently reported spiro-oxindole inhibitors focusing on the crucial interaction with the amino acid side-chain of His96MDM2. The designed molecules required the targeted synthesis of structurally complex spiro[indole-3,2' pyrrolo[2,3-c]pyrrole]-2,4'-diones for which we developed an unprecedented intramolecular azomethine ylide cycloaddition and investigated the results by computational methods. One of the new compounds showed superior cellular potency over previously reported BI-0252. This finding is a significant step towards an inhibitor suitable to potentially mitigate hematological on-target adverse effects. PMID- 30458063 TI - Frontal pattern hair loss among Chinese women is frequently associated with ponytail hairstyle. AB - Female alopecia patients in China often present with a frontal pattern hair loss. This feature is seen less frequently in western women. Women in China frequently style their hair in a ponytail. Thus, we hypothesized that the high prevalence of frontal pattern hair loss in Chinese women is due to traction alopecia. To better understand this, we studied 43 women presenting frontal alopecia at a hair clinic. Among the women presenting frontal alopecia, 79% reported styling their hair in a ponytail four or more days per week for an average period of 10 years. To our knowledge, this is the first study to elucidate the cause of frequent frontal alopecia in Chinese women. Although cultural style changes are difficult to change, we believe that awareness of the medical implications of frequent ponytail styling will reduce the rate of frontal alopecia among Chinese women. PMID- 30458064 TI - Efficiency of coculture with angiogenic cells or physiological BMP-2 administration on improving osteogenic differentiation and bone formation of MSCs. AB - Cell-based bone regeneration with mesenchymal stem cells (MSCs) represents the current challenge toward repair of bone defects and fractures. The supposed hurdles for satisfactory performance of cell-based constructs include inadequate vascularization and osteogenic signals. Considering the reported beneficial role of angiogenic cells in promoting vascularization and osteogenic differentiation and the osteogenic potential of bone morphogenetic protein 2 (BMP-2), we here evaluated the efficiency of coculture with angiogenic cells or a physiological dose of BMP-2 on improving osteogenic differentiation of MSCs and bone formation in vivo. In three dimensional (3D) collagen hydrogels in vitro, cocultured human umbilical vein endothelial cells (HUVECs) in a 1:1 ratio or with a physiological dose of BMP-2 (2 ng/MUL) promoted the osteogenic potential of MSCs evidenced by enhanced alkaline phosphatase activity and gene expression of osteogenic markers. Notably, HUVECs evoked similar osteogenic stimulation as BMP-2, albeit in a delayed manner. When their bone formation capacity was further evaluated in a mouse subcutaneous implantation model, MSCs with BMP-2 demonstrated the highest efficiency with reproducible bone formation. In contrast, MSCs cocultured with HUVECs constructs displayed substantial blood vessel-like structures with fibrous tissue rather than ectopic bone as MSC monoculture controls. Our findings confirm the priority of generating cell-based bone constructs with physiological BMP-2 administration and indicate the potential of using angiogenic cells to develop vascularized constructs. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 00A: 1-11, 2018. PMID- 30458065 TI - Transcriptional profiling of dendritic cells in a mouse model of food-antigen induced anaphylaxis reveals the upregulation of multiple immune-related pathways. AB - SCOPE: Much of our knowledge about gene expression during anaphylaxis comes from candidate gene studies. Despite their potential role, expression changes in dendritic cells (DCs) have not been studied in this context using high throughput methods. We investigated the molecular mechanisms underlying food-antigen induced anaphylaxis using DCs from an animal model. METHODS AND RESULTS: We used RNA sequencing to study gene expression in lymph node derived DCs from anaphylactic mice sensitized intranasally with the major peach allergen Pru p 3, during the acute reaction phase, induced intraperitoneally. In total, 237 genes changed significantly, 181 showing at least two-fold changes. Almost three quarters of these increased during anaphylaxis. A subset was confirmed using RT-PCR in a second set of samples obtained from a new batch of mice. Enrichment analysis showed an overrepresentation of genes involved in key immune system and inflammatory processes including TGF-beta signalling. Comparison with a study using anaphylactic human subjects showed significant overlap. CONCLUSIONS: Our findings provide a comprehensive overview of the transcriptional changes occurring in DCs during anaphylaxis and help elucidate the mechanisms involved. They add further weight to the putative role of these cells in anaphylaxis and highlights genes that may represent potential therapeutic targets. This article is protected by copyright. All rights reserved. PMID- 30458066 TI - First Report about Mineral Content, Fatty Acids Composition and Biological Activities of Four Wild Edible Mushrooms. AB - The goal of this research was a comprehensive analysis of four wild edible mushroom species, Cantharellus cinereus, Clavariadelphus pistillaris, Clitocybe nebularis and Hygrocybe punicea, which have not been analyzed so far. Extracts of different polarities have been prepared and evaluated their antioxidant activities by DPPH, ABTS, FRAP, TRP and CUPRAC methods. Also, for all extracts total phenol content was determined. Based on the analysis, it was shown that solvent type has a significant effect on the antioxidant capacities of mushroom extracts, so water extracts show the highest activity. Furthermore, the analysis includes determination of mineral composition, fatty acid profiles, and antimicrobial activity. Unsaturated fatty acids, which are very important for human health, are dominant in the studied mushroom species. Linoleic and oleic acid consist of over 50% of the total fatty acid composition. Seventeen biologically important and toxic elements have been analyzed by ICP-OES and ICP MS and results showed that the element concentrations were species-dependent. Also, it has been found that analyzed mushrooms didn't show antimicrobial activity. The underlying interrelations between the extracts different polarities were studied using chemometric methods for data elaboration. Chemometric analysis were used to understand the connection between the extracts of different polarities. PMID- 30458067 TI - Influence of Linker length on Ligase-Catalyzed Oligonucleotide Polymerization. AB - Ligase-catalyzed oligonucleotide polymerization (LOOPER) has been recently developed to enable the sequence-defined generation of DNA with up to 16 different modifications. This approach was used to evolve new classes of diversely-modified DNA aptamers for molecular recognition. The modifications in LOOPER are appended via a long hexamethylenediamine linker, which could negatively impact binding thermodynamics. Herein we explore the incorporation of modifications via shorter linkers using commercially available phosphoramidites and assess their efficiency and fidelity of incorporation. We observed that shorter linkers are less tolerated during LOOPER, with very short linkers providing high levels of error and sequence bias. An ethylenediamine linker was found to be optimal in terms of yield, efficiency, and bias; however, codon adjustment was necessary. This shorter linker anticodon set for LOOPER should prove valuable in exploring the impact of diverse chemical modifications on the molecular function of DNA. PMID- 30458069 TI - Methods of cell - transdifferentiation technology based on defined factors in order to regenerate heart function. PMID- 30458068 TI - Photoreceptor projection from a four-tiered retina to four distinct regions of the first optic ganglion in a jumping spider. AB - Jumping spiders have four pairs of eyes (ocelli) of which only the principal eyes (PEs) are used to detect features of objects. Photoreceptors in the retina of the PEs form four layers (PL1-4) and terminate in the first optic ganglion (FOG). Here we focus on Hasarius adansoni because it has unique depth vision besides color vision and its FOG appears to contribute to the initial processing of these visual modalities. We first investigated the neuroanatomical organization of the FOG. The three-dimensional structure of the FOG revealed by synapsin immunostaining is horseshoe-shaped and consists of four terminal zones (TZ1-4). Then we traced single photoreceptors through serial sections and found that green sensitive receptors of PL1 and 2 terminate in TZ1 and 2, respectively, by keeping retinotopic organization. In contrast to TZ1 and 2, TZ3 receives terminals of ultraviolet-sensitive receptors from lateral regions of both PL3 and 4, while photoreceptors of the medial region of PL3 and 4 terminate in TZ4. We further studied details of photoreceptor terminals and the branching pattern of interneurons in the FOG in Golgi stained preparations. Photoreceptors have long lateral processes in each terminal zone. Some photoreceptors terminating in TZ3 have branches innervating TZ1, indicating that TZ1 receives different spectral information. A type of interneuron connects TZ1 and 2, while others have branches within a single terminal zone or in the entire FOG. These results suggest that TZ1 and 2 contribute to color, shape, and depth vision, while TZ3 and 4 have specific roles for UV vision. This article is protected by copyright. All rights reserved. PMID- 30458070 TI - Development of cell transplantation therapy for intractable myopathies. PMID- 30458071 TI - Regenerative therapy for retinal degeneration. PMID- 30458072 TI - Current topics in differentiation of islets and the application for regenerative therapy. PMID- 30458073 TI - Development of mucosal regenerative therapies for inflammatory bowel diseases using cultured intestinal epithelial stem cells. PMID- 30458075 TI - Systematic identification of master transcription factors. PMID- 30458074 TI - Establishment of directed differentiation systems by manipulating transcription factors in pluripotent stem cells. PMID- 30458076 TI - Development of culture substrates for pluripotent stem cells. PMID- 30458077 TI - Development of iPS cell culture platform for regenerative medicine. PMID- 30458079 TI - iPS-cell research using swine. PMID- 30458078 TI - Development of novel techniques for quality evaluation of processed cells for regenerative medicine derived from iPS cells or from somatic stem cells. PMID- 30458080 TI - A novel single - cell RNA sequencing method for safety and effective cell transplantation. PMID- 30458082 TI - Disease modeling using induced pluripotent stem cells (general remarks). PMID- 30458081 TI - Establishment of a transplantation - immunotolerant cynomolgus monkey colony and application to regenerative medicine. PMID- 30458083 TI - ALS disease modeling using patient - specific iPS cells. PMID- 30458084 TI - Applications of induced pluripotent stem cells in studying the Alzheimer's disease. PMID- 30458085 TI - Pathophysiological analysis of Parkinson's disease using iPS cells. PMID- 30458086 TI - Pathophysiological analysis of Parkinson's disease using iPS cells. PMID- 30458087 TI - Pathological analysis of dysmyelinating disorders using iPSCs. PMID- 30458088 TI - Exploring new therapeutic approaches for retinitis pigmentosa using patient's iPS cells. PMID- 30458089 TI - Modeling inherited cardiac disease using patient specific iPS cell derived cardiomyocytes. PMID- 30458091 TI - Studies of hematopoietic and immunological disorders using disease - associated iPS cells. PMID- 30458090 TI - Application of patients - derived iPS cells for intractable musculoskeletal diseases. PMID- 30458092 TI - Disease modeling using human embryonic stem cells. PMID- 30458094 TI - Regenerative medicine for age - related macular degeneration using IPS cells. PMID- 30458093 TI - Intravenous autologous bone narrow mononuclear cell transplantation for stroke: phase 1/2a clinical trial. PMID- 30458095 TI - Clinical study of autologous cultivated oral mucosal epithelial transplantation for severe ocular surface disorders. PMID- 30458096 TI - Tympanoplasty with nasal mucosal epithelial cell sheet transplantation. PMID- 30458097 TI - Prevention of esophageal stricture after endoscopic submucosal dissection using tissue - engineered autologous oral mucosal epithelial cell sheets. PMID- 30458098 TI - Intrathecal administration of recombinant human hepatocyte growth factor for acute spinal cord injury: the road from bench to clinical trial and future perspective. PMID- 30458099 TI - Clinical trial for idiopathic osteonecrosis of femoral head by multipotent mesenchynal stromal cells. PMID- 30458100 TI - Application of cultured autogenous periosteal cell sheets for periodontal and alveolar bone regeneration. PMID- 30458101 TI - Development of implant - type tissue - engineered cartilage for cleft lip - nose deformity. PMID- 30458102 TI - Adipose - derived stem cell in autologous fat grafting for reconstruction of the breast. PMID- 30458103 TI - Liver regeneration therapy by intrahepatic arterial administration of autologous adipose tissue derived stromal cells. PMID- 30458104 TI - Conformation-dependent Coordination of Carboxylic Acids with Fe3O4 Nanoparticles Studied by ATR-FTIR Spectral Deconvolution. AB - The coordination of valeric acid (VA), glutaric acid (GA) and tricarballylic acid (TA) with Fe-OH on the Fe3O4 nanoparticle surface has been systematically studied to elucidate the effect of COOH, molecular configuration and ligand concentration on the coordination by the combining use of attenuated total reflectance Fourier transform infrared (ATR-FTIR) and thermogravimetric analysis (TGA). The results show that the binding ability of the acids increases with the increase of the COOH number. Multiple conformations coexist for the dicarboxylic and tricarboxylic acid coordinated on the iron oxide NPs. Saturated coordination formed with only one-, two- or three-COOH conformation for VA, GA and TA, respectively, occurs under ligand-scarce conditions while unsaturated coordination formed with the mixture of uncoordinated, one- and/or two-COOH conformations for VA, GA and TA, respectively, exists under ligand-abundant conditions. The maximum coordination number for monolayer adsorption for VA, GA and TA on Fe3O4 NPs is 9, 2.4 and 2.7 nm-2, respectively. This study helps to understand the fine coordination mechanism caused by the acid molecules with different configuration and elucidate, for the first time, the fine conformation variance incurred by the surrounding ligand with different concentration and the way by which the ligand is added. PMID- 30458105 TI - Self-assembly of stimuli-responsive biohybrid synthetic-b-recombinant block copolypeptides. AB - The synthesis and original thermoresponsive behavior of hybrid diblock copolypeptides composed of synthetic and recombinant polypeptides are herein reported. A thermoresponsive recombinant elastin-like polypeptide was used as macroinitiator to synthesize a range of poly(L-glutamic acid)-block-elastin-like polypeptide (PGlu-b-ELP) diblock copolypeptides with variable PGlu block lengths. Their temperature-triggered self-assembly in water and in phosphate-buffered saline (PBS) was investigated at the macroscopic scale using complementary techniques such as turbidimetry, dynamic and static light scattering, small-angle neutron scattering, and at the molecular scale by 1H NMR and circular dichroism (CD). In deionized water, PGlu-b-ELP copolypeptides showed one transition from free soluble chains below the transition temperature (Tt) of the ELP block to macroscopic aggregates above the Tt. In contrast, in PBS, four successive regimes were observed upon increasing temperature: below the Tt, copolypeptides were soluble, above the Tt, large aggregates appeared and fell apart into discrete and defined spherical nanoparticles at a temperature named critical micellization temperature (CMT), before finally reaching an equilibrium. During the last regime, neutron scattering experiments revealed that the micelle-like structures underwent a densification step and expelled water from their core. In addition, 1H NMR and CD experiments revealed, in deionized water, the formation of type II beta-turns into the ELP block upon temperature increase. These beta-turns are known to participate in the intrinsic thermoresponsive behavior of the ELPs. In contrast, in PBS, circular dichroism measurements showed an attenuation of folded structure during the self-assembly phase, leading to less cohesive aggregates able to reorganize into nanoparticles at the CMT. PMID- 30458106 TI - NanoSQUID Magnetometry on Individual As-grown and Annealed Co Nanowires at Variable Temperature. AB - Performing magnetization studies on individual nanoparticles is a highly demanding task, especially when measurements need to be carried out under large sweeping magnetic fields or variable temperature. Yet, characterization under varying ambient conditions is paramount in order to fully understand the magnetic behavior of these objects, e.g., the formation of nonuniform states or the mechanisms leading to magnetization reversal and thermal stability. This, in turn, is necessary for the integration of magnetic nanoparticles and nanowires into useful devices, e.g., spin-valves, racetrack memories, or magnetic tip probes. Here, we show that nanosuperconducting quantum interference devices based on high critical temperature superconductors are particularly well suited for this task. We have successfully characterized a number of individual Co nanowires grown through focused electron beam induced deposition and subsequently annealed at different temperatures. Magnetization measurements performed under sweeping magnetic fields (up to ~100 mT) and variable temperature (1.4-80 K) underscore the intrinsic structural and chemical differences between these nanowires. These point to significant changes in the crystalline structure and the resulting effective magnetic anisotropy of the nanowires, and to the nucleation and subsequent vanishing of antiferromagnetic species within the nanowires annealed at different temperatures. PMID- 30458107 TI - Diastereodivergent synthesis of chiral tetrahydropyrrolodiazepinediones via a one pot intramolecular aza-Michael/lactamization sequence. AB - A modular and diastereodivergent synthesis of tetrahydro-1H pyrrolo[1,2d]diazepin(2,5)-diones is presented. The tetrahydropyrrolodiazepindione scaffold is obtained via a base-mediated three step isomerization/tandem cyclization of amino acid-coupled homoallylic amino esters. Diastereoselectivity of the process is mediated by the interplay of a kinetic cyclization event and a propensity for thermodynamic epimerization at two labile chiral centers, giving rise to two distinct major diastereomers dependent on starting material stereochemistry and reaction conditions selected. Herein, we present a synthetic and computational study for this tandem process on a variety of amino ester substrates. PMID- 30458108 TI - Central-to-Helical-to-Axial-to-Central Transfer of Chirality with a Photoresponsive Catalyst. AB - Recent advances in molecular design have displayed striking examples of dynamic chirality transfer between various elements of chirality, e.g. from central to either helical or axial chirality and vice versa. While considerable progress in atroposelective synthesis has been made, it is intriguing to design chiral molecular switches able to provide selective and dynamic control of axial chirality with an external stimulus to modulate stereochemical functions. Here, we report the synthesis and characterization of a photoresponsive bis(2-phenol) substituted molecular switch 1. The unique design exhibits a dynamic hybrid central-helical-axial transfer of chirality. The change of preferential axial chirality in the biaryl motif is coupled to the reversible switching of helicity of the overcrowded alkene core, dictated by the fixed stereogenic center. The potential for dynamic control of axial chirality was demonstrated by using (R)-1 as switchable catalyst to direct the stereochemical outcome of the catalytic enantioselective addition of diethylzinc to aromatic aldehydes, with successful reversal of enantioselectivity for several substrates. PMID- 30458109 TI - Phosphate Lock Residues of Acidothermus cellulolyticus Cas9 Are Critical to Its Substrate Specificity. AB - Despite being utilized widely in genome sciences, CRISPR-Cas9 remains limited in achieving high fidelity in cleaving DNA. A better understanding of the molecular basis of Cas9 holds the key to improve Cas9-based tools. We employed direct evolution and in vitro characterizations to explore structural parameters that impact the specificity of the thermophilic Cas9 from Acidothermus cellulolyticus (AceCas9). By identifying variants that are able to cleave mismatched protospacers within the seed region, we found a critical role of the phosphate lock residues in substrate specificity in a manner that depends on their sizes and charges. Removal of the negative charge from the phosphate lock residues significantly decreases sensitivity to the guide-DNA mismatches. An increase in size of the substituted residues further reduces the sensitivity to mismatches at the first position of the protospacer. Our findings identify the phosphate lock residues as an important site for tuning the specificity and catalytic efficiency of Cas9. PMID- 30458110 TI - Single Au Atom Doping of Silver Nanoclusters. AB - Ag29 nanoclusters capped with lipoic acid (LA) can be doped with Au. The doped clusters show enhanced stability and increased luminescence efficiency. We attribute the higher quantum yield to an increase in the rate of radiative decay. With mass spectrometry, the Au-doped clusters were found to consist predominantly of Au1Ag28(LA)123-. The clusters were characterized using X-ray absorption spectroscopy at the Au L3-edge. Both the extended absorption fine structure (EXAFS) and the near edge structure (XANES) in combination with electronic structure calculations confirm that the Au dopant is preferentially located in the center of the cluster. A useful XANES spectrum can be recorded for lower concentrations, or in shorter time, than the more commonly used EXAFS. This makes XANES a valuable tool for structural characterization. PMID- 30458111 TI - Ferrous-Supply-Regeneration Nanoengineering for Cancer-Cell-Specific Ferroptosis in Combination with Imaging-Guided Photodynamic Therapy. AB - Non-apoptotic ferroptosis is of clinical importance because it offers a solution to the inevitable biocarriers of traditional apoptotic therapeutic means. Inspired by industrial electro-Fenton technology featured with electrochemical iron cycling, we construct ferrous-supply-regeneration nanoengineering to intervene tumorous iron metabolism for enhanced ferroptosis. Fe3+ ion and naturally derived tannic acid (TA) spontaneously form a network-like corona onto sorafenib (SRF) nanocores. The formed SRF@FeIIITA nanoparticles can respond to a lysosomal acid environment with corona dissociation, permitting SRF release to inhibit GPX4 enzyme for ferroptosis initiation. TA is arranged to chemically reduce the liberated and the ferroptosis-generated Fe3+ to Fe2+, offering iron redox cycling to, thus, effectively produce lipid peroxide required in ferroptosis. Sustained Fe2+ supply leads to long-term cytotoxicity, which is identified to be specific to H2O2-overloaded cancer cells but minimal in normal cells. SRF@FeIIITA-mediated cell death proves to follow the ferroptosis pathway and strongly inhibits tumor proliferation. Moreover, SRF@FeIIITA provides a powerful platform capable of versatile integration between apoptosis and non apoptosis means. Typically, photosensitizer-adsorbed SRF@FeIIITA demonstrates rapid tumor imaging owing to the acid-responsive fluorescence recovery. Together with ferroptosis, imaging-guided photodynamic therapy induces complete tumor elimination. This study offers ideas about how to advance anticancer ferroptosis through rational material design. PMID- 30458112 TI - The fibrinolytic factor tPA drives LRP1-mediated melanoma growth and metastasis. AB - The multifunctional endocytic receptor low-density lipoprotein receptor-related protein (LRP)1 has recently been identified as a hub within a biomarker network for multicancer clinical outcome prediction. The mechanism how LRP1 modulates cancer progression is poorly understood. In this study we found that LRP1 and one of its ligands, tissue plasminogen activator (tPA), are expressed in melanoma cells and control melanoma growth and lung metastasis in vivo. Mechanistic studies were performed on 2 melanoma cancer cell lines, B16F10 and the B16F1 cells, both of which form primary melanoma tumors, but only B16F10 cells metastasize to the lungs. Tumor-, but not niche cell-derived tPA, enhanced melanoma cell proliferation in tPA-/- mice. Gain-of-function experiments revealed that melanoma LRP1 is critical for tumor growth, recruitment of mesenchymal stem cells into the tumor bed, and metastasis. Melanoma LRP1 was found to enhance ERK activation, resulting in increased matrix metalloproteinase (MMP)-9 RNA, protein, and secreted activity, a well-known modulator of melanoma metastasis. Restoration of LRP1 and tPA in the less aggressive, poorly metastatic B16F1 tumor cells enhanced tumor cell proliferation and led to massive lung metastasis in murine tumor models. Antimelanoma drug treatment induced tPA and LRP1 expression. tPA or LRP1 knockdown enhanced chemosensitivity in melanoma cells. Our results identify the tPA-LRP1 pathway as a key switch that drives melanoma progression, in part by modulating the cellular composition and proteolytic makeup of the tumor niche. Targeting this pathway may be a novel treatment strategy in combination treatments for melanoma.-Salama, Y., Lin, S.-Y., Dhahri, D., Hattori, K., Heissig, B. The fibrinolytic factor tPA drives LRP1-mediated melanoma growth and metastasis. PMID- 30458113 TI - Timing of shift in antithyroid drug therapy and birth defects. AB - Not required for this type of manuscript. PMID- 30458114 TI - Factors Associated with Regional Adoption of Ureteroscopy in California from 2005 to 2016. AB - Purpose To explore regional adoption of URS over SWL in the state of California (CA) and to identify factors associated with this adoption over time. Materials and Methods We used the California Office of Statewide Health Planning and Development (OSHPD) public data to identify URS and SWL procedures performed for renal and ureteral stones from 2005-2016. The level of analysis was the region wherein each procedure was performed, defined by the 19 California labor market regions. OSHPD data were supplemented with the Area Health Resource File to provide information on regional characteristics. Generalized linear regression was used to determine procedural rates adjusted for age, gender and race. Choropleth time series maps were used to illustrate adoption of URS by region over time. Results A total of 328,795 URS and SWL procedures were identified from 2005-2016. The number of URS procedures surpassed the number of SWL procedures in 2011. Fourteen regions became URS predominant by 2016 and were characterized as having a higher per capita income, higher percentages with a college education and lower percentage of female heads-of-household (all p values <0.05). A higher percentage of patients in these regions were male and had private or Medicare insurance (p=0.03 for both). Conclusions From 2005-2016, most CA regions adopted URS as the primary renal and ureteral stone management strategy. These regions demonstrated characteristics of higher socioeconomic status compared to regions that remained SWL predominant. A better understanding of such differences in practice patterns will allow urologists to better negotiate for the capital expenditures required to conform to evolving standards of care and allow patients the ability to make more informed decisions on where they receive care. PMID- 30458115 TI - In vitro Effects of a Novel Coating Agent on Bacterial Biofilm Development on Ureteral Stents. AB - OBJECTIVES: Ureteral stenting is a widely used method for non-invasive urinary drainage in ureteral obstruction. However, biofilm development due to transient bacteriuria can cause severe complications such as incrustation with subsequent obstruction as well as recurrent urinary tract infection. Apart from local ailment such as dysuria, this increases both stent replacement frequency and incidence of complications. In this work, we investigated in vitro the bacterial adhesion to a surface-attached and crosslinked poly(N,N-dimethylacrylamide) (PDMAA) hydrogel network, which is known for its non-fouling and protein repellent characteristics. MATERIALS AND METHODS: To mimic the conditions encountered in vivo, PDMAA coated and uncoated Cyclic Olefin Polymer (COP) slides as well as polyurethane coated glass slides were incubated in sterile human urine for 48 h. Colonization was then simulated by adding known uropathogens, cultivated from clinical urine samples (such as E. coli). After further incubation for 24 and 48 h, slides were washed and remaining, adherent bacteria solubilized by ultrasound. CFUs were counted after plating and incubation for 48 h of the resulting solution. RESULTS: PDMAA reduced adherent E. coli about 5-fold on coated polyurethane glass slides as well as in PDMAA coated COP slides. With adherent E. faecalis and K. pneumoniae there was a tendency to decreased biofilm formation, but the difference was not statistically significant. CONCLUSIONS: PDMAA reduces surface adherence of the most common uropathogen significantly. Assessment of clinical relevance and of the effect on further uropathogens needs further experimental and clinical evaluations. PMID- 30458116 TI - Intermittent administration of haloperidol after cortical impact injury neither impedes spontaneous recovery nor attenuates the efficacy of environmental enrichment. AB - The administration of haloperidol (HAL) once daily for 19 days after experimental traumatic brain injury (TBI) impedes recovery and attenuates the efficacy of environmental enrichment (EE). However, it is unknown how intermittent administration of HAL affects the recovery process when paired with EE. Addressing the uncertainty is relevant because daily HAL is not always warranted to manage TBI-induced agitation in the clinic, and indeed intermittent therapy may be a more common approach. Hence, the aim of the study was to test the hypothesis that intermittent HAL would neither impair recovery in standard (STD) housed controls nor attenuate the efficacy of EE. Anesthetized adult male rats received a cortical impact or sham injury and beginning 24 hours later were administered HAL (0.5 mg/kg; i.p.) either once daily for 19 days or once every other-day while housed in EE or STD conditions, while vehicle (VEH; 1 mL/kg; i.p.) was administered daily. Motor performance and cognition were assessed on post-injury days 1-5 and 14-19, respectively. Cortical lesion volume was quantified on day 21. SHAM controls performed better than all TBI groups on motor and spatial learning [p<0.05], but did not differ from the TBI+EE+daily VEH group on memory retention [p>0.05]. The TBI+EE daily VEH and TBI+EE intermittent HAL groups did not differ from one another on beam-walk or spatial learning [p>0.05], and both performed better than all other TBI groups [p < 0.05]. In contrast, the TBI+STD+daily HAL group performed worse than all TBI groups on spatial learning [p<0.05]. No difference in any endpoint was revealed between the TBI+STD+intermittent HAL and TBI+STD+daily VEH groups [p>0.05]. The results support the hypothesis that HAL is not detrimental when provided intermittently. If translatable to the clinic, intermittent HAL may be used to control TBI induced agitation without negatively affecting spontaneous recovery or rehabilitative efficacy. PMID- 30458117 TI - Spinal cord disruption is associated with a loss of Cushing-like blood pressure interactions. AB - The capacity of the cerebrovasculature to buffer changes in blood pressure (BP) likely plays an important role in the prevention of stroke, which is three- to four-fold more common after spinal cord injury (SCI). Although the directional relationship between BP and cerebral blood flow (CBF) has traditionally been thought to travel solely from BP to CBF, a Cushing-like mechanism functioning in the inverse direction, where changes in CBF influence BP, has recently been revealed using Granger causality analysis. Although both CBF buffering of BP and Cushing-like mechanism are influenced by the sympathetic nervous system, we do not understand the impact of disruption of descending sympathetic pathways within the spinal cord due to cervical SCI on these regulatory systems. We hypothesized that cervical SCI patients would have greater BP to CBF transmission, as well as a reduced Cushing-like mechanism. The directional relationships between mean arterial BP (MAP; Finometer Pro) and middle cerebral artery blood velocity (MCAv; transcranial Doppler) were assessed at rest in 14 cervical SCI subjects and 16 uninjured individuals using Granger causality analysis, while also accounting for end-tidal CO2 tension. Those with SCI exhibit 66% increased forward MAP MCAv information transmission as compared to the uninjured group ( =0.0003), indicating reduced cerebrovascular buffering of BP, and do not have a predominant backward Cushing-like MCAv MAP phenotype. These results indicate that both forward and backward communication between BP and CBF are influenced by SCI, which may be associated with impaired cerebrovascular BP buffering after SCI as well as widespread BP instability. PMID- 30458118 TI - A novel thyroid hormone receptor beta mutation (G357R) in a family with resistance to thyroid hormone beta: extending the borders of the 'hot' region in the THRB gene. AB - Resistance to thyroid hormone (RTH) beta is a syndrome characterized by high serum levels of thyroid hormone and unsuppressed serum thyrotropin (or thyroid stimulating hormone [TSH]) concentrations. RTHbeta is caused by mutations in the thyroid hormone receptor beta (THRB) gene, which are mostly clustered in three 'hot regions' along the gene. Here we report on a family with RTHbeta caused by a novel mutation in the THRB gene (c.1069 G>C, p.G357R) occurring outside the historically known 'hot' regions. PMID- 30458119 TI - Transparenchymal renal pelvis injection of recombinant AAV9 vectors is a practical approach for gene delivery in the kidney. AB - Gene therapy has great potential in treating human diseases, but little progress has been made in preclinical and clinical studies of renal diseases. To find an effective gene delivery approach in the kidney, we developed transparenchymal renal pelvis injection. Using AAV9 vectors, we evaluated the gene delivery efficiency and safety of this administration method. The results showed that the exogenous gene was expressed in the tubular epithelial cells of the injected kidney, with a much lower expression level in the contralateral kidney. Extrarenal transduction in the liver was also observed in this study, with the liver function of AAV9-injected mice comparable to that of control mice. Altogether, the administration of AAV9 vectors by newly established transparenchymal renal pelvis injection achieved the desired exogenous gene expression in renal tubular cells, hence might be one possible way for gene therapy in renal diseases. PMID- 30458120 TI - Transforming institutional racism at an Australian hospital. AB - Objectives The aims of this study were to: (1) examine institutional racism's role in creating health outcome discrepancies for Aboriginal and Torres Strait Islander peoples; and (2) assess the management of institutional racism in an Australian hospital and health service (HHS).Methods A literature review informed consideration of institutional racism and the health outcome disparities it produces. Publicly available information, provided by an Australian HHS, was used to assess change in an Australian HHS in five key areas of institutional racism: inclusion in governance, policy implementation, service delivery, employment and financial accountability. These findings were compared with a 2014 case study.Results The literature concurs that outcome disparity is a defining characteristic of institutional racism, but there is contention about processes. Transformative change was detected in the areas of governance, service delivery and employment at an Australian HHS, but there was no change in financial accountability or policy implementation.Conclusions The health outcomes of some racial groups can be damaged by institutional racism. An external assessment tool can help hospitals and health services to change.What is known about the topic? Institutional racism theory is still developing. An external assessment tool to measure, monitor and report on institutional racism has been developed in Australia.What does this paper add? This study on institutional racism has useful propositions for healthcare organisations experiencing disparities in outcomes between racial groups.What are the implications for practitioners? The deleterious effects of institutional racism occur regardless of practitioner capability. The role for practitioners in ameliorating institutional racism is to recognise the key indicator of poorer health outcomes, and to then seek change within their hospital or healthcare organisation. PMID- 30458121 TI - The pore-forming action of polyenes: From model membranes to living organisms. AB - The incidence of resistant fungal pathogens has been increasing, especially in immuno-compromised people. As such, considerable research has been focused on discovering anti-fungal agents with new mechanisms of action and on optimizing the use of existing agents. In this context, interest in the polyene group of anti-fungals has recently been renewed, since they are known to be effective against a broad spectrum of fungal pathogens that only rarely develop a resistance to them. In the past 10 years considerable efforts have been made to improve their efficacy and, simultaneously, to reduce their toxicity. Knowledge about the basic mechanisms of their action will be of crucial importance to further optimizing their use. The mechanisms of polyene action at the membrane level are reviewed here, focusing primarily on their pore-forming activity and on the resulting osmotic responses of artificial lipid vesicles and different eukaryotic cells. PMID- 30458122 TI - Past, present and future of Aedes aegypti in its South American southern distribution fringe: What do temperature and population tell us? AB - Aedes aegypti (Diptera: Culicidae) (Linnaeus) is currently the major threat among arbovirus vectors in the Americas. We examined its past, present, and future distribution patterns in the South American fringe in association with environmental and demographic variables at two spatial scales. We updated the database of the occurrence of Ae. aegypti per locality and modelled by GLMM the past occurrence (until 2000) and its expansion (2001-2017) as a function of air temperature, precipitation, altitude, and population. We also conducted a field survey in 7 pairs of urban/rural cemeteries along the entire temperature range within the expansion region. At both scales, mean annual air temperature and human population were significantly associated with the distribution of Ae. aegypti. Projection of the expansion models for 2030 under two climatic change scenarios showed a vast infestation, mainly driven by the shift of the 16 degrees C isotherm. We postulate a quantitative compromise between air temperature and human population associated with vector occurrence, along with potential thresholds for their mutual favourability. PMID- 30458123 TI - Lateral flow dipstick antigen assay for human cystic echinococcosis. AB - Cystic echinococcosis (CE) is a neglected zoonotic disease with a worldwide distribution and is a major public health problem in some areas. Diagnosis of CE is mainly based on clinical symptoms, imaging and serological testing, however, improvement in serodiagnosis is still needed. This study was aimed at detecting circulating Echinococcus antigen in CE patients using a lateral flow dipstick (LFD) assay. Three types of hydatid antigens i.e. hydatid cyst fluid (HCF), native antigen B (nAgB) and recombinant antigen B (rAgB) were prepared and polyclonal rabbit antiserum was raised against each antigen. Purified IgG fractions were prepared and a portion was conjugated to gold nanoparticles. After a series of optimizations, a final antigen detection LFD assay was developed using a combination of anti-nAgB-IgG and gold-conjugated anti-HCF-IgG. Evaluation of the assay showed that 27 out of 35 (77%) serum samples from CE patients gave positive results. Meanwhile, the test showed a diagnostic specificity of 82% when tested with sera from 38 healthy individuals and 13 patients with other parasitic diseases. In conclusion, the antigen detection LFD assay seemed to be useful for diagnosis of CE and possibly for post-treatment follow-up, and merit further evaluation studies. We foresee that it may improve serodiagnosis of CE when used in tandem with an antibody detection test. PMID- 30458124 TI - Crystal violet stains proteins in SDS-PAGE gels and zymograms. AB - Coomassie brilliant blue R250, an anionic dye is the most popular stain to detect proteins resolved in SDS-PAGE gels. Crystal violet, a cationic dye was found to be versatile and stained proteins in SDS-PAGE gels and in zymograms. Stained proteins can be transferred to nitrocellulose and the stained proteins on the western detected with enzyme coupled antibodies. Staining can be reversed. Staining takes 3 h at RT or 30 min at 60 degrees C. Crystal violet stained some E. coli high and low molecular weight proteins not stained by Coomassie blue R250. Crystal violet stained down to 16 ng of protein, some five-fold lower than Coomassie blue, though the two stains had a similar linear dynamic range. The staining sensitivity could be increased to 2 ng when crystal violet and Coomassie blue were combined in a double staining/counterion dye formulation. The low concentrations of the dye without a destaining step reduces the costs of the technique and results in a more environmentally friendly stain compared to traditional staining methods. PMID- 30458125 TI - Simplified LC/MS assay for the measurement of isolevuglandin protein adducts in plasma and tissue samples. AB - Isolevuglandins (IsoLGs) are a family of highly reactive 4-ketoaldehydes formed by lipid peroxidation that modify the lysyl residues of cellular proteins. Modification of proteins by IsoLGs have been shown to contribute to disease processes such as the development of hypertension. Accurate quantitation of the extent of protein modification by IsoLGs is essential for understanding the mechanisms whereby these modifications contribute to disease and the efficacy of interventions designed to prevent this modification. The previously described LC/MS assay to quantitate IsoLG protein adducts was extremely labor-intensive and time consuming, and while it offered reasonably low intra-day variation for replicate samples, variation when replicate samples were processed on separate days was significant. These limitations significantly restricted utilization of this approach. We therefore performed a series of studies to optimize the assay. We now report a significantly simplified LC/MS assay for measurement of IsoLG protein adducts with increased sensitivity and lower intra-day and inter-day variability. PMID- 30458126 TI - Comparative Evaluation of Clinical Outcomes of Laser Skin Resurfacing Using an Ultra-Pulse Carbon Dioxide Laser and Manual Dermabrasion Using a Medium-Grit Drywall Sand Screen for Scar Revision in Adults: A Split-Scar Prospective Study. AB - PURPOSE: The purpose was to evaluate the clinical outcomes of laser skin resurfacing using an ultra-pulse carbon dioxide (CO2) laser and manual dermabrasion with a medium-grit drywall sand screen for scar revision in adults with Fitzpatrick skin type III to V. MATERIALS AND METHODS: A total of 20 postsurgical and post-traumatic scars in individuals with Fitzpatrick skin type III to V were included in this study. Preoperative evaluation of the scars was performed by 3 blinded observers using the Manchester scar rating scale. Each scar to be treated was divided into 2 equal halves, and each half was randomly allotted to either ultra-pulse CO2 laser resurfacing (group A) or manual dermabrasion (group B). Postoperative clinical evaluation was performed by the same observers using the Manchester scar rating scale at the end of the first month, third month, and sixth month. RESULTS: This study showed that both methods were effective in improving the appearance of the postsurgical and post-traumatic scars. No significant difference was found between them (P = .978). Hyperpigmentation occurred in 4 scars in both the half treated with manual dermabrasion and the half treated with laser resurfacing; however, it had resolved by the end of the sixth month in all 4 scars. CONCLUSIONS: CO2 laser resurfacing and manual dermabrasion are equally efficacious and safe methods for scar resurfacing in adults with Fitzpatrick skin type III to V. PMID- 30458127 TI - Comparison of Complications With Semisolid Versus Liquid Diet Via Nasogastric Feeding Tube After Orthognathic Surgery. AB - PURPOSE: The aim of this retrospective study was to compare the effectiveness of nasogastric tube (NGT) feeding of a semisolid diet versus a liquid diet after orthognathic surgery. PATIENTS AND METHODS: The orthognathic surgery patients were relatively young and generally healthy, without severe medical disease. Of the patients, 26 received liquid feeding (liquid diet group [LG], with an administration rate of 100 mL/hour), 30 received semisolid feeding at a high administration rate (semisolid diet-rapid administration group [SSRAG], 200 to 500 mL/hour), and 33 received semisolid feeding at a slower rate (semisolid diet slow administration group [SSSAG], 100 mL/hour). We retrospectively investigated the complications of NGT feeding in each group. RESULTS: The incidence of diarrhea was clearly lower in the SSRAG than in the LG. Among patients with lower gastrointestinal tract symptoms, stool form scale scores and maximum defecation frequency per day were significantly lower in the SSRAG than in the LG (P = .001 for both). Rapid administration of a semisolid diet via an NGT resulted in fewer complications and shorter feeding times for orthognathic surgery patients. CONCLUSIONS: The rapid administration of a semisolid diet via an NGT should decrease the complications of NGT feeding and improve the quality of the perioperative period for patients. The findings of this study will help clinicians select NGT diets for relatively young, healthy patients, such as orthognathic surgery patients. PMID- 30458128 TI - SIRT1 activation promotes angiogenesis in diabetic wounds by protecting endothelial cells against oxidative stress. AB - OBJECTIVE: Chronic wounds are a devastating complication of diabetes and can lead to amputations or even death. Current medical therapies are insufficient to accelerate its repair. The objective of this study was to explore the role of Sirtuin1 (SIRT1) in diabetic wounds. METHODS AND MATERIALS: Perilesional skin tissue samples from diabetic ulcers and normoglycemic trauma wounds were used to detect SIRT1 expression and oxidative stress levels. In a diabetic mouse model, SIRT1 was pharmacologically activated to attenuate angiogenesis and accelerate wound closure. Finally, in vitro experiments were performed to elucidate some of the mechanisms by which SIRT1 activation promotes angiogenesis in diabetic wound healing. RESULTS: We found that skin tissue from diabetes patients showed lower expression of SIRT1 and severe oxidative stress. Decreased SIRT1 expression was observed in skin tissue from streptozocin (STZ)-induced diabetic mice and was associated with impaired wound healing. In addition, the wounds of STZ-induced diabetic mice treated with SRT1720 (a specific SIRT1 activator) demonstrated locally improved wound healing and angiogenesis. In the in vitro experiment, similar results were observed. Under hyperglycemia conditions, human umbilical vein endothelial cells (HUVECs) showed lower expression of SIRT1 and higher levels of reactive oxygen species (ROS) production. Furthermore, the migration, proliferation and in vitro tube formation ability of HUVECs were impaired under hyperglycemia conditions, and SRT1720 treatment rescued these impairments and decreased ROS production in HUVECs. CONCLUSIONS: This study provides experimental evidence that SIRT1 activation could improve angiogenesis in wounds in vitro and in vivo and that sirtuin1 activation accelerates wound healing in diabetic mice by promoting angiogenesis. These positive therapeutic effects may be mediated by protecting vascular endothelial cells from oxidative stress injury. This study suggested that SIRT1 may serve as a potentially important and potent therapeutic target for treating diabetic ulcers. PMID- 30458129 TI - Cleavage specificity of recombinant Giardia intestinalis cysteine proteases: Degradation of immunoglobulins and defensins. AB - Giardia intestinalis is a protozoan parasite and the causative agent of giardiasis, a common diarrheal disease. Cysteine protease (CP) activities have been suggested to be involved in Giardia's pathogenesis and we have recently identified and characterized three secreted Giardia CPs; CP14019, CP16160 and CP16779. Here we have studied the cleavage specificity of these CPs using substrate phage display and recombinant protein substrates. The phage display analyses showed that CP16160 has both chymase and tryptase activity and a broad substrate specificity. This was verified using recombinant protein substrates containing different variants of the cleavage sites. Phage display analyses of CP14019 and CP16779 failed but the substrate specificity of CP14019 and CP16779 was tested using the recombinant substrates generated for CP16160. CP16160 and CP14019 showed similar substrate specificity, while CP16779 has a slightly different substrate specificity. The consensus sequence for cleavage by CP16160, obtained from phage display analyses, was used in an in silico screen of the human intestinal proteome for detection of potential targets. Immunoglobulins, including IgA and IgG and defensins (alpha-HD6 and beta-HD1) were predicted to be targets and they were shown to be cleaved by the recombinant CPs in vitro. Our results suggest that the secreted Giardia CPs are key players in the interaction with host cells during Giardia infections since they can cleave several components of the human mucosal defense machinery. PMID- 30458130 TI - A Space for Women's Voices. PMID- 30458131 TI - Developing Evolutionary Cell Biology. AB - Recent advances in both phylogenetic comparisons and the development of experimentally tractable organisms, in the growing field of evolutionary cell biology, pave the way for gaining a molecular understanding of the development of multicellularity in the animal lineage. PMID- 30458132 TI - The Inner Nuclear Membrane Takes On Lipid Metabolism. AB - Challenging the idea of the inner nuclear membrane (INM) being an inert compartment, recent work in S. cerevisiae shows that the INM can metabolize lipids and that local lipid metabolism can regulate transcription in response to lipid availability, suggesting a functional role for the INM in cellular lipid homeostasis. PMID- 30458133 TI - Strengthening Microtubules by Cuts that Heal. AB - Microtubule-severing enzymes, which can remove tubulin dimers from microtubule lattices, participate in cytoskeletal remodeling in various contexts. A recent study showed that partially damaged microtubule shafts and new microtubule ends generated by these enzymes can incorporate GTP-tubulin and serve as sites of microtubule rescue and re-growth, explaining how severing enzymes can amplify microtubule arrays. PMID- 30458134 TI - What Doesn't Kill You Makes You Stronger. AB - The microtubule-severing proteins spastin and katanin were long thought to destabilize microtubules. Recent work demonstrates that these enzymes inflict nano-damage on the microtubule lattice that is then rapidly repaired by new GTP tubulin incorporation, for a net stabilization of the polymer, a process that has implications for neurodegenerative disease. PMID- 30458135 TI - Neutrophil Reverse Migration and a Chemokinetic Resolution. AB - Neutrophil migration to sites of injury or infection is a critical first step in innate immunity. Resolution of neutrophil inflammation is essential for tissue repair but is less well understood. Recent work using intravital imaging in mice to visualize neutrophil dynamics at sterile injuries has advanced our understanding of neutrophil reverse migration and resolution of inflammation in mammals. PMID- 30458136 TI - Strengthen Your Junctions to Resist the Force. AB - In this issue of Developmental Cell, Acharya et al. (2018) uncover a mechanosensitive pathway that activates RhoA in epithelial cells exposed to acute tensile stress. This pathway serves to preserve tissue integrity via regulation of tensile strength, the threshold force above which adherens junctions rupture. PMID- 30458138 TI - Adherens Junction Length during Tissue Contraction Is Controlled by the Mechanosensitive Activity of Actomyosin and Junctional Recycling. AB - During epithelial contraction, cells generate forces to constrict their surface and, concurrently, fine-tune the length of their adherens junctions to ensure force transmission. While many studies have focused on understanding force generation, little is known on how junctional length is controlled. Here, we show that, during amnioserosa contraction in Drosophila dorsal closure, adherens junctions reduce their length in coordination with the shrinkage of apical cell area, maintaining a nearly constant junctional straightness. We reveal that junctional straightness and integrity depend on the endocytic machinery and on the mechanosensitive activity of the actomyosin cytoskeleton. On one hand, upon junctional stretch and decrease in E-cadherin density, actomyosin relocalizes from the medial area to the junctions, thus maintaining junctional integrity. On the other hand, when junctions have excess material and ruffles, junction removal is enhanced, and high junctional straightness and tension are restored. These two mechanisms control junctional length and integrity during morphogenesis. PMID- 30458137 TI - Oxidative Stress in Cells with Extra Centrosomes Drives Non-Cell-Autonomous Invasion. AB - Centrosomal abnormalities, in particular centrosome amplification, are recurrent features of human tumors. Enforced centrosome amplification in vivo plays a role in tumor initiation and progression. However, centrosome amplification occurs only in a subset of cancer cells, and thus, partly due to this heterogeneity, the contribution of centrosome amplification to tumors is unknown. Here, we show that supernumerary centrosomes induce a paracrine-signaling axis via the secretion of proteins, including interleukin-8 (IL-8), which leads to non-cell-autonomous invasion in 3D mammary organoids and zebrafish models. This extra centrosomes associated secretory phenotype (ECASP) promotes invasion of human mammary cells via HER2 signaling activation. Further, we demonstrate that centrosome amplification induces an early oxidative stress response via increased NOX generated reactive oxygen species (ROS), which in turn mediates secretion of pro invasive factors. The discovery that cells with extra centrosomes can manipulate the surrounding cells highlights unexpected and far-reaching consequences of these abnormalities in cancer. PMID- 30458141 TI - Inactivation of Medial Frontal Cortex Changes Risk Preference. PMID- 30458139 TI - S-Palmitoylation Sorts Membrane Cargo for Anterograde Transport in the Golgi. AB - While retrograde cargo selection in the Golgi is known to depend on specific signals, it is unknown whether anterograde cargo is sorted, and anterograde signals have not been identified. We suggest here that S-palmitoylation of anterograde cargo at the Golgi membrane interface is an anterograde signal and that it results in concentration in curved regions at the Golgi rims by simple physical chemistry. The rate of transport across the Golgi of two S-palmitoylated membrane proteins is controlled by S-palmitoylation. The bulk of S-palmitoylated proteins in the Golgi behave analogously, as revealed by click chemistry-based fluorescence and electron microscopy. These palmitoylated cargos concentrate in the most highly curved regions of the Golgi membranes, including the fenestrated perimeters of cisternae and associated vesicles. A palmitoylated transmembrane domain behaves similarly in model systems. PMID- 30458142 TI - Sleepwalking. AB - Arnulf describes the fascinating behavior of sleepwalking and its associated parasomnias. PMID- 30458140 TI - A Cell/Cilia Cycle Biosensor for Single-Cell Kinetics Reveals Persistence of Cilia after G1/S Transition Is a General Property in Cells and Mice. AB - The cilia and cell cycles are inextricably linked. Centrioles in the basal body of cilia nucleate the ciliary axoneme and sequester pericentriolar matrix (PCM) at the centrosome to organize the mitotic spindle. Cilia themselves respond to growth signals, prompting cilia resorption and cell cycle re-entry. We describe a fluorescent cilia and cell cycle biosensor allowing live imaging of cell cycle progression and cilia assembly and disassembly kinetics in cells and inducible mice. We define assembly and disassembly in relation to cell cycle stage with single-cell resolution and explore the intercellular heterogeneity in cilia kinetics. In all cells and tissues analyzed, we observed cilia that persist through the G1/S transition and into S/G2/M-phase. We conclude that persistence of cilia after the G1/S transition is a general property. This resource will shed light at an individual cell level on the interplay between the cilia and cell cycles in development, regeneration, and disease. PMID- 30458143 TI - Ex vivo recordings reveal desert locust forelimb control is asymmetric. AB - Lateralized behaviours are widespread among the animals, including insects with their miniature brains, perhaps being a way of maximising neural capacity (reviewed in [1,2]). However, evidence for functional asymmetries in the neural circuitry itself is scarce. Here, using bilateral simultaneous recordings from the ex vivo nervous system of desert locusts, we show that the neural control of their forelimbs is asymmetric. This asymmetry was retained throughout the experimental period and either with or without the suboesophageal ganglion (SOG). These findings provide evidence for hard-wired neural sidedness and contribute to our understanding of the lateralization observed in in-vivo motor behaviours. PMID- 30458144 TI - A vast 4,000-year-old spatial pattern of termite mounds. AB - The origins of many large-scale 'biogenic' earthen structures are controversial, because often the species that built them have vanished. This is especially true when they form regular (over-dispersed), self-organized vegetation patterns [1]. Here, we describe a vast array of soil mounds constructed by termites (Syntermes dirus) that has persisted for up to 4000 years and covers an estimated 230,000 km2 of seasonally dry tropical forest in a relatively undisturbed and climatically stable region of Northeast Brazil. The mounds are not nests, but rather they are generated by the excavation of vast inter-connecting tunnel networks, resulting in approximately 10 km3 of soil being deposited in 200 million conical mounds that are 2.5 m tall and approximately 9 m in diameter. S. dirus termites are still present in the soil surrounding the mounds and we found that intra-specific aggression occurred at a scale much larger than an individual mound. We suggest that the complex network of tunnels built to access episodic leaf-fall has allowed for the optimization of waste soil removal, which over thousands of years has formed an over-dispersed spatial pattern of mounds. PMID- 30458145 TI - Multisensory perception of looming and receding objects in human newborns. AB - When newborns leave the enclosed spatial environment of the uterus and arrive in the outside world, they are faced with a new audiovisual environment of dynamic objects, actions and events both close to themselves and further away. One particular challenge concerns matching and making sense of the visual and auditory cues specifying object motion [1-5]. Previous research shows that adults prioritise the integration of auditory and visual information indicating looming (for example [2]) and that rhesus monkeys can integrate multisensory looming, but not receding, audiovisual stimuli [4]. Despite the clear adaptive value of correctly perceiving motion towards or away from the self - for defence against and physical interaction with moving objects - such a perceptual ability would clearly be undermined if newborns were unable to correctly match the auditory and visual cues to such motion. This multisensory perceptual skill has scarcely been studied in human ontogeny. Here we report that newborns only a few hours old are sensitive to matches between changes in visual size and in auditory intensity. This early multisensory competence demonstrates that, rather than being entirely naive to their new audiovisual environment, newborns can make sense of the multisensory cue combinations specifying motion with respect to themselves. PMID- 30458146 TI - Gravity Perception: The Role of the Cerebellum. AB - The cerebellum is known to support motor behaviors, including postural stability, but new research supports the view that cerebellar function is also critical for perception of spatial orientation, particularly because of its role in vestibular processing. PMID- 30458147 TI - Animal Communication: Chit-Chat in Meerkats. AB - Coordinated behaviors are the hallmark of animal societies. General mechanisms for the emergence of social group dynamics are still unknown. New research suggests that a vocal feedback loop explains the appearance of coordinated vocal exchanges in large groups of meerkats. PMID- 30458148 TI - Sexual Reproduction: Preventing Re-fertilization in Fission Yeast. AB - During sexual reproduction, two haploid cells fuse to produce a diploid cell called a zygote. A new study describes how fission yeast prevents a zygote from being formed by the fusion of more than two cells. PMID- 30458149 TI - Evolution: Directives from Sea Anemone Hox Genes. AB - A new study in a sea anemone shows that, as in bilaterian animals, an axis patterning Hox code exists in cnidarians. Surprisingly, it acts along the directive axis, orthogonal to the oral-aboral axis. PMID- 30458150 TI - Spatial Instability: The Paradox of Place Cell Remapping. AB - How do memories persist stably over time when the spatial maps upon which they are constructed are unstable? New insights resolve this paradox by finding coherent structure in the instability of spatial maps arising from dynamic switches in reference frames. PMID- 30458151 TI - Mitotic Spindle: Illuminating Spindle Positioning with a Biological Lightsaber. AB - In metazoans, positioning of the mitotic spindle is controlled by the microtubule dependent motor protein dynein, which associates with the cell cortex. Using optogenetic tools, two new studies examine how the levels and activity of dynein are regulated at the cortex to ensure proper positioning of the mitotic spindle. PMID- 30458152 TI - Sleep and Metabolism: Eaat-ing Your Way to ZZZs. AB - A new study in fruit flies identifies a molecule, Eaat2, that regulates both sleep and metabolic rate. Surprisingly, Eaat2 acts in a specific glial subtype to modulate both processes, suggesting a cellular link in the brain between sleep and metabolism. PMID- 30458153 TI - Sex Chromosome Effects on Male-Female Differences in Mammals. AB - Fundamental differences exist between males and females, encompassing anatomy, physiology, behaviour, and genetics. Such differences undoubtedly play a part in the well documented, yet poorly understood, disparity in disease susceptibility between the sexes. Although traditionally attributed to gonadal sex hormone effects, recent work has begun to shed more light on the contribution of genetics - and in particular the sex chromosomes - to these sexual dimorphisms. Here, we explore the accumulating evidence for a significant genetic component to mammalian sexual dimorphism through the paradigm of sex chromosome evolution. The differences between the extant X and Y chromosomes, at both a sequence and regulatory level, arose across 166 million years. A functional result of these differences is cell autonomous sexual dimorphism. By understanding the process that changed a pair of homologous ancestral autosomes into the extant mammalian X and Y, we believe it easier to consider the mechanisms that may contribute to hormone-independent male-female differences. We highlight key roles for genes with homologues present on both sex chromosomes, where the X-linked copy escapes X chromosome inactivation. Finally, we summarise current experimental paradigms and suggest areas for developments to further increase our understanding of cell autonomous sexual dimorphism in the context of health and disease. PMID- 30458154 TI - Large coronary sinus hematoma resembling thrombus in the left atrium. PMID- 30458155 TI - Comparison between Stereotactic Radiotherapy and Sublobar Resection for Non-Small Cell Lung Cancer. AB - BACKGROUND: The aim of this study was to compare outcomes of primary treatment with stereotactic body radiation therapy (SBRT) versus sublobar resection (SLR) for clinical stage I non-small cell lung cancer (NSCLC) in patients with medical comorbidities. METHODS: Consecutive patients who underwent SBRT (n=106) or SLR (wedge resection: n=100 and segmentectomy: n=41) because of medical comorbidities associated with stage I NSCLC were enrolled. Lesions located in the outer third of the lung field on CT were defined as external, and others were defined as internal. A propensity matched analysis was also performed that compared SBRT and SLR results. Charts were reviewed to determine local tumor recurrence, disease specific survival (DSS), and overall survival (OS). RESULTS: A propensity matched analysis, recurrence-free survival (RFS) became significant in favor of surgery (p=0.036). For large nodules of >2.0 cm in diameter, RFS was significantly better in the surgery group (p=0.042). No significant differences in OS, DSS, or RFS were observed with small nodules of <2.0 cm in diameter. In the external group, a higher recurrence rate was seen for SBRT group. For internal group, there was no statistical difference between each treatment. Local recurrence rate was higher in the SBRT group (p=0.0082) in the external group. CONCLUSIONS: In a matched comparison of stage I NSCLC in patients with medical comorbidities, RFS was in favor of surgery comparing SBRT, but there were no significant differences in OS or DSS. The tumor size, tumor location should be considered before deciding whether to perform SBRT or surgery. PMID- 30458156 TI - Prothrombin complex concentrate in cardiac surgery: A systematic review and meta analysis. AB - BACKGROUND: Prothrombin complex concentrate (PCC) has recently emerged as effective alternative to fresh frozen plasma (FFP) in treating excessive perioperative bleeding. We performed a systematic review and meta-analysis to evaluate the safety and efficacy of PCC administration as first-line treatment for coagulopathy following adult cardiac surgery. METHODS: We searched PubMed/MEDLINE, EMBASE, and the Cochrane Library from inception to the end of March 2018 to identify eligible articles. Adult patients undergoing cardiac surgery and receiving perioperative PCC were compared to those receiving FFP. RESULTS: A total of 861 adult patients from 4 studies were retrieved. No randomized studies were identified. Pooled odds ratio (OR) showed that PCC cohort was associated with a significant reduction in the risk of RBC transfusion (OR: 2.22; 95% confidence interval [CI] 1.45-3.40) and units of RBC received (OR: 1.34; 95%CI: 0.78-1.90). No differences were observed between the groups for re exploration for bleeding (OR: 1.09; 95%CI: 0.66-1.82), chest drain output at 24 hours (OR: 66.36; 95%CI: -82.40-216.11), hospital mortality (OR: 0.94; 95%CI: 0.59-1.49), stroke (OR: 0.80; 95%CI: 0.41-1.56), and occurrence of acute kidney injury (OR: 0.80; 95%CI: 0.58-1.12). A trend toward increased risk of renal replacement therapy was observed in the PCC group (OR: 0.41; 95%CI: 0.16-1.02). CONCLUSIONS: In patients with significant bleeding following cardiac surgery, PCC administration seems to be more effective than FFP in reducing perioperative blood transfusions. No additional risks of thromboembolic events or other adverse reactions were observed. Randomized controlled trials are needed to definitively establish the safety of PCC in cardiac surgery. PMID- 30458157 TI - Long-Term Results Following Lung Volume Reduction Surgery: A Single Institution's Experience. AB - BACKGROUND: The National Emphysema Treatment Trial (NETT) showed a clear survival and quality of life benefit for patients selected for lung volume reduction surgery (LVRS). However, long-term outcomes following LVRS are still lacking. The aim of this study is to evaluate overall mortality and functional durability in this single institutional cohort of patients undergoing LVRS. METHODS: A single institution registry identified all patients who had undergone LVRS from January 2006 through August of 2017. Records were retrospectively reviewed, and data was collected to include pulmonary functions test values, shortness of breath questionnaire (University of California, San Diego SOBQ), complication and mortality rate. RESULTS: LVRS was performed in 135 patients with a 2.2% 90-day mortality rate (n=3). Estimated 1-, 2- and 5- year survival of 0.94 (95% CI 0.88 to 0.97), 0.91 (95% CI 0.83 to 0.95), and 0.71 (95% CI 0.57 to 0.81) respectively. Mean improvement in FEV% predicted from pre-operative baseline at 1 and 2- year of 5.3 (95% CI 3.1 to 7.4) and 4.3 (95% CI 1.9 to 6.6) respectively. There was a mean improvement in max workload of 5.2 W (95% CI 0.9 to 9.4) at 1 year. Also, SOBQ scores had a mean decrease of -17.3 points (95% CI -21.8 to -13) at 6-months and -13.9 points (95% CI -18.4 to -9.3) at 1-year. CONCLUSIONS: LVRS is an effective operation with overall improvement in functional status and quality of life among appropriately selected patients. PMID- 30458158 TI - Hospital Costs Related to Early Extubation after Infant Cardiac Surgery. AB - BACKGROUND: The Pediatric Heart Network Collaborative Learning Study (PHN CLS) increased early extubation rates after infant Tetralogy of Fallot (TOF) and coarctation (CoA) repair across participating sites by implementing a clinical practice guideline (CPG). The impact of the CPG on hospital costs has not been studied. METHODS: PHN CLS clinical data were linked to cost data from Children's Hospital Association by matching on indirect identifiers. Hospital costs were evaluated across active and control sites in the pre- and post-CPG periods using generalized linear mixed effects models. A difference-in-difference approach was used to assess whether changes in cost observed in active sites were beyond secular trends in control sites. RESULTS: Data were successfully linked on 410/428 (96%) of eligible patients from 4 active and 4 control sites. Mean adjusted cost/case for TOF repair was significantly reduced in the post-CPG period at active sites ($42,833 vs. $56,304, p<0.01) and unchanged at control sites ($47,007 vs. $46,476, p=0.91), with an overall cost reduction of 27% in active vs. control sites (p=0.03). Specific categories of cost reduced in the TOF cohort included clinical (-66%, p<0.01), pharmacy (-46%, p=0.04), lab (-44%, p<0.01), and imaging (-32%, p<0.01). There was no change in costs for CoA repair at active or control sites. CONCLUSIONS: The early extubation CPG was associated with a reduction in hospital costs for infants undergoing repair of TOF, but not CoA repair. This CPG represents an opportunity to both optimize clinical outcome and reduce costs for certain infant cardiac surgeries. PMID- 30458159 TI - Antithrombotic Strategies after Bioprosthetic Aortic Valve Replacement: A Systematic Review. AB - BACKGROUND: The optimal antithrombotic regimen after bioprosthetic aortic valve replacement (bAVR) is unclear. We conducted a systematic review of various anticoagulation strategies following surgical or transcatheter bAVR (TAVR). METHODS: We searched MEDLINE, PubMed, EMBASE, EBM Reviews, and grey literature through June 2017 for controlled clinical trials and cohort studies that directly compared different antithrombotic strategies in non-pregnant adults who had undergone bAVR. We assessed risk of bias and graded the strength of the evidence using established methods. RESULTS: Of 4,554 titles reviewed, 6 clinical trials and 13 cohort studies met inclusion criteria. We found moderate-strength evidence that mortality, thromboembolic events, and bleeding rates are similar between aspirin and warfarin after surgical bAVR. Observational data suggest lower mortality and thromboembolic events with aspirin combined with warfarin compared to aspirin alone after surgical bAVR, but the effect size is small and the combination is associated with a substantial increase in bleeding risk. We found insufficient evidence for all other treatment comparisons in surgical bAVR. In TAVR patients, we found moderate-strength evidence that mortality, stroke, and major cardiac events are similar between dual antiplatelet therapy (DAPT) and aspirin alone, though a non-significantly lower rate of bleeding occurred with aspirin alone. CONCLUSIONS: Treatment with warfarin or aspirin both lead to similar outcomes after surgical bAVR. Combining aspirin with warfarin may lead to a small decrease in thromboembolism and mortality but is accompanied by increased bleeding. For TAVR patients, aspirin is equivalent to DAPT for reducing thromboembolism and mortality, with a possible decrease in bleeding. PMID- 30458160 TI - Double burden of disease: A global health challenge (Reply). PMID- 30458161 TI - The neural basis for understanding imitation-induced musical meaning: The role of the human mirror system. AB - Music can convey meanings by imitating phenomena of the extramusical world, and these imitation-induced musical meanings can be understood by listeners. Although the human mirror system (HMS) is implicated in imitation, little is known about the HMS's role in making sense of meaning that derives from musical imitation. To answer this question, we used fMRI to examine listeners' brain activities during the processing of imitation-induced musical meaning with a cross-modal semantic priming paradigm. Eleven normal individuals and 11 individuals with congenital amusia, a neurodevelopmental disorder of musical processing, participated in the experiment. Target pictures with either an upward or downward movement were primed by semantically congruent or incongruent melodic sequences characterized by the direction of pitch change (upward or downward). When contrasting the incongruent with the congruent condition between the two groups, we found greater activations in the left supramarginal gyrus/inferior parietal lobule and inferior frontal gyrus in normals but not in amusics. The implications of these findings in terms of the role of the HMS in understanding imitation-induced musical meaning are discussed. PMID- 30458162 TI - Paced mating increases the expression of MU opioid receptors in the ventromedial hypothalamus of male rats. AB - Paced mating induces a positive affective state which is blocked by naloxone, an opioid antagonist. Opioids are released in the medial preoptic area (mPOA) and other brain regions during sexual behavior and MU opioid receptors (MOR) are activated in males that copulate until ejaculation. The aim of the present study was to determine if paced mating increases the expression of MOR in areas involved in the control of sexual behavior in male rats. Sexually experienced rats were assigned to one of the following groups: Paced, males that paced the sexual interaction; Non-Paced, males that did not pace the sexual interaction; Control, males were able to hear, see and smell a sexually receptive female, but no physical contact was possible. Males were sacrificed 4, 8 and 12 h after the behavioral tests. The mPOA, ventromedial hypothalamus (VMH), amygdala, olfactory bulbs (OB) and cortex were dissected and expression of MOR was determined by qPCR. In the VMH, the expression of MOR increased in the Paced group compared to the Non-Paced and Control groups at 4 h. No significant differences were found in the mPOA and the amygdala regardless of the time of sacrifice. In the OB and cortex, expression of MOR was not detectable. Interestingly, we found that the expression of MOR varied at the different times of sacrifice. In conclusion, our results show that the expression of MOR increased in the ventromedial hypothalamus after paced mating and it also varied in different brain areas depending on the time of the day. PMID- 30458163 TI - Cognitive decline in Tg2576 mice shows sex-specific differences and correlates with cerebral amyloid-beta. AB - Patients suffering from Alzheimer's disease show a sex-dependent decline of cognitive function. The aim of this investigation was to show these differences in an animal model for Alzheimer's disease and to determine whether this effect is correlated to amyloid-beta-induced pathophysiological changes. Therefore, we assessed cognitive performance with the modified hole-board test in female and male Tg2576 and wild type mice at the age of 6, 8, 10, 12, 14, and 16 months and correlated these findings to the total amount of soluble amyloid-beta and insoluble amyloid deposits in the brain. Tg2576 mice perform worse than wild types. Female Tg2576 mice develop an accentuated cognitive impairment (wrong choice total) beginning at the age of 12 months compared to their male littermates. Alterations in the mice's behaviour do not show interference with these deficits. Cognitive impairment is correlated to the amount of soluble amyloid-beta and insoluble amyloid deposits in the brain in a sex-dependent manner. PMID- 30458164 TI - Statistical analysis of word usage in biological publications since 1965: Historical delineation highlighting an emergence of function-oriented discourses in contemporary molecular and cellular biology. AB - Typical studies on the history of science, or particularly of biology, have been focused on a particular scientist or book, but this selection has a risk of being arbitrary. To find a more objective way of studying history of biology, we applied a statistical method. First, we downloaded from the PubMed database all available titles and abstracts of 934,807 articles in 32 selected journals from 1965 to 2014, and extracted most frequently used 322 terms by text mining. Clustering of these terms according to the annual frequency of usage resulted in three main clusters: Cluster 1 represented terms that were no longer used frequently, Cluster 3 included terms that became abundantly used recently, and Cluster 2 contained terms constantly used. Three phases were delineated in the history of biology over the past 50 years, with transitions in 1987 and 1997. In contrast with our tacit understanding that "function" is a key notion in biological thinking, the results suggest that function-oriented discourses are a new habit of biologists in the genomic era after 1997, in which biological researches focus on identifying a link between a molecule or a structure with its function. We hypothesize that, in spite of repeated warnings, function-related discourses have a teleological connotation, which is easily misunderstood by general audience and, with emphatic expressions such as "important" and "essential", fit to the need for justification of researches as part of researcher's responsibility for public funding. PMID- 30458165 TI - Characterization of Ring-opening Reaction of Succinimide Linkers in ADCs. AB - A new class of highly potent biopharmaceutical drugs, antibody-drug conjugates (ADCs), has been proven to be clinically effective to treat oncology diseases. ADCs contain three major components: the monoclonal antibody, cytotoxic drug, and chemical linker. THIOMABTM drug conjugates and interchain-cysteine ADCs are common ADC platforms that apply thiol-maleimide chemistry via Michael addition to conjugate linker-drugs to cysteine residues. However, the resulting succinimide ring in the linker is susceptible to ring-opening reactions via hydrolysis, especially at high pH and elevated temperatures. Once the succinimide ring is opened, in vivo stability of the ADCs can be changed and the therapeutic activity will be altered. In this study, we investigated the impact of conjugation sites on succinimide ring opening for ADCs. A new methodology based on imaged capillary isoelectric focusing (iCIEF) was developed to monitor the formation of succinimide ring-opened products. In addition, a reverse phase high-performance liquid chromatography (RP-HPLC) method was used to monitor site-specific ring opening reactions. Our data confirmed that succinimide ring-opening rates in ADCs are conjugation site dependent. With a good understanding of the conjugation site impact on final product's stability, it is potentially feasible to modify ring opening rates in vitro to achieve desirable in vivo stability and biological activity. PMID- 30458166 TI - Microscopic Models of Drug/Chemical Diffusion Through the Skin Barrier: Effects of Diffusional Anisotropy of the Intercellular Lipid. AB - Owing to the systematic alignment and ordering of fatty acid and/or ceramide chains, lipid layers in biological membranes have strongly anisotropic diffusion properties. The diffusivity D||lip for solute transport in the direction parallel to the lipid layer is typically 103-105 times the diffusivity D?lip for the perpendicular direction. This paper explores the consequences of this strong degree of anisotropy on solute diffusion through the stratum corneum (SC, barrier) layer of skin based upon a realistic representation of a unit cell of the microstructure. Complementary numerical methods (smoothed particle hydrodynamics, finite differences) are used to solve the steady state unit-cell diffusion problem leading to the average (homogenized, coarse-grained) diffusion tensor characterizing the tissue as an effective continuum. A parametric study is presented characterizing solute concentration profiles in detail for testosterone and caffeine-like permeants, and it is shown that the results cannot be mimicked by calculations based on an isotropic lipid-phase diffusivity. The ratio of lateral to transdermal effective diffusivities calculated by the present model is of the order of 40 and 300 for fully hydrated (in vitro) and partially hydrated (in vivo) states, respectively. These values compare favorably with the results of recent experiments. PMID- 30458167 TI - Loss of MD1 exacerbates myocardial ischemia/reperfusion injury and susceptibility to ventricular arrhythmia. AB - Myeloid differentiation protein 1(MD1), also known as lymphocyte antigen 86 (LY86), plays an important role in the toll-like receptor 4 (TLR4) signaling pathway. Recent studies show that MD1 is involved in regulating pressure overload induced cardiac structural and electrical remodeling. However, the effect of MD1 on myocardial ischemia-reperfusion (I/R) injury and I/R related arrhythmia remains unknown. To further investigate that, the present study used MD1-knockout (MD1-KO) mice to study the role of MD1 in regulating myocardial I/R injury and its electrophysiology. The results demonstrate that the loss of MD1 led to a larger infarct size, increased activity of cardiac injury markers, aggravated histological damage, worsened cardiac function and decreased survival rate after myocardial I/R. Meanwhile, MD1 deficiency also aggravated inflammatory responses, promoted cardiomyocyte apoptosis and increased susceptibility to ventricular arrhythmia in mice subjected to myocardial I/R. Furthermore, loss of MD1 enhanced the activation of toll-like receptor 4 (TLR4) / nuclear factor kappa B (NF kappaB) signaling pathway after myocardial I/R. Therefore, loss of MD1 exacerbated myocardial I/R injury and increased the susceptibility to ventricular arrhythmia, both of which are possibly related to the up-regulation of TLR4/NF kappaB signaling pathway. PMID- 30458168 TI - Pharmacological inhibition of prolyl hydroxylase protects against inflammation induced anemia via efficient erythropoiesis and hepcidin downregulation. AB - Chronic inflammatory diseases are often associated with anemia. In such conditions, anemia is generally treated with erythropoiesis stimulating agents (ESAs) which are associated with potentially hazardous side effects and poor outcomes. Suboptimal erythropoiesis in chronic inflammation is believed to be caused by elevated hepcidin levels, which causes blockade of iron in tissue stores. In the current work using rodent models of inflammation, an orally available small molecule prolyl hydroxylase inhibitor desidustat was assessed as an effective treatment of anemia of inflammation. In BALB/c mice, a single dose treatment of desidustat attenuated the effect of lipopolysaccharide (LPS) - or turpentine oil-induced inflammation and increased serum erythropoietin (EPO), iron, and reticulocyte count, and decreased serum hepcidin levels. In turpentine oil-induced anemia in BALB/c mice, repeated dose desidustat treatment increased hemoglobin, RBC and hematocrit in a dose related manner. In female Lewis rats, treatment with desidustat markedly reduced PGPS-induced anemia and increased hemoglobin, red blood cell (RBC) and white blood cell (WBC) count, hematocrit, serum iron and spleen iron. These effects of desidustat were associated with reduction in hepcidin (HAMP) expression as well as reduction in serum hepcidin, and increased EPO expression in liver and kidneys. Desidustat treatment caused a significant increase in expression of Duodenal cytochrome B (DcytB), ferroportin (FPN1) and divalent metal transporter 1 (DMT1) in duodenum, and FPN1 and monocyte chemoattractant protein-1 (MCP-1) in liver suggesting an overall influence on iron metabolism. Thus, pharmacological inhibition of prolyl hydroxylase enzymes can be useful in treatment of anemia of inflammation. PMID- 30458169 TI - From pediatrics to geriatrics: Mechanisms of heart failure across the life course. AB - Heart failure (HF) is a significant public health problem and a disease with high 5-year mortality. Although age is the primary risk factor for development of HF, it is a disease which impacts patients of all ages. Historically, HF has been studied as a one-size fits all strategy- with the majority of both clinical and basic science investigations employing adult male subjects or adult male pre clinical animal models. We postulate that inclusion of biological variables in HF studies is necessary to improve our understanding of mechanisms of HF and improve outcomes. In this review, we will discuss age-specific differences in HF patients, particularly focusing on the pediatric and geriatric age groups. In addition, we will also discuss the biological variable of sex. Characterizing and understanding the mechanistic differences in these distinct HF populations can provide insights that will benefit and personalize therapeutic interventions. Further, we propose that future investigations into the cellular mechanisms involved in the developing and juvenile heart may provide valuable insights for targets that would be beneficial in aging patients. PMID- 30458170 TI - Ascidian notochord elongation. AB - The elongation of embryo and tissue is a key morphogenetic event in embryogenesis and organogenesis. Notochord, a typical chordate organ, undergoes elongation to perform its regulatory roles and to form the structural support in the embryo. Notochord elongation is morphologically similar across all chordates, but ascidian has evolved distinct molecular and cellular processes. Here, we summarize the current understanding of ascidian notochord elongation. We divide the process into three phases and discuss the underlying molecular mechanisms in each phase. In the first phase, the notochord converges and extends through invagination and mediolateral intercalation, and partially elongates to form a single diameter cell column along the anterior-posterior axis. In the second phase, a cytokinesis-like actomyosin ring is constructed at the equator of each cell and drives notochord to elongate approximately two-fold. The molecular composition and architecture of the ascidian notochord contractile ring are similar to that of the cytokinetic ring. However, the notochord contractile ring does not impose cell division but only drives cell elongation followed by disassembly. We discuss the self-organizing property of the circumferential actomyosin ring, and why it disassembles when certain notochord length is achieved. The similar ring structures are also present in the elongation process of other organs in evolutionarily divergent animals such as Drosophila and C. elegans. We hereby propose that actomyosin ring-based circumferential contraction is a common mechanism adopted in diverse systems to drive embryo and tissue elongation. In the third phase, the notochord experiences tubulogenesis and the endothelial-like cells crawl bi-directionally on the notochord sheath to further lengthen the notochord. In this review, we also discuss extracellular matrix proteins, notochord sheath, and surrounding tissues that may contribute to notochord integrity and morphogenesis. PMID- 30458171 TI - Axonal regrowth is impaired during digit tip regeneration in mice. AB - Mice are intrinsically capable of regenerating the tips of their digits after amputation. Mouse digit tip regeneration is reported to be a peripheral nerve dependent event. However, it is presently unknown what types of nerves and Schwann cells innervate the digit tip, and to what extent these cells regenerate in association with the regenerative response. Given the necessity of peripheral nerves for mammalian regeneration, we investigated the neuroanatomy of the unamputated, regenerating, and regenerated mouse digit tip. Using immunohistochemistry for beta-III-tubulin (beta3T) or neurofilament H (NFH), substance P (SP), tyrosine hydroxylase (TH), myelin protein zero (P0), and glial fibrillary acidic protein (GFAP), we identified peripheral nerve axons (sensory and sympathetic), and myelinating- and non-myelinating-Schwann cells. Our findings show that the digit tip is innervated by two digital nerves that each bifurcate into a bone marrow (BM) and connective tissue (CT) branch. The BM branches are composed of sympathetic axons that are ensheathed by non-myelinating Schwann cells whereas the CT branches are composed of sensory and sympathetic axons and are ensheathed by myelinating- and non-myelinating-Schwann cells. The regenerated digit neuroanatomy differs from unamputated digit in several key ways. First, there is 7.5 fold decrease in CT branch axons in the regenerated digit compared to the unampuated digit. Second, there is a 5.6 fold decrease in myelinating-Schwann cells in the regenerated digit compared to the unamputated digit that is consistent with the decrease in CT branch axons. Importantly, we also find that the central portion of the regenerating digit blastema is aneural, with axons and Schwann cells restricted to peripheral and distal blastema regions. Finally, we show that even with impaired innervation, digits maintain the ability to regenerate after re-amputation. Taken together, these data indicate that nerve regeneration is impaired in the context of mouse digit tip regeneration. PMID- 30458173 TI - UFM1-Activating Enzyme 5 (Uba5) Requires an Extension to Get the Job Done Right. PMID- 30458172 TI - Clustering, Spatial Distribution and Phosphorylation of Discoidin Domain Receptors 1 and 2 in Response to Soluble Collagen Type I. AB - Discoidin Domain Receptors (DDR1 and DDR2) are receptor tyrosine kinases that signal in response to collagen. We had previously shown that collagen binding leads to clustering of DDR1b, a process partly mediated by its extracellular domain (ECD). In this study, we investigated (i) the impact of the oligomeric state of DDR2 ECD on collagen binding and fibrillogenesis, (ii) the effect of collagen binding on DDR2 clustering, and (iii) the spatial distribution and phosphorylation status of DDR1b and DDR2 after collagen stimulation. Studies were conducted using purified recombinant DDR2 ECD proteins in monomeric, dimeric or oligomeric state, and MC3T3-E1 cells expressing full-length DDR2-GFP or DDR1b YFP. We show that the oligomeric form of DDR2 ECD displayed enhanced binding to collagen and inhibition of fibrillogenesis. Using atomic force and fluorescence microscopy we demonstrate that unlike DDR1b, DDR2 ECD and DDR2-GFP do not undergo collagen-induced receptor clustering. However, after prolonged collagen stimulation, both DDR1b-YFP and DDR2-GFP formed filamentous structures consistent with spatial re-distribution of DDRs in cells. Immunocytochemistry revealed that while DDR1b clusters co-localized with non-fibrillar collagen, DDR1b/DDR2 filamentous structures associated with collagen fibrils. Antibodies against a tyrosine phosphorylation site in the intracellular juxtamembrane region of DDR1b displayed positive signals in both DDR1b clusters and filamentous structures. However, only the filamentous structures of both DDR1b and DDR2 co-localized with antibodies directed against tyrosine phosphorylation sites within the receptor kinase domain. Our results uncover key differences and similarities in the clustering abilities and spatial distribution of DDR1b and DDR2 and their impact on receptor phosphorylation. PMID- 30458174 TI - Apatite nanoparticles mediate intracellular delivery of trehalose and increase survival of cryopreserved cells. AB - Cryopreservation of tissue cells is an important method to maintain cell viability and cellular function. However, cell viability and function are less than ideal by conventional cell cryopreservation methods, which may result in apoptosis and necrosis of cells in cryopreservation. Trehalose plays a role in maintaining cell structure and protecting cells from stress. However, owing to the difficulty in transport of trehalose across the cell membrane, its antifreeze effect is limited. A large amount of trehalose (up to 237 +/- 8.5 mM) can be delivered to smooth muscle cells incubated in a medium containing trehalose and apatite nanomaterials at 37 degrees C for 6 h. Our data showed that trehalose was efficiently delivered intracellularly with the aid of nanoparticles (NP), with a loading efficiency up to 137.3 +/- 34.5%, thus allowing for cryopreservation of LMC with nontoxic sugar as the sole cryoprotectant. Colloidal bioelastic apatite NP were used as bioactive promoters for the cryopreservation of tissue cells with trehalose. The addition of apatite NP in the medium substantially increased aortic smooth muscle cell cryosurvival, up to 83.6% (30% improvement over control without NP), a level comparable to that associated with the traditional Me2SO cryoprotective regimen. Furthermore, the cytotoxicity of nanocapsules in the intracellular delivery of trehalose was negligible. This method provides a new option to enhance the activity of valvular cells for cryopreservation. PMID- 30458176 TI - Could the endocrine disruptor bisphenol-a be implicated in the pathogenesis of oral and oropharyngeal cancer? Metabolic considerations and future directions. AB - Bisphenol-A (BPA), a prototype endocrine disrupting molecule, has been associated with many disease entities such as diabetes mellitus, obesity, polycystic ovarian disease, cardiovascular disease, reproductive and neurodevelopmental disorders. BPA has also been associated mainly with hormone sensitive cancers such as breast, prostate, endometrial, ovarian, testicular and thyroid cancers but also non-hormonal sensitive cancers such as cervical and lung cancers, osteosarcoma and meningioma. Recent research has investigated the sources of contamination which are responsible for higher BPA concentrations in the oral cavity and oropharyngeal space, representing the first site of BPA exposure after ingestion. Besides growing awareness and case registration, the incidence and prevalence of oral (OC) and oropharyngeal cancer (OPC) have increased during the last decades correlating with the increased production of BPA worldwide. So far, no study in the medical literature has explored the association of BPA with OC and OPC. BPA may be linked to the etiopathogenesis of OC and OPC through a multitude of mechanisms encompassing and interconnecting genetic, epigenetic, inflammatory, immune, metabolic, hormonal and oxidative stress alterations as well as modulation of oral microbiome. Hence, it is not possible to rule out a potential role of BPA exposure in oral and oropharyngeal tissue carcinogenesis, especially knowing its potential to participate in other non hormonal sensitive malignancies and to deregulate signaling pathways implicated in OC and OPC. This perspective aims at outlining evidence and proposing for the first time a potential link between BPA with OC and OPC, the most frequent subtypes of head and neck malignancies. PMID- 30458175 TI - Genetic suppression of cryoprotectant toxicity. AB - We report here a new, unbiased forward genetic method that uses transposon mediated mutagenesis to enable the identification of mutations that confer cryoprotectant toxicity resistance (CTR). Our method is to select for resistance to the toxic effects of M22, a much-studied whole-organ vitrification solution. We report finding and characterizing six mutants that are resistant to M22. These mutants fall into six independent biochemical pathways not previously linked to cryoprotectant toxicity (CT). The genes associated with the mutations were Gm14005, Myh9, Nrg2, Pura, Fgd2, Pim1, Opa1, Hes1, Hsbp1, and Ywhag. The mechanisms of action of the mutations remain unknown, but two of the mutants involve MYC signaling, which was previously implicated in CT. Several of the mutants may up-regulate cellular stress defense pathways. Several of the M22 resistant mutants were also resistant to dimethyl sulfoxide (Me2SO), and many of the mutants showed significantly improved survival after freezing and thawing in 10% (v/v) Me2SO. This new approach to overcoming CT has many advantages over alternative methods such as transcriptomic profiling. Our method directly identifies specific genetic loci that unequivocally affect CT. More generally, our results provide the first direct evidence that CT can be reduced in mammalian cells by specific molecular interventions. Thus, this approach introduces remarkable new opportunities for pharmacological blockade of CT. PMID- 30458177 TI - Metabolically healthy versus metabolically unhealthy obesity. AB - Obesity-related disease complications reduce life quality and expectancy and increase health-care costs. Some studies have suggested that obesity not always entails metabolic abnormalities and increased risk of cardiometabolic complications. Because of the lack of universally accepted criteria to identify metabolically healthy obesity (MHO), its prevalence varies widely among studies. Moreover, the prognostic value of MHO is hotly debated, mainly because it likely shifts gradually towards metabolically unhealthy obesity (MUO). In this review, we outline the differential factors contributing to the metabolic heterogeneity of obesity by discussing the behavioral, genetic, phenotypical, and biological aspects associated with each of the two metabolic phenotypes (MHO and MUO) of obesity and their clinical implications. Particular emphasis will be laid on the role of adipose tissue biology and function, including genetic determinants of body fat distribution, depot-specific fat metabolism, adipose tissue plasticity and, particularly, adipogenesis. Finally, the emerging role of gut microbiota in obesity and adipose tissue dysfunction as well as the search for novel biomarkers for the obesity-related metabolic traits and associated diseases will be briefly presented. A better understanding of the main determinants of a healthy metabolic status in obesity would allow promotion of this favorable condition by targeting the relevant pathways. PMID- 30458178 TI - Activin A regulates activities of peripheral blood natural killer cells of mouse in an autocrine and paracrine manner. AB - Activin A, a multifunctional cytokine of transforming growth factor-beta (TGF beta) superfamily, can be produced by the diverse immune cells. NK cells in peripheral blood are one of the major immune cells applied to cancer therapy in recent years. However, whether activin A can be produced by natural killer (NK) cells and be involved in regulation of peripheral blood NK cells activities of mouse are not well characterized. Here, we found that activin type IIA and IIB receptors and signaling molecules Smad2, 3 were expressed in peripheral blood NK cells of mouse by flow cytometry and RT-PCR. The cultured blood NK cells of mouse not only produced activin betaA chain protein by intracellular cytokine staining, but also secreted mature activin A protein by enzyme-linked immunosorbent assay (ELISA), and the production was promoted by IL-2. In addition, IL-2 as a positive control obviously promoted IFNgamma production of mouse blood NK cells in vitro. However, activin A suppressed IFNgamma production, but enhanced IL-2 synthesis and did not alter IL-10 production. Moreover, we found that activin A significantly suppressed the ability of NK cells to lyse target cells. These data revealed that blood NK cells of mouse were not only the target cells in response to activin A, but also the source of activin A, suggesting that activin A may play an important role in regulation of NK cells activities of mouse in an autocrine / paracrine manner. PMID- 30458179 TI - Hypoxia induced delta-Catenin to enhance mice hepatocellular carcinoma progression via Wnt signaling. AB - Hypoxia frequently occurs in solid tumors, hepatocellular carcinoma included. Hypoxia-inducible factors (HIFs) upregulated in hypoxia can induce various downstream target genes to resist hypoxia stress, resulting in tumor growth, angiogenesis and metastasis in vivo. Therefore, hypoxia associated genes are usually cancer progression associated genes and can be potential therapy targets for cancer therapy. In our present work, we find that the hypoxia-inducible transcriptional factor, HIF1alpha, can directly upregulate the expression of the gene Ctnnd2, which codes the protein delta-Catenin. Then, delta-Catenin can stabilize beta-Catenin by disrupting the destruction complex, which leads to the activation of Wnt signaling. As a result, delta-Catenin can promote the proliferation and migration of HCC cells in vitro, further enhance mice HCC tumorigenesis in vivo. In summary, our work reveals that delta-Catenin is a direct downstream target gene of HIF1alpha. It can activate Wnt signaling via beta-Catenin stabilization. delta-Catenin can enhance HCC progression. PMID- 30458180 TI - The metastasis suppressor NME1 inhibits melanoma cell motility via direct transcriptional induction of the integrin beta-3 gene. AB - Expression of the metastasis suppressor NME1 in melanoma is associated with reduced cellular motility, invasion, and metastasis, but mechanisms underlying these activities are not completely understood. Herein we report a novel mechanism through which NME1 drives formation of large, stable focal adhesions (FAs) in melanoma cells via induction of integrin beta3 (ITGbeta3), and in one cell line, concomitant suppression of integrin beta1 (ITGbeta1) transcripts. Forced expression of NME1 resulted in a strong activation of the promoter region (-301 to +13) of the ITGB3 gene. Chromatin immunoprecipitation (ChIP) analysis revealed the transcriptional induction was associated with direct recruitment of NME1 and an increase in the epigenetic activation mark, acetylation of histone 3 on lysine 27 (H3K27Ac) to a 1 kb stretch of 5'-flanking sequence of the ITGB3 gene. Unexpectedly, NME1 did not affect the amount either ITGbeta1 or ITGbeta3 proteins were internalized and recycled, processes commonly associated with regulating expression of integrins at the cell surface. The ability of NME1 to suppress motile and invasive phenotypes of melanoma cells was dependent on its induction of ITGbeta3. Expression of ITGbeta3 mRNA was associated with increased disease-free survival time in melanoma patients of the TCGA collection, consistent with its potential role as an effector of the metastasis suppressor function of NME1. Together, these data indicate metastasis suppressor activity of NME1 in melanoma is mediated by induction of ITGB3 gene transcription, with NME1 driven enrichment of ITGbeta3 protein at the cell membrane resulting in attenuated cell motility through the stabilization of large focal adhesions. PMID- 30458181 TI - The guard cell ionome: Understanding the role of ions in guard cell functions. AB - The ionome is critical for plant growth, productivity, defense, and it eventually affects human food quantity and quality. Located on the leaf surface, stomatal guard cells are critical gatekeepers for water, gas, and pathogens. Insights form ionomics (metallomics) is imperative as we enter an omics-driven systems biology era where an understanding of guard cell function and physiology is advanced through efforts in genomics, transcriptomics, proteomics, and metabolomics. While the roles of major cations (K, Ca) and anions (Cl) are well known in guard cell function, the related physiology, movement and regulation of trace elements, metal ions, and heavy metals are poorly understood. The majority of the information on the role of trace elements in guard cells emanates from classical feeding experiments, field or in vitro fortification, micropropagation, and microscopy studies, while novel insights are available from limited metal ion transporter and ion channel studies. Given the rejuvenated and recent interest in the constantly changing ionome in plant mineral balance and eventually in human nutrition and health, we looked into the far from established guard cell ionome in lieu of the modern omics era of high throughput research endeavors. Newer technologies and tools i.e., high resolution mass spectrometry, advanced imaging, and phenomics are now available to delve into the guard cell ionomes. In this review, research efforts on guard cell ionomes were collated and categorized, and we highlight the underlying role of the largely unknown ionome in guard cell function towards a systems physiology understanding of plant health and productivity. PMID- 30458183 TI - The Atopic March and Atopic Multimorbidity: Many Trajectories, Many Pathways. AB - The "atopic march" recognizes the increased occurrence of asthma and/or allergic rhinitis after atopic dermatitis (AD) onset. Mechanisms for developing atopic comorbidities after AD onset are poorly understood, but may involve the impaired cutaneous barrier, which facilitates cutaneous sensitization. The association may also be driven or amplified in susceptible individuals by a systemic Th2-dominant immune response to cutaneous inflammation. However, these associations may merely involve shared genetic loci and environmental triggers, including microbiome dysregulation, with the temporal sequence reflecting tissue-specific peak time of occurrence of each disease, suggesting more of a clustering of disorders than a march. Prospective longitudinal cohort studies provide an opportunity to explore the relationships between post-dermatitis development of atopic disorders and potential predictive phenotypic, genotypic, and environmental factors. Recent investigations implicate disease severity and persistence, age of onset, parental atopic history, FLG (filaggrin) mutations, polysensitization, and the non-rural environment among risk factors for development of multiple atopic comorbidities in young children with AD. Early intervention studies to repair the epidermal barrier or alter exposure to the microbiome or allergens may elucidate the relative roles of barrier defects, genetic locus alterations, and environmental exposures in the risk and sequence of occurrence of Th2 activation disorders. PMID- 30458182 TI - Anti-inflammatory effects of Ang-(1-7) via TLR4-mediated inhibition of the JNK/FoxO1 pathway in lipopolysaccharide-stimulated RAW264.7 cells. AB - Targeting inflammation is considered a challenging pharmacological strategy to prevent or delay the development of inflammatory diseases, such as severe asthma, Crohn's disease, and rheumatoid arthritis. The angiotensin-(1-7) -Mas axis ((Ang (1-7)-Mas axis) was confirmed to antagonize the effects of the Angiotensin II-AT1 receptor axis and the latter is reported to regulate cardiovascular and renal function, as well as contribute to the inflammatory process. In this paper, we aim to explore the crucial effect of Ang-(1-7) in inflammation and disclose the mechanisms in lipopolysaccharide (LPS)-induced murine macrophages RAW264.7. We found that Ang-(1-7) inhibited the production and secretion of tumor necrosis factor-alpha and interleukin-6 in a concentration-dependent manner in LPS-induced macrophages. The overexpression of TLR4, phospho-JNK, and FoxO1 induced by LPS were also inhibited by incubation with Ang-(1-7). These inhibitory effects were reversed by A-779. Moreover, we also used a selective JNK inhibitor Sp600125 to further corroborate the involvement of TLR4, JNK, and FoxO1 in the anti inflammatory action of Ang-(1-7). Our research reveals a new mechanism that Ang (1-7) may drive anti-inflammatory effects via the Mas receptor through inhibition of the TLR4-mediated JNK/FoxO1 signaling pathway in LPS-induced macrophages. Our findings open new perspectives of Ang-(1-7)-Mas axis in local inflammation. PMID- 30458184 TI - What can urban/rural differences in food allergy prevalence tell us about the drivers of food allergy? PMID- 30458185 TI - Menstrual cycle-related fluctuations in oxytocin concentrations: A systematic review and meta-analysis. AB - Oxytocin affects physiological and psychological functions that are often expressed sex-specifically, suggesting interactions between oxytocin and sex hormones. As female sex hormone concentrations change during the menstrual cycle, oxytocin might fluctuate, too. This systematic review and meta-analysis investigated endogenous oxytocin concentrations across menstrual cycle phases in healthy women. Data from 13 studies (120 women) showed a significant increase of oxytocin concentrations from the early follicular phase to ovulation (g = 0.39 [0.25; 0.53], p < .001) and a significant decrease from ovulation to the mid luteal phase (g = -0.50 [-0.81; -0.18], p < .001). There were no significant differences between the early follicular and mid-luteal phase (g = -0.19 [-0.70; 0.32], p = .471). These findings contribute to a deeper understanding of differences in normal and abnormal psychobiological processes in women. They highlight the necessity to consider the menstrual cycle phase in studies on oxytocin in women. PMID- 30458186 TI - Saikosaponin d causes apoptotic death of cultured neocortical neurons by increasing membrane permeability and elevating intracellular Ca2+ concentration. AB - Saikosaponins (SSs) are a class of naturally occurring oleanane-type triterpenoid saponins found in Radix bupleuri that has been widely used in traditional Chinese medicine. As the main active principals of Radix bupleuri, SSs have been shown to suppress mouse motor activity, impair learning and memory, and decrease hippocampal neurogenesis. In the present study, we investigated the effect of five SSs (SSa, SSb1, SSb2, SSc, and SSd) on neuronal viability and the underlying mechanisms in cultured murine neocortical neurons. We demonstrate that SSa, SSb1 and SSd produce concentration-dependent apoptotic neuronal death and induce robust increase in intracellular Ca2+ concentration ([Ca2+]i) at low micromolar concentrations with a rank order of SSd > SSa > SSb1, whereas SSb2 and SSc have no detectable effect on both neuronal survival and [Ca2+]i. Mechanistically, SSd induced elevation in [Ca2+]i is the primary result of enhanced extracellular Ca2+ influx, which likely triggers Ca2+-induced Ca2+ release through ryanodine receptor activation, but not SERCA inhibition. SSd-induced Ca2+ entry occurs through a non-selective mechanism since blockers of major neuronal Ca2+ entry pathways, including L-type Ca2+ channel, NMDA receptor, AMPA receptor, Na+-Ca2+ exchanger, and TRPV1, all failed to attenuate the Ca2+ response to SSd. Further studies demonstrate that SSd increases calcein efflux and induces an inward current in neocortical neurons. Together, these data demonstrate that SSd elevates [Ca2+]i due to its ability to increase membrane permeability, likely by forming pores in the surface of membrane, which leads to massive Ca2+ influx and apoptotic neuronal death in neocortical neurons. PMID- 30458187 TI - Increase interval training intensity improves plasma volume variations and aerobic performances in response to intermittent exercise. AB - PURPOSE: We studied the effect of two interval training programs of varying intensities (100% vs. 110% of maximal aerobic velocity [MAV]) on hematocrit (Ht), hemoglobin (Hb), and plasma volume variations (PVV) in young men. METHODS: Thirty nine male volunteered were assigned to two control groups (CG100, n = 9 and CG110, n = 10), and two training groups (one with 100% MAV [EG100, n = 10] and one with 110% MAV [EG110, n = 10]). All participants performed a maximal graded exercise test and an intermittent exercise (IE) protocol. Blood was collected at rest, at the end of the IE and after 15 min of recovery, before and after 8-weeks training. Interval training (IT) sessions consist of 30s IE run at 100% or 110% MAV with 30s recovery at 50% MAV. RESULTS: After training, time to exhaustion (TTE) was improved in EG110 (+613.7) and EG100 (+397.5). This improvement was greater in EG110 than EG100 (p < 0.005). After training, Hb deceased in EG100 and EG110 at rest (p < 0.01), at the end of IE (p = 0.000) and after 15 min of recovery (p = 0.01). This decrease was more slightly more substantial at rest in EG100 (-0.6%) than EG110 (-0.3%). After training, Ht decreased in EG100 and EG110 at rest (p = 0.001), at the end of IE (p = 0.000) and at 15 min of recovery (p = 0.01). This decrease was more important in EG110 than EG100 at rest (-2.7%), at the end of IE (-2.1%) and after 15 min recovery. After training, PVVrest and PVVend increased in EG100 (+2.2%) and EG110 (+3.2%). No significant difference between EG100 and EG110 was observed. CONCLUSION: Increasing IT intensity by 10% MAV increases PVVrest and PVVend. Despite the fact that EG100 and EG110 had the same PVVend after training, greater performances were recorded in EG110. PMID- 30458188 TI - Equilin displays similar endothelium-independent vasodilator potential to 17beta estradiol regardless of lower potential to inhibit calcium entry. AB - Conjugated equine estrogens (CEE) have been widely used by women who seek to relieve symptoms of menopause. Despite evidence describing protective effects against risk factors for cardiovascular diseases by naturally occurring estrogens, little is known about the vascular effects of equilin, one of the main components of CEE and not physiologically present in women. In this regard, the present study aims to compare the vascular effects of equilin in an experimental model of hypertension with those induced by 17beta-estradiol. Resistance mesenteric arteries from female spontaneously hypertensive rats (SHR) were used for recording isometric tension in a small vessel myograph. As effectively as 17beta-estradiol, equilin evoked a concentration-dependent relaxation in mesenteric arteries from female SHRs contracted with KCl, U46619, PDBu or ET-1. Equilin-induced vasodilation does not involve classical estrogen receptor activation, since the estrogen receptor antagonist (ICI 182,780) failed to inhibit relaxation in U46619-precontracted mesenteric arteries. Vasorelaxation was not affected by either endothelium removal or by inhibiting the release or action of endothelium-derived factors. Incubation with L-NAME (NOS inhibitor), ODQ (guanylyl cyclase inhibitor) or KT5823 (inhibitor of protein kinase G) did not affect equilin-induced relaxation. Similarly, indomethacin (COX inhibitor) or blockage of potassium channels with tetraethylammonium, glibenclamide, 4 aminopyridine, or ouabain did not affect equilin-induced relaxation. Inhibitors of adenylyl cyclase SQ22536 or protein kinase A (KT5720) also had no effects on equilin-induced relaxation. While 17beta-estradiol inhibited calcium (Ca2+) induced contractions in high-K+ depolarization medium in a concentration dependent manner, equilin induced a slight rightward-shift in the contractile responses to Ca2+. Comparable pattern of responses were observed in the concentration-response curves to (S)-(-)-Bay K 8644, a L-type Ca2+ channel activator. Equilin was unable to block the transitory contraction produced by caffeine-induced Ca2+ release from intracellular stores. In conclusion, equilin blocks L-type Ca2+ channels less effectively than 17beta-estradiol. Despite its lower effectiveness, equilin equally relaxes resistance mesenteric arteries by blocking Ca2+ entry on smooth muscle. PMID- 30458189 TI - Effect of saponins from quinoa on a skin-mimetic lipid monolayer containing cholesterol. AB - The study discusses the effect of a quinoa seed coat extract on a cholesterol based Langmuir monolayer mimicking the intercellular lipid mixture in the skin's outermost layer - stratum corneum. Besides cholesterol (CHOL), the monolayer contains also stearic acid (SA) and ceramide VI (CER), in a molar ratio of 10:14:14. Three quinoa extracts were tested for their surface activity: a) from the whole seed, b) from the dehulled seed, and c) from the seed coat. The latter shows significantly higher ability to reduce surface tension (increase surface pressure) than the others. Its adsorbed layers display also reasonable surface dilational elasticity (storage) modulus, E'. These observations are in line with the literature reports on the high concentrations of triterpenoid glycosidic biosurfactants - saponins, in quinoa seed, especially in its coat. The saponin rich extract of quinoa seed coat was thus introduced underneath the pre-formed lipid monolayer compressed to surface pressure, Pi = 30 mN/m in a Langmuir trough, in order to register the surface pressure response. The increase of both the surface pressure and surface dilational elasticity modulus suggests that saponins, and possibly other surface-active components of the extract, incorporate into the model lipid monolayer, without solubilizing it. This opens new perspectives for the saponin-rich quinoa seed extract as skin penetration enhancing active components for cosmetics or pharmaceutical purposes. PMID- 30458190 TI - Bioavailability and structural study of 20-hydroxyecdysone complexes with cyclodextrins. AB - 20-Hydroxyecdysterone - (2beta,3beta,5beta,22R)-2,3,14,20,22,25 hexahydroxycholest-7-en-6-one was isolated in satisfactory yield using ethanol extraction from the aerial part of Silene wolgensis (Hornem.) Otth; sometimes Silene wolgensis (Willd.) Bess. ex Spreng. The complexation of the phytoecdysteroid with beta-cyclodextrin was studied by NMR spectroscopy. By studying the changes in chemical shifts of protons of substrates and receptors it was found that ecdysterone interacts with cyclodextrins to form supramolecular inclusion complexes of stoichiometric composition of 1:1 or 1:2. Ecdysterone-beta cyclodextrin complexes exhibit 100 times higher solubility in water than the parent compound. PMID- 30458191 TI - The core structure characterization and of ginseng neutral polysaccharide with the immune-enhancing activity. AB - The study aims to clarify the structural domain required for the immune enhancement of ginseng neutral polysaccharide (GPN). GPN was first obtained through water extraction and ion-exchange chromatography from Panax ginseng. GPN was hydrolyzed by alpha-amylase for 24 h and fractionated through gel permeation chromatography to give two final fragments GPNE-I and GPNE-II, with molecular weight of 8.03 * 104 Da for GPNE-I and 3.15 * 104 Da for respectively. FT-IR, methylation and 1D/2D NMR analysis demonstrated that GPNE-I was a heteropolysaccharide consisting mainly of a glucan domain and type I and II arabinogalactans (AG-I and AG-II). GPNE II was a glucan consisting of (1 -> 4) alpha-d-Glcp backbone with a substitution at O-6 on every two residues. (1 -> 3) alpha-d-Glcp and (1 -> 6)-alpha-d-Glcp were located at the branches. In the two fractions, both alpha- and beta-t-Glcp as reductive terminals and ->4)-alpha-Glcp as a non-reducing end were detected. The branching degrees of GPNE-I and GPNE-II were 38.17% and 50.78%, respectively. Immunological experiments revealed that GPNE-I exhibited more effectively stimulated lymphocyte proliferation than GPN and GPNE-II, indicating the former showed potential for immunomodulators applications, indicating that GPNE-I might be the core active domain and necessary for GPN to promote lymphocyte proliferation. PMID- 30458193 TI - Cross-linked chitosan/thiolated graphene quantum dots as a biocompatible polysaccharide towards aptamer immobilization. AB - Chitosan has a number of commercial and possible biomedical uses. Chitosan as a polysaccharide is a bioactive polymer with a variety of applications due to its functional properties such as antibacterial activity, non-toxicity, ease of modification, and biodegradability. In this work, cross-linked chitosan/thiolated graphene quantum dot as a biocompatible polysaccharide was modified by gold nanoparticle and used for immobilization of ractopamine (RAC) aptamer. A highly specific DNA-aptamer (5'-SH-AAAAAGTGCGGGC-3'), selected to RAC was immobilized onto thiolated graphene quantum dots (GQDs)-chitosan (CS) nanocomposite modified by gold nanostructures (Au NSs) and used for quantification of RAC. Different shapes of gold nanostructures with various sizes from zero-dimensional nanoparticles to spherical structures were prepared by one-step template assistant green electrodeposition method. Fully electrochemical methodology was used to prepare a new transducer on a glassy carbon surface which provided a high surface area to immobilize a high amount of the aptamer. Therefore, a label free electrochemical (EC) apta-assay for ultrasensitive detection of RAC was developed. A special immobilization media consisting of Au NSs/GQDs-CS/Cysteamine (CysA) was utilized to improve conductivity and performance of the biosensor. The RAC aptamer was attached on the Au NSs of the composite membrane via AuS bond. The fabrication process of the EC aptamer based assay was characterized by some electrochemical techniques. The peak currents obtained by differential pulse voltammetry decreased linearly with the increasing of RAC concentrations and the apta-assay responds approximately over a wide dynamic range of RAC concentration from 0.0044 fM to 19.55 MUM. The low limit of quantification was 0.0044 fM. PMID- 30458192 TI - Studies on the effect of the J-domain on the substrate binding domain (SBD) of Hsp70 using a chimeric human J-SBD polypeptide. AB - DnaJ/Hsp40 chaperones deliver unfolded proteins and stimulate the ATPase activity of DnaK/Hsp70 via their J-domain. However, the interaction is transient, creating a challenge for detailed analysis. We investigated whether it would be possible to gain further understanding of this interaction by engineering a chimeric polypeptide where the J-domain of Hsp40 was covalently attached to the substrate binding domain (SBD) of Hsp70 by a flexible linker. The rationale is to increase the proximity between the interacting partners to promote their natural interaction and facilitate the characterization of the interaction. The resulting chimera, termed J-SBD, was properly folded and had properties not present in the full-length Hsp70 or in the SBD alone, for instance a higher protective effect against aggregation and being a monomer. Substrate binding also appear to exceed that of SBD alone as revealed by a decreased binding to bis-ANS, a probe for hydrophobic patches. This hypothesis is supported by the structural model created by small angle X-ray scattering, suggesting that the lid subdomain (SBDalpha) is partially opened in the J-SBD. Collectively, our results suggest a model in which J-domain binding may shift the Hsp70 equilibrium towards the monomer state, exposing hydrophobic sites prone to substrate accommodation. PMID- 30458194 TI - Lignin oxidation with an organic peroxide and subsequent aromatic ring opening. AB - The oxidation of an organosolv lignin with tert-butylhydroperoxide, initiated by titanium grafted into the lignin structure, was investigated. Titanation of reactive groups on lignin is responsible for the cross-linking of the lignin structure. IR and MAS 13C NMR spectroscopy spectra confirmed the oxidation of the lignin structure and other pronounced structural changes. A study with guaiacol as a model compound helped to recognise that aromatic ring opening occurs under the given conditions and is catalysed by the grafted titanium. The structure of the oxidised lignin becomes less robust and therefore potentially more susceptible to be depolymerised and converted into monomeric units. PMID- 30458195 TI - Loss of DUSP2 predicts a poor prognosis in patients with bladder cancer. AB - Dual-specificity phosphatase 2 (DUSP2), a member of nuclear type I DUSP family, abolishes the activation of mitogen-activated protein kinases (MAPKs) and plays critical roles in the immune processes, inflammatory responses and cancer progression. Currently, whether DUSP2 is involved in pathogenesis of bladder cancer remains unclear. In this study, we demonstrate that the expression level of DUSP2 was predominantly down-regulated in bladder cancer tissues and cell lines as compared with that of paired normal tissues and benign urothelial cells. Besides, the expression of DUSP2 was significantly associated with pathological grade (P=.009), AJCC stage (P=.017) and subtype (P=.001) in the Cancer Genome Atlas (TCGA) cohort and mainly related to TNM stage (P=.016) in the tissue microarray (TMA) cohort. Kaplan-Meier analysis suggested that patients with low DUSP2 expression had a shorter 5-years overall survival (P=.018 in TCGA; P=.012 in TMA) and lower recurrence-free survival (P=.008). Cox regression analysis indicated that reduced DUSP2 was an independent high risk factor for survival prognosis in both cohorts. Taken together, our findings for the first time suggested that DUSP2 as a progression and prognosis biomarker for bladder cancer. Whether DUSP2 functions as a tumor suppressor in bladder cancer deserves further studies. PMID- 30458196 TI - Cortactin expression in non-Hodgkin B-cell lymphomas: a new marker for the differential diagnosis between chronic lymphocytic leukemia and mantle cell lymphoma. AB - Cortactin is a cytoskeletal-remodeling adaptor protein, playing an oncogenic role in solid tumors. Little is known on Cortactin expression in non-Hodgkin B-cell lymphomas (B-NHL). The present study aimed to characterize Cortactin expression in B-NHL and to assess its role in the differential diagnosis of such entities. Cortactin protein expression was first assessed by immunohistochemistry in a series of 131 B-NHL, including B-cell chronic lymphocytic leukemia (CLL; n=17), mantle cell lymphoma (MCL; n=16), follicular lymphoma (FL; n=25), marginal zone lymphoma (MZL; n=30), hairy cell leukemia (HCL; n=10), splenic diffuse red pulp small B-cell lymphomas (SDRPBL; n=3) and diffuse large B-cell lymphoma (DLBCL; n=30) cases. Cortactin was expressed in 14/17 CLLs, 10/10 HCLs and 22/30 DLBCLs. MCLs, SDRPBLs, most FLs and MZLs were Cortactin-negative. The immunohistochemical results were in keeping with in silico gene expression data. In CLL, Cortactin positivity did correlate with LEF1 and CD200 expression and the combined positivity for >=2 markers strongly predicted CLL diagnosis. Such preliminary data suggested a role for Cortactin in the differential diagnosis between CLL and MCL. This hypothesis was confirmed in a large validation set of 112 CLLs (n=55) and MCLs (n=57), which also disclosed rare Cortactin-expressing MCLs. The immunohistochemical and gene expression results were sustained by flow cytometry and Western blot analysis on CLL and MCL cell lines. In conclusion, Cortactin is mainly expressed in subsets of CLL and DLBCL and in HCL. Cortactin may represent a novel marker for the differential diagnosis between CLL and MCL. PMID- 30458197 TI - Heterogeneous mutational profile and prognosis conferred by TP53 mutations in Appendiceal mucinous neoplasms. AB - The 8th edition of American Joint Committee on Cancer (AJCC) advocates a three tier grading system for appendiceal mucinous tumors. The mutational profile for each tumor grade and the impact of TP53 mutation on survival is unknown.We classified appendiceal mucinous tumors into 3 grades based on the 8th edition of AJCC: 21G1 low-grade mucinous neoplasms, 21G2 appendiceal adenocarcinomas, and 26G3 signet ring cell carcinomas (SRC). Mutation profiles were obtained using next generation sequencing (NGS). The impact of TP53 on prognosis was investigated by multivariable analysis. The vast majority of G1 tumors harbor KRAS/GNAS mutations with TP53 and SMAD4 in a small subset of cases. G2 and G3 tumors show a more complex mutation pattern carrying PIK3CA, BRAF, or TP53 mutations in addition to KRAS/GNAS. PTEN mutations were detected exclusively in G2 tumors. The prevalence of KRAS and GNAS mutations is significantly lower in G3 tumors relative to G1/G2, whereas TP53, PIK3CA or BRAF mutations are common. Mutations in NRAS, IDH2, CDH1, RB1, CTNNB1, CDKN2A, PTPN11, and KIT genes were observed in single cases. Patients with TP53-mutated disseminated G2 and G3 tumors had worse progression-free survival than those with TP53-wild type tumors (P=.0315). A trend toward worse overall survival was observed in TP53-mutated G3 tumors (P=.102). p53 expression correlated with mutation status. We demonstrate a distinct but overlapping pattern of gene mutations in each grade of appendiceal mucinous tumors and the independent impact of TP53 mutation on progression-free survival but not overall survival. PMID- 30458198 TI - Evaluation of miR-16 as an internal control in the patients with breast cancer. PMID- 30458199 TI - Frontal EEG theta/beta ratio during mind wandering episodes. AB - BACKGROUND: In resting-state EEG, the ratio between frontal power in the slow theta frequency band and the fast beta frequency band (the theta/beta ratio, TBR) has previously been negatively related to attentional control. Also, increased theta and reduced beta power were observed during mind wandering (MW) compared to episodes of focused attention. Thus, increased resting-state frontal TBR could be related to MW, suggesting that previously observed relationships between TBR and attentional control could reflect MW episodes increasing the average resting state TBR in people with low attentional control. GOALS: To replicate and extend the previous theta and beta MW effects for frontal TBR recordings and test if MW related changes in frontal TBR are related to attentional control. METHOD: Twenty six healthy participants performed a 40-minute breath-counting task, after a baseline EEG recording, while EEG was measured and participants indicated MW episodes with button presses. RESULTS: Frontal TBR was significantly higher during MW episodes than during on-task periods. However, no relation between frontal TBR and attentional control was found. CONCLUSIONS: This confirms that frontal TBR varies with MW, which is thought to reflect, among other things, a state of reduced top-down attentional control over thoughts. PMID- 30458200 TI - Estradiol modulates the palatability of 0.3 M NaCl in female rats during sodium appetite. AB - Excessive salt intake has been associated with the development or worsening of chronic diseases such as hypertension and spontaneously hypertensive rats (SHR) have a typical increased sodium preference. Estrogens reduce sodium appetite, but we do not know whether such effect relates to alterations in sodium palatability. Here we evaluated the influence of ovarian hormones on orofacial motor responses, an index of palatability, to intra-oral infusion of 0.3 M NaCl (IONaCl). Adult female SHR and normotensive Holtzman rats (HTZ) were used. Sodium appetite was produced by water deprivation followed immediately by partial rehydration by drinking water to satiation (WD-PR protocol). Immediately at the end of WD-PR, animals received an IO-NaCl for videotape recording of orofacial motor responses. At the end of IO-NaCl, they had access to two bottles containing 0.3 M NaCl and water to ingest (sodium appetite test). Bilateral ovariectomy (OVX) enhanced 0.3 M NaCl intake during the sodium appetite test and increased the frequency of orofacial hedonic responses to IO-NaCl in both strains. It had no effect on aversive responses. Estradiol treatment in SHR-OVX decreased hedonic responses and increased aversive responses to IO-NaCl. It also reduced 0.3 M NaCl intake during the sodium appetite test, but had no effect on baseline mean arterial pressure and heart rate. The results suggest that ovarian hormones restrain WD-PR induced sodium appetite by reducing the hedonic properties of sodium taste. The results also suggest that estrogens mediate such reduction, particularly in SHR. PMID- 30458201 TI - Endocannabinoid interactions in the regulation of acquisition of contextual conditioned fear. AB - Endocannabinoids (eCBs) anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were shown to be involved in the basis of trauma-induced behavioral changes, particularly contextual conditioned fear, however, their ligand-specific effects and possible interactions are poorly understood. Here we assessed specific eCB effects and interactions on acquisition of contextual conditioned fear employing electric footshocks in a rat model. We selectively increased eCB levels by pharmacological blockade of the degrading enzymes of AEA by URB597 and 2-AG by JZL184 before traumatization either systemically or locally in relevant brain areas, the prelimbic cortex (PrL), ventral hippocampus (vHC) and basolateral amygdala (BLA). Following traumatization, a series of contextual reminders were conducted during which conditioned fear was assessed. While systemic URB597 treatment during traumatization only slightly enhanced the acquisition of contextual conditioned fear, administration of the compound in the PrL and vHC led to the acquisition of stable, lasting conditioned fear, resistant to extinction. These effects of URB597 were blocked by simultaneous administration of JZL184. Similar treatment effects did not occur in the BLA. Treatment effects were not secondary to alterations in locomotor activity or nociception. Our findings suggest that AEA and 2-AG functionally interact in the regulation of acquisition of contextual conditioned fear. AEA signaling in the PrL and vHC is a crucial promoter of fear acquisition while 2-AG potentially modulates this effect. The lack of eCB effects in the BLA suggests functional specificity of eCBs at distinct brain sites. PMID- 30458202 TI - The lonely driver or the orchestra of mutations? How next generation sequencing datasets contradict the concept of single driver checkpoint mutations in solid tumours - NSCLC as a scholarly example. AB - Driver mutations are considered to be responsible for the majority of cancers and several of those mutations provide targets in order to set up personalized therapies. So far the generally accepted opinion had been that driver mutations occur as stand-alone factors, but novel sequencing technologies induced an essential rethink. Next generation sequencing approaches have shown that double, triple or multiple concurrent mutations could occur within the same tumour and may by interaction influence sensitivity to anticancer drugs and therapy success. This review focusses on this novel concept and discusses the challenges for molecular pathology and laboratory diagnostics while providing putative solutions to overcome the present pitfalls, thereby taking NSCLC as an example. PMID- 30458203 TI - Stimulating brain recovery after stroke using theranostic albumin nanocarriers loaded with nerve growth factor in combination therapy. AB - For many years, delivering drug molecules across the blood brain barrier has been a major challenge. The neuropeptide nerve growth factor is involved in the regulation of growth and differentiation of cholinergic neurons and holds great potential in the treatment of stroke. However, as with many other compounds, the biomolecule is not able to enter the central nervous system. In the present study, nerve growth factor and ultra-small particles of iron oxide were co encapsulated into a chemically crosslinked albumin nanocarrier matrix which was modified on the surface with apolipoprotein E. These biodegradable nanoparticles with a size of 212 +/- 1 nm exhibited monodisperse size distribution and low toxicity. They delivered NGF through an artificial blood brain barrier and were able to induce neurite outgrowth in PC12 cells in vitro. In an animal model of stroke, the infarct size was significantly reduced compared to the vehicle control. The combination therapy of NGF and the small-molecular MEK inhibitor U0126 showed a slight but not significant difference compared to U0126 alone. However, further in vivo evidence suggests that successful delivery of the neuropeptide is possible as well as the synergism between those two treatments. PMID- 30458204 TI - Second update of the International Registry of HLA Epitopes I. The HLA-ABC epitope database. AB - The International Registry of HLA Epitopes (http://www.epregistry.com.br) is a website-based resource for HLA epitopes important in transplant rejection and platelet transfusion refractoriness. Its primary goal is to document epitopes that are verified experimentally with specific antibodies. Such epitopes can be defined by single eplets and by eplets paired with certain polymorphic residues within a 15-Angstrom radius, the dimension of the corresponding structural epitope. This report is an update of the HLA-ABC repertoire including descriptions of 72 antibody-verifications of epitopes defined by eplets and/or eplet pairs. The newly updated version 2.0 EpRegistry shows also the polymorphic residue compositions of structural epitopes corresponding to eplets shared between groups of alleles. At present, 151 eplets have not been antibody verified, and we ranked them with a so-called ElliPro score as a potential predictor of immunogenicity. Sixty eplets with low ElliPro scores might be considered non-epitopes incapable of inducing specific antibodies. PMID- 30458205 TI - Vulvar Paget disease: a national retrospective cohort study. AB - BACKGROUND: Vulvar Paget disease (VPD) is a rare skin disorder, considered premalignant. OBJECTIVE: To assess the clinical course, treatment schedules and the effect of invasion and treatment on recurrence and survival in patients with VPD. METHODS: Data on women with VPD were retrieved from the medical files and pathology reports in all Dutch tertiary university medical centres. Disease free survival (DFS) and 5-year disease specific survival (DSS) were estimated using Kaplan-Meier curves. RESULTS: Data of 113 patients diagnosed between 1991 and 2016 were analysed. Seventy-seven percent had non-invasive VPD. Most women underwent surgery (65%). Recurrences were reported in 40%. Of women with non invasive VPD 8% developed invasion. There were no disease specific deaths reported in women with non-invasive VPD. The 5 year DSS was over 98% in non invasive and micro-invasive VPD, but significantly worse in invasive VPD: 50% (p<0.0005). LIMITATIONS: The main limitations of this study are its retrospective character and that original pathology samples were not available for reassessment. CONCLUSIONS: VPD is extremely rare and recurrence rates are high. Most patients have non-invasive VPD, which does not affect survival and should be considered a chronic disorder with a limited invasive potential. In case of invasive disease survival decreases significantly. PMID- 30458206 TI - Melanomas of the head and neck have high local recurrence risk features and require tissue rearranging reconstruction more commonly than BCC and SCC: A comparison of indications for microscopic margin control prior to reconstruction in 13,664 tumors. AB - BACKGROUND: Consensus guidelines recommend microscopic margin control based on high local recurrence risk features and tissue-rearranging reconstruction for keratinocyte carcinomas (KC) but not for cutaneous melanoma. OBJECTIVE: To compare high local recurrence risk features and frequency of tissue-rearranging reconstruction for head and neck KC versus melanoma. METHODS: Retrospective cohort study of KC versus melanoma treated at the Hospital of the University of Pennsylvania with Mohs micrographic surgery (MMS). RESULTS: 12,189 KCs (8,743 BCC, 3,343 SCC) and 1,475 melanomas (1065 melanomas in situ, 410 invasive melanomas) were identified from a prospectively updated MMS database. Compared to KCs, melanomas were significantly more likely to have high local recurrence risk features, including larger preoperative size [2.10 cm vs 1.30 cm, (p <0.0001)], recurrent status [5.08% vs 3.91%, (p = 0.031)], and subclinical spread [31.73% vs 26.52%, (p <0.0001)]. Tissue rearranging reconstruction was significantly more common for melanoma versus KCs [44.68% vs 33.02%, (p < 0.0001); OR 1.98 (p<0.0001)]. LIMITATIONS: This was a retrospective study and did not compare outcomes to other treatment methods, such as "slow-Mohs" or conventional excision. CONCLUSION: Melanomas of the head and neck have high local recurrence risk features and require tissue rearranging reconstruction more frequently than KCs. PMID- 30458207 TI - Association of antinuclear antibody status with clinical features and malignancy risk in adult-onset dermatomyositis. AB - BACKGROUND: The clinical significance of antinuclear antibody (ANA) status in adults with dermatomyositis (DM) has yet to be fully defined. OBJECTIVE: We compared the incidence of amyopathic disease, risk of malignancy, and clinical findings in ANA-positive and ANA-negative patients with adult-onset DM. METHODS: This was a retrospective cohort study of patients with ANA-positive or ANA negative adult-onset DM determined by enzyme-linked immunosorbent assay. RESULTS: Of 231 patients, 140 (61%) were ANA-positive and 91 (39%) were ANA-negative. Compared to ANA-negative patients, ANA-positive patients had a lower frequency of dysphagia (15% vs 26%, P=0.033) and heliotrope rash (38% vs 53%, P=0.026). Fifty four patients (23%) developed malignancy within 3 years of DM diagnosis. Eleven percent of ANA-positive patients developed malignancy versus 43% of ANA-negative patients (P<0.001). There was a strong association between ANA positivity and lower likelihood of malignancy in multivariable analysis (OR: 0.16, P<0.001). Conversely, ANA positivity was not associated with amyopathic disease (OR: 0.94, P=0.87). LIMITATIONS: The retrospective nature of the study was a limitation. CONCLUSION: In patients with adult-onset DM, negative ANA is associated with increased likelihood of developing malignancy within three years of DM diagnosis. Particularly close follow-up and frequent malignancy screening may be warranted in ANA-negative individuals with DM. PMID- 30458209 TI - Overall and Subgroup Prevalence of Acne Vulgaris Among Patients with Hidradenitis Suppurativa. PMID- 30458208 TI - Comparative effectiveness of treatment of actinic keratosis with topical fluorouracil and imiquimod in the prevention of keratinocyte carcinoma: a cohort study. AB - BACKGROUND: The effectiveness of 5-fluorouracil compared to imiquimod for preventing keratinocyte carcinoma is unknown. OBJECTIVE: To compare the effectiveness of 5-fluorouracil and imiquimod in preventing keratinocyte carcinoma in a real-world practice setting. METHODS: We identified 5,700 subjects who filled prescriptions for 5-fluorouracil or imiquimod for actinic keratosis treatment in 2007. An intention-to-treat analysis controlling for potential confounding variables was used to calculate 2- and 5-year cumulative risk differences for subsequent keratinocyte carcinoma overall and in field-treated areas. RESULTS: 5-fluorouracil was associated with a statistically significant decreased risk of any keratinocyte carcinoma compared to imiquimod (adjusted hazard ratio [aHR] 0.86, 95% CI 0.76-0.97), but there were no significant differences in risk by tumor subtype (squamous cell carcinoma aHR 0.89, 95% CI 0.74-1.07; basal cell carcinoma aHR 0.87, 95% CI 0.74-1.03), or site-specific keratinocyte carcinoma (aHR 0.96, 95% CI 0.81-1.14). There were no significant differences in 2- or 5-year cumulative risk for keratinocyte carcinoma among those treated with 5-fluorouracil versus imiquimod. LIMITATIONS: Generalizability to other practice settings may be limited. CONCLUSIONS: Whereas 5-fluorouracil was more effective in reducing keratinocyte carcinoma risk overall, we found no differences in the short- or long-term risk of subsequent site-specific keratinocyte carcinoma in a real-world practice setting. PMID- 30458210 TI - Acne Vulgaris in Patients with Hidradenitis Suppurativa. PMID- 30458211 TI - Use of a cotton tip applicator for epidermal closures in dermatologic surgery, a video walkthrough. PMID- 30458213 TI - The immobilization of Candida rugosa lipase on the modified polyethersulfone with MOF nanoparticles as an excellent performance bioreactor membrane. AB - In this study, the modified nanocomposite membrane of polyethersulfone (PES) with NH2-MIL-101(Cr) as a metal-organic framework (MOF) is exploited for Candida rugosa lipase (CRL) immobilization. To that end, the various amounts of NH2-MIL 101(Cr) nanoparticles are blended into PES casting solution to fabricate ultrafiltration membrane via phase inversion technique. The incorporation efficiency of NH2-MIL-101(Cr) nanoparticles on the membrane morphology is investigated using various techniques, namely atomic force microscopy (AFM), X ray diffraction (XRD), and contact angle goniometry. In terms of water pure flux and CRL immobilization efficiency, the best performance is observed for PES-NH2 MIL1% membrane. This bioactive membrane (CRL@GA@PES-NH2-MIL1%) displays an improvement in pH and thermal stability and separation performance that makes it a fruitful candidate for using in bioreactors. The examination of the wet- and dry-storage stability of CRL@GA@PES-NH2-MIL1% demonstrates the high stability for the wet bioactive membrane. The reusability inspection of CRL@GA@PES-NH2-MIL1% represents about 50% conservation of the residual activity after 12 sequential usage cycles. PMID- 30458212 TI - Nipple and areola lesions: dermoscopy and reflectance confocal microscopy features. PMID- 30458214 TI - Transglutaminase-mediated cross-linking of WDR54 regulates EGF receptor signaling. AB - WDR54 is a member of the WD40 repeat (WDR) domain-containing protein family that was recently identified as a novel oncogene in colorectal cancer. However, the molecular mechanism of WDR54 and its functional association with other molecules related to tumor cell growth are unknown. Here, we show that WDR54 can be cross linked by the action of transglutaminase (TG) 2, which enhances the activation of EGF receptor-mediated signaling pathway. The most carboxyl-terminal WD domain was required for cross-linking. In addition, lysine 280 in WDR54, also in this WD domain, was an important residue for both cross-linking and ubiquitination. Cross linked WDR54 was found in vesicles aggregated at the plasma membrane. The activated EGF receptor was co-localized with this vesicle, and the internalization of the EGF receptor into the cytosol was sustained. As a result, Erk activity in response to EGF stimulation was enhanced. Furthermore, the growth of the cells lacking WDR54 expression generated by genome editing was delayed compared with that in wild-type cells. Because TG2 is also has been proposed to activate the EGF receptor-signaling and proliferation of tumor cells, WDR54 might have a functional relationship with the EGF receptor and TG2. Our study on the mechanism of biological function of WDR54 may provide rationale for the design and development of a cancer drug based on inhibiting the post-translational modification of this oncogene product. PMID- 30458215 TI - Central inspiratory activity rhythmically activates synaptic currents of airway vagal preganglionic neurons in neonatal rats. AB - The airway vagal preganglionic neurons (AVPNs) in the external formation of the nucleus ambiguus (eNA) can be separated into inspiratory-activated AVPNs (IA AVPNs) and inspiratory-inhibited AVPNs (II-AVPNs). IA-AVPNs are activated by excitatory presynaptic inputs during inspiratory bursts, but the composition and the roles of these excitatory inputs still remain obscure. II-AVPNs are inhibited by inhibitory presynaptic inputs but whether these inhibitory inputs are regulated by excitatory inputs is also unclear. In the current study, AVPNs were retrogradely fluorescent labeled. The IA-AVPNs were discriminated from II-AVPNs by their different synaptic inputs during inspiratory bursts. The excitatory inputs to IA-AVPNs and the presynaptic regulation of II-AVPNs were examined by whole-cell patch clamping. Topical application of 6-Cyano-7-nitroquinoxaline-2,3 dione (CNQX) to the recorded IA-AVPNs almost abolished the tonic EPSCs during inspiratory intervals, inhibited the phasic excitatory currents during inspiratory bursts and attenuated the phasic inspiratory inward currents (PIICs) driven by central inspiratory activity. Blockade of alpha4beta2 and alpha7 nicotinic acetylcholine receptors (nAChRs) respectively inhibited PIICs in some IA-AVPNs. Carbenoxolone, a gap junction uncoupler, partly inhibited the PIICs of IA-AVPNs. Focal application of CNQX to the II-AVPNs significantly inhibited the frequency, peak amplitude and area of the phasic inspiratory outward currents (PIOCs). These findings demonstrated that glutamatergic non-NMDA receptors played a predominant role in the excitatory drive to the IA-AVPNs, and that alpha4beta2, alpha7 nAChRs and gap junctions were also rhythmically activated by central inspiratory activity. Additionally, glycinergic neurons making inhibitory inputs to the II-AVPNs were pre-synaptically facilitated by excitatory glutamatergic synaptic inputs. PMID- 30458216 TI - Prenatal therapeutics and programming of cardiovascular function. AB - Cardiovascular diseases (CVD) are a leading cause of mortality worldwide. Despite recognizing the importance of risk factors in dictating CVD susceptibility and onset, patient treatment remains a challenging endeavor. Increasingly, the benefits of prevention and mitigation of risk factors earlier in life are being acknowledged. The developmental origins of health and disease posits that insults during specific periods of development can influence long-term health outcomes; this occurs because the developing organism is highly plastic, and hence vulnerable to environmental perturbations. By extension, targeted therapeutics instituted during critical periods of development may confer long-term protection, and thus reduce the risk of CVD in later life. This review provides a brief overview of models of developmental programming, and then discusses the impact of perinatal therapeutic interventions on long-term cardiovascular function in the offspring. The discussion focuses on bioactive food components, as well as pharmacological agents currently approved for use in pregnancy; in short, those agents most likely to be used in pregnancy and early childhood. PMID- 30458217 TI - Intermittent Low-level Noise Causes Negative Neural Gain in the Inferior Colliculus. AB - The central auditory system shows a remarkable ability to rescale its neural representation of loudness following long-term, low-level acoustic exposures; even when the noise is presented intermittently. Circadian rhythms exert potent biological effects, but it remains unclear if acoustic exposures occurring during the light or dark cycle affect the neurophysiological changes involved in loudness rescaling. To address this issue we exposed rats to intermittent (12 h/day), low-level noise (10-20 kHz, 75 dB SPL) for 5 weeks; exposures occurred during either the light (inactive) or dark (active) phase of the circadian cycle. The 12-h exposures, whether occurring during the light or dark phase, did not significantly alter cochlear function as reflected in distortion product otoacoustic emissions and compound action potential responses. However, neural activity in the inferior colliculus demonstrated negative gain in a frequency- and intensity-specific manner compared to unexposed controls; the magnitude and direction of the neuroplastic changes in the inferior colliculus were largely the same regardless of whether the 12-h noise exposures occurred during the light or dark phase of the circadian cycle. These neuroplastic changes could become relevant for low-level sound therapies used to treat hyperacusis. PMID- 30458218 TI - Postsynaptic SNARE Proteins: Role in Synaptic Transmission and Plasticity. AB - Soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) proteins mediate membrane fusion events in eukaryotic cells. Traditionally recognized as major players in regulating presynaptic neurotransmitter release, accumulative evidence over recent years has identified several SNARE proteins implicated in important postsynaptic processes such as neurotransmitter receptor trafficking and synaptic plasticity. Here we analyze the emerging data revealing this novel functional dimension for SNAREs with a focus on the molecular specialization of vesicular recycling and fusion in dendrites compared to those at axon terminals and its impact in synaptic transmission and plasticity. PMID- 30458219 TI - Light-Induced Opening of the TRP Channel in Isolated Membrane Patches Excised from Photosensitive Microvilli from Drosophila Photoreceptors. AB - Drosophila phototransduction occurs in light-sensitive microvilli arranged in a longitudinal structure of the photoreceptor, termed the rhabdomere. Rhodopsin (Rh), isomerized by light, couples to G-protein, which activates phospholipase C (PLC), which in turn cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) generating diacylglycerol (DAG), inositol trisphosphate and H+. This pathway opens the light-dependent channels, transient receptor potential (TRP) and transient receptor potential like (TRPL). PLC and TRP are held together in a protein assembly by the scaffold protein INAD. We report that the channels can be photoactivated in on-cell rhabdomeric patches and in excised patches by DAG. In excised patches, addition of PLC-activator, m-3M3FBS, or G-protein-activator, GTP gamma-S, opened TRP. These reagents were ineffective in PLC-mutant norpA and in the presence of PLC inhibitor U17322. However, DAG activated TRP even when PLC was pharmacologically or mutationally suppressed. These observations indicate that PLC, G-protein, and TRP were retained functional in these patches. DAG also activated TRP in the protein kinase C (PKC) mutant, inaC, excluding the possibility that PKC could mediate DAG-dependent TRP activation. Labeling diacylglycerol kinase (DGK) by fusion of fluorescent mCherry (mCherry-DGK) indicates that DGK, which returns DAG to dark levels, is highly expressed in the microvilli. In excised patches, TRP channels could be light-activated in the presence of GTP, which is required for G-protein activation. The evidence indicates that the proteins necessary for phototransduction are retained functionally after excision and that DAG is necessary and sufficient for TRP opening. This work opens up unique possibilities for studying, in sub-microscopic native membrane patches, the ubiquitous phosphoinositide signaling pathway and its regulatory mechanisms in unprecedented detail. PMID- 30458220 TI - Auditory Midbrain Hypoplasia and Dysmorphology after Prenatal Valproic Acid Exposure. AB - Prenatal exposure to the antiepileptic valproic acid (VPA) is associated with an increased risk of autism spectrum disorder (ASD) in humans and is used as an animal model of ASD. The majority of individuals with ASD exhibit adverse reactions to sensory stimuli and auditory dysfunction. Previous studies of animals exposed to VPA reveal abnormal neuronal responses to sound and mapping of sound frequency in the cerebral cortex and hyperactivation, hypoplasia and abnormal neuronal morphology in the cochlear nuclei (CN) and superior olivary complex (SOC). Herein, we examine the neuronal populations in the lateral lemniscus and inferior colliculus in animals exposed in utero to VPA. We used a combination of morphometric techniques, histochemistry and immunofluorescence to examine the nuclei of the lateral lemniscus (NLL) and the central nucleus of the inferior colliculus (CNIC). We found that the VPA exposure resulted in larger neurons in the CNIC and the dorsal nucleus of the lateral lemniscus (DNLL). However, we found that there were significantly fewer neurons throughout all nuclei examined in the auditory brainstem of VPA-exposed animals. Additionally, we found significantly fewer calbindin-immunopositive neurons in the DNLL. VPA exposure had no impact on the proportions of perineuronal nets in the NLL or CNIC. Finally, consistent with our observations in the CN and SOC, VPA exposure resulted in fewer dopaminergic terminals in the CNIC. Together, these results indicate that in utero VPA exposure significantly impacts structure and function of nearly the entire central auditory pathway. PMID- 30458221 TI - Mecp2 Disruption in Rats Causes Reshaping in Firing Activity and Patterns of Brainstem Respiratory Neurons. AB - People with Rett Syndrome (RTT), a neurodevelopmental disorder caused by mutations in the MECP2 gene, have breathing abnormalities manifested as periodical hypoventilation with compensatory hyperventilation, which are attributable to a high incidence of sudden death. Similar breathing abnormalities have been found in animal models with Mecp2 disruptions. Although RTT-type hypoventilation is believed to be due to depressed central inspiratory activity, whether this is true remains unknown. Here we show evidence for reshaping in firing activity and patterns of medullary respiratory neurons in RTT-type hypoventilation. Experiments were performed in decerebrate rats in vivo. In Mecp2 null rats, abnormalities in breathing patterns were apparent in both decerebrate rats and awake animals, suggesting that RTT-type breathing abnormalities take place in the brainstem without forebrain input. In comparison to their wild-type counterparts, both inspiratory and expiratory neurons in Mecp2-null rats extended their firing duration, and fired more action potentials during each burst. No changes in inspiratory or expiratory neuronal distributions were found. Most inspiratory neurons started firing in the middle of expiration and changed their firing pattern to a phase-spanning type. The proportion of post-inspiratory neurons was reduced in the Mecp2-null rats. With the increased firing activity of both inspiratory and expiratory neurons in null rats, phrenic discharges shifted to a slow and deep breathing pattern. Thus, the RTT-type hypoventilation appears to result from reshaping of firing activity of both inspiratory and expiratory neurons without evident depression in central inspiratory activity. PMID- 30458222 TI - Brain Sub/Region-Specific Effects of Olanzapine on c-Fos Expression of Chronically Socially Isolated Rats. AB - Olanzapine (Olz) is an atypical antipsychotic used to treat depression, anxiety and schizophrenia, which can be caused by chronic psychosocial stress. c-Fos protein expression has been used as an indirect marker of neuronal activity in response to various forms of stress or pharmacological treatments. We examined the effects of a 3-week treatment of Olz (7.5 mg/kg/day) on c-Fos protein expression in stress-relevant brain sub/regions, its relationship with isolation induced behavioral changes, and potential sites of Olz action on control and male rats exposed to 6 weeks of chronic social isolation (CSIS), an animal model of depression. Olz treatment reversed depression- and anxiety-like behaviors induced by CSIS and suppressed a CSIS-induced increase in the number of c-Fos-positive cells in subregions of the dorsal hippocampus, ventral (v) DG, retrosplenial cortex, and medial prefrontal cortex. In contrast, no change in c-Fos expression was seen in the CA3v, amygdala and thalamic, hypothalamic or striatal subregions in Olz-treated CSIS rats, suggesting different brain sub/regions' susceptibility to Olz. An increased number of c-Fos-positive cells in the CA1v, amygdala and thalamic, hypothalamic and striatal subregions in controls as well as in the CA1v and subregion of the hypothalamus and nucleus accumbens in Olz-treated CSIS rats was found. Results suggest the activation of brain sub/regions following CSIS that may be involved in depressive and anxiety-like behaviors. Olz treatment showed region-specific effects on neuronal activation. Our data contribute to a better understanding of the mechanisms underlying the CSIS response and potential brain targets of Olz in socially isolated rats. PMID- 30458223 TI - Diversity and Specificity of Astrocyte-neuron Communication. AB - Astrocytes are emerging as important players in synaptic function, and, consequently, on brain function and animal behavior. According to the Tripartite Synapse concept, astrocytes are integral elements involved in synaptic function. They establish bidirectional communication with neurons, whereby they respond to synaptically released neurotransmitters and, in turn, release gliotransmitters that influence neuronal and synaptic activity. Accumulating evidence is revealing that the mechanisms and functional consequences of astrocyte-neuron signaling are more complex than originally thought. Furthermore, astrocyte-neuron signaling is not based on broad, unspecific interaction; rather, it is a synapse-, cell- and circuit-specific phenomenon that presents a high degree of complexity. This diversity and complexity of astrocyte-synapse interactions greatly enhance the degrees of freedom of the neural circuits and the consequent computational power of the neural systems. PMID- 30458224 TI - Glycated proteins in nutrition: Friend or foe? AB - Advanced glycation end products (AGEs) are formed in in vivo, and accumulate in tissues and body fluids during ageing. Endogenous AGE-modified proteins show altered structure and function, and may interact with receptor for AGEs (RAGE) resulting in production of reactive oxygen species, inflammatory, atherogenic and diabetogenic responses. AGEs are also formed in thermally processed foods. Studies in rodents document that dietary AGEs are partially absorbed into circulation, and accumulate in different tissues. Knowledge on the health effects of high dietary intake of AGEs is incomplete and contradictory. In this overview we discuss the data from experimental and clinical studies, either those supporting the assumption that restriction of dietary AGEs associated with health benefits, or data suggesting that dietary intake of AGEs associates with positive health outcomes. We polemicize whether the effects of exaggerated intake or restriction of highly thermally processed foods might be straightforward interpreted as the effects of AGEs-rich vs. AGEs-restricted diets. We also underline the lack of studies, and thus a poor knowledge, on the effects of different single chemically defined AGEs administration, concurrent intake of different dietary AGEs, of load with dietary AGEs corresponding to the habitual diet in humans, and on those of dietary AGEs in vulnerable populations, such as infants and particularly elderly. PMID- 30458225 TI - Flavonoid biosynthetic pathways in plants: Versatile targets for metabolic engineering. AB - Plants, fungi, and microorganisms are equipped with biosynthesis machinery for producing thousands of secondary metabolites. These compounds have important functions in nature as a defence against predators or competitors as well as other ecological significances. The full utilization of these compounds for food, medicine, and other purposes requires a thorough understanding of their structures and the distinct biochemical pathways of their production in cellular systems. In this review, flavonoids as classical examples of secondary metabolites are employed to highlight recent advances in understanding how valuable compounds can be regulated at various levels. With extensive diversity in their chemistry and pharmacology, understanding the metabolic engineering of flavonoids now allows us to fine-tune the eliciting of their production, accumulation, and extraction from living systems. More specifically, recent advances in the shikimic acid and acetate biosynthetic pathways of flavonoids production from metabolic engineering point of view, from genes expression to multiple principles of regulation, are addressed. Specific examples of plants and microorganisms as the sources of flavonoids-based compounds with particular emphasis on therapeutic applications are also discussed. PMID- 30458226 TI - Assessing the use of wing ornamentation and visual display in female choice sexual selection. AB - Conspicuous sexual dimorphism is often ascribed to sexual selection. When the differences between the sexes are ornamental, this is thought to indicate a role for female choice. In spotted winged Drosophila species courtship, a male positioned in front of a female waves his wings, which have a patch of melanization on the exterior margin. In this study, we examine both female preference for wing spots and the role of vision in mating success in three species of the suzukii group: Drosophila biarmipes, D. suzukii, and D. subpulchrella. To assess female preference for wing spot, we removed the spot with a novel, non-invasive method, and competed spotless males with males with two spots. Phenotype did not affect mating success in any species. To eliminate the potential effect of competitive behavior on male mating success, we also ran a no-choice analysis. Mating frequency and timing was not different between phenotypes within these species. The effect of vision on mating success was assessed by comparing mating success of spotted males between light and dark conditions, both for frequency of mating, as well as timing of multiple courtship parameters. Species varied in the extent that lack of vision negatively affected mating success. Though vision is important for mating success, the spot itself may not be providing the signal that females use to make mating decisions. PMID- 30458227 TI - Time Course of Memory Formation for an Appetitive, One-Trial, Water-Reward Task in Day-Old Chicks. AB - Researchers studying learning and memory in the day-old chick have developed a one-trial taste avoidance learning task, in which a chick pecks a bead coated with an aversive-tasting liquid such as methylanthranilate. The current study examined, in two experiments, whether chicks could demonstrate learning of an appetitive version of the one-trial task, and how long this memory might last. The results demonstrate that chicks show significantly decreased latencies to peck a test bead similar to that pecked at training coated with water, and that this memory lasted for at least 6 hours after training. These results demonstrate that this appetitive task produces significant learning. PMID- 30458228 TI - Hepatotoxicity effect of short-term Bradykinin potentiating factor in cholestatic rats. AB - BACKGROUND: Drug-induced hepatotoxicity is an extremely widespread condition and is responsible for a variety of pathological effects on the liver. It was reported that hepatotoxicity induced by angiotensin converting enzyme inhibitors (ACEIs) is cholestasis mediated hepatitis. Bradykinin-potentiating factor (BPF) is one of the natural ACEIs. Although prolonged treatment with ACEIs provides protection against liver injury, the effect of short-term treatment with ACEIs has not been fully elucidated before. Thereby, the present study sought to determine if transient ACE inhibition may exacerbate the hepatotoxicity caused by bile duct ligation (BDL) in rats. METHODS: Twenty one Wistar rats were divided into 3 groups: Sham-operated group, bile duct ligated (BDL) rats, and BDL rats treated for short-term with BPF (1 MUg/kg body weight) day after day for one week and biochemical parameters were measured. Also, we assessed expression level of ACE1 and detection of hepatotoxicity in the liver tissues of different groups. RESULTS: There was a significant increase in liver enzymes, bilirubin levels, and oxidative stress in the BDL group after treatment with BPF as compared to BDL group. We found overexpression of ACE1 gene in BDL group compared to BPF and Sham operated control group. Histopathological examination of liver treated with BPF showed severe degeneration hepatic architecture and hepatocytes as compared to BDL group. Collagen deposition increased after BPF treatment as compared to BDL groups. CONCLUSION: The present investigation suggests and recommends that short- term ACE inhibition pathway potentiates liver fibrosis during cholestasis disease. PMID- 30458229 TI - Atropine counteracts the depressive-like behaviour elicited by acute exposure to commercial chlorpyrifos in rats. AB - Acute organophosphate (OP) poisoning induces well-known signs of toxicosis related to acetylcholinesterase (AChE) inhibition. However, the relationship between acute OP poisoning and the onset of psychiatric disorders remains unclear. Thus, we investigated behavioural and biochemical consequences of acute exposure to the OP chlorpyrifos in male rats and also the effectiveness of the antidotes atropine and pralidoxime on reversing these changes. A sub-lethal dose of commercial chlorpyrifos (20 mg/kg, i.p.) elicited signs of acute toxicosis during the first hours after its injection in rats. Twenty-four hours after treatment, this single dose of chlorpyrifos induced a depressive-like behaviour in the rat forced swimming test without impairing locomotor activity. At this time (24 h), chlorpyrifos decreased plasma butyrylcholinesterase (BChE) activity and hippocampal, striatal and prefrontal cortical AChE activity in rats. The behavioural and biochemical consequences of acute chlorpyrifos poisoning do not seem to be long lasting, since 30 days later they were absent. We evaluated whether these behavioural and biochemical consequences of acute chlorpyrifos treatment would be reversed by the antidotes atropine (10 mg/kg i.p.) and/or pralidoxime (40 mg/kg; i.p.) given 1 h after poisoning. Pralidoxime partially reactivated the AChE activity in the prefrontal cortex, but not in the hippocampus and striatum. Atropine attenuated the depressive-like behaviour induced by chlorpyrifos in rats. Our results suggest that acute chlorpyrifos poisoning induces a transient depressive-like behaviour possible related to hippocampal AChE inhibition. They suggest that treatment with atropine and pralidoxime seems to be insufficient to counteract all the effects of OP acute poisoning, at least in rats. PMID- 30458230 TI - Upregulated BMP-Smad signaling activity in the glucuronyl C5-epimerase knock out MEF cells. AB - Glucuronyl C5-epimerase (Hsepi) catalyzes the conversion of glucuronic acid to iduronic acid in the process of heparan sulfate biosynthesis. Targeted interruption of the gene, Glce, in mice resulted in neonatal lethality with varied defects in organ development. To understand the molecular mechanisms of the phenotypes, we used mouse embryonic fibroblasts (MEF) as a model to examine selected signaling pathways. Our earlier studies found reduced activities of FGF 2, GDNF, but increased activity of sonic hedgehog in the mutant cells. In this study, we focused on the bone morphogenetic protein (BMP) signaling pathway. Western blotting detected substantially elevated endogenous Smad1/5/8 phosphorylation in the Hsepi mutant (KO) MEF cells, which is reverted by re expression of the enzyme in the KO cells. The mutant cells displayed an enhanced proliferation and elevated alkaline phosphatase activity, marking higher differentiation, when cultured in osteogenic medium. The high level of Smad1/5/8 phosphorylation was also found in primary calvarial cells isolated from the KO mice. Analysis of the genes involved in the BMP signaling pathway revealed upregulation of a number of BMP ligands, but reduced expression of several Smads and BMP antagonist (Grem1) in the KO MEF cells. The results suggest that Hsepi expression modulates BMP signaling activity, which, at least partially, is associated with defected molecular structure of heparan sulfate expressed in the cells. PMID- 30458231 TI - Reduction of matrix metalloproteinase 9 (MMP-9) protects motor neurons from TDP 43-triggered death in rNLS8 mice. AB - Therapeutic strategies are needed for the treatment of amyotrophic lateral sclerosis (ALS). One potential target is matrix metalloproteinase-9 (MMP-9), which is expressed only by fast motor neurons (MNs) that are selectively vulnerable to various ALS-relevant triggers. Previous studies have shown that reduction of MMP-9 function delayed motor dysfunction in a mouse model of familial ALS. However, given that the majority of ALS cases are sporadic, we propose preclinical testing in a mouse model which may be more clinically translatable: rNLS8 mice. In rNLS8 mice, neurodegeneration is triggered by the major pathological hallmark of ALS, TDP-43 mislocalization and aggregation. MMP-9 was targeted in 3 different ways in rNLS8 mice: by AAV9-mediated knockdown, using antisense oligonucleotide (ASO) technology, and by genetic modification. All 3 strategies preserved the motor unit during disease, as measured by MN counts, tibialis anterior (TA) muscle innervation, and physiological recordings from muscle. However, the strategies that reduced MMP-9 beyond the motor unit lead to premature deaths in a subset of rNLS8 mice. Therefore, selective targeting of MMP 9 in MNs could be beneficial in ALS, but side effects outside of the motor circuit may limit the most commonly used clinical targeting strategies. PMID- 30458232 TI - Administration of dendritic cells and anti-PD-1 antibody converts X-ray irradiated tumors into effective in situ vaccines. AB - PURPOSE: Danger signals and release of tumor-specific antigens after exposure to ionizing radiation can convert an irradiated tumor into an in situ vaccine. However, radiation alone is not sufficient to induce an effective systemic immune response. In this study, we investigated whether a combination of X-ray irradiation with bone marrow-derived dendritic cell (BM-DC) and anti-PD-1 antibody (alphaPD1-ab) administration can enhance both local tumor control and the systemic abscopal effect in murine subcutaneous tumor models. METHODS AND MATERIALS: B16/BL6 melanoma and Lewis lung carcinoma (LLC) cells were examined of radiosensitivity and expression of H-2kb and PD-L1 before and after irradiation. The tumor cells were implanted subcutaneously in the left thigh of C57BL/6 mice as primary tumors. BM-DCs were induced from mouse bone marrow cells using GM-CSF and IL-4. The primary tumors were treated with 8 Gy of X-ray, followed by simultaneous intratumoral injection of BM-DCs and intraperitoneal injection of alphaPD1-ab. To examine the abscopal effect, the same tumor cells were also inoculated in the right thighs as metastatic tumors 4 days after the primary tumor inoculation, and only the primary tumors were treated with the same protocols. In vivo analyses of tumor growth and survival rates as well as in vitro analyses of splenic T-cell proliferation and interferon-gamma (INF-gamma) release were performed. RESULTS: The triple combination treatment of X-ray irradiation with BM-DC and alphaPD1-ab administration inhibited primary tumor growth and significantly extended the survival time in association with significant increase of T-cell proliferation and INF-gamma release. In addition, this triple combination treatment significantly inhibited the growth of metastatic tumors. CONCLUSIONS: The results indicated that BM-DC and alphaPD1-ab administration led to the conversion of irradiated tumors into effective in situ vaccines. This combination therapy can be a promising approach to develop a novel individualized therapy for patients with solid cancers. PMID- 30458233 TI - Image-guided brachytherapy for cancer of the nasal vestibule: achieving high local-regional control while preserving cosmesis. AB - OBJECTIVE: To evaluate the efficacy of modern image-guided brachytherapy for squamous cell carcinoma of the nasal vestibule and to explore tumor volume as prognostic factor for local and regional recurrence. Furthermore, to assess patient satisfaction with nasal function and appearance post-treatment. METHODS: In a retrospective analysis, we reviewed the medical records of 102 patients with Wang T1-T2 nasal vestibule cancer treated with brachytherapy as the sole treatment at a single institution. Median follow-up time was 42 months (range 3 210 months). A patient satisfaction study using the validated Nasal Appearance and Function Evaluation Questionnaire was conducted among 42 patients >1 year after treatment. A statistically significant cutoff point for tumor volume as prognostic factor of local control was established using Youden's index method. RESULTS: 77 out of 102 patients were treated with interstitial implants and 25 by an intracavitary mould technique. The 5-year control rates were 95%, 91% and 83% for local, regional and local-regional control, respectively. Tumor volume >=2.3 cm3 resulted in worse 3-year regional control compared to volume <2.3cm3 (62% vs 96%; p = .01). Ultimate regional control after salvage treatment was 96%, with no significant difference between subgroups by tumor volume (92% for >=2.3 cm3 vs 96% for <2.3 cm3; p = .57). Three patients with regional failure developed distant metastases. 5-year disease-specific survival and overall survival were 94% and 74% respectively. Patient assessed cosmetic and functional satisfaction were both rated high (mean 3.7 and 4.0 out of 5, respectively). CONCLUSION: We report the largest cohort to date treated with brachytherapy as the sole treatment for nasal vestibule carcinoma. Brachytherapy offers excellent local control for Wang T1-T2 tumors with high patient satisfaction. Tumor volume is an adequate predictive factor for patients at risk of regional recurrence, but ultimate control rates after salvage treatment are high. Therefore, we do not recommend elective treatment of the neck. PMID- 30458234 TI - Moderate hypofractionation in intermediate and high risk, localized prostate cancer: Health-related quality of life from the randomized, phase 3 HYPRO trial. AB - PURPOSE: The phase 3 HYPRO trial compared hypofractionated radiotherapy with conventionally fractionated radiotherapy in patients with localized prostate cancer. Similar 5-year relapse-free survival rates were achieved, whereas non inferiority of hypofractionation was not confirmed for genitourinary and gastrointestinal toxicity. Here, we present the secondary trial endpoint on patient-reported quality of life. METHODS AND MATERIALS: A total of 820 patients with intermediate or high-risk prostate cancer were randomized to hypofractionation (19 fractions of 3.4 Gy) or conventional fractionation (39 fractions of 2.0 Gy). Quality of life was measured using the validated EORTC-QLQ PR25 questionnaire. Subscales (score range 0-100) on urinary symptoms, gastrointestinal symptoms, androgen deprivation therapy-related symptoms, sexual function, and sexual activity were analyzed. Changes from baseline of at least 5 points were considered clinically relevant. Inferiority of hypofractionation for separate subscales was rejected if the mean difference in 3-year incidence of clinically relevant deterioration between treatments was <8.0%. RESULTS: A total of 697 men were eligible for this quality of life analysis. Baseline characteristics were comparable between both groups. At 3-year follow-up, the incidence of clinically relevant deterioration of urinary symptoms was 33% for both treatments (difference 0.49% in favor of conventional fractionation, 90% CI: -7.20%- 8.18%), whereas such deterioration of gastrointestinal symptoms was reported in 38% for hypofractionation versus 36% for conventional fractionation (2.03% in favor of conventional fractionation, 90% CI: -6.18%- 10.23%). Therefore, we could not demonstrate non-inferiority of hypofractionation for genitourinary and gastrointestinal quality-of-life. For all other subscales, non inferiority of hypofractionation was demonstrated. CONCLUSIONS: Non-inferiority of the hypofractionated treatment was not demonstrated for genitourinary and gastrointestinal quality of life, and therefore we cannot rule out that relevant differences may exist between both treatments. Non-inferiority of hypofractionation was demonstrated for androgen-deprivation therapy-related symptoms, sexual activity and sexual function. PMID- 30458236 TI - The last common ancestor of Ecdysozoa had an adult terminal mouth. AB - The Ecdysozoa is a major animal clade whose main uniting feature is a distinctive growth strategy that requires the periodical moulting of the external cuticle. The staggering diversity within Ecdysozoa has prompted substantial efforts to reconstruct their origin and early evolution. Based on palaentological and developmental data, we proposed a scenario for the early evolution of the ecdysozoan clade Panarthropoda (Onychophora, Tardigrada, Euarthropoda), and postulated that a terminal mouth is ancestral for this lineage. In light of the accompanying comment by Claus Nielsen, we take this opportunity to clarify the significance of our argumentation for Panarthropoda in the phylogenetic context of Ecdysozoa, and Bilateria more broadly. We conclude that the ancestral ecdysozoan most likely had an adult terminal mouth, and that the last common ancestors of all the phyla that constitute Ecdysozoa almost certainly also had an adult terminal mouth. The occurrence of a ventral-facing mouth in various adult ecdysozoans - particularly panarthropods - is the result of convergence. Despite the paucity of embryological data on fossil taxa, we contemplate the likelihood that a developmentally early ventral mouth opening could be ancestral for Ecdysozoa, and if so, then this would represent a symplesiomorphy of Bilateria as a whole. PMID- 30458235 TI - Inorganic nitrate alleviates total body irradiation-induced systemic damage by decreasing reactive oxygen species levels. AB - PURPOSE/OBJECTIVE: To evaluate the protective effect of inorganic nitrate against systemic damage in a mouse model of total body gamma irradiation (TBI). METHODS/MATERIALS: C57BL/6 mice in the IR (irradiation) + NaNO3 group were pretreated with 2 mmol/L NaNO3 in their drinking water for one week before receiving 5 Gy irradiation. Animals that received only 5 Gy irradiation were designated as the IR group. Survival and body weight were monitored. The peripheral blood lymphocytes (PBL), heart, liver, lung, and submandibular gland, were harvested and assessed. Reactive oxygen species (ROS) were measured in the lung and submandibular gland. Phosphorylated histone H2AX (p-H2AX) and p53 binding protein 1 (53BP1), as markers of early stage DNA damage, as well as terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Bax/Caspase 3 mRNA expression, as markers of apoptosis, were examined. RESULTS: No improvement of survival was observed in the IR + NaNO3 group after TBI, but the body weight loss after 5 Gy TBI was significantly attenuated in the IR + NaNO3 group. The levels of peripheral blood erythrocytes, leukocytes, and platelets at 7 days post-irradiation recovered with nitrate treatment; moreover, the p-H2AX level in the PBL was much lower in the IR + NaNO3 group at 2 h and 4 h post-irradiation. In the lung and submandibular gland, the levels of p-H2AX, 53BP1, and ROS as well as TUNEL staining were significantly decreased in the IR + NaNO3 group compared to those in the IR group. Gene expression of Bax and caspase 3 was decreased in both the lung and submandibular gland with nitrate treatment, indicating attenuation of apoptosis. CONCLUSION: Inorganic nitrate delivery could effectively prevent TBI-induced systemic damage. Nitrate-mediated decreases in ROS levels may contribute to this systemic protective effect. PMID- 30458238 TI - Mirror image hypermetropic anisometropia in a pair of monozygotic twins. PMID- 30458237 TI - Ansa cervicalis - A new classification approach. AB - Normally, the inferior root of Ansa cervicalis passes around the internal jugular vein and runs in an anterior direction to meet the superior root ventral to the common carotid artery. However, anatomical variants of the Ansa cervicalis are as yet not well investigated and understood. To close this gap the present study was undertaken. The Ansa cervicalis was examined in 54 human formalin-fixed cadavers and preparations of the head and neck by conventional dissection. In 66% of the specimens the Ansa cervicalis displayed the typical course that was classified as "internal type" (located medial to the internal jugular vein inside the carotid sheath). The remaining 34% pertained to the "external type" of the Ansa cervicalis (lateral to the internal jugular vein). The distance of the Ansa cervicalis relative to the superior margin of the thyroid cartilage was measured in every specimen. The external type Ansa cervicalis was located significantly lower than the internal type relative to the superior margin of thyroid cartilage. Regarding its location relative to the internal jugular vein four variants of combinations of the external and internal types of Ansa cervicalis on the right and left sides were distinguished. Based on their distance from the superior margin of the thyroid cartilage three types of Ansa cervicalis were defined. PMID- 30458239 TI - Return of function after CNS axon regeneration: Lessons from injury-responsive intrinsically photosensitive and alpha retinal ganglion cells. AB - This review addresses issues relating to the survival and axon regeneration of both intrinsically photosensitive retinal ganglion cells (ipRGC) and alphaRGC, and possible ensuing patterns of functional recovery after optic nerve crush, all of which are broadly relevant to recovery from injury in the central nervous system (CNS) as whole. Although much needs to be clarified about the connectivity, function and patterns of myelination of regenerated CNS axons, the results of recent research on activity-induced alphaRGC axon regeneration associated with functional restitution have highlighted key focal obstacles to recovery including neurotrophic support, axon misguidance, target recognition failure and dysmyelination. Pan RGC survival/axon regeneration requires receptor binding and downstream signalling by a cocktail of growth factors, more generally defined in the CNS by the individual trophic requirements of neuronal subsets within a given disconnected centre. Resolution of the problem of failed axon guidance and target recognition is complicated by a confounding paradox that axon growth inhibitory ligand disinhibition required for axon regeneration may mask axon guidance cues that are essential for accurate re-innervation. The study of the temporal parameters of remyelination of regenerated alphaRGC axons may become feasible if they establish permanent homologous connections, allowing time for new myelin sheaths to fully form. Unless near complete re-innervation of denervated targets is re-instated in the CNS, debilitating dysfunctional neurological sequelae may ensue from the resulting imbalance in connectivity. PMID- 30458240 TI - Efficient mining of natural NADH-utilizing dehydrogenases enables systematic cofactor engineering of lysine synthesis pathway of Corynebacterium glutamicum. AB - Increasing the availability of NADPH is commonly used to improve lysine production by Corynebacterium glutamicum since 4 mol of NADPH are required for the synthesis of 1 mol of lysine. Alternatively, engineering of enzymes in lysine synthesis pathway to utilize NADH directly can also be explored for cofactor balance during lysine overproduction. To achieve such a goal, enzyme mining was used in this study to quickly identify a full set of NADH-utilizing dehydrogenases, namely aspartate dehydrogenase from Pseudomonas aeruginosa (PaASPDH), aspartate-semialdehyde dehydrogenase from Tistrella mobilis (TmASADH), dihydrodipicolinate reductase from Escherichia coli (EcDHDPR), and diaminopimelate dehydrogenase from Pseudothermotoga thermarum (PtDAPDH). This allowed us to systematically perturb cofactor utilization of lysine synthesis pathway of C. glutamicum for the first time. Individual overexpression of PaASPDH, TmASADH, EcDHDPR, and PtDAPDH in C. glutamicum LC298, a basic lysine producer, increased the production of lysine by 30.7%, 32.4%, 17.4%, and 36.8%, respectively. Combinatorial replacement of NADPH-dependent dehydrogenases in C. glutamicum ATCC 21543, a lysine hyperproducer, also resulted in significantly improved lysine production. The highest increase of lysine production (30.7%) was observed for a triple-mutant strain (27.7 g/L, 0.35 g/g glucose) expressing PaASPDH, TmASADH, and EcDHDPR. A quadruple-mutant strain expressing all of the four NADH-utilizing enzymes allowed high lysine production (24.1 g/L, 0.30 g/g glucose) almost independent of the oxidative pentose phosphate pathway. Collectively, our results demonstrated that a combination of enzyme mining and cofactor engineering was a highly efficient approach to improve lysine production. Similar strategies can be applied for the production of other amino acids or their derivatives. PMID- 30458241 TI - Changing times: Fluorescence-lifetime analysis of amyloidogenic SF-IAPP fusion protein. AB - In a number of conformational diseases, intracellular accumulation of proteins bearing non-native conformations occurs. The search for compounds that are capable of hindering the formation and accumulation of toxic protein aggregates and fibrils is an urgent task. Present fluorescent methods of fibrils' detection prevent simple real-time observations. We suppose to use green fluorescent protein fused with target protein and fluorescence lifetime measurement technique for this purpose. The recombinant proteins analyzed were produced in E. coli. Mass spectrometry was used for the primary structure of the recombinant proteins and post-translational modifications identification. The fluorescence lifetime of the superfolder green fluorescent protein (SF) and the SF protein fused with islet amyloid polypeptide (SF-IAPP) were studied in polyacrylamide gel using Fluorescent-Lifetime Imaging Microscopy (FLIM). It was shown that the SF average fluorescence lifetime in gel slightly differs from that of the SF-IAPP monomer under these conditions. SF-IAPP does not lose the ability to form amyloid-like fibrils. Under the same conditions (in polyacrylamide gel), SF and SF-IAPP monomers have similar fluorescence time characteristics and the average fluorescence lifetime of SF-IAPP in fibrils significantly decreases. We propose the application of FLIM to the measurement of average fluorescence lifetimes of fusion proteins (amyloidogenic protein-SF) in the context of studies using cellular models of conformational diseases. PMID- 30458242 TI - Enhancing chondrogenesis and mechanical strength retention in physiologically relevant hydrogels with incorporation of hyaluronic acid and direct loading of TGF-beta. AB - Cell-loaded hydrogels are frequently applied in cartilage tissue engineering for their biocompatibility, ease of application, and ability to conform to various defect sites. As a bioactive adjunct to the biomaterial, transforming growth factor beta (TGF-beta) has been shown to be essential for cell differentiation into a chondrocyte phenotype and maintenance thereof, but the low amounts of endogenous TGF-beta in the in vivo joint microenvironment necessitate a mechanism for controlled delivery and release of this growth factor. In this study, TGF beta3 was directly loaded with human bone marrow-derived mesenchymal stem cells (MSCs) into poly-d,l-lactic acid/polyethylene glycol/poly-d,l-lactic acid (PDLLA PEG) hydrogel, or PDLLA-PEG with the addition of hyaluronic acid (PDLLA/HA), and cultured in vitro. We hypothesize that the inclusion of HA within PDLLA-PEG would result in a controlled release of the loaded TGF-beta3 and lead to a robust cartilage formation without the use of TGF-beta3 in the culture medium. ELISA analysis showed that TGF-beta3 release was effectively slowed by HA incorporation, and retention of TGF-beta3 in the PDLLA/HA scaffold was detected by immunohistochemistry for up to 3 weeks. By means of both in vitro culture and in vivo implantation, we found that sulfated glycosaminoglycan production was higher in PDLLA/HA groups with homogenous distribution throughout the scaffold than PDLLA groups. Finally, with an optimal loading of TGF-beta3 at 10 MUg/mL, as determined by RT-PCR and glycosaminoglycan production, an almost twofold increase in Young's modulus of the construct was seen over a 4-week period compared to TGF beta3 delivery in the culture medium. Taken together, our results indicate that the direct loading of TGF-beta3 and stem cells in PDLLA/HA has the potential to be a one-step point-of-care treatment for cartilage injury. STATEMENT OF SIGNIFICANCE: Stem cell-seeded hydrogels are commonly used in cell-based cartilage tissue engineering, but they generally fail to possess physiologically relevant mechanical properties suitable for loading. Moreover, degradation of the hydrogel in vivo with time further decreases mechanical suitability of the hydrogel due in part to the lack of TGF-beta3 signaling. In this study, we demonstrated that incorporation of hyaluronic acid (HA) into a physiologically stiff PDLLA-PEG hydrogel allowed for slow release of one-time preloaded TGF beta3, and when loaded with adult mesenchymal stem cells and cultured in vitro, it resulted in higher chondrogenic gene expression and constructs of significantly higher mechanical strength than constructs cultured in conventional TGF-beta3-supplemented medium. Similar effects were also observed in constructs implanted in vivo. Our results indicate that direct loading of TGF-beta3 combined with HA in the physiologically stiff PDLLA-PEG hydrogel has the potential to be used for one-step point-of-care treatment of cartilage injury. PMID- 30458243 TI - Co-transport of graphene oxide and heavy metal ions in surface-modified porous media. AB - The ability to predict the transport of heavy metal ions in porous media with different surface characteristics is crucial to protect groundwater quality and public health. In this study, the effects of graphene oxide (GO) on co-transport and remobilization of Pb2+ and Cd2+ in humic acid (HA), smectite, kaolinite, and ferrihydrite-coated sand media were evaluated via laboratory packed-column experiments. Scanning electron microscope and energy dispersive X-ray analysis showed that the surface morphology of the coated sands was quite different and that ~56.7-89.9% of the surface was covered by the coating and the major elemental components were C, O, Si, Al, and Fe. GO exhibited high mobility in HA, kaolinite, and smectite-coated sand, but showed high retention in ferrihydrite coated sand. While GO reduced the transport of Pb2+ and Cd2+, both metal ions also reduced the mobility of GO in coated-sand columns. Elution experiments revealed that GO led to the remobilization and release of the previously sorbed Pb2+ and Cd2+ from the coated sand. However, GO could not release Pb2+ and Cd2+ from smectite-coated sand columns, probably because smectite has stronger adsorption affinity to the heavy metals than GO. Derjaguin-Landau-Verwey-Overbeek calculations were employed and explained the GO transport behavior in the columns well. Furthermore, the advection-dispersion-reaction equation simulated the cotransport of Pb2+ and Cd2+ with GO in the coated sand well. These results are expected to provide insight into the potential impact of coexisting nanomaterials with contaminants in vulnerable soil and groundwater systems. PMID- 30458244 TI - Age-related diseases as vicious cycles. AB - The mortality rates of age-related diseases (ARDs) increase exponentially with age. Processes described by the exponential growth function typically involve a branching chain reaction or, more generally, a positive feedback loop. Here I propose that each ARD is mediated by one or several positive feedback loops (vicious cycles). I then identify critical vicious cycles in five major ARDs: atherosclerosis, hypertension, diabetes, Alzheimer's and Parkinson's. I also propose that the progression of ARDs can be halted by selectively interrupting the vicious cycles and suggest the most promising targets. PMID- 30458245 TI - Healthcare delivery in meibomian gland dysfunction and blepharitis. PMID- 30458246 TI - Population-based trends in prevalence of nonalcoholic fatty liver disease in US adults with type 2 diabetes. PMID- 30458247 TI - Low-Normal Thyroid Function is Associated with Advanced Fibrosis among Adults in the United States. PMID- 30458248 TI - Efficacy of Induction Therapy with High-intensity Tofacitinib in 4 Patients with Acute Severe Ulcerative Colitis. PMID- 30458249 TI - P2X receptors and acupuncture analgesia. AB - Purinergic signaling has recently been suggested to constitute the cellular mechanism underlying acupuncture-induced analgesia (AA). By extending the original hypothesis on endogenous opioids being released during AA, Geoffrey Burnstock and Maiken Nedergaard supplied evidence for the involvement of purinoceptors (P2 and P1/A1 receptors) in the beneficial effects of AA. In view of certain pain states (e.g. neuropathic pain) which respond only poorly to therapy with standard analgesics, as well as with respect to the numerous unwanted effects of opioids and non-steroidal anti-inflammatory drugs, it is of great significance to search for alternative therapeutic options. Because clinical studies on AA yielded sometimes heterogeneous results, it is of eminent importance to relay on experiments carried out on laboratory animals, by evaluating the data with stringent statistical methods including comparison with a sufficient number of control groups. In this review, we summarize the state of the art situation with respect to the participation of P2 receptors in AA and try to forecast how the field is likely to move forward in the future. PMID- 30458250 TI - Purinergic signaling in the retina: From development to disease. AB - Retinal injuries and diseases are major causes of human disability involving vision impairment by the progressive and permanent loss of retinal neurons. During development, assembly of this tissue entails a successive and overlapping, signal-regulated engagement of complex events that include proliferation of progenitors, neurogenesis, cell death, neurochemical differentiation and synaptogenesis. During retinal damage, several of these events are re-activated with both protective and detrimental consequences. Purines and pyrimidines, along with their metabolites are emerging as important molecules regulating both retinal development and the tissue's responses to damage. The present review provides an overview of the purinergic signaling in the developing and injured retina. Recent findings on the presence of vesicular and channel-mediated ATP release by retinal and retinal pigment epithelial cells, adenosine synthesis and release, expression of receptors and intracellular signaling pathways activated by purinergic signaling in retinal cells are reported. The pathways by which purinergic receptors modulate retinal cell proliferation, migration and death of retinal cells during development and injury are summarized. The contribution of nucleotides to the self-repair of the injured zebrafish retina is also discussed. PMID- 30458251 TI - Neurological manifestations in Onchocerca volvulus infection: A review. AB - Human onchocerciasis, caused by infection by the filarial nematode Onchocerca volvulus, is a major neglected public health problem that affects millions of people in the endemic regions of sub-Saharan Africa and Latin America. Onchocerciasis is known to be associated with skin and eye disease and more recently, neurological features have been recognized as a major manifestation. Especially the latter poses a severe burden on affected individuals and their families. Although definite studies are awaited, preliminary evidence suggests that neurological disease may include the nodding syndrome, Nakalanga syndrome and epilepsy but to date, the exact pathophysiological mechanisms remain unclear. Currently, the only way to prevent Onchocera volvulus associated disease is through interventions that target the elimination of onchocerciasis through community distribution of ivermectin and larviciding the breeding sites of the Similium or blackfly vector in rivers. In this review, we discuss the epidemiology, potential pathological mechanisms as well as prevention and treatment strategies of onchocerciasis, focusing on the neurological disease. PMID- 30458252 TI - Satureja montana L. essential oil and its antimicrobial activity alone or in combination with gentamicin. AB - Many essential oils (EOs) are screened as potential sources of antimicrobial compounds. EOs from the genus Satureja have recognized biological properties, including analgesic, anti-inflammatory, immunomodulatory, anticancer, and antimicrobial activity. This study aimed to obtain a metabolite profile of commercial essential oil of S. montana L. (SEO) and to evaluate its antimicrobial properties, both alone and combined with gentamicin towards Gram-negative and Gram-positive bacterial strains. Untargeted analyses based on direct infusion Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and on GC MS have provided a high metabolome coverage, allowing to identify carvacrol, cymene and thymol as the major components of commercial SEO. SEO exerted an antimicrobial activity and induced a synergistic interaction with gentamicin against both reference and clinical bacterial strains. A significant reduction of Escherichia coli, Staphylococcus aureus and Listeria monocytogenes biofilm formation was induced by SEO. As a result of SEO treatment, clear morphological bacterial alterations were visualized by scanning electron microscopy: L. monocytogenes and S. aureus showed malformed cell surface or broken cells with pores formation, whereas E. coli displayed collapsed cell surface. These results encourage further studies about bactericidal and antibiotic synergistic effect of SEO for combined therapy in clinical setting as well as in agricultural systems. PMID- 30458253 TI - Reactive oxygen species inhibit biofilm formation of Listeria monocytogenes. AB - Although the level of reactive oxygen species (ROS) is altered upon the formation of bacterial biofilm, the relationship between ROS alteration and biofilm formation is still unclear. The aim of the present study is to use Listeria monocytogenes (L. monocytogenes) as a model organism to examine whether ROS have an effect on the biofilm formation. After eliminating ROS by treatment with NAD(P)H oxidase inhibitor Diphenyleneiodonium chloride (DPI) or scavenging reagents N-acetylcysteine (NAC), the biofilm formation of L. monocytogenes was examined. Our data demonstrate that DPI and NAC induced-reduction of ROS enhances the biofilm formation in L. monocytogenes without affecting bacterial growth and activity. These data provide the evidence that ROS produced by L. monocytogenes inhibit the biofilm formation. PMID- 30458254 TI - Complete genome sequence of Burkholderia sp. JP2-270, a rhizosphere isolate of rice with antifungal activity against Rhizoctonia solani. AB - Burkholderia sp. JP2-270, a bacterium with a strong ability to inhibit the growth of Rhizoctonia solani, was isolated from the rhizosphere of rice. The phylogenetic analysis based on 16S rRNA gene revealed that JP2-270 belonged to Burkholderia cepacia complex. Here, we present the complete genome sequence of Burkholderia sp. JP2-270, which consists of three circular chromosomes (Chr1 3,723,585 bp, Chr2 3,274,969 bp, Chr3 1,483,367 bp) and two plasmids (Plas1 15,126 bp, Plas2 428,263 bp). A total of 8193 protein coding genes were predicted in the genome, including 67 tRNA genes, 18 rRNA genes and 4 ncRNA genes. In addition, mutation analysis of Burkholderia sp. JP2-270 revealed that the gene bysR (DM992_17470), encoding a lysR-type transcriptional regulator, was essential for the antagonistic activity of Burkholderia sp. JP2-270 against R. solani GD118 in vitro and in vivo. Identification of regulatory gene associated with antagonistic activity will contribute to understand the antagonistic mechanism of Burkholderia sp. JP2-270. PMID- 30458255 TI - Decrease of growth, biofilm and secreted virulence in opportunistic nosocomial Pseudomonas aeruginosa ATCC 25619 by glycyrrhetinic acid. AB - The present study elucidates the antibiofilm and antivirulent capability of glycyrrhetinic acid (GRA) against Pseudomonas aeruginosa ATCC 25619. The minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) of GRA against P. aeruginosa were found to be 160 MUg/mL and 420 MUg/mL respectively. In an acclimatization resistance analysis using P. aeruginosa, no resistance towards GRA was observed during the habituation period. Adequate penetration of GRA over the biofilm matrix was proposed with the membrane penetration model assembly constructed with the preformed biofilm exhibited the prospective penetration of GRA above the mature biofilm. Furthermore, GRA resulted in the attenuation of virulence factors such as motility, biofilm formation, pyocyanin secretion, secreted proteases with its sub MIC concentrations. The antibiofilm property of GRA was assessed with the light microscopy and high content screening fluorescent imaging system, which clearly demonstrates, the thickness of P. aeruginosa biofilm was reduced to 11.33 +/- 2.08 MUm from 39 +/- 2.51 MUm. Transmission Electron Microscopy (TEM) images depicted the morphological changes in cells such as disaggregation of colonies, cell disruption with loss of intracellular material, cytolytic damage, the process of morphological transformation, bacteriolysis indicating the potential effect of GRA. PMID- 30458257 TI - SPIONs embedded in polyamino acid nanogels to synergistically treat tumor microenvironment and breast cancer cells. AB - The extremely complex tumor microenvironment (TME) in humans is the major responsible for the therapeutic failure in cancer nanomedicine. A new concept of disease-driven nanomedicine, henceforth named "Theranomics", which attempts to target cancer cells and TME on the whole, represents an attractive alternative. Herein, a nanomedicine able to co-deliver doxorubicin and a tumor suppressive proteolytic protein such as collagenase-2 was developed. We successfully obtained superparamagnetic nanogels (SPIONs/Doco@Col) via the intermolecular azide-alkyne Huisgen cycloaddition. We demonstrated that a local ECM degradation and remodeling in solid tumors by means of collagenase-2 could enhance tumor penetration of nanomedicines and the in situ sustained release of the drug payload throughout 3-D tumor spheroids up to the core (parenchyma), thus enabling a synergistic and efficient anticancer effect toward highly invasive breast tumors. We illustrate that SPIONs/Doxo@Col is also capable of reducing the invasivity of cancer cells. PMID- 30458256 TI - Exploratory studies in heat-assisted continuous twin-screw dry granulation: A novel alternative technique to conventional dry granulation. AB - Dry granulation is the preferred technique for solvent-sensitive products, especially drugs with stability problems such as hydrolysis. Twin-screw granulation is a continuous granulation technique, offering a potential alternative to conventional dry granulation techniques such as roller compaction. The major advantage of twin-screw granulation is the ability to adjust process parameters of dry granulation without compromising the compression properties. This study was aimed to perform exploratory studies of heat-assisted continuous twin-screw dry granulation process to formulate sustained release tablets for APIs with different melting points: theophylline, acetaminophen and lidocaine hydrochloride hydrate. Granulation feasibility was studied with different binders (e.g. KlucelTM EF, Kollidon(r) VA64), sustained release agents (e.g. KlucelTM MF, Eudragit(r) RSPO) and diluents at various drug loads. The processing conditions were below the melting point or glass transition temperature of the formulation ingredients. After successful granulation, DSC and XRD studies revealed the crystalline nature of the granules and FTIR studies showed no interaction of the API with the excipients. The granules were compressed into sustained release tablets without any compressibility issues. The tablets were stable after testing for 6 months at 25 degrees C/60% RH. This novel continuous dry granulation technique may offer an excellent alternative to conventional dry granulation techniques. PMID- 30458258 TI - Analysis of phase behavior and morphology during freeze-thaw applications of lysozyme. AB - Knowledge of protein behavior/stability during freeze/thaw (FT) operations is essential for storage and production processes in the biopharmaceutical industry. FT stress involves freeze concentration, cold denaturation, and ice crystals formation which can result in protein aggregation. Therefore, it is important to understand the ongoing FT processes, and the influence of different solution parameters. In order to evaluate the ongoing processes during FT (up to -80 degrees C), phase diagrams with lysozyme from chicken egg white and sodium chloride were generated. Thereby, three different buffer systems with varying buffer substances and ionic strengths at pH 3 and pH 5 were investigated. As indicators for the ongoing FT processes, the phase behavior, crystal morphology and solubility were used. An increased number of cycles led, for example, to the formation of micro crystals, sea urchin crystals - indicating LLPS and/or high supersaturation - and precipitate. Furthermore, the buffer substances had a more distinct influence on the phase behavior and morphology compared to the ionic strength differences. The solubility line itself was only shifted when distinct changes in the phase behavior could be observed. In summary, a tool was developed for using the phase behavior and especially the crystal morphology as indicator for underlying processes during FT operations. PMID- 30458259 TI - Amorphous multi-system of celecoxib improves its anti-inflammatory activity in vitro and oral absorption in rats. AB - In the present study, a multi-system for solid dispersion (SD) of celecoxib (CXB) was designed to improve its solubility and anti-inflammatory effects in vitro as well as oral absorption in rats. The SD formulations were prepared by a solvent evaporation with a multi-system as the solubilizer; an alkalizer; and fumed silica (Aerosil(r) 200). The physicochemical properties of the SD formulations were evaluated. Polyoxyl 15 hydroxystearate (HS 15(r)) was chosen as the solubilizer based on the apparent solubility test. The optimal SD formulation (SD6, CXB: HS 15(r): K30(r): meglumine: Aerosil(r) 200 = 200: 50: 50: 100: 100, weight ratio) improved the dissolution (%) over 2-fold compared to that by the commercial product (Celebrex(r)) at pH 1.2, in distilled water (DW), and in a pH 6.8 buffer (sodium lauryl sulfate [SLS], 0.25% w/v). The SD6 formulation altered physical properties such as crystallinity, thermal stability, and intra-molecular interaction. Moreover, SD6 showed a good stability for 6 months. The anti inflammatory effect of SD6 significantly improved 2.2-fold compared to that of Celebrex(r) in the cell study. The relative bioavailability (BA) of SD6 was significantly improved to 209.4% compared to that of Celebrex(r). In conclusion, intra-molecular interactions between CXB and solubilizers in multi-systems increase its solubility, dissolution (%), anti-inflammatory effects in vitro, and the relative BA (%) in rats. Thus, SD6 would be effective for the treatment of inflammation in rats and should be evaluated in detail in future clinical studies. PMID- 30458260 TI - Powder bed 3D-printing of highly loaded drug delivery devices with hydroxypropyl cellulose as solid binder. AB - 3D-printing is a promising tool to pave the way to the widespread adaption of individualized medicine. Several printing techniques have been investigated and introduced to pharmaceutical research. Until now, only one 3D-printed medicine is approved on the US market. The medicine is manufactured via drop-on-powder deposition, which uses inkjet printing to jet a liquid binder on a powder bed to create 3D objects. However, inkjet processes are prone to nozzle clogging when binders or active pharmaceutical ingredients (APIs) are included in the printing ink. This renders the formulation development of the ink the most challenging step. In this study, different hydroxypropyl cellulose (HPC) grades were investigated as solid binders in the powder formulation on a commercially available DoP printer. The printed ink only consisted of a water/ethanol mixture. Formulations containing 70% caffeine as model API were developed and tablets printed. It was found that the friability of the tablets greatly depends on the particle size of the employed binder, whereas disintegration time and dissolution properties mainly depend on the viscosity of the employed binders. Higher viscous binders led to slower disintegration and dissolution whereas lower viscous binders led to faster disintegration and dissolution. The study demonstrates that HPC is a suitable solid binder for DoP printing and that 3D-DoP printing can be used to print robust dosage forms. PMID- 30458261 TI - Systematic review showed that stepped wedge cluster randomized trials often did not reach their planned sample size. AB - OBJECTIVE: To determine, how often stepped wedge cluster randomized controlled trials reach their planned sample size, and what reasons are reported for choosing a stepped wedge trial design. STUDY DESIGN AND SETTING: We conducted a PubMed literature search (period 2012 to 2017) and included papers describing the results of a stepped wedge cluster randomized trial. We calculated the percentage of studies reaching their pre-specified number of participants and clusters, and we summarized the reasons for choosing the stepped-wedge trial design as well as difficulties during enrollment. RESULTS: Forty-six individual stepped wedge studies from a total of 53 articles were included in our review. Of the 35 studies, for which recruitment rate could be calculated, 69% recruited their planned number of participants, with 80% having recruited the planned number of clusters. Ethical reasons were the most common motivation for choosing the stepped wedge trial design. Most important difficulties during study conduct were drop-out of clusters and delayed implementation of the intervention. CONCLUSION: About half of recently published stepped wedge trials reached their planned sample size indicating that recruitment is also a major problem in these trials. Still, the stepped wedge trial design can yield practical, ethical and methodological advantages. PMID- 30458262 TI - Stratification by quality induced selection bias in a meta-analysis of clinical trials. AB - OBJECTIVE: The inconsistency demonstrated across strata when using different scales has been attributed to quality scores and stratification continues to be done using risk of bias domain judgments. This study examines if restricting primary meta-analyses to studies at low risk of bias or presenting meta-analyses stratified according to risk of bias is indeed the right approach to explore potential methodological bias. STUDY DESIGN AND SETTING: Re-analysis of quality subgroups in an existing meta-analysis based on 25 different scales RESULTS: We demonstrate that quality stratification itself is the problem because it induces a spurious association between effect size and precision within stratum. Studies with larger effects or lesser precision tend to be of lower quality - a form of collider stratification bias (stratum being the common effect of the reasons for these two outcomes) that leads to inconsistent results across scales. We also show that the extent of this association determines the variability in effect size and statistical significance across strata when conditioning on quality. CONCLUSIONS: We conclude that stratification by quality leads to a form of selection bias (collider stratification bias) and should be avoided. We demonstrate consistent results with an alternative method that includes all studies. PMID- 30458264 TI - Generalizability of findings from Randomized Controlled Trials is limited in the Leading General Medical Journals. AB - OBJECTIVE: To document reporting of study characteristics of RCTs in the four leading general medical journals ; and to appraise the generalizability of the evidence. STUDY DESIGN AND SETTING: All RCTs in BMJ, JAMA, Lancet and NEJM from 1.1.2017 to 30.9.2017 were searched by hand; and data was extracted according to the Benchmarking method. RESULTS: 161 RCTs were found; 67% assessed pharmacological therapy. The percentages of adequate documentation were: patients' path prior to randomisation 3% to 33% of trials; characteristics of the health care settings 0% to 75%; at least two co-morbid conditions 25% to 50%; at least one measure was reported of functioning 42% to 54%, of behavioral factors 25% to 58%, of environmental factors 3% to 25%, and of inequity related factors 28% to 68%; co-interventions 6% to 25%, and reasons for dropping out of follow-up 39% to 100%. CONCLUSION: Almost all RCTs showed deficiencies in description of patient selection and study setting; and in reporting of patient characteristics related to functioning, co-morbidities, and to behavioral, environmental and inequity factors. The findings indicate that generalizability of this evidence may be limited. The benchmarking method can be used for planning and appraisal of clinical trials and systematic reviews. PMID- 30458263 TI - Randomised trial seeking to induce the Hawthorne effect found no evidence for any effect on self-reported alcohol consumption online. AB - OBJECTIVE: We tested the hypothesis that participants who know the behavioural focus of a study and are thus aware that a particular behaviour is being studied, will modify that behaviour, independently of any possible effect of assessment, thereby dismantling a Hawthorne effect into two putative components. STUDY DESIGN AND SETTING: We undertook a three-arm individually randomised trial online among students: Group A (control) were told they were completing a lifestyle survey; Group B were told the focus of the survey was alcohol consumption; Group C additionally answered 20 questions on their alcohol use and its consequences before answering the same lifestyle questions as Groups A and B. Non-drinkers were excluded and all groups were aware they would be followed-up after one month. RESULTS: Outcome data were obtained for 4583/5478 trial participants (84% follow-up rate). There were no differences between the three groups on primary (overall volume consumed) or secondary outcome measures (drinking frequency and amount per typical occasion) in the intervening four weeks. CONCLUSIONS: There is no evidence that any form of Hawthorne effect exists in relation to self-reported alcohol consumption online among university students in usual research practice. Attention to study contexts is warranted for investigating research participation effects. PMID- 30458265 TI - "An Error in An Old Paper Illustrates the Need for Data/Code Archives". PMID- 30458266 TI - The azole fungicide tebuconazole affects human CYP1A1 and CYP1A2 expression by an aryl hydrocarbon receptor-dependent pathway. AB - Tebuconazole, a member of the triazole group of fungicides, exerts hepatotoxicity in rodent studies. Knowledge on the molecular mechanisms underlying tebuconazole toxicity is limited. Previous studies suggest that activation of xenobiotic sensing nuclear receptors plays a role in triazole fungicide-mediated hepatotoxicity. This study aimed to characterize the ability of tebuconazole to activate gene expression via the aryl hydrocarbon receptor (AHR). Results demonstrate a statistically significant induction of the AHR target genes CYP1A1 and CYP1A2 in HepG2 and HepaRG human liver cells in vitro at concentrations corresponding to tebuconazole tissue levels reached under subtoxic conditions in vivo. CYP1A1 and CYP1A2 induction was abolished in the presence of an AHR antagonist or in AHR-knockout HepaRG cells, substantiating the importance of the AHR for the observed effects. Although the results indicate that tebuconazole is a weak inducer of AHR-dependent genes, combined exposure of HepaRG cells to tebuconazole and the previously identified AHR agonist propiconazole showed additive effects on CYP1A1 and CYP1A2 expression. In summary, we demonstrate that AHR-downstream gene expression is affected by tebuconazole in an AHR-dependent manner. Data indicate that dose addition may be assumed for the assessment of AHR related effects of triazole fungicide mixtures. PMID- 30458267 TI - RIFM fragrance ingredient safety assessment, octahydro-4,7-methano-1H indenemethyl formate, CAS Registry Number 68039-78-1. PMID- 30458269 TI - Uncertainty surrounding the mechanism and safety of the post-harvest fungicide fludioxonil. AB - Fludioxonil is a phenylpyrrole pesticide that is applied to fruit and vegetable crops post-harvest to minimize losses to mold, both during transport and at point of sale. Its effectiveness is reflected in the dramatic increase in its production/usage since its introduction in 1994, an increase that has peaked in recent years as it became licenced for use abroad. Recently, doubts as to the nature of its mechanism of action have been raised. Given that the pesticide has long been known to induce stress intermediates in target and non-target organisms alike, the lack of a firmly established mechanism might be cause for concern. Troubling reports further delineate a capacity to disrupt hepatic, endocrine and neurological systems, indicating that fludioxonil may represent a health threat to consumers. In the absence of a clear, safe mechanism of action, fludioxonil should be re-evaluated for its potential to impact human health. PMID- 30458268 TI - Plumbagin from a tropical pitcher plant (Nepenthes alata Blanco) induces apoptotic cell death via a p53-dependent pathway in MCF-7 human breast cancer cells. AB - Plumbagin (5-hydroxy-2-methyl-1,4-naphthaquinone) has displayed antitumor activity in vitro and in animal models; however, the underlying molecular mechanisms have not been fully explored. The aim of this study was to investigate the anticancer effects of plumbagin isolated from Nepenthes alata against MCF-7 breast cancer cells. We examined the cytotoxicity, cell cycle regulation, apoptotic cell death, and generation of intracellular reactive oxygen species (ROS) in MCF-7 cells. Plumbagin exhibited potent cytotoxicity in MCF-7 cells (wild-type p53) compared to that in SK-OV-3 (null-type) human epithelial ovarian cancer cells. Specifically, plumbagin upregulated the expression of p21CIP1/WAF1 in MCF-7 cells, causing cell cycle arrest in the G2/M phase through inhibition of cyclin B1 levels. Plumbagin also significantly increased the ratio of Bax/Bcl-2 and release of cytochrome c, resulting in apoptotic cell death in MCF-7 cells. Furthermore, plumbagin dramatically increased the intracellular ROS level, whereas pretreatment with the ROS scavenger N-acetyl cysteine protected against plumbagin-induced cytotoxicity, suggesting that ROS formation plays a pivotal role in antitumor activity in MCF-7 cells. In mice bearing MCF-7 cell xenografts, plumbagin significantly reduced tumor growth and weight without apparent side effects. We therefore concluded that plumbagin exerts anticancer activity against MCF-7 cells through the generation of intracellular ROS, resulting in the induction of apoptosis via a p53-dependent pathway. This study thus identifies a new anticancer mechanism of plumbagin against p53-dependent breast cancer cells and suggests a novel strategy for overcoming of breast cancer therapy. PMID- 30458272 TI - Comparative transcriptome analyses of venom glands from three scorpionfishes. AB - Scorpionfishes (Scorpaenidae) are a relatively common cause of human envenomation. They often enter coastal waters and their stings can be quite hazardous, provoking extreme pain and causing the victims to take days to recover. There are few genomic resources available for the scorpionfishes. In this study, we elucidated the transcriptomic profile of the venom glands from three different scorpionfish species, namely Scorpaenopsis cirrosa, S. neglecta and S. possi. This is the first report of scorpionfish transcriptomes. After functional and pathway annotation, we employed toxin annotation to identify many species-specific (18, 13 and 19 respectively) and overlapping putative toxins among the three species. Our study represents a significant improvement in the genetic information about the venoms from these three species. Moreover, this work also provides an archive for future studies on evolution of fish toxins and can be used for comparative studies of other fishes. PMID- 30458270 TI - RIFM fragrance ingredient safety assessment, ethyl 2-methylbutyrate, CAS Registry Number 7452-79-1. PMID- 30458271 TI - RIFM fragrance ingredient safety assessment, methyl isobutyrate, CAS Registry Number 547-63-7. PMID- 30458273 TI - Transcriptome profiling and histology changes in juvenile blunt snout bream (Megalobrama amblycephala) liver tissue in response to acute thermal stress. AB - To understand the precise mechanism and the pathways activated by thermal stress in fish, we sampled livers from juvenile Megalobrama amblycephala exposed to control (25 degrees C) and test (35 degrees C) conditions, and performed short read (100 bp) next-generation RNA sequencing (RNA-seq). Using reads from different temperature, expression analysis identified a total of 440 differentially-expressed genes. These genes were related to oxidative stress, apoptosis, immune responses and so on. We used quantitative real-time reverse transcriptase PCR to assess the differential mRNA expression of selected genes that encode antioxidant enzymes and heat shock proteins in response to thermal stress. Fish exposed to thermal stress also showed liver damage associated with serum biochemical parameter changes. The set of genes identified showed regulatory modulation at different temperatures, and therefore could be further studied to determine how thermal stress damages M. amblycephala livers and the possible roles of reactive oxygen species in this process. PMID- 30458274 TI - Identification of novel phasiRNAs loci on long non-coding RNAs in Arabidopsis thaliana. AB - Long non-coding RNAs (lncRNAs) are the "dark matters"involved in gene regulation with complex mechanisms. However, the functions of most lncRNAs remain to be determined. Our previous work revealed a massive number of degradome-supported cleavage signatures on Arabidopsis lncRNAs. Some of them have been confirmed associated with miRNAs-like sRNAs production, while others without long stem structure remain unexplored. A systematical search for phasiRNAs generating ability of these lncRNAs was conducted. Eight novel small RNA triggered lncRNA phasiRNA pathways were discovered and three of them were found to be conserved in Arabidopsis, Oryza sativa, Glycine max and Gossypium hirsutum. Besides, Five novel ta-siRNAs derived from these lncRNAs were further identified to be involved in the regulation of plant development, stress responses and aromatic amino acids synthesis. These results substantially expanded the gene regulation mechanisms of lncRNAs. PMID- 30458275 TI - Complete genome sequence and in silico analysis of L. interrogans Canicola strain DU114: A virulent Brazilian isolate phylogenetically related to serovar Linhai. AB - Canine leptospirosis is often caused by Leptospira interrogans serovar Canicola. Infected dogs may become asymptomatic carriers of the pathogen, which leads to many public health concerns. In this work, we present the complete genome sequencing and in silico analysis from a virulent Brazilian strain of L. interrogans serovar Canicola, previously isolated from a stray dog in Sao Paulo City. Comparative genomic analysis with a reference genome allowed identification of 1031 INDELs and several arrangement variations. Out of 35,361 SNPs identified, 6780 were missense mutations and 16,114 were synonymous mutations. The Gene Ontology terms more affected by mutations were described. Interestingly, phylogenetic analyses indicated a genetic relatedness of the isolate with serovar Linhai strain 56,609. In addition, we found several virulence-related genes and main outer membrane proteins associated with pathogenesis. This genomic information about canine isolates may help to elucidate the molecular diversity and mechanisms of Leptospira spp. pathogenicity. PMID- 30458276 TI - Carbonate-radical-anions, and not hydroxyl radicals, are the products of the Fenton reaction in neutral solutions containing bicarbonate. AB - The Fenton reaction, Fe(H2O)62+ + H2O2 -> Oxidizing product, is of major importance in biology as the major cause of oxidative stress, and in advanced oxidation processes. It is commonly assumed that .OH is the product of the Fenton reaction. The results presented herein point out that .OH is indeed the oxidizing product in acidic solutions for [Fe(H2O)62+] > [H2O2]; FeIVaq is the active oxidizing product in neutral solutions; in slightly acidic solutions for [H2O2] > [Fe(H2O)62+] a mixture of .OH and FeIVaq is formed. However CO3.- is the active oxidizing product in neutral solutions containing HCO3- even at low concentrations, i.e. under physiological conditions. The implications to our understanding of the origins of oxidative stress and of catalytic oxidations in advanced oxidation processes are discussed. PMID- 30458277 TI - Pretreatment with Korean red ginseng or dimethyl fumarate attenuates reactive gliosis and confers sustained neuroprotection against cerebral hypoxic-ischemic damage by an Nrf2-dependent mechanism. AB - The transcriptional factor Nrf2, a master regulator of oxidative stress and inflammation that are tightly linked to the development and progression of cerebral ischemia pathology, plays a vital role in inducing the endogenous neuroprotective process. Here, hypoxic-ischemia (HI) was performed in adult Nrf2 knockout and wildtype mice that were orally pretreated either with standardized Korean red ginseng extract (Ginseng) or dimethyl fumarate (DMF), two candidate Nrf2 inducers, to determine whether the putative protection was through an Nrf2 dependent mechanism involving the attenuation of reactive gliosis. Results show that Nrf2 target cytoprotective genes were distinctly elevated following HI. Pretreatment with Ginseng or DMF elicited robust neuroprotection against the deterioration of acute cerebral ischemia damage in an Nrf2-dependent manner as revealed by the reductions of neurological deficits score, infarct volume and brain edema, as well as enhanced expression levels of Nrf2 target antioxidant proteins and anti-inflammation mediators. In both ischemic striatum and cortex, the dynamic pattern of attenuated reactive gliosis in astrocytes and microglia, including affected astrocytic dysfunction in glutamate metabolism and water homeostasis, correlated well with the Nrf2-dependent neuroprotection by Ginseng or DMF. Furthermore, such neuroprotective benefits extended to the late phase of ischemic brain damage after HI, as evidenced by improvements in neurobehavioral outcomes, infarct volume and brain edema. Overall, pretreatment with Ginseng or DMF identically attenuates reactive gliosis and confers long-lasting neuroprotective efficacy against ischemic brain damage through an Nrf2-dependent mechanism. This study also provides new insight into the profitable contribution of reactive gliosis in the Nrf2-dependent neuroprotection in acute brain injury. PMID- 30458278 TI - The interaction of Atg4B and Bcl-2 plays an important role in Cd-induced crosstalk between apoptosis and autophagy through disassociation of Bcl-2-Beclin1 in A549 cells. AB - Cadmium (Cd) is a highly ubiquitous detrimental metal in the environment. It is a well-known inducer of tumorigenesis, but the mechanism is not clear. In our previous study, we found that ROS-dependent Atg4B upregulation mediated Cd induced autophagy and autophagy played an important role in Cd-induced proliferation and invasion in A549 cells. In this study, we found that Cd induced both apoptosis and autophagy in A549 cells, and apoptosis preceded autophagy. Z VAD-FMK repressed Cd-induced LC3 and Beclin1, indicating that apoptosis was essential for Cd-induced autophagy. 3MA destroyed the recovery of mitochondrial membrane potential and increased Cd-induced CL-CASP9 and CL-CASP3 expression, suggesting that Cd-induced autophagy prevented A549 cells from apoptosis. Further study showed that Atg4B upregulation was mediated by mitochondrial dysfunction and conversely affected mitochondrial function by decreasing Bcl-2 protein expression and its localization in mitochondria, and played an important role in Cd-induced apoptosis. Moreover, Bcl-2 was involved in Cd-induced autophagy. Co-IP assay showed that Atg4B could directly bind to Bcl-2, and consequently promote disassociation of Bcl-2-Beclin1 and released autophagic protein Beclin1 to activate autophagic pathway. Taken together, our results demonstrated that the interaction of Atg4B and Bcl-2 might play an important role in Cd-induced crosstalk between apoptosis and autophagy through disassociation of Bcl-2 Beclin1. Cd-induced autophagy is apoptosis-dependent and prevents apoptotic cell death to ensure the growth and proliferation of A549 cells. PMID- 30458279 TI - A promising redox cycle-based strategy for designing a catechol-type diphenylbutadiene as a potent prooxidative anti-melanoma agent. AB - Developing anti-melanoma agents with increased activity and specificity is highly desirable due to the increasing incidence, highly metastatic malignancy, and high mortality rate of melanoma. Abnormal redox characteristics such as higher levels of tyrosinase, NAD(P)H: quinone oxidoreductase-1 (NQO1) and reactive oxygen species (ROS) observed in melanoma cells than in other cancer cells and normal cells illustrate their redox vulnerability and have opened a window for developing prooxidative anti-melanoma agents (PAAs) to target the vulnerability. However, how to design PAAs which promote selectively the ROS accumulation in melanoma cells remains a challenge. This work describes a promising redox cycle based strategy for designing a catechol-type diphenylbutadiene as such type of PAA. This molecule is capable of constructing an efficient catalytic redox cycle with tyrosinase and NQO1 in melanoma B16F1 cells to induce selectively the ROS (mainly including hydrogen peroxide, H2O2) accumulation in the cells, resulting in highly selective suppression of melanoma B16F1 cells over tyrosinase-deficient HeLa and normal L-02 cells. PMID- 30458280 TI - Hepatoprotective potential of standardized Ficus species in intrahepatic cholestasis rat model: Involvement of nuclear factor-kappaB, and Farnesoid X receptor signaling pathways. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ficus is an important commercial crop not only for its nutritive value but also, for its medicinal value. Several Ficus species have been traditionally used in the Egypt, Indian and Chinese as carminative, astringent, antibacterial, hepatoprotective, and hypolipidemic agents. AIM OF THE STUDY: To standardize and compare the possible hepatoprotective potential of the ethanolic extract of leaves of five tested Ficus species namely: Ficus mysorensis Roth ex Roem. & Schult, Ficus pyriformis Hook. & Arn., Ficus auriculata Lour., Ficus trigonata L., and Ficus spragueana Mildbr. & Burret in the intrahepatic cholestasis rat model induced by 17alpha-Ethinylestradiol (EE) and to explore the mechanism of action with respect to their phytochemical constituents. MATERIALS AND METHODS: Determination of the total phenolic and flavonoid contents, chromatographic examination and acute oral toxicity test were performed on the tested Ficus extracts. Animals were divided into 8 groups. Group 1, served as control for 2 weeks. Group 2, untreated cholestatic rats. Groups 3-8, pretreated with Ficus extracts (100 mg/Kg/day, p.o) or ursodeoxycholic acid (as reference drug) for 2 weeks and injected by EE in the last 5 days. Serum liver function test, 5'-nucleotidase (5'-N), total bile acids (TBA), total cholesterol (T.C) and phospholipids were assayed. Also, hepatic Na+/K+-ATPase, nuclear factor-kappaB (NF-kappaB), tumor necrosis factor-alpha (TNF-alpha), hepatocyte growth factor (HGF), hemeoxygenase-1 (HO-1), and markers of oxidative stress were investigated. Furthermore, molecular docking study was performed to explore the ability of the major constituents of Ficus to interact with Farnesoid X receptor (FXR). RESULTS: Four phenolic compounds (gallic, chlorogenic acid, caffeic acids and rutin) were identified. Chlorogenic acid and rutin represented the major constituents of Ficus extracts. Simultaneous administration of Ficus extracts with EE effectively: i- preserved liver function, TBA, T.C and phospholipids, ii- suppressed the pro-inflammatory cytokines (NF-kappaB and TNF-alpha), iii- enhanced hepatic regeneration (HGF) and antioxidant defense system. Furthermore, molecular docking reveals that rutin and chlorogenic acid effectively act as FXR agonists. CONCLUSION: Among the tested extracts, Ficus spragueana Mildbr. & Burret enriched with phenolics exhibited a pronounced hepatoprotective activity and may provide a new therapeutic approach for estrogen-induced cholestasis. PMID- 30458281 TI - Therapeutic potential of mistletoe in CNS-related neurological disorders and the chemical composition of Viscum species. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Viscum album L., commonly known as mistletoe, has been used for centuries in traditional medicine to treat various neurological diseases, including epilepsy, hysteria, nervousness, hysterical psychosis, dizziness and headaches. AIM OF THE STUDY: The aim of this review is to summarize existing evidence confirming the influence of mistletoe on the central nervous system and to investigate the compounds that may be responsible for this activity. MATERIALS AND METHODS: Available information from studies of various species of the Viscum L. genus was collected from scientific journals, books, and reports via a library and an electronic data search (Elsevier, Google Scholar, PubMed, Springer, Science Direct, ResearchGate, and ACS). RESULTS: The main chemical constituents of Viscum L. species are viscotoxins, lectins, flavonoids, phenolic acids, terpenoids, sterols, phenylpropanoids, and alkaloids. Various extracts of Viscum album L. showed central nervous system activity, including antiepileptic, sedative, antipsychotic, anxiolytic, antidepressant and antinociceptive effects in mice and rats. Additionally, the extracts increased the level of brain-derived neurotrophic factor, prevented apoptotic neuronal death induced by amyloid beta and weakly inhibited cholinesterase activity. CONCLUSIONS: Numerous historical references describe the use of mistletoe for the treatment of central nervous system disorders. In recent years, studies have started to confirm the antiepileptic, antipsychotic, sedative and antinociceptive effects of mistletoe. Additionally, mistletoe can be used as a complementary treatment for Alzheimer's disease. The therapeutic effect of mistletoe might be a result of the synergistic interactions of various secondary metabolites, including mistletoe-specific lectins. Further studies of the chemical composition and CNS activity of mistletoe are required. The mechanisms of action, target sites, pharmacokinetics, metabolic mechanisms, adverse effects and interactions of mistletoe with other drugs must also be investigated, as well. PMID- 30458282 TI - PACAP increases Arc/Arg 3.1 expression within the extended amygdala after fear conditioning in rats. AB - The stress-related neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is implicated in neuromodulation of learning and memory. PACAP can alter synaptic plasticity and has direct actions on neurons in the amygdala and hippocampus that could contribute to its acute and persistent effects on the consolidation and expression of conditioned fear. We recently demonstrated that intracerebroventricular (ICV) infusion of PACAP prior to fear conditioning (FC) results in initial amnestic-like effects followed by hyper expression of conditioned freezing with repeated testing, and analyses of immediate-early gene c-Fos expression suggested that the central nucleus of the amygdala (CeA), but not the lateral/basolateral amygdala (LA/BLA) or hippocampus, are involved in these PACAP effects. Here, we extend that work by examining the expression of the synaptic plasticity marker activity-regulated cytoskeleton associated protein (Arc/Arg 3.1) after PACAP administration and FC. Male Sprague Dawley rats were implanted with cannula for ICV infusion of PACAP-38 (1.5 ug) or vehicle followed by FC and tests for conditioned freezing. One hour after FC, Arc protein expression was significantly elevated in the CeA and bed nucleus of the stria terminalis (BNST), interconnected structures that are key elements of the extended amygdala, in rats that received the combination of PACAP + FC. In contrast, Arc expression within the subdivisions of the hippocampus, or the LA/BLA, were unchanged. A subpopulation of Arc-positive cells in both the CeA and BNST also express PKCdelta, an intracellular marker that has been used to identify microcircuits that gate conditioned fear in the CeA. Consistent with our previous findings, on the following day conditioned freezing behavior was reduced in rats that had been given the combination of PACAP + FC-an amnestic-like effect and Arc expression levels had returned to baseline. Given the established role of Arc in modifying synaptic plasticity and memory formation, our findings suggest that PACAP-induced overexpression of Arc following fear conditioning may disrupt neuroplastic changes within populations of CeA and BNST neurons normally responsible for encoding fear-related cues that, in this case, results in altered fear memory consolidation. Hence, PACAP systems may represent an axis on which stress and experience-driven neurotransmission converge to alter emotional memory, and mediate pathologies that are characteristic of psychiatric illnesses such as post-traumatic stress disorder. PMID- 30458283 TI - Hippocampal orexin receptor blocking prevented the stress induced social learning and memory deficits. AB - Stress as a homeostatic challenge leads to the malfunction of learning and memory processes, namely social learning and memory. The orexin system is involved in stress responses through connections to the hypothalamic-pituitary axis (HPA). In addition, the hippocampus, a structure vulnerable to stress-induced changes, expresses orexin receptors 1 and 2 (OXr1 and OXr2) in various sub-regions. The present study is aimed at assessing the effects of hippocampal orexin receptor blockade on social learning and memory impairments and anxiety development following stress. Male Wistar rats (220-250 g) underwent cannula implantation in the hippocampus. Acute (two mild electric shocks, 5.5 mA) and chronic stresses (ten days of restraint, 6 h daily) were applied with or without injection of orexin receptor antagonists (SB-334867 or TCS OX 29). Sociability and social novelty in animals were assessed in a three-chamber social maze at the end of stress application. Anxiety and exploratory behavior of animals were then examined, with 20 min intervals, using the open field (OF) and elevated plus maze (EPM) tests, respectively. Cisterna Magna cerebro-spinal fluid (CSF) was drained, before sacrifice, for orexin (OX) assay and trunk blood was collected to measure the plasma corticosterone (CRT). Neither the acute nor the chronic stress could affect the sociability. The acute but not chronic stress prevented the animal from sniffing the familiar caged rat in the novelty session, a response which was reversed following the blockade of both OXRs. Furthermore, acute but not chronic stress, led to increased anxiety and immobility behavior which were both impeded by blocking the orexin receptor (OXR). Conversely, OX content in CSF increased due to chronic restraint stress, an effect that was reversed by orexin blockade. Finally, elevated plasma CRT was recorded in response to both acute and chronic stresses. The observed increase in plasma CRT in chronically-stressed rats was abolished following inhibition of OXRs, however a similar effect was not seen in the acute-stress group. Our results identify hippocampal OXRs as potential candidates capable of preventing acute stress-induced impairments of social novelty and anxiety behavior, and chronic stress-induced plasma CRT and CSF orexin, changes. OXR manipulation may improve adaptation to stress pathophysiology. PMID- 30458284 TI - Chronic administration of gonadotropin releasing-hormone improves learning in old gonadectomized rats. AB - The aim of this study was to determine whether chronic administration of GnRH improves performance of learning tasks and expression of spinophilin in the hippocampus of gonadectomized old rats. Eighteen-month-old male Wistar rats were used and divided into three groups: control (intact rats); gonadectomized; and gonadectomized + GnRH. The latter group was injected intramuscularly with GnRH (100 nM) twice a day for five weeks. The learning tasks we used were the novel object recognition task (NOR), elevated T-maze (ETM) and active avoidance test (AAT). Results showed that in NOR and ETM learning tasks, gonadectomized rats treated with GnRH had a significantly better performance than gonadectomized rats without treatment. GnRH-treated gonadectomized rats displayed performance comparable to that of intact rats. Furthermore, the expression of spinophilin in the hippocampus of gonadectomized rats treated with GnRH increased with respect to untreated gonadectomized rats. In conclusion, the chronic administration of GnRH improves learning in old gonadectomized rats. It is possible that the mechanism could involve a greater number of dendritic contacts associated with a higher expression of spinophilin. PMID- 30458285 TI - Distinct subcellular changes in proteasome activity and linkage-specific protein polyubiquitination in the amygdala during the consolidation and reconsolidation of a fear memory. AB - Numerous studies have supported a critical role for the ubiquitin-proteasome system (UPS) in the memory consolidation and reconsolidation processes. The protein targets and functional role of ubiquitin-proteasome activity can vary widely across cellular compartments, however, it is unknown how UPS activity changes within the nuclear, cytoplasmic, and synaptic regions in response to learning or memory retrieval. Additionally, while previous studies have focused on degradation-specific protein polyubiquitination, it is unknown how learning alters other polyubiquitin tags that are not targeted by the proteasome. Using cellular fractionation protocols in combination with linkage-specific polyubiquitin antibodies, we examined subcellular changes in ubiquitin-proteasome activity in the amygdala during memory consolidation and reconsolidation. Following memory acquisition, overall protein ubiquitination and proteasome activity simultaneously increased in the nucleus and decreased in the synaptic and cytoplasmic regions. The nuclear increases were associated with upregulation of degradation-specific (K48) and degradation-independent (K63, M1) polyubiquitin tags, suggesting multiple functions for ubiquitin signaling within this region. Interestingly, retrieval induced a very different pattern of ubiquitin-proteasome activity in the amygdala, consisting of increases in overall protein ubiquitination and proteasome activity and K48-, K63-, and M1-polyubiquitin tags in the synaptic, but not nuclear or cytoplasmic regions. Collectively, learning and memory retrieval dynamically and differentially alter degradation-dependent and degradation-independent ubiquitin-proteasome activity across different cellular compartments, suggesting that the UPS may serve unique functions during memory consolidation and reconsolidation. PMID- 30458286 TI - LncRNAs expression in adriamycin-induced rats reveals the potential role of LncRNAs contributing to chronic glomerulonephritis pathogenesis. AB - BACKGROUND: Chronic glomerulonephritis (CGN) is the most common form of primary glomerular disease with unclear molecular mechanisms. Currently, limited study on long non-coding RNAs (lncRNAs) in CGN is available. Our study aimed to identify potential lncRNAs and genes in the normal and adriamycin-induced CGN rats, which to explore the potential molecular mechanisms of CGN pathogenesis. METHODS: To identify LncRNAs specifically expressed in CGN, the expression of LncRNAs in glomerular tissues of rats from the adriamycin-induced group (n = 3) was compared with that in the control group (n = 3) using RNA-sequencing and real-time polymerase chain reaction (RT-PCR). Identification of differentially expressed lncRNAs and mRNAs were performed between the 2 groups. Gene ontology (GO) and pathway enrichment analyses were performed to analyze the biological functions and pathways for the differentially expressed mRNAs. LncRNA-mRNA co-expression network was constructed to analyses for the genes. The protein-protein interaction (PPI) network was visualized. RESULTS: A total of 114 significantly up-regulated and 86 down-regulated lncRNAs, 1038 up-regulated and 88 down regulated mRNAs were identified. Additionally, Il6, with the highest connectivity degree in PPI network, was noteworthy enriched in various kinds pathways. Coding non-coding gene co-expression networks (CNC network) were drawn based on the correlation analysis between the differentially expressed LncRNAs and mRNAs. Ten LncRNAs, NONRATT000964.2, NONRATT018086.2, NONRATT023684.2, NONRATT009530.2, NONRATT006315.2, NONRATT026805.2, MSTRG.9260.1, NONRATT009155.2, MSTRG.7681.1, NONRATT009275.2, were selected to analyze the relationship between LncRNAs and CGN via the CNC network and GO analysis. Real-time PCR result confirmed that the six LncRNAs were specifically expressed in the CGN rats. CONCLUSIONS: The ten LncRNAs were differentially expressed and might play important roles in the development of CGN. Key genes, such as Il6, Ptprc, TOP2a, Fos, Myc, etc., may be crucial biomarkers for CGN. PMID- 30458287 TI - MiR-202-3p regulates interleukin-1beta-induced expression of matrix metalloproteinase 1 in human nucleus pulposus. AB - MicroRNAs (miRNAs), small noncoding RNA molecules, have emerged as important factors during intervertebral disc degeneration. This study was to determine whether miR-202-3p regulates interleukin-1beta (IL-1beta)-induced expression of matrix metalloproteinase 1 (MMP-1) in human nucleus pulposus (NP) cells. Human NP cells were stimulated with IL-1beta in vitro. MicroRNA arrays were used to determine the expression profile of 1971 human miRNAs and the miRNAs targets were identified using bioinformatics. In IL-1beta-stimulated NP cells, 10 microRNAs were down-regulated, 2 microRNAs were up-regulated. There was a significant reduction in hsa-miR-202-3p (miR-202-3p) expression in the severe degenerative disc compared with mild degenerative disc. Down-regulation of miR-202-3p expression by IL-1beta was correlated with up-regulation of MMP-1 expression in human NP cells. IL-1beta-induced activation of MAP kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) decreased miR-202-3p expression and induced MMP-1 expression. MiR-202-3p suppressed IL-1beta-induced MMP-1 production. Conversely, treatment with anti-miR-202-3p remarkably increased MMP-1 production. In addition, mutation of the miR-202-3p binding site in the 3'-UTR of MMP-1 mRNA abolished miR-202-3p-mediated repression of reporter activity. Functional analysis showed that miR-202-3p could decrease type II collagen degradation, whereas overexpression of MMP-1 by Lentiviral-shMMP-1 abolished the effect of miR 202-3p on type II collagen degradation. These results suggest that miR-202-3p is an important regulator of MMP-1 in human nucleus pulposus and may contribute to the development of intervertebral disc degeneration. PMID- 30458288 TI - A panel of seven-miRNA signature in plasma as potential biomarker for colorectal cancer diagnosis. AB - Colorectal cancer (CRC) has been one of the most commonly diagnosed cancers in global. The differential expression profiles of microRNAs (miRNAs) in CRC plasma of patients have the potential to serve as a diagnostic biomarker. We conducted a four-stage study to identify the potential plasma miRNAs for CRC detection. In the initial screening phase, Exiqon panel (miRCURY-Ready-to-Use-PCR-Human-panel-I + II-V1.M) including 3 CRC pools and 1 normal controls (NCs) pool were applied to acquire miRNA profiles. In the training stage (30 CRC VS. 30 NCs) and testing stage (79 CRC VS. 76 NCs), quantitative real-time polymerase chain reaction (qRT PCR) was utilized to conduct candidate miRNA profiles. Then the identified miRNAs were verified in external validation stage (30 CRC VS. 26 NCs). Expression levels of identified miRNAs were assessed in tissue samples (24 pairs) and plasma exosomes (18 CRC VS. 18 NCs). Receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic accuracy. Seven miRNAs (miR-103a-3p, miR 127-3p, miR-151a-5p, miR-17-5p, miR-181a-5p, miR-18a-5p and miR-18b-5p) were significantly overexpressed in CRC compared with NCs. Area under the ROC curve of the seven-miRNA signature was 0.762, 0.824 and 0.895 for the training, testing and the external validation stages, respectively. Additionally, miR-103a-3p, miR 127-3p, miR-17-5p and miR-18a-5p were discovered significantly up-regulated in CRC tissues; while miR-17-5p, miR-181a-5p, miR-18a-5p and miR-18b-5p were significantly elevated in CRC plasma exosomes. In conclusion, we established a seven-miRNA signature in the peripheral plasma for CRC detection. PMID- 30458290 TI - The effect of Colchicum pusillum in human colon cancer cells via Wnt/beta-catenin pathway. AB - OBJECTIVE: Colchicum pusillum belongs to the family Colchicaceae that particularly rich in tropolonic alkaloids. The aim of this study was to investigate the cytotoxicity and in vitro anticancer activity of Colchicum pusillum ethanolic extract on Colo-320 primer and Colo-741 metastatic colon adenocarcinoma cell lines. MATERIALS AND METHODS: Colchicum pusillum was collected and extracted with ethanol. Different concentrations of Colchicum pusillum extract were incubated for 24 h and 48 h with Colo-320 and Colo-741 cells. Cell growth and cytotoxicity were measured by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assays. Anticancer and antiproliferative activities of Colchicum pusillum were investigated by immunocytochemistry using antibodies directed against to beta-catenin, Ki-67, LGR-5 Ki-67, DKK1, Frizzled 4, Wnt4, Wnt7a and caspase3 in Colo-741 cells. RESULTS: All concentrations of Colchicum pusillum extract had toxic effect in Colo-320 cells. Because of this, we used Colchicum pusillum extract at 20 MUg/ml for evaluate anticancer activities only in Colo-741 cells. As a result of immunohistochemical staining, beta-catenin, LGR-5 and caspase-3 immunoreactivities were significantly increased while Wnt7a immunostaining intensity was decreased in Colo-741 cells. Conclusion We conclude that Colchicum pusillum extract increased beta-catenin and LGR-5 via Wnt/beta-catenin pathway in colon cancer cells. Interestingly, it decreased other signaling molecule, Wnt7a which is assumed to play protective role during carcinogenesis. Also, it increased significantly caspase-3 immunoreactivity showing that apoptotic pathways were triggered. PMID- 30458289 TI - Mutation analysis and pathogenicity identification of Mucopolysaccharidosis type IVA in 8 south China families. AB - BACKGROUND: Mucopolysaccharidosis type IVA (MPS IVA) is a rare autosomal recessive lysosomal storage disorder caused by GALNS gene mutation. The aim of our study is to detect pathogenic variants for patients suspected of MPS IVA and set the base for subsequent prenatal diagnosis and preimplantation genetic diagnosis. METHODS: In our study, 9 MPS IVA patients from south China families were investigated. Urine glycosaminoglycans (GAGS) screening was used as an initial method. For patients with abnormal result, all 14 exons and intron-exon junctions of the GALNS gene were sequenced after amplification from genomic DNA. The pathogenicity of novel mutations were analyzed with molecular genetics, bioinformatics and structure modeling in light of clinical manifestations and biochemical results. RESULTS: Among 12 mutations detected, direct sequencing found 3 novel mutations (c.686A>C, p.Y229S; c.1498G>T, p.G500C; c.278T>C, p.I93T). The pathogenicity of these novel mutations was illustrated by correlating clinical symptoms with pedigree analysis and bioinformatics analysis. CONCLUSION: The detection and variant analysis are essential for accurate diagnosis of MPS IVA patients. Our results enrich GALNS gene mutation spectrum of Chinese population. This information has important clinical value for molecular diagnosis and genetic counseling of patients with this disease. PMID- 30458291 TI - The Kdm/Kmt gene families in the self-fertilizing mangrove rivulus fish, Kryptolebias marmoratus, suggest involvement of histone methylation machinery in development and reproduction. AB - Histone modifications such as methylation of key lysine residues play an important role in embryonic development in a variety of organisms such as of Pacific oysters, zebrafish and mice. The action of demethylase ("erasers") and methyltransferase ("writers") enzymes regulates precisely the methylation status of each lysine residue. However, despite fishes being very useful model organisms in medicine, evolution and ecotoxicology, most studies have focused on mammalian and plant model organisms, and mechanisms underlying regulation of histones are unknown in fish development outside of zebrafish. Here, putative histone lysine demethylases (Kdm) and methyltransferases (Kmt) were identified in an isogenic lineage of the self-fertilizing hermaphroditic vertebrate, the mangrove rivulus fish, Kryptolebias marmoratus. Evolutionary relationships with other animal demethylases and methyltransferases were examined, and expression patterns during embryonic development and in adult tissues were characterized. Twenty-five Kdm orthologues (Jarid2, Jmjd1c, Jmjd4, Jmjd6, Jmjd7, Jmjd8, Kdm1a, Kdm1b, Kdm2a, Kdm2b, Kdm3b, Kdm4a, Kdm4b, Kdm4c, Kdm5a, Kdm5b, Kdm5c, Kdm6a, Kdm6b, Kdm7a, Kdm8, Kdm9, UTY, Phf2 and Phf8) and forty-eight Kmt orthologues (Ezh1, Ezh2, Setd2, Nsd1, Nsd2, Nsd3, Ash1l, Kmt2e, Setd5, Prdm1, Prdm2, Prdm4, Prdm5, Prdm6, Prdm8, Prdm9, Prdm10, Prdm11, Prdm12, Prdm13, Prdm14, Prdm15, Prdm16, Setd3, Setd4, Setd6, Setd1a, Setd1b, Kmt2a, Kmt2b, Kmt2c, Kmt2d, Kmt5a, Kmt5b, Ehmt1, Ehmt2, Suv39h1, Setmar, Setdb1, Setdb2, Smyd1, Smyd2, Smyd3, Smyd4, Smyd5, Setd7, Setd9, Dot1l) were discovered. Expression patterns of both Kdm and Kmt were variable during embryonic development with a peak in gastrula stage and a reduction in later embryogenesis. Expression of both Kdm and Kmt was higher in male brains compared to hermaphrodite brains whereas specific expression patterns of Kdm and Kmt were observed in the hermaphrodite ovotestes and male testes, respectively. Putative histone demethylases (Kdm) and methyltransferases (Kmt) were for the first time characterized in a teleost besides zebrafish, the mangrove rivulus. Their domain conservation and expression profiles suggest that they might play important roles during development, gametogenesis and neurogenesis, which raises questions about epigenetic regulation of these processes by histone lysine methylation in K. marmoratus. Due to its peculiar mode of reproduction and the natural occurrence of isogenic lineages, this new model species is of great interest for understanding epigenetic contributions to the regulation of development and reproduction. PMID- 30458292 TI - Morphological and genetic characterization of Syphabulea tjanschani () (Nematoda: Oxyuridae), with phylogenetic position of Syphabulea in Oxyuridae. AB - Pinworms are important parasitic nematodes in animals and humans, and many species are of medical and veterinary importance. The genus Syphabulea is a poorly known group of pinworms. The systematic position of Syphabulea in Oxyuridae remains unclear. Moreover, there is still a paucity of detailed information on some morphological aspects of the type species S. tjanschani (Ablasov, 1962). In the present study, the detailed morphology of S. tjanschani was studied using light microscopy and, for the first time, scanning electron microscopy. The results revealed three traits useful for the characterization of the species including: cuticular depression around excretory pore, non-prominent labial teeth and number of adhesive ridges in three ventral mammelons. The ribosomal [small ribosomal DNA (18S), internal transcribed spacer (ITS) and large ribosomal DNA (28S)] and mitochondrial [cytochrome c oxidase subunit 1 (cox1)] target regions of S. tjanschani were also firstly amplified and sequenced for future use in the molecular identification of this poorly known species. In addition, in order to investigate the systematic position of Syphabulea in Oxyuridae, the phylogenetic analyses of representatives of the Oxyuridae were performed using maximum likelihood (ML) and maximum parsimony (MP) methods based on 18S, 28S and 18S + 28S + cox1 sequence data, respectively. The phylogenetic results based on different sequence data all supported the genus Syphabulea to be a member of the subfamily Syphaciinae. The phylogenetic analysis based on 28S sequence data also showed Syphabulea as sister to the genus Syphatineria. Our present study represents the first attempt to resolve the systematic position of the genus Syphabulea using phylogenetic analyses based on molecular data. PMID- 30458293 TI - Phylogenetic analysis of Alphapapillomavirus based on L1, E6 and E7 regions suggests that carcinogenicity and tissue tropism have appeared multiple times during viral evolution. AB - Members of the Alphapapillomavirus genus are causative agents for cervix cancer and benign lesions in humans. These viruses are classified according to sequence similarities in their L1 region. Yet, viral carcinogenicity has been associated with variations in the proteins encoded by the E6 and E7 genes. In order to relate evolutionary history with origin of carcinogenicity, we performed phylogenetic reconstructions using both nucleotide and predicted amino acid sequences of the L1, E6 and E7 genes. Whilst phylogenetic analysis of L1 reconstructed genus evolutionary history, phylogenies based on E6 and E7 proteins support the idea that mutations at amino acids S/Tx [V/L] (E6) and LxCxE (E7) might be responsible for carcinogenic potential. These findings indicate that virulence within Alphapapillomavirus have appeared multiple times during evolution. Our results reveal that oncogenic potential is not a monophyletic clade-specific adaptation but might be the result of positive selection on random mutations occurring on proteins involved in host infection during viral diversification. PMID- 30458294 TI - Anti-perlecan antibodies and acute humoral rejection in hypersensitized patients without forbidden HLA specificities after kidney transplantation. AB - BACKGROUND: The improvement in the definition of serum anti-HLA antibodies (HLA Abs) profiles after Luminex-assay implementation in transplant patients follow-up is clear. This success has permitted the development of hypersensitized-recipient allocation and donor-paired exchange programs improving the access to transplantation. However, non-HLA Abs have been described in transplanted patients but their effect in hypersensitized transplanted recipients is unclear. METHODS: Twenty-seven HLA hypersensitized patients awaiting for kidney transplantation (KT) were studied and 11 of them were followed after KT. The HLA Abs profile was confirmed in serum by Single Antigen Luminex assay and panel reactive of antigens >98% was achieved in all patients. Subsequently, the ability to fix complement by C1q test was also assessed. Serum non-HLA Abs before and 1 month after transplantation were measured in the 11 hypersensitized recipients. RESULTS: 95.2% of the hypersensitized on waiting list had concomitant serum anti HLA and non-HLA Abs. The more frequent specificity in non-HLA Abs were found against Glutathione S-transferase theta-1 (GSST-1) (in 62%) and C-terminal fragment of perlecan (LG3) (in 52%). Four out of 11 transplanted patients presented early antibody-mediated rejection (ABMR) confirmed by biopsy and had serum anti-LG3 antibodies, two of them with concomitant anti-anti-angiotensin II type I receptor. Only one patient developed de novo-donor specific HLA antibodies. CONCLUSIONS: The incidence of non-HLA antibodies in patients in the waiting list is largely underestimated. The concomitance anti-HLA and non-HLA Abs in hypersensitized patients is very common and the detection of non-HLA Abs in this population could allow to identify patients with an increased risk of humoral rejection. PMID- 30458295 TI - Regulatory effects of dermal papillary pluripotent stem cells on polarization of macrophages from M1 to M2 phenotype in vitro. AB - The M1:M2 macrophage ratio is important for spinal cord injury (SCI) repair. Bone marrow mesenchymal stem cells (BMSCs) can alter macrophage activation, promoting M1 to M2 macrophage conversion and SCI repair; however, clinical BMSC applications have limitations. Previously, we found DPCs to be superior to BMSCs in promoting tissue repair after SCI, which we hypothesized to be mediated by M1 to M2 macrophage conversion. We investigated the regulatory effect of DPCs on M1/M2 macrophage polarization. Dermal papilla cells (DPCs) were isolated from rat vibrissae and characterized. Bone marrow-derived macrophages (BMDMs) were isolated and identified based on specific marker expression, and stimulated to differentiate into M1 macrophages with GM-CSF, IFN-gamma, and LPS. These cells were co-cultured with DPCs to evaluate the effect on macrophage differentiation. DPCs expressed dermal papillae-specific markers, including ALP and Sox2, had MSC expression patterns like those of BMSCs, and were capable of multi differentiation. BMDMs expressed ANAE and CD68. Three days after induction, differentiated cells exhibited morphology typical of M1-like macrophages and expressed the macrophage marker CD68 and the M1 macrophage markers iNOS, but lacked expression of the M2 macrophage marker CD206. Co-culture with DPCs resulted in a shift to anti-inflammatory M2-like macrophage differentiation, characterized by morphological changes typical of M2 macrophages, downregulation of the characteristic cytokine TNF-alpha and the proportion of iNOS+ cells, and upregulation of the characteristic cytokine IL-10 and the cell-surface marker CD206. The number of CD206-expressing M2 macrophages also increased. These findings demonstrate that DPCs reprogram macrophages to an anti-inflammatory M2 phenotype, which could improve adverse inflammatory microenvironments and promote tissue repair. Thus, DPCs may be an interesting alternative cell source and merit further investigation in applications for SCI therapy. PMID- 30458296 TI - Activation of the language control network in bilingual visual word recognition. AB - Research into bilingual language production has identified a language control network that subserves control operations when bilinguals produce speech. Here we explore which brain areas are recruited for control purposes in bilingual language comprehension. In two experimental fMRI sessions, Dutch-English unbalanced bilinguals read words that differed in cross-linguistic form and meaning overlap across their two languages. The need for control operations was further manipulated by varying stimulus list composition across the two experimental sessions. We observed activation of the language control network in bilingual language comprehension as a function of both cross-linguistic form and meaning overlap and stimulus list composition. These findings suggest that the language control network is shared across bilingual language production and comprehension. We argue that activation of the language control network in language comprehension allows bilinguals to quickly and efficiently grasp the context-relevant meaning of words. PMID- 30458297 TI - Molecular detection of Anaplasma ovis in small ruminants and ixodid ticks from Mongolia. AB - Anaplasma ovis is a tick-borne obligate intracellular rickettsial bacterium that causes anaplasmosis in domestic and wild small ruminants. Sheep and goats, whose combined population is approximately 48.5-million in Mongolia, play a vital role in the country's economy. In this study, we conducted an epidemiological survey of A. ovis in sheep and goats from 19 of 21 provinces in Mongolia. Additionally, DNA samples extracted from unfed ticks collected in 11 Mongolian provinces were also screened for A. ovis. Of 1179 and 871 blood DNA samples from sheep and goats, 813 (69.0%) and 621 (71.3%), respectively, were positive for A. ovis when screened by a PCR assay based on major surface protein 4 gene (msp4). On a per province basis, A. ovis infection rates ranged from 7.4%-93.3% and 13.3%-100% in sheep and goats, respectively. Subsequently, DNA samples prepared from 721 unfed ticks, including Dermacentor nuttalli (n = 378), Ixodes persulcatus (n = 95), Haemaphysalis pospelovashtromae (n = 120), and Hyalomma asiaticum (n = 128), were screened for A. ovis using the same PCR assay. Although nine D. nuttalli were A. ovis-positive, all other tick DNA samples were negative. In addition to reporting A. ovis in sheep and goats from all over Mongolia, this study identified D. nuttalli as a potential transmission vector of A. ovis in Mongolia. The present data highlight the importance of monitoring Mongolian sheep and goats for possible episodes of clinical anaplasmosis and controlling D. nuttalli throughout the country. PMID- 30458298 TI - Frequency and Antimicrobial Susceptibility of Bacterial Isolates from Patients Hospitalised with Community-Acquired Skin and Skin Structure Infection in Europe, Asia, and Latin America. AB - BACKGROUND: Ceftaroline fosamil is approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI), including those caused by methicillin-resistant Staphylococcus aureus (MRSA). We evaluated the frequency and antimicrobial susceptibility of organisms isolated from patients hospitalised with community-acquired (CA) SSSI in Europe (EUR), the Asia-Pacific region (APAC), and Latin America (LATAM). METHODS: Isolates (n=5,120) were consecutively collected from patients hospitalised with CA-SSSI in 2014-2016 from 63 medical centres in 41 nations, stratified as: western EUR (W-EUR; 20 centres/10 nations), eastern EUR and the Mediterranean region (E-EUR; 16 centres/12 nations), APAC (16 centres/10 nations), and LATAM (11 centres/9 nations). Isolates obtained from outpatients or <48hours after hospitalisation were considered CA. Organisms were tested for susceptibility by reference broth microdilution methods in a central laboratory. RESULTS: S. aureus was the most common CA-SSSI organism in all regions, except LATAM, and represented 43.3% of the overall collection. MRSA rates varied from 15.8% (E-EUR) to 21.4% (APAC); 18.5% overall. In general, 98.9% of S. aureus and 94.2% of MRSA isolates were susceptible to ceftaroline, with 99.5% of MRSA isolates inhibited at <=2mg/L (0.5% resistant). Escherichia coli (14.2%) and beta-haemolytic streptococci (BHS; 8.2%), ranked second and third overall, respectively, with wide regional variation. BHS isolates were highly susceptible to ceftaroline (highest MIC, 0.03mg/L), but exhibited decreased susceptibility to tetracycline and erythromycin. CONCLUSIONS: The frequency and antimicrobial susceptibility of CA-SSSI bacteria varied broadly by geographic region. Ceftaroline exhibited potent activity against S. aureus (including MRSA), BHS, and ceftriaxone-susceptible Enterobacterales isolates. PMID- 30458299 TI - The emergence of psychotic experiences in the early adolescence of 22q11.2 Deletion Syndrome. AB - Individuals with 22q11.2 Deletion Syndrome (22q11.2DS) are at substantial increased risk of psychosis spectrum outcomes including schizophrenia. We conducted a prospective, longitudinal study of the psychopathological and neurocognitive correlates of early psychotic phenomena in young people with 22q11.2DS (n = 75, mean age time 1 (T1) 9.9 years, time 2 (T2) 12.5 years). We also assessed unaffected control siblings (n = 33, mean age T1 10.6 years, T2 13.4 years). The prevalence of psychotic experiences, defined as subthreshold psychotic phenomena, substantially increased in children with 22q11.2DS from 4% (n = 3) in childhood (T1) to 21% (n = 16) in early adolescence (T2) (p = 0.001), and at T2 prevalence was significantly elevated (p = 0.020) relative to control siblings (3%). The emergence of psychotic experiences was associated with levels of childhood anxiety symptoms at T1 and differential development of the attention executive domain. IQ ability and IQ change, however, were not associated with the emergence of psychotic experiences, indicating that initial changes in attention executive functioning may precede the decline in global cognition that has been reported to be associated with later stages of psychosis development. Our study highlights that psychotic phenomena emerge early in 22q11.2DS and we implicate attention-executive functioning and anxiety as key domains associated with the development of these psychotic experiences. PMID- 30458300 TI - Palaeopermeability anisotropy and geometrical properties of sealed-microfractures from micro-CT analyses: An open-source implementation. AB - Fault zone permeability and the real 3D-spatial distribution of the fault-related fracture networks are critical in the assessment of fault zones behavior for fluids. The study of the real 3D-spatial distribution of the microfracture network, using X-ray micro-computed tomography, is a crucial factor to unravel the real structural permeability conditions of a fault-zone. Despite the availability of several commercial software for rock properties estimation from X ray micro-computed tomography scanning, their high cost and lack of programmability encourage the use of open-source data treatment. This work presents the implementation of a methodology flow for the quantification of both structural and geometrical parameters (fractures density, fractures aperture, fractures porosity, and fractures surface area), and the modeling of palaeopermeability of fault-related fractured samples, with focus in the proper spatial orientation of both the sample and the results. This is performed with an easy to follow step-by-step implementation, by a combination of open-source software, newly implemented codes, and numerical methods. This approach keeps track of the sample's spatial orientation from the physical to the virtual world, thus assessing any fault-related palaeopermeability anisotropy. PMID- 30458301 TI - Performance of gender- and age-specific cut-points versus NCEP pediatric cutpoints in dyslipidemia screening among Chinese children. AB - BACKGROUND AND AIMS: Considerable attention is given nowadays to the presence of cardiovascular diseases risk factors in children. The current blood lipid classification system for Chinese children was based on the United States National Cholesterol Education Program (NCEP) cutpoints, which did not take the age, gender and race differences into consideration. This study aimed to develop gender- and age-specific lipid cutpoints for dyslipidemia screening in Chinese children and compare the ability of new cutpoints and NCEP pediatric cutpoints to predict obesity and unfavorable blood pressure (BP) levels. METHODS: Data were obtained from a nationwide multicenter cross-sectional study: The China Child and Adolescent Cardiovascular Health Study, comprising 12,875 Chinese children aged 6 18 years. We calculated cutpoints for abnormal levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) that were linked to Chinese adult abnormal lipid thresholds using the General Additive Model for Location Scale and Shape method. RESULTS: Borderline-high and high cutpoints (TC, LDL-C and TG) as well as low cutpoints (HDL-C) were developed to classify the abnormal blood lipid levels in Chinese children. Better performance for prediction of obesity, elevated BP, and hypertension were found with the proposed cutpoints in comparison with the NCEP pediatric cutpoints (AUC for obesity: 0.612 vs. 0.597, p = 0.017; AUC for elevated BP: 0.529 vs. 0.521, p = 0.017; AUC for hypertension: 0.536 vs. 0.527, p = 0.016). CONCLUSIONS: The gender- and age-specific cutpoints should improve the accuracy of dyslipidemia screening in China and be more reasonable in practice. PMID- 30458302 TI - Inhibition of endoplasmic reticulum stress protected DOCA-salt hypertension induced vascular dysfunction. AB - Hypertension has complex vascular pathogenesis and therefore the molecular etiology remains poorly elucidated. Endoplasmic reticulum stress (ERS), which is a condition of the unfolded/misfolded protein accumulation in the endoplasmic reticulum, has been defined as a potential target for cardiovascular disease. In the present study, the effects of ERS inhibition on hypertension-induced alterations in the vessels were investigated. In male Wistar albino rats, hypertension was induced through unilateral nephrectomy, deoxycorticosterone acetate (DOCA) injection (20 mg/kg, twice a week) and 1% NaCl with 0.2% KCI added to drinking water for 12 weeks. An ERS inhibitor, tauroursodeoxycolic acid (TUDCA) (150 mg/kg/day, i.p.), was administered for the final four weeks. ERS inhibition in DOCA-salt induced hypertension was observed to have reduced systolic blood pressure, improved endothelial dysfunction, enhanced plasma nitric oxide (NO) level, reduced protein expressions of phosphorylated-double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (pPERK), 78 kDa glucose-regulated protein (GRP78), Inositol trisphosphate receptor1 (IP3R1) and Epidermal growth factor receptor (EGFR), increased expressions of endoplasmic reticulum Ca2+-ATPase2 (SERCA2) and B cell lymphoma2 (Bcl2) in vessels. These findings suggest that the beneficial effects of ERS inhibition on hypertension may be related to protection of vessel functions through restoration of endoplasmic reticulum calcium homeostasis, and apoptotic and mitotic pathways. PMID- 30458303 TI - Implicit visual cues tune oscillatory motor activity during decision-making. AB - Motor decisions entails a buildup of choice-selective activity in the motor cortex. The rate of this buildup crucially depends on the amount of evidence favoring the selection of each action choice in the visual environment. Though numerous studies have characterized how sensory evidence drives motor activity when processed consciously, very little is known about the neural mechanisms that underlie the integration of implicit sources of information. Here, we used electroencephalography to investigate the impact of implicit visual cues on response-locked potentials and oscillatory activity in the motor cortex during decision-making. Subjects were required to select between left and right index finger responses according to the motion direction of a cloud of dots presented in one of three possible colors. Unbeknown to the participants, the color cue could bring evidence either in favor of or against the selection of the correct response. Implicit color cues tuned choice-selective oscillatory activity in the low beta range (16-25 Hz), boosting the buildup of contralateral activity when evidence favored the selection of the correct action, while weakening it when evidence biased against the correct response. This modulation of oscillatory activity influenced the speed at which the correct action was eventually chosen. Implicit cues also altered oscillatory activity in a non-selective way in the low frequency oscillation (1-7 Hz) and high beta ranges (25-35 Hz), impacting both contralateral and ipsilateral activity. The current findings yield a critical extension of prior observations by indicating that the integration of both explicit and implicit sources of evidence tunes oscillatory motor activity during decision-making. PMID- 30458304 TI - Brain reading and behavioral methods provide complementary perspectives on the representation of concepts. AB - The advent of brain reading techniques has enabled new approaches to the study of concept representation, based on the analysis of multivoxel activation patterns evoked by the contemplation of individual concepts such as animal concepts. The present fMRI study characterized the representation of 30 animal concepts. Dimensionality reduction of the multivoxel activation patterns underlying the individual animal concepts indicated that the semantic building blocks of the brain's representations of the animals corresponded to intrinsic animal properties (e.g. fierceness, intelligence, size). These findings were compared to behavioral studies of concept representation, which have typically collected pairwise similarity ratings between two concepts (e.g. Henley, 1969). Behavioral similarity judgments, by contrast, indicated that the animals were organized into taxonomically defined groups (e.g. canine, feline, equine). The difference in the results between the brain reading and behavioral approaches might derive from differences in cognitive processing during judging similarities versus contemplating one animal at a time. Brain reading approaches may have an advantage in describing thoughts about an individual concept, owing to the ability to decode brain activation patterns elicited by the brief consideration of a single concept (e.g. word reading) without a complex cognitive or behavioral task (e.g. similarity judgments). On the other hand, some behavioral tasks may tend to evoke a concept from numerous perspectives, yielding a representation of the breadth and sophistication of the concept knowledge. These results suggest that neural and behavioral measures offer complementary perspectives that together characterize the content and structure of concept representations. PMID- 30458305 TI - Nonlinear Distributional Mapping (NoDiM) for harmonization across amyloid-PET radiotracers. AB - INTRODUCTION: There is a growing need in clinical research domains for direct comparability between amyloid-beta (Abeta) Positron Emission Tomography (PET) measures obtained via different radiotracers and processing methodologies. Previous efforts to provide a common measurement scale fail to account for non linearities between measurement scales that can arise from these differences. We introduce a new application of distribution mapping, based on well established statistical orthodoxy, that we call Nonlinear Distribution Mapping (NoDiM). NoDiM uses cumulative distribution functions to derive mappings between Abeta-PET measurements from different tracers and processing streams that align data based on their location in their respective distributions. METHODS: Utilizing large datasets of Florbetapir (FBP) from the Alzheimer's Disease Neuroimaging Initiative (n = 349 female (%) = 53) and Pittsburgh Compound B (PiB) from the Harvard Aging Brain Study (n = 305 female (%) = 59.3) and the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (n = 184 female (%) = 53.3), we fit explicit mathematical models of a mixture of two normal distributions, with parameter estimates from Gaussian Mixture Models, to each tracer's empirical data. We demonstrate the accuracy of these fits, and then show the ability of NoDiM to transform FBP measurements into PiB-like units. RESULTS: A mixture of two normal distributions fit both the FBP and PiB empirical data and provides a strong basis for derivation of a transfer function. Transforming Abeta-PET data with NoDiM results in FBP and PiB distributions that are closely aligned throughout their entire range, while a linear transformation does not. Additionally the NoDiM transform better matches true positive and false positive profiles across tracers. DISCUSSION: The NoDiM transformation provides a useful alternative to the linear mapping advocated in the Centiloid project, and provides improved correspondence between measurements from different tracers across the range of observed values. This improved alignment enables disparate measures to be merged on to continuous scale, and better enables the use of uniform thresholds across tracers. PMID- 30458306 TI - Pharmacological stress impairs working memory performance and attenuates dorsolateral prefrontal cortex glutamate modulation. AB - Working memory processes are associated with the dorsolateral prefrontal cortex (dlPFC). Prior research using proton functional magnetic resonance spectroscopy (1H fMRS) observed significant dlPFC glutamate modulation during letter 2-back performance, indicative of working memory-driven increase in excitatory neural activity. Acute stress has been shown to impair working memory performance. Herein, we quantified dlPFC glutamate modulation during working memory under placebo (oral lactose) and acute stress conditions (oral yohimbine 54 mg + hydrocortisone 10 mg). Using a double-blind, randomized crossover design, participants (N = 19) completed a letter 2-back task during left dlPFC 1H fMRS acquisition (Brodmann areas 45/46; 4.5 cm3). An automated fitting procedure integrated with LCModel was used to quantify glutamate levels. Working memory induced glutamate modulation was calculated as percentage change in glutamate levels from passive visual fixation to 2-back levels. Results indicated acute stress significantly attenuated working memory-induced glutamate modulation and impaired 2-back response accuracy, relative to placebo levels. Follow-up analyses indicated 2-back performance significantly modulated glutamate levels relative to passive visual fixation during placebo but not acute stress. Biomarkers, including blood pressure and saliva cortisol, confirmed that yohimbine + hydrocortisone dosing elicited a significant physiological stress response. These findings support a priori hypotheses and demonstrate that acute stress impairs dlPFC function and excitatory activity. This study highlights a neurobiological mechanism through which acute stress may contribute to psychiatric dysfunction and derail treatment progress. Future research is needed to isolate noradrenaline vs. cortisol effects and evaluate anti-stress medications and/or behavioral interventions. PMID- 30458307 TI - Towards a better understanding of allograft-induced stress response in the pearl oyster Pinctada fucata martensii: Insights from iTRAQ-based comparative proteomic analysis. AB - Implantation of a spherical nucleus into a recipient oyster is a critical step in artificial pearl production. The implanted nucleus is known to trigger cellular stress responses at several levels, yet the molecular mechanism underpinning physiological adaptation of the pearl oysters to nucleus implantation is still poorly understood. In this study, we took advantage of the iTRAQ-based proteomics and LC-MS/MS approach to look into allograft induced gene regulation at the protein expression level in the pearl oyster Pinctada fucata martensii, across a period of 30 days following nucleus implantation. A wide variety of proteins, including a group of immune-related proteins such as E3 ubiquitin-ligase and heat shock proteins, exhibited differential expression in response to the surgical operation. Further comparisons between different sampling points revealed that GO terms including "translation" and "oxidation-reduction process" and KEGG pathways including "glycolysis/gluconeogenesis" and "pyruvate metabolism" were significantly enriched at several time points, indicating the important roles of these molecular events in the stress response of pearl oysters to nucleus implantation. In addition, considerable discrepancy between protein expression level and gene transcript abundancy was identified, as only a few genes showed at least 2-fold expression changes at both proteomic and transcriptomic levels. The result implies that post-transcriptional gene regulation for the key proteins may represent an important aspect of allograft-induced stress response in the pearl oysters. Taken together, the data obtained would contribute to a deeper understanding of the molecular mechanisms enabling stress adaptation of the pearl oysters in response to nucleus implantation. PMID- 30458308 TI - Transcriptome-wide analysis of wild Asari (=Manila) clams affected by the Brown Muscle Disease: Etiology and impacts of the disease. AB - Recently, we reported an emerging pathology named Brown Muscle Disease (BMD) affecting Asari clams inhabiting the most productive area for this species in France, the Arcachon Bay. The main macroscopic feature of the pathology relies on the atrophy of the posterior adductor muscle, affecting the ability of clams to burry. The research of the etiological agent of BMD privileged a viral infection. Contrary to healthy clams, infected animals are always found at the surface of the sediment and exhibit 30 nm virus-like particles in muscle, granulocytic and rectal cells. In order to get more insights on the etiology and impacts of the BMD on clams, we took advantage in the present study of next generation sequencing technologies. An RNA-Seq approach was used (i) to test whether viral RNA sequences can be specifically found in the transcriptome of diseased animals and (ii) to identify the genes that are differentially regulated between diseased and healthy clams. Contrary to healthy buried animals, in diseased clams one sequence showing extensive homologies with retroviridae-related genes was detected. Among the biological processes that were affected in diseased clams, the synaptic transmission process was the most represented. To deepen this result, a new sampling was carried out and the transcription level of genes involved in synaptic transmission was determined in healthy and diseased clams but also in clams with no visible sign of pathology but located at the surface of the sediment. Our findings suggest that muscle atrophy is a latter sign of the pathology and that nervous system could be instead a primary target of the BMD agent. PMID- 30458309 TI - In vitro gill cell monolayer successfully reproduces in vivo Atlantic salmon host responses to Neoparamoeba perurans infection. AB - An in vitro model to study the host response to Neoparamoeba perurans, the causative agent of amoebic gill disease (AGD), was evaluated. The rainbow trout gill derived cell line, RTgill-W1, was seeded onto permeable cell culture supports and maintained asymmetrically with apical seawater. Cells were inoculated with either a passage attenuated or a recent wild clone of N. perurans. Amoebae, loaded with phagocytosed fluorescent beads, were observed associated with host cells within 20 min post inoculation (pi). By 6 h small foci of cytopathic effect appeared and at 72 h cytolysis was observed, with total disruption of the cell monolayer at 96 h pi. Due to cell monolayer disruption, the platform could not support proliferation of amoebae, which showed a 3-log reduction in parasite 18S rRNA mRNA after 72 h (106 copies at 1 h to 103 at 72 h pi). SEM observations showed amoebae-like cells with either short pseudopodia and a malleiform shape, or, long pseudopodia embedded within the gill cells and erosion of the cell monolayer. To study the host immune response, inoculated gill cells were harvested from triplicate inserts at 0, 1, 3, 6, 24 and 48 h pi, and expression of 12 genes involved in the Atlantic salmon response to AGD was compared between infected and uninfected cells and between amoebic clones. Both clones induced similar host inmate immune responses, with the up-regulation of proinflammatory cytokine IL1beta, complement C3 and cell receptor MHC-1. The Th2 pathway was up-regulated, with increased gene expression of the transcription factor GATA3, and Th2 cytokines IL10, IL6 and IL4/13A. PCNA and AG-2 were also up regulated. The wild clone induced significantly higher up-regulation of IL1beta, MHC-1, PCNA, lysozyme and IL10 than the attenuated clone for at least some exposure times, but AG-2 gene expression was higher in cells inoculated with the attenuated one. A principal component analysis showed that AG-2 and IL10 were key genes in the in vitro host response to N. perurans. This in vitro model has proved to be a promising tool to study host responses to amoebae and may therefore reduce the requirement for in vivo studies when evaluating alternative therapeutants to AGD control. PMID- 30458310 TI - Involvement of JNK signaling pathway in lipopolysaccharide-induced complement C3 transcriptional activation from amphioxus Branchiostoma belcheri. AB - Complement C3 is a pivotal component of three cascades of complement activation. C3 in circulation is mainly provided by the hepatic cecum. The expression and secretion of C3 by hepatocytes is increased during acute inflammation. The detailed information on the regulationary mechanism underlying C3 transcriptional activation is limited. Here, we characterized the 5'-flanking region of the amphioxus C3 gene. To functionally analyze the upstream regulatory region of the C3 gene, a series of luciferase reporter gene constructs containing deleted or mutant regulatory elements were prepared. Using luciferase assay, we revealed that a potential C-JUN-1 binding sites within the proximal promoter region were necessary for full activation of the C3 promoter, whereas NF-kappaB, AP-1, C-JUN 2 and NFAT transcription factor binding sites played roles in governing the promoter activity at a homeostatic level. Our data also indicated that sp600125, a c-Jun N-terminal kinase (JNK) inhibitor, decreased lipopolysaccharide (LPS) stimulated C3 promoter activity, mRNA expression and protein secretion using western blotting and quantitative real-time PCR analysis. These findings demonstrated that JNK signaling pathway is involved in the regulation of C3 gene transcription by targeting C-JUN transcription factor binding sites in the 5' flanking promoter region, leading to LPS-induced C3 activation and therefore providing a potential target for regulating C3 expression. PMID- 30458311 TI - Gill symbionts of the cold-seep mussel Bathymodiolus platifrons: Composition, environmental dependency and immune control. AB - Deep-sea Bathymodiolus mussels depend on the organic carbon supplied by symbionts inside their gills. In this study, optimized methods of quantitative real-time PCR and fluorescence in situ hybridization targeted to both mRNA and 16S rRNA were used to investigate the gill symbionts of the cold-seep mussel Bathymodiolus platifrons, including species composition, environmental dependency and immune control by the host. Our results showed that methanotrophs were the major symbiotic bacteria in the gills of B. platifrons, while thiotrophs were scarce. In the mussels freshly collected from the deep sea, methanotrophs were housed in bacteriocytes in a unique circular pattern, and a lysosome-related gene (VAMP) encoding a vesicle-associated membrane protein was expressed at a high level and presented exactly where the methanotrophs occurred. After the mussels were reared for three months in aquaria without methane supply, the abundance of methanotrophs decreased significantly and their circle-shaped distribution pattern disappeared; in addition, the expression of VAMP decreased significantly. These results suggest that the symbiosis between B. platifrons and methanotrophs is influenced by the environment and that the lysosomal system plays an important immune role in controlling the abundance of endosymbionts in host. This study provides a reliable method for investigating symbionts in deep-sea mussels and enriches the knowledge about symbionts in B. platifrons. PMID- 30458312 TI - Molecular characterization of big-belly seahorse (Hippocamus abdominalis) arachidonate 5-lipoxygenase (HaALOX5): First evidence of an immune defensive role by induced immunological stress in teleost. AB - Arachidonate 5-lipoxygenase (ALOX5) is an essential enzyme for the biosynthesis of leukotrienes, which are pro-inflammatory and anti-inflammatory mediators. In this study, the ALOX5 paralog of the big-belly seahorse (Hippocampus abdominalis; HaALOX5) was identified from our transcriptome database, and then molecularly and functionally characterized to determine its oxygenation capability and expression under pathogenic stress. The coding sequence of HaALOX5 consisted of 2025 bp and encoded a protein of 674 amino acids in length. Sequence and phylogenetic tree analysis of HaALOX5 revealed a close relationship with its corresponding teleost HaALOX5 counterparts. Structure prediction detected an N-terminal regulatory C2 like domain and a C-terminal catalytic domain, which are the two main functional domains in ALOX5 enzymes. Quantitative PCR showed that HaALOX5 was expressed in all the analyzed tissues at different magnitudes. The highest expression was detected in the intestine and stomach. In blood cells, the liver and the intestine, HaALOX5 transcripts were significantly elevated at many post injection time points, when immune challenged with lipopolysaccharide, polyinosinic:polycytidylic acid, and Streptococcus iniae, indicating its contribution to post immune defense mechanisms in the seahorse. PMID- 30458313 TI - Adipogenic differentiation of murine bone marrow mesenchymal stem cells induced by visible light via photo- induced biomodulation. AB - BACKGROUND: Bone marrow mesenchymal stem cells (BM-MSCs) are undifferentiated cells that can proliferate and differentiate into specialized cells for tissue self-repair. Low-level laser (LLL) can induce biomodulatory effects such as cellular proliferation, differentiation, and migration. We investigated the biomodulatory effects of the photoactive compound chloroaluminum phthalocyanine nanoemulsion (AlClPc/NE) on the adipogenic differentiation of BM-MSCs, when combined with LLL (AlClPc/NE-LLL). METHODS: The BM-MSCs used in this work were isolated from green fluorescent protein-positive (GFP+) C57BL6 mice. Cells were first treated with AlClPc/NE, a well-designed photoactive nano-drug and were then subjected to in vitro expansion, morphological and immunophenotypic characterization, and cellular cytotoxicity analysis. Subsequently, BM-MSCs were induced to differentiate into adipocytes by photo-induced biomodulation with AlClPc/NE-LLL. RESULTS: Our results showed that the isolated cell population was consistent with murine BM-MSCs. The cellular cytotoxicity analysis revealed that the optimal nanoemulsion dose to induce BM-MSC biomodulation was 5.0 umol/L. Twenty-four hours following treatment with AlClPc/NE, BM-MSC were subjected to visible light irradiation of 20 mJ/cm2 at 670 nm. Six days after photo-induced biomodulation, cells maintained high GFP expression level, and expressed detectable mRNA levels of adipogenic genes (lipoprotein lipase and PPARgamma); formation of lipid vacuoles was observed, and the cells did not show any tumorigenic potential in vivo. CONCLUSIONS: Our results indicated that photo induced biomodulation via visible light using AlClPc/NE and LLL can induce adipogenic differentiation of murine BM-MSCs. Therefore, cell therapy with BM MSCs and photo-induced biomodulation may contribute to the development of new therapeutic strategies that are faster and more effective than traditional methods to trigger MSC differentiation. PMID- 30458314 TI - The Effect of Health Insurance on Prescription Drug Use Among Low-Income Adults:Evidence from Recent Medicaid Expansions. AB - This study examines how subsidized coverage affects prescription drug utilization among low-income non-elderly adults. Using the Affordable Care Act's Medicaid expansions as a source of variation and a national, all-payer pharmacy transactions database, we find that within the first 15 months of new health insurance availability, aggregate Medicaid-paid prescriptions increased 19 percent, amounting to nearly 9 new prescriptions a year, per new enrollee. We find no evidence of reductions in uninsured or privately-insured prescriptions, suggesting that new coverage did not simply substitute for other payment sources. The largest increases occurred for medications treating conditions such as diabetes and heart disease, suggesting greater price elasticity for chronic medications. Generics increased more than brand-name drugs; and utilization increased less in expansion states with higher Medicaid drug copayments. Overall, these findings suggest that prescription drug demand among low-income populations exhibits substantial price sensitivity, and insurance expansion can increase medication treatment for chronic conditions. PMID- 30458315 TI - The dynamic effect of context on interval timing in children and adults. AB - Human reproductions of time intervals are often biased toward previously perceived durations, resulting in a central tendency effect. The aim of the current study was to compare this effect of temporal context on time reproductions within children and adults. Children aged from 5 to 7 years, as well as adults, performed a ready-set-go reproduction task with a short and a long duration distribution. A central tendency effect was observed both in children and adults, with no age-difference in the effect of global context on temporal performance. However, the analysis of the effect of local context (trial by-trial) indicated that younger children relied more on the duration (objective duration) presented in the most recent trial than adults. In addition, statistical analyses of the influence on temporal performance of recently reproduced durations by subjects (subjective duration) revealed that temporal reproductions in adults were influenced by performance drifts, i.e., their evaluation of their temporal error, while children simply relied on the value of reproduced durations on the recent trials. We argue that the central tendency effect was larger in young children due to their noisier internal representation of durations: A noisy system led participants to base their estimation on experienced duration rather than on the evaluation of their judgment. PMID- 30458316 TI - Accelerating deep learning with memcomputing. AB - Restricted Boltzmann machines (RBMs) and their extensions, often called "deep belief networks", are powerful neural networks that have found applications in the fields of machine learning and artificial intelligence. The standard way to train these models resorts to an iterative unsupervised procedure based on Gibbs sampling, called "contrastive divergence", and additional supervised tuning via back-propagation. However, this procedure has been shown not to follow any gradient and can lead to suboptimal solutions. In this paper, we show an efficient alternative to contrastive divergence by means of simulations of digital memcomputing machines (DMMs) that compute the gradient of the log likelihood involved in unsupervised training. We test our approach on pattern recognition using a modified version of the MNIST data set of hand-written numbers. DMMs sample effectively the vast phase space defined by the probability distribution of RBMs, and provide a good approximation close to the optimum. This efficient search significantly reduces the number of generative pretraining iterations necessary to achieve a given level of accuracy in the MNIST data set, as well as a total performance gain over the traditional approaches. In fact, the acceleration of the pretraining achieved by simulating DMMs is comparable to, in number of iterations, the recently reported hardware application of the quantum annealing method on the same network and data set. Notably, however, DMMs perform far better than the reported quantum annealing results in terms of quality of the training. Finally, we also compare our method to recent advances in supervised training, like batch-normalization and rectifiers, that seem to reduce the advantage of pretraining. We find that the memcomputing method still maintains a quality advantage (>1% in accuracy, corresponding to a 20% reduction in error rate) over these approaches, despite the network pretrained with memcomputing defines a more non-convex landscape using sigmoidal activation functions without batch-normalization. Our approach is agnostic about the connectivity of the network. Therefore, it can be extended to train full Boltzmann machines, and even deep networks at once. PMID- 30458317 TI - Maternal stress, prenatal medical illnesses and obstetric complications: Risk factors for schizophrenia spectrum disorder, bipolar disorder and major depressive disorder. AB - Maternal stress and medical illnesses during early life are well-documented environmental indicators of an increased risk of schizophrenia. Few studies, conversely, have confirmed an association with major affective disorders. The present study examined the impact of maternal stress, medical illnesses and obstetric complications on the development of severe mental disorder in 240 patients with a diagnosis of schizophrenia spectrum disorder, bipolar disorder, or major depressive disorder and matched with 85 controls. Mothers of participants were asked about stressful events during pregnancy using the Social Readjustment Scale; information on prenatal/perinatal illnesses were acquired from medical records. Schizophrenia spectrum disorder was positively associated with maternal stress (OR = 2.16), infections (OR = 7.67), inadequate weight gain (OR = 9.52) during pregnancy, and peripartum asphyxia (OR = 4.00). An increased risk of bipolar disorder was associated with head circumference < 32 cm at birth (OR = 5.40) and inversely with inadequate weight gain (OR = 0.29). Major depressive disorder diagnosis was inversely related to inadequate weight gain (OR = 0.22). These results support a role for maternal stress, medical illnesses and obstetric complications as risk factors for subsequent severe mental illness in adulthood. Further research is needed, especially with regard to affective disorders. PMID- 30458318 TI - The Besancon affective picture set-adult (BAPS-Adult): Development and validation. AB - We developed and validated a new picture database of attachment-related photographs, the BAPS-Adult. Participants (N = 315) rated 256 pictures, according to dimension (valence, arousal, and dominance) using Self-Assessment Manikins (SAM), emotional category (positive, negative, mixed, and neutral) using labels, and discrete emotion (comfort, joy, complicity, distress, horror, and hate) using linear scales. Pictures were then classified into four types, depending on content (distress, comfort, complicity-joy, and neutral). Dimensional ratings of valence, arousal, and dominance, as well as discrete emotion ratings, differed significantly from each other between picture types. The BAPS-Adult is a new, highly discriminated database, allowing researchers to select from a variety of pre-rated, attachment-related pictures. PMID- 30458319 TI - Systemic lupus erythematosus and lymphoma: Incidence, pathogenesis and biology. AB - Systemic Lupus Erythematosus (SLE), a well recognized systemic autoimmune disease is associated with an increased risk of malignancies, particularly lymphoma. Various studies have shown this risk to be as high as 4-7-fold compared to the general population. The pathogenesis of lymphoma in patients with SLE is still not well understood. In this review we summarize the world literature and update current knowledge on the interesting link between SLE and lymphomagenesis. We relate in turn to incidence rates of lymphoma in SLE and subtypes of lymphoma encountered; pathogenesis and relevant theories proposed; links with EBV and the possible role of continued activity of lupus and of immunosuppressive therapy in lymphomagenesis. It is clearly evident that further studies are needed to improve the understanding of this association. Some cytokines and proteins associated with cell survival and proliferation, such as BAFF, APRIL, IL6 and BCL2, have been found to be elevated both in SLE and lymphoma. These factors may well impact pathogenesis, however, a direct "cause and effect" relationship is yet to be demonstrated. PMID- 30458320 TI - Allogeneic hematopoietic stem cell transplantation for the treatment of BCR-ABL1 negative atypical chronic myeloid leukemia and chronic neutrophil leukemia: A retrospective nationwide study in Japan. AB - Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) are rare BCR-ABL1 fusion gene-negative myeloid neoplasms with a predominance of neutrophils. Since no standard therapeutic strategy currently exists for these diseases, we retrospectively evaluated the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aCML and CNL. Data from 14 aCML and 5 CNL patients as their diagnoses were collected using a nationwide survey. Allo HSCT was performed between 2003 and 2014. Preconditioning regimens included myeloablative (n = 15), reduced-intensity (n = 3), and non-myeloablative (n = 1) regimens. Transplanted stem cells were obtained from HLA-matched related donors (n = 5) and alternative donors (n = 14). Neutrophil engraftment was successfully achieved in 17 patients. One-year overall survival rates (OS) were 54.4% (95% confidence interval [CI], 24.8 to 76.7%) and 40.0% (95% CI, 5.2 to 75.3%) in patients with aCML and CNL, respectively. Among aCML patients, 1-year OS were 76.2% (95% CI, 33.2 to 93.5%) and 20.0% (95% CI, 0.8 to 58.2%) in patients with <5% myeloblasts (n = 9) and >=5% myeloblasts (n = 5) in peripheral blood before allo-HSCT, respectively. These results suggest that allo-HSCT achieves long-term survival in patients with aCML and CNL. Better pre-transplant management is required to improve the outcomes of aCML patients with >=5% blasts in peripheral blood. PMID- 30458322 TI - Piezosurgery for infra- and supratentorial craniotomies in brain tumors surgery. AB - OBJECTIVE: Piezoelectric surgery represents an innovative technique to perform safe and effective osteotomies, alternative to traditional bony tissue management using rotating or perforating instruments. We evaluated safety and feasibility of craniotomies using an ultrasonic device that allows the selective cut of mineralized structures, avoiding damages to the vascular, dural and parenchymal structures. METHODS: We analyzed a series of 300 patients (range 1-81 years, SD+/ 15.2) that underwent elective cranial surgery for brain tumors, in which the craniotomy was performed using a piezoelectric device. Preoperative and postoperative imaging, clinical notes and intraoperative details were collected. RESULTS: 197 patients (66%) underwent surgery for supratentorial tumors, the remaining 103 (34%) for infratentorial ones. Tumors involved the skull base in 125 cases. Meningiomas, gliomas and schwannomas represented the most common histotypes. Duraplasty for dural damages was not necessary in all cases; no venous sinuses or parenchymal injuries were reported during bone work. We noted in 13 cases (4,3%) a minor dural tear, requiring only direct sutures. Bone flaps were always intact after craniotomy. No subgaleal cerebrospinal fluid (CSF) collection or CSF leak were recorded. Due to the minimal bone gap, we always achieved correct bone flaps ossification. No reabsorption or mobilization of bone flap was noted. CONCLUSION: We illustrate the feasibility and safety of a piezosurgical cutter to perform craniotomies. This alternative technique appears to be safe, with excellent cosmetic effects. adding another tool to the neurosurgical armamentarium. PMID- 30458321 TI - Enhanced inter-compartmental Ca2+ flux modulates mitochondrial metabolism and apoptotic threshold during aging. AB - BACKGROUND: Senescence is characterized by a gradual decline in cellular functions, including changes in energy homeostasis and decreased proliferation activity. As cellular power plants, contributors to signal transduction, sources of reactive oxygen species (ROS) and executors of programmed cell death, mitochondria are in a unique position to affect aging-associated processes of cellular decline. Notably, metabolic activation of mitochondria is tightly linked to Ca2+ due to the Ca2+ -dependency of several enzymes in the Krebs cycle, however, overload of mitochondria with Ca2+ triggers cell death pathways. Consequently, a machinery of proteins tightly controls mitochondrial Ca2+ homeostasis as well as the exchange of Ca2+ between the different cellular compartments, including Ca2+ flux between mitochondria and the endoplasmic reticulum (ER). METHODS: In this study, we investigated age-related changes in mitochondrial Ca2+ homeostasis, mitochondrial-ER linkage and the activity of the main ROS production site, the mitochondrial respiration chain, in an in vitro aging model based on porcine aortic endothelial cells (PAECs), using high resolution live cell imaging, proteomics and various molecular biological methods. RESULTS: We describe that in aged endothelial cells, increased ER mitochondrial Ca2+ crosstalk occurs due to enhanced ER-mitochondrial tethering. The close functional inter-organelle linkage increases mitochondrial Ca2+ uptake and thereby the activity of the mitochondrial respiration, but also makes senescent cells more vulnerable to mitochondrial Ca2+-overload-induced cell death. Moreover, we identified the senolytic properties of the polyphenol resveratrol, triggering cell death via mitochondrial Ca2+ overload exclusively in senescent cells. CONCLUSION: By unveiling aging-related changes in the inter organelle tethering and Ca2+ communications we have advanced the understanding of endothelial aging and highlighted a potential basis to develop drugs specifically targeting senescent cells. PMID- 30458323 TI - Hybrid Surgery for Non-taper or Non-stump Lesions in Symptomatic Subacute or Chronic Internal Carotid Occlusion: A Better Solution. AB - OBJECTIVE: Internal carotid artery occlusion (ICAO) causes transient ischemic attack (TIA) and cerebral infarction. ICAO management remains clinically challenging. We discuss a hybrid treatment combining carotid endarterectomy (CEA) and endovascular intervention (E-I) for patients with non-taper or non-stump lesion of symptomatic ICAO. METHODS: Thirty-two consecutive non-taper or non stump ICAO patients with neurological symptoms were treated with hybrid treatment or endovascular recanalization. We analyzed the epidemiology, symptomatology, angiographic morphology, technical success rate, and perioperative complications. RESULTS: Seventeen patients were treated with hybrid surgery and 15 with E-I. The demographics and lesion characteristics were similar between groups. The overall recanalization success rate was 71.9%; the rate for hybrid surgery was better than that for E-I (88.2% vs. 53.3%). The postoperative cerebral hyperperfusion rate showed no difference between groups (11.8% vs. 6.7%). Ipsilateral cerebral perfusion improved after treatment. MTT and TTP were above normal (<6 s, <8 s, respectively); both increased significantly after treatment (MTT 11.30 s vs. 7.25 s; TTP 19.30 s vs. 15.50 s). Perioperative complications of the hybrid surgery were less than those of E-I (5.9% vs. 40.0%). Recurrent cerebrovascular events (5.9% vs. 13.3%) and 3-month modified Rankin Scale score (2.76+/-0.66 vs. 2.93+/ 0.70) did not differ between groups. CONCLUSION: Recanalization of non-taper or non-stump ICAO with the hybrid treatment is more successful than with the E-I, with fewer perioperative complications. The CEA procedure enables easier wire crossing across the occlusion and reduces potential technology-related complications by requiring a shorter lesion and fewer dissections and minimizing the effect of calcification. PMID- 30458324 TI - Vertebral Arteriovenous Fistula: A Review Article. AB - OBJECT: Vertebro-vertebral fistulas (VVFs) are uncommon lesions that can arise spontaneously or secondarily to iatrogenic or mechanical trauma. We performed a systematic review of the literature to obtain information regarding demographics, clinical presentation, treatment modalities, outcome, and complications associated with treatment. METHODS: A literature search was performed by a reference librarian and after screening, 128 case reports and 16 case series were left for inclusion in the review. All possible data was abstracted by three authors, results were tabulated and descriptive statistics (mean, range; and proportions) were reported. No formal statistical analysis was performed as part of this study. RESULTS: 280 patients were analyzed. VVFs can be categorized in three subgroups: iatrogenic, spontaneous and traumatic, based on the mechanism of formation, and these different etiologies share different underlying demographics that bear important treatment considerations. Traumatic VVFs are more commonly seen in young men; the spontaneous form is more commonly seen in young women. Iatrogenic VVFs are more commonly seen in elderly people. Spontaneous VVFs are most commonly located between C1 and C2. Most iatrogenic (n=39; 57%), spontaneous (n=106; 82%), and traumatic (n=53; 73%) VVFs were treated with deconstructive (defined as occlusion of fistula and feeding vessels) endovascular therapy. Overall treatment-related permanent morbidity was 3.3% (9/270) and mortality was 1.5% (4/270). CONCLUSIONS: Vertebro-vertebral fistulas are uncommon lesions, and treatment is often indicated, even in patients without retrograde venous drainage. When undertaken, the etiology of presentation and associated patient demographics should be considered when planning the treatment strategy. PMID- 30458325 TI - The relationship between phospho-p38, MMP-9, and MICA expression in pituitary adenomas demonstrates a new mechanism of pituitary adenoma immune escape. AB - BACKGROUND: The MHC class I chain-related molecule A (MICA) is one of the Natural Killer Group 2D (NKG2D) ligands. soluble MHC class I chain-related molecule A (sMICA) mediates tumor immune escape, but the mechanism is not fully understood. In this study, we examined the expression of phospho-p38, matrix metalloproteinase 9 (MMP-9), and MICA and their relationships among each other in pituitary adenoma tissues in order to provide a histological basis for the mechanism of pituitary adenoma immune escape. METHODS: We applied immunohistochemistry (IHC), real-time quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and Western blot to detect phospho-p38, MMP 9, and MICA expression at the mRNA and protein levels in pituitary adenoma tissues. Enzyme-linked immunosorbent assay (ELISA) was used to examine the expression levels of MMP-9 and sMICA in peripheral blood serum from pituitary adenoma patients. RESULTS: We found that p38, MICA and MMP-9 mRNA levels were higher in pituitary adenomas than in normal tissues. The phospho-p38, MMP-9, and MICA proteins were overexpressed in pituitary adenomas, and the expression of MMP 9 and MICA were positively correlated with the expression of phospho-p38. In addition, the serum levels of sMICA and MMP-9 proteins in pituitary adenoma patients were significantly higher than those in normal controls. CONCLUSION: These findings suggest that activation of the p38/mitogen-activated protein kinase (p38/MAPK) pathway may increase MICA expression and induce MMP-9 expression. MMP-9 is involved in the shedding of sMICA from MICA to promote tumor immune escape. Furthermore, p38/MAPK could potentially represent a novel target for inhibiting pituitary adenoma immune escape. PMID- 30458326 TI - Granulomatous reaction on a double-level cervical total disc arthroplasty : case report. AB - BACKGROUND: Cervical Total Disc Arthroplasty (TDA) or cervical artificial disc replacement (C-ADR) is an alternative technique to anterior cervical discectomy and fusion (ACDF) for the treatment of symptomatic degenerative cervical spine disease. The main goal of TDA is to maintain cervical motion and therefore lower the risk of adjacent levels' deterioration. Granuloma formation on a cervical TDA is exceptional. We report such a case. CLINICAL PRESENTATION: A 48-year-old female suffering from left cervico-brachialgia underwent a double-level TDA (SpinalKinetics(r) M6-C Artificial Cervical Disc) on C5-C6 and C6-C7 in another hospital in 2010. Two years later, she reported a recurrence of cervicalgia, refractory to conservative treatment by rigid collar and painkillers. Cervical MRI suggested a granulomatous formation on the C6-C7 prosthesis. She underwent the removal of her C6-C7 prosthesis which showed a rupture with nylon thread extrusion. We followed by an arthrodesis with plate. Follow-up showed improvement of her clinical status. Histopathologic studies showed a giant cell granulomatous formation in contact with nylon threads described in hip, shoulder and ankle arthroplasty. It has been described in 6 cases following lumbar TDA and 2 cases following cervical TDA. CONCLUSION: We report a third case of granulomatous reaction on nylon thread extrusion after partial breakdown of a prosthesis for cervical TDA. PMID- 30458327 TI - Contra-lateral sublaminar endoscopic approach for removal of lumbar juxtafacet cysts using percutaneous biportal endoscopic surgery: Technical report and preliminary results. AB - BACKGROUND: Use of a contralateral sublaminar endoscopic approach may minimize facet violation and better visualize the dura and cystic lesions during operation. The purpose of the current study was to introduce a surgical technique for contralateral sublaminar endoscopic removal of lumbar juxtafacet cysts using a percutaneous biportal endoscopic approach. MATERIALS AND METHODS: Eleven cases of lumbar juxtafacet cyst were consecutively treated via a contralateral sublaminar endoscopic approach using percutaneous biportal endoscopic surgery. Postoperative magnetic resonance imaging (MRI) scans were evaluated on postoperative Day 1 for optimal removal of the cysts and neural decompression status. Clinical findings were evaluated in the preoperative and postoperative periods using a visual analog scale (VAS) for the legs and the Oswestry Disability Index (ODI). RESULTS: A total of 10 lumbar juxtafacet cysts in ten patients were treated using the contralateral sublaminar biportal endoscopic approach. Postoperative MRI depicted complete removal of the juxtafacet cysts and optimal neural decompression of the treated segments in all patients. Preoperative VAS and ODI scores improved significantly after surgery: VAS scores changed from 7.64 +/- 0.71 preoperatively to 1.63 +/- 1.28 at the last follow-up visit (p < 0.05), while ODI scores changed from 45.35 +/- 16.15 to 15.82 +/- 10.21 (p < 0.05). The mean operative time was 60.1 +/- 23.4 minutes. CONCLUSIONS: Considering the outcomes of this study, a contralateral sublaminar approach using percutaneous biportal endoscopy may be an alternative treatment for symptomatic lumbar juxtafacet cysts. This approach may minimize iatrogenic facet violation and traumatization of posterior musculoligamentous structures. PMID- 30458328 TI - Autologous bone marrow cell infusion therapy for hepatitis C virus infected liver cirrhosis. PMID- 30458329 TI - Transitions sit to stand and stand to sit in persons post-stroke: Path of centre of mass, pelvic and limb loading - A pilot study. AB - BACKGROUND: To explore the movement patterns utilized by persons post stroke from the simultaneous perspective of pelvic and limb loading with the path of centre of mass during the movement transitions sit to stand and stand to sit. METHODS: A descriptive pilot study where kinetic and kinematic data were collected and compared between the contribution made by the less affected versus more affected lower limb and trunk during sit to stand and stand to sit following stroke. Movement analysis was undertaken using force-plates and a 3D VICON motion capture system. FINDINGS: Data were successfully collected on nine subjects of whom four presented with left side more affected and eight were male. Two patterns were demonstrated for pelvic loading, four patterns for limb loading and five patterns for deviation of centre of mass. There were no consistent patterns of movement demonstrated dependent upon the more or less affected side. There was no consistent relationship between pelvic and limb loading and deviation of centre of mass throughout the movement phases. INTERPRETATION: In contrast to assumptions often made with respect to limb loading, we found large variability in movement patterns utilized by person's with a hemiparetic presentation during sit to stand and stand to sit. The findings suggest that movement problems encountered by persons post-stroke are complex and identifies limitations with respect to current measurement techniques. PMID- 30458330 TI - 'Pre-launch' finite element analysis of a short-stem total hip arthroplasty system consisting of two implant types. AB - BACKGROUND: We applied a previously established and validated numerical model to a novel short-stemmed implant for a 'pre-launch' investigation. METHODS: The implant system consists of two different implant geometries for valgus/varus positioned proximal femurs with differences in volume distribution, head/neck angle, and calcar alignment. The aim of the design was to achieve a better adaption to the anatomic conditions, resulting in a favourable load transfer. The implant type G showed the best fit to our model, but both stem geometries were implanted; the implant type B was used to compute an 'imperfection scenario'. FINDINGS: Apparent bone density decreased by 4.3% in the entire femur with the implant type G, and by 12.3% with the implant type B. Bone mass loss was pronounced in the proximal calcar region. Apparent bone density increased at the lateral cortical ring and in the minor trochanter. The apparent bone density in the imperfection scenario was very similar to that of a straight stem, indicating a distal load transfer. INTERPRETATION: No adverse effects of the A2 short stemmed implant system on bone remodeling could be detected. The overall bone density reduction was acceptable, and wedge fixation was not observed, indicating that there was no distal load transfer. The simulation of an incongruous implant indicates the sensitivity of our model in response to modifications of implant positioning. Correct implant selection and positioning is crucial when using the A2 system. PMID- 30458331 TI - Diffusion based MR measurements correlates with age-related changes in human intervertebral disks. AB - BACKGROUND: Understanding the association between MR parameters and age related deterioration in human intervertebral disks forms an important step in the development of clinical diagnostic protocols for disk disease. METHODS: Ten unfixed thoracic and lumbar cadaver disk joints, age 37-81 years were imaged at 9.4 T using T2 relaxation (CPMG) and ADC (DWI spin echo) MR protocols. For each MR parameter, spatial maps were computed from the axial images, with the AF and NP segmented based on the T2 maps. Linear regression tested for the correlation between mean and variance (COV) of T2 and ADC with age in the disk, nucleus and annulus, and the effect of thoracic vs. lumbar spine on these correlations. FINDINGS: In the disk, age negatively correlated with mean ADC (P < 0.001) and positively with COV of ADC (P < 0.001) and T2 (P < 0.05). Age was negatively correlated with mean T2 (P < 0.01), mean ADC (P < 0.001) and positively with COV of ADC (P < 0.001) and T2 (P < 0.05) in the NP and positively correlated with mean T2 (P < 0.05), COV of ADC (P < 0.01) and T2 (P < 0.05) and negatively with mean ADC (P < 0.05) in the AF. Compared to thoracic disks, lumbar disks showed higher mean ADC (P < 0.05), lower mean T2 (P < 0.001) and higher COV of ADC (P < 0.01) and T2 (P < 0.05). INTERPRETATION: Compared to T2, MR diffusion was a more sensitive measure of age mediated changes in disk tissues. Strong differences in the association of MR parameters with age between the lumbar and thoracic suggest that mechanical environment effects tissue specific MR parameters' association with age. PMID- 30458332 TI - Exploring the impacts of speed variances on safety performance of urban elevated expressways using GPS data. AB - Speed variation on urban expressways has been frequently noted as a key factor associated with high crash risk. However, it was often difficult to capture the safety impact of speed variance with spaced sensor measurements. As an alternative, this paper aims to leverage the use of the floating car data (FCD) to capture the speed variance in a morning rush hour on urban elevated expressways and examine its effect on safety. A semi-automatic filtering process was introduced to distinguish taxi GPS data points on the elevated expressways from the ones on the surface roads under the expressways. Subsequently, the standard deviation of the cross-sectional speed mean (SDCSM) and the cross section speed standard deviation (MCSSD) were derived to capture the spatial and temporal speed variances, respectively. Together with other explanatory variables, both hierarchical and non-hierarchical Poisson-gamma measurement error models were developed to model the crash frequencies of the expressways. The modeling results showed that the hierarchical model performed better and both SDCSM and MCSSD were found to be positively related to the crash occurrence. This secures the need for addressing the impact of speed variation when modeling crashes occurred on the elevated expressways. PMID- 30458333 TI - Cognitive functions in young adults with generalized anxiety disorder. AB - BACKGROUND: Anxiety and worry are central symptoms of Generalized Anxiety Disorder (GAD) that have been theorized to negatively impact cognitive functions. However, most of the research has focused on threat-related or emotionally charged stimuli, and a surprisingly small number of investigations examined 'cold' cognitive functions using classic neuropsychological tests. Such investigations are particularly important given that some theoretical models suggest compensatory mechanisms associated with anxiety that in certain circumstances may result in intact performance. The aim of the present study is to assess the neuropsychological profile associated with GAD, using a comprehensive neuropsychological battery. METHODS: A sample of 23 college students meeting criteria for DSM-5 GAD and 20 control participants completed a psychometrically valid comprehensive computerized neuropsychological battery and clinical questionnaires. RESULTS: The GAD sample presented with significantly elevated symptomatic rates of anxiety, worry, depression and stress. However, no significant differences were found on any neuropsychological outcome measures or domain indexes. Effect sizes were small, some of which favored the GAD sample. CONCLUSION: Despite substantial psychopathological burden, GAD exhibited intact cognitive functioning. These results support the Cognitive Control Theory of Anxiety, suggesting that elevated primary anxiety may not impact 'cold' cognitive functions in the absence of threat or substantial cognitive load. Given that this is one of the only studies employing a comprehensive neuropsychological battery in GAD, more research is needed in this population to replicate these results and to examine the impact of anxiety on cognitive functions at varying degrees of cognitive load in this population. PMID- 30458334 TI - Increased phantom recollection after sleep. AB - Sleep is known to benefit memory consolidation, but its effect on false memory is less clear. We applied the simplified conjoint recognition paradigm to investigate how sleep affects the cognitive processes behind correct or false recognition, according to fuzzy-trace theory, and measured the retrieval of verbatim traces, retrieval of gist traces, and phantom recollection. Participants studied 24 lists of semantically related words lacking the strongest common associate or theme word. Recognition was tested 12 h later, following either a night's sleep or daytime wakefulness. The recognition test featured studied words, nonstudied theme words (false recognition), and unrelated words. False recognition rate was higher after sleep than after daytime wakefulness. True recognition rate was the same. Analysis of the cognitive processes underlying recognition showed that phantom recollection was higher after sleep. Assuming that phantom recollection reflects the retrieval of strong gist traces, sleep may strengthen gist traces and promote gist extraction. PMID- 30458335 TI - Getting to know the neighborhood: using proximity-dependent biotinylation to characterize protein complexes and map organelles. AB - The use of proximity-dependent biotinylation approaches combined with mass spectrometry (e.g. BioID and APEX) has revolutionized the study of protein protein interactions and organellar proteomics. These powerful techniques are based on the fusion of an enzyme (e.g. a biotin ligase or peroxidase) to a 'bait' protein of interest, which is then expressed in a relevant biological setting. Addition of enzyme substrate enables covalent biotin labeling of proteins in the vicinity of the bait in vivo. These approaches thus allow for the capture and identification of 'neighborhood' proteins in the context of a living cell, and provide data that are complementary to more established techniques such as fractionation or affinity purification. As compared to standard affinity-based purification approaches, proximity-dependent biotinylation (PDB) can help to: first, identify interactions with and amongst membrane proteins, and other polypeptide classes that are less amenable to study by standard pulldown techniques; second, enrich for transient and/or low affinity interactions that are not readily captured using affinity purification approaches; third, avoid post-lysis artefacts associated with standard biochemical purification experiments and; fourth, provide deep insight into the organization of membrane less organelles and other subcellular structures that cannot be easily isolated or purified. Given the increasing use of these techniques to answer a variety of different types of biological questions, it is important to understand how best to design PDB-MS experiments, what type of data they generate, and how to analyze and interpret the results. PMID- 30458336 TI - Tuning strain-induced gamma-to-epsilon martensitic transformation of biomedical Co-Cr-Mo alloys by introducing parent phase lattice defects. AB - In this study, we examined the effect of pre-existing dislocation structures in a face-centered cubic gamma-phase on strain-induced martensitic transformation (SIMT) to produce a hexagonal close-packed epsilon-phase in a hot-rolled biomedical Co-Cr-Mo alloy. The as-rolled microstructure was characterized by numerous dislocations as well as stacking faults and deformation twins. SIMT occurred just after macroscopic yielding in tensile deformation. Using synchrotron X-ray diffraction line-profile analysis, we successfully captured the nucleation of epsilon-martensite during tensile deformation in terms of structural evolution in the surrounding gamma-matrix: many dislocations that were introduced into the gamma-matrix during the hot-rolling process were consumed to produce epsilon-martensite, together with strong interactions between dislocations in the gamma-matrix. As a result, the SIMT behavior during tensile deformation was accelerated through the consumption of these lattice defects, and the nucleation sites for the SIMT epsilon-phase transformed into intergranular regions upon hot rolling. Consequently, the hot-rolled Co-Cr-Mo alloy simultaneously exhibited an enhanced strain hardening and a high yield strength. The results of this study suggest the possibility of a novel approach for controlling the gamma -> epsilon SIMT behavior, and ultimately, the performance of the alloy in service by manipulating the initial dislocation structures. PMID- 30458337 TI - The influence of specific mutations in the AT gene (SERPINC1) on the type of pregnancy related complications. AB - BACKGROUND: Inherited antithrombin (AT) deficiency is a rare autosomal dominant disorder, caused by mutations in the SERPINC1 gene. The most common clinical presentation in AT deficient patients includes venous thrombosis and pulmonary embolism, while the association of AT deficiency and its effect on the development of pregnancy complications has been less studied. The aim of our research was to evaluate the effect of AT deficiency types, determined by genotyping, on pregnancy outcomes. METHODS: A retrospective cohort study included 28 women with AT deficiency, and their 64 pregnancies were analyzed. RESULTS: With regard to live birth rate, a significant difference was observed among women who were carriers of different SERPINC1 mutations, as the rate varied from 100% in cases of type I to the extremely low rate of 8% for women with type II HBS (AT Budapest 3) in the homozygous variant, P = 0.0005. All pregnancies from the type I group, even untreated ones, resulted in live births. In women with AT Budapest 3 in homozygous variant the overall live birth rate increased to 28.5% in the treated pregnancies. In this group the highest incidence of fetal death was observed of 62%; repeated fetal losses in 30%; fetal growth restriction in 22% and placental abruption in 7% of all pregnancies. CONCLUSION: Our study results indicate a difference between type I and type II AT deficiency. The risk of pregnancy related VTE was equally present in both groups, except for AT Budapest 3 in the heterozygous variant, while adverse pregnancy outcomes were strictly related to type II, especially AT Budapest 3 in the homozygous variant. PMID- 30458338 TI - Evaluation the combined diagnostic value of TAT, PIC, tPAIC, and sTM in disseminated intravascular coagulation: A multi-center prospective observational study. AB - BACKGROUND: Accurate and early diagnosis is important in the management of disseminated intravascular coagulation (DIC). We employed new automation technology to detect plasma biomarkers, including thrombin-antithrombin complex (TAT), alpha2-plasmininhibitor-plasmin complex (PIC), soluble thrombomodulin (sTM), and tissue plasminogen activator-inhibitor complex (tPAIC), and evaluated their diagnostic performance and prognostic value for DIC in Chinese population. METHODS: This prospective observational study included 444 patients with suspected DIC and 137 healthy people. The molecular markers were measured by qualitative chemiluminescence enzyme immunoassay performed on HISCL automated analyzers. All patients with suspected DIC were followed for 7 days to screen for the development of overt-DIC and 28 days for mortality. RESULTS: According to the International Society of Thrombosis and Haemostasis (ISTH) scoring system, 157 patients were diagnosed as overt-DIC and 36 were diagnosed as pre-DIC. All four biomarkers were significantly higher in DIC patients than in non-overt DIC patients; TAT, tPAIC, and sTM were significantly higher in pre-DIC patients than in non-overt DIC patients. Four molecular markers behaved differently among various underlying diseases. TAT, tPAIC, and sTM were also good predictors of 28 day mortality, high levels were associated with poor outcomes. CONCLUSIONS: TAT, PIC, tPAIC, and sTM demonstrated good diagnostic performance and prognostic value in DIC patients with different underlying diseases. Besides, TAT, tPAIC and sTM have certain implications in pre-DIC stage. Combination of four makers was demonstrated better behavior than single one. PMID- 30458339 TI - Candidate gene and pathway analyses identifying genetic variations associated with prasugrel pharmacokinetics and pharmacodynamics. AB - AIM: We aimed to investigate the genetic polymorphisms and pharmacogenetic variability associated with the pharmacodynamics (PD) and pharmacokinetics (PK) of prasugrel, in healthy Han Chinese subjects. PATIENTS & METHODS: Healthy, native, Han Chinese subjects (n = 36) aged 18 to 45 years with unknown genotypes were included. All subjects received a loading dose (LD) on day 1 and a maintenance dose (MD) from day 2 until day 11. Candidate gene association and gene-set analysis of biological pathways related to prasugrel and platelet activity were analyzed. RESULTS: 28 SNPs of 17 candidate genes previously associated with prasugrel or platelet activity were selected after a literature search. In the 30 mg LD groups (n = 24), ITGA2-rs28095 was found to be significantly associated with the P2Y12 reaction unit (PRU) value at 24 h after the LD (p = 0.015). 165 study genes related to platelet activation-related processes and prasugrel activity were selected from the MSigDB database, including curated gene sets from KEGG, Bio Carta, and Gene Cards. 14 SNPs of 9 genes were found to be significantly correlated both at 24 h and 12 days after LD: ADAMTSL1, PRKCA, ITPR2, P2RY12, P2RY14, PLCB4, PRKG1, ADCY1, and LYN. Seven SNPs of 6 protein-coding genes associated with area under the concentration-time curve (AUC0-tlast) were significantly identified among the 47 selected genes, including ADAMTSL1, CD36, P2RY1, PCSK9, PON1, and SCD. CONCLUSION: These results show that genetic variation affects the PK and PD of prasugrel in normal individuals. Further studies with larger sample sizes are required to explore whether the SNPs are associated only with prasugrel activity or also with cardiovascular events and all-cause mortality. PMID- 30458340 TI - Quality of life in metastatic pancreatic cancer patients receiving liposomal irinotecan plus 5-fluorouracil and leucovorin. AB - BACKGROUND: The NAPOLI-1 study (NCT01494506) reported that liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) improved overall survival vs 5-FU/LV with manageable toxicity in patients with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-based therapy. Yet, clinicians need treatment strategies that also maintain the patient's health-related quality of life (HRQOL). Here, we report the HRQOL data. METHODS: Patients completed the European Organisation for Research and Treatment of Cancer QOL core questionnaire C30 (EORTC QLQ-C30) at baseline, every 6 weeks, and at 30 days after discontinuation of study treatment. Patient-reported outcomes (PROs) were scored according to EORTC guidelines. nal-IRI+5-FU/LV HRQOL was compared with 5-FU/LV. The PRO population comprised intent-to-treat patients who completed baseline and at least one subsequent assessment on the EORTC QLQ-C30. Data were also analysed for missingness. RESULTS: Of 236 patients in the intent-to-treat population, 128 (54.2%) comprised the PRO population (71 in the nal-IRI+5-FU/LV arm; 57 the in 5 FU/LV arm). Of the remaining 108 patients (45.8%) not included in the PRO population, most progressed rapidly, making participation difficult. Median change from baseline was <=10 points at weeks 6 and 12 in global health status or functional and symptom scale scores, except for fatigue, which deteriorated by 11.1 points with nal-IRI+5-FU/LV but did not change vs 5-FU/LV. The proportion of patients whose HRQOL improved or deteriorated was not significantly different between the arms. CONCLUSION: In the NAPOLI-1 study, HRQOL was maintained with nal-IRI+5-FU/LV in patients with metastatic pancreatic adenocarcinoma previously treated with a gemcitabine-based regimen, while survival was significantly extended. PMID- 30458341 TI - New-onset seizure presenting as status epilepticus: Etiology and clinical characteristics in a cohort of 236 children. AB - PURPOSE: Evaluation of the etiology, clinical characteristics and outcome of the first status epilepticus (fSE) event in children. METHOD: The patients with fSE hospitalized in our Institute from 1995 to 2011 were included. The etiology was characterized as either known (symptomatic) or unknown (cryptogenic). Outcome was assessed at the end of hospitalization. Logistic regression analyses were used to assess predictors of the outcome, with odds ratio adjusted by age as a measure effect. RESULTS: The study included 236 patients with a median age of 2.0 years (IQR 4.0). Etiology was identified as secondary to: defined electroclinical syndromes 108 (45.8), acute symptomatic conditions 63 (26.7%), unknown 24 (10.1%), progressive encephalopathy 23 (9.7%), or remote symptomatic 18 (7.6%). Recurrence rate was 16.9%, neurological consequences were in 24.6% and case fatality ratio was 4.7%. The main predictors were for: a) death - progressive encephalopathy (OR = 14.68, 95% CI 4.06-23.11. p = 0.001); b) neurological sequelae - acute symtomatic (OR 3.44, 95% CI 4.82-6.47) p = 0.001, remote symptomatic (OR = 13.84, 95% CI 4.34-44.12. p = 0.001), progressive encephalopathy (OR = 3.94, 95% CI 1.64-9.56. p = 0.002), seizure duration >60 min (OR = 0.44, 95% CI 0.24-0.81. p = 0.001); c) seziure recurrence - acute symptomatic etiology (OR = 3.59, 95% CI 41.76-7.21. p = 0.001), seizure duration >60 min (OR = 0.30, 95% CI 0.15-0.61. p = 0.001). CONCLUSIONS: In children with fSE, exploring acute disorders and immediate etiological treatment is essential. The outcome of fSE is favorable concerning the recurrence rate, while neurological sequelae are seen in one quarter of the patients. The etiology and fSE duration are the main determinants of outcome. PMID- 30458342 TI - Early maladaptive schemas in patients with schizophrenia and non-patients with high and low schizotypal traits and their differences based on depression severity. AB - BACKGROUND: The aims of this study were to predict positive and negative symptoms of psychosis via early maladaptive schemas (EMSs) in patients with schizophrenia (SZ); to compare EMSs among SZ patients, non-patients with high schizotypal traits, and non-patients with low schizotypal traits; and to compare EMSs among subgroups concerning depression severity. METHODS: We applied three groups of participants including SZ patients (n = 105), non-patients with low schizotypal traits (n = 90), and non-patients with high schizotypal traits (n = 90). Participants completed the Young Schema Questionnaire-Short Form (YSQ-SF), the Positive and Negative Syndrome Scale (PANSS), the Schizotypal Personality Scale (STA), and the Beck Depression Inventory-II (BDI-II). RESULTS: The results indicated that the mistrust/abuse and social isolation schemas were significant predictors of positive and negative symptoms in SZ patients respectively. SZ patients and non-patients with high schizotypal traits exceeded non-patients with low schizotypal traits on all EMSs. There were no differences between SZ patients and non-patients with high schizotypal traits regarding EMSs. In the subgroups with high depression, SZ patients showed higher levels of EMSs than non-patients with low and high schizotypal traits. In the subgroups with low depression, both SZ patients and non-patients with high schizotypal traits had higher scores on EMSs than non-patients with low schizotypal traits. CONCLUSION: The findings suggest that mistrust/abuse and social isolation may be specific to psychosis symptoms. Also, SZ and schizotypal traits may overlap in relation to EMSs. In addition, the activated EMSs may contribute to high depression in SZ. PMID- 30458343 TI - Dynamic blebbing: A bottleneck to human embryonic stem cell culture that can be overcome by Laminin-Integrin signaling. AB - This study characterizes dynamic and apoptotic blebbing in human embryonic stem cells (hESC), identifies dynamic blebbing as a bottleneck to successful cell attachment during passaging, and demonstrates that dynamic blebbing can be rapidly stopped by plating cells on recombinant human laminin. In freshly plated hESC, dynamic and apoptotic blebbing differed in time of occurrence, bleb retraction rate, mitochondrial membrane potential, and caspase 3&7 activation. While dynamic blebbing can be controlled with drugs that inhibit myosin II, these methods have off-target effects and are not suitable for clinical applications. Recombinant human laminin-521 or addition of laminin-111 to Matrigel provided a safe method to drastically decrease dynamic blebbing and improve cell attachment with proteins normally found in the inner cell mass. Inhibition of focal adhesion kinase, which is activated by binding of integrins to laminin, prolonged dynamic blebbing and inhibited attachment. These data show that hESC bind rapidly to laminins through an integrin, which activates focal adhesion kinase that in turn downregulates dynamic blebbing. Laminins enabled hESC to rapidly attach during passaging, improved plating efficiency, enabled passaging of single pluripotent stem cells, and avoided use of inhibitors that have non-specific off-target effects. These data provide a strategy for improving hESC culture using biologically safe recombinant human proteins. PMID- 30458344 TI - Lycium barbarum polysaccharides protects H9c2 cells from hypoxia-induced injury by down-regulation of miR-122. AB - BACKGROUND: Lycium barbarum polysaccharides (LBPs) are major ingredients of fructus lycii, which have multiple pharmacological activities, such as antioxidant, neuroprotective, and anti-inflammatory activities. This study attempted to reveal the potential of LBPs in hypoxia-injured H9c2 cells and the possible underlying mechanisms. METHODS: H9c2 cells were treated by 300 MUg/mL LBPs for 24 h upon hypoxia. Subsequently, the changes in cell viability, migration and apoptosis were evaluated. pre-miR-122 or miR-122 sponge was transfected into H9c2 cells to investigate whether miR-122 was involved in the mechanisms of LBPs' action. Besides, an animal model of myocardial infarction (MI) was established, and the in vivo effects of LBPs were further investigated. RESULTS: LBPs increased cell viability, down-regulated p53, p21 and p16 protein expressions, improved migration, and repressed apoptosis in hypoxia-injured H9c2 cells. miR-122 was highly expressed in response to hypoxia, while was down regulated by addition of LBPs. The protective actions of LBPs in hypoxia-injured H9c2 cells were attenuated by miR-122 overexpression, while were accelerated by miR-122 suppression. Also, LBPs-induced the activation of MEK/ERK and AMPK signaling pathways were attenuated by miR-122 overexpression, and were accelerated by miR-122 suppression. in vivo investigation revealed that, MI rats administrated with LBPs decreased infarct size and improved cardiac function via down-regulation of miR-122. CONCLUSION: LBPs exhibited in vitro and in vivo cardioprotective activities via down-regulating miR-122. LBPs may have potential for the treatment of acute myocardial infarction (AMI). PMID- 30458345 TI - Synergistic inhibition of melanoma xenografts by Brequinar sodium and Doxorubicin. AB - Malignant melanoma continues to be a fatal disease for which novel and long-term curative breakthroughs are desired. One such innovative idea would be to assess combination therapeutic treatments - by way of combining two potentially effective and very different therapy. Previously, we have shown that DHODH inhibitors, A771726 and Brequinar sodium (BQR) induced cell growth impairment in melanoma cells. Similar results were seen with DHODH RNA interference (shRNA). In the present study, we showed that combination of BQR with doxorubicin resulted in synergistic and additive cell growth inhibition in these cells. In addition, in vivo studies with this combination of drugs demonstrated an almost 90% tumor regression in nude mice bearing melanoma tumors. Cell cycle regulatory proteins, cyclin B1 and its binding partner pcdc-2 and p21 were significantly downregulated and upregulated respectively following the combined treatment. Given that we have observed synergistic effects with BQR and doxorubicin, both in vitro and in vivo, these drugs potentially represent a new combination in the targeted therapy of melanoma. PMID- 30458346 TI - Synergistic therapeutic effects of Vitis vinifera extract and Silymarin on experimentally induced cardiorenal injury: The pertinent role of Nrf2. AB - BACKGROUND: Cardiorenal crosstalk has gained growing scientific curiosity recently. Clinical observations have approved that heart and kidney performances are intimately interrelated; acute or chronic dysfunction of either is inevitably mirrored on the other. This coexistence usually has the poor prognosis and worsened outcome. METHODS: We designed this study to explore therapeutic potentials of combined Vitis vinifera and Silymarin extracts on histopathological alterations of experimentally induced cardiorenal injury model. Moreover, to examine the pertinent role of Nrf2 in their bio-molecular actions. Sixty adult male Wistar albino rats were utilized, further subdivided into control, doxorubicin (DXR), DXR + Silymarin, DXR + Aqueous Vitis, DXR + Ethanolic Vitis, DXR + Ethanolic Vitis + Silymarin. Left ventricle and renal cortex sections from all groups were processed for histopathological examination, biochemical estimation of serum Urea, Creatinine, BUN, lipid profile and hs-CRP and real-time PCR of Nrf2 expression in cardiac and renal tissue homogenate were performed. RESULTS: Our results proved that combined ethanolic extract of Vitis vinifera and Silymarin restored normal renal and cardiac histomorphology. Significant improvement of Creatinine, BUN, lipid profile and hs-CRP cardiac and renal biochemical indicators confirmed our results. Moreover, significant elevation of mRNA expression levels of Nrf2 proved that combined Vitis vinifera and Silymarin action was directly related to the redox-sensitive regulator pathway. CONCLUSIONS: We concluded that synergistic therapeutic effect of Vitis vinifera extract and Silymarin on experimental cardiorenal injury model owes principally to promoting activation of the Keap1/Nrf2 signaling pathway. PMID- 30458347 TI - An application of reflectance spectroscopy to differentiate of entomopathogenic fungi species. AB - Fourier Transform Infrared Spectroscopy (FTIR) methods are the most commonly used spectroscopic techniques for differentiation of fungi species, however reflectance spectroscopy as a non-invasive technique can also be used. The aim of the study was to develop a method to rapidly differentiate fungi by means of reflectance spectroscopy using visible-infrared spectrum. Spectral measurements were conducted on six entomopathogenic fungi: Beauveria bassiana, Isaria fumosorosea, I. farinosa, I. tenuipes, Lecanicillium lecanii, L. muscarium cultured on Petri-dishes. The FieldSpec3 ASD spectroradiometer. Recording reflected radiance in the range 350-2500 nm was used. Measurements were performed in two modes: contact and proximal and obtained spectra were transformed using two methods: Savitzky-Golay (SG) and baseline alignment (BA) smoothing and derivative. The success rate of 100% in differentiate between fungi species was achieved with spectra recorded in visible-near infrared range with contact and proximal measurement and after SG transformation. Two wavelengths (411 nm and 520 nm) were needed to differentiate fungi using SG and proximal measurement while seven wavelengths were necessary to get full separation with contact measurement. BA spectra transformation method gave separation accuracy of 84, and 90% with four to five wavelengths for contact and proximal measurements, respectively, however, BA do not require full spectrum of wavelengths to fungi discrimination. Proposed reflectance spectroscopy method could discriminate between fungi species very similar macroscopically e.g. L. lecanii and L. muscarium until recently recognized as one species. PMID- 30458348 TI - Controllable and facile synthesis of CsPbBr3-Cs4PbBr6 perovskite composites in pure polar solvent. AB - Here, we present a single atomic supersaturated recrystallization method to synthesize the green-emitting CsPbBr3-Cs4PbBr6 perovskite composites in solid state with the highest PLQY of 40.8% in pure polar solvent. The component, morphology, and optical properties of the microcrystals can be tuned by varying growth time, the content of ammonium bromide, and bromine source. The developed method provides a new route to large-scale synthesize high quality perovskite composites emitters for light-emitting diodes. PMID- 30458349 TI - Probing ligand removal and ordering at quantum dot surfaces using vibrational sum frequency generation spectroscopy. AB - HYPOTHESIS: Controlling nanomaterial interfaces for emerging technologies has driven the need to understand the molecular species located there; however, challenges arise using traditional analytical techniques to directly characterize the molecular structure and local environments of these interfacial species due to their low relative populations. We hypothesized that vibrational sum frequency generation (vSFG) spectroscopy would be uniquely sensitive to the chemical modification of nanoparticle surfaces that is obscured using traditional bulk sensitive methods. EXPERIMENTS: Octadecylamine ligands were removed from model CdSe quantum dot surfaces using a common precipitation-resuspension procedure with polar protic and aprotic nonsolvents. Vibrational spectra of the ligands at the surface were collected with vSFG to directly probe the ligand ordering and coverage. Photoluminescence (PL), optical absorption, NMR, and mass spectrometry measurements were conducted for comparison. FINDINGS: vSFG was found to be sensitive to subtle changes in ligand disorder over multiple precipitation resuspension washes, and a limit to the number of ligand molecules removed from the surface and subsequent amount of disorder introduced to their packing was clearly observed. We also find that nonsolvents do not remain associated with the surface after washing. PMID- 30458350 TI - Climate change and occupational heat stress risks and adaptation strategies of mining workers: Perspectives of supervisors and other stakeholders in Ghana. AB - Increasing air temperatures as a result of climate change are worsening the impact of heat exposure on working populations, including mining workers, who are at risk of suffering heat-related illnesses, injury and death. However, inadequate awareness of climate change-related occupational heat stress risks and adaptation strategies have been shown to render occupational heat stress management ineffective. A concurrent mixed-methods approach was used to assess the perceptions of climate change and occupational heat stress risks and adaptation strategies of mining workers among supervisory personnel and other stakeholders in Ghana. Questionnaires and interviews were used to elicit data from 19 respondents. Data were processed and interpreted using descriptive statistics, chi-square and Fisher's exact tests, and thematic analysis. Supervisors' climate change risks perception was adequate, and their concern about workplace heat exposure risks was moderate. Mining workers' occupational heat stress risks experiences were linked to heat-related illness and minor injuries. Mining workers' adaptation strategies included water intake, use of cooling mechanisms, work-break practices, and clothing use. The related differences in job experience in the distribution of climate change risk perception and occupational heat stress risk experiences, and the difference in educational attainment in the distribution of adaptation strategies of occupational heat stress were significant (p < 0.05). Hence, an effective workplace heat management policy requires adequate understanding of occupational heat stress risks and adaptation policies and continued education and training for mining workers. PMID- 30458351 TI - A relationship between environmental pollutants and enteric viruses in mussels(Mytilus galloprovincialis). AB - Mussels can be affected by environmental contaminants, as non-dioxin-like polychlorinated biphenyls (NDL-PCBs), polycyclic aromatic hydrocarbons (PAHs) and cadmium (Cd). Moreover, mussels may concentrate human enteric viruses, like noroviruses (NoVGI/GII), astrovirus (AsV) and rotavirus (RV). Herein, to establish a relationship between environmental and viral contamination, with the aim to ensure human food safety, both chemical and microbiological analysis were carried out in mussels Mytilus galloprovincialis, farmed in Campania region (Italy). Chemical analysis revealed ranges below the European maximum limits, and were: ?6 NDL-PCBs (28, 52, 101, 138, 153, 180) 0.579-16.857 ng g-1 wet weight (ww); BaP LOQ (<0.2 ug kg-1)- 2.9 ug kg-1 ww, and ?4 PAHs (BaA, CHR, BbFA, BaP) 0.7-23.7 ug kg-1 ww; Cd LOQ (<0.005 mg kg-1)- 0.078 mg kg-1 ww. In addition, mussels exhibited a prevalence of NoVGI (18%), NoVGII (43%), AsV (40%), RV (30%) and the presence of more than one viruses resulted in about 35%. Overall, a simultaneous contamination, both chemical and viral, was found in 62% of samples. Interestingly, virus-positive mussels showed levels of chemicals higher than negative ones. PMID- 30458352 TI - Evaluation of potential carcinogenicity of organic chemicals in synthetic turf crumb rubber. AB - Currently, there are >11,000 synthetic turf athletic fields in the United States and >13,000 in Europe. Concerns have been raised about exposure to carcinogenic chemicals resulting from contact with synthetic turf fields, particularly the infill material ("crumb rubber"), which is commonly fabricated from recycled tires. However, exposure data are scant, and the limited existing exposure studies have focused on a small subset of crumb rubber components. Our objective was to evaluate the carcinogenic potential of a broad range of chemical components of crumb rubber infill using computational toxicology and regulatory agency classifications from the United States Environmental Protection Agency (US EPA) and European Chemicals Agency (ECHA) to inform future exposure studies and risk analyses. Through a literature review, we identified 306 chemical constituents of crumb rubber infill from 20 publications. Utilizing ADMET PredictorTM, a computational program to predict carcinogenicity and genotoxicity, 197 of the identified 306 chemicals met our a priori carcinogenicity criteria. Of these, 52 chemicals were also classified as known, presumed or suspected carcinogens by the US EPA and ECHA. Of the remaining 109 chemicals which were not predicted to be carcinogenic by our computational toxicology analysis, only 6 chemicals were classified as presumed or suspected human carcinogens by US EPA or ECHA. Importantly, the majority of crumb rubber constituents were not listed in the US EPA (n = 207) and ECHA (n = 262) databases, likely due to an absence of evaluation or insufficient information for a reliable carcinogenicity classification. By employing a cancer hazard scoring system to the chemicals which were predicted and classified by the computational analysis and government databases, several high priority carcinogens were identified, including benzene, benzidine, benzo(a)pyrene, trichloroethylene and vinyl chloride. Our findings demonstrate that computational toxicology assessment in conjunction with government classifications can be used to prioritize hazardous chemicals for future exposure monitoring studies for users of synthetic turf fields. This approach could be extended to other compounds or toxicity endpoints. PMID- 30458353 TI - Heterogeneous condensation of magnetized water vapor on fine SiO2 particles. AB - The emission of fine particles from coal-fired power plants is one of the major healthy and environmental concerns. The enlargement of particles seems to be a promising pretreatment technology due to the low removal efficiency of traditional dusting devices. The study of particle amplification by heterogeneous condensation of magnetized water vapor was carried out based on the growth tube. And, the major component of particles from coal combustion SiO2 was tested. The experimental results indicate that the particle growth is more favored by the magnetized water compared with non-magnetized water. And the particle growth is closely related to the magnetic field strength. Additionally, the surface tension of magnetized water is reduced and the wettability of particle surface is improved to some extent. Meanwhile, the particle concentration has stronger effect on the particle growth with magnetized water at lower level of supersaturation. Numerical calculation results demonstrate that the critical supersaturation is lower and nucleation rate is elevated when the water magnetized. This work reveals the facilitating process of particle growth by magnetized water that is the physical method of ameliorating particle surface performance. PMID- 30458354 TI - Fusing fine-tuned deep features for skin lesion classification. AB - Malignant melanoma is one of the most aggressive forms of skin cancer. Early detection is important as it significantly improves survival rates. Consequently, accurate discrimination of malignant skin lesions from benign lesions such as seborrheic keratoses or benign nevi is crucial, while accurate computerised classification of skin lesion images is of great interest to support diagnosis. In this paper, we propose a fully automatic computerised method to classify skin lesions from dermoscopic images. Our approach is based on a novel ensemble scheme for convolutional neural networks (CNNs) that combines intra-architecture and inter-architecture network fusion. The proposed method consists of multiple sets of CNNs of different architecture that represent different feature abstraction levels. Each set of CNNs consists of a number of pre-trained networks that have identical architecture but are fine-tuned on dermoscopic skin lesion images with different settings. The deep features of each network were used to train different support vector machine classifiers. Finally, the average prediction probability classification vectors from different sets are fused to provide the final prediction. Evaluated on the 600 test images of the ISIC 2017 skin lesion classification challenge, the proposed algorithm yields an area under receiver operating characteristic curve of 87.3% for melanoma classification and an area under receiver operating characteristic curve of 95.5% for seborrheic keratosis classification, outperforming the top-ranked methods of the challenge while being simpler compared to them. The obtained results convincingly demonstrate our proposed approach to represent a reliable and robust method for feature extraction, model fusion and classification of dermoscopic skin lesion images. PMID- 30458355 TI - Tubulin post-translational modifications in developing dog primary neurons obtained with methods according to the 3Rs principles. AB - Microtubules play a crucial role during neuronal morphogenesis regulating many functions. In the study of these phenomena in vitro cellular models have been employed, mainly resorting to housed experimental animals. Among alternative models in neurobiological study, recently dog caught particular attention. In fact, the complexity of the canine brain, the life long span and the neurodegenerative pathologies render the dog a species more close to humans than rodents. Lately, growing interest in the limitation of the use of experimental animals, has stimulated the search for alternative experimental protocols. Starting from fetal dog brain, obtained by alternative way of sampling, we set neuronal primary cultures. Through immunofluorescence, we examined the presence and the cellular distribution of tubulin post-translational modifications as tyrosinated and acetylated alpha-tubulin, as markers of dynamic and stable microtubule respectively. In addition, we evaluated the pattern of two associated proteins which may slide on these two tubulin modifications, i.e. CLIP-170 and Kinesin-1. A clear positivity for tyrosinated and acetylated alpha-tubulin, was found. As far as the motor proteins are concerned, we detected a prevalence of CLIP-170 compared to kinesin-1 with a better overlapping between tyrosinated alpha-tubulin and CLIP-170. Our findings highlighted some original data about the role of the microtubular network during early phases of canine neuronal morphogenesis. In addition, the experimental protocol underlined the utility of this alternative model that allows to bypass both the scarcity of commercial canine neuronal cell lines and the need to resort to experimental dogs, respecting the 3Rs principles (reduction, refinement, and replacement). PMID- 30458356 TI - Reduced delta-band modulation underlies the loss of P300 responses in disorders of consciousness. AB - OBJECTIVE: The P300 component of a sensory event-related potential is one of the major electrophysiological markers used to explore remnants of cognitive function in patients with disorders of consciousness (DoC). However, measuring the P300 in patients is complicated by significant inter-trial variability commonly observed in levels of arousal and awareness. To overcome this limitation, we analyzed single-trial modulation of power in the delta and theta frequency bands, which underlie the P300. METHODS: In a preliminary cross-sectional study using a 24 channel EEG and a passive own-name oddball paradigm, we analyzed event-related synchronization (ERS) across trials in the delta and theta bands in a sample of 10 control and 12 DoC subjects. RESULTS: In comparison to controls, DoC subjects presented a low percentage of trials where delta ERS was observed. In particular, coordinated modulation between delta and theta in response to the stimulus was absent, with a high percentage of trials where only theta ERS was observed. Further, we found a positive correlation between the percentage of epochs with delta ERS and the strength of the P300. CONCLUSIONS: Reduced modulation of spectral activity in the delta band in response to stimuli indicates a dissociation in the activity of the neural networks that oscillate in delta and theta ranges and contribute to the generation of the P300. SIGNIFICANCE: The reduction in spectral modulation observed in DoC provides a deeper understanding of neurophysiological dysfunction and the means to develop a more fine-grained marker of residual cognitive function in individual patients. PMID- 30458357 TI - Lignin-based polymers and nanomaterials. AB - Approximately 50 million tons of lignin are currently produced annually as a by product of the pulp- and paper industry, and this amount is likely to double in the future with the anticipated production of renewable fuels and chemicals from lignocellulosic biomass, as a sustainable alternative to petroleum. The latter process can be expedited by valorizing lignin, which entails making products from lignin that generate additional revenues for biorefineries so that the production of biofuels becomes more competitive with gasoline. Industrially produced lignin is considered a low-value material that is used as a boiler fuel to generate heat and electricity, and as an ingredient of adhesives, cement, and drilling fluids for underwater oil wells. The aromatic nature of lignin, its ability to participate in radical-mediated cross-linking reactions, the many functional groups available for derivatization or chemical reactions, and its amenability to existing procedures for making thermoplastics, make it attractive as an additive to polymers to enhance UV-tolerance and/or other physico-chemical properties. Lignin can also be used as the basis for various nanomaterials, either per se or in combination with other polymers. This review summarizes recent developments in the synthesis of lignin-containing polymers and nanomaterials, whereby inherent variation in lignin subunit composition and structure, as a function of plant species and lignin extraction method, offer unique opportunities for fine-tuning material properties (e.g. tensile strength, hardness, elasticity) to match specific applications. PMID- 30458358 TI - Active wrinkles to drive self-cleaning: A strategy for anti-thrombotic surfaces for vascular grafts. AB - The inner surfaces of arteries and veins are naturally anti-thrombogenic, whereas synthetic materials placed in blood contact commonly experience thrombotic deposition that can lead to device failure or clinical complications. Presented here is a bioinspired strategy for self-cleaning anti-thrombotic surfaces using actuating surface topography. As a first test, wrinkled polydimethylsiloxane planar surfaces are constructed that can repeatedly transition between smooth and wrinkled states. When placed in contact with blood, these surfaces display markedly less platelet deposition than control samples. Second, for the specific application of prosthetic vascular grafts, the potential of using pulse pressure, i.e. the continual variation of blood pressure between systole and diastole, to drive topographic actuation was investigated. Soft cylindrical tubes with a luminal surface that transitioned between smooth and wrinkled states were constructed. Upon exposure to blood under continual pressure pulsation, these cylindrical tubes also showed reduced platelet deposition versus control samples under the same fluctuating pressure conditions. In both planar and cylindrical cases, significant reductions in thrombotic deposition were observed, even when the wrinkles had wavelengths of several tens of MUm, far larger than individual platelets. We speculate that the observed thrombo-resistance behavior is attributable to a biofilm delamination process in which the bending energy within the biofilm overcomes interfacial adhesion. This novel strategy to reduce thrombotic deposition may be applicable to several types of medical devices placed into the circulatory system, particularly vascular grafts. PMID- 30458359 TI - pH-sensitive polymer micelles provide selective and potentiated lytic capacity to venom peptides for effective intracellular delivery. AB - Endocytosed biomacromolecule delivery systems must escape the endosomal trafficking pathway in order for their cargo to exert effects in other cellular compartments. Although endosomal release is well-recognized as one of the greatest barriers to efficacy of biologic drugs with intracellular targets, most drug carriers have relied on cationic materials that passively induce endosomal swelling and membrane rupture with low efficiency. To address the endosome release challenge, our lab has developed a diblock copolymer system for nucleic acid delivery that selectively displays a potent membrane-lytic peptide (melittin) in response to the pH drop during the endosomal maturation. To further optimize this system, we evaluated a panel of peptides with reported lytic activity in comparison to melittin. Nineteen different lytic peptides were synthesized and their membrane-lytic properties at both neutral and acidic pH characterized using a red blood cell hemolysis assay. The top five performing peptides were then conjugated to our pH-sensitive diblock copolymer via disulfide linkers and used to deliver a variety of nucleic acids to cultured mammalian cells as well as in vivo to the mouse brain. We demonstrate that the sharp pH transition of VIPER compensates for potential advantages from pH-sensitive peptides, such that polymer-peptide conjugates with poorly selective but highly lytic peptides achieve safe and effective transfection both in vitro and in vivo. In addition, peptides that require release from polymer backbones for lysis were less effective in the VIPER system, likely due to limited endosomal reducing power of target cells. Finally, we show that certain peptides are potentiated in lytic ability by polymer conjugation and that these peptide-polymer constructs are most effective in vivo. PMID- 30458360 TI - Dual carrier-cargo hydrophobization and charge ratio optimization improve the systemic circulation and safety of zwitterionic nano-polyplexes. AB - While polymeric nano-formulations for RNAi therapeutics hold great promise for molecularly-targeted, personalized medicine, they possess significant systemic delivery challenges including rapid clearance from circulation and the potential for carrier-associated toxicity due to cationic polymer or lipid components. Herein, we evaluated the in vivo pharmacokinetic and safety impact of often overlooked formulation parameters, including the ratio of carrier polymer to cargo siRNA and hydrophobic siRNA modification in combination with hydrophobic polymer components (dual hydrophobization). For these studies, we used nano polyplexes (NPs) with well-shielded, zwitterionic coronas, resulting in various NP formulations of equivalent hydrodynamic size and neutral surface charge regardless of charge ratio. Doubling nano-polyplex charge ratio from 10 to 20 increased circulation half-life five-fold and pharmacokinetic area under the curve four-fold, but was also associated with increased liver enzymes, a marker of hepatic damage. Dual hydrophobization achieved by formulating NPs with palmitic acid-modified siRNA (siPA-NPs) both reduced the amount of carrier polymer required to achieve optimal pharmacokinetic profiles and abrogated liver toxicities. We also show that optimized zwitterionic siPA-NPs are well-tolerated upon long-term, repeated administration in mice and exhibit greater than two-fold increased uptake in orthotopic MDA-MB-231 xenografts compared to commercial transfection reagent, in vivo-jetPEI(r). These data suggest that charge ratio optimization has important in vivo implications and that dual hydrophobization strategies can be used to maximize both NP circulation time and safety. PMID- 30458361 TI - In vivo evaluation of post-operative pain reduction on rat model after implantation of intraperitoneal PET meshes functionalised with cyclodextrins and loaded with ropivacaine. AB - The avoidance of post-herniorrhaphy pain can be challenging for hernia repair and has the greatest impact on patient's quality of life, health care utilisation and cost to society. Visceral meshes, functionalised with an efficient drug carrier system - hydroxypropyl beta-cyclodextrin polymer (polyHPbetaCD) coating, were developed to give a prolonged intraperitoneal analgesic drug release. We attempted to evaluate the in vivo pain-relief efficacy of ropivacaine loaded polyHPbetaCD functionalised polyester meshes in a rat model of visceral pain induced by colorectal distension (CRD). In vivo safety, pharmacokinetic profile and biodegradation were measured via histological analysis and high-performance liquid chromatography, etc. The results confirmed that the polyHPbetaCD on the functionalised meshes has a high adsorption capacity of ropivacaine and resulted in a sustained drug release in rats after mesh implantation. This was further reaffirmed by an elevated pain threshold (30%) up to 4 days after implantation in the rat CRD model, compared to 1-2 days for non-adapted meshes. Neither polyHPbetaCD nor the loaded ropivacaine had a major impact on the inflammatory response. This evidence strongly suggests that polyHPbetaCD functionalised visceral mesh could be a promising approach for post-operative pain control by improving the intraperitoneal drug delivery and bioavailability. PMID- 30458362 TI - Localized immune tolerance from FasL-functionalized PLG scaffolds. AB - Intraportal allogeneic islet transplantation has been demonstrated as a potential therapy for type 1 diabetes (T1D). The placement of islets into the liver and chronic immunosuppression to control rejection are two major limitations of islet transplantation. We hypothesize that localized immunomodulation with a novel form of FasL chimeric with streptavidin, SA-FasL, can provide protection and long-term function of islets at an extrahepatic site in the absence of chronic immunosuppression. Allogeneic islets modified with biotin and engineered to transiently display SA-FasL on their surface showed sustained survival following transplantation on microporous scaffolds into the peritoneal fat in combination with a short course (15 days) of rapamycin treatment. The challenges with modifying islets for clinical translation motivated the modification of scaffolds with SA-FasL as an off-the-shelf product. Poly (lactide-co-glycolide) (PLG) was conjugated with biotin and fabricated into particles and subsequently formed into microporous scaffolds to allow for rapid and efficient conjugation with SA-FasL. Biotinylated particles and scaffolds efficiently bound SA-FasL and induced apoptosis in cells expressing Fas receptor (FasR). Scaffolds functionalized with SA-FasL were subsequently seeded with allogeneic islets and transplanted into the peritoneal fat under the short-course of rapamycin treatment. Scaffolds modified with SA-FasL had robust engraftment of the transplanted islets that restored normoglycemia for 200 days. Transplantation without rapamycin or without SA-FasL did not support long-term survival and function. This work demonstrates that scaffolds functionalized with SA-FasL support allogeneic islet engraftment and long-term survival and function in an extrahepatic site in the absence of chronic immunosuppression with significant potential for clinical translation. PMID- 30458363 TI - Stimulus-activatable echogenic maltodextrin nanoparticles as nanotheranostic agents for peripheral arterial disease. AB - Reactive oxygen species (ROS) are closely related with various pathological disorders. Therefore, real-time detection of ROS is essential for understanding the procedure of diseases and diagnosing the accurate lesion sites. Hydrogen peroxide (H2O2) accounts for a large portion of ROS and has a longer half-life than other ROS, which makes it a highly promising diagnostic and therapeutic biomarker. In this work, we developed H2O2-activatable CO2 bubble generating indocyanine green-loaded boronated maltodextrin (ICG-BM) nanoparticles for imaging and therapy of peripheral arterial disease. ICG-BM nanoparticles displayed increasing fluorescence, ultrasound and photoacoustic signals in H2O2 triggered manners and exerted significant anti-inflammatory and proangiogenic effects in H2O2-stimulated vascular endothelial cells. In mouse models of hindlimb ischemia, ICG-BM nanoparticles also showed H2O2-triggered amplification of fluorescence, ultrasound and photoacoustic signals in the ischemic hindlimb muscles. ICG-BM nanoparticles also significantly reduced the level of overproduced H2O2 and exerted highly potent anti-inflammatory and proangiogenic activities in the ischemic tissues. We therefore believe that pathological stimulus-activatable echogenic ICG-BM nanoparticles provide a new avenue for imaging and treatment of peripheral arterial disease. PMID- 30458364 TI - Working on Womanhood (WOW): A participatory formative evaluation of a community developed intervention. AB - The well-documented disparities in availability, accessibility, and quality of behavioral health services suggest the need for innovative programs to address the needs of ethnic minority youth. The current study aimed to conduct a participatory, formative evaluation of "Working on Womanhood" (WOW), a community developed, multifaceted, school-based intervention serving primarily ethnic minority girls living in underserved urban communities. Specifically, the current study aimed to examine the feasibility, acceptability, and initial promise of WOW using community-based participatory research (CBPR) and represented the third phase of a community-academic partnership. Qualitative and quantitative data were collected from 960 WOW participants in 21 urban public schools, as well as WOW counselors, parents, and school staff over the course of one academic year. Results demonstrated evidence of acceptability of WOW and noteworthy improvements for WOW participants in targeted outcomes, including mental health, emotion regulation, and academic engagement. Findings also indicated several challenges to implementation feasibility and acceptability, including screening and enrollment processes and curriculum length. Additionally, we discuss how, consistent with participatory and formative research, findings were used by program implementers to inform program improvements, including modifications to screening processes, timelines, curriculum, and trainings - all in preparation for a rigorous effectiveness evaluation. PMID- 30458365 TI - CSF soluble TREM2 as a measure of immune response along the Alzheimer's disease continuum. AB - TREM2 was suggested to be an important regulator of microglia during neurodegeneration, but previous studies report conflicting results in relation to soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) when using clinical criteria to classify Alzheimer's disease (AD). The present study explores sTREM2 CSF levels and their associations with other biomarkers and cognitive measures in a prospective AD cohort. Based on the available CSF biomarker information, 497 subjects were classified according to the 2018 National Institute on Aging Alzheimer's Association research framework guidelines, which group biomarkers into those of amyloid-beta deposition, tau pathology, and neurodegeneration. CSF sTREM2 concentrations were associated with markers of neurodegeneration and fibrillar tau pathology, but not amyloidosis; sTREM2 concentrations were increased in total tau-positive versus -negative individuals; sTREM2 was not related to cognitive and other biomarker changes over time; and sTREM2 concentrations increased over time in total tau-positive versus -negative individuals with AD pathophysiology. The present study provides evidence in support of sTREM2 in CSF as a marker of neuroinflammation across the spectrum of early clinical AD. sTREM2 is linked to neuronal injury and may therefore offer complementary information relevant for diagnostic purposes and novel treatment approaches targeting the immune system in AD. PMID- 30458366 TI - Carbon monoxide sensitizes cisplatin-resistant ovarian cancer cell lines toward cisplatin via attenuation of levels of glutathione and nuclear metallothionein. AB - Cisplatin resistance remains a major impediment to effective treatment of ovarian cancer. Despite initial platinum responsiveness, thiol-containing peptides and proteins, glutathione (GSH) and metallothionein (MT), bind and inactivate cisplatin in cancer cells. Indeed, high levels of GSH and MT in ovarian cancers impart cisplatin resistance and are predictive of poor prognosis. Cystathionine beta-synthase (CBS), an enzyme involved in sulfur metabolism, is overexpressed in ovarian cancer tissues and is itself associated with cisplatin resistance. Treatment with exogenous carbon monoxide (CO), a known inhibitor of CBS, may mitigate cisplatin resistance in ovarian cancer cells by attenuation of GSH and MT levels. Using a photo-activated CO-releasing molecule (photoCORM), [Mn(CO)3(phen)(PTA)]CF3SO3 (phen = 1,10-phenanthroline, PTA = 1,3,5-triza-7 phosphaadamantane) we assessed the ability of CO to sensitize established cisplatin-resistant ovarian cancer cell lines to cisplatin. Cisplatin-resistant cells, treated with both cisplatin and CO, exhibited significantly lower cell viability and increased poly (ADP-ribose) polymerase (PARP) cleavage versus those treated with cisplatin alone. These cisplatin-resistant cell lines overexpressed CBS and had increased steady state levels of GSH and expression of nuclear MT. Both CO treatment and lentiviral-mediated silencing of CBS attenuated GSH and nuclear MT expression in cisplatin resistant cells. We have demonstrated that CO, delivered from a photoCORM, sensitizes established cisplatin-resistant cell lines to cisplatin. Furthermore, we have presented strong evidence that the effects of CO in circumventing chemotherapeutic drug resistance is at least in part mediated by the inactivation of endogenous CBS. PMID- 30458367 TI - Ternary copper(II) complexes with 1,10-phenanthroline and various aminoacidates: A spectroscopic and voltammetric study in aqueous solution. AB - Ternary copper(II) complexes with 1,10-phenanthroline and the aminoacids l arginine, l-aspartic acid, l-histidine, l-glutamic acid, l-glutamine, l-leucine, l-lysine, l-methionine, l-phenylalanine, l-tryptophan, l-tyrosine, l-valine, were studied in aqueous solution by means of UV-Vis-NIR spectrophotometry, EPR spectroscopy either at room or at low temperatures, and Square Wave Voltammetry. From the experimental data it is possible to conclude that most of these ternary complexes show a pseudo-octahedral geometry with a CuN3O in plane chromophore and two oxygen atoms coming from water molecules perpendicularly bound to the equatorial plane. An exception to this general behaviour is given by the ternary copper(II) complex with 1,10-phenanthroline and histidine at pH value near the neutrality because of the terdentate nature of histidine when it coordinates by means of its histamine-like mode. In this case, evidence for a probable square based pyramidal stereochemistry is given in support. At pH values around 5 the histidine behaves as bidentate ligand coordinating by its glycine-like mode, so as the copper(II) ternary complex with 1,10-phenathroline shows the pseudo octahedral geometry found for all the ternary complexes with the other aminoacids. Moreover the ternary complex species with histidine at pH 5 and 7 are in equilibrium with each other as a function of the aqueous solution pH value and the temperature. In fact, the examination of low temperature EPR spectra at pH near 7 revealed not only a square-based pyramid complex but also products of decomposition. These results were also confirmed by the trend found in the formal redox potentials by the voltammetric measurements on many of these ternary complexes. PMID- 30458368 TI - Organotins in obesity and associated metabolic disturbances. AB - The objective of the present study was to review the mechanisms of organotin induced adipogenesis, obesity, and associated metabolic disturbances. Peroxisome proliferator-activated receptor gamma (PPARgamma) and retinoid X receptor alpha (RXRalpha) activation is considered as the key mechanism of organotin-induced adipogenesis. Particularly, organotin exposure results in increased adipogenesis both in cell and animal models. Moreover, transgenerational inheritance of organotin-induced obese phenotype was demonstrated in vivo. At the same time, the existing data demonstrate that organotin compounds (OTCs) induces aberrant expression of PPARgamma-targeted genes, resulting in altered of adipokine, glucose transporter, proinflammatory cytokines levels, and lipid and carbohydrate metabolism. The latter is generally characterized by hyperglycemia and insulin resistance. Other mechanisms involved in organotin-induced obesity may include estrogen receptor and corticosteroid signaling, altered DNA methylation, and gut dysfunction. In addition to cellular effects, organotin exposure may also affect neural circuits of appetite regulation, being characterized by neuropeptide Y (NPY) up-regulation in parallel with of pro-opiomelanocortin (POMC), Agouti related protein (AgRP), and cocaine and amphetamine regulated transcript (CART) down-regulation in the arcuate nucleus. These changes result in increased orexigenic and reduced anorexigenic signaling, leading to increased food intake. The existing data demonstrate that organotins are potent adipogenic agents, however, no epidemiologic studies have been performed to reveal the association between organotin exposure and obesity and the existing indirect human data are contradictory. PMID- 30458369 TI - Prediction of residual film perception of cosmetic products using an instrumental method and non-biological surfaces: The example of stickiness after skin application. AB - Prediction of sensory texture attributes using instrumental measurements is a very important challenge for cosmetic industry because in vivo sensory studies are expensive, time consuming and limited by the safety issue of applied products. The aim of this work is to investigate how residual sensory properties of cosmetic products can be predicted without using a panel of assessors, focusing on the residual film attribute "Stickiness". 10 cosmetic products with different galenics have been selected and evaluated in vivo using a classical sensory protocol, developed according to the SpectrumTM Descriptive Analysis method. In addition to this study, products were evaluated after their application on non-biological skin models in order to compare perceptions onto in vivo skin and artificial surfaces. Results obtained show that in vivo perceptions can be compared with the ones on artificial surfaces meaning that residual film stickiness is similar between in vivo skin and non-biological skin models. An instrumental protocol using a texture analyzer has been set up to evaluate residual film adhesiveness. This protocol has been tested and validated in vivo (r2adjusted = 0.90; RPD = 3.07) before being optimized on a selected non biological skin model Bioskin(r) (Beaulax, Co. Ltd. Tokyo, Japan) owning good correlation with in vivo perceptions. Established model shows excellent predictive ability with a r2adjusted of 0.94 and a RPD of 3.38, as highlighted by the 4 steps cross-validation performed. It proves that physical stimulus responsible for cosmetic film stickiness can be instrumentally measured on both in vivo skin and artificial skin. PMID- 30458370 TI - Chronic histamine 3 receptor antagonism alleviates depression like conditions in mice via modulation of brain-derived neurotrophic factor and hypothalamus pituitary adrenal axis. AB - The last two decades of research has established histamine (HA) as a neurotransmitter. Since H3R antagonists are known to modulate several neurotransmitters besides HA, H3R antagonists have shown potential for the treatment of different central nervous system disorders, including depression. However, molecular mechanisms underlying the beneficial effects of H3R antagonism in depression are not clear, yet. In the present study, we investigated the antidepressant potential of ciproxifan, a selective H3R antagonist, in chronic unpredictable stress (CUS) model of depression in C57BL/6 J mice. We observed that chronic treatment of CUS mice with ciproxifan (3 mg/kg i.p.; for three weeks) alleviates depression-like symptoms such as helplessness measured by forced swim and tail suspension test (FST and TST), anhedonia measured by sucrose preference test (SPT) and social deficit measured in social behavior test. Chronic ciproxifan treatment restored CUS induced BDNF expression in the prefrontal cortex (PFC) and hippocampus. We also observed that ciproxifan modulates CUS induced NUCB2/nesfatin-1 and CRH expression in the hypothalamus and plasma corticosterone. We also determined the direct effect of HA on BDNF expression in neurons by western blotting and immunocytochemistry, and found that HA significantly induced BDNF expression, which was blocked by the H4R selective antagonist, but not by other HA receptor selective antagonists. Furthermore, ciproxifan significantly modulated NMDA glutamate receptor subunits NR2B and NR2A. Thus, these results suggest that increased HA signaling in the brain produces antidepressant-like effects in mice and modulates BDNF expression and HPA-axis. PMID- 30458371 TI - The endogenous oxytocin system in depressive disorders: A systematic review and meta-analysis. AB - The oxytocin system is involved in psychological functions and interacts with biological systems that are altered in patients suffering from depressive disorders. This suggests a possible role of oxytocin in the development and maintenance of depression. We provide the first systematic review and meta analysis that specifically addresses differences in basal endogenous oxytocin concentrations between patients with depressive disorders and healthy controls. A systematic literature search was conducted to identify studies that measured basal endogenous oxytocin concentrations in depressive patients and healthy controls. We included k = 13 studies (n = 368 patients and n = 346 healthy controls) in the qualitative review and k = 9 studies (n = 273 patients and n = 273 healthy controls) in the meta-analytic procedure. Standardized mean group differences were non-significant (g = -0.02, CI = [-0.41; 0.36]), indicating that depressive patients and healthy controls did not differ in basal endogenous oxytocin concentrations. The overall effect was heterogeneous. Effects within studies showing comparable risks of biases, as rated according to the Newcastle Ottawa Quality Assessment Scale, were non-significant as well, but homogeneous. The findings suggest that more complex research designs and methodological approaches should be employed to detect and understand a possible role of the oxytocin system in depressive disorders. We provide recommendations for subsequent promising study designs, involving the consideration of illness phase, comorbidities and correlations with psychological functions or symptoms. We point out the strengths of reactivity designs and multidimensional measurement approaches and recommend to linking future research questions to theories of depression. PMID- 30458372 TI - Differences among cigarette-only smokers compared to dual users of cigarettes and little cigars/cigarillos in the criminal justice population. AB - INTRODUCTION: The FDA has restrictions on cigarettes; however, little cigars and cigarillos (LCCs) remain largely absent from these regulations. Due to their low prices and flavoring, many engage in dual use of both LCCs and cigarettes. Dual use is particularly prevalent among low income racial/ethnic minority groups. The purpose of this study was to (U.S. Department of Health and Human Services, 2014) conduct an exploratory examination among cigarette users compared to dual users on smoking characteristics; and (Centers for Disease Control and Prevention, 2016) to examine racial differences (White and Black) among cigarette users compared to dual users. METHODS: Participants (N = 500) were recruited from community corrections (i.e., parole/probation) and categorized as either cigarette-only (66.4%) or dual users (33.6%) if they used little cigars or cigarillos over a one-year period during a smoking cessation clinical trial. RESULTS: Dual users were more likely to be younger, Black, males with lower educational attainment compared to cigarette-only smokers. Smokers with increased nicotine dependence were 17% more likely to be cigarette-only smokers compared to dual users. Racial differences revealed that White/cigarette-only smokers were more likely to report non-menthol use and higher cigarette consumption at the end of treatment compared to Black/cigarette-only or Black/dual users. CONCLUSIONS: This study contributes to our understanding of dual use among a disenfranchised group of smokers. Overall, dual users were more likely to be younger, Black, and male with lower reported nicotine dependence compared to cigarette-only users. Racial differences revealed that non-menthol smokers as well as smokers with greater cigarettes smoked at the end of treatment were more likely White/cigarette-only smokers. PMID- 30458373 TI - Bioaccumulation and ecotoxicological responses of juvenile white seabream (Diplodus sargus) exposed to triclosan, warming and acidification. AB - Triclosan (TCS) is a synthetic microbial compound widely used in the formulation of various personal care products. Its frequent detection in marine ecosystems, along with its physical and chemical properties, suggest that TCS can be highly persistent, being easily bioaccumulated by biota and, therefore, eliciting various toxicological responses. Yet, TCS's mechanisms of bioaccumulation and toxicity still deserve further research, particularly focusing on the interactive effects with climate change-related stressors (e.g. warming and acidification), as both TCS chemical behaviour and marine species metabolism/physiology can be strongly influenced by the surrounding abiotic conditions. Hence, the aim of this study was to assess TCS bioaccumulation and ecotoxicological effects (i.e. animal fitness indexes, antioxidant activity, protein chaperoning and degradation, neurotoxicity and endocrine disruption) in three tissues (i.e. brain, liver and muscle) of juvenile Diplodus sargus exposed to the interactive effects of TCS dietary exposure (15.9 MUg kg-1 dw), seawater warming (DeltaToC = +5 degrees C) and acidification (DeltapCO2 ~ +1000 MUatm, equivalent to DeltapH = -0.4 units). Muscle was the primary organ of TCS bioaccumulation, and climate change stressors, particularly warming, significantly reduced TCS bioaccumulation in all fish tissues. Furthermore, the negative ecotoxicological responses elicited by TCS were significantly altered by the co-exposure to acidification and/or warming, through either the enhancement (e.g. vitellogenin content) or counteraction/inhibition (e.g. heat shock proteins HSP70/HSC70 content) of molecular biomarker responses, with the combination of TCS plus acidification resulting in more severe alterations. Thus, the distinct patterns of TCS tissue bioaccumulation and ecotoxicological responses induced by the different scenarios emphasized the need to further understand the interactive effects between pollutants and abiotic conditions, as such knowledge enables a better estimation and mitigation of the toxicological impacts of climate change in marine ecosystems. PMID- 30458374 TI - Anthropogenic 129I in the sediment cores in the East China sea: Sources and transport pathways. AB - With the increased numbers of nuclear power plants constructed along the east coast of China, it is important to know radioactive sources and transport pathways between land and sea, in order to better understand the impact of these nuclear facilities to the marine environment. Two sediment cores collected from the East China Sea dated to 1959-2010 were analyzed for long-lived radioactive 129I and stable 127I. It was observed that 129I levels (129I/127I ratio of (15.0 75.0) * 10-12) were significantly increased compared to the pre-nuclear value (129I/127I = 1.5 * 10-12). Some 129I peaks were observed in layers of 1959, 1966, 1971 and 1976 (1977), corresponding to the atmospheric nuclear weapon tests at Pacific Proving Grounds and Lop Nor. The high values of 129I after the late 1970s are attributed to the releases from the European reprocessing plants. In addition to ocean current transport, the atmospheric dispersion through the interaction of the Westerlies with East Asia monsoon is the important pathway of large-scale transport of pollutants from high latitude West Europe to middle latitude East Asia. Riverine input is the main transport pathway of radioactive pollutants released from Lop Nor to the East China Sea through the atmospheric dispersion, deposition and runoff processes. PMID- 30458375 TI - Maternal urinary metabolites of PAHs and its association with adverse birth outcomes in an intensive e-waste recycling area. AB - Polycyclic aromatic hydrocarbons (PAHs) are well-known carcinogenic and endocrine disrupting chemicals that have been concerned over the past few decades. We aimed to determine the hydroxylated PAH (OHPAH) metabolite concentrations in maternal urine collected from the e-waste-contaminated area of Guiyu and the reference area of Haojiang, China, and to evaluate their health effects on birth outcomes. The median ?OHPAH concentration was 6.87 MUg/g creatinine from Guiyu, and 3.90 MUg/g creatinine from Haojiang. 2-OHNap and 1-OHPyr were the predominant metabolites. Residence in Guiyu and recycling in houses were associated with elevated 2-OHNap and 1-OHPyr. Standardized mean difference revealed that compared to low PAH metabolite levels in the first quartile, high PAH metabolite levels in the fourth quartile especially for 1-OHPyr, ?OHPAHs and sometimes hydroxylphenanthrene compounds, presented a reduced size in birth outcomes (overall SMD: -0.09; 95% CI: -0.15, -0.03), including head circumference, BMI and Apgar 1 score, and increased size in height. After adjusting for confounders in regression models, an interquartile increase in SigmaOHPAHs was associated with a decrease of 234.56 g in weight (95% CI: -452.00, -17.13), 1.72 cm in head circumference (95% CI: -2.96, -0.48), 1.06 kg/m2 in BMI (95% CI: -1.82, -0.31) and 0.42 in Apgar 1 score (95% CI: -0.66, -0.18), respectively. These findings suggest high exposure to PAHs during pregnancy in e-waste areas, posing a potential threat to neonatal development, which likely can be attributed to direct e-waste recycling activities. Ongoing studies should be continued to monitor human exposure and health, in particular for vulnerable individuals in e waste-polluted areas. PMID- 30458376 TI - Toxicological effects of two organic ultraviolet filters and a related commercial sunscreen product in adult corals. AB - Corals are exposed to organic ultraviolet (UV) filters and other personal care product (PCP) ingredients in the environment, but the toxicities of organic UV filters and their related PCP to corals are not well understood. In this study, 7 day exposures were conducted to evaluate the toxicities and bioaccumulation of two organic UV filters, ethylhexylmethoxy-cinnamate (EHMC; octinoxate) and octocrylene (OC) (single- and combined-chemical tests), and diluted sunscreen wash-off water containing both active ingredients to the adult life stage of two hard coral species, Seriatopora caliendrum and Pocillopora damicornis. In the single-chemical tests, death (33.3%) and bleaching (83.3%) were only observed in the 1000 MUg/L EHMC treatment of S. caliendrum. In the sunscreen product exposures, 5% sunscreen water (containing 422.34 +/- 37.34 MUg/L of EHMC and 33.50 +/- 7.60 MUg/L of OC at Day 0) caused high mortality in S. caliendrum (66.7 83.3%) and P. damicornis (33.3-50%), and tissue concentrations were up to 10 times greater than in the single-chemical exposures; co-exposure to EHMC and OC at similar levels to those in the sunscreen product resulted in bioaccumulation similar to the single-chemical tests. These results confirm the bioaccumulation potential of EHMC and OC and show that other ingredients in sunscreen products may increase the bioavailability of active ingredients to corals and exacerbate the toxicity of sunscreen products. Future studies on the toxicities of PCPs to aquatic organisms should not only focus on the toxicities of active ingredients. PMID- 30458377 TI - Petroleum hydrocarbon (PHC) uptake in plants: A literature review. AB - Crude oil and its constituents can have adverse effects on ecological and human health when released into the environment. The Canadian Council of Ministers of the Environment (CCME) has developed remedial guidelines and a risk assessment framework for both ecological and human exposure to PHC. One of the assumptions used in the derivation of these guidelines is that plants are unable to take up PHC from contaminated soil and therefore subsequent exposure at higher trophic levels is not a concern. However, various studies suggest that plants are indeed able to take up PHC into their tissues. Consumption of plants is a potential exposure pathway in both ecological (e.g., herbivorous and omnivorous birds, and mammals) and human health risk assessments. If plants can uptake PHC, then the current approach for risk assessment of PHC may underestimate exposures to ecological and human receptors. The present review aims to assess whether or not plants are capable of PHC uptake and accumulation. Twenty-one articles were deemed relevant to the study objective and form the basis of this review. Of the 21 primary research articles, 19 reported detectable PHC and/or its constituents in plant tissues. All but five of the 21 articles were published after the publication of the CCME Canada-Wide Standards. Overall, the present literature review provides some evidence of uptake of PHC and its constituents into plant tissues. Various plant species, including some edible plants, were shown to take up PHC from contaminated soil and aqueous media in both laboratory and field studies. Based on the findings of this review, it is recommended that the soil plant-wildlife/human pathway should be considered in risk assessments to avoid underestimating exposure and subsequent toxicological risks to humans and wildlife. PMID- 30458378 TI - Assessment of sperm DNA integrity within the Palaemon longirostris (H. ) population of the Seine estuary. AB - The interpretation of biomarkers in natura should be based on a referential of expected values in uncontaminated conditions. Nevertheless, to build a reference data set of biomarker responses in estuarine areas, which receive chronic pollution loads due to their transition position between continent and sea, is impossible. In this context, the aim of the present work was to propose the use of laboratory recovery period to define a baseline for the measurement of sperm DNA damage by Comet assay in the estuarine prawn Palaemon longirostris. For that, sperm DNA integrity was observed after both a passive (i.e. 20 days in a clean environment) and an active (i.e. forced renewal of spermatophores) recovery of wild P. longirostris specimens from the Seine estuary, in laboratory conditions. Then, the levels of sperm DNA damage recorded within the P. longirostris population of the Seine estuary, during six campaigns of sampling from April 2015 to October 2017, have been interpreted according to the defined threshold values. The results showed a persistence in the level of DNA damage after 20-day in clean environment with the passive recovery. This strategy was inconclusive to reach a baseline level but it revealed the lack of DNA repair mechanisms. For the active recovery, a decrease of 54% of the level of DNA damage has been observed after the first renewal of spermatophores and this level stabilized after the second renewal. On the basis of this second strategy, we defined a mean basal value of sperm DNA damage of 54.9 A.U. and a maximum threshold of 69.7 A.U. (i.e. 95 %CI). The analysis of the results using the reference value highlighted significant abnormal sperm DNA damage within the native population of P. longirostris from the Seine estuary on all stations during the six-sampling campaigns. PMID- 30458379 TI - Retrotransposon methylation and activity in wild fish (A. anguilla): A matter of size. AB - Understanding how organisms cope with global change is a major question in many fields of biology. Mainly, understanding the molecular mechanisms supporting rapid phenotypic changes of organisms in response to stress and linking stress induced molecular events to adaptive or adverse outcomes at the individual or population levels remain a major challenge in evolutionary biology, ecology or ecotoxicology. In this view, the present study aimed to test (i) whether environmental factors, especially pollutants, can trigger changes in the activity of retrotransposons (RTs) in wild fish and (ii) if changes in RT DNA methylation or transcription levels can be linked to modifications at the individual level. RTs are genetic elements that have the ability to replicate and integrate elsewhere in the genome. Although RTs are mainly quiescent during normal development, they can be experimentally activated under life-threatening conditions, affecting the fitness of their host. Wild eels were collected in four sampling sites presenting differing levels of contamination. The methylation level and the transcriptional activity of two RTs and two genes involved in development and cell differentiation were analyzed in fish liver in addition to the determination of fish contaminants levels and diverse growth and morphometric indices. An up-regulation of RTs associated to lower methylation levels and lower growth indices were observed in highly contaminated fish. Our results suggest that RT activation in fish experiencing stress conditions could have both detrimental and beneficial implications, affecting fish growth but promoting resistance to environmental stressors such as pollutants. PMID- 30458380 TI - Genotoxicological analyses of insectivorous bats (Mammalia: Chiroptera) in central Brazil: The oral epithelium as an indicator of environmental quality. AB - The micronucleus (MN) test of the human buccal mucosa was developed more than 30 years ago, although this technique has only recently been applied to wild mammals. This paper presents a pioneering study in the genotoxicological evaluation of the exfoliated cells of the buccal mucosa of bats. The assay was applied to two insectivorous bat species (Noctilio albiventris and Pteronotus parnellii) sampled in riparian corridors located in the city of Palmas (capital of the Brazilian state of Tocantins), with the results being compared with those obtained for a third insectivorous species (Nyctinomops laticaudatus), which has established a colony under a road bridge in the same region. This colony represents one of the largest molossidae populations ever recorded in Brazil. A significantly higher frequency of micronuclei was recorded in this colony, as well as a number of other nuclear abnormalities, including binucleated cells, cells with condensed chromatin and karyolysis, in comparison with the bats from the riparian corridors, indicating that the bats from the bridge colony are more susceptible to genotoxic damage. Thus, it is demonstrated the importance of the biomarker (MN) for use in wild animals and allows to conclude that colony bats are more susceptible to genotoxic damages. PMID- 30458381 TI - Different dynamic accumulation and toxicity of ZnO nanoparticles and ionic Zn in the soil sentinel organism Enchytraeus crypticus. AB - There is still no consensus over the specific effects of metal-based nanoparticles when compared with the conventional metal salts. Here, the accumulation and toxicity of ZnO-NPs and ZnCl2 in Enchytraeus crypticus over time (1-14 d) were investigated using a sand-solution exposure medium and applying a toxicokinetics and toxicodynamics approach. For both Zn forms, body Zn concentration in the organisms was dependent on both the exposure concentration and exposure time, with equilibrium being reached after 7-14 days of exposure. Generally, the uptake and elimination rate constants (Ku and Ke1) were smaller for ZnO-NPs (5.74-12.6 mg kg-1d-1 and 0.17-0.39 d-1) than for ZnCl2 (8.32-40.1 mg kg-1d-1 and 0.31-2.05 d-1), suggesting that ionic Zn was more accessible for E. crypticus than nanoparticulate Zn. Based on external exposure concentrations, LC50s for ZnO-NPs and ZnCl2 decreased with time from 123 to 67 Zn mg L-1 and from 86 to 62 Zn mg L-1, reaching an almost similar ultimate value within 14 d. LC50s based on body Zn concentrations were almost constant over time (except for 1 d) for both ZnO-NPs and ZnCl2, with overall LC50body of Zn being 1720 and 1306 mg kg 1 dry body weight, respectively. Body Zn concentration, which considers all available pathways, was a good predictor of dynamic toxicity of ZnCl2, but not for ZnO-NPs. This may be attributed to the specific internal distribution and detoxification mechanisms of ZnO-NPs. The particles from ZnO-NPs dominated the accumulation (>75%) and toxicity (~100%). Our results suggest that dynamic aspects should be taken into account when assessing and comparing NPs and metals uptake and consequent patterns of toxicity. PMID- 30458382 TI - Clinical and radiological characteristics of restless legs syndrome following acute lacunar infarction. AB - BACKGROUND: Recent studies have suggested that cerebral ischemic infarction may contribute to the development of restless legs syndrome (RLS). This study analyzed the clinical and radiological profiles of RLS with onset after acute lacunar infarction. METHODS: In this retrospective study we enrolled 244 consecutive patients with acute lacunar infarction between January 2012 and June 2014. RLS was identified and evaluated based on the International RLS Rating Scale (IRLS-RS). Individual sleep quality was assessed using the Epworth Sleepiness Scale (ESS). Psychological state was also assessed using the Hamilton Depression Scale (HDS) and the Hamilton Anxiety Scale (HAS). RESULTS: The incidence of RLS in patients with lacunar infarction was 5.33%. Our participant group consisted of nine males and four females. Three patients had symptoms in bilateral limbs, and 10 patients had symptoms only contralateral to the cerebral infarction. The infarctions were localized to the pons, centrum semiovale, thalamus, putamen, medulla, and occipital lobe. Contralateral paralysis was found in 13 patients, and contralateral sensory deficit in seven patients. The average IRLS-RS, ESS, HDS, HAS scores were 19.07 +/- 8.70, 4.69 +/- 5.82, 4.38 +/- 4.68, and 3.85 +/- 4.76, respectively. Nine patients had diabetes mellitus. After administration of dopaminergic drugs, patients' RLS significantly improved. CONCLUSIONS: The incidence of RLS after acute lacunar infarction was 5.33%. Pons, centrum semiovale, and basal ganglia were the common locations of responsible lesions. Compared to idiopathic RLS, symptoms of RLS after acute lacunar infarction appeared more unilateral and more likely involved the arm. Moreover, diabetes mellitus may be a risk factor for RLS in stroke patients. PMID- 30458383 TI - Intracochlear near infrared stimulation: Feasibility of optoacoustic stimulation in vivo. AB - Intracochlear optical stimulation has been suggested as an alternative approach to hearing prosthetics in recent years. This study investigated the properties of a near infrared laser (NIR) induced optoacoustic effect. Pressure recordings were performed at the external meatus of anaesthetized guinea pigs during intracochlear NIR stimulation. The sound pressure and power spectra were determined. The results were compared to multi unit responses in the inferior colliculus (IC). Additionally, the responses to NIR stimulation were compared to IC responses induced by intracochlear electric stimulation at the same cochlear position to investigate a potentially confounding contribution of direct neural NIR stimulation. The power spectra of the sound recorded at the external meatus (n = 7) had most power at frequencies below 10 kHz and showed little variation for different stimulation sites. The mean spike rates of IC units responding to intracochlear NIR stimulation (n = 222) of 17 animals were significantly correlated with the power of the externally recorded signal at frequencies corresponding to the best frequencies of the IC units. The response strength as well as the sound pressure at the external meatus depended on the pulse peak power of the optical stimulus. The sound pressure recorded at the external meatus reached levels above 70 dB SPL peak equivalent. In hearing animals a cochlear activation apical to the location of the fiber was found. The absence of any NIR responses after pharmacologically deafening and the comparison to electric stimulation at the NIR stimulation site revealed no indication of a confounding direct neural NIR stimulation. Intracochlear optoacoustic stimulation might become useful in combined electro-acoustic stimulation devices in the future. PMID- 30458384 TI - Whole-cell based synthetic enzyme cascades-light and shadow of a promising technology. AB - Mimicking Nature by biocatalytic cascade reactions in a whole-cell environment is a revolutionary development in multistep synthesis for the production of bulk and fine chemicals. In the past decade, several proof of concept success stories demonstrated the power of those synthetic cascades and paved the road for future industrial applications. Although enzymes and their promiscuity are best suited to construct such artificial pathways, the complexity and the lack of understanding of the cellular machinery slowed down this progress significantly. In this review, recent achievements in the field of whole-cell biocatalysis are described, challenges and hidden traps that have to be overcome are depicted, and strategies are illustrated how to increase overall cascade productivity. PMID- 30458385 TI - A novel strategy to screen inhibitors of multiple aminoglycoside-modifying enzymes with ultra-high performance liquid chromatography-quadrupole-time-of flight mass spectrometry. AB - Resistance to aminoglycoside antibiotics occurs primarily as a result of aminoglycoside-modification enzymes (AMEs) that modify the antibiotics. In this work, a novel strategy to combat the effects of antibiotic resistance was developed by screening multiple AMEs inhibitors with ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UHPLC-QTOF MS). The method screened inhibitors of three AMEs (AAC(6')-APH(2"), AAC(6') and APH(2")) simultaneously through measuring the acetyltransferase activity and phosphotransferase activity of AAC(6')-APH(2") enzyme in a single assay. Screening inhibitors of multiple targets could greatly improve the screening efficiency at early-stages of drug discovery. In this study, enzyme reaction conditions including cosubstrate, enzyme concentration and cosubstrate concentration were optimized. The inhibition constants (Ki) for two known inhibitors, paromomycin and quercetin, were determined to be 1.23 and 20.27 MUM, respectively. The assay was further validated through the determination of a high Z' factor value of 0.73. The developed assay was applied to screen a chemical library against bifunctional AAC(6')-APH(2'') enzyme. Using this assay, two pyrimidinyl indole derivatives were found to be potent, and effective AAC(6') APH(2'') inhibitors. The assay of exploring the selective inhibitory effect on two AAC(6')-APH(2'') active sites was further performed. Two pyrimidinyl indole derivatives were found to exhibit striking inhibitory activities on AAC(6'). PMID- 30458387 TI - NDMA impurity in valsartan and other pharmaceutical products: Analytical methods for the determination of N-nitrosamines. AB - Batch recalls for valsartan containing pharmaceutical products in July 2018 initiated a discussion on possible contaminations with N-nitrosodimethylamine (NDMA). It appeared that NDMA was generated during synthesis of the active pharmaceutical ingredient (API) from the solvent dimethylformamide (DMF) and the reagent nitrite. Discussion on NDMA as API impurity is extended to other drugs since then. Already several years before scientific literature reported NDMA as impurity of several other drugs, thus underlining the apparent risk. At present none of the pharmacopoeias tests for NDMA and only very limited publications of methods for its determination in pharmaceuticals are published so far. This review summarizes aspects for the analyses of nitrosamines (NAs) with special focus on NDMA and discusses their potential applicability for drug analyses. The majority of recent publications utilize GC-MS or GC-MS/MS due to its high selectivity and low detection levels. GC-TEA also provides high selectivity for nitrosamines. However, current availability of this combination is very limited. Alternatively, LC-MS/MS is also performed in NA analysis. An integration of a general test in future pharmacopoeias is suggested due to the toxicological relevance and broader spectrum of possible APIs that may be affected. PMID- 30458386 TI - Influence of moisture variation on the performance of Raman spectroscopy in quantitative pharmaceutical analyses. AB - To develop a robust quantitative calibration model for spectroscopy, different sources of variability that are not directly related to the components of interest should be included in the calibration samples; this variability should be similar to that which is anticipated during validation and routine operation. Moisture content of pharmaceutical samples can vary as a function of supplier, storage conditions, geographic origin or seasonal variation. Additionally, some pharmaceutical operations (e. g., wet granulation) cause exposure of excipients and API to water. Although water is a weak Raman scatterer, moisture variability has an indirect effect on analytical model performance. Because many pharmaceutical components have intrinsic fluorescent characteristics (with broad spectral features), moisture variability may cause spectral artifacts in the form of baseline variation associated with fluorescence quenching. This work investigates the deleterious effects of water quenching on quantitative prediction accuracy of a multivariate calibration algorithm for Raman spectroscopy. To demonstrate this, a formulation composed of acetaminophen, lactose, microcrystalline cellulose, HPMC and magnesium stearate was used. Tablets were manufactured using laboratory scale equipment. A full-factorial design was used to vary acetaminophen (5 levels), and excipient ratios (3 levels) to generate tablets for calibration and testing. Tablet moisture variation was introduced by placing samples in different humidity chambers. Significant spectral effects arising from fluorescence were identified in the Raman spectra and due to moisture variation: the fluorescence related spectral variability caused substantial degradation of the prediction performance for API. The work demonstrated that accounting for moisture variation during method development reduced the prediction error of the multivariate prediction model. PMID- 30458388 TI - Comparative two-dimensional HepG2 and L02/ cell membrane chromatography/ C18/ time-of-flight mass spectrometry for screening selective anti-hepatoma components from Scutellariae Radix. AB - Screening active components from Chinese traditional medicine is an effective approach to discover new drugs or active structures. Cell membrane chromatography (CMC), developed rapidly because of its high sensitivity and effectiveness, has achieved a wide application in screening active components on pathological cells or tissues. However, it is hard to clarify the selectivity between pathological and normal tissues through simply using pathological cells. In this study, a novel comparative two-dimensional (2D) cell membrane chromatography system was established. Briefly, hepatic carcinoma HepG2 CMC columns and normal hepatic L02 CMC columns were simultaneously loaded to screen potential selective antitumor components from Scutellariae Radix by comparing the retention behaviors on two kinds of cells. Totally 13 components in Scutellariae Radix retained on both HepG2/ CMC and L02/ CMC columns. Among them, three components, oroxylin A, wogonin and chrysin, were screened out to perform stronger affinity on HepG2 columns, and in further cell proliferation assay, IC50 of these three compounds of HepG2 cells were 9.66 MUM, 66.77 MUM and 36.26 MUM respectively, while of L02 cells, IC50 of chrysin was 59.10 MUM and over 200 MUM of the other two components. On the whole, the toxity of these three compounds to hepatoma cells was stronger than to normal cells. It can be supposed that oroxylin A, wogonin, and chrysin own the potential to be developed as selective anti-hepatoma active components, which expects further research to validate. PMID- 30458389 TI - Influence of doping ion, capping agent and pH on the fluorescence properties of zinc sulfide quantum dots: Sensing of Cu2+ and Hg2+ ions and their biocompatibility with cancer and fungal cells. AB - Herein, a facile one-pot synthetic method was explored for the fabrication of glutathione capped Mn2+ doped-zinc sulphide quantum dots (GSH-Mn2+-ZnS QDs) for both fluorescent detection of Cu2+ and Hg2+ ions and for fluorescence imaging of two cancer (RIN5F and MDAMB231) and fungal (Rhizopus oryzae) cells. Particularly, doping of Mn2+ into ZnS QDs nanocrystal structure resulted a great improvement in the fluorescence properties of ZnS QDs. The emission peak of undoped ZnS QDs was found at 447 nm, which is due to the large number of surface defects in the ZnS QDs nanostructures. Under identical conditions, there is a good linear relationship between the quenching of fluorescence intensity and analytes (Cu2+ and Hg2+ ions) concentration in the range of 0.005 to 0.2 mM and of 0.025 to 0.4 mM for Cu2+ and Hg2+ ions, respectively. The GSH-Mn2+-ZnS QDs exhibit least cytotoxicity against RIN5F and MDAMB231 cells, demonstrating the multifunctional applications in sensing of metal ions and biocompatibility towards cancer (RIN5F and MDAMB231) and fungal (Rhizopus oryzae) cells. PMID- 30458390 TI - Spectroscopic and thermal properties of stannadithiane compounds bearing endocyclic ether and lactone groups. AB - Four related stannadithiane compounds containing different endocyclic functional groups -including ether (1), diether (2), lactone (3), and spirolactone (4)- were prepared. The conformational landscape has been fully determined for the 8 membered representative (compound 1) resulting in a distorted crown form with the butyl chains adopting an extended conformation. The infrared and Raman spectra of stannadithiane species have been measured and interpreted, aided by quantum chemical calculations and potential energy surface analysis. Special attention has been devoted to the analysis of the vibrational features of the heterocyclic moieties. The characteristic nuas(SnS) and nus(SnS) stretching modes of the SnS2endo-cyclic group were clearly observed in the Raman spectra at around 340 and 315 cm-1, respectively. The exo-cyclic nu(SnC) stretching modes were found near 590 and 565 cm-1 for the antisymmetric and symmetric motions, respectively. Thermal behavior for compounds 2-4 has been determined by thermogravimetric methods. PMID- 30458391 TI - Synthesis and photochromic properties of some N-phthalimide azo-azomethine dyes. A DFT quantum mechanical calculations on imine-enamine tautomerism and trans-cis photoisomerization. AB - This paper presents synthesis, photophysical characterization and quantum mechanical calculations of some N-phthalimide azo-azomethine dyes. The dyes were synthesized via azo coupling reaction between 2,4-substituted aromatic anilines and salicylic aldehyde followed by condensation reactions between azo dyes and N aminophtalimide. Quantum chemical calculations to optimise the molecular geometry and to determine the electron densities of the trans (E) imine ? enamine and the cis (Z) imine ? enamine isomers and their vibrational frequencies have been computed by using DFT at B3LYP/6-31 + G(d,p) level of theory in vacuo. The effect of the used DMF solvent on the molecular structure and bond energies has been determined by using the IEFPCM model. Thermodynamic parameters such as total electronic energy E(RB3LYP), enthalpy H298 (sum of electronic and thermal enthalpies), free Gibbs energy G298 (sum of electronic and thermal free Gibbs energies) and dipole moment MU were computed in order to estimate the DeltaE, DeltaMU, DeltaH, DeltaG and DeltaS values. The NBO analysis was performed in order to understand the intramolecular charge transfer and the energy of resonance stabilization. After molecular geometry optimization, the electronic spectra were obtained by TD-DFT calculations at the above mentioned basis set using the IEFPCM model of DMF as a solvent. The solvatochromic effect of the dyes in four solvents with different polarity has been studied by UV-VIS spectroscopy and compared with the theoretically predicted. The coincidence between measured and calculated spectra is satisfactory. The dynamic photoisomerization experiments were performed in DMF under irradiation with UV light at lambda = 365 nm (mostly E -> Z) and with VIS light at lambda = 400-800 nm (mostly Z -> E). The spectra were recorded in the spectral region from 300 to 800 nm at identical sample concentrations of the three dyes and illumination times in order to investigate the photodynamical E -> Z -> E conversion of the NN chromophore group of the dyes as well as the imine ? enamine tautomerization. PMID- 30458392 TI - Description of an air temperature sensor based on O2 absorption spectroscopy. AB - In this paper, we describe in detail an assembled open-path optical cavity to act as a temperature sensor of air. A metal absorption cell in a temperature regulated tube furnace is placed at the center of an optical cavity. The optical cavity consists of two mirrors, two nitrogen buffer sleeves, and the open cell. The air is injected through a fitting in one extreme of the metal tube and travels half the tube length through a channel in the wall of the tube. The channel directs the air towards the center of the cell. The air flowing is heated at the temperature of the metal tube in contact with the furnace. The heated air injected at the center of the tube, flows towards the open extremes of the tube. The nitrogen buffer sleeves protect the mirrors from the heated air. The temperature of the air flowing through the tube is determined by measuring the absorption of the A band of oxygen as a function of the wavenumber in the 769-755 nm wavelength range. The absorption technique is phase-shift cavity ring down spectroscopy. To obtain the temperature, the energy of the lower rotational state for eleven selected rotational transitions is linearly fitted to a logarithmic function that contains the relative intensity of the rotational transition, the initial and final rotational quantum numbers and the energy of the transition. Accuracy of the measurement is determined by comparing the calculated temperature from the spectra with the analog reading of the temperature-regulated tube furnace. This technique is proposed for exhaust air temperature measurements of combustion chambers and cooling air after passing through the blades of a turbine. PMID- 30458393 TI - A colorimetric paper sensor for citrate as biomarker for early stage detection of prostate cancer based on peroxidase-like activity of cysteine-capped gold nanoclusters. AB - Citrate is currently considered a preferred biomarker for the early stage detection of prostate cancer. In the present work, based on the highly efficient catalytic properties of gold nanoclusters, a novel system for optical determination of citrate was successfully established under optimized conditions. Cysteine-capped gold nanoclusters (Cys-AuNCs) are shown to have an intrinsic peroxidase-mimetic activity. In the presence of H2O2, Cys-AuNCs nanostructures are able to catalyse the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) with high efficiency to produce a blue dye (with an absorbance maximum at 650 nm). Citrate has carboxylic and hydroxyl groups that can bind with free amino and free carboxyl cysteine groups via hydrogen bonds, thus creating a coating on the surface of the gold nanocluster and inhibiting the cluster oxidation activity. Accordingly, a visual, sensitive and simple colorimetric method using Cys-AuNCs as peroxidase mimetic was developed for detecting citrate. A suitable linear relationship for citrate was obtained for the range of 0.5 to 1000 MUM. The limit of detection (LOD) of the proposed method was calculated as 0.1 MUM and the relative standard deviation (RSD) was obtained to be less than 4.0%. Moreover, the biosensor was used to perform a paper assay on a Y-shaped microfluidic device and make use of the distinctive features of microchannels such as short response time, very low reagent volume required, low fabrication cost etc. A detection limit of 0.4 MUM was achieved through the paper test and a good linear range was observed between 1.0 MUM-10 mM. The proposed method was further applied to citrate detection in the human urine sample. PMID- 30458394 TI - iTRAQ-based comparative proteomic analysis of differentially expressed proteins in Rhodococcus sp. BAP-1 induced by fluoranthene. AB - To reveal the molecular mechanism at the level of regulation of proteins in Rhodococcus sp. BAP-1 induced by fluoranthene comparative proteomic analysis was performed on proteins extracted from fluoranthene-exposed cells on 1 d, 3 d, 6 d and 8 d compared with control cells using isobaric tags for relative and absolute quantization (iTRAQ) labeling and LC-MS/MS analysis to access differentially expressed proteins. As a result, we detected a total of 897 significantly differentially expressed proteins, including 30 shared proteins in four comparison clusters. We were able to short-list 190, 329, 101 and 90 proteins that were over-represented, and 394, 234, 65 and 49 under-represented proteins, in 1d/control, 3d/control, 6d/control and 8d/control comparisons, respectively. Functional analysis relied on Clusters of Orthologous Groups (COG), gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed that fluoranthene significantly altered the expression of proteins involved in metabolic and biosynthesis processes. Furthermore, BAP-1 up-regulates aldehyde dehydrogenase, cytochrome c oxidase, and oligopeptide transport ATP-binding protein, while down-regulates several other proteins in order to adapt to fluoranthene exposure. These findings provide important clues to reveal fluoranthene degradation mechanism in BAP-1 and promote its bioremediation applications. PMID- 30458395 TI - Simultaneous mitigation of tissue cadmium and lead accumulation in rice via sulfate-reducing bacterium. AB - The objectives of this study were to investigate the mechanism responsible for Cd and Pb immobilization by sulfate reduction to sulfide and effectiveness of decreasing Cd2+ and Pb2+ bioavailability in culture solution and paddy soils via sulfate-reducing bacterium (SRB1-1). The SRB1-1 strain, exhibiting high resistances to Cd2+ and Pb2+, was isolated from bulk soils in the metal(loid) contaminated paddy field. During the culture of the SRB1-1 strain, the removal percentages of Cd2+ and Pb2+ from culture solution reached 99.5% and 76.0% in 72 h, respectively. The surface morphology and composition of metal precipitates formed by SRB1-1 strain were analyzed by transmission electron microscopy (TEM) and further confirmed to be CdS and PbS by X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). When living SRB1-1 strain was applied in Cd and Pb-contaminated soils, the SRB1-1 strain could stably colonize using its resistance to rifampicin, and showed significantly impact on the bacterial community composition. Cd and Pb contents in rice grains were decreased by 29.5% and 26.2%, respectively, while Cd and Pb contents in the roots, culms, leaves, and husk were also decreased ranging from 19.1% to 43%, respectively. Due to growth in highly Cd and Pb contaminated soils, Cd content of the rice grains did not meet the standard for limit of Cd and Pb, but safe production of rice plants may be obtained in slightly or moderately metal(loid)-contaminated soils in the presence of the living SRB1-1 strain. These results indicated that the SRB1-1 strain could effectively reduce the Cd and Pb bioavailability in soils and uptake in rice plants. Our results highlighted the possibility to develop a new bacterial-assisted technique for reduced metal accumulation in rice grains, and also showed potential for effective synergistic bioremediation of SRB1-1 strain and rice plants in metal(loid)-contaminated soils. PMID- 30458396 TI - Atmospheric PM2.5 aspiration causes tauopathy by disturbing the insulin signaling pathway. AB - Epidemiological and toxicological studies have shown that ambient fine particulate matter (PM2.5) is a healthy risk factor for neurodegenerative diseases. Hyperphosphorylated tau is the common feature of numerous neurodegenerative diseases known as tauopathy, which could be inhibited by insulin stimulation. However, the effects of PM2.5 on tau protein injury by disturbing the insulin signaling pathway still need to be illuminated. In present study, male C57BL/6 J mice were administered with PM2.5 to determine whether PM2.5 inhalation can induce tauopathy via the insulin resistance (IR) related pathway (IRS-1/AKT/GSK-3beta signaling pathway). The results showed that PM2.5 treatment induced the generation of phosphorylated tau (P-tau) and contributed to the development of tauopathy because of the insulin signaling disorders in insulin targeting organs. As expected, the occurrence of central and peripheral IR and accompanying hyperinsulinemia aggravated the disturbance of the IRS 1/AKT/GSK-3beta signaling pathway. These observations indicated that PM2.5 exposure led to neurodegenerative tau lesion, and insulin signaling pathway might be a potential therapeutic target for tauopathy. PMID- 30458397 TI - Complementarity of co-planting a hyperaccumulator with three metal(loid)-tolerant species for metal(loid)-contaminated soil remediation. AB - Co-planting with multiple plant species has great value for the remediation of soil co-contaminated with metal(loid)s. A pot experiment has been conducted to study the growth, phytoextraction of metal(loid) and complementarity by co planting Pteris vittata L. with three metal(loid)-tolerant species with large biomass (namely Arundo donax L., Morus alba L., and Broussonetia papyrifera L.) on soil co-contaminated with As, Cd, Pb, and Zn. The results showed that the co planting can favor the growth and uptake of As in hyperaccumulator P. vittata L., and improve comprehensive extraction of metal(loid). The total biomass and content of As in the roots of P. vittata L. under the co-planting system were significantly (p < 0.05) improved by 117.5% and 122.0%, respectively, compared with that in monoculture, while the content of As, Cd, Pb and Zn in the tissues of A. donax L., M. alba L. and B. papyrifera L. was slightly increased. The comprehensive accumulation amounts for As, Cd, Pb, and Zn by the four plants co planting in contaminated soil were higher than that in part of plant's monoculture. Moreover, availability of As, Cd, and Zn in the contaminated soil was decreased in the co-planting system, meanwhile soil urease and acid phosphatase activities in soil significantly (p < 0.05) promoted as compared to the monocultures. The results suggested that positive interaction between hyperaccumulator and three metal(loid)-tolerant species can effectively enhance the growth of P. vittata L., regulate the comprehensive metal(loid)s accumulation capacity, and improve the environmental quality of contaminated soil, which drives high phytoremediation potential for metal(loid)s-contaminated soil by the co-planting. PMID- 30458398 TI - Sequential prediction of quantitative health risk assessment for the fine particulate matter in an underground facility using deep recurrent neural networks. AB - Particulate matter with aerodynamic diameter less than 2.5 um (PM2.5) in indoor public spaces such as subway stations, has represented a major public health concern; however, forecasting future sequences of quantitative health risk is an effective method for protecting commuters' health, and an important tool for developing early warning systems. Despite the existence of several predicting methods, some tend to fail to forecast long-term dependencies in an effective way. This paper aims to implement a multiple sequences prediction of a comprehensive indoor air quality index (CIAI) traced by indoor PM2.5, utilizing different structures of recurrent neural networks (RNN). A standard RNN (SRNN), long short-term memory (LSTM) and a gated recurrent unit (GRU) structures were implemented due to their capability of managing sequential, and time-dependent data. Hourly indoor PM2.5 concentration data collected in the D-subway station, South Korea, were utilized for the validation of the proposed method. For the selection of the most suitable predictive model (i.e. SRNN, LSTM, GRU), a point by-point prediction on the PM2.5 was conducted, demonstrating that the GRU structure outperforms the other RNN structures (RMSE = 21.04 ug/m3, MAPE = 32.92%, R2 = 0.65). Then, this model is utilized to sequentially predict the concentration and quantify the health risk (i.e. CIAI) at different time lags. For a 6-h time lag, the proposed model exhibited the best performance metric (RMSE = 29.73 ug/m3, MAPE = 29.52%). Additionally, for the rest of the time lags including 12, 18 and 24 h, achieved an acceptable performance (MAPE = 29-37%). PMID- 30458400 TI - Alcohol ethoxylate degradation of activated sludge is enhanced by bioaugmentation with Pseudomonas sp. LZ-B. AB - An effective bioaugmentation strategy was developed for the removal of alcohol ethoxylates (AEs) from municipal wastewater. An AE-degrading strain, Pseudomonas sp. LZ-B, was isolated from an activated sludge. Strain LZ-B was able to degrade 96.8% of 200 mg/L C12E4 (Brij 30) within 24 h and showed significant biomass increase and removal of total oxygen concentration (TOC). The optimal degradation temperature and pH value were 37 degrees C and 6.0, respectively. The strain demonstrated greater potential to degrade five different molecular weight AEs within 5 days. HPLC-MS/MS analysis demonstrated that the major metabolites obtained were polyethylene glycol (PEG) and carboxylated AE chains. Activated sludge has a low ability to remove AEs. After inoculation of strain LZ-B into the activated sludge reactor, Strain LZ-B successfully colonized the activated sludge, and AE removal efficiency increased to more than 95% when the hydraulic retention time (HRT) was 10 h. After strain LZ-B cleaved the AE chains, the sludge microbial communities easily removed PEG fragments to facilitate complete biodegradation of AEs. This is the first report describing bioaugmentation to increase AE degradation in an activated sludge system. PMID- 30458399 TI - Polybrominated diphenyl ethers (PBDEs) in dust in typical indoor public places in Hangzhou: Levels and an assessment of human exposure. AB - Polybrominated diphenyl ethers (PBDEs) are organic pollutants (POPs) with the characteristics of environmental persistence, long-distance transmission in nature, biological accumulation and toxic effects on human health. To investigate the level of contamination due to PBDEs in typical indoor public places in Hangzhou, dust samples were collected from ten supermarkets, three electronic markets and five different areas throughout one commodity market. Based on sample pretreatment and GC-ECD instrumental analysis, the contamination characteristics, sources and the influencing factors of 14 PBDE congeners were analyzed. The results revealed that the mean of ?14PBDEs in dust in the supermarkets and electronic markets was 546.13 ng/g and 1140.05 ng/g, respectively, while in the commodity market the mean was 1005.42 ng/g and varied in the five different areas as follows: shoe areas (1367.22 ng/g) > parking lot (1001.05 ng/g) > waiting halls (970.31 ng/g) > packet areas (933.23 ng/g) > curtain areas (755.28 ng/g). The high levels of PBDE were attributed to the quantity of electrical appliances in the supermarkets (r = 0.708*, p < 0.05) and the electronic markets (r = 0.799**, p < 0.05) through Spearman correlation coefficient analysis. BDE-209 was the dominant congener, accounting for 53.72% in supermarkets and 64.25% in electronic markets. The calculated inhalation exposure revealed that the exposure level of PBDEs varied in supermarkets, electronic markets and commodity markets, with values of 0.476 ng/day/kg, 0.993 ng/day/kg and 0.876 ng/day/kg, respectively. Moreover, BDE-209's contribution to the total intake of PBDEs was the highest, with a value of 0.072-0.970 ng/day/kg, while the value of BDE-183 was the lowest, with a value of 0-0.020 ng/day/kg. The exposure level of PBDEs in the studied indoor public places was lower than the reference dose of EPA. PMID- 30458401 TI - Excessive use of enrofloxacin leads to growth inhibition of juvenile giant freshwater prawn Macrobrachium rosenbergii. AB - Giant freshwater prawn Macrobrachium rosenbergii is an economically important species. However, its growth retardant have brought serious economic losses in recent years. Antibiotics abuse is suggested as a reason for M. rosenbergii's growth retardant, while few studies focused on the toxic effect of antibiotics on M. rosenbergii. To investigate the effect of enrofloxacin, a widely used antibiotic, on juvenile M. rosenbergii, a 14 days exposure study was carried out within 0.2, 1 and 5 mg/L enrofloxacin and followed by 7 days decontamination. Results showed that during the test period, enrofloxacin had the largest accumulation in juvenile shrimp at day 3, and gradually decreased at day 7 and 14, and almost all the drugs are cleared after 3 days decontamination. Short-term exposure to low dose enrofloxacin can promote the growth of juveniles. High dose enrofloxacin inhibited the growth of juvenile shrimp, to gill and liver damage, and induced apoptosis of the hepatopancreatic cells. These adverse effects was possibly caused by enrofloxacin-induced oxidative stress. Moreover, we also found the damage caused by high concentrations of enrofloxacin was irreversible in the short term. Collectively, these data indicated that enrofloxacin did affect the juvenile shrimp growth and development, and high level enrofloxacin abuse may contributed to M. rosenbergii's growth retardant. PMID- 30458402 TI - Insight into effects of citric acid on adsorption of phthalic acid esters (PAEs) in mangrove sediments. AB - The adsorption of phthalate esters (PAEs) in mangrove sediment greatly influences their availability to aquatic organisms, however, the adsorption processes of PAEs in mangrove sediment, as well as the effects of root exudates, are poorly understood. In this study, dimethyl phthalate (DMP), diethyl phthalate (DEP) and dibutyl phthalate (DBP) was used as model PAEs to determine the effects and mechanism of citric acid on the adsorption kinetics and isotherms of PAEs in the mangrove sediments. The adsorption kinetics followed pseudo-second order model, describing the characteristics of heterogeneous chemisorption of PAEs in mangrove sediments. The adsorption isotherms of DMP and DEP followed Freundlich model, implying the characteristics of surface multilayer heterogeneous adsorption; while the Henry model better described the adsorption isotherms of DBP, suggesting that hydrophobic partition accounted for DBP adsorption in the mangrove sediments. Inter-chemical variability was observed in adsorption capacity (qe) with the sequence of DBP > DEP > DMP. Surface polarity index ((C-O + COOH + C?O)%) of particulate organic matter (POM) regulated the adsorption capacity of DMP and DEP in mangrove sediments, while different POM content among mangrove sediments explained the difference in the sorption strength for DBP. The presence of citric acid enhanced the qe of the three PAEs by 6.4-12.6%. These findings are of great significance to reveal that the root exudates play a crucial role in the PAEs adsorption in mangrove sediments, and provide valuable information for availability of PAEs in mangrove ecosystem. PMID- 30458403 TI - A real time QSAR-driven toxicity evaluation and monitoring of iron containing fine particulate matters in indoor subway stations. AB - A fine particulate matter less than 2.5 um (PM2.5) in the underground subway system are the cause of many diseases. The iron containing PMs frequently confront in underground stations, which ultimately have an impact on the health of living beings especially in children. Hence, it is necessary to conduct toxicity assessment of chemical species and regularized the indoor air pollutants to ensure the good health of children. Therefore, in this study, a new indoor air quality (IAQ) index is proposed based on toxicity assessment by quantitative structure-activity relationship (QSAR) model. The new indices called comprehensive indoor air toxicity (CIAT) and cumulative comprehensive indoor air toxicity (CCIAT) suggests the new standards based on toxicity assessment of PM2.5. QSAR based deep neural network (DNN) exhibited the best model in predicting the toxicity assessment of chemical species in particulate matters, which yield lowest RMSE and QF32 values of 0.6821 and 0.8346, respectively, in the test phase. After integration with a standard concentration of PM2.5, two health risk indices of CIAT and CCIAT are introduced based on toxicity assessment results, which can be use as the toxicity standard of PM2.5 for detail IAQ management in a subway station. These new health risk indices suggest more sensitive air pollutant level of iron containing fine particulate matters or molecular level contaminants in underground spaces, alerting the health risk of adults and children in "unhealthy for sensitive group". PMID- 30458404 TI - Cauliflower ear in late onset psychosis. PMID- 30458405 TI - Divergent gene expression in the gills of juvenile turbot (Psetta maxima) exposed to chronic severe hypercapnia indicates dose-dependent increase in intracellular oxidative stress and hypoxia. AB - Elevated concentrations of carbon dioxide are a common stressor for fish and other aquatic animals. In particular, intensive aquaculture can impose prolonged periods of severe environmental hypercapnia, manifold exceeding CO2 concentrations of natural habitats. In order to cope with this stressor, gills are essential and constitute the primary organ in the acclimatization process. Yet, despite a general understanding of changes in ion regulation, not much is known with regard to other cellular mechanisms. In this study, we apply RT-qPCR to investigate changes in the expression of several genes associated with metabolism, stress and immunity within gills of juvenile turbot (Psetta maxima) after an eight-week exposure to different concentrations of CO2 (low = ~3000 MUatm, medium = ~15,000 MUatm and high = ~25,000 MUatm CO2). Histological examination of the gill tissue only found a significant increase of hypertrophied secondary lamella in the highest tested treatment level. gene expression results, on the other hand, implied both, mutual and dose-dependent transcriptional adjustments. Comparable up-regulation of IL-1beta, LMP7 and Grim19 at medium and high hypercapnia indicated an increase of reactive oxygen species (ROS) within gill cells. Simultaneous increase in Akirin and PRDX transcripts at medium CO2 indicated enhanced anti-oxidant activity and regulation of transcription, while reduced mRNA concentrations of COX, EF1alpha and STAT2 at high CO2 denoted suppressed protein synthesis and reduced metabolic capacity. In addition to upregulated DFAD and ApoE expression, implying compensating repair measures, gills exposed to the highest tested treatment level seemed to operate close to or even beyond their maximum capacity. Thus, fitting the model of capacity limitation, our results provide evidence for accretive intracellular hypoxia and oxidative stress in the gills of turbot, dependent on the level of environmental hypercapnia. Further, genes, such as COX, may be valuable biomarkers when attempting to discriminate between a successful and an overpowered stress response. PMID- 30458406 TI - Reprogramming the brain with synthetic neurobiology. AB - The mammalian brain is among the most complex organs known in biology. Historically, neuroscience techniques have consisted primarily of low-throughput microscopy and electrophysiological approaches. While these methods will continue to serve the community, the emerging field of synthetic neurobiology may be better equipped to scale with systems neuroscience. By using genetic techniques to achieve cell-type specificity, a map of the connectome, neural activation and recording, and ultimately to program neural development itself, we can begin to build a better framework with which to understand the brain's mechanisms. PMID- 30458407 TI - Probabilistic genotyping software: An overview. AB - The interpretation of mixed profiles from DNA evidentiary material is one of the more challenging duties of the forensic scientist. Traditionally, analysts have used a "binary" approach to interpretation where inferred genotypes are either included or excluded from the mixture using a stochastic threshold and other biological parameters such as heterozygote balance, mixture ratio, and stutter ratios. As the sensitivity of STR multiplexes and capillary electrophoresis instrumentation improved over the past 25 years, coupled with the change in the type of evidence being submitted for analysis (from high quality and quantity (often single-source) stains to low quality and quantity (often mixed) "touch" samples), the complexity of DNA profile interpretation has equally increased. This review provides a historical perspective on the movement from binary methods of interpretation to probabilistic methods of interpretation. We describe the two approaches to probabilistic genotyping (semi-continuous and fully continuous) and address issues such as validation and court acceptance. Areas of future needs for probabilistic software are discussed. PMID- 30458408 TI - Adsorptive remediation of cobalt oxide nanoparticles by magnetized alpha cellulose fibers from waste paper biomass. AB - Remediation of engineered-nanomaterials is an up-coming major environmental concern. This study demonstrates adsorptive-remediation of cobalt oxide nanoparticles (CoO NPs) from the water. The alpha-cellulose-fibers were extracted from waste-paper biomass (WP-alphaCFs) and magnetized with Fe3O4 NPs (M-WP alphaCFs). The XRD, FT-IR, and TGA were performed for detailed characterization of the newly developed bioadsorbent. The M-WP-alphaCFs was then applied for adsorptive remediation of CoO NPs. The adsorptive kinetics of CoO NPs adsorption onto the M-WP-alphaCFs reveals the pseudo-second-order model. The various adsorption isotherm studies revealed Langmuir is a best-fit isotherm. A prominently high adsorption capacity qm (1567 mg/g) corroborated extraordinary adsorptive potential of M-WP-alphaCFs. Furthermore, CoO NPs were adsorbed onto M WP-alphaCFs were analyzed by the XPS, VSM, and TEM. Therefore, this study gave rise WP biomass extracted and rapidly-separable nano-biocomposite of 'M-WP alphaCFs' with a high-capacity for CoO NPs remediation and can be further applied in remediation of several other engineered-nanomaterials. PMID- 30458409 TI - Effects and mechanisms of ultrasound- and alkali-assisted enzymolysis on production of water-soluble yeast beta-glucan. AB - This study investigated the effects and related mechanisms of ultrasound- and alkali-assisted enzymolysis on production of water-soluble yeast beta-glucan (WSYG). Results indicated that ultrasound and alkali pretreatments reduced the particle size of yeast beta-glucan (YG) from 8.80 MUm to 1.77 and 7.19 MUm, respectively. Ultrasound-induced cavitation disrupted YG aggregates to a coarse appearance and exposed internal structure. Alkali penetrated into YG particles and broke the YG aggregates into a flake-like morphology by cleaving the linkages within YG chains. Both pretreatments facilitated enzymolysis by enlarging the YG surface area and increased the WSYG yield to 32.3% and 36.2%, respectively. Meanwhile, the purity of WSYG reached 98.8% after zymoprotein removal by DEAE Sepharose fast flow column. This work not only provides a green method for producing high-purity and high-yield WSYG, but also reveals the mechanisms of ultrasound and alkali pretreatments for improving enzymolysis efficiency by loosening the YG structure and increasing the surface area. PMID- 30458410 TI - The student experience of clinical supervision across health disciplines - Perspectives and remedies to enhance clinical placement. AB - Effective clinical practice supervision for health students is essential prior to commencing their respective professions. Students require adequate preparation before their clinical practice event with an experienced clinical supervisor able to impart professional 'know how' and skills to students. The purpose of this study was to describe final year health students' perspectives and experiences of clinical supervision, and to develop an interprofessional model of clinical supervision. Focus groups and semi-structured interviews were conducted with undergraduate health students across a range of disciplines. Some students provided email comments. Qualitative data was analysed thematically using NVivo (V11). Six key themes and their various sub-themes (refer Table 1) were identified: (1) undergraduate learning valued by the CP provider; (2) effective connections (communications) between student, CS, CP provider and university; (3) undergraduate student learning not being valued; (4) ineffective connections; (5) mitigating factors for students; and (6) the impact of increasing student numbers. Undergraduate health student clinical placement requires careful educational preparation, structuring and adequate support for both the student undergoing the practice event and for the clinical supervisor stewarding the undergraduate health professional. A prospective plan to ensure an excellent experience is required (Fig. 1). PMID- 30458411 TI - Experiential learning in nursing and allied health education: Do we need a national framework to guide ethical practice? AB - Experiential learning is widely used in health courses to develop students' clinical skills. Students act as models for demonstrations of practical techniques and work in small groups to practise clinical skills. These classes present a number of ethical challenges including removing clothing, physical touch and disclosing personal information. The aim of this study was to ascertain the views of nursing and allied health regulators and professional associations regarding the need for a national framework to facilitate ethical experiential learning in health courses. Ten semi-structured interviews were conducted either face-to-face or by phone and their audio-recordings transcribed verbatim for thematic analysis. Students' willingness to participate as models was taken-for granted by educators. Risks to students' wellbeing were considered minor and outweighed by the benefits of experiential learning. The increasing diversity of students enrolled in health courses has increased awareness of students' rights, including choosing not to participate in some learning activities. Ongoing cycles of curriculum review provided an opportunity to respond to changing social values, including increased collective awareness and respect for, students' rights, cultural diversity, professional standards, and risk/benefit analysis of all student activities. There is a need for a national framework to guide ethical experiential learning in practical classes. PMID- 30458412 TI - The HEIPS framework: Scaffolding interprofessional education starts with health professional educators. AB - The link between interprofessional collaboration and interprofessional education has been at the centre of discourse for some time. To understand some of the challenges of interprofessional collaboration, a research study was undertaken. The study investigated the interprofessional socialisation experiences of health professional educators, across five higher education faculties in Perth, Western Australia (WA). An interpretive phenomenological framework was utilised to explore the phenomena of interprofessional socialisation. Twenty-six professional educators were interviewed from a variety of health-related disciplines and qualitative content analysis was undertaken with the aid of NVivo 10 software. Examination of the data discovered a range of barriers that were potentially preventing professionals from working together effectively, within education. Overcoming some of these obstacles were identified, such as, professional language, organizational support, time and workload and the proximity of professionals. The research also recommended a framework that would support health educators. Currently, there are conceptual frameworks that guide the professional and interprofessional socialisation of healthcare graduates within education. Whereas, there is very little guidance or frameworks to support professional educators interprofessional experiences. The heath educators' interprofessional socialisation (HEIPS) framework is presented within this paper, and is a four-step process to encourage the interprofessional socialisation of educators within universities. PMID- 30458413 TI - Design, synthesis and in vitro apoptotic mechanism of novel pyrrolopyrimidine derivatives. AB - In this work we described the synthesis and evaluation of cytotoxic and apoptotic activity of novel pyrrolopyrimidine derivatives against A549, PC3 and MCF-7 cells. Among the synthesized compounds, 6b, 8a, 9a and 7a, 8b displayed the significant cytotoxic activities against A549 and PC3 cells with IC50 value of 0.35, 1.48, 1.56 and 1.04, 1.89 uM, respectively. It was found that A549 cells were more sensitive to synthesized compounds than PC3 and MCF-7 cells. In order to evaluate the mechanism of cytotoxic activity in A549, compounds 6b, 8a and 9a were selected for further studies. Annexin V binding assay and western blot analysis results revealed that 6b, 8a and 9a induced apoptosis in A549 cells by intrinsic apoptotic pathway through the activation pro-apoptotic proteins such as Bim, Bax, Bak, Puma and deactivation of anti-apoptotic proteins including Bcl-2, Mcl-1 and Bcl-XL accompanied by the activation of caspase-3, caspase-9 and cleavage of PARP. Also, compounds 6b, 8a and 9a triggered apoptosis in HCT116 wt cells via activation of caspase-3 and caspase-9, but not in HCT116 Bax/Bak KO cells, indicating resistance to 6b, 8a and 9a treatment. PMID- 30458414 TI - Clinical research of regenerative treatment of knee cartilage using chondrocyte cell - sheet technology. PMID- 30458415 TI - A novel combination of bioelectrochemical system with peroxymonosulfate oxidation for enhanced azo dye degradation and MnFe2O4 catalyst regeneration. AB - Advanced oxidation process (AOP) based on peroxymonosulfate (PMS) activation was established in microbial fuel cell (MFC) system with MnFe2O4 cathode (MFC MnFe2O4/PMS) aimed to enhance azo dye degradation and catalyst regeneration. The effects of loading amount of MnFe2O4 catalyst, applied voltage, catholyte pH and PMS dosage on the degradation of Orange II were investigated. The stability of the MnFe2O4 cathode for successive PMS activation was also evaluated. The degradation of Orange was accelerated in the MFC-MnFe2O4/PMS with apparent degradation rate constant increased to 1.8 times of that in the MnFe2O4/PMS control. A nearly complete removal of Orange II (100 mg L-1) was attained in the MFC-MnFe2O4/PMS under the optimum conditions of 2 mM PMS, 10 mg cm-2 MnFe2O4 loading, pH 7-8 and 480 min reaction time. MFC driven also extended the longevity of the MnFe2O4 catalyst for PMS activation due to the in-situ regeneration of =Mn2+ and =Fe2+ through accepting electrons from the cathode, and over 80% of Orange II was still removed in the 7th run. Additionally, the MFC-MnFe2O4/PMS system could recover electricity during Orange II degradation with a maximum power density of 206.2 +/- 3.1 mW m-2. PMS activation by MnFe2O4 was the primary pathway for SO4- generation, and SO4- based oxidation was the primary mechanism for Orange II degradation. MFCs driven coupled with PMS activated AOP systems provides a novel strategy for efficient and persistent azo dye degradation. PMID- 30458416 TI - Development and regeneration of composite of cationic gel and iron hydroxide for adsorbing arsenic from ground water. AB - Globally, arsenic contaminated groundwater is a serious concern for human health. Previous studies have developed various methods to remove arsenic. But, most of them fail to selectively adsorb arsenic and regenerate. In this study, we developed an adsorbent, a cationic polymer gel loaded with iron hydroxide, which can adsorb arsenic from groundwater more effectively than the other adsorbents. The cationic polymer gel is N,N-dimethylamino propylacrylamide, methyl chloride quaternary (DMAPAAQ). The preparation of the gel is different from the other polymer gels used for adsorption of arsenic and other metals, and it ensures that the gel contains 53.7% FeOOH particles. It should also provide good selectivity, be simple to use and be cost-effective in terms of reusability. The study showed that the gel selectively adsorbed arsenic effectively at neutral pH levels. The results demonstrate that the maximum amount of As(V) adsorption was 123.4 mg/g, which is higher than the other adsorbents. In addition, the gel adsorbed As(V) selectively in the presence of Sulphate. Also, regeneration of the gel was performed for eight consecutive days with 87.6% effectiveness. Additionally, the adsorption mechanism of this gel composite and time required for reaching the equilibrium adsorption is discussed in this paper. PMID- 30458417 TI - Toxicity assessment of molybdenum slag as a mineral fertilizer: A case study with pakchoi (Brassica chinensis L.). AB - Large quantities of molybdenum (Mo) slag are generated as a by-product during mining and smelting, which not only occupy huge stretches of arable land and natural habitats but also threaten the local ecosystem and environment. How to recycle this Mo slag is becoming an urgent issue. Here, we reported the toxicity assessment of Mo slag as a mineral fertilizer for slag recycling in agricultural practices. The results showed the following: (1) Lower rates of slag (1.0%, 2.5%, and 5.0%) fertilization, especially 5.0% slag, increased the activities of antioxidant enzymes (superoxide dismutase, catalase, and peroxidase), the contents of chlorophyll, and both the maximum quantum yield and quantum efficiency of photosystem II; decreased the content of malondialdehyde and the non-photochemical quenching of photosystem II; and eventually increased the height, leaf area, and biomass of pakchoi seedlings; (2) Higher rates (7.5% and 10.0%) of Mo slag application resulted in a reduction in the aforementioned physiological and morphological parameters (except for peroxidase activity) of pakchoi seedlings; and (3) Although fertilization with 5.0% slag increased the accumulation of the non-essential elements arsenic (As), lead (Pb), and cadmium (Cd) in pakchoi seedlings, their contents were still lower than the maximum levels of the Codex Alimentarius Commission, European Union, and standards of China. From the perspectives of plant nutrition and food safety, our results showed that Mo slag fertilization at rates lower than 5.0% can be applied as a mineral fertilizer for pakchoi grown on calcareous soils. PMID- 30458418 TI - Relationship between selenium removal efficiency and production of lipid and hydrogen by Chlorella vulgaris. AB - In our previous studies, Chlorella vulgaris had proven highly efficient in removing selenium (Se) from water, while the disposal of Se containing in algal biomass was still an issue of concern. Firstly, this research suggests algal Se could be released back to water, posing risks to aquatic wildlife. Thus, we further explored the possibility of using C. vulgaris to remove Se and produce lipid and hydrogen simultaneously. Our results show the higher percentage of saturated fatty acids, especially palmitic acid, was found in the sulfur (S) deprived algae exposed to either selenate or selenite, although the highest lipid content (21.9%) was found in the selenite treated algae in full BG11 medium. In addition, compared with the Se free algae, hydrogen production rate was 2.1- and 4.3-fold higher for the selenate and selenite treated algae, respectively. Se removal efficiency achieved by the selenite treated algae through accumulation and volatilization was 2.3-fold higher than the selenate treatment under hypoxic condition with S deprived, which is in contrast to the results obtained under aerobic conditions. PMID- 30458420 TI - Discrimination of rare earth element geochemistry and co-occurrence in sediment from Poyang Lake, the largest freshwater lake in China. AB - Geochemical distribution of trace elements in sediments could reflect the impact of anthropogenic activities on environmental changes in aquatic ecosystems. In this study, rare earth elements (REEs) were used as geochemical tracers to study the environmental processes in a complex and dynamic aquatic environment. Both surface and core sediment samples were collected from Poyang Lake, the largest freshwater lake located in the middle-low region of the Yangtze River. Sediment samples were analyzed for their respective REE spatial distributions, fractionation, and co-occurrence patterns. The inner relationships and geochemistry characters of REEs were assessed by geostatistics and co-occurrence network analysis. Results indicated that total REE concentrations in the sediments from Poyang Lake ranged from 145.1 to 351.1 MUg g-1, with an average concentration of 254.0 MUg g-1. Light rare earth element (LREE, La - Sm) enrichment was evident in all sediment samples, indicating the effects of river lake interactions and the contributions from terrestrial inputs. The negative Ce and Eu anomalies were found in most sediment samples, indicating the differentiation between Ce, Eu, and other REEs in the processes of sediment transportation and deposition. Collectively, the identification of the major contamination sources of REEs in sediment, analyzed by the patterns of the co occurrence networks and REE fractionation, revealed that the REEs in sediments from Poyang Lake originated both natural and anthropogenic sources and were disturbed by the impact of anthropogenic activities. PMID- 30458419 TI - Immobilizing laccase on kaolinite and its application in treatment of malachite green effluent with the coexistence of Cd (P). AB - Malachite green effluent with the Coexistence of Cd (P) was efficiently decolorized by kaolinite-laccase (Kaolin-Lac). Laccase from Trametes versicolor was immobilized onto the kaolinite through physical adsorption contact. The optimal conditions were 180 min of immobilization time and 0.8 mg/mL of enzyme solution. Kaolin-Lac could obtain a loading efficiency of 88.22%, a loading capacity of 12.25 mg/g, and the highest activity of 839.01 U/g. Moreover, the process of immobilization increased its pH stability and operational stability. Kaolin-Lac retained above 50% of the original activity and nearly 80% decolorization for MG after 5 cycles. In the presence of 3, 5-Dimethoxy-4 hydroxybenzaldehyde (SA), Kaolin-Lac could degrade over 98% of malachite green. The coexistence of Cd (P) was beneficial to the decolorization of malachite green by Kaolin-Lac. The structural and morphological features of kaolinite, Kaolin-Lac and Kaolin-Lac after degradation were determined by scanning electron microscopy energy spectrum analysis (SEM-EDS) and Fourier transform infrared spectroscopy (FTIR). Cadmium appeared on the Kaolin-Lac after degradation. After immobilization and degradation, the surface groups on kaolinite were changed. Kaolin-Lac showed its more potential continuous employment than free laccase in practical malachite green dyes effluent mixed with Cd (P). PMID- 30458421 TI - Transformation products of citalopram: Identification and in-silico toxicological assessment. AB - The objective of this study was to identify transformation products (TPs) of citalopram (CIT), an antidepressant drug, in laboratory experiments. Moreover, toxicity predictions and analyzes in wastewater samples were performed. For the formation of TPs, raw water was used for the processes of hydrolysis; photodegradation under ultraviolet (UV) irradiation and chlorination. The toxicities were predicted by computational toxicity assessment. The TPs were identified by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) in broadband collision induced dissociation (bbCID) acquisition mode and product ion scan mode (MS/MS). The probable structures of the TPs under study were established based on accurate mass, fragmentations observed in the MS spectra and prediction tools software. The experiments resulted in seventeen possible identified TPs and their stability and formation was monitored over time in the experiments. Two of these TPs were identified in wastewater samples It was also observed that most of TPs formed were either less toxic then CIT or had a similar toxicity. PMID- 30458422 TI - Reusable magnetic Ag/Fe, N-TiO2/Fe3O4@SiO2 composite for simultaneous photocatalytic disinfection of E. coli and degradation of bisphenol A in sewage under visible light. AB - A visible-light-driven and magnetic photocatalyst Ag/Fe,N-TiO2/Fe3O4@SiO2 (AgFeNTFS) was synthesized through a multi-step method. AgFeNTFS was tested for the photocatalytic disinfection of Escherichia coli (E. coli) and degradation of bisphenol A (BPA) under visible light irradiation, separately and simultaneously. The results showed that a 6.3-log reduction in cell density of E. coli was achieved and BPA (2 mg/L) was completely removed by AgFeNTFS in the separated photocatalytic processes within 120 min. In the simultaneous process, the photocatalytic disinfection of E. coli was not influenced in the presence of BPA, but the efficiency of BPA degradation was dropped by 10%. This was likely due to the competition for the same dominant reactive species of O2- and H2O2 between E. coli and BPA in the simultaneous process, as evidenced by the scavenger study and the interactions between the pollutants and AgFeNTFS. Moreover, the simultaneous photocatalytic activity of E. coli disinfection and BPA degradation by AgFeNTFS was investigated in the sewage obtained from a local wastewater treatment plant. The photocatalysis treated sewage could meet with the local disinfection discharge standard with a 3-log reduction of E. coli after 90 min, and a complete removal of BPA was achieved simultaneously after 360 min. Moreover, AgFeNTFS showed high magnetic separation efficiency and had a good reusability over three cycles for the simultaneous photocatalytic disinfection and degradation of BPA in both synthetic water and sewage. This study provides insights on the application of a reusable magnetic photocatalyst for simultaneous disinfection and degradation of BPA in sewage. PMID- 30458423 TI - Microplastic abundance, distribution and composition in the Pearl River along Guangzhou city and Pearl River estuary, China. AB - Like many urban rivers, the Pearl River in China is contaminated with microplastics. Compared with marine environments, microplastic pollution in freshwater is less understood, especially in urban rivers. In the present study, the abundance and distribution of microplastics in water from the Pearl River was investigated, including the estuary and the urban section along Guangzhou. The average abundance of microplastics was 19,860 items/m3 and 8902 items/m3 in the urban section and estuary, respectively. Wastewater effluents from cities might be a main source of microplastics in the Pearl River, and the urban tributaries might act as retention systems for microplastics. Among these microplastics, over 80% of them were less than 0.5 mm. The main shapes of microplastics were film, fragment, and fiber, mostly blue or transparent. Moreover, the most common polymer types of these microplastics were polyamide (26.2%) and cellophane (23.1%). This study reveals the contamination and characteristics of microplastics in the Pearl River, and provides important data for further research on microplastics in freshwater ecosystems. PMID- 30458424 TI - How can a rare protected plant cope with the metal and metalloid soil pollution resulting from past industrial activities? Phytometabolites, antioxidant activities and root symbiosis involved in the metal tolerance of Astragalus tragacantha. AB - Astragalus tragacantha is a protected plant species in France that grows even in the trace metal and metalloid (TMM) polluted soils of the Calanques National Park (PNCal). Soils are mainly contaminated by lead, copper, zinc and arsenic. An ex situ experiment was conducted, firstly to determine the molecular responses and root traits involved in the TMM tolerance of this plant species by growing individuals in a soil from the surroundings of one of the brownfields of the PNCal, known as l'Escalette, where this plant species grows spontaneously. Secondly, in order to determine the plasticity of these responses, seeds were collected from three different populations, 1 at l'Escalette (polluted site), one from the Frioul archipelago (non-polluted, insular site) and one from La Seyne (non-polluted, littoral site). The results of this study confirmed the capacity of A. tragacantha to germinate and grow in TMM contaminated soils. Only moderate significant variations in chlorophyll and flavonol indices, proline content and antioxidant activities were detected between polluted and control soil conditions for all populations. The main driver for A. tragacantha TMM tolerance seemed to be its ability to be associated with root symbionts i.e. arbuscular mycorrhizal fungi and dark septate endophytes, corresponding to a nutrient-uptake strategy trait. This work provides support for the challenge of A. tragacantha conservation along the littoral of the PNCal, because increasing the number of A. tragacantha individuals would both increase vegetation cover of the polluted soils to reduce the pollution transfer and reinforce the populations of this species. PMID- 30458425 TI - The collaborative effect of Chlorella vulgaris-Bacillus licheniformis consortia on the treatment of municipal water. AB - In this study, the effects of nutrient and dissolved organic matter removal, stress resistance (DNA methylation), and the algae-bacteria dynamic ratio of algal-bacterial consortia in actual municipal wastewater were investigated. Results indicate that the presence of a Chlorella vulgaris-Bacillus licheniformis consortium had profound effects. The removal rates of total nitrogen, ammonium, orthophosphate phosphorus and chemical oxygen demand were 88.82%, 84.98%, 84.87% and 82.25%, respectively. Protein-like substances, which are difficult to degrade in the natural water environment, were significantly degraded in actual municipal wastewater. Furthermore, the microbial diversity was measured. The algal bacterial consortium did not disrupt the microbial in-situ diversity of the actual municipal wastewater under suitable conditions. The global nuclear DNA methylation level peaked at 7.80%. These results help to understand the effects of algal-bacterial consortia on nutrient and pollutant removal and adaptability in actual municipal wastewater. PMID- 30458426 TI - Management of the third stage of labor in second-trimester deliveries: How long is too long? AB - BACKGROUND: Retained placenta is the most common second-trimester delivery complication. As the optimal third stage of labor duration remains undefined, complications associated with retained placentas are difficult to study. OBJECTIVE(S): To determine the optimal third stage of labor duration in second trimester deliveries based on estimates of time-specific probabilities of placental delivery, placental intervention, and postpartum complication. STUDY DESIGN: We retrospectively studied adult women with singleton second-trimester vaginal deliveries. We identified third stage of labor duration, placental delivery method (spontaneous vs. manual/operative intervention), and indication for intervention. Postpartum complication was examined as a composite outcome. Differences among groups defined by delivery method and postpartum complication were tested using parametric and nonparametric tests. Probability curves describing the time-specific probabilities of placental delivery were derived using lifetable methods with group differences tested using the log-rank test. Probability of placental intervention and complication by time to placental delivery were examined using logistic regression with adjustment for confounders and other predictors. RESULTS: We identified 215 second-trimester placental deliveries (77% spontaneous, 23% intervention). Overall, 27% experienced postpartum complication, primarily hemorrhage (91%). Complication rates differed significantly between spontaneous placental deliveries (16%) and interventions (61%, P < 0.01). Both placental intervention and postpartum complication were strongly associated with longer time to placental delivery. Spontaneous placental deliveries occurred earlier than deliveries requiring intervention (P < 0.01). At 2 h, placental delivery rates were 93% in spontaneous deliveries and 39% in those requiring intervention. The overall postpartum complication rate for spontaneous placental deliveries (16%) was used as the threshold of tolerable risk and the criterion for placental intervention. Adjusted probability curves for deliveries of average gestational age (21.6 weeks) suggested that most patients (63.9%) may not require intervention until approximately 2 h following fetal delivery. Patients with PPROM would require intervention by 34 min, and those with intrapartum fever or delivery EBL >=500 mL would already exceed the risk threshold at fetal delivery. CONCLUSIONS: Our study suggests that an optimal third stage of labor duration of approximately 2 h maximizes probability of spontaneous delivery and minimizes complication risk. Timing of intervention may be further individualized for patients based on maternal characteristics and intrapartum conditions. PMID- 30458427 TI - Ethical and religious dilemmas of modern reproductive choices and the Islamic perspective. AB - Advances in the field of Assisted Reproductive Technologies (ART) are constantly evolving, starting from Artificial Insemination (AI) and in-vitro fertilization (IVF), to the current state of the art technologies that enable embryo biopsy for Pre-implantation Genetic Testing (PGT). The future includes gene mapping and DNA replacement technologies with the potential for the so-called "designer babies." In other words, shortly, a modern couple may be in a position to decide how to procreate and with whom; which pregnancy to keep and which one to terminate depending on their prior knowledge about the pregnancy and the available choices. This article addresses the moral, ethical, legal and religious dilemmas as a result of these technological advances in the field of ART and how these new challenges are addressed theologically in the Islamic world where the state law is strongly influenced by religion. This article sets out to discuss relevant issues and dilemmas but does not seek to prioritize or promote any opinion or view over any other religion/sect, ethical or legal opinion or view. PMID- 30458428 TI - Local dynamic stability of the lower extremity in novice and trained runners while running intraditional and minimal footwear. AB - BACKGROUND: Understanding how footwear cushioning influences movement stability may be helpful in reducing injuries related to repetitive loading. RESEARCH QUESTION: The purpose of this study was to identify the relationship between running experience and midsole cushioning on local dynamic stability of the ankle, knee and hip. METHODS: Twenty-four trained and novice runners were recruited to run on a treadmill for five minutes at the same relative intensity. Midsole thickness (thick/thin) and stiffness (soft / hard) were manipulated yielding four unique conditions. Lyapunov exponents were estimated using the Wolf algorithm from sagittal ankle, knee and hip kinematics. RESULTS: Trained runners had increased movement stability in all shoe conditions compared to their novice counterparts. Midsole thickness and stiffness, overall, did not affect movement stability within each of the running groups. Novice runners displayed decreased movement stability at the hip while running in the thick/soft running shoes. It was found that running experience has a greater influence on movement stability in the lower limbs compared to the midsole characteristics that were manipulated in this experiment. The hip was most stable followed by the knee and the ankle highlighting decreased stability in distal joints. CONCLUSIONS: It appears that midsole design within current design ranges do not have the ability to influence movement stability. PMID- 30458429 TI - Immediate effects of valgus knee bracing on tibiofemoral contact forces and knee muscle forces. AB - Background Valgus knee braces have been reported to reduce the external knee adduction moment during walking. However, mechanistic investigations into the effects of valgus bracing on medial compartment contact forces using electromyogram-driven neuromusculoskeletal models are limited. Research question What are the immediate effects of valgus bracing on medial tibiofemoral contact forces and muscular loading of the tibiofemoral joint? Methods Sixteen (9 male) healthy adults (27.7 +/- 4.4 years) performed 20 over-ground walking trials at self-selected speed both with and without an Ossur Unloader One(r) brace. Assessment order (i.e., with or without brace) was randomised and counterbalanced to prevent order effects. While walking, three-dimensional lower-body motion, ground reaction forces, and surface electromyograms from eight lower-limb muscles were acquired. These data were used to calibrate an electromyogram-driven neuromusculoskeletal model of muscle and tibiofemoral contact forces (N), from which muscle and external load contributions (%) to those contact forces were determined. Results Although walking with the brace resulted in no significant changes in peak tibiofemoral contact forces at the group-level, individual responses were variable and non-uniform. At the group-level, wearing the brace resulted in a 2.35% (95% CI 0.46-4.24; p = 0.02) greater relative contribution of muscle to lateral compartment contact loading (54.2 +/- 11.1%) compared to not wearing the brace (51.8 +/- 12.1%) (p < 0.05). Average relative contributions of muscle and external loads to medial compartment loading were comparable between brace and no brace conditions (p >= 0.05). Significance Wearing a valgus knee brace did not immediately reduce peak tibiofemoral contact forces in healthy adults during normal walking. It appears this population may modulate muscle activation patterns to support brace-generated valgus moments, thereby maintaining normal walking knee moments and tibiofemoral contact forces. Future investigations are warranted to better understand effects of valgus knee brace in people with medial knee osteoarthritis using an electromyogram-driven neuromusculoskeletal model. PMID- 30458430 TI - Revisiting 'awareness contexts' in the 21st century hospital: How fragmented and specialized care shape patients' Awareness of Dying. AB - In 1965, Glaser and Strauss (1965) offered the concept of "awareness contexts" to explain what patients in hospitals do or don't know about their death trajectories. Awareness ranges from closed (where patients are completely unaware and family and providers protect "the secret") to open (where all parties communicate openly and honestly). While closed awareness was the norm in 1960s, open awareness is now considered standard practice in US, a reflection of mounting evidence that patients, families, and providers benefit from clear and honest communication at end of life (Seale et al., 1997; Wright et al., 2008). Despite the known benefits of open awareness, many terminal patients remain unaware or confused about their prognoses (Chen et al., 2017). This paper asks why, in an era of open awareness, are patients and families uncertain about dying? To answer this question, we focus on an aspect of Glaser and Strauss's theory that remains relatively understudied by researchers, namely the role of institutional and organizational realities in shaping awareness contexts. Based on interviews with 43 family members of deceased patients who died at General Hospital in the Midwestern US, we argue that two related conditions in hospitals the increased specialization of medical professionals and the fragmentation of patient care-serve as important context for the death awareness of patients and families. PMID- 30458431 TI - Metabolomics based on UHPLC-QToF- and APGC-QToF-MS reveals metabolic pathways reprogramming in response to tidal cycles in the sub-littoral species Mimachlamys varia exposed to aerial emergence. AB - Mimachlamys varia is a sub-littoral bivalve encountered from Norway to the Mediterranean Sea, which lives mostly byssally attached to rocks. During the low tide period, M. varia individuals, located highest on the shore, may experience short time of aerial exposure and face a low availability of oxygen. Here we report a comparative metabolomic profiling of gill samples of M. varia obtained by both LC-QToF and APGC-QToF mass spectrometry, to analyze metabolic changes occurring during emersion in comparison with immersion. Scallops were grown in aquaria with a simulated intertidal environment mimicking short-duration air exposure that they might experience during extreme tides: alternating 2 h emersion and 10 h immersion. Our results show a switch from aerobic to anaerobic metabolism after only 2 h of emersion, with the resort to different pathways: glucose-lactate, glucose-succinate and aspartate-succinate pathways. Furthermore, carnitine-conjugated metabolites were found to accumulate during emersion, as well as urate. The level of tyrosine on the contrary was found to decrease. These findings indicate a complex metabolic reprogramming that occurs after a two hour emersion period and upon re-immersion. Furthermore, M. varia is used as sentinel species in pollution biomonitoring, through the assay of biomarkers to evaluate the effects of pollutants. Here we show that emersion induces a significant decrease of superoxide dismutase activity, an enzyme developed by bivalves to face oxidative stress and used as biomarker. These findings have to be taken into account to normalize sampling during campaigns of environmental monitoring, by taking in situ, as far as possible only immersed individuals. PMID- 30458432 TI - [Direct Oral Anticoagulants in Acute Phase Management of Ischemic Stroke]. PMID- 30458433 TI - [Availability of Early Balloon Kyphoplasty for the Treatment of Osteoporotic Compression Fractures]. AB - INTRODUCTION: Japan has many patients with osteoporosis; however, only about one fifth of these patients receive treatment. Although some treatment guidelines exist for osteoporosis, the number of newly diagnosed patients with osteoporotic compression fractures is increasing and protocols for treatment of osteoporotic compression fractures vary from one hospital to another. This study aims to investigate the availability of early balloon kyphoplasty(BKP)in relation to our treatment strategy for osteoporotic compression fractures. METHODS: In our hospital, patients diagnosed with osteoporotic compression fractures were treated conservatively with a corset and rehabilitation. In cases where pain was prolonged and computed tomography(CT)imaging revealed formation of a cavity, we performed BKP. We divided the patients admitted between April 2016 and December 2016 with osteoporotic compression fractures into 2 groups, based on whether they received conservative treatment or BKP. We assessed the patients' age, fracture site, CT and MRI findings, bone density, Numerical Rating Scale(NRS), duration of hospital stay, and outcomes. RESULTS: In the BKP group, the number of Th12 and L1 compression fractures was higher than fractures to other vertebral bodies. No difference was observed in bone density, improvement of NRS, and outcomes between groups. CT cavity signs were more frequently observed in the BKP group than in the conservative group. CONCLUSIONS: This study establishes a correlation between the appearance of CT cavity sign and prolonged pain, which increases the likelihood of a patient undergoing BKP. The CT cavity sign and prolonged pain could be indicators of pre-stage pseudoarthrosis. BKP performed in the early stages of a fracture is safe and does not result in complications. However, BKP should be performed according to appropriate indications, including delayed neurological deficit, pain, and reduced bone adhesion. PMID- 30458434 TI - [Treatment of Brain Metastases from Papillary Thyroid Carcinomas:Five Surgical Cases in Our Hospital and a Literature Review]. AB - Papillary thyroid carcinoma is the most common thyroid malignancy and usually has an indolent clinical course with a good prognosis. Brain metastasis from thyroid cancer is very rare, occurring in only 0.8-1.3% of all papillary thyroid carcinomas; therefore, the prognosis and treatment of the metastatic tumor are unclear. We describe 5 cases of brain metastases from papillary thyroid carcinoma treated with surgery between 2013 and 2017. Intracranial tumor resection was performed and brain metastases were pathologically diagnosed as papillary thyroid carcinoma in 2 men and 3 women aged 62-72 years(mean 67 years). The surgical treatment for the thyroid cancer was total thyroidectomy in 3 patients, hemithyroidectomy in 1, and no treatment in 1. The duration from initial diagnosis to brain metastasis was 0-155 months(mean 73.2 months). Two patients also received radioiodine therapy. Three patients had multiple lesions and 2 had single lesions. Four patients also had other metastases. Neuroimaging demonstrated intratumoral hemorrhages in 2 patients. The other 2 patients had intratumoral hemorrhage during the course of the disease. All patients received radiation therapy after surgery for brain metastases. Two patients died, but the other 3 have survived to date. The other 2 patients who had intratumoral hemorrhage during the course of the disease received 131I radioiodine therapy. It was reported that 131I radioiodine therapy resulted in collapse of the fragile peritumoral vessels. It is safe to perform head magnetic resonance imaging(MRI)before radioiodine therapy for thyroid cancer. Papillary thyroid carcinomas carry a good prognosis but some brain metastases have a poor prognosis due to the presence of other metastases or the patient's poor general condition. Treatments for patients in good general condition are needed to improve the clinical course and prognosis. PMID- 30458435 TI - [A Case of Successful Drug Management with Dabigatran and Idarucizumab to Address Embolic and Hemorrhagic Complications for Asymptomatic and Traumatic Subdural Hematoma with Non-valvular Atrial Fibrillation]. AB - A 93-year-old woman incurred a head bruise 5 days prior to presentation, and head CT revealed right subacute subdural hematoma. As she was on direct oral anti coagulant(DOAC)treatment for non-valvular atrial fibrillation(NVAF), the DOAC administration was stopped temporarily to prevent an increase in the size of the hematoma. Dabigatran treatment was initiated after the confirmation of no change in hematoma size and the follow-up CT revealed a reduction in the hematoma. However, left upper limb paresis occurred on day 12 of dabigatran treatment and head CT revealed the onset of right chronic subdural hematoma. Emergency burr hole surgery was performed after intravenous administration of idarucizumab to neutralize the dabigatran. Her neurologic symptoms improved after the operation and no recurrence of subdural hematoma was observed even after dabigatran treatment was resumed. Dabigatran could be administered relatively safely, even for subacute intracranial hemorrhage complicated with NVAF, suggesting the possibility of the prevention of ischemic stroke. Moreover, even when intracranial hemorrhage recurred, the prompt neutralizing effect of idarucizumab, a dabigatran-specific neutralizing agent, was useful in the surgical intervention and perioperative management. PMID- 30458436 TI - [Treatment of a Traumatic Direct Carotid Cavernous Fistula with an Intradural Internal Carotid Artery Pseudoaneurysm Using a Low-profile Visualized Intraluminal Support(LVIS)Stent:A Case Report]. AB - Traumatic carotid cavernous fistula(CCF)is known to present a direct connection between the cavernous segment of the internal carotid artery(ICA)and the cavernous sinus(CS). In rare cases, the fistula is formed between the intradural internal carotid artery(ICA)and the cavernous sinus(CS)via a pseudoaneurysm(pAN), requiring appropriate management and aggressive surgical treatment. We describe a 58-year-old man who sustained a severe head injury diagnosed as traumatic CCF treated with an intradural pAN procedure and transarterial coil embolization combined with a Low-profile Visualized Intraluminal Support(LVIS)stent. While slow arteriovenous shunt flow persisted at the end of the surgery, the fistula was completely occluded on the digital subtraction angiography obtained 2 weeks after the procedure. It was suspected that the flow-diversion effect of the LVIS stent might have caused the curable progression of the fistula occlusion. PMID- 30458437 TI - [Frontal Base Penetrating Brain Injury by a Gardening Scissors:A Case Report]. AB - A 43-year-old woman accidentally fell from a 1.5-m height with gardening scissors, and the cutting edge of the scissors pierced into her skull base through the left nasal cavity. After she pulled the scissors out by herself, her consciousness immediately deteriorated. She was transferred to Juntendo University Shizuoka Hospital by an ambulance helicopter. Intracerebral hematoma in the right frontal lobe caused by the middle cerebral artery injury was detected using brain computed tomography. Emergent hematoma evacuation with decompressive craniectomy was performed. In this procedure, cerebrospinal fluid(CSF)leakage was repaired using a multi-layered flap technique, which placed both the free autologous dura mater and pedicled temporalis muscle flaps into the damaged skull base space. After the surgery, CSF drainage was managed to control both intracranial pressure and CSF leakage. Upon discussion, several clinical issues can be highlighted. First, the gardening scissors were pulled out by the patient herself. Second, the foreign material penetrating the intracranial space might have conferred a high infection risk. Finally, it might be difficult to repair the severe damage inflicted upon the skull base by the large gardening scissors. In conclusion, it was considered that favorable results were obtained by the emergent surgical intervention and by repairing the skull base through forming a multi-layered flap with a combination of free and pedicled tissues. PMID- 30458438 TI - [Benedikt Syndrome Associated with Neck Clipping of Ruptured Basilar-Superior Cerebellar Artery Aneurysm:A Case Report]. AB - Benedikt syndrome is caused by a rare type of brain damage to the red nucleus and nearby locations. Clinically, it presents as ipsilateral oculomotor palsy and specific contralateral involuntary movement. These involuntary movements may affect activities of daily living(ADLs)in affected patients. We treated a case of Benedikt syndrome associated with neck clipping of a ruptured basilar-superior cerebellar artery aneurysm. A 66-year-old female patient was admitted to our department with headache. Initial computed tomography imaging and angiography showed subarachnoid hemorrhage and left basilar-superior cerebellar artery aneurysm. We performed neck clipping of the aneurysm. Immediately after the surgery, left oculomotor nerve palsy occurred. Right involuntary movement gradually developed from the fifth day after the surgery. Postoperative magnetic resonance imaging(MRI)showed an infarction around the left red nucleus. This specific involuntary movement significantly impaired the ADLs of the patient and persisted for two months. From three months after the surgery, it gradually improved. One and a half years after the surgery, the ADLs of the patient improved notably. It is important to preserve perforators in the treatment of distal basilar artery aneurysm. However, while ischemia of the red nucleus(e.g., due to perforator damage)may cause specific involuntary movements, they could recover spontaneously after a period of months. PMID- 30458439 TI - [Acute Changes in the Computed Tomography Findings of Mucocele Combined with Pituitary Adenoma:A Case Report]. AB - INTRODUCTION: We report a rare case in which a pituitary tumor co-occurred with a giant mucocele. The mucocele's computed tomography(CT)values fell markedly when it collapsed, and we report the associated considerations. CASE: This case involved a 42-year-old male patient. For 20 years, his visual acuity had progressively declined, and it suddenly rapidly worsened over a month. Cranial CT revealed a massive tumor in the sphenoid sinus and a pituitary tumor. A region of high absorption extended from the paranasal sinus to the skull base. Two days after the patient's initial presentation, he experienced a sudden loss of vision. Therefore, we performed an urgent re-examination. The CT value of the paranasal lesion was found to have sharply declined. The sinus lesion was diagnosed as a mucocele. Emergent endoscopic surgery was performed. Actinomyces meyeri was detected in the samples cultures. DISCUSSION: The causes of mucocele exhibiting abnormally high signal intensity on CT include the accumulation of hemosiderin due to repeated bleeding in the cyst. Furthermore, we inferred that the Actinomyces meyeri had been taking up metallic elements in vivo for a long time. The marked reduction in the lesion's CT value was considered to have been due to the destruction of the mucocele. The contents of the mucocele flowed out and were replaced with newly produced mucus, which exhibits low absorption values. CONCLUSION: We treated a patient with a giant mucocele involving distraction of the frontal base and a pituitary adenoma. In such cases, surgery should be performed when visual acuity deteriorates suddenly. PMID- 30458441 TI - [(3)Neurocritical Care for Traumatic Brain Injury]. PMID- 30458440 TI - [A Case of Metastatic Malignant Melanoma with Symptomatic Hemorrhage Developing after Treatment with Immune Checkpoint Inhibitors and Radiotherapy]. PMID- 30458442 TI - miR-1-3p Contributes to Cell Proliferation and Invasion by Targeting Glutaminase in Bladder Cancer Cells. AB - BACKGROUND/AIMS: Increasing evidence showed that miR-1-3p plays a major role in malignant tumor progression. However, the specific biological function of miR-1 3p in bladder cancer is yet unknown. METHODS: The expression levels of miR-1-3p in bladder cancer tissues and cell lines were examined by qRT-PCR. Bisulfite sequencing PCR was used for DNA methylation analysis. The target of miR-1-3p was validated by a dual luciferase reporter assay, and the effects of miR-1-3p on phenotypic changes in bladder cancer cells were investigated in vitro and in vivo. RESULTS: The expression of miR-1-3p in bladder cancer cells was downregulated as compared to normal SV-HUC-1 cells. Also, the expression of miR-1 3p was significantly lower in bladder cancer tissues than the corresponding non cancerous tissues. The methylation status of CpG islands was involved in the regulation of miR-1-3p expression. miR-1-3p inhibited the bladder cancer cell proliferation, migration, and invasion by directly targeting the 3'-UTR of glutaminase. It also exerted an anti-tumor effect by negatively regulating the glutaminase in a xenograft mouse model. Furthermore, GLS depletion resulted in the prolonged expression of gammaH2AX. CONCLUSION: Taken together, these results demonstrated that miR-1-3p acts as a tumor suppressor via regulation of glutaminase expression in bladder cancer progression, and miR-1-3p might represent a novel therapeutic target for the treatment of bladder cancer. PMID- 30458443 TI - Isavuconazole: Case Report and Pharmacokinetic Considerations. AB - Invasive fungal disease (IFD) is one of the major causes of morbidity and mortality in immunocompromised patients. Voriconazole (VCZ) and posaconazole (PCZ) remain the most widely used antifungals for the prophylaxis and treatment of IFD. However, VCZ and PCZ are liable for drug-drug interactions and show a pharmacokinetic variability that requires therapeutic drug monitoring (TDM). Isavuconazole (IVZ) is a newest generation triazole antifungal approved for the treatment of invasive aspergillosis (IA) in adult patients and for the treatment of invasive mucormycosis in adult patients for whom treatment with amphotericin B is inappropriate. In clinical trials, IVZ showed linear pharmacokinetics and little or no evidence for interactions with other drugs. There is only modest evidence on IVZ pharmacokinetics and TDM in real-life settings. Here, we report on IVZ pharmacokinetics in a young adult with Ph chromosome-negative acute lymphoblastic leukemia (ALL) who developed a "probable" IA during induction chemotherapy. The patient was initially treated with VCZ, but she developed a severe hepatic toxicity that was associated to the high plasma levels of VCZ. Therefore, VCZ was discontinued and the patient was switched to IVZ. After a loading dose of IVZ, the patient remained on IVZ for 5 months while also receiving standard maintenance chemotherapy for ALL. At day 65 after the start of IVZ, the patient experienced a significant hepatic toxicity; however, no change in IVZ plasma concentrations was observed in the face of a concomitant administration of many other drugs (cancer drugs, antiemetics, other anti infectives). Hepatic toxicity resolved after discontinuing maintenance chemotherapy but not IVZ. These results show that (i) IVZ plasma concentrations remained stable throughout and were not affected by concomitant ALL therapy, and (ii) there was no relation between IVZ plasma concentration and hepatic toxicity. Thus, in clinical practice IVZ may not require TDM. PMID- 30458444 TI - Bronchial Asthma and Bronchial Hyperresponsiveness and Their Characteristics in Patients with Common Variable Immunodeficiency. AB - BACKGROUND: Common variable immunodeficiency (CVID) is one of the most frequent primary immunodeficiencies and is characterized by disturbed immunoglobulin production and dysregulation of the immune system. Results of previous studies suggest a higher prevalence of bronchial asthma (BA) in CVID patients than in the general population. We initiated this study to evaluate lung functions and identify risk factors for BA and bronchial hyperresponsiveness (BHR) in patients with CVID. METHODS: Twenty-three patients with CVID were included in this study. In all of them, spirometry and a metacholine bronchoprovocation test were performed. We also investigated the role of atopy, eosinophilic inflammation, and potential risk factors such as gender, age, or immunoglobulin levels at the time of diagnosis. RESULTS: BHR was confirmed in 12 patients (52%), all of whom had normal FEV1 and FEV1/FVC. However, BHR-positive patients had significantly decreased MEF25. BHR-positive patients had also more symptoms related to bronchial obstruction, with 8 of them (35%) being suspected of having BA at the end of the study. A higher prevalence of BHR was found in females, with a relative risk of 2.89. CONCLUSIONS: An increased prevalence of BHR and BA was detected in CVID patients compared to the general population. BA may develop despite the disturbed immunoglobulin production, and the majority of patients display nonatopic and noneosinophilic properties. These results suggest a limited role of atopy and eosinophilic inflammation in the pathogenesis of BA in CVID patients. PMID- 30458445 TI - Taurolidine Sensitivity of Eryptosis, the Suicidal Erythrocyte Death. AB - BACKGROUND/AIMS: The taurine derivative Taurolidine is effective against diverse bacteria and tumor growth. In the treatment of cancer, the substance is effective in part by triggering suicidal death or apoptosis of tumor cells. The Taurolidine induced apoptosis involves mitochondria. Erythrocytes lack mitochondria but are nevertheless able to enter suicidal erythrocyte death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling of eryptosis includes increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress and ceramide. The present study explores, whether Taurolidine induces eryptosis and, if so, which cellular mechanisms are involved. METHODS: Phosphatidylserine exposure at the cell surface was estimated using annexin-V binding, cell volume using forward scatter, [Ca2+]i using Fluo3-fuorescence, reactive oxygen species (ROS) formation using 2',7'-dichlorodihydrofuorescein (DCF)-dependent fluorescence, and ceramide abundance using specific antibodies. RESULTS: A 48 hours exposure of human erythrocytes to Taurolidine (60 ug/ml) significantly enhanced the percentage of annexin-V-binding cells, significantly decreased forward scatter and significantly increased Fluo3-fluorescence and ceramide abundance, but not DCF-fluorescence. The effect of Taurolidine on annexin-V-binding was virtually abrogated by removal of extracellular Ca2+. CONCLUSION: Taurolidine triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca2+ entry and paralleled by increase of ceramide abundance. PMID- 30458446 TI - Cluster Analysis of Chronic Rhinosinusitis Suggests Gender-Based Differences. AB - PURPOSE: We aimed to evaluate the interaction between the overall severity of chronic rhinosinusitis (CRS) before treatment and subjective improvement following surgical or medical treatment. PROCEDURES: A group of 97 patients with CRS completed the visual analog scale (VAS) symptom score and the Sino-Nasal Outcome Test 22 (SNOT-22) questionnaire in the moment of their sinus computerized tomography (CT) scan. Data were analyzed via a 2-step cluster analysis based on gender, polyp presence, CT scan, and VAS scores for symptoms. RESULTS: There were 3 clusters: the first cluster comprised 37 female patients with CRS without nasal polyps (CRSsNP), the second cluster comprised 30 patients with CRS and NP (CRSwNP; 15 males and 15 females); and third cluster had 30 male patients with CRS without NP (CRSsNP). Different symptom patterns between clusters were identified. After adjustment for polyp presence, gender, eosinophilia (p = 0.021), and the SNOT-22 score (p = 0.005) were found to be better outcome predictors than the CT score (p = 0.26). CONCLUSION: Long-term patient satisfaction is significantly associated with the subjective symptom severity prior to treatment, i.e., postnasal drip and overall disease severity (SNOT-22 score), but not with the objective severity of the disease (CT score and inflammation). PMID- 30458448 TI - The 53rd Congress of the European Society for Surgical Research. PMID- 30458447 TI - Association between rs120963, rs152451, rs249935, rs447529, rs8053188, and rs16940342 Polymorphisms in the PALB2 Gene and Breast Cancer Susceptibility: A Meta-Analysis. AB - BACKGROUND: The aim of this study was to explore the association between single nucleotide polymorphisms (SNPs) in the rs120963, rs152451, rs249935, rs447529, rs8053188, and rs16940342 loci in the PALB2 gene and breast cancer risk. METHODS: Studies investigating the association between SNPs in the PALB2 gene and breast cancer susceptibility were retrieved from the PubMed, Embase, Web of Science, CNKI (Chinese National Knowledge Infrastructure), WanFang, and CBM (China Biology Medicine) databases. Eligible studies were screened according to inclusion/exclusion criteria and principles of quality evaluation. Meta-analysis was performed using Stata 14.0 software. Odds ratios with their corresponding 95% confidence intervals were pooled to assess the association between SNPs in the PALB2 gene loci rs249935, rs447529, rs8053188, rs16940342, rs152451, and rs120963 and breast cancer susceptibility. RESULTS: A total of 9 case-control studies were eligible for this meta-analysis. SNPs in the PALB2 gene loci rs120963, rs249935, and rs447529 were significantly associated with an increased or decreased risk of breast cancer. No significant association was detected for rs152451, rs8053188, and rs16940342 under 4 genetic models. CONCLUSION: The results of this study suggest that SNPs in the PALB2 loci rs120963/rs249935/rs447529, but not in the other 3 loci (rs152451/rs8053188/rs16940342), may contribute to breast cancer susceptibility. PMID- 30458449 TI - Tumor-Secreted Exosomal miR-222 Promotes Tumor Progression via Regulating P27 Expression and Re-Localization in Pancreatic Cancer. AB - BACKGROUND/AIMS: MicroRNAs (miRNAs) or exosomes have recently been shown to play vital regulatory or communication roles in cancer biology. However, the roles and mechanisms of exosomal miRNAs in pancreatic ductal adenocarcinoma (PDAC) remain unknown. We aimed to investigate the detailed roles and mechanisms of tumor generated exosomal miRNAs in progression of PDAC. METHODS: miR-222 was identified by miRNA microarray studies in exosomes of PDAC cells, and further analyzed in plasma exosomes of PDAC patients. The regulatory mechanisms of miR-222 were explored by qRT-PCR, WB, dual-luciferase assays and immunofluorescence or confocal analysis. Other biological assays include transwell, xenograft models and so on. RESULTS: miR-222 is significantly high in tumor exosomes or highly invasive PDAC cells. miR-222 could directly regulate p27 to promote cell invasion and proliferation. miR-222 could also activate AKT by inhibiting PPP2R2A expression, thus inducing p27 phosphorylation and cytoplasmic p27 expression to promote cell survival, invasion and metastasis. Expressions of miR-222 and p27 were significantly inversely correlated, and cytoplasmic p27, instead of nuclear p27, was associated with tumor malignancy. miR-222 could be transmitted between PDAC cells via exosome communication, and the exosomal miR-222 communication is functional. Plasma exosomal miR-222 in PDAC patients was high and significantly correlated to tumor size and TNM stage, and was an independent risk factor for PDAC patient survival. CONCLUSION: Tumor-generated exosomes could promote invasion and proliferation of neighboring tumor cells via miR-222 transmission, the plasma exosomal miR-222 plays important roles and may be a useful prognostic maker in PDAC. PMID- 30458450 TI - 6- and 8-Prenylnaringenin, Novel Natural Histone Deacetylase Inhibitors Found in Hops, Exert Antitumor Activity on Melanoma Cells. AB - BACKGROUND/AIMS: Prenylnaringenins are natural prenylflavonoids with anticancer properties. However, the underlying mechanisms have not been elucidated yet. Here we report a novel mode of action of 6- and 8-prenylnaringenin (PN) on human melanoma cells: Inhibition of cellular histone deacetylases (HDACs). METHODS: We performed in silico and in vitro analyses using 6-PN or 8-PN to study a possible interaction of 6-PN or 8-PN with HDAC as well as Western blot and FACS analyses, real-time cell proliferation and cell viability assays to assess the impact of 6 PN and 8-PN on human metastatic melanoma cells. RESULTS: In silico, 6-PN and 8-PN fit into the binding pocket of HDAC2, 4, 7 and 8, binding to the zinc ion of their catalytic center that is essential for enzymatic activity. In vitro, 100 umol/L of 6-PN or 8-PN inhibited all 11 conserved human HDAC of class I, II and IV. In clinical oncology HDAC inhibitors are currently investigated as new anticancer compounds. In line, treatment of SK-MEL-28 cells with 6-PN or 8-PN induced a hyperacetylation of histone complex H3 within 2 h. Further, 6-PN or 8 PN mediated a prominent, dose-dependent reduction of cellular proliferation and viability of SK-MEL-28 and BLM melanoma cells. This effect was apoptosis independent and accompanied by down-regulation of mTOR-specific pS6 protein via pERK/pP90 in SK-MEL-28 cells. CONCLUSION: The identification of a broad inhibitory capacity of 6-PN and 8-PN for HDAC enzymes with antiproliferative effects on melanoma cells opens the perspective for clinical application as novel anti-melanoma drugs and the usage as innovative lead structures for chemical modification to enhance pharmacology or inhibitory activities. PMID- 30458451 TI - Why Do Cancer Patients Have Difficulties Evaluating the Need for a Second Opinion and What Is Needed to Lower the Barrier? A Qualitative Study. AB - BACKGROUND: Requesting a second opinion (SO) is common in oncology. The reasons and barriers for patients not seeking an SO have yet been to be investigated. Why do patients have difficulties evaluating their need for an SO and what could be done to minimize these barriers? PATIENTS AND METHODS: A 2-stage qualitative study was conducted. 1) Participants were studied in 3 focus groups (FGs). The participants themselves analyzed and then grouped their statements into defined categories. 2) Results of the FGs were discussed with 7 experts from different professional backgrounds. The interviews were unstructured and detailed in the protocol. The statements underwent thematic analysis. RESULTS: The following 4 main barriers were identified: 1) state of shock, 2) pressure of time, 3) sense of excessive demands and uncertainty triggered by information overload, 4) fear of jeopardizing the patient-physician relationship. The following 4 main suggestions for minimizing the barriers were identified: 1) written patient information, 2) improvement of communication, 3) patient empowerment (PE), 4) holistic approach. CONCLUSION: These barriers incapacitate the patients from evaluating the need for an SO. To minimize the barriers, PE, self-management support and shared decision making is recommended. While the implementation of these concepts advances, patients can be empowered by psycho-oncological assistance. PMID- 30458452 TI - Sulforaphane-N-Acetyl-Cysteine Induces Autophagy Through Activation of ERK1/2 in U87MG and U373MG Cells. AB - BACKGROUND/AIMS: Sulforaphane-N-acetyl-cysteine (SFN-NAC) is a sulforaphane (SFN) metabolite with a longer half-life and better blood-brain barrier permeability than those of SFN. Previous studies have found that SFN-NAC can act via ERK to destroy microtubules and inhibit cell growth in lung cancer cells. However, the underlying mechanisms are unclear, and it is unknown whether SFN-NAC can inhibit the growth of glioma. Here, we have demonstrated for the first time that SFN-NAC activates autophagy-mediated downregulation of alpha-tubulin expression via the ERK pathway. METHODS: U87MG and U373MG cells, two widely used glioma cell lines, were utilized in this study. Apoptosis assay, western blot analysis, co immunoprecipitation, immunostaining, and electron microscopy were used to analyze the effect of SFN-NAC on alpha-tubulin and its interaction with microtube associated protein 1 light-chain 3 (LC3). RESULTS: SFN-NAC induced cell-cycle arrest in the G2/M phase and dose-dependently induced intracellular ERK activation, autophagy, and alpha-tubulin downregulation. These SFN-NAC-induced effects were reversed by inhibiting the ERK pathway with its inhibitor PD98059. U87MG and U373MG cells were transfected with LC3 small interfering RNA, and the subsequent inhibition of autophagy reversed the downregulation of alpha-tubulin by SFN-NAC. Furthermore, co-immunoprecipitation experiments and confocal microscopy confirmed that SFN-NAC promotes the binding of LC3 with alpha-tubulin in the cytoplasm. Cell viability experiments demonstrate that SFN-NAC inhibits the growth of U87MG and U373MG cell colonies. CONCLUSION: These findings suggest that SFN-NAC is a novel potential anti-glioma agent. PMID- 30458453 TI - Barriers to Using a Nationwide Skin Cancer Screening Program: Findings from Germany. AB - BACKGROUND: In 2008, a nationwide standardized and systematic skin cancer screening (SCS) service, which is globally unique, was implemented in Germany. We aimed to provide current data on SCS use, to explore barriers to SCS usage, and to identify population groups with lower rates of SCS use. METHODS: We analyzed data from 2,635 participants (18-45 years) in the National Cancer Aid Monitoring on Sunbed Use. Data on SCS use, barriers to SCS, and sociodemographic characteristics were obtained. Chi-square tests and logistic regression analyses were performed to analyze the data. Data was weighted by age, sex, educational level, and federal state. RESULTS: In total, 39.0% of participants reported having been screened for skin cancer at least once in their lifetime. The subjective importance of different barriers varied depending on the participants' educational level. SCS use was negatively associated with male sex (odds ratio (OR) = 0.63, p < 0.001), low level of education (OR = 0.83, not significant), immigrant background (OR = 0.63; p < 0.001), and having no employment. CONCLUSION: Although the SCS is part of the regular healthcare services offered in Germany, our data showed lower usage among certain population groups. Barriers relevant for these groups should be considered when developing measures to increase SCS use. PMID- 30458455 TI - Prognostic Value of microRNA-133a Expression and Its Clinicopathologic Significance in Non-Small Cell Lung Cancer: A Comprehensive Study Based on Meta Analysis and the TCGA Database. AB - BACKGROUND: The role of microRNA-133a (miR-133a) in non-small cell lung cancers (NSCLCs) is controversial. Thus, we conducted a comprehensive study based on meta analysis and The Cancer Genome Atlas (TCGA) database. METHODS: Publications were searched in both English and Chinese databases, and meta-analysis was performed using Stata 12.0. The clinical value of miR-133a in NSCLC was investigated by collecting and calculating data from the TCGA database, and the statistical analysis was performed in R 3.5.0. RESULTS: 5 studies with 364 cases were included in this meta-analysis. The combined pooled result showed that high expression of miR-133a was associated with a favorable survival outcome in NSCLC patients (hazard ratio 0.561, 95% confidence interval 0.396-0.794, p = 0.001). Meanwhile, a total of 984 NSCLC patients were extracted from the TCGA database. Results showed an area under the ROC curve value for miR-133a-3p of 0.902, and the expression of miR-133a-3p was linked with clinicopathologic parameters of NSCLC (p < 0.05), including sex, age, social status, and lymph node metastasis. CONCLUSION: Our study indicated that miR-133a might act as a tumor suppressor and be a valuable independent prognostic and diagnostic biomarker for NSCLC, and NSCLC patients with high expression of miR-133 might have a better prognosis. PMID- 30458454 TI - The Spleen Promotes the Secretion of CCL2 and Supports an M1 Dominant Phenotype in Hepatic Macrophages During Liver Fibrosis. AB - BACKGROUND/AIMS: Liver fibrosis is a complex process of tissue remodeling in response to injury. Hepatic macrophages have been identified as a key player in this process. As the largest lymphoid organ in the body, the spleen exerts both local and systemic effects on immune cell response. Splenectomy can improve hepatic function during the treatment of liver cirrhosis. However, whether the spleen influences disease progression through the modulation of hepatic macrophages remains unclear. METHODS: We examined ex vivo hepatic macrophage responses from splenectomized or sham operated rats and performed splenocyte adoptive transfer studies, in combination with in vivo CCL2 blockade, in splenectomized or sham operated rats. RESULTS: We found that splenectomy reduced fibrosis severity and monocyte/ macrophage infiltration within the injured liver. Splenectomy also reduced secretion of the monocyte chemokine CCL2 by hepatic macrophages. Ex vivo, splenocytes, especially splenic macrophages, promoted CCL2 secretion via upregulation of SOCS3 signaling in hepatic macrophages. Migration of splenic monocytes in response to conditioned medium from hepatic macrophages was inhibited by the blockade of SOCS3-CCL2-CCR2 signaling. Splenectomy also attenuated the establishment of an M1-dominant hepatic macrophage phenotype whilst the adoptive transfer of splenocytes could partly reverse this effect and exacerbate fibrosis. However, CCL2 blockade following adoptive splenocyte transfer restored the protective effects of splenectomy. CONCLUSION: Our study demonstrates that splenic macrophages can promote hepatic macrophage secretion of CCL2, which in turn facilitates monocyte recruitment and the establishment of an M1-dominant hepatic macrophage phenotype, and thus increase the severity of liver fibrosis. PMID- 30458456 TI - Intrinsic Surface Effects of Tantalum and Titanium on Integrin alpha5beta1/ ERK1/2 Pathway-Mediated Osteogenic Differentiation in Rat Bone Mesenchymal Stromal Cells. AB - BACKGROUND/AIMS: Accumulating evidence demonstrates the superior osteoinductivity of tantalum (Ta) to that of titanium (Ti); however, the mechanisms underlying these differences are unclear. Thus, the objective of the present study was to examine the effects of Ta and Ti surfaces on osteogenesis using rat bone mesenchymal stromal cells (rBMSCs) as a model. METHODS: Ta and Ti substrates were polished to a mirror finish to minimize the influences of structural factors, and the intrinsic surface effects of the two materials on the integrin alpha5beta1/mitogen-activated protein kinases 3 and 1 (ERK1/2) cascade-mediated osteogenesis of rBMSCs were evaluated. Alkaline phosphatase (ALP) activity, Alizarin Red staining, real-time polymerase chain reaction, and western blot assays of critical osteogenic markers were conducted to evaluate the effects of the two substrates on cell osteogenesis. Moreover, the role of the integrin alpha5beta1/ERK1/2 pathway on the osteoinductive performance of Ta and Ti was assessed by up- and down-regulation of integrin alpha5 and beta1 with RNA interference, as well as through ERK1/2 inhibition with U0126. RESULTS: Osteogenesis of rBMSCs seeded on the Ta surface was superior to that of cells seeded on the Ti surface in terms of ALP activity, extracellular matrix calcification, and the expression of integrin alpha5, integrin beta1, ERK1/2, Runt-related transcription factor 2, osteocalcin, collagen type I, and ALP at both the mRNA and protein levels. Moreover, down-regulation of integrin alpha5 or integrin beta1, or ERK1/2 inhibition severely impaired the osteoblastic differentiation on the Ta surface. By contrast, over-expression of integrin alpha5 or integrin beta1 improved osteogenesis on the Ti substrates, while subsequent ERK1/2 inhibition abrogated this effect. CONCLUSION: The integrin alpha5beta1/ERK1/2 pathway plays a crucial role in regulating rBMSCs osteogenic differentiation; thus, the greater ability of a Ta surface to trigger integrin alpha5beta1/ERK1/2 signaling may explain its better osteoinductivity. The different effects of Ta and Ti surfaces on rBMSC osteogenesis are considered to be related to the conductive behaviors between integrin alpha5beta1 and the oxides spontaneously formed on the two metals. These results should facilitate the development of engineering strategies with Ta and Ti surfaces for improved osteogenesis in endosteal implants. PMID- 30458457 TI - High Expression of CCDC34 Is Associated with Poor Survival in Cervical Cancer Patients. AB - BACKGROUND The present study explored the expression of coiled-coil domain containing 34 (CCDC34) in cervical cancer (CC) and its prognostic value. MATERIAL AND METHODS GEPIA and Oncomine cancer databases were mined to predict the CCDC34 differential expression level between a CC group and a normal group. Immunohistochemistry was performed to examine the CCDC34 expression in 67 CC and corresponding adjacent tissues. CD31 and vascular endothelial growth factor (VEGF) were stained to reflect tumor angiogenesis in 67 CC tissues. Kaplan-Meier univariate and Cox multivariate survival analysis were done to evaluate the correlation between CCDC34 expression and prognosis of CC patients. RESULTS Both GEPIA and Oncomine cancer databases mining results revealed that CCDC34 was more highly expressed in the CC group than in the normal group (all P<0.05). Our immunochemical staining data showed that CCDC34 expression was dramatically higher in CC than in adjacent normal tissues (71.6 vs. 20.9%; P<0.001). High expression of CCDC34 was strongly associated with histological grade (P=0.022), lymph node metastasis (P=0.044), and FIGO stage (P=0.002). Furthermore, patients with CCDC34-positive expression had much more MVD than those with CCDC34-negative expression (P<0.001). Kaplan-Meier survival analysis showed that CCDC34-positive expression was associated with worse overall survival (OS) (P=0.004) and disease free survival (DFS) (P=0.005). Additionally, Cox multivariate analysis revealed that CCDC34 was an independent unfavorable prognostic parameter of DFS and OS (P=0.040 and 0.039, respectively). CONCLUSIONS High expression of CCDC34 is an independent unfavorable prognostic parameter for OS and DFS of CC patients, which was strongly associated with tumor angiogenesis. PMID- 30458458 TI - [Evolution and spatial analysis of leishmaniasis cases in a rural area bordering a community outbreak in Madrid: 2001-2017]. AB - OBJECTIVE: Leishmaniasis is a zoonotic disease, widely spread all over the world, and an endemic disease in some Spanish regions. Within the Autonomous Region of Madrid, some south populations were affected by an outbreak from 2009. This outbreak had special features and implications related to epidemiology, reservoir and environment intervention. An increased rate in rural areas bordering the outbreak area was detected by epidemiological surveillance. This area has the same environment characteristics. The objective of this study was to research and analyze the evolution of leishmaniasis cases declared in a rural area and their comparison with the cases of the outbreak area. METHODS: The cases declared to Epidemiology Surveillance Network have been used. Kulldorff's tools were used for the cluster analysis. A hot spot analysis (Getis-Ord Gi*) was made. Leporidae and vector information of the area was related to the location of cases. RESULTS: The number of observed cases exceeded the number of expected cases in this area (epidemic index 7.8 in 2013), after the outbreak. This showed a relation between both incidence rates. It seemed to be spatial correlation when the number of cases was analyzed by census sections and grids (Moran's I 0,208; z= 9,336). Using the hot-spot analysis, a higher incidence of the study area could be observed, and within Health Basic Area of Grinon after the outbreak years. A spatial relation between cases and a greater presence of vectors and leporidae was found. CONCLUSIONS: The distribution of leishmaniasis cases, in the period and study area suggests a link between the community outbreak and the increase of cases in the study area last years, overall in the rural area. It would be useful to strengthen surveillance and it should apply effective measures used in the bordering area if they were necessary. These measures can help to control the spread of the outbreak. PMID- 30458464 TI - Mesh sensitivity analysis for quantitative shear stress assessment in blood pumps using computational fluid dynamics. AB - The reduction of excessive, nonphysiologic shear stresses leading to blood trauma can be the key to overcome many of the associated complications in blood recirculating devices. In that regard, Computational Fluid Dynamics (CFD) are gaining in importance for the hydraulic and hemocompatibility assessment. Still, direct hemolysis assessments with CFD remain inaccurate and limited to qualitative comparisons rather than quantitative predictions. An underestimated quantity for improved blood damage prediction accuracy is the influence of near wall mesh resolution on shear stress quantification in regions of complex flows. This study investigated the necessary mesh refinement to quantify shear stress for two selected, meshing sensitive hotspots within a rotary centrifugal blood pump. The non-dimensional mesh characteristic number y+, which is known in the context of turbulence modelling, underestimated the maximum wall shear stress by 60% on average with the recommended value of 1, but was found to be exact below 0.1. To evaluate the meshing related error on the numerical hemolysis prediction, three-dimensional simulations of a generic centrifugal pump were performed with mesh sizes from 3 to 30 million elements. The respective hemolysis was calculated using an Eulerian scalar transport model. Mesh insensitivity was found below a maximum y+ of 0.2 necessitating 18 million mesh elements. A meshing related error of up to 25% was found for the coarser meshes. Further investigations need to address: 1) the transferability to other geometries and 2) potential adaptions on blood damage estimation models to allow better quantitative predictions. PMID- 30458466 TI - Switching to High-Deductible Health Plans: It Is Going to Be a Bumpy Ride. PMID- 30458465 TI - Writing Changes and Perceptions After Traumatic Brain Injury: "Oh, by the way, I can't write". AB - Purpose: Language and cognitive disruptions following traumatic brain injury (TBI) can negatively affect written expression and may result in increased difficulty achieving academic, vocational, social, and personal goals; however, scarce literature exists about TBI's effect on writing abilities. The purpose of this qualitative study was to describe the experiences and perceptions of people with TBI regarding their engagement in writing activities. Method: A transcendental phenomenological design structured the research. Data collection from 11 adults with TBI included gathering demographic and background information, completion of a TBI Symptom Checklist, and engagement in semistructured interviews. Results: Four major themes and 21 subthemes about postinjury writing recovery and current writing status emerged from the data analysis. Participants reported the extent to which writing difficulties interfered with daily activities and identified support strategies used to address persistent challenges. Conclusion: Understanding the writing experiences and perceptions of people with TBI can guide professionals in designing assessments and interventions to facilitate educational, vocational, social, and personal success following injury. PMID- 30458467 TI - The Changing Definition of a Primary Care Provider. PMID- 30458468 TI - 2018 AOA Research Abstracts and Poster Competition. PMID- 30458469 TI - A Study of Social Media Utilization by Individuals With Tinnitus. AB - Purpose: As more people experience tinnitus, social awareness of tinnitus has consequently increased, due in part to the Internet. Social media platforms are being used increasingly by patients to seek health-related information for various conditions including tinnitus. These online platforms may be used to seek guidance from and share experiences with individuals suffering from a similar disorder. Some social media platforms can also be used to communicate with health care providers. The aim of this study was to investigate the prevalence of tinnitus-related information on social media platforms. Method: The present investigation analyzed the portrayal of tinnitus-related information across 3 social media platforms: Facebook (pages and groups), Twitter, and YouTube. We performed a comprehensive analysis of the platforms using the key words "tinnitus" and "ringing in the ears." The results on each platform were manually examined by 2 reviewers based on social media activity metrics, such as "likes," "followers," and "comments." Results: The different social media platforms yielded diverse results, allowing individuals to learn about tinnitus, seek support, advocate for tinnitus awareness, and connect with medical professionals. The greatest activity was seen on Facebook pages, followed by YouTube videos. Various degrees of misinformation were found across all social media platforms. Conclusions: The present investigation reveals copious amounts of tinnitus related information on different social media platforms, which the community with tinnitus may use to learn about and cope with the condition. Audiologists must be aware that tinnitus sufferers often turn to social media for additional help and should understand the current climate of how tinnitus is portrayed. Clinicians should be equipped to steer individuals with tinnitus toward valid information. PMID- 30458470 TI - Verbal Agreement Inflection in German Children With Down Syndrome. AB - Purpose: The study aims to explore whether finite verbal morphology is affected in children/adolescents with Down syndrome (DS), whether observed deficits in this domain are indicative of a delayed or deviant development, and whether they are due to phonetic/phonological problems or deficits in phonological short-term memory. Method: An elicitation task on subject-verb agreement, a picture-naming task targeting stem-final consonants that also express verbal agreement, a nonword repetition task, and a test on grammar comprehension were conducted with 2 groups of monolingual German children: 32 children/adolescents with DS (chronological age M = 11;01 [years;months]) and a group of 16 typically developing children (chronological age M = 4;00) matched on nonverbal mental age. Results: Analyses reveal that a substantial number of children/adolescents with DS are impaired in marking verbal agreement and fail to reach an acquisition criterion. The production of word-final consonants succeeds, however, when these consonants do not express verbal agreement. Performance with verbal agreement and nonword repetition are related. Conclusions: Data indicate that a substantial number of children/adolescents with DS display a deficit in verbal agreement inflection that cannot be attributed to phonetic/phonological problems. The influence of phonological short-term memory on the acquisition of subject-verb agreement has to be further explored. PMID- 30458472 TI - Pitfalls and Potential in Medicare's Move Toward Outpatient Care Episodes. PMID- 30458473 TI - Current Practice of Child Grammar Intervention: A Survey of Speech-Language Pathologists. AB - Purpose: The aim of this study was to better understand current grammatical intervention approaches. Despite grammatical language being a common weakness among children with language impairment, relatively little is known about current grammatical intervention practices of speech-language pathologists (SLPs). Such information is needed to guide the development and evaluation of grammatical interventions and to identify areas in which the current practice is not empirically supported. Method: Participants included 338 SLPs working primarily with children. Participants completed an online survey regarding their implementation of nine different grammatical intervention components, including goals, procedures, dosage, agents, contexts, goal attack strategies, service delivery models, activities, and outcome measurements. Participants also indicated how they would alter the intervention setting and dosage if resources were unlimited. Results: We grouped participants based on the ages of children that represent the largest percentage of their caseload resulting in an early education group (n = 114) and an elementary group (n = 224). We aggregated responses from each question to gain an estimate of current implementation practices associated with each intervention component queried. Conclusions: This study provides general guidelines of current clinical practices to help guide research on grammatical interventions for children and to promote successful translation and implementations of evidence-based treatment approaches. Results may also help clinicians and researchers better understand misalignments between empirically supported intervention approaches and current approaches for treating grammatical weaknesses. PMID- 30458474 TI - Comparing Diabetes Outcomes for Primary Care Provided by Physicians, Nurse Practitioners, and Physician Assistants. PMID- 30458475 TI - For Difficult-to-Model Brain Diseases, Brain Organoids Come to the Rescue. PMID- 30458476 TI - FDA Joins New Effort to Strengthen Medical Device Cybersecurity. PMID- 30458478 TI - Blood Group Genotyping Test Goes Beyond A, B, and O. PMID- 30458477 TI - Will Naloxone Become Available OTC? PMID- 30458480 TI - Progress in Primary Care-From Alma-Ata to Astana. PMID- 30458481 TI - Current Comment. PMID- 30458482 TI - Joint Prevalence of Sitting Time and Leisure-Time Physical Activity Among US Adults, 2015-2016. PMID- 30458483 TI - Maryland's Hospital Global Budget Program. PMID- 30458484 TI - Odds Ratios vs Risk Ratios. PMID- 30458485 TI - Validity of the qSOFA Score in Low- and Middle-Income Countries. PMID- 30458486 TI - Breakthrough Therapy Designation for New Drugs. PMID- 30458487 TI - Maryland's Hospital Global Budget Program-Reply. PMID- 30458488 TI - Odds Ratios vs Risk Ratios-Reply. PMID- 30458489 TI - Validity of the qSOFA Score in Low- and Middle-Income Countries-Reply. PMID- 30458490 TI - Breakthrough Therapy Designation for New Drugs-Reply. PMID- 30458491 TI - Endoscopic Retrograde Cholangiopancreatography. PMID- 30458495 TI - Mapping Yellow Fever Virus in Brazil. PMID- 30458493 TI - Solving the Silence. PMID- 30458496 TI - Global Hunger on the Rise as Climate Extremes Increase. PMID- 30458498 TI - The Effect of High-Deductible Insurance Plans on Diabetes Care. PMID- 30458497 TI - Guidelines for Ending Childhood and Adolescent Tuberculosis. PMID- 30458499 TI - High-Deductible Insurance and Delay in Care for the Macrovascular Complications of Diabetes. AB - Background: Little is known about the long-term effects of high-deductible insurance on care for chronic medical conditions. Objective: To determine whether a transition from low-deductible to high-deductible insurance is associated with delayed medical care for macrovascular complications of diabetes. Design: Observational longitudinal comparison of matched groups. Setting: A large national health insurer during 2003 to 2012. Participants: The intervention group comprised 33 957 persons with diabetes who were continuously enrolled in low deductible (<=$500) insurance plans during a baseline year followed by up to 4 years in high-deductible (>=$1000) plans. The control group included 294 942 persons with diabetes who were enrolled in low-deductible plans contemporaneously with matched intervention group members. Intervention: Employer-mandated transition to a high-deductible plan. Measurements: The number of months it took for persons in each study group to seek care for their first major macrovascular symptom, have their first major diagnostic test for macrovascular disease, and have their first major procedure-based treatment was determined. Between-group differences in time to reach a midpoint event rate were then calculated. Results: No baseline differences were found between groups. During follow-up, the delay for the high-deductible group was 1.5 months (95% CI, 0.8 to 2.3 months) for seeking care for the first major symptom, 1.9 months (CI, 1.4 to 2.3 months) for the first diagnostic test, and 3.1 months (CI, 0.5 to 5.8 months) for the first procedure-based treatment. Limitation: Health outcomes were not examined. Conclusion: Among persons with diabetes, mandated enrollment in a high-deductible insurance plan was associated with delays in seeking care for the first major symptoms of macrovascular disease, the first diagnostic test, and the first procedure-based treatment. Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases. PMID- 30458500 TI - Prevalence of Publication Bias Tests in Speech, Language, and Hearing Research. AB - Purpose: The purpose of this research note is to systematically document the extent that researchers who publish in American Speech-Language-Hearing Association (ASHA) journals search for and include unpublished literature in their meta-analyses and test for publication bias. Method: This research note searched all ASHA peer-reviewed journals for published meta-analyses and reviewed all qualifying articles for characteristics related to the acknowledgment and assessment of publication bias. Results: Of meta-analyses published in ASHA journals, 75% discuss publication in some form; however, less than 50% test for publication bias. Further, only 38% (n = 11) interpreted the findings of these tests. Conclusion: Findings reveal that more attention is needed to the presence and impact of publication bias. This research note concludes with 5 recommendations for addressing publication bias. Supplemental Material: https://doi.org/10.23641/asha.7268648. PMID- 30458501 TI - Relations Between Teacher Talk Characteristics and Child Language in Spoken Language Deaf and Hard-of-Hearing Classrooms. AB - Purpose: The aim of this study was to examine relations between teachers' conversational techniques and language gains made by their deaf and hard-of hearing students. Specifically, we considered teachers' reformulations of child utterances, language elicitations, explicit vocabulary and syntax instruction, and wait time. Method: This was an observational, longitudinal study that examined the characteristics of teacher talk in 25 kindergarten through second grade classrooms of 68 deaf and hard-of-hearing children who used spoken English. Standardized assessments provided measures of child vocabulary and morphosyntax in the fall and spring of a school year. Characteristics of teacher talk were coded from classroom video recordings during the winter of that year. Results: Hierarchical linear modeling indicated that reformulating child statements and explicitly teaching vocabulary were significant predictors of child vocabulary gains across a school year. Explicitly teaching vocabulary also significantly predicted gains in morphosyntax abilities. There were wide individual differences in the teachers' use of these conversational techniques. Conclusion: Reformulation and explicit vocabulary instruction may be areas where training can help teachers improve, and improvements in the teachers' talk may benefit their students. PMID- 30458502 TI - Characterizing the Biomechanical Properties of the Pubovisceralis Muscle Using a Genetic Algorithm and the Finite Element Method. AB - To better understand the disorders in the pelvic cavity associated with the pelvic floor muscles (PFM) using computational models, it is fundamental to identify the biomechanical properties of these muscles. For this purpose, we implemented an optimization scheme, involving a genetic algorithm (GA) and an inverse finite element analysis (FEA), in order to estimate the material properties of the pubovisceralis muscle (PVM). The datasets of five women were included in this noninvasive analysis. The numerical models of the PVM were built from static axial magnetic resonance (MR) images, and the hyperplastic Mooney Rivlin constitutive model was used. The material parameters obtained were compared with the ones established through a similar optimization scheme, using Powell's algorithm. To validate the values of the material parameters that characterize the passive behavior of the PVM, the displacements obtained via the numerical models with both methods were compared with dynamic MR images acquired during Valsalva maneuver. The material parameters (c1 and c2) were higher for the GA than for Powell's algorithm, but when comparing the magnitude of the displacements in millimeter of the PVM, there was only a 5% difference, and 4% for the principal logarithmic strain. The GA allowed estimating the in vivo biomechanical properties of the PVM of different subjects, requiring a lower number of simulations when compared to Powell's algorithm. PMID- 30458503 TI - A Data-Driven Personalized Model of Glucose Dynamics Taking Account of the Effects of Physical Activity for Type 1 Diabetes: An In Silico Study. AB - This paper aims to develop a data-driven model for glucose dynamics taking into account the effects of physical activity (PA) through a numerical study. It intends to investigate PA's immediate effect on insulin-independent glucose variation and PA's prolonged effect on insulin sensitivity. We proposed a nonlinear model with PA (NLPA), consisting of a linear regression of PA and a bilinear regression of insulin and PA. The model was identified and evaluated using data generated from a physiological PA-glucose model by Dalla Man et al. integrated with the uva/padova Simulator. Three metrics were computed to compare blood glucose (BG) predictions by NLPA, a linear model with PA (LPA), and a linear model with no PA (LOPA). For PA's immediate effect on glucose, NLPA and LPA showed 45-160% higher mean goodness of fit (FIT) than LOPA under 30 min-ahead glucose prediction (P < 0.05). For the prolonged PA effect on glucose, NLPA showed 87% higher FIT than LPA (P < 0.05) for simulations using no previous measurements. NLPA had 25-37% and 31-54% higher sensitivity in predicting postexercise hypoglycemia than LPA and LOPA, respectively. This study demonstrated the following qualitative trends: (1) for moderate-intensity exercise, accuracy of BG prediction was improved by explicitly accounting for PA's effect; and (2) accounting for PA's prolonged effect on insulin sensitivity can increase the chance of early prediction of postexercise hypoglycemia. Such observations will need to be further evaluated through human subjects in the future. PMID- 30458504 TI - Numerical Simulation of the Heat Transfer in the Cryoprobe of an Innovative Apparatus for Cryosurgery. AB - Cryosurgery is a rapidly developing discipline, alternative to conventional surgical techniques, used to destroy cancer cells by the action of low temperatures. Currently, the refrigeration is obtained via the adiabatic expansion of gases in probes used for surgeries, with the need of inherently dangerous pressurized vessels. The proposed innovative prototypal apparatus aims to reach the cryosurgical temperatures exploiting a closed-loop refrigeration system, avoiding the hazardous presence of pressurized vessels in the operating room. This study preliminarily examines the technical feasibility of the cryoablation with this machine focusing the attention on the cryoprobe design. Cryoprobe geometry and materials are assessed and the related heat transfer taking place during the cryoablation process is simulated with the aid of the computational fluid dynamics software ANSYS(r)Fluent. Parametric analyses are carried out varying the length of the collecting tubes and the inlet velocity of the cold carrier fluid in the cryoprobe. The values obtained for physical quantities such as the temperature reached in the treated tissue, the width of the obtained cold front, and the maximum pressure required for the cold carrier fluid are calculated and discussed in order to prove the effectiveness of the experimental apparatus and develop the machine further. PMID- 30458505 TI - An Integrative Analysis of Spontaneous Storytelling Discourse in Aphasia: Relationship With Listeners' Rating and Prediction of Severity and Fluency Status of Aphasia. AB - Purpose: This study investigated which of the three analytic approaches of oral discourse, including linguistically based measures, proposition-based measures, and story grammar, best correlated with aphasia severity and with naive listeners' ratings on aphasic productions. The predictive power of these analytic approaches to aphasia severity and fluency status of people with aphasia (PWA) was examined. Finally, which approach best discriminated fluent versus nonfluent PWA was determined. Method: Audio files and orthographic transcriptions of the storytelling task "The Boy Who Cried Wolf" from 68 PWA and 68 controls were extracted from the Cantonese AphasiaBank. Each transcript was analyzed using these 3 systems. Results: The linguistic approach of discourse analysis best correlated with aphasia severity and naive listeners' subjective ratings. Although both linguistically based and proposition-based measures significantly predicted aphasia severity, a subset of linguistic measures focusing on the quantity and efficiency of production were particularly useful for clinical estimation of the fluency status of aphasia. Conclusions: The linguistically based measures appeared to be the most clinically effective and powerful in reflecting PWA's performance of spoken discourse. PMID- 30458506 TI - Intermediate Diabetes Outcomes in Patients Managed by Physicians, Nurse Practitioners, or Physician Assistants: A Cohort Study. AB - Background: Primary care provided by nurse practitioners (NPs) and physician assistants (PAs) has been proposed as a solution to expected workforce shortages. Objective: To examine potential differences in intermediate diabetes outcomes among patients of physician, NP, and PA primary care providers (PCPs). Design: Cohort study using data from the U.S. Department of Veterans Affairs (VA) electronic health record. Setting: 568 VA primary care facilities. Patients: 368 481 adult patients with diabetes treated pharmaceutically. Measurements: The relationship between the profession of the PCP (the provider the patient visited most often in 2012) and both continuous and dichotomous control of hemoglobin A1c (HbA1c), systolic blood pressure (SBP), and low-density lipoprotein cholesterol (LDL-C) was examined on the basis of the mean of measurements in 2013. Inverse probability of PCP type was used to balance cohort characteristics. Hierarchical linear mixed models and logistic regression models were used to analyze continuous and dichotomous outcomes, respectively. Results: The PCPs were physicians (n = 3487), NPs (n = 1445), and PAs (n = 443) for 74.9%, 18.2%, and 6.9% of patients, respectively. The difference in HbA1c values compared with physicians was -0.05% (95% CI, -0.07% to -0.02%) for NPs and 0.01% (CI, -0.02% to 0.04%) for PAs. For SBP, the difference was -0.08 mm Hg (CI, -0.34 to 0.18 mm Hg) for NPs and 0.02 mm Hg (CI, -0.42 to 0.38 mm Hg) for PAs. For LDL-C, the difference was 0.01 mmol/L (CI, 0.00 to 0.03 mmol/L) (0.57 mg/dL [CI, 0.03 to 1.11 mg/dL]) for NPs and 0.03 mmol/L (CI, 0.01 to 0.05 mmol/L) (1.08 mg/dL [CI, 0.25 to 1.91 mg/dL]) for PAs. None of these differences were clinically significant. Limitation: Most VA patients are men who receive treatment in a staff-model health care system. Conclusion: No clinically significant variation was found among the 3 PCP types with regard to diabetes outcomes, suggesting that similar chronic illness outcomes may be achieved by physicians, NPs, and PAs. Primary Funding Source: VA Health Services Research and Development. PMID- 30458507 TI - The Effect of Textiles Impregnated with Particles of High Emissivity in the Far Infrared, on the Temperature of the Cold Hand. AB - In engineering and medicine, there is a growing interest in using textiles made of composites with enhanced thermal properties. One such type of textile is fabric impregnated with ceramics and mineral particles. This material has high emissivity in the infrared range and may have therapeutic benefits for treatments of diseases, like Raynaud's syndrome. While there is significant clinical and commercial interest, there is an evident lack of fundamental studies on the heat transfer aspects of these fabrics. The goal of this technical brief is to presents results from a fundamental study examining the thermal effects of fabric with ceramics and minerals (produced by Nanobionic Inc.) on the temperatures of the hands. With a confidence level of 90%, the results show that the textile with ceramics and minerals has an enhanced thermal effect on warming a cold hand in comparison to a placebo fabric without ceramics or minerals. Much more research is needed to increase the level of confidence and develop a fundamental understanding of the mechanism. PMID- 30458508 TI - Losing Embryos, Finding Justice: Life, Liberty, and the Pursuit of Personhood. PMID- 30458509 TI - Clinical Progression in Four Cases of Primary Progressive Apraxia of Speech. AB - Purpose: This case series details the clinical progression of patients with primary progressive apraxia of speech (PPAOS) to illustrate, using several methods and supplemental material examples, the changes that occur in speech and language functioning in this patient population. Method: Four patients who presented with PPAOS were followed between 5 and 6 years. Two patients had predominant articulatory abnormalities (termed phonetic PPAOS), 1 had predominant prosodic abnormalities (prosodic PPAOS), and 1 had relatively equal articulatory and prosodic abnormalities (mixed PPAOS). Detailed speech (including acoustics), language, neurologic, and neuropsychological data were collected. Results: At initial exam, the patients ranged from 60 to 77 years old, with presenting disease duration of 1.5-10 years. Although all patients presented with an isolated apraxia of speech, all developed varying degrees of aphasia and dysarthria. Patients with phonetic PPAOS developed relatively more severe aphasia than the other 2 patients. All patients eventually had severe functional communication limitations and required alternative or augmentative means of communication, although at varying times postonset of their initial speech problem. Two patients developed dysphagia, 3 showed mild-moderate Parkinsonism, and 2 developed depression. For all patients, simple temporal acoustic measurements documented slowed speech rate over time. Conclusions: This case series demonstrates that patients who initially present with PPAOS may develop aphasia and dysarthria, cognitive and behavioral changes, and other neurologic signs. Whether these changes can be predicted by the perceptual characteristics of the apraxia of speech is yet to be determined. The detailed longitudinal profiles provide valuable clinical insight into the progression of disease in people with PPAOS. Supplemental Material: https://doi.org/10.23641/asha.7051616. PMID- 30458510 TI - The contribution of local and global motion adaptation in the repulsive direction aftereffect. AB - After adapting to a certain motion direction, our perception of a similar direction will be repelled away from the adapting direction, a phenomenon known as the direction aftereffect (DAE). As the motion system consists of local and global processing stages, it remains unclear how the adaptation of the two stages contributes in producing the DAE. The present study addresses this question by independently inducing adaptation at local and global motion-processing levels. Local adaptation was manipulated by presenting test stimuli at either adapted or nonadapted locations. Global adaptation was manipulated by embedding one or five global motion directions in the adapting motion. Repulsive DAE, when measured using a multiple-element test pattern, was stronger when it was produced by global adaptation than when produced by local adaptation. Specifically, the DAE resulting from local adaptation (a) decreased when test orientations differed from adapting orientation, (b) decreased when local directions were disambiguated using plaid stimuli, (c) remained the same even when attention was focused at specific test locations during adaptation, and (d) increased when tested with a single element. Overall, these findings suggest that the strength of repulsive DAE depends on both the motion-processing level at which adaptation occurs and the level at which the DAE was tested. Furthermore, the repulsive DAE arising from local adaptation alone can be explained by the propagation of local speed repulsion instead of local direction repulsion. Findings are discussed in the context of how motion aftereffects arise from the adaptation of a hierarchical motion system. PMID- 30458511 TI - Bottom-up processing of curvilinear visual features is sufficient for animate/inanimate object categorization. AB - Animate and inanimate objects differ in their intermediate visual features. For instance, animate objects tend to be more curvilinear compared to inanimate objects (e.g., Levin, Takarae, Miner, & Keil, 2001). Recently, it has been demonstrated that these differences in the intermediate visual features of animate and inanimate objects are sufficient for categorization: Human participants viewing synthesized images of animate and inanimate objects that differ largely in the amount of these visual features classify objects as animate/inanimate significantly above chance (Long, Stormer, & Alvarez, 2017). A remaining question, however, is whether the observed categorization is a consequence of top-down cognitive strategies (e.g., rectangular shapes are less likely to be animals) or a consequence of bottom-up processing of their intermediate visual features, per se, in the absence of top-down cognitive strategies. To address this issue, we repeated the classification experiment of Long et al. (2017) but, unlike Long et al. (2017), matched the synthesized images, on average, in the amount of image-based and perceived curvilinear and rectilinear information. Additionally, in our synthesized images, global shape information was not preserved, and the images appeared as texture patterns. These changes prevented participants from using top-down cognitive strategies to perform the task. During the experiment, participants were presented with these synthesized, texture-like animate and inanimate images and, on each trial, were required to classify them as either animate or inanimate with no feedback given. Participants were told that these synthesized images depicted abstract art patterns. We found that participants still classified the synthesized stimuli significantly above chance even though they were unaware of their classification performance. For both object categories, participants depended more on the curvilinear and less on the rectilinear, image-based information present in the stimuli for classification. Surprisingly, the stimuli most consistently classified as animate were the most dangerous animals in our sample of images. We conclude that bottom-up processing of intermediate features present in the visual input is sufficient for animate/inanimate object categorization and that these features may convey information associated with the affective content of the visual stimuli. PMID- 30458512 TI - Adaptive stimulus selection for multi-alternative psychometric functions with lapses. AB - Psychometric functions (PFs) quantify how external stimuli affect behavior, and they play an important role in building models of sensory and cognitive processes. Adaptive stimulus-selection methods seek to select stimuli that are maximally informative about the PF given data observed so far in an experiment and thereby reduce the number of trials required to estimate the PF. Here we develop new adaptive stimulus-selection methods for flexible PF models in tasks with two or more alternatives. We model the PF with a multinomial logistic regression mixture model that incorporates realistic aspects of psychophysical behavior, including lapses and multiple alternatives for the response. We propose an information-theoretic criterion for stimulus selection and develop computationally efficient methods for inference and stimulus selection based on adaptive Markov-chain Monte Carlo sampling. We apply these methods to data from macaque monkeys performing a multi-alternative motion-discrimination task and show in simulated experiments that our method can achieve a substantial speed-up over random designs. These advances will reduce the amount of data needed to build accurate models of multi-alternative PFs and can be extended to high dimensional PFs that would be infeasible to characterize with standard methods. PMID- 30458513 TI - Impact of higher-order aberrations on depth-of-field. AB - It is well known that depth-of-focus (DOF) is influenced by optical factors (such as pupil size and monochromatic aberrations). However, neural factors such as blur sensitivity and defocus adaptation may play an important role on the extent of DOF. A series of experiments were conducted to study if optical or neural factors are most pertinent in explaining the variability of DOF across subjects. An adaptive optics system with a black and white target, a 3.8-mm artificial pupil, and a subjective criterion (based on objectionable blur) were used to measure depth of field ([DOFi]; DOF computed in the object space) in 11 participants, after at least 6 min of adaptation. This was done under three conditions: (a) with their own higher order aberrations (HOA); (b) after correction of their monochromatic HOA; and (c) after altering the HOA pattern for some participants to reflect the HOA pattern measured for a different participant. Natural DOFi and DOFi after HOA correction were positively correlated (R2 = 0.461), but a significant decrease in DOFi (21% on average) was found after HOA correction (p = 0.042). Effect of HOA on the intersubject variability of DOFi was 3.9 times smaller than the effect of the image neural processing. This study shows that DOFi depends on both optical and neural factors, but the latter seems to play a more important role than the former. PMID- 30458514 TI - Magnetoencephalography adaptation reveals depth-cue-invariant object representations in the visual cortex. AB - Independent of edges and 2-D shape that can be highly informative of object identity, depth cues alone can also give rise to vivid and effective object percepts. The processing of different depth cues engages segregated cortical areas, and an efficient object representation would be one that is invariant to depth cues. Here, we investigated depth-cue invariance of object representations by measuring the category-specific response to faces-the M170 response measured with magnetoencephalography. The M170 response is strongest to faces and is sensitive to adaptation, such that repeated presentation of a face diminishes subsequent M170 responses. We used this feature of the M170 and measured the degree to which the adaptation effect is affected by variations in depth cue and 3-D object shape. Subjects viewed a rapid presentation of two stimuli-an adaptor and a test stimulus. The adaptor was either a face, a chair, or a face-like oval surface, and rendered with a single depth cue (shading, structure from motion, or texture). The test stimulus was always a shaded face of a random identity, thus completely controlling for low-level influences on the M170 response to the test stimulus. In the left fusiform face area, we found strong M170 adaptation when the adaptor was a face regardless of its depth cue. This adaptation was marginal in the right fusiform and negligible in the occipital regions. Our results support the presence of depth-cue-invariant representations in the human visual system, alongside size, position, and viewpoint invariance. PMID- 30458515 TI - Natural visual behavior in individuals with peripheral visual-field loss. AB - Retinitis pigmentosa (RP) is an inherited disease that causes progressive peripheral visual-field loss. In this study, we investigated how such loss affects visual exploration of natural images. Individuals with varying degrees of visual-field loss and healthy control participants freely observed images of different sizes while eye movements were recorded. We examined whether visual behavior differed when the scene content was shown in various extents of the visual field, and investigated the spatial bias, saccade amplitudes, and number and duration of fixations. We found that the healthy control group showed a central spatial bias during image viewing. The RP group showed similar biases on the group level, but with reproducible individual exploration patterns. For saccade amplitudes, the healthy control group and the RP group showed similar behavior throughout all image sizes. The RP group with severe loss of peripheral vision thus tended to target saccades toward blind areas of their visual field. The number of fixations did not change between the two groups, although fixation durations decreased in the RP group. In conclusion, the RP group scanned the images surprisingly similarly to the healthy control group; however, they showed individual idiosyncratic explorative strategies when the observed scene exceeded their visible field. Thus, although RP leads to a severe loss of the visual field, there is no general adaptive mechanism to change visual exploration. Instead, individuals rely on individual strategies, leading to high heterogeneity in the RP group. PMID- 30458516 TI - Investigating overt and covert shifts of attention within social naturalistic scenes. AB - Eye-tracking studies on social attention have consistently shown that humans prefer to attend to other human beings. Much less is known about whether a similar preference is also evident in covert attentional processes. To enable a direct comparison, this study examined covert and overt attentional guidance within two different experimental setups using complex naturalistic scenes instead of isolated single features. In the first experiment, a modified version of the dot-probe paradigm served as a measure of covert reflexive attention toward briefly presented scenes containing a social feature in one half of the visual field compared to nonsocial elements in the other while controlling for low-level visual saliency. Participants showed a stable congruency effect with faster reaction times and fewer errors for probes presented on the social side of the scene. In a second experiment, we tracked eye movements for the same set of stimuli while manipulating the presentation time to allow for differentiating reflexive and more sustained aspects of overt attention. Supportive of the first results, analyses revealed a robust preference for social features concerning initial saccade direction as well as fixation allocation. Collectively, these experiments imply preferential processing of social features over visually salient aspects for automatic allocation of covert as well as overt attention. PMID- 30458517 TI - An object-tracking model that combines position and speed explains spatial and temporal responses in a timing task. AB - Many tasks require synchronizing our actions with particular moments along the path of moving targets. However, it is controversial whether we base these actions on spatial or temporal information, and whether using either can enhance our performance. We addressed these questions with a coincidence timing task. A target varying in speed and motion duration approached a goal. Participants stopped the target and were rewarded according to its proximity to the goal. Results showed larger reward for responses temporally (rather than spatially) equidistant to the goal across speeds, and this pattern was promoted by longer motion durations. We used a Kalman filter to simulate time and space-based responses, where modeled speed uncertainty depended on motion duration and positional uncertainty on target speed. The comparison between simulated and observed responses revealed that a single position-tracking mechanism could account for both spatial and temporal patterns, providing a unified computational explanation. PMID- 30458518 TI - Surface continuity and discontinuity bias the perception of stereoscopic depth. AB - Binocular disparity signals can provide high acuity information about the positions of points, surfaces, and objects in three-dimensional space. For some stimulus configurations, however, perceived depth is known to be affected by surface organization. Here we examine the effects of surface continuity and discontinuity on such surface organization biases. Participants were presented with a series of random dot surfaces, each with a cumulative Gaussian form in depth. Surfaces varied in the steepness of disparity gradients, via manipulation of the standard deviation of the Gaussian, and/or the presence of differing forms of surface discontinuity. By varying the relative disparity between surface edges, we measured the points of subjective equality, where surfaces of differing steepness and/or discontinuity were perceptually indistinguishable. We compare our results to a model that considers sensitivity to different frequencies of disparity modulation. Across a series of experiments, the observed patterns of change in points of subjective equality suggest that perceived depth is determined by the integration of measures of relative disparity, with a bias toward sharp changes in disparity. Such disparities increase perceived depth when they are in the same direction as the overall disparity. Conversely, perceived depth is reduced by the presence of sharp disparity changes that oppose the sign of the overall depth change. PMID- 30458519 TI - The role of global cues in the perceptual grouping of natural shapes. AB - Perceptual grouping of the bounding contours of objects is a crucial step in visual scene understanding and object recognition. The standard perceptual model for this task, supported by a convergence of physiological and psychophysical evidence, is based upon an association field that governs local grouping, and a Markov or transitivity assumption that allows global contours to be inferred solely from these local cues. However, computational studies suggest that these local cues may not be sufficient for reliable identification of object boundaries in natural scenes. Here we employ a novel psychophysical method to assess the potential role of more global factors in the perceptual grouping of natural object contours. Observers were asked to detect briefly presented fragmented target contours in oriented element noise. We employed natural animal shape stimuli, which in addition to local grouping cues possess global regularities that could potentially be exploited to guide grouping and thereby improve target detection performance. To isolate the role of these global regularities we contrasted performance with open and closed control target stimuli we call local metamers, as they afford the same local grouping cues as animal shapes. We found that performance for closed metamers exceeded performance for open metamers, while performance for animal targets exceeded both, indicating that global grouping cues represented in higher visual areas codetermine the association between orientation signals coded in early visual cortex. These results demand a revision to the standard model for perceptual grouping of contours to accommodate feedback from higher visual areas coding global shape properties. PMID- 30458520 TI - The Coexistence of Disabling Conditions in Children Who Stutter: Evidence From the National Health Interview Survey. AB - Purpose: Stuttering is a disorder that has been associated with coexisting developmental disorders. To date, detailed descriptions of the coexistence of such conditions have not consistently emerged in the literature. Identifying and understanding these conditions can be important to the overall management of children who stutter (CWS). The objective of this study was to generate a profile of the existence of disabling developmental conditions among CWS using national data. Method: Six years of data from the National Health Interview Survey (2010 2015) were analyzed for this project. The sample consisted of children whose respondents clearly indicated the presence or absence of stuttering. Chi-square tests of independence were used for comparing categorical variables; and independent-samples t tests, for comparing continuous variables. Multiple logistic regression analyses were used for determining the odds of having a coexisting disabling developmental condition. Results: This study sample included 62,450 children, of which 1,231 were CWS. Overall, the presence of at least 1 disabling developmental condition was 5.5 times higher in CWS when compared with children who do not stutter. The presence of stuttering was also associated with higher odds of each of the following coexisting developmental conditions: intellectual disability (odds ratio [OR] = 6.67, p < .001), learning disability (OR = 5.45, p < .001), attention-deficit hyperactivity disorder/attention-deficit disorder (OR = 3.09, p < .001), seizures (OR = 7.52, p < .001), autism/Asperger's/pervasive developmental disorder (OR = 5.48, p < .001), and any other developmental delay (OR = 7.10, p < .001). Conclusion: Evidence from the National Health Interview Survey suggests a higher prevalence of coexisting developmental disabilities in CWS. The existence of coexisting disabling developmental conditions should be considered as part of an overall management plan for CWS. PMID- 30458521 TI - A Comparison of Personal Sound Amplification Products and Hearing Aids in Ecologically Relevant Test Environments. AB - Purpose: The aim of this study was to compare the benefit of self-adjusted personal sound amplification products (PSAPs) to audiologist-fitted hearing aids based on speech recognition, listening effort, and sound quality in ecologically relevant test conditions to estimate real-world effectiveness. Method: Twenty five older adults with bilateral mild-to-moderate hearing loss completed the single-blinded, crossover study. Participants underwent aided testing using 3 PSAPs and a traditional hearing aid, as well as unaided testing. PSAPs were adjusted based on participant preference, whereas the hearing aid was configured using best-practice verification protocols. Audibility provided by the devices was quantified using the Speech Intelligibility Index (American National Standards Institute, 2012). Outcome measures assessing speech recognition, listening effort, and sound quality were administered in ecologically relevant laboratory conditions designed to represent real-world speech listening situations. Results: All devices significantly improved Speech Intelligibility Index compared to unaided listening, with the hearing aid providing more audibility than all PSAPs. Results further revealed that, in general, the hearing aid improved speech recognition performance and reduced listening effort significantly more than all PSAPs. Few differences in sound quality were observed between devices. All PSAPs improved speech recognition and listening effort compared to unaided testing. Conclusions: Hearing aids fitted using best-practice verification protocols were capable of providing more aided audibility, better speech recognition performance, and lower listening effort compared to the PSAPs tested in the current study. Differences in sound quality between the devices were minimal. However, because all PSAPs tested in the study significantly improved participants' speech recognition performance and reduced listening effort compared to unaided listening, PSAPs could serve as a budget-friendly option for those who cannot afford traditional amplification. PMID- 30458522 TI - Firearm Injury Prevention: AFFIRMing That Doctors Are in Our Lane. PMID- 30458523 TI - Normative Data for a Rapid, Automated Test of Spatial Release From Masking. AB - Purpose: The purpose of this study is to report normative data and predict thresholds for a rapid test of spatial release from masking for speech perception. The test is easily administered and has good repeatability, with the potential to be used in clinics and laboratories. Normative functions were generated for adults varying in age and amounts of hearing loss. Method: The test of spatial release presents a virtual auditory scene over headphones with 2 conditions: colocated (with target and maskers at 0 degrees ) and spatially separated (with target at 0 degrees and maskers at +/- 45 degrees ). Listener thresholds are determined as target-to-masker ratios, and spatial release from masking (SRM) is determined as the difference between the colocated condition and spatially separated condition. Multiple linear regression was used to fit the data from 82 adults 18-80 years of age with normal to moderate hearing loss (0-40 dB HL pure-tone average [PTA]). The regression equations were then used to generate normative functions that relate age (in years) and hearing thresholds (as PTA) to target-to-masker ratios and SRM. Results: Normative functions were able to predict thresholds with an error of less than 3.5 dB in all conditions. In the colocated condition, the function included only age as a predictive parameter, whereas in the spatially separated condition, both age and PTA were included as parameters. For SRM, PTA was the only significant predictor. Different functions were generated for the 1st run, the 2nd run, and the average of the 2 runs. All 3 functions were largely similar in form, with the smallest error being associated with the function on the basis of the average of 2 runs. Conclusion: With the normative functions generated from this data set, it would be possible for a researcher or clinician to interpret data from a small number of participants or even a single patient without having to first collect data from a control group, substantially reducing the time and resources needed. Supplemental Material: https://doi.org/10.23641/asha.7080878. PMID- 30458524 TI - Spontaneous Otoacoustic Emissions Reveal an Efficient Auditory Efferent Network. AB - Purpose: Understanding speech often involves processing input from multiple modalities. The availability of visual information may make auditory input less critical for comprehension. This study examines whether the auditory system is sensitive to the presence of complementary sources of input when exerting top down control over the amplification of speech stimuli. Method: Auditory gain in the cochlea was assessed by monitoring spontaneous otoacoustic emissions (SOAEs), which are by-products of the amplification process. SOAEs were recorded while 32 participants (23 women, nine men; Mage = 21.13) identified speech sounds such as "ba" and "ga." The speech sounds were presented either alone or with complementary visual input, as well as in quiet or with 6-talker babble. Results: Analyses revealed that there was a greater reduction in the amplification of noisy auditory stimuli compared with quiet. This reduced amplification may aid in the perception of speech by improving the signal-to-noise ratio. Critically, there was a greater reduction in amplification when speech sounds were presented bimodally with visual information relative to when they were presented unimodally. This effect was evidenced by greater changes in SOAE levels from baseline to stimuli presentation in audiovisual trials relative to audio-only trials. Conclusions: The results suggest that even the earliest stages of speech comprehension are modulated by top-down influences, resulting in changes to SOAEs depending on the presence of bimodal or unimodal input. Neural processes responsible for changes in cochlear function are sensitive to redundancy across auditory and visual input channels and coordinate activity to maximize efficiency in the auditory periphery. PMID- 30458525 TI - Effect of Dual-Carrier Processing on the Intelligibility of Concurrent Vocoded Sentences. AB - Purpose: The goal of this study was to examine the role of carrier cues in sound source segregation and the possibility to enhance the intelligibility of 2 sentences presented simultaneously. Dual-carrier (DC) processing (Apoux, Youngdahl, Yoho, & Healy, 2015) was used to introduce synthetic carrier cues in vocoded speech. Method: Listeners with normal hearing heard sentences processed either with a DC or with a traditional single-carrier (SC) vocoder. One group was asked to repeat both sentences in a sentence pair (Experiment 1). The other group was asked to repeat only 1 sentence of the pair and was provided additional segregation cues involving onset asynchrony (Experiment 2). Results: Both experiments showed that not only is the "target" sentence more intelligible in DC compared with SC, but the "background" sentence intelligibility is equally enhanced. The participants did not benefit from the additional segregation cues. Conclusions: The data showed a clear benefit of using a distinct carrier to convey each sentence (i.e., DC processing). Accordingly, the poor speech intelligibility in noise typically observed with SC-vocoded speech may be partly attributed to the envelope of independent sound sources sharing the same carrier. Moreover, this work suggests that noise reduction may not be the only viable option to improve speech intelligibility in noise for users of cochlear implants. Alternative approaches aimed at enhancing sound source segregation such as DC processing may help to improve speech intelligibility while preserving and enhancing the background. PMID- 30458526 TI - Time Course of the Second Morpheme Processing During Spoken Disyllabic Compound Word Recognition in Chinese. AB - Purpose: This study aimed to investigate the time course of meaning activation of the 2nd morpheme processing of compound words during Chinese spoken word recognition using eye tracking technique with the printed-word paradigm. Method: In the printed-word paradigm, participants were instructed to listen to a spoken target word (e.g., "", /da4fang1/, generous) while presented with a visual display composed of 3 words: a morphemic competitor (e.g., "", /yuan2xing2/, circle), which was semantically related to the 2nd morpheme (e.g., "", /fang1/, square) of the spoken target word; a whole-word competitor (e.g., "", /lin4se4/, stingy), which was semantically related to the spoken target word at the whole word level; and a distractor, which was semantically related to neither the morpheme or the whole target word. Participants were asked to respond whether the spoken target word was on the visual display or not, and their eye movements were recorded. Results: The logit mixed-model analysis showed both the morphemic competitor and the whole-word competitor effects. Both the morphemic and whole word competitors attracted more fixations than the distractor. More importantly, the 2nd-morphemic competitor effect occurred at a relatively later time window (i.e., 1000-1500 ms) compared with the whole-word competitor effect (i.e., 200 1000 ms). Conclusion: Findings in this study suggest that semantic information of both the 2nd morpheme and the whole word of a compound was activated in spoken word recognition and that the meaning activation of the 2nd morpheme followed the activation of the whole word. PMID- 30458527 TI - A Survey of Clinician Decision Making When Identifying Swallowing Impairments and Determining Treatment. AB - Purpose: Speech-language pathologists (SLPs) are the primary providers of dysphagia management; however, this role has been criticized with assertions that SLPs are inadequately trained in swallowing physiology (Campbell-Taylor, 2008). To date, diagnostic acuity and treatment planning for swallowing impairments by practicing SLPs have not been examined. We conducted a survey to examine how clinician demographics and swallowing complexity influence decision making for swallowing impairments in videofluoroscopic images. Our goal was to determine whether SLPs' judgments of swallowing timing impairments align with impairment thresholds available in the research literature and whether or not there is agreement among SLPs regarding therapeutic recommendations. Method: The survey included 3 videofluoroscopic swallows ranging in complexity (easy, moderate, and complex). Three hundred three practicing SLPs in dysphagia management participated in the survey in a web-based format (Qualtrics, 2005) with frame-by frame viewing capabilities. SLPs' judgments of impairment were compared against impairment thresholds for swallowing timing measures based on 95% confidence intervals from healthy swallows reported in the literature. Results: The primary impairment in swallowing physiology was identified 67% of the time for the easy swallow, 6% for the moderate swallow, and 6% for the complex swallow. On average, practicing clinicians mislabeled 8 or more swallowing events as impaired that were within the normal physiologic range compared with healthy normative data available in the literature. Agreement was higher among clinicians who report using frame-by-frame analysis 80% of the time. A range of 19-21 different treatments was recommended for each video, regardless of complexity. Conclusions: Poor to modest agreement in swallowing impairment identification, frequent false positives, and wide variability in treatment planning recommendations suggest that additional research and training in healthy and disordered swallowing are needed to increase accurate dysphagia diagnosis and treatment among clinicians. PMID- 30458528 TI - Vocal Biomarkers of Mild-to-Moderate Hearing Loss in Children and Adults: Voiceless Sibilants. AB - Purpose: The purpose of this study was to determine if an objective measure of speech production could serve as a vocal biomarker for the effects of high frequency hearing loss on speech perception. It was hypothesized that production of voiceless sibilants is governed sufficiently by auditory feedback that high frequency hearing loss results in subtle but significant shifts in the spectral characteristics of these sibilants. Method: Sibilant production was examined in individuals with mild to moderately severe congenital (22 children; 8-17 years old) and acquired (23 adults; 55-80 years old) hearing losses. Measures of hearing level (pure-tone average thresholds at 4 and 8 kHz), speech perception (detection of nonsense words within sentences), and speech production (spectral center of gravity [COG] for /s/ and /?/) were obtained in unaided and aided conditions. Results: For both children and adults, detection of nonsense words increased significantly as hearing thresholds improved. Spectral COG for /?/ was unaffected by hearing loss in both listening conditions, whereas the spectral COG for /s/ significantly decreased as high-frequency hearing loss increased. The distance in spectral COG between /s/ and /?/ decreased significantly with increasing hearing level. COG distance significantly predicted nonsense-word detection in children but not in adults. Conclusions: At least one aspect of speech production (voiceless sibilants) is measurably affected by high-frequency hearing loss and is related to speech perception in children. Speech production did not predict speech perception in adults, suggesting a more complex relationship between auditory feedback and feedforward mechanisms with age. Even so, these results suggest that this vocal biomarker may be useful for identifying the presence of high-frequency hearing loss in adults and children and for predicting the impact of hearing loss in children. PMID- 30458529 TI - Constrained Dynamic Optimization of Sit-to-Stand Motion Driven by Bezier Curves. AB - The purpose of this work is twofold: first, to synthesize a motion pattern imitating sit-to-stand (STS) and second, to compare the kinematics and dynamics of the resulting motion to healthy STS. Predicting STS in simulation inspired the creation of three models: a biomechanical model, a motion model, and performance criteria as a model of preference. First, the human is represented as three rigid links in the sagittal plane. This model captures aspects of joint, foot, and buttocks physiology, which makes it the most comprehensive planar model for predicting STS to date. Second, candidate STS trajectories are described geometrically by a set of Bezier curves which seem well suited to predictive biomechanical simulations. Third, with the assumption that healthy people naturally prioritize mechanical efficiency, disinclination to a motion is described as a cost function of joint torques, and for the first time, physical infeasibility including slipping and falling. This new dynamic optimization routine allows for motions of gradually increasing complexity while the model's performance is improving. Using these models and optimal control strategy together has produced gross motion patterns characteristic of healthy STS when compared with normative data from the literature. PMID- 30458530 TI - Bilingual Speech Sound Development During the Preschool Years: The Role of Language Proficiency and Cross-Linguistic Relatedness. AB - Purpose: The purpose of this study was to investigate typical Spanish-English speech sound development longitudinally in a group of bilingual preschoolers enrolled in a Head Start Program and to examine the extent to which such development is linked to language proficiency. The study also aimed to identify whether speech development is related cross-linguistically and to improve our understanding of error patterns in this population. Method: Thirty-five bilingual preschool children produced single-word speech samples in Spanish and English both at the beginning of their first and their second year in a Head Start Program. Conversational samples in both languages were also collected at these data points to calculate mean length of utterance in words (MLUw) and thus assess the children's linguistic proficiency. The phonetically transcribed speech samples were compared over time in terms of segmental accuracy measures and error pattern frequencies. Correlation analyses were run to examine the relation between segmental accuracy measures across languages and between speech sound production and MLUw. Results: One-way within-subject analysis of variance revealed significant improvements in accuracy over time in both languages, but not always for cross-linguistically unshared segments, nor for all consonant manner classes. Overall error rates decreased over time in both languages; although, certain error types showed no change. Cross-linguistic interactions were low in both languages. The results also revealed significant cross linguistic correlations in segmental accuracy between Spanish and English, as well as between MLUw and speech sound production in both languages on a range of measures, with language-specific differences in Year 2 of the Head Start Program, but not in Year 1. Conclusions: This study is the first to document developmental changes in the speech patterns of Spanish-English bilingual preschool children over 1 year. Accuracy rates improved significantly in both languages, suggesting that enhanced exposure to the majority language at school may not impede phonological development in the home language. Bootstrapping effects were particularly pronounced on cross-linguistically shared sounds, which suggests that the same underlying skills are utilized in both languages, whereas language specific singleton consonants and consonant clusters did not appear to benefit from exposure to the other language. The results also suggest an intricate link between phonological skills and morphosyntactic performance at the early stages of development, but a more complex pattern thereafter with differences that may be based on language-specific phonological properties. PMID- 30458531 TI - Examining Factors Influencing the Viability of Automatic Acoustic Analysis of Child Speech. AB - Purpose: Heterogeneous child speech was force-aligned to investigate whether (a) manipulating specific parameters could improve alignment accuracy and (b) forced alignment could be used to replicate published results on acoustic characteristics of /s/ production by children. Method: In Part 1, child speech from 2 corpora was force-aligned with a trainable aligner (Prosodylab-Aligner) under different conditions that systematically manipulated input training data and the type of transcription used. Alignment accuracy was determined by comparing hand and automatic alignments as to how often they overlapped (%-Match) and absolute differences in duration and boundary placements. Using mixed-effects regression, accuracy was modeled as a function of alignment conditions, as well as segment and child age. In Part 2, forced alignments derived from a subset of the alignment conditions in Part 1 were used to extract spectral center of gravity of /s/ productions from young children. These findings were compared to published results that used manual alignments of the same data. Results: Overall, the results of Part 1 demonstrated that using training data more similar to the data to be aligned as well as phonetic transcription led to improvements in alignment accuracy. Speech from older children was aligned more accurately than younger children. In Part 2, /s/ center of gravity extracted from force-aligned segments was found to diverge in the speech of male and female children, replicating the pattern found in previous work using manually aligned segments. This was true even for the least accurate forced alignment method. Conclusions: Alignment accuracy of child speech can be improved by using more specific training and transcription. However, poor alignment accuracy was not found to impede acoustic analysis of /s/ produced by even very young children. Thus, forced alignment presents a useful tool for the analysis of child speech. Supplemental Material: https://doi.org/10.23641/asha.7070105. PMID- 30458532 TI - Perceptual Organization of Interrupted Speech and Text. AB - Purpose: Visual recognition of interrupted text may predict speech intelligibility under adverse listening conditions. This study investigated the nature of the linguistic information and perceptual processes underlying this relationship. Method: To directly compare the perceptual organization of interrupted speech and text, we examined the recognition of spoken and printed sentences interrupted at different rates in 14 adults with normal hearing. The interruption method approximated deletion and retention of rate-specific linguistic information (0.5-64 Hz) in speech by substituting either white space or silent intervals for text or speech in the original sentences. Results: A similar U-shaped pattern of cross-rate variation in performance was observed in both modalities, with minima at 2 Hz. However, at the highest and lowest interruption rates, recognition accuracy was greater for text than speech, whereas the reverse was observed at middle rates. An analysis of word duration and the frequency of word sampling across interruption rates suggested that the location of the function minima was influenced by perceptual reconstruction of whole words. Overall, the findings indicate a high degree of similarity in the perceptual organization of interrupted speech and text. Conclusion: The observed rate-specific variation in the perception of speech and text may potentially affect the degree to which recognition accuracy in one modality is predictive of the other. PMID- 30458534 TI - Omalizumab Rescue Therapy for Refractory Status Asthmaticus. PMID- 30458535 TI - Language Sample Practices With Children Who Are Deaf and Hard of Hearing. AB - Purpose: In this study, we aimed to identify common language sample practices of professionals who work with children who are Deaf/hard of hearing (DHH) who use listening and spoken language as a means to better understand why and how language sampling can be utilized by speech-language pathologists serving this population. Method: An electronic questionnaire was disseminated to professionals who serve children who are DHH and use listening and spoken language in the United States. Participant responses were coded in an Excel file and checked for completeness. Descriptive statistics were used to analyze trends. Results: A total of 168 participants participated in the survey. A majority of participants reported that they use language sampling as a part of their intervention when working with children who are DHH. However, approximately half of participants reported using norm-referenced testing most often when evaluating language of children who are DHH, regardless of the fact that they felt that language samples were more sensitive in identifying the errors of children who are DHH. Participants reported using language samples to monitor progress and set goals for clients. Participants rarely used language samples for eligibility and interprofessional collaboration. Conclusions: Language samples offer a unique way to examine a child's language development that norm-referenced assessments are not sensitive enough to detect, particularly for children who are DHH. This offers insights into current practice and implications for the development of a more clearly defined language sample protocol to guide practices in the use of language samples with children who are DHH and use listening and spoken language. PMID- 30458537 TI - What Speech-Language Pathologists Need to Know About Dyslexia. AB - Purpose: The purpose of this clinical forum is to provide a broad survey of up-to date, evidence-based information about dyslexia that can be readily applied to clinical practice by speech-language pathologists. Topics include (a) theoretical and clinical frameworks for understanding dyslexia in relation to other language based communication disorders, (b) the neurobiological basis of dyslexia, (c) the current state of dyslexia legislation, (d) issues around identification of dyslexia, (e) and evidence-based reviews of instruction for reading and writing. Conclusion: Though there have been numerous papers written on the topic of dyslexia, this clinical forum is unique in that it is the only combination of articles to focus on dyslexia with the speech-language pathologist in mind. PMID- 30458538 TI - Understanding Dyslexia in the Context of Developmental Language Disorders. AB - Purpose: The purpose of this tutorial is to discuss the language basis of dyslexia in the context of developmental language disorders (DLDs). Whereas most studies have focused on the phonological skills of children with dyslexia, we bring attention to broader language skills. Method: We conducted a focused literature review on the language basis of dyslexia from historical and theoretical perspectives with a special emphasis on the relation between dyslexia and DLD and on the development of broader language skills (e.g., vocabulary, syntax, and discourse) before and after the identification of dyslexia. Results: We present clinically relevant information on the history of dyslexia as a language-based disorder, the operational definitions used to diagnose dyslexia in research and practice, the relation between dyslexia and DLD, and the language abilities of children with dyslexia. Conclusions: We discuss 3 clinical implications for working with children with dyslexia in school settings: (a) Children with dyslexia-with and without comorbid DLDs-often have language deficits outside the phonological domain; (b) intervention should target a child's strengths and weaknesses relative to reading outcomes, regardless of diagnostic labels; and (c) those who have dyslexia, regardless of language abilities at the time of diagnosis, may be at risk for slower language acquisition across their lifetime. Longitudinal studies are needed to assess multiple language skills early, at the time of the diagnosis of dyslexia, and years later to better understand the complex development of language and reading in children with dyslexia. PMID- 30458539 TI - Exploring the Overlap Between Dyslexia and Speech Sound Production Deficits. AB - Purpose: Children with dyslexia have speech production deficits in a variety of spoken language contexts. In this article, we discuss the nature of speech production errors in children with dyslexia, including those who have a history of speech sound disorder and those who do not, to familiarize speech-language pathologists with speech production-specific risk factors that may help predict or identify dyslexia in young children. Method: In this tutorial, we discuss the role of a phonological deficit in children with dyslexia and how this may manifest as speech production errors, sometimes in conjunction with a speech sound disorder but sometimes not. We also briefly review other factors outside the realm of phonology that may alert the speech-language pathologist to possible dyslexia. Results: Speech-language pathologists possess unique knowledge that directly contributes to the identification and remediation of children with dyslexia. We present several clinical recommendations related to speech production deficits in children with dyslexia. We also review what is known about how and when children with speech sound disorder are most at risk for dyslexia. Conclusion: Speech-language pathologists have a unique opportunity to assist in the identification of young children who are at risk for dyslexia. PMID- 30458540 TI - Reading Disabilities in Adolescents and Adults. AB - Purpose: Reading skills continue to develop into adolescence and adulthood. Difficulties in reading have lifelong repercussions. Many speech-language pathologists who work with older individuals in the school setting face significant issues, including those mandated by recent changes in legislation. Theoretical topics related to reading development and disorders include the variety of orthographic systems across languages and the ways in which adults who are literate in an alphabetic orthographic system experience changes to their spoken and written language processing. In addition, older readers with intellectual or developmental disabilities may benefit from the use of leveled books and the inclusion of illustrations or drawings along with text. Method: I completed a focused literature review regarding typical reading skills, dyslexia in adolescence and adulthood, recent changes in legislation, orthography, and the use of leveled books for adolescents and adults with intellectual or developmental disabilities. Conclusions: Further study of reading in older individuals may lead to important theoretical and clinical applications. Speech language pathologists should keep in mind the various components of reading (such as decoding and comprehension), how these factors relate to oral language, and how they may be addressed in therapy. PMID- 30458541 TI - Cognitive Neuroscience of Dyslexia. AB - Purpose: This review summarizes what is known about the structural and functional brain bases of dyslexia. Method: We review the current literature on structural and functional brain differences in dyslexia. This includes evidence about differences in gray matter anatomy, white matter connectivity, and functional activations in response to print and language. We also summarize findings concerning brain plasticity in response to interventions. Results: We highlight evidence relating brain function and structure to instructional issues such as diagnosis and prognosis. We also highlight evidence about brain differences in early childhood, before formal reading instruction in school, which supports the importance of early identification and intervention. Conclusion: Neuroimaging studies of dyslexia reveal how the disorder is related to differences in structure and function in multiple neural circuits. PMID- 30458542 TI - The State of Dyslexia: Recent Legislation and Guidelines for Serving School-Age Children and Adolescents With Dyslexia. AB - Purpose: The purpose of this article is to provide an overview of recent dyslexia legislation and guidelines pertaining to services for students with dyslexia in public school settings and to describe possible implications for speech-language pathologists (SLPs). Method: In recent years, there has been increased attention focused on effectively meeting the needs of students with dyslexia nationwide. The Decoding Dyslexia organization has chapters in all 50 states in the nation, and they have been instrumental in promoting public awareness of the importance of improving services for students with dyslexia. As a result, new legislation, policies and guidelines have been introduced and developed in many states. California is an example of 1 state that has recently passed legislation in this area and released guidelines that serve as recommendations related to this law. This article provides a broad overview of recent dyslexia legislation, with more specific information pertaining to recent legislation and guidelines in the state of California. Clinical implications for SLPs who serve this population in school settings are also discussed. Conclusion: The information discussed in this article may serve as a useful model for states that are in the process of developing or revising their own policies or guidelines for meeting the needs of students with dyslexia. PMID- 30458543 TI - Early Identification of Dyslexia: Understanding the Issues. AB - Purpose: The purpose of this tutorial is to provide an overview of the benefits and challenges associated with the early identification of dyslexia. Method: The literature on the early identification of dyslexia is reviewed. Theoretical arguments and research evidence are summarized. An overview of response to intervention as a method of early identification is provided, and the benefits and challenges associated with it are discussed. Finally, the role of speech language pathologists in the early identification process is addressed. Conclusions: Early identification of dyslexia is crucial to ensure that children are able to maximize their educational potential, and speech-language pathologists are well placed to play a role in this process. However, early identification alone is not sufficient-difficulties with reading may persist or become apparent later in schooling. Therefore, continuing progress monitoring and access to suitable intervention programs are essential. PMID- 30458544 TI - Elementary Grade Intervention Approaches to Treat Specific Learning Disabilities, Including Dyslexia. AB - Purpose: The purpose of this narrative review of the literature is to provide a description of intensive interventions for elementary grade students with dyslexia, students with learning disabilities, and students with intensive reading and writing needs. Method: First, we provide a brief overview of response to intervention. Second, we explain our theoretical framework for the review. Third, we describe evidence-based interventions, which are divided into predominantly reading or writing interventions. Fourth, we explain data-based individualization for these programs based on a taxonomy of intensity, and we provide an illustrative case study. Conclusion: We conclude by describing a set of links to websites and technical assistance resources that may be helpful for speech-language pathologists, teachers, and other interventionists to stay current with this research base and to lead professional learning communities. PMID- 30458545 TI - Why Children With Dyslexia Struggle With Writing and How to Help Them. AB - Purpose: Children with dyslexia often have related writing difficulties. In the simple view of writing model, high-quality writing depends on good transcription skills, working memory, and executive function-all of which can be difficult for children with dyslexia and result in poor spelling and low overall writing quality. In this article, we describe the challenges of children with dyslexia in terms of the simple view of writing and instructional strategies to increase spelling and overall writing quality in children with dyslexia. Method: For spelling strategies, we conducted systematic searches across 2 databases for studies examining the effectiveness of spelling interventions for students with dyslexia as well as including studies from 2 meta-analyses. To locate other instructional practices to increase writing quality (e.g., handwriting and executive function), we examined recent meta-analyses of writing and supplemented that by conducting forward searches. Results: Through the search, we found evidence of effective remedial and compensatory intervention strategies in spelling, transcription, executive function, and working memory. Some strategies included spelling using sound-spellings and morphemes and overall quality using text structure, sentence combining, and self-regulated strategy development. Conclusions: Many students with dyslexia experience writing difficulty in multiple areas. However, their writing (and even reading) skills can improve with the instructional strategies identified in this article. We describe instructional procedures and provide links to resources throughout the article. PMID- 30458546 TI - From Deficit Remediation to Capacity Building: Learning to Enable Rather Than Disable Students With Dyslexia. AB - Purpose: In this article, we explore the deficit view of dyslexia and consider how it may narrow research so as to hamper the progress of scientific discovery and constrain best practices to the detriment of the overall well-being and growth of students with dyslexia. We consider the neurodiversity view of dyslexia as an alternative to the deficit view and explore how strengths-based approaches such as Universal Design for Learning can be used to support the overall well being and development of students with dyslexia. Practical strategies are provided for applying a strengths-based approach in the speech-language pathologist setting to support students with dyslexia. Method: We completed a focused literature review of the history of the deficit view of dyslexia, the alternate neurodiversity view, exceptional abilities related to dyslexia, and strategies for Universal Design for Learning. Results: Although the research literature that deals with visual-spatial affordances associated with dyslexia is limited, there is significant evidence that a strengths-based approach to learning experience design can be leveraged by practitioners to improve student self-development, motivation, and academic outcomes. Conclusion: We find that further research is needed to explore strengths associated with dyslexia and argue that a shift in mindset from the deficit view toward the neurodiversity view is required to build the capacity of students with dyslexia to thrive in learning and life. PMID- 30458547 TI - Predicting Reading Problems 6 Years Into the Future: Dynamic Assessment Reduces Bias and Increases Classification Accuracy. AB - Purpose: The purpose of this study was to examine how well a kindergarten dynamic assessment of decoding predicts future reading difficulty at 2nd, 3rd, 4th, and 5th grade and to determine whether the dynamic assessment improves the predictive validity of traditional static kindergarten reading measures. Method: With a small variation in sample size by grade, approximately 370 Caucasian and Hispanic students were administered a 3-min dynamic assessment of decoding and static measures of letter identification and phonemic awareness at the beginning of kindergarten. Oral reading fluency was then assessed at the end of Grades 2-5. In this prospective, longitudinal study, predictive validity was estimated for the Caucasian and Hispanic students by examining the amount of variance the static and dynamic assessments explained and by referring to area under the curve and sensitivity and specificity values. Results: The dynamic assessment accounted for variance in reading ability over and above the static measures, with fair to good area under the curve values and sensitivity and specificity. Classification accuracy worsened when the static measures were included as predictor measures. The results of this study indicate that a very brief dynamic assessment can predict with approximately 75%-80% accuracy, which kindergarten students will have difficulty in learning to decode up to 6 years into the future. Conclusions: Dynamic assessment of decoding is a promising approach to identifying future reading difficulty of young kindergarten students, mitigating the cultural and linguistic bias found in traditional static early reading measures. PMID- 30458548 TI - Eligibility for Special Education in Elementary School: The Role of Diverse Language Experiences. AB - Purpose: We examined the association between language experience and elementary students' eligibility for special education in Massachusetts. Method: A secondary descriptive data analysis was conducted on the anonymized demographic data obtained from the Massachusetts Department of Elementary and Secondary Education. Third, 4th, and 5th grade students were categorized into native English speakers, English-proficient bilinguals, and emerging bilinguals. Eligibility for free or reduced lunch was also considered. Proportions of students eligible for autism, communication disorders, and specific learning disabilities (including those with dyslexia) were calculated. Results: A strong association was observed between students' language background and whether they were eligible for free/reduced lunch. Children eligible for free/reduced lunch were more likely to be eligible for special education. Relative to native English speakers, English-proficient bilingual students were less likely to be considered eligible for special education. However, for emerging bilinguals, eligibility was lowest in 3rd grade and highest in 5th grade. This observation was most apparent in the category of specific learning disabilities. Conclusions: Students from diverse language and low-income backgrounds were disproportionately represented in special education. More substantial research-practice partnerships are warranted to understand how bilingual experience and socioeconomic status interact with eligibility for special education services in public school settings. PMID- 30458549 TI - Five Ways Speech-Language Pathologists Can Positively Impact Children With Dyslexia. AB - Purpose: The purpose of this epilogue is to offer five ways speech-language pathologists can positively impact children with dyslexia, drawing from and expanding on the articles presented in this clinical forum on dyslexia. PMID- 30458550 TI - Acute Effects of Pedaling Cadence at Low Intensity on Arterial Stiffness in Healthy Young Men. AB - To examine the acute influence of pedaling cadence on arterial stiffness in young men, 15 healthy men (21.8+/-0.4 years) underwent 3 trials in self-control crossover design: non-cycling control (CON), cycling at 60 (RPM60) and 90 rounds per min (RPM90). Cycling lasted 30 min at intensity of 35% heart rate reserve. Arterial stiffness in cardio-ankle vascular index (CAVI) was measured at baseline (BL), immediately after (0 min) and 40 min after cycling. There were no significant CAVI changes over time in CON. CAVI in RPM60 decreased immediately after exercise and returned to baseline afterwards (6.1+/-0.2, 5.6+/-0.2 and 6.0+/-0.2 at BL, 0 and 40 min, respectively). RPM90 elicited significant CAVI reduction from 6.2+/-0.2 at BL to 5.5+/-0.2 at 0 min, and reverted to 5.7+/-0.1 at 40 min, maintaining significant difference to its baseline. There was no significant CAVI difference between RPM60 and CON, whereas CAVI in RPM90 was significantly lower than that in CON at 0 min (5.5+/-0.2 vs 6.1+/-0.2, P<0.01) and 40 min (5.7+/-0.1 vs 6.3+/-0.1, P<0.05). Despite equivalent exercise volume, arterial stiffness improvement induced by cycling was influenced by pedaling cadence. Higher cadence resulted in superior effect on arterial stiffness. PMID- 30458551 TI - Bubble Formation in Children and Adolescents after Two Standardised Shallow Dives. AB - Circulating venous bubbles after dives are associated with symptoms of decompression sickness in adults. Up to now it is not known to what extent children and adolescents are subjected to a bubble formation during their shallow dives and if there are possible indications for that. The aim of this pilot study is to investigate whether bubbles and/or symptoms occur after standardised repeated dives performed by young divers. 28 children and adolescents (13.5+/-1.1 years) carried out two 25 min dives to a depth of 10 m with a 90 min surface interval. Before and after, echocardiographic data were recorded and evaluated with regard to circulating bubbles with an extended Eftedal-Brubakk-Scale by 2 different examiners. Bubbles were observed for a total of 6 subjects, Grade I (n=5) and Grade III (n=1). None of them showed any symptoms of decompression sickness. No differences were established regarding potential influencing factors on bubble formation between the groups with and without bubbles. The results indicate that even relatively shallow and short dives can generate venous bubbles in children and adolescents. To what extent this relates to the decompression sickness or clinical symptoms cannot be validated at this point. PMID- 30458552 TI - The Gut Microbiota as an Influencing Factor of Arterial Thrombosis. AB - The mutualistic gut microbiota does not only impact the development and function of various immune cell types, but it also influences the function of the hepatic vascular endothelium and prothrombotic platelet function. With germ-free mouse models, we have demonstrated that gut-derived microbial-associated molecular patterns could stimulate hepatic von Willebrand factor (VWF) synthesis and plasmatic VWF levels through Toll-like receptor-2 (TLR2), thus defining the extent of platelet deposition to the subendothelial matrix of the ligation injured common carotid artery. In addition to the microbiota-derived choline metabolite trimethylamine N-oxide and the microbiota's regulatory role on the colonic serotonin biosynthesis pathway, affecting prothrombotic platelet function, TLR2-regulated hepatic endothelial VWF synthesis and elevated VWF plasma levels constitute a pivotal mechanism of how the gut microbiota is linked to arterial thrombosis. Conceptually, in addition to the identified functions of the gut microbiota in modulating host nutrition and metabolism, our work places the innate immune functions of the liver sinusoidal endothelium as an actuating variable in arterial thrombus growth. PMID- 30458553 TI - Gastroesophageal Reflux in Asymptomatic Patients with Diabetes: An Impedance Study Diabetes, Obesity and Gastroesophageal Reflux. AB - INTRODUCTION: Gastroesophageal reflux disease (GERD) is more frequent in patients with diabetes mellitus (DM).The aim of the present study was to evaluate GER in asymptomatic patients with DM using 24-h pH impedance. MATERIALS AND METHODS: 19 healthy controls and 35 patients with DM without typical GERD symptoms were enrolled in the study. A 24-h pH-impedance study, esophageal manometry and gastroscopy were performed on all patients with DM. In the control group, an impedance study was performed on all subjects, and gastroscopy and esophageal manometry were performed on those who consented to the procedures.Patients with diabetes were categorized as obese [body mass index (BMI)>30 kg/m2] or non-obese (BMI<30 kg/m2) and both groups were compared with healthy controls. RESULTS: The mean BMI was similar in the control group (27.3+/-2.6 kg/m2) and the diabetic group (28.7+/-5 kg/m2)(p>0.05).Erosive esophagitis was found in 7.5% of the DM group. Esophageal dysmotility was higher in diabetics compared to the control group (45.5 vs. 11%, p=0.04). Neuropathy was found to be an independent risk factor for dysmotility. The mean DeMeester score (DMS) (25.6+/-32.5 vs. 11.2+/ 17, p=0.01) and bolus exposure time (2.1+/-1.3 vs.1.3+/-1.3 min, p=0.009) were higher in the DM group compared with the control group.The difference was mainly observed between obese diabetics and the control group (p<0.05). The mean DMS, pathologic acid reflux, and esophageal dysmotility rate were higher in patients without complications of DM (p<0.05). BMI was higher in these patients than in patients with complications. CONCLUSION: Acid reflux is common in patients with diabetes.GER is associated with the existence of obesity rather than hyperglycemia. PMID- 30458554 TI - An Assessment of a Public Health Initiative of Homeopathy for Primary Teething. AB - BACKGROUND: During primary teething, children suffer from running nose, mild fever, diarrhoea and other mild irritations and inflammations. A public health programme, 'Homoeopathy for the Healthy Child', was undertaken on a pilot basis focusing on promotion of healthy teething by provision of home-based care through six pre-identified homeopathic medicines for complaints commonly observed during primary teething. This article assesses the feasibility of this programme and reports the impact of this initiative on teething profile in children and episodes of diarrhoea and upper respiratory tract infection (URTI). METHODS: Accredited Social Health Activists (ASHAs) were trained in child care and usage of a kit comprising six medicines, namely Calcarea phosphoricum 6X (CP), Ferrum phosphoricum 3X, Magnesium phosphoricum 6X, Belladonna 30C, Chamomilla 30C and Podophyllum 30C. Calcarea phosphoricum was given regularly to each participating child from 6 months to 1 year of age. Home-based care for diarrhoea, URTI and mild fever was provided by ASHAs using the other five medicines in the kit. Dentition pattern and diarrhoea/URTI episodes were recorded over a period of the next 12 months. RESULTS: Eleven thousand four-hundred and twenty-six children were followed up regularly. Amongst those who enrolled at 6-7 months, a larger proportion of children were approaching expected teething in successive months as compared with children enrolled at 12 months, thus indicating that teething delays, if any, were overcome during this period. Incidence of diarrhoea and URTI showed decrease in the months after enrolment. Children responded favourably to the medicines given by ASHAs at the time of diarrhoea/URTI episodes, and ASHAs expressed satisfaction with the programme. CONCLUSION: An approach with regular use of CP and home-based care with homeopathy through health workers for common problems in teething children is acceptable to the community and enhances outreach of services to the public at large. Observations in terms of the healthy teething period may be further validated through studies of homeopathy with suitable comparator group. PMID- 30458555 TI - Immune and Antioxidant Enzyme Response of Longfin Yellowtail (Seriola rivoliana) Juveniles to Ultra-diluted Substances Derived from Phosphorus, Silica and Pathogenic Vibrio. AB - BACKGROUND: This research aimed to observe the effect of homeopathic treatments prepared from Vibrio parahaemolyticus and V. alginolyticus (H1) and commercial homeopathic medication Phosphoricum acidum and Silicea terra (H2) on the immune and antioxidant response in Seriola rivoliana juveniles under usual culture conditions and challenged with V. parahaemolyticus. METHODS: Quantitative polymerase chain reaction analysis was used to study changes in the expression of key genes related to immune response, cytokines (interleukin-1beta [IL-1beta]), adapter protein for cytokine release (MyD88) and piscidin and spectrophotometric techniques to analyze the activity of antioxidant superoxide dismutase (SOD) and catalase (CAT) enzymes in Seriola rivoliana juveniles at 30 (weaning stage [WS]) and 60 (early juveniles [EJ]) days post-hatching. RESULTS: The H1 treatment led to over-expression of the IL-1beta and MyD88 genes in fish at WS and EJ with respect to control, contrary to the H2 treatment that led to under-expression of the IL-1beta, MyD88 and piscidin genes at the EJ stage. In fish challenged with V. parahaemolyticus, both H1 and H2 led to over-expression of IL-1beta and MyD88; H2 caused an over-expression of piscidin. The SOD activity was higher in H1 with respect to H2 and the control group. CAT remained relatively stable with both H1 and H2 treatments. CONCLUSIONS: The results suggest that the overall effect of H1 was due to the presence of unknown antigens in low concentrations, while the response to H2-specifically during challenge-may have been due to a stimulating effect of nano-structures, prevailing from mother tincture after sequential dilution/succussion, in a pathway similar to that attributed to nano-vaccines. PMID- 30458556 TI - Optimizing Stroke and Bleeding Risk Assessment in Patients with Atrial Fibrillation: A Balance of Evidence, Practicality and Precision. PMID- 30458557 TI - ? PMID- 30458559 TI - [Publons - How Reviewers' Work Is Made Visible]. PMID- 30458558 TI - Transcranial Color-Coded Sonography for Monitoring Idiopathic Intracranial Hypertension. PMID- 30458560 TI - [Editorial]. PMID- 30458561 TI - [Visual Acuity, Contrast Sensitivity, Colour Vision: Thoughts on Psychophysical Exams in Neuro-ophthalmology]. AB - Despite many technical advances, psychophysical testing of perceptual performance continues to play an important role in ophthalmic diagnostics, including neuro ophthalmology. The present article considers methodological and clinical aspects of examining visual acuity, contrast sensitivity, and colour vision. In contrast to acuity, contrast sensitivity is at present rarely tested, despite often being a more sensitive marker of disease. In general, standardised procedures have the advantage of a high degree of comparability. However, tests that deviate from the standard might be better adapted to detect the characteristic impairments associated with a specific visual disorder, which justifies their application in certain cases. This also applies to colour vision testing. Preliminary evidence suggests that the measurement of colour saturation thresholds might be a more efficient and more sensitive alternative to conventional colour vision tests in cases of acquired colour vision deficiencies. PMID- 30458562 TI - [Reaching Beyond the Retina with Clinical Electrophysiology]. AB - Electrophysiological recordings from the retina and cortex are pivotal to reach beyond the retina for ophthalmological and neuro-ophthalmological diagnostic testing. Pattern electroretinograms (PERG) can be used to examine retinal ganglia cells and visual evoked potentials (VEP) help to investigate overall visual pathways. Thus, they support objective functional tests of visual pathways, as well as differential diagnosis. Conventional electrophysiology is of limited value in detecting local defects in the visual field. This gap is filled by applications of multifocal electrophysiology. This permits spatially resolved testing with multifocal PERG (mfPERG) and multifocal VEP (mfVEP), and eventually objective visual field testing with mfVEP. It is important for this spectrum of methods to consider possible confounds when performing the measurements and when interpreting the results. This is explained in the present article on the basis of a series of typical examples. PMID- 30458563 TI - [Genetic Causes and Genetic Diagnostic Testing of Inherited Optic Atrophies]. AB - Hereditary optic atrophies are a heterogeneous group of rare degenerative disease affecting the retinal ganglion cells and their axons which form the optic nerve. With an estimated prevalence of 1 : 10 000 to 1 : 20 000, hereditary optic atrophies in their entirety affect about 4000 to 8000 people in Germany. The most common forms are Leber's hereditary optic atrophy (LHON) and autosomal dominant optic atrophy (ADOA). Besides the common forms of isolated optic atrophies which exclusively affect the visual system, there are a variety of conditions in which the optic atrophy is part of a syndromic disease with additional symptoms that are mostly neurosensory, neurological or neuromuscular. The mode of inheritance is heterogeneous with LHON showing maternal inheritance and an autosomal dominant inheritance in families with ADOA. There are rarer cases of optic atrophy following an autosomal recessive or X-linked recessive mode of inheritance. The penetrance is incomplete. Moreover, in LHON, there are many more males than females who develop the disease. The genetic causes of hereditary optic atrophies are complex in terms of the diversity of the involved genes. However, most of these causes are already known. Therefore, molecular genetic diagnostic testing yields a meaningful result in the majority of tested subjects and enables confirmation of the suspected clinical diagnosis, reliable counseling of the families with respect to the genetic risk, and - in subjects with genetically confirmed LHON - initiation of therapeutic intervention. This article provides an overview of current knowledge of the genetic causes of hereditary optic neuropathies, and the options and modalities of molecular genetic diagnostic testing, including practical guidelines. PMID- 30458564 TI - [Optical Coherence Tomography in Disorders of the Central Nervous System]. AB - Retinal changes and visual symptoms are present in several inflammatory, degenerative and tumorous disorders of the central nervous system (CNS). Optical coherence tomography (OCT) is a method that can be used in clinical practice to detect and quantify the structural correlates of these visual symptoms in neurological disorders. OCT is a non-invasive imaging technique, based on interferometry, which can create high-resolution images of the retina and measure the thickness and volume of the different retinal layers. The combined ganglion cell- and inner plexiform layer (GCIPL) and the peripapillary retinal nerve fibre layer (pRNFL) are of particular interest in the field of neurological disorders, since they contain the neuronal bodies (ganglion cells) and their axons that form the optic nerve. In acute optic neuritis (ON), initial swelling of the pRNFL can be detected by OCT and this may contribute to the diagnosis and differential diagnosis of ON; moreover, the extent of the GCIPL-thinning within the first 4 weeks after an acute ON can contribute to the prediction of the long-term visual recovery. However, the role of OCT in the field of multiple sclerosis (MS) is not restricted in patients with ON, since even eyes without an ON-history show mild thinning of the pRNFL and GCIPL. This thinning seems to be associated with neurodegenerative processes in the entire CNS. Several studies showed correlations between these OCT-parameters and a higher risk of clinical deterioration (disability progression), cognitive deficits and disease activity in patients with MS. However, it is often still unclear how these correlations can be useful in the management of the individual patient. In recent years, OCT has been applied to a greater extent to neurodegenerative diseases, such as Parkinson's disease, amyotrophic lateral sclerosis (ALS) and various forms of dementia. However, routine clinical use is still further away than for inflammatory CNS diseases, since the role of OCT in the diagnosis, differential diagnosis and prediction of the clinical course of neurodegenerative diseases is still unclear. This review article offers a summary of the available study results on OCT parameters and their role in inflammatory, degenerative and tumorous diseases of the central nervous system (CNS). PMID- 30458565 TI - [Magnetic Resonance Imaging of the Optic Pathway]. AB - This overview is especially intended for practitioners in ophthalmology. It focuses on how to handle diseases affecting the optic pathway with MRI in general and in particular. Several tables accompany this article, in order to illustrate the different MRI scanning protocols, properties of frequently used MRI sequences, as well as common pathologies to be found in the optic pathway. With the help of exemplary cases, the application and interpretation of MRI imaging will be shown. There is a tremendous variety of diseases influencing the optic pathway - which is why this article does not intend to give a complete representation of this medical issue, but rather focuses on giving hands-on guidance (through multiple tables) for daily routine. Moreover, the article also addresses the issue of retained gadolinium in the brain. PMID- 30458566 TI - [Health Care for Asylum Seekers in Germany according to Asylum Seekers' Benefits Act: Public Perceptions and Preferences]. AB - OBJECTIVE: This study analyses public perceptions and preferences regarding scope, access and funding of health care for asylum seekers (AS). METHODS: Standardized survey addressing the population >18 years, combined quota plan, descriptive and inferential statistics. RESULTS: The sample (n=419) was rather badly informed about this topic. We found heterogeneous preferences. 47.0% preferred to maintain current regulations of the scope of health care, 22.7% wanted an expansion. 56.1% favored a health card. The EU, tax payers, countries of origin and AS were preferred as funders. CONCLUSION: A consideration of preferences might strengthen the acceptance and legitimation of decisions. Our results indicate that this would lead to moderate changes in health care for AS. Since participants were not well informed subjectively, we suggest qualitative research. PMID- 30458568 TI - Organization and Application of ECLS Therapy-A Nationwide Survey in German Cardiosurgical Departments. AB - BACKGROUND: In context of the multidisciplinary German scientific guideline "Use of extracorporeal circulation (extracorporeal life support [ECLS]/extracorporeal membrane oxygenation) for cardiac and circulatory failure," a nationwide survey should depict the status of organization and application of ECLS therapy in Germany. METHODS: Between June and October 2017, a standardized questionnaire consisting of 30 items related to ECLS therapy was sent to all German cardiosurgical departments, and all returned results were analyzed and evaluated. RESULTS: The return rate amounted to 92.9% (78 out of 84 departments). In the participating departments, ECLS therapy is subject to different responsibilities, and exhibits divergent processes and various ways for specialization of the involved personnel. This also concerns local application standards, such as cannulation strategies, anticoagulation management, left ventricular unloading, antiwatershed treatment, and weaning from circulatory support. CONCLUSION: This nationwide survey underlines the necessity of a multidisciplinary guideline concerning ECLS therapy. PMID- 30458567 TI - Reprocessing of flexible endoscopes and endoscopic accessories used in gastrointestinal endoscopy: Position Statement of the European Society of Gastrointestinal Endoscopy (ESGE) and European Society of Gastroenterology Nurses and Associates (ESGENA) - Update 2018. AB - This Position Statement from the European Society of Gastrointestinal Endoscopy (ESGE) and the European Society of Gastroenterology Nurses and Associates (ESGENA) sets standards for the reprocessing of flexible endoscopes and endoscopic devices used in gastroenterology. An expert working group of gastroenterologists, endoscopy nurses, chemists, microbiologists, and industry representatives provides updated recommendations on all aspects of reprocessing in order to maintain hygiene and infection control. PMID- 30458569 TI - In Vivo Biocompatibility of a Novel Expanded Polytetrafluoroethylene Suture for Annuloplasty. AB - BACKGROUND: Expanded polytetrafluoroethylene (ePTFE) is a suture material for annuloplasty in aortic valve repair. For this particular application, it should induce minimal local stress and promote rapid tissue incorporation. To achieve this, a novel ePTFE suture with a larger diameter and high porosity in its midsection has been developed. Herein, we analyzed the acute and chronic tissue reaction to this suture material compared with a commercially available control ePTFE suture. METHODS: Novel and control suture samples were implanted into dorsal skinfold chambers of BALB/c mice to analyze the early inflammatory response using intravital fluorescence microscopy over 14 days. Additional suture samples were implanted for 4 and 12 weeks in the flank musculature of mice and analyzed by histology and immunohistochemistry. RESULTS: The implantation of novel and control ePTFE suture into the dorsal skinfold chamber did not induce an acute inflammation, as indicated by physiological numbers of rolling and adherent leukocytes in all analyzed venules. Chronic implantation into the flank musculature showed a better tissue incorporation of the novel ePTFE suture with more infiltrating cells and a higher content of Sirius red+ collagen fibers when compared with controls. Cell proliferation and viability as well as numbers of recruited CD68+ macrophages, myeloperoxidase+ neutrophilic granulocytes and CD3+ lymphocytes did not significantly differ between the groups. CONCLUSION: The novel ePTFE suture exhibits a good in vivo biocompatibility which is comparable to that of the control suture. Due to its improved tissue incorporation, it may provide a better long-term stability during annuloplasty. PMID- 30458571 TI - ? PMID- 30458570 TI - Diagnosis and Management of Acquired von Willebrand Disease in Heart Disease: A Review of the Literature. AB - The incidence of acquired von Willebrand syndrome (AvWS) in patients with heart disease is commonly perceived as rare. However, its occurrence is underestimated and underdiagnosed, potentially leading to inadequate treatment resulting in increased morbidity and mortality.In patients with cardiac disease, AvWS frequently occurs in patients with structural heart disease and in those undergoing mechanical circulatory support (MCS).The clinical manifestation of an AvWS is usually characterized by apparent or occult gastrointestinal (GI) or mucocutaneous hemorrhage frequently accompanied by signs of anemia and/or increased bleeding during surgical procedures. The primary change is loss of high molecular weight von Willebrand factor multimers (HMWM). Whereas the loss of HMWM in patients with structural heart disease is caused by increased HMWM cleavage by von Willebrand factor (vWF)-cleaving protease, ADAMTS13, AvWS in MCS patients is predominantly a result of a high shear stress coupled with mechanical destruction of vWF itself.This manuscript provides a comprehensive review of the evidence regarding both diagnosis and contemporary management of AVWS in patients with heart disease. PMID- 30458572 TI - [Safe Paediatric Anaesthesia: Update on Drug Safety]. AB - Drug errors occur in all areas of care. Due to age-group-specific characteristics and the need for dose calculation, the probability of errors in children increases compared to adults. The recognition of the fallibility of every supplier and the acceptance of security structures are essential. The article describes a catalogue of measures for drug safety suitable for everyday use. PMID- 30458573 TI - [Management of Pediatric Airway in Anesthesia]. AB - Airway management is a major competence of clinical anesthesia. Knowledge of available materials and skills in the use of specific methods and techniques are essential and should be trained routinely. In 2011 the scientific working group in pediatric anesthesia (WAKKA) of the German Society for anesthesia and intensive care medicine (DGAI) published a treatment recommendation for the management of the unexpected difficult pediatric airway. Furthermore, a recommendation for the management of the expected difficult pediatric airway is currently being compiled and the draft is available on the WAKKA homepage. For the airway management in pediatric patients, special materials, techniques, individual and institutional expertise must be present. This article presents a selection of materials, methods and techniques of the treatment recommendations for the management of a difficult airway. PMID- 30458574 TI - [Drama in the Recovery Unit: Paediatric Emergence Delirium]. AB - The upcoming and ongoing debate on neurotoxicity of anesthetics at a young age put a new spotlight on the emergence delirium of children (paedED). The European Society for Anesthesiology published a consensus guideline on prevention and therapy in 2017 which can be a useful guidance in daily clinical practice. Patient data management systems with their clear documentation concerning pain/therapy of pain and paedED will be valuable tools in order to assess the real incidence of paedED. Differentiating between pain/agitation and paedED migth not always be easy. Age-adapted scores should always be applied. Main focus in the prevention of paedED is the reduction of anxiety. The way this is achieved by the dedicated pediatric anesthesia teams caring for children, e.g. by oral midazolam, clowns, music, smartphone induction, does not matter. Using alpha2 agonists in the perioperative phase and applying propofol seems to be effective. A quiet supportive environment for recovery adds to a relaxed, stress-free awakening. For the future detecting paedED on normal wards becomes an important issue. This may be achieved by structured interviews or questionnaires assessing postoperative negative behavioural changes at the same time. PMID- 30458575 TI - [Echocardiography in Acute Right Heart Insufficiency]. AB - The anesthetist is increasingly faced with more complex operations in combination with an aging patient population characterized by pre-existing conditions. Acute right heart failure is often not recognized as the cause of cardiopulmonary insufficiency. Echocardiography has emerged as an important diagnostic tool. Not only perioperatively and in the intensive care unit, transesophageal (TEE) and transthoracic echocardiography (TTE) allow the diagnosis of right heart failure at bedside, promptly and with low invasiveness. Possible causes of right heart insufficiency on the level of afterload, preload and contractility can be clarified. Life-saving immediate measures can be initiated and, in addition, the success of the therapy can be visualized virtually "live". If indicated, a peri /intraoperative echocardiographic examination also has a direct influence on therapy control. With a focused cardiac examination crucial information can be gained and the outcome of the patient can be positively influenced by adapted therapy control. By using standard ultrasound views, right heart failure can be detected as the cause of hemodynamic instability. PMID- 30458576 TI - [Beta-blockers in Septic Shock]. AB - The therapy of patients suffering from sepsis and septic shock is one of the greatest challenges in critical care medicine. In the initial phase of septic shock patients often present with hyperdynamic circulatory conditions with elevated cardiac index, tachycardia and progressive hemodynamic instability. The type of tachycardia differs from atrial fibrillation or flatter to sinus tachycardia. The latter might be persistent even in case of adequate volume therapy according to the surviving sepsis campaign recommendations and may represent an independent pathology due to adrenergic overstimulation. Despite predominantly beta2-mediated immunomodulatory effects the administration of a selective beta1-adrenergic blocker may be beneficial in some cases. On the other hand, incautious administration of beta-blockers especially in case of insufficient volume replacement may result in direct negative inotropic effects rapidly aggravating hypotension and shock. This review focused on pharmacology of the beta-adrenergic system, the pathophysiological rationale and current literature on clinical practice of the use of beta-blockers in sepsis and septic shock. PMID- 30458577 TI - [3D-CAM Guideline-Conform Translation for German-Speaking Countries]. AB - Postoperative delirium (POD) is an acute change in the mental state with consciousness and attention deficits. It is a common complication after surgical procedures and can have serious consequences. Thus, the evidence- and consensus based guidelines for POD appeals with the highest recommendation level that patients be regularly screened for delirium in the postoperative phase, from the recovery room to the fifth postoperative day and at least once per shift, using a validated test instrument for the detection of POD. In 2014, Marcantonio et al. published the 3D-CAM (3-Minute Diagnostic Interview for CAM-defined Delirium). In the 3D-CAM, the algorithm of the Confusion Assessment Method (CAM) is maintained by using individual elements that operationalize the evaluation of the criteria. Therefore, it requires less training, be faster to use, and, due to a standardized approach, has less interrater variability than the CAM, whereas the high sensitivity and specificity are maintained. Our goal was to translate the 3D CAM from English to German, so as to make this instrument available to German speaking countries. The translation of the 3D-CAM was based on the 2005 published guideline on Translation and Cultural Adaptation of Patient Reported Outcome Measures of the International Society for Pharmacoeconomics and Outcome Research. Three independent forward translations were harmonized to a preliminary translation, which then was translated back into the original language. Original authors reviewed the back translation. According to a cognitive debriefing, the translation was revised and in addition was adapted for use in the recovery room. Due to close contact with the original authors during the translation process, it was possible to ensure that the contents of the test instrument were remained intact during the translation process. PMID- 30458578 TI - ? PMID- 30458580 TI - Analysis of the nucleotide content of Escherichia coli promoter sequences related to the alternative sigma factors. AB - Promoters are DNA sequences located upstream of the transcription start site of genes. In bacteria, the RNA polymerase enzyme requires additional subunits, called sigma factors (sigma) to begin specific gene transcription in distinct environmental conditions. Currently, promoter prediction still poses many challenges due to the characteristics of these sequences. In this paper, the nucleotide content of Escherichia coli promoter sequences, related to five alternative sigma factors, was analyzed by a machine learning technique in order to provide profiles according to the sigma factor which recognizes them. For this, the clustering technique was applied since it is a viable method for finding hidden patterns on a data set. As a result, 20 groups of sequences were formed, and, aided by the Weblogo tool, it was possible to determine sequence profiles. These found patterns should be considered for implementing computational prediction tools. In addition, evidence was found of an overlap between the functions of the genes regulated by different sigma factors, suggesting that DNA structural properties are also essential parameters for further studies. PMID- 30458579 TI - On estimands and the analysis of adverse events in the presence of varying follow up times within the benefit assessment of therapies. AB - The analysis of adverse events (AEs) is a key component in the assessment of a drug's safety profile. Inappropriate analysis methods may result in misleading conclusions about a therapy's safety and consequently its benefit-risk ratio. The statistical analysis of AEs is complicated by the fact that the follow-up times can vary between the patients included in a clinical trial. This paper takes as its focus the analysis of AE data in the presence of varying follow-up times within the benefit assessment of therapeutic interventions. Instead of approaching this issue directly and solely from an analysis point of view, we first discuss what should be estimated in the context of safety data, leading to the concept of estimands. Although the current discussion on estimands is mainly related to efficacy evaluation, the concept is applicable to safety endpoints as well. Within the framework of estimands, we present statistical methods for analysing AEs with the focus being on the time to the occurrence of the first AE of a specific type. We give recommendations which estimators should be used for the estimands described. Furthermore, we state practical implications of the analysis of AEs in clinical trials and give an overview of examples across different indications. We also provide a review of current practices of health technology assessment (HTA) agencies with respect to the evaluation of safety data. Finally, we describe problems with meta-analyses of AE data and sketch possible solutions. PMID- 30458581 TI - Health behaviours, intentions and barriers to change among obesity classes I, II and III. AB - Health behaviour change is a cornerstone in the management of obesity, and data on health behaviours, intentions and barriers to change would be useful to inform the development of interventions. The aim of this study was to describe these variables in individuals with obesity, and to compare obesity classes. The study obtained data from the Canadian Community Health Survey 2011-2012 including 5614 adults with body mass index (BMI) >=30 kg m-2 . The majority of participants reported eating four or more fruits and vegetables daily (65.3% [95% confidence interval {CI}: 64.1-66.6]), being a regular drinker (59.6% [95% CI: 58.4-61.0]) and inactive (58.0% [95% CI: 56.7-59.3]). About 84% of participants answered they should do and/or intend to do something in the next year to improve their health, with increasing exercise being the most reported choice (69.2% [95% CI: 67.1 71.5]). Among the 58.0% (95% CI: 55.9-60.2) of participants facing barriers to change, the lack of willpower was the most reported (37.0% [95% CI: 34.2-39.7]). No difference between classes for intention to change and barriers were found. Comorbidities were the most important factor explaining several health behaviours and barriers to change. The vast majority of participants, regardless of the severity of obesity, know they should do and also want to do something to improve their health, but faced a lack of willpower. Thus, the most important thing to consider during an obesity intervention is the lack of motivation to modify health behaviours and beyond BMI, the presence of comorbidities. PMID- 30458582 TI - Mental health quality of life after bariatric surgery: A systematic review and meta-analysis of randomized clinical trials. AB - Recent literature has raised concerns regarding the risk of adverse psychiatric events among bariatric surgery patients. However, the relationship between weight loss therapy and psychiatric outcomes is confounded by baseline psychosocial characteristics in observational studies. To understand the impact of bariatric surgery on the risk of adverse mental health outcomes, we conducted a systematic review and meta-analysis of randomized controlled trials that compared surgical and non-surgical treatments and assessed mental health quality of life (QoL). We evaluated the PubMed, EMBASE, Web of Science PsycINFO, Clinicaltrials.gov and Cochrane databases through 7 March 2018. Pooled standardized mean differences (SMDs) for mental health QoL scores were estimated using random effects models. Eleven randomized trials with 731 participants were included in the final analyses. Surgery was not associated with an improvement in mental health QoL from baseline as compared to non-surgical intervention (SMD: 0.02, 95% confidence interval [CI] -0.22 to 0.25). Final mental health QoL scores were similar for surgically and non-surgically treated patients (SMD: 0.37, 95% CI -0.07 to 0.81). Subgroup analyses assessing the effect of specific surgical interventions, and varying lengths of follow-up did not identify a beneficial effect of bariatric surgery on mental health QoL outcomes. These results, in conjunction with the fact that individuals who choose bariatric surgery tend to have high-risk baseline characteristics, suggest that intensive mental health follow-up following surgery should be routinely considered. PMID- 30458583 TI - Phase II trial design with growth modulation index as the primary endpoint. AB - Molecularly targeted, genomic-driven, and immunotherapy-based clinical trials continue to be advanced for the treatment of relapse or refractory cancer patients, where the growth modulation index (GMI) is often considered a primary endpoint of treatment efficacy. However, there little literature is available that considers the trial design with GMI as the primary endpoint. In this article, we derived a sample size formula for the score test under a log-linear model of the GMI. Study designs using the derived sample size formula are illustrated under a bivariate exponential model, the Weibull frailty model, and the generalized treatment effect size. The proposed designs provide sound statistical methods for a single-arm phase II trial with GMI as the primary endpoint. PMID- 30458584 TI - Metformin inhibits prostate cancer growth induced by a high-fat diet in Pten deficient model mice. PMID- 30458585 TI - Response to Editorial Comment to Impact of prior local therapy on overall survival in men with metastatic castration-resistant prostate cancer: Results from Shared Equal Access Regional Cancer Hospital. PMID- 30458587 TI - Intra - articular injection of autologous bone marrow mesenchymal stem cells for articular cartilage repair. PMID- 30458586 TI - Immigrant Women's Access to Sexual and Reproductive Health Coverage and Care in the United States. AB - Issue: Immigrant women of reproductive age in the U.S. face significant challenges obtaining comprehensive and affordable health insurance coverage and care--including sexual and reproductive health services--compared with U.S.-born women, because of myriad policy and systemic factors. Goals: Synthesize recent evidence on immigrant women's access to sexual and reproductive health coverage and care and provide recommendations for policymaking and research. Methods: A rapid literature review to identify and summarize evidence from peer-reviewed and select grey literature published since 2011 on health insurance coverage and sexual and reproductive health care services use among immigrant women in the U.S. Where available, evidence is compared to U.S.-born women. Findings and Conclusions: Immigrant women are less likely to have coverage and use sexual and reproductive health services than U.S.-born women, which may increase their risk of negative outcomes. Federal and state policymakers could take actions to advance immigrant women's sexual and reproductive health, including expanding eligibility for coverage and shoring up the nation's health care safety net. Further research is needed to understand the needs, use of services, and outcomes of immigrant women, as well as the factors that contribute to differences between immigrant and U.S.-born women, and among groups of immigrant women. PMID- 30458588 TI - Transplantation of synovial stem cells to promote healing after meniscal suture repair. PMID- 30458589 TI - Changes to the Merit-based Incentive Payment System Pertinent to Small and Rural Practices, 2018. AB - This brief highlights key regulatory changes to the Merit-based Incentive Payment System (MIPS) in 2018. We discuss the importance of these changes, particularly as they affect small and rural practices. PMID- 30458591 TI - Development of therapy for amyotrophic lateral sclerosis using HGF protein. PMID- 30458590 TI - Techique of scaffold - free three - dimensional tissue - engineered construct (TEC) into articular cartilage injury. PMID- 30458593 TI - Ethical, legal and social issues in iPS cell research. PMID- 30458592 TI - Therapeutic angiogenesis by adipose - derived regenerative cell transplantation for severe peripheral artery disease. PMID- 30458595 TI - Laws related to the regulation of regenerative medicines. PMID- 30458594 TI - Ethical issues relaring to differentiation of iPS cell to germ line cells. PMID- 30458597 TI - Critical path initiative for regenerative in Japan. PMID- 30458596 TI - Regenerative medicine industry in Japan PMID- 30458598 TI - The physiological roles of dead cell clearance. PMID- 30458599 TI - Health care economics of regenerative medicine. PMID- 30458600 TI - Bioprinting in Vascularization Strategies AB - Three-dimensional (3D) printing technology has revolutionized tissue engineering field because of its excellent potential of accurately positioning cell-laden constructs. One of the main challenges in the formation of functional engineered tissues is the lack of an efficient and extensive network of microvessels to support cell viability. By printing vascular cells and appropriate biomaterials, the 3D printing could closely mimic in vivo conditions to generate blood vessels. In vascular tissue engineering, many various approaches of 3D printing have been developed, including selective laser sintering and extrusion methods, etc. The 3D printing is going to be the integral part of tissue engineering approaches; in comparison with other scaffolding techniques, 3D printing has two major merits: automation and high cell density. Undoubtedly, the application of 3D printing in vascular tissue engineering will be extended if its resolution, printing speed, and available materials can be improved. PMID- 30458601 TI - Cell Surface Antigen Display for Neuronal Differentiation-Specific Tracking. AB - Cell therapeutic agents for treating degenerative brain diseases using neural stem cells are actively being developed. However, few systems have been developed to monitor in real time whether the transplanted neural stem cells are actually differentiated into neurons. Therefore, it is necessary to develop a technology capable of specifically monitoring neuronal differentiation in vivo. In this study, we established a system that expresses cell membrane-targeting red fluorescent protein under control of the Synapsin promoter in order to specifically monitor differentiation from neural stem cells into neurons. In order to overcome the weak expression level of the tissue-specific promoter system, the partial 5' UTR sequence of Creb was added for efficient expression of the cell surface-specific antigen. This system was able to track functional neuronal differentiation of neural stem cells transplanted in vivo, which will help improve stem cell therapies. PMID- 30458602 TI - Can Wideband Tympanometry Be Used as a Screening Test for Superior Semicircular Canal Dehiscence? AB - Objectives: We explored whether wideband tympanometry (WBT) could be used as a screening test for superior semicircular canal dehiscence (SSCD), and obtained new WBT data (given that the test is not yet in common clinical use) on patients with SSCD. Methods: We compared the WBT data of patients clinically and radiologically diagnosed with SSCD in our hospital between 2013 and 2018 to those of healthy volunteers. We compared the resonance frequency (RF), maximum absorbance frequency (MAF), and maximum absorbance ratio (MAR). The t-test was used for statistical analysis with the significance level set to P<0.05. In addition, we used receiver operating characteristic analysis to derive cutoff values for SSCD diagnosis in terms of sensitivity and specificity. Results: Seventeen patients (four with bilateral and 13 with unilateral disease; 17 ears) diagnosed with SSCD and 27 healthy volunteers (47 ears) were included. The mean RFs of the SSCD patients and healthy subjects were 548.7 Hz (range, 243 to 853 Hz) and 935.1 Hz (range, 239 to 1,875 Hz), respectively (P<0.001). The mean MARs of the SSCD patients and healthy subjects were 89.4% (range, 62% to 100%) and 82.4% (range, 63% to 99%), respectively (P=0.005). The mean MAFs of the SSCD patients and healthy subjects were 1,706.3 Hz (range, 613 to 3,816 Hz) and 2,668 Hz (range, 876 to 4,387 Hz), respectively (P<0.001). In terms of SSCD diagnosis, a MAR above 86% afforded 81% sensitivity and 77% specificity; an RF below 728 Hz, 86% sensitivity and 81% specificity; and an MAF below 1,835 Hz, 79% sensitivity and 67% specificity. Conclusion: WBT may be a useful clinical screening test for SSCD. The RF and MAF were lower, and the MAR higher, in SSCD patients than in normal controls. PMID- 30458603 TI - Comparison Between Endoscopic Prelacrimal Medial Maxillectomy and Caldwell-Luc Approach for Benign Maxillary Sinus Tumors. AB - Objectives: Endoscopic prelacrimal medial maxillectomy (EPMM) was previously reported to treat maxillary inverted papilloma. This study aimed to compare prelacrimal recess approach with the conventional Caldwell-Luc approach (CLA) to remove benign maxillary sinus tumors and to evaluate the usefulness of this approach based on our experience. Methods: Ten patients who underwent EPMM at our hospital from January 2013 to December 2017 were reviewed. We also reviewed 30 patients who underwent benign maxillary sinus tumor resection via CLA during the same period. From medical records, postoperative pathological results, complications due to surgery, and recurrence rate were evaluated. Results: There were eight inverted papilloma, one ameloblastoma, and one ossifying fibroma in the EPMM group. In the CLA group, all 30 cases were inverted papilloma. There were no cases of failure at gross total removal during surgery, and no recurrences were observed during follow-up in either groups. Mean follow-up period was 13.0 months in CLA group and 10.8 months in EPMM group. Regarding postoperative complications, 11 patients of the CLA group (37%) and three patients of the EPMM group (30%) had numbness around the cheek and upper lip area after surgery (P=0.715). In the CLA group, there were eight patients who had numbness lasting more than 3 months after surgery, and two patients had numbness for more than 1 year. However, facial numbness disappeared within 3 months in all patients in the EPMM group, in which epiphora was not observed. Conclusion: EPMM is the effective surgical approach for resecting benign maxillary sinus tumor compared with CLA. Although facial numbness was reported in EPMM, the duration of numbness was shorter than CLA. PMID- 30458604 TI - Magnified Endoscopic Findings of Multiple White Flat Lesions: A New Subtype of Gastric Hyperplastic Polyps in the Stomach. AB - BACKGROUND/AIMS: While the occurrence of multiple whitish flat elevated lesions (MWFL) was first reported in 2007, no studies on MWFL have been published to date. The present retrospective observational study aimed to clarify the endoscopic findings and clinicopathological features of MWFL. METHODS: Subjects were consecutive patients who underwent upper gastrointestinal endoscopy as part of routine screening between April 2014 and March 2015. The conventional white light, non-magnifying and magnifying narrow-band images were reviewed. Clinical features were compared between patients with and without MWFL. RESULTS: The conventional endoscopic findings of MWFL include multiple whitish, flat, and slightly elevated lesions of various sizes, mainly located in the gastric body and fundus. Narrow-band imaging enhanced the contrast of MWFL and background mucosa, and magnifying narrow-band imaging depicted a uniformly long, narrow, and elliptical marginal crypt epithelium with an unclear microvascular pattern. Histopathological findings revealed hyperplastic changes of the foveolar epithelium, and parietal cell protrusions and oxyntic gland dilatations were observed in the fundic glands, without any intestinal metaplasia. The rate of acid-reducing drug use was significantly higher in patients with MWFL than in those without (100% [13/13] vs. 53.7% [88/164], p<0.001). CONCLUSION: The present study indicated a relationship between the presence and endoscopic features of MWFL and history of acidreducing drug use. PMID- 30458605 TI - Summary of the 2017 thyroid radiofrequency ablation guideline and comparison with the 2012 guideline. AB - Radiofrequency ablation (RFA) is a new, minimally invasive modality that serves as an alternative to surgery in patients with thyroid tumors. The Task Force Committee of the Korean Society of Thyroid Radiology developed recommendations for the optimal use of RFA for thyroid tumors in 2012 and revised them in 2017. Herein, we review and summarize the 2017 thyroid RFA guideline and compare it with the 2012 thyroid RFA guideline. PMID- 30458606 TI - Interobserver agreement in breast ultrasound categorization in the Mammography and Ultrasonography Study for Breast Cancer Screening Effectiveness (MUST-BE) trial: results of a preliminary study. AB - PURPOSE: The purpose of this study was to record and evaluate interobserver agreement as quality control for the modified categorization of screening breast ultrasound developed by the Alliance for Breast Cancer Screening in Korea (ABCS K) for the Mammography and Ultrasonography Study for Breast Cancer Screening Effectiveness (MUST-BE) trial. METHODS: Eight breast radiologists with 4-16 years of experience participated in 2 rounds of quality control testing for the MUST-BE trial. Two investigators randomly selected 125 and 100 cases of breast lesions with different ratios of malignant and benign lesions. Two versions of the modified categorization were tested. The initially modified classification was developed after the first quality control workshop, and the re-modified classification was developed after the second workshop. The re-modified categorization established by ABCS-K added size criteria and the anterior posterior ratio compared with the initially modified classification. After a brief lecture on the modified categorization system prior to each quality control test, the eight radiologists independently categorized the lesions using the modified categorization. Interobserver agreement was measured using kappa statistics. RESULTS: The overall kappa values for the modified categorizations indicated moderate to substantial degrees of agreement (initially modified categorization and re-modified categorization: kappa=0.52 and kappa=0.63, respectively). The kappa values for the subcategories of category 4 were 0.37 (95% confidence interval [CI], 0.24 to 0.52) and 0.39 (95% CI, 0.31 to 0.49), respectively. The overall kappa values for both the initially modified categorization and the re-modified categorization indicated a substantial degree of agreement when dichotomizing the interpretation as benign or suspicious. CONCLUSION: The preliminary results demonstrated acceptable interobserver agreement for the modified categorization. PMID- 30458607 TI - Multiplicity of Advanced T Category-Tumors Is a Risk Factor for Survival in Patients with Colorectal Carcinoma. AB - BACKGROUND: Previous studies on synchronous colorectal carcinoma (SCRC) have reported inconsistent results about its clinicopathologic and molecular features and prognostic significance. METHODS: Forty-six patients with multiple advanced tumors (T2 or higher category) who did not receive neoadjuvant chemotherapy and/or radiotherapy and who are not associated with familial adenomatous polyposis were selected and 99 tumors from them were subjected to clinicopathologic and molecular analysis. Ninety-two cases of solitary colorectal carcinoma (CRC) were selected as a control considering the distributions of types of surgeries performed on patients with SCRC and T categories of individual tumors from SCRC. RESULTS: SCRC with multiple advanced tumors was significantly associated with more frequent nodal metastasis (p = .003) and distant metastasis (p = .001) than solitary CRC. KRAS mutation, microsatellite instability, and CpG island methylator phenotype statuses were not different between SCRC and solitary CRC groups. In univariate survival analysis, overall and recurrence-free survival were significantly lower in patients with SCRC than in patients with solitary CRC, even after adjusting for the extensiveness of surgical procedure, adjuvant chemotherapy, or staging. Multivariate Cox regression analysis revealed that tumor multiplicity was an independent prognostic factor for overall survival (hazard ratio, 4.618; 95% confidence interval, 2.126 to 10.030; p < .001), but not for recurrence-free survival (p = .151). CONCLUSIONS: Findings suggested that multiplicity of advanced T category-tumors might be associated with an increased risk of nodal metastasis and a risk factor for poor survival, which raises a concern about the guideline of American Joint Committee on Cancer's tumor-node metastasis staging that T staging of an index tumor determines T staging of SCRC. PMID- 30458608 TI - Medication Adherence in Korean Hypertensive Patients. PMID- 30458609 TI - Association between Body Mass Index and Gastric Cancer Risk According to Effect Modification by Helicobacter pylori Infection. AB - Purpose: Few studies investigated roles of body mass index (BMI) on gastric cancer (GC) risk according to Helicobacter pylori infection status. This study was conducted to evaluate associations between BMI and GC risk with consideration of H. pylori infection information. Materials and Methods: We performed a case cohort study (n=2,458) that consists of a subcohort, (n=2,193 including 67 GC incident cases) randomly selected from the Korean Multicenter Cancer Cohort (KMCC) and 265 incident GC cases outside of the subcohort. H. pylori infection was assessed using an immunoblot assay. GC risk according to BMI was evaluated by calculating hazard ratios (HRs) and their 95% confidence intervals (95% CIs) using weighted Cox hazard regression model. Results: Increased GC risk in lower BMI group (< 23 kg/m2) with marginal significance, (HR, 1.32; 95% CI, 0.98 to 1.77) compared to the reference group (BMI of 23-24.9 kg/m2) was observed. In the H. pylori non-infection, both lower (< 23 kg/m2) and higher BMI (>= 25 kg/m2) showed non-significantly increased GC risk (HR,10.82; 95% CI, 1.25 to 93.60 and HR, 11.33; 95% CI, 1.13 to 113.66, respectively). However, these U-shaped associations between BMI and GC risk were not observed in the group who had ever been infected by H. pylori. Conclusion: This study suggests the U-shaped associations between BMI and GC risk, especially in subjects who had never been infected by H. pylori. PMID- 30458610 TI - Blood test strategy of blood donors, ALT and HBsAg HCV-Ab correlation study. AB - BACKGROUND: The relationship between ALT and HBsAg and anti-HCV was explored. The effects of different detection methods on blood test results of blood donors were analyzed, and the best blood test mode for blood donors was proposed. METHODS: Rate method was used to detect ALT, and ELISA was used to detect HBsAg, anti-HCV, anti-TP, and anti-HIV. Negative samples were detected by ELISA for NAT detection (PCR). HBV-NAT-negative specimens and HBV-NAT-positive specimens were detected by electrochemiluminescence for HBsAg, HBs-Ab, HBeAg, HBe-Ab, HBc-Ab (two-and-a half). The ELISA reagents of different reagent manufacturers were evaluated by serum test disc and quality control method. RESULTS: The total ALT failure rate of blood donors was 2.48%, of which the single ALT failure rate was 2.45%, accounting for 98.81% (5957/6029). The positive rate of HBsAg was 0.36%, the anti HCV positive rate was 0.40%, the anti-TP positive rate was 0.46%, and the anti HIV positive rate was 0.09%. ELISA-negative specimens were detected by NAT, HBV nucleic acid-positive 164 persons, accounting for 0.09%, no HCV, HIV-positive. HBV-NAT positive specimens were detected by nucleic acid quantitative test; the positive rate of HBV- DNA was 56.67 %. HCV-positive blood donors were followed up for 24 weeks and re- examined; negative nucleic acid cases accounted for 98.92%. The detection results of serum test disc and quality control method were not the same. CONCLUSIONS: There was no correlation between ALT positive and HBV and HCV in blood donors. HIV detection are better detection modes by two-pass enzyme elimination and one-time NAT detection (PCR), which can effectively reduce transfusion infection caused by occult infection of HBV and improve blood safety. HBsAg, HCV-Ab positive blood donors after ELISA and nucleic acid test negative after 24 weeks (maximum window period) are recommended to return to the blood donation team to participate in blood donation. The two ELISA reagents were tested by different manufacturers, which were complementary and improved the detection accuracy. PMID- 30458611 TI - Different peas in a pod: two cases of clenched fist syndrome with long-term follow-up. PMID- 30458613 TI - Nortrachelogenin, a major lignan component of Pinus sylvestris knot extract, suppresses IL-4 and IL-13 -induced alternative macrophage activation and partially reverses bleomycin-induced dermal fibrosis. AB - Excessive alternative macrophage activation contributes to fibrosis. We studied the effects of nortrachelogenin, the major lignan component of Pinus sylvestris knot extract, on alternative (M2) macrophage activation. J774 murine and THP-1 human macrophages were cultured with IL-4+IL-13 to induce alternative activation, together with the extract and its components. Effects of nortrachelogenin were also studied in bleomycin-induced murine dermal fibrosis model. Knot extract significantly decreased the expression of alternative activation markers: arginase 1 in murine macrophages (97.4+/-1.3% inhibition at 30 MUg/ml), and CCL13 and PDGF in human macrophages, as did nortrachelogenin (94.9+/-2.4% inhibition of arginase 1 at 10MUM). Nortrachelogenin also decreased PPARgamma expression but had no effect on STAT6 phosphorylation. In vivo, nortrachelogenin reduced bleomycin-induced increase in skin thickness and the expression of collagens COL1A1, COL1A2 and COL3A1, all three by >50%. In conclusion, nortrachelogenin suppressed IL-4+IL-13 -induced alternative macrophage activation and ameliorated bleomycin-induced fibrosis, indicating therapeutic potential in fibrosing conditions. PMID- 30458612 TI - Poly(thymine)-CuNPs: Bimodal Methodology for Accurate and Selective Detection of TNT at Sub-PPT Levels. AB - Accurate, sensitive, and selective detection of explosives is of vital importance in antiterrorism and homeland security. Fluorescence sensors are prevalent for sensitive and fast in-field explosive detection but are sometimes compromised by accuracy and stability due to the similar structures of explosives, photobleaching, and complex sample matrixes. Herein, we developed a first bimodal methodology capable of both sensitive in-field fluorescence detection and accurate laboratory mass spectrometric quantification of 2,4,6-trinitrotoluene (TNT) by utilizing the characteristic fluorescent and mass spectrometric response of copper nanoparticles (CuNPs). An excellent selectivity was also realized by involving aptamer recognition. The methodology is capable of detecting TNT at subpart per trillion (PPT) levels, with a detection limit of 0.32 pg mL-1 by inductively coupled plasma mass spectrometry (ICPMS) and 0.17 ng mL-1 by fluorimetry. The signal response was accurate and stable for at least 60 days by ICPMS. Thanks to the biospecificity of the aptamer, this bimodal methodology is potentially applicable to a large panel of explosives. PMID- 30458614 TI - Effect of tebuconazole enantiomers and environmental factors on fumonisins accumulation and FUM genes expression in Fusarium verticillioides. AB - Fusarium verticillioides is a important corn pathogen that can produce fumonisins under certain environmental conditions. In this study, we evaluated the enantioselective impact of tebuconazole enantiomers on the growth and fumonisins production of F.verticillioides on maize-based media at different abiotic factors. The expression of fumonisin biosynthetic genes (FUM1 and FUM6) was quantified by real time RT-PCR. The results showed that water activity (aw), temperature and the types of tebuconazole significantly affected the growth of F. verticillioides. The order of fungicidal activity was: (-)-tebuconazole > rac tebuconazole > (+)-tebuconazole. (-)-tebuconazole exhibited the maximal selective fungicidal activity (242-fold) against F. verticillioides at 0.95 aw and 35 degrees C. Production of fumonisin B1 (FB1) and B2 (FB2) by F. verticillioides was influenced by aw, temperature, types of tebuconazole and dose. Under most conditions, (-)-tebuconazole showed stronger inhibition for FB1 and FB2 production than that of (+)-tebuconazole (1.87-2.85 fold reduction in FBs) and rac-tebuconazole. The optimal environmental condition for fumonisin production was at water activity 0.99 and 25 degrees C. Tebuconazole enantiomers differently affected fumonisins biosynthetic gene (FUM1 and FUM6) expression, but the effects on fumonisins production and genes expression showed no positive correlation. The present study provides a better understanding on ways to minimize fumonisin production in corn treated with fungicides. PMID- 30458615 TI - Continuous Ammonia Recovery from Wastewaters Using an Integrated Capacitive Flow Electrode Membrane Stripping System. AB - We have previously described a novel flow-electrode capacitive deionization (FCDI) unit combined with a hydrophobic gas-permeable hollow fiber membrane contactor (designated "CapAmm") and presented results showing efficient recovery of ammonia from dilute synthetic wastewaters (Zhang et al., ES&T Letters 2018, 5, 43-49). We extend this earlier study here with description of an FCDI system with integrated flat sheet gas permeable membrane with comprehensive assessment of ammonia recovery performance from both dilute and concentrated wastewaters. The integrated CapAmm cell exhibited excellent ammonia removal and recovery efficiencies (up to ~90% and ~80% respectively). The energy consumptions for ammonia recovery from low-strength (i.e., domestic) and high-strength (i.e., synthetic urine) wastewaters were 20.4 kWh kg-1 N and 7.8 kWh kg-1 N, respectively, with these values comparable to those of more conventional alternatives. Stable ammonia recovery and salt removal performance was achieved over more than two days of continuous operation with ammonia concentrated by ~80 times that of the feed stream. These results demonstrate that the integrated CapAmm system described here could be a cost-effective technology capable of treating wastewaters and realizing both nutrient recovery and water reclamation in a sustainable manner. PMID- 30458616 TI - Spatial Organization of Superparamagnetic Iron Oxide Nanoparticles in/on Nano/Micro-Sized Carriers Modulates the Magnetic Resonance Signal. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) are often encapsulated into drug-carrying nano/micro-sized particles for simultaneous magnetic resonance (MR) imaging and treatment of diseased tissues. Unfortunately, encapsulated SPIONs may have a limited ability to modulate the T2-weighted relaxation of water protons, but this insight has not been examined systematically. This study demonstrates that SPIONs immobilized on 200 nm-diameter poly(lactic-co-glycolic acid) (PLGA) nanoparticles using Pickering emulsification present 18-fold higher relaxivity than encapsulated SPIONs, and 1.5-fold higher relaxivity than free SPIONs. In contrast, the SPIONs immobilized on 10 ?m-diameter PLGA particles exhibit a minor increase in MR relaxivity. This interesting finding will significantly impact current efforts to synthesize and assemble advanced MR contrast agents. PMID- 30458617 TI - Molecular Mechanics Simulations and Improved Tight-Binding Hamiltonians for Artificial Light Harvesting Systems: Predicting Geometric Distributions, Disorder, and Spectroscopy of Chromophores in a Protein Environment. AB - We present molecular mechanics and spectroscopic calculations on prototype artificial light harvesting systems consisting of chromophores attached to a tobacco mosaic virus (TMV) protein scaffold. These systems have been synthesized and characterized spectroscopically, but information about the microscopic configurations and geometry of these TMV-templated chromophore assemblies is largely unknown. We use a Monte Carlo conformational search algorithm to determine the preferred positions and orientations of two chromophores, Coumarin 343 together with its linker, and Oregon Green 488, when these are attached at two different sites (104 and 123) on the TMV protein. The resulting geometric information shows that the extent of disorder and aggregation properties, and therefore the optical properties of the TMV-templated chromophore assembly, are highly dependent on the choice of chromophores and protein site to which they are bound. We used the results of the conformational search as geometric parameters together with an improved tight-binding Hamiltonian to simulate the linear absorption spectra and compare with experimental spectral measurements. The ideal dipole approximation to the Hamiltonian is not valid since the distance between chromophores can be very small. We found that using the geometries from the conformational search is necessary to reproduce the features of the experimental spectral peaks. PMID- 30458618 TI - Preparation of 3,4-substituted-5-aminopyrazoles and 4-substituted-2 aminothiazoles. AB - 3,4-Substituted-5-aminopyrazoles and 4-substituted-2-aminothiazoles are frequently used intermediates in medicinal chemistry and drug discovery projects. We report an expedient flexible synthesis of 3,4-substituted-5-aminopyrazoles (35 examples), based on palladium-mediated alpha-arylation of beta-ketonitriles with aryl bromides. A library of 4-substituted-2-aminothiazoles (21 examples) was assembled by a sequence employing Suzuki coupling of newly prepared properly protected pinacol ester and MIDA ester of 4-boronic acid-2-aminothiazole with (hetero)aryl halides. PMID- 30458619 TI - Beyond the Amyloid Hypothesis of Alzheimer's Disease: Tau Pathology Takes Center Stage. PMID- 30458620 TI - In This Issue, Volume 9, Issue 11. PMID- 30458622 TI - Enhanced uptake of plasmid at boronic acid decorated linear polyethylenimines results in higher transfection efficiency. AB - High molecular weight polyethylenimines (PEIs) are considered as gold standard for transfection studies; however, cytotoxicity associated with branched ones and lower charge density on linear PEIs as well as lower uptake of the resulting deoxyribonucleic acid (DNA) complexes have limited their applications in clinical studies. In order to address these concerns and improve the uptake efficiency of the DNA complexes of linear polyethylenimine (25 kDa), the polymer was grafted with variable amounts of butylboronic acid to obtain a small series of linear polyethylenimine-butylboronic acid polymers. These modified polymers were allowed to interact with plasmid DNA and the resulting complexes were characterized by physicochemical techniques. Dynamic light scattering data showed the formation of nanosized complexes with positive zeta potential values. Furthermore, when these complexes were evaluated in vitro, they not only showed enhanced cell viability but also exhibited higher transfection efficiency as compared to native linear and branched PEIs and a commercially available standard transfection reagent, Lipofectamine 2000. PMID- 30458623 TI - Association of cultural affinity and island food consumption in the Pacific Islander health study. AB - OBJECTIVES: The dietary patterns of Pacific Islander Americans are partially influenced by a rich cultural heritage. There is little known about how cultural affinity affects the dietary choices of this small, but quickly growing population. This analysis attempts to understand how the association of cultural affinity on island foods consumption (IFC) varies by key demographic characteristics. DESIGN: A sample of 240 Samoan and Tongan adults in California from the Pacific Islander Health Study (PIHS) was used. Psychometric properties of a novel 11-item cultural affinity scale were assessed. Univariate and bivariate analyses of the cultural affinity scale were completed to understand the distribution of cultural affinity score. Separate multivariable Poisson regression was used to assess the effect of interactions between cultural affinity and five key demographic factors on IFC. RESULTS: Psychometric analysis of the PIHS cultural affinity scale revealed two unique factors. Significant interactions were found between cultural affinity and ethnicity and birthplace: the association between cultural affinity and IFC was larger among Samoans compared to Tongans and Samoan or Tongan birthplace was found to have a weaker association between cultural affinity and IFC. Interactions between cultural affinity and age, financial insecurity, and educational attainment were not significant. CONCLUSION: Understanding how cultural affinity varies in its effect on IFC is a part of understanding overall dietary patterns in this population. PMID- 30458624 TI - Ideal Cardiovascular Health Status and Risk of Cardiovascular Disease or All Cause Mortality in Chinese Middle-Aged Population. AB - We estimated the prevalence of ideal cardiovascular health (CVH), and its relationship with cardiovascular disease (CVD) and all-cause mortality in a Chinese population. A cross-sectional survey of CVD risk factors was conducted among Chinese participants aged 35 to 64 years in 2009 to 2010. In 2017, 8965 participants completed follow-up assessments in which CVD and all-cause mortality were collected; 8754 participants were eligible for analysis. The percentage of meeting all 7 ideal CVH metrics was 0.10%. During a median follow-up of 6.3 years, the incidence of CVD and all-cause mortality were 6.02% and 4.85% per 1000 person-year in participants with 0 to 1 ideal CVH metrics, 3.33% and 3.57% in those with 2 to 5, 0.40% and 0.79% in those with 6 to 7, respectively. After adjusting for covariates, the risk of CVD was significantly lower in participants with 2 to 5 (hazard ratio [HR]: 0.67, 95% confidence interval [CI]: 0.45-0.98) and 6 to 7 (HR: 0.12, 95%CI: 0.02-0.87) ideal CVH metrics compared to those with 0 to 1 ideal CVH metrics. The risk of all-cause mortality was decreased as ideal CVH metrics increased (HR: 0.78, 95%CI: 0.70-0.88). A greater number of ideal CVH metrics was associated with a lower risk of CVD and all-cause mortality, but the prevalence of all 7 ideal CVH metrics was low in a Chinese population. PMID- 30458625 TI - The effect of early intervention of mirror visual feedback on pain, disability and motor function following hand reconstructive surgery: a randomized clinical trial. AB - OBJECTIVE:: To determine the effect of mirror visual feedback (MVF) on disability, pain, and motor function on patients who underwent hand reconstructive surgery. DESIGN:: Randomized, single-blinded controlled trial. SETTING:: Rehabilitation center. SUBJECTS:: A total of 40 patients who were randomly assigned into the intervention group ( n = 20) and control group ( n = 20) participated in this study. INTERVENTIONS:: The rehabilitation sessions took place twice a week for eight weeks. The control group received traditional rehabilitation for 75 minutes. While the intervention group performed MVF and traditional rehabilitation for 30 and 45 minutes, respectively. MEASURES:: Pain and disability of the hand were assessed with McGill pain questionnaire and Disability of Arm, Shoulder, and Hand (DASH) scores. The range of joint motion was evaluated by Goniometer, and the strength of grip and pinch was evaluated by Dynamometer and Pinch gauge and dexterity evaluated by Minnesota Manual Muscle test. RESULTS:: The results indicated that both traditional and MVF methods induced significant decreasing pain (Pain Rate Index: F = 68.48, P = 0.000; Number of Word Count: F = 70.96, P = 0.000), disability ( F = 50.08, P = 0.000) and increasing dexterity (placing test: F = 28.73, P = 0.000), and range of motion ( F = 33.16, P = 0.000). The results also showed that the positive effect of MVF on pain, disability, dexterity, and range of motion was significantly greater than that of controls ( P < 0.05), but there was no significant result in grip and lateral pinch strength between the intervention and control group ( P > 0.05). CONCLUSION:: MVF, in conjunction with traditional rehabilitation programs, may lead to greater improvements in pain, disability, placing dexterity, and range of motion. But it seems not to be effective on pinch and grip power and turning dexterity. PMID- 30458626 TI - Predictors and growth in receptive vocabulary from 4 to 8 years in children with and without autism spectrum disorder: A population-based study. AB - Few studies have examined growth and predictors of receptive vocabulary in children with autism spectrum disorder. Here we aimed to compare receptive vocabulary from 4 to 8 years and identify predictors of receptive vocabulary, at 8 years, in children with and without autism spectrum disorder. Participants were drawn from a nationally representative population-based study with two cohorts recruited at birth (N = 4983) and kindergarten (N = 5107). Receptive vocabulary growth was compared for children with and without autism spectrum disorder at 4 (n = 188, n = 7136), 6 (n = 215, n = 7297) and 8 (n = 216, n = 7408) years. Predictors of receptive vocabulary were analysed. Estimated mean receptive vocabulary scores for children without autism spectrum disorder were 2.3 units higher than the autism spectrum disorder group across three time points. This difference was significant (p = 0.004; 95% confidence interval 0.769-3.927). Children with and without autism spectrum disorder progressed at a similar pace. There was no significant difference between the proportions of children with and without autism spectrum disorder who had stable, improving and declining trajectories. Age was the only significant predictor of greater receptive vocabulary growth in children with autism spectrum disorder. Baseline receptive language and nonverbal IQ were significant predictors of receptive vocabulary ability at 8 years. These findings inform prognostic advice given to families on language outcomes. PMID- 30458627 TI - Adverse Metabolic Effects of Diltiazem Treatment During Diabetic Cardiomyopathy. AB - Diabetes is a global epidemic disease, which leads to multiorgan dysfunction, including heart disease. Diabetes results from the limited absorption of glucose into insulin-sensitive tissues. The heart is one of the main organs to utilize glucose as an energy substrate. Glucose uptake into striated muscle is regulated by a family of membrane proteins called glucose transporters (GLUTs). Although calcium channel blockers, including diltiazem, are widely prescribed drugs for cardiovascular diseases, including in patients with diabetes, their pharmacological effects on glucose metabolism are somewhat controversial. We hypothesized that diltiazem treatment will exhibit detrimental effects on whole body glucose homeostasis and glucose transport in the striated muscle of patients with diabetes. Healthy and streptozotocin-treated rats were randomly assigned to receive diltiazem treatment or a placebo for 8 weeks. Blood glucose was significantly increased in the untreated diabetic groups, which worsened after diltiazem treatment. Diabetes decreased protein content of both GLUT4 (the predominate insulin-sensitive glucose transporter) and AS160 (Akt Substrate at 160 kDa, the downstream protein in the signaling cascade that regulates GLUT4 trafficking) in striated muscle of diabetic rats, with a more pronounced alteration after diltiazem treatment. We additionally reported that diabetic rodents displayed marked systolic dysfunction, which was not rescued by diltiazem treatment. In conclusion, diltiazem treatment worsened the effects of diabetes induced hyperglycemia and diabetes-induced alterations in the regulation of glucose transport in striated muscle. PMID- 30458628 TI - Application of whole-lesion intravoxel incoherent motion analysis using iZOOM DWI to differentiate malignant from benign thyroid nodules. AB - BACKGROUND: Intravoxel incoherent motion (IVIM) parameters derived from iZOOM diffusion-weighted imaging (DWI) can be used to quantitatively identify malignant thyroid nodules. However, the criteria are not standardized. PURPOSE: To determine IVIM parameter values derived from iZOOM DWI that can differentiate malignant from benign thyroid nodules. MATERIAL AND METHODS: Forty-two patients with 46 pathologically confirmed thyroid nodules. All patients underwent preoperative examinations with conventional and iZOOM DWI. A three-dimensional region of interest was drawn on multiple slices to cover the entire nodule. IVIM parameters ( D, pure diffusion; f, perfusion fraction; and D*, pseudodiffusion) were measured. The IVIM parameters of the malignant and benign thyroid nodules were compared using independent samples t -tests, a multiple logistic regression, and receiver operating characteristic (ROC) curve analysis. RESULTS: D, D*, and f exhibited good reproducibility. The D and f values in the malignant nodules ( D = [0.72 +/- 0.14] * 10-3 mm2/s, [29.94 +/- 7.36] %) were significantly lower than those in benign nodules ( D = [1.23 +/- 0.35] * 10-3 mm2/s, [36.00 +/- 8.35] %). The D value achieved the highest area under curve (0.939). The optimal cut-off value for D was 0.87 * 10-3 mm2/s (sensitivity = 95.83%, specificity = 90.91%, positive predictive value [PPV] = 92.00%, negative predictive value [NPV] = 95.24%, and accuracy rate = 93.48%). The area under ROC curve (AUC) of D combined with the f value did not significantly differ from that of D. CONCLUSION: IVIM parameter D derived from iZOOM DWI may be helpful in differentiating malignant from benign thyroid nodules. PMID- 30458629 TI - Quantitative parameters correlated well with differentiation of squamous cell carcinoma at head and neck: a study of dynamic contrast-enhanced MRI. AB - BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is widely used for the diagnosis and prognostic assessment of head and neck squamous cell carcinoma (HNSCC). However, no research on grading HNSCC using DCE-MRI has been found. We hypothesize that DCE-MRI can grade the HNSCC non-invasively. PURPOSE: To verify the hypothesis that DCE-MRI can grade the HNSCC non invasively. MATERIAL AND METHODS: Forty-two patients with histopathologically proved HNSCC from September 2013 to February 2016 were retrospectively analyzed. Chi-square test was used to compare patterns of time intensity curves (TICs) between well and poorly differentiated HNSCC. Two-sample t-test was performed to calculate the difference of volume transfer constant (Ktrans), extravascular extracellular volume fraction (Ve), and initial area under the curve (iAUC) between groups. The diagnostic ability and cut-off value were assessed by receiver operator characteristic analysis. RESULTS: Most TICs of HNSCC are type III; no difference between well and poorly differentiated HNSCC has been found ( P > 0.05). The value of Ktrans, Ve, and iAUC for well and poorly differentiated HNSCC are (0.218 +/- 0.048; 0.383 +/- 0.074) min-1, (0.605 +/- 0.108; 0.712 +/- 0.150), and (27.552 +/- 6.238; 43.157 +/- 9.148), respectively. Ktrans, Ve, and iAUC are higher in poorly differentiated HNSCC, compared with well differentiated HNSCC ( P < 0.001, 0.013, and < 0.001, respectively). Ktrans has the greatest diagnostic significance with Youden's index being 0.859 by cut-off value 0.270 min-1. The diagnostic sensitivity and specificity were 95.0% and 90.9%, respectively. CONCLUSION: The Ktrans, Ve, and iAUC of HNSCC can be reliable quantitative parameters for evaluating well and poorly differentiated HNSCC where Ktrans has the highest value. PMID- 30458630 TI - Work and the Family in Later Life: The Effects of Role Stressors, Role Enhancement, and Role Conflict on Self-Perceptions on Aging. AB - The growing aging workforce comprises older workers with a concurrent family role. Guided by life span development and role theories, the primary study hypothesis was that rewards and stressors in the family and work domains would impact self-perceptions on aging because of the enhancement and conflict between these domains. The study sample consisted of workers older than 50 years with at least one of four family roles (spouse, parent of adult children, caregiver to an aging parent, and grandparent) from the 2010 and 2012 Health and Retirement Study ( N = 5,628). Results showed that self-perceptions on aging were impacted directly by family and work stressors and indirectly by these stressors through work-family enhancement and conflict . Work and family roles are thus crucial to the identity of adults in later life. PMID- 30458631 TI - Proposal for a Migraine Aura Complexity Score. AB - OBJECTIVES: Currently, there is no scoring system for assessing the complexity of migraine aura. Our goal was to develop a Migraine Aura Complexity Score that synthesizes the quantity and quality of aura symptoms and to test its applicability in neuroimaging studies. METHODS: Patients with migraine aura were interviewed in order to obtain characteristics of migraine aura. Explorative and confirmatory analyses were used to develop the Migraine Aura Complexity Score. Median values were derived from 10 consecutive migraine auras in each patient. The Migraine Aura Complexity Score was correlated with an average cortical thickness of different brain areas in studied patients. The Surface-based Morphometric Analysis approach was used to estimate cortical thickness. RESULTS: This study included 23 (16 females and seven males) migraineurs with aura. Confirmatory factor analysis suggested the second-order model with three-factor measurement for grading migraine aura. The first factor is linked to higher cortical dysfunction during migraine aura, while the second is associated with the degree of involvement of primary visual and somatosensory cortices; the third linked symptoms of somatosensory aura and hand and head involvement. Positive correlation of Migraine Aura Complexity Score and averaged cortical thickness were found in the left and right hemispheres overall (r = 0.568, p = 0.007; r = 0.617, p = 0.003) and in some of their regions. CONCLUSIONS: This study demonstrates that the Migraine Aura Complexity Score could be a valuable tool for assessing migraine aura. The score could be used in neuroradiological studies in order to achieve a stratification of patients with migraine aura. PMID- 30458632 TI - Metacognitive Reflection and Insight Therapy (MERIT) for Persons With a Schizophrenia Spectrum Disorder and Interpersonal Trauma. AB - Schizophrenia often involves a loss of metacognitive capacity, the ability to form complex and integrated representations of self and others. Independent of symptoms and neurocognition, deficits in synthetic metacognition are related to difficulties engaging in goal-directed activities in social and vocational settings. Against this backdrop, the authors provide a case report of the effects of metacognitive reflection and insight therapy (MERIT) provided over the course of seven months to assist a client with persistent schizophrenia. Eight elements of MERIT that stimulate and promote metacognitive capacity are presented. As illustrated in this article, these elements helped the client to move from a state in which he had virtually no complex ideas about himself or others to one in which he had developed integrated and realistic ideas about his own identity and that of others. He then could use these representations to understand and effectively respond to life challenges. PMID- 30458633 TI - Metacognitive Interpersonal Therapy for Treating Persecutory Delusions in Schizophrenia. AB - A persecutory delusion (PD) is a person's false belief that others are focusing their attention on him or her with malevolent intentions, which often results in intense anxiety and significant disruption of daily life. PDs are common in schizophrenia, and many patients with schizophrenia do not respond well to current pharmacological treatments. Therefore, effective psychological treatments are needed. The most well-known intervention for PDs continues to be cognitive behavioral therapy. It aims to reduce patients' stigma and then help them to question the delusional meaning they attribute to events. The authors hypothesized that it is possible to reinforce the clinical approach to PDs on the basis of two important considerations: delusions have a meaning that is connected to a fundamental experiencing of the self as being ontologically vulnerable, and PDs seem to be correlated to dysfunctions in metacognition, a spectrum of mental activities involving thinking about one's own and others' mental states. The authors describe the treatment with metacognitive interpersonal therapy of a young man with paranoid schizophrenia and pervasive PD. The four main stages described are: regulating the therapeutic relationship to avoid potential rupture; reducing the emotional suffering caused by the PD and teaching the patient behavioral strategies for coping with this suffering, promoting the patient's ability to reflect on his own mind and thereby to develop a more sophisticated metacognitive mastery of the PD, and promoting a more nuanced understanding of the other's mind. PMID- 30458634 TI - Effectiveness of rehabilitation after cervical disk surgery: a systematic review of controlled studies. AB - OBJECTIVES:: To present a synopsis of evidence on the efficacy of rehabilitation after cervical disk surgery performed for neck pain and radiculopathy. DATA SOURCES:: The databases of Medline, EMBASE, and Cochrane Central were searched for studies reporting effects of rehabilitation interventions in patients undergoing surgery due to cervical disk disease with pain and radicular syndrome, published before 31 August 2018. REVIEW METHODS:: Project was registered with PROSPERO database (number CRD42018085937). Randomized controlled trials that evaluated the efficacy of rehabilitation interventions versus other, sham, or no treatment were selected. The primary outcomes were disability and pain. Secondary outcomes were other measures assessing biological, psychological or social effect of rehabilitation. Two reviewers independently screened studies for eligibility, assessed risk of bias and extracted data. Evaluation of evidence was performed with the GRADE system. RESULTS:: Five papers were included in the review. The eligible studies were heterogeneous in intervention and outcome reporting. There are low- to very-low-quality evidence that some interventions (use of cervical collars after non-plated anterior cervical diskectomy an fusion, structured physiotherapy, and interactive patients' education) provide some benefit within functioning, pain, and selected psychological variables in patients undergoing cervical disk surgery. Controlled trials addressing comprehensive interdisciplinary rehabilitation, multidisciplinary pain management, occupational therapy, psychotherapy, social and vocational interventions were not identified. CONCLUSION:: There is insufficient evidence with few trials of low quality to allow any conclusion to be drawn about the effectiveness, harms, and general ineffectiveness of rehabilitation for people who have had cervical disk surgery for pain or radiculopathy. PMID- 30458635 TI - An Individual Housing-Based Socioeconomic Status Measure Predicts Advance Care Planning and Nursing Home Utilization. AB - BACKGROUND:: Socioeconomic status (SES) is an important determinant of disparities in health care and may play a role in end-of-life care and decision making. The SES is difficult to retrospectively abstract from current electronic medical records and data sets. OBJECTIVE:: Using a validated SES measuring tool derived from home address, the HOUsing-based SocioEconomic Status index, termed HOUSES we wanted to determine whether SES is associated with differences in end of-life care and decision-making. DESIGN/SETTING/PARTICIPANTS:: This cross sectional study utilized a cohort of Olmsted County adult residents admitted to 7 intensive care units (ICUs) at Mayo Rochester between June 1, 2011, and May 31, 2014. MEASUREMENTS:: Multiple variables that reflect decision-making and care at end of life and during critical illness were evaluated, including presence of advance directives and discharge disposition. The SES was measured by individual housing-based SES index (HOUSES index; a composite index derived from real property as a standardized z-score) at the date of admission to the ICU which was then divided into 4 quartiles. The greater HOUSES, the higher SES, outcomes were adjusted for age, 24-hour Acute Physiology and Chronic Health Evaluation III score, sex, race/ethnicity, and insurance. RESULTS:: Among the eligible 4134 participants, the addresses of 3393 (82%) were successfully geocoded and formulated into HOUSES. The adjusted odds ratios comparing HOUSES 1 versus 2, 3, and 4 demonstrated lower likelihood of advance directives -0.77(95% CI: 0.63 0.93) and lower likelihood of discharge to home -0.60(95% CI: 1.0.5-0.72). CONCLUSION:: Lower SES, derived from a composite index of housing attributes, was associated with lower rates of advance directives and lower likelihood of discharge to home. PMID- 30458636 TI - Effect of phototherapy on oxidant/antioxidant status: A randomized controlled trial. AB - In order to evaluate the effect of different types of phototherapy on oxidant/antioxidant status in hyperbilirubinemic neonates, an interventional randomized control trial was conducted on 120 neonates >= 35 weeks' gestational age with indirect hyperbilirubinemia reaching phototherapy level. This study is registered with ClinicalTrials.gov as NCT03074292 . Neonates were assigned to three groups; 40 neonates received conventional phototherapy, 40 received intensive phototherapy and 40 received blue light-emitting diodes (LED) phototherapy. Complete blood count (CBC), total serum bilirubin (TSB), total antioxidant capacity (TAC), malondialdehyde (MDA), nitric oxide (NO), copper (Cu), zinc (Zn), and iron (Fe) levels were measured before and 24 hours after phototherapy. TSB decreased postphototherapy in all three groups (p < 0.05 for all), with significantly lower levels following intensive and LED phototherapy compared to conventional phototherapy (p < 0.05 for both). TAC decreased postphototherapy in the three groups (p < 0.05 for all). MDA and NO increased postphototherapy (p < 0.05 for all), with the intensive phototherapy group having the highest levels followed by the conventional while LED phototherapy group showed the lowest levels in comparison to the other groups (p < 0.05). Cu, Zn and Fe increased postphototherapy in all three groups (p < 0.05 for all). Positive correlations were found between postphototherapy TSB with TAC, Cu and Zn (p < 0.05) and negative correlations with MDA, NO and Fe (p < 0.05) among neonates of the 3 studied groups. In conclusion, different photo therapies have an impact on oxidant/antioxidant balance and are associated with increased oxidative stress markers with the LED phototherapy being the safest. PMID- 30458637 TI - Emerging role of SIRT3 in mitochondrial dysfunction and cardiovascular diseases. AB - As a nicotinamide adenine dinucleotide (NAD)+-dependent protein deacetylase, SIRT3 is highly expressed in tissues with high metabolic turnover and mitochondrial content. It has been demonstrated that SIRT3 plays a critical role in maintaining normal mitochondrial biological function through reversible protein lysine deacetylation. SIRT3 has a variety of substrates that are involved in mitochondrial biological processes such as energy metabolism, reactive oxygen species (ROS) production and clearance, electron transport chain (ETC) flux, mitochondrial membrane potential maintenance and mitochondrial dynamics. In the suppression of SIRT3, functional deficiencies of mitochondria contribute to the development of various cardiovascular disorders. Activation of SIRT3 may represent a promising therapeutic strategy for the improvement of mitochondrial function and the treatment of relevant cardiovascular disorders. In current review, we discuss the emerging roles of SIRT3 in mitochondrial derangements and subsequent cardiovascular malfunctions, including cardiac hypertrophy and heart failure, ischemia-reperfusion (IR) injury, and endothelial dysfunction in hypertension and atherosclerosis. PMID- 30458638 TI - Motherhood and highly sensitive children in an online discussion forum. AB - Discourse on the highly sensitive child as a mode of individual coming-into-being is transforming notions of good motherhood. Mothering a child is weighted with practical challenges, normative expectations, and moral implications, all of which can be accentuated when parenting a child that appears to differ from the average. How mothers address themselves to a highly sensitive child can reveal much about contemporary currents in family life. Through analysis of the online discussions in a Swedish forum, I examine mothers' discourse regarding categorization of highly sensitive children, elaboration on the behaviors that constitute this category of protean individuality, and the negotiation of motherhood norms. Three themes are identified: the way in which participants established entitlement to the application of the highly sensitive child label through a process of "enlightenment" based on observing their children and scrutinizing their own childrearing practices; discourse on the "allure" of the highly sensitive child since it depicts the children as super-normal and themselves as mothers called to the custodianship of a "different child"; and finally, how the highly sensitive child label deflects the guilt and frustration linked with handling challenging behaviors, in tension with permitting the sensitive child's self-determined development. The article suggests that the mothers' discourse reflects the intensive mothering norms of child-centered parenting that prevail in Western countries such as Sweden. Through the lens of the highly sensitive child, however, motherhood acquires new anticipatory, considerate and susceptible norms, and strategies that constitute a highly sensitive parenting style. PMID- 30458639 TI - Effect of kinesio taping direction on force sense in wrist flexor muscles in healthy persons. AB - The aim of this study was to investigate the effect of direction of kinesio taping of wrist flexor muscles on force sense. Forty-five healthy women took part in this study, in three groups: kinesio taping application from origin to insertion (OI group) or from insertion to origin (IO group), and no kinesio taping (control group). Absolute and relative force sense errors were calculated with 50% maximal grip strength as the target force value. Absolute and relative force sense errors in the dominant hand were recorded before and 24 h after the application of kinesio tape to the forearm. Relative force sense error was significantly lower in the OI group than in the control group (P = 0.028). However, absolute force sense error did not differ significantly among the three groups (P = 0.431). Our results suggest that kinesio taping in the OI direction enhances relative force sense compared to no taping. PMID- 30458640 TI - Diabetes and blindness in people with diabetes in Hungary. AB - INTRODUCTION:: The purpose of the study was to estimate the number of people with diabetes mellitus, the prevalence of diabetes mellitus and the prevalence of blindness and severe visual impairment among people with diabetes mellitus in Hungary based on our recent national representative survey. METHODS:: Altogether 105 clusters of 35 people aged 50 years or older were randomly selected. Standardized rapid assessment of avoidable blindness with the diabetic retinopathy module was used. Each individual received a visual acuity assessment, and every person with diabetes mellitus underwent dilated fundus examination. RESULTS:: The estimated number of people with diabetes mellitus was 807,885 in the adult (?18 years) population in Hungary with 9.9% prevalence. Diabetic retinopathy exhibited an increasing tendency with age. The prevalence rates of blindness and severe visual impairment in people with diabetes mellitus aged ?50 years were 1.0% and 0.9%, respectively. Diabetic retinopathy was responsible for 28% of blindness and 50% of severe visual impairment among participants aged ?50 years with diabetes mellitus. CONCLUSION:: The estimated number of people with diabetes mellitus and prevalence of diabetes mellitus were lower than those recently reported. However, if we extend our estimation, prevalence of undiagnosed diabetes mellitus may be higher and thus prevalence of diabetes mellitus may reach a higher value (between 9.9% and 13.4%). Because of the high number of ophthalmologically uncontrolled diabetic eyes and high rate of blindness due to diabetic retinopathy, primary eye care should be improved, and a nationwide telemedical eye-screening programme should be undertaken. PMID- 30458641 TI - Calls for routine collection of patient-reported outcome measures are getting louder. PMID- 30458642 TI - Sociodemographic, Anthropometric, and Dietary Predictors of Polyunsaturated Fatty Acids in Adipose Tissue Among Mesoamerican Children and Their Parents. AB - BACKGROUND:: Polyunsaturated fatty acid (PUFA) intake is low throughout Latin America. Improving PUFA status could be an effective intervention against chronic disease, but information on sociodemographic and dietary patterning of PUFA status in the region is limited. OBJECTIVE:: To characterize sociodemographic, anthropometric, and dietary predictors of PUFA status biomarkers in adipose tissue among children and their parents from Mesoamerica. METHODS:: This was a cross-sectional study of 220 children aged 7 to 12 years and 471 parents from capital cities of Guatemala, El Salvador, the Dominican Republic, Honduras, Nicaragua, Panama, Costa Rica, and Belize, as well as Tuxtla Gutierrez in Mexico. The PUFA from gluteal adipose tissue was quantified using gas chromatography. Participants reported sociodemographic information and the type of vegetable oil used for cooking. We estimated percent mean differences in linoleic acid (LA), total long-chain n-6 PUFA (n-6 LCPUFA), alpha-linolenic acid (ALA), and total long-chain n-3 PUFA (n-3 LCPUFA) between levels of predictors using multivariable adjusted linear regression models. RESULTS:: Country was the strongest predictor of any PUFA, whereas body mass index was positively associated with n-6 LCPUFA in children and adults. Cooking primarily with soybean oil was positively associated with LA in children and adults and ALA in adults. Cooking with canola oil was positively related to n-6 LCPUFA in adults and n-3 LCPUFA in children and adults. Cooking with palm oil was associated with low adipose tissue levels of all n-6 and n-3 PUFA. CONCLUSIONS:: Adipose tissue PUFA status in Mesoamerica is associated with country of origin and the type of oil used for cooking. PMID- 30458643 TI - Vitamin D attenuates gentamicin-induced acute renal damage via prevention of oxidative stress and DNA damage. AB - BACKGROUND:: Despite being one of the most nephrotoxic drugs, gentamicin (GM) remains a mainstay as a first-choice agent in a vast variety of clinical situations owing to its superlative efficiency as a broad-spectrum antibiotic in treating several life-threatening bacterial infections. This urgently calls for the need for in-depth analysis of the mechanisms governing GM-induced nephrotoxicity and entails the necessity of presenting novel protective agents capable of ameliorating those renal deleterious effects. The reactive oxygen species and redox-sensitive transcription factors in GM-induced nephrotoxicity have recently called attention. PURPOSE:: This study has been designed to shed light on the possible mechanisms of GM-induced nephrotoxicity and to provide a consensus set of histopathological, immunohistochemical, genetic and biochemical parameters elucidating the protective role of vitamin D against this nephrotoxicity. METHODS:: Twenty-four adult male albino rats were equally divided into four groups: group I (control group), group II (GM), group III (GM + vitamin D) and group IV (vitamin D only). Kidney function tests, histopathological examination, gene expression of nuclear factor 2, nuclear factor kappa beta (NF kappaB) and western blot of NF-kappaB p65, assessment of glutathione peroxidase and nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase by ELISA, as well as immunohistochemical evaluation of inducible nitric oxide, malondialdehyde, 8-hydroxy 2 deoxyguanine and vitamin D receptor, have been carried out. RESULTS:: The kidney function deterioration, tissue oxidative stress development and the histopathological changes induced by GM were significantly attenuated by vitamin D administration. CONCLUSION:: Vitamin D attenuates GM nephrotoxicity through its antioxidant properties and prevention of DNA damage. PMID- 30458644 TI - Multistage delivery of CDs-DOX/ICG-loaded liposome for highly penetration and effective chemo-photothermal combination therapy. AB - Nanoparticles (NPs) have proven to be effective drug carriers in diagnosis and therapy of cancer. But, they faced a contradictory issue that NPs with large size appear weak tumor penetration, meanwhile small size resulted in poor tumor retention. Herein, we fabricated doxorubicin conjugated carbon dots (CDs-DOX) and indocyanine green (ICG)-loaded liposomes (ICG-LPs) named CDs-ICG-LPs using a modified reverse phase evaporation process, and with high incorporation in the aqueous core. The CDs-ICG-LPs exhibited good monodispersity, excellent fluorescence/size stability, and consistent spectra characteristics compared with free ICG or DOX. Moreover, the CDs-ICG-LPs showed higher temperature response, faster DOX release under laser irradiation. In the meantime, the fluorescence of DOX and ICG in CDs-ICG-LPs was also visualized for the process of subcellular location in vitro. In comparison with chemo or photothermal treatment alone, the combined treatment of CDs-ICG-LPs with laser irradiation synergistically induced the apoptosis and death of DOX-sensitive HepG2 cells. In vivo antitumor activities demonstrated CDs-ICG-LPs could reach higher antitumor activity compared with CDs-DOX and ICG-LPs for H22 tumor cells, and suppressed H22 tumor growth in vivo. Notably, no systemic toxicity occurrence was observed after repeated dose of CDs-ICG-LPs with laser irradiation. Hence, the well-defined CDs ICG-LPs exhibited great potential in targeting cancer imaging and chemo photothermal therapy. PMID- 30458645 TI - The profile analysis of circular RNAs in human placenta of preeclampsia. AB - IMPACT STATEMENT: The abnormal expression of many regulatory factors may be involved in the development of PE. circRNAs are proved to have a series of important biological functions; however, reports about circRNA and PE are rare. In this work, we evaluated the profile analysis of circRNAs in human placenta of PE by RNA-seq and found some newly differentially expressed circRNAs which might be involved in PE. Combined with bioinformatics analysis, their possible functions were preliminarily discussed. PMID- 30458646 TI - A scientist engineer's contribution to therapeutic discovery and development. AB - IMPACT STATEMENT: Many untreated diseases are not monogenic and are instead caused by multiple genetic defects. Because of this complexity, computational, logical, and systems understanding will be essential to discovering novel therapies. The scientist engineer is uniquely disposed to use this type of understanding to advance therapeutic discovery. This work highlights benefits of the scientist engineer perspective and underscores the potential impact of these approaches for future therapeutic development. By framing the scientist engineer's tool set and increasing awareness about this approach, this article stands to impact future therapeutic development efforts in an age of rising development costs and high drug attrition. PMID- 30458647 TI - A systematic review of measures of adherence to physical exercise recommendations in people with stroke. AB - OBJECTIVE:: To review methods for measuring adherence to exercise or physical activity practice recommendations in the stroke population and evaluate measurement properties of identified tools. DATA SOURCES:: Two systematic searches were conducted in eight databases (MEDLINE, CINAHL, PsycINFO, Cochrane Library of Systematic Reviews, Sports Discus, PEDro, PubMed and EMBASE). Phase 1 was conducted to identify measures. Phase 2 was conducted to identify studies investigating properties of these measures. REVIEW METHODS:: Phase 1 articles were selected if they were published in English, included participants with stroke, quantified adherence to exercise or physical activity recommendations, were patient or clinician reported, were defined and reproducible measures and included patients >18 years old. In phase 2, articles were included if they explored psychometric properties of the identified tools. Included articles were screened based on title/abstract and full-text review by two independent reviewers. RESULTS:: In phase 1, seven methods of adherence measurement were identified, including logbooks ( n = 16), diaries ( n = 18), 'record of practice' ( n = 3), journals ( n = 1), surveys ( n = 2) and questionnaires ( n = 4). One measurement tool was identified, the Physical Activity Scale for Individuals with Physical Disabilities ( n = 4). In phase 2, no eligible studies were identified. CONCLUSION:: There is not a consistent measure of adherence that is currently utilized. Diaries and logbooks are the most frequently utilized tools. PMID- 30458648 TI - Partnership Processes to Develop SHE Tribe: A Healthy Lifestyle Intervention. AB - Chronic diseases, like diabetes and heart disease, disproportionately impact women of color as compared to White women. Community-engaged and participatory approaches are proposed as a means to address chronic disease health disparities in minority communities, as they allow for tailoring and customization of strategies that align with community needs, interests, and priorities. While community-based participatory research (CBPR) is a framework that offers a clear set of principles to guide intervention design and development, the complexity and diversity of community contexts make it challenging to anticipate all of the possible pathways to implementation. This article describes the application of CBPR principles in the design and development of SHE Tribe (She's Healthy and Empowered), a social network-based healthy lifestyle intervention intended to promote the adoption of sustainable health behaviors in underserved communities. Practical and specific strategies are described to aid practitioners, researchers, and community partners as they engage in community-academic partnerships. These strategies uncover some of the inner workings of this partnership to promote trust and collaboration and maximize partner strengths, with the aim to aid others with key elements and practical steps in the application of participatory methods. PMID- 30458649 TI - Sexually Dimorphic Faciometrics in Black Racial Groups From Early Adulthood to Late Middle Age. AB - An increasing body of research focusing on gender-related traits has utilized faciometrics in order to consider sexual dimorphism: Aspects as diverse as social heuristics, facial attractiveness, sexual orientation, aggression, and trustworthiness have all been investigated. However, the majority of these studies have tended to focus on White or Caucasian student populations and have paid little regard to either older populations or racial background. The current study therefore investigated sexual dimorphism in 450 participants (225 women) from a Black population across four age groups (20s, 30s, 40s, and 50s). In line with much previous research using White or Caucasian faces, the expected sexual dimorphism was seen in the younger age-group in three of the four indices (cheekbone prominence, facial width to lower facial height, and lower face height to full face height). However, consistent with more recent literature, the facial width to height ratio (fWHR) was not found to be significantly different between men and women in this age-group. Contrary to previous research, when considering broader age groups, the three established measures of facial sexual dimorphism, when looked at independently, remained static over time, but this was not true for fWHR. It is concluded that facial structure does not follow the same aging trajectory in all populations and care should be taken in choice of facial metric, depending on the nature of the sample under investigation. PMID- 30458650 TI - Hydrogeological responses in tropical mountainous springs. AB - This study presents a hydrogeochemical analysis of spring responses (2013-2017) in the tropical mountainous region of the Central Valley of Costa Rica. The isotopic distribution of delta18O and delta2H in rainfall resulted in a highly significant meteoric water line: delta2H = 7.93.delta18O + 10.37 (r2 = 0.97). Rainfall isotopic composition exhibited a strong amount-dependent seasonality. The isotopic variation (delta18O) of two springs within the Barva aquifer was simulated using the FlowPC program to determine mean transit times (MTTs). Exponential-piston and dispersion distribution functions provided the best-fit to the observed isotopic composition at Flores and Sacramento springs, respectively. MTTs corresponded to 1.23 +/- 0.03 (Sacramento) and 1.42 +/- 0.04 (Flores) years. The greater MTT was represented by a homogeneous geochemical composition at Flores, whereas the smaller MTT at Sacramento is reflected in a more variable geochemical response. The results may be used to enhance modelling efforts in central Costa Rica, whereby scarcity of long-term data limits water resources management plans. PMID- 30458651 TI - Prenatal diagnosis of cervical masses by magnetic resonance imaging and 3D virtual models: perinatal and long-term follow-up outcomes. AB - OBJECTIVE: To assess perinatal and long-term follow-up outcomes of fetal cervical masses diagnosed by three-dimensional (3D) magnetic resonance imaging (MRI) and 3D virtual models. METHODS: This retrospective cohort study evaluated 15 pregnant women (age, 21-38 years) at 29-40 weeks of singleton gestation, whose fetuses exhibited congenital oral and cervical masses. These women were referred to our facility because of suspected fetal malformations on routine obstetric ultrasound, and the cases were confirmed, excluded, or complemented by MRI. Demographic data and perinatal and long-term follow-up outcomes were assessed. RESULTS: Cervical masses were predominant in females (3:2), and the most frequent diagnosis was lymphatic-venous malformation (71%). The masses were cystic in 53.3% of the cases and solid in 46.7%. The esophagus and trachea were displaced in 46.6% of the cases. Associated malformations were diagnosed in 13.3% of the cases. There was complete agreement between prenatal MRI and postnatal diagnoses. Among the newborns, 40% had complications and 46.6% were admitted to the neonatal intensive care unit. Two infants died from complications due to epignathus. Surgical resection was performed in 33.3% of the cases, including complete resection in 26.6%. Sclerotherapy was administered to 53.3% of the cases, with complete remission achieved in 50% of these cases. CONCLUSION: Cervical masses diagnosed in the prenatal period had good postnatal outcomes except for cases of epignathus, which were associated with high mortality. MRI demonstrated the relationship between cervical masses and adjacent organs and allowed 3D virtual reconstruction of the airways. There was complete agreement between the prenatal diagnosis of cervical masses on MRI and postnatal diagnosis. Surgical treatment was effective in most cases, and sclerotherapy was satisfactory in cases with intrathoracic components. PMID- 30458652 TI - Prevention of preeclampsia in high-risk patients with low-molecular-weight heparin: a meta-analysis. AB - OBJECTIVE: To assess the secondary preventive effect of low-molecular-weight heparin (LMWH) on pregnant women with prior early-onset or severe preeclampsia (PE). METHODS: A systematic literature search of several databases was conducted for randomized controlled trials comparing LMWH with either aspirin or no treatment in pregnant women at a high risk of placental-mediated pregnancy complications (PMPCs). Odds ratios and associated 95% confidence intervals (CI) and weighted mean differences and 95% CI were calculated. RESULTS: Seven studies including 1035 patients were evaluated. These studies showed a risk reduction in composite PMPC outcome (relative risk (RR) 0.635 (95% CI: 0.436-0.925); p=.018), PE (RR 0.522 (95% CI: 0.334-0.815); p=.004), a small-for-gestational-age neonate (RR 0.622 (95% CI: 0.440-0.880); p=.007), and an increase in gestational length (SMD 0.312 (95% CI: 0.017-0.607); p=.038) and neonatal weight (SMD 0.428 (95% CI: 0.066-0.791); p=.020). CONCLUSIONS: LMWH has a secondary preventive effect on early or severe PE and improves neonatal outcomes. In the future, additional large multicenter studies will need to focus on high-risk PE groups by more accurate screening to obtain more information before clinical application. PMID- 30458654 TI - Seroepidemiological study of cystic echinococcosis in nomadic communities in the southwest of Iran: A population-based study. AB - The current study aimed at the seroepidemiological survey of human cystic echinococcosis (CE) in nomadic people in Boyer-Ahmad District in the southwest of Iran. One thousand and five nomads were selected by cross-sectional sample collection in nomadic tribes of Boyer-Ahmad District in the southwest of Iran. Blood samples were taken from each individual, and the sera were tested for detection of anti-hydatid cyst antibodies using antigen B-ELISA. A predesigned questionnaire which contained basic epidemiological and individual information related to hydatid cyst was filled for each subject during sample collecting. Subjects of the study were 227 males (22.6%) and 778 (77.4%) females. The mean age of the participants was 40.4 years old (+/-16.6). Anti-hydatid cyst antibodies were detected in 81 (8.1%) of the subjects. Seroprevalence rate for CE in females (9%) was more than males (4.8%). Multivariate logistic regression revealed significant associations between CE seropositivity and sex (odds ratio [OR] = 1.88; 95% confidence interval [CI] = 0.93-3.80) and dog ownership (OR = 8.3; 95% CI = 3.94-16.37). The rate of infection with CE in nomadic people in southwest of Iran is considerable. Treatment of dogs and increasing the level of people awareness may contribute a substantial advancement in the control of the disease in the area. PMID- 30458653 TI - Metformin-treated-GDM has lower risk of macrosomia compared to diet-treated GDM- A retrospective cohort study. AB - BACKGROUND: The diagnosis of gestational diabetes (GDM) has undergone several revisions. The broad adoption of the 2013 WHO criteria for hyperglycaemia in pregnancy has increased the prevalence of GDM with no apparent benefit on pregnancy outcomes. The study aims to investigate the pregnancy outcomes in women with GDM diagnosed based on the WHO criteria compared to a control group; the impact of other confounders; and the difference in outcomes between GDM women who needed pharmacotherapy (GDM-T) and those who did not (GDM-D) Methods: This is a retrospective cohort study that included GDM women compared to normoglycaemic controls between March 2015-December 2016 in the Women's Hospital, Qatar. RESULTS: The study included 2221 women; of which 1420 were normoglycaemic, and 801 were GDM (358 GDM-D and 443 GDM-T). At conception, GDM women were older (mean age 32.5 +/- 5.4 versus 29.6 +/- 5.6 years, p < 0.001) and had higher prepregnancy BMI (mean BMI 32.2 +/- 6.2 versus 28.2 +/- 6.1, kg/m2, p < 0.01) compared to the controls, respectively. After correction for age, prepregnancy weight, and gestational weight gain (GWG) ; women with GDM had a higher risk of preterm labour (OR 1.72; 95% CI 1.32-2.23), large for gestational age (OR 1.67; 95% CI 1.22-2.29), neonatal ICU admission (OR 1.57; 95% CI 1.15-2.13), and neonatal hypoglycaemia (OR 3.22; 95% CI 2.06-5.03). At conception, GDM-T women were older (mean age 33.3 +/- 5.0 versus 31.5 +/- 5.7 years, p < 0.001) and had higher BMI (mean BMI 32.9 +/- 6.3 versus 231.2 +/- 6.0, kg/m2, p,0.01) compared to GDM-D, respectively. Metformin was used in 90.7% of the GDM-T women. Women in the GDM-T group had lower GWG/week compared to GDM-D (-0.01 +/- 0.7 versus 0.21 +/- 0.51 kg/week; p < 0.001). After correcting for age, prepregnancy weight and GWG; GDM-T had higher risk of preterm labour (OR 1.66; 95% CI 1.20-2.22), and C section (OR 1.37, 95% CI 1.02-1.85) and reduced risk of macrosomia (OR 0.56; 95% CI 0.32-0.96) and neonatal hypoglycaemia (OR 0.49; 95% CI 0.28-0.82). CONCLUSION: In addition to hyperglycaemia, the adverse effects of GDM on pregnancy outcomes are multifactorial and includes maternal age, maternal obesity, and gestational weight gain. Treatment with metformin reduces maternal weight gain, the risk of macrosomia and neonatal hypoglycaemia compared to diet alone. PMID- 30458655 TI - Citrulline Malate Fails to Improve German Volume Training Performance in Healthy Young Men and Women. AB - Citrulline malate (CM) is purported to buffer lactic acid, enhance oxygen delivery, and attenuate muscle soreness. Anaerobic exercise trials with CM have produced conflicting results. The aim of the current investigation was to test the efficacy of CM on resistance training (RT) with the hypothesis that CM would improve performance. A double-blind, counter-balanced, randomized control trial was utilized to assess the effects of CM on RT. Nineteen participants (8 female) (25.7 +/- 7.7 years), regularly engaged in RT, consumed either 8 g of CM (1.1:1 ratio) or a placebo (6 g citric acid). Participants attempted to perform a German Volume Training (GVT) protocol comprising 10 sets of 10 repetitions of barbell curls at 80% of their one repetition maximum. Repeated ANOVA suggested no effect of CM on RT performance (treatment * time * order p = .217). There was no difference (p = .320) in the total number of reps over the 10 sets (CM median = 57, IQR 45-73; placebo median = 61, IQR 51-69). Blood lactate and creatine kinase did not differ between CM and placebo (p > .05). Finally, total muscle soreness was reduced significantly in CM compared to placebo (treatment * time * order p = .004). These results require corroboration; an ergogenic benefit is yet to be established, and weight trainers should exercise caution when assessing the efficacy of CM. Future research should focus on the potential effects of loading doses of CM. PMID- 30458656 TI - Xanthohumol, a hop-derived prenylflavonoid present in beer, impairs mitochondrial functionality of SW620 colon cancer cells. AB - Xanthohumol (XN) is a hop-derived prenylflavonoid and have been reported to exhibit anticancer properties in several types of cancer. It presents a great interest against colon cancer due to high exposure of this compound in this tissue. Metastatic SW620 cell line was treated with doses ranging from 0.001 to 10 uM of XN to assess their effects on cell viability and mitochondrial function. At low concentrations, XN had no effect on assays carried out, but high concentration of XN led to a decrease in cell viability. In addition, at 10 MUM XN, it gave rise to an increase in ROS production accompanied by a decrease in OXPHOS complexes and sirtuin 1 protein expression levels. These results suggest that XN could act as a mitocan and impairs mitochondrial function. PMID- 30458658 TI - TIP41 network analysis and mutant phenotypes predict interactions between the TOR and ABA pathways. AB - Environmental conditions inform the rate of plant growth and development. The target of rapamycin (TOR) signalling pathway is a central regulator of plant growth in response to nutrients and energy, while abscisic acid (ABA) is a main mediator of abiotic stress responses. We recently characterized Arabidopsis TIP41, a predicted TOR pathway component involved in the ABA-mediated response to abiotic stress. Here, we report the ABA sensitivity of tip41 mutants, supporting the relation between TIP41 and the hormone pathway. The analysis of predicted TIP41 functional network identified several protein phosphatases. In particular, candidate protein interactors included catalytic subunits of type 2A protein phosphatases and protein phosphatases 6, which regulate different developmental processes and responses to environmental stimuli. These results provide important information on the role of TIP41 in the cross talk between TOR and ABA pathways. PMID- 30458657 TI - Clinical Use and Efficacy of Levetiracetam for Absence Epilepsies. AB - BACKGROUND:: Levetiracetam is prescribed for a broad spectrum of seizure types but does not have a specific indication for absence epilepsy. We hypothesized that levetiracetam is commonly prescribed for children with absence epilepsies and evaluated the efficacy of this medication for absence epilepsy treatment in clinical practice. We also hypothesized that electroencephalographic (EEG) findings could help predict levetiracetam efficacy. METHODS:: We reviewed the charts of all patients treated for new-onset absence epilepsies at our pediatric neurology clinic between January 2011 and January 2016. Among 158 children diagnosed with absence epilepsies, 72 were treated with levetiracetam. RESULTS:: Levetiracetam was discontinued in 74% (n = 53/72) because of incomplete seizure control (59%, n = 35/72) and/or intolerable side effects (41%, n = 24/72) after a median 8.5 months (interquartile range 2, 17 months). Among patients for whom levetiracetam was effective, 44% (n = 8/18) had polyspikes on their initial EEG, versus 27% (n = 14/52) of patients for whom levetiracetam was discontinued ( P = .17). The maximal prescribed dose was lower for children in whom levetiracetam was effective (29 +/- 13 mg/kg/d) than those for whom levetiracetam failed (42 +/ 20 mg/kg/d; P = .005). CONCLUSION:: In routine clinical practice, levetiracetam is often chosen for patients with absence seizures. However, only about one quarter of children with absence epilepsy in this study became seizure free with levetiracetam. When effective, levetiracetam can control absence epilepsy at a relatively low dose. Lack of seizure control requiring continued dose escalation should prompt early consideration of a therapeutic medication transition. PMID- 30458659 TI - Structural and bone marrow stem cell biocompatibility studies of hydrogel synthesized via chemo-enzymatic route. AB - Natural biopolymers have many attractive medical applications; however, complications due to fibrosis caused a reduction in diffusion and dispersal of nutrients and waste products. Consequently, severe immunocompatibility problems and poor mechanical and degradation properties in synthetic polymers ensue. Hence, the present study investigates a novel hydrogel material synthesized from caprolactone, ethylene glycol, ethylenediamine, polyethylene glycol, ammonium persulfate, and tetramethylethylenediamine via chemo-enzymatic route. Spectroscopic analyses indicated the formation of polyurea and polyhydroxyurethane as the primary building block of the hydrogel starting material. Biocompatibility studies showed positive observation in biosafety test using direct contact cytotoxicity assay in addition to active cellular growth on the hydrogel scaffold based on fluorescence observation. The synthesized hydrogel also exhibited (self)fluorescence properties under specific wavelength excitation. Hence, synthesized hydrogel could be a potential candidate for medical imaging as well as tissue engineering applications as a tissue expander, coating material, biosensor, and drug delivery system. PMID- 30458660 TI - Fetal pancreatic hyperechogenicity may be an early ultrasonographic sign of gestational diabetes mellitus. AB - AIM: To determine whether fetal pancreatic echogenicity assessment is associated with gestational diabetes mellitus (GDM). METHODS: A prospective cross-sectional study was conducted in a cohort of 160 pregnant women with uncomplicated singleton pregnancies. Fetal ultrasonography was performed between 24 and 28 weeks of gestation for conventional fetal biometry. Based on their pancreatic sonogram results, subjects were divided into two groups ie hyperechogenic pancreas group and iso-moderate echogenic pancreas group. Birth characteristics (mode of delivery) and fetal outcomes (gestational age at birth, fetal gender, birth length and weight, Apgar for 1. Versus 5. Minutes) were recorded and the relationship between pancreatic hyperechogenicity and presence of GDM was assessed. RESULTS: Sixty-six cases with hyperechogenic pancreas (group 1) and 70 cases with iso-moderate echogenic pancreas (group 2) were included to the study. There were no significant differences in maternal demographic and obstetric features between the groups. Fetal birth weight and length were significantly higher in the hyperechogenic pancreas group (p < 0.0001, p = 0.013; respectively). Hyperechogenic pancreas was significantly and positively associated with GDM risk. Hyperechogenic pancreas was significantly and positively associated with an increased GDM risk by 29.8 times compared to grade 1 isoechogenic group (p < 0.0001). CONCLUSION: An accurate prediction model for GDM among pregnant women via hyperechogenic pancreas may be created. Fetal hyperechogenic pancreas may be used as a complementary biomarker for the detection of pregnant women suspected of GDM. PMID- 30458661 TI - Multi-drug resistance protein 2 (MRP2) expression, adjuvant tamoxifen therapy, and risk of breast cancer recurrence: a Danish population-based nested case control study. AB - BACKGROUND: Adjuvant tamoxifen therapy approximately halves the risk of recurrence in estrogen receptor-positive (ER+) breast cancer patients, but many women respond insufficiently to therapy. Expression of multi-drug resistance protein 2 (MRP2) in breast cancer may potentiate tamoxifen resistance. Thus, we investigated the expression of MRP2 in breast cancer as a predictor of tamoxifen therapy effectiveness. MATERIAL AND METHODS: We conducted a case-control study nested in the Danish Breast Cancer Group clinical database. The study included women aged 35-69 years diagnosed with stage l-lll breast cancer during 1985-2001, in Jutland, Denmark. We identified 541 recurrent breast cancers (cases) among women with estrogen receptor positive (ER+) disease treated with tamoxifen for at least 1 year (ER+/TAM+) and 300 cases among women with estrogen receptor-negative (ER-) disease, never treated with tamoxifen (ER-/TAM-). We matched one recurrence free control to each recurrent case. We retrieved paraffin-embedded primary tumor tissue for all patients, and all available recurrent tumor tissue from pathology archives. MRP2 expression was evaluated using immunohistochemistry. We computed odds ratios (ORs) and 95% confidence intervals (95% CIs) associating MRP2 expression (positive vs. none) with breast cancer recurrence in conditional logistic regression models. We compared MRP2 expression in paired primary- and recurrent tumors. RESULTS: MRP2 expression was more prevalent in the ER+/TAM + group, than in the ER-/TAM - group. No predictive utility of MRP2 for breast cancer recurrence was found in the ER+/TAM + group (ORadj = 0.96, 95% CI 0.70, 1.33). Further, no prognostic utility was found in the ER-/TAM - group (ORadj = 0.81, 95% CI 0.53, 1.23). MRP2 expression was not increased in recurrent versus primary tumors. CONCLUSIONS: MRP2 expression is neither a predictive marker of tamoxifen effectiveness nor a prognostic marker in breast cancer. PMID- 30458662 TI - Delineating the Clinical Spectrum Associated With Xq25q26.2 Duplications: Report of 2 Families and Review of the Literature. AB - To date, 13 patients with interstitial microduplications involving Xq25q26.2 have been reported. Here, we report 6 additional patients from 2 families with duplications involving Xq25q26.2. Family I carries a 5.3-Mb duplication involving 26 genes. This duplication was identified in 3 patients and was associated with microcephaly, growth failure, developmental delay, and dysmorphic features. Family II carries an overlapping 791-kb duplication that involves 3 genes. This duplication was identified in 3 patients and was associated with learning disability and speech delay. The size and gene content of published overlapping Xq25q26.2 duplications vary, making it difficult to define a critical region or establish a genotype-phenotype correlation. However, patients with overlapping duplications have been found to share common clinical features including microcephaly, growth failure, intellectual disability, learning difficulties, and dysmorphic features. The 2 families presented here provide additional insight into the phenotypic spectrum and clinical significance of duplications in this region. PMID- 30458663 TI - In vitro performance of a nanobiocomposite scaffold containing boron-modified bioactive glass nanoparticles for dentin regeneration. AB - Every year, many dental restoration methods are carried out in the world and most of them do not succeed. High cost of these restorations and rejection possibility of the implants are main drawbacks. For this reason, a regenerative approach for repairing the damaged dentin-pulp complex or generating a new tissue is needed. In this study, the potential of three-dimensional cellulose acetate/oxidized pullulan/gelatin-based dentin-like constructs containing 10 or 20% bioactive glass nanoparticles was studied to explore their potential for dentin regeneration. Three-dimensional nano biocomposite structures were prepared by freeze-drying/metal mold pressing methods and characterized by in vitro degradation analysis, water absorption capacity and porosity measurements, scanning electron microscopy, in vitro biomineralization analysis. During one month incubation in phosphate buffered saline solution at 37 degrees C, scaffolds lost about 25-30% of their weight and water absorption capacity gradually decreased with time. Scanning electron microscopy examinations showed that mean diameter of the tubular structures was about 420 um and the distance between walls of the tubules was around 560 um. Calcium phosphate precipitates were formed on scaffolds surfaces treated with simulated body fluid, which was enhanced by boron-modified bioactive glass addition. For cell culture studies human dental pulp stem cells were isolated from patient teeth. An improvement in cellular viability was observed for different groups over the incubation period with the highest human dental pulp stem cells viability on B7-20 scaffolds. ICP OES analysis revealed that concentration of boron ion released from the scaffolds was between 0.2 and 1.1 mM, which was below toxic levels. Alkaline phosphatase activity and intracellular calcium amounts significantly increased 14 days after incubation with highest values in B14-10 group. Von Kossa staining revealed higher levels of mineral deposition in these groups. In this work, results indicated that developed dentin-like constructs are promising for dentin regeneration owing to presence of boron-modified bioactive glass nanoparticles. PMID- 30458664 TI - Brain Volumetric Correlates of Right Unilateral Versus Bitemporal Electroconvulsive Therapy for Treatment-Resistant Depression. AB - The selection of a bitemporal (BT) or right unilateral (RUL) electrode placement affects the efficacy and side effects of ECT. Previous studies have not entirely described the neurobiological underpinnings of such differential effects. Recent neuroimaging research on gray matter volumes is contributing to our understanding of the mechanism of action of ECT and could clarify the differential mechanisms of BT and RUL ECT. To assess the whole-brain gray matter volumetric changes observed after treating patients with treatment-resistant depression with BT or RUL ECT, the authors used MRI to assess 24 study subjects with treatment resistant depression (bifrontotemporal ECT, N=12; RUL ECT, N=12) at two time points (before the first ECT session and after ECT completion). Study subjects receiving BT ECT showed gray matter volume increases in the bilateral limbic system, but subjects treated with RUL ECT showed gray matter volume increases limited to the right hemisphere. The authors observed significant differences between the two groups in midtemporal and subcortical limbic structures in the left hemisphere. These findings highlight that ECT-induced gray matter volume increases may be specifically observed in the stimulated hemispheres. The authors suggest that electrode placement may relevantly contribute to the development of personalized ECT protocols. PMID- 30458665 TI - Profile of Anger in Acute Stroke: A Multifactorial Model of Anger Determinants. AB - Higher levels of anger can have a major impact on treatment and recovery among stroke patients. The authors identified the presence of anger in patients with acute stroke, as well as state and trait anger and anger expression and control, and analyzed its association with demographic, clinical, brain lesion, and psychosocial variables. The authors screened anger prospectively in 114 consecutive patients by using the State-Trait Anger Expression Inventory-2, which enabled them to distinguish between the experience, expression, and control of anger. State anger was detected in 21 (18%) patients, whereas trait anger was present in 22 patients (20%). The best regression model revealed that age, hypertension, complaints about environment, anxiety symptoms, and disability were independent predictive factors for anger (R2=54%). Anger appears to be explained by prestroke variables such as age, hypertension, and the profile of anger, stroke itself as a sudden and potentially disabling condition, the environment, and the psychological and functional consequences of stroke. PMID- 30458666 TI - Effects of extracellular ATP on local and systemic responses of bean (Phaseolus vulgaris L) leaves to wounding. AB - Wounding increased the extracellular Adenosine 5'-triphosphate (eATP) level of kidney bean leaves. Treatment with wounding or exogenous ATP increased the hydrogen peroxide (H2O2) content, activities of catalase and polyphenol oxidase, and malondialdehyde content in both the treated and systemic leaves. Pre treatment with ATP-degrading enzyme, apyrase, to the wounded leaves reduced the wound-induced local and systemic increases in H2O2 content, activities of catalase and polyphenol oxidase, and malondialdehyde content. Application of dimethylthiourea (DMTU) and diphenylene iodonium (DPI) to the wounded and ATP treated leaves, respectively, reduced the wound- and ATP-induced local and systemic increases in H2O2 content, activities of catalase and polyphenol oxidase, and malondialdehyde content. Moreover, the wound- and ATP-induced systemic increases of these physiological parameters were suppressed when DMTU or DPI applied to leaf petiole of the wounded and ATP-treated leaves. These results suggest that eATP at wounded sites could mediate the wound-induced local and systemic responses by H2O2-dependent signal transduction. PMID- 30458667 TI - Biomechanics and wear comparison between mechanical and kinematic alignments in total knee arthroplasty. AB - The uses of mechanical and kinematic alignments in total knee arthroplasty are under debate in recent clinical investigations. In this study, the differences in short-term biomechanics and long-term wear volume between mechanical and kinematic alignments in total knee arthroplasty were investigated, based on a subject-specific musculoskeletal multi-body dynamics model during walking gait simulation. An increase of 8.2% in the peak tibiofemoral medial contact force, a posterior contact translation by maximum 4.7 mm and a decrease of 5.5% in the wear volume after a 10-million-cycle simulation were predicted in the kinematic alignment, compared with the mechanical alignment. Nevertheless, the tibiofemoral contact mechanics, the range of motions and the long-term wear were not markedly different between mechanical and kinematic alignments. Furthermore, the mechanical alignment with a posterior tibial slope similar to that under the kinematic alignment was found to produce similar anterior-posterior translation and the range of motion, and an approximate wear volume, compared with the kinematic alignment. The ligament forces under the kinematic alignment were influenced markedly by as much as 25%, 50% and 77% for the medial collateral ligament, lateral collateral ligament and posterior cruciate ligament forces, respectively. And, a maximum increase of 40% for patellofemoral contact force was predicted under the kinematic alignment. These findings suggest that the kinematic alignment is an alternative alignment principle but no marked advantages in biomechanics and wear to the mechanical alignment. The adverse effects of the kinematic alignment on patella loading and soft tissue forces should be noticed. PMID- 30458668 TI - Physical Performance and Fall Risk in Persons With Traumatic Brain Injury. AB - Injuries sustained from traumatic brain injury (TBI) culminate in both cognitive and neuromuscular deficits. Patients often progress to higher functioning on the Rancho continuum even while mobility deficits persist. Although prior studies have examined physical performance among persons with chronic symptoms of TBI, less is known about the relatively acute phase of TBI as patients prepare for rehabilitation discharge. The aims of this cross-sectional study were to (a) compare balance and gait performance in 20 ambulant persons with moderate to severe TBI who were nearing rehabilitation discharge with their age-matched controls and (b) describe performance with thresholds for fall risk and community navigation. During a designed task circuit, 40 participants (20 persons with TBI and 20 controls) performed the Timed Up and Go (TUG), gait velocity, and Walking and Remembering tests. Balance testing included the Fullerton Advanced Balance Scale (FABS) and instrumented Modified Clinical Test for Sensory Interaction in Balance (MCTSIB). Statistical analyses included analysis of covariance for group comparisons and a multivariate analysis of covariance for MCTSIB sway velocities with anthropometric controls. The TBI group (mean [ M] age = 42, standard deviation [ SD] =19.5 years; 70% males) performed significantly more poorly on all mobility tests ( p < .05) and their scores reflected a potential fall risk. Gait velocity was significantly slower for the TBI versus control group ( M = .96, SD = 2.6 vs. M = 1.5, SD = 2.2 m/s; p < .001), including TUG times ( M = 13.5, SD = 4.9 vs. M = 7.7, SD = 1.4; p < .001). TBI participants also demonstrated significantly greater sway velocity on all MCTSIB conditions ( p < .01) and lower performance on the FABS ( p < .001). Performance indices indicate potential fall risk and community navigation compromise for individuals with moderate to severe TBI. Physical performance scores support the need for continued interventions to optimize functional mobility upon discharge. PMID- 30458669 TI - Initial balance in human standing postures: Roles of the joint mechanisms. AB - The static initial postures of standing before applying perturbations may affect the maintenance of postural balance. The goal of this article was to find the stable set of postures and then determine the roles of joint mechanisms. The set of posture was defined in a biomechanical model based on three joint angles of the lower limbs. Optimized inverse dynamics method was used to solve for muscle forces in a precise model of the human musculoskeletal system posed in 4096 static sets of posture using AnyBody software. Results showed that the overall body muscular activity in standing is reduced by knee flexion. Moderate knee angles between 20 degrees and 60 degrees provided safer postures against possible perturbations because of higher collaboration levels of the joint mechanisms. About 36% of the overall postural infeasibilities were attributed to the inability of the ankle muscles to more sustain the exerted loads. Although the roles of the joint mechanisms were closely dependent on the postures, there was no direct relation between the joint kinematics and activation levels of their supporting muscles. Lower extremity muscle groups collaborate to maintain the balance in a considerable number of static postures. PMID- 30458670 TI - A Canadian Academic Hospital's Initial MAID Experience: A Health-Care Systems Review. AB - BACKGROUND:: Following the Supreme Court of Canada's Carter Decision, medical assistance in dying (MAID) became possible with individual court orders in February 2016. Subsequently, on June 17, 2016, legislation was passed that eliminated the need for court orders, essentially making physicians the arbiters of these requests. Canadian health-care facilities now face the challenge of addressing this unprecedented patient health-care need. AIM:: To describe the manner in which London Health Sciences Center has approached local and regional requests for MAID, including the administration, ethics, privacy, and clinical process. DESIGN:: A health-care systems descriptive study. SETTING/PARTICIPANTS:: Between June 6, 2016, and May 30, 2018, London Health Sciences Center's MAID Internal Resource Committee triaged and referred 260 cases. Ninety-six received the requisite assessments were deemed eligible for and received MAID. RESULTS:: The procedure was completed in hospital 59 (61%) times, and 37 (39%) times in the community (either private residence or long-Term Care facility). Nineteen patients did not meet MAID criteria and 63 patients died while awaiting the procedure. The median wait time between first request and referral was 1 day. The median time between referral and the procedure was 12.0 days. The ratio of referrals to completed cases is 96 of 260 (or 37% conversion rate). CONCLUSION:: Our MAID processes, including our committee structure, referral triage process, and physical site have all undergone extensive review and improvement cycles throughout these first 2 years with the aim of ensuring that this procedure is managed in a respectful, confidential, safe, efficient, and patient-centered manner. PMID- 30458672 TI - High Tie or not in Resection for Cancer in the Sigmoid Colon? AB - BACKGROUND AND AIMS:: The optimal extent of mesenteric resection in colon cancer surgery remains elusive. The aim was to assess the impact on perioperative morbidity and oncological outcome depending on the height of central vessel ligation in sigmoid resection for adenocarcinomas. MATERIAL AND METHODS:: All cases of stage I-III sigmoid cancers, operated on with locally radical resections (2007-2009), were identified in the Swedish Colorectal Cancer Registry and categorized according to the position of the vascular ligature, that is, ligation of the inferior mesenteric artery, ligation of the superior rectal artery, or ligation of the sigmoid branches. RESULTS:: In total, 999 cases were identified and possible to categorize. Although higher ligation level yielded a higher number of lymph nodes, 3- or 5-year overall survival, 5-year disease-free survival, or recurrence rate did not differ between the groups (p = 0.79, p = 0.41, p = 0.67, p = 0.51). No differences in survival were detected after multivariate analysis adjusted for age, sex, T-stage, N-stage, American Society of Anesthesiologists classification, and adjuvant therapy. CONCLUSION:: This large population-based study showed increased lymph node yield but no survival benefit or any decreased recurrence rate by high tie in resection of sigmoid cancer. PMID- 30458671 TI - Endosperm enzyme activity is responsible for texture and eating quality of cooked rice grains in Japanese cultivars. AB - Eating quality of cooked rice grains is an important determinant of its market price and consumer acceptance. To comprehensively assess the variation of eating quality traits in 152 Japanese rice cultivars, we evaluated activities of eight endosperm enzymes related to degradation of starch and cell-wall polysaccharides. Endosperm enzyme activities showed a wide range of variations and were lower in recently developed cultivars than in landraces and old improved cultivars. Activities of most endosperm enzymes correlated significantly with the eating quality score and surface texture of cooked rice grains. Principal component analysis revealed that rice cultivars with high eating-quality scores had high stickiness of the grain surface and low levels of endosperm enzyme activities. These results suggest that endosperm enzyme activities control texture and eating quality of cooked rice grains in Japanese rice cultivars. PMID- 30458673 TI - Psychometric Properties of the Expanded Version of the Inventory of Depression and Anxiety Symptoms in a Turkish Population. AB - The study examined psychometric properties of the Turkish version of the Inventory of Depression and Anxiety Symptoms-II (IDAS-II) in a Turkish sample. The sample consisted of nonclinical ( N = 931) and clinical ( N = 208) individuals. Confirmatory factor analysis showed that Turkish IDAS-II was similar to the original IDAS-II and supported the construct validity of the test. The Turkish IDAS-II showed good internal consistency, significant acceptable retest correlations, and was sensitive to changes over time. The Turkish IDAS-II also showed good convergent and discriminant validity in relation to the Beck Depression Inventory, the Beck Anxiety Inventory, the Mood Disorder Questionnaire, the Maudsley Obsessive Compulsive Inventory, the Panic Agoraphobia Scale, and the Post-Traumatic Stress Disorder Checklist-Civilian Version. Discriminant analyses revealed that the subscales of the Turkish IDAS-II significantly differentiated healthy controls from outpatients. The Turkish IDAS II is a reliable and valid measure for assessing symptoms of depression and anxiety in Turkish-speaking participants. PMID- 30458674 TI - A Study Evaluating Mindfulness and Naikan-Based Therapy: AEON-HO for Attachment Style, Self-Actualization, and Depression. AB - AEON-HO (Altering emotional organization-holistic operation) contains methods of Naikan therapy and mindfulness. Naikan and mindfulness are originally from Buddhism tradition, and they have a high affinity. AEON-HO was conceptualized to improve attachment issues and the growth of self-actualization, because Naikan and mindfulness are known to be effective for attachment issues but partially if they are used independently. Naikan can approach to attachment avoidance, while mindfulness can approach to attachment anxiety. The primary purpose of this study was to assess the effectiveness of AEON-HO on attachment styles, self actualization, and depression by using "attachment style scale the Experiences in Close Relationships inventory-the generalized-other-version (ECR-GO)," "self actualization scale" translated to Japanese, and "center for epidemiologic studies for depression scale." Participants have taken these three psychological questionnaires before and after the eight-week program of AEON-HO, and the results of scales were compared. Participants were 36 adults with a mean age of 49 years ( SD = 3.9). Changes in two attachment styles, anxiety and avoidance and depressive state, were observed between pre- and posttest, while there were no significant changes in self-actualization. However, attachment anxiety and self actualization were correlated negatively in pre- and posttest, while attachment avoidance and self-actualization were correlated negatively only in pretest. PMID- 30458675 TI - Studying the Human Health and Ecological Impacts of the Deepwater Horizon Oil Spill Disaster (Part 2): Introduction to This Special Issue of New Solutions. AB - This introduction to the special issue continues an examination of the Gulf Coast Health Alliance: Health Risks Related to the Macondo Spill (GC-HARMS) project that began in New Solutions 28:3. GC-HARMS was part of a National Institute of Environmental Health Sciences-funded Gulf-wide consortium that created regional community-university research partnerships addressing health impacts from the oil spill exposures. Findings from this program enhanced regional preparedness and reinforced existing disaster-response networks. This special issue of New Solutions includes an article exploring the outcomes and implications of using a community-based participatory research-citizen science approach in implementing the project's exposure assessment/population health study and another article that describes analytic processes used to characterize toxicity of petrogenic Polycyclic Aromatic Hydrocarbons which provided data used to develop the project's risk message. Finally, this issue includes three Movement Voices interviews from individuals and nonprofits that served as GC-HARMS community hubs during the project. PMID- 30458676 TI - The elephant in the room: How a technology's name affects its interpretation. AB - In this work, using experiments, we investigate the role of the name of a technology on the informed evaluation of that technology. We argue that a name can influence interpretations by activating cognitive structures. Using genomics accelerated breeding as a case, we show that the name 'genomics' makes people evaluate related information as similar to genetic modification. Replacing the name 'genomics' with 'natural crossing' causes evaluations similar to those for traditional breeding. The results show that a name can have a strong influence on public attitudes, and we call for more consideration in choosing a name for a technology. PMID- 30458677 TI - The distinct effect of multiple sources of stereotype threat. AB - Stereotype threat (ST) refers to the risk of confirming a negative stereotype about one's group. Distinct forms of ST can be elicited based on both the target and the source of the threat. Here, we focused on how peculiar ST sources distinctly impact performance for individuals who face self-based threats. More particularly, we hypothesized that the decrease in performance would be stronger for individuals who face a self-concept threat (triggered by a private self evaluation) in comparison with those who face an own-reputation threat (triggered by a public evaluation). In two studies, participants were randomly assigned to one of the following experimental conditions: control, self-concept, or own reputation threat. Results confirmed the hypothesis by showing that participants in the control condition perform better than those in the own-reputation threat condition, who performed better than those in the self-concept threat condition. The contributions of this work as well as the limitations are discussed. PMID- 30458678 TI - Bone Marrow Mesenchymal Stem Cells (BMSCs) Restore Functional Endometrium in the Rat Model for Severe Asherman Syndrome. AB - OBJECTIVE:: To investigate the feasibility to restore functional endometrium using bone marrow mesenchymal stem cells (BMSCs) in the Sprague Dawley (SD["SD" has been defined as both "Sprague Dawley" and "standard deviation." Please clarify which one is to be followed.]) rat model for Asherman syndrome (AS). DESIGN:: Basic research on treatment of AS utilizing an optimized rat model. SETTING:: University research laboratories. ANIMAL(S):: Sprague Dawley rat model in which AS was induced in accordance to an optimized protocol. INTERVENTION(S):: Bone marrow mesenchymal stem cells were harvested from the rat's bone marrow and labeled with green fluorescent protein (GFP) in the second passage of BMSCs. The fifth passage of GFP-labeled BMSCs was injected systemically through the tail vein in the optimized AS rat model. MAIN OUTCOME MEASURE(S):: We examined the reproliferation of the endometrial lining and the expression of markers for endometrium and endometrial receptivity. The localization of engrafted GFP labeled BMSCs was determined by a laser scanning confocal microscope and a fluorescence microscope. The number of pregnant rats and implanted embryos in each uterus was recorded to evaluate the function of endometrium. RESULT(S):: We had demonstrated that in the in vivo experiments on our rat model for AS, the group which received BMSC injection had significantly improved reproductive outcomes-70% of these rats conceived, whereas none of the rats in the control group got pregnant ( P < .01, chi2 test). The mean number of embryos undergoing implantation was 14 +/- 1.24 in the sham group and 7 +/- 5.70 in the BMSC group (Levene test, P = .001). There was no significant difference between the groups from the time of coitus to conception. To further determine how BMSC injection could have resulted in the improved reproductive outcomes in rats with AS, we employed immunohistochemical techniques to examine the endometrium of these treated rats. On hematoxylin-eosin staining, we noted the reproliferation of all layers of the endometrium and with Masson staining, we noted significant reduction in fibrosis in the damaged endometrium of rats treated with BMSCs. Counterstaining for GFP and cytokeratin-positive cells was noted in the endometrial lining of treated rats, which might suggest the action of BMSCs in regenerating the damaged endometrial lining. The expression of the endometrial receptivity marker, Leukemia inhibitory factor (LIF), in this regenerated endometrial lining could have resulted in the improved reproductive outcomes observed in the AS rat model treated with BMSCs. CONCLUSION:: Bone marrow mesenchymal stem cells were likely to play an important role in the reconstruction of the injured endometrium and improvement of reproductive outcomes in the optimized AS rat model. PMID- 30458680 TI - Newborn pulse oximetry screening: it's time to have recommendation and universal implementation in India. PMID- 30458679 TI - Influence and safety of electronic apex locators in patients with cardiovascular implantable electronic devices: a systematic review. AB - : The widespread use of cardiovascular implantable electronic devices has increased concerns regarding using electronic apex locators in patients with these devices. This systematic review investigated the effects and safety of using electronic apex locators in patients with cardiovascular implantable electronic devices. METHODS: An electronic search in the Cochrane Library, PubMed (MEDLINE), ScienceDirect, and Scientific Electronic Library Online (Scielo) databases for relevant articles published between December 2000 and December 2018 was performed. The search strategy centered on terms related to electronic apex locators use during root canal treatment in patients with cardiovascular implantable electronic devices. RESULTS: Seven studies (five in vitro and two in vivo) fulfilled the inclusion criteria for this review. It was found that electronic apex locators can be used safely in patients with cardiovascular implantable electronic devices, when general precautions are followed. CONCLUSIONS: Although the present review suggests that electronic apex locators can be used safely in patients with implantable cardioverter defibrillators, consultation with patients' cardiologists remains advisable. PMID- 30458681 TI - Role of RFRP-3 in the Regulation of Kiss-1 Gene Expression in the AVPV Hypothalamic Cell Model mHypoA-50. AB - Kisspeptin, encoded by the Kiss-1 gene, plays a crucial role in reproductive function by governing the hypothalamic-pituitary-gonadal axis. The recently established Kiss-1-expressing cell model mHypoA-50 displays characteristics of neuronal cells of the anteroventral periventricular (AVPV) region of the mouse hypothalamus. Because Kiss-1 gene expression in these cells is upregulated by estradiol (E2), mHypoA-50 cells are regarded as a valuable model for the study of Kiss-1-expressing neurons in the AVPV region. These cells also express RFamide related peptide-3 (RFRP-3), a mammalian homolog of gonadotropin inhibitory hormone. The RFRP-3 expression in mHypoA-50 cells was increased by melatonin stimulation. In addition, E2 stimulation increased RFRP-3 expression in these cells. Treatment of the mHypoA-50 cells with exogenous RFRP-3 resulted in the increase of Kiss-1 messenger RNA expression within the cells; however, RFRP-3 did not modify gonadotropin-releasing hormone or kisspeptin-induced Kiss-1 gene expression in these cells. In addition, we found that RFRP-3 stimulation increased the expression of corticotropin-releasing hormone, which may be involved in E2-induced positive feedback in mHypoA-50 cells. Our observations suggest that RFRP-3 might be involved in positive feedback regulation by directly or indirectly increasing Kiss-1 gene expression. PMID- 30458682 TI - Equivalent comfort contours for fore-and-aft, lateral, and vertical whole-body vibration in the frequency range 1.0 to 10 Hz. AB - Standards assume vibration discomfort depends on the frequency and direction of whole-body vibration, with the same weightings for frequency and direction at all magnitudes. This study determined equivalent comfort contours from 1.0 to 10 Hz in each of three directions (fore-and-aft, lateral, vertical) at magnitudes in the range 0.1 to 3.5 ms-2 r.m.s. Twenty-four subjects sat on a rigid flat seat with and without a beanbag, altering the pressure distribution on the seat but not the transmission of vibration. The rate of growth of vibration discomfort with increasing magnitude of vibration differed between the directions of vibration and varied with the frequency of vibration. The frequency-dependence and direction-dependence of discomfort, therefore, depended on the magnitude of vibration. The beanbag did not affect the frequency-dependence or direction dependence of vibration discomfort. It is concluded that different weightings for the frequency and direction of vibration are required for low and high magnitude vibration. Practitioner summary: When evaluating whole-body vibration to predict vibration discomfort, the weightings appropriate to different frequencies and different directions of vibration should depend on the magnitude of vibration. This is overlooked in all current methods of evaluating the severity of whole body vibration. PMID- 30458683 TI - Characterization of 5-Fluorouracil Daily Oral Dosing versus Dietary Restriction on Femoral Growth Plates in Rats. AB - We evaluated the growth plates (GPs) of rats after a 14-day reduction in food consumption caused by either daily oral dosing with 5-fluorouracil (5-FU: a positive control reducing food consumption and affecting the GPs) or a direct reduction in food consumption to determine whether the observed changes were attributable to a direct effect of drug toxicity. Histomorphometric analyses of the femoral GP were performed for a nontreated (NT) control group, three groups treated with 5-FU (12, 15, and 18 mg/kg/day) and three groups with food intake restricted to levels corresponding to those consumed by the rats in the three 5 FU-treated groups. Compared with the NT group, the GP widths and the number of chondrocytes in the proliferative zone decreased significantly in all the 5-FU treated groups and the dietary restriction groups. Importantly, no significant differences between the 5-FU-treated groups and the groups with matched dietary restrictions were seen for most parameters. Thus, the 14-day dietary restriction caused significant changes in the proliferative zone of the GP, and similar changes observed in the 5-FU-treated groups were presumed to result from the comparable reduction in food intake rather than being a direct toxic effect of the drug. PMID- 30458684 TI - Comparison of clear effect and the complications, and short and mid-term effects between ultrasound-guided and non-guided catheter-directed thrombolysis in the treatment of deep venous thrombosis of lower extremity. AB - OBJECTIVE: To compare the therapeutic effects of ultrasound-guided and non-guided catheter-directed thrombolysis in the treatment of deep venous thrombosis of lower extremity. METHODS: From August 2015 to April 2016, 60 patients with lower extremity deep venous thrombosis were randomly divided into two groups ( n = 30 for each) to receive catheter-directed thrombolysis. Group A was treated under the ultrasound guidance, while Group B was treated without guidance. RESULTS: Catheter-directed thrombolysis was successfully performed by only one intubate in Group A but by 5.9 intubates in Group B. It took 15.4 +/- 3.2 min in Group A, significantly less than that in Group B (30.8 +/- 6.6 min, p < 0.05). The incidences of hematoma were also remarkably different between the two groups (3.33% vs. 26.67%, p = 0.026). No pseudoaneurysm or arteriovenous fistula was found in Group A, but there were two cases of pseudoaneurysm and two cases of arteriovenous fistula in Group B (both 6.67%, p = 0.492). The circumference differences of the affected limb between before and after thrombolysis were 49.47 +/- 2.484 mm in Group A, significantly higher than that in Group B (28.40 +/- 2.856 mm, p < 0.001). After treatment, the venous unobstructed improvement rates and deep vein patency rate were both better than those in Group B (77 + 2.603% vs. 57.23 + 1.828% and 80% vs. 46.67%, respectively; p < 0.001). There were only three cases of PTS in Group A (10%, 3/30), but there were 11 cases in Group B (36.67%, 11/30). CONCLUSION: Ultrasound-guided catheter-directed thrombolysis has advantages, with improvement of venous patency and decrease of the incidence of PTS. PMID- 30458685 TI - Percutaneous mechanical thrombectomy using Rotarex catheter in peripheral artery occlusion diseases - Experience from a single center. AB - AIMS: The aim of this retrospective single-center study was to analyze the immediate results, failures and complications of percutaneous mechanical thrombectomy using the Rotarex catheter in the treatment of peripheral artery occlusion. METHODS: In this study, we identified a total of 42 patients who underwent mechanical thrombectomy using Rotarex catheter at our institution. Procedural outcomes and complications were evaluated. RESULTS: The cohort consisted of 42 patients (31 men and 11 women), aged 32-93 years (median 68 years). The number of external iliac artery occlusion was 5, with common femoral artery 5, superficial femoral artery 28, femoral profound artery 2, popliteal artery 12, and brachial artery 2. The causes of occlusion were thrombosis (29 cases, 69%), embolism (6 cases, 14%), and reocclusion after percutaneous intervention (7 cases, 17%). We achieved primary success in 100% of the patients with mechanical thrombectomy, associated with balloon angioplasty (40/42, 95.2%) and stent deployment (16/42, 38.1%). The median time of the interventional procedure was 145 min. We encountered lower percentage of distal embolization (2.4%) and artery dissection (2.4%) during usage of Rotarex catheter in our cohort. CONCLUSIONS: Rotarex thrombectomy was a useful tool to recanalize occluded vessels with additional treatment such as balloon angioplasty or stent deployment, with a low rate of failures and complications. And prospective studies in this issue are recommended. PMID- 30458686 TI - The Deferred Embryo Transfer Strategy Seems Not to be a Good Option After Repeated IVF/ICSI Cycle Failures. AB - OBJECTIVE:: The aim of this study was to assess whether a deferred frozen-thawed embryo transfer (Def-ET) offers any benefits compared to a fresh ET strategy in women who have had 2 or more consecutive in vitro fertilization (IVF)/intracytoplasmic injection (ICSI) cycle failures. DESIGN:: An observational cohort study in a tertiary referral care center including 416 cycles from women with a previous history of 2 or more consecutive IVF/ICSI failures cycles. Both Def-ET and fresh ET strategies were compared using univariate and multivariate logistic regression models. The main outcome measured was the cumulative live birth rate (CLBR). RESULTS:: A total of 416 cycles were included in the analysis: 197 in the fresh ET group and 219 in the Def-ET group. The CLBR was not significantly different between the fresh and Def-ET groups (58/197 [29.4%] and 57/219 [26.0%], respectively, P = .437). In addition, after the first ET, there was no significant difference in the live birth rate between the fresh ET and Def ET groups (50/197 [25.4%] vs 44/219 [20.1%], respectively). Multivariate logistic regression analysis indicated that compared to the fresh strategy, the Def-ET strategy was not associated with a higher probability of live birth. CONCLUSIONS:: In cases with 2 or more consecutive prior IVF/ICSI cycle failures, a Def-ET strategy did not result in better ART outcomes than a fresh ET strategy. PMID- 30458687 TI - Apolipoprotein A-I directly interacts with extracellular domain 1 of human ABCA1. AB - ATP-binding cassette transporter A1 (ABCA1) is critical for the generation of nascent high-density lipoprotein (HDL) and plays important roles in cholesterol homeostasis. ABCA1 has two large extracellular domains (ECDs), which may interact directly with apolipoprotein A-I (apoA-I). However, the molecular mechanisms underlying HDL formation and the importance of ABCA1-apoA-I interactions in HDL formation remain unclear. We investigated the ABCA1-apoA-I interaction in photo activated crosslinking experiments using sulfo-SBED-labeled apoA-I. ApoA-I bound to cells expressing ABCA1, but not to untransfected cells or cells expressing non functional ABCA1. Binding was inhibited by sulfo-SBED-labeled apoA-I, and crosslinking of sulfo-SBED-labeled apoA-I with ABCA1 was inhibited by non-labeled apoA-I, suggesting that sulfo-SBED-labeled apoA-I specifically binds and crosslinks with functional ABCA1. Proteolytic digestion of crosslinked ABCA1 revealed that apoA-I bound the N-terminal half of ABCA1, and that the first ECD of ABCA1 is an apoA-I binding site. Abbreviations: ABC: ATP-binding cassette; apoA-I: apolipoprotein A-I; ATP: adenosine triphosphate; CHAPS: 3-(3 cholamidepropyl)dimethylammonio-1- propanesulphonate; DTT: dithiothreitol; ECD: extra cellular domain; EDTA: ethylenediaminetetraacetic acid; GFP: green fluorescent protein; HA: hemagglutinin; HDL: high density lipoprotein; HEK: human embryonic kidney; HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; sulfo-SBED: (sulfosuccinimidyl-2-[6-(biotinamido)-2-(p azidobenzamido)hexanoamido] ethyl-1,3'-dithiopropionate; NHS-ester, N hydroxysuccinimide-ester. PMID- 30458688 TI - Is complete anatomical endoscopic laser enucleation of the prostate always necessary? Yes, it is! AB - INTRODUCTION:: Thulium laser enucleation of the prostate is gaining popularity due to its short learning curve and low postoperative morbidity. The aim of Thulium laser enucleation of the prostate is the complete endoscopic enucleation of the adenoma. We report an unusual case of bladder outlet obstruction developed 6 weeks after Thulium laser enucleation of the prostate. CASE DESCRIPTION:: A 74 year-old man complained of severe voiding phase symptoms lasting 2 weeks, starting 6 weeks after Thulium laser enucleation of the prostate. He underwent a transrectal ultrasound, which showed a wide prostatic fossa. A cystoscopy revealed that the prostatic fossa was filled with whitish tissue arising from two tiny residual adenomas. The obstructing tissue was resected with the aid of Thulium laser and the histopathology report showed necrotic prostatic glands. CONCLUSION:: Partially enucleated and left inside adenoma may become necrotic and cause bladder outlet obstruction several weeks after Thulium laser enucleation of the prostate. Transrectal ultrasound control at the end of enucleation may help reduce this complication. PMID- 30458689 TI - Blood Transfusions in Major Pancreatic Surgery: A 10-Year Cohort Study Including 1404 Patients Undergoing Pancreatic Resections in Finland. AB - BACKGROUND:: Despite guidelines on blood transfusion (TF) thresholds, there seems to be great variation in transfusion policies between hospitals and surgeons. In order to improve and unify blood transfusion policies, the Finnish Red Cross Blood Service carried out a project concerning the optimal use of blood products (Verivalmisteiden optimaalinen kaytto) between 2002 and 2011. In this study, we determined the blood transfusion trends in major pancreatic surgery in Finland. METHODS:: Initially, 1337 patients who underwent major pancreatic resections between 2002 and 2011 were classified into the TF+ or TF- groups. Centers were divided into high-, medium-, and low-volume centers. The blood transfusion trends and the trigger points for blood transfusions in these patients were determined. RESULTS:: There were no differences between high-, medium- and low-volume centers in blood usage, trigger points or the use of reserved blood units after pancreatoduodenectomy or total pancreatectomy. However, the trigger points were lowered significantly during the study period at high-volume centers (p = 0.003), and a better use of reserved blood units was found in high- (p < 0.001) and medium-volume (p = 0.043) centers. In addition, a better use of reserved blood units was found in high-volume centers after distal pancreatectomy (p = 0.020). CONCLUSION:: Although only minor changes in blood transfusion trends after pancreatoduodenectomy or total pancreatectomy were found generally, the lowering of the transfusion trigger point and the best use of reserved blood units during the study period occurred in high-volume centers. PMID- 30458690 TI - The use of octagam and gammanorm in immunodeficiency associated with hematological malignancies: a prospective study from 21 French hematology departments. AB - OBJECTIVE: Immunoglobulin replacement therapy (IgRT) is increasingly used in secondary immunodeficiency (SID) related to hematological malignancies (HM) to prevent infections. Study's objective was to document prospectively the efficacy and safety of IgRT in patients with HM-associated SID. METHODS: Non interventional, prospective French longitudinal study. RESULTS: One-hundred and sixty patients starting IgRT for HM-associated SID (myeloma: 54 cases, chronic lymphoid leukemia: 54, aggressive non-Hodgkin B-cell lymphoma: 19, indolent non Hodgkin B-cell lymphoma: 29, and Hodgkin disease: 4. entered an observational, prospective, longitudinal study and were followed-up for 8.7 +/- 4.0 months. Seventeen patients died (five within the context of sepsis). Compared to baseline, IgRT increased serum immunoglobulin levels by 3.4 +/- 2.4 g/L and decreased frequency and severity of infections. Treatment was discontinued in 9% of patients, stopped for futility in 31%, temporally interrupted in 8%, suspended during summertime in 14% and pursued without interruption in 38% of patients. CONCLUSION: Our data confirm the efficacy of IgRT in reducing the risk of infections in HM-associated SID therefore fulfilling physicians' main expectations. They also illustrate the heterogeneity of management policies within the community setting. PMID- 30458691 TI - Incidence and risk factors of osteomyelitis in adult and pediatric systemic lupus erythematosus: a nationwide, population-based cohort study. AB - OBJECTIVE: The objective of this paper is to investigate the incidence rate, risk factors and outcome of osteomyelitis among patients with systemic lupus erythematosus (SLE). MATERIALS AND METHODS: We conducted a cohort study using data for patients enrolled in the Taiwan National Health Insurance Database from 2000 to 2012. Patients with SLE and age- and sex-matched controls without SLE were enrolled. Primary endpoint was the first occurrence of osteomyelitis. Risks of osteomyelitis in SLE patients were analyzed with Cox proportional hazards regression models, including age, sex, comorbidities and medications. RESULTS: Among 24,705 SLE patients (88.4% women, mean age 35.8 years) with a median follow up of 9.1 years, 386 patients had osteomyelitis. The incidence rate ratio (IRR) of osteomyelitis in the SLE group vs the control group was 8.52 (95% confidence interval (CI) 7.24-10.05). The SLE group had higher incidence rates of osteomyelitis than the control group, especially in pediatric subgroups (IRR 41.1 95% CI 18.57-107.35). Compared to controls, SLE patients experienced osteomyelitis at a younger age (42.3 vs 58.1 years) but did not have an increased risk of mortality (hazard ratio 0.7; 95% CI 0.21-2.38). Age >60 years, male gender, malignancy within five years, prior bone fracture and higher daily prednisolone dose (>7.5 mg) cumulatively for >180 days increased risk for osteomyelitis. CONCLUSIONS: SLE patients have a higher IRR of osteomyelitis than controls. Pediatric and elder SLE patients, patients with a history of bone fracture, malignancy within five years and higher-dose glucocorticoid use have a higher risk of osteomyelitis and should be carefully monitored. PMID- 30458692 TI - Systemic lupus erythematosus among male patients in Malaysia: how are we different from other geographical regions? AB - BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease which predominantly affects females. The disease characteristics in male SLE patients are reported to be distinct and may vary across ethnicities and geographical regions. OBJECTIVE: To determine and compare the clinical phenotype and organ damage between male and female patients with SLE in Malaysia. METHODOLOGY: This was a cross-sectional study involving SLE patients from Universiti Kebangsaan Malaysia Medical Centre from June 2016 until June 2017. Information on their socio-demographics and disease characteristics were obtained from the clinical records. Disease damage was assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index (SDI) scores. The disease characteristics, autoantibody profiles and organ damage were compared between male and female patients, and multivariable analysis using male sex as dependent variable was then performed. RESULTS: A total of 418 patients were recruited and a total of 59 (14.1%) patients were male. Male patients presented with lower SLE ACR criteria at initial presentation but a significantly higher number of them had renal involvement (lupus nephritis) (78.0% versus 63.8%, p = 0.04). Male patients had less musculoskeletal involvement (45.8% versus 63.0%, p = 0.02) and tended to have lesser mucocutaneous involvement. Immunologic profile revealed that a lower number of male patients had positive anti-Ro antibody (22.7% versus 44.7%, p = 0.04) and they tended to have positive lupus anticoagulant antibody (27.6% versus 14.3%, p = 0.06). Presence of organ damage (SDI score >= 1) was significantly higher among males (55.9% versus 39.6%, p = 0.02) with higher renal damage (25.4% versus 9.2%, p = 0.004) and cardiovascular event of ischaemic heart disease or stroke (20.3% versus 7.0%, p = 0.004). They were also inclined to develop damage much earlier as compared to female patients, 3 (interquartile range (IQR) 7.5) versus 5 (IQR 7) years, p = 0.08. The occurrence of disease damage was independently associated with male gender with odds ratio of 1.9 (95% confidence interval 1.1-3.5), p = 0.02. CONCLUSION: Male patients with SLE have more severe disease with renal damage and cardiovascular event. PMID- 30458693 TI - Review - EPIGENETICS, 2018 Inheritable Epigenetic Response towards Foreign DNA Entry by Mammalian Host Cells: A Guardian of Genomic Stability. AB - Apart from its well-documented role in long-term promoter silencing, the genome wide distribution patterns of ~28 million methylated or unmethylated CpG dinucleotides, e. g. in the human genome, is in search of genetic functions. We have set out to study changes in the cellular CpG methylation profile upon introducing foreign DNA into mammalian cells. As stress factors served the genomic integration of foreign (viral or bacterial plasmid) DNA, virus infections or the immortalization of cells with Epstein Barr Virus (EBV). In all instances investigated, alterations in cellular CpG methylation and transcription profiles were observed to different degrees. In the case of adenovirus DNA integration in adenovirus type 12 (Ad12)-transformed hamster cells, the extensive changes in cellular CpG methylation persisted even after the complete loss of all transgenomic Ad12 DNA. Hence, stress-induced alterations in CpG methylation can be inherited independent of the continued presence of the transgenome. Upon virus infections, changes in cellular CpG methylation appear early after infection. In EBV immortalized as compared to control cells, CpG hypermethylation in the far upstream region of the human FMR1 promoter decreased four-fold. We conclude that in the wake of cellular stress due to foreign DNA entry, preexisting CpG methylation patterns were altered, possibly at specific CpG dinucleotides. Frequently, transcription patterns were also affected. As a working concept, we view CpG methylation profiles in mammalian genomes as a guarding sensor for genomic stability under epigenetic control. As a caveat towards manipulations of cells with foreign DNA, such cells can no longer be considered identical to their un-manipulated counterparts. PMID- 30458694 TI - Role of velamentous cord insertion in monochorionic twin pregnancies: a PRISMA compliant systematic review and meta-analysis of observational studies. AB - BACKGROUND: Velamentous cord insertion (VCI) has been proposed to be associated with some specific complications among monochorionic (MC) twin pregnancies. This meta-analysis and systematic review aims to determine the role of VCI in MC twin pregnancies. METHODS: The PubMed, Embase and Web of Science databases and reference lists were searched for relevant studies. Outcomes of interest included twin-to-twin transfusion syndrome (TTTS), birthweight discordance (BWD) and selective intrauterine growth restriction (sIUGR). The methodological quality of the included studies was assessed by using the Newcastle-Ottawa Scale. The pooled results were calculated by means of a random or fixed effect model to obtain odds ratio with 95% confidential interval (CI). Subgroup analyses were utilized to detect the sources of heterogeneity. RESULTS: Twenty studies were eligible for inclusion. The pooled result suggested a significant association between VCI and TTTS (OR, 1.542; 95% CI, 1.116-2.129) with a moderate level of heterogeneity (Q test: p = 0.024; I2 = 50.2%). Subgroup analysis reported single-center study, methodological quality and exclusion of laser-coagulated TTTS as the sources of heterogeneity. Another analysis revealed an increased risk of BWD among twin pregnancies with VCI (OR, 2.945; 95% CI, 2.176-3.984) with a low heterogeneity (Q test: p = 0.347; I2 = 10.5%). None of study level characteristics was found to be an influencing factor. Three studies reporting on sIUGR suggested a significant association between VCI and sIUGR. CONCLUSIONS: The meta-analysis and systematic review suggests an association between VCI and BWD and sIUGR. However, the association between VCI and TTTS may be overestimated and high-quality studies with a representative sample are needed in further research. PMID- 30458695 TI - Preclinical Evaluation of Mesh Implants: The Pathologist's Perspective. AB - Surgical and laparoscopic implantation of mesh devices is on the rise for a variety of applications. The complexity and range of evolving mesh designs calls for consistent and detailed pathologic evaluation in determining host responses and assessing overall safety. This review addresses the components of evaluation of mesh implants in animal models, with emphasis on histologic parameters, semiquantitative scoring matrices, and morphometric analyses that have been specifically adapted to this class of implants. Necropsy assessment should include implant persistence, architecture, and associated host responses such as exudation and adhesions. Microscopic evaluation should focus on primary relevant responses such as bioresorption, integration/tissue ingrowth, neovascularization, and inflammation. Selection of the best means of processing and evaluation can be complicated, as meshes may include one or more biologic components (e.g., collagen), synthetic polymer fibers, coatings, and other molecules. The architecture of some meshes can influence tissue responses and complicate sampling, sectioning, and evaluation. Recognition of specific study objectives and knowledge of anticipated responses helps to determine the appropriate histologic or immunochemical stains, while understanding of mesh composition and anticipated persistence in tissue determines the suitability of paraffin or resin embedding, and both guide the evaluation of mesh devices in the preclinical setting. PMID- 30458697 TI - Christmas 1864: death from bedsores in a workhouse-the politics of wound care, the media and social reform in Victorian London. PMID- 30458698 TI - The Impact of Immunosuppressive Drugs on Human Placental Explants. AB - The use of immunosuppressive drugs guarantees the vitality of the graft and allows gestation in spite of intercurrences such as prematurity and intrauterine growth restriction. However, little is known about the direct effects of immunosuppressive drugs on placental cells. We investigated the effects of immunosuppressive drugs in the chorionic villous explants from human term placentas of healthy gestations. Human placental explants from term gestations (37-39 week gestational age, n = 12) were exposed to cyclosporine A (CSA, 0, 62.5, 125, 1250 ng/mL) or azathioprine (AZA, 0, 5, 10, 100 ng/mL) separately or, in combination for up to 48 hours. 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assays showed a significant decrease in the explant metabolic activity between AZA and the control group (24 hours, 100 ng/mL, 48 hours, all concentrations, P < .005). Cyclosporin A (CsA) reduced cell activity when associated with AZA (48 hours, P < .005). Fibrinoid deposits increased in AZA-treated explants alone (5 ng/mL, 48 hours; 10 ng/mL, 24-48 hours; P < .005) or when associated with CsA (10 AZA/125 CsA, P < .05), whereas in CsA treatment alone, there was an augment in syncytial knots (24-48 hours, P < .005). The sFLT1 gene (24 hours, P < .05) and protein ( P < .005) expression increased in AZA and CsA-treatments separately or in combination ( P < .05). Placental growth factor increased in AZA (24 hours, 10 ng/mL) and CsA (125 ng/mL; P < .05). In conclusion, our data indicate that AZA primarily acts on the villous metabolism, perturbing placental homeostasis. Since these drugs may alter the balance of angiogenic factors in its selection for clinical application, their impact on the behavior of placental villous should be considered. PMID- 30458696 TI - Oncological treatment and outcome of colorectal cancer in Greenland. AB - Oncological treatment of colorectal cancer (CRC) has been available in Greenland since 2004. Treatment is provided by Queen Ingrid's Hospital (QIH), under supervision from the Department of Oncology, Rigshospitalet, Denmark. The study describes patient characteristics, oncological treatment and survival for the first 8 years of treatment. The study was a registry-based observational study of all patients in Greenland diagnosed with histologically verified CRC from August 2004 to August 2012. Analyses were stratified according to stage and discussed in relation to reported data from patients with CRC in Denmark. 180 patients were included. . Stage I, II, III, and IV comprised 15, 34, 23, and 23%, respectively. 5% presented with unknown stage. A total of 51% received oncological treatment. 79% of patients with Stage III disease received adjuvant chemotherapy, 61% of patients with metastatic CRC received palliative chemotherapy. Five-year survival was 48 and 53% for colon and rectum cancer, respectively. An insignificant trend towards higher survival in men than in women was seen; adjusted hazard ratio for death (women vs men) = 1.46 (95% CI = 0.97-2.19). In conclusion; Stage distribution, provision of oncological treatment and 5-year survival were comparable to patients diagnosed and treated in Denmark. PMID- 30458699 TI - Death, Dying, and End-of-Life Experiences Among Refugees: A Scoping Review. AB - BACKGROUND:: The objective of this scoping review is to identify and map the global literature on death, dying, and end-of-life experiences among refugees. The study aims at identifying gaps in the literature produced on the topic and informs areas for future research in the field. METHODS:: We included articles that met the following inclusion criteria: (1) Population: Refugees and/or internally or externally displaced individuals due to wars, conflicts, nonnatural disasters, or emergencies; (2) Setting: End-of-life phase, dying, and death that took place following the refuge or displacement and reported after the year 1980; and (3) Study Design: All types of studies including but not limited to primary studies, narrative reviews, systematic reviews, news, editorials, commentaries, opinion pieces, technical reports, and policy briefs. A systematic search of the following electronic databases: Medline, Scopus, CINAHL, and JSTOR yielded 11 153 records. The search of the United Nations High Commissioner for Refugees database Refworld retrieved an additional 7510 records. RESULTS:: Seven articles met our inclusion criteria. All articles were coauthored by scholars in universities/research institutes in high-income countries, and except for one, all were conducted in the country of the final settlement of refugees. One article adopted a qualitative approach, another article adopted a mixed-methods approach, one was a narrative review, and 4 articles were reviews of the literature. Three articles discussed access to medical/palliative care among older refugees, and 3 others addressed bereavement and death arrangements. Moreover, one article examined how transmigration and previous experiences from 2 cultural settings in home countries affect the contemplation of death and dying. IMPLICATIONS:: Research on end-of-life experiences among refugees is sorely lacking. This study raises awareness of the need for empirical data on end-of life challenges and palliative care among refugees, thus equipping humanitarian agencies with a more explicit and culturally sensitive lens targeting those with life-limiting conditions. PMID- 30458700 TI - Impact of rare and low-frequency sequence variants on reliability of genomic prediction in dairy cattle. AB - BACKGROUND: Availability of whole-genome sequence data for a large number of cattle and efficient imputation methodologies open a new opportunity to include rare and low-frequency variants (RLFV) in genomic prediction in dairy cattle. The objective of this study was to examine the impact of including RLFV that are within genes and selected from whole-genome sequence variants, on the reliability of genomic prediction for fertility, health and longevity in dairy cattle. RESULTS: All genic RLFV with a minor allele frequency lower than 0.05 were extracted from imputed sequence data and subsets were created using different strategies. These subsets were subsequently combined with Illumina 50 k single nucleotide polymorphism (SNP) data and used for genomic prediction. Reliability of prediction obtained by using 50 k SNP data alone was used as reference value and absolute changes in reliabilities are referred to as changes in percentage points. Adding a component that included either all the genic or a subset of selected RLFV into the model in addition to the 50 k component changed the reliability of predictions by - 2.2 to 1.1%, i.e. hardly no change in reliability of prediction was found, regardless of how the RLFV were selected. In addition to these empirical analyses, a simulation study was performed to evaluate the potential impact of adding RLFV in the model on the reliability of prediction. Three sets of causal RLFV (containing 21,468, 1348 and 235 RLFV) that were randomly selected from different numbers of genes were generated and accounted for 10% additional genetic variance of the estimated variance explained by the 50 k SNPs. When genic RLFV based on mapping results were included in the prediction model, reliabilities improved by up to 4.0% and when the causal RLFV were included they improved by up to 6.8%. CONCLUSIONS: Using selected RLFV from whole genome sequence data had only a small impact on the empirical reliability of genomic prediction in dairy cattle. Our simulations revealed that for sequence data to bring a benefit, the key is to identify causal RLFV. PMID- 30458701 TI - A comprehensive fungi-specific 18S rRNA gene sequence primer toolkit suited for diverse research issues and sequencing platforms. AB - BACKGROUND: Several fungi-specific primers target the 18S rRNA gene sequence, one of the prominent markers for fungal classification. The design of most primers goes back to the last decades. Since then, the number of sequences in public databases increased leading to the discovery of new fungal groups and changes in fungal taxonomy. However, no reevaluation of primers was carried out and relevant information on most primers is missing. With this study, we aimed to develop an 18S rRNA gene sequence primer toolkit allowing an easy selection of the best primer pair appropriate for different sequencing platforms, research aims (biodiversity assessment versus isolate classification) and target groups. RESULTS: We performed an intensive literature research, reshuffled existing primers into new pairs, designed new Illumina-primers, and annealing blocking oligonucleotides. A final number of 439 primer pairs were subjected to in silico PCRs. Best primer pairs were selected and experimentally tested. The most promising primer pair with a small amplicon size, nu-SSU-1333-5'/nu-SSU-1647-3' (FF390/FR-1), was successful in describing fungal communities by Illumina sequencing. Results were confirmed by a simultaneous metagenomics and eukaryote specific primer approach. Co-amplification occurred in all sample types but was effectively reduced by blocking oligonucleotides. CONCLUSIONS: The compiled data revealed the presence of an enormous diversity of fungal 18S rRNA gene primer pairs in terms of fungal coverage, phylum spectrum and co-amplification. Therefore, the primer pair has to be carefully selected to fulfill the requirements of the individual research projects. The presented primer toolkit offers comprehensive lists of 164 primers, 439 primer combinations, 4 blocking oligonucleotides, and top primer pairs holding all relevant information including primer's characteristics and performance to facilitate primer pair selection. PMID- 30458702 TI - Histone acetyltransferase CBP-related H3K23 acetylation contributes to courtship learning in Drosophila. AB - BACKGROUND: Histone modifications are critical in regulating neuronal processes. However, the impacts of individual histone modifications on learning and memory are elusive. Here, we investigated the contributions of histone H3 lysine modifications to learning and memory in Drosophila by using histone lysine-to alanine mutants. RESULTS: Behavioural analysis indicated that compared to the H3WT group, mutants overexpressing H3K23A displayed impaired courtship learning. Chromatin immunoprecipitation analysis of H3K23A mutants showed that H3K23 acetylation (H3K23ac) levels were decreased on learning-related genes. Knockdown of CREB-binding protein (CBP) decreased H3K23ac levels, attenuated the expression of learning-related genes, led to a courtship learning defect and altered development of the mushroom bodies. A decline in courtship learning ability was observed in both larvae and adult treatments with ICG-001. Furthermore, treatment of Drosophila overexpressing mutated H3K23A with a CBP inhibitor did not aggravate the learning defect. CONCLUSIONS: H3K23ac, catalysed by the acetyltransferases dCBP, contributes to Drosophila learning, likely by controlling the expression of specific genes. This is a novel epigenetic regulatory mechanism underlying neuronal behaviours. PMID- 30458704 TI - A case report of multiple anesthesia for pediatric surgery: 80 anesthesia applications in a period of 6 years. AB - BACKGROUND: The side and adverse effects of anesthesia and its neurotoxicity to children have become major concerns of anesthesiologists in recent years. Currently, no clinical trials have provided clear evidence indicating the suitable minimum age for a patient's first anesthetic application, importance of anesthesia duration, number of anesthetic applications or interval between two consecutive anesthesia applications. A very rare case concerning the side, adverse and neurotoxic effects of multiple anesthesia in a child is presented. CASE PRESENTATION: A case of a 9-year-old child who received 80 applications of anesthesia in 6 years because of corrosive esophagitis is presented. The commonly used anesthetic agents were propofol, fentanyl, rocuronium and sevoflurane. CONCLUSION: In our case, there were no permanent side or adverse effects due to multiple anesthesia. The minimal psychological and scholastic problems of our case were tied to frequent hospitalization by the pediatric psychiatry consultation. PMID- 30458703 TI - Minimal change nephrotic syndrome in patients infected with human immunodeficiency virus: a retrospective study of 8 cases. AB - BACKGROUND: Human immunodeficiency virus (HIV) is associated with diverse glomerular diseases. Characteristics of minimal change nephrotic syndrome (MCNS) in this setting have been little studied, and the specific features of this uncommon association remain to be determined. METHODS: We conduct a retrospective study. Clinical, biological and pathological characteristics of patients with MCNS and HIV infection were assessed. We evaluated HIV infection by in situ hybridization and CMIP expression by immunochemistry on kidney biopsies and compared it to HIV-associated nephropathy (HIVAN) and idiopathic MCNS. RESULTS: Eight patients were identifies. In all but one of these cases, MCNS occurred after HIV diagnosis (mean of 9.5 years). Acute kidney injury was detected in three cases. Mean CD4+ lymphocyte count was 733/mm3 and three patients had a detectable HIV viral load. In situ hybridization for HIV-1 RNA detection yielded a positive signal in a few tubular cells in the renal parenchyma in two of four patients with HIV infection associated with MCNS. Podocytes of these patients presented strong positive immunostaining for CMIP (4/4). Three patients suffered steroid-dependent nephrotic syndrome, and another two patients had at least one relapse. Rituximab treatment was initiated in four cases. After a median follow up of 20 months, all patients were in remission (complete in 5 cases). CONCLUSIONS: In patients with MCNS occurring in a context of HIV infection, podocyte injury seems to be associated with CMIP induction rather than renal HIV infection but further studies are needed to determine the molecular link between these two conditions. PMID- 30458705 TI - Dissecting clinical outcome of porcine circovirus type 2 with in vivo derived transcriptomic signatures of host tissue responses. AB - BACKGROUND: Porcine Circovirus Type 2 (PCV2) is a pathogen that has the ability to cause often devastating disease manifestations in pig populations with major economic implications. How PCV2 establishes subclinical persistence and why certain individuals progress to lethal lymphoid depletion remain to be elucidated. RESULTS: Here we present PorSignDB, a gene signature database describing in vivo porcine tissue physiology that we generated from a large compendium of in vivo transcriptional profiles and that we subsequently leveraged for deciphering the distinct physiological states underlying PCV2-affected lymph nodes. This systems genomics approach indicated that subclinical PCV2 infections suppress a myeloid leukocyte mediated immune response. However, in contrast an inflammatory myeloid cell activation is promoted in PCV2 patients with clinical manifestations. Functional genomics further uncovered STAT3 as a druggable PCV2 host factor candidate. Moreover, IL-2 supplementation of primary lymphocytes enabled ex vivo study of PCV2 replication in its target cell, the lymphoblast. CONCLUSION: Our systematic dissection of the mechanistic basis of PCV2 reveals that subclinical and clinical PCV2 display two diametrically opposed immunotranscriptomic recalibrations that represent distinct physiological states in vivo, which suggests a paradigm shift in this field. Finally, our PorSignDB signature database is publicly available as a community resource ( http://www.vetvirology.ugent.be/PorSignDB/ , included in Gene Sets from Community Contributors http://software.broadinstitute.org/gsea/msigdb/contributed_genesets.jsp ) and provides systems biologists with a valuable tool for catalyzing studies of human and veterinary disease. Finally, a primary porcine lymphoblast cell culture system paves the way for unraveling the impact of host genetics on PCV2 replication. PMID- 30458706 TI - Seedless mutant 'Wuzi Ougan' (Citrus suavissima Hort. ex Tanaka 'seedless') and the wild type were compared by iTRAQ-based quantitative proteomics and integratedly analyzed with transcriptome to improve understanding of male sterility. AB - BACKGROUND: Bud mutation is a vital method of citrus. 'Wuzi Ougan' (mutant type, MT) as a bud variant of 'Ougan' (wild type, WT) was first found in 1996 and has become popular because of its male sterility and seedless character. Previous analysis of its cytological sections and transcriptome revealed that the abnormal microsporogenesis that occurs before the tetrad stage of anther development might be the result of down-regulated oxidation-reduction biological processes in MT. To reveal the mechanism behind the male sterility in MT at the post transcriptional stage, proteome profiling and integrative analysis on previously obtained transcriptome and proteome data were performed in two strains. RESULTS: The proteome profiling was performed by iTRAQ (isobaric Tags for relative and absolute quantitation) analysis and 6201 high-confidence proteins were identified, among which there were 487 differentially expressed proteins (DEPs) in one or more developmental stages of anthers between MT and WT. The main functional subcategories associated with the main category biological process into which the DEPs were classified were sporopollenin biosynthesis process and pollen exine formation. The enriched pathways were phenylpropanoid biosynthesis, flavonoid biosynthesis, and phenylalanine metabolism. Moreover, there were eight pathways linked in terms of being related to phenylpropanoid metabolism. Eighteen important genes related to phenylpropanoid metabolism were also analysized by qRT PCR (quantitative real time PCR). An integrative analysis of the fold change at the transcript (log2 FPKM ratios) and protein (log1.2 iTRAQ ratios) levels was performed to reveal the consistency of gene expression at transcriptional and proteomic level. In general, the expression of genes and proteins tended to be positively correlated, in which the correlation coefficients were 0.3414 (all genes and all proteins) and 0.5686 (DEPs and according genes). CONCLUSION: This study is the first to offer a comprehensive understanding of the gene regulation in 'Wuzi Ougan' and its wild type, especially during the microsporocyte to meiosis stage. Specifically, the involved genes include those in phenylpropanoid biosynthesis, flavonoid biosynthesis, and phenylalanine metabolism, as determined by integrative transcriptome and proteome analysis. PMID- 30458708 TI - Parallel identification of novel antimicrobial peptide sequences from multiple anuran species by targeted DNA sequencing. AB - BACKGROUND: Antimicrobial peptides (AMPs) are multifunctional effector molecules that often combine direct antimicrobial activities with signaling or immunomodulatory functions. The skin secretions of anurans contain a variety of such bioactive peptides. The identification of AMPs from frog species often requires sacrificing several specimens to obtain small quantities of crude peptides, followed by activity based fractionation to identify the active principles. RESULTS: We report an efficient alternative approach to selectively amplify AMP-coding transcripts from very small amounts of tissue samples, based on RNA extraction and cDNA synthesis, followed by PCR amplification and high throughput sequencing of size-selected amplicons. This protocol exploits the highly conserved signal peptide region of the AMP precursors from Ranidae, Hylidae and Bombinatoridae for the design of family-specific, forward degenerate primers, coupled with a reverse primer targeting the mRNA poly-A tail. CONCLUSIONS: Analysis of the assembled sequencing output allowed to identify more than a hundred full-length mature peptides, mostly from Ranidae species, including several novel potential AMPs for functional characterization. This (i) confirms the effectiveness of the experimental approach and indicates points for protocol optimization to account for particular cases, and (ii) encourages the application of the same methodology to other multigenic AMP families, also from other genera, sharing common features as in anuran AMPs. PMID- 30458709 TI - Targeted gene panel for genetic testing of south Indian children with steroid resistant nephrotic syndrome. AB - BACKGROUND: Steroid resistant nephrotic syndrome (SRNS) is a genetically heterogeneous disease with significant phenotypic variability. More than 53 podocyte-expressed genes are implicated in SRNS which complicates the routine use of genetic screening in the clinic. Next generation sequencing technology (NGS) allows rapid screening of multiple genes in large number of patients in a cost effective manner. METHODS: We developed a targeted panel of 17 genes to determine relative frequency of mutations in south Indian ethnicity and feasibility of using the assay in a clinical setting. Twenty-five children with SRNS and 3 healthy individuals were screened. RESULTS: In this study, novel variants including 1 pathogenic variant (2 patients) and 3 likely pathogenic variants (3 patients) were identified. In addition, 2 novel variants of unknown significance (VUS) in 2 patients (8% of total patients) were also identified. CONCLUSIONS: The results show that genetic screening in SRNS using NGS is feasible in a clinical setting. However the panel needs to be screened in a larger cohort of children with SRNS in order to assess the utility of the customised targeted panel in Indian children with SRNS. Determining the prevalence of variants in Indian population and improvising the bioinformatics-based filtering strategy for a more accurate differentiation of pathogenic variants from those that are benign among the VUS will help in improving medical and genetic counselling in SRNS. PMID- 30458707 TI - Kif17 phosphorylation regulates photoreceptor outer segment turnover. AB - BACKGROUND: KIF17, a kinesin-2 motor that functions in intraflagellar transport, can regulate the onset of photoreceptor outer segment development. However, the function of KIF17 in a mature photoreceptor remains unclear. Additionally, the ciliary localization of KIF17 is regulated by a C-terminal consensus sequence (KRKK) that is immediately adjacent to a conserved residue (mouse S1029/zebrafish S815) previously shown to be phosphorylated by CaMKII. Yet, whether this phosphorylation can regulate the localization, and thus function, of KIF17 in ciliary photoreceptors remains unknown. RESULTS: Using transgenic expression in zebrafish photoreceptors, we show that phospho-mimetic KIF17 has enhanced localization along the cone outer segment. Importantly, expression of phospho mimetic KIF17 is associated with greatly enhanced turnover of the photoreceptor outer segment through disc shedding in a cell-autonomous manner, while genetic mutants of kif17 in zebrafish and mice have diminished disc shedding. Lastly, cone expression of constitutively active tCaMKII leads to a kif17-dependent increase in disc shedding. CONCLUSIONS: Taken together, our data support a model in which phosphorylation of KIF17 promotes its photoreceptor outer segment localization and disc shedding, a process essential for photoreceptor maintenance and homeostasis. While disc shedding has been predominantly studied in the context of the mechanisms underlying phagocytosis of outer segments by the retinal pigment epithelium, this work implicates photoreceptor-derived signaling in the underlying mechanisms of disc shedding. PMID- 30458710 TI - Natural variation in a CENTRORADIALIS homolog contributed to cluster fruiting and early maturity in cotton. AB - BACKGROUND: Plant architecture and the vegetative-reproductive transition have major impacts on the agronomic success of crop plants, but genetic mechanisms underlying these traits in cotton (Gossypium spp.) have not been identified. RESULTS: We identify four natural mutations in GoCEN-Dt associated with cluster fruiting (cl) and early maturity. The situ hybridization shows that GhCEN is preferentially expressed in cotton shoot apical meristems (SAM) of the main stem and axillary buds. Constitutive GhCEN-Dt overexpression suppresses the transition of the cotton vegetative apex to a reproductive shoot. Silencing GoCEN leads to early flowering and determinate growth, and in tetraploids causes the main stem to terminate in a floral bud, a novel phenotype that exemplifies co-adaptation of polyploid subgenomes and suggests new research and/or crop improvement approaches. Natural cl variations are enriched in cottons adapted to high latitudes with short frost-free periods, indicating that mutants of GoCEN have been strongly selected for early maturity. CONCLUSION: We show that the cotton gene GoCEN-Dt, a homolog of Antirrhinum CENTRORADIALIS, is responsible for determinate growth habit and cluster fruiting. Insight into the genetic control of branch and flower differentiation offers new approaches to develop early maturing cultivars of cotton and other crops with plant architecture appropriate for mechanical harvesting. PMID- 30458711 TI - Exploration of exosomal microRNA expression profiles in pigeon 'Milk' during the lactation period. AB - BACKGROUND: Pigeon crop has the unique ability to produce a nutrient rich substance termed pigeon 'milk' (PM), which has functional resemblance with the mammalian milk. Previous researches have demonstrated that a large number of exosomes and exosomal miRNAs exist in mammalian milk, and many of them are associated with immunity, growth and development. However, to date, little is known about the exosomes and exosomal miRNAs in PM. RESULTS: In this study, we isolated the exosomes from PM and used small RNA sequencing to investigate the distribution and expression profiles of exosomal miRNAs. A total of 301 mature miRNAs including 248 conserved and 53 novel miRNAs were identified in five lactation stages i.e. 1d, 5d, 10d, 15d, and 20d. From these, four top 10 conserved miRNAs (cli-miR-21-5p, cli-miR-148a-3p, cli-miR-10a-5p and cli-miR-26a 5p) were co-expressed in all five stages. We speculate that these miRNAs may have important role in the biosynthesis and metabolism of PM. Moreover, similar to the mammalian milk, a significant proportion of immune and growth-related miRNAs were also present and enriched in PM exosomes. Furthermore, we also identified 41 orthologous miRNAs group (giving rise to 81 mature miRNA) commonly shared with PM, human, bovine and porcine breast milk. Additionally, functional enrichment analysis revealed the role of exosomal miRNAs in organ development and in growth related pathways including the MAPK, Wnt and insulin pathways. CONCLUSIONS: To sum-up, this comprehensive analysis will contribute to a better understanding of the underlying functions and regulatory mechanisms of PM in squabs. PMID- 30458712 TI - Coexistence of two sympatric cryptic bat species in French Guiana: insights from genetic, acoustic and ecological data. AB - BACKGROUND: The distinction between lineages of neotropical bats from the Pteronotus parnellii species complex has been previously made according to mitochondrial DNA, and especially morphology and acoustics, in order to separate them into two species. In these studies, either sample sizes were too low when genetic and acoustic or morphological data were gathered on the same individuals, or genetic and other data were collected on different individuals. In this study, we intensively sampled bats in 4 caves and combined all approaches in order to analyse genetic, morphologic, and acoustic divergence between these lineages that live in the same caves in French Guiana. RESULTS: A multiplex of 20 polymorphic microsatellite markers was developed using the 454-pyrosequencing technique to investigate for the first time the extent of reproductive isolation between the two lineages and the population genetic structure within lineages. We genotyped 748 individuals sampled between 2010 and 2015 at the 20 nuclear microsatellite loci and sequenced a portion of the cytochrome c oxydase I gene in a subset of these. Two distinct, non-overlapping haplogroups corresponding to cryptic species P. alitonus and P. rubiginosus were revealed, in accordance with previous findings. No spatial genetic structure between caves was detected for both species. Hybridization appeared to be quite limited (0.1-4%) using microsatellite markers whereas introgression was more common (7.5%) and asymmetric for mitochondrial DNA (mtDNA). CONCLUSIONS: The extremely low rate of hybridization could be explained by differences in life cycle phenology between species as well as morphological and acoustical distinction between sexes in one or the other species. Taken together, these results add to our growing understanding of the nature of species boundaries in Pteronotus parnelli, but deserve more in-depth studies to understand the evolutionary processes underlying asymmetric mtDNA introgression in this group of cryptic species. PMID- 30458714 TI - Utility and effectiveness of the Scandinavian guidelines to exclude computerized tomography scanning in mild traumatic brain injury - a prospective cohort study. AB - BACKGROUND: In 2013 the Scandinavian Neurotrauma Committee (SNC) published updated guidelines for the initial management of minimal, mild and moderate traumatic head injuries (MTHI) that included serum analysis of protein S100B as a marker for brain tissue damage. This study reviews the effectiveness of the new guidelines in a clinical setting. METHODS: For all patients admitted to Akershus University Hospital (AHUS) from June 30th 2014 to December 15th 2014 with MTHI a separate form was filled in recording the time, indication and result of any S100B sampling and/or head computer tomography (CT) examinations. Data from these forms were compared to information derived from the electronic patient records for patients with MTHI and related diagnoses and data from the laboratory for all patients that had undergone the S100B analysis within the same period. RESULTS: Five hundred seventy-five patients were identified with MTHI, S100B sampling was indicated for 223 (38.8%) patients and carried out for 188 (84.3%) of these patients. 69 (36.7%) of the patients had a negative S100B test, but a head CT scan was still performed in 31 cases despite the negative S100B test. In total the guidelines were followed for 362 of 575 patients (63.0%). 180 (31.3%) of the MTHI cases were discharged without further observation or CT examinations, including 38 (21.1%) as a direct result of S100B testing. No re-admissions or missed initial traumatic brain injuries were observed. CONCLUSION: The implementation of the updated SNC guidelines resulted in direct discharge of more than one third of the MTHI cases without further observation or CT examinations. One in five of these discharges was a direct result of S100B testing. However, compliance to the guidelines were poor and the guidelines were only followed in 40%. While this study showed benefits of implementing SNC guidelines to reduce the number of CT scans, additional training is needed for optimal use. PMID- 30458713 TI - Comparative genomics analysis to differentiate metabolic and virulence gene potential in gastric versus enterohepatic Helicobacter species. AB - BACKGROUND: The genus Helicobacter are gram-negative, microaerobic, flagellated, mucus-inhabiting bacteria associated with gastrointestinal inflammation and classified as gastric or enterohepatic Helicobacter species (EHS) according to host species and colonization niche. While there are over 30 official species, little is known about the physiology and pathogenic mechanisms of EHS, which account for most in the genus, as well as what genetic factors differentiate gastric versus EHS, given they inhabit different hosts and colonization niches. The objective of this study was to perform a whole-genus comparative analysis of over 100 gastric versus EHS genomes in order to identify genetic determinants that distinguish these Helicobacter species and provide insights about their evolution/adaptation to different hosts, colonization niches, and mechanisms of virulence. RESULTS: Whole-genome phylogeny organized Helicobacter species according to their presumed gastric or EHS classification. Analysis of orthologs revealed substantial heterogeneity in physiological and virulence-related genes between gastric and EHS genomes. Metabolic reconstruction predicted that unlike gastric species, EHS appear asaccharolytic and dependent on amino/organic acids to fuel metabolism. Additionally, gastric species lack de novo biosynthetic pathways for several amino acids and purines found in EHS and instead rely on environmental uptake/salvage pathways. Comparison of virulence factor genes between gastric and EHS genomes identified overlapping yet distinct profiles and included canonical cytotoxins, outer membrane proteins, secretion systems, and survival factors. CONCLUSIONS: The major differences in predicted metabolic function suggest gastric species and EHS may have evolved for survival in the nutrient-rich stomach versus the nutrient-devoid environments, respectively. Contrasting virulence factor gene profiles indicate gastric species and EHS may utilize different pathogenic mechanisms to chronically infect hosts and cause inflammation and tissue damage. The findings from this study provide new insights into the genetic differences underlying gastric versus EHS and support the need for future experimental studies to characterize these pathogens. PMID- 30458715 TI - Provision of post-crash first aid by traffic police in Dar es Salaam, Tanzania: a cross-sectional survey. AB - BACKGROUND: The availability of prehospital trauma care is an important means of reducing serious injuries and fatalities associated with road traffic injuries (RTIs). Lay responders such as traffic police play an important role in the provision of prehospital trauma care to RTI victims, especially where there is no established prehospital care system. Therefore, the objective of the present study was to investigate knowledge, self-reported practice, and attitudes toward post-crash first aid among traffic police officers in Tanzania. METHOD: A cross sectional survey was conducted in Dar es Salaam, Tanzania between July-September 2017 to investigate knowledge, self-reported practice and attitude among traffic police officers during provision of post-crash care. We used simple random technique to recruit 340 traffic police officers, self -administered questionnaires were used to collect data. The researchers used descriptive statistics and Pearson's chi-square tests to analyze the data. RESULTS: A total of 340 traffic police officers were surveyed. Nearly two thirds (65.3%) reported having had post-crash first aid on-the job training; a slightly larger proportion (70.9%) reported that they had cared for RTI victims in the previous year. The survey responses showed that, generally, traffic police officers' level of knowledge about post-crash first aid to RTI victims was low-about 3% of the surveyed officers possessed knowledge at a level considered good. Also, there was a statistically significant correlation between higher educational attainment and greater knowledgeability (p = 0.015). Almost all of the officers (96%) had a positive attitude toward providing post-crash first aid to RTI victims. CONCLUSIONS: Improved training of Tanzania traffic police officers, by means of an updated post-crash first aid curriculum and updated resources is recommended. Also, user-friendly post-crash first aid leaflets should be provided to traffic police for their reference. PMID- 30458716 TI - Disruption of ureide degradation affects plant growth and development during and after transition from vegetative to reproductive stages. AB - BACKGROUND: The ureides allantoin and allantoate are major metabolic intermediates of purine catabolism with high nitrogen-to-carbon ratios. Ureides play a key role in nitrogen utilization in ureide-type legumes, but their effects on growth and development in non-legume plants are poorly understood. Here, we examined the effects of knocking out genes encoding ureide-degrading enzymes, allantoinase (ALN) and allantoate amidohydrolase (AAH), on the vegetative-to reproductive transition and subsequent growth of Arabidopsis plants. RESULTS: The ureide-degradation mutants (aln and aah) showed symptoms similar to those of nitrogen deficiency: early flowering, reduced size at maturity, and decreased fertility. Consistent with these phenotypes, carbon-to-nitrogen ratios and nitrogen-use efficiencies were significantly decreased in ureide-degradation mutants; however, adding nitrogen to irrigation water did not alleviate the reduced growth of these mutants. In addition to nitrogen status, levels of indole 3-acetic acid and gibberellin in five-week-old plants were also affected by the aln mutations. To test the possibility that ureides are remobilized from source to sink organs, we measured ureide levels in various organs. In wild-type plants, allantoate accumulated predominantly in inflorescence stems and siliques; this accumulation was augmented by disruption of its catabolism. Mutants lacking ureide transporters, ureide permeases 1 and 2 (UPS1 and UPS2), exhibited phenotypes similar to those of the ureide-degradation mutants, but had decreased allantoate levels in the reproductive organs. Transcript analysis in wild-type plants suggested that genes involved in allantoate synthesis and ureide transport were coordinately upregulated in senescing leaves. CONCLUSIONS: This study demonstrates that ureide degradation plays an important role in supporting healthy growth and development in non-legume Arabidopsis during and after transition from vegetative to reproductive stages. PMID- 30458717 TI - Retinal vascular tortuosity assessment: inter-intra expert analysis and correlation with computational measurements. AB - BACKGROUND: The retinal vascular tortuosity can be a potential indicator of relevant vascular and non-vascular diseases. However, the lack of a precise and standard guide for the tortuosity evaluation hinders its use for diagnostic and treatment purposes. This work aims to advance in the standardization of the retinal vascular tortuosity as a clinical biomarker with diagnostic potential, allowing, thereby, the validation of objective computational measurements on the basis of the entire spectrum of the expert knowledge. METHODS: This paper describes a multi-expert validation process of the computational vascular tortuosity measurements of reference. A group of five experts, covering the different clinical profiles of an ophthalmological service, and a four-grade scale from non-tortuous to severe tortuosity as well as non-tortuous / tortuous and asymptomatic / symptomatic binary classifications are considered for the analysis of the the multi-expert validation procedure. The specialists rating process comprises two rounds involving all the experts and a joint round to establish consensual rates. The expert agreement is analyzed throughout the rating procedure and, then, the consensual rates are set as the reference to validate the prognostic performance of four computational tortuosity metrics of reference. RESULTS: The Kappa indexes for the intra-rater agreement analysis were obtained between 0.35 and 0.83 whereas for the inter-rater agreement in the asymptomatic / symptomatic classification were between 0.22 and 0.76. The Area Under the Curve (AUC) for each expert against the consensual rates were placed between 0.61 and 0.83 whereas the prognostic performance of the best objective tortuosity metric was 0.80. CONCLUSIONS: There is a high inter and intra-rater variability, especially for the case of the four grade scale. The prognostic performance of the tortuosity measurements is close to the experts' performance, especially for Grisan measurement. However, there is a gap between the automatic effectiveness and the expert perception given the lack of clinical criteria in the computational measurements. PMID- 30458718 TI - Primary palliative care team perspectives on coordinating and managing people with advanced cancer in the community: a qualitative study. AB - BACKGROUND: Primary health care teams are key to the delivery of care for patients with advanced cancer during the last year of life. The Gold Standards Framework is proposed as a mechanism for coordinating and guiding identification, assessment, and support. There are still considerable variations in practice despite its introduction. The aim of this qualitative study is to improve understanding of variations in practice through exploring the perspectives and experiences of members of primary health care teams involved in the care of patients with advanced cancer. METHODS: Qualitative, semi-structured interviews, focus groups, and non-participatory observations involving 67 members of primary health care teams providing palliative care. Data were analysed using a grounded theory approach. RESULTS: We identified distinct differences in the drivers and barriers of community advanced cancer care coordination, which relate to identification and management, and access to effective pain management, and go some way to understanding variations in practice. These include proactive identification processes, time and resource pressures, unclear roles and responsibilities, poor multidisciplinary working, and inflexible models for referral and prescribing. These provide valuable insight into how professionals work together and independently within an infrastructure that can both support and hinder the provision of effective community palliative care. CONCLUSIONS: Whilst the GSF is a guide for good practice, alone it is not a mechanism for change. Rather it provides a framework for describing quality of practice that was already occurring. Consequently, there will continue to be variations in practice. PMID- 30458719 TI - A novel compound heterozygous mutation in VARS2 in a newborn with mitochondrial cardiomyopathy: a case report of a Chinese family. AB - BACKGROUND: Genetic defects in the mitochondrial aminoacyl-tRNA synthetase are important causes of mitochondrial disorders. VARS2 is one of the genes encoding aminoacyl-tRNA synthetases. Recently, an increasing number of pathogenic variants of VARS2 have been reported. CASE PRESENTATION: We report the novel compound heterozygous pathogenic VARS2 mutations c.643 C > T (p. His215Tyr) and c.1354 A > G (p. Met452Val) in a female infant who presented with poor sucking at birth, poor activity, hyporeflexia, hypertonia, persistent pulmonary hypertension of newborn (PPHN), metabolic acidosis, severe lactic acidosis, expansion and hypertrophic cardiomyopathy. These heterozygous mutations were carried individually by the proband's parents and elder sister; the two mutations segregated in the family and were the cause of the disease in the proband.The c.643 C > T (p. His215Tyr) mutation was not described in the ExaC, GNomAD and 1000 Genomes Project databases, and the frequency of c.1354 A > G (p. Met452Val) was < 0.001 in these gene databases.The two mutated amino acids were located in a highly conserved region of the VARS2 protein that is important for its interaction with the cognate tRNA. The two missense mutations were predicted by online tools to be damaging and deleterious. CONCLUSIONS: Our report expands the spectrum of known pathogenicVARS2 variants associated with mitochondrial disorders in humans.VARS2 deficiency may cause a severe neonatal presentation with structural cardiac abnormalities. PMID- 30458720 TI - Two MYB transcription factors (CsMYB2 and CsMYB26) are involved in flavonoid biosynthesis in tea plant [Camellia sinensis (L.) O. Kuntze]. AB - BACKGROUND: Flavonoids are secondary metabolites that play important roles in the entire tea plant life cycle and have potential health-promoting properties. MYB transcription factors (TFs) are considered potentially important regulators of flavonoid biosynthesis in plants. However, the molecular mechanisms by which MYB TFs regulate the flavonoid pathway in tea plant remain unknown. RESULTS: In this study, two R2R3-MYB TFs (CsMYB2 and CsMYB26) involved in flavonoid biosynthesis in tea plant were investigated. The genes encoding CsMYB2 and CsMYB26 were cloned from the tea plant cultivar 'Longjing 43'. Phylogenetic analysis showed that CsMYB2 and CsMYB26 were grouped into the proanthocyanidin biosynthesis-related MYB clade. Multiple sequence alignment revealed that conserved motif 1 in the two MYB factors was related to the bHLH TF. Subcellular localization assays suggested that CsMYB2 localized in the nucleus. Promoter analysis indicated that CsMYB2, CsMYB26 and the related structural genes contain MYB recognition elements. The expression levels of the CsMYB2 and CsMYB26 genes and the structural genes in the flavonoid biosynthesis pathway were determined in leaves from various sites in the two tea plant cultivars 'Longjing 43' and 'Baiye 1 hao'. CONCLUSIONS: The expression levels of these genes were correlated with the accumulated flavonoid content. The results demonstrated that the expression level of CsF3'H may be regulated by CsMYB2 and that CsMYB26 expression is positively correlated with CsLAR expression. The relative transcriptional level of CsMYB26 may be the main reason for the different epigallocatechin contents between the tea plant cultivars 'Longjing 43' and 'Baiye 1 hao'. Our results will serve as a reference for the potential regulatory roles of CsMYB2 and CsMYB26 in flavonoid biosynthesis in tea plant and may also assist biologists in improving tea quality. PMID- 30458721 TI - Catheter-associated bacterial flora in patients with benign prostatic hyperplasia: shift in antimicrobial susceptibility pattern. AB - BACKGROUND: Men with urinary retention secondary to benign prostatic hyperplasia (BPH) are prone to genitourinary infections. Physicians should be aware of the current antimicrobial susceptibility pattern in this population if empirical treatment is needed. The goal of this study was to evaluate variations in prevalence, composition and antimicrobial susceptibility of bacterial flora in men with indwelling catheters subjected to surgery for BPH in chosen time periods since 1994. Necessary changes in empirical therapy were also assessed. METHODS: All patients with indwelling catheters admitted to a single urological center for BPH surgery in the years 1994-1996, 2004-2006, and 2011-2015 were considered. Catheterization times and results of urine cultures from samples collected at admission were evaluated. Susceptibility for selected antimicrobials was compared separately for Gram negative and Gram positive species. For each agent and for their combinations effectiveness of empirical therapy was calculated dividing the number of patients with bacteriuria susceptible to the agents by the total number of patients with bacteriuria. RESULTS: Bacteriuria was present in 70% of 169, 72% of 132, and 69% of 156 men in the respective time periods. The incidence of Gram positive strains increased from 10 to 37% (P < 0.001). Their susceptibility to amoxicillin/clavulanate was fluctuating (81, 61, 77%; P=NS). No vancomycin resistant strain was present. Gram-negative flora composition was stable. Their susceptibility decreased to ciprofloxacin (70 to 53%; P = 0.01) and amoxicillin/clavulanate (56 to 37%; P < 0.01) while it increased to gentamycin (64 to 88%; P < 0.001) and co-trimoxazole (14 to 62%; P < 0.001); susceptibility to amikacin remained high (> 85%). Only two cases of resistance to carbapenems in 2004-2006 were found. In vitro effectiveness of amikacin + amoxicillin/clavulanate in empirical therapy was slowly decreasing (87 to 77%; P=NS). Imipenem was found the most effective single agent (90-95%) and its efficacy was even improved by adding vancomycin (97-98%). CONCLUSIONS: Substantial rise in the incidence of Gram-positive species and fluctuations in antimicrobial susceptibility patterns were found. Empirical therapy of genitourinary infection in catheterized men with BPH should now involve antimicrobial agents effective both to Enterococci and Enterobacteriaceae. Periodic monitoring and publishing data on antimicrobial susceptibility for this population is necessary. PMID- 30458722 TI - Driving following defibrillator implantation: development and pilot results from a nationwide questionnaire. AB - BACKGROUND: Implantable cardioverter defibrillator (ICD) implantation is associated with driving restrictions which may have profound effects on the patient's life. However, there is limited patient-reported data on the information given about driving restrictions, the adherence to the restrictions, the incidence of arrhythmic symptoms while driving, and the driving restrictions' effect on ICD patients' daily life and quality of life factors. A specific questionnaire was designed to investigate these objectives, intended for use in a nationwide ICD cohort. METHODS: The conceptual framework based on literature review and expert opinion was refined in qualitative semi-structured focus group interviews with ten ICD patients. Content validity was pursued through pre testing, including expert review and 28 cognitive interviews with patients at all ICD implanting centres in Denmark. Finally, the Danish Pacemaker and ICD registry was used to randomly select 50 ICD patients with a first-time implantation between January 1, 2013 and November 30, 2016 for pilot testing, followed by a test-retest on 25 respondents. Test-retest agreement was assessed using kappa statistics or intraclass correlation coefficients. RESULTS: The pilot test achieved a response rate of 78%, whereof the majority were web-based (69%). Only 49% stated they had been informed about any driving restrictions after ICD implantation, whereas the number was 75% after appropriate ICD shock. Among respondents, 95% had resumed private driving, ranging from 1 to 90 days after ICD implantation. In those informed of a significant (>= 1 month) driving ban, 55% stated the driving restrictions had impeded with daily life, especially due to limitations in maintaining employment or getting to/from work and 25% admitted they had knowingly been driving during the restricted period. There were six episodes of dizziness or palpitations not necessitating stopping the vehicle. Test-retest demonstrated good agreement of questionnaire items, with 69% of Kappa coefficients above 0.60. CONCLUSIONS: We have developed a comprehensive questionnaire on ICD patients' perspective on driving. Pre-testing and pilot testing demonstrated good content validity, feasible data collection methods, and a robust response rate. Thus, we believe the final questionnaire, distributed to almost 4000 ICD patients, will capture essential evidence to help inform driving guidelines in this population. PMID- 30458723 TI - Levosimendan is superior to epinephrine on coronary flow for lipid-base resuscitation of bupivacaine-induced asystole in the isolated rat heart. AB - BACKGROUND: Successful resuscitation from asystole induced by bupivacaine requires the reestablishment of a sufficient coronary flow (CF) quickly. This study was designed to test whether levosimendan was superior to epinephrine in the reestablishment of crucial coronary flows after bupivacaine-induced asystole. METHODS: The isolated, perfused, nonrecirculating, Langendorff rat heart preparation was used. Bupivacaine 100 MUmol/L was perfused into rat hearts to induce asystole, and then for 3 min thereafter. Three experimental groups were assessed after asystole with infusions as follow: (1) a mixture of 2% lipid emulsion and 40 MUmol/L bupivacaine (control group), (2) a mixture of 0.15 MUg/mL epinephrine combined with 2% lipid emulsion and 40 MUmol/L bupivacaine (epinephrine group), and (3) a mixture of 5 MUmol/L levosimendan combined with a 2% lipid emulsion and 40 MUmol/L bupivacaine mixture (levosimendan group). Coronary flow (CF), the time to recovery (Trecovery), the number of ventricular arrhythmias, and cardiac function parameters were recorded for 40 min after heartbeat recovery. RESULTS: All hearts in the control, epinephrine and levosimendan groups had heartbeat recovery. The rank order of the mean CF from highest to lowest was the levosimendan group > the epinepgrine group > the control group (P < 0.05). The rank order of Trecovery from shortest to longest was the levosimendan group < the epinephrine group < the control group (P < 0.01). During the recovery phase, isolated rat hearts developed more ventricular arrhythmias in the epinephrine group than in the levosimendan group (P = 0.01). CONCLUSION: Levosimendan is superior to epinephrine in producing higher CFs and faster recovery when reversing bupivacaine-induced asystole in the isolated rat hearts. PMID- 30458724 TI - Association of Uncoupling Protein 1 (UCP1) gene polymorphism with obesity: a case control study. AB - BACKGROUND: Obesity is one of the main causes of morbidity and mortality worldwide. More than 120 genes have been shown to be associated with obesity related phenotypes. The aim of this study was to determine the effect of selected genetic polymorphisms in Uncoupling protein 1 (UCP1) and Niemann-Pick C1 (NPC1) genes in an obese population in Saudi Arabia. METHODS: The genotypes of rs1800592, rs10011540 and rs3811791 (UCP1 gene) and rs1805081 and rs1805082 (NPC1 gene) were determined in a total of 492 subjects using TaqMan chemistry by Real time PCR. In addition, capillary sequencing assay was performed to identify two specific polymorphisms viz., rs45539933 (exon 2) and rs2270565 (exon 5) of UCP1 gene. RESULTS: A significant association of UCP1 polymorphisms rs1800592 [OR, 1.52 (1.10-2.08); p = 0.009] was observed in the obese cohort after adjusting with age, sex and type 2 diabetes. Further BMI based stratification revealed that this association was inconsistent with both moderate and extreme obese cohort. A significant association of UCP1 polymorphisms rs3811791 was observed only in the moderate-obese cohort [OR = 2.89 (1.33-6.25); p = 0.007] but not in the extreme obese cohort indicating an overlying genetic complexity between moderate-obesity and extreme-obesity. The risk allele frequencies, which were higher in moderate obese cohort, had abnormal HDL, LDL and triglyceride levels. CONCLUSION: The rs1800592 and rs3811791 of UCP1 gene are associated with obesity in general and in the moderate-obese group in particular. The associated UCP1 polymorphisms in the moderate-obese group may regulate the impaired energy metabolism which plays a significant role in the initial stages of obesity. PMID- 30458725 TI - ASGAL: aligning RNA-Seq data to a splicing graph to detect novel alternative splicing events. AB - BACKGROUND: While the reconstruction of transcripts from a sample of RNA-Seq data is a computationally expensive and complicated task, the detection of splicing events from RNA-Seq data and a gene annotation is computationally feasible. This latter task, which is adequate for many transcriptome analyses, is usually achieved by aligning the reads to a reference genome, followed by comparing the alignments with a gene annotation, often implicitly represented by a graph: the splicing graph. RESULTS: We present ASGAL (Alternative Splicing Graph ALigner): a tool for mapping RNA-Seq data to the splicing graph, with the specific goal of detecting novel splicing events, involving either annotated or unannotated splice sites. ASGAL takes as input the annotated transcripts of a gene and a RNA-Seq sample, and computes (1) the spliced alignments of each read in input, and (2) a list of novel events with respect to the gene annotation. CONCLUSIONS: An experimental analysis shows that ASGAL allows to enrich the annotation with novel alternative splicing events even when genes in an experiment express at most one isoform. Compared with other tools which use the spliced alignment of reads against a reference genome for differential analysis, ASGAL better predicts events that use splice sites which are novel with respect to a splicing graph, showing a higher accuracy. To the best of our knowledge, ASGAL is the first tool that detects novel alternative splicing events by directly aligning reads to a splicing graph. AVAILABILITY: Source code, documentation, and data are available for download at http://asgal.algolab.eu . PMID- 30458726 TI - Copper-induced increased expression of genes involved in photosynthesis, carotenoid synthesis and C assimilation in the marine alga Ulva compressa. AB - BACKGROUND: The marine alga Ulva compressa is the dominant species in coastal areas receiving effluents from copper mines. The alga can accumulate high amounts of copper and possesses a strong antioxidant system. Here, we performed short term transcriptomic analyses using total RNA of the alga cultivated with 10 MUM of copper for 0, 3, 6, 12 and 24 h by RNA-seq. RESULTS: De novo transcriptomes were assembled using the Trinity software, putative proteins were annotated and classified using Blast2GO. Differentially expressed transcripts were identified using edgeR. Transcript levels were compared by paired times 0 vs 3, 0 vs 6, 0 vs 12 and 0 vs 24 h at an FDR < 0.01 and Log2 Fold Change > 2. Up-regulated transcripts encode proteins belonging to photosystem II (PSII), Light Harvesting II Complex (LHCII), PSI and LHCI, proteins involved in assembly and repair of PSII, and assembly and protection of PSI. In addition, transcripts encoding enzymes leading to beta-carotene synthesis and enzymes belonging to the Calvin Benson cycle were also increased. We further analyzed photosynthesis and carotenoid levels in the alga cultivated with 10 MUM of copper for 0 to 24 h. Photosynthesis was increased from 3 to 24 h as well as the level of total carotenoids. The increase in transcripts encoding enzymes of the Calvin-Benson cycle suggests that C assimilation may also be increased. CONCLUSIONS: Thus, U. compressa displays a short-term response to copper stress enhancing the expression of genes encoding proteins involved in photosynthesis, enzymes involved carotenoids synthesis, as well as those belonging to the Calvin-Benson cycle, which may result in an increase in C assimilation. PMID- 30458728 TI - Haploid females in the isomorphic biphasic life-cycle of Gracilaria chilensis excel in survival. AB - BACKGROUND: Conditional differentiation is one of the most fundamental drivers of biodiversity. Competitive entities (usually species) differ in environmental or ecological niche enabling them to co-exist. Conditional differentiation of haploid and diploid generations is considered to be a requirement for the evolutionary stability of isomorphic biphasic life-cycles and the cause for the natural occurrence of both phases at uneven abundances. Theoretically, stage dependent survival rates are the most efficient way to explain conditional differentiation. RESULTS: We tested for conditional differentiation in survival rates among life stages (haploid males, haploid females, and diploids) of Gracilaria chilensis, an intertidal red alga occurring along the Chilean shores. Therefore, the fate of individuals was followed periodically for 3 years in five intertidal pools and, for the first time in isomorphic red algae, a composite model of the instantaneous survival rates was applied. The results showed the survival dependency on density (both competition and Allee effects), fertility, age, size, season and location, as well as the differentiation among stages for the survival dependencies of these factors. The young haploid females survived more than the young of the other stages under Allee effects during the environmentally stressful season at the more exposed locations, and under self thinning during the active growth season. Furthermore, fertile haploid females had a higher survival than fertile haploid males or fertile diploids. CONCLUSIONS: Here, we show a survival advantage of haploids over diploids. The haploid females probably optimize their resource management targeting structural and physiological adaptations that significantly enhance survival under harsher conditions. In a companion paper we demonstrate a fertility advantage of diploids over haploids. Together, the survival and fertility differentiation support the evolution and prevalence of biphasic life-cycles. PMID- 30458727 TI - Prognostic models for intracerebral hemorrhage: systematic review and meta analysis. AB - BACKGROUND: Prognostic tools for intracerebral hemorrhage (ICH) patients are potentially useful for ascertaining prognosis and recommended in guidelines to facilitate streamline assessment and communication between providers. In this systematic review with meta-analysis we identified and characterized all existing prognostic tools for this population, performed a methodological evaluation of the conducting and reporting of such studies and compared different methods of prognostic tool derivation in terms of discrimination for mortality and functional outcome prediction. METHODS: PubMed, ISI, Scopus and CENTRAL were searched up to 15th September 2016, with additional studies identified using reference check. Two reviewers independently extracted data regarding the population studied, process of tool derivation, included predictors and discrimination (c statistic) using a predesignated spreadsheet based in the CHARMS checklist. Disagreements were solved by consensus. C statistics were pooled using robust variance estimation and meta-regression was applied for group comparisons using random effect models. RESULTS: Fifty nine studies were retrieved, including 48,133 patients and reporting on the derivation of 72 prognostic tools. Data on discrimination (c statistic) was available for 53 tools, 38 focusing on mortality and 15 focusing on functional outcome. Discrimination was high for both outcomes, with a pooled c statistic of 0.88 for mortality and 0.87 for functional outcome. Forty three tools were regression based and nine tools were derived using machine learning algorithms, with no differences found between the two methods in terms of discrimination (p = 0.490). Several methodological issues however were identified, relating to handling of missing data, low number of events per variable, insufficient length of follow up, absence of blinding, infrequent use of internal validation, and underreporting of important model performance measures. CONCLUSIONS: Prognostic tools for ICH discriminated well for mortality and functional outcome in derivation studies but methodological issues require confirmation of these findings in validation studies. Logistic regression based risk scores are particularly promising given their good performance and ease of application. PMID- 30458729 TI - Metabolite differences between glutamate carboxypeptidase II gene knockout mice and their wild-type littermates after traumatic brain injury: a 7-tesla 1H-MRS study. AB - BACKGROUND: Traumatic brain injury (TBI) is a complex condition and remains a prominent public and medical health issue in individuals of all ages. A rapid increase in extracellular glutamate occurs after TBI, leading to glutamate induced excitotoxicity, which causes neuronal damage and further functional impairments. Although inhibition of glutamate carboxypeptidase II (GCP II) is considered a potential approach for reducing glutamate-induced excitotoxicity after TBI, further detailed evidence regarding its efficacy is required. Therefore, in this study, we examined the differences in the metabolite status between wild-type (WT) and GCP II gene-knockout (KO) mice after TBI using proton magnetic resonance spectroscopy (1H-MRS) and T2-weighted magnetic resonance (MR) imaging with a 7-tesla imaging system, and brain water-content analysis. RESULTS: Evaluation of glutamate and N-acetylaspartate concentrations revealed a decrease in both levels in the ipsilateral hippocampus at 24 h post-TBI; however, the reduction in glutamate and N-acetylaspartate levels was less marked in GCP II-KO mice than in WT mice (p < 0.05). T2 MR data and brain water-content analysis demonstrated that the extent of cortical edema and brain swelling was less in KO than in WT mice after TBI (p < 0.05). CONCLUSION: Using two non-invasive methods, 1H-MRS and T2 MR imaging, as well as in vitro brain-water content measurements, we demonstrated that the mechanism underlying the neuroprotective effects of GCP II-KO against brain swelling in TBI involves changes in glutamate and N acetylaspartate levels. This knowledge may contribute towards the development of therapeutic strategies for TBI. PMID- 30458730 TI - Relationship between transforming growth factor-beta1 and type 2 diabetic nephropathy risk in Chinese population. AB - BACKGROUND: Diabetes mellitus (DM) is divided into four different etiological categories: type 1 DM (T1DM), type 2 DM (T2DM), other specific types, and gestational DM. One severe complication of T2DM is type 2 diabetic nephropathy (T2DN). The possible association of serum transforming growth factor-beta1 (TGF beta1) levels and the TGF-beta1 T869C gene polymorphism with patient susceptibility to T2DN in Chinese population is unclear at present. This study was conducted to assess these relationships in Chinese population by a meta analysis. METHODS: Association reports were searched and pulled from the Cochrane Library, the China Biological Medicine Database (CBM), and PubMed on March 1, 2018, and eligible studies were selected and used for calculations. The results were expressed as weighted mean differences (MD) for continuous data. Odds ratios (OR) were used to express the results for dichotomous data. Additionally, 95% confidence intervals (CI) were calculated. RESULTS: Forty-eight reports for the relationship between serum TGF-beta1 levels and the risk of T2DN and 13 studies on the association of the TGF-beta1 T869C gene polymorphism with susceptibility to T2DN in Chinese population were retrieved from this study. Serum TGF-beta1 levels in the T2DM group were higher than those in the normal control group (MD = 17.30, 95% CI: 12.69-21.92, P < 0.00001). The serum TGF-beta1 level in the T2DN group was significantly higher than that in the normal control group (MD = 70.03, 95% CI: 60.81-79.26, P < 0.00001;). The serum TGF-beta1 level in the T2DN group was significantly higher than that in the T2DM group (MD = 56.18, 95% CI: 46.96 65.39, P < 0.00001). Serum TGF-beta1 levels in T2DM patients with microalbuminuria were increased when compared with those in T2DM patients with normoalbuminuria. Furthermore, serum TGF-beta1 levels in T2DM patients with macroalbuminuria were increased when compared with those in T2DM patients with microalbuminuria. The TGF-beta1 T allele, TT allele and CC genotype were associated with T2DN susceptibility in Chinese population (T: OR = 0.74, 95% CI: 0.59-0.92, P = 0.007; TT: OR = 0.55, 95% CI: 0.31-0.96, P = 0.04; CC: OR = 1.38, 95% CI: 1.14-1.67, P = 0.001). CONCLUSIONS: High levels of TGF-beta1 are associated with susceptibility to T2DM, T2DN and the progression of proteinuria in T2DN patients in Chinese population. Further, the TGF-beta1 T allele, and TT genotype were protective factors against the onset of T2DN and CC genotype was a risk factor for the susceptibility of T2DN in Chinese populations. PMID- 30458731 TI - Prediction of pathogenesis-related secreted proteins from Stemphylium lycopersici. AB - BACKGROUND: Gray leaf spot is a devastating disease caused by Stemphylium lycopersici that threatens tomato-growing areas worldwide. Typically, many pathogenesis-related and unrelated secreted proteins can be predicted in genomes using bioinformatics and computer-based prediction algorithms, which help to elucidate the molecular mechanisms of pathogen-plant interactions. RESULTS: S. lycopersici-secreted proteins were predicted from 8997 proteins using a set of internet-based programs, including SignalP v4.1 TMHMM v2.0, big-PI Fungal Predictor, ProtComp V9.0 and TargetP v1.1. Analysis showed that 511 proteins are predicted to be secreted. These proteins vary from 51 to 600 residues in length, with signal peptides ranging from 14 to 30 residues in length. Functional analysis of differentially expressed proteins was performed using Blast2GO. Gene ontology analysis of 305 proteins classified them into 8 groups in biological process (BP), 6 groups in molecular function (MF), and 10 groups in cellular component (CC). Pathogen-host interaction (PHI) partners were predicted by performing BLASTp analysis of the predicted secreted proteins against the PHI database. In total, 159 secreted proteins in S. lycopersici might be involved in pathogenicity and virulence pathways. Scanning S. lycopersici-secreted proteins for the presence of carbohydrate-active enzyme (CAZyme)-coding gene homologs resulted in the prediction of 259 proteins. In addition, 12 of the 511 proteins predicted to be secreted are small cysteine-rich proteins (SCRPs). CONCLUSIONS: S. lycopersici secretory proteins have not yet been studied. The study of S. lycopersici genes predicted to encode secreted proteins is highly significant for research aimed at understanding the hypothesized roles of these proteins in host penetration, tissue necrosis, immune subversion and the identification of new targets for fungicides. PMID- 30458732 TI - Selecting the optimal position of CDK4/6 inhibitors in hormone receptor-positive advanced breast cancer - the SONIA study: study protocol for a randomized controlled trial. AB - BACKGROUND: Combining cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors with endocrine therapy is an effective strategy to improve progression-free survival in hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. There is a lack of comparative data to help clinicians decide if CDK4/6 inhibitors can best be added to first- or second line endocrine therapy. Improvement in median progression-free survival in first line studies is larger than in second-line studies, but CDK4/6 inhibitors have not consistently shown to improve overall survival or quality of life. They do come with added toxicity and costs, and many patients have lasting disease remission on endocrine therapy alone. No subgroup has been identified to select patients who are most likely to benefit from the addition of CDK4/6 inhibition in any line of treatment. Altogether, these factors make that the optimal strategy for using CDK4/6 inhibitors in clinical practice is unknown. METHODS: The SONIA study is an investigator-initiated, multicenter, randomized phase III study in patients with HR+/HER2-negative advanced breast cancer. Patients are randomly assigned to receive either strategy A (first-line treatment with a non-steroidal aromatase inhibitor combined with CDK4/6 inhibition, followed on progression by fulvestrant) or strategy B (first-line treatment with a non-steroidal aromatase inhibitor, followed on progression by fulvestrant combined with CDK4/6 inhibition). The primary objective is to test whether strategy A is more effective than strategy B. The primary endpoint is time from randomization to second objective progression (PFS2). Secondary endpoints include overall survival, safety, quality of life, and cost-effectiveness. Five-hundred seventy four events yield 89% power to show that strategy A has statistically significant, clinically meaningful superior PFS2 (according to ESMO-MCBS) in a log-rank test at the two-sided 95% confidence level. Given an accrual period of 42 months and an additional 18 months follow-up, inclusion of 1050 evaluable patients is required. DISCUSSION: This study design represents daily clinical practice, and the results will aid clinicians in deciding when adding CDK4/6 inhibitors to endocrine therapy will benefit their patients most. Additional biomarker analyses may help to optimize patient selection. TRIAL REGISTRATION: http://clinicaltrials.gov: NCT03425838 (8 February 2018). EudraCT-number: 2017 002334-23 (29 September 2017). PMID- 30458733 TI - The treatment and risk factors of retinopathy of prematurity in neonatal intensive care units. AB - BACKGROUND: Retinopathy of prematurity (ROP) is a vascular proliferative disorder of the developing retina and a significant cause of childhood blindness around the world. The incidence of ROP is affected by many factors, and the incidence rate varies from country to country. The purpose of this study is to report the incidence and risk factors of ROP in neonatal intensive care unit (NICU) of Guangzhou First People's Hospital in China. METHODS: A retrospective review was performed on 436 premature infants who were consecutive ROP screened in the NICU of Guangzhou First People's Hospital from March 2013 to October 2017. The single factor analysis and the logistic multivariate regression analysis were used to detect risk factors of ROP. RESULTS: Total 436 premature infants were consecutive ROP screened, 138 (31.65%) were found ROP, and 61(13.99%) were treated. The single-factor analysis revealed that the incidence of ROP was associated with multiple births, gestational age, birth weight, mechanical ventilation, intravascular hemolysis, the number of operations and blood culture results. The logistic multivariate regression analysis revealed that gestational age; birth weight, mechanical ventilation, minimum SaO2 and daily weight gain were independent risk factors for ROP onset. Forty-nine patients underwent retinal laser photocoagulation with recurrence 20 patients. Twelve patients underwent anti-VEGF drug (Ranibizumab) via intraocular injection with 5 patients of recurrence. CONCLUSIONS: The incidence of ROP in NICU of Guangzhou China will match those in middle-income countries, but higher than high-income countries. Anti-VEGF drugs could be preferred as a good treatment method for zone 1 ROP and aggressive posterior ROP. PMID- 30458734 TI - CEA clearance pattern as a predictor of tumor response to neoadjuvant treatment in rectal cancer: a post-hoc analysis of FOWARC trial. AB - BACKGROUND: The clinical factors that accurately predict the response to preoperative treatment in rectal cancer were yet unknown. The carcinoembryonic antigen (CEA) clearance pattern during neoadjuvant treatment has been developed and the predictive value explored in rectal cancer patients with elevated CEA levels (> 5 ng/mL). METHODS: The training cohort was derived from the FOWARC prospective phase III trial, and 71/483 eligible patients were included. The validation cohort consisted of 75/587 consecutive rectal cancer patients from Xiangya Hospital between 2014 and 2015. The kinetic changes in serum CEA were measured at different time points during the neoadjuvant treatment. An exponential trend line was drawn using the CEA values. The patients were categorized into two groups based on the R2 value of the trend line, which indicates the correlation coefficient between the exponential graph and measured CEA values: exponential decrease group (0.9 < R2 <= 1.0) and non-exponential decrease group (R2 <= 0.9). RESULTS: In multivariate analysis, the patients in the CEA exponential decrease group had significantly high adequate rate of downstaging (ypT0-2N0M0), and pathologic complete response (pCR) rates after neoadjuvant treatment in the training cohort. The predictive values of the CEA clearance pattern for tumor downstaging and pCR were further confirmed in an independent validation cohort. CONCLUSIONS: The CEA clearance pattern was an independent predictor of tumor response to neoadjuvant treatment in patients with rectal cancer. It might serve as an adjunct in the assessment of complete clinical response and guide individualized treatment strategies. TRIAL REGISTRATION: NCT01211210. PMID- 30458735 TI - Validation of the Farsi version of the medical outcomes study-social support survey for mammography. AB - BACKGROUND: Social support can provide psychosocial benefits to promote positive health behaviors such as mammography screening. The purpose of this study was to assess the psychometric properties of the Mammography Social Support (MSS) scale among Iranian woman. METHODS: Participants were selected from women referring to healthcare centers in Sanandaj, Iran. A total of 434 questionnaires were completed (response rate 91%). The study sample for study 1 included 204 participants for the Exploratory Factor Analysis (EFA). Construct validity was determined by confirmatory factor analysis (CFA) using a study sample of 230 women in study 2. The reliability coefficient for each scale was calculated using Cronbach's alpha, corrected item-total correlations and test-retest respectively. RESULTS: CFA affirmed the three-factor structure of the MSS in measuring the functional dimensions of social support for mammography behavior consisting of 19 items. Initial results of the CFA did not fully support the proposed three-factor model. After the model was modified, the fit indices indicated, x2 was 2.3, Comparative Fit Index (CFI) = 0.96, Tucker- Lewis Index (TLI) = 0.95 providing a strong fit to the data. Cronbach's alphas for the subscales ranged from 0.82 and 0.90, whereas the alpha for the overall scale was 0.91. The 2-week test-retest reliability of MSS was 0.95. CONCLUSION: This study provides evidence for the psychometric properties to support the Farsi version of the MSS when applied to Iranian women. Exploring the three-factor model in relation to related concepts is suggested for future studies. PMID- 30458736 TI - An IgA1-lambda-type monoclonal immunoglobulin deposition disease associated with membranous features in a patient with IgG4-related kidney disease: a case report. AB - BACKGROUND: IgG4-related disease (IgG4-RD) is a newly recognized fibroinflammatory condition. The kidney is one of the organs commonly affected by IgG4-RD. Tubulointerstitial nephritis (TIN) is the main feature, and membranous nephropathy (MN) has also been described frequently. In MN, polyclonal immunoglobulins and complements are deposited in granular form along the glomerular basement membranes (GBMs). Unusual cases of monoclonal immunoglobulin deposition disease (MIDD) associated with membranous features have been reported. MIDD is morphologically similar to MN but contains immunoglobulins considered to be derived from single B-cell clone. CASE PRESENTATION: We describe a 65-year-old man who was referred to our hospital because of hyperproteinaemia, eosinophilia, anaemia, and proteinuria. A renal biopsy demonstrated infiltration of plasma cells and eosinophils in the interstitium, and the ratio of IgG4-positive plasma cells to IgG-positive plasma cells was 55%. The patient was diagnosed as having IgG4-related TIN. Periodic acid methenamine silver staining under light microscopy revealed a bubbling appearance and spike formation in the GBM. On immunofluorescence, the expression of IgG and complements was negative; however, IgA was positively expressed in a granular pattern along the GBM. An IgA subclass analysis revealed a significant deposition of IgA1-lambda (IgA1-lambda). Electron microscopy revealed irregular and small non-organized and non-Randall-type granular electron-dense deposits in the GBM that were shaped like snow leopard spots. CONCLUSIONS: After corticosteroid therapy was initiated, the patient's eosinophilia remarkably improved and his serum creatinine, IgG, and IgG4 levels decreased to within the normal ranges. However, massive proteinuria persisted. To our knowledge, this is the first reported case of IgG4-related TIN associated with IgA1-lambda-type MIDD with membranous features. PMID- 30458737 TI - Rehabilitation of Executive function in Paediatric Traumatic brain injury (REPeaT): protocol for a randomized controlled trial for treating working memory and decision-making. AB - BACKGROUND: Working memory allows us to hold information in an active state for short periods of time, and is essential in facilitating goal directed cognitive functioning. Difficulties in working memory and decision-making are common post childhood Traumatic Brain Injury (TBI). Despite this, there is a paucity of research pertaining to implementation and effectiveness of interventions to reduce these common difficulties which impact significantly on one's ability to function independently. One such intervention, Cogmed Working Memory Training Program, has shown success in improving working memory in other childhood clinical populations, but has received little evaluation in the TBI area. This study aims to evaluate whether Cogmed improves working memory and decision-making post childhood TBI and whether these benefits generalize to functional areas. METHODS: The study is a randomized controlled trial (RCT) of the Cogmed (RM version) intervention for children post-TBI. Children aged 7-15 years are initially screened for working memory impairments. Eligible participants are then randomized into either the treatment group (Cogmed) or the active-control group (Lexia Reading). Each group trains online for 50 min each day, 5 days per week, for 5 consecutive weeks. The online training is supported by online clinician meetings each week. Outcome neuropsychological and functional assessments are carried out immediately at the completion of the intervention and at 6 months follow-up. DISCUSSION: This study follows gold standard methodology in intervention research; uses a novel measure of decision-making; measures the effects of intervention on functional outcomes immediately and longer-term post intervention; uses online clinician support in order to allow more families easy access to the program; and promotes the use of technology to improve health services. If efficacious in improving working memory, decision-making, and functional outcomes, our team will then take a key role in implementing Cogmed into clinical care. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12617000085370 . Trial Registration Date: 16/01/2017. Protocol Version/Date: HREC 35181G/18.08.2017. Study Status: Ongoing. PMID- 30458738 TI - A novel MRI- and CT-based scoring system to differentiate malignant from osteoporotic vertebral fractures in Chinese patients. AB - BACKGROUND: Various types of magnetic resonance imaging (MRI) and computed tomography (CT) findings are used to differentiate malignant vertebral fractures (MVFs) from osteoporotic vertebral fractures (OVFs). The distinguishing ability of any single finding is limited. This study developed a novel scoring system that integrates multiple MRI and CT signs for improved accuracy of differential diagnosis between MVFs and OVFs. METHODS: A total of 150 MVFs and 150 OVFs in thoracolumbar vertebrae were analyzed. MRI and CT images were obtained within 2 months of the probable time of fracture. The sensitivity and specificity of 15 MRI and CT image findings were evaluated. A stepwise discriminant analysis using these signs as variables was used to create a scoring system to differentiate MVFs from OVFs. RESULTS: All 15 image findings had strong specificity and moderate sensitivity. Seven MRI and three CT image findings were selected and assigned integral values in the final scoring system. A total score of 4 or greater points indicated MVF, whereas a total score of 3 or fewer points indicated OVF. The classification accuracy was 98.3% in the test set. CONCLUSIONS: This novel scoring system using MRI and CT radiologic findings to differentiate MVFs from OVFs in Chinese patients was efficient with high accuracy and good applicability. PMID- 30458739 TI - Marked deterioration in the quality of life of patients with idiopathic pulmonary fibrosis during the last two years of life. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic disease with a high symptom burden and poor survival that influences patients' health-related quality of life (HRQOL). We aimed to evaluate IPF patients' symptoms and HRQOL in a well documented clinical cohort during their last two years of life. METHODS: In April 2015, we sent the Modified Medical Research Council Dyspnea Scale (MMRC), the modified Edmonton Symptom Assessment Scale (ESAS) and a self-rating HRQOL questionnaire (RAND-36) to 300 IPF patients, of which 247 (82%) responded. Thereafter, follow-up questionnaires were sent every six months for two years. RESULTS: Ninety-two patients died by August 2017. Among these patients, HRQOL was found to be considerably low already two years before death. The most prominent declines in HRQOL occurred in physical function, vitality, emotional role and social functioning (p < 0.001). The proportion of patients with MMRC scores >=3 increased near death. Breathlessness and fatigue were the most severe symptoms. Symptom severity for the following symptoms increased significantly and reached the highest mean scores during the last six months of life (numeric rating scale/standard deviation): breathlessness (7.1/2.8), tiredness (7.0/2.3), dry mouth (6.0/3.0), cough (5.8/2.9), and pain with movement (5.0/3.5). CONCLUSIONS: To our knowledge this is the first study demonstrating, that IPF patients experience remarkably low HRQOL already two years before death, especially regarding physical role. In addition, they suffer from severe breathlessness and fatigue. Furthermore, physical, social and emotional wellbeing deteriorate, and symptom burden increases near death. Regular symptom and HRQOL measurements are essential to assess palliative care needs in patients with IPF. PMID- 30458740 TI - Preventing neonatal sepsis in rural Uganda: a cross-over study comparing the tolerance and acceptability of three alcohol-based hand rub formulations. AB - BACKGROUND: Neonatal sepsis causes 0.5 million deaths annually, mostly in low resource settings. Babies born in African rural homes without running water or toilet facilities are especially vulnerable. Alcohol-based hand rub (ABHR) may be used by mothers and carers as an alternative to hand washing with soap to prevent neonatal infection. However, no definite study has established the preferred formulation of hand rub for the mothers. This study aimed to assess the effects of addition of bitterants and perfume towards the acceptability of the alcohol based hand rubs by the mothers in their homes after childbirth. METHODS: This was a 3-way blinded cross-over study design. Mothers with children aged <=3 months were recruited from immunisation clinics at 3 local health facilities in rural eastern Uganda and received 3-different ABHR formulations (in the order plain, bitterant and perfumed) packed in 100 ml bottles. Each ABHR was used for 5 consecutive days followed by a 2-day 'washout' period (evaluation period). Overall satisfaction with each hand rub was evaluated at the end of each week using a 7-point Likert scale. RESULTS: A total of 43 women were recruited, whose ages ranged from 16 to 45 years (mean 26.2 years old). None of the participants normally used a hand protective lotion/cream. The three formulations were used for a mean of 5 (range 3-7) days. A significantly greater volume of the "bitterant" and "perfumed" formulations (mean 91 and 83 ml respectively) were used in comparison to the "plain" formulation (mean 64 ml). Overall satisfaction was high with all the hand rubs, but the perfumed formulation had a significantly higher overall satisfaction score [mean 6.7, range 4-7] compared with the plain [6.4, 3-7] and bitterant [6.2, 2-7] formulations. CONCLUSIONS: All the 3 ABHR formulations were well accepted with little to choose between them. The ABHR with added perfume scored highest on overall satisfaction and was used significantly more often than plain ABHR. ABHR with bitterant additive did, however, score highly and may be a preferable choice to those with concern over alcohol misuse. TRIAL REGISTRATION: ISRCTN67852437 , prospectively registered on 18/03/2018. PMID- 30458741 TI - Borderline grades in high stakes clinical examinations: resolving examiner uncertainty. AB - BACKGROUND: Objective Structured Clinical Exams are used to increase reliability and validity, yet they only achieve a modest level of reliability. This low reliability is due in part to examiner variance which is greater than the variance of students. This variance often represents indecisiveness at the cut score with apparent confusion over terms such as "borderline pass". It is amplified by a well reported failure to fail. METHODS: A borderline grade (meaning performance is neither a clear pass nor a clear fail) was introduced in a high stakes undergraduate medical clinical skills exam to replace a borderline pass grade (which was historically resolved as 50%) in a 4 point scale (distinction, pass, borderline, fail). Each Borderline grade was then resolved into a Pass or Fail grade by a formula referencing the difficulty of the station and the performance in the same domain by the student in other stations. Raw pass or fail grades were unaltered. Mean scores and 95%CI were calculated per station and per domain for the unmodified and the modified scores/grades (results are presented on error bars). To estimate the defensibility of these modifications, similar analysis took place for the P and the F grades which resulted from the modification of the B grades. RESULTS: Of 14,634 observations 4.69% were Borderline. Application of the formula did not impact the mean scores in each domain but the failure rate for the exam increased from 0.7 to 4.1%. Examiners and students expressed satisfaction with the Borderline grade, resolution formula and outcomes. Mean scores (by stations and by domains respectively) of students whose B grades were modified to P were significantly higher than their counterparts whose B grades were modified to F. CONCLUSIONS: This study provides a feasible and defensible resolution to situations where the examinee's performance is neither a clear pass nor a clear fail, demonstrating the application of the resolution of borderline formula in a high stakes exam. It does not create a new performance standard but utilises real data to make judgements about these small number of candidates. This is perceived as a fair approach to Pass/Fail decisions. PMID- 30458742 TI - A workplace intervention to reduce alcohol and drug consumption: a nonrandomized single-group study. AB - BACKGROUND: The consumption of alcohol and other drugs causes social and health problems in industrialized societies. Furthermore, alcohol and drug consumption in the workplace is associated with work accidents, absenteeism and low productivity. The aim of the current study is to reduce alcohol and drug consumption among workers in the service industry and, as a secondary aim, to improve their healthy habits through the reduction of alcohol and other drug consumption in their leisure time. METHODS: This nonrandomized, single-group study was conducted in 12 work centers. The intervention began in 2009 and emphasized 1) health promotion and health monitoring, which included a) alcohol and drug awareness and b) the evaluation and monitoring of alcohol and drug consumption through a semistructured interview designed to assess risky consumption; urine tests aimed at detecting alcohol, cannabis and cocaine use; an Alcotest based on expired air to test for the recent consumption of alcohol and a saliva exam to test for the recent consumption of six drugs; and 2) secondary prevention if risky consumption was identified. Risky alcohol consumption was defined as the ingestion of more than 28 standard drink units (SDUs)/week among men and more than 17 SDUs/week among women (taking into account both work and leisure time). Drug consumption was considered risky consumption. RESULTS: A total of 1103 workers participated, and each received 5 h of awareness training. Those who presented with risky consumption received secondary prevention training. The prevalence of risky alcohol consumption decreased by 4.1% (baseline: 14.7% reduced to 10.6% in the first year; p = 0.001), a reduction that was maintained over a 3-year follow-up period. CONCLUSION: A comprehensive program of worker health surveillance that involves stakeholders and includes monitoring can be a means of potentially improving compliance with workplace promotion programs, resulting in the facilitation of such beneficial, desired behavior change in areas such as alcohol and drug consumption. PMID- 30458744 TI - Bilateral Xp11.2 translocation renal cell carcinoma: a case report. AB - BACKGROUND: Xp11.2 translocation renal cell carcinoma (RCC) is a rare variety of a kidney neoplasm. We report a case of bilateral Xp11.2 translocation RCC occurring metachronously and discuss this very rare entity with reference to the literature. CASE PRESENTATION: The patient was a 56-year-old woman who presented with a right renal tumor. The patient had undergone left radical nephrectomy 7 years previously, which resulted in a histopathological diagnosis of clear cell RCC. Open right partial nephrectomy was performed under the presumptive diagnosis of recurrence of clear cell RCC. The present right renal tumor was pathologically diagnosed Xp11.2 translocation RCC. More than 70% of the tumor cells in the present right tumor were strongly positive for transcription factor E3 (TFE3) expression by immunohistochemical analysis with an anti-TFE3 antibody. A break apart of the TFE3 genes in the bilateral tumors was identified by fluorescence in situ hybridization analysis. Real time-polymerase chain reaction analysis for the alveolar soft part sarcoma locus-TFE3 fusion gene was performed, which gave a positive result in the bilateral tumors. Pathological comparison of each of the tumors might lead to a final diagnosis of Xp11.2 translocation RCC occurring metachronously. CONCLUSIONS: We present the bilateral Xp11.2 translocation RCC. A combination of immunohistochemical, cytogenetic and molecular biological approaches allowed the final diagnosis of such a rare RCC. PMID- 30458743 TI - MiR-155, a potential serum marker of extramammary Paget's disease. AB - BACKGROUND: Extramammary Paget's disease (EMPD), a rare skin malignancy with non specific manifestations, is often misdiagnosed as eczema of scrotum or tinea cruris. Although the diagnosis of EMPD could be confirmed by biopsy, it can be delayed as patients are reluctant to receive invasive operations. Herein, we investigated the serum miRNA expressions of EMPD patients and compared to that of the eczema of scrotum or tinea cruris patients as well as health volunteers for potential diagnostic markers for EMPD. METHODS: Altogether 45 subjects including 16 patients diagnosed with EMPD, 12 patients diagnosed with eczema of scrotum or tinea cruris and 17 healthy volunteers were enrolled in this study. Serum from all of subjects were collected to identify miRNAs (by miRNA array global normalization, RT-PCR validation, and receiver operating characteristic curve analysis) that could be potential diagnostic markers for EMPD. RESULTS: The miRNA array analyses revealed that the expressions of 37 miRNAs from the EMPD patients were different (change >=4-fold) from health volunteers. Among these miRNAs, the expression of miR-155 was significantly increased (p < 0.01) in the EMPD patients as compared with that of the health volunteers and the eczema of scrotum or the tinea cruris patients (no difference between these two control groups). In addition, receiver operating characteristic (ROC) curve analysis showed that diagnostic capacities (defined as the area under curve of ROC) of miR-155 are 0.85 (as compared with health volunteers group) and 0.81 (as compared with the eczema of scrotum or the tinea cruris patients group), respectively. CONCLUSION: The serum miRNA expression of gene miR-155 in the EMPD patients was differentiated from that of other subjects warranting further validation of miR 155 as a diagnostic marker of EMPD. PMID- 30458745 TI - Clinical implications of fracture-associated vascular damage in extremity and pelvic trauma. AB - BACKGROUND: Vascular damage in polytrauma patients is associated with high mortality and morbidity. Therefore, specific clinical implications of vascular damage with fractures in major trauma patients are reassessed. METHODS: This comprehensive nine-year retrospective single center cohort study analyzed demography, laboratory, treatment and outcome data from 3689 patients, 64 patients with fracture-associated vascular injuries were identified and were compared to a control group. RESULTS: Vascular damage occurred in 7% of patients with upper and lower limb and pelvic fractures admitted to the trauma room. Overall survival was 80% in pelvic fracture and 97% in extremity fracture patients and comparable to non-vascular trauma patients. Additional arterial damage required substantial fluid administration and was visible as significantly anemia and disturbed coagulation tests upon admission. Open procedures were done in over 80% of peripheral extremity vascular damage. Endovascular procedures were predominant (87%) in pelvic injury. CONCLUSION: Vascular damage is associated with high mortality rates especially in combination with pelvic fractures. Initial anemia, disturbed coagulation tests and the need for extensive pre clinical fluid substitution were observed in the cohort with vascular damage. Therefore, fast diagnosis and early interventional and surgical procedures are necessary to optimize patient-specific outcome. PMID- 30458746 TI - Anticipatory grief of spousal and adult children caregivers of people with dementia. AB - BACKGROUND: Anticipatory grief (AG) among caregivers of people with dementia is common and has been found to be related to negative health outcomes. Previous studies showed different patterns of AG between spousal and adult children caregivers of people with dementia (PWD) at different stages; however, the levels of such grief are not yet compared. The findings in Western studies are very limited, and inconsistencies have also been found in Asian studies. METHODS: One hundred and eight primary caregivers (54 spousal and 54 adult children) of community-dwelling PWD were recruited from elderly community services sectors in Hong Kong, China through quota sampling. The demographics, AG (measured by the Marwit-Meuser Caregiver Grief Inventory-short form), subjective caregiver burden, and well-being of the participants were assessed. A Functional Assessment Staging Test was used to grade the stages of dementia of the PWD. In this study, those in stages 4 and 5 were regarded as being at an earlier stage, and those in stages 6 and 7 at a later stage of dementia. The Mann-Whitney U-test and the Chi-square test were used to compare the variables between spousal and adult children caregivers, and the Kruskal-Wallis test was used to compare the outcomes among the sub-groups (spousal caregivers caring for relatives with earlier/later stage dementia; and adult children caregivers caring for relatives with earlier/later stage dementia). A post-hoc analysis was also conducted to identify differences between the sub-groups. Pearson's correlation was performed to investigate the bivariate relationships among AG, subjective caregiver burden, and well-being. RESULTS: The results showed that spousal caregivers caring for relatives in a later stage of dementia experienced the highest level of AG and subjective caregiving burden, as compared with spousal caregivers caring for relatives in an earlier stage of dementia and adult children caregivers. Well-being was significantly negatively correlated with AG and subjective caregiver burden, while AG was also significantly correlated with subjective caregiver burden. CONCLUSION: This study found that spousal caregivers of relatives in a later stage of dementia have significantly higher levels of AG, warranting special attention and extra support from palliative professionals. PMID- 30458748 TI - Longitudinal association between obesity and periodontal diseases among secondary school students in Hong Kong: a prospective cohort study. AB - BACKGROUND: There is no consensus opinion regarding the association between obesity and periodontal diseases among children and adolescents in the literature. METHODS: A prospective observational cohort study was conducted in a Hong Kong cohort at age 12, 15 and 18. CPI and various obesity indices including BMI, WC, WHR, WHtR, and TRSKF were recorded during each wave of data collection. Information on socioeconomic status and oral health behaviors were collected through self-completed questionnaires. RESULTS: Two hundred and eighty-two (male: 122 and female: 160) participants completed all three rounds of data collection. Prevalence of overweight/obesity was 27.0, 19.1, and 14.2% at 12, 15, and 18 years, respectively. 19.9% participants had healthy periodontal conditions at age 12. While the percentage dropped to 10.3% at 15 years and 5.7% at 18 years. The proportion of 15-year-old adolescents who brushed teeth more than twice a day was significantly higher among participants belonging to the lower BMI, WC, WHR, and WHtR category (P < 0.05). The fully adjusted model revealed that participants with lower BMI at age 15 had higher probability of having more than 50% index teeth free from periodontal diseases at age 18 (OR: 2.78; 95% CI: 1.16, 6.64; P = 0.022). CONCLUSIONS: Although higher BMI at 15 years was associated with more extensive periodontal inflammation at age 18, this was believed to be an indirect association confounded by the poor oral health care among overweight/obese individuals. Oral health promotions should be directed to improve periodontal conditions of overweight/obese secondary school students. PMID- 30458747 TI - A post-market, prospective, multi-center, single-arm clinical investigation of PhasixTM mesh for VHWG grade 3 midline incisional hernia repair: a research protocol. AB - BACKGROUND: Incisional heia is a frequent complication of midline laparotomy. The use of mesh in hernia repair has been reported to lead to fewer recurrences compared to primary repair. However, in Ventral Hernia Working Group (VHWG) Grade 3 hernia patients, whose hernia is potentially contaminated, synthetic mesh is prone to infection. There is a strong preference for resorbable biological mesh in contaminated fields, since it is more able to resist infection, and because it is fully resorbed, the chance of a foreign body reaction is reduced. However, when not crosslinked, biological resorbable mesh products tend to degrade too quickly to facilitate native cellular ingrowth. PhasixTM Mesh is a biosynthetic mesh with both the biocompatibility and resorbability of a biological mesh and the mechanical strength of a synthetic mesh. This multi-center single-arm study aims to collect data on safety and performance of PhasixTM Mesh in Grade 3 hernia patients. METHODS: A total of 85 VHWG Grade 3 hernia patients will be treated with PhasixTM Mesh in 15 sites across Europe. The primary outcome is Surgical Site Occurrence (SSO) including hematoma, seroma, infection, dehiscence and fistula formation (requiring intervention) through 3 months. Secondary outcomes include recurrence, infection and quality of life related outcomes after 24 months. Follow-up visits will be at drain removal (if drains were not placed, then on discharge or staple removal instead) and in the 1st, 3rd, 6th, 12th, 18th and 24th month after surgery. CONCLUSION: Based on evidence from this clinical study Depending on the results this clinical study will yield, PhasixTM Mesh may become a preferred treatment option in VHWG Grade 3 patients. TRIAL REGISTRATION: The trial was registered on March 25, 2016 on clinicaltrials.gov: NCT02720042 . PMID- 30458749 TI - Classifying development stages of primeval European beech forests: is clustering a useful tool? AB - BACKGROUND: Old-growth and primeval forests are passing through a natural development cycle with recurring stages of forest development. Several methods for assigning patches of different structure and size to forest development stages or phases do exist. All currently existing classification methods have in common that a priori assumptions about the characteristics of certain stand structural attributes such as deadwood amount are made. We tested the hypothesis that multivariate datasets of primeval beech forest stand structure possess an inherent, aggregated configuration of data points with individual clusters representing forest development stages. From two completely mapped primeval beech forests in Albania, seven ecologically important stand structural attributes characterizing stand density, regeneration, stem diameter variation and amount of deadwood are derived at 8216 and 9666 virtual sampling points (moving window, focal filtering). K-means clustering is used to detect clusters in the datasets (number of clusters (k) between 2 and 5). The quality of the single clustering solutions is analyzed with average silhouette width as a measure for clustering quality. In a sensitivity analysis, clustering is done with datasets of four different spatial scales of observation (200, 500, 1000 and 1500 m2, circular virtual plot area around sampling points) and with two different kernels (equal weighting of all objects within a plot vs. weighting by distance to the virtual plot center). RESULTS: The clustering solutions succeeded in detecting and mapping areas with homogeneous stand structure. The areas had extensions of more than 200 m2, but differences between clusters were very small with average silhouette widths of less than 0.28. The obtained datasets had a homogeneous configuration with only very weak trends for clustering. CONCLUSIONS: Our results imply that forest development takes place on a continuous scale and that discrimination between development stages in primeval beech forests is splitting continuous datasets at selected thresholds. For the analysis of the forest development cycle, direct quantification of relevant structural features or processes might be more appropriate than classification. If, however, the study design demands classification, our results can justify the application of conventional forest development stage classification schemes rather than clustering. PMID- 30458750 TI - The association between multisite musculoskeletal pain and cardiac autonomic modulation during work, leisure and sleep - a cross-sectional study. AB - BACKGROUND: The prevention and rehabilitation of multisite musculoskeletal pain would benefit from studies aiming to understand its underlying mechanism. Autonomic imbalance is a suggested mechanism for multisite pain, but hardly been studied during normal daily living. Therefore, the aim of the study is to investigate the association between multisite musculoskeletal pain and cardiac autonomic modulation during work, leisure and sleep. METHODS: This study is based on data from the "Danish Physical activity cohort with objective measurements" among 568 blue-collar workers. Pain intensity scales were dichotomized according to the median of each scale, and the number of pain sites was calculated. No site was regarded as the pain-free, one site was considered as single-site musculoskeletal pain and pain in two or more sites was regarded as multisite musculoskeletal pain. Heart rate variability (HRV) was measured by an electrocardiogram system (ActiHeart) and physical activity using accelerometers (Actigraph). Crude and adjusted linear mixed models were applied to investigate the association between groups and cardiac autonomic regulation during work, leisure and sleep. RESULTS: There was no significant difference between groups and no significant interaction between groups and domains in the crude or adjusted models for any HRV index. Significant differences between domains were found in the crude and adjusted model for all indices, except SDNN; sleep time showed higher values than leisure and work time, except for LF and LF/HF, which were higher during work. CONCLUSION: This cross-sectional study showed that multisite musculoskeletal pain is not associated with imbalanced cardiac autonomic regulation during work, leisure and sleep time. PMID- 30458751 TI - Erlotinib versus gefitinib for brain metastases in Asian patients with exon 19 EGFR-mutant lung adenocarcinoma: a retrospective, multicenter study. AB - BACKGROUND: The purpose of this study was to compare clinical outcomes of Erlotinib versus Gefitinib in the treatment of Asian patients with exon 19 EGFR mutant lung adenocarcinoma and newly diagnosed brain metastases. METHODS: Consecutive Asian patients with exon 19 EGFR-mutant lung adenocarcinoma and newly diagnosed brain metastases were identified and initially received peroral administration of 150 mg/d erlotinib or 250 mg/d gefitinib during 2009-2015. Overall survival (OS) was the primary endpoint. Progression-free survival (PFS) was the second endpoint. RESULTS: The cohort consisted of 227 Asian patients (erlotinib-treated cohort: n = 112, mean age = 58.5 years [SD: 20.13]; gefitinib treated cohort: n = 115, mean age = 58.4 years [SD: 19.52]). In a multivariate analysis controlling for age, sex and time span of smoking history, significant difference was detected in the 36-month OS between erlotinib and gefitinib groups (58.3% vs. 49.1%, p = 0.012). There was also significant difference in the 36 month PFS between erlotinib and gefitinib groups (64% vs. 53%, p = 0.013). CONCLUSION: For Asian patients with exon 19 EGFR-mutant lung adenocarcinoma and brain metastases, erlotinib was associated with a significantly longer OS and a more prolonged PFS and compared with gefitinib. PMID- 30458752 TI - First trimester medication use in pregnancy in Cameroon: a multi-hospital survey. AB - BACKGROUND: There is a paucity of epidemiological data on medication use in pregnancy in Cameroon. METHODS: Between March and August 2015, 795 pregnant women attending 8 urban and 12 rural hospitals in Cameroon for antenatal (ANC) or other care were interviewed on first trimester medication use using structured questionnaires. Multivariate logistic regression was used to analyse the association of 18 sociodemographic factors with medication use. RESULTS: A total of 582 (73.2%) women took at least one orthodox (Western) medication during the first trimester, 543 (68.3%) women a non-pregnancy related orthodox medication, and 336 (42.3%)women a pregnancy related orthodox medication. 44% of the women took anti-infectives including antimalarials (33.6%) and antibiotics (20.8%).The other most common medications were analgesics (48.8%) and antianaemias (38.6%). Sulfadoxine/pyrimethamine, contraindicated in the first trimester of pregnancy, was the most commonly used antimalarial(13% of women).0.2% of women reported antiretroviral use. Almost 80% of all orthodox medications consumed by women were purchased from the hospital. 12.8% of the women self-prescribed. Health unit and early gestational age at ANC booking were consistent determinants of prescribing of non-pregnancy related, pregnancy related and anti-infective medications. Illness and opinion on the safety of orthodox medications were determinants of the use of non-pregnancy related medications and anti-infectives. Age and parity were associated only with non-pregnancy related medications. CONCLUSION: This study has confirmed the observations of studies across Africa indicating the increasing use of medications during pregnancy. This is an indication that access to medicine is improving and more emphasis now must be placed on medication safety systems targeting pregnant women, especially during the first trimester when the risk of teratogenicity is highest. PMID- 30458753 TI - Validity assessment of quantitative light-induced fluorescence-digital (QLF-D) for the dental plaque scoring system: a cross-sectional study. AB - BACKGROUND: The aim of this study was to analyze the correlation between the dental plaque indices measured using quantitative light-induced fluorescence digital (QLF-D) and conventional clinical indices that assess gingival status. METHODS: From among the patients who visited Ewha Womans University Mokdong Hospital, 33 adults in their 20s who had relatively even teeth were selected for full-mouth QLF-D imaging. The images were used to analyze the QLF-D score and the QLF-D DeltaR score. As clinical indices, the gingival index (GI), bleeding on probing (BOP), probing pocket depth (PPD), and patient hygiene performance (PHP) index were measured. The correlations between the QLF-D score and QLF-D DeltaR score and each clinical index were analyzed. Analyses were performed comparing the indices of maxillary and mandibular teeth, the teeth on right and left sides of the mouth, anterior and posterior teeth, and buccal and lingual surfaces of each tooth. Pearson's correlation analysis was conducted (p < 0.05). RESULTS: The mean full-mouth QLF-D score was highly correlated with the GI, BOP, PPD, PHP index (p < 0.01). The mean full-mouth QLF-D score showed the highest correlation with GI (r = 0.749) and the lowest correlation with PPD (r = 0.683). The correlations between the QLF-D score were higher in the mandible than in the maxilla and in the anterior teeth than in the posterior teeth, while no significant differences were seen between the buccal and lingual surfaces of tooth. CONCLUSIONS: This study concluded that the correlations between the plaque indices measured for each tooth surface area using QLF-D and the clinical indices assessed were significantly high, and it allowed objective determination of the gingival status. Therefore, the plaque index measured using QLF-D may be used as an alternative to supplement the shortcomings of conventional clinical indices for educating patients about plaque control and continued patient oral care. PMID- 30458754 TI - Impact of financial burden, resulting from prescription co-payments, on antihypertensive medication adherence in an older publically insured population. AB - INTRODUCTION: Medication co-payments represent a financial barrier to antihypertensive medication adherence. The introduction of co-payments for Irish publically insured patients was associated with a 5% reduction in adherence. However there is socioeconomic variability within this population, and the impact may be greater for those on lower income. We evaluated medication-related financial burden of the co-payment in a cohort of Irish publically insured antihypertensive users and tested its association with adherence at 12 months. METHODS: This was a prospective cohort study of community dwelling older (> 65 yrs) adults (n = 1152) from 106 Irish community pharmacies. Participants completed a structured telephone interview at baseline, and a follow-up interview at 12-months, which we linked to pharmacy records. We assessed medication-related financial burden at baseline using a single questionnaire item, and adherence at 12 months via questionnaire and refill-adherence as Proportion of Days Covered (PDC). RESULTS: A third of participants (30.1%) reported financial burden due to medication costs. In adjusted linear regression models financially burdened participants had significantly lower self-reported adherence (beta = - 0.29, 95% CI -0.48 to - 0.11), although this was not evident with PDC (beta = - 2.76, 95% CI -5.65 to 0.14). CONCLUSION: This co-payment represents a financial barrier to antihypertensive adherence for many older Irish publically insured patients. The negative impact to adherence will potentially increase the risk of adverse outcomes, such as stroke, and increase long-term healthcare costs. PMID- 30458755 TI - CAR-T bridging to allo-HSCT as a treatment strategy for relapsed adult acute B lymphoblastic leukemia: a case report. AB - BACKGROUND: Adults with relapsed acute lymphoblastic leukemia (ALL) have a poor prognosis, especially in patients who relapsed within 6 months of complete remission 1 (CR1). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the treatment of choice. However, this can only be considered after complete remission 2 (CR2) is achieved. Therefore, bridging treatment is urgently needed. CASE PRESENTATION: In the present study, we report a relapsed adult B-cell ALL case that achieved CR2 after treatment with CD19-directed chimeric antigen receptor (CAR)-modified T cell (CAR-T) therapy. After subsequent allo-HSCT, the patient acquired 21 months of disease-free survival. CONCLUSION: The present results confirm that both CAR-T and allo-HSCT are effective for treating refractory or relapsed B-ALL. However, a novel sequential treatment strategy with these two therapeutic methods may achieve longer disease-free survival time. PMID- 30458756 TI - Is intrauterine exposure to acetaminophen associated with emotional and hyperactivity problems during childhood? Findings from the 2004 Pelotas birth cohort. AB - BACKGROUND: Longitudinal studies have consistently reported that prenatal exposure to acetaminophen can to lead to an increased risk of attention deficit hyperactivity disorder during childhood. This study aimed to investigate the association between intrauterine exposure to acetaminophen and the presence of emotional and behavioral problems at the ages of 6 and 11 years in a low-middle income country. METHODS: We performed a prospective longitudinal population-based study using data from the 2004 Pelotas birth cohort. From the 4231 initial cohort participants, 3722 and 3566 children were assessed at 6 and 11 years of age, respectively. The outcomes were assessed using the parent version of Strengths and Difficulties Questionnaire (SDQ). The cut-off points established for the Brazilian population were used to categorize the outcomes. Crude and adjusted odds ratio were obtained through logistic regression. RESULTS: Acetaminophen was used by 27.5% (95% confidence interval [CI]: 26.1-28.9) of the mothers at least once during pregnancy. The prevalence of emotional problems at 6 and 11 years was 13.6 and 19.9%, respectively. For hyperactivity problems, prevalence was 13.9 and 16.1%, respectively. Intrauterine exposure to acetaminophen increased the odds of having emotional (odds ratio [OR] = 1.47; 95% CI: 1.07-2.02) and hyperactivity/inattention (OR = 1.42; 95% CI: 1.06-1.92) problems in 6-year-old boys. At the age of 11, a small decrease in the effect was observed for both outcomes after adjustment: OR = 1.31 (95% CI: 0.99-1.73) for emotional problems and OR = 1.25 (95% CI: 0.95-1.65) for hyperactivity/inattention in boys. No association for any phenotypes at both ages was observed for girls. CONCLUSION: The effect of intrauterine exposure to acetaminophen in emotional and hyperactivity symptoms was dependent on sex in a Brazilian cohort. While it seemed to be important for boys, mainly at 6 years of age, for girls, no association was observed. PMID- 30458757 TI - Length of time periods in treatment effect descriptions and willingness to initiate preventive therapy: a randomised survey experiment. AB - BACKGROUND: Common measures used to describe preventive treatment effects today are proportional, i.e. they compare the proportions of events in relative or absolute terms, however they are not easily interpreted from the patient's perspective and different magnitudes do not seem to clearly discriminate between levels of effect presented to people. METHODS: In this randomised cross-sectional survey experiment, performed in a Swedish population-based sample (n = 1041, response rate 58.6%), the respondents, aged between 40 and 75 years were given information on a hypothetical preventive cardiovascular treatment. Respondents were randomised into groups in which the treatment was described as having the effect of delaying a heart attack for different periods of time (Delay of Event, DoE): 1 month, 6 months or 18 months. Respondents were thereafter asked about their willingness to initiate such therapy, as well as questions about how they valued the proposed therapy. RESULTS: Longer DoE:s were associated with comparatively greater willingness to initiate treatment. The proportions accepting treatment were 81, 71 and 46% when postponement was 18 months, 6 months and 1 month respectively. In adjusted binary logistic regression models the odds ratio for being willing to take therapy was 4.45 (95% CI 2.72-7.30) for a DoE of 6 months, and 6.08 (95% CI 3.61-10.23) for a DoE of 18 months compared with a DoE of 1 month. Greater belief in the necessity of medical treatment increased the odds of being willing to initiate therapy. CONCLUSIONS: Lay people's willingness to initiate preventive therapy was sensitive to the magnitude of the effect presented as DoE. The results indicate that DoE is a comprehensible effect measure, of potential value in shared clinical decision-making. PMID- 30458759 TI - Institutionalizing healthcare hackathons to promote diversity in collaboration in medicine. AB - BACKGROUND: Medical students and healthcare professionals can benefit from exposure to cross-disciplinary teamwork and core concepts of medical innovation. Indeed, to address complex challenges in patient care, diversity in collaboration across medicine, engineering, business, and design is critical. However, a limited number of academic institutions have established cross-disciplinary opportunities for students and young professionals within these domains to work collaboratively towards diverse healthcare needs. METHODS: Drawing upon best practices from computer science and engineering, healthcare hackathons bring together interdisciplinary teams of students and professionals to collaborate, brainstorm, and build solutions to unmet clinical needs. Over the course of six months, a committee of 20 undergraduates, medical students, and physician advisors organized Stanford University's first healthcare hackathon (November 2016). Demographic data from initial applications were supplemented with responses from a post-hackathon survey gauging themes of diversity in collaboration, professional development, interest in medical innovation, and educational value. In designing and evaluating the event, the committee focused on measurable outcomes of diversity across participants (skillset, age, gender, academic degree), ideas (clinical needs), and innovations (projects). RESULTS: Demographic data (n = 587 applicants, n = 257 participants) reveal participants across diverse academic backgrounds, age groups, and domains of expertise were in attendance. From 50 clinical needs presented representing 19 academic fields, 40 teams ultimately formed and submitted projects spanning web (n = 13) and mobile applications (n = 13), artificial intelligence-based tools (n = 6), and medical devices (n = 3), among others. In post-hackathon survey responses (n = 111), medical students and healthcare professionals alike noted a positive impact on their ability to work in multidisciplinary teams, learn from individuals of different backgrounds, and address complex healthcare challenges. CONCLUSIONS: Healthcare hackathons can encourage diversity across individuals, ideas, and projects to address clinical challenges. By providing an outline of Stanford's inaugural event, we hope more universities can adopt the healthcare hackathon model to promote diversity in collaboration in medicine. PMID- 30458758 TI - The weekend effect: does hospital mortality differ by day of the week? A systematic review and meta-analysis. AB - BACKGROUND: The concept of a weekend effect, poorer outcomes for patients admitted to hospitals at the weekend is not new, but is the focus of debate in England. Many studies have been published which consider outcomes for patients on admitted at the weekend. This systematic review and meta-analysis aims to estimate the effect of weekend admission on mortality in UK hospitals. METHODS: This is a systematic review and meta-analysis of published studies on the weekend effect in UK hospitals. We used EMBASE, MEDLINE, HMIC, Cochrane, Web of Science and Scopus to search for relevant papers. We included systematic reviews, randomised controlled trials and observational studies) on patients admitted to hospital in the UK and published after 2001. Our outcome was death; studies reporting mortality were included. Reviewers identified studies, extracted data and assessed the quality of the evidence, independently and in duplicate. Discrepancy in assessment was considered by a third reviewer. All meta-analyses were performed using a random-effects meta-regression to incorporate the heterogeneity into the weighting. RESULTS: Forty five articles were included in the qualitative synthesis. 53% of the articles concluded that outcomes for patients either undergoing surgery or admitted at the weekend were worse. We included 39 in the meta-analysis which contributed 50 separate analyses. We found an overall effect of 1.07 [odds ratio (OR)] (95%CI:1.03-1.12), suggesting that patients admitted at the weekend had higher odds of mortality than those admitted during the week. Sub-group analyses suggest that the weekend effect remained when measures of case mix severity were included in the models (OR:1.06 95%CI:1.02 1.10), but that the weekend effect was not significant when clinical registry data was used (OR:1.03 95%CI: 0.98-1.09). Heterogeneity was high, which may affect generalisability. CONCLUSIONS: Despite high levels of heterogeneity, we found evidence of a weekend effect in the UK, even after accounting for severity of disease. Further work is required to examine other potential explanations for the "weekend effect" such as staffing levels and other organisational factors. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews -registration number: CRD42016041225 . PMID- 30458760 TI - Precise A*T to G*C base editing in the zebrafish genome. AB - BACKGROUND: Base editors are a class of genome editing tools with the ability to efficiently induce point mutations in genomic DNA, without inducing double-strand breaks or relying on homology-direct repair as in other such technologies. Recently, adenine base editors (ABEs) have been developed to mediate the conversion of A*T to G*C in genomic DNA of human cells, mice, and plants. Here, we investigated the activity and efficiency of several adenine base editors in zebrafish and showed that base editing can be used to create new models of pathogenic diseases caused by point mutations. RESULTS: The original ABE7.10 exhibits almost no activity in zebrafish. After codon optimization, we found that a zABE7.10 variant could induce targeted conversion of adenine to guanine in zebrafish at multiple tested genomic loci, and all the target sites showed a high rate of germline targeting efficiency. Furthermore, using this system, we established a zebrafish model of 5q-Syndrome that contained a new point mutation in rps14. The further modification of zABE7.10 by a bipartite nuclear localization signals (bpNLS) resulted in 1.96-fold average improvement in ABE mediated editing efficiency at four sites. CONCLUSIONS: Collectively, this system, designated as zABE7.10, provides a strategy to perform A*T to G*C base editing in zebrafish and enhances its capacity to model human diseases. PMID- 30458761 TI - Reducing wait time from referral to first visit for community outpatient services may contribute to better health outcomes: a systematic review. AB - BACKGROUND: Many people wait long periods for community outpatient services. However little is known about the impact of waiting from referral to first visit on patient outcomes. The aim of this systematic review is to investigate whether waiting for community outpatient services is associated with adverse effects on patient outcomes. METHODS: Medline, Embase, Psych Info and CINAHL databases were searched, combining the key concepts of waiting for healthcare and patient outcomes. Studies were included if they reported data comparing health outcomes for patients with different waiting times for the same period. Three reviewers applied inclusion and exclusion criteria to identified studies and assessed quality using the McMaster Critical Review Forms. Levels of evidence were assessed using National Health and Medical Research Council guidelines. Included studies were analysed using a descriptive synthesis, and summarised according to levels of evidence and clinical significance for key outcomes. RESULTS: Fourteen studies that included 69,606 adult patients were selected. Selected studies included patients referred for treatment for musculoskeletal disorders (n = 28,722) or to cardiac rehabilitation (n = 40,884). There was low-level evidence that reduced wait time is associated with moderate improvement in workplace participation for patients seeking care for musculoskeletal conditions; and moderate improvement in exercise tolerance for patients referred to cardiac rehabilitation. There was inconsistent evidence that improvements in quality of life, patient satisfaction and psychological symptoms may be associated with shorter wait times. Pain, function and physical activity outcomes were not associated with wait time. CONCLUSIONS: This review found low-level evidence suggesting an association between early access to community outpatient services and improvement of some patient outcomes. Specifically, shorter wait times from referral to first visit for musculoskeletal pain services may improve patient work participation. Shorter wait times for cardiac rehabilitation may improve patient exercise capacity. The effects of a short wait time for other patient conditions and patient outcomes, including quality of life, psychological symptoms and patient experience, are inconclusive. The modest benefits in health outcomes observed in reducing wait time for community outpatient services suggest that other possible benefits such as increasing patient flow should be explored. TRIAL REGISTRATION: PROSPERO registration no: CRD42016047003. PMID- 30458763 TI - Advanced integration of fluid dynamics and photosynthetic reaction kinetics for microalgae culture systems. AB - BACKGROUND: Photosynthetic microalgae have been in the spotlight of biotechnological production (biofuels, lipids, etc), however, current barriers in mass cultivation of microalgae are limiting its successful industrialization. Therefore, a mathematical model integrating both the biological and hydrodynamical parts of the cultivation process may improve our understanding of relevant phenomena, leading to further optimization of the microalgae cultivation. RESULTS: We introduce a unified multidisciplinary simulation tool for microalgae culture systems, particularly the photobioreactors. Our approach describes changes of cell growth determined by dynamics of heterogeneous environmental conditions such as irradiation and mixing of the culture. Presented framework consists of (i) a simplified model of microalgae growth in a culture system (the advection-diffusion-reaction system within a phenomenological model of photosynthesis and photoinhibition), (ii) the fluid dynamics (Navier-Stokes equations), and (iii) the irradiance field description (Beer-Lambert law). To validate the method, a simple case study leading to hydrodynamically induced fluctuating light conditions was chosen. The integration of computational fluid dynamics (ANSYS Fluent) revealed the inner property of the system, the flashing light enhancement phenomenon, known from experiments. CONCLUSION: Our physically accurate model of microalgae culture naturally exhibits features of real system, can be applied to any geometry of microalgae mass cultivation and thus is suitable for biotechnological applications. PMID- 30458762 TI - Deceased organ donation activity and efficiency in Switzerland between 2008 and 2017: achievements and future challenges. AB - BACKGROUND: Various actions have been taken during the last decade to increase the number of organs from deceased donors available for transplantation in Switzerland. This study provides an overview on key figures of the Swiss deceased organ donation and transplant activity between 2008 and 2017. In addition, it puts the evolution of the Swiss donation program's efficiency in relation to the situation in the neighboring countries. METHODS: This study is an analysis of prospective registry data, covering the period from 1 January 2008 to 31 December 2017. It includes all actual deceased organ donors (ADD) in Switzerland. Donor data were extracted from the Swiss Organ Allocation System. The "donor conversion index" (DCI) methodology and data was used for the comparison of donation program efficiency in Switzerland, Germany, Austria, Italy and France. RESULTS: During the study period there were 1116 ADD in Switzerland. The number of ADD per year increased from 91 in 2008 to 145 in 2017 (+ 59%). The reintroduction of the donation after cardiocirculatory death (DCD) program in 2011 resulted in the growth of annual percentages of DCD donors, reaching a maximum of 27% in 2017. The total number of organs transplanted from ADD was 3763 (3.4 +/- 1.5 transplants per donor on average). Of these, 48% were kidneys (n = 1814), 24% livers (n = 903), 12% lungs (n = 445), 9% hearts (n = 352) and 7% pancreata or pancreatic islets (n = 249). The donation program efficiency assessment showed an increase of the Swiss DCI from 1.6% in 2008 to 2.7% in 2017 (+ 69%). The most prominent efficiency growth was observed between 2012 and 2017. Even though Swiss donation efficiency increased during the study period, it remained below the DCI of the French and Austrian donation programs. CONCLUSION: Swiss donation activity and efficiency grew during the last decade. The increased donation efficiency suggests that measures implemented so far were effective. The lower efficiency of the Swiss donation program, compared to the French and Austrian programs, may likely be explained by the lower consent rate in Switzerland. This issue should be addressed in order to achieve the goal of more organs available for transplantation. PMID- 30458764 TI - Effectiveness of PBL methodology in a hybrid dentistry program to enhance students' knowledge and confidence. (a pilot study). AB - BACKGROUND: Knowledge and self-confidence are two critical determinants of future success of dental students. The present pilot study was conducted with an objective to simultaneously assess both knowledge and confidence gained by dental undergraduate students in the Head and Neck Anatomy course by employing didactic lecture-based and problem-based learning methods. METHODS: A paper-based assessment tool comprising of 30 Multiple choice questions to assess knowledge, followed by a Likert's scale to assess students' confidence to answer the given knowledge question was designed. This tool was used in a cohort of first year dental students before the commencement of Head and Neck Anatomy course (Pre course), immediately after the completion of Head and Neck Anatomy course (Post course), and again in third year before the same cohort entered their clinical courses (Pre-clinics). The difference in students' knowledge and confidence through both pedagogies was evaluated by Paired 't' test. Pearson correlation analysis was done to determine the correlation between knowledge scores and self reported confidence. RESULTS: A statistically significant increase (p < 0.05) was noted in the mean knowledge and confidence scores in the post-course evaluation, through both didactic lecture-based and problem-based learning methods. On the other hand, a significant decrease (p < 0.05) in the mean knowledge and confidence scores of didactic lecture-based items in comparison to problem-based items was noted in the pre-clinics evaluation.. The post-course evaluation results yielded a Pearson correlation coefficient of r = 0.514, p = 0.002 for lecture-based items and r = 0.495, p = 0.003 for problem-based items, denoting a positive moderate correlation between the knowledge and confidence scores for both lecture-based and problem-based methods. CONCLUSION: A significant improvement in both knowledge and self-reported confidence demonstrated at the end of Head and Neck Anatomy course proves both didactic lectures and problem based learning methods to be equally effective in a hybrid dentistry program in the short term. However, the non-significant reduction in the pre-clinics knowledge and confidence scores among the PBL lessons proves it to be a potent learning tool for long term retention of knowledge, and sustainability of confidence. PMID- 30458765 TI - Quality of primary care from patients' perspective: a cross sectional study of outpatients' experience in public health facilities in rural Malawi. AB - BACKGROUND: Assessing patients' experience with primary care complements measures of clinical health outcomes in evaluating service performance. Measuring patients' experience and satisfaction are among Malawi's health sector strategic goals. The purpose of this study was to investigate patients' experience with primary care and to identify associated patients' sociodemographic, healthcare and health characteristics. METHODS: This was a cross sectional survey using questionnaires administered in public primary care facilities in Neno district, Malawi. Data on patients' primary care experience and their sociodemographic, healthcare and health characteristics were collected through face to face interviews using a validated Malawian version of the primary care assessment tool (PCAT-Mw). Mean scores were derived for the following dimensions: first contact access, continuity of care, comprehensiveness, community orientation and total primary care. Linear regression models were used to assess association between primary care dimension scores and patients' characteristics. RESULTS: From 631 completed questionnaires, first contact access, relational continuity and comprehensiveness of services available scored below the defined minimum. Sex, geographical location, self-rated health status, duration of contact with facility and facility affiliation were associated with patients' experience with primary care. These factors explained 10.9% of the variance in total primary care scores; 25.2% in comprehensiveness of services available and 29.4% in first contact access. CONCLUSION: This paper presents results from the first use of the validated PCAT-Mw. The study provides a baseline indicating areas that need improvement. The results can also be used alongside clinical outcome studies to provide comprehensive evaluation of primary care performance in Malawi. PMID- 30458766 TI - SWIFOLD: Smith-Waterman implementation on FPGA with OpenCL for long DNA sequences. AB - BACKGROUND: The Smith-Waterman (SW) algorithm is the best choice for searching similar regions between two DNA or protein sequences. However, it may become impracticable in some contexts due to its high computational demands. Consequently, the computer science community has focused on the use of modern parallel architectures such as Graphics Processing Units (GPUs), Xeon Phi accelerators and Field Programmable Gate Arrays (FGPAs) to speed up large-scale workloads. RESULTS: This paper presents and evaluates SWIFOLD: a Smith-Waterman parallel Implementation on FPGA with OpenCL for Long DNA sequences. First, we evaluate its performance and resource usage for different kernel configurations. Next, we carry out a performance comparison between our tool and other state-of the-art implementations considering three different datasets. SWIFOLD offers the best average performance for small and medium test sets, achieving a performance that is independent of input size and sequence similarity. In addition, SWIFOLD provides competitive performance rates in comparison with GPU-based implementations on the latest GPU generation for the large dataset. CONCLUSIONS: The results suggest that SWIFOLD can be a serious contender for accelerating the SW alignment of DNA sequences of unrestricted size in an affordable way reaching on average 125 GCUPS and almost a peak of 270 GCUPS. PMID- 30458767 TI - Drug quality analysis of isometamidium chloride hydrochloride and diminazene diaceturate used for the treatment of African animal trypanosomosis in West Africa. AB - BACKGROUND: Diminazene diaceturate (DA) and isometamidium chloride hydrochloride (ISM) are with homidium bromide, the main molecules used to treat African Animal Trypanosomosis (AAT). These drugs can be purchased from official suppliers but also from unofficial sources like local food markets or street vendors. The sub standard quality of some of these trypanocides is jeopardizing the efficacy of treatment of sick livestock, leading thus to economic losses for the low-resource farmers and is contributing to the emergence and spread of drug resistance. The objective of this study was to assess the quality of trypanocidal drugs sold in French speaking countries of West Africa. In total, 308 drug samples including 282 of DA and 26 of ISM were purchased from official and unofficial sources in Benin, Burkina Faso, Cote d'Ivoire, Mali, Niger and Togo. All samples were analysed at LACOMEV (Dakar, Senegal), a reference laboratory of the World Organisation for Animal Health, by galenic inspection and high performance liquid chromatography. RESULTS: The results showed that 51.90% of the samples were non compliant compared to the standards and were containing lower quantity of the active ingredient compared to the indications on the packaging. The non compliances ranged from 63.27% in Togo to 32.65% in Burkina Faso (61.82% in Benin, 53.84% in Mali, 50% in Cote d'Ivoire, 47.36% in Niger). The rates of non compliance were not statistically different (P = 0.572) from official or unofficial suppliers and ranged from 30 to 75% and from 0 to 65% respectively. However, the non-compliance was significantly higher for ISM compared to DA (P = 0.028). CONCLUSIONS: The high non-compliance revealed in this study compromises the efficacy of therapeutic strategies against AAT, and is likely to exacerbate chemoresistance in West Africa. Corrective actions against sub-standard trypanocides urgently need to be taken by policy makers and control authorities. PMID- 30458769 TI - Guideline developers are not the only experts: Utilising the FRAM method in sepsis pathways. AB - Improving clinical outcomes and quality of care in diseases such as sepsis, which are heterogeneous in their presenting signs and symptoms, is a challenge. One approach is to utilise the Functional Analysis Resonance Method (FRAM), which enables systems to examine process and sociocontextual issues in treatment and management pathways. McNab et al. applied FRAM to group of primary care (family) practices to understand the barriers and enablers in the management of sepsis and determined a suite of possible interventions that might improve patient care. This commentary reviews the FRAM process and highlights some core issues for systems to consider when tackling diseases like sepsis.Please see related article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-018-1164 x. PMID- 30458768 TI - Development and evaluation of serotype-specific recombinase polymerase amplification combined with lateral flow dipstick assays for the diagnosis of foot-and-mouth disease virus serotype A, O and Asia1. AB - BACKGROUND: Foot-and-mouth disease (FMD) caused by foot-and-mouth disease virus (FMDV) is one of the most highly infectious diseases in livestock, and leads to huge economic losses. Early diagnosis and rapid differentiation of FMDV serotype is therefore integral to the prevention and control of FMD. In this study, a series of serotype-specific reverse transcription recombinase polymerase amplification assays combined with lateral flow dipstick (RPA-LFD) were establish to differentiate FMDV serotypes A, O or Asia 1, respectively. RESULTS: The serotype-specific primers and probes of RPA-LFD were designed to target conserved regions of the FMDV VP1 gene sequence, and three primer and probe sets of serotype-specific RPA-LFD were selected for amplification of FMDV serotypes A, O or Asia 1, respectively. Following incubation at 38 degrees C for 20 min, the RPA amplification products could be visualized by LFD. Analytical sensitivity of the RPA assay was then determined with ten-fold serial dilutions of RNA of VP1 gene and the recombinant vector respectively containing VP1 gene from FMDV serotypes A, O or Asia1, the detection limits of these assays were 3 copies of plasmid DNA or 50 copies of viral RNA per reaction. Moreover, the specificity of the assay was assessed, and there was no cross reactions with other viruses leading to bovine vesicular lesions. Furthermore, 126 clinical samples were respectively detected with RPA-LFD and real-time PCR (rPCR), there was 98.41% concordance between the two assays, and two samples were positive by RPA-LFD but negative in rPCR, these were confirmed as FMDV-positive through viral isolation in BHK-21 cells. It showed that RPA-LFD assay was more sensitive than the rPCR method in this study. CONCLUSION: The development of serotype-specific RPA-LFD assay provides a rapid, sensitive, and specific method for differentiation of FMDV serotype A, O or Asia1, respectively. It is possible that the serotype specific RPA-LFD assay may be used as a integral protocol for field detection of FMDV. PMID- 30458770 TI - A harmful traditional practice exposing young girls to experience virgin pregnancy (Shilshalo): a qualitative study in Argoba community, Amhara National Regional State, Ethiopia. AB - BACKGROUND: There are various harmful traditional practices and beliefs across the different parts of Ethiopia. Shilshalo, which is yet little known about, is one of these practices existing in Argoba, a community in Amhara National Regional State of Ethiopia. This study was conducted to explore the various features associated with the practice of Shilshalo. METHODS: To address the objective of the study, qualitative approach with case study design was employed. Purposive sampling technique was used to select the participants of the study. Data were collected through interview and focus group discussion and analyzed using thematic qualitative analysis technique. RESULTS: This study found that Shilshalo is practiced by unmarried young boys and girls as a substitute for sexual intercourse. The actors conduct all activities performed during sexual intercourse except inserting the boy's genital organ (penis) into the girl's (vagina). The activities include warming up the girls' body by hand, kissing and brushing the girl's thigh and the areas around the outer part of the vagina with the erected penis. Shilshalo is practiced in two ways, i.e. between a boy and a girl, and between boys and a girl. This study also indicated that most members of the Argoba community including the actors consider Shilshalo as a beneficial cultural practice, yet the most shocking story is that some teenage girls experienced unwanted pregnancy without losing their virginity. In addition to virgin pregnancy, Shilshalo exposed girls to STIs, psycho-social problems and physical injuries. CONCLUSION: This study concluded that Shilshalo is a harmful traditional practice that severely affects the lives of girls. The overall health and social well beings of girls are affected by different saddles that came from it. It brings almost all kinds of consequences that the other harmful traditional practices such as female genital mutilation and early marriage bring. It is also worse than the other harmful traditional practices as it poses virgin pregnancy as an additional consequence. Therefore, it is suggested that international and national organizations working on issues related to harmful traditional practice should pay due attention to Shilshalo just like what they are doing with female genital mutilation and early marriage. PMID- 30458771 TI - Retrospective analysis of doxorubicin and prednisone as first-line therapy for canine B-cell lymphoma. AB - BACKGROUND: A doxorubicin (DOX)-based chemotherapy protocol, CHOP, is the most effective treatment for canine high-grade B-cell lymphoma; however, the cost and time requirements associated with this protocol are not feasible for many pet owners. An alternative treatment option is the use of DOX, the most effective drug, in combination with prednisone. Prior studies with single-agent DOX included dogs with T-cell lymphoma, a known negative prognostic factor, which may have resulted in shorter reported survival times than if dogs with B-cell lymphoma were analyzed separately. The purpose of this study was to evaluate the outcome of dogs with high-grade B-cell lymphoma when treated with DOX and prednisone with or without L-asparaginase (L-ASP). Identification of prognostic factors was of secondary interest. RESULTS: Thirty-three dogs were included in the study; 31 dogs were evaluable for response with an overall response rate of 84%. The median progression free survival (PFS) and overall survival (OS) were 147 days and 182 days, respectively. The one-year survival fraction was 23%. No variable other than protocol completion was found to be significant for either PFS or OS including historical prognostic factors such as substage, thrombocytopenia, and body weight. CONCLUSIONS: Dogs with high-grade B-cell lymphoma treated with DOX and prednisone with or without L-ASP have similar response rates, PFS, and OS to prior studies that did not differentiate between lymphoma immunophenotype. This protocol is not a replacement for CHOP; however, it is an alternative if time and cost are factors, while providing therapeutic benefit greater than prednisone alone. PMID- 30458772 TI - Assessing the effects of the percentage of chronic disease in households on health payment-induced poverty in Shaanxi Province, China. AB - BACKGROUND: Chronic disease has become one of the leading causes of poverty in China, which posed heavy economic burden on individuals, households and society, and accounts for an estimated 80% of deaths and 70% of disability-adjusted life years lost now in China. This study aims to assess the effect of chronic diseases on health payment-induced poverty in Shaanxi Province, China. METHODS: The data was from the 5th National Health Survey of Shaanxi Province, which was part of China's National Health Service Survey (NHSS) conducted in 2013. Totally, 20,700 households were selected for analysis. We used poverty headcount, poverty gap and mean positive poverty gap to assess the incidence, depth and intensity of poverty before and after health payment, respectively. Logistic regression models were further undertaken to evaluate the influence of percentage of chronic patients in households on the health payment-induced poverty with the control of other covariates. RESULTS: In rural areas, the incidence of poverty increased 31.90% before and after health payment in the household group when the percentage of chronic patients in the households was 0, and the poverty gap rose from 932.77 CNY to 1253.85 CNY (50.56% increased). In the group when the percentage of chronic patients in the households was 1-40% and 41-50%, the poverty gap increased 76.78 and 89.29%, respectively. In the group when the percentage of chronic patients in the households was 51~ 100%, the increase of poverty headcount and poverty gap was 49.89 and 46.24%. In the logistic model, we found that the proportion of chronic patients in the households was closely related with the health payment-induced poverty. The percentage of chronic disease in the households increased by 1 %, the incidence of poverty increased by 1.01 times. On the other hand, the male household head and the household's head with higher educational lever were seen as protective factors for impoverishment. CONCLUSIONS: With the percentage of chronic patients in the households growing, the health payment-induced poverty increases sharply. Furthermore, the households members with more chronic diseases in rural areas were more likely to suffer poverty than those in urban areas. Our analysis emphasizes the need to protect households from the impoverishment of chronic diseases, and our findings will provide suggestions for further healthcare reforms in China and guidance for vulnerable groups. PMID- 30458773 TI - Health literacy profile of recently hospitalised patients in the private hospital setting: a cross sectional survey using the Health Literacy Questionnaire (HLQ). AB - BACKGROUND: Health service providers should understand and attend to the health literacy needs of their population in view of the known association between low health literacy and poorer health outcomes. This study aimed to determine the health literacy profile of patients treated at a large private hospital in Melbourne, Australia, and any associations between this profile and socio economic position, health behaviours, health status and use of hospital services. METHODS: A mailed survey was sent to 9173 people aged >=18 years with a hospital admission between February and October 2014. It included the Health Literacy Questionnaire (HLQ), a multidimensional tool comprising nine independent scales, and socio-demographic and clinical questions. For both respondents and non respondents, we also extracted residential postcode and admission and follow up details from the Patient Administrative Services database. Differences in demographic, socio-economic and hospital use patterns between respondents and non respondents were analysed using descriptive statistics. Regression-tests were used to identify differences in health literacy between socio-economic subgroups, with the magnitude of these differences determined using Cohen's d effect sizes. RESULTS: There were 3121 respondents (response rate: 35% excluding 154 returned invitations), the majority born in Australia (74.6%) and living in areas of high socio-economic advantage. Respondents were slightly older than non-respondents (mean (SD) age 65.6 (17.0) versus 60.6 (20.8) years) and included proportionately less females (51.9 versus 59.1%) but were similar with regard to other socio demographic factors and health service use. Participants who did not speak English at home, reported lower scores across several HLQ scales, including those that measure health provider support and engagement. Those who smoked and reported low physical activity had lower scores for actively managing their health. No relationship was seen between HLQ scale scores and use of hospital services. CONCLUSIONS: Based upon the health literacy profile of a large cohort of patients attending a large private hospital, we found no relationship between HLQ scale scores and use of hospital services. However we did identify significant health literacy needs particularly among patients whose primary language at home was not English and patients needing assistance completing the survey. Identifying ways of addressing these needs may improve patient outcomes. PMID- 30458774 TI - Measuring antigen-specific responses in Mycobacterium bovis-infected warthogs (Phacochoerus africanus) using the intradermal tuberculin test. AB - BACKGROUND: Bovine tuberculosis (bTB) caused by Mycobacterium bovis has previously been diagnosed in warthogs and infection can be highly prevalent (> 30%) in endemic areas. Thus, warthogs could potentially be an important species to consider as sentinels for disease surveillance. However, disease surveillance is dependent on availability of accurate diagnostic assays and only a few diagnostic tests have been investigated for warthogs. Furthermore, the tests that have been used in this species require laboratory equipment and trained personnel to obtain results. Therefore, this study investigated the use of the intradermal tuberculin test (ITT) to screen warthogs for bTB, which can be done with minimal equipment and under field conditions by most veterinarians and other qualified professionals. Changes in skin fold thickness measurements at the bovine purified protein derivative (PPD) administration site, between 0 and 72 h, were compared with differential changes between the bovine and avian PPD sites, for 34 warthogs, to evaluate the performance when different interpretation criteria for the ITT was used. RESULTS: Using an increase of 1.8 mm or more at the bovine PPD site as a cut-off for positive responders, 69% of 16 M. bovis culture-positive warthogs had a positive test result, with 100% of the 18 culture-negative warthogs considered as test negative. When a differential of 1.2 mm or more in skin fold thickness at the bovine PPD compared to the avian PPD site was used as a cut-off for the comparative ITT, 81% of culture-positive warthogs were considered as test positive, with 100% of culture-negative warthogs considered as test negative. CONCLUSION: The findings in this study suggest that the ITT is a promising tool to use when screening warthogs for M. bovis infection. PMID- 30458775 TI - BLASSO: integration of biological knowledge into a regularized linear model. AB - BACKGROUND: In RNA-Seq gene expression analysis, a genetic signature or biomarker is defined as a subset of genes that is probably involved in a given complex human trait and usually provide predictive capabilities for that trait. The discovery of new genetic signatures is challenging, as it entails the analysis of complex-nature information encoded at gene level. Moreover, biomarkers selection becomes unstable, since high correlation among the thousands of genes included in each sample usually exists, thus obtaining very low overlapping rates between the genetic signatures proposed by different authors. In this sense, this paper proposes BLASSO, a simple and highly interpretable linear model with l1 regularization that incorporates prior biological knowledge to the prediction of breast cancer outcomes. Two different approaches to integrate biological knowledge in BLASSO, Gene-specific and Gene-disease, are proposed to test their predictive performance and biomarker stability on a public RNA-Seq gene expression dataset for breast cancer. The relevance of the genetic signature for the model is inspected by a functional analysis. RESULTS: BLASSO has been compared with a baseline LASSO model. Using 10-fold cross-validation with 100 repetitions for models' assessment, average AUC values of 0.7 and 0.69 were obtained for the Gene-specific and the Gene-disease approaches, respectively. These efficacy rates outperform the average AUC of 0.65 obtained with the LASSO. With respect to the stability of the genetic signatures found, BLASSO outperformed the baseline model in terms of the robustness index (RI). The Gene specific approach gave RI of 0.15+/-0.03, compared to RI of 0.09+/-0.03 given by LASSO, thus being 66% times more robust. The functional analysis performed to the genetic signature obtained with the Gene-disease approach showed a significant presence of genes related with cancer, as well as one gene (IFNK) and one pseudogene (PCNAP1) which a priori had not been described to be related with cancer. CONCLUSIONS: BLASSO has been shown as a good choice both in terms of predictive efficacy and biomarker stability, when compared to other similar approaches. Further functional analyses of the genetic signatures obtained with BLASSO has not only revealed genes with important roles in cancer, but also genes that should play an unknown or collateral role in the studied disease. PMID- 30458776 TI - Delay in diagnosis and treatment among adult multidrug resistant tuberculosis patients in Yangon Regional Tuberculosis Center, Myanmar: a cross-sectional study. AB - BACKGROUND: Delays in diagnosis and treatment initiation may allow the emergence of new cases by transmission to the community, and is one of the challenges facing programme management of drug resistance in Myanmar. This study aimed to explore delays in diagnosis and treatment initiation, and associated factors among patients with multidrug-resistant tuberculosis. METHODS: A cross-sectional study was conducted at Yangon Regional Tuberculosis Centre, Myanmar. Data were collected by face-to-face interviews and treatment-card reviews of all adult patients who had registered and started treatment with the standard regimen from May to November, 2017. Delay time was categorized by using median cut-off and analyzed using SPSS version 23.0. Logistic regression analysis was performed to assess the relative impact of predictor variables on diagnosis and treatment delays. RESULTS: A total of 210 patients participated in this study. The median diagnosis delay was 9 days, IQR 3 (8-11) and 58.6% of the patients experienced a long diagnosis delay. Below middle school education (adjusted odds ratio [AOR] = 2.75, 95% CI = 1.22-6.21), non-permanent salaried employment (AOR = 3.03, 95% CI = 1.32-6.95), co-existing diabetes mellitus (AOR = 5.06, 95% CI = 1.97-13.01) and poor awareness (AOR = 2.99, 95% CI = 1.29-6.92) were independent predictors of long diagnosis delay. The median treatment delay was 13 days, IQR 9 (8-17) and 51% of the patients experienced long treatment delay. Age 31-50 years (AOR = 4.50, 95% CI = 1.47-13.97) and age > 50 years (AOR = 9.40, 95% CI = 2.55-34.83), history with MDR-TB patient (AOR = 3.16, 95% CI = 1.29-7.69), > 20 km away from a Regional TB Centre (AOR = 14.33, 95% CI = 1.91-107.64) and poor awareness (AOR = 4.62, 95% CI = 1.56-13.67) were independent predictors of long treatment delay. CONCLUSIONS: Strengthening comprehensive health education, enhancing treatment adherence counseling, providing more Xpert MTB/RIF machines, expanding decentralized MDR-TB treatment centers, ensuring timely sputum transportation, provision of a patient support package immediately after confirmation, and strengthening contact-tracing for all household contacts with MDR-TB patients and active tuberculosis screening were the most effective ways to shorten delays in MDR-TB diagnosis and treatment initiation. PMID- 30458777 TI - Interaction between avian influenza subtype H9N2 and Newcastle disease virus vaccine strain (LaSota) in chickens. AB - BACKGROUND: H9N2 avian influenza virus is endemic in Egyptian poultry flocks. The role of the live viral vaccines such as LaSota in exaggeration of the clinical picture of H9N2 infection under field conditions is significantly important leading to severe economic losses due to higher mortality and lower growth performance. This experiment was designed to identify the possible interaction between experimental infection with H9N2 virus and NDV live vaccine (LaSota strain) in broiler chickens. Six groups each of 20 broiler chicks were used. Three groups (G1-3) were infected with H9N2 and vaccinated with LaSota, 3 days before, at the same day or 3 days post vaccination (dpv), while the remaining groups (G4-6) were non-vaccinated infected, vaccinated non-infected and non vaccinated non-infected. RESULTS: The highest mortality rate (37.5%) was noticed in chickens of G1 (H9N2 infected 3 days prior LaSota vaccination). Also, this bird group had the most severe clinical signs, histopathological lesions and the longest viral shedding for 9 days post infection (dpi). In the 2nd and 3rd groups, the mortality rate was the similar (31.2%) with less pronounced clinical signs, histopathological lesions and H9N2 shedding was for only 6 dpi with the least shedding quantity in chickens of G3. The control non-vaccinated infected chickens (G4) had 18.7% mortality with the least degree of clinical signs, lesions and the highest viral shedding quantity but only for 6 dpi. At 35 days of age, there was a statistical significant decrease (P < 0.05) in chicken's body weight of all H9N2 infected groups from G1 to G4 compared to non-infected control groups, G5 and G6 respectively. CONCLUSION: It was clear that laSota vaccination significantly affect H9N2 infection in broiler chickens regarding clinical signs, mortality rate, lesions, performance and viral shedding. PMID- 30458778 TI - The impact of integrating medical assistants and community health workers on diabetes care management in community health centers. AB - OBJECTIVE: To compare the impact of implementing team-based diabetes care management involving community health workers (CHWs) vs. medical assistants (MA) in community health centers (CHCs) on diabetes care processes, intermediate outcomes, and patients' experiences of chronic care. DATA SOURCES: Clinical and administrative data (n = 6111) and patient surveys (n = 698) pre-intervention and post-intervention. Surveys (n = 285) and key informant interviews (n = 48) of CHC staff assessed barriers and facilitators of implementation. STUDY DESIGN: A three arm cluster-randomized trial of CHC sites integrating MAs (n = 3) or CHWs (n = 3) for diabetes care management compared control CHC sites (n = 10). Difference-in difference multivariate regression with exact matching of patients estimated intervention effects. PRINCIPAL FINDINGS: Patients in the CHW intervention arm had improved annual glycated hemoglobin testing (18.5%, p < 0.001), while patients in the MA intervention arm had improved low-density lipoprotein cholesterol control (8.4%, p < 0.05) and reported better chronic care experiences over time (beta=7.5, p < 0.001). Except for chronic care experiences (p < 0.05) for patients in the MA intervention group, difference-in-difference estimates were not statistically significant because control group patients also improved over time. Some diabetes care processes improved significantly more for control group patients than intervention group patients. Key informant interviews revealed that immediate patient care issues sometimes crowded out diabetes care management activities, especially for MAs. CONCLUSIONS: Diabetes care improved in CHCs integrating CHWs and MAs onto primary care teams, but the improvements were no different than improvements observed among matched control group patients. Greater improvement using CHW and MA team-based approaches may be possible if practice leaders minimize use of these personnel to cover shortages that often arise in busy primary care practices. PMID- 30458779 TI - How does training in anesthesia residency shape residents' approaches to patient care handoffs? A single-center qualitative interview study. AB - BACKGROUND: Handoffs are a complex procedure whose success relies on mutual discussion rather than simple information transfer. Particularly among trainees, handoffs present major opportunities for medical error. Previous research has explored best practices and pitfalls in general handoff education but has not discussed barriers specific to anesthesiology residents. This study characterizes the experiences of residents in anesthesiology as they learn handoff technique in order to inform strategies for teaching this important component of perioperative care. METHODS: In 2016, we conducted a semi-structured interview study of 30 anesthesia residents across all three postgraduate years at a major academic hospital. Interviews were coded by two coders using a grounded theory approach and an iterative process designed to enhance reliability and validity. RESULTS: Residents cited lack of consistency as a major impediment to proper handoff education. They found the impact of lectures and written materials to be limited. The level of guidance and direction they received from one-to-one attendings was described as highly variable. Residents' comfort in executing handoffs was heavily dependent on location and situation. They felt that coordination among the parties involved in the handoff was difficult to achieve, causing confusion about the importance of handoffs as well as proper protocol. Finally, residents offered opinions on when handoff education should occur during the residency and had several recommendations for its improving, including standardization of key handoff topics. CONCLUSIONS: In a single center study of anesthesiology resident handoff education, residents exhibited confusion related to a perceived disconnect between the stated importance of effective handoffs and a lack of consensus on proper handoff technique. Standardization of curriculum and framing expectations has the potential to enhance resident handoff training in academic anesthesia departments. PMID- 30458780 TI - Assessment of the development of assisted reproductive technology in Liaoning province of China, from 2012 to 2016. AB - BACKGROUND: The development of assisted reproduction techniques (ART) has resulted in rapid advances in the treatment of infertility. However, a systematic assessment of ART and its processes and outcomes in China has never been carried out. The goal of this study was to assess the features of ART status from 2012 to 2016 in clinics and in vitro fertilization (IVF) laboratories in Liaoning, the largest IVF province in the northeast of China. METHODS: Data from Jan 1, 2012 to Dec 31, 2016 was retrieved from the assisted reproductive certificate registry of Liaoning province. We extracted data from: i) fresh and thawed cycles; ii) donor sperm and donor egg cycles; iii) intrauterine insemination with husband semen and donor semen (AIH and AID). RESULTS: We showed that: (i) there has been a significant increase in the number of IVF fresh and thawed cycles, and the proportion of cases of primary infertility and secondary infertility has decreased and increased, respectively; (ii) standard long GnRH agonist was the major ovarian stimulation protocol. During the observation period, increasing trends in the use of GnRH antagonists, mild stimulation, and natural cycles were observed; (iii) significant differences in the number of cycles, number of retrieved oocytes, fertilization rates, implantation rates, and sex ratio were noticed between conventional IVF and intracytoplasmic sperm injection; (iv) significant differences in age at treatment for infertility, number of cycles, and ectopic pregnancy rates were noticed between donor sperm cycles and donor egg cycles; (v) significant differences in number of thawed cycles, number of thawed embryos, embryo recovery rates, implantation rates, and clinical pregnancy rates were noticed between day 3 and day 5 embryos; (vi) significant differences in age at treatment for infertility, number of cycles, clinical pregnancy rates, ectopic pregnancy rates, and live birth ratio were noticed between AIH and AID. CONCLUSIONS: ART in Liaoning province has undergone substantial development from 2012 to 2016 in clinics and IVF laboratories. This presentation of detailed ART data will provide researchers, policy makers, and potential ART users a rich source of information about IVF characteristics in the northeast of China. PMID- 30458781 TI - Ni-hemin metal-organic framework with highly efficient peroxidase catalytic activity: toward colorimetric cancer cell detection and targeted therapeutics. AB - BACKGROUND: Given the great benefits of artificial enzymes, a simple approach is proposed via assembling of Ni2+ with hemin for synthesis of Ni-hemin metal organic-frameworks (Ni-hemin MOFs) mimic enzyme. The formation of the Ni-hemin MOFs was verified by scanning electron microscopy, Transmission electron microscopy, X-ray powder diffraction, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, Energy-dispersive X-ray spectroscopy and UV-vis absorption spectroscopy. This novel nanocomposite exhibited surprising peroxidase like activity monitored by catalytic oxidation of a typical peroxidase substrate, 3,3,5,5'-tetramethylbenzidine, in the presence of H2O2. By using folic acid conjugated MOF nanocomposite as a recognition element, we develop a colorimetric assay for the direct detection of cancer cells. RESULTS: The proposed sensor presented high sensitivity and selectivity for the detection of human breast cancer cells (MCF-7) and Human Caucasian gastric adenocarcinoma. By measuring UV vis absorbance response, a wide detection range from 50 to 105 cells/mL with a detection limit as low as 10 cells/mLwas reached for MCF-7 cells. We further discuss therapeutics efficiency of Ni-hemin MOFs in the presence of H2O2 and ascorbic acid. Peroxidase-mimic Ni-hemin MOFs as reactive oxygen species which could damage MCF-7 cancer cells, however for normal cells (human embryonic kidney HEK 293 cells) killing effect was negligible. CONCLUSIONS: Based on these behaviors, the developed method offers a fast, easy and cheap assay for the interest in future diagnostic and treatment application. PMID- 30458783 TI - Human activity monitoring system based on wearable sEMG and accelerometer wireless sensor nodes. AB - BACKGROUND: The human activity monitoring technology is one of the most important technologies for ambient assisted living, surveillance-based security, sport and fitness activities, healthcare of elderly people. The activity monitoring is performed in two steps: the acquisition of body signals and the classification of activities being performed. This paper presents a low-cost wearable wireless system specifically designed to acquire surface electromyography (sEMG) and accelerometer signals for monitoring the human activity when performing sport and fitness activities, as well as in healthcare applications. RESULTS: The proposed system consists of several ultralight wireless sensing nodes that are able to acquire, process and efficiently transmit the motion-related (biological and accelerometer) body signals to one or more base stations through a 2.4 GHz radio link using an ad-hoc communication protocol designed on top of the IEEE 802.15.4 physical layer. A user interface software for viewing, recording, and analysing the data was implemented on a control personal computer that is connected through a USB link to the base stations. To demonstrate the capability of the system of detecting the user's activity, data recorded from a few subjects were used to train and test an automatic classifier for recognizing the type of exercise being performed. The system was tested on four different exercises performed by three people, the automatic classifier achieved an overall accuracy of 85.7% combining the features extracted from acceleration and sEMG signals. CONCLUSIONS: A low cost wireless system for the acquisition of sEMG and accelerometer signals has been presented for healthcare and fitness applications. The system consists of wearable sensing nodes that wirelessly transmit the biological and accelerometer signals to one or more base stations. The signals so acquired will be combined and processed in order to detect, monitor and recognize human activities. PMID- 30458782 TI - Pipeline design to identify key features and classify the chemotherapy response on lung cancer patients using large-scale genetic data. AB - BACKGROUND: During the last decade, the interest to apply machine learning algorithms to genomic data has increased in many bioinformatics applications. Analyzing this type of data entails difficulties for managing high-dimensional data, class imbalance for knowledge extraction, identifying important features and classifying individuals. In this study, we propose a general framework to tackle these challenges with different machine learning algorithms and techniques. We apply the configuration of this framework on lung cancer patients, identifying genetic signatures for classifying response to drug treatment response. We intersect these relevant SNPs with the GWAS Catalog of the National Human Genome Research Institute and explore the Regulomedb, GTEx databases for functional analysis purposes. RESULTS: The machine learning based solution proposed in this study is a scalable and flexible alternative to the classical uni-variate regression approach to analyze large-scale data. From 36 experiments executed using the machine learning framework design, we obtain good classification performance from the top 5 models with the highest cross validation score and the smallest standard deviation. One thousand two hundred twenty four SNPs corresponding to the key features from the top 20 models (cross validation F1 mean >= 0.65) were compared with the GWAS Catalog finding no intersection with genome-wide significant reported hits. From these, new genetic signatures in MAE, CEP104, PRKCZ and ADRB2 show relevant biological regulatory functionality related to lung physiology. CONCLUSIONS: We have defined a machine learning framework using data with an unbalanced large data-set of SNP-arrays and imputed genotyping data from a pharmacogenomics study in lung cancer patients subjected to first-line platinum-based treatment. This approach found genome signals with no genome-wide significance in the uni-variate regression approach (GWAS Catalog) that are valuable for classifying patients, only few of them with related biological function. The effect results of these variants can be explained by the recently proposed omnigenic model hypothesis, which states that complex traits can be influenced mostly by genes outside not only by the "core genes", mainly found by the genome-wide significant SNPs, but also by the rest of genes outside of the "core pathways" with apparent unrelated biological functionality. PMID- 30458784 TI - Invasion-related circular RNA circFNDC3B inhibits bladder cancer progression through the miR-1178-3p/G3BP2/SRC/FAK axis. AB - BACKGROUND: Increasing evidence has revealed that circular RNAs (circRNAs) play crucial roles in cancer biology. However, the role and underlying regulatory mechanisms of circFNDC3B in bladder cancer (BC) remain unknown. METHODS: A cell invasion model was established by repeated transwell assays, and invasion-related circRNAs in BC were identified through an invasion model. The expression of circFNDC3B was detected in 82 BC tissues and cell lines by quantitative real-time PCR. Functional assays were performed to evaluate the effects of circFNDC3B on proliferation, migration and invasion in vitro-, and on tumorigenesis and metastasis in vivo. The relationship between circFNDC3B and miR-1178-3p was confirmed by fluorescence in situ hybridization, pull-down assay and luciferase reporter assay. RESULTS: In the present study, we identified a novel circRNA (circFNDC3B) through our established BC cell invasion model. We found that circFNDC3B was dramatically downregulated in BC tissues and correlated with pathological T stage, grade, lymphatic invasion and patients' overall survival rate. Functionally, overexpression of circFNDC3B significantly inhibited proliferation, migration and invasion both in vitro and in vivo. Mechanistically, circFNDC3B could directly bind to miR-1178-3p, which targeted the 5'UTR of the oncogene G3BP2. Moreover, circFNDC3B acted as a miR-1178-3p sponge to suppress G3BP2, thereby inhibiting the downstream SRC/FAK signaling pathway. CONCLUSIONS: CircFNDC3B may serve as a novel tumor suppressive factor and potential target for new therapies in human BC. PMID- 30458785 TI - Clinical validity and diagnostic accuracy of the Maslach Burnout Inventory Student Survey in Sri Lanka. AB - BACKGROUND: Absence of context-specific clinically validated cut-off values for assessing burnout as a dichotomous phenomenon has hindered the progress of student burnout research with regard to quantifying the magnitude of the problem. Hence, the present study was aimed at developing clinically validated cut-off values and evaluating the diagnostic accuracy of the Sinhala translation of the 15-item Maslach Burnout Inventory-Student Survey (MBI-SS) in assessing burnout among collegiate cycle students in Sri Lanka. METHODS: This prospective validation study was conducted among 194 grade thirteen students in the Kurunegala district, Sri Lanka. Clinically validated cut-off values for the subscale scores of the MBI-SS test was developed by computing ROC curves, using the clinical diagnosis made by the Consultant Psychiatrist as the reference standard. Diagnostic accuracy of the MBI-SS test results based on "exhaustion+ 1" criterion was assessed comparing with the results of the clinical diagnosis. RESULTS: The clinically validated cut-off values for the exhaustion, cynicism and reduced professional efficacy subscale scores were 12.5, 7.5 and 10.5 for the respectively. The sensitivity, specificity, positive and negative predictive values of the Sinhala translation of the 15-item MBI-SS were 91.9% (95% CI = 82.5 96.5%), 93.2% (95% CI = 87.5-96.4%), 86.4% (95% CI = 76.1-92.7%) and 96.1% (95% CI = 91.2-98.3%) respectively. The positive and negative likelihood ratios were 13.48 (95% CI = 7.15-25.44) and 0.09 (95% CI = 0.04-0.20) respectively. CONCLUSIONS: By using the clinically validated cut-off values for the subscale scores and based on the "exhaustion + 1" criterion, the Sinhala translation of the 15-item MBI-SS could be effectively used as a screening tool to assess burnout among collegiate cycle students. The study findings broaden the global evidence base pertaining to validated cut-off values of the MBI-SS. PMID- 30458786 TI - Systematic reviews for policy-making - critical reflections are needed. PMID- 30458787 TI - LncRNA MIR31HG targets HIF1A and P21 to facilitate head and neck cancer cell proliferation and tumorigenesis by promoting cell-cycle progression. AB - LncRNAs are involved in the initiation and progression of cancer. However, the molecular mechanism and diverse clinical prognosis of MIR31HG in head and neck squamous cell carcinoma (HNSCC) are still unclear. Our previous microarray analysis showed that lncRNA MIR31HG interacted with HIF1A may play an oncogenic role in laryngeal squamous cell cancer (LSCC). To determine whether lncRNA MIR31HG served as a poor prognosis factor and targeted HIF1A to facilitate cell proliferation and tumorigenesis in human HNSCC, we found MIR31HG and HIF1A were overexpressed in LSCC, MIR31HG overexpression or co-expression of HIF1A-positive and p21-negative could serve as a poor prognostic factor for LSCC patients. We further confirmed that MIR31HG promoted cell proliferation, cell cycle progression, and inhibited cell apoptosis in vitro and in vivo. The ingenuity pathway analysis and Western blot indicated that MIR31HG regulated cell cycle progression via HIF1A and p21 in HNSCC. The current results provide evidences for the role of MIR31HG in promoting HNSCC progression and identify MIR31HG as a prognostic biomarker and putative therapeutic target in HNSCC. PMID- 30458788 TI - Modeling hind-limb kinematics using a bio-inspired algorithm with a local search. AB - BACKGROUND: Laboratory rats play a critical role in research because they provide a biological model that can be used for evaluating the affectation of diseases and injuries, and for the evaluation of the effectiveness of new drugs and treatments. The analysis of locomotion in laboratory rats facilitates the understanding of motor defects in many diseases, as well as the damage and recovery after peripheral and central nervous system injuries. However, locomotion analysis of rats remains a great challenge due to the necessity of labor intensive manual annotations of video data required to obtain quantitative measurements of the kinematics of the rodent extremities. In this work, we present a method that is based on the use of a bio-inspired algorithm that fits a kinematic model of the hind limbs of rats to binary images corresponding to the segmented marker of images corresponding to the rat's gait. The bio-inspired algorithm combines a genetic algorithm for a group of the optimization variables with a local search for a second group of the optimization variables. RESULTS: Our results indicate the feasibility of employing the proposed approach for the automatic annotation and analysis of the locomotion patterns of the posterior extremities of laboratory rats. CONCLUSIONS: The adjustment of the hind limb kinematic model to markers of the video frames corresponding to rat's gait sequences could then be used to analyze the motion patterns during the steps, which, in turn, can be useful for performing quantitative evaluations of the effect of lesions and treatments on rats models. PMID- 30458789 TI - Study and characterization of morphogeometric parameters to assist diagnosis of keratoconus. AB - BACKGROUND: In case of significant imperfections on the cornea, data acquisition is difficult and a significant level of missing data could require the interpolation of important areas of the cornea, resulting in a very ambiguous model. The development of methods to define in vivo customised geometric properties of the cornea based only on real raw data is extremely useful to diagnose and assess the progression of diseases directly related to the corneal architecture. The present work tries to improve the prognostic of corneal ectasia creating a 3D customised model of the cornea and analysing different geometric variables from this model to determine which variables or combination of them could be defined as an indicator of susceptibility to develop keratoconus. METHODS: A corneal geometric reconstruction was performed using zonal functions and retrospective Scheimpflug tomography data from 187 eyes of 187 patients. Morphology of healthy and keratoconic corneas was characterized by means of geometric variables. The performance of these variables as predictors of a new geometric marker was assessed and their correlations were analysed. RESULTS: The more representative variable to classify the corneal anomalies related to keratoconus was posterior apex deviation (area under receiver operating characteristic curve > 0.899; p < 0.0001). However, the strongest correlations in both healthy and pathological corneas were provided by the metrics directly related to the thickness, as deviations of the anterior/posterior minimum thickness points. CONCLUSIONS: The presented morphogeometric approach based on the analysis and custom geometric modelling of the cornea demonstrates to be useful for the characterization and diagnosis of keratoconus disease, stating that geometrical deformation is an effective marker of the ectatic disease's progression. PMID- 30458791 TI - Improving the EFMs quality by augmenting their representativeness in LP methods. AB - BACKGROUND: Although cellular metabolism has been widely studied, its fully comprehension is still a challenge. A main tool for this study is the analysis of meaningful pieces of knowledge called modes and, in particular, specially interesting classes of modes such as pathways and Elementary Flux Modes (EFMs). Its study often has to deal with issues such as the appearance of infeasibilities or the difficulty of finding representative enough sets of modes that are free of repetitions. Mode extraction methods usually incorporate strategies devoted to mitigate this phenomena but they still get a high ratio of repetitions in the set of solutions. RESULTS: This paper presents a proposal to improve the representativeness of the full set of metabolic reactions in the set of computed modes by penalizing the eventual high frequency of occurrence of some reactions during the extraction. This strategy can be applied to any linear programming based extraction existent method. CONCLUSIONS: Our strategy enhances the quality of a set of extracted EFMs favouring the presence of every reaction in it and improving the efficiency by mitigating the occurrence of repeated solutions. The new proposed strategy can complement other EFMs extraction methods based on linear programming. The obtained solutions are more likely to be diverse using less computing effort and improving the efficiency of the extraction. PMID- 30458790 TI - Associations of context-specific sitting time with markers of cardiometabolic risk in Australian adults. AB - BACKGROUND: High volumes of sitting time are associated with an elevated risk of type 2 diabetes and cardiovascular disease, and with adverse cardiometabolic risk profiles. However, previous studies have predominately evaluated only total sitting or television (TV) viewing time, limiting inferences about the specific cardiometabolic health impacts of sitting accumulated in different contexts. We examined associations of sitting time in four contexts with cardiometabolic risk biomarkers in Australian adults. METHODS: Participants (n = 3429; mean +/- SD age 58 +/- 10 years) were adults without clinically diagnosed diabetes or cardiovascular disease from the 2011-2012 Australian Diabetes, Obesity and Lifestyle (AusDiab) study. Multiple linear regressions examined associations of self-reported context-specific sitting time (occupational, transportation, TV viewing and leisure-time computer use) with a clustered cardiometabolic risk score (CMR) and with individual cardiometabolic risk biomarkers (waist circumference, BMI, resting blood pressure, triglycerides, HDL- and LDL cholesterol, and fasting and 2-h post-load plasma glucose). RESULTS: Higher CMR was significantly associated with greater TV-viewing and computer sitting time (b [95%CI] = 0.07 [0.04, 0.09] and 0.06 [0.03, 0.09]), and tended to be associated with higher occupational and transport sitting time (0.01 [- 0.01, 0.03] and 0.03 [- 0.00, 0.06]), after adjustment for potential confounders. Furthermore, keeping total sitting time constant, accruing sitting via TV-viewing and computer use was associated with significantly higher CMR (0.05 [0.02, 0.08] and 0.04 [0.01, 0.06]), accruing sitting in an occupational context was associated with significantly lower CMR (- 0.03 [- 0.05, - 0.01]), while no significant association was seen for transport sitting (0.00 [- 0.03, 0.04]). Results varied somewhat between the respective biomarkers; however, higher sitting time in each domain tended to be associated detrimentally with individual biomarkers except for fasting glucose (non-significant associations) and systolic blood pressure (a beneficial association was observed). Overall, associations were stronger for TV viewing and computer use, and weaker for occupational sitting. CONCLUSIONS: Higher context-specific sitting times tended to be detrimentally associated, albeit modestly, with CMR and several cardiometabolic risk biomarkers. There was some evidence suggesting that the context in which people sit is relevant above and beyond total sitting time. Methodological issues notwithstanding, these findings may assist in identifying priorities for sitting-reduction initiatives, in order to achieve optimal cardiometabolic health benefits. PMID- 30458793 TI - Ultraviolet (IUV) and mass spectrometry (IMS) imaging for the deconvolution of microbial interactions. AB - BACKGROUND: Spatial localization of natural products or proteins during microbial interactions can help to identify new antimicrobials both as offensive or defensive agents. Visible spatial interactions have been used for decades to enhance Drug Discovery processes both in industry and academia. RESULTS: Herein we describe an automated micro-extraction methodology, that coupled with the previously described HPLC-Studio 2.0 software and the new development, the MASS Studio 1.0 software, can combine multiple chemical analyses to generate ultraviolet (UV) and mass spectrometry (MS) images from traditional affordable analytical equipment. As a proof of concept, we applied this methodology on two microbial antagonisms observed among co-habitant endophytes isolated from endemic plants of arid areas of the south of Europe. CONCLUSIONS: The use of UV and MS images highlighted interacting naturals products and allowed clear identification of induced molecules of interest not produced by the strains when cultured individually. PMID- 30458792 TI - How does membership in local savings groups influence the determinants of national health insurance demand? A cross-sectional study in Kisumu, Kenya. AB - BACKGROUND: Rotating savings and credit associations (ROSCAs) are highly active in many sub-Saharan African countries, serving as an important gateway for coping with financial risk. In light of the Kenya's National Hospital Insurance Fund's (NHIF's) strategy of targeting ROSCAs for membership enrolment, this study sought to estimate how ROSCA membership influences the determinants of voluntary health insurance enrolment. METHODS: A cross-sectional survey of 444 households was carried out in Kisumu City between July and August 2016. A structured questionnaire was administered on health insurance membership, household attributes, headship characteristics and health-seeking behaviour. We assessed the influence of ROSCA membership on the associations between NHIF enrolment and the explanatory variables using univariate logistic regression. RESULTS: The study found that education was associated with NHIF demand regardless of ROSCA membership. Both ROSCA and non-ROSCA households with high socioeconomic status showed stronger health insurance demand compared with poorer households; there was, however, no evidence that the strength of this association was influenced by ROSCA status (p-value = 0.47). Participants who were self-employed were significantly less likely to enrol into the NHIF if they did not belong to a ROSCA (interaction test p-value = 0.03). NHIF enrolment was found to be lower among female-headed households. There was a borderline effect of ROSCA membership on this association, with a lower odds ratio amongst non-ROSCA members (p-value = 0.09): the low treatment numbers amongst the insured infers that ROSCA membership may play a role on the association between gender and NHIF demand. CONCLUSIONS: Our findings suggest that ROSCA membership may play a role in increasing health insurance demand amongst some traditionally under-represented groups such as women and the self-employed. However, the strategy of targeting ROSCAs to increase national health insurance enrolment may yield exiguous results, given that ROSCA membership is itself influenced by several non-observable factors - such as time-availability and self-selection. It is therefore important to anchor outreach to ROSCAs within a broader, multi-pronged approach that targets households within their social, economic and political realities. PMID- 30458794 TI - Subjective judgements - no more, no less? A response to Malterud, Bjelland and Elvbakken. AB - In 2016, three researchers published a report where they concluded that systematic reviews from my institution, the Norwegian Knowledge Centre for the Health Services, are of little use for health policy decision-making. Based on their reading of the conclusion section in 14 reports, they argue that our systematic reviews are not useful due to their lack of clear and conclusive findings. I have reviewed the same documents and I beg to differ. Unfortunately, the description of their methodological approach is both sparse and difficult to grasp, making it very hard to understand how they arrived at their conclusions. PMID- 30458795 TI - Machine learning in critical care: state-of-the-art and a sepsis case study. AB - BACKGROUND: Like other scientific fields, such as cosmology, high-energy physics, or even the life sciences, medicine and healthcare face the challenge of an extremely quick transformation into data-driven sciences. This challenge entails the daunting task of extracting usable knowledge from these data using algorithmic methods. In the medical context this may for instance realized through the design of medical decision support systems for diagnosis, prognosis and patient management. The intensive care unit (ICU), and by extension the whole area of critical care, is becoming one of the most data-driven clinical environments. RESULTS: The increasing availability of complex and heterogeneous data at the point of patient attention in critical care environments makes the development of fresh approaches to data analysis almost compulsory. Computational Intelligence (CI) and Machine Learning (ML) methods can provide such approaches and have already shown their usefulness in addressing problems in this context. The current study has a dual goal: it is first a review of the state-of-the-art on the use and application of such methods in the field of critical care. Such review is presented from the viewpoint of the different subfields of critical care, but also from the viewpoint of the different available ML and CI techniques. The second goal is presenting a collection of results that illustrate the breath of possibilities opened by ML and CI methods using a single problem, the investigation of septic shock at the ICU. CONCLUSION: We have presented a structured state-of-the-art that illustrates the broad-ranging ways in which ML and CI methods can make a difference in problems affecting the manifold areas of critical care. The potential of ML and CI has been illustrated in detail through an example concerning the sepsis pathology. The new definitions of sepsis and the relevance of using the systemic inflammatory response syndrome (SIRS) in its diagnosis have been considered. Conditional independence models have been used to address this problem, showing that SIRS depends on both organ dysfunction measured through the Sequential Organ Failure (SOFA) score and the ICU outcome, thus concluding that SIRS should still be considered in the study of the pathophysiology of Sepsis. Current assessment of the risk of dead at the ICU lacks specificity. ML and CI techniques are shown to improve the assessment using both indicators already in place and other clinical variables that are routinely measured. Kernel methods in particular are shown to provide the best performance balance while being amenable to representation through graphical models, which increases their interpretability and, with it, their likelihood to be accepted in medical practice. PMID- 30458796 TI - Combination of serum lipids and cancer antigens as a novel marker for colon cancer diagnosis. AB - BACKGROUND: Colon cancer is a malignancy of the large intestine with high mortality and economic burden. Recent studies reveal a new relationship between blood lipids and the risk of cancer. The presents study aims to investigate the combination of serum lipids with cancer antigens as a novel diagnostic marker for colon cancer. METHODS: Two hundred of colon cancer patients or healthy subjects were recruited. Serum lipids and cancer antigens such as total cholesterol (TC), high-density lipoprotein (HDL), carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were measured. RESULTS: There were significantly lower level of serum TC or HDL, and significantly higher level of serum CEA or CA19-9 in patients than in healthy subjects. Serum TC or HDL in patients with advanced colon cancer was significantly lower than the ones with early stage disease. The level of serum TC or HDL in patients after surgical removal of colon cancer was significantly higher compared to the ones before surgery, but serum CEA or CA19-9 after surgery was significantly reduced in comparison with the ones before surgery. Combined TC, HDL, CEA and CA19-9 as a diagnostic marker for colon cancer had the highest positive predictive rate in comparison with individual, two or three of the parameters. CONCLUSIONS: The combination of serum TC, HDL, CEA and CA19-9 can be used as an effective marker for colon cancer, and offers a novel strategy for clinical diagnosis and monitoring the disease. PMID- 30458797 TI - Comprehensive study of instable regions in Pseudomonas aeruginosa and Mycobacterium tuberculosis. AB - BACKGROUND: Pseudomonas aeruginosa is a common bacterium which is recognized for its association with hospital-acquired infections and its advanced antibiotic resistance mechanisms. Tuberculosis, one of the major causes of mortality, is initiated by the deposition of Mycobacterium tuberculosis. Accessory sequences shared by a subset of strains of a species play an important role in a species' evolution, antibiotic resistance and infectious potential. RESULTS: Here, with a multiple sequence aligner, we segmented 25 P. aeruginosa genomes and 28 M. tuberculosis genomes into core blocks (include sequences shared by all the input genomes) and dispensable blocks (include sequences shared by a subset of the input genomes), respectively. For each input genome, we then constructed a scaffold consisting of its core and dispensable blocks sorted by blocks' locations on the chromosomes. Consecutive dispensable blocks on these scaffold formed instable regions. After a comprehensive study of these instable regions, three characteristics of instable regions are summarized: instable regions were short, site specific and varied in different strains. Three DNA elements (directed repeats (DRs), transposons and integrons) were then studied to see whether these DNA elements are associated with the variation of instable regions. A pipeline was developed to search for DR pairs on the flank of every instable sequence. 27 DR pairs in P. aeruginosa strains and 6 pairs in M. tuberculosis strains were found to exist in the instable regions. On the average, 14% and 12% of instable regions in P. aeruginosa strains covered transposase genes and integrase genes, respectively. In M. tuberculosis strains, an average of 43% and 8% of instable regions contain transposase genes and integrase genes, respectively. CONCLUSIONS: Instable regions were short, site specific and varied in different strains for both P. aeruginosa and M. tuberculosis. Our experimental results showed that DRs, transposons and integrons may be associated with variation of instable regions. PMID- 30458798 TI - Machine learning approaches for predicting high cost high need patient expenditures in health care. AB - BACKGROUND: This paper studies the temporal consistency of health care expenditures in a large state Medicaid program. Predictive machine learning models were used to forecast the expenditures, especially for the high-cost, high need (HCHN) patients. RESULTS: We systematically tests temporal correlation of patient-level health care expenditures in both the short and long terms. The results suggest that medical expenditures are significantly correlated over multiple periods. Our work demonstrates a prevalent and strong temporal correlation and shows promise for predicting future health care expenditures using machine learning. Temporal correlation is stronger in HCHN patients and their expenditures can be better predicted. Including more past periods is beneficial for better predictive performance. CONCLUSIONS: This study shows that there is significant temporal correlation in health care expenditures. Machine learning models can help to accurately forecast the expenditures. These results could advance the field toward precise preventive care to lower overall health care costs and deliver care more efficiently. PMID- 30458799 TI - AMPK-dependent and independent actions of P2X7 in regulation of mitochondrial and lysosomal functions in microglia. AB - BACKGROUND: P2X7 is ubiquitously expressed in myeloid cells and regulates the pathophysiology of inflammatory diseases. Since mitochondrial function in microglia is highly associated with microglial functions in controlling neuronal plasticity and brain homeostasis, we interested to explore the roles of P2X7 in mitochondrial and lysosomal functions as well as mitophagy in microglia. METHODS: P2X7-/- bone marrow-derived macrophages (BMDM), primary microglia and BV-2 immortalized microglial cells were used to detect the particular protein expression by immunoblotting. Mitochondrial reactive oxygen species (mitoROS), intracellular calcium, mitochondrial mass and lysosomal integrity were examined by flow cytometry. Mitochondrial oxygen consumption rate (OCR) was recorded using Seahorse XF flux analyzer. Confocal microscopic images were performed to indicate the mitochondrial dynamics and mitophagy after P2X7 activation. RESULTS: In primary microglia, BV-2 microglial cells and BMDM, P2X7 agonist BzATP triggered AMPK activation and LC3II accumulation through reactive oxygen species (ROS) and CaMKKII pathways, and these effects were abolished by P2X7 antagonist A438079 and P2X7 deficiency. Moreover, we detected the dramatic decreases of mitochondrial OCR and mass following P2X7 activation. AMPK inhibition by compound C or AMPK silencing reversed the P2X7 actions in reduction of mitochondrial mass, induction of mitochondrial fission and mitophagy, but not in uncoupling of mitochondrial respiration. Interestingly, we found that P2X7 activation induced nuclear translocation of TFEB via an AMPK-dependent pathway and led to lysosomal biogenesis. Mimicking the actions of BzATP, nigericin also induced ROS-dependent AMPK activation, mitophagy, mitochondrial fission and respiratory inhibition. Longer exposure of BzATP induced cell death, and this effect was accompanied by the lysosomal instability and was inhibited by autophagy and cathepsin B inhibitors. CONCLUSION: Altogether ROS- and CaMKK-dependent AMPK activation is involved in P2X7-mediated mitophagy, mitochondrial dynamics and lysosomal biogenesis in microglial cells, which is followed by cytotoxicity partially resulting from mitophagy and cathepsin B activation. PMID- 30458800 TI - Blood pressure waveform contour analysis for assessing peripheral resistance changes in sepsis. AB - BACKGROUND: This paper proposes a methodology for helping bridge the gap between the complex waveform information frequently available in an intensive care unit and the simple, lumped values favoured for rapid clinical diagnosis and management. This methodology employs a simple waveform contour analysis approach to compare aortic, femoral and central venous pressure waveforms on a beat-by beat basis and extract lumped metrics pertaining to the pressure drop and pressure-pulse amplitude attenuation as blood passes through the various sections of systemic circulation. RESULTS: Validation encompasses a comparison between novel metrics and well-known, analogous clinical metrics such as mean arterial and venous pressures, across an animal model of induced sepsis. The novel metric Ofe -> vc, the direct pressure offset between the femoral artery and vena cava, and the clinical metric, DeltaMP, the difference between mean arterial and venous pressure, performed well. However, Ofe -> vc reduced the optimal average time to sepsis detection after endotoxin infusion from 46.2 min for DeltaMP to 11.6 min, for a slight increase in false positive rate from 1.8 to 6.2%. Thus, the novel Ofe -> vc provided the best combination of specificity and sensitivity, assuming an equal weighting to both, of the metrics assessed. CONCLUSIONS: Overall, the potential of these novel metrics in the detection of diagnostic shifts in physiological behaviour, here driven by sepsis, is demonstrated. PMID- 30458801 TI - Salient networks: a novel application to study Alzheimer disease. AB - BACKGROUND: Extracting fundamental information from data, thus underlining hidden structures or removing noisy information, is one of the most important aims in different scientific fields especially in biological and medical sciences. In this article, we propose an innovative complex network application able to identify salient links for detecting the effect of Alzheimer's disease on brain connectivity. We first build a network model of brain connectivity from structural Magnetic Resonance Imaging (MRI) data, then we study salient networks retrieved from the original ones. RESULTS: Investigating informative power of the salient skeleton features in combination with those of the original networks we obtain an accuracy of [Formula: see text] for the distinction of Alzheimer disease (AD) patients from normal controls (NC). This performance significantly overcomes accuracy of the original network features. Moreover salient networks are able to correctly discriminate normal controls (NC) from AD patients and NC from subjects with mild cognitive impairment that will convert to AD (cMCI). These evaluations, performed on an independent dataset, give an accuracy of [Formula: see text] and [Formula: see text] respectively for NC-AD and NC-cMCI classifications. Therefore, most of the informative content of the original networks is kept after the 92 [Formula: see text] and 82 [Formula: see text] reduction respectively in the number of nodes and links. In addition, the present approach, applied to a publicly available MRI dataset from the Alzheimer Disease Neuroimaging Initiative (ADNI), brings out also some interesting aspects related to the topologies and hubs of the networks. CONCLUSIONS: The experimental results demonstrate how salient networks can highlight important brain network characteristics and structural pathological changes, while reducing considerably data complexity and computational requirements. PMID- 30458802 TI - BioGraph: a web application and a graph database for querying and analyzing bioinformatics resources. AB - BACKGROUND: Several online databases provide a large amount of biomedical data of different biological entities. These resources are typically stored in systems implementing their own data model, user interface and query language. On the other hand, in many bioinformatics scenarios there is often the need to use more than one resource. The availability of a single bioinformatics platform that integrates many biological resources and services is, for those reasons a fundamental issue. DESCRIPTION: Here, we present BioGraph, a web application that allows to query, visualize and analyze biological data belonging to several online available sources. BioGraph is built upon our previously developed graph database called BioGraphDB, that integrates and stores heterogeneous biological resources and make them available by means of a common structure and a unique query language. BioGraph implements state-of-the-art technologies and provides pre-compiled bioinformatics scenarios, as well as the possibility to perform custom queries and obtaining an interactive and dynamic visualization of results. CONCLUSION: We present a case study about functional analysis of microRNA in breast cancer in order to demonstrate the functionalities of the system. BioGraph is freely available at http://biograph.pa.icar.cnr.it . Source files are available on GitHub at https://github.com/IcarPA-TBlab/BioGraph. PMID- 30458803 TI - Maternal health care access among migrant women labourers in the selected brick kilns of district Faridabad, Haryana: mixed method study on equity and access. AB - BACKGROUND: Socio-economic inequity leads to health inequity. Inequity is closely intertwined with internal migration. This study was planned with the objective of documenting the maternal health care utilization among women labourers working in brick kilns situated in an area of Haryana, north India. METHODS: A community based mixed method study was done in select brick kilns of Faridabad district in north India. A mixed method study was done to assess maternal health care utilization in a sample of 500 women in the reproductive age group. Focus group discussions were also carried out. Descriptive analysis was done. Qualitative data was analysed using the thematic framework approach. RESULTS: The mean age of the women was 30 (SD 0.3) years. Mean number of pregnancies per woman was 3.1 (SD 1.7). Only 22.9% ever had institutional delivery. About one third of women had ever received cash benefit under Janani SurakshaYojana (JSY) or had ever used free ambulance services. Seven major themes emerged from the qualitative analysis. Important themes include-Gaps in knowledge regarding local health system; Sub-standard private health care delivered at brick kilns prevent migrants from accessing the basic public health services; Misconceptions and mistrust about public health system influenced maternal health care utilization; Barriers to avail universal health coverage: location of brick kilns, time, apathy of public health system, partial health insurance cover. CONCLUSIONS: A typical migrant woman labourer in the brick kiln was an illiterate, had migrated from poor states, belonged to a socially disadvantaged community and worked long hours, and had been doing so for many years. This study has identified migrant women working in brick kilns as a vulnerable population subgroup in terms of maternal health utilization. To achieve universal health care it is important to understand the needs of all population subgroups and make concerted efforts at the health system level. PMID- 30458804 TI - Hospital mortality statistics in Tanzania: availability, accessibility, and quality 2006-2015. AB - BACKGROUND: Accurate and reliable hospital information on the pattern and causes of death is important to monitor and evaluate the effectiveness of health policies and programs. The objective of this study was to assess the availability, accessibility, and quality of hospital mortality data in Tanzania. METHODS: This cross-sectional study involved selected hospitals of Tanzania and was carried out from July to October 2016. Review of hospital death registers and forms was carried out to cover a period of 10 years (2006-2015). Interviews with hospital staff were conducted to seek information as regards to tools used to record mortality data, staff involved in recording and availability of data storage and archiving facilities. RESULTS: A total of 247,976 death records were reviewed. The death register was the most (92.3%) common source of mortality data. Other sources included the International Classification of Diseases (ICD) report forms, Inpatient registers, and hospital administrative reports. Death registers were available throughout the 10-year period while ICD-10 forms were available for the period of 2013-2015. In the years between 2006 and 2010 and 2011-2015, the use of death register increased from 82 to 94.9%. Three years after the introduction of ICD-10 procedure, the forms were available and used in 28% (11/39) hospitals. The level of acceptable data increased from 69% in 2006 to 97% in 2015. Inconsistency in the language used, use of non-standard nomenclature for causes of death, use of abbreviations, poorly and unreadable handwriting, and missing variables were common data quality challenges. About 6.3% (n = 15,719) of the records had no patient age, 3.5% (n = 8790) had no cause of death and ~ 1% had no sex indicated. The frequency of missing sex variable was most common among under-5 children. Data storage and archiving in most hospitals was generally poor. Registers and forms were stored in several different locations, making accessibility difficult. CONCLUSION: Overall, this study demonstrates gaps in hospital mortality data availability, accessibility, and quality, and highlights the need for capacity strengthening in data management and periodic record reviews. Policy guidelines on the data management including archiving are necessary to improve data. PMID- 30458805 TI - Combination of inspiratory and expiratory muscle training in same respiratory cycle versus different cycles in COPD patients: a randomized trial. AB - BACKGROUND: Difference between combined inspiratory and expiratory muscle training in same respiratory cycle or different cycles remained unclarified. We explored the difference between both patterns of combined trainings in patients with COPD. METHODS: In this randomized, open-label, controlled trial, stable COPD subjects trained for 48 minutes daily, for 8 weeks, using a monitoring device for quality control. Ninety-two subjects were randomly and equally assigned for sham training, inspiratory muscle training(IMT), combined inspiratory and expiratory muscle training in same cycle(CTSC) or combined inspiratory and expiratory muscle training in different cycles(CTDC). Respiratory muscle strength, as the primary endpoint, was measured before and after training. Registry: ClinicalTrials.gov (identifier: NCT02326181). RESULTS: Respiratory muscle training improved maximal inspiratory pressure(PImax), while no significant difference was found in PImax among IMT, CTSC and CTDC. Maximal expiratory pressure(PEmax) in CTSC and CTDC was greater than IMT(P = 0.026, and P=0.04, respectively) and sham training (P = 0.001). IMT, CTSC, and CTDC shortened inhalation and prolonged exhalation(P < 0.01). Subjects with respiratory muscle weakness in IMT and CTDC exhibited greater increase in PImax than those without. IMT, CTSC and CTDC showed no difference in symptoms and quality of life scales among themselves(P > 0.05). CONCLUSION: Both patterns of CTSC and CTDC improved inspiratory and expiratory muscle strength, while IMT alone only raised PImax. Respiratory muscle training might change the respiratory cycles, and be more beneficial for COPD patients with inspiratory muscle weakness. PMID- 30458806 TI - Autologous blood transfusion augments impaired wound healing in diabetic mice by enhancing lncRNA H19 expression via the HIF-1alpha signaling pathway. AB - BACKGROUND: Impaired wound healing frequently occurs in diabetes mellitus (DM) and is implicated in impaired angiogenesis. Long non-coding RNA (lncRNA) H19 has been reported as being reduced in DM and played a critical role in inducing angiogenesis. Thus, we hypothesized that H19 may affect impaired wound healing in streptozotocin (STZ)-induced diabetic mice transfused with autologous blood preserved in standard preservative fluid or modified preservative fluid. METHODS: Fibroblasts in injured skin were isolated and cultured in vitro. After location of H19 in fibroblasts using fluorescence in situ hybridization (FISH), RNA-pull down, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), Co immunoprecipitation (COIP) and dual luciferase reporter gene assay were used to verify the binding of H19 to HIF-1alpha. RESULTS: The modified preservative fluid preserved autologous blood increased the H19 expression in fibroblasts, and maintained better oxygen-carrying and oxygen release capacities as well as coagulation function. Furthermore, H19 promoted HIF-1alpha histone H3K4me3 methylation and increased HIF-1alpha expression by recruiting EZH2. H19 promoted fibroblast activation by activating HIF-1alpha signaling pathway in fibroblasts and enhanced wound healing in diabetic mice. CONCLUSIONS: Taken together, H19 accelerated fibroblast activation by recruiting EZH2-mediated histone methylation and modulating the HIF-1alpha signaling pathway, whereby augmenting the process of modified preservative fluid preserved autologous blood enhancing the postoperative wound healing in diabetic mice. PMID- 30458808 TI - Determination of the volatile and polyphenol constituents and the antimicrobial, antioxidant, and tyrosinase inhibitory activities of the bioactive compounds from the by-product of Rosa rugosa Thunb. var. plena Regal tea. AB - BACKGROUND: The phytochemical constituents and biological activities of Rosa rugosa Thunb. var. plena Regal flower cell sap (RFCS) were investigated. METHODS: Volatile constituent, such as linalool, phenylethyl alcohol, citronellol, alpha bisabolol, were identified by GC-MS. The contents of hyperoside, kaempferol-3-O rutinosid, rutin, and luteolin as well as the total flavonoid content in RFCS were determined by HPLC and HPLC-MS. The total polyphenol content was evaluated by the Folin-Ciocalteu colorimetric method. The antioxidant activities of RFCS and the standards were evaluated by DPPH and ABTS radical scavenging assays. The tyrosinase inhibitory activities of the rose samples and standard substance were determined by a spectrophotometric method. The antimicrobial effects of RFCS were evaluated in terms of minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) or minimum Fungicidal concentrations (MFCs). RESULTS: The rose fraction exhibited a high content of biologically active ingredients. The total content of volatile compounds in RFCS was approximately 48.21 +/- 2.76 ng/mL. The total phenolic acid content and total flavonoid content were 0.31 +/- 0.01 mg/mL and 0.43 +/- 0.01 mg/mL, respectively. Its IC50 value in the DPPH assay was 1120 +/- 42 MUg/mL, and its IC50 value for ABTS radical scavenging activity was 1430 +/- 42 MUg/mL.RFCS strongly inhibited L-tyrosine oxidation with an IC50 value of 570 +/- 21 MUg/mL. Every compound identified in RFCS exhibited broad-spectrum antimicrobial activity. F. nucleatum was most susceptible to RFCS with an MIC of 64 MUg/mL and MBC of 250 MUg/mL. CONCLUSIONS: Due to its rose-like aroma, phenylethyl alcohol may be combined with linalool for use as a natural skin-whitening agent and skin care additive in the and pharmaceutical industries. PMID- 30458807 TI - Achieving Thoracic Oncology data collection in Europe: a precursor study in 35 Countries. AB - BACKGROUND: A minority of European countries have participated in international comparisons with high level data on lung cancer. However, the nature and extent of data collection across the continent is simply unknown, and without accurate data collection it is not possible to compare practice and set benchmarks to which lung cancer services can aspire. METHODS: Using an established network of lung cancer specialists in 37 European countries, a survey was distributed in December 2014. The results relate to current practice in each country at the time, early 2015. The results were compiled and then verified with co-authors over the following months. RESULTS: Thirty-five completed surveys were received which describe a range of current practice for lung cancer data collection. Thirty countries have data collection at the national level, but this is not so in Albania, Bosnia-Herzegovina, Italy, Spain and Switzerland. Data collection varied from paper records with no survival analysis, to well-established electronic databases with links to census data and survival analyses. CONCLUSION: Using a network of committed clinicians, we have gathered validated comparative data reporting an observed difference in data collection mechanisms across Europe. We have identified the need to develop a well-designed dataset, whilst acknowledging what is feasible within each country, and aspiring to collect high quality data for clinical research. PMID- 30458810 TI - Clinical outcomes of femoral shaft non-union: dual plating versus exchange nailing with augmentation plating. AB - BACKGROUND: By comparing clinical outcomes between dual plating (DP) and exchange nailing with augmentation plating (EN/AP), we aimed to provide better treatment strategies for femoral shaft non-union. METHODS: We retrospectively reviewed 30 patients with aseptic femoral shaft non-union at our level 1 trauma center between January 2014 and January 2017. All patients underwent a one-stage, definitive revision procedure, including DP for 16 patients and EN/AP for 14 patients. Perioperative surgical trauma, fracture healing, complications, and the time to return to work were evaluated. RESULTS: Twenty-nine patients achieved fracture healing. In the EN/AP group, the fracture healing rate was 100%, the healing time was 5.7 +/- 1.7 months, and the time of return to work was 8.2 +/- 2.9 months. In the DP group, the fracture healing rate was 94%, the healing time was 8.4 +/- 4.1 months, and the time of return to work was 18.4 +/- 10.3 months. In terms of fracture healing and return to work, the patients in the EN/AP group required less time than those in the DP group, and the differences were statistically significant (p = 0.024 and p < 0.01 respectively). Except for the length of the incision, the two groups showed no statistically significant differences in operative time, postoperative deformity, and complications. CONCLUSIONS: Both EN/AP and DP are important surgical options for femoral shaft non-union. Compared to DP, EN/AP resulted in a shorter incision, faster fracture healing, and a shorter time to return to work. TRIAL REGISTRATION: ChiCTR-ORC 17014062. PMID- 30458809 TI - Stakeholder views regarding ethical issues in the design and conduct of pragmatic trials: study protocol. AB - BACKGROUND: Randomized controlled trial (RCT) trial designs exist on an explanatory-pragmatic spectrum, depending on the degree to which a study aims to address a question of efficacy or effectiveness. As conceptualized by Schwartz and Lellouch in 1967, an explanatory approach to trial design emphasizes hypothesis testing about the mechanisms of action of treatments under ideal conditions (efficacy), whereas a pragmatic approach emphasizes testing effectiveness of two or more available treatments in real-world conditions. Interest in, and the number of, pragmatic trials has grown substantially in recent years, with increased recognition by funders and stakeholders worldwide of the need for credible evidence to inform clinical decision-making. This increase has been accompanied by the onset of learning healthcare systems, as well as an increasing focus on patient-oriented research. However, pragmatic trials have ethical challenges that have not yet been identified or adequately characterized. The present study aims to explore the views of key stakeholders with respect to ethical issues raised by the design and conduct of pragmatic trials. It is embedded within a large, four-year project that seeks to develop guidance for the ethical design and conduct of pragmatic trials. As a first step, this study will address important gaps in the current empirical literature with respect to identifying a comprehensive range of ethical issues arising from the design and conduct of pragmatic trials. By opening up a broad range of topics for consideration within our parallel ethical analysis, we will extend the current debate, which has largely emphasized issues of consent, to the range of ethical considerations that may flow from specific design choices. METHODS: Semi structured interviews with key stakeholders (e.g. trialists, methodologists, lay members of study teams, bioethicists, and research ethics committee members), across multiple jurisdictions, identified based on their known experience and/or expertise with pragmatic trials. DISCUSSION: We expect that the study outputs will be of interest to a wide range of knowledge users including trialists, ethicists, research ethics committees, journal editors, regulators, healthcare policymakers, research funders and patient groups. All publications will adhere to the Tri-Agency Open Access Policy on Publications. PMID- 30458811 TI - Association between breakfast composition and abdominal obesity in the Swiss adult population eating breakfast regularly. AB - BACKGROUND: Evidence from experimental and observational studies is limited regarding the most favorable breakfast composition to prevent abdominal fat accumulation. We explored the association between breakfast composition (a posteriori derived dietary patterns) and abdominal obesity among regular breakfast eaters from a Swiss population-based sample. METHODS: The cross sectional survey assessed diet using two 24-h dietary recalls in a nationally representative sample of adults aged 18 to 75 years. We derived dietary patterns using principal component analysis based on the intake of 22 breakfast-specific food groups. All regular breakfast eaters were predicted an individual score for each identified pattern, and then classified into tertiles (T1, T2, T3). We defined abdominal obesity as waist-to-hip ratio (WHR) >= 0.9 in men and >= 0.85 in women. Logistic models were adjusted for sociodemographic characteristics, relevant nutrition- and health-related behaviors, and diet quality during the rest of the day. RESULTS: Of the 2019 included survey participants, 1351 (67%) were regular breakfast eaters. Among them, we identified three breakfast types: 1) 'traditional' - white bread, butter, sweet spread, 2) 'prudent' - fruit, unprocessed and unsweetened cereal flakes, nuts/seeds, yogurt, and 3) 'western' - processed breakfast cereals, and milk. The 'prudent' breakfast was negatively associated with abdominal obesity. After full adjustment, including diet quality during the rest of the day, the association was weaker (T3 vs. T1: OR 0.72, 95% CI: 0.47 to 1.08). People taking a 'prudent' breakfast (in T3) had 1.2% lower WHR compared to people taking a breakfast distant from 'prudent' (in T1) (P = 0.02, fully adjusted model with continuous log-WHR). We found no association between 'traditional' or 'western' breakfasts and WHR (OR 1.00, 95% CI: 0.67 to 1.50 and OR 1.16, 95% CI: 0.79 to 1.71, respectively). Findings were in the same directions for the three breakfast types when defining obesity with waist circumference, waist-to-height ratio, or body mass index (>= 30 kg/m2, for 'prudent' breakfast: OR 0.51, 95% CI: 0.31 to 0.85). CONCLUSIONS: Regular breakfast consumers had less abdominal obesity if their breakfast was composed of fruit, natural cereal flakes, nuts/seeds and yogurt. This association was partly explained by their healthier diet during the rest of the day. TRIAL REGISTRATION: ISRCTN16778734 . PMID- 30458812 TI - Anal canal adenocarcinoma with neuroendocrine features accompanying secondary extramammary Paget disease, successfully treated with modified FOLFOX6: a case report. AB - BACKGROUND: Anal canal cancer occasionally accompanies extramammary Paget disease. Although most of them are squamous cell carcinoma, anal canal adenocarcinoma with neuroendocrine features accompanying secondary extramammary Paget disease has never been reported. CASE PRESENTATION: Here, we report a 76 year-old man presented with pruritus in the perianal area. Investigation revealed a fist-sized perianal erythema, diffuse liver tumors, and right inguinal lymph node swelling. Pathological examination of biopsies from the erythema suggested secondary extramammary Paget disease with positive cytokeratin-7 and -20 expressions and negative GCDFP-15 expression. The anal canal tumor was confirmed by digital examination and endoscopy. Biopsies from the anal canal tumor, swollen lymph node, and Paget lesion all showed poorly differentiated adenocarcinoma with neuroendocrine features expressing synaptophysin and chromogranin A. Serum CEA and NSE levels were high, 809.4 ng/ml and 85.8 ng/ml, respectively. After chemotherapy with modified FOLFOX6 for 2 months, the Paget lesion disappeared, and the primary anal canal tumor and liver metastases shrunk remarkably. Serum CEA and NSE levels decreased promptly to within normal ranges. CONCLUSIONS: This is a clinically significant case, as it reveals novel pathological features about anal canal cancer with secondary Paget disease and successfully treated with modified FOLFOX6. Careful pathological investigation and appropriate treatment choice are needed for this rare cancer. PMID- 30458813 TI - Caries-related risk factors of obesity among 18-year-old adolescents in Hong Kong: a cross-sectional study nested in a cohort study. AB - BACKGROUND: Socio-economic status, health awareness, and dietary habits have been reported as common risk factors of dental caries and obesity. The present study aimed to explore shared mediators between caries and obesity and to estimate the effects of caries-related factors on adiposity. METHODS: This was a cross sectional study among adolescents aged 18 years. The study was nested in a population-representative cohort of Chinese in Hong Kong. The number of decayed, missing, and filled permanent teeth (DMFT) was recorded during the oral examinations. Body Mass Index (BMI), Waist Circumference (WC), Waist-Hip-Ratio (WHR), Waist-Height-Ratio (WHtR), and Triceps Skinfold Thickness (TRSKF) were used as adiposity indices. Data on socio-economic status, oral health behavior (tooth brushing habit, use of fluoride toothpaste, dental flossing habit, and mouth rinse habit), and dietary record (frequency and amount of different food) were collected through self-completed questionnaires. Chi-square tests and binary logistic regressions were used for analysis. RESULTS: Three hundred eighty-three participants were included. The mean (standard deviation, SD) of BMI, WC, WHR, WHtR, TRSKF, and DMFT were 21.26 (3.72), 69.11 (9.25), 0.77 (0.06), 0.42 (0.05), 15.72 (6.33), and 2.06 (2.43), respectively. Males were more likely to be overweight/obese than females. Various factors including gender, parental employment status, mouth rinse habit, frequency and amount of meat intake, frequency of oil intake, use of fluoride toothpaste, and DMFT were found significant (p < 0.05) in different final models of adiposity status. CONCLUSIONS: More mediators should be included in future research to elucidate mechanism of the association between caries and obesity. PMID- 30458814 TI - Incidence and predictors of surgical site infection after ORIF in calcaneus fractures, a retrospective cohort study. AB - BACKGROUND: Occurrence of calcaneus fractures is on the up trend. Owing to its unique anatomical morphology and limited soft-tissue envelope, management of calcaneus fractures is a challenge to the orthopaedic surgeon, and surgical site infection (SSI) is one of the serious postoperative complications. In order to decrease the incidence of wound breakdown and improve clinical outcomes, it is necessary to understand which factors were associated with SSI. The aim of this study was to identify predictors of SSI and quantify the incidence of SSI in calcaneus fractures following open reduction and internal fixation (ORIF). METHODS: This retrospective study was performed at a level 1 trauma center from January 2014 to June in 2017. Data of adult patients with calcaneus fractures treated by ORIF were extracted from the electronic medical records. A total of 681 patients were collected. We reviewed the patients' demographics, characteristics of fracture, treatment-related variables, and indexes of laboratory examination. Univariate and multivariate logistic analysis models were performed respectively to determine independent predictors of SSI. RESULTS: Sixty six patients developed SSI in this study. The overall incidence of SSI after ORIF of calcaneus fracture was 9.7%, with 2.9% for deep infection and 6.8% for superficial SSI. Independent predictors of SSI identified by multivariate analysis were open fracture (odds ratio = 9.48, 95% CI = 4.53-19.85, P = 0.00007), high-energy injury (odds ratio = 2.07, 95% CI = 1.16-3.70, P = 0.01437), ASA class 3 or higher (odds ratio = 3.50, 95% CI = 1.18-10.37, P = 0.02401), and intraoperative temperature < 36.0 degrees C (odds ratio = 1.69, 95% CI = 1.13-2.28, P = 0.04410). CONCLUSION: The SSI incidence was high (9.7%) for calcaneus fractures following ORIF. External fixation plays an important role in the treatment of severely displaced and depressed intra-articular or open calcaneus fractures. Increased ASA class and intraoperative hypothermia were associated with wound breakdown, and elaborative evaluation of fracture and soft tissue damage was vitally necessary in this at-risk population. PMID- 30458815 TI - Adrenal cavernous hemangioma: a case report. AB - BACKGROUND: Adrenal cavernous hemangiomas are very rare benign tumors that usually present as incidental findings on abdominal imaging. Preoperative differential diagnosis from other benign or malignant adrenal neoplasms may be challenging. CASE PRESENTATION: A 70-year old man was referred for an 8-cm abdominal mass incidentally discovered on a contrast-enhanced computed tomography (CT) performed to investigate a pulmonary nodule. Biochemical tests ruled out any endocrine dysfunction and iodine 123 metaiodobenzylguanidine whole body scintiscan single-photon emission CT excluded a pheocromocitoma. Findings on magnetic resonance imaging were non-specific and the patient was elected for a left adrenalectomy. Histopathological diagnosis revealed a cavernous hemangioma. A portion of the resected tissue was tested for drug sensitivity to mitotane, doxorubicin, and sunitinib. CONCLUSIONS: Adrenal hemangioma is a rare disease but should be included in the differential diagnosis of adrenal tumors. The surgical resection is generally required to exclude malignant disease, resolve pressure related symptoms, and prevent retroperitoneal hemorrhage. Although specific features in diagnostic imaging are often lacking, if the diagnosis is established preoperatively a laparoscopic adrenalectomy can be performed due to the benign nature of the lesion. Doxorubicin and sunitinib were both capable of reducing primary culture cell viability, this suggest that similar drugs may be useful in the medical treatment of adrenal hemangiomas. PMID- 30458816 TI - The effects of postoperative radiotherapy on survival outcomes in patients under 65 with estrogen receptor positive tubular breast carcinoma. AB - BACKGROUND: The value of postoperative radiotherapy in tubular breast carcinoma patients under 65 years is uncertain. METHODS: Data on patients with estrogen receptor positive T1N0M0 tubular breast carcinoma who were younger than 65 years and who received breast-conserving surgery between 2000 and 2013 were retrieved from the Surveillance, Epidemiology and End Results database. Demographic, clinicopathologic features, and receipt of postoperative radiotherapy were analyzed to investigate effects on survival. RESULTS: Data from 2442 patients were analyzed, of whom 2020 (82.7%) received postoperative radiotherapy and 422 (17.3%) did not. The number of patients treated with or without postoperative radiotherapy showed no differences during the study period (p = 0.184). Radiotherapy was more likely to be administered in patients with well differentiated tumors. Multivariate Cox analysis showed that postoperative radiotherapy delivery was significantly correlated with better breast cancer specific survival (BCSS) (hazard ratio [HR] 0.297, 95% confidence interval [CI] 0.105-0.836, p = 0.022) and overall survival (OS) (HR 0.656, 95% CI 0.441-0.978, p = 0.038). Ten 10-year BCSS was 99.3% in patients who received postoperative radiotherapy and 98.1% in those who did not (p = 0.020), and 10-year OS was 93.4 and 91.0%, respectively (p = 0.029). Postoperative radiotherapy increased BCSS and OS in the subgroups of age < 50 years, non-Hispanic white, well differentiated tumors, and progesterone receptor positive tumors. CONCLUSIONS: Postoperative radiotherapy after breast-conserving surgery improved survival outcomes in tubular breast carcinoma patients aged < 50 years. However, omitting postoperative radiotherapy may not decrease survival in patients aged >=50 years. PMID- 30458817 TI - Survey on patients with undiagnosed diseases in Japan: potential patient numbers benefiting from Japan's initiative on rare and undiagnosed diseases (IRUD). AB - BACKGROUND: There is now an international partnership to establish global programs for patients with rare and undiagnosed diseases, involving interdisciplinary expert panels and phenotype-driven genetic analyses utilizing next-generation sequencing and analytics. Whereas it is crucial to have data such as the actual number of undiagnosed patients, to help inform the implementation plan with such programs, there have been no systematic studies to quantitate the numbers of patients principally because of the inherent difficulty in most health systems to identify patients whose condition has not yet been diagnosed and coded. Our national experience with a rare disease program, Nan-Byo which was established in 1972, and the more recently expanded Initiative on Rare and Undiagnosed Diseases (IRUD), provided a unique opportunity to design a cross sectional study to ascertain the undiagnosed patients in Japan based on the IRUD referral criteria. RESULTS: Two rounds of online surveys were performed: one survey targeting physicians affiliated with general hospitals (GH) and family clinics (FC) (the response rate: 30.6% (242/792)) and one nationwide survey targeting university hospitals (UH) in Japan (47.1% (839/1781)). A high percentage of doctors needing IRUD was seen in pediatrics at GH, FC, while there was a clear demand for IRUD in most departments at UH. We calculated the number of undiagnosed patients in Japan, as the "percentage of doctors needing IRUD" * "number of patients who would be referred to IRUD per doctor needing IRUD (cases/person)" * "total number of doctors in the relevant facilities in Japan (persons)", resulting in 3681 cases in pediatrics/pediatric surgery and 33,703 cases in other departments, for a total of 37,384 cases. CONCLUSIONS: Our study revealed the extant demand for IRUD in most departments and 37,000+ potential patients with undiagnosed diseases in the Japanese health system. These data inform the establishment of an equitable, sustainable, efficient and effective outpatient-based IRUD. These findings would serve as a valuable reference for undiagnosed diseases programs in different international jurisdictions and for countries and regions who also share vision(s) for societal implementation that help to advance international efforts to support patients with rare diseases who are direly waiting for diagnosis, subsequent treatment and care. PMID- 30458819 TI - Correction to: Planning comparison of five automated treatment planning solutions for locally advanced head and neck cancer. AB - Following publication of the original article [1], the authors reported that one of the authors' names was processed incorrectly. PMID- 30458820 TI - Pigmented villonodular synovitis does not influence the outcome following cementless total hip arthroplasty using ceramic-on-ceramic articulation: a case control study with middle-term follow-up. AB - BACKGROUND: Pigmented villonodular synovitis (PVNS) is a relatively rare, locally aggressive, and potentially recurrent synovial disease of large joints. The purpose of this study was to investigate (1) the disease recurrence rate and (2) the treatment outcomes including Harris hip scores, complications, and revision following cementless total hip arthroplasty (THA) with ceramic-on-ceramic (CoC) articulation in patients with PVNS. METHODS: Twenty-two patients (14 females and 8 males) with histologically confirmed PVNS underwent cementless THA using CoC bearings between 2000 and 2013. Three patients with less than 5-year follow-up were excluded. The mean age was 35.2 years (range, 22-58 years) with a mean follow-up of 8.6 years (range, 6.9-10.8 years). A control group was matched in a 2:1 ratio with the PVNS group for age, sex, body mass index (BMI), year of surgery, and American Society of Anesthesiologists score (ASA). Postoperative outcome variables included disease recurrence, Harris Hip Scores (HHS) at the latest follow-up, complications (dislocation, squeaking, ceramic fracture), and any-cause revision. A Kaplan-Meier implant survivorship curve with 95% confidence interval (CI) of the two groups was generated. RESULTS: No recurrence of PVNS was noted in the follow-up period. The HSS in the PVNS group was 92.6 +/- 5.5, which was similar to the control group (93.4 +/- 4.6, p = 0.584) at the last follow-up visit. No patients sustained dislocation, osteolysis, or any ceramic fracture within the study duration. One patient in the PVNS group had a complication of squeaking, but did not require revision. Another patient in the PVNS group underwent revision surgery due to aseptic loosening. There was no significant difference in revision rates between the two groups (p = 1.000). The implant survivorship free of any revision was 90.0% (95% CI, 73.2% to 100%) in the PVNS group and 92.5% (95% CI, 82.6% to 100%) in the control group at 10 years (p = 0.99). CONCLUSIONS: For young and active patients with end-stage PVNS of the hips, cementless THA using CoC bearing has similar functional outcome scores, a low complication rate, and similar implant survivorship compared to the control group. PMID- 30458821 TI - Intra-thymic bronchogenic cyst an extremely rare tumor of anterior mediastinum in adults. AB - BACKGROUND: Intra-thymic bronchogenic cysts are a rare entity but should be considered in the differential of all non-invasive thymic masses. CASE PRESENTATION: We describe a 50-year-old patient who was found to have an incidental thymic mass on computer tomography of the chest. Non-invasive thymoma was suspected and a thoracoscopic thymectomy was performed. Final pathology revealed a bronchogenic cyst. CONCLUSION: Intra-thymic bronchogenic cysts are extremely rare tumors of the anterior mediastinum. It should be considered in differential diagnosis of anterior mediastinal masses. PMID- 30458823 TI - Expression of DENDRIN in several glomerular diseases and correlation to pathological parameters and renal failure - preliminary study. AB - BACKGROUND: In glomerular injury dendrin translocates from the slit diaphragm to the podocyte nucleus, inducing apoptosis. We analyzed dendrin expression in IgA glomerulonephritis and Henoch Schonlein purpura (IgAN/HSP) versus in podocytopathies minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), and compared it to pathohistological findings and renal function at the time of biopsy and the last follow-up. METHODS: Twenty males and 13 females with median of age 35 years (min-max: 3-76) who underwent percutaneous renal biopsy and had diagnosis of glomerular disease (GD) were included in this retrospective study. Fifteen patients had IgAN/HSP and eighteen podocytopathy. Control group consisted of ten patients who underwent nephrectomy due to renal cancer. Dendrin expression pattern (membranous, dual, nuclear or negative), number of dendrin positive nuclei and proportion of dendrin negative glomeruli were analyzed. RESULTS: In GD and the control group significant differences in number of dendrin positive nuclei and proportion of dendrin negative glomeruli were found (P = 0.004 and P = 0.003, respectively). Number of dendrin positive nuclei was higher in podocytopathies than in IgAN/HSP, 3.90 versus 1.67 (P = 0.028). Proportion of dendrin negative glomeruli correlated to higher rates of interstitial fibrosis (P = 0.038), tubular atrophy (P = 0.011) and globally sclerotic glomeruli (P = 0.008). Dual and nuclear dendrin expression pattern were connected with lower rate of interstitial fibrosis and tubular atrophy than negative dendrin expression pattern (P = 0.024 and P = 0.017, respectively). Proportion of dendrin negative glomeruli correlated with lower creatinine clearance (CC) at the time of biopsy and the last follow-up (P = 0.010 and P < 0.001, respectively). Dendrin expression pattern correlated to CC at the last follow-up (P = 0.009), being lower in patients with negative than nuclear or dual dendrin expression (P = 0.034 and P = 0.004, respectively). CONCLUSION: In this pilot study the number of dendrin positive nuclei was higher in podocytopathies than in inflammatory GD. Negative dendrin expression pattern correlated to chronic tubulointerstitial changes and lower CC, which needs to be confirmed in a larger series. PMID- 30458818 TI - Molecular characterization of sessile serrated adenoma/polyps with dysplasia/carcinoma based on immunohistochemistry, next-generation sequencing, and microsatellite instability testing: a case series study. AB - BACKGROUND: Colorectal sessile serrated adenoma/polyps (SSA/Ps) are considered early precursor lesions in the serrated neoplasia pathway. Recent studies have shown associations of SSA/Ps with lost MLH1 expression, a CpG island methylator phenotype, and BRAF mutations. However, the molecular biological features of SSA/Ps with early neoplastic progression have not yet been fully elucidated, owing to the rarity of cases of SSA/P with advanced histology such as cytologic dysplasia or invasive carcinoma. In this study, we aimed to elucidate the molecular biological features of SSA/Ps with dysplasia/carcinoma, representing relatively early stages of the serrated neoplasia pathway. METHODS: We performed immunostaining for beta-catenin, MLH1, and mucins (e.g., MUC2, MUC5AC, MUC6, and CD10); targeted next-generation sequencing; and microsatellite instability (MSI) testing in 8 SSA/P lesions comprised of 4 SSA/Ps with high-grade dysplasia and 4 SSA/Ps with submucosal carcinoma. RESULTS: Lost MLH1 expression was found in 5 cases. All lesions studied were positive for nuclear beta-catenin expression. Regarding phenotypic mucin expression, all lesions were positive for MUC2, but negative for CD10. MUC5AC and MUC6 positivity was observed in 7 cases. Genetically, the most frequently mutated gene was BRAF (7 cases), and other mutations were detected in FBXW7 (3 cases); TP53 (2 cases), and KIT, PTEN, SMAD4, and SMARCB1 (1 case each). Furthermore, 4 of 8 lesions were MSI-high and the remaining 4 lesions were microsatellite-stable (MSS). Interestingly, all 4 MSI high lesions displayed MLH1 loss, 3 of which harbored a FBXW7 mutation, but not a TP53 mutation. However, 2 MSS lesions harbored a TP53 mutation, although none harbored a FBXW7 mutation. CONCLUSIONS: SSA/Ps with dysplasia/carcinoma frequently harbored BRAF mutations. Activation of the WNT/beta-catenin signaling pathway may facilitate the development of dysplasia in SSA/Ps and progression to carcinoma. Furthermore, our results suggested that these lesions might be associated with both MSI-high and MSS colorectal cancer, which might be distinguished by distinct molecular biological features such as lost MLH1 expression, FBXW7 mutations, and TP53 mutations. PMID- 30458824 TI - Application of different laboratory techniques to monitor the behaviour of a Mycoplasma synoviae vaccine (MS-H) in broiler breeders. AB - BACKGROUND: Mycoplasma synoviae (MS) is a major poultry pathogen which causes severe economic losses in all the productive sectors. The prevalence of MS in European countries has increased in the last few years, leading to greater attention to the available methods to prevent its spread. The main strategy currently applied for its containment is the development and maintenance of MS free breeder flocks. A live MS vaccine (MS-H) obtained by mutagenizing an Australian field strain has recently been introduced in Italy. The aim of the present study was to evaluate the vaccine behaviour in broiler breeder groups at different production stages and the effectiveness of the available laboratory tests in discriminating the MS-H from a field strain. RESULTS: The vaccine diffused extensively through the population, shown by the wide serological response (over 80% of positive samples in RSA and 85% in ELISA), the high serological titres, the positivity of all the tracheal samples collected during the production phase by MS PCR and the positivity by cultivation from tracheal swabs at the end-point (55 weeks after vaccination). In contrast, only one swab from a sternal bursa was positive in MS PCR, while all the joint and oviduct samples were negative. There was no evidence of vertical transmission. Different genotyping techniques were used to achieve a clear classification of the MS positive samples. The vlhA and the obg gene analysis showed that most of the strains were homologous with the vaccine, but some ambiguous samples were further investigated with the multi locus sequence typing (MLST) scheme which confirmed the homology. CONCLUSIONS: The development of a multi-technique approach to monitor vaccinated avian flocks, based both on serological and biomolecular methods, is advised as well as the use of effective genotyping techniques to analyse the MS strains circulating in high densely populated poultry areas. PMID- 30458825 TI - Searching Embase and MEDLINE by using only major descriptors or title and abstract fields: a prospective exploratory study. AB - BACKGROUND: Researchers performing systematic reviews (SRs) must carefully consider the relevance of thousands of citations retrieved from bibliographic database searches, the majority of which will be excluded later on close inspection. Well-developed bibliographic searches are generally created with thesaurus or index terms in combination with keywords found in the title and/or abstract fields of citation records. Records in the bibliographic database Embase contain many more thesaurus terms than MEDLINE. Here, we aim to examine how limiting searches to major thesaurus terms (in MEDLINE called focus terms) in Embase and MEDLINE as well as limiting to words in the title and abstract fields of those databases affects the overall recall of SR searches. METHODS: To examine the impact of using search techniques aimed at higher precision, we analyzed previously completed SRs and focused our original searches to major thesaurus terms or terms in title and/or abstract only in Embase.com or in Embase.com and MEDLINE (Ovid) combined. We examined the total number of search results in both Embase and MEDLINE and checked whether included references were retrieved by these more focused approaches. RESULTS: For 73 SRs, we limited Embase searches to major terms only while keeping the search in MEDLINE and other databases such as Web of Science as they were. The overall search yield (or total number of search results) was reduced by 8%. Six reviews (9%) lost more than 5% of the relevant references. Limiting Embase and MEDLINE to major thesaurus terms, the number of references was 13% lower. For 15% of the reviews, the loss of relevant references was more than 5%. Searching Embase for title and abstract caused a loss of more than 5% in 16 reviews (22%), while limiting Embase and MEDLINE that way this happened in 24 reviews (33%). CONCLUSIONS: Of the four search options, two options substantially reduced the overall search yield. However, this also resulted in a greater chance of losing relevant references, even though many references were still found in other databases such as Web of Science. PMID- 30458822 TI - Inhaled nanomaterials and the respiratory microbiome: clinical, immunological and toxicological perspectives. AB - Our development and usage of engineered nanomaterials has grown exponentially despite concerns about their unfavourable cardiorespiratory consequence, one that parallels ambient ultrafine particle exposure from vehicle emissions. Most research in the field has so far focused on airway inflammation in response to nanoparticle inhalation, however, little is known about nanoparticle-microbiome interaction in the human airway and the environment. Emerging evidence illustrates that the airway, even in its healthy state, is not sterile. The resident human airway microbiome is further altered in chronic inflammatory respiratory disease however little is known about the impact of nanoparticle inhalation on this airway microbiome. The composition of the airway microbiome, which is involved in the development and progression of respiratory disease is dynamic, adding further complexity to understanding microbiota-host interaction in the lung, particularly in the context of nanoparticle exposure. This article reviews the size-dependent properties of nanomaterials, their body deposition after inhalation and factors that influence their fate. We evaluate what is currently known about nanoparticle-microbiome interactions in the human airway and summarise the known clinical, immunological and toxicological consequences of this relationship. While associations between inhaled ambient ultrafine particles and host immune-inflammatory response are known, the airway and environmental microbiomes likely act as intermediaries and facilitate individual susceptibility to inhaled nanoparticles and toxicants. Characterising the precise interaction between the environment and airway microbiomes, inhaled nanoparticles and the host immune system is therefore critical and will provide insight into mechanisms promoting nanoparticle induced airway damage. PMID- 30458826 TI - Validation of the SOS-PD scale for assessment of pediatric delirium: a multicenter study. AB - BACKGROUNDS: Reports of increasing incidence rates of delirium in critically ill children are reason for concern. We evaluated the measurement properties of the pediatric delirium component (PD-scale) of the Sophia Observation Withdrawal Symptoms scale Pediatric Delirium scale (SOS-PD scale). METHODS: In a multicenter prospective observational study in four Dutch pediatric ICUs (PICUs), patients aged >= 3 months and admitted for >= 48 h were assessed with the PD-scale thrice daily. Criterion validity was assessed: if the PD-scale score was >= 4, a child psychiatrist clinically assessed the presence or absence of PD according to the Diagnostic and statistical manual of mental disorders (DSM)-IV. In addition, the child psychiatrist assessed a randomly selected group to establish the false negative rate. The construct validity was assessed by calculating the Pearson coefficient (rp) for correlation between the PD-scale and Cornell Assessment Pediatric Delirium (CAP-D) scores. Interrater reliability was determined by comparing paired nurse-researcher PD-scale assessments and calculating the intraclass correlation coefficient (ICC). RESULTS: Four hundred eighty-five patients with a median age of 27.0 months (IQR 8-102) were included, of whom 48 patients were diagnosed with delirium by the child psychiatrist. The PD-scale had overall sensitivity of 92.3% and specificity of 96.5% compared to the psychiatrist diagnosis for a cutoff score >=4 points. The rp between the PD-scale and the CAP-D was 0.89 (CI 95%, 0.82-0.93; p < 0.001). The ICC of 75 paired nurse researcher observations was 0.99 (95% CI, 0.98-0.99). CONCLUSIONS: The PD-scale has good reliability and validity for early screening of PD in critically ill children. It can be validly and reliably used by nurses to this aim. PMID- 30458829 TI - Massive Localized Lymphedema in an Unreported Location (Retroperitoneum). AB - BACKGROUND: Massive localized lymphedema (MLL) is a non-neoplastic benign soft tissue lesion that may be confused with sarcomas or other neoplastic proliferations both clinically and morphologically. Most occur in morbidly obese adults on the lower extremities. The objective of this article is to document a case of MLL in the retroperitoneal cavity which is a previously unreported site for this lesion, and to highlight its unusual clinical features. CASE PRESENTATION: The patient was a non-obese male who had undergone major abdominal surgery due to bladder extrophy 17 years ago. Abdominal ultrasonography detected a large incidental mass in the right renal sinus during his investigation for nephrolithiasis. The lesion extending from renal pelvis down to pelvis was resected and its histopathological findings were compatible with massive localized lymphedema. CONCLUSIONS: Retroperitoneum has to be added to the list of locations that MLL can be found. Liposarcoma will be a challenging differential diagnosis when the lesion is encountered in an unusual site. PMID- 30458828 TI - Large scale study of anti-sense regulation by differential network analysis. AB - BACKGROUND: Systems biology aims to analyse regulation mechanisms into the cell. By mapping interactions observed in different situations, differential network analysis has shown its power to reveal specific cellular responses or specific dysfunctional regulations. In this work, we propose to explore on a large scale the role of natural anti-sense transcription on gene regulation mechanisms, and we focus our study on apple (Malus domestica) in the context of fruit ripening in cold storage. RESULTS: We present a differential functional analysis of the sense and anti-sense transcriptomic data that reveals functional terms linked to the ripening process. To develop our differential network analysis, we introduce our inference method of an Extended Core Network; this method is inspired by C3NET, but extends the notion of significant interactions. By comparing two extended core networks, one inferred with sense data and the other one inferred with sense and anti-sense data, our differential analysis is first performed on a local view and reveals AS-impacted genes, genes that have important interactions impacted by anti-sense transcription. The motifs surrounding AS-impacted genes gather transcripts with functions mostly consistent with the biological context of the data used and the method allows us to identify new actors involved in ripening and cold acclimation pathways and to decipher their interactions. Then from a more global view, we compute minimal sub-networks that connect the AS-impacted genes using Steiner trees. Those Steiner trees allow us to study the rewiring of the AS-impacted genes in the network with anti-sense actors. CONCLUSION: Anti sense transcription is usually ignored in transcriptomic studies. The large-scale differential analysis of apple data that we propose reveals that anti-sense regulation may have an important impact in several cellular stress response mechanisms. Our data mining process enables to highlight specific interactions that deserve further experimental investigations. PMID- 30458830 TI - Preliminary experience in treating thoracic spinal tuberculosis via a posterior modified transfacet debridement, instrumentation, and interbody fusion. AB - BACKGROUND: Posterior transfacet approach has been proved to be a safe and effective access to treat thoracic disc herniation. However, the therapeutic effect and safety of modified transfacet approach for treating thoracic spinal tuberculosis (TST) has not been reported in the clinical literature. In this study, the clinical efficacy and safety of a single-stage posterior modified transfacet debridement, posterior instrumentation, and interbody fusion for treating TST were retrospectively evaluated. PATIENTS AND METHODS: From 2009 to 2014, 37 patients with TST underwent a posterior modified transfacet debridement, interbody fusion following posterior instrumentation, under the cover of 18 months of antituberculosis chemotherapy. The patients were evaluated preoperatively and postoperatively in terms of Frankel Grade, visual analog scale (VAS) pain score, kyphotic Cobb angle, and bony fusion. RESULTS: The follow-up time was 39.8 +/- 5.1 months (29-50 months). No postoperative complication or recurrence of spinal tuberculosis was observed. Definitive bony fusion was achieved in all patients. At the final follow-up, 2 cases were rated as Frankel grade D, 35 as grade E. VAS was recovered from 8.4 +/- 1.0 cm to 0.4 +/- 0.8 cm. The kyphotic angles were corrected from 29.4 +/- 10.9 degrees to 17.6 +/- 6.3 degrees . Using the Kirkaldy-Willis criteria, functional outcome was excellent in 29 patients, good in 7, and fair in 1. CONCLUSIONS: Our preliminary results showed that single-stage posterior modified transfacet debridement, posterior instrumentation, and interbody fusion are effective and safe surgical options for treating TST. PMID- 30458827 TI - Health-related quality of life in children with inflammatory brain disease. AB - OBJECTIVE: To quantify the impact of inflammatory brain diseases in the pediatric population on health-related quality of life, including the subdomains of physical, emotional, school and social functioning. METHODS: This was a multicenter, observational cohort study of children (< 18 years of age) diagnosed with inflammatory brain disease (IBrainD). Patients were included if they had completed at least one Health Related Quality of Life Questionnaire (HRQoL). HRQoL was measured using the Pediatric Quality of Life Inventory Version 4.0 (PedsQL) Generic Core Scales, which provided a total score out of 100. Analyses of trends were performed using linear regression models adjusted for repeated measures over time. RESULTS: In this study, 145 patients were included of which 80 (55%) were females. Cognitive dysfunction was the most common presenting symptoms (63%), and small vessel childhood primary angiitis of the CNS was the most common diagnosis (33%). The mean child's self-reported PedsQL total score at diagnosis was 68.4, and the mean parent's proxy-reported PedsQL score was 63.4 at diagnosis. Child's self-reported PedsQL scores reflected poor HRQoL in 52.9% of patients at diagnosis. Seizures or cognitive dysfunction at presentation was associated with statistically significant deficits in HRQoL. CONCLUSION: Pediatric IBrainD is associated with significantly diminished health-related quality of life. Future research should elucidate why these deficits occur and interventions should focus on improving HRQoL in the most affected subdomains, in particular for children presenting with seizures and cognitive dysfunction. PMID- 30458831 TI - West-Nile virus encephalitis in an immunocompetent pediatric patient: successful recovery. AB - BACKGROUND: West Nile virus (WNV) is a mosquito-borne RNA virus belonging to the Flaviviridae family. Symptomatic infection happens in only about 20% of the cases, while WNV neuroinvasive disease (WNND) is rare and accounts for less than 1%. There is insufficient information about natural history and clinical course in children, because underdiagnosis is common, and reports are scarce. On the other hand, Europe has seen a dramatic increase of WNV infections in the last decades, and the Po valley itself, in Northern Italy, has become an endemic region since 2013. CASE PRESENTATION: We hereby report a case of West-Nile virus neuroinvasive disease in a 12-year-old boy. This is one of the very few cases diagnosed in the Italian pediatric population. The clinical presentation was compatible with acute encephalitis. Diagnosis was made by detection of specific IgM in both serum and cerebrospinal fluid. He finally was discharged with complete recovery, and no neurologic sequelae after a 12-months follow up period. CONCLUSIONS: Given its non-specific clinical presentation, the diffusion of WNV constitutes a crucial and emerging concern. Even though rare, neuroinvasive WNV infection should always be suspected in pediatric patients, living or traveling in endemic areas, presenting with meningitis, encephalitis or acute flaccid paralysis during the WNV transmission season. PMID- 30458832 TI - Comparing Indigenous and public health infant feeding recommendations in Peru: opportunities for optimizing intercultural health policies. AB - BACKGROUND: The problem of childhood undernutrition in low-income countries persists despite long-standing efforts by local governmental and international development agencies. In order to address this problem, the Peruvian Ministry of Health has focused on improving access to primary healthcare and providing maternal and child health monitoring and education. Current maternal-child health policies in Peru introduce recommendations that are in some respect distinct from those of Indigenous highland communities. This paper analyses the similarities and differences between public health and mothers' infant feeding recommendations. Furthermore, it analyses persistence and change in those recommendations among women who were mothers before and after the introduction of current public health policies. METHODS: Semi-structured interviews were conducted with 18 older mothers, 15 currently breastfeeding mothers, and 15 public health staff in highland rural communities of Peru. During data analysis, thematic codes and text passages were used in an iterative analytic process to document emerging themes. RESULTS: The results highlight the existence of a traditional corpus of beliefs surrounding infant feeding and care that is consistent with Andean ethnomedical beliefs. This is illustrated by mother's accounts referring to the importance of maintaining a dietary balance of fluids and semi-fluids and of maintaining harmony with the elements in the natural environment. Mothers also incorporate aspects of public health recommendations that they find useful including initiating breastfeeding immediately after birth and exclusive breastfeeding up until 6 months. There are also tensions between the two systems including differences in the conceptualization of breastfeeding and infant food, the imposition of public health care services by coercive means, and negative stereotyping of rural Andean diets and mothers. CONCLUSIONS: Identifying similarities and differences between distinct systems may provide useful input for effective intercultural health policies. Sources of tension should be carefully assessed with the aim of improving public health policies. Such efforts should apply a process of cultural humility engaging health care professionals in exchange and conversations with patients and communities acknowledging the assumptions and beliefs that are embedded in their own understanding. This process should also recognize and value the knowledge and practices of Andean mothers and their role as primary caretakers. PMID- 30458833 TI - Ethnopharmaceutical knowledge in Samogitia region of Lithuania: where old traditions overlap with modern medicine. AB - BACKGROUND: Modern ethnopharmaceutical studies are still quite unusual in Northern Europe. Data regarding the medicinal use of plants, animals, and fungi and also of spiritual rituals of healing is obtained mostly from ethnographic and folkloric sources in Lithuania. The aim of this study was to assess the ethnopharmaceutical knowledge regarding traditional use of natural substances for medicinal purposes in the Samogitia region and compare with prior research conducted 10 years prior in the same region. METHODS: The study was performed during 2016-2017 in the Samogitia region (Lithuania) using the conventional technique of ethnobotanical studies. Twenty-eight respondents aged between 50 and 92 years were selected for the study using snowball techniques. Information was collected using semi-structured and structured interviews. The obtained information was recorded indicating local names of plants, their preparation techniques, parts used, modes of administration, and application for therapeutic purposes. RESULTS: During the research, 125 records of raw materials of herbal origin belonging to 55 families were made. The Asteraceae family had the highest number of references, 147 (16.6%). It was stated that the most commonly used medicinal plants were the raspberry (Rubus idaeus L.) (100%), marigold (Calendula officinalis L.) (96.4%), camomile (Matricaria recutita L.) (92.9%), and small linden tree (Tilia cordata Mill.) (92.9%). The most commonly used material of animal origin was the toad (Bufo bufo) (89%). The most commonly used kind of fungi was the common stinkhorn (Phallus impudicus) (71%), and the material of the mineral origin was sand (50%). Comparative analysis of the two surveys in this region showed similar results and produced a large amount of ethnopharmaceutical information. CONCLUSIONS: Lithuania belongs to the countries known for urban ethnobotany where old traditions overlap with modern healing methods. Also, because modern medical assistance is quite expensive, self-medication with home made medicines is still popular in Lithuania. It is important to collect and systematize this information as soon as possible, to save it as a traditional Lithuanian heritage and also use it for scientific investigations. PMID- 30458834 TI - Mapping evidence on decision-making on contraceptive use among adolescents: a scoping review protocol. AB - BACKGROUND: Contraceptive use among adolescents remains consistently low globally. Numerous studies have been done investigating factors that contribute to low contraceptive prevalence rates in this special population. It is particularly vital to understand decision-making processes that adolescents undergo when deciding whether or not to use contraceptives. Therefore, this scoping review seeks to map available evidence on decision-making processes in contraceptive use among adolescents. METHODS: We will conduct a scoping review to explore, describe and map literature on the adolescent decision-making regarding contraceptive use. The primary search will include peer-reviewed and review articles. Databases, including PubMed, MEDLINE with Full Text via EBSCOhost, PsychINFO via EBSCOhost, CINAHL with Full Text via EBSCOhost, Google Scholar, Science Direct and Scopus, will be searched for articles that meet the eligibility criteria. Keyword searches will be used, and for articles included after title screening, abstract and full articles will be screened by two independent reviewers with a third as a decider on any disputes. Content analysis will be used to present the narrative account of the reviews. DISCUSSION: Understanding how adolescents make decisions about whether or not to use contraception is essential for improving contraceptive prevalence rates in this special population. It is envisioned that the results from this review will highlight key evidence on how adolescent make decisions regarding contraceptive use as well as gaps and opportunities for future research. It will also be important in enhancing and re-focusing adolescent sexual and reproductive health policies and programmes. PMID- 30458835 TI - Clinicopathologic implication of PD-L1 and phosphorylated STAT3 expression in diffuse large B cell lymphoma. AB - BACKGROUND: Antitumor immune response of programmed cell death ligand (PD-L1) has shown clinical value not only in Hodgkin lymphoma and EBV-associated lymphomas but also in EBV-negative diffuse large B cell lymphoma (DLBCL) of non-germinal center B cell-like (non-GCB) subtype. Signal transducer and activator of transcription 3 (STAT3) is known to induce PD-L1 in immune cells and its activated form, phosphorylated STAT3 (pSTAT3), is also frequently expressed in non-GCB DLBCL. Herein, we investigated associations between PD-L1 expression/gene alteration, pSTAT3 expression and clinicopathologic variables in EBV-negative DLBCL. METHODS: In 107 cases of DLBCLs with non-GCB subtype (67%; 72/107), GCB subtype (25%; 27/107) and unclassifiable cases (8%; 8/107), we performed PD-L1 and pSTAT3 immunohistochemistry and fluorescence in situ hybridization for PD-L1 gene translocation and copy number gain/amplification. RESULTS: PD-L1 was expressed in tumor cells (PD-L1t) in 21% (23/107; 30% cutoff), immune cells (PD L1i) in 36% (38/107; 20% cutoff), and pSTAT3 in tumor nuclei in 41% (44/107; 40% cutoff). PD-L1 gene alteration was observed in 10% (10/102) including translocation in 6% (6/102) and copy number gain/amplification in 4% (4/102). Non GCB subtype was associated with PD-L1t and pSTAT3 (p = 0.006 and p = 0.042), and tended to have PD-L1 gene alteration (p = 0.058). Tumoral PD-L1 expression without gene alteration (PD-L1t+ GA-) correlated with pSTAT3-positive tumor cell proportions (%) (p = 0.033). In survival analysis, pSTAT3 expression independently predicted shorter PFS in total cohort (p = 0.017) and R-CHOP treated group (p = 0.007), and in pSTAT3-negative R-CHOP-treated subset, PD-L1 expression in immune cells (PD-L1i) correlated with shorter PFS (p = 0.042). CONCLUSIONS: Gene alteration and protein expression of PD-L1 and pSTAT3 expression were closely related in DLBCL and constituted features of non-GCB subtype. In addition to known clinical significance of pSTAT3, immune cell expression of PD-L1 (PD-L1i) had also clinical value in pSTAT3-dependent manner. These findings may provide an insight into immunotherapeutic strategy and risk stratification in DLBCL patients. PMID- 30458836 TI - Reversible dilated cardiomyopathy as a complication of adrenal cortex insufficiency: a case report. AB - BACKGROUND: Cardiovascular manifestations associated with Addison's disease are previously documented. We described a case of an 11-year-old girl who developed dilated cardiomyopathy as a complication to Addison's disease. Glucocorticoid replacement therapy resulted in near-complete recovery of cardiac function. It is the first reported case of reversible cardiomyopathy as a complication of primary adrenal insufficiency in Syria. CASE PRESENTATION: An 11-year-old Caucasian girl with no significant past medical history presented with abdominal pain, vomiting after meals, and a low-grade fever. A physical examination and laboratory evaluation suggested primary adrenal insufficiency. An echocardiogram showed changes consistent with dilated cardiomyopathy. Causes of primary adrenal insufficiency other than autoimmune were excluded. CONCLUSIONS: Dilated cardiomyopathy is a rare complication of primary adrenal insufficiency. Proper treatment of adrenal insufficiency with glucocorticoid replacement therapy resulted in restoration of normal cardiac function. PMID- 30458837 TI - Hospital clinical pathways for children affected by juvenile idiopathic arthritis. AB - BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common pediatric chronic rheumatic disease, which requires constant follow-up over the years, due to relapses during its progression. To maintain a good quality of life, it is important to limit admissions as far as possible. With the development of a Diagnostic Therapeutic Assistance Pathway (DTAP), we aim to select patients with suitable clinical conditions to be moved from routine hospital management to day care or outpatient treatment, evaluating the number of patients to whom this would apply. METHODS: Monocentric study regarding admissions for JIA between 2014 and 2016 in a Pediatric Unit of a university hospital in Milan. Through an analysis of the medical records, relevant information was extracted and collected in a MicrosoftTM Excel database; starting from the data collected during the first year, a DTAP was prepared for patients with active arthritis and appropriate clinical conditions. RESULTS: The study includes data from 223 JIA hospitalization cases involving 127 patients. Applying DTAP criteria, 32% patients would have avoided admissions and 23% would have been admitted less frequently. The data concerning the activities of the Unit for JIA patients showed a relevant drop in the number of hospitalizations since 2015, from 89 in 2014 to 66 and 68 in 2015 and 2016 respectively. CONCLUSION: The opportunity offered by DTAP, has suggested feasible changes in hospitalization management and it's use would promote the possibility of treating the children without hospitalization, or minimizing it. In conclusion DTAP application is a priority for the continuous improvement of clinical practice and quality of life for patients and their families. PMID- 30458838 TI - On the design of EEG-based movement decoders for completely paralyzed stroke patients. AB - BACKGROUND: Brain machine interface (BMI) technology has demonstrated its efficacy for rehabilitation of paralyzed chronic stroke patients. The critical component in BMI-training consists of the associative connection (contingency) between the intention and the feedback provided. However, the relationship between the BMI design and its performance in stroke patients is still an open question. METHODS: In this study we compare different methodologies to design a BMI for rehabilitation and evaluate their effects on movement intention decoding performance. We analyze the data of 37 chronic stroke patients who underwent 4 weeks of BMI intervention with different types of association between their brain activity and the proprioceptive feedback. We simulate the pseudo-online performance that a BMI would have under different conditions, varying: (1) the cortical source of activity (i.e., ipsilesional, contralesional, bihemispheric), (2) the type of spatial filter applied, (3) the EEG frequency band, (4) the type of classifier; and also evaluated the use of residual EMG activity to decode the movement intentions. RESULTS: We observed a significant influence of the different BMI designs on the obtained performances. Our results revealed that using bihemispheric beta activity with a common average reference and an adaptive support vector machine led to the best classification results. Furthermore, the decoding results based on brain activity were significantly higher than those based on muscle activity. CONCLUSIONS: This paper underscores the relevance of the different parameters used to decode movement, using EEG in severely paralyzed stroke patients. We demonstrated significant differences in performance for the different designs, which supports further research that should elucidate if those approaches leading to higher accuracies also induce higher motor recovery in paralyzed stroke patients. PMID- 30458839 TI - Overground walking with a robotic exoskeleton elicits trunk muscle activity in people with high-thoracic motor-complete spinal cord injury. AB - BACKGROUND: The trunk muscles are critical for postural control. Recent neurophysiological studies have revealed sparing of trunk muscle function in individuals with spinal cord injury (SCI) classified with thoracic or cervical motor-complete injuries. These findings raise the possibility for recruiting and retraining this spared trunk function through rehabilitation. Robotic gait training devices may provide a means to promote trunk muscle activation. Thus, the objective of this study was to characterize and compare the activation of the trunk muscles during walking with two robotic gait training devices (Ekso and Lokomat) in people with high thoracic motor-complete SCI. METHODS: Participants with chronic motor-complete paraplegia performed 3 speed-matched walking conditions: Lokomat-assisted walking, Ekso-assisted walking overground, and Ekso assisted walking on a treadmill. Surface electromyography (EMG) signals were recorded bilaterally from the rectus abdominis (RA), external oblique (EO), and erector spinae (ES) muscles. RESULTS: Greater recruitment of trunk muscle EMG was elicited with Ekso-assisted walking compared to the Lokomat. Similar levels of trunk EMG activation were observed between Ekso overground and Ekso on the treadmill, indicating that differences between Ekso and Lokomat could not be attributed to the use of a hand-held gait aid. The level of trunk EMG activation during Lokomat walking was not different than that recorded during quiescent supine lying. CONCLUSIONS: Ekso-assisted walking elicits greater activation of trunk muscles compared to Lokomat-assisted walking, even after controlling for the use of hand-held assistive devices. The requirement of the Ekso for lateral weight-shifting in order to activate each step could lead to better postural muscle activation. PMID- 30458840 TI - Information sharing across generations and environments (InfoSAGE): study design and methodology protocol. AB - BACKGROUND: Longevity creates increasing care needs for healthcare providers and family caregivers. Increasingly, the burden of care falls to one primary caregiver, increasing stress and reducing health outcomes. Additionally, little has been published on adults', over the age of 75, preferences in the development of health information sharing with family members using online platforms. This study aims to assess a novel, Internet based, family-centric communication and collaboration platform created to address the information needs of elders and their informal caregivers in a community setting. METHODS: This study is an internet-based, open prospective cohort study, enrolling dyad pairs of one adult over the age of 75 with one informal caregiver. Dyads will be offered to use the InfoSAGE online platform without prospective assignment. Participants will consent using an online process that enables participation from any location and shares important study and privacy details. The platform will enable the capture of search queries and tracking of functions such as tasks and discussions. Surveys every six months assess health status, health and social needs, and caregiver burden using validated instruments over a two-year period. We will use a mixed methods approach, utilizing qualitative survey data along with website usage analytic data. DISCUSSION: Analysis of the longitudinal usage and survey data will help to examine the patterns of family communication and health information seeking as the central older adult ages. We will use the study data to inform design recommendations relevant to a complex mixture of users, with special consideration to the needs of older adult users and potential physical limitations. PMID- 30458841 TI - Integrated models of care for diabetes and hypertension in low- and middle-income countries (LMICs) : Protocol for a systematic review. AB - BACKGROUND: In low- and middle-income countries (LMICs), the burden of non communicable diseases (NCDs) is growing against an existing burden of other diseases such as HIV/AIDS. Integrated models of care can help address the rising burden of multi-morbidity. Although integration of care can occur at various levels and has been defined in numerous ways, our aim is to assess the effects of integration of service delivery at primary healthcare level in LMICs. METHODS: We will consider randomised controlled trials (RCTs), cluster RCTs, non-randomised trials, controlled before-after studies and interrupted time series that examine integrated models of care among people with multi-morbidities, of which diabetes or hypertension is one, living in LMICs. We will compare fully integrated models of care to stand-alone care, partially integrated models of care to stand-alone care and fully integrated models to partially integrated models of care. Primary outcomes include all-cause mortality, disease-specific morbidity, HbA1c, systolic blood pressure and cholesterol levels. Secondary outcomes include access to care, retention in care, adherence, continuity of care, quality of care and cost of care. We will conduct a comprehensive search in the following databases: MEDLINE, EMBASE, the Cochrane Central Register of Control Trials, LILACS, Africa-Wide Information, CINAHL and Web of Science. In addition, we will search trial registries, relevant conference abstracts and check references lists of included studies. Selection of studies, data extraction and assessment of risk of bias will be performed independently by two review authors. We will resolve discrepancies through discussion with a third author. We will contact study authors in case of missing data. If included studies are sufficiently homogenous, we will pool results in a meta-analysis. Clinical heterogeneity related to the population, intervention, outcomes and context will be documented in table format and explored through subgroup analysis. We will assess chi2and I2 tests for statistical heterogeneity. We will use GRADE to make judgements about the certainty of evidence and present findings in a summary of findings table. DISCUSSION: In light of limited evidence on the provision of comprehensive care for diabetes and hypertension, and its comorbidity in LMCIs, we believe that the findings of this systematic review will provide a synthesis of evidence on effective models of integrated care for diabetes and hypertension and their comorbidities at primary healthcare level. This will enable policy-makers to device policies and programs that are evidence informed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018099314 . PMID- 30458842 TI - On the reconstruction of the ancestral bacterial genomes in genus Mycobacterium and Brucella. AB - BACKGROUND: To reconstruct the evolution history of DNA sequences, novel models of increasing complexity regarding the number of free parameters taken into account in the sequence evolution, as well as faster and more accurate algorithms, and statistical and computational methods, are needed. More particularly, as the principal forces that have led to major structural changes are genome rearrangements (such as translocations, fusions, and so on), understanding their underlying mechanisms, among other things via the ancestral genome reconstruction, are essential. In this problem, since finding the ancestral genomes that minimize the number of rearrangements in a phylogenetic tree is known to be NP-hard for three or more genomes, heuristics are commonly chosen to obtain approximations of the exact solution. The aim of this work is to show that another path is possible. RESULTS: Various algorithms and software already deal with the difficult nature of the problem of reconstruction of the ancestral genome, but they do not function with precision, in particular when indels or single nucleotide polymorphisms fall into repeated sequences. In this article, and despite the theoretical NP-hardness of the ancestral reconstruction problem, we show that an exact solution can be found in practice in various cases, encompassing organelles and some bacteria. A practical example proves that an accurate reconstruction, which also allows to highlight homoplasic events, can be obtained. This is illustrated by the reconstruction of ancestral genomes of two bacterial pathogens, belonging in Mycobacterium and Brucella genera. CONCLUSIONS: By putting together automatically reconstructed ancestral regions with handmade ones for problematic cases, we show that an accurate reconstruction of ancestors of the Brucella genus and of the Mycobacterium tuberculosis complex is possible. By doing so, we are able to investigate the evolutionary history of each pathogen by computing their common ancestors. They can be investigated extensively, by studying the gene content evolution over time, the resistance acquisition, and the impacts of mobile elements on genome plasticity. PMID- 30458843 TI - Seven years since defining the top five research priorities in physician-provided pre-hospital critical care - what did it lead to and where are we now? PMID- 30458844 TI - Implementation study of an interprofessional medication adherence program for HIV patients in Switzerland: quantitative and qualitative implementation results. AB - BACKGROUND: An interprofessional medication adherence program (IMAP) for chronic patients was developed and successfully implemented in the community pharmacy of the Department of ambulatory care and community medicine (Lausanne, Switzerland). This study assesses the capacity of a physician and a nurse at the infectious diseases service of a public hospital and of community pharmacists in the Neuchatel area (Switzerland) to implement the IMAP in their practice. METHODS: Mixed method, prospective, observational study. Quantitative and qualitative analyses of the implementation process were conducted following the RE-AIM model (reach, effectiveness, adoption, implementation and maintenance). RESULTS: Implementation started in November 2014. One physician, one nurse, and five pharmacists agreed to participate. Healthcare professionals perceived the benefits of the program and were motivated to implement it in their practice (adoption). Seventeen patients were included in the program; 13 refused to participate. The inclusion of naive HIV patients was easier than the inclusion of experienced patients with difficult psychosocial issues (reach). Pharmacists were engaged in reinforcing patient medication adherence in 25% of interviews (effectiveness). Key facilitators expressed by healthcare professionals were patient inclusion by the physician and the nurse instead of the pharmacist and the organisation of regular meetings between all stakeholders. In contrast, the encountered barriers were the lack of time and resources, the lack of team uptake, and the lack of adoption by senior managers (implementation). Interviewed patients were all satisfied with this new program, encouraging healthcare professionals to scale it up. Structural changes allowed the hospital and one pharmacy to enter the maintenance stage (maintenance). CONCLUSION: The research team and collaboration between all professionals involved played an important role in this implementation. However, the dissemination of such a program to a larger scale and for the long term requires financial and structural resources as well as transitional external support. PMID- 30458845 TI - Comparing oral health in patients with different levels of dental anxiety. AB - BACKGROUND: Dental Anxiety is still today one of the most common fears and is therefore a great challenge for every dental practitioner. The aim of this study was to identify patients with dental anxiety using the Dental Anxiety Scale and comparing different levels of dental anxiety with oral health using DMF-T and DMF S index. METHODS: This study questioned 1549 patients over the course of three years (2002-2005). DAS questionnaires were handed out before treatment and the state of oral health was evaluated using DMF-T and DMF-S. RESULTS: There is no significant relation between high anxiety and the global DMF-T Score (p = 0.237), missing teeth (p = 0.034) and filled teeth (p = 0.237). There is however a significant increase in destroyed teeth, the higher the level of dental anxiety in the patient (p < 0.0001). There is as well a significant relationship between the global DMF-S Score (p = 0.042) and dental anxiety. No relationship was found comparing missing surfaces (p = 0.107) and filled surfaces (p = 0.516) with dental anxiety. Destroyed 16 surfaces are, however, significantly higher in patients with more dental anxiety (p < 0.0001). A higher dental anxiety therefore often causes minimalistic dentistry to fail due to more teeth being destroyed. CONCLUSIONS: Patients with dental anxiety still have a worse oral hygiene than patients without dental anxiety. It is still necessary, in this time of caries prevention rather than over-treatment, to be educated so that patients suffering dental fear receive the right treatment. PMID- 30458846 TI - Level of job satisfaction and associated factors among health care professionals working at University of Gondar Referral Hospital, Northwest Ethiopia: a cross sectional study. AB - OBJECTIVES: The main aim of this study was to assess the level of job satisfaction and associated factors among healthcare professionals working at University of Gondar Referral Hospital, Northwest Ethiopia. An institution based cross-sectional study was conducted among 416 healthcare professionals from March 27, 2017 to April 25, 2017. Simple random sampling technique was employed and data were collected with a pre-tested interviewer administered questionnaire. Data were entered into Epi-Info version 7, and analyzed using SPSS 20 softwares. Binary logistic regression analysis was employed. RESULTS: A total of 383 participants were involved in the study. The overall level of job satisfaction among health care professionals was 54% [95% CI (49.3-58.8)]. Marital status [AOR = 1.79 (1.140, 2.797)], salary [AOR = 2.75 (1.269, 5.958)], leadership style [AOR = 2.19 (1.31-3.65)], and supportive supervision [AOR = 2.05 (1.27-3.32)] were found significant determinants of job satisfaction. The overall level of job satisfaction among health care professionals at the University of Gondar Referral Hospital was low. Therefore, health service managers should focus their leadership style and provide supportive supervision in the hospital to improve the level of job satisfaction of health care professionals. PMID- 30458847 TI - Role of mustelids in the life-cycle of ixodid ticks and transmission cycles of four tick-borne pathogens. AB - BACKGROUND: Elucidating which wildlife species significantly contribute to the maintenance of Ixodes ricinus populations and the enzootic cycles of the pathogens they transmit is imperative in understanding the driving forces behind the emergence of tick-borne diseases. Here, we aimed to quantify the relative contribution of four mustelid species in the life-cycles of I. ricinus and Borrelia burgdorferi (sensu lato) in forested areas and to investigate their role in the transmission of other tick-borne pathogens. Road-killed badgers, pine martens, stone martens and polecats were collected in Belgium and the Netherlands. Their organs and feeding ticks were tested for the presence of tick borne pathogens. RESULTS: Ixodes hexagonus and I. ricinus were found on half of the screened animals (n = 637). Pine martens had the highest I. ricinus burden, whereas polecats had the highest I. hexagonus burden. We detected DNA from B. burgdorferi (s.l.) and Anaplasma phagocytophilum in organs of all four mustelid species (n = 789), and Neoehrlichia mikurensis DNA was detected in all species, except badgers. DNA from B. miyamotoi was not detected in any of the investigated mustelids. From the 15 larvae of I. ricinus feeding on pine martens (n = 44), only one was positive for B. miyamotoi DNA, and all tested negative for B. burgdorferi (s.l.), N. mikurensis and A. phagocytophilum. The two feeding larvae from the investigated polecats (n = 364) and stone martens (n = 39) were negative for all four pathogens. The infection rate of N. mikurensis was higher in feeding nymphs collected from mustelids compared to questing nymphs, but not for B. burgdorferi (s.l.), B. miyamotoi or A. phagocytophilum. CONCLUSIONS: Although all stages of I. ricinus can be found on badgers, polecats, pine and stone martens, their relative contribution to the life-cycle of I. ricinus in forested areas is less than 1%. Consequently, the relative contribution of mustelids to the enzootic cycles of I. ricinus-borne pathogens is negligible, despite the presence of these pathogens in organs and feeding ticks. Interestingly, all four mustelid species carried all stages of I. hexagonus, potentially maintaining enzootic cycles of this tick species apart from the cycle involving hedgehogs as main host species. PMID- 30458848 TI - A longitudinal epidemiological study on the triglyceride and glucose index and the incident nonalcoholic fatty liver disease. AB - BACKGROUND: Triglyceride and glucose (TyG) index and nonalcoholic fatty liver disease (NAFLD) both bave been related to insulin resistance (IR). The study aimed to investigate the longitudinal relationship between TyG index and NAFLD and to evaluate the ability of TyG, through comparing with the predictive value of other indexes, to identify individuals at risk for NAFLD. METHODS: Four thousand and five hundred thirty nine subjects without NAFLD initially were followed up for 9 years. Cox regression models were used to analyze the risk factors of NAFLD. RESULTS: Cox regression analyses indicated the TyG index was independently and positively associated with the risk of incident NAFLD. In receiver operating characteristic (ROC) curve analysis, the optimal cut-off level for TyG to predict incident NAFLD was 8.52 and the area under the ROC curve (AUC) was 0.76 (95% CI 0.74-0.77), which was larger than that of TG, ALT and FPG. CONCLUSION: This study demonstrated that the elevation of the TyG index might predict increase risk for incident NAFLD and it may be suitable as a diagnostic criterion for NAFLD. PMID- 30458849 TI - Molecular basis of permethrin and DDT resistance in an Anopheles funestus population from Benin. AB - BACKGROUND: Insecticide resistance in Anopheles mosquitoes is threatening the success of malaria control programmes. In order to implement suitable insecticide resistance management strategies, it is necessary to understand the underlying mechanisms involved. To achieve this, the molecular basis of permethrin and DDT resistance in the principal malaria vector, Anopheles funestus from inland Benin (Kpome), was investigated. RESULTS: Here, using a microarray-based genome-wide transcription and qRT-PCR analysis, we showed that metabolic resistance mechanisms through over-expression of cytochrome P450 and glutathione S transferase genes (GSTs) are a major contributor to DDT and permethrin resistance in Anopheles funestus from Kpome. The GSTe2 gene was the most upregulated detoxification gene in both DDT- [fold-change (FC: 16.0)] and permethrin resistant (FC: 18.1) mosquitoes suggesting that upregulation of this gene could contribute to DDT resistance and cross-resistance to permethrin. CYP6P9a and CYP6P9b genes that have been previously associated with pyrethroid resistance were also significantly overexpressed with FC 5.4 and 4.8, respectively, in a permethrin resistant population. Noticeably, the GSTs, GSTd1-5 and GSTd3, were more upregulated in DDT-resistant than in permethrin-resistant Anopheles funestus suggesting these genes are more implicated in DDT resistance. The absence of the L1014F or L1014S kdr mutations in the voltage-gated sodium channel gene coupled with the lack of directional selection at the gene further supported that knockdown resistance plays little role in this resistance. CONCLUSIONS: The major role played by metabolic resistance to pyrethroids in this An. funestus population in Benin suggests that using novel control tools combining the P450 synergist piperonyl butoxide (PBO), such as PBO-based bednets, could help manage the growing pyrethroid resistance in this malaria vector in Benin. PMID- 30458850 TI - The U&I study: study protocol for a feasibility randomised controlled trial of a pre-cognitive behavioural therapy digital 'informed choice' intervention to improve attitudes towards uptake and implementation of CBT for psychosis. AB - BACKGROUND: At least 40% of people with psychosis have persistent distressing symptoms despite optimal medication treatment. Cognitive behaviour therapy for psychosis (CBTp) is the only NICE-recommended individual therapy for psychosis, with effects on symptoms, distress and quality of life. Yet <10% of service-users receive it and 94% of trusts struggle to provide it. Of those offered it, 22-43% refuse or do not attend. We have developed a new pre-CBTp informed choice intervention to address knowledge and attitudes that influence uptake and implementation and now want to test it in a feasibility trial. METHODS: The design is a two-arm, feasibility randomised controlled trial (RCT), with 1:1 randomisation, stratified by participant group and site. Participants are 40 psychosis patients and 40 clinicians, who are ambivalent towards uptake or implementation of CBTp. Sites are community and inpatient services in Sussex and London. The intervention is a pre-CBT digital psychoeducation intervention designed to address identified knowledge and attitudinal barriers to uptake and implementation of CBTp, incorporating behaviour change mechanisms, and supported by animated introductory, patient and clinician stories. The comparator is the NHS choices website for CBT. The primary aim is to assess clinical feasibility (recruitment, randomisation, acceptability, use, delivery, outcome measurement, retention). A secondary aim is a preliminary evaluation of efficacy. Outcomes will be assessed at baseline, post intervention, and one-month follow-up (blind to treatment arm). The primary efficacy outcome is likelihood of offering/taking up CBTp. Secondary outcomes include knowledge and attitudes towards CBTp, illness perceptions, empowerment, psychological wellbeing (patients only) and CBTp implementation (clinicians only). Use of the intervention and CBT behaviours during the follow-up period will be recorded and captured in a feedback questionnaire. Use, acceptability and experience of outcome assessment will be explored in qualitative interviews with participants (n = 6 per group). The efficacy evaluation will report descriptive data, key model parameters and 95% highest probability density intervals in a Bayesian growth model. DISCUSSION: This is the first feasibility trial of a digital 'informed choice' decision aid for the implementation of CBTp. If the trial proves feasible and demonstrates preliminary evidence of efficacy, a large multi-site trial will be warranted. TRIAL REGISTRATION: ISRCTN registry, ISRCTN53107879 . Registered prospectively on 2 August 2017. PMID- 30458851 TI - The impact of musculoskeletal injuries sustained in road traffic crashes on work related outcomes: a protocol for a systematic review. AB - BACKGROUND: Musculoskeletal injuries (strains/sprains, contusions, dislocations, and fractures) are the most common injury sustained in a road traffic crash. They can have a long-term impact upon the ability to engage in work. Persisting symptoms as well as poor physical and psychological recovery may reduce the ability to return to or remain at work necessitating the use of sick leave or alternate duties to enable a gradual return to full duties. There is also a need to investigate rates of return to work, along with other work-related outcomes in this population so that interventions designed to facilitate return to work can be targeted to this clinical population. In addition, there is a need to explore factors associated with work-related outcomes in people with musculoskeletal injuries subsequent to a road traffic crash. METHODS: A systematic review will be conducted to determine the impact of sustaining a musculoskeletal injury during a road traffic crash on an individual's ability to work. Observational studies will be identified by searching six electronic databases for reports of adults having sustained musculoskeletal injuries during a road traffic crash. Studies featuring paediatric cohorts or those with neurological injuries will be excluded. To be eligible for inclusion, studies must report at least one of the following work related outcomes: return to work status/rate, sick leave, work ability, work capacity, and health-related work productivity loss. The methodological quality of included studies will be assessed with the National Institutes of Health National Heart, Lung, and Blood Institute Study Quality Assessment Tools for observational cohort and cross-sectional studies, and case-control studies. DISCUSSION: The results of this systematic review may increase our knowledge of work-related outcomes and understanding of the associated factors for people with musculoskeletal injuries following road traffic crashes. Future studies could use the results to plan interventions and influence policy and legislation, and raise awareness of the needs of this clinical population. SYSTEMATIC REVIEW REGISTRATION: Registered on PROSPERO, reference number CRD42018099252 , dated 14 August 2018. PMID- 30458852 TI - Resistance to anti-PD-1-based immunotherapy in basal cell carcinoma: a case report and review of the literature. AB - BACKGROUND: Immunotherapy with immune checkpoint inhibitors has radically changed the management of a broad spectrum of tumors. In contrast, only very limited information is available about the efficacy of these therapies in non-melanoma skin cancers, especially in basal cell carcinoma. The latter malignancy is often associated with both an impairment of the host immune response and a high mutation burden, suggesting that immune checkpoint inhibitor-based immunotherapy may be effective in the treatment of this tumor. CASE PRESENTATION: A 78-year-old woman was diagnosed with a metastatic non-small-cell-lung-cancer. Following the lack of response to two lines of systemic chemotherapy, she was treated with the anti-PD-1 monoclonal antibody nivolumab, obtaining a prolonged stable disease. Under nivolumab treatment, the patient developed a basal cell carcinoma of the nose. The latter was surgically resected. Immunohistochemical staining of tumor tissue showed a PD-L1 expression < 1% and lack of human leukocyte antigen class I subunit (i.e. heavy and light chain) expression on tumor cells. In addition, a limited number of T cells (CD3+) was present in the tumor microenvironment, with a higher number of regulatory T cells (Foxp3+) and macrophages (Cd11b+) as compared to a low infiltration of activated cytotoxic T cells (CD8+/ Granzyme B+). Two months following the surgical removal of the tumor, while still on nivolumab treatment, the patient relapsed with a basal cell carcinoma in the same anatomic site of the previous surgical excision. The tumor displayed the same pathological characteristics. CONCLUSION: Preclinical lines of evidence suggest a potential role of immune checkpoint inhibitors for basal cell carcinoma treatment. However, limited clinical data is available. In the patient we have described administration of the immune checkpoint inhibitor nivolumab for the treatment of a responsive non-small cell carcinoma was associated with the development and relapse of a basal cell carcinoma tumor. This association is likely to reflect the resistance of basal cell carcinoma cells to anti-PD-1 based immunotherapy because of a "cold" tumor microenvironment characterized by lack of human leukocyte antigen class I expression, low PD-L1 expression and high number of immune regulatory cells. PMID- 30458853 TI - Musculoskeletal manifestations occur predominantly in patients with later-onset familial Mediterranean fever: Data from a multicenter, prospective national cohort study in Japan. AB - BACKGROUND: We showed previously that Japanese individuals with familial Mediterranean fever (FMF) have a more atypical phenotype compared to endemic areas. The clinical differences between young-onset FMF (YOFMF), adult-onset FMF (AOFMF), and late-onset FMF (LOFMF) in Japan are unclear. METHODS: We enrolled 395 consecutive patients. We defined YOFMF, AOFMF, and LOFMF as the onset of FMF at < 20, 20-39, and >= 40 years of age, respectively. We compared clinical manifestations and MEFV mutations patterns among these groups. RESULTS: Median ages at onset were YOFMF 12.5 years (n = 182), AOFMF 28 years (n = 115), and LOFMF 51 years (n = 90). A family history, MEFV mutations in exon 10, and more than two MEFV mutations were significantly more frequent in the earlier-onset groups (p < 0.01, p < 0.0001, and p < 0.001, respectively). In the accompanying manifestations, thoracic and abdominal pain were significantly more frequent in the earlier-onset groups (p < 0.01 and p < 0.0001, respectively), whereas arthritis and myalgia were significantly more frequent in the later-onset groups (p < 0.0001 and p < 0.01, respectively). The multiple logistic regression analysis revealed that the presence of MEFV exon 10 mutations and earlier onset were significantly associated with serositis, whereas the absence of MEFV exon 10 mutations, later onset, and the presence of erysipelas-like erythema were significantly associated with musculoskeletal manifestations. There was no significant between-group difference in the responsiveness to colchicine. CONCLUSIONS: Our results indicate that the later-onset FMF patients had a lower percentage of MEFV mutations in exon 10 and predominantly presented arthritis and myalgia. It is important to distinguish their FMF from other inflammatory diseases. PMID- 30458855 TI - Reduced hospitalization rates are not associated with increased mortality or readmission rates in an emergency department in Israel. AB - BACKGROUND AND AIM: In 2011 the Israeli Ministry of Health (MOH) instructed hospitals to limit occupancy in the internal medicine wards to 120%, which was followed by a nationwide reduction in hospitalization rates. We examined how readmission and mortality rates changed in the five years following the changes in occupancy rates and hospitalization rates. METHODS: All visits to the Tel Aviv Medical Center internal Emergency Medicine Department (ED) in 2010, 2014 and 2016 were captured, with exclusion of visits by patients below 16 of age and patients with incomplete or faulty data. The main outcomes were one-week readmission rates and one-month death rates. The secondary outcomes were admission rate, ED visit length & admission-delay time (minutes), and rates of admission-delayed patients. RESULTS: After exclusion, a total of 168,891 internal medicine ED patients were included in the analysis. Mean age was 58.0 and 49% were males. During the relevant period (2010-2016), total medical ED visits increased by 11% - 53,327, 56,588 and 59,066 in 2010, 2014 and 2016 respectively. Hospitalization rates decreased from 46% in 2010 to 35% in 2015 (p < 0.001), with the most prominent reduction in the elderly population. One-week readmission rates were 6.5, 6.4 and 6.7% in 2010, 2014 and 2016 respectively (p = 0.347 and p = 0.21). One-month mortality was similar in 2010 and 2014 (4.4 and 4.5%, p = 0.388) and lower in 2016 (4.1%, p = 0.048 compared with 2010). Average ED visit length increased from 184 min in 2010 to 238 and 262 min in 2014 & 2016 (p < 0.001 for both) and average delay time to ward admission increased from 97 min in 2010 to 179 and 240 in 2014 & 2016 (p < 0.001 for both). In 2010 24% of the admitted patients were delayed in the ED more than 2 h, numbers that increased to 53% in 2014 and 66% in 2016 (p < 0.001 for both). CONCLUSION: Following the 2011 MOH's decision to establish a 120% occupancy limit for internal medicine wards along with natural growth in population volume, significant changes were noted in the work of a large, presumably representative emergency department in Israel. Although a steady increase in total ED visits along with a steady reduction in hospitalization rates were observed, the readmission and mortality rates remained low. The increase in the average length of ED visits and in the delay from ED admission to a ward reflects higher burden on the ED. The study was not able to establish a causal connection between the MOH directive and the subsequent changes in ED activity. Nonetheless, the study has significant potential implications for policy makers, including the presence of senior ED physicians during afterhours, creation of short-stay diagnostic units and proper adjustments in ED size and personnel. PMID- 30458856 TI - Statin drugs to reduce breast cancer recurrence and mortality. AB - Epidemiologic studies have, variably, shown the concomitant use of statin drugs to be beneficial to cancer outcomes. Statin drugs have been FDA approved for three decades for the treatment of high cholesterol and atherosclerotic coronary artery disease and are widely used. This has engendered studies as to their influence on concomitant diseases, including cancers. In this context, statin use has been correlated, variably, with a decrease in deaths from breast cancer. However, there is no extant model for this effect, and the extent of efficacy is open to question.The overarching goal of this article is to communicate to the reader of the potential of statins to reduce breast cancer progression and mortality. This is the use as a secondary prevention measure, and not as a therapy to directly counter active cancer. First, salient aspects of statin pharmacology, as relates to cardiovascular disease, will be discussed. Second, the basic and clinical research studies that investigate statin usage in breast cancer will be presented. Additionally, statin effects in other cancer types will be included for context. Finally, proposals for future basic and clinical research studies to determine the role of statins in breast cancer management will be presented. PMID- 30458857 TI - Comorbidities in polymyalgia rheumatica: a systematic review. AB - BACKGROUND AND AIM: Comorbidities are known to exist in many rheumatological conditions. Polymyalgia rheumatica (PMR) is a common inflammatory rheumatological condition affecting older people which, prior to effective treatment, causes severe disability. Our understanding of associated comorbidities in PMR is based only on case reports or series and small cohort studies. The objective of this study is to review systematically the existing literature on the comorbidities associated with PMR. METHODS: MEDLINE, EMBASE, PsycINFO and CINAHL databases were searched for original observational research from inception to November 2016. Papers containing the words 'Polymyalgia Rheumatica' OR 'Giant Cell Arteritis' OR the terms 'PMR' OR 'GCA' were included. Article titles were reviewed based on pre defined criteria by two reviewers. Following selection for inclusion, studies were quality assessed using the Newcastle-Ottawa tool and data were extracted. RESULTS: A total of 17,329 papers were reviewed and 41 were incorporated in this review, including three published after the search took place. Wide variations were found in study design, comorbidities reported and populations studied. Positive associations were found between PMR diagnosis and stroke, cardiovascular disease, peripheral arterial disease, diverticular disease and hypothyroidism. Two studies reported a positive association between PMR and overall malignancy rate. Seven studies reported an association between PMR and specific types of cancer, such as leukaemia, lymphoma, myeloproliferative disease and specified solid tumours, although nine studies found either no or negative association between cancer and PMR. CONCLUSION: Quantification of the prevalence of comorbidities in PMR is important to accurately plan service provision and enable identification of cases of PMR which may be more difficult to treat. This review highlights that research into comorbidities in PMR is, overall, methodologically inadequate and does not comprehensively cover all comorbidities. Future studies should consider a range of comorbidities in patients with a validated diagnosis of PMR in representative populations. PMID- 30458854 TI - Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis. AB - BACKGROUND: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. METHODS: A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients. RESULTS: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (>= 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with >= 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays. CONCLUSIONS: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials. PMID- 30458858 TI - Mitochondrial genomes of two diplectanids (Platyhelminthes: Monogenea) expose paraphyly of the order Dactylogyridea and extensive tRNA gene rearrangements. AB - BACKGROUND: Recent mitochondrial phylogenomics studies have reported a sister group relationship of the orders Capsalidea and Dactylogyridea, which is inconsistent with previous morphology- and molecular-based phylogenies. As Dactylogyridea mitochondrial genomes (mitogenomes) are currently represented by only one family, to improve the phylogenetic resolution, we sequenced and characterized two dactylogyridean parasites, Lamellodiscus spari and Lepidotrema longipenis, belonging to a non-represented family Diplectanidae. RESULTS: The L. longipenis mitogenome (15,433 bp) contains the standard 36 flatworm mitochondrial genes (atp8 is absent), whereas we failed to detect trnS1, trnC and trnG in L. spari (14,614 bp). Both mitogenomes exhibit unique gene orders (among the Monogenea), with a number of tRNA rearrangements. Both long non-coding regions contain a number of different (partially overlapping) repeat sequences. Intriguingly, these include putative tRNA pseudogenes in a tandem array (17 trnV pseudogenes in L. longipenis, 13 trnY pseudogenes in L. spari). Combined nucleotide diversity, non-synonymous/synonymous substitutions ratio and average sequence identity analyses consistently showed that nad2, nad5 and nad4 were the most variable PCGs, whereas cox1, cox2 and cytb were the most conserved. Phylogenomic analysis showed that the newly sequenced species of the family Diplectanidae formed a sister-group with the Dactylogyridae + Capsalidae clade. Thus Dactylogyridea (represented by the Diplectanidae and Dactylogyridae) was rendered paraphyletic (with high statistical support) by the nested Capsalidea (represented by the Capsalidae) clade. CONCLUSIONS: Our results show that nad2, nad5 and nad4 (fast-evolving) would be better candidates than cox1 (slow evolving) for species identification and population genetics studies in the Diplectanidae. The unique gene order pattern further suggests discontinuous evolution of mitogenomic gene order arrangement in the Class Monogenea. This first report of paraphyly of the Dactylogyridea highlights the need to generate more molecular data for monogenean parasites, in order to be able to clarify their relationships using large datasets, as single-gene markers appear to provide a phylogenetic resolution which is too low for the task. PMID- 30458859 TI - Trans-activation-based risk assessment of BRCA1 BRCT variants with unknown clinical significance. AB - BACKGROUND: Deleterious variants in the tumour suppressor BRCA1 are known to cause hereditary breast and ovarian cancer syndrome (HBOC). Missense variants in BRCA1 pose a challenge in clinical care, as their effect on protein functionality often remains unknown. Many of the pathogenic missense variants found in BRCA1 are located in the BRCA1 C-terminal (BRCT) domains, domains that are known to be vital for key functions such as homologous recombination repair, protein-protein interactions and trans-activation (TA). We investigated the TA activity of 12 BRCA1 variants of unknown clinical significance (VUSs) located in the BRCT domains to aid in the classification of these variants. RESULTS: Twelve BRCA1 VUSs were investigated using a modified version of the dual luciferase TA activity assay (TA assay) that yielded increased sensitivity and sample throughput. Variants were classified according to American College of Medical Genetics and Genomics (ACMG) criteria using TA assay results and available data. In combining our TA-assay results and available data, in accordance with the ACMG guidelines for variant classification, we proposed the following variant classifications: c.5100A>G, c.5326C>T, c.5348T>C and c.5477A>T as likely benign (class 2) variants. c.5075A>C, c.5116G>A and c.5513T>G were likely pathogenic (class 4), whereas c.5096G>A likely represents a likely pathogenic variant with moderate penetrance. Variants c.5123C>T, c.5125G>A, c.5131A>C and c.5504G>A remained classified as VUSs (class 3). CONCLUSIONS: The modified TA assay provides efficient risk assessment of rare missense variants found in the BRCA1 BRCT-domains. We also report that increased post-transfection incubation time yielded a significant increase in TA assay sensitivity. PMID- 30458860 TI - Long-term follow-up of autologous hematopoietic stem cell transplantation for refractory juvenile dermatomyositis: a case-series study. AB - OBJECTIVE: To follow up the refractory juvenile dermatomyositis (JDM) with autologous hematopoietic stem cell transplantation (AHSCT) in a long time and to investigate whether AHSCT is effective and safe to treat refractory JDM. METHODS: We collected the AHSCT and follow-up data of three patients with refractory JDM who received autologous peripheral blood CD34+ cell transplantation in our hospital between June 2004 and July 2015. Those data include: hight, weight, routine blood and urine tests, ESR, CK, ALT, AST, LDH, renal functional tests, lymphocyte subpopulations, HRCT and muscle MRI. The last follow-up was done in June 2017. RESULTS: All three patients had complete remission and could stop prednisone after 3-12 months. None of them relapsed at 144, 113 and 23 months follow-up. Twelve months after their AHSCT, all of their monitoring indexes have returned to normal and they have stopped all medications. Until the date of this article, none of them relapsed or need medicine. CONCLUSION: Our study suggests that AHSCT is safe and effective in treating refractory JDM, and it can provides long term drug-free survival. However, more cases are needed for further confirmation. PMID- 30458862 TI - The evidence-and acceptability-of taxes on unhealthy foods. AB - The global obesity pandemic has public advocates and policymakers grappling with the question of how best to respond. Among the various policy options, unhealthy food and beverage taxes have gained attention as a potentially effective intervention to reduce non-nutritive caloric intake, while raising government funds for health promotion programs at the community level. Yet in many countries, including in Israel, such proposals have not gained broad support. Cities in both United States and Mexico have found that taxes on sugar-sweetened beverages reduce consumption. Yet the food industry has successfully fought many such policies. Looking forward, those supporting taxation policies will need to provide clear evidence, a compelling use of funds raised, a convincing answer to industry claims, and attention to equity in implementation. With no easy fixes in sight to obesity, it is likely that taxes will remain viable - if contested - options for the foreseeable future. PMID- 30458861 TI - Cleavage of the extracellular domain of junctional adhesion molecule-A is associated with resistance to anti-HER2 therapies in breast cancer settings. AB - BACKGROUND: Junctional adhesion molecule-A (JAM-A) is an adhesion molecule whose overexpression on breast tumor tissue has been associated with aggressive cancer phenotypes, including human epidermal growth factor receptor-2 (HER2)-positive disease. Since JAM-A has been described to regulate HER2 expression in breast cancer cells, we hypothesized that JAM-dependent stabilization of HER2 could participate in resistance to HER2-targeted therapies. METHODS: Using breast cancer cell line models resistant to anti-HER2 drugs, we investigated JAM-A expression and the effect of JAM-A silencing on biochemical/functional parameters. We also tested whether altered JAM-A expression/processing underpinned differences between drug-sensitive and -resistant cells and acted as a biomarker of patients who developed resistance to HER2-targeted therapies. RESULTS: Silencing JAM-A enhanced the anti-proliferative effects of anti-HER2 treatments in trastuzumab- and lapatinib-resistant breast cancer cells and further reduced HER2 protein expression and Akt phosphorylation in drug-treated cells. Increased epidermal growth factor receptor expression observed in drug resistant models was normalized upon JAM-A silencing. JAM-A was highly expressed in all of a small cohort of HER2-positive patients whose disease recurred following anti-HER2 therapy. High JAM-A expression also correlated with metastatic disease at the time of diagnosis in another patient cohort resistant to trastuzumab therapy. Importantly, cleavage of JAM-A was increased in drug resistant cell lines in conjunction with increased expression of ADAM-10 and -17 metalloproteases. Pharmacological inhibition or genetic silencing studies suggested a particular role for ADAM-10 in reducing JAM-A cleavage and partially re-sensitizing drug-resistant cells to the anti-proliferative effects of HER2 targeted drugs. Functionally, recombinant cleaved JAM-A enhanced breast cancer cell invasion in vitro and both invasion and proliferation in a semi-in vivo model. Finally, cleaved JAM-A was detectable in the serum of a small cohort of HER2-positive patients and correlated significantly with resistance to HER2 targeted therapy. CONCLUSIONS: Collectively, our data suggest a novel model whereby increased expression and cleavage of JAM-A drive tumorigenic behavior and act as a biomarker and potential therapeutic target for resistance to HER2 targeted therapies. PMID- 30458863 TI - A multi-centre, double-blind, placebo-controlled, randomised trial of combination methotrexate and gefitinib versus methotrexate alone to treat tubal ectopic pregnancies (GEM3): trial protocol. AB - BACKGROUND: Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. Treatment options include surgery and medical management. Stable women with tEPs with pre-treatment serum human chorionic gonadotrophin (hCG) levels < 1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate. However, tEPs with hCG > 1000 IU/L can take significant time to resolve with methotrexate and require multiple outpatient monitoring visits. In pre-clinical studies, we found that tEP implantation sites express high levels of epidermal growth factor receptor. In early-phase trials, we found that combination therapy with gefitinib, an orally active epidermal growth factor receptor antagonist, and methotrexate resolved tEPs without the need for surgery in over 70% of cases, did not cause significant toxicities, and was well tolerated. We describe the protocol of a randomised trial to assess the efficacy of combination gefitinib and methotrexate, versus methotrexate alone, in reducing the need for surgical intervention for tEPs. METHODS AND ANALYSIS: We propose to undertake a multi-centre, double-blind, placebo-controlled, randomised trial (around 70 sites across the UK) and recruit 328 women with tEPs (with pre-treatment serum hCG of 1000-5000 IU/L). Women will be randomised in a 1:1 ratio by a secure online system to receive a single dose of intramuscular methotrexate (50 mg/m2) and either oral gefitinib or matched placebo (250 mg) daily for 7 days. Participants and healthcare providers will remain blinded to treatment allocation throughout the trial. The primary outcome is the need for surgical intervention for tEP. Secondary outcomes are the need for further methotrexate treatment, time to resolution of the tEP (serum hCG <= 15 IU/L), number of hospital visits associated with treatment (until resolution or scheduled/emergency surgery), and the return of menses by 3 months after resolution. We will also assess adverse events and reactions until day of resolution or surgery, and participant-reported acceptability at 3 months. DISCUSSION: A medical intervention that reduces the need for surgery and resolves tEP faster would be a favourable treatment alternative. If effective, we believe that gefitinib and methotrexate could become standard care for stable tEPs. TRIAL REGISTRATION: ISRCTN Registry ISRCTN67795930 . Registered 15 September 2016. PMID- 30458864 TI - Trimethoprim-sulfamethoxazole induced circulatory shock in a human immunodeficiency virus uninfected patient: a case report and review. AB - BACKGROUND: Severe systemic reactions resembling septic shock have been described following trimethoprim-sulfamethoxazole (TMP-SMX) administration. Nearly all cases described in the literature occurred in HIV-infected patients. CASE PRESENTATION: We present a 42-year-old woman with a history of systemic lupus erythematosus (SLE) who was admitted to the Intensive Care Unit (ICU) twice with fever and circulatory shock after taking a dose of TMP-SMX 800-160 mg. She had no respiratory distress, urticarial rash or eosinophilia on presentation. Infectious workup during both admissions was negative and treatment with antibiotics, steroids and vasopressors was de-escalated with clinical improvement. She was found to be HIV negative, however, labs revealed a low CD4+ count. CONCLUSIONS: TMP-SMX can rarely result in a severe, non-anaphylactic circulatory shock; if initially unrecognized, patients may undergo repeat drug exposure with an associated high morbidity risk. While more commonly reported in HIV individuals, this case demonstrates that TMP-SMX related circulatory shock can occur in a HIV negative patient. PMID- 30458865 TI - Molecular patterns of cancer colonisation in lymph nodes of breast cancer patients. AB - Lymph node (LN) metastasis is an important prognostic parameter in breast carcinoma, a crucial site for tumour-immune cell interaction and a gateway for further dissemination of tumour cells to other metastatic sites. To gain insight into the underlying molecular changes from the pre-metastatic, via initial colonisation to the fully involved LN, we reviewed transcriptional research along the evolving microenvironment of LNs in human breast cancers patients. Gene expression studies were compiled and subjected to pathway-based analyses, with an emphasis on immune cell-related genes. Of 366 studies, 14 performed genome-wide gene expression comparisons and were divided into six clinical-biological scenarios capturing different stages of the metastatic pathway in the LN, as follows: metastatically involved LNs are compared to their patient-matched primary breast carcinomas (scenario 1) or the normal breast tissue (scenario 2). In scenario 3, uninvolved LNs were compared between LN-positive patients and LN negative patients. Scenario 4 homed in on the residual uninvolved portion of involved LNs and compared it to the patient-matched uninvolved LNs. Scenario 5 contrasted uninvolved and involved LNs, whilst in scenario 6 involved (sentinel) LNs were assessed between patients with other either positive or negative LNs (non-sentinel).Gene lists from these chronological steps of LN metastasis indicated that gene patterns reflecting deficiencies in dendritic cells and hyper proliferation of B cells parallel to tumour promoting pathways, including cell adhesion, extracellular matrix remodelling, cell motility and DNA repair, play key roles in the changing microenvironment of a pro-metastatic to a metastatically involved LN. Similarities between uninvolved LNs and the residual uninvolved portion of involved LNs hinted that LN alterations expose systemic tumour-related immune responses in breast cancer patients. Despite the diverse settings, gene expression patterns at different stages of metastatic colonisation in LNs were recognised and may provide potential avenues for clinical interventions to counteract disease progression for breast cancer patients. PMID- 30458866 TI - Cost-effectiveness analysis of umeclidinium bromide/vilanterol 62.5/25 mcg versus tiotropium/olodaterol 5/5 mcg in symptomatic patients with chronic obstructive pulmonary disease: a Spanish National Healthcare System perspective. AB - BACKGROUND: A head-to-head study demonstrated the superiority of once-daily umeclidinium bromide/vilanterol (UMEC/VI) 62.5/25 mcg on trough forced expiratory volume in 1 s (FEV1) versus once-daily tiotropium/olodaterol (TIO/OLO) 5/5 mcg in symptomatic patients with chronic obstructive pulmonary disease (COPD). This analysis evaluated the cost effectiveness of UMEC/VI versus TIO/OLO from a Spanish National Healthcare System perspective, using data from this study and Spanish literature. METHODS: This analysis was conducted from the perspective of the Spanish National Healthcare System with a 3-year horizon as base case. A disease progression model using a linked risk equation approach was used to estimate disease progression and associated healthcare costs, and quality adjusted life years (QALYs). The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study was used to develop the statistical risk equations for clinical endpoints, and costs were calculated using a health state approach (by dyspnea severity). Utilities for QALY calculation were estimated using patient baseline characteristics within a regression fit to Spanish observational data. Treatment effect, expressed as change from baseline in FEV1 was obtained from the head-to-head study and used in the model (UMEC/VI minus TIO/OLO difference: + 52 mL [95% confidence interval: 28, 77]). Baseline patient characteristics were sourced from Spanish literature or the head-to-head study if unavailable. A scenario analysis using only the intent-to-treat (ITT) population from the head-to-head study, and sensitivity analyses (including probabilistic sensitivity analyses), were conducted. Direct healthcare costs (2017 Euro) were obtained from Spanish sources and costs and benefits were discounted at 3% per annum. RESULTS: UMEC/VI was associated with small improvements in QALYs (+ 0.029) over a 3-year time horizon, compared with TIO/OLO, alongside cost savings of ?393/patient. The ITT scenario analysis and sensitivity analyses had similar results. All probabilistic simulations resulted in UMEC/VI being less costly and more effective than TIO/OLO. CONCLUSION: UMEC/VI dominated TIO/OLO (more effective and less expensive). These results may aid payers and decision-makers in Spain when making judgements on which long-acting muscarinic antagonist/long-acting beta2-agonist (LAMA/LABA) treatments can be considered cost effective in Spain. PMID- 30458867 TI - Correction to: High-resolution ISR amplicon sequencing reveals personalized oral microbiome. AB - Following publication of the original article, the authors recognized that the left and right panels in Fig. 6b had been inadvertently switched during reformatting. PMID- 30458868 TI - A deliberative dialogue as a knowledge translation strategy on road traffic injuries in Burkina Faso: a mixed-method evaluation. AB - INTRODUCTION: Deliberative dialogues are increasingly being used, particularly on the African continent. They are a promising interactive knowledge translation strategy that brings together and leverages the knowledge of diverse stakeholders important to the resolution of a societal issue. Following a research project carried out in Burkina Faso on road traffic injuries, a 1-day workshop in the form of a deliberative dialogue was organised in November 2015. The workshop brought together actors involved in road safety, such as researchers, police and fire brigades, health professionals, non-governmental and civil society organisations, and representatives of government structures. The objective was to present the research results, propose recommendations to improve the situation and develop a collective action plan. METHOD: To better understand the workshop's utility and effects, a mixed-method evaluation was conducted. Data were obtained from two questionnaires distributed at the end of the workshop (n = 37) and 14 qualitative interviews with participants 6-10 weeks after the workshop. Descriptive statistics were used to analyse the quantitative data, and a thematic analysis was conducted for the qualitative data. RESULTS: The data revealed several positive impacts of the workshop, such as the acquisition of new knowledge about road safety, the opportunity for participants to learn from each other, the creation of post-workshop collaborations, and individual behaviour changes. However, several challenges were encountered that constrained the potential effects of the workshop, including the limited presence of political actors, the lack of engagement among participants to develop an action plan, and the difficulty in setting up a monitoring committee following the workshop. CONCLUSION: While the deliberative workshop is not the standard format for reporting research results in Burkina Faso, this model should be reproduced in different contexts. This interactive knowledge translation strategy is useful to benefit from the experiential knowledge of the various actors and to encourage their involvement in formulating recommendations. PMID- 30458869 TI - Risk assessment and management of preoperative venous thromboembolism following femoral neck fracture. AB - BACKGROUND: Limited studies are available to investigate the prevalence of preoperative venous thromboembolism (VTE) in elderly patients with femoral neck fractures. Our primary aim was to determine the incidences of VTE and its risk or protective factors in such patient population. The secondary objective was to evaluate the need of therapeutic anticoagulation for isolated calf muscular venous thrombosis (ICMVT) prior to femoral neck fracture surgery. METHODS: This is a retrospective case-control study, including 301 femoral neck fracture patients who were admitted to our institution between January 2014 and March 2017. Bilateral Doppler ultrasonography was performed in each of the patients as a preoperative VTE screening. The event rate of VTE was calculated, and significant risk or protective factors were determined by using a multivariate logistic regression model. Patients with ICMVT were divided into anticoagulation and no anticoagulation groups to assess the efficacy and safety of preoperative therapeutic anticoagulation. Intraoperative blood loss, drainage volume, blood transfusion, perioperative hemoglobin change, and rate of thrombosis extension were compared between the two groups. RESULTS: The overall preoperative incidence of VTE in patients with femoral neck fracture was 18.9% (57/301), in which deep vein thrombosis (DVT) was 18.9% and pulmonary embolism (PE) was 1%. Among the DVT cases, 77.2% (44/57) were ICMVTs. Multiple fractures (odds ratio [OR] = 9.418; 95% confidence interval [CI] = 2.537 to 34.96), coexisting movement disorder (OR = 3.862; 95% CI = 1.658 to 8.993), bed rest for more than 7 days (OR = 2.082; 95% CI = 1.011 to 4.284) as well as elevated levels of D-dimer (OR = 1.019; 95% CI = 1.002 to 1.037) and fibrinogen (OR = 1.345; 95% CI = 1.008 to 1.796) led to an increase in the risk of VTE, while the recent use of antiplatelet drug (OR = 0.424; 95% CI = 0.181 to 0.995) and prophylactic anticoagulation (OR = 0.503; 95% CI = 0.263 to 0.959) decreased the risk of VTE. For the 39 patients with ICMVT undergoing femoral neck fracture surgery, there were no significant differences in the rate of thrombosis extension between anticoagulation and no anticoagulation groups, but significantly decreased postoperative hemoglobin was observed in the anticoagulation group. CONCLUSION: Our findings showed a high prevalence of preoperative VTE in elderly patients with femoral neck fracture, with risk factors identified. We found that the most detected VTE were ICMVTs. Our study suggested that a direct surgery without preoperative use of therapeutic anticoagulation for ICMVT would not reduce the risk of thrombus extension, and the therapeutic use of anticoagulation may worsen postoperative anemia. PMID- 30458870 TI - MUC1 deficiency mediates corticosteroid resistance in chronic obstructive pulmonary disease. AB - BACKGROUND: Lung inflammation in COPD is poorly controlled by inhaled corticosteroids (ICS). Strategies to improve ICS efficacy or the search of biomarkers who may select those patients candidates to receive ICS in COPD are needed. Recent data indicate that MUC1 cytoplasmic tail (CT) membrane mucin can mediate corticosteroid efficacy in chronic rhinosinusitis. The objective of this work was to analyze the previously unexplored role of MUC1 on corticosteroid efficacy in COPD in vitro and in vivo models. METHODS: MUC1-CT expression was measured by real time PCR, western blot, immunohistochemistry and immunofluorescence. The inflammatory mediators IL-8, MMP9, GM-CSF and MIP3alpha were measured by ELISA. The effect of MUC1 on inflammation and corticosteroid anti-inflammatory effects was measured using cell siRNA in vitro and Muc1-KO in vivo animal models. RESULTS: MUC1-CT expression was downregulated in lung tissue, bronchial epithelial cells and lung neutrophils from smokers (n = 11) and COPD (n = 11) patients compared with healthy subjects (n = 10). MUC1 was correlated with FEV1% (rho = 0.7479; p < 0.0001) in smokers and COPD patients. Cigarette smoke extract (CSE) decreased the expression of MUC1 and induced corticosteroid resistance in human primary bronchial epithelial cells and human neutrophils. MUC1 Gene silencing using siRNA-MUC1 impaired the anti-inflammatory effects of dexamethasone and reduced glucocorticoid response element activation. Dexamethasone promoted glucocorticoid receptor alpha (GRalpha) and MUC1-CT nuclear translocation and co-localization that was inhibited by CSE. Lung function decline and inflammation induced by lipopolysaccharide and cigarette smoke in Muc1 KO mice was resistant to dexamethasone. CONCLUSIONS: These results confirm a role for MUC1-CT mediating corticosteroid efficacy in COPD. PMID- 30458871 TI - The multi-biomarker disease activity score tracks response to rituximab treatment in rheumatoid arthritis patients: a post hoc analysis of three cohort studies. AB - BACKGROUND: A multi-biomarker disease activity (MBDA) score has been validated as an objective measure of disease activity in rheumatoid arthritis (RA) and shown to track response to treatment with several disease-modifying anti-rheumatic drugs (DMARDs). The objective of this study was to evaluate the ability of the MBDA score to track response to treatment with rituximab. METHODS: Data were used from 57 RA patients from three cohorts treated with rituximab 1000 mg and methylprednisolone 100 mg at days 1 and 15. The MBDA score was assessed in serum samples obtained at baseline and 6 months. Spearman's rank correlation coefficients were calculated for baseline values, 6-month values, and change from baseline to 6 months (?), between MBDA score and the following measures: disease activity score assessing 28 joints (DAS28) using erythrocyte sedimentation rate (ESR) or high-sensitivity C-reactive protein (hsCRP), ESR, (hs)CRP, swollen and tender joint counts assessing 28 joints (SJC28, TJC28), patient visual analogue scale for general health (VAS-GH), health assessment questionnaire (HAQ), and radiographic progression over 12 months using Sharp/van der Heijde score (SHS), as well as six bone turnover markers. Additionally, multivariable linear regression analyses were performed using these measures as dependent variable and the MBDA score as independent variable, with adjustment for relevant confounders. The association between ?MBDA score and European League Against Rheumatism (EULAR) response at 6 months was assessed with adjustment for relevant confounders. RESULTS: At baseline, the median MBDA score and DAS28-ESR were 54.0 (IQR 44.3-70.0) and 6.3 (IQR 5.4-7.1), respectively. MBDA scores correlated significantly with DAS28-ESR, DAS28-hsCRP, ESR and (hs)CRP at baseline and 6 months. ?MBDA score correlated significantly with changes in these measures. ?MBDA score was associated with EULAR good or moderate response (adjusted OR = 0.89, 95% CI = 0.81-0.98, p = 0.02). Neither baseline MBDA score nor DeltaMBDA score correlated statistically significantly with ?SHS (n = 11) or change in bone turnover markers (n = 23), although ?SHS >= 5 was observed in 5 (56%) of nine patients with high MBDA scores. CONCLUSIONS: We have shown, for the first time, that the MBDA score tracked disease activity in RA patients treated with rituximab and that change in MBDA score reflected the degree of treatment response. PMID- 30458872 TI - Double Fogarty balloon catheter technique for difficult to retrieve esophageal foreign bodies. AB - BACKGROUND: Foreign body ingestion is common, especially in the pediatric population. Plans for retrieval should be tailored to the specific esophageal foreign bodies. CASE PRESENTATION: We present a difficult to retrieve esophageal foreign body in a 3-year-old girl who ingested a 2 cm glass pebble. Intraoperatively, attempts using conventional optical forceps and retrieval baskets were unsuccessful due to the size and smooth texture of the object. A novel strategy using double Fogarty embolectomy balloon catheters for retrieval of blunt esophageal foreign bodies was devised and described. CONCLUSION: The double fogarty retrieval technique described appeared to be safe and efficacious, allowing for extraction of large esophageal foreign bodies under direct visualization. PMID- 30458873 TI - No association between low-dose aspirin use and breast cancer outcomes overall: a Swedish population-based study. AB - BACKGROUND: Results from previous studies indicate that use of low-dose aspirin may improve breast cancer prognosis. We evaluated aspirin use and breast cancer outcomes in relation to clinical characteristics as well as dose and duration of aspirin use. METHODS: We used information from the Regional Breast Cancer Quality of-Care Registries in three Swedish regions to identify 21,414 women diagnosed with a first stage I-III breast cancer between 1 April 2006 and 31 December 2012. The cohort was further linked to nationwide registers to retrieve information about dispensing low-dose aspirin before and after breast cancer diagnosis, comorbidity and causes of death. In a separate analysis, we investigated time to breast cancer death among 621 women with stage IV disease at diagnosis. Associations were evaluated using a multivariable Cox proportional hazards model. RESULTS: Among women with stage I-III breast cancer, 2660 (12.4%) used low-dose aspirin shortly before breast cancer diagnosis and 4091 (19.1%) were users during follow-up. Women were followed for a median of 3.8 years after diagnosis. There was no association between aspirin use and breast cancer-specific death in multivariable analyses (use before diagnosis: hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.77-1.12; use after diagnosis: HR 1.00, 95% CI 0.74 1.37). Similarly, aspirin use was not associated with risk of first recurrence/metastases in a subgroup of stage I-III breast cancer patients (HR 0.97, 95% CI 0.86-1.10). However, in analyses stratified by stage, an inverse association between low-dose aspirin use after diagnosis and breast cancer death was found for women with stage I tumors (HR 0.53, 95% CI 0.29-0.96). Among women with stage IV disease at diagnosis, aspirin use was not associated with time to breast cancer death (HR 0.91, 95% CI 0.67-1.23). CONCLUSION: In this large population-based cohort study there was no evidence that low-dose aspirin use before or after breast cancer diagnosis is associated with a reduced risk of adverse outcomes overall in breast cancer. However, a potential benefit was noted among women with stage I tumors, warranting further investigation. PMID- 30458874 TI - Processes and dynamics of linkage to care from mobile/outreach and facility-based HIV testing models in hard-to-reach settings in rural Tanzania. Qualitative findings of a mixed methods study. AB - BACKGROUND: Like other countries, Tanzania instituted mobile and outreach testing approaches to address low HIV testing rates at health facilities and enhance linkage to care. Available evidence from hard-to-reach rural settings of Mbeya region, Tanzania suggests that clients testing HIV+ at facility-based sites are more likely to link to care, and to link sooner, than those testing at mobile sites. This paper (1) describes the populations accessing HIV testing at mobile/outreach and facility-based testing sites, and (2) compares processes and dynamics from testing to linkage to care between these two testing models from the same study context. METHODS: An explanatory sequential mixed-method study (a) reviewed records of all clients (n = 11,773) testing at 8 mobile and 8 facility based testing sites over 6 months; (b), reviewed guidelines; (c) observed HIV testing sites (n = 10) and Care and Treatment Centers (CTCs) (n = 8); (d) applied questionnaires at 0, 3 and 6 months to a cohort of 1012 HIV newly-diagnosed clients from the 16 sites; and (e) conducted focus group discussions (n = 8) and in-depth qualitative interviews with cohort members (n = 10) and health care providers (n = 20). RESULTS: More clients tested at mobile/outreach than facility based sites (56% vs 44% of 11,733, p < 0.001). Mobile site clients were more likely to be younger and male (p < 0.001). More clients testing at facility sites were HIV positive (21.5% vs. 7.9% of 11,733, p < 0.001). All sites in both testing models adhered to national HIV testing and care guidelines. Staff at mobile sites showed more proactive efforts to support linkage to care, and clients report favouring the confidentiality of mobile sites to avoid stigma. Clients who tested at mobile/outreach sites faced longer delays and waiting times at treatment sites (CTCs). CONCLUSIONS: Rural mobile/outreach HIV testing sites reach more people than facility based sites but they reach a different clientele which is less likely to be HIV +ve and appears to be less "linkage-ready". Despite more proactive care and confidentiality at mobile sites, linkage to care is worse than for clients who tested at facility-based sites. Our findings highlight a combination of (a) patient-level factors, including stigma; and (b) well-established procedures and routines for each step between testing and initiation of treatment in facility-based sites. Long waiting times at treatment sites are a further barrier that must be addressed. PMID- 30458875 TI - CYP genetic variants and toxicity related to anti-tubercular agents: a systematic review and meta-analysis. AB - BACKGROUND: Treatment with anti-tuberculosis drugs may cause patients to experience serious adverse effects. Genetic factors, such as polymorphisms of CYP genes, may increase the likelihood of a patient experiencing such adverse drug reactions. In this systematic review and meta-analysis, we synthesised evidence for associations between CYP genetic variants and anti-tuberculosis drug-related toxicity outcomes. METHODS: We searched MEDLINE, PubMed, EMBASE, BIOSIS and Web of Science to identify relevant studies. We performed meta-analyses to obtain an effect estimate for each genetic variant on each outcome, and stratified all analyses by country. We qualitatively assessed the methodological quality of the included studies. RESULTS: We included data from 28 distinct cohorts of patients in the review. We identified many areas of concern with regard to the quality of included studies. Patients with homozygous mutant-type or heterozygous genotype at the CYP2E1 RsaI polymorphism were significantly less likely to experience hepatotoxicity than patients with homozygous wild-type genotype (odds ratio [OR] = 0.75, 95% confidence interval [CI] 0.56-1.00; p = 0.047, I2 = 58.2%). No significant differences were observed for the CYP2E1 DraI and PstI polymorphisms. For the 96-bp deletion-insertion single-nucleotide polymorphism (SNP) of the CYP2E1 gene, homozygous mutant-type significantly increased hepatotoxicity risk compared with homozygous wild-type (OR = 8.20, 95% CI 1.38-48.68, I2 = 0%); no significant difference was observed for heterozygous genotype compared with homozygous wild-type (OR = 0.77, 95% CI 0.19-3.21, I2 = 0%). CONCLUSIONS: Generally, we identified that coverage of the association between SNPs of CYP genes and anti-tuberculosis drug-related toxicity outcomes is incomplete. We observed significant associations between the RsaI and 96-bp deletion-insertion SNPs of the CYP2E1 gene and anti-tuberculosis drug-related hepatotoxicity. We were unable to comment on the impact of ethnicity on the investigated associations, as information on participants' ethnicity was sparsely reported in the included studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number: CRD42017068448. PMID- 30458876 TI - Regenerative peripheral nerve interfaces for real-time, proportional control of a Neuroprosthetic hand. AB - INTRODUCTION: Regenerative peripheral nerve interfaces (RPNIs) are biological constructs which amplify neural signals and have shown long-term stability in rat models. Real-time control of a neuroprosthesis in rat models has not yet been demonstrated. The purpose of this study was to: a) design and validate a system for translating electromyography (EMG) signals from an RPNI in a rat model into real-time control of a neuroprosthetic hand, and; b) use the system to demonstrate RPNI proportional neuroprosthesis control. METHODS: Animals were randomly assigned to three experimental groups: (1) Control; (2) Denervated, and; (3) RPNI. In the RPNI group, the extensor digitorum longus (EDL) muscle was dissected free, denervated, transferred to the lateral thigh and neurotized with the residual end of the transected common peroneal nerve. Rats received tactile stimuli to the hind-limb via monofilaments, and electrodes were used to record EMG. Signals were filtered, rectified and integrated using a moving sample window. Processed EMG signals (iEMG) from RPNIs were validated against Control and Denervated group outputs. RESULTS: Voluntary reflexive rat movements produced signaling that activated the prosthesis in both the Control and RPNI groups, but produced no activation in the Denervated group. Signal-to-Noise ratio between hind-limb movement and resting iEMG was 3.55 for Controls and 3.81 for RPNIs. Both Control and RPNI groups exhibited a logarithmic iEMG increase with increased monofilament pressure, allowing graded prosthetic hand speed control (R2 = 0.758 and R2 = 0.802, respectively). CONCLUSION: EMG signals were successfully acquired from RPNIs and translated into real-time neuroprosthetic control. Signal contamination from muscles adjacent to the RPNI was minimal. RPNI constructs provided reliable proportional prosthetic hand control. PMID- 30458877 TI - Effectiveness of discovery learning using a mobile otoscopy simulator on knowledge acquisition and retention in medical students: a randomized controlled trial. AB - BACKGROUND: Portable educational technologies, like simulators, afford students the opportunity to learn independently. A key question in education, is how to pair self-regulated learning (SRL) with direct instruction. A cloud-based portable otoscopy simulator was employed to compare two curricula involving SRL. Pre-clerkship medical students used a prototype smartphone application, a 3D ear attachment and an otoscope to complete either otoscopy curriculum. METHODS: Pre clerkship medical students were recruited and randomized to two curriculum designs. The "Discovery then Instruction" group received the simulator one week before a traditional lecture, while the "Instruction then Discovery" group received it after the lecture. To assess participants' ability to identify otoscopic pathology, we used a 100-item test at baseline, post-intervention and 2 week retention time points. Secondary outcomes included self-reported comfort, time spent using the device, and a survey on learning preferences. RESULTS: Thirty-four students completed the study. Analysis of knowledge acquisition and retention showed improvement in scores of both groups and no significant effects of group (F1,31 = 0.53, p = 0.47). An analysis of participants' self-reported comfort showed a significant group x test interaction (F1,36 = 4.61, p = 0.04), where only the discovery then instruction group's comfort improved significantly. Overall device usage was low, as the discovery then instruction group spent 21.47 +/- 26.28 min, while the instruction then discovery group spent 13.84 +/- 18.71 min. The discovery first group's time spent with the simulator correlated moderately with their post-test score (r = 0.42, p = 0.07). After the intervention, most participants in both groups (63-68%) stated that they would prefer the instruction then discovery sequence. CONCLUSIONS: Both curricular sequences led to improved knowledge scores with no statistically significant knowledge differences. When given minimal guidance, students engaged in discovery learning minimally. There is value in SRL in simulation education, and we plan to further improve our curricular design by considering learner behaviours identified in this study. PMID- 30458878 TI - Chimeric antigen receptor-modified T cell therapy in chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL), a common type of B cell chronic lymphoproliferative disorder in adults, has witnessed enormous development in its treatment in recent years. New drugs such as ibrutinib, idelalisib, and venetoclax have achieved great success in treating relapsed and refractory (R/R) CLL. In addition, with the development of immunotherapy, chimeric antigen receptor-engineered T cells (CAR-T) therapy, a novel adoptive immune treatment, has also become more and more important in treating R/R CLL. It combines the advantages of T cells and B cells via ex vivo gene transfer technology and is able to bind targets recognized by specific antibodies without antigen presentation, thus breaking the restriction of major histocompatibility complex. So far, there have been lots of studies exploring the application of CAR-T therapy in CLL. In this review, we describe the structure of chimeric antigen receptor, the preclinical, and clinical results of CAR-T therapy against CLL, along with its adverse events and advances in efficacy. PMID- 30458879 TI - Denosumab treatment is associated with the absence of circulating tumor cells in patients with breast cancer. AB - BACKGROUND: The presence of circulating tumor cells (CTCs) in patients with breast cancer correlates to a bad prognosis. Yet, CTCs are detectable in only a minority of patients with progressive breast cancer, and factors that influence the abundance of CTCs remain elusive. METHODS: We conducted CTC isolation and enumeration in a selected group of 73 consecutive patients characterized by progressive invasive breast cancer, high tumor load and treatment discontinuation at the time of CTC isolation. CTCs were quantified with the Parsortix microfluidic device. Clinicopathological variables, blood counts at the time of CTC isolation and detailed treatment history prior to blood sampling were evaluated for each patient. RESULTS: Among 73 patients, we detected at least one CTC per 7.5 ml of blood in 34 (46%). Of these, 22 (65%) had single CTCs only, whereas 12 (35%) featured both single CTCs and CTC clusters. Treatment with the monoclonal antibody denosumab correlated with the absence of CTCs, both when considering all patients and when considering only those with bone metastasis. We also found that low red blood cell count was associated with the presence of CTCs, whereas high CA 15-3 tumor marker, high mean corpuscular volume, high white blood cell count and high mean platelet volume associated specifically with CTC clusters. CONCLUSIONS: In addition to blood count correlatives to single and clustered CTCs, we found that denosumab treatment associates with most patients lacking CTCs from their peripheral circulation. Prospective studies will be needed to validate the involvement of denosumab in the prevention of CTC generation. PMID- 30458882 TI - HER4 expression in estrogen receptor-positive breast cancer is associated with decreased sensitivity to tamoxifen treatment and reduced overall survival of postmenopausal women. AB - BACKGROUND: The sensitivity of estrogen receptor-positive breast cancers to tamoxifen treatment varies considerably, and the molecular mechanisms affecting the response rates are manifold. The human epidermal growth factor receptor related receptor HER2 is known to trigger intracellular signaling cascades that modulate the activity of coregulators of the estrogen receptor which, in turn, reduces the cell sensitivity to tamoxifen treatment. However, the impact of HER2 related receptor tyrosine kinases HER1, HER3, and, in particular, HER4 on endocrine treatment is largely unknown. METHODS: Here, we retrospectively evaluated the importance of HER4 expression on the outcome of tamoxifen- and aromatase inhibitor-treated estrogen receptor-positive breast cancer patients (n = 258). In addition, we experimentally analyzed the efficiency of tamoxifen treatment as a function of HER4 co-expression in vitro. RESULTS: We found a significantly improved survival in tamoxifen-treated postmenopausal breast cancer patients in the absence of HER4 compared with those with pronounced HER4 expression. In accordance with this finding, the sensitivity to tamoxifen treatment of estrogen and HER4 receptor-positive ZR-75-1 breast cancer cells can be significantly enhanced by HER4 knockdown. CONCLUSION: We suggest an HER4/estrogen receptor interaction that impedes tamoxifen binding to the estrogen receptor and reduces treatment efficiency. Whether the sensitivity to tamoxifen treatment can be enhanced by anti-HER4 targeting needs to be prospectively evaluated. PMID- 30458881 TI - Saccharomyces cerevisiae adapted to grow in the presence of low-dose rapamycin exhibit altered amino acid metabolism. AB - BACKGROUND: Rapamycin is a potent inhibitor of the highly conserved TOR kinase, the nutrient-sensitive controller of growth and aging. It has been utilised as a chemotherapeutic agent due to its anti-proliferative properties and as an immunosuppressive drug, and is also known to extend lifespan in a range of eukaryotes from yeast to mammals. However, the mechanisms through which eukaryotic cells adapt to sustained exposure to rapamycin have not yet been thoroughly investigated. METHODS: Here, S. cerevisiae response to long-term rapamycin exposure was investigated by identifying the physiological, transcriptomic and metabolic differences observed for yeast populations inoculated into low-dose rapamycin-containing environment. The effect of oxygen availability and acidity of extracellular environment on this response was further deliberated by controlling or monitoring the dissolved oxygen level and pH of the culture. RESULTS: Yeast populations grown in the presence of rapamycin reached higher cell densities complemented by an increase in their chronological lifespan, and these physiological adaptations were associated with a rewiring of the amino acid metabolism, particularly that of arginine. The ability to synthesise amino acids emerges as the key factor leading to the major mechanistic differences between mammalian and microbial TOR signalling pathways in relation to nutrient recognition. CONCLUSION: Oxygen levels and extracellular acidity of the culture were observed to conjointly affect yeast populations, virtually acting as coupled physiological effectors; cells were best adapted when maximal oxygenation of the culture was maintained in slightly acidic pH, any deviation necessitated more extensive readjustment to additional stress factors. PMID- 30458884 TI - Cost-effectiveness of nivolumab plus ipilimumab as first-line therapy in advanced renal-cell carcinoma. AB - BACKGROUND: Nivolumab plus ipilimumab improves overall survival and is associated with less toxicity compared with sunitinib in the first-line setting of advanced renal-cell carcinoma (RCC). The current study aimed to assess the cost effectiveness of nivolumab plus ipilimumab for first-line treatment of advanced RCC from the payer perspectives high- and middle-income regions. METHODS: A decision-analytic model was constructed to evaluate the health and economic outcomes of first-line sunitinib and nivolumab plus ipilimumab treatment associated with advanced RCC. The clinical and utility data were obtained from published reports. The cost data were acquired for the payer perspectives of the United States (US), United Kingdom (UK), and China. Sensitivity analyses were performed to test the uncertainties of the results. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were used. RESULTS: Nivolumab plus ipilimumab gained 0.70-0.76 QALYs compared with sunitinib. Our analysis determined the following ICERs for nivolumab plus ipilimumab over sunitinib in first-line advanced RCC treatment: US $ 85,506 /QALY; UK $ 126,499/QALY; and China $ 4682/QALY. Sensitivity analyses found the model outputs to be most affected for body weight and for the prices of nivolumab, sunitinib and ipilimumab. CONCLUSIONS: Nivolumab plus ipilimumab as first-line treatment could gain more health benefits for advanced RCC in comparison with standard sunitinib, which is considered to be cost-effective in the US and China but not in the UK. PMID- 30458883 TI - Matrine attenuates endoplasmic reticulum stress and mitochondrion dysfunction in nonalcoholic fatty liver disease by regulating SERCA pathway. AB - BACKGROUND: Endoplasmic reticulum (ER) stress, which can promote lipid metabolism disorders and steatohepatitis, contributes significantly to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Calcium (Ca2+) homeostasis is considered to play a key role in ER stress. Matrine (Mat) has been applied for the treatment of hepatitis B, but its effect on NAFLD is still unknown, and there is no unified view of Mat on the regulation of ER stress in the previous literature. METHODS: The pharmacological effects were studied in high-fat-diet or methionine-choline-deficient diet induced C57BL/6J mice models and in palmitic acid (PA) induced L02 human liver cell model. Calcium fluorescence experiments, computational virtual docking analysis and biochemical assays were used in identifying the locus of Mat. RESULTS: The results showed that Mat-treated mice were more resistant to steatosis in the liver than vehicle-treated mice and that Mat significantly reduced hepatic inflammation, lipid peroxides. The beneficial effect of Mat was associated with suppressing ER stress and restoring mitochondrial dysfunction. Additionally, Mat decreased the PA-induced lipid accumulation, ER stress and cytosolic calcium level ([Ca2+]c) in hepatocyte cell lines in low and middle dose. However, the high dose Mat did not show satisfactory results in cell model. Calcium fluorescence experiments showed that Mat was able to regulate [Ca2+]c. By computational virtual docking analysis and biochemical assays, Mat was shown to influence [Ca2+]c via direct inhibition of SERCA. CONCLUSIONS: The results showed that the bi-directional regulation of Mat to endoplasmic reticulum at different doses was based on the inhibition of SERCA. In addition, the results also provide a theoretical basis for Mat as a potential therapeutic strategy in NAFLD/NASH. PMID- 30458885 TI - An early diagnosis of trichorhinophalangeal syndrome type 1: a case report and a review of literature. AB - BACKGROUND: Trichorhinophalangeal syndrome (TRPS) is a rare autosomal dominant disorder caused by defects involving the TRPS1 gene. It exhibits distinctive craniofacial, ectodermal and skeletal abnormalities, such as sparse hair, bulbous nasal tip and short deformed fingers, with extremely variable expressivity. CASE PRESENTATION: We report the case of a 17 months old girl, who presented growth retardation and dysmorphic features. Postnatal growth was always below - 2 Standard Deviation for both weight and length and physical examination revealed relative macrocephaly, sparse hair, bulbous nasal tip, thin upper lip, protruding ears, prominent forehead, small jaw, and short hands and feet. Patient's mother shared the same facial features, and presented sparse hair and small hands. The maternal grandfather and two uncles presented short stature, bulbous nasal tip, thin hair, and premature alopecia. Molecular analysis of TRPS1 gene showed a heterozygous c.2086C > T;(p.Arg696Ter) mutation both in the patient and her mother, confirming the diagnosis of TRPS, type I. CONCLUSIONS: Clinical phenotype of TRPS can be subtle and the syndrome often remains undiagnosed. A comprehensive clinical examination and an exhaustive family history are crucial to reach the correct diagnosis, which is essential to perform adequate follow-up and timely therapeutic procedures. PMID- 30458880 TI - Microcirculatory perfusion disturbances in septic shock: results from the ProCESS trial. AB - BACKGROUND: We sought to determine the effects of alternative resuscitation strategies on microcirculatory perfusion and examine any association between microcirculatory perfusion and mortality in sepsis. METHODS: This was a prospective, formally designed substudy of participants in the Protocolized Care in Early Septic Shock (ProCESS) trial. We recruited from six sites with the equipment and training to perform these study procedures. All subjects were adults with septic shock, and each was assigned to alternative resuscitation strategies. The two main analyses assessed (1) the impact of resuscitation strategies on microcirculatory perfusion parameters and (2) the association of microcirculatory perfusion with 60-day in-hospital mortality. We measured sublingual microcirculatory perfusion using sidestream dark field in vivo video microscopy at the completion of the 6-h ProCESS resuscitation protocol and then again at 24 and 72 h. RESULTS: We enrolled 207 subjects (demographics were similar to the overall ProCESS cohort) and observed 40 (19.3%) deaths. There were no differences in average perfusion characteristics between treatment arms. Analyzing the relationship between microcirculatory perfusion and mortality, we found an association between vascular density parameters and mortality. Total vascular density (beta = 0.006, p < 0.003), perfused vascular density (beta = 0.005, p < 0.04), and De Backer score (beta = 0.009, p < 0.01) were higher overall in survivors in a generalized estimating equation model, and this association was significant at the 72-h time point (p < 0.05 for each parameter). CONCLUSIONS: Microcirculatory perfusion did not differ between three early septic shock treatment arms. We found an association between microcirculatory perfusion parameters of vascular density at 72 h and mortality. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00510835 . Registered on August 2, 2007. PMID- 30458886 TI - Insulin-like growth factor receptor signaling in breast tumor epithelium protects cells from endoplasmic reticulum stress and regulates the tumor microenvironment. AB - BACKGROUND: Early analyses of human breast cancer identified high expression of the insulin-like growth factor type 1 receptor (IGF-1R) correlated with hormone receptor positive breast cancer and associated with a favorable prognosis, whereas low expression of IGF-1R correlated with triple negative breast cancer (TNBC). We previously demonstrated that the IGF-1R acts as a tumor and metastasis suppressor in the Wnt1 mouse model of TNBC. The mechanisms for how reduced IGF-1R contributes to TNBC phenotypes is unknown. METHODS: We analyzed the METABRIC dataset to further stratify IGF-1R expression with patient survival and specific parameters of TNBC. To investigate molecular events associated with the loss of IGF-1R function in breast tumor cells, we inhibited IGF-1R in human cell lines using an IGF-1R blocking antibody and analyzed MMTV-Wnt1-mediated mouse tumors with reduced IGF-1R function through expression of a dominant-negative transgene. RESULTS: Our analysis of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset revealed association between low IGF-1R and reduced overall patient survival. IGF-1R expression was inversely correlated with patient survival even within hormone receptor-positive breast cancers, indicating reduced overall patient survival with low IGF-1R was not due simply to low IGF-1R expression within TNBCs. Inhibiting IGF-1R in either mouse or human tumor epithelial cells increased reactive oxygen species (ROS) production and activation of the endoplasmic reticulum stress response. IGF-1R inhibition in tumor epithelial cells elevated interleukin (IL)-6 and C-C motif chemokine ligand 2 (CCL2) expression, which was reversed by ROS scavenging. Moreover, the Wnt1/dnIGF-1R primary tumors displayed a tumor-promoting immune phenotype. The increased CCL2 promoted an influx of CD11b+ monocytes into the primary tumor that also had increased matrix metalloproteinase (MMP)-2, MMP-3, and MMP-9 expression. Increased MMP activity in the tumor stroma was associated with enhanced matrix remodeling and collagen deposition. Further analysis of the METABRIC dataset revealed an increase in IL-6, CCL2, and MMP-9 expression in patients with low IGF 1R, consistent with our mouse tumor model and data in human breast cancer cell lines. CONCLUSIONS: Our data support the hypothesis that reduction of IGF-1R function increases cellular stress and cytokine production to promote an aggressive tumor microenvironment through infiltration of immune cells and matrix remodeling. PMID- 30458887 TI - Long term follow-up demonstrating stability and patient satisfaction of minimally invasive punch technique for percutaneous bone anchored hearing devices. AB - OBJECTIVE: Minimally Invasive Ponto Surgery (MIPS) was recently described to facilitate the placement of percutaneous bone anchored hearing devices. As early adopters of this new procedure, we sought to perform a quality assurance project using our own small prospective cohort to justify this change in practice. We chose to examine device stability and to gauge our patients' perspective of the surgery and their overall satisfaction with the process. METHODS: A total of 12 adult patients who underwent MIPS between 2016 and 2017 with a minimum post operative follow-up of 12 months were included in this study. A prospective MIPS research clinic was used to follow patients, assess the implant site soft tissue status and gather qualitative information through patient interviews and surveys. RESULTS: The mean (SD) soft tissue status score averages using the IPS Scale were low for inflammation 0.1 (0.1), pain 0.1 (0.1), skin height 0.2 (0.1) and total IPS score 0.4 (0.3) indicating minimal soft tissue changes. Patient experiences with MIPS were overwhelmingly positive in reports through the MIPS modified SSQ 8. All patients reported speedy recoveries and no long-term complications. There were zero device losses. CONCLUSION: The series presented in this paper represents the first MIPS cohort with long term follow-up to be published to date in North America. Our findings conclude both device stability and patient satisfaction with no loss of fixtures. Consequently, we have adopted MIPS as our procedure of choice for the placement of all percutaneous BAHDs. PMID- 30458888 TI - Acquired resistance to immunotherapy in MMR-D pancreatic cancer. AB - BACKGROUND: MMR-D pancreatic cancer have been reported to respond to checkpoint inhibitor therapy. Here, we report the first case of acquired resistance to immunotherapy in MMR-D pancreatic cancer. CASE PRESENTATION: A 45-year-old woman with unresectable MMR-D pancreatic cancer was initially treated with FOLFIRINOX, FOLFIRI, and stereotactic body radiation with stable disease burden. After 3 months, imaging showed progression of disease with an increase in CA19-9. She was subsequently enrolled in a clinical trial of an anti-PD-L1 antibody in combination with an IDO1 inhibitor. She demonstrated a partial response to therapy by RECIST 1.1 criteria with declining tumor markers. Twenty-two months after beginning immunotherapy, imaging revealed an increasing left ovarian cystic mass. There were no other sites of progressive disease. The patient underwent a total hysterectomy and bilateral salpingo-oophorectomy, appendectomy, omentectomy and pelvic lymphadenopathy. Pathology was consistent with a metastasis from the pancreas involving the endometrium and left ovary. Thereafter, the patient continued with PD-1 blockade therapy off protocol with no further progressive disease. Immune profiling showed high levels of CD8+ T cells and PD-1 positive immune cells infiltrating the tumor, with a moderate level of PD-L1 expression in both the immune cells and the tumor cells. Next generation sequencing found only the KRAS G12D and RNF43 G659Vfs*41 mutations were retained from the pre-treatment tumor in the treatment-resistant tumor. CONCLUSIONS: This is the first report describing acquired resistance to immunotherapy in MMR-D pancreatic cancer with accompanying genomic and immune profiling. This case of oligoprogression in the setting of immunotherapy demonstrates the feasibility of localized treatment followed by continuation of immunotherapy to sustain ongoing response. PMID- 30458890 TI - Informant-specific reports of peer and teacher relationships buffer the effects of harsh parenting on children's oppositional defiant disorder during kindergarten. AB - Harsh and restrictive parenting are well-established contributors to the development of oppositional defiant disorder (ODD) among children. However, few studies have explored whether interpersonal relationships that develop outside the family environment attenuate the risk for ODD that is associated with harsh parenting. The current study tested multireporter measures of teacher-child closeness and peer acceptance as moderators of the association between harsh parenting and children's ODD as children's social worlds widen during the kindergarten year (N = 338 children, 48% girls, M age = 5.32 years). Harsh parenting interacted with peer nominations of peer acceptance and children's report of teacher-child closeness to predict children's ODD symptoms in the spring, adjusting for fall symptoms. Children exposed to harsh parenting exhibited greater symptom increases when they were less liked/accepted playmates and in the context of lower teacher-child closeness. However, harsh parenting was not associated with symptom change among children with higher levels of peer nominated acceptance and those who reported closer relationships with teachers. There were no significant interactions using teacher's report of peer acceptance or teacher's report of teacher-child closeness. Findings highlight positive peer and teacher relationships as promising targets of intervention among children exposed to harsh parenting and support the importance of assessing multiple perspectives of children's social functioning. PMID- 30458891 TI - Impact of a dietary challenge with peroxidized oil on the glutathione redox status and integrity of the small intestine in weaned piglets. AB - Glutathione (GSH) is considered to play an important role in maintaining the integrity of the small intestine. In piglets, altered mucosal GSH levels might therefore be involved in weaning-induced changes of the small intestinal morphology and barrier function. To test this hypothesis, we aimed to challenge the mucosal GSH redox status during the first 28 days after weaning, by feeding diets containing 5% fresh linseed oil (CON), or 2.5% (OF1) or 5% (OF2) peroxidized linseed oil (peroxide value 225 mEq O2/kg oil) and exploring the effects on gut integrity. Piglets were pair-fed and had a total daily feed allowance of 32 g/kg BW. A fourth treatment included animals that were fed the control diet ad libitum (ACON). Animals were sampled at days 5 and 28 post weaning. The malondialdehyde (MDA) concentration and GSH redox status (GSH/GSSG Eh) were determined in blood, liver and small intestinal mucosa. Histomorphology of the duodenal and jejunal mucosa was determined, and Ussing chambers were used to assess fluorescein isothiocyanate dextran (FD4) and horseradish peroxidase (HRP) fluxes across the mucosa. Results show that peroxidized linseed oil imposed an oxidative challenge at day 28, but not at day 5 post-weaning. At day 28, increasing levels of dietary peroxides to pair-fed pigs linearly increased MDA levels in duodenal and jejunal mucosa. Moreover, FD4 fluxes were significantly increased in OF1 (+75%) and OF2 (+64%) in the duodenum, and HRP fluxes tended (P=0.099) to show similar differences, as compared to CON. This co-occurred with a significant 11 mV increase of the hepatic GSH/GSSG Eh, potentiated by a significantly increased GSH peroxidase activity for treatments OF1 (+47%) and OF2 (+63%) in liver as compared to CON. Furthermore; duodenal HRP flux significantly correlated with the hepatic glutathione disulphide (GSSG) level (r=0.650), as also observed in the jejunum for hepatic GSSG (r=0.627) and GSH/GSSG Eh (r=0.547). The jejunal permeability was not affected, but FD4 and HRP fluxes significantly correlated with the local GSH (r=0.619; r=0.733) and GSSG (r=0.635; r=0586) levels. Small intestinal histomorphology was not affected by dietary lipid peroxides, nor were there any correlations found with the GSH redox system. To conclude, under oxidative stress conditions, jejunal barrier function is related to the local and hepatic GSH redox system. It is suggested that the hepatic GSH system participates in the elimination of luminal peroxides, and thereby impacts on duodenal barrier function. PMID- 30458892 TI - Human Genetics Society of Australasia Position Statement: Genetic Testing and Personal Insurance Products in Australia. AB - The expansion of genetic and genomic testing in clinical practice and research and the growing market for at home personal genome testing has led to increased awareness about the impact of this form of testing on insurance. Genetic or genomic information can be requested by providers of mutually rated insurance products, who may then use it when setting premiums or determining eligibility for cover under a particular product. Australian insurers are subject to relevant legislation and an industry standard that was updated in late 2016. In 2018, the Human Genetics Society of Australasia updated its position statement on genetic testing and life insurance to account for these changes and to increase the scope of the statement to include a wider scope of insurance products that are not rated according to community risk, such as life, critical care, and income protection products. Recommendations include that providers of professional education involving genetics should include ethical, legal, and social aspects of insurance discrimination in their curricula; that the Australian government take a more active role in regulating use of genetic information in personal insurance, including enacting a moratorium on use of genetic test results; that information obtained in the course of a research project be excluded; and that there is improved engagement between the insurance industry, regulators, and the genetics profession. PMID- 30458893 TI - Review: passive immunity in beef-suckler calves. AB - Colostrum-derived passive immunity is central to the health, performance and welfare of neonatal beef-suckler calves, and economics of beef-farming enterprises. Compared to dairy calves, mainly Holstein-Friesian, there is much less research carried out on passive immunity and associated factors in beef calves. Thus, this review aimed to summarise and interpret published information and highlight areas requiring further research. The transfer of immunoglobulin G1 (IgG1) from blood to mammary secretions is greater for beef * dairy cows compared to most beef breed types. Considerable between-animal variance is evident in first-milking colostrum yield and immunoglobulin concentration of beef-suckler cow breed types. First-milking colostrum immunoglobulin concentrations are similar for within-quarter fractions and for the front and rear quarters of the udder. First-milking colostrum yield is higher for beef * dairy cows than beef * beef and purebred beef breeds, and higher for multiparous than primiparous cows, but generally colostrum immunoglobulin concentration is relatively similar for each of the respective categories. Consequently, colostrum immunoglobulin mass (volume * concentration) production in beef cows seems to be primarily limited by colostrum volume. The effect of maternal nutrition during late gestation on colostrum yield is not well documented; however, most studies provide evidence that colostrum immunoglobulin concentration is not adversely affected by under nutrition. Factors that impinge upon the duration between birth and first suckling, including dam parity, udder and teat anatomy and especially dystocia, negatively impact on calf passive immunity. Colostrum immunoglobulin mass ingested relative to birth weight post-parturition is the most important variable determining calf passive immunity. Research indicates that feeding the beef calf a colostrum volume equivalent to 5% of birth weight shortly after parturition, with subsequent suckling of the dam (or a second feed) 6 to 8 h later, ensures adequate passive immunity, equivalent to a well-managed suckling situation. Within beef-suckler cow genotypes, calf passive immunity is similar for many common beef breeds, but is generally higher for calves from beef * dairy cows. Compared to older cows, calves from younger cows, especially primiparous animals, have lower serum immunoglobulin concentrations. Most studies have shown no adverse impact of maternal dietary restriction on calf passive immunity. The prevalence of failure of passive transfer (FPT) in beef calves varies considerably across studies depending on the test used, and what cut-off value is assumed or how it is classified. The accuracy and precision of methodologies used to determine immunoglobulin concentrations is concerning; caution is required in interpreting laboratory results regarding defining colostrum 'quality' and calf passive immune 'status'. Further research is warranted on colostrum-related factors limiting passive immunity of beef calves, and on the validation of laboratory test cut-off points for determining FPT, based on their relationships with key health and performance measures. PMID- 30458894 TI - Robot utilisation of pasture-based dairy cows with varying levels of milking frequency. AB - Achieving a consistent level of robot utilisation throughout 24 h maximises automatic milking system (AMS) utilisation. However, levels of robot utilisation in the early morning hours are typically low, caused by the diurnal feeding behaviour of cows, limiting the inherent capacity and total production of pasture based AMS. Our objective was to determine robot utilisation throughout 24 h by dairy cows, based on milking frequency (MF; milking events per animal per day) in a pasture-based AMS. Milking data were collected from January and February 2013 across 56 days, from a single herd of 186 animals (Bos taurus) utilising three Lely A3 robotic milking units, located in Tasmania, Australia. The dairy herd was categorised into three equal sized groups (n=62 per group) according to the cow's mean daily MF over the duration of the study. Robot utilisation was characterised by an interaction (P< 0.001) between the three MF groups and time of day, with peak milking time for high MF cows within one h of a fresh pasture allocation becoming available, followed by the medium MF and low MF cows 2 and 4 h later, respectively. Cows in the high MF group also presented for milking between 2400 and 0600 h more frequently (77% of nights), compared to the medium MF group (57%) and low MF group (50%). This study has shown the formation of three distinct groups of cows within a herd, based on their MF levels. Further work is required to determine if this finding is replicated across other pasture-based AMS farms. PMID- 30458895 TI - Cognitive Indicators of Preclinical Behavioral Variant Frontotemporal Dementia in MAPT Carriers. AB - OBJECTIVES: The cognitive indicators of preclinical behavioral variant Frontotemporal Dementia (bvFTD) have not been identified. To investigate these indicators, we compared cross-sectional performance on a range of cognitive measures in 12 carriers of pathogenic MAPT mutations not meeting diagnostic criteria for bvFTD (i.e., preclinical) versus 32 demographically-matched familial non-carriers (n = 44). Studying preclinical carriers offers a rare glimpse into emergent disease, environmentally and genetically contextualized through comparison to familial controls. METHODS: Evaluating personnel blinded to carrier status administered a standardized neuropsychological battery assessing attention, speed, executive function, language, memory, spatial ability, and social cognition. Results from mixed effect modeling were corrected for multiplicity of comparison by the false discovery rate method, and results were considered significant at p < .05. To control for potential interfamilial variation arising from enrollment of six families, family was treated as a random effect, while carrier status, age, gender, and education were treated as fixed effects. RESULTS: Group differences were detected in 17 of 31 cognitive scores and spanned all domains except spatial ability. As hypothesized, carriers performed worse on specific measures of executive function, and social cognition, but also on measures of attention, speed, semantic processing, and memory storage and retrieval. CONCLUSIONS: Most notably, group differences arose on measures of memory storage, challenging long-standing ideas about the absence of amnestic features on neuropsychological testing in early bvFTD. Current findings provide important and clinically relevant information about specific measures that may be sensitive to early bvFTD, and advance understanding of neurocognitive changes that occur early in the disease. (JINS, 2018, 00, 1-11). PMID- 30458889 TI - Lipid nanoparticles that deliver IL-12 messenger RNA suppress tumorigenesis in MYC oncogene-driven hepatocellular carcinoma. AB - Interleukin-12 (IL-12) is a promising candidate for cancer immunotherapy because of its ability to activate a number of host immune subsets that recognize and destroy cancer cells. We found that human hepatocellular carcinoma (HCC) patients with higher than median levels of IL-12 have significantly favorable clinical outcomes. Here, we report that a messenger RNA (mRNA) lipid nanoparticle delivering IL-12 (IL-12-LNP) slows down the progression of MYC oncogene-driven HCC. IL-12-LNP was well distributed within the HCC tumor and was not associated with significant animal toxicity. Treatment with IL-12-LNP significantly reduced liver tumor burden measured by dynamic magnetic resonance imaging (MRI), and increased survival of MYC-induced HCC transgenic mice in comparison to control mice. Importantly, IL-12-LNP exhibited no effect on transgenic MYC levels confirming that its therapeutic efficacy was not related to the downregulation of a driver oncogene. IL-12-LNP elicited marked infiltration of activated CD44+ CD3+ CD4+ T helper cells into the tumor, and increased the production of Interferon gamma (IFNgamma). Collectively, our findings suggest that IL-12-LNP administration may be an effective immunotherapy against HCC. PMID- 30458896 TI - Overlapping dimensional phenotypes of impulsivity and compulsivity explain co occurrence of addictive and related behaviors. AB - OBJECTIVE: Impulsivity and compulsivity have been implicated as important transdiagnostic dimensional phenotypes with potential relevance to addiction. We aimed to develop a model that conceptualizes these constructs as overlapping dimensional phenotypes and test whether different components of this model explain the co-occurrence of addictive and related behaviors. METHODS: A large sample of adults (N=487) was recruited through Amazon's Mechanical Turk and completed self-report questionnaires measuring impulsivity, intolerance of uncertainty, obsessive beliefs, and the severity of 6 addictive and related behaviors. Hierarchical clustering was used to organize addictive behaviors into homogenous groups reflecting their co-occurrence. Structural equation modeling was used to evaluate fit of the hypothesized bifactor model of impulsivity and compulsivity and determine the proportion of variance explained in the co occurrence of addictive and related behaviors by each component of the model. RESULTS: Addictive and related behaviors clustered into 2 distinct groups: Impulse-Control Problems, consisting of harmful alcohol use, pathological gambling, and compulsive buying, and Obsessive-Compulsive-Related Problems, consisting of obsessive-compulsive symptoms, binge eating, and internet addiction. The hypothesized bifactor model of impulsivity and compulsivity provided the best empirical fit, with 3 uncorrelated factors corresponding to a general Disinhibition dimension, and specific Impulsivity and Compulsivity dimensions. These dimensional phenotypes uniquely and additively explained 39.9% and 68.7% of the total variance in Impulse-Control Problems and Obsessive Compulsive-Related Problems. CONCLUSION: A model of impulsivity and compulsivity that represents these constructs as overlapping dimensional phenotypes has important implications for understanding addictive and related behaviors in terms of shared etiology, comorbidity, and potential transdiagnostic treatments. PMID- 30458897 TI - Production Effect in Adults With ADHD With and Without Methylphenidate (MPH): Vocalization Improves Verbal Learning. AB - OBJECTIVES: Reading aloud (vocal production) enhances memory relative to reading silently, the Production Effect (PE) in memory. Thus, vocalization has been suggested as a mnemonic device. The current study tested the PE in a sample of adults with ADHD and in a control sample, evaluating verbal learning. METHODS: Twenty adults with ADHD and 21 controls learned a list of words, half by reading aloud and half by reading silently. Free recall test followed. The participants with ADHD performed the task twice (in two different sessions in a counterbalanced order), before self-administration of a single dose of methylphenidate (MPH) and 60-min after dosage. RESULTS: PEs were found for all groups. Memory was better for the controls than for the ADHD group (with or without MPH). In the ADHD group, recall rates and the PE were higher with than without MPH. CONCLUSIONS: These results suggest that vocalization yields a larger memory gain with MPH. Possibly, MPH enables the ADHD participants to better shift their attention to the aloud words, enhancing their retrieval rates. Theoretically, these findings stress the role of attention in the PE. (JINS, 2018, 00, 1-6). PMID- 30458898 TI - Myelitis with Hypoglycorrhachia due to Herpes Simplex Virus 2 in an Immunocompetent Man. PMID- 30458899 TI - Valbenazine and Deutetrabenazine as possible treatments for neuroleptic-induced supersensitivity psychosis and antipsychotic dependence. PMID- 30458900 TI - Cinnamon - Differentiation of Four Species by Linking Classical Botany to an Automated Chromatographic Authentication System. AB - One of the world's oldest spices, cinnamon is also one of the most popular. Species of the genus Cinnamomum offer a variety of extractable oils with aroma and flavor characteristics of importance to the flavor industry, so differentiating cinnamon samples for culinary-based applications is very important. Cinnamon also has reported health benefits associated with specific phytochemical constituents, but its composition can vary greatly depending on species and source region. A substantial amount of the research reported on cinnamon does not provide thorough documentation of the source and taxonomic identification of the study material, a very common issue with studies of food and medicinal plants. In the interest of providing some clarity to the discussion of the health benefits and culinary attributes of the different cinnamon types in the marketplace, we offer the results of a long-term chemotaxonomic study of cinnamon samples sourced from different regions of the world and link those chemical data to classical taxonomic identification of the source plants. We provide details of the effective use of an automated chemotaxonomic analytical method to differentiate cinnamons from various geographic regions. Also included are chromatographic data for the polyphenolic/procyanidin fractions of each species, as cinnamon type-A procyanidins are often the purported source of biological activity in cinnamon and cinnamon extracts. PMID- 30458901 TI - Validation of Biomode S.A. Probe4CronobacterTM for the Identification of Cronobacter spp. By AOAC Research Institute. AB - Background: Probe4Cronobacter test kit is based on the use of a fluorescence labeled peptide nucleic acid probe (PNA) allied to fluorescence microscopy. A sample is taken after a 24 h enrichment of rehydrated 30 g portions of powdered infant formula (PIF). The method uses ready to use dropper solutions applied directly in the sample. This simple process takes less than 2 h to provide a result. In the presence of Cronobacter species, bright red rod-shaped cells will be visible under a fluorescence microscope. Objective: Probe4Cronobacter validation as a new method for the detection Cronobacter species in Powdered Infant Formula (PIF) under the AOAC Performance Tested MethodsSM (License No. 081702). Methods: The validation study encompassed matrix comparison study, inclusivity and exclusivity testing and robustness studies (stability, kit variation, and ruggedness). Results: The inclusivity and exclusivity testing (50 and 35 strains, respectively) yielded no false negative or false positive results. Probe4Cronobacter was compared to the ISO/TS 22964:2006 in 30 g of PIF samples within method comparison in an unpaired study. A total of 30 samples with both low and high level of inoculation were analyzed by Probe4Cronobacter and compared to the same number of samples screened by ISO/TS 22964:2006. No statistically significant differences between presumptive and confirmed results or between candidate and reference method results were observed. Robustness studies showed a high level of consistency and integrity of the kit when different parameters were varied. The deviation conditions tested did not affect the performance of the kit. Conclusions: Probe4Cronobacter test kit has shown to be a accurate, highly sensitive and robust methods for the detection of Cronobacter spp. in PIF samples. PMID- 30458903 TI - Match Made in Heaven. PMID- 30458902 TI - Effects of Rodent Thermoregulation on Animal Models in the Research Environment. AB - To best promote animal wellbeing and the efficacy of biomedical models, scientific, husbandry, and veterinary professionalsmust consider the mechanisms, influences, and outcomes of rodent thermoregulation in contemporary research environments.Over the last 2 decades, numerous studies have shown that laboratory mice and rats prefer temperatures that are several degrees warmer than the environments in which they typically are housed within biomedical facilities. Physiologic changes torodents that are cage-housed under standard temperatures (20 to 26 degrees C) are attributed to 'cold stress' and include alterationsin metabolism, cardiovascular parameters, respiration, and immunologic function. This review article describes commonbehavioral and physiologic adaptations of laboratory mice and rats to cold stress within modern vivaria, with emphasis onenvironmental enrichment and effects of anesthesia and procedural support efforts. In addition, potential interventions andoutcomes for rodents are presented, relative to the importance of repeating and reproducing experiments involving laboratoryrodent research models of human disease. PMID- 30458904 TI - Chronic Care Management: An Emerging Opportunity for Pharmacists. AB - Chronic care management (CCM) aims to improve health outcomes by enhancing care coordination for patients with multiple chronic conditions. However, few incentives have been provided in recent years for health care professionals to engage in models that improve care coordination. These potential models could help avoid poor health outcomes that lead to hospitalizations and rehospitalizations. Fortunately, in January 2015, under Medicare's physician fee schedule, Medicare began paying separately for CCM services. Qualified health care providers are reimbursed for these coordination of care services. Though pharmacists cannot bill Medicare for these services, they are in a prime position to deliver CCM services and be paid by forming contractual and collaborative partnerships with qualified providers. CCM bridges the gap between fee-for service and value-based payment models by focusing on care coordination among health care providers. PMID- 30458905 TI - Potentially Inappropriate Medication Use Among Institutionalized Older Adults at Nursing Homes in Puerto Rico. AB - OBJECTIVES: Prevalence of potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs). DESIGN: Cross-sectional study through review of residents' records. SETTING: Three nursing homes of Puerto Rico's metropolitan area. PARTICIPANTS: Nursing home residents. INTERVENTION: Records of residents 65 years of age and older with documented medications and chronic diseases were reviewed. Hospitalized and hospice/palliative care residents were excluded. Beers criteria-2015 and START-STOPP criteria-2014 were applied to identify PIMs and PPOs. Beers criteria versus STOPP criteria findings were compared. MAIN OUTCOME MEASURE: Prevalence of PIMs and PPOs in relation to residents' baseline characteristics. RESULTS: One hundred four records were reviewed. Categorical variables were analyzed by Fisher's exact test and chi square test; t-tests established a relationship between variables and the prevalence of PIMs and PPOs. The quantity of PIMs was analyzed through frequency and percentage values. A statistically significant correlation was found between prescribed medications and PIMs detected using Beers criteria (P-value = 0.031) and STOPP modified criteria (P-value = 0.0002). No statistically significant data were obtained from the START criteria. CONCLUSION: Beers criteria were more effective identifying PIMs compared with STOPP criteria. The number of prescribed medications correlated directly to the number of identified PIMs. Additional studies where these tools are applied, and clinical pharmacist interventions are performed, should confirm an improved management of nursing home residents' drug therapy in Puerto Rico. PMID- 30458906 TI - Deprescribing in Primary Care in Singapore: Barriers and Facilitators. AB - OBJECTIVES: To describe the prevalence of potentially inappropriate medications (PIMs) in older patients (65 years of age and older) in three selected polyclinics (PCs) and gather the perceptions of the health care providers in these PCs on the barriers and facilitators of deprescribing in their practice. To analyze the patients' age, number of active chronic diseases, and number of medicines, and investigate if they could influence the presence of PIMs. DESIGN: The study has two separate parts: The first part is a retrospective cross sectional data collection of prescriptions; the second part is a prospective cross-sectional analysis of questionnaires by health care providers. SETTING: The study is in an institutional primary care setting. PATIENTS, PARTICIPANTS: Prescriptions were from 210 randomly selected patients 65 years of age or older with at least five long-term medications, who had attended the PCs over a selected 10-day period. Health care providers from the PCs were surveyed via an anonymous questionnaire. RESULTS: The prevalence of PIMs is 44% of the prescriptions. The most prevalent PIM is "long-term proton pump inhibitor (PPI) without documented indication" at 45.7%. The number of active chronic diseases and total number of medications are associated with prevalence of PIMs. Facilitators and barriers of deprescribing highlighted are motivation and goals of the health care providers, knowledge, lack of time for deprescribing, and communication between specialists and primary care providers. CONCLUSION: PPI is a feasible drug class to start deprescribing in primary care. Knowing the barriers and facilitators would set the impetus for future work to make deprescribing more widespread and acceptable for primary care in Singapore. PMID- 30458907 TI - Clinically Significant Food-Drug Interactions. AB - OBJECTIVE: Provide an up-to-date review for health care providers regarding clinically significant food-drug interactions and summarize recommendations for optimal medication administration in older adults and long-term care patients. DATA SOURCES: A literature search was performed using MEDLINE, PUBMED, and IPA abstracts to locate relevant articles published between January 1982 and July 2017. DAILYMED was used to identify manufacturer-specific medication administration recommendations. STUDY SELECTION AND DATA EXTRACTION: Articles were reviewed for inclusion based on their relevance to this subject matter and the integrity of the information provided. Additionally, the package labeling of included products was reviewed. DATA SYNTHESIS: The current recommendations for specific medication administration with regard to food are summarized descriptively. CONCLUSION: Clinically significant food-drug interactions are common and have been reported with multiple classes of medications. However, there are a limited number of studies examining food-drug interactions, and the majority of recommendations are made by product-specific manufacturers. Pharmacists should be aware of common food-drug interactions in the community, assisted living, long-term care, subacute care, and hospital settings. To optimize medication therapy and improve therapeutic outcomes, it is important for pharmacists and other health care providers to identify agents with potential for food-drug interactions and to understand the clinical relevance of such interactions. PMID- 30458908 TI - Management of Non-Cystic Fibrosis Bronchiectasis. AB - OBJECTIVE: The purpose of this report is to describe the case of a 43-year-old male with asthma who was hospitalized for an exacerbation of non-cystic fibrosis bronchiectasis (NCFB), a chronic lung disease that is characterized by dilation of the airways, persistent cough, chronic sputum production, and recurrent respiratory infections. He was treated with oral and inhaled antibiotics, inhaled bronchodilators, and aggressive airway-clearance techniques including nebulized 7% sodium chloride, flutter valve, and high-frequency chest wall oscillation. SETTINGS: Community pharmacy, nursing facility pharmacy, consultant pharmacy practice. PRACTICE CONSIDERATIONS: As the number of patients diagnosed with NCFB continues to increase, it is crucial to recognize that specific guidance for management of NCFB is warranted, as treatment responses differ from cystic fibrosis bronchiectasis or chronic obstructive pulmonary disease. CONCLUSION: It is important for pharmacists to understand the pharmacologic and nonpharmacologic treatments for NCFB to better assist physicians and patients and improve therapeutic outcomes. PMID- 30458909 TI - The Prescription Drug Cost-Containment Debate: The Outcome Affects Us. PMID- 30458910 TI - Antimicrobial prescribing and infections in long-term care facilities (LTCF): a multilevel analysis of the HALT 2016 study, Ireland, 2017. AB - BackgroundThe 2016 point prevalence survey (PPS) of healthcare-associated infections (HAI) and antimicrobial use (AMU) in Irish long-term care facilities (LTCF) (HALT) showed a 9.8% AMU and 4.4% HAI prevalence, based on aggregated data analysis.AimOur aim was to identify institutional and resident risk factors of AMU and HAI.MethodsHALT 2016 gathered information using institutional and resident questionnaires, for residents who met the surveillance definition of active HAI and/or AMU, limiting analysis to the aggregated institutional level. In January 2017, we requested additional data on age, sex, urinary catheter use and disorientation of current residents from HALT 2016 LTCF and matched to 2016 HALT data.ResultsOf 224 HALT 2016 LTCF, 80 provided additional information on 3,816 residents; prevalence of AMU was 10.6% and HAI was 4.7%. Presence of a coordinating physician (Odds ratio (OR): 0.3; 95% confidence interval (CI): 0.2 0.6), antimicrobial stewardship committee (OR: 0.2; 95%; CI: 0.1-0.6), healthcare assistants (OR: 0.9; 95% CI: 0.9-1.0), antimicrobial consumption feedback (OR: 0.3; 95% CI: 0.1-0.6) and medical care by personal general practitioner (OR: 0.6; 95% CI: 0.7-1.0) were associated with less AMU and feedback on surveillance of infection prevention and control (IPC) practices (OR: 0.6; 95% CI: 0.3-1.0) with less HAI. AMU and HAI varied significantly between LTCF.ConclusionsMultilevel modelling identified significant inter-facility variation, as well as institutional factors associated with AMU and HAI. An antimicrobial stewardship committee linked with feedback on IPC and prescribing was associated with reduced AMU and HAI. PMID- 30458911 TI - Severe enterovirus A71 associated hand, foot and mouth disease, Vietnam, 2018: preliminary report of an impending outbreak. AB - Since January 2018, over 53,000 hospitalisations and six deaths due to hand, foot and mouth disease (HFMD) have occurred across Vietnam with most cases from September onward. In a large tertiary referral hospital, Ho Chi Minh City, enterovirus A71 subgenogroup C4 was predominant, while B5 was only sporadically detected. The re-emergence of C4 after causing a severe HFMD outbreak with > 200 deaths in 2011-12 among susceptible young children raises concern of another impending severe outbreak. PMID- 30458912 TI - Prevalence of healthcare-associated infections, estimated incidence and composite antimicrobial resistance index in acute care hospitals and long-term care facilities: results from two European point prevalence surveys, 2016 to 2017. AB - Point prevalence surveys of healthcare-associated infections (HAI) and antimicrobial use in the European Union and European Economic Area (EU/EEA) from 2016 to 2017 included 310,755 patients from 1,209 acute care hospitals (ACH) in 28 countries and 117,138 residents from 2,221 long-term care facilities (LTCF) in 23 countries. After national validation, we estimated that 6.5% (cumulative 95% confidence interval (cCI): 5.4-7.8%) patients in ACH and 3.9% (95% cCI: 2.4-6.0%) residents in LTCF had at least one HAI (country-weighted prevalence). On any given day, 98,166 patients (95% cCI: 81,022-117,484) in ACH and 129,940 (95% cCI: 79,570-197,625) residents in LTCF had an HAI. HAI episodes per year were estimated at 8.9 million (95% cCI: 4.6-15.6 million), including 4.5 million (95% cCI: 2.6-7.6 million) in ACH and 4.4 million (95% cCI: 2.0-8.0 million) in LTCF; 3.8 million (95% cCI: 3.1-4.5 million) patients acquired an HAI each year in ACH. Antimicrobial resistance (AMR) to selected AMR markers was 31.6% in ACH and 28.0% in LTCF. Our study confirmed a high annual number of HAI in healthcare facilities in the EU/EEA and indicated that AMR in HAI in LTCF may have reached the same level as in ACH. PMID- 30458913 TI - Antimicrobial use in European long-term care facilities: results from the third point prevalence survey of healthcare-associated infections and antimicrobial use, 2016 to 2017. AB - Antimicrobials are commonly prescribed and contribute to the development of antimicrobial resistance in long-term care facilities (LTCFs). In 2010, the European Centre for Disease Prevention and Control initiated point prevalence surveys (PPS) of healthcare-associated infections and antimicrobial use in European LTCFs, performed by external contractors as the Healthcare-Associated infections in Long-Term care facilities (HALT) projects. Here, we investigated prevalence and characteristics of antimicrobial use and antimicrobial stewardship indicators in European LTCFs in 2016-17. Twenty-four European Union/European Economic Area (EU/EEA) countries, the former Yugoslav Republic of Macedonia and Serbia participated in the third PPS in European LTCFs. Overall, 4.9% (95% confidence interval: 4.8-5.1) of LTCF residents in the EU/EEA participating countries received at least one antimicrobial. The most commonly reported Anatomical Therapeutic Chemical (ATC) groups were beta-lactam antibacterials/penicillins (J01C), other antibacterials (J01X) (e.g. glycopeptide antibacterials, polymyxins), quinolones (J01M), sulfonamides and trimethoprim (J01E), and other beta-lactams (J01D). Urinary tract infections and respiratory tract infections were the main indications for antimicrobial prescription. This PPS provides updated and detailed information on antimicrobial use in LTCFs across the EU/EEA that can be used to identify targets for future interventions, follow-up of these interventions and promote prudent use of antimicrobials in European LTCFs. PMID- 30458914 TI - Antimicrobial prescribing in long-term care facilities: a nationwide point prevalence study, Slovenia, 2016. AB - Residents in long-term care are at high risk of infections because of their old age and many related health problems that lead to frequent antibiotic prescribing. The aim of the study was to assess antibiotic use in Slovenian long term care facilities (LTCFs). The point-prevalence study was conducted between April and June 2016. Online questionnaires were sent to all Slovenian LTCFs. Eighty (68.4%) of the 117 LTCFs contacted, caring for 13,032 residents (70.6% of all Slovenian LTCF residents), responded to the survey. On the day of the study, the mean antibiotic prevalence per LTCF was 2.4% (95% confidence interval: 1.94 2.66). Most (70.2%) of the residents taking antibiotics were female. Most residents were being treated for respiratory tract (42.7%) or urinary tract (33.3%) infections. Co-amoxiclav and fluoroquinolones were the most frequently prescribed antibiotics (41.0% and 22.3% respectively). Microbiological tests were performed for 5.2% of residents receiving antibiotics. Forty nine (19.8%) residents receiving antibiotics were colonised with multidrug-resistant bacteria (MDR). Antibiotic use in Slovenian LTCFs is not very high, but most prescribed antibiotics are broad-spectrum. Together with low use of microbiological testing and high prevalence of colonisation with MDR bacteria the situation is worrisome and warrants the introduction of antimicrobial stewardship interventions. PMID- 30458916 TI - 7th Eurosurveillance scientific seminar 'Artificial intelligence (AI) in epidemiology: a reality in 2018?' at ESCAIDE 2018 in Malta. PMID- 30458915 TI - Prospective enterovirus D68 (EV-D68) surveillance from September 2015 to November 2018 indicates a current wave of activity in Wales. AB - Since 7 June 2018, an enterovirus D-68 (EV-D68) season (the third since 2015) is ongoing in Wales, with 114 confirmed cases thus far. Median age of the 220 cases since 2015 is 2.5 years (2.5 years in intensive care cases), 94% were hospitalised, 17% (n = 38) in intensive care. All had respiratory symptoms; bronchiolitis symptoms were reported in 60 cases, severe respiratory symptoms in 23 and acute flaccid myelitis in two cases. PMID- 30458918 TI - Antimicrobials in acute and long-term care: a point in time along the way to improved use. PMID- 30458919 TI - Sperm macrocephaly syndrome in the ostrich Struthio camelus: morphological characteristics and implications for motility. AB - Sperm macrocephaly syndrome (SMS) is characterised by a high percentage of spermatozoa with enlarged heads and multiple tails, and is related to infertility. Although this multiple sperm defect has been described in other mammalian species, little is known about this anomaly in birds. Morphological examination of semen from nine South African black ostriches (Struthio camelus var. domesticus) involved in an AI trial revealed the variable presence of spermatozoa with large heads and multiple tails. Ultrastructural features of the defect were similar to those reported in mammals except that the multiple tails were collectively bound within the plasmalemma. The tails were of similar length and structure to those of normal spermatozoa, and the heads were 1.6-fold longer, emphasising the uniformity of the anomaly across vertebrate species. Flow cytometry identified these cells as diploid and computer-aided sperm analysis revealed that they swim slower but straighter than normal spermatozoa, probably due to the increased drag of the large head and constrained movement of the merged multiple tails. The high incidence of this defect in one male ostrich indicates that, although rare, SMS can occur in birds and may potentially have an adverse effect on breeding programs, particularly for endangered species. PMID- 30458917 TI - Antimicrobial use in European acute care hospitals: results from the second point prevalence survey (PPS) of healthcare-associated infections and antimicrobial use, 2016 to 2017. AB - Antimicrobial agents used to treat infections are life-saving. Overuse may result in more frequent adverse effects and emergence of multidrug-resistant microorganisms. In 2016-17, we performed the second point-prevalence survey (PPS) of healthcare-associated infections (HAIs) and antimicrobial use in European acute care hospitals. We included 1,209 hospitals and 310,755 patients in 28 of 31 European Union/European Economic Area (EU/EEA) countries. The weighted prevalence of antimicrobial use in the EU/EEA was 30.5% (95% CI: 29.2-31.9%). The most common indication for prescribing antimicrobials was treatment of a community-acquired infection, followed by treatment of HAI and surgical prophylaxis. Over half (54.2%) of antimicrobials for surgical prophylaxis were prescribed for more than 1 day. The most common infections treated by antimicrobials were respiratory tract infections and the most commonly prescribed antimicrobial agents were penicillins with beta-lactamase inhibitors. There was wide variation of patients on antimicrobials, in the selection of antimicrobial agents and in antimicrobial stewardship resources and activities across the participating countries. The results of the PPS provide detailed information on antimicrobial use in European acute care hospitals, enable comparisons between countries and hospitals, and highlight key areas for national and European action that will support efforts towards prudent use of antimicrobials. PMID- 30458920 TI - Intracellular localisation of platelet-activating factor during mammalian embryo development invitro: a comparison of cattle, mouse and human. AB - Platelet-activating factor (PAF) is a well-known marker for embryo quality and viability. For the first time, we describe an intracellular localisation of PAF in oocytes and embryos of cattle, mice and humans. We showed that PAF is represented in the nucleus, a signal that was lost upon nuclear envelope breakdown. This process was confirmed by treating the embryos with nocodazole, a spindle-disrupting agent that, as such, arrests the embryo in mitosis, and by microinjecting a PAF-specific antibody in bovine MII oocytes. The latter resulted in the absence of nuclear PAF in the pronuclei of the zygote and reduced further developmental potential. Previous research indicates that PAF is released and taken up from the culture medium by preimplantation embryos in vitro, in which bovine serum albumin (BSA) serves as a crucial carrier molecule. In the present study we demonstrated that nuclear PAF does not originate from an extracellular source because embryos cultured in polyvinylpyrrolidone or BSA showed similar levels of PAF in their nuclei. Instead, our experiments indicate that cytosolic phospholipase A2 (cPLA2) is likely to be involved in the intracellular production of PAF, because treatment with arachidonyl trifluoromethyl ketone (AACOCF3), a specific cPLA2 inhibitor, clearly lowered PAF levels in the nuclei of bovine embryos. PMID- 30458921 TI - The Controversies, Challenges and Complexities of Lyme Disease: A Narrative Review. AB - PURPOSE: Lyme disease has become an increasingly important global public health concern. METHOD: A narrative review was conducted and designed to present a broad perspective on Lyme disease, and describe its history and development in terms of clinical care and public health implications. A structured literature search was conducted based on the question; what is currently known about Lyme disease? RESULTS: The narrative review is presented in chronological order in terms of a summary of the history of Lyme disease, the complexities of clinical diagnosis, the problematic interpretation of serologic testing, the conflicting guidelines for diagnosis, treatment and management of chronic Lyme, and benefits of antibiotic treatment. CONCLUSION: Despite growing global incidence of the Lyme disease, treatment has not attracted pharmaceutical investment, and the evidence base and international guidelines for treatment and management of chronic Lyme continue to be conflicting and controversial. The challenges of this immune mediated tick borne disease for public health policy and clinical practice are summarised, alongside directions for future research. PMID- 30458922 TI - Targeting Interleukin-23 in the Treatment of Noninfectious Uveitis. AB - The interleukin (IL)-23/IL-17 axis plays a central role in the pathogenesis of immune-mediated diseases such as psoriasis, psoriatic arthritis, Crohn's disease, and uveitis. Therefore, targeting the IL-23/IL-17 axis has become the focus of multiple clinical trials for drug development in patients with autoimmune diseases. We briefly describe the biology of the IL-23/IL-17 axis and its relevance to the pathogenesis of experimental and clinical uveitis, and review the monoclonal antibody therapies targeting this pathway. Finally, 2 ongoing phase 2 trials of the anti-IL-23 biologic therapy ustekinumab (STELARA, Janssen Biotech Inc, Horsham, PA) in patients with noninfectious uveitis are introduced. PMID- 30458923 TI - [Iris and iridocorneal angle tumor secondary to bronchial carcinoma]. PMID- 30458924 TI - In vivo confocal microscopy and optical coherence tomography as innovative tools for the diagnosis of limbal stem cell deficiency. AB - The limbus is the anatomical and functional barrier between the corneal and conjunctival epithelia. It is characterized by the presence of the limbal stem cell niche, which allows corneal homeostasis to be maintained. Limbal stem cell deficiency is characterized by a dual process: insufficient regeneration of corneal epithelium, which cannot therefore assure its function of physiological support, associated with corneal invasion by conjunctival proliferation. Diagnosis is currently made via routine clinical examination, corneal impression cytology and in vivo confocal microscopy (IVCM). Slit lamp examination shows abnormal limbal anatomy, thin and irregular epithelium with late fluorescein staining, and superficial vascularization. With its high resolution, IVCM allows identification of limbal and corneal epithelial changes at a cellular level in en face views parallel to the corneal surface, but with a restricted viewing field of the corneal surface. It shows a poor transition between the corneal and conjunctival epithelia, associated with a loss of the normal corneal epithelial stratification, low basal cell and sub-basal nerve plexus densities, and subepithelial fibrosis. Spectral domain optical coherence tomography of the central cornea and limbus, with scans in variable orientations, allows a quick, global and non-invasive analysis of normal eyes and those with limbal stem cell deficiency. It shows a thin limbal epithelium, lacking normal thickening, featuring absence of stromal undulations and limbal crypts in cross-sections and sections parallel to the limbus, lack of visible limbal crypts in en face sections, loss of clear transition between the hyporeflective corneal epithelium and the hyperreflective conjunctival epithelium, and hyperreflective subepithelial fibrosis. The limbus is the anatomical and functional barrier between the corneal and conjunctival epithelia. It is characterized by the presence of the limbal stem cell niche, which allows corneal homeostasis to be maintained. Limbal stem cell deficiency (LSCD) is characterized by a dual process: insufficient regeneration of corneal epithelium, which cannot therefore assure its function of physiological support, associated with corneal invasion by conjunctival proliferation. PMID- 30458925 TI - Epigenetics in Age-related Macular Degeneration (AMD). AB - Age-related Macular Degeneration (AMD) is a complex multifactorial condition involving multiple genetic, environmental and constitutional factors. Inflammation, oxidative stress and lipid metabolism seem to be the most important factors in the pathogenesis of the disease. The importance of genetic factors has mainly been revealed with the influence of histocompatibility complement factor H (CFH) variations and the ARSM2 susceptibility gene. Another component, epigenetics, could help to explain some of the relationships between environmental and genetic factors. Epigenetics is defined as the study of modulations of gene activity that can be transmitted over cell divisions without involving mutation of the DNA sequence. The molecules that are involved in these mechanisms are referred to as the epigenome. The mechanisms involve DNA methylation, histone modification, chromatin remodeling, and gene inhibition by non-coding RNA. Epigenetics could explain how the environment may induce relatively stable changes in traits or even diseases, possibly inheritable over several generations. Epigenetic traits established during development, and/or acquired under the influence of nutritional factors or other environmental factors, could influence the interactions between genes and the environment. Several authors have recently shown the influence of epigenetic factors in the pathogenesis of ocular diseases such as cataract, dry eye, glaucoma, diabetic retinopathy and more recently AMD. A better understanding of the involvement of genetic variants at risk, their relationship with epigenetics and environmental factors would certainly help to better assess the risk of developing AMD or better understand recent changes in the incidence of the disease. PMID- 30458926 TI - Bilateral persistent pupillary membrane in an adult patient: A case report. PMID- 30458927 TI - [Roth spots suggestive of myeloid leukemia: Case report]. PMID- 30458928 TI - Preclinical Toxicity Studies for Regenerative Medicine in Japan. AB - PURPOSE: Advances in methods designed to evaluate preclinical toxicity have not kept up with progress in regenerative medicine. Preclinical toxicity studies of regenerative therapies must be designed logically and should be flexible to accurately reflect toxicity of products under development. The purpose of this review is to discuss requirements of preclinical toxicity studies of this type developed in Japan. METHODS: We conducted MEDLINE and PubMed literature searches to identify recent reports relevant to regenerative medicine. Information regarding approved drugs and public announcements, including existing guidelines and guidance in Japan, was collected from the website of Japan's Ministry of Health, Labor and Welfare (https://www.mhlw.go.jp/index.html) and the Pharmaceuticals and Medical Devices Agency (https://www.pmda.go.jp/). FINDINGS: Four cell therapy products have been developed and approved in Japan so far. The principal preclinical toxicity data submitted to regulatory authorities in the Pharmaceuticals and Medical Devices Agency in Japan are summarized here. The potential for tumor formation, a major concern in such clinical applications, is assessed in 3 ways: tumor-forming capacity of the original cell, quantitation of residual pluripotent stem cells in the product, and the possibility that a tumor will form at the product's engraftment site. Although gene therapy and oncolytic virus products are under development, these types of products are not yet approved in Japan. Guidelines relevant to the development of these products are now being created based on existing guidelines and considerations established by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. IMPLICATIONS: Because of cell tropism and heterologous immunity, animal species or strains useful for preclinical studies of regenerative therapies are often restricted. Nonetheless, preclinical toxicity studies must be designed to predict results relevant to humans. PMID- 30458929 TI - Intellectual Property in the Field of Regenerative Medicine in Japan. AB - PURPOSE: Although most pharmaceutical companies and bio-ventures have not yet created a practical business model or a credible exit thus far, most are expecting potential new business to be derived from regenerative medicine. This article discusses and proposes some ideas regarding a patent strategy for regenerative medicine. METHODS: PubMed literature searches were conducted to identify recent reports relevant to regenerative medicine. Information regarding patents and patent applications were obtained from the database service of the Japan Platform for Patent Information on the website of the National Center for Industrial Property Information and Training at https://www.j platpat.inpit.go.jp/web/all/top/BTmTopEnglishPage and the Japan Patent Office at https://www.jpo.go.jp/index.htm. FINDINGS: The infrastructure of regenerative medicine in Japan is still maturing. Patent protection is important in regenerative medicine considering its special characteristics. IMPLICATIONS: Based on the understanding of the special characteristics of regenerative medicine, this article discusses and proposes some ideas regarding a patent strategy for the field, which is different from that of a typical patent strategy as in the case of a small-molecule drug. PMID- 30458930 TI - Safety, Pharmacokinetics, and Pharmacodynamics of ME-401, an Oral, Potent, and Selective Inhibitor of Phosphatidylinositol 3-Kinase P110delta, Following Single Ascending Dose Administration to Healthy Volunteers. AB - PURPOSE: ME-401 is a novel selective inhibitor of phosphatidylinositol 3 kinase p110delta, an enzyme often found overexpressed and overactive in B-cell malignancies. The current study was performed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending oral doses of ME-401 in healthy volunteers. METHODS: This analysis was an open-label, nonrandomized study in healthy male volunteers. Three sequential groups were dosed. Each group received single doses of ME-401 on two occasions; the doses tested ranged from 10 to 150 mg. Blood was drawn at various time points to analyze plasma concentrations of ME-401 and inhibition of basophil activation, a marker of phosphatidylinositol 3 kinase p110delta inhibition. FINDINGS: Fifteen subjects received a single dose of ME-401 on two occasions. Three adverse events that were considered possibly related to the study drug were reported: one event of pain, one event of headache, and one event of upper abdominal pain. ME-401 exhibited dose proportionality up to 60 mg, and supra-proportional increases in exposure were observed above doses of 60 mg. In addition, there was a dose-proportional increase in the inhibition of basophil activation up to 60 mg. Mean t1/2 ranged from 9.36 to 29.23 hours across the dose range. A 60 mg dose of ME-401 approached 90% inhibition of basophil activation, and thereafter no further increase to the percent inhibition of basophil activation was observed for higher doses. Once daily dosing of 60 mg ME-401 was forecasted to result in trough plasma levels exceeding the concentration needed for 90% inhibition of basophil activation. IMPLICATIONS: This first-in-human study showed that ME-401 was well tolerated after single doses up to 150 mg. Pharmacologic activity was confirmed after administration of single ascending oral doses of 10 to 150 mg. ME-401 60 mg, administered once daily, was selected as the starting dose for patient studies. ClinicalTrials.gov identifier: NCT02521389. PMID- 30458931 TI - The Role of Double and Triple Therapy with Direct Oral Anticoagulants in Coronary Artery Disease, Peripheral Artery Disease, and Stroke. AB - PURPOSE: Combining antiplatelet and anticoagulant therapy is often necessary in clinical practice. However, there is limited literature on tolerability and efficacy for triple therapy with the newer direct oral anticoagulants (DOACs). The objective of this study is to characterize the discharge prescribing practice of double versus triple antithrombotic therapy with a DOAC at a large, tertiary academic medical center. METHODS: In this retrospective, cross-sectional, observational study, patients were identified if they had received any combination of a DOAC, aspirin, and a P2Y12 inhibitor during an admission at our institution from June 1, 2015, to May 31, 2016. Patients were included in the analysis if they had any indication for anticoagulation and antiplatelet therapies and were discharged from the hospital with prescriptions for a DOAC and single or dual antiplatelet agents (aspirin and/or P2Y12 inhibitor). Patients were excluded if they had an unclear indication for antiplatelet therapy. Patient characteristics and 6-month efficacy and tolerability outcomes were collected via review of the electronic medical record. FINDINGS: A total of 367 patients were included in this analysis. Most patients at our institution who required both antiplatelet and anticoagulant agents were discharged on a regimen of aspirin and a DOAC. Patients across all groups most commonly received antiplatelet therapy for coronary artery disease and acute coronary syndrome-related events, whereas they received anticoagulation for stroke prophylaxis in atrial fibrillation. Within 6 months of discharge, there were 16 bleeding-related readmissions in the DOAC-aspirin group, 1 in the DOAC-P2Y12 group, and 0 in the triple therapy group. IMPLICATIONS: This analysis found that varying combinations of antiplatelet agents and anticoagulants are used, depending on clinical indications. Further studies are needed that focus on patients with indications for dual antiplatelet therapy and anticoagulation to compare double and triple therapy strategies for efficacy and bleeding risk. PMID- 30458932 TI - Identifying Myocardial Ischemia due to Coronary Microvascular Dysfunction in the Emergency Department: Introducing a New Paradigm in Acute Chest Pain Evaluation. AB - Chest pain stands as one of the most frequent patient presentations in the emergency department (ED). Despite established diagnostic algorithms for identifying several important causes of chest pain, such as acute myocardial infarction (AMI), aortic dissection, and pulmonary embolism, guidance on managing patients with recurrent chest pain, one of the top 3 reasons for repeated hospitalization in the United States, is less defined. The assessment of symptoms, serial ECG, and necrosis biomarkers plays a major role in patient management. Notably, the recently introduced high-sensitivity troponin T (hs-TnT) assay is helping to identify ischemia in patients previously undiagnosed by conventional testing. In Europe, with the use of this assay for over a decade, the identification of patients with AMI has substantially increased, particularly of patients with type 2 AMI, which is seen in the absence of atherosclerotic obstruction of the epicardial coronaries on angiography. Use of hs-TnT is in particular relevant in women, in whom the use of a sex-specific threshold for elevated hs-TnT has almost doubled the diagnosis of AMI. With the advent of the hs-TnT assay in the United States in 2017, a similar phenomenon is expected. Thus, it is important to learn from the European experience and to develop sex specific nuanced algorithms for the evaluation of additional causes of myocardial ischemia/necrosis, such as coronary artery vasomotor disorders and coronary microvascular dysfunction. The latter has a high prevalence among symptomatic women presenting to the ED, a group in whom recurrent chest pain is common. This commentary describes the tools available for diagnosing epicardial- and non epicardial-related myocardial ischemia in patients with recurrent chest pain in the ED setting. A sex-specific, nuanced approach applied to select groups of patients being observed in the ED has the potential to reduce admissions and to allow for the initiation of timely, appropriate medical treatment and outpatient follow-up in an at-risk population. The costs and availability of advanced diagnostics may pose some limitation to the widespread adoption of such protocols. PMID- 30458933 TI - On the Policy of the Italian Government in the Discovery, Development, and Access to Medicines. AB - This commentary outlines how discovery, development, and access to medicines are regulated and promoted in Italy by the government through the Ministry of University and Research, the Ministry of Health, and the Italian Medicines Agency. We describe and comment on the existing research programs stimulating preclinical, translational, and clinical research and how access to medicines and their pricing is regulated by Italy's National Health Service both at the national and regional levels. Finally, we describe the current scenario of industrial research and medicines manufacturing. The resulting picture shows a country in which high-level competitive research on medicines is promoted alongside an excellent national health system working toward fairness of access to health care services for all citizens and fiscal solidarity as a fundamental form of system financing. Critical challenges still exist, including the relative scarcity of public funding for research and the non-uniform access to the benefits of the National Health Service across Italian regions. PMID- 30458934 TI - UV damage of the anterior ocular surface - microstructural evidence by in vivo confocal microscopy. AB - PURPOSE: To evaluate and describe the microstructural changes at the ocular surface in response to habitual ocular sun exposure, correlate them with the UV protection habits and follow their dynamics using in vivo confocal microscopy(ICM). METHODS: For a period of minimum 4 months 200 subjects (400 eyes), aged 28 +/- 7.3 years, were recruited with the agreement that they will spend their summer exclusively in the region of the Black Sea coast at 43 degrees N latitude and will be examined before and after the summer. All subjects filled in a questionnaire about habitual UV protection and were examined clinically and by ICM. RESULTS: Questionnaire results demonstrated that 83.5% (167 participants) of the subjects considered the sun dangerous for their eyes, but 78% (156 subjects) believed that there is danger exclusively during the summer period. Although no clinical changes were detected, microstructural analysis of the cornea demonstrated statistically significant (p = 0.021) decrease of the basal epithelial density - from 6167 +/- 151 cells/mm2 before to 5829 +/- 168 cells/mm2 after the summer period. Microstructural assessment of the conjunctiva demonstrated characteristic cystic lesions with dark centres and bright borders encountered in only 25 eyes(6%) before, and affecting 118 eyes(29.5%) after the summer. The total area of the cysts after the summer increased fivefold. Spearman analysis proved negative correlation between sun protection habits and number of cysts. CONCLUSION: Summer sun exposure for one season leads to clinically undetectable, microstructural changes affecting the cornea, bulbar and palpebral conjunctiva with transient, but possibly cumulative nature. PMID- 30458936 TI - From the editor's perspective.... PMID- 30458937 TI - Improving outcomes in patients with peripheral arterial disease. AB - The benefits of risk-factor reduction associated with peripheral arterial disease (PAD) is established and supported by the literature. The purpose of this quality improvement project was to reduce modifiable risk factors such as diabetes mellitus (DM), hypertension (HTN), hyperlipidemia (HLD), and tobacco use in patients with PAD, as well as to demonstrate improvement in quality of life (QoL) and 6-minute-walk distances. For this quality-improvement project, 29 patients from three providers within a cardiology office were identified over a 6-week period. Those patients had a baseline 6-minute-walk test and completed a vascular quality-of-life (Vas QoL-6) questionnaire at visit 1. They were assessed for their Rutherford classification, a clinical staging system used to describe PAD. In visit 2, patients underwent endovascular intervention as per cardiologist recommendation. At clinic visit 3, an individualized plan was initiated to address all risk factors including diabetes mellitus, hypertension, hyperlipidemia, and tobacco use. Medications were adjusted to meet current guidelines appropriate for disease processes. Patients were also asked to start a regimented walking program as used by the Cleveland Clinic. At clinic visit 4, 90 days from patient's first visit, they were assessed for improvement in blood pressure, cholesterol, diabetes, and tobacco use. Vas QoL-6 and 6-minute-walk test were repeated at visit 4 for comparison. A total of 24 participants were included in the study. The average age was 66.92 years (standard deviation = 8.75), and the majority reported their race as white (n = 18, 75.0%). There were 10 (41.7%) males and 14 (58.3%) females. No statistically significant improvement was shown for A1c levels (P = .091) and total cholesterol (P = .066). Statistically significant improvement was revealed for low-density lipoprotein cholesterol (P = .007). Of the seven patients (29.2%) who used tobacco at visit 3, four (57.1%) reported a reduction in their tobacco use by the end of the study. Vas QoL-6 scores improved significantly (P < 0.001), and the distance during 6-minute walk also increased significantly (P = 0.03). There was a statistically significant decrease in Rutherford class scores from visit 1 to visit 4 (P < .001). Regarding compliance with the PAD Walking Program, 13 (54.2%) of the patients walked 10 or fewer times total. In conclusion, these data indicate that PAD risk factors can be improved, including control of blood pressure, cholesterol, A1c levels, and smoking cessation. Controlling risk factors that contribute to the progression of PAD is not only important for improving morbidity and mortality but may contribute to improved quality of life. This quality-improvement study also suggests that close follow-up and management after endovascular intervention increases the distance patients can ambulate without claudication symptoms. These results suggest that compliance with an unsupervised walking program is difficult, and supervised exercise programs should be considered as an alternative. PMID- 30458938 TI - Postoperative major surgery patients developing silent deep vein thrombosis: A prospective observational study. AB - Surgical patients are at high risk for developing deep vein thrombosis (DVT). There are many reports concerning DVT, but little is known about silent deep vein thrombosis (sDVT). This study aimed to determine the incidence of sDVT. Secondary objective is to identify the associated factors for the use of DVT prophylaxis and Caprini risk scores among major surgery patients. This prospective observational study involved postoperative surgical patients who are at risk of developing sDVT. The Caprini risk-assessment scores were calculated, and each subject had a preoperative and postoperative compression ultrasound complemented by duplex venous ultrasonography of deep venous system. No patient from the study experienced sDVT. There were significant associations between Caprini risk score group (odds ratio, 8.16; 95% confidence interval [CI], 1.01-68.74; P = .016) and the use of central venous catheter (odds ratio, 6.34; 95% CI, 1.62-24.80; P = .008) with DVT prophylaxis. Interestingly, the use of central venous catheter resulted in more than four-point increment of Caprini risk scores (mean increment, 4.19; 95% CI, 3.16-5.21; P < .001). Besides that, age was also significantly associated with Caprini risk scores (beta coefficient, 0.06; 95% CI, 0.02-0.11). Result from our study shows that the sDVT was nonexistent in this study setting. High-Caprini risk score group and the presence of central venous catheter were the significant predictor factors for the use of DVT prophylaxis. Significant predictor factors for Caprini risk scores were age and the presence of central venous catheter. PMID- 30458939 TI - Patient experiences of living with coronary stent. AB - Cardiovascular disease is among the most important disorders in the developed world and the main cause of death and disability in all countries considered. Using coronary stent in cardiovascular patients, as an effective treatment, has greatly reduced the requirement for cardiac surgery. The study was carried out to explore lived experiences of patients living with coronary stents.The qualitative phenomenological study was performed to explore lived experiences of patient with coronary stent. The participants (11 patients) were selected purposively. Data were collected through individual semistructured in-depth interviews. The interviews were analyzed according to Colaizzi's seven-stage method. Authenticity is demonstrated using Lincoln and Guba's 4 criteria. The mean age of participant was 49.6 +/- 11 years. The researcher obtained as many as 577 codes from patients' statements, and by merging or removing duplicated codes, they were decreased to 217 codes. The analysis of data collected on the cardiovascular patients living with stents showed some basic issues such as concern about future and social anxiety, which constitute the basic theme of anxiety. Basic issues such as lack of knowledge and supporting needs led to the major theme of feeling of necessity, and major issues such as body deformation and lifestyle change resulted in major theme of change. In conclusion, the result showed that an important step to fixing the problems is reducing concerns, increasing the level of awareness, and satisfying the needs (physical and mental). For improving patient's health, the rehab and care programs may modify patients' problems. PMID- 30458935 TI - Targeting Autophagy in Aging and Aging-Related Cardiovascular Diseases. AB - Aging, an irreversible biological process, serves as an independent risk factor for chronic disease including cancer, pulmonary, neurodegenerative, and cardiovascular diseases. In particular, high morbidity and mortality have been associated with cardiovascular aging, but effective clinical therapeutic remedies are suboptimal for the ever-rising aging population. Recent evidence suggests a unique role for aberrant aggregate clearance and the protein quality control machinery - the process of autophagy - in shortened lifespan, compromised healthspan, and the onset and development of aging-associated cardiovascular diseases. Autophagy degrades and removes long-lived or damaged cellular organelles and proteins, the functions of which decline with advanced aging. Induction of autophagy using rapamycin, resveratrol, nicotinamide derivatives, metformin, urolithin A, or spermidine delays aging, prolongs lifespan, and improves cardiovascular function in aging. Given the ever-rising human lifespan and aging population as well as the prevalence of cardiovascular disease provoked by increased age, it is pertinent to understand the contribution and underlying mechanisms of autophagy and organelle-selective autophagy (e.g., mitophagy) in the regulation of lifespan, healthspan, and cardiovascular aging. Here we dissect the mechanism of action for autophagy failure in aging and discuss the potential rationale of targeting autophagy using pharmacological agents as new avenues in the combating of biological and cardiovascular aging. PMID- 30458940 TI - Contemporary nursing care in transcatheter aortic valve replacement. AB - The purpose of this article is to inform nurses of the latest trend in the care of patients with aortic stenosis using transcatheter aortic valve replacement and pertinent knowledge regarding the care of these patients. PMID- 30458941 TI - Impact of Patient Safety Indicators on readmission after abdominal aortic surgery. AB - Patient safety is a critical component of health-care quality and measures created by the Agency for Healthcare Research and Quality (AHRQ) to identify hospitalizations with potentially preventable adverse events. This analysis evaluated whether Patient Safety Indicator (PSI) events after open surgical repair (OSR) or endovascular aneurysm repair (EVAR) of abdominal aortic aneurysm (AAA) were associated with increased risk of readmission. Patients undergoing elective repair of nonruptured AAA from 2009 to 2012 were selected in the Medicare Provider Analysis and Review files using the International Classification of Diseases, Ninth Revision, Clinical Modification codes. To identify PSI events, we used the AHRQ PSI International Classification of Diseases, Ninth Revision, Clinical Modification numerator codes. Chi-square test, multivariable logistic regression analysis, nonparametric Wilcoxon rank sum test, and Kaplan-Meier survival analysis were used for statistics. A total of 66,923 patients undergoing elective AAA repair were evaluated: (1) 9,315 with OSR and (2) 57,608 with EVAR. The most frequent PSI events after OSR versus EVAR were postoperative respiratory failure (PSI, 11; 17.7% vs 1.8%; P < .0001); perioperative hemorrhage/hematoma (PSI, 9; 3.6% vs 2.6%; P < .0001); postoperative sepsis (PSI, 13; 3.5% vs 0.4%; P < .0001); accidental puncture or laceration (PSI, 15; 2.1% vs 0.6%; P < .0001); and postoperative acute kidney injury requiring dialysis (PSI, 10; 1.4% vs 0.2%; P < .0001). The overall 30-day readmission rate was 10.5%. The occurrence of any PSI event overall significantly increased 30-day readmission compared with no event cases (odds ratio [OR] = 1.71; 95% confidence interval [CI], 1.57-1.86). Likelihood of 30-day readmission was greater for postoperative acute kidney injury requiring dialysis (OR = 1.66; 95% CI, 1.28-2.15), postoperative respiratory failure (OR = 1.36; 95% CI, 1.22 1.52), perioperative hemorrhage (OR = 1.34; 95% CI, 1.18-1.52), and postoperative pressure ulcer (OR = 2.88; 95% CI, 1.99-4.17). Occurrence of any PSI event was associated with an increased total hospital and intensive care unit length of stay and total hospital charges (all P < .001). In conclusion, AHRQ PSI events may be used to identify patients at the greatest risk for readmission after AAA repair. The risk for 30-day readmission was 71% higher when a PSI event occurred and was not associated with the type of repair. Minimizing preventable PSI events may be beneficial to reducing hospital readmissions after open and endovascular AAA repair and to improving hospital resource utilization. PMID- 30458943 TI - Teaching module for improving oncology nurses' knowledge and self-confidence about central line catheters caring, complications, and application: A pretest posttest quasi-experimental design. AB - The aim of the present study was to assess the effectiveness of implementing an educational module based on the Centers for Disease Control and Prevention guidelines on the nurses' knowledge and self-confidence regarding central line catheters (CVCs) caring, complications, and application. A pretest-posttest quasi experimental design was used. A sample of 100 oncology nurses from oncology units participated in two groups, experimental group (N = 50) and control group (N = 50). The participants completed knowledge test and self-confidence scale before and after the educational program. The results showed that there was a significant difference between the experimental and control groups regarding knowledge related to CVC guidelines and management after the interventional sessions (t = -7.85, P = .001). The mean and standard deviation for experimental group were 15.95 (5.45) and 7.35 (2.73) for the control group. Furthermore, the results showed significant difference (t = -22.20, P = .001) between the experimental group (M = 61.50, SD = 14.20) and the control group (M = 35.50, SD = 7.20) regarding self-confidence in managing CVCs. It is concluded that using educational program strengthens nurses' skills, improves safety, and increases opportunity to learn, and thus, it will increase the self-confidence. PMID- 30458942 TI - Problems associated with performance of peripheral intravenous catheterization in relation to working experience. AB - The aim of this study was to explore general registered nurses' (RNs) assessments of problems associated with difficult peripheral intravenous catheterization (PIVC) depending on their years of working experience, that is, those who had worked 3 years or less and those who had worked more than 3 years. The design was a quantitative, nonexperimental, descriptive, and analytic survey. The participating RNs (n = 83) were divided into two groups according to the length of their working experience, and the analysis was performed using the SPSS, version 24, software. The RNs also had the opportunity to answer a free-text question related to the aim. The results showed that less experienced RNs assessed to a significantly higher extent that they lacked time, experience, and ability and that there was no blood return; however, they assessed that the peripheral venous catheters were in the vein. If critical care nurses had been requested for support earlier, this request was seen as a reason not to try PIVC at all because critical care nurses were assessed as more experienced and skilled. To develop the kind of effective problem-solving and clinical reasoning needed for practice, a supportive setting must be created throughout nursing education as well as after graduation. Further research should focus on the education needs associated with PIVC and seek to understand to what extent learning in clinical skill simulation laboratories is transferred to actions in the clinical setting. PMID- 30458944 TI - Comparison of abdominal and arm areas in patients receiving subcutaneous heparin in terms of development of pain, hematoma, and ecchymosis. AB - The purpose of this study was to compare the abdominal and arm areas in the patients using subcutaneous heparin in terms of pain, hematoma, and ecchymosis development. As a result of subcutaneous heparin injections, complications such as pain, ecchymosis, and hematoma may develop in the injection site. The injection site chosen for injection is one of the factors that are effective on complications. This quasi-experimental study was conducted with 54 patients at orthopedics-traumatology and cardiothoracic surgery clinics of a university hospital. The data were collected using a patient description and follow-up form, visual analog scale, transparent film, and a chronometer. Ecchymosis and hematoma were evaluated at the 48th hour after injection, whereas the pain level was evaluated right after the injection, and the pain duration was evaluated during the injection. The rate of pain in the arm area was statistically higher. Differences between the areas in terms of level and duration of pain and development and size of ecchymosis and hematoma were not significant. More pain developed due to heparin injection in the arm area than in the abdominal area. No differences were observed between the areas in terms of level and duration of pain, development and size of ecchymosis, or development and size of hematoma. PMID- 30458945 TI - Review of article: Obesity and Clotting: BMI independently contributes to hypercoagulability after injury. J Trauma Acute Care Surgery. 2015 January;78(1):30-38. PMID- 30458946 TI - Update: The role of antiplatelet medications in cardiovascular patients. PMID- 30458947 TI - Mobile emergency care service: A time-course assessment and characterization of demand. AB - INTRODUCTION: Prehospital care is defined as any medical attention provided outside the hospital environment. This study aims to study the operation of a regional SAMU by assessing electronic records of cases managed and to evaluate demand patterns over time. METHODS: A retrospective, cross-sectional study was conducted through an analysis of emergency calls handled between the years of 2009 and 2013 by the SAMU Metropolitan 2 Region mobile emergency care service, located in Niteroi, Brazil. Nonparametric tests were used to evaluate differences in the variables of interest between the two halves of the 5-year period of analysis and annually. RESULTS: The total call volume during the period of analysis was 590,902 (monthly mean [SD], 9848 [3764]; 95%CI = 8875 to 10,820). Analysis of calls over time revealed a significant decline in call volume (p = 0.008), mainly between the year 2009 and subsequent years (p < 0.001). The vast majority of patients were adults with clinical conditions (average = 2311). Predominantly, calls were made to request prehospital assistance at the patient's home, and the most prevalent age range was 41-50 years. CONCLUSION: The SAMU Metropolitan 2 regional emergency medical service predominantly attended to middle-aged women at their homes. Total call volume has been decreasing, perhaps reflecting a multifactorial phenomenon and improvements in the primary health care network. PMID- 30458948 TI - Educational interventions promoting evidence-based practice among emergency nurses: A systematic review. AB - INTRODUCTION: Emergency nurses are expected to adopt evidence-based practice (EBP). The aim of this systematic review was to describe educational interventions promoting EBP and their outcomes among emergency nurses, compared with no education, to inform clinicians and researchers about effective educational interventions suitable for use in emergency departments (EDs). METHODS: CINAHL, Cochrane, PubMed and Scopus were systematically searched to identify studies published between January 1, 2006 and October 20, 2016 describing educational interventions designed to promote EBP among emergency nurses. 711 studies were identified and screened; 10 were selected for inclusion and quality assessment. The studies were analyzed using deductive content analysis, and the review's results are presented in accordance with the PRISMA guidelines. RESULTS: Ten relevant studies on nine different self-developed educational interventions were identified. Eight studies had highly significant or significant results. Interventions involving face-to-face contact led to significant or highly significant effects on patient benefits and emergency nurses' knowledge, skills, and behavior. Interventions using written self directed learning material led to significant improvements in nurses' knowledge of EBP. All the descriptions of the interventions were incomplete, and the reported details varied considerably between the studies. CONCLUSIONS: There have been few studies on educational interventions to promote EBP among emergency nurses but the available results are promising. PMID- 30458949 TI - Muscle-Strengthening Exercise Among 397,423 U.S. Adults: Prevalence, Correlates, and Associations With Health Conditions. AB - INTRODUCTION: Although muscle-strengthening exercise has multiple independent health benefits, little is known about muscle-strengthening exercise participation and associations with adverse health conditions among U.S. adults. METHODS: In 2017, data were analyzed from the U.S. 2015 Behavioral Risk Factor Surveillance System. During telephone surveys, respondents reported how many times during the past week they engaged in muscle-strengthening exercise. Weighted weekly muscle-strengthening exercise frequencies were calculated for the total sample and across sociodemographic and lifestyle characteristics. A multivariable logistic regression assessed the odds of having self-reported adverse health conditions (e.g., diabetes, coronary heart disease) according to weekly muscle-strengthening exercise frequency. RESULTS: Data were available on 397,423 adults (aged 18-80 years). Overall, 30.2% (95% CI=29.9, 30.5) met the muscle-strengthening exercise recommendations (two or more times/week) and 57.8% (95% CI=57.5, 58.2) reported no muscle-strengthening exercise. Older age, insufficient aerobic activity, lower income, lower education, poorer self-rated health, being female, and being overweight/obese were significantly associated with lower odds of meeting the muscle-strengthening exercise recommendations independently of other characteristics. After adjusting for confounders (e.g., age, sex, income, smoking, aerobic activity), when compared with those who did none, muscle-strengthening exercise was associated with lower odds for several adverse health conditions, including prevalent diabetes, cancer (non-skin), poor self-rated health, and obesity. CONCLUSIONS: Three in five U.S. adults do not engage in any muscle-strengthening exercise, despite an association for muscle strengthening exercise with better health conditions. Future muscle-strengthening exercise promotion strategies should target older adults, females, those with low education/income, and those with a poor health status. PMID- 30458950 TI - NIH Primary and Secondary Prevention Research in Humans During 2012-2017. AB - INTRODUCTION: This paper provides the first detailed analysis of the NIH prevention research portfolio for primary and secondary prevention research in humans and related methods research. METHODS: The Office of Disease Prevention developed a taxonomy of 128 topics and applied it to 11,082 projects representing 91.7% of all new projects and 84.1% of all dollars used for new projects awarded using grant and cooperative agreement activity codes that supported research in fiscal years 2012-2017. Projects were coded in 2016-2018 and analyzed in 2018. RESULTS: Only 16.7% of projects and 22.6% of dollars were used for primary and secondary prevention research in humans or related methods research. Most of the leading risk factors for death and disability in the U.S. were selected as an outcome in <5% of the projects. Many more projects included an observational study, or an analysis of existing data, than a randomized intervention. These patterns were consistent over time. CONCLUSIONS: The appropriate level of support for primary and secondary prevention research in humans from NIH will differ by field and stage of research. The estimates reported here may be overestimates, as credit was given for a project even if only a portion of that project addressed prevention research. Given that 74% of the variability in county-level life expectancy across the U.S. is explained by established risk factors, it seems appropriate to devote additional resources to developing and testing interventions to address those risk factors. PMID- 30458951 TI - A Machine Learning Approach to Identify NIH-Funded Applied Prevention Research. AB - INTRODUCTION: To fulfill its mission, the NIH Office of Disease Prevention systematically monitors NIH investments in applied prevention research. Specifically, the Office focuses on research in humans involving primary and secondary prevention, and prevention-related methods. Currently, the NIH uses the Research, Condition, and Disease Categorization system to report agency funding in prevention research. However, this system defines prevention research broadly to include primary and secondary prevention, studies on prevention methods, and basic and preclinical studies for prevention. A new methodology was needed to quantify NIH funding in applied prevention research. METHODS: A novel machine learning approach was developed and evaluated for its ability to characterize NIH funded applied prevention research during fiscal years 2012-2015. The sensitivity, specificity, positive predictive value, accuracy, and F1 score of the machine learning method; the Research, Condition, and Disease Categorization system; and a combined approach were estimated. Analyses were completed during June-August 2017. RESULTS: Because the machine learning method was trained to recognize applied prevention research, it more accurately identified applied prevention grants (F1 = 72.7%) than the Research, Condition, and Disease Categorization system (F1 = 54.4%) and a combined approach (F1 = 63.5%) with p<0.001. CONCLUSIONS: This analysis demonstrated the use of machine learning as an efficient method to classify NIH-funded research grants in disease prevention. PMID- 30458952 TI - DGCNN: A convolutional neural network over large-scale labeled graphs. AB - Exploiting graph-structured data has many real applications in domains including natural language semantics, programming language processing, and malware analysis. A variety of methods has been developed to deal with such data. However, learning graphs of large-scale, varying shapes and sizes is a big challenge for any method. In this paper, we propose a multi-view multi-layer convolutional neural network on labeled directed graphs (DGCNN), in which convolutional filters are designed flexibly to adapt to dynamic structures of local regions inside graphs. The advantages of DGCNN are that we do not need to align vertices between graphs, and that DGCNN can process large-scale dynamic graphs with hundred thousands of nodes. To verify the effectiveness of DGCNN, we conducted experiments on two tasks: malware analysis and software defect prediction. The results show that DGCNN outperforms the baselines, including several deep neural networks. PMID- 30458953 TI - Corrigendum to "Polyglutamic acid-based nanocomposites as efficient non-viral gene carriers in vitro and in vivo" [Euro. J. Pharm. Biopharm. 79 (2011) 473 484]. PMID- 30458954 TI - Corrigendum to "Mimicking brain tissue binding in an in vitro model of the blood brain barrier illustrates differences between in vitro and in vivo methods for assessing the rate of brain penetration" [Eur. J. Pharm. Biopharm. 127 (2018) 453 461]. PMID- 30458955 TI - Retraction Notice to "CD163 AND ITS EXPANDING FUNCTIONAL REPERTOIRE". PMID- 30458956 TI - Corrigendum to "ATF3 is positively involved in particulate matter-induced airway inflammation in vitro" [Toxicol. Lett. 287 (2018) 113-121]. PMID- 30458957 TI - Daylight Photodynamic Therapy in the Treatment of Actinic Keratosis in Carriers of Oculocutaneous Albinism: Report of Three Cases. PMID- 30458958 TI - Role of the Dermatologist in the Care of Hospitalized Transplant Patients. PMID- 30458959 TI - Evaluating residual strain throughout the murine female reproductive system. AB - Mounting evidence suggests that cells within soft tissues seek to maintain a preferred biomechanical state. Residual stress is defined as the stress that remains in a tissue when all external loads are removed and contributes to tissue mechanohomeostasis by decreasing the transmural gradient of wall stress. Current computational models of pelvic floor mechanics, however, often do not consider residual stress. Residual strain, a result of residual stress can be quantitatively measured through opening angle experiments. Therefore, the objective of this study is to quantify the regional variations in opening angles along the murine female reproductive system at estrus and diestrus, to quantify residual strain in the maintenance state of sexually mature females. Further, evidence suggests that hydrophilic glycosaminoglycan/proteoglycans are integral to cervical remodeling. Thus, variations in opening angles following hypo-osmotic loading are evaluated. Opening angle experiments were performed along the murine reproductive system in estrus (n = 8) and diestrus (n = 8) and placed in hypo osmotic solution. Measurements of thickness and volume were also obtained for each group. Differences (p < 0.05) in opening angle were observed with respect to region and loading, however, differences with respect to estrous stage were not significant. Thickness values were significant (p < 0.05) with respect to region only. The effects of both estrous cycle and region resulted in significant differences (p < 0.05) in observed volume. The observed regional differences indicate variation in the stress-free state among the reproductive system which may have implications for future computational models to advance women's reproductive health. PMID- 30458960 TI - Consider others better than yourself: Social decision-making and partner preference in Borderline Personality Disorder. AB - BACKGROUND AND OBJECTIVES: Patients with Borderline Personality Disorder (BPD) suffer from interpersonal difficulties. They have been shown to be distrustful and yet involved in abusive relationships. In this study, we want to examine whether the perception of fairness and partner preference are altered in BPD. METHODS: We employed a coalition formation game in which a participant can choose whether to interact in dyads or triads, thus exclusion or inclusion of a third potential interaction partner. Furthermore, triads get a higher endowment, such that dyads are not only unfair to one partner, but also economically inefficient, as the participant reduces the overall amount of money available for distribution. Subsequently, we compared how participants predicted another person's game strategy (inclusive, exclusive, or mixed) and rated its fairness, and which partner the participant would select. RESULTS: The majority of the BPD group (n = 26) as well as of the healthy group (n = 29) preferred triads over dyads and offered a near-to-equal split to their interaction partners in the first two rounds. In contrast to the healthy group, the BPD group did not show a drop of the average level of investment in the final round. In both groups, the inclusive strategy was perceived as the fairest strategy. Most interestingly, despite a similar perception of fairness, half of the BPD group preferred an interaction partner with an exclusive or mixed strategy while the majority of the HC group would choose an interaction partner with an inclusive strategy. LIMITATIONS: This is a preliminary study which needs further replications before strong conclusions can be drawn. CONCLUSIONS: Our study demonstrates no differences in fairness perception but an alteration in partner preference of patients with BPD which might contribute to unfavorable partner choices and impairments of interpersonal functioning in BPD. PMID- 30458961 TI - Scale-invariant structures of spiral waves. AB - BACKGROUND: Spiral waves are considered to be one of the potential mechanisms that maintain complex arrhythmias such as atrial and ventricular fibrillation. The aim of the present study was to quantify the complex dynamics of spiral waves as the organizing manifolds of information flow at multiple scales. METHOD: We simulated spiral waves using a numerical model of cardiac excitation in a two dimensional (2-D) lattice. We created a renormalization group by coarse graining and re-scaling the original time series in multiple spatiotemporal scales, and quantified the Lagrangian coherent structures (LCS) of the information flow underlying the spiral waves. To quantify the scale-invariant structures, we compared the value of the finite-time Lyapunov exponent between the corresponding components of the 2-D lattice in each spatiotemporal scale of the renormalization group with that of the original scale. RESULTS: Both the repelling and the attracting LCS changed across the different spatial and temporal scales of the renormalization group. However, despite the change across the scales, some LCS were scale-invariant. The patterns of those scale-invariant structures were not obvious from the trajectory of the spiral waves based on voltage mapping of the lattice. CONCLUSIONS: Some Lagrangian coherent structures of information flow underlying spiral waves are preserved across multiple spatiotemporal scales. PMID- 30458962 TI - Reversible pulmonary toxicity by nitrofurantoin. PMID- 30458963 TI - Skin ultrasound in the diagnosis of odontogenic cutaneous fistula. PMID- 30458964 TI - Coronary heart disease mortality in severe vs. non-severe familial hypercholesterolaemia in the Simon Broome Register. AB - BACKGROUND AND AIMS: The International Atherosclerosis Society (IAS) has proposed that patients with "severe" FH (SFH) would warrant early and more aggressive cholesterol-lowering treatment such as with PCSK9 inhibitors. SFH is diagnosed if LDL-cholesterol (LDLC) > 10 mmol/L, or LDLC >8.0 mmol/L plus one high-risk feature, or LDLC >5 mmol/L plus two high-risk features. Here we compare CHD mortality in SFH and non-SFH (NSFH) patients in the UK prospective Simon Broome Register since 1991, when statin use became routine. METHODS: 2929 definite or possible PFH patients (51% women) aged 20-79 years were recruited from 21 UK lipid clinics and followed prospectively between 1992 and 2016. The excess CHD standardised mortality ratio (SMR) compared to the England and Wales population was calculated (with 95% confidence intervals). RESULTS: 1982 (67.7%) patients met the SFH definition. Compared to the non-SFH, significantly (p < 0.001) more SFH patients had diagnosed CHD at baseline (24.6% vs. 17.5%), were current smokers (21.9% vs 10.2%) and had a BMI > 30 kg/m2 (14.9% vs. 7.8%). The SMR for CHD mortality was significantly (p = 0.007) higher for SFH (220 (184-261) (34,134 person years, 129 deaths observed, vs. 59 expected) compared to NSFH of 144 (98 203) (15,432 person years, 32 observed vs. 22 expected). After adjustment for traditional risk factors, the Hazard Ratio for CHD mortality in SFH vs. NSFH was 1.22 (0.80-1.87) p = 0.36, indicating that the excess risk was largely accounted for by these factors. CONCLUSIONS: CHD mortality remains elevated in treated FH, especially for SFH, emphasising the importance of optimal lipid-lowering and management of other risk factors. PMID- 30458965 TI - Cholesterol and inflammatory risk: Insights from secondary and primary prevention. PMID- 30458966 TI - [Prostate cancer screening: Reasons of controversy]. AB - We propose herein a short synthesis of evidence leading to deny organized screening of prostate cancer using PSA plus or minus rectal digital examination. Nevertheless, many scientific societies support opportunistic screening on basis of shared decision. Today, numerous proposals had been made to reduce the overdiagnosis and overtreatreatment. PMID- 30458967 TI - Grid index subspace constructed locally weighted learning identification modeling for high dimensional ship maneuvering system. AB - For off-line locally weighted learning (LWL), all training data points need to be stored in memory, which would lead to a heavy computational burden, especially for large amount of training data. To avoid heavy computational burden in LWL, the grid index subspace constructed algorithm is presented for high dimensional ship maneuvering system in this study. First, high dimensional training data can be encoded and stored in equal interval grid, and training data are divided into grids. Second, query point is encoded by using the same strategy as in the first step, and the grid number which belongs to the query point is obtained. Third, the subspace would be per-allocated to the query point by using the grid index which has a light computational complexity. Different from the general cluster algorithm, a subspace rather than a neighborhood is assigned to query point. This way, LWL is carried out in a subspace, and the computational complexity is significantly reduced. As a consequence, real-time performance is effectively guaranteed. Finally, theoretical calculations and simulation examples are given to validate the effectiveness of the proposed scheme. PMID- 30458968 TI - New stains for anterior capsule surgery. AB - PURPOSE: To investigate whether new dyes and dye combinations can give equivalent or better staining in anterior capsule surgery than existing dyes with a low degree of toxicity on relevant cells. SETTING: University laboratory of Jacobs University Bremen, Germany. DESIGN: Laboratory experimental study. METHODS: Pig eyes were collected post mortem. Cataract was induced by microwave irradiation. Access to the lens capsule was through open-sky surgery. Staining was performed and results were documented by photography. The toxicity of the dyes was evaluated in 3 different cell lines immediately after exposure and with a delay of 24 hours, with exposure in the dark or subsequent strong illumination. RESULTS: A new cyanine dye, BIP (2-[5-[3,3-dimethyl-1-(4-sulfobutyl)-1,3-dihydro indol-2-ylidene]-penta-1,3-dienyl]-3,3-dimethyl-1-(4-sulfobutyl)-3H-indolium sodium), was found to lead to green staining, with reduced toxicity on corneal endothelial cells. Staining could be further enhanced by combining it with trypan blue. Methylene blue was very toxic, whereas its combination with trypan blue was much less toxic. CONCLUSIONS: With BIP alone or in combination with trypan blue, safe staining of the capsule can be achieved, resulting in a green color. PMID- 30458969 TI - Pneumomediastinum and Subcutaneous Emphysema after Flexible Bronchoscopy. PMID- 30458970 TI - [Education care in patients with psychiatric disorders in France: Psychoeducation or therapeutic patient education?] AB - CONTEXT: Psychoeducation and therapeutic patient education can be effectively included in treatments for patients with psychiatric disorders. These two effective educational therapies have the common purpose of improving disorder related morbidity, compliance with treatment and patients' quality of life. While they have different methods of application, both teach patients to play an active role in their own care. However, it is still critical to combine them for care of patients with psychiatric and addiction disorders in a manner that allows for specificity. To do this, the differences between psychoeducation and therapeutic patient education must be considered, and their potential for the management of patients with psychiatric and addiction disorders must be determined. METHODS: In our article, we review the literature concerning therapeutic education programs for patients and discuss the literature based on the experiences of psychiatrists trained in these therapies. RESULTS: Despite rather nonrestrictive guidelines, and after reviewing numerous studies, we found that psychoeducation seems to be rarely used in psychiatry. The use of therapeutic patient education programs for psychiatric patients has doubled in four years but still accounts for less than 4% of validated programs in France. Only 154 programs were developed in 1175 public psychiatric facilities in 2016. Therapeutic patient education has a legal framework and recommendations, which make it suitable for inclusion in care and in the training of care providers. The rigor in the development of therapeutic patient education programs and the requirement for training and financial support reinforce the need for their establishment in healthcare institutions. As such, they could help to modify professional practices and the culture of care in mental health fields. CONCLUSION: There is a place for therapeutic patient education in psychiatry as it provides a real benefit for patients. It could modify care practices and costs, and is suitable for patients with psychiatric or addiction disorders by helping them play an active role in their care, thereby improving treatment outcomes and quality of life. PMID- 30458971 TI - Humanistic communication in the evaluation of shared decision making: A systematic review. AB - OBJECTIVE: To assess the extent to which evaluations of shared decision making (SDM) assess the extent and quality of humanistic communication (i.e., respect, compassion, empathy). METHODS: We systematically searched Web of Science and Scopus for prospective studies published between 2012 and February 2018 that evaluated SDM in actual clinical decisions using validated SDM measures. Two reviewers working independently and in duplicate extracted all statements from eligible studies and all items from SDM measurement instruments that referred to humanistic patient-clinician communication. RESULTS: Of the 154 eligible studies, 14 (9%) included >=1 statements regarding humanistic communication, either in framing the study (N = 2), measuring impact (e.g., empathy, respect, interpersonal skills; N = 9), as patients'/clinicians' accounts of SDM (N = 2), in interpreting study results (N = 3), and in discussing implications of study findings (N = 3). Of the 192 items within the 11 SDM measurement instruments deployed in the included studies, 7 (3.6%) items assessed humanistic communication. CONCLUSION: Assessments of the quality of SDM focus narrowly on SDM technique and rarely assess humanistic aspects of patient-clinician communication. PRACTICE IMPLICATIONS: Considering SDM as merely a technique may reduce SDM's patient-centeredness and undermine its' contribution to patient care. PMID- 30458972 TI - Reply to the Letter, "Leigh syndrome with spinal cord involvement due to a hemizygous NDUFA1 mutation". PMID- 30458973 TI - The effect of neonatal maternal separation on short-chain fatty acids and airway inflammation in adult asthma mice. AB - BACKGROUND: To investigate neonatal maternal separation (NMS) effects on airway inflammation of asthma and potential mechanism using a mouse model. METHODS: 80 Balb/c neonatal male mice were randomly assigned to NMS and non-NMS groups. Feces were collected on PND21, 28, 35 and 42 to analyze microbiota and short-chain fatty acids (SCFAs). Non-NMS group were then divided into control (group A) and asthma groups (group B), while NMS group was assigned to NMS+asthma (group C) and NMS+SCFAs+asthma groups (group D). Inflammatory cells and eosinophils (EOS) in bronchoalveolar lavage fluid (BALF) were assessed. Pathological changes and cytokines in lung tissue were observed. Protein expression of Occludin and E cadherin in airway epithelial was examined. RESULTS: The number of S', diversity index H' and dominance index D', as well as content butyric acid in NMS group C were significantly lower than non-NMS group B (p<0.05). Mice in group C had a higher level of inflammatory cells and EOS compared with group A, B and D. EOS moderate infiltration was found in mice of group B, C and D. Mice in group C had significantly higher levels of cytokines and showed slightly increased bronchial epithelium goblet cells and a small amount of visceral secretions. Occludin and E cadherin expression in lung in B, C and D groups was depressed, and protein level in group C was significantly lower than group B and D. CONCLUSIONS: NMS is associated with exacerbated inflammation of adult asthma by changing intestinal microflora resulting in butanoic acid decline and airway epithelial barrier damage. PMID- 30458974 TI - Congenital heart disease: New challenges. PMID- 30458975 TI - The CRUSADE score and bleeding in acute coronary syndrome. PMID- 30458976 TI - Pediatric sleep disorder medicine training in Canada: past, present and future. AB - Pediatric sleep medicine is rapidly evolving in Canada. As pediatric sleep disorders are increasingly recognized, there is a growing need for clinicians educated in the evaluation and treatment of pediatric sleep disorders. Current pediatric sleep resources in Canada are inadequate to meet the needs of the population. Until this year, there was no formal pathway or specific requirements for pediatric sleep disorder medicine training in Canada and exposure to this field of medicine in post-graduate training was limited. In 2018, the Royal College of Physicians of Canada approved an Area of Focused Competence program for certification and maintenance of competence in Sleep Disordered Medicine. It was designed to ensure adequate breadth and depth of training experiences in this diverse field. The goals of the program are to ensure competence in the assessment and management of adults and children with a range of sleep-wake disorders and sleep-disordered breathing, to interpret sleep investigations, to administratively manage a sleep laboratory and to advance the discipline of Sleep Disorder Medicine through research. The program follows a competency-based model in which, within the year of training, trainees accumulate a dossier of experiences which are evaluated by a Royal College of Physicians and Surgeons committee. This new program will ensure that a critical mass of trained sleep medicine physicians is developed to meet the needs of the Canadian pediatric population and to contribute to advancement of the field of pediatric sleep medicine. PMID- 30458977 TI - Obstetric brachial plexus palsy - A prospective, population-based study of incidence, recovery and long-term residual impairment at 10 to 12 years of age. AB - AIM: To assess the long-term outcome and evaluate prognostic factors in obstetric brachial plexus palsy (OBPP). METHODS: Of all 114 children with OBPP born in western Sweden in 1999-2001, 98 (61 males, 37 females) were invited to participate. A questionnaire on the symptoms of the OBPP was sent out and those with persisting symptoms were examined in terms of muscle strength, range of motion (ROM), activities of daily living (ADL), pain and sensibility at the age of 10-12 years. Contact was made by 87 children. RESULTS: The incidence of persisting OBPP at 10-12 years of age was calculated as 19 per 38,749 live births or 0.49 per 1000. Symptoms were reduced muscle strength and ROM in the arm. Eight children reported pain, four had impaired sensibility and ten children described some difficulties in ADL. Muscle strength in forearm supination, shoulder external rotation and elbow flexion at three months of age can be used to predict outcome. INTERPRETATION: Most children with an OBPP recover completely, but one in five has symptoms of the injury at 10-12 years of age. Muscle strength in the arm at three months of age can be used to predict outcome. PMID- 30458978 TI - Development and validation of a robust multiplex serological assay to quantify antibodies specific to pertussis antigens. AB - Despite wide spread vaccination, the public health burden of pertussis remains substantial. Current acellular pertussis vaccines comprise upto five Bordetella pertussis (Bp) antigens. Performing an ELISA to quantify antibody for each antigen is laborious and challenging to apply to pediatric samples where serum volume may be limited. We developed a microsphere based multiplex antibody capture assay (MMACA) to quantify antibodies to five pertussis antigens; pertussis toxin, pertactin, filamentous hemagglutinin and fimbrial antigens 2/3, and adenylate cyclase toxin in a single reaction (5-plex) with a calibrated reference standard, QC reagents and SAS(r) based data analysis program. The goodness of fit (R2) of the standard curves for five analytes was >=0.99, LLOQ 0.04-0.15 IU or AU/mL, accuracy 1.9%-23.8% (%E), dilutional linearity slopes 0.93 1.02 and regression coefficients r2 = 0.91-0.99. MMACA had acceptable precision within a median CV of 16.0%-22.8%. Critical reagents, antigen conjugated microsphere and reporter antibody exhibited acceptable (<12.3%) lot-lot variation. MMACA can be completed in <3 h, requires low serum volume (5MUL/multiplex assay) and has fast data turnaround time (<1 min). MMACA has been successfully developed and validated as a sensitive, specific, robust and rugged method suitable for simultaneous quantification of anti-Bp antibodies in serum, plasma and DBS. PMID- 30458979 TI - Development and translation of novel therapeutics targeting tumor-associated macrophages. AB - Tumor-associated macrophages (TAMs) regulate an array of tumor functions and have critical roles in both the progression and the eradication of cancer. Numerous therapies targeting TAMs are under development in cancer and many have demonstrated success at the preclinical and clinical levels. Most of these therapies fall within 3 main categories: systemic depletion of TAMs, inhibition of TAM recruitment and polarization, and promoting the antitumor functions of TAMs. In this article, the rationale behind these various therapies and approaches is reviewed along with supporting preclinical and clinical data. PMID- 30458980 TI - Open Surgical Access for Transfemoral TAVR Should Not Be a Contraindication for Conscious Sedation. AB - OBJECTIVES: The use of monitored anesthesia care (MAC) for transcatheter aortic valve replacement (TAVR) is gaining favor in the United States, although general anesthesia (GA) continues to be common for these procedures. Open surgical cutdown for transfemoral TAVR has been a relative contraindication for TAVR with MAC at most centers. The objective of this study was to review the authors' results of transfemoral TAVR performed in patients with open surgical cutdown with the use of MAC. DESIGN: Retrospective study design from a prospectively recorded database. SETTING: Tertiary academic (teaching) hospital. PARTICIPANTS: Two hundred eighty-two patients undergoing transfemoral TAVR with open surgical cutdown under MAC from 2015 to 2017. INTERVENTIONS: Transfemoral TAVR under MAC with surgical cutdown for femoral vascular access. MEASUREMENTS AND MAIN RESULTS: The study cohort consisted of 282 patients with severe aortic stenosis (mean area 0.65 [+/- 0.16] cm2, mean gradient of 48.9 [+/-13.3] mmHg, and mean age of 82.7 [+/- 7.31] years). Eleven (3.9%) patients required conversion to GA. First postoperative pain score (0-10) was 2.9 and highest postoperative pain score was 4.6. Major and minor vascular complications occurred in 2 (0.7%) and 6 (2.1%) patients, respectively. Twenty-nine (10.3%) patients were readmitted within 30 days, and 6 (2.1%) patients had in-hospital mortality. CONCLUSIONS: Open surgical cutdown for transfemoral TAVR can be performed safely using MAC and ilioinguinal block with low rates of conversion to general anesthesia and acceptable postoperative outcomes and pain scores. PMID- 30458982 TI - Influence of luminal stenosis in aneurysmal and non-aneurysmal blunt cerebrovascular injury. AB - BACKGROUND: Current blunt cerebrovascular injury (BCVI) grading grossly differentiates injury characteristics such as luminal stenosis (LS) and aneurysmal disease. The effect of increasing degree of LS beyond the current BCVI grading scale on stroke formation is unknown. STUDY DESIGN: BCVI over a 3-year period were retrospectively reviewed. To investigate influence of LS beyond the BCVI grading scale within aneurysmal and non-aneurysmal BCVI, grade 2 BCVI were subdivided into BCVI with >= 25% and <= 50% LS and BCVI with > 50% and <= 99% LS. Grade 3 BCVI were subdivided into BCVI with pseudoaneurysm (PSA) without LS and BCVI with PSA and LS. We hypothesized increased LS beyond the current BCVI grade distinctions would be associated with higher rates of stroke formation. RESULTS: 312 BCVI were included, of which 140 were carotid BCVI and 172 vertebral BCVI. Sixteen carotid BCVI underwent endovascular intervention (EI) and 19 suffered a stroke. In carotid BCVI stroke rates increased sequentially with BCVI grade except in grade 3. There was a stroke rate of 12% in grade 1 carotid BCVI, 18% in grade 2, 6% in grade 3, and 31% in grade 4. In subgroup analysis for grade 2 carotid BCVI, BCVI with > 50% and <= 99% LS had higher rates of stroke (22% vs. 15%, p = 0.44) than BCVI with >= 25% and <= 50% LS. In subgroup analysis of grade 3 carotid BCVI, BCVI with PSA and LS had higher rates of stroke (9% vs. 4%, p = 0.48) than BCVI with PSA without LS. Higher rates of EI in grade 2 carotid BCVI with > 50% and <= 99% LS (22% vs. 5%, p = 0.14) and grade 3 carotid BCVI with PSA and LS (35% vs. 4%, p = 0.01) were noted in subgroup analysis. CONCLUSION: Higher percentage LS beyond the currently used BCVI grading scale has a non significantly increased rate of stroke in both aneurysmal and non-aneurysmal BCVI. Grade 3 BCVI with PSA and LS seems to be a high-risk subgroup. Use of EI confounds modern measurement of stroke risk in higher LS BCVI. PMID- 30458983 TI - Dutch combat operation experiences in Iraq and Afghanistan: The conundrum of low surgical workload deployments. AB - INTRODUCTION: The Combined Joined Task Force - Operation Inherent Resolve is the military intervention of Iraq and Coalition Forces in the battle against Islamic State of Iraq and Syria (ISIS). Al Assad Airbase (AAAB) is one of the key airbases. It contains a Role 2 Medical Treatment Facility, primarily to perform Damage Control Surgery in Coalition Forces, Iraqi National Security Forces and Local Nationals. We present a six month medical exposure in order to provide insight into the treatment of casualties and to optimize medical planning of combat operations and (pre-/post-) deployment training. PATIENTS AND METHODS: This is a cohort study of casualties that were admitted to the Role 2 Medical Treatment Facility AAAB from November 2017 to April 2018. Their mechanisms and types of injury are described and compared to those sustained in Uruzgan, Afghanistan between 2006-2010. Additionally, they are compared to the caseload in the Dutch civilian medical centers of the medical specialist team at AAAB. RESULTS: There were significant differences in both mechanism and type of injury between Coalition Forces and Iraqi Security Forces (p = 0.0001). Coalition Forces had 100% disease and non-battle injuries, where Iraqi Security Forces had 86% battle injuries and 14% non-battle casualties. The most common surgical procedures performed were debridement of wounds (38%), (exploratory) laparotomy (10%) and genital procedures (7%). The surgical caseload in Uruzgan, Afghanistan was significantly different in aspect and quantity, being 4.1 times higher. When compared to the workload at home all team members had at least a tenfold lower workload than in their civilian hospitals. DISCUSSION: The deployed surgical teams were scarcely exposed to casualties at AAAB, Iraq. These low workload deployments could cause a decline in surgical skills. Military medical planning should be tailormade and should include adjusting length of stay, (pre-/post )deployment refresher training and early consultation of military medical specialists. Future research should focus on optimizing this process by investigating fellowships in combat matching trauma centers, regional and international collaboration and refresher training possibilities to maintain the expertise of the acute military care provider. PMID- 30458981 TI - A Hippo-like Signaling Pathway Controls Tracheal Morphogenesis in Drosophila melanogaster. AB - Hippo-like pathways are ancient signaling modules first identified in yeasts. The best-defined metazoan module forms the core of the Hippo pathway, which regulates organ size and cell fate. Hippo-like kinase modules consist of a Sterile 20-like kinase, an NDR kinase, and non-catalytic protein scaffolds. In the Hippo pathway, the upstream kinase Hippo can be activated by another kinase, Tao-1. Here, we delineate a related Hippo-like signaling module that Tao-1 regulates to control tracheal morphogenesis in Drosophila melanogaster. Tao-1 activates the Sterile 20 like kinase GckIII by phosphorylating its activation loop, a mode of regulation that is conserved in humans. Tao-1 and GckIII act upstream of the NDR kinase Tricornered to ensure proper tube formation in trachea. Our study reveals that Tao-1 activates two related kinase modules to control both growth and morphogenesis. The Hippo-like signaling pathway we have delineated has a potential role in the human vascular disease cerebral cavernous malformation. PMID- 30458984 TI - Male Genital Dermatology: A Primer for the Sexual Medicine Physician. AB - INTRODUCTION: The dermatologic conditions affecting the male genitalia are diverse and range from normal variants and benign growths to overt malignancy. Unfortunately, there is a dearth of urologic dermatology training in most residency programs, and many dermatologic lesions with a classic appearance on other areas of the body may have atypical presentations on the genitalia. Patients may present to a variety of physicians without receiving a definitive diagnosis, which can be highly distressing to the afflicted individual. AIM: To provide sexual medicine physicians tools to aid in the evaluation and diagnosis of urologic dermatology lesions, whether they are limited to the genitalia or part of a widespread systemic disease. METHODS: Comprehensive review of the literature pertaining to genital dermatology in men. MAIN OUTCOME MEASURE: We stratify each condition into 1 of 5 groups (normal variants and benign lesions, inflammatory lesions, transmissible lesions, premalignant lesions, and malignant lesions) and focus on presentation and prevalence of these conditions. RESULTS: Sexual medicine physicians should emphasize the non-pathologic nature of normal variants of genital anatomy (ie, penile hyperpigmentation, pearly penile papules) and stress that removal of these lesions is only appropriate for cosmetic purposes. Benign genital growths (ie, sebaceous cysts, seborrheic keratoses) may not require intervention, but they should be monitored for atypical features and infection. In contrast, transmissible (ie, herpes, syphilis) and inflammatory (ie, psoriasis) lesions may necessitate prompt intervention to reduce transmission and complications of late-stage disease. Premalignant and malignant lesions may mimic many of the aforementioned conditions; it is important that patients receive routine follow-up after treatment. All suspicious non-healing or ulcerating lesions should undergo pathologic evaluation to rule out malignancy. CONCLUSION: Urologic dermatology can be a diagnostic challenge for sexual medicine physicians. This review simplifies the diagnostic approach and emphasizes pathologic features of each condition to guide management. Gabrielson AT, Le TV, Fontenot C, et al. Male genital dermatology: A primer on evaluation for the sexual medicine physician. Sex Med Rev 2018;XX:XXX-XXX. PMID- 30458985 TI - Effect of Thyroid Hormone Derangements on Sexual Function in Men and Women. AB - INTRODUCTION: Sexual dysfunction affects many people, with 33-60% of women reporting sexual dysfunction and 8-52% of men with erectile dysfunction or premature ejaculation. In an effort to determine the constellation of factors responsible for sexual dysfunction, the effect of thyroid hormone derangements has been of recent interest. AIM: To investigate the associations between thyroid hormones and sexual dysfunction in women and men. METHODS: Literature was reviewed to examine the effects of hypo- and hyperthyroidism on sexual function. MAIN OUTCOME MEASURE: We present a summary of the effects of thyroid dysfunction on domains of sexual functioning. RESULTS: Most studies demonstrate that men with hypo- and hyperthyroidism have increased rates of sexual dysfunction, including erectile dysfunction in men with hypothyroidism. However, studies vary on the strength of correlation between hormonal derangement and level of sexual dysfunction. In both men with hyper- and hypothyroidism, treating the thyroid disorder at least partially reverses sexual dysfunction. In contrast, the current literature provides no consensus on the effect of hypothyroidism, hyperthyroidism, or Hashimoto's thyroiditis on female sexual function. In studies that observed increased rates of sexual dysfunction in women with thyroid disorders, correction of the thyroid derangement resulted in resolution of some sexual dysfunction. Studies are also conflicted on whether there is a relationship between the degree of sexual dysfunction and the degree of hormone derangement in women. However, prior work has demonstrated a relationship between thyroid autoantibodies and sexual dysfunction in women. CONCLUSION: Thyroid dysfunction is an important factor in the pathogenesis of sexual dysfunction in men and possibly women. Evidence suggests a reversibility of sexual dysfunction with correction of thyroid dysfunction, although the exact pathophysiology of thyroid-mediated sexual dysfunction remains unknown. However, current evidence supports thyroid derangements rather than autoantibodies as the causative factor in men, whereas autoantibodies appear to play a more prominent role in women. Bates JN, Kohn TP, Pastuszak AW. Effect of Thyroid Hormone Derangements on Sexual Function in Men and Women. Sex Med Rev 2018;XX:XXX-XXX. PMID- 30458987 TI - Exosomal transfer of miR-214 mediates gefitinib resistance in non-small cell lung cancer. AB - Recent studies have demonstrated that exosomal miRNAs mediate as intercellular bio-messengers of drug resistance in lung cancer. Our objective was to investigate whether exosomes derived from gefitinib resistant non-small cell lung cancer cells could confer resistance to its recipient cells. Exosomes were successfully isolated by ultracentrifugation and exosomes morphologies and sizes were determined by transmission electron microscopy and dynamic light scattering analysis. Fluorescent PKH-67 labeled exosomes derived from PC-9GR cells could be taken up and internalized by PC-9 cells. CCK8 measurement showed that PC-9GR derived exosomes could confer gefitinib resistance in PC-9 cells. MiRNA-214 was upregulated in gefitinib resistant PC-9GR cells and its derived exosomes by qPCR analysis. Inhibition of exosomal miR-214 with antagomir reversed gefitinib resistance conferred by PC-9GR-derived exosomes in vitro, which was confirmed by flow cytometry analysis and westernblot of apoptotic protein (caspase-3, caspase 3 cleaved, bax) and anti-apoptotic protein (bcl-2). Finally, exosomes enriched with miR-214 antagomir was further confirmed to reverse gefitinib resistance in vivo. Our results are the first to show that exosomes derived from gefitinib resistant PC-9GR cells could transfer resistance to its recipient sensitive PC-9 cells, which might be mediated by exosomal transfer of miR-214. PMID- 30458986 TI - White matter injury predicts disrupted functional connectivity and microstructure in very preterm born neonates. AB - OBJECTIVE: To determine whether the spatial extent and location of early identified punctate white matter injury (WMI) is associated with regionally specific disruptions in thalamocortical-connectivity in very-preterm born neonates. METHODS: 37 very-preterm born neonates (median gestational age: 28.1 weeks; interquartile range [IQR]: 27-30) underwent early MRI (median age 32.9 weeks; IQR: 32-35), and WMI was identified in 13 (35%) neonates. Structural T1 weighted, resting-state functional Magnetic Resonance Imaging (rs-fMRI, n = 34) and Diffusion Tensor Imaging (DTI, n = 31) sequences were acquired using 3 T-MRI. A probabilistic map of WMI was developed for the 13 neonates demonstrating brain injury. A neonatal atlas was applied to the WMI maps, rs-fMRI and DTI analyses to extract volumetric, functional and microstructural data from regionally-specific brain areas. Associations of thalamocortical-network strength and alterations in fractional anisotropy (FA, a measure of white-matter microstructure) with WMI volume were assessed in general linear models, adjusting for age at scan and cerebral volumes. RESULTS: WMI volume in the superior (beta = -0.007; p = .02) and posterior corona radiata (beta = -0.01; p = .01), posterior thalamic radiations (beta = -0.01; p = .005) and superior longitudinal fasciculus (beta = 0.02; p = .001) was associated with reduced connectivity strength between thalamus and parietal resting-state networks. WMI volume in the left (beta = 0.02; p = .02) and right superior corona radiata (beta = -0.03; p = .008), left posterior corona radiata (beta = -0.03; p = .01), corpus callosum (beta = -0.11; p < .0001) and right superior longitudinal fasciculus (beta = -0.02; p = .02) was associated with functional connectivity strength between thalamic and sensorimotor networks. Increased WMI volume was also associated with decreased FA values in the corpus callosum (beta = -0.004, p = .015). CONCLUSIONS: Regionally specific alterations in early functional and structural network complexity resulting from WMI may underlie impaired outcomes. PMID- 30458988 TI - Short-term administration of iso-alpha-acids increases transthyretin transcription in the hippocampus. AB - Cognitive decline and dementia are currently recognized as major problems in the aging population; however, there is still no promising treatment for these conditions. Previously, our group reported that iso-alpha-acids (IAAs), which are hop-derived bitter components present in beer, prevent inflammation and cognitive impairment in an Alzheimer's disease model mice (5xFAD mice) and yield significant reduction in amyloid beta (Alphabeta) in the brain. However, data on the molecular mechanisms underlying these physiological effects of IAAs remain limited. Here, we used transcriptome analysis and found that oral administration of IAAs to 5xFAD mice for 7 days induces a 58.9-fold increase in the expression of transthyretin (TTR; Ttr) in the hippocampus compared with controls. In addition, real-time quantitative PCR showed that oral administration of IAAs significantly increased Ttr transcription in the hippocampi of wild type C57BL/6J mice but not in the cerebral cortex. TTR is an Alphabeta protein scavenger; thus, an increase in its expression could prevent amyloid aggregate formation. These results indicate that IAAs reduce Alphabeta in the brain by elevating TTR levels. PMID- 30458989 TI - The interacting domains in cereblon differentially modulate the immunomodulatory drug-mediated ubiquitination and degradation of its binding partners. AB - Cereblon (CRBN), a substrate receptor of the cullin-4 RING E3 ligase (CRL4), has been utilized for the targeted protein degradation via small molecular weight CRBN modulators. However, it is unclear whether and how proteins that interact with CRBN at different domains are affected by these modulators. Here, we use CRBN and its four binding partners, c-Jun, chloride channel protein CLC-1, transcription factor IKZF1, and MEIS2, as model proteins to investigate the effect of immunomodulatory drugs (IMiDs) including thalidomide, lenalidomide, and pomalidomide, on their stability, ubiquitination, and interaction with CRBN. Together with previous discoveries, domain mapping experiment shows that these four proteins interact with CRBN at three distinct regions. Immunoblotting analyses reveal that the protein level of CRBN-binding partners could be enhanced, attenuated, or not affected by IMiDs. Interaction analyses and ubiquitination assay demonstrate that IMiDs modulate the interaction between CRBN and its binding partners in three distinct ways and thus differentially regulate their ubiquitination. This work suggests that the binding domain in CRBN is a critical factor which influences the regulation of IMiDs on the ubiquitination and stability of these CRBN-interacting partners. PMID- 30458990 TI - PACS-1 and adaptor protein-1 mediate ACTH trafficking to the regulated secretory pathway. AB - The regulated secretory pathway is a specialized form of protein secretion found in endocrine and neuroendocrine cell types. Pro-opiomelanocortin (POMC) is a pro hormone that utilizes this pathway to be trafficked to dense core secretory granules (DCSGs). Within this organelle, POMC is processed to multiple bioactive hormones that play key roles in cellular physiology. However, the complete set of cellular membrane trafficking proteins that mediate the correct sorting of POMC to DCSGs remain unknown. Here, we report the roles of the phosphofurin acidic cluster sorting protein - 1 (PACS-1) and the clathrin adaptor protein 1 (AP-1) in the targeting of POMC to DCSGs. Upon knockdown of PACS-1 and AP-1, POMC is readily secreted into the extracellular milieu and fails to be targeted to DCSGs. PMID- 30458991 TI - Clinical course of depression symptoms and predictors of enduring depression risk in women with polycystic ovary syndrome: Results of a longitudinal study. AB - OBJECTIVE: To [1] characterize depression symptoms over time and [2] test the hypothesis that adverse metabolic parameters would associate with risk of enduring depression risk in women with polycystic ovary syndrome (PCOS). DESIGN: Prospective cohort study. SETTING: University center. PATIENT(S): One hundred sixty-three women with PCOS. INTERVENTION(S): The Beck Depression Inventory Fast Screen (BDI-FS) was self-administered at baseline and follow-up to identify depression risk, using a cutoff score >4. MAIN OUTCOME MEASURE(S): BDI-FS scores. RESULT(S): Median baseline age was 29.0 years, and median follow-up interval was 5.5 years. Fifty-nine of 163 women had positive depression screens at baseline (36%); 52 women (32%) screened positive at follow-up. Median change in BDI-II score was 0 (interquartile range, -2, 1) over the study period. Of the 59 women at risk for depression at baseline, 22 screened negative at follow-up (37%), while 37 women remained at risk (63%). Considering these 59 women with positive depression screens at baseline, higher body mass index (BMI) was associated with increased odds of enduring depression risk at follow-up (adjusted odds ratio = 1.09; 95% confidence interval, 1.00, 1.18), in a multivariate logistic regression model. Compared with women with normal body weight at baseline, obese women (BMI >30 kg/m2) had five-fold increased odds of enduring depression risk at follow-up (adjusted odds ratio = 5.07; 95% confidence interval, 1.07, 24.0). CONCLUSION(S): The prevalence of depression was relatively stable over time in a cohort of women with PCOS. Elevated BMI is a hallmark of enduring depression risk. These results may assist providers in developing targeted intervention strategies to reduce the prevalence of long-term depressive symptoms in women with PCOS. PMID- 30458992 TI - Self-reported infertility, metabolic dysfunction, and cardiovascular events: a cross-sectional analysis among U.S. women. AB - OBJECTIVE: To explore associations between infertility and metabolic syndrome, and cardiovascular events. Infertility is increasingly a public health issue, with emerging links to chronic disease. Existing literature on infertility focuses primarily on known causes, which likely excludes a substantial number of women for whom there is no known cause or formal diagnosis. DESIGN/SETTING: We conducted a cross-sectional analysis examining the association between self reported infertility (i.e., ever experiencing inability to conceive after 12 months of trying to become pregnant) and metabolic syndrome and cardiovascular events (i.e., congestive heart failure, coronary heart disease, heart attack, or stroke). Data were analyzed using multivariate logistic regression. PATIENT(S): A total of 744 U.S. women, 20-59 years of age, from the National Health and Nutrition Examination Survey (2013-2014), participated in the study. Among them, 15.7% reported ever experiencing infertility, 27.6% met the definition of metabolic syndrome, and 2.84% reported ever having a cardiovascular event. INTERVENTION(S): N/A. MAIN OUTCOME MEASURE(S): Metabolic syndrome and cardiovascular events. RESULTS: Compared to women who had never experienced infertility, women who reported infertility had a 1.79 (95% confidence interval [CI] 1.04, 3.08) higher odds of reporting symptoms of metabolic syndrome and 1.83 (95% CI 1.15, 2.89) times higher odds of having experienced a cardiovascular event. Furthermore, women with self-reported infertility had a 71% higher odds of reporting a cardiovascular event after controlling for metabolic syndrome (95% CI 1.01, 3.00). CONCLUSIONS: Our results suggest that among U.S. women, the experience of infertility at any point in a woman's reproductive window may be associated with later-life cardiovascular health. PMID- 30458993 TI - Effect of in vitro culture period on birth weight after vitrified-warmed transfer cycles: analysis of 4,201 singleton newborns. AB - OBJECTIVE: To investigate the effect of embryo culture duration on birth weight in vitrified-warmed cycles. DESIGN: Retrospective cohort study. SETTING: Tertiary care academic medical center. PATIENT(S): A total of 4,201 women who gave birth to 3,520, 215, and 466 live-born singletons after frozen-thawed cleavage-stage (day 3) and day 5 and day 6 blastocyst transfer, respectively. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Neonatal birth weight. RESULT(S): The mean birth weight did not differ between the three study groups. However, the gestational age- and sex-adjusted birth weight (Z-scores) of singletons and the proportion of large-for-gestational-age (LGA) babies were significantly higher after day 5 and day 6 transfer than after transfer of day 3 embryos. Furthermore, multiple linear regression analysis indicated that gestational age, parental body mass index, neonatal sex, and length of the culture period all had significant and strong impacts on birth weight of singleton newborns. CONCLUSION(S): In the vitrified warmed transfer cycles, birth weight Z-scores and the proportion of LGA infants were both higher in singletons born after blastocyst transfer than after transfer of cleavage-stage embryos. This finding suggests that the effect of culture duration was not overcome by transfer of embryos into a more physiologic uterine environment. PMID- 30458994 TI - Inhibition of tumor cell proliferation in human uterine leiomyomas by vitamin D via Wnt/beta-catenin pathway. AB - OBJECTIVE: To assess the effect of vitamin D (VitD) on human uterine leiomyomas through Wnt/beta-catenin pathway inhibition, apoptosis induction, and cell growth arrest. DESIGN: A prospective study comparing leiomyoma vs. myometrium tissues. Paired design study comparing human uterine leiomyoma primary (HULP) cells treated with or without VitD. SETTING: Hospital Universitario-Politecnico La Fe, Fundacion IVI/INCLIVA, Universidad de Valencia, Valencia, Spain. PATIENT(S): Human uterine leiomyoma and myometrium were collected from women (aged 35-52 years) without hormonal treatment. INTERVENTION(S): Samples were collected from women undergoing surgery due to symptomatic uterine leiomyoma pathology. MAIN OUTCOME MEASURE(S): Uterine leiomyoma and myometrium tissues were analyzed by western blot (WB) to determine proliferation, Wnt/beta-catenin, and apoptosis pathways. HULP cells were used to study VitD effect in cell proliferation (WB), cell cycle (flow cytometry), Wnt/beta-catenin and apoptosis genes (polymerase chain reaction arrays), Wnt-related proteins (protein array), and apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling [TUNEL] assay). RESULTS: Human leiomyoma tissues compared with matched myometrium showed higher proliferation (fold change = 8.16; P=.0006) and altered Wnt/beta-catenin pathway (fold change = 5.5; P<.0001), whereas no differences in apoptosis were observed. VitD induced cell growth arrest and decreased proliferation in HULP cells (fold change = 0.74; P=.007). Moreover, VitD decreased Wnt-pathway expression in HULP cells at gene (activity score = -0.775; P<.001) and protein levels. However, VitD did not induce apoptosis expression. CONCLUSION: Increased proliferation and Wnt/beta-catenin pathway deregulation play a role in the development and growth of leiomyomas, whereas apoptosis appears not to contribute. VitD exerts an antiproliferative action on HULP cells through cell growth arrest and Wnt/beta-catenin pathway inhibition, but not through apoptosis regulation, suggesting VitD as an effective therapy to stabilize leiomyoma size and prevent its growth. PMID- 30458995 TI - Braden score may be associated with time to onset of catheter-associated urinary tract infection in high-risk patients: Lessons learned from a root cause analysis tool. AB - Timely removal of the urinary catheter is an important strategy for decreasing catheter-associated urinary tract infections (CAUTIs). Data were aggregated from an electronic root cause analysis tool, which is used to collect and guide discussions on patient factors following a CAUTI event at our facility. This identified the Braden Scale score as a possible important predictor of early onset CAUTI in high-risk patients and could potentially be leveraged for early action in urinary catheter removal. PMID- 30458996 TI - Long-term implantation of acoustic transmitters induces chronic inflammatory cytokine expression in adult rainbow trout (Oncorhynchus mykiss). AB - Telemetry transmitters are frequently used in studies of wild fish migration and behavior. Although the effects of surgically implanted transmitters on survival, tag retention, healing and growth have been studied, there has been little research regarding the potential immune response induced by these transmitters. In the current study, mature rainbow trout received either surgical implantation of an acoustic transmitter or a sham surgical procedure. These fish were then sampled over a 10-week period so that pro-inflammatory cytokine expression in the spleen, peritoneal cavity lymphocytes and muscle at the surgical site could be analyzed. There were no significant differences in transcript expression for the spleen and muscle tissue between fish that had a transmitter and those that received the surgical procedure alone. However, transmitter presence significantly increased the expression of IL-6, IL-1beta and TNFalpha in the peritoneal cells at 10 weeks indicating that tagged fish may be coping with chronic inflammation. Furthermore, tagged male fish had a higher inflammatory response in 10-week peritoneal lavage samples when compared to their tagged mature female counterparts, providing some evidence that mature female rainbow trout may have suppressed immune function when sexually mature. Externally, fish appeared to heal at similar rates regardless of the presence or absence of the transmitter, but the tag itself was prone to encapsulation and adhesion to the body wall and/or surgical site. This suggests that fish tagged with large intraperitoneal implants may not behave similarly to their wild counterparts. This research could aid in the development of improved telemetry tags that are more biocompatible, economical and better able to track fish behavior/movement. PMID- 30458997 TI - Protein expression in the liver and blood serum in chickens in response to Salmonella Enteritidis infection. AB - Events occurring in the chicken caecum following Salmonella Enteritidis infection are relatively well-described. However, mechanisms of the immune response and defence beyond the intestinal tract are less well-described. In this study, we therefore determined changes in protein abundance in the liver and blood serum in response to S. Enteritidis infection using the unbiased approach of shotgun proteomics. Complement and coagulation cascades, TNF signalling, antigen processing and presentation was activated in the liver following infection with S. Enteritidis. Chicken proteins that decreased in the liver were involved in glycolysis, the citrate cycle, oxidative phosphorylation and fatty acid metabolism. No functional category was significantly activated or suppressed in the serum. Concerning individual proteins, VNN1, SAA, AVD, SERPINA3, SERPINB10, AGT, MRP126 or CP increased in abundance both in the liver and serum. MT4, MT3, PTGDS, GLRX and TGM4, though highly inducible in the liver, did not increase in the serum. PIGR, SERPINF2 and IGJ increased in the serum but not in the liver. SERPINA4, apoAIV, CLEC3B, SERPINF1, HRG, AHSG and ALB decreased both in the liver and serum. Avidin-like LOC431660, THRSP, GATM, GGACT, ACOX1, ALDOB or FABP7 decreased in the liver but not in the serum. Finally, CKM, CKB, PLTP, COMP, IGFALS, AMY1A or SERPIND1 decreased in the serum after S. Enteritidis infection but not in the liver. Differently abundant proteins characterise the chicken's response to infection and can be also used as markers of chicken health status. PMID- 30458998 TI - Actinobacillus pleuropneumoniae triggers IL-10 expression in tonsils to mediate colonisation and persistence of infection in pigs. AB - Actinobacillus pleuropneumoniae (APP) persisting in clinically healthy pigs may be the causative agent of sudden outbreaks of severe respiratory disease in swine herds. During the course of acute disease, the pathogen is eliminated from inflamed lung tissue, which is characterized by the expression of pro inflammatory cytokines and an influx of neutrophils. However, if clearance by the porcine immune system fails, APP may switch to a persistent form. At later stages of infection, the pathogen may reside in tonsillar tissue without being eliminated by the host immune defence. To better understand the host immune response at different stages of infection, expression pattern of cytokines in tonsils and lung were recorded. In contrast to lung tissue, in which APP presence was associated with a pronounced pro-inflammatory character, APP presence in the tonsils elicited an increased IL-10 expression. In both organs of infected animals, a marked reciprocal correlation of the pro-inflammatory IL-17A and the anti-inflammatory IL-10 was found, supporting the idea that both cytokines are produced in highly associated, but reciprocal differentiated cell types, possibly APP-specific Th17 subsets. It appears that a persistent phenotype of APP triggers the anti-inflammatory immune response in tonsillar tissue in an attempt to evade the porcine immune defence. PMID- 30458999 TI - Co-administration of saponin quil A and PRRSV-1 modified-live virus vaccine up regulates gene expression of type I interferon-regulated gene, type I and II interferon, and inflammatory cytokines and reduces viremia in response to PRRSV-2 challenge. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is a devastating virus which suppresses the expression of type I and II interferons (IFNs) as well as several pro-inflammatory cytokines. Our previous study reported that saponin quil A had a potential to up-regulate the expression of type I IFN-regulated genes and type I and II IFNs in porcine peripheral blood mononuclear cells (PBMC) inoculated with PRRSV. The present study evaluated the immunostimulatory effect of quil A on potentiating cross protective immunity of PRRSV-1 modified-live virus (MLV) vaccine against PRRSV-2 challenge. Twenty-four 4-week-old PRRSV seronegative pigs were divided into four groups of six pigs. Group 1 and group 2 pigs were vaccinated with PRRSV-1 MLV vaccine at 0 dpv (day post vaccination), and additionally group 2 pigs were injected intramuscularly with quil A at -1, 0, 1 dpv. Group 3 pigs were injected with PRRSV-1 MLV vaccine solvent at 0 dpv and served as challenge control, while group 4 pigs served as strict control. Group 1 3 pigs were challenged intranasally with PRRSV-2 at 28 dpv and immune and clinical parameters were observed from 0 until 49 dpv. Group 1 pigs showed significantly reduced PRRSV viremia, number of viremic pigs, and clinical scores, and significantly improved average daily weight gain (ADWG), compared to group 3 pigs. Group 2 pigs showed significantly increased mRNA expressions of interferon regulatory factor 3, 2'-5'-oligoadenylatesynthetase 1, osteopontin, IFNalpha, IFNbeta, IFNgamma, interleukin-2 (IL-2), IL-13 and tumor necrosis factor alpha, compared to group 1 pigs. The animals demonstrated significantly reduced PRRSV viremia and number of viremic pigs, but did not demonstrate any further improved PRRSV-specific antibody levels, neutralizing antibody titers, rectal temperature, clinical scores, and ADWG as compared to group 1 pigs. Our findings suggest that quil A up-regulates type I IFN-regulated gene, type I and II IFNs, and inflammatory cytokine expressions which may contribute to further reducing PRRSV viremia and number of viremic pigs which were conferred by PRRSV-1 MLV vaccine. Our findings also suggest that quil A may serve as an effective immunostimulator for potentiating cell-mediated immune defense to PRRSV. PMID- 30459000 TI - Dissect the mode of action of probiotics in affecting host-microbial interactions and immunity in food producing animals. AB - Prophylactic antimicrobials have been widely used in food animal production with the aim to prevent infectious diseases, enhance feed efficiency, and promote growth. However, the extensive use of antimicrobials in food animal production systems has led to the emergence of antimicrobial resistant pathogens, which are potential threats to human and animal health. Probiotics have been proposed to be a promising alternative of prophylactic antimicrobials, with potential beneficial effects on the host animal by improving the balance of intestinal microbiota and host immunity. Although an increasing body of evidence shows that probiotics could directly or indirectly affect gut microbiota and host immune functions, the lack of the understanding of how probiotics influence host-microbial interaction and immunity is one of the reasons for controversial findings from many animal trials, especially in food production animals. Therefore, in this review we focused on the most recent (last ten years) studies on how gut microbiota and host immune function changes in response to probiotics in food production animals (swine, poultry, and ruminant). In addition, the relationship between microbial changes and host immune function was illustrated, and how such relationship differs among animal species was further compared. Moreover, the future directions concerning the mechanisms of how probiotics modulate host-microbial interactions and host immunity were highlighted, which may assist in the optimal supplementation strategy to maximize the efficacy of probiotics to improve animal gut health and productivity. PMID- 30459001 TI - Altered hematological, biochemical and immunological parameters as predictive biomarkers of severity in experimental myocardial infarction. AB - Preclinical studies in cardiovascular medicine are necessary to translate basic research to the clinic. The porcine model has been widely used to understand the biological mechanisms involved in cardiovascular disorders for which purpose different closed-chest models have been developed in the last years to mimic the pathophysiological events seen in human myocardial infarction. In this work, we studied hematological, biochemical and immunological parameters, as well as Magnetic resonance derived cardiac function measurements obtained from a swine myocardial infarction model. We identified some blood parameters which were significantly altered after myocardial infarction induction. More importantly, these parameters (gamma-glutamyl transferase, glutamic pyruvic transaminase, red blood cell counts, hemoglobin concentration, hematocrit, platelet count and plateletcrit) correlated positively with cardiac function, infarct size and/or cardiac enzymes (troponin I and creatine kinase-MB). Thus several blood-derived parameters have allowed us to predict the severity of myocardial infarction in a clinically relevant animal model. Therefore, here we provide a simple, affordable and reliable way that could prove useful in the follow up of myocardial infarction and in the evaluation of new therapeutic strategies in this animal model. PMID- 30459002 TI - Clinical-pathological and immunological biomarkers in dogs with atopic dermatitis. AB - Canine atopic dermatitis (CAD) is a chronic, pruritic, genetic, and inflammatory disease. Its pathogenesis is very complex and involves skin barrier defects and immune system dysfunction. This study aimed to investigate hematological, biochemical, clinical, and immunological parameters to contribute to the identification of biomarkers applied to CAD. The results of the analysis on hematologic and clinical parameters showed increased neutrophil numbers and decreased lymphocyte counts. The ex vivo immunophenotyping of leukocytes demonstrated increased counts of circulating neutrophils, in addition to a high frequency of CD4+ T-cells and elevated CD4+/CD8+ T-cell ratio, which were the hallmark of atopic animals. Moreover, atopic dogs presented a mixed immune response, displaying both CD4+ and CD8+ T-cell subsets as relevant sources of IFN gamma and IL-4 cytokines. The morbidity analyzed by the CADESI index demonstrated that CAD severity is related to the low frequency of circulating CD14+ monocytes, CD21+ B-cells, and CD8+ T-cells. The reported biomarkers would be useful in CAD monitoring for treatment and prognosis analysis. PMID- 30459003 TI - Endometrial transcripts of proinflammatory cytokine and enzymes in prostaglandin synthesis are upregulated in the bitches with atrophic pyometra. AB - Inflammatory markers of endometrial origin are valuable in order to differentiate the pyometra from cystic endometrial hyperplasia in the bitch. In the present study, we hypothesized that histological categorization would distinguish the differential regulation of the proinflammatory genes in the endometrium of bitches with pyometra. Ovariohysterectomy was done on bitches with confirmatory diagnosis of pyometra (n = 18). Using endometrium to myometrium ratio of 0.79 as threshold, the uteri (n = 8/group) were categorized into hyperplastic pyometra (HP) and atrophic pyometra (AP). Two samples were excluded as the diagnosis was inconclusive. In parallel, endometrial tissue was collected for total RNA extraction to study the differential expression of TLR4, IL-6, IL-8, COX-2 and PGFS through real time PCR. Diestrus uterus of non-pyometra bitches (n = 6) served as control. The mean fold change (2-DeltaDeltaCt) for the target genes was determined using beta-actin as endogenous control and non-pyometra uterus as calibrator group. Except TLR4, other inflammatory genes were upregulated significantly by 1.82 to 3.74 times in the AP as compared to HP with maximum upregulation of COX-2 and PGFS. Further, correlation matrix with Spearman's rho revealed that IL-8 had strong positive correlation with COX-2 and PGFS in the AP group (P < 0.05). It is concluded that histological grading of pyometra into HP and AP revealed differential regulation of inflammatory cytokines and enzymes in the PG synthetic pathway in the canine endometrium that has diagnostic potential under clinical settings. PMID- 30459004 TI - Interleukin-4 (IL-4) may regulate alternative activation of macrophage-like cells in chickens: A sequential study using novel and specific neutralizing monoclonal antibodies against chicken IL-4. AB - In mammals, alternatively activated macrophages (AAMs) are well-recognized and are produced by stimulation with Th2 cytokines such as interleukin 4 (IL-4) and IL-13. On their mammalian counterparts, AAMs in chickens has neither been reported nor the functionality of chicken IL-4 (chIL-4) has been studied till date. Therefore, present study developed mouse monoclonal antibodies (mAbs) against chIL-4 and used these antibodies to investigate whether chIL-4 induces activation of HD11 chicken macrophage cell line. Upon characterization of mAbs using western blot, immunocytochemistry (ICC), flow cytometry and capture ELISA, activation of HD11 cells was investigated by measuring nitric oxide (NO) production, inducible nitric oxide synthase (iNOS) expression, arginase activity and gene expressions of iNOS, CD80 and CD86 (associated with mammalian M1 phenotype) and chemokine (C-C motif) ligand 17 (ccl17) and mannose receptor C type1 (MRC1L-A) (as possible chicken M2 markers) in HD11 cells treated with chIL 4, lipopolysaccharide (LPS), chIL-4+LPS, chIL-4+LPS + mAbs. The newly developed mAbs displayed wide applicability in detecting chIL-4 by capture ELISA, ICC and flow cytometry with no cross reactivities with human or mouse IL-4 and other chicken cytokines. Further, our results showed that chIL-4 inhibited NO production by LPS-stimulated HD11 cells and primary monocyte/macrophage cells with reduced iNOS expression and increased arginase activity and, induced robust expression of genes associated with M2 phenotype than M1-related genes. All these effects were neutralized by anti-chIL-4 antibodies. In summary, present study results showed a possible application of anti-chIL-4 mAbs as valuable immune reagents to explore chIL-4 functionality. In addition, our results demonstrated that chIL-4 may override LPS functionality and regulates alternative activation of HD11 cells in chicken via increased arginase activity and expression of M2 associated markers and thus may indicate the possible existence of M1/M2 paradigm in chickens. PMID- 30459005 TI - Isolation and characterization of ovine monocyte-derived macrophages from peripheral blood. AB - As key elements and targets for various intracellular pathogens, macrophages play an essential role in host defense. Although ovine peripheral blood monocyte derived cell lines have been established, their phenotypic characteristics and functional properties remain unknown. We have established several ovine macrophage cell lines from peripheral blood adherent cells that can proliferate spontaneously in long-term culture in vitro. Characteristics of macrophages were shaped by cell morphology, cell adhesion, expression of cell surface markers, phagocytic activity and inflammatory response. Furthermore, the differences of genes expression (such as membrane proteins, pro-inflammatory cytokines and chemokine) were compared between blood macrophages (BMs) and alveolar macrophages (AMs), and between BMs and splenic macrophages (SMs), respectively. The expression of membrane genes (CD11b and CD80), pro-inflammatory cytokines (IL 1beta and TNFalpha) and chemokines (IL-8/CXCL8 and CCL-21) was lower than that in AMs or SMs, but not CD200. Moreover, BMs maintained lower expression level of M1 macrophage related genes (iNOS and IDO), but high expression levels of M2 macrophage related genes (ARG2 and TGFbeta1). BMs showed lower phagocytic ability than AMs and SMs. Compared with AMs, BMs showed higher salmonella proliferation rate within cells. Collectively, BMs could suppress inflammatory responses and possessed partly phenotypic characteristics of M2 macrophages. PMID- 30459006 TI - Compatibility between a rabies vaccine and a combined vaccine against canine distemper, adenovirosis, parvovirosis, parainfluenza virus and leptospirosis. AB - In many cicumstances, veterinarians are requiring to be able to administer rabies vaccine in dogs at the same time as vaccinating against canine distemper, adenovirus, parvovirus, parainfluenza virus and leptospirosis. The aim of this study was to assess the compatibility between a multivalent vaccine and a rabies vaccine when injected at two separate sites. Lack of interference was assessed by comparing serological response to viral components during one year following primary vaccination with vaccines administered alone or concomitantly. Antibody response to all tested components was comparable, irrespective of whether vaccines were administered individually or concurrently. Notably, the rabies vaccine induced very strong and protective seroconversion in dogs, whether it was administered concomitantly with the combo vaccine or not. This facilitates administration of rabies vaccine, which is a key factor for controlling the disease. PMID- 30459007 TI - Microbiome modulates intestinal homeostasis against inflammatory diseases. AB - Eliminating prophylactic antibiotics in food animal production has exerted pressure on discovering antimicrobial alternatives (e.g. microbiome) to reduce elevated intestinal diseases. Intestinal tract is a complex ecosystem coupling host cells with microbiota. The microbiota and its metabolic activities and products are collectively called microbiome. Intestinal homeostasis is reached through dynamic and delicate crosstalk between host immunity and microbiome. However, this balance can be occasionally broken, which results in intestinal inflammatory diseases such as human Inflammatory Bowel Diseases, chicken necrotic enteritis, and swine postweaning diarrhea. In this review, we introduce the intestinal immune system, intestinal microbiome, and microbiome modulation of inflammation against intestinal diseases. The purpose of this review is to provide updated knowledge on host-microbe interaction and to promote using microbiome as new antimicrobial strategies to reduce intestinal diseases. PMID- 30459008 TI - Mortality Rate and Mid-Term Outcomes of Total Hip Arthroplasty Using Dual Mobility Cups for the Treatment of Femoral Neck Fractures in a Middle Eastern Population. AB - BACKGROUND: The dual mobility cups (DMCs) were shown to reduce dislocation rate following total hip arthroplasty for any etiology, including femoral neck fractures. No reported studies evaluating DMC results for femoral neck fracture in a Middle Eastern population were found in the literature. METHODS: This study aims to look for mortality rate, clinical, and functional outcomes in a population having specific rituals involving extreme hip positions as part of their daily activities. RESULTS: Of an initial sample of 174 patients (177 operated hips), 18 (10.3%) patients (20 hips) died after a mean of 39.6 +/- 13.8 months (ranging from 2 to 49 months) with only 3 (1.7%) during the first post operative year. Twelve patients (13 hips) were lost to follow-up and 19 patients (19 hips) had their radiological data incomplete. In the final sample of 125 patients (125 hips), no dislocation, aseptic loosening, or infection was encountered. The mean modified Hip Harris Score was of 94.8 +/- 8.4. The mean modified Hip Harris Score of 40 patients who used to practice regularly oriental sitting position or prayers was 94.1 +/- 3.1. After surgery, 36 of these 40 patients (90%) described their hip as "a forgotten hip." Multivariate analyses found correlation only between mortality and cardiovascular co-morbidities. CONCLUSION: DMC implants showed excellent clinical and functional results. The majority of patients having rituals and customs involving extreme hip positions were able to resume their daily activities. The observed low mortality rate should incite future research to investigate its correlation with the use of DMCs. PMID- 30459009 TI - Does renal function improve after parathyroidectomy in primary hyperparathyroidism? AB - INTRODUCTION: Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterised by hypercalcaemia and parathormone increase. Decreased glomerular filtration rate (<60ml/min) continues to be a parathyroidectomy (PTX) criterion in asymptomatic PHPT. The influence of PTX on renal function evolution is the subject of debate. OBJECTIVE: To analyse the clinical, laboratory and histological characteristics of patients undergoing PHPT, as well as renal function evolution after PTX. MATERIAL AND METHODS: Retrospective study of 297 patients diagnosed with PHPT and referred to surgery in a single centre between 1998 and 2016. Laboratory parameters were determined at baseline, one week and one year after PTX. RESULTS: The Incidence of PTX was 38 cases/million/year. Mean age was 60+/-14 years and 80.5% of the patients were female. Approximately 65.3% were asymptomatic. Nephrolithiasis was the most common clinical finding (33%), followed by bone involvement (29.5%). PTX indications were: clinical symptoms (34.7%), hypercalcaemia>11.2mg/dl (27%), nephrolithiasis (13%), low bone mass (12%), age<50 years (11%) and decreased glomerular filtration rate<60ml/min (2.3%). For diagnostic localisation, spect-MIBI had a sensitivity of 92% and cervical ultrasound of 70%. A total of 94.3% of PHPT cases were due to a parathyroid adenoma. After PTX, normalisation of PHPT-related parameters was observed. We found a significant increase in serum creatinine levels (0.81 vs 0.85mg/dl, P<.001) from the first week post-PTX until the end of the first year. The renal function was only found to be significant in patients with glomerular filtration rate>60ml/min (baseline serum creatinine levels 0.77mg/dl vs serum creatinine levels after one year 0.81mg/dl, P<.001). CONCLUSIONS: PHPT was asymptomatic in most patients who underwent surgery. Hypercalcaemia and nephrolithiasis were the most common indications of parathyroidectomy in asymptomatic patients. MIBI scan was the most useful localisation method. Surgical treatment of PHPT is followed by renal function impairment, which persists after the first week post-PTX. PMID- 30459010 TI - Improving handoff efficiency for admitted patients: A multidisciplinary, lean based approach. PMID- 30459011 TI - C-reactive protein or erythrocyte sedimentation rate results reliably exclude invasive bacterial infections. AB - BACKGROUND: Clinicians utilize inflammatory markers, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), to identify febrile children who may have an occult serious illness or infection. OBJECTIVES: Our objective was to determine the relationship between invasive bacterial infections (IBIs) and CRP and ESR in febrile children. METHODS: We performed a retrospective cross sectional study of 1460 febrile children <21 years of age, who presented to a single Emergency Department (ED) between 2012 and 2014 for evaluation of fever of <14 days' duration, who had both CRP and ESR obtained. Our primary outcome was IBI, defined as growth of pathogenic bacteria from a culture of cerebrospinal fluid or blood. We reviewed all ED encounters that occurred within three days of the index visits for development of IBI. We examined the negative predictive value (NPV) of CRP and ESR for IBI. RESULTS: Of the 1460 eligible ED encounters, the median patient age was 5.3 years [interquartile range (IQR) 2.4-10.0 years] and 762 (50.4%) were hospitalized. The median duration of fever was 4 days (IQR 1 7 days). Overall, 20 had an IBI (20/1460; 1.4%, 95% confidence interval (CI) 0.9 2.1%). None of those with a normal CRP (NPV 273/273; 100%, 95% CI 98.6-100%) or a normal ESR (NPV 486/486; 100%, 95% CI 99.2-100%) had an IBI. CONCLUSIONS: In our cross-sectional study of febrile children, IBI was unlikely with either a normal CRP or ESR. Inflammatory markers could be used to assist clinical decision-making while awaiting results of bacterial cultures. PMID- 30459014 TI - Discussion. PMID- 30459012 TI - Predicting the occurrence of complications following corrective cervical deformity surgery: Analysis of a prospective multicenter database using predictive analytics. AB - We developed a predictive model to describe risk factors for complications in cervical deformity surgeries. Cervical deformity (CD) surgical patients are growing in number, but remain under-studied in the literature. CD was defined as at least one of the following: C2-C7 Cobb >10 degrees , CL >10 degrees , cSVA >4 cm, CBVA >25 degrees . Patient demographics and clinical data were assessed as risk factors for medical/surgical complications using multivariate regression models. 123 patients underwent CD surgery (60.6 yrs, 60.8% F). The most common complications were neurologic (24.4%), dysphagia (13.0%), cardiopulmonary (11.4%), infection (9.7%). 51 (41.5%) of patients experienced a medical complication and 73 (59.3%) had a surgical complication. An overall complication was predicted with high accuracy (AUC = 0.79) by the following combinations of factors: higher baseline EQ5D pain and lower baseline EQ5D anxiety/depression scores, and higher cervical and global SVA. A medical complication can be predicted by male gender, baseline mJOA score, and cervical SVA (AUC = 0.770). A surgical complication can be predicted by higher estimated blood loss, lower anxiety scores, and larger global SVA (AUC = 0.739). 64.2% of patients undergoing cervical deformity correction sustained any complication. While the most reliable predictor of the occurrence of a complication involved a cluster of risk factors, a radiographic baseline sagittal parameter of cervical SVA was the strongest isolated predictor for complications across categories. Although these findings are specific to a cervical population with moderate to severe deformities, collectively they can be utilized for pre-operative risk assessment and patient education. PMID- 30459013 TI - Penumbra Occlusion Device for neurovascular vessel sacrifice: Feasibility and application. AB - PURPOSE: The purpose of this study is to describe the use of the Penumbra Occlusion Device (POD), which is a coil with an enhanced anchor segment, along with standard coils for carotid and vertebral artery sacrifice, and to assess its feasibility, safety, and efficacy. METHODS: This is a retrospective chart review of patients with vessel sacrifices who were treated using POD. For the procedure, a balloon test occlusion was performed prior to permanent arterial sacrifice. Following this, a POD was deployed followed by subsequent angiography to confirm occlusion. Secondary PODs or standard coils were deployed as necessary. RESULTS: A total of 5 internal carotid arteries and 5 vertebral arteries were treated in 10 patients. The mean vessel diameter of the vessel sacrificed was 4 mm (range 2.9-7.7 mm). The total mean number of coils required for vessel sacrifice was 7 (range 3-17). The mean number of PODs used for vessel sacrifice was 2.4 (range, 1 6). The mean number of additional standard coils used was 4.1 (range, 0-13). 9/10 (90%) parent arteries were successfully occluded. One patient had slow flow distal to the occluded segment. One (10%) of the patients had a delayed ischemic event. There were no immediate periprocedural complications including coil migrations or vessel dissections. 6/10 patients had follow-up imaging and no patients developed recanalization during the follow-up period. CONCLUSION: Parent vessel sacrifice using a combination of PODs and standard coils appear to be a feasible, safe and effective alternative to the traditional vessel sacrifice techniques. PMID- 30459015 TI - Poor glycemic control is a strong predictor of postoperative morbidity and mortality in patients undergoing vascular surgery. AB - OBJECTIVE: Hyperglycemia is a common occurrence in patients undergoing cardiovascular surgery. It has been identified in several surgical cohorts that improved perioperative glycemic control reduced postoperative morbidity and mortality. A significant portion of the population with peripheral arterial disease suffers from the sequelae of diabetes or metabolic syndrome. A paucity of data exists regarding the relationship between perioperative glycemic control and postoperative outcomes in vascular surgery patients. The objective of this study was to better understand this relationship and to determine which negative perioperative outcomes could be abated with improved glycemic control. METHODS: This is a retrospective review of a vascular patient database at a large academic center from 2009 to 2013. Eligible procedures included carotid endarterectomy and stenting, endovascular and open aortic aneurysm repair, and all open bypass revascularization procedures. Data collected included standard demographics, outcome parameters, and glucose levels in the perioperative period. Perioperative hyperglycemia was defined as at least one glucose value >180 mg/dL within 72 hours of surgery. The primary outcome was 30-day mortality, with secondary outcomes of complications, need to return to the operating room, and readmission. RESULTS: Of the total 1051 patients reviewed, 366 (34.8%) were found to have perioperative hyperglycemia. Hyperglycemic patients had a higher 30-day mortality (5.7% vs 0.7%; P < .01) and increased rates of acute renal failure (4.9% vs 0.9%; P < .01), postoperative stroke (3.0% vs 0.7%; P < .01), and surgical site infections (5.7% vs 2.6%; P = .01). In addition, these patients were also more likely to undergo readmission (12.3% vs 7.9%; P = .02) and reoperation (6.3% vs 1.8%; P < .01). Furthermore, multivariable logistic regression demonstrated that perioperative hyperglycemia had a strong association with increased 30-day mortality and multiple negative postoperative outcomes, including myocardial infarction, stroke, renal failure, and wound complications. CONCLUSIONS: This study demonstrates a strong association between perioperative glucose control and 30-day mortality in addition to multiple other postoperative outcomes after vascular surgery. PMID- 30459016 TI - Noninvasive brain stimulation over dorsolateral prefrontal cortex for pain perception and executive function in aging. AB - OBJECTIVES: Based on the evidence that the dorsolateral prefrontal cortex (DLPFC) is the main region affected by the aging process, and that tDCS modulates cortical excitability, the aim of the study is to prove the feasibility of tDCS for pain perception and executive function of community-dwelling elderly individuals. METHODS: We performed a double-blind, single-arm trial, including a sham period. 5 consecutive anodal tDCS was applied over DLPFC of twenty-four elderly for 20 min during each intervention periods (in order of Sham-1 mA-2 mA). First, we classified chronic non-inflammatory pain sites into three domain (Neck and upper extremity, low back, lower extremity). Then, we used visual analogue scale, pain self-efficacy scale, Tampa scale for kinesiophobia, and Global perceived Effect scale to observe the change in pain perception, as well as Trailing Making Test and Timed Up and Go (dual) to observe the change in executive function. The changes in maximal grip strength and 12-item Short Form survey were measured secondarily. RESULTS: In the results, we observed significant improvement in pain perception and quality of life, while executive function and grip strength did not change significantly. CONCLUSION: Our findings demonstrated the feasibility of tDCS for aging-related pain perception and suggest that further randomized controlled trials with longer duration are necessary to examine the effects on executive function. PMID- 30459017 TI - Past responsibility: History and the ethics of research on ethnic groups. AB - The article argues for the possibility of researchers' historical responsibility vis-a-vis ethnic groups. Such responsibility for a discipline's past transgressions is often attributed to anthropology, human genetics, parts of archaeology, and medicine, but without a clear conception of the nature of a responsibility supposedly going beyond the individual's own actions. Two concretizations are presented in order to show the fruitfulness and challenges of what I shall call a continuity approach: first, the case of the reburial of Sami human remains in Neiden, Norway; second, the use of the race concept in ethical and scientific contexts following the so-called New Synthesis in biology, which according to many marks a break with a racist past. Since no theory of researchers' historical responsibility towards ethnic groups exists, two partly relevant theories are brought in to provide a basis: Jenna Thompson's theory of nation states' responsibilities for past transgressions against peoples and a stance in political theory arguing that the beneficiary should pay even in cases where the beneficiary was not to blame for the original transgression. On this basis I sketch a continuity theory of historical responsibility, without which a notion of historical responsibility would be inapplicable in most actual cases. PMID- 30459018 TI - [Breastfeeding: Basic competence of primary health care professionals]. PMID- 30459019 TI - NdFeB content in ancillary motors of U.S. conventional passenger cars and light trucks: Results from the field. AB - Research into secondary recovery of rare earth elements (REE) has focused mostly on hard disk drives and automotive applications. While REE content in Japanese and European vehicles is relatively well-known, understanding of U.S. vehicles is mostly based on database analysis. An attempt to pinpoint which components contain the most REEs was conducted on four different vehicle models including the Ford F-150, Chevrolet Silverado, Toyota Corolla and Honda Accord. The disassembly data were combined with 2017 vehicles in operation to estimate stocks and flows of Neodymium-Iron-Boron (NdFeB). Results showed that U.S. vehicles had major differences compared to Japanese and European vehicles. NdFeB magnets were only found in speakers ranging from 16 to 114 g/vehicle. An estimated 3.0-14 tonnes of NdFeB could be available from end-of-life vehicles in 2018 from different cohorts of the four aforementioned models. While opportunities for recycling NdFeB in vehicles exist, challenges are also present. PMID- 30459020 TI - Association of early social environment with the onset of pediatric Kawasaki disease. AB - PURPOSE: The purpose of this study was to investigate the association of early social environment with Kawasaki disease (KD). METHODS: We analyzed the data of children aged up to 10 years derived from the 21st Century Longitudinal Survey in Newborns (n = 41,872) in Japan. Parental education, total household income, and family size were obtained via a questionnaire at 0.5 years after birth. Physician's diagnosis of KD during the past year was surveyed via a questionnaire for caregiver with children aged up to 10 years. We used Cox proportional hazards modeling to examine the risk factors for KD onset. RESULTS: Children born in households with an annual income of JPY 10 million or more were 1.76 times more likely to have KD onset compared with children born in households with an income of less than JPY 4 million (hazard ratio: 1.76, 95% confidence interval [CI]: 1.15-2.69). Children born in households with three or less persons were 1.62 times more likely to have KD onset compared with those born in households with six or more persons (95% CI: 1.10-2.40). The children who were born in urban municipalities also showed higher risk of KD onset compared with those born in rural municipalities (hazard ratio: 1.55, 95% CI: 1.06-2.26). CONCLUSIONS: Higher household income, smaller family size, and urbanization at birth were associated with increased KD incidence. This study, however, did not find a significant association between lack of exposure to infection in early life and onset of KD. PMID- 30459021 TI - Body temperature and clinical thermometry. AB - In this chapter, the nuance of body temperature is explored in the context of contemporary clinical medicine and technology. It takes the reader through the concept of body and shell as a route to explain the variety of temperature measurements that are observed in health and disease and the interdependence between skin and core temperature in maintaining thermal stability and thermal comfort perception. Methods for the measurement of temperature using different thermometer devices are discussed from the perspective of fundamental clinical assessment and vital signs, temperature monitoring and measurement for life critical decision making, thermometry in mass screening, and to the future with advances in thermometry and thermography in new applications for diagnosis. PMID- 30459022 TI - Brain temperature: from physiology and pharmacology to neuropathology. AB - Brain temperature is a physiologic parameter that depends on metabolism-related intracerebral heat production and heat loss by cerebral circulation to the rest of the body and then to the external environment. Despite the importance of temperature as a metabolism-related parameter and a factor affecting neural activity and function, it is generally believed that brain temperature is a tightly regulated and highly stable homeostatic parameter. To challenge this view, we present data on fluctuations in brain temperature occurring in rats following exposure to various arousing stimuli and during different behaviors and discuss their mechanisms. Since most psychoactive drugs affect brain metabolism and vascular tone, thereby altering heat production and heat loss, we consider changes in brain temperature induced by several types of psychoactive drugs. Our focus here is on several widely used drugs of abuse (i.e., cocaine, heroin, methylenedioxymethamphetamine (MDMA)), which are used by humans at widely varying doses and often under conditions of psychophysiologic activation and in environments limiting natural heat loss. In contrast to physiologic brain hyperthermia that has a clear adaptive significance, drug-induced hyperthermia can reach pathologic levels, resulting in irreversible damage of brain cells, profound leakage of the blood-brain barrier, and multiple functional perturbations that can, in certain instances, be incompatible with life. We also discuss the complexities of considering brain temperature within the frameworks of physiologic regulation and homeostasis. While different adaptive mechanisms could, within some limits, compensate for an altered heat balance of the brain, real-life challenges often create situations where this balance cannot be adequately compensated for, resulting in acute life-threatening health complications and chronic neuropathology. PMID- 30459023 TI - Heat exhaustion. AB - Heat exhaustion is part of a spectrum of heat-related illnesses that can affect all individuals, although children, older adults, and those with chronic disease are particularly vulnerable due to their impaired ability to dissipate heat. If left uninterrupted, there can be progression of symptoms to heatstroke, a life threatening emergency. Signs and symptoms of heat exhaustion may develop suddenly or over time. Exposure to a hot environment for a prolonged period and performing exercise or work in the heat can overwhelm the body's ability to cool itself, causing heat exhaustion. Heat exhaustion can be worsened by dehydration due to inadequate access to water or insufficient fluid replacement. Heat exhaustion can be managed by the immediate reduction of heat gain by discontinuing exercise and reducing radiative heat source exposure. The individual should be encouraged to drink cool fluids and remove or loosen clothing to facilitate heat loss. In more extreme situations, more aggressive cooling strategies (e.g., cold shower, application of wet towels) to lower core temperature should be employed. Heat related illnesses such as heat exhaustion can be prevented by increasing public awareness of the risks associated with exposure to high temperatures and prolonged exercise. PMID- 30459024 TI - Heatstroke. AB - Heatstroke is an acute medical emergency that is always fatal if left untreated. The diagnosis of heatstroke should be considered in any hyperthermic patient with altered mental status during a heat wave or following vigorous muscle exertion. Heat can damage the structure and function of essential macromolecules, including proteins, membrane lipids, and nucleic acids, and thereby lead to multiple-organ failure, culminating in death. The cytotoxic effect of heat is a function of degree and duration of hyperthermia; thus, an early diagnosis and prompt initiation of cooling are paramount to halt progression to tissue damage and death. PMID- 30459025 TI - Accidental hypothermia. AB - Accidental hypothermia causes profound changes to the body's physiology. After an initial burst of agitation (e.g., 36-37 degrees C), vital functions will slow down with further cooling, until they vanish (e.g. <20-25 degrees C). Thus, a deeply hypothermic person may appear dead, but may still be able to be resuscitated if treated correctly. The hospital use of minimally invasive rewarming for nonarrested, otherwise healthy patients with primary hypothermia and stable vital signs has the potential to substantially decrease morbidity and mortality for these patients. Extracorporeal life support (ECLS) has revolutionized the management of hypothermic cardiac arrest, with survival rates approaching 100%. Hypothermic patients with risk factors for imminent cardiac arrest (i.e., temperature <28 degrees C, ventricular arrhythmia, systolic blood pressure <90 mmHg), and those who have already arrested, should be transferred directly to an ECLS center. Cardiac arrest patients should receive continuous cardiopulmonary resuscitation (CPR) during transfer. If prolonged transport is required or terrain is difficult, mechanic CPR can be helpful. Intermittent CPR may be appropriate in hypothermic arrest when continuous CPR is impossible. Modern postresuscitation care should be implemented following hypothermic arrest. Structured protocols should be in place to optimize prehospital triage, transport, and treatment as well as in-hospital management, including detailed criteria and protocols for the use of ECLS and postresuscitation care. PMID- 30459026 TI - Fever and hypothermia in systemic inflammation. AB - Systemic inflammation-associated syndromes (e.g., sepsis and septic shock) often have high mortality and remain a challenge in emergency medicine. Systemic inflammation is usually accompanied by changes in body temperature: fever or hypothermia. In animal studies, systemic inflammation is often modeled by administering bacterial lipopolysaccharide, which triggers autonomic and behavioral thermoeffector responses and causes either fever or hypothermia, depending on the dose and ambient temperature. Fever and hypothermia are regulated changes of body temperature, which correspond to mild and severe forms of systemic inflammation, respectively. Mediators of fever and hypothermia are called endogenous pyrogens and cryogens; they are produced when the innate immune system recognizes an infectious pathogen. Upon an inflammatory challenge, hepatic and pulmonary macrophages (and later brain endothelial cells) start to release lipid mediators, of which prostaglandin (PG) E2 plays the key role, and cytokines. Blood PGE2 enters the brain and triggers fever. At later stages of fever, PGE2 synthesized within the blood-brain barrier maintains fever. In both cases, PGE2 is synthesized by cyclooxygenase-2 and microsomal PGE2synthase-1. Mediators of hypothermia are not well established. Both fever and hypothermia are beneficial host defense responses. Based on evidence from studies in laboratory animals and clinical trials in humans, fever is beneficial for fighting mild infection. Based mainly on animal studies, hypothermia is beneficial in severe systemic inflammation and infection. PMID- 30459027 TI - Stress-induced hyperthermia and hypothermia. AB - Stress affects core body temperature (Tc). Many kinds of stress induce transient, monophasic hyperthermia, which diminishes gradually if the stressor is terminated. Stronger stressors produce a longer-lasting effect. Repeated/chronic stress induces anticipatory hyperthermia, reduces diurnal changes in Tc, or slightly increases Tc throughout the day. Animals that are exposed to chronic stress or a cold environment exhibit an enhanced hyperthermic response to a novel stress. These changes persist for several days after cessation of stress exposure. In contrast, long-lasting inescapable stress sometimes induces hypothermia. In healthy humans, psychologic stress induces slight increases in Tc, which are within the normal range of Tc or just above it. Some individuals, however, develop extremely high Tc (up to 41 degrees C) when they are exposed to emotional events or show persistent low-grade high Tc (37-38 degrees C) during or after chronic stress situations. In addition to the nature of the stressor itself, such stress-induced thermal responses are modulated by sex, age, ambient temperature, cage mates, past stressful experiences and cold exposure, and coping. Stress-induced hyperthermia is driven by mechanisms distinct from infectious fever, which requires inflammatory mediators. However, both stress and infection activate the dorsomedial hypothalamus-rostral medullary raphe region sympathetic nerve axis to increase Tc. PMID- 30459028 TI - Body temperature regulation and drugs of abuse. AB - Phenethylamine-induced hyperthermia can occur following exposure to several different types of illicit stimulants, such as amphetamine, methamphetamine, 3,4 methylenedioxymethamphetamine ("Molly"), synthetic cathinones ("bath salts"), and N-methoxybenyl ("NBOMe"), to name a few. Peripheral norepinephrine release mediated by these sympathomimetic agents induces a double-edged sword of heat accumulation through beta-adrenoreceptor-dependent activation of uncoupling protein (UCP1 and 3)-regulated thermogenesis and loss of heat dissipation through alpha1-adrenoreceptor-mediated vasoconstriction. Additionally, thyroid hormones are important determinants of the capacity of thermogenesis induced by phenethylamines through the regulation of free fatty acid release and the transcriptional activation of a host of metabolic genes, including adrenergic receptors and mitochondrial uncoupling proteins. Here, we review the central and peripheral mechanistic "triggers" of phenethylamine-induced hyperthermia and outline potential pharmacologic interventions for managing phenethylamine-induced hyperthermia based on these recently discovered hyperthermia mediators. PMID- 30459029 TI - Body temperature regulation and anesthesia. AB - General anesthesia is the induction and maintenance of a state of unconsciousness with the absence of pain sensation. General anesthesia is accomplished by the administration of a combination of inhaled anesthetic gases and intravenous drugs. These medications eliminate behavioral thermoregulatory compensations, leaving only autonomic defenses to offset environmental perturbations. Anesthetics inhibit thermoregulatory control in a dose-dependent fashion over the entire clinical range. Impairment of thermoregulatory control is observed by a change in thermoregulatory thresholds with the vasoconstriction threshold being affected about three times as much as the sweating threshold. Consequently, the zone between sweating and vasoconstriction thresholds, called interthreshold range, is widened dose-dependently. Impairment of thermoregulation, triggered by general anesthesia, typically causes inadvertent hypothermia. In febrile patients, general anesthesia reduces the magnitude of perioperative fever. PMID- 30459030 TI - Malignant hyperthermia. AB - Malignant hyperthermia (MH) is a form of heat illness caused by increased heat generation exceeding the body's capacity for heat loss. It is classified separately from other forms of heat illness as the latter require assessment of mental function for differential diagnosis. This is not possible with MH which occurs during general anesthesia when mental function cannot be assessed. MH occurs in genetically predisposed individuals exposed to inhalation anesthetics or succinylcholine. The genetic defects identified so far cause perturbation of skeletal muscle excitation-contraction coupling resulting in myoplasmic calcium dysregulation. The most commonly involved gene is RYR1. Increased myoplasmic calcium leads to hypermetabolism and sustained muscle contractile activity with consequent increased oxygen consumption, carbon dioxide production, sympathetic stimulation, muscle rigidity, heat production, rhabdomyolysis, and disseminated intravascular coagulation. Untreated reactions are fatal. In this chapter we summarize clinical features and management and review current understanding of the pathophysiology and molecular genetics of MH. PMID- 30459031 TI - Neuroleptic malignant syndrome and serotonin syndrome. AB - The clinical manifestation of drug-induced abnormalities in thermoregulation occurs across a variety of drug mechanisms. The aim of this chapter is to review two of the most common drug-induced hyperthermic states, serotonin syndrome and neuroleptic malignant syndrome. Clinical features, pathophysiology, and treatment strategies will be discussed, in addition to differentiating between these two syndromes and differentiating them from other hyperthermic or febrile syndromes. Our goal is to both review the current literature and to provide a practical guide to identification and treatment of these potentially life-threatening illnesses. The diagnostic and treatment recommendations made by us, and by other authors, are likely to change with a better understanding of the pathophysiology of these syndromes. PMID- 30459032 TI - Acral coldness - severely reduced blood flow to fingers and toes. AB - The term acral coldness is used to describe physiologic or pathologic situations in humans where the fingers and toes are exceptionally cold in spite of normal central body temperature. In the thermoneutral zone, the blood flow to acral skin normally shows large fluctuations between high and low values, with a frequency of about 3 cycles per minute. At an acral skin temperature of about 21 degrees C, finger blood flow is constantly low. At lower temperatures the fingers and toes become painful. This is a normal physiologic reaction, probably because of ischemia. The characteristics of the most frequent acral vascular syndromes, Raynaud phenomenon, acrocyanosis, and chilblains, are discussed. Common to all three is pathologically low blood flow and disappearance of physiologic fluctuations even in the thermoneutral zone. Ischemic vascular diseases in acral skin are usually diagnosed from clinical observations. Measurements of fluctuating blood flow by laser or ultrasound Doppler could be useful, but should be carried out at a room temperature of 24-25 degrees C. PMID- 30459033 TI - Consequences of perioperative hypothermia. AB - Perioperative hypothermia is common, with an incidence ranging between 20 and 70%, and is defined by a body core temperature below 36.0 degrees C. Perioperative warming was rare during the previous century, but was subsequently identified as a significant contributor to perioperative morbidity and mortality. Perioperative hypothermia causes impaired pharmacodynamics, surgical site infections, blood loss and coagulopathy, transfusion requirements, thermal discomfort, prolonged recovery, and prolonged duration of hospitalization. Measurement of central core temperature, maintaining normothermia, and consequent warming of patients in the perioperative period are therefore essential. Several warming devices are commercially available, including active skin warming as the most efficient, inexpensive, easy-to-use and mostly having a good cost/benefit ratio for the majority of patients and surgeries. PMID- 30459034 TI - Thermoregulatory dysfunction in multiple sclerosis. AB - Multiple sclerosis (MS) is a progressive neurologic disorder that disrupts axonal myelin in the central nervous system. Demyelination produces alterations in saltatory conduction, slowed conduction velocity, and a predisposition to conduction block. An estimated 60-80% of MS patients experience temporary worsening of clinical signs and neurologic symptoms with heat exposure (Uhthoff's phenomenon). This heat intolerance in MS is related to the detrimental effects of increased temperature on action potential propagation in demyelinated axons, resulting in conduction slowing and/or block. Additionally, MS may produce impaired neural control of autonomic and endocrine functions. Isolating and interpreting mechanisms responsible for autonomic dysfunction due to MS can be difficult as it may involve sensory impairments, altered neural integration within the central nervous system, impaired effector responses, or combinations of all of these factors. MS lesions occur in areas of the brain responsible for the control and regulation of body temperature and thermoregulatory effector responses, resulting in impaired neural control of sudomotor pathways or neural induced changes in eccrine sweat glands, as evidenced by observations of reduced sweating responses in MS patients. Although not comprehensive, some evidence exists concerning treatments (cooling, precooling, and pharmacologic) for the MS patient to preserve function and decrease symptom worsening during heat stress. This review focuses on four main themes influencing current understanding of thermoregulatory dysfunction in MS: (1) heat intolerance; (2) central regulation of body temperature; (3) thermoregulatory effector responses; and (4) countermeasures to improve or maintain function during thermal stress. PMID- 30459035 TI - Thermoregulation in Parkinson disease. AB - Autonomic dysfunction in Parkinson disease encompasses thermoregulatory symptoms and was first noted by Gowers in the late 19th century when he described abnormal temperature sensation and sweating in Parkinson disease patients. These thermoregulatory symptoms became more recognized in the postlevodopa era when Parkinson disease patients were more readily tested with objective autonomic function tests. Objective thermoregulatory testing in Parkinson disease reveals deficits of sweating and vasomotor tone which often correlate with the severity of other autonomic deficits. Tests of thermoregulatory function can also be used to differentiate Parkinson disease from other neurodegenerative disorders. The pathophysiology of thermoregulatory dysfunction in Parkinson disease encompasses both central and peripheral mechanisms; involvement of the brainstem and hypothalamus with alpha-synuclein pathology is well recognized with increasing evidence of peripheral neuropathy in Parkinson disease that influences thermoregulation. Medications used to treat Parkinson disease also affect thermoregulatory symptoms. Disorders of thermoregulation significantly affect the quality of life for patients and their caregivers and can be severe and even life threatening, such as in the parkinsonism-hyperpyrexia syndrome. PMID- 30459036 TI - Hypothermia as a risk factor for Alzheimer disease. AB - Alzheimer disease (AD), which is associated with chronic and progressive neurodegeneration, is the most prevalent cause of dementia linked to aging. Among the risk factors for AD, age stands as the greatest one, with the vast majority of people with AD being 65 years of age or older. Nevertheless, the pathophysiologic mechanisms underlying the link between aging and the development of AD, although not completely understood, might reveal important aspects for the understanding of this pathology. Thus, there is significant evidence that the impaired thermal homeostasis associated with normal aging leads to a variety of metabolic changes that could be associated with AD development. In this chapter, we assess the clinical and biochemical evidence implicating hypothermia as a risk factor for the development of AD and the impact of hypothermia on the two pathologic hallmarks of AD: accumulation of senile plaques of amyloid-beta and neurofibrillary tangles of aberrant hyperphosphorylated tau protein. PMID- 30459037 TI - Thermoregulation in epilepsy. AB - Several aspects of thermoregulation play a role in epilepsy. Circuitries involved in thermoregulation are affected by seizures and epilepsy, hyperthermia may be both cause and result of seizures, and hypothermia may prevent or abort seizures. Autonomic manifestations of seizures including thermoregulatory disturbances are common in a variety of clinical epilepsy syndromes. Experimental hyperthermia has been studied extensively, predominantly to investigate febrile seizures of childhood. In particular prolonged or complex febrile seizures have been associated with the later development of epilepsy in adulthood and the pathophysiology of how febrile seizures cause epilepsy is of tremendous interest. Febrile seizures represent an opportunity to potentially intervene early in life in susceptible individuals and affect epileptogenesis. The pathophysiologic underpinnings of how hyperthermia induces seizures and how this in turn results in epilepsy are controversial, but likely involve multiple factors. Both glutamatergic and GABAergic neurotransmission is affected, and numerous mutations in genes encoding ion channels have been identified. Cytokines such as interleukin-1beta have been implicated in febrile seizures as well as susceptibility to provoked seizures later in life. Hyperthermia is a common feature of generalized convulsive status epilepticus, but may also be seen with nonconvulsive seizures, indicating involvement of thermoregulatory centers. PMID- 30459038 TI - Thermoregulation in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is the major adult-onset motor neuron disease, and is clinically, pathologically, and genetically associated with frontotemporal dementia, the second cause of dementia in the elderly. Here, we review the evidence linking thermoregulation and ALS. Indeed, while ALS is not classically associated with defective thermoregulatory function, its progression severely affects key brain regions controlling body temperature and impacts multiple sensors and effectors of this homeostatic function. Furthermore, animal models of ALS display disturbed thermoregulation as a consequence of disrupted energy homeostasis. All these lines of indirect evidence call for studies directly addressing the body temperature regulatory system, both as a potential biomarker and as a possible modifier of disease progression in ALS. PMID- 30459039 TI - Thermoregulatory disorders in Huntington disease. AB - Huntington disease (HD) is a paradigmatic autosomal-dominant adult-onset neurodegenerative disease. Since the identification of an abnormal expansion of a trinucleotide repeat tract in the huntingtin gene as the underlying genetic defect, a broad range of transgenic animal models of the disease has become available and these have helped to unravel the relevant molecular pathways in unprecedented detail. Of note, some of the most informative of these models develop thermoregulatory defects such as hypothermia, problems with adaptive thermogenesis, and an altered circadian temperature rhythm. Both central, e.g., in the hypothalamus and peripheral, i.e., the brown adipose tissue and skeletal muscle, problems contribute to the phenotype. Importantly, these structures and pathways are also affected in human HD. Yet, currently the evidence for bona fide thermodysregulation in human HD patients remains anecdotal. This may be due to a lack of reliable tools for monitoring body temperature in an outpatient setting. Regardless, study of the temperature phenotype has contributed to the identification of unexpected molecular targets, such as the PGC-1alpha pathway. PMID- 30459040 TI - Thermoregulation in neuropathies. AB - Peripheral neuropathy affecting autonomic and small sensory fibers can cause abnormalities of both autonomic and behavioral thermoregulation. Quantitative autonomic and sensory neurophysiologic tests and quantification of the linear density of intraepidermal nerve fibers potentially can stratify those at risk of impaired thermoregulation during cold and heat challenges. New data relating to thermoregulatory sweating impairment in neuropathy are presented in this chapter. Of 516 neuropathy patients analyzed, 345 were found to have thermoregulatory sweat test (TST) abnormalities with a mean percentage of anterior body surface anhidrosis (TST%) of 12% and a significant reduction in total body sweat rate, although the rate of core temperature rise with heating (slope) was not significantly different from that of patients with a normal TST. However a subset of abnormal TST patients having 25% or greater TST% showed a significantly more rapid rise in core temperature (lower slope) than age- and sex-matched neuropathy patients with a normal TST. Etiologies of neuropathy in this more severe group included diabetes, erythromelalgia, immune-mediated autonomic neuropathy, primary systemic amyloidosis, and neuropathy associated with postganglionic-autonomic degenerative disorders. PMID- 30459041 TI - Thermoregulation in brain injury. AB - Different mechanisms explain thermoregulatory dysfunction following ischemic stroke, hemorrhagic stroke, and traumatic brain injury. Temperature instability following brain injury likely involves hypothalamic injury, pathologic changes in cerebral blood flow, metabolic derangement, and a neurogenic inflammatory response. Although targeted temperature management (TTM) exerts pleiotropic effects, the heterogeneity of brain injury has hindered identification of patient subsets most likely to benefit from TTM. Early optimism about TTM's role in brain injury has been tempered by the failure of successive clinical trials to show improved patient outcomes. However, given the deleterious effects of fever, aggressive fever management is still warranted in the critically ill neurologic patient. PMID- 30459042 TI - Thermoregulation following spinal cord injury. AB - Spinal cord injury results in physiologic adaptations affecting heat production (reduced muscle mass) and heat dissipation (blood redistribution and reduced sweating capacity below the level of lesion). However, it is the balance between these factors which determines whether heat balance is achieved. Core temperature estimates are generally consistent with those for the able-bodied, with cooler values reported in some instances. More notable differences are demonstrated through cooler lower-body skin temperatures at rest and a loss of anticipatory control during exposure to heat and cold when compared to the able-bodied. During exercise in cool conditions persons with paraplegia demonstrate similar body temperature responses as for the able-bodied but retain heat during recovery. Persons with tetraplegia demonstrate continual increases in core temperature and thus thermal imbalance along with greater heat retention. During exercise in the heat, athletes with paraplegia appear to be able to regulate body temperature to a similar extent as the able-bodied. Those with tetraplegia again show thermal imbalance but to a much greater extent than in the cold. Future work should focus upon specific sweating responses and adaptations following spinal cord injury, the effects of completeness of lesion, perceptual responses to environmental challenges, and how these translate to undertaking activities of daily living. PMID- 30459043 TI - Hypothermia in acute ischemic stroke therapy. AB - Therapeutic hypothermia (TH) is a potent neuroprotective therapy in experimental cerebral ischemia, with multiple effects at several stages of the ischemic cascade. In animals, TH is so powerful that all preclinical stroke studies require strict temperature control. In humans, multiple clinical studies documented powerful protection with TH after accidental neonatal hypoxic-ischemic injury and global cerebral ischemia with return of spontaneous circulation after cardiac arrest. National and international guidelines recommend TH for selected survivors of global ischemia, with profound benefits seen. Recently, a study comparing target temperature 33-36 degrees C failed to demonstrate significant effects in cardiac arrest patients. Additionally, clinical trials of TH for head trauma and stroke have so far failed to confirm benefit in humans despite a vast preclinical literature. Therefore, it is now critical to understand the fundamental explanation for the success of TH in some, but famously not all, clinical trials. TH in animals appears to work when used soon after ischemia onset; for a short duration; and at a deep target temperature. PMID- 30459044 TI - Selective brain hypothermia. AB - Selective brain hypothermia is a powerful concept for neuroprotection that has been successfully investigated in a variety of animal models of global and focal ischemia. Its major advantages over systemic hypothermia include rapid induction of cooling, ability to achieve profound target brain temperatures, organ selective cooling, and temperature control. Clinical systems and devices are available or are currently under development that utilize conductive (surface cooling pads, closed-loop catheters), convective (transnasal coolant delivery), or mass and energy transport (cold intra-arterial infusion) methods to achieve and maintain selective brain hypothermia. The "ideal" brain-cooling system that is characterized by rapid cooling to profound hypothermia, its ability to maintain selective cooling over several days, and is noninvasive in nature, remains unrealistic. Instead, systems may be identified by their distinct advantages to meet a specific need in the care of a patient. This involves the consideration of the timing of ischemic injury (preischemic, intraischemic, postischemic), extent of ischemic damage (excitotoxicity, inflammation, necrosis, edema), and type and setting of therapeutic intervention (intensive care, interventional therapy, surgery). The successful translation of these systems into clinical practice will depend on smart engineering, safety and efficacy, and usability in current clinical work flow. PMID- 30459045 TI - Therapeutic hyperthermia. AB - The term hyperthermia broadly refers to either an abnormally high fever or the treatment of a disease by the induction of fever. Its effect depends on the temperature and exposure time. The increasing number of applications and clinical trials at universities, clinics, and hospitals prove the feasibility and applicability of clinical therapeutic hyperthermia. This chapter aims to outline and discuss the means by which electromagnetic energy and other techniques can provide elevation of temperature within the human body. Because of the individual characteristic of each type of treatment, different modalities of heating systems have evolved. The chapter concludes with a discussion of challenges and opportunities for further improvement in technology and routine clinical application. PMID- 30459046 TI - Antipyretic therapy: clinical pharmacology. AB - Fever depends on a complex physiologic response to infectious agents and other conditions. To alleviate fever, many medicinal agents have been developed over a century of trying to improve upon aspirin, which was determined to work by inhibiting prostaglandin synthesis. We present the process of fever induction through prostaglandin synthesis and discuss the development of pharmaceuticals that target enzymes and receptors involved in prostaglandin-mediated signal transduction, including prostaglandin H2 synthase (also known as cyclooxygenase), phospholipase A2, microsomal prostaglandin E2 synthase-1, EP receptors, and transient potential cation channel subfamily V member 1. Clinical use of established antipyretics will be discussed as well as medicinal agents under clinical trials and future research. PMID- 30459049 TI - Prevalence of depression in a sample of non-institutionalized peruvian elderly. PMID- 30459050 TI - Adherence to inhaled therapy in the outpatient setting. AB - OBJECTIVE: To find out the degree of adherence to inhaled therapy in patients with Chronic Obstructive Pulmonary Disease (COPD) and asthma in a pulmonology clinic. To identify the type of non-compliance and the different factors affecting it. METHOD: A descriptive, cross-sectional study in which 124 patients were included. Adherence was assessed using the 'Test of Adherence to Inhalers' (TAI) questionnaire. RESULTS: A total of 62 women and 62 men were recruited and the average age was 63. Fifty-one point 6percent of the patients had COPD, and 48.4% were asthmatics. Thirty-eight point 7percent of the them showed high adherence, 37.9% showed intermediate adherence and 23.4%, low adherence. In terms of non-compliance, 13.7% was erratic, 4.8% was deliberate, and 28.2%, unwitting. Patients with a basic level of education had better compliance than the others (P=.05), and patients with COPD showed higher adherence than the asthmatics (P=.02). Age, gender and the trainer did not indicate significant statistical differences. CONCLUSION: 38.7% of patients show high adherence to inhaled therapy, with a predominance of unwitting non-compliance. Patients with COPD and with a basic level of education showed higher levels of adherence. The training given by the pulmonologist and the respiratory nurse seemed to improve adherence to these treatments, although no significant differences were found. PMID- 30459051 TI - The emotional universe of women affected by hepatitis C: A hermeneutic approach. AB - OBJECTIVES: Understanding the emotional universe of women from Cordoba affected by hepatitis C. METHOD: Hermeneutic qualitative study. Participants met the criteria of being adult women with a current diagnosis of hepatitis C and belonging to the Plataforma de Afectad@s por la Hepatitis C of Cordoba. The intentional sampling was nominated and followed a criterion of intensity. Data collection was conducted through in-depth interviews. The analysis took place in 3levels: Explanation, naive understanding and in-depth understanding. In the second level, the metaphor universe of emotions was incorporated, which is a taxonomy that organizes emotions into clusters of galaxies to facilitate understanding of affective phenomena. RESULTS: Four participants were included. Seven themes roam the galaxies in the emotional universe of women. "Damned disease" explores their disgust, sadness and shame. "Intimate affections" focuses on happiness and love as well as sadness. "Friendship-platform" focuses on understanding, welfare and affection. "Physicians" deal with distrust and disappointment regarding new treatment, and with "curing" sadness, fear, anxiety and hope. "State of ill-being" focuses on anxiety. And "universal access now" explores anger. CONCLUSIONS: Despite the presence of love in the complex emotional universe of women with hepatitis C, anger, sadness and anxiety are highlighted. Hermeneutics of their emotions facilitates nursing care and nursing research humanization. PMID- 30459052 TI - Individual and environmental factors associated with green exercise in urban and suburban areas. AB - In this study, we mainly aimed to explore the associations of personal and socio demographic factors, and the supply of green areas and built sports facilities with green exercise (GE). We also compared the residents of the core urban area and suburban areas according to the level of leisure time physical activity (LTPA) they had. A population-based sample of 3730 adults (aged 25-101 y) from Finland, filled out a questionnaire in 2015. Variables describing the supply of green areas and built sports facilities were objectively calculated. The green areas were classified into small (<25 ha), middle-sized (25-150 ha) and large (>150 ha) areas to reflect their qualities for GE. The data analysis methods included multinomial logistic regression, t-, and Chi Square tests. Our results indicate that having a short distance to at least a middle-sized green area and high nature relatedness are important for participation in GE, both in core urban and suburban areas. More factors were found to be related to GE in the suburban areas compared to core urban areas and among the low LTPA compared to the high LTPA group. PMID- 30459053 TI - Weight loss but not gains in cardiorespiratory fitness after exercise-training predicts improved health risk factors in metabolic syndrome. AB - BACKGROUND AND AIMS: To examine the relationship between changes in cardiorespiratory fitness (CRF; estimated by VO2max) and metabolic syndrome (MetS) after an exercise training intervention to confirm/contradict the high association found in cross-sectional observational studies. METHODS AND RESULTS: MetS individuals (54 +/- 8 yrs old; BMI of 32 +/- 5) were randomly allocated (6:1 ratio) to a group that exercised trained for 16-weeks (EXER; n = 138) or a control sedentary group (CONT; n = 22). At baseline, MetS components, body composition and exercise responses were similar between groups (all P > 0.05). After 16 weeks of intervention, only EXER reduced body weight, waist circumference (-1.21 +/- 0.22 kg and -2.7 +/- 0.3 cm; P < 0.001), mean arterial blood pressure and hence the composite MetS Z-score (-7.06 +/- 0.77 mmHg and 0.21 +/- 0.03 SD; P < 0.001). In the EXER group, CRF increased by 16% (0.302 +/- 0.026, 95% CI 0.346 to 0.259 LO2.min-1; P < 0.001) but was not a significant predictor of MetS Z-score improvements (r = -0.231; beta = -0.024; P = 0.788). Instead, body weight reductions predicted 25% of MetS Z-score changes (r = 0.508; beta = 0.360; P = 0.001). CONCLUSIONS: In MetS individuals, the exercise-training increases in CRF are not predictive of the improvements in their health risk factors. Instead, body weight loss (<2%) was a significant contributor to the improved MetS Z-score and thus should be emphasized in exercise training programs. ClinicalTrials.gov identifier: NCT03019796. PMID- 30459054 TI - Comparison of a Mediterranean to a low-fat diet intervention in adults with type 1 diabetes and metabolic syndrome: A 6-month randomized trial. AB - BACKGROUND AND AIMS: The metabolic syndrome (MS) is an emerging complication in patients with type 1 diabetes (T1D), with no preventive or therapeutic treatment reported yet. We wanted to compare the impact of two 6-month nutritional interventions, based on a Mediterranean (MED) or a low-fat diet, on waist circumference, anthropometric and metabolic outcomes in patients with both T1D and the MS. METHODS AND RESULTS: Participants were randomized into 2 intervention groups: 1) MED-diet or 2) low-fat diet. The 6-month study included 9 teaching sessions with a registered dietitian. Anthropometric (primary outcome: waist circumference), metabolic and nutritional assessments were performed at inclusion, 3 and 6-month. We used mixed effects models to assess the effects of both interventions. 28 participants were included (50.9 +/- 10.3 years old) with a mean BMI of 30.7 +/- 3.3 kg/m2 and a waist circumference of 105.5 +/- 8.9 cm at inclusion. A trend towards a greater reduction of dietary fat intakes in the low fat diet group was observed (P-interaction = 0.09). Waist circumference was reduced at 6-month in both groups (-3.5 cm low-fat; -1.5 cm MED-diet) with no significant difference between groups (P-interaction = 0.43). Body mass index also significantly decreased in both groups (-0.7 kg/m2 low-fat; -1.1 kg/m2 MED diet; P-interaction = 0.56). No significant differences between groups were observed for other metabolic parameters. CONCLUSIONS: This study suggests that a 6-month non-restrictive dietary intervention in patients with T1D and MS could contribute to weight management, without significant differences between interventions for anthropometric and metabolic parameters. Further studies should investigate the long-term benefits of these diets. CLINICAL TRIAL REGISTRY: NCT02821585 (https://clinicaltrials.gov/). PMID- 30459055 TI - Elevated high density lipoprotein cholesterol and low grade systemic inflammation is associated with increased gut permeability in normoglycemic men. AB - BACKGROUND & AIMS: Serum lipids and lipoproteins are established biomarkers of cardiovascular disease risk that could be influenced by impaired gut barrier function via effects on the absorption of dietary and biliary cholesterol. The aim of this study was to examine the potential relationship between gut barrier function (gut permeability) and concentration of serum lipids and lipoproteins, in an ancillary analysis of serum samples taken from a previous study. METHODS AND RESULTS: Serum lipids, lipoproteins and functional gut permeability, as assessed by the percentage of the urinary recovery of 51Cr-labelled EDTA absorbed within 24 h, were measured in a group of 30 healthy men. Serum lipopolysaccharide, high sensitivity C-reactive protein and interleukin-6 were also measured as markers of low-grade inflammation. The group expressed a 5-fold variation in total gut permeability (1.11-5.03%). Gut permeability was unrelated to the concentration of both serum total and low density lipoprotein (LDL) cholesterol, but was positively associated with serum high density lipoprotein (HDL)-cholesterol (r = 0.434, P = 0.015). Serum HDL-cholesterol was also positively associated with serum endotoxaemia (r = 0.415, P = 0.023). CONCLUSION: The significant association between increased gut permeability and elevated serum HDL-cholesterol is consistent with the role of HDL as an acute phase reactant, and in this situation, potentially dysfunctional lipoprotein. This finding may have negative implications for the putative role of HDL as a cardio-protective lipoprotein. PMID- 30459056 TI - Is lower low-density lipoprotein cholesterol associated with lower androgen and erectile dysfunction in men? AB - BACKGROUND AND AIMS: Therapeutic possibilities now exist to lower low-density lipoprotein cholesterol (LDL-C) to very low levels. However, substantial controversy remains in clinical practice with regard to its safety, and the question of whether low LDL-C levels per se may provoke adverse effects in humans arises. We aimed to explore the association of LDL-C with androgen and erectile dysfunction (ED) in a general population of men. METHODS AND RESULTS: A total of 4203 men without hormone replacement therapy were enrolled from 22 sites in East China. Total testosterone (T) and Free T were assessed. Free androgen index (FAI) was calculated. The IIEF-5 questionnaire was used to assess ED. We found that free T and FAI gradually and markedly increased with increasing LDL-C levels. Using linear regression, after adjusting for age, educational level, economic status, smoking status, drinking status, BMI, diabetes, and use of lipid-lowering medication, LDL-C was positively associated with free T (B = 0.175, 95% CI: 0.084, 0.266) and FAI (B = 0.064, 95% CI: 0.016, 0.112). Meanwhile, there was a U shaped curvilinear relationship between LDL-C and prevalence of ED. In the logistic regression analysis, compared to those with LDL-C among the 10th-90th percentile, the ORs of ED in men in the lowest and highest deciles were 1.938 (95% CI: 1.121, 3.349) and 1.804 (95% CI: 1.117, 2.916), respectively. CONCLUSION: Lower LDL-C levels were significantly associated with lower free T and lower FAI in a general population of men. Moreover, both low and high levels of LDL-C might be risk factors for ED. PMID- 30459057 TI - Iron deficiency anaemia secondary to small-bowel diaphragm disease not associated with NSAIDs. Is there anything else to consider? PMID- 30459058 TI - Utility of histology for the diagnosis of portal hypertensive gastroenteropathy. Concordance between the endoscopic image and gastrointestinal biopsies. Role of the CD34 marker. AB - INTRODUCTION: Upper gastroscopy in patients with cirrhosis often reveals non specific lesions, which are usually oriented as portal hypertensive gastropathy (PHG). However, the diagnosis of PHG can be difficult, both from an endoscopic and histological point of view. The study of CD34 expression, which enhances the endothelial cells of the microvasculature, could help the differential diagnosis. The objectives of this study were to evaluate the correlation between endoscopy and histology in the diagnosis of PHG and to assess the utility of CD34 in the diagnosis of PHG. MATERIAL AND METHODS: The results of immunostaining with CD34 gastric fundus biopsies from 100 cirrhotic patients and 20 controls were compared with the endoscopic images. RESULTS: The correlation between the histology and the endoscopic diagnosis of PHG was very low (kappa=0.15). In addition, the measurement of the diameter of the gastric vessels enhanced by the use of immunohistochemical staining (CD34) did not show good correlation with the endoscopic diagnosis (p=.26) and did not provide relevant information for the histological diagnosis of PHG either. DISCUSSION: The correlation between histology and endoscopy is low for the diagnosis of PHG. The use of immunostaining for CD34 does not seem to improve the diagnostic yield of the histological study. PMID- 30459059 TI - Zieve's syndrome, an underdiagnosed entity. PMID- 30459060 TI - Faecal immunochemical tests for haemoglobin (FIT) in the assessment of patients with lower abdominal symptoms: current controversies. AB - Faecal immunochemical tests for haemoglobin (FIT), as an adjunct to clinical information, assist in the triage of patients presenting in primary care with lower abdominal symptoms. Controversy remains regarding whether and which qualitative and quantitative FIT can be used, which groups of patients would benefit most from FIT, whether FIT should be done in primary and/or secondary care, and how FIT should be incorporated into diagnostic pathways. Controversy also exists as to the optimum cut-off used for referral for colonoscopy. A single sample of faeces may be sufficient. Reporting of results requires consideration. FIT provide a good rule in test for colorectal cancer and a good rule out test for significant bowel disease, but robust safety-netting is required for patients with negative results and ongoing symptoms. Risk scoring models have been developed, but their value is unclear as yet. Further evaluation of these topics is required to inform good practice. PMID- 30459061 TI - Racial and Ethnic Disparities in Renal Cell Carcinoma: An Analysis of Clinical Characteristics. AB - BACKGROUND: Racial/ethnic minority groups, including Hispanic Americans (HAs) and Native Americans (NAs), have a heavier burden of kidney cancer than European Americans (EAs). We investigated variations in clinical characteristics of HA and NA patients with renal cell carcinoma (RCC) who were previously underrepresented. MATERIALS AND METHODS: Clinical records of 294 patients with RCC (151 EAs, 95 HAs, 22 NAs, and 26 others) without prior diagnosis of cancer were reviewed. Logistic regression analysis was performed to understand patients' clinical characteristics. RESULTS: HAs had about 5 years younger average age at diagnosis than EAs (55.8 vs. 60.5 years) and an almost 3-fold increased odds of diagnosis before age 50 years (odds ratio [OR], 2.77; 95% confidence interval [CI], 1.39 5.54). The mean age of diagnosis among NAs was 49.7 years, and NAs had an over 6 fold higher odds of diagnosis at a younger age (OR, 6.23; 95% CI, 2.00-19.46). Clear-cell RCC (ccRCC) was more common in HAs and NAs than EAs. Over 90% of HA patients had ccRCC, whereas only 78.8% of EA patients had ccRCC. HAs had increased odds of diagnosis with ccRCC compared with EAs (OR, 2.79; 95% CI, 1.15 6.80). Among HAs, older patients and patients who spoke Spanish as their primary language were more likely to have advanced stage RCC at diagnosis (OR, 10.48; 95% CI, 1.69-64.89 and OR, 4.61; 95% CI, 1.38-15.40). CONCLUSION: HA and NA patients with RCC had different clinical characteristics than EA patients. It is necessary to better understand the clinical characteristics of these underserved HA and NA populations with high kidney cancer burden. PMID- 30459062 TI - Donor organ turn-downs and outcomes after listing for pediatric heart transplant. AB - BACKGROUND: Pediatric heart transplant waitlist mortality remains significant but allograft offer refusals are common and allografts continue to be discarded. Our aim in this study was to assess the impact of donor organ refusals on mortality after listing using a multi-institutional data set. METHODS: In this study we conducted a retrospective review of donor offers made to pediatric (<18 years) recipients in the United States in the period from 2007 to 2017. Candidates were stratified by whether they refused an acceptable donor offer (ADO). Acceptance was defined as an offer from a donor <40 years old and within 1,000 miles that was ultimately accepted by a waitlist candidate. Candidate survival after an offer was assessed. RESULTS: There were 12,447 hearts offered at least once to a pediatric candidate. Most candidates (n = 4,282, 84.4%) refused the first offer, and 677 (15.4%) of these subsequently died or were removed from the list for deterioration. Refusal of an ADO was associated with higher mortality after listing, independent of transplant, in both univariate (1 year: 92% vs 87%, p = 0.002) and multivariate (hazard ratio 1.5, 95% CI 1.2 to 1.7, p < 0.0001) Cox regression analyses. ADO refusals were not correlated with improved post transplant survival and >8 ADO refusals was associated with higher risk-adjusted post-transplant mortality (odds ratio 1.7, 95% confidence interval 1.0 to 2.9, p = 0.04). CONCLUSIONS: Refusal of ADOs is associated with higher risk-adjusted mortality after listing (independent of transplantation), without improvement in post-transplant outcomes. So, although a "perfect" organ would be ideal, acceptance of one that is "good enough" has the potential to improve survival among pediatric candidates for heart transplantation. PMID- 30459064 TI - Maternal occupational exposures to nanoscale particles and small for gestational age outcome in the French Longitudinal Study of Children. AB - OBJECTIVES: To investigate the association between maternal occupational exposures to nanoscale particles (NPs) during pregnancy and small for gestational age (SGA). METHODS: This study included 11,224 mothers and singleton birth pairs from the French Longitudinal Study of Children (ELFE cohort), which included infants born after 33 weeks of gestation or more in continental France in 2011. Mothers who did not work during pregnancy were excluded from the analyses. Maternal occupational exposures to NPs was estimated using a job-exposure matrix for the probability (>50%: occupationally exposed group, n = 569; 0%: occupationally non-exposed group, n = 9113; between these two thresholds: uncertain group, n = 1542) and frequency of exposure. Associations were estimated from multivariate logistic regression models for occupationally exposed vs occupationally unexposed groups in a first analysis, and with the frequency weighted duration of work for the occupationally exposed group only in a second analysis. RESULTS: Among working mothers, 5.1% were occupationally exposed to NPs. Maternal occupational exposures to NPs was associated with SGA (ORa = 1.63, 95% CI: 1.22, 2.18). The frequency-weighted duration of work for the occupationally exposed group (n = 569) was not associated with SGA (ORa = 1.02, 95% CI: 0.97, 1.08) in adjusted analyses. CONCLUSIONS: These results, showing a significant association between occupational exposures to NPs and SGA, should encourage further studies to examine the adverse effect of NPs exposure on fetal development. PMID- 30459063 TI - Outcomes of children with congenital heart disease implanted with ventricular assist devices: An analysis of the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs). AB - BACKGROUND: The reported ventricular assist device (VAD) experience in the pediatric congenital heart disease (CHD) population is limited. We sought to describe contemporary use and outcomes of VADs in children with CHD and compare these outcomes to those of non-CHD children. METHODS: Patients enrolled in the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) between September 19, 2012 through June 30, 2017 were included. CHD was classified as biventricular vs single ventricle (Stages 1, 2, or 3). Outcomes were compared between groups and multivariable analysis was used to identify factors associated with mortality on the device. RESULTS: Among the 471 patients enrolled, 108 (24%) had CHD (45 biventricular and 63 single ventricle). CHD patients were younger (5.7 +/- 5.7 years vs 9.8 +/- 6.5 years; p < 0.0001) and smaller (0.8 +/- 0.5 m2 vs 1.2 +/- 0.7 m2; p < 0.0001) compared with non-CHD patients. CHD patients were more likely to receive a paracorporeal continuous flow VAD (36.1% vs 12.9%; p < 0.0001) and less likely to receive an implantable continuous-flow VAD (27.8% vs 55.0%; p < 0.0001) compared with non-CHD patients. After 6 months on a VAD, CHD patients had higher mortality (36.4% vs 12.1%) and a lower transplantation rate (29.1% vs 59.9%) than non-CHD patients (p < 0.0001). In the multivariable analysis, CHD was the factor most strongly associated with mortality on VAD (hazard ratio [HR] = 2.9; p < 0.0001), whereas the factors implantable continuous-flow device and high-volume center were protective (HR = 0.3, p < 0.0001, and HR = 0.6, respectively; p = 0.02). CONCLUSIONS: VAD use in children with CHD is associated with increased mortality and decreased transplant rates compared to children without CHD. For the subgroup of children with CHD who received implantable continuous-flow VADs, survival rates were higher and comparable to those of children without CHD. Increased experience correlated with better survival in pediatric VADs. PMID- 30459065 TI - Three-dimensional soft tissue effects of mandibular midline distraction and surgically assisted rapid maxillary expansion: an automatic stereophotogrammetry landmarking analysis. AB - Studies on mandibular midline distraction (MMD) are mostly performed using conventional research methods. Concerning surgically assisted rapid maxillary expansion (SARME), more research is conducted using three-dimensional (3D) techniques. Research on bimaxillary expansion, the combination of MMD and SARME, is reported sparsely. The main objective of this study was to provide a 3D evaluation of soft tissue effects following SARME and/or MMD. Patients who underwent SARME and/or MMD between 2008 and 2013 were included. Stereophotogrammetry was undertaken at the following time points: preoperative (T1), immediately post-distraction (T2), 1year postoperative (T3). An automatic 3D facial landmarking algorithm using two-dimensional Gabor wavelets was applied for the analysis. Twenty patients who had undergone SARME were included, 12 of whom had undergone bimaxillary expansion. Age at the time of surgery ranged from 16 to 47 years. There was a significant downward displacement of soft tissue pogonion. Furthermore, there was a significant mean increase of 2.20mm in inter alar width and a non-significant mean increase of 1.77mm in inter-alar curvature point width. In conclusion, automatic stereophotogrammetry landmarking analysis of soft tissue effects showed downward displacement of soft tissue pogonion following bimaxillary expansion and transverse widening of the inter-alar width and a tendency towards an increase in inter-alar curvature point width after SARME. PMID- 30459066 TI - Forty cases of acquired oral syphilis and a review of the literature. AB - The aim of this study was to describe 40 cases of acquired oral syphilis (AOS) and to discuss the distribution of demographic characteristics, clinical features, and differential diagnosis of the disease. A retrospective study was conducted covering a 17-year period at a single institution in southern Brazil. Moreover, a literature review was performed through a search of the PubMed database for articles on AOS published between 1955 and March 2018. Data were analyzed descriptively. The predominant group within the case series was male patients in their twenties. The vast majority of cases (92.5%) were in the secondary stage of the disease. The lips were the most commonly affected site, with greyish-white mucous patches and reddish ulcers. In the literature review, the largest number of reported cases came from North America. Male patients in the third and fourth decades of life were most affected. AOS occurred more commonly as mucous patches and ulcers on the tongue and palate. Similarities regarding the distribution by sex, age, and anatomical location were found in the present study when compared to cases reported elsewhere. Clinicians, oral pathologists, and maxillofacial surgeons should familiarize themselves with the variable spectrum of signs and symptoms of AOS in their clinical practice to improve diagnosis and management. PMID- 30459067 TI - Green synthesis of o-hydroxyazobenzene porous organic polymer for efficient adsorption of aromatic compounds. AB - This work presents a simple and eco-friendly synthetic approach to fabricate a novel o-hydroxyazobenzene porous organic polymer (HAzo-POP) by diazo-coupling of 2,6-diaminoanthraquinone with m-trihydroxybenzene in aqueous solution. The prepared HAzo-POP possesses good stability and high adsorption capability towards aromatic organic pollutants due to its porous nature, highly conjugated structure and strong hydrogen bonding ability. The HAzo-POP was successfully used for the solid-phase extraction of phenylurea herbicides from six real samples prior to high performance liquid chromatography with ultraviolet detection. The analytical method showed good linearity in the range of 0.5-160.0 ng g-1 for celery, lettuce and tomato samples, and 0.4-160.0 ng mL-1 for milk, soybean milk and juice samples, with low limits of detection in the range from 0.05 to 0.30 ng g-1 (or mL-1). The HAzo-POP has a promising application potential for the adsorption of more aromatic organic compounds. PMID- 30459069 TI - Revealing lncRNA Structures and Interactions by Sequencing-Based Approaches. AB - Long noncoding RNAs (lncRNAs) have emerged as significant players in almost every level of gene function and regulation. Thus, characterizing the structures and interactions of lncRNAs is essential for understanding their mechanistic roles in cells. Through a combination of (bio)chemical approaches and automated capillary and high-throughput sequencing (HTS), the complexity and diversity of RNA structures and interactions has been revealed in the transcriptomes of multiple species. These methods have uncovered important biological insights into the mechanistic and functional roles of lncRNA in gene expression and RNA metabolism, as well as in development and disease. In this review, we summarize the latest sequencing strategies to reveal RNA structure, RNA-RNA, RNA-DNA, and RNA-protein interactions, and highlight the recent applications of these approaches to map functional lncRNAs. We discuss the advantages and limitations of these strategies, and provide recommendations to further advance methodologies capable of mapping RNA structure and interactions in order to discover new biology of lncRNAs and decipher their molecular mechanisms and implication in diseases. PMID- 30459070 TI - Seroprevalence of pertussis among healthcare workers: A cross-sectional study from Tunisia. AB - This cross-sectional study aimed to assess pertussis seroprevalence among healthy healthcare workers (HCW) of the Children's Hospital of Tunis, Tunisia. During the study period, 236 blood samples were obtained to determine HCW exposure to pertussis. Concentrations of immunoglobulin G (IgG) to pertussis toxin (PT) were measured using a commercial enzyme-linked immunosorbent assay. Cut-offs values used were 40 and 100 IU/ml, respectively indicative of an infection within the last year and a current/recent infection. Overall, seropositivity rate was 11.4% (95% CI 7.4-15.5) and 2.5% (95% CI 0.5-4.6) of ELISA results were indicative of a current infection. Seroprevalence was significantly most important in nurses (p = 0.03) and in participants aged 21-31y (p = 0.009). Our study confirmed that pertussis is circulating in hospital settings and affecting Tunisian HCW, in close contact with infants. Therefore, a booster dose of acellular pertussis vaccine needs to be considered. PMID- 30459071 TI - Vaccine synergy with virus-like particle and immune complex platforms for delivery of human papillomavirus L2 antigen. AB - Diverse HPV subtypes are responsible for considerable disease burden worldwide, necessitating safe, cheap, and effective vaccines. The HPV minor capsid protein L2 is a promising candidate to create broadly protective HPV vaccines, though it is poorly immunogenic by itself. To create highly immunogenic and safe vaccine candidates targeting L2, we employed a plant-based recombinant protein expression system to produce two different vaccine candidates: L2 displayed on the surface of hepatitis B core (HBc) virus-like particles (VLPs) or L2 genetically fused to an immunoglobulin capable of forming recombinant immune complexes (RIC). Both vaccine candidates were potently immunogenic in mice, but were especially so when delivered together, generating very consistent and high antibody titers directed against HPV L2 (>1,000,000) that correlated with virus neutralization. These data indicate a novel immune response synergy upon co-delivery of VLP and RIC platforms, a strategy that can be adapted generally for many different antigens. PMID- 30459072 TI - Interferon gamma (IFN-gamma) negative CD4+ and CD8+ T-cells can produce immune mediators in response to viral antigens. AB - Evaluation of antigen-specific T-cell responses to viral antigens is frequently performed on IFN-gamma secreting cells. However, T-cells are capable of producing many more functions than just IFN-gamma, some of which, like Perforin, are associated with immune protection in HIV-1 disease elite controllers. We evaluated the extent of missed T-cell functions when IFN-gamma secretion is used as a surrogate marker for further evaluation of T-cell functions. Intracellular cytokine staining assay and flow cytometry were used to assess peripheral blood mononuclear cells (PBMCs) from 31 HIV-infected ART-naive individuals for the extent to which gated CD4+ and CD8+ IFN-gamma producing and non-producing T-cells also secreted IL-2, Perforin, and TNF-alpha functions. Similarly, the extent of missed virus-specific responses in IFN-gamma ELISpot assay negative T-cells from 5 HIV-1 uninfected individuals was evaluated. Cells from HIV-infected individuals were stimulated with pooled consensus group M (Con M) peptides; and those from healthy individuals were stimulated with pooled adenovirus (Ad) peptides. Overall, frequencies of virus-specific IFN-gamma secreting CD4+ and CD8+ cells were low. Proportions of IFN-gamma negative CD4+ expressing IL-2, Perforin, or TNF-alpha to Con M were significantly higher (5 of 7 functional profiles) than the corresponding IFN-gamma positive CD4+ (0 of 7) T-cell phenotype, p = 0.02; Fisher's Exact test. Likewise, proportions of CD8+ T-cells expressing other functions were significantly higher in 4 of the 7 IFN-gamma negative CD8+ T cells. Notably, newly stimulated Perforin, identified as Perforin co-expression with IL-2 or TNF-alpha, was significantly higher in IFN-gamma negative CD8+ T cell than in the positive CD8+ T-cells. Using SEB, lower responses in IFN-gamma positive cells were most associated with CD4+ than CD8+ T-cells. These findings suggest that studies evaluating immunogenicity in response to HIV and Adenovirus viral antigens should not only evaluate T-cell responsiveness among IFN-gamma producing cells but also among those T-cells that do not express IFN-gamma. PMID- 30459073 TI - The impact of a nutritional intervention based on egg white for phosphorus control in hemodialyis patients. AB - BACKGROUND AND AIMS: Here we describe a dietary intervention for hyperphosphatemia in dialysis patients based on the partial replacement of meat and fish, which are one of the main sources of alimentary phosphorous, with egg white, a virtually phosphorous-free protein source. This intervention aims to reduce phosphorous intake without causing protein wasting. PATIENTS AND METHODS: As many as 23 hyperphosphatemic patients (15 male and 8 female, mean age 53.0 +/- 10.0 years) on chronic standard 4 h, three times weekly, bicarbonate hemodialysis were enrolled in this open-label, randomized controlled trial. Patients in the intervention group were instructed to replace fish or meat with egg white in three meals a week for three months whereas diet was unchanged in the control group. RESULTS: Serum phosphate concentrations were significantly lower in the intervention group than in controls after three (4.9 +/- 1.0 vs 6.6 +/- 0.8; p < 0.001) but not after one month of treatment. Phosphate concentrations decreased more from baseline in the intervention than in the control group both after one ( 1,2 +/- 1,1 vs 0,5 +/- 1,1; p = 0.004) and after three (-1,7 +/- 1,1 vs -0,6 +/- 1,1; p < 0.001) months of follow-up. No change either in body weight or in body composition assessed with bioelectrical impedance analysis or in serum albumin concentration was observed in either group. CONCLUSION: The partial replacement of meat and fish with egg white induces a significant decrease in serum phosphate without causing protein malnutrition and could represent a useful instrument to control serum phosphate levels in hemodialysis patients. CLINICALTRIALS. GOV IDENTIFIER: NCT03236701. PMID- 30459074 TI - Total polyphenol intake, polyphenol subtypes and incidence of cardiovascular disease: The SUN cohort study. AB - BACKGROUND AND AIMS: Polyphenol-rich diets have been associated with reduced risk of cardiovascular disease (CVD). However, few prospective epidemiological studies have examined the relationship between classes of ingested polyphenols and risk of CVD. Our aim was to evaluate the association between polyphenol intake and risk of major cardiovascular events in a prospective Spanish cohort. METHODS AND RESULTS: We included 17,065 university graduates (60.7% women, mean age: 37.2 years, age range: 20-89) followed-up for a mean of 10.1 years. Polyphenol intake was assessed at baseline using a validated semi-quantitative 136-item food frequency questionnaire and matching food consumption data with the Phenol Explorer database. Cox proportional hazards models were used to estimate the adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) for incident cardiovascular events (myocardial infarction, stroke or cardiovascular death). Cherries, chocolate, coffee, apples, and olives were the major sources of variability in polyphenol intake. Participants with higher flavonoids intake (fifth quintile) had a 47% lower incidence of cardiovascular events compared to those in the lowest quintile (HR: 0.53, 95% CI: 0.29-0.98; P for trend = 0.09) after adjusting for potential confounders. The results were non-significant for other polyphenol types. CONCLUSION: The intake of flavonoids showed an inverse association with risk of cardiovascular events in a prospective cohort of Spanish middle-aged adult university graduates. REGISTRATION NUMBER FOR CLINICAL TRIALS: NCT02669602 in Clinical Trials. PMID- 30459075 TI - Gender differences in homocysteine concentrations, a population-based cross sectional study. AB - BACKGROUND AND AIMS: High concentrations of homocysteine are considered a risk factor for atherosclerosis and coronary artery disease. The aim of this study was to assess whether or not there are gender differences in the plasma concentrations of homocysteine. METHODS AND RESULTS: Data were collected from medical records of individuals examined at a screening center in Israel between the years 2000-2014. Cross sectional analysis was carried out on 9237 men and 4353 women. Mean (SD) age of the study sample was 48.4 (9.7) and 47.7 (9.7) years for men and women respectively. Average homocysteine concentrations were 12.6 (5.9) and 9.6 (3.2) MUmol/L in men and women respectively (p < 0.001). Prevalence of homocysteine concentrations above 15 MUmol/L was found to be significantly higher in men than in women; 15.5% vs 3.9% respectively (p < 0.001). Low concentrations of vitamin (B12 < 200 pmol/L) and low concentrations of folate (<12 nmol/L) were found to be significantly higher in men than in women 20.4% vs. 16.0% and 18.5% vs. 10.8% respectively. Compared to women, men had a significantly higher odds ratio (95% CI) of having homocysteine concentrations above 15 MUmol/L: non adjusted model, 4.47 (3.80-5.26); adjusted model for age, smoking status, body mass index, diabetes mellitus, kidney function and low serum concentrations of vitamin B12 and folate, 3.44 (2.89-4.09). CONCLUSION: Plasma homocysteine concentrations are higher in men than in women. This may be a contributing factor to gender differences for developing atherosclerosis and coronary artery disease. PMID- 30459076 TI - Plasma Dynamics of RAS/RAF Mutations in Patients With Metastatic Colorectal Cancer Receiving Chemotherapy and Anti-EGFR Treatment. AB - BACKGROUND: RAS and RAF mutations in colorectal cancer (CRC) hold value in precision medicine. Liquid biopsy is an alternative to tumor tissue biopsy, and circulating tumor DNA (ctDNA) has been intensively investigated, but the clinical relevance of RAS and RAF mutations in plasma is yet to be determined. This study aimed to investigate the clinical aspects of RAS/RAF mutations during combination treatment. PATIENTS AND METHODS: Patients with RAS/RAF tumor wild-type metastatic CRC treated with combination chemotherapy and an EGFR inhibitor were included. Blood samples were collected at baseline and every treatment cycle and analyzed for 31 RAS, RAF, and EGFR mutations until progressive disease or censoring using droplet digital PCR. RESULTS: Forty-six patients were prospectively enrolled onto the study. At baseline, 7% had detectable RAS/RAF mutations in ctDNA. During the treatment course, the fraction of patients with mutated ctDNA increased to 22%. The emergence of mutations did not correlate with response or risk of progression while receiving treatment (P = 1.0). CONCLUSION: Emergence of plasma RAS/RAF mutations was not correlated with the effect of combination chemotherapy and EGFR inhibition in patients with RAS/RAF wild-type metastatic CRC. PMID- 30459077 TI - Assessment of bioavailability of gold bhasma in human participants - A pilot study. AB - Bioavailability of the well-known Ayurvedic drug Swarnabhasma (gold bhasma or calcined gold) is unknown. It is orally administered either sublingually or directly with various Anupanas like black pepper powder (Piper nigrum Linn.) and cow ghee in the dose range of 15-240 mg by Ayurvedic physicians. Study of bioavailability of Swarnabhasma is necessary as this metal-derived drug is administered for long duration for rejuvenation. The pilot study was carried out in healthy human male participants to assess bioavailability of Swarnabhasma in three doses, viz. 30 mg plain sublingual, 30 mg oral dose mixed with black pepper powder (250 mg) and cow ghee (2.5 gm); and 240 mg oral dose mixed with black pepper powder (250 mg) and cow ghee (2.5 gm). Blood samples were withdrawn at 0, 1, 2 and 4 h after administration of dose. Estimation of gold levels in blood was carried out by inductively coupled plasma mass spectrometry (ICP-MS). Results show that gold is absorbed in traces from single dose of Swarnabhasma. Maximum concentration of gold was bioavailable from 30 mg sublingual dose with Cmax 0.983 MUg/L at 2 h (Tmax). Oral dose of 30 mg Swarnabhasma mixed with black pepper powder and ghee showed faster absorption with Tmax at 1 h and Cmax 0.867 MUg/L, and 240 mg dose with black pepper and ghee showed Cmax 0.668 MUg/L and Tmax at 2 h. PMID- 30459078 TI - Design and Development of Unani Emulgel for Vitiligo. AB - BACKGROUND: Vitiligo is not only a cosmetic problem, but also a social and psychological problem worldwide with the prevalence rate being highest in India. Treatment is unsatisfactory in Western System of Medicine. Unani System of Medicine (USM) possesses various drugs to treat vitiligo in both topical and oral dosage forms. Safoof-e-Bars (SB) is an important powdered dosage form used widely to treat vitiligo, internally as Zulal. Externally as Sufl (Sediment remained after decanting the soaked drug) is used. Babchi, a component of SB, is reported to contain psoralen, an important therapeutically active compounds for treating vitiligo. But as Psoralen - the active marker compound is very slightly soluble in water, so only negligible amount of it comes in zulal and most of the amount remains in sufl. That might be the reason for local application of sufl as recommended by Hakeems. But clinically it is observed that application of sufl is not followed by most of the patients, due to side effects associated with its application on skin. OBJECTIVES: The present study is designed to convert Safoof e-Bars into a more convenient and appealing newly evolved dosage form 'emulgel' of same composition as of SB, so that it can be used by the patients easily without any side effects. MATERIALS & METHODS: Various batches of emulgel were prepared as preliminary batches and final batches using hydro-alcoholic extract of SB and different excipients in different concentrations. Preliminary batches were formed for selecting composition and concentration of extract and excipients for final batches. Total eight batches (F1F8) were prepared as final batches. Among these eight batches, batch F7 was selected as final batch, which was further evaluated on various parameters. Comparative quantitative analysis was done in Zulal, Hydro-alcoholic extract of SB and emulgel using HPLC. RESULTS: Optimized emulgel showed good result in physicochemical parameters. Highest percentage of psoralen was found in SB extract while lowest percentage was found in zulal. No growth of yeast and mould, and viable aerobic were found in emulgel on microbiological analysis. Emulgel was found to be stable for 3 months at three different temperatures i.e., 4 degrees C, 25 degrees C and 40 degrees C. CONCLUSION: Newly developed emulgel may be recommended with zulal instead of traditionally used sufl with zulal. In future emulgel will provide a solution for topical delivery of hydrophobic drugs and more convenient dosage form to apply locally. PMID- 30459079 TI - In vitro and in vivo evaluation of pterostilbene for the management of diabetic complications. AB - BACKGROUND: Aldose reductase (AR) and Advanced glycation end product (AGE) are known to play important roles in the development of diabetic complications. The inhibitors of AR and AGE would be potential agents for the prevention of diabetic complications. OBJECTIVE: The present study was aimed to evaluate the aldose reductase (AR) and advanced glycation end product (AGE) inhibitory potential of pterostilbene for its possible role in the treatment of diabetic complications such as cataract. MATERIALS AND METHODS: The compound was studied for its inhibitory activity against rat lens AR (RLAR) and rat kidney AR (RKAR) in vitro along with its ability to inhibit the formation of AGEs. Anticataract activity of pterostilbene was demonstrated using sugar induced lens opacity model in isolated cattle lens. Further, the involvement of pterostilbene in galactosemia in rats was investigated by assessing the key markers in the polyol pathway and the results were compared with that of a potent AR inhibitor, fidarestat. RESULTS: Pterostilbene exhibited inhibitory activity against RLAR and RKAR with IC50 values of 5.49 mg/ml (21.4 mM) and 6.40 mg/ml (25.02 mM), respectively. In sugar induced lens opacity model, pterostilbene displayed a significant protective effect by preventing opacification and formation of polyols in cattle lens. Besides, the compound exhibited in vivo inhibition of galactitol accumulation in lens and sciatic nerves of galactose fed rats. CONCLUSION: The results obtained in the study underline the potential of pterostilbene as possible therapeutic agent against long-term diabetic complications. PMID- 30459080 TI - Ayurveda and medicalisation today: The loss of important knowledge and practice in health? AB - Ayurveda translates as 'life science'. Its knowledge is not limited to medicine, cure or therapy and is for laypersons, households, communities, as well as for physicians. Throughout its evolutionary history, Ayurveda and Local Health Traditions have reciprocally influenced each other. In modern times, the influence of biomedicine on Ayurveda is leading to its medicalisation. Over the past century, the introduction and perspective of biomedicine into India has made the human being an object for positive knowledge, a being who can be understood with scientific reason and can be governed and controlled through medical knowledge. This paper explores how this shift towards medicalisation is affecting the knowledge, teaching, and practice of Ayurveda. It examines the impact and contribution of processes like standardisation, professionalisation, bio medicalisation and pharmaceuticalisation on Ayurveda education, knowledge, practice and policies. To maintain health and wellbeing Ayurveda's ancient knowledge and practice needs to be applied at individual, community and health care provider levels and not be limited to the medical system. The current over medicalisation of society is a potential threat to human health and well-being. Ayurveda and LHT knowledge can provide essential teachings and practices to counter-balance this current trend through encouraging a population's self reliance in its health. PMID- 30459081 TI - Morphological acclimation to agronomic manipulation in leaf dispersion and orientation to promote "Ideotype" breeding: Evidence from 3D visual modeling of "super" rice (Oryza sativa L.). AB - Food security is confronted by major threats from crop yield stagnation and global climate change. The benefits of phenotypic plasticity across environments for given crop genotypes are thought to be imperative for high-yielding cropping systems. Given that 3D modeling is increasingly recognized for dissecting crop phenotypic plasticity, it requires an assessment of the potential benefits of architectural adaptation of super rice to different agronomic practices. In this study, we focused on a comprehensive evaluation of the phenotypic plasticity of super rice on the aspects of 3D architectural "reoptimization," photosynthetic productivity, nitrogen economy, and grain yield. A super rice phenotype in superhigh-yielding practice (SH) displays a "reoptimized" morphogenesis in the leaf vertical dispersion and orientation in comparison to that in Farmer's practice (FP). Specifically, a super rice phenotype in SH is provided with a high cumulative rate and peaks of leaf area, increasing the distribution of high leaf inclination angles in comparison to that in FP, particularly in the upper parts of the canopy. These "reoptimizations" sustained profits in light environment within a canopy, leaf area duration, photosynthetic light harvest, and light utilization efficiency and were coordinated with improving nitrogen uptake and assimilation. The current literature indicates that the agronomic plasticity of super rice in architectural "reoptimization" is a promising perspective for high yield formation. Our results suggest that more emphasis should be placed upon agronomic adaptation strategies for super rice across diverse genotypes and environments to further improve crop establishment and photosynthetic productivity. PMID- 30459082 TI - Limited ventilation causes stress and changes in Arabidopsis morphological, physiological and molecular phenotype during in vitro growth. AB - A huge number of experiments in plant biology are conducted in sterile, sealed containers, providing environmental stability and full control of factors influencing the plant system. With respect to roots the in vitro growth has another benefit - the ease of conducting visual observations when grown in transparent media. Moreover, straightforward measurements of in vitro grown root systems make them a sensitive and convenient sensor of multiple stresses which may occur during experiments. In order to optimize root nematode infection tests for Arabidopsis mutants with relatively mild phenotypes, two Petri dish sealing techniques were tested (permeable medical adhesive tape and a popular non permeable plastic film). Using standard experimental settings applied for infection tests, the root architecture, nematode infections, ion leakage, efficiency of photosynthesis, ethylene (ET) production, and CO2 accumulation were monitored in Arabidopsis thaliana Ws-0 wild-type and lsd1 (lesion stimulating disease 1) plants, which is a conditional dependent programmed cell death mutant. All tested parameters gave statistically significant differences between the analyzed sealing tapes, indicating the importance of air exchange. This factor is quite obvious but often ignored in experiments performed in Petri dishes. The results clearly indicate that stress is greater in air-tight sealed plates. These observations were supported by the great expression variation of several marker genes associated with reactive oxygen species (ROS), ET, salicylic (SA), and jasmonic acid (JA) biosynthesis and signaling in two-week-old seedlings. These results are discussed in light of the observed changes in the ET and CO2 concentration. Our results clearly indicate the importance of culture parameters for monitoring of abiotic and biotic stress responses in laboratory conditions, including accurate mutant phenotyping. PMID- 30459083 TI - Preadipocyte factor-1 in maternal, umbilical cord serum and breast milk: The impact of fetal growth. AB - BACKGROUND/OBJECTIVE: To study the concentrations of preadipocyte factor-1 (Pref 1) -an inhibitor of adipocyte differentiation, implicated in adipose tissue metabolism, late metabolic disorders and fetal growth- in maternal and umbilical cord serum, as well as maternal milk and correlate above concentrations with intrauterine growth and other perinatal parameters. MATERIAL AND METHODS: Pref-1 concentrations were determined by ELISA in antepartum maternal and umbilical cord serum, as well as day 3 to 4 postpartum breast milk, deriving from 80 women, who delivered 40 appropriate (AGA), 20 large for gestational age (LGA) and 20 intrauterine growth restricted (IUGR) neonates, classified by the use of customized birth-weight standards adjusted for significant determinants of fetal growth. RESULTS: Umbilical cord serum Pref-1 concentrations were significantly higher than antepartum maternal ones (p < 0.001), while breast milk concentrations were the lowest (p < 0.001 concerning umbilical serum, p < 0.001 concerning maternal serum). Umbilical cord serum Pref-1 concentrations were significantly lower in the LGA group than in the AGA one (p = 0.044). Breast milk and maternal serum Pref-1 concentrations did not differ between the three intrauterine growth groups. Maternal serum and breast milk Pref-1 concentrations did not correlate with maternal age, body mass index before and after gestation, birth weight, body length, and customized centile. A positive weak correlation was recorded between maternal serum and milk Pref-1 concentrations (r = 0.238, p = 0.034). CONCLUSIONS: Pref-1 concentrations in umbilical cord serum are higher than in antepartum maternal serum, probably pointing to its fetal origin and role in intrauterine growth. Breast milk concentrations, being extremely low, and possibly implying infant protection from metabolic disorders, positively correlate with maternal serum ones, conceivably suggesting a transfer of the substance from the circulation to the breast. Umbilical cord serum Pref-1 concentrations were lower in LGA fetuses/neonates, as compared to respective AGA ones. PMID- 30459084 TI - Tick parasitism in the Mediterranean spur-thighed tortoise in the Maamora forest, Morocco. AB - Macroparasites in general, and ectoparasites in particular, have the potential to regulate host population dynamics. In this context, this study addresses the tick parasitism traits of the Mediterranean spur-thighed tortoise (Testudo graeca) in the core area of its distribution range (northwestern Morocco, Maamora). It was discovered that 92.5% of the tortoises were parasitized by ticks in spring, with an infestation intensity and an abundance of 6.7 and 6.2 tick/tortoise, respectively. The observed parasitization rates were among the highest reported worldwide for T. graeca, which could relate to density-depended effects driving host-parasite interactions. The main tick species that parasitized the tortoises were Hyalomma aegyptium (95.6% of the ticks and in the 100% of the parasitized tortoises), Hy. marginatum, Hy. excavatum and Hy. scupense. Individual predictors for the tortoises, such as age, sex and the interaction between body condition and sex, were significantly related to tick abundance. Age-related behavioural differences might favour a higher host-tick effective contact in adults than in juveniles. The fact that males are more active in spring - the breeding season - might explain the observed male-bias in tick abundance and may also be responsible for the negative effect of male body condition on tick infestation rate in contrast to females. Given the potential role played by parasites as regards modulating population dynamics, our results suggest that ticks should be taken into account in the conservation and management programmes of this tortoise species. PMID- 30459085 TI - Wonders of tick saliva. AB - Saliva of ticks is arguably the most complex saliva of any animal. This is particularly the case for ixodid species that feed for many days firmly attached to the same skin site of their obliging host. Sequencing and spectrometry technologies combined with bioinformatics are enumerating ingredients in the saliva cocktail. The dynamic and expanding saliva recipe is helping decipher the wonderous activities of tick saliva, revealing how ticks stealthily hide from their hosts while satisfying their gluttony and sharing their individual resources. This review takes a tick perspective on the composition and functions of tick saliva, covering water balance, gasket and holdfast, control of host responses, dynamics, individuality, mate guarding, saliva-assisted transmission, and redundancy. It highlights areas sometimes overlooked - feeding aggregation and sharing of sialomes, and the contribution of salivary gland storage granules and questions whether the huge diversity of tick saliva molecules is 'redundant' or more a reflection on the enormous adaptability wonderous saliva confers on ticks. PMID- 30459086 TI - Corrigendum to "Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab" [Lung Cancer 115 (2018) 71 74]. PMID- 30459087 TI - [The effect of anesthetic preconditioning with sevoflurane on intracellular signal-transduction pathways and apoptosis, in a lung autotransplant experimental model]. AB - BACKGROUND: Anesthetic pre-conditioning attenuates inflammatory response during ischemia-reperfusion lung injury. The molecular mechanisms to explain it are not fully understood. The aim of our investigation was to analyze the molecular mechanism that explain the anti-inflammatory effects of anesthetic pre conditioning with sevoflurane focusing on its effects on MAPKs (mitogen-activated protein kinases), NF-kappaB (nuclear factor kappa beta) pathways, and apoptosis in an experimental lung autotransplant model. METHODS: Twenty large white pigs undergoing pneumonectomy plus lung autotransplant were divided into two 10-member groups on the basis of the anesthetic received (propofol or sevoflurane). Anesthetic pre-conditioning group received sevoflurane 3% after anesthesia induction and it stopped when one-lung ventilation get started. Control group did not receive sevoflurane in any moment during the whole study period. Intracellular signal-transduction pathways (MAPK family), transcription factor (NF-kappaB), and apoptosis (caspases 3 and 9) were analyzed during experiment. RESULTS: Pigs that received anesthetic pre-conditioning with sevoflurane have shown significant lower values of MAPK-p38, MAPK-P-p38, JNK (c-Jun N-terminal kinases), NF-kappaB p50 intranuclear, and caspases (p<0.05) than pigs anesthetized with intravenous propofol. CONCLUSIONS: Lung protection of anesthetic pre-conditioning with sevoflurane during experimental lung autotransplant is, at least, partially associated with MAPKs and NF kappaB pathways attenuation, and antiapoptotic effects. PMID- 30459088 TI - [Erector spinae plane block as a multiple catheter technique for open esophagectomy: a case report]. AB - BACKGROUND AND OBJECTIVE: Erector spinae plane block is a valid technique to provide simultaneously analgesia for combined thoracic and abdominal surgery. CASE REPORT: A patient underwent open esophagectomy followed by reconstructive esophagogastroplasty but refused thoracic epidural analgesia; a multi-modal analgesia with a multiple erector spinae plane block was then planned. Three erector spinae plane catheters (T5 and T10 on the right side and T9 on the left side) for continuous analgesia were placed before surgery. During the first 48h pain was never reported in the thoracic area but the patient reported multiple times to feel a pain well localized in epigastrium, but never localized in any other abdominal quadrant. DISCUSSION: Erector spinae plane block is a valid technique to provide analgesia simultaneously for combined thoracic and abdominal surgery and could be a valid alternative strategy if the use of epidural analgesia is contraindicated. PMID- 30459089 TI - A qualitative study exploring the decision of parents to use medication in attention-deficit hyperactivity disorder. AB - BACKGROUND: Reported prevalence of ADHD in children varies greatly from country to country. There is a similar disparity between rates of medication prescriptions for ADHD, with significant variation existing between rates in USA and Europe. North American studies report that parents have concerns about starting and continuing ADHD medication in children, though little is known about experiences in other geographies and healthcare systems. These studies may inform supports required, and help understand if these concerns may result in different treatment patterns, in other geographies. OBJECTIVE: To explore experiences of parents of children who used ADHD medication in Ireland. METHODS: A qualitative methodology was employed. Data were gathered through in-depth semi-structured interviews with ten parents who had a child with ADHD and had commenced medication. Analysis was performed using a phenomenographic approach. RESULTS: Four descriptive categories relating to parents' experiences of decision-making emerged. Symptom severity prior to diagnosis, duration of ADHD symptoms and parental struggle to make an informed risk/benefit decision influenced decision making. The child's immediate response to medication was identified as an important factor facilitating persistence and adherence. Over time, parents sought to regain some control over and gain confidence in medication management and decision-making. CONCLUSIONS: The decision to use medication in ADHD is difficult and dynamic for parents in Ireland. It is driven by a sense of urgency and powerlessness, mobilizing feelings of doubt, anxiety and guilt before concluding with a sense of autonomy and increased confidence. Lack of awareness of ADHD and treatments, alongside access to care issues, add to parental anxiety in Ireland. This is in contrast to previous North American studies. Current provisions of support and information at the time of ADHD diagnosis are insufficient. Initial reaction to medication options should be explored by clinicians and support continued over time. PMID- 30459090 TI - Enhanced removal of uranium(VI) from aqueous solution by a novel Mg-MOF-74 derived porous MgO/carbon adsorbent. AB - The elimination and safe treatment of U(VI) from radioactive wastewater has attracted widespread attention with the development of the nuclear power industry. In this work, a MgO/carbon adsorbent was successfully prepared by one step Mg-MOF-74 pyrolyzation and used for U(VI) removal from aqueous solution. Characteristic results indicated that the as-prepared composite was a typical porous structure. The adsorption performance of the MgO/carbon towards U(VI) was studied by batch experiments. The results indicated that the MgO/carbon can rapidly and effectively remove U(VI) and showed an excellent adsorption capacity (777.51 mg/g), which is much higher than other reported adsorbent materials. In addition, the intraparticle diffusion model provides a good explanation for each adsorption process. The adsorption capacity of the MgO/carbon towards U(VI) is greatly promoted by the large specific surface area and well-defined porous structure. Based on the zeta potential and XPS analysis, the possible mechanism for U(VI) removal involved the surface complexation and electrostatic attraction. The results indicate that the MgO/carbon can be regarded as an efficient adsorbent for U(VI) removal from wastewater, which has a very broad application prospect. PMID- 30459091 TI - Hierarchical C/NiO-ZnO nanocomposite fibers with enhanced adsorption capacity for Congo red. AB - Wastewater containing organic dyestuff has caused worldwide concern, hence, it is imperative to develop materials to remove organic dyes from wastewater. Herein, we report the synthesis of carbon fiber-based bimetallic oxide nanocomposite with high efficiency for the adsorptive removal of Congo red (CR), a typical anionic dye. Composite nanosheets of nickel(II) oxide (NiO) and zinc oxide (ZnO) were in situ grown over electrospun carbon fibers via one-step oil bath coprecipitation and subsequent calcination in air at 350 degrees C. The C/NiO-ZnO nanocomposite fibers exhibited fast adsorption rates towards CR at circumneutral pH, and maximal adsorption capacity according to the Langmuir model reached 613 mg g-1, much higher than aggregated NiO-ZnO microspheres and the carbon fiber alone. The high adsorption capacity of the C/NiO-ZnO nanocomposite was attributed to its high specific surface area (222 m2 g-1), hierarchically porous structure with abundant mesopores and macropores, and the positive surface charge at circumneutral pH. Therefore, the flexible and easily recyclable C/NiO-ZnO nanocomposite fibers can become an alternative adsorbent for the treatment of anionic dye wastewater. PMID- 30459092 TI - A retrospective population-based cohort study to evaluate the impact of an older sibling with undescended testis and hypospadias on the known maternal and fetal risk factors for undescended testis and hypospadias in Ontario, Canada, 1997 2007. AB - INTRODUCTION: There are several reported risk factors for undescended testis (UDT) and hypospadias (HYP). Also, a family history of UDT or HYP has not been accounted for in prior studies, and doing so may influence these independent risk estimates. STUDY DESIGN: A population-based retrospective cohort study was conducted using linked administrative databases in Ontario, Canada, to identify all live male newborns born between 1997 and 2007, and it was determined whether they underwent an orchidopexy or HYP repair within 5 years of birth. Baseline maternal and fetal risk factors were obtained using appropriate ICD codes. A statistical analysis using a generalized estimating equation with a logit link was performed, adjusting for clustering in mothers with a previous child born in the 5 years before the proband with UDT or HYP, to evaluate the adjusted risk factors of UDT and HYP. RESULTS: A total of 709,968 male infants were followed up from birth for 5 years, of which 5830 underwent an orchidopexy and 2722 had an HYP repair. On multivariable analysis, factors associated with a higher risk of UDT included prematurity, small for gestational age (SGA), associated HYP, gestational hypertension, use of assisted fertility techniques, increased maternal age, Cesarean section, previous sibling with UDT, and disorders of sexual differentiation (DSDs). After adjusting for clustering in mothers with a previous baby with UDT, DSD, associated HYP (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.0-4.1), and a previous sibling with UDT (OR, 3.6; 95% CI, 2.5 5.2) remained significant risk factors. The risk factors on multivariable analysis predicting the risk of HYP included SGA, prematurity, higher income families, and associated anomalies such as UDT. After adjusting for clustering in mothers with a previous sibling with HYP, SGA (OR, 1.8; 95% CI, 1.0-3.1), higher income families (OR, 1.5-1.6), associated UDT (OR, 7.1; 95% CI, 4.9-10.0), and a previous sibling with HYP (OR, 12.8; 95% CI, 9.1-18.1) remained significant risk factors. DISCUSSION: Studies estimating risk factors for UDT and HYP have used variable methodologies to identify index cases and perform statistical analysis. This study suggests that having an older sibling with UDT or HYP is a significant independent risk factor. Performing an analysis adjusting for clustering in mothers with a previous child with UDT or HYP leads to loss of statistical significance for other described risk factors. CONCLUSION: Underlying genetic or similar environmental exposures may be a key risk factor for UDT and HYP, which confounds known maternal and fetal risk factors for these anomalies. PMID- 30459093 TI - The potential of three-dimensional printing technologies to unlock the development of new 'bio-inspired' dental materials: an overview and research roadmap. AB - PURPOSE: Bio-inspiration is an approach in engineering aimed at optimizing artificial systems by borrowing biological concepts from nature. This review sets out to summarize the fundamental aspects employed by nature to avoid premature dental failures. On the basis of these findings, it then defines and evaluates rules for 'post-modern' manufacturing processes to imitate or regenerate complex biological systems. STUDY SELECTION: A thorough literature search was conducted using PubMed, the Cochrane Library database and Google Scholar. Peer-reviewed articles and other scientific literature provided up-to-date information addressing two topics: (a) how natural dental tissues combine to create a structure as tough, strong and highly resistant to fatigue failure as tooth, and (b) how 'bio-inspiration' can be applied to the manufacture of dental restorations, taking into consideration the limitations of techniques currently used in dentistry. RESULTS: Bio-inspired concepts have already been successfully applied in a range of engineering fields to enhance the toughness and strength of artificial materials. The area of technology with greatest potential to unlock the development of these new approaches is additive manufacturing. Consequently, these technologies and concepts could be applied to dentistry to improve the mechanical properties of dental restorations. Three-dimensional (3D) printing technologies also offer a new and promising prospect of regenerating dental tissues. CONCLUSIONS: Considering the limitations to both conventional and subtractive computer-aided design/computer-aided manufacturing (CAD/CAM) methods, further research should focus on new, additive 3D-printing techniques. This may open new research paths in dentistry that will enhance the clinical performance of artificial dental materials. PMID- 30459094 TI - Haloferax volcanii. AB - In this infographic we present the main tools available for the halophilic archaeon Haloferax volcanii, which have enabled successful research on its biology, including its genetics, proteostasis, cell surface structures, metabolic pathways, and adaptation to high salt environments. Isolated from the Dead Sea in 1975, Haloferax volcanii thrives in high salt environments and has emerged as an important archaeal model system. An extensive repertoire of genetic, molecular biological, and biochemical tools has been developed for this fast-growing, easily cultivated haloarchaeon, including expression vectors and gene-deletion strategies, including CRISPR. Its low mutation rate and ability to grow on defined media allow straightforward application of methods such as metabolic labeling, and the sequenced genome laid the foundation for transcriptomics and proteomics studies. These tools have allowed examination of key pathways such as transcription, noncoding RNAs, protein synthesis and degradation, protein glycosylation, motility, and biofilm formation. With the collaborative spirit of the H. volcanii community, this model system has become invaluable not only for enhancing our understanding of archaea but also for improving the development of biotech applications. PMID- 30459095 TI - Healthcare use among persons with visual impairment: Difference-in-difference estimations. AB - BACKGROUND: Studies on healthcare service use among persons with visual impairments in countries with different healthcare systems are needed for drawing global inferences. OBJECTIVE: The goal was to assess the impact of visual impairment on healthcare service use. METHODS: A retrospective cohort study on health insurance claims data from the National Health Insurance System (NHIS) was conducted. All data from 2002 to 2013 for 2206 and 8824 persons with and without visual impairments, respectively, were extracted and aggregated monthly, generating a total of 162,876 and 568,459 person-month observations, respectively. The dependent variable was total expenditures. Difference-in difference estimations based on a multivariate log-normal random-effect regression were employed. RESULTS: Persons with visual impairments spent 5.7% and 6.8% more on total healthcare expenditures per month and outpatient healthcare expenditures, respectively, than those without visual impairments, after adjusting for pre-impairment differences. Further results revealed an upward trend in expenditures, particularly among those with visual impairments; this increase was the highest during the year prior impairment (approximately 32% and 21% more for total and outpatient services, respectively, compared with baseline). Inpatient healthcare expenditures showed a similar increase (by approximately 26%) during the year prior impairment compared with baseline; however, the magnitude dropped to approximately 14% and 6% during the 1st and 2nd years of impairment, respectively. Conversely, the annual pattern of expenditure increase was parallel over time for persons without visual impairments, regardless of service. CONCLUSION: Our findings suggest a need for health management and effective care use, particularly the year prior to visual impairment onset. PMID- 30459096 TI - Vitamin E-inspired multi-scale imaging agent. AB - The production and use of multi-modal imaging agents is on the rise. The vast majority of these imaging agents are limited to a single length scale for the agent (e.g. tissues only), which is typically at the organ or tissue scale. This work explores the synthesis of such an imaging agent and discusses the applications of our vitamin E-inspired multi-modal and multi-length scale imaging agents TB-Toc ((S,E)-5,5-difluoro-7-(2-(5-((6-hydroxy-2,5,7,8-tetramethylchroman 2-yl) methyl) thiophen-2-yl) vinyl)-9-methyl-5H-dipyrrolo-[1,2-c:2',1' f][1,3,2]diazaborinin-4-ium-5-uide). We investigate the toxicity of TB-Toc along with the starting materials and lipid based delivery vehicle in mouse myoblasts and fibroblasts. Further we investigate the uptake of TB-Toc delivered to cultured cells in both solvent and liposomes. TB-Toc has low toxicity, and no change in cell viability was observed up to concentrations of 10 mM. TB-Toc shows time-dependent cellular uptake that is complete in about 30 min. This work is the first step in demonstrating our vitamin E derivatives are viable multi-modal and length scale diagnostic tools. PMID- 30459097 TI - Cluster analysis of autoimmune rheumatic diseases based on autoantibodies. New insights for polyautoimmunity. AB - Autoimmune diseases (ADs) are a chronic and clinically heterogeneous group of diseases characterized by share common immunopathogenic mechanisms and risk factors (i.e., the autoimmune tautology), which explain the fact that one AD may coexist with others (i.e., polyautoimmunity - PolyA). In the present exploratory study, a mixed-cluster analysis of the most common autoimmune rheumatic diseases (ARDs) was done. A total of 187 consecutive women with established systemic lupus erythematosus (n = 70), rheumatoid arthritis (n = 51), systemic sclerosis (n = 35) and Sjogren's syndrome (n = 31) were included. A comprehensive clinical, autoantibody and cytokine assessment was simultaneously done. Total PolyA was registered in 142 (75.9%) patients. Six clusters were obtained, built mainly on autoantibodies: PolyA-I to -VI. The PolyA-III cluster showed the highest frequency of overt PolyA (p = 0.01), and the PolyA-I, -III, and -IV clusters exhibited the highest positivity for IL-12/23p40 (p = 0.015). These results provide new insights into the pathophysiology of PolyA and warrant prospective validation to enable development of a more accurate taxonomy of ARDs. PMID- 30459098 TI - Reduced intestinal FADS1 gene expression and plasma omega-3 fatty acids following Roux-en-Y gastric bypass. AB - BACKGROUND & AIMS: Roux-en-Y gastric bypass (RYGB) limits food ingestion and may alter the intestinal expression of genes involved in the endogenous synthesis of polyunsaturated fatty acids (PUFAs). These changes may decrease the systemic availability of bioactive PUFAs after RYGB. To study the impact of RYGB on the dietary ingestion and plasma concentration of PUFAs and on the intestinal expression of genes involved in their endogenous biosynthesis in severely obese women with type 2 diabetes. METHODS: Before, and 3 and 12 months after RYGB, obese women (n = 20) self-reported a seven-day dietary record, answered a food frequency query and provided plasma samples for alpha-linolenic (ALA), eicosapentaenoic (EPA), docosahexaenoic (DHA) and arachidonic (ARA) acid assessment by gas chromatography. Intestinal biopsies (duodenum, jejunum and ileum) were collected through double-balloon endoscopy before and 3 months after RYGB for gene expression analysis by microarray (Human GeneChip 1.0 ST array) and RT-qPCR validation. RESULTS: Compared to the preoperative period, patients had decreased intakes of PUFAs, fish and soybean oil (p < 0.05) and lower plasma concentrations of ALA and EPA (p < 0.001) 3 and 12 months after RYGB. FADS1 gene expression was lower in duodenum (RT-qPCR fold change = -1.620, p < 0.05) and jejunum (RT-qPCR fold change = -1.549, p < 0.05) 3 months following RYGB, compared to before surgery. CONCLUSION: RYGB decreased PUFA ingestion, plasma ALA and EPA levels, and intestinal expression of FADS1 gene. The latter encodes a key enzyme involved in endogenous biosynthesis of PUFAs. These data suggest that supplementation of omega-3 PUFAs may be required for obese patients undergoing RYGB. Clinical Trial Registry number and website: www.clinicaltrials.gov - NCT01251016; Plataforma Brasil - 19339913.0.0000.0068. PMID- 30459099 TI - The effects of vitamin D and probiotic co-supplementation on glucose homeostasis, inflammation, oxidative stress and pregnancy outcomes in gestational diabetes: A randomized, double-blind, placebo-controlled trial. AB - BACKGROUND AND AIMS: This study was designed to assess the effects of combined vitamin D and probiotic supplementation on metabolic status and pregnancy outcomes in women with gestational diabetes (GDM). METHODS: This randomized, double-blind, placebo-controlled clinical trial was performed in 87 women with GDM. Patients were randomly assigned three groups to receive either vitamin D (50,000 IU/every 2 weeks) plus probiotic (8 * 109 CFU/day) (n = 30), probiotic (8 * 109 CFU/day) (n = 29) or placebo (n = 28) for 6 weeks. RESULTS: Vitamin D and probiotic co-supplementation significantly reduced fasting plasma glucose (beta 10.99 mg/dL; 95% CI, -14.26, -7.73; P < 0.001), serum insulin levels (beta -1.95 MUIU/mL; 95% CI, -3.05, -0.84; P = 0.001) and homeostasis model of assessment insulin resistance (beta -0.76; 95% CI, -1.06, -0.45; P < 0.001), and significantly increased the quantitative insulin sensitivity check index (beta 0.01; 95% CI, 0.008, 0.03; P = 0.001) compared with the placebo. In addition, vitamin D and probiotic co-supplementation resulted in a significant reduction in triglycerides (beta -37.56 mg/dL; 95% CI, -51.55, -23.56; P < 0.001), VLDL- (beta -7.51 mg/dL; 95% CI, -10.31, -4.71; P < 0.001), HDL-/total cholesterol ratio (beta -0.52; 95% CI, -0.79, -0.24; P < 0.001), high sensitivity C-reactive protein (beta -1.80 mg/L; 95% CI, -2.53, -1.08; P < 0.001) and malondialdehyde (beta -0.43 MUmol/L; 95% CI, -0.77, -0.09; P = 0.01); also, a significant rise in HDL-cholesterol (beta 4.09 mg/dL; 95% CI, 1.11, 7.08; P = 0.008) and total antioxidant capacity (TAC) levels (beta 97.77 mmol/L; 95% CI, 52.34, 143.19; P < 0.001) were observed compared with the placebo. Vitamin D and probiotic co supplementation did not change other metabolic parameters. Vitamin D and probiotic co-supplementation significantly decreased triglycerides (P = 0.02), VLDL-cholesterol (P = 0.02) and hs-CRP (P = 0.01), and significantly increased TAC (P = 0.006) and total glutathione levels (P = 0.04) compared with only probiotic group. CONCLUSIONS: In conclusion, vitamin D and probiotic co supplementation in women with GDM had beneficial effects on metabolic status. This trial was registered at www.irct.ir as IRCT201706075623N119. PMID- 30459100 TI - Effect of rewarming in oxygenation and respiratory condition after neonatal exposure to moderate therapeutic hypothermia. AB - BACKGROUND: To assess changes in clinical condition and oxygenation in neonates after rewarming following moderate therapeutic hypothermia (MTH) for neonatal encephalopathy. METHODS: Retrospective study of 28 neonates receiving MTH in a tertiary neonatal intensive care unit in Israel. We compared pre-and 24 h post rewarming arterial oxygen saturation (SaO2) as measured by the blood gases analyzer, pulse-oximetry saturation (SpO2), and cardio-respiratory condition. RESULTS: The SpO2 declined from 96.9% (+/-2.9) before rewarming to 95.2% (+/-2.6) after rewarming (p < 0.001). Twelve neonates (42.9%) had clinical respiratory impairment (needing higher respiratory support or had new onset desaturations). In 16 neonates (57.1%) with no change in respiratory support after rewarming, SpO2 decreased from 98.3 +/- 1.9% to 95.6 +/- 3.0% (p < 0.001) and SaO2 decreased from 97.1 +/- 1.7% to 96.0 +/- 2.3% (p = 0.002). The mean SpO2 decrease was greater than mean SaO2 decrease (2.63 +/- 1.8 and 1.1 +/- 1.3 respectively, p = 0.021). CONCLUSION: Neonates who underwent MTH showed reduction in oxygenation after rewarming either by decreasing SpO2 or increasing FiO2 requirements. The SpO2 decline was larger than the SaO2 decline. We suggest careful monitoring of neonates after rewarming. PMID- 30459101 TI - Novel understandings of host cell mechanisms involved in chronic lung infection: Pseudomonas aeruginosa in the cystic fibrotic lung. AB - As one of the most debilitating and underdiagnosed hereditary conditions across the globe, cystic fibrosis requires intensive support from the healthcare system particularly due to the increased susceptibility to chronic infection and resulting respiratory failure which can rapidly lead to death. In turn, the prevalence and action of a certain strain of bacterium - Pseudomonas aeruginosa - has gained a great deal of interest. Life-threatening chronic infections by P. aeruginosa have been shown to involve biofilm formation, proliferation and the release of quorum-sensing signaling molecules. Understanding the mechanism cascade by which this strain attacks cells within the respiratory epithelium, most notably airway epithelial cells, could offer insight into the pathway and components, which are attractive targets for therapeutic interventions. PMID- 30459102 TI - The Duration of the correction loss after removing cheneau brace in patients with adolescent idiopathic scoliosis. AB - OBJECTIVE: The aim of the study was to evaluate the loss of truncal rotation over 54 hours after removing Cheneau brace. METHODS: The studied groups consisted of 39 girls aged 10-18 years old, diagnosed with adolescent idiopathic scoliosis (AIS) and treated with Cheneau brace (CAST) and 20 AIS girls aged 10-18 years old, not treated with bracing. Posterior-anterior radiographs were obtained from the clinical assessment of all subjects and were subsequently used to determine Cobb angles. The measurements of the angle of trunk rotation (ATR) were taken with the Scoliometer(r) and back-contour device during Adams forward bending test by the two evaluators. The changes in ATRs during 54 hours of observation were performed after the brace had been taken off (0, 2, 24, 30, 48 and 54 hours after debracing). This was described using VATR variable, defined as the change in the absolute Scoliometer(r) readings in the time intervals against the time interval Deltat between the measurements. During back-contour assessment the differential factor (kra) has been used for the digital analysis. The changes in kra over 54 hours of observation were expressed as Vkra factor, defined as the difference in the absolute value of the amplitude differential factor (kra) in the time intervals against the time interval Deltat between the measurements. RESULTS: The highest changes were observed in the thoracic as well as in lumbar spine in patients with Cobb angle >=30 degrees , axial rotation of the apical vertebrae within 5-15 degrees , Risser sign 0-2. The biggest change in the trunk rotation after Cheneau brace had been taken off was noted within the first two hours of observation. CONCLUSION: The patients should be advised to take the brace off for a minimum of two hours before the scheduled x-ray, to allow full relaxation of the trunk in order to obtain reliable radiological images of the deformation. LEVEL OF EVIDENCE: Level III Therapeutic study. PMID- 30459105 TI - Loeys-Dietz: Anything special for tomorrow's case? PMID- 30459104 TI - Biologic versus mechanical valves: Wandering in the dark. PMID- 30459106 TI - My patients heart needs surgery, but the rest of his body... not so sure: Operative indications and options in frail patients. PMID- 30459107 TI - Postoperative kidney oxygen saturation as a novel marker for acute kidney injury after adult cardiac surgery. AB - OBJECTIVE: Acute kidney injury is a severe complication and one of the stronger risk factors for death in patients undergoing cardiac surgery. The relationship between postoperative brain oxygen saturation and kidney oxygen saturation with acute kidney injury in adults undergoing cardiac surgery has not been determined. We designed a single-center prospective study to determine if the continuous monitoring of postoperative brain oxygen saturation and kidney oxygen saturation could predict postoperative acute kidney injury. METHODS: We conducted a prospective open cohort study from January to September 2017. The primary outcome was postoperative acute kidney injury using the Kidney Disease: Improving Global Outcomes criteria. Brain oxygen saturation and kidney oxygen saturation, the metrics of which were area measurements (%-min), were recorded during the surgery and the first 48 hours after the cardiac procedure. Receiver operating characteristic curve analysis was used to evaluate the predictive power of kidney oxygen saturation for acute kidney injury. RESULTS: A total of 121 consecutive patients were enrolled. Thirty-five patients (28.9%) developed acute kidney injury. Brain oxygen saturation showed no statistical difference in both groups; however, kidney oxygen saturation was related to acute kidney injury (P = .001). Receiver operating characteristic curve analysis showed that kidney oxygen saturation could predict the risk of acute kidney injury. Kidney oxygen saturation less than 65% (area under the curve-receiver operating characteristic, 0.679 +/- 0.054, 95% confidence interval, 0.573-0.785, P = .002) and 20% decrease from baseline (area under the curve-receiver operating characteristic, 0.639 +/- 0.059, 95% confidence interval, 0.523-0.755, P = .019) showed the better performance, respectively. CONCLUSIONS: Postoperative kidney oxygen saturation is related to the development of cardiac surgery-associated acute kidney injury. Continuous kidney saturation monitoring might be a promising, noninvasive tool for predicting acute kidney injury during the postoperative period for adult patients after cardiac surgery. PMID- 30459108 TI - You can't have your cake and eat it too: The value paradox in outcomes. PMID- 30459103 TI - Tranexamic acid in coronary artery surgery: One-year results of the Aspirin and Tranexamic Acid for Coronary Artery Surgery (ATACAS) trial. AB - BACKGROUND: Tranexamic acid reduces blood loss and transfusion requirements in cardiac surgery but may increase the risk of coronary graft thrombosis. We previously reported the 30-day results of a trial evaluating tranexamic acid for coronary artery surgery. Here we report the 1-year clinical outcomes. METHODS: Using a factorial design, we randomly assigned patients undergoing coronary artery surgery to receive aspirin or placebo and tranexamic acid or placebo. The results of the tranexamic acid comparison are reported here. The primary 1-year outcome was death or severe disability, the latter defined as living with a modified Katz activities of daily living score of less than 8. Secondary outcomes included a composite of myocardial infarction, stroke, and death from any cause through to 1 year after surgery. RESULTS: The rate of death or disability at 1 year was 3.8% in the tranexamic acid group and 4.4% in the placebo group (relative risk, 0.85; 95% confidence interval, 0.64-1.13; P = .27), and this did not significantly differ according to aspirin exposure at the time of surgery (interaction P = .073). The composite rate of myocardial infarction, stroke, and death up to 1 year after surgery was 14.3% in the tranexamic acid group and 16.4% in the placebo group (relative risk, 0.87; 95% CI, 0.76-1.00; P = .053). CONCLUSIONS: In this trial of patients having coronary artery surgery, tranexamic acid did not affect death or severe disability through to 1 year after surgery. Further work should be done to explore possible beneficial effects on late cardiovascular events. PMID- 30459109 TI - Joint effects of uric acid and lymphocyte count on adverse outcomes in elderly patients with rheumatic heart disease undergoing valve replacement surgery. AB - OBJECTIVES: Increased uric acid and decreased lymphocyte count are common in elderly patients or those with heart failure, which were prognostic markers. We aimed to investigate the joint effect of uric acid and lymphocyte count for risk stratification in elderly patients with rheumatic heart disease undergoing valve replacement surgery. METHODS: Uric acid to lymphocyte ratio was calculated as serum uric acid (mg/dL)/lymphocyte count (*109/L). Univariate and multivariate analyses were performed to investigate the association of uric acid to lymphocyte ratio, with adverse events in 949 elderly patients with rheumatic heart disease undergoing valve replacement surgery. For clinical use, the uric acid to lymphocyte ratio was classified into 3 groups by the tertile, and a cutoff was also selected according to the receiver operator characteristic curve. RESULTS: Uric acid to lymphocyte ratio produced relatively higher predictive value (area under the curve, 0.703; 95% confidence interval [CI], 0.630-0.776; P < .001) than uric acid or lymphocyte count for in-hospital mortality, and the optimal cutoff was 3.7 (sensitivity, 82.1%; specificity, 52.4%). Uric acid to lymphocyte ratio was an independent predictor for in-hospital (adjusted odds ratio, 1.17; 95% CI, 1.07-1.29; P = .001) and 1-year mortality (adjusted hazard ratio, 1.13; 95% CI, 1.03-1.25; P = .010). The in-hospital mortality increased from the lowest to the highest uric acid to lymphocyte ratio tertile (P < .001) and significantly higher in patients with uric acid to lymphocyte ratio greater than 3.7 (P < .001). The cumulative 1-year postoperative mortality risk was significantly higher in patients with uric acid to lymphocyte ratio greater than 3.7 (P < .001) or upper uric acid to lymphocyte ratio tertile (P < .001). CONCLUSIONS: Uric acid to lymphocyte ratio, combining the effect of uric acid and lymphocyte count, produced more prognostic value in elderly patients with rheumatic heart disease undergoing valve replacement surgery, which could be considered as a preoperative risk-stratified method. PMID- 30459110 TI - If RITA did not exist, it would be necessary to invent it so if you can't beat them join them. PMID- 30459111 TI - Ivor Lewis minimally invasive esophagectomy for esophageal cancer: An excellent operation that improves with experience. AB - OBJECTIVE: Esophagectomy is associated with major morbidity. In this study we sought to assess the learning curve of minimally invasive Ivor Lewis esophagectomy (MIILE) and to evaluate perioperative outcomes, including anastomotic leak and hospital readmission, as a function of graduated surgeon experience. METHODS: Data were extracted from the electronic medical records of patients who underwent MIILE, performed by a single surgeon over an 8-year period (2009-2017). Primary outcomes were 5-year overall survival, postoperative complications, and 90-day readmission rates. Surgeon experience was divided into 4 quartiles, representing graduated experience. Statistical analysis was performed using univariate and multivariate logistic regression, whereas Kaplan Meier estimators were used to assess survival outcomes. RESULTS: A total of 170 patients underwent MIILE and were analyzed after exclusion criteria were applied. Five-year overall survival was 50.1% (95% confidence interval, 39.7%-63.2%). Mortality at 90 days was 3.9% (95% confidence interval, 0.8%-6.9%). Major complications occurred in 25.3% (n = 43) and 25.9% (n = 44) were readmitted to the hospital within 90 days after surgery. Conversion to open surgery, anastomotic leaks, and readmissions decreased over time. CONCLUSIONS: MIILE can be performed safely and effectively with improving results as the surgeon's experience evolves. PMID- 30459112 TI - Size still matters. PMID- 30459113 TI - Advanced imaging techniques (CT and MR): Gender-based diagnostic work-up in ischemic heart disease? AB - It is ascertained that the epidemiology and social impact of ischemic heart disease is substantially different between the two genders. Moreover, there is substantial evidence that gender is able to modulate the clinical manifestation of most cardiac diseases, and specifically of coronary artery disease. Particularly, women present less angiographically significant coronary artery disease, smaller vessel lumen, and less plaque rupture occurrence as compared to men. On the contrary, manifestations as vasospasm, impaired vasodilatation at epicardial level, and microvascular dysfunction are more common in female. In clinical practice, it is important to know the gender-based aspects of clinical disease expression and how to diversify the diagnostic work-up. Cardiac Computed Tomography and Cardiac Magnetic Resonance are relatively new diagnostic imaging tools employed for studying both the cardiac structures and the pathophysiology of the cardiovascular system. In this paper, we aim to overview the non-invasive diagnostic role in a gender's dimension, mainly focusing on Cardiac Computed Tomography and Cardiac Magnetic Resonance in ischemic heart disease, and to understand whether the existing evidences support a different diagnostic work-up approach. PMID- 30459114 TI - Multivariate analysis of genome-wide data to identify potential pleiotropic genes for type 2 diabetes, obesity and coronary artery disease using MetaCCA. AB - BACKGROUND: Although genome-wide association studies (GWAS) have been extensively applied in identifying SNP associated with metabolic diseases, the SNPs identified by this prevailing univariate approach only explain a small percentage of the genetic variance of traits. The extensive previous studies have repeatedly shown type2 diabetes (T2D), obesity and coronary artery disease (CAD) have common genetic mechanisms and the overlapping pathophysiological pathways. METHODS: The genetic pleiotropy-informed metaCCA method was applied on summary statistics data from three independent meta-GWAS summary statistics to identify shared variants and pleiotropic effect between T2D, obesity and CAD. Furthermore, to refine all genes, we performed gene-based association analyses for these three diseases respectively using VEGAS2. Gene enrichment analysis was applied to explore the potential functional significance of the identified genes. RESULTS: After metaCCA analysis, 833 SNPs reached the Bonferroni corrected threshold (p < 7.99 * 10-7) in the univariate SNP-multivariate phenotype analysis, and 327 genes with a significance threshold (p < 3.73 * 10-6) were identified as potentially pleiotropic genes in the multivariate SNP-multivariate phenotype analysis. By screening the results of gene-based p-values, we identified 22 putative pleiotropic genes which achieved significance threshold in metaCCA analyses and were also associated with at least one disease in the VEGAS2 analyses. CONCLUSIONS: The metaCCA method identified novel variants associated with T2D, obesity and CAD by effectively incorporating information from different GWAS datasets. Our analyses may provide insights for some common therapeutic approaches of metabolic diseases based on the pleiotropic genes and common mechanisms identified. PMID- 30459115 TI - Recurrent tendosynovitis as a rare manifestation of a lipid disorder. AB - A 33-year-old female had suffered from spontaneously recurrent bursitis and tendosynovitis/enthesitis of the patellar and Achilles tendons for about 10 years. The episodes of immobilization increased. Ultrasound imaging of the swollen and painful tendons showed chronic inflammation with neoangiogenesis within the tendons and hypoechoic lesions. Clinical and laboratory tests did not provide evidence for a rheumatic disease. Low density lipoprotein cholesterol was elevated. Biopsies of skin lesions did not confirm the suspicion of cutaneous xanthomas. Genetic testing for familial hypercholesterolemia was negative. Campesterol and sitosterol were elevated 7- to 12-fold and 20- to 38-fold over the upper limit of normal on two occasions. There was no relevant mutation in ABCG5. In ABCG8, we identified a missense mutation c.1267G>A in exon 9 changing glutamic acid 423 into lysine within the transmembrane domain, and an insertion of adenine (c.1487insA) leading to a frameshift and a premature stop codon (Ile497Aspfs*105). The patient had no clinical evidence of premature atherosclerosis. Therapeutic approaches with nonsteroidal antirheumatic drugs, prednisone, statins, and ezetimibe accompanied by a diet poor in plant sterols led to a relief of symptoms. This case report shows that tendon xanthoma along with tendosynovitis, especially on extensor areas, is suspicious for hypercholesterolemia as the underlying cause. The absence of atherosclerotic plaques in the abdominal aorta and in the carotid arteries on ultrasound may suggest that phytosterolemia is not necessarily accompanied by premature vascular disease. PMID- 30459116 TI - Comparison of Cognitive Intervention Strategies for Older Adults With Mild to Moderate Alzheimer's Disease: A Bayesian Meta-analytic Review. AB - OBJECTIVES: We aimed to identify the best form of cognitive therapy among 3 main cognitive interventions of Alzheimer's disease (AD) including cognitive training (CT), cognitive stimulation (CS), and cognitive rehabilitation (CR). DESIGN: Systematic review and Bayesian network meta-analysis. SETTING AND PARTICIPANTS: An exhaustive literature search was conducted based on PubMed, Embase, the Cochrane Central Register of Controlled Trials, PsycINFO, the China National Knowledge Infrastructure database, the Chinese Biomedical Literature database, the Wan Fang database, and Web of Science and other database and randomized controlled trials were identified from their inception to May 1, 2018. Older adult participants diagnosed with AD were recruited. MEASURES: We conducted a Bayesian network meta-analysis (NMA) to rank the included treatments. Cognitive functions were measured based on the Mini-Mental State Examination (MMSE). A series of analyses and assessments, such as the Pairwise meta-analysis and the risk of bias, were performed concurrently. RESULTS: Only 22 studies were included in our analysis based on a series of rigorous screenings, which comprised 1368 participants. No obvious heterogeneities were found in NMA (I2 = 32.7%, P = .07) after the data were pooled. The mean difference (MD) of CT [MD = 2.1, confidence interval [CI]: 1.0, 3.2), CS (MD = 0.92, CI: -0.20, 2.0), and CR (MD = 2.0, CI: 0.73, 3.4) showed that CT and CR could significantly improve cognitive function as measured by MMSE in the treatment group whereas the CS was less effective. CT had the highest probability among the 3 cognitive interventions [the surface under the cumulative ranking curve (SUCRA) = 84.7%], followed by CR (SUCRA = 50.0%) and CS (SUCRA = 47.4%). CONCLUSIONS/RELEVANCE: Our study indicated that the CT might be the best method for improving the cognitive function of AD patients. The findings from our study may be useful for policy makers and service commissioners when they make choices among different alternatives. PMID- 30459117 TI - Development of artificial neural network tools for predicting sugar yields from inorganic salt-based pretreatment of lignocellulosic biomass. AB - This study developed two Artificial Neural Network (ANN) tools for predicting sugar yields from inorganic salt-based pretreatment of lignocellulosic biomass. Pretreatment data from 90 experimental runs with 8 different input conditions were used to develop a microwave-based and a steam-based model. Both models exhibited high coefficients of determination (R2) of 0.97. Knowledge extraction revealed reducing sugar yields from the steam- and microwave-based models exhibited high sensitivity to both salt and alkali concentration. These models may be employed as initial screening tools in lignocellulosic bioprocesses, thereby potentially enhancing the economic and productivity of lignocellulosic based bioprocesses. PMID- 30459118 TI - The molecular and evolutionary basis of reproductive isolation in plants. AB - Reproductive isolation is defined as processes that prevent individuals of different populations from mating, survival or producing fertile offspring. Reproductive isolation is critical for driving speciation and maintaining species identity, which has been a fundamental concern in evolutionary biology. In plants, reproductive isolation can be divided into prezygotic and postzygotic reproductive barriers, according to its occurrence at different developmental stages. Postzygotic reproductive isolation caused by reduced fitness in hybrids is frequently observed in plants, which hinders gene flow between divergent populations and has substantial effects on genetic differentiation and speciation, and thus is a major obstacle for utilization of heterosis in hybrid crops. During the past decade, China has made tremendous progress in molecular and evolutionary basis of prezygotic and postzygotic reproductive barriers in plants. Present understandings in reproductive isolation especially with new data in the last several years well support three evolutionary genetic models, which represent a general mechanism underlying genomic differentiation and speciation. The updated understanding will offer new approaches for the development of wide compatibility or neutral varieties, which facilitate breeding of hybrid rice as well as other hybrid crops. PMID- 30459119 TI - The forty years of medical genetics in China. AB - Medical genetics is the newest cutting-edge discipline that focuses on solving medical problems using genetics knowledge and methods. In China, medical genetics research activities initiated from a poor inner basis but a prosperous outer environment. During the 40 years of reform and opening-up policy, Chinese scientists contributed significantly in the field of medical genetics, garnering considerable attention worldwide. In this review, we highlight the significant findings and/or results discovered by Chinese scientists in monogenic diseases, complex diseases, cancer, genetic diagnosis, as well as gene manipulation and gene therapy. Due to these achievements, China is widely recognized to be at the forefront of medical genetics research and development. However, the significant progress and development that has been achieved could not have been accomplished without sufficient funding and a well-constructed logistics network. The successful implementation of translational and precise medicine sourced from medical genetics will depend on an open ethics policy and intellectual property protection, along with strong support at the national industry level. PMID- 30459121 TI - Left and Right Atrial Strain in Healthy Caucasian Children by Two-Dimensional Speckle-Tracking Echocardiography. PMID- 30459120 TI - Prognostic Value of Preserved Coronary Flow Velocity Reserve by Noninvasive Transthoracic Doppler Echocardiography in Patients With Angiographically Intermediate Left Main Stenosis. AB - BACKGROUND: The potential of angiography to evaluate the hemodynamic severity of a left main coronary artery (LM) stenosis is limited. Noninvasive transthoracic Doppler echocardiographic coronary flow velocity reserve (CFVR) evaluation of intermediate coronary stenosis has demonstrated remarkably high negative prognostic value. The aim of this study was to assess clinical outcomes in patients with angiographically intermediate LM stenosis and preserved CFVR (>2.0) as evaluated by transthoracic Doppler echocardiographic CFVR. METHODS: The initial study population included 102 patients with intermediate coronary stenosis of the LM referred for transthoracic Doppler echocardiographic CFVR assessment. Peak diastolic CFVR measurements were performed in the distal segment of the left anterior descending coronary artery after intravenous adenosine (140 MUg/kg/min), and CFVR was calculated as the ratio between maximal hyperemic and baseline coronary flow velocity. Nineteen patients had impaired CFVR (<=2.0) and were excluded from further analysis, as well as two patients with poor acoustic windows. The final group consisted of 81 patients (mean age, 60 +/- 9 years; 76 men) evaluated for adverse cardiac events including death, myocardial infarction, and revascularization. RESULTS: Mean follow-up duration was 62 +/- 26 months. Mean CFVR was 2.4 +/- 0.4. Total event-free survival was 75 of 81 (92.6%), as six patients were referred for revascularization (five patients with coronary artery bypass grafting, one patient with percutaneous coronary intervention). There were no documented myocardial infarctions or cardiovascular deaths in the follow-up period. CONCLUSIONS: In patients with angiographically intermediate and equivocal LM stenosis and preserved CFVR values of >2.0, revascularization can be safely deferred. PMID- 30459122 TI - Echocardiographic Assessment of the Tricuspid Annulus: The Effects of the Third Dimension and Measurement Methodology. AB - BACKGROUND: Evaluation of the tricuspid annulus is crucial for the decision making at the time of left heart surgery. Current recommendations for tricuspid valve repair are based on two-dimensional (2D) transthoracic echocardiography (TTE), despite the known underestimation compared with three-dimensional (3D) echocardiography. However, little is known about the differences in 3D tricuspid annular (TA) sizing using TTE versus transesophageal echocardiography (TEE). The aims of this study were to (1) compare 2D and 3D TA measurements performed with both TTE and TEE and (2) compare two 3D methods for TA measurements: multiplanar reconstruction (MPR) and dedicated software (DS) designed to take into account TA nonplanarity. METHODS: Seventy patients underwent 2D and 3D TTE and TEE. Two dimensional images were used to measure TA diameter from apical four-chamber, right ventricular-focused (TTE), and midesophageal four-chamber (TEE) views. Three-dimensional full-volume data sets were analyzed using both MPR and DS, to obtain major and minor axes, perimeter, and area. Intertechnique agreement was assessed using Bland-Altman analysis. RESULTS: Measurements on 2D TTE and TEE, which were view dependent, underestimated TA major dimensions in all views compared with 3D values, irrespective of the 3D method. MPR and DS measurements were significantly different, with DS resulting in larger values for all parameters, irrespective of approach. No differences were found between 3D TTE and 3D TEE for both MPR and DS. CONCLUSIONS: Our findings highlight the need for methodology that respects the 3D geometry of the tricuspid annulus, including its nonplanarity, which cannot be accurately assessed from 2D images and is not equally taken into account by different 3D measurement methodologies. Accordingly, a 3D cutoff value for TA enlargement needs to be established and is likely to be larger than the guideline-recommended 2D-based 40-mm cutoff. Importantly, noninvasive 3D TTE can be used instead of 3D TEE because TA measurements are not different. PMID- 30459123 TI - Echocardiographic Assessment for the Detection of Cardiotoxicity Due to Vascular Endothelial Growth Factor Inhibitor Therapy in Metastatic Renal Cell and Colorectal Cancers. AB - BACKGROUND: Cardio-oncology is a recently established discipline that focuses on the management of patients with cancer who are at risk for developing cardiovascular complications as a result of their underlying oncologic treatment. In metastatic colorectal cancer (mCRC) and metastatic renal cell carcinoma (mRCC), vascular endothelial growth factor inhibitor (VEGF-i) therapy is commonly used to improve overall survival. Although these novel anticancer drugs may lead to the development of cardiotoxicity, whether early detection of cardiac dysfunction using serial echocardiography could potentially prevent the development of heart failure in this patient population requires further study. The aim of this study was to investigate the role of two-dimensional speckle tracking echocardiography in the detection of cardiotoxicity due to VEGF-i therapy in patients with mCRC or mRCC. METHODS: Patients with mRCC or mCRC were evaluated using serial echocardiography at baseline and 1, 3, and 6 months following VEGF-i treatment. RESULTS: A total of 40 patients (34 men; mean age, 63 +/- 9 years) receiving VEGF-i therapy were prospectively recruited at two academic centers: 26 (65%) were receiving sunitinib, eight (20%) pazopanib, and six (15%) bevacizumab. The following observations were made: (1) 8% of patients developed clinically asymptomatic cancer therapeutics-related cardiac dysfunction; (2) 30% of patients developed clinically significant decreases in global longitudinal strain, a marker for early subclinical cardiac dysfunction; (3) baseline abnormalities in global longitudinal strain may identify a subset of patients at higher risk for developing cancer therapeutics-related cardiac dysfunction; and (4) new or worsening hypertension was the most common adverse cardiovascular event, afflicting nearly one third of the study population. CONCLUSIONS: Cardiac dysfunction defined by serial changes in myocardial strain assessed using two-dimensional speckle-tracking echocardiography occurs in patients undergoing treatment with VEGF-i for mCRC or mRCC, which may provide an opportunity for preventive interventions. PMID- 30459124 TI - Need for a Global Definition of Normative Echo Values-Rationale and Design of the World Alliance of Societies of Echocardiography Normal Values Study (WASE). PMID- 30459125 TI - Ethical Challenges in the Practice of Echocardiography: What Is Right and How Do We Do It? AB - At the 2018 Scientific Sessions, the American Society of Echocardiography inaugurated the Richard E. Kerber Ethics/Humanitarian Lecture, continuing its tradition of providing ethics education and exploring the use of echocardiography to improve cardiovascular care in medically underserved settings. Echocardiography is one of the most widely applicable, safe, and cost-effective diagnostic tools available in cardiovascular medicine. The American Society of Echocardiography Foundation is well known for harnessing the power of echocardiography in its many successful humanitarian outreaches all over the world. Some practitioners might conclude that because of its important advantages, echocardiography involves few ethical complexities; however, several historical and recent scandals involving conflicts of interest and lapses in quality suggest otherwise. Every day, sonographers and echocardiographers grapple with ethical issues: integrity, truth telling, doing good and avoiding harm, altruism, and humanism. In the near future, population aging and technological advances, among other issues, will ensure that a steady stream of ethical issues will confront the practitioners of echocardiography. Medical science and engineering have given us many things that can be done, but central to the art of medical practice and research are decisions about what should be done. In this article, based in part on the first Richard E. Kerber Ethics/Humanitarian Lecture, the authors discuss ethical challenges in the practice of echocardiography, illustrated by accompanying online videos, and offer a general principle for meeting these challenges. PMID- 30459126 TI - An agonist of a zinc-sensing receptor GPR39 enhances tight junction assembly in intestinal epithelial cells via an AMPK-dependent mechanism. AB - Intestinal barrier function depends on integrity of tight junctions, which serve as barriers to transepithelial influx of noxious substances/microorganisms from gut lumen. The G-protein coupled receptor 39 (GPR39) is a zinc-sensing receptor, which is expressed in several cell types including intestinal epithelial cells (IECs). The main objective of this study was to investigate the effect of GPR39 activation on tight junction assembly in IECs. Treatment with TC-G 1008 (1 MUM 10 MUM), a GPR39 agonist, and zinc (10 MUM -100 MUM) increased tight junction assembly in T84 cells. This effect was suppressed by pretreatment with compound C, an inhibitor of AMP-activated protein kinase (AMPK). In addition, western blot analysis revealed that treatment with TC-G 1008 induced AMPK activation in time- and concentration-dependent manners. Interestingly, inhibitors of phospholipase C (PLC) and calcium/calmodulin-dependent protein kinase kinase beta (CaMKKbeta) abrogated the effect of TC-G 1008 on inducing AMPK activation, tight junction assembly and zonula occludens-1 re-organization. Collectively, this study reveals a novel role of GPR39 in enhancing tight junction assembly in IECs via PLC CaMKKbeta-AMPK pathways. GPR39 agonists may be beneficial in the treatment of diseases associated impaired intestinal barrier function. PMID- 30459127 TI - Level of serum soluble Tim-3 expression in early-phase acute pancreatitis. AB - BACKGROUND/AIMS: T-cell immunoglobulin and mucin domain 3 (Tim-3) assumedly play a crucial immunomodulatory role in inflammatory response. Data on the potential role of soluble Tim-3 (sTim-3) in acute pancreatitis (AP) are scarce. We conducted a prospective clinical study to characterize its role in the early phase AP. METHODS: In total, 44 patients with AP (16 mild and 28 none-mild) who presented within 24 hours on admission and 20 healthy volunteers (NC) were included in our study. Serum interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-alpha, and sTim-3 levels were detected using enzyme-linked immunosorbent assay (ELISA). RESULTS: Levels of the pro-inflammatory cytokines IL-6 and TNF alpha and the anti-inflammatory cytokine IL-10 in the none-mild and mild groups were significantly elevated compared with those of the NC group. The sTim-3 levels of the none-mild and mild group were significantly increased compared with the NC. The sTim-3 level positively correlated with the IL-6 and TNF-alpha but showed no obvious correlations with the IL-10 level. The sTim-3 level positively correlated with the APACHE II score. CONCLUSION: The results indicate that sTim-3 participates in the early progression of AP by positively regulating the pro inflammatory cytokines and that the measurement of serum sTim-3 is an early marker for predicting AP. PMID- 30459128 TI - Endoscopic retrograde cholangiopancreatography in children: Retrospective series with a long-term follow-up and literature review. AB - BACKGROUND/AIMS: To investigate the safety and long-term results of endoscopic retrograde cholangiopancreatography (ERCP) in children with a literature review. MATERIALS AND METHODS: All patients within the age range of 6-17 years who underwent ERCP between 1994 and 2014 at our institution were retrospectively evaluated. RESULT: Twenty-four patients with a median age of 15 years underwent ERCP. Cannulation of the papilla was achieved in all patients (100%) without the use of needle-knife papillotomy. Before 1999, ERCP was used as a diagnostic method only in 7 patients (29%). In 17 (71%) patients, the procedure was used for therapeutic purposes. The indications were choledocholithiasis (10 cases, 42%), postoperative complications (5 patients, 21%), and recurrent pancreatitis (2 cases, 8%). In 2 patients (8%), the therapeutic effect was not achieved, thus requiring subsequent operations. There were no major complications. Mild pancreatitis occurred in only 1 patient (4%). Long-term follow-up information was obtained in 16 (67%) patients (median, 18 years; range, 3.5-22.5 years), and no long-term complications were detected. CONCLUSION: Endoscopic retrograde cholangiopancreatography is a valuable tool in the diagnosis and treatment of pancreatobiliary disorders in the pediatric population. Large-scale studies are required to create evidence-based guidelines specific to children. PMID- 30459129 TI - Littre hernia in children: A clinical aspect. AB - BACKGROUND/AIMS: Littre hernia (LH) is difficult to distinguish from other hernias until complications arise. In this research, we present the details of diagnosis, treatment, and frequency of LH cases with differentiated clinical properties. MATERIALS AND METHODS: Littre hernia prevalence, clinical properties, and treatment details of cases diagnosed as incarceration/strangulation (I/S) of hernias between December 1996 and December 2017 were retrospectively investigated. RESULTS: Incarceration/strangulation was detected in 403 out of 3758 hernias within 21 years. Four cases were detected as LH (0.09%) in 403 I/S patients. Partly reduced 2 cases were treated by resection/anastomosis with the abdominal approach. CONCLUSION: The possibility of LH in strangulated or partly reduced hernias should be considered. The abdominal approach may be necessary in nonreducible hernia with possible LH patients. PMID- 30459130 TI - Covered metal stent as a rescue therapy for impacted Dormia basket in the biliary tract. PMID- 30459131 TI - Current approach to early gastrointestinal and liver complications of hematopoietic stem cell transplantation. AB - The gastrointestinal (GI) system is one of the most commonly affected sites during a hematopoietic stem cell transplantation (HSCT) due to toxicities of preparative regimens, the accompanying immunodeficiency, and organ damage caused by graft versus host disease. In this review, we focus on early GI and liver complications following autologous (auto-) and allogeneic (allo-) HSCT and clarify both the risk factors and therapeutic strategies. Early GI and liver complications associated with HSCT remain challenging issues. Despite the improvements in this field during the last decade, treatments for these complications still place a significant burden on both patients and the physicians treating these patients. GI and liver complications remain some of the causes of mortality associated with HSCT. For practicing hematologists, oncologists, and gastroenterologists in this field, the awareness and early diagnosis of the GI complications remain important factors to obtain optimal outcomes in this patient population. PMID- 30459133 TI - Probable association of acute pancreatitis with dicyclomine. PMID- 30459132 TI - Acute variceal bleeding in patients with primary myelofibrosis successfully treated with endoscopic histoacryl injection. PMID- 30459134 TI - Safety of flexible endoscopic evaluation of swallowing examination in gastroenterological practice. AB - BACKGROUND/AIMS: In South Korea, the flexible endoscopic evaluation of swallowing (FEES) has been increasingly performed by gastroenterologists. The principal concern was the safety of the FEES performed by gastroenterologists without any involvement of speech-language pathologists. We aimed to characterize the safety and tolerance of gastroenterologist-directed FEES examinations (GDFEES). MATERIALS AND METHODS: We evaluated the GDFEES failures, safety profile (laryngospasm, epistaxis, vasovagal syncope, airway compromise, heart rate, blood pressure, and significant change in cardiovascular function), and discomfort level in patients undergoing GDFEES. These outcomes were also analyzed based on gender, age, and calendar period. RESULTS: A total 303 examinations in 268 adult patients with dysphagia were performed during the study period. The GDFEES failures occurred in 5 patients (1.7%). The causes of failures were poor co operation and insertion difficulty. There were no instances of laryngospasm or vasovagal syncope or significant cardiovascular changes in any of the examinations. Self-limiting epistaxis occurred in 22 examinations (7.3%). The discomfort ratings were as follows: 128 examinations (43.0%) rated the overall discomfort of the test as none, 150 (50.3%) as mild, 18 (6.0%) as moderate, and 2 (0.7%) as severe discomfort. The discomfort level was significantly different only between the first and second half periods (p <0.001), but it was related to neither gender nor age. CONCLUSION: The GDFEES can be endorsed as an appropriate paradigm for clinical practice based on our study investigating its safety and tolerance. PMID- 30459135 TI - Are there predictors that can determine neoadjuvant treatment responses in rectal cancer? AB - BACKGROUND/AIMS: This study aimed to determine a predictive bioindicator that would detect the treatment response of patients diagnosed with rectal cancer and treated with neoadjuvant chemoradiotherapy (nCRT). MATERIALS AND METHODS: The data collected from 37 patients receiving nCRT were retrospectively evaluated. The p53 score and gene instability in MLH1 and MSH2, which are among the DNA mismatch repair (MMR) genes, were evaluated using immunohistochemical methods. The neutrophils-leukocytes ratio (NLR), carcinoembryonic antigen (CEA), and carbohydrate antigen (CA) 19-9 values were obtained as hematological parameters from computer records. The pathologic analysis of the therapy response after nCRT was classified according to the modified grading system by Ryan et al. Results: The changes in the NLR, CEA, and CA19-9 values before and after treatment were statistically significant (p<=0.001 and p=0.005). A near significant effect of the decrease of the CEA value in the 5th week after treatment was detected on the pathological response score (p=0.075). The p53 mutation score in those patients with any residue was higher than the total response. Overall, 89.2% of the patients exhibited MMR positivity (stability), and 10.8% of the cases with MRM negativity (instability) had a macroscopic residue. Cases with pathological total response were MRM positive. CONCLUSION: Consequently, in most of the patients treated with nCRT, the treatment caused tumor and nodal remission. In the prediction of this therapy response, hematological and genetic parameters, such as NLR, P53, MLH1, and MSH2, play a predictive role. PMID- 30459136 TI - A case of entecavir-associated bullous fixed drug eruption and a review of literature. AB - Fixed drug eruption (FDE) is a type of drug reaction characterized by localized erythema, hyperpigmentation, and bullous at the same site(s), generally observed following every intake of a causative drug. Delayed-type cellular hypersensitivity (Type IVC) is considered to play a role in FDE etiology. Several antibiotics, barbiturates, oral contraceptives, nonsteroidal anti-inflammatory drugs, laxative-containing phenolphthalein, metronidazole, and quinine are known to be the primary drugs responsible for FDE. Bullous FDE, on the other hand, is a relatively rare form of FDE. Hepatitis B is a significant worldwide health problem, and entecavir is a common nucleoside (deoxyguanosine) analog used for treating hepatitis B; however, it has various side effects, such as lactic acidosis, myalgia, azotemia, hypophosphatemia, headache, diarrhea, pancreatitis, and neuropathy, and, in rare cases, cutaneous drug eruption. Our aim is to present a case of entecavir-associated bullous drug reaction, which has not been reported in the literature. Furthermore, we performed a review of literature to compile previously reported entecavir-associated drug reactions. PMID- 30459137 TI - CT features of asymptomatic heterotopic pancreas in jejunal mesentery. AB - Heterotopic pancreas (HP) is localized pancreatic tissue that has no relation to orthotopic pancreas and has its own channel and vascular structures. Usually, the submucosa is located in the upper gastrointestinal tract; mesenteric placement is rarely reported. It is frequently asymptomatic and is detected incidentally in imaging, laparotomies, or autopsies. Rarely, pancreatitis may be the cause of small bowel obstruction, massive gastrointestinal bleeding, and malignant transformation. However, this has usually been reported in localized submucosal HP cases. The imaging findings are typical, and the diagnosis can be verified without the need for a histopathological diagnosis. In this case report, we aimed to present the imaging findings of asymptomatic HP located in the proximal jejunum mesentery of a 44-year-old woman. To avoid unnecessary surgical procedures, the characteristic imaging findings of HP are understood and should be considered in the differential diagnosis of masses seen in the mesentery. PMID- 30459138 TI - Comparing the Effectiveness of Clinicians and Paraprofessionals to Reduce Disparities in Perinatal Depression via the Mothers and Babies Course: Protocol for a Cluster-Randomized Controlled Trial. AB - BACKGROUND: Postpartum depression is highly prevalent in low-income women and has significant health and mental health effects on mother and child. Home visiting (HV) programs provide services to large numbers of perinatal women in the United States and are a logical setting for delivering mental health services. Although there are interventions that reduce the risk of developing postpartum depression among low-income women, none have used nonhealth or nonmental health professionals as interventionists. OBJECTIVE: This study aimed to outline the protocol of a cluster randomized trial funded by the Patient-Centered Outcomes Research Institute that evaluates whether the Mothers and Babies (MB) group intervention, when led by paraprofessional home visitors, is more efficacious than usual care. It will also examine if MB, when led by home visitors, is not inferior to MB delivered by mental health professionals (MHPs). MB has previously demonstrated efficacy when delivered by MHPs, and pilot work indicated promising results using home visitors to deliver the intervention. METHODS: A cluster randomized trial is being conducted with 38 HV programs. Sixteen HV programs will deliver MB using MHPs, 16 will deliver MB using paraprofessional home visitors, and 6 will deliver usual HV services. The study employs a modified covariate constrained randomization design at the site level. We anticipate recruiting 933 women aged >=16 years enrolled in HV programs, who are 33 or more weeks' gestation and speak either English or Spanish. Women in the 2 intervention arms will receive the 6-session MB group intervention. Baseline, postintervention, 12 week postpartum, and 24-week postpartum assessments will be conducted to assess client outcomes. The primary outcome will be the change in Quick Inventory of Depressive Symptomatology Self-Report 16 scores from baseline to 24-week follow up. Secondary outcomes associated with core MB content will also be examined. Semistructured interviews will be conducted with home visitors and MHPs who are group facilitators and 90 study participants to gain data on intervention successes and challenges. Analyses will proceed at the participant level. Primary analyses for depressive symptoms score at 24 weeks postpartum will involve a linear mixed model, controlling for baseline symptoms and other covariates, and random effects to account for clustering. RESULTS: We have recruited 838 women through the end of August 2018. Recruitment will be completed at the end of September 2018. CONCLUSIONS: There is considerable potential to disseminate MB to HV programs throughout the United States. Should our results demonstrate home visitor efficacy when compared with usual care and/ noninferiority between home visitors and MHPs in improving mental health outcomes, no additional financial resources would be required for the existing HV staff to implement MB. Should this study determine that home visitors are less effective than MHPs, we will generate more wide-scale evidence on MB effectiveness when led by MHPs. TRIAL REGISTRATION: ClinicalTrials.gov NCT02979444; https://clinicaltrials.gov/ct2/show/NCT02979444 (Archived by Webcite at http://www.webcitation.org/archive.php). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/11624. PMID- 30459139 TI - A Novel Mobile Phone App (OncoFood) to Record and Optimize the Dietary Behavior of Oncologic Patients: Pilot Study. AB - BACKGROUND: Catabolism and tumor-specific therapy lead to reduced nutrient intake and weight loss in cancer patients. Maintaining a specific individualized diet can be challenging for the patient as the nutritional counseling options are limited. Monitoring of nutrient intake and frequent feedback are, however, vital for successful nutritional therapy because they support the patient's compliance and realization of dietary therapeutic goals. OBJECTIVE: This study aimed at investigating the feasibility and applicability of a novel mobile phone app to assess and evaluate dietary behaviors in oncologic patients. METHODS: To determine dietary habits and food preferences in oncologic patients, initially 1400 nutritional records were evaluated and analyzed. The results provided the basis for creating a nutritional mobile phone app. Key requirements for the app included simple handling, recording the daily intake, and a comparison of nutrient targets and current status. In total, 39 cancer patients were recruited for the study; 15 patients dropped out prior to the study. All patients received a nutritional anamnesis, nutritional analysis, and nutritional counseling. Individual energy and nutrient aims were defined. The intervention group (n=12) additionally used the app. Weight and body composition of each group were evaluated after 4 weeks. RESULTS: The app group gained significantly more weight (P=.045; mean weight 1.03 kg vs -1.46 kg). Also, skeletal muscle mass showed a significant increase in the app group (P=.009; mean skeletal muscle mass 0.58 kg vs -0.61 kg) compared with the control group. There was no significant difference between groups relating to the daily protein intake (P=.06). Additionally, there was a decrease in macronutrient intake during the study period in the control group. CONCLUSIONS: Our study indicates that patients who track their daily dietary habits using a mobile phone app are more likely to reach their nutritional goals than the control patients. Further large-scale studies are needed to confirm these initial findings and test the applicability on a broader basis. PMID- 30459140 TI - Description of Cardiological Apps From the German App Store: Semiautomated Retrospective App Store Analysis. AB - BACKGROUND: In the app stores of mobile platforms, consumers are confronted with an enormous number of mobile apps. Over the past few years, considerable research has been undertaken into to identifying, characterizing, and evaluating apps, be it in health-related or other contexts. However, many of these projects are restricted to specific areas of application and offer little flexibility in adapting the applied criteria. OBJECTIVE: This paper presents an adaptable method for selecting and characterizing mobile apps listed in a mobile App Store (the Apple App Store). The method is based on filtering processes using predefined criteria, through a semiautomated retrospective App Store analysis (SARASA). METHODS: To illustrate the SARASA process, keyword-based filtering and metadata based description, review, and ranking steps were applied to a dataset, more specifically, an April 2018 readout of the Medical category of the German App Store, with the aim of obtaining a list of cardiology-related apps. RESULTS: From the original list of 39,427 apps within the "Medical" category of the App Store on April 14, 2018, 34,382 apps with store descriptions in languages other than German were removed. For the remaining 5045 apps, keywords related to cardiology were applied to filter the output, obtaining a final total of 335 subject specific apps for further analysis and description. CONCLUSIONS: SARASA provides an easy to use method for applying filtering processes to identify apps matching predefined, formal criteria from app stores. The criteria can be well adapted to the needs of users. Automatic and manual analyses are easily combined when using SARASA. In the future, additional features, such as algorithmic topic analyses, may supplement the process. Although the area of application is currently limited to Apple's App Store, expansion to other stores is planned. The method stands or falls with the transparency of the app store providers and the manufacturers to make relevant meta-information available. It is up to them to liberalize information and restrict censorship to provide clients, customers, and users truly fair circumstances finding their way around the app market. PMID- 30459141 TI - Preferences of Underserved Chilean Women on a Mobile Technology Intervention for Cervical Cancer Screening: Qualitative Study. AB - BACKGROUND: In Chile and Latin America, cervical cancer disproportionately affects women of low socioeconomic status. Mobile technology (mobile health, mHealth) may be able to address this disparity by targeting women in underserved populations. However, there is a lack of information regarding barriers to the implementation of mHealth interventions in underserved populations. OBJECTIVE: The objective of this study was to investigate the use of cell phones and text messaging (short message service, SMS) in Latina women from disadvantaged communities to design an mHealth intervention for improving cervical cancer screening rates. METHODS: We conducted 9 focus groups among women aged 25-64 years to better understand the implementation barriers and perceptions of a text message (SMS)-based intervention designed to improve cervical cancer screening rates. We used the PRECEDE-PROCEED model to categorize identified themes using template analysis. RESULTS: Focus group results indicated that older women use mobile phones to receive calls from family and friends but seldom send text messages. Furthermore, they prefer personal contact with their health care providers regarding Papanicolaou (Pap) testing. Younger women, on the other hand, find text messaging easy to use and frequently send texts to family and friends. Importantly, women of all ages mentioned they would like to receive text messages about Pap tests. Factors that facilitate the uptake of the intervention include ease of access to Pap testing, inclusion of family members, and reminder messaging. Potential barriers include cost and the impersonal nature of messaging. Health team members support an mHealth intervention even though they acknowledge the potential barriers to this strategy. Overall, these results support the implementation of an mHealth intervention to increase cervical cancer screening rates. CONCLUSIONS: This study describes the opinions of women nonadherent to Pap testing on the potential use of mobile technologies for cervical cancer screening. Although the overall acceptance was positive, older women prefer personal contact and phone calls over text messaging. Information surrounding these preferences will aid in the implementation of effective strategies to improve cancer screening in underserved populations. PMID- 30459142 TI - Monitoring the Control of Sexually Transmissible Infections and Blood-Borne Viruses: Protocol for the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance (ACCESS). AB - BACKGROUND: New biomedical prevention interventions make the control or elimination of some blood-borne viruses (BBVs) and sexually transmissible infections (STIs) increasingly feasible. In response, the World Health Organization and governments around the world have established elimination targets and associated timelines. To monitor progress toward such targets, enhanced systems of data collection are required. This paper describes the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance (ACCESS). OBJECTIVE: This study aims to establish a national surveillance network designed to monitor public health outcomes and evaluate the impact of strategies aimed at controlling BBVs and STIs. METHODS: ACCESS is a sentinel surveillance system comprising health services (sexual health clinics, general practice clinics, drug and alcohol services, community-led testing services, and hospital outpatient clinics) and pathology laboratories in each of Australia's 8 states and territories. Scoping was undertaken in each jurisdiction to identify sites that provide a significant volume of testing or management of BBVs or STIs or to see populations with particular risks for these infections ("priority populations"). Nationally, we identified 115 health services and 24 pathology laboratories as relevant to BBVs or STIs; purposive sampling was undertaken. As of March 2018, we had recruited 92.0% (104/113) of health services and 71% (17/24) of laboratories among those identified as relevant to ACCESS. ACCESS is based on the regular and automated extraction of deidentified patient data using specialized software called GRHANITE, which creates an anonymous unique identifier from patient details. This identifier allows anonymous linkage between and within participating sites, creating a national cohort to facilitate epidemiological monitoring and the evaluation of clinical and public health interventions. RESULTS: Between 2009 and 2017, 1,171,658 individual patients attended a health service participating in ACCESS network comprising 7,992,241 consultations. Regarding those with unique BBV and STI-related health needs, ACCESS captured data on 366,441 young heterosexuals, 96,985 gay and bisexual men, and 21,598 people living with HIV. CONCLUSIONS: ACCESS is a unique system with the ability to track efforts to control STIs and BBVs-including through the calculation of powerful epidemiological indicators-by identifying response gaps and facilitating the evaluation of programs and interventions. By anonymously linking patients between and within services and over time, ACCESS has exciting potential as a research and evaluation platform. Establishing a national health surveillance system requires close partnerships across the research, government, community, health, and technology sectors. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/11028. PMID- 30459143 TI - Assessing and Improving the Use of Online Information About Child Development, Education, Health, and Well-Being in Low-Education, Low-Income Parents: Protocol for a Mixed-Methods Multiphase Study. AB - BACKGROUND: This study is born from a partnership between Web editors of Naitre et grandir (N&G) and AboutKidsHealth (AKH) and researchers who developed and validated the Information Assessment Method (IAM). N&G and AKH are popular Canadian websites with high-quality comprehensive information about child development, education, health, and well-being. IAM allows parents to assess online information and provide feedback to Web editors. High-quality online consumer health information improves knowledge, self-efficacy, and health. However, low-socioeconomic status (SES) parents underuse N&G and IAM, despite these parents being more likely to report decreased worries and increased confidence as outcomes from N&G information. OBJECTIVE: The study is aimed to improve low-SES parents' use of online child information and interaction with Web editors and explore subsequent health outcomes for parents and children. METHODS: Multiphase mixed-methods design. Our general approach is centered on organizational participatory research. In phase 1, we will conduct a qualitative interpretive study to identify barriers and facilitators to using N&G information and to interacting with N&G editors via IAM; interview more than 10 low-SES parents about their experience with N&G and IAM and more than 10 nonusers of N&G and IAM; and use thematic analysis to identify main barriers and facilitators. In phase 2, we will integrate parents' views (phase 1 findings) in N&G and IAM and implement a new version: IAM+N&G+. In phase 3, we will conduct a quantitative prospective longitudinal study (pre-/postimplementation monitoring of knowledge use and outcomes). We will compare the use of original (IAM and N&G) and new (IAM+ and N&G+) versions using Google Analytics variables, IAM variables, a material and social deprivation index, and demographics. We anticipate increased use post implementation (linear mixed modeling). In phase 4, we will conduct a qualitative descriptive study on outcomes of information use. We will interview more than 30 low-SES parents who receive and rate the N&G+ newsletter using IAM+ and analyze data in the form of life histories to describe how parents and children experience perceived outcomes. RESULTS: The project was funded in 2017 by the Canadian Institutes of Health Research and received an ethics approval by the McGill University's institutional review board. Data collection for phase 1 was completed in 2018. Phases 2 to 4 will be conducted until 2020. Findings from this study will also be used to develop a free toolkit, useful to all Web editors, with recommendations for improving health information for low-SES persons and interactions with them using IAM. CONCLUSIONS: The results of this study will provide a deep understanding of how low-SES parents use online child information and interact with Web editors. Following the implementation of IAM+N&G+, results will also elucidate subsequent health outcomes for low-SES parents and children after interaction with Web editors has been optimized. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/9996. PMID- 30459144 TI - A Patient Registry for the Management of Uterine Fibroids in Canada: Protocol for a Multicenter, Prospective, Noninterventional Study. AB - BACKGROUND: Uterine fibroids are the most common benign tumor in women. Among those with fibroids, approximately 30% become symptomatic, with abnormal uterine bleeding, pelvic pain, and bulk symptoms. Despite the high prevalence of fibroids, little information is available regarding symptoms, treatment choices, and outcomes for patients. OBJECTIVE: A Canada-wide patient registry was established to understand the real-world practice. This registry included patient presentation and treatment preferences, health care provider attitudes, and clinical outcomes in the management of symptomatic uterine fibroids. METHODS: This study is a prospective, noninterventional, observational patient registry. It will include women diagnosed with uterine fibroids and being managed for symptoms. Participant inclusion criteria were (1) at least 18 years of age, (2) premenopausal with a confirmed diagnosis of uterine fibroids, and associated symptoms, and (3) initiating treatment (drug intervention, procedure intervention, or a combination of both) or watchful waiting. Patients (or legal representative) must understand the nature of the project and provide written informed consent before enrollment. Participant exclusion criteria were (1) they have known or suspected clinically significant pelvic pathology not associated with uterine fibroids, and (2) they are undergoing an emergency hysterectomy at the initial visit. Outcomes will be evaluated in the context of routine clinical practice. RESULTS: Participant recruitment of this registry began in July 2015. This study currently has a total sample of 1500 patients. CONCLUSIONS: This registry, a first in Canada, will accumulate evidence on the risks and benefits of watchful waiting, and medical and procedural interventions. It will contribute to enhancing access to treatment options for patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02580578; https://clinicaltrials.gov/ct2/show/NCT02580578 (Archived by WebCite at http://www.webcitation.org/6yax4Hpvr). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/10926. PMID- 30459146 TI - Using Video Technology to Increase Treatment Completion for Patients With Latent Tuberculosis Infection on 3-Month Isoniazid and Rifapentine: An Implementation Study. AB - BACKGROUND: Since January 2013, the New York City (NYC) Health Department Tuberculosis (TB) Program has offered persons diagnosed with latent TB infection (LTBI) the 3-month, once-weekly isoniazid and rifapentine (3HP) treatment regimen. Patients on this treatment are monitored in-person under directly observed therapy (DOT). To address patient and provider barriers to in-person DOT, we piloted the use of a videoconferencing software app to remotely conduct synchronous DOT (video directly observed therapy; VDOT) for patients on 3HP. OBJECTIVE: The objective of our study was to evaluate the implementation of VDOT for patients on 3HP and to assess whether treatment completion for these patients increased when they were monitored using VDOT compared with that using the standard in-person DOT. METHODS: Between February and October 2015, patients diagnosed with LTBI at any of the four NYC Health Department TB clinics who met eligibility criteria for treatment with 3HP under VDOT (V3HP) were followed until 16 weeks after treatment initiation, with treatment completion defined as ingestion of 11 doses within 16 weeks. Treatment completion of patients on V3HP was compared with that of patients on 3HP under clinic-based, in-person DOT who were part of a prior study in 2013. Furthermore, outcomes of video sessions with V3HP patients were collected and analyzed. RESULTS: During the study period, 70% (50/71) of eligible patients were placed on V3HP. Treatment completion among V3HP patients was 88% (44/50) compared with 64.9% (196/302) among 3HP patients on clinic DOT (P<.001). A total of 360 video sessions were conducted for V3HP patients with a median of 8 (range: 1-11) sessions per patient and a median time of 4 (range: 1-59) minutes per session. Adherence issues (eg, >15 minutes late) during video sessions occurred 104 times. No major side effects were reported by V3HP patients. CONCLUSIONS: The NYC TB program observed higher treatment completion with VDOT than that previously seen with clinic DOT among patients on 3HP. Expanding the use of VDOT may improve treatment completion and corresponding outcomes for patients with LTBI. PMID- 30459145 TI - Web-Based Signal Detection Using Medical Forums Data in France: Comparative Analysis. AB - BACKGROUND: While traditional signal detection methods in pharmacovigilance are based on spontaneous reports, the use of social media is emerging. The potential strength of Web-based data relies on their volume and real-time availability, allowing early detection of signals of disproportionate reporting (SDRs). OBJECTIVE: This study aimed (1) to assess the consistency of SDRs detected from patients' medical forums in France compared with those detected from the traditional reporting systems and (2) to assess the ability of SDRs in identifying earlier than the traditional reporting systems. METHODS: Messages posted on patients' forums between 2005 and 2015 were used. We retained 8 disproportionality definitions. Comparison of SDRs from the forums with SDRs detected in VigiBase was done by describing the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, receiver operating characteristics curve, and the area under the curve (AUC). The time difference in months between the detection dates of SDRs from the forums and VigiBase was provided. RESULTS: The comparison analysis showed that the sensitivity ranged from 29% to 50.6%, the specificity from 86.1% to 95.5%, the PPV from 51.2% to 75.4%, the NPV from 68.5% to 91.6%, and the accuracy from 68% to 87.7%. The AUC reached 0.85 when using the metric empirical Bayes geometric mean. Up to 38% (12/32) of the SDRs were detected earlier in the forums than that in VigiBase. CONCLUSIONS: The specificity, PPV, and NPV were high. The overall performance was good, showing that data from medical forums may be a valuable source for signal detection. In total, up to 38% (12/32) of the SDRs could have been detected earlier, thus, ensuring the increased safety of patients. Further enhancements are needed to investigate the reliability and validation of patients' medical forums worldwide, the extension of this analysis to all possible drugs or at least to a wider selection of drugs, as well as to further assess performance against established signals. PMID- 30459147 TI - Text Messages Sent to Household Tuberculosis Contacts in Kampala, Uganda: Process Evaluation. AB - BACKGROUND: Previous studies have reported the inconsistent effectiveness of text messaging (short message service, SMS) for improving health outcomes, but few have examined to what degree the quality, or "fidelity," of implementation may explain study results. OBJECTIVE: The aim of this study was to determine the fidelity of a one-time text messaging (SMS) intervention to promote the uptake of tuberculosis evaluation services among household contacts of index patients with tuberculosis. METHODS: From February to June 2017, we nested a process evaluation of text message (SMS) delivery within the intervention arm of a randomized controlled trial of tuberculosis contact investigation in Kampala, Uganda. Because mobile service providers in Uganda do not provide delivery confirmations, we asked household tuberculosis contacts to confirm the receipt of a one-time tuberculosis-related text message (SMS) by sending a text message (SMS) reply through a toll-free "short code." Two weeks later, a research officer followed up by telephone to confirm the receipt of the one-time text message (SMS) and administer a survey. We considered participants lost to follow-up after 3 unsuccessful call attempts on 3 separate days over a 1-week period. RESULTS: Of 206 consecutive household contacts, 119 had a text message (SMS) initiated from the server. While 33% (39/119) were children aged 5-14 years, including 20% (24/119) girls and 13% (15/119) boys, 18 % (21/119) were adolescents or young adults, including 12% (14/119) young women and 6% (7/119) young men. 50% (59/119) were adults, including 26% (31/119) women and 24% (28/119) men. Of 107 (90%) participants for whom we could ascertain text message (SMS) receipt status, 67% (72/107) confirmed text message (SMS) receipt, including 22% (24/107) by reply text message (SMS) and 45% (48/107) during the follow-up telephone survey. No significant clinical or demographic differences were observed between those who did and did not report receiving the text message (SMS). Furthermore, 52% (56/107) reported ever reading the SMS. The cumulative likelihood of a text message (SMS) reaching its target and being read and retained by a participant was 19%. CONCLUSIONS: The fidelity of a one-time text message (SMS) intervention to increase the uptake of household tuberculosis contact investigation and linkage to care was extremely low, a fact only discoverable through detailed process evaluation. This study suggests the need for systematic process monitoring and reporting of implementation fidelity in both research studies and programmatic interventions using mobile communications to improve health. PMID- 30459149 TI - Monitoring glycaemic control in patients with diabetes mellitus. PMID- 30459148 TI - Mobile Ecological Momentary Diet Assessment Methods for Behavioral Research: Systematic Review. AB - BACKGROUND: New methods for assessing diet in research are being developed to address the limitations of traditional dietary assessment methods. Mobile device assisted ecological momentary diet assessment (mEMDA) is a new dietary assessment method that has not yet been optimized and has the potential to minimize recall biases and participant burden while maximizing ecological validity. There have been limited efforts to characterize the use of mEMDA in behavioral research settings. OBJECTIVE: The aims of this study were to summarize mEMDA protocols used in research to date, to characterize key aspects of these assessment approaches, and to discuss the advantages and disadvantages of mEMDA compared with the traditional dietary assessment methods as well as implications for future mEMDA research. METHODS: Studies that used mobile devices and described mEMDA protocols to assess dietary intake were included. Data were extracted according to Preferred Reporting of Systematic Reviews and Meta-Analyses and Cochrane guidelines and then synthesized narratively. RESULTS: The review included 20 studies with unique mEMDA protocols. Of these, 50% (10/20) used participant-initiated reports of intake at eating events (event-contingent mEMDA), and 50% (10/20) used researcher-initiated prompts requesting that participants report recent dietary intake (signal-contingent mEMDA). A majority of the study protocols (60%, 12/20) enabled participants to use mobile phones to report dietary data. Event-contingent mEMDA protocols most commonly assessed diet in real time, used dietary records for data collection (60%, 6/10), and provided estimates of energy and nutrient intake (60%, 6/10). All signal-contingent mEMDA protocols used a near real-time recall approach with unannounced (ie, random) abbreviated diet surveys. Most signal-contingent protocols (70%, 7/10) assessed the frequency with which (targeted) foods or food groups were consumed. Relatively few (30%, 6/20) studies compared mEMDA with the traditional dietary assessment methods. CONCLUSIONS: This review demonstrates that mEMDA has the potential to reduce participant burden and recall bias, thus advancing the field beyond current dietary assessment methods while maximizing ecological validity. PMID- 30459150 TI - Histone demethylase KDM4B promotes DNA damage by activating long interspersed nuclear element-1. AB - The histone demethylase KDM4B is frequently overexpressed in various cancer types, and previous studies have indicated that the primary oncogenic function of KDM4B is its ability to demethylate H3K9me3 in different tumors, resulting in altered gene expression and genome instability. A genome-wide analysis to evaluate the effect of KDM4B on the global or local H3K9me3 level has not been performed. In this study, we assess whole-genome H3K9me3 distribution in cancer cells and find that H3K9me3 is largely enriched in long interspersed nuclear element-1 (LINE-1). A significant proportion of KDM4B-dependent H3K9me3 was located in evolutionarily young LINE-1 elements, which likely retain retrotransposition activity. Ectopic expression of KDM4B promoted LINE-1 expression, while depletion of KDM4B reduced it. Furthermore, KDM4B overexpression enhanced LINE-1 retrotransposition efficacy, copy number, and associated DNA damage, presumably via the histone demethylase activity of KDM4B. Breast cancer cell lines expressing high levels of KDM4B also exhibited increased LINE-1 expression and copy number compared with other cell lines. Pharmacological inhibition of KDM4B significantly reduced LINE-1 expression and DNA damage in breast cancer cells with excessive KDM4B. Our study not only identifies KDM4B as a novel regulator of LINE-1, but it also suggests an unexpected oncogenic role for KDM4B overexpression in tumorigenesis, providing clues for the development of new cancer prevention strategies and therapies. PMID- 30459151 TI - Hyperpolarized MRI visualizes Warburg effects and predicts treatment response to mTOR inhibitors in patient-derived ccRCC xenograft models. AB - The ever-changing tumor-microenvironment constantly challenges individual cancer cells to balance supply and demand, presenting tumor vulnerabilities and therapeutic opportunities. Everolimus and temsirolimus are inhibitors of mTOR (mTORi) approved for treating metastatic renal cell carcinoma (mRCC). However, treatment outcome varies greatly among patients. Accordingly, administration of mTORi in mRCC is diminishing, which could potentially result in missing timely delivery of effective treatment for select patients. Here we implemented a clinically applicable, integrated platform encompassing a single dose of [1-13C] pyruvate to visualize the in vivo effect of mTORi on the conversion of pyruvate to lactate using hyperpolarized MRI. A striking difference that predicts treatment benefit was demonstrated using two preclinical models derived from clear cell RCC (ccRCC) patients who exhibited primary resistance to VEGFRi and quickly succumbed to their diseases within 6 months after the diagnosis of metastasis without receiving mTORi. Our findings suggest that hyperpolarized MRI could be further developed to personalize kidney cancer treatment. PMID- 30459152 TI - LncRNA-MM2P identified as a Modulator of Macrophage M2 Polarization. AB - M2 polarization of macrophages is essential for their function in immunological tolerance, which might promote tumorigenesis. However, the molecular mechanism behind the polarization process is not fully understood. Given that several lines of evidence have suggested that long noncoding RNAs (lncRNAs) could be involved in regulating immune cell differentiation and function, the current study aimed to identify the lncRNAs that specifically modulate M2 macrophage polarization. By utilizing a series of cell-based M2 macrophage polarization models, a total of 25 lncRNAs with altered expression were documented based on lncRNA microarray-based profiling assays. Among them, lncRNA-MM2P was the only lncRNA upregulated during M2 polarization but downregulated in M1 macrophages. Knockdown of lncRNA-MM2P blocked cytokine-driven M2 polarization of macrophages and weakened the angiogenesis-promoting feature of M2 macrophages by reducing phosphorylation on STAT6. Moreover, manipulating lncRNA-MM2P in macrophages impaired macrophage mediated promotion of tumorigenesis, tumor growth in vivo and tumor angiogenesis. Collectively, our study identifies lncRNA-MM2P as a modulator required for macrophage M2 polarization and uncovers its role in macrophage-promoted tumorigenesis. PMID- 30459153 TI - PD-L1 microSPECT/CT imaging for longitudinal monitoring of PD-L1 expression in syngeneic and humanized mouse models for cancer. AB - Antibodies that block the interaction between programmed death ligand 1 (PD-L1) and PD-1 have shown impressive responses in subgroups of cancer patients. PD-L1 expression in tumors seems to be a prerequisite for treatment response. However, it is heterogeneously expressed within tumor lesions and may change upon disease progression and treatment. Imaging of PD-L1 could aid in patient selection. Previously, we showed the feasibility to image PD-L1+ tumors in immunodeficient mice. However, PD-L1 is also expressed on immune cell subsets. Therefore, the aim of this study was to assess the potential of PD-L1 micro single-photon emission tomography/computed tomography (microSPECT/CT) using radiolabeled PD-L1 antibodies to: 1) measure PD-L1 expression in two immunocompetent tumor models (syngeneic mice and humanized mice harboring PD-L1 expressing immune cells) and 2) monitor therapy-induced changes in tumor PD-L1 expression. We showed that radiolabeled PD-L1 antibodies accumulated preferentially in PD-L1+ tumors, despite considerable uptake in certain normal lymphoid tissues (spleen and lymph nodes) and non-lymphoid tissues (duodenum and brown fat). PD-L1 microSPECT/CT imaging could also distinguish between high and low PD-L1-expressing tumors. The presence of PD-L1+ immune cells did not compromise tumor uptake of the human PD L1 antibodies in humanized mice, and we demonstrated that radiotherapy-induced upregulation of PD-L1 expression in murine tumors could be monitored with microSPECT/CT imaging. Together, these data demonstrate that PD-L1 microSPECT/CT is a sensitive technique to detect variations in tumor PD-L1 expression, and in the future, this technique may enable patient selection for PD-1/PD-L1-targeted therapy. PMID- 30459154 TI - Why we shouldn't use the term "illegal migrant". PMID- 30459156 TI - Preclinical evaluation of AZ12601011 and AZ12799734, inhibitors of transforming growth factor beta superfamily type 1 receptors. AB - The transforming growth factor beta (TGFbeta superfamily includes TGFbeta, activins, inhibins and bone morphogenetic proteins (BMPs). These extracellular ligands have essential roles in normal tissue homeostasis by co-ordinately regulating cell proliferation, differentiation, and migration. Aberrant signalling of superfamily members, however, is associated with fibrosis as well as tumourigenesis, cancer progression, metastasis and drug-resistance mechanisms in a variety of cancer sub-types. Given their involvement in human disease, the identification of novel selective inhibitors of TGFbetasuperfamily receptors is an attractive therapeutic approach. Seven mammalian type 1 receptors have been identified that have context specific roles depending on the ligand and the complex formation with the type 2 receptor. Here we characterise the biological effects of two TGFBR1 kinase inhibitors designed to target TGFbeta signalling. AZ12601011 (structure previously undisclosed) and AZ12799734 (IC50s, 18nM and 47nM respectively) were more effective inhibitors of TGFbeta-induced reporter activity than SB-431542 (IC50, 84nM) and LY2157299 (galunisertib) (IC50, 380nM). AZ12601011 inhibited phosphorylation of SMAD2 via the type 1 receptors ALK4, TGFBR1 and ALK7. AZ12799734, however, is a pan TGFbeta/BMP inhibitor, inhibiting receptor-mediated phosphorylation of SMAD1 by ALK1, BMPR1A and BMPR1B and phosphorylation of SMAD2 by ALK4, TGFBR1 and ALK7. AZ12601011 was highly effective at inhibiting basal and TGFbeta-induced migration of HaCaT keratinocytes and furthermore inhibited tumour growth and metastasis to the lungs in a 4T1 syngeneic orthotopic mammary tumour model. These inhibitors provide new reagents for investigating in vitro and in vivo pathogenic processes and the contribution of TGFbeta and BMP regulated signalling pathways to disease states. PMID- 30459157 TI - Sensing danger through a "finger". AB - In this issue of JEM, the study by Chen et al. (https://doi.org/10.1084/jem.20181031) reveals a previously unrecognized role of cellular nucleic acid-binding protein (Cnbp) as a novel transcriptional regulator of interleukin-12beta (IL-12beta) transcription and IL-12-driven, Th1-mediated immune responses, which has important implications for both host defense and inflammatory disease. PMID- 30459155 TI - Neuromuscular degeneration and locomotor deficit in a Drosophila model of mucopolysaccharidosis VII is attenuated by treatment with resveratrol. AB - Mucopolysaccharidosis VII (MPS VII) is a recessively inherited lysosomal storage disorder caused by beta-glucuronidase enzyme deficiency. The disease is characterized by widespread accumulation of non-degraded or partially degraded glycosaminoglycans, leading to cellular and multiple tissue dysfunctions. The patients exhibit diverse clinical symptoms, and eventually succumb to premature death. The only possible remedy is the recently approved enzyme replacement therapy, which is an expensive, invasive and lifelong treatment procedure. Small molecule therapeutics for MPS VII have so far remained elusive primarily due to lack of molecular insights into the disease pathogenesis and unavailability of a suitable animal model that can be used for rapid drug screening. To address these issues, we developed a Drosophila model of MPS VII by knocking out the CG2135 gene, the fly beta-glucuronidase orthologue. The CG2135 -/- fly recapitulated cardinal features of MPS VII, such as reduced lifespan, progressive motor impairment and neuropathological abnormalities. Loss of dopaminergic neurons and muscle degeneration due to extensive apoptosis was implicated as the basis of locomotor deficit in this fly. Such hitherto unknown mechanistic links have considerably advanced our understanding of the MPS VII pathophysiology and warrant leveraging this genetically tractable model for deeper enquiry about the disease progression. We were also prompted to test whether phenotypic abnormalities in the CG2135 -/- fly can be attenuated by resveratrol, a natural polyphenol with potential health benefits. Indeed, resveratrol treatment significantly ameliorated neuromuscular pathology and restored normal motor function in the CG2135 -/- fly. This intriguing finding merits further preclinical studies for developing an alternative therapy for MPS VII.This article has an associated First Person interview with the first author of the paper. PMID- 30459158 TI - IgM's exit route. AB - In this issue of JEM, Thierry et al. (https://doi.org/10.1084/jem.20180344) demonstrate that, once secreted by freshly activated plasmablasts, IgM leaves the lymph node via the microarchitecture of the fibroblastic reticular cell conduit. This work demonstrates how the very peculiar stromal compartment of lymphatic organs optimizes the systemic distribution of immune effectors. PMID- 30459159 TI - All (animal) models (of neurodegeneration) are wrong. Are they also useful? AB - Richard M. Ransohoff, Entrepreneur-in-Residence at Third Rock Ventures and Visiting Scientist at Harvard Medical School, provides his personal opinion on using animal models to address current challenges and opportunities in drug development for neurodegeneration. PMID- 30459160 TI - How I treat infant leukemia. AB - Leukemia in infants is rare but generates tremendous interest due to its aggressive clinical presentation in a uniquely vulnerable host, its poor response to current therapies, and its fascinating biology. Increasingly, these biological insights are pointing the way towards novel therapeutic approaches. Using representative clinical case presentations, we review the key clinical, pathologic and epidemiologic features of infant leukemia, including the high frequency of KMT2A gene rearrangements. We describe the current approach to risk stratified treatment of infant leukemia in the major international cooperative groups. We highlight recent discoveries that elucidate the molecular biology of infant leukemia and suggest novel targeted therapeutic strategies, including modulation of aberrant epigenetic programs, inhibition of signaling pathways, and immunotherapeutics. Finally, we underscore the need for increased global collaboration to translate these discoveries into improved outcomes. PMID- 30459161 TI - Increased Ferritin Concentration and Risk of Atrial Fibrillation and Heart Failure in Men and Women: Three Studies of the Danish General Population Including 35799 Individuals. AB - BACKGROUND: Moderately increased plasma ferritin, as a biomarker of iron overload, has been associated with higher rates of cardiovascular death and heart failure. However, the association of moderately increased plasma ferritin with risk of atrial fibrillation in the general population is unknown. METHODS: We examined the association of plasma ferritin concentrations with risk of atrial fibrillation and heart failure in meta-analyses of 35799 men and women from 3 studies of the Danish general population: the Copenhagen City Heart Study, the Danish General Suburban Population Study, and the Copenhagen General Population Study. RESULTS: Multivariable adjusted fixed effects odds ratios for atrial fibrillation were 1.23 (95% CI, 1.05-1.44; P = 0.005) in men for ferritin concentration >=300 MU g/L vs <300 MU g/L, 1.13 (95% CI, 0.93-1.38; P = 0.22) in women for >=200 MU g/L vs <200 MU g/L, and 1.19 (95% CI, 1.06-1.35; P = 0.005) in both sexes combined (P sex interaction = 0.52). Corresponding fixed effects odds ratios for heart failure were 1.16 (95% CI, 0.98-1.37; P = 0.08) in men, 0.86 (95% CI, 0.67-1.10; P = 0.23) in women, and 1.05 (95% CI, 0.91-1.21; P = 0.45) in both sexes combined (P sex interaction = 0.05). Multivariable adjusted fixed effects odds ratio for atrial fibrillation per step increase in ferritin concentrations was 1.13 (95% CI, 1.06-1.21; P trend = 0.0005) in both sexes combined (P sex interaction = 0.59); the corresponding value for heart failure was 1.03 (95% CI, 0.95-1.11; P trend = 0.47) (P sex interaction = 0.08). In sensitivity analyses, there was no evidence of U-shaped relationships between plasma ferritin concentrations and risk of atrial fibrillation or heart failure in men or women. CONCLUSIONS: Increased ferritin concentration is associated with increased risk of atrial fibrillation in the general population. PMID- 30459162 TI - Germline Genetics of Prostate Cancer: Time to Incorporate Genetics into Early Detection Tools. AB - BACKGROUND: Prostate cancer (PCa) remains the most common solid malignancy in men, and its prevalence makes understanding its heritability of paramount importance. To date, the most common factors used to estimate a man's risk of developing PCa are age, race, and family history. Despite recent advances in its utility in multiple malignancies (e.g., breast and colon cancer), genetic testing is still relatively underutilized in PCa. CONTENT: Multiple highly penetrant genes (HPGs) and single-nucleotide polymorphisms (SNPs) have been show to increase a patient's risk of developing PCa. Mutations in the former, like DNA damage repair genes, can confer a 2- to 3-fold increased risk of developing PCa and can increase the risk of aggressive disease. Similarly, PCa-risk SNPs can be used to create risk scores (e.g., genetic or polygenic risk scores) that can be used to further stratify an individual's disease susceptibility. Specifically, these genetic risk scores can provide more specific estimates of a man's lifetime risk ranging up to >6-fold higher risk of PCa. SUMMARY: It is becoming increasingly evident that in addition to the standard family history and race information, it is necessary to obtain genetic testing (including an assessment of HPG mutation status and genetic risk score) to provide a full risk assessment. The additional information derived thereby will improve current practices in PCa screening by risk-stratifying patients before initial prostate-specific antigen testing, determining a patient's frequency of visits, and even help identify potentially at-risk family members. PMID- 30459163 TI - The ERSPC Study: Quality Takes Time and Perseverance. PMID- 30459164 TI - Identifying and Eliminating Laboratory Contamination by Topical Testosterone Therapeutics. AB - Many prescription and over-the-counter drugs are available as topical formulations. Contamination of clinical laboratory workspaces by topical drugs may increase the risk of potential interference with diagnostic testing. An example of localized workspace contamination attributed to a topical hormonal drug (testosterone, T) is presented to highlight significant challenges in identifying and resolving this potential problem. Investigation included precision studies, instrument service and parts replacement, instrument replacement, airflow analysis, environmental dust sampling, and the development of customized methods for workspace monitoring and cleaning. Laboratory policies and procedures were also revised to minimize future risk. PMID- 30459165 TI - The Microbiome and Men's Health. PMID- 30459166 TI - Perspective on Prostate Cancer Screening. PMID- 30459167 TI - Integrated Extreme Real-Time PCR and High-Speed Melting Analysis in 52 to 87 Seconds. AB - BACKGROUND: Extreme PCR in <30 s and high-speed melting of PCR products in <5 s are recent advances in the turnaround time of DNA analysis. Previously, these steps had been performed on different specialized instruments. Integration of both extreme PCR and high-speed melting with real-time fluorescence monitoring for detection and genotyping is presented here. METHODS: A microfluidic platform was enhanced for speed using cycle times as fast as 1.05 s between 66.4u degrees C and 93.7u degrees C, with end point melting rates of 8u degrees C/s. Primer and polymerase concentrations were increased to allow short cycle times. Synthetic sequences were used to amplify fragments of hepatitis B virus (70 bp) and Clostridium difficile (83 bp) by real-time PCR and high-speed melting on the same instrument. A blinded genotyping study of 30 human genomic samples at F2 c.*97, F5 c.1601, MTHFR c.665, and MTHFR c.1286 was also performed. RESULTS: Standard rapid-cycle PCR chemistry did not produce any product when total cycling times were reduced to <1 min. However, efficient amplification was possible with increased primer (5 MU mol/L) and polymerase (0.45 U/MU L) concentrations. Infectious targets were amplified and identified in 52 to 71 s. Real-time PCR and genotyping of single-nucleotide variants from human DNA was achieved in 75 to 87 s and was 100% concordant to known genotypes. CONCLUSIONS: Extreme PCR with high speed melting can be performed in about 1 min. The integration of extreme PCR and high-speed melting shows that future molecular assays at the point of care for identification, quantification, and variant typing are feasible. PMID- 30459168 TI - Metabolic Factors and Prostate Cancer Risk. PMID- 30459169 TI - Recommendations for Reporting Low and High Values for Urine Albumin and Total Protein. PMID- 30459170 TI - Determinants of Vascular Age: An Epidemiological Perspective. AB - BACKGROUND: Vascular age is an emerging health indicator and predictor of end organ damage to the heart, brain, and kidney. Although there have been many review publications concerning risk factors for vascular aging, most include cross-sectional epidemiological studies, limiting inferences about temporality. There is a need for a review of longitudinal epidemiological studies with repeated measures of vascular structure and function to allow for a systematic examination of determinants of vascular age and the association of vascular aging with outcomes. CONTENT: Arterial stiffness is the most frequently used measure of vascular aging. We report here results of an extensive literature review of longitudinal cohort studies with repeated measures of arterial stiffness to characterize determinants of vascular age. Additionally, we summarize population based studies that have focused on the association of arterial stiffness with end organ damage and adverse cardiovascular outcomes. SUMMARY: Changes in arterial stiffness are evident in early childhood. In adults, arterial stiffness has been observed to progress at the average rate of 0.2 to 0.7 m/s for every 5 years of life. The state of the science is limited by the small number of studies with repeated measures of arterial stiffness and determinants of arterial stiffness progression, as well as limited studies in children and diverse race/ethnic groups. Several extant studies suggest that beyond age, cardiometabolic risk factors and adverse lifestyle behaviors contribute to arterial stiffening. Therefore, arterial stiffness is important in the assessment of healthy vascular aging and a possible target for the prevention of subclinical and clinical disease. PMID- 30459172 TI - Patterns of borrowing to finance out-of-pocket prescription drug costs in Canada: a descriptive analysis. AB - BACKGROUND: Out-of-pocket drug costs lead many Canadians to engage in cost related nonadherence to prescription medications, but our understanding of other consequences such as borrowing money remains incomplete. In this descriptive study, we sought to quantify the frequency of borrowing to pay for prescription drugs in Canada and characteristics of Canadians who borrowed money for this purpose. METHODS: In partnership with Statistics Canada, we designed and administered a cross-sectional rapid-response module in the Canadian Community Health Survey administered by telephone to Canadians aged 12 years or more between January and June 2016. We restricted our analyses to participants who responded to the question regarding borrowing money to pay for prescription drugs and used logistic regression to identify characteristics associated with borrowing. RESULTS: A total of 28 091 Canadians responded to the survey (overall response rate 61.8%). The weighted proportion of respondents who reported having borrowed money to pay for prescription drugs in the previous year was 2.5% (95% confidence interval 2.2%-2.8%), an estimated 731 000 Canadians. The odds of borrowing were higher among younger adults, people in poor health and people lacking prescription drug insurance. Other factors associated with increased adjusted odds of borrowing were having 2 or more chronic conditions, low household income and higher out-of-pocket prescription drug costs. INTERPRETATION: Many Canadians reported borrowing money to pay for out-of-pocket prescription drug costs, and borrowing was more prevalent among already vulnerable groups that also report other compensatory behaviours to address challenges in paying for prescription drugs. Future research should investigate policy responses intended to increase equity in access to prescription drugs. PMID- 30459171 TI - Mapping the O-glycoproteome using site-specific extraction of O-linked glycopeptides (EXoO). AB - Protein glycosylation is one of the most abundant post-translational modifications. However, detailed analysis of O-linked glycosylation, a major type of protein glycosylation, has been severely impeded by the scarcity of suitable methodologies. Here, a chemoenzymatic method is introduced for the site-specific extraction of O-linked glycopeptides (EXoO), which enabled the mapping of over 3,000 O-linked glycosylation sites and definition of their glycans on over 1,000 proteins in human kidney tissues, T cells, and serum. This large-scale localization of O-linked glycosylation sites demonstrated that EXoO is an effective method for defining the site-specific O-linked glycoproteome in different types of sample. Detailed structural analysis of the sites identified revealed conserved motifs and topological orientations facing extracellular space, the cell surface, the lumen of the Golgi, and the endoplasmic reticulum (ER). EXoO was also able to reveal significant differences in the O-linked glycoproteome of tumor and normal kidney tissues pointing to its broader use in clinical diagnostics and therapeutics. PMID- 30459174 TI - Correction: Screening for a new primary cancer in patients with existing metastatic cancer: a retrospective cohort study Correction. PMID- 30459173 TI - Improved hospital safety performance and reduced medicolegal risk: an ecological study using 2 Canadian databases. AB - BACKGROUND: Few empirical studies have validated the relation between medicolegal risk and hospital patient safety performance. We sought to determine whether there was a relation between in-hospital patient safety events and medicolegal cases involving Canadian physicians. METHODS: In this ecological study, we used Poisson regression to compare data from the Canadian Institute for Health Information's Discharge Abstract Database and the database of the Canadian Medical Protective Association (CMPA) of medicolegal cases over 10 years (2005/06 to 2014/15). We identified incidents and cases based on 15 Agency for Healthcare Research and Quality patient safety indicators within the Canadian Institute for Health Information and CMPA data sets. We performed subgroup analyses for obstetrical and surgical cases. RESULTS: We found a statistically significant positive association between volume changes in patient safety indicator events (n = 339 741) and medicolegal cases (n = 15 180) (parameter estimate 1.15, 95% confidence interval [CI] 0.4 to 1.9). This association suggests that, on average, a 10% decrease in events would correspond to a decrease of 11% in medicolegal cases. The degree of positive association varied by practice type, with obstetrics (97 982 patient safety indicator events, 865 cases) showing a 25% decrease in medicolegal cases for every 10% decrease in events (parameter estimate 2.9, 95% CI 0.5 to 5.3) and surgery (168 886 patient safety indicator events, 4568 cases) showing a decrease of 9% for every 10% decrease in events (parameter estimate 0.9, 95% CI 0.2 to 1.7). INTERPRETATION: The statistically significant positive association between patient safety indicator events and medicolegal cases quantifies a relation between patient safety and physician medicolegal risk in Canadian hospitals. This suggests new, practical uses for both medicolegal and patient safety indicator data in system-level quality improvement efforts. PMID- 30459175 TI - Person centred care that includes antipsychotic review reduces agitation in dementia patients, finds study. PMID- 30459178 TI - Using Maize Chromosome Segment Substitution Line Populations for the Identification of Loci Associated with Multiple Disease Resistance. AB - Southern Leaf Blight (SLB), Northern Leaf Blight (NLB), and Gray Leaf Spot (GLS) caused by Cochliobolus heterostrophus, Setosphaeria turcica, and Cercospora zeae maydis respectively, are among the most important diseases of corn worldwide. Previously, moderately high and significantly positive genetic correlations between resistance levels to each of these diseases were identified in a panel of 253 diverse maize inbred lines. The goal of this study was to identify loci underlying disease resistance in some of the most multiple disease resistant (MDR) lines by the creation of chromosome segment substitution line (CSSL) populations in multiple disease susceptible (MDS) backgrounds. Four MDR lines (NC304, NC344, Ki3, NC262) were used as donor parents and two MDS lines (Oh7B, H100) were used as recurrent parents to produce eight BC3F4:5 CSSL populations comprising 1,611 lines in total. Each population was genotyped and assessed for each disease in replicated trials in two environments. Moderate to high heritabilities on an entry mean basis were observed (0.32 to 0.83). Several lines in each population were significantly more resistant than the MDS parental lines for each disease. Multiple quantitative trait loci (QTL) for disease resistance were detected for each disease in most of the populations. Seventeen QTLs were associated with variation in resistance to more than one disease (SLB/NLB: 2; SLB/GLS: 7; NLB/GLS: 2 and 6 to all three diseases). For most populations and most disease combinations, significant correlations were observed between disease scores and also between marker effects for each disease. The number of lines that were resistant to more than one disease was significantly higher than would be expected by chance. Using the results from individual QTL analyses, a composite statistic based on Mahalanobis distance (Md) was used to identify joint marker associations with multiple diseases. Across all populations and diseases, 246 markers had significant Md values. However further analysis revealed that most of these associations were due to strong QTL effects on a single disease. Together, these findings reinforce our previous conclusions that loci associated with resistance to different diseases are clustered in the genome more often than would be expected by chance. Nevertheless true MDR loci which have significant effects on more than one disease are still much rarer than loci with single disease effects. PMID- 30459179 TI - Genetic Basis of Variation in Heat and Ethanol Tolerance in Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae has the capability of fermenting sugar to produce concentrations of ethanol that are toxic to most organisms. Other Saccharomyces species also have a strong fermentative capacity, but some are specialized to low temperatures, whereas S. cerevisiae is the most thermotolerant. Although S. cerevisiae has been extensively used to study the genetic basis of ethanol tolerance, much less is known about temperature dependent ethanol tolerance. In this study, we examined the genetic basis of ethanol tolerance at high temperature among strains of S. cerevisiae We identified two amino acid polymorphisms in SEC24 that cause strong sensitivity to ethanol at high temperature and more limited sensitivity to temperature in the absence of ethanol. We also identified a single amino acid polymorphism in PSD1 that causes sensitivity to high temperature in a strain dependent fashion. The genes we identified provide further insight into genetic variation in ethanol and temperature tolerance and the interdependent nature of these two traits in S. cerevisiae. PMID- 30459180 TI - Wolbachia Infection Associated with Increased Recombination in Drosophila. AB - Wolbachia is a maternally-transmitted endosymbiotic bacteria that infects a large diversity of arthropod and nematode hosts. Some strains of Wolbachia are parasitic, manipulating host reproduction to benefit themselves, while other strains of Wolbachia exhibit obligate or facultative mutualisms with their host. The effects of Wolbachia on its host are many, though primarily relate to host immune and reproductive function. Here we test the hypothesis that Wolbachia infection alters the frequency of homologous recombination during meiosis. We use D. melanogaster as a model system, and survey recombination in eight wild-derived Wolbachia-infected (strain wMel) and Wolbachia-uninfected strains, controlling for genotype. We measure recombination in two intervals of the genome. Our results indicate that Wolbachia infection is associated with increased recombination in one genomic interval and not the other. The effect of Wolbachia infection on recombination is thus heterogenous across the genome. Our data also indicate a reproductive benefit of Wolbachia infection; infected females show higher fecundity than their uninfected genotypic controls. Given the prevalence of Wolbachia infection in natural populations, our findings suggest that Wolbachia infection is likely to contribute to recombination rate and fecundity variation among individuals in nature. PMID- 30459181 TI - Towards Identifying Subnetworks from FBF Binding Landscapes in Caenorhabditis Spermatogenic or Oogenic Germlines. AB - Metazoan PUF (Pumilio and FBF) RNA-binding proteins regulate various biological processes, but a common theme across phylogeny is stem cell regulation. In Caenorhabditis elegans, FBF (fem-3 Binding Factor) maintains germline stem cells regardless of which gamete is made, but FBF also functions in the process of spermatogenesis. We have begun to "disentangle" these biological roles by asking which FBF targets are gamete-independent, as expected for stem cells, and which are gamete-specific. Specifically, we compared FBF iCLIP binding profiles in adults making sperm to those making oocytes. Normally, XX adults make oocytes. To generate XX adults making sperm, we used a fem-3(gf) mutant requiring growth at 25 degrees ; for comparison, wild-type oogenic hermaphrodites were also raised at 25 degrees . Our FBF iCLIP data revealed FBF binding sites in 1522 RNAs from oogenic adults and 1704 RNAs from spermatogenic adults. More than half of these FBF targets were independent of germline gender. We next clustered RNAs by FBF RNA complex frequencies and found four distinct blocks. Block I RNAs were enriched in spermatogenic germlines, and included validated target fog-3, while Block II and III RNAs were common to both genders, and Block IV RNAs were enriched in oogenic germlines. Block II (510 RNAs) included almost all validated FBF targets and was enriched for cell cycle regulators. Block III (21 RNAs) was enriched for RNA-binding proteins, including previously validated FBF targets gld 1 and htp-1 We suggest that Block I RNAs belong to the FBF network for spermatogenesis, and that Blocks II and III are associated with stem cell functions. PMID- 30459182 TI - Examining the relationship of vaping to smoking initiation among US youth and young adults: a reality check. AB - BACKGROUND: The 2018 National Academies of Sciences, Engineering, and Medicine Report found substantial evidence that electronic cigarette use (vaping) by youth is strongly associated with an increased risk of ever using cigarettes (smoking) and moderately associated with progressing to more established smoking. However, the Report also noted that recent increases in vaping have been associated with declining rates of youth smoking. This paper examines the temporal relationship between vaping and youth smoking using multiple data sets to explore the question of whether vaping promotes smoking initiation in the USA. METHODS: Using publicly available, nationally representative data on smoking and vaping among youth and young adults, we conducted a trend line analysis of deviations from long-term trends in smoking starting from when vaping became more prevalent. RESULTS: There was a substantial increase in youth vaping prevalence beginning in about 2014. Time trend analyses showed that the decline in past 30-day smoking prevalence accelerated by two to four times after 2014. Indicators of more established smoking rates, including the proportion of daily smokers among past 30-day smokers, also decreased more rapidly as vaping became more prevalent. CONCLUSIONS: The inverse relationship between vaping and smoking was robust across different data sets for both youth and young adults and for current and more established smoking. While trying electronic cigarettes may causally increase smoking among some youth, the aggregate effect at the population level appears to be negligible given the reduction in smoking initiation during the period of vaping's ascendance. PMID- 30459184 TI - Including practical issues and patient perspectives in Rapid Recommendations. PMID- 30459183 TI - The secret lives of cancer cell lines. AB - The extent of genetic and epigenetic diversity between and within patient tumors is being mapped in ever more detail. It is clear that cancer is an evolutionary process in which tumor cell intrinsic and extrinsic forces shape clonal selection. The pre-clinical oncology pipeline uses model systems of human cancer including mouse models, cell lines, patient-derived organoids and patient derived xenografts - to study tumor biology and assess the efficacy of putative therapeutic agents. Model systems cannot completely replicate the environment of human tumors and, even within the same cancer model, data are often irreproducible between laboratories. One hypothesis is that ongoing evolutionary processes remain relevant in laboratory models, leading to divergence over time. In a recent edition of Nature, Ben-David and colleagues showed that different stocks of widely used cancer cell lines - a staple of cancer research over many decades - are highly heterogeneous in terms of their genetics, transcriptomics and responses to therapies. The authors find compelling evidence of positive selection based on ongoing mutational processes and chromosomal instability. Thus, the origin, culture conditions and cumulative number of population doublings of cell lines likely influence experimental outcomes. Here, we summarize the key findings of this important study and discuss the practical implications of this work for researchers using cell lines in the laboratory. PMID- 30459185 TI - Towards evidence-based medicine for paediatricians. PMID- 30459187 TI - Tenacious Researchers Identify a Weakness in All Ebolaviruses. AB - The Ebolavirus genus has at least five members, four of which are known to cause deadly disease in humans. An ideal therapy or a vaccine would protect against all ebolaviruses, but identifying a common weakness in all of them has remained elusive. West et al. [B. R. West, C. L. Moyer, L. B. King, M. L. Fusco, et al., mBio 9(5):e01674-18, 2018, https://doi.org/10.1128/mBio.01674-18] make the exciting discovery of an "Achilles' heel," a cryptic and conserved pocket, on the surface antigen glycoprotein (GP) that is nearly identical in all known ebolaviruses. Key to this discovery was their study of antibody ADI-15878, the only isolated human antibody that can block infectivity of all known ebolaviruses. Following tenacious efforts in X-ray crystallography, West et al. report the high-resolution crystal structures of the Ebola virus GP and the Bundibugyo virus GP, each bound to antibody ADI-15878. These structures reveal a highly conserved but partially obscured site on the virus GP, providing a foundation for design of vaccine antigens or antiviral therapies. PMID- 30459188 TI - Defining the Metabolic Pathways and Host-Derived Carbon Substrates Required for Francisella tularensis Intracellular Growth. AB - Francisella tularensis is a Gram-negative, facultative, intracellular bacterial pathogen and one of the most virulent organisms known. A hallmark of F. tularensis pathogenesis is the bacterium's ability to replicate to high densities within the cytoplasm of infected cells in over 250 known host species, including humans. This demonstrates that F. tularensis is adept at modulating its metabolism to fluctuating concentrations of host-derived nutrients. The precise metabolic pathways and nutrients utilized by F. tularensis during intracellular growth, however, are poorly understood. Here, we use systematic mutational analysis to identify the carbon catabolic pathways and host-derived nutrients required for F. tularensis intracellular replication. We demonstrate that the glycolytic enzyme phosphofructokinase (PfkA), and thus glycolysis, is dispensable for F. tularensis SchuS4 virulence, and we highlight the importance of the gluconeogenic enzyme fructose 1,6-bisphosphatase (GlpX). We found that the specific gluconeogenic enzymes that function upstream of GlpX varied based on infection model, indicating that F. tularensis alters its metabolic flux according to the nutrients available within its replicative niche. Despite this flexibility, we found that glutamate dehydrogenase (GdhA) and glycerol 3 phosphate (G3P) dehydrogenase (GlpA) are essential for F. tularensis intracellular replication in all infection models tested. Finally, we demonstrate that host cell lipolysis is required for F. tularensis intracellular proliferation, suggesting that host triglyceride stores represent a primary source of glycerol during intracellular replication. Altogether, the data presented here reveal common nutritional requirements for a bacterium that exhibits characteristic metabolic flexibility during infection.IMPORTANCE The widespread onset of antibiotic resistance prioritizes the need for novel antimicrobial strategies to prevent the spread of disease. With its low infectious dose, broad host range, and high rate of mortality, F. tularensis poses a severe risk to public health and is considered a potential agent for bioterrorism. F. tularensis reaches extreme densities within the host cell cytosol, often replicating 1,000-fold in a single cell within 24 hours. This remarkable rate of growth demonstrates that F. tularensis is adept at harvesting and utilizing host cell nutrients. However, like most intracellular pathogens, the types of nutrients utilized by F. tularensis and how they are acquired is not fully understood. Identifying the essential pathways for F. tularensis replication may reveal new therapeutic strategies for targeting this highly infectious pathogen and may provide insight for improved targeting of intracellular pathogens in general. PMID- 30459189 TI - Molecular Basis for the Evolution of Species-Specific Hemoglobin Capture by Staphylococcus aureus. AB - Metals are a limiting resource for pathogenic bacteria and must be scavenged from host proteins. Hemoglobin provides the most abundant source of iron in the human body and is required by several pathogens to cause invasive disease. However, the consequences of hemoglobin evolution for bacterial nutrient acquisition remain unclear. Here we show that the alpha- and beta-globin genes exhibit strikingly parallel signatures of adaptive evolution across simian primates. Rapidly evolving sites in hemoglobin correspond to binding interfaces of IsdB, a bacterial hemoglobin receptor harbored by pathogenic Staphylococcus aureus Using an evolution-guided experimental approach, we demonstrate that the divergence between primates and staphylococcal isolates governs hemoglobin recognition and bacterial growth. The reintroduction of putative adaptive mutations in alpha- or beta-globin proteins was sufficient to impair S. aureus binding, providing a mechanism for the evolution of disease resistance. These findings suggest that bacterial hemoprotein capture has driven repeated evolutionary conflicts with hemoglobin during primate descent.IMPORTANCE During infection, bacteria must steal metals, including iron, from the host tissue. Therefore, pathogenic bacteria have evolved metal acquisition systems to overcome the elaborate processes mammals use to withhold metal from pathogens. Staphylococcus aureus uses IsdB, a hemoglobin receptor, to thieve iron-containing heme from hemoglobin within human blood. We find evidence that primate hemoglobin has undergone rapid evolution at protein surfaces contacted by IsdB. Additionally, variation in the hemoglobin sequences among primates, or variation in IsdB of related staphylococci, reduces bacterial hemoglobin capture. Together, these data suggest that S. aureus has evolved to recognize human hemoglobin in the face of rapid evolution at the IsdB binding interface, consistent with repeated evolutionary conflicts in the battle for iron during host-pathogen interactions. PMID- 30459190 TI - Silver and Copper Acute Effects on Membrane Proteins and Impact on Photosynthetic and Respiratory Complexes in Bacteria. AB - Silver (Ag+) and copper (Cu+) ions have been used for centuries in industry, as well as antimicrobial agents in agriculture and health care. Nowadays, Ag+ is also widely used in the field of nanotechnology. Yet, the underlying mechanisms driving toxicity of Ag+ ions in vivo are poorly characterized. It is well known that exposure to excess metal impairs the photosynthetic apparatus of plants and algae. Here, we show that the light-harvesting complex II (LH2) is the primary target of Ag+ and Cu+ exposure in the purple bacterium Rubrivivax gelatinosus Ag+ and Cu+ specifically inactivate the 800-nm absorbing bacteriochlorophyll a (B800), while Ni2+ or Cd2+ treatment had no effect. This was further supported by analyses of CuSO4- or AgNO3-treated membrane proteins. Indeed, this treatment induced changes in the LH2 absorption spectrum related to the disruption of the interaction of B800 molecules with the LH2 protein. This caused the release of B800 molecules and subsequently impacted the spectral properties of the carotenoids within the 850-nm absorbing LH2. Moreover, previous studies have suggested that Ag+ can affect the respiratory chain in mitochondria and bacteria. Our data demonstrated that exposure to Ag+, both in vivo and in vitro, caused a decrease of cytochrome c oxidase and succinate dehydrogenase activities. Ag+ inhibition of these respiratory complexes was also observed in Escherichia coli, but not in Bacillus subtilis IMPORTANCE The use of metal ions represents a serious threat to the environment and to all living organisms because of the acute toxicity of these ions. Nowadays, silver nanoparticles are one of the most widely used nanoparticles in various industrial and health applications. The antimicrobial effect of nanoparticles is in part related to the released Ag+ ions and their ability to interact with bacterial membranes. Here, we identify, both in vitro and in vivo, specific targets of Ag+ ions within the membrane of bacteria. This include complexes involved in photosynthesis, but also complexes involved in respiration. PMID- 30459191 TI - Metatranscriptomes Reveal That All Three Domains of Life Are Active but Are Dominated by Bacteria in the Fennoscandian Crystalline Granitic Continental Deep Biosphere. AB - The continental subsurface is suggested to contain a significant part of the earth's total biomass. However, due to the difficulty of sampling, the deep subsurface is still one of the least understood ecosystems. Therefore, microorganisms inhabiting this environment might profoundly influence the global nutrient and energy cycles. In this study, in situ fixed RNA transcripts from two deep continental groundwaters from the Aspo Hard Rock Laboratory (a Baltic Sea influenced water with a residence time of <20 years, defined as "modern marine," and an "old saline" groundwater with a residence time of thousands of years) were subjected to metatranscriptome sequencing. Although small subunit (SSU) rRNA gene and mRNA transcripts aligned to all three domains of life, supporting activity within these community subsets, the data also suggested that the groundwaters were dominated by bacteria. Many of the SSU rRNA transcripts grouped within newly described candidate phyla or could not be mapped to known branches on the tree of life, suggesting that a large portion of the active biota in the deep biosphere remains unexplored. Despite the extremely oligotrophic conditions, mRNA transcripts revealed a diverse range of metabolic strategies that were carried out by multiple taxa in the modern marine water that is fed by organic carbon from the surface. In contrast, the carbon dioxide- and hydrogen-fed old saline water with a residence time of thousands of years predominantly showed the potential to carry out translation. This suggested these cells were active, but waiting until an energy source episodically becomes available.IMPORTANCE A newly designed sampling apparatus was used to fix RNA under in situ conditions in the deep continental biosphere and benchmarks a strategy for deep biosphere metatranscriptomic sequencing. This apparatus enabled the identification of active community members and the processes they carry out in this extremely oligotrophic environment. This work presents for the first time evidence of eukaryotic, archaeal, and bacterial activity in two deep subsurface crystalline rock groundwaters from the Aspo Hard Rock Laboratory with different depths and geochemical characteristics. The findings highlight differences between organic carbon-fed shallow communities and carbon dioxide- and hydrogen-fed old saline waters. In addition, the data reveal a large portion of uncharacterized microorganisms, as well as the important role of candidate phyla in the deep biosphere, but also the disparity in microbial diversity when using standard microbial 16S rRNA gene amplification versus the large unknown portion of the community identified with unbiased metatranscriptomes. PMID- 30459192 TI - The Mechanism behind Bacterial Lipoprotein Release: Phenol-Soluble Modulins Mediate Toll-Like Receptor 2 Activation via Extracellular Vesicle Release from Staphylococcus aureus. AB - The innate immune system uses Toll-like receptor (TLR) 2 to detect conserved bacterial lipoproteins of invading pathogens. The lipid anchor attaches lipoproteins to the cytoplasmic membrane and prevents their release from the bacterial cell envelope. How bacteria release lipoproteins and how these molecules reach TLR2 remain unknown. Staphylococcus aureus has been described to liberate membrane vesicles. The composition, mode of release, and relevance for microbe-host interaction of such membrane vesicles have remained ambiguous. We recently reported that S. aureus can release lipoproteins only when surfactant like small peptides, the phenol-soluble modulins (PSMs), are expressed. Here we demonstrate that PSM peptides promote the release of membrane vesicles from the cytoplasmic membrane of S. aureus via an increase in membrane fluidity, and we provide evidence that the bacterial turgor is the driving force for vesicle budding under hypotonic osmotic conditions. Intriguingly, the majority of lipoproteins are released by S. aureus as components of membrane vesicles, and this process depends on surfactant-like molecules such as PSMs. Vesicle disruption at high detergent concentrations promotes the capacity of lipoproteins to activate TLR2. These results reveal that vesicle release by bacterium-derived surfactants is required for TLR2-mediated inflammation.IMPORTANCE Our study highlights the roles of surfactant-like molecules in bacterial inflammation with important implications for the prevention and therapy of inflammatory disorders. It describes a potential pathway for the transfer of hydrophobic bacterial lipoproteins, the major TLR2 agonists, from the cytoplasmic membrane of Gram positive bacteria to the TLR2 receptor at the surface of host cells. Moreover, our study reveals a molecular mechanism that explains how cytoplasmic and membrane-embedded bacterial proteins can be released by bacterial cells without using any of the typical protein secretion routes, thereby contributing to our understanding of the processes used by bacteria to communicate with host organisms and the environment. PMID- 30459193 TI - The Capsule Regulatory Network of Klebsiella pneumoniae Defined by density TraDISort. AB - Klebsiella pneumoniae infections affect infants and the immunocompromised, and the recent emergence of hypervirulent and multidrug-resistant K. pneumoniae lineages is a critical health care concern. Hypervirulence in K. pneumoniae is mediated by several factors, including the overproduction of extracellular capsule. However, the full details of how K. pneumoniae capsule biosynthesis is achieved or regulated are not known. We have developed a robust and sensitive procedure to identify genes influencing capsule production, density-TraDISort, which combines density gradient centrifugation with transposon insertion sequencing. We have used this method to explore capsule regulation in two clinically relevant Klebsiella strains, K. pneumoniae NTUH-K2044 (capsule type K1) and K. pneumoniae ATCC 43816 (capsule type K2). We identified multiple genes required for full capsule production in K. pneumoniae, as well as putative suppressors of capsule in NTUH-K2044, and have validated the results of our screen with targeted knockout mutants. Further investigation of several of the K. pneumoniae capsule regulators identified-ArgR, MprA/KvrB, SlyA/KvrA, and the Sap ABC transporter-revealed effects on capsule amount and architecture, serum resistance, and virulence. We show that capsule production in K. pneumoniae is at the center of a complex regulatory network involving multiple global regulators and environmental cues and that the majority of capsule regulatory genes are located in the core genome. Overall, our findings expand our understanding of how capsule is regulated in this medically important pathogen and provide a technology that can be easily implemented to study capsule regulation in other bacterial species.IMPORTANCE Capsule production is essential for K. pneumoniae to cause infections, but its regulation and mechanism of synthesis are not fully understood in this organism. We have developed and applied a new method for genome-wide identification of capsule regulators. Using this method, many genes that positively or negatively affect capsule production in K. pneumoniae were identified, and we use these data to propose an integrated model for capsule regulation in this species. Several of the genes and biological processes identified have not previously been linked to capsule synthesis. We also show that the methods presented here can be applied to other species of capsulated bacteria, providing the opportunity to explore and compare capsule regulatory networks in other bacterial strains and species. PMID- 30459194 TI - Using Lipoamidase as a Novel Probe To Interrogate the Importance of Lipoylation in Plasmodium falciparum. AB - Lipoate is a redox active cofactor that is covalently bound to key enzymes of oxidative metabolism. Plasmodium falciparum is auxotrophic for lipoate during the intraerythrocytic stages, but it is not known whether lipoate attachment to protein is required or whether attachment is required in a specific subcellular compartment of the parasite. To address these questions, we used an enzyme called lipoamidase (Lpa) as a probe of lipoate metabolism. Lpa was first described in Enterococcus faecalis, and it specifically cleaves protein-bound lipoate, inactivating enzymes requiring this cofactor. Enzymatically active Lpa could be expressed in the cytosol of P. falciparum without any effect on protein lipoylation or parasite growth. Similarly, Lpa could be expressed in the apicoplast, and although protein lipoylation was reduced, parasite growth was not inhibited. By contrast, while an inactive mutant of Lpa could be expressed in the mitochondrion, the active enzyme could not. We designed an attenuated mutant of Lpa and found that this enzyme could be expressed in the parasite mitochondrion, but only in conjunction with a chemical bypass system. These studies suggest that acetyl-CoA production and a cryptic function of the H protein are both required for parasite survival. Our study validates Lpa as a novel probe of metabolism that can be used in other systems and provides new insight into key aspects of mitochondrial metabolism that are responsible for lipoate auxotrophy in malaria parasites.IMPORTANCE Lipoate is an essential cofactor for a small number of enzymes that are important for central metabolism. Malaria parasites require lipoate scavenged from the human host for growth and survival; however, it is not known why this cofactor is so important. To address this question, we designed a probe of lipoate activity based on the bacterial enzyme lipoamidase (Lpa). Expression of this probe in different subcellular locations allowed us to define the mitochondrion as the compartment housing essential lipoate metabolism. To gain further insight into the specific uses of lipoate in the mitochondrion, we designed a series of catalytically attenuated probes and employed the probes in conjunction with a chemical bypass system. These studies suggest that two lipoylated proteins are required for parasite survival. We were able to express Lpa with different catalytic abilities in different subcellular compartments and driven by different promoters, demonstrating the versatility of this tool and suggesting that it can be used as a probe of lipoate metabolism in other organisms. PMID- 30459195 TI - Streptococcus agalactiae Induces Placental Macrophages To Release Extracellular Traps Loaded with Tissue Remodeling Enzymes via an Oxidative Burst-Dependent Mechanism. AB - Streptococcus agalactiae, or group B Streptococcus (GBS), is a common perinatal pathogen. GBS colonization of the vaginal mucosa during pregnancy is a risk factor for invasive infection of the fetal membranes (chorioamnionitis) and its consequences such as membrane rupture, preterm labor, stillbirth, and neonatal sepsis. Placental macrophages, or Hofbauer cells, are fetally derived macrophages present within placental and fetal membrane tissues that perform vital functions for fetal and placental development, including supporting angiogenesis, tissue remodeling, and regulation of maternal-fetal tolerance. Although placental macrophages as tissue-resident innate phagocytes are likely to engage invasive bacteria such as GBS, there is limited information regarding how these cells respond to bacterial infection. Here, we demonstrate in vitro that placental macrophages release macrophage extracellular traps (METs) in response to bacterial infection. Placental macrophage METs contain proteins, including histones, myeloperoxidase, and neutrophil elastase similar to neutrophil extracellular traps, and are capable of killing GBS cells. MET release from these cells occurs by a process that depends on the production of reactive oxygen species. Placental macrophage METs also contain matrix metalloproteases that are released in response to GBS and could contribute to fetal membrane weakening during infection. MET structures were identified within human fetal membrane tissues infected ex vivo, suggesting that placental macrophages release METs in response to bacterial infection during chorioamnionitis.IMPORTANCE Streptococcus agalactiae, also known as group B Streptococcus (GBS), is a common pathogen during pregnancy where infection can result in chorioamnionitis, preterm premature rupture of membranes (PPROM), preterm labor, stillbirth, and neonatal sepsis. Mechanisms by which GBS infection results in adverse pregnancy outcomes are still incompletely understood. This study evaluated interactions between GBS and placental macrophages. The data demonstrate that in response to infection, placental macrophages release extracellular traps capable of killing GBS. Additionally, this work establishes that proteins associated with extracellular trap fibers include several matrix metalloproteinases that have been associated with chorioamnionitis. In the context of pregnancy, placental macrophage responses to bacterial infection might have beneficial and adverse consequences, including protective effects against bacterial invasion, but they may also release important mediators of membrane breakdown that could contribute to membrane rupture or preterm labor. PMID- 30459196 TI - Cryptococcus neoformans Cda1 and Its Chitin Deacetylase Activity Are Required for Fungal Pathogenesis. AB - Chitin is an essential component of the cell wall of Cryptococcus neoformans conferring structural rigidity and integrity under diverse environmental conditions. Chitin deacetylase genes encode the enyzmes (chitin deacetylases [Cdas]) that deacetylate chitin, converting it to chitosan. The functional role of chitosan in the fungal cell wall is not well defined, but it is an important virulence determinant of C. neoformans Mutant strains deficient in chitosan are completely avirulent in a mouse pulmonary infection model. C. neoformans carries genes that encode three Cdas (Cda1, Cda2, and Cda3) that appear to be functionally redundant in cells grown under vegetative conditions. Here we report that C. neoformans Cda1 is the principal Cda responsible for fungal pathogenesis. Point mutations were introduced in the active site of Cda1 to generate strains in which the enzyme activity of Cda1 was abolished without perturbing either its stability or localization. When used to infect CBA/J mice, Cda1 mutant strains produced less chitosan and were attenuated for virulence. We further demonstrate that C. neoformans Cda genes are transcribed differently during a murine infection from what has been measured in vitro IMPORTANCE Cryptococcus neoformans is unique among fungal pathogens that cause disease in a mammalian host, as it secretes a polysaccharide capsule that hinders recognition by the host to facilitate its survival and proliferation. Even though it causes serious infections in immunocompromised hosts, reports of infection in hosts that are immunocompetent are on the rise. The cell wall of a fungal pathogen, its synthesis, composition, and pathways of remodelling are attractive therapeutic targets for the development of fungicides. Chitosan, a polysaccharide in the cell wall of C. neoformans is one such target, as it is critical for pathogenesis and absent in the host. The results we present shed light on the importance of one of the chitin deacetylases that synthesize chitosan during infection and further implicates chitosan as being a critical factor for the pathogenesis of C. neoformans. PMID- 30459197 TI - Prion Seeds Distribute throughout the Eyes of Sporadic Creutzfeldt-Jakob Disease Patients. AB - Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common prion disease in humans and has been iatrogenically transmitted through corneal graft transplantation. Approximately 40% of sCJD patients develop visual or oculomotor symptoms and may seek ophthalmological consultation. Here we used the highly sensitive real-time quaking-induced conversion (RT-QuIC) assay to measure postmortem prion seeding activities in cornea, lens, ocular fluid, retina, choroid, sclera, optic nerve, and extraocular muscle in the largest series of sCJD patient eyes studied by any assay to date. We detected prion seeding activity in 100% of sCJD eyes, representing three common sCJD subtypes, with levels varying by up to 4 log-fold among individuals. The retina consistently showed the highest seed levels, which in some cases were only slightly lower than brain. Within the retina, prion deposits were detected by immunohistochemistry (IHC) in the retinal outer plexiform layer in most sCJD cases, and in some eyes the inner plexiform layer, consistent with synaptic prion deposition. Prions were not detected by IHC in any other eye region. With RT-QuIC, prion seed levels generally declined in eye tissues with increased distance from the brain, and yet all corneas had prion seeds detectable. Prion seeds were also present in the optic nerve, extraocular muscle, choroid, lens, vitreous, and sclera. Collectively, these results reveal that sCJD patients accumulate prion seeds throughout the eye, indicating the potential diagnostic utility as well as a possible biohazard.IMPORTANCE Cases of iatrogenic prion disease have been reported from corneal transplants, yet the distribution and levels of prions throughout the eye remain unknown. This study probes the occurrence, level, and distribution of prions in the eyes of patients with sporadic Creutzfeldt-Jakob disease (sCJD). We tested the largest series of prion-infected eyes reported to date using an ultrasensitive technique to establish the prion seed levels in eight regions of the eye. All 11 cases had detectable prion seeds in the eye, and in some cases, the seed levels in the retina approached those in brain. In most cases, prion deposits could also be seen by immunohistochemical staining of retinal tissue; other ocular tissues were negative. Our results have implications for estimating the risk for iatrogenic transmission of sCJD as well as for the development of antemortem diagnostic tests for prion diseases. PMID- 30459198 TI - Differentially Detectable Mycobacterium tuberculosis Cells in Sputum from Treatment-Naive Subjects in Haiti and Their Proportionate Increase after Initiation of Treatment. AB - Recent reports indicate that the sputum of 80% or more of treatment-naive subjects with tuberculosis recruited in England or South Africa contained more viable Mycobacterium tuberculosis cells detected by limiting dilution (LD) in liquid culture than detected as CFU. Efforts to generate such differentially detectable (DD) M. tuberculosis populations in vitro have been difficult to reproduce, and the LD assay is prone to artifact. Here, we applied a stringent version of the LD assay to sputum from 33 treatment-naive, HIV-negative Haitian subjects with drug-sensitive tuberculosis (TB) and to a second sputum sample after two weeks of standard treatment with isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) for 13 of these subjects. Twenty-one percent had statistically defined levels of DD M. tuberculosis in their pretreatment sputum at an average proportional excess over CFU of 3-fold. Sixty-nine percent of those who received HRZE had statistically defined levels of DD M. tuberculosis in their sputum, and of these, the mean proportionate excess over CFU was 7.9-fold. Thus, DD M. tuberculosis is detectable in pretreatment sputum from a significant proportion of subjects in the Western Hemisphere, and certain drugs or drug regimens, while reducing CFU, may at the same time increase the proportional representation of DD M. tuberculosis among the surviving bacilli. Monitoring DD M. tuberculosis may improve our ability to predict the efficacy of efforts to shorten treatment.IMPORTANCE Measurement of the reduction in CFU in sputum of patients with TB up to 2 weeks after the initiation of treatment is the gateway test for a new TB treatment. Reports have suggested that CFU assays fail to detect the majority of viable M. tuberculosis cells in sputum samples from the majority of patients when the number of M. tuberculosis is estimated by limiting dilution (LD). In an effort to avoid potential methodologic confounders, we applied a modified version of the LD assay in a study of a geographically distinct population. We confirmed that differentially detectable (DD) M. tuberculosis is often found before treatment, albeit at lower proportionate levels than in earlier reports. Strikingly, the prevalence and proportionate representation of DD M. tuberculosis increased during standard treatment. Sublethal exposure to certain antibiotics may help generate DD M. tuberculosis cells or enrich their representation among the surviving bacteria, and this may contribute to the need for prolonged treatment with those agents in order to achieve durable cures. PMID- 30459199 TI - Antibody-Mediated Protection against Plasmodium Sporozoites Begins at the Dermal Inoculation Site. AB - Plasmodium sporozoites are injected into the skin as mosquitoes probe for blood. From here, they migrate through the dermis to find blood vessels which they enter in order to be rapidly carried to the liver, where they invade hepatocytes and develop into the next life cycle stage, the exoerythrocytic stage. Once sporozoites enter the blood circulation, they are found in hepatocytes within minutes. In contrast, sporozoite exit from the inoculation site resembles a slow trickle and occurs over several hours. Thus, sporozoites spend the majority of their extracellular time at the inoculation site, raising the hypothesis that this is when the malarial parasite is most vulnerable to antibody-mediated destruction. Here, we investigate this hypothesis and demonstrate that the neutralizing capacity of circulating antibodies is greater at the inoculation site than in the blood circulation. Furthermore, these antibodies are working, at least in part, by impacting sporozoite motility at the inoculation site. Using actively and passively immunized mice, we found that most parasites are either immobilized at the site of injection or display reduced motility, particularly in their net displacement. We also found that antibodies severely impair the entry of sporozoites into the bloodstream. Overall, our data suggest that antibodies targeting the migratory sporozoite exert a large proportion of their protective effect at the inoculation site.IMPORTANCE Studies in experimental animal models and humans have shown that antibodies against Plasmodium sporozoites abolish parasite infectivity and provide sterile immunity. While it is well documented that these antibodies can be induced after immunization with attenuated parasites or subunit vaccines, the mechanisms by and location in which they neutralize parasites have not been fully elucidated. Here, we report studies indicating that these antibodies display a significant portion of their protective effect in the skin after injection of sporozoites and that one mechanism by which they work is by impairing sporozoite motility, thus diminishing their ability to reach blood vessels. These results suggest that immune protection against malaria begins at the earliest stages of parasite infection and emphasize the need of performing parasite challenge in the skin for the evaluation of protective immunity. PMID- 30459200 TI - A Distinct, Non-Virion Plant Virus Movement Protein Encoded by a Crinivirus Essential for Systemic Infection. AB - Plant-infecting viruses utilize various strategies involving multiple viral and host factors to achieve successful systemic infections of their compatible hosts. Lettuce infectious yellows virus (LIYV), genus Crinivirus, family Closteroviridae, has long, filamentous flexuous virions and causes phloem-limited infections in its plant hosts. The LIYV-encoded P26 is a distinct non-virion protein that shows no similarities to proteins in current databases: it induces plasmalemma deposits over plasmadesmata (PD) pit fields and is speculated to have roles in LIYV virion transport within infected plants. In this study, P26 was demonstrated to be a PD-localized protein, and its biological significance was tested in planta by mutagenesis analysis. An LIYV P26 knockout mutant (P26X) showed viral RNA replication and virion formation in inoculated leaves of Nicotiana benthamiana plants, but failed to give systemic infection. Confirmation by using a modified green fluorescent protein (GFP)-tagged LIYV P26X showed GFP accumulation only in infiltrated leaf tissues, while wild-type LIYV GFP readily spread systemically in the phloem. Attempts to rescue P26X by complementation in trans were negative. However a translocated LIYV P26 gene in the LIYV genome rescued systemic infection, but P26 orthologs from other criniviruses did not. Mutagenesis in planta assays showed that deletions in P26, as well as 2 of 11 specific alanine-scanning mutants, abolished the ability to systemically infect N. benthamiana IMPORTANCE Plant viruses encode specific proteins that facilitate their ability to establish multicellular/systemic infections in their host plants. Relatively little is known of the transport mechanisms for plant viruses whose infections are phloem limited, including those of the family Closteroviridae. These viruses have complex, long filamentous virions that spread through the phloem. Lettuce infectious yellows virus (LIYV) encodes a non-virion protein, P26, which forms plasmalemma deposits over plasmodesmata pit fields, and LIYV virions are consistently found attached to those deposits. Here we demonstrate that P26 is a unique movement protein required for LIYV systemic infection in plants. LIYV P26 shows no sequence similarities to other proteins, but other criniviruses encode P26 orthologs. However, these failed to complement movement of LIYV P26 mutants. PMID- 30459201 TI - Diagnostic Potential and Interactive Dynamics of the Colorectal Cancer Virome. AB - Human viruses (those that infect human cells) have been associated with many cancers, largely due to their mutagenic and functionally manipulative abilities. Despite this, cancer microbiome studies have focused almost exclusively on bacteria instead of viruses. We began evaluating the cancer virome by focusing on colorectal cancer, a primary cause of morbidity and mortality throughout the world and a cancer linked to altered colonic bacterial community compositions but with an unknown association with the gut virome. We used 16S rRNA gene, whole shotgun metagenomic, and purified virus metagenomic sequencing of stool to evaluate the differences in human colorectal cancer virus and bacterial community composition. Through random forest modeling, we identified differences in the healthy and colorectal cancer viromes. The cancer-associated virome consisted primarily of temperate bacteriophages that were also predicted to be bacterium virus community network hubs. These results provide foundational evidence that bacteriophage communities are associated with colorectal cancer and potentially impact cancer progression by altering the bacterial host communities.IMPORTANCE Colorectal cancer is a leading cause of cancer-related death in the United States and worldwide. Its risk and severity have been linked to colonic bacterial community composition. Although human-specific viruses have been linked to other cancers and diseases, little is known about colorectal cancer virus communities. We addressed this knowledge gap by identifying differences in colonic virus communities in the stool of colorectal cancer patients and how they compared to bacterial community differences. The results suggested an indirect role for the virome in impacting colorectal cancer by modulating the associated bacterial community. These findings both support the idea of a biological role for viruses in colorectal cancer and provide a new understanding of basic colorectal cancer etiology. PMID- 30459203 TI - Insights into leptin signaling and male reproductive health: the missing link between overweight and subfertility? AB - Obesity stands as one of the greatest healthcare challenges of the 21st century. Obesity in reproductive-age men is ever more frequent and is reaching upsetting levels. At the same time, fertility has taken an inverse direction and is decreasing, leading to an increased demand for fertility treatments. In half of infertile couples, there is a male factor alone or combined with a female factor. Furthermore, male fertility parameters such as sperm count and concentration went on a downward spiral during the last few decades and are now approaching the minimum levels established to achieve successful fertilization. Hence, the hypothesis that obesity and deleterious effects in male reproductive health, as reflected in deterioration of sperm parameters, are somehow related is tempting. Most often, overweight and obese individuals present leptin levels directly proportional to the increased fat mass. Leptin, besides the well-described central hypothalamic effects, also acts in several peripheral organs, including the testes, thus highlighting a possible regulatory role in male reproductive function. In the last years, research focusing on leptin effects in male reproductive function has unveiled additional roles and molecular mechanisms of action for this hormone at the testicular level. Herein, we summarize the novel molecular signals linking metabolism and male reproductive function with a focus on leptin signaling, mitochondria and relevant pathways for the nutritional support of spermatogenesis. PMID- 30459202 TI - Chemical biology probes of mammalian GLUT structure and function. AB - The structure and function of glucose transporters of the mammalian GLUT family of proteins has been studied over many decades, and the proteins have fascinated numerous research groups over this time. This interest is related to the importance of the GLUTs as archetypical membrane transport facilitators, as key limiters of the supply of glucose to cell metabolism, as targets of cell insulin and exercise signalling and of regulated membrane traffic, and as potential drug targets to combat cancer and metabolic diseases such as type 2 diabetes and obesity. This review focusses on the use of chemical biology approaches and sugar analogue probes to study these important proteins. PMID- 30459205 TI - GSK tops ranking for making drugs available to poor people. PMID- 30459204 TI - Type 3 innate lymphoid cell (ILC3): a new player in liver fibrosis progression. AB - Type 3 innate lymphoid cell (ILC3) has recently emerged as a crucial effector in inflammatory and fibrotic diseases. This study was designed to determine the roles of ILC3 in liver fibrosis. By flow cytometry, we documented increased frequencies of peripheral ILC3 (Lin-CD127+CD117+CD294- lymphocytes) in patients, especially at the advanced stage of hepatitis B virus (HBV)-related chronic liver diseases, and demonstrated their correlations with disease progression. The in vitro fibrogenic effects by ILC3 were determined by co-culture experiments with LX-2 [a human hepatic stellate cell (HSC) line]. The data indicate that pathogenic ILC3 can directly promote LX-2 fibrogenesis in non-contact manners by producing interleukin (IL)-17A and IL-22. Additionally, they had indirect fibrogenic effects by producing IL-22 to suppress IFN-gamma (a well-known anti fibrotic cytokine) production by other immune cells. In carbon tetrachloride (CCl4)-induced wild-type mouse liver fibrosis models, we also documented significantly increased frequencies of both non-natural killer (NK) ILC (Lin CD127+ lymphocytes) and ILC3 (Lin-CD127+RORgammat+ lymphocytes) in liver and spleen specimens. Furthermore, the ILC3 from fibrotic mice contained more IL 17A+ILC3 and IL-22+ILC3 subsets than those from normal and less-fibrotic mice. The in vivo effects of ILC3 in liver fibrogenesis were further determined using RAG-1-/- mice with ILC depletion and further adoptive transfer of ILC3 from wild type mice. The immunohistochemical staining of liver specimens showed the beneficial effects by ILC depletion and the detrimental effects by ILC3 transfer in CCl4-induced mouse liver fibrosis models. Collectively, ILC3 plays a pro fibrotic role in liver fibrosis progression. PMID- 30459206 TI - Correction for Giuntini et al., "Identification and Characterization of Human Monoclonal Antibodies for Immunoprophylaxis against Enterotoxigenic Escherichia coli Infection". PMID- 30459207 TI - Acknowledgment of Ad Hoc Reviewers. PMID- 30459208 TI - Receipt of Colonoscopy Following Diagnosis of Advanced Adenomas: An Analysis within Integrated Healthcare Delivery Systems. AB - Background: To reduce colorectal cancer incidence and mortality, experts recommend surveillance colonoscopy 3 years after advanced adenoma removal. Little is known about adherence to that interval.Methods: We describe patterns of and factors associated with subsequent colonoscopy among persons with >=3 adenomas and/or >=1 adenoma with villous/tubulovillous histology in four U.S. integrated healthcare delivery systems. We report Kaplan-Meier estimators of the cumulative percentage of patients undergoing colonoscopy 6 months to 3.5 years after an index colonoscopy with high-risk findings. Combining data from three healthcare systems, we used multivariable logistic regression with inverse probability of censoring weights to estimate ORs and 95% confidence intervals (CI) for associations between patient characteristics and receipt of subsequent colonoscopy.Results: Among 6,909 persons with advanced adenomas, the percent receiving a subsequent colonoscopy 6 months to 3.5 years later ranged from 18.3% (95% CI: 11.7%-27.8%) to 59.5% (95% CI: 53.8%-65.2%) across healthcare systems. Differences remained significant in the multivariable model. Patients with >=3 adenomas were more likely than those with 1 to 2 villous/tubulovillous adenomas to undergo subsequent colonoscopy. Subsequent colonoscopy was also more common for patients ages 60-74 and less common for patients ages 80 to 89 compared with those ages 50 to 54 years at their index colonoscopy. Sex, race/ethnicity, and comorbidity index score were generally not associated with subsequent colonoscopy receipt.Conclusions: Colonoscopy within the recommended interval following advanced adenoma was underutilized and varied by healthcare system, age, and number of adenomas.Impact: Strategies to improve adherence to surveillance colonoscopy following advanced adenomas are needed. Cancer Epidemiol Biomarkers Prev; 1-8. (c)2018 AACR. PMID- 30459209 TI - GP at Hand: patient eligibility restrictions are lifted after NHS review. PMID- 30459210 TI - Comparison of Effects of Diet on Mammary Cancer: Efficacy of Various Preventive Agents and Metabolomic Changes of Different Diets and Agents. AB - To determine the effects of diet, rats were placed on a standard diet (4% fat) or on a modified Western (high-fat diet, HFD) diet (21% fat) at 43 days of age (DOA) and administered methylnitrosourea (MNU) at 50 DOA. Rats were administered effective (tamoxifen, vorozole, and Targretin) or ineffective (metformin and Lipitor) chemopreventive agents either by daily gavage or in the diet beginning at 57 DOA and continuing until sacrifice (190 DOA). Latency period of the tumors was determined by palpation, and multiplicity and cancer weights per rat were determined at final sacrifice. Rats on the HFD versus standard diet had: (i) a 6% increase in final body weights; (ii) significant decreases in tumor latency; and (iii) significant increases in final tumor multiplicity and average tumor weight. Tamoxifen, vorozole, and Targretin were highly effective preventive agents, whereas Lipitor and metformin were ineffective in rats on either diet. Serum was collected at 78 DOA and at sacrifice (190 DOA), and metabolomics were determined to identify the metabolite changes due to diets and effective agents. Rats given the HFD had increased levels of saturated free fatty acids (including myristate) and decreased levels of 2-aminooctanoate. Furthermore, rats on the HFD diet had increased levels of 2-aminobutyrate and decreases in glycine markers previously identified as indicators of prediabetes. Targretin increased long-chain glycophospholipids (e.g., oleyl-linoleoyl-glycerophosphocholine) and decreased primary bile acids (e.g., taurocholate). Tamoxifen increased palmitoyl-linoleoyl glycophosphocholine and decreased stearoyl-arachidonyl glycophosphocholine. Finally, increased levels of methylated nucleotides (5-methylcytidine) and decreased levels of urea cycle metabolites (N-acetylcitrulline) were associated with the presence of mammary cancers. Cancer Prev Res; 11(12); 1-10. (c)2018 AACR. PMID- 30459211 TI - Absence of functional compensation between coagulation factor VIII and plasminogen in double-knockout mice. AB - Plasminogen deficiency is associated with severely compromised fibrinolysis and extravascular deposition of fibrin. In contrast, coagulation factor VIII (FVIII) deficiency leads to prolonged and excessive bleeding. Based on opposing biological functions of plasminogen and FVIII deficiencies, we hypothesized that genetic elimination of FVIII would alleviate the systemic formation of fibrin deposits associated with plasminogen deficiency and, in turn, elimination of plasminogen would limit bleeding symptoms associated with FVIII deficiency. Mice with single and combined deficiencies of FVIII (F8-/-) and plasminogen (Plg-/-) were evaluated for phenotypic characteristics of plasminogen deficiency, including wasting disease, shortened lifespan, rectal prolapse, and multiorgan fibrin deposition. Conversely, to specifically examine the role of plasmin mediated fibrinolysis on bleeding caused by FVIII deficiency, F8-/- and F8-/-/Plg /- mice were subjected to a bleeding challenge. Mice with a combined deficiency in FVIII and plasminogen displayed no phenotypic differences relative to mice with single FVIII or plasminogen deficiency. Plg-/- and F8-/-/Plg-/- mice exhibited the same penetrance and severity of wasting disease, rectal prolapse, extravascular fibrin deposits, and reduced viability. Furthermore, following a tail vein-bleeding challenge, no significant differences in bleeding times or total blood loss could be detected between F8-/- and F8-/-/Plg-/- mice. Moreover, F8-/- and F8-/-/Plg-/- mice responded similarly to recombinant FVIII (rFVIII) therapy. In summary, the pathological phenotype of Plg-/- mice developed independently of FVIII-dependent coagulation, and elimination of plasmin-driven fibrinolysis did not play a significant role in a nonmucosal bleeding model in hemophilia A mice. PMID- 30459212 TI - Stroke patients can't ask for a second opinion: a multi-specialty response to The Joint Commission's recent suspension of individual stroke surgeon training and volume standards. PMID- 30459213 TI - Quantification of somatic mutation flow across individual cell division events by lineage sequencing. AB - Mutation data reveal the dynamic equilibrium between DNA damage and repair processes in cells and are indispensable to the understanding of age-related diseases, tumor evolution, and the acquisition of drug resistance. However, available genome-wide methods have a limited ability to resolve rare somatic variants and the relationships between these variants. Here, we present lineage sequencing, a new genome sequencing approach that enables somatic event reconstruction by providing quality somatic mutation call sets with resolution as high as the single-cell level in subject lineages. Lineage sequencing entails sampling single cells from a population and sequencing subclonal sample sets derived from these cells such that knowledge of relationships among the cells can be used to jointly call variants across the sample set. This approach integrates data from multiple sequence libraries to support each variant and precisely assigns mutations to lineage segments. We applied lineage sequencing to a human colon cancer cell line with a DNA polymerase epsilon (POLE) proofreading deficiency (HT115) and a human retinal epithelial cell line immortalized by constitutive telomerase expression (RPE1). Cells were cultured under continuous observation to link observed single-cell phenotypes with single-cell mutation data. The high sensitivity, specificity, and resolution of the data provide a unique opportunity for quantitative analysis of variation in mutation rate, spectrum, and correlations among variants. Our data show that mutations arrive with nonuniform probability across sublineages and that DNA lesion dynamics may cause strong correlations between certain mutations. PMID- 30459214 TI - Damage-responsive elements in Drosophila regeneration. AB - One of the most important questions in regenerative biology is to unveil how and when genes change expression and trigger regeneration programs. The resetting of gene expression patterns during response to injury is governed by coordinated actions of genomic regions that control the activity of multiple sequence specific DNA binding proteins. Using genome-wide approaches to interrogate chromatin function, we here identify the elements that regulate tissue recovery in Drosophila imaginal discs, which show a high regenerative capacity after genetically induced cell death. Our findings indicate there is global coregulation of gene expression as well as a regeneration program driven by different types of regulatory elements. Novel enhancers acting exclusively within damaged tissue cooperate with enhancers co-opted from other tissues and other developmental stages, as well as with endogenous enhancers that show increased activity after injury. Together, these enhancers host binding sites for regulatory proteins that include a core set of conserved transcription factors that control regeneration across metazoans. PMID- 30459216 TI - A Vaccine Against Cervical Cancer: Context for the Global Public Health Practitioner. PMID- 30459217 TI - Human stress-inducible Hsp70 has a high propensity to form ATP-dependent antiparallel dimers that are differentially regulated by co-chaperone binding. AB - Eukaryotic protein homeostasis (proteostasis) is largely dependent on the action of highly conserved Hsp70 molecular chaperones. Recent evidence indicates that, apart from conserved molecular allostery, Hsp70 proteins have retained and adapted the ability to assemble as functionally relevant ATP-bound dimers throughout evolution. Here, we have compared the ATP-dependent dimerization of DnaK, human stress-inducible Hsp70, Hsc70 and BiP Hsp70 proteins, showing that their dimerization propensities differ, with stress-inducible Hsp70 being predominantly dimeric in the presence of ATP. Structural analyses using hydrogen/deuterium exchange mass spectrometry, native electrospray ionization mass spectrometry and small-angle X-ray scattering revealed that stress-inducible Hsp70 assembles in solution as an antiparallel dimer with the intermolecular interface closely resembling the ATP-bound dimer interfaces captured in DnaK and BiP crystal structures. ATP-dependent dimerization of stress-inducible Hsp70 is necessary for its efficient interaction with Hsp40, as shown by experiments with dimerization-deficient mutants. Moreover, dimerization of ATP-bound Hsp70 is required for its participation in high molecular weight protein complexes detected ex vivo, supporting its functional role in vivo. As human cytosolic Hsp70 has the ability to interact with tetratricopeptide repeat (TPR) domain containing co-chaperones, we tested the interaction of Hsp70 ATP-dependent dimers with Chip and Tomm34 co-chaperones. While Chip associates with intact Hsp70 dimers to form a larger complex, binding of Tomm34 disrupts the Hsp70 dimer and this event plays an important role in Hsp70 activity regulation. In summary, this study provides structural evidence of robust ATP-dependent antiparallel dimerization of human inducible Hsp70 protein and suggests a novel role of TPR domain co-chaperones in multichaperone complexes involving Hsp70 ATP-bound dimers. PMID- 30459218 TI - Extrasynaptic NMDA receptors on rod pathway amacrine cells: molecular composition, activation, and signaling. AB - In the rod pathway of the mammalian retina, axon terminals of glutamatergic rod bipolar cells are presynaptic to AII and A17 amacrine cells in the inner plexiform layer. Recent evidence suggests that both amacrines express NMDA receptors, raising questions concerning molecular composition, localization, activation, and function of these receptors. Using dual patch-clamp recording from synaptically connected rod bipolar and AII or A17 amacrine cells in retinal slices from female rats, we found no evidence that NMDA receptors contribute to postsynaptic currents evoked in either amacrine. Instead, NMDA receptors on both amacrine cells were activated by ambient glutamate and blocking glutamate uptake increased their level of activation. NMDA receptor activation also increased the frequency of GABAergic postsynaptic currents in rod bipolar cells, suggesting NMDA receptors can drive release of GABA from A17 amacrines. A striking dichotomy was revealed by pharmacological and immunolabeling experiments, which found GluN2B-containing NMDA receptors on AII amacrines and GluN2A-containing NMDA receptors on A17 amacrines. Immunolabeling also revealed a clustered organization of NMDA receptors on both amacrines and a close spatial association between GluN2B subunits and connexin 36 on AII amacrines, suggesting that NMDA receptor modulation of gap junction coupling between these cells involves the GluN2B subunit. Using multi-photon Ca2+ imaging, we verified that activation of NMDA receptors evoked an increase of intracellular Ca2+ in dendrites of both amacrines. Our results suggest that AII and A17 amacrines express clustered, extrasynaptic NMDA receptors, with different and complementary subunits that are likely to contribute differentially to signal processing and plasticity.SIGNIFICANCE STATEMENTGlutamate is the most important excitatory neurotransmitter in the central nervous system, but not all glutamate receptors transmit fast excitatory signals at synapses. NMDA-type glutamate receptors act as voltage- and ligand-gated ion channels, with functional properties determined by their specific subunit composition. These receptors can be found at both synaptic and extrasynaptic sites on neurons, but the role of extrasynaptic NMDA receptors is unclear. Here, we demonstrate that retinal AII and A17 amacrine cells, postsynaptic partners at rod bipolar dyad synapses, express extrasynaptic (but not synaptic) NMDA receptors, with different and complementary GluN2 subunits. The localization of GluN2A-containing receptors to A17s and GluN2B containing receptors to AIIs suggests a mechanism for differential modulation of excitability and signaling in this retinal microcircuit. PMID- 30459219 TI - Temporal dynamics and response modulation across the human visual system in a spatial attention task: an ECoG study. AB - The selection of behaviorally relevant information from cluttered visual scenes (often referred to as 'attention') is mediated by a cortical large-scale network consisting of areas in occipital, temporal, parietal, and frontal cortex that is organized into a functional hierarchy of feedforward and feedback pathways. In the human brain, little is known about the temporal dynamics of attentional processing from studies at the mesoscopic level of electrocorticography (ECoG), that combines millisecond temporal resolution with precise anatomical localization of recording sites. We analyzed high frequency broadband responses (HFB) responses from 626 electrodes implanted in 8 epilepsy patients, who performed a spatial attention task. Electrode locations were reconstructed using a probabilistic atlas of the human visual system. HFB responses showed high spatial selectivity and tuning, constituting ECoG response fields (RFs), within and outside the topographic visual system. In accordance with monkey physiology studies, both RF widths and onset latencies increased systematically across the visual processing hierarchy. We utilized the spatial specificity of HFB responses to quantitatively study spatial attention effects and their temporal dynamics to probe a hierarchical top-down model suggesting that feedback signals back propagate the visual processing hierarchy. Consistent with such a model, the strengths of attentional modulation were found to be greater and modulation latencies to be shorter in posterior parietal cortex, middle temporal cortex and ventral extrastriate cortex as compared to early visual cortex. However, inconsistent with such a model, attention effects were weaker and more delayed in anterior parietal and frontal cortex.SIGNIFICANCE STATEMENTIn the human brain, visual attention has been predominantly studied using methods with high spatial, but poor temporal resolution such as fMRI, or high temporal, but poor spatial resolution such as EEG/MEG. Here, we investigate temporal dynamics and attention effects across the human visual system at a mesoscopic level that combines precise spatial and temporal measurements by using electrocorticography in epilepsy patients performing a classical spatial attention task. Electrode locations were reconstructed using a probabilistic atlas of the human visual system, thereby relating them to topography and processing hierarchy. We demonstrate regional differences in temporal dynamics across the attention network. Our findings do not fully support a top-down model that promotes influences on visual cortex by reversing the processing hierarchy. PMID- 30459220 TI - Agrp neurons project to the medial preoptic area and modulate maternal nest building. AB - Agrp (Agouti related neuropeptide) expressing inhibitory neurons sense caloric needs of an animal to coordinate homeostatic feeding. Recent evidence suggests that Agrp neurons also suppress competing actions and motivations to mediate adaptive behavioral selection during starvation. Here, in adult mice of both sexes we show that Agrp neurons form inhibitory synapses onto ~30% neurons in the medial preoptic area (mPOA), a region critical for maternal care. Remarkably, optogenetically stimulating Agrp neurons decreases maternal nest-building while minimally affecting pup retrieval, partly recapitulating suppression of maternal behaviors during food restriction. In parallel, optogenetically stimulating Agrp projections to the mPOA or to the PVH (paraventricular nucleus of hypothalamus) but not to the LHA (lateral hypothalamus area) similarly decreases maternal nest building. Chemogenetic inhibition of mPOA neurons that express Vgat (vesicular GABA transporter), the population targeted by Agrp terminals, also decreases maternal nest-building. In comparison, chemogenetic inhibition of neurons in the LHA that express Vglut2 (vesicular glutamate transporter 2), another hypothalamic neuronal population critical for feeding and innate drives, is ineffective. Importantly, nest-building during low temperature thermal challenge is not affected by optogenetic stimulation of Agrp->mPOA projections. Finally, via optogenetic activation and inhibition we show that distinctive subsets of mPOA Vgat+ neurons likely underlie pup retrieval and maternal nest-building. Together, these results show that Agrp neurons can modulate maternal nest-building, in part through direct projections to the mPOA. This study corroborates other recent discoveries and underscores the broad functions that Agrp neurons play in antagonizing rivalry motivations to modulate behavioral outputs during hunger.SIGNIFICANCE STATEMENTIn order for animals to initiate ethologically appropriate behaviors, they must typically decide between behavioral repertoires driven by multiple and often conflicting internal states. How neural pathways underlying individual behaviors interact to coherently modulate behavioral outputs, in particular to achieve a proper balance between behaviors that serve immediate individual needs versus those that benefit the propagation of the species, remains poorly understood. Here, by investigating projections from a neuronal population known to drive hunger behaviors to a brain region critical for maternal care, we show that activation of Agrp->mPOA projections in females dramatically inhibits maternal nest-building while leaving mostly intact pup retrieval behavior. Our findings shed new light on neural organization of behaviors and neural mechanisms that coordinate behavioral selection. PMID- 30459215 TI - Modeling epigenetic modifications in renal development and disease with organoids and genome editing. AB - Understanding epigenetic mechanisms is crucial to our comprehension of gene regulation in development and disease. In the past decades, different studies have shown the role of epigenetic modifications and modifiers in renal disease, especially during its progression towards chronic and end-stage renal disease. Thus, the identification of genetic variation associated with chronic kidney disease has resulted in better clinical management of patients. Despite the importance of these findings, the translation of genotype-phenotype data into gene-based medicine in chronic kidney disease populations still lacks faithful cellular or animal models that recapitulate the key aspects of the human kidney. The latest advances in the field of stem cells have shown that it is possible to emulate kidney development and function with organoids derived from human pluripotent stem cells. These have successfully recapitulated not only kidney differentiation, but also the specific phenotypical traits related to kidney function. The combination of this methodology with CRISPR/Cas9 genome editing has already helped researchers to model different genetic kidney disorders. Nowadays, CRISPR/Cas9-based approaches also allow epigenetic modifications, and thus represent an unprecedented tool for the screening of genetic variants, epigenetic modifications or even changes in chromatin structure that are altered in renal disease. In this Review, we discuss these technical advances in kidney modeling, and offer an overview of the role of epigenetic regulation in kidney development and disease. PMID- 30459221 TI - Balancing prediction and sensory input in speech comprehension: The spatiotemporal dynamics of word-recognition in context. AB - Spoken word recognition in context is remarkably fast and accurate, with recognition times of around 200ms, typically well before the end of the word. The neurocomputational mechanisms underlying these contextual effects are still poorly understood. This study combines source-localised electro- and magnetoencephalographic (EMEG) measures of real-time brain activity with multivariate Representational Similarity Analysis (RSA) to determine directly the timing and computational content of the processes evoked as spoken words are heard in context, and to evaluate the respective roles of bottom-up and predictive processing mechanisms in the integration of sensory and contextual constraints. Male and female human participants heard simple (modifier-noun) English phrases that varied in the degree of semantic constraint that the modifier (W1) exerted on the noun (W2), as in pairs like yellow banana We used gating tasks to generate estimates of the probabilistic predictions generated by these constraints as well as measures of their interaction with the bottom-up perceptual input for W2. RSA models of these measures were tested against EMEG brain data across a bilateral fronto-temporo-parietal language network. Consistent with probabilistic predictive processing accounts we found early activation of semantic constraints in frontal cortex (LBA45) as W1 was heard. The effects of these constraints (at 100ms post W2 onset in L middle temporal gyrus and at 140ms in L Heschl's gyrus) were only detectable, however, after the initial phonemes of W2 had been heard. Within an overall predictive processing framework, bottom-up sensory inputs are still required to achieve early and robust spoken word recognition in context.SIGNIFICANCE STATEMENTHuman listeners recognise spoken words in natural speech contexts with remarkable speed and accuracy, often identifying a word well before all of it has been heard. In this study we investigate the brain systems that support this important capacity, using neuroimaging techniques that can track real-time brain activity during speech comprehension. This makes it possible to locate the brain areas that generate predictions about upcoming words and to show how these expectations are integrated with the evidence provided by the speech being heard. We use the timing and localisation of these effects to provide the most specific account to date of how the brain achieves an optimal balance between prediction and sensory input in the interpretation of spoken language. PMID- 30459222 TI - Electrical stimulation over human posterior parietal cortex selectively enhances the capacity of visual short-term memory. AB - Visual short-term memory (VSTM) provides an online mental space for incoming sensory information to be temporally maintained in order to carry out complex behavioral tasks. Despite its essential functions, the capacity at which VSTM could maintain sensory information is limited (i.e., VSTM can hold only about 3-4 visual items at once). Moreover, the quality of sensory representation (i.e., precision) degrades as more information has to be maintained in VSTM. Correlational evidence suggests that the level and the pattern of neural activity measured in the posterior parietal cortex (PPC) track both VSTM capacity and precision. However, the causal contributions of the PPC to these different VSTM operations are unclear. Here, we tested whether stimulating the PPC with transcranial direct-current stimulation (tDCS) could increase VSTM capacity or precision. We found that stimulating the PPC in male and female human participants selectively enhanced VSTM capacity when the number of memory items exceeded capacity limit, without significant effects on VSTM precision. Moreover, this enhancement of VSTM capacity is region-specific as stimulating the prefrontal cortex did not change VSTM capacity or precision. Null stimulation effects in the sensory memory condition confirmed that the tDCS-induced enhancement of VSTM capacity was not simply due to changes in sensory or attentional processes. Altogether these results provide causal evidence suggesting that the PPC has a more dominant role in supporting the storage capacity of VSTM compared to maintaining the quality of sensory representations. Furthermore, tDCS could be used as a promising non-invasive method to enhance this PPC VSTM-related function.SIGNIFICANCE STATEMENTCorrelational evidence from neuroimaging and electrophysiology suggests that the posterior parietal cortex (PPC) supports the storage capacity of visual short-term memory (VSTM) and the precision of sensory representations maintained in VSTM. However, the causal contributions of the PPC to these different VSTM functions were unclear. Here, we found that electrical stimulation over the PPC selectively enhanced VSTM capacity without changing VSTM precision. Overall, our findings suggest that the PPC has a dominant and causal role in supporting the storage capacity of VSTM. PMID- 30459223 TI - Directing voluntary temporal attention increases fixational stability. AB - Our visual input is constantly changing, but not all moments are equally relevant. Visual temporal attention, the prioritization of visual information at specific points in time, increases perceptual sensitivity at behaviorally relevant times. The dynamic processes underlying this increase are unclear. During fixation, humans make small eye movements called microsaccades, and inhibiting microsaccades improves perception of brief stimuli. Here we asked whether temporal attention changes the pattern of microsaccades in anticipation of brief stimuli. Human observers (female and male) judged stimuli presented within a short sequence. Observers were given either an informative precue to attend to one of the stimuli, which was likely to be probed, or an uninformative (neutral) precue. We found strong microsaccadic inhibition before the stimulus sequence, likely due to its predictable onset. Critically, this anticipatory inhibition was stronger when the first target in the sequence (T1) was precued (task-relevant) than when the precue was uninformative. Moreover, the timing of the last microsaccade before T1 and the first microsaccade after T1 shifted, such that both occurred earlier when T1 was precued than when the precue was uninformative. Finally, the timing of the nearest pre- and post-T1 microsaccades affected task performance. Directing voluntary temporal attention therefore impacts microsaccades, helping to stabilize fixation at the most relevant moments, over and above the effect of predictability. Just as saccading to a relevant stimulus can be an overt correlate of the allocation of spatial attention, precisely timed gaze stabilization can be an overt correlate of the allocation of temporal attention.SIGNIFICANCE STATEMENTWe pay attention at moments in time when a relevant event is likely to occur. Such temporal attention improves our visual perception, but how it does so is not well understood. Here we discovered a new behavioral correlate of voluntary, or goal-directed, temporal attention. We found that the pattern of small fixational eye movements called microsaccades changes around behaviorally relevant moments in a way that stabilizes the position of the eyes. Microsaccades during a brief visual stimulus can impair perception of that stimulus. Therefore, such fixation stabilization may contribute to the improvement of visual perception at attended times. This link suggests that in addition to cortical areas, subcortical areas mediating eye movements may be recruited with temporal attention. PMID- 30459224 TI - Association of mGluR-dependent LTD of excitatory synapses with endocannabinoid dependent LTD of inhibitory synapses leads to EPSP to spike potentiation in CA1 pyramidal neurons. AB - The input-output relationships in neural circuits are determined not only by synaptic efficacy but also by neuronal excitability. Activity-dependent alterations of synaptic efficacy have been extensively investigated, but relatively less is known about how the neuronal output is modulated when synaptic efficacy changes are associated with neuronal excitability changes. In this study, we demonstrate that paired pulses of low-frequency stimulation (PP-LFS) induced metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) at Schaffer collateral (SC)-CA1 synapses in Sprague-Dawley rats (both sexes), and this LTD was associated with excitatory postsynaptic potential to spike (E-S) potentiation, leading to the increase in action potential (AP) outputs. Threshold voltage (Vth) for APs evoked by synaptic stimulation and that by somatic current injection were hyperpolarized significantly after PP-LFS. Blockers of GABA receptors mimicked and occluded PP-LFS effects on E-S potentiation and Vth hyperpolarization, suggesting that suppression of GABAergic mechanisms is involved in E-S potentiation after PP-LFS. Indeed, inhibitory postsynaptic currents (IPSCs) and tonic inhibitory currents were reduced after PP LFS. The IPSC reduction was accompanied by increased paired-pulse ratio, and abolished by AM251, a blocker for type 1 cannabinoid receptors, suggesting that PP-LFS suppresses presynaptic GABA release by mGluR-dependent endocannabinoids signaling. By contrast, a group 1 mGluR agonist--3, 5-dihydroxyphenylglycine- induced LTD at SC-CA1 synapses but failed to induce significant IPSC reduction and AP output increase. We propose that mGluR signaling that induces LTD co expression at excitatory and inhibitory synapses regulates an excitation inhibition balance to increase neuronal output in CA1 neurons.SIGNIFICANCE STATEMENTLong-lasting forms of synaptic plasticity are usually associated with excitability changes, the ability to fire action potentials (AP). However, excitability changes have been regarded to play subsidiary roles to synaptic plasticity in modifying neuronal output. We demonstrate that when metabotropic glutamate receptor (mGluR)-dependent long term depression is induced by paired pulses of low-frequency stimulation, the AP output in response to a given input paradoxically increases, indicating that increased excitability is more powerful than synaptic depression. This increase is mediated by the suppression of a presynaptic GABA release via mGluR-dependent endocannabinoid signaling. Our study shows that neuronal output changes do not always follow the direction of synaptic plasticity at excitatory synapses, highlighting the importance of regulating inhibitory tone via endocannabinoid signaling. PMID- 30459225 TI - Resilience to Pain: A Peripheral Component Identified using induced Pluripotent Stem Cells and Dynamic Clamp. AB - Pain is a complex process that involves both detection in the peripheral nervous system and perception in the central nervous system. Individual-to-individual differences in pain are well-documented, but not well-understood. Here we capitalized on inherited erythromelalgia (IEM), a well-characterized human genetic model of chronic pain, and studied a unique family containing related IEM subjects with the same disease-causing Nav1.7 mutation, which is known to make dorsal root ganglion (DRG) neurons hyperexcitable, but different pain profiles (affected son with severe pain, affected mother with moderate pain and an unaffected father). We show, first, that at least in some cases, relative sensitivity to pain can be modeled in subject-specific iPSC-derived sensory neurons in vitro; second, that in some cases, mechanisms operating in peripheral sensory neurons contribute to inter-individual differences in pain; and third, using Whole Exome Sequencing (WES) and dynamic clamp we show that it is possible to pinpoint a specific variant of another gene, KCNQ in this particular kindred, that modulates the excitability of iPSC-derived sensory neurons in this family. While different gene variants may modulate DRG neuron excitability and thereby contribute to inter-individual differences in pain in other families, this study shows that subject-specific iPSCs can be used to model inter-individual differences in pain. We further provide proof-of-principle that iPSCs, WES, and dynamic clamp can be used to investigate peripheral mechanisms and pinpoint specific gene variants that modulate pain signaling and contribute to inter individual differences in pain.SIGNIFICANCE STATEMENTIndividual-to-individual differences in pain are well-documented, but not well-understood. In this study we show, first, that at least in some cases, relative sensitivity to pain can be modeled in subject-specific iPSC-derived sensory neurons in vitro; second, that in some cases, mechanisms operating in peripheral sensory neurons contribute to inter-individual differences in pain; and third, using Whole Exome Sequencing (WES) and dynamic clamp we show that it is possible to pinpoint a specific gene variant that modulates pain signaling and contributes to inter-individual differences in pain. PMID- 30459226 TI - Layer 3 dynamically coordinates columnar activity according to spatial context. AB - To reduce statistical redundancy of natural inputs and increase the sparseness of coding, neurons in primary visual cortex (V1) show tuning for stimulus size and surround suppression. This integration of spatial information is a fundamental, context-dependent neural operation involving extensive neural circuits that span across all cortical layers of a V1 column, and reflects both feedforward and feedback processing. How spatial integration is dynamically coordinated across cortical layers remains poorly understood. We recorded single- and multi-unit activity and local field potentials across V1 layers of awake mice (both sexes) while they viewed stimuli of varying size, and used dynamic Bayesian model comparisons to identify when laminar activity and inter-laminar functional interactions showed surround suppression, the hallmark of spatial integration. We found that surround suppression is strongest in layer 3 (L3) and L4 activity, where suppression is established within ~10 ms after response onset, and receptive fields dynamically sharpen while suppression strength increases. Importantly, we also found that specific directed functional connections were strongest for intermediate stimulus sizes and suppressed for larger ones, particularly for connections from L3 targeting L5 and L1. Taken together, the results shed light on the different functional roles of cortical layers in spatial integration and on how L3 dynamically coordinates activity across a cortical column depending on spatial context.SIGNIFICANCE STATEMENTNeurons in primary visual cortex (V1) show tuning for stimulus size, where responses to stimuli exceeding the receptive field can be suppressed (surround suppression). We demonstrate that functional connectivity between V1 layers can also have a surround-suppressed profile. A particularly prominent role seems to have layer 3, whose functional connections to layers 5 and 1 are strongest for stimuli of optimal size and decreased for large stimuli. Our results therefore point towards a key role of layer 3 in coordinating activity across the cortical column according to spatial context. PMID- 30459227 TI - Auditory thalamostriatal and corticostriatal pathways convey complementary information about sound features. AB - Multiple parallel neural pathways link sound-related signals to behavioral responses. For instance, the striatum, a brain structure involved in action selection and reward-related learning, receives neuronal projections from both the auditory thalamus and auditory cortex. It is not clear whether sound information that reaches the striatum through these two pathways is redundant or complementary. We used an optogenetic approach in awake mice of both sexes to identify thalamostriatal and corticostriatal neurons during extracellular recordings, and characterized neural responses evoked by sounds of different frequencies and amplitude modulation rates. We found that neurons in both pathways encode sound frequency with similar fidelity, but display different coding strategies for amplitude modulated noise. While corticostriatal neurons provide a more accurate representation of amplitude modulation rate in their overall firing rate, thalamostriatal neurons convey information about the precise timing of acoustic events. These results demonstrate that auditory thalamus and auditory cortex neurons provide complementary information to the striatum, and suggest that these pathways could be differentially recruited depending on the requirements of a sound-driven behavior.SIGNIFICANCE STATEMENTSensory signals from the cerebral cortex and the thalamus converge onto the striatum, a nucleus implicated in reward-related learning. It is not clear whether these two sensory inputs convey redundant or complementary information. By characterizing the sound evoked responses of thalamostriatal and corticostriatal neurons, our work demonstrates that these neural pathways convey complementary information about the temporal features of sounds. This work opens new avenues for investigating how these pathways could be selectively recruited depending on task demands, and provides a framework for studying convergence of cortical and thalamic information onto the striatum in other sensory systems. PMID- 30459228 TI - Occurrence of hippocampal ripples is associated with activity suppression in the mediodorsal thalamic nucleus. AB - Forming reliable memories requires coordinated activity within distributed brain networks. At present, neural mechanisms underlying systems-level consolidation of declarative memory beyond the hippocampal-prefrontal interactions remain largely unexplored. The mediodorsal thalamic nucleus (MD) is reciprocally connected with the medial prefrontal cortex (mPFC) and also receives inputs from parahippocampal regions. The MD may thus modulate functional connectivity between the hippocampus (HPC) and the mPFC at different stages of information processing. Here, we characterized in freely behaving Sprague Dawley male rats the MD neural activity around hippocampal ripples, indicators of memory replay and hippocampal-cortical information transfer. Overall, the MD firing rate was transiently (0.76 +/- 0.06 sec) decreased around ripples with the MD activity suppression preceding the ripple onset for 0.41 +/- 0.04 sec (range: 0.01 - 0.95 sec). The degree of MD modulation correlated with ripple amplitude, differed across behavioral states, and also depended on the dynamics of hippocampal-cortical population activity. The MD suppression was the strongest and the most consistent during awake ripples. During NREM sleep, the MD firing decreased around spindle-uncoupled ripples, while enhanced around spindle-coupled ripples. Our results suggest a competitive interaction between the thalamo-cortical and hippocampal-cortical networks supporting 'online' and 'offline' information processing, respectively. We hypothesize that thalamic activity suppression during spindle-uncoupled ripples is favorable for memory replay as it reduces interference from sensory relay. In turn, the thalamic input during hippocampal-cortical communication, as indicated by spindle/ripple coupling, may contribute to selectivity and reliability of information transfer. Both predictions need to be tested in future experiments.SIGNIFICANCE STATEMENTSystems mechanisms of declarative memory consolidation beyond the hippocampal-prefrontal interactions remain largely unexplored. The connectivity of the mediodorsal thalamic nucleus (MD) with extra hippocampal regions and with medial prefrontal cortex (mPFC) underlies its role in execution of diverse cognitive functions. However, little is known about the MD involvement in 'offline' consolidation. We found that MD neural activity is transiently suppressed around hippocampal ripples, except for ripples co occurring with sleep spindles, when the MD activity was elevated. The thalamic activity suppression at times of spindle-uncoupled ripples may be favorable for memory replay as it reduces interference with sensory relay. In turn, the thalamic input during hippocampal-cortical communication, as indicated by spindle/ripple coupling, may contribute to selectivity and reliability of information transfer. PMID- 30459230 TI - Apo-opsin exists in equilibrium between a predominant inactive and a rare highly active state. AB - Bleaching adaptation in rod photoreceptors is mediated by apo-opsin, which activates phototransduction with effective activity 105-106 fold lower than that of photoactivated rhodopsin (Meta II). However, the mechanism that produces such low opsin activity is unknown. To address this question, we sought to record single opsin responses in mouse rods. We used mutant mice lacking efficient calcium feedback to boosts rod responses, and generated a small fraction of opsin by photobleaching ~1% of rhodopsin. The bleach produced dramatic increase in the frequency of discrete photoresponse-like events. This activity persisted for hours, was quenched by 11-cis-retinal, and was blocked by uncoupling opsin from phototransduction, all indicating opsin as its source. Opsin-driven discrete activity was also observed in rods containing unactivatable rhodopsin, ruling out transactivation of rhodopsin by opsin. We conclude that bleaching adaptation is mediated by opsin that exists in equilibrium between a predominant inactive and a rare Meta II-like state.SIGNIFICANCE STATEMENTElectrophysiolgical analysis is used to show that the G protein-coupled receptor opsin exists in equilibrium between a predominant inactive and a rare highly active state that mediates bleaching adaptation in photoreceptors. PMID- 30459229 TI - Nociceptor translational profiling reveals the Ragulator-Rag GTPase complex as a critical generator of neuropathic pain. AB - Nociceptors, sensory neurons in the dorsal root ganglion (DRG) that detect damaging or potentially damaging stimuli, are key drivers of neuropathic pain. Injury to these neurons causes activation of translation regulation signaling including the mechanistic target of rapamycin complex 1 (mTORC1) and mitogen activated protein kinase interacting kinase (MNK) eukaryotic initiation factor (eIF) 4E pathways. This is a mechanism driving changes in excitability of nociceptors that is critical for the generation of chronic pain states, however, the mRNAs that are translated to lead to this plasticity have not been elucidated. To address this gap in knowledge, we used translating ribosome affinity purification (TRAP) in male and female mice to comprehensively characterize mRNA translation in Scn10a-positive nociceptors in chemotherapy induced neuropathic pain (CIPN) caused by paclitaxel treatment. This unbiased method creates a new resource for the field, confirms many findings in the CIPN literature and also find extensive evidence for new target mechanisms that may cause CIPN. We provide evidence that an underlying mechanism of CIPN is sustained mTORC1 activation driven by MNK1-eIF4E signaling. RagA, a GTPase controlling mTORC1 activity, is identified as a novel target of MNK1-eIF4E signaling. This demonstrates a novel translation regulation signaling circuit wherein MNK1-eIF4E activity drives mTORC1 via control of RagA translation. CIPN and RagA translation are strongly attenuated by genetic ablation of eIF4E phosphorylation, MNK1 elimination or treatment with the MNK inhibitor eFT508. We identify a novel translational circuit for the genesis of neuropathic pain caused by chemotherapy with important implications for therapeutics.SIGNIFICANCE STATEMENTNeuropathic pain affects up to 10% of the population but its underlying mechanisms are incompletely understood leading to poor treatment outcomes. We used TRAP technology to create a comprehensive translational profile of DRG nociceptors in naive mice and at the peak of neuropathic pain induced by paclitaxel treatment. We reveal new insight into how mTORC1 is activated in neuropathic pain pointing to a key role of MNK1-eIF4E-mediated translation of a complex of mRNAs that control mTORC1 signaling at the surface of the lysosome. We validate this finding using genetic and pharmacological techniques. Our work strongly suggests that MNK1-eIF4E signaling drives CIPN and that a drug in human clinical trials, eFT508, may be a new therapeutic for neuropathic pain. PMID- 30459231 TI - Interactome mapping defines BRG1, a component of the SWI/SNF chromatin remodeling complex, as a new partner of the transcriptional regulator CTCF. AB - The highly conserved zinc finger CCCTC-binding factor (CTCF) regulates genomic imprinting and gene expression by acting as a transcriptional activator or repressor of promoters and insulator of enhancers. The multiple functions of CTCF are accomplished by co-association with other protein partners and are dependent on genomic context and tissue specificity. Despite the critical role of CTCF in the organization of genome structure, to date, only a subset of CTCF interaction partners have been identified. Here we present a large-scale identification of CTCF binding partners using affinity purification and high-resolution LC-MS/MS analysis. In addition to functional enrichment of specific protein families such as the ribosomal proteins and the DEAD box helicases, we identified novel high confidence CTCF interactors that provide a still unexplored biochemical context for CTCF's multiple functions. One of the newly validated CTCF interactors is BRG1, the major ATPase subunit of the chromatin remodeling complex SWI/SNF, establishing a relationship between two master regulators of genome organization. This work significantly expands the current knowledge of the human CTCF interactome and represents an important resource to direct future studies aimed at uncovering molecular mechanisms modulating CTCF pleiotropic functions throughout the genome. PMID- 30459232 TI - HJURP interacts with and specifies the centromeric assembly of CENP-T. AB - Centromere is an evolutionarily conserved eukaryotic protein machinery essential for precision segregation of parental genome into two daughter cells during mitosis. CENP-A organizes functional centromere via constitutive centromere associated network composing CENP-T complex. However, it remains elusive how CENP T assembles onto centromere. Here, we show CENP-T directly binds to HJURP, an evolutionarily conserved chaperone involving in loading CENP-A. The binding interface of HJURP was mapped to the C-terminal CENP-T. Depletion of HJURP by CRISPR-elicited knockout minimized recruitment of CENP-T to the centromere, indicating the importance of HJURP in CEPN-T loading. Our immunofluorescence analyses indicate HJURP recruits CENP-T to centromere in S/G2 phase during cell division cycle. Significantly, HJURP-binding deficient mutant CENP-T6L failed to locate to the centromere. Importantly, CENP-T insufficiency resulted in chromosome misalignment, in particular, chromosome 15 and 18. Taken together, these data define a novel molecular mechanism underlying the assembly of CENP-T onto the centromere by a temporally regulated HJURP-CENP-T interaction. PMID- 30459233 TI - Forkhead box protein O1 (FoxO1) regulates hepatic serine protease inhibitor B1 (serpinB1) expression in a cell non-autonomous fashion. AB - FoxO proteins are major targets of insulin action and FoxO1 mediates effects of insulin on hepatic glucose metabolism. We previously reported that serpinB1 is a liver secreted factor (hepatokine) that promotes adaptive beta-cell proliferation in response to insulin resistance in the liver-specific insulin receptor knockout (LIRKO) mouse. Here, we report that FoxO1 plays a critical role in promoting serpinB1 expression in hepatic insulin resistance in a cell non-autonomous manner. Mice lacking both insulin receptor and FoxO1 (LIRFKO) exhibit reduced beta-cell mass compared to LIRKO mice, due to attenuation of beta-cell proliferation. While hepatic expression of serpinB1 mRNA and protein levels were increased in LIRKO mice, both mRNA and protein levels returned to control levels in LIRFKO mice. Furthermore, liver-specific expression of constitutively active FoxO1 in transgenic mice induced an increase in hepatic serpinB1 mRNA and protein levels in refed mice. Conversely, serpinB1 mRNA and protein levels were reduced in mice lacking FoxO proteins in the liver. Chromatin immunoprecipitation studies demonstrated that FoxO1 binds to 3 distinct sites located ~9 kb upstream of the serpinb1 gene in primary mouse hepatocytes and that this binding is enhanced in hepatocytes from LIRKO mice. However, adenoviral expression of wild type or constitutively active FoxO1, and insulin treatment is sufficient to regulate other FoxO1 target genes (IGFBP-1, PEPCK), but not serpinB1 expression in mouse primary hepatocytes. These results indicate that liver FoxO1 promotes serpinB1 expression in hepatic insulin resistance, and that cell non-autonomous factors contribute to FoxO1-dependent effects on serpinB1 expression in the liver. PMID- 30459234 TI - The ubiquitin ligase SspH1 from Salmonella uses a modular and dynamic E3 domain to catalyze substrate ubiquitylation. AB - SspH/IpaH bacterial effector E3 ubiquitin ligases, unrelated in sequence or structure to eukaryotic E3s, are utilized by a wide variety of gram-negative bacteria during pathogenesis. These E3s function in a eukaryotic environment, utilize host cell E2 ubiquitin-conjugating enzymes of the Ube2D family, and target host proteins for ubiquitylation. Despite several crystal structures, details of Ube2D~Ub binding and the mechanism of ubiquitin transfer are poorly understood. Here we show that the catalytic E3 ligase domain of SspH1 can be divided into two subdomains; an N-terminal subdomain that harbors the active site cysteine, and a C-terminal subdomain containing the Ube2D~Ub binding site. SspH1 mutations designed to restrict subdomain motions show rapid formation of an E3~Ub intermediate, but impaired Ub transfer to substrate. NMR experiments using paramagnetic spin labels reveal how SspH1 binds Ube2D~Ub and targets the E2~Ub active site. Unexpectedly, hydrogen/deuterium exchange mass spectrometry shows that the E2~Ub binding region is dynamic but stabilized in the E3~Ub intermediate. Our results support a model in which both subunits of an Ube2D~Ub clamp onto a dynamic region of SspH1 promoting an E3 conformation poised for transthiolation. A conformational change is then required for Ub transfer from E3~Ub to substrate. PMID- 30459235 TI - The inflammasome adapter ASC assembles into filaments with integral participation of its two Death Domains, PYD and CARD. AB - The inflammasome is a multi-protein complex necessary for the onset of inflammation. The adapter protein ASC assembles inflammasome components by acting as a molecular glue between danger-signal sensors and procaspase-1. The assembly is mediated by ASC self-association and protein interactions via its two Death Domains, PYD and CARD. Truncated versions of ASC have been shown to form filaments, but information on the filaments formed by full-length ASC is needed to construct a meaningful model of inflammasome assembly. To gain insights into this system, we used a combination of TEM, NMR and computational analysis to investigate intact ASC structures. We show that ASC forms ~ 6-7 nm width filaments that stack laterally to form bundles. The structural characteristics and dimensions of the bundles indicate that both PYD and CARD are integral parts of the filament. A truncated version of ASC with only the CARD domain (ASCCARD) forms different filaments (~ 3-4 nm width), providing further evidence that both domains work in concert in filament assembly. Ring-shaped protein particles bound to pre-existing filaments match the size of ASC dimer structures generated by NMR based protein docking, suggesting that the ASC dimer could be a basic building block for filament formation. Solution NMR binding studies identified the protein surfaces involved in the ASCCARD - ASCCARD interaction. These data provide new insights into the structural underpinnings of the inflammasome and should inform future efforts to interrogate this important biological system. PMID- 30459237 TI - Evidence Underlying Recommendations and Payments from Industry to Authors of the National Comprehensive Cancer Network Guidelines. AB - BACKGROUND: The National Comprehensive Cancer Network (NCCN) guidelines are among the most widely used guidance in oncology. It is critical to understand the extent to which the recommendations in these guidelines are supported by evidence and to investigate whether these recommendations have been influenced by payments from industry to authors. MATERIALS AND METHODS: We examined the quality and consistency of evidence, as scored by guidelines authors, for systemic treatment incorporated in the NCCN guidelines. Payments data in 2015 were manually abstracted using the Open Payments database, which discloses all payments between the industry and American physicians. Correlations between the percentage of authors who received payments and the proportion of recommendations developed from low-level evidence per guideline were calculated using Spearman rank correlation. RESULTS: In total, 1,782 recommendations were identified in 29 guidelines, of which 1,282 (71.9%) were based on low-quality or low-consistency evidence (low-level evidence), including "case reports or clinical experience only" (18.9%). A substantial proportion (31/143, 21.7%) of category 1 (the highest level) recommendations were based on low-level evidence. The majority of authors (87.1%) received payments from industry. However, no association was found between the prevalence of payments among authors and the percentage of recommendations developed from low-level evidence per guideline. CONCLUSION: The majority of systemic treatment recommendations in the NCCN guidelines are based on low-level evidence, including more than one in five category 1 recommendations. Payments from industry were prevalent among authors. However, industrial payments among authors were not associated with inclusion of regimen/agent for which there is no conclusive evidence in the guidelines. IMPLICATIONS FOR PRACTICE: The authors found that the majority (71.9%) of systemic treatment recommendations issued in the current National Comprehensive Cancer Network guidelines were based on low-level evidence. Physicians should remain cautious when using current guidelines as the sole source guiding patient care decisions. PMID- 30459238 TI - Association of Modified-FOLFIRINOX-Regimen-Based Neoadjuvant Therapy with Outcomes of Locally Advanced Pancreatic Cancer in Chinese Population. AB - LESSONS LEARNED: Modification of FOLFIRINOX significantly improves safety and tolerability in Chinese patients with locally advanced pancreatic cancer.Patients with locally advanced pancreatic cancer benefit from neoadjuvant therapy and experience a much better survival than patients with upfront surgery. BACKGROUND: The objective of this study was to evaluate the efficacy of modified-FOLFIRINOX (mFOLFIRINOX) regimens in Chinese patients with locally advanced pancreatic cancer (LAPC) and to compare outcomes between patients with LAPC treated with mFOLFIRINOX-based neoadjuvant therapy (LAPC-N) and patients with LAPC who underwent upfront surgery (LAPC-S). METHODS: Forty-one patients with LAPC-N were enrolled prospectively. Imaging features, chemotherapy response, adverse events, perioperative complications, histology, and survival were analyzed. Seventy-four patients with resectable pancreatic cancer (RPC) (from April 2012 to November 2017) and 19 patients with LAPC-S (from April 2012 to March 2014) were set as observational cohorts, and data were collected retrospectively. LAPC-N patients with adequate response underwent surgical treatment, whereas continuous chemotherapy was given to LAPC-N patients who were not deemed resectable after treatment, and the response was re-evaluated every 2 months. RESULTS: Forty-one patients with LAPC received mFOLFIRINOX with a response rate of 37.1%. The most common severe adverse events were neutropenia and anemia. mFOLFIRINOX-based neoadjuvant therapy contributed to a remarkable decrease in CA19-9 level and tumor diameter. Fourteen LAPC-N patients underwent surgery (LAPC-N-S) after downstaging. Compared with LAPC-N-S cases, LAPC-S patients had longer operative time, more blood loss, and a higher risk of grade 5 complications. The median overall survival (OS) and progression-free survival (PFS) of LAPC-N-S patients were 27.7 months and 19.3 months, respectively, which were similar to those of patients with RPC (30.0 months and 23.0 months) and much longer than those of patients with LAPC-S (8.9 months and 7.6 months), respectively. CONCLUSION: Neoadjuvant chemotherapy such as the mFOLFIRINOX regimen can be recommended for Chinese patients with LAPC after dose modification. Patients with LAPC-N who underwent surgery obtained significantly improved survival compared with patients in the observational LAPC-S cohort, who did not undergo neoadjuvant therapy. PMID- 30459239 TI - Osteogenic protein-1 attenuates nucleus pulposus cell apoptosis through activating the PI3K/Akt/mTOR pathway in a hyperosmotic culture. AB - BACKGROUND: Previous studies have indicated that osteogenic protein-1 has protective effects on the biological functions of intervertebral disc cells. Hyper-osmolarity is an important physicochemical factor within the disc nucleus pulposus (NP) region, which obviously promotes NP cell apoptosis. OBJECTIVE: To study the effects of osteogenic protein-1 (OP-1) on NP cell apoptosis induced by hyper-osmolarity and the potential signaling transduction pathway. METHODS: Rat NP cells were cultured in a hyperosmotic medium with or without OP-1 addition for 7 days. Inhibitor 294002 and inhibitor FK-506 were used to investigate the role of the PI3K/Akt/mTOR pathway in this process. NP cell apoptosis were evaluated by cell apoptosis ratio, activity of caspases 3/9 and gene/protein expression of apoptosis-related molecules (Bax, Bcl-2, caspase-3/cleaved caspase-3, cleaved PARP). Results: OP-1 addition obviously decreased cell apoptosis ratio and caspase-3/9 activity, down-regulated gene/protein expression of pro-apoptosis molecules (Bax, caspase-3/cleaved casepase-3 and cleaved PARP), up-regulated gene/protein expression of anti-apoptosis molecule (Bcl-2) in a hyperosmotic culture. Moreover, OP-1 addition significantly increased protein expression of p Akt and p-mTOR. Further analysis showed that addition of LY294002 and FK-506 partly attenuated these protective effects of OP-1 against NP cell apoptosis and activation of the PI3K/Akt/mTOR pathway in a hyperosmotic culture. CONCLUSION: OP 1 can attenuate NP cell apoptosis through activating the PI3K/Akt/mTOR pathway in a hyperosmotic culture. This study sheds a new light on the protective role of OP 1 in regulating disc cell biology, and provides some theoretical basis for the application of OP-1 in retarding/regenerating disc degeneration. PMID- 30459240 TI - The effect of Euphorbia szovitsii Fisch. & C.A.Mey extract on the viability and the proliferation of MDA-MB-231 cell line. AB - The aim of this study was to determine the anticancer effects of Euphorbia szovitsii Fisch. & C.A.Mey. on the breast cancer cells to reveal the underlying mechanism of its anti-breast cancer properties. In this experimental study, triple negative breast cancer cell line (MDA-MB-231) was cultivated in RPMI 1640 medium. Hydroalcoholic extract (70:30) of aerial parts of the plant was prepared. The cultured cells were treated with different concentrations (0-1000 MUg/ml) of E. szovitsii extract for 24 and 48 hours. Toxicity of the extract on MDA-MB-231 cells was examined using MTT (3-[4,5-dimethyl-2-thiazolyl]-2, 5 diphenyl tetrazolium bromide) test. The Annexin V-FITC Apoptosis Detection Kit was used to evaluate apoptosis and necrosis. Flow cytometry technique was employed to differentiate different phases of the cell cycle in the cells. Data were analyzed by GraphPad Prism and SPSS software. After 24 and 48h, the IC50 values were respectively 76.78 (95% CI=60.75 to 97.05; R=0.8588) and 59.71 (95% CI=46.25 to 77.09; R=0.8543) MUg/ml for E. szovitsii, The extract exhibited antiproliferative effects against MDA-MB-231 cells in a dose-dependent manner. Annexin V-FITC/PI assay confirmed that the extract was able to induce apoptosis in MDA-MB-231 cells. Moreover, treatment with the extract resulted in cell cycle arrest at G1 phase. Therefore, E. szovitsii could induce apoptosis and arrest cycle arrest in the MDA-MB-231 cell line. It might be a good resource of natural products for producing anti-breast cancer drugs. PMID- 30459241 TI - NFAT1 enhances the effects of tumor-associated macrophages on promoting malignant melanoma growth and metastasis. AB - Tumor-associated macrophages (TAMs) play substantial roles in tumor growth, invasion, and metastasis. NFAT1 has been shown to promote melanoma growth and metastasis in vivo. We herein aim to investigate whether NFAT1 is capable to promote melanoma growth and metastasis by influencing TAM properties. Melanoma conditioned TAMs was obtained from human monocytes after incubation with conditioned medium from A375 cell culture. The phenotype of the macrophages was detected. Cell proliferation, migration, and invasion were evaluated. Human malignant melanoma tissues exhibited increased CD68+-macrophages infiltration and NFAT1 expression compared with the normal pigmented nevus tissues. Melanoma conditioned TAMs displayed M2-like phenotype. Melanoma-conditioned TAMs also promoted proliferation, migration, and invasion of human malignant melanoma cell lines A375 and WM451. Furthermore, NFAT1 expression in TAMs was significantly increased compared with the M0 group. NFAT1 overexpression significantly strengthened the melanoma-conditioned TAMs-mediated promotion of cell migration and invasion in A375 and WM451 cells, whereas NFAT1 knockdown exerted the opposite effects. Moreover, NFAT1 overexpression in melanoma-conditioned TAMs promoted CD68+-macrophage infiltration, tumor growth and metastasis in vivo NFAT1 may play a critical role in enhancing the TAMs-mediated promotion of growth and metastasis in malignant melanoma. PMID- 30459242 TI - Desaturations During 6-Minute Walk Test and Predicting Nocturnal Desaturations in Adult Subjects With Cystic Fibrosis. AB - BACKGROUND: Nocturnal desaturation in cystic fibrosis (CF) may have prognostic implications because a significant and maintained nocturnal desaturation can contribute to the development and progression of pulmonary hypertension with cor pulmonale. Its relation with the desaturation in exercise has not been sufficiently studied. We aimed to determine whether desaturation during 6MWT can be an indicator of nocturnal desaturation in adult subjects with CF. METHODS: 57 subjects were included: 50.9% male, 27.5 +/- 7.7 y old, mean FEV1 = 2.37 +/- 0.74 L, and %FEV1 67 +/- 18.1%. Desaturation during 6MWT was defined as oxygen saturation (S pO2 ) <= 90% or a decline of > 4 points in S pO2 from baseline, and nocturnal desaturation as a desaturation index > 4 or > 5% of sleep time with S pO2 <= 90%. RESULTS: Desaturation observed during 6MWT in adult subjects with CF did not correlate with nocturnal desaturation (P = .27). Subjects with %FEV1 <= 55% and diffusion capacity of carbon monoxide (DLCO) <= 50 mmol/min/mm Hg were at higher risk of 6MWT desaturation. Nocturnal desaturation was more frequent in males, with P aO2 <= 71 mm Hg in blood gas analysis. CONCLUSIONS: Desaturation observed in 6MWT cannot predict desaturation at night in adults with CF. Other parameters were identified as predictors of desaturation. PMID- 30459243 TI - In This Issue of Diabetes Care. PMID- 30459244 TI - The Dynamic Origins of Type 1 Diabetes. PMID- 30459245 TI - SGLT Inhibitors for Type 1 Diabetes: An Obvious Choice or Too Good to Be True? PMID- 30459246 TI - John A. Galloway, MD, FACP: A Pharmaceutical Physician and Leader in Diabetes Therapy. PMID- 30459247 TI - Fasiglifam-Induced Liver Injury in Patients With Type 2 Diabetes: Results of a Randomized Controlled Cardiovascular Outcomes Safety Trial. AB - OBJECTIVE: To evaluate the cardiovascular (CV) safety of fasiglifam, a first-in man G-protein-coupled receptor 40 (GPR40) agonist, in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A phase 3 multicenter randomized double blind placebo-controlled two-arm trial was intended to randomize 5,000 participants with type 2 diabetes at high CV risk to fasiglifam or placebo. The primary objective of the trial was to rule out an upper noninferiority bound >1.3 for a one-sided 97.5% confidence limit of the hazard ratio (HR) for CV composite events during treatment with fasiglifam compared with placebo. The primary outcome was the time to first occurrence of any component of the major adverse CV event composite of CV death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina. RESULTS: The study enrolled 3,207 participants but was terminated because of liver safety concerns. Increased rates of liver enzyme elevation (AST/ALT >=3-5 * upper limit of normal [ULN]) with fasiglifam were observed. The incidence of ALT or AST >=3 * ULN with fasiglifam compared with placebo was 2.1% vs. 0.5%, P < 0.001, and the incidence for >=10 * ULN was 0.31% vs. 0.06%, P < 0.001. A primary CV composite outcome occurred in 40 participants, 2.5% each in the fasiglifam and placebo arms at 12 months (HR 1.05; 95% CI 0.67, 1.63). CONCLUSIONS: Development of fasiglifam was terminated due to concerns of drug-induced liver injury. Performance of a U.S. Food and Drug Administration-mandated CV outcomes trial supported the termination of the fasiglifam clinical program. PMID- 30459249 TI - FDA announces crackdown on e-cigarettes in bid to reduce teenage vaping. PMID- 30459250 TI - In This Issue of Diabetes. PMID- 30459253 TI - Comment on Bu et al. Insulin Regulates Lipolysis and Fat Mass by Upregulating Growth/Differentiation Factor 3 in Adipose Tissue Macrophages. Diabetes 2018;67:1761-1772. PMID- 30459254 TI - Response to Comment on Bu et al. Insulin Regulates Lipolysis and Fat Mass by Upregulating Growth/Differentiation Factor 3 in Adipose Tissue Macrophages. Diabetes 2018;67:1761-1772. PMID- 30459255 TI - Influences: Russian training. PMID- 30459251 TI - Targeting Metabolism, Insulin Resistance, and Diabetes to Treat Nonalcoholic Steatohepatitis. AB - Obesity, insulin resistance, and diabetes are strongly linked to the accumulation of excessive lipids in the liver parenchyma, a condition known as nonalcoholic fatty liver disease (NAFLD). Given its association with obesity and related metabolic diseases, it is not surprising that the prevalence of NAFLD has dramatically increased in the past few decades. NAFLD has become the most common liver disease in many areas of the world. The term, NAFLD, encompasses a spectrum of disorders that ranges from simple steatosis to steatosis with inflammatory lesions (nonalcoholic steatohepatitis [NASH]). Although simple steatosis might be relatively benign, epidemiologic studies have linked NASH to greatly increased risk of developing cirrhosis and hepatocellular carcinoma. Yet despite this, there are no approved treatments for the disease, and it remains a significant unmet medical need. This Perspective will review some of the relevant literature on the topic and examine approved and experimental NASH therapeutic concepts that target intermediary metabolism, insulin resistance, and diabetes to treat this emerging public health problem. PMID- 30459256 TI - Austerity in the UK: rising poverty threatens stability and health. PMID- 30459257 TI - Sixty seconds on . . . reverse mentoring. PMID- 30459260 TI - GMC checks 3000 doctors' credentials after fraudulent psychiatrist practised for 23 years. PMID- 30459258 TI - Adherence of Newborn-Specific Antibiotic Stewardship Programs to CDC Recommendations. AB - : : media-1vid110.1542/5839992664001PEDS-VA_2017-4322Video Abstract BACKGROUND: The Centers for Disease Control and Prevention (CDC) published the Core Elements of Hospital Antibiotic Stewardship Programs (ASPs), while the Choosing Wisely for Newborn Medicine Top 5 list identified antibiotic therapy as an area of overuse. We identify the baseline prevalence and makeup of newborn-specific ASPs and assess the variability of NICU antibiotic use rates (AURs). METHODS: Data were collected using a cross-sectional audit of Vermont Oxford Network members in February 2016. Unit measures were derived from the 7 domains of the CDC's Core Elements of Hospital ASPs, including leadership commitment, accountability, drug expertise, action, tracking, reporting, and education. Patient-level measures included patient demographics, indications, and reasons for therapy. An AUR, defined as the number of infants who are on antibiotic therapy divided by the census that day, was calculated for each unit. RESULTS: Overall, 143 centers completed structured self-assessments. No center addressed all 7 core elements. Of the 7, only accountability (55%) and drug expertise (62%) had compliance >50%. Centers audited 4127 infants for current antibiotic exposure. There were 725 infants who received antibiotics, for a hospital median AUR of 17% (interquartile range 10%-26%). Of the 412 patients on >48 hours of antibiotics, only 26% (107 out of 412) had positive culture results. CONCLUSIONS: Significant gaps exist between CDC recommendations to improve antibiotic use and antibiotic practices during the newborn period. There is wide variation in point prevalence AURs. Three-quarters of infants who received antibiotics for >48 hours did not have infections proven by using cultures. PMID- 30459259 TI - Minister to Their Instruction: Revisiting the Minister-Vaccinator Rowland Hill. PMID- 30459261 TI - High school personality traits and 48-year all-cause mortality risk: results from a national sample of 26 845 baby boomers. AB - BACKGROUND: It is unclear if adolescent personality predicts mortality into late life, independent of adolescent socioeconomic status (SES). METHODS: Over 26 000 members of Project Talent, a US population cohort of high school students, completed a survey including 10 personality scales and SES in 1960. Multi-source mortality follow-up obtained vital status data through an average 48-year period ending in 2009. Cox proportional hazard models examined the relative risk associated with personality traits, as well as confounding by both a measure of SES and by race/ethnicity. RESULTS: Adjusted for sex and grade, higher levels of vigour, calm, culture, maturity and social sensitivity in high school were associated with reduced mortality risk (HRs=0.92 to. 96), while higher levels of impulsivity were associated with greater mortality risk. Further adjustment for SES and school racial/ethnic composition mildly attenuated (eg, 12%), but did not eliminate these associations. Final HRs for a 1 SD change in personality traits were similar to that for a 1 SD change in SES. CONCLUSIONS: Adaptive personality traits in high school are associated with all-cause mortality in the USA as far into the future as the seventh decade, and to a degree similar to high school socioeconomic disadvantage. PMID- 30459262 TI - Cell-cycle control of cell polarity in yeast. AB - In many cells, morphogenetic events are coordinated with the cell cycle by cyclin dependent kinases (CDKs). For example, many mammalian cells display extended morphologies during interphase but round up into more spherical shapes during mitosis (high CDK activity) and constrict a furrow during cytokinesis (low CDK activity). In the budding yeast Saccharomyces cerevisiae, bud formation reproducibly initiates near the G1/S transition and requires activation of CDKs at a point called "start" in G1. Previous work suggested that CDKs acted by controlling the ability of cells to polarize Cdc42, a conserved Rho-family GTPase that regulates cell polarity and the actin cytoskeleton in many systems. However, we report that yeast daughter cells can polarize Cdc42 before CDK activation at start. This polarization operates via a positive feedback loop mediated by the Cdc42 effector Ste20. We further identify a major and novel locus of CDK action downstream of Cdc42 polarization, affecting the ability of several other Cdc42 effectors to localize to the polarity site. PMID- 30459263 TI - Characterisation of CRISPR mutants targeting genes modulating pectin degradation in ripening tomato. AB - Tomato (Solanum lycopersicum) is a globally important crop with an economic value in the tens of billions of dollars, and a significant supplier of essential vitamins, minerals and phytochemicals in the human diet. Shelf life is a key quality trait related to alterations in cuticle properties and remodelling of the fruit cell walls. Studies with transgenic tomato plants undertaken over the last 20 years have indicated that a range of pectin degrading enzymes are involved in cell wall remodelling. These studies usually involved silencing of only a single gene and it has proved difficult to compare the effects of silencing these genes across the different experimental systems. Here we report the generation of CRISPR-based mutants in the ripening-related genes encoding the pectin degrading enzymes pectate lyase (PL), polygalacturonase 2a (PG2a) and beta-galactanase (TBG4). Comparison of the physiochemical properties of the fruits from a range of PL, PG2a and TBG4 CRISPR lines demonstrated that only mutations in PL resulted in firmer fruits, although mutations in PG2a and TBG4 influenced fruit colour and weight. Pectin localisation, distribution and solubility in the pericarp cells of the CRISPR mutant fruits were investigated using the monoclonal antibody probes LM19 to de-esterified homogalacturonan (HG), INRA-RU1 to rhamnogalacturonan I, LM5 to beta1-4-galactan and LM6 to arabinan epitopes, respectively. The data indicate that PL, PG2a and TBG4 act on separate cell wall domains and the importance of cellulose microfibril-associated pectin is reflected in its increased occurrence in the different mutant lines. PMID- 30459264 TI - Auxin and pattern formation of the Asteraceae flower head (capitulum). AB - Nature often creates complex structures by rearranging pre-existing units. One such example is the flower head (capitulum) in daisies, where a group of flowers (florets) and phyllaries (modified bracts) are arranged to superficially mimic a single flower. The capitulum is a key taxonomical innovation that defines the daisy family (Asteraceae), the largest flowering plant group. However, patterning mechanisms underlying its structure remain elusive. Here, we show that auxin, a plant hormone, provides a developmental patterning cue for the capitulum. During capitulum development, a temporal auxin gradient occurs, regulating the successive and centripetal formation of distinct florets and phyllaries. Disruption of the endogenous auxin gradient led to homeotic conversions of florets and phyllaries in the capitulum. Furthermore, auxin regulates floral meristem identity genes, such as Matricaria inodora RAY2 and Matricaria inodora LFY, which determine floret and phyllary identity. This study reveals the mechanism of capitulum patterning and highlights how common developmental tools, such as hormone gradients, have independently evolved in plants and animals. PMID- 30459265 TI - The Largest Subunit of DNA Polymerase Delta is Required for Normal Formation of Meiotic Type I Crossovers. AB - Meiotic recombination contributes to the maintenance of association between homologous chromosomes (homologs) and ensures the accurate segregation of homologs during anaphase I, thus facilitating the redistribution of alleles among progeny. As in the experimentally supported double strand break repair (DSBR) model, meiotic recombination is initiated by the programmed formation of DNA double strand breaks (DSBs). DSB repair requires DNA synthesis, but the role of DNA synthesis proteins during meiosis is largely unknown. Our previous analysis of DNA Replication Factor 1 suggested a role for lagging strand synthesis in meiotic recombination, raising the possibility that the lagging strand-specific DNA polymerase delta might be important for meiotic recombination. Null mutants of the catalytic subunit of POL delta, encoded by AtPOLD1, are embryo lethal, so we used a meiocyte-specific knockdown strategy to test this hypothesis. We found that reduced expression of AtPOLD1 in meiocytes causes decreased fertility and meiotic defects, including incomplete synapsis, formation of multivalents, improper segregation, and chromosome fragmentation. Analysis of meiotic crossover (CO) frequencies showed that the AtPOLD1RNAi plants have significantly fewer interference-sensitive COs than wild type, indicating that AtPOL delta participates in Type I CO formation. The AtPOLD1RNAi atpol2a double mutant meiocytes displayed more severe meiotic phenotypes than those of either single mutant, suggesting that their functions are not identical in meiotic recombination. Given that POL delta is highly conserved among eukaryotes, we hypothesize that this newly described role for POL delta in meiotic recombination likely exists widely in eukaryotes. PMID- 30459266 TI - A synthetic oxygen sensor for plants based on animal hypoxia signalling. AB - Due to the involvement of oxygen in many essential metabolic reactions, all living organisms have developed molecular systems that allow adaptive physiological and metabolic transitions depending on oxygen availability. In mammals, the expression of hypoxia-response genes is controlled by the heterodimeric Hypoxia-Inducible Factor (HIF). The activity of this transcriptional regulator is mainly linked to the oxygen-dependent hydroxylation of conserved proline residues in its alpha subunit, carried out by Prolyl Hydroxylases (PHDs), and subsequent ubiquitination via the E3 ligase von Hippel Lindau tumor suppressor (pVHL), which targets HIF-alpha to the proteasome. By exploiting bioengineered versions of this mammalian oxygen sensor, we designed and optimized a synthetic device that drives gene expression in an oxygen dependent fashion in plants. Transient assays in Arabidopsis thaliana mesophyll protoplasts indicated that a combination of the yeast Gal4/UAS system and the mammalian oxygen sensor machinery can be effectively used to engineer a modular, oxygen-inducible transcriptional regulator. This synthetic device was also shown to be selectively controlled by oxygen in whole plants, when its components were stably expressed in Arabidopsis seedlings. We envision the exploitation of our genetically encoded controllers to generate plants able to switch gene expression selectively depending on oxygen availability, thereby providing a proof-of concept for the potential of synthetic biology to assist agricultural practices in environments with variable oxygen provision. PMID- 30459267 TI - News Feature: Exposing the exposome to elucidate disease. PMID- 30459269 TI - What it takes for a cough to expel mucus from the airway. PMID- 30459270 TI - Bots increase exposure to negative and inflammatory content in online social systems. AB - Societies are complex systems, which tend to polarize into subgroups of individuals with dramatically opposite perspectives. This phenomenon is reflected and often amplified-in online social networks, where, however, humans are no longer the only players and coexist alongside with social bots-that is, software controlled accounts. Analyzing large-scale social data collected during the Catalan referendum for independence on October 1, 2017, consisting of nearly 4 millions Twitter posts generated by almost 1 million users, we identify the two polarized groups of Independentists and Constitutionalists and quantify the structural and emotional roles played by social bots. We show that bots act from peripheral areas of the social system to target influential humans of both groups, bombarding Independentists with violent contents, increasing their exposure to negative and inflammatory narratives, and exacerbating social conflict online. Our findings stress the importance of developing countermeasures to unmask these forms of automated social manipulation. PMID- 30459271 TI - Environmentalism, norms, and identity. PMID- 30459272 TI - Precise tracking of vaccine-responding T cell clones reveals convergent and personalized response in identical twins. AB - T cell receptor (TCR) repertoire data contain information about infections that could be used in disease diagnostics and vaccine development, but extracting that information remains a major challenge. Here we developed a statistical framework to detect TCR clone proliferation and contraction from longitudinal repertoire data. We applied this framework to data from three pairs of identical twins immunized with the yellow fever vaccine. We identified 600 to 1,700 responding TCRs in each donor and validated them using three independent assays. While the responding TCRs were mostly private, albeit with higher overlap between twins, they could be well-predicted using a classifier based on sequence similarity. Our method can also be applied to samples obtained postinfection, making it suitable for systematic discovery of new infection-specific TCRs in the clinic. PMID- 30459273 TI - Mechanistic insights into the interactions of NAP1 with the SKICH domains of NDP52 and TAX1BP1. AB - NDP52 and TAX1BP1, two SKIP carboxyl homology (SKICH) domain-containing autophagy receptors, play crucial roles in selective autophagy. The autophagic functions of NDP52 and TAX1BP1 are regulated by TANK-binding kinase 1 (TBK1), which may associate with them through the adaptor NAP1. However, the molecular mechanism governing the interactions of NAP1 with NDP52 and TAX1BP1, as well as the effects induced by TBK1-mediated phosphorylation of NDP52 and TAX1BP1, remains elusive. Here, we report the atomic structures of the SKICH regions of NDP52 and TAX1BP1 in complex with NAP1, which not only uncover the mechanistic bases underpinning the specific interactions of NAP1 with the SKICH domains of NDP52 and TAX1BP1 but also reveal the binding mode of a SKICH domain. Moreover, we uncovered that the SKICH domains of NDP52 and TAX1BP1 share a general binding mode to interact with NAP1. Finally, we also evaluated the currently known TBK1-mediated phosphorylation sites in the SKICH domains of NDP52 and TAX1BP1 on the basis of their interactions with NAP1. In all, our findings provide mechanistic insights into the interactions of NAP1 with NDP52 and TAX1BP1, and are valuable for further understanding the functions of these proteins in selective autophagy. PMID- 30459274 TI - Intrinsically ultrastrong plasmon-exciton interactions in crystallized films of carbon nanotubes. AB - In cavity quantum electrodynamics, optical emitters that are strongly coupled to cavities give rise to polaritons with characteristics of both the emitters and the cavity excitations. We show that carbon nanotubes can be crystallized into chip-scale, two-dimensionally ordered films and that this material enables intrinsically ultrastrong emitter-cavity interactions: Rather than interacting with external cavities, nanotube excitons couple to the near-infrared plasmon resonances of the nanotubes themselves. Our polycrystalline nanotube films have a hexagonal crystal structure, ~25-nm domains, and a 1.74-nm lattice constant. With this extremely high nanotube density and nearly ideal plasmon-exciton spatial overlap, plasmon-exciton coupling strengths reach 0.5 eV, which is 75% of the bare exciton energy and a near record for room-temperature ultrastrong coupling. Crystallized nanotube films represent a milestone in nanomaterials assembly and provide a compelling foundation for high-ampacity conductors, low-power optical switches, and tunable optical antennas. PMID- 30459275 TI - Intrinsic cellular chirality regulates left-right symmetry breaking during cardiac looping. AB - The vertebrate body plan is overall symmetrical but left-right (LR) asymmetric in the shape and positioning of internal organs. Although several theories have been proposed, the biophysical mechanisms underlying LR asymmetry are still unclear, especially the role of cell chirality, the LR asymmetry at the cellular level, on organ asymmetry. Here with developing chicken embryos, we examine whether intrinsic cell chirality or handedness regulates cardiac C looping. Using a recently established biomaterial-based 3D culture platform, we demonstrate that chick cardiac cells before and during C looping are intrinsically chiral and exhibit dominant clockwise rotation in vitro. We further show that cells in the developing myocardium are chiral as evident by a rightward bias of cell alignment and a rightward polarization of the Golgi complex, correlating with the direction of cardiac tube rotation. In addition, there is an LR polarized distribution of N cadherin and myosin II in the myocardium before the onset of cardiac looping. More interestingly, the reversal of cell chirality via activation of the protein kinase C signaling pathway reverses the directionality of cardiac looping, accompanied by a reversal in cellular biases on the cardiac tube. Our results suggest that myocardial cell chirality regulates cellular LR symmetry breaking in the heart tube and the resultant directionality of cardiac looping. Our study provides evidence of an intrinsic cellular chiral bias leading to LR symmetry breaking during directional tissue rotation in vertebrate development. PMID- 30459276 TI - Design and in vitro realization of carbon-conserving photorespiration. AB - Photorespiration recycles ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) oxygenation product, 2-phosphoglycolate, back into the Calvin Cycle. Natural photorespiration, however, limits agricultural productivity by dissipating energy and releasing CO2 Several photorespiration bypasses have been previously suggested but were limited to existing enzymes and pathways that release CO2 Here, we harness the power of enzyme and metabolic engineering to establish synthetic routes that bypass photorespiration without CO2 release. By defining specific reaction rules, we systematically identified promising routes that assimilate 2-phosphoglycolate into the Calvin Cycle without carbon loss. We further developed a kinetic-stoichiometric model that indicates that the identified synthetic shunts could potentially enhance carbon fixation rate across the physiological range of irradiation and CO2, even if most of their enzymes operate at a tenth of Rubisco's maximal carboxylation activity. Glycolate reduction to glycolaldehyde is essential for several of the synthetic shunts but is not known to occur naturally. We, therefore, used computational design and directed evolution to establish this activity in two sequential reactions. An acetyl-CoA synthetase was engineered for higher stability and glycolyl-CoA synthesis. A propionyl-CoA reductase was engineered for higher selectivity for glycolyl-CoA and for use of NADPH over NAD+, thereby favoring reduction over oxidation. The engineered glycolate reduction module was then combined with downstream condensation and assimilation of glycolaldehyde to ribulose 1,5 bisphosphate, thus providing proof of principle for a carbon-conserving photorespiration pathway. PMID- 30459277 TI - Molecular structure of the ATP-bound, phosphorylated human CFTR. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel important in maintaining proper functions of the lung, pancreas, and intestine. The activity of CFTR is regulated by ATP and protein kinase A dependent phosphorylation. To understand the conformational changes elicited by phosphorylation and ATP binding, we present here the structure of phosphorylated, ATP-bound human CFTR, determined by cryoelectron microscopy to 3.2-A resolution. This structure reveals the position of the R domain after phosphorylation. By comparing the structures of human CFTR and zebrafish CFTR determined under the same condition, we identified common features essential to channel gating. The differences in their structures indicate plasticity permitted in evolution to achieve the same function. Finally, the structure of CFTR provides a better understanding of why the G178R, R352Q, L927P, and G970R/D mutations would impede conformational changes of CFTR and lead to cystic fibrosis. PMID- 30459278 TI - Antinuclear autoantibodies: discordance among four different assays. PMID- 30459280 TI - Local PCA Shows How the Effect of Population Structure Differs Along the Genome. AB - Population structure leads to systematic patterns in measures of mean relatedness between individuals in large genomic datasets, which are often discovered and visualized using dimension reduction techniques such as principal component analysis (PCA). Mean relatedness is an average of the relationships across locus specific genealogical trees, which can be strongly affected on intermediate genomic scales by linked selection and other factors. We show how to use local principal components analysis to describe this intermediate-scale heterogeneity in patterns of relatedness, and apply the method to genomic data from three species, finding in each that the effect of population structure can vary substantially across only a few megabases. In a global human dataset, localized heterogeneity is likely explained by polymorphic chromosomal inversions. In a range-wide dataset of Medicago truncatula, factors that produce heterogeneity are shared between chromosomes, correlate with local gene density, and may be caused by linked selection, such as background selection or local adaptation. In a dataset of primarily African Drosophila melanogaster, large-scale heterogeneity across each chromosome arm is explained by known chromosomal inversions thought to be under recent selection, and after removing samples carrying inversions, remaining heterogeneity is correlated with recombination rate and gene density, again suggesting a role for linked selection. The visualization method provides a flexible new way to discover biological drivers of genetic variation, and its application to data highlights the strong effects that linked selection and chromosomal inversions can have on observed patterns of genetic variation. PMID- 30459279 TI - Humanised effector-null FcgammaRIIA antibody inhibits immune complex-mediated proinflammatory responses. AB - OBJECTIVE: Immune complexes (ICs) play a critical role in the pathology of autoimmune diseases. The aim of this study was to generate and characterise a first-in-class anti-FcgammaRIIA antibody (Ab) VIB9600 (previously known as MEDI9600) that blocks IgG immune complex-mediated cellular activation for clinical development. METHODS: VIB9600 was humanised and optimised from the IV.3 Ab. Binding affinity and specificity were determined by Biacore and ELISA. Confocal microscopy, Flow Cytometry-based assays and binding competition assays were used to assess the mode of action of the antibody. In vitro cell-based assays were used to demonstrate suppression of IC-mediated inflammatory responses. In vivo target suppression and efficacy was demonstrated in FcgammaRIIA-transgenic mice. Single-dose pharmacokinetic (PK)/pharmacodynamic study multiple dose Good Laboratory Practice (GLP) toxicity studies were conducted in non-human primates. RESULTS: We generated a humanised effector deficient anti-FcgammaRIIA antibody (VIB9600) that potently blocks autoantibody and IC-mediated proinflammatory responses. VIB9600 suppresses FcgammaRIIA activation by blocking ligand engagement and by internalising FcgammaRIIA from the cell surface. VIB9600 inhibits IC-induced type I interferons from plasmacytoid dendritic cells (involved in SLE), antineutrophil cytoplasmic antibody (ANCA)-induced production of reactive oxygen species by neutrophils (involved in ANCA-associated vasculitis) and IC-induced tumour necrosis factor alpha and interleukin-6 production (involved in rheumatoid arthritis). In FcgammaRIIA transgenic mice, VIB9600 suppressed antiplatelet antibody-induced thrombocytopaenia, acute anti-GBM Ab-induced nephritis and anticollagen Ab induced arthritis. VIB9600 also exhibited favourable PK and safety profiles in cynomolgus monkey studies. CONCLUSIONS: VIB9600 is a specific humanised antibody antagonist of FcgammaRIIA with null effector function that warrants further clinical development for the treatment of IC-mediated diseases. PMID- 30459281 TI - Phosphoproteome and gene expression profiling of ALK inhibition in neuroblastoma cell lines reveals conserved oncogenic pathways. AB - Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that is a clinical target of major interest in cancer. Mutations and rearrangements in ALK trigger the activation of the encoded receptor and its downstream signaling pathways. ALK mutations have been identified in both familial and sporadic neuroblastoma cases as well as in 30 to 40% of relapses, which makes ALK a bona fide target in neuroblastoma therapy. Tyrosine kinase inhibitors (TKIs) that target ALK are currently in clinical use for the treatment of patients with ALK-positive non small cell lung cancer. However, monotherapy with the ALK inhibitor crizotinib has been less encouraging in neuroblastoma patients with ALK alterations, raising the question of whether combinatorial therapy would be more effective. In this study, we established both phosphoproteomic and gene expression profiles of ALK activity in neuroblastoma cells exposed to first- and third-generation ALK TKIs, to identify the underlying molecular mechanisms and identify relevant biomarkers, signaling networks, and new therapeutic targets. This analysis has unveiled various important leads for novel combinatorial treatment strategies for patients with neuroblastoma and an increased understanding of ALK signaling involved in this disease. PMID- 30459283 TI - Integrated proximal proteomics reveals IRS2 as a determinant of cell survival in ALK-driven neuroblastoma. AB - Oncogenic anaplastic lymphoma kinase (ALK) is one of the few druggable targets in neuroblastoma, and therapy resistance to ALK-targeting tyrosine kinase inhibitors (TKIs) comprises an inevitable clinical challenge. Therefore, a better understanding of the oncogenic signaling network rewiring driven by ALK is necessary to improve and guide future therapies. Here, we performed quantitative mass spectrometry-based proteomics on neuroblastoma cells treated with one of three clinically relevant ALK TKIs (crizotinib, LDK378, or lorlatinib) or an experimentally used ALK TKI (TAE684) to unravel aberrant ALK signaling pathways. Our integrated proximal proteomics (IPP) strategy included multiple signaling layers, such as the ALK interactome, phosphotyrosine interactome, phosphoproteome, and proteome. We identified the signaling adaptor protein IRS2 (insulin receptor substrate 2) as a major ALK target and an ALK TKI-sensitive signaling node in neuroblastoma cells driven by oncogenic ALK. TKI treatment decreased the recruitment of IRS2 to ALK and reduced the tyrosine phosphorylation of IRS2. Furthermore, siRNA-mediated depletion of ALK or IRS2 decreased the phosphorylation of the survival-promoting kinase Akt and of a downstream target, the transcription factor FoxO3, and reduced the viability of three ALK-driven neuroblastoma cell lines. Collectively, our IPP analysis provides insight into the proximal architecture of oncogenic ALK signaling by revealing IRS2 as an adaptor protein that links ALK to neuroblastoma cell survival through the Akt FoxO3 signaling axis. PMID- 30459282 TI - The HDAC3-SMARCA4-miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood with an unmet clinical need for decades. A single oncogenic fusion gene is associated with treatment resistance and a 40 to 45% decrease in overall survival. We previously showed that expression of this PAX3:FOXO1 fusion oncogene in alveolar RMS (aRMS) mediates tolerance to chemotherapy and radiotherapy and that the class I-specific histone deacetylase (HDAC) inhibitor entinostat reduces PAX3:FOXO1 protein abundance. Here, we established the antitumor efficacy of entinostat with chemotherapy in various preclinical cell and mouse models and found that HDAC3 inhibition was the primary mechanism of entinostat-induced suppression of PAX3:FOXO1 abundance. HDAC3 inhibition by entinostat decreased the activity of the chromatin remodeling enzyme SMARCA4, which, in turn, derepressed the microRNA miR-27a. This reexpression of miR-27a led to PAX3:FOXO1 mRNA destabilization and chemotherapy sensitization in aRMS cells in culture and in vivo. Furthermore, a phase 1 clinical trial (ADVL1513) has shown that entinostat is tolerable in children with relapsed or refractory solid tumors and is planned for phase 1B cohort expansion or phase 2 clinical trials. Together, these results implicate an HDAC3-SMARCA4-miR-27a-PAX3:FOXO1 circuit as a driver of chemoresistant aRMS and suggest that targeting this pathway with entinostat may be therapeutically effective in patients. PMID- 30459285 TI - [Effect of antidepressants in comorbid oncological and depressed patients]. AB - When facing comorbidity, effects of medicating one disorder on the other disease is a key question for the clinician. As depression influences both development and outcome of oncological diseases, early diagnosis and therapy, primarily with antidepressants, is of paramount importance. This paper gives a survey on the effects of antidepressants on comorbid mood disorders, on the course of cancerous diseases and on the tumor itself. Response to therapy is similar for patients with comorbid and primary depression, just as there is no significant difference in tolerability. Early studies have shown that antidepressants increase the risk of tumor development, have negative effects on the outcome of oncological diseases and even increase mortality. However, recent epidemiological and clinical studies show opposing results and demonstrate beneficial action of antidepressants on various oncological diseases such as glioma and hepatocellular cancer. Like any drug, antidepressants have effects not only on targets in the brain but also on other organs, hence on tumor tissues as well. Latest preclinical studies demonstrate that certain antidepressants facilitate apoptosis, autophagy of tumor cells and potentiate the efficacy of anticancer agents acting as chemosensitizers. Direct and indirect antitumor effects of antidepressants are proven, however, their clinical use requires further studies focusing on the specificity of agents on different tumor types. PMID- 30459284 TI - IFN-gamma-inducible antiviral responses require ULK1-mediated activation of MLK3 and ERK5. AB - It is well established that activation of the transcription factor signal transducer and activator of transcription 1 (STAT1) is required for the interferon-gamma (IFN-gamma)-mediated antiviral response. Here, we found that IFN gamma receptor stimulation also activated Unc-51-like kinase 1 (ULK1), an initiator of Beclin-1-mediated autophagy. Furthermore, the interaction between ULK1 and the mitogen-activated protein kinase kinase kinase MLK3 (mixed lineage kinase 3) was necessary for MLK3 phosphorylation and downstream activation of the kinase ERK5. This autophagy-independent activity of ULK1 promoted the transcription of key antiviral IFN-stimulated genes (ISGs) and was essential for IFN-gamma-dependent antiviral effects. These findings define a previously unknown IFN-gamma pathway that appears to be a key element of the antiviral response. PMID- 30459286 TI - [Psychological disorders and tumorous diseases]. AB - Oncopsychology affects and intensively increasing number of patients due to the growing prevalence of cancers and the rapid development of oncological therapies. The comorbidity between tumorous diseases and psychiatric disorders has been known for a long time but its significance has become outstanding in the recent years. The relationship between these two types of disorders is considerably complex and may have determining consequences for clinical practice therefore dealing with these conditions is a serious challenge for clinicians. Our knowledge concerning the association of mental illnesses and oncological diseases has been undergoing a significant change in recent years thanks to big data researches and more precise measurements of psychiatric phenotypes. This review provides a summary of the latest epidemiological results related to comorbitiy between mental and oncological illnesses. The novel, more sophisticated studies reinforce the importance of managing comorbid patients in a multidisciplinary team. PMID- 30459287 TI - [The role of positron emission tomography (PET) in tumor diagnostics and therapy monitoring]. AB - Positron emission tomography (PET) is a medical imaging method belonging to the realm of nuclear medicine. It has been a clinical research tool since the sixties but during the late nineties it became widely utilized in clinical practice too. PET technique requires special radioactive isotopes, which may be generated only in particle accelerators (cyclotrons) and their transport is limited owing to the short physical half-life. PET/CT was born from the combination of PET and CT (computer tomography). The first combined PET/CT scanner began to operate in 1998 and the method has been used in clinical practice since 2001. It is a hybrid (multi-modality) medical imaging equipment which can provide anatomical, morphologic (CT) and functional, metabolic information (PET) simultaneously. PET/CT imaging has gained clinical acceptance mainly in oncology - owing to the attributes of the most frequently used PET tracer, fluoro-deoxy glucose (FDG) - and in a lesser extent in neuropsychiatry and cardiology. The authors in this paper review the basics and key indications of the method, the wider used radiofarmacons, including potential neurological and psychiatric applications, and the possible causes of false positivity and false negativity. PMID- 30459288 TI - [Chemobrain]. AB - Over the past ten years, in oncology there is an increased interest in understanding the cognitive dysfunction caused by chemotherapy also known as chemobrain or chemofog. As a result of oncological therapies the number of survivors of malignant diseases has increased considerably, but the side effects also appear to be more prevalent and severe including persistent cognitive symptoms. Symptoms of chemobrain include memory impairment, loss of concentration, speech and psychomotor deceleration, attention and learning coordination problems, and disturbance of executive functions. The symptoms may be transient but are often long-lasting, the latter negatively affecting functionality and quality of life. Structural and functional imaging studies (MRI, fMRI, PET) and neuropsychological tests are not consistent in the diagnosis of chemobrain. Several factors are suspected leading to the appearance of symptoms, but the specific patomechanism is not yet known. Nutrition status, age, anemia, inflammatory cytokines, stress, and depression can all affect the quality of life and may be related to cognitive symptoms. Currently, there is no treatment strategy for preventing or alleviating cognitive impairement related to chemobrain, and several pharmacotherapies are under investigation. Results imply that understanding the patomechanism of chemobrain can also yield a deeper understanding of cognitive dysfunction associated with depression. PMID- 30459289 TI - Prevalence of alopecia in gray seals Halichoerus grypus atlantica in Massachusetts, USA, 2004-2013. AB - There has been an increase in the presence of alopecia among gray seals Halichoerus grypus atlantica in Massachusetts, USA. To understand the prevalence and describe the presentation of this condition, data records and photographs of 10070 gray seals from 2004-2013 were reviewed; there were sufficient data to confidently assess the presence or absence of alopecia in 2134 seals. Mild hair loss presented in multifocal patches with minimal to no skin lesions or erythema. In severe cases, alopecia was concentrated over the dorsal head, neck, and shoulders and extended down the ventrum, affecting >50% of the body. Associated skin lesions and erythema were often present. Alopecia was documented in 7.1% of the surveyed seals, and was centered in Nantucket. Alopecia was more prevalent in stranded/sighted animals in spring and summer, with 81% of cases documented from April to July. There was no sex bias, and weanlings were the most affected age class (38%). The etiology for alopecia in Massachusetts gray seals is unknown. Possible causes of alopecia in wildlife are infectious disease, nutritional deficiencies, endocrinopathies, or chronic physiologic stress. High population density around Nantucket may escalate intraspecific competition for resources, which may indirectly lead to stress-induced immunosuppression or nutritional deficiencies. Crowded haul-out sites increase the opportunity for disease transmission. The weanling age class may be prone to alopecia due to naive immune systems and inexperienced foraging capabilities. Diagnostic sample collection from gray seals will be required to characterize the etiology, pathogenesis, and significance of alopecia in this population. PMID- 30459290 TI - First report of carp edema virus in the mortality of wild common carp Cyprinus carpio in North America. AB - Carp edema virus (CEV) is an unclassified poxvirus that infects skin and gill tissue to cause koi sleepy disease. In the USA, CEV was first detected in 1996 in a California koi wholesaler, and has since been reported sporadically only within imported and domestic koi. Common carp Cyprinus carpio are a non-native species now present in most waterways in the USA. In May 2017, >526 large adult common carp in spawning condition died in Mill Pond, Park Ridge, NJ, USA. The water temperature during the kill was 15 degrees C and the affected fish displayed marked lethargy prior to death. The presence of CEV was confirmed by endpoint PCR, real-time quantitative PCR (qPCR), and transmission electron microscopy (TEM), making this the first report of CEV associated with a wild carp kill in North America. Phylogenetic analysis of a region of the 4a gene encoding the major core protein clustered the CEV strain among others in genogroup I, which includes CEV strains previously detected in common carp cultured in Europe. Gill histopathology included severe lamellar fusion and apoptosis in the interlamellar region and TEM identified cytoplasmic virions consistent in morphology with CEV in the branchial epithelial cells. Five months following the mortality, surviving fish were collected and screened for CEV by purifying and concentrating virus from the gills and testing with qPCR. No evidence of CEV was found, supporting previous studies showing CEV is not detectable in gills after abatement of clinical signs. PMID- 30459291 TI - Wild fish are negligible transmitters of viral haemorrhagic septicaemia virus (VHSV) genotype Id in the VHS restriction zone in Finland. AB - Wild fish were suspected to be the source of reinfection by viral haemorrhagic septicaemia virus (VHSV) in Finnish brackish water rainbow trout farms located in a restriction zone regarding viral haemorrhagic septicaemia (VHS) comprising the entire Province of Aland, Baltic Sea, in the 2000s. Altogether, 1636 wild fish of 17 different species living in the vicinity of infected fish farms were screened for VHSV during the years 2005-2008. Additionally, 2 uninfected wild fish species as well as farmed whitefish were introduced into a VHS-positive fish farm to test whether they became infected by VHSV from the clinically diseased rainbow trout. Wild fish did not test positive for VHSV on any occasion. In contrast, whitefish introduced to a VHS-positive farm were infected with VHSV genotype Id and started to replicate the virus for a short time during the trial. Whitefish are farmed together with, or in the vicinity of, farmed rainbow trout in the study area and, according to this study, are a possible source of the recurring infection in the restriction area. A sprivivirus was isolated from all fish species in the infection trial without causing mortality in the test groups. PMID- 30459292 TI - Population dynamics and development of the rhizocephalan Sacculina carcini, parasitic on the shore crab Carcinus maenas. AB - The ecologically important shore crab Carcinus maenas is commonly infected in its native range by the rhizocephalan Sacculina carcini. However, several aspects of this host-parasite interaction are poorly understood. Here, we analyse data from approximately 60000 Danish crabs to unravel factors governing infection patterns in time and space, and according to host sex and size. Female crabs were more frequently infected (12.6%) than males (7.9%). Sites with high salinity supported the highest infection prevalence. Infection prevalence peaked in summer (10 to 15%) and winter (20 to 35%) due in part to emergence of virginal externae in summer (main outbreak) and autumn (minor outbreak) preceded by peaks in crabs with lost externa (scars). Younger externae and scars dominated among males, whereas adult externae were most frequent among females. Infection prevalence increased with size in females but decreased in males, and modified (feminized) males showed lower scar frequency than unmodified ones. Modified males occurred frequently among the smaller size classes, whereas unmodified males dominated the larger size classes. Externa size was positively related to host size in both genders (same linear relationship). Molecular analyses suggested that hosts below 16 mm in carapace width do not become infected. Dissections of infected hosts revealed marked reduction of ovaries, whereas testes were unaffected by sacculinization. Our study demonstrates great spatio-temporal variation in infection prevalence mainly related to the parasite's life history. S. carcini appears capable of infecting all host sizes except the smallest. Owing to incomplete feminization of males, infections are rapidly lost from the larger and highly profitable male hosts. PMID- 30459293 TI - Microbiome dynamics of two differentially resilient corals. AB - Coral bleaching and disease are 2 common occurrences that are contributing to global coral cover decline. Understanding the interactions between the coral animal and its microbial associates, and how they may change in the presence of stressors such as warming and acidification, is a crucial component to understanding both susceptibility and resistance to disease and bleaching. The coral Diploria labyrinthiformis has been shown to be more disease resistant than its relative Pseudodiploria strigosa, providing an ideal study system for disease resistance. In this study, we examined the bacterial communities of these 2 coral species on the Florida Reef tract every 6 mo for 18 mo (in situ sampling), and under experimental (laboratory) thermal and pH manipulation. The in situ sampling encompassed wide fluctuations in temperature, including an anomalously warm summer period. The laboratory experiments involved exposure to both increased temperature (31 degrees C) and lowered pH (7.7). The in situ bacterial communities of both coral species were highly similar in the winter, but diverged during summer, with the D. labyrinthiformis bacterial community being more stable than that of P. strigosa. Differences in the bacterial community between the 2 coral species included 29 operational taxonomic units (OTUs) that were specific to D. labyrinthiformis in all seasons, while only 2 OTUs were specific to P. strigosa. The comparative stability of the D. labyrinthiformis microbiome, in addition to harboring a more specific microbiome, may be a key component of the relative disease resistance of this coral. PMID- 30459294 TI - Omphalitis, urachocystitis and septicemia by Streptococcus dysgalactiae in a southern right whale calf Eubalaena australis, Brazil. AB - Southern right whales Eubalaena australis (SRW) use the southern coast of Brazil as a wintering and calving ground. Other than anthropogenic threats, there is limited knowledge on health and disease aspects for this species. We report the gross and microscopic findings and microbiological identification of streptococcal septicemia in a SRW calf. Main gross findings included fibrinosuppurative omphalitis and urachocystitis, suppurative cystitis, valvular endocarditis and myocarditis, embolic pneumonia, suppurative myositis and osteoarthritis, and lymphadenomegaly. Histological examination confirmed the above inflammatory processes and indicated disseminated Gram-positive coccoid septicemia. PCR analysis, based on the 16S rRNA gene from bacteria isolated on blood agar, identified Streptococcus dysgalactiae. Pathologic and microbiologic analysis indicated that beta-hemolytic S. dysgalactiae septicemia, presumably initiated as ascending omphalic infection, was responsible for stranding and death in this individual. These results further confirm pathogenicity of streptococci in cetaceans and add to the limited health and disease related pathology knowledge for this species. PMID- 30459295 TI - Widespread occurrence of the antifungal cutaneous bacterium Janthinobacterium lividum on Andean water frogs threatened by fungal disease. AB - Amphibian diversity has declined due to the infectious disease chytridiomycosis, caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd). Coexistence between amphibian hosts and this pathogen in some locations is attributed to the presence of the cutaneous bacterium Janthinobacterium lividum (Jliv). This microbe inhibits the growth of Bd on the host, reduces morbidity, and improves survival. Andean water frogs in the genus Telmatobius seem to be particularly vulnerable to the disease yet populations of T. intermedius and T. marmoratus persist in southern and central Peru. We investigated the presence of Jliv on these 2 frog species and assessed the relationship of Jliv presence with prevalence and intensity of Bd infection. By sampling 125 frogs from 7 streams (3323-3950 m a.s.l.) and 27 from a city market, we found spatial variation in the mutualism among populations (range 0-40% proportion of Jliv-positives). Overall, 57% of frogs were infected with Bd, 12.5% of frogs hosted both Jliv and Bd, while 7.2% hosted just Jliv. We found that the probability of an individual being infected with Bd was independent of the presence of Jliv; however, we did detect a protective effect of Jliv with respect to intensity of infection. The extent of Jliv distribution in the high Andes stands in stark contrast to the rarity of Jliv on frogs in lower elevation cloud forest biomes. PMID- 30459296 TI - Toxics source reduction and sewage upgrades eliminated winter flounder liver neoplasia (1984-2017) from Boston Harbor, MA, USA. AB - Chemical carcinogen biomarkers can validate public investment in environmental remediation. A major factor driving the clean-up of Boston Harbor, MA, USA, induced by the federal Clean Water Act legislation of 1972, was the high prevalence of petroleum and halogenated aromatic hydrocarbon contaminant associated liver neoplasia in winter flounder Pseudopleuronectes americanus in the harbor in the 1980s. In the present study, we examined the spatial and temporal relationships between the suspended solids and contaminants in the municipal sewage discharge, and liver neoplasia and histopathology in flounder, from 1987 to 2017. Toxics source reduction, sewage treatment, and sludge removal in the 1990s and outfall relocation offshore in 2000 enabled a decreasing prevalence of persistent toxic chemicals in flounder, effluent, and sediment, and consequent disappearance of liver neoplasia and reduction of neoplasm-associated, hydropically vacuolated biliary epithelial cells to background levels. This supports long-term investment in elimination and treatment of anthropogenic waste streams and the value of federal regulatory mandates to maintain and improve regional environmental quality. PMID- 30459297 TI - Appearance of an anomalous black band disease at upper mesophotic depths after coral bleaching. AB - In the summer of 2016, extensive coral bleaching occurred on the coral reefs of Okinawa, Japan, which was often lethal in shallow waters. In November 2016, after the coral bleaching event, an anomalous black band disease (ABBD) was noticed during regular monitoring of the Pachyseris-dominated upper mesophotic Ryugu Reef in Okinawa. We subsequently conducted 10 * 1 m belt transects in deeper (30-35 m depth, n = 5) and shallower areas (27-29 m, n = 7) of the reef and obtained data on coral percentage coverage, Pachyseris percentage coverage, occurrence (numbers of lesions) of ABBD, and ABBD percentage coverage on Pachyseris. Both depths showed high live coral coverage (>90%), indicating little mortality from the summer 2016 bleaching event, and Pachyseris percentage coverage was significantly higher in the deeper area (mean +/- SD = 48.6 +/- 45.0%) compared to the shallower area (5.1 +/- 5.0%). Additionally, although numbers of ABBD occurrences (= lesions) were significantly higher in the deeper area (81.0 +/- 52.8 as opposed to 8.3 +/- 6.7 at shallower depths), total ABBD percentage coverage on Pachyseris was not significantly different between shallow and deep areas (7.0 +/ 3.2% versus 4.7 +/- 3.6%). ABBD was observed to be Pachyseris-specific at Ryugu Reef. These results indicate that similar to shallower reefs, mesophotic reefs can experience increased disease occurrences subsequent to non-lethal coral bleaching events. PMID- 30459298 TI - Isolated Fornix Infarction with Damage to the Limbic System as a Cause of Persistent Amnesia: A Case Report. AB - BACKGROUND The fornix is a white matter tract bundle that acts as the major output of the hippocampus and is an important component of the Papez circuit. We present an instructive imaging case of sudden onset of persistent amnesia due to selective ischemic damage of the anterior fornix. CASE REPORT A 54-year-old Japanese male came to our attention for a sudden onset of retrograde amnesia, associated with severe anterograde amnesia. The brain magnetic resonance imaging demonstrated a bright diffusion restriction, which was associated with swollen fornices bilaterally. His symptoms gradually improved, but episodic memory impairment still persisted after 1 month. The coronal T1-weighted MPRAGE (magnetization-prepared rapid acquisition with gradient echo) sequence clearly showed disruption of the left anterior fornix. Diffusion tensor tracking showed decrease in the density of entire fiber tracts on the Papez circuit as well as location of the left fornix. CONCLUSIONS When dealing with sudden, persistent amnesia associated with small fornix infarction, it is prudent to consider the possibility of tract damage along with limbic system damage using MPRAGE sequence. PMID- 30459299 TI - Methylenetetrahydrofolate Dehydrogenase 1 (MTHFD1) is Underexpressed in Clear Cell Renal Cell Carcinoma Tissue and Transfection and Overexpression in Caki-1 Cells Inhibits Cell Proliferation and Increases Apoptosis. AB - BACKGROUND The aims of this study were to investigate the expression of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) in human tissue containing clear cell renal cell carcinoma (CCRCC) compared with normal renal tissue, and the effects of upregulating the expression of MTHFD1 in the human CCRCC cell line, Caki-1. MATERIAL AND METHODS Tumor and adjacent normal renal tissue were obtained from 44 patients who underwent radical nephrectomy for CCRCC. Caki-1 human CCRCC cells were divided into the control group, the empty vector (EV) group, and the plasmid-treated group that overexpressed MTHFD1. MTHFD1 mRNA and protein levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot, respectively. The cell counting kit-8 (CCK-8) assay measured cell viability. Flow cytometry evaluated apoptosis and the cell cycle. Western blot measured the protein levels of MTHFD1, Bax, Bcl-2, Akt, p53, and cyclin D1, and qRT-PCR determined the gene expression profiles. RESULTS MTHFD1 mRNA and protein levels in CCRCC tumor tissues were significantly lower compared with adjacent normal renal tissue. MTHFD1 over-expression in Caki-1 cells inhibited cell proliferation, arrested cells in the G1 phase, increased cell apoptosis, and upregulated gene and protein expression of Bax/Bcl-2 and p53 and inhibited p-Akt, and cyclin D1. CONCLUSIONS MTHFD1 was underexpressed in CCRCC tissue when compared with normal renal tissue. MTHFD1 transfection of human CCRCC Caki-1 cells in vitro inhibited cell proliferation and promoted apoptosis, associated with reduced expression of cyclin D1, reduced Akt phosphorylation, and increased expression of Bax/Bcl-2 and p53. PMID- 30459300 TI - Melatonin protects endothelial progenitor cells against AGE-induced apoptosis via autophagy flux stimulation and promotes wound healing in diabetic mice. AB - Wound healing is delayed in diabetic patients. Increased apoptosis and endothelial progenitor cell (EPC) dysfunction are implicated in delayed diabetic wound healing. Melatonin, a major secretory product of the pineal gland, promotes diabetic wound healing; however, its mechanism of action remains unclear. Here, EPCs were isolated from the bone marrow of mice. Treatment of EPCs with melatonin alleviated advanced glycation end product (AGE)-induced apoptosis and cellular dysfunction. We further examined autophagy flux after melatonin treatment and found increased light chain 3 (LC3) and p62 protein levels in AGE-treated EPCs. However, lysosome-associated membrane protein 2 expression was decreased, indicating that autophagy flux was impaired in EPCs treated with AGEs. We then evaluated autophagy flux after melatonin treatment and found that melatonin increased the LC3 levels, but attenuated the accumulation of p62, suggesting a stimulatory effect of melatonin on autophagy flux. Blockage of autophagy flux by chloroquine partially abolished the protective effects of melatonin, indicating that autophagy flux is involved in the protective effects of melatonin. Furthermore, we found that the AMPK/mTOR signaling pathway is involved in autophagy flux stimulation by melatonin. An in vivo study also illustrated that melatonin treatment ameliorated impaired wound healing in a streptozotocin induced diabetic wound healing model. Thus, our study shows that melatonin protects EPCs against apoptosis and dysfunction via autophagy flux stimulation and ameliorates impaired wound healing in vivo, providing insight into its mechanism of action in diabetic wound healing. PMID- 30459301 TI - Characterising routes of H5N1 and H7N9 spread in China using Bayesian phylogeographical analysis. AB - Avian influenza H5N1 subtype has caused a global public health concern due to its high pathogenicity in poultry and high case fatality rates in humans. The recently emerged H7N9 is a growing pandemic risk due to its sustained high rates of human infections, and recently acquired high pathogenicity in poultry. Here, we used Bayesian phylogeography on 265 H5N1 and 371 H7N9 haemagglutinin sequences isolated from humans, animals and the environment, to identify and compare migration patterns and factors predictive of H5N1 and H7N9 diffusion rates in China. H7N9 diffusion dynamics and predictor contributions differ from H5N1. Key determinants of spatial diffusion included: proximity between locations (for H5N1 and H7N9), and lower rural population densities (H5N1 only). For H7N9, additional predictors included low avian influenza vaccination rates, low percentage of nature reserves and high humidity levels. For both H5N1 and H7N9, we found viral migration rates from Guangdong to Guangxi and Guangdong to Hunan were highly supported transmission routes (Bayes Factor > 30). We show fundamental differences in wide-scale transmission dynamics between H5N1 and H7N9. Importantly, this indicates that avian influenza initiatives designed to control H5N1 may not be sufficient for controlling the H7N9 epidemic. We suggest control and prevention activities to specifically target poultry transportation networks between Central, Pan-Pearl River Delta and South-West regions. PMID- 30459303 TI - Correction to: ZIKA virus elicits P53 activation and genotoxic stress in human neural progenitors similar to mutations involved in severe forms of genetic microcephaly. AB - The authors wish to point out that the name of the first author is appearing incorrectly on Pubmed: it should be El Ghouzzi V (and not Ghouzzi VE). In addition, the words "and p53" appear at the end of the title in the original publication ( https://www.nature.com/articles/cddis2016266 ) and in the previous erratum version ( https://www.nature.com/articles/cddis2016446 ). This is not correct. PMID- 30459302 TI - A neonatal mouse model of central nervous system infections caused by Coxsackievirus B5. AB - As one of the key members of the coxsackievirus B group, coxsackievirus B5 (CV B5) can cause many central nervous system diseases, such as viral encephalitis, aseptic meningitis, and acute flaccid paralysis. Notably, epidemiological data indicate that outbreaks of CV-B5-associated central nervous system (CNS) diseases have been reported worldwide throughout history. In this study, which was conducted to promote CV-B5 vaccine and anti-virus drug research, a 3-day-old BALB/c mouse model was established using a CV-B5 clinical isolate (CV-B5/JS417) as the challenge strain. Mice challenged with CV-B5/JS417 exhibited a series of neural clinical symptoms and death with necrosis of neuronal cells in the cerebral cortex and the entire spinal cord, hindlimb muscles, and cardiomyocytes. The viral load of each tissue at various post-challenge time points suggested that CV-B5 replicated in the small intestine and was subsequently transmitted to various organs via viremia; the virus potentially entered the brain through the spinal axons, causing neuronal cell necrosis. In addition, this mouse model was used to evaluate the protective effect of a CV-B5 vaccine. The results indicated that both the inactivated CV-B5 vaccine and anti-CVB5 serum significantly protected mice from a lethal infection of CV-B5/JS417 by producing neutralizing antibodies. In summary, the first CV-B5 neonatal mouse model has been established and can sustain CNS infections in a manner similar to that observed in humans. This model will be a useful tool for studies on pathogenesis, vaccines, and anti viral drug evaluations. PMID- 30459304 TI - Muscarinic acetylcholine receptor 3 mediates vagus nerve-induced gastric cancer. AB - Increasing evidence shows that the vagus nerve plays an important role in tumourigenesis. However, the effects and underlying mechanisms of the vagus nerve on gastric cancer (GC) development have not been established. In this study, we performed a unilateral truncal vagotomy at the subdiaphragmatic level in a mouse xenograft GC model to study the effects of the vagus nerve on GC development. Gene microarray analysis was used to explore the mechanism underlying this process. Significantly altered genes and pathways were analysed by Kyoto Encyclopaedia of Genes and Genomes analysis tool. We also detected muscarinic acetylcholine receptor 3 (M3) mRNA and protein levels by quantitative real-time polymerase chain reaction and immunohistochemical staining in mouse stomach tissue. To further confirm the functional role of M3, an in vivo M3 selective antagonist (darifenacin) assay was applied. Finally, we determined the M3 protein levels in human GC tissues and paired non-cancerous gastric tissues by immunohistochemical staining. We found that the surgical vagotomy inhibited the development of GC in an orthotopic xenograft mouse model. Further analysis showed that multiple signalling pathways participated in this process and that M3 was a key factor in these pathways. We established that the M3 mRNA and protein levels decreased in the vagotomy group relative to the sham group. We also demonstrated that the M3 antagonist suppressed the development of GC. Finally, we revealed that M3 protein level was up-regulated in human GC tissues. In conclusions, we revealed the functional role of M3 on mediating the effects of the vagus nerve on GC. Our study contributes to understanding the mechanism underlying the interaction between GC and the vagus nerve and may help to identify new therapeutic targets for GC. PMID- 30459305 TI - Early childhood investment impacts social decision-making four decades later. AB - Early childhood educational investment produces positive effects on cognitive and non-cognitive skills, health, and socio-economic success. However, the effects of such interventions on social decision-making later in life are unknown. We recalled participants from one of the oldest randomized controlled studies of early childhood investment-the Abecedarian Project (ABC)-to participate in well validated interactive economic games that probe social norm enforcement and planning. We show that in a repeated-play ultimatum game, ABC participants who received high-quality early interventions strongly reject unequal division of money across players (disadvantageous or advantageous) even at significant cost to themselves. Using a multi-round trust game and computational modeling of social exchange, we show that the same intervention participants also plan further into the future. These findings suggest that high quality early childhood investment can result in long-term changes in social decision-making and promote social norm enforcement in order to reap future benefits. PMID- 30459306 TI - Tailoring atomic layer growth at the liquid-metal interface. AB - Engineering atomic structures at metal surfaces represents an important step in the development of novel nanomaterials and nanodevices, but relies predominantly on atomic/molecular beam epitaxy under ultrahigh vacuum conditions, where controlling the deposition processes remains challenging. By using solution-borne nanosized gold clusters as a precursor, here we develop a wet deposition protocol to the fabrication of atomically flat gold nanoislands, so as to utilize the dynamic exchange of surface-active molecules at the liquid-metal interface for manipulating the growth kinetics of ultrathin metallic nanostructures. While remarkable shape and size selection of gold nanoislands is observed, our experimental and theoretical investigations provide compelling evidences that organic adsorbates can impart a bias to the island orientation by preferred adsorption and alignment and intervene in the assembly and disassembly of adatom islands by complexing with Au adatoms. This approach offers a simple solution to regulate atomic layer growth of metals at ambient conditions. PMID- 30459307 TI - Author Correction: Atomically precise graphene etch stops for three dimensional integrated systems from two dimensional material heterostructures. AB - The original version of this Article contained an error in the second sentence of the second paragraph of the 'Electrical properties of fluorinated graphene contacts' section of the Results, which incorrectly read 'The mobility was calculated by the Drude model, MU = ne/sigma where MU, n, e, and sigma are the carrier mobility, carrier density, electron charge, and sheet conductivity, respectively'. The correct version states 'MU = sigma/ne ' in place of 'MU = ne/sigma '. This has been corrected in both the PDF and HTML versions of the Article. PMID- 30459308 TI - Bimodal sensing of guidance cues in mechanically distinct microenvironments. AB - Contact guidance due to extracellular matrix architecture is a key regulator of carcinoma invasion and metastasis, yet our understanding of how cells sense guidance cues is limited. Here, using a platform with variable stiffness that facilitates uniaxial or biaxial matrix cues, or competing E-cadherin adhesions, we demonstrate distinct mechanoresponsive behavior. Through disruption of traction forces, we observe a profound phenotypic shift towards a mode of dendritic protrusion and identify bimodal processes that govern guidance sensing. In contractile cells, guidance sensing is strongly dependent on formins and FAK signaling and can be perturbed by disrupting microtubule dynamics, while low traction conditions initiate fluidic-like dendritic protrusions that are dependent on Arp2/3. Concomitant disruption of these bimodal mechanisms completely abrogates the contact guidance response. Thus, guidance sensing in carcinoma cells depends on both environment architecture and mechanical properties and targeting the bimodal responses may provide a rational strategy for disrupting metastatic behavior. PMID- 30459309 TI - Using single nucleotide variations in single-cell RNA-seq to identify subpopulations and genotype-phenotype linkage. AB - Despite its popularity, characterization of subpopulations with transcript abundance is subject to a significant amount of noise. We propose to use effective and expressed nucleotide variations (eeSNVs) from scRNA-seq as alternative features for tumor subpopulation identification. We develop a linear modeling framework, SSrGE, to link eeSNVs associated with gene expression. In all the datasets tested, eeSNVs achieve better accuracies than gene expression for identifying subpopulations. Previously validated cancer-relevant genes are also highly ranked, confirming the significance of the method. Moreover, SSrGE is capable of analyzing coupled DNA-seq and RNA-seq data from the same single cells, demonstrating its value in integrating multi-omics single cell techniques. In summary, SNV features from scRNA-seq data have merits for both subpopulation identification and linkage of genotype-phenotype relationship. PMID- 30459310 TI - Retroactive and graded prioritization of memory by reward. AB - Many decisions are based on an internal model of the world. Yet, how such a model is constructed from experience and represented in memory remains unknown. We test the hypothesis that reward shapes memory for sequences of events by retroactively prioritizing memory for objects as a function of their distance from reward. Human participants encountered neutral objects while exploring a series of mazes for reward. Across six data sets, we find that reward systematically modulates memory for neutral objects, retroactively prioritizing memory for objects closest to the reward. This effect of reward on memory emerges only after a 24-hour delay and is stronger for mazes followed by a longer rest interval, suggesting a role for post-reward replay and overnight consolidation, as predicted by neurobiological data in animals. These findings demonstrate that reward retroactively prioritizes memory along a sequential gradient, consistent with the role of memory in supporting adaptive decision-making. PMID- 30459311 TI - Publisher Correction: Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes. AB - In the original PDF version of this article, affiliation 1, 'Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD), Neuherberg, Germany', was incorrectly given as 'Institute of Diabetes and Regeneration Research, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany '. This has now been corrected in the PDF version of the article; the HTML version was correct at the time of publication. PMID- 30459312 TI - Pannexin 1 inhibits rhabdomyosarcoma progression through a mechanism independent of its canonical channel function. AB - Rhabdomyosarcoma (RMS) is an aggressive soft tissue sarcoma of childhood thought to arise from impaired differentiation of skeletal muscle progenitors. We have recently identified Pannexin 1 (PANX1) channels as a novel regulator of skeletal myogenesis. In the present study, we determined that PANX1 transcript and protein levels are down-regulated in embryonal (eRMS) and alveolar RMS (aRMS) patient derived cell lines and primary tumor specimens as compared to differentiated skeletal muscle myoblasts and tissue, respectively. While not sufficient to overcome the inability of RMS to reach terminal differentiation, ectopic expression of PANX1 in eRMS (Rh18) and aRMS (Rh30) cells significantly decreased their proliferative and migratory potential. Furthermore, ectopic PANX1 abolished 3D spheroid formation in eRMS and aRMS cells and induced regression of established spheroids through induction of apoptosis. Notably, PANX1 expression also significantly reduced the growth of human eRMS and aRMS tumor xenografts in vivo. Interestingly, PANX1 does not form active channels when expressed in eRMS (Rh18) and aRMS (Rh30) cells and the addition of PANX1 channel inhibitors did not alter or reverse the PANX1-mediated reduction of cell proliferation and migration. Moreover, expression of channel-defective PANX1 mutants not only disrupted eRMS and aRMS 3D spheroids, but also inhibited in vivo RMS tumor growth. Altogether our findings suggest that PANX1 alleviates RMS malignant properties in vitro and in vivo through a process that is independent of its canonical channel function. PMID- 30459313 TI - Evaluating metabarcoding to analyse diet composition of species foraging in anthropogenic landscapes using Ion Torrent and Illumina sequencing. AB - DNA metabarcoding of faecal samples is being successfully used to study the foraging niche of species. We assessed the ability of two benchtop high throughput sequencing (HTS) platforms, to identify a large taxonomic array of food items from domestic cats Felis silvestris catus, including prey and human related food taxa (pet food and leftovers leaving undetectable solid remains in faeces). Scats from a captive feeding trial (n = 41) and from free-ranging individuals (n = 326) were collected and analysed using a cytb mini-barcode in independent PCR replicates on the Ion PGM and the MiSeq platforms. Outputs from MiSeq were more sensitive and reproducible than those from Ion PGM due to a higher sequencing depth and sequence quality on MiSeq. DNA from intact prey taxa was detected more often (82% of the expected occurrences) than DNA from pet food (54%) and raw fish and meat (31%). We assumed that this variability was linked to different degree of DNA degradation: The Ion PGM detected significantly less human-linked food, birds, field voles, murids and shrews in the field-collected samples than the MiSeq platform. Pooling the replicates from both platforms and filtering the data allowed identification of at least one food item in 87.4% of the field-collected samples. Our DNA metabarcoding approach identified 29 prey taxa, of which 25 to species level (90% of items) including 9 rodents, 3 insectivores, 12 birds and 1 reptile and 33 human-related food taxa of which 23 were identified to genus level (75% of items). Our results demonstrate that using HTS platforms such as MiSeq, which provide reads of sufficiently high quantity and quality, with sufficient numbers of technical replicates, is a robust and non invasive approach for further dietary studies on animals foraging on a wide range of food items in anthropogenic landscapes. PMID- 30459315 TI - Piezoresistive temperature sensors fabricated by a surface micromachining CMOS MEMS process. AB - This paper presents a micromachined monocrystalline silicon piezoresistive temperature sensor fabricated by a surface micromachining CMOS (Complementary Metal Oxide Semiconductor) MEMS (Micro-Electro-Mechanical System) process. The design of the temperature sensor is based on the structure of the multi-layer cantilever beam and the bimetallic effect. The temperature change of the cantilever beam is translated into the change of the piezoresistance's value. The test results show that the sensitivities of the sensors are 27.9 mV/ degrees C with 100 Omega/? piezoresistance between -40 degrees C to 60 degrees C and 7.4 mV/ degrees C with 400 Omega/? piezoresistance between -90 degrees C to 60 degrees C. The temperature sensor proposed in this paper can be used in radiosondes for its low operating temperature (as low as -90 degrees C), small size (below 1 mm2) and low heat capacity. PMID- 30459314 TI - p66Shc activation promotes increased oxidative phosphorylation and renders CNS cells more vulnerable to amyloid beta toxicity. AB - A key pathological feature of Alzheimer's disease (AD) is the accumulation of the neurotoxic amyloid beta (Abeta) peptide within the brains of affected individuals. Previous studies have shown that neuronal cells selected for resistance to Abeta toxicity display a metabolic shift from mitochondrial dependent oxidative phosphorylation (OXPHOS) to aerobic glycolysis to meet their energy needs. The Src homology/collagen (Shc) adaptor protein p66Shc is a key regulator of mitochondrial function, ROS production and aging. Moreover, increased expression and activation of p66Shc promotes a shift in the cellular metabolic state from aerobic glycolysis to OXPHOS in cancer cells. Here we evaluated the hypothesis that activation of p66Shc in CNS cells promotes both increased OXPHOS and enhanced sensitivity to Abeta toxicity. The effect of altered p66Shc expression on metabolic activity was assessed in rodent HT22 and B12 cell lines of neuronal and glial origin respectively. Overexpression of p66Shc repressed glycolytic enzyme expression and increased both mitochondrial electron transport chain activity and ROS levels in HT22 cells. The opposite effect was observed when endogenous p66Shc expression was knocked down in B12 cells. Moreover, p66Shc activation in both cell lines increased their sensitivity to Abeta toxicity. Our findings indicate that expression and activation of p66Shc renders CNS cells more sensitive to Abeta toxicity by promoting mitochondrial OXPHOS and ROS production while repressing aerobic glycolysis. Thus, p66Shc may represent a potential therapeutically relevant target for the treatment of AD. PMID- 30459316 TI - Mycorrhizal fungal community structure in tropical humid soils under fallow and cropping conditions. AB - Little is known to what extent soil biota, in particular, the mycorrhizae are altered through different fallow durations/types in tropical soils. We found that soil-N, -C, -Al, -K and -Ca contents significantly differed due to the fallow durations/types. Subsequently, the effects of fallow types and soil depths on the diversity, species richness and community structure of arbuscular mycorrhizal (AM) fungi were examined. A higher AM species richness was identified in the cropping than in forest fallow fields, suggesting a positive cropping feedback on the AM community composition. Distribution of the AM species was positively related to soil properties, specifically soil-pH, and soil-Pi, -Ca and -Mg contents. The soil properties conjointly accounted for 78.5% of explained variation in the AM community composition, signifying that the main factors altering the community structure under different fallow and cropping systems were the soil properties. Among the soil chemical characteristics, the soil-pH disclosed a significant explained variation in the AM community composition in the topsoil layer under the short fallow. Structural modeling equation to understand multiple predictive pathways that connect soil properties, fallow practices and AM community structures indicated that soil-C, -N and -Ca contents were highlighted as important factors influencing the AM community compositions. PMID- 30459317 TI - Novel Insect Florivory Strategy Initiates Autogamy in Unopened Allogamous Flowers. AB - Insects may influence plant development via pollination, galling, and a range of herbivorous interactions, including florivory. Here, we report a novel form of insect-plant interaction in the form of florivory-initiated autogamy. Mompha capella larvae, feeding on petal bases of Crocanthemum canadense before flowers open, while providing no benefit to the plant, cause autogamy and subsequent seed and fruit development. This interaction provides a clear benefit to the florivore because it enters the developing fruit and consumes most seeds; however, surviving seeds are viable. This novel interaction is discussed with respect to the dimorphic cleistogamous reproduction employed by this plant species. Moreover, this represents a previously undocumented insect-plant interaction in the form of a florivory-initiated pollination. PMID- 30459318 TI - A small molecule approach to degrade RAS with EGFR repression is a potential therapy for KRAS mutation-driven colorectal cancer resistance to cetuximab. AB - Drugs targeting the epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab, have been prescribed for metastatic colorectal cancer (CRC), but patients harboring KRAS mutations are insensitive to them and do not have an alternative drug to overcome the problem. The levels of beta-catenin, EGFR, and RAS, especially mutant KRAS, are increased in CRC patient tissues due to mutations of adenomatous polyposis coli (APC), which occur in 90% of human CRCs. The increases in these proteins by APC loss synergistically promote tumorigenesis. Therefore, we tested KYA1797K, a recently identified small molecule that degrades both beta-catenin and Ras via GSK3beta activation, and its capability to suppress the cetuximab resistance of KRAS-mutated CRC cells. KYA1797K suppressed the growth of tumor xenografts induced by CRC cells as well as tumor organoids derived from CRC patients having both APC and KRAS mutations. Lowering the levels of both beta-catenin and RAS as well as EGFR via targeting the Wnt/beta-catenin pathway is a therapeutic strategy for controlling CRC and other types of cancer with aberrantly activated the Wnt/beta-catenin and EGFR-RAS pathways, including those with resistance to EGFR-targeting drugs attributed to KRAS mutations. PMID- 30459319 TI - Transcriptome analysis provides insight into prickle development and its link to defense and secondary metabolism in Solanum viarum Dunal. AB - Prickles are epidermal outgrowth found on the aerial surface of several terrestrial plants. Microscopic studies on prickles of S. viarum Dunal indicated a crucial role of glandular trichomes (GTs) in their development. A spontaneously obtained prickleless mutant showed normal epidermal GTs, but its downstream developmental process to prickle was perturbed. Thus, prickleless mutant offers an ideal opportunity to unveil molecular regulators working downstream to GTs in the prickle formation. Differential transcriptome analysis of epidermis of prickly and prickleless mutant revealed that expression of several defense regulators like ethylene, salicylic acid, PR-proteins, etc. were significantly down-regulated in prickleless mutant, provide an important link between defense and prickle development. It was also noteworthy that the expression of few essential development related TFs like MADS-box, R2R3-MYB, REM, DRL1, were also down-regulated in the stem, petioles, and leaves of prickleless mutant indicating their potential role in prickle development. Interestingly, the gene expression of terpenoid, steroid, flavonoid, glucosinolate, and lignin biosynthesis pathways were up-regulated in prickleless mutant. The biochemical and qRT-PCR analysis also confirmed metabolite elevation. These results indicated that the loss of prickle was compensated by elevated secondary metabolism in the prickleless mutant which played important role in the biotic and abiotic stress management. PMID- 30459322 TI - Genome-wide identification and analysis of non-specific Lipid Transfer Proteins in hexaploid wheat. AB - Non-specific Lipid Transfer Proteins (nsLTPs) are involved in numerous biological processes. To date, only a fraction of wheat (Triticum aestivum L.) nsLTPs (TaLTPs) have been identified, and even fewer have been functionally analysed. In this study, the identification, classification, phylogenetic reconstruction, chromosome distribution, functional annotation and expression profiles of TaLTPs were analysed. 461 putative TaLTPs were identified from the wheat genome and classified into five types (1, 2, C, D and G). Phylogenetic analysis of the TaLTPs along with nsLTPs from Arabidopsis thaliana and rice, showed that all five types were shared across species, however, some type 2 TaLTPs formed wheat specific clades. Gene duplication analysis indicated that tandem duplications contributed to the expansion of this gene family in wheat. Analysis of RNA sequencing data showed that TaLTPs were expressed in most tissues and stages of wheat development. Further, we refined the expression profile of anther-enriched expressed genes, and identified potential cis-elements regulating their expression specificity. This analysis provides a valuable resource towards elucidating the function of TaLTP family members during wheat development, aids our understanding of the evolution and expansion of the TaLTP gene family and, additionally, provides new information for developing wheat male-sterile lines with application to hybrid breeding. PMID- 30459320 TI - Decreased microbial co-occurrence network stability and SCFA receptor level correlates with obesity in African-origin women. AB - We compared the gut microbial populations in 100 women, from rural Ghana and urban US [50% lean (BMI < 25 kg/m2) and 50% obese (BMI >= 30 kg/m2)] to examine the ecological co-occurrence network topology of the gut microbiota as well as the relationship of short chain fatty acids (SCFAs) with obesity. Ghanaians consumed significantly more dietary fiber, had greater microbial alpha-diversity, different beta-diversity, and had a greater concentration of total fecal SCFAs (p value < 0.002). Lean Ghanaians had significantly greater network density, connectivity and stability than either obese Ghanaians, or lean and obese US participants (false discovery rate (FDR) corrected p-value <= 0.01). Bacteroides uniformis was significantly more abundant in lean women, irrespective of country (FDR corrected p < 0.001), while lean Ghanaians had a significantly greater proportion of Ruminococcus callidus, Prevotella copri, and Escherichia coli, and smaller proportions of Lachnospiraceae, Bacteroides and Parabacteroides. Lean Ghanaians had a significantly greater abundance of predicted microbial genes that catalyzed the production of butyric acid via the fermentation of pyruvate or branched amino-acids, while obese Ghanaians and US women (irrespective of BMI) had a significantly greater abundance of predicted microbial genes that encoded for enzymes associated with the fermentation of amino-acids such as alanine, aspartate, lysine and glutamate. Similar to lean Ghanaian women, mice humanized with stool from the lean Ghanaian participant had a significantly lower abundance of family Lachnospiraceae and genus Bacteroides and Parabacteroides, and were resistant to obesity following 6-weeks of high fat feeding (p-value < 0.01). Obesity-resistant mice also showed increased intestinal transcriptional expression of the free fatty acid (Ffa) receptor Ffa2, in spite of similar fecal SCFAs concentrations. We demonstrate that the association between obesity resistance and increased predicted ecological connectivity and stability of the lean Ghanaian microbiota, as well as increased local SCFA receptor level, provides evidence of the importance of robust gut ecologic network in obesity. PMID- 30459323 TI - Mutational and phenotypic spectrum of phenylalanine hydroxylase deficiency in Zhejiang Province, China. AB - Phenylalanine hydroxylase deficiency (PAHD), one of the genetic disorders resulting in hyperphenylalaninemia, has a complex phenotype with many variants and genotypes among different populations. Here, we describe the mutational and phenotypic spectrum of PAHD in a cohort of 420 patients from neonatal screening between 1999 and 2016. The observed phenotypes comprised 43.57% classic phenylketonuria, 33.10% mild PKU, and 23.33% mild hyperphenylalaninemia, with an overall PAHD incidence of 1 in 20,445. Genetic testing was performed for 209 patients and 72 variants including seven novel variants were identified. These included two synonymous and five pathogenic nonsynonymous variants (p.S36*, p.T186I, p.L255W, p.F302V and p.R413H). The most common variant among all patients was p.R243Q, followed by p.R241C, p.Y204C, p.R111* and c.442-1G > A. Variants p.R53H and p.F392I occurred only in MHP with 19.3% and 8.0% of the observed alleles respectively. The genotypes p.[R241C];[R243Q], p.[R243Q];[R243Q], and p.[Y204C];[R243Q] were abundant across all PAHD patients. The distributions of the null allele and the three defined genotypes, null/null, null/missense, and missense/missense, were significantly different between the cPKU and mPKU patients. However, no significant differences were found between mPKU and MHP patients, indicating that other modifier factors influence the phenotypic outcome in these patients. The data presented here will provide a valuable tool for improved genetic counseling and management of future cases of PAHD in China. PMID- 30459321 TI - BAFopathies' DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin-Siris and Nicolaides-Baraitser syndromes. AB - Coffin-Siris and Nicolaides-Baraitser syndromes (CSS and NCBRS) are Mendelian disorders caused by mutations in subunits of the BAF chromatin remodeling complex. We report overlapping peripheral blood DNA methylation epi-signatures in individuals with various subtypes of CSS (ARID1B, SMARCB1, and SMARCA4) and NCBRS (SMARCA2). We demonstrate that the degree of similarity in the epi-signatures of some CSS subtypes and NCBRS can be greater than that within CSS, indicating a link in the functional basis of the two syndromes. We show that chromosome 6q25 microdeletion syndrome, harboring ARID1B deletions, exhibits a similar CSS/NCBRS methylation profile. Specificity of this epi-signature was confirmed across a wide range of neurodevelopmental conditions including other chromatin remodeling and epigenetic machinery disorders. We demonstrate that a machine-learning model trained on this DNA methylation profile can resolve ambiguous clinical cases, reclassify those with variants of unknown significance, and identify previously undiagnosed subjects through targeted population screening. PMID- 30459325 TI - Publisher Correction: A shear-dependent NO-cGMP-cGKI cascade in platelets acts as an auto-regulatory brake of thrombosis. AB - The original version of this Article contained an error in the description of Supplementary Movie 4, in which the final sentence was inadvertently truncated. The HTML has been updated to include a corrected version of the 'Description of Additional Supplementary Files' file. PMID- 30459324 TI - Large variability in the motility of spiroplasmas in media of different viscosities. AB - Spiroplasmas are bacteria that do not possess flagella and their motility is linked to kink propagation coupled to changes in the cell body helicity. While the motility of bacteria with flagellar motion has been studied extensively, less work has been devoted to the motility of spiroplasmas. We first show that the motility of such bacteria has large variability from individual to individual as well as large fluctuations in time. The Brownian motion of such bacteria both in orientation and translation is also highlighted. We propose a simple model to disentangle the different components of this motility by examining trajectories of single bacteria in different viscosity solvents. The mean velocity of the bacteria turns out to depend on the viscosity of the medium as it increases with viscosity. Further, the temporal fluctuations of the bacteria motility turn out to be very strong with a direct link to tumbling events particular to this bacteria. PMID- 30459327 TI - Publisher Correction: Effects of porosity on dynamic indentation resistance of silica nanofoam. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30459326 TI - Hybrid perovskite light emitting diodes under intense electrical excitation. AB - Hybrid perovskite semiconductors represent a promising platform for color-tunable light emitting diodes (LEDs) and lasers; however, the behavior of these materials under the intense electrical excitation required for electrically-pumped lasing remains unexplored. Here, we investigate methylammonium lead iodide-based perovskite LEDs under short pulsed drive at current densities up to 620 A cm-2. At low current density (J < 10 A cm-2), we find that the external quantum efficiency (EQE) depends strongly on the time-averaged history of the pulse train and show that this curiosity is associated with slow ion movement that changes the internal field distribution and trap density in the device. The impact of ions is less pronounced in the high current density regime (J > 10 A cm-2), where EQE roll-off is dominated by a combination of Joule heating and charge imbalance yet shows no evidence of Auger loss, suggesting that operation at kA cm-2 current densities relevant for a laser diode should be within reach. PMID- 30459328 TI - Exogenously applied growth regulators protect the cotton crop from heat-induced injury by modulating plant defense mechanism. AB - Episodes of extremely high temperature during reproductive stages of cotton crops are common in many parts of the world. Heat stress negatively influences plant growth, physiology and ultimately lint yield. This study attempts to modulate heat-induced damage to cotton crops via application of growth regulators e.g. hydrogen peroxide (H2O2 30ppm), salicylic acid (SA 50ppm), moringa leaf extract (MLE 30 times diluted) and ascorbic acid (ASA 70ppm). Cotton plants were exposed to different thermal regimes by staggering sowing time (field) or exposing to elevated temperatures (38/24 degrees C and 45/30 degrees C) for one week during reproductive growth stages (glasshouse). Elevated temperatures significantly induced lipid membrane damage, which was evident from an increased malondialdehyde (MDA) level in cotton leaves. Heat-stressed plants also experienced a significant reduction in leaf chlorophyll contents, net photosynthetic rate and lint yield. Hydrogen peroxide outclassed all the other regulators in increasing leaf SOD, CAT activity, chlorophyll contents, net photosynthetic rate, number of sympodial branches, boll weight and fiber quality components. For example, hydrogen peroxide improved boll weight of heat stressed plants by 32% (supra), 12% (sub) under glasshouse and 18% (supra) under field conditions compared with water treated plants under the same temperatures. Growth regulators, specifically, H2O2 protected physiological processes of cotton from heat-induced injury by capturing reactive oxygen species and modulating antioxidant enzymes. Thus, cotton performance in the future warmer climates may be improved through regulation (endogenous) or application (exogenous) hormones during reproductive phases. PMID- 30459329 TI - The discovered chimeric protein plays the cohesive role to maintain scallop byssal root structural integrity. AB - Adhesion is essential for many marine sessile organisms. Unraveling the compositions and assembly of marine bioadheisves is the fundamental to understand their physiological roles. Despite the remarkable diversity of animal bioadhesion, our understanding of this biological process remains limited to only a few animal lineages, leaving the majority of lineages remain enigmatic. Our previous study demonstrated that scallop byssus had distinct protein composition and unusual assembly mechanism apart from mussels. Here a novel protein (Sbp9) was discovered from the key part of the byssus (byssal root), which contains two Calcium Binding Domain (CBD) and 49 tandem Epidermal Growth Factor-Like (EGFL) domain repeats. Modular architecture of Sbp9 represents a novel chimeric gene family resulting from a gene fusion event through the acquisition of CBD2 domain by tenascin like (TNL) gene from Na+/Ca2+ exchanger 1 (NCX1) gene. Finally, free thiols are present in Sbp9 and the results of a rescue assay indicated that Sbp9 likely plays the cohesive role for byssal root integrity. This study not only aids our understanding of byssus assembly but will also inspire biomimetic material design. PMID- 30459330 TI - Pendimethalin-induced oxidative stress, DNA damage and activation of anti inflammatory and apoptotic markers in male rats. AB - Male Wistar rats were exposed to herbicide, pendimethalin (PND) at varying oral doses of 62.5, 125 and 250 mg/kg b.w. for 14 days. Toxiological effects were assessed in terms of oxidative stress, DNA damage, histopathological alterations and induction of anti-inflammatory and apoptotic responses linked Bax, Bcl-2, IFN gamma, TNF-alpha and caspase-3 gene expression. In comparison with respective untreated controls, all exposure groups of PND exhibited significant changes in the oxidative stress markers (protein carbonylation and lipid peroxidation) and antioxidant defenses (GSH, SOD, CAT and GST) in liver and kidney tissues. The histopathological changes including leucocyte infiltration, pyknotic nuclei, necrosis, large bowman's space, shrinked renal cortex, were observed in the liver and kidney tissues of PND exposed rats. Significant DNA damage was recorded through comet assay in liver and kidney cells of treated animals as compared to control. Alteration in anti-inflammatory and apoptotic genes expression determined by RT-PCR, revealed the activation of intrinsic apoptotic pathway(s) under the PND induced cellular stress. A pronounced increase in Bax expression, caspase-3 activities and decreased Bcl-2 expressions were also associated with PND-induced apoptosis. Data from this study suggests that PND induces cellular toxicity and genetic perturbations which can alter the normal cellular and physiological functioning in rats. PMID- 30459331 TI - Comparison of machine learning models for the prediction of mortality of patients with unplanned extubation in intensive care units. AB - Unplanned extubation (UE) can be associated with fatal outcome; however, an accurate model for predicting the mortality of UE patients in intensive care units (ICU) is lacking. Therefore, we aim to compare the performances of various machine learning models and conventional parameters to predict the mortality of UE patients in the ICU. A total of 341 patients with UE in ICUs of Chi-Mei Medical Center between December 2008 and July 2017 were enrolled and their demographic features, clinical manifestations, and outcomes were collected for analysis. Four machine learning models including artificial neural networks, logistic regression models, random forest models, and support vector machines were constructed and their predictive performances were compared with each other and conventional parameters. Of the 341 UE patients included in the study, the ICU mortality rate is 17.6%. The random forest model is determined to be the most suitable model for this dataset with F1 0.860, precision 0.882, and recall 0.850 in the test set, and an area under receiver operating characteristic (ROC) curve of 0.910 (SE: 0.022, 95% CI: 0.867-0.954). The area under ROC curves of the random forest model was significantly greater than that of Acute Physiology and Chronic Health Evaluation (APACHE) II (0.779, 95% CI: 0.716-0.841), Therapeutic Intervention Scoring System (TISS) (0.645, 95% CI: 0.564-0.726), and Glasgow Coma scales (0.577, 95%: CI 0.497-0.657). The results revealed that the random forest model was the best model to predict the mortality of UE patients in ICUs. PMID- 30459332 TI - Evaluation of dormancy breaking methods for enhanced germination in four biotypes of Brassica tournefortii. AB - Brassica tournefortii is an important broadleaf weed of the winter season in the northern grain region of Australia. Knowledge of germination ecology of this weed would help in implementing effective weed control programs. A series of experiments were conducted to study the germination and dormancy behavior of four biotypes of B. tournefortii seeds, biotypes A (collected from barley crop), B (barley fence lines), C (chickpea crop), and D (chickpea fence lines), collected from the St George region of Queensland. The aim of this research was to determine the effectiveness of various methods on the seed dormancy release of B. tournefortii. Water, potassium nitrate and a soil extract did not release dormancy in B. tournefortii seeds (biotype A) at 20/10 degrees C in the light/dark regime. Cold stratification (5 degrees C) also did not improve germination. However, gibberellic acid (GA3; 100-300 mg kg-1) stimulated germination (>88%). Germination also improved when seeds were immersed in sodium hypochlorite (NaOCl; 42 g L-1) for 10 minutes and the effect was more pronounced under the complete dark environment (89% germination at a day/night temperature of 20/10 degrees C). The NaOCl treatment makes seeds more porous and decreases sensitivity to light. Another experiment in light/dark conducted at 25/15 degrees C with two biotypes (A and D) showed that, without NaOCl treatment, biotype A was more sensitive to light (29% germination) as compared to biotype D (92% germination). Our results suggest that dormancy in B. tournefortii seeds can be broken by the combination of NaOCl (10 min) and a dark environment. A day/night temperature of 25/15 degrees C was found best for optimum germination (>87%) for all the biotypes (A-D) when incubated in dark after treating with NaOCl. This research indicated a high degree of variability in germination responses for various biotypes of B. tournefortii seeds to various sets of conditions, which may be due to metabolic changes in response to maternal environments or genetically controlled mechanisms. Information gained from this study will be important in developing a better understanding of the dormancy behavior of B. tournefortii seeds in response to tillage systems or maternal environments that could influence the weed seed bank in the soil and therefore help in designing suitable weed management programs. PMID- 30459333 TI - Structure and Function Studies of Asian Corn Borer Ostrinia furnacalis Pheromone Binding Protein2. AB - Lepidopteran male moths have an extraordinarily sensitive olfactory system that is capable of detecting and responding to minute amounts of female-secreted pheromones over great distances. Pheromone-binding proteins (PBPs) in male antennae ferry the hydrophobic ligand across the aqueous lymph to the olfactory receptor neuron triggering the response. PBPs bind ligands at physiological pH of the lymph and release them at acidic pH near the receptor while undergoing a conformational change. In Anthereae polyphemus PBP1, ligand binding to the hydrophobic pocket and its release is regulated by two biological gates: His70 and His95 at one end of the pocket and C-terminus tail at the other end. Interestingly, in Asian corn borer Ostrinia furnacalis PBP2 (OfurPBP2), critical residues for ligand binding and release are substituted in both biological gates. The impact of these substitutions on the ligand binding and release mechanism in OfurPBP2 is not known. We report here overexpression of soluble OfurPBP2 and structural characterization at high and low pH by circular dichroism (CD) and NMR. Ligand binding and ab initio model development were carried out with fluorescence and small-angle X-ray scattering (SAXS) respectively. OfurPBP2 in solution at pH 6.5 is homogeneous, well-folded and has a compact globular shape. PMID- 30459335 TI - Discordant sex between fetal screening and postnatal phenotype requires evaluation. AB - OBJECTIVE: Non-invasive prenatal screening (NIPS) utilizes circulating cell-free DNA (cfDNA) to screen for fetal genetic abnormalities. NIPS is the first widely available prenatal screen to assess genotypic sex. Most pediatricians have limited familiarity with NIPS technology and potential etiologies of discordant results. Increased familiarity may provide diagnostic insight and improve clinical care. STUDY DESIGN: We reviewed all patients with discordant genotypic fetal sex assessed by cfDNA and neonatal phenotypic sex referred to our medical center. RESULT: Four infants with discordant cfDNA result and phenotypic sex were identified. Etiologies include vanishing twin syndrome, difference of sexual development, sex chromosome aneuploidy and maternal chimerism. CONCLUSIONS: We present four cases illustrating potential etiologies of discordant cfDNA result and postnatal phenotypic sex. Unanticipated cfDNA results offer the perinatologist a unique opportunity for early diagnosis and targeted treatment of various conditions, many of which may not have otherwise been detected in the perinatal period. PMID- 30459334 TI - Quantitative metaproteomics of medieval dental calculus reveals individual oral health status. AB - The composition of ancient oral microbiomes has recently become accessible owing to advanced biomolecular methods such as metagenomics and metaproteomics, but the utility of metaproteomics for such analyses is less explored. Here, we use quantitative metaproteomics to characterize the dental calculus associated with the remains of 21 humans retrieved during the archeological excavation of the medieval (ca. 1100-1450 CE) cemetery of Tjaerby, Denmark. We identify 3671 protein groups, covering 220 bacterial species and 81 genera across all medieval samples. The metaproteome profiles of bacterial and human proteins suggest two distinct groups of archeological remains corresponding to health-predisposed and oral disease-susceptible individuals, which is supported by comparison to the calculus metaproteomes of healthy living individuals. Notably, the groupings identified by metaproteomics are not apparent from the bioarchaeological analysis, illustrating that quantitative metaproteomics has the potential to provide additional levels of molecular information about the oral health status of individuals from archeological contexts. PMID- 30459336 TI - Wash-free, label-free immunoassay for rapid electrochemical detection of PfHRP2 in whole blood samples. AB - Currently, the diagnosis of many diseases relies on laboratory-based immunoassays (ELISA, Western Blot), which are laborious, time-consuming and expensive. To address these limitations, we report a wash-free and label-free electrochemical immunoassay for rapid measurements of protein biomarkers in blood samples. This immunosensor employs a unique detection scheme based on electrochemical-chemical (EC) redox cycling for signal amplification combined with an affinity-based protein quantification strategy. All of the reagents required for this assay are dried and stored on a stacked membrane assembly, consisting of a Vivid Plasma Separation membrane and two cellulose membranes situated above the sensor, enabling excellent stability at room temperature for up to 2 months. Proof of concept was carried out by performing measurements of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) in whole blood samples, which could be detected from 100 ng/mL to 100 ug/mL with excellent specificity and reproducibility. Each measurement requires only two liquid dispensing steps and can completed in 5 min, making this diagnostic platform promising for point-of-care testing in resource limited settings. PMID- 30459337 TI - Recent topics: the diagnosis, molecular genesis, and treatment of mitochondrial diseases. AB - Mitochondrial diseases are inherited metabolic diseases based on disorders of energy production. The expansion of exome analyses has led to the discovery of many pathogenic nuclear genes associated with these diseases, and research into the pathogenesis of metabolic diseases has progressed. In cases of Leigh syndrome, it is desirable to perform both biochemical and genetic analyses, and pathogenic gene mutations have been identified in over half of the cases analyzed this way. Tandem mass screening and organic acid analyses of urine can sometimes provide important information that leads to the identification of pathogenic genes. Our comprehensive gene analyses have led to the discovery of several novel genes for mitochondrial diseases. Indeed, we reported that GTPBP3 and QRSL1 are involved in mitochondrial DNA maturation. In 2017, as a result of international collaboration, we also identified that mutations in ATAD3 and C1QBP cause mitochondrial disease. Given the varied pathogeneses, treatments for mitochondrial diseases should be specifically tailored to the mutated gene. Clinical trials of sodium pyruvate, 5-aminolevulinic acid with sodium ferrous citrate, and taurine as a treatment for mitochondrial disease have begun in Japan. Given that some mitochondrial diseases may respond well to certain treatments if the pathogenic gene can be identified, an early genetic diagnosis is crucial. Additionally, in Japan, prenatal diagnoses for mitochondrial diseases caused by nuclear genes have been achieved for genes shown to be pathogenic. Treatment and management approaches, including prenatal diagnoses, specifically tailored to the various phenotypes and pathologies of mitochondrial diseases are expected to become increasingly available. PMID- 30459338 TI - Associations between maternal dietary patterns and infant birth weight, small and large for gestational age in the Norwegian Mother and Child Cohort Study. AB - BACKGROUND/OBJECTIVES: To assess whether quality of maternal diet affects birth weight and the risk of small for gestational age (SGA) and/or large for gestational age (LGA) babies. SUBJECTS/METHODS: This study is based on the Norwegian Mother and Child Cohort Study (MoBa) and includes 65,904 pregnant women who answered a validated food frequency questionnaire at mid-pregnancy. Three maternal dietary patterns were extracted based on characteristics of food items in each pattern. From these we created four non-overlapping groups: "high prudent," "high Western," "high traditional," and "mixed". We obtained information about birth weight from the Norwegian Medical Birth Registry and calculated birth weight z-scores, SGA, and LGA according to an ultrasound-based, population-based, and a customized growth standards. Associations were studied by linear and multiple logistic regression. RESULTS: Compared to the high Western group, the high prudent group was associated with lower birth weight (betaultrasound z-scores -0.041 (95% confidence interval (CI): -0.068, -0.013)) and the high traditional group with higher birth weight (betaultrasound 0.067 (95% CI: 0.040, 0.094)) for all three growth standards. The high prudent pattern was associated with increased SGA risk (SGAultrasound odds ratio (OR) 1.25 (95% CI: 1.02, 1.54)) and decreased LGA risk (LGApopulation OR 0.84 (95% CI: 0.75, 0.94)), while the high traditional group on the contrary was associated with decreased SGA (SGAcustomized OR 0.92 (95% CI: 0.84, 0.99)) and increased LGA risk (LGApopulation OR 1.12 (95% CI: 1.02, 1.24)). CONCLUSIONS: Food quality was associated with birth weight in this well-nourished Norwegian population. Food quality may affect a woman's risk of giving birth to a SGA or LGA baby. PMID- 30459340 TI - Demographic inferences after a range expansion can be biased: the test case of the blacktip reef shark (Carcharhinus melanopterus). AB - The evolutionary history of species is a dynamic process as they modify, expand, and contract their spatial distributions over time. Range expansions (REs) occur through a series of founder events that are followed by migration among neighboring demes. The process usually results in structured metapopulations and leaves a distinct signature in the genetic variability of species. Explicitly modeling the consequences of complex demographic events such as REs is computationally very intensive. Here we propose an an alternative approach that requires less computational effort than a comprehensive RE model, but that can recover the demography of species undergoing a RE, by combining spatially explicit modelling with simplified but realistic metapopulation models. We examine the demographic and colonization history of Carcharhinus melanopterus, an abundant reef-associated shark, as a test case. We first used a population genomics approach to statistically confirm the occurrence of a RE in C. melanopterus, and identify its origin in the Indo-Australian Archipelago. Spatial genetic modelling identified two waves of stepping-stone colonization: an eastward wave moving through the Pacific and a westward one moving through the Indian Ocean. We show that metapopulation models best describe the demographic history of this species and that not accounting for this may lead to incorrectly interpreting the observed genetic variation as signals of widespread population bottlenecks. Our study highlights insights that can be gained about demography by coupling metapopulation models with spatial modeling and underscores the need for cautious interpretation of population genetic data when advancing conservation priorities. PMID- 30459339 TI - Upregulation of HBV transcription by sodium taurocholate cotransporting polypeptide at the postentry step is inhibited by the entry inhibitor Myrcludex B. AB - Sodium taurocholate cotransporting polypeptide (NTCP) is a functional receptor for hepatitis B virus (HBV) entry. However, little is known regarding whether NTCP is involved in regulating the postentry steps of the HBV life cycle. Here, we found that NTCP expression upregulated HBV transcription at the postentry step and that the NTCP-targeting entry inhibitor Myrcludex B (MyrB) effectively suppressed HBV transcription both in an HBV in vitro infection system and in mice hydrodynamically injected with an HBV expression plasmid. Mechanistically, NTCP upregulated HBV transcription via farnesoid X receptor alpha (FxRalpha)-mediated activation of the HBV EN2/core promoter at the postentry step in a manner that was dependent on the bile acid (BA)-transport function of NTCP, which was blocked by MyrB. Our findings uncover a novel role for NTCP in the HBV life cycle and provide a reference for the use of novel NTCP-targeting entry inhibitors to suppress HBV infection and replication. PMID- 30459341 TI - Enhanced fluorescent intensity of magnetic-fluorescent bifunctional PLGA microspheres based on Janus electrospraying for bioapplication. AB - Microspheres with magnetic-fluorescent functions have received attention due to fluorescent tracking and target positioning. To improve the accuracy of optical imaging and the fluorescent tracking of drug release, it is essential to enhance the fluorescent intensity of microparticles. Magnetic-fluorescent bifunctional poly lactic-co-glycolic acid (PLGA) Janus microspheres [PLGA/TbLa3(Bim)12]//[PLGA/Fe3O4] with double chambers were fabricated with the double-needle electrospraying method. The fluorescent drug TbLa3(Bim)12 with dual rare earth ions was encapsulated in one chamber, while Fe3O4 magnetic nanoparticles (Fe3O4 MNPs) were simultaneously encapsulated in another chamber. In comparison, magnetic-fluorescent PLGA composite microspheres PLGA/TbLa3(Bim)12/Fe3O4 were also prepared, which encapsulated fluorescent drugs TbLa3(Bim)12 with dual rare earth (RE) ions and Fe3O4 MNPs in one chamber. The fluorescent intensity at 542 nm of Janus microspheres was about three times higher than that of composite microspheres due to a decrease in contact between fluorescent-labeling RE drug and MNPs. The fluorescent intensities of Janus microspheres with different contents of Fe3O4 MNPs and TbLa3(Bim)12 were investigated. Furthermore, the magnetic properties, thermostability, cell toxicity and hemolytic properties of Janus microspheres were also assayed to conduct a tentative exploration of their bioapplication. The Janus microspheres provide many opportunities for application in biofields such as drug delivery. PMID- 30459342 TI - MPL-mutated essential thrombocythemia: a morphologic reappraisal. PMID- 30459343 TI - Unfolding of hidden white blood cell count phenotypes for gene discovery using latent class mixed modeling. AB - Resting-state white blood cell (WBC) count is a marker of inflammation and immune system health. There is evidence that WBC count is not fixed over time and there is heterogeneity in WBC trajectory that is associated with morbidity and mortality. Latent class mixed modeling (LCMM) is a method that can identify unobserved heterogeneity in longitudinal data and attempts to classify individuals into groups based on a linear model of repeated measurements. We applied LCMM to repeated WBC count measures derived from electronic medical records of participants of the National Human Genetics Research Institute (NHRGI) electronic MEdical Record and GEnomics (eMERGE) network study, revealing two WBC count trajectory phenotypes. Advancing these phenotypes to GWAS, we found genetic associations between trajectory class membership and regions on chromosome 1p34.3 and chromosome 11q13.4. The chromosome 1 region contains CSF3R, which encodes the granulocyte colony-stimulating factor receptor. This protein is a major factor in neutrophil stimulation and proliferation. The association on chromosome 11 contain genes RNF169 and XRRA1; both involved in the regulation of double-strand break DNA repair. PMID- 30459345 TI - Paramagnon-Enhanced Spin Currents in a Lattice near the Curie Point. AB - Spin transport phenomena have been shown to be highly enhanced when the temperature approaches the Curie point of the material sustaining a spin flow. Here we propose a simple - yet unifying - explanation for such enhancements, based on a random-phase model accounting for the spin fluctuations within a ferromagnetic material in the paramagnetic phase. We show that pure spin currents carried by conduction electrons injected into a paramagnetic lattice of mutually interacting localized magnetic moments can be enhanced close to the Curie temperature by the exchange interaction between the lattice sites and the non vanishing spin density associated with the spin current. The latter partially aligns the magnetic moments of the lattice, generating a flow of paramagnons that contribute to the total spin current, resulting in an enhancement that can be as large as tenfold. PMID- 30459344 TI - USP15 inhibits multiple myeloma cell apoptosis through activating a feedback loop with the transcription factor NF-kappaBp65. AB - USP15 has been shown to stabilize transcription factors, to be amplified in many cancers and to mediate cancer cell survival. However, the underlying mechanism by which USP15 regulates multiple myeloma (MM) cell proliferation and apoptosis has not been established. Here, our results showed that USP15 mRNA expression was upregulated in MM patients. USP15 silencing induced MM cell proliferation inhibition, apoptosis, and the expression of nuclear and cytoplasmic NF kappaBp65, while USP15 overexpression exhibited an inverse effect. Moreover, in vivo experiments indicated that USP15 silencing inhibited MM tumor growth and NF kappaBp65 expression. PDTC treatment significantly inhibited USP15 overexpression induced cell proliferation, apoptosis inhibition, and NF-kappaBp65 expression. USP15 overexpression promoted NF-kappaBp65 expression through inhibition of its ubiquitination, whereas NF-kappaBp65 promoted USP15 expression as a positive regulator. Taken together, the USP15-NF-kappaBp65 loop is involved in MM tumorigenesis and may be a potential therapeutic target for MM. PMID- 30459346 TI - High-throughput sequencing for the molecular diagnosis of Usher syndrome reveals 42 novel mutations and consolidates CEP250 as Usher-like disease causative. AB - Usher syndrome is a rare disorder causing retinitis pigmentosa, together with sensorineural hearing loss. Due to the phenotypic and genetic heterogeneity of this disease, the best method to screen the causative mutations is by high throughput sequencing. In this study, we tested a semiconductor chip based sequencing approach with 77 unrelated patients, as a molecular diagnosis routine. In addition, Multiplex Ligation-dependent Probe Amplification and microarray based Comparative Genomic Hybridization techniques were applied to detect large rearrangements, and minigene assays were performed to confirm the mRNA processing aberrations caused by splice-site mutations. The designed panel included all the USH causative genes (MYO7A, USH1C, CDH23, PCDH15, USH1G, CIB2, USH2A, ADGRV1, WHRN and CLRN1) as well as four uncertainly associated genes (HARS, PDZD7, CEP250 and C2orf71). The outcome showed an overall mutation detection ratio of 82.8% and allowed the identification of 42 novel putatively pathogenic mutations. Furthermore, we detected two novel nonsense mutations in CEP250 in a patient with a disease mimicking Usher syndrome that associates visual impairment due to cone rod dystrophy and progressive hearing loss. Therefore, this approach proved reliable results for the molecular diagnosis of the disease and also allowed the consolidation of the CEP250 gene as disease causative for an Usher-like phenotype. PMID- 30459349 TI - Author Correction: Directional sound beam emission from a configurable compact multi-source system. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30459348 TI - Stable pH Suppresses Defense Signaling and is the Key to Enhance Agrobacterium Mediated Transient Expression in Arabidopsis Seedlings. AB - Agrobacterium-mediated transient expression is a powerful analysis platform for diverse plant gene functional studies, but the mechanisms regulating the expression or transformation levels are poorly studied. Previously, we developed a highly efficient and robust Agrobacterium-mediated transient expression system, named AGROBEST, for Arabidopsis seedlings. In this study, we found that AGROBEST could promote the growth of agrobacteria as well as inhibit the host immunity response. When the factor of agrobacterial growth is minimized, maintaining pH at 5.5 with MES buffer was the key to achieving optimal transient expression efficiency. The expression of plant immunity marker genes, FRK1 and NHL10, was suppressed in the pH-buffered medium as compared with non-buffered conditions in Col-0 and an efr-1 mutant lacking the immunity receptor EFR recognizing EF-Tu, a potent pathogen- or microbe-associated molecular pattern (PAMP or MAMP) of A. tumefaciens. Notably, such immune suppression could also occur in Arabidopsis seedlings without Agrobacterium infection. Furthermore, the PAMP-triggered influx of calcium ions was compromised in the pH-buffered medium. We propose that the enhanced transient expression efficiency by stable pH was due to inhibiting calcium ion uptake and subsequently led to suppressing immunity against Agrobacterium. PMID- 30459347 TI - Autapses enhance bursting and coincidence detection in neocortical pyramidal cells. AB - Autapses are synaptic contacts of a neuron's axon onto its own dendrite and soma. In the neocortex, self-inhibiting autapses in GABAergic interneurons are abundant in number and play critical roles in regulating spike precision and network activity. Here we examine whether the principal glutamatergic pyramidal cells (PCs) also form functional autapses. In patch-clamp recording from both rodent and human PCs, we isolated autaptic responses and found that these occur predominantly in layer-5 PCs projecting to subcortical regions, with very few in those projecting to contralateral prefrontal cortex and layer 2/3 PCs. Moreover, PC autapses persist during development into adulthood. Surprisingly, they produce giant postsynaptic responses (~5 fold greater than recurrent PC-PC synapses) that are exclusively mediated by AMPA receptors. Upon activation, autapses enhance burst firing, neuronal responsiveness and coincidence detection of synaptic inputs. These findings indicate that PC autapses are functional and represent an important circuit element in the neocortex. PMID- 30459350 TI - Helical organization of microtubules occurs in a minority of tunneling membrane nanotubes in normal and cancer urothelial cells. AB - Tunneling membrane nanotubes (TnTs) are membrane protrusions connecting nearby or distant cells in vitro and in vivo. Functions of TnTs in cellular processes are various and rely on TnT structure, which also depends on cytoskeletal composition. In the present study, we focused on the organization of microtubules (MTs) and intermediate filaments (IFs) in TnTs of urothelial cells. We analysed TnTs of normal porcine urothelial cells, which morphologically and physiologically closely resemble normal human urothelial cells, and of cancer cells derived from invasive human urothelial neoplasm. Wide-field fluorescence, confocal and super-resolution microscopy techniques, together with image analyses and 3D reconstructions enlightened specific MT-IF organization in TnTs, and for the first time revealed that MTs and IFs co-occur in the majority of normal and cancer urothelial cell TnTs. Our findings show that in the initiation segment of TnTs, MTs are cross-linked with each other into filamentous network, however in the middle and the attaching segment of TnT, MTs can helically enwrap IFs, the phenomenon that has not been shown before within the TnTs. In this study, we assess MT-IF co-occurrence in TnTs and present evidence that such helical organization of MTs enwrapping IFs is only occurring in a minority of the TnTs. We also discuss the possible cell-biological and physiological reasons for helical organization of MTs in TnTs. PMID- 30459351 TI - Annexin A1-suppressed autophagy promotes nasopharyngeal carcinoma cell invasion and metastasis by PI3K/AKT signaling activation. AB - Annexin A1 (ANXA1) is dysregulated in the various tumors. However, the role and mechanism of ANXA1 in the cancers are poorly understood. In this study, we first showed a clinically positive correlation between ANXA1 and autophagy-associated protein SQSTM1 expression in nasopharyngeal carcinoma (NPC) and ANXA1-regulating SQSTM1 expression through autophagy, and further demonstrated that ANXA1 inhibited BECN1 and ATG5-dependent autophagy in the NPC cells. Using phospho kinase antibody array to identify signaling through which ANXA1 regulated NPC cell autophagy, we found that ANXA1-suppressed autophagy was associated with PI3K/AKT signaling activation. We also showed that ANXA1 expression was significantly increased in the NPCs with metastasis relative to NPCs without metastasis and positively correlated with lymphonode and distant metastasis; high ANXA1 expression in the NPC cells promoted in vitro tumor cell migration and invasion and in vivo metastasis. Lastly, we showed that inhibition of autophagy restored the ability of tumor cell migration and invasion, epithelial-mesenchymal transition (EMT)-like alterations and in vivo metastasis in the ANXA1 knockdown NPC cells with autophagy activation; ANXA1-suppresed autophagy induced EMT-like alterations possibly by inhibiting autophagy-mediated degradation of Snail. Our data suggest that ANXA1-suppressed autophagy promotes NPC cell migration, invasion and metastasis by activating PI3K/AKT signaling pathway, highlighting that the activation of autophagy may inhibit metastasis of NPC with high ANXA1 expression. PMID- 30459352 TI - Phosphopantetheinyl transferase (Ppt)-mediated biosynthesis of lysine, but not siderophores or DHN melanin, is required for virulence of Zymoseptoria tritici on wheat. AB - Zymoseptoria tritici is the causal agent of Septoria tritici blotch (STB) disease of wheat. Z. tritici is an apoplastic fungal pathogen, which does not penetrate plant cells at any stage of infection, and has a long initial period of symptomless leaf colonisation. During this phase it is unclear to what extent the fungus can access host plant nutrients or communicate with plant cells. Several important primary and secondary metabolite pathways in fungi are regulated by the post-translational activator phosphopantetheinyl transferase (Ppt) which provides an essential co-factor for lysine biosynthesis and the activities of non ribosomal peptide synthases (NRPS) and polyketide synthases (PKS). To investigate the relative importance of lysine biosynthesis, NRPS-based siderophore production and PKS-based DHN melanin biosynthesis, we generated deletion mutants of ZtPpt. The ?ZtPpt strains were auxotrophic for lysine and iron, non-melanised and non pathogenic on wheat. Deletion of the three target genes likely affected by ZtPpt loss of function (Aar- lysine; Nrps1-siderophore and Pks1- melanin), highlighted that lysine auxotrophy was the main contributing factor for loss of virulence, with no reduction caused by loss of siderophore production or melanisation. This reveals Ppt, and the lysine biosynthesis pathway, as potential targets for fungicides effective against Z. tritici. PMID- 30459353 TI - A third generation of radical fluorinating agents based on N-fluoro-N arylsulfonamides. AB - Radical fluorination has been known for a long time, but synthetic applications were severely limited by the hazardous nature of the first generation of reagents such as F2 and the strongly electrophilic nature of the second generation of reagents such as N-fluorobenzenesulfonimide (NFSI) and Selecfluor(r). Here, we report the preparation, use and properties of N-fluoro-N-arylsulfonamides (NFASs), a class of fluorinating reagents suitable for radical fluorination under mild conditions. Their N-F bond dissociation energies (BDE) are 30-45 kJ mol-1 lower than the N-F BDE of the reagents of the second generation. This favors clean radical fluorination processes over undesired side reactions. The utility of NFASs is demonstrated by a metal-free radical hydrofluorination of alkenes including an efficient remote C-H fluorination via a 1,5-hydrogen atom transfer. NFASs have the potential to become the reagents of choice in many radical fluorination processes. PMID- 30459355 TI - Oncogenic activity of poly (ADP-ribose) glycohydrolase. AB - Poly (ADP-ribosylation), known as PARylation, is a post-translational modification catalyzed by poly (ADP-ribose) polymerases (PARP) and primarily removed by the enzyme poly (ADP-ribose) glycohydrolase (PARG). While the aberrant removal of post-translation modifications including phosphorylation and methylation has known tumorigenic effects, deregulation of PARylation has not been widely studied. Increased hydrolysis of PARylation chains facilitates cancer growth through enhancing estrogen receptor (ER)-driven proliferation, but oncogenic transformation has not been linked to increased PARG expression. In this study, we find that elevated PARG levels are associated with a poor prognosis in breast cancers, especially in HER2-positive and triple-negative subtypes. Using both in vitro and in vivo models, we demonstrate that heightened expression of catalytically active PARG facilitates cell transformation and invasion of normal mammary epithelial cells. Catalytically inactive PARG mutants did not recapitulate these phenotypes. Consistent with clinical data showing elevated PARG predicts poor outcomes in HER2+ patients, we observed that PARG acts in synergy with HER2 to promote neoplastic growth of immortalized mammary cells. In contrast, PARG depletion significantly impairs the growth and metastasis of triple-negative breast tumors. Mechanistically, we find that PARG interacts with SMAD2/3 and significantly decreases their PARylation in non transformed cells, leading to enhanced expression of SMAD target genes. Further linking SMAD-mediated transcription to the oncogenicity of PARG, we show that PARG-mediated anchorage-independent growth and invasion are dependent, at least in part, on SMAD expression. Overall, our study underscores the oncogenic impact of aberrant protein PARylation and highlights the therapeutic potential of PARG inhibition in breast cancer. PMID- 30459356 TI - Macrophage-mediated transfer of cancer-derived components to stromal cells contributes to establishment of a pro-tumor microenvironment. AB - Tumor-derived extracellular vesicles (TEVs) secreted into the blood create a pre metastatic niche in distant organs; however, it is unclear how TEVs are delivered and how they affect stromal cells in the tumor microenvironment. Tumor-associated macrophages (TAMs) have pivotal roles in cancer progression by interacting with cancer cells and other stromal cells. Here, we report a novel function of TAMs: delivery and transmission of TEV contents. TEV-incorporating macrophages (TEV MPhis) showed increased invasiveness and were disseminated widely. Upon contact with host stromal cells (peritoneal mesothelial cells (PMCs), fibroblasts, and endothelial cells), TEV-MPhis released membrane blebs containing TEVs, a process dependent upon localized activation of caspase-3 in MPhis. Scattered blebs were incorporated into stromal cells, leading to transfer of cancer-derived RNA and proteins such as TGF-beta, activated Src, Wnt3, and HIF1alpha. TEV-MPhi-secreted blebs containing cancer-derived components contributed to myofibroblastic changes in recipient stromal cells. TEVs delivered by MPhis penetrated deep into the parenchyma of the stomach in TEV-injected mice, and transmitted TEVs to PMCs lining the stomach surface; this process induced PMCs to undergo mesothelial mesenchymal transition. PMCs infiltrated the gastric wall and created a niche, thereby promoting tumor invasion. Depletion of MPhis prevented these events. Moreover, TEV-MPhis created a pro-metastatic niche. Taken together, these results suggest a novel function for TAMs: transfer of cancer-derived components to surrounding stromal cells and induction of a pro-tumor microenvironment via an increase in the number of CAF-like cells. PMID- 30459354 TI - Energy/Electron Transfer Switch for Controlling Optical Properties of Silicon Quantum Dots. AB - The superior optical properties of Silicon Quantum Dots (SQDs) have made them of increasing interest for a variety of biological and opto-electronic applications. The surface functionalization of the SQDs with aromatic ligands plays a key role in controlling their optical properties due to the interaction of the ligands with the electronic wave function of SQDs. However, there is limited reports in literature describing the impact of spacer groups connecting the aromatic chromophore to SQDs on the optical properties of the SQDs. Herein, we report the synthesis of two SQDs assemblies (1.6 nm average diameter) functionalized with perylene-3,4,9,10-tetracarboxylic acid diimide (PDI) chromophore through N propylurea and propylamine spacers. Depending on the nature of the spacer, the photophysical measurements provide clear evidence for efficient energy and/or electron transfer between the SQDs and PDI. Energy transfer was confirmed to be the operative process when propylurea spacer was used, in which the rate was estimated to be ~2 * 109 s-1. On the other hand, the propylamine spacer was found to facilitate electron transfer process within the SQDs assembly. To illustrate functionality, the water soluble SQD-N-propylurea-PDI assembly was proven to be nontoxic and efficient for fluorescent imaging of embryonic kidney HEK293 cells and human bone cancerous U2OS cells. PMID- 30459357 TI - miR-155 drives oncogenesis by promoting and cooperating with mutations in the c Kit oncogene. AB - MicroRNAs (miRNAs) have emerged as crucial players in the development and maintenance of disease. miR-155 is an inflammation-associated, oncogenic miRNA, frequently overexpressed in hematological malignancies and solid tumors. However, the mechanism of oncogenesis by miR-155 is not well characterized, and research has focused primarily on individual, direct targets, which does not recapitulate the complexities of cancer. Using a powerful, inducible transgenic mouse model that overexpresses miR-155 and develops miR-155-addicted hematological malignancy, we describe here a multi-step process of oncogenesis by miR-155, which involves cooperation between miR-155, its direct targets, and other oncogenes. miR-155 is known to target DNA-repair proteins, leading to a mutator phenotype, and we find that over 93% of tumors in our miR-155 overexpressing mice contain activating mutations in a single oncogene, c-Kit. Treating mice with dasatinib or imatinib, which target c-Kit, resulted in complete tumor regression, indicating that c-Kit activity is crucial in the oncogenic process. Interestingly, c-Kit expression is high when miR-155 is overexpressed, indicating further cooperation between miR-155 and c-Kit. Our findings support a multi-step model of oncogenesis by miR-155 in which miR-155 promotes both a mutator phenotype and a cellular environment particularly susceptible to mutations in a given oncogene. PMID- 30459358 TI - Eicosapentaenoic acid in combination with EPHA2 inhibition shows efficacy in preclinical models of triple-negative breast cancer by disrupting cellular cholesterol efflux. AB - Triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype, currently lacks effective targeted therapy options. Eicosapentaenoic acid (EPA), an omega-3 fatty acid and constituent of fish oil, is a common supplement with anti-inflammatory properties. Although it is not a mainstream treatment, several preclinical studies have demonstrated that EPA exerts anti-tumor activity in breast cancer. However, against solid tumors, EPA as a monotherapy is clinically ineffective; thus, we sought to develop a novel targeted drug combination to bolster its therapeutic action against TNBC. Using a high-throughput functional siRNA screen, we identified Ephrin type-A receptor 2 (EPHA2), an oncogenic cell surface receptor tyrosine kinase, as a therapeutic target that sensitizes TNBC cells to EPA. EPHA2 expression was uniquely elevated in TNBC cell lines and patient tumors. In independent functional expression studies in TNBC models, EPHA2 gene-silencing combined with EPA significantly reduced cell growth and enhanced apoptosis compared with monotherapies, both in vitro and in vivo. EPHA2 specific inhibitors similarly enhanced the therapeutic action of EPA. Finally, we identified that therapy-mediated apoptosis was attributed to a lethal increase in cancer cell membrane polarity due to ABCA1 inhibition and subsequent dysregulation of cholesterol homeostasis. This study provides new molecular and preclinical evidence to support a clinical evaluation of EPA combined with EPHA2 inhibition in patients with TNBC. PMID- 30459359 TI - Strengthening long-lasting insecticidal nets effectiveness monitoring using retrospective analysis of cross-sectional, population-based surveys across sub Saharan Africa. AB - Bed nets averted 68% of malaria cases in Africa between 2000 and 2015. However, concerns over insecticide resistance, bed net durability and the effectiveness of long-lasting insecticidal nets (LLIN) are growing. To assess the effectiveness of LLINs of different ages and insecticides against malaria, we conducted a population-based, cross-sectional study using data from 162,963 children younger than 5 years of age participating in 33 Demographic and Health and Malaria Indicator Surveys conducted in 21 countries between 2009 and 2016. We used Bayesian logistic regression to estimate associations between LLIN age, insecticide type, and malaria. Children sleeping under LLINs the previous night experienced 21% lower odds of malaria infection than children who did not (odds ratio [OR] 0.79; 95% Uncertainty Interval [UI] 0.76-0.82). Nets less than one year of age exhibited the strongest protective effect (OR 0.75; 95% UI 0.72 0.79), and protection weakened as net age increased. LLINs containing different insecticides exhibited similar protection (ORdeltamethrin 0.78 [0.75-0.82]; ORpermethrin 0.79 [0.75-0.83]; ORalphacypermethrin 0.85 [0.76-0.94]). Freely available, population-based surveys can enhance and guide current entomological monitoring amid concerns of insecticide resistance and bed net durability, and be used with locally-collected data to support decisions on LLIN redistribution campaign timing which insecticide to use. PMID- 30459360 TI - The paracrine effects of human induced pluripotent stem cells promote bone-like structures via the upregulation of BMP expression in a mouse ectopic model. AB - Use of human induced pluripotent stem cells (h-iPSCs) for bone tissue engineering is most appealing, because h-iPSCs are an inexhaustible source of osteocompetent cells. The present study investigated the contribution of undifferentiated h iPSCs and elucidated aspects of the underlying mechanism(s) of the involvement of these cells to new bone formation. Implantation of undifferentiated h-iPSCs seeded on coral particles in ectopic sites of mice resulted in expression of osteocalcin and DMP-1, and in mineral content similar to that of the murine bone. The number of the implanted h-iPSCs decreased with time and disappeared by 30 days post-implantation. In contrast, expression of the murine osteogenic genes at day 15 and 30 post-implantation provided, for the first time, evidence that the implanted h-iPSCs affected the observed outcomes via paracrine mechanisms. Supporting evidence was provided because supernatant conditioned media from h iPSCs (h-iPSC CM), promoted the osteogenic differentiation of human mesenchymal stem cells (h-MSCs) in vitro. Specifically, h-iPSC CM induced upregulation of the BMP-2, BMP-4 and BMP-6 genes, and promoted mineralization of the extracellular matrix. Given the current interest in the use of h-iPSCs for regenerative medicine applications, our study contributes new insights into aspects of the mechanism underlying the bone promoting capability of h-iPSCs. PMID- 30459361 TI - Author Correction: Phosphorylation Dynamics Dominate the Regulated Proteome during Early Xenopus Development. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30459363 TI - Customizing supercontinuum generation via on-chip adaptive temporal pulse splitting. AB - Modern optical systems increasingly rely on complex physical processes that require accessible control to meet target performance characteristics. In particular, advanced light sources, sought for, for example, imaging and metrology, are based on nonlinear optical dynamics whose output properties must often finely match application requirements. However, in these systems, the availability of control parameters (e.g., the optical field shape, as well as propagation medium properties) and the means to adjust them in a versatile manner are usually limited. Moreover, numerically finding the optimal parameter set for such complex dynamics is typically computationally intractable. Here, we use an actively controlled photonic chip to prepare and manipulate patterns of femtosecond optical pulses that give access to an enhanced parameter space in the framework of supercontinuum generation. Taking advantage of machine learning concepts, we exploit this tunable access and experimentally demonstrate the customization of nonlinear interactions for tailoring supercontinuum properties. PMID- 30459362 TI - C-Terminal Residue of Ultrashort Peptides Impacts on Molecular Self-Assembly, Hydrogelation, and Interaction with Small-Molecule Drugs. AB - Single molecular changes on a tripeptide can have dramatic effects on their self assembly and hydrogelation. Herein, we explore C-terminal residue variation on two consistent ultrashort peptide backbones, i.e. acetylated-Leu-Ile-Val-Ala-Gly Xaa and acetylated-Ile-Val-Xaa (Xaa = His, Arg, Asn). The objective of this study is to identify candidates that can form hydrogels for small-molecule drug (SMD) delivery. Haemolysis and cytotoxicity (with human adipose-derived mesenchymal stem cells) assays showed that the new soluble peptides (Xaa = His, Arg) are cytocompatible. Gelation studies showed that all but acetylated-Ile-Val-Arg could gel under physiological conditions. Longer peptidic backbones drive self-assembly more effectively as reflected in field emission scanning electron microscopy (FESEM) and circular dichroism spectroscopy studies. Rheological studies revealed that the resultant hydrogels have varying stiffness and yield stress, depending on the backbone and C-terminal residue. Visible spectroscopy-based elution studies with SMDs (naltrexone, methotrexate, doxorubicin) showed that besides the C-terminal residue, the shape of the SMD also determines the rate and extent of SMD elution. Based on the elution assays, infrared spectroscopy, and FESEM, we propose models for the peptide fibril-SMD interaction. Our findings highlight the importance of matching the molecular properties of the self-assembling peptide and SMD in order to achieve the desired SMD release profile. PMID- 30459365 TI - Rhythms of life: circadian disruption and brain disorders across the lifespan. AB - Many processes in the human body - including brain function - are regulated over the 24-hour cycle, and there are strong associations between disrupted circadian rhythms (for example, sleep-wake cycles) and disorders of the CNS. Brain disorders such as autism, depression and Parkinson disease typically develop at certain stages of life, and circadian rhythms are important during each stage of life for the regulation of processes that may influence the development of these disorders. Here, we describe circadian disruptions observed in various brain disorders throughout the human lifespan and highlight emerging evidence suggesting these disruptions affect the brain. Currently, much of the evidence linking brain disorders and circadian dysfunction is correlational, and so whether and what kind of causal relationships might exist are unclear. We therefore identify remaining questions that may direct future research towards a better understanding of the links between circadian disruption and CNS disorders. PMID- 30459364 TI - Probing tumor microenvironment in patients with newly diagnosed glioblastoma during chemoradiation and adjuvant temozolomide with functional MRI. AB - Functional MRI may identify critical windows of opportunity for drug delivery and distinguish between early treatment responders and non-responders. Using diffusion-weighted, dynamic contrast-enhanced, and dynamic susceptibility contrast MRI, as well as pro-angiogenic and pro-inflammatory blood markers, we prospectively studied the physiologic tumor-related changes in fourteen newly diagnosed glioblastoma patients during standard therapy. 153 MRI scans and blood collection were performed before chemoradiation (baseline), weekly during chemoradiation (week 1-6), monthly before each cycle of adjuvant temozolomide (pre-C1-C6), and after cycle 6. The apparent diffusion coefficient, volume transfer coefficient (Ktrans), and relative cerebral blood volume (rCBV) and flow (rCBF) were calculated within the tumor and edema regions and compared to baseline. Cox regression analysis was used to assess the effect of clinical variables, imaging, and blood markers on progression-free (PFS) and overall survival (OS). After controlling for additional covariates, high baseline rCBV and rCBF within the edema region were associated with worse PFS (microvessel rCBF: HR = 7.849, p = 0.044; panvessel rCBV: HR = 3.763, p = 0.032; panvessel rCBF: HR = 3.984; p = 0.049). The same applied to high week 5 and pre-C1 Ktrans within the tumor region (week 5 Ktrans: HR = 1.038, p = 0.003; pre-C1 Ktrans: HR = 1.029, p = 0.004). Elevated week 6 VEGF levels were associated with worse OS (HR = 1.034; p = 0.004). Our findings suggest a role for rCBV and rCBF at baseline and Ktrans and VEGF levels during treatment as markers of response. Functional imaging changes can differ substantially between tumor and edema regions, highlighting the variable biologic and vascular state of tumor microenvironment during therapy. PMID- 30459367 TI - A neurodegenerative-disease protein forms beneficial aggregates in healthy muscle. PMID- 30459366 TI - Publisher Correction: Improved collective influence of finding most influential nodes based on disjoint-set reinsertion. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30459368 TI - A new road to cancer-drug resistance. PMID- 30459369 TI - Nanofibres induce remodelling of cell membranes. PMID- 30459370 TI - Rock legend retells the race to the Moon - in 3D. PMID- 30459371 TI - Improved mosquito genome points to population-control strategies. PMID- 30459372 TI - Ancient Celts embalmed enemy heads as trophies. PMID- 30459373 TI - Plump mice help to unravel the tangled ties between obesity and cancer. PMID- 30459374 TI - A dragon that prefers a quiet life at home. PMID- 30459375 TI - Massive trial shows limited value for popular supplements. PMID- 30459376 TI - Crater gouged by huge space rock found under Greenland ice. PMID- 30459377 TI - Brexit: what the draft deal means for science. PMID- 30459378 TI - Ban on 'gene drives' is back on the UN's agenda - worrying scientists. PMID- 30459379 TI - World's first automated volcano forecast predicts Mount Etna's eruptions. PMID- 30459380 TI - Photobombing stars lead to cosmic false identity. PMID- 30459381 TI - Molecular net fishes sugar from blood. PMID- 30459382 TI - Lab-grown 'mini brains' produce electrical patterns that resemble those of premature babies. PMID- 30459383 TI - Why graduate students should get involved in advocacy. PMID- 30459384 TI - Why extreme rains are gaining strength as the climate warms. PMID- 30459385 TI - America, don't throw global talent away. PMID- 30459386 TI - Antarctic scientists begin hunt for sky's 'detergent'. PMID- 30459387 TI - Brexit end game leaves much to play for. PMID- 30459388 TI - Early red cell transfusion is associated with development of severe retinopathy of prematurity. AB - OBJECTIVE: To evaluate the association between early (within 10 d) pRBC transfusion and the development of severe ROP. STUDY DESIGN AND METHODS: This was a single-center retrospective study. Inclusion criteria were preterm infants born <=32 weeks gestation or weighing <=1500 g. Severe ROP was defined as infants requiring retinal laser ablation or bevacizumab injection. Logistic regression was used to identify the association between transfusions and severe ROP. RESULTS: A total of 1635 infants were included in the final analysis. The severe ROP incidence was 8% (126/1635). Ninety-one percent (115/126) of infants who developed severe ROP received a pRBC transfusion in the first 10 d. Early transfusion was associated with severe ROP; adjusted odds ratio of 3.8 (95% CI: 1.8-8.1). CONCLUSION: pRBC transfusions in the first 10 days of life are associated with an almost four-fold increased risk of severe ROP, independent of gestational age at birth or bronchopulmonary dysplasia (BPD) status. PMID- 30459389 TI - Radiation exposure by digital radiographic imaging in very low birth weight infants. AB - OBJECTIVE: The aim of this study was to determine the cumulative effective doses (CED) from digital radiographic imaging in very low birth weight infants treated in a tertiary care neonatal intensive care unit (NICU). STUDY DESIGN: The CED for each infant was retrospectively calculated using a voxel-based model. The results were compared with previous studies applying conventional radiography. RESULTS: Two hundred and six preterm infants were included into this study. Neonates received a median of four radiographs (range: 1-68) and a CED of 50 uSv (4-883 uSv). Overall mean CED was lower than in previously published data applying conventional radiography. Factors contributing to a lower radiation dose per infant in our study were a lower number of radiographs and smaller field sizes per radiographic image. CONCLUSIONS: The number of conducted radiographs per patient and the employed field size had a higher impact on the CED than the applied radiographic technology. PMID- 30459390 TI - Design of an inherently-stable water oxidation catalyst. AB - While molecular water-oxidation catalysts are remarkably rapid, oxidative and hydrolytic processes in water can convert their active transition metals to colloidal metal oxides or hydroxides that, while quite reactive, are insoluble or susceptible to precipitation. In response, we propose using oxidatively-inert ligands to harness the metal oxides themselves. This approach is demonstrated by covalently attaching entirely inorganic oxo-donor ligands (polyoxometalates) to 3 nm hematite cores, giving soluble anionic structures, highly resistant to aggregation, yet thermodynamically stable to oxidation and hydrolysis. Using orthoperiodate (at pH 8), and no added photosensitizers, the hematite-core complex catalyzes visible-light driven water oxidation for seven days (7600 turnovers) with no decrease in activity, far exceeding the documented lifetimes of molecular catalysts under turnover conditions in water. As such, a fundamental limitation of molecular complexes is entirely bypassed by using coordination chemistry to harness a transition-metal oxide as the reactive center of an inherently stable, homogeneous water-oxidation catalyst. PMID- 30459392 TI - Zebrafish miR-462-731 regulates hematopoietic specification and pu.1-dependent primitive myelopoiesis. AB - MicroRNAs (miRNAs) play significant roles in both embryonic hematopoiesis and hematological malignancy. Zebrafish miR-462-731 cluster is orthologous of miR-191 425 in human which regulates proliferation and tumorigenesis. In our previous work, miR-462-731 was found highly and ubiquitously expressed during early embryogenesis. In this study, by loss-of-function analysis (morpholino knockdown combined with CRISRP/Cas9 knockout) and mRNA profiling, we suggest that miR-462 731 is required for normal embryonic development by regulating cell survival. We found that loss of miR-462/miR-731 caused a remarkable decrease in the number of erythroid cells as well as an ectopic myeloid cell expansion at 48 hpf, suggesting a skewing of myeloid-erythroid lineage differentiation. Mechanistically, miR-462-731 provides an instructive input for pu.1-dependent primitive myelopoiesis through regulating etsrp/scl signaling combined with a novel pu.1/miR-462-731 feedback loop. On the other hand, morpholino (MO) knockdown of miR-462/miR-731 resulted in an expansion of posterior blood islands at 24 hpf, which is a mild ventralization phenotype resulted from elevation of BMP signaling. Rescue experiments with both BMP type I receptor inhibitor dorsomorphin and alk8 MO indicate that miR-462-731 acts upstream of alk8 within the BMP/Smad signaling pathway and functions as a novel endogenous BMP antagonist. Besides, an impairment of angiogenesis was observed in miR-462/miR 731 morphants. The specification of arteries and veins was also perturbed, as characterized by the irregular patterning of efnb2a and flt4 expression. Our study unveils a previously unrecognized role of miR-462-731 in BMP/Smad signaling mediated hematopoietic specification of mesodermal progenitors and demonstrates a miR-462-731 mediated regulatory mechanism driving primitive myelopoiesis in the ALPM. We also show a requirement for miR-462-731 in regulating arterial-venous specification and definitive hematopoietic stem cell (HSC) production. The current findings might provide further insights into the molecular mechanistic basis of miRNA regulation of embryonic hematopoiesis and hematological malignancy. PMID- 30459391 TI - Resolving laminar activation in human V1 using ultra-high spatial resolution fMRI at 7T. AB - The mesoscopic organization of the human neocortex is of great interest for cognitive neuroscience. However, fMRI in humans typically maps the functional units of cognitive processing on a macroscopic level. With the advent of ultra high field MRI (>=7T), it has become possible to acquire fMRI data with sub millimetre resolution, enabling probing the laminar and columnar circuitry in humans. Currently, laminar BOLD responses are not directly observed but inferred via data analysis, due to coarse spatial resolution of fMRI (e.g. 0.7-0.8 mm isotropic) relative to the extent of histological laminae. In this study, we introduce a novel approach for mapping the cortical BOLD response at the spatial scale of cortical layers and columns at 7T (an unprecedented 0.1 mm, either in the laminar or columnar direction). We demonstrate experimentally and using simulations, the superiority of the novel approach compared to standard approaches for human laminar fMRI in terms of effective spatial resolution in either laminar or columnar direction. In addition, we provide evidence that the laminar BOLD signal profile is not homogeneous even over short patches of cortex. In summary, the proposed novel approach affords the ability to directly study the mesoscopic organization of the human cortex, thus, bridging the gap between human cognitive neuroscience and invasive animal studies. PMID- 30459393 TI - Publisher Correction: Mixed matrix formulations with MOF molecular sieving for key energy-intensive separations. AB - In the version of this Article originally published, the units of the y axis of Fig. 3b were incorrectly given as '106 cm2 s-1'; they should have been '10-8 cm2 s-1'. This has been corrected in the online versions of the Article. PMID- 30459394 TI - Laboratory analysis of amino acids, 2018 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG). AB - Amino acid abnormalities are observed in a broad spectrum of inherited metabolic diseases, such as disorders of amino acid metabolism and transport, organic acidemias, and ureagenesis defects. Comprehensive analysis of physiologic amino acids in blood, urine, and cerebrospinal fluid is typically performed in the following clinical settings: evaluation of symptomatic patients in whom a diagnosis is not known; evaluation of previously diagnosed patients to monitor treatment efficacy; evaluation of asymptomatic or presymptomatic (at-risk) relatives of known patients; follow-up testing for an abnormal newborn screen; and assessment of dietary protein adequacy or renal function in general patient populations. Currently, the most common analytical method to quantify amino acids is based on ion exchange chromatography using post-column derivatization with ninhydrin and spectrophotometric detection. Newer methodologies are based on liquid chromatographic separation with detection by mass spectrometry or spectrophotometry. Amino acid analysis by nonseparation methods, such as the flow injection-tandem mass spectrometric (MS/MS) method used for newborn screening, is considered inadequate for the diagnosis of at-risk patients. The purpose of this document is to provide a technical standard for amino acid analysis as applied to the diagnosis and management of inborn errors of metabolism. PMID- 30459396 TI - The relative effects of forest amount, forest configuration, and urban matrix quality on forest breeding birds. AB - Urbanization modifies landscape structure in three major ways that impact avian diversity in remnant habitat: habitat amount is reduced and habitat configuration and matrix quality are altered. The relative effects of these three components of landscape structure are relatively well-studied in agricultural landscapes, but little is known about the relative effect of urban matrix quality. We addressed this gap by investigating the relative effects of forest amount, forest configuration, and matrix quality, indicated by degree of urbanization and agriculture amount, on the diversity of three guilds of forest birds using data from 13,763 point counts from Pennsylvania, USA. Forest amount had the largest independent effect on forest bird diversity, followed by matrix quality, then forest configuration. In particular, urbanization had strong negative effects on the relative abundance and species evenness of all forest birds and the relative abundance of forest generalist birds. To our knowledge, these are the first results of the effect of urban matrix quality on forest bird relative abundance and species evenness independent of forest amount and forest configuration. Our results imply that conservation practitioners in human-modified landscapes prioritize maximizing forest amount, then reducing the effects of disturbances originating in the matrix, and then preserving large, spatially-dispersed forest patches to most effectively conserve forest birds. PMID- 30459395 TI - Whole-Transcriptome Profiling of Canine and Human in Vitro Models Exposed to a G Quadruplex Binding Small Molecule. AB - G-quadruplexes (G4) are secondary nucleic acid structures that have been associated with genomic instability and cancer progression. When present in the promoter of some oncogenes, G4 structures can affect gene regulation and, hence, represent a possible therapeutic target. In this study, RNA-Seq was used to explore the effect of a G4-binding anthraquinone derivative, named AQ1, on the whole-transcriptome profiles of two common cell models for the study of KIT pathways; the human mast cell leukemia (HMC1.2) and the canine mast cell tumor (C2). The highest non-cytotoxic dose of AQ1 (2 uM) resulted in 5441 and 1201 differentially expressed genes in the HMC1.2 and C2 cells, respectively. In both cell lines, major pathways such as cell cycle progression, KIT- and MYC-related pathways were negatively enriched in the AQ1-treated group, while other pathways such as p53, apoptosis and hypoxia-related were positively enriched. These findings suggest that AQ1 treatment induces a similar functional response in the human and canine cell models, and provide news insights into using dogs as a reliable translational model for studying G4-binding compounds. PMID- 30459397 TI - Rationalising drug delivery using nanoparticles: a combined simulation and immunology study of GnRH adsorbed to silica nanoparticles. AB - Silica nanoparticles (SiNPs) have been shown to have significant potential for drug delivery and as adjuvants for vaccines. We have simulated the adsorption of GnRH-I (gonadotrophin releasing hormone I) and a cysteine-tagged modification (cys-GnRH-I) to model silica surfaces, as well as its conjugation to the widely used carrier protein bovine serum albumin (BSA). Our subsequent immunological studies revealed no significant antibody production was caused by the peptide SiNP systems, indicating that the treatment was not effective. However, the testosterone response with the native peptide-SiNPs indicated a drug effect not found with cys-GnRH-I-SiNPs; this behaviour is explained by the specific orientation of the peptides at the silica surface found in the simulations. With the BSA systems, we found significant testosterone reduction, particularly for the BSA-native conjugates, and an antibody response that was notably higher with the SiNPs acting as an adjuvant; this behaviour again correlates well with the epitope presentation predicted by the simulations. The range of immunological and hormone response can therefore be interpreted and understood by the simulation results and the presentation of the peptides to solution, paving the way for the future rational design of drug delivery and vaccine systems guided by biomolecular simulation. PMID- 30459398 TI - ERCC6L that is up-regulated in high grade of renal cell carcinoma enhances cell viability in vitro and promotes tumor growth in vivo potentially through modulating MAPK signalling pathway. AB - Renal cell carcinoma (RCC), which is one of the most diagnosed urological malignancies worldwide, is usually associated with abnormality in both genetic and cellular processes. In the present study, through analyzing The Cancer Genome Atlas (TCGA) dataset, we screened out ERCC6L as a candidate gene that is potentially related to the development of RCC based on its increased expression in ccRCC tissues compared with normal kidney tissues as well as its possible relevance to cancer prognosis. Evidence indicates that ERCC6L is an indispensable component of mammalian cell mitosis, while it fails to disclose the role of ERCC6L in tumorigenesis. By using RT-PCR, it was confirmed that the mRNA expression of ERCC6L was upregulated in RCC tissues as compared to normal controls in 28 pared samples. In addition, the immunohistochemistry study in a tissue microarray (TMA) containing 150 ccRCC samples showed that the staining score of ERCC6L was positively correlated with the Fuhrman grade of cancers. Next, when the expression of ERCC6L was lowered by specific shRNA, the cell viability was significantly inhibited in 786-O and Caki-1 cells, while the apoptosis was induced accordingly. At the same time, RCC cells those were transfected with shRNA targeting to ERCC6L grew significantly slower than parental cells in immunodeficient mice. These results consistently suggest that ERCC6L may play a role in regulating the cell viability of RCC both in vitro and in vivo. Further, gene expression microarray analysis followed by the validating western blot after knocking down ERCC6L expression in 786-O cells highlighted the involvement of MAPK signaling pathway in regulation of ERCC6L on cellular process of RCC. In conclusion, the present study suggests a likely promoting role of ERCC6L on the development of RCC. Thus, further study to explore the potential utility of ERCC6L as a novel therapeutic target of RCC is clearly needed. PMID- 30459399 TI - Author Correction: Misestimation of heritability and prediction accuracy of male pattern baldness. AB - The original version of this Article contained an error in the spelling of the author Julia Sidorenko, which was incorrectly given as Julia Sirodenko. This has now been corrected in both the PDF and HTML versions of the Article. Further, the sixth sentence of the second paragraph of the Correspondence and the legend to Fig. 1 incorrectly omitted citation of work by Heilmann-Helmbach, S. et al. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 30459401 TI - Short-term weight gain is associated with accumulation of multimorbidity in mid aged women: a 20-year cohort study. AB - BACKGROUND/OBJECTIVES: Although weight change has been studied in relation to many individual chronic conditions, limited studies have focused on weight change and multimorbidity. This study examines the relationship between short-term weight change and the accumulation of multimorbidity in midlife. METHODS: We used data from 7357 women aged 45-50 years without a history of any chronic conditions. The women were surveyed approximately every 3 years from 1996 to 2016. Associations between short-term weight change and accumulation of multimorbidity (two or more of nine chronic conditions) over each 3-year period, adjusting for baseline body mass index (BMI) or time-varying BMI (3-year period), were examined using repeated measures models. Short-term weight change was categorised into seven groups of annual weight change from high weight loss ( <= 5%) to high weight gain (> + 5%). RESULTS: Over 20 years, 60.4% (n = 4442) of women developed multimorbidity. Baseline BMI, time-varying BMI and short-term weight gain were all associated with the accumulation of multimorbidity. After controlling for sociodemographic, lifestyle factors and menopausal status, high weight gain was associated with a 25% increased odds of multimorbidity (odds ratio (OR) 1.25, 95% confidence interval (CI) 1.08-1.45) compared with maintaining a stable weight. The results were consistent among models adjusting for baseline BMI (OR 1.24, 95% CI 1.07-1.44) or time-varying BMI (OR 1.34, 95% CI 1.16-1.54). Weight loss was associated with increased odds of multimorbidity in women with normal BMI (baseline or time-varying). CONCLUSIONS: Short-term weight gain is associated with significantly increased odds of multimorbidity in mid aged women. This association is independent from baseline BMI (at 45-50 years) and time-varying BMI. These findings support a persistent weight management regime and prevention of weight gain throughout women's midlife. PMID- 30459400 TI - Variations in oral microbiome profiles in rheumatoid arthritis and osteoarthritis with potential biomarkers for arthritis screening. AB - The key to arthritis management is early diagnosis and treatment to prevent further joint destruction and maximize functional ability. Osteoarthritis (OA) and rheumatoid arthritis (RA) are two common types of arthritis that the primary care provider must differentiate, in terms of diagnosis and treatment. Effective and non-invasive strategies for early detection and disease identification are sorely needed. Growing evidence suggests that RA has a correlation with oral microbiome and may be affected by its dynamic variations. There is already a study comparing oral microbiome in patients with RA and OA, however, it did not screen for potential biomarkers for arthritis. In this study, we assessed the oral microbiome in saliva samples from 110 RA patients, 67 OA patients and 155 healthy subjects, using 16S rRNA gene amplicon sequencing. The structure and differences in oral microbiome between RA, OA and healthy subjects were analyzed. Eight oral bacterial biomarkers were identified to differentiate RA from OA. This report provides proof of oral microbiota as an informative source for discovering non-invasive biomarkers for arthritis screening. PMID- 30459402 TI - Serum asprosin levels and bariatric surgery outcomes in obese adults. AB - BACKGROUND/OBJECTIVES: Asprosin is a novel fasting-induced glucogenic and orexigenic protein hormone. The clinical function of asprosin in obesity is currently unknown. This study investigated the association between asprosin abundance and the outcome of bariatric surgery. SUBJECTS/METHODS: Patients with body mass index more than 35 kg/m2 were recruited for the Obesity and Clock for Elegant Aging Registry in 2011-2016. Body weight changes, blood sugar, and asprosin were assessed in 117 patients receiving bariatric surgery and 57 non obese subjects as normal control. Primary outcomes of excess weight loss percentage at 6 months after bariatric surgery were determined at follow-up. RESULTS: Asprosin levels were significantly higher in obese patients than in non obese subjects (2360 +/- 5094 vs. 307 +/- 832 ng/ml, p < 0.0001). Multivariate analyses showed a significant association of asprosin abundance with excess body weight loss percentage at 6 months after surgery (p < 0.0001). After adjusted for age, sex, smoking, HbA1c, cholesterol, and triglyceride, serum asprosin level was the only independent predictor of 6 months excess weight loss percentage after bariatric surgery. Asprosin levels decreased significantly 6 months after bariatric surgery (162.2 +/- 169.1 ng/ml). Furthermore, there was no association between asprosin and serum glucose levels in our study. CONCLUSION: This study provides novel evidence that higher asprosin concentrations before bariatric surgery were associated with the weight reduction magnitude at 6 months after surgery. Further studies are warranted to investigate whether asprosin has direct functions to modulate body weight regulation in humans after bariatric surgery. PMID- 30459403 TI - Association between cardiorespiratory fitness, obesity, and health care costs: The Veterans Exercise Testing Study. AB - BACKGROUND/OBJECTIVE: Obesity is a chronic disease, a risk factor for other chronic conditions and for early mortality, and is associated with higher health care utilization. Annual spending among obese individuals is at least 30% higher vs. that for normal-weight peers. In contrast, higher cardiorespiratory fitness (CRF) is related to many health benefits. We sought to examine the association between CRF and health care costs across the spectrum of body mass index (BMI). METHODS: Data from 3,924 men (58.1 +/- 11.1 years, 29.2 +/- 5.3 kg.m-2) who completed a maximal exercise test for clinical reasons and to estimate CRF were recorded prospectively at the time of testing. Cost data (USD) from each subject during a 6-year period after the exercise test were merged with the exercise database and compared according to BMI and estimated CRF (CRFe). Subjects were categorized as normal-weight (BMI < 25.0 kg.m-2), overweight (BMI 25.0-29.9 kg.m 2), and obese (BMI >= 30.0 kg.m-2). We also formed four CRFe categories based on age-stratified quartiles of metabolic equivalents (METs) achieved: least-fit (5.1 +/- 1.5 METs; n = 1,044), moderately-fit (7.6 +/- 1.5 METs; n = 938), fit (9.4 +/ 1.5 METs; n = 988), and highly-fit (12.4 +/- 2.2 METs; n = 954). RESULTS: Average annual costs per person adjusted for age and presence of cardiovascular disease were $37,018, $40,572, and $45,683 for normal-weight, overweight, and obese subjects, respectively (p < 0.01). For each 1-MET incremental increase in CRFe, annual cost savings per person were $3,272, $4,252, and $6,103 for normal weight, overweight, and obese subjects, respectively. Stratified by CRFe categories, annual costs for normal-weight, overweight, and obese subjects in the highest CRFe quartile were $28,028, $31,669, and $32,807 lower, respectively, compared to subjects in the lowest CRFe quartile (p < 0.01). CONCLUSION: Higher CRFe is associated with lower health care costs. Cost savings were particularly evident in obese subjects, suggesting that the economic burden of obesity may be reduced through interventions that target improvements in CRF. PMID- 30459404 TI - All-optical generation and ultrafast tuning of non-linear spin Hall current. AB - Spin Hall effect, one of the cornerstones in spintronics refers to the emergence of an imbalance in the spin density transverse to a charge flow in a sample under voltage bias. This study points to a novel way for an ultrafast generation and tuning of a unidirectional nonlinear spin Hall current by means of subpicosecond laser pulses of optical vortices. When interacting with matter, the optical orbital angular momentum (OAM) carried by the vortex and quantified by its topological charge is transferred to the charge carriers. The residual spin orbital coupling in the sample together with confinement effects allow exploiting the absorbed optical OAM for spatio-temporally controlling the spin channels. Both the non-linear spin Hall current and the dynamical spin Hall angle increase for a higher optical topological charge. The reason is the transfer of a higher amount of OAM and the enhancement of the effective spin-orbit interaction strength. No bias voltage is needed. We demonstrate that the spin Hall current can be all-optically generated in an open circuit geometry for ring-structured samples. These results follow from a full-fledged propagation of the spin dependent quantum dynamics on a time-space grid coupled to the phononic environment. The findings point to a versatile and controllable tool for the ultrafast generation of spin accumulations with a variety of applications such as a source for ultrafast spin transfer torque and charge and spin current pulse emitter. PMID- 30459405 TI - Estrogen receptor beta promotes bladder cancer growth and invasion via alteration of miR-92a/DAB2IP signals. AB - Although early studies suggested that bladder cancer (BCa) is more prevalent in men than in women, muscle-invasive rates are higher in women than in men, suggesting that sex hormones might play important roles in different stages of BCa progression. In this work, we found that estrogen receptor beta (ERbeta) could increase BCa cell proliferation and invasion via alteration of miR-92a mediated DAB2IP (DOC-2/DAB2 interacting protein) signals and that blocking miR 92a expression with an inhibitor could partially reverse ERbeta-enhanced BCa cell growth and invasion. Further mechanism dissection found that ERbeta could increase miR-92a expression at the transcriptional level via binding to the estrogen-response-element (ERE) on the 5' promoter region of its host gene C13orf25. The ERbeta up-regulated miR-92a could decrease DAB2IP tumor suppressor expression via binding to the miR-92a binding site located on the DAB2IP 3' UTR. Preclinical studies using an in vivo mouse model also confirmed that targeting this newly identified ERbeta/miR-92a/DAB2IP signal pathway with small molecules could suppress BCa progression. Together, these results might aid in the development of new therapies via targeting of this ERbeta-mediated signal pathway to better suppress BCa progression. PMID- 30459407 TI - Author Correction: Comprehensive comparative analysis of 5'-end RNA-sequencing methods. AB - The original version of this paper contained an incorrect primer sequence. In the Methods subsection "Rampage libraries," the text for modification 3 stated that the reverse primer used for library indexing was 5' CAAGCAGAAGACGGCATACGAGATXXXXXXXXGTGACTGGAGT-3'. The correct sequence of the oligonucleotide used is 5' CAAGCAGAAGACGGCATACGAGATXXXXXXXXGTGACTGGAGTTCAGACGTGTGCTCTTCCGATCT-3'. This error has been corrected in the PDF and HTML versions of the paper. PMID- 30459406 TI - Novel AR-12 derivatives, P12-23 and P12-34, inhibit flavivirus replication by blocking host de novo pyrimidine biosynthesis. AB - The genus Flavivirus contains many important pathogens, including dengue virus (DENV), Zika virus (ZIKV), and Japanese encephalitis virus (JEV). AR-12 is a celecoxib-derived anticancer agent that possesses antiviral activity against a broad range of viruses. We pharmacologically exploited this unique activity to develop additional antiviral agents, resulting in the production of the AR-12 derivatives P12-23 and P12-34. At nanomolar concentrations, these compounds were effective in suppressing DENV, ZIKV and JEV replication, exhibiting 10-fold improvements in the efficacy and selectivity indices as compared to AR-12. Regarding the mode of antiviral action, P12-23 and P12-34 inhibited viral RNA replication but had no effect on viral binding, entry or translation. Moreover, these AR-12 derivatives co-localized with mitochondrial markers, and their antiviral activity was lost in mitochondria-depleted cells. Interestingly, exogenous uridine or orotate, the latter being a metabolite of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), abolished the antiviral activity of AR-12 and its derivatives. As DHODH is a key enzyme in the de novo pyrimidine biosynthesis pathway, these AR-12 derivatives may act by targeting pyrimidine biosynthesis in host cells to inhibit viral replication. Importantly, treatment with P12-34 significantly improved the survival of mice that were subcutaneously challenged with DENV. Thus, P12-34 may warrant further evaluation as a therapeutic to control flaviviral outbreaks. PMID- 30459408 TI - Elimination of Intracardiac Shunting Provides Stable Gas Anesthesia in Tortoises. AB - Inhalant anesthesia is challenging in chelonians due to a great capacity for breath-holding and an incomplete separation of the cardiac ventricle. Deoxygenated blood can recirculate back into systemic circulation by bypassing the lung in a process referred to as intracardiac right to left (R-L) shunting. Via electrocardiogram gated magnetic resonance imaging, a novel modality to investigate arterial flows in reptiles, intracardiac shunting and its elimination via atropine during gas anesthesia in tortoises (Chelonoidis carbonaria) was demonstrated. The great vessels of the heart were visualized confirming that after shunt-elimination, the flow (mean +/- sd) in the pulmonary arteries increased significantly (54.6 +/- 9.5 mL min-1 kg-1 vs 10.8 +/- 3.4 mL min-1 kg 1; P < 0.008). Consequently, animals required significantly lower concentrations of inhaled anesthetics to maintain a stable anesthesia. To that end, the minimum anesthetic concentration (MAC) of isoflurane needed to maintain surgical anesthesia was measured. A significantly lower MAC was found after administration of atropine (mean MAC +/- sd 2.2 +/- 0.3% vs 3.2 +/- 0.4%; P < 0.002). Previously, MAC has been indeterminable in chelonians likely due to intracardiac shunting, so this report constitutes the first MAC study performed in a tortoise. PMID- 30459410 TI - Testing the generality of non-genetic inheritance. PMID- 30459409 TI - The hippocampus underlies the association between self-esteem and physical health. AB - Self-esteem refers to the extent to which we feel positive or negative about ourselves, and reflects an individual's subjective evaluation of personal worth and attitudes about the self. As one kind of positive psychosocial resources, high self-esteem has been found to buffer the effects of stress on physical health. However, little is known about the possible neural basis underlying the association between physical health and self-esteem. In the present study, we investigated whether the hippocampus served as a neuroanatomical basis for the association between self-esteem and physical health in a large population of healthy young adults. We examined self-esteem and self-reported physical health with the Rosenberg Self Esteem Scale (RSES) and the Chinese Constitution Questionnaire (CCQ) respectively, and gray matter volume of the hippocampus was measured using magnetic resonance imaging. As expected, we found that individuals with higher levels of self-esteem had better self-reported physical health. Importantly, the mediation analysis showed that the gray matter volume of the hippocampus mediated the link between self-esteem and physical health, suggesting its critical role in the neural circuitry through which self-esteem is related to physical health. PMID- 30459411 TI - Publisher Correction: In vivo neutralization of dendrotoxin-mediated neurotoxicity of black mamba venom by oligoclonal human IgG antibodies. AB - In the original version of this Article, the sixth sentence of the first paragraph of the Introduction incorrectly read 'Particularly, elapid antivenoms often have an unbalanced antibody content with relatively low amounts of antibodies against small neurotoxic venom components that have low immunogenicity, which often leads to low immune cgqtns in production animals8 10'. The correct version states 'responses' instead of 'cgqtns'. This has been corrected in both the PDF and HTML versions of the Article. PMID- 30459412 TI - The shift in ocular dominance from short-term monocular deprivation exhibits no dependence on duration of deprivation. AB - Deprivation of visual information from one eye for a 120-minute period in normal adults results in a temporary strengthening of the patched eye's contribution to binocular vision. This plasticity for ocular dominance in adults has been demonstrated by binocular rivalry as well as binocular fusion tasks. Here, we investigate how its dynamics depend on the duration of the monocular deprivation. Using a binocular combination task, we measure the magnitude and recovery of ocular dominance change after durations of monocular deprivation ranging from 15 to 300 minutes. Surprisingly, our results show that the dynamics are of an all-or none form. There was virtually no significant dependence on the duration of the initial deprivation. PMID- 30459413 TI - Patterns of adenoid and tonsil growth in Japanese children and adolescents: A longitudinal study. AB - Lymphoid tissues, such as adenoids (Ad) and tonsils (Tn), are suggested to undergo hypertrophy during childhood and involution in adulthood. Enlargement of Ad and Tn can cause transient obstruction of the respiratory airways, thus inducing obstructive sleep apnoea. To date, the standard Ad and Tn sizes have not been reported, and there are no explicit objective criteria for evaluating their sizes or deducing whether they have enlarged, reduced, or remained constant over time. Our previous cross-sectional study revealed the age-dependent airway occupation ratio of Ad and Tn in Japanese individuals. We conducted a longitudinal observational study of the Ad and Tn sizes in Japanese individuals aged 6-20 years. Ninety individuals were retrospectively enrolled. The average and standard deviation of the sizes was calculated in 5 age-based groups. PMID- 30459415 TI - The spread of low-credibility content by social bots. AB - The massive spread of digital misinformation has been identified as a major threat to democracies. Communication, cognitive, social, and computer scientists are studying the complex causes for the viral diffusion of misinformation, while online platforms are beginning to deploy countermeasures. Little systematic, data based evidence has been published to guide these efforts. Here we analyze 14 million messages spreading 400 thousand articles on Twitter during ten months in 2016 and 2017. We find evidence that social bots played a disproportionate role in spreading articles from low-credibility sources. Bots amplify such content in the early spreading moments, before an article goes viral. They also target users with many followers through replies and mentions. Humans are vulnerable to this manipulation, resharing content posted by bots. Successful low-credibility sources are heavily supported by social bots. These results suggest that curbing social bots may be an effective strategy for mitigating the spread of online misinformation. PMID- 30459414 TI - A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts. AB - Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted re sequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G > T located in intron 4 of the MEF2D gene encoding the myocyte-specific enhancer factor 2D transcription factor and associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls, p = 0.014, CI = 1.1-10). Fisher's exact test revealed an association between the genetic variant and a triad of disease manifestations including Raynaud, anti-U1-ribonucleoprotein (anti-RNP), and anti-Smith (anti-Sm) antibodies (p = 0.00037) among the patients. The DNA-binding activity of the allele was further studied by EMSA, reporter assays, and minigenes. The region has properties of an active cell-specific enhancer, differentially affected by the alleles of rs200395694:G > T. In addition, the risk allele exerts an inhibitory effect on the splicing of the alternative tissue-specific isoform, and thus may modify the target gene set regulated by this isoform. These findings emphasize the potential of dissecting traits of complex diseases and correlating them with rare risk alleles with strong biological effects. PMID- 30459416 TI - Genome sequences identify three families of Coleoptera as morphologically derived click beetles (Elateridae). AB - Plastoceridae Crowson, 1972, Drilidae Blanchard, 1845 and Omalisidae Lacordaire, 1857 (Elateroidea) are families of the Coleoptera with obscure phylogenetic relationships and modified morphology showing neotenic traits such as soft bodies, reduced wing cases and larviform females. We shotgun sequenced genomes of Plastocerus, Drilus and Omalisus and incorporated them into data matrices of 66 and 4202 single-copy nuclear genes representing Elateroidea. Phylogenetic analyses indicate their terminal positions within the broadly defined well sclerotized and fully metamorphosed Elateridae and thus Omalisidae should now be considered as Omalisinae stat. nov. in Elateridae Leach, 1815. The results support multiple independent origins of incomplete metamorphosis in Elateridae and indicate the parallel evolution of morphological and ecological traits. Unlike other neotenic elateroids derived from the supposedly pre-adapted aposematically coloured and unpalatable soft-bodied elateroids, such as fireflies (Lampyridae) and net-winged beetles (Lycidae), omalisids and drilids evolved from well-sclerotized click beetles. These findings suggest sudden morphological shifts through incomplete metamorphosis, with important implications for macroevolution, including reduced speciation rate and high extinction risk in unstable habitats. Precise phylogenetic placement is necessary for studies of the molecular mechanisms of ontogenetic shifts leading to profoundly changed morphology. PMID- 30459417 TI - Chemical and sensorial investigation of in-mouth sensory properties of grape anthocyanins. AB - Anthocyanins are water-soluble pigments found in the cell vacuoles of fruits and flowers, performing several roles from insects attraction to stress protection. Their antioxidant activity contributes to human health, and consuming plant derived products provides their higher source in the diet. Although their colour and nutritional features, their contribution to sensory properties of foods has not been widely investigated. In wine, preferences are connected with sensory attributes of colour, aroma, taste, and mouthfeel. In this study, grape anthocyanin extracts (TAE) were fractionated using centrifugal partition chromatography (CPC) and preparative HPLC in three fractions, i.e glucoside (GF), acetylated (AF) and cinnamoylated (CF) anthocyanins. Sensory properties were investigated by chemical analysis, as reactivity towards bovin serum albumin (BSA) and salivary proteins, and in tasting sessions to assess anthocyanins best estimated thresholds (BET) in wine-like solution. Anthocyanins reacted with both BSA and salivary proteins, but to different extents, because higher interaction between salivary proteins and anthocyanins were found. Cinnamoylated anthocyanins are the most reactive to salivary proteins. Tasting sessions suggested an involvement of anthocyanins as in-mouth contributors in wine, since their BETs were 255, 297, 68, and 58 mg/L for TAE, GF, AF, and CF, respectively, and the descriptors reported were astringency and bitterness. PMID- 30459419 TI - Unsung heroes of the scientific record deserve credit. PMID- 30459420 TI - Three-dimensional (3D) morphology of Sansha Yongle Blue Hole in the South China Sea revealed by underwater remotely operated vehicle. AB - The Sansha Yongle Blue Hole (SYBH) is the deepest blue hole found anywhere to date. Study of the SYBH can provide insight into the interactions between hole wall morphology and many geological/hydrological mechanisms. A comprehensive investigation of the SYBH was carried out for the first time in 2017 using a professional-grade underwater remotely operated vehicle (ROV) to obtain accurate depth and three-dimensional (3D) topographic data. The SYBH resembles a ballet dancer's shoe and has a volume of ~499609 m3. The observed deepest portion of the SYBH is at 301.19 m below the local 10-year mean sea level. The cave bottom laterally deviates from its entrance by 118 m at an azimuth of 219 degrees. The cave entrance is shaped like a comma and has an average width of 130 m; the widest part is 162.3 m wide, while the narrowest part is 26.2 m wide and is at 279 mbsl (meters below sea level). The 3D topography of the SYBH and underwater photography revealed two large transitions at ~76 to 78 mbsl and at 158 mbsl, indicating that the initiation of the blue hole was likely a step wise process and that the hole wall morphology was subsequently remolded through a paleo-sea level stillstand (at or near Younger Dryas). The topographic data also indicated that the blue hole is situated within an isolated environment with no water or material exchange with the outside open sea. PMID- 30459418 TI - A single-cycle replicable Rift Valley fever phlebovirus vaccine carrying a mutated NSs confers full protection from lethal challenge in mice. AB - Rift Valley fever phlebovirus (RVFV) is a pathogen of Rift Valley fever, which is a mosquito-borne zoonotic disease for domestic livestock and humans in African countries. Currently, no approved vaccine is available for use in non-endemic areas. The MP-12 strain is so far the best live attenuated RVFV vaccine candidate because of its good protective efficacy in animal models. However, there are safety concerns for use of MP-12 in humans. We previously developed a single cycle replicable MP-12 (scMP-12) which lacks NSs gene and undergoes only a single round of viral replication because of its impaired ability to induce membrane membrane fusion. In the present study, we generated an scMP-12 mutant (scMP-12 mutNSs) carrying a mutant NSs, which degrades double-stranded RNA-dependent protein kinase R but does not inhibit host transcription. Immunization of mice with a single dose (105 PFU) of scMP-12-mutNSs elicited RVFV neutralizing antibodies and high titers of anti-N IgG production and fully protected the mice from lethal wild-type RVFV challenge. Immunogenicity and protective efficacy of scMP-12-mutNSs were better than scMP-12, demonstrating that scMP-12-mutNSs is a more efficacious vaccine candidate than scMP-12. Furthermore, our data suggested that RVFV vaccine efficacy can be improved by using this specific NSs mutant. PMID- 30459421 TI - The structure and function of the global citrus rhizosphere microbiome. AB - Citrus is a globally important, perennial fruit crop whose rhizosphere microbiome is thought to play an important role in promoting citrus growth and health. Here, we report a comprehensive analysis of the structural and functional composition of the citrus rhizosphere microbiome. We use both amplicon and deep shotgun metagenomic sequencing of bulk soil and rhizosphere samples collected across distinct biogeographical regions from six continents. Predominant taxa include Proteobacteria, Actinobacteria, Acidobacteria and Bacteroidetes. The core citrus rhizosphere microbiome comprises Pseudomonas, Agrobacterium, Cupriavidus, Bradyrhizobium, Rhizobium, Mesorhizobium, Burkholderia, Cellvibrio, Sphingomonas, Variovorax and Paraburkholderia, some of which are potential plant beneficial microbes. We also identify over-represented microbial functional traits mediating plant-microbe and microbe-microbe interactions, nutrition acquisition and plant growth promotion in citrus rhizosphere. The results provide valuable information to guide microbial isolation and culturing and, potentially, to harness the power of the microbiome to improve plant production and health. PMID- 30459422 TI - Cell wall mannan of Candida krusei mediates dendritic cell apoptosis and orchestrates Th17 polarization via TLR-2/MyD88-dependent pathway. AB - Dendritic cells (DCs) abundantly express diverse receptors to recognize mannans in the outer surface of Candida cell wall, and these interactions dictate the host immune responses that determine disease outcomes. C. krusei prevalence in candidiasis worldwide has increased since this pathogen has developed multidrug resistance. However, little is known how the immune system responds to C. krusei. Particularly, the molecular mechanisms of the interplay between C. krusei mannan and DCs remain to be elucidated. We investigated how C. krusei mannan affected DC responses in comparison to C. albicans, C. tropicalis and C. glabrata mannan. Our results showed that only C. krusei mannan induced massive cytokine responses in DCs, and led to apoptosis. Although C. krusei mannan-activated DCs underwent apoptosis, they were still capable of initiating Th17 response. C. krusei mannan mediated DC apoptosis was obligated to the TLR2 and MyD88 pathway. These pathways also controlled Th1/Th17 switching possibly by virtue of the production of the polarizing cytokines IL-12 and IL-6 by the C. krusei mannan activated-DCs. Our study suggests that TLR2 and MyD88 pathway in DCs are dominant for C. krusei mannan recognition, which differs from the previous reports showing a crucial role of C-type lectin receptors in Candida mannan sensing. PMID- 30459423 TI - Morphological evolution of upconversion nanoparticles and their biomedical signal generation. AB - Advancements in the fabrication of upconversion nanoparticles (UCNPs) for synthetic control can enable a broad range of applications in biomedical systems. Herein, we experimentally verified the role of the hydrothermal reaction (HR) time in the synthesis of NaYF4:20%Yb3+/3%Er3+ UCNPs on their morphological evolution and phase transformation at different temperatures. Characterizations of the as-prepared UCNPs were conducted using X-ray diffraction (XRD), electron microscopy and spectroscopy, and thermogravimetric and upconversion (UC) luminescence analysis. We demonstrated that determining the optimal HR time, also referred to here as the threshold time, can produce particles with good homogeneity, hexagonal phase, and UC luminescence efficiency. Subsequently, the polymer coated UCNPs maintained their original particle size distribution and luminescence properties, and showed improved dispersibility in a variety of solvents, cellular nontoxicity, in vitro bioimaging, and biocompatibility as compared to the bare UCNP. Besides this, polyacrylic acid conjugated UCNPs (UCNP@PAA) also revealed the strong anticancer effect by conjugating with doxorubicin (DOX) as compared to the free DOX. Based on these findings, we suggest that these particles will be useful in drug-delivery systems and as in vivo bioimaging agents synchronously. PMID- 30459424 TI - Author Correction: Evaluating Tumor Evolution via Genomic Profiling of Individual Tumor Spheroids in a Malignant Ascites. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30459425 TI - Activation Stoichiometry and Pore Architecture of TRPA1 Probed with Channel Concatemers. AB - The nociceptor ion channel TRPA1 detects a wide range of hazardous chemicals, including reactive electrophiles such as cinnamaldehyde, which gate the channel allowing Na+ and Ca2+ entry. TRPA1 assembles as a tetramer, with a central pore within which an aspartate residue (D918) determines Ca2+ permeability. Here, we report that introduction of histidine at this position, D918H, makes TRPA1 channels sensitive to block by nanomolar concentration of Zn2+ and can be used to functionally tag subunits in concatemers. Concatemers with increasing numbers of D918H subunits display increasing sensitivity to Zn2+ inhibition, indicating that the four side chains at position 918 of the tetramer directly coordinate Zn2+ and other permeating divalent cations. In the published structure of TRPA1, this requires a rearrangement of the pore region which may represent the true open state of the channel. Concatemeric channels containing subunits mutated to be insensitive to reactive electrophiles (C622S) could be activated by cinnamaldehyde when as few as two subunits contained intact ligand binding sites. Activation upon liganding of just two of the four possible subunits may represent an optimal strategy to rapidly and reliably detect noxious chemicals. PMID- 30459426 TI - Observation of bound state self-interaction in a nano-eV atom collider. AB - Quantum mechanical scattering resonances for colliding particles occur when a continuum scattering state couples to a discrete bound state between them. The coupling also causes the bound state to interact with itself via the continuum and leads to a shift in the bound state energy, but, lacking knowledge of the bare bound state energy, measuring this self-energy via the resonance position has remained elusive. Here, we report on the direct observation of self interaction by using a nano-eV atom collider to track the position of a magnetically-tunable Feshbach resonance through a parameter space spanned by energy and magnetic field. Our system of potassium and rubidium atoms displays a strongly non-monotonic resonance trajectory with an exceptionally large self interaction energy arising from an interplay between the Feshbach bound state and a different, virtual bound state at a fixed energy near threshold. PMID- 30459427 TI - Mapping heterogeneous polarity in multicompartment nanoparticles. AB - Understanding polarity gradients inside nanomaterials is essential to capture their potential as nanoreactors, catalysts or in drug delivery applications. We propose here a method to obtain detailed, quantitative information on heterogeneous polarity in multicompartment nanostructures. The method is based on a 2-steps procedure, (i) deconvolution of complex emission spectra of two solvatochromic probes followed by (ii) spectrally resolved analysis of FRET between the same solvatochromic dyes. While the first step yields a list of polarities probed in the nanomaterial suspension, the second step correlates the polarities in space. Colocalization of polarities falling within few nanometer radius is obtained via FRET, a process called here nanopolarity mapping. Here, Prodan and Nile Red are tested to map the polarity of a water-dispersable, multicompartment nanostructure, named PluS nanoparticle (NPs). PluS NPs are uniform core-shell nanoparticles with silica cores (diameter ~10 nm) and Pluronic F127 shell (thickness ~7 nm). The probes report on a wide range of nanopolarities among which the dyes efficiently exchange energy via FRET, demonstrating the coexistence of a rich variety of environments within nanometer distance. Their use as a FRET couple highlights the proximity of strongly hydrophobic sites and hydrated layers, and quantitatively accounts for the emission component related to external water, which remains unaffected by FRET processes. This method is general and applicable to map nanopolarity in a large variety of nanomaterials. PMID- 30459428 TI - Cryo-EM structure of Type III-A CRISPR effector complex. PMID- 30459429 TI - Cytarabine + G-CSF is more effective than cyclophosphamide + G-CSF as a stem cell mobilization regimen in multiple myeloma. AB - Cyclophosphamide (Cy) plus granulocyte-colony stimulating factor (G-CSF) is currently a standard regimen for hematopoietic stem cell (HSC) mobilization in patients with multiple myeloma (MM). However, cytarabine (AraC) in intermediate doses plus G-CSF seems to have a higher mobilization efficacy. The aim of this study was to retrospectively compare mobilization using AraC and Cy. Thirty consecutive MM patients were mobilized by Cy + G-CSF, and the subsequent 40 patients by AraC + G-CSF. Both groups were comparable. The target yield of 10 * 106 CD34+ cells/kg (for tandem and 2 additional transplantations) was achieved in 98% (AraC) and 57% (Cy) of patients (p < 0.0001) by 1.2 and 2.1 apheresis (means), and by single apheresis in 83 and 17% of patients, respectively. AraC mobilization resulted in higher peak concentration of CD34+ cells in blood (median 238.0 vs. 87.9/uL, p < 0.0001) and higher CD34+ yield (median 28.6 * 106 vs. 10.4 * 106/kg, p < 0.0001) compared to Cy mobilization. Toxicities were comparable except for thrombocytopenia gr. 4, observed in 50% of patients after AraC (Cy 7%). In view of these results, we conclude that mobilization with AraC plus G-CSF is very effective with acceptable toxicity and could be considered in MM patients with planned or expected higher numbers of transplantations. PMID- 30459430 TI - Crossover from positive to negative optical torque in mesoscale optical matter. AB - The photons in circularly polarized light can transfer their quantized spin angular momentum to micro- and nanostructures via absorption and scattering. This normally exerts positive torque on the objects wher the sign (i.e., handedness or angular direction) follows that of the spin angular momentum. Here we show that the sign of the optical torque can be negative in mesoscopic optical matter arrays of metal nanoparticles (NPs) assembled in circularly polarized optical traps. Crossover from positive to negative optical torque, which occurs for arrays with different number, separation and configuration of the constituent particles, is shown to result from many-body interactions as clarified by electrodynamics simulations. Our results establish that both positive and negative optical torque can be readily realized and controlled in optical matter arrays. This property and reconfigurability of the arrays makes possible programmable materials for optomechanical, microrheological and biological applications. PMID- 30459431 TI - Interannual and decadal variability of the North Equatorial Undercurrents in an eddy-resolving ocean model. AB - In the present study, the mean states of the North Equatorial Undercurrents (NEUCs) simulated in an eddy-resolving ocean model are evaluated, and the variability of the three NEUC jets is analyzed. This analysis provides a reference for future observations regarding how long the in-situ observations should be conducted to obtain a complete picture of NEUCs. We show that the primary features of the three eastward NEUC jets are fairly well reproduced by the high-resolution model of LICOM, such as the locations, tilting directions and widths of the three jets. However, the simulated NEUCs have slightly weaker magnitude and are located at shallower depths. In addition, two dominant time scales on interannual (2-7 years) and decadal (12-19 years) time scales for all three NEUC jets are found in a 39-year high-resolution LICOM simulation, although the latter is not statistically significant. The variation of these jets is related to the remarkable interannual and decadal variability in the Pacific Ocean. Our decomposition analysis indicates that both the small- and large-scale currents contribute to the total variation. Furthermore, the low-pass temporal filter of zonal velocity shows that the quasi-steady cross-basin NEUC jets can only emerge on time scales longer than the interannual periodicity. PMID- 30459432 TI - Assessing the elastic properties of skeletal muscle and tendon using shearwave ultrasound elastography and MyotonPRO. AB - The purposes of this study were to compare Young's modulus values determined by shear wave ultrasound elastography (SWUE) with stiffness index obtained using a hand-held MyotonPRO device on the resting stiffness of gastrocnemius muscle belly and Achilles tendon; and to examine the test-retest reliability of those stiffness measurement using hand-held MyotonPRO. Twenty healthy volunteers participated in the study. The measurement values of muscle and tendon was determined in dominant legs. Each marker point was assessed using MyotonPRO and SWUE, respectively. Intra-operator reliability of MyotonPRO was established in 10 of the subjects. The correlation coefficients between the values of muscle and tendon stiffness indices determined by MyotonPRO and SWUE were calculated. Significant correlations were found for muscle and tendon stiffness and Young's modulus ranged from 0.463 to 0.544 (all P < 0.05). The intra-operator reliability ranged from good to excellent (ICC(3,1) = 0.787~0.928). These results suggest that the resting stiffness of gastrocnemius muscle belly and Achilles tendon measured by MyotonPRO is related to the Young's modulus of those quantified by SWUE. The MyotonPRO shows good intra-operator repeatability. Therefore, the present study shows that MyotonPRO can be used to assess mechanical properties of gastrocnemius muscle belly and Achilles tendon with a resting condition. PMID- 30459433 TI - Direct isotopic evidence of biogenic methane production and efflux from beneath a temperate glacier. AB - The base of glaciers and ice sheets provide environments suitable for the production of methane. High pressure conditions beneath the impermeable 'cap' of overlying ice promote entrapment of methane reserves that can be released to the atmosphere during ice thinning and meltwater evacuation. However, contemporary glaciers and ice sheets are rarely accounted for as methane contributors through field measurements. Here, we present direct field-based evidence of methane production and release from beneath the Icelandic glacier Solheimajokull, where geothermal activity creates sub-oxic conditions suited to methane production and preservation along the meltwater flow path. Methane production at the glacier bed (48 tonnes per day, or 39 mM CH4 m-2 day-1), and evasion to the atmosphere from the proglacial stream (41 tonnes per day, or 32 M CH4 m-2 day-1) indicates considerable production and release to the atmosphere during the summer melt season. Isotopic signatures (-60.20/00 to -7.60/00 for delta13CCH4 and -324.30/00 to +161.10/00 for DCH4), support a biogenic signature within waters emerging from the subglacial environment. Temperate glacial methane production and release may thus be a significant and hitherto unresolved contributor of a potent greenhouse gas to the atmosphere. PMID- 30459434 TI - Establishment of an efficient in vitro propagation system for Iris sanguinea. AB - Iris sanguinea is a perennial flowering plant that is typically cultivated through seeds or bulbs. However, due to limitations in conventional propagation, an alternate regeneration system using seeds was developed. The protocol included optimization of sterilization, stratification and scarification methods as iris seeds exhibit physiological dormancy. In addition to chlorine-based disinfection, alkaline or heat treatment was used to break seed dormancy and reduce contamination. When seeds were soaked in water at 80 degrees C overnight, and sterilized with 75% EtOH for 30 s and 4% NaOCl solution for 20 minutes, contamination was reduced to 10% and a 73.3% germination was achieved. The germinated seedlings with 2-3 leaves and radicle were used as explants to induce adventitious buds. The optimal MS medium with 0.5 mg L-1 6-benzylaminopurine, 0.2 mg L-1 NAA, and 1.0 mg L-1 kinetin resulted in 93.3% shoot induction and a proliferation coefficient of 5.30. Medium with 0.5 mg L-1 NAA achieved 96.4% rooting of the adventitious shoots. The survival rate was more than 90% after 30 days growth in the cultivated matrix. In conclusion, a successful regeneration system for propagation of I. sanguinea was developed using seeds, which could be utilized for large-scale propagation of irises of ecological and horticultural importance. PMID- 30459435 TI - Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have differential effects on cystic fibrosis macrophage function. AB - Despite the addition of cystic fibrosis transmembrane conductance regulator (CFTR) modulators to the cystic fibrosis (CF) treatment regimen, patients with CF continue to suffer from chronic bacterial infections that lead to progressive respiratory morbidity. Host immunity, and macrophage dysfunction specifically, has an integral role in the inability of patients with CF to clear bacterial infections. We sought to characterize macrophage responses to CFTR modulator treatment as we hypothesized that there would be differential effects based on patient genotype. Human CF and non-CF peripheral blood monocyte-derived macrophages (MDMs) were analyzed for CFTR expression, apoptosis, polarization, phagocytosis, bacterial killing, and cytokine production via microscopy, flow cytometry, and ELISA-based assays. Compared to non-CF MDMs, CF MDMs display decreased CFTR expression, increased apoptosis, and decreased phagocytosis. CFTR expression increased and apoptosis decreased in response to ivacaftor or lumacaftor/ivacaftor therapy, and phagocytosis improved with ivacaftor alone. Ivacaftor restored CF macrophage polarization responses to non-CF levels and reduced Pseudomonas aeruginosa bacterial burden, but did not reduce other bacterial loads. Macrophage inflammatory cytokine production decreased in response to ivacaftor alone. In summary, ivacaftor and lumacaftor/ivacaftor have differential impacts on macrophage function with minimal changes observed in CF patients treated with lumacaftor/ivacaftor. Overall improvements in macrophage function in ivacaftor-treated CF patients result in modestly improved macrophage mediated bacterial killing. PMID- 30459436 TI - Downregulation of intratumoral expression of miR-205, miR-200c and miR-125b in primary human cutaneous melanomas predicts shorter survival. AB - While only 15-25 percent of melanoma patients develop distant metastasis and die, this disease is still responsible for the majority of skin cancer-related deaths. The availability of adjuvant therapies makes the selection of high-risk patients essential. We evaluated the intratumoral expression of ten miRNAs in primary melanomas in relation to its ability to predict melanoma survival. To this end, we correlated miRNA expression in 132 cryopreserved primary and metastatic tumors with clinicopathological factors and clinical outcome. We found sequential downregulation of intratumoral expression of miR-125b, miR-182, miR-200c and miR 205 over the full spectrum of melanoma progression. Moreover, downregulation of these miRNAs occurred in primary melanomas that further disseminated to distant sites. Furthermore, miR-125b, miR-200c and miR-205 correlated as independent factors with shorter survival. Our in vitro findings demonstrate that loss of miR 205 potentiates the invasive ability of melanoma cells. We conclude that the downregulation of miR-205 in primary melanomas is an intrinsic property that might contribute to distant metastasis. In particular, the interaction of melanoma cells with the extracellular matrix is one of the key mechanisms by which miR-205 influences melanoma metastasis. In conclusion, miR-125b, miR-200c and miR-205 are useful prognostic biomarkers at the time of diagnosis to select high-risk patients. PMID- 30459438 TI - Real-time tropospheric delay retrieval with GPS, GLONASS, Galileo and BDS data. AB - The precise point positioning (PPP) is a promising technology for the real-time retrieval of atmospheric parameters with a single receiver in anywhere, all weather and any time. The real-time atmospheric parameters can be applied to the time-critical meteorology, such as the severe weather nowcasting. The PPP is a satellite-based technology. Multi-constellation integration can enhance satellite geometry and increase measurement redundancy so that the solutions of atmospheric parameters are expected to be improved. Currently, the Global Navigation Satellite System (GNSS) family includes recovered GLONASS and modernized GPS as well as the emerging Galileo and BDS. A week of GNSS observations from 160 stations are processed to retrieve the tropospheric zenith total delay (ZTD) in real time. The four-constellation mixed real-time precise products including satellite orbit and clock corrections are adopted, and their quality is evaluated. The performance of ZTD estimates is assessed in terms of accuracy and convergence time by comparing with final tropospheric ZTD products provided by two analysis centers. The ZTDs retrieved from different constellation combinations (i.e., GPS/GLONASS/Galileo/BDS, GPS/GLONASS, and GPS-only), different processing models for ionospheric delays (i.e., ionospheric-free (IF) combined PPP, and uncombined (UC) PPP), and different modes (i.e., real-time mode, and post-processing mode) are compared. PMID- 30459437 TI - Photobiomodulation (PBM) promotes angiogenesis in-vitro and in chick embryo chorioallantoic membrane model. AB - The application of light in various therapeutic settings known as Photobiomodulation (PBM) is well established. Indications are the improvement of wound healing and tissue regeneration, scarring, and perfusion as well as pain therapy. Tissue perfusion is mandatory for successful wound healing. Nevertheless, there is a lack of mechanistic studies. We investigate the potential effect of PBM from light emitting diodes (LED) at 635 nm, 80 mW/cm2, 24 J/cm2 on angiogenesis in a two-part study: 1.) Investigation of the effect of PBM on the proliferation of endothelial cells and on vasculogenesis in a co-culture model of endothelial cells and stem cells. 2.) Investigation of the influence of PBM at chick egg chorioallantoic membrane (CAM) assays with fresh human skin xenografts. In both study phases, we observed a stimulating effect of PBM at 635 nm; in part 1: for proliferation of HUVEC (human umbilical vein endothelial cells) (25833 +/- 12859 versus 63002 +/- 35760 cells/well, p < 0.05, for cellular network formation (2.1 +/- 2.1 versus 4.6 +/- 3.5, p < 0.05) and for less cell compactness p = 0.01; in part 2: for the increase of number of vessel junctions per ROI (region of interest) (15.9 +/- 2.6 versus 20.8 +/- 5.4, p < 0.05). Our results suggest significant promotion of angiogenesis by PBM at 635 nm in vitro and in vivo. PMID- 30459439 TI - Understanding the Thalidomide Chirality in Biological Processes by the Self disproportionation of Enantiomers. AB - Twenty years after the thalidomide disaster in the late 1950s, Blaschke et al. reported that only the (S)-enantiomer of thalidomide is teratogenic. However, other work has shown that the enantiomers of thalidomide interconvert in vivo, which begs the question: why is teratogen activity not observed in animal experiments that use (R)-thalidomide given the ready in vivo racemization ("thalidomide paradox")? Herein, we disclose a hypothesis to explain this "thalidomide paradox" through the in-vivo self-disproportionation of enantiomers. Upon stirring a 20% ee solution of thalidomide in a given solvent, significant enantiomeric enrichment of up to 98% ee was observed reproducibly in solution. We hypothesize that a fraction of thalidomide enantiomers epimerizes in vivo, followed by precipitation of racemic thalidomide in (R/S)-heterodimeric form. Thus, racemic thalidomide is most likely removed from biological processes upon racemic precipitation in (R/S)-heterodimeric form. On the other hand, enantiomerically pure thalidomide remains in solution, affording the observed biological experimental results: the (S)-enantiomer is teratogenic, while the (R) enantiomer is not. PMID- 30459440 TI - Collagen density modulates triple-negative breast cancer cell metabolism through adhesion-mediated contractility. AB - Extracellular matrix (ECM) mechanical properties upregulate cancer invasion, cell contractility, and focal adhesion formation. Alteration in energy metabolism is a known characteristic of cancer cells (i.e., Warburg effect) and modulates cell invasion. There is little evidence to show if collagen density can alter cancer cell metabolism. We investigated changes in energy metabolism due to collagen density in five breast cell lines by measuring the fluorescence lifetime of NADH. We found that only triple-negative breast cancer cells, MDA-MB231 and MDA-MB468 cells, had an increased population of bound NADH, indicating an oxidative phosphorylation (OXPHOS) signature, as collagen density decreased. When inhibiting ROCK and cell contractility, MDA-MB231 cells on glass shifted from glycolysis (GLY) to OXPHOS, confirming the intricate relationship between mechanosensing and metabolism. MCF10A cells showed less significant changes in metabolism, shifting towards GLY as collagen density decreased. The MCF-7 and T 47D, less invasive breast cancer cells, compared to the MDA-MB231 and MDA-MB468 cells, showed no changes regardless of substrate. In addition, OXPHOS or GLY inhibitors in MDA-MB231 cells showed dramatic shifts from OXPHOS to GLY or vice versa. These results provide an important link between cellular metabolism, contractility, and collagen density in human breast cancer. PMID- 30459442 TI - IL-23R Signaling Plays No Role in Myocardial Infarction. AB - Ischemic heart diseases are the most frequent diseases in the western world. Apart from Interleukin (IL-)1, inflammatory therapeutic targets in the clinic are still missing. Interestingly, opposing roles of the pro-inflammatory cytokine IL 23 have been described in cardiac ischemia in mice. IL-23 is a composite cytokine consisting of p19 and p40 which binds to IL-23R and IL-12Rbeta1 to initiate signal transduction characterized by activation of the Jak/STAT, PI3K and Ras/Raf/MAPK pathways. Here, we generate IL-23R-Y416FDeltaICD signaling deficient mice and challenged these mice in close- and open-chest left anterior descending coronary arteria ischemia/reperfusion experiments. Our experiments showed only minimal changes in all assayed parameters in IL-23R signaling deficient mice compared to wild-type mice in ischemia and for up to four weeks of reperfusion, including ejection fraction, endsystolic volume, enddiastolic volume, infarct size, gene regulation and alpha smooth muscle actin (alphaSMA) and Hyaluronic acid (HA) protein expression. Moreover, injection of IL-23 in wild-type mice after LAD ischemia/reperfusion had also no influence on the outcome of the healing phase. Our data showed that IL-23R deficiency has no effects in myocardial I/R. PMID- 30459444 TI - 3D Inkjet Printing of Complex, Cell-Laden Hydrogel Structures. AB - Inkjet printing is widely considered a promising strategy to pattern hydrogels and living cells into three-dimensional (3D) constructs that structurally resemble tissues in our body. However, this approach is currently constrained by the limited control over multi-component deposition: the variable droplet ejection characteristics of different bioinks and dispensing units make synchronized printing very challenging. This invariably results in artificial tissues that lack the complexity and function of their native counterparts. By careful optimization of the printing parameters for two different bioink formulations, here we report the inkjet-based 3D-patterning of hydrogels according to relatively complex blueprints. 3D printing of bioinks containing living cells resulted in high-resolution, multi-component living constructs. Finally, we describe a sacrificial material approach to inkjet print perfuseable channels for improved long-term cultures of larger samples. We believe that this work provides a foundation for the generation of more complex 3D tissue models by inkjet printing. PMID- 30459441 TI - Metabolomics and transcriptomics pathway approach reveals outcome-specific perturbations in COPD. AB - Chronic obstructive pulmonary disease (COPD) comprises multiple phenotypes such as airflow obstruction, emphysema, and frequent episodes of acute worsening of respiratory symptoms, known as exacerbations. The goal of this pilot study was to test the usefulness of unbiased metabolomics and transcriptomics approaches to delineate biological pathways associated with COPD phenotypes and outcomes. Blood was collected from 149 current or former smokers with or without COPD and separated into peripheral blood mononuclear cells (PBMC) and plasma. PBMCs and plasma were analyzed using microarray and liquid chromatography mass spectrometry, respectively. Statistically significant transcripts and compounds were mapped to pathways using IMPaLA. Results showed that glycerophospholipid metabolism was associated with worse airflow obstruction and more COPD exacerbations. Sphingolipid metabolism was associated with worse lung function outcomes and exacerbation severity requiring hospitalizations. The strongest associations between a pathway and a certain COPD outcome were: fat digestion and absorption and T cell receptor signaling with lung function outcomes; antigen processing with exacerbation frequency; arginine and proline metabolism with exacerbation severity; and oxidative phosphorylation with emphysema. Overlaying transcriptomic and metabolomics datasets across pathways enabled outcome and phenotypic differences to be determined. Findings are relevant for identifying molecular targets for animal intervention studies and early intervention markers in human cohorts. PMID- 30459443 TI - CMV and EBV targets recognized by tumor-infiltrating B lymphocytes in pancreatic cancer and brain tumors. AB - Targeted antiviral immune responses to the widespread human pathogens cytomegalovirus (CMV) and Epstein-Barr virus (EBV) play a pivotal role in determining immune fitness. We show here for the first time that tumor infiltrating B cell (TIB)- derived immunoglobulin G (IgG) from patients with pancreatic cancer or glioblastoma have unique anti-CMV/EBV immune recognition patterns compared to serum IgG. There is also great heterogeneity between patients, as well as between serum and TIB-IgG, while some viral targets elicited strongly both T-cell and IgG reactivity in tumor infiltrating T- and B-cells. These observations suggest that the anti-CMV/EBV humoral immune response in situ is highly unique and can be instrumental in developing next-generation immuno biomarkers in addition to supplementing cellular therapy strategies for personalized cancer therapy targeting CMV or EBV in the tumor microenvironment. PMID- 30459445 TI - Correction: ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations. AB - Following the publication of this article the authors noted an error in figure 4. In sub-panels D-F, the y-axis should read "apoE (ng/mg protein)" as opposed to "apoE (ng/ml)". The authors apologize for any inconvenience caused. PMID- 30459447 TI - The obese adipose tissue microenvironment in cancer development and progression. AB - Obesity is associated with both increased cancer incidence and progression in multiple tumour types, and is estimated to contribute to up to 20% of cancer related deaths. These associations are driven, in part, by metabolic and inflammatory changes in adipose tissue that disrupt physiological homeostasis both within local tissues and systemically. However, the mechanisms underlying the obesity-cancer relationship are poorly understood. In this Review, we describe how the adipose tissue microenvironment (ATME) evolves during body weight gain, and how these changes might influence tumour initiation and progression. We focus on multiple facets of ATME physiology, including inflammation, vascularity and fibrosis, and discuss therapeutic interventions that have the potential to normalize the ATME, which might be translationally relevant for cancer prevention and therapy. Given that the prevalence of obesity is increasing on an international scale, translational research initiatives are urgently needed to provide mechanistic explanations for the obesity-cancer relationship, and how to best identify high-risk individuals without relying on crude measures, such as BMI. PMID- 30459446 TI - GBF1 and Arf1 interact with Miro and regulate mitochondrial positioning within cells. AB - The spatial organization of cells depends on coordination between cytoskeletal systems and intracellular organelles. The Arf1 small G protein and its activator GBF1 are important regulators of Golgi organization, maintaining its morphology and function. Here we show that GBF1 and its substrate Arf1 regulate the spatial organization of mitochondria in a microtubule-dependent manner. Miro is a mitochondrial membrane protein that interacts through adaptors with microtubule motor proteins such as cytoplasmic dynein, the major microtubule minus end directed motor. We demonstrate a physical interaction between GBF1 and Miro, and also between the active GTP-bound form of Arf1 and Miro. Inhibition of GBF1, inhibition of Arf1 activation, or overexpression of Miro, caused a collapse of the mitochondrial network towards the centrosome. The change in mitochondrial morphology upon GBF1 inhibition was due to a two-fold increase in the time engaged in retrograde movement compared to control conditions. Electron tomography revealed that GBF1 inhibition also resulted in larger mitochondria with more complex morphology. Miro silencing or drug inhibition of cytoplasmic dynein activity blocked the GBF1-dependent repositioning of mitochondria. Our results show that blocking GBF1 function promotes dynein- and Miro-dependent retrograde mitochondrial transport along microtubules towards the microtubule organizing center, where they form an interconnected network. PMID- 30459448 TI - Vasoinhibin comprises a three-helix bundle and its antiangiogenic domain is located within the first 79 residues. AB - Vasoinhibin belongs to a family of angiogenesis inhibitors generated when the fourth alpha-helix (H4) of the hormone prolactin (PRL) is removed by specific proteolytic cleavage. The antiangiogenic properties are absent in uncleaved PRL, indicating that conformational changes create a new bioactive domain. However, the solution structure of vasoinhibin and the location of its bioactive domain are unknown. Molecular dynamic simulation (MD) showed that the loss of H4 exposes the hydrophobic nucleus of PRL and leads to the compression of the molecule into a three-helix bundle that buries the hydrophobic nucleus again. Compression occurs by the movement of loop 1 (L1) and its interaction with alpha-helix 1 (H1) generating a new L1 conformation with electrostatic and hydrophobic surfaces distinct from those of PRL, that may correspond to a bioactive domain. Consistent with this model, a recombinant protein containing the first 79 amino acids comprising H1 and L1 of human PRL inhibited the proliferation and migration of endothelial cells and upregulated the vasoinhibin target genes, IL1A and ICAM1. This bioactivity was comparable to that of a conventional vasoinhibin having the 123 residues encompassing H1, L1, Eta2, L2, and Eta3 of human PRL. These findings extend the vasoinhibin family to smaller proteins and provide important structural information, which will aid in antiangiogenic drug development. PMID- 30459449 TI - Expression of the POTE gene family in human ovarian cancer. AB - The POTE family includes 14 genes in three phylogenetic groups. We determined POTE mRNA expression in normal tissues, epithelial ovarian and high-grade serous ovarian cancer (EOC, HGSC), and pan-cancer, and determined the relationship of POTE expression to ovarian cancer clinicopathology. Groups 1 & 2 POTEs showed testis-specific expression in normal tissues, consistent with assignment as cancer-testis antigens (CTAs), while Group 3 POTEs were expressed in several normal tissues, indicating they are not CTAs. Pan-POTE and individual POTEs showed significantly elevated expression in EOC and HGSC compared to normal controls. Pan-POTE correlated with increased stage, grade, and the HGSC subtype. Select individual POTEs showed increased expression in recurrent HGSC, and POTEE specifically associated with reduced HGSC OS. Consistent with tumors, EOC cell lines had significantly elevated Pan-POTE compared to OSE and FTE cells. Notably, Group 1 & 2 POTEs (POTEs A/B/B2/C/D), Group 3 POTE-actin genes (POTEs E/F/I/J/KP), and other Group 3 POTEs (POTEs G/H/M) show within-group correlated expression, and pan-cancer analyses of tumors and cell lines confirmed this relationship. Based on their restricted expression in normal tissues and increased expression and association with poor prognosis in ovarian cancer, POTEs are potential oncogenes and therapeutic targets in this malignancy. PMID- 30459450 TI - Comparison of the genomic background of MET-altered carcinomas of the lung: biological differences and analogies. AB - Although non-small-cell lung cancer is a leading cause of cancer-related deaths, the molecular characterization and classification of its genetic alterations has drastically changed treatment options and overall survival within the last few decades. In particular, tyrosine kinase inhibitors targeting specific molecular alterations, among other MET, have greatly improved the prognosis of non-small cell lung cancer patients. Here, we compare the genomic background of a subset of non-small-cell lung cancer cases harboring either a MET high-level amplification (n = 24) or a MET exon 14 skipping mutation (n = 26), using next-generatison sequencing, fluorescence in situ hybridization, immunohistochemistry, and Nanostring nCounter(r) technology. We demonstrate that the MET-amplified cohort shows a higher genetic instability, compared with the mutant cohort (p < 0.001). Furthermore, MET mutations occur at high allele frequency and in the presence of co-occurring TP53 mutations (n = 7), as well as MDM2 (n = 7), CDK4 (n = 6), and HMGA2 (n = 5) co-amplifications. No other potential driver mutation has been detected. Conversely, in the MET-amplified group, we identify co-occurring pathogenic NRAS and KRAS mutations (n = 5) and a significantly higher number of TP53 mutations, compared with the MET-mutant cohort (p = 0.048). Of note, MET amplifications occur more frequently as subclonal events. Interestingly, despite the significantly (p = 0.00103) older age at diagnosis of stage IIIb/IV of MET mutant patients (median 77 years), compared with MET high-level amplified patients (median 69 years), MET-mutant patients with advanced-stage tumors showed a significantly better prognosis at 12 months (p = 0.04). In conclusion, the two groups of MET genetic alterations differ, both clinically and genetically: our data strongly suggest that MET exon 14 skipping mutations represent an early driver mutation. In opposition, MET amplifications occur usually in the background of other strong genetic events and therefore MET amplifications should be interpreted in the context of each tumor's genetic background, rather than as an isolated driver event, especially when considering MET-specific treatment options. PMID- 30459451 TI - Antimicrobial Photodynamic Inactivation Mediated by Tetracyclines in Vitro and in Vivo: Photochemical Mechanisms and Potentiation by Potassium Iodide. AB - Tetracyclines (including demeclocycline, DMCT, or doxycycline, DOTC) represent a class of dual-action antibacterial compounds, which can act as antibiotics in the dark, and also as photosensitizers under illumination with blue or UVA light. It is known that tetracyclines are taken up inside bacterial cells where they bind to ribosomes. In the present study, we investigated the photochemical mechanism: Type 1 (hydroxyl radicals); Type 2 (singlet oxygen); or Type 3 (oxygen independent). Moreover, we asked whether addition of potassium iodide (KI) could potentiate the aPDI activity of tetracyclines. High concentrations of KI (200-400 mM) strongly potentiated (up to 5 logs of extra killing) light-mediated killing of Gram-negative Escherichia coli or Gram-positive MRSA (although the latter was somewhat less susceptible). KI potentiation was still apparent after a washing step showing that the iodide could penetrate the E. coli cells where the tetracycline had bound. When cells were added to the tetracycline + KI mixture after light, killing was observed in the case of E. coli showing formation of free molecular iodine. Addition of azide quenched the formation of iodine but not hydrogen peroxide. DMCT but not DOTC iodinated tyrosine. Both E. coli and MRSA could be killed by tetracyclines plus light in the absence of oxygen and this killing was not quenched by azide. A mouse model of a superficial wound infection caused by bioluminescent E. coli could be treated by topical application of DMCT and blue light and bacterial regrowth did not occur owing to the continued anti biotic activity of the tetracycline. PMID- 30459452 TI - Craniofacial abnormality with skeletal dysplasia in mice lacking chondroitin sulfate N-acetylgalactosaminyltransferase-1. AB - Chondroitin sulfate (CS) proteoglycan is a major component of the extracellular matrix and plays an important part in organogenesis. To elucidate the roles of CS for craniofacial development, we analyzed the craniofacial morphology in CS N acetylgalactosaminyltransferase-1 (T1) gene knockout (KO) mice. T1KO mice showed the impaired intramembranous ossification in the skull, and the final skull shape of adult mice included a shorter face, higher and broader calvaria. Some of T1KO mice exhibited severe facial developmental defect, such as eye defects and cleft lip and palate, causing embryonic lethality. At the postnatal stages, T1KO mice with severely reduced CS amounts showed malocclusion, general skeletal dysplasia and skin hyperextension, closely resembling Ehlers-Danlos syndrome-like connective tissue disorders. The production of collagen type 1 was significantly downregulated in T1KO mice, and the deposition of CS-binding molecules, Wnt3a, was decreased with CS in extracellular matrices. The collagen fibers were irregular and aggregated, and connective tissues were dysorganized in the skin and calvaria of T1KO mice. These results suggest that CS regulates the shape of the craniofacial skeleton by modulating connective tissue organization and that the remarkable reduction of CS induces hypoplasia of intramembranous ossification and cartilage anomaly, resulting in skeletal dysplasia. PMID- 30459455 TI - Author Correction: Biofilm-associated infection by enterococci. AB - In the section on initial attachment and in Figure 1 it was erroneously indicated that enterococcal surface protein (Esp) binds collagen and fibrinogen. The text and figure were changed to remove this binding interaction both online and in the pdf. The authors apologize for any confusion caused. PMID- 30459453 TI - Transcriptomic analysis of Bifidobacterium longum subsp. longum BBMN68 in response to oxidative shock. AB - Bifidobacterium longum strain BBMN68 is sensitive to low concentrations of oxygen. A transcriptomic study was performed to identify candidate genes for B. longum BBMN68's response to oxygen treatment (3%, v/v). Expression of genes and pathways of B. longum BBMN68 involved in nucleotide metabolism, amino acid transport, protein turnover and chaperones increased, and that of carbohydrate metabolism, translation and biogenesis decreased to adapt to the oxidative stress. Notably, expression of two classes of ribonucleotide reductase (RNR), which are important for deoxyribonucleotide biosynthesis, was rapidly and persistently induced. First, the class Ib RNR NrdHIEF was immediately upregulated after 5 min oxygen exposure, followed by the class III RNR NrdDG, which was upregulated after 20 min of exposure. The upregulated expression of branched chain amino acids and tetrahydrofolate biosynthesis-related genes occurred in bifidobacteria in response to oxidative stress. These change toward to compensate for DNA and protein damaged by reactive oxygen species (ROS). In addition, oxidative stress resulted in improved B. longum BBMN68 cell hydrophobicity and autoaggregation. These results provide a rich resource for our understanding of the response mechanisms to oxidative stress in bifidobacteria. PMID- 30459454 TI - Evaluation of Dynamic Tumor-tracking Intensity-modulated Radiotherapy for Locally Advanced Pancreatic Cancer. AB - Intensity-modulated radiotherapy (IMRT) is now regarded as an important treatment option for patients with locally advanced pancreatic cancer (LAPC). To reduce the underlying tumor motions and dosimetric errors during IMRT as well as the burden of respiratory management for patients, we started to apply a new treatment platform of the dynamic tumor dynamic tumor-tracking intensity-modulated radiotherapy (DTT-IMRT) using the gimbaled linac, which can swing IMRT toward the real-time tumor position under patients' voluntary breathing. Between June 2013 and March 2015, ten patients were treated, and the tumor-tracking accuracy and the practical benefits were evaluated. The mean PTV size in DTT-IMRT was 18% smaller than a conventional ITV-based PTV. The root-mean-squared errors between the predicted and the detected tumor positions were 1.3, 1.2, and 1.5 mm in left right, anterior-posterior, and cranio-caudal directions, respectively. The mean in-room time was 24.5 min. This high-accuracy of tumor-tracking with reasonable treatment time are promising and beneficial to patients with LAPC. PMID- 30459457 TI - Optically active iodohelicene derivatives exhibit histamine N-methyl transferase inhibitory activity. AB - Optically active helicene derivatives inhibit the activity on histamine N-methyl transferase (HNMT). Specifically, methyl (P)-1,12-dimethylbenzo[c]phenanthrene-8 carboxylate with 6-iodo and 5-trifluoromethanesulfonyloxy groups inhibits HNMT activity on the MUM order of IC50. Chirality is important, and (M)-isomers exhibits substantially reduced activity. The 6-iodo group is also essential, which suggests the involvement of halogen bonds in protein binding. Substituents on the sulfonate moiety also affect the inhibitory activity. PMID- 30459456 TI - An integrative transcriptome analysis indicates regulatory mRNA-miRNA networks for residual feed intake in Nelore cattle. AB - Residual Feed Intake (RFI) is an economically relevant trait in beef cattle. Among the molecular regulatory mechanisms, microRNAs (miRNAs) are an important dimension in post-transcriptional regulation and have been associated with different biological pathways. Here, we performed differential miRNAs expression and weighted gene co-expression network analyses (WGCNA) to better understand the complex interactions between miRNAs and mRNAs expressed in bovine skeletal muscle and liver. MiRNA and mRNA expression data were obtained from Nelore steers that were genetically divergent for RFI (N = 10 [low RFI or feed efficient]; N = 10 [high RFI or feed inefficient]). Differentially expressed and hub miRNAs such as bta-miR-486, bta-miR-7, bta-miR15a, bta-miR-21, bta-miR 29, bta- miR-30b, bta-miR 106b, bta-miR-199a-3p, bta-miR-204, and bta-miR 296 may have a potential role in variation of RFI. Functional enrichment analysis of differentially expressed (DE) miRNA's target genes and miRNA-mRNA correlated modules revealed that insulin, lipid, immune system, oxidative stress and muscle development signaling pathways might potentially be involved in RFI in this population. Our study identified DE miRNAs, miRNA - mRNA regulatory networks and hub miRNAs related to RFI. These findings suggest a possible role of miRNAs in regulation of RFI, providing new insights into the potential molecular mechanisms that control feed efficiency in Nelore cattle. PMID- 30459458 TI - Publisher Correction: Epigenetic changes in myelofibrosis: Distinct methylation changes in the myeloid compartments and in cases with ASXL1 mutations. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30459459 TI - Type IV galactosemia. PMID- 30459460 TI - Diminished circadian blood pressure variability in elderly individuals with nuclear cataracts: cross-sectional analysis in the HEIJO-KYO cohort. AB - The present study aimed to determine the relationship between cataract subtypes and circadian blood pressure (BP) variability in elderly individuals. In this cross-sectional study of a community-based cohort, we assessed bilateral lens opacity using slit lamp photographs of 458 elderly individuals (mean age, 69.1 years). Cataract status was defined as a bilateral Lens Opacities Classification System III grade of >=3 for nuclear cataract, >=2 for cortical cataract, and >=2 for posterior subcapsular cataract (PSC). Ambulatory BP monitoring was performed at 30-min intervals for 48 h. A nondipper pattern of BP was defined as a <10% decline in the mean nighttime systolic BP relative to the mean daytime systolic BP. The prevalence of nondipper patterns was 42.4% and 25.9% in the groups with nuclear cataracts (n = 66) and without cataracts for both eyes (n = 290), respectively. Multivariable logistic regression analysis adjusted for potential confounders revealed a significantly higher odds ratio (OR) for nondipper pattern in the group with nuclear cataract than in that without cataract (OR, 1.81; 95% confidence interval, 1.01-3.24; P = 0.047) but not in the group with cortical cataract (P = 0.61) or PSC (P = 0.95). In conclusion, circadian BP variability was significantly diminished in elderly individuals with nuclear cataracts but not in those with cortical cataracts or PSCs. These associations were independent of daytime light exposure, physical activity, and known risk factors of cataracts, such as aging, obesity, and diabetes. PMID- 30459461 TI - Blood pressure and hypertension in people living at high altitude in Nepal. AB - This study aimed to describe blood pressure (BP) and hypertension (HT) in samples of high altitude populations of Nepal and to explore associations of systolic and diastolic BP with altitude. This was a cross-sectional survey of cardiovascular disease and associated risk factors among 521 people living at four different altitude levels, all above 2800 m, in the Mustang and Humla districts of Nepal. Data on BP was available for all 521 participants. Systolic and diastolic BP levels were highest at the altitude of 3620 m (the highest area surveyed) but did not consistently increase with altitude. Using the cut-point of >= 140/90 mmHg (systolic/diastolic), the prevalence of HT (or on anti-hypertensive medication) was 46.1%, 40.9% and 54.5%, respectively, at 2800, 3270 and 3620 m of Mustang district, and 29.1% at 2890 m of Humla district. In a multivariate model adjusting for potential confounders, there was strong evidence of a relationship between systolic BP and altitude; mean systolic BP increased by 15.6 mmHg (95% CI: 4.0-27.2), P = 0.009 for every 1000 m elevation. Although diastolic BP and the probability for HT or on anti-hypertensive medication also tended to increase with increasing altitude levels, there was no evidence of a relationship. In the present study three out of four communities living at higher altitude levels showed a greater prevalence of HT among those aged 30 years or older compared with the overall national data. These findings indicate a probable high risk of raised BP in high altitude populations in Nepal. PMID- 30459462 TI - Publisher Correction: Cytoplasmic localization of GRHL3 upon epidermal differentiation triggers cell shape change for epithelial morphogenesis. AB - The original version of this Article contained an error in the labelling of Fig. 4. In panel i, the sixth column was incorrectly labelled as NSC23766 negative, and should have been NSC23766 positive. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 30459463 TI - Understanding of metal-insulator transition in VO2 based on experimental and theoretical investigations of magnetic features. AB - The metal-insulator transition temperature Tc in VO2 is experimentally shown to be almost the same as a magnetic transition temperature Tm characterized by an abrupt decrease in susceptibility, suggesting the evidence of the same underlying origin for both transitions. The measurement of susceptibility shows that it weakly increases on cooling for temperature range of T > Tm, sharply decreases near Tm and then unusually increases on further cooling. A theoretical approach for such unusual observations in susceptibility near Tm or below is performed by modeling electrons from each two adjacent V4+ ions distributed along V-chains as a two-electron system, which indicates that the spin exchange between electrons could cause a level splitting into a singlet (S = 0) level of lower energy and a triplet (S = 1) level of higher energy. The observed abrupt decrease in susceptibility near Tm is explained to be due to that the sample enters the singlet state in which two electrons from adjacent V4+ ions are paired into dimers in spin antiparallel. By considering paramagnetic contribution of unpaired electrons created by the thermal activation from singlet to triplet levels, an expression for susceptibility is proposed to quantitatively explain the unusual temperature-dependent susceptibility observed at low temperatures. Based on the approach to magnetic features, the observed metal-insulator transition is explained to be due to a transition from high-temperature Pauli paramagnetic metallic state of V4+ions to low-temperature dimerized state of strong electronic localization. PMID- 30459464 TI - High-Density Porous Graphene Arrays Enable Detection and Analysis of Propagating Cortical Waves and Spirals. AB - Cortical propagating waves have recently attracted significant attention by the neuroscience community. These travelling waves have been suggested to coordinate different brain areas and play roles in assisting neural plasticity and learning. However, it is extremely challenging to record them with very fine spatial scales over large areas to investigate their effect on neural dynamics or network connectivity changes. In this work, we employ high-density porous graphene microelectrode arrays fabricated using laser pyrolysis on flexible substrates to study the functional network connectivity during cortical propagating waves. The low-impedance porous graphene arrays are used to record cortical potentials during theta oscillations and drug-induced seizures in vivo. Spatiotemporal analysis on the neural recordings reveal that theta oscillations and epileptiform activities have distinct characteristics in terms of both synchronization and resulting propagating wave patterns. To investigate the network connectivity during the propagating waves, we perform network analysis. The results show that the propagating waves are consistent with the functional connectivity changes in the neural circuits, suggesting that the underlying network states are reflected by the cortical potential propagation patterns. PMID- 30459465 TI - Regulation and overexpression studies of YidC in Mycobacterium tuberculosis. AB - The preprotein translocase, YidC is an envelope protein which controls respiratory metabolism in Mycobacterium tuberculosis. Previously, we have established that depletion of yidC is deleterious for both extra- and intracellular proliferation of M. tuberculosis; however, it remains unclear how YidC expression is regulated under different growth conditions and whether its altered expression impact mycobacterial physiology. Herein, we show that yidC is expressed as an operon with upstream genes. Interestingly, expression analysis under various stress conditions reveals a distinct paradox in the profile of the yidC mRNA transcripts and the YidC protein. While YidC protein level is moderately elevated upon bacterial exposure to cell surface stresses, the corresponding mRNA transcript levels are significantly repressed under these conditions. In contrast, overexpression of M. tuberculosis yidC under a strong anhydrotetracycline-inducible promoter results in significant induction of YidC protein. Additionally, we also observe that overexpression of M. tuberculosis yidC, and not of its counterpart from fast-growing M. smegmatis, results in altered in vitro growth of bacteria, compromised integrity of bacterial cell envelope and differential expression of a small set of genes including those which are regulated under detergent stress. Overall findings of our study suggest that YidC proteins of slow- and fast-growing mycobacteria are functionally distinct despite exhibiting a great deal of identity. PMID- 30459466 TI - Homozygous PCDH12 variants result in phenotype of cerebellar ataxia, dystonia, retinopathy, and dysmorphism. AB - We report on a sib pair of Indian origin born of a consanguineous parentage with a novel phenotype of distinct facial dysmorphism, cerebellar ataxia, dystonia, and exudative retinopathy due to homozygous PCDH12 nonsense variations. cDNA studies showed >90% reduction in transcript levels in both patients, indicating nonsense-mediated decay and loss of function as the probable causative molecular mechanism of the phenotype. PMID- 30459467 TI - A comparative analysis of KMT2D missense variants in Kabuki syndrome, cancers and the general population. AB - Determining the clinical significance of germline and somatic KMT2D missense variants (MVs) in Kabuki syndrome (KS) and cancers can be challenging. We analysed 1920 distinct KMT2D MVs that included 1535 germline MVs in controls (Control-MVs), 584 somatic MVs in cancers (Cancer-MVs) and 201 MV in individuals with KS (KS-MVs). The proportion of MVs likely to affect splicing was significantly higher for Cancer-MVs and KS-MVs than in Control-MVs (p = 0.000018). Our analysis identified significant clustering of Cancer-MVs and KS MVs in the PHD#3 and #4, RING#4 and SET domains. Areas of enrichment restricted to just Cancer-MVs (FYR-C and between amino acids 3043-3248) or KS-MVs (coiled coil#5, FYR-N and between amino acids 4995-5090) were also found. Cancer-MVs and KS-MVs tended to affect more conserved residues (lower BLOSUM scores, p < 0.001 and p = 0.007). KS-MVs are more likely to increase the energy for protein folding (higher ELASPIC ??G scores, p = 0.03). Cancer-MVs are more likely to disrupt protein interactions (higher StructMAn scores, p = 0.019). We reclassify several presumed pathogenic MVs as benign or as variants of uncertain significance. We raise the possibility of as yet unrecognised 'non-KS' phenotype(s) associated with some germline pathogenic KMT2D MVs. Overall, this work provides insights into the disease mechanism of KMT2D variants and can be extended to other genes, mutations in which also cause developmental syndromes and cancer. PMID- 30459468 TI - The immediate effects of breathing with oscillated inspiratory and expiratory airflows on secretion clearance in intubated patients with cervical spinal cord injury. AB - STUDY DESIGN: A prospective, randomized crossover trial. OBJECTIVES: To evaluate the efficacy of the combination of incentive spirometry with oscillation (OIS) and positive expiratory pressure with oscillation (OPEP) to promote secretion clearance in intubated patients with cervical spinal cord injury. SETTING: Spinal cord unit, tertiary care hospital, North East Thailand. METHODS: Thirteen intubated patients (C4-7, AIS score C) with secretion retention performed three interventions randomly allocated on consecutive days, a Sham deep breathing, OPEP and OPEP + OIS breathing exercise. Secretions were collected by sterile suction for 3 h before, and 3 h after, each intervention and wet weight recorded. Cardiopulmonary parameters were measured before and after each intervention. RESULTS: The median (IQR) secretion wet weight pre-intervention was 2.61 g (2.21, 3.85) and in the 3 h after Sham there was an increase of 1.97 g (0.6, 3.6). The increase after OPEP was 2.67 g (1.7, 3.9) and after OPEP + OIS, 4.28 g (2.4, 6.7); all the increases being significant (p <= 0.007). The clearance after OPEP and OPEP + OIS were both greater than Sham while OPEP + OIS was greater than OPEP (p <= 0.019). There were no significant changes in cardiopulmonary measures following any intervention or when compared between interventions. CONCLUSIONS: Deep breathing with an oscillated and humidified air flow in a combination of OIS + OPEP more than doubled secretion clearance and was more effective than OPEP or Sham deep breathing. There were no adverse effects of the procedures which were well tolerated by the patients and may be used to complement existing methods for secretion clearance. PMID- 30459469 TI - Ophthalmology research in the UK's National Health Service: the structure and performance of the NIHR's Ophthalmology research portfolio. AB - PURPOSE: To report on the composition and performance of the portfolio of Ophthalmology research studies in the United Kingdom's National Institute for Health Research (NIHR) Clinical Research Network (UK CRN). METHODS: Ophthalmology studies open to recruitment between 1 April 2010 and 31 March 2018 were classified by: sub-specialty, participant age, gender of Chief Investigator, involvement of genetic investigations, commercial/ non-commercial, interventional/observational design. Frequency distributions for each covariate and temporal variation in recruitment to time and target were analysed. RESULTS: Over 8 years, 137,377 participants were recruited (average of 15,457 participants/year; range: 5485-32,573) with growth by year in proportion of commercial studies and hospital participation in England (76% in 2017/18). Fourteen percent of studies had a genetic component and most studies (82%) included only adults. The majority of studies (41%) enrolled patients with retinal diseases, followed by glaucoma (17%), anterior segment and cataract (13%), and ocular inflammation (6%). Overall, 68% of non-commercial studies and 55% of commercial studies recruited within the anticipated time set by the study and also recruited to or exceeded the target number of participants. CONCLUSIONS: High levels of clinical research activity, growth and improved performance have been observed in Ophthalmology in UK over the past 8 years. Some sub-specialties that carry substantial morbidity and a very high burden on NHS services are underrepresented and deserve more patient-centred research. Yet the NIHR and its CRN Ophthalmology National Specialty Group has enabled key steps in achieving the goal of embedding research into every day clinical care. PMID- 30459470 TI - Author Correction: The selective tRNA aminoacylation mechanism based on a single G*U pair. AB - In Fig. 1b of this Article, a U was inadvertently inserted after G15 in the D loop. The original Article has not been corrected. PMID- 30459471 TI - Diagnostic accuracy of salivary gland ultrasonography with different scoring systems in Sjogren's syndrome: a systematic review and meta-analysis. AB - Noninvasive objective salivary gland ultrasonography (SGU) had been widely used to evaluate major salivary gland involvement in primary Sjogren's syndrome (pSS) and treatment responses. However, the evaluation score, diagnostic sensitivity, and diagnostic specificity significantly varied among clinical studies. We conducted this meta-analysis to assess the diagnostic accuracy of different SGU scoring systems using the American-European Consensus Group criteria. Of the 1301 articles retrieved from six databases, 24 met the criteria for quality assessment and 14 for meta-analyses. The pooled sensitivities were 75% (0-4) with I2 = 92.0%, 84% (0-16) with I2 = 63.6%, and 75% (0-48) with I2 = 90.9%; the pooled specificities were 93% (0-4) with I2 = 71.5%, 88% (0-16) with I2 = 65.4%, and 95% (0-48) with I2 = 83.9%; the pooled diagnostic odds ratios were 71.26 (0-4) with I2 = 0%, 46.3 (0-16) with I2 = 73.8%, and 66.07 (0-48) I2 = 0%; the areas under the SROC curves were 0.95 (0-4), 0.93 (0-16), and 0.94 (0-48). These results indicated that the 0-4 scoring system has a higher specificity and a less heterogeneity than other systems, and could be used as a universal SGU diagnostic standard. PMID- 30459472 TI - Gene Expression Signatures Point to a Male Sex-Specific Lung Mesenchymal Cell PDGF Receptor Signaling Defect in Infants Developing Bronchopulmonary Dysplasia. AB - Male sex is a risk factor for development of bronchopulmonary dysplasia (BPD), a common chronic lung disease following preterm birth. We previously found that tracheal aspirate mesenchymal stromal cells (MSCs) from premature infants developing BPD show reduced expression of PDGFRalpha, which is required for normal lung development. We hypothesized that MSCs from male infants developing BPD exhibit a pathologic gene expression profile deficient in PDGFR and its downstream effectors, thereby favoring delayed lung development. In a discovery cohort of 6 male and 7 female premature infants, we analyzed the tracheal aspirate MSCs transcriptome. A unique gene signature distinguished MSCs from male infants developing BPD from all other MSCs. Genes involved in lung development, PDGF signaling and extracellular matrix remodeling were differentially expressed. We sought to confirm these findings in a second cohort of 13 male and 12 female premature infants. mRNA expression of PDGFRA, FGF7, WNT2, SPRY1, MMP3 and FOXF2 were significantly lower in MSCs from male infants developing BPD. In female infants developing BPD, tracheal aspirate levels of proinflammatory CCL2 and profibrotic Galectin-1 were higher compared to male infants developing BPD and female not developing BPD. Our findings support a notion for sex-specific differences in the mechanisms of BPD development. PMID- 30459474 TI - Luminescent color control of Langmuir-Blodgett film by emission enhancement using a planar metal layer. AB - A metal enhanced emission of more than 20-fold is observed from a Langmuir Blodgett (LB) monolayer on a planar aluminum layer with a polymer spacer. The spectral change of the metal enhanced emission using the metal layer is discussed experimentally and theoretically. Finite-difference time-domain simulations and transfer matrix calculations have been performed to investigate the cause of the enhancement. The analytical solution of the enhancement factor of the interference enhancement is also derived assuming the planar aluminum layer as a perfect electric conductor. Furthermore, we have demonstrated control of emission color of the LB film from the yellow-green to blue or red using the metal enhanced emission. PMID- 30459476 TI - New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. AB - Epithelial-mesenchymal transition (EMT) is a cellular programme that is known to be crucial for embryogenesis, wound healing and malignant progression. During EMT, cell-cell and cell-extracellular matrix interactions are remodelled, which leads to the detachment of epithelial cells from each other and the underlying basement membrane, and a new transcriptional programme is activated to promote the mesenchymal fate. In the context of neoplasias, EMT confers on cancer cells increased tumour-initiating and metastatic potential and a greater resistance to elimination by several therapeutic regimens. In this Review, we discuss recent findings on the mechanisms and roles of EMT in normal and neoplastic tissues, and the cell-intrinsic signals that sustain expression of this programme. We also highlight how EMT gives rise to a variety of intermediate cell states between the epithelial and the mesenchymal state, which could function as cancer stem cells. In addition, we describe the contributions of the tumour microenvironment in inducing EMT and the effects of EMT on the immunobiology of carcinomas. PMID- 30459475 TI - Diagnosis of known sarcoma fusions and novel fusion partners by targeted RNA sequencing with identification of a recurrent ACTB-FOSB fusion in pseudomyogenic hemangioendothelioma. AB - Integration of morphological, immunohistochemical, and molecular methods is often necessary for the precise diagnosis and optimal clinical management of sarcomas. We have validated and implemented a clinical molecular diagnostic assay, MSK- Fusion Solid, for detection of gene fusions in solid tumors, including sarcomas. Starting with RNA extracted from formalin-fixed paraffin-embedded tumor material, this targeted RNA sequencing assay utilizes anchored multiplex PCR to detect oncogenic fusion transcripts involving 62 genes known to be recurrently rearranged in solid tumors including sarcomas without prior knowledge of fusion partners. From 1/2016 to 1/2018, 192 bone and soft tissue tumors were submitted for MSK- Fusion Solid analysis and 96% (184/192) successfully passed all the pre sequencing quality control parameters and sequencing steps. These sarcomas encompass 24 major tumor types, including 175 soft tissue tumors and 9 osteosarcomas. Ewing and Ewing-like sarcomas, rhabdomyosarcoma, and sarcoma-not otherwise specified were the three most common tumor types. Diagnostic in-frame fusion transcripts were detected in 43% of cases, including 3% (6/184) with novel fusion partners, specifically TRPS1-PLAG1, VCP-TFE3, MYLK-BRAF, FUS-TFCP2, and ACTB-FOSB, the latter in two cases of pseudomyogenic hemangioendothelioma, representing a novel observation in this sarcoma. Our experience shows that this targeted RNA sequencing assay performs in a robust and sensitive fashion on RNA extracted from most routine clinical specimens of sarcomas thereby facilitating precise diagnosis and providing opportunities for novel fusion partner discovery. PMID- 30459473 TI - Multimodal assessments of Zika virus immune pathophysiological responses in marmosets. AB - Animal models that recapitulate the human pathophysiology have been developed as useful research tools. Although laboratory mice are widely used, they are phylogenetically "distant" to humans. New world monkeys, such as the common marmoset (Callithrix jacchus) have steadily gained prominence. In this report, marmosets are explored as an alternate in vivo model to investigate infection and immunity of Zika virus (ZIKV). Multimodal platforms, including ultrasound and magnetic resonance imaging (MRI), flow cytometry, and multiplex microbead immunoassays were established to comprehensively decipher immune responses and pathophysiological outcomes. While ZIKV-infected marmosets had detectable ZIKV RNA load in various body fluids, animals did not develop any observable lesions in their testes and brains as shown by ultrasound and MRI. Immune-phenotyping detected differences in the numbers of B cells, CD8+ T cells and HLADR+ NK cells during the first two weeks of infection. Neutralizing ZIKV-specific antibodies were elicited to high levels and targeted epitopes in the E protein. This study presents a one-stop-shop platform to study infection and pathophysiology in marmosets. While marmoset-specific research tools are being refined, the research values of these animals present them as a good model for immune-based therapies. PMID- 30459477 TI - A Systematic View on the Use of History for Current Debates in Sociology, and on the Potential and Problems of a Historical Epistemology of Sociology. AB - For various reasons, among them changes in the global higher education regime and competitive knowledge claims from other disciplines, the field of the history of sociology (HoS) has experienced an increased pressure to justify its own existence during the last decade. Positing that the best approach to justify the existence of a thing is to show its usefulness, the article discusses four types of claims to usefulness made by historians of sociology. The history of sociology can be said to be relevant in (I) shaping and maintaining the discipline's identity; (II) in providing a rich fund of teaching future sociologists; (III) in informing current research and theorizing; and (IV) in reflecting more broadly on the cultural status of sociology in modern societies. The article then assesses the potential and problems of aspiring a historical epistemology of sociology, a proposal made recently especially in German and Anglophone contexts to link the history of science with its philosophy in the sense described as type III. It concludes that selected principles or ideas of historical epistemology can be very fruitfully applied in HoS. However, the project of transferring the whole program of historical epistemology into HoS is bound to fail. Nonetheless, there is plenty of reason to continue conceiving of HoS as an integral part of sociology. PMID- 30459478 TI - Vertical distribution of the relic species Eurytemora lacustris (Copepoda, Calanoida) in stratified mesotrophic lakes. AB - The aim of this study was to determine factors affecting the vertical distribution of Eurytemora lacustris in mesotrophic lakes (Wigry, Hancza, Szurpily; north-eastern Poland) during the summer stagnation. Eurytemora lacustris was found in all of the studied lakes, with the highest abundance (8 ind. L-1) in Lake Wigry. In Lake Szurpily, E. lacustris has never been recorded before. The results of this study revealed that E. lacustris was most numerous in thermocline zones, suggesting that this species could temporarily tolerate warmer water and lower oxygen concentrations due to better food resources. During the study, it was found that a large part of the E. lacustris population had epibiont ciliates, in contrast to other species of zooplankton that did not have any epibionts. The improvement in the water quality of many deep lakes could lead to an increase in the abundance of E. lacustris. However, epibiont ciliates may be a threat for this species and may play a substantial role in determining the production, distribution, and community dynamics of E. lacustris. PMID- 30459479 TI - Is the Capacity for Vocal Learning in Vertebrates Rooted in Fish Schooling Behavior? AB - The capacity to learn and reproduce vocal sounds has evolved in phylogenetically distant tetrapod lineages. Vocal learners in all these lineages express similar neural circuitry and genetic factors when perceiving, processing, and reproducing vocalization, suggesting that brain pathways for vocal learning evolved within strong constraints from a common ancestor, potentially fish. We hypothesize that the auditory-motor circuits and genes involved in entrainment have their origins in fish schooling behavior and respiratory-motor coupling. In this acoustic advantages hypothesis, aural costs and benefits played a key role in shaping a wide variety of traits, which could readily be exapted for entrainment and vocal learning, including social grouping, group movement, and respiratory-motor coupling. Specifically, incidental sounds of locomotion and respiration (ISLR) may have reinforced synchronization by communicating important spatial and temporal information between school-members and extending windows of silence to improve situational awareness. This process would be mutually reinforcing. Neurons in the telencephalon, which were initially involved in linking ISLR with forelimbs, could have switched functions to serve vocal machinery (e.g. mouth, beak, tongue, larynx, syrinx). While previous vocal learning hypotheses invoke transmission of neurons from visual tasks (gestures) to the auditory channel, this hypothesis involves the auditory channel from the onset. Acoustic benefits of locomotor-respiratory coordination in fish may have selected for genetic factors and brain circuitry capable of synchronizing respiratory and limb movements, predisposing tetrapod lines to synchronized movement, vocalization, and vocal learning. We discuss how the capacity to entrain is manifest in fish, amphibians, birds, and mammals, and propose predictions to test our acoustic advantages hypothesis. PMID- 30459481 TI - A Dignified Standard of Living in Mexico: Results of a Pilot Study of the Minimum Income Standard Approach. AB - This paper explores the ways in which consensually-defined, socially-constructed living standards could be helpful in providing new ways of understanding living standards in Mexico. A pilot study formulating a "Minimum Income Standard", carried out in the country in 2016, asked members of Mexican society what they consider to be necessary to achieve a dignified standard of living in urban Mexico today. Participants discussed the meaning of a dignified standard of living and translated such definition into concrete items in a hypothetical living room and in leisure time. Our study reveals that social participation, security, and employment are seen as important elements to live a dignified standard of living, which permeate the rationale for identifying the goods and services seen as needed to achieve a dignified living standard. The definition of a dignified standard of living could usefully inform and contribute to the ongoing debate on wage adequacy in the country. PMID- 30459480 TI - Extrinsic Mortality Can Shape Life-History Traits, Including Senescence. AB - The Williams' hypothesis is one of the most widely known ideas in life history evolution. It states that higher adult mortality should lead to faster and/or earlier senescence. Theoretically derived gradients, however, do not support this prediction. Increased awareness of this fact has caused a crisis of misinformation among theorists and empirical ecologists. We resolve this crisis by outlining key issues in the measurement of fitness, assumptions of density dependence, and their effect on extrinsic mortality. The classic gradients apply only to a narrow range of ecological contexts where density-dependence is either absent or present but with unrealistic stipulations. Re-deriving the classic gradients, using a more appropriate measure of fitness and incorporating density, shows that broad ecological contexts exist where Williams' hypothesis is supported. PMID- 30459482 TI - The scent of infanticide risk? Behavioural allocation to current and future reproduction in response to mating opportunity and familiarity with intruder. AB - Abstract: The killing of young by unrelated males is widespread in the animal kingdom. In short-lived small rodents, females can mate immediately after delivery (post-partum oestrus) and invest in future reproduction, but infanticide may put the nestlings, their current reproductive investment, at risk. Here, we investigated the behavioural trade-offs between mating interest and nest protection in an arena experiment with bank voles (Myodes glareolus). Non-gravid females (n = 33) were housed at one end of a large structured arena with their nestlings. Different scents (cage bedding) were presented to each female in a replicated design. Three combinations of mating opportunities and male-female familiarity were simulated using different scent donors: mating opportunity with the sire of the nestlings with whom the female was familiar; mating opportunity with a male unrelated to the offspring and unfamiliar to the female, thus posing a higher risk to the offspring; and neither risk nor mating opportunity (clean control). Most females investigated male scents, regardless of familiarity, leaving their litter unprotected. During control treatment, females with larger litters spent less time at the scent area, indicating increasing nursing demands or better protection. Females with older litters visited scents more often, suggesting an increased interest in reproduction while they are non-gravid alongside the decreased risk of infanticide for older young. In the presence of unfamiliar scents, females spent more time protecting their nests, supporting the perceived association of unfamiliarity with infanticide risk. Thus, rodent females flexibly allocate time spent between searching for a mate and protecting their nest, which is modulated by their familiarity with a potential intruder. Significance statement: Infanticide by conspecific males is an extreme form of sexual conflict and has large costs on females, abolishing their investment into current offspring. In an experimental approach, we exposed lactating female bank voles to different combinations of mating opportunity and familiarity to a (simulated) intruder: (1) the sire of the nestlings with whom the female was familiar and, therefore, potentially less risky in terms of infanticide; (2) a male which was unrelated and unfamiliar to the female and thus posed a higher risk to the offspring; or (3) as a control, cage bedding, which posed neither risk of infanticide nor a mating opportunity. We show that females flexibly allocated pup protection and mating interest based on their familiarity with the male, indicating that the unfamiliar males pose a threat to offspring, which is perceived by the females. Females further adjusted their behaviour to the size and/or age of their current litter, investing more time in male scents when offspring were older, thus balancing future and current investments into reproduction. PMID- 30459483 TI - Associations Between Conduct Disorder, Neurodevelopmental Problems and Psychopathic Personality Traits in a Swedish Twin Youth Population. AB - Previous research has found a complex relationship between psychopathic traits, neurodevelopmental problems (NDPs), and conduct disorder (CD) in children. This study explores associations between psychopathic traits, assessed with the Child Problematic Traits Inventory-Short Version (CPTI-SV), and CD in children with and without coexisting NDPs (i.e., attention deficit/hyperactivity disorder [ADHD] and autism spectrum disorder [ASD]) in a community-based sample of Swedish twins (n = 8762). Findings indicate weak to moderately strong correlations between psychopathic traits and CD, ADHD, and ASD, respectively. Furthermore, in univariable analyses, both psychopathic traits and NDPs displayed significant positive associations with being screened positive for CD, though only the grandiose-deceitful dimension of CPTI-SV and the ADHD domain concentration and attention deficits remained significantly associated with CD in a multivariable regression model. The results are relevant to screening and assessment in child and youth psychiatry, as a grandiose and deceitful interpersonal style may also be a valid sign of children at risk of developing CD. PMID- 30459484 TI - Normative and Maladaptive Personality Trait Models of Mood, Psychotic, and Substance Use Disorders. AB - The Personality Inventory for DSM-5 (PID-5) is a questionnaire developed to assess the five domains represented in the alternative model for personality disorders proposed in Section III of the DSM-5. This study examined the ability of the PID-5 to distinguish between different mental disorders compared to a questionnaire measure of the five-factor model (FFM) of normative personality. The study included the administration of the PID-5 and Revised NEO Personality Inventory (NEO PI-R), a measure of the FFM, to treatment-seeking individuals with Depressive, Bipolar, Psychotic, and Alcohol Use Disorders (AUD). Diagnostic groups were compared at the domain level of PID-5 and NEO PI-R, with sex and age as covariates. The main findings on the PID-5 included higher Detachment scores for Bipolar and Depressive Disorders than Psychotic and AUDs, lower Psychoticism/higher Disinhibition scores for the AUD group compared to all other groups, and lower Negative Affect for the Psychotic Disorders versus AUD group. On the NEO PI-R, the AUD diagnostic group was associated with lower Conscientiousness and Agreeableness scores compared to all other groups, and lower Neuroticism scores than the Bipolar and Depressive groups. Group pairwise comparisons did not appear to show many differences between the PID-5 and NEO PI R. The results suggest that the alternative DSM-5 model for personality disorders may have clinical utility in distinguishing personality profiles between diagnostic groups. These findings emphasize the importance of additional research on the capacity of maladaptive personality to contribute to the assessment of differential diagnoses. PMID- 30459485 TI - In-Game Play Behaviours during an Applied Video Game for Anxiety Prevention Predict Successful Intervention Outcomes. AB - Anxiety disorder is the most prevalent and frequently diagnosed disorder in youth, and associated with serious negative health outcomes. Our most effective prevention programs, however, have several limitations. These limitations can be addressed using game-based interventions. Results from two randomized controlled trials on the video game MindLight show improvements in anxiety that are maintained up to 6 months. The game was designed based on evidence-based therapeutic techniques; however, it is unclear if children's engagement with these techniques actually predict improvements in anxiety symptoms. An important advantage of game-based interventions is that they provide excellent opportunities to isolate therapeutic action mechanisms and test their impact on intervention outcomes. In the current study, on-screen videotaped output while playing MindLight was coded and analysed for forty-three 8 to 12-year old children with elevated levels of anxiety. Results showed that changes in in-game play behaviours representing therapeutic exposure techniques predicted improvements in anxiety symptoms 3 months later (when children had not played the game for 3 months). The current study is a first step towards identifying and validating game mechanics that can be used in new applied games to target anxiety symptoms or other psychopathologies with the same underlying deficits. PMID- 30459487 TI - Autosomal dominant intellectual disability. AB - Intellectual disability (ID) is a heterogeneous entity defined as a substantial impairment of cognitive and adaptive function with an onset in early childhood and an IQ measure of less than 70. During the last few years, the next generation technologies, namely whole exome (WES) and whole genome sequencing (WGS), have given rise to the identification of many new genes for autosomal dominant (ADID), autosomal recessive (ARID) and X-linked forms of ID (XLID). The prevalence of ID is 1.5-2% for milder forms (IQ < 70) and 0.3-0.5% for more severe forms of ID (IQ < 50). Up to now, about 650 genes for ADID have been reported and it is expected that there are at least 350 genes still unidentified. Although the ADID genes can easily be classified according to the associated clinical findings, e. g. different kind of seizures, abnormal body measurements, an advanced selection of reasonable genes for analyses is challenging. Many different panels for ID genes have been developed for a first diagnostic step, but more meaningful is the use of trio exome sequencing in individuals with sporadic ID. Using trio WES the mutation detection rate for de novo mutations in ID varies from 20 to 60%. Further research is needed for the identification of the remaining ID genes, a deeply understanding of the pathways and the development of therapies for the mostly rare causes of ID. PMID- 30459486 TI - The Factor Structure of the Forms of Self-Criticising/Attacking & Self-Reassuring Scale in Thirteen Distinct Populations. AB - There is considerable evidence that self-criticism plays a major role in the vulnerability to and recovery from psychopathology. Methods to measure this process, and its change over time, are therefore important for research in psychopathology and well-being. This study examined the factor structure of a widely used measure, the Forms of Self-Criticising/Attacking & Self-Reassuring Scale in thirteen nonclinical samples (N = 7510) from twelve different countries: Australia (N = 319), Canada (N = 383), Switzerland (N = 230), Israel (N = 476), Italy (N = 389), Japan (N = 264), the Netherlands (N = 360), Portugal (N = 764), Slovakia (N = 1326), Taiwan (N = 417), the United Kingdom 1 (N = 1570), the United Kingdom 2 (N = 883), and USA (N = 331). This study used more advanced analyses than prior reports: a bifactor item-response theory model, a two-tier item-response theory model, and a non-parametric item-response theory (Mokken) scale analysis. Although the original three-factor solution for the FSCRS (distinguishing between Inadequate-Self, Hated-Self, and Reassured-Self) had an acceptable fit, two-tier models, with two general factors (Self-criticism and Self-reassurance) demonstrated the best fit across all samples. This study provides preliminary evidence suggesting that this two-factor structure can be used in a range of nonclinical contexts across countries and cultures. Inadequate Self and Hated-Self might not by distinct factors in nonclinical samples. Future work may benefit from distinguishing between self-correction versus shame-based self-criticism. PMID- 30459488 TI - Genetics of autosomal recessive intellectual disability. AB - In the last few years, next-generation sequencing has led to enormous progress in deciphering monogenic forms of intellectual disability. Autosomal dominant intellectual disability (ADID) and X chromosomal intellectual disability (XLID) have been the focus of research. Apart from metabolic disorders, autosomal recessive intellectual disability (ARID) is still behind, probably because it is more heterogeneous and less prevalent in industrial populations. The prevalence of ARID in a cohort of affected children of an outbred population is estimated to be about 10%, with an upward tendency in still unclarified cases. The risk for ARID in children of first cousins or closer is a magnitude higher than for children of unrelated parents. Taken together, it seems that children of related parents are at a 2 to 3 times higher risk for ID. There are no prevalent ARID genes, pathways, or protein complexes and the functions of the affected proteins are very diverse and limited not only to neurological aspects. Thus, in a regular case, there is no reasoning for picking a few genes for a first diagnostic step, and a genetic diagnosis of ID in general, and ARID specifically, is better made using large panels or exome sequencing. In addition, in the last few months, evidence has been growing that many ARID genes are pleiotropic and that the resulting phenotypes may have a broad spectrum. For an exhaustive deciphering of the genetics of ARID, we suggest research at the level of single genes rather than large meta-analyses. PMID- 30459489 TI - Nonautonomous Young Differential Equations Revisited. AB - In this paper we prove that under mild conditions a nonautonomous Young differential equation possesses a unique solution which depends continuously on initial conditions. The proofs use estimates in p-variation norms, the construction of greedy sequence of times, and Gronwall-type lemma with the help of Shauder theorem of fixed points. PMID- 30459490 TI - Improved and synchronized maturation of Norway spruce (Picea abies (L.) H.Karst.) somatic embryos in temporary immersion bioreactors. AB - Somatic embryogenesis offers many benefits for clonal propagation in large-scale plant production of conifers. A key rate-limiting step is the conversion from early-stage somatic embryos in pro-embryogenic masses (PEMs) to the maturation stage. Immature embryos in PEMs are present at different developmental stages, where some are unable to respond to the maturation treatment, thus limiting yields of mature embryos. Synchronization of early somatic embryo development in PEMs could greatly improve subsequent yields of mature embryos. A temporary immersion bioreactor designed for Norway spruce (Picea abies (L.) H.Karst.) was used in this study. Through a specific system for dispersion, connected tissue of PEMs, composed of immature embryos grown in liquid medium in the temporary immersion bioreactors or on solid medium as a control, was dispersed and redistributed in a more uniform spatial arrangement. It was demonstrated that development of mature embryos could be significantly stimulated by dispersion, compared to controls, in both medium types. Synchronization of maturation was evaluated by a statistical approach. The present study shows that the yield of mature embryos from dispersed PEMs was three to five times higher than that from non-dispersed controls in three of four cell lines of Norway spruce tested, both in bioreactors and on solid medium. PMID- 30459491 TI - Family Businesses and Adaptation: A Dynamic Capabilities Approach. AB - The main objective of this research was to propose a framework centred on the dynamic capabilities approach, and to be applied in the context of family businesses' adaption to their changing business environment. Data were gathered through interviews with ten FBs operating in Western Australia. Based on the findings, the clusters of activities, sensing, seizing, and transforming emerged as key factors for firms' adaptation, and were reinforced by firms' open culture, signature processes, idiosyncratic knowledge, and valuable, rare, inimitable and non-substitutable attributes. Thus, the usefulness of the proposed framework was confirmed. Implications and future research opportunities are presented. PMID- 30459492 TI - Experience and Utility of Using the Participatory Research Method, Photovoice, in Individuals With Spinal Cord Injury. AB - Background: There is a need to engage persons with spinal cord injuries/disorders (SCI/D) in research methodologies beyond traditional approaches. This provides an opportunity for individuals to convey their perspectives in a variety of ways. Photovoice empowers people to share their perspectives through photographs and narrative; this is well-suited for individuals who are less comfortable speaking up when other methods are used, such as focus groups. Objective: To examine photovoice methodology in US Veterans with SCI/D to describe their experiences with and the utility of photovoice. We also provide a sample of content (qualitative data) to illustrate how individuals with SCI/D conceptualized function and factors important to them. Methods: Photovoice, a qualitative participatory research method, was used to collect photographs from Veterans with SCI/D, which was followed by personal narratives describing the meaning of their photos. Results: Participants (N = 9) were 64 years old, on average, and 75% had paraplegia. Participants discussed the challenges with taking photographs, but they enjoyed participating, appreciated inclusion, and hoped the information they provided would help others with disabilities. Conclusion: These findings suggest that despite challenges and ethical barriers, individuals with SCI/D are interested in, highly capable of, and should be given the opportunity to be included in studies like this that empower participants to share their views using novel ways of expression. These findings demonstrate the desirability, feasibility, and utility of using photovoice in individuals with SCI/D. This method may be used to understand factors impacting health and well-being and can be made available to individuals with SCI/D to minimize inequalities in research opportunities. PMID- 30459493 TI - Relationships Between Community Reintegration and Clinical and Psychosocial Attributes in Individuals With Spinal Cord Injury in a Nigerian City. AB - Background: The bio-psychosocial model for comprehensive understanding of community reintegration among individuals with spinal cord injury (SCI) varies across communities. Yet, information about community reintegration in Nigeria is not available. Objective: To investigate the association between community reintegration and clinical and psychosocial attributes among Nigerians with SCI. Methods: Fifty individuals (31 females; 19 males) with SCI aged 38.6 +/- 11.1 years participated in this longitudinal survey. Pain, functional ability, and severity of injury were assessed at discharge and at 1, 2, and 3 months post discharge from inpatient care using the Visual Analogue Scale (VAS), FIM(r), and American Spinal Injury Association Impairment Scale (AIS), respectively. Self esteem (SE), social support (SS), and depression were also assessed using the Self-Esteem Questionnaire, Social Support Questionnaire, and Beck Depression Inventory, respectively. CR was assessed at 1, 2, and 3 months post-discharge using the Reintegration to Normal Living Index (RNLI). Data were analyzed using Spearman's rho correlation and Friedman test. Results: The psychosocial and clinical attributes were significantly different from baseline and across the 3 months post-discharge (p < .0001), except for SS. CR significantly correlated with level of injury, function ability, SE, and depression across the 3 months post-discharge (p < .01). CR was significantly correlated with SS only at 1 month post-discharge (p = .027). Conclusion: Individuals with SCI had significant improvement in clinical and psychosocial attributes from discharge to 3 months post-discharge. Improvements in these variables were associated with better reintegration into the community. PMID- 30459494 TI - Experiences With Navigating and Managing Information in the Community Following Spinal Cord Injury. AB - Background: People living with spinal cord injury (SCI) have reported difficulties managing information in the community, which can negatively impact their functional independence and ability to prevent secondary complications. Objective: This exploratory qualitative study aimed to describe the experiences of people living with SCI with navigating and managing information in the community from their perspective. Methods: Participants were recruited through the Australian Quadriplegic Association. Twenty-two semi-structured in-depth interviews were conducted with purposively selected participants to ensure representation of age, gender, SCI level, and compensation status. Data were thematically analyzed using a framework approach. Results: People living with SCI reported using multiple, complementary sources of information to prevent and manage secondary conditions. Over time, they learned to appraise the content, relevance, timing, and sources of information. Information delivered by health professionals in the rehabilitation setting was appraised as lacking personalization, but it acted as a springboard to search for more relevant information. Participants described the process of becoming experts about their condition to overcome the lack of knowledge of many general practitioners, guide their own care, and act as a source of information for others. Due to a lack of information provision, some participants missed health improvement opportunities and experienced frustration at the uncertainty of their future with SCI. Conclusion: Greater support is required for individuals with SCI to navigate information sources in the community. Rehabilitation is an opportune time to provide education related to finding and appraising information. Improved access to community health providers with SCI knowledge is also required. PMID- 30459495 TI - Quality of Life Outcomes for Veterans With Spinal Cord Injury Receiving Individual Placement and Support (IPS). AB - Background: Individual Placement and Support (IPS) is an evidence-based practice that helps persons with mental and/or physical disabilities, including spinal cord injury, find meaningful employment in the community. While employment is associated with positive rehabilitation outcomes, more research is needed on the impact of IPS participation on non-vocational outcomes, particularly quality of life (QOL). Objective: To identity QOL outcomes experienced with (1) IPS participation and (2) IPS participation leading to employment. Methods: Using a mixed method design, data on quality of life outcomes were collected from 151 interviews and 213 surveys completed by veterans with SCI participating in IPS. Results: At 12 months, participants who obtained competitive employment (CE) and those who did not (no-CE) showed improvement on most measures. In months 12-24, the CE group showed improvements on all study measures while the no-CE group declined on many indices. Statistically significant changes were observed between participants who obtained CE versus no-CE on several measures. Themes were identified from interview data related to productivity and well-being. Productivity themes were (1) contributing to society, (2) earning an income, and (3) maintaining employment. Themes for well-being were (1) mental health/self confidence, (2) physical health, and (3) goal setting. Themes were associated with IPS participation irrespective of employment outcomes. Conclusion: IPS participants who were competitively employed report consistent improvement in handicap, health-related QOL, and life satisfaction measures across time. Qualitative findings revealed improved QOL outcomes in productivity and well being for veterans participating in IPS overall, regardless of employment outcomes. PMID- 30459496 TI - Examining the Effects of a Powered Exoskeleton on Quality of Life and Secondary Impairments in People Living With Spinal Cord Injury. AB - Background: Secondary impairments associated with spinal cord injury (SCI) limit one's independent functionality and negatively impact quality of life (QoL). Objective: The purpose of this study was to explore changes in secondary health conditions that may result from using a powered exoskeleton as well as their potential impact on QoL. Methods: Forty-five participants presenting with SCI ranging from T3-L2 were included in this study. Outcome measures included self reported assessments of pain, spasticity, bladder/bowel function, Satisfaction with Life Scale (SWLS), and Modified Ashworth Scale (MAS). Results: Participants reported significantly less spasticity at the conclusion of the study, 0.9 +/- 1.7, compared to baseline, 1.6 +/- 0.9 [t (44) = 2.83, p < .001]. MAS testing revealed that 26.7% of participants presented with decreased spasticity at the conclusion of the trial. Participants reported less pain at the end of the trial, 0.9 +/- 1.6, compared to the start, 1.1 +/- 1.7 [t (44) = 1.42, p > .05]. No negative changes in bowel and bladder were reported; positive changes were reported by 20% and 9% of participants with respect to bowel and bladder management. There was no statistically significant change in SWLS sum score from baseline, 20.4 +/- 8.0, to conclusion of the study, 21.3 +/- 7.6 [t (44) = -1.1, p > .05]. Conclusion: Findings suggest using a powered exoskeleton may decrease spasticity in people living with SCI. Although improvements in secondary impairments did not result in a significant improvement in QoL, it is believed that using a powered exoskeleton in one's community will lead to increased community integration facilitating an improvement in QoL. PMID- 30459497 TI - Strength and Step Activity After Eccentric Resistance Training in Those With Incomplete Spinal Cord Injuries. AB - Background: Individuals with spinal cord injuries (SCIs) often experience general weakness in the lower extremities that undermines daily step activity. Objective: To investigate the efficacy of eccentrically biased resistance training on lower extremity strength and physical activity of individuals with spinal injuries. Methods: Individuals with long-standing incomplete SCIs (N = 11) capable of completing a 10-meter walk assessment were included. All participants who completed the familiarization period finished the training. Individuals trained two times per week for 12 weeks on a lower body eccentric resistance training machine. It was hypothesized that the outcome variables (eccentric strength, isometric strength, and daily step physical activity) would improve as a result of the training intervention. Results: Eccentric strength [F(1.27, 12.71) = 8.42, MSE = 1738.35, H-F p = .009] and isometric strength [F(1.97, 19.77) = 7.10, MSE = 11.29, H-F p = .005] improved as a result of the training while daily step activity remained unchanged [F(2.00, 18.00) = 2.73, MSE = 216,836.78, H-F p = .092]. Conclusions: Eccentric resistance training improves eccentric and isometric strength. These physiological adaptations may translate to improved gait mechanics, but further study is required to identify this potential crossover effect. PMID- 30459498 TI - Effectiveness of 4-Aminopyridine for the Management of Spasticity in Spinal Cord Injury: A Systematic Review. AB - Background: Spasticity is a common secondary complication of spinal cord injury (SCI), which can severely impact functional independence and quality of life. 4 Aminopyridine (4-AP) is a potassium channel blocker that has been studied as an intervention for spasticity in individuals with SCI. Objective: To conduct a systematic review of the available evidence regarding the effectiveness of 4-AP for the management of spasticity in individuals with SCI. Methods: A comprehensive literature search was conducted on five electronic databases for articles published in English up to January 2017. Studies were included if (1) the sample size was three or more subjects, (2) the population was >=50% SCI, (3) the subjects were >=18 years old, (4) the treatment was 4-AP via any route, and (5) spasticity was assessed before and after the intervention. Subject characteristics, study design, intervention protocol, assessment methods, side effects, adverse events, and outcomes were extracted from selected studies. Randomized controlled trials (RCTs) were evaluated for methodological quality using the Physiotherapy Evidence Database (PEDro) tool. Levels of evidence were assigned using a modified Sackett scale. Results: Nine studies met inclusion criteria with a pooled sample size of 591 subjects. Six studies were RCTs (PEDro = 6-10, Level 1 evidence) and three studies were pre-post tests (Level 4 evidence). There was a wide range in duration, severity, and level of SCI across subjects. Oral 4-AP was investigated in five studies; one study reported significant improvements on the Ashworth Scale (AS), while the remaining four studies found no improvement. Three studies found no significant improvements on the Spasm Frequency Scale. Intravenous 4-AP was investigated in three studies; no significant improvements were found on the AS or in the Reflex Score. Intrathecal 4-AP was investigated in one study, which did not find significant improvements on the AS. Conclusion: There is weak evidence supporting the effectiveness of 4 AP in reducing spasticity post SCI. Future research should utilize contemporary measures of spasticity and address methodological limitations such as small sample sizes. PMID- 30459499 TI - Psychosocial and Health Outcomes of Adults With Violently Acquired Pediatric Spinal Cord Injury. AB - Objective: To describe the psychosocial and medical outcomes of individuals with pediatric-onset spinal cord injury (SCI) as a result of violent injuries. Methods: This was a cross-sectional study assessing adult outcomes associated with pediatric-onset SCI. Participants completed measures assessing demographics, injury characteristics, secondary conditions, and psychosocial functioning. Results: Participants included 483 adults (ages 19-51 years; M = 32.89, SD = 6.81) who sustained an SCI prior to age 19 (0-18 years; M = 14.25, SD = 4.40). Participants tended to have complete injuries (68%) and tetraplegia (53%) and were predominantly male (63%) and Caucasian (85%). The violent (n = 42) and nonviolent (n = 441) etiology groups tended to be similar in terms of gender. The violent etiology (VE) group, however, was significantly more likely to have paraplegia (chi2 = 7.45, p = .01), identify as an ethnic minority (chi2 = 5.40, p = .02), and have decreased odds of completing a college degree (odds ratio [OR], 0.40; 95% CI, 0.19-0.83). After controlling for significant covariates, individuals in the VE group were more likely to have moderate depression symptoms (OR, 3.73; 95% CI, 1.35-10.30) and significantly lower odds of economic independence (OR, 0.39; 95% CI, 0.19-0.84). The VE group was also 2 times as likely as the nonviolent group to report a pressure injury (OR, 2.04; 95% CI, 1.05-3.94) or activity interfering pain (OR, 2.34; 95% CI, 1.15-4.74). Conclusion: The results of this study reveal significantly greater psychosocial health concerns and more medical complications for individuals with violent SCI than those with nonviolent SCI. Children with an SCI from a violent etiology may warrant additional attention and services aimed at promoting stability and long term resilience. PMID- 30459500 TI - Ultrasonography Detects Deep Tissue Injuries in the Subcutaneous Layers of the Buttocks Following Spinal Cord Injury. AB - Background: Ultrasonography may have potential as an effective diagnostic tool for deep tissue injury (DTI) in tissues overlying bony prominences that are vulnerable when under sustained loading in sitting. Methods: Three cases of DTI in the fat and muscle layers overlying the ischial tuberosity of the pelvis in 3 persons with spinal cord injury (SCI) with different medical histories and abnormal tissue signs are described. Conclusion: There is a need for prospective studies using a reliable standardized ultrasonography protocol to diagnose DTI and to follow its natural history to determine its association with the development of pressure injuries. PMID- 30459502 TI - The role of muscle ultrasound in helping the clinical diagnosis of muscle diseases. AB - Background: Selective involvement of certain muscles is an indicator for muscle diseases and helps to direct the diagnosis, but in some cases, it cannot be detected clinically; hence, the roles of muscle MRI and ultrasound are to detect this selectivity and facilitate the diagnosis. Objectives: The possibility of using muscle ultrasound as a screening tool when muscle diseases are suspected and as an alternative to MRI. Subjects and methods: This cross-sectional descriptive study included 38 patients presented with clinical manifestations suggestive of muscle diseases. The patients were selected over a period of 1 year. All patients were subjected to thorough clinical assessment and muscle ultrasound of the thigh and leg for all patients, while 15 were subjected to MRI. Clinical and radiological assessments were performed separately, followed by both clinical and radiological findings to assess the power of combining the clinical and radiological assessments for the diagnosis of muscle diseases. Results: The clinical assessment reached a main provisional probable diagnosis in 53% cases, and radiological assessment blind to clinical data suggested diagnosis in 18 of the total cases, while the combination of both ultrasound and MRI could suggest diagnosis in 87% of the cases. The concordance ratio of ultrasound to MRI ranged between 78 and 100%. Conclusion: The combination of clinical and radiological assessments of muscle diseases can suggest a main provisional probable diagnosis, especially when genetic diagnosis is not accessible, or to direct the genetic testing when it is available. Ultrasound can be used as a routine tool in screening and follow-up of muscle diseases. PMID- 30459503 TI - Evaluating sex hormones and cytokine profile in Egyptian females with relapsing remitting multiple sclerosis. AB - Background: Sexual dimorphism shown in multiple sclerosis suggests an interaction between immune system and sex hormones. The objective of this study is to determine the hormonal profile and serum cytokine levels in Egyptian female patients with relapsing-remitting MS (RRMS) compared with healthy controls and their associations with disease disability. Methods: This study was conducted on 40 female patients with RRMS and 20 age-matched controls subjected to measurements of the hormonal profile (estrogen, testosterone) and cytokine levels (interleukin 10 and 4 and tumor necrosis factor alpha) and disability assessment using Expanded Disability Status Scale (EDSS). Results: Levels of estrogen, testosterone, interleukin 10 and 4 (IL-10 and IL-4), and tumor necrosis factor alpha (TNF-alpha) were higher in patients compared to control with no statistically significant difference. Estrogen levels were positively correlated with interleukin 10 and interleukin 4 levels and negatively correlated with tumor necrosis factor alpha (TNF-alpha), but there was no statistically significant correlation between hormonal profile or cytokine profile (IL-10, IL-4, and TNF alpha) and EDSS. Conclusions: It is suggested that estrogen has an anti inflammatory effect on cytokine milieu; therefore, it can be tried as a treatment option in multiple sclerosis. PMID- 30459501 TI - Identification and Management of Cardiometabolic Risk after Spinal Cord Injury: Clinical Practice Guideline for Health Care Providers. PMID- 30459504 TI - Quantitative evaluation of shoulder proprioception 6 months following stroke. AB - Background: Chronic shoulder pain following cerebrovascular stroke (CVS) is a major problem that persists after maximum recovery of motor functions. Such pain has been attributed to altered shoulder joint kinematics causing soft tissue damage. Aim: Evaluation of shoulder proprioception in the ipsilateral paretic arm and contralateral unaffected side 6 months following cerebrovascular event. Subject and method: Thirty adult patients (G1) with ischemic strokes ranging from 6 months to 1 year and 30 healthy control (G2) were assessed for shoulder proprioception. Angular displacement error was measured during active and passive repositioning of shoulder external and internal rotation in both patients' shoulders and in control's dominant upper limb. Results: Statistically significant increase in angular displacement error was found in all tests in the affected shoulder compared to the unaffected contralateral shoulder and dominant arm of control subjects. The contralateral unaffected shoulder of patients showed within normal values and no differences with control values. Passive external and internal rotations showed statistically higher errors in patients with cortical lesions compared to those with subcortical lesions. Conclusion: Six months following the CVS, shoulder proprioception deficit in the affected hemiparetic side persists. Contralateral side shows no abnormalities. Cortical lesions might be associated with late shoulder proprioception recovery compared to subcortical lesions. The side of the lesion does not seem to affect the severity of proprioception deficit. PMID- 30459506 TI - Endovascular coiling for cerebral aneurysm: single-center experience in Egypt. AB - Background: Endovascular management for cerebral saccular aneurysm has evolved in the last decade with evolution in both equipment and material. Coiling is still the mainstay of cerebral aneurysm endovascular management. In Egypt, practice outcome needs evaluation especially at low-volume centers. Purpose: To discuss the technical and management outcomes of our first symptomatic and asymptomatic cerebral saccular aneurysm case series treated with simple coiling. Patients and methods: Clinical, treatment, and outcome variables of consecutive symptomatic and asymptomatic cerebral aneurysm cases treated with simple coiling between January 2011 and June 2016 in one center were analyzed. Results: In 31 patients, 35 aneurysms were found, 34 aneurysms (97.1%) were treated by endovascular coiling, and only one aneurysm (2.9%) was not fit for endovascular treatment. Total occlusion was achieved in 29 aneurysms (82.9%). Neck remnants were present in 4 aneurysms (11.4%). Partial coiling (incomplete occlusion) was achieved in 1 aneurysm (2.9%). Regarding functional outcome (mRS at discharge), 25 patients had good outcome (mRS = 0, 1, 2, 3) and 6 patients had poor outcome (mRS = 4, 5, 6). Conclusion: The endovascular coiling could be used as a first-choice option for treatment of saccular cerebral aneurysms at our center despite the low case rate. PMID- 30459505 TI - Effect of transcranial direct current stimulation on cognitive function in stroke patients. AB - Background: Cognitive impairment after stroke is common and can cause disability with major impacts on quality of life and independence. Transcranial direct current stimulation may represent a promising tool for reconstitution of cognitive functions in stroke patients. Objectives: This study aimed to investigate the effect of transcranial direct current stimulation on cognitive functions in stroke patients. Patients and methods: Forty male stroke patients were included. Patients were divided randomly into two equal groups (A and B). Group A received transcranial direct current stimulation (tDCS) in combination with selected cognitive training program by RehaCom. Group B received sham transcranial direct current stimulation in combination with the same cognitive training program.Cognitive evaluation and functional independence measure (FIM) were done for all patients before and after treatment. Results: There was a significant improvement in the scores of attention and concentration, figural memory, logical reasoning, reaction behavior, and FIM post treatment in both groups; the improvement was significantly higher in group A compared to group B. Conclusion: tDCS is a safe and effective neuro-rehabilitation modality that improves post stroke cognitive dysfunctions. Moreover, tDCS has a positive impact on performance of daily activities. PMID- 30459508 TI - Burosumab in X-linked hypophosphatemia: a profile of its use in the USA. AB - Burosumab (Crysvita(r)), a fully human IgG1 monoclonal antibody directed at fibroblast growth factor 23 (FGF23), is indicated for the treatment of X-linked hypophosphatemia (XLH), a condition associated with excessive FGF23 production. It directly addresses the excessive FGF23 activity in patients with XLH by binding to FGF23, and inhibiting its signaling. This leads to increased gastrointestinal phosphate absorption and renal phosphate reabsorption, thereby improving serum phosphate levels, and, ultimately, bone mineralization and the risk of bone disease. In clinical trials, subcutaneous burosumab increased serum phosphorus levels in pediatric and adult patients with XLH, as well as significantly improving the severity of rickets in children, and improving pain, stiffness, physical functioning, and fracture/pseudofracture healing in adults. Burosumab is well tolerated by children and adults with XLH, with most treatment emergent adverse events being of mild to moderate severity. PMID- 30459507 TI - Fostamatinib in chronic immune thrombocytopenia: a profile of its use in the USA. AB - Oral fostamatinib is an orally administered small molecule spleen tyrosine kinase (SYK) inhibitor approved for the treatment of adults with chronic immune thrombocytopenia (ITP) who have an inadequate response to a previous treatment. Fostamatinib has a unique mechanism of action, whereby its active metabolite targets the SYK-mediated pathway of platelet destruction. In clinical trials, fostamatinib provided durable responses in adults with chronic ITP who had not responded or had relapsed following treatment with one or more prior ITP therapies, including corticosteroids, thrombopoietin receptor agonists, rituximab, and/or splenectomy. Most patients who respond to fostamatinib maintain platelet counts of > 50 * 109/L for periods of >= 12 months. The most common adverse events reported with fostamatinib in clinical trials were diarrhea, hypertension, nausea, and increased transaminase levels. PMID- 30459509 TI - Andexanet alfa in the treatment of acute major bleeding related to apixaban and rivaroxaban: a profile of its use in the USA. AB - Andexanet alfa (Andexxa(r)), a first-in-class recombinant modified factor Xa protein, is currently the only specific agent available to reverse life threatening or uncontrolled bleeding with the factor Xa inhibitors apixaban and rivaroxaban. Andexanet alfa acts as a decoy and competes with endogenous factor Xa to bind factor Xa inhibitors, thereby reversing the anticoagulant effects of factor Xa inhibitors, and restoring the activity of endogenous factor Xa. In adults with major bleeding associated with the use of apixaban or rivaroxaban, intravenous administration of andexanet alfa effectively and rapidly reduces anti factor Xa levels, with reduced levels being maintained during continued treatment. The tolerability profile of andexanet alfa in patients is generally similar to that reported of other approved anticoagulation reversal agents. With the known increased risk of thromboembolic events following andexanet alfa treatment, anticoagulant therapy should be resumed as soon as medically appropriate. PMID- 30459510 TI - Erratum. AB - [This corrects the article on p. 92 in vol. 52, PMID: 28747840.]. PMID- 30459511 TI - Overview of breastfeeding in Turkey in consideration of World Breastfeeding Week. PMID- 30459512 TI - Breastfeeding problems and interventions performed on problems: systematic review based on studies made in Turkey. AB - To determine the breastfeeding problems encountered in the postpartum period and effect of interventions done in relation to the problems based on breastfeeding studies in Turkey. This study is a systematic review and was conducted by performing a scan of the Turkish and English literature over the period October 2016-February 2017. The study included 27 articles and seven theses, which were published in 2000-2015 in Turkey and published in 2008-2017. Data are presented tabulating and the aggregate percentages were calculated for some data showing common characteristics. A total of 6736 parents and 592 babies were included in these studies. As a result of the combined percentage calculation based on the data of cross-sectional and case-control studies, the most frequently reported problems were having breastfeeding problem (24.5%), mother's milk deficiency/worry about milk deficiency/thinking her baby is not satisfied/baby's inadequate weight gain (15.7%), lack of knowledge and experience about breastfeeding/need for education and support (17.8%). Again, these studies showed that women stated the problems about have flat/depressed/small nipple (7.7%), pain/sensitivity (3.9%), swelling/fullness/engorgement (10.8%), redness (28.8%), crack/wound/bleeding (26.1%) and mastitis (5.6%). Methods of prenatal education/counselling/motivation/follow-up, strong motivation, proactive lactation management and social support, moist warm application, using of breast milk and olive oil and using of breast shield and feeding with container and pacifier using have been reported to be effective in the experimental/quasi experimental and case report studies included in this systematic review. This study showed that women experienced a lot problem with breastfeeding and that more prenatal education/counselling/monitoring was used in reducing problems. PMID- 30459514 TI - Risk factors affecting obesity development in high school students: a community based case-control study. AB - Aim: Obesity which is described as a "global epidemics" and qualified as "excessive accumulation of fat impairing health" by the World Health Organization is an important public health problem affecting children and adolescents as well as adults. The aim of this study was to determine the factors that affected obesity in high school students in a city center. Material and Methods: A total of 386 students including 193 subjects and 193 controls were included in this case-control study. The data were collected by applying a questionnaire which questioned sociodemographic properties, eating and physical activity behaviors and factors which were considered to have an impact on body weight. Descriptive statistics were evaluated using chi-square and logistic regression analysis. A p value of <0.05 was considered statistically significant. Results: In univariate analysis, presence of an obese person in the family/neighborhood, way of transportation to school, thoughts and wish of best friend of the same sex related to body weight and desire for weight loss were defined as variables which were associated with obesity. In multivariate regression analysis, it was found that presence of an obese person in the family/neighborhood, transportation to school by vehicle and having a best friend of the same sex who wanted the subject to stay at the same weight could be predictors of obesity. In the obese group, regarding oneself as obese and desire to lose weight were more common. Conclusion: In this study, it was found that presence of an obese person in the family/neighborhood, transportation to school by vehicle and having a best friend of the same sex who wanted the subject to stay at the same weight were significant risk factors in terms of obesity. However, levels of perceiving oneself as obese and desire to lose weight were found to be higher in the obese group. Consumption of unhealthy food in the home environment should be prevented by performing awareness studies for parents. In addition, physical exercises performed together by family members will be helpful for adolescents in terms of developing healthy lifestyle behaviors. PMID- 30459513 TI - Comparison of practical application steps of the previously used adrenaline auto injector in Turkey (EpiPen) and the currently available adrenaline auto injector (Penepin): a multi-center study. AB - Aim: It has been shown by a great number of studies that the correct use of adrenaline auto injectors prescribed to patients with anaphylaxis is associated with the design of the auto injector, in addition to training. The aim of this study was to compare the skills of adults in using two different auto injectors prescribed to patients with anaphylaxis. Material and Methods: Parents of patients aged between 1 and 18 years who referred to allergy outpatients were included in the study. Results: A total of 630 volunteers from nine centers were included in the study. Four hundred fifty-seven (72.5%) of the participants were females and 235 (37.3%) were undergraduates. The rate of showing all the steps of auto injector trainers correctly by the participants was found as (60.2%) (n=379) for EpiPen and 42.9% (n=270) for Penepin (p<0.001). The most frequent mistake with both auto injector trainers was the step of "place appropriate injection tip into outer thigh/press the trigger so it clicks." When the preferences of the volunteers were asked after training and application, 527 (83.7%) chose EpiPen, stating that it was easier and simpler to use. Conclusions: Our study showed that the correct usage rates of both adrenaline auto injectors were much lower than expected and there could be mistakes in the application of both. It could be appropriate to make improvements in the design of Penepin, which is still the only available adrenaline auto injector in Turkey, such that its application steps will be simpler and quicker. PMID- 30459515 TI - Knowledge and awareness of optimal use of reporting guidelines in paediatricians: A cross-sectional study. AB - Aim: The aim of this study was to investigate pediatricians' ideas and awareness of reporting guidelines of scientific researches, as well as the use of these guidelines in routine practice. Material and Methods: This cross-sectional survey was conducted among pediatricians working at two of the largest pediatric hospitals in Ankara. The pediatricians were asked to complete a 13-item questionnaire in Turkish about reporting guidelines and the Enhancing the Quality and Transparency of Health Research internet network, and their level of knowledge, awareness, and use of these guidelines were investigated. Results: A total of 224 physicians from both centers agreed to participate in the study (56.4% of the target population). The average age of the participants was 34+/ 9.24 years, their median age was 31 (min-max: 24-63) years, and 71.4% were female physicians. The participants' median duration in their careers was 6 (min-max: 1 39) years and 63.8% had participated in a scientific study as a researcher. Forty five (20%) of the participants had known about the reporting guidelines before and reported that they had most frequently heard about them via journals, congresses, and seminars. Twenty (26.6%) of these physicians had used the guidelines. Sixty-five (29%) of the participants had served as a reviewer for a scientific article, but only three (4.6%) stated that they had made use of the guidelines while reviewing the articles. Some 83.5% of the participants reported that they would like to be informed about reporting guidelines. Both centers had similar knowledge levels about the use of the guidelines. Conclusion: The awareness and use of reporting guidelines of scientific researches by pediatricians is insufficient. PMID- 30459516 TI - Effective sociodemographic and clinical factors in weight loss in childhood obesity. AB - Aim: Obesity is a more common and important health problem in childhood. We aimed to determine sociodemographic and clinical factors contributing weight loss. Material and Methods: Medical records of 120 obese patients (6-18 years old) applied at least twice for follow-up between 2012 (January)-2016 (September) were reviewed. Age, gender, socioeconomic status, family obesity, comorbidities, medications, operations, exercise frequency, screen time, physical examination findings and biochemical/hormone values [thyroid hormone, fasting insulin/glucose, cholesterol levels, Homeostasis model assesment insulin resistance (HOMA-IR), oral glucose tolerance test results (if applied) were recorded. Patients with a difference between the initial and last body mass index standart deviation higher than -0.2 were defined as "the good losing weight" group; the rest as "the poorly losing weight" group. The SPSS 22.0 program was used for analyzes. Results: Puberty stage showed a significant difference (p=0,019); 65% of patients in the poorly losing weight group but 54% of other group were at stage 4-5. The initial body mass index standart deviation and exercise frequency were higher in the good losing weight group, the last measured body mass index standart deviation was lower (p=0). In the other group, baseline HOMA-IR was higher (p=0.037); there were more metformin-initiated patients but the difference was not significant. Conclusion: We observed that exercise frequency was higher in cases with good weight loss; therefore, we consider that increasing physical activity is an important step. Other crucial outcomes are that the initial body mass index standart deviation is higher while HOMA-IR is lower in those cases and that puberty stage is higher in poorly weight losing patients. PMID- 30459517 TI - The outcomes of children with tracheostomy in a tertiary care pediatric intensive care unit in Turkey. AB - Aim: We aimed to describe which clinical characteristics were associated with the outcome of tracheostomy in our tertiary care pediatric intensive care unit. Material and Methods: This was a retrospective review of medical records of pediatric patients who underwent tracheostomy in our Pediatric Intensive Care unit from 2008 to 2014 in Turkey. Results: Sixty-three patients were included the study. The median age of patients was 11 (range, 1-195) months. Twenty-five (39.7%) patients were female. The tracheostomy rate was 8.5% over a six-year period. Forty-nine (77.7%) patients were able to be discharged and sent home. The decannulation rate was 12.6% (n=8). The indications for tracheostomy were upper airway obstruction (n=9) and prolonged mechanical ventilation (n=54). The median intubation period before tracheostomy was 32 (range, 1-122) days and the median duration of pediatric intensive care unit stay after tracheostomy was 37 days. A total of 21 (52.5%) patients were weaned off mechanical ventilation. The rate of successful weaning from mechanical ventilation was higher in patients with upper airway obstruction than in those in the prolonged mechanical ventilation group (p=0.021). The complication rate was 25.3% in the pediatric intensive care unit and 11.1% at home. Conclusions: Tracheostomy seems safe and improves pediatric patients' outcomes. The most important factor that affects the prognosis of children who underwent tracheostomy is the indication for tracheostomy. The outcomes are always better if the tracheostomy has been performed because of upper airway obstruction. Performing tracheostomy helps weaning from and off ventilator support and finally the discharge of patients with prolonged mechanical ventilation from the pediatric intensive care unit setting. PMID- 30459518 TI - An unusual cause of stridor: congenital laryngeal web. AB - Respiratory distress and stridor are some of the common presenting symptoms for children in Pediatric Emergency Department. Most of these children are diagnosed as having common illnesses such as laryngitis, croup or laryngomalacia. However, Pediatric Emergency physicians must keep in mind other rare respiratory diseases other than laryngitis or croup in the differential diagnosis of stridor. Stridor may occur due to congenital and acquired diseases. Laryngeal web is one of the rare congenital causes of stridor, which usually presents in the first weeks of life; however, it is very rarely diagnosed in the later period. Herein, we report a one-year-old boy who was evaluated for croup and was diagnosed as having laryngeal web. PMID- 30459519 TI - Primary cavitary tuberculosis in an infant. AB - In infants, tuberculosis usually progresses as hilar lymphadenopathy and parenchyma changes in lungs; associating cavitary lesions are rare. A six-month old infant was admitted to our hospital with fever. Physical examination revealed decreased breathe sounds in the right lung. Chest radiograph showed pneumonic infiltration in the right middle lobe. The patient was hospitalized with a diagnosis of lobar pneumonia and antibiotic treatment was started. On the sixth day, because no clinical improvement was observed in the patient, computerized thorax tomography was performed. Tomography revealed multiple lymphadenopathies in the right hilar pretracheal and subcarinal region. The patient's tuberculin and acid-resistant bacteria tests were negative; however, the quantiferon test was positive. Family screening revealed active tuberculosis in the mother. Tuberculosis in infants may present with unusual clinical and radiologic findings, and primary cavitary tuberculosis can also be seen in this age group. PMID- 30459520 TI - Wilkie's syndrome admitted for acute abdomen: A case presentation. AB - Superior mesenteric artery syndrome, also known as Wilkie's Syndrome, is a life threatening clinical entity which developes as a result of obstructed second or third part of duodenum compressed between aorta and superior mesenteric artery. In this rare syndrome, a rapid weight loss is accompanied by stomach ache, abdominal distension, lack of appetite, nausea and vomiting after meals. In patients admitted for acute abdomen, superior mesenteric artery syndrome should be included in the differential diagnosis in case of a preceeding rapid weight loss. X-ray of barium passage, abdominal ultrasound, gastroscopy, abdominal angio tomography or abdominal magnetic resonance angiography may be useful for diagnosis. Conservative and surgical approaches are available for the treatment. In this report we aimed to emphasize that superior mesenteric artery syndrome cases may admit for acute abdomen and that superior mesenteric artery syndrome should be included in differential diagnosis. PMID- 30459521 TI - Syncope due to complete atrioventricular block and treatment with a transient pacemaker in acute rheumatic fever. AB - Various rhythm and connection disorders can be seen in the acute phase of acute rheumatic fever. First degree atrioventricular block, one of the minor signs of acute rheumatic fever, is the most common connection disturbance in this disease. Complete atrioventricular block, which seriously affects the conduction pathways, is rare in the literature. A 15-year-old boy was admitted because of syncope caused by complete atrioventricular block and a temporary pacemaker was employed because of symptomatic complete atrioventricular block. The transient pacemaker treatment was terminated due to recovery of complete atrioventricular block on the third day of antiinflammatory treatment. Acute rheumatic fever should be kept in mind as a possible cause of acquired complete atrioventricular block. Connection disturbances in acute rheumatic fever improve with antiinflammatory treatment. Transient pacemaker treatment is indicated for patients with symptomatic transient complete atrioventricular block. PMID- 30459522 TI - Anaphylaxis with midazolam in pediatric hematology-oncology unit: a case report. PMID- 30459523 TI - Context matters. AB - Eliciting the level of risk aversion of experimental subjects is of crucial concern to experimenters. In the literature there are a variety of methods used for such elicitation; the concern of the experiment reported in this paper is to compare them. The methods we investigate are the following: Holt-Laury price lists; pairwise choices, the Becker-DeGroot-Marschak method; allocation questions. Clearly their relative efficiency in measuring risk aversion depends upon the numbers of questions asked; but the method itself may well influence the estimated risk-aversion. While it is impossible to determine a 'best' method (as the truth is unknown) we can look at the differences between the different methods. We carried out an experiment in four parts, corresponding to the four different methods, with 96 subjects. In analysing the data our methodology involves fitting preference functionals; we use four, Expected Utility and Rank Dependent Expected Utility, each combined with either a CRRA or a CARA utility function. Our results show that the inferred level of risk aversion is more sensitive to the elicitation method than to the assumed-true preference functional. Experimenters should worry most about context. PMID- 30459524 TI - Disapproval aversion or inflated inequity acceptance? The impact of expressing emotions in ultimatum bargaining. AB - Past experimental research has shown that when rating systems are available, buyers are more generous in accepting unfair offers in ultimatum bargaining. However, it also suggests that, under these conditions, sellers behave more fairly to avoid receiving negative feedback. This paper experimentally investigates which effect is stronger with the use of a rating system: buyers' inflated inequity acceptance or sellers' disapproval aversion. We explore this question by varying the information condition on the buyers' side. Our experiment shows that in a setup where the size of the pie is common knowledge for both buyers and sellers, when a rating system is present, the sellers exhibit disapproval aversion but the buyers do not display greater acceptance of inequity. By contrast, when only sellers are aware of the size of the pie, sellers behave aggressively to exploit buyers and their behavior does not change in the presence of a rating system; however, buyers display greater acceptance of inequity when a rating system is present. We discuss how these results can be explained by a theoretical model that includes sellers' social disapproval aversion and buyers' disappointment aversion in addition to the players' inequality aversion. PMID- 30459525 TI - Advancing mobile learning in Australian healthcare environments: nursing profession organisation perspectives and leadership challenges. AB - Background: Access to, and use of, mobile or portable devices for learning at point of care within Australian healthcare environments is poorly governed. An absence of clear direction at systems, organisation and individual levels has created a mobile learning paradox, whereby although nurses understand the benefits of seeking and retrieving discipline or patient-related knowledge and information in real-time, mobile learning is not an explicitly sanctioned nursing activity. The purpose of this study was to understand the factors influencing mobile learning policy development from the perspective of professional nursing organisations. Methods: Individual semi-structured interviews were undertaken with representatives from professional nursing organisations in December 2016 and January 2017. Recruitment was by email and telephone. Qualitative analysis was conducted to identify the key themes latent in the transcribed data. Results: Risk management, perceived use of mobile technology, connectivity to information and real-time access were key themes that emerged from the analysis, collectively identifying the complexity of innovating within an established paradigm. Despite understanding the benefits and risks associated with using mobile technology at point of care, nursing representatives were reluctant to exert agency and challenge traditional work patterns to alter the status quo. Conclusions: The themes highlighted the complexity of accessing and using mobile technology for informal learning and continuing professional development. Mobile learning cannot occur at point of care until the factors identified are addressed. Additionally, a reluctance by nurses within professional organisations to advance protocols to govern digital professionalism needs to be overcome. For mobile learning to be perceived as a legitimate nursing function requires a more wholistic approach to risk management that includes all stakeholders, at all levels. The goal should be to develop revised protocols that establish a better balance between the costs and benefits of access to information technology in real-time by nurses. PMID- 30459526 TI - IL-2 augments the sorafenib-induced apoptosis in liver cancer by promoting mitochondrial fission and activating the JNK/TAZ pathway. AB - Background: Sorafenib is the standard targeted drug used to treat hepatocellular carcinoma (HCC), but the therapeutic response between individuals varies markedly. Recently, cytokine-based immunotherapy has been a topic of intense discussion in the fight against cancer. The aim of this study was to explore whether cytokine IL-2 could augment the anti-tumour effects of sorafenib on HCC. Methods: HepG2 and Huh7 cells were co-treated with sorafenib and IL-2 in vitro, and cellular viability and death were analysed through the MTT assay, TUNEL staining, LDH release assay, and western blotting. Mitochondrial function was measured via ELISA, immunofluorescence, and western blotting. Pathway blockers were used to establish the role of the JNK-TAZ pathways in regulating cancer cell phenotypes. Results: Our data demonstrated that sorafenib treatment increased the HCC apoptotic rate, repressed cell proliferation, and inhibited migratory responses, and these effects were enhanced by IL-2 supplementation. Mechanistically, the combination of IL-2 and sorafenib interrupted mitochondrial energy metabolism by downregulating mitochondrial respiratory proteins. In addition, IL-2 and sorafenib co-treatment promoted mitochondrial dysfunction, as evidenced by the decreased mitochondrial potential, elevated mitochondrial ROS production, increased leakage of mitochondrial pro-apoptotic factors, and activation of the mitochondrial death pathway. A molecular investigation revealed that mitochondrial fission was required for the IL-2/sorafenib-mediated mitochondrial dysfunction. Mitochondrial fission was triggered by sorafenib and was largely amplified by IL-2 supplementation. Finally, we found that IL 2/sorafenib regulated mitochondrial fission via the JNK-TAZ pathways; blockade of the JNK-TAZ pathways abrogated the inhibitory effects of L-2/sorafenib on cancer survival, growth and mobility. Conclusions: Altogether, these data strongly suggest that additional supplementation with IL-2 enhances the anti-tumour activity of sorafenib by promoting the JNK-TAZ-mitochondrial fission axis. This finding will pave the way for new treatment modalities to control HCC progression by optimizing sorafenib-based therapy. PMID- 30459527 TI - Predictive significance of TMRPSS2-ERG fusion in prostate cancer: a meta analysis. AB - Background: Prostate cancer is a major malignancy in males. TMPRSS2-ERG is a high frequency fusion gene expressed in prostate cancer and plays a vital role in carcinogenesis. Recent studies showed that TMPRSS2-ERG is a potential predictive biomarker for prostate cancer. However, the predictive value of TMPRSS2-ERG fusion is yet unclear. Methods: A total of 76 relevant articles, published from 2015 to 2017, were obtained from PubMed, Web of Science, EMBASE, Scopus, the Cochrane Library, and CNKI databases to investigate the predictive significance of TMPRSS2-ERG fusion in prostate cancer. Pooled odds ratio (ORs) with 95% confidence intervals (CIs) were calculated to estimate the correlation between TMPRSS2-ERG fusion gene and tumor features. Results: The pooled or stratified analysis showed that the TMPRSS2-ERG fusion gene had a highly predictive potential. First, TMPRSS2-ERG fusion was associated with T-stage at diagnosis (T3 4 vs. T1-2 OR: 1.40; 95% CI 1.33-1.48) and metastasis (M1 vs. M0 OR: 1.35; 95% CI 1.02-1.78) but not with biochemical recurrence or prostate cancer-specific mortality. Furthermore, the subgroup analysis found that the TMPRSS2-ERG fusion gene was correlated with Gleason (G) scores, and the fusion was common in prostate cancer with G <= 7. Additionally, the meta-analysis demonstrated that the fusion was likely to occur in young patients (> 65 vs. <= 65 OR: 0.68; 95% CI 0.52-0.89), in patients with high PSA levels (> 10 vs. <= 10 OR: 1.30; 95% CI 1.21-1.38), and in patients with peripheral involvement (positive vs. negative OR: 1.17; 95% CI 1.08-1.28), while not associated with tumor volume. Finally, the subgroup analysis of different fusion types demonstrated that the deletion-type fusion was significantly associated with the malignant degree of prostate cancer (pooled OR: 5.67; 95% CI 2.85-11.28). Moreover, the deletion-type was common in Africa patients, followed by Caucasian patients, and no significant difference was observed in the incidence of different fusion types in the Asian population. Conclusions: The meta-analysis findings suggested that the TMPRSS2-ERG fusion gene might be a predictive marker for prostate cancer patients, and might be valuable for assessing the characteristics of prostate cancer for individualized treatment and prognosis evaluation. PMID- 30459528 TI - TEAD4 overexpression promotes epithelial-mesenchymal transition and associates with aggressiveness and adverse prognosis in head neck squamous cell carcinoma. AB - Background: Deregulated Hippo signaling has been uncovered to be intricately involved in tumorigenesis. Transcriptional factor TEADs serve as key mediators of Hippo signaling and have been increasingly appreciated as putative oncogenes driving cancer initiation and progression. However, its expression pattern and oncogenic role of TEAD4 in head and neck squamous cell carcinoma (HNSCC) remain largely unexplored. Methods: TEAD4 mRNA expression in HNSCC was determined by data mining and analyses from TCGA dataset and four independent cohorts with transcriptional profiling data publically available. The protein abundance of TEAD4 was measured by immunohistochemistry in 105 primary HNSCC samples and associations between its expression and clinicopathological parameters and patient survival were evaluated. The oncogenic roles of TEAD4 was further determined by 4-nitroquinoline 1-oxide (4NQO)-induced animal model, both knockdown/overexpression assay and TGF-beta1-induced epithelia-mesenchymal transition (EMT) in vitro. Results: Both mRNA and protein abundance of TEAD4 were significantly increased in HNSCC as compared to its non-tumor counterparts. Overexpression of TEAD4 significantly associated with high pathological grade, cervical node metastasis, advanced clinical stage and reduced overall and disease free survival. In the 4NQO-induced HNSCC mouse model, increased TEAD4 immunostaining was found associated with disease progression. TEAD4 knockdown significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis in HNSCC cells, while its overexpression resulted in opposite effects and EMT. Moreover, TEAD4 was critically involved in TGF-beta1-induced EMT in HNSCC cells. Conclusions: Our findings reveal that TEAD4 serves as a novel prognostic biomarker and putative oncogene for HNSCC by promoting cell proliferation, migration and invasion, and EMT. PMID- 30459529 TI - Research progresses in roles of LncRNA and its relationships with breast cancer. AB - Some progresses have been made in research of long non-coding RNA (hereunder referred to as LncRNA) related to breast cancer. Lots of data about LncRNA transcription concerning breast cancer have been obtained from large-scale omics research (e.g. transcriptomes and chips). Some LncRNAs would become indices for detecting breast cancer and judging its development and prognosis. LncRNAs may affect genesis and development of breast cancer in multiple ways. Perhaps they could develop into potential targets for treating breast cancer if they are carcinogenic. Like those from other studies of breast cancer, many data gained from omics research remain to be validated by much experimental work. For instance, it is still necessary to demonstrate reliability of LncRNAs as indices for diagnosing breast cancer and judging its prognosis (particularly for various subtypes of breast cancer), effectiveness and feasibility of these genes for treating breast cancer as targets. In this paper, recent years' literatures about LncRNAs which are related to breast cancer are summarized and sorted out to review the research progresses in relationships between LncRNAs and breast cancer. PMID- 30459530 TI - Chimeric antigen receptors: unleashing a new age of anti-cancer therapy. AB - Background: Chimeric antigen receptors (CARs) represent a novel facet of modern day synthetic biology that exemplifies personalized medicine at work through their ability to harness and redirect a patient's immune system to fight cancer. Body: By combining the target-specificity of antibodies to the effector capabilities of T cells, CARs have yielded high remission rates for many late staged and relapsed/refractory (r/r) hematological malignancies, including acute lymphoblastic leukemias (ALL) and Non-Hodgkin's lymphomas. Despite toxicities of cytokine release syndrome and neurotoxicity, recent studies have uncovered their underlying mechanisms and devised effective therapies to manage and possibly prevent them. In 2017, CAR T cell therapy became a reality for the general public despite the high costs, when Novartis's Kymriah, became the first product to receive FDA approval for pediatric r/r B cell ALL with Gilead's Yescarta following several months later. Although effective in hematological malignancies, CAR response has been limited in solid tumors largely attributed to the heterogeneous and immunosuppressive tumor microenvironment along tumor defense mechanisms, such as antigenic escape. Conclusion: Despite the current challenges of CAR T therapy, this technology is still in its infancy and its promise will continue to grow as scientists continue to develop novel approaches to enhance its efficacy. As its prevalence continues to increase, institutions and pharmaceuticals worldwide are investing in this technology in hopes of driving therapeutic innovation, while providing greater access to their respective populations through clinical trials. PMID- 30459532 TI - Impact of drug substitution on cost of care: an example of economic analysis of cetuximab versus panitumumab. AB - Background: The alarming increase in the cost of cancer care is forcing all stakeholders to re-evaluate their approach to treatment. Drugs are the main contributor to the cost. To evaluate the significance of drug substitution on the cost of care we assessed the economic value of panitumumab vs. cetuximab in chemo refractory metastatic CRC (mCRC) with wild-type KRAS from a US societal perspective. Methods: We developed a Markov model with three health states: progression-free, progressive, and death. We calculated the transition probabilities between states using the ASPECCT trial report and US life tables. Costs of drug and administration were based on the Medicare reimbursement rates. Published data were used for cost of toxicities and utilities. All costs were converted to 2017 US dollars. The model used quality-adjusted life-years (QALYs) to measure health outcomes for each treatment option. Results: Panitumumab and cetuximab produced 0.45 QALYs at a per patient cost of $66,006 and $71,956, respectively. The incremental net monetary benefit of panitumumab compared to cetuximab is $5237 under a societal willingness-to-pay threshold of $150,000. The model showed robustness to one-way sensitivity analyses and various alternative scenarios and was found to be most sensitive to the cost of cetuximab. Conclusions: Panitumumab can lower the cost of care without impacting outcomes in chemo-refractory mCRC settings. This finding provides a strong argument to consider panitumumab in lieu of cetuximab in these patients. PMID- 30459531 TI - SKA3 promotes cell proliferation and migration in cervical cancer by activating the PI3K/Akt signaling pathway. AB - Background: Cervical cancer (CC) is one of the most common cancers among females worldwide. Spindle and kinetochore-associated complex subunit 3 (SKA3), located on chromosome 13q, was identified as a novel gene involved in promoting malignant transformation in cancers. However, the function and underlying mechanisms of SKA3 in CC remain unknown. Using the Oncomine database, we found that expression of SKA3 mRNA is higher in CC tissues than in normal tissues and is linked with poor prognosis. Methods: In our study, immunohistochemistry showed increased expression of SKA3 in CC tissues. The effect of SKA3 on cell proliferation and migration was evaluated by CCK8, clone formation, Transwell and wound-healing assays in HeLa and SiHa cells with stable SKA3 overexpression and knockdown. In addition, we established a xenograft tumor model in vivo. Results: SKA3 overexpression promoted cell proliferation and migration and accelerated tumor growth. We further identified that SKA3 is involved in regulating cell cycle progression and the PI3K/Akt signaling pathway via RNA-sequencing (RNA-Seq) and gene set enrichment analyses. Western blotting results revealed that SKA3 overexpression increased levels of p-Akt, cyclin E2, CDK2, cyclin D1, CDK4, E2F1 and p-Rb in HeLa cells. Additionally, the use of an Akt inhibitor (GSK690693) significantly reversed the cell proliferation capacity induced by SKA3 overexpression in HeLa cells. Conclusions: We suggest that SKA3 overexpression contributes to CC cell growth and migration by promoting cell cycle progression and activating the PI3K-Akt signaling pathway, which may provide potential novel therapeutic targets for CC treatment. PMID- 30459534 TI - Editorial. PMID- 30459533 TI - Genetic diversity of Bletilla striata assessed by SCoT and IRAP markers. AB - Background: Bletilla striata is a well-known traditional Chinese herb with varieties of functions. In China, the natural resources of Bletilla striata have been severely damaged because of the excessive exploitation and destruction of natural habitats. The aim of present study was to provide a reference for fully exploiting and utilizing the germplasm resources of Bletilla striata. Results: The genetic diversity of 50 varieties of Bletilla striata from different area in China was analyzed by SCoT and IRAP molecular marker technique. A total of 209 bands were amplified by 20 groups of SCoT primers, of which 201 (96.17%) were polymorphic, and 47 polymorphic bands (94%) were observed in 50 bands amplified by 8 groups of IRAP primers. The 50 populations of Bletilla striata were divided into two major groups by SCoT and IRAP at the genetic similarity coefficient value of 0.60 and 0.68 individually. The partition of clusters in the unweighted pair group method with arithmetic mean dendrogram and principal coordinate analysis plot based on the SCoT and IRAP markers was similar. Conclusions: Results indicated the abundant genetic diversity of Bletilla striata among different areas. Our results will provide useful information for resource protection. PMID- 30459535 TI - Optimal Analytical Performance for POCT. AB - Quality specifications for the reliability performance characteristics of laboratory tests, particularly precision and bias, are necessary prerequisites for creation and control of analytical quality. Many strategies have been promulgated for setting these. Recently, the available approaches have been fixed into a hierarchical framework that has now been agreed by experts in the field to be the best current approach to a global strategy to set quality specifications in laboratory medicine. They should be incorporated into quality planning strategies everywhere i rrespective of the settings in which laboratory medicine is practised, including POCT. Models higher in the hierarchy are preferred to lower approaches but lower approaches are better than none and should be used if all that are available. PMID- 30459536 TI - Preanalytical Variables and Their Influence on the Quality of Laboratory Results. AB - While analytical standards have been developed by established quality control criteria, there has been a paucity in the development of standards for the preanalytical phase. Only recently recommendations have been published regarding the quality of samples including the definition of the optimal sample size, the use of anticoagulants and stabilizers, stability criteria regarding transport and storage and handling of hemolytic, lipemic and icteric samples. Technical recommendations regarding sampling, transport and identification have been developed by national and international consensus organizations. The development of a preanalytical quality manual takes on an urgency in the goal towards achieving total quality control. Every day the laboratory is confronted with data arising out of preanalytical errors. Ability to recognize such data is critical to maintaining total laboratory quality and will be illustrated with case studies. PMID- 30459537 TI - Proposal for Another Step on the Path to Total Quality Management. PMID- 30459538 TI - Uncertainty in Measurement - Introduction and Examples from Laboratory Medicine. PMID- 30459539 TI - IFCC Professional Scientific Exchange Programme Report - Biochemical Markers of Bone Turnover. PMID- 30459540 TI - IFCC Professional Scientific Exchange Programme Report - Link Between Paraoxonase Genotype and Prognosis in Suicides with Organophosphorus Pesticides. PMID- 30459543 TI - Editorial: Biomechatronics: Harmonizing Mechatronic Systems With Human Beings. PMID- 30459542 TI - A Characterization of Brain-Computer Interface Performance Trade-Offs Using Support Vector Machines and Deep Neural Networks to Decode Movement Intent. AB - Laboratory demonstrations of brain-computer interface (BCI) systems show promise for reducing disability associated with paralysis by directly linking neural activity to the control of assistive devices. Surveys of potential users have revealed several key BCI performance criteria for clinical translation of such a system. Of these criteria, high accuracy, short response latencies, and multi functionality are three key characteristics directly impacted by the neural decoding component of the BCI system, the algorithm that translates neural activity into control signals. Building a decoder that simultaneously addresses these three criteria is complicated because optimizing for one criterion may lead to undesirable changes in the other criteria. Unfortunately, there has been little work to date to quantify how decoder design simultaneously affects these performance characteristics. Here, we systematically explore the trade-off between accuracy, response latency, and multi-functionality for discrete movement classification using two different decoding strategies-a support vector machine (SVM) classifier which represents the current state-of-the-art for discrete movement classification in laboratory demonstrations and a proposed deep neural network (DNN) framework. We utilized historical intracortical recordings from a human tetraplegic study participant, who imagined performing several different hand and finger movements. For both decoders, we found that response time increases (i.e., slower reaction) and accuracy decreases as the number of functions increases. However, we also found that both the increase of response times and the decline in accuracy with additional functions is less for the DNN than the SVM. We also show that data preprocessing steps can affect the performance characteristics of the two decoders in drastically different ways. Finally, we evaluated the performance of our tetraplegic participant using the DNN decoder in real-time to control functional electrical stimulation (FES) of his paralyzed forearm. We compared his performance to that of able-bodied participants performing the same task, establishing a quantitative target for ideal BCI-FES performance on this task. Cumulatively, these results help quantify BCI decoder performance characteristics relevant to potential users and the complex interactions between them. PMID- 30459541 TI - Central Role of Glucocorticoid Receptors in Alzheimer's Disease and Depression. AB - Alzheimer's disease (AD) is the principal neurodegenerative pathology in the world displaying negative impacts on both the health and social ability of patients and inducing considerable economic costs. In the case of sporadic forms of AD (more than 95% of patients), even if mechanisms are unknown, some risk factors were identified. The principal risk is aging, but there is growing evidence that lifetime events like chronic stress or stress-related disorders may increase the probability to develop AD. This mini-review reinforces the rationale to consider major depressive disorder (MDD) as an important risk factor to develop AD and points the central role played by the hypothalamic-pituitary adrenal (HPA) axis, glucocorticoids (GC) and their receptors (GR) in the etiology of MDD and AD. Several strategies directly targeting GR were tested to neutralize the HPA axis dysregulation and GC overproduction. Given the ubiquitous expression of GR, antagonists have many undesired side effects, limiting their therapeutic potential. However, a new class of molecules was developed, highly selective and acting as modulators. They present the advantage to selectively abrogate pathogenic GR-dependent processes, while retaining beneficial aspects of GR signaling. In fact, these "selective GR modulators" induce a receptor conformation that allows activation of only a subset of downstream signaling pathways, explaining their capacity to combine agonistic and antagonistic properties. Thus, targeting GR with selective modulators, alone or in association with current strategies, becomes particularly attractive and relevant to develop novel preventive and/or therapeutic strategies to tackle disorders associated with a dysregulation of the HPA axis. PMID- 30459544 TI - Automatic Human Sleep Stage Scoring Using Deep Neural Networks. AB - The classification of sleep stages is the first and an important step in the quantitative analysis of polysomnographic recordings. Sleep stage scoring relies heavily on visual pattern recognition by a human expert and is time consuming and subjective. Thus, there is a need for automatic classification. In this work we developed machine learning algorithms for sleep classification: random forest (RF) classification based on features and artificial neural networks (ANNs) working both with features and raw data. We tested our methods in healthy subjects and in patients. Most algorithms yielded good results comparable to human interrater agreement. Our study revealed that deep neural networks (DNNs) working with raw data performed better than feature-based methods. We also demonstrated that taking the local temporal structure of sleep into account a priori is important. Our results demonstrate the utility of neural network architectures for the classification of sleep. PMID- 30459545 TI - Axonal Stimulations With a Higher Frequency Generate More Randomness in Neuronal Firing Rather Than Increase Firing Rates in Rat Hippocampus. AB - Deep brain stimulation (DBS) has been used for treating many brain disorders. Clinical applications of DBS commonly require high-frequency stimulations (HFS, ~100 Hz) of electrical pulses to obtain therapeutic efficacy. It is not clear whether the electrical energy of HFS functions other than generating firing of action potentials in neuronal elements. To address the question, we investigated the reactions of downstream neurons to pulse sequences with a frequency in the range 50-200 Hz at afferent axon fibers in the hippocampal CA1 region of anesthetized rats. The results show that the mean rates of neuronal firing induced by axonal HFS were similar even for an up to fourfold difference (200:50) in the number and thereby in the energy of electrical pulses delivered. However, HFS with a higher pulse frequency (100 or 200 Hz) generated more randomness in the firing pattern of neurons than a lower pulse frequency (50 Hz), which were quantitatively evaluated by the significant changes of two indexes, namely, the peak coefficients and the duty ratios of excitatory phase of neuronal firing, induced by different frequencies (50-200 Hz). The findings indicate that a large portion of the HFS energy might function to generate a desynchronization effect through a possible mechanism of intermittent depolarization block of neuronal membranes. The present study addresses the demand of high frequency for generating HFS-induced desynchronization in neuronal activity, which may play important roles in DBS therapy. PMID- 30459546 TI - Assessing Panic: Bridging the Gap Between Fundamental Mechanisms and Daily Life Experience. AB - Panic disorder (PD) is one of the most common psychiatric disorders. Recurrent, unexpected panic attacks (PAs) are the primary symptom and strongly impact patients' quality of life. Clinical manifestations are very heterogeneous between patients, emphasizing the need for a dimensional classification integrating various aspects of neurobiological and psychological circuits in line with the Research Domain Criteria (RDoC) proposed by the US National Institute of Mental Health. To go beyond data that can be collected in the daily clinical situation, experimental panic provocation is widely used, which has led to important insights into involved brain regions and systems. Genetic variants can determine the sensitivity to experimental models such as carbon dioxide (CO2) exposure and can increase the risk to develop PD. Recent developments now allow to better assess the dynamic course of PAs outside the laboratory in patients' natural environment. This can provide novel insights into the underlying mechanisms and the influence of environmental factors that can alter gene regulation by changing DNA methylation. In this mini review, we discuss assessment of PAs in the clinic, in the laboratory using CO2 exposure, genetic associations, and the benefits of real-life assessment and epigenetic research. PMID- 30459547 TI - Multicellular Crosstalk Between Exosomes and the Neurovascular Unit After Cerebral Ischemia. Therapeutic Implications. AB - Restorative strategies after stroke are focused on the remodeling of cerebral endothelial cells and brain parenchymal cells. The latter, i.e., neurons, neural precursor cells and glial cells, synergistically interact with endothelial cells in the ischemic brain, providing a neurovascular unit (NVU) remodeling that can be used as target for stroke therapies. Intercellular communication and signaling within the NVU, the multicellular brain-vessel-blood interface, including its highly selective blood-brain barrier, are fundamental to the central nervous system homeostasis and function. Emerging research designates cell-derived extracellular vesicles and especially the nano-sized exosomes, as a complex mean of cell-to-cell communication, with potential use for clinical applications. Through their richness in active molecules and biological information (e.g., proteins, lipids, genetic material), exosomes contribute to intercellular signaling, a condition particularly required in the central nervous system. Cerebral endothelial cells, perivascular astrocytes, pericytes, microglia and neurons, all part of the NVU, have been shown to release and uptake exosomes. Also, exosomes cross the blood-brain and blood-cerebrospinal fluid barriers, allowing communication between periphery and brain, in normal and disease conditions. As such exosomes might be a powerful diagnostic tool and a promising therapeutic shuttle of natural nanoparticles, but also a means of disease spreading (e.g., immune system modulation, pro-inflammatory action, propagation of neurodegenerative factors). This review highlights the importance of exosomes in mediating the intercellular crosstalk within the NVU and reveals the restorative therapeutic potential of exosomes harvested from multipotent mesenchymal stem cells in ischemic stroke, a frequent neurologic condition lacking an efficient therapy. PMID- 30459548 TI - Disentangling Multispectral Functional Connectivity With Wavelets. AB - The field of brain connectomics develops our understanding of the brain's intrinsic organization by characterizing trends in spontaneous brain activity. Linear correlations in spontaneous blood-oxygen level dependent functional magnetic resonance imaging (BOLD-fMRI) fluctuations are often used as measures of functional connectivity (FC), that is, as a quantity describing how similarly two brain regions behave over time. Given the natural spectral scaling of BOLD-fMRI signals, it may be useful to represent BOLD-fMRI as multiple processes occurring over multiple scales. The wavelet domain presents a transform space well suited to the examination of multiscale systems as the wavelet basis set is constructed from a self-similar rescaling of a time and frequency delimited kernel. In the present study, we utilize wavelet transforms to examine fluctuations in whole brain BOLD-fMRI connectivity as a function of wavelet spectral scale in a sample (N = 31) of resting healthy human volunteers. Information theoretic criteria measure relatedness between spectrally-delimited FC graphs. Voxelwise comparisons of between-spectra graph structures illustrate the development of preferential functional networks across spectral bands. PMID- 30459549 TI - Maturation of Speech-Sound ERPs in 5-6-Year-Old Children: A Longitudinal Study. AB - The maturation of 5-6-year-old children's auditory discrimination - indicated by the development of the auditory event-related-potentials (ERPs) - has not been previously studied in longitudinal settings. For the first time, we present here the results based on extensive dataset collected from 75 children. We followed the 5- to 6-year-olds for 20 months and measured their ERPs four times with the same multifeature paradigm with phonemic stimuli. The amplitude of the mismatch negativity (MMN) response increased during this time for vowel, vowel duration and frequency changes. Furthermore, the P3a component started to mature toward adult-like positivity for the vowel, intensity and frequency deviants and the late discriminative negativity (LDN) component decreased with age for vowel and intensity deviants. All the changes in the components seemed to happen during the second follow-up year, when Finnish children are taught letter symbols and other preliminary academic skills before going to school at the age of seven. Therefore, further studies are needed to clarify if these changes in the auditory discrimination are purely age-related or due to increasing linguistic knowledge of the children. PMID- 30459550 TI - Item-Wise Interindividual Brain-Behavior Correlation in Task Neuroimaging Analysis. AB - Brain-behavior correlations are commonly used to explore the associations between the brain and human behavior in cognitive neuroscience studies. There are many critics of the correlation approach, however. Most problems associated with correlation approaches originate in the weak statistical power of traditional correlation procedures (i.e., the mean-wise interindividual brain-behavior correlation). This paper proposes a new correlation procedure, the item-wise interindividual brain-behavior correlation, which enhances statistical power via testing the significance of small correlation coefficients from trials against zero rather than simply pursuing the highest correlation coefficient. The item wise and mean-wise correlation were compared in simulations and an fMRI experiment on mathematical problem-solving. Simulations show that the item-wise correlation relative to the mean-wise correlation results in higher t-values when signal-to-noise ratio is equal to or larger than 6%. Item-wise correlation displayed more voxels with significant brain-behavior correlation than did mean wise correlation. Analyses with item-wise (rather than mean-wise) correlation showed significant brain-behavior correlation at the threshold of p < 0.05 corrected. Cross validation showed that odd- and even-ordered trials have greater stability in terms of the item-wise correlation (r = 0.918) than the mean-wise correlation (r = 0.686). The simulations and example analyses altogether demonstrate the effectiveness of the proposed correlation procedure for task neuroimaging studies. PMID- 30459552 TI - Growth Cone Tctp Is Dynamically Regulated by Guidance Cues. AB - Translationally controlled tumor protein (Tctp) contributes to retinal circuitry formation by promoting axon growth and guidance, but it remains unknown to what extent axonal Tctp specifically influences axon development programs. Various genome-wide profiling studies have ranked tctp transcripts among the most enriched in the axonal compartment of distinct neuronal populations, including embryonic retinal ganglion cells (RGCs), suggesting its expression can be regulated locally and that this may be important during development. Here, we report that growth cone Tctp levels change rapidly in response to Netrin-1 and Ephrin-A1, two guidance cues encountered by navigating RGC growth cones. This regulation is opposite in effect, as we observed protein synthesis- and mTORC1 dependent increases in growth cone Tctp levels after acute treatment with Netrin 1, but a decline upon exposure to Ephrin-A1, an inhibitor of mTORC1. Live imaging with translation reporters further showed that Netrin-1-induced synthesis of Tctp in growth cones is driven by a short 3'untranslated region (3'UTR) tctp mRNA isoform. However, acute inhibition of de novo Tctp synthesis in axons did not perturb the advance of retinal projections through the optic tract in vivo, indicating that locally produced Tctp is not necessary for normal axon growth and guidance. PMID- 30459551 TI - Reduced Cytosolic Calcium as an Early Decisive Cellular State in Parkinson's Disease and Synucleinopathies. AB - The more than 30-year-old Calcium hypothesis postulates that dysregulation in calcium dependent processes in the aging brain contributes to its increased vulnerability and this concept has been extended to Alzheimer's disease and Parkinson's disease. Central to the hypothesis is that increased levels of intracellular calcium develop and contributes to neuronal demise. We have studied the impact on cells encountering a gradual build-up of aggregated alpha synuclein, which is a central process to Parkinson's disease and other synucleinopathies. Surprisingly, we observed a yet unrecognized phase characterized by a reduced cytosolic calcium in cellular and neuronal models of Parkinson's disease, caused by alpha-synuclein aggregates activating the endoplasmic calcium ATPase, SERCA. Counteracting the initial phase with low calcium rescues the subsequent degenerative phase with increased calcium and cell death - and demonstrates this early phase initiates decisive degenerative signals. In this review, we discuss our findings in relation to literature on calcium dysregulation in Parkinson's disease and dementia. PMID- 30459553 TI - Inhibition of Heat Shock Protein 90 by 17-AAG Reduces Inflammation via P2X7 Receptor/NLRP3 Inflammasome Pathway and Increases Neurogenesis After Subarachnoid Hemorrhage in Mice. AB - Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular disease that usually has a poor prognosis. Heat shock proteins (HSPs) have been implicated in the mechanisms of SAH-associated damage, including increased inflammation and reduced neurogenesis. The aim of this study was to investigate the effects of HSP90 inhibition on inflammation and neurogenesis in a mouse model of experimental SAH induced by endovascular surgery. Western blotting showed HSP90 levels to be decreased, while neurogenesis, evaluated by 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry, was decreased in the hippocampuses of SAH mice. SAH also induced pro-inflammatory factors such as interleukin-1beta (IL-1beta), capase-1 and the NLRP3 inflammasome. However, intraperitoneal administration of the specific HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) reduced the levels of HSP90, NLRP3, ASC, caspase-1 and IL-1beta, while increasing the levels of brain-derived neurotrophic factor and doublecortin (DCX), as well as the number of BrdU-positive cells in SAH mice. In addition, 17-AGG improved short- and long-term neurobehavioral outcomes. The neuroprotective and anti inflammatory effects of 17-AGG were reversed by recombinant HSP90 (rHSP90); this detrimental effect of HSP90 was inhibited by the specific P2X7 receptor (P2X7R) inhibitor A438079, indicating that SAH-induced inflammation and inhibition of neurogenesis were likely mediated by HSP90 and the P2X7R/NLRP3 inflammasome pathway. HSP90 inhibition by 17-AAG may be a promising therapeutic strategy for the treatment of SAH. PMID- 30459554 TI - Antidepressant but Not Prophylactic Ketamine Administration Alters Calretinin and Calbindin Expression in the Ventral Hippocampus. AB - Ketamine has been found to have rapid, long-lasting antidepressant effects in treatment-resistant (TR) patients with major depressive disorder (MDD). Recently, we have also shown that ketamine acts as a prophylactic to protect against the development of stress-induced depressive-like behavior in mice, indicating that a preventative treatment against mental illness using ketamine is possible. While there is significant investigation into ketamine's antidepressant mechanism of action, little is known about ketamine's underlying prophylactic mechanism. More specifically, whether ketamine's prophylactic action is molecularly similar to or divergent from its antidepressant action is entirely unknown. Here, we sought to characterize immunohistochemical signatures of cell populations governing ketamine's antidepressant and prophylactic effects. 129S6/SvEv mice were treated with saline (Sal) or ketamine (K) either before a social defeat (SD) stressor as a prophylactic, or after SD as an antidepressant, then subsequently assessed for depressive-like behavior. Post-fixed brains were processed for doublecortin (DCX), calretinin (CR) and calbindin (CB) expression. The number of DCX+ neurons in the dentate gyrus (DG) of the hippocampus (HPC) was not affected by prophylactic or antidepressant ketamine treatment, while the number of CR+ neurons in the ventral hilus increased with antidepressant ketamine under SD conditions. Moreover, antidepressant, but not prophylactic ketamine administration significantly altered CR and CB expression in the ventral HPC (vHPC). These data show that while antidepressant ketamine treatment mediates some of its effects via adult hippocampal markers, prophylactic ketamine administration does not, at least in 129S6/SvEv mice. These data suggest that long-lasting behavioral effects of prophylactic ketamine are independent of hippocampal DCX, CR and CB expression in stress-susceptible mice. PMID- 30459555 TI - Switching of the Microglial Activation Phenotype Is a Possible Treatment for Depression Disorder. AB - Major depressive disorder (MDD) is a common emotional cognitive disorder that seriously affects people's physical and mental health and their quality of life. Due to its clinical and etiological heterogeneity, the molecular mechanisms underpinning MDD are complex and they are not fully understood. In addition, the effects of traditional drug therapy are not ideal. However, postmortem and animal studies have shown that overactivated microglia can inhibit neurogenesis in the hippocampus and induce depressive-like behaviors. Nonetheless, the molecular mechanisms by which microglia regulate nerve regeneration and determine depressive-like behaviors remain unclear. As the immune cells of the central nervous system (CNS), microglia could influence neurogenesis through the M1 and M2 subtypes, and these may promote depressive-like behaviors. Microglia may be divided into four main states or phenotypes. Under stress, microglial cells are induced into the M1 type, releasing inflammatory factors and causing neuroinflammatory responses. After the inflammation fades away, microglia shift into the alternative activated M2 phenotypes that play a role in neuroprotection. These activated M2 subtypes consist of M2a, M2b and M2c and their functions are different in the CNS. In this article, we mainly introduce the relationship between microglia and MDD. Importantly, this article elucidates a plausible mechanism by which microglia regulate inflammation and neurogenesis in ameliorating MDD. This could provide a reliable basis for the treatment of MDD in the future. PMID- 30459557 TI - Blood-Brain Barrier Cellular Responses Toward Organophosphates: Natural Compensatory Processes and Exogenous Interventions to Rescue Barrier Properties. AB - Organophosphorus compounds (OPs) are highly toxic chemicals widely used as pesticides (e.g., paraoxon (PX)- the active metabolite of the insecticide parathion) and as chemical warfare nerve agents. Blood-brain barrier (BBB) leakage has been shown in rodents exposed to PX, which is an organophosphate oxon. In this study, we investigated the cellular mechanisms involved in BBB reaction after acute exposure to PX in an established in vitro BBB system made of stem-cell derived, human brain-like endothelial cells (BLECs) together with brain pericytes that closely mimic the in vivo BBB. Our results show that PX directly affects the BBB in vitro both at toxic and non-toxic concentrations by attenuating tight junctional (TJ) protein expression and that only above a certain threshold the paracellular barrier integrity is compromised. Below this threshold, BLECs exhibit a morphological coping mechanism in which they enlarge their cell area thus preventing the formation of meaningful intercellular gaps and maintaining barrier integrity. Importantly, we demonstrate that reversal of the apoptotic cell death induced by PX, by a pan-caspase-inhibitor ZVAD-FMK (ZVAD) can reduce PX-induced cell death and elevate cell area but do not prevent the induced BBB permeability, implying that TJ complex functionality is hindered. This is corroborated by formation of ROS at all toxic concentrations of PX and which are even higher with ZVAD. We suggest that while lower levels of ROS can induce compensating mechanisms, higher PX-induced oxidative stress levels interfere with barrier integrity. PMID- 30459556 TI - Dysregulated Glucose Metabolism as a Therapeutic Target to Reduce Post-traumatic Epilepsy. AB - Traumatic brain injury (TBI) is a significant cause of disability worldwide and can lead to post-traumatic epilepsy. Multiple molecular, cellular, and network pathologies occur following injury which may contribute to epileptogenesis. Efforts to identify mechanisms of disease progression and biomarkers which predict clinical outcomes have focused heavily on metabolic changes. Advances in imaging approaches, combined with well-established biochemical methodologies, have revealed a complex landscape of metabolic changes that occur acutely after TBI and then evolve in the days to weeks after. Based on this rich clinical and preclinical data, combined with the success of metabolic therapies like the ketogenic diet in treating epilepsy, interest has grown in determining whether manipulating metabolic activity following TBI may have therapeutic value to prevent post-traumatic epileptogenesis. Here, we focus on changes in glucose utilization and glycolytic activity in the brain following TBI and during seizures. We review relevant literature and outline potential paths forward to utilize glycolytic inhibitors as a disease-modifying therapy for post-traumatic epilepsy. PMID- 30459559 TI - Oscillatory Cortical Activity in an Animal Model of Dystonia Caused by Cerebellar Dysfunction. AB - The synchronization of neuronal activity in the sensorimotor cortices is crucial for motor control and learning. This synchrony can be modulated by upstream activity in the cerebello-cortical network. However, many questions remain over the details of how the cerebral cortex and the cerebellum communicate. Therefore, our aim is to study the contribution of the cerebellum to oscillatory brain activity, in particular in the case of dystonia, a severely disabling motor disease associated with altered sensorimotor coupling. We used a kainic-induced dystonia model to evaluate cerebral cortical oscillatory activity and connectivity during dystonic episodes. We performed microinjections of low doses of kainic acid into the cerebellar vermis in mice and examined activities in somatosensory, motor and parietal cortices. We showed that repeated applications of kainic acid into the cerebellar vermis, for five consecutive days, generate reproducible dystonic motor behavior. No epileptiform activity was recorded on electrocorticogram (ECoG) during the dystonic postures or movements. We investigated the ECoG power spectral density and coherence between motor cortex, somatosensory and parietal cortices before and during dystonic attacks. During the baseline condition, we found a phenomenon of permanent adaptation with a change of baseline locomotor activity coupled to an ECoG gamma band increase in all cortices. In addition, after kainate administration, we observed an increase in muscular activity, but less signs of dystonia together with modulations of the ECoG power spectra with an increase in gamma band in motor, parietal and somatosensory cortices. Moreover, we found reduced coherence in all measured frequency bands between the motor cortex and somatosensory or parietal cortices compared to baseline. In conclusion, examination of cortical oscillatory activities in this animal model of chronic dystonia caused by cerebellar dysfunction reveals a disruption in the coordination of neuronal activity across the cortical sensorimotor/parietal network, which may underlie motor skill deficits. PMID- 30459560 TI - Diverse Protein Profiles in CNS Myeloid Cells and CNS Tissue From Lipopolysaccharide- and Vehicle-Injected APPSWE/PS1DeltaE9 Transgenic Mice Implicate Cathepsin Z in Alzheimer's Disease. AB - Neuroinflammation, characterized by chronic activation of the myeloid-derived microglia, is a hallmark of Alzheimer's disease (AD). Systemic inflammation, typically resulting from infection, has been linked to the progression of AD due to exacerbation of the chronic microglial reaction. However, the mechanism and the consequences of this exacerbation are largely unknown. Here, we mimicked systemic inflammation in AD with weekly intraperitoneal (i.p.) injections of APPSWE/PS1DeltaE9 transgenic mice with E. coli lipopolysaccharide (LPS) from 9 to 12 months of age, corresponding to the period with the steepest increase in amyloid pathology. We found that the repeated LPS injections ameliorated amyloid pathology in the neocortex while increasing the neuroinflammatory reaction. To elucidate mechanisms, we analyzed the proteome of the hippocampus from the same mice as well as in unique samples of CNS myeloid cells. The repeated LPS injections stimulated protein pathways of the complement system, retinoid receptor activation and oxidative stress. CNS myeloid cells from transgenic mice showed enrichment in pathways of amyloid-beta clearance and elevated levels of the lysosomal protease cathepsin Z, as well as amyloid precursor protein, apolipoprotein E and clusterin. These proteins were found elevated in the proteome of both LPS and vehicle injected transgenics, and co-localized to CD11b+ microglia in transgenic mice and in primary murine microglia. Additionally, cathepsin Z, amyloid precursor protein, and apolipoprotein E appeared associated with amyloid plaques in neocortex of AD cases. Interestingly, cathepsin Z was expressed in microglial-like cells and co-localized to CD68+ microglial lysosomes in AD cases, and it was expressed in perivascular cells in AD and control cases. Taken together, our results implicate systemic LPS administration in ameliorating amyloid pathology in early-to-mid stage disease in the APPSWE/PS1DeltaE9 mouse and attract attention to the potential disease involvement of cathepsin Z expressed in CNS myeloid cells in AD. PMID- 30459561 TI - Peripheral Inflammation Enhances Microglia Response and Nigral Dopaminergic Cell Death in an in vivo MPTP Model of Parkinson's Disease. AB - The impact of systemic inflammation in nigral dopaminergic cell loss remains unclear. Here, we have investigated the role of peripheral inflammation induced by systemic lipopolysaccharide (LPS) administration in the MPTP-based model of Parkinson's disease. Brain inflammation, microglia and astroglia activation, disruption of the blood-brain barrier (BBB) and integrity of the nigrostriatal dopaminergic system were evaluated in response to i.p. injection of LPS, MPTP or the combination of both. Our results showed that combinative treatment exacerbates microglia activation and enhances (i) the appearance of galectin-3 positive microglia, recently identified as microglial disease-associated phenotypic marker, (ii) the up-regulation of pro-inflammatory cytokines, (iii) the occurrence of A1 neurotoxic astrocytes, (iv) the breakdown of the BBB, and (v) the loss of dopaminergic neurons in the substantia nigra. Microglia activation was triggered earlier than other degenerative events, suggesting that over-activation of microglia (including different polarization states) may induce dopaminergic neuron loss by itself, initiating the endless cycle of inflammation/degeneration. Our study revitalizes the importance of peripheral inflammation as a potential risk factor for Parkinson's disease and raises the possibility of using new anti-inflammatory therapies to improve the course of neurodegenerative diseases, including those directly aimed at modulating the deleterious activity of disease-associated microglia. PMID- 30459558 TI - Neuromodulatory Effects of Guanine-Based Purines in Health and Disease. AB - The function of guanine-based purines (GBPs) is mostly attributed to the intracellular modulation of heteromeric and monomeric G proteins. However, extracellular effects of guanine derivatives have also been recognized. Thus, in the central nervous system (CNS), a guanine-based purinergic system that exerts neuromodulator effects, has been postulated. The thesis that GBPs are neuromodulators emerged from in vivo and in vitro studies, in which neurotrophic and neuroprotective effects of these kinds of molecules (i.e., guanosine) were demonstrated. GBPs induce several important biological effects in rodent models and have been shown to reduce seizures and pain, stabilize mood disorder behavior and protect against gliomas and diseases related with aging, such as ischemia or Parkinson and Alzheimer diseases. In vitro studies to evaluate the protective and trophic effects of guanosine, and of the nitrogenous base guanine, have been fundamental for understanding the mechanisms of action of GBPs, as well as the signaling pathways involved in their biological roles. Conversely, although selective binding sites for guanosine have been identified in the rat brain, GBP receptors have not been still described. In addition, GBP neuromodulation may depend on the capacity of GBPs to interact with well-known membrane proteins in glutamatergic and adenosinergic systems. Overall, in this review article, we present up-to-date GBP biology, focusing mainly on the mechanisms of action that may lead to the neuromodulator role of GBPs observed in neurological disorders. PMID- 30459563 TI - Validation and Optimization of an Image-Based Screening Method Applied to the Study of Neuronal Processes on Nanogrooves. AB - Research on neuronal differentiation and neuronal network guidance induced through nanotopographical cues generates large datasets, and therefore the analysis of such data can be aided by automatable, unbiased image screening tools. To link such tools, we present an image-based screening method to evaluate the influence of nanogroove pattern dimensions on neuronal differentiation. This new method consists of combining neuronal feature detection software, here HCA Vision, and a Frangi vesselness algorithm to calculate neurite alignment values and quantify morphological aspects of neurons, which are measured via neurite length, neuronal polarity, and neurite branching, for differentiated SH-SY5Y cells cultured on nanogrooved polydimethylsiloxane (PDMS) patterns in the 200 2000 nm range. The applicability of this method is confirmed by our results, which find that the level of alignment is dependent on nanogroove dimensions. Furthermore, the screening method reveals that differentiation and alignment are correlated. In particular, patterns with groove widths >200 nm and with a low ridge width to pattern period ratio have a quantifiable influence on alignment, neurite length, and polarity. In summary, the novel combination of software that forms a base for this statistical analysis method demonstrates good potential for evaluating tissue microarchitecture, which depends on subtle design variation in substrate topography. Using the screening method, we obtained automated and sensitive quantified readouts from large datasets. PMID- 30459562 TI - Ryanodine Receptor-Mediated Calcium Release Has a Key Role in Hippocampal LTD Induction. AB - The induction of both long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission entails pre- and postsynaptic Ca2+ signals, which represent transient increments in cytoplasmic free Ca2+ concentration. In diverse synapse types, Ca2+ release from intracellular stores contributes to amplify the Ca2+ signals initially generated by activation of neuronal Ca2+ entry pathways. Here, we used hippocampal slices from young male rats to evaluate whether pharmacological activation or inhibition of Ca2+ release from the endoplasmic reticulum (ER) mediated by ryanodine receptor (RyR) channels modifies LTD induction at Schaffer collateral-CA1 synapses. Pre-incubation of slices with ryanodine (1 MUM, 1 h) or caffeine (1 mM, 30 min) to promote RyR-mediated Ca2+ release facilitated LTD induction by low frequency stimulation (LFS), but did not affect the amplitude of synaptic transmission, the profiles of field excitatory postsynaptic potentials (fEPSP) or the paired-pulse (PP) responses. Conversely, treatment with inhibitory ryanodine (20 MUM, 1 h) to suppress RyR-mediated Ca2+ release prevented LTD induction, but did not affect baseline synaptic transmission or PP responses. Previous literature reports indicate that LTD induction requires presynaptic CaMKII activity. We found that 1 h after applying the LTD induction protocol, slices displayed a significant increase in CaMKII phosphorylation relative to the levels exhibited by un-stimulated (naive) slices. In addition, LTD induction (1 h) enhanced the phosphorylation of the presynaptic protein Synapsin I at a CaMKII-dependent phosphorylation site, indicating that LTD induction stimulates presynaptic CaMKII activity. Pre-incubation of slices with 20 MUM ryanodine abolished the increased CaMKII and Synapsin I phosphorylation induced by LTD, whereas naive slices pre-incubated with inhibitory ryanodine displayed similar CaMKII and Synapsin I phosphorylation levels as naive control slices. We posit that inhibitory ryanodine suppressed LTD induced presynaptic CaMKII activity, as evidenced by the suppression of Synapsin I phosphorylation induced by LTD. Accordingly, we propose that presynaptic RyR mediated Ca2+ signals contribute to LTD induction at Schaffer collateral-CA1 synapses. PMID- 30459565 TI - Block Face Scanning Electron Microscopy of Fluorescently Labeled Axons Without Using Near Infra-Red Branding. AB - In this article, we describe the method that allows fluorescently tagged structures such as axons to be targeted for electron microscopy (EM) analysis without the need to convert their labels into electron dense stains, introduce any fiducial marks, or image large volumes at high resolution. We optimally preserve and stain the brain tissue for ultrastructural analysis and use natural landmarks, such as cell bodies and blood vessels, to locate neurites that had been imaged previously using confocal microscopy. The method relies on low and high magnification views taken with the light microscope, after fixation, to capture information of the tissue structure that can later be used to pinpoint the position of structures of interest in serial EM images. The examples shown here are td Tomato expressing cortico-thalamic axons in the posteromedial nucleus of the mouse thalamus, imaged in fixed tissue with confocal microscopy, and subsequently visualized with serial block-face EM (SBEM) and reconstructed into 3D models for analysis. PMID- 30459564 TI - Cell-Type-Specific Afferent Innervation of the Nucleus Accumbens Core and Shell. AB - The nucleus accumbens (NAc) is clearly implicated in reward processing and drug addiction, as well as in numerous neurological and psychiatric disorders; nevertheless, the circuit mechanisms underlying the diverse functions of the NAc remain poorly understood. Here, we characterized the whole-brain and monosynaptic inputs to two main projection cell types - D1 dopamine receptor expressing medium spiny neurons (D1R-MSNs) and D2 dopamine receptor expressing medium spiny neurons (D2R-MSNs) - within the NAc core and NAc shell by rabies-mediated trans-synaptic tracing. We discovered that D1R-MSNs and D2R-MSNs in both NAc subregions receive similar inputs from diverse sources. Inputs to the NAc core are broadly scattered, whereas inputs to the NAc shell are relatively concentrated. Furthermore, we identified numerous brain areas providing important contrasting inputs to different NAc subregions. The anterior cortex preferentially innervates the NAc core for both D1R-MSNs and D2R-MSNs, whereas the lateral hypothalamic area (LH) preferentially targets D1R-MSNs in the NAc shell. Characterizing the cell-type-specific connectivity of different NAc subregions lays a foundation for studying how diverse functions of the NAc are mediated by specific pathways. PMID- 30459566 TI - The Nomenclature of Human White Matter Association Pathways: Proposal for a Systematic Taxonomic Anatomical Classification. AB - The heterogeneity and complexity of white matter (WM) pathways of the human brain were discretely described by pioneers such as Willis, Stenon, Malpighi, Vieussens and Vicq d'Azyr up to the beginning of the 19th century. Subsequently, novel approaches to the gross dissection of brain internal structures have led to a new understanding of WM organization, notably due to the works of Reil, Gall and Burdach highlighting the fascicular organization of WM. Meynert then proposed a definitive tripartite organization in association, commissural and projection WM pathways. The enduring anatomical work of Dejerine at the turn of the 20th century describing WM pathways in detail has been the paramount authority on this topic (including its terminology) for over a century, enriched sporadically by studies based on blunt Klingler dissection. Currently, diffusion-weighted magnetic resonance imaging (DWI) is used to reveal the WM fiber tracts of the human brain in vivo by measuring the diffusion of water molecules, especially along axons. It is then possible by tractography to reconstitute the WM pathways of the human brain step by step at an unprecedented level of precision in large cohorts. However, tractography algorithms, although powerful, still face the complexity of the organization of WM pathways, and there is a crucial need to benefit from the exact definitions of the trajectories and endings of all WM fascicles. Beyond such definitions, the emergence of DWI-based tractography has mostly revealed strong heterogeneity in naming the different bundles, especially the long-range association pathways. This review addresses the various terminologies known for the WM association bundles, aiming to describe the rules of arrangements followed by these bundles and to propose a new nomenclature based on the structural wiring diagram of the human brain. PMID- 30459568 TI - Corrigendum: Inflammation and Tissue Remodeling in the Bladder and Urethra in Feline Interstitial Cystitis. AB - [This corrects the article DOI: 10.3389/fnsys.2018.00013.]. PMID- 30459567 TI - Operating in a Reverberating Regime Enables Rapid Tuning of Network States to Task Requirements. AB - Neural circuits are able to perform computations under very diverse conditions and requirements. The required computations impose clear constraints on their fine-tuning: a rapid and maximally informative response to stimuli in general requires decorrelated baseline neural activity. Such network dynamics is known as asynchronous-irregular. In contrast, spatio-temporal integration of information requires maintenance and transfer of stimulus information over extended time periods. This can be realized at criticality, a phase transition where correlations, sensitivity and integration time diverge. Being able to flexibly switch, or even combine the above properties in a task-dependent manner would present a clear functional advantage. We propose that cortex operates in a "reverberating regime" because it is particularly favorable for ready adaptation of computational properties to context and task. This reverberating regime enables cortical networks to interpolate between the asynchronous-irregular and the critical state by small changes in effective synaptic strength or excitation inhibition ratio. These changes directly adapt computational properties, including sensitivity, amplification, integration time and correlation length within the local network. We review recent converging evidence that cortex in vivo operates in the reverberating regime, and that various cortical areas have adapted their integration times to processing requirements. In addition, we propose that neuromodulation enables a fine-tuning of the network, so that local circuits can either decorrelate or integrate, and quench or maintain their input depending on task. We argue that this task-dependent tuning, which we call "dynamic adaptive computation," presents a central organization principle of cortical networks and discuss first experimental evidence. PMID- 30459569 TI - NF-KappaB Pathway Is Involved in Bone Marrow Stromal Cell-Produced Pain Relief. AB - Bone marrow stromal cells (BMSCs) produce long-lasting attenuation of pain hypersensitivity. This effect involves BMSC's ability to interact with the immune system and activation of the endogenous opioid receptors in the pain modulatory circuitry. The nuclear factor kappa B (NF-kappaB) protein complex is a key transcription factor that regulates gene expression involved in immunity. We tested the hypothesis that the NF-kappaB signaling plays a role in BMSC-induced pain relief. We focused on the rostral ventromedial medulla (RVM), a key structure in the descending pain modulatory pathway, that has been shown to play an important role in BMSC-produced antihyperalgesia. In Sprague-Dawley rats with a ligation injury of the masseter muscle tendon (TL), BMSCs (1.5 M/rat) from donor rats were infused i.v. at 1 week post-TL. P65 exhibited predominant neuronal localization in the RVM with scattered distribution in glial cells. At 1 week, but not 8 weeks after BMSC infusion, western blot and immunostaining showed that p65 of NF-kappaB was significantly increased in the RVM. Given that chemokine signaling is critical to BMSCs' pain-relieving effect, we further evaluated a role of chemokine signaling in p65 upregulation. Prior to infusion of BMSCs, we transduced BMSCs with Ccl4 shRNA, incubated BMSCs with RS 102895, a CCR2b antagonist, or maraviroc, a CCR5 antagonist. The antagonism of chemokines significantly reduced BMSC-induced upregulation of p65, suggesting that upregulation of p65 was related to BMSCs' pain-relieving effect. We then tested the effect of a selective NF-kappaB activation inhibitor, BAY 11-7082. The mechanical hyperalgesia of the rat was assessed with the von Frey method. In the pre-treatment experiment, BAY 11-7082 (2.5 and 25 pmol) was injected into the RVM at 2 h prior to BMSC infusion. Pretreatment with BAY 11-7082 attenuated BMSCs' antihyperalgesia, but post-treatment at 5 weeks post-BMSC was not effective. On the contrary, in TL rats receiving BAY 11-7082 without BMSCs, TL-induced hyperalgesia was attenuated, consistent with dual roles of NF-kappaB in pain hypersensitivity and BMSC-produced pain relief. These results indicate that the NF-kappaB signaling pathway in the descending circuitry is involved in initiation of BMSC-produced behavioral antihyperalgesia. PMID- 30459570 TI - Empathic Cognitions Affected by Undetectable Social Chemosignals: An EEG Study on Visually Evoked Empathy for Pain in an Auditory and Chemosensory Context. AB - Reduction of mu activity within the EEG is an indicator of cognitive empathy and can be generated in response to visual depictions of others in pain. The current study tested whether this brain response can be modulated by an auditory and a chemosensory context. Participants observed pictures of painful and non-painful actions while pain associated and neutral exclamations were presented (Study 1, N = 30) or while chemosensory stimuli were presented via a constant flow olfactometer (Study 2, N = 22). Chemosensory stimuli were sampled on cotton pads while donors participated in a simulated job interview (stress condition) or cycled on a stationary bike (sport condition). Pure cotton was used as a control. The social chemosignals could not be detected as odors. Activity within the 8-13 Hz band at electrodes C3, C4 (mu activity) and electrodes O1, O2 (alpha-activity) was calculated using Fast-Fourier-Transformation (FFT). As expected, suppression of power in the 8-13 Hz band was stronger when painful as compared to non-painful actions were observed (Study 1, p = 0.020; Study 2, p = 0.005). In addition, as compared to the neutral auditory and chemosensory context, painful exclamations (Study 1, p = 0.039) and chemosensory stress signals (Study 2, p = 0.014) augmented mu-/alpha suppression also in response to non-painful pictures. The studies show that processing of social threat-related information is not dominated by visual information. Rather, cognitive appraisal related to empathy can be affected by painful exclamations and subthreshold chemosensory social information. PMID- 30459571 TI - Role of Prefrontal Cortex Anti- and Pro-inflammatory Cytokines in the Development of Abnormal Behaviors Induced by Disconnection of the Ventral Hippocampus in Neonate Rats. AB - Neonatal disconnection of ventral hippocampus (VH) outputs in rats has been reported to lead to post-pubertal behavioral and synaptic changes of relevance to schizophrenia. Increased oxidative and inflammatory load in the prefrontal cortex (PFC) has been suggested to mediate some of the effects of neonatal VH lesion (NVHL). In this study, we hypothesized that developmental imbalance of anti- and pro-inflammatory factors within the PFC might affect synaptic development thus contributing to the adult NVHL-induced behavioral deficits. Ibotenic acid-induced excitotoxic NVHL was performed in postnatal day (PD) 7 male Sprague-Dawley rats and the mRNA levels of select pro- and anti-inflammatory cytokines were measured in the medial PFC (mPFC) at two developmental time points (PD15 and PD60). We observed a development-specific increase of pro-inflammatory cytokine, interleukin (IL)-1beta mRNA at PD15, and an overall reduction in the expression and signaling of transforming growth factor beta 1 (TGF-beta1), an anti inflammatory cytokine, at both PD15 and PD60 in the NVHL animals. These cytokine changes were not seen in the somatosensory cortex (SSC) or tissue surrounding the lesion site. Daily administration of systemic recombinant TGF-beta1 from PD7-14 prevented the appearance of hyperlocomotion, deficits in prepulse inhibition (PPI) of startle and social interaction (SI) in post-pubertal (PD60) NVHL rats. Neonatal supplementation of TGF-beta1 was also able to attenuate dendritic spine loss in the layer 3 mPFC pyramidal neurons of NVHL animals. These results suggest that early damage of the VH has long-lasting inflammatory consequences in distant connected structures, and that TGF-beta1 has potential to confer protection against the deleterious effects of developmental hippocampal damage. PMID- 30459573 TI - Psychoanalysis and Neuroscience - A Disclosure. PMID- 30459572 TI - Spontaneous Discriminative Response to the Biological Motion Displays Involving a Walking Conspecific in Mice. AB - Recent translational studies using mice have contributed toward elucidating the neural, genetic, and molecular basis of social communication deficits. Nevertheless, many components of visual processes underlying mice sociality remain unresolved, including perception of bodily-movement. Here, we aimed to reveal the visual sensitivity of mice to information on bodily motion using biological motion displays depicted by simple geometric dots. We introduced biological motions extracted from walking mice vs. corresponding meaningless scrambled motions, in which the spatial configurations of each path of dots were shuffled. The apparatus was a three-chambered box with an opening between the chambers, and each side chamber had a monitor. We measured the exploration time of mice within the apparatus during the test, with two types of displays being presented. Mice spent more time in the chamber with the scrambled motion displays, indicating that animals spontaneously discriminated stimuli, with the scrambled motion being relatively novel. Furthermore, mice might have detected socially familiar cues from the biological motion displays. Subsequent testing revealed that additional mice showed no bias to the static versions of the stimuli used in the Movie test. Thus, we confirmed that mice modulated their behavior by focusing on the motion information of the stimuli, rather than the spatial configurations of each dot. Our findings provide a new perspective on how visual processing contributes to underlying social behavior in mice, potentially facilitating future translational studies of social deficits with respect to genetic and neural bases. PMID- 30459574 TI - Oral Probiotics Ameliorate the Behavioral Deficits Induced by Chronic Mild Stress in Mice via the Gut Microbiota-Inflammation Axis. AB - In recent years, a burgeoning body of research has revealed links between depression and the gut microbiota, leading to the therapeutic use of probiotics for stress-related disorders. In this study, we explored the potential antidepressant efficacy of a multi-strain probiotics treatment (Lactobacillus helveticus R0052, Lactobacillus plantarum R1012, and Bifidobacterium longum R0175) in a chronic mild stress (CMS) mouse model of depression and determined its probable mechanism of action. Our findings revealed that mice subjected to CMS exhibited anxiety- and depressive-like behaviors in the sucrose preference test, elevated plus maze, and forced swim test, along with increased interferon gamma, tumor necrosis factor-alpha, and indoleamine 2,3-dioxygenase-1 levels in the hippocampus. Moreover, the microbiota distinctly changed from the non-stress group and was characterized by highly diverse bacterial communities associated with significant reductions in Lactobacillus species. Probiotics attenuated CMS induced anxiety- and depressive-like behaviors, significantly increased Lactobacillus abundance, and reversed the CMS-induced immune changes in the hippocampus. Thus, the possible mechanism involved in the antidepressant-like activity of probiotics is correlated with Lactobacillus species via the gut microbiota-inflammation-brain axis. PMID- 30459575 TI - Insights About the Neuroplasticity State on the Effect of Intramuscular Electrical Stimulation in Pain and Disability Associated With Chronic Myofascial Pain Syndrome (MPS): A Double-Blind, Randomized, Sham-Controlled Trial. AB - Background: There is limited evidence concerning the effect of intramuscular electrical stimulation (EIMS) on the neural mechanisms of pain and disability associated with chronic Myofascial Pain Syndrome (MPS). Objectives: To provide new insights into the EIMS long-term effect on pain and disability related to chronic MPS (primary outcomes). To assess if the neuroplasticity state at baseline could predict the long-term impact of EIMS on disability due to MPS we examined the relationship between the serum brain-derived-neurotrophic-factor (BDNF) and by motor evoked potential (MEP). Also, we evaluated if the EIMS could improve the descending pain modulatory system (DPMS) and the cortical excitability measured by transcranial magnetic stimulation (TMS) parameters. Methods: We included 24 right-handed female with chronic MPS, 19-65 years old. They were randomically allocated to receive ten sessions of EIMS, 2 Hz at the cervical paraspinal region or a sham intervention (n = 12). Results: A mixed model analysis of variance revealed that EIMS decreased daily pain scores by 73.02% [95% confidence interval (CI) = -95.28 to -52.30] and disability due to pain -43.19 (95%CI, -57.23 to -29.39) at 3 months of follow up. The relative risk for using analgesics was 2.95 (95% CI, 1.36 to 6.30) in the sham group. In the EIMS and sham, the change on the Numerical Pain Scale (NPS0-10) throughout CPM task was -2.04 (0.79) vs. -0.94 (1.18), respectively, (P = 0.01). EIMS reduced the MEP -28.79 (-53.44 to -4.15), while improved DPMS and intracortical inhibition. The MEP amplitude before treatment [(Beta = -0.61, (-0.58 to -0.26)] and a more significant change from pre- to post-treatment on serum BDNF) (Beta = 0.67; CI95% = 0.07 to 1.26) were predictors to EIMS effect on pain and disability due to pain. Conclusion: These findings suggest that a bottom-up effect induced by the EIMS reduced the analgesic use, improved pain, and disability due to chronic MPS. This effect might be mediated by an enhancing of corticospinal inhibition as seen by an increase in IC and a decrease in MEP amplitude. Likewise, the MEP amplitude before treatment and the changes induced by the EIMS in the serum BDNF predicted it's long-term clinical impact on pain and disability due MPS. The trial is recorded in ClinicalTrials.gov: NCT02381171. PMID- 30459576 TI - Endurance Exercise Enhances Emotional Valence and Emotion Regulation. AB - Acute exercise consistently benefits both emotion and cognition, particularly cognitive control. We evaluated acute endurance exercise influences on emotion, domain-general cognitive control and the cognitive control of emotion, specifically cognitive reappraisal. Thirty-six endurance runners, defined as running at least 30 miles per week with one weekly run of at least 9 miles (21 female, age 18-30 years) participated. In a repeated measures design, participants walked at 57% age-adjusted maximum heart rate (HRmax; range 51%-63%) and ran at 70% HRmax (range 64%-76%) for 90 min on two separate days. Participants completed measures of emotional state and the Stroop test of domain general cognitive control before, every 30 min during and 30 min after exercise. Participants also completed a cognitive reappraisal task (CRT) after exercise. Functional near-infrared spectroscopy (fNIRS) tracked changes in oxygenated and deoxygenated hemoglobin (O2Hb and dHb) levels in the prefrontal cortex (PFC). Results suggest that even at relatively moderate intensities, endurance athletes benefit emotionally from running both during and after exercise and task-related PFC oxygenation reductions do not appear to hinder prefrontal-dependent cognitive control. PMID- 30459577 TI - On the Neurophysiological Mechanisms Underlying the Adaptability to Varying Cognitive Control Demands. AB - Cognitive control processes are advantageous when routines would not lead to the desired outcome, but this can be ill-advised when automated behavior is advantageous. The aim of this study was to identify neural dynamics related to the ability to adapt to different cognitive control demands - a process that has been referred to as 'metacontrol.' A sample of N = 227 healthy subjects that was split in a 'high' and 'low adaptability' group based on the behavioral performance in a task with varying control demands. To examine the neurophysiological mechanisms, we combined event-related potential (ERP) recordings with source localization and machine learning approaches. The results show that individuals who are better at strategically adapting to different cognitive control demands benefit from automatizing their response processes in situations where little cognitive control is needed. On a neurophysiological level, neither perceptual/attentional selection processes nor conflict monitoring processes paralleled the behavioral data, although the latter showed a descriptive trend. Behavioral differences in metacontrol abilities were only significantly mirrored by the modulation of response-locked P3 amplitudes, which were accompanied by activation differences in insula (BA13) and middle frontal gyrus (BA9). The machine learning result corroborated this by identifying a predictive/classification feature near the peak of the response-locked P3, which arose from the anterior cingulate cortex (BA24; BA33). In short, we found that metacontrol is associated to the ability to manage response selection processes, especially the ability to effectively downregulate cognitive control under low cognitive control requirements, rather than the ability to upregulate cognitive control. PMID- 30459578 TI - Preserved but Less Efficient Control of Response Interference After Unilateral Lesions of the Striatum. AB - Previous research on the neural basis of cognitive control processes has mainly focused on cortical areas, while the role of subcortical structures in cognitive control is less clear. Models of basal ganglia function as well as clinical studies in neurodegenerative diseases suggest that the striatum (putamen and caudate nucleus) modulates the inhibition of interfering responses and thereby contributes to an important aspect of cognitive control, namely response interference control. To further investigate the putative role of the striatum in the control of response interference, 23 patients with stroke-induced lesions of the striatum and 32 age-matched neurologically healthy controls performed a unimanual version of the Simon task. In the Simon task, the correspondence between stimulus location and response location is manipulated so that control over response interference can be inferred from the reaction time costs in incongruent trials. Results showed that stroke patients responded overall slower and more erroneous than controls. The difference in response times (RTs) between incongruent and congruent trials (known as the Simon effect) was smaller in the ipsilesional/-lateral hemifield, but did not differ significantly between groups. However, in contrast to controls, stroke patients exhibited an abnormally stable Simon effect across the reaction time distribution indicating a reduced efficiency of the inhibition process. Thus, in stroke patients unilateral lesions of the striatum did not significantly impair the general ability to control response interference, but led to less efficient selective inhibition of interfering responses. PMID- 30459580 TI - BCI to Potentially Enhance Streaming Images to a VR Headset by Predicting Head Rotation. AB - While numerous studies show that brain signals contain information about an individual's current state that are potentially valuable for smoothing man machine interfaces, this has not yet lead to the use of brain computer interfaces (BCI) in daily life. One of the main challenges is the common requirement of personal data that is correctly labeled concerning the state of interest in order to train a model, where this trained model is not guaranteed to generalize across time and context. Another challenge is the requirement to wear electrodes on the head. We here propose a BCI that can tackle these issues and may be a promising case for BCI research and application in everyday life. The BCI uses EEG signals to predict head rotation in order to improve images presented in a virtual reality (VR) headset. When presenting a 360 degrees video to a headset, field-of view approaches only stream the content that is in the current field of view and leave out the rest. When the user rotates the head, other content parts need to be made available soon enough to go unnoticed by the user, which is problematic given the available bandwidth. By predicting head rotation, the content parts adjacent to the currently viewed part could be retrieved in time for display when the rotation actually takes place. We here studied whether head rotations can be predicted on the basis of EEG sensor data and if so, whether application of such predictions could be applied to improve display of streaming images. Eleven participants generated left- and rightward head rotations while head movements were recorded using the headsets motion sensing system and EEG. We trained neural network models to distinguish EEG epochs preceding rightward, leftward, and no rotation. Applying these models to streaming EEG data that was withheld from the training showed that 400 ms before rotation onset, the probability "no rotation" started to decrease and the probabilities of an upcoming right- or leftward rotation started to diverge in the correct direction. In the proposed BCI scenario, users already wear a device on their head allowing for integrated EEG sensors. Moreover, it is possible to acquire accurately labeled training data on the fly, and continuously monitor and improve the model's performance. The BCI can be harnessed if it will improve imagery and therewith enhance immersive experience. PMID- 30459579 TI - Resting State Connectivity Between Medial Temporal Lobe Regions and Intrinsic Cortical Networks Predicts Performance in a Path Integration Task. AB - Humans differ in their individual navigational performance, in part because successful navigation relies on several diverse abilities. One such navigational capability is path integration, the updating of position and orientation during movement, typically in a sparse, landmark-free environment. This study examined the relationship between path integration abilities and functional connectivity to several canonical intrinsic brain networks. Intrinsic networks within the brain reflect past inputs and communication as well as structural architecture. Individual differences in intrinsic connectivity have been observed for common networks, suggesting that these networks can inform our understanding of individual spatial abilities. Here, we examined individual differences in intrinsic connectivity using resting state magnetic resonance imaging (rsMRI). We tested path integration ability using a loop closure task, in which participants viewed a single video of movement in a circle trajectory in a sparse environment, and then indicated whether the video ended in the same location in which it started. To examine intrinsic brain networks, participants underwent a resting state scan. We found that better performance in the loop task was associated with increased connectivity during rest between the central executive network (CEN) and posterior hippocampus, parahippocampal cortex (PHC) and entorhinal cortex. We also found that connectivity between PHC and the default mode network (DMN) during rest was associated with better loop closure performance. The results indicate that interactions between medial temporal lobe (MTL) regions and intrinsic networks that involve prefrontal cortex (PFC) are important for path integration and navigation. PMID- 30459581 TI - Diffusion Tensor Imaging Detects Microstructural Differences of Visual Pathway in Patients With Primary Open-Angle Glaucoma and Ocular Hypertension. AB - Ocular hypertension (OHT), the common situation in adult patients in the outpatients, occurs ~5% worldwide. However, there are still some practical problems in differentiation of OHT with early primary open-angle glaucoma (POAG) using current standard methods. Application of high resolution diffusion tensor imaging (DTI) enables us to the differentiate axonal architecture of visual pathway between POAG and OHT subjects. Among 32 POAG patients recruited (15 OHT and 14 control subjects), 62.5% of glaucoma were in early stage for the current study. All subjects underwent ophthalmological assessments with standard automated perimetry and optical coherence tomography (OCT). DTI was applied to measure fraction anisotropy (FA) and mean diffusivity (MD) of optic tract (OT), lateral geniculate body (LGN) and optic radiation (OR) using voxel-based analysis. Our data demonstrated that FA values of bilateral OR in POAG were significantly lower in the right or left than that of OHT patients (left OR: 0.51 +/- 0.04 vs. 0.54 +/- 0.03, p < 0.05; right OR: 0.51 +/- 0.05 vs. 0.54 +/- 0.03, p < 0.05). In right LGN, MD values were higher in POAG patients compared with OHT subjects (9.81 +/- 1.45 vs. 8.23 +/- 0.62, p < 0.05). However, no significant difference of all of the DTI parameters was observed between OHT and control subjects. DTI parameters in POAG patients were positively correlated with morphological and functional measurements (p < 0.05). Vertical cup to disc ratio (VCDR) was correlated with ipsilateral FA of OT (p < 0.05), ipsilateral MD of OT (p < 0.05), ipsilateral MD of LGN (p < 0.05), and contralateral MD of OT (p < 0.05). Mean deviation of visual field (MDVF) was correlated with ipsilateral FA of OT (p < 0.05), ipsilateral MD of OT (p < 0.05), and ipsilateral FA of LGN (p < 0.05). Our study demonstrated that DTI can differentiate POAG from OHT subjects in optic pathway, particularly in early POAG, and DTI parameters can quantify the progression of POAG. PMID- 30459582 TI - Strong Conscious Cues Suppress Preferential Gaze Allocation to Unconscious Cues. AB - Visual attention allows relevant information to be selected for further processing. Both conscious and unconscious visual stimuli can bias attentional allocation, but how these two types of visual information interact to guide attention remains unclear. In this study, we explored attentional allocation during a motion discrimination task with varied motion strength and unconscious associations between stimuli and cues. Participants were instructed to report the motion direction of two colored patches of dots. Unbeknown to participants, dot colors were sometimes informative of the correct response. We found that subjects learnt the associations between colors and motion direction but failed to report this association using the questionnaire filled at the end of the experiment, confirming that learning remained unconscious. The eye movement analyses revealed that allocation of attention to unconscious sources of information occurred mostly when motion coherence was low, indicating that unconscious cues influence attentional allocation only in the absence of strong conscious cues. All in all, our results reveal that conscious and unconscious sources of information interact with each other to influence attentional allocation and suggest a selection process that weights cues in proportion to their reliability. PMID- 30459583 TI - Music Familiarity Affects EEG Entrainment When Little Attention Is Paid. AB - To investigate the brain's response to music, many researchers have examined cortical entrainment in relation to periodic tunes, periodic beats, and music. Music familiarity is another factor that affects cortical entrainment, and electroencephalogram (EEG) studies have shown that stronger entrainment occurs while listening to unfamiliar music than while listening to familiar music. In the present study, we hypothesized that not only the level of familiarity but also the level of attention affects the level of entrainment. We simultaneously presented music and a silent movie to participants and we recorded an EEG while participants paid attention to either the music or the movie in order to investigate whether cortical entrainment is related to attention and music familiarity. The average cross-correlation function across channels, trials, and participants exhibited a pronounced positive peak at time lags around 130 ms and a negative peak at time lags around 260 ms. The statistical analysis of the two peaks revealed that the level of attention did not affect the level of entrainment, and, moreover, that in both the auditory-active and visual-active conditions, the entrainment level is stronger when listening to unfamiliar music than when listening to familiar music. This may indicate that the familiarity with music affects cortical activities when attention is not fully devoted to listening to music. PMID- 30459585 TI - Unsupervised Manifold Learning Using High-Order Morphological Brain Networks Derived From T1-w MRI for Autism Diagnosis. AB - Brain disorders, such as Autism Spectrum Disorder (ASD), alter brain functional (from fMRI) and structural (from diffusion MRI) connectivities at multiple levels and in varying degrees. While unraveling such alterations have been the focus of a large number of studies, morphological brain connectivity has been out of the research scope. In particular, shape-to-shape relationships across brain regions of interest (ROIs) were rarely investigated. As such, the use of networks based on morphological brain data in neurological disorder diagnosis, while leveraging the advent of machine learning, could complement our knowledge on brain wiring alterations in unprecedented ways. In this paper, we use conventional T1-weighted MRI to define morphological brain networks (MBNs), each quantifying shape relationship between different cortical regions for a specific cortical attribute at both low-order and high-order levels. While typical brain connectomes investigate the relationship between two ROIs, we propose high-order MBN which better captures brain complex interactions by modeling the morphological relationship between pairs of ROIs. For ASD identification, we present a connectomic manifold learning framework, which learns multiple kernels to estimate a similarity measure between ASD and normal controls (NC) connectional features, to perform dimensionality reduction for clustering ASD and NC subjects. We benchmark our ASD identification method against both supervised and unsupervised state-of-the-art methods, while depicting the most discriminative high- and low-order relationships between morphological regions in the left and right hemispheres. PMID- 30459584 TI - A Neurobiologically Constrained Cortex Model of Semantic Grounding With Spiking Neurons and Brain-Like Connectivity. AB - One of the most controversial debates in cognitive neuroscience concerns the cortical locus of semantic knowledge and processing in the human brain. Experimental data revealed the existence of various cortical regions relevant for meaning processing, ranging from semantic hubs generally involved in semantic processing to modality-preferential sensorimotor areas involved in the processing of specific conceptual categories. Why and how the brain uses such complex organization for conceptualization can be investigated using biologically constrained neurocomputational models. Here, we improve pre-existing neurocomputational models of semantics by incorporating spiking neurons and a rich connectivity structure between the model 'areas' to mimic important features of the underlying neural substrate. Semantic learning and symbol grounding in action and perception were simulated by associative learning between co-activated neuron populations in frontal, temporal and occipital areas. As a result of Hebbian learning of the correlation structure of symbol, perception and action information, distributed cell assembly circuits emerged across various cortices of the network. These semantic circuits showed category-specific topographical distributions, reaching into motor and visual areas for action- and visually related words, respectively. All types of semantic circuits included large numbers of neurons in multimodal connector hub areas, which is explained by cortical connectivity structure and the resultant convergence of phonological and semantic information on these zones. Importantly, these semantic hub areas exhibited some category-specificity, which was less pronounced than that observed in primary and secondary modality-preferential cortices. The present neurocomputational model integrates seemingly divergent experimental results about conceptualization and explains both semantic hubs and category-specific areas as an emergent process causally determined by two major factors: neuroanatomical connectivity structure and correlated neuronal activation during language learning. PMID- 30459586 TI - Measuring Alterations of Spontaneous EEG Neural Coupling in Alzheimer's Disease and Mild Cognitive Impairment by Means of Cross-Entropy Metrics. AB - Alzheimer's Disease (AD) represents the most prevalent form of dementia and is considered a major health problem due to its high prevalence and its economic costs. An accurate characterization of the underlying neural dynamics in AD is crucial in order to adopt effective treatments. In this regard, mild cognitive impairment (MCI) is an important clinical entity, since it is a risk-state for developing dementia. In the present study, coupling patterns of 111 resting-state electroencephalography (EEG) recordings were analyzed. Specifically, we computed Cross-Approximate Entropy (Cross-ApEn) and Cross-Sample Entropy (Cross-SampEn) of 37 patients with dementia due to AD, 37 subjects with MCI, and 37 healthy control (HC) subjects. Our results showed that Cross-SampEn outperformed Cross-ApEn, revealing higher number of significant connections among the three groups (Kruskal-Wallis test, FDR-corrected p-values < 0.05). AD patients exhibited statistically significant lower similarity values at theta and beta1 frequency bands compared to HC. MCI is also characterized by a global decrease of similarity in all bands, being only significant at beta1. These differences shows that beta band might play a significant role in the identification of early stages of AD. Our results suggest that Cross-SampEn could increase the insight into brain dynamics at different AD stages. Consequently, it may contribute to develop early AD biomarkers, potentially useful as diagnostic information. PMID- 30459587 TI - The CAMH Neuroinformatics Platform: A Hospital-Focused Brain-CODE Implementation. AB - Investigations of mental illness have been enriched by the advent and maturation of neuroimaging technologies and the rapid pace and increased affordability of molecular sequencing techniques, however, the increased volume, variety and velocity of research data, presents a considerable technical and analytic challenge to curate, federate and interpret. Aggregation of high-dimensional datasets across brain disorders can increase sample sizes and may help identify underlying causes of brain dysfunction, however, additional barriers exist for effective data harmonization and integration for their combined use in research. To help realize the potential of multi-modal data integration for the study of mental illness, the Centre for Addiction and Mental Health (CAMH) constructed a centralized data capture, visualization and analytics environment-the CAMH Neuroinformatics Platform-based on the Ontario Brain Institute (OBI) Brain-CODE architecture, towards the curation of a standardized, consolidated psychiatric hospital-wide research dataset, directly coupled to high performance computing resources. PMID- 30459588 TI - Most Popular Signal Processing Methods in Motor-Imagery BCI: A Review and Meta Analysis. AB - Brain-Computer Interfaces (BCI) constitute an alternative channel of communication between humans and environment. There are a number of different technologies which enable the recording of brain activity. One of these is electroencephalography (EEG). The most common EEG methods include interfaces whose operation is based on changes in the activity of Sensorimotor Rhythms (SMR) during imagery movement, so-called Motor Imagery BCI (MIBCI).The present article is a review of 131 articles published from 1997 to 2017 discussing various procedures of data processing in MIBCI. The experiments described in these publications have been compared in terms of the methods used for data registration and analysis. Some of the studies (76 reports) were subjected to meta-analysis which showed corrected average classification accuracy achieved in these studies at the level of 51.96%, a high degree of heterogeneity of results (Q = 1806577.61; df = 486; p < 0.001; I 2 = 99.97%), as well as significant effects of number of channels, number of mental images, and method of spatial filtering. On the other hand the meta-regression failed to provide evidence that there was an increase in the effectiveness of the solutions proposed in the articles published in recent years. The authors have proposed a newly developed standard for presenting results acquired during MIBCI experiments, which is designed to facilitate communication and comparison of essential information regarding the effects observed. Also, based on the findings of descriptive analysis and meta-analysis, the authors formulated recommendations regarding practices applied in research on signal processing in MIBCIs. PMID- 30459589 TI - Human-In-The-Loop Control and Task Learning for Pneumatically Actuated Muscle Based Robots. AB - Pneumatically actuated muscles (PAMs) provide a low cost, lightweight, and high power-to-weight ratio solution for many robotic applications. In addition, the antagonist pair configuration for robotic arms make it open to biologically inspired control approaches. In spite of these advantages, they have not been widely adopted in human-in-the-loop control and learning applications. In this study, we propose a biologically inspired multimodal human-in-the-loop control system for driving a one degree-of-freedom robot, and realize the task of hammering a nail into a wood block under human control. We analyze the human sensorimotor learning in this system through a set of experiments, and show that effective autonomous hammering skill can be readily obtained through the developed human-robot interface. The results indicate that a human-in-the-loop learning setup with anthropomorphically valid multi-modal human-robot interface leads to fast learning, thus can be used to effectively derive autonomous robot skills for ballistic motor tasks that require modulation of impedance. PMID- 30459590 TI - Emergence of Endocytosis-Dependent mGlu1 LTD at Nucleus Accumbens Synapses After Withdrawal From Cocaine Self-Administration. AB - Extended-access cocaine self-administration induces a progressive intensification of cue-induced drug craving during withdrawal termed "incubation of cocaine craving". Rats evaluated after >1 month of withdrawal (when incubation of craving is robust) display alterations in excitatory synapses onto medium spiny neurons (MSNs) of the nucleus accumbens (NAc), including elevated levels of Ca2+ permeable AMPA receptors (CP-AMPAR) and a transition from group I metabotropic glutamate receptor (mGluR) mGlu5- to mGlu1-mediated synaptic depression. It is important to further characterize the emergent form of mGlu1-mediated synaptic depression because it has been demonstrated that mGlu1 stimulation, by normalizing CP-AMPAR transmission, reduces cue-induced cocaine craving. In the present study, we conducted whole-cell patch-clamp recordings in NAc core MSNs, comparing rats that underwent >35 days of withdrawal from cocaine self administration to control rats that had self-administered saline. Bath application of the nonselective group I mGluR agonist dihydroxyphenylglycine (DHPG) produced a transient mGlu5-mediated synaptic depression in saline controls, whereas a persistent mGlu1-mediated synaptic depression emerged in cocaine rats. This form of long-term depression (LTD) was abolished by the inclusion of dynamin inhibitory peptide (DIP) in the recording electrode, indicating that it is mediated by removal of CP-AMPARs through a dynamin dependent endocytosis mechanism. We further showed that CP-AMPAR endocytosis is normally coupled to the PICK1-mediated insertion of Ca2+-impermeable AMPARs (CI AMPAR). Interestingly, this coupling is not obligatory because disruption of PICK1-mediated CI-AMPAR insertion with pep2-EVKI spared mGlu1-mediated CP-AMPAR endocytosis. Collectively, these results reveal similarities but also differences from mGlu1-LTD observed in other brain regions, and further our understanding of a form of plasticity that may be targeted to reduce cue-induced craving for cocaine and methamphetamine. PMID- 30459591 TI - Older Adults With Hearing Loss Have Reductions in Visual, Motor and Attentional Functioning. AB - Evidence from epidemiological, laboratory and clinical research suggests a link between age-related auditory declines and domain-general cognitive declines. Nevertheless, few studies have experimentally compared measures of non-auditory cognitive functions in younger normal hearing adults (YN), older adults with typical hearing thresholds for their age (ONHA) and older adults with clinically significant threshold hearing loss (OHL). The current study investigated the differences between these groups on measures of attentional response selection and execution to visual stimuli. A visual reaction time (RT) paradigm involving four tasks with differing and hierarchical attentional demands was administered. RTs on trials with differing foreperiods (FPs; pre-stimulus waiting times) were analyzed to assess context-related slowing, error commission and related cognitive control and strategic and automatic neural preparatory processes. The OHL group demonstrated a general slowing that was most apparent on the simplest tasks. Although the number of errors was similar when comparing all three groups, the OHL group exhibited less control over recovery from an error compared to the younger and ONHA groups. Unlike the YN and ONHA groups, the OHL group also showed difficulties with both strategic and automatic response preparation, although automatic preparation was more affected across all tasks. This pattern of results suggests that in older adults with hearing loss there is an underlying difficulty in automatic temporal processing that can affect higher order cognitive functions, although there may not be a completely generalized decline in cognitive functioning that is associated with hearing loss. PMID- 30459592 TI - Temporal Aspects of Memory: A Comparison of Memory Performance, Processing Speed and Time Estimation Between Young and Older Adults. AB - Cognitive abilities are often reported to decline across the lifespan, particularly when assessed with working memory (WM) measures such as the auditory backward digit span and complex N-back tasks. However, some debate still exists regarding which aspects of cognition are most susceptible to the aging process and which may remain intact. Additionally, time estimation, though a complex psychological dimension, is often studied in relative isolation and is particularly neglected in traditional studies of WM, with little research from the viewpoint of retrospective temporal estimation. In particular, research seldom considers whether the ability to accurately estimate time retrospectively, is correlated with performance on traditional memory and processing speed measures in healthy populations. Thus, we chose to investigate performance of comparably educated young and older adult groups on both classical memory tasks including auditory and visual digit spans, N-back, Wechsler Adult Intelligence Scale (WAIS)-based measures of processing speed (i.e., Symbol Search [SS] and Coding [Cod]) and a temporal measure of WM with a focus on retrospective time estimation. Our sample included 66 university students (58 F, 8 M) between the ages of 18-29, and 33 university-educated healthy older adults (25 F, 8 M) between the ages of 60-81. Results indicated that older adults performed significantly worse on auditory but not the visual digit span tasks, as well as on both the SS and Cod, though performed equally well on the N = 1 back task. Results also showed that retrospective time estimation was not significantly different between young and older adults, with both groups substantially underestimating duration of a simple task. Retrospective time estimation was not significantly correlated to any memory or processing speed measure, emphasizing the need for future research into the specific cognitive domains underlying the subjective estimation of a temporal interval. PMID- 30459594 TI - Korean Red Ginseng Enhances Neurogenesis in the Subventricular Zone of 1-Methyl-4 Phenyl-1,2,3,6-Tetrahydropyridine-Treated Mice. AB - Regulation of adult neurogenesis plays an important role in therapeutic strategies for various neurodegenerative diseases. Recent studies have suggested that the enhancement of adult neurogenesis can be helpful in the treatment of Parkinson's disease (PD). In this study, we investigated whether Korean red ginseng (KRG) can enhance neurogenesis in the subventricular zone (SVZ) of a PD mouse model. To accomplish this, male 8-week-old C57BL/6 mice were injected with vehicle or 20 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) four times at 2 h intervals. After the final injection, they were administered water or 100 mg/kg of KRG extract and injected intraperitoneally with 50 mg/kg of 5' bromo-2'-deoxyuridine-monophosphate (BrdU) once a day for 14 consecutive days. After the last pole test, dopaminergic neuronal survival in the striatum and the substantia nigra (SN), cell proliferation in the SVZ and mRNA expression of neurotrophic factors and dopamine receptors in the striatum were evaluated. KRG administration suppressed dopaminergic neuronal death induced by MPTP in the striatum as well as the SN, augmented the number of BrdU- and BrdU/doublecortin (Dcx)-positive cells in the SVZ and enhanced the expression of proliferation cell nuclear antigen, brain derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF), ciliary neurotrophic factor (CNTF), dopamine receptor D3 (DRD3) and D5 mRNAs. These results suggest that KRG administration augments neurogenesis in the SVZ of the PD mouse model. PMID- 30459593 TI - Age-Dependent Up-Regulation of HCN Channels in Spiral Ganglion Neurons Coincide With Hearing Loss in Mice. AB - Age-related hearing loss (AHL) is the most common sensory disorder in the elderly population, and the etiologies are diverse. To understand the underlying mechanisms of AHL, one strategy is to identify correlates of the disease for comprehensive evaluation of treatment approaches. Dysfunction and degeneration of spiral ganglion neurons (SGNs) are major contributors to AHL. Previously, we showed that one of the changes in the aging auditory system is SGN excitability increase in mice. Since hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play important roles in determining neuronal excitability, we predicted that HCN channels in SGNs are involved in AHL. To investigate the contribution of HCN channels to AHL, we examined the expression and biophysical properties of HCN channels in SGNs from adult (2-3 months) and 11-12-month-old mice. We report a dramatic increase of HCN channel current (Ih) in SGNs in old mice (11-12 months old). The results matched well with increased expression of HCN1 and HCN2 subunits, suggesting that upregulation of HCN channels in SGNs is one of the important facets of the aging SGNs. Moreover, the activity of Ih produced a major impact on the firing properties of SGNs in older mice. The upregulation of Ih may contribute to AHL by regulating SGN excitability. We assessed whether increased SGNs excitability dovetail with neurodegeneration. Apoptosis-inducing factor (AIF)-mediated apoptosis in SGNs was observed in old mice and activation of HCN channels mediates AIF activation. Thus, these findings demonstrate stark correlation between age-dependent increased expression of HCN channels and Ih, and apoptosis in SGNs, which may contribute towards the varied mechanisms of AHL. PMID- 30459595 TI - Neural Correlates of Working Memory Maintenance in Advanced Aging: Evidence From fMRI. AB - Working memory (WM)-related brain activity is known to be modulated by aging; particularly, older adults demonstrate greater activity than young adults. However, it is still unclear whether the activity increase in older adults is also observed in advanced aging. The present functional magnetic resonance imaging (fMRI) study was designed to clarify the neural correlates of WM in advanced aging. Further, we set out to investigate in the case that adults of advanced age do show age-related increase in WM-related activity, what the functional significance of this over-recruitment might be. Two groups of older adults - "young-old" (61-70 years, n = 17) and "old-old" (77-82 years, n = 16) - were scanned while performing a visual WM task (the n-back task: 0-back and 1 back). WM effects (1-back > 0-back) common to both age groups were identified in several regions, including the bilateral dorsolateral prefrontal cortex (DLPFC), the inferior parietal cortex, and the insula. Greater WM effects in the old-old than in the young-old group were identified in the right caudal DLPFC. These results were replicated when we performed a separate analysis between two age groups with the same level of WM performance (the young-old vs. a "high performing" subset of the old-old group). There were no regions where WM effects were greater in the young-old group than in the old-old group. Importantly, the magnitude of the over-recruitment WM effects positively correlated with WM performance in the old-old group, but not in the young-old group. The present findings suggest that cortical over-recruitment occurs in advanced old age, and that increased activity may serve a compensatory function in mediating WM performance. PMID- 30459596 TI - Heme Oxygenase-1 and Brain Oxysterols Metabolism Are Linked to Egr-1 Expression in Aged Mice Cortex, but Not in Hippocampus. AB - Throughout life, stress stimuli act upon the brain leading to morphological and functional changes in advanced age, when it is likely to develop neurodegenerative disorders. There is an increasing need to unveil the molecular mechanisms underlying aging, in a world where populations are getting older. Egr 1 (early growth response 1), a transcriptional factor involved in cell survival, proliferation and differentiation - with a role also in memory, cognition and synaptic plasticity, can be implicated in the molecular mechanism of the aging process. Moreover, Heme Oxygenase-1a (HO), a 32 kDa heat-shock protein that converts heme to iron, carbon monoxide and biliverdin, is a key enzyme with neuroprotective properties. Several in vitro and in vivo studies reported that HO 1 could regulate the metabolism of oxysterols, oxidation products of cholesterol that include markers of oxidative stress. Recently, a link between Egr-1 and HO-1 has been demonstrated in mouse lung cells exposed to cigarette smoke. In view of these data, we wanted to investigate whether Egr-1 can be implicated also in the oxysterol metabolism during brain aging. Our results show that Egr-1 expression is differently expressed in the cortex and hippocampus of old mice, as well as the oxysterol profile between these two brain areas. In particular, we show that the cortex experiences in an age-dependent fashion increasing levels of the Egr-1 protein, and that these correlate with the level of HO-1 expression and oxysterol abundance. Such a situation was not observed in the hippocampus. These results are further strenghtened by our observations made with Egr-1 KO mice, confirming our hypothesis concerning the influence of Egr-1 on oxysterol production and accumulation via regulation of the expression of HO-1 in the cortex, but not the hippocampus, of old mice. It is important to notice that most of the oxysterols involved in this process are those usually stimulated by oxidative stress, which would then represent the triggering factor for this mechanism. PMID- 30459598 TI - GLP-1 Improves Adipocyte Insulin Sensitivity Following Induction of Endoplasmic Reticulum Stress. AB - Glucagon-like peptide 1 (GLP-1) improves insulin resistance of adipose tissue in obese humans. However, the mechanism of this effect is unclear. Perturbation of endoplasmic reticulum (ER) homeostasis impairs insulin signaling. We hypothesized that GLP-1 could directly improve insulin signaling in ER-stressed adipocytes. Here, we examined the effects of GLP-1 on ER stress response in fat cells in an obese and insulin-resistant murine model. We found that GLP-1 analog liraglutide reduced ER stress related gene expression in visceral fat cells accompanied by improved systemic insulin tolerance. Consistently, GLP-1 decreased CHOP expression and increased insulin stimulated AKT phosphorylation (p-AKT) in thapsigargin, a ER stress inducer, treated white fat cells differentiated from visceral stromal vascular fraction. We further found blocking CHOP expression increased insulin stimulated p-AKT in ER-stressed fat cells. Of note, we found mTOR signaling pathway contributed to the expression of ATF4 and subsequently the CHOP expression in ER stress response, while GLP-1 inhibited mTOR activity as exemplified by elevated autophagosome formation and increased LC3II/LC3I ratio. These findings suggest that GLP-1 directly modulates the ER stress response partially via inhibiting mTOR signaling pathway, leading to increased insulin sensitivity in adipocytes. PMID- 30459599 TI - Assessing the Pharmacological and Therapeutic Efficacy of Traditional Chinese Medicine Liangxue Tongyu Prescription for Intracerebral Hemorrhagic Stroke in Neurological Disease Models. AB - Intracerebral hemorrhage is a fatal subtype of stroke, with crucial impact on public health. Surgical removal of the hematoma as an early-stage treatment for ICH can't improve long-term prognosis remarkably. Liangxue tongyu prescription (LP), a Traditional Chinese Medicine (TCM) formula, includes eight ingredients and has been used to treat ICH in the clinical. In the study, we elucidated the pharmacological efficacy and therapeutic efficacy of LP to dissect the mechanism of LP against ICH via network analysis and experimental validation. First, we discovered 34 potential compounds and 146 corresponding targets in LP based on network prediction. 24 signal pathway were obtained by the Clue Go assay based on potential compounds in LP against ICH. Second, we found that LP can not only decreased the level of high sensitive C reactive protein (HS-CRP), tumor necrosis factor-alpha (TNF-alpha), NF-kbeta, D-dimmer (D2D), estradiol (E2), S-100B, neuron specific enolase (NSE), and interleukin 1 (IL-1) in plasma on spontaneously hypertensive rats (SHRs), but also promoted cell proliferation and inhibited cell apoptosis on the glutamate-induced PC12 cell. The compounds including Taurine, Paeonol, and Ginsenoside Rb1 in LP can activate PI3K/AKT pathway. Third, from the three-factor two-level factorial design, compound combinations in LP, such as Taurine and Paeonol, Taurine and Geniposide, Ginsenoside Rg1, and Ginsenoside Rb1, had first-level interactions on cell proliferation. Compound combinations including Taurine and Paeonol, Ginsenoside Rg1 and Ginsenoside Rb1 had as significant increase in efficiency on inhibiting the apoptosis of PC12 cells at the low concentration and up-regulating of PI3K and AKT. Overall, our results suggested that LP had integrated therapeutic effect on ICH due to activities of anti-inflammatory, anti-coagulation, blood vessel protection, and protection neuron from excitotoxicity based on the way of "multi component, multi-target, multi-pathway," and compound combination in LP can offer protection neuron from excitotoxicity at the low concentration by activation of the PI3K/Akt signal pathway. PMID- 30459601 TI - Therapeutic Potential of Luffa acutangula: A Review on Its Traditional Uses, Phytochemistry, Pharmacology and Toxicological Aspects. AB - Luffa acutangula (Cucurbitaceae), a perennial plant grows mainly in India, Southeast Asia, China, Japan, Egypt, and other parts of Africa, it is widely used in the traditional Indian medicinal system to treat various health conditions. The plant has been used in jaundice, diabetes, hemorrhoids, dysentery, headache, ringworm infection, and leprosy. More than 50 chemical compounds have been isolated from a plant which mainly comprises flavonoids, anthraquinones, proteins, fatty acids, saponin triterpene, volatile components, and other phytoconstituents. Crude extract of plant and its isolated compounds possess broad pharmacological activities such as antidiabetic, hepatoprotective, antiulcer, anticancer, immunomodulatory, antihyperlipidemic, antioxidant, antimicrobial, CNS depressant, analgesic, and anti-inflammatory. The toxicological evaluation in preclinical studies reported safety of the plant for human consumption, but comprehensive evaluation in clinical studies is required. However, further investigation is necessary for transformation of experience based treatment of plant into evidence based information. Evaluation of pharmacological activity with indicative biomarkers will help to reveal the mechanism of action of chemical constituents of plant extract. The data from preclinical studies recommends clinical evaluation of safety and efficacy of the plant. The current paper summarizes up-to-date information about a review of the traditional uses, phytochemistry, pharmacological activities, and toxicology to highlight the future prospects of the plant. PMID- 30459600 TI - Human Adipose Tissue-Derived Mesenchymal Stem Cells Attenuate Atopic Dermatitis by Regulating the Expression of MIP-2, miR-122a-SOCS1 Axis, and Th1/Th2 Responses. AB - The objective of this study was to investigate the effect of human adipose tissue derived mesenchymal stem cells (AdMSCs) on atopic dermatitis (AD) in the BALB/c mouse model. The AdMSCs attenuated clinical symptoms associated with AD, decreased numbers of degranulated mast cells (MCs), IgE level, amount of histamine released, and prostaglandin E2 level. Atopic dermatitis increased the expression levels of cytokines/chemokines, such as interleukin-5 (IL-5), macrophage inflammatory protein-1beta (MIP-1beta), MIP-2, chemokine (C-C motif) ligand 5 (CCL5), and IL-17, in BALB/c mouse. The AdMSCs showed decreased expression levels of these cytokines in the mouse model of AD. In vivo downregulation of MIP-2 attenuated the clinical symptoms associated with AD. Atopic dermatitis increased the expression levels of hallmarks of allergic inflammation, induced interactions of Fc??RIbeta with histone deacetylase 3 (HDAC3) and Lyn, increased beta-hexosaminidase activity, increased serum IgE level, and increased the amount of histamine released in an MIP-2-dependent manner. Downregulation of MIP-2 increased the levels of several miRNAs, including miR-122a-5p. Mouse miR-122a-5p mimic inhibited AD, while suppressor of cytokine signaling 1 (SOCS1), a predicted downstream target of miR-122a-5p, was required for AD. The downregulation of SOCS1 decreased the expression levels of MIP-2 and chemokine (C-X-C motif) ligand 13 (CXCL13) in the mouse model of AD. The downregulation of CXCL13 attenuated AD and allergic inflammation such as passive cutaneous anaphylaxis. The role of T cell transcription factors in AD was also investigated. Atopic dermatitis increased the expression levels of T-bet and GATA 3 [transcription factors of T-helper 1 (Th1) and T-helper 2 (Th2) cells, respectively] but decreased the expression of Foxp3, a transcription factor of regulatory T (Treg) cells, in an SOCS1-dependent manner. In addition to this, miR 122a-5p mimic also prevented AD from regulating the expression of T-bet, GATA-3, and Foxp3. Atopic dermatitis increased the expression of cluster of differentiation 163 (CD163), a marker of M2 macrophages, but decreased the expression of inducible nitric oxide synthase (iNOS), a marker of M1 macrophages. Additionally, SOCS1 and miR-122a-5p mimic regulated the expression of CD163 and iNOS in the mouse model of AD. Experiments employing conditioned medium showed interactions between MCs and macrophages in AD. The conditioned medium of AdMSCs, but not the conditioned medium of human dermal fibroblasts, negatively inhibited the features of allergic inflammation. In summary, we investigated the anti atopic effects of AdMSCs, identified targets of AdMSCs, and determined the underlying mechanism for the anti-atopic effects of AdMSCs. PMID- 30459602 TI - Psoralen Induced Liver Injury by Attenuating Liver Regenerative Capability. AB - Psoralen is a major component of the common traditional Chinese medicine Fructus Psoraleae (FP). In this study, we focused on psoralen to explore FP-induced hepatotoxicity and the underlying mechanisms. The acute oral median lethal dose of psoralen in ICR mice was determined to be 1,673 mg/kg. C57BL/6 mice were administered psoralen intragastrically at doses of 400 mg/kg or 800 mg/kg, and were sacrificed 24 h after treatment. Changes in various hepatotoxicity indicators demonstrated that psoralen can cause mild liver injury in mice. Psoralen inhibited the viability of normal human liver L02 cells in vitro by inducing S-phase arrest. In addition, psoralen in both the mouse livers and L02 cells upregulated cyclin E1 and p27 protein levels. The 2/3 partial hepatectomy mouse model was used to further explore the effects of psoralen on the liver regeneration and hepatocellular cycle arrest in vivo. The results showed that the decrease of liver regenerative and self-healing capabilities induced by hepatocellular cycle arrest may play an important role in the hepatotoxicity of psoralen. The further mechanism researches indicated that psoralen-induced hepatotoxicity was associated with inhibition of mTOR signalling pathway and mitochondrial injury; furthermore, MHY, an mTOR activator, partly alleviated the inhibition of mTOR and S-phase cycle arrest induced by psoralen in L02 cells. In conclusion, in this study we showed for the first time, that psoralen significantly induced liver injury in mice; the decrease of liver regenerative and compensatory capabilities induced by hepatocellular cycle arrest may play an important role in the progression of hepatotoxicity associated with the upregulation of cyclin E1 and p27, as well as the inhibition of mTOR signalling and mitochondrial injury. Our findings may contribute to the reduction of hepatotoxicity risk induced by Fructus Psoraleae. PMID- 30459597 TI - Anakinra Therapy for Non-cancer Inflammatory Diseases. AB - Interleukin-1 (IL-1) is the prototypical inflammatory cytokine: two distinct ligands (IL-1alpha and IL-1beta) bind the IL-1 type 1 receptor (IL-1R1) and induce a myriad of secondary inflammatory mediators, including prostaglandins, cytokines, and chemokines. IL-1alpha is constitutively present in endothelial and epithelial cells, whereas IL-1beta is inducible in myeloid cells and released following cleavage by caspase-1. Over the past 30 years, IL-1-mediated inflammation has been established in a broad spectrum of diseases, ranging from rare autoinflammatory diseases to common conditions such as gout and rheumatoid arthritis (RA), type 2 diabetes, atherosclerosis, and acute myocardial infarction. Blocking IL-1 entered the clinical arena with anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra); IL 1Ra prevents the binding of IL-1alpha as well as IL-1beta to IL-1R1. Quenching IL 1-mediated inflammation prevents the detrimental consequences of tissue damage and organ dysfunction. Although anakinra is presently approved for the treatment of RA and cryopyrin-associated periodic syndromes, off-label use of anakinra far exceeds its approved indications. Dosing of 100 mg of anakinra subcutaneously provides clinically evident benefits within days and for some diseases, anakinra has been used daily for over 12 years. Compared to other biologics, anakinra has an unparalleled record of safety: opportunistic infections, particularly Mycobacterium tuberculosis, are rare even in populations at risk for reactivation of latent infections. Because of this excellent safety profile and relative short duration of action, anakinra can also be used as a diagnostic tool for undefined diseases mediated by IL-1. Although anakinra is presently in clinical trials to treat cancer, this review focuses on anakinra treatment of acute as well as chronic inflammatory diseases. PMID- 30459603 TI - Icariin Ameliorates Palmitate-Induced Insulin Resistance Through Reducing Thioredoxin-Interacting Protein (TXNIP) and Suppressing ER Stress in C2C12 Myotubes. AB - Both thioredoxin-interacting protein (TXNIP) and endoplasmic reticulum (ER) stress are implicated in skeletal muscle insulin resistance. Icariin has been found to mimic insulin action in normal skeletal muscle C2C12 cells and display anti-diabetic properties in diet-induced obese mice. However, the underlying molecular mechanism remains to be well-established. Herein, we tested the hypothesis that the protective effects of icariin on free fatty acid-induced insulin resistance were attributed to its regulation on TXNIP protein levels and ER stress in skeletal muscle cells. We found that TXNIP mediated the saturated fatty acid palmitate (PA)-induced insulin resistance in C2C12 myotubes. Icariin treatment significantly restored PA-reduced proteasome activity resulting in reduction of TXNIP protein and suppression of ER stress, as well as improvement of insulin sensitivity. Proteasome inhibition by its specific inhibitor MG132 obviously abolished the inhibitory effect of icariin on PA-induced insulin resistance. In addition, MG132 supplementation markedly abrogated the impacts of icariin on ER stress and TXNIP-mediated downstream events such as inflammation and STAT3 phosphorylation. These results clearly indicate that icariin improves PA-induced skeletal muscle insulin resistance through a proteasome-dependent mechanism, by which icariin downregulats TXNIP levels and inhibits ER stress. PMID- 30459604 TI - Cerium Oxide Nanoparticles Re-establish Cell Integrity Checkpoints and Apoptosis Competence in Irradiated HaCat Cells via Novel Redox-Independent Activity. AB - Cerium oxide nanoparticles (CNPs) are potent radical scavengers protecting cells from oxidative insults, including ionizing radiation. Here we show that CNPs prevent X-ray-induced oxidative imbalance reducing DNA breaks on HaCat keratinocytes, nearly abating mutagenesis. At the same time, and in spite of the reduced damage, CNPs strengthen radiation-induced cell cycle arrest and apoptosis outcome, dropping colony formation; notably, CNPs do not possess any intrinsic toxicity toward non-irradiated HaCat, indicating that they act on damaged cells. Thus CNPs, while exerting their antioxidant action, also reinforce the stringency of damage-induced cell integrity checkpoints, promoting elimination of the "tolerant" cells, being in fact radio-sensitizers. These two contrasting pathways are mediated by different activities of CNPs: indeed Sm-doped CNPs, which lack the Ce3+/Ce4+ redox switch and the correlated antioxidant action, fail to decrease radiation-induced superoxide formation, as expected, but surprisingly maintain the radio-sensitizing ability and the dramatic decrease of mutagenesis. The latter is thus attributable to elimination of damaged cells rather than decreased oxidative damage. This highlights a novel redox-independent activity of CNPs, allowing selectively eliminating heavily damaged cells through non-toxic mechanisms, rather reactivating endogenous anticancer pathways in transformed cells. PMID- 30459606 TI - Astilbin Inhibits High Glucose-Induced Inflammation and Extracellular Matrix Accumulation by Suppressing the TLR4/MyD88/NF-kappaB Pathway in Rat Glomerular Mesangial Cells. AB - Diabetic nephropathy (DN) is characterized by inflammatory responses and extracellular matrix (ECM) accumulation. Astilbin is an active natural compound and possesses anti-inflammatory activity. The aim of this study was to evaluate the anti-inflammatory effect of astilbin on high glucose (HG)-induced glomerular mesangial cells and the potential mechanisms. The results showed that HG induced cell proliferation of HBZY-1 cells in a time-dependent manner, and astilbin inhibited HG-induced cell proliferation. The expression and secretion of inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), and ECM components, including collagen IV (Col IV) and fibronectin (FN), were induced by HG. Moreover, TGF-beta1 and CTGF were also induced by HG. The induction by HG on inflammatory response and ECM accumulation was inhibited after astilbin treatment. Astilbin treatment also attenuated HG induced decrease in expression of matrix metalloproteinase (MMP)-2 and MMP-9. The TLR4/MyD88/NF-kappaB pathway was activated by HG, and the inhibitor of TLR4 exhibited the same effect to astilbin on reversing the induction of HG. TLR4 overexpression attenuated the effect of astilbin on HG-induced inflammatory cytokine production and ECM accumulation. The results suggested that astilbin attenuated inflammation and ECM accumulation in HG-induced rat glomerular mesangial cells via inhibiting the TLR4/MyD88/NF-kappaB pathway. This work provided evidence that astilbin can be considered as a potential candidate for DN therapy. PMID- 30459605 TI - Potentiation of Glutamatergic Synaptic Transmission Onto Dorsal Raphe Serotonergic Neurons in the Valproic Acid Model of Autism. AB - Autism spectrum disorder (ASD) is characterized by social and communicative impairments and increased repetitive behaviors. These symptoms are often comorbid with increased anxiety. Prenatal exposure to valproic acid (VPA), an anti-seizure and mood stabilizer medication, is a major environmental risk factor of ASD. Given the important role of the serotonergic (5-HT) system in anxiety, we examined the impact of prenatal VPA exposure on the function of dorsal raphe nucleus (DRn) 5-HT neurons. We found that male rats prenatally exposed to VPA exhibited increased anxiety-like behaviors revealed by a decreased time spent on the open arms of the elevated plus maze. Prenatal VPA exposed rats also exhibited a stereotypic behavior as indicated by excessive self-grooming in a novel environment. These behavioral phenotypes were associated with increased electrical activity of putative DRn 5-HT neurons recorded in vitro. Examination of underlying mechanisms revealed that prenatal VPA exposure increased excitation/inhibition ratio in synapses onto these neurons. The effect was mainly mediated by enhanced glutamate but not GABA release. We found reduced paired pulse ratio (PPR) of evoked excitatory postsynaptic currents (EPSCs) and increased frequency but not amplitude of miniature EPSCs in VPA exposed rats. On the other hand, presynaptic GABA release did not change in VPA exposed rats, as the PPR of evoked inhibitory postsynaptic currents was unaltered. Furthermore, the spike-timing-dependent long-term potentiation at the glutamatergic synapses was occluded, indicating glutamatergic synaptic transmission is maximized. Lastly, VPA exposure did not alter the intrinsic membrane properties of DRn 5-HT neurons. Taken together, these results indicate that prenatal VPA exposure profoundly enhances glutamatergic synaptic transmission in the DRn and increases spontaneous firing in DRn 5-HT neurons, which could lead to increased serotonergic tone and underlie the increased anxiety and stereotypy after prenatal VPA exposure. PMID- 30459607 TI - Zebrafish Larvae Are a Suitable Model to Investigate the Metabolic Phenotype of Drug-Induced Renal Tubular Injury. AB - Prevention and treatment of drug-induced renal injury (DIRI) rely on the availability of sensitive and specific biomarkers of early kidney injury and predictive animal models of human pathophysiology. This study aimed to evaluate the potential of zebrafish larvae as translational model in metabolic profiling of DIRI. Zebrafish larvae were exposed to the lethal concentration for 10% of the larvae (LC10) or 1/2 LC10 of gentamicin, paracetamol and tenofovir as tenofovir disoproxil fumarate (TDF) and tenofovir (TFV). Metabolites were extracted from whole larvae and analyzed by liquid chromatography-mass spectrometry. Principal component analysis showed that drug exposition to the LC10 of paracetamol, TFV, and TDF was the main source of the variance of the data. To identify the metabolites responsible for the toxic effects of the drugs, partial least squares discriminant analyses were built between the LC10 and 1/2 LC10 for each drug. Features with variable importance in projection> 1.0 were selected and Venn diagrams were built to differentiate between the common and drug specific metabolites of DIRI. Creatine, tyrosine, glutamine, guanosine, hypoxanthine were identified as common metabolites, adenosine and tryptophan as paracetamol specific and xanthine and oxidized glutathione as tenofovir-specific. Those metabolic changes can be associated with alterations in energy metabolism, xenobiotic detoxification and protein catabolism, all described in the human pathophysiology of DIRI. Thus, zebrafish proved to be a suitable model to characterize the metabolic changes associated with DIRI. This information can be useful to early diagnose DIRI and to improve our knowledge on the mechanisms of DIRI. PMID- 30459608 TI - Comparison of Long-Term Clinical Implications of Beta-Blockade in Patients With Obstructive Airway Diseases Exposed to Beta-Blockers With Different beta1 Adrenoreceptor Selectivity: An Italian Population-Based Cohort Study. AB - Rationale: Long-term clinical implications of beta-blockade in obstructive airway diseases remains controversial. We investigated if within the first 5 years of treatment patients with heart failure and obstructive airway diseases using non beta1-adrenoreceptor selective beta-blockers have an increased risk of being hospitalized for all-causes, heart failure, and chronic obstructive pulmonary disease (COPD) when compared to patient using selective beta-blockers. Methods: Carvedilol users were propensity matched 1:1 for co-treatments, age, gender, and year of inclusion in the cohort with metoprolol/bisoprolol/nebivolol users. Cox proportional hazard regression model was used to compare all causes, COPD, and heart failure hospitalization or the beta-blocker discontinuation between cohorts. For statistically significant associations, we computed the rate difference and the attributable risk. Results: Overall, 11,844 patients out of the 51,214 (23.1%) were exposed to carvedilol and 39,370 (76.9%) to metoprolol/bisoprolol/nebivolol. Carvedilol users had a higher hazard for heart failure hospitalization (HR 1.29; 95% Confidence Interval [CI] 1.18-1.40) with 106 (95%CI 76-134; p-value < 0.001) additional cases of heart failure hospitalization per 10000 person-years if compared to metoprolol/bisoprolol/nebivolol users. In all, 26.8% (95%CI 22.5-30.9%; p-value < 0.001) of heart failure hospitalizations in the study population could be attributed to being exposed to carvedilol. Carvedilol users had a higher hazard (HR 1.06; 95%CI 1.02-1.10) of discontinuing the pharmacological treatment with 131 (95%CI 62-201; p-value < 0.001) additional cases of beta-blocker discontinuation per 10000 person-years metoprolol/bisoprolol/nebivolol users. In all, 6.5% (95%CI 3.9-9.0%; p-value < 0.001) of beta-blocker discontinuation could be attributed to being exposed to carvedilol. Conclusion: On long-term follow-up period, carvedilol was associated with a higher risk of heart failure hospitalization and discontinuation if compared to metoprolol/bisoprolol/nebivolol users among patients with heart failure and obstructive airway diseases. PMID- 30459609 TI - Pravastatin Attenuates Acute Radiation-Induced Enteropathy and Improves Epithelial Cell Function. AB - Background and Aim: Radiation-induced enteropathy is frequently observed after radiation therapy for abdominal and pelvic cancer or occurs secondary to accidental radiation exposure. The acute effects of irradiation on the intestine might be attributed to inhibition of mitosis in the crypts, as the loss of proliferative functions impairs development of the small intestinal epithelium and its barrier function. Especially, oxidative damage to intestinal epithelial cells is a key event in the initiation and progression of radiation-induced enteropathy. Pravastatin is widely used clinically to lower serum cholesterol levels and has been reported to have anti-inflammatory effects on endothelial cells. Here, we investigated the therapeutic effects of pravastatin on damaged epithelial cells after radiation-induced enteritis using in vitro and in vivo systems. Materials and Methods: To evaluate the effects of pravastatin on intestinal epithelial cells, we analyzed proliferation and senescence, oxidative damage, and inflammatory cytokine expression in an irradiated human intestinal epithelial cell line (InEpC). In addition, to investigate the therapeutic effects of pravastatin in mice, we performed histological analysis, bacterial translocation assays, and intestinal permeability assays, and also assessed inflammatory cytokine expression, using a radiation-induced enteropathy model. Results: Histological damage such as shortening of villi length and impaired intestinal crypt function was observed in whole abdominal-irradiated mice. However, damage was attenuated in pravastatin-treated animals, in which normalization of intestinal epithelial cell differentiation was also observed. Using in vitro and in vivo systems, we also showed that pravastatin improves the proliferative properties of intestinal epithelial cells and decreases radiation induced oxidative damage to the intestine. In addition, pravastatin inhibited levels of epithelial-derived inflammatory cytokines including IL-6, IL-1beta, and TNF-alpha in irradiated InEpC cells. We also determined that pravastatin could rescue intestinal barrier dysfunction via anti-inflammatory effects using the mouse model. Conclusion: Pravastatin has a therapeutic effect on intestinal lesions and attenuates radiation-induced epithelial damage by suppressing oxidative stress and the inflammatory response. PMID- 30459610 TI - Warfarin and the Risk of Death, Stroke, and Major Bleeding in Patients With Atrial Fibrillation Receiving Hemodialysis: A Systematic Review and Meta Analysis. AB - Background: Up to date, the efficacy and safety of warfarin treatment in atrial fibrillation patients receiving hemodialysis remain controversial. So we performed this meta-analysis to try to offer recommendations regarding warfarin management in this population. Methods: We searched Pubmed, Embase, and Cochrane library and reviewed relevant reference lists from 1980 to March 2018. Studies were included if they described the risks of mortality, stroke, and bleeding events with or without warfarin in atrial fibrillation patients receiving hemodialysis. Results: Overall, the use of warfarin was not associated with mortality (OR = 0.95, 95%CI = 0.89-1.02), stroke (OR = 1.06, 95% CI = 0.87-1.30) and ischemic stroke (OR = 0.85, 95% CI = 0.68-1.05), but its use could increase the risks of hemorrhagic stroke (OR = 1.34, 95% CI = 1.13-1.59) and major bleeding (OR = 1.24, 95% CI = 1.14, 1.35). In subgroup analyses, when analyses were mainly restricted to atrial fibrillation patients who were undergoing hemodialysis and taking other anticoagulation agents, warfarin therapy didn't reduce the risks for mortality (OR = 0.98, 95% CI = 0.68-1.42) and ischemic stroke (OR = 1.03, 95% CI = 0.89-1.19), but significantly increased the risks of stroke (OR:1.14, 95% CI = 1.01-1.29) and bleeding events such as hemorrhagic stroke (OR = 1.42, 95% CI = 1.14-1.77) and major bleeding (OR = 1.24, 95% CI = 1.14-1.35). While in patients who didn't take other anticoagulation agents or aspirin, warfarin use was not associated with all-cause mortality (OR = 0.90, 95% CI = 0.78-1.04), or any stroke (OR = 1.00, 95% CI = 0.71-1.40). Its use was associated with significantly decreased risk of ischemic stroke (OR = 0.71, 95% CI = 0.60-0.85), but not associated with hemorrhagic stroke (OR = 1.45, 95% CI = 0.83-2.55). Besides, another subgroup analysis showed that warfarin therapy didn't exert a protective role in patients with normal serum lipid levels (OR = 1.04, 95% CI = 0.85-1.26), but seemed to decrease the risk of ischemic stroke in patients with hyperlipidemia (OR = 0.38, 95% CI = 0.11-1.29). Conclusion: Our results suggested that it was necessary to prescribe warfarin for the prevention of ischemic events in hemodialysis patients with atrial fibrillation, but if these patients were already prescribed with other anticoagulants for the treatment of other co-existing diseases, then warfarin was not recommended. PMID- 30459611 TI - Extracellular Neuroleukin Enhances Neuroleukin Secretion From Astrocytes and Promotes Axonal Growth in vitro and in vivo. AB - Under pathological conditions in the central nervous system (CNS), including spinal cord injury, astrocytes show detrimental effects against neurons. It is also known that astrocytes sometimes exert beneficial effects, such as neuroprotection and secretion of axonal growth factors. If beneficial effects of astrocytes after injury could be induced, dysfunction of the injured CNS may improve. However, a way of promoting beneficial functions in astrocytes has not been elucidated. In the current study, we focused on neuroleukin (NLK), which is known to have axonal growth activities in neurons. Although NLK is secreted from astrocytes, the function of NLK in astrocytes is poorly understood. We aimed to clarify the mechanism of NLK secretion in astrocytes and the functional significance of secreted NLK from astrocytes. Stimulation of cultured astrocytes with recombinant NLK significantly elevated the secretion of NLK from astrocytes. Furthermore, astrocyte conditioned medium treated with NLK increased axonal density in cultured cortical neurons. Recombinant NLK itself directly increased axonal density in cultured neurons. These results indicated that NLK secreted from astrocytes acted as an axonal growth factor and that secretion was stimulated by extracellular NLK. To elucidate a direct binding molecule of NLK on astrocytes, drug affinity responsive target stability (DARTS) analysis was performed. A 78 kDa glucose regulated protein (GRP78) was identified as a receptor for NLK, which was related to the secretion of NLK from astrocytes. When NLK was injected into the lesion site of spinal cord injured mice, axonal density in the injured region was significantly increased and hindlimb motor function improved. These results suggested that NLK-GRP78 signalling was important for the beneficial effects of astrocytes. This study strengthens the potential of astrocytes for use as therapeutic targets in CNS traumatic injury. PMID- 30459612 TI - Maintenance Chemotherapy With Chinese Herb Medicine Formulas vs. With Placebo in Patients With Advanced Non-small Cell Lung Cancer After First-Line Chemotherapy: A Multicenter, Randomized, Double-Blind Trial. AB - Background: Chinese Herb Medicine Formulas (CHMF) was reported to improve the quality of life (QoL) in advanced NSCLC patients. The present study was designed to investigate whether maintenance chemotherapy plus CHMF in patients would improve QoL and progression-free survival (PFS). Methods: Seventy-one patients were enrolled from 8 medical centers in China, and were randomly assigned to a maintenance chemotherapy plus CHMF group (n = 35) or a maintenance chemotherapy plus placebo group (n = 36). The outcome measures included PFS, Karnofsky performance status (KPS) scores, QoL (assessed with the lung cancer symptom scale (LCSS) questionnaire), and adverse events (AEs). Results: Patients in the CHMF group showed significant improvements in median PFS (HR = 0.55, 95% CI 0.28-0.88, P = 0.019), KPS scores (P = 0.047), fatigue (cycle [C] 3: P = 0.03), interference with daily activities (C3: P = 0.04) and dyspnea (C2: P = 0.03) compared with patients in the placebo group. Compared with the placebo group, the incidence of AEs decreased in the CHMF group, including loss of appetite (C2: P = 0.011, C4: P = 0.004) and dry mouth (C4: P = 0.011). Conclusion: The essential finding of our study is that maintenance chemotherapy combined with CHMF may prolong PFS, relieve symptoms, improve QoL and alleviate the side effects. PMID- 30459613 TI - Aqueous Extract of Mori Folium Exerts Bone Protective Effect Through Regulation of Calcium and Redox Homeostasis via PTH/VDR/CaBP and AGEs/RAGE/Nox4/NF-kappaB Signaling in Diabetic Rats. AB - Purpose: The present study is aimed to explore whether the aqueous extract of Mori Folium (MF) exhibits bone protective effect by regulating calcium and redox homeostasis in diabetic rats, and to identify the signaling pathways involved in this process. Methods: Diabetic rats were established using high-sugar and high fat diet and streptozotocin (STZ) (30 mg/kg for 3 consecutive days). The serum levels of osteocalcin (OC), insulin-like growth factor-1 (IGF-1), tartrate resistant acid phosphatase (TRAP), phosphorus (P), calcium (Ca), 1,25 dihydroxyvitamin D3 [1,25(OH)2D3], parathormone (PTH), advanced glycation end products (AGEs), superoxide dismutase (SOD), and malondialdehyde (MDA), total antioxidant capacity (TAC), 8-hydroxy-2'-deoxyguanosine (8-OH-dG), and interleukin 6 (IL-6) were determined by ELISA or biochemical assays. Histopathological alterations in the femurs were evaluated by the stainings of hematoxylin-eosin (H&E) and alizarin red S. In addition, femoral strength was detected by a three-point bending assay, bone microstructure was detected with micro-computer tomography. Bone material properties were examined by Fourier transform infrared spectroscopy. Furthermore, the expressions of IGF-1, runt related transcription factor 2 (Runx2), osteoprotegerin (OPG), receptor activator of nuclear factor kappa-B ligand (RANKL), cathepsin K, AGEs, receptor of advanced glycation end products (RAGE), NADPH oxidase 4 (Nox4), and nuclear factor kappa-B (NF-kappaB) in the femurs and tibias, and the alterations in the levels of calcium-binding protein-28k (CaBP-28k), transient receptor potential V6 (TRPV6), and vitamin D receptor (VDR) in the kidneys and duodenums were determined by western blot and immunohistochemical analysis. Results: Treatment of diabetic rats with MF aqueous extract induces an increase in the levels of OC and IGF-1 as well as a decrease in TRAP level in serum. MF treatment also upregulates the expression of OPG, downregulates the expressions of AGEs, RAGE, Nox4, NF-kappaB, and RANKL, which leads to improve bone microstructure and strength exhibited by an increase in cortical area ratio, cortical thickness, and trabecular area ratio as well as ultimate load, elastic modulus, and bending stress in the femurs and tibias of diabetic rats. In addition, MF aqueous extract preserves bone material properties by decreasing the ratio of fatty acid/collagen and increasing the ratio of mineral/matrix in the femurs of diabetic rats. Moreover, MF treatment increases the levels of P, Ca, and 1,25(OH)2D3, and decreases the level of PTH in the serum, as well as upregulates the expressions of TRPV6 and VDR in the duodenums and CaBP-28k in the kidneys of diabetic rats. Additionally, MF has ability of rebuilding redox homeostasis and eliminating inflammatory stress by increasing the levels of SOD and TAC as well as decreasing the levels of IL-6, AGEs, MDA, and 8-OH-dG. Conclusions: MF treatment may improve bone quality through maintenance of calcium homeostasis via regulating the PTH/VDR/CaBP signaling, and elimination of oxidative stress via regulating the AGEs/RAGE/Nox4/NF-kappaB signaling. These results may suggest the potential of MF in preventing the development of diabetic osteoporosis. PMID- 30459614 TI - Xiaoaiping Induces Developmental Toxicity in Zebrafish Embryos Through Activation of ER Stress, Apoptosis and the Wnt Pathway. AB - The aim of the study was to determine the developmental toxicity of the traditional Chinese medicine Xiaoaiping (XAP) and to investigate its underlying mechanism of action. Zebrafish embryos were incubated with 0.4, 0.8, 1.2, and 1.6 mg/mL XAP. Endpoints such as mortality, hatching rate, malformation, body length, morphology score, swimming behavior, histological changes, reactive oxygen species (ROS) production, total superoxide dismutase (T-SOD) activity, and the mRNA expression of genes related to oxidative stress, endoplasmic reticulum (ER) stress, apoptosis, and the Wnt pathway were evaluated. Our results demonstrated that XAP exposure increased mortality and malformation and reduced the hatching rate. XAP resulted in severe malformation, including swim bladder deficiency, yolk retention, pericardial edema, and tail curvature. Histopathological analysis showed that XAP induced liver, heart and muscle injury. High doses (>=1.2 mg/mL) of XAP notably decreased the locomotor capacity of zebrafish. ROS generation was remarkably increased and T-SOD activity was decreased, confirming that oxidative stress was induced by XAP. The mRNA expression levels of ER stress-related genes (chop, hspa5, hsp90b1, and perk), apoptosis-related genes (caspase-3, bax, and p53) and wnt11 were significantly upregulated by XAP exposure. The expression levels of the oxidative stress-related genes (cat, sod1, and gstp2), Wnt pathway related genes (beta-catenin, wnt3a, and wnt8a) and bcl-2 initially increased and then decreased as the XAP exposure dose increased. In conclusion, we provide evidence for the first time that XAP can induce dose-related developmental toxicity, and ER stress, apoptosis and the Wnt pathway participate in the toxicity regulation. PMID- 30459616 TI - Is Resveratrol a Cancer Immunomodulatory Molecule? PMID- 30459617 TI - Predicting Off-Target Binding Profiles With Confidence Using Conformal Prediction. AB - Ligand-based models can be used in drug discovery to obtain an early indication of potential off-target interactions that could be linked to adverse effects. Another application is to combine such models into a panel, allowing to compare and search for compounds with similar profiles. Most contemporary methods and implementations however lack valid measures of confidence in their predictions, and only provide point predictions. We here describe a methodology that uses Conformal Prediction for predicting off-target interactions, with models trained on data from 31 targets in the ExCAPE-DB dataset selected for their utility in broad early hazard assessment. Chemicals were represented by the signature molecular descriptor and support vector machines were used as the underlying machine learning method. By using conformal prediction, the results from predictions come in the form of confidence p-values for each class. The full pre processing and model training process is openly available as scientific workflows on GitHub, rendering it fully reproducible. We illustrate the usefulness of the developed methodology on a set of compounds extracted from DrugBank. The resulting models are published online and are available via a graphical web interface and an OpenAPI interface for programmatic access. PMID- 30459618 TI - Metabolism and Bioactivation of Corynoline With Characterization of the Glutathione/Cysteine Conjugate and Evaluation of Its Hepatotoxicity in Mice. AB - Corynoline (CRL), an isoquinoline alkaloid, is the major constituent derived from Corydalis bungeana Herba, which is a well-known Chinese herbal medicine widely used in many prescriptions. The purpose of this study was to comprehensively investigate the metabolism and bioactivation of CRL, and identify the CYP450 isoforms involved in reactive ortho-benzoquinone metabolites formation and evaluate its hepatotoxicity in mice. Here, high resolution and triple quadrupole mass spectrometry were used for studying the metabolism of CRL. Three metabolites (M1-M3) and four glutathione conjugates (M4-M7) of CRL ortho-benzoquinone reactive metabolite were found in vitro using rat and human liver microsomes supplemented with NADPH and glutathione. Four cysteine conjugates (M8-M11) were trapped in mice besides M1-M7. Using human recombinant CYP450 enzymes and chemical inhibitor method, we found that CYP3A4, CYP2C19, CYP2C9, and CYP2D6 were mainly involved in the bioactivation of CRL. Furthermore, CRL had no obvious hepatotoxicity and did not induce acute liver injuries in the experimental dosage (125-500 mg/kg) used in this study. However, phenomena of abnormal behaviors and low body temperature appeared in mice after drug administration, and three of them were dead. Tissue distribution study of CRL in mice showed that the main target organ of CRL was liver, then kidney, heart, and brain. CRL could traverse the blood-brain barrier, and have relative high concentration in brain. So, we surmise that toxicity effect of CRL on other organs may have occurred, and more attention should be paid on the traditional Chinese medicine contained CRL in clinic. PMID- 30459615 TI - Natural Product Interventions for Chemotherapy and Radiotherapy-Induced Side Effects. AB - Cancer is the second leading cause of death in the world. Chemotherapy and radiotherapy are the common cancer treatments. However, the development of adverse effects resulting from chemotherapy and radiotherapy hinders the clinical use, and negatively reduces the quality of life in cancer patients. Natural products including crude extracts, bioactive components-enriched fractions and pure compounds prepared from herbs as well as herbal formulas have been proved to prevent and treat cancer. Of significant interest, some natural products can reduce chemotherapy and radiotherapy-induced oral mucositis, gastrointestinal toxicity, hepatotoxicity, nephrotoxicity, hematopoietic system injury, cardiotoxicity, and neurotoxicity. This review focuses in detail on the effectiveness of these natural products, and describes the possible mechanisms of the actions in reducing chemotherapy and radiotherapy-induced side effects. Recent advances in the efficacy of natural dietary supplements to counteract these side effects are highlighted. In addition, we draw particular attention to gut microbiotan in the context of prebiotic potential of natural products for the protection against cancer therapy-induced toxicities. We conclude that some natural products are potential therapeutic perspective for the prevention and treatment of chemotherapy and radiotherapy-induced side effects. Further studies are required to validate the efficacy of natural products in cancer patients, and elucidate potential underlying mechanisms. PMID- 30459619 TI - Similar Gastro-Intestinal Exposure to Florfenicol After Oral or Intramuscular Administration in Pigs, Leading to Resistance Selection in Commensal Escherichia coli. AB - Florfenicol, which is licensed for veterinary use only, proves to be a potent antimicrobial for treatment of respiratory disease. However, the subsequent exposure of the gut microbiota to florfenicol is not well described. Hence, the effect of various administration protocols on both plasma and gastro-intestinal florfenicol concentrations in pigs was evaluated. In field situations were simulated by application of different administration routes and dosages [single oral bolus at 10 or 5 mg/kg body weight (BW), medicated feed at 10 or 5 mg/kg BW and intramuscular injections at 15 or 30 mg/kg BW]. After intramuscular administration of 30 mg florfenicol/kg BW, gastro-intestinal concentrations of florfenicol, quantified 10 h after the last administration, were significantly elevated in comparison with the other treatment groups and ranging between 31.5 and 285.8 MUg/g over the different gut segments. For the other treatment groups, the influence of dose and administration route was not significantly different. Bacteriological analysis of the fecal samples from the animals at the start of the experiment, demonstrated the presence of both florfenicol susceptible (with minimal inhibitory concentration (MIC) values of 2-16 MUg/mL) and florfenicol resistant (MIC >= 256 MUg/mL) Escherichia coli isolates in all treatment groups. Following, at 10 h after the last administration the susceptible E. coli population was eradicated in all treatment groups due to the high intestinal florfenicol concentrations measured. Moreover, selection of the resistant E. coli strains during treatment occurred in all groups. This is likely related to the fact that the different treatment strategies led to high gastro-intestinal concentrations albeit not reaching the high magnitude of MIC values associated with florfenicol resistance (>=256 MUg/mL). Conclusively, in our experimental setup the administration route and dose alterations studied, had no influence on monitored florfenicol resistance selection in E. coli from the microbiota. PMID- 30459620 TI - Metformin Modulates High Glucose-Incubated Human Umbilical Vein Endothelial Cells Proliferation and Apoptosis Through AMPK/CREB/BDNF Pathway. AB - Cardiovascular disease (CVD) is a leading cause of mortality and morbidity among patients with diabetes. Endothelial dysfunction is an early physiological event in CVD. Metformin, a common oral antihyperglycemic agent, has been demonstrated to directly affect endothelial cell function. Brain-derived neurotrophic factor (BDNF), originally discovered in the brain as a neurotrophin, has also been reported to play a protective role in the cardiovascular system. In our study, we demonstrated that high glucose (HG) reduced cell proliferation and induced cell apoptosis via changes in BDNF expression and that metformin reversed the effects of HG injury by upregulating BDNF expression. Furthermore, we found that cyclic AMP response element binding (CREB) phosphorylation was reduced in HG-treated human umbilical vein endothelial cells (HUVECs), and this effect was reversed by the metformin treatment. However, the metformin effect on BDNF levels in HG incubated HUVECs was blocked by a CREB inhibitor, which indicated that BDNF expression is regulated by metformin through CREB activation. In addition, we found that adenosine monophosphate-activated protein kinase (AMPK) activation is involved in CREB/BDNF regulation in HG-incubated HUVECs treated with metformin and that an AMPK inhibitor impaired the protective effects of metformin on HG treated HUVECs. In conclusion, this study demonstrated that metformin affects cell proliferation and apoptosis via the AMPK/CREB/BDNF pathway in HG-incubated HUVECs. PMID- 30459621 TI - Painful Understanding of VEGF. PMID- 30459622 TI - Effect of the BH3 Mimetic Polyphenol (-)-Gossypol (AT-101) on the in vitro and in vivo Growth of Malignant Mesothelioma. AB - Malignant mesothelioma (MM) is a primary tumor arising from mesothelial cells. The survival of MM patients following traditional chemotherapy is poor, thus innovative treatments for MM are needed. (-)-gossypol (AT-101) is a BH3 mimetic compound which possesses anti-tumoral activity by targeting multiple signaling transduction pathways. Several clinical trials employing AT-101 have been performed and some of them are still ongoing. Accordingly, we investigated the in vitro effects of AT-101 on cell proliferation, cell cycle regulation, pro survival signaling pathways, apoptosis and autophagy of human (MM-B1, H-Meso-1, and MM-F1) and mouse (#40a) MM cell lines. In addition, we explored the in vivo anti-tumor activities of AT-101 in a mouse model, in which the transplantation of MM cells induces ascites in the peritoneal space. AT-101 inhibited in vitro MM cells survival in a dose- and time-dependent manner and triggered autophagy, but the process was then blocked and was coincident with apoptosis activation. To confirm the effect of AT-101 in inducing the apoptosis of MM cells, MM cells were simultaneously treated with AT-101 and with the caspase inhibitor, Z-VAD-FMK. Z VAD-FMK was able to significantly reduce the number of cells in the subG1 phase compared to the treatment with AT-101 alone. This result corroborates the induction of cell death by apoptosis following treatment with AT-101. Indeed, Western blotting results showed that AT-101 increases Bax/Bcl-2 ratio, modulates p53 expression, activates caspase 9 and the cleavage of PARP-1. In addition, the treatment with AT-101 was able to: (a) decrease the ErbB2 protein expression; (b) increase the EGFR protein expression; (c) affect the phosphorylation of ERK1/2, p38 and AKT; (d) stimulate JNK1/2 and c-jun phosphorylation. Our in vivo results showed that the intraperitoneal administration of AT-101 increased the median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells and reduced the risk of developing tumors. Our findings may have important implications for the design of MM therapies by employing AT-101 as an anticancer agent in combination with standard therapies. PMID- 30459623 TI - Identification of the Toxicity Pathways Associated With Thioacetamide-Induced Injuries in Rat Liver and Kidney. AB - Ingestion or exposure to chemicals poses a serious health risk. Early detection of cellular changes induced by such events is vital to identify appropriate countermeasures to prevent organ damage. We hypothesize that chemically induced organ injuries are uniquely associated with a set (module) of genes exhibiting significant changes in expression. We have previously identified gene modules specifically associated with organ injuries by analyzing gene expression levels in liver and kidney tissue from rats exposed to diverse chemical insults. Here, we assess and validate our injury-associated gene modules by analyzing gene expression data in liver, kidney, and heart tissues obtained from Sprague-Dawley rats exposed to thioacetamide, a known liver toxicant that promotes fibrosis. The rats were injected intraperitoneally with a low (25 mg/kg) or high (100 mg/kg) dose of thioacetamide for 8 or 24 h, and definite organ injury was diagnosed by histopathology. Injury-associated gene modules indicated organ injury specificity, with the liver being most affected by thioacetamide. The most activated liver gene modules were those associated with inflammatory cell infiltration and fibrosis. Previous studies on thioacetamide toxicity and our histological analyses supported these results, signifying the potential of gene expression data to identify organ injuries. PMID- 30459624 TI - Targeting Anion Exchange of Osteoclast, a New Strategy for Preventing Wear Particles Induced- Osteolysis. AB - Joint replacement is essential for the treatment of serious joint disease. However, prosthetic failure remains an important clinical issue, with periprosthesis osteolysis (PO), caused by osteoclastic bone resorption induced by wear particles, being the leading cause of failure. Nuclear factor of activated T cells c1 (NFATc1) appears to play an important role in wear particle-induced osteoclastogenesis, with bicarbonate/chloride exchanger, solute carrier family 4, anion exchanger, member 2, (SLC4A2) being upregulated during osteoclastogenesis in an NFATc1-dependent manner. Anion exchange mediated by SLC4A2 in osteoclasts could affect the bone resorption activity by regulating pHi. This study investigated the role and mechanism of SLC4A2 in wear particle-induced osteoclast differentiation and function in vitro. The use of 4, 4'-diisothiocyano-2,2' stilbenedisulfonic acid (DIDS), an anion exchange inhibitor, suppressed wear particle-induced PO in vivo. Furthermore, controlled release of DIDS from chitosan microspheres can strengthen the PO therapy effect. Therefore, anion exchange mediated by osteoclastic SLC4A2 may be a potential therapeutic target for the treatment of aseptic loosening of artificial joints. PMID- 30459625 TI - Activating Cannabinoid Receptor 2 Protects Against Diabetic Cardiomyopathy Through Autophagy Induction. AB - Cannabinoid receptor 2 (CB2) has been reported to produce a cardio-protective effect in cardiovascular diseases such as myocardial infarction. Here in this study, we investigated the role of CB2 in diabetic cardiomyopathy (DCM) and its underlying mechanisms. HU308 was used for the selective activation of CB2. Bafilomycin A1 was used for the blockade of autophagy and compound C was used to inhibit AMPK signaling. An streptozotocin (STZ)-induced mice model and high glucose (HG)-challenged cardiomyocytes were applied for study. Cardiac function was detected by echocardiography and Western blot for the detection of autophagy related and its signaling-related proteins. Transmission electron microscopy was used for the analysis of autophagosome number. Cell viability was detected by Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) release assays. We found that activating CB2 by HU308 improved cardiac function in DCM as well as cell viability in cardiomyocytes under HG challenge, while the administration of bafilomycin A1 attenuated the protective effects. HU308 enhanced the level of autophagy in the heart tissues from DCM mice as well as cardiomyocytes under HG challenge. HU308 triggered the AMPK-mTOR-p70S6K signaling pathway, while the administration of compound C attenuated the cardio-protective effect of HU308 in cardiomyocytes under HG challenge. In conclusion, we initially demonstrated that activating CB2 produced a cardio-protective effect in DCM as well as cardiomyocytes under HG challenge through inducing the AMPK-mTOR-p70S6K signaling mediated autophagy. PMID- 30459626 TI - Phospholipase Cgamma2 Signaling Cascade Contribute to the Antiplatelet Effect of Notoginsenoside Fc. AB - Scope: Bleeding, the main drawback of clinically used chemical anti-thrombotic drug is resulted from the unidirectional suppression of platelet activity. Therefore, dual-directional regulatory effect on platelet is the main preponderance of Panax notoginseng over these drugs. The dual-directional regulatory effect should be ascribed to the resourceful Panax notoginseng saponins (PNS). Clarifying the mechanism of main PNS in both inhibiting and promoting platelet aggregation will give a full outlook for the dual-directional regulatory effect. The present study is aimed at explaining the mechanism of Notoginsenoside Fc (Fc), a main PNS, in inhibiting platelet aggregation. Methods: In the in vitro study, after incubating platelets with Fc and m-3M3FBS, platelet aggregation was triggered by thrombin, collagen or ADP. Platelet aggregation was measured by aggregometer. Phospholipase Cgamma2 (PLCgamma2) and protein kinase C (PKC) activities were studied by western blotting. Diacylglycerol (DAG), thromboxane B2 (TXB2) and 1,4,5-inositol trisphosphate (IP3) concentrations were measured by corresponding ELISA kits. Calcium concentrations ([Ca2+]) were estimated through the fluorescence intensity emitted from Fluo-4. In the in vivo study, thrombus model was induced by FeCl3. The effect of Fc on thrombosis was evaluated by measurement of protein content and observation of injured blood vessel. Results: thrombin, collagen and ADP induced platelet aggregation were all suppressed by incubating platelets with Fc. Platelet PLCgamma2 and subsequent DAG PKC-TXA2 and IP3 were down-regulated by Fc as well. However, the basal [Ca2+] in platelet was not altered by Fc. Nevertheless, thrombin triggered activation of PLCgamma2 and subsequent DAG-PKC-TXA2 and IP3-[Ca2+] were all abolished by Fc. Fc also attenuated platelet aggregation and PLCgamma2 signaling activation induced by PLC activator, m-3M3FBS. In the in vivo study, FeCl3 induced thrombosis in rat femoral artery was significantly alleviated by administration of Fc. Conclusion: The results above suggested the antiplatelet and antithrombotic effects of Fc are carried out through oppression of PLCgamma2 and subsequent DAG-PKC-TXA2 and IP3 [Ca2+]. The present study provided theoretical support for new anti-thrombotic drug exploitation by Panax notoginseng. PMID- 30459627 TI - The SMAC Mimetic APG-1387 Sensitizes Immune-Mediated Cell Apoptosis in Hepatocellular Carcinoma. AB - The inhibitor of apoptosis protein (IAP) genes are frequently overexpressed in malignancies. Second mitochondria-derived activator of caspase (SMAC) mimetics, which target IAPs, have potential to trigger cancer cell death and sensitize tumor cells to cytotoxic therapy. The aim of this study was to investigate the anti-tumor potential of a novel bivalent SMAC mimetic, APG-1387, in hepatocellular carcinoma (HCC). The mRNA and protein expressions of IAPs, including cellular IAPs (cIAP1 and cIAP2) and X chromosome-linked IAP (XIAP), were increased in HCC tumors compared with normal liver tissue. APG-1387 treatment alone significantly reduced the protein levels of IAPs, but had only a modest effect on the viability and apoptosis of HCC cells in vitro. However, APG 1387 in combination with tumor necrosis factor-alpha (TNF-alpha) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) significantly reduced cell viability and proliferation, and induced apoptosis in HepG2 cells, as well as in HCCLM3 cells that harbors cancer stem cell-like properties. These synergistic killing effects were caspase-dependent and partially dependent on RIPK1 kinase activity. Furthermore, APG-1387 also promoted the killing effect of Natural Killer cells on HCC cells in vitro and the combination therapy significantly inhibited tumor growth by inducing cell apoptosis in xenograft mice model. In conclusion, our study clarified that APG-1387 could sensitize HCC cells to cytokines or immune cells mediated cell killing and implied that potential of SMAC mimetic based combination immunotherapy for HCC treatment. PMID- 30459628 TI - Radio-Frequency Safety Assessment of Stents in Blood Vessels During Magnetic Resonance Imaging. AB - Purpose: The purpose of this study was to investigate the need for high resolution detailed anatomical modeling to correctly estimate radio-frequency (RF) safety during magnetic resonance imaging (MRI). RF-induced heating near metallic implanted devices depends on the electric field tangential to the device (Etan ). Etan and specific absorption rate (SAR) were analyzed in blood vessels of an anatomical model to understand if a standard gel phantom accurately represents the potential heating in tissues due to passive vascular implants such as stents. Methods: A numerical model of an RF birdcage body coil and an anatomically realistic virtual patient with a native spatial resolution of 1 mm3 were used to simulate the in vivo electric field at 64 MHz (1.5 T MRI system). Maximum values of SAR inside the blood vessels were calculated and compared with peaks in a numerical model of the ASTM gel phantom to see if the results from the simplified and homogeneous gel phantom were comparable to the results from the anatomical model. Etan values were also calculated in selected stent trajectories inside blood vessels and compared with the ASTM result. Results: Peak SAR values in blood vessels were up to ten times higher than those found in the ASTM standard gel phantom. Peaks were found in clinically significant anatomical locations, where stents are implanted as per intended use. Furthermore, Etan results showed that volume-averaged SAR values might not be sufficient to assess RF safety. Conclusion: Computational modeling with a high-resolution anatomical model indicated higher values of the incident electric field compared to the standard testing approach. Further investigation will help develop a robust safety testing method which reflects clinically realistic conditions. PMID- 30459629 TI - Gene Expression Is Not Random: Scaling, Long-Range Cross-Dependence, and Fractal Characteristics of Gene Regulatory Networks. AB - Gene expression is a vital process through which cells react to the environment and express functional behavior. Understanding the dynamics of gene expression could prove crucial in unraveling the physical complexities involved in this process. Specifically, understanding the coherent complex structure of transcriptional dynamics is the goal of numerous computational studies aiming to study and finally control cellular processes. Here, we report the scaling properties of gene expression time series in Escherichia coli and Saccharomyces cerevisiae. Unlike previous studies, which report the fractal and long-range dependency of DNA structure, we investigate the individual gene expression dynamics as well as the cross-dependency between them in the context of gene regulatory network. Our results demonstrate that the gene expression time series display fractal and long-range dependence characteristics. In addition, the dynamics between genes and linked transcription factors in gene regulatory networks are also fractal and long-range cross-correlated. The cross-correlation exponents in gene regulatory networks are not unique. The distribution of the cross-correlation exponents of gene regulatory networks for several types of cells can be interpreted as a measure of the complexity of their functional behavior. PMID- 30459631 TI - Breathing Patterns Indicate Cost of Exercise During Diving and Response to Experimental Sound Exposures in Long-Finned Pilot Whales. AB - Air-breathing marine predators that target sub-surface prey have to balance the energetic benefit of foraging against the time, energetic and physiological costs of diving. Here we use on-animal data loggers to assess whether such trade-offs can be revealed by the breathing rates (BR) and timing of breaths in long-finned pilot whales (Globicephela melas). We used the period immediately following foraging dives in particular, for which respiratory behavior can be expected to be optimized for gas exchange. Breath times and fluke strokes were detected using onboard sensors (pressure, 3-axis acceleration) attached to animals using suction cups. The number and timing of breaths were quantified in non-linear mixed models that incorporated serial correlation and individual as a random effect. We found that pilot whales increased their BR in the 5-10 min period prior to, and immediately following, dives that exceeded 31 m depth. While pre-dive BRs did not vary with dive duration, the initial post-dive BR was linearly correlated with duration of >2 min dives, with BR then declining exponentially. Apparent net diving costs were 1.7 (SE 0.2) breaths per min of diving (post-dive number of breaths, above pre-dive breathing rate unrelated to dive recovery). Every fluke stroke was estimated to cost 0.086 breaths, which amounted to 80-90% average contribution of locomotion to the net diving costs. After accounting for fluke stroke rate, individuals in the small body size class took a greater number of breaths per diving minute. Individuals reduced their breathing rate (from the rate expected by diving behavior) by 13-16% during playbacks of killer whale sounds and their first exposure to 1-2 kHz naval sonar, indicating similar responses to interspecific competitor/predator and anthropogenic sounds. Although we cannot rule out individuals increasing their per-breath O2 uptake to match metabolic demand, our results suggest that behavioral responses to experimental sound exposures were not associated with increased metabolic rates in a stress response, but metabolic rates instead appear to decrease. Our results support the hypothesis that maximal performance leads to predictable (optimized) breathing patterns, which combined with further physiological measurements could improve proxies of field metabolic rates and per-stroke energy costs from animal-borne behavior data. PMID- 30459632 TI - Do Thirty-Second Post-activation Potentiation Exercises Improve the 50-m Freestyle Sprint Performance in Adolescent Swimmers? AB - Objectives: The purpose of the study was to investigate performance, biomechanical, physiological, and psychophysiological effects of a simple and easily organized post-activation potentiation (PAP) re-warm-up performed before a 50-m freestyle swimming sprint. Methods: Regional level male adolescent swimmers [age: 13.0 +/- 2.0 years; (min 11 years - max 15 years)] performed four trial conditions (three experimental, one control) on different days. The control trial involved a standardized 1200-m warm-up followed by 30 min of rest and a maximal 50-m freestyle swimming sprint. The experimental trials involved the same protocol but added a PAP component after a 20-min rest (10 min pre-50-m): The different PAP component involved the subjects in completing a 30-s maximal effort of: (1) push-ups (PU - upper body), (2) squats (SQ - lower body), and (3) burpees (BP - lower and upper body). Performance (time-trial), biomechanical (stroke length, stroke frequency), physiological (blood lactate concentrations, heart rate), and psychophysiological (ratings of perceived exertion) variables were collected. Results: The results demonstrated that the PAP protocols used in this investigation had no effect on swimming performance. Before the 50-m swimming sprint, the lactate values were significantly higher after the PU, BP, and SQ PAP loads compared to the control condition [P(CC-PU) = 0.02; P(CC-BP) = 0.01; P(CC SQ) = 0.04]. For Lactate values, a significant and large effect of experimental condition compared to control condition was found (p < 0.05, eta2 = 0.68). At 1 min after the 50-m time trial, significant differences were observed between the control condition and the different PAP loads [P(CC-PU) = 0.01; P(CC-BP) = 0.04; P(CC-SQ) = 0.01]. At 3 min after the 50-m sprint, significant differences were found between the control condition and the PU and SQ PAP loads [P(CC-PU) = 0.018; P(CC-SQ) = 0.008, respectively]. Additionally, a significant and large effect of experimental condition was found at 1 and 3 min after the 50-m swimming sprint (p < 0.05, eta2 (1 min) = 0.73; eta2 (3 min) = 0.59). There were medium sized but non-significant effects of interaction between the conditions, was illustrated for the mean HR values in response to the different conditions (p > 0.05; eta2 = 0.083). Conclusion: None of the three PAP protocols showed any significant improvement in performance, biomechanical, physiological, and psychophysiological variables before, during and after the 50-m swimming time trial. Further studies are warranted to investigate ways to improve swimming performance with simple body mass exercises performed in-between the end of pool warm-up and race start. PMID- 30459633 TI - Influence of Exercise Mode on Post-exercise Arterial Stiffness and Pressure Wave Measures in Healthy Adult Males. AB - Background: Exercise mode has been reported to be an important determinant of arterial stiffness and wave reflection changes following a brief bout of exercise with inconsistent results to date. This study examined the impact of exercise mode on arterial stiffness and pressure wave measures following acute aerobic exercise (AER), resistance exercise (RES), and a control (CON) condition with no exercise. Methods: In a randomized, cross-over, repeated measures design, 21 healthy adult males (26.7 +/- 7.2 years) undertook three experimental intervention sessions: AER (30-min cycle ergometry at 70-75% maximum heart rate), RES (3 * 10 repetitions of six upper and lower body exercises at 80-90% of 10 repetition maximum) and CON (30-min seated rest). Measures of arterial stiffness and pressure waves, such as carotid-femoral pulse wave velocity (cf-PWV), augmentation index (AIx), AIx corrected for heart rate of 75 (AIx75), and forward wave (Pf), backward wave (Pb) and reflection magnitude, were assessed at Rest and at 10-min intervals for 60 min after the intervention sessions. Comparisons between interventions and over time were assessed via repeated measures ANOVA and post-hoc Tukey's tests. Results: No significant differences in cf-PWV were noted between the three interventions at rest or post-intervention. However, RES led to significantly greater post-intervention AIx, AIx75, Pf, and Pb compared to AER and CON with AIx75 also remaining significantly elevated throughout the post intervention period. In contrast, AER resulted in a brief, significant elevation of AIx75 and no change in cf-PWV, Pf, Pb, and reflection magnitude. Conclusions: Exercise mode, specifically RES and AER, significantly influenced the time course of pressure wave reflection responses following a brief bout of exercise in healthy adult males. Distinct adjustments during exercise including changes in blood pressure and vasomotor tone may be key modulators of post-exercise arterial function. Identification of modal differences may assist in understanding the impact of exercise on cardiovascular function and the mechanisms by which exercise benefits vascular health. PMID- 30459634 TI - Molecular Ontogeny of First-Feeding European Eel Larvae. AB - Digestive system functionality of fish larvae relies on the onset of genetically pre-programmed and extrinsically influenced digestive functions. This study explored how algal supplementation (green-water) until 14 days post hatch (dph) and the ingestion of food [enriched rotifer (Brachionus plicatilis) paste] from 15 dph onward affects molecular maturation and functionality of European eel larval ingestion and digestion mechanisms. For this, we linked larval biometrics to expression of genes relating to appetite [ghrelin (ghrl), cholecystokinin (cck)], food intake [proopiomelanocortin (pomc)], digestion [trypsin (try), triglyceride lipase (tgl), amylase (amyl)], energy metabolism [ATP synthase F0 subunit 6 (atp6), cytochrome-c-oxidase 1 (cox1)], growth [insulin-like growth factor (igf1)] and thyroid metabolism [thyroid hormone receptors (thralphaA, thrbetaB)]. Additionally, we estimated larval nutritional status via nucleic acid analysis during transition from endogenous and throughout the exogenous feeding stage. Results showed increased expression of ghrl and cck on 12 dph, marking the beginning of the first-feeding window, but no benefit of larviculture in green water was observed. Moreover, expression of genes relating to protein (try) and lipid (tgl) hydrolysis revealed essential digestive processes occurring from 14 to 20 dph. On 16 dph, a molecular response to initiation of exogenous feeding was observed in the expression patterns of pomc, atp6, cox1, igf1, thralphaA and thrbetaB. Additionally, we detected increased DNA contents, which coincided with increased RNA contents and greater body area, reflecting growth in feeding compared to non-feeding larvae. Thus, the here applied nutritional regime facilitated a short-term benefit, where feeding larvae were able to sustain growth and better condition than their non-feeding conspecifics. However, RNA:DNA ratios decreased from 12 dph onward, indicating a generally low larval nutritional condition, probably leading to the point-of-no-return and subsequent irreversible mortality due to unsuccessful utilization of exogenous feeding. In conclusion, this study molecularly identified the first-feeding window in European eel and revealed that exogenous feeding success occurs concurrently with the onset of a broad array of enzymes and hormones, which are known to regulate molecular processes in feeding physiology. This knowledge constitutes essential information to develop efficient larval feeding strategies and will hopefully provide a promising step toward sustainable aquaculture of European eel. PMID- 30459635 TI - Blockade of Rostral Ventrolateral Medulla Apelin Receptors Does Not Attenuate Arterial Pressure in SHR and L-NAME-Induced Hypertensive Rats. AB - Dysfunction of the apelinergic system, comprised of the neuropeptide apelin mediating its effects via the G protein-coupled apelin receptor (APJ), may underlie the onset of cardiovascular disease such as hypertension. Apelin expression is increased in the rostral ventrolateral medulla (RVLM) in spontaneously hypertensive rats (SHRs) compared to Wistar-Kyoto (WKY) normotensive rats, however, evidence that the apelinergic system chronically influences mean arterial blood pressure (MABP) under pathophysiological conditions remains to be established. In this study we investigated, in conscious unrestrained rats, whether APJ contributes to MABP and sympathetic vasomotor tone in the progression of two models of hypertension - SHR and L-NAME-treated rats - and whether APJ contributes to the development of hypertension in pre hypertensive SHR. In SHR we showed that APJ gene (aplnr) expression was elevated in the RVLM, and there was a greater MABP increase following microinjection of [Pyr1]apelin-13 to the RVLM of SHR compared to WKY rats. Bilateral microinjection of a lentiviral APJ-specific-shRNA construct into the RVLM of WKY, SHR, and L NAME-treated rats, chronically implanted with radiotelemeters to measure MABP, decreased aplnr expression in the RVLM and abolished acute [Pyr1]apelin-13 induced increases in MABP. However, chronic knockdown of aplnr in the RVLM did not affect MABP in either SHR or L-NAME-treated rats. Moreover, knockdown of aplnr in the RVLM of prehypertensive SHR did not protect against the development of hypertension. These results show that endogenous apelin, acting via APJ, is not involved in the genesis or maintenance of hypertension in either animal model used in this study. PMID- 30459630 TI - Atrial Fibrillation Mechanisms and Implications for Catheter Ablation. AB - AF is a heterogeneous rhythm disorder that is related to a wide spectrum of etiologies and has broad clinical presentations. Mechanisms underlying AF are complex and remain incompletely understood despite extensive research. They associate interactions between triggers, substrate and modulators including ionic and anatomic remodeling, genetic predisposition and neuro-humoral contributors. The pulmonary veins play a key role in the pathogenesis of AF and their isolation is associated to high rates of AF freedom in patients with paroxysmal AF. However, ablation of persistent AF remains less effective, mainly limited by the difficulty to identify the sources sustaining AF. Many theories were advanced to explain the perpetuation of this form of AF, ranging from a single localized focal and reentrant source to diffuse bi-atrial multiple wavelets. Translating these mechanisms to the clinical practice remains challenging and limited by the spatio-temporal resolution of the mapping techniques. AF is driven by focal or reentrant activities that are initially clustered in a relatively limited atrial surface then disseminate everywhere in both atria. Evidence for structural remodeling, mainly represented by atrial fibrosis suggests that reentrant activities using anatomical substrate are the key mechanism sustaining AF. These reentries can be endocardial, epicardial, and intramural which makes them less accessible for mapping and for ablation. Subsequently, early interventions before irreversible remodeling are of major importance. Circumferential pulmonary vein isolation remains the cornerstone of the treatment of AF, regardless of the AF form and of the AF duration. No ablation strategy consistently demonstrated superiority to pulmonary vein isolation in preventing long term recurrences of atrial arrhythmias. Further research that allows accurate identification of the mechanisms underlying AF and efficient ablation should improve the results of PsAF ablation. PMID- 30459637 TI - Rat Strain and Housing Conditions Alter Oxidative Stress and Hormone Responses to Chronic Intermittent Hypoxia. AB - Sleep apnea has been associated with elevated risk for metabolic, cognitive, and cardiovascular disorders. Further, the role of hypothalamic-pituitary-adrenal (HPA) activation in sleep apnea has been controversial in human studies. Chronic intermittent hypoxia (CIH) is a rodent model, which mimics the hypoxemia experienced by patients with sleep apnea. Most studies of CIH in rats have been conducted in the Sprague Dawley rat strain. Previously published literature suggests different strains of rats exhibit various responses to disease models, and these effects can be further modulated by the housing conditions experienced by each strain. This variability in response is similar to what has been observed in clinical populations, especially with respect to the HPA system. To investigate if strain or housing (individual or pair-housed) can affect the results of CIH (AHI 8 or 10) treatment, we exposed individual and pair-housed Sprague Dawley and Long-Evans male rats to 7 days of CIH treatment. This was followed by biochemical analysis of circulating hormones, oxidative stress, and neurodegenerative markers. Both strain and housing conditions altered oxidative stress generation, hyperphosphorylated tau protein (tau tangles), circulating corticosterone and adrenocorticotropic hormone (ACTH), and weight metrics. Specifically, pair-housed Long-Evans rats were the most sensitive to CIH, which showed a significant association between oxidative stress generation and HPA activation under conditions of AHI of 8. These results suggest both strain and housing conditions can affect the outcomes of CIH. PMID- 30459638 TI - Intermittent Hypoxia Severity in Animal Models of Sleep Apnea. PMID- 30459640 TI - Respiratory Metabolism Responses of Chinese Mitten Crab, Eriocheir sinensis and Chinese Grass Shrimp, Palaemonetes sinensis, Subjected to Environmental Hypoxia Stress. AB - Environmental hypoxia represents a major physiological challenge for Eriocheir sinensis and Palaemonetes sinensis and is a severe problem in aquaculture. Therefore, understanding the metabolic response mechanisms of E. sinensis and P. sinensis, which are economically important species, to environmental hypoxia and reoxygenation is essential. However, little is known about the intrinsic mechanisms by which E. sinensis and P. sinensis cope with environmental hypoxia at the metabolic level. Hypoxia-reoxygenation represents an important physiological challenge for their culture. In this study, respiratory metabolism and respiratory metabolic enzymes of E. sinensis and P. sinensis were evaluated after different hypoxia and reoxygenation times. The results showed that environmental hypoxia had a dramatic influence on the respiratory metabolism and activities of related enzymes. The oxygen consumption rates (OCR) significantly increased as hypoxia time increased, while the ammonia excretion rate (AER) was significantly lower than that in the control group after 8 h hypoxia. The oxygen to nitrogen ratio (O:N) in the control group was <16, indicating that all the energy substrates were proteins. After environmental hypoxia, the O:N significantly increased, and the energy substrate shifted from protein to a protein-lipid mixture. The OCR, AER, and O:N did not restore to initial levels after 2 h or 12 h reoxygenation and was still the same as after 8 h hypoxia. As environmental hypoxia time increased, succinate dehydrogenase (SDH) gradually decreased and lactate dehydrogenase (LDH) gradually increased. Both SDH and LDH were gradually restored to normal levels after reoxygenation. Therefore, environmental hypoxia should be avoided as much as possible during aquaculture breeding of E. sinensis and P. sinensis. Further, since OCR will significantly increase after a short period of reoxygenation, secondary environmental hypoxia due to rapid consumption of oxygen should also be avoided in aquaculture. PMID- 30459636 TI - Drug Transport at the Brain and Endothelial Dysfunction in Preeclampsia: Implications and Perspectives. AB - Transport of drugs across biological barriers has been a subject of study for decades. The discovery and characterization of proteins that confer the barrier properties of endothelia and epithelia, including tight junction proteins and membrane transporters belonging to the ATP-binding cassette (ABC) and Solute Carrier (SLC) families, represented a significant step forward into understanding the mechanisms that govern drug disposition. Subsequently, numerous studies, including both pre-clinical approaches and clinical investigations, have been carried out to determine the influence of physiological and pathological states on drug disposition. Importantly, there has been increasing interest in gaining a better understanding of drug disposition during pregnancy, since epidemiological and clinical studies have demonstrated that the use of medications by pregnant women is significant and this condition embodies a series of significant anatomical and physiological modifications, particularly at excretory organs and barrier sites (e.g., placenta, breast) expressing transporter proteins which influence pharmacokinetics. Currently, most of the research in this field has focused on the expression profiling of transporter proteins in trophoblasts and endothelial cells of the placenta, regulation of drug-resistance mechanisms in disease states and pharmacokinetic studies. However, little attention has been placed on the influence that the cerebrovascular dysfunction present in pregnancy related disorders, such as preeclampsia, might exert on drug disposition in the mother's brain. This issue is particularly important since recent findings have demonstrated that preeclamptic women suffer from long-term alterations in the integrity of the blood-brain barrier (BBB). In this review we aim to analyze the available evidence regarding the influence of pregnancy on the expression of transporters and TJ proteins in brain endothelial cells, as well the mechanisms that govern the pathophysiological alterations in the BBB of women who experience preeclampsia. Future research efforts should be focused not only on achieving a better understanding of the influence of preeclampsia-associated endothelial dysfunction on drug disposition, but also in optimizing the pharmacological treatments of women suffering pregnancy-related disorders, its comorbidities and to develop new therapies aiming to restore the integrity of the BBB. PMID- 30459639 TI - Plasticity in the Sensitivity to Light in Aging: Decreased Non-visual Impact of Light on Cognitive Brain Activity in Older Individuals but No Impact of Lens Replacement. AB - Beyond its essential visual role, light, and particularly blue light, has numerous non-visual effects, including stimulating cognitive functions and alertness. Non-visual effects of light may decrease with aging and contribute to cognitive and sleepiness complaints in aging. However, both the brain and the eye profoundly change in aging. Whether the stimulating effects light on cognitive brain functions varies in aging and how ocular changes may be involved is not established. We compared the impact of blue and orange lights on non-visual cognitive brain activity in younger (23.6 +/- 2.5 years), and older individuals with their natural lenses (NL; 66.7 +/- 5.1 years) or with intraocular lens (IOL) replacement following cataract surgery (69.6 +/- 4.9 years). Analyses reveal that blue light modulates executive brain responses in both young and older individuals. Light effects were, however, stronger in young individuals including in the hippocampus and frontal and cingular cortices. Light effects did not significantly differ between older-IOL and older-NL while regression analyses indicated that differential brain engagement was not underlying age-related differences in light effects. These findings show that, although its impact decreases, light can stimulate cognitive brain activity in aging. Since lens replacement did not affect light impact, the brain seems to adapt to the progressive decrease in retinal light exposure in aging. PMID- 30459643 TI - Effect of a Habitual Late-Evening Physical Task on Sleep Quality in Neither-Type Soccer Players. AB - Purpose: The aim of this study was to investigate objective and subjective sleep quality, daytime tiredness and sleepiness in response to a late-evening high intensity interval training (HIIT) session in neither-type soccer players that habitually trained late in the day. This is the first study that considered both athletes' chronotype and habitual training time as crucial factors when assessing sleep quality in relation to an evening physical task. Methods: In this longitudinal, prospective, observational study, 14 Italian soccer players were recruited (mean age: 26.1 +/- 4.5 years; height: 1.81 +/- 0.06 m; weight: 78.9 +/ 6.1 kg) and performed an extra-routine 4 * 4-min HIIT session at 09:00 p.m. Players used to train always between 09:00 and 11:00 p.m during the competitive season. All subjects wore an actigraph to evaluate their objective sleep parameters and a sleep diary was used to record subjective values of sleep quality, daytime tiredness, and daytime sleepiness. All data were analyzed as: the mean of the two nights before (PRE), the night after (POST 1), and the mean of the two nights after (POST 2) the extra-routine HIIT session. The subjects' chronotype was assessed by the morningness-eveningness questionnaire (MEQ). Results: All players were classified as N-types (mean MEQ score: 49.4 +/- 3.7). None of the actigraph parameters nor the subjective values of sleep quality, tiredness, and sleepiness showed significant changes in PRE, POST 1, and POST 2. Conclusion: The results of our study added more information regarding sleep quality outcomes in response to a late-evening HIIT session. Athletic trainers and medical staff should always control for chronotype and habitual training time when assessing variations to sleep quality in athletes. PMID- 30459644 TI - Corrigendum: Cell Type-Dependent Activation Sequence During Rhythmic Bursting in the PreBotzinger Complex in Respiratory Rhythmic Slices From Mice. AB - [This corrects the article DOI: 10.3389/fphys.2018.01219.]. PMID- 30459642 TI - Antioxidants and Oxidative Stress: Focus in Obese Pregnancies. AB - The prevalence of obesity in women of childbearing age around the globe has dramatically increased in the last decades. Obesity is characterized by a low state chronic inflammation, metabolism impairment and oxidative stress, among other pathological changes. Getting pregnant in this situation involves that gestation will occur in an unhealthy environment, that can potentially jeopardize both maternal and fetal health. In this review, we analyze the role of maternal obesity-induced oxidative stress as a risk factor to develop adverse outcomes during gestation, including reduced fertility, spontaneous abortion, teratogenesis, preeclampsia, and intrauterine growth restriction. Evidences of macromolecule oxidation increase in reactive oxygen species generation and antioxidant defense alterations are commonly described in maternal and fetal tissues. Thus, antioxidant supplementation become an interesting prophylactic and therapeutic tool, that yields positive results in cellular, and animal models. However, the results from most meta-analysis studying the effect of these therapies in complicated gestations in humans are not really encouraging. It is still to be analyzed whether these therapies could work if applied to cohorts of patients at a high risk, such as those with low concentration of antioxidants or obese pregnant women. PMID- 30459641 TI - Selection of Reference Genes for the Normalization of RT-qPCR Data in Gene Expression Studies in Insects: A Systematic Review. AB - Reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) is a reliable technique for quantifying expression levels of targeted genes during various biological processes in numerous areas of clinical and biological research. Selection of appropriate reference genes for RT-qPCR normalization is an elementary prerequisite for reliable measurements of gene expression levels. Here, by analyzing datasets published between 2008 and 2017, we summarized the current trends in reference gene selection for insect gene expression studies that employed the most widely used SYBR Green method for RT-qPCR normalization. We curated 90 representative papers, mainly published in 2013-2017, in which a total of 78 insect species were investigated in 100 experiments. Furthermore, top five journals, top 10 frequently used reference genes, and top 10 experimental factors have been determined. The relationships between the numbers of the reference genes, experimental factors, analysis tools on the one hand and publication date (year) on the other hand was investigated by linear regression. We found that the more recently the paper was published, the more experimental factors it tended to explore, and more analysis tools it used. However, linear regression analysis did not reveal a significant correlation between the number of reference genes and the study publication date. Taken together, this meta analysis will be of great help to researchers that plan gene expression studies in insects, especially the non-model ones, as it provides a summary of appropriate reference genes for expression studies, considers the optimal number of reference genes, and reviews the average number of experimental factors and analysis tools per study. PMID- 30459645 TI - Social Cognition in Schizophrenia and Autism Spectrum Disorders: A Systematic Review and Meta-Analysis of Direct Comparisons. AB - Background: Deficits in social cognition are well-recognized in both schizophrenia and autism spectrum disorders (ASD). However, it is less clear how social cognition deficits differ between both disorders and what distinct mechanisms may underlie such differences. We aimed at reviewing available evidence from studies directly comparing social cognitive performance between individuals with schizophrenia and ASD. Methods: We performed a systematic review of literature up to May 22, 2018 on Pubmed, Web of Science, and Scopus. Search terms included combinations of the keywords "social cognition," "theory of mind," "autism," "Asperger," "psychosis," and "schizophrenia." Two researchers independently selected and extracted data according to PRISMA guidelines. Random effects meta-analyses were conducted for performance on social cognitive tasks evaluating: (1) emotion perception; (2) theory of mind (ToM); (3) emotional intelligence (managing emotions score of the Mayer-Salovey-Caruso Emotional Intelligence Test); and (4) social skills. Results: We identified 19 eligible studies for meta-analysis including a total of 1,040 patients (558 with schizophrenia and 482 with ASD). Eight studies provided data on facial emotion perception that evidenced a better performance by participants with schizophrenia compared to those with ASD (Hedges' g = 0.43; p = 0.031). No significant differences were found between groups in the Reading the Mind in the Eyes Test (8 studies; Hedges' g = 0.22; p = 0.351), other ToM tasks (9 studies; Hedges' g = 0.03; p = 0.903), emotional intelligence (3 studies; Hedges' g = -0.17; p = 0.490), and social skills (3 studies; Hedges' g = 0.86; p = 0.056). Participants' age was a significant moderator of effect size in emotion perception and RMET analyzes, with larger differences favoring patients with schizophrenia being observed in studies with younger participants. Conclusions: The instruments that are currently available to evaluate social cognition poorly differentiate between individuals with schizophrenia and ASD. Combining behavioral tasks with neurophysiologic assessments may better characterize the differences in social cognition between both disorders. PMID- 30459648 TI - The Sense of Commitment in Individuals With Borderline Personality Traits in a Non-clinical Population. AB - This is the first study to test the hypothesis that individuals' sense of commitment in joint activities and relationships may be influenced by personality traits characteristic of borderline personality disorder (BPD). This study consisted of 3 online experiments implemented via Amazon Mechanical Turk. Participants were presented with videos (Experiment 1) or vignettes (Experiments 2, 3) describing situations in which everyday commitments were violated. Participants then reported their perceptions, interpretations, and affective and behavioral responses to those situations. Participants' BPD traits (BPDt) were assessed using the short form of the Five-Factor Borderline Inventory on the basis of which they were divided into two groups: High and Low BPDt. The results revealed that participants with High BPD traits were less optimistic about others acting in accordance with an implicit sense of commitment (Experiment 1), although there was no difference between groups when the commitment was explicitly stated (Experiment 3). Participants in the High BPDt group also reported heightened emotional responses (Experiments 1-3) and less adaptive behavioral responses (Experiments 1, 3) to perceived or anticipated violations of commitment. Our findings suggest that high levels of BPD traits may give rise to a difficulty in adapting one's social expectations and behavior in light of interpersonal commitments and in a manner that is calibrated to the social norms in the community. Future research should investigate to what extent a disturbed sense of commitment may contribute to the difficulties in interpersonal functioning experienced by many individuals with a clinical diagnosis of BPD. PMID- 30459646 TI - A Review of the Potential Mechanisms of Action of Baclofen in Alcohol Use Disorder. AB - Baclofen, a GABA-B receptor agonist, is a promising treatment for alcohol use disorder (AUD). Its mechanism of action in this condition is unknown. GABA-B receptors interact with many biological systems potentially involved in AUD, including transduction pathways and neurotransmitter systems. Preclinical studies have shown that GABA-B receptors are involved in memory storage and retrieval, reward, motivation, mood and anxiety; neuroimaging studies in humans show that baclofen produces region-specific alterations in cerebral activity; GABA-B receptor activation may have neuroprotective effects; baclofen also has anti inflammatory properties that may be of interest in the context of addiction. However, none of these biological effects fully explain the mechanism of action of baclofen in AUD. Data from clinical studies have provided a certain number of elements which may be useful for the comprehension of its mechanism of action: baclofen typically induces a state of indifference toward alcohol; the effective dose of baclofen in AUD is extremely variable from one patient to another; higher treatment doses correlate with the severity of the addiction; many of the side effects of baclofen resemble those of alcohol, raising the possibility that baclofen acts as a substitution drug; usually, however, there is no tolerance to the effects of baclofen during long-term AUD treatment. In the present article, the biological effects of baclofen are reviewed in the light of its clinical effects in AUD, assuming that, in many instances, clinical effects can be reliable indicators of underlying biological processes. In conclusion, it is proposed that baclofen may suppress the Pavlovian association between cues and rewards through an action in a critical part of the dopaminergic network (the amygdala), thereby normalizing the functional connectivity in the reward network. It is also proposed that this action of baclofen is made possible by the fact that baclofen and alcohol act on similar brain systems in certain regions of the brain. PMID- 30459647 TI - BDNF Plasma Levels and BDNF Exon IV Promoter Methylation as Predictors for Antidepressant Treatment Response. AB - Major problems of current antidepressant pharmacotherapy are insufficient response rates and difficulties in response prediction. We recently provided preliminary evidence in a small study that patients with major depressive disorder (MDD) with a hypomethylation of the CpG-87 site of the promoter IV region of the brain-derived neurotrophic factor (BDNF) gene are less likely to benefit from antidepressants. Here, we aimed at replicating this finding in a secondary analysis of 561 MDD patients (mean age 40.0 +/- 11.9 years, 56% female) included into the Early Medication Change study (EMC). We measured BDNF exon IV promoter and p11 gene methylation at Baseline (BL) as well as BDNF-plasma-levels (pBDNF) at BL and day 14 and related them to treatment outcome. Although we were not able to replicate the predictor function of hypomethylation of the BDNF exon IV promoter, a subgroup of patients with severe depression (Hamilton Depression Rating Scale [HAMD-17] >= 25) (n = 199) and hypermethylation at CpG-87 of the BDNF exon IV promoter had significantly higher remission rates than patients without a methylation (p = 0.032). We also found that 421 (75%) of 561 patients showed an early improvement (>= 20% HAMD-17 reduction after 2 weeks), which was associated with a 4.24-fold increased likelihood to remit at study end compared to the 140 patients without early improvement. However, specificity of response prediction of early improvement was low (34%) and false positive rate high (66%). The combination of early improvement with a pBDNF increase between BL and day 14, however, increased the specificity of response prediction from 34 to 76%, and the combination with methylation of the CpG-87 site of the BDNF exon IV promoter from 34 to 62%. Thus, the combined markers reduced false positives rates from 66 to 24% and 38%, respectively. Methylation at other sites or p11 promoter methylation failed to increase specificity of early improvement prediction. In sum, the results add to previous findings that BDNF, BDNF promoter methylation and the combination of clinical and biological markers may be interesting candidates for therapy response prediction which has to be confirmed in further studies. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00974155, identifier: NCT00974155. PMID- 30459649 TI - Eating Disorders Impact on Vigilance and Decision Making of a Community Sample of Treatment Naive Attention-Deficit/Hyperactivity Disorder Young Adults. AB - Although impulsivity is suggested as a possible link to explain the association of Attention-Deficit/Hyperactivity Disorder (ADHD) with an Eating Disorder (ED), there is little research on how clinical and cognitive/neuropsychological functioning might change when this comorbidity occurs. ADHD individuals are at a higher of developing ED and also obesity. Some research has described the impact of ADHD in clinical treatment-seeking samples of ED patients. Consequently, we investigated how ED impacted on clinical and cognitive variables of a community sample of treatment-naive ADHD individuals. Ninety college students arranged in three groups (ADHD+ED, ADHD only and Controls) were analyzed using semi structured interviews for ADHD (K-SADS), the Iowa Gambling Task, the Conner's Continuous Performance Test, Digit and Visual span, as well as rating scales for anxiety (STAI), depression (BDI) and impulsivity (BIS-11), and binge eating (BES). We found that ADHD+ED individuals significantly differed from both groups, presenting with a higher body mass index; more hyperactivity-impulsivity symptoms; higher binge eating scores; more omission errors on the Continuous Performance Test; disadvantageous choices on the Iowa Gambling Task. Also, we demonstrated through a moderation/mediation analysis that a greater level of binge eating mediated the increases in body mass index on our sample. There were no significant paths to explain binge-eating severity through changes on any of the neuropsychological tests used. The presence of an ED in normal weight in a community sample of ADHD individuals is associated with higher body mass index and a worse cognitive functioning. PMID- 30459651 TI - A Research of Methamphetamine Induced Psychosis in 1,430 Individuals With Methamphetamine Use Disorder: Clinical Features and Possible Risk Factors. AB - Background and Aims: Methamphetamine (MA) abuse is commonly associated with the development of psychotic symptoms. The predictors and related risk factors of MA induced psychosis (MIP) are poorly understood. We investigated the occurrence of MIP, and analyzed the clinical features and possible risk factors among individuals with MA use disorder Method: One thousand four hundred and thirty participants with MA use disorder were recruited from compulsory rehabilitation centers in Shanghai. A structured questionnaire including demographic characteristics, drug use history, visual analog scales, Beck Depression Inventory-13 (BDI-13), and Hamilton anxiety scale-14 (HAMA-14) were used to collect clinical related information. Fifty-six participants had accomplished the test of CogState Battery. Results: Among the 1430 individuals with MA use disorder, 37.1% were diagnosed as MIP according DSM-IV. There were significant differences in age, marital status, age of drug use onset, MA use years, Average MA use dose, interval of MA use, maximum dose, concurrent use of alcohol, and other drugs, VAS score, MA dependence, BDI-13 scores, HAMA-14 scores, verbal learning memory, and visual learning memory between the MIP group and the none MIP group (P < 0.05). The age of drug use onset (OR = 0.978, p = 0.011), average drug use dose (OR = 1.800, p = 0.015), craving score (OR = 1.069, p = 0.031), MA dependence (OR = 2.214, p < 0.001), and HAMA scores (OR = 1.028, p < 0.001) were associated to MIP. Conclusion: Individuals with MIP had more severe drug use problems, emotional symptoms and cognitive impairment. Earlier onset of drug use, higher quantity of drug use, higher craving, middle or severe drug use disorder and more anxiety symptoms may be related risk factors of MIP. PMID- 30459652 TI - Neural Activation During Tonic Pain and Interaction Between Pain and Emotion in Bipolar Disorder: An fMRI Study. AB - Objective: Pain and affective disorders have clear clinical relevance; however, very few studies have investigated the association between pain and bipolar disorder. This study investigated the brain activity of patients with bipolar disorder (BPs) undergoing tonic pain and assessed the interaction between pain and emotion. Methods: Ten BPs and ten healthy controls (HCs) were exposed to emotional pictures (positive, neutral, or negative), tonic pain only (pain session), and emotional pictures along with tonic pain (combined session). A moderate tonic pain was induced by the infusion of hypertonic saline (5% NaCl) into the right masseter muscle with a computer-controlled system. Whole-brain blood oxygenation level dependent (BOLD) signals were acquired using 3T functional resonance imaging (fMRI). Results: Ten BPs and ten healthy participants were included in the final analysis. During the pain session, BPs accepted more saline, but showed lower pain rating scores than HCs. When experiencing pain, BPs showed a significant decrease in the BOLD signal in the bilateral insula, left inferior frontal gyrus (IFG), and left cerebellum as compared with HCs. In the combined session, the activated regions for positive mood (pain with positive mood > baseline) in BPs were the left cerebellum, right temporal gyrus, and left occipital gyrus; the activated regions for negative mood (pain with negative mood > baseline) were the right occipital gyrus, left insula, left IFG, and bilateral precentral gyrus. Conclusions: This study presents the preliminary finding of the interaction between pain and emotion in BPs. BPs exhibited lower sensitivity to pain, and the activation of insula and IFG may reflect the interaction between emotion and pain stimulus. PMID- 30459650 TI - Astrocytic Regulation of Glutamate Transmission in Schizophrenia. AB - According to the glutamate hypothesis of schizophrenia, the abnormality of glutamate transmission induced by hypofunction of NMDA receptors (NMDARs) is causally associated with the positive and negative symptoms of schizophrenia. However, the underlying mechanisms responsible for the changes in glutamate transmission in schizophrenia are not fully understood. Astrocytes, the major regulatory glia in the brain, modulate not only glutamate metabolism but also glutamate transmission. Here we review the recent progress in understanding the role of astrocytes in schizophrenia. We focus on the astrocytic mechanisms of (i) glutamate synthesis via the glutamate-glutamine cycle, (ii) glutamate clearance by excitatory amino acid transporters (EAATs), (iii) D-serine release to activate NMDARs, and (iv) glutamatergic target engagement biomarkers. Abnormality in these processes is highly correlated with schizophrenia phenotypes. These findings will shed light upon further investigation of pathogenesis as well as improvement of biomarkers and therapies for schizophrenia. PMID- 30459653 TI - A Community-Based Addiction Rehabilitation Electronic System to Improve Treatment Outcomes in Drug Abusers: Protocol for a Randomized Controlled Trial. AB - Introduction: Relapse is very common in drug abusers and contributes to a series of negative consequences. Effective addiction treatment exists but there are some problems in the implementation process. Mobile health (mHealth) offers a potential solution to improving recovery outcome for drug abusers in the community. The research team developed a community-based addiction rehabilitation electronic system (CAREs). The primary aim of this study is to explore whether the integrated rehabilitation based on program CAREs promotes drug abusers to keep abstinence. The secondary aim is to evaluate the impact of CAREs on interaction between drug users and service providers, and on addiction-related physical and social functions. Method and analysis: A randomized controlled trial (RCT) will be conducted. The study is a superiority trial with parallel group design. Seventy drug abusers who are newly ordered to undergo community rehabilitation will be recruited from the community in Shanghai. Participants will be 1:1 randomly assigned to receive integrated community rehabilitation by using CAREs or only receiving routine community rehabilitation for 6 months. Corresponding social workers will provide service and monitor their drug use behavior in accordance with the routine work-flow. Outcomes will be assessed at baseline and in the 6th month. The primary outcome is the performance on illicit drug urine test which will be carried out regularly twice per week during the study period. Secondary study outcomes include longest duration of sustained abstinence, days that participants interact with social workers, and the decrease rate of addiction-related issues severity index. Chi-square tests and ANOVAs will be used to compare characteristics of the members of the two groups. GEE will be used to compare the seven dimensions scores of the ASI between groups. Discussion: The study provides evidence for the feasibility and effectiveness of the "CAREs" system through comparing the results of the intervention group with the control group. This paper describes the design and methodology of the study. Ethics and dissemination: The Ethical Board of SMHC approved the study protocol. All participants will present for the informed consent process. After study completion, the results will be published. Trial Registration: ClinicalTrials.gov NCT03451344, https://clinicaltrials.gov/ct2/show/NCT03451344. PMID- 30459654 TI - Minocycline Attenuates Stress-Induced Behavioral Changes via Its Anti inflammatory Effects in an Animal Model of Post-traumatic Stress Disorder. AB - Accumulating evidences have suggested that anxiety-like behavior and impairment of learning and memory are key symptoms of post-traumatic stress disorder (PTSD), and pharmacological treatment can ameliorate anxiety and cognitive impairments. Recent studies have shown that minocycline exhibits anxiolytic effects. The aims of the present study were to determine whether minocycline administration would alter anxiety-like behavior and cognitive deficits induced by inescapable foot shock (IFS) and to explore the underlying mechanisms. Male Wistar rats were exposed to the IFS protocol for a period of 6 days to induce PTSD. The PTSD-like behavior was tested using the open field test, elevated plus maze test, and Morris water maze test. The effects of minocycline on pro-inflammatory cytokines, activation of microglia, and NF-kappaB in the PFC and hippocampus were also examined. Treatment with minocycline significantly reversed the IFS induced behavioral and cognitive parameters (impaired learning and memory function) in stressed rats. Additionally, IFS was able to increase pro-inflammatory cytokines, activate microglia, and enhance NF-kappaB levels, while minocycline significantly reversed these alterations. Taken together, our results suggest that the anxiolytic effect of minocycline is related to its ability to decrease the levels of pro-inflammatory cytokines and inhibit activation of microglia and NF-kappaB in the PFC and hippocampus. PMID- 30459656 TI - The Implementation of China's Mental Health Law-Defined Risk Criteria for Involuntary Admission: A National Cross-Sectional Study of Involuntarily Hospitalized Patients. AB - Objective: Involuntary admission is one of the most controversial issues in psychiatry in China. This study aimed to examine the implementation of the new risk criteria for involuntary admission, as defined by the new Mental Health Law (MHL), in major psychiatric hospitals; and to explore factors associated with the implementation. Method: We selected 32 psychiatric hospitals in 29 provincial capital cities in mainland China. We included all involuntarily admitted psychiatric inpatients who were discharged from December 25 to 27, 2017. Patients' demographic and clinical data and reasons for admission were retrieved. Hospitals' information was also collected. Multilevel logistic regression was applied to explore factors associated with the implementation. Results: We collected valid data from 814 inpatients. Rates of risk criteria implementation ranged from 7.9 to 88.5% in these hospitals. Only 369 inpatients (45.3%) met the MHL-defined risk criteria. Overall, between 62.2 and 78.5% of the variance in risk criteria implementation was at the patient level, and between 21.5 and 37.8% of the variance was at the hospital level. Patients with higher Global Assessment of Functioning (GAF) scores at admission were less likely to meet the risk criteria (OR 1.02, 95% CI 1.01-1.03). No statistically significant association was found between risk criteria implementation and other patient level or hospital level factors. Conclusion: Our findings show the implementation rate of the MHL's risk criteria overall was low, with only 45.3% of involuntary admissions meeting the MHL-defined criteria. This suggests that some patients' civil rights might have been violated. PMID- 30459655 TI - The Emerging Role of Altered d-Aspartate Metabolism in Schizophrenia: New Insights From Preclinical Models and Human Studies. AB - Besides d-serine, another d-amino acid with endogenous occurrence in the mammalian brain, d-aspartate, has been recently shown to influence NMDA receptor (NMDAR)-mediated transmission. d-aspartate is present in the brain at extracellular level in nanomolar concentrations, binds to the agonist site of NMDARs and activates this subclass of glutamate receptors. Along with its direct effect on NMDARs, d-aspartate can also evoke considerable l-glutamate release in specific brain areas through the presynaptic activation of NMDA, AMPA/kainate and mGlu5 receptors. d-aspartate is enriched in the embryonic brain of rodents and humans and its concentration strongly decreases after birth, due to the post natal expression of the catabolising enzyme d-aspartate oxidase (DDO). Based on the hypothesis of NMDAR hypofunction in schizophrenia pathogenesis, recent preclinical and clinical studies suggested a relationship between perturbation of d-aspartate metabolism and this psychiatric disorder. Consistently, neurophysiological and behavioral characterization of Ddo knockout (Ddo -/-) and d-aspartate-treated mice highlighted that abnormally higher endogenous d aspartate levels significantly increase NMDAR-mediated synaptic plasticity, neuronal spine density and memory. Remarkably, increased d-aspartate levels influence schizophrenia-like phenotypes in rodents, as indicated by improved fronto-hippocampal connectivity, attenuated prepulse inhibition deficits and reduced activation of neuronal circuitry induced by phencyclidine exposure. In healthy humans, a genetic polymorphism associated with reduced prefrontal DDO gene expression predicts changes in prefrontal phenotypes including greater gray matter volume and enhanced functional activity during working memory. Moreover, neurochemical detections in post-mortem brain of schizophrenia-affected patients have shown significantly reduced d-aspartate content in prefrontal regions, associated with increased DDO mRNA expression or DDO enzymatic activity. Overall, these findings suggest a possible involvement of dysregulated embryonic d aspartate metabolism in schizophrenia pathophysiology and, in turn, highlight the potential use of free d-aspartate supplementation as a new add-on therapy for treating the cognitive symptoms of this mental illness. PMID- 30459657 TI - Elevated Glutamate and Glutamine Levels in the Cerebrospinal Fluid of Patients With Probable Alzheimer's Disease and Depression. AB - Recent evidence suggests that Alzheimer's disease (AD) and depression share common mechanisms of pathogenesis. In particular, deregulation of glutamate mediated excitatory signaling may play a role in brain dysfunction in both AD and depression. We have investigated levels of glutamate and its precursor glutamine in the cerebrospinal fluid (CSF) of patients with a diagnosis of probable AD or major depression compared to healthy controls and patients with hydrocephalus. Patients with probable AD or major depression showed significantly increased CSF levels of glutamate and glutamine compared to healthy controls or hydrocephalus patients. Furthermore, CSF glutamate and glutamine levels were inversely correlated to the amyloid tau index, a biomarker for AD. Results suggest that glutamate and glutamine should be further explored as potential CSF biomarkers for AD and depression. PMID- 30459658 TI - A Systematic Review of Psychosocial Barriers and Facilitators to Smoking Cessation in People Living With Schizophrenia. AB - Background: People living with schizophrenia are less likely to quit smoking compared with the general population and people living with other psychiatric disorders. Understanding the schizophrenia-specific psychosocial barriers and facilitators to smoking cessation is important for designing effective smoking cessation interventions. We aimed to systematically review research examining psychosocial barriers and facilitators to smoking cessation in people living with schizophrenia. Methods: We followed the PRISMA statement to conduct a systematic literature review examining psychosocial barriers and facilitators to smoking cessation in people living with schizophrenia. We searched EMBASE, Medline, PsycINFO, and CINAHL databases from inception to 14 June 2018 to identify relevant articles. We included peer-reviewed original research articles that examined psychosocial barriers and facilitators to smoking cessation, as well as factors associated with maintenance of smoking habits in people living with schizophrenia spectrum disorders. Qualitative, quantitative, or mixed-methods study designs were included. Three authors screened titles, abstracts, and full texts using the eligibility criteria. We conducted a narrative synthesis of the data to account for the heterogeneity of study designs. We analyzed qualitative and quantitative studies separately. Results: We identified 685 studies from our systematic search and screened the full-text of 134 articles. The final set of 23 articles included 20 quantitative studies and 3 qualitative studies. The most commonly cited barrier to smoking cessation in people living with schizophrenia was cravings and addiction, followed by a perceived increased risk of negative affect associated with quitting smoking. People living with schizophrenia reported smoking to manage stress and to maintain social relationships. People living with schizophrenia were found to be less likely to receive cessation support from health professionals than smokers without schizophrenia. Health concerns were the most commonly mentioned facilitator to quit smoking. Conclusions: People living with schizophrenia experience a wide range of barriers to smoking cessation. The influence of these barriers on smoking cessation likelihood may be greater among people living with schizophrenia than people without psychiatric disorders. Health professionals play an important role in smoking cessation for people living with schizophrenia and should consider barriers and facilitators identified in this review to support quitting in this vulnerable population. PMID- 30459659 TI - Combination of G72 Genetic Variation and G72 Protein Level to Detect Schizophrenia: Machine Learning Approaches. AB - The D-amino acid oxidase activator (DAOA, also known as G72) gene is a strong schizophrenia susceptibility gene. Higher G72 protein levels have been implicated in patients with schizophrenia. The current study aimed to differentiate patients with schizophrenia from healthy individuals using G72 single nucleotide polymorphisms (SNPs) and G72 protein levels by leveraging computational artificial intelligence and machine learning tools. A total of 149 subjects with 89 patients with schizophrenia and 60 healthy controls were recruited. Two G72 genotypes (including rs1421292 and rs2391191) and G72 protein levels were measured with the peripheral blood. We utilized three machine learning algorithms (including logistic regression, naive Bayes, and C4.5 decision tree) to build the optimal predictive model for distinguishing schizophrenia patients from healthy controls. The naive Bayes model using two factors, including G72 rs1421292 and G72 protein, appeared to be the best model for disease susceptibility (sensitivity = 0.7969, specificity = 0.9372, area under the receiver operating characteristic curve (AUC) = 0.9356). However, a model integrating G72 rs1421292 only slightly increased the discriminative power than a model with G72 protein alone (sensitivity = 0.7941, specificity = 0.9503, AUC = 0.9324). Among the three models with G72 protein alone, the naive Bayes with G72 protein alone had the best specificity (0.9503), while logistic regression with G72 protein alone was the most sensitive (0.8765). The findings remained similar after adjusting for age and gender. This study suggests that G72 protein alone, without incorporating the two G72 SNPs, may have been suitable enough to identify schizophrenia patients. We also recommend applying both naive Bayes and logistic regression models for the best specificity and sensitivity, respectively. Larger-scale studies are warranted to confirm the findings. PMID- 30459661 TI - Prenatal Alcohol Exposure and Child Psychosocial Behavior: A Sibling Fixed Effects Analysis. AB - Background: The association between low levels of alcohol consumption during pregnancy and children's health remains unclear because of the difficulty in ruling out residual genetic and environmental confounding factors. In this study, using a within-family sibling fixed effects design, we sought to examine the association between low prenatal alcohol exposures (PAE) and children's overall psychosocial behavior in a Japanese cohort. Methods: We used maternal and sibling data from the Japanese Study of Stratification, Health, Income and Neighborhood 2012-2013. Households were recruited from the Tokyo metropolitan area through clustered random sampling. Children under 18 years old who have siblings (n = 1,600) and their mothers were selected. PAE status was retrospectively measured, and classified by binominal and continuous measurements. Outcome measures of children's psychosocial behavior were assessed with the Child Behavior Checklist T-score. Results: Low PAE was significantly associated with the offspring's anxiety problems (beta = 1.54, 95%CI = 0.26, 2.82) and internalizing problems (beta = 2.73, 95%CI = 0.87, 4.60), and marginally significant with the offspring's total problem scores (beta = 2.34, 95%CI = -0.24, 4.92). There was no significant difference in PAE between boys and girls when it comes to behavioral problems. Conclusions: Low PAE was associated with children's anxiety, internalizing problems and overall problems, taking into account possible unobserved genetic and environmental confounding influences. PMID- 30459662 TI - The Clinic of Identifications in the Different Processes of Metamorphosis Into Woman. AB - This article examines, from a psychoanalytical perspective, the function of identification in the relationship between the subject of the unconscious and his body, his body image, and the other. To this effect, the article leans on the clinic of the metamorphosis into a woman in psychosis, both in the way that it is presented by patients in the context of treatment, and in the form of testimonies extracted from literature. It demonstrates how specular identification allows the subject to unify himself, so long as there is an avoidance of possible deformations of the psychical body, including for example the delusion of transforming into a woman. It also turns its attention to the second logical moment of identification, when identification becomes sexed and organizes a certain relation to the other. A failure in this process sometimes leads the subject to opt for an identification of a gendered look, so as to stabilize himself. Indeed, transsexualism, which does not derive from any biological or sociological determination, and which can be observed in all subjective structures, is a possible way for the psychotic subject to problematize his relation to the body and to the other by identification with the woman, now that progress in science and law have enabled this. PMID- 30459663 TI - Do Chinese Traditional and Modern Cultures Affect Young Adults' Moral Priorities? AB - Dramatic cultural change has occurred in Mainland China over the past four decades, yet little is known about how this cultural shift impacts Chinese peoples' moral values. The present research aims to fill this gap by examining whether Chinese traditional and modern cultures influence young adults' moral judgments. Study 1 investigated the relation between psychological traditionality/modernity and moral concerns. Results indicated that participants who strongly endorsed Chinese traditional culture prioritize relationship concern rather than justice concern. Study 2 used the cultural priming method and tested the effects of traditional and modern icons on moral concerns. Results suggested that participants who were primed with traditional or modern or neutral icons did not give priority to relationship or justice concern. Together, our findings provide initial empirical evidence on whether Chinese traditional and modern cultures shift the moral mindsets of bicultural young Chinese among alternative (and even competing) moral codes. PMID- 30459660 TI - Lifestyle Interventions and Prevention of Suicide. AB - Over the past years, there has been a growing interest in the association between lifestyle psychosocial interventions, severe mental illness, and suicide risk. Patients with severe mental disorders have higher mortality rates, poor health states, and higher suicide risk compared to the general population. Lifestyle behaviors are amenable to change through the adoption of specific psychosocial interventions, and several approaches have been promoted. The current article provides a comprehensive review of the literature on lifestyle interventions, mental health, and suicide risk in the general population and in patients with psychiatric disorders. For this purpose, we investigated lifestyle behaviors and lifestyle interventions in three different age groups: adolescents, young adults, and the elderly. Several lifestyle behaviors including cigarette smoking, alcohol use, and sedentary lifestyle are associated with suicide risk in all age groups. In adolescents, growing attention has emerged on the association between suicide risk and internet addiction, cyberbullying and scholastic and family difficulties. In adults, psychiatric symptoms, substance and alcohol abuse, weight, and occupational difficulties seems to have a significant role in suicide risk. Finally, in the elderly, the presence of an organic disease and poor social support are associated with an increased risk of suicide attempt. Several factors may explain the association between lifestyle behaviors and suicide. First, many studies have reported that some lifestyle behaviors and its consequences (sedentary lifestyle, cigarette smoking underweight, obesity) are associated with cardiometabolic risk factors and with poor mental health. Second, several lifestyle behaviors may encourage social isolation, limiting the development of social networks, and remove individuals from social interactions; increasing their risk of mental health problems and suicide. PMID- 30459664 TI - Emotional Empathy as a Mechanism of Synchronisation in Child-Robot Interaction. AB - Simulating emotional experience, emotional empathy is the fundamental ingredient of interpersonal communication. In the speaker-listener scenario, the speaker is always a child, the listener is a human or a toy robot. Two groups of neurotypical children aged 6 years on average composed the population: one Japanese (n = 20) and one French (n = 20). Revealing potential similarities in communicative exchanges in both groups when in contact with a human or a toy robot, the results might signify that emotional empathy requires the implication of an automatic identification. In this sense, emotional empathy might be considered a broad idiosyncrasy, a kind of synchronisation, offering the mind a peculiar form of communication. Our findings seem to be consistent with the assumption that children's brains would be constructed to simulate the feelings of others in order to ensure interpersonal synchronisation. PMID- 30459665 TI - Resounding Meaning: A PERMA Wellbeing Profile of Classical Musicians. AB - While music has been linked with enhanced wellbeing across a wide variety of contexts, the professional pursuit of a music career is frequently associated with poor psychological health. Most research has focused on assessing negative functioning, and to date, few studies have attempted to profile musicians' wellbeing using a positive framework. This study aimed to generate a profile that represents indicators of optimal functioning among classical musicians. The PERMA model, which reconciles hedonic and eudaimonic wellbeing, was adopted and its five elements assessed with a sample of professional classical musicians: Positive Emotion, Engagement, Relationships, Meaning and Accomplishment. 601 participants (298 women, 303 men) engaged in careers as orchestral (n = 236), solo (n = 158), chamber (n = 112), and choral musicians (n = 36), as well as composers (n = 30) and conductors (n = 29), answered the PERMA-Profiler, a self report questionnaire built to assess the five components of PERMA. Results point to high scores across all dimensions, with Meaning emerging as the highest rated dimension. Musicians scored significantly higher than general population indicators on Positive Emotion, Relationships and Meaning. When wellbeing is assessed as positive functioning and not the absence of illbeing, musicians show promising profiles. The reconciliation between these findings and the previous body of research pointing to the music profession as highly challenging for healthy psychological functioning is discussed. PMID- 30459666 TI - Placebo Groups in Research on the Effectiveness of ABA Therapeutic Techniques. AB - Behavior analysts have shown that a single-subject experimental design (SSED) is a useful tool for identifying the effectiveness of specific therapeutic techniques, whereas researchers outside applied behavior analysis (ABA) maintain that randomized placebo-controlled trials (RPCT) provide the most definite test of efficacy. In this paper the possible benefits that could result from supporting SSED studies by placebo control groups are discussed. However, the use of placebo groups in psychotherapy research arouses considerable controversy and many researchers argue against it. The main aim of this paper is to clarify theoretical and methodological problems associated with using placebo groups in psychotherapy research and to demonstrate that these problems can be solved if the assumptions on which they are based are reformulated. The article also discusses ethical issues about the use of placebo groups in research on the effectiveness of psychotherapy. PMID- 30459667 TI - The Effect of Cognitive Reappraisal on Reactive Aggression: An fMRI Study. AB - A number of empirical researches have shown that reactive aggression, which is the behavior that is impulsive, thoughtless, driven by anger, and causes harm toward another individual, can lead to a series of negative effects. Cognitive reappraisal may have the potential to reduce reactive aggression, but evidence for this effect in healthy populations is lacking. We randomly assigned participants to a Reappraisal Group (n = 19) or Control Group (n = 20) in a functional magnetic resonance imaging (fMRI) version of the well-established Taylor Aggression Paradigm (TAP). TAP was employed to elicit and measure reactive aggression, during which participants were informed that they would play a competitive reaction time task against two opponents in turn and the winner would punish the loser. The TAP used in this study separates the decision-making (during which participants were asked to set a punishment level for the opponent) and affective processes (during which the punishment was applied or received) that underlie reactive aggression. Behavioral data showed that there was no difference between the Reappraisal Group and Control Group in the punishment level selections (i.e., reactive aggression). However, on the neural level, cognitive reappraisal reduced the activation of left insula, right cuneus, and right middle frontal gyrus (MFG) during the decision phase, independently of the level of provocation. In addition, cognitive reappraisal reduced the activation of the caudate under the provocative condition when making decisions about aggressive behavior. The results of the outcome phase showed that, after winning a competition, cognitive reappraisal increased the activation of the right orbital middle frontal gyrus (OMFG) under the provocative condition and reduced the activation of the bilateral supplementary motor area (SMA) under the non provocative condition. The results suggest that cognitive reappraisal would be effective in modulating the neural activity of reactive aggression. PMID- 30459668 TI - My Action, My Self: Recognition of Self-Created but Visually Unfamiliar Dance Like Actions From Point-Light Displays. AB - Previous research has shown that motor experience of an action can facilitate the visual recognition of that action, even in the absence of visual experience. We conducted an experiment in which participants were presented point-light displays of dance-like actions that had been recorded with the same group of participants during a previous session. The stimuli had been produced with the participant in such a way that each participant experienced a subset of phrases only as observer, learnt two phrases from observation, and created one phrase while blindfolded. The clips presented in the recognition task showed movements that were either unfamiliar, only visually familiar, familiar from observational learning and execution, or self-created while blind-folded (and hence not visually familiar). Participants assigned all types of movements correctly to the respective categories, showing that all three ways of experiencing the movement (observed, learnt through observation and practice, and created blindfolded) resulted in an encoding that was adequate for recognition. Observed movements showed the lowest level of recognition accuracy, whereas the accuracy of assigning blindfolded self-created movements was on the same level as for unfamiliar and learnt movements. Self-recognition was modulated by action recognition, as participants were more likely to identify themselves as the actor in clips they had assigned to the category "created" than in clips they had assigned to the category "learnt," supporting the idea of an influence of agency on self-recognition. PMID- 30459669 TI - A Network Model of Goals Boosts Convergent Creativity Performance. AB - To increase employee creativity is critical for organizational success, and yet we still know very little about what organizational contexts promote creative performance. Our research proposes that goal regulation in the workplace may have consequences for creativity. While there is an increasing trend for organizations and workers to visualize the structure of their goals (e.g., management hierarchy, concept-map, flowchart), prior research suggests the visualization approaches differ as one of the three types: hierarchical, network, and sequential models. Because a network model (vs. hierarchical and sequential models) highlights multiple connections between goals and reveals unobvious connections between them, we hypothesized that the use of a network goal model might increase people's ability to integrate seemingly unrelated ideas, even on subsequent unrelated tasks, leading to higher (convergent) creative performance. To test the hypothesis, we conducted an experiment in 2017 manipulating participants' goal models (hierarchical, network, sequential; N = 191, median age = 19) and measured their creativity. Results suggest that those in the network model condition performed better in the kind of creativity task that requires meaningful integration of unrelated ideas (i.e., convergent creativity); in contrast, there was no difference between goal model conditions on divergent creative performance. These findings thus illuminate how goal models may influence creativity, providing new insights into situational inductions that can boost creative performance. Theoretical and practical implications, limitations, and future directions of the work are discussed. PMID- 30459670 TI - Dual-Tasking in the Near-Hand Space: Effects of Stimulus-Hand Proximity on Between-Task Shifts in the Psychological Refractory Period Paradigm. AB - Two decades of research indicate that visual processing is typically enhanced for items that are in the space near the hands (near-hand space). Enhanced attention and cognitive control have been thought to be responsible for the observed effects, amongst others. As accumulating experimental evidence and recent theories of dual-tasking suggest an involvement of cognitive control and attentional processes during dual tasking, dual-task performance may be modulated in the near-hand space. Therefore, we performed a series of three experiments that aimed to test if the near-hand space affects the shift between task component processing in two visual-manual tasks. We applied a Psychological Refractory Period Paradigm (PRP) with varying stimulus-onset asynchrony (SOA) and manipulated stimulus-hand proximity by placing hands either on the side of a computer screen (near-hand condition) or on the lap (far-hand condition). In Experiment 1, Task 1 was a number categorization task (odd vs. even) and Task 2 was a letter categorization task (vowel vs. consonant). Stimulus presentation was spatially segregated with Stimulus 1 presented on the right side of the screen, appearing first and then Stimulus 2, presented on the left side of the screen, appearing second. In Experiment 2, we replaced Task 2 with a color categorization task (orange vs. blue). In Experiment 3, Stimulus 1 and Stimulus 2 were centrally presented as a single bivalent stimulus. The classic PRP effect was shown in all three experiments, with Task 2 performance declining at short SOA while Task 1 performance being relatively unaffected by task-overlap. In none of the three experiments did stimulus-hand proximity affect the size of the PRP effect. Our results indicate that the switching operation between two tasks in the PRP paradigm is neither optimized nor disturbed by being processed in near-hand space. PMID- 30459672 TI - Vocabulary, Metalinguistic Awareness and Language Dominance Among Bilingual Preschool Children. AB - Awareness of language structure has been studied in bilinguals, but there is limited research on how language dominance is related to metalinguistic awareness, and whether metalinguistic awareness predicts vocabulary size. The present study aims to explore the role of language dominance in the relation between vocabulary size in both languages of bilingual children and metalinguistic awareness in the societal language. It evaluates the impact of two metalinguistic awareness abilities, morphological and lexical awareness, on receptive and expressive vocabulary size. This is of special interest since most studies focus on the impact of exposure on vocabulary size but very few explore the impact of the interaction between metalinguistic awareness and dominance. 5-6 year-old preschool children with typical language development participated in the study: 15 Russian-Hebrew bilingual children dominant in the societal language (SL) Hebrew, 21 Russian-Hebrew bilingual children dominant in the Heritage language (HL) Russian and 32 monolingual children. Dominance was determined by relative proficiency, based on standardized tests in the two languages. Tasks of morphological and lexical awareness were administered in SL-Hebrew, along with measures of receptive and expressive vocabulary size in both languages. Vocabulary size in SL-Hebrew was significantly higher for SL-dominant bilinguals (who performed like monolinguals) than for HL-dominant bilinguals, while HL Russian vocabulary size was higher for HL-dominant bilinguals than for SL dominant bilinguals. A hierarchical regression analyzing the relationship between vocabulary size and metalinguistic awareness showed that dominance, lexical metalinguistic awareness and the interaction between the two were predictors of both receptive and expressive vocabulary size. Morphological metalinguistic awareness was not a predictor of vocabulary size. The relationship between lexical awareness and SL-vocabulary size was limited to the HL-dominant group. HL dominant bilinguals relied on lexical metalinguistic awareness, measured by fast mapping abilities, that is, the abilities to acquire new words, in expanding their vocabulary size, whereas SL-dominant bilinguals and monolinguals did not. This difference reflects the milestones of lexical acquisition the different groups have reached. These findings show that metalinguistic awareness should also be taken into consideration when evaluating the variables that influence vocabulary size among bilinguals though different ways in different dominance groups. PMID- 30459671 TI - Impact of Language Experience on Attention to Faces in Infancy: Evidence From Unimodal and Bimodal Bilingual Infants. AB - Faces capture and maintain infants' attention more than other visual stimuli. The present study addresses the impact of early language experience on attention to faces in infancy. It was hypothesized that infants learning two spoken languages (unimodal bilinguals) and hearing infants of Deaf mothers learning British Sign Language and spoken English (bimodal bilinguals) would show enhanced attention to faces compared to monolinguals. The comparison between unimodal and bimodal bilinguals allowed differentiation of the effects of learning two languages, from the effects of increased visual communication in hearing infants of Deaf mothers. Data are presented for two independent samples of infants: Sample 1 included 49 infants between 7 and 10 months (26 monolinguals and 23 unimodal bilinguals), and Sample 2 included 87 infants between 4 and 8 months (32 monolinguals, 25 unimodal bilinguals, and 30 bimodal bilingual infants with a Deaf mother). Eye-tracking was used to analyze infants' visual scanning of complex arrays including a face and four other stimulus categories. Infants from 4 to 10 months (all groups combined) directed their attention to faces faster than to non-face stimuli (i.e., attention capture), directed more fixations to, and looked longer at faces than non-face stimuli (i.e., attention maintenance). Unimodal bilinguals demonstrated increased attention capture and attention maintenance by faces compared to monolinguals. Contrary to predictions, bimodal bilinguals did not differ from monolinguals in attention capture and maintenance by face stimuli. These results are discussed in relation to the language experience of each group and the close association between face processing and language development in social communication. PMID- 30459674 TI - First Language Attrition and Dominance: Same Same or Different? AB - We explore the relationship between first language attrition and language dominance, defined here as the relative availability of each of a bilingual's languages with respect to language processing. We assume that both processes might represent two stages of one and the same phenomenon (Schmid and Kopke, 2017; Kopke, 2018). While many researchers agree that language dominance changes repeatedly over the lifespan (e.g., Silva-Corvalan and Treffers-Daller, 2015), little is known about the precise time scales involved in dominance shifts and attrition. We investigate these time scales in a longitudinal case study of pronominal subject production by a near-native L2-German (semi-null subject and topic-drop but non-pro-drop) and L1-Bulgarian (pro-drop) bilingual speaker with 17 years of residence in Germany. This speaker's spontaneous speech showed a significantly higher rate of overt pronominal subjects in her L1 than the controls' rates when tested in Germany. After 3 weeks of L1-reexposure in Bulgaria, however, attrition effects disappeared and the overt subject rate fell within the monolinguals' range (Genevska-Hanke, 2017). The findings of this first investigation are now compared to those of a second investigation 5 years later, involving data collection in both countries with the result that after 17 years of immigration, no further attrition was attested and the production of overt subjects remained monolingual-like for the data collections in both language environments. The discussion focuses on the factors that are likely to explain these results. First, these show that attrition and language dominance are highly dependent on immediate language use context and change rapidly when the language environment is modified. Additionally, the data obtained after L1-reexposure illustrate that time scales involved in dominance shift or attrition are much shorter than previously thought. Second, the role of age of acquisition in attrition has repeatedly been acknowledged. The present study demonstrates that attrition of a highly entrenched L1 is a phenomenon affecting language processing only temporarily and that it is likely to regress quickly after reexposure or return to balanced L1-use. The discussion suggests that dominance shift and attrition probably involve similar mechanisms and are influenced by the same external factors, showing that both may be different steps of the same process. PMID- 30459673 TI - Borderline Personality Disorder in Adolescence as a Generalization of Disorganized Attachment. AB - Several researchers point to disorganized attachment as a core feature of borderline personality disorder (BPD). However, recent studies suggest that specific internal working models (IWMs) of each parent combine to account for child outcomes and that a secure relationship with one parent can protect against the deleterious effects of an insecure relationship with the other parent. It was thus hypothesized that adolescents with BPD are more likely to be disorganized with both their parents, whereas non-clinical controls are more secure with at least one of their caregivers. Thirty-six adolescents with BPD and 30 control participants (aged 13-19) were included. Psychiatrist diagnosis was verified with the Structured Interview for DSM-IV Personality Disorders (SIDP-IV) and comorbidity was assessed using the Kiddie-SADS. Reported trauma was assessed with the Childhood Trauma Questionnaire (CTQ). Attachment IWMs of each parent were assessed with the Attachment Multiple Model Interview (AMMI), which enables separate coding for each attachment figure and in which disorganization is conceptualized as conflicting attachment strategies within a specific relationship. Results of a logistic regression analysis suggested that beyond insecure attachment, being disorganized not just with one but with both parents is particularly characteristic of adolescents with BPD. Conversely, belonging to the non-clinical group was predicted by higher security scores with the father and lower deactivation with the mother. Although higher levels of childhood abuse or neglect were reported by adolescents with BPD, the retained attachment dimensions predicted group membership over and above reported trauma. These findings have important implications for clinical intervention and highlight the protective role fathers may have. PMID- 30459675 TI - Testing Trait-State Isomorphism in a New Domain: An Exploratory Manipulation of Openness to Experience. AB - The trait-state isomorphism hypothesis holds that personality traits and states (i.e., trait-related behavior) are characterized by similar outcomes (Fleeson, 2001). Openness is associated with creative thinking, personal growth, and positive affect. Engaging in behavior associated with openness has also been found to covary with feelings of authenticity. In the present experiment, participants (N = 210) completed a pre-test assessment, five daily exercises designed to either be inert (control condition) or engage the behaviors and cognitions associated with openness (experimental condition), a post-test assessment, and a 2 week follow up assessment. Results supported the isomorphism hypothesis for positive affect but not creative thinking ability or personal growth. Furthermore, open behavior was only associated with authenticity for individuals high on trait openness. PMID- 30459678 TI - Colombian Elders and Their Use of Handheld Digital Devices. AB - Technological advances in the information and knowledge society have influenced and transformed economic, social, and educational dynamics. Currently there are many digital gaps related to the access to technology, level of digital literacy, and social use. These gaps vary based on the age of the population and become more noticeable among elders. Digital illiteracy leads to the underusing of technological developments of the 21st century, making it difficult to take advantage of all the possibilities that they offer to our society. This study aims to analyze the level of penetration and use of handheld digital devices, especially the cellular phone, among the adult population. This study is based on the 2016 National Survey of Life Quality in Colombia, elaborated by Departamento Administrativo Nacional de Estadistica-DANE, specifically on the module of ownership and use of ICT goods. Results of four age groups are compared, which include 32 year olds or under, from ages 33 to 45 years, 46 to 59 years, and over 60 years. The sample consists of 37047 inhabitants of the Colombian territory, grouped by regions (Antioquia, Bogota, Caribbean, Eastern Central, Orinoquia, Amazonia, Pacific, San Andres, and Valle del Cauca). Data have been analyzed by descriptive and inferential statistical procedures, contingency tables analyses, and logistic regression, in order to identify and know the effect of age on the level of penetration and use of handheld digital devices when comparing results in young adults and elderly people. Findings show that young adults use these technologies to a greater proportion when compared to older adults, showing a significant correlation between age and the increase of digital gaps in access and social use of handheld digital devices. Results also make evident that digital divide in Colombia may be associated to the place of residence, as people who live in rural zones are the ones who suffer greater from inequalities. PMID- 30459677 TI - Measuring the Timing of the Bilingual Advantage. AB - Empirical evidence has supported the idea that the bilingual advantage is a question of nuanced differences between bilinguals and monolinguals. In this article, I review findings from studies using eye tracking, mouse tracking, and event-related potentials (ERPs) which are particularly suited to measure time. Understanding the timing of the processes underlying executive function is crucial in evaluating the intricacies of the bilingual mind. Furthermore, I provide recommendations on how to best use these timing techniques to compare bilinguals and monolinguals. Temporal differences can characterize ongoing discussions of the bilingual advantage and help explain conflicting findings. Methodological and analytical innovations to better investigate the timing of the cognitive processes at play will inform a wide range of areas in cognitive science. PMID- 30459676 TI - The Effect of Art Expertise on Eye Fixation-Related Potentials During Aesthetic Judgment Task in Focal and Ambient Modes. AB - This study aimed to determine the effect of expertise on the eye fixation-related potentials (EFRPs) during the aesthetic evaluation of images, independently in focal and ambient modes of visual processing. Focal and ambient modes were identified by averaging EFRP waveforms about the beginning of long eye fixations followed by short saccades and short fixations followed by long saccades, respectively. Thirty experts with formal training in visual arts and thirty-two non-experts freely viewed 150 figurative paintings presented for 20 s, each. After viewing the painting, the participant answered the question: "Is this painting beautiful?" Differences were found between the group of experts and non experts due to the amplitude of EFRPs but only in focal mode, which is related to top-down, focused attention on the objects. Long fixations of experts had a higher amplitude of the parietal P2 recorded from right site than non-experts. In the group of experts, the frontal P2 was higher for long fixations on not beautiful paintings in comparison to long fixation on beautiful paintings. Moreover, in focal mode, there were higher occipital lambda response and N1-P2 complex for not beautiful than beautiful paintings. These results are discussed in the light of the results of studies on the effect of visual art expertise on event-related potentials (ERPs), ERP studies during aesthetic judgment task, and the knowledge of different modes of visual processing and EFRPs. PMID- 30459679 TI - The Role of Auditory Feedback at Vocalization Onset and Mid-Utterance. AB - Auditory feedback plays an important role in monitoring and correcting for errors during speech production. Previous research suggests that at vocalization onset, auditory feedback is compared to a sensory prediction generated by the motor system to ensure the desired fundamental frequency (F0) is produced. After vocalization onset, auditory feedback is compared to the most recently perceived F0 in order to stabilize the vocalization. This study aimed to further investigate whether after vocalization onset, auditory feedback is used strictly to stabilize speakers' F0, or if it is also influenced by the sensory prediction generated by the motor system. Event-related potentials (ERP) were recorded while participants produced vocalizations and heard the F0 of their auditory feedback perturbed suddenly mid-utterance by half a semitone. For half of the vocalizations, at vocalization onset, participants' F0 was also raised by half a semitone. Thus, half of the perturbations occurred while participants heard their unaltered auditory feedback, and the other half occurred in auditory feedback that had also been perturbed 50 cents at vocalization onset. If after vocalization onset auditory feedback is strictly used to stabilize speakers' F0, then similarly sized vocal and ERP responses would be expected across all trials, regardless of whether the perturbation occurred while listening to altered or unaltered auditory feedback. Results indicate that the perturbations to the participants' unaltered auditory feedback resulted in larger vocal and N1 and P2 ERP responses than perturbations to their altered auditory feedback. These results suggest that after vocalization onset auditory feedback is not strictly used to stabilize speakers' F0, but is also used to ensure the desired F0 is produced. PMID- 30459680 TI - Sustained Effectiveness of Evidence-Based Parenting Programs After the Research Trial Ends. AB - Despite ample evidence of the efficacy and effectiveness of evidence-based parenting programs (EBPPs) within research-led environments, there is very little evidence of maintenance of effectiveness when programs are delivered as part of regular service provision. The present study examined the effectiveness of EBPPs provided during a period of sustained service-led implementation in comparison to research-led effectiveness evaluation. Data from 3706 parents who received EBPPs during sustained implementation by services were compared to data from 1390 parents who had participated in an earlier researcher-led effectiveness trial of a national roll-out of EBPPs in England. In both phases, parents completed measures of child behavior problems, parenting style and parental mental well being prior to starting parenting programs (pre-test), at the end of the programs (post) and at 12-months follow up. Results from Generalized Estimating Equations controlling for potential covariates indicated significant improvements in child behavior problems during sustained implementation, similar to the effectiveness phase; significant improvements in parenting style which were larger than the effectiveness phase at 12-month follow up; and significant improvements in parental mental well- being. Our findings demonstrate effective maintenance of gains when EBPPs are provided as part of regular provision across a large sample of English parents. Successful long-term implementation should consider effectiveness of EBPPs across the population, given the large contextual changes that take place between researcher-led evaluations and service take-up. Our findings support the integration of EBPPs in public health approaches to addressing child behavior problems and parent well-being. PMID- 30459681 TI - The Past, Present, and Future of Virtual and Augmented Reality Research: A Network and Cluster Analysis of the Literature. AB - The recent appearance of low cost virtual reality (VR) technologies - like the Oculus Rift, the HTC Vive and the Sony PlayStation VR - and Mixed Reality Interfaces (MRITF) - like the Hololens - is attracting the attention of users and researchers suggesting it may be the next largest stepping stone in technological innovation. However, the history of VR technology is longer than it may seem: the concept of VR was formulated in the 1960s and the first commercial VR tools appeared in the late 1980s. For this reason, during the last 20 years, 100s of researchers explored the processes, effects, and applications of this technology producing 1000s of scientific papers. What is the outcome of this significant research work? This paper wants to provide an answer to this question by exploring, using advanced scientometric techniques, the existing research corpus in the field. We collected all the existent articles about VR in the Web of Science Core Collection scientific database, and the resultant dataset contained 21,667 records for VR and 9,944 for augmented reality (AR). The bibliographic record contained various fields, such as author, title, abstract, country, and all the references (needed for the citation analysis). The network and cluster analysis of the literature showed a composite panorama characterized by changes and evolutions over the time. Indeed, whether until 5 years ago, the main publication media on VR concerned both conference proceeding and journals, more recently journals constitute the main medium of communication. Similarly, if at first computer science was the leading research field, nowadays clinical areas have increased, as well as the number of countries involved in VR research. The present work discusses the evolution and changes over the time of the use of VR in the main areas of application with an emphasis on the future expected VR's capacities, increases and challenges. We conclude considering the disruptive contribution that VR/AR/MRITF will be able to get in scientific fields, as well in human communication and interaction, as already happened with the advent of mobile phones by increasing the use and the development of scientific applications (e.g., in clinical areas) and by modifying the social communication and interaction among people. PMID- 30459683 TI - How to Address Non-normality: A Taxonomy of Approaches, Reviewed, and Illustrated. AB - The linear model often serves as a starting point for applying statistics in psychology. Often, formal training beyond the linear model is limited, creating a potential pedagogical gap because of the pervasiveness of data non-normality. We reviewed 61 recently published undergraduate and graduate textbooks on introductory statistics and the linear model, focusing on their treatment of non normality. This review identified at least eight distinct methods suggested to address non-normality, which we organize into a new taxonomy according to whether the approach: (a) remains within the linear model, (b) changes the data, and (c) treats normality as informative or as a nuisance. Because textbook coverage of these methods was often cursory, and methodological papers introducing these approaches are usually inaccessible to non-statisticians, this review is designed to be the happy medium. We provide a relatively non-technical review of advanced methods which can address non-normality (and heteroscedasticity), thereby serving a starting point to promote best practice in the application of the linear model. We also present three empirical examples to highlight distinctions between these methods' motivations and results. The paper also reviews the current state of methodological research in addressing non-normality within the linear modeling framework. It is anticipated that our taxonomy will provide a useful overview and starting place for researchers interested in extending their knowledge in approaches developed to address non-normality from the perspective of the linear model. PMID- 30459684 TI - Putative Markers of Repression in Patients Suffering From Mental Disorders. AB - Background: The concept of psychodynamic conflict is essential to psychodynamic theory and therapy. In classical psychodynamic therapy, unconscious conflict themes need to be identified by the therapist and brought to the patient's awareness, in order to work through and ultimately solve them. According to theory, touching upon conflict-related topics leads to arousal, followed by activation of defense mechanisms such as repression. Starting with C.G. Jung's association studies more than 100 years ago, various proposals have been made to investigate psychodynamic conflicts based on free association and psychophysiological measures. This study presents an attempt to identify and differentiate between psychodynamic conflict themes in patients, using an adopted version of Jung's paradigm that had in previous studies been applied to healthy subjects. Method: Seventeen patients suffering from depression and other mental disorders associated freely to different cue sentences. Prior to the experimental procedure, patients' individual psychodynamic conflict types were assessed through clinical interviews. Sentences were either neutral, negative (but not conflict-related), or related to specific types of psychodynamic conflicts. Memory for the first three associations was later tested in an unexpected recall task. Skin conductance response (SCR) was recorded and analyzed together with reaction times (RTs) and self-ratings of emotional valence, arousal, and agreement with cue sentences. Results: Patients showed reduced memory performance for associations to conflict-related sentences in general, compared with negative and neutral sentences. Agreement with conflict-related sentences was lower compared to neutral but not negative sentences. Memory was negatively correlated with RTs and SCR. RTs were longer for conflict types that had been rated as relevant in clinical interviews prior to the association task, compared to the other, non-relevant conflict types. Conclusion: Our study shows that some putative markers of repression of psychodynamic conflicts previously established in healthy participants also occur in patients. Moreover, it provides evidence that general conflict effects differ from specific effects of personally relevant conflicts. PMID- 30459682 TI - Better, Not Just More-Contrast in Qualitative Aspects of Reward Facilitates Impulse Control in Pigs. AB - Delay-of-gratification paradigms, such as the famous "Marshmallow Test," are designed to investigate the complex cognitive concepts of self-control and impulse control in humans and animals. Such tests determine whether a subject will demonstrate impulse control by choosing a large, delayed reward over an immediate, but smaller reward. Documented relationships between impulsive behavior and aggression in humans and animals suggest important implications for farm animal husbandry and welfare, especially in terms of inadequate social behavior, tail biting and maternal behavior. In a preliminary study, we investigated whether the extent of impulse control would differ between quantitatively and qualitatively different aspects of reward in pigs. Twenty female piglets were randomly divided into two groups, with 10 piglets each. After a preference test to determine individual reward preference among six different food items, a discrimination test was conducted to train for successful discrimination between different amounts of reward (one piece vs. four pieces) and different qualitative aspects of reward (highly preferred vs. least preferred food item). Then, an increasing delay (2, 4, 8, 16, 24, 32 s) was introduced for the larger/highly preferred reward. Each piglet could choose to get the smaller/least preferred reward immediately or to wait for the larger/highly preferred reward. Piglets showed clear differences in their preference for food items. Moreover, the "quality group" displayed faster learning in the discrimination test (number of sessions until 90% of the animals completed the discrimination test: "quality group"-3 days vs. "quantity group"-5 days) and reached a higher level of impulse control in the delay-of-gratification test compared to the "quantity group" (maximum delay that was mastered: "quality group"-24 s vs. "quantity group"-8 s). These results demonstrate that impulse control is present in piglets but that the opportunity to get a highly preferred reward is more valued than the opportunity to get more of a given reward. This outcome also underlines the crucial role of motivation in cognitive test paradigms. Further investigations will examine whether impulse control is related to traits that are relevant to animal husbandry and welfare. PMID- 30459685 TI - When Suddenly Nothing Works Anymore Within a Team - Causes of Collective Sport Team Collapse. AB - Collective team collapse occurs when multiple players of a sport team experience a sudden and extreme underperformance within a game. To date, minimal research has been conducted on the causes of collective team collapse. Thus, goals of this study were to explore perceived causes of collective team collapse in different sports and to define team collapse in contrast to negative momentum. To investigate factors causing and maintaining collective sport team collapse, an inductive, exploratory qualitative analysis of individual interviews was conducted. Semi-structured interviews were carried out with 10 athletes of professional German teams of various sports playing in between first and fourth division. Participants were interviewed about a team collapse event they had experienced with their team during the past year. Data were collected and analyzed using a grounded theory methodology. Collective team collapse appeared to be induced by a temporal cascade of causes rather than by single triggers. This cascade included antecedents, which represent factors that make the occurrence of a team collapse more likely; critical events, which include specific events within the game that trigger a team collapse; as well as affective, cognitive, and behavioral outcomes that foster a maintenance of the collapse. Within this theoretical framework, social factors, such as decreased performance contagion or emotional contagion, played crucial roles in causing a team collapse. These results illustrate that collective team collapse is more than the sum of individual choking of multiple players at the same time. In conclusion, a new definition, differentiating team collapse from negative momentum, is introduced. Furthermore, a process model of causes of collective team collapse is proposed. The results provide first insights into causes of collective collapse in a variety of team sports. The developed model is supposed to help future research to better connect to practice and to support athletes, coaches, and sport psychologists. PMID- 30459686 TI - General Parenting Styles and Children's Obesity Risk: Changing Focus. PMID- 30459687 TI - Magic Performances - When Explained in Psychic Terms by University Students. AB - Paranormal beliefs (PBs), such as the belief in the soul, or in extrasensory perception, are common in the general population. While there is information regarding what these beliefs correlate with (e.g., cognitive biases, personality styles), there is little information regarding the causal direction between these beliefs and their correlates. To investigate the formation of beliefs, we use an experimental design, in which PBs and belief-associated cognitive biases are assessed before and after a central event: a magic performance (see also Mohr et al., 2018). In the current paper, we report a series of studies investigating the "paranormal potential" of magic performances (Study 1, N = 49; Study 2, N = 89; Study 3, N = 123). We investigated (i) which magic performances resulted in paranormal explanations, and (ii) whether PBs and a belief-associated cognitive bias (i.e., repetition avoidance) became enhanced after the performance. Repetition avoidance was assessed using a random number generation task. After the performance, participants rated to what extent the magic performance could be explained in psychic (paranormal), conjuring, or religious terms. We found that conjuring explanations were negatively associated with religious and psychic explanations, whereas religious and psychic explanations were positively associated. Enhanced repetition avoidance correlated with higher PBs ahead of the performance. We also observed a significant increase in psychic explanations and a drop in conjuring explanations when performances involved powerful psychic routines (e.g., the performer contacted the dead). While the experimentally induced enhancement of psychic explanations is promising, future studies should account for potential variables that might explain absent framing and before after effects (e.g., emotion, attention). Such effects are essential to understand the formation and manipulation of belief. PMID- 30459689 TI - Digital Media, the Right to an Open Future, and Children 0-5. PMID- 30459688 TI - Can Simulator Sickness Be Avoided? A Review on Temporal Aspects of Simulator Sickness. AB - Simulator sickness is a syndrome similar to motion sickness, often experienced during simulator or another virtual reality (VR) exposure. Many theories have been developed or adapted from the motion sickness studies, in order to explain the existence of the syndrome. The simulator sickness can be measured using both subjective and objective methods. The most popular self-report method is the Simulator Sickness Questionnaire. Attempts have also been made to discover a physiological indicator of the described syndrome, but no definite conclusion has been reached on this issue. In the present paper, three temporal aspects of the simulator sickness are discussed: the temporal trajectory of the progression of simulator sickness, possibility of adapting VR users in advance and persistence of the symptoms after VR exposure. Evidence found in 39 articles is widely described. As for the first aspect, it is clear that in most cases severity of the simulator sickness symptoms increases with time of exposure, although it is impossible to develop a single, universal pattern for this effect. It has also been proved, that in some cases a threshold level or time point exists, after which the symptoms stop increasing or begin to decrease. The adaptation effect was proved in most of the reviewed studies and observed in different study designs - e.g., with a couple of VR exposures on separate days or on 1 day and with a single, prolonged VR exposure. As for the persistence of the simulator sickness symptoms after leaving the VR, on the whole the study results suggest that such an effect exists, but it varies strongly between individual studies - the symptoms may persist for a short period of time (10 min) or a relatively long one (even 4 h). Considering the conclusions reached in the paper, it is important to bear in mind that the virtual reality technology still evokes unpleasant sensations in its users and that these sensations should be cautiously controlled while developing new VR tools. Certainly, more research on this topic is necessary. PMID- 30459690 TI - Can Interpersonal Behavior Influence the Persistence and Adherence to Physical Exercise Practice in Adults? A Systematic Review. AB - Objective: Motivation seems to be a fundamental indicator of long-term physical exercise adherence. Self-Determination Theory (SDT) argues that social environment plays a central role in the satisfaction of basic psychological needs, which might directly affect the quality of one's motivation. Individuals who appear to be more self-determined tend to persist longer at certain behaviors. Therefore, this body of work intends to analyze the relationship between motivational variables and behavioral outcomes in the exercise context, having as theoretical background the Self-Determination Theory. Methods: This systematic review was conducted through an electronic search on Web of Science, PubMed, SPORTDiscus, and PsycINFO. Data such as instruments, main predictors and results were collected from studies published between 1985 and 2018. A total of 35 empirical studies were considered for a detailed analysis. Results: Results showed the relevance of autonomy support performed by exercise professionals, as well as the major contribution that these behaviors have toward the satisfaction of basic psychological needs, besides the inherent benefits of developing more autonomous regulations. According to the literature, few studies have analyzed interpersonal thwarting behavior and the way this relates to basic psychological needs' frustration. Nether less, there seems to be a negative relationship between less self-determined regulations and exercise practice. Conclusion: Despite the existence of numerous cross-sectional studies that demonstrate positive correlations between SDT and behavioral outcomes in the exercise context, longitudinal research that analyzes all six dimensions of interpersonal behaviors and their relationship with persistence and adherence to exercise proves to be crucial. However, according to this review, interventions based on SDT appear to be fundamental when it comes to promote the maintenance of a long term exercise practice. PMID- 30459691 TI - Integrating Differential Evolution Optimization to Cognitive Diagnostic Model Estimation. AB - A log-linear cognitive diagnostic model (LCDM) is estimated via a global optimization approach- differential evolution optimization (DEoptim), which can be used when the traditional expectation maximization (EM) fails. The application of the DEoptim to LCDM estimation is introduced, explicated, and evaluated via a Monte Carlo simulation study in this article. The aim of this study is to fill the gap between the field of psychometric modeling and modern machine learning estimation techniques and provide an alternative solution in the model estimation. PMID- 30459692 TI - Incorporating a Professional-Grade All-Class Project Into a Research Methods Course. PMID- 30459693 TI - Temporal Generalization of Synchronized Saccades Beyond the Trained Range in Monkeys. AB - Synchronized movements with external periodic rhythms, such as dancing to a beat, are commonly observed in daily life. Although it has been well established that some vocal learning species (including parrots and humans) spontaneously develop this ability, it has only recently been shown that monkeys are also capable of predictive and tempo-flexible synchronization to periodic stimuli. In our previous study, monkeys were trained to make predictive saccades for alternately presented visual stimuli at fixed stimulus onset asynchronies (SOAs) to obtain a liquid reward. The monkeys generalized predictive synchronization to novel SOAs in the middle of trained range, suggesting a capacity for tempo-flexible synchronization. However, it is possible that when encountering a novel tempo, the monkeys might sample learned saccade sequences from those for the short and long SOAs so that the mean saccade interval matched the untrained SOA. To eliminate this possibility, in the current study we tested monkeys on novel SOAs outside the trained range. Animals were trained to generate synchronized eye movements for 600 and 900-ms SOAs for a few weeks, and then were tested for longer SOAs. The accuracy and precision of predictive saccades for one untrained SOA (1200 ms) were comparable to those for the trained conditions. On the other hand, the variance of predictive saccade latency and the proportion of reactive saccades increased significantly in the longer SOA conditions (1800 and 2400 ms), indicating that temporal prediction of periodic stimuli was difficult in this range, similar to previous results on synchronized tapping in humans. Our results suggest that monkeys might share similar synchronization mechanisms with humans, which can be subject to physiological examination in future studies. PMID- 30459695 TI - Emotional Distress of Patients at End-of-Life and Their Caregivers: Interrelation and Predictors. AB - Background: Patients at the end of life and their families experience a strong emotional impact. The well-being of these patients and that of their family caregiver are related. Aim: To study the variables related with the emotional well-being of patients with and without cognitive impairment at the end of life and that of their primary family caregivers. Design: Cross- sectional study. Participants: Data was collected from 202 patients at the end of life with different diagnosis (COPD, cancer, and frail elderly) as well as from their respective 202 primary family caregivers. Results: Structural equation models indicated that the emotional state of the patients was best predicted by their functional independence and the burden of their family caregivers. In addition, the emotional state of the primary family caregiver was predicted by their burden and not by the cognitive state or the functional independence of the patient. Nevertheless, the burden of the family caregiver, which is the only variable predicting both the emotional state of the patient and that of the caregiver, was directly related with the functional independence of the patient and indirectly with the patient's cognitive state. Conclusion: The family caregiver's burden is an important factor to take into consideration when aiming to reduce the emotional distress of patients at the end of life with different diagnosis whether or not they present significant cognitive impairment- and that of their family caregivers. PMID- 30459696 TI - Virtual Integration Environment as an Advanced Prosthetic Limb Training Platform. AB - Background: Despite advances in prosthetic development and neurorehabilitation, individuals with upper extremity (UE) loss continue to face functional and psychosocial challenges following amputation. Recent advanced myoelectric prostheses offer intuitive control over multiple, simultaneous degrees of motion and promise sensory feedback integration, but require complex training to effectively manipulate. We explored whether a virtual reality simulator could be used to teach dexterous prosthetic control paradigms to individuals with UE loss. Methods: Thirteen active-duty military personnel with UE loss (14 limbs) completed twenty, 30-min passive motor training sessions over 1-2 months. Participants were asked to follow the motions of a virtual avatar using residual and phantom limbs, and electrical activity from the residual limb was recorded using surface electromyography. Eight participants (nine limbs), also completed twenty, 30-min active motor training sessions. Participants controlled a virtual avatar through three motion sets of increasing complexity (Basic, Advanced, and Digit) and were scored on how accurately they performed requested motions. Score trajectory was assessed as a function of time using longitudinal mixed effects linear regression. Results: Mean classification accuracy for passive motor training was 43.8 +/- 10.7% (14 limbs, 277 passive sessions). In active motor sessions, >95% classification accuracy (which we used as the threshold for prosthetic acceptance) was achieved by all participants for Basic sets and by 50% of participants in Advanced and Digit sets. Significant improvement in active motor scores over time was observed in Basic and Advanced sets (per additional session: beta-coefficient 0.125, p = 0.022; beta-coefficient 0.45, p = 0.001, respectively), and trended toward significance for Digit sets (beta-coefficient 0.594, p = 0.077). Conclusions: These results offer robust evidence that a virtual reality training platform can be used to quickly and efficiently train individuals with UE loss to operate advanced prosthetic control paradigms. Participants can be trained to generate muscle contraction patterns in residual limbs that are interpreted with high accuracy by computer software as distinct active motion commands. These results support the potential viability of advanced myoelectric prostheses relying on pattern recognition feedback or similar controls systems. PMID- 30459694 TI - A Critical Appraisal of the Social Norms Approach as an Interventional Strategy for Health-Related Behavior and Attitude Change. AB - The Social Norms Approach is a widely used intervention strategy for promoting positive health-related behaviors. The Approach operates on the premise that individuals misperceive their peers' behaviors and attitudes, with evidence of under- and over-estimations of behaviors and peer approval for a range of positive and negative behaviors respectively. The greater these misperceptions, the more likely an individual is to engage in negative behaviors such as consuming heavier amounts of alcohol and other substances and reduce positive behaviors such as eating healthily and using sun protection. However, there are many complexities associated with the use of social norms feedback in interventions and empirical studies. Many social norms interventions do not attempt to change misperceptions of social norms or measure changes in normative perceptions pre- and post-intervention. This has led to a conflation of generic social norms interventions with those that are explicitly testing the Approach's assumptions that it is misperceptions of peer norms which drive behavior. The aim of the present review was to provide a critical appraisal of the use of the Social Norms Approach as an intervention strategy for health-related behaviors, identify the current issues with its evidence base, highlight key opportunities and challenges facing the approach, and make recommendations for good practice when using the approach. There are three core challenges and areas for improved practice when using the Social Norms Approach. Firstly, improvements in the methodological rigor and clarity of reporting of 'social norms' research, ensuring that studies are testing the approach's assumption of the role of misperceptions on behaviors are differentiated from studies investigating other forms of 'social norms.' Secondly, the need for a more explicit, unified and testable theoretical model outlining the development of normative misperceptions which can be translated into interventional studies. Finally, a need for a more robust evaluation of social norms interventions in addition to randomized controlled trials, such as the inclusion of process evaluations, qualitative studies of participant experiences of social norms feedback, and alternative study designs better suited for real-world public health settings. Such improvements are required to ensure that the Social Norms Approach is adequately tested and evaluated. PMID- 30459697 TI - Manipulation of Human Verticality Using High-Definition Transcranial Direct Current Stimulation. AB - Background: Using conventional tDCS over the temporo-parietal junction (TPJ) we previously reported that it is possible to manipulate subjective visual vertical (SVV) and postural control. We also demonstrated that high-definition tDCS (HD tDCS) can achieve substantially greater cortical stimulation focality than conventional tDCS. However, it is critical to establish dose-response effects using well-defined protocols with relevance to clinically meaningful applications. Objective: To conduct three pilot studies investigating polarity and intensity-dependent effects of HD-tDCS over the right TPJ on behavioral and physiological outcome measures in healthy subjects. We additionally aimed to establish the feasibility, safety, and tolerability of this stimulation protocol. Methods: We designed three separate randomized, double-blind, crossover phase I clinical trials in different cohorts of healthy adults using the same stimulation protocol. The primary outcome measure for trial 1 was SVV; trial 2, weight bearing asymmetry (WBA); and trial 3, electroencephalography power spectral density (EEG-PSD). The HD-tDCS montage comprised a single central, and 3 surround electrodes (HD-tDCS3x1) over the right TPJ. For each study, we tested 3x2 min HD tDCS3x1 at 1, 2 and 3 mA; with anode center, cathode center, or sham stimulation, in random order across days. Results: We found significant SVV deviation relative to baseline, specific to the cathode center condition, with consistent direction and increasing with stimulation intensity. We further showed significant WBA with direction governed by stimulation polarity (cathode center, left asymmetry; anode center, right asymmetry). EEG-PSD in the gamma band was significantly increased at 3 mA under the cathode. Conclusions: The present series of studies provide converging evidence for focal neuromodulation that can modify physiology and have behavioral consequences with clinical potential. PMID- 30459698 TI - The Epidemiological Characteristics of Epilepsy in the Province of Khyber Pakhtunkhwa, Pakistan. AB - Previous studies have shown that Khyber Pakhtunkhwa, Pakistan has a high incidence of epilepsy and a high proportion of low socioeconomic background and high treatment gap. Considering the changes over the past 20 years little is known about the current epidemiological characteristics of epilepsy in Khyber Pakhtunkhwa, Pakistan. The current study was focused to find the impact of various contributing factors on the clinical response to anti-epileptic drugs in the KP population, Pakistan. A total of 315 participants aged 19.1 +/- 8.6 years were examined. Mean age of the patients was 18 +/- 8.1 year. Epilepsy was high in male patients (64.39%) and urban areas (60.1%). Mostly, 88.6% of patients were belonging to low socioeconomic status background. 42.4% patients have positive family history for epilepsy and 42.8% patients had consanguineous marriages. Middle SES class patients (OR, 2.22 [CI, 0.54-9.1]) were slightly associated with controlled response to CBZ and VPA therapy. Absence seizure (OR, 1.16 [CI, 0.59 2.3]), and Complex partial seizure (OR, 1.29 [CI, 0.58-6.3]) showed good response to CBZ therapy while, Myoclonic seizure (OR, 2.23 [CI, 0.05-8.8]) was responsive to VPA therapy. However, non-compliance (R 2 0.82, P < 0.0001) and nature of seizures (R 2 0.83, P < 0.0001) were associated with the high risk for poor response to both CBZ and VPA therapy. Epilepsy was high in male patients and in urban areas. Most patients were belonging to low socioeconomic status. Non compliance, low socioeconomic and nature of seizures strongly predict poor clinical response of anti-epileptic drugs therapy. PMID- 30459699 TI - Optical Coherence Tomography of Spontaneous Basilar Artery Dissection in a Patient With Acute Ischemic Stroke. AB - The diagnosis of intracranial arterial dissection (IAD) may be challenging and multimodal imaging techniques are often needed to confirm the diagnosis. Previous studies have based their criteria for diagnosis of IAD on conventional angiography, computed tomography, or magnetic resonance imaging. We report a case with acute ischemic stroke due to spontaneous basilar artery dissection in which intravascular optical coherence tomography (OCT) was used to show features of IAD. A 59-years-old woman presented with symptoms of acute ischemic stroke. Thrombosis related to basilar artery (BA) stenosis was assumed on conventional angiography; however, no clot was retrieved after mechanical thrombectomy (MT) and a restored BA caliber was observed after a rescue recanalization with the detachment of a self-expanding stent was performed. Spontaneous IAD was suspected; however, angiographic findings were ambiguous for confirming IAD. The patient remained symptom-free until 18-months follow-up. At this point, angiography showed restenosis at the proximal tapered length of the stent. In vivo OCT was performed to assess the pathological changes of the restenosis and confirm the diagnosis of IAD.OCT revealed BA dissection with the presence of remnant transverse flap, double lumen and mural hematoma. Imaging at multiple levels identified intimal disruption that originated in the right vertebral artery and extended distally to the BA. The use of intravascular imaging with OCT enabled the accurate diagnosis of IAD. Care should be taken as the procedure may add additional risks to the patient. Future studies are needed to validate the safety of OCT in IAD. PMID- 30459701 TI - MRI Lesion Load of Cerebral Small Vessel Disease and Cognitive Impairment in Patients With CADASIL. AB - Background and objective: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the best known and the most common monogenic small vessel disease (SVD). Cognitive impairment is an inevitable feature of CADASIL. Total SVD score and global cortical atrophy (GCA) scale were found to be good predictors of poor cognitive performance in community dwelling adults. We aimed to estimate the association between the total SVD score, GCA scale and the cognitive performance in patients with CADASIL. Methods: We enrolled 20 genetically confirmed CADASIL patients and 20 controls matched by age, gender, and years of education. All participants underwent cognitive assessments to rate the global cognition and individual domain of executive function, information processing speed, memory, language, and visuospatial function. The total SVD score and GCA scale were rated. Results: The CADASIL group performed worse than the controls on all cognition measures. Neither global cognition nor any separate domain of cognition was significantly different among patients grouped by total SVD score. Negative correlations between the GCA score and cognitive performance were observed. Approximately 40% of the variance was explained by the total GCA score in the domains of executive function, information processing speed, and language. The superficial atrophy score was associated with poor performance in most of the domains of cognition. Adding the superficial atrophy score decreased the prediction power of the deep atrophy score on cognitive impairment alone. Conclusions: The GCA score, not the total SVD score, was significantly associated with poor cognitive performance in patients with CADASIL. Adding the superficial atrophy score attenuated the prediction power of the deep atrophy score on cognitive impairment alone. PMID- 30459702 TI - Recurrent Cerebral Infarctions in Primary Sjogren Syndrome: A Case Report and Literature Review. AB - Recurrent cerebral infarctions are extremely rare in patients with primary Sjogren syndrome. We report a 66-year-old woman who was admitted to our hospital due to acute cerebral infarction with exacerbation of dysphagia and right-sided hemiplegia as the main symptoms. In the past 3 months, she had developed cerebral infarction twice, even though she had no risk factors for atherosclerosis. She was eventually diagnosed with primary Sjogren syndrome based on a long history of dryness of the eyes and mouth, positive anti-Ro(SSA) antibodies, and the findings of a labial salivary gland biopsy. The response to pulse methylprednisolone therapy after recurrent cerebral infarctions was poor. Thus we consider primary Sjogren syndrome patients with central nervous system involvement should be treated as soon as possible. PMID- 30459703 TI - Cerebral Venous Drainage in Patients With Space-Occupying Middle Cerebral Artery Infarction: Effects on Functional Outcome After Hemicraniectomy. AB - Background: Cerebral venous drainage might influence brain edema characteristics and functional outcome of patients with severe ischemic stroke. The purpose of the study was to evaluate whether hypoplasia of transverse sinuses or the internal jugular veins is associated with poor functional outcome in patients with space-occupying middle cerebral artery (MCA) infarction who underwent decompressive surgery. Methods: We performed a retrospective analysis of patients with space-occupying MCA infarction treated with decompressive surgery at our university hospital. The transverse sinuses and the internal jugular veins were evaluated on baseline images and categorized as normal, hypoplastic or occluded. We defined composite variables for ipsilateral, contralateral or any abnormal cerebral venous drainage. We assessed the functional outcome at 12 months with the modified Rankin scale (mRS) score and defined poor functional outcome as mRS scores 5 and 6. Results: We analyzed 88 patients with available baseline imaging data [mean [SD] patient age 53 (+/-9) years; median[IQR] time to decompressive surgery 31(22-51) h]. At 12 months 44 patients (50%) had a poor outcome. In univariate analysis neither ipsilateral (OR 1.98;95%CI: 0.75-5.40), nor contralateral (OR 1.56;95%CI: 0.59-4.24) or any (OR 1.6; 95%CI: 0.68-3.79) hypoplasia or occlusion of venous drainage were significantly associated with poor functional outcome. In multivariate analyses, higher patient age (OR 1.07;95%CI 1.01-1.14) and baseline stroke severity (OR 3.42;95%CI 1.31-9.40) were independent predictors of poor functional outcome, but not ipsilateral hypoplasia or occlusion of venous drainage (OR 1.31;95%CI 0.47-3.67). Conclusions: The cerebral venous drainage pattern was not significantly associated with poor functional outcome in our cohort of patients with space-occupying MCA infarction who underwent decompressive surgery. PMID- 30459700 TI - Outside in: Unraveling the Role of Neuroinflammation in the Progression of Parkinson's Disease. AB - Neuroinflammation is one of the most important processes involved in the pathogenesis of Parkinson's disease (PD). The current concept of neuroinflammation comprises an inflammation process, which occurs in the central nervous system due to molecules released from brain-resident and/or blood-derived immune cells. Furthermore, the evidence of the contribution of systemic delivered molecules to the disease pathogenesis, such as the gut microbiota composition, has been increasing during the last years. Under physiological conditions, microglia and astrocytes support the well-being and well-function of the brain through diverse functions, including neurotrophic factor secretion in both intact and injured brain. On the other hand, genes that cause PD are expressed in astrocytes and microglia, shifting their neuroprotective role to a pathogenic one, contributing to disease onset and progression. In addition, growth factors are a subset of molecules that promote cellular survival, differentiation and maturation, which are critical signaling factors promoting the communication between cells, including neurons and blood-derived immune cells. We summarize the potential targeting of astrocytes and microglia and the systemic contribution of the gut microbiota in neuroinflammation process archived in PD. PMID- 30459704 TI - The Clinical Picture of Psychosis in Manifest Huntington's Disease: A Comprehensive Analysis of the Enroll-HD Database. AB - Background: Psychotic symptoms have been under-investigated in Huntington's disease (HD) and research is needed in order to elucidate the characteristics linked to the unique phenotype of HD patients presenting with psychosis. Objective: To evaluate the frequency and factors associated with psychosis in HD. Methods: Cross-sectional study including manifest individuals with HD from the Enroll-HD database. Both conventional statistical analysis (Stepwise Binary Logistic Regression) and five machine learning algorithms [Least Absolute Shrinkage and Selection Operator (LASSO); Elastic Net; Support Vector Machines (SVM); Random Forest; and class-weighted SVM] were used to describe factors associated with psychosis in manifest HD patients. Results: Approximately 11% of patients with HD presented history of psychosis. Logistic regression analysis indicated that younger age at HD clinical diagnosis, lower number of CAG repeats, history of [alcohol use disorders, depression, violent/aggressive behavior and perseverative/obsessive behavior], lower total functional capacity score, and longer time to complete trail making test-B were associated with psychosis. All machine learning algorithms were significant (chi-square p < 0.05) and capable of distinguishing individual HD patients with history of psychosis from those without a history of psychosis with prediction accuracy around 71-73%. The most relevant variables were similar to those found in the conventional analyses. Conclusions: Psychiatric and behavioral symptoms as well as poorer cognitive performance were related to psychosis in HD. In addition, psychosis was associated with lower number of CAG repeats and younger age at clinical diagnosis of HD, suggesting that these patients may represent a unique phenotype in the HD spectrum. PMID- 30459705 TI - MicroRNA-21 Overexpression Promotes the Neuroprotective Efficacy of Mesenchymal Stem Cells for Treatment of Intracerebral Hemorrhage. AB - Intracerebral hemorrhage (ICH) has high morbidity and mortality, with no effective treatment at present. One possible therapeutic strategy involves the use of mesenchymal stem cells (MSCs), which have shown promise in experimental models and have great potential for treating nervous illnesses in humans. However, many deficiencies in MSC treatment still need to be addressed, including their poor survival rate post-transplantation. Previously, we reported that the microRNA-21 (miR-21) is downregulated in ICH patients' blood and brain tissue. In this study, we aimed to examine its role and therapeutic efficacy in ICH using miR-21-overexpressing MSCs. We found that this microRNA can enhance MSC survival and recovery of neurological function in ICH rats. Its mechanism of action involves reduced neuronal apoptosis. In addition, we demonstrated that miR-21 can be transported to neurons through exosomes derived from MSCs and that it can target transient receptor potential melastatin 7 (TRPM7) to alleviate neuronal injury following ICH. We also observed that the NF-kappaB pathway is involved in the regulation of miR-21 in neural cells. In conclusion, miR-21 significantly enhances the survival of MSCs in ICH, and miR-21-overexpressing MSCs clearly improved neurological function in ICH rats. Transplantation of miR-21 overexpressing MSCs may, therefore, provide an effective strategy for neuroprotection and treatment of cerebrovascular diseases. PMID- 30459706 TI - Low Risk Monitoring in Neurocritical Care. AB - Background/Rationale: Patients are admitted to Intensive care units (ICUs) either because they need close monitoring despite a low risk of hospital mortality (LRM group) or to receive ICU specific active treatments (AT group). The characteristics and differential outcomes of LRM patients vs. AT patients in Neurocritical Care Units are poorly understood. Methods: We classified 1,702 patients admitted to our tertiary and quaternary care center Neuroscience-ICU in 2016 and 2017 into LRM vs. AT groups. We compared demographics, admission diagnosis, goal of care status, readmission rates and managing attending specialty extracted from the medical record between groups. Acute Physiology, Age and Chronic Health Evaluation (APACHE) IVa risk predictive modeling was used to assess comparative risks for ICU and hospital mortality and length of stay between groups. Results: 56.9% of patients admitted to our Neuroscience-ICU in 2016 and 2017 were classified as LRM, whereas 43.1% of patients were classified as AT. While demographically similar, the groups differed significantly in all risk predictive outcome measures [APACHE IVa scores, actual and predicted ICU and hospital mortality (p < 0.0001 for all metrics)]. The most common admitting diagnosis overall, cerebrovascular accident/stroke, was represented in the LRM and AT groups with similar frequency [24.3 vs. 21.3%, respectively (p = 0.15)], illustrating that further differentiating factors like symptom duration, neurologic status and its dynamic changes and neuro-imaging characteristics determine the indication for active treatment vs. observation. Patients with intracranial hemorrhage/hematoma were significantly more likely to receive active treatments as opposed to having a primary focus on monitoring [13.6 vs. 9.8%, respectively (p = 0.017)]. Conclusion: The majority of patients admitted to our Neuroscience ICU (56.9%) had <10% hospital mortality risk and a focus on monitoring, whereas the remaining 43.1% of patients received active treatments in their first ICU day. LRM Patients exhibited significantly lower APACHE IVa scores, ICU and hospital mortality rates compared to AT patients. Observed-over expected ICU and hospital mortality ratios were better than predicted by APACHE IVa for low risk monitored patients and close to prediction for actively treated patients, suggesting that at least a subset of LRM patients may safely and more cost effectively be cared for in intermediate level care settings. PMID- 30459707 TI - Self-Care and Self-Management Among Adolescent T2DM Patients: A Review. AB - Uncontrolled hyperglycaemia can lead to macro- and microvascular complications. Adolescents with T2DM develop similar complications as in adults, including cardiovascular disease, stroke, myocardial infarction, renal insufficiency, and chronic renal failure. Although regular medical follow-up is essential to avoid long-term complications, patients with diabetes mellitus need to perform holistic self-care activities such as opting for a healthy diet, physical activity, self monitoring, and proper medication. To the best of our knowledge, only a limited number of studies have focused on self-care activities and self-management, including self-care practices, supportive networks, and self-care education programs in adolescent with T2DM. Some of the studies focused on the appreciation of self-care in adolescents with T2DM. This review aimed to analyse self-care and self-management among adolescents with T2DM, and discuss the impact of self-care and self-management on glycaemic control. The difficulties faced by adolescents in self-managing their disease are also highlighted. Such information is essential for healthcare providers in promoting self-care practices among adolescents with T2DM. A thorough search of the literature was performed using three databases: Medline, Google Scholar, and Scopus. The articles focused on self-care and self-management of adolescents patients with T2DM aged between 12 and 19 years old were included. Findings from this review reveal that healthy food adaptation, adequate physical activity, proper medication practices, and regular glucose monitoring are the most common self-care practices. Parental involvement and clinician encouragement also contribute toward the practice of self-care and self-management among the adolescents with T2DM. In conclusion, independent self-management regimens and supportive networks for appropriate administration are vital factors to enhance clinical outcomes of adolescents with T2DM. PMID- 30459709 TI - The Impact of the Biological Variability or Assay Performance on AMH Measurements: A Prospective Cohort Study With AMH Tested on Three Analytical Assay-Platforms. AB - This study examined longitudinal, age-related and intra-individual variation in Anti-Mullerian Hormone (AMH) in regular menstruating women and correlated the hormonal levels to the antral follicle count (AFC). The impact of variations on an algorithm for calculation of follitropin-dose for ovarian stimulation were also tested. The study was carried out at a fertility clinic of a tertiary university hospital and had a prospective trial design. Twenty-six healthy women not receiving infertility treatment aged 22 to 50 years participated. Blood sampling for hormonal analysis was done every fifth day throughout three consecutive menstrual cycles, AFC was determined with 3-dimentional ultrasound and AMH measured by different assays from Beckman Coulter, Roche and Ansh Labs. Outcome measures were maximum and minimum difference in absolute and relative terms for each study subject during the test-period, coefficient of variation (Cv) for AMH for each cycle and cycle-day and correlation between AMH and AFC. The impact from variable AMH levels on an algorithm calculating follitrophin delta dose in ovarian stimulation was explored. A significant longitudinal age independent variation in AMH-levels and coefficient of variation in cycles and cycle days was found. A strong correlation between AMH-levels and AFC was confirmed and a case of significant divergence between assays was seen. Variations in AMH had a significant impact on an algorithm calculated dosage of gonadotrophins in ovarian stimulation. The finding of a substantial longitudinal variation in AMH question one recording being sufficient in quantifying gonadotrophins for ovarian stimulation, decision making and prognostication related to infertility treatment and counseling. Occasionally, commercial assays may fail to recognize specific AMH cleavage-products. PMID- 30459708 TI - Involvement of O-GlcNAcylation in the Skeletal Muscle Physiology and Physiopathology: Focus on Muscle Metabolism. AB - Skeletal muscle represents around 40% of whole body mass. The principal function of skeletal muscle is the conversion of chemical energy toward mechanic energy to ensure the development of force, provide movement and locomotion, and maintain posture. This crucial energy dependence is maintained by the faculty of the skeletal muscle for being a central place as a "reservoir" of amino acids and carbohydrates in the whole body. A fundamental post-translational modification, named O-GlcNAcylation, depends, inter alia, on these nutrients; it consists to the transfer or the removal of a unique monosaccharide (N-acetyl-D-glucosamine) to a serine or threonine hydroxyl group of nucleocytoplasmic and mitochondrial proteins in a dynamic process by the O-GlcNAc Transferase (OGT) and the O GlcNAcase (OGA), respectively. O-GlcNAcylation has been shown to be strongly involved in crucial intracellular mechanisms through the modulation of signaling pathways, gene expression, or cytoskeletal functions in various organs and tissues, such as the brain, liver, kidney or pancreas, and linked to the etiology of associated diseases. In recent years, several studies were also focused on the role of O-GlcNAcylation in the physiology and the physiopathology of skeletal muscle. These studies were mostly interested in O-GlcNAcylation during muscle exercise or muscle-wasting conditions. Major findings pointed out a different "O GlcNAc signature" depending on muscle type metabolism at resting, wasting and exercise conditions, as well as depending on acute or long-term exhausting exercise protocol. First insights showed some differential OGT/OGA expression and/or activity associated with some differential stress cellular responses through Reactive Oxygen Species and/or Heat-Shock Proteins. Robust data displayed that these O-GlcNAc changes could lead to (i) a differential modulation of the carbohydrates metabolism, since the majority of enzymes are known to be O GlcNAcylated, and to (ii) a differential modulation of the protein synthesis/degradation balance since O-GlcNAcylation regulates some key signaling pathways such as Akt/GSK3beta, Akt/mTOR, Myogenin/Atrogin-1, Myogenin/Mef2D, Mrf4 and PGC-1alpha in the skeletal muscle. Finally, such involvement of O GlcNAcylation in some metabolic processes of the skeletal muscle might be linked to some associated diseases such as type 2 diabetes or neuromuscular diseases showing a critical increase of the global O-GlcNAcylation level. PMID- 30459711 TI - The Usefulness of Magnetic Resonance Imaging of the Cardiovascular System in the Diagnostic Work-Up of Patients With Turner Syndrome. AB - Cardiovascular defects occur in 50% of patients with Turner syndrome (TS). The aim of the study was to estimate the usefulness of cardiac magnetic resonance imaging (CMR) and magnetic resonance angiography (angio-MR) as diagnostics in children and adolescents with TS. Forty-one females with TS, aged 13.9 +/- 2.2 years, were studied. CMR was performed in 39 patients and angio-MR in 36. Echocardiography was performed in all patients. The most frequent anomalies diagnosed on CMR and angio-MR were as follows: elongation of the ascending aorta (AA) and aortic arch, present in 16 patients (45.7%), a bicuspid aortic valve (BAV), present in 16 patients (41.0%), and partial anomalous pulmonary venous return (PAPVR), present in six patients (17.1%). Aortic dilatation (Z-score > 2) was mostly seen at the sinotubular junction (STJ) (15 patients; 42.8%), the AA (15 patients; 42.8%), the thoracoabdominal aorta at the level of a diaphragm (15 patients; 42.8%), and the transverse segment (14 patients; 40.0%). An aortic size index (ASI) above 2.0 cm/m2 was present in six patients (17.1%) and above 2.5 cm/m2 in three patients (8.6%). The left ventricular end-diastolic volume (EDV), end-systolic volume (ESV), and stroke volume (SV) were diminished (Z-score < -2) in 10 (25.6%), 9 (23.1%), and 8 patients (20.5%), respectively. A webbed neck was correlated with the presence of vascular anomalies (p = 0.006). The age and body mass index (BMI) were correlated with the diameter of the aorta. Patients with BAV had a greater aortic diameter at the ascending aorta (AA) segment (p = 0.026) than other patients. ASI was correlated with aortic diameter and descending aortic diameter (AD/DD) ratio (p = 0.002; r = 0.49). There was a significant correlation between the right ventricular (p = 0.002, r = 0.46) and aortic diameters at the STJ segment (p = 0.0047, r = 0.48), as measured by echocardiography and CMR. Magnetic resonance can identify cardiovascular anomalies, dilatation of the aorta, pericardial fluid, and functional impairment of the ventricles not detected by echocardiography. BMI, age, BAV, and elongation of the AA influence aortic dilatation. The ASI and AD/DD ratio are important markers of aortic dilatation. The performed diagnostics did not indicate a negative influence of GH treatment on the cardiovascular system. PMID- 30459712 TI - Tissue-Based Mapping of the Fathead Minnow (Pimephales promelas) Transcriptome and Proteome. AB - Omics approaches are broadly used to explore endocrine and toxicity-related pathways and functions. Nevertheless, there is still a significant gap in knowledge in terms of understanding the endocrine system and its numerous connections and intricate feedback loops, especially in non-model organisms. The fathead minnow (Pimephales promelas) is a widely used small fish model for aquatic toxicology and regulatory testing, particularly in North America. A draft genome has been published, but the amount of available genomic or transcriptomic information is still far behind that of other more broadly studied species, such as the zebrafish. Here, we used a proteogenomics approach to survey the tissue specific proteome and transcriptome profiles in adult male fathead minnow. To do so, we generated a draft transcriptome using short and long sequencing reads from liver, testis, brain, heart, gill, head kidney, trunk kidney, and gastrointestinal tract. We identified 30,378 different putative transcripts overall, with the assembled contigs ranging in size from 264 to over 9,720 nts. Over 17,000 transcripts were >1,000 nts, suggesting a robust transcriptome that can be used to interpret RNA sequencing data in the future. We also performed RNA sequencing and proteomics analysis on four tissues, including the telencephalon, hypothalamus, liver, and gastrointestinal tract of male fish. Transcripts ranged from 0 to 600,000 copies per gene and a large portion were expressed in a tissue specific manner. Specifically, the telencephalon and hypothalamus shared the most expressed genes, while the gastrointestinal tract and the liver were quite distinct. Using protein profiling techniques, we identified a total of 4,045 proteins in the four tissues investigated, and their tissue-specific expression pattern correlated with the transcripts at the pathway level. Similarly to the findings with the transcriptomic data, the hypothalamus and telencephalon had the highest degree of similarity in the proteins detected. The main purpose of this analysis was to generate tissue-specific omics data in order to support future aquatic ecotoxicogenomic and endocrine-related studies as well as to improve our understanding of the fathead minnow as an ecological model. PMID- 30459713 TI - Intraoperative Decision-Making and Technical Aspects of Parathyroidectomy in Young Patients With MEN1 Related Hyperparathyroidism. AB - One in 5,000 to 1 in 50,000 births have multiple endocrine neoplasia type 1 (MEN1). MEN1 is a hereditary syndrome clinically defined by the presence of two of the following endocrine tumors in the same patient: parathyroid adenomas, entero-pancreatic endocrine tumors and pituitary tumors. Most commonly, patients with MEN1 manifest primarily with signs and symptoms linked to primary hyperparathyroidism. By age 50, it is estimated that 100% of patients with MEN1 will have been diagnosed with primary hyperparathyroidism. These patients will need to undergo resection of their hyperfunctioning glands, however there is no clear consensus on which procedure to perform and when to perform it in these patients. In this original study we describe and explain the rational of our peri operative approach and management at MD Anderson Cancer Center of MEN1 patients with hyperparathyroidism. This protocol includes preoperative evaluation, intraoperative decision-making and detailed surgical technique adopted for these patients' care. Additionally we review follow-up and disease management in instances of recurrent primary hyperparathyroidism in patients with MEN1 syndrome. PMID- 30459714 TI - Association Between Bone Mineral Density, Bone Turnover Markers, and Serum Cholesterol Levels in Type 2 Diabetes. AB - Purpose: The association between bone mineral density (BMD), bone turnover markers, and serum cholesterol in healthy population has already been proved. However, in patients with type 2 diabetes mellitus (T2D), it has not been adequately analyzed. In this study, we investigated the correlation between BMD, bone turnover markers, and serum cholesterol levels in people with T2D. Methods: We enrolled 1,040 men and 735 women with T2D from Zhongshan Hospital between October 2009 and January 2013. Their general condition, history of diseases and medication, serum markers, and BMD data were collected. We used logistic regression analysis to identify the association between serum cholesterol levels and BMD as well as bone turnover markers. Results: In multivariate regression analysis, we observed that in men with T2D, high high-density lipoprotein cholesterol and total cholesterol levels were significantly associated with low total lumbar, femur neck, and total hip BMD, while low-density lipoprotein cholesterol level was only inversely associated with total lumbar and femur neck BMD. Total cholesterol and low-density lipoprotein-cholesterol levels were also negatively associated with osteocalcin, procollagen type I N-terminal propeptide, and beta-crosslaps. In women with T2D, high-density lipoprotein-cholesterol level was observed to be negatively correlated with total lumbar, femur neck, and total hip BMD, while total cholesterol and low-density lipoprotein-cholesterol levels were only associated with BMD at the total lumbar. Furthermore, total cholesterol was also negatively associated with osteocalcin, procollagen type I N-terminal propeptide, and beta-crosslaps; high-density lipoprotein-cholesterol was only related to osteocalcin and parathyroid hormone, while low-density lipoprotein cholesterol was only related to beta-crosslaps in women. Conclusion: Our study suggests a significantly negative correlation between serum cholesterol levels and BMD in both men and women with T2D. The associations between serum cholesterol levels and bone turnover markers were also observed in T2D patients. PMID- 30459710 TI - A Novel Glycoproteomics Workflow Reveals Dynamic O-GlcNAcylation of COPgamma1 as a Candidate Regulator of Protein Trafficking. AB - O-linked beta-N-acetylglucosamine (O-GlcNAc) is an abundant and essential intracellular form of protein glycosylation in animals and plants. In humans, dysregulation of O-GlcNAcylation occurs in a wide range of diseases, including cancer, diabetes, and neurodegeneration. Since its discovery more than 30 years ago, great strides have been made in understanding central aspects of O-GlcNAc signaling, including identifying thousands of its substrates and characterizing the enzymes that govern it. However, while many O-GlcNAcylated proteins have been reported, only a small subset of these change their glycosylation status in response to a typical stimulus or stress. Identifying the functionally important O-GlcNAcylation changes in any given signaling context remains a significant challenge in the field. To address this need, we leveraged chemical biology and quantitative mass spectrometry methods to create a new glycoproteomics workflow for profiling stimulus-dependent changes in O-GlcNAcylated proteins. In proof-of principle experiments, we used this new workflow to interrogate changes in O GlcNAc substrates in mammalian protein trafficking pathways. Interestingly, our results revealed dynamic O-GlcNAcylation of COPgamma1, an essential component of the coat protein I (COPI) complex that mediates Golgi protein trafficking. Moreover, we detected 11 O-GlcNAc moieties on COPgamma1 and found that this modification is reduced by a model secretory stress that halts COPI trafficking. Our results suggest that O-GlcNAcylation may regulate the mammalian COPI system, analogous to its previously reported roles in other protein trafficking pathways. More broadly, our glycoproteomics workflow is applicable to myriad systems and stimuli, empowering future studies of O-GlcNAc in a host of biological contexts. PMID- 30459716 TI - Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation. AB - Metformin has been proposed to operate as an agonist of SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that mimics most of the metabolic responses to calorie restriction. Herein, we present an in silico analysis focusing on the molecular docking and dynamic simulation of the putative interactions between metformin and SIRT1. Using eight different crystal structures of human SIRT1 protein, our computational approach was able to delineate the putative binding modes of metformin to several pockets inside and outside the central deacetylase catalytic domain. First, metformin was predicted to interact with the very same allosteric site occupied by resveratrol and other sirtuin-activating compounds (STATCs) at the amino-terminal activation domain of SIRT1. Second, metformin was predicted to interact with the NAD+ binding site in a manner slightly different to that of SIRT1 inhibitors containing an indole ring. Third, metformin was predicted to interact with the C-terminal regulatory segment of SIRT1 bound to the NAD+ hydrolysis product ADP-ribose, a "C-pocket" related mechanism that appears to be essential for mechanism-based activation of SIRT1. Enzymatic assays confirmed that the net biochemical effect of metformin and other biguanides such as a phenformin was to improve the catalytic efficiency of SIRT1 operating in conditions of low NAD+ in vitro. Forthcoming studies should confirm the mechanistic relevance of our computational insights into how the putative binding modes of metformin to SIRT1 could explain its ability to operate as a direct SIRT1-activating compound. These findings might have important implications for understanding how metformin might confer health benefits via maintenance of SIRT1 activity during the aging process when NAD+ levels decline. PMID- 30459715 TI - Future Perspectives on GLP-1 Receptor Agonists and GLP-1/glucagon Receptor Co agonists in the Treatment of NAFLD. AB - Along the obesity pandemic, the prevalence of non-alcoholic fatty liver disease (NAFLD), often regarded as the hepatic manifestation of the metabolic syndrome, increases worldwide representing now the prevalent liver disease in western countries. No pharmacotherapy is approved for the treatment of NAFLD and, currently, the cornerstone treatment is lifestyle modifications focusing on bodyweight loss, notoriously difficult to obtain and even more difficult to maintain. Thus, novel therapeutic approaches are highly demanded. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are approved for the treatment of type 2 diabetes and obesity. They exert their body weight-lowering effect by reducing satiety and food intake. GLP-1RAs have also been shown to reduce liver inflammation and fibrosis. Furthermore, glucagon receptor agonism is being investigated for the treatment of NAFLD due to its appetite and food intake reducing effects, as well as its ability to increase lipid oxidation and thermogenesis. Recent studies suggest that glucagon receptor signaling is disrupted in NAFLD, indicating that supra-physiological glucagon receptor agonism might represent a new NAFLD treatment target. The present review provides (1) an overview in the pathophysiology of NAFLD, including the potential involvement of GLP-1 and glucagon, (2) an introduction to the currently available GLP-1RAs and (3) outlines the potential of emerging GLP-1RAs and GLP-1/glucagon receptor co agonists in the treatment of NAFLD. PMID- 30459718 TI - A Rapid Procedure for Identification and Antifungal Susceptibility Testing of Yeasts From Positive Blood Cultures. AB - The development of rapid diagnostic assays for the identification and analysis of antimicrobial resistance of fungal pathogens causing invasive mycoses is of utmost importance to reduce morbidity and mortality. We evaluated the performance of a novel rapid procedure directly applied to monomicrobial blood cultures from patients with bloodstream infection caused by yeast species, including nine Candida and three non-Candida species. For the rapid procedure herein developed, samples of positive blood cultures were transferred into serum separator tubes and treated with sodium dodecyl sulfate; the yeast layer was recovered and directly used for microbial identification by MALDI-TOF mass spectrometry and antifungal susceptibility testing (AFST) by the Sensititre YeastOne Y010 panel. The results were compared with those obtained by the same methods applied to colonies isolated on solid media. Using a score value of 1.700 as cut-off for valid identification, the rapid procedure identified 66 of 124 (53.2%) isolates, all of which concordantly with the reference method. However, adopting a cut-off >=1.300 and >=4 consecutive repetitions of the same species in the list of matches would extend concordant identification to 107/124 (86.3%) samples. Importantly, AFST revealed essential agreement between the two methods for all the isolate/antifungal drug combinations tested, including misidentified and not identified isolates. Therefore, the procedure herein developed represents a valid alternative for AFST of yeasts from positive blood cultures, yielding accurate and reliable results at least 24 h earlier than with the routine procedure, thus allowing clinicians to promptly streamline antifungal therapy. PMID- 30459717 TI - Insights Into the Bovine Milk Microbiota in Dairy Farms With Different Incidence Rates of Subclinical Mastitis. AB - Bovine mastitis continues to be a complex disease associated with significant economic loss in dairy industries worldwide. The incidence rate of subclinical mastitis (IRSCM) can show substantial variation among different farms; however, the milk microbiota, which have a direct influence on bovine mammary gland health, have never been associated with the IRSCM. Here, we aimed to use high throughput DNA sequencing to describe the milk microbiota from two dairy farms with different IRSCMs and to identify the predominant mastitis pathogens along with commensal or potential beneficial bacteria. Our study showed that Klebsiella, Escherichia-Shigella, and Streptococcus were the mastitis-causing pathogens in farm A (with a lower IRSCM), while Streptococcus and Corynebacterium were the mastitis-causing pathogens in farm B (with a higher IRSCM). The relative abundance of all pathogens in farm B (22.12%) was higher than that in farm A (9.82%). However, the genus Bacillus was more prevalent in farm A. These results may be helpful for explaining the lower IRSCM in farm A. Additionally, the gut associated genera Prevotella, Ruminococcus, Bacteroides, Rikenella, and Alistipes were prevalent in all milk samples, suggesting gut bacteria can be one of the predominant microbial contamination in milk. Moreover, Listeria monocytogenes (a foodborne pathogen) was found to be prevalent in farm A, even though it had a lower IRSCM. Overall, our study showed complex diversity between the milk microbiota in dairy farms with different IRSCMs. This suggests that variation in IRSCMs may not only be determined by the heterogeneity and prevalence of mastitis causing pathogens but also be associated with potential beneficial bacteria. In the future, milk microbiota should be considered in bovine mammary gland health management. This would be helpful for both the establishment of a targeted mastitis control system and the control of the safety and quality of dairy products. PMID- 30459719 TI - Evaluating the Potential for Resistance Development to Antimicrobial Blue Light (at 405 nm) in Gram-Negative Bacteria: In vitro and in vivo Studies. AB - Antimicrobial resistance is a threat to public health that requires our immediate attention. With increasing numbers of microbes that are becoming resistant to routinely used antimicrobials, it is vital that we look to other, non-traditional therapies for the treatment of infections. Antimicrobial blue light (aBL) is an innovative approach that has demonstrated efficacy for the inactivation of an array of microbial pathogens. In the present study, we investigated the potential for resistance development to aBL in Gram-negative pathogenic bacteria by carrying out multiple aBL exposures on bacteria. In the first aBL exposure, clinical isolates of Pseudomonas aeruginosa, Acinetobacter baumannii, and uropathogenic Escherichia coli [107 colony forming units/mL (CFU/mL)] were irradiated in phosphate-buffered saline with aBL at 405 nm until a >99.99% reduction in bacterial viability was achieved. Irradiation was then repeated for each bacterial species over 20 cycles of aBL exposure. The potential for resistance development to aBL was also investigated in vivo, in superficial mouse wounds infected with a bioluminescent strain of P. aeruginosa (PAO1; 108 CFU) and irradiated with a sub-curative radiant exposures of 108 or 216 J/cm2 aBL over 5 cycles of treatment (over 5 days) prior to bacterial isolation from the animal tissue. PAO1 isolated from infected tissue were treated with aBL at 216 J/cm2, in vitro, in parallel with unexposed PAO1 or PAO1 isolates from mouse wound infections not treated with aBL. No statistically significant correlation was found between the aBL-susceptibility of bacteria in vitro and the number of cycles of aBL exposure any bacterial species (P >= 0.26). In addition, serial exposure of infected mouse wounds to aBL did not result in any change in the susceptibility to aBL of PAO1 (P = 0.97). In conclusion, it is unlikely that sequential exposure to aBL will result in aBL-resistance in Gram-negative bacteria. Also, multiple aBL treatments may potentially be administered to an infected wound without resistance development becoming a concern. PMID- 30459720 TI - Genomic Characterization of Extended-Spectrum Cephalosporin-Resistant Salmonella enterica in the Colombian Poultry Chain. AB - Salmonella enterica serovars have been isolated from Colombian broilers and broiler meat. The aim of this study was to investigate the diversity of ESBL/pAmpC genes in extended-spectrum cephalosporin resistant Salmonella enterica and the phylogeny of ESBL/pAmpC-carrying Salmonella using Whole Genome Sequencing (WGS). A total of 260 cefotaxime resistant Salmonella isolates, obtained between 2008 and 2013 from broiler farms, slaughterhouses and retail, were included. Isolates were screened by PCR for ESBL/pAmpC genes. Gene and plasmid subtyping and strain Multi Locus Sequence Typing was performed in silico for a selection of fully sequenced isolates. Core-genome-based analyses were performed per ST encountered. bla CMY-2-like was carried in 168 isolates, 52 carried bla CTX-M-2 group, 7 bla SHV, 5 a combination of bla CMY-2-like-bla SHV and 3 a combination of bla CMY-2-like-bla CTX-M-2 group. In 25 isolates no ESBL/pAmpC genes that were screened for were found. WGS characterization of 36 selected strains showed plasmid-encoded bla CMY-2 in 21, bla CTX-M-165 in 11 and bla SHV-12 in 7 strains. These genes were mostly carried on IncI1/ST12, IncQ1, and IncI1/ST231 plasmids, respectively. Finally, 17 strains belonged to S. Heidelberg ST15, 16 to S. Paratyphi B variant Java ST28, 1 to S. Enteritidis ST11, 1 to S. Kentucky ST152 and 1 to S. Albany ST292. Phylogenetic comparisons with publicly available genomes showed separate clustering of Colombian S. Heidelberg and S. Paratyphi B var. Java. In conclusion, resistance to extended-spectrum cephalosporins in Salmonella from Colombian poultry is mainly encoded by bla CMY-2 and bla CTX-M 165 genes. These genes are mostly associated with IncI1/ST12 and IncQ1 plasmids, respectively. Evolutionary divergence is observed between Colombian S. Heidelberg and S. Paratyphi B var. Java and those from other countries. PMID- 30459721 TI - Association of the Human Bocavirus With Tonsil Squamous Cell Carcinomas. AB - Background: The human bocavirus (HBoV) is known to persist latently in the infected host cells and seems to replicate its DNA via the DNA damage response system, which is frequently defect in tumors and correlates with microsatellite instability (MSI). Because HBoV is able to persist in the infected tissues, induces pro-fibrotic and pro- cancerogenic cytokines in vivo and in vitro, and is detected in colorectal and lung tumors, the virus may be involved in cancerogenesis at least as a cofactor. Recently it was shown that the adenotonsillar tissue is an important site of HBoV1 persistence and replication. Considering the background that approximately 60% of oropharyngeal cancers were thought to be attributable to a HPV infection, a co-participation of HBoV in terms of a chronic virus infection might play a role in the cancerogenesis of tonsil tumors. Methods: Formalin-fixed, paraffin-embedded tonsil tumor samples were screened for HBoV and HPV DNA. Positive tissue sections were afterward subjected to fluorescence in situ hybridization (FISH) analysis to identify HBoV and HPV infected cells. By use of an in vitro cell culture model with primary tonsil fibroblasts, keratinocytes, and lymphocytes infected by HBoV we tried to find the target cells of virus replication. MSI testing was based on a previously published protocol using a de-multiplexed PCR followed by fluorescent detection of PCR products in a capillary sequencing device. Results: In total 62 of 103 (60, 19%) of the tonsil squamous cell carcinomas tested positive for HBoV DNA and 66 of 103 (66%) samples were identified as HPV positive. The FISH analysis revealed both double infection of HPV and HBoV in the same cells as well as single infections of both viruses within the tumor tissue. Twenty-two of 62 HBoV positive tumors tested HPV negative, 40 of 62 tissue sections were HBoV and HPV positive. We analyzed 21 out of the 62 HBoV positive tumors for MSI. Of those four tonsils displayed MSI in at least 1 of 10 microsatellite markers. Conclusion: Our findings support the hypothesis that human bocavirus infections as a cofactor may have an impact on tumor development in tonsils, although it still remains possible that HBoV solely displays a tumor tropism. PMID- 30459722 TI - A Novel Alkaliphilic Streptomyces Inhibits ESKAPE Pathogens. AB - In an effort to stem the rising tide of multi-resistant bacteria, researchers have turned to niche environments in the hope of discovering new varieties of antibiotics. We investigated an ethnopharmacological (cure) from an alkaline/radon soil in the area of Boho, in the Fermanagh Scarplands (N. Ireland) for the presence of Streptomyces, a well-known producer of antibiotics. From this soil we isolated a novel (closest relative 57% of genome relatedness) Streptomyces sp. capable of growth at high alkaline pH (10.5) and tolerant of gamma radiation to 4 kGy. Genomic sequencing identified many alkaline tolerance (antiporter/multi-resistance) genes compared to S. coelicolor M145 (at 3:1), hence we designated the strain Streptomyces sp. myrophorea, isolate McG1, from the Greek, myro (fragrance) and phorea (porter/carrier). In vitro tests demonstrated the ability of the Streptomyces sp. myrophorea, isolate McG1 to inhibit the growth of many strains of ESKAPE pathogens; most notably carbapenem resistant Acinetobacter baumannii (a critical pathogen on the WHO priority list of antibiotic-resistant bacteria), vancomycin-resistant Enterococcus faecium, and methicillin-resistant Staphylococcus aureus (both listed as high priority pathogens). Further in silico prediction of antimicrobial potential of Streptomyces sp. myrophorea, isolate McG1 by anti-SMASH and RAST software identified many secondary metabolite and toxicity resistance gene clusters (45 and 27, respectively) as well as many antibiotic resistance genes potentially related to antibiotic production. Follow-up in vitro tests show that the Streptomyces sp. myrophorea, isolate McG1 was resistant to 28 out of 36 clinical antibiotics. Although not a comprehensive analysis, we think that some of the Boho soils' reputed curative properties may be linked to the ability of Streptomyces sp. myrophorea, isolate McG1 to inhibit ESKAPE pathogens. More importantly, further analysis may elucidate other key components that could alleviate the tide of multi-resistant nosocomial infections. PMID- 30459724 TI - Metagenomic Insights Into the Contribution of Phages to Antibiotic Resistance in Water Samples Related to Swine Feedlot Wastewater Treatment. AB - In this study, we examined the types of antibiotic resistance genes (ARGs) possessed by bacteria and bacteriophages in swine feedlot wastewater before and after treatment using a metagenomics approach. We found that the relative abundance of ARGs in bacterial DNA in all water samples was significantly higher than that in phages DNA (>10.6-fold), and wastewater treatment did not significantly change the relative abundance of bacterial- or phage-associated ARGs. We further detected the distribution and diversity of the different types of ARGs according to the class of antibiotics to which they confer resistance, the tetracycline resistance genes were the most abundant resistance genes and phages were more likely to harbor ATP-binding cassette transporter family and ribosomal protection genes. Moreover, the colistin resistance gene mcr-1 was also detected in the phage population. When assessing the contribution of phages in spreading different groups of ARGs, beta-lactamase resistance genes had a relatively high spreading ability even though the abundance was low. These findings possibly indicated that phages not only could serve as important reservoir of ARG but also carry particular ARGs in swine feedlot wastewater, and this phenomenon is independent of the environment. PMID- 30459723 TI - Coli Surface Antigen 26 Acts as an Adherence Determinant of Enterotoxigenic Escherichia coli and Is Cross-Recognized by Anti-CS20 Antibodies. AB - The coli surface antigen 26 (CS26) of enterotoxigenic Escherichia coli (ETEC) had been described as a putative adhesive pilus based on the partial sequence of the crsH gene, detected in isolates from children with diarrhea in Egypt. However, its production and activity as adherence determinant has not been experimentally addressed. The crsH was identified as a homolog of genes encoding structural subunits of ETEC colonization factors (CFs) CS12, CS18, and CS20. These CFs, along with the recently discovered CS30, belong to the gamma2 family of pili assembled by the chaperone-usher pathway (CU pili). Further, the complete CS26 locus, crsHBCDEFG, was described in an O141 ETEC strain (ETEC 100664) obtained from a diarrhea case in The Gambia, during the Global Enterics Multicenter Study. Here, we report that CS26 is a pilus of ~10 nm in diameter, with the capacity to increase the cell adherence of the non-pathogenic strain E. coli DH10B. As for other related pili, production of CS26 seems to be regulated by phase variation. Deletion of crsHBCDEFG in ETEC 100664 significantly decreased its adherence capacity, which was recovered by in trans complementation. Furthermore, CrsH was cross-recognized by polyclonal antibodies directed against the major structural subunit of CS20, CsnA, as determined by Western blotting and immunogold labeling. ETEC CS26+ strains were found to harbor the heat-labile enterotoxin only, within three different sequence types of phylogroups A and B1, the latter suggesting acquisition through independent events of horizontal transfer. Overall, our results demonstrate that CS26 is an adhesive pilus of human ETEC. In addition, cross-reactivity with anti-CsnA antibodies indicate presence of common epitopes in gamma2-CFs. PMID- 30459726 TI - Comparative Genomics of Wolbachia-Cardinium Dual Endosymbiosis in a Plant Parasitic Nematode. AB - Wolbachia and Cardinium are among the most important and widespread of all endosymbionts, occurring in nematodes and more than half of insect and arachnid species, sometimes as coinfections. These symbionts are of significant interest as potential biocontrol agents due to their abilities to cause major effects on host biology and reproduction through cytoplasmic incompatibility, sex ratio distortion, or obligate mutualism. The ecological and metabolic effects of coinfections are not well understood. This study examined a Wolbachia-Cardinium coinfection in the plant-parasitic nematode (PPN), Pratylenchus penetrans, producing the first detailed study of such a coinfection using fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), and comparative genomic analysis. Results from FISH and single-nematode PCR showed 123/127 individuals in a focal population carried Cardinium (denoted strain cPpe), and 48% were coinfected with Wolbachia strain wPpe. Both endosymbionts showed dispersed tissue distribution with highest densities in the anterior intestinal walls and gonads. Phylogenomic analyses confirmed an early place of cPpe and long distance from a sister strain in another PPN, Heterodera glycines, supporting a long history of both Cardinium and Wolbachia in PPNs. The genome of cPpe was 1.36 Mbp with 35.8% GC content, 1,131 predicted genes, 41% having no known function, and missing biotin and lipoate synthetic capacity and a plasmid present in other strains, despite having a slightly larger genome compared to other sequenced Cardinium. The larger genome revealed expansions of gene families likely involved in host-cellular interactions. More than 2% of the genes of cPpe and wPpe were identified as candidate horizontally transferred genes, with some of these from eukaryotes, including nematodes. A model of the possible Wolbachia-Cardinium interaction is proposed with possible complementation in function for pathways such as methionine and fatty acid biosynthesis and biotin transport. PMID- 30459727 TI - Ultrasound-Induced Escherichia coli O157:H7 Cell Death Exhibits Physical Disruption and Biochemical Apoptosis. AB - Ultrasound has attracted great interest of both industry and scientific communities for its potential use as a physical processing and preservation tool. In this study, Escherichia coli O157:H7 was selected as the model microbe to investigate the ultrasound-induced cell death. Slight variations in membrane potential and ion exchanges across membrane induced by low-intensity ultrasound increased the membrane permeability of E. coli O157:H7, and this reversible sublethal effect can preserve the viability of E. coli O157:H7 and meanwhile be beneficial for bioprocessing application. In comparison, high-intensity ultrasound resulted in irreversible lethal effect on E. coli O157:H7, which can be applied in the field of microbial inactivation. In addition, both low- and high-intensity ultrasound induced either physical destruction or trigger genetically encoded apoptosis of E. coli O157:H7. Accumulation of reactive oxygen species and decrease of adenosine tri-phosphate might be related to the physiological and biochemical hallmarks of apoptosis, including exposed phosphatidylserine and activated caspases in E. coli O157:H7. The result provides novel insight into the mechanisms of non-thermal physical treatment on the inactivation of bacteria and lays foundation for the further research on the cell signaling and metabolic pathway in apoptotic bacteria. PMID- 30459725 TI - Plant Phenotypic Traits Eventually Shape Its Microbiota: A Common Garden Test. AB - Plant genotype drives the development of plant phenotypes and the assembly of plant microbiota. The potential influence of the plant phenotypic characters on its microbiota is not well characterized and the co-occurrence interrelations for specific microbial taxa and plant phenotypic characters are poorly understood. We established a common garden experiment, which quantifies prokaryotic and fungal communities in the phyllosphere and rhizosphere of six spruce (Picea spp.) tree species, through Illumina amplicon sequencing. We tested for relationships between bacterial/archaeal and fungal communities and for the phenotypic characters of their plant hosts. Host phenotypic characters including leaf length, leaf water content, leaf water storage capacity, leaf dry mass per area, leaf nitrogen content, leaf phosphorous content, leaf potassium content, leaf delta13C values, stomatal conductance, net photosynthetic rate, intercellular carbon dioxide concentration, and transpiration rate were significantly correlated with the diversity and composition of the bacterial/archaeal and fungal communities. These correlations between plant microbiota and suites of host plant phenotypic characters suggest that plant genotype shape its microbiota by driving the development of plant phenotypes. This will advance our understanding of plant-microbe associations and the drivers of variation in plant and ecosystem function. PMID- 30459729 TI - Bacterial Microbiota and Metabolic Character of Traditional Sour Cream and Butter in Buryatia, Russia. AB - Traditional sour cream and butter are widely popular fermented dairy products in Russia for their flavor and nutrition, and contain rich microbial biodiversity, particularly in terms of lactic acid bacteria (LAB). However, few studies have described the microbial communities and metabolic character of traditional sour cream and butter. The objective of this study was to determine the bacterial microbiota and metabolic character of eight samples collected from herdsmen in Buryatia, Russia. Using single-molecule real-time (SMRT) sequencing techniques, we identified a total of 294 species and/or subspecies in 169 bacterial genera, belonging to 14 phyla. The dominant phylum was Firmicutes (81.47%) and the dominant genus was Lactococcus (59.28%). There were differences between the bacterial compositions of the sour cream and butter samples. The relative abundances of Lactococcus lactis, Lactococcus raffinolactis, and Acetobacter cibinongensis were significantly higher in sour cream than in butter, and the abundance of Streptococcus thermophilus was significantly lower in sour cream than in butter. Using a pure culture method, 48 strains were isolated and identified to represent seven genera and 15 species and/or subspecies. Among these isolates, Lactococccus lactis subsp. lactis (22.50%) was the dominant LAB species. Ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry at elevated energy was used in combination with statistical methods to detect metabolite differences between traditional sour cream and butter. A total of 27,822 metabolites were detected in all samples, and Lys-Lys, isohexanal, palmitic acid, Leu-Val, and 2'-deoxycytidine were the most dominant metabolites found in all samples. In addition, 27 significantly different metabolites were detected between the sour cream and butter samples, including short peptides, organic acids, and amino acids. Based on correlation analyses between the most prevalent bacterial species and the main metabolites in sour cream, we conclude that there may be a connection between the dominant LAB species and these metabolites. This study combined omics techniques to analyze the bacterial diversity and metabolic character of traditional sour cream and butter, and we hope that our findings will enrich species resource libraries and provide valuable resources for further research on dairy product flavor. PMID- 30459728 TI - Sodium Acetate Responses in Saccharomyces cerevisiae and the Ubiquitin Ligase Rsp5. AB - Recent studies have revealed the feasibility of sodium acetate as a potentially novel inhibitor/stressor relevant to the fermentation from neutralized lignocellulosic hydrolysates. This mini-review focuses on the toxicity of sodium acetate, which is composed of both sodium and acetate ions, and on the involved cellular responses that it elicits, particularly via the high-osmolarity glycerol (HOG) pathway, the Rim101 pathway, the P-type ATPase sodium pumps Ena1/2/5, and the ubiquitin ligase Rsp5 with its adaptors. Increased understanding of cellular responses to sodium acetate would improve our understanding of how cells respond not only to different stimuli but also to composite stresses induced by multiple components (e.g., sodium and acetate) simultaneously. Moreover, unraveling the characteristics of specific stresses under industrially related conditions and the cellular responses evoked by these stresses would be a key factor in the industrial yeast strain engineering toward the increased productivity of not only bioethanol but also advanced biofuels and valuable chemicals that will be in demand in the coming era of bio-based industry. PMID- 30459730 TI - Biofilm Microbiome (Re)Growth Dynamics in Drinking Water Distribution Systems Are Impacted by Chlorine Concentration. AB - Biofilms are the dominant form of microbial loading (and organic material) within drinking water distribution systems (DWDS), yet our understanding of DWDS microbiomes is focused on the more easily accessible bulk-water. Disinfectant residuals are commonly provided to manage planktonic microbial activity in DWDS to safeguard water quality and public health, yet the impacts on the biofilm microbiome are largely unknown. We report results from a full-scale DWDS facility used to develop biofilms naturally, under one of three chlorine concentrations: Low, Medium, or High. Increasing the chlorine concentration reduced the bacterial concentration within the biofilms but quantities of fungi were unaffected. The chlorine regime was influential in shaping the community structure and composition of both taxa. There were microbial members common to all biofilms but the abundance of these varied such that at the end of the Growth phase the communities from each regime were distinct. Alpha-, Beta-, and Gamma proteobacteria were the most abundant bacterial classes; Sordariomycetes, Leotiomycetes, and Microbotryomycetes were the most abundant classes of fungi. Mechanical cleaning was shown to immediately reduce the bacterial and fungal concentrations, followed by a lag effect on the microbiome with continued decreases in quantity and ecological indices after cleaning. However, an established community remained, which recovered such that the microbial compositions at the end of the Re-growth and initial Growth phases were similar. Interestingly, the High-chlorine biofilms showed a significant elevation in bacterial concentrations at the end of the Re-growth (after cleaning) compared the initial Growth, unlike the other regimes. This suggests adaptation to a form a resilient biofilm with potentially equal or greater risks to water quality as the other regimes. Overall, this study provides critical insights into the interaction between chlorine and the microbiome of DWDS biofilms representative of real networks, implications are made for the operation and maintenance of DWDS disinfectant and cleaning strategies. PMID- 30459731 TI - Proline Accumulation Influenced by Osmotic Stress in Arbuscular Mycorrhizal Symbiotic Plants. AB - Salinity and drought are the major osmotic stress limitations that affect plant growth and crop yield in agriculture worldwide. The alternative response mediated by plants in response to salinity and drought are principally proline accumulation which regulates stress combat strategies owing to sustainable production in the realm of agricultural production even under severe stress. Symbiotic and soil associated arbuscular mycorrhizal fungi (AMF) are regarded as efficient biofertilizers in several crops under these stresses. Summarily AMF is renowned for effective scavengers of free radicals in soil thereby increasing soil parameters optimal for plant growth. AMF contribute to augment host plant tolerance to stress specifically salinity and drought. Mycorrhizal colonization positively regulates root uptake of available nutrients and enhance growth even when bestowed by water constraints which has contributory roles due to proline accumulation providing several intriguing researches on AMF symbiosis pertaining to plant productivity and yield. Mycorrhizal plants and their non-mycorrhizal counterparts show varied expression pattern regarding proline amass. Hence, the precise role of proline with respect to stress tolerance and equivocal mechanisms involved in evasion of osmotic stress has not been extensively reviewed earlier. Further molecular forecasting in this arena is still an underexploited research field. This review comprehensively addresses the observable facts pertaining to proline accumulation upon AMF association and adherence relevant to stress tolerance and host plant efficiency and efficacy. PMID- 30459732 TI - The Characteristics and Dynamics of Cyanobacteria-Heterotrophic Bacteria Between Two Estuarine Reservoirs - Tropical Versus Sub-Tropical Regions. AB - In this study, Illumina MiSeq sequencing technique was employed to explore the characteristics and dynamics of cyanobacteria-heterotrophic bacteria between two estuarine reservoirs in sub-tropical (reservoir A in Shanghai) and tropical (reservoir B in Singapore) regions. The results indicated that significant differences in bacterial community composition were found between two estuarine reservoirs, which influenced by varied environmental variables. The environmental heterogeneity in reservoir A was much higher, which indicated that the composition of bacterial community in reservoir A was more complex. In contrast, reservoir B provided a suitable and temperate water environment conditions for bacterial growth, which resulted in higher community diversity and less co exclusion correlations. The molecular ecological network indicated that the presence of dominant bacterial community in each of the reservoir were significant different. These differences mainly reflected the responses of bacterial community to the variations of environmental variables. Although Synechococcus was the dominant cyanobacterial species in both reservoirs, it exhibited co-occurrence patterns with different heterotrophic bacteria between reservoirs. In addition, the cyanobacteria-heterotrophic bacteria interaction exhibited highly dynamic variations, which was affected by nutrition and survive space. Also, the co-occurrence of Microcystis and Pseudanabaena found in reservoir B implied that the non-N-fixing Microcystis accompanied with N-fixing Pseudanabeana occurrence in freshwater lakes, so as to better meet the demand for nitrogen source. PMID- 30459733 TI - Novel Self-Transmissible and Broad-Host-Range Plasmids Exogenously Captured From Anaerobic Granules or Cow Manure. AB - Novel self-transmissible plasmids were exogenously captured from environmental samples by triparental matings with pBBR1MCS-2 as a mobilizable plasmid and Pseudomonas resinovorans as a recipient. A total of 272 recipients were successfully obtained as plasmid host candidates from granules of an anaerobic methane fermentation plant and from cow manure. The whole nucleotide sequences of six plasmids were determined, including one IncP-1 plasmid (pSN1104-59), four PromA-like plasmids (pSN1104-11, pSN1104-34, pSN0729-62, and pSN0729-70), and one novel plasmid (pSN1216-29), whose incompatibility group has not been previously identified. No previously known antibiotic resistance genes were found in these plasmids. In-depth phylogenetic analyses showed that the PromA-like plasmids belong to subgroups of PromA (designated as PromAgamma and PromAdelta) different from previously proposed subgroups PromAalpha and PromAbeta. Twenty-four genes were identified as backbone genes by comparisons with other PromA plasmids. The nucleotide sequences of pSN1216-29 share high identity with those found in clinical isolates. A minireplicon of pSN1216-29 was successfully constructed from repA encoding a replication initiation protein and oriV. All the captured plasmids were found to have a broad host range and could be transferred to and replicated in different classes of Proteobacteria. Notably, repA and oriV of pSN1216-29 showed high similarity with one of two replication systems of pSRC119 A/C, known as a plasmid with multidrug resistance genes found in Salmonella enterica serovar Senftenberg. Our findings suggest that these "cryptic" but broad host-range plasmids may be important for spreading several genes as "vehicles" in a wider range of bacteria in natural environments. PMID- 30459734 TI - Virulent Epidemic Pneumonia in Sheep Caused by the Human Pathogen Acinetobacter baumannii. AB - The human pathogen Acinetobacter baumannii has emerged as a frequent cause of hospital-acquired infections, but infection of animals has rarely been observed. Here we analyzed an outbreak of epidemic pneumonia killing hundreds of sheep on a farm in Pakistan and identified A. baumannii as the infecting agent. A pure culture of strain AbPK1 isolated from lungs of sick animals was inoculated into healthy sheep, which subsequently developed similar disease symptoms. Bacteria re isolated from the infected animals were shown to be identical to the inoculum, fulfilling Koch's postulates. Comparison of the AbPK1 genome against 2283 A. baumannii genomes from the NCBI database revealed that AbPK1 carries genes for unusual surface structures, including a unique composition of iron acquisition genes, genes for O-antigen synthesis and sialic acid-specific acetylases of cell surface carbohydrates that could enable immune evasion. Several of these unusual and otherwise rarely present genes were also identified in genomes of phylogenetically unrelated A. baumannii isolates from combat-wounded US military from Afghanistan indicating a common gene pool in this geographical region. Based on core genome MLST this virulent isolate represents a newly emerging lineage of Global Clone 2, suggesting a human source for this disease outbreak. The observed epidemic, direct transmission from sheep to sheep, which is highly unusual for A. baumannii, has important consequences for human and animal health. First, direct animal-to-animal transmission facilitates fast spread of pathogen and disease in the flock. Second, it may establish a stable ecological niche and subsequent spread in a new host. And third, it constitutes a serious risk of transmission of this hyper-virulent clone from sheep back to humans, which may result in emergence of contagious disease amongst humans. PMID- 30459735 TI - Molecular Mass and Localization of alpha-1,3-Glucan in Cell Wall Control the Degree of Hyphal Aggregation in Liquid Culture of Aspergillus nidulans. AB - alpha-1,3-Glucan is one of the main polysaccharides in the cell wall of filamentous fungi. Aspergillus nidulans has two alpha-1,3-glucan synthase genes, agsA and agsB. We previously revealed that AgsB is a major alpha-1,3-glucan synthase in vegetative hyphae, but the function of AgsA remained unknown because of its low expression level and lack of phenotypic alteration upon gene disruption. To clarify the role of alpha-1,3-glucan in hyphal aggregation, we constructed strains overexpressing agsA (agsAOE ) or agsB (agsBOE ), in which the other alpha-1,3-glucan synthase gene was disrupted. In liquid culture, the wild type and agsBOE strains formed tightly aggregated hyphal pellets, whereas agsAOE hyphae aggregated weakly. We analyzed the chemical properties of cell wall alpha 1,3-glucan from the agsAOE and agsBOE strains. The peak molecular mass of alpha 1,3-glucan from the agsAOE strain (1,480 +/- 80 kDa) was much larger than that from the wild type (147 +/- 52 kDa) and agsBOE (372 +/- 47 kDa); however, the peak molecular mass of repeating subunits in alpha-1,3-glucan was almost the same (after Smith degradation: agsAOE , 41.6 +/- 5.8 kDa; agsBOE , 38.3 +/- 3.0 kDa). We also analyzed localization of alpha-1,3-glucan in the cell wall of the two strains by fluorescent labeling with alpha-1,3-glucan-binding domain-fused GFP (AGBD-GFP). alpha-1,3-Glucan of the agsBOE cells was clearly located in the outermost layer, whereas weak labeling was detected in the agsAOE cells. However, the agsAOE cells treated with beta-1,3-glucanase were clearly labeled with AGBD GFP. These observations suggest that beta-1,3-glucan covered most of alpha-1,3 glucan synthesized by AgsA, although a small amount of alpha-1,3-glucan was still present in the outer layer. We also constructed a strain with disruption of the amyG gene, which encodes an intracellular alpha-amylase that synthesizes alpha 1,4-glucooligosaccharide as a primer for alpha-1,3-glucan biosynthesis. In this strain, the hyphal pellets and peak molecular mass of alpha-1,3-glucan (94.5 +/- 1.4 kDa) were smaller than in the wild-type strain, and alpha-1,3-glucan was still labeled with AGBD-GFP in the outermost layer. Overall, these results suggest that hyphal pellet formation depends on the molecular mass and spatial localization of alpha-1,3-glucan as well as the amount of alpha-1,3-glucan in the cell wall of A. nidulans. PMID- 30459737 TI - Lactobacillus crispatus BC5 Interferes With Chlamydia trachomatis Infectivity Through Integrin Modulation in Cervical Cells. AB - Lactobacilli play a crucial role in maintaining the ecological equilibrium of the vaginal niche, preventing the colonization of exogenous microorganisms. Although many studies have discussed the mechanisms displayed by lactobacilli in counteracting several urogenital pathogens, a few data are available on the interaction between lactobacilli and Chlamydia trachomatis. This study aimed to elucidate the molecular bases of the interaction among vaginal lactobacilli, the sexually transmitted pathogen C. trachomatis and the epithelial cervical cells. We evaluated the in vitro activity of 15 Lactobacillus strains, belonging to different species (i.e., L. crispatus, L. gasseri, L. vaginalis), against C. trachomatis. In particular, we evaluated the capability of lactobacilli cells to interfere with C. trachomatis infection in HeLa cells, by exclusion assays. Lactobacilli significantly reduced C. trachomatis infectivity, being L. crispatus the most active species. Although a dose-dependent effect was noticed, a significant antagonistic activity was maintained even at lower doses. As other Gram-positive bacteria (i.e., Streptococcus agalactiae, Enterococcus faecalis, and Bacillus subtilis) failed to interfere with C. trachomatis infectivity, Lactobacillus activity proved to be specific. The potential mechanism of protection was investigated in Lactobacillus crispatus BC5, chosen as the model strain. The incubation of HeLa cell line with BC5 cells induced important modifications in the epithelial plasma membrane, by altering lipid composition and alpha5 integrin subunit exposure. When alpha5 integrin subunits were masked by a specific blocking antibody or ITGA5 gene expression was silenced, Chlamydia infection was significantly reduced. It follows that alpha5 integrin subunit is crucial for the pathogen infection process, and the anti-Chlamydia activity can be directly linked to membrane properties modifications in cervical cells. The three Gram-positive bacteria used as controls failed to modify the expression of alpha5beta1 integrin. In conclusion, we identified a potential molecular mechanism at the basis of the protection exerted by L. crispatus BC5 against C. trachomatis, getting insights into the role of the cervico-vaginal microbiota for the woman's health. PMID- 30459736 TI - Hydroxytyrosol (HT) Analogs Act as Potent Antifungals by Direct Disruption of the Fungal Cell Membrane. AB - Fungal infections constitute an emerging threat and a prevalent health problem due to increasing number of immunocompromised people and pharmacological or other treatments aiming at viral infections, cancer or allergies. Currently used antifungals suffer from inefficiency, toxic side effects and developing drug resistance. Additionally, over the last two decades no new classes of antifungals have been approved, emphasizing the urgent need for developing a novel generation of antifungals. Here, we investigate the antifungal activity of a series of chemically synthesized Hydroxytyrosol (HT) analogs. HT is one of the major phenolic compounds in olive oil, shown to possess radical-scavenging antioxidant, antiproliferative, proapoptotic and anti-inflammatory activities. No previous report has studied HT analogs as antifungals. We show that specific analogs have broad and strong antifungal activity, significantly stronger than the parent compound HT. Using Aspergillus nidulans as an in vivo cellular model system, we show that antifungal HT analogs have an unprecedented efficiency in fungal plasma membrane destruction. Importantly, antifungal HT analogs did not show toxicity in a mammalian cell line, whereas no resistance to HT analogs was obtained by standard mutagenesis. Our results open the way for the development of a novel, efficient and safer class of antifungals. PMID- 30459738 TI - Suppression of Fluconazole Resistant Candida albicans Biofilm Formation and Filamentation by Methylindole Derivatives. AB - Candida albicans is an opportunistic fungal pathogen and most prevalent species among clinical outbreaks. It causes a range of infections, including from mild mucosal infections to serious life-threatening candidemia and disseminated candidiasis. Multiple virulence factors account for the pathogenic nature of C. albicans, and its morphological transition from budding yeast to hyphal form and subsequent biofilm formation is regarded as the most important reason for the severity of Candida infections. To address the demanding need for novel antifungals, we investigated the anti-biofilm activities of various methylindoles against C. albicans using a crystal violet assay, and the metabolic activity was assessed by using a 2,3-bis (2-methoxy-4-nitro-5-sulfo-phenyl)-2H-tetrazolium-5 carboxanilide reduction assay. Changes in biofilm morphologies and thicknesses were determined by confocal laser scanning microscopy and scanning electron microscopy, respectively. Of the 21 methylindoles tested, 1-methylindole-2 carboxylic acid (1MI2CA) at 0.1 mM (17.5 MUg ml-1) and 5-methylindole-2 carboxylic acid (5MI2CA) at 0.1 mM effectively inhibited biofilm formation by C. albicans DAY185 and ATCC10231 strains. Moreover, 1MI2CA and 5MI2CA both effectively inhibited hyphal formation, and thus, improved C. albicans infected nematode survival without inducing acute toxic effects. Furthermore, our in silico molecular modeling findings were in-line with in vitro observations. This study provides information useful for the development of novel strategies targeting candidiasis and biofilm-related infections. PMID- 30459739 TI - The Antihistamine Drugs Carbinoxamine Maleate and Chlorpheniramine Maleate Exhibit Potent Antiviral Activity Against a Broad Spectrum of Influenza Viruses. AB - Influenza A viruses (IAV) comprise some of the most common infectious pathogens in humans, and they cause significant mortality and morbidity in immunocompromised people as well as children and the elderly. After screening an FDA-approved drug library containing 1280 compounds by cytopathic effect (CPE) reduction assay using the Cell Counting Kit-8, we found two antihistamines, carbinoxamine maleate (CAM) and S-(+)-chlorpheniramine maleate (SCM) with potent antiviral activity against A/Shanghai/4664T/2013(H7N9) infection with IC50 (half maximal inhibitory concentration) of 3.56 and 11.84 MUM, respectively. Further studies showed that CAM and SCM could also inhibit infection by other influenza A viruses, including A/Shanghai/37T/2009(H1N1), A/Puerto Rico/8/1934(H1N1), A/Guizhou/54/1989(H3N2), and one influenza B virus, B/Shanghai/2017(BY). Mice were challenged intranasally with A/H7N9/4664T/2013 (H7N9) virus and intraperitoneally injected with CAM (10 mg/kg per day) or SCM (1 mg/kg per day) for 5 days. CAM or SCM (10 mg/kg per day) were fully protected against challenge with A/Shanghai/4664T/2013(H7N9). The results from mechanistic studies indicate that both could inhibit influenza virus infection by blocking viral entry into the target cell, the early stage of virus life cycle. However, CAM and SCM neither blocked virus attachment, characteristic of HA activity, nor virus release, characteristic of NA activity. Such data suggest that these two compounds may interfere with the endocytosis process. Thus, we have identified two FDA-approved antihistamine drugs, CAM and SCM, which can be repurposed for inhibiting infection by divergent influenza A strains and one influenza B strain with potential to be used for treatment and prevention of influenza virus infection. PMID- 30459741 TI - Plant Litter Type Dictates Microbial Communities Responsible for Greenhouse Gas Production in Amended Lake Sediments. AB - The microbial communities of lake sediments play key roles in carbon cycling, linking lakes to their surrounding landscapes and to the global climate system as incubators of terrestrial organic matter and emitters of greenhouse gasses, respectively. Here, we amended lake sediments with three different plant leaf litters: a coniferous forest mix, deciduous forest mix, cattails (Typha latifolia) and then examined the bacterial, fungal and methanogen community profiles and abundances. Polyphenols were found to correlate with changes in the bacterial, methanogen, and fungal communities; most notably dominance of fungi over bacteria as polyphenol levels increased with higher abundance of the white rot fungi Phlebia spp. Additionally, we saw a shift in the dominant orders of fermentative bacteria with increasing polyphenol levels, and differences in the dominant methanogen groups, with high CH4 production being more strongly associated with generalist groups of methanogens found at lower polyphenol levels. Our present study provides insights into and basis for future study on how shifting upland and wetland plant communities may influence anaerobic microbial communities and processes in lake sediments, and may alter the fate of terrestrial carbon entering inland waters. PMID- 30459740 TI - Sex Modulates Lactobacillus johnsonii N6.2 and Phytophenol Effectiveness in Reducing High Fat Diet Induced mTOR Activation in Sprague-Dawley Rats. AB - Metabolic syndrome (MetS) is the underlying cause of some devastating diseases, including type 2 diabetes and cardiovascular disease. These diseases have been associated with over-activation of the mechanistic Target of Rapamycin (mTOR) pathway. This study utilizes a high fat diet (HFD) to induce MetS and to dissect the effects of a beneficial bacterium, L. johnsonii N6.2, and natural phenolics on mTOR complex 1 (mTORC1) expression compared to a reduced energy density diet (REDD). HFD significantly elevated MetS markers in males, as noted through an increase in weight, glucose levels, and triglyceride levels. Treatments were effective in reducing mTORC1-activating phosphorylation of pAKT-T308 and pAKT S473 (p = 0.0012 and 0.0049, respectively) in HFD-fed females, with the combined treatments of L. johnsonii and phytophenols reducing phosphorylation below REDD fed control levels, and significantly below HFD-fed control levels. Meanwhile, diet was the significant factor influencing male mTORC1-activating phosphorylation (p < 0.0001), as treatments were only effective in reducing phosphorylation in REDD-fed animals. Downstream analysis of mTORC1 activated genes phosphogluconate dehydrogenase (pgd) and phosphofructose kinase (pfk) followed this similar trend, enforcing the significant effect sex has on a treatments' ability to modulate diet induced abnormalities. Analyzing mTORC1 stimulators such as insulin, inflammatory cytokines, and tryptophan, revealed no significant differences among groups. These results indicate that the effects observed on mTORC1 are a direct consequence of the treatments, and not exerted indirectly via the modulation of stimuli. This study highlights the potential use of commensal microorganisms and natural compounds in reducing the onset of metabolic diseases through mTORC1. PMID- 30459742 TI - Antibiotic-Resistant Bacteria in Greywater and Greywater-Irrigated Soils. AB - This study represents the first systematic attempt to evaluate antibiotic resistant bacteria (ARB) occurrence in treated greywater and the potential spread of these bacteria from the greywater to greywater-irrigated soil. Treated greywater from three recirculating vertical flow constructed wetlands, each located in a household in the central Negev Desert, Israel, was surveyed. The presence of antibiotic-resistant bacteria in raw and treated greywater was investigated with culture and molecular methods, as well as their presence in the corresponding treated-greywater-irrigated soils. Additionally, the effectiveness of chlorination to prevent the spread of ARB was tested. The total count of tetracycline-resistant bacteria significantly increased in the treated greywater, likely due to their concentration on the filter matrix of the treatment systems. Twenty-four strains of tetracycline-resistant bacteria were isolated and identified at the genus level by 16Sr RNA gene sequencing. All the tetracycline resistant bacteria showed high resistance traits, and some of them presented multiple antibiotic resistances. Six tetracycline resistance genes (coding for efflux and ribosomal resistance mechanisms) and five beta-lactamase genes were detected. In 14 of the isolated strains, the gene tet39, which is phylogenetically related to both environmental and clinical strains, was identified. All the tet39 resistant bacteria were positive to at least one of the beta-lactamase genes tested. Chlorination was found to be an efficient method to reduce ARB in treated greywater. We concluded that disinfection of treated greywater may reduce the risks not only from the potential presence of pathogens but also from the presence of ARB and antibiotic resistance genes. PMID- 30459743 TI - Activation of the PhoPR-Mediated Response to Phosphate Limitation Is Regulated by Wall Teichoic Acid Metabolism in Bacillus subtilis. AB - Phosphorous is essential for cell viability. To ensure an adequate supply under phosphate limiting conditions, bacteria induce a cohort of enzymes to scavenge for phosphate, and a high affinity transporter for its uptake into the cell. This response is controlled by a two-component signal transduction system named PhoBR in Escherichia coli and PhoPR in Bacillus subtilis. PhoR is a sensor kinase whose activity is responsive to phosphate availability. Under phosphate limiting conditions, PhoR exists in kinase mode that phosphorylates its cognate response regulator (PhoB, PhoP). When activated, PhoB~P/PhoP~P execute changes in gene expression that adapt cells to the phosphate limited state. Under phosphate replete conditions, PhoR exists in phosphatase mode that maintains PhoB/PhoP in an inactive, non-phosphorylated state. The mechanism by which phosphate availability is sensed and how it controls the balance between PhoR kinase and phosphatase activities has been studied in E. coli and B. subtilis. Two different mechanisms have emerged. In the most common mechanism, PhoR activity is responsive to phosphate transport through a PstSCAB/PhoU signaling complex that relays the conformational status of the transporter to PhoR. In the second mechanism currently confined to B. subtilis, PhoR activity is responsive to wall teichoic acid metabolism whereby biosynthetic intermediates can promote or inhibit PhoR autokinase activity. Variations of both mechanisms are found that allow each bacterial species to adapt to phosphate availability in their particular environmental niche. PMID- 30459744 TI - Lactic Acid Bacteria With Antioxidant Activities Alleviating Oxidized Oil Induced Hepatic Injury in Mice. AB - In order to screening new Lactic acid bacteria (LAB) strains to alleviating liver injury induced by oxidized oil, we isolated and screened LAB from Chinese fermented foods. Lactobacillus plantarum AR113, Pediococcus pentosaceus AR243, and Lactobacillus plantarum AR501 showed higher scavenging activity of alpha, alpha-Diphenyl-beta-Picrylhydrazyl (DPPH) free radical and hydrogen radical, stronger inhibition of lipid peroxidation, and better protective effect on yeast cells in vitro. In vivo, oral administration of L. plantarum AR501 improved the antioxidant status of injury mice induced by oxidized oil including decreasing lipid peroxidation, recovering activities of antioxidant enzymes. Meanwhile, the gene expression of Nuclear factor erythroid 2-related factor 2 (Nrf2) of L. plantarum AR501 group was markedly elevated, and several antioxidant genes such as glutathione S-transferase (GSTO1), heme oxygenase-1 (HO-1), Glutamate cysteine ligase (GCL), and NAD(P)H:quinone oxidoreductase-l (NQO1) were subsequently up regulated in mice liver. Therefore, L. plantarum AR501 could be considered as potential candidates for production of functional foods that can alleviate the oxidative damage induced by oxidized oil. PMID- 30459745 TI - Uterine Microbiota of Dairy Cows With Clinical and Subclinical Endometritis. AB - The objective of this study was to characterize the uterine microbiota of dairy cows with clinical and subclinical endometritis and to identify the potential bacterial genera as well as their interactions associated with uterine disease. Uterine flush samples (n = 27) were collected from 13 healthy, 5 subclinical endometritic (SE), and 9 clinical endometritic (CE) cows at 30 days postpartum. Microbial DNA from uterine flush samples was subjected to sequencing of the 16S rRNA gene on the Illumina MiSeq platform. The uterine microbiota of healthy, SE, and CE cows had similarly complex microbial diversity, and shared 293 of 445 operational taxonomic units. However, endometritic and healthy cows could be discriminated by the relative abundance of bacterial genera. In CE cows, the uterine microbiota was characterized by increased abundance of Fusobacterium and unique presence of Trueperella and Peptoniphilus. For SE cows, known intrauterine pathogens were almost absent and the uterine microbiota was characterized by enrichment of Lactobacillus and Acinetobacter. Analysis of correlations between bacterial genera showed that the uterine microbiota exhibited two co-occurrence groups (i.e., the Lactococcus and the Fusobacterium COGs), indicating that the synergistic effect by co-occurred bacteria may be an important aspect of pathogenesis. Our findings support that common uterine pathogens are not associated with subclinical endometritis at 30 days postpartum and indicate the need of investigating the role of commensal bacteria such as Lactobacillus, and Acinetobacter in the inflammatory process of uterine endometrium. PMID- 30459747 TI - Subinhibitory Concentrations of Amoxicillin, Lincomycin, and Oxytetracycline Commonly Used to Treat Swine Increase Streptococcus suis Biofilm Formation. AB - Streptococcus suis is a bacterial swine pathogen with a significant economic burden. It typically colonizes the tonsil and nasal cavity of swine causing a variety of symptoms ranging from asymptomatic carriage to lethal systemic disease. A key barrier toward the development of improved vaccines or interventions for S. suis infections is a gap in our understanding of the mechanisms contributing to persistence in the host, in which colonized pigs continue to shed and transmit S. suis. We hypothesized that exposure to sub-MICs of antibiotics commonly used by the swine industry would increase the biofilm capacity of S. suis strains. Using a 96-well plate MIC protocol, we experimentally determined the MIC for each of 12 antibiotics for a virulent strain of S. suis strain that consistently formed biofilms using a standard crystal violet assay. Using this static biofilm assay, we demonstrated that sub MICs of bacitracin, carbadox, chlortetracycline, enrofloxacin, gentamicin, neomycin, sulfadimethoxine, tiamulin, and tylosin did not increase S. suis biofilms. In contrast, we demonstrated that sub-MICs of amoxicillin, lincomycin, and oxytetracycline increased overall biofilm formation under both static and flow conditions. The biofilm formation of 11 additional clinical isolates were measured using the relevant concentrations of amoxicillin, lincomycin, and oxytetracycline. Eight of the eleven strains increased the biofilm formation with lincomycin, seven with amoxicillin, and three with oxytetracycline. Collectively, our data demonstrate that exposure to sub-MICs of these commonly used antibiotics contributes to increased biofilm formation of S. suis, thereby potentially increasing survival and persistence within the respiratory tract of swine. PMID- 30459748 TI - Erratum: A Class 1 Histone Deacetylase as Major Regulator of Secondary Metabolite Production in Aspergillus nidulans. AB - [This corrects the article DOI: 10.3389/fmicb.2018.02212.]. PMID- 30459746 TI - Daptomycin Resistant Staphylococcus aureus Clinical Strain With Novel Non synonymous Mutations in the mprF and vraS Genes: A New Insight Into Daptomycin Resistance. AB - Objectives: Daptomycin (DAP) resistance in Staphylococcus aureus is uncommon but there are increasing reports of the emergence of resistance during DAP therapy. Most clinical DAP-resistant S. aureus isolates investigated carried mutations in the mprF gene. The aim of this study was to identify mutations between a clinical pair of methicillin-susceptible S. aureus (MSSA) isolates (DAP-susceptible and DAP-resistant). Additionally, the activity of genes previously associated with DAP resistance was assessed. Materials and Methods: Two MSSA isolates from patient with left-sided endocarditis were analyzed by whole genome sequencing (WGS) and reverse transcription-quantitative real-time PCR (RT-qPCR). The first isolate, DAP-susceptible, was obtained before initiation of treatment and the second isolate, DAP-resistant, was recovered after 4 weeks of DAP therapy. Results: Comparison of complete genomes of DAP-susceptible and its DAP-resistant variant identified two non-synonymous and one synonymous mutations. The non synonymous mutations consisted of a S829L substitution in mprF and a T331I substitution in vraS. The RT-qPCR experiments revealed an increased expression of vraS, dltA, mprF, and sceD genes in DAP-resistant variant. Strikingly, the expression of dltA and mprF genes was significantly downregulated by DAP. Conclusion: The mprF and vraS genes were previously associated with DAP resistance, however, none of the mutations described in this study had been previously identified and linked to DAP resistance. Moreover, we provide a new insight into the DAP action on S. aureus, in which the expression of key genes in DAP resistance is decreased by the antibiotic. PMID- 30459749 TI - Compounded Disturbance Chronology Modulates the Resilience of Soil Microbial Communities and N-Cycle Related Functions. AB - There is a growing interest of overcoming the uncertainty related to the cumulative impacts of multiple disturbances of different nature in all ecosystems. With global change leading to acute environmental disturbances, recent studies demonstrated a significant increase in the possible number of interactions between disturbances that can generate complex, non-additive effects on ecosystems functioning. However, how the chronology of disturbances can affect ecosystems functioning is unknown even though there is increasing evidence that community assembly history dictates ecosystems functioning. Here, we experimentally examined the importance of the disturbances chronology in modulating the resilience of soil microbial communities and N-cycle related functions. We studied the impact of 3-way combinations of global change related disturbances on total bacterial diversity and composition, on the abundance of N cycle related guilds and on N-cycle related activities in soil microcosms. The model pulse disturbances, i.e., short-term ceasing disturbances studied were heat, freeze-thaw and anaerobic cycles. We determined that repeated disturbances of the same nature can either lead to the resilience or to shifts in N-cycle related functions concomitant with diversity loss. When considering disturbances of different nature, we demonstrated that the chronology of compounded disturbances impacting an ecosystem determines the aggregated impact on ecosystem properties and functions. Thus, after 3 weeks the impact of the 'anoxia/heat/freeze-thaw' sequence was almost two times stronger than that of the 'heat/anoxia/freeze-thaw' sequence. Finally, we showed that about 29% of the observed variance in ecosystem aggregated impact caused by series of disturbances could be attributed to changes in the microbial community composition measured by weighted UniFrac distances. This indicates that surveying changes in bacterial community composition can help predict the strength of the impact of compounded disturbances on N-related functions and properties. PMID- 30459750 TI - Phage Lysins for Fighting Bacterial Respiratory Infections: A New Generation of Antimicrobials. AB - Lower respiratory tract infections and tuberculosis are responsible for the death of about 4.5 million people each year and are the main causes of mortality in children under 5 years of age. Streptococcus pneumoniae is the most common bacterial pathogen associated with severe pneumonia, although other Gram-positive and Gram-negative bacteria are involved in respiratory infections as well. The ability of these pathogens to persist and produce infection under the appropriate conditions is also associated with their capacity to form biofilms in the respiratory mucous membranes. Adding to the difficulty of treating biofilm forming bacteria with antibiotics, many of these strains are becoming multidrug resistant, and thus the alternative therapeutics available for combating this kind of infections are rapidly depleting. Given these concerns, it is urgent to consider other unconventional strategies and, in this regard, phage lysins represent an attractive resource to circumvent some of the current issues in infection treatment. When added exogenously, lysins break specific bonds of the peptidoglycan and have potent bactericidal effects against susceptible bacteria. These enzymes possess interesting features, including that they do not trigger an adverse immune response and raise of resistance is very unlikely. Although Gram negative bacteria had been considered refractory to these compounds, strategies to overcome this drawback have been developed recently. In this review we describe the most relevant in vitro and in vivo results obtained to date with lysins against bacterial respiratory pathogens. PMID- 30459751 TI - Glycyrrhizin Attenuates Salmonella enterica Serovar Typhimurium Infection: New Insights Into Its Protective Mechanism. AB - Glycyrrhizin (GL), a triterpenoid glycoside, serves important functions in various biological activities, including antiviral and antitumor immune responses. However, the anti-inflammatory effects of GL on Salmonella enterica serovar Typhimurium (ST)-induced injury in mice and the mechanisms underlying the protection of GL are poorly understood. Here, we investigated the effects of GL on host immune responses against ST infection in mice. A phenotypic analysis using hematoxylin and eosin (H&E) staining and transmission electron microscopy showed that GL relieved ST-induced weight loss and intestinal mucosal injury. A colonization assay showed that GL significantly reduced ST colonization in the ileum and colon and translocation to the liver and spleen. An antibacterial activity assay and real-time PCR revealed that GL had no direct inhibitory impact on ST growth or virulence gene expression. ELISA showed that GL pretreatment significantly decreased proinflammatory cytokine (IFN-gamma, TNF-alpha, IL-6) secretion and increased anti-inflammatory cytokine (IL-10) secretion in the ileum, colon and serum of ST-infected mice. Moreover, flora analysis showed that GL reduced Akkermansia, Sutterella, Prevotella and Coprococcus but enriched Parabacteroides and Anaerotruncus in the cecum of ST-infected mice. These results suggest that GL promotes the secretion of immune factors and modulates intestinal flora to prevent further ST infection. We also analyzed the effect of GL on immunocytes and found that GL promoted the phenotypic and functional maturation of murine bone marrow-derived dendritic cells (BMDCs). Flow cytometry and western blotting demonstrated that NF-kappaB, ERK, and p38 MAPK were required for GL induced BMDC maturation. The above findings indicate that GL attenuates ST infection by modulating immune function and intestinal flora. This study enriches our current knowledge of GL-mediated immunological function and provides a new perspective on the prevention of Salmonella infection in animals and humans. PMID- 30459753 TI - Targeting Immune Checkpoint Molecules to Eliminate Latent HIV. AB - The advent of antiretroviral therapy (ART) has seen a dramatic decrease in the morbidity and mortality of individuals infected with human immunodeficiency virus (HIV). However, ART is not curative and HIV persists in treated individuals within a pool of infected CD4+ memory T cells. The targeting and elimination of these cells, termed the latent HIV reservoir, may be essential in establishing a cure for HIV. Current HIV reservoir research is focused on identifying cells that harbor latent, replication-competent, HIV provirus using specific cell surface markers. Recently, studies have turned to immune checkpoint (IC) molecules, such as programmed cell death protein 1 (PD-1). IC molecules are regulators of the immune system and have previously been linked to HIV infection. Furthermore, cells isolated from treated individuals co-expressing PD-1 alongside other IC molecules are enriched for HIV DNA. Administration of a IC blocking antibodies resulted in an increase of cell-associated HIV RNA within an individual, indicating the potential for this therapeutic to be utilized as a latency reversing agent. IC inhibitors could target CD4+ T cells expressing IC molecules and possibly enhance HIV transcription, allowing for the elimination of these cells by either ART or the immune system. However, treatment with IC inhibitors has been associated with toxicities such as immune-related adverse events and therefore future studies should proceed with caution. PMID- 30459754 TI - Resolving Viral-Induced Secondary Bacterial Infection in COPD: A Concise Review. AB - Chronic obstructive pulmonary disease (COPD) is a leading cause of disability and death world-wide, where chronic inflammation accelerates lung function decline. Pathological inflammation is worsened by chronic bacterial lung infections and susceptibility to recurrent acute exacerbations of COPD (AECOPD), typically caused by viral and/or bacterial respiratory pathogens. Despite ongoing efforts to reduce AECOPD rates with inhaled corticosteroids, COPD patients remain at heightened risk of developing serious lung infections/AECOPD, frequently leading to hospitalization and infection-dependent delirium. Here, we review emerging mechanisms into why COPD patients are susceptible to chronic bacterial infections and highlight dysregulated inflammation and production of reactive oxygen species (ROS) as central causes. This underlying chronic infection leaves COPD patients particularly vulnerable to acute viral infections, which further destabilize host immunity to bacteria. The pathogeneses of bacterial and viral exacerbations are significant as clinical symptoms are more severe and there is a marked increase in neutrophilic inflammation and tissue damage. AECOPD triggered by a bacterial and viral co-infection increases circulating levels of the systemic inflammatory marker, serum amyloid A (SAA). SAA is a functional agonist for formyl peptide receptor 2 (FPR2/ALX), where it promotes chemotaxis and survival of neutrophils. Excessive levels of SAA can antagonize the protective actions of FPR2/ALX that involve engagement of specialized pro-resolving mediators, such as resolvin-D1. We propose that the anti-microbial and anti-inflammatory actions of specialized pro-resolving mediators, such as resolvin-D1 should be harnessed for the treatment of AECOPD that are complicated by the co-pathogenesis of viruses and bacteria. PMID- 30459752 TI - The Development of Serum Amyloid P as a Possible Therapeutic. AB - Pentraxins such as serum amyloid P (SAP; also known as PTX2) regulate several aspects of the innate immune system. SAP inhibits the differentiation of monocyte derived fibroblast-like cells called fibrocytes, promotes the formation of immuno regulatory macrophages, and inhibits neutrophil adhesion to extracellular matrix proteins. In this minireview, we describe how these effects of SAP have led to its possible use as a therapeutic, and how modulating SAP effects might be used for other therapeutics. Fibrosing diseases such as pulmonary fibrosis, cardiac fibrosis, liver fibrosis, and renal fibrosis are associated with 30-45% of deaths in the US. Fibrosis involves both fibrocyte differentiation and profibrotic macrophage differentiation, and possibly because SAP inhibits both of these processes, in 9 different animal models, SAP inhibited fibrosis. In Phase 1B and Phase 2 clinical trials, SAP injections reduced the decline in lung function in pulmonary fibrosis patients, and in a small Phase 2 trial SAP injections reduced fibrosis in myelofibrosis patients. Acute respiratory distress syndrome/ acute lung injury (ARDS/ALI) involves the accumulation of neutrophils in the lungs, and possibly because SAP inhibits neutrophil adhesion, SAP injections reduced the severity of ARDS in an animal model. Conversely, depleting SAP is a potential therapeutic for amyloidosis, topically removing SAP from wound fluid speeds wound healing in animal models, and blocking SAP binding to one of its receptors makes cultured macrophages more aggressive toward tuberculosis bacteria. These results suggest that modulating pentraxin signaling might be useful for a variety of diseases. PMID- 30459755 TI - Rheumatoid Arthritis-Associated Autoimmunity Due to Aggregatibacter actinomycetemcomitans and Its Resolution With Antibiotic Therapy. AB - Background: Aggregatibacter actinomycetemcomitans (Aa) is a Gram-negative coccobacillus recognized as a pathogen in periodontitis and infective endocarditis. By producing a toxin (leukotoxin A, LtxA) that triggers global hypercitrullination in neutrophils, Aa has been recently linked to rheumatoid arthritis (RA) pathogenesis. Although mechanistic and clinical association studies implicate Aa infection in the initiation of autoimmunity in RA, direct evidence in humans is lacking. Case:We describe a 59-year-old man with anti citrullinated protein antibody (ACPA)-positive RA who presented for evaluation of refractory disease. He was found to have Aa endocarditis. Following antibiotic treatment, joint symptoms resolved and ACPAs normalized. Given the implications for RA immunopathogenesis, we further investigated the bacterial, genetic and immune factors that may have contributed to the patient's clinical and autoimmune phenotypes. Methods:DNA was extracted from serum and used to amplify the Aa leukotoxin (ltx) promoter region by PCR, which was further analyzed by Sanger sequencing. High-resolution identification of HLA alleles was performed by sequenced based typing (SBT). TNF-alpha, IFN-gamma, GM-CSF, IL-1beta, IL-6, IL-8, IL-17A, IL-18, IL-21, and IL-22 were quantified in serum by a multiplex immunoassay. IgG and IgA antibodies to Aa LtxA were assayed by ELISA. Results: Aa genotyping confirmed infection with a highly leukotoxic strain carrying a 530-bp ltx promoter deletion, shown to result in 10- to 20-fold higher bacterial expression of LtxA. Immuno-phenotyping showed high anti-LtxA antibodies, elevated cytokines implicated in RA pathogenesis (Th1/Th17), and specific host susceptibility conferred by three HLA alleles strongly linked to ACPAs and RA (DRB1*04:04, DRB1*15:01, and DPB1*04:01). One year after eradication of Aa, the patient remained free of arthritis and anti-CCP antibodies. Conclusion: In the context of genetic risk for RA, systemic subacute infection with a leukotoxic strain of Aa can drive ACPA production and a clinical phenotype similar to RA. PMID- 30459756 TI - Hypoxia Modifies the Transcriptome of Human NK Cells, Modulates Their Immunoregulatory Profile, and Influences NK Cell Subset Migration. AB - Hypoxia, which characterizes most tumor tissues, can alter the function of different immune cell types, favoring tumor escape mechanisms. In this study, we show that hypoxia profoundly acts on NK cells by influencing their transcriptome, affecting their immunoregulatory functions, and changing the chemotactic responses of different NK cell subsets. Exposure of human peripheral blood NK cells to hypoxia for 16 or 96 h caused significant changes in the expression of 729 or 1,100 genes, respectively. Gene Set Enrichment Analysis demonstrated that these changes followed a consensus hypoxia transcriptional profile. As assessed by Gene Ontology annotation, hypoxia-targeted genes were implicated in several biological processes: metabolism, cell cycle, differentiation, apoptosis, cell stress, and cytoskeleton organization. The hypoxic transcriptome also showed changes in genes with immunological relevance including those coding for proinflammatory cytokines, chemokines, and chemokine-receptors. Quantitative RT PCR analysis confirmed the modulation of several immune-related genes, prompting further immunophenotypic and functional studies. Multiplex ELISA demonstrated that hypoxia could variably reduce NK cell ability to release IFNgamma, TNFalpha, GM-CSF, CCL3, and CCL5 following PMA+Ionomycin or IL15+IL18 stimulation, while it poorly affected the response to IL12+IL18. Cytofluorimetric analysis showed that hypoxia could influence NK chemokine receptor pattern by sustaining the expression of CCR7 and CXCR4. Remarkably, this effect occurred selectively (CCR7) or preferentially (CXCR4) on CD56bright NK cells, which indeed showed higher chemotaxis to CCL19, CCL21, or CXCL12. Collectively, our data suggest that the hypoxic environment may profoundly influence the nature of the NK cell infiltrate and its effects on immune-mediated responses within tumor tissues. PMID- 30459757 TI - Integrating Immunology and Microfluidics for Single Immune Cell Analysis. AB - The field of immunoengineering aims to develop novel therapies and modern vaccines to manipulate and modulate the immune system and applies innovative technologies toward improved understanding of the immune system in health and disease. Microfluidics has proven to be an excellent technology for analytics in biology and chemistry. From simple microsystem chips to complex microfluidic designs, these platforms have witnessed an immense growth over the last decades with frequent emergence of new designs. Microfluidics provides a highly robust and precise tool which led to its widespread application in single-cell analysis of immune cells. Single-cell analysis allows scientists to account for the heterogeneous behavior of immune cells which often gets overshadowed when conventional bulk study methods are used. Application of single-cell analysis using microfluidics has facilitated the identification of several novel functional immune cell subsets, quantification of signaling molecules, and understanding of cellular communication and signaling pathways. Single-cell analysis research in combination with microfluidics has paved the way for the development of novel therapies, point-of-care diagnostics, and even more complex microfluidic platforms that aid in creating in vitro cellular microenvironments for applications in drug and toxicity screening. In this review, we provide a comprehensive overview on the integration of microsystems and microfluidics with immunology and focus on different designs developed to decode single immune cell behavior and cellular communication. We have categorized the microfluidic designs in three specific categories: microfluidic chips with cell traps, valve-based microfluidics, and droplet microfluidics that have facilitated the ongoing research in the field of immunology at single-cell level. PMID- 30459760 TI - Serum microRNA Profiles Serve as Novel Biomarkers for Autoimmune Diseases. AB - Autoimmune diseases involve a complex dysregulation of immunity. Autoimmune diseases include many members [e.g., rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)], and most of them are classified according to what organs and tissues are targeted by the damaging immune response. Many studies have focused on finding specific biomarkers for single autoimmune diseases, but so far, there are no universal biomarkers for detecting almost all autoimmune diseases. Serum miRNAs have served as potential biomarkers for detecting various diseases. The purpose of this study was to find a universal biomarker for diagnosing autoimmune diseases. Regulatory T cells (Tregs) play a crucial role in protecting an individual from autoimmunity, and depletion of Tregs in mice is considered a representative animal model of autoimmune disease. Two mouse models for Treg depletion, in which Treg was depleted by CD25mAb (in C57 mice) or by diphtheria toxin (DT) (in Foxp3DTR mice), were investigated, and 381 miRNAs were identified in the serum of mice with Treg depletion. A distinctive circulating miRNA profile was identified in Treg-depleted mice and in patients with autoimmune disease. QRT-PCR confirmation and ROC curve analysis determined that six miRNAs (miR-551b, miR-448, miR-9, miR-124, miR-148, and miR-34c) in the Treg depleted mouse models and three miRNAs [miR-551b (specificity 73.5%, sensitivity 88.4%), miR-448 (specificity 82.4%, sensitivity 91.3%), and miR-124 (specificity 76.5%, sensitivity 91.3%)] in patients with RA, SLE, Sjogren's syndrome (SS), and ulcerative colitis (UC) could serve as valuable specific biomarkers. These circulating miRNAs may represent potential universal biomarkers for autoimmune diseases diagnosis and prognosis. PMID- 30459758 TI - Pattern Recognition Receptors and the Host Cell Death Molecular Machinery. AB - Pattern Recognition Receptors (PRRs) are proteins capable of recognizing molecules frequently found in pathogens (the so-called Pathogen-Associated Molecular Patterns-PAMPs), or molecules released by damaged cells (the Damage Associated Molecular Patterns-DAMPs). They emerged phylogenetically prior to the appearance of the adaptive immunity and, therefore, are considered part of the innate immune system. Signals derived from the engagement of PRRs on the immune cells activate microbicidal and pro-inflammatory responses required to eliminate or, at least, to contain infectious agents. Molecularly controlled forms of cell death are also part of a very ancestral mechanism involved in key aspects of the physiology of multicellular organism, including the elimination of unwanted, damaged or infected cells. Interestingly, each form of cell death has its particular effect on inflammation and on the development of innate and adaptive immune responses. In this review article, we discuss some aspects of the molecular interplay between the cell death machinery and signals initiated by the activation of PRRs by PAMPs and DAMPs. PMID- 30459762 TI - Extended Cleavage Specificity of Human Neutrophil Elastase, Human Proteinase 3, and Their Distant Ortholog Clawed Frog PR3-Three Elastases With Similar Primary but Different Extended Specificities and Stability. AB - Serine proteases are major granule constituents of several of the human hematopoietic cell lineages. Four proteolytically active such proteases have been identified in human neutrophils: cathepsin G (hCG), N-elastase (hNE), proteinase 3 (hPR-3), and neutrophil serine protease 4 (hNSP-4). Here we present the extended cleavage specificity of two of the most potent and most abundant of these enzymes, hNE and hPR-3. Their extended specificities were determined by phage display and by the analysis of a panel of chromogenic and recombinant substrates. hNE is an elastase with a relatively broad specificity showing a preference for regions containing several aliphatic amino acids. The protease shows self-cleaving activity, which results in the loss of activity during storage even at +4 degrees C. Here we also present the extended cleavage specificity of hPR-3. Compared with hNE, it shows considerably lower proteolytic activity. However, it is very stable, shows no self-cleaving activity and is actually more active in the presence of SDS, possibly by enhancing the accessibility of the target substrate. This enables specific analysis of hPR-3 activity even in the presence of all the other neutrophil enzymes with addition of 1% SDS. Neutrophils are the most abundant white blood cell in humans and one of the key players in our innate immune defense. The neutrophil serine proteases are very important for the function of the neutrophils and therefore also interesting from an evolutionary perspective. In order to study the origin and functional conservation of these neutrophil proteases we have identified and cloned an amphibian ortholog, Xenopus PR-3 (xPR-3). This enzyme was found to have a specificity very similar to hPR-3 but did not show the high stability in the presence of SDS. The presence of an elastase in Xenopus closely related to hPR-3 indicates a relatively early appearance of these enzymes during vertebrate evolution. PMID- 30459759 TI - CAR T Cell Therapy for Neuroblastoma. AB - Patients with high risk neuroblastoma have a poor prognosis and survivors are often left with debilitating long term sequelae from treatment. Even after integration of anti-GD2 monoclonal antibody therapy into standard, upftont protocols, 5-year overall survival rates are only about 50%. The success of anti GD2 therapy has proven that immunotherapy can be effective in neuroblastoma. Adoptive transfer of chimeric antigen receptor (CAR) T cells has the potential to build on this success. In early phase clinical trials, CAR T cell therapy for neuroblastoma has proven safe and feasible, but significant barriers to efficacy remain. These include lack of T cell persistence and potency, difficulty in target identification, and an immunosuppressive tumor microenvironment. With recent advances in CAR T cell engineering, many of these issues are being addressed in the laboratory. In this review, we summarize the clinical trials that have been completed or are underway for CAR T cell therapy in neuroblastoma, discuss the conclusions and open questions derived from these trials, and consider potential strategies to improve CAR T cell therapy for patients with neuroblastoma. PMID- 30459761 TI - The Pentraxins 1975-2018: Serendipity, Diagnostics and Drugs. AB - The phylogenetically ancient, pentraxin family of plasma proteins, comprises C reactive protein (CRP) and serum amyloid P component (SAP) in humans and the homologous proteins in other species. They are composed of five, identical, non covalently associated protomers arranged with cyclic pentameric symmetry in a disc-like configuration. Each protomer has a calcium dependent site that mediates the particular specific ligand binding responsible for all the rigorously established functional properties of these proteins. No genetic deficiency of either human CRP or SAP has been reported, nor even any sequence polymorphism in the proteins themselves. Although their actual functions in humans are therefore unknown, gene deletion studies in mice demonstrate that both proteins can contribute to innate immunity. CRP is the classical human acute phase protein, routinely measured in clinical practice worldwide to monitor disease activity. Human SAP, which is not an acute phase protein, is a universal constituent of all human amyloid deposits as a result of its avid specific binding to amyloid fibrils of all types. SAP thereby contributes to amyloid formation and persistence in vivo. Whole body radiolabelled SAP scintigraphy safely and non invasively localizes and quantifies systemic amyloid deposits, and has transformed understanding of the natural history of amyloidosis and its response to treatment. Human SAP is also a therapeutic target, both in amyloidosis and Alzheimer's disease. Our drug, miridesap, depletes SAP from the blood and the brain and is currently being tested in the DESPIAD clinical trial in Alzheimer's disease. Meanwhile, the obligate therapeutic partnership of miridesap, to deplete circulating SAP, and dezamizumab, a humanized monoclonal anti-SAP antibody that targets residual SAP in amyloid deposits, produces unprecedented removal of amyloid from the tissues and improves organ function. Human CRP binds to dead and damaged cells in vivo and activates complement and this can exacerbate pre existing tissue damage. The adverse effects of CRP are completely abrogated by compounds that block its binding to autologous ligands and we are developing CRP inhibitor drugs. The present personal and critical perspective on the pentraxins reports, for the first time, the key role of serendipity in our work since 1975. (345 words). PMID- 30459763 TI - Survival of Surfactant Protein-A1 and SP-A2 Transgenic Mice After Klebsiella pneumoniae Infection, Exhibits Sex-, Gene-, and Variant Specific Differences; Treatment With Surfactant Protein Improves Survival. AB - Surfactant protein A (SP-A) is involved in lung innate host defense and surfactant-related functions. The human SFTPA1 and SFTPA2 genes encode SP-A1 and SP-2 proteins, and each gene has been identified with numerous genetic variants. SP-A1 and SP-A2 differentially enhance bacterial phagocytosis. Sex differences have been observed in pulmonary disease and in survival of wild type and SP-A knockout (KO) mice. The impact of human SP-A variants on survival after infection is unknown. In this study, we determined whether SP-A variants differentially affect survival of male and female mice infected with Klebsiella pneumoniae. Transgenic (TG) mice, where each carries a different human (h) SP-A1 (6A2, 6A4), SP-A2 (1A0, 1A3) variant or both variants SP-A1/SP-A2 (6A2/1A0, co-ex), and SP-A- KO, were utilized. The hTG and KO mice were infected intratracheally with K. pneumoniae bacteria, and groups of KO mice were treated with SP-A1 or SP-A2 either prior to and/or at the time of infection and survival for both experimental groups was monitored over 14 days. The binding of purified SP-A1 and SP-A2 proteins to phagocytic and non-phagocytic cells and expression of cell surface proteins in alveolar macrophages (AM) from SP-A1 and SP-A2 mice was examined. We observed gene-, variant-, and sex-specific (except for co-ex) differences with females showing better survival: (a) Gene-specific differences: co-ex = SP-A2 > SP-A1 > KO (both sexes); (b) Variant-specific survival co-ex (6A2/1A0) = 1A0 > 1A3 = 6A2 > 6A4 (both sexes); (c) KO mice treated with SPs (SP A1 or SP-A2) proteins exhibit significantly (p < 0.05) better survival; (d) SP-A1 and SP-A2 differentially bind to phagocytic, but not to non-phagocytic cells, and AM from SP-A1 and SP-A2 hTG mice exhibit differential expression of cell surface proteins. Our results indicate that sex and SP-A genetics differentially affect survival after infection and that exogenous SP-A1/SP-A2 treatment significantly improves survival. We postulate that the differential SP-A1/SP-A2 binding to the phagocytic cells and the differential expression of cell surface proteins that bind SP-A by AM from SP-A1 and SP-A2 mice play a role in this process. These findings provide insight into the importance of sex and innate immunity genetics in survival following infection. PMID- 30459765 TI - Rationale for an Association Between PD1 Checkpoint Inhibition and Therapeutic Vaccination Against HIV. AB - The pathogenesis of HIV immunodeficiency is mainly dependent on the cytopatic effects exerted by the virus against infected CD4+ T cells. However, CD4+ T cell loss cannot be the only pathogenic factor since severe opportunistic infections may develop in HIV infected patients with normal CD4+ T cell counts and since the recent START study indicated that absolute CD4+ T cell counts are not predictive for AIDS and non-AIDS events. Recently our group demonstrated that CD8+CD28 CD127lowCD39+ regulatory T lymphocytes, previously found highly concentrated within tumor microenvironment, circulate with elevated frequency in the peripheral blood of HIV infected patients. Here, we show that these cells, that at least in part are HIV specific, express the PD1 immune checkpoint. Based on these evidences and considerations, in this Perspective article we speculate on the opportunity to treat HIV infected patients with anti-PD1 immune checkpoint inhibitors as a way to counteract the T regulatory cell compartment and to unleash virus-specific immune responses. In order to potentiate the immune responses against HIV we also propose the potential utility to associate immune checkpoint inhibition with HIV-specific therapeutic vaccination, reminiscent of what currently applied in oncologic protocols. We suggest that such an innovative strategy could permit drug-sparing regimens and, perhaps, lead to eradication of the infection in some patients. PMID- 30459764 TI - Sepsis and Nosocomial Infection: Patient Characteristics, Mechanisms, and Modulation. AB - Sepsis is a leading cause of death worldwide. After initial trials modulating the hyperinflammatory phase of sepsis failed, generations of researchers have focused on evaluating hypo-inflammatory immune phenotypes. The main goal has been to develop prognostic biomarkers and therapies to reduce organ dysfunction, nosocomial infection, and death. The depressed host defense in sepsis has been characterized by broad cellular reprogramming including lymphocyte exhaustion, apoptosis, and depressed cytokine responses. Despite major advances in this field, our understanding of the dynamics of the septic host response and the balance of inflammatory and anti-inflammatory cellular programs remains limited. This review aims to summarize the epidemiology of nosocomial infections and characteristic immune responses associated with sepsis, as well as immunostimulatory therapies currently under clinical investigation. PMID- 30459766 TI - Latitude, Vitamin D, Melatonin, and Gut Microbiota Act in Concert to Initiate Multiple Sclerosis: A New Mechanistic Pathway. AB - Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). While the etiology of MS is still largely unknown, scientists believe that the interaction of several endogenous and exogenous factors may be involved in this disease. Epidemiologists have seen an increased prevalence of MS in countries at high latitudes, where the sunlight is limited and where the populations have vitamin D deficiency and high melatonin levels. Although the functions and synthesis of vitamin D and melatonin are contrary to each other, both are involved in the immune system. While melatonin synthesis is affected by light, vitamin D deficiency may be involved in melatonin secretion. On the other hand, vitamin D deficiency reduces intestinal calcium absorption leading to gut stasis and subsequently increasing gut permeability. The latter allows gut microbiota to transfer more endotoxins such as lipopolysaccharides (LPS) into the blood. LPS stimulates the production of inflammatory cytokines within the CNS, especially the pineal gland. This review summarizes the current findings on the correlation between latitude, sunlight and vitamin D, and details their effects on intestinal calcium absorption, gut microbiota and neuroinflammatory mediators in MS. We also propose a new mechanistic pathway for the initiation of MS. PMID- 30459768 TI - Monogenic Lupus: A Developing Paradigm of Disease. AB - Monogenic lupus is a form of systemic lupus erythematosus (SLE) that occurs in patients with a single gene defect. This rare variant of lupus generally presents with early onset severe disease, especially affecting the kidneys and central nervous system. To date, a significant number of genes have been implicated in monogenic lupus, providing valuable insights into a very complex disease process. Throughout this review, we will summarize the genes reported to be associated with monogenic lupus or lupus-like diseases, and the pathogenic mechanisms affected by the mutations involved upon inducing autoimmunity. PMID- 30459769 TI - Outer-Membrane-Vesicle-Associated O Antigen, a Crucial Component for Protecting Against Bordetella parapertussis Infection. AB - Bordetella parapertussis is a respiratory-disease pathogen producing symptomatology similar to that of pertussis but of underestimated incidence and with no specific vaccine existing. We recently designed a vaccine candidate from B. parapertussis outer-membrane vesicles (OMVs) that proved to be safe and protective in a murine-infection model. Based on protection recently reported for the B. parapertussis O antigen in aqueous solution, we assessed here whether the B. parapertussis O-antigen-containing lipopolysaccharide (BppLPS-O+) embedded in the membranes, as present in B. parapertussis-derived OMVs (OMVs(Bpp-LPS-O+)), was the component responsible for that previously observed protection by OMVs. By performing a comparative study with OMVs from a human strain with undetectable O antigen (OMVs(Bpp-LPS-O-)), we demonstrated that the OMVs(Bpp-LPS-O+), but not the OMVs(Bpp-LPS-O-), protected mice against sublethal B. parapertussis infections. Indeed, the B. parapertussis loads were significantly reduced in the lungs of OMVs(Bpp-LPS-O+) -vaccinated animals, with the CFUs recovered being decreased by 4 log units below those detected in the non-immunized animals or in the animals treated with the OMVs(Bpp-LPS-O-), (p < 0.001). We detected that the OMVs(Bpp-LPS-O+) induced IgG antibodies against B. parapertussis whole-cell lysates, which immunocomponents recognized, among others, the O antigen and accordingly conferred protection against B. parapertussis infection, as observed in in-vivo-passive-transfer experiments. Of interest was that the OMVs(Bpp-LPS O+) -generated sera had opsonophagocytic and bactericidal capabilities that were not detected with the OMVs(Bpp-LPS-O-)-induced sera, suggesting that those activities were involved in the clearance of B. parapertussis. Though stimulation of cultured spleen cells from immunized mice with formulations containing the O antigen resulted in gamma interferon (IFN-gamma) and interleukin-17 production, spleen cells from OMVs(Bpp-LPS-O+) -immunized mice did not significantly contribute to the observed protection against B. parapertussis infection. The protective capability of the B. parapertussis O antigen was also detected in formulations containing both the OMVs derived from B. pertussis and purified BppLPS-O+. This combined formulation protected mice against B. pertussis along with B. parapertussis. PMID- 30459767 TI - Schistosoma "Eggs-Iting" the Host: Granuloma Formation and Egg Excretion. AB - Schistosomiasis is a major cause of morbidity in humans invoked by chronic infection with parasitic trematodes of the genus Schistosoma. Schistosomes have a complex life-cycle involving infections of an aquatic snail intermediate host and a definitive mammalian host. In humans, adult male and female worms lie within the vasculature. Here, they propagate and eggs are laid. These eggs must then be released from the host to continue the life cycle. Schistosoma mansoni and Schistosoma japonicum reside in the mesenteric circulation of the intestines with egg excreted in the feces. In contrast, S. haematobium are present in the venus plexus of the bladder, expelling eggs in the urine. In an impressive case of exploitation of the host immune system, this process of Schistosome "eggs-iting" the host is immune dependent. In this article, we review the formation of the egg granuloma and explore how S. mansoni eggs laid in vasculature must usurp immunity to induce regulated inflammation, to facilitate extravasation through the intestinal wall and to be expelled in the feces. We highlight the roles of immune cell populations, stromal factors, and egg secretions in the process of egg excretion to provide a comprehensive overview of the current state of knowledge regarding a vastly unexplored mechanism. PMID- 30459770 TI - T Cells in Adipose Tissue: Critical Players in Immunometabolism. AB - Adipose tissue performs immunoregulatory functions in addition to fat storage. Various T cells in different fat depots either help maintain metabolic homeostasis under healthy conditions or contribute to metabolic disorders in pathological conditions such as obesity, diabetes, cardiovascular diseases, or even cancer. These T cells play critical roles in immunometabolism, which refers to the intersection of immunity and metabolism. Numerous studies have examined the presence and changes of different T cell subsets, including helper T cells, regulatory T cells, cytotoxic T cells, and natural killer T cells, in adipose depots in health and diseases. In this review, we will discuss the adipose tissue niches that influence the patterns and functions of T cell subsets and in turn the impact of these T cells on cell- or body-based immunometabolism accounting for health and obesity. PMID- 30459772 TI - Perspectives for the Development of CD38-Specific Heavy Chain Antibodies as Therapeutics for Multiple Myeloma. AB - The NAD+-metabolizing ectoenzyme CD38 is an established therapeutic target in multiple myeloma. The CD38-specific monoclonal antibodies daratumumab and isatuximab show promising results in the clinic. Nanobodies correspond to the single variable domains (VHH) derived from heavy chain antibodies that naturally occur in camelids. VHHs display high solubility and excellent tissue penetration in vivo. We recently generated a panel of CD38-specific nanobodies, some of which block or enhance the enzymatic activity of CD38. Fusion of such a nanobody to the hinge, CH2, and CH3 domains of human IgG1 generates a chimeric llama/human hcAb of about half the size of a conventional moAb (75 vs. 150 kDa). Similarly, a fully human CD38-specific hcAb can be generated using a CD38-specific human VH3 instead of a CD38-specific camelid nanobody. Here we discuss the advantages and disadvantages of CD38-specific hcAbs vs. conventional moAbs and provide an outlook for the potential use of CD38-specific hcAbs as novel therapeutics for multiple myeloma. PMID- 30459771 TI - Preparations for Invasion: Modulation of Host Lung Immunity During Pulmonary Aspergillosis by Gliotoxin and Other Fungal Secondary Metabolites. AB - Pulmonary aspergillosis is a severe infectious disease caused by some members of the Aspergillus genus, that affects immunocompetent as well as immunocompromised patients. Among the different disease forms, Invasive Aspergillosis is the one causing the highest mortality, mainly, although not exclusively, affecting neutropenic patients. This genus is very well known by humans, since different sectors like pharmaceutical or food industry have taken advantage of the biological activity of some molecules synthetized by the fungus, known as secondary metabolites, including statins, antibiotics, fermentative compounds or colorants among others. However, during infection, in response to a hostile host environment, the fungal secondary metabolism is activated, producing different virulence factors to increase its survival chances. Some of these factors also contribute to fungal dissemination and invasion of adjacent and distant organs. Among the different secondary metabolites produced by Aspergillus spp. Gliotoxin (GT) is the best known and better characterized virulence factor. It is able to generate reactive oxygen species (ROS) due to the disulfide bridge present in its structure. It also presents immunosuppressive activity related with its ability to kill mammalian cells and/or inactivate critical immune signaling pathways like NFkB. In this comprehensive review, we will briefly give an overview of the lung immune response against Aspergillus as a preface to analyse the effect of different secondary metabolites on the host immune response, with a special attention to GT. We will discuss the results reported in the literature on the context of the animal models employed to analyse the role of GT as virulence factor, which is expected to greatly depend on the immune status of the host: why should you hide when nobody is seeking for you? Finally, GT immunosuppressive activity will be related with different human diseases predisposing to invasive aspergillosis in order to have a global view on the potential of GT to be used as a target to treat IA. PMID- 30459774 TI - Editorial: Cytokine-Ion Channel Interactions in Pulmonary Inflammation. PMID- 30459773 TI - The Role of BACH2 in T Cells in Experimental Malaria Caused by Plasmodium chabaudi chabaudi AS. AB - BTB and CNC Homology 1, Basic Leucine Zipper Transcription Factor 2 (BACH2) is a transcription factor best known for its role in B cell development. More recently, it has been associated with T cell functions in inflammatory diseases, and has been proposed as a master transcriptional regulator within the T cell compartment. In this study, we employed T cell-specific Bach2-deficient (B6.Bach2 DeltaT ) mice to examine the role of this transcription factor in CD4+ T cell functions in vitro and in mice infected with Plasmodium chabaudi AS. We found that under CD4+ T cell polarizing conditions in vitro, Th2, and Th17 helper cell subsets were more active in the absence of Bach2 expression. In mice infected with P. chabaudi AS, although the absence of Bach2 expression by T cells had no effect on blood parasitemia or disease pathology, we found reduced expansion of CD4+ T cells in B6.Bach2 DeltaT mice, compared with littermate controls. Despite this reduction, we observed increased frequencies of Tbet+ IFNgamma+ CD4+ (Th1) cells and IL-10-producing Th1 (Tr1) cells in mice lacking Bach2 expression by T cells. Studies in mixed bone marrow chimeric mice revealed T cell intrinsic effects of BACH2 on hematopoietic cell development, and in particular, the generation of CD4+ and CD8+ T cell subsets. Furthermore, T cell intrinsic BACH2 was needed for efficient expansion of CD4+ T cells during experimental malaria in this immunological setting. We also examined the response of B6.Bach2 DeltaT mice to a second protozoan parasitic challenge with Leishmania donovani and found similar effects on disease outcome and T cell responses. Together, our findings provide new insights into the role of BACH2 in CD4+ T cell activation during experimental malaria, and highlight an important role for this transcription factor in the development and expansion of T cells under homeostatic conditions, as well as establishing the composition of the effector CD4+ T cell compartment during infection. PMID- 30459776 TI - Identification of a Novel QTL for Panicle Length From Wild Rice (Oryza minuta) by Specific Locus Amplified Fragment Sequencing and High Density Genetic Mapping. AB - Wild rice possesses a large number of valuable genes that have been lost or do not exist in cultivated rice. To exploit the desirable gene controlling panicle length (PL) in wild rice Oryza minuta, a recombinant inbred line (RIL) population was constructed that was derived from a cross between the long panicle introgression line K1561 with Oryza minuta segments and a short panicle accession G1025. Specific Locus Amplified Fragment (SLAF) sequencing technology was used to uncover single nucleotide polymorphisms (SNPs) and construct the high-density genetic linkage map. Using 201 RIL populations, a high-density genetic map was developed, and spanned 2781.76 cM with an average genetic distance 0.45 cM. The genetic map was composed of 5, 521 markers on 12 chromosomes. Based on this high density genome map, quantitative trait loci (QTL) for PL were analyzed for 2 years under four environments. Seven QTLs were detected, which were distributed within chromosomes 4, 9, and 10, respectively. pl4.1 was detected twice, and pl10.1 was only detected once. Although pl9.1 was only detected once, it was very near pl9.2 in the genetic map which was detected three times. Thus, we speculate one major QTL exists in the region of pl9.1 and pl9.2 to control PL (temporarily referred to as pl9). pl9 is a potentially novel allele derived from Oryza minuta, and it can be used for genetic improvement of cultivar rice. PMID- 30459775 TI - Phytoextraction of Heavy Metals: A Promising Tool for Clean-Up of Polluted Environment? AB - Pollution by heavy metals (HM) represents a serious threat for both the environment and human health. Due to their elemental character, HM cannot be chemically degraded, and their detoxification in the environment mostly resides either in stabilization in situ or in their removal from the matrix, e.g., soil. For this purpose, phytoremediation, i.e., the application of plants for the restoration of a polluted environment, has been proposed as a promising green alternative to traditional physical and chemical methods. Among the phytoremediation techniques, phytoextraction refers to the removal of HM from the matrix through their uptake by a plant. It possesses considerable advantages over traditional techniques, especially due to its cost effectiveness, potential treatment of multiple HM simultaneously, no need for the excavation of contaminated soil, good acceptance by the public, the possibility of follow-up processing of the biomass produced, etc. In this review, we focused on three basic HM phytoextraction strategies that differ in the type of plant species being employed: natural hyperaccumulators, fast-growing plant species with high biomass production and, potentially, plants genetically engineered toward a phenotype that favors efficient HM uptake and boosted HM tolerance. Considerable knowledge on the applicability of plants for HM phytoextraction has been gathered to date from both lab-scale studies performed under controlled model conditions and field trials using real environmental conditions. Based on this knowledge, many specific applications of plants for the remediation of HM-polluted soils have been proposed. Such studies often also include suggestions for the further processing of HM-contaminated biomass, therefore providing an added economical value. Based on the examples presented here, we recommend that intensive research be performed on the selection of appropriate plant taxa for various sets of conditions, environmental risk assessment, the fate of HM-enriched biomass, economical aspects of the process, etc. PMID- 30459777 TI - New Insights Into Sunflower (Helianthus annuus L.) FatA and FatB Thioesterases, Their Regulation, Structure and Distribution. AB - Sunflower seeds (Helianthus annuus L.) accumulate large quantities of triacylglycerols (TAG) between 12 and 28 days after flowering (DAF). This is the period of maximal acyl-acyl carrier protein (acyl-ACP) thioesterase activity in vitro, the enzymes that terminate the process of de novo fatty acid synthesis by catalyzing the hydrolysis of the acyl-ACPs synthesized by fatty acid synthase. Fatty acid thioesterases can be classified into two families with distinct substrate specificities, namely FatA and FatB. Here, some new aspects of these enzymes have been studied, assessing how both enzymes contribute to the acyl composition of sunflower oil, not least through the changes in their expression during the process of seed filling. Moreover, the binding pockets of these enzymes were modeled based on new data from plant thioesterases, revealing important differences in their volume and geometry. Finally, the subcellular location of the two enzymes was evaluated and while both possess an N-terminal plastid transit peptide, only in FatB contains a hydrophobic sequence that could potentially serve as a transmembrane domain. Indeed, using in vivo imaging and organelle fractionation, H. annuus thioesterases, HaFatA and HaFatB, appear to be differentially localized in the plastid stroma and membrane envelope, respectively. The divergent roles fulfilled by HaFatA and HaFatB in oil biosynthesis are discussed in the light of our data. PMID- 30459778 TI - On the Roles of Wheat Endosperm ADP-Glucose Pyrophosphorylase Subunits. AB - The ADP-glucose pyrophosphorylase from wheat endosperm controls starch synthesis in seeds and has unique regulatory properties compared to others from this family. It comprises two types of subunits, but despite its importance little is known about their roles. Here, we synthesized de novo the wheat endosperm ADP glucose pyrophosphorylase small (S) and large (L) subunit genes, heterologously expressed them in Escherichia coli, and kinetically characterized the recombinant proteins. To understand their distinct roles, we co-expressed them with well characterized subunits from the potato tuber enzyme to obtain hybrids with one S subunit from one source and an L subunit from the other. After kinetic analyses of these hybrids, we concluded that the unusual insensitivity to activation of the wheat endosperm enzyme is caused by a pre-activation of the L subunit. In addition, the heat stability and sensitivity to phosphate are given by the S subunit. PMID- 30459779 TI - Carotenoid Accumulation and Its Contribution to Flower Coloration of Osmanthus fragrans. AB - Among naturally occurring pigments, carotenoids are importantly involved in the photosynthesis of plants and responsible for the coloration of petals and fruits. Osmanthus fragrans Lour., a famous ornamental plant, has many cultivars with different flower color. Petal coloration in O. fragrans mainly depends on the kinds of carotenoids and their contents. To investigate the mechanism of flower coloration in different cultivars, an analysis of phenotypic classification, phytochemistry, as well as the expression of carotenoid metabolism genes based on different groups was performed in the present study. Two main clusters including the orange-red cluster containing Aurantiacus cultivars and the yellowish-white cluster containing the other three cultivar groups were classified using the CIEL*a*b* system. No significant differences in flavonoid contents were observed between these two clusters. However, carotenoids, especially alpha-carotene and beta-carotene, were found to have crucial roles in the diversity of floral coloration among the different cultivars. Carotenoid compositions in the petals of cultivars from both clusters consisted of alpha-carotene, beta-carotene, alpha cryptoxanthin, beta-cryptoxanthin, lutein, and zeaxanthin, but carotenoid accumulation patterns during the flowering process were different. The petals of the yellowish-white cultivars exhibited high contents of beta-carotene, lutein and alpha-carotene, whereas the petals of the orange-red cultivars mainly contained beta-carotene and alpha-carotene. The profound diversity in the total carotenoid concentrations in the two clusters was determined by the transcript levels of OfCCD4. Furthermore, the accumulation of upstream products with orange color in orange-red cultivars was partially due to the low expression of OfCHYB, whereas the relatively higher OfCHYB expression in the petals of the yellowish white cultivars led to higher proportions of lutein, which is yellow. We also found that downregulation of OfLCYE, which encodes ??-ring cyclase, indicated that the carotenoid flux of most cultivars mainly resulted in more beta, beta branched products. Additionally, carotenoid biosynthesis in green tissues and petals was compared, revealing the tissue specificity of carotenoid accumulation in O. fragrans. Therefore, the effects of multiple genes on carotenoid accumulation give rise to the colorful O. fragrans. PMID- 30459780 TI - Manipulation of Growth and Architectural Characteristics in Trees for Increased Woody Biomass Production. AB - Growth and architectural traits in trees are economically and environmentally important and thus of considerable importance to the improvement of forest and fruit trees. These traits are complex and result from the operation of a number of molecular mechanisms. This review will focus on the regulation of crown architecture, secondary woody growth and adventitious rooting. These traits and processes have significant impact on deployment, management, and productivity of tree crops. The majority of the described work comes from experiments in model plants, poplar, apple, peach, and plum because these species allow functional analysis of the involved genes and have significant genomics resources. However, these studies convincingly show conserved mechanisms for elaboration of specific growth and architectural traits. The conservation of these mechanisms suggest that they can be used as a blueprint for the improvement of these traits and processes in phylogenetically diverse tree crops. We will specifically consider the involvement of flowering time, transcription factors and hormone-associated genes. The review will also discuss the impact of recent technological advances as well as the challenges to the dissection of these traits in trees. PMID- 30459781 TI - Pasta-Making Quality QTLome From Mediterranean Durum Wheat Landraces. AB - In order to identify genome regions related to pasta-making quality traits, association mapping (AM) was performed in a set of 165 durum wheat landraces from 21 Mediterranean countries. The collection was genotyped using 1149 DArT markers and 872 of them with a known genetic position were used for AM. The collection was grown in north-east Spain during 3 years. Results of ANOVA showed that trait variation for quality traits, except for grain protein content (GPC), was mainly explained by genetic effects. Landraces showed higher GPC than modern cultivars but lower gluten strength (GS). Modern and eastern landraces showed the highest yellow color index (YI). Balkan landraces showed the lowest test weight (TW). A total of 92 marker-trait associations were detected, 20 corresponding to GS, 21 to GPC, 21 to YI and 30 to TW. With the aim of detecting new genomic regions involved in grain quality, the position of the associations was compared with previously mapped QTL by a meta-QTL analysis. A total of 249 QTLs were projected onto the same map used for AM, identifying 45 meta-QTL (MQTL) regions and the remaining 15 QTLs as singletons. The position of known genes involved in grain quality was also included, and gene annotation within the most significant regions detected by AM was carried out using the wheat genome sequence. PMID- 30459782 TI - Down-Selection and Outdoor Evaluation of Novel, Halotolerant Algal Strains for Winter Cultivation. AB - Algae offer promising feedstocks for the production of renewable fuel and chemical intermediates. However, poor outdoor winter cultivation capacity currently limits deployment potential. In this study, 300 distinct algal strains were screened in saline medium to determine their cultivation suitability during winter conditions in Mesa, Arizona. Three strains, from the genera Micractinium, Chlorella, and Scenedesmus, were chosen following laboratory evaluations and grown outdoors in 1000 L raceway ponds during the winter. Strains were down selected based on doubling time, lipid and carbohydrate amount, final biomass accumulation capacity, cell size and phylogenetic diversity. Algal biomass productivity and compositional analysis for lipids and carbohydrates show successful outdoor deployment and cultivation under winter conditions for these strains. Outdoor harvest-yield biomass productivities ranged from 2.9 to 4.0 g/m2/day over an 18 days winter cultivation trial, with maximum productivities ranging from 4.0 to 6.5 g/m2/day, the highest productivities reported to date for algal winter strains grown in saline media in open raceway ponds. Peak fatty acid levels ranged from 9 to 26% percent of biomass, and peak carbohydrate levels ranged from 13 to 34% depending on the strain. Changes in the lipid and carbohydrate profile throughout outdoor growth are reported. This study demonstrates that algal strain screening under simulated outdoor environmental conditions in the laboratory enables identification of strains with robust biomass productivity and biofuel precursor composition. The strains isolated here represent promising winter deployment candidates for seasonal algal biomass production when using crop rotation strategies. PMID- 30459783 TI - Turbidity, Waterfowl Herbivory, and Propagule Banks Shape Submerged Aquatic Vegetation in Ponds. AB - The aquatic vegetation in nutrient-rich shallow lakes and ponds is structured by the interplay of multiple biotic and abiotic drivers. We tested the contribution of the macrophyte propagule bank and the delayed as well as direct impact of waterbirds on submerged aquatic vegetation in a peri-urban pond system. To clarify the functional hierarchy of predictor variables, effects of herbivorous waterfowl and propagule bank potential were ranked relative to environmental, phytoplankton, and zooplankton indicators. Two aspects of the aquatic vegetation community composition and total pond-scale cover - were discriminated. Within vegetation communities, phytoplankton biovolume and waterfowl herbivory during summer were linked to low macrophyte abundance, whereas propagule density of angiosperms was positively associated with specific assemblages of submerged macrophytes. High algal biovolume and summer waterfowl grazing seemed to affect maximal pond-scale cover of submerged aquatic vegetation. The presence of waterfowl in cold and spring periods was unrelated to vegetation structure in the consecutive main growth season. In addition, availability of propagules in the sediment did not automatically prompt pond-wide vegetation cover (especially when overruled by high waterfowl densities), nor did it guarantee a position in the submerged macrophyte community. Nonetheless, propagule bank potential was related to the waterbody's general ecological status, since turbid ponds exhibited impoverished propagule reserves compared to ponds residing in a clear, macrophyte dominated state. Inadequate recruitment therefore represents a plausible bottleneck for macrophyte establishment. We conclude that phytoplankton-caused turbidity and high waterfowl biomass densities greatly restrict submerged macrophyte abundance. Propagule banks also participate in structuring submerged aquatic vegetation, though a stronger role is reserved for herbivorous waterfowl. PMID- 30459784 TI - The Role of Promoter-Associated Histone Acetylation of Haem Oxygenase-1 (HO-1) and Giberellic Acid-Stimulated Like-1 (GSL-1) Genes in Heat-Induced Lateral Root Primordium Inhibition in Maize. AB - In plants, lateral roots play a crucial role in the uptake of water and nutrients. Several genes such as Zea mays Haem Oxygenase-1 (ZmHO-1) and Giberellic Acid-Stimulated Like-1 (ZmGSL-1) have been found to be involved in lateral root development. In the present investigation, we observed that heat treatment might be involved in the inhibition of lateral root primordium (LRP) formation in maize, accompanied by an increase in global acetylation levels of histone 3 lysine residue 9 (H3K9) and histone 4 lysine residue 5 (H4K5), suggesting that histone modification was related to LRP inhibition. However, Trichostatin A (TSA), an inhibitor of histone deacetylases (HDACs), apparently did not inhibit the LRP formation, revealing that global hyperacetylation might not be the determining factor in the LRP inhibition induced by heat stress. Furthermore, expression of genes related to lateral root development in maize, ZmHO-1 and ZmGSL-1, was down-regulated and the acetylation levels in the promoter region of these two genes were decreased under heat stress, suggesting that promoter-associated histone acetylation might be associated with the expression of ZmHO-1 and ZmGSL-1 genes which were found to be involved in the heat-induced LRP inhibition in maize. PMID- 30459785 TI - Structural and Chemical Profiles of Myrcia splendens (Myrtaceae) Leaves Under the Influence of the Galling Nexothrips sp. (Thysanoptera). AB - Thysanoptera-induced galls commonly culminate in simple folding or rolling leaf gall morphotypes. Most of these galls are induced by members of the suborder Tubulifera, with only a few species of the suborder Terebrantia being reported as gall inducers. The Terebrantia, as most of the gall inducers, manipulates the host plant cellular communication system, and induces anatomical and biochemical changes in its host plant. In an effort to keep its homeostasis, the host plant reacts to the stimuli of the galling insect and triggers chemical signaling processes. In contrast to free-living herbivores, the signaling processes involving galling herbivores and their host plants are practically unknown. Current investigation was performed into two steps: first, we set the structural profile of non-galled and galled leaves, and looked forward to find potential alterations due to gall induction by an undescribed species of Nexothrips (suborder Terebrantia) on Myrcia splendens. Once oil glands had been altered in size and number, the second step was the investigation of the chemical profile of three tissue samples: (1) non-galled leaves of a control individual, (2) non galled leaves of galled plants, and (3) galls. This third sample was divided into two groups: (3.1) galls from which the inducing thrips were manually removed and (3.2) galls macerated with the inducing thrips inside. The chemical profile was performed by gas chromatography/ mass spectrometric detector after headspace solid-phase extraction. The galling activity of the Nexothrips sp. on M. splendens culminates in mesophyll compactness interspersed to diminutive hypersensitive spots, development of air cavities, and the increase in size and number of the secretory glands. Seventy-two compounds were completely identified in the volatile profile of the three samples, from which, sesquiterpenes and aldehydes, pertaining to the "green leaf volatile" (GLVs) class, are the most abundant. The rare event of gall induction by a Terebrantia revealed discrete alterations toward leaf rolling, and indicated quantitative differences related to the plant bioactivity manipulated by the galling thrips. Also, the content of methyl salicylate has varied and has been considered a potential biomarker of plant resistance stimulated as a long-distance effect on M. splendens individuals. PMID- 30459786 TI - Eco-Metabolomics and Metabolic Modeling: Making the Leap From Model Systems in the Lab to Native Populations in the Field. AB - Experimental high-throughput analysis of molecular networks is a central approach to characterize the adaptation of plant metabolism to the environment. However, recent studies have demonstrated that it is hardly possible to predict in situ metabolic phenotypes from experiments under controlled conditions, such as growth chambers or greenhouses. This is particularly due to the high molecular variance of in situ samples induced by environmental fluctuations. An approach of functional metabolome interpretation of field samples would be desirable in order to be able to identify and trace back the impact of environmental changes on plant metabolism. To test the applicability of metabolomics studies for a characterization of plant populations in the field, we have identified and analyzed in situ samples of nearby grown natural populations of Arabidopsis thaliana in Austria. A. thaliana is the primary molecular biological model system in plant biology with one of the best functionally annotated genomes representing a reference system for all other plant genome projects. The genomes of these novel natural populations were sequenced and phylogenetically compared to a comprehensive genome database of A. thaliana ecotypes. Experimental results on primary and secondary metabolite profiling and genotypic variation were functionally integrated by a data mining strategy, which combines statistical output of metabolomics data with genome-derived biochemical pathway reconstruction and metabolic modeling. Correlations of biochemical model predictions and population-specific genetic variation indicated varying strategies of metabolic regulation on a population level which enabled the direct comparison, differentiation, and prediction of metabolic adaptation of the same species to different habitats. These differences were most pronounced at organic and amino acid metabolism as well as at the interface of primary and secondary metabolism and allowed for the direct classification of population-specific metabolic phenotypes within geographically contiguous sampling sites. PMID- 30459787 TI - Organic Nitrogen Uptake and Assimilation in Cucumis sativus Using Position Specific Labeling and Compound-Specific Isotope Analysis. AB - Organic nitrogen is now considered a significant source of N for plants. Although organic management practices increase soil organic C and N content, the importance of organic N as a source of crop N under organic farming management systems is still poorly understood. While dual-labeled (13C and 15N) molecule methods have been developed to study amino acid uptake by plants, multiple biases may arise from pre-uptake mineralization by microorganisms or post-uptake metabolism by the plant. We propose the combination of different isotopic analysis methods with molecule isotopologues as a novel approach to improve the accuracy of measured amino acid uptake rates in the total N budget of cucumber seedlings and provide a better characterization of post-uptake metabolism. Cucumber seedlings were exposed to solutions containing L-Ala-1-13C,15N or U-L Ala-13C3,15N, in combination with ammonium nitrate, at total N concentrations ranging from 0 to 15 mM N and at inorganic/organic N ratios from 10:1 to 500:1. Roots and shoots were then subjected to bulk stable isotope analysis (BSIA) by Isotope Ratio Mass Spectrometry (IRMS), and to compound-specific stable isotope analysis (CSIA) of the free amino acids by Gas Chromatography - Combustion - Isotope Ratio Mass Spectrometry (GC-C-IRMS). Plants exposed to a lower inorganic:organic N ratio acquired up to 6.84% of their N from alanine, compared with 0.94% at higher ratio. No 13C from L-Ala-1-13C,15N was found in shoot tissues suggesting that post-uptake metabolism of Ala leads to the loss of the carboxyl-C as CO2. CSIA of the free amino acids in roots confirmed that intact Ala is indeed taken up by the roots, but that it is rapidly metabolized. C atoms other than from the carboxyl group and amino-N from Ala are assimilated in other amino acids, predominantly Glu, Gln, Asp, and Asn. Uptake rates reported by CSIA of the free amino acids are nevertheless much lower (16-64 times) than those reported by BSIA. Combining the use of isotopologues of amino acids with compound specific isotope analysis helps reduce the bias in the assessment of organic N uptake and improves the understanding of organic N assimilation especially in the context of organic horticulture. PMID- 30459788 TI - UV-B Pre-treatment Alters Phenolics Response to Monilinia fructicola Infection in a Structure-Dependent Way in Peach Skin. AB - Phenolic compounds represent a large class of secondary metabolites, involved in multiple functions not only in plant life cycle, but also in fruit during post harvest. phenolics play a key role in the response to biotic and abiotic stresses, thus their accumulation is regulated by the presence of environmental stimuli. The present work aimed to investigate how different pre-UV-B-exposures can modulate the phenolic response of peach fruit infected with Monilinia fructicola. Through HPLC-DAD-MSn, several procyanidins, phenolic acids, flavonols, and anthocyanins were detected. Both UV-B radiation and fungal infection were able to stimulate the accumulation of phenolics, dependent on the chemical structure. Regarding UV-B exposure, inoculated with sterile water, 3 h of UV-B radiation highest concentration of phenolics was found, especially flavonols and cyanidin-3-glucoside far from the wound. However, wounding decreased the phenolics in the region nearby. When peaches were pre-treated with 1 h of UV-B radiation, the fungus had an additive effect in phenolic accumulation far from the infection, while it had a subtractive effect with 3 h of UV-B radiation, especially for flavonols. Canonical discriminant analysis and Pearson correlation revealed that all phenolic compounds, except procyanidin dimer, were highly regulated by UV-B radiation, with particularly strong correlation for quercetin and kaempferol glycosides, while phenolics correlated with the fungus infection were quercetin-3-galactoside, quercetin-3-glucoside, kaempferol-3 galactoside and isorhamnetin-3-glucoside. Modulation of pathogen-induced phenolics also far from inoculation site might suggest a migration of signaling molecules from the infected area to healthy tissues. PMID- 30459789 TI - Functional Characterization of BoaMYB51s as Central Regulators of Indole Glucosinolate Biosynthesis in Brassica oleracea var. alboglabra Bailey. AB - R2R3-MYB transcription factor MYB51 is known to control indole glucosinolate (indole GSL) biosynthesis in Arabidopsis. Here, two copies of BoaMYB51 have been isolated in Chinese kale (Brassica oleracea var. alboglabra Bailey), designated BoaMYB51.1 and BoaMYB51.2, which exhibit overlapping but distinct expression levels among different organs and respond to signaling molecules in a similar pattern. It has been demonstrated a structural and functional conservation between BoaMYB51s and AtMYB51 by phylogenetic analysis, complementation studies and transient expression assay. To further investigate the transcriptional mechanism, we identified the transcriptional activation domain (TAD) and putative interacting proteins of BoaMYB51s by means of yeast (Saccharomyces cerevisiae) two hybrid. Using tobacco (Nicotiana benthamiana) transient expression assay, we confirmed that the carboxy-end is required for transcriptional activation activity of BoaMYB51s. In addition, several BoaMYB51-interacting proteins have been identified by yeast two-hybrid screening. These results provide important insights into the molecular mechanisms by which MYB51 transcriptionally regulates indole GSL biosynthesis. PMID- 30459790 TI - Functional Characterization of SMG7 Paralogs in Arabidopsis thaliana. AB - SMG7 proteins are evolutionary conserved across eukaryotes and primarily known for their function in nonsense mediated RNA decay (NMD). In contrast to other NMD factors, SMG7 proteins underwent independent expansions during evolution indicating their propensity to adopt novel functions. Here we characterized SMG7 and SMG7-like (SMG7L) paralogs in Arabidopsis thaliana. SMG7 retained its role in NMD and additionally appears to have acquired another function in meiosis. We inactivated SMG7 by CRISPR/Cas9 mutagenesis and showed that, in contrast to our previous report, SMG7 is not an essential gene in Arabidopsis. Furthermore, our data indicate that the N-terminal phosphoserine-binding domain is required for both NMD and meiosis. Phenotypic analysis of SMG7 and SMG7L double mutants did not indicate any functional redundancy between the two genes, suggesting neofunctionalization of SMG7L. Finally, protein sequence comparison together with a phenotyping of T-DNA insertion mutants identified several conserved regions specific for SMG7 that may underlie its role in NMD and meiosis. This information provides a framework for deciphering the non-canonical functions of SMG7-family proteins. PMID- 30459791 TI - The Beneficial Endophytic Fungus Fusarium solani Strain K Alters Tomato Responses Against Spider Mites to the Benefit of the Plant. AB - Beneficial microorganisms are known to promote plant growth and confer resistance to biotic and abiotic stressors. Soil-borne beneficial microbes in particular have shown potential in protecting plants against pathogens and herbivores via the elicitation of plant responses. In this study, we evaluated the role of Fusarium solani strain K (FsK) in altering plant responses to the two spotted spider mite Tetranychus urticae in tomato. We found evidence that FsK, a beneficial endophytic fungal strain isolated from the roots of tomato plants grown on suppressive compost, affects both direct and indirect tomato defenses against spider mites. Defense-related genes were differentially expressed on FsK colonized plants after spider mite infestation compared to clean or spider mite infested un-colonized plants. In accordance, spider mite performance was negatively affected on FsK-colonized plants and feeding damage was lower on these compared to control plants. Notably, FsK-colonization led to increased plant biomass to both spider mite-infested and un-infested plants. FsK was shown to enhance indirect tomato defense as FsK-colonized plants attracted more predators than un-colonized plants. In accordance, headspace volatile analysis revealed significant differences between the volatiles emitted by FsK-colonized plants in response to attack by spider mites. Our results highlight the role of endophytic fungi in shaping plant-mite interactions and may offer the opportunity for the development of a novel tool for spider mite control. PMID- 30459792 TI - Resistance to Thrips in Peanut and Implications for Management of Thrips and Thrips-Transmitted Orthotospoviruses in Peanut. AB - Thrips are major pests of peanut (Arachis hypogaea L.) worldwide, and they serve as vectors of devastating orthotospoviruses such as Tomato spotted wilt virus (TSWV) and Groundnut bud necrosis virus (GBNV). A tremendous effort has been devoted to developing peanut cultivars with resistance to orthotospoviruses. Consequently, cultivars with moderate field resistance to viruses exist, but not much is known about host resistance to thrips. Integrating host plant resistance to thrips in peanut could suppress thrips feeding damage and reduce virus transmission, will decrease insecticide usage, and enhance sustainability in the production system. This review focuses on details of thrips resistance in peanut and identifies future directions for incorporating thrips resistance in peanut cultivars. Research on thrips-host interactions in peanut is predominantly limited to field evaluations of feeding damage, though, laboratory studies have revealed that peanut cultivars could differentially affect thrips feeding and thrips biology. Many runner type cultivars, field resistant to TSWV, representing diverse pedigrees evaluated against thrips in the greenhouse revealed that thrips preferred some cultivars over others, suggesting that antixenosis "non preference" could contribute to thrips resistance in peanut. In other crops, morphological traits such as leaf architecture and waxiness and spectral reflectance have been associated with thrips non-preference. It is not clear if foliar morphological traits in peanut are associated with reduced preference or non-preference of thrips and need to be evaluated. Besides thrips non-preference, thrips larval survival to adulthood and median developmental time were negatively affected in some peanut cultivars and in a diploid peanut species Arachis diogoi (Hoehne) and its hybrids with a Virginia type cultivar, indicating that antibiosis (negative effects on biology) could also be a factor influencing thrips resistance in peanut. Available field resistance to orthotospoviruses in peanut is not complete, and cultivars can suffer substantial yield loss under high thrips and virus pressure. Integrating thrips resistance with available virus resistance would be ideal to limit losses. A discussion of modern technologies such as transgenic resistance, marker assisted selection and RNA interference, and future directions that could be undertaken to integrate resistance to thrips and to orthotospoviruses in peanut cultivars is included in this article. PMID- 30459793 TI - Effects of Short- and Long-Term Variation in Resource Conditions on Soil Fungal Communities and Plant Responses to Soil Biota. AB - Soil biota can strongly influence plant performance with effects ranging from negative to positive. However, shifts in resource availability can influence plant responses, with soil pathogens having stronger negative effects in high resource environments and soil mutualists, such as arbuscular mycorrhizal fungi (AMF), having stronger positive effects in low-resource environments. Yet the relative importance of long-term vs. short-term variation in resources on soil biota and plant responses is not well-known. To assess this, we grew the perennial herb Asclepias speciosa in a greenhouse experiment that crossed a watering treatment (wet vs. dry treatment) with a manipulation of soil biota (live vs. sterilized soil) collected from two geographic regions (Washington and Minnesota) that vary greatly in annual precipitation. Because soil biota can influence many plant functional traits, we measured biomass as well as resource acquisition (e.g., root:shoot, specific leaf area) and defense (e.g., trichome and latex production) traits. Due to their important role as mutualists and pathogens, we also characterized soil fungal communities in the field and greenhouse and used curated databases to assess fungal composition and potential function. We found that the experimental watering treatment had a greater effect than soil biota origin on plant responses; most plant traits were negatively affected by live soils under wet conditions, whereas responses were neutral or positive in live dry soil. These consistent differences in plant responses occurred despite clear differences in soil fungal community composition between inoculate origin and watering treatments, which indicates high functional redundancy among soil fungi. All plants grown in live soil were highly colonized by AMF and root colonization was higher in wet than dry soil; root colonization by other fungi was low in all treatments. The most parsimonious explanation for negative plant responses in wet soil is that AMF became parasitic under conditions that alleviated resource limitation. Thus, plant responses appeared driven by shifts within rather than between fungal guilds, which highlights the importance of coupling growth responses with characterizations of soil biota to fully understand underlying mechanisms. Collectively these results highlight how short-term changes in environmental conditions can mediate complex interactions between plants and soil biota. PMID- 30459796 TI - Phosphorus Efficiency Mechanisms of Two Wheat Cultivars as Affected by a Range of Phosphorus Levels in the Field. AB - Phosphorus (P) efficiency includes both P acquisition efficiency (PAE) and internal P utilization efficiency (PUE). Despite substantial research, genotypic variation in PAE and PUE remains incompletely understood in the field. A 2-year field study was conducted to compare PAE and PUE and related morphological, physiological, and molecular root traits of two winter wheat cultivars (Triticum aestivum L. cv. SJZ8 and KN92) in response to six P application rates in a P deficient calcareous soil. Both cultivars showed similar growth and yield potential at each P supply level, reaching optimal growth at the same P application rate of about 100 kg P ha-1. However, the two cultivars differed in how they achieved yield and P efficiency. As P supply increased for both cultivars, root dry weight (RDW), root length density, and expression of the phosphate transporter gene TaPHT1.2 in roots initially increased and then stabilized, but arbuscular mycorrhizal fungal colonization, rhizosphere acid phosphatase activity, expressions of the P-starvation marker gene TaIPS1.1 and the purple acid phosphatase gene TaPAP16 in roots initially decreased and then stabilized. To enhance P acquisition when the P supply was deficient, KN92 modified the morphology of its roots, while SJZ8 increased the physiological activities in its roots. With an adequate P supply, high expression of TaPHT1.2 in roots might account for efficient P uptake for both cultivars, especially for KN92. Although P uptake per RDW was similar for both cultivars at anthesis, PAE was higher for KN92 than SJZ8 in terms of total P uptake in aboveground parts, whereas shoot and grain PUE were higher in SJZ8 than in KN92, mainly during the reproductive growth stage. These results indicate that P efficiency is under genotypic control at all P supply levels tested in both wheat cultivars, and that the two cultivars depend on different root strategies for P acquisition and utilization in response to changes in the P supply. PMID- 30459795 TI - Recent Advances in Synthetic Chemical Inducers of Plant Immunity. AB - Different from the conventional biocidal agrochemicals, synthetic chemical inducers of plant immunity activate, bolster, or prime plant defense machineries rather than directly acting on the pathogens. Advances in combinatorial synthesis and high-throughput screening methods have led to the discovery of various synthetic plant immune activators as well as priming agents. The availability of their structures and recent progress in the mechanistic understanding of plant immune responses have opened up the possibility of identifying new or more potent chemical inducers through rational design. In this review, we first summarize the chemical inducers identified through large-scale screening and then discuss the emerging trends in the identification and development of novel plant immune inducers including natural elicitor based chemical derivation, bifunctional combination, and computer-aided design. PMID- 30459797 TI - Belowground Phytolith-Occluded Carbon of Monopodial Bamboo in China: An Overlooked Carbon Stock. AB - Phytolith-occluded carbon (PhytOC), a highly stable carbon (C) fraction resistant to decomposition, plays an important role in long-term global C sequestration. Previous studies have demonstrated that bamboo plants contribute greatly to PhytOC sink in forests based on their aboveground biomass. However, little is known about the contribution of belowground parts of bamboo to the PhytOC stock. Here, we reported the phytolith and PhytOC accumulation in belowground trunk and rhizome of eight monopodial bamboo species that widely distributed across China. The results showed that the belowground parts made up an average of 39.41% of the total plant biomass of the eight bamboo species. There were significant (p < 0.05) variations in the phytolith and PhytOC concentrations in the belowground trunk and rhizome between the bamboo species. The mean concentrations of PhytOC in dry biomass ranged from 0.34 to 0.83 g kg-1 in the belowground rhizome and from 0.10 to 0.94 g kg-1 in the belowground trunk across the eight bamboo species, respectively. The mean PhytOC stocks in belowground biomass ranged from 2.57 to 23.71 kg ha-1, occupying an average of 23.36% of the total plant PhytOC stocks. This implies that 1.01 * 105 t PhytOC was overlooked based on the distribution of monopodial bamboos across China. Therefore, our results suggest that the belowground biomass of bamboo represents an important PhytOC stock, and should be taken into account in future studies in order to better quantifying PhytOC sequestration capacity. PMID- 30459794 TI - Pectin Methylesterases: Cell Wall Remodeling Proteins Are Required for Plant Response to Heat Stress. AB - Heat stress (HS) is expected to be of increasing worldwide concern in the near future, especially with regard to crop yield and quality as a consequence of rising or varying temperatures as a result of global climate change. HS response (HSR) is a highly conserved mechanism among different organisms but shows remarkable complexity and unique features in plants. The transcriptional regulation of HSR is controlled by HS transcription factors (HSFs) which allow the activation of HS-responsive genes, among which HS proteins (HSPs) are best characterized. Cell wall remodeling constitutes an important component of plant responses to HS to maintain overall function and growth; however, little is known about the connection between cell wall remodeling and HSR. Pectin controls cell wall porosity and has been shown to exhibit structural variation during plant growth and in response to HS. Pectin methylesterases (PMEs) are present in multigene families and encode isoforms with different action patterns by removal of methyl esters to influencing the properties of cell wall. We aimed to elucidate how plant cell walls respond to certain environmental cues through cell wall-modifying proteins in connection with modifications in cell wall machinery. An overview of recent findings shed light on PMEs contribute to a change in cell wall composition/structure. The fine-scale modulation of apoplastic calcium ions (Ca2+) content could be mediated by PMEs in response to abiotic stress for both the assembly and disassembly of the pectic network. In particular, this modulation is prevalent in guard cell walls for regulating cell wall plasticity as well as stromal aperture size, which comprise critical determinants of plant adaptation to HS. These insights provide a foundation for further research to reveal details of the cell wall machinery and stress-responsive factors to provide targets and strategies to facilitate plant adaptation. PMID- 30459798 TI - Oxidation of P700 Ensures Robust Photosynthesis. AB - In the light, photosynthetic cells can potentially suffer from oxidative damage derived from reactive oxygen species. Nevertheless, a variety of oxygenic photoautotrophs, including cyanobacteria, algae, and plants, manage their photosynthetic systems successfully. In the present article, we review previous research on how these photoautotrophs safely utilize light energy for photosynthesis without photo-oxidative damage to photosystem I (PSI). The reaction center chlorophyll of PSI, P700, is kept in an oxidized state in response to excess light, under high light and low CO2 conditions, to tune the light utilization and dissipate the excess photo-excitation energy in PSI. Oxidation of P700 is co-operatively regulated by a number of molecular mechanisms on both the electron donor and acceptor sides of PSI. The strategies to keep P700 oxidized are diverse among a variety of photoautotrophs, which are evolutionarily optimized for their ecological niche. PMID- 30459799 TI - Thermal-Enhanced bri1-301 Instability Reveals a Plasma Membrane Protein Quality Control System in Plants. AB - Brassinosteroids (BRs) are essential phytohormones mainly perceived by a single pass transmembrane receptor-like protein kinase (RLK), BRASSINOSTEROID INSENSITIVE 1 (BRI1). bri1-5 and bri1-9, two distinct mutants with point mutations in the extracellular domain of BRI1, show weak defective phenotypes. Previous studies indicated that bri1-5 and bri1-9 mutated proteins can be recognized and eliminated via an endoplasmic reticulum quality control (ERQC) mechanism. Most of these two proteins, therefore, cannot reach their destination, plasma membrane. Here, we report our functional characterization of bri1-301, another BRI1 mutant protein with an amino acid substitution in the cytoplasmic kinase domain. bri1-301 is a partially functional BR receptor with significantly decreased protein abundance. Interestingly, protein stability and subcellular localization of bri1-301 are temperature-sensitive. At 22 degrees C, an optimal temperature for indoor Arabidopsis growth, bri1-301 shows a weak defective phenotype. At a lower temperature condition such as 18 degrees C, bri1-301 exhibits subtle morphological defects. At a higher temperature condition such as 28 degrees C, on the other hand, bri1-301 displays an extremely severe phenotype reminiscent to that of a null bri1 mutant due to greatly increased bri1-301 internalization and degradation. Our detailed analyses suggest that bri1-301 stability is controlled by ERQC and plasma membrane quality control (PMQC) systems. Since PMQC has not been well studied in plants, bri1-301 can be used as a model mutant for future genetic dissection of this critical process. PMID- 30459801 TI - Comprehensively Characterizing the Cytological Features of Saccharum spontaneum by the Development of a Complete Set of Chromosome-Specific Oligo Probes. AB - Chromosome-specific identification is a powerful technique in the study of genome structure and evolution. However, there is no reliable cytogenetic marker to unambiguously identify each of the chromosomes in sugarcane (Saccharum spp., Poaceae), which has a complex genome with a high level of ploidy and heterozygosity. In this study, we developed a set of oligonucleotide (oligo) based probes through bioinformatic design and massive synthetization. These probes produced a clear and bright single signal in each of the chromosomes and their eight homologous chromosomes in the ancient species Saccharum spontaneum (2n = 8x = 64). Thus, they can be used as reliable markers to robustly label each of the chromosomes in S. spontaneum. We then obtained the karyotype data and established a nomenclature based on chromosomal sizes for the eight chromosomes of the octoploid S. spontaneum. In addition, we also found that the 45S and 5S rDNAs demonstrated high copy number variations among different homologous chromosomes, indicating a rapid evolution of the highly repeated sequence after polyploidization. Our fluorescence in situ hybridization (FISH) assay also demonstrated that these probes could be used as cross-species markers between or within the genera of Sorghum and Saccharum. By comparing FISH analyses, we discovered that several chromosome rearrangement events occurred in S. spontaneum, which might have contributed to the basic chromosome number reduction from 10 in sorghum to 8 in sugarcane. Consistent identification of individual chromosomes makes molecular cytogenetic study possible in sugarcane and will facilitate fine chromosomal structure and karyotype evolution of the genus Saccharum. PMID- 30459802 TI - NADP-Dependent Malic Enzyme 1 Participates in the Abscisic Acid Response in Arabidopsis thaliana. AB - Arabidopsis thaliana possesses three cytosolic (NADP-ME1-3) and one plastidic (NADP-ME4) NADP-dependent malic enzymes. NADP-ME2 and -ME4 show constitutive expression, in contrast to NADP-ME1 and -ME3, which are restricted to particular tissues. Here, we show that NADP-ME1 transcript and protein were almost undetectable during normal vegetative growth, but gradually increased and reached levels higher than those of the other isoforms in the latest stages of seed development. Accordingly, in knockout nadp-me1 mature seeds the total NADP-ME activity was significantly lower than in wild type mature seeds. The phenotypic analysis of nadp-me1 plants indicated alterations of seed viability and germination. Besides, the treatment with abscisic acid (ABA), NaCl and mannitol specifically induced the accumulation of NADP-ME1 in seedlings. In line with this, nadp-me1 plants show a weaker response of primary and lateral root length and stomatal opening to the presence of ABA. The results suggest that NADP-ME1 plays a specialized role, linked to ABA signaling during the seed development as well as in the response to water deficit stress. PMID- 30459800 TI - Evolution of the Symbiosis-Specific GRAS Regulatory Network in Bryophytes. AB - Arbuscular mycorrhiza is one of the most common plant symbiotic interactions observed today. Due to their nearly ubiquitous occurrence and their beneficial impact on both partners it was suggested that this mutualistic interaction was crucial for plants to colonize the terrestrial habitat approximately 500 Ma ago. On the plant side the association is established via the common symbiotic pathway (CSP). This pathway allows the recognition of the fungal symbiotic partner, subsequent signaling to the nucleus, and initiation of the symbiotic program with respect to specific gene expression and cellular re-organization. The downstream part of the CSP is a regulatory network that coordinates the transcription of genes necessary to establish the symbiosis, comprising multiple GRAS transcription factors (TFs). These regulate their own expression as an intricate transcriptional network. Deduced from non-host genome data the loss of genes encoding CSP components coincides with the loss of the interaction itself. Here, we analyzed bryophyte species with special emphasis on the moss Physcomitrella patens, supposed to be a non-host, for the composition of the GRAS regulatory network components. We show lineage specific losses and expansions of several of these factors in bryophytes, potentially coinciding with the proposed host/non host status of the lineages. We evaluate losses and expansions and infer clade specific evolution of GRAS TFs. PMID- 30459803 TI - BPLLDA: Predicting lncRNA-Disease Associations Based on Simple Paths With Limited Lengths in a Heterogeneous Network. AB - In recent years, it has been increasingly clear that long noncoding RNAs (lncRNAs) play critical roles in many biological processes associated with human diseases. Inferring potential lncRNA-disease associations is essential to reveal the secrets behind diseases, develop novel drugs, and optimize personalized treatments. However, biological experiments to validate lncRNA-disease associations are very time-consuming and costly. Thus, it is critical to develop effective computational models. In this study, we have proposed a method called BPLLDA to predict lncRNA-disease associations based on paths of fixed lengths in a heterogeneous lncRNA-disease association network. Specifically, BPLLDA first constructs a heterogeneous lncRNA-disease network by integrating the lncRNA disease association network, the lncRNA functional similarity network, and the disease semantic similarity network. It then infers the probability of an lncRNA disease association based on paths connecting them and their lengths in the network. Compared to existing methods, BPLLDA has a few advantages, including not demanding negative samples and the ability to predict associations related to novel lncRNAs or novel diseases. BPLLDA was applied to a canonical lncRNA-disease association database called LncRNADisease, together with two popular methods LRLSLDA and GrwLDA. The leave-one-out cross-validation areas under the receiver operating characteristic curve of BPLLDA are 0.87117, 0.82403, and 0.78528, respectively, for predicting overall associations, associations related to novel lncRNAs, and associations related to novel diseases, higher than those of the two compared methods. In addition, cervical cancer, glioma, and non-small-cell lung cancer were selected as case studies, for which the predicted top five lncRNA disease associations were verified by recently published literature. In summary, BPLLDA exhibits good performances in predicting novel lncRNA-disease associations and associations related to novel lncRNAs and diseases. It may contribute to the understanding of lncRNA-associated diseases like certain cancers. PMID- 30459804 TI - Clinical Genetics of Polydactyly: An Updated Review. AB - Polydactyly, also known as hyperdactyly or hexadactyly is the most common hereditary limb anomaly characterized by extra fingers or toes, with various associated morphologic phenotypes as part of a syndrome (syndromic polydactyly) or may occur as a separate event (non-syndromic polydactyly). Broadly, the non syndromic polydactyly has been classified into three types, i.e.; preaxial polydactyly (radial), central polydactyly (axial), and postaxial polydactyly (ulnar). Mostly inherited as an autosomal dominant entity with variable penetrance and caused by defects that occur in the anterior-posterior patterning of limb development. In humans, to-date at least 10 loci and six genes causing non-syndromic polydactyly have been identified, including the ZNF141, GLI3, MIPOL1, IQCE, PITX1, and the GLI1. In the present review, clinical, genetic and molecular characterization of the polydactyly types has been presented including the recent genes and loci identified for non-syndromic polydactyly. This review provides an overview of the complex genetic mechanism underlie polydactyly and might help in genetic counseling and quick molecular diagnosis. PMID- 30459805 TI - Genetic Risk for Psychiatric Disorders and Telomere Length. AB - Background: Previous studies have revealed associations between psychiatric disorder diagnosis and shorter telomere length. Here, we attempt to discern whether genetic risk for psychiatric disorders, or use of pharmacological treatments (i.e., antidepressants), predict shorter telomere length and risk for aging-related disease in a United Kingdom population sample. Methods: DNA samples from blood were available from 351 participants who were recruited as part of the South East London Community Health (SELCoH) Study, and for which whole-genome genotype data was available. Leukocyte telomere length was characterized using quantitative polymerase chain reactions. Individualized polygenic risk scores for major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) were calculated using Psychiatric Genomics Consortium summary statistics. We subsequently performed linear models, to discern the impact polygenic risk for psychiatric disorders (an etiological risk factor) and antidepressant use (common pharmacological treatment) have on telomere length, whilst accounting for other lifestyle/health factors (e.g., BMI, smoking). Results: There were no significant associations between polygenic risk for any of the psychiatric disorders tested and telomere length (p > 0.05). Antidepressant use was significantly associated with shorter telomere length and this was independent from a depression diagnosis or current depression severity (p <= 0.01). Antidepressant use was also associated with a significantly higher risk of aging-related disease, which was independent from depression diagnosis (p <= 0.05). Conclusion: Genetic risk for psychiatric disorders is not associated with shorter telomere length. Further studies are now needed to prospectively characterize if antidepressant use increases risk for aging-related disease and telomere shortening, or whether people who age faster and have aging-related diseases are just more likely to be prescribed antidepressants. PMID- 30459806 TI - eIF4E-Dependent Translational Control: A Central Mechanism for Regulation of Pain Plasticity. AB - Translational control of gene expression has emerged as a key mechanism in regulating different forms of long-lasting neuronal plasticity. Maladaptive plastic reorganization of peripheral and spinal nociceptive circuits underlies many chronic pain states and relies on new gene expression. Accordingly, downregulation of mRNA translation in primary afferents and spinal dorsal horn neurons inhibits tissue injury-induced sensitization of nociceptive pathways, supporting a central role for translation dysregulation in the development of persistent pain. Translation is primarily regulated at the initiation stage via the coordinated activity of translation initiation factors. The mRNA cap-binding protein, eukaryotic translation initiation factor 4E (eIF4E), is involved in the recruitment of the ribosome to the mRNA cap structure, playing a central role in the regulation of translation initiation. eIF4E integrates inputs from the mTOR and ERK signaling pathways, both of which are activated in numerous painful conditions to regulate the translation of a subset of mRNAs. Many of these mRNAs are involved in the control of cell growth, proliferation, and neuroplasticity. However, the full repertoire of eIF4E-dependent mRNAs in the nervous system and their translation regulatory mechanisms remain largely unknown. In this review, we summarize the current evidence for the role of eIF4E-dependent translational control in the sensitization of pain circuits and present pharmacological approaches to target these mechanisms. Understanding eIF4E-dependent translational control mechanisms and their roles in aberrant plasticity of nociceptive circuits might reveal novel therapeutic targets to treat persistent pain states. PMID- 30459807 TI - Single Cell Transcriptomics Reveal Abnormalities in Neurosensory Patterning of the Chd7 Mutant Mouse Ear. AB - The chromatin remodeling protein CHD7 is critical for proper formation of the mammalian inner ear. Humans with heterozygous pathogenic variants in CHD7 exhibit CHARGE syndrome, characterized by hearing loss and inner ear dysplasia, including abnormalities of the semicircular canals and Mondini malformations. Chd7 Gt/+ heterozygous null mutant mice also exhibit dysplastic semicircular canals and hearing loss. Prior studies have demonstrated that reduced Chd7 dosage in the ear disrupts expression of genes involved in morphogenesis and neurogenesis, yet the relationships between these changes in gene expression and otic patterning are not well understood. Here, we sought to define roles for CHD7 in global regulation of gene expression and patterning in the developing mouse ear. Using single-cell multiplex qRT-PCR, we analyzed expression of 192 genes in FAC sorted cells from Pax2Cre;mT/mGFP wild type and Chd7 Gt/+ mutant microdissected mouse otocysts. We found that Chd7 haploinsufficient otocysts exhibit a relative enrichment of cells adopting a neuroblast (vs. otic) transcriptional identity compared with wild type. Additionally, we uncovered disruptions in pro-sensory and pro-neurogenic gene expression with Chd7 loss, including genes encoding proteins that function in Notch signaling. Our results suggest that Chd7 is required for early cell fate decisions in the developing ear that involve highly specific aspects of otic patterning and differentiation. PMID- 30459809 TI - Predicting Diabetes Mellitus With Machine Learning Techniques. AB - Diabetes mellitus is a chronic disease characterized by hyperglycemia. It may cause many complications. According to the growing morbidity in recent years, in 2040, the world's diabetic patients will reach 642 million, which means that one of the ten adults in the future is suffering from diabetes. There is no doubt that this alarming figure needs great attention. With the rapid development of machine learning, machine learning has been applied to many aspects of medical health. In this study, we used decision tree, random forest and neural network to predict diabetes mellitus. The dataset is the hospital physical examination data in Luzhou, China. It contains 14 attributes. In this study, five-fold cross validation was used to examine the models. In order to verity the universal applicability of the methods, we chose some methods that have the better performance to conduct independent test experiments. We randomly selected 68994 healthy people and diabetic patients' data, respectively as training set. Due to the data unbalance, we randomly extracted 5 times data. And the result is the average of these five experiments. In this study, we used principal component analysis (PCA) and minimum redundancy maximum relevance (mRMR) to reduce the dimensionality. The results showed that prediction with random forest could reach the highest accuracy (ACC = 0.8084) when all the attributes were used. PMID- 30459808 TI - Sorting mRNA Molecules for Cytoplasmic Transport and Localization. AB - In eukaryotic cells, gene expression is highly regulated at many layers. Nascent RNA molecules are assembled into ribonucleoprotein complexes that are then released into the nucleoplasmic milieu and transferred to the nuclear pore complex for nuclear export. RNAs are then either translated or transported to the cellular periphery. Emerging evidence indicates that RNA-binding proteins play an essential role throughout RNA biogenesis, from the gene to polyribosomes. However, the sorting mechanisms that regulate whether an RNA molecule is immediately translated or sent to specialized locations for translation are unclear. This question is highly relevant during development and differentiation when cells acquire a specific identity. Here, we focus on the RNA-binding properties of heterogeneous nuclear ribonucleoproteins (hnRNPs) and how these mechanisms are believed to play an essential role in RNA trafficking in polarized cells. Further, by focusing on the specific hnRNP protein CBF-A/hnRNPab and its naturally occurring isoforms, we propose a model on how hnRNP proteins are capable of regulating gene expression both spatially and temporally throughout the RNA biogenesis pathway, impacting both healthy and diseased cells. PMID- 30459810 TI - A Meta-Analysis Including Pre-selected Sequence Variants Associated With Seven Traits in Three French Dairy Cattle Populations. AB - A within-breed genome-wide association study (GWAS) is useful when identifying the QTL that segregates in a breed. However, an across-breed meta-analysis can be used to increase the power of identification and precise localization of QTL that segregate in multiple breeds. Precise localization will allow including QTL information from other breeds in genomic prediction due to the persistence of the linkage phase between the causal variant and the marker. This study aimed to identify and confirm QTL detected in within-breed GWAS through a meta-analysis in three French dairy cattle breeds. A set of sequence variants selected based on their functional annotations were imputed into 50 k genotypes for 46,732 Holstein, 20,096 Montbeliarde, and 11,944 Normande cows to identify QTL for milk production, the success rate at insemination of cows (fertility) and stature. We conducted within-breed GWAS followed by across-breed meta-analysis using a weighted Z-scores model on the GWAS summary data (i.e., P-values, effect direction, and sample size). After Bonferroni correction, the GWAS result identified 21,956 significantly associated SNP (P FWER < 0.05), while meta analysis result identified 9,604 significant SNP (P FWER < 0.05) associated with the phenotypes. The meta-analysis identified 36 QTL for milk yield, 48 QTL for fat yield and percentage, 29 QTL for protein yield and percentage, 13 QTL for fertility, and 16 QTL for stature. Some of these QTL were not significant in the within-breed GWAS. Some previously identified causal variants were confirmed, e.g., BTA14:1802265 (fat percentage, P = 1.5 * 10-760; protein percentage, P = 7.61 * 10-348) both mapping the DGAT1-K232A mutation and BTA14:25006125 (P = 8.58 * 10-140) mapping PLAG1 gene was confirmed for stature in Montbeliarde. New QTL lead SNP shared between breeds included the intronic variant rs109205829 (NFIB gene), and the intergenic variant rs41592357 (1.38 Mb upstream of the CNTN6 gene and 0.65 Mb downstream of the CNTN4 gene). Rs110425867 (ZFAT gene) was the top variant associated with fertility, and new QTL lead SNP included rs109483390 (0.1 Mb upstream of the TNFAIP3 gene and 0.07 Mb downstream of PERP gene), and rs42412333 (0.45 Mb downstream of the RPL10L gene). An across-breed meta-analysis had greater power to detect QTL as opposed to a within breed GWAS. The QTL detected here can be incorporated in routine genomic predictions. PMID- 30459811 TI - Long Non-coding RNAs as Local Regulators of Pancreatic Islet Transcription Factor Genes. AB - The transcriptional programs of differentiated cells are tightly regulated by interactions between cell type-specific transcription factors and cis-regulatory elements. Long non-coding RNAs (lncRNAs) have emerged as additional regulators of gene transcription. Current evidence indicates that lncRNAs are a very heterogeneous group of molecules. For example, selected lncRNAs have been shown to regulate gene expression in cis or trans, although in most cases the precise underlying molecular mechanisms is unknown. Recent studies have uncovered a large number of lncRNAs that are selectively expressed in pancreatic islet cells, some of which were shown to regulate beta cell transcriptional programs. A subset of such islet lncRNAs appears to control the expression of beta cell-specific transcription factor (TF) genes by local cis-regulation. In this review, we discuss current knowledge of molecular mechanisms underlying cis-regulatory lncRNAs and discuss challenges involved in using genetic perturbations to define their function. We then discuss known examples of pancreatic islet lncRNAs that appear to exert cis-regulation of TF genes. We propose that cis-regulatory lncRNAs could represent a molecular target for modulation of diabetes-relevant genes. PMID- 30459812 TI - Macrophage Depletion in Elderly Mice Improves Response to Tumor Immunotherapy, Increases Anti-tumor T Cell Activity and Reduces Treatment-Induced Cachexia. AB - Most cancers emerge in the elderly, including lung cancer and mesothelioma, yet the elderly remain an underrepresented population in pre-clinical cancer studies and clinical trials. The immune system plays a critical role in the effectiveness of many anti-cancer therapies in young hosts via tumor-specific T cells. However, immunosuppressive macrophages can constitute up to 50% of the tumor burden and impair anti-tumor T cell activity. Altered macrophage phenotype and function during aging may further impact anti-tumor T cell responses. Yet, the impact of macrophages on anti-tumor T cell responses and immunotherapy in the elderly is unknown. Therefore, we examined macrophages and their interaction with T cells in young (3 months) and elderly (20-24 months) AE17 mesothelioma-bearing female C57BL/6J mice during tumor growth. Mesothelioma tumors grew faster in elderly compared with young mice, and this corresponded with an increase in tumor associated macrophages. During healthy aging, macrophages increase in bone marrow and spleens suggesting that these sites have an increased potential to supply cancer-promoting macrophages. Interestingly, in tumor-bearing mice, bone marrow macrophages increased proliferation whilst splenic macrophages had reduced proliferation in elderly compared with young mice, and macrophage depletion using the F4/80 antibody slowed tumor growth in young and elderly mice. We also examined responses to treatment with intra-tumoral IL-2/anti-CD40 antibody immunotherapy and found it was less effective in elderly (38% tumor regression) compared to young mice (90% regression). Tumor-bearing elderly mice decreased in vivo anti-tumor cytotoxic T cell activity in tumor draining lymph nodes and spleens. Depletion of macrophages using F4/80 antibody in elderly, but not young mice, improved IL-2/anti-CD40 immunotherapy up to 78% tumor regression. Macrophage depletion also increased in vivo anti-tumor T cell activity in elderly, but not young mice. All the tumor-bearing elderly (but not young) mice had decreased body weight (i.e., exhibited cachexia), which was greatly exacerbated by immunotherapy; whereas macrophage depletion prevented this immunotherapy-induced cachexia. These studies strongly indicate that age-related changes in macrophages play a key role in driving cancer cachexia in the elderly, particularly during immunotherapy, and sabotage elderly anti-tumor immune responses. PMID- 30459813 TI - Pilot Safety Evaluation of a Novel Strain of Bacteroides ovatus. AB - Bacteroides ovatus ELH-B2 is considered as a potential next-generation probiotic due to its preventive effects on lipopolysaccharides-associated inflammation and intestinal microbiota disorders in mice. To study safety issues associated with B. ovatus ELH-B2, we conducted comprehensive and systematic experiments, including in vitro genetic assessments of potential virulence and antimicrobial resistance genes, and an in vivo acute toxicity study of both immunocompetent and immunosuppressed mice via cyclophosphamide treatment. The results indicated that this novel strain is non-toxigenic, fragilysin is not expressed, and most of potential virulence genes are correlated with cellular structures such as capsular polysaccharide and polysaccharide utilizations. The antibiotic resistance features are unlikely be transferred to other intestinal microorganisms as no plasmids nor related genomic islands were identified. Side effects were not observed in mice. B. ovatus ELH-B2 also alleviated the damages caused by cyclophosphamide injection. PMID- 30459814 TI - Hilar en bloc resection for hilar cholangiocarcinoma in patients with limited liver capacities-preserving parts of liver segment 4. AB - Background: A right trisectionectomy with portal vein resection represents the conventional approach for hilar cholangiocarcinoma. Here, we present a technical modification of hilar en bloc resection in order to increase the remnant volume by partially preserving liver segment 4. Methods: The caudal parenchymal dissection line starts centrally between the left lateral and left medial segments. Cranially, the resection line switches to the right towards Cantlie's line and turns again upwards perpendicularly. Hence, segment 4a and subtotal segment 4b are partially preserved by this novel technique. The left hepatic duct is dissected at the segmental ramification and reconstruction is performed as a single hepaticojejunostomy. The feasibility of the novel parenchyma-sparing approach for hilar cholangiocarcinoma was proven in a case series and medical records were reviewed retrospectively. Results: Ten patients (6 male, 4 female) underwent segment 4 partially preserving right trisectionectomy for hilar cholangiocarcinoma. Estimated future liver remnant volume was significantly increased (FLRV 38.3%), when compared to standard right trisectionectomy (FLRV 23.9%; p < 0.01). Three of 10 liver resections were associated with major surgical complications (>=IIIb; n = 3); categorized according to the Dindo Clavien classification. No patient died due to complications associated with postoperatively impaired liver function. Tumor-free margins could be achieved in 8 patients while median overall survival and disease-free survival were 547 and 367 days, respectively. Conclusion: This novel parenchyma-sparing modification of hilar en bloc resection by partially preserving segment 4 allows to safely increase the remnant liver volume without neglecting principles of local radicality. PMID- 30459815 TI - Systematic analysis of genes involved in oral cancer metastasis to lymph nodes. AB - Oral cancer remains a deadly disease worldwide. Lymph node metastasis and invasion is one of the causes of death from oral cancer. Elucidating the mechanism of oral cancer lymph node metastasis and identifying critical regulatory genes are important for the treatment of this disease. This study aimed to identify differentially expressed genes (gene signature) and pathways that contribute to oral cancer metastasis to lymph nodes. The GSE70604-associated study compared gene profiles in lymph nodes with metastasis of oral cancer to those of normal lymph nodes. The GSE2280-associated study compared gene profiles in primary tumor of oral cancer with lymph node metastasis to those in tumors without lymph node metastasis. There are 28 common differentially expressed genes (DEGs) showing consistent changes in both datasets in overlapping analysis. GO biological process and KEGG pathway analysis of these 28 DEGs identified the gene signature CCND1, JUN and SPP1, which are categorized as key regulatory genes involved in the focal adhesion pathway. Silencing expression of CCND1, JUN and SPP1 in the human oral cancer cell line OECM-1 confirmed that those genes play essential roles in oral cancer cell invasion. Analysis of clinical samples of oral cancer found a strong correlation of these genes with short survival, especially JUN expression associated with metastasis. Our study identified a unique gene signature - CCND1, JUN and SPP1 - which may be involved in oral cancer lymph node metastasis. PMID- 30459816 TI - Subcutaneous immunotherapy induces alterations in monocytes and dendritic cells homeostasis in allergic rhinitis patients. AB - Background: Specific subcutaneous immunotherapy (SCIT) can achieve long-term remission in patients with allergic rhinitis (AR) through complex and still unknown mechanisms. The aim of this study is to evaluate the effect of SCIT over CD16+ and CD16- monocytes, myeloid (mDCs) and plasmacytoid dendritic cells (pDCs) in patients with AR, comparatively to pharmacological standard treatment (non SIT). Methods: The relative frequency and absolute number of monocytes and DC subsets, the frequency of these cells producing TNFalpha after in vitro stimulation with Dermatophagoides pteronyssinus (Dpt) extract, and the expression levels of receptor-bound IgE or IgG were assessed by flow cytometry, in peripheral blood samples from 23 healthy individuals (HG) and 43 participants with AR mono-sensitized to Dpt; 10 with non-SIT treatment and 33 under SCIT, just before (SCIT-T0) and 4 h after administration (SCIT-T4). Moreover, IFNalpha mRNA expression was evaluated in purified pDCs, by qRT-PCR. Results: After SCIT administration we observed a strong decrease of circulating pDCs, although accompanied by higher levels of IFNalpha mRNA expression, and an increase of circulating CD16+ monocytes. AR participants under SCIT exhibited a higher expression of receptor-bound IgE in all cell populations that expressed the high affinity receptor for IgE (FcepsilonRI) and a higher frequency of CD16+ monocytes producing TNFalpha. Conversely, we observed a decrease in the frequency of mDCs producing TNFalpha in AR under SCIT, similar to the observed in the control group. Conclusions: SCIT seems to induce numeric, phenotypic, and functional changes in circulating monocytes and dendritic cells, contributing at least in part to the well described immunological alterations induced by this type of immunotherapy. PMID- 30459818 TI - Hematopoietic cell transplantation for asymptomatic X-linked lymphoproliferative syndrome type 1. AB - Background: X-linked lymphoproliferative disease type 1 (XLP1) is a rare primary immune deficiency, which is caused by SH2D1A gene mutations. XLP1 is commonly associated with Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, and/or lymphoma. The only curative treatment for XLP1 is allogeneic hematopoietic cell transplantation. However, published data detailing the clinical course of, and indications for, allogeneic hematopoietic cell transplantation in asymptomatic patients with XLP1 is lacking. Although relevant family history could be useful in identifying patients with XLP1 before disease onset, no guidelines have been established on the management of asymptomatic patients with XLP1. Therefore, clinicians and families face dilemmas in balancing between the risk of waiting for the disease onset, and the risk of transplant-related mortality associated with allogeneic hematopoietic cell transplantation, which is often performed at a very young age. We first describe the detailed clinical course of an asymptomatic patient with XLP1 who successfully underwent allogeneic hematopoietic cell transplantation. Case presentation: A boy was born at 39 weeks of gestation, weighing 3016 g at birth. He appeared fine, but he underwent genetic testing because his maternal cousin had XLP1. He was found to have a novel c.207_208insC (p.Pro70ProfsX4) mutation in exon 3 of SH2D1A, which was also found in his cousin. There was no HLA-identical donor in his family. Immunoglobulin was administered monthly to prevent EBV infection while searching for an alternative donor. He underwent allogeneic bone marrow transplantation (BMT) from an allele HLA 8/8 fully matched, unrelated donor with a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, melphalan, and low-dose total body irradiation (TBI) at 20 months of age. The patient has been doing well for 2 years post transplantation and maintaining complete donor chimerism without any evidence of chronic graft versus host disease. Conclusions: We describe a case of an asymptomatic patient with XLP1, who successfully underwent unrelated BMT with RIC regimen consisting of fludarabine, melphalan, and 3 Gy TBI. That was well tolerated and successfully generated complete chimerism in every subpopulation. This case delineates the option of allogeneic hematopoietic cell transplantation even in asymptomatic patients with XLP1. PMID- 30459817 TI - Aberrant localization of FOXJ1 correlates with the disease severity and comorbidities in patients with nasal polyps. AB - Background: Upper airway inflammatory diseases are associated with abnormal expression of nasal epithelial forkhead-box J1 (FOXJ1) which regulates motile cilia formation. We sought to investigate whether aberrant FOXJ1 localizations correlate with the disease severity and the co-existence of allergic rhinitis (AR) or asthma in patients with nasal polyps (NPs). Methods: We elucidated localization patterns of FOXJ1 by performing immunofluorescence assays in nasal specimens and cytospin samples from controls and patients with NPs. We also assayed mRNA expression levels of FOXJ1 by using quantitative real-time polymerase chain reaction. Four localization patterns [normal (N), intermediate (I), mislocalization (M), and absence (A)] were defined. A semi-quantitative scoring system was applied for demonstrating FOXJ1 localization in five areas per paraffin section, with individual sections being scored between 0 and 2. Results: FOXJ1 localization score was significantly higher in samples from NPs than in controls (P < 0.001). Elevated FOXJ1 localization scores and down-regulation of FOXJ1 mRNA levels were observed in NPs with co-existing AR or asthma (all P < 0.05). Moreover, FOXJ1 localization scores positively correlated with Lund-Mackay score (r = 0.362, P = 0.007). Of primary cytospin samples, the mean percentage of patients with FOXJ1 localization patterns N, I, M and A was 15.0%, 3.3%, 53.3% and 28.3% in NPs, and 82.5%, 5.0%, 5.0% and 7.5% in controls, respectively (P < 0.001). Conclusions: Aberrant localization of FOXJ1 correlates with the severity and co-existence of AR or asthma in patients with NPs, and might be a novel target for assessment and intervention in NPs. PMID- 30459821 TI - The effect of training interventions of stigma associated with mental illness on family caregivers: a quasi-experimental study. AB - Background: Stigma is one of the most destructive features of mental illnesses that may affect the family caregivers. This study aimed to analyze the effect of training interventions of stigma on family caregivers of the mental illness patients. Materials and methods: This quasi-experimental pre- and post-test study was performed on a single group of 43 family caregivers of mental illness patients in Hamadan Psychiatric Hospital, Iran, in 2015. The samples were taken through convenience sampling method and the data collection tool was a stigma questionnaire made by the researchers. The questionnaires were filled by the participants within pre-intervention and 1-month post-intervention. All the data were analyzed by SPSS version 16, and the mean and standard deviation by paired t test and Wilcoxon test. Results: Findings of this study demonstrated that women included 60% of the family caregivers. The average age of caregivers and the duration of caregiving were 41.67 +/- 11.62 years and 66.28 +/- 7.99 months, respectively. The mean and standard deviation for pre-intervention stigma score were 82.47 +/- 12.23 indicating that the family caregivers suffered from some problems arisen from living with mental patients. They include not getting married, unable to find a job, embarrassment, humiliation by others, disgrace, and shame. Our results revealed that the mean and standard deviation of stigma score decreased to 29.28 +/- 7.52 after training, and this difference was statistically significant (P < 0.001). Conclusions: According to the results of present study, training interventions reduce the issues caused by stigma and help the family members of mental patients to face and cope with the problem. PMID- 30459819 TI - Repurposing existing drugs for cardiovascular risk management: a focus on methotrexate. AB - About 20% of patients with a history of atherosclerotic cardiovascular disease will experience further cardiovascular events despite maximal pharmacological treatment with cardioprotective drugs. This highlights the presence of residual cardiovascular risk in a significant proportion of patients and the need for novel, more effective therapies. These therapies should ideally target different pathophysiological pathways involved in the onset and the progression of atherosclerosis, particularly the inflammatory and immune pathways. Methotrexate is a first-line disease-modifying antirheumatic drug that is widely used for the management of autoimmune and chronic inflammatory disorders. There is some in vitro and in vivo evidence that methotrexate might exert a unique combination of anti-inflammatory, blood pressure lowering, and vasculoprotective effects. Pending the results of large prospective studies investigating surrogate end points as well as morbidity and mortality, repurposing methotrexate for cardiovascular risk management might represent a cost-effective strategy with immediate public health benefits. This review discusses the current challenges in the management of cardiovascular disease; the available evidence on the effects of methotrexate on inflammation, blood pressure, and surrogate markers of arterial function; suggestions for future research directions; and practical considerations with the use of methotrexate in this context. PMID- 30459820 TI - Delineating species along shifting shorelines: Tropheus (Teleostei, Cichlidae) from the southern subbasin of Lake Tanganyika. AB - Background: Species delineation is particularly challenging in taxa with substantial intra-specific variation. In systematic studies of fishes, meristics and linear measurements that describe shape are often used to delineate species. Yet, little is known about the taxonomic value of these two types of morphological characteristics. Here, we used Tropheus (Teleostei, Cichlidae) from the southern subbasin of Lake Tanganyika to test which of these types of characters best matched genetic lineages that could represent species in this group of stenotypic rock-dwelling cichlids. We further investigated intra population variation in morphology. By linking this to a proxy of a population's age, we could assess the evolutionary stability of different kinds of morphological markers. Results: Morphological data was collected from 570 specimens originating from 86 localities. An AFLP approach revealed the presence of five lineages in the southern subbasin: T. moorii, T. brichardi, T. sp. 'maculatus', T. sp. 'Mpimbwe' and T. sp. 'red', which we consider to represent distinct species. Although both types of morphological data supported this classification, a comparison of PST-values that describe inter-population morphological differentiation, revealed a better correspondence between the taxon delineation based on AFLP data and the patterns revealed by an analysis of meristics than between the AFLP-based taxon delineation and the patterns revealed by an analysis of shape. However, classifying southern populations of Tropheus was inherently difficult as they contained a large amount of clinal variation, both in genetic and in morphological data, and both within and among species. A scenario is put forward to explain the current-day distribution of the species and colour varieties and the observed clinal variation across the subbasin's shoreline. Additionally, we observed that variation in shape was larger in populations from shallow shores whereas populations from steep shores were more variable in meristics. This difference is explained in terms of the different timescales at which small and large scale lake level fluctuations affected populations of littoral cichlids at steep and shallow shores. Conclusions: Our results showed meristics to be more evolutionary stable, and of higher taxonomic value for species delimitation in Tropheus, than linear measurements that describe shape. These results should be taken into account when interpreting morphological differences between populations of highly stenotypic species, such as littoral cichlids from the Great East African Lakes. PMID- 30459822 TI - Detection and analysis of wheat spikes using Convolutional Neural Networks. AB - Background: Field phenotyping by remote sensing has received increased interest in recent years with the possibility of achieving high-throughput analysis of crop fields. Along with the various technological developments, the application of machine learning methods for image analysis has enhanced the potential for quantitative assessment of a multitude of crop traits. For wheat breeding purposes, assessing the production of wheat spikes, as the grain-bearing organ, is a useful proxy measure of grain production. Thus, being able to detect and characterize spikes from images of wheat fields is an essential component in a wheat breeding pipeline for the selection of high yielding varieties. Results: We have applied a deep learning approach to accurately detect, count and analyze wheat spikes for yield estimation. We have tested the approach on a set of images of wheat field trial comprising 10 varieties subjected to three fertilizer treatments. The images have been captured over one season, using high definition RGB cameras mounted on a land-based imaging platform, and viewing the wheat plots from an oblique angle. A subset of in-field images has been accurately labeled by manually annotating all the spike regions. This annotated dataset, called SPIKE, is then used to train four region-based Convolutional Neural Networks (R-CNN) which take, as input, images of wheat plots, and accurately detect and count spike regions in each plot. The CNNs also output the spike density and a classification probability for each plot. Using the same R-CNN architecture, four different models were generated based on four different datasets of training and testing images captured at various growth stages. Despite the challenging field imaging conditions, e.g., variable illumination conditions, high spike occlusion, and complex background, the four R-CNN models achieve an average detection accuracy ranging from 88 to Conclusion: With the availability of good training datasets such us the SPIKE dataset proposed in this article, deep learning techniques can achieve high accuracy in detecting and counting spikes from complex wheat field images. The proposed robust R-CNN model, which has been trained on spike images captured during different growth stages, is optimized for application to a wider variety of field scenarios. It accurately quantifies the differences in yield produced by the 10 varieties we have studied, and their respective responses to fertilizer treatment. We have also observed that the other R-CNN models exhibit more specialized performances. The data set and the R CNN model, which we make publicly available, have the potential to greatly benefit plant breeders by facilitating the high throughput selection of high yielding varieties. PMID- 30459823 TI - Kif18a regulates Sirt2-mediated tubulin acetylation for spindle organization during mouse oocyte meiosis. AB - Background: During oocyte meiosis, the cytoskeleton dynamics, especially spindle organization, are critical for chromosome congression and segregation. However, the roles of the kinesin superfamily in this process are still largely unknown. Results: In the present study, Kif18a, a member of the kinesin-8 family, regulated spindle organization through its effects on tubulin acetylation in mouse oocyte meiosis. Our results showed that Kif18a is expressed and mainly localized in the spindle region. Knock down of Kif18a caused the failure of first polar body extrusion, dramatically affecting spindle organization and resulting in severe chromosome misalignment. Further analysis showed that the disruption of Kif18a caused an increase in acetylated tubulin level, which might be the reason for the spindle organization defects after Kif18a knock down in oocyte meiosis, and the decreased expression of deacetylase Sirt2 was found after Kif18a knock down. Moreover, microinjections of tubulin K40R mRNA, which could induce tubulin deacetylation, protected the oocytes from the effects of Kif18a downregulation, resulting in normal spindle morphology in Kif18a-knock down oocytes. Conclusions: Taken together, our results showed that Kif18a affected Sirt2-mediated tubulin acetylation level for spindle organization during mouse oocyte meiosis. Our results not only revealed the critical effect of Kif18a on microtubule stability, but also extended our understanding of kinesin activity in meiosis. PMID- 30459824 TI - Multi-organ protection of ulinastatin in traumatic cardiac arrest model. AB - Background: Post-cardiac arrest syndrome, which has no specific curative treatment, contributes to the high mortality rate of victims who suffer traumatic cardiac arrest (TCA) and initially can be resuscitated. In the present study, we investigated the potential of ulinastatin to mitigate multiple organ injury after resuscitation in a swine TCA model. Methods: Twenty-one male pigs were subjected to hemodynamic shock (40% estimated blood loss in 20 min) followed by cardiac arrest (electrically induced ventricular fibrillation) and respiratory suspension for 5 min, and finally manual resuscitation. At 5 min after resuscitation, pigs were randomized to receive 80,000 U/kg ulinastatin (n = 7) or the same volume of saline (n = 9) in the TCA group. Pigs in the sham group (n = 5) were not exposed to bleeding or cardiac arrest. At baseline and at 1, 3, and 6 h after the return of spontaneous circulation, blood samples were collected and assayed for tumor necrosis factor-alpha, interleukin 6, and other indicators of organ injury. At 24 h after resuscitation, pigs were sacrificed and apoptosis levels were assessed in samples of heart, brain, kidney, and intestine. Results: One pig died in the ulinastatin group and one pig died in the TCA group; the remaining animals were included in the final analysis. TCA and resuscitation caused significant increases in multiple organ function biomarkers in serum, increases in tumor necrosis factor-alpha, and interleukin 6 in serum and increases in the extent of apoptosis in key organs. All these increases were lower in the ulinastatin group. Conclusion: Ulinastatin may attenuate multiple organ injury after TCA, which should be explored in clinical studies. PMID- 30459825 TI - ProSave: an application for restoring quantitative data to manipulated subsets of protein lists. AB - Background: In proteomics studies, liquid chromatography tandem mass spectrometry data (LC-MS/MS) is quantified by spectral counts or by some measure of ion abundance. Downstream comparative analysis of protein content (e.g. Venn diagrams and network analysis) typically does not include this quantitative data and critical information is often lost. To avoid loss of spectral count data in comparative proteomic analyses, it is critical to implement a tool that can rapidly retrieve this information. Results: We developed ProSave, a free and user friendly Java-based program that retrieves spectral count data from a curated list of proteins in a large proteomics dataset. ProSave allows for the management of LC-MS/MS datasets and rapidly retrieves spectral count information for a desired list of proteins. Conclusions: ProSave is open source and freely available at https://github.com/MahajanLab/ProSave. The user manual, implementation notes, and description of methodology and examples are available on the site. PMID- 30459826 TI - What influenced provision of non-communicable disease healthcare in the Syrian conflict, from policy to implementation? A qualitative study. AB - Background: There has been increasing focus on tackling the growing burden of non communicable diseases (NCD) in crisis settings. The complex and protracted crisis in Syria is unfolding against a background of increasing NCD burden. This study investigated factors influencing implementation of NCD healthcare in Syria. Methods: This is a qualitative study, whereby semi-structured interviews were conducted with fourteen humanitarian health staff working on NCD healthcare in Syria. Results: Challenges to NCD care implementation were reflected at several stages, from planning services through to healthcare delivery. There was a lack of information on unmet population need; little consensus among humanitarian actors regarding an appropriate health service package; and no clear approach for prioritising public health interventions. The main challenges to service delivery identified by participants were conflict-related insecurity and disruption to infrastructure, hampering continuity of chronic illness care. Collaboration was a key factor which influenced implementation at all stages. Conclusions: The historical context, the conflict situation, and the characteristics of health actors and their relationships, all impacted provision of NCD care. These factors influenced each other, so that the social views and values (of individuals and organisations), as well as politics and relationships, interacted with the physical environment and security situation. Infrastructure damage has implications for wider healthcare across Syria, and NCD care requires an innovative approach to improve continuity of care. There is a need for a transparent approach to resource allocation, which may be generalisable to the wider humanitarian health sector. PMID- 30459827 TI - Accessibility and factors associated with utilization of mental health services in youth health centers. A qualitative comparative analysis in northern Sweden. AB - Background: Youth-friendly health care services can facilitate young people's access to health care services and promote their health, including their mental health. In Sweden, a network of youth health centers exist since the 1970s, incorporated within the public health system. Even if such centers take a holistic approach to youth health, the focus has been in sexual and reproductive health care, and the extent of integrating mental health care services is less developed though it varies notably between different centers. This study aims to analyse the various conditions that are sufficient and/or necessary to make Swedish youth health centers accessible for mental and psychosocial health. Methods: Multiple case study design, using qualitative comparative analysis to assess the various conditions that makes a youth health center accessible for mental and psychosocial issues and mental health. The cases included 18 youth health centers (from a total of 22) in the four northern counties of Sweden. Results: In order to enhance accessibility for mental health services, youth health centers need to be trusted by young people. Trust was necessary but not sufficient, meaning that it had to be combined with other conditions: either having a team with a variety of professions represented in the youth health center, or being a youth health center that is both easy to contact and well staffed with mental health professionals. Conclusions: Differentiated, first-line services for youth can play an important role in promoting youth mental health if certain conditions are fulfilled. Trust is necessary, but has to be combined with either multidisciplinary teams, or expertise on mental health and easy accessibility. PMID- 30459829 TI - Measures of effective population size in sea otters reveal special considerations for wide-ranging species. AB - Conservation genetic techniques and considerations of the evolutionary potential of a species are increasingly being applied to species conservation. For example, effective population size (N e) estimates are useful for determining the conservation status of species, yet accurate estimates of current N e remain difficult to obtain. The effective population size can contribute to setting federal delisting criteria, as was done for the southern sea otter (Enhydra lutris nereis). After being hunted to near extinction during the North Pacific fur trade, the southern sea otter has recovered over part of its former range, but remains at relatively low numbers, making it desirable to obtain accurate and consistent estimates of N e. Although theoretical papers have compared the validity of several methods, comparisons of estimators using empirical data in applied conservation settings are limited. We combined thirteen years of demographic and genetic data from 1,006 sea otters to assess multiple N e estimators, as well as temporal trends in genetic diversity and population genetic structure. Genetic diversity was low and did not increase over time. There was no evidence for distinct genetic units, but some evidence for genetic isolation by distance. In particular, estimates of N e based on demographic data were much larger than genetic estimates when computed for the entire range of the population, but were similar at smaller spatial scales. The discrepancy between estimates at large spatial scales could be driven by cryptic population structure and/or individual differences in reproductive success. We recommend the development of new delisting criteria for the southern sea otter. We advise the use of multiple estimates of N e for other wide-ranging species, species with overlapping generations, or with sex-biased dispersal, as well as the development of improved metrics of genetic assessments of populations. PMID- 30459828 TI - Pathogens in space: Advancing understanding of pathogen dynamics and disease ecology through landscape genetics. AB - Landscape genetics has provided many insights into how heterogeneous landscape features drive processes influencing spatial genetic variation in free-living organisms. This rapidly developing field has focused heavily on vertebrates, and expansion of this scope to the study of infectious diseases holds great potential for landscape geneticists and disease ecologists alike. The potential application of landscape genetics to infectious agents has garnered attention at formative stages in the development of landscape genetics, but systematic examination is lacking. We comprehensively review how landscape genetics is being used to better understand pathogen dynamics. We characterize the field and evaluate the types of questions addressed, approaches used and systems studied. We also review the now established landscape genetic methods and their realized and potential applications to disease ecology. Lastly, we identify emerging frontiers in the landscape genetic study of infectious agents, including recent phylogeographic approaches and frameworks for studying complex multihost and host-vector systems. Our review emphasizes the expanding utility of landscape genetic methods available for elucidating key pathogen dynamics (particularly transmission and spread) and also how landscape genetic studies of pathogens can provide insight into host population dynamics. Through this review, we convey how increasing awareness of the complementarity of landscape genetics and disease ecology among practitioners of each field promises to drive important cross-disciplinary advances. PMID- 30459830 TI - Mosaics, mixtures, rotations or pyramiding: What is the optimal strategy to deploy major gene resistance? AB - Once deployed uniformly in the field, genetically controlled plant resistance is often quickly overcome by pathogens, resulting in dramatic losses. Several strategies have been proposed to constrain the evolutionary potential of pathogens and thus increase resistance durability. These strategies can be classified into four categories, depending on whether resistance sources are varied across time (rotations) or combined in space in the same cultivar (pyramiding), in different cultivars within a field (cultivar mixtures) or among fields (mosaics). Despite their potential to differentially affect both pathogen epidemiology and evolution, to date the four categories of deployment strategies have never been directly compared together within a single theoretical or experimental framework, with regard to efficiency (ability to reduce disease impact) and durability (ability to limit pathogen evolution and delay resistance breakdown). Here, we used a spatially explicit stochastic demogenetic model, implemented in the R package landsepi, to assess the epidemiological and evolutionary outcomes of these deployment strategies when two major resistance genes are present. We varied parameters related to pathogen evolutionary potential (mutation probability and associated fitness costs) and landscape organization (mostly the relative proportion of each cultivar in the landscape and levels of spatial or temporal aggregation). Our results, broadly focused on qualitative resistance to rust fungi of cereal crops, show that evolutionary and epidemiological control are not necessarily correlated and that no deployment strategy is universally optimal. Pyramiding two major genes offered the highest durability, but at high mutation probabilities, mosaics, mixtures and rotations can perform better in delaying the establishment of a universally infective superpathogen. All strategies offered the same short-term epidemiological control, whereas rotations provided the best long-term option, after all sources of resistance had broken down. This study also highlights the significant impact of landscape organization and pathogen evolutionary ability in considering the optimal design of a deployment strategy. PMID- 30459831 TI - Population genomics through time provides insights into the consequences of decline and rapid demographic recovery through head-starting in a Galapagos giant tortoise. AB - Population genetic theory related to the consequences of rapid population decline is well-developed, but there are very few empirical studies where sampling was conducted before and after a known bottleneck event. Such knowledge is of particular importance for species restoration, given links between genetic diversity and the probability of long-term persistence. To directly evaluate the relationship between current genetic diversity and past demographic events, we collected genome-wide single nucleotide polymorphism data from prebottleneck historical (c.1906) and postbottleneck contemporary (c.2014) samples of Pinzon giant tortoises (Chelonoidis duncanensis; n = 25 and 149 individuals, respectively) endemic to a single island in the Galapagos. Pinzon giant tortoises had a historically large population size that was reduced to just 150-200 individuals in the mid 20th century. Since then, Pinzon's tortoise population has recovered through an ex situ head-start programme in which eggs or pre-emergent individuals were collected from natural nests on the island, reared ex situ in captivity until they were 4-5 years old and subsequently repatriated. We found that the extent and distribution of genetic variation in the historical and contemporary samples were very similar, with the latter group not exhibiting the characteristic genetic patterns of recent population decline. No population structure was detected either spatially or temporally. We estimated an effective population size (N e) of 58 (95% CI = 50-69) for the postbottleneck population; no prebottleneck N e point estimate was attainable (95% CI = 39-infinity) likely due to the sample size being lower than the true N e. Overall, the historical sample provided a valuable benchmark for evaluating the head-start captive breeding programme, revealing high retention of genetic variation and no skew in representation despite the documented bottleneck event. Moreover, this work demonstrates the effectiveness of head-starting in rescuing the Pinzon giant tortoise from almost certain extinction. PMID- 30459832 TI - Managing the emergence of pathogen resistance via spatially targeted antimicrobial use. AB - From agriculture to public health to civil engineering, managing antimicrobial resistance presents a considerable challenge. The dynamics underlying resistance evolution reflect inherently spatial processes. Resistant pathogen strains increase in frequency when a strain that emerges in one locale can spread and replace pathogen subpopulations formerly sensitive to the antimicrobial agent. Moreover, the strength of selection for antimicrobial resistance is in part governed by the extent of antimicrobial use. Thus, altering how antimicrobials are used across a landscape can potentially shift the spatial context governing the dynamics of antimicrobial resistance and provide a potent management tool. Here, we model how the efficacy of adjusting antimicrobial use over space to manage antimicrobial resistance is mediated by competition among pathogen strains and the topology of pathogen metapopulations. For several pathogen migration scenarios, we derive critical thresholds for the spatial extent of antimicrobial use below which resistance cannot emerge, and relate these thresholds to (a) the ability to eradicate antimicrobial-sensitive pathogens locally and (b) the strength of the trade-off between resistance ability and competitive performance where antimicrobial use is absent. We find that in metapopulations where patches differ in connectedness, constraining antimicrobial use across space to mitigate resistance evolution only works if the migration of the resistant pathogen is modest; yet, this situation is reversed if the resistant strain has a high colonization rate, with variably connected metapopulations exhibiting less sensitivity to reducing antimicrobial use across space. Furthermore, when pathogens are alternately exposed to sites with and without the antimicrobial, bottlenecking resistant strains through sites without an antimicrobial is only likely to be effective under a strong competition-resistance trade-off. We therefore identify life-history constraints that are likely to suggest which pathogens can most effectively be controlled by a spatially targeted antimicrobial regime. We discuss implications of our results for managing and thinking about antimicrobial resistance evolution in spatially heterogeneous contexts. PMID- 30459834 TI - Walking in a heterogeneous landscape: Dispersal, gene flow and conservation implications for the giant panda in the Qinling Mountains. AB - Understanding the interaction between life history, demography and population genetics in threatened species is critical for the conservations of viable populations. In the context of habitat loss and fragmentation, identifying the factors that underpin the structuring of genetic variation within populations can allow conservationists to evaluate habitat quality and connectivity and help to design dispersal corridors effectively. In this study, we carried out a detailed, fine-scale landscape genetic investigation of a giant panda population from the Qinling Mountains for the first time. With a large microsatellite data set and complementary analysis methods, we examined the role of isolation-by-barriers (IBB), isolation-by-distance (IBD) and isolation-by-resistance (IBR) in shaping the pattern of genetic variation in this giant panda population. We found that the Qinling population comprises one continuous genetic cluster, and among the landscape hypotheses tested, gene flow was found to be correlated with resistance gradients for two topographic factors, slope aspect and topographic complexity, rather than geographical distance or barriers. Gene flow was inferred to be facilitated by easterly slope aspect and to be constrained by topographically complex landscapes. These factors are related to benign microclimatic conditions for both the pandas and the food resources they rely on and more accessible topographic conditions for movement, respectively. We identified optimal corridors based on these results, aiming to promote gene flow between human induced habitat fragments. These findings provide insight into the permeability and affinities of giant panda habitats and offer important reference for the conservation of the giant panda and its habitat. PMID- 30459833 TI - Landscape genomics provides evidence of climate-associated genetic variation in Mexican populations of Quercus rugosa. AB - Local adaptation is a critical evolutionary process that allows plants to grow better in their local compared to non-native habitat and results in species-wide geographic patterns of adaptive genetic variation. For forest tree species with a long generation time, this spatial genetic heterogeneity can shape the ability of trees to respond to rapid climate change. Here, we identify genomic variation that may confer local environmental adaptations and then predict the extent of adaptive mismatch under future climate as a tool for forest restoration or management of the widely distributed high-elevation oak species Quercus rugosa in Mexico. Using genotyping by sequencing, we identified 5,354 single nucleotide polymorphisms (SNPs) genotyped from 103 individuals across 17 sites in the Trans Mexican Volcanic Belt, and, after controlling for neutral genetic structure, we detected 74 F ST outlier SNPs and 97 SNPs associated with climate variation. Then, we deployed a nonlinear multivariate model, Gradient Forests, to map turnover in allele frequencies along environmental gradients and predict areas most sensitive to climate change. We found that spatial patterns of genetic variation were most strongly associated with precipitation seasonality and geographic distance. We identified regions of contemporary genetic and climatic similarities and predicted regions where future populations of Q. rugosa might be at risk due to high expected rate of climate change. Our findings provide preliminary details for future management strategies of Q. rugosa in Mexico and also illustrate how a landscape genomic approach can provide a useful tool for conservation and resource management strategies. PMID- 30459835 TI - Transgenerational plasticity and selection shape the adaptive potential of sticklebacks to salinity change. AB - In marine climate change research, salinity shifts have been widely overlooked. While widespread desalination effects are expected in higher latitudes, salinity is predicted to increase closer to the equator. We took advantage of the steep salinity gradient of the Baltic Sea as a space-for-time design to address effects of salinity change on populations. Additionally, genetic diversity, a prerequisite for adaptive responses, is reduced in Baltic compared to Atlantic populations. On the one hand, adaptive transgenerational plasticity (TGP) might buffer the effects of environmental change, which may be of particular importance under reduced genetic variation. On the other hand, physiological trade-offs due to environmental stress may hamper parental provisioning to offspring thereby intensifying the impact of climate change across generations (nonadaptive TGP). Here, we studied both hypothesis of adaptive and nonadaptive TGP in the three spined stickleback (Gasterosteus aculeatus) fish model along the strong salinity gradient of the Baltic Sea in a space-for-time experiment. Each population tolerated desalination well, which was not altered by parental exposure to low salinity. Despite a common marine ancestor, populations locally adapted to low salinity lost their ability to cope with fully marine conditions, resulting in lower survival and reduced relative fitness. Negative transgenerational effects were evident in early life stages, but disappeared after selection via mortality occurred during the first 12-30 days posthatch. Modeling various strengths of selection, we showed that nonadaptive transgenerational plasticity accelerated evolution by increasing directional selection within the offspring generation. Qualitatively, when genetic diversity is large, we predict that such effects will facilitate rapid adaptation and population persistence, while below a certain threshold populations suffer a higher risk of local extinction. Overall, our results suggest that transgenerational plasticity and selection are not independent of each other and thereby highlight a current gap in TGP studies. PMID- 30459836 TI - Influence of a growth hormone transgene on the genetic architecture of growth related traits: A comparative analysis between transgenic and wild-type coho salmon. AB - Genetic engineering has been increasingly applied to many commercially important plant and animal species, generating phenotypic changes that are not observed in natural populations and creating genetic interactions that have not experienced natural selection. The degree to and way in which such human-induced genetic variation interacts with the rest of the genome is currently largely unknown. Integrating such information into ecological and risk assessment frameworks is crucial to understand the potential effects of genetically modified organisms in natural environments. Here, we performed QTL mapping to investigate the genetic architecture of growth-related traits in nontransgenic (NT) and growth hormone transgenic (T) coho salmon with large changes in growth and related physiology, with the aim of identifying how an inserted transgene might influence the opportunity for selection. These fish shared the same parental genetic background, thus allowing us to determine whether the same or different loci influence these traits within the two groups. The use of over 1,700 loci, derived from restriction site-associated DNA sequencing, revealed that different genomic regions were linked with growth over time between the two groups. Additionally, the effect sizes of detected QTL appear to have been influenced by the transgene. Direct comparison of QTL between the T and NT fish during two size-matched periods identified little overlap in their location. Taken together, the results showed that the transgene altered the genetic basis of growth-related traits in this species. The study has important implications for effective conservation and management of wild populations experiencing introduction of transgenes. Evolutionary changes and their ecological consequences may occur at different rates and in different directions in NT versus T individuals in response to selection. Thus, assessments of phenotypic change, and hence ecological risk, should be determined periodically to evaluate whether initial estimates made with founder strains remain valid. PMID- 30459837 TI - Metabarcoding using multiplexed markers increases species detection in complex zooplankton communities. AB - Metabarcoding combines DNA barcoding with high-throughput sequencing, often using one genetic marker to understand complex and taxonomically diverse samples. However, species-level identification depends heavily on the choice of marker and the selected primer pair, often with a trade-off between successful species amplification and taxonomic resolution. We present a versatile metabarcoding protocol for biomonitoring that involves the use of two barcode markers (COI and 18S) and four primer pairs in a single high-throughput sequencing run, via sample multiplexing. We validate the protocol using a series of 24 mock zooplanktonic communities incorporating various levels of genetic variation. With the use of a single marker and single primer pair, the highest species recovery was 77%. With all three COI fragments, we detected 62%-83% of species across the mock communities, while the use of the 18S fragment alone resulted in the detection of 73%-75% of species. The species detection level was significantly improved to 89% 93% when both markers were used. Furthermore, multiplexing did not have a negative impact on the proportion of reads assigned to each species and the total number of species detected was similar to when markers were sequenced alone. Overall, our metabarcoding approach utilizing two barcode markers and multiple primer pairs per barcode improved species detection rates over a single marker/primer pair by 14% to 35%, making it an attractive and relatively cost effective method for biomonitoring natural zooplankton communities. We strongly recommend combining evolutionary independent markers and, when necessary, multiple primer pairs per marker to increase species detection (i.e., reduce false negatives) in metabarcoding studies. PMID- 30459838 TI - Population genetic structure of the deep-sea mussel Bathymodiolus platifrons (Bivalvia: Mytilidae) in the Northwest Pacific. AB - Studying population genetics of deep-sea animals helps us understand their history of habitat colonization and population divergence. Here, we report a population genetic study of the deep-sea mussel Bathymodiolus platifrons (Bivalvia: Mytilidae) widely distributed in chemosynthesis-based ecosystems in the Northwest Pacific. Three mitochondrial genes (i.e., atp6, cox1, and nad4) and 6,398 genomewide single nucleotide polymorphisms (SNPs) were obtained from 110 individuals from four hydrothermal vents and two methane seeps. When using the three mitochondrial genes, nearly no genetic differentiation was detected for B. platifrons in the Northwest Pacific. Nevertheless, when using SNP datasets, all individuals in the South China Sea (SCS) and three individuals in Sagami Bay (SB) together formed one genetic cluster that was distinct from the remaining individuals. Such genetic divergence indicated a genetic barrier to gene flow between the SCS and the open Northwest Pacific, resulting in the co-occurrence of two cryptic semi-isolated lineages. When using 125 outlier SNPs identified focusing on individuals in the Okinawa Trough (OT) and SB, a minor genetic subdivision was detected between individuals in the southern OT (S-OT) and those in the middle OT (M-OT) and SB. This result indicated that, although under the influence of the Kuroshio Current and the North Pacific Intermediate Water, subtle geographic barriers may exist between the S-OT and the M-OT. Introgression analyses based on these outlier SNPs revealed that Hatoma Knoll in the S-OT represents a possible contact zone for individuals in the OT-SB region. Furthermore, migration dynamic analyses uncovered stronger gene flow from Dai-yon Yonaguni Knoll in the S-OT to the other local populations, compared to the reverse directions. Taken together, the present study offered novel perspectives on the genetic connectivity of B. platifrons mussels, revealing the potential interaction of ocean currents and geographic barriers with adaption and reproductive isolation in shaping their migration patterns and genetic differentiation in the Northwest Pacific. PMID- 30459839 TI - Combining mitochondrial and nuclear genome analyses to dissect the effects of colonization, environment, and geography on population structure in Pinus tabuliformis. AB - The phylogeographic histories of plants in East Asia are complex and shaped by both past large-scale climatic oscillations and dramatic tectonic events. The impact of these historic events, as well as ecological adaptation, on the distribution of biodiversity remains to be elucidated. Pinus tabuliformis is the dominant coniferous tree in northern China, with a large distribution across wide environmental gradients. We examined genetic variation in this species using genotyping-by-sequencing and mitochondrial (mt) DNA markers. We found population structure on both nuclear and mt genomes with a geographic pattern that corresponds well with the landscape of northern China. To understand the contributions of environment, geography, and colonization history to the observed population structure, we performed ecological niche modeling and partitioned the among-population genomic variance into isolation by environment (IBE), isolation by distance (IBD), and isolation by colonization (IBC). We used mtDNA, which is transmitted by seeds in pine, to reflect colonization. We found little impact of IBE, IBD, and IBC on variation in neutral SNPs, but significant impact of IBE on a group of outlier loci. The lack of IBC illustrates that the maternal history can be quickly eroded from the nuclear genome by high rates of gene flow. Our results suggest that genomic variation in P. tabuliformis is largely affected by neutral and stochastic processes, and the signature of local adaptation is visible only at robust outlier loci. This study enriches our understanding on the complex evolutionary forces that shape the distribution of genetic variation in plant taxa in northern China, and guides breeding, conservation, and reforestation programs for P. tabuliformis. PMID- 30459840 TI - Intestinal probiotics restore the ecological fitness decline of Bactrocera dorsalis by irradiation. AB - The sterile insect technique (SIT) as an eco-friendly and reliable strategy has been used to control populations of insect pests of agricultural, veterinary and human health importance. Successful applications of SIT rely on the high-level ecological fitness of sterile males. A suitable and stable gut microbiome can contribute to the ecological fitness of insect by influencing their physiology, biochemistry and development processes. Here, we show that a shift in the gut bacterial composition and structure by sterilizing irradiation, characterized by a decrease in the major gut microbiota community Enterobacteriaceae, an expansion of the minor members (e.g., Bacillaceae) and a higher richness and diversity, is tightly linked to radiation-induced ecological fitness (male mating competitiveness, flight capacity, survival rate and life span) decline in Bactrocera dorsalis (Hendel) sterile males. Function prediction of gut microbiota indicated that changes in microbiome taxonomy tend to drive microbiome functional shifts. A higher nutrient consumption of the flourishing minor gut microbiota may cause a decline in nutrients and energy metabolic activity of host and then result in the reduced ecological fitness of irradiated flies. Furthermore, we found that a gut bacterial strain Klebsiella oxytoca (BD177) can restore ecological fitness by improving food intake and increasing haemolymph sugar and amino acid levels of irradiated B. dorsalis flies. Our findings suggest that gut symbiont-based probiotics can be used as agents for reversing radiation-induced ecological fitness decrease. PMID- 30459841 TI - Weed evolution: Genetic differentiation among wild, weedy, and crop radish. AB - Approximately 200 weed species are responsible for more than 90% of crop losses and these comprise less than one percent of all named plant species, suggesting that there are only a few evolutionary routes that lead to weediness. Agricultural weeds can evolve along three main paths: they can be escaped crops, wild species, or crop-wild hybrids. We tested these three hypotheses in weedy radish, a weed of small grains and an emerging model for investigating the evolution of agricultural weeds, using 21 CAPS and SSR markers scored on 338 individuals from 34 populations representing all major species and sub-species in the radish genus Raphanus. To test for adaptation of the weeds to the agricultural environment, we estimated genetic differentiation in flowering time in a series of common garden experiments with over 2,400 individuals from 43 populations (all but one of the genotyped populations plus 10 additional populations). Our findings suggest that the agricultural weed radish R. r. raphanistrum is most genetically similar to native populations of R. r. raphanistrum and is likely not a feral crop or crop hybrid. We also show that weedy radish flowers more rapidly than any other Raphanus population or cultivar, which is consistent with rapid adaptation to the frequent and severe disturbance that characterizes agricultural fields. PMID- 30459842 TI - Modelling the invasion history of Sinanodonta woodiana in Europe: Tracking the routes of a sedentary aquatic invader with mobile parasitic larvae. AB - Understanding the invasive potential of species outside their native range is one of the most pressing questions in applied evolutionary and ecological research. Admixture of genotypes of invasive species from multiple sources has been implicated in successful invasions, by generating novel genetic combinations that facilitate rapid adaptation to new environments. Alternatively, adaptive evolution on standing genetic variation, exposed by phenotypic plasticity and selected by genetic accommodation, can facilitate invasion success. We investigated the population genetic structure of an Asian freshwater mussel with a parasitic dispersal stage, Sinanodonta woodiana, which has been present in Europe since 1979 but which has expanded rapidly in the last decade. Data from a mitochondrial marker and nuclear microsatellites have suggested that all European populations of S. woodiana originate from the River Yangtze basin in China. Only a single haplotype was detected in Europe, in contrast to substantial mitochondrial diversity in native Asian populations. Analysis of microsatellite markers indicated intensive gene flow and confirmed a lower genetic diversity of European populations compared to those from the Yangtze basin, though that difference was not large. Using an Approximate Bayesian Modelling approach, we identified two areas as the probable source of the spread of S. woodiana in Europe, which matched historical records for its establishment. Their populations originated from a single colonization event. Our data do not support alternative explanations for the rapid recent spread of S. woodiana; recent arrival of a novel (cold-tolerant) genotype or continuous propagule pressure. Instead, in situ adaptation, facilitated by repeated admixture, appears to drive the ongoing expansion of S. woodiana. We discuss management consequences of our results. PMID- 30459843 TI - Population structure of a global agricultural invasive pest, Bactrocera dorsalis (Diptera: Tephritidae). AB - Bactrocera dorsalis, the Oriental fruit fly, is one of the world's most destructive agricultural insect pests and a major impediment to international fresh commodity trade. The genetic structuring of the species across its entire geographic range has never been undertaken, because under a former taxonomy B. dorsalis was divided into four distinct taxonomic entities, each with their own, largely non-overlapping, distributions. Based on the extensive sampling of six a priori groups from 63 locations, genetic and geometric morphometric datasets were generated to detect macrogeographic population structure, and to determine prior and current invasion pathways of this species. Weak population structure and high genetic diversity were detected among Asian populations. Invasive populations in Africa and Hawaii are inferred to be the result of separate, single invasions from South Asia, while South Asia is also the likely source of other Asian populations. The current northward invasion of B. dorsalis into Central China is the result of multiple, repeated dispersal events, most likely related to fruit trade. Results are discussed in the context of global quarantine, trade, and management of this pest. The recent expansion of the fly into temperate China, with very few associated genetic changes, clearly demonstrates the threat posed by this pest to ecologically similar areas in Europe and North America. PMID- 30459844 TI - Natural selection on plasticity of thermal traits in a highly seasonal environment. AB - For ectothermic species with broad geographical distributions, latitudinal/altitudinal variation in environmental temperatures (averages and extremes) is expected to shape the evolution of physiological tolerances and the acclimation capacity (i.e., degree of phenotypic plasticity) of natural populations. This can create geographical gradients of selection in which environments with greater thermal variability (e.g., seasonality) tend to favor individuals that maximize performance across a broader range of temperatures compared to more stable environments. Although thermal acclimation capacity plays a fundamental role in this context, it is unknown whether natural selection targets this trait in natural populations. Additionally, understanding whether and how selection acts on thermal physiological plasticity is also highly relevant to climate change and biological conservation. Here, we addressed such an important gap in our knowledge in the northernmost population of the four-eyed frog, Pleurodema thaul. We measured plastic responses of critical thermal limits for activity, behavioral thermal preference, and thermal sensitivity of metabolism to acclimation at 10 and 20 degrees C. We monitored survival during three separate recapture efforts and used mark-recapture integrated into an information-theoretic approach to evaluate the relationship between survivals as a function of the plasticity of thermal traits. Overall, we found no evidence that thermal acclimation in this population is being targeted by directional selection, although there might be signals of selection on individual traits. According to the most supported models, survival increased in individuals with higher tolerance to cold when cold-acclimated, probably because daily low extremes are frequent during the cooler periods of the year. Furthermore, survival increased with body size. However, in both cases, the directional selection estimates were nonsignificant, and the constraints of our experimental design prevented us from evaluating more complex models (i.e., nonlinear selection). PMID- 30459845 TI - Manipulating plant phylogenetic diversity for green roof ecosystem service delivery. AB - Plant species and functional trait diversity have each been shown to improve green roof services. Species and trait differences that contribute to ecosystem services are the product of past evolutionary change and phylogenetic diversity (PD), which quantifies the relatedness among species within a community. In this study, we present an experimental framework to assess the contribution of plant community PD for green roof ecosystem service delivery, and data from one season that support our hypotheses that PD would be positively correlated with two services: building cooling and rainwater management. Using 28 plant species in 12 families, we created six community combinations with different levels of PD. Each of these communities was replicated at eight green roofs along an elevation gradient, as well as a ground level control. We found that the minimum and mean roof temperature decreased with increasing PD in the plant community. Increasing PD also led to an increase in the volume of rainwater captured, but not the proportion of water lost via evapotranspiration 48 hr following the rain event. Our findings suggest that considering these evolutionary relationships could improve functioning of green infrastructure and we recommend that understanding how to make PD (and other measures of diversity) serviceable for plant selection by practitioners will improve the effectiveness of design and ecosystem service delivery. Lastly, since no two green roof sites are the same and can vary tremendously in microclimate conditions, our study illustrates the importance of including multiple independent sites in studies of green roof performance. PMID- 30459846 TI - Population history provides foundational knowledge for utilizing and developing native plant restoration materials. AB - A species' population structure and history are critical pieces of information that can help guide the use of available native plant materials in restoration treatments and decide what new native plant materials should be developed to meet future restoration needs. In the western United States, Pseudoroegneria spicata (bluebunch wheatgrass; Poaceae) is an important component of grassland and shrubland plant communities and commonly used for restoration due to its drought resistance and competitiveness with exotic weeds. We used next-generation sequencing data to investigate the processes that shaped P. spicata's geographic pattern of genetic variation across the Intermountain West. Pseudoroegneria spicata's genetic diversity is partitioned into populations that likely differentiated since the Last Glacial Maximum. Adjacent populations display varying magnitudes of historical gene flow, with migration rates ranging from multiple migrants per generation to multiple generations per migrant. When considering the commercial germplasm sources available for restoration, genetic identities remain representative of the wildland localities from which germplasm sources were originally developed, and they maintain high levels of heterozygosity and nucleotide diversity. However, the commercial germplasm sources represent a small fraction of the overall genetic diversity of P. spicata in the Intermountain West. Given the low migration rates and long divergence times between some pairs of P. spicata populations, using commercial germplasm sources could facilitate undesirable restoration outcomes when used in certain geographic areas, even if the environment in which the commercial materials thrive is similar to that of the restoration site. As such, population structure and history can be used to provide guidance on what geographic areas may need additional native plant materials so that restoration efforts support species and community resilience and improve outcomes. PMID- 30459848 TI - Distributed retrieval engine for the development of cloud-deployed biological databases. AB - The integration of cloud resources with federated data retrieval has the potential of improving the maintenance, accessibility and performance of specialized databases in the biomedical field. However, such an integrative approach requires technical expertise in cloud computing, usage of a data retrieval engine and development of a unified data-model, which can encapsulate the heterogeneity of biological data. Here, a framework for the development of cloud-based biological specialized databases is proposed. It is powered by a distributed biodata retrieval system, able to interface with different data formats, as well as provides an integrated way for data exploration. The proposed framework was implemented using Java as the development environment, and MongoDB as the database manager. Syntactic analysis was based on BSON, jsoup, Apache Commons and w3c.dom open libraries. Framework is available in: http://nbel lab.com and is distributed under the creative common agreement. PMID- 30459849 TI - Characterization and CRISPR-based genotyping of clinical trh-positive Vibrio parahaemolyticus. AB - Background: Vibrio parahaemolyticus is a causative agent of gastroenteritis. Most of the clinical isolates carry either tdh and/or trh genes which are considered as the major virulence genes of this pathogen. In this study, the clinical isolates of V. parahaemolyticus carrying trh gene (n = 73) obtained from 1886 to 2012 from various countries were investigated for the urease production, haemolytic activity, and biofilm formation. In addition, the potential of clustered regularly interspaced short palindromic repeats (CRISPR)-based genotyping among these isolates was investigated. Results: In this study, no significant differences were observed in the urease production between tdh + trh1+ and tdh + trh2+ isolates (p = 0.063) and between the tdh - trh1+ and tdh - trh2+ isolates (p = 0.788). The isolates carrying only the trh gene showed variation in their haemolytic activity. The ratio of urease production and haemolytic activity between the trh1+ and trh2+ isolates and biofilm formation of trh + V. parahaemolyticus isolates were not significantly different. Sixteen of thirty-four tested isolates (47.0%) of trh + V. parahaemolyticus were positive for CRISPR detection. The discriminatory power index (DI) of CRISPR-virulence typing was higher than the DI obtained by CRISPR typing alone. Conclusion: The tdh and trh genes were not involved in urease production in the trh + V. parahaemolyticus, and variation of haemolytic activity detected in V. parahaemolyticus carrying only the trh gene might be correlated to the sequence variation within trh1 and trh2 genes. Additionally, biofilm production of V. parahaemolyticus was not associated with harboring of virulence genes. For genotyping, CRISPR sequences combined with virulence genes can be used as genetic markers to differentiate trh + V. parahaemolyticus strains. PMID- 30459847 TI - Endangered Pere David's deer genome provides insights into population recovering. AB - The Milu (Pere David's deer, Elaphurus davidianus) were once widely distributed in the swamps (coastal areas to inland areas) of East Asia. The dramatic recovery of the Milu population is now deemed a classic example of how highly endangered animal species can be rescued. However, the molecular mechanisms that underpinned this population recovery remain largely unknown. Here, different approaches (genome sequencing, resequencing, and salinity analysis) were utilized to elucidate the aforementioned molecular mechanisms. The comparative genomic analyses revealed that the largest recovered Milu population carries extensive genetic diversity despite an extreme population bottleneck. And the protracted inbreeding history might have facilitated the purging of deleterious recessive alleles. Seventeen genes that are putatively related to reproduction, embryonic (fatal) development, and immune response were under high selective pressure. Besides, SCNN1A, a gene involved in controlling reabsorption of sodium in the body, was positively selected. An additional 29 genes were also observed to be positively selected, which are involved in blood pressure regulation, cardiovascular development, cholesterol regulation, glycemic control, and thyroid hormone synthesis. It is possible that these genetic adaptations were required to buffer the negative effects commonly associated with a high-salt diet. The associated genetic adaptions are likely to have enabled increased breeding success and fetal survival. The future success of Milu population management might depend on the successful reintroduction of the animal to historically important distribution regions. PMID- 30459851 TI - Role of Hypertonic Sodium Lactate in Traumatic Brain Injury Management. AB - Traumatic brain injury (TBI) following increased intracranial pressure (ICP) is a neuroemergency case which should be managed promptly to prevent secondary brain injury. This will lead to a condition called cerebral energy dysfunction which is an important determinant factor toward worse outcome. Lactate, which was historically known as an end waste product, now is considered as an alternative cerebral energetic fuel. Hypertonic sodium lactate (HSL) is a promising hyperosmolar fluid which serves not only to decrease ICP but also to readily supply exogenous lactate to fulfill increased cerebral energy demand. Pioneer studies have shown the harmlessness and usefulness of HSL in treating pathological condition including TBI. PMID- 30459852 TI - The Role of Medical Treatment in Chronic Subdural Hematoma. AB - Surgery is the standard treatment for chronic subdural hematoma (CSDH), one of the common problems in neurosurgical practice. Although medical treatment was used by some authors and found some positive results, it is not accepted by many authors. The aim of this review is to give overall view of the medical management of CSDH. Action of various drugs in the pathophysiological cascade of formation of CSDH was depicted. The review of literature is done under three headings - the primary medical treatment of CSDH, adjuvant medical treatment with surgery, and the treatment of the recurrence. Various classifications of CSDH and the factors influencing the outcome of medical treatment are discussed. There is a role of medical treatment in a selected group of patients with CSDH. Well-designed, multicenter, randomized controlled trials are required to define the indications and standard protocols for the medical treatment of CSDH. PMID- 30459853 TI - Frequency of Ischemic Stroke Subtypes Based on Toast Classification at a Tertiary Care Center in Pakistan. AB - Background: The purpose of this study was to determine the frequency of ischemic stroke subtypes based on Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification at a tertiary care center in Pakistan. Materials and Methods: A cross-sectional study was conducted in Stroke Unit of Shifa International Hospital, Islamabad. We included 145 patients who presented to us from November 2015 to February 2016 with radiological confirmed neurological deficits consistent with ischemic stroke. The causes of ischemic stroke were classified according to TOAST criteria. Regression analysis and Chi-square test were used to compute P value. Results: Among the 145 patients diagnosed with ischemic stroke, there were 54.1% males and 45.9% females with a mean age of 65 +/- 14 years. Nearly 62.7% patients had hypertension (HTN) as the most common risk factor, followed by 38.6% diabetes mellitus (DM), 27.5% heart failure, 19.3% valvular disease, 18.6% previous stroke, 16.4% smoking, 15.1% dyslipidemia, 13.7% ischemic heart disease, and 13.1% atrial fibrillation. HTN was significantly associated with large vessel disease (P = 0.028). DM was significantly associated with small vessel disease (P = 0.001). Smoking and atrial fibrillation both were associated with unknown etiology of stroke (P = 0.001 and P = 0.039, respectively). Most common etiology of stroke was cardioembolism (40%), and atrial fibrillation is found to be the most common cause of cardioembolic stroke with 30.6% incidence. Conclusion: Our study concludes that cardioembolic stroke is the most common cause of acute ischemic stroke in our stroke unit. Atrial fibrillation is found to be the most common cause of cardioembolic stroke. PMID- 30459854 TI - Using of the Chicken Wing's Bone in the Microneusurgical Training Model for Microdrilling. AB - Background and Objective: Repetitive practicing of microneurosurgical techniques in experimental laboratory using real surgical instruments on training models is extremely important before starting the real surgical interventions. The modeling of the surgical steps with creating of suitable laboratory models is also another important issue in the successfully gaining of microneurosurgical practice. Materials and Methods: In this experimental study, it was created a laboratory training model for microneurosurgical drilling of cranial bones including the close location with the neural and vascular structures. All steps of this study were performed under the operating microscope. Twenty-five fresh chicken wings obtained from supermarket were used for this study. The difficulty and suitability of the model was evaluated in terms of the usability in the training of microneruosurgical microdrilling. Difficulty of the procedure was divided as three degree (very easy, easy, and difficult). The objective criterion for the evaluation of the difficulty of the procedure was the protection of the neurovascular and muscular structures during the procedure. Results: The suitability of the procedure was also evaluated within three groups as bad, good, and perfect. In four (16%) chicken wing's bone, the difficulty of the microdirilling was evaluated as difficult. Fifteen (60%) of the chicken wing's bones were microsurgically drilled with easy procedure. The remaining six (24%) of the wing's bone microdrilling was evaluated as very easy procedure. The suitability of the model was evaluated as bad in three (12%) of the chicken wing's bone. The suitability was found as good in 16 (64%) of the bones. In the remaining three (24%) of the chicken wing's bone microdrilling, the suitability of the model was evaluated as perfect. Conclusion: Microsurgical drilling of the chicken wing's bone without any vascular and muscular injury is accepted as the indication of the successfully surgical microdrilling process. Consolidation of the surgical practice in a laboratory setting, grasping and using of microsurgical instruments, can be repeated in several times in this model. We believe that this model will contribute to the practical training of microneurosurgery. PMID- 30459850 TI - A Comprehensive Review of Skull Base Osteomyelitis: Diagnostic and Therapeutic Challenges among Various Presentations. AB - Skull base osteomyelitis (SBO) is a complex and fatal clinical entity that is often misdiagnosed for malignancy. SBO is commonly a direct complication of otogenic, sinogenic, odontogenic, and rhinogenic infections and can present as central, atypical, or pediatric clival SBO. This review describes the clinical profile, investigational approach, and management techniques for these variants. A comprehensive literature review was performed in PubMed, MEDLINE, Research Gate, EMBASE, Wiley Online Library, and various Neurosurgical and Neurology journals with the keywords including: SBO, central or atypical SBO, fungal osteomyelitis, malignant otitis externa, temporal bone osteomyelitis, and clival osteomyelitis. Each manuscript's reference list was reviewed for potentially relevant articles. The search yielded a total of 153 articles. It was found that with early and aggressive culture guided long-term intravenous broad-spectrum antibiotic therapy decreases post-infection complications. In cases of widespread soft tissue involvement, an early aggressive surgical removal of infectious sequestra with preferentially Hyperbaric Oxygen (HBO) therapy is associated with better prognosis of disease, less neurologic sequelae and mortality rate. Complete resolution of the SBO cases may take several months. Since early treatment can improve mortality rates, it is paramount that the reporting radiologists and treating clinicians are aware of the cardinal diagnostic signs to improve clinical outcomes of the disease. It will decrease delayed diagnosis and under treatment of the condition. However, due to rarity of the condition, complete prognostic factors have not fully been analyzed and discussed in the literature. PMID- 30459855 TI - Clinical Characteristics of Cerebellar Infarction Due to Arterial Dissection. AB - Objectives and Background: Arterial dissection (AD) of the vertebral artery (VA) or its branches may cause ischemic stroke of the posterior circulation. However, clinical and radiological characteristics of patients with AD-related cerebellar infarction (CI) have rarely been reported. Methods: Forty-nine patients with CI admitted to our department from April 2008 to March 2015 were identified from our database. After dichotomization into the AD and non-AD group, their demographics and presenting symptoms were compared. Subsequently, a multivariate regression analysis was performed to identify variables that correlated with AD. Results: During the 7-year period, 14 and 35 patients were identified in the AD and non-AD group, respectively. The AD group was significantly younger than the non-AD group (55.0 +/- 16.3 vs. 69.7 +/- 10.7 years, P = 0.001) and was also more likely to experience acute pain at onset (86% vs. 17%, P < 0.001). Using a multivariate regression analysis, these two variables and the male sex were found to correlate with AD. AD was located in extracranial VA (n = 3); intracranial VA (n = 8); posterior inferior cerebellar artery (PICA) (n = 3); and superior cerebellar artery (n = 1). Identification of AD was delayed in one patient with an extracranial VA and one patient with a PICA dissection. Conclusions: AD was responsible for approximately 30% of CI in our cohort. Pain at onset may be a useful symptom to identify patients with AD-related CI. While intracranial VA was the most common location of AD, physicians should be aware of the possibility of extracranial VA or PICA dissection in patients with seemingly unremarkable radiological findings. PMID- 30459857 TI - Unravelling Hitherto Unreported Masses Camouflaged as Pituitary Macro Adenomas. AB - Background: Lesions of the pituitary gland and the juxtasellar region are quite frequently encountered in daily practise of a neurologist/neurosurgeon. While the differentials of sellar masses are quite large and form an extensive list and the management protocol varies in each case, the onus of properly categorizing and diagnosing the pituitary mass often falls on the reporting radiologist. We hereby present two such unusual masses in the sellar-suprasellar region which were masquerading as pituitary macro adenomas. Materials and Methods: Two cases of sellar-suprasellar masses which were preoperatively diagnosed as pituitary macro adenomas on radiological imaging proved out to be pituitary natural killer cell lymphoma and lepromatous abscess. Results: The first one is a rare case of pituitary abscess seen in a lepromatous patient which is not yet reported in the literature. The second case is of primary pituitary natural killer cell lymphoma which is almost entirely unknown, with only two such cases being reported worldwide till date. Conclusion: It is important to realize that all enhancing pituitary lesions are not macro adenomas and it is necessary to have a high index of suspicion in such cases. The clinical implications of such an error and steps that can be taken to prevent misinterpretations of unusual sellar masses camouflaging as pituitary macro adenomas have been briefly outlined. PMID- 30459856 TI - Early Surgical Outcome of Endoscopic Third Ventriculostomy in the Management of Obstructive Hydrocephalus: A Randomized Control Trial. AB - Background: Management of obstructive hydrocephalus is an important issue for the reduction of mortality and morbidity. Objectives: The aim of the present study was to assess the early surgical outcome of endoscopic third ventriculostomy (ETV) in the management of obstructive hydrocephalus. Methodology: This randomized controlled trial was conducted at the Department of Neurosurgery at Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh, from April 2009 to September 2010 for 11/2 years. All patients presenting with obstructive hydrocephalus with the obstruction at or distal to the third ventricle and age 6 months and above were included in the study population. All the patients were divided into two groups named as Group A (experimental group) who were treated with ETV and Group B (control group) who were treated with ventriculoperitoneal shunt (VPS). The early surgical outcome was defined as outcomes within 1 month following surgical interventions. Pre- and post-operative outcomes of this study were measured. Results: A total number of sixty patients were recruited from which thirty patients were in Group A and the rest thirty patients were in Group B. The mean postoperative head circumference was 43.4 +/- 7.1 cm and 47.8 +/- 5.6 cm in VPS and ETV surgery, respectively (P <= 0.01). Postoperative vomiting was improved 24 (92.3%) in Group A and 23 (88.5%) in Group B (P < 0.05). Postoperative infection occurred in 1 (3.3%) case in Group A and 8 (26.7%) cases in Group B (P < 0.05). The success of the operation in Group A and Group B included 25 (83.3%) cases and 12 (40%) cases, respectively (P < 0.05). Conclusion: Early surgical outcome following ETV is better than VPS surgery in patients with obstructive hydrocephalus. PMID- 30459858 TI - Ruptured Posterior Circulation Aneurysms with Bilateral Internal Carotid Artery Occlusion: Surgical Nuance. AB - Background: Craniotomy and surgical clipping is the standard modality of treatment in patients of cerebral aneurysms. However, the surgical clipping of aneurysm may pose serious difficulties in the case of a bilateral carotid artery occlusion. The endovascular treatment has shown promising results in this disease. Methods: A retrospective study of all patients of posterior circulation aneurysms in the background of carotid occlusive disease at our department was performed. The aim of this study was to describe the clinical, radiological characteristics, and the treatment of this rare entity. Results: Four patients were treated from January 2009 to October 2015. The mean age of our patients was 34 years with ages that ranged from 17 to 45 without any gender predominance. The mean period between onset of symptoms and diagnosis was 6 weeks. Angiographic localization of the disease was observed in all patients. All patients were treated by endovascular techniques. The postoperative course has been satisfactory with a complete neurological recovery in all patients. Conclusions: Rupture of posterior circulation aneurysms in the setting of bilateral internal carotid artery occlusion is extremely rare. Treatment is exclusively endovascular intervention. The functional outcome of ruptured posterior circulation aneurysms in setting of bilateral carotid occlusive disease is particularly favorable with good neurological recovery. PMID- 30459859 TI - Moulded Osteomyofascial Pedicled Split (MOPS) Craniotomy Flap in Reconstruction of Anterior Cranial Fossa Defects: Pilot Study of a Novel Technique. AB - Introduction: Anterior cranial fossa (ACF) defects still remains a reconstructive challenge to neurosurgeons due to the difficult location, inaccessibility, and unfavorable vascular anatomy. Usual reconstructive methods reported complications such as recurrent cerebrospinal fluid leak due to bone resorption and tissue breakdown. This is mainly due to the avascularity of the bone graft and inability to provide bony structural support for the skull base. An ideal reconstructive modality should provide a rigid bony support to prevent brain herniation as well as ensure a water tight barrier between sinonasal tract and intracranial compartment. Methodology: Hence, we thought of a novel technique of taking the outer table of the primary craniotomy flap with its intact myofascial pedicle and moulded it with multiple osteotomies (moulded osteomyofascial pedicled split (MOPS) craniotomy flap) to fit into uneven ACF defects. Advantages of our flap include (1) It is a pedicled vascularized bone flap. (2) It is taken from primary craniotomy flap; hence, no separate craniotomy is required. (3) The inner table is intact and leaves no secondary calvarial bone defect on the donor site. (4) Osteoplastic flap is moulded to fit into the defect, thus providing good contour. Results: MOPS flap was used in five patients with ACF defects due to varied etiologies such as encephalocele defect, frontal mucocele, skull base meningioma, and complex naso ethmoid fracture. Age of the patients included in the study varied from 21 to 60 years. Male:female ratio was 4:1. ACF defects were reconstructed using MOPS flap in all cases. There were no postoperative complications and 1-month postoperative computerized tomography scan showed no evidence of bone resorption with acceptable cosmesis. Conclusion: MOPS craniotomy flap provides a novel, easily mastered, and cost-effective technique with minimal complication in reconstruction of complex ACF defects with acceptable esthetic and functional outcome. PMID- 30459860 TI - Therapeutic Evaluation of Tumor Necrosis Factor-alpha Antagonist Etanercept against Traumatic Brain Injury in Rats: Ultrastructural, Pathological, and Biochemical Analyses. AB - Purpose: The aim of the present study was to investigate the effect of etanercept (ETA) on histopathological and biochemical changes after traumatic brain injury (TBI) in rats. Materials and Methods: Thirty-six male Wistar albino rats were distributed into three groups (n = 12 each). Control group rats were not subjected to trauma. Trauma group rats were subjected to TBI only. ETA group rats were subjected to TBI plus ETA (5 mg/kg intraperitoneal [i.p.]). The groups were further subdivided into those sacrificed in the hyperacute stage (1 h after TBI) (control-1, trauma-1, and ETA-1 groups) and the acute stage (6 h after TBI) (control-6, trauma-6, and ETA-6 groups). Tissue levels of tumour necrosis factor alpha, interleukin-1 beta, malondialdehyde, catalase, glutathione peroxidase, and superoxide dismutase were analyzed. Histopathological and ultrastructural evaluations were also performed. Results: i.p. administration of ETA at 1 and 6 h significantly reduced inflammatory cytokine expression, attenuated oxidative stress and lipid peroxidation, prevented apoptosis, and increased antioxidant defense mechanism activity in comparison to trauma group. Histopathological and ultrastructural abnormalities were significantly reduced in ETA-treated rats compared to closed head injury trauma groups. Conclusions: ETA significantly improves neural function and prevents post-TBI histopathological damage in rats. PMID- 30459861 TI - P53 and Ki-67 Expression in Primary Pediatric Brain Tumors: Does it Correlate with Presentation, Histological Grade, and Outcome? AB - Context: Pediatric brain tumors are a vexing problem for the neurosurgeon due to the fragile patient cohort. We attempt to find parameters which can help us to treat and prognosticate these patients in a better way. Aims: This study aims to correlate clinical presentation, outcome, and histological grade with P53 and Ki 67 expression in primary pediatric brain tumors. Setting Design: This was a prospective, observational study. Patients and Methods: Forty-seven patients with primary brain tumors in the age group 0-18 years were included in this study. Clinical presentation was noted. Patients were operated, and specimen was sent for histopathological and immunohistochemistry examination for p53 and Ki-67. The WHO classification of 2007 was used to grade the tumors. Follow-up was done at 3 and 6 months with Glasgow outcome score. Expression of p53 and Ki-67 in different tumors was correlated with clinical presentation, tumor grade and outcome. Analysis Method: Statistical Package for Social Science version 17. P < 0.05 was considered statistically significant. Results: There was statistically significant correlation between high tumor grade and high Ki-67 levels (P = 0.000). On post hoc analysis, there was a significant difference between p53 levels in Grade 1 and Grade 4 tumors. There was statistically significant correlation between neurological deficit and higher p53 levels (P = 0.040). There was statistically significant correlation between poor outcome and higher p53 (P = 0.034) and Ki-67 (P = 0.000) levels at 3 months follow-up which continued at 6 months. Conclusions: From this study, we conclude that p53 and Ki-67 expression in pediatric brain tumors is associated with poor outcome and correlates with tumor grade. Moreover, p53 expression correlates with neurological deficit. PMID- 30459862 TI - Intradural Disc a Diagnostic Dilemma: Case Series and Review of Literature. AB - Introduction: We present a case series of six cases of intradural disc herniation at L4-L5 level diagnosed on the basis of intraoperative findings. Result: All our cases, on preoperative magnetic resonance imaging (MRI) were reported as having diffuse annular bulge with large posterocentral extrusion. Our study comprised patients in age group of 30-60 years. Four cases out of six presented with cauda equina syndrome. In three cases, cauda equina was associated with sudden deterioration in the power of lower limb muscle groups. Discussion: We suspect that intradural herniation of disc was synchronous with cauda equina syndrome in these cases, which was very well documented in one of the cases. On retrospective analysis, MRI findings of mass effect in the form of displacement of the traversing nerve roots due to large central disc with crumble disc sign were suggestive of early evidence of intradural disc herniation. Y sign in ventral dura due to splitting of ventral dura and arachnoid mater by disc material was a good diagnostic sign to suspect intradural extra-arachnoid disc. The presence of hypointense structure inside the dura with no continuity with the adjacent intervertebral disc on MRI was highly suggestive of an intradural disc. Conclusion: Intradural disc prolapse remains a diagnostic dilemma as it is very difficult to diagnose all the cases preoperatively. The presence of above mentioned radiological signs on MRI in patients having the large central disc on MRI, especially at L4-L5 levels, should raise suspicion of intradural herniation of disc. PMID- 30459863 TI - Gamma Knife Management of Skull Base Chordomas: Is it a Choice? AB - Background: Skull base chordomas are locally invasive tumors which able to extend in different directions with skull base invasion. Although they are histologically benign, they have invasive nature makes total resection virtually impossible to achieve in most cases and this lead to residual tumors after surgery. To decrease postoperative surgical resection morbidity of these tumors, gamma knife radiosurgery (GKRS) was performed as alternative management for these residual chordomas to evaluate its safety and efficacy. Materials and Methods: A retrospective study was made on eight residual skull base chordomas treated with GKRS between 2011 and 2015. The mean patient age was 49 years (range 30-73 years). Four patients harboring chordoma were male, and four patients were females with 1:1 ratio. All patients had undergone one prior surgery. Patients were treated with peripheral dose ranged between 12-15 gray (Gy) (mean 13.75 Gy) usually at 35% to 50% isodose curve (mean 38.8%). The maximum dose to the adjacent brain stem area ranged between 10 and 12 Gy. All patients were followed up from 8 to 39 months (mean 18 months). Results: The tumor control rate was 50% and 25% after 18 and 36 months, respectively, but we found that their wasdeclined in the tumor control rate with long follow-up time. Four tumors were stable in their size just for 18 months, and then there two of these tumors were progressed in their size, the other four patients showed progression in their tumors in their 1st year of treatment without sign of central tumor necrosis. Conclusion: Skull base chordoma patients complained from symptoms due to tumor mass effect which were not prospected to respond to GKRS alone as the aim of this type of treatment was the local tumor control, the tumor control rate declined with long follow-up time and this correlated with radioresistant nature of skull base chordoma. We advise a gross total resection to decrease the tumor volume, and this making gamma knife a reasonable treatment modality. PMID- 30459864 TI - Controlled Trial to Compare Therapeutic Efficacy of Endoscopic Third Ventriculostomy Plus Choroid Plexus Cauterization with Ventriculoperitoneal Shunt in Infants with Obstructive Hydrocephalus. AB - Context: Ventriculoperitoneal (VP) shunt and endoscopic third ventriculostomy (ETV) are the established surgical treatments for obstructive hydrocephalus (HCP). Powerful evidence regarding the best therapeutic approach for infants with obstructive HCP is lacked. Aims: Comparison of the therapeutic efficacy of VP shunt and ETV/choroid plexus cauterization (CPC) in infants with obstructive HCP. Settings and Design: This was a randomized, active control, unblind, single center, clinical trial. Methods: Infants with obstructive HCP were randomly allocated to each intervention group (ETV/CPC or VP shunt). They were monitored for at least 6 months for any sign of raised intracranial pressure (rICP). The recurrence of rICP signs requiring surgical intervention was considered as intervention failure. Statistical Analysis: The association between intervention group and outcome was tested with Chi-square test, and P = 0.05 or less was considered statistically significant. Results: Of the total fifty patients entering the study, 49 were included in the final analysis, 27 of them were in VP shunt and 22 in ETV/CPC group. Seventeen patients (34%) were female and 33 (66%) were male with mean age of 3.74 +/- 3.1 months (range = 10 days - 11 months). Thirty-nine (79.6%) were under 6 months of age and the remaining were 6 months or older. The overall success rate in 36-month follow-up was 88.5% and 68.2% for VP shunt and ETV/CPC, respectively, with the difference being not statistically significant. Conclusion: The current study determined no inferiority of ETV/CPC compared to VP shunt, and therefore, it may become an efficient treatment for obstructive HCP in infants. PMID- 30459865 TI - Type I Spinal Arteriovenous Fistula with Ventral Intradural Venous Drainage: A Proposal of a Modified Classification. AB - Objectives: Spinal arteriovenous fistula (AVF) is the most common spinal vascular lesion and constitutes an abnormal communication between a feeder artery and a draining vein. Arterialization of the venous plexus leads to venous hypertension; consequent edema and congestion of the spinal cord are associated with progressive neurological decline. Patients and Methods: In this report, we describe two unique cases of type I cervical spinal AVF, in which a radiculomeningeal artery forms an intradural fistula that drains into the ventral venous plexus. Results: Both patients underwent surgical obliteration of the fistula with complete occlusion confirmed on postoperative angiography. Conclusion: Both cases do not fit into the current classification scheme. A modified classification is proposed. PMID- 30459866 TI - Outcome of Decompressive Craniectomy in Traumatic Closed Head Injury. AB - Objective: The aim of the current study was to observe functional outcomes of patients undergoing decompressive craniectomy (DC) for raised intracranial pressure (ICP) after blunt head injury and to assess possible predictive factors. Methodology: This study was a prospective cohort study which was conducted at Aga Khan University Hospital, Karachi over a period of 2 years (January 2015-December 2016). Adult patients, aged between 15 and 65 years of both genders undergoing DC during the study period were selected. Outcomes of DC were assessed at an interval of 3 months following injury using the Glasgow outcome score. The data were analyzed on IBM statistics SPSS version 21. Results: Seventy-two patients underwent DC for raised and refractory ICP. Glasgow Outcome Scale (GOS) at discharge, 1-month and 3-month follow-up were reported. GOS at 3-month follow-up showed 21 patients (29.2%) patients had a good recovery, moderate disability was reported in 16 patients (22.2%), and severe disability in 12 patients (16.7%), persistent vegetative state was seen in five patients (6.9%). Eighteen patients had in hospital mortality (25.0%). Tracheostomy and sphenoid fractures were found to be negative predictors of good functional outcome. Conclusions: DC is associated with an in hospital mortality of 25.0%. Favorable outcomes were seen in 51.4% patients. Tracheostomy and sphenoid fractures were negative predictors of good functional outcome. The results are comparable to international literature. PMID- 30459867 TI - Preemptive Effect of Intraurethral Instillation of Ketamine-lidocaine Gel on Postoperative Catheter-related Bladder Discomfort after Lumbar Spine Surgery. AB - Background: Catheter-related bladder discomfort (CRBD) is one of the main reasons of agitation after surgery, leading to urgency and frequency during recovery. Ketamine has been used as an effective drug for reducing the signs and severity of this problem. We hypothesized that intraurethral instillation of ketamine lidocaine gel before urinary catheterization can reduce the incidence of CRBD in the postoperative period. Materials and Methods: A total of 136 male patients, who underwent two-level laminectomy/discectomy were enrolled in this randomized clinical trial. Patients were randomized into the two groups before urinary catheterization. The ketamine group received urethral lubrication with 5 mL xylocaine jelly (2%) in conjunction with 2 mL (100 mg) ketamine. Patients in control group received urethral lubrication with 5 mL xylocaine jelly (2%) in conjunction with 2 mL distilled water. The primary outcome was the incidence of CRBD. CRBD was assessed using four-stage criteria when arriving in the recovery room and at 1, 2, and 6 h after surgery. Postsurgical pain and the number of sedatives given and opioid requirement were also the secondary outcomes in this study. Results: Intraurethral instillation of ketamine-lidocaine gel reduced the incidence of CRBD at recovery (P < 0.001) along with a reduction in the severity of CRBD (P < 0.05) during the 1st and 2nd visit compared with control group. The mean pain intensity score (visual analog scale) and opioid requirement to relieve postsurgical pain were lower in the ketamine group during all the study timepoints from recovery and after transfer to the ward (P < 0.008). A higher rate of sedation (72% vs. 11%) also was seen at recovery period in the ketamine group (P < 0.008). Conclusion: Intraurethral instillation of ketamine-lidocaine gel before bladder catheterization is an effective technique for reducing the incidence and severity of postoperative CRBD. PMID- 30459869 TI - Cochlear Implant Device Failure in the Postoperative Period: An Institutional Analysis. AB - Introduction: As the cochlear implant (CI) surgeries are on rise, there is a compelling need to understand its long-term complications and revision surgery protocols. Our experience in the management of CI devices failure is shared in this paper. Aim: To review the experience in patients who underwent CI device manipulation/explanation in terms of failure rate, etiology, surgical considerations, and preoperative and postoperative auditory and speech outcome. Study Design: This was a retrospective study. Materials and Methods: A retrospective study of 250 patients (201 children and 49 adults) with normal cochlea at a tertiary care center from June 2004 to June 2014 was done. All cases were implanted multichannel devices via Veria technique of CI surgery. Preoperative assessment, surgical considerations, and postoperative auditory and speech outcomes were analyzed. Preoperative and postoperative auditory/speech outcomes were analyzed using Category of Auditory Perception (CAP) and Speech Intelligibility Rating (SIR) scores. Results: Reimplantation rate was 4%. The causes of revision CI surgery were hard device failure (n = 3), surgical site infection (n = 3), magnet displacement (n = 2), and electrode extrusion (n = 2). In one patient, recurrent cutaneous infection on the implanted site ultimately resulted in reimplantation in the opposite ear after multiple surgical interventions on the same side. The preoperative and postoperative CAP and SIR scores showed improvement in the postoperative period with P < 0.05 as compared with the paired t-test. Conclusions: Preoperative counseling for device failure should always be emphasized. The success rate is high in revision surgery with good performance in the postoperative audiological outcome. There is a compelling need for an agreed international definition of CI failure and the adoption of uniform reporting protocols. PMID- 30459870 TI - Endoluminal Shuntscope-Guided Ventricular Catheter Placement: Early Experience. AB - Background: Placement of ventricular catheter (VC) in an optimal position is the most important factor in determining the outcome of shunt surgery. VC obstruction due to shunt tube placement in brain parenchyma, across the septa, tangled in the choroid plexuses and clogging of VC due to brain matter or other debris are common reasons resulting in shunt complete or partial dysfunction. To resolve these hurdles, many technical advancements have been made including navigation, stereotaxy, sonography, and ventriculoscope-guided VC placement. Objective: To report early experience, technique, and result of placing VC with shuntscope. Methods: We are publishing our experience of shuntscope-guided ventriculoperitoneal shunt in 9 cases done from June 2015 to April 2016. Shuntscope is a 1 mm outer diameter semi-rigid scope from Karl Storz with 10000 pixel of magnification. It has a fiber optic lens system with camera and light source attachment away from the scope to make it light weight and easily maneuverable. Results: In all cases, VC was placed in the ipsilateral frontal horn away from choroid plexuses, septae, or membranes. Septum pellucidum perforation and placement to opposite side of ventricle was identified with shunt scope assistance and corrected. Conclusion: Although our initial results are encouraging, larger case series would be helpful. Complications and cost due to shunt dysfunction can thus be reduced to a great extent with shuntscope. PMID- 30459868 TI - Study of Fatigue and Associated Factors in Traumatic Brain Injury and Its Correlation with Insomnia and Depression. AB - Introduction: Fatigue has been cited as a common problem associated with traumatic brain injury. A positive association of fatigue has been suggested with insomnia and depression which are also considered to be significantly associated with traumatic brain injury. Aims and Objectives: The present study in post traumatic brain injury patients is planned to assess the prevalence of fatigue, depression and insomnia, the correlation of fatigue with depression and insomnia and the risk factors associated with fatigue. Material and Methodology: Total 100 patients were recruited in the present study. Interview was focused on assessment of severity of traumatic brain injury, fatigue, insomnia and depression using Glasgow Coma Scale, Fatigue Severity Scale, Insomnia Severity Index and Patients Health Questionnaire(PHQ-9) respectively. Results: Prevalence of depression was found 84% while that of fatigue and insomnia was 50% and 49% respectively. All patients with fatigue had depression whereas those patients without fatigue were also found to have depression (68%) and this correlation was found statistically significant. Similarly, insomnia was reported in 70% of patients who were fatigued against 28% of patients with no fatigue. This was also found statistically significant (P <0.0002). Conclusion: Fatigue in common in post TBI patients. Insomnia and depression are closely associated with fatigue. Clinical and research investigations of fatigue in post-traumatic brain injury should include concomitant screening for treatable depressive symptoms and sleep disorders. PMID- 30459871 TI - Role of Diffusion-weighted Imaging in Detecting Early Ischemic Brain Injury Following Aneurysmal Subarachnoid Hemorrhage. AB - Background: Aneurysmal SAH is the significant cause of morbidity and mortality in stroke patients. Early brain injury and delayed cerebral ischemia are the two main responsible pathophysiologic processes. Cerebral ischemia needs to be detected early so that early aggressive therapy could be started. Although Diffusion weighted imaging (DWI) has often been utilized for the measurement of acute ischemic strokes, its role in the detection of early cerebral ischemia due to aneurysmal subarachnoid hemorrhage has not been extensively investigated. This study is being carried out to describe the role of DWI in detecting early ischemic brain injury and outcome after aneurysmal SAH. Aim: Efficacy of DWI in detecting ischemic injury and predicting outcome after aneurysmal SAH. Material and Methods: In this prospective study 44 consecutive patients who had aneurysmal SAH; admitted within 7 days of their ictus were included. Hunt and Hess grade on admission and modified Fisher grade of SAH were noted. Plain CT brain and MR DWI was done on day before surgery. Diffusion restriction on DWI was correlated with postoperative neurological deficit, postoperative CT finding and outcome of the patient at 1 month follow-up. Results: DWI revealed restricted diffusion in 12 patients, out of which 1 patient was having infarction in preoperative CT scan, 6 patients were having postoperative deficit in the form of disorientation, hemiparesis and aphasia, and all patients were having infarction in postoperative CT scan. When DWI findings were compared on the basis of postoperative neurological deficit, postoperative CT finding and modified Rankin outcome score at 1month follow-up, results were statistically significant. Conclusion: DWI shows cerebral ischemia much earlier than CT scan in cases of aneurysmal SAH. It has significant correlation with postoperative neurological status and outcome of the patient. PMID- 30459872 TI - Evaluation of the Correlation of Magnetic Resonance Imaging and Electrodiagnostic Findings in Chronic Low Backache Patients. AB - Background: Low back pain (LBP) is one of the most common medical complaints and leading cause of workforce loss in many countries. Magnetic resonance imaging (MRI) is a highly sensitive method for the detection of lesions in the spine because of its excellent imaging of anatomical detail. However, MRI does not provide information about physiological nerve function and has relatively low specificity. Electrodiagnostic (EDX) study, including needle electromyography (EMG), is a specific test to assess the physiological functions of nerve roots or peripheral nerves. The aim of the present study was to correlate the electrophysiological and MRI findings in chronic low backache patients. Materials and Methods: Fifty patients (26 males and 24 females) with mean age 33.54 +/- 8.33 years with a history of LBP of minimum 3 consecutive months were evaluated with MRI and EDX (bilateral nerve conduction study of three nerves [tibial, peroneal, and sural nerve] and bilateral EMG of three muscles [paraspinal, tibialis anterior, vastus medialis]) studies. Results: Twenty-seven patients showed disc involvement on MRI and 23 MRI were normal. Mean conduction velocity was mildly decreased in tibial and sural nerves in all the patients either with normal MRI or disc involvement on MRI. In disc involvement conduction velocity, decrease was more as compared to normal MRI. About 39% patients with normal MRI and 78% patients with disc involvement showed abnormal EMG. This data represented statistically significant association of EDX study with MRI (P < 0.05). Conclusions: In patients with LBP, EDX studies are significantly more correlated with clinical data than MRI. Therefore, EMG may be a useful diagnostic tool to establish management protocols and prevent unnecessary interventions. EDX gives a better representation of physiological status of nerve and muscle, a supra added benefit which MRI lacks. However, MRI gives better visualization of anatomic parameters and structural details which may or may not be associated with chronic LBP. PMID- 30459873 TI - Epidemiology of Spinal Injury in North East India: A Retrospective Study. AB - Aim: To find out the epidemiology of spinal injury in North East India. Material and Methods: This study is a retrospective hospital-based analysis of spine injury patients admitted to Central Referral Hospital, Sikkim Manipal University from July 2013 to June 2017July 2013 to June 2017. Results: During the study period 57 patients with spinal injury were admitted and treated. Out of the 57 patients, 46 (81%) were male and 11 (19%) were female. The most common mode of injury was fall from height (59.64%) followed by RTA (35.08%). Most common affected age group in this study was 20-39 years followed by 50-59 years age group. Cervical spine injury was the most common (52.63%) followed by thoracic (19.29%) spine. Most common injury found was fracture dislocation of C5-C6 level. Most common associated injury is head trauma (10.52 %) followed by chest injury and 82.45% cases had no associated trauma. Average period of hospital stay was 22.83 days with maximum period of stay was 111 days. During treatment period one patient died due to respiratory complications. Conclusion: The epidemiology of spinal injuries in Sikkim & North Eastern India is different from rest of the India and other developing countries. In present study most common cause of spine injury was fall from height followed by motor vehicle accidents. RTA was the main cause in younger age group and fall from height was more common in elderly group. PMID- 30459874 TI - Outcome of Posttraumatic Delayed Intracerebral Tension Pneumatocele: Prospective Study of Four Cases: Single Institutional Experience. AB - Aim: Delayed intracerebral tension pneumatocele (DITP) is an uncommon cause of raised intracranial pressure following trauma. However, it can cause herniation syndrome due to a sudden increase in intracranial pressure which requires emergent intervention. Pneumocephalus is a complication of head injury in 3.9% 9.7% of the cases. The accumulation of intracranial air can be acute (<72 h) or delayed (>=72 h). Method: When intracranial air causes intracranial hypertension and has a mass effect with neurological deterioration, it is called tension pneumocephalus. In our case series, we demonstrated four cases of DITP in adult patients from January 2012 to January 2017 in the Department of Neurosurgery at R. N. T. Medical College and M. B. Hospital, Udaipur, Rajasthan. Result: During this period, a total number of patients admitted of head injury are 1768 and hence, the incidence of DITP in our series is 0.226% which is very less as compared to previous literature. All patients are male; age ranging from 17 years to 55 years (mean age was 31.75 years). All patients have a history of head injury, and mode of injury had road traffic accidents. Glasgow Coma Score (GCS) at readmission were 12-13 (mean GCS 12.75). Duration of developed DITP 1 month to 21/2 months (mean 1.375 months), all patients had gone to surgical intervention, and outcome assessed using Glasgow outcome score. All patients had a good outcome and average follow-up was 12.5 months. Conclusion: long term observation of patients with simple pneumocephalus following trauma is beneficial as there is an expected risk of developing delayed tension pneumocephalus which may manifest with raised intracranial pressure. PMID- 30459875 TI - Comparison of Phenytoin versus Levetiracetam in Early Seizure Prophylaxis after Traumatic Brain Injury, at a Tertiary Care Hospital in Karachi, Pakistan. AB - Aims: The aim of the study was to compare the efficacy of phenytoin and levetiracetam for seizure prophylaxis in patients with severe traumatic brain injury (TBI). Subjects and Methods: A randomized controlled trial was conducted over a period of 6 months, at a tertiary health care center in Karachi, Pakistan. Patients with TBI were divided into two groups. Patients in Group A were given phenytoin, whereas Group B patients received levetiracetam. The first dose of the drugs was given within 24 h of injury and continued for 7 days. Data were collected using a predesigned pro forma. All the patients who were in a state of persistent coma, had altered mental status, or had clinical signs of seizures underwent a 1-h electroencephalographic (EEG) recording to observe the seizures, the first EEG was done on the 1st day posttrauma and a second one was done on day 7 of drug use, both the EEGs were compared for changes. We also analyzed the patients according to their duration of antiepileptic drug therapy, length of hospital stay, and complications during therapy. Results: One hundred and forty (117 males and 23 females) patients who presented with TBI having a mean age of 29.48 +/- 16.24 years were part of the study. The most prevalent cause of brain injury was road traffic accidents in 72.85% patients. There was no significant relationship between the antiepileptic drug used with the initial EEG (P = 0.313) and seizure activity (P = 0.502). However, a significant correlation of the antiepileptic drug used was found with EEG (P = 0.002) and seizure activity (P = 0.014) on follow-up. Patients who took levetiracetam had decreased the incidence of abnormal EEG and seizure activity on follow-up. There was not any correlation between GCS both initially (P = 0.845) and on follow-up (P = 0.104) with the antiepileptic drug used. Conclusion: The incidence of abnormal EEGs and seizure activity in patients with TBI is the same for both levetiracetam and phenytoin for the initial 7 days post-TBI; however, the incidence of seizures is lower for patients who used levetiracetam on the subsequent follow-up. PMID- 30459876 TI - Spinal Cord-derived Neural Precursor Cells as a Preventive Therapy for Spinal Cord Injury. AB - Background: Spinal cord injury (SCI) as one of the most important diseases of central nervous system (CNS) without any definite treatment is still growing in incidence. In addition to trauma, some surgeries such as cardiac and thoracic aorta surgery may result in SCI as a complication. In last years, a promising approach has shed light on this CNS injury thanks to stem cell technology. Stem cell therapy could be considered as a good candidate for transplantation and enhancing neural regeneration in SCI. In this study, we identified the effects of spinal cord-derived neural precursor cells (NPCs) transplantation on SCI in after and before injury injection. Materials and Methods: NPCs were isolated from the adult rat spinal cord and cultured in vitro using complete culture media. After neurosphere formation, the cells were differentiated to neurons, oligodendrocytes, and astrocyte. The cells were transplanted to the rat model of SCI in 1 day before and 1 day after injury. The animals were followed for 12 weeks to assess their neurological performance. In addition, histological study and inflammatory cytokines levels have been studied. Results: Our results indicate that NPCs infusion both pre- and post-SCI could decrease the level of inflammatory cytokines. In addition, the neurological performance and histologic studies showed recovery after this type of injury using NPCs, and it might be due to inflammation modulatory effects on neural stem cells. Conclusion: NPCs therapy for SCI in both two-time points (before and after SCI) could be beneficial and make a neurological recovery. In other words, NPCs therapy could be considered as a therapeutic and also preventive approach for SCI. PMID- 30459877 TI - Does Age Affects the Surgical Outcome in Patients with Unruptured Cerebral Aneurysms? A 2-Year Retrospective Study from a Single Center in Japan. AB - Background: The management of unruptured cerebral aneurysms (UCA) in elderly population is a challenge. With a very high life expectancy and high risk of rupture in Japan, the need for identifying the best treatment modality is essential to help the patients in decision-making. Methods: This was a 2-year single-center retrospective comparative analysis of the outcomes of surgical clipping (SC) in patients aged above 75 and <75 years. The modified Rankin score was used to stratify the patients and to analyze the functional outcome. Functional status at discharge was the primary end point. Results: There were 224 patients with 239 aneurysms. About 12.5% of the patients were more than 75 years with a mean age of 77.85. The mean age of patients <75 years was 60.96, and it was statistically significant. The overall male-to-female ratio was 1:3.3. The most common location was the middle cerebral artery followed by internal carotid artery at the posterior communicating and ophthalmic segments, and 22 patients had aneurysms of the posterior circulation. Nearly 77% of the aneurysms were <6 mm. There was no significant difference in size of the aneurysm as the age increased to more than 75 years. There were complications in 6 patients, and there was no mortality in the study population. There was no statistically significant difference in the outcome between the groups. Conclusions: SC can be considered a safe option for UCA in the aging population. PMID- 30459878 TI - Pediatric Intracranial Tumors over a 5-Year Period in a Tertiary Care Center of North Kerala, India: A Retrospective Analysis. AB - Background: Pediatric brain tumors are unique in terms of distribution, clinical presentation, pathologic types, management, and prognosis. There are not many studies from India which have looked into the epidemiology of pediatric brain tumors. Aims: This study aimed to analyze the epidemiology of pediatric brain tumors in North Kerala and compare it with data from the rest of India and other countries. Materials and Methods: This is a retrospective study of 5-year data of pediatric brain tumors which were operated in a tertiary referral center in North Kerala, India, from 2009 to 2013. The data were procured from the departments of neurosurgery and pathology of the institution. The data were tabulated and analyzed using SPSS software. Results: A total of 71 children had histologically proven brain tumors during the 5-year period. There were 34 boys and 37 girls. Distribution in different age groups was as follows: infancy -5 (7%), 1-5 years 22 (31%), 6-10 years - 21 (29.6%), and 11-18 years - 23 (32.4%). The most common tumors were primitive neuroectodermal tumors (PNETs). In infancy, the number of high-grade tumors was more, whereas in the 11-18 years' age group, there were a significantly higher number of low-grade tumors (P = 0.04). Discussion: Pediatric brain tumors were distributed almost equally in both sexes. PNET was the most common. We could not get statistical significance in many of our values due to small sample size. Conclusion: This study highlights the need for diligent collection of data and maintenance of a registry for brain tumors to study the disease in the Indian population. PMID- 30459879 TI - Clinical and Radiological Outcomes of Day-care Posterior Foraminotomy and Decompression of the Cervical Spine. AB - Purpose: Anterior cervical procedures are associated with many intra- and post operative complications leading to long-term patient morbidity. In this study, we have evaluated the clinical and radiological Outcome of day care posterior cervical foraminotomy in patients with single-level cervical radiculopathy with or without neurodeficit. Materials and Methods: Seventeen patients underwent single-level posterior cervical foraminotomy for radicular symptoms were studied between June 2011 and May 2016. Clinical outcome was studied by visual analog scale (VAS) score, neck disability index (NDI), and Odom's criteria. Adjacent segment degeneration was evaluated on lateral cervical radiograph at every follow up by calculating the focal and global angulation of the cervical spine and disc height at the operated level and adjacent segments. Dynamic lateral cervical spine radiograph was done to evaluate segmental instability. Results: After a mean follow-up duration of 30.64 months, 13 patients had excellent, three patients had good, and one patient had fair outcome as per Odom's criteria. The mean VAS score for radicular pain, neck pain, and NDI was significantly reduced postoperatively (P < 0.001). The mean focal angulation, mean global angulation, the disc height at operated and adjacent level were not changed significantly (P > 0.05). There was no instability noted postoperatively on lateral dynamic cervical spine radiographs. There was no complication in our study. Conclusion: Posterior cervical foraminotomy is an effective surgical method for treatment of patients with single-level cervical radiculopathy and helps to achieve good clinical and radiological outcome, prevents postoperative adjacent segment degeneration and instability with minimal complications. PMID- 30459880 TI - Comparative Study of Derangement of Coagulation Profile between Adult and Pediatric Population in Moderate to Severe Traumatic Brain Injury: A Prospective Study in a Tertiary Care Trauma Center. AB - Object: Coagulopathy is a common occurrence following traumatic brain injury (TBI). There are various studies showing incidence and risk factors of coagulopathy and their correlation with poor outcome in adult as well as paediatric age groups. Exact incidence, associated risk factors, treatment guideline for coagulopathy and its impact on outcome are still lacking. In our study we compared the adults and paediatric age groups TBI patients for incidence and risk factors of coagulopathy and its impact on outcome. Methods: Prospective study of 200 patients including 152 adult patients (age > 18 years) and 48 paediatric (Age < 18 years) patients of TBI admitted in intensive care unit of trauma centre of a tertiary care centre was performed from august 2015 to march 2016. Both population were further subdivided into moderate TBI and severe TBI as per Glasgow coma score (GCS). Patient with long bone injury, chest injury and abdominal injuries, coagulation disorder, liver disease, medical disease like diabetes mellitus and hypertension were excluded from study. Coagulation profile were compared in the both groups (Adult and paediatric) and correlated with the outcome. Chi- Square test, student t test and Odds ratios were used for statistical analysis. Results: Mean age among the adult and paediatric population were 37.89 +/- 11.88 years and 11.41 +/- 5.90, respectively. Among the patient with moderate TBI, coagulopathy was seen in 30% patients of adult TBI whereas it was 12.5% among the paediatric TBI (P = 0.185). Among the severe TBI group coagulopathy was observed in 68.03% and 37.5% of adult and paediatric age group respectively (P = 0.0016). There was significant correlation found between midline shift and coagulopathy in the paediatric age group (P = 0.022; OR - 4.58). E. There was significant association of coagulopathy and contusion on CT scan among the adult population (P = 0.007; OR - 3.487) found whereas no such correlation were observed in paediatric population. Conclusion: Coagulopathy was significantly higher among the adult patient with severe TBI as compare to paediatric patient with severe TBI. There was no statistically significant difference in mortality among patients of both the age groups with coagulopathy. PMID- 30459881 TI - Laminectomy Versus Laminoplasty in the Surgical Management of Long-Segment Intradural Spinal Tumors: Any Difference in Neurological Outcomes? AB - Background: Previous comparative studies have shown that apart from lack of any significant difference in neurologic outcomes between laminoplasty and laminectomy following resection of intradural spinal tumours, spinal column issues such as postoperative deformities, malalignment, and adjacent level disease have also been clearly demonstrated to be quite similar for both techniques. However, there is no study yet that describes any difference in neurologic outcomes for long-segment intradural lesions as a rare subset of these lesions (in terms of number of spinal segments involved) following surgical management between these two techniques. Materials and Methods: This is a retrospective review of surgical treatment with either laminectomy or laminoplasty done for patients with long-segment intradural tumors at a tertiary health-care institution in India. Results: Out of over 167 patients surgically treated for intradural tumors during the study period, a total of 60 patients were included in the evaluation. The long-segment tumors were intramedullary in 22 (36.7%) patients and intradural-extramedullary in the remaining 38 (63.3%) patients. No patient in both cohorts had any revisional surgery after initial resection or any serious complications. The incidence of neurologic function remaining unchanged at the end of follow-up was similar between laminoplasty and laminectomy (12.5% vs. 11.1%). There was no significant correlation between the preoperative McCormick score and postoperative McCormick score (P > 0.05 at 95% degree of confidence; Spearman's rho = 0.028), suggesting that functional outcomes were not dependent on the initial neurologic status. Multivariate logistic regression analysis showed that : the two independent variables (Extent of surgery and Choice of procedure) were not significant predictors of the dependent variable (Functional outcome following surgery) (odds ratio = 3.836; p = 0.071). Conclusion: This retrospective evaluation demonstrates laminoplasty not to be more or less likely to have any better functional outcome or need for revision compared to laminectomy in the resection of long-segment intradural lesions. A quality randomized controlled study on a much larger scale will be required to validate this finding. PMID- 30459882 TI - Proposal of Treatment Strategies for Bilateral Chronic Subdural Hematoma Based on Laterality of Treated Hematoma. AB - Background: Chronic subdural hematoma (CSDH) is a disorder that is commonly seen in routine neurosurgery. Although risk factors for recurrence have been studied, the findings are inconsistent. Furthermore, bilateral CSDHs are operated unilaterally or bilaterally depending on symptoms or hematoma volume. Although there are cases in which hematomas on nonoperated side in unilaterally operated bilateral CSDHs requiring for additional operation, little have been studied on the effect of the surgical selection. The purpose of this study is to identify risk factors for recurrence in operated hematomas and additional operation in nonoperated hematomas and improve surgical strategy. Materials and Methods: We retrospectively reviewed patients who underwent surgery in our facility for bilateral CSDHs between January 2011 and December 2016. Univariate and multivariate analyses were performed to examine the relationship between recurrence or requirement for additional operation and clinical and radiological variables. Results: Recurrence was observed significantly more frequent for operated hematomas when hematoma type was separated type as reported previously. In unilaterally operated bilateral CSDHs, there were 22 hematomas on nonoperated side, and five hematomas required an additional operation after the first hospitalization. Increased volume of hematoma on the nonoperated side was the risk factors for additional operation (P = 0.022). Receiver operating characteristic (ROC) curve revealed that requirement for additional operation significantly increased when hematoma volume enlarged to approximately 44 cm3 or greater 1 day after operation. Conclusions: In unilaterally operated bilateral CSDHs, when hematoma volume on nonoperated side increased 1 day after the last operation, additional operation in the early stage is considerable to prevent re hospitalization and deterioration of activities of daily living. PMID- 30459883 TI - A Randomized Study Comparing Endoscopic Third Ventriculostomy versus Ventriculoperitoneal Shunt in the Management of Hydrocephalus Due to Tuberculous Meningitis. AB - Objectives: The objective of this study was to compare safety and efficacy of endoscopic third ventriculostomy (ETV) versus ventriculoperitoneal (VP) shunt in the treatment of hydrocephalus in tuberculous meningitis (TBM) and to assess clinical and radiological profiles of patients with TBM that would be better suited to either VP shunt or ETV. Methods: This study was a single-center randomized prospective study on 52 patients with TBM hydrocephalus in the pediatric age group (<18 years of age). Patients included in the study were randomized into undergo either VP shunt or ETV. Both groups were followed up for a minimum of 5 months and assessed for success and failure rates as well as procedural complications and neurologic sequelae. Results: Twenty-six patients underwent ETV with a success rate of 65.4% with six of nine failures occurring within the first 16 days after surgery (median time to failure - 3 days). In the VP shunt group, there was a success rate of 61.54% and a median time to failure of 50 days. Modified Vellore grading was found to be a significant factor in determining outcome in both ETV and VP shunt groups with high-grade TBM consistently associated with poor outcome (odds ratio = 4.2). Conclusions: ETV can be performed effectively in young children including infants, as well as those with communicating hydrocephalus, high cerebrospinal fluid (CSF) cell counts, and protein levels with a lower rate of failure than that of VP shunt. Hence, ETV should be attempted as the first-choice CSF diversion procedure in hydrocephalus secondary to TBM where technical expertise and experience with this procedure is available as it avoids the myriad of lifelong complications associated with shunts. PMID- 30459884 TI - Multimodality Techniques in Microsurgical Clipping as the Gold Standard Treatment in the Management of Basilar Tip Aneurysm: A Case Series. AB - Introduction: Basilar aneurysms represent 5%-7% of all intracranial aneurysms. The main goal of open surgery is to achieve complete obliteration of the aneurysmal sac using minimal invasive technique while emphasizing on avoidance of complication. Materials and Methods: We performed a retrospective cohort study of nine cases of unruptured basilar tip aneurysm referred to the Fujita Health University Banbuntane-Hotokukai Hospital, Japan. The objective of the study was to analyze the surgical outcomes of unruptured basilar tip aneurysm. Results: Nine patients with unruptured basilar tip aneurysm were referred to our hospital between 2015 and 2017. The median size of the aneurysm and age were 4.00 mm (interquartile range [IQR] = 3.25-6.75 mm) and 58 years (IQR = 54-70 years), respectively. Five patients (55.6%) were presented with multiple intracranial aneurysms. Surgical adjuncts such as intraoperative neuromonitoring, intraoperative indocyanine green (ICG) angiography with dual-image videoangiography (DIVA), and neuroendoscope were used. Two patients developed transient postoperative oculomotor nerve palsy which resolved spontaneously. The median duration of surgery and days of hospitalization were 292 min (IQR = 237.5 350.5 min) and 12 days (IQR = 12-25 days), respectively. There was no mortality recorded in this case series. Conclusion: Microsurgical clipping of basilar tip aneurysm is safe in unruptured basilar tip aneurysm with a low risk of postoperative mortality or morbidity. All complications reported in this case series were transient with no long-term sequalae. The improved safety profile of microsurgical technique is due to the availability of intraoperative neuromonitoring, neuroendoscope, ICG, and DIVA. The application of multimodality technique in neurovascular surgery has also helped to achieve complication avoidance. The obliteration of the aneurysmal sac helps to restore the laminar blood flow in the bifurcation and distal blood vessels and improves the brain perfusion. PMID- 30459885 TI - The Optimal Operative Timing of Traumatic Intracranial Acute Subdural Hematoma Correlated with Outcome. AB - Objective: Acute subdural hematoma (ASDH) has been associated with mortality in traumatic brain injury. The timing of surgical evacuation for ASDH has still been controversial. The object of this study was to determine the temporal and clinical factors associated with outcome following surgery for ASDH. Materials and Methods: The study retrospectively viewed medical records and neuroimaging studies of ASDH patients who underwent surgical evacuation. Surgical outcomes were dichotomized into favorable and unfavorable outcomes, and operative times compared between the groups. Results: The records of 145 ASDH patients who underwent surgery were reviewed. Almost two-thirds of the patients were admitted for surgical evacuation, of whom 71% underwent a decompressive operation. The temporal variables were as follows: mean time from scene of accident to emergency department (ED) was 70 (Standard deviation [SD] 256.0) min, mean time from ED to obtaining CT of the brain was 45.6 (SD 38.9) min, mean time from brain computed tomographic to operating room arrival was 68.6 (SD 50.0) min, and mean time from ED arrival to skin incision was 160.1 (SD 88.1) min. The mean time from ED arrival to skin incision was significantly shorter in the unfavorable outcome group. Because of this reverse association between time from ED to surgery, multivariate analysis was applied to adjust the timing factors with other clinical factors, and the results indicated that temporal factors were not associated with functional outcome, as features such as increased intracranial pressure due to obliterated basal cistern and brain herniation were significantly associated with functional outcome. Conclusions: The optimal times for surgical evacuation of ASDH are challenging to estimate because compressed brainstem signs are more important than time factors. ASDH patients with compressed brainstem should have surgery as soon as possible. PMID- 30459886 TI - Surgical Strategies for Ruptured Complex Aneurysms Using Skull Base Technique and Revascularization Surgeries. AB - Object: Surgical clipping of paraclinoid aneurysm, thrombosed large aneurysm, and/or vertebral-basilar dissecting aneurysms can be very difficult and has relatively high morbidity. We describe our experience using skull base and bypass technique and discuss the advantages and its pitfalls. Patients and Methods: We retrospectively reviewed medical charts of 22 consecutive patients with complex aneurysmal lesions underwent skull base and/or bypass techniques between March 2012 and April 2017. Results: There were 5 patients with paraclinoid or internal carotid artery (ICA) aneurysm underwent modified extradural temporopolar approach with mini-peeling of the dura propria with suction decompression, 3 patients with ICA aneurysm underwent intradural anterior clinoidectomy, 12 patients with vertebral dissecting aneurysm through transcondylar fossa approach (6 patients underwent occipital artery-posterior inferior cerebellar artery [OA-PICA] bypass), 1 patients with vertebral artery dissection underwent superficial temporal artery-superior cerebellar artery and OA-PICA bypass through posterior transpetrosal approach, 1 patient with arteriovenous fistula at the ventral side of the craniovertebral junction through extremely far lateral approach. Surgical outcome was good recovery in 10 patients, moderate disability in 4, severe disability in 4, vegetative state in 2, and dead is 2 patients. The favorable outcome was 63.6%, and poor outcome was 36.4%, which showed poor grade subarachnoid hemorrhagic patients. No patient suffered any complication related to re-rupture and/or incomplete clipping. Conclusion: Skull base technique, which can create a wide and shallow operative space, allowed us to improve surgical outcome and to reduce the risk of intraoperative neurovascular injury for surgical treatment of deeply located complex aneurysms. PMID- 30459887 TI - Adverse Event with the Use of Carmustine Wafers and Postoperative Radiochemotherapy for the Treatment of High-grade Glioma. AB - Randomized, controlled trials have shown significant improvement of survival after implantation of 1,3-bis(2-Chloroethyl)-1-nitrosourea (BCNU) wafers for patients suffering from high-grade glioma. A combination of local chemotherapy with BCNU and concomitant radiochemotherapy with temozolomide (TMZ) appears to be attractive to enhance the overall survival, even though these treatments may potentially cumulate their toxicity. We report a clinical case of a patient submitted to this combined treatment protocol. Severe brain edema and a cystic formation in the surgical cavity rapidly developed. Data supporting the use of Gliadel(r) combined with TMZ comes from small retrospective studies, and some series have shown a very high rate of adverse events (AEs) when this multimodality treatment is applied. Combined protocols of local and systemic chemotherapy might provide survival benefits, although AEs seem currently underestimated. PMID- 30459888 TI - Armored Brain Associated with Secondary Craniostenosis Development at 7-year following Ventriculoperitoneal Shunt Surgery during Infancy: Extremely Unusual Association and Review. AB - Calcification is uncommon in chronic subdural hematoma and popularly known as calcified chronic subdural hematoma (CSSDH), and about hundred cases are reported in the form of isolated cases report. The calcified inner membrane of chronic subdural hematoma gets adherent to underlying cerebral cortex preventing re expansion of the brain and producing mass effect. Calcification can develop in chronic subdural hematoma of traumatic origin or postmeningitic effusion or extremely rarely after shunt surgery. CCSDH is also known as armored brain or Matrioska head and those related to cerebrospinal fluid diversion ventriculoperitoneal (VP) shunt surgery, constitute one of the rare complications of shunt, and development is attributed to overdrainage of shunt. Authors report a unique case with bilateral calcified chronic subdural hematoma in an 8-year-old boy, who had VP shunt surgery for obstructive hydrocephalus at the age of 1 year of life, presented with feature of nonlocalized raised intracranial pressure; a diagnosis of suspected VP shunt malfunction was also considered; however, cranial computed tomography scan on current admission revealed the presence of bilateral calcified chronic subdural hematoma with secondary craniostenosis and managed successfully with burr-hole craniostomy and drainage of CCSDH. In a detailed PubMed and Medline search, authors could not get any publication regarding CSSDH associated with secondary craniostenosis developing following VP shunt surgery in infancy. The current case represents the first case in the Western literature developing secondary craniostenosis-associated CCSDH following shunt surgery in infancy, requiring surgical management. The clinical features, neuroimaging, and management of such rare case along with pertinent literature are reviewed briefly. PMID- 30459889 TI - Endoscopic Endonasal Resection of the Odontoid Process in a Patient with Chronic Injury of the C1 Transverse Ligament. AB - Atlas dislocation after transverse ligament injury is one of the most rare types of trauma to the upper cervical level. If magnetic resonance imaging of the craniovertebral junction reveals the Kassam line passing through the cervix of the odontoid process, a transnasal approach can be used for surgical treatment. Here, we present a case in which an endoscopic endonasal approach was used to treat chronic traumatic transligamentous atlas dislocation. A 26-year-old male underwent two-stage surgical treatment; during the first stage, posterior decompression and fixation were performed under halo immobilization. In the second stage, a transnasal endoscopic approach to the odontoid process was used. A transnasal approach permitted complete decompression of the medulla oblongata and facilitated early extubation of the patient without any postoperative complications such as respiratory or pharyngopalatine deficiency. The patient was discharged in good condition 9 days after the surgery. PMID- 30459890 TI - Adult Thoracic Intradural Exophytic Mature Teratoma: Case Report and Literature Review. AB - Mature thoracic intraspinal teratomas are rare tumors in adults. In this case study, we present a case of intradural, extramedullary teratoma, which was surgically resected. A 50 year old man presented with progressive bilateral leg pain, severe myelopathy and weakness. Magnetic Resonance Imaging (MRI) revealed a cystic mass lesion in the T11-12 region region. Microsurgical resection of the tumor using CO2 laser with neuromonitoring was performed. Postoperatively, the patient had a remarkable clinical improvement. Mature spinal teratomas are rare, slow growing spinal tumors. Surgical resection provides excellent recovery, and recurrence rates are low. PMID- 30459891 TI - Angiocentric Glioma: Report of a Rare Case Presenting with Psychosis. AB - Angiocentric glioma (AG), first described in 2005, was included as a distinct entity in the 2007 World Health Organization Classification of Tumors of the Central Nervous System. It is a very rare cerebrocortical tumor mainly affecting children and young adults with a history of intractable partial seizures. The histopathological features of this entity are perivascular arrangement of monomorphic, bipolar spindled cells with subpial aggregation of tumor cells and variable neuroparenchymal colonization. Of uncertain histogenesis, this is a stable/slowly growing tumor. Prognosis following total surgical resection is favorable. We describe an AG in a 16-year-old, intellectually disabled, male patient, with psychosis. This is a rare presentation with only one such case in literature. Patient's symptoms ameliorated following surgery. PMID- 30459892 TI - Pilocytic Astrocytoma with Gangliocytic Differentiation to Pilomyxoid Astrocytoma expanding the Morphological Spectrum: Case Report and Literature Review. AB - We present a rare case of pilocytic astrocytoma (PA) with gangliocytic differentiation arising in the suprasellar/chiasmatic region in a young boy that showed a rapid regrowth after the 1st subtotal resection and "differentiated" into pilomyxoid astrocytoma (PMA) in subsequent recurrences. The clinical course, imaging, and histological features have been described with a review of the literature. While PA is well-circumscribed, biphasic tumors with bipolar piloid cells, those arising in the diencephalic region often contain myxoid stroma, angiocentric pattern, and "intermediate" features between PA and PMA. Examples of PMA "maturing" to PA are also on record; however, PA with gangliocytic component differentiating to PMA has not been described in the literature to the best of our knowledge. PMID- 30459894 TI - Extensive Paraspinal Tuberculosis Masquerading Malignant Tumor in an Elderly Male. AB - Paraspinal tuberculosis is an uncommon manifestation of extrapulmonary tuberculosis, and in rare cases, these lesions can mimic malignant lesions. We report a case of an elderly man where imaging showed extensive left paraspinal lesion which was mimicking malignant neoplasm. The patient underwent L3-L4 unilateral partial laminotomy, there was grayish, relatively avascular lesion in the left paraspinal region, involving the left psoas muscle and going into the neural foramina, and a subtotal resection of the lesion could be performed. However, after biopsy, it turned out to be tuberculoma, and the patient was on antitubercular therapy and doing well. The present case illustrates that extensive involvement of the paraspinal soft tissue and adjacent bony structures on imaging in tuberculosis can mimic malignant tumors. Conservative surgical excision will help in preserving the bony elements and in establishing the diagnosis. PMID- 30459893 TI - Sellar Embryonal Tumor: A Case Report and Review of the Literature. AB - Primitive neuroectodermal tumors (PNETs) are aggressive, poorly differentiated tumors in children and young adults. However, the embryonal tumor group did not include the central nervous system (CNS) PNET title and ependymoblastoma subtitle in the 2016 World Health Organization CNS tumor classification. Here, we report the case of a 6-year-old boy with a sellar embryonal tumor and present a review of the related literature. To the best of our knowledge, this is the first case of an endoscopically operated sellar embryonal tumor in the pediatric age group. PMID- 30459895 TI - Assessment of Primary Brain Lymphoma Using Multimodal Magnetic Resonance Imaging and Proton Magnetic Resonance Spectroscopy. AB - Objectives: The primary lymphoma of the central nervous system is a cancer rare. The diagnosis of this tumoral entity must be considered as an emergency considering the therapeutical involved. Therefore, we report this entity while reporting diagnostic challenges. Patients and Methods: Unfortunately, the conventional clinical and imaging signs can be confusing and might contribute to delay the diagnosis process of potentially curable pathological entity. The diagnosis confirmation in immunocompetent patients is based on a stereotaxic biopsy. Results and Conclusion: In this paper, we report a case illustrating the contribution of multimodal imaging including diffusion-weighted magnetic resonance imaging (MRI), diffusion tensor MRI, perfusion MRI, and proton MR spectroscopy to the diagnostic approach of the atypical primary lymphoma of the central nervous system. PMID- 30459896 TI - Intramedullary Glioblastoma Multiforme of Spine with Intracranial Supratentorial Metastasis: Progressive Disease with a Multifocal Picture. AB - Primary spinal glioblastoma multiforme (GBM) is very uncommon while an intramedullary spinal GBM with intracranial metastasis is rarely heard of. A 23 year-old male presented with bilateral paraplegia associated with bowel and bladder incontinence. Craniospinal radiograph showed an intramedullary spinal mass lesion, for which he underwent laminectomy and histopathology revealed GBM. He received local radiotherapy (RT) with temozolomide (TMZ). While on adjuvant TMZ, he developed severe headache and recurrent episodes of vomiting. Brain and spine imaging showed intracranial mass lesions associated with expansion of the entire cord. Biopsy from the intracranial lesion was confirmed as GBM on immunohistopathology. He was treated with palliative RT to the brain and was put on metronomic TMZ; however, he succumbed to his illness. Review of literature reveals that our case may be the fourth such case in the world and probably the first case reported in India where the intracranial metastatic GBM again presented with a reverse spinal dissemination. PMID- 30459897 TI - Extradural Hematoma Following Decompressive Craniectomy for Acute Subdural Hematoma: Two Case Reports Illustrating Different Mechanisms. AB - The occurrence of extradural hematoma (EDH) after decompressive craniectomy (DC) for traumatic brain injury is uncommon. We report two cases, one developing ipsilateral EDH and another developing contralateral simultaneous EDH and subdural hematoma after DC. The strategies to anticipate the occurrence of such concurrent hematomas (CH) are highlighted. We propose a subclassification of CH into "immediate" and "delayed," based on their difference in clinical presentation, image findings, pathogenesis, and surgical management. PMID- 30459898 TI - A Rare Case of Dumbbell-shaped Primary Intraspinal Peripheral Primitive Neuroectodermal Tumor Involving Thoracic Spinal Epidural Space. AB - Primary intraspinal primitive neuroectodermal tumor (PNET) is a type of round cell malignant tumor which is reported only above 100 in literature. We report a case of epidural thoracic peripheral PNET, discuss its pathological features, radiology, and treatment options. PMID- 30459899 TI - Persisting Embryonal Infundibular Recess Masquerading as a Nasal Mass. AB - Persisting embryonal infundibular recess (PEIR) is a rare anomaly of the development of the posterior pituitary wherein there is a defect in the third ventricular floor. Earlier reports have found PEIR descending only up to the sella. However, this is the first case of PEIR presenting as a pulsatile nasal mass. A 35-year-old female presented to the otorhinolaryngologist with hyposmia. Diagnostic nasal endoscopy revealed a pulsatile nasal mass. Magnetic resonance imaging revealed a cystic lesion extending from the third ventricular floor to the nasal cavity. There was no associated hydrocephalus or empty sella. The case was successfully managed by the endoscopic endonasal transsphenoidal approach. PMID- 30459900 TI - Bilateral Orbital Cavernous Hemangioma. AB - Cavernous hemangioma of the orbit (CHO) is a benign slow-growing lesion of intracanal space. Bilateral orbital cavernous hemangiomas are extremely rare, so that only a few cases have been reported in scientific literature. A 54-year-old patient presented a 1-year history of impaired visual acuity of the left eye. Physical examination showed a left axial propotosis. Orbital magnetic resonance imaging showed a 28 mm diameter intraconal space mass of the left orbit, as well as another 11 mm diameter lesion in the right eye, in the superomedial extraconal space. A superior wall left orbitotomy was performed with a total removal of the tumor. The right lesion was respected. Histopathological examination confirmed the diagnosis of CHO. Bilateral cavernous hemangiomas are extremely rare. Orbital imaging guides the diagnosis. The neurosurgeons prefer craniotomy while ophthalmologists favor various modifications of orbitotomies. PMID- 30459901 TI - Peroneal Nerve Palsy Due to Subparaneurial Ganglion Cyst, a Rare Variant of Intraneural Ganglion Cyst. AB - Intraneural ganglion cysts are rare mucinous cysts originating within the epineurium of peripheral nerves. Although ganglion cysts are the most frequent tumors of the upper and lower extremities, ganglion cysts rarely result in peripheral nerve compression. We report a case of a 30-year-old patient who presented with foot drop due to subparaneurial ganglion cyst, a variant of an intraneural ganglion cyst. Characteristic magnetic resonance imaging findings were essential in the preoperative diagnosis of intraneural ganglion cyst. The common peroneal nerve and its branches were recognized and traced to its bifurcation during the operation. The articular branches were addressed. The mucious content of the ganglion was typically found to be located within the subparaneurial compartment. Incision of the subparaneurial ganglion cyst was performed, and mucinous content was evacuated. At 2 months after the surgery, paralyzed peroneal nerve was recovered completely. Therefore, early diagnosis of intraneural ganglion, precise identification of the pathology, and proper treatment of the articular branch with atraumatic dissection of ganglion cyst are essential in the successful management of this rare lesion. PMID- 30459902 TI - Chronic Unilateral Temporo-Occipital Headache Attributed to Unilateral C3 Radiculopathy. AB - Although C1-C3 upper cervical radiculopathy can cause a headache, most case reports are occipital neuralgia (ON), not headache. Here, we report a unique case of chronic temporo-occipital headache due to C3 radiculopathy. A 62-year-old male presented with a chronic left-sided temporo-occipital headache with duration of 4 years. The headache was aching and pressure like in nature. It had a typical radiating pattern on every occasion. It started in the posterior temporal area above the ear. It then extended to retroauricular area, then suboccipital area, and lateral neck. No hypesthesia, allodynia, or limitation in neck motion was noted. Myelographic computed tomography revealed a left-sided C2/C3 foraminal stenosis. Subsequent foraminotomy and decompression of the left C3 completely alleviated the chronic left-sided temporo-occipital headache. Unilateral C3 radiculopathy can cause chronic temporo-occipital headache besides ON. The present case might be a typical example of "headache attributed to upper cervical radiculopathy" (A11.2.4) rather than cervicogenic headache according to the International Classification of Headache Disorders, 3rd edition (beta version). PMID- 30459903 TI - Left Deep Frontal Cavernous Angioma Mimicking a Glioma in an Adult Patient. AB - Cerebral cavernous angiomas are vascular malformations characterized by large adjacent vessels. Usually, these lesions are smaller than 3 cm, the mean age at presentation occurs between 20 and 40 years, and the neuroradiological findings are well described, especially for magnetic resonance imaging, where the "popcorn balls" appearance is due to the presence of locules containing blood. Among these, the giant cavernous angiomas are very rare, particularly in adults. We collected clinical and neuroradiological data from clinical file and hospital diagnostic archive. A comprehensive review of similar cases was performed. We describe the clinical, diagnostic, and surgical management of a giant cerebral cavernous angioma located in the left deep frontal lobe mimicking a high-grade glioma in an adult Chinese patient. Giant cerebral cavernous angioma may be misdiagnosed and should be considered as differential diagnosis. PMID- 30459904 TI - Embolization with NBCA for Ruptured Aneurysm Located in the Moyamoya-like Collateral Network Associated with Isolated Middle Cerebral Artery Occlusion. AB - Collateral vessel formation in moyamoya disease is a well-described phenomenon. However, the occurrence of unusual anastomosis pattern (moyamoya-like) associated with isolated middle cerebral artery (MCA) stenosis or occlusion has been reported very rarely and is not well known the relationship with aneurysm. We report a case of ruptured aneurysm treated with N-butyl cyanoacrylate (NBCA) located in moyamoya like collateral network with isolated MCA occlusion. PMID- 30459905 TI - Congenital Hydrocephalus, Corpus Callosum Agenesis, and Prosencephalic Cyst with Supernumerary Nostril: A Neurocristopathy. AB - A 3-month-old-male infant presented with enlargement of head since birth. Clinical and radiological evaluation revealed congenital hydrocephalus, corpus callosum agenesis, prosencephalic cyst, and cranial vault deficiency with supernumerary nostril on the left side. Right ventriculoperitoneal shunt (Chhabra shunt) surgery was performed. The patient did well postoperatively. Parents of the patient have been counseled for repair of supernumerary nostril. Congenital hydrocephalus with corpus callosum agenesis is rare. Furthermore, supernumerary nostril is a very rare anomaly with <40 cases reported in the literature till date. To the best of our knowledge, congenital hydrocephalus, corpus callosum agenesis, prosencephalic cyst, and cranial vault deficiency associated with supernumerary nostril have not been reported till date. We herein briefly review the pertinent literature and describe the embryopathogenesis of this rare association. We propose that this association is a neurocristopathy. PMID- 30459906 TI - Coil Embolisation of Post Traumatic Giant Supraclinoid Pseudoaneurysm Presenting as Carotid Cavernous Fistula. AB - This report documents the occurrence, diagnosis and treatment of a 29 year-old male patient who presented with progressive swelling of the left eye with associated progressive loss of vision, three months after sustaining a closed head injury in a road traffic accident. Magnetic resonance imaging (MRI) showed a large, ill-defined lesion in the left supraclinoid and paraclinoid region with variable contrast enhancement. A four vessel Digital Subtraction Angiography (DSA) showed a large, supra-clinoid pseudoaneurysm which had ruptured inferiorly into the roof of cavernous sinus, forming direct carotid cavernous fistula (CCF) which lead to dilatation of the superior ophthalmic vein and subsequent peri orbital oedema and chemosis of conjunctiva. Complete obliteration of the indirect CCF was achieved by coiling of the aneurysm alone. During follow up, patient reported a significant improvement in vision and follow up DSA after one year shows no recurrence with this technique. PMID- 30459907 TI - Spinal-epidural Abscess Presenting as an Acute Abdomen in a Child: A Case Report and Review of the Literature. AB - Abdominal presentations in patients with spinal-epidural abscess (SEA) are not uncommon. However, it needs to be continually emphasized that the atypical presentations of these diseases could delay the timely diagnosis and consequently prompt management, which threatens spinal cord, leading to potential to paralysis or even death. We report a case of a young girl who presented with abdominal pain and fever. The diagnosis of SEA was unfortunately so delayed that the patient did not show any functional recovery postoperatively. This report aims to highlight the importance of high level of clinical suspicion to recognize an atypical presentation of the SEA. Moreover, the fully detailed history-taking and physical examination are of paramount importance. Spinal underlying pathologies should always be considered as a cause of abdominal pain, especially in children. PMID- 30459908 TI - Posterior Fossa Arteriovenous Malformation with Multiple Pedicle Aneurysms and Recruitment of Meningeal Supply. AB - Cerebral aneurysms arising on the peripheral posterior inferior cerebellar artery (PICA) are rare. Here, we present a unique case of arteriovenous malformation (AVM) with pedicle aneurysms arising on the peripheral PICA and recruited by meningeal supply. A 67-year-old woman presented with subarachnoid hemorrhage. Cerebral angiography revealed two saccular aneurysms on the peripheral PICA, which formed an abnormal arteriovenous shunt adjacent to the transverse sinus. The shunt was also fed by the ipsilateral superior cerebellar and contralateral posterior meningeal arteries. The proximal aneurysm was larger and deep seated while the distal aneurysm was smaller and located superficially. The patient underwent coil embolization of the proximal aneurysm followed by microsurgical trap of the distal aneurysm and resection of the arteriovenous shunt lying superficially in the cerebellar hemisphere. The shunt was histologically verified as AVM. Staged approach with coil embolization and open microsurgery can be a treatment option for multiple PICA aneurysms associated with an AVM. PMID- 30459909 TI - Is Transposition of Deep Brain Stimulation Device a Solution in Patients with Recurrent Skin Erosions? AB - Skin erosion and infection are common but serious problems in deep brain stimulation (DBS). They can lead to the removal of the entire DBS device and consequently stop the entire treatment. Of critical importance, therefore, is to find surgical solutions that allow to leave the complex DBS device in place when medical treatment fails in repeated skin complications, to allow continuing treatment in otherwise pharmacological refractory patients. We present a patient with repeated retro-auricular skin erosions, who failed to respond to surgical revisions and antibiotic treatment. However, instead of removing the DBS device as it would be general practice we succeeded with a right to left transposition of connecting cables to save the entire DBS system. There is lack of data on therapeutic surgical options in repeated skin complications. We propose the transposition of DBS device as possible solution for multiple skin erosions in DBS surgery. PMID- 30459910 TI - An Unusual Cause of Posterior Reversible Encephalopathy Syndrome. AB - Posterior reversible encephalopathy syndrome (PRES) is a clinical radiographic diagnosis of heterogeneous etiologies. The pathogenesis of PRES remains unclear, but may be related to impaired cerebral autoregulation and endothelial dysfunction. We present a case of intravascular nonionic contrast-induced PRES observed after cerebral angiography. The index patient was a follow-up case of large vertebrobasilar artery-dissecting aneurysm for which endovascular coiling was done 6 months back. She improved completely within a week. Contrast-induced PRES is a reversible benign condition, knowledge of which is crucial for appropriate management. PMID- 30459911 TI - Diprosopus a Rare Craniofacial Malformation. AB - Diprosopus is an extremely rare form of craniofacial malformation seen in newborns where there is duplication of face which may be partial or complete. The baby usually has a single trunk and normal limbs. We report a case of diprosopus admitted in our institute and analyze the anomalies and clinical problems and outcome of the case. PMID- 30459912 TI - Airway Management in Case of Diffuse Idiopathic Skeletal Hyperostosis. AB - Diffuse idiopathic skeletal hyperostosis (DISH) is associated with abnormal ossification of spinal and extraspinal appendages. Incidence of DISH is high in old age with predilection for males. Cervical hyperostosis can make intubation difficult in multiple ways. Here, we report a case of DISH bridging the cervical spine from C2 to C7 vertebrae managed using awake fiberoptic technique and a small-sized endotracheal tube. PMID- 30459913 TI - Pituitary Apoplexy Producing Internal Carotid and Basilar Artery Compression: A Rare Case Report. AB - Pituitary apoplexy is a rare disease followed by ischemic or hemorrhagic process within the pituitary adenoma. Here, we report two cases of pituitary apoplexy with a history of sudden onset of headache, vomiting, and diminished vision. Our aim is to share our experience and discuss these cases as follows: the first one to know the compression of basilar artery along with the compression of basilar part of pons and in both the cases with compression of an internal carotid artery leading to cerebral infarcts. PMID- 30459914 TI - Sporadic Cisternal Oculomotor Nerve Schwannoma: A Rare Case with Review of Literature. AB - Cranial nerve schwannomas usually arise from sensory nerve and the occurrence of schwannoma in a motor nerve is rare, especially in sporadic cases. Oculomotor nerve schwannomas (ONS) are rare and they are unique as they arise from motor nerve. ONS palsy may or may not be the presenting feature of oculomotor schwannoma. We present the case of a young male with ONS, presenting with oculomotor nerve palsy along with features of raised intracranial pressure. Oculomotor schwannoma is described in literature only as case reports, and oculomotor nerve is also a rare site for schwannoma as being a motor nerve. In this article, we describe a case of cisternal ONS with review of pertinent literature. PMID- 30459915 TI - Secondary Arachnoid Cyst - A Late Complication of Craniotomy: A Case Report and Review of Literature. AB - Arachnoid cyst can be defined as cerebral-spinal fluid entrapment within the central nervous system. It may occur primarily as a congenital malformation or secondary as a complication following trauma, infection, bleeding, or surgical manipulation. Congenital arachnoid cyst usually asymptomatic and cause no pressure symptoms. No treatment is needed unless size increase and cause pressure symptoms and increased intracranial pressure. We report a case presented to the hospital with neurological signs of increased intracranial pressure, 3 years Post aborted craniotomy for meningioma resection. Radiological imaging showed postoperative newly developed arachnoid cyst with mass effect. He underwent the urgent cerebral spinal fluid diversionary procedure with cystoperitoneal shunt. PMID- 30459916 TI - Venous Infarct after Sacrifice of Single Cortical Vein during Deep-Brain Stimulation Surgery. AB - Intracerebral hemorrhage (ICH) is the most feared and dreadful complication related to deep-brain stimulation (DBS). Bleeding may originate from arterial or venous damage. Commonly, hemorrhage is detected by postoperative imaging performed to assess lead positioning in asymptomatic patients. Rarely, hemorrhage leads to stroke, coma, or even death. We present the case of a patient who suffered a severe ICH of venous origins after bilateral DBS. Deep-brain hemorrhages are the most difficult to be predicted and to be prevented because they are caused by small vessels. As superficial hemorrhages are secondary to venous coagulation or sulcal hemorrhage, neurosurgeons must drive all efforts to minimize their occurrence. PMID- 30459917 TI - Two-Level Spontaneous Pedicle Fracture above a Degenerative Spondylolisthesis and Minimally Invasive Treatment. AB - This is a case report and literature review. The objectives of the study are to describe minimally invasive treatment of pedicle fractures, to show contralateral pedicle changes with pedicle fracture treatment, and to review literature on incidence and mechanism of neural arch fractures. After conservative therapy, there are several options for the treatment of pedicle fractures including pediculoplasty, osteosynthesis, or fusion. As patients' age increases, the incidence of pedicle fracture may rise and minimally invasive pedicle screw treatment represents a good motion-preserving option to stabilize without fusion. We report a patient with spontaneous pedicle fractures above a degenerative spondylolisthesis and evidence of contralateral pedicle changes at L2 and L3. After minimally invasive pedicle screw placement, postoperative imaging demonstrated trabeculation across both L2 and L3 fractures with a resolution of contralateral pedicle sclerotic changes and healing of incompletely fracture contralateral pedicle at L2. Pedicle fractures lead to contralateral pedicle sclerotic changes and potential fracture and may cause significant back pain. Stabilization and healing of the neural arch can be achieved with minimally invasive placement of pedicle screws without need for fusion. PMID- 30459919 TI - Isolated Intraventricular Rosai-Dorfman Disease. AB - Rosai-Dorfman disease (RDD) is a benign histioproliferative disorder characterized by generalized lymphadenopathy, weakness, anemia, and rarely extranodal involvement. The disease affects the central nervous system (CNS) very rarely and at a relatively older age. Isolated intracranial involvement is very rare. RDD tends to present as dural masses mimicking meningioma, though very rare case reports describe isolated parenchymal involvement in the CNS. Only one case of intraventricular RDD has been described so far to the best of our knowledge. We present a very rare presentation of this disease as an isolated intraventricular presentation in the region of the atria of the lateral ventricles. PMID- 30459918 TI - Intramedullary Spinal Cord Lipoma Mimicking a Late Subacute Hematoma. AB - Spinal cord lipomas are rare and benign tumors which may cause progressive neurological deficits due to their local expansion. We present the case of a 59 year-old male patient with severe lumbosacral pain and slowly progressive paresis of the right leg, misdiagnosed with degenerative spine disease. Repeated magnetic resonance (MR) T1-weighted images of the thoracic spine suggested a subacute intramedullary hematoma. Due to progression of the neurological deficit, the patient was referred to a neurosurgeon, who indicated surgical evacuation of the hematoma. The intraoperative finding revealed an intramedullary spinal cord lipoma, which was later confirmed by histological analysis. Since subacute intramedullary hematomas and intramedullary spinal cord lipomas present with similar clinical and radiological features, diffusion-weighted MR imaging should be used to distinguish these entities. PMID- 30459920 TI - Surgical Management of Intracranial Giant Epidermoid Cysts in Adult: A Case-Based Update. AB - Epidermoid cysts (ECs) are benign and slow-growing lesions that account for about 0.2%-2% of all intracranial tumors. Symptoms appear slowly and tumors may have already grown to giant proportions when patients receive their first diagnosis. The optimal treatment for ECs is surgical removal, which includes the total resection of the entire capsule of the lesion in order to minimize the risk of malignant transformation associated with partial removal. However, considering the giant size that the ECs can reach at the time of the diagnosis, and their adherence to the surrounding structures, the risks and benefits of total versus subtotal resections in the short- and long-term patients' outcome are still under debate. Here, we report a case of an extensive giant EC and offer a discussion of its characteristics, surgical management, and postoperative outcome, taking a cue to argue about the recent literature based in the latest case studies. PMID- 30459921 TI - Retrobulbar Lymphangioma: A Rare Case Report. AB - We report a case of biopsy-proven retrobulbar lymphangioma in a 14-year-old girl. She presented with chief complaints of swelling in the left eye for 2 months. The patient underwent imaging evaluation and it was diagnosed as cavernous hemangioma, radiologically. However, later on, the patient underwent surgery, and the specimen was sent for histopathology which revealed it to be a lymphangioma. PMID- 30459923 TI - Ipsa Scientia Potestas Est: Regional Epidemiological Studies Lead to Regional Strategies for Stroke Prevention. PMID- 30459922 TI - A Giant Tumefactive Perivascular Space: A Rare Cause of Obstructive Hydrocephalus and Monoparesis. AB - Cerebral perivascular spaces (PVSs), otherwise known as Virchow-Robin spaces, are interstitial fluid-filled channels, <2 mm in diameter that form around arterial perforators as they course from the cortex into the brain parenchyma. In contrast, a giant tumefactive PVS is a rare entity comprising of clusters of such channels larger than 15mm resembling a neoplastic process as the name suggests. We report a 55-year-old male who presented with unsteady gait, cognitive decline, and left lower limb weakness for 6 months. Magnetic resonance imaging revealed a noncontrast enhancing multicystic intraaxial lesion of the right mesencephalon diencephalon junction extending into the anterior third ventricle causing obstructive hydrocephalus. A ventriculoperitoneal shunt was inserted with a complete reversal of his neurological symptoms. Such PVSs can easily be misidentified for a cystic tumor, and their unique radiological features are discussed to prevent unnecessary surgery. We also demonstrate that when they cause hydrocephalus and midbrain compression symptoms cerebrospinal fluid shunting alone can result in excellent outcomes. PMID- 30459924 TI - Unfolding the Truth; the Way Towards Painfree Spine Surgery. PMID- 30459925 TI - Oligo swapping method for in vitro DNA repair substrate containing a single DNA lesion at a specific site. AB - Background: A wide variety of DNA lesions interfere with replication and transcription, leading to mutations and cell death. DNA repair mechanisms act upon these DNA lesions present in the genomic DNA. To investigate a DNA repair mechanism elaborately, an in vitro DNA repair substrate containing DNA lesions at a specific site is required. Previously, to prepare the substrate, phagemid ssDNA and DNA lesion-harboring oligonucleotides were employed with considerable amounts of DNA polymerase and DNA ligase. However, preparing in vitro DNA repair substrate in general is difficult and labor intensive. Results: Here, we modified the construction method of in vitro mismatch repair substrate using a nicking endonuclease, which produces gap corresponding to the ssDNA in the plasmid DNA, and swaps DNA lesion-containing oligonucleotide upon addition of restriction enzyme and T5 exonuclease. This modified method is able to produce in vitro DNA repair substrates containing adenine:cytosine mismatch basepair, 8-oxoG, and uracil. The DNA repair enzyme, each Fpg, hOGG1 could cleave an 8-oxoG-containing DNA substrate, the mixture of UDG and APE1 could cleave a uracil-containing DNA substrate. Omitting a column purification step, DNA repair substrates were prepared by one-pot synthesis. Conclusions: We were able to prepare in vitro DNA repair substrates using this simple method involving restriction enzymes and T5 exonuclease. It is anticipated that this method, termed as "Oligo Swapping Method", will be valuable for understanding the DNA repair machinery. PMID- 30459926 TI - Amyloid beta directly interacts with NLRP3 to initiate inflammasome activation: identification of an intrinsic NLRP3 ligand in a cell-free system. AB - Background: Alzheimer's disease is a neurodegenerative disease characterized by the interstitial deposition of amyloid beta (Abeta) plaque, which is thought to be related to chronic neuroinflammation. Abeta is known to make fibrils via oligomers from monomers. Abeta has been reported to activate the NLRP3 inflammasome in infiltrated macrophages. NLRP3, an intracellular pattern recognition receptor, has been reported to recognize numerous pathogens and/or metabolites and form complexes with adopter protein ASC to make the inflammasome, an interleukin (IL)-1beta-processing platform. Although reactive oxygen species from mitochondria have been reported to be involved in the activation of the NLRP3 inflammasome in microglial cells upon the deposition of Abeta, whether Abeta directly or indirectly activates the NLRP3 inflammasome remains unclear. Methods: We prepared monomers, oligomers, and fibrils of Abeta, which promoted the interaction between NLRP3 and each form of Abeta and analyzed the interaction between NLRP3 and ASC induced by each form of Abeta in a cell-free system with the amplified luminescent proximity homogeneous assay. We also confirmed the physiological relevance in a cell-based assay using human embryonic kidney 293T cells and human peripheral mononuclear cells. Results: Monomers, oligomers, and fibrils of Abeta were successfully prepared. Abeta oligomers and fibrils interacted with NLRP3. Abeta oligomers and fibrils induced the interaction between NLRP3 and ASC. However, Abeta monomers did not interact with NLRP3 or induce interaction between NLRP3 and ASC in the cell-free system, and IL-1beta was not secreted according to the cell-based assay. Conclusion: Oligomerized Abeta originating from non-toxic Abeta monomers directly interacted with NLRP3, leading to the activation of the NLRP3 inflammasome. This may be an attractive target for the treatment of Alzheimer's disease. PMID- 30459929 TI - New insights in melanoma resistance to BRAF inhibitors: a role for microRNAs. PMID- 30459927 TI - Health care costs and resource utilization for different asthma severity stages in Colombia: a claims data analysis. AB - Background: Asthma is one of the most common chronic respiratory conditions worldwide. Asthma-related economic burden has been reported in Latin America, but knowledge about its economic impact to the Colombian health care system and the influence of disease severity is lacking. This study estimated direct medical costs and health care resource utilization (HCRU) in patients with asthma according to severity in Colombia. Methods: This study identified all-age patients who had at least one medical event linked to an asthma diagnosis (CIE 10: J45-J46) between 2004 and 2014. Patients were selected if they had a continuous enrollment and uninterrupted insurance coverage between January 1-2015 and December 31-2015 and were categorized into 4 different severity levels using a modified algorithm based on Leidy criteria. Healthcare utilization and costs were estimated in a 1-year period after the identification period. A Generalized Linear Model (GLM) with gamma distribution and log link was used to analyze costs adjusting for patient demographics. Results: A total of 20,410 patients were included: 69.5% had mild intermittent, 18.0% mild persistent, 6.9% moderate persistent and 5.5% severe persistent asthma; with mean costs (SD) of $67 (134), $482 (1506), $1061 (1983), $2235 (3426) respectively (p < 0.001). The mean total direct cost was estimated at $331 (1278) per patient. Medication and hospitalization had the higher proportion in total costs (46% and 31% respectively). General physician visits was the most used service (57.2%) and short-acting beta-2 agonists the most used medication (24%). Conclusions: Health services utilization and direct costs of asthma were highly related to disease severity. Nationwide health policies aimed at the effective control of asthma are necessary and would play an important role in reducing the associated economic impact. PMID- 30459928 TI - Confounders of severe asthma: diagnoses to consider when asthma symptoms persist despite optimal therapy. AB - Asthma can often be challenging to diagnose especially when patients present with atypical symptoms. Therefore, it is important to have a broad differential diagnosis for asthma to ensure that other conditions are not missed. Clinicians must maintain a high index of suspicion for asthma mimickers, especially when patients fail to respond to conventional therapy. The purpose of this review is to briefly review some of the more common causes of asthma mimickers that clinicians should consider when the diagnosis of asthma is unclear. PMID- 30459930 TI - Targeting age-related inflammation in myelodysplastic syndromes. PMID- 30459931 TI - NOX2 oxidase expressed in endosomes promotes cell proliferation and prostate tumour development. AB - Reactive oxygen species (ROS) promote growth factor signalling including for VEGF A and have potent angiogenic and tumourigenic properties. However, the precise enzymatic source of ROS generation, the subcellular localization of ROS production and cellular targets in vivo that influence tumour-promoting processes, are largely undefined. Here, using mRNA microarrays, we show increased gene expression for NOX2, the catalytic subunit of the ROS-generating NADPH oxidase enzyme, in human primary prostate cancer compared to non-malignant tissue. In addition, NOX4 gene expression was markedly elevated in human metastatic prostate cancers, but not in primary prostate tumours. Using a syngeneic, orthotopic mouse model of prostate cancer the genetic deletion of NOX2 (i.e. NOX2 -/y mouse) resulted in reduced angiogenesis and an almost complete failure in tumour development. Furthermore, pharmacological inhibition of NOX2 oxidase suppressed established prostate tumours in mice. In isolated endothelial cells, and in human normal and prostate cancer cells, NOX2 co-located to varying degrees with early endosome markers including EEA1, Appl1 and Rab5A and the late endosome marker Rab7A, and this correlated with significant VEGF-A-dependent ROS production within acidified endosomal compartments and endothelial cell proliferation that was NOX2 oxidase- and hydrogen peroxide dependent. We concluded that NOX2 oxidase expression and endosomal ROS production were important for prostate cancer growth and that this was required to positively regulate the VEGF pathway. The research provides a paradigm for limiting tumour growth through a better understanding of NOX2 oxidase's effect on VEGF signalling and how controlling the development of tumour vasculature can limit prostate tumour development and metastasis. PMID- 30459932 TI - Personalized identification of tumor-associated immunogenic neoepitopes in hepatocellular carcinoma in complete remission after sorafenib treatment. AB - Sorafenib, a multi-targeted kinase inhibitor, is the current standard systemic treatment for advanced hepatocellular carcinoma. Sorafenib has anti-angiogenic and anti-proliferative properties and is also known to favor anti-tumor T cell responses by reducing the population of immunosuppressive cells such as Treg and MDSC. Anti-tumor immune responses, especially mediated by CD4+ T-cells, are critical for tumor cells eradication and therapies modulating those responses are appealing in a growing number of cancers. Here, we report and investigate the case of a patient diagnosed with an advanced HCC treated by sorafenib who experienced a complete histological response. We aimed to identify immunogenic peptides derived from tumor mutated proteins that stimulated CD4+ T cells responses thus favoring the exceptional recovery process of this patient. Tumor neoantigens were identified using whole exome sequencing of normal and tumor tissue and peptide MHC binding prediction algorithms. Among 442 tumor-specific somatic variants, 50 missense mutations and 20 neoepitopes predicted to bind MHC II were identified. Candidate neoepitopes immunogenicity was assessed by IFN gamma ELISpot after culture of patient's PBMCs in presence of synthetic neopeptides. CD4+ memory T cell responses were detected against a mutated IL 1betaS230F peptide and two additional neoepitopes from HELZ2V241M and MLL2A4458V suggesting that efficient anti-tumor immune response occurred in this patient. These results showed that T cells can recognize neoantigens and may lead to the cancer elimination after immunomodulation in the tumor-microenvironment induced by sorafenib. This observation indicates that other immunotherapies in combination with sorafenib could potentially increase the response rate in HCC at advanced stage. PMID- 30459933 TI - Synergistic effects of BET and MEK inhibitors promote regression of anaplastic thyroid tumors. AB - Anaplastic thyroid cancer (ATC) is an aggressive malignancy with limited options for treatment. Targeting epigenetic modifications via interfering with the interaction between the bromodomain and extra-terminal domain (BET) proteins and acetylated histones by using BET inhibitors (e.g., JQ1) has shown some efficacy in thyroid cancer. To improve the efficacy, an inhibitor of MEK, trametinib, was tested together with JQ1 as a combined treatment via cell-based approaches and xenograft studies. We examined the effects of combined treatment of JQ1 and trametinib on the proliferation of human ATC cell lines (THJ-11T and THJ-16) in vitro. We further evaluated the effects of the combined treatment on tumor development in vivo using mouse xenograft models. We elucidated the underlying molecular pathways affected by double treatment. We showed that the combined treatment totally blocked proliferation, while either JQ1 or trametinib alone only had partial effects. Combined treatment suppressed MYC expression more than single treatment, resulting in decreased expression of pro-survival regulators and increased pro-apoptotic regulators to collaboratively induce apoptosis. In xenograft studies, single treatment only partially inhibited tumor growth, but the combined treatment inhbited tumor growth by >90%. The reduction of tumor growth was mediated by synergistic suppression of MYC, to affect apoptotic regulators to markedly promote tumor apoptosis. Combined treatment of BET and MEK ERK inhibitors was more effective to treat ATC than single targeted treatment. Synergistic suppression of MYC transcription via collaborative actions on chromatin modifications suggested that targeting epigenetic modifications could provide novel treatment opportunities for ATC. PMID- 30459934 TI - The adaptive regulation of thiamine pyrophosphokinase-1 facilitates malignant growth during supplemental thiamine conditions. AB - Supplemental levels of vitamin B1 (thiamine) have been implicated in tumor progression. Tumor cells adaptively up-regulate thiamine transport during hypoxic stress. Upon uptake, thiamine pyrophosphokinase-1 (TPK1) facilitates the rapid phosphorylation of thiamine into thiamine pyrophosphate (TPP). However, the regulation of TPK1 during hypoxic stress is undefined. Understanding how thiamine homeostasis changes during hypoxia will provide critical insight into the malignant advantage supplemental thiamine may provide cancer cells. Using Western blot analysis and RT-PCR, we have demonstrated the post-transcriptional up regulation of TPK1 in cancer cells following hypoxic exposure. TPK1 expression was also adaptively up-regulated following alterations of redox status by chemotherapeutic and antioxidant treatments. Although TPK1 was functionally up regulated by hypoxia, HPLC analysis revealed a reduction in intracellular TPP levels. This loss was reversed by treatment with cell-permeable antioxidants and corresponded with reduced ROS production and enhanced cellular proliferation during supplemental thiamine conditions. siRNA-mediated knockdown of TPK1 directly enhanced basal ROS levels and reduced tumor cell proliferation. These findings suggest that the adaptive regulation of TPK1 may be an essential component in the cellular response to oxidative stress, and that during supplemental thiamine conditions its expression may be exploited by tumor cells for a redox advantage contributing to tumor progression. PMID- 30459935 TI - Systematic review and meta-analysis of third-line salvage therapy for the treatment of advanced non-small-cell lung cancer: A meta-analysis of randomized controlled trials. AB - Purpose: We performed a systematic review and meta-analysis to investigate the efficacy of third-line treatment for advanced non-small-cell lung cancer (NSCLC). Materials and Methods: Relevant trials were identified by searching electronic databases and conference meetings. Prospective randomized controlled trials (RCTs) assessing third-line therapy in advanced NSCLC patients were included. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). Results: A total of 1,985 advanced NSCLC patients received third-line treatment from 11 RCTs were included for analysis. The use of single targeted agent as third-line therapy for advanced NSCLC did not significantly improved PFS (HR 0.75, 95% CI: 0.28-2.04, p = 0.58) and OS (HR 1.01, 95% CI: 0.86-1.17, p = 0.95) when compared to docetaxel alone. In addition, erlotinib-based doublet combination therapy did not significantly improved PFS (HR 0.94, 95% CI: 0.78 1.13, p = 0.49) and OS (HR 1.08, 95% CI: 0.78-1.51, p = 0.65) in comparison with erlotinib alone. Conclusions: The findings of this study show that the efficacy of single novel targeted agent is comparable to that of docetaxel alone in terms of PFS and OS for heavily pretreated NSCLC patients. In addition, no survival benefits are obtained from erlotinib-based doublet therapy, thus single agent erlotinib could be recommended as third-line treatment for unselected advanced NSCLC patients. PMID- 30459936 TI - Naturally occurring compounds as pancreatic cancer therapeutics. AB - Naturally occurring small molecule compounds have long been in the spotlight of pancreatic cancer research as potential therapeutics to prevent cancer progression and sensitize chemoresistant tumors. The hope is that terminal pancreatic cancer patients receiving aggressive chemotherapy can benefit from an increase in treatment efficacy without adding further toxicity by way of utilizing natural compounds. While preclinical studies on a number of natural compounds, such as resveratrol, curcumin, rapalogs and cannabinoids, show promising preclinical results, little has translated into clinical practice, though a number of other compounds hold clinical potential. Nevertheless, recent advances in compound formulation may increase the clinical utility of these compounds. PMID- 30459938 TI - Combination therapy for metastatic melanoma: a pharmacist's role, drug interactions & complementary alternative therapies. AB - The incidence of metastatic melanoma has been increasing dramatically over the last decades. Yet, there have been many new innovative therapies, such as targeted therapies and checkpoint inhibitors, which have made progress in survival for these patients. The oncology pharmacist is part of the healthcare team and can help in optimizing these newer therapies. There will be discussion about combination therapies, the oncology pharmacist's role, and issues at the core of his interest, such as drug interactions and complementary and alternative therapies. PMID- 30459937 TI - Constitutional mismatch repair-deficiency: current problems and emerging therapeutic strategies. AB - Mismatch repair (MMR) proteins remove errors from newly synthesized DNA, improving the fidelity of DNA replication. A loss of MMR causes a mutated phenotype leading to a predisposition to cancer. In the last 20 years, an increasing number of patients have been described with biallelic MMR gene mutations in which MMR defects are inherited from both parents. This leads to a syndrome with recessive inheritance, referred to as constitutional mismatch repair-deficiency (CMMRD). CMMRD is a rare childhood cancer predisposition syndrome. The spectrum of CMMRD tumours is broad and CMMRD-patients possess a high risk of multiple cancers including hematological, brain and intestinal tumors. The severity of CMMRD is highlighted by the fact that patients do not survive until later life, emphasising the requirement for new therapeutic interventions. Many tumors in CMMRD-patients are hypermutated leading to the production of truncated protein products termed neoantigens. Neoantigens are recognized as foreign by the immune system and induce antitumor immune responses. There is growing evidence to support the clinical efficacy of neoantigen based vaccines and immune checkpoint inhibitors (collectively referred to as immunotherapy) for the treatment of CMMRD cancers. In this review, we discuss the current knowledge of CMMRD, the advances in its diagnosis, and the emerging therapeutic strategies for CMMRD-cancers. PMID- 30459939 TI - Preoperative BRAF inhibition in patients with irresectable locally advanced stage III melanoma. AB - Aim: Neoadjuvant treatment of locally advanced disease with BRAF inhibitors is expected to increase the likelihood of a R0 resection. We present six patients with stage III unresectable melanoma, neoadjuvantly treated with BRAF inhibitors. Methods: Patients with unresectable, BRAF-mutated, stage III melanoma, were treated with BRAF inhibitors between 2012 and 2015. Unresectability was determined based on clinical and/or radiological findings. At maximal response, resection was performed. The specimen was reviewed to determine the degree of response. Results: In five of six patients a radical resection was achieved. Postoperative complications were unremarkable. In five of six resected specimens, vital tumor tissue was found. Conclusion: Neoadjuvant BRAF inhibitor treatment of locally advanced melanoma is feasible and has the potential to facilitate an R0 resection. PMID- 30459940 TI - Next-generation melanoma prevention efforts for overlooked populations and populations with health disparities: a South African perspective. PMID- 30459941 TI - Combatting mucosal melanoma: recent advances and future perspectives. AB - Mucosal melanomas are a rare subtype of melanoma and are associated with a particularly poor prognosis. Due to the rarity of the diagnosis, and the pace with which the management of cutaneous melanoma has evolved over recent years, there is little good evidence to guide management and evidence-based clinical guidelines are still in development in the UK. In this review we provide an overview of the management of mucosal melanoma, highlighting the critical differences between cutaneous and mucosal melanomas, before examining recent advances in the systemic treatment of this disease and likely future directions. PMID- 30459942 TI - Checkpoint inhibitor use in two heart transplant patients with metastatic melanoma and review of high-risk populations. AB - Due to the unique side-effect profile of immune checkpoint inhibitors (ICIs), groups of patients deemed to be at high risk of complications were excluded from trials that proved the efficacy and safety of these agents in patients with various malignancies. Among these excluded patients were those with prior solid organ transplantation, chronic viral infections and pre-existing autoimmune diseases including paraneoplastic syndromes. We present follow-up on a patient from a previously published case report with an orthotopic heart transplantation who was treated with both cytotoxic T-lymphocyte antigen 4 and PD-1 inhibition safely, without organ rejection. Additionally, we describe the case of a patient with a cardiac allograft who also did not experience organ rejection after treatment with pembrolizumab. Through smaller trials, retrospective analyses, case series and individual case reports, we are accumulating initial data on how these agents are tolerated by the aforementioned groups. Our survey of the literature has found more evidence of organ transplant rejection in patients treated with PD-1 inhibitors than those treated with inhibitors of cytotoxic T lymphocyte antigen 4. Patients with chronic viral infections, especially hepatitis C, seem to have little to no risk of treatment-related increase in serum RNA levels. The literature contains few documented cases of devastating exacerbations of pre-existing autoimmune disease during treatment with ICIs, and flares seem to be easily controlled by immunosuppression in the vast majority of cases. Last, several cases allude to a promising role for disease-specific antibodies and other serum biomarkers in identifying patients at high risk of developing certain immune-related adverse events, detecting subclinical immune related adverse event onset, and monitoring treatment response to immunosuppressive therapy in patients treated with ICIs. Though these excluded populations have not been well studied in randomized placebo-controlled trials, we may be able to learn and derive hypotheses from the existing observational data in the literature. PMID- 30450199 TI - Could differences in implicit attitudes to sexual concurrency play a role in generalized HIV epidemics? AB - Background: Sexual partner concurrency has been implicated in the genesis of generalized HIV epidemic in South Africa. Most South Africans, however, disapprove of concurrency in surveys. These surveys test individuals' explicit attitudes which are susceptible to a number of important biases such as the social desirability bias. Assessment of implicit cognitions have been found to be better predictors of behaviour in socially sensitive domains. We hypothesized that South Africans may have implicit attitudes more tolerant of concurrency than lower concurrency prevalence populations. Methods: To test this hypothesis, we developed a concurrency-implicit association test (C-IAT) and compared the C-IATs of samples of South African and Belgian university students. Results: We found a large and statistically significant difference in the C-IAT between the South Africans (D600-score = -0.009, indicating absence of preference for concurrency or monogamy) and Belgians (D600-score = 0.783, indicating a strong preference for monogamy; t-test = 13.3; P < 0.0001). The effect size measure, Cohen's d, was found to be 0.88, which is considered a large effect size in this field. Conclusions: Our results are compatible with the thesis that differences in implicit attitudes to concurrency play a role in the genesis of generalised HIV epidemics. PMID- 30459943 TI - Class 2 CRISPR/Cas: an expanding biotechnology toolbox for and beyond genome editing. AB - Artificial nuclease-dependent DNA cleavage systems (zinc-finger nuclease, ZFN; transcription activator like effectors, TALENs) and exogenous nucleic acid defense systems (CRISPR/Cas) have been used in the new era for genome modification. The most widely used toolbox for genome editing, modulation and detection contains Types II, V and VI of CRISPR/Cas Class 2 systems, categorized and characterized by Cas9, Cas12a and Cas13 respectively. In this review, we (1) elaborate on the definition, classification, structures of CRISPR/Cas Class 2 systems; (2) advance our understanding of new molecular mechanisms and recent progress in their applications, especially beyond genome-editing applications; (3) provide the insights on the specificity, efficiency and versatility of each tool; (4) elaborate the enhancement on specificity and efficiency of the CRISPR/Cas toolbox. The expanding and concerted usage of the CRISPR/Cas tools is making them more powerful in genome editing and other biotechnology applications. PMID- 30459945 TI - The importance of adjusting for enterococcus species when assessing the burden of vancomycin resistance: a cohort study including over 1000 cases of enterococcal bloodstream infections. AB - Background: Infections caused by vancomycin-resistant enterococci (VRE) are on the rise worldwide. Few studies have tried to estimate the mortality burden as well as the financial burden of those infections and found that VRE are associated with increased mortality and higher hospital costs. However, it is unclear whether these worse outcomes are attributable to vancomycin resistance only or whether the enterococcal species (Enterococcus faecium or Enterococcus faecalis) play an important role. We therefore aimed to determine the burden of enterococci infections attributable to vancomycin resistance and pathogen species (E. faecium and E. faecalis) in cases of bloodstream infection (BSI). Methods: We conducted a retrospective cohort study on patients with BSI caused by Enterococcus faecium or Enterococcus faecalis between 2008 and 2015 in three tertiary care hospitals. Data was collected on true hospital costs (in ?), length of stay (LOS), basic demographic parameters, and underlying diseases including the results of the Charlson comorbidity index (CCI). We used univariate and multivariable regression analyses to compare risk factors for in-hospital mortality and length of stay (i) between vancomycin-susceptible E. faecium- (VSEm) and vancomycin-susceptible E. faecalis- (VSEf) cases and (ii) between vancomycin-susceptible E. faecium- (VSEm) and vancomycin-resistant E. faecium cases (VREm). We calculated total hospital costs for VSEm, VSEf and VREm. Results: Overall, we identified 1160 consecutive cases of BSI caused by enterococci: 596 (51.4%) cases of E. faecium BSI and 564 (48.6%) cases of E. faecalis BSI. 103 cases of E. faecium BSI (17.3%) and 1 case of E. faecalis BSI (0.2%) were infected by vancomycin-resistant isolates. Multivariable analyses revealed (i) that in addition to different underlying diseases E. faecium was an independent risk factor for in-hospital mortality and prolonged hospital stay and (ii) that vancomycin-resistance did not further increase the risk for the described outcomes among E. faecium-isolates. However, the overall hospital costs were significantly higher in VREm-BSI cases as compared to VSEm- and VSEf-BSI cases (80,465? vs. 51,365? vs. 31,122? p < 0.001). Conclusion: Our data indicates that in-hospital mortality and infection-attributed hospital stay in enterococci BSI might rather be influenced by Enterococcus species and underlying diseases than by vancomycin resistance. Therefore, future studies should consider adjusting for Enterococcus species in addition to vancomycin resistance in order to provide a conservative estimate for the burden of VRE infections. PMID- 30459946 TI - Applying a meal coding system to 16-d weighed dietary record data in the Japanese context: towards the development of simple meal-based dietary assessment tools. AB - Data on the combination of foods consumed simultaneously at specific eating occasions are scarce, primarily due to a lack of assessment tools. We applied a recently developed meal coding system to multiple-day dietary intake data for assessing its ability to estimate food and nutrient intakes and characterise meal based dietary patterns in the Japanese context. A total of 242 Japanese adults completed sixteen non-consecutive-day weighed dietary records, including 14 734 eating occasions (3788 breakfasts, 3823 lunches, 3856 dinners and 3267 snacks). Common food group combinations were identified by meal type to identify a range of generic meals. Dietary intake was calculated on the basis of not only the standard food composition database but also the substituted generic meal database. In total, eighty generic meals (twenty-three breakfasts, twenty-one lunches, twenty-four dinners and twelve snacks) were identified. The Spearman correlation coefficients between food group intakes calculated based on the standard food composition database and the substituted generic meal database ranged from 0.26 to 0.85 (median 0.69). The corresponding correlations for nutrient intakes ranged from 0.17 to 0.82 (median 0.61). A total of eleven meal patterns were established using principal components analysis, and these accounted for 39.1 % of total meal variance. Considerable variation in patterns was seen in meal type inclusion and choice of staple foods (bread, rice and noodles) and drinks, and also in meal constituents. In conclusion, this study demonstrated the usefulness of a meal coding system for assessing habitual diet, providing a scientific basis towards the development of simple meal-based dietary assessment tools. PMID- 30459948 TI - Autoimmune pulmonary alveolar proteinosis presenting peripheral ground-glass opacities. AB - Autoimmune pulmonary alveolar proteinosis should be considered in the differential diagnosis of peripheral ground-glass opacities. PMID- 30459947 TI - Neonatal vitamin A injection promotes cattle muscle growth and increases oxidative muscle fibers. AB - Background: Vitamin A and its metabolite, retinoic acid (RA), are important regulators of cell differentiation and organ morphogenesis. Its impact on beef cattle muscle growth remains undefined. Method: Angus steer calves were administrated with 0 (control) or 150,000 IU vitamin A (retinyl palmitate in glycerol, i.m.) per calf at birth and 1 month of age. At 2 months of age, a biopsy of the Biceps femoris muscle was obtained to analyze the immediate effects of vitamin A injection on myogenic capacity of muscle cells. The resulting steers were harvested at 14 months of age. Results: Vitamin A administration increased cattle growth at 2 months. At 2 months of age, Vitamin A increased PAX7 positive satellite cells and the expression of myogenic marker genes including PAX7, MYF5, MYOD and MYOG. Muscle derived mononuclear cells were further isolated and induced myogenesis in vitro. More myotubes and a higher degree of myogenesis was observed in vitamin A groups. Consistently, vitamin A increased Latissimus dorsi (LD) muscle fiber size at harvest. In addition, vitamin A increased the ratio of oxidative type I and type IIA fibers and reduced the glycolic type IIX fibers. Furthermore, we found that RA, a key bioactive metabolite of vitamin A, activated PPARGC1A promoter, which explains the upregulated expression of PPARGC1A in skeletal muscle. Conclusion: Vitamin A administration to neonatal calves enhanced postnatal muscle growth by promoting myogenesis and increasing satellite cell density, accompanied with a shift to oxidative muscle fibers. PMID- 30459949 TI - Emotional reactivity to appraisals in patients with a borderline personality disorder: a daily life study. AB - Background: Emotional instability, consisting of patterns of strong emotional changes over time, has consistently been demonstrated in daily life of patients with a borderline personality disorder (BPD). Yet, little empirical work has examined emotional changes that occur specifically in response to emotional triggers in daily life, so-called emotional reactivity. The goal of this study was to examine emotional reactivity in response to general emotional appraisals (i.e. goal congruence or valence, goal relevance or importance, and emotion focused coping potential) and BPD-specific evaluations (trust and disappointment in self and others) in daily life of inpatients with BPD. Methods: Thirty inpatients with BPD and 28 healthy controls participated in an experience sampling study and repeatedly rated the intensity of their current emotions, emotional appraisals, and evaluations of trust and disappointment in self and others. Results: Results showed that the BPD group exhibited stronger emotional reactivity in terms of negative affect than healthy controls, however only in response to disappointment in someone else. BPD patients also showed weaker reactivity in positive affect in response to the appraised importance of a situation; the more a situation was appraised as important, the higher the subsequent positive affect for healthy controls only, not the patient group. Conclusions: These findings show that appraisals can trigger strong emotional reactions in BPD patients, and suggest that altered emotional reactivity might be a potential underlying process of emotional instability in the daily life. PMID- 30459950 TI - Evaluating the discriminating capacity of cell death (apoptotic) biomarkers in sepsis. AB - Background: Sepsis biomarker panels that provide diagnostic and prognostic discrimination in sepsis patients would be transformative to patient care. We assessed the mortality prediction and diagnostic discriminatory accuracy of two biomarkers reflective of cell death (apoptosis), circulating cell-free DNA (cfDNA), and nucleosomes. Methods: The cfDNA and nucleosome levels were assayed in plasma samples acquired in patients admitted from four emergency departments with suspected sepsis. Subjects with non-infectious systemic inflammatory response syndrome (SIRS) served as controls. Samples were acquired at enrollment (T0) and 24 h later (T24). We assessed diagnostic (differentiating SIRS from sepsis) and prognostic (28-day mortality) predictive power. Models incorporating procalcitonin (diagnostic prediction) and APACHE II scores (mortality prediction) were generated. Results: Two hundred three subjects were included (107 provided procalcitonin measurements). Four subjects exhibited uncomplicated sepsis, 127 severe sepsis, 35 septic shock, and 24 had non-infectious SIRS. There were 190 survivors and 13 non-survivors. Mortality prediction models using cfDNA, nucleosomes, or APACHEII yielded AUC values of 0.61, 0.75, and 0.81, respectively. A model combining nucleosomes with the APACHE II score improved the AUC to 0.84. Diagnostic models distinguishing sepsis from SIRS using procalcitonin, cfDNA(T0), or nucleosomes(T0) yielded AUC values of 0.64, 0.65, and 0.63, respectively. The three parameter model yielded an AUC of 0.74. Conclusions: To our knowledge, this is the first head-to-head comparison of cfDNA and nucleosomes in diagnosing sepsis and predicting sepsis-related mortality. Both cfDNA and nucleosome concentrations demonstrated a modest ability to distinguish sepsis survivors and non-survivors and provided additive diagnostic predictive accuracy in differentiating sepsis from non-infectious SIRS when integrated into a diagnostic prediction model including PCT and APACHE II. A sepsis biomarker strategy incorporating measures of the apoptotic pathway may serve as an important component of a sepsis diagnostic and mortality prediction tool. PMID- 30459951 TI - The role of loops B and C in determining the potentiation of GABAA receptors by midazolam. AB - Many benzodiazepines are positive allosteric modulators (PAMs) of GABAA receptors that cause sedation, hypnosis, and anxiolysis. Benzodiazepines bind GABAA receptors at the extracellular interface of the alpha and gamma subunits. Within the alpha subunit, the benzodiazepine binding site is defined by three highly conserved structural loops, loops A-C. Although previous mutagenesis studies have identified His102 in Loop A as important for benzodiazepine modulation of GABAA receptors, the functional roles of many of the other conserved residues in loops A-C remain incompletely understood. In this study, we made single mutations in loops A-C of the benzodiazepine binding-site across all six alpha subunits. We used whole-cell patch clamp recording to measure the functional effects of these mutations on midazolam potentiation. The results showed that mutating the threonine in loop B and serine in loop C (Thr163 and S206 in human alpha1) did not abolish the receptors' responsiveness to midazolam, as the alpha1(H102R) mutation did. The loop C mutations exhibited a novel array of alpha-isoform specific effects on midazolam potentiation. The alpha3(S230I) and alpha5(S209I) mutations had the largest effect on midazolam potentiation, increasing the efficacy of midazolam. Novel benzodiazepines targeting loop C may represent a future direction for designing new drugs that specifically alter the activity of alpha3- and alpha5-containing GABAA receptors. PMID- 30459952 TI - Utility of Glycosylated TIMP3 molecules: Inhibition of MMPs and TACE to improve cardiac function in rat myocardial infarct model. AB - Tissue Inhibitor of Metalloproteinase 3 (TIMP3) is a secreted protein that has a great utility to inhibit elevated metalloproteinase (MMP) activity in injured tissues including infarcted cardiac tissue, inflamed vessels, and joint cartilages. An imbalance between TIMP3 and active MMP levels in the local tissue area may cause worsening of disease progression. To counter balance elevated MMP levels, exogenous administration of TIMP3 appeared to be beneficial in preclinical studies. However, the current form of WT-TIMP3 molecule has a limitation to be a therapeutic candidate due to low production yield, short plasma half-life, injection site retention, and difficulty in delivery, etc. We have engineered TIMP3 molecules by adding extra glycosylation sites or fusing with albumin, Fc, and antibody to improve pharmacokinetic properties. In general, the C-terminal fusion of TIMP3 improved expression and production in mammalian cells and extended half-lives dramatically 5-20 folds. Of note, a site-specific glycosylation at K22S/F34N resulted in a higher level of expression and better cardiac function compared to other fusion proteins in the context of left ventricle ejection fraction (LVEF) changes in a rat myocardial infarction model. It appeared that cardiac efficacy depends on a high ECM binding affinity, in which K22S/F34N and N-TIMP3 showed a higher binding to the ECM compared to other engineered molecules. In conclusion, we found that the ECM binding and sustained residence of injected TIMP3 molecules are important for cardiac tissue localization and inhibition of adverse remodeling activity. PMID- 30459953 TI - Prevalence of anemia and its associated factors in human immuno deficiency virus infected adult individuals in Ethiopia. A systematic review and meta-analysis. AB - Background: Anemia is a common hematologic disorder among human Immunodeficiency virus (HIV) infected adult Individuals. However, there is no concrete scientific evidence established at national level in Ethiopia. Hence, this review gave special emphasis on Ethiopian HIV infected adult individuals to estimate pooled prevalence of anemia and its associated factors at national level. Methods: Studies were retrieved through search engines in PUBMED/Medline, Cochrane Library, and the web of science, Google and Google scholar following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). Joanna Briggs Institute Meta-Analysis of Statistical Assessment and Review Instrument (JBI-MAStARI) was used for critical appraisal of the included studies. Random effects meta-analysis was used to estimate the pooled prevalence of anemia and associated factors at 95% Confidence interval with its respective odds ratio (OR). Meta regression was also carried out to identify the factors. Moreover, Sub-group analysis, begs and egger test followed by trim-and-fill analysis were employed to assess heterogeneity and publication bias respectively. Result: A total of 532 articles were identified through searching of which 20 studies were included in the final review with a total sample size of 8079 HIV infected adult individuals. The pooled prevalence of anemia was 31.00% (95% CI: 23.94, 38.02). Cluster of Differentiation 4 (CD4) count <= 200 cells/MUl with OR = 3.01 (95% CI: 1.87, 4.84), World Health Organization (WHO) clinical stage III&IV with OR = 2.5 (95% CI: 1.29, 4.84), opportunistic infections (OIs) with OR = 1.76 (95% CI: 1.07, 2.89) and body mass index (BMI) < 18.5 kg/M2 with OR = 1.55 ((95% CI: 1. 28, 1.88) were the associated factors. Conclusion: This review demonstrates high prevalence of anemia among HIV infected adults. Low CD4 count, WHO clinical stage III&IV, OIs and low level of BMI were found to have significant association with the occurrence of anemia. Therefore, the responsible stockholders including anti retro viral treatment (ART) clinics should strengthen the system and procedures for the early diagnosis of opportunistic infection and screening of underlying problems. There should be also early screening for OIs and under nutrition with strict and frequent monitoring of HIV infected individuals CD4 count. PMID- 30459955 TI - Assessment of knowledge, attitude and practice towards disposal of unused and expired pharmaceuticals among community in Harar city, Eastern Ethiopia. AB - Background: Pharmaceuticals are produced and consumed in increasing volume every year. Unfortunately, not all medications that go in to the hand of the consumers get consumed; large quantities remain unused or expire. The accumulation of medication at household and unsafe disposal of unwanted medicines could lead to inappropriate medicine sharing, accidental childhood poisonings and diversion of medicines to illicit use. Methods: A descriptive cross-sectional study was conducted among 695 residents in kebele(ward) 16 of Jinela woreda(district), Harar city from February 27-April 27. A multi-stage sampling technique was used to select individual households. Face-to-face interview using structured questionnaires were conducted to collect data from each study subject. The cleaned data was entered in to epidata analyzed using SPSS version 20 software. Descriptive statistics on sample characteristics was computed including frequencies and percentage and presented using tables and figures. Results: Most participants displayed correct understanding toward medication waste (72.9%) and its effect on environmental if disposed improperly (86%). A large portion of the respondents did not know about drug-take-back system 464 (66.9%). In order to minimize the entry of pharmaceuticals into environment, 68.6% of the participants suggested the need for proper guidance to the consumer. Majority of the respondents believed risk related to the presence of unwanted drug in home, potential harm to children, lack of adequate information on safe disposal practice and need for take-back program. Approximately 66% of the respondents had unused medicine stored at home and the common types of medicines kept in households were analgesics (62.7%) and antibiotics (24%). Preferred ways of disposal of both unused and expired medicine was throwing away in household garbage (53.2%) and two third of them disposed the pharmaceuticals in its original package and dosage form. Conclusion: In present study, there was high practice of keeping medication at home and most disposal approach indicated by the participants was not recommended methods. Awareness about proper disposal of unused and expired medicines among the public should be created. Guidelines on safe disposal are required and an organized method of collecting unused and expired pharmaceuticals needs to be introduced. PMID- 30459954 TI - A ten year review of the sickle cell program in Muhimbili National Hospital, Tanzania. AB - Background: Africa has the highest burden of Sickle cell disease (SCD) but there are few large, systematic studies providing reliable descriptions of the disease spectrum. Tanzania, with 11,000 SCD births annually, established the Muhimbili Sickle Cell program aiming to improve understanding of SCD in Africa. We report the profile of SCD seen in the first 10 years at Muhimbili National Hospital (MNH). Methods: Individuals seen at MNH known or suspected to have SCD were enrolled at clinic and laboratory testing for SCD, haematological and biochemical analyses done. Ethnicity was self-reported. Clinical and laboratory features of SCD were documented. Comparison was made with non-SCD population as well as within 3 different age groups (< 5, 5-17 and >= 18 years) within the SCD population. Results: From 2004 to 2013, 6397 individuals, 3751 (58.6%) SCD patients, were enrolled, the majority (47.4%) in age group 5-17 years. There was variation in the geographical distribution of SCD. Individuals with SCD compared to non-SCD, had significantly lower blood pressure and peripheral oxygen saturation (SpO2). SCD patients had higher prevalence of severe anemia, jaundice and desaturation (SpO2 < 95%) as well as higher levels of reticulocytes, white blood cells, platelets and fetal hemoglobin. The main causes of hospitalization for SCD within a 12-month period preceding enrolment were pain (adults), and fever and severe anemia (children). When clinical and laboratory features were compared in SCD within 3 age groups, there was a progressive decrease in the prevalence of splenic enlargement and an increase in prevalence of jaundice. Furthermore, there were significant differences with monotonic trends across age groups in SpO2, hematological and biochemical parameters. Conclusion: This report confirms that the wide spectrum of clinical expression of SCD observed elsewhere is also present in Tanzania, with non-uniform geographical distribution across the country. Age-specific analysis is consistent with different disease-patterns across the lifespan. PMID- 30459956 TI - Neuter status as a risk factor for canine intervertebral disc herniation (IVDH) in dachshunds: a retrospective cohort study. AB - Background: Intervertebral disc herniation (IVDH) involves displacement of the intervertebral disc secondary to disc degeneration and is extremely common in dachshunds. Clinical signs include pain with or without paresis or paralysis. Mortality rate is high and some cases are left with permanent disability even after treatment. Aims of this study were twofold: Firstly, to investigate whether neutering, i.e. gonadectomy, is associated with increased risk of IVDH in dachshunds, and secondly to investigate whether age of neutering alters risk of IVDH in this breed.Information was obtained for 1964 dachshunds from the owner survey, "Dachslife 2015". For dachshunds that were >= 3 years and < 10 years old at the time of the survey (1073 individuals) incidence of IVDH was compared between early-neutered (< 12 months), late-neutered (> 12 months) and entire animals of each gender. Results: Neutered females were at significantly higher risk of IVDH than entire females (risk ratio 1.81, 95% CI 1.28-2.54). For males, incidence of IVDH in neutered as compared with entire dachshunds was increased but this difference was not quite statistically significant (risk ratio 1.38, 95% CI 0.96-1.99).For both genders, this study demonstrated significantly increased risk of IVDH in early-neutered dachshunds (before 12 months old) as compared with those neutered late (after 12 months old). For early neutered males, risk ratio was 1.54 (95% CI 1.07-2.22). For early-neutered females, risk ratio was 2.12 (95% CI 1.44-3.11). Conclusion: Results from this retrospective study suggest that gonadectomy, especially if performed before 12 months old, increases risk of IVDH in this breed. Decisions regarding neutering should be made on an individual basis, taking a range of pros and cons into account. Considering the high prevalence, morbidity and mortality of IVDH in dachshunds, increased IVDH risk associated with neutering is a key factor to consider in deciding whether and when to neuter. PMID- 30459957 TI - Effect of coadministration of rifampicin on the pharmacokinetics of linezolid: clinical and animal studies. AB - Background: Combination therapy of linezolid (LZD) and rifampicin (RFP) may be more effective than monotherapy for treating gram-positive bacterial infections, but several studies have suggested that RFP decreases LZD exposures, thereby increasing the risk of therapeutic failure and emergence of LZD-resistant strains. However, the mechanism of the drug-drug interaction between LZD and RFP is unknown. Methods: We conducted a prospective, open-label, uncontrolled clinical study in Japanese patients receiving LZD and RFP to evaluate the effect of coadministered RFP on the concentration of LZD. In animal study in rats, the influence of coadministered RFP on the pharmacokinetics of LZD administered intravenously or orally was examined. Intestinal permeability was investigated with an Ussing chamber to assess whether coadministered RFP alters the absorption process of LZD in the intestine. Results: Our clinical study indicated that multiple doses of RFP reduced the dose-normalized trough concentration of LZD at the first assessment day by an average of 65%. In an animal study, we found that multiple doses of RFP significantly decreased the area under the concentration time curve, the maximum concentration and the bioavailability of orally administered LZD by 48%, 54% and 48%, respectively. In contrast, the pharmacokinetics of intravenously administered LZD was unaffected by the RFP pretreatment. However, investigation of the intestinal permeability of LZD revealed no difference in absorptive or secretory transport of LZD in the upper, middle and lower intestinal tissues between RFP-pretreated and control rats, even though RFP induced gene expression of multidrug resistance protein 1a and multidrug resistance-associated protein 2. Conclusions: Therapeutic drug monitoring may be important for avoiding subtherapeutic levels of LZD in the combination therapy. The drug-drug interaction between LZD and RFP may occur only after oral administration of LZD, but is not due to any change of intestinal permeability of LZD. Trial registration: UMIN, UMIN000004322. Registered 4 October 2010. PMID- 30459958 TI - Vaccination of 1-day-old pigs with a porcine reproductive and respiratory syndrome virus (PRRSV) modified live attenuated virus vaccine is able to overcome maternal immunity. AB - Background: The objective of the study was to evaluate the influence of maternally derived antibodies (MDA) on the efficacy of a PRRSV-1 based attenuated vaccine, when administered in 1 day-old piglets by the intramuscular route. The protective immunity of the modified live virus vaccine was evaluated in pigs born from seropositive sows, vaccinated at 1 day of age, upon inoculation with a PRRSV 1 isolate. The animals were challenged when the levels of MDAs detected by seroneutralization test (SNT) in the non-vaccinated control group became undetectable (10 weeks after vaccination). Results: A protective effect of vaccination was observed since a significant reduction of viral load in serum compared to the control group was detected in all sampling days after challenge; efficacy was supported by the significant reduction of nasal and oral shedding as well as in rectal temperatures. Clinical signs were not expected after the inoculation of a PRRSV-1 subtype 1 challenge strain. However, the challenge virus was able to develop fever in 61% of the control pigs. Vaccination had a positive impact on rectal temperatures since the percentage of pigs that had fever at least once after challenge was reduced to 31% in vaccinated animals, and control pigs had significantly higher rectal temperatures than vaccinated pigs 3 days post-challenge. The lack of a vaccination effect in body weight gain was probably due to the short evaluation period after challenge (10 days). In the vaccinated group, 9/16 pigs (56%) experienced an increase in ELISA S/P ratio from the day of vaccination to 67 days post-vaccination. All vaccinated pigs were seropositive before challenge, indicating the development of an antibody response following vaccination even in the face of MDAs. In contrast to ELISA results, only 2/16 vaccinated pigs developed neutralizing antibodies detectable by a SNT that used a subtype 1 MA-104 adapted strain. Even in the absence of SN antibodies, vaccinated pigs were protected from challenge with a heterologous strain. The role of cell mediated immunity should be considered, if protection was not mediated by SN antibodies only. Conclusions: The efficacy of the attenuated PRRSV-1 vaccine in 1 day-old pigs seropositive to PRRSV prior to a PRRSV-1 challenge was demonstrated by improvement of clinical, virological and immunological variables. With the current experimental design, maternal immunity did not interfere with the development of a protective immune response against a PRRSV-1 challenge, after vaccination of 1 day-old pigs. Confirmation of these results under field conditions will be needed. PMID- 30459959 TI - Testing the effectiveness of REACH Pregnancy Circles group antenatal care: protocol for a randomised controlled pilot trial. AB - Background: Antenatal care is an important public health priority. Women from socially disadvantaged, and culturally and linguistically diverse groups often have difficulties with accessing antenatal care and report more negative experiences with care. Although group antenatal care has been shown in some settings to be effective for improving women's experiences of care and for improving other maternal as well as newborn health outcomes, these outcomes have not been rigorously assessed in the UK. A pilot trial will be conducted to determine the feasibility of, and optimum methods for, testing the effectiveness of group antenatal care in an NHS setting serving populations with high levels of social deprivation and cultural, linguistic and ethnic diversity. Outcomes will inform the protocol for a future full trial. Methods: This protocol outlines an individual-level randomised controlled external pilot trial with integrated process and economic evaluations. The two trial arms will be group care and standard antenatal care. The trial will involve the recruitment of 72 pregnant women across three maternity services within one large NHS Acute Trust. Baseline, outcomes and economic data will be collected via questionnaires completed by the participants at three time points, with the final scheduled for 4 months postnatal. Routine maternity service data will also be collected for outcomes assessment and economic evaluation purposes. Stakeholder interviews will provide insights into the acceptability of research and intervention processes, including the use of interpreters to support women who do not speak English. Pre-agreed criteria have been selected to guide the decision about whether or not to progress to a full trial. Discussion: This pilot trial will determine if it is appropriate to proceed to a full trial of group antenatal care in this setting. If progression is supported, the pilot will provide authoritative high-quality evidence to inform the design and conduct of a trial in this important area that holds significant potential to influence maternity care, outcomes and experience. Trial registration: ISRCTN ISRCTN66925258. Registered 03 April 2017. Retrospectively registered. PMID- 30459960 TI - Research protocol: general practice organ donation intervention-a feasibility study (GPOD). AB - Background: New interventions are required to increase the number of people donating their organs after death. In the United States of America (USA), general practice has proved to be a successful location to increase organ donor registration. However, a dearth of research exists examining this in the United Kingdom (UK). due to the unique challenges presented by the National Health Service (NHS). This protocol outlines a feasibility study to assess whether UK general practice is a feasible and acceptable location for organ donation intervention targeting NHS Organ Donor Register (NHS ODR) membership. Methods: The primary intervention element, prompted choice, requires general practice to ask patients in consultations if they wish to join the NHS ODR. Two additional intervention techniques will be used to support prompted choice: staff training and leaflets and posters. The intervention will run for 3 months (April-July 2018) followed by a period of data collection. The following methods will be used to assess feasibility, acceptability and fidelity: registration data, a training evaluation survey, focus groups with staff and online surveys for staff and patients. Discussion: By examining the feasibility, acceptability and fidelity of a prompted choice intervention in UK general practice, important knowledge can be gathered on whether it is a suitable location to conduct this. Additional learning can also be gained generally for implementing interventions in general practice. This could contribute to the knowledge base concerning the feasibility of NHS general practice to host interventions. Trial registration: International Standard Randomised Controlled Trial Number ISRTN44530504 (Jones et al, General practice organ donation intervention: a feasibility study ISRCTN44530504, 2017) Registration on 26 September 2017. PMID- 30459962 TI - Liver involvement by multiple myeloma presenting as hypervascular focal lesions in a patient with chronic hepatitis B infection. AB - Extramedullary myeloma refers to the infiltration of neoplastic monoclonal plasma cells in either organs or soft tissues. The disease is clinically and radiologically underestimated compared with the autopsy findings and is usually associated with a more aggressive clinical course and poorer outcome. A minority of patients with extramedullary myeloma show hepatic involvement, usually in the form of diffuse parenchymal infiltration. When focal infiltration is present, variable imaging findings have been described both on CT scan and MRI. We report the case of a 63-year-old male with hepatitis B virus-related liver disease and biopsy-proven multiple myeloma involving the liver, manifesting as hypervascular focal liver lesions on MRI. A brief review of the literature is also proposed. PMID- 30459961 TI - The help for people with money, employment or housing problems (HOPE) intervention: pilot randomised trial with mixed methods feasibility research. AB - Background: Job loss, austerity measures, financial difficulties and house repossession contribute to the risk of self-harm and suicide during recessions. Navigating the benefits system and accessing sources of welfare and debt advice is a difficult experience for vulnerable people, further contributing to their distress. Whilst there is some evidence that advice-type interventions can lead to financial gain, there is mixed evidence for their effectiveness in improving mental health in those experiencing financial difficulties. There have been no interventions targeting those who have self-harmed due to economic hardship. Methods: Our aim was to determine the feasibility and acceptability of a brief psychosocial intervention (the 'HOPE' service) for people presenting to hospital emergency departments (ED) following self-harm or in acute distress because of financial, employment or welfare (benefit) difficulties. Nineteen people consented to random allocation to the intervention or control arm on a 2:1 basis. Participants randomised to the intervention arm (n = 13) received up to six sessions of 1:1 support provided by community support staff trained in Motivational Interviewing (MI). Control participants (n = 6) received a one-off session signposting them to relevant support organisations. Fourteen participants were followed up after 3 months. Participants and mental health workers took part in qualitative interviews. The acceptability of outcome measures including the PHQ-9, GAD-7, repeat self-harm, EQ5D-5 L and questions about debt, employment and welfare benefits were explored. Results: Interviews indicated the main benefits of the service as the resolution of specific financial problems and receiving support when participants were feeling most vulnerable. Randomisation was acceptable to most participants although not always fully understood and control participants could be disappointed. Recruitment was slow (1-2 per month). The outcome measures were acceptable and appeared sensitive to change. Discussion: The HOPE intervention is feasible and acceptable. There was evidence of need and it is a relatively inexpensive intervention. Refining aspects of the intervention would be straightforward. A full-scale RCT would be feasible, if broadened eligibility criteria led to increased recruitment and improvements were made to staff training and support. Trial registration: ISRCTN58531248. PMID- 30459963 TI - Imaging characteristics of nodal metastases in paraganglioma, ameloblastoma and olfactory neuroblastoma: case reports and literature review. AB - Paraganglioma, ameloblastoma and olfactory neuroblastoma are uncommon primary head and neck tumours. When nodal metastases from these tumours occur, they may present later than and with different imaging characteristics compared with squamous cell carcinoma (SCC), demonstrating appearances similar to the primary tumour type rather than features typical of metastatic nodal SCC. We present three cases in which imaging characteristics of nodal metastases in paraganglioma, ameloblastoma and olfactory neuroblastoma mimicked the primary tumour and discuss their implications for clinicoradiological follow-up. PMID- 30459964 TI - An unusual case of ectomesenchymal chondromyxoid tumour of the left tonsillar bed: imaging and histopathologic features. AB - We describe a case of a rare soft-palatal and parapharyngeal mass in an adult woman. A 71-year-old female presented with a huge mass protruding from the soft palate, complaining about difficulty in swallowing for the past 4 months. After inspection and ear nose and throat fibroscopy, in which the mass appeared regular shaped and with a regular mucosa, the patient underwent a CT scan and MRI examination. The CT scan showed an oval, not-infiltrating, hypodense mass including a discrete irregular-shaped central calcification, while the MRI examination confirmed the non-infiltrating growth and showed that around the calcified core, the lesion was surrounded by fat. After surgical removal, the histopathologic diagnosis was that of an "ectomesenchymal chondromyxoid tumour". Ectomesenchymal chondromyxoid tumour is a rare benign neoplasm arising from the tongue. Although only 45 cases have been reported in the literature, there are several unique features that define this lesion. Ours is the first case with a complete CT scan and MRI with diffusion imaging description. PMID- 30459965 TI - Enlargement of the brachial plexus on magnetic resonance imaging: a novel finding in adult-onset Krabbe disease. AB - Adult-onset Krabbe disease is an autosomal recessive degenerative leukodystrophy that presents with bilateral corticospinal tract involvement on MRI. Although peripheral nerve involvement is a known manifestation of Krabbe disease, MRI findings of peripheral nerve abnormalities are limited to the cranial nerves and spinal nerve roots. In this case report, we discuss two cases of adult-onset Krabbe disease with brachial plexus enlargement on MRI. Adult-onset Krabbe disease should be included in the differential diagnoses when brachial plexus enlargement and white matter lesions involving corticospinal tracts present simultaneously. PMID- 30459967 TI - Renal fungal ball-two case reports and review of literature. AB - Fungal ball or fungal bezoar is the saprophytic colonization of a pre-formed cavity by a conglomerate of fungal mycelia without invasion of the adjacent tissue. Fungal bezoar is seen commonly in immunocompromised individuals. We describe the cross-sectional imaging characteristics of two cases of renal fungal ball, a rare clinical entity. The first case is that of a 36-year-old female with diabetes who presented with a single fungal ball that caused ballooning of the renal pelvis by coelomycetes, a rare species of fungi. The second case is that of a 45-year-old immunosuppressed male with diabetes who presented with multiple Candida albicans fungal balls and emphysematous pyelonephritis. Awareness about the various imaging findings of this rare clinical entity and a high index of suspicion in high-risk individuals will help in overcoming the challenges in early diagnosis and, thereby, institution of proper treatment. PMID- 30459966 TI - Fibromatosis involving pelvic floor muscles. AB - Fibromatosis or desmoid tumour is a benign fibroblastic proliferation with aggressive infiltrative growth. High incidence of recurrence is noted after incomplete resection of the involved margins of the lesion. Pelvic fibromatosis is a rare condition and usually affects females. Patients frequently complain of pelvic pain, which can mimic gynaecological abnormalities. A case of pelvic fibromatosis involving pelvic floor muscles with unchanged appearance during 5 years of follow-up is presented. PMID- 30459968 TI - Disseminated peritoneal leiomyomatosis: a rare cause of enigmatic peritoneal masses. AB - Disseminated peritoneal leiomyomatosis (DPL) is an unusual extrauterine form of leiomyoma that has been found to coexist with its intrauterine counterpart in individuals who have previously undergone laparoscopic myomectomy. The presence of extrauterine masses with the density of smooth muscle on CT imaging and/or with a low signal intensity similar to that of smooth muscle on T 2 weighted MRI in a patient presenting with associated intrauterine leiomyoma and/or a history of previous laparoscopic myomectomy suggests the possibility of DPL. Imaging studies help in diagnosing and delineating the location and extent of the lesion and also follow-up the masses to look for sarcomatous transformation. Here we report the case of a 43-year-old female who presented initially with right lower quadrant pain. Her CT scan and MRI demonstrated a fundal fibroid with multiple intraperitoneal soft tissue masses of similar appearance and contrast enhancement in the sigmoid mesocolon, the left paracolic gutter and adjacent to the ascending colon. The suspected diagnosis of DPL was confirmed during abdominal hysterectomy, bilateral salphingo-oophorectomy and excision of peritoneal masses. PMID- 30459969 TI - Ischaemic stroke induced by neurocysticerosis, presenting as a clinical and radiological dilemma. AB - Neurocysticercosis (NCC) is a central nervous system parasitic infection with various clinical presentations, rarely manifesting as an acute stroke. The radiological appearance of this disease entity may be non-specific, at times mimicking an intracranial neoplasm. Early diagnosis requires a high index of suspicion. Serological testing is helpful and, if utilized early, can reduce the morbidity associated with invasive diagnostic techniques. We describe a case of a 32-year-old previously healthy male who presented with neurological deficits. A cystic lesion in the right sylvian cistern was noted, initially identified as a benign arachnoid cyst. The patient's symptoms rapidly progressed to an acute stroke. Follow-up imaging including an MRI of the brain demonstrated a right middle cerebral artery territory infarct adjacent to the cystic lesion, which had been diagnosed as an arachnoid cyst on an initial CT scan. Appearance of the cystic lesion on MRI, however, was concerning for a brain neoplasm or an abscess. Given the contiguity of the cystic mass to the right middle cerebral artery, it was suggested that the mass was the likely aetiology of the patient's symptoms. A stereotactic biopsy of the cystic lesion was performed and revealed it to be NCC. The hospital course was complicated by intracranial hypertension and cerebral oedema requiring craniectomy. Our case highlights the importance of considering NCC in the differential diagnosis of stroke in patients coming from endemic regions, especially in younger patients lacking the usual risk factors for cerebrovascular disease. PMID- 30459970 TI - Transjugular retrieval of a knotted peripherally inserted central venous catheter (Epicutaneo-Cava catheter) in a neonate. AB - Knotting of intravascular catheters has been well described, and all such cases documented in the literature have occurred during catheter insertion. Knot formation has not been reported during the removal of a peripherally inserted central venous line (Epicutaneo-Cava 2 French 24 gauge) in a neonate. The mechanism of knotting in our case is not fully understood. This case emphasizes the value of plain radiography in detecting the presence of a knot in the line, and is being presented to raise the awareness about knot formation if undue resistance is felt during line removal. Early recognition of this rare but serious complication may avoid line fracture and potential fragment embolization. PMID- 30459971 TI - Gallbladder volvulus: it's a small whirl. AB - An 85-year-old female with an extensive past medical history attended our accident and emergency department with vague abdominal pain and distension. Clinical examination and initial blood tests demonstrated features of sepsis and she was commenced on broad spectrum antibiotics. Following admission, a contrast enhanced CT scan of the abdomen and pelvis was performed, which showed an unusual configuration of the gallbladder. There was significant luminal distension of the gallbladder, which was found to lie in an unusual horizontal position anterior to the liver edge. This was a new finding compared with a recent CT pulmonary angiogram that demonstrated a normal gallbladder anatomy. In addition, there was abrupt angulation of the gallbladder neck, demonstrating a "beak" sign as well as indrawing of the vascular pedicle forming a mini "swirl" sign. The constellation of gallbladder distension, abnormal lie, "beak" and mini "swirl" sign together is a strong indicator of gallbladder torsion. Coexistent right lower lobe pneumonia was noted. The patient was too frail for surgical intervention and succumbed to underlying sepsis. Post-mortem examination demonstrated a gangrenous gallbladder secondary to volvulus. We present a rare case of gallbladder volvulus and highlight CT findings to help the radiologist make a pre-operative diagnosis. PMID- 30459972 TI - Proximal tibiofibular dislocation: a case report of this often overlooked injury. AB - Tibiofibular dislocation is a condition that is a recognized cause of lateral knee pain in trauma patients and can occur in isolation or as a part of multiple injuries. There is usually prominence of the fibular head on clinical examination, with tenderness to palpation. Radiological investigation can confirm the diagnosis, and in the case or our patient, both plain radiographs and MRI were performed. MRI permitted pre-reduction assessment of the intrinsic knee ligaments, as well as the common peroneal nerve. The dislocated fibular head was successfully relocated under general anaesthesia as a closed reduction. PMID- 30459973 TI - Tram-track-like calcification in adult optic pathway glioma. AB - Gliomas of the optic pathways that occur in adults are rare tumours. The tram track-like calcification of the optic nerve, which classically occurs with meningioma, has not been reported so far in optic pathway gliomas. Here, we present a case of high-grade glioma of the optic pathway with tram-track-like calcification of the optic nerve in a 42-year-old male. This case enhances our understanding of the MRI features of adult malignant optic pathway glioma. PMID- 30459974 TI - Unilateral sublingual salivary gland hypertrophy with herniation through a boutonniere defect and contralateral sublingual gland hypoplasia. AB - A 74-year-old male attended our ear, nose and throat clinic with left-sided otalgia. MRI highlighted an area of abnormal signal in the region of the right mylohyoid muscle in the floor of the oral cavity. The patient was called back for a post-contrast MRI scan for clarification. Post-contrast MRI demonstrated a left sided hypoplastic sublingual salivary gland and a hypertrophied right-sided sublingual salivary gland. The left sublingual gland hypoplasia had resulted in compensatory hypertrophy of the contralateral (right) sublingual salivary gland, extending through the mylohyoid gap or "boutonniere defect". This is a common incidental variant often encountered in radiological imaging. This is the only report of a case of contralateral compensatory hypertrophy of sublingual salivary gland, as all the others have reported ipsilateral hypertrophy of either submandibular salivary glands. PMID- 30459975 TI - Brachial pseudoaneurysm of the neonate with partial response to thrombin injections and late spontaneous thrombosis and regression during expectant management. AB - We illustrate the case of a brachial pseudoaneurysm in a 32-week preterm baby male who presented with a large pulsatile mass in the right antecubital fossa, with no clear aetiologic factor. The management of this type of lesion has been controversial and based mainly on case reports. In this case, after obtaining partial response with two thrombin injections, it spontaneously regressed during expectant management. This combination of therapeutic options may be an alternative for the management of complex lesions and, to the best of our knowledge, has not been previously reported. PMID- 30459976 TI - MRI of giant cell tumour of larynx: marked T 2 hypointensity due to abundant haemosiderin deposition. AB - Giant cell tumours (GCTs) are benign tumours commonly found in the long bones. Rarely, they may occur in the larynx, often resulting in hoarseness and anterior neck swelling. Since Wessely reported the first case of laryngeal GCT in 1940, 35 cases have been identified. Herein, we present a case of a 53-year-old male with GCT of the larynx that showed T 1 and T 2 hypointense signal on MRI, presumably owing to abundant haemosiderin deposition. We also discuss the imaging findings of CT and 18F-fludeoxyglucose positron emission tomography scans, as well as the pathological correlation. PMID- 30459977 TI - An uncommon cause of ascites: uroperitoneum from iatrogenic bladder fistula detected by CT urography. AB - We report the case of a female who underwent laparoscopic hysterectomy and was referred to the emergency department with massive ascites 10 days later. Anamnestic background and clinical presentation suggested the occurrence of a urinary lesion, which was investigated by CT urography. CT urography with ultra late excretory phase showed the leakage of iodinated contrast agent from the bladder dome into the peritoneal cavity, as expected in uroperitoneum from iatrogenic bladder laceration. CT cystography is the reference standard for the assessment of bladder leakage; however, this technique is quite invasive, time consuming and does not provide a panoramic overview of the entire excretory system. Conversely, CT urography provides a complete overview of the entire excretory system by means of an optimized protocol with optional ultra-late acquisition to gain adequate bladder distension and depict minor urinary leakage. PMID- 30459978 TI - Implantation cutaneous tuberculosis after ultrasound-guided fine needle aspiration cytology. AB - A 45-year-old female presented with recurrent biliary pain, fever, anorexia and weight loss of 3 months duration. She was on highly active antiretroviral therapy for underlying human immunodeficiency virus infection for the past 5 months. Clinical examination revealed a 3-cm firm hepatomegaly. Investigations suggested mild anaemia, elevated erythrocyte sedimentation rate, deranged liver function tests, Mantoux test of 25 mm and CD4 count of 417 cells MUl-1. Ultrasonography revealed mild central intrahepatic biliary radical dilatation with a dilated common bile duct and multiple periportal and peripancreatic lymph nodes. Ultrasound-guided fine needle aspiration cytology (FNAC) from the periportal lymph node was performed twice. Both were reported as only bloody aspirate. The patient developed an erythematous tender skin nodule at the site of insertion of the FNAC needle 15 days after the second FNAC procedure. An excision biopsy of the nodule showed ill-formed epithelioid cell granulomas with acid-fast bacilli, indicating tuberculosis. The patient was started on antitubercular therapy with complete response. PMID- 30459979 TI - A case of I-cell disease (mucolipidosis II) presenting with short femurs on prenatal ultrasound and profound diaphyseal cloaking. AB - A 28-year-old G3 P1 SAB1 female with no prior health concerns was found to have a foetus with short femurs on prenatal ultrasound following an abnormal maternal serum screen result. Fluid obtained by amniocentesis revealed an elevated alpha fetoprotein level with absence of an acetylcholinesterase band and normal male karyotype (46,XY). Follow-up ultrasound 3 weeks later again demonstrated short femur lengths, but no other abnormalities. At birth, the child was noted to have multiple dysmorphic features, including short humeri and femurs, coarse facial features, retrognathia and yellowish hypertrophic gums in addition to hyperbilirubinaemia and thrombocytopenia. Radiological studies demonstrated bony demineralization with profound diaphyseal cloaking in the long bones. Genetic testing diagnosed I-cell disease. PMID- 30459980 TI - MUGA image artefacts caused by metallic injection ports in breast reconstruction tissue expanders: a report of two breast cancer patients. AB - Expander-based breast reconstruction is a popular form of post-mastectomy reconstruction and involves the temporary subcutaneous implantation of breast tissue expanders that require periodic, incremental inflation with sterile saline by injection until the desired amount of tissue is developed. One type of tissue expander injection port system currently on the market is made of titanium and rare-earth magnets that enhance injection accuracy. These highly dense metallic materials, however, can cause attenuation artefacts on multiple gated acquisition cardiac studies. In this report, we present the cases of two breast cancer patients with artefacts on multiple gated acquisition scans, characteristic of these tissue breast expanders. PMID- 30459981 TI - Use of 18F-fludeoxyglucose positron emission tomography-CT in the management of breast implant-associated anaplastic large cell lymphoma. AB - The prognosis and preferred management of breast implant-associated anaplastic large cell lymphoma is dependent on whether lymphoproliferative cells are confined to within the fibrous capsule, in an effusion or lining the fibrous capsule, or if there is spread beyond the capsule in the form of a mass lesion. We describe a case where 18F-fludeoxyglucose positron emission tomography-CT was used to confirm localized disease and guide management decisions. PMID- 30459982 TI - Scrotal migration of inguinal hernia repair mesh: an unusual cause of testicular mass. AB - Scrotal masses are common findings in primary care and can develop from all anatomical structures of the scrotum. They are usually painless, although pain may be present occasionally. In this report, we present the case of an unusual testicular mass caused by the migration in the scrotum of a mesh used for inguinal hernia repair. The patient was treated conservatively owing to the spontaneous resolution of symptoms. PMID- 30459983 TI - Bilateral variant origin of subclavian artery branches. AB - Subclavian artery branching patterns have been studied in cadaveric series and frequencies of the many variations have been documented. However, such variations have been seldom noticed antemortem. Here, we present the case of a very rare type of bilaterally different branching pattern of the subclavian artery. PMID- 30459984 TI - Intra-abdominal desmoplastic small round cell tumour: staging and surveillance with 18F-FDG PET/CT following peritonectomy and HIPEC. AB - Intra-abdominal desmoplastic small round cell tumours are rare aggressive tumours of mesothelial origin with less than 60 cases reported in the literature. They are difficult to treat and the role of 18F-fludeoxyglucose positron emission tomography (PET)/CT scan in their management has not been established. A 41-year old male presented with a 21-cm desmoplastic small round cell tumour and was managed with radiotherapy, surgery and chemotherapy, with each treatment monitored and guided by 18F-fludeoxyglucose PET/CT scan. We present the imaging findings of the serial PET/CT scans of this patient and their impact on management. PMID- 30459986 TI - MRA-based 3D-printed heart model-an effective tool in the pre-surgical planning of DORV. AB - A three-dimensional (3D) printed heart model based on contrast-enhanced MR angiography data was obtained in an 8-month-old male child with double-outlet right ventricle. The model could successfully show the spatial relationship between the aortic annulus, the pulmonary valve and the ventricular septal defect. The patient underwent complete intracardiac repair based on the 3D model. MR angiography images could be successfully used to create a true-size 3D heart model, which significantly helped in assessing the routability of the ventricular septal defect to the aorta, leading to successful intracardiac repair in our patient. PMID- 30459985 TI - Tumoral calcinosis in the lumbar spine secondary to systemic sclerosis: a rare cause of radiculopathy in an adult with advanced disease. AB - Calcinosis is frequently associated with systemic sclerosis (SSc) and can be located at various sites, although it is most commonly seen in the hands. When it presents around the synovial joints and is associated with a mass-like appearance, it is classically called tumoral calcinosis. Few cases of tumoral calcinosis have been reported in the paraspinal region. They are usually located in the cervical segment and rarely in the lumbar region. Occasionally, they have been associated with nerve root compression and intraspinal extension. We report the case of a 47-year-old female with advanced SSc who presented to our hospital's radiology department with chronic low back pain and right L5 radiculopathy due to tumoral calcinosis. An initial lumbar spine MRI showed multifocal, low signal, mass-like lesions involving the right paraspinal soft tissues. At the L5-S1 level, one lesion compressed the right L5 exiting nerve root. A CT scan of the lumbar spine performed later demonstrated the calcified nature of the lesions depicted by MRI and evidenced signs of pulmonary fibrosis at the base of the lungs. Further clinical work-up also showed that the patient had Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, dyspnoea, facial telangiectasias, generalized weakness and arthralgia. The diagnosis of a subtype of SSc, called limited cutaneous SSc, was made. Our case describes the CT and MRI findings of tumoral calcinosis in an unusual location secondary to limited cutaneous SSc. Knowledge of the imaging features of this uncommon manifestation of SSc could potentially increase its prospective diagnosis and hence improve patient management. PMID- 30459987 TI - Extensive polyostotic fibrous dysplasia evaluated for malignant transformation with 99mTc-MDP bone scan and 18F-FDG PET/CT. AB - Fibrous dysplasia accounts for approximately 7% of benign bone tumours and is a developmental disorder of unknown aetiology. Malignant transformation has been reported in 0.4% of all cases of fibrous dysplasia, and the use of 18F fludeoxyglucose positron emission tomography/CT scan in the evaluation of malignant transformation has not yet been established. A 72-year-old male with a long-standing history of polyostotic fibrous dysplasia presented with chest and back pain and was evaluated with a 99mTc-methylene diphosphonate bone scan as well as an 18F-fludeoxyglucose positron emission tomography/CT scan to define the extent of bone involvement and assess for possible malignant transformation. We present the imaging findings as well as the long-term follow-up of this case. PMID- 30459988 TI - Imaging appearance of a post-intubation cricoid chondronecrosis. AB - Chondronecrosis is a known complication of external beam radiation therapy and endotracheal intubation. Radiation therapy is the most common cause of chondronecrosis owing to local cartilage ischaemia following treatment. Prolonged endotracheal intubation can lead to chondronecrosis as it is associated with excessive pressure on the cartilage by the endotracheal tube or its cuff. The cricoid ring is the most commonly affected cartilage. CT imaging is an integral part of the workup, although reports on imaging appearances are scant. We report the imaging and clinical presentation of a case of chondronecrosis secondary to the use of endotracheal tube ventilation. The patient was managed conservatively with good clinical outcome. PMID- 30459989 TI - Appearance of CNS histoplasmosis on 18F-FDG PET/CT with MRI correlation. AB - Disseminated histoplasmosis is an opportunistic infection encountered in immunocompromised patients such as those with human immunodeficiency virus infection/acquired immune deficiency syndrome. Involvement of the central nervous system (CNS) can occur in 5-20% of cases of disseminated histoplasmosis, and CNS histoplasmosis can be very difficult to diagnose via conventional imaging modalities such as CT or MRI. The role of 18F-fludeoxyglucose positron emission tomography/CT scan in the diagnosis of CNS histoplasmosis has not been established. A 66-year-old female presented with dizziness and unsteady gait and was diagnosed with human immunodeficiency virus infection and CNS histoplasmosis. In this report, we present the MRI and 18F-fludeoxyglucose positron emission tomography/CT image findings. PMID- 30459990 TI - 18F-FDG PET/CT imaging and PET-guided biopsy in evaluation and treatment decision in adrenal histoplasmosis. AB - Histoplasmosis is a rare opportunistic fungal infection. It is commonly seen in immunocompromised individuals from endemic areas. Adrenal glands are frequently involved in the disseminated disease. Here, we present the case of a retropositive patient with constitutional symptoms, where whole-body positron emission tomography/CT scan revealed intense 18F-fludeoxyglucose uptake in bulky adrenal glands, and subsequent positron emission tomography-guided biopsy helped in establishing the diagnosis of adrenal histoplasmosis. PMID- 30459991 TI - Lipoma of vallecula-a case report. AB - Lipomas of the larynx, oropharynx and hypopharynx are rare, accounting for approximately 1% of benign laryngeal neoplasms. We present a rare case of a simple lipoma arising from the right vallecula. A 55-year-old male presented with worsening dysphagia for 1 week. CT scan revealed a lesion of fat attenuation in the right vallecula. The patient underwent surgical excision and recovered uneventfully. To our knowledge, there are only two cases of vallecular lipoma that have been reported and they are both of spindle cell subtype and located on the left side. This is the first reported case of a simple lipoma arising from the right vallecula and causing obstructive symptoms. CT scan or MRI is essential in confirming the diagnosis and assessing the extent, thus allowing prompt excision, especially when the patient is symptomatic. PMID- 30459992 TI - 76-year-old gentlemen with primary cardiac lymphoma presenting as acute coronary syndrome and atrioventricular block. AB - We report the case of an immunocompetent patient who presented with symptoms suggestive of acute coronary syndrome and was found to be in complete heart block. He re-presented within 2 months with worsening breathlessness and investigations confirmed infiltrative cardiac disease. We describe here an uncommon presentation of primary cardiac lymphoma as acute coronary syndrome and atrioventricular block. PMID- 30459993 TI - CT: the imaging of choice in the diagnosis of coronary artery fistulae. AB - Coronary artery fistulae are rare abnormal communications between coronary arteries and cardiac chambers or great vessels. We report a patient with a complex congenital fistula between the pulmonary artery and both the left anterior descending and the right coronary artery, originally diagnosed on routine coronary angiography and subsequently followed up and further elucidated with CT coronary angiography. PMID- 30459994 TI - Combination of dabrafenib and radiotherapy: could skin toxicity be affected by different irradiation techniques? AB - The prognosis of patients with metastatic melanoma is changing owing to the introduction of selective BRAF inhibitors combined with MEK inhibitors. Management of these patients continues to be a challenge, especially when systemic therapy has to be combined with concomitant radiotherapy, particularly owing to skin toxicity. Here we report a case of a patient who underwent concomitant treatment for two vertebral sites using two different radiotherapy techniques. An unexpected acute skin toxicity was reported at one of the treated sites. This finding might be owing to the different absorbed dose to the subcutaneous tissues linked with the technique of irradiation. PMID- 30459995 TI - Calcifying pseudoneoplasm of the neuraxis (CaPNoN): an unusual cause of third nerve palsy in a teenager. AB - An 18-year-old part-time teacher presented with headache and diplopia. Physical examination showed partial left oculomotor palsy. Neurology examination was otherwise unremarkable. Cross-sectional imaging was arranged for investigation of third nerve palsy. On CT scan, the lesion was calcified, and on MRI, hypointense on T 1 and T 2 weightedimages with thin rim enhancement, resembling an atypical meningioma. CT angiogram showed no vascular connection. Following worsening diplopia and a slight increase in lesion size on follow-up MRI, the patient was re-reviewed in our regional skull base multidisciplinary team meeting, where a decision for excision was made. Pre-operatively, the absence of a vascular connection was confirmed on catheter angiogram. Histopathological examination demonstrated features typical of calcified pseudoneoplasm of the neuraxis, with extensive metaplastic calcification with stroma containing variable fibrovascular tissue and focal inflammatory cell infiltrates, spindle and epithelioid cells, and psammoma bodies at the rim of the lesion. Following surgery, the patient had persisting diplopia. He remains under clinical review. As surgical resection is considered curative, no further imaging follow-up is planned. PMID- 30459996 TI - Amoebic encephalitis: case report and literature review of neuroimaging findings. AB - We present a fatal case of amoebic encephalitis due to Acanthamoeba spp. in an immunosuppressed male. Amoebic encephalitis can be a diagnostic challenge as clinical features are non-specific and imaging findings resemble other more common diagnoses such as tumours, haemorrhage or encephalitis from other causes. Here, we present the diagnostic imaging findings in this case and review the reported imaging findings in other cases throughout the literature. PMID- 30459997 TI - Cerebral and pulmonary lymphomatoid granulomatosis and EBV positive oesophageal ulcer in an immunosuppressed renal transplant patient staged and followed with serial MRI and 18F-FDG PET/CT after rituximab therapy. AB - Lymphomatoid granulomatosis is a rare Epstein-Barr virus-related lymphoproliferative disorder. We describe a case of a 42-year-old female with lupus nephritis and immunosuppression post renal transplant, who was diagnosed with central nervous system and lung lymphomatoid granulomatosis, as well as an Epstein-Barr virus-positive oesophageal ulcer, and was staged and followed up long term with multiple 18F-fludeoxyglucose positron emission tomography/CT scans and brain MRIs after achieving a complete metabolic response with rituximab. PMID- 30459998 TI - A ruptured aneurysm in the vasa corona at the craniocervical junction with dysgenesis of the posterior inferior cerebellar artery. AB - This paper reports the case of a ruptured aneurysm in the vasa corona at the craniocervical junction with dysgenesis of the posterior inferior cerebellar artery (PICA). Dysgenesis of the proximal PICA in the present case caused the development of a pial anastomosis in the vasa corona, resulting in the formation of an aneurysm because of increased haemodynamic stress at the vasa corona. The aneurysm was successfully treated with transarterial coil embolization. The clinical entity in the present case is extremely rare and it is important to consider an aberrant vascular anomaly as the cause of an isolated spinal aneurysm. PMID- 30459999 TI - Spontaneous regression of a chiari malformation type 1 in a 58-year-old female. AB - Studies have established a complex age-related variation of the position of the cerebellar tonsils relative to the foramen magnum (FM). Chiari malformation type 1 (CM1) is generally defined by a protrusion >5 mm from the FM and may be an asymptomatic incidental finding. Symptoms include headache, nausea and neurological disturbances, including trigeminal neuralgia. Moreover, tonsils are often peg shaped and associated with syringohydromyelia. Symptomatic CM1 may be managed with decompression of the posterior cranial fossa, but spontaneous regression in adults has been reported occasionally. Theories include restoration of normal cerebrospinal fluid dynamics around the FM after rupture of subarachnoid adhesions or the syrinx itself during transient episodes of raised intracranial pressure. Supratentorial neurosurgery has also been implicated. We present a 58-year-old female diagnosed with CM1 and no associated syringohydromyelia following MRI investigation of trigeminal neuralgia. Managed medically, she re-presented 6 years later with new neurological symptoms. A subsequent MR study of the posterior cranial fossa showed resolution of the CM1, with only residual tonsillar ectopia. At no point was intracranial intervention performed, nor were there any events that might favour CM1 regression. This case demonstrates spontaneous resolution of CM1 without surgical intervention. PMID- 30460000 TI - A case report of racemose pattern of intracranial tuberculoma with brain stem and hypophyseal involvement developing paradoxically during treatment. AB - Tuberculosis involving the central nervous system, a source of considerable morbidity and mortality, forms 5-10% of the disease burden associated with tuberculosis. Central nervous system tuberculosis may present as meningitis, tuberculoma, abscesses, cerebritis or miliary tuberculosis. The most common site of tuberculoma has been reported to be at the grey-white matter junction and the periventricular region. They may even be found in the epidural, subdural and subarachnoid spaces, and the brain stem, with the rarer sites of involvement being the cavernous sinus, sella turcica, hypophysis, hypothalamus, sphenoid sinus and the mastoid air cells. Although tuberculosis is very common in developing countries, with the increasing prevalence of immunosuppression owing to human immunodeficiency virus and patients surviving chemotherapy or organ transplantation, the incidence of tubercular infections has been rising in developed countries. The authors report a case of intracranial tuberculosis in a human immunodeficiency virus-negative patient, who underwent incomplete treatment for tubercular peritonitis and presented with unilateral ptosis. Tuberculous involvement was noted in a racemose pattern in the subarachnoid space, cavernous sinuses, suprasellar cistern and parasellar region. To the best of our knowledge, the term racemose pattern of tuberculoma has not been described before, while about 10 cases of tuberculoma involving the cavernous sinuses have been reported in the literature. Furthermore, the racemose pattern of tuberculosis in the subarachnoid space, as well as involvement of the cavernous sinus, hypothalamus, pituitary and the cisterns, developed paradoxically after initiation of antitubercular chemotherapy. PMID- 30460001 TI - Management of refractory haematuria following radiation therapy and recurrent adenocarcinoma of the prostate with fluoroscopic-guided selective pelvic embolization. AB - Haematuria is a known complication of prostatic malignancy and in severe cases can be unresponsive to bladder irrigation and endoscopic interventions. This report describes selective angiographic embolization as a means of haemorrhage control in adenocarcinoma of the prostate. A patient with locally advanced prostatic adenocarcinoma and prior history of prostate brachytherapy, androgen deprivation therapy and chemotherapy presented with persistent haematuria that did not respond to endourological intervention. He was successfully treated with selective embolization of the vesical and prostatic vessels under fluoroscopic guidance. Angiographic embolization represents a safe and effective means of achieving haemostasis in patients not fit for surgerywho would otherwise be resigned to terminal care treatment. PMID- 30460002 TI - HRCT diagnosis of combined pulmonary fibrosis and emphysema in a patient of chronic obstructive pulmonary disease with pulmonary hypertension and clinical or radiograph suspicion of pulmonary fibrosis. AB - Combined pulmonary fibrosis and emphysema (CPFE) is a unique pulmonary condition characterized by simultaneous coexistence of both upper lobe emphysema and lower lobe fibrosis. Pulmonologists should be aware of the entity while evaluating patients with chronic obstructive pulmonary disease (COPD) or pulmonary fibrosis. Airflow and lung volume are relatively preserved but oxygenation is disproportionately impaired in patients with CPFE. We describe a case of an 83 year-old male patient with past history of heavy smoking, in whom the search for the cause of pulmonary arterial hypertension and exercise-induced arterial oxygen desaturation disproportionate to be explained by COPD resulted in a diagnosis of CPFE. He complained of dyspnoea on exertion and non-productive cough. Physical examination revealed basal Velcro rales and clubbing. Chest radiography showed prominent vascular markings, preserved lung volume and subtle fibrosis of the bases. Definitive diagnosis was made on CT scan of the chest, which revealed upper lobe emphysema and lower lobe fibrosis and honeycombing. The patient was managed by long-term oxygen therapy, inhaled corticosteroid, long-acting bronchodilator and antimuscarinic agents, diuretic, pirfenidone (antifibrotic agent), proton pump inhibitor and N-acetyl cysteine (antioxidant). We emphasize the importance of the diagnosis of CPFE in early stages through CT in a case of COPD with clinical, laboratory and chest radiographic evidence of fibrosis and the fact that CPFE is associated with pulmonary hypertension, a poor prognostic indicator. PMID- 30460003 TI - The "sausage" abscess: abscess of the liagamentum teres hepatis. AB - An abscess of the ligamentum teres hepatis is a very rare cause of acute abdomen and can present a diagnostic dilemma. A 40-year-old diabetic male presented with obstructive jaundice and cholangitis. An ill-defined, sausage-shaped, tender parasagittal supraumbilical mass was palpable on the right side. Murphy's sign was negative. Laboratory investigations revealed polymorphonuclear leukocytosis (total leukocyte count 19,000 mm-3), elevated alkaline phosphatase (400 IU l-1), conjugated hyperbilirubinaemia (16 mg dl-1) and elevated blood glucose (240 mg dl 1). Ultrasonography and MR cholangiopancreatography revealed cholecystolithiasis, obstructive choledocholithiasis, abscess of the ligamentum teres hepatis and left portal thrombosis. Under ultrasound guidance, pus was aspirated from the abscess and the patient was started on broad-spectrum intravenous antibiotics, insulin and low-molecular-weight heparin. He subsequently underwent endoscopic retrograde cholangiopancreatography with sphincterotomy and stone extraction. On the tenth day post admission, he underwent laparoscopic cholecystectomy and excision of the ligament. The patient made an uneventful recovery and was discharged on the seventh post-operative day. On follow-up, the patient remained asymptomatic with normal biochemical parameters. This article highlights the importance of suspecting and identifying an abscess of the ligamentum teres hepatis when a patient with acute abdomen presents with a sausage-shaped right parasagittal mass, especially in the setting of cholangitis, cholecystitis or omphalitis. PMID- 30460004 TI - Mass-forming renal Crohn's disease: a case report with multimodality imaging. AB - The most common extraintestinal manifestations of Crohn's disease involve the eyes, skin, hepatobiliary tract, and the musculoskeletal and respiratory systems. Mass-forming granulomatous inflammation in extraintestinal organs is extremely rare and there are only a few reports of patients with Crohn's disease presenting with inflammatory pseudotumours of the liver, pancreas and kidneys. We present a case of a mass-forming renal granulomatous inflammation in an adult female with Crohn's disease. The clinical, pathological and imaging features of this case illustrate that renal inflammatory pseudotumour is a rare but important differential diagnosis of a renal mass in patients with Crohn's disease and that radiologists should be aware of its existence when considering other more common pathologies, such as focal pyelonephritis and renal tumours. Renal inflammatory pseudotumour may have relatively non-specific imaging features and a biopsy may be required to make the diagnosis. PMID- 30460005 TI - Acute post-traumatic encephalocele in a child: CT and MRI features. AB - Orbital trauma is a commonly encountered entity in clinical practice, especially in cases of head trauma. Although fractures of the orbit are rare, they can present in an emergency setting owing to associated complications such as orbital encephaloceles. We present a case of a paediatric male patient who presented with post-traumatic proptosis and diminution of vision and was diagnosed with orbital encephalocele. The child's vision recovered completely and proptosis of the eye decreased, compared with the time of presentation. Despite persistent counselling, the patient and his parents did not give consent for surgical correction and he was discharged as leaving against medical advice. Post traumatic orbital encephaloceles are caused as a result of blunt cranial trauma. Early treatment and diagnosis is extremely important in the optimum management and good long-term prognosis of the patient. PMID- 30460006 TI - Primary systemic amyloidosis: imaging interpretation of this complex multisystemic disease. AB - This report highlights the diagnostic complexities involved in the case of a 63 year-old female who presented with a non-productive cough and shortness of breath on exertion. Initial chest radiograph demonstrated generalized abnormal interstitial lung markings with thickened peripheral septal lines. Further characterization was sought by CT scan of the chest, and given the possibility of lymphangitic carcinomatosis, a CT scan of the abdomen and pelvis was also performed. The CT scan findings revealed septal line thickening, abnormal omental soft tissue with calcified deposits and wall thickening of the stomach and proximal duodenum. A preliminary differential diagnosis of peritoneal carcinomatosis was made, but cancer markers were equivocal. A CT-guided biopsy of the "omental cake" was non-diagnostic, hence formal biopsy via laparoscopy was undertaken. While awaiting the results, the patient was readmitted with acute haematemesis. Gastric and duodenal biopsies from the endoscopic assessment were positive for Congo red stain and birefringent under polarizsed light, which was consistent with amyloidosis. Histology from the omental biopsies and additional haematological tests concurred. The patient was diagnosed with advanced systemic amyloid light-chain amyloidosis comprising diffuse pulmonary amyloidosis, calcified omental soft tissue deposits, and extensive soft tissue amyloid with cardiac and gastrointestinal involvement. We discuss the spectrum of differential diagnoses posed by the imaging findings and the difficulties faced in interpreting this complex case of systemic amyloidosis. PMID- 30460007 TI - Primary renal primitive neuroectodermal tumour causing Budd-Chiari syndrome: a rare case report. AB - Primary Ewing's sarcoma/primitive neuroectodermal tumour (ES/PNET) of the kidney is a rare neoplasm characterized by an aggressive clinical course. Most often, ES/PNET arises in the chest wall and paraspinal locations, and less commonly in the limbs or the genitourinary tract. We present a rare case of renal ES/PNET presenting as Budd-Chiari syndrome. PMID- 30460008 TI - Diffuse leukoencephalopathy in a 29-year-old male with hypertensive emergency. AB - Severe hypertension is associated with multiple symptoms that reflect the end organ damage effect of rapidly increasing blood pressure. Encephalopathy is a manifestation of the clinical spectrum of hypertensive emergencies. Hypertensive encephalopathy was initially described as part of the posterior reversible encephalopathy syndrome, which mostly involved the parieto-occipital white matter of the brain. A more detailed review of this syndrome reveals many cases where the brain abnormalities are distributed in a more random pattern. We describe a case of diffuse leukoencephalopthy in a young male who presented with altered mental status, ataxia, and blurred vision. This is the most diffuse brain involvement ever described in hypertensive statuses. PMID- 30460009 TI - Imaging and clinical findings in a case of linear scleroderma en coup de sabre. AB - We present the case of a 58-year-old female presenting with acute onset headache and decrease in left-sided facial sensation. The patient's background included diabetes Type 2, hypertension, migraine, anxiety with depression and scleroderma in her childhood. Imaging revealed foci of right frontal calcification and confluent white matter changes, reported as sequelae of a previous ischaemic episode. Following a second presentation with the same symptoms, further imaging showed a linear soft tissue scar overlying these changes, which suggested a diagnosis of linear scleroderma (en coup de sabre). On questioning, it was found that this had developed during the patient's late teens but had not progressed since that time. Coup de sabre type linear scleroderma is often associated with intracranial imaging findings, even in the absence of symptoms. The pathogenesis of neurological symptoms is poorly understood but does seem to respond to immunosuppression. PMID- 30460010 TI - What is that? HIV-negative plasmablastic lymphoma with intramuscular masses. AB - Plasmablastic lymphoma is a relatively new clinical entity described as a distinct subtype of diffuse large B-cell lymphoma, although in the last decade several case reports and series have been published. This case is presented because of its rarity, as this pathology is rare in immunocompetent patients and intramuscular masses are present. We report the case of a 63-year-old male with no significant clinical background. He was referred to the emergency department of our hospital with a 10-day history of pain on the left side of the chest that was described as burning and spreading to the right side. On physical examination, he had no fever or recent weight loss. The abdomen was soft and non distended, and no peritoneal signs were present but he had three palpable masses located in the soft tissues of the breast, right gluteal region and left leg. Histological examination of the biopsy specimens disclosed the diagnosis of plasmablastic lymphoma. To our knowledge, this will be the second case report referring to intramuscular masses in the English language literature. PMID- 30460011 TI - Disseminated hydatidosis with rare presentation as "cystovesical fistula". AB - Disseminated hydatidosis is a rare disease and may involve any organ of the human body. In this case, an elderly female got infected by Echinococcus and presented with disseminated disease. A fistulous communication developed between one of the hydatid cysts present in the retrovesical region and the bladder, because of which the patient presented with hydatiduria. PMID- 30460012 TI - CT and MR of recurrent primary cutaneous adenoid cystic carcinoma with multiple metastases. AB - Primary cutaneous adenoid cystic carcinoma is a rare slow-growing neoplasm, with limited literature reporting the involvement of the scalp. It has a tendency to recur locally; however, lymph node, distant pulmonary and bony metastases are exceptionally rare. We highlight the case of a 65-year-old female with primary cutaneous adenoid cystic carcinoma with distant pulmonary and bony metastases and the importance of imaging in diagnosing distant metastasis and perineural spread. PMID- 30460013 TI - Primary intraosseous squamous cell carcinoma of the mandible: a case with atypical imaging features. AB - Primary intraosseous squamous cell carcinoma is a rare malignant tumour that exclusively arises within the jaws. Its diagnosis requires an appropriate clinical, imaging and histological correlation. The exclusion of primary oral mucosa lesions and metastatic disease is mandatory. We report an atypical imaging appearance of this uncommon entity, characterized by new bone formation and periosteal reaction that resemble sarcomatous or malignant odontogenic tumours. A comprehensive discussion on the embryological principles of primary intraosseous squamous cell carcinoma is also provided. PMID- 30460014 TI - Acute scrotal swelling following perforated rectal carcinoma with abscess formation. AB - A 59-year-old cachectic male was referred to the surgical outpatient department with intermittent haematochezia and a longstanding change in bowel habit with associated weight loss and anaemia. Following investigation, he was diagnosed with a large rectal tumour with multiple metastases. 7 days later, the patient presented again with fevers, bilious vomiting, abdominal pain and distension. On examination, he had a generally tender abdomen,= although no peritonism, but an enlarged, extremely tender hemiscrotum with no cough reflex. Imaging revealed a perforated rectum and subsequent abscess formation, which tracked via an unusual anatomical route to present as scrotal swelling. PMID- 30460015 TI - Fibrous dysplasia of the middle nasal turbinate: imaging and clinical significance. AB - Two cases of fibrous dysplasia involving the middle nasal turbinate are presented. Fibrous dysplasia is a common benign fibro-osseous disease involving the flat bones, often affecting the bony structures of the skull and facial skeleton. Primary occurrence or secondary involvement of the nasal turbinate is not a common manifestation of the disease. Involvement of the inferior turbinate generally does not have specific management-related issues; however, involvement of the middle turbinate, especially the lateral lamella, can predispose to surgical morbidity during endoscopic surgical management. Clinical presentation, management and features of the disease on CT imaging are presented. PMID- 30460016 TI - Track density imaging of hypertrophic olivary degeneration from multiple sclerosis plaque. AB - A 32-year-old female with relapsing-remitting multiple sclerosis (MS) presented with severe new onset ataxia and diplopia. MRI showed a new inflammatory MS lesion that involved the right dorsal pons and extended into the adjacent superior cerebellar peduncle. The patient improved with aggressive immunotherapy; however, repeat MRI 3 months later revealed a new non-enhancing lesion in the left inferior medullary olive. The differential diagnosis for this new lesion included an MS lesion vs hypertrophic olivary degeneration, with infarct or neoplasm as the less likely considerations. We used track density imaging, which provides unprecedented anatomic details based on probabilistic tractography streamlines, to demonstrate apparent changes in the integrity of the dentato rubro-olivary pathway (Guillain-Mollaret triangle) that were consistent with the diagnosis of hypertrophic olivary degeneration from the antecedent MS lesion involving the right superior cerebellar peduncle. Further medical therapy was avoided, and follow-up MRI 1 year later showed interval involution of the left olivary lesion. This case demonstrates the potential clinical utility of using track density imaging to detect lesion-induced alterations in brainstem connectivity and characterize neurodegeneration in patients. PMID- 30460017 TI - Assessment of head gunshot wounds by means of post-mortem computed tomography in exhumed anonymous cadaver. AB - Autopsy of corpses with advanced post-mortem changes is the most challenging aspect of medico-legal activities. In many cases, owing to soft tissue decomposition, making a final diagnosis as to the mechanism and cause of death is very difficult, and sometimes impossible (Carcione P, Argo G, Pincone D, Zgo S, Scopelliti L, Sortino C, Procaccianti P. Role of MCT vitropsy in evaluation of burned bodies and its comparison with traditional autopsy. Poster No.: C-1156, ECR 2014, Scientific exhibit). In such cases, the diagnostic process can be supported by post-mortem CT imaging. Post-mortem multislice CT imaging used in the field of forensic medicine is widely reported to be a good method for visualizing injuries and natural pathologies; however, only a limited number of forensic departments use this method in everyday practice. This method enables accurate assessment of bony injuries (fracture type, degree of bone displacement); has the ability to detect radiopaque foreign bodies, most frequently fragments of bullets; and in some cases enables soft tissue delineation (Hardy K. CT autopsy. Radiology Today 2008; 9: 20. Available from: http://www.radiologytoday.net/archive/rt01282008p20.shtml). In cadavers with advanced post-mortem changes, it is extremely difficult to retrieve the whole bullet or its parts. Owing to decomposition and reduced cohesion of the tissues, standard autopsy preparation techniques are impossible to perform. Post-mortem changes may also cause displacement of the bullet within the body in the long term, as well as at the time of transport following exhumation (Maiese A, Gitto L, De Matteis A, Panebianco V, Bolino G. Post mortem computed tomography: useful or unnecessary in gunshot wounds deaths? Two case reports. Leg Med (Tokyo) 2014; 16: 357-63). It is therefore important to perform post-mortem CT imaging directly after extraction of corpses in a similar position to how the dead body was exhumed. Interpretation of the images requires cooperation of forensic medicine specialists and radiologists to correlate radiological findings with autopsy. PMID- 30460018 TI - Oesophageal perforation as a complication of ingested partial denture. AB - We report herein the case of a 53-year-old female who came to the emergency room with the chief complaints of severe dysphagia and chest pain following accidental swallowing of her denture. The patient had swelling of the face, neck and eyelids with difficulty in breathing. A skull radiograph was taken, which revealed a missing partial denture from the right lower jaw. Anteroposterior radiograph of the chest showed two metallic objects in the mid-thorax, adjacent to the descending aorta. CT scan of the neck and chest revealed two metallic objects (measuring approximately 17mm each) in the middle one-third of the oesophagus (right posterolateral aspect), causing perforation of the oesophagus and leading to pneumomediastinum, and left pneumothorax with subcutaneous emphysema of the neck and chest. An emergency thoracoscopic removal of the foreign body (partial denture) was performed with subsequent repair of the oesophageal tear in the same sitting. Post surgery, the patient was shifted to intensive care unit and she recovered well over a course of time. In summary, accidental ingestion of a partial denture can lead to grave complications such as oesophageal perforation, which should be managed on an emergency basis with thoracoscopic removal of the foreign body. PMID- 30460019 TI - Large ganglioneuroma presenting as presacral mass. AB - Ganglioneuromas are benign tumours of the sympathetic nervous system that originate from neural crest cells. They are extremely rare in the presacral region. Here, we report a case of a presacral mass in a 14-year-old female who presented with complaints of pelvic discomfort, difficulty with micturition and constipation. Ultrasonogram showed a large heteroechoic solid mass in the pelvis with bilateral hydroureteronephrosis. It appeared as a well-circumscribed, hypodense mass lesion on CT scan, measuring 14 x 11 x 10 cm. It appeared isointense to muscle on T 1 and heterogeneously hyperintense on T 2 weighted images with heterogeneous post-contrast enhancement on MRI. The lesion was seen in the presacral region displacing the rectum and bladder anteriorly, and extending posteriorly, causing widening of the sacral foramina. The mass was surgically excised and her symptoms resolved. Histopathological examination of the mass revealed features of ganglioneuroma. We report this case in view of the large size of the mass and its rare location. PMID- 30460020 TI - The "frosted liver" appearance in hepatic tuberculosis: a rare presentation. AB - Tuberculosis is a major re-emerging global health concern. The disease may involve any body system and is a great mimicker of various pathologies owing to its non-specific imaging findings. Herein we report an extremely rare case of atypical tuberculosis of the liver in a young female with complaints of abdominal pain and haematemesis for 10 weeks. Isolated hepatic tuberculosis is a rare entity with < 100 cases reported in the literature. It is therefore important to have a high index of suspicion and be familiar with the atypical imaging findings of abdominal tuberculosis. This discussion highlights the clinical presentation, imaging findings and types of hepatic involvement in tuberculosis. PMID- 30460021 TI - Actinomycotic brain abscess. AB - Actinomycosis is caused by Gram-positive filamentous anaerobic organisms of genus Actinomyces, which are commensals of mucosal membranes of the oropharyngeal cavity, and gastrointestinal and genitourinary tracts. Central nervous system involvement is rare and may present as cerebral abscess, meningitis, meningoencephalitis, subdural empyema or epidural abscess. The radiological appearances of actinomycotic brain abscesses are not well recognized. Here, we present the characteristic imaging features of an actinomycotic brain abscess. PMID- 30460022 TI - Pineal parenchymal tumour of intermediate differentiation: a rare differential diagnosis of pineal region tumours. AB - Pineal parenchymal tumours of intermediate differentiation are a rare type of pineal parenchymal tumours. As indicated by their name, these tumours fall between pineoblastoma (a malignant pineal parenchymal tumour) and pineocytoma (a benign pineal parenchymal tumour). In this article, we present a case of pineal parenchymal tumour of intermediate differentiation that was successfully treated by resection via the supracerebellar approach. We also discuss the differential consideration based on epidemiological, pathological and radiological findings. PMID- 30460023 TI - Radiological findings in pelvic solitary fibrous tumour. AB - Solitary fibrous tumour (SFT) is an uncommon, usually benign mesenchymal neoplasm. SFT was first described in the pleura, but has subsequently been reported to occur in numerous anatomic locations including the abdomen and pelvis. Abdominopelvic SFTs are typically an indolent process, in spite of reaching a large size by the time of diagnosis. The preferred treatment is complete resection followed by extended follow-up surveillance. The risk of local recurrence and metastasis correlates with tumour size and the histological status of surgical margins. We present the imaging findings of a large pelvic SFT in a 61-year-old female, including ultrasound, CT and MRI. PMID- 30460024 TI - Brachial metastatic plexopathy as the inaugural manifestation of lung cancer: multimodality imaging. AB - Metastatic infiltration of a peripheral plexus, also named metastatic plexopathy (MP), often results in severe pain and muscular weakness. This rather rare event may have a dramatic impact on the quality of life of patients affected by cancer. We hereby report a rare case of painful MP of the left cervicobrachial plexus presenting as the inaugural manifestation of poorly differentiated large-cell lung carcinoma in a 53-year-old patient. This responsible lung carcinoma was fortuitously diagnosed during MRI of the brachial plexus (BP). Complementary cancer staging was completed by contrast-enhanced multidetector CT, 18 fludeoxyglucose-positron emission tomography/CT and colour Doppler ultrasound of the BP. Although MRI remains the gold standard method for imaging the BP, our reported case emphasizes the alternative diagnostic capabilities of contrast enhanced multidetector CT and ultrasound and confirms the high specificity of 18 fludeoxyglucose-positron emission tomography/CT in distinguishing brachial MP from secondary radiation plexopathy. PMID- 30460025 TI - Transcatheter arterial chemoembolization with spherical embolic material for locally advanced breast cancer: first report of HepaSphereTM treatment for primary breast cancer. AB - A 57-year-old female was diagnosed as having primary breast cancer (invasive carcinoma of no special type), which was immunohistochemically negative for oestrogen receptor, androgen receptor and human epidermal growth factor receptor Type 2. The main tumour was 54 * 35 mm in size and was located in the internal upper area of the left breast. The tumour had markedly invaded the skin and a daughter nodule was observed in the external upper area of the ipsilateral breast. An enlarged lymph node measuring 12mm in diameter was present in the axilla and an affected parasternal lymph node was also observed. A blood test showed no abnormalities and the patient was negative for tumour markers. We performed three sessions of transcatheter arterial chemoembolization with docetaxel-loaded HepaSphereTM. The treatment procedure was successfully performed in all the three sessions. No adverse events higher than Grade 3 were observed. The sizes of the primary lesion and axillary lymph node decreased to 26 * 14 mm (37% reduction) and 10mm, respectively. The parasternal lymph node completely resolved. 2 months later, left total mastectomy and axillary lymph node dissection were performed. The histopathological post-therapy effect was considered to be a mild response (Grade 1a) in the breast lesion and a complete response (Grade 3) in the axillary lymph node. The mean+/-standard deviation of the minor axis of the vessels embolized with spherical particles was 183.0+/-96.5 MUm. Our results indicate that transcatheter arterial chemoembolization used together with HepaSphere can be an alternative and effective therapy for locally advanced breast cancer. PMID- 30460026 TI - The wanderlust of a gallstone: a case report of intrathoracic migration of a gallstone post complicated cholecystectomy mimicking lung cancer. AB - Gallstones migrating into the right hemithorax post complicated cholecystectomy may be misdiagnosed for lung cancer, especially in the context of a distant history of cholecystectomy, poor recall of medical history and incomplete patient data. We present a case of a female patient with heavy smoking history who presented to our emergency department with haemoptysis and mild weight loss. Imaging workup showed an 18F-fludeoxyglucose positron emission tomography positive heterogeneous nodule with central calcification in the right lower lobe, carrying lung cancer as a differential diagnosis. The resected specimen revealed an inflammatory pseudomass formed around a gallstone. This case illustrates the importance of knowing the spectrum of clinical and radiological presentation of a gallstone migrating into the right hemithorax, in order to prompt appropriate management and prevent misdiagnosis and mistreatment. PMID- 30460027 TI - Spontaneous diaphragmatic hernia with bowel perforation complicated by tension hydropneumothorax. AB - In this case report, we describe a rare case of spontaneous diaphragmatic hernia with perforation of the incarcerated ascending colon and subsequent formation of tension pneumothorax. A 73-year-old male with a past medical history of chronic right pleural effusion, restrictive ventilatory impairment and hypertension presented to us for evaluation of severe right chest pain of few days' duration and severe dyspnoea. The chest radiograph revealed the presence of a loop of bowel in the basal right hemithorax with associated air/fluid levels. A CT scan of the chest confirmed the hydropneumothorax and revealed a right lower lobe ipo expansion and a flogistic lung consolidation. After surgery, the patient underwent a contrast-enhanced CT scan of the chest, which showed no abnormal findings. PMID- 30460028 TI - An unusual case of intercostal muscle flap ossification mimicking an intrathoracic rib. AB - We present a unique case of intercostal muscle flap (ICMF) ossification mimicking an intrathoracic rib diagnosed 3 years after oesophageal perforation repair. A 58 year-old male presented with complaints of mild chest discomfort. Three years ago he had undergone left thoracotomy and primary repair of post-emetic oesophageal perforation. An ICMF had been used to strengthen the repair. Chest X-ray identified a linear calcific density within the left hemithorax. Subsequent thoracic CT characterized the anomaly as ossification of the ICMF. The lesion had the appearance of a well-differentiated intrathoracic rib coursing through the left lower lobe. We discuss the typical appearances of ossified ICMFs and the potential complications resulting from this ossification. PMID- 30460029 TI - Sporadic Burkitt's lymphoma of the axilla: CT and MR imaging findings. AB - Burkitt's lymphoma (BL) is a high-grade B-cell non-Hodgkin's lymphoma, which can be divided into endemic, sporadic and human immunodeficiency-associated subtypes. The sporadic BL typically presents as an intra-abdominal tumour but that of cutaneous or subcutaneous origin is very uncommon. We present a case of sporadic BL arising from the axillary soft tissue and discuss the CT and MRI findings. PMID- 30460030 TI - Primary phosphaturic mesenchymal tumour of the lumbar spine: utility of 68Ga DOTATOC PET/CT findings. AB - Primary phosphaturic mesenchymal tumours (PMTs) frequently occur in the soft tissue or bone, but rarely in the spine. The majority of patients experience long term ostalgia and recurrent fractures. Detection of PMT can be challenging, but the clinical symptoms dramatically improve after removal of the tumour.Wepresent a case of primary PMT in the lumbar spine. CT scan showed a low-density tumour with a well-defined sclerotic margin in the L5 vertebra. MRI revealed a hypointense tumour on T2 weighted imaging and heterogeneous enhancement. 68Ga labelled 1,4,7,10-tetraazacyclododecane-N,N',N", N'''-tetraacetic acid-D-Phe1 Tyr3-octreotide (68Ga-DOTATOC) positron emission tomography/CT scan demonstrated intense focal uptake within the tumour. Histologically, proliferation of oval to short spindle-shaped cells with fibrocollagenous stroma, abundant various-sized vessels, microcysts and thickened anastomosed bone trabeculae were seen. Mitotic figures were rarely seen. Immunohistochemically, the tumour cells were focally positive for fibroblast growth factor 23. The imaging findings in the current case are in accordance with the histological features. Among them, 68Ga-DOTATOC positron emission tomography/CT scan for somatostatin receptor imaging provides valuable information for determining PMT localization and characterization. PMID- 30460031 TI - Pancreatic lipoma: a pancreatic incidentaloma; diagnosis with ultrasound, computed tomography and magnetic resonance imaging. AB - Pancreatic lipomas are rare. We present a case of incidentally discovered pancreatic lipoma in a 45-year-old female suffering from metastatic ovarian carcinoma who was referred to radiology for follow-up imaging. Fat-containing tumours originating from the pancreas are very rare. Most lipomasshow characteristic features on imaging that allow their differentiation. In most cases, accurate diagnosis is attained without any histopathological confirmation. We present the imaging features of pancreatic lipoma on ultrasound, CT scan and MRI, the differential diagnosis and a brief review of the literature. PMID- 30460032 TI - The "reverse breast-oesophagus syndrome": metastatic carcinosis of breast in oesophageal cancer. AB - A "breast-oesophagus syndrome" has been described previously, wherein breast carcinoma metastasizes to the inner layers of the oesophagus. The entity is extremely rare, but rarer still is metastatic breast carcinosis from oesophageal cancer (EC), a clinical event that might be termed as "reverse breast-oesophagus syndrome". Considered as the sixth most lethal malignancy, 50% EC patients present with metastatic disease. However, they rarely ever metastasize to the breast. For that reason, a malignant breast mass, which develops following EC, is often thought of as a second malignancy. We report a 62-year-old female who had EC, who was treated with oesophagectomy 2 years ago, and represented with a painful left breast mass. Radiological evaluation revealed suspicious findings (breast imaging-reporting and data system score of 4C), while cytology demonstrated squamous pearls, consistent with metastatic squamous cell EC, which probably disseminated to the breast at the time of surgery. She was treated with local excision of the breast mass, which is the treatment of choice in isolated metastasis to the breast. Such an unusual presentation reminds us that, in any "radiologically suspicious" breast lesion in patients with a history of carcinoma of the oesophagus, the possibility of breast metastasis must not be negated. PMID- 30460033 TI - Transgastric biopsy of a submucosal gastric tumour. AB - Endoscopic biopsy is thought to be the best method to obtain biopsy samples of the gastrointestinal tract. In our case, however, an endoscopic forceps biopsy failed to confirm malignancy of an intramural gastric tumour. Since the tumour, about 4 cm in diameter, was well delineated on the CT scan, the patient was referred for a percutaneous CT-guided needle biopsy, which confirmed a gastrointestinal stromal tumour. PMID- 30460034 TI - Carcinosarcoma of the gallbladder-an exceedingly rare tumour. AB - Carcinosarcoma of the gallbladder (CSGB) is an extremely rare tumour that presents variable proportions of malignant epithelial and mesenchymal elements. Preoperative diagnosis of CSGB is challenging owing to its non-specific clinical presentation and imaging findings. The final diagnosis requires histopathological confirmation of both the epithelial and mesenchymal components. Owing to the low incidence and poor prognosis of this tumour, it is essential to gather all the individual experience-based information. We report a case of a 52-year-old female who presented with right upper abdominal pain and vomiting for 2 weeks and a painless palpable mass on the right upper quadrant of the abdomen. Imaging studies showed a complex gallbladder mass, which was pathologically confirmed to be CSGB. To our knowledge, this is the first CSGB presented from a radiological perspective. A short literature revision of CSGB is provided. PMID- 30460035 TI - Optimization of CT calcium scoring doses on the General Electric Discovery single photon emission computed tomography/CT D670, 8-slice scanner. AB - Manufacturer-recommended exposure mA was typically resulting in 3-5 times greater patient doses for calcium score scans compared with other dedicated CT scanners at Nottingham University Hospitals. Image noise was used as a measure of image quality in phantom and patient data. The noise was quantified from the standard deviation in Hounsfield units within regions of interest in the myocardium. Noise in phantom data was found to vary linearly with the inverse square root of the applied mAs. It was assumed that a linear relationship would also apply to patient data but it was predicted that the linear gradient would vary between patients owing to differing patient size and composition. This noise model was used to calculate the exposure mA required to achieve a target noise level of 25 Hounsfield units in the myocardium for each patient. To maintain the image quality for patients of different sizes, three measures of size, weight, body mass index (BMI) and lateral dimension, were all tested for goodness of fit to the noise model. It was found that BMI correlated best with the noise model for small patients, and therefore, BMI was chosen as a measure of patient size for the revised mA table. Using this methodology, doses to small patients were reduced by a factor of four compared with manufacturer-recommended settings. PMID- 30460037 TI - Nasal paraganglioma: differential diagnosis from a radiologic and pathologic perspective. AB - A 33-year-old Asian male presented with spontaneous nosebleeds and olfactory sense problems for the past several years. CT scan and MRI demonstrated a large soft tissue mass in the nasal cavity and paranasal sinus with avid and homogeneous contrast enhancement, focal osseous destruction and a non-enhancing cyst at the intracranial tumour-brain margin. After complete endonasal resection, histopathological examination revealed a paraganglioma. This case highlights the non-specific imaging features of a rare paraganglioma of the anterior skull base and the differential diagnosis from both radiological and pathological perspective. PMID- 30460036 TI - Percutaneous aspiration embolectomy of superior mesenteric artery using a 5MAX ACE reperfusion catheter. AB - Acute mesenteric ischaemia is a rare abdominal emergency that commonly results in bowel infarction and has a very high mortality rate. Therefore, prompt recognition and treatment are crucial for a successful outcome. A thrombectomy for embolism in the mid portion of the main trunk of the superior mesenteric artery (SMA) is proposed. A near-complete thrombi removal from the main trunk of the SMA was achieved by using a 5MAX ACE reperfusion catheter, which was designed for treating cerebral embolism. This is the first report describing the treatment of acute mesenteric ischaemia using this catheter. Percutaneous aspiration embolectomy with this catheter is a useful modality for recanalization of embolic occlusion of not only the cerebral artery but also the SMA. PMID- 30460038 TI - Cystic dystrophy of the duodenal wall in heterotopic pancreas: an atypical case in non-alcoholic female. AB - Cystic dystrophy of the duodenal wall in heterotopic pancreas, recently described as paraduodenal pancreatitis, is a rare condition characterized by multiple cysts or pseudocysts located in the submucosa or muscularis propria of a thickened duodenal wall. They result from multiple episodes of obstruction of the small ducts in aberrant pancreatic islets. Cystic dystrophy of the duodenal wall in heterotopic pancreas usually affects alcoholic males, but here we present the case of a female without a history of alcohol abuse who was referred to our emergency department with abdominal pain and vomiting. She was treated by a pancreas-preserving surgical approach, thanks to a proper pre-operative differential diagnosis. Even though differentiating this benign condition from pancreatic cancer is a challenge, some characteristic findings on multidetector CT scan and MRI/MR cholangiopancreatography, such as a thickened duodenal wall containing cysts and sheet-like tissues in the pancreaticoduodenal groove, could lead to the correct diagnosis. PMID- 30460039 TI - Imaging findings of gastric calcifying fibrous tumour. AB - Calcifying fibrous tumours (CFTs) are rare benign lesions that usually affect the soft tissues, the mesentery and the peritoneum. Gastric CFT is particularly rare. Here, we report a CFT found incidentally in a 31-year-old male. The mass was well circumscribed and showed partial calcification on the CT scan, with dark signal intensity seen on T2 weighted MRI. To the best of our knowledge, there is very limited published information concerning imaging findings of CFTs. We discuss the CT scan and MRI findings of this patient, which can be considered typical for gastric CFT, and present a review of the limited literature available. PMID- 30460040 TI - Ovarian hormones modulate multidrug resistance transporters in the ovary. AB - Background: Multidrug resistance transporters (MDRs) are transmembrane proteins that efflux metabolites and xenobiotics. They are highly conserved in sequence and function in bacteria and eukaryotes and play important roles in cellular homeostasis, as well as in avoidance of antibiotics and cancer therapies. Recent evidence also documents a critical role in reproductive health and in protecting the ovary from environmental toxicant effects. The most well understood MDRs are MDR-1 (P-glycoprotein (P-gp) also known as ABCB1) and BCRP (breast cancer resistance protein) and are both expressed in the ovary. We have previously shown that MDR-1 mRNA steady state expression changes throughout the murine estrous cycle, but expression appears to increase in association with the surge in estradiol during proestrus. Methods: Here we test the model that MDR-1 and BCRP are regulated by estrogen, the major hormonal product of the ovary. This was performed by administering 6-week-old female mice either sesame oil (vehicle control) or oral ethinyl estradiol at 1 MUg, 10 MUg, and 100 MUg or PROGESTERONE at 0.25mg, 0.5 mg or 1 mg or a combination of both for 5 days. The mice were then sacrificed, and the ovaries were removed and cleaned. Ovaries were used for qPCR, immunoblotting, and immnunolabeling. Results: We found that oral ethinyl estradiol did not influence the steady state mRNA of MDR-1 or BCRP. Remarkably, the effect on mRNA levels neither increased or decreased in abundance upon estrogen exposures. Conversely, we observed less MDR-1 protein expression in the groups treated with 1 MUg and 10 MUg, but not 100 MUg of ethinyl estradiol compared to controls. MDR-1 and BCRP are both expressed in pre-ovulatory follicles. When we tested progesterone, we found that MDR-1 mRNA increased at the dosages of 0.25 mg and 0.5 mg, but protein expression levels were not statistically significant. Combined oral ethinyl estradiol and progesterone significantly lowered both MDR-1 mRNA and protein. Conclusions: Progesterone appears to influence MDR-1 transcript levels, or steady state levels. This could have implications for better understanding how MDR-1 can be modulated during times of toxic exposure. Understanding the normal physiology of MDR-1 in the ovary will expand the current knowledge in cancer biology and reproduction. PMID- 30460041 TI - Are the effects of blood pressure lowering treatment diminishing?: meta regression analyses. AB - Background: Previous studies have suggested that the effects of medical interventions tend to diminish over time. We investigated whether the effects of blood pressure lowering treatment on all-cause mortality and stroke have diminished over time. Methods: We conducted meta-regression analyses. We extracted the target trials from two recently published comprehensive systematic reviews and meta-analyses. Adopted variables were relative risk (RR) of all-cause mortality and stroke, trial start year, mean age, sample size, baseline systolic blood pressure (SBP), difference in attained SBP reduction between intervention groups and control groups (SBP difference), and regional dummies. We implemented single meta-regressions, in which the dependent variable was the log of RR and the explanatory variable was each of other adopted variables. We also conducted multiple meta-regressions, in which the dependent variable was the log of RR and explanatory variables were all of other adopted variables. Our variable of greatest interest was trial start year. Results: The included reviews assessed 85 trials with a total of 343,126 participants. Although trial start year was positively associated with the log of RR in the results of single meta regressions, it lost significance in multiple meta-regressions for both all-cause mortality and stroke. Conclusions: The effects of blood pressure lowering treatment on all-cause mortality and stroke have not diminished over time. PMID- 30460042 TI - Stakeholder involvement in health research priority setting in low income countries: the case of Zambia. AB - Summary: While there is increasing recognition of the importance of stakeholder involvement in health research priority setting there is a paucity of literature reporting on stakeholder involvement in health research priority setting in low income countries. This paper fills this gap by identifying and discussing the roles and legitimacy of different stakeholders (including the public and patients) involved in the health research priority setting process in Zambia; identifying the barriers to public participation and proposing improvement strategies.We interviewed 28 policy makers and practitioners who had participated in the national level health research priority setting in Zambia. Reported participants in health research priority setting included research users, researchers, research funders and the community/ public. Research funders were thought to have undue influence while the public and patients were not effectively involved. This could be due to the public's lack of education, lack of resources to facilitate public involvement and limited skills to meaningfully engage the public. Participation of people from rural areas, women and young professionals was also limited.While there is a commitment to broad stakeholder involvement in health research priority setting, there's limited public/patient involvement. Public education, availing more resources, and skills to meaningfully engage the public need to be explored. The undue influence of research funders should be mitigated and incentives availed to ensure that they align their research funding with the national priorities. These efforts would strengthen meaningful stakeholder engagement in health research prioritization within Zambia and other similar contexts. Abstract: Background Stakeholder involvement in health research priority setting contributes to the legitimacy and acceptability of the priorities. Hence legitimate priority setting should involve a broad representation of stakeholders including the public. While there is a growing body of literature on health research prioritization in low income countries, there is a paucity of literature reporting on stakeholder involvement in the process. The objectives of this paper are to; 1) identify the stakeholders who were involved in the health research priority setting process in Zambia; 2) discuss the roles and perceived legitimacy of the stakeholders and analyze the degree to which patients/ public was involved; 3) To discuss some of the barriers to stakeholder participation in Zambia and similar contexts and to propose improvement strategies.Methods This was a qualitative study involving 28 in-depth interviews with stakeholders who had participated in the national level health research priority setting exercises in Zambia. An interview guide was used. Audio recorded interviews were transcribed and analyzed using INVIVO 10. Analysis of the Stakeholders' theme involved identifying the different dimensions of stakeholder involvement as discussed in the interviews.Results Identified stakeholders included; research users, researchers, research funders and the community/ public. We found that health research priority setting involved research users, researchers, research funders and the community/ public. However, research funders were thought to have undue influence while the public and patients were not effectively involved. While the respondents recognized the advantages of involving the public and patients, they were not effectively involved. This could be due to the public's limited understanding of the technicalities of priority setting, lack of resources to facilitate public involvement and limited skills to meaningfully engage the public. Participation from rural areas, women, and young professionals was also limited.Conclusions While there is a commitment to broad stakeholder involvement in health research priority setting, the public is left out. Efforts such as public education, availing more resources, and skills to meaningfully engage the public need to be explored. The undue influence of research funders should be mitigated through their direct involvement in the prioritization process and incentives to ensure that they align their research funding with the national priorities. These efforts would strengthen meaningful stakeholder engagement in health research prioritization within Zambia and other similar contexts. PMID- 30460043 TI - Ocular kinetics and safety of intravitreally injected angiotensin converting enzyme inhibitor lisinopril. AB - Background and objectives: The study investigated the intravitreal safety and vitreous disposition of lisinopril, an angiotensin converting enzyme inhibitor in rabbits for its projected use in retinopathy. Methods: For the safety study, following the baseline ERG recording and fundus photography, 40 ug/50 ul of lisinopril sterile injection was injected unilaterally in the rabbit eyes (n = 4), where other eye served as a control. The electroretinogram and fundus images were obtained at 24, 48, 72 and 168 h following the intravitreal injection. For pharmacokinetics evaluation of the lisinopril, one eye of each rabbit (n = 4) received an intravitreal injection of lisinopril (40 ug/50 ul). The concentration of lisinopril in the ocular tissues, humours, plasma, lung, kidney and liver were measured through ESI-LC-MS/MS. Results: Upon the electroretinography studies, no significant difference was observed in the ERG pattern in the lisinopril injected eye when compared to the baseline of the respective animals till the 7th day of the study. In the fundus imaging, no morphological changes were observed in the retina of the animal. The concentration of the lisinopril was found to be above to the IC50 in the retina-choroid till 36 h. The concentration found in the plasma and body tissues were many folds less than the IC50 of the lisinopril. Conclusions: Intravitreal injection of 40 ug/50 ul of lisinopril found to be safe in the rabbit eye as evidenced by the electroretinography and fundus imaging studies. The average half-life of lisinopril is 12.6 h and the above-mentioned dose able to sustain its IC50 value till the 36 h. PMID- 30460044 TI - Correction to: The changing forms and expectations of peer review. AB - [This corrects the article DOI: 10.1186/s41073-018-0051-5.]. PMID- 30460045 TI - IL2 is required for functional maturation of regulatory T cells. AB - Regulatory T cells (Tregs), specified by the expression of transcription factor Foxp3, operate Foxp3-dependent programs to maintain self-tolerance. In addition to Foxp3, other tissue-specific transcription factors are also required by Tregs to control the corresponding immune responses like follicular Tregs which express both Foxp3 and Bcl6 controlling germinal center reactions. Here, we show that Interleukin 2 (IL2) is required for the optimal expression of T helper type 1 (Th1) transcription factor T-box 21 (Tbx21, T-bet) in Tregs. The expression levels of CXCR3 and T-bet were reduced in IL2 deficient Tregs. Furthermore, IL2 deficient Treg cells failed to control the proliferation of CD4+ T cells in vitro and could not prevent the progression of colitis characterized by Th1 immune responses. Taken together, our data suggest that IL2 is essential for the functional maturation of Tregs including the optimal suppressive activity and the expression of tissue-specific transcription factors like T-bet. PMID- 30460046 TI - Distinct regulations of ARF1 by two Aplysia Sec7 isoforms. AB - Sec7 protein is a guanine nucleotide exchange factor in the ADP-ribosylation factor (ARF) family of small GTP-binding proteins. Aplysia Sec7 proteins (ApSec7s) play many roles in neurite outgrowth and synaptic facilitation in Aplysia neurons. However, the binding property of Aplysia ARF1 by ApSec7 isoforms has not been examined. In this study, we found that the cloned Aplysia ARF1 (ApARF1) protein only localized to the Golgi complex when it was expressed alone in HEK293T cells; however, if ApARF1 was co-expressed with plasma membrane targeted ApSec7, it localized to both the plasma membrane and the Golgi complex via association with the Sec7 domain of ApSec7. Moreover, in HEK293T cells expressing both ApARF1 and another Sec7 isoform, ApSec7(VPKIS), the pleckstrin homology domain of ApSec7(VPKIS) associated with ApARF1, resulting in its localization to the Golgi complex. Overall, we propose a model in which ApSec7(VPKIS) activates ApARF1 in the Golgi complex, while ApSec7 recruits ApARF1 to the plasma membrane where it activates ApARF1/6 downstream signaling. PMID- 30460047 TI - Mitotic control by mRNA splicing regulators ensures primary cilia formation. AB - The biogenesis of the primary cilium is coordinated with cell cycle exit/re-entry in most types of cells. After serum starvation, the cilia-generating cells enter quiescence and produce the primary cilium; upon re-addition of serum, they re enter the cell cycle and resorb the cilium. We previously identified novel mechanisms to link cell cycle progression and ciliogenesis by high-content genome wide RNAi cell-based screening. In the present study, we pay attention to reveal the impact of mRNA splicing on cilia assembly after mitosis of cell cycle. We demonstrate that splicing regulators such as SON and XAB2 play an important role in mitosis exit, and thus affect ciliogenesis in G1/G0 phases. Knockdown of the splicing regulators in hTERT-RPE1 cells caused abnormal G2/M arrest under both serum addition and serum starvation, indicating defects in mitosis exit. Moreover, the knockdown cells failed to assemble the cilia under serum starvation and an inhibition of mRNA splicing using SSA, a spliceosome inhibitor, also revealed ciliogenesis defect. Finally, we show that the SSA-treated zebrafish display abnormal vascular development as a ciliary defect. These findings suggest the pivotal role of mRNA splicing regulators in cilia assembly and underscore the importance of mitotic regulation in ciliogenesis. PMID- 30460048 TI - Cell specific stress responses of cadmium-induced cytotoxicity. AB - Cadmium is one of the age old toxic heavy metal, detrimental to the biological system. In this study, we explored the cellular and molecular mechanisms induced on exposure to different concentrations of cadmium chloride (CdCl2), on three different human cell lines with wild type p53, viz., A549, HEK293 and HCT116. We investigated whether the cellular responses followed, displayed any specific pattern related to their viability, mitochondrial respiration, DNA damage and apoptotic gene expression. All the cell lines showed decrease in viability following exposure to CdCl2. p53 was transcriptionally down regulated in all the three cell lines, but with different extents, in response to increasing concentration of cadmium. The cellular responses of the three cell lines were compared with that of a p53 knock out cell line (HCT116p53-/-). The p53 knock out cell line was highly sensitive to cadmium-induced toxicity; so was the cell line in which p53 mRNA expression was highly down regulated. This might implicate an unknown protective role of p53 signaling during heavy metal toxicity and that one of the possible mechanisms by which cadmium manifests its cytotoxic effect is through the transcriptional down regulation of p53 gene. PMID- 30460049 TI - Excessive retinoic acid inhibit mouse embryonic palate mesenchymal cell growth through involvement of Smad signaling. AB - All-trans retinoic acid (atRA), the oxidative metabolite of retinoic acid (RA), is essential for palatogenesis. Overdose RA is capable of inducing cleft palate in mice and humans. Normal embryonic palatal mesenchymal (EPM) cell growth is crucial for shelf growth. Smad signaling is involved in many biological processes. However, it is not much clear if atRA could affect Smad signaling during EPM cells growth. In this study, the timed pregnant mice with maternal administration of 100 mg/kg body weight of RA by gastric intubation were cervical dislocation executed to evaluate growth changes of palatal shelves by hematoxylin and eosin (H&E) staining. At the same time, a primary mouse EPM (MEPM) cell culture model was also established. MEPM cells were treated with atRA (0.1, 0.5, 1, 5 and 10 MUM) for 24, 48 and 72 h. The results indicated that the sizes of the shelves were smaller than those in control. AtRA inhibited MEPM cell growth with both increasing concentration and increasing incubation time, especially at 72 h in vitro. Moreover, atRA significantly increased the mRNA and protein expression levels of Smad7 (P < .05), but the mRNA and protein expression levels of PCNA were reduced (P < .05). We also found atRA inhibited phosphorylation of Smad2 compared with untreated group (P < .05). However, the protein and mRNA levels of Smad2 did not change both in atRA-treated and untreated group (P > .05). We demonstrated that RA induced inhibition of MEPM cell growth that could cause cleft palate partly by down-regulation of Smad pathway. PMID- 30460050 TI - Metagenomic analysis of the marine coastal invertebrates of South Korea as assessed by Ilumina MiSeq. AB - Metagenomic analysis was carried out for the first time on the marine coastal invertebrates of South Korea. Samples collected from coastal areas of Korea were filtered through a 63 um mesh, then their 18S rDNA V4 regions were amplified. High-throughput sequencing of PCR amplicons using Illumina MiSeq and BLAST against the SILVA database showed that a total of 319 eukaryotic Operational Taxonomic Units were identified at the species level. Annelida, Arthropoda, Mollusca, Nematoda, and Platyhelminthes and for 92.23% of the total 103 metazoan species belonging to 101 genera, 75 families, and 10 phyla. Of these, several taxa previously unreported to exist in Korea were detected at the family level compared with the integrated database from three main Korean biodiversity DBs (MABIK, KOMBIS, and MRBR). Analysis of beta diversity of the community structure of invertebrates indicated that the composition of marine invertebrates is likely to be affected by habitat type rather than geographical distance. The present study showed that metagenomic high-throughput technology can be used to unravel species diversity and for various studies regarding marine invertebrate community structure. PMID- 30460051 TI - The differentiation of cellular structure during encystment in the soil hypotrichous ciliate Australocirrus cf. australis (Protista, Ciliophora). AB - Ciliates are able to form resting cysts as a survival strategy in response to stressful environmental factors. Studies on the characteristics of cellular structure during encystment may provide useful information for further understanding of the regulatory mechanism of cellular patterns and supply new clues regarding the phylogeny of ciliates. Scanning and transmission electron microscopies were used to observe the ultrastructure of cells during encystment of the soil ciliate Australocirrus cf. australis. The dedifferentiation of ciliature was revealed for the first time. Ciliary shafts first shortened, and the remaining ciliature, including basal bodies and the fibrillar cirral basket, retracted into the cytoplasm and was surrounded by the autophagic vacuoles and then gradually digested. A large number of autophagic vacuoles were observed in mature resting cysts. Autophagy might not only be necessary for the differentiation of cellular structures during encystment but might also be important to sustain the basic life activities in the resting stage. Australocirrus cf. australis formed a kinetosome-resorbing cyst and contained four layers in the cyst wall: the ectocyst, mesocyst, endocyst and granular layer. The ciliature resorbing state and the number of layers in the cyst wall were consistent with those found in other oxytrichous ciliates. However, the phenomenon wherein the two macronuclear nodules are not fused during encystment is not commonly observed among oxytrichids. Additionally, the octahedral granules in the mesocyst of this species exhibit different morphology from the congeners. PMID- 30460052 TI - Characteristics of the alula in relation to wing and body size in the Laridae and Sternidae. AB - The alula is a small structure present on the leading edge of bird wings and is known to enhance lift by creating a small vortex at its tip. Alula size vary among birds, but how this variation is associated with the function of the alula remains unclear. In this study, we investigated the relationship between the size and shape of the alula and the features of the wing in the Laridae and Sternidae. Laridae birds have generally longer wings and greater loadings than Sternidae birds. The two families differed in the relationships between body size or wing length and the size or shape of the alula. In the Laridae, the aspect ratio of the alula was smaller in the species that have relatively longer wings, but the pattern was opposite in the Sternidae. The aspect ratio of the alula was greater in the species that are relatively heavier in the Sternidae but not in the Laridae. Combined, these results suggest that the species with high loading potential and long wings exhibit long alula. We hypothesize that heavier species may benefit from having longer alula if they perform flights with higher attack angles than lighter species, as longer alula would better suppress flow separation at higher attack angles. Our results suggest that the size and shape of the alula can be explained in one allometric landscape defined by wing length and loading in these two closely related families of birds with similar wing shapes. PMID- 30460053 TI - Influence of tree thinning on the abundance of mammals in a Japanese larch Larix kaempferi plantation. AB - We examined the influence of tree thinning on the abundance of mammals in a Japanese larch Larix kaempferi plantation in Mt Gariwang, Pyeongchang, South Korea. In 2014 and 2015, from April to October, we recorded the presence of tracks as a proxy for abundance, for the following seven mammalian species: Korean hare Lepus coreanus, raccoon dog Nyctereutes procyonoides, Siberian weasel Mustela sibirica, Eurasian badger Meles meles, water deer Hydropotes inermis, roe deer Capreolus pygargus, and wild boar Sus scrofa. We also assessed how the intensity of tree thinning affected vegetation cover; there were significant differences in number of standing trees, basal area, coverage of vegetation layers, and number and volume of downed trees among the control, moderately thinned, and intensively thinned stands. We found significant differences in the abundance of tracks among the stands for three mammal species. In four mammal species, the abundance of track was significantly correlated with volume of downed trees, coverage of ground vegetation, number of downed trees, and number of standing trees, according to stepwise analysis. The presence and abundance of mammals is linked to habitat variables and forest managers should consider how habitat modifications will affect wildlife. PMID- 30460054 TI - From sequencing data to gene functions: co-functional network approaches. AB - Advanced high-throughput sequencing technology accumulated massive amount of genomics and transcriptomics data in the public databases. Due to the high technical accessibility, DNA and RNA sequencing have huge potential for the study of gene functions in most species including animals and crops. A proven analytic platform to convert sequencing data to gene functional information is co functional network. Because all genes exert their functions through interactions with others, network analysis is a legitimate way to study gene functions. The workflow of network-based functional study is composed of three steps: (i) inferencing co-functional links, (ii) evaluating and integrating the links into genome-scale networks, and (iii) generating functional hypotheses from the networks. Co-functional links can be inferred from DNA sequencing data by using phylogenetic profiling, gene neighborhood, domain profiling, associalogs, and co expression analysis from RNA sequencing data. The inferred links are then evaluated and integrated into a genome-scale network with aid from gold-standard co-functional links. Functional hypotheses can be generated from the network based on (i) network connectivity, (ii) network propagation, and (iii) subnetwork analysis. The functional analysis pipeline described here requires only sequencing data which can be readily available for most species by next generation sequencing technology. Therefore, co-functional networks will greatly potentiate the use of the sequencing data for the study of genetics in any cellular organism. PMID- 30460055 TI - Neurotrophin-4 induces myelin protein zero expression in cultured Schwann cells via the TrkB/PI3K/Akt/mTORC1 pathway. AB - Myelin formation during peripheral nervous system development, as well as myelin repair after injury and in disease, requires multiple intrinsic and extrinsic signals. Neurotrophin-4 (NT-4) is a member of the neurotrophin family, which regulates the development of neuronal networks by participating in the growth of neuronal processes, synaptic development and plasticity, neuronal survival, and differentiation. However, the intracellular signaling pathways by which NT-4 participates in myelination by Schwann cells remain elusive. In this study, we examined the effects of NT-4 on the expression of compact myelin proteins in cultured Schwann cells. Using real-time quantitative RT-PCR and western blotting, we found that NT-4 could significantly enhance the expression of myelin protein zero (MPZ) but not the expression of myelin basic protein or peripheral myelin protein 22. Further, knockdown of truncated TrkB with small interfering RNA could eliminate the effect of NT-4 on MPZ expression. Moreover, we demonstrated that the NT-4-enhanced MPZ expression depended on Akt and mTORC1 signaling. Taken together, these results suggest that NT-4 binds TrkB to enhance the expression of MPZ in Schwann cells, probably through the PI3K/Akt/mTORC1 signaling pathway, thus contributing to myelination. PMID- 30460056 TI - Sinup is essential for the integrity of centrosomes and mitotic spindles in zebrafish embryos. AB - Fish lineage-specific gene, sinup [Siaz-interacting nuclear protein], modulates neural plate formation in embryogenesis and shares homology with human TPX2 protein, a member of the vertebrate mitogen-activating protein family. In spite of the presence of the TPX2 domain in Sinup, its cellular function has been unknown. As an initial approach to this question, we expressed Sinup by injecting sinup-EGFP mRNAs into zebrafish embryos at the one- to two-cell stage. First of all, Sinup-EGFP was associated with centrosomes and mitotic spindles. In particular, Sinup was localized to the spindle poles and midbody microtubules during the period between anaphase and cytokinesis. Second, various deleted mutants of Sinup-EGFP failed to be associated with the centrosomes and mitotic spindles. Third, a Sinup mutant, where the 144th Serine residue was converted to alanine, not only disturbed the mitotic spindle organization, such as multipolar spindles, fragmented spindle poles, and flattened spindles, but also arrested the cell cycle at metaphase and cell movement. Finally, Sinup is phosphorylated by Aurora A and the 144th Serine mutant of Sinup is partially phosphorylated by Aurora A kinase. We thus propose that Sinup is an essential element for the integrity of centrosomes and mitotic spindle fibers as well as for the normal process of cell cycle and cellular movement in vertebrate embryos. PMID- 30460057 TI - Measurement of altered APP isoform expression in adipose tissue of diet-induced obese mice by absolute quantitative real-time PCR. AB - Obesity is associated with increased risk of Alzheimer's disease. Previous studies have demonstrated that amyloid-beta precursor protein (APP) is expressed in subcutaneous adipose tissue (SAT), upregulated with obesity, and correlates with insulin resistance and adipose tissue inflammation. APP is alternatively spliced into several isoforms, which may be indicative of the pathogenesis of APP related diseases, but the accurate quantification has been difficult to standardize and reproduce. In light of this, we developed isoform-specific absolute cDNA standards for absolute quantitative real-time PCR (AQ-PCR), and measured transcript copy numbers for three major APP isoforms (APP770, APP751, and APP695), in SAT from C57BL/6 mice fed either a normal or high-fat diet. Expression of all three major APP isoforms was increased in diet-induced obese mice. Transcript copy numbers of APP770 and APP695 correlated with plasma insulin and CCL2 gene expression. The ratios of APP770 and APP751 to APP695 gradually decreased with aging, and correlated with plasma glucose levels. In addition, APP770 was significantly decreased in thiazolidinedione-treated mice. We describe quantification of APP isoform transcripts by AQ-PCR, which allows for direct comparison of gene copy number across isoforms, between experiments, and across studies conducted by independent research groups, which relative quantitative PCR does not allow. Our results suggest a possible role of differential expression of APP isoforms in the development of obesity-related insulin resistance and adipose tissue inflammation. In addition, it is important to determine if altered ratios of APP isoforms in SAT contribute to higher circulating Abeta peptides and increased risk of abnormalities in obesity. PMID- 30460058 TI - Functional restoration of replicative senescent mesenchymal stem cells by the brown alga Undaria pinnatifida. AB - The brown alga Undaria pinnatifida, which is called Mi-Yoek in Korea, has been traditionally consumed as a health food in East Asian countries. Recent studies have reported that U. pinnatifida has beneficial effects on arteriosclerosis, inflammation, fat metabolism, and tumors. In this study, we examined the anti senescence effects of ethanol extracts of U. pinnatifida (UP-Ex) in human bone marrow mesenchymal stem cells (hBM-MSCs). UP-Ex protected hBM-MSCs against oxidative injury, as determined by MTT assays. This effect was confirmed by immunoblot analysis of the oxidation-sensitive protein p53 and the apoptotic protein cleaved caspase-3. Excessive intracellular reactive oxygen species (ROS) accumulation induced by oxidative stress was moderated in UP-Ex-treated hBM-MSCs (UP-Ex-MSCs). Similarly, expression of the ROS-scavenging enzymes superoxide dismutase 1 (SOD1), SOD2, and catalase was recovered in UP-Ex-MSCs. Excessive ROS induced by long-term cell expansion (passage 17) was significantly decreased along with restoration of the senescence proteins p53, p21, and p16 in UP-Ex MSCs. UP-Ex treatment also improved the ability of these replicative, senescent hBM-MSCs (passage 17) to differentiate into osteocytes or adipocytes, suggesting that UP-Ex ameliorates the functional decline of senescent stem cells and may provide better therapeutic efficacy in stem cell therapy. Abbreviations: hBM MSCs: human bone marrow mesenchymal stem cells; DCF: 2',7' dichlorodihydrofluorescein; DCFH-DA: 2',7'-dichlorofluorescein diacetate; MTT: 3 (4,5-dimethylthiazol-2-yl-)2,5-diphenyltetrazolium bromide; PBS: phosphate buffered saline; PFA: paraformaldehyde; RIPA: radioimmunoprecipitation assay; ROS: reactive oxygen species; SOD1: superoxide dismutase 1; SOD2: superoxide dismutase 2. PMID- 30460059 TI - Phenotypic and proteomic analysis of positively regulated gellan biosynthesis pathway in Sphingomonas elodea. AB - Sphingomonas elodea is a Gram-negative bacterium capable of producing 'gellan gum' exopolysaccharide that is the most extensively studied expolysaccharides of microbial origin. In this study, we investigated the phenotypic and proteomic alterations in S. elodea by homogeneously expressing both gelA and gelN involved in positive regulation and extracellular secretion of metabolites in gellan biosynthesis, respectively. Expression of six histidine-tagged GelA and GelN was determined by Western blot analysis. Successful expression of GelA and GelN resulted in both morphological changes of colonies and enhanced secretion of gellan into the growth medium (GelA, 21.2% more and GelN, 48.3% more) overexpressed compared to the wile-type. Comparative two-dimensional gel electrophoresis analysis revealed a differential proteome expression in S. elodea overexpressing GelA and GelN. Proteins up- or down-regulated by GelA and GelN overexpression were found to be mainly sugar transportation proteins, two component regulatory proteins, and proteins involved in secretion pathways. The results suggest that the effect of GelA and GelN overexpression on gellan biosynthesis might be mainly caused by increased transportation of sugar units or enhanced exportation of gellan. PMID- 30460060 TI - Transcriptome sequencing combined with bioinformatics predicts potential genes and pathways associated with bupivacaine-induced apoptosis. AB - This study aimed to explore the potential genes and pathways associated with bupivacaine-induced apoptosis. Human neuroblastoma cell line SH-SY5Y was used in this study. The effect of bupivacaine on cell viability of SH-SY5Y was detected by Cell Counting Kit-8. Transcriptome sequencing was performed for SH-SY5Y cells that were treated and untreated with bupivacaine based on the HiSeq 4000 sequencing platform. The sequencing results were analyzed using bioinformatics methods, including differentially expressed genes (DEGs) identification, functional enrichment analysis, protein-protein interaction (PPI) network analysis and module analysis. The cell viability of SH-SY5Y cells decreased significantly after bupivacaine treatment (p < .01). Based on the HiSeq 4000 sequencing platform, we obtained a global overview of the transcriptome of SH SY5Y treated with/without bupivacaine. Bioinformatics analysis identified 335 up regulated and 294 down-regulated DEGs in bupivacaine group. They were significantly enriched in cell cycle-associated functions and pathways and cAMP signaling pathway. In the PPI network, proliferating cell nuclear antigen (PCNA), v-Akt murine thymoma viral oncogene homolog 3 (AKT3), cyclin-dependent kinase inhibitor 1A (CDKN1A) and cell division cycle 6 (CDC6) had high topology scores. Module analysis obtained two sub-network modules (cluster 1 and cluster 2). PCNA, CDC6, CDKN1A and AKT3 may play important roles in bupivacaine-induced apoptosis. Additionally, bupivacaine may also induce apoptosis via pathways of cell cycle and cAMP signaling pathway. PMID- 30460061 TI - Comparison of taxon-based and trophi-based response patterns of rotifer community to water quality: applicability of the rotifer functional group as an indicator of water quality. AB - Rotifer community is often used as a taxon-based bioindicator for water quality. However, studies of the planktonic community from the viewpoint of functional groups in freshwater ecosystems have been limited, particularly for rotifers. Because rotifers have various trophi types determining their feeding strategies, thereby representing an ecological niche, their functional feeding groups can act as biological and ecological indicators in lakes and reservoirs where planktonic communities are dominant. We analyzed the patterns of spatial distribution of the rotifer community in various reservoirs and then its relationship with water quality through redundancy and regression analyses. Compared with taxon-based composition, the response of trophi-based composition appears simplistic and showed clearer tendency in relation with water-quality variables. Each trophi responded differently by the degree of eutrophication indicating that each trophi group is possibly affected by environments such as the combinations of water quality variables in different ways. PMID- 30460062 TI - A preliminary analysis of the diet composition of overwintering Bean geese (Anser fabalis) and greater white-fronted geese (A. albifrons) in Korea using PCR on fecal samples. AB - Bean geese (Anser fabalis) and Greater white-fronted geese (Anser albifrons) are the dominant wintering waterfowl in South Korea. Although they are commonly observed in estuaries and rice fields during the winter, the diet composition of the geese during the winter has rarely been studied. In this study, we provide the results from preliminary analyses on the diet of these two geese species overwintering in Daebu Island of South Korea. We used a total of 13 fecal samples from Bean geese (n = 4) and Greater white-fronted geese (n = 9), and performed a BLAST search for the sequences obtained from 87 clones (n = 36 for Bean geese and n = 51 for Greater white-fronted geese). The diet of Bean geese consisted of five families of plants: Caryophyllaceae (75.0%), Poaceae (13.9%), Asteraceae (5.5%), Polygonaceae (2.8%) and Cucurbitacea (2.8%). On the other hand, the diet of Greater white-fronted geese consisted of 6 families of plants: Poaceae (74.5%), Caryophyllaceae (9.8%), Solanacea (5.9%), Portulacaceae (3.9%), Lamiaceae (3.9%) and Brassicaceae (2.0%). We found that plants of the rice family (Poaceae) are important in the diet of wintering geese, especially for Greater white-fronted geese. This knowledge can be used to establish conservation strategies of the geese overwintering in South Korea. PMID- 30460063 TI - Causes of low vision and major low-vision devices prescribed in the low-vision clinic of Nepal Eye Hospital, Nepal. AB - Visual impairment is a major public health problem. Identifying the main causes of low vision and the major low-vision devices prescribed will help to develop and implement the low-vision rehabilitation service. We find out the causes of low vision and the low-vision devices prescribed in the low-vision clinic of Nepal Eye Hospital. A retrospective cross-sectional review of all patients attending the low-vision clinic from 1 May 2009 to 31 April 2011. Patients having visual acuity less than 3/60 in the better eye with best refractive correction were excluded. Of the 137 patients, the mean age was 32.53 +/- 22.90 years; 71.5% were male and 67.88% were under 40. The major causes of low vision were nystagmus (30.70%), high refractive error (22.62%), cataract (15.30%), retinitis pigmentosa (15.30%) and age-related macular degeneration (13.10%); 78.10% patents were wearing glasses while telescopes were prescribed for 29.20% patients. Nystagmus, high refractive error and cataract are the main causes of low vision in Nepal. The majority of the low-vision patients seen in this clinic are of working age. Telescopes are the major low-vision device prescribed. We review approach the cause of low-vision problem in low-vision clinic Nepal Eye Hospital, Nepal. PMID- 30460064 TI - Identification of molecular markers distinguishing adult neural stem cells in the subventricular and subcallosal zones. AB - Neural stem cells (NSCs) in the adult subventricular zone (SVZ) are regionally specified and have distinct molecular gene expression signatures. Recently, we identified the subcallosal zone (SCZ) as a novel brain region where adult NSCs maintain and spontaneously produce neuroblasts. In an attempt to isolate genes specifically expressed in the SCZ or SVZ, microarray analyses of their differentially expressing transcripts were done. The comparison between neurospheres generated from SVZ and SCZ revealed differential expression >1.5 fold in two groups in only 83 genes, representing <0.03% of the genes examined, suggesting that these two populations are largely similar. The differential expression patterns SCZ and SVZ genes were confirmed by RT-PCR and Western blots. The selective expressions of two genes (CRBP1, HMGA1) in SVZ-NSCs were further confirmed by immunohistochemistry. These molecular markers could be useful for further molecular and cellular characterization of NSCs. PMID- 30460065 TI - Phenotypic differences between Drosophila Alzheimer's disease models expressing human Abeta42 in the developing eye and brain. AB - Drosophila melanogaster expressing amyloid-beta42 (Abeta42) transgenes have been used as models to study Alzheimer's disease. Various Abeta42 transgenes with different structures induce different phenotypes, which make it difficult to compare data among studies which use different transgenic lines. In this study, we compared the phenotypes of four frequently used Abeta42 transgenic lines, UAS Abeta422X , UAS-Abeta42BL33770 , UAS-Abeta4211C39 , and UAS-Abeta42H29.3 . Among the four transgenic lines, only UAS-Abeta422X has two copies of the upstream activation sequence-amyloid-beta42 (UAS-Abeta42) transgene, while remaining three have one copy. UAS-Abeta42BL33770 has the 3' untranslated region of Drosophila alpha-tubulin, while the others have that of SV40. UAS-Abeta4211C39 and UAS Abeta42H29.3 have the rat pre-proenkephalin signal peptide, while UAS-Abeta422X and UAS-Abeta42BL33770 have that of the fly argos protein. When the transgenes were expressed ectopically in the developing eyes of the flies, UAS-Abeta422X transgene resulted in a strongly reduced and rough eye phenotype, while UAS Abeta42BL33770 only showed a strong rough eye phenotype; UAS-Abeta42H29.3 and UAS Abeta4211C39 had mild rough eyes. The levels of cell death and reactive oxygen species (ROS) in the eye imaginal discs were consistently the highest in UAS Abeta422X , followed by UAS-Abeta42BL33770 , UAS-Abeta4211C39 , and UAS Abeta42H29.3 . Surprisingly, the reduction in survival during the development of these lines did not correlate with cell death or ROS levels. The flies which expressed UAS-Abeta4211C39 or UAS-Abeta42H29.3 experienced greatly reduced survival rates, although low levels of ROS or cell death were detected. Collectively, our results demonstrated that different Drosophila AD models show different phenotypic severity, and suggested that different transgenes may have different modes of cytotoxicity. Abbreviations: Abeta42: amyloid-beta42; AD: Alzheimer's disease; UAS: upstream activation sequence. PMID- 30460066 TI - Autophagy mediates SUMO-induced degradation of a polyglutamine protein ataxin-3. AB - Previously, we reported that small ubiquitin-like modifier-1 (SUMO-1) promotes the degradation of a polyglutamine (polyQ) protein ataxin-3 and proposed that proteasomes mediate the proteolysis. Here, we present evidence that autophagy is also responsible for SUMO-induced degradation of this polyQ protein. The autophagy inhibitor 3-MA increased the steady-state level of ataxin-3 and stabilized SUMO-modified ataxin-3 more prominently than the proteasome inhibitor MG132. Interestingly, SUMO-1 overexpression enhanced the co-localization of ataxin-3 and autophagy marker LC3 without increasing LC3 puncta formation suggesting that SUMO-1 is involved in the substrate recruitment rather than the induction of autophagy. To assess the importance of a putative SUMO-interacting motif (SIM) in ataxin-3 for SUMO-induced degradation, we constructed a SIM mutant of ataxin-3. Substitution of putative SIM (V165G) facilitated the degradation of polyQ-expanded ataxin-3, which is more resistant to SUMO-induced degradation than the normal ataxin-3. These results together indicate that SUMO-1 promotes the degradation of ataxin-3 via autophagy and the putative SIM of ataxin-3 plays a role in this process. PMID- 30460067 TI - Expression and regulation of Angiopoietins and their receptor Tie-2 in sika deer antler. AB - The cartilage vascularization and chondrocyte survival are essential for endochondral ossification which occurs in the process of antler growth. Angiopoietins (Ang) is a family of major angiogenic growth factors and involved in regulating the vascularization. However, the expression and regulation of Angs in the antler are still unknown. The aim of this study is to localize the expression of Ang-1, Ang-2 and their receptor Tie-2 in sika deer antler using in situ hybridization and focused on analyzing the regulation of testosterone, estrogen, all-trans-retinoic acid (ATRA) and 9cRA on their expression in antler chondrocytes. The results showed that Ang-1, Ang-2 and Tie-2 were highly expressed in antler chondrocytes. Administration of testosterone to antler chondrocytes led to a notable increase in the expression of Ang-1 and Tie-2, and a reduction in the expression of Ang-2. The similar result was also observed after estrogen treatment. In contrast, ATRA and 9cRA could inhibit the expression of Ang-1 in antler chondrocytes and heighten the expression of Ang-2. Simultaneously, ATRA could downregulate the expression of Tie-2 in antler chondrocytes at 12 and 24 h, while 9cRA upregulate the expression of Tie-2 at 3 and 6 h. Collectively, Ang-1, Ang-2 and Tie-2 are expressed in antler chondrocytes and their expression can be affected by testosterone, estrogen, ATRA and 9cRA. PMID- 30460068 TI - CFL-1, a novel F-box protein with leucine-rich repeat may interact with UNC-10 for the regulation of defecation and daumone response in Caenorhabditis elegans. AB - Previously we reported that CFL-1, the single LRR-type F-box protein in the Caenorhabditis elegans genome, affected defecation behavior and daumone response. CFL-1 is highly homologous to the FBXL20 in mammals, which regulates synaptic vesicle release by targeting its substrate Rim1 for ubiquitin-mediated degradation. The worm homolog of Rim1 is UNC-10, a presynaptic membrane protein that triggers synaptic vesicle fusion through interaction with RAB-3 GTPase. To examine if CFL-1 exerts its modulatory effect on the defecation and daumone response via ubiquitination of UNC-10, we performed RNAi knock-down of CFL-1 in the unc-10(e102) mutant background. We noticed additive increase in defecation interval when the activities of both CFL-1 and UNC-10 were compromised. Also, the degree of dauer formation upon daumone treatment in unc-10 mutants treated with CFL-1 RNAi decreased further than the level observed in untreated mutants or wild type N2 worms with CFL-1 RNAi knock-down. Our data suggest that CFL-1 affects defecation frequency and daumone response in C. elegans through the ubiquitination of UNC-10. PMID- 30460069 TI - Differences in the starvation-induced autophagy response in MDA-MB-231 and MCF-7 breast cancer cells. AB - Breast cancer is a heterogeneous disease with distinct subtypes that have made targeted therapy of breast cancer challenging. Previous studies have demonstrated that an altered autophagy capacity can influence the development of breast cancer. However, the molecular differences in starvation-induced autophagic responses in MDA-MB-231 and MCF-7 cells have not been fully elucidated. In this study, we found that an increase of LC3B-II protein expression level and a decrease of the p62 protein expression level in both cells treated by Earle's balanced salt solution. Meanwhile, we observed an increase of autophagosome using transmission electron microscopy and an enhancement in the green fluorescence intensity of LC3B protein by confocal microscopy. Furthermore, we detected the expression of 13 autophagy-related (ATG) genes and 11 autophagy signaling pathway related genes using qPCR. Among 13 ATG genes, we found that 6 genes were up regulated in treated MDA-MB-231 cells, while 4 genes were up-regulated and 1 gene was down-regulated in treated MCF-7 cells. In addition, among 11 autophagy signaling pathway-related genes, 7 genes were up-regulated in treated MDA-MB-231 cells, while 5 genes were up-regulated and 1 gene was down-regulated in treated MCF-7 cells. These findings suggest that the autophagic response to starvation was different in the two treated cell lines, which will contribute to further study on the molecular mechanism of starvation-induced autophagy and improve the targeted therapy of breast cancer. PMID- 30460070 TI - Microstructure and mechanical properties of rostrum in Cyrtotrachelus longimanus (Coleoptera: Curculionidae). AB - The microstructure, composition and mechanical properties of the rostrum in Cyrtotrachelus longimanus (JHC Fabre) were studied utilizing light, fluorescent, scanning electron microscopy (SEM) and energy-dispersive spectroscopy. SEM images show the morphological characteristics of rostrum's cross section; it is a typical lightweight multilayer structure - one rigid exocuticle layer and dense endocuticle layers, which construct unevenly overlapping fiber structures. The composition analysis of the rostrum shows that it is mainly composed of C, H, N, O, as well as some metal elements and microelements, such as Mg, Si, Zn, Ca and Na, which contribute to its mechanical performance. The mechanical properties of the rostrum were tested by the electronic universal testing machine, which shows it has high-specific strength and is almost the same as that of the stainless steel. The results may provide a biological template to inspire biomimetic lightweight structure design. PMID- 30460071 TI - Impact of human activities on changes of ichthyofauna in Dongjin River of Korea in the past 30 years. AB - Ichthyofauna and fish community were investigated at 17 representative stations of the Dongjin River drainage system from spring to fall in 2014. The survey resulted in a list of 53 species belonging to 14 families structured into 4 distinctive parts along the river: uppermost-stream, upper-stream, mid-stream, and lower-stream. Comparison of species lists with 30-year interval exhibited significant decreases in peripheral freshwater fishes, Acheilognathinae, endemic, and indigeneity species, but increases in exotic, epipelagic, and lentic species. Moreover, in the estuary of the Dongjin River drainage system, peripheral freshwater fish species were replaced by pure freshwater fish species due to the Saemangeum sea-wall project. In the upper region of the river, introduced eight alien species from Seomjin River via water diversion tunnels. In the mid-lower region, the construction of floodgates and numerous small weirs caused expansion of lentic water areas, facilitating the spread of problematic exotic species such as Micropterus salmoides, Lepomis macrochirus, and Carassius cuvieri. Also, water deterioration in this region resulted in an increase of tolerant species and a decrease of sensitive and endemic species. Our results suggest that a recovery strategy for a healthy ecosystem in the Dongjin River drainage system should reflect this compartmentalized cause and effect on the changes of icthyofauna. PMID- 30460072 TI - Effect of increased pCO2 in seawater on survival rate of different developmental stages of the harpacticoid copepod Tigriopus japonicus. AB - The rapid increase in carbon dioxide levels in seawater is causing ocean acidification and is expected to have significant effects on marine life. To explore the ability of the harpacticoid copepod Tigriopus japonicus to adapt to an increased concentration of dissolved carbon dioxide (CO2) in seawater, we compared the survival rates of adult and nauplius stages at 400, 1000, and 1550 ppm pCO2 over a 14-day period. The survival rate of T. japonicus dramatically decreased over time with increase in pCO2 concentration. At 1550 ppm, the survival rate showed a decrease of more than 20% at the end of the experimental period over that at 400 ppm. Furthermore, the survival rate decreased by a greater amount at all concentrations in nauplii than in adults, with a greater effect in wild-collected specimens than in culture-derived individuals. The results suggest that future ocean acidification may negatively influence the sustainability of T. japonicus and thus may eventually influence benthic ecosystems. PMID- 30460073 TI - Epigenetic suppression of the anti-aging gene KLOTHO in human prostate cancer cell lines. AB - KLOTHO was originally identified as an aging-suppressor gene that causes a human aging-like phenotype when tested in KLOTHO-deficient-mice. Recent evidence suggests that KLOTHO functions as a tumor suppressor by inhibiting Wnt signaling. KLOTHO gene silencing, including DNA methylation, has been observed in some human cancers. Aberrant activation of Wnt signaling plays a significant role in aging, and its silencing may be related to prostate cancer and other types of cancers. Thus, we investigated whether the expression of the anti-aging gene KLOTHO was associated with epigenetic changes in prostate cancer cell lines. KLOTHO mRNA was detected in the 22Rv1 cell line while it was not detected in DU145 and PC-3 cell lines. The restoration of KLOTHO mRNA in the DU145 and PC-3 cell lines was induced with a DNA methyltransferase inhibitor. Methylation-specific PCR was performed to determine the specific CpG sites in the KLOTHO promoter responsible for expression. In addition, the level of methylation was assessed in each CpG by performing bisulfite sequencing and quantitative pyrosequencing analysis. The results suggested a remarkable inverse relationship between KLOTHO expression and promoter methylation in prostate cancer cell lines. PMID- 30460074 TI - Differentiation potential of neural stem cells derived from fetal sheep. AB - Neural stem cells (NSCs) are multipotent stem cells that can differentiate into many cell types in vitro. In this study, we isolated and established an NSC line from fetal Ovis aries. Based on the results of immunofluorescence staining, NSCs expressed Nestin, Pax6 and MAP2. Moreover, a reverse transcription-polymerase chain reaction assay was used to biologically characterize the cell line. NSCs were induced to differentiate into neurogenic cells in vitro. They expressed MAP2, glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP). In this study, we successfully isolated and cultivated NSCs from the hippocampal tissue of fetal sheep. NSCs not only displayed a self-renewal capacity but also had the potential to differentiate into neurons and glial cells. This study provided valuable experimental data for NSC transplant research. PMID- 30460075 TI - Induction of telomere shortening and cellular apoptosis by sodium meta-arsenite in human cancer cell lines. AB - The present study assessed the cytotoxicity of sodium meta-arsenite (SMA) on telomere shortening and cellular apoptosis in human A-549, MDA-MB-231 and U87-MG cancer cell lines. Following 2 weeks of 1 MUM SMA treatment, population doubling time (PDT) was significantly (P < .05) increased by the inhibition of cell proliferation in all the cancer cell lines compared to that in untreated controls. Level of telomerase activity by relative-quantitative telomerase repeat amplification protocol was significantly (P < .05) downregulated by SMA treatment with significant (P < .05) decrease of both telomerase reverse transcriptase and telomerase RNA component transcripts, responsible for telomerase activity. A significant (P < .05) shortening of telomeric repeats by telomere restriction fragment analysis was consequently observed in SMA-treated cells. Moreover, high incidence of cells with senescence-associated beta-glucosidase activity was observed in SMA-treated cells and some cells were also differentiated into adipocytes probably due to the loss of tumorous characterizations. Cellular apoptosis proven by DNA fragmentation was observed, and intrinsic apoptotic transcripts (BAX, caspase 3 and caspase 9) and stress-related transcripts (p21, HSP70 and HSP90) were significantly (P < .05) increased in three cancer cell lines treated with SMA. Based on the present study, SMA treatment apparently induced a shortening of telomere length and cytotoxicity, such as induction of cell senescence, apoptosis and cell differentiation. Therefore, we conclude that SMA treatment at specific concentration can lead to gradual loss of tumorous characterizations and can be considered as a potential anti-cancer drug for chemotherapy treatment. PMID- 30460076 TI - Gastroprotective and gastric motility benefits of AD-lico/Healthy GutTM Glycyrrhiza inflata extract. AB - The aim of this study was to evaluate in vivo both the anti-Helicobacter and the gastric-relaxing effects of AD-lico/Healthy GutTM in rat models. AD-lico/Healthy GutTM is a specially prepared commercial formulation of Glycyrrhiza inflata extract that is under clinical development for indications of gastrointestinal disease and inflammatory bowel disease. In the current study, the oral administration of AD-lico/Healthy GutTM significantly reduced mucosal damage from Helicobacter pylori in rats and decreased the expression of the inflammatory markers iNOS and COX-2 in the test cells. AD-lico/Healthy GutTM also reduced mucosal damage caused by water immersion stress in rats. The accelerated gastric emptying in normal rats was also seen with AD-lico/Healthy GutTM, providing relief in gastric relaxation in the test animals. The special formulation of AD lico/Healthy GutTM with reduced levels of component glycyrrhizin also has benefits in minimizing the potential side effects attributed to glycyrrhizin seen with similar Glycyrrhiza extracts in terms of induction of hypokalemia and muscle weakness. The preparation has a relatively high phenolic compound content relative to other methods of preparation and is indicative of lower glycyrrhizin levels. These results suggest that AD-lico/Healthy GutTM may provide the necessary relief from a number of stomach discomfort issues faced by a large population of people. PMID- 30460077 TI - Regulation of INSIG2 by microRNA-96. AB - Mature forms of the microRNAs miR-96, -182, and -183 originate from a single genomic locus and have been shown to be elevated approximately 50-fold in the livers of sterol regulatory element-binding protein-1a and -2 (SREBP-1a and -2) transgenic mice. Our study attempted to identify the possible targets of these microRNAs using miRNA target prediction software. This revealed putative sites in insulin-induced genes (INSIGs). The 3' untranslated region (UTR) of insulin induced gene 1 (INSIG1) contained sites corresponding to miR-182, and -183, while the 3' UTR of INSIG2 featured an miR-96 site. Among these putative sites, only miR-96 demonstrated an inhibitory effect that was specific to the 3' UTR of INSIG2. As INSIG proteins are the main components of SREBP cleavage complexes that act to release active SREBPs, we assessed the effects of miR-96 on INSIG and SREBP levels and activities. We found that miR-96 reduced the levels of INSIG2 in INSIG1 knockout human fibroblasts, resulting in an increase in SREBP-1 and -2 nuclear forms and a subsequent increase in the abundance of the mRNA of their target genes. These results suggest that miR-96, an miRNA induced by SREBP-2 activation, regulates downstream targets of SREBPs and may increase the abundance of active SREBP. PMID- 30460078 TI - MicroRNA-129-5p inhibits 3T3-L1 preadipocyte proliferation by targeting G3BP1. AB - MicroRNAs have been regarded to play a crucial role in the proliferation of different cell types including preadipocytes. In our study, we observed that miR 129-5p was down-regulated during 3T3-L1 preadipocyte proliferation, while the expression of G3BP1 showed a contrary tendency. 5-Ethynyl-2'-deoxyuridine (EdU) incorporation assay and flow cytometry showed that overexpression of miR-129-5p could bring about a reduction in S-phase cells and G2-phase arrest. Additional study indicated that miR-129-5p impaired cell cycle-related genes in 3T3-L1 preadipocytes. Importantly, it showed that miR-129-5p directly targeted the 3'UTR of G3BP1 and the expression of G3BP1 was inhibited by miR-129-5p mimic. Moreover, miR-129-5p mimic activated the p38 signaling pathway through up-regulating p38 and the phosphorylation level of p38. In a word, results in our study revealed that miR-129-5p suppressed preadipocyte proliferation via targeting G3BP1 and activating the p38 signaling pathway. PMID- 30460079 TI - Spinal beta-adrenergic receptors' activation increases the blood glucose level in mice. AB - We examined the role of spinally located beta-adrenergic receptors in the regulation of the blood glucose level. The intrathecal (i.t.) injections with dobutamine (beta1-adrenergic receptor agonist) or terbutaline (beta2-adrenergic receptor agonist) caused an elevation of the blood glucose level, whereas metoprolol (beta1-adrenergic receptor antagonist) or butoxamine (beta2-adrenergic receptor antagonist) did not. In addition, i.t. pretreatment with pertussis toxin (PTX) attenuated the hyperglycemic effect induced by dobutamine or terbutaline. Moreover, plasma insulin level was increased by dobutamine but not by terbutaline, and PTX reduced dobutamine-induced up-regulation of the plasma insulin level. Terbutaline significantly increased plasma corticosterone level, and PTX further enhanced terbutaline-induced corticosterone level. Furthermore, intraperitoneal (i.p.) pretreatment with hexamethonium- (a preganglionic blocker) attenuated dobutamine- and terbutaline-induced hyperglycemic effects. Our results suggest that activation of spinal beta1- and beta2-adrenergic receptors produces hyperglycemic effects in a different manner. Spinally located PTX-sensitive G proteins appear to be involved in hyperglycemic effect induced by terbutaline. Furthermore, dobutamine- or terbutaline-induced hyperglycemia appears to be mediated through the spinal nerves. PMID- 30460080 TI - Distribution status and habitat characteristics of the endangered freshwater fish, Microphysogobio rapidus (Cyprinidae). AB - To investigate distribution, habitat characteristics, and current conservation status of the endangered endemic species, rapid small gudgeon Microphysogobio rapidus (Cyprinidae), we surveyed a total of 79 sites from the historic records (20 sites) plus additional sites (59 sites) with good habitat conditions, analyzed their sites, and compared them with historic recorded sites to reveal the factors of extinction threats and causes. We found only eight out of 79 sites in the Nam River areas. The habitats were greatly reduced and restricted compared with the historic sites, which mainly cause from habitat modification, such as various types of river renovations at the main stream and tributary streams of the Nakdong River. The present habitats are higher water temperature and more number of fish species than the absent ones, but conductivity, total nitrogen, and number of weir are lower. In addition, the present sites are lower low velocity at pool and higher mean substrate at pool. From this study, we suggest that maintaining good water quality and preventing anthropogenic impacts greatly aid conservation of the M. rapidus in South Korea. PMID- 30460081 TI - Influence of vegetation area and edge length on mammals in urban woods. AB - We investigated the relationships between vegetation area, edge length, and mammals in the urban woods of Daejeon Metropolitan City, South Korea. The vegetation patches included in this study varied from 2.1 to 501.0 ha in size. Surveys were conducted monthly between February and October 2015, with a survey route measuring 1 km in length and 10 m width established in each forest patch. Field signs of 14 species of mammals were recorded in the 33 chosen forest patches over the course of the study period, and the number of species in each patch varied from 2 to 11. Mammal species richness was positively correlated with vegetation area, and field sign frequency was positively correlated with vegetation area and negatively correlated with edge length. The field sign frequencies of large moles Mogera robusta, Siberian chipmunks Tamias sibiricus, leopard cats Prionailurus bengalensis, Korean hares Lepus coreanus, water deer Hydropotes inermis, and wild boars Sus scrofa were positively correlated with vegetation area. Moreover, that of large moles, leopard cats, Korean hares, and water deer were negatively correlated with edge length. Remnant vegetation area and edge length are the primary determinants of mammal species richness and field sign frequency in urban woods, highlighting the importance of vegetation patch size for mammal conservation in fragmented urban landscapes. PMID- 30460082 TI - Carboxy-terminal domain of Cas differentially modulates c-Jun expression, DNA synthesis, and membrane ruffling induced by insulin, EGF, and IGF-1. AB - p130 Crk-associated substrate (Cas) is an adaptor protein associating with many other signaling proteins and regulates a various biological processes including cell adhesion, migration, and growth factor stimulation. However, the exact functional role of Cas in growth factor signaling pathway was poorly understood. Here we investigated the role of Cas and its domains in the effects of insulin, EGF, and IGF-1 on c-Jun gene expression, DNA synthesis, cytoskeletal reorganization. We found that microinjection of anti-Cas antibody and C-terminal domain of Cas (Cas-CT) specifically inhibited EGF-induced, but not insulin- or IGF-1-induced, c-Jun expression. Cell cycle progression and cytoskeleton reorganization induced by insulin and EGF, but not by IGF-1, were inhibited by microinjected anti-Cas and Cas-CT. In contrast, microinjection of the substate domain (Cas-SD) of Cas did not have any inhibitory effects. These results revealed that the Cas-CT is differentially implicated in insulin and EGF mediated, but not IGF-1-mediated, c-Jun expression, DNA synthesis and membrane ruffling. PMID- 30460083 TI - Generation of motor neurons requires spatiotemporal coordination between retinoic acid and Mib-mediated Notch signaling. AB - Mind bomb (Mib) is an E3 ubiquitin ligase that activates the Notch signaling pathway. A previous study demonstrated that the generation of late-born GABAergic neurons may be regulated by the interplay between Mib and retinoic acid (RA). However, the relationship between Mib function and the retinoid pathway during the generation of late-born motor neurons remains unclear. We investigated the differentiation of neural progenitors into motor neurons by inhibition of Notch signaling and administration of RA to Tg[hsp70-Mib:EGFP] embryos. The number of motor neurons in the ventral spinal cord increased or decreased depending on the temporal inhibition of Mib-mediated Notch signaling. Inhibition of the retinoid pathway by citral treatment had a synergistic effect with overexpression of Mib:EGFP on the generation of ectopic motor neurons. Additionally, the proteolytic fragment of Mib was detected in differentiated P19 cells following treatment with RA. Our observations imply that the function of Mib may be attenuated by the retinoid pathway, and that Mib-mediated Notch signaling and the retinoid pathway play critical roles in the spatiotemporal differentiation of motor neurons. PMID- 30460084 TI - Gene microarray analysis revealed a potential crucial gene RACK1 in oral squamous cell carcinoma (OSCC). AB - Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide, which appears as a consequence of multiple molecular genetic events in various chromosomes and genes. In order to unveil the possible mechanisms underlying OSCC tumorigenesis, the OSCC-related gene expression variance and the gene interaction network should be further investigated. Herein, we conducted the NimbleGen Human Gene Expression Microarray to analyze expression heterogeneity between OSCC primary tumor tissue and its adjacent normal tissue from two patients. A total number of 7872 out of 32,448 detected genes are differentially expressed in OSCC. Gene ontology (GO) analysis demonstrated that these differentially expressed transcripts were critical in a series of metabolic processes, cancer-related signal pathways, and biological regulations. KEGG signaling pathway enrichment suggested a number of pathways (metabolic process and immune response) which are frequently enrolled during cancer progression. 15 most differential regulated genes between OSCC tumor and non-tumor were confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Furthermore, the interaction network analysis of these confirmed genes by STRING database showed the two subunits of RACK1 had direct interaction with 14 differential proteins. This bioinformatics research lends support about the critical role of RACK1 which functions as a key node protein driving OSCC development. PMID- 30460085 TI - Up-regulation of fibrinogen-like protein 2 in porcine endothelial cells by xenogeneic CD40 signal. AB - Acute humoral xenograft rejection (AHXR), characterized by thrombin generation and endothelial cell activation, should be overcome for the success of xenotransplantation. Fibrinogen-like protein 2 (fgl2) expressed on endothelial cells can convert prothrombin to thrombin directly, which indicates that the induced fgl2 expression in activated endothelial cells can contribute to thrombosis. In xenotransplant condition, the interaction between human CD40L and porcine endothelial CD40 can activate endothelial cells. In this study, we investigated the effect of endothelial cell activation through the interaction between human CD40L and porcine CD40 on fgl2 expression and its function as a direct prothrombinase. We found that CD40 stimulation up-regulated fgl2 expression as well as its enzymatic activity in porcine endothelial cells. Moreover, functional studies using knock-down system showed that the major factor converting human prothrombin to thrombin is fgl2 protein expressed on porcine endothelial cells. Overall, this study demonstrates that fgl2 expression can be induced by xenogeneic CD40 signal on endothelial cells and contribute to thrombin generation. PMID- 30460086 TI - Long-term characteristics of soil respiration in a Korean cool-temperate deciduous forest in a monsoon climate. AB - Analysis of relationship between soil respiration and environmental factors has become essential for understanding changes in ecosystem carbon cycles under global warming. However, rough predictions have been made that soil respiration will increase with increasing temperature, but long-term data to support this theory were scarce. We measured soil respiration and environmental factors continuously using an automatic open-closed chamber system in a Korean cool temperate forest from 2004 to 2016 to ascertain the reliability of this prediction and to more accurately predict changes in carbon cycle. Average air and soil temperatures were 11.0 degrees C and 10.2 degrees C. The increase in temperature was greater in winter (the inactive period for soil respiration) than in summer (the active period). Additionally, precipitation decreased sharply because of patter changes in 2012, and through 2016, it was approximately 69% of the previous period. Effect of precipitation on soil respiration was expected to be larger than temperature because the change in precipitation appeared in summer. Soil respiration exhibited a significant decline in 2012 because of precipitation. From 2004 to 2011, it averaged 344.4 mgCO2 m-2 h-1 and from 2012 to 2016 the average was 205.3 mgCO2 m-2 h-1. This phenomenon hasn't been detected in short-term studies, suggesting that the prediction of previous studies is inaccurate. Additionally, to predict future ecosystem carbon cycle changes in a cool-temperate monsoon climate, changes in precipitation pattern should be regarded as equally important to temperature, and the prediction cannot be based solely on temperature. Therefore, long-term and continuous measurements are needed with consideration of the effects of both precipitation and temperature. Abbreviations: Rs: soil respiration; Ts: soil temperature; Ta: air temperature; AOCC: automatic open/closed chamber. PMID- 30460088 TI - Vigilance responding to number of conspecifics among mixed groups of cranes in demilitarized zone. AB - Numerous studies have addressed antipredatory benefits of mixed-species flocks of foragers, but studies on individual's vigilance as a function of group size are limited. In the Cheolwon area of the Korean Demilitarized Zone, vigilance of the subordinate White-naped cranes (Grus vipio) in 11 groups composed of conspecifics and the dominant Red-crowned cranes (Grus japonensis) was examined. Vigilance correlated negatively with group size due to negative correlation with the number of conspecifics, but not the dominant heterospecifics. This is consistent with the hypothesis that a decrease in vigilance in larger groups is due to antipredatory benefits from increased predator detection in larger groups (associated with the presence of a larger number of conspecifics). This suggested that the mechanism leads to canceling out of the otherwise expected antipredatory benefits to the subordinate species from the increased predator detection by larger group size (associated with larger number of dominants). This is one of only a few behavioral studies of these endangered crane species in the relatively inaccessible wintering area of international importance in the areas of high conservation value. PMID- 30460087 TI - Oleuropein reduces anxiety-like responses by activating of serotonergic and neuropeptide Y (NPY)-ergic systems in a rat model of post-traumatic stress disorder. AB - Post-traumatic stress disorder (PTSD) is a stress-related mental disorder caused by traumatic experiences. This psychopathological response to traumatic stressors induces anxiety in rats. Oleuropein (OLE), a major compound in olive leaves, reportedly possesses several pharmacological properties, including anti-cancer, anti-diabetic, and anti-atherosclerotic and neuropsychiatric activities. However, the anxiolytic-like effects of OLE and its mechanism of action in PTSD are unclear. The present study used several behavioral tests to examine the effects of OLE on symptoms of anxiety in rats after a single prolonged stress (SPS) exposure by inhibiting the hypothalamic-pituitary-adrenal axis. Male Sprague Dawley rats received OLE (10, 50 and 70 mg/kg, i.p., once daily) for 14 days after SPS exposure. Daily OLE (70 mg/kg) administration significantly increased the number and duration of open arm visits in the elevated plus maze (EPM) test, reduced the anxiety index and grooming behavior in the EPM test, and increased the time spent and number of central zone crossings in the open field test. OLE also blocked the SPS-induced decrease in hippocampal serotonin and neuropeptide Y expression in hippocampus. These findings suggest that OLE has anxiolytic-like effects on behavioral and biochemical symptoms similar to those observed in patients with PTSD. PMID- 30460089 TI - Feather holes and flight performance in the barn swallow Hirundo rustica. AB - Feather holes are small (0.5-1 mm in diameter) deformities that appear on the vanes of flight feathers. Such deformities were found in many bird species, including galliforms and passerines. Holey flight feathers may be more permeable to air, which could have a negative effect on their ability to generate aerodynamic forces. However, to date the effects of feather holes on flight performance in birds remained unclear. In this study we investigated the relationship between the number of feather holes occurring in the wing or tail feathers and short term flight performance traits - aerial manoeuvrability, maximum velocity and maximum acceleration - in barns swallows, which are long distance migrating aerial foragers. We measured short-term flight performance of barn swallows in a standardized manner in flight tunnels. We found that acceleration and velocity were significantly negatively associated with the number of holes in the wing flight feathers, but not with those in the tail feathers. In the case of acceleration the negative relationship was sex specific while acceleration significantly decreased with the number of feather holes in females, there was no such significant association in males. Manoeuvrability was not significantly associated with the number of feather holes. These results are consistent with the hypothesis that feather holes are costly in terms of impaired flight. We discuss alternative scenarios that could explain the observed relationships. We also suggest directions for future studies that could investigate the exact mechanism behind the negative association between the number of feather holes and flight characteristics. PMID- 30460090 TI - Optimization of episomal reprogramming for generation of human induced pluripotent stem cells from fibroblasts. AB - Generation of induced pluripotent stem cells (iPSCs) by defined factors (OCT4, SOX2, C-MYC, and KLF4) from various human primary cells has been reported. Human fibroblasts have been widely used as a cellular source in reprogramming studies over recent decades. The original method of iPSC generation uses retro- or lentivirus vectors that require integration of viral DNA into the target cells. The integration of exogenous genes encoding transcription factors (OCT4, SOX2, C MYC, and KLF4) can be detected in iPSCs, raising concern about the risk of mutagenesis and tumor formation. Therefore, stem cell therapy would ideally require generation of integration-free iPSCs using non-integration gene delivery system such as Sendai virus, recombinant proteins, synthetic mRNA, and episomal vectors. Several groups have reported that episomal vectors are capable of reprogramming human fibroblasts into iPSCs. Although vector concentration and cell density are important in the episomal vector reprogramming method, optimization of this method for human fibroblasts has not been reported. In this study, we determined optimal conditions for generating integration-free iPSCs from human fibroblasts through the use of different concentrations of episomal vectors (OCT4/p53, SOX2/KLF4, L-MYC/LIN28A) and different plating cell density. We found that optimized vector concentration and cell density accelerate reprogramming and improve iPSC generation. Our study provides a detailed stepwise protocol for improved generation of integration-free iPSCs from human fibroblasts by transfection with episomal vectors. PMID- 30460092 TI - Visual deprivation modifies oscillatory activity in visual and auditory centers. AB - Loss of vision may enhance the capabilities of auditory perception, but the mechanisms mediating these changes remain elusive. Here, visual deprivation in rats resulted in altered oscillatory activities, which appeared to be the result of a common mechanism underlying neuronal assembly formation in visual and auditory centers. The power of high-frequency beta and gamma oscillations in V1 (the primary visual cortex) and beta oscillations in the LGN (lateral geniculate nucleus) was increased after one week of visual deprivation. Meanwhile, the power of beta oscillations in A1 (the primary auditory cortex) and the power of beta and gamma oscillations in the MGB (medial geniculate body) were also enhanced in the absence of visual input. Furthermore, nerve tracing revealed a bidirectional nerve fiber connection between V1 and A1 cortices, which might be involved in transmitting auditory information to the visual cortex, contributing to enhanced auditory perception after visual deprivation. These results may facilitate the better understanding of multisensory cross-modal plasticity. PMID- 30460091 TI - Characterization of Parkinson's disease-related pathogenic TMEM230 mutants. AB - Parkinson's disease (PD) is the second most common neurodegenerative disease. Although most PD cases are sporadic, 5-10% of them are hereditary and several pathogenic mutations in related genes have been identified. Mutations in TMEM230 were recently identified as a cause of autosomal dominant PD. However, the basic properties of the mutant proteins are not yet known. We examined stability and neurotoxicity, important characteristics of PD pathogenesis-related proteins, of WT TMEM230 and two pathogenic mutants, R78L and PG5ext, in a dopaminergic neuronal cell line. Our study showed that amount of protein expressed in the same vector backbone was R78L > WT > PG5ext. The stabilities of the mutant proteins were similar to each other, but lower than that of the WT. In addition, overexpression of mutants and WT TMEM230 caused similar levels of neurotoxicity upon MPP+ treatment when compared to the cells transfected with an empty vector. Because the proteins encoded by two PD-causing genes, TMEM230 and LRRK2, function in vesicle trafficking, we tested whether they interact. LRRK2 neither interacts with, nor phosphorylates TMEM230. We also investigated the levels of several Rab proteins (Rab1A, 5, 7, 8A and 11) involved in vesicle trafficking after TMEM230 overexpression. However, there was no clear difference of any Rab proteins among cells transfected with an empty vector, TMEM230 WT and mutants-expressing cells, suggesting that TMEM230 does not directly regulate these Rab proteins. Thus, these TMEM230 PG5ext and R78L mutant proteins are not distinctly different from the WT proteins except for their stability. Abbreviations: LRRK2: Leucine-rich repeat kinase 2; PD: Parkinson's disease; AD: Alzheimer's disease; RT-PCR: reverse transcription-polymerase chain reaction; SDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresis; FACS: fluorescence-activated cell sorting; PBS: phosphate buffered saline; FBS: fetal bovine serum; PI: propidium iodide. PMID- 30460093 TI - GM1 Induced the inflammatory response related to the Raf-1/MEK1/2/ERK1/2 pathway in co-culture of pig mesenchymal stem cells with RAW264.7. AB - Pig-human xenotransplantation can trigger cell-mediated immune responses. We explored the role of gangliosides in inflammation related to immune rejection in xenotransplantation. Co-culture of xenogeneic cells (pig-MSCs and RAW264.7) was used to emulate xenotransplantation conditions. MTT assay results indicated that cell viability was significantly decreased in pADMSCs co-cultured with RAW264.7 cells. GM1 and GM3 were highly expressed in pADMSCs co-cultured with RAW264.7 cells. pADMSCs co-cultured with RAW264.7 cells strongly expressed pro inflammatory proteins such as COX-2, iNOS, p50, p65, pIkappaBalpha, and TNF alpha. GM1-knockdown pADMSCs co-cultured with RAW 264.7 cells did not show significantly altered cell viability, but pro-inflammatory proteins were markedly inhibited. Co-culture of pADMSCs with RAW264.7 cells induced significant phosphorylation (p) of JNK1/2 and pERK1/2. However, pERK1/2 and pJNK1/2 were decreased and MEK1/2 and Raf1 were suppressed in GM1-knockdown pADMSCs co cultured with RAW264.7 cells. Thus, the Raf-1/MEK1/2/ERK1/2 and JNK1/2 pathways were significantly upregulated in response to increases of GM1 in co-cultured xenogeneic cells. However, the inflammatory response was suppressed in co-culture of GM1-knockdown pADMSCs with RAW264.7 cells via down-regulation of the Raf 1/MEK1/2/ERK1/2 and JNK1/2 pathways. Therefore, the ganglioside GM1 appears to play a major role in the inflammatory response in xenotransplantation via the Raf 1/MEK1/2/ERK1/2 and JNK1/2 pathways. PMID- 30460094 TI - Differential regulation of neuronal excitability by nicotine and substance P in subdivisions of the medial habenula. AB - The medial habenula (MHb) plays an important role in nicotine-related behaviors, such as aversion and withdrawal. The MHb is composed of distinct subregions with unique neurotransmitter expression and neuronal connectivity. Here, we showed that nicotine and substance P (SP) differentially regulate neuronal excitability in subdivisions of the MHb (ventrolateral division, MHbVL; dorsal division; MHbD and superior division: MHbS). Nicotine remarkably increased spontaneous neuronal firing in the MHbVL and MHbD, but not in the MHbS, which was consistent with different magnitudes of whole-cell inward currents evoked by nicotine in each subdivision. Meanwhile, SP enhanced neuronal excitability in the MHbVL and MHbS. Although the MHbD is composed of SP-expressing neurons, they did not respond to SP. Neurons in the MHbVL increased their firing in response to bath-applied nicotine, which was attenuated by neurokinin receptor antagonists. Furthermore, nicotine addiction and withdrawal attenuated and augmented excitatory SP effects in the MHbVL, respectively. On the whole, we suggest that MHb-involving nicotine related behaviors might be associated with SP signaling in MHb subdivisions. PMID- 30460095 TI - Promoter DNA methylation contributes to human beta-defensin-1 deficiency in atopic dermatitis. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease caused by epidermal barrier dysfunction and dysregulation of innate and adaptive immunity. Epigenetic regulation of human beta-defensin-1 (HBD-1) might be associated with a variety of defects in the innate immune system during AD pathogenesis. We investigated the possible mechanism of decreased HBD-1 gene expression in AD and demonstrated the restoration of HBD-1 transcription in undifferentiated normal human epidermal keratinocyte cells after treatment with a DNA methyltransferase inhibitor. We also conducted an in vitro methylated reporter assay using a reporter containing 14 CpG sites. Methylation of the 14 CpG sites within the HBD-1 5' region resulted in an approximately 86% reduction in promoter activity and affected HBD-1 transcriptional regulation. We then compared methylation frequencies at CpG 3 and CpG 4 between non-lesional and lesional epidermis samples of patients with severe AD and between these paired tissues and healthy control epidermis from normal volunteers without AD history. Bisulfite pyrosequencing data showed significantly higher methylation frequencies at the CpG 3 and 4 sites in AD lesional samples than in non-lesional AD skin and normal skin samples (P < 0.05). These results suggest that the DNA methylation signature of HBD-1 is a novel diagnostic/prognostic marker and a promising therapeutic target for the compromised stratum corneum barrier attributed to HBD-1 deficiency. PMID- 30460096 TI - Inhibition of cell growth by cellular differentiation into adipocyte-like cells in dexamethasone sensitive cancer cell lines. AB - The stress responses in human body lead to secretion of cortisol hormone. The present study investigated the cellular responses on cell growth and cellular differentiation into adipocytes by exposure of synthetic stress hormone, dexamethasone (DEX) in various human cancer and normal cells. After prolonged exposure of cells with 1 MUg/ml DEX for 2 weeks, population doubling time (PDT) was significantly (P < .05) increased by inhibited cell growth in A-549 and MCF-7 cancer cells, and was unchanged in MDA-MB-231 cancer cells, normal MRC-5 fibroblasts, umbilical cord matrix-derived mesenchymal stem cells (UCMSCs) and dental papilla tissue-derived mesenchymal stem cells (DSCs). Whereas, PDT was significantly (P < .05) decreased in U87-MG cancer cells by increased cell growth. Glucose uptake was significantly (P < .05) increased in all the cancer cell lines compared to that in normal cell lines. Further, adiposome-like vesicles were noted in A-549 and MCF-7 cancer cells indicating retarded cell growth by DEX treatment, and the vesicles were stained with Oil-Red O solution. Further, the expression of adipocyte-specific genes such as glucose transporter type 4 (GLUT4), glucocorticoid receptors beta (GRbeta) and peroxisome proliferator-activated receptor gamma (PPARgamma) were significantly (P < .05) increased in A-549 and MCF-7 with lipid vesicles. The level of telomerase activity was found to be significantly (P < .05) downregulated in DEX-treated A 549 and MCF-7 cancer cells. Our results have clearly shown that DEX treatment induces inhibition of cell growth by differentiating into adipocyte-like cells in dexamethasone sensitive cancer cells. PMID- 30460098 TI - VIG-1 is required for maintenance of genome stability in Caenorhabditis elegans. AB - To explore the function of VIG-1 in Caenorhabditis elegans, we analyzed the phenotypes of two vig-1 deletion mutants: vig-1(tm3383) and vig-1(ok2536). Both vig-1 mutants exhibited phenotypes associated with genome instability, such as a high incidence of males (Him) and increased embryonic lethality. These phenotypes became more evident in succeeding generations, implying that the germline of vig 1 accumulates DNA damage over generations. To examine whether vig-1 causes a defect in the DNA damage response, we treated worms with UV or camptothecin, a specific topoisomerase I inhibitor. We observed that the embryonic survival of the vig-1 mutants was reduced compared with that of the wild-type worms. Our results thus suggest that VIG-1 is required for maintaining genome stability in response to endogenous and exogenous genotoxic stresses. PMID- 30460097 TI - Augmented reduction in colonic inflammatory markers of dextran sulfate sodium induced colitis with a combination of 5-aminosalicylic acid and AD-licoTM from Glycyrrhiza inflata. AB - The primary aim of this study was to determine whether the oral administration of AD-licoTM, a functional extract from Glycyrrhiza inflata in combination with 5 aminosalicylic acid (5-ASA) could ameliorate the inflammatory symptoms in dextran sulfate sodium (DSS)-induced colitis in rodents. This DSS rodent model is used to study drug candidates for colitis, as part of the spectrum of diseases falling under the inflammatory bowel disease (IBD) category. Here, with oral AD-licoTM administration, there was a substantial disruption of the colonic architectural changes due to DSS and a significant reduction in colonic myeloperoxidase (MPO) activity, a marker of colitis. In the same samples, there were also reduced levels of colonic and serum IL-6 in the oral AD-licoTM treated rats. This study also addressed the possible mechanisms for AD-licoTM mediated changes on colonic inflammation markers. These included the observations that AD-licoTM dampened the IL-6 proinflammatory-signaling pathway in THP-1 human monocytic cells and reduced the TNFalpha-mediated upregulation of surface adhesion molecule ICAM-1 in human umbilical vein endothelial cells (HUVECs). Finally, it was shown that AD-licoTM could be combined with 5-ASA in reducing the inflammatory markers for colorectal sites affected by colitis, a first study of its kind for a combination therapy. PMID- 30460099 TI - Preference for natural borders in rice paddies by two treefrog species. AB - In the Republic of Korea, one of the biggest threats to amphibians is habitat modification such as urbanisation and land conversion. With the loss of natural habitats, rice paddies play an important role as substitute habitats for amphibians that originally inhabited wetlands. However, since the 70's, traditional rice agriculture has been modernised, leading to an increase in the number of concrete ditches and roads bordering rice paddies. This modernisation could have affected the distribution and density of amphibians. In this study, we investigated the preferred position, based on the advertisement calls for two treefrog species (Dryophytes japonicus and D. suweonensis), in relation to different types of borders such as natural ditch, concrete ditch, one-lane dirt road and vegetation. The results show that treefrogs seem to avoid rice paddies with concrete ditches, and with no ditch, which provided no resting microhabitat. The sides of the paddies preferred by the two treefrog species were the ones with vegetation of 30 cm wider or higher, while the two species seemed to avoid the side of paddies with roads. Our results are important for the conservation of anuran species in rice paddies in general as it highlights the need for vegetated areas, preferentially along natural ditches. PMID- 30460101 TI - Repeated immune activation with low-dose lipopolysaccharide attenuates the severity of Huntington's disease in R6/2 transgenic mice. AB - Huntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the huntingtin gene. Previously, therapeutic approaches using anti-inflammatory agents were reportedly not effective for preventing HD progression. Since whether immune responses contribute to the onset of HD is not entirely understood, we herein investigated the role of immune activation in HD using the R6/2 transgenic (Tg) HD model mouse. IL12 production and the expression of costimulatory molecules (e.g. CD86 and CD40) on innate immune cells (DCs and macrophages) were diminished in the disease stage of R6/2 Tg mice. Moreover, the number of adaptive T cells (CD4+ and CD8+ T cells) and the frequency of effector memory phenotype CD4+ T cells were decreased in these mice. These results suggest that the severity of HD is closely related to an impaired immune system and might be reversed by activation of the immune system. Since lipopolysaccharide (LPS), a potent TLR4 agonist, activates immune cells, we evaluated the effect of immune activation on the pathogenesis of HD using LPS. The repeated immune activation with low-dose LPS significantly recovered the impaired immune status back to normal levels and attenuated both severe weight loss and the increased clasping phenotype found in the disease stage of R6/2 Tg mice, consequently resulting in prolonged survival. Taken together, these results strongly indicate that immune activation has beneficial influences on alleviating HD pathology and could provide new therapeutic strategies for HD. PMID- 30460100 TI - Exploring glia to better understand Alzheimer's disease. AB - The amyloid-beta (Abeta) hypothesis has been the leading explanation for the pathogenesis of Alzheimer's disease (AD). The most common traits of AD are cognitive impairments and memory loss, which are associated with the accumulation of Abeta. Abeta aggregates activate glial cells, which in turn remove Abeta. Because microglia act as immune cells in the brain, most glia-related studies of AD have focused primarily on this cell type. However, astrocytes, another type of glial cell, also participate in the brain immune system, synaptic formation, brain homeostasis, and various other brain functions. Accordingly, many studies on the underlying mechanisms of AD have investigated not only neurons but also glial cells. Although these studies suggest that microglia and astrocytes are effective targets for AD therapeutics, other recent studies have raised questions regarding whether microglial cells and/or astrocytes serve a neuroprotective or neurotoxic function in AD. To gain a better understanding of the mechanisms of AD and identify novel targets for AD treatment, in this review, we consider the role of both microglia and astrocytes in AD. PMID- 30460102 TI - Characterization of changes of pain behavior and signal transduction system in food-deprived mice. AB - Fasting in general causes several metabolic changes. In the present study, we examined the possible changes of several types of nociception during the food deprivation were investigated in mice. After the mice were forced into the fasting for 12, 24, or 48 h, the changes of nociception were measured by the tail flick, writhing, formalin or von-frey tests. We found that the nociceptive behavior induced by intraperitoneally (i.p.) administered acetic acid (writhing response) or intraplantar injection of 5% formalin into the hind-paw were reduced in fasted group. In addition, the tail-flick response and threshold for nociception in mechanical von-frey test were also elevated in fasted group. Moreover, the p-CREB and p-ERK levels in the dorsal root ganglia (DRG) and the spinal cord were reduced in food-deprived group. Furthermore, p-AMPKalpha1 expressions in DRG and the spinal cord were up-regulated, whereas p-mTOR in DRG and the spinal cord was down-regulated in food-deprived group. Our results suggest that the chemical, mechanical, and thermal nociceptions appear to be reduced in a food-deprived mouse group. Additionally, reduction of nociception in food-deprived group appears to be closely associated with the expressions of several signal transduction molecules such as ERK, CREB, AMPKalpha1 and mTOR proteins in DRG and the spinal cord. PMID- 30460103 TI - Time-series transcriptomic analysis of the kelp grouper Epinephelus moara in response to low salinity stress. AB - The Kelp grouper Epinephelus moara is one of the most widely consumed and economically important marine fish in China. The species can tolerate a wide range of salinity, but genomic resources are not available, and the molecular mechanisms underlying adaptation to salinity at the transcriptomic level remain largely unclear. In this study, the transcriptomic responses of the liver of E. moara under low salinity were investigated using the Illumina digital gene expression system. After de novo assembly, 499,356 transcripts were generated and contributed 445,068 unigenes. A total of 14, 19, 33 and 3101 genes were differentially expressed following exposure to low salinity stress for 2, 6, 24 and 48 h, respectively. Only two genes were differentially expressed in all groups. Four genes related to metabolism and ambient salinity adaption were randomly selected to validate the differentially expressed genes (DEGs) by real time PCR. Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to analyse the functional significance of DEGs, including those responding to salinity through diverse biological processes, cellular components, molecular functions, and pathways associated with metabolic and osmotic responses. This work provides new insight into the response to salinity challenges in E. moara, and the findings expand our knowledge of the molecular basis of metabolic regulation mechanisms in this species. Additionally, the transcriptional data provide a valuable resource for future molecular and genetic studies on E. moara. PMID- 30460104 TI - High-fat-diet impaired mitochondrial function of cumulus cells but improved the efficiency of parthenogenetic embryonic quality in mice. AB - Global human health has been compromised by high-fat diets. This study aimed to investigate the relationship between a high-fat diet and parthenogenetic embryo quality. Mice fed a high-fat or a normal diet was used as treated or control groups, respectively. Estradiol (E2), total cholesterol (TC) and total triglyceride (TG) were detected by Enzyme-Linked ImmunoSorbent Assay (ELISA). Cumulus-oocyte complexes (COCs) were collected from the mice in the treated and control groups. The ultrastructure of COCs, the expression level of genes involved in mitochondrial and nuclear functions in cumulus cells and oocytes quality were evaluated with transmission electron microscopy, real-time quantitative polymerase chain reaction (RT-PCR) and artificial parthenogenesis, respectively. The results showed that the efficiency of parthenogenetic embryonic development in vitro was significantly higher in the treated group than in the control group (p < .05). The expression level of genes involved in mitochondrial function was lower in cumulus cells from the treated group than that from the control group (p < .05). The estradiol and cholesterol level in the serum and the expression level of P450 arom were higher in the treated group than the control group (p < .05). The reactive oxygen species (ROS) level was higher in culumus cells from the treated group than the control group, while the mitochondrial membrane potential was lower in cumulus cells from the treated group (p < .05). Accumulation of lipid droplets was only in cumulus but in oocyte, the results demonstrated that mitochondrial functions were impaired by a high-fat diet, but parthenogenetic embryonic development in vitro was improved, in controllable range of damage for the body. PMID- 30460105 TI - Genetic individualization of sable (Martes zibellina L. 1758) using microsatellites. AB - Genetic individualization based on non-invasive sampling is crucial for estimating the numbers of individuals in endangered mammalian populations. In sable (Martes zibellina)-poaching cases, identifying the number of animals involved is critical for determining the penalty. In addition, investigating animal numbers for wild sable populations requires genetic individualization when collecting several samples in neighboring regions. Microsatellites have been demonstrated to be reliable markers for individual identification. Thirty-three microsatellite loci derived from Mustelidae were selected to develop a genetic individualization method for sable. Three reference populations containing 54 unrelated sables were used to calculate allele number, allelic frequencies, and the polymorphic information content of each locus. The data were subsequently used to assess the validity of a combination of twelve loci for sable individualization. We defined twelve polymorphic loci that were easy to be amplified and genotyped. Four significant deviations from Hardy-Weinberg equilibrium were observed among the 12 loci in the three populations. The match probability of an individual from the reference populations with a random individual based on the 12 loci was 1.37 * 10-13. Using the combination of the twelve loci provides sufficient power to individualize sables considering the levels of microsatellite polymorphism observed. These loci were successfully applied to a case of sable poaching and provided valid evidence to determine the penalty. The genetic individualization of sable based on these loci might also be useful to investigate the numbers of animals in wild populations. PMID- 30460106 TI - Breeding biology of two wagtail subspecies on Ulleung Island, Korea: Amur Wagtails, Motacilla alba leucopsis and Black-backed Wagtails, M. a. lugens. AB - There is much controversy over the species and subspecies status of the white wagtail complex, which is further compounded by interbreeding between two subspecies, the Amur Wagtail (Motacilla alba leucopsis) and the Black-backed Wagtail (M. a. lugens). This study presents preliminary information on the breeding biology of both subspecies on Ulleung Island, Korea, over two breeding seasons (2012-2013). Mixed pairs of the two subspecies were common on this island, with almost 50% of all pairs being heterotypic or intermediate pairs; however, assortative mating was still present. Females of both subspecies were more likely to be paired with Amur wagtail males, whereas intermediate females were more likely to be paired with Black-backed Wagtail males. Clutch size, egg size and mass, and reproductive parameters (such as hatching success and nest success) did not significantly differ from each other. However, the mean values were low in intermediate pairs. Our results indicate no reproductive barrier between the two subspecies, but that some post-isolating mechanisms are still in progress. PMID- 30460107 TI - Directional raids by army ants as an adaption to patchily distributed food: a simulation model. AB - A typical colony of Neotropical army ants (subfamily Ecitoninae) regularly raids a large area around their bivouac by forming a narrow directional column that can reach up to one hundred meters in length. The raid is finished and then relaunched 12-17 times, each time toward different orientation. After completing all bouts the colony relocates to a new area. A hypothetical alternative to this foraging mode is raiding radially and symmetrically by expanding the search front in every direction like a circular bubble. Using an existing agent-based modeling software that simulates army ants' behavior, we compared the two possible modes of foraging in different food distributions. Regardless of the food patch abundance, the radial raiding was superior to the directional raiding when food patches had low quality, and the directional raiding was favorable when the patches were rich. In terms of energy efficiency, the radial raiding was the better strategy in a wide range of conditions. In contrast, the directional raiding tended to yield more food per coverage area. Based on our model, we suggest that the directional raiding by army ants is an adaptation to the habitats with abundance of high-quality food patches. This conclusion fits well with the ecology of army ants. PMID- 30460108 TI - Increase in anti-apoptotic molecules, nucleolin, and heat shock protein 70, against upregulated LRRK2 kinase activity. AB - Leucine-rich repeat kinase 2 (LRRK2) is involved in Parkinson's disease (PD) pathology. A previous study showed that rotenone treatment induced apoptosis, mitochondrial damage, and nucleolar disruption via up-regulated LRRK2 kinase activity, and these effects were rescued by an LRRK2 kinase inhibitor. Heat-shock protein 70 (Hsp70) is an anti-oxidative stress chaperone, and overexpression of Hsp70 enhanced tolerance to rotenone. Nucleolin (NCL) is a component of the nucleolus; overexpression of NCL reduced cellular vulnerability to rotenone. Thus, we hypothesized that rotenone-induced LRRK2 activity would promote changes in neuronal Hsp70 and NCL expressions. Moreover, LRRK2 G2019S, the most prevalent LRRK2 pathogenic mutant with increased kinase activity, could induce changes in Hsp70 and NCL expression. Rotenone treatment of differentiated SH-SY5Y (dSY5Y) cells increased LRKK2 levels and kinase activity, including phospho-S935-LRRK2, phospho-S1292-LRRK2, and the phospho-moesin/moesin ratio, in a dose-dependent manner. Neuronal toxicity and the elevation of cleaved poly (ADP-ribose) polymerase, NCL, and Hsp70 were increased by rotenone. To validate the induction of NCL and Hsp70 expression in response to rotenone, cycloheximide (CHX), a protein synthesis blocker, was administered with rotenone. Post-rotenone increased NCL and Hsp70 expression was repressed by CHX; whereas, rotenone induced kinase activity and apoptotic toxicity remained unchanged. Transient expression of G2019S in dSY5Y increased the NCL and Hsp70 levels, while administration of a kinase inhibitor diminished these changes. Similar results were observed in rat primary neurons after rotenone treatment or G2019S transfection. Brains from G2019S-transgenic mice also showed increased NCL and Hsp70 levels. Accordingly, LRRK2 kinase inhibition might prevent oxidative stress mediated PD progression. Abbreviations: 6-OHDA: 6-hydroxydopamine; CHX: cycloheximide; dSY5Y: differentiated SH-SY5Y; g2019S tg: g2019S transgenic mouse; GSK/A-KI: GSK2578215A kinase inhibitor; HSP70: heat shock protein 70; LDH: lactose dehydrogenase; LRRK2: leucine rich-repeat kinase 2; MPTP: 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine; myc-GS LRRK2: myc-tagged g2019S LRRK2; NCL: nucleolin; PARP: poly(ADP-ribose) polymerase; PD: Parkinson's disease; PINK1: PTEN-induced putative kinase 1; pmoesin: phosphorylated moesin at t558; ROS: reactive oxygen species. PMID- 30460109 TI - Novel peptides derived from neuropeptide Y prevent chemotherapy-induced bone marrow damage by regulating hematopoietic stem cell microenvironment. AB - Chemotherapy-induced bone marrow damage is accompanied by acute nerve injury in the bone marrow (BM), resulting in sensory and autonomic neuropathy. Cisplatin, a popular chemotherapy drugs, induces the impairment of hematopoietic stem cells (HSCs) and bone marrow regeneration, leading to chronic bone marrow abnormalities. Previously, we reported the protective roles of neuropeptide Y (NPY) against cisplatin-induced bone marrow impairment. In this study, we identified novel peptides, generated from full-length NPY that rescued cisplatin induced sensory neuropathy and HSC suppression by regulating cell survival in the BM microenvironment. One of these peptides, especially, showed a better protective property against these impairments compared to that seen in full length NPY. Therefore, we suggest the NPY sequences most effective against the chemotherapy-induced bone marrow dysfunction that could be potentially useful as therapeutic agents for patients receiving chemotherapy. PMID- 30460110 TI - Betaine enhances the cellular survival via mitochondrial fusion and fission factors, MFN2 and DRP1. AB - Betaine is a key metabolite of the methionine cycle and known for attenuating alcoholic steatosis in the liver. Recent studies have focused on the protection effect of betaine in mitochondrial regulation through the enhanced oxidative phosphorylation system. However, the mechanisms of its beneficial effects have not been clearly identified yet. Mitochondrial dynamics is important for the maintenance of functional mitochondria and cell homeostasis. A defective mitochondrial dynamics and oxidative phosphorylation system have been closely linked to several pathologies, raising the possibility that novel drugs targeting mitochondrial dynamics may present a therapeutic potential to restore the cellular homeostasis. In this study, we investigated betaine's effect on mitochondrial morphology and physiology and demonstrated that betaine enhances mitochondrial function by increasing mitochondrial fusion and improves cell survival. Furthermore, it rescued the unbalance of the mitochondrial dynamics from mitochondrial oxidative phosphorylation dysfunction induced by oligomycin and rotenone. The elongation properties by betaine were accompanied by lowering DRP1 and increasing MFN2 expression. These data suggest that betaine could play an important role in remodeling mitochondrial dynamics to enhance mitochondrial function and cell viability. PMID- 30460111 TI - The microRNA-127-3p directly targeting Vamp2 in C2C12 myoblasts. AB - MicroRNAs (miRNAs) have been reported that can regulate skeletal muscle growth and development. Previously, we demonstrated that miR-127-3p were differently expressed in skeletal muscle and muscle cells. However, the molecular mechanism of miR-127-3p regulation of skeletal myogenesis are not well elucidated. In this study, we transfected miR-127-3p into C2C12 cells, and found miR-127-3p induces myogenesis by targeting Vamp2. Moreover, the regulatory mechanism of Vamp2 in myoblasts proliferation and differentiation was further confirmed. In conclusion, our data providedevidences that miR-127-3p reciprocally regulated myoblasts proliferation and differentiation through directly targeting Vamp2. PMID- 30460112 TI - Gypenosides attenuate lipopolysaccharide-induced neuroinflammation and anxiety like behaviors in rats. AB - Neuroinflammation is considered a major factor in several neuropsychiatric disorders. Gypenosides (GPS) have pharmacological properties with multiple beneficial effects including antiinflammatory, antioxidative, and protective properties. The present study was performed to examine whether GPS shows anxiolytic-like effects in a model of chronic inflammation induced by injection of lipopolysaccharide (LPS) into the rat hippocampus. The effects of GPS on inflammatory factors in the hippocampus and the downstream mechanisms of these effects were also examined. Introduction of LPS into the lateral ventricle caused inflammatory reactions and anxiety-like symptoms in the rats. Daily treatment with GPS (25, 50, and 100 mg/kg) for 21 consecutive days significantly increased the time spent and number of visits to the open arm in the elevated plus maze test, and significantly increased the number of central zone crossings in the open field test. Moreover, GPS administration significantly reduced the freezing response to contextual fear conditioning, and significantly decreased the levels of proinflammatory mediators, such as interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and nuclear factor-kappaB (NF-kappaB), levels in the brain. Furthermore, GPS reduced LPS-induced elevated levels of Toll-like receptor 4 (TLR4) mRNA and inhibition of brain-derived neurotrophic factor (BDNF) mRNA levels. Taken together, these results suggest that GPS may have anxiolytic-like effects and may have novel therapeutic potential for anxiety-like behaviors caused by neuroinflammation. GPS may be useful for developing an agents for the treatment of neuropsychiatric disorders, such as anxiety, due to its antiinflammatory activities and the modulation of NF-kappaB/iNOS/TLR4/BDNF. PMID- 30460113 TI - The effects of mouse ovarian granulosa cell function and related gene expression by suppressing BMP/Smad signaling pathway. AB - BMP I type receptor inhibitor can selectively inhibit BMP/Smad signaling pathways, mainly by inhibiting the BMP I type receptor activity to prevent phosphorylation of Smad1, Smad5 and Smad9. The aim of the present study was to explore the effects of mouse ovarian granulosa cell function and related gene expression by suppressing BMP/Smad signaling pathway with LDN-193189(A type of BMP I type receptor inhibitor). In this study, we cultivate the original generation of mouse ovarian granular cells then collect cells and cell culture medium after treatment. Cellular localization and expression of Smad9 and P-smad9 proteins was studied by immunofluorescence (IF) in the ovarian granulosa cells of mouse; Related genes mRNA and proteins expression was checked by QRT-PCR and Western blot; Detected the concentration of related hormones by using ELISA kit; finally, the growth of the cells was analyzed by plotting cell growth curve with CCK-8 assay. The results indicate that, suppression of BMP/Smad signaling pathway can inhibit the expression of LHR and FSHR, inhibit cell proliferation and decrease E2 secretion, the mechanism of action maybe reduce the expression of smad9, at the same time, we found that the feedback regulation of smad9 may affect the expression of FSHR and cell proliferation. PMID- 30460114 TI - Modulatory effect of linoleic and oleic acid on cell proliferation and lipid metabolism gene expressions in primary bovine satellite cells. AB - This study was performed to elucidate the effects of linoleic acid (LA), oleic acid (OA) and their combination (LA + OA) on cell proliferation, apoptosis, necrosis, and the lipid metabolism related gene expression in bovine satellite cells (BSCs), isolated from bovine muscles. Cell viability was significantly increased with the OA and LA treatment. Furthermore, LA + OA enhanced cell proliferation in a dose-dependent manner (10 to 100 uM), whereas it lowered at 250 uM. In addition, a cell-cycle analysis showed that 100 uM of LA and OA markedly decreased the G0/G1 phase proportion (62.58% and 61.33%, respectively), compared to controls (68.02%), whereas the S-phase cells' proportion was increased. The ratio of G2/M phase cells was not significantly different among the groups. Moreover, analyses with AO/EtBr staining showed that no apoptosis occurred. Necrosis were determined by flow cytometry using Annexin V-FITC/PI staining which revealed no early apoptosis in the cells pretreated with LA or OA, but occurred in the LA + OA group. We also analyzed the mRNA expression of lipid metabolizing genes such as peroxisome proliferator receptor alfa (PPARalpha), peroxisome proliferator receptor gamma (PPARgamma), acyl-CoA oxidase (ACOX), lipoprotein lipase (LPL), carnitine palmitoyl transferase (CPT-1), and fatty-acid binding protein4 (FABP4), which were upregulated in LA or OA treated cells compared to the control group. In essence, LA and OA alone promote the cell proliferation without any apoptosis and necrosis, which might upregulate the lipid metabolism related gene expressions, and increase fatty-acid oxidation in the BSCs' lipid metabolism. PMID- 30460115 TI - Bromelain effectively suppresses Kras-mutant colorectal cancer by stimulating ferroptosis. AB - Here, we investigated the possible anti-cancer properties of bromelain in Kras mutant human colorectal carcinoma cell lines and a mouse model harboring a Kras mutation. Cell growth and proliferation were significantly reduced in the Kras mutant colorectal carcinoma cell lines following treatment with 50 MUg/mL bromelain as assessed by crystal violet staining and a proliferation assay. To identify the molecules responsible for this action, the expression levels of genes involved in signaling pathways and miRNAs were analyzed by real-time PCR. Among the genes tested, down-regulation of ACSL-4 and up-regulation of miRNAs targeting ASCL-4 were observed in Caco2 cells. Compared to the Kras wild-type colorectal carcinoma cell lines, Kras mutant colorectal carcinoma cell lines exhibited a remarkably up-regulated expression of ACSL-4, which is responsible for ferroptosis sensitivity. Moreover, the knockdown of ACSL-4 by a specific shRNA inhibited erastin-induced ferroptosis in Kras mutant DLD-1 cells as assessed by propidium iodide staining and lipid reactive oxygen species measurement. Our findings indicate that bromelain effectively exerts cytotoxic effects in Kras mutant colorectal cancer cells compared to in Kras wild-type colorectal cancer cells. Differential expression of ACSL-4 is responsible for the differential action of bromelain in regulating ferroptotic cell death. PMID- 30460116 TI - Multiple calmodulin genes of the Pacific abalone, Haliotis discus hannai (Mollusca: Vetigastropoda: Haliotidae). AB - In this study, we identified four canonical calmodulin genes in the Pacific abalone, Haliotis discus hannai. Their full-length cDNAs were variable in the 5' and 3' untranslated regions, but highly similar (91-97%) in the coding region. Each of the genes encoded 149 amino acids, with 93-97% similarity among themselves and 94-98% similarity with human CAM I. There were 54 substitutions distributed unevenly throughout the coding regions, found mostly in the third codon position. Gene structure analysis revealed that each of the calmodulin genes comprised five exons and four introns. The intron positions and phases were identical and there were no introns in the fourth exon. The corresponding introns differed in their sequences and sizes. Expression profiles of nine tissues from abalone revealed that the calmodulin genes were transcribed in common in gill and mantle tissue, but differentially in the other tissues. A phylogenetic analysis based on the amino acid sequences revealed that calmodulin C was the most common isoform in Gastropoda and calmodulin was the most diverged isoform. An in silico analysis of the calmodulin genes identified paralogous genes in other Haliotis species, indicating that gene duplication might have occurred in the last common ancestor of Haliotis. Abbreviations: ORF: open reading frame; RACE: random amplification of cDNA end; TSA: transcriptome shotgun assembly; UTR: untranslated region. PMID- 30460117 TI - Holmium:yttrium-aluminum-garnet laser induced lithotripsy: in-vitro investigations on fragmentation, dusting, propulsion and fluorescence. AB - The fragmentation efficiency on Bego artificial stones during lithotripsy and the propulsive effect (via video tracking) was investigated for a variety of laser settings. A variation of the laser settings (pulse energy, pulse duration, repetition rate) altered the total application time required for stone fragmentation, the stone break up time, and the propulsion. The obtained results can be used to develop lithotripsy devices providing an optimal combination of low stone propulsion and high fragmentation efficacy, which can then be evaluated in a clinical setting. Additionally, the fluorescence of human kidney stones was inspected endoscopically in vivo. Fluorescence light can be used to detect stone free areas or to clearly distinguish calculi from surrounding tissue or operation tools. PMID- 30460118 TI - Speckle noise reduction in optical coherence tomography images based on edge sensitive cGAN. AB - Speckle noise in optical coherence tomography (OCT) impairs both the visual quality and the performance of automatic analysis. Edge preservation is an important issue for speckle reduction. In this paper, we propose an end-to-end framework for simultaneous speckle reduction and contrast enhancement for retinal OCT images based on the conditional generative adversarial network (cGAN). The edge loss function is added to the final objective so that the model is sensitive to the edge-related details. We also propose a novel method for obtaining clean images for training from outputs of commercial OCT scanners. The results show that the overall denoising performance of the proposed method is better than other traditional methods and deep learning methods. The proposed model also has good generalization ability and is capable of despeckling different types of retinal OCT images. PMID- 30460119 TI - MEDnet, a neural network for automated detection of avascular area in OCT angiography. AB - Screening and assessing diabetic retinopathy (DR) are essential for reducing morbidity associated with diabetes. Macular ischemia is known to correlate with the severity of retinopathy. Recent studies have shown that optical coherence tomography angiography (OCTA), with intrinsic contrast from blood flow motion, is well suited for quantified analysis of the avascular area, which is potentially a useful biomarker in DR. In this study, we propose the first deep learning solution to segment the avascular area in OCTA of DR. The network design consists of a multi-scaled encoder-decoder neural network (MEDnet) to detect the non perfusion area in 6 * 6 mm2 and in ultra-wide field retinal angiograms. Avascular areas were effectively detected in DR subjects of various disease stages as well as in the foveal avascular zone of healthy subjects. PMID- 30460120 TI - Feasibility of co-registered ultrasound and acoustic-resolution photoacoustic imaging of human colorectal cancer. AB - Colorectal cancer is the second leading cause of cancer death in the United States. Significant limitations in screening and surveillance modalities continue to hamper early detection of primary cancers or recurrences after therapy. In this study, we describe a new registered ultrasound (US) and acoustic-resolution photoacoustic microscopy (AR-PAM) system and report its initial testing in ex vivo human colorectal tissue. A total of 8 colorectal specimens were imaged, which included 2 polyps, 4 malignant colon cancers, and 2 treated colorectal cancers. In each specimen, normal tissue was also imaged for internal control. Initial data have demonstrated the feasibility of identifying colorectal cancer imaging features and the invasion depth using co-registered US and an AR-PAM system. In normal tissue, we found that our system consistently demonstrates the multi-layer structure of normal colonic tissue while differentiating layers with elevated vascularity; these findings highly correlated with histologic findings of each specimen. For malignant colorectal samples, the tissue structure is highly disorganized as seen in US, and photoacoustic imaging revealed distorted vascular distribution inside the tumor. Notably, AR-PAM of tumor beds after complete tumor destruction by radiation and chemotherapy yielded a pattern identical to benign tissue. Quantitative analysis of photoacoustic spectral slope has demonstrated more high-frequency components in malignant tissue as compared to the normal colon tissue, which may be caused by significantly increased microvessel networks. In summary, we demonstrate the successful differentiation of benign and malignant colorectal tissue with our co-registered ultrasound and photoacoustic system. PMID- 30460121 TI - Algebraic determination of back-projection operators for optoacoustic tomography. AB - The simplicity and computational efficiency of back-projection formulae have made them a popular choice in optoacoustic tomography. Nonetheless, exact back projection formulae exist for only a small set of tomographic problems. This limitation is overcome by algebraic algorithms, but at the cost of higher numerical complexity. In this paper, we present a generic algebraic framework for calculating back-projection operators in optoacoustic tomography. We demonstrate our approach in a two-dimensional optoacoustic-tomography example and show that once the algebraic back-projection operator has been found, it achieves a comparable run time to that of the conventional back-projection algorithm, but with the superior image quality of algebraic methods. PMID- 30460122 TI - Biophysical investigation of living monocytes in flow by collaborative coherent imaging techniques. AB - We implemented a completely label-free biophysical (morphometric and optical) property characterization of living monocytes in flow, using measurements obtained from two coherent imaging techniques: a pure light scattering approach to obtain an optical signature (OS) of cells, and a digital holography (DH) approach to achieve optical cell reconstructions in flow. A precise 3D cell alignment platform, taking advantage of viscoelastic fluid properties and microfluidic channel geometry, was used to investigate the OS of cells to achieve their refractive index, ratio of the nucleus over cytoplasm, and overall cell dimension. Further quantitative phase-contrast reconstructions by DH were employed to calculate surface area, dry mass, and biovolume of monocytes by using the OS outcomes as input parameters. The results show significantly different biophysical cell properties, confirming the possibility to differentiate monocytes from other cell classes in flow, thus avoiding chemical cell staining or labeling, which are nowadays used. PMID- 30460123 TI - Perception enhancement using importance-driven hybrid rendering for augmented reality based endoscopic surgical navigation. AB - Misleading depth perception may greatly affect the correct identification of complex structures in image-guided surgery. In this study, we propose a novel importance-driven hybrid rendering method to enhance perception for navigated endoscopic surgery. First, the volume structures are enhanced using gradient based shading to reduce the color information in low-priority regions and improve the distinctions between complicated structures. Second, an importance sorting method based on the order-independent transparency rendering is introduced to intensify the perception of multiple surfaces. Third, volume data are adaptively truncated and emphasized with respect to the perspective orientation and the illustration of critical information for viewing range extension. Various experimental results prove that with the combination of volume and surface rendering, our method can effectively improve the depth distinction of multiple objects both in simulated and clinical scenes. Our importance-driven surface rendering method demonstrates improved average performance and statistical significance as rated by 15 participants (five clinicians and ten non-clinicians) on a five-point Likert scale. Further, the average frame rate of hybrid rendering with thin-layer sectioning reaches 42 fps. Given that the process of the hybrid rendering is fully automatic, it can be utilized in real-time surgical navigation to improve the rendering efficiency and information validity. PMID- 30460124 TI - Standard-unit measurement of cellular viability using dynamic light scattering optical coherence microscopy. AB - Dynamic light scattering optical coherence microscopy (DLS-OCM) integrates DLS, which measures diffusion or flow of particles by analyzing fluctuations in light scattered by the particles, and OCM, which achieves single-cell resolution by combining coherence and confocal gating, integratively enabling cellular resolution 3D mapping of the diffusion coefficient, and flow velocity. The diffusion coefficient mapping has a potential for the non-destructive measurement of cellular viability in the standard unit but has not been validated yet. Here, we present DLS-OCM imaging of intra-cellular motility (ICM) as a surrogate of cellular viability. For this purpose, we have simultaneously obtained and compared ICM-contrast DLS-OCM images and calcium fluorescence-contrast images of retinal ganglion cells, and then characterized the responses of the measured ICM to a change in cellular viability induced by environmental conditions such as temperature and pH. The diffusion-coefficient-represented ICM exhibits consistent changes with the manipulated cellular viability. PMID- 30460125 TI - Slide-free virtual histochemistry (Part I): development via nonlinear optics. AB - Histochemistry is a microscopy-based technology widely used to visualize the molecular distribution in biological tissue. Recent developments in label-free optical imaging has demonstrated the potential to replace the conventional histochemical labels/markers (fluorescent antibodies, organic dyes, nucleic acid probes, and other contrast agents) with diverse optical interactions to generate histochemical contrasts, allowing "virtual" histochemistry in three spatial dimensions without preparing a microscope slide (i.e. labor-intensive sample preparation). However, the histochemical information in a label-free optical image has often been rather limited due to the difficulty in simultaneously generating multiple histochemical contrasts with strict spatial co-registration. Here, in the first part (Part I) of this two-part series study, we develop a technique of slide-free virtual histochemistry based on label-free multimodal multiphoton microscopy, and simultaneously generate up to four histochemical contrasts from in vivo animal and ex vivo human tissue. To enable this functionality, we construct and demonstrate a robust fiber-based laser source for clinical translation and phenotype a wide variety of vital cells in unperturbed mammary tissue. PMID- 30460126 TI - Slide-free virtual histochemistry (Part II): detection of field cancerization. AB - Tumor-adjacent "normal" tissue constitutes a peri-tumoral field that affects early cancer detection, risk assessment, surgical decision, and postoperative surveillance. Modern genetic analysis has revealed valuable information from this field, but without the spatial resolution of optical microscopy to understand the vital microenvironments that surround individual cells. Rapidly advanced optical imaging techniques free of labor-intensive sample preparation, despite great promise to perform slide-free imaging of cell structure and shift the histology centered cancer diagnostic paradigm, have lacked compatible and complementary histochemical imaging of cell function or phenotype to interrogate the peri tumoral field. In the first part (Part I) of this two-part series study, we developed a technique of slide-free virtual histochemistry to phenotype various cells in in vivo animal and ex vivo human tissue. Here, in the second part (Part II) of this two-part series study, we employ this technique to examine various peri-tumoral fields and produce the volumetric histochemical evidence of field cancerization consistent with the structural changes at larger spatial scales. We also link the field cancerization with cancer dormancy in a significant portion of breast cancer patients. PMID- 30460127 TI - Rapid quantification of mitochondrial fractal dimension in individual cells. AB - An improved technique for fractal characterization called the modified blanket method is introduced that can quantify surrounding fractal structures on a pixel by pixel basis without artifacts associated with scale-dependent image features such as object size. The method interprets images as topographical maps, obtaining information regarding the local surface area as a function of image resolution. Local fractal dimension (FD) can be quantified from the power law exponent derived from the surface area and image resolution relationship. We apply this technique on simulated cell images of known FD and compared the obtained values to power spectral density (PSD) analysis. Our method is sensitive to a wider FD range (2.0-4.5), having a mean error of 1.4% compared to 6% for PSD analysis. This increased sensitivity and an ability to compute regional FD properties enabled the discrimination of the differences in radiation resistant cancer cell responses that could not be detected using PSD analysis. PMID- 30460128 TI - Phase-stability optimization of swept-source optical coherence tomography. AB - Phase-resolved imaging of swept-source optical coherence tomography (SS-OCT) is subject to phase measurement instabilities involved with the sweep variation of a frequency-swept source. In general, optically generated timing references are utilized to track the variations imposed on OCT signals. But they might not be accurately synchronized due to relative time delays. In this research, we investigated the impact of the signal delays on the timing instabilities and the consequent deviations of the measured phases. We considered two types of timing signals utilized in a popular digitizer operation mode: a sweep trigger from a fiber Bragg grating (FBG) that initiates a series of signal sampling actions clocked by an auxiliary Mach-Zehnder interferometer (MZI) signal. We found that significant instabilities were brought by the relative delays through incoherent timing corrections and timing collisions between the timing references. The best to-worst ratio of the measured phase errors was higher than 200 while only the signal delays varied. Noise-limited phase stability was achieved with a wide dynamic range of OCT signals above 50 dB in optimized delays. This demonstrated that delay optimization is very effective in phase stabilization of SS-OCT. PMID- 30460129 TI - Directional changes in information flow between human brain cortical regions after application of anodal transcranial direct current stimulation (tDCS) over Broca's area. AB - Little work has been done on the information flow in functional brain imaging and none so far in fNIRS. In this work, alterations in the directionality of net information flow induced by a short-duration, low-current (2 min 40 s; 0.5 mA) and a longer-duration, high-current (8 min; 1 mA) anodal tDCS applied over the Broca's area of the dominant language hemisphere were studied by fNIRS. The tDCS induced patterns of information flow, quantified by a novel directed phase transfer entropy (dPTE) analysis, were distinct for different hemodynamic frequency bands and were qualitatively similar between low and high-current tDCS. In the endothelial band (0.003-0.02 Hz), the stimulated Broca's area became the strongest hub of outgoing information flow, whereas in the neurogenic band (0.02 0.04 Hz) the contralateral homologous area became the strongest information outflow source. In the myogenic band (0.04-0.15 Hz), only global patterns were seen, independent of tDCS stimulation that were interpreted as Mayer waves. These findings showcase dPTE analysis in fNIRS as a novel, complementary tool for studying cortical activity reorganization after an intervention. PMID- 30460130 TI - Automatic classification of dual-modalilty, smartphone-based oral dysplasia and malignancy images using deep learning. AB - With the goal to screen high-risk populations for oral cancer in low- and middle income countries (LMICs), we have developed a low-cost, portable, easy to use smartphone-based intraoral dual-modality imaging platform. In this paper we present an image classification approach based on autofluorescence and white light images using deep learning methods. The information from the autofluorescence and white light image pair is extracted, calculated, and fused to feed the deep learning neural networks. We have investigated and compared the performance of different convolutional neural networks, transfer learning, and several regularization techniques for oral cancer classification. Our experimental results demonstrate the effectiveness of deep learning methods in classifying dual-modal images for oral cancer detection. PMID- 30460131 TI - Propagation-based phase-contrast tomography of a guinea pig inner ear with cochlear implant using a model-based iterative reconstruction algorithm. AB - Propagation-based phase-contrast computed tomography has become a valuable tool for visualization of three-dimensional biological samples, due to its high contrast between materials with similar attenuation properties. However, one of the most-widely used phase-retrieval algorithms imposes a homogeneity assumption onto the sample, which leads to artifacts for numerous applications where this assumption is violated. Prominent examples are biological samples with highly absorbing implants. Using synchrotron radiation, we demonstrate by the example of a guinea pig inner ear with a cochlear implant electrode, how a recently developed model-based iterative algorithm for propagation-based phase-contrast computed tomography yields distinct benefits for such a task. We find that the model-based approach improves the overall image quality, removes the detrimental influence of the implant and accurately visualizes the cochlea. PMID- 30460132 TI - Doppler OCT clutter rejection using variance minimization and offset extrapolation. AB - Doppler optical coherence tomography (OCT) is widely used for high-resolution mapping of flow velocities and is based on analysis of temporal changes in the phase of an OCT signal (i.e., how fast the OCT signal rotates in the complex plane). Determination of the rate of phase change or rotation speed critically depends on the center of rotation. Here, we demonstrate the bias in high-pass filtering, the current widely used method to determine the center of rotation, and propose two advanced methods for Doppler OCT clutter rejection. The bias in the high-pass filtering method becomes increasingly significant with lower velocities or larger signal noise. Two novel methods based on variance minimization and offset extrapolation can potentially reduce this bias and thereby improve the accuracy of Doppler OCT measurements of flow velocities, even for low-velocity and/or high-noise signals. The two novel methods and the current standard method (high-pass filtering) have been tested in combination with several currently used velocity measurement algorithms: Kasai, autocorrelation function fitting, and maximum likelihood estimation. The newly proposed methods are shown to improve the accuracy in both the center of rotation and resultant velocity by up to 60 percentage points and reduce the flow conservation error by 30% when applied to in vivo cerebral blood flow imaging of the rodent brain cortex. PMID- 30460134 TI - Convolutional neural networks for whole slide image superresolution. AB - We present a computational approach for improving the quality of the resolution of images acquired from commonly available low magnification commercial slide scanners. Images from such scanners can be acquired cheaply and are efficient in terms of storage and data transfer. However, they are generally of poorer quality than images from high-resolution scanners and microscopes and do not have the necessary resolution needed in diagnostic or clinical environments, and hence are not used in such settings. The driving question of this presented research is whether the resolution of these images could be enhanced such that it would serve the same diagnostic purpose as high-resolution images from expensive scanners or microscopes. This need is generally known as the image super-resolution (SR) problem in image processing, and it has been studied extensively. Even so, none of the existing methods directly work for the slide scanner images, due to the unique challenges posed by this modality. Here, we propose a convolutional neural network (CNN) based approach, which is specifically trained to take low resolution slide scanner images of cancer data and convert it into a high resolution image. We validate these resolution improvements with computational analysis to show the enhanced images offer the same quantitative results. In summary, our extensive experiments demonstrate that this method indeed produces images that are similar to images from high-resolution scanners, both in quality and quantitative measures. This approach opens up new application possibilities for using low-resolution scanners, not only in terms of cost but also in access and speed of scanning for both research and possible clinical use. PMID- 30460135 TI - Contactless monitoring of the blood-flow changes in upper limbs. AB - Vasomotor reactivity, which is important to estimate neurogenic regulation of blood vessels in patients with different pathologies, is still assessed by occlusion plethysmography using sensors contacting the limbs. Recently we proposed a contactless approach for measuring blood flow changes during venous occlusion using imaging photoplethysmography [Kamshilin et al., Sci. Rep.7, 4642017]. In this work, the response of the vascular system on the occlusion was studied simultaneously by contact air-plethysmography system and remote optical system under illumination by incoherent polarized green light. A high correlation (r > 0.93) between the waveforms measured by both system was observed. Moreover, we found that the response of the optical system on the venous occlusion is uniform at the whole area of the forearm. The new optical technique is more convenient for assessment of the blood flow dynamics because it can be used for measurements in any part of the body. Method of imaging photoplethysmography is very promising for use in equipment intended for evaluation of neurogenic mechanisms of regulation of vascular blood flow. PMID- 30460133 TI - Automated identification of cone photoreceptors in adaptive optics optical coherence tomography images using transfer learning. AB - Automated measurements of the human cone mosaic requires the identification of individual cone photoreceptors. The current gold standard, manual labeling, is a tedious process and can not be done in a clinically useful timeframe. As such, we present an automated algorithm for identifying cone photoreceptors in adaptive optics optical coherence tomography (AO-OCT) images. Our approach fine-tunes a pre-trained convolutional neural network originally trained on AO scanning laser ophthalmoscope (AO-SLO) images, to work on previously unseen data from a different imaging modality. On average, the automated method correctly identified 94% of manually labeled cones when compared to manual raters, from twenty different AO-OCT images acquired from five normal subjects. Voronoi analysis confirmed the general hexagonal-packing structure of the cone mosaic as well as the general cone density variability across portions of the retina. The consistency of our measurements demonstrates the high reliability and practical utility of having an automated solution to this problem. PMID- 30460136 TI - Characterization of human cutaneous tissue autofluorescence: implications in topical drug delivery studies with fluorescence microscopy. AB - In pharmacokinetic studies of topical drugs, fluorescence microscopy methods can enable the direct visualization and quantification of fluorescent drugs within the skin. One potential limitation of this approach, however, is the strong endogenous fluorescence of skin tissues that makes straightforward identification of specific drug molecules challenging. To study this effect and quantify endogenous skin fluorescence in the context of topical pharmacokinetics, an integrating sphere-based screening tool was designed to collect fluorescence yield data from human skin specimens. Such information could be utilized to select specific donors in the investigation of drug uptake and distribution. Results indicated human facial skin specimens from a group of more than 35 individuals exhibited an at least 6-fold difference in endogenous fluorescence. In visualizing drug distributions, the negative impact of autofluorescence could be exacerbated in cases where there are overlapping spatial distributions or spectral emission profiles between endogenous fluorophores and the exogenous fluorophore of interest. We demonstrated the feasibility of this approach in measuring the range of tissue endogenous fluorescence and selecting specimens for the study of drug pharmacokinetics with fluorescence microscopy. PMID- 30460137 TI - Multi-purpose SLM-light-sheet microscope. AB - By integrating a phase-only Spatial Light Modulator (SLM) into the illumination arm of a cylindrical-lens-based Selective Plane Illumination Microscope (SPIM), we have created a versatile system able to deliver high quality images by operating in a wide variety of different imaging modalities. When placed in a Fourier plane, the SLM permits modulation of the microscope's light-sheet to implement imaging techniques such as structured illumination, tiling, pivoting, autofocusing and pencil beam scanning. Previous publications on dedicated microscope setups have shown how these techniques can deliver improved image quality by rejecting out-of-focus light (structured illumination and pencil beam scanning), reducing shadowing (light-sheet pivoting), and obtaining a more uniform illumination by moving the highest-resolution region of the light-sheet across the imaging Field of View (tiling). Our SLM-SPIM configuration is easy to build and use, and has been designed to allow all of these techniques to be employed on an easily reconfigurable optical setup, compatible with the OpenSPIM design. It offers the possibility to choose between three different light-sheets, in thickness and height, which can be selected according to the characteristics of the sample and the imaging technique to be applied. We demonstrate the flexibility and performance of the system with results obtained by applying a variety of different imaging techniques on samples of fluorescent beads, zebrafish embryos, and optically cleared whole mouse brain samples. Thus our approach allows easy implementation of advanced imaging techniques while retaining the simplicity of a cylindrical-lens-based light-sheet microscope. PMID- 30460138 TI - Robust reconstruction of local optic axis orientation with fiber-based polarization-sensitive optical coherence tomography. AB - It is challenging to recover local optic axis orientation from samples probed with fiber-based polarization-sensitive optical coherence tomography (PS-OCT). In addition to the effect of preceding tissue layers, the transmission through fiber and system elements, and imperfect system alignment, need to be compensated. Here, we present a method to retrieve the required correction factors from measurements with depth-multiplexed PS-OCT, which accurately measures the full Jones matrix. The correction considers both retardation and diattenuation and is applied in the wavenumber domain, preserving the axial resolution of the system. The robustness of the method is validated by measuring a birefringence phantom with a misaligned system. Imaging ex-vivo lamb trachea and human bronchus demonstrates the utility of reconstructing the local optic axis orientation to assess smooth muscle, which is expected to be useful in the assessment of airway smooth muscle thickness in asthma, amongst other fiber-based applications. PMID- 30460139 TI - Motion-resolved quantitative phase imaging. AB - The temporal resolution of quantitative phase imaging with Differential Phase Contrast (DPC) is limited by the requirement for multiple illumination-encoded measurements. This inhibits imaging of fast-moving samples. We present a computational approach to model and correct for non-rigid sample motion during the DPC acquisition in order to improve temporal resolution to that of a single shot method and enable imaging of motion dynamics at the framerate of the sensor. Our method relies on the addition of a simultaneously-acquired color-multiplexed reference signal to enable non-rigid registration of measurements prior to phase retrieval. We show experimental results where we reduce motion blur from fast moving live biological samples. PMID- 30460140 TI - Gaussian numerical analysis and terahertz spectroscopic measurement of homocysteine. AB - Homocysteine is an amino acid related to metabolism in human vivo, which is closely related to cardiovascular disease, senile dementia, bone fracture, et al. Currently, the usual medical test methods for homocysteine include high performance liquid chromatography (HPLC), fluorescence polarization immunoassay (FPIA) and enzyme-linked immunosorbent assay (ELISA), which are time-consuming or expensive. In this paper, we first analyze the vibration and rotation of homocysteine molecules by using density functional theory, and then we ensure that the theoretical absorption peaks are located in the range of the terahertz spectrum. Then, based on the terahertz time-domain spectroscopy system, we measured the absorption spectrum of homocysteine under different concentrations. It is found that as the detection of the concentration, the terahertz results present higher accuracy than that of the laser Raman spectrum, which can be used as the reference for the evaluation of pathological stage. These results are of great significance for the exact and quick diagnosis of homocysteine-related diseases in clinical medicine. PMID- 30460141 TI - Versatile multi-detector scheme for adaptive optics scanning laser ophthalmoscopy. AB - Adaptive optics scanning laser ophthalmoscopy (AOSLO) is a powerful tool for imaging the retina at high spatial and temporal resolution. In this paper, we present a multi-detector scheme for AOSLO which has two main configurations: pixel reassignment and offset aperture imaging. In this detection scheme, the single element detector of the standard AOSLO is replaced by a fiber bundle which couples the detected light into multiple detectors. The pixel reassignment configuration enables high resolution imaging with an increased light collection. The increase in signal-to-noise ratio (SNR) from this configuration can improve the accuracy of motion registration techniques. The offset aperture imaging configuration enhances the detection of multiply scattered light, which improves the contrast of retinal vasculature and inner retinal layers similar to methods such as nonconfocal split-detector imaging and multi-offset aperture imaging. PMID- 30460142 TI - Mapping the phase and amplitude of ossicular chain motion using sound-synchronous optical coherence vibrography. AB - The sound-driven vibration of the tympanic membrane and ossicular chain of middle ear bones is fundamental to hearing. Here we show that optical coherence tomography in phase synchrony with a sound stimulus is well suited for volumetric, vibrational imaging of the ossicles and tympanic membrane. This imaging tool - OCT vibrography - provides intuitive motion pictures of the ossicular chain and how they vary with frequency. Using the chinchilla ear as a model, we investigated the vibrational snapshots and phase delays of the manubrium, incus, and stapes over 100 Hz to 15 kHz. The vibrography images reveal a previously undescribed mode of motion of the chinchilla ossicles at high frequencies. PMID- 30460143 TI - Low-cost compact multispectral spatial frequency domain imaging prototype for tissue characterization. AB - We present a low-cost, compact, and multispectral spatial frequency domain imaging prototype. Illumination components, including 9 LEDs (660 nm - 950 nm) placed on a custom-designed printed circuit board, linear and rotational motors, a printed sinusoidal pattern, and collimation and projection optics as well as the detection components are incorporated in a compact custom-designed 3D-printed probe. Reconstruction of absorption and reduced scattering coefficients is evaluated via imaging tissue mimicking phantoms and potentials of the probe for biological tissue imaging are evaluated via imaging human ovarian tissue ex vivo. PMID- 30460144 TI - Super-resolution microscopy for biological specimens: lensless phase retrieval in noisy conditions. AB - The paper is devoted to a computational super-resolution microscopy. A complex valued wavefront of a transparent biological cellular specimen is restored from multiple intensity diffraction patterns registered with noise. For this problem, the recently developed lensless super-resolution phase retrieval algorithm [Optica, 4(7), 786 (2017)] is modified and tuned. This algorithm is based on a random phase coding of the wavefront and on a sparse complex-domain approximation of the specimen. It is demonstrated in experiments, that the reliable phase and amplitude imaging of the specimen is achieved for the low signal-to-noise ratio provided a low dynamic range of observations. The filterings in the observation domain and specimen variables are specific features of the applied algorithm. If these filterings are omitted the algorithm becomes a super-resolution version of the standard iterative phase retrieval algorithms. In comparison with this simplified algorithm with no filterings, our algorithm shows a valuable improvement in imaging with much smaller number of observations and shorter exposure time. In this way, presented algorithm demonstrates ability to work in a low radiation photon-limited mode. PMID- 30460145 TI - Instrumental, optical and geometrical parameters affecting time-gated diffuse optical measurements: a systematic study. AB - In time-domain diffuse optics the sensitivity to localized absorption changes buried inside a diffusive medium depends strongly on the interplay between instrumental, optical and geometrical parameters, which can hinder the theoretical advantages of novel measurement strategies like the short source detector distance approach. Here, we present a study based on experimental measurements and simulations to comprehensively evaluate the effect of all different parameters. Results are evaluated exploiting standardized figures of merit, like contrast and contrast-to-noise ratio, to quantify the system sensitivity to deep localized absorption perturbations. Key findings show that the most critical hardware parameter is the memory effect which ultimately limits the dynamic range. Further, a choice of the source-detector distance around 10 mm seems to be a good compromise to compensate non-idealities in practical systems still preserving the advantages of short distances. This work provides both indications for users about the best measurement conditions and strategies, and for technology developers to identify the most crucial hardware features in view of next generation diffuse optics systems. PMID- 30460146 TI - Light propagation and capture in cone photoreceptors. AB - The light capturing properties of cone photoreceptors create the elementary signals that form the basis of vision. Variation in the amplitude of individual cone signals has been found physiologically as part of normal retinal circuit processing. Less well characterized is how cone signals may vary due to purely optical properties. We present a model of light propagation in cones using a finite difference beam propagation method to simulate how light from a small stimulus travels through a cone plus its immediate neighbors. The model calculates the amount of light absorbed in the cone outer segments, from which an estimate of the photoresponse can be made. We apply the method to adaptive optics microstimulation to find the optimum optical conditions that will confine the most light into a single cone in the human retina. We found that light capture is especially sensitive to beam size at the pupil and to the cone diameter itself, with the two factors having a complex relationship leading to sizable variation in light capture. Model predictions were validated with two types of psychophysical data. The model can be employed with arbitrary stimuli and photoreceptor parameters, making it a useful tool for studying photoreceptor function in normal or diseased conditions. PMID- 30460147 TI - Additive noise models for photoacoustic spatial coherence theory. AB - Directly displaying the spatial coherence of photoacoustic signals (i.e., coherence-based photoacoustic imaging) remarkably improves image contrast, signal to-noise ratio (SNR), contrast-to-noise ratio (CNR), and imaging depth when compared to conventional amplitude-based reconstruction techniques (e.g., backprojection, delay-and-sum beamforming, and Fourier-based reconstruction). We recently developed photoacoustic-specific theory to describe the spatial coherence process as a function of the element spacing on a receive acoustic aperture to enable photoacoustic image optimization without requiring experiments. However, this theory lacked noise models, which contributed to significant departures in coherence measurements when compared to experimental data, particularly at higher values of element separation. In this paper, we develop and implement two models based on experimental observations of noise in photoacoustic spatial coherence measurements to improve our existing spatial coherence theory. These models were derived to describe the effects of incident fluence variations, low-energy light sources (e.g., pulsed laser diodes and light emitting diodes), averaging multiple signals from low-energy light sources, and imaging with light sources that are > 5mm from photoacoustic targets. Results qualitatively match experimental coherence functions and provide similar contrast, SNR, and CNR to experimental SLSC images. In particular, the added noise affects image quality metrics by introducing large variations in target contrast and significantly reducing target CNR and SNR when compared to minimal noise cases. These results provide insight into additional requirements for optimization of coherence-based photoacoustic image quality. PMID- 30460148 TI - Automated instrument designed to determine visual photosensitivity thresholds. AB - The Ocular Photosensitivity Analyzer (OPA), a new automated instrument to quantify the visual photosensitivity thresholds (VPT) in healthy and light sensitive subjects, is described. The OPA generates light stimuli of varying intensities utilizing unequal ascending and descending steps to yield the VPT. The performance of the OPA was evaluated in healthy subjects, as well as light sensitive subjects with achromatopsia or traumatic brain injury (TBI). VPT in healthy, achromatopsia, and TBI subjects were 3.2 +/- 0.6 log lux, 0.5 +/- 0.5 log lux, and 0.4 +/- 0.6 log lux, respectively. Light sensitive subjects manifested significantly lower VPT compared to healthy subjects. Longitudinal analysis revealed that the OPA reliably measured VPT in healthy subjects. PMID- 30460149 TI - Non-contact dynamic diffuse optical tomography imaging system for evaluating lower extremity vasculature. AB - A novel multi-view non-contact dynamic diffuse optical tomographic imaging system for the clinical evaluation of vasculature in the lower extremities is presented. The system design and implementation are described in detail, including methods for simultaneously obtaining and reconstructing diffusely reflected and transmitted light using a system of mirrors and a single CCD camera. The system and its performance using numeric simulations and optical phantoms. Measurements of a healthy foot in vivo demonstrates the potential of the system in assessing perfusion within the foot. PMID- 30460150 TI - Data compression and improved registration for laser speckle contrast imaging of rodent brains. AB - Single-frame blood flow maps from laser speckle contrast imaging (LSCI) contain high spatiotemporal variation that obscures high spatial-frequency vascular features, making precise image registration for signal amplification challenging. In this work, novel bivariate standardized moment filters (BSMFs) were used to provide stable measures of vessel edge location, permitting more robust LSCI registration. Relatedly, BSMFs enabled the stable reconstruction of vessel edges from sparsely distributed blood flow map outliers, which were found to retain most of the temporal dynamics. Consequently, data discarding and BSMF-based reconstruction enable efficient real-time quantitative LSCI data compression. Smaller LSCI-kernels produced log-normal blood flow distributions, enhancing sparse-to-dense inference. PMID- 30460151 TI - Robot-assisted laser tissue soldering system. AB - Fast and reliable incision closure is critical in any surgical intervention. Common solutions are sutures and clips or adhesives, but they all present difficulties. These difficulties are especially pronounced in classical and robot assisted minimally-invasive interventions. Laser soldering methods present a promising alternative, but their reproducibility is limited. We present a system that combines a previously reported laser soldering system with a robotic system, and demonstrate its feasibility on the incision-closure of ex-vivo mice skins. In this demonstration, we measured tearing forces of ~2.5N, 73% of the tearing force of a mouse skin without an incision. This robot-assisted laser soldering technique has the potential to make laser tissue soldering more reproducible and revolutionize surgical tissue bonding. PMID- 30460152 TI - High-energy, nanosecond pulsed Cr:CdSe laser with a 2.25-3.08 MUm tuning range for laser biomaterial processing. AB - We have developed a mid-infrared (mid-IR) tunable Cr:CdSe laser with nanosecond pulse operation. A broad tuning range from 2.25 to 3.08 um and an output energy exceeding 4 mJ at 2.64 MUm were demonstrated. The maximum energy conversion for absorbed energy reached 35% when the pump fluence was 2.1 J/cm2. We showed that Cr:CdSe is an attractive laser material for obtaining high-energy pulses in the mid-IR region and that the Cr:CdSe laser has high potential for laser biomaterial processing. PMID- 30460153 TI - Scattering reduction by structured light illumination in line-scanning temporal focusing microscopy. AB - Line-scanning temporal focusing microscopy (LineTFM) is capable of imaging biological samples more than 10 times faster than two-photon laser point-scanning microscopy (TPLSM), while achieving nearly the same lateral and axial spatial resolution. However, the image contrast taken by LineTFM is lower than that by TPLSM because LineTFM is severely influenced by biological tissue scattering. To reject the scattered photons, we implemented LineTFM using both structured illumination and uniform illumination combined with the HiLo post-processing algorithm, called HiLL microscopy (HiLo-Line-scanning temporal focusing microscopy). HiLL microscopy significantly reduces tissue scattering and improves image contrast. We demonstrate HiLL microscopy with in vivo brain imaging. This approach could potentially find applications in monitoring fast dynamic events and in mapping high resolution structures over a large volume. PMID- 30460155 TI - Depth-multiplexed optical coherence tomography dual-beam manually-actuated distortion-corrected imaging (DMDI) with a micromotor catheter. AB - We present a new micromotor catheter implementation of dual-beam manually actuated distortion-corrected imaging (DMDI). The new catheter called a depth multiplexed dual-beam micromotor catheter, or mDBMC, maintains the primary advantage of unlimited field-of-view distortion-corrected imaging along the catheter axis. The mDBMC uses a polarization beam splitter and cube mirror to create two beams that scan circularly with approximately constant separation at the catheter surface. This arrangement also multiplexes both imaging channels into a single optical coherence tomography channel by offsetting them in depth, requiring half the data bandwidth compared to previous DMDI demonstrations that used two parallel image acquisition systems. Furthermore, the relatively simple scanning pattern of the two beams enables a straightforward automated distortion correction algorithm. We demonstrate the imaging capabilities of this catheter with a printed paper phantom and in a section of dragon fruit. PMID- 30460154 TI - Noninvasive label-free detection of circulating white and red blood clots in deep vessels with a focused photoacoustic probe. AB - Blood clotting is a serious clinical complication of many medical procedures and disorders including surgery, catheterization, transplantation, extracorporeal circuits, infections, and cancer. This complication leads to high patient morbidity and mortality due to clot-induced pulmonary embolism, stroke, and in some cases heart attack. Despite the clear medical significance, little progress has been made in developing the methods for detection of circulating blood clots (CBCs), also called emboli. We recently demonstrated the application of in vivo photoacoustic (PA) flow cytometry (PAFC) with unfocused ultrasound transducers for detection of CBCs in small vessels in a mouse model. In the current study, we extend applicability of PAFC for detection of CBCs in relatively large (1.5-2 mm) and deep (up to 5-6 mm) blood vessels in rat and rabbit models using a high pulse rate 1064 nm laser and focused ultrasound transducer with a central hole for an optic fiber. Employing phantoms and chemical activation of clotting, we demonstrated PA identification of white, red, and mixed CBCs producing negative, positive, and mixed PA contrast in blood background, respectively. We confirmed that PAFC can detect both red and white CBCs induced by microsurgical procedures, such as a needle or catheter insertion, as well as stroke modeled by injection of artificial clots. Our results show great potential for a PAFC diagnostic platform with a wearable PA fiber probe for diagnosis of thrombosis and embolism in vivo that is impossible with existing techniques. PMID- 30460156 TI - Polarimetric measurement utility for pre-cancer detection from uterine cervix specimens. AB - Prior work demonstrated significant contrast in visible wavelength Mueller matrix images for healthy and pre-cancerous regions of excised cervical tissue. This work demonstrates post-processing compressions of the full Mueller matrix that preserve detection performance. The purpose of this post-processing is to understand polarimetric measurement utility for computing mathematical observers and designing future imaging protocols. The detection performance of the full Mueller matrix, and both linear and non-linear parameters of the Mueller matrix will be compared. The area under the receiver operating characteristic (ROC) curve, otherwise known as the AUC, is the gold standard metric to quantify detection performance in medical applications. An AUC = 1 is perfect detection and AUC = 0.5 is the performance of guessing. Either the scalar retardance or the 3 smallest eigenvalues of the coherency matrix yield an average AUC of 0.94 or 0.93, respectively. When these four non-linear parameters are used simultaneously the average AUC is 0.95. The J-optimal Channelized Quadratic Observer (J-CQO) method for optimizing polarimetric measurements demonstrates equivalent AUC values for the full Muller matrix and 6 J-CQO optimized measurements. The advantage of this optimization is that only 6 measurements, instead of 16 for the full Mueller matrix, are required to achieve this AUC. PMID- 30460157 TI - Anti-cancer effect of bee venom on human MDA-MB-231 breast cancer cells using Raman spectroscopy. AB - We demonstrated the apoptotic effect of bee venom (BV) on human MDA-MB-231 breast cancer cells using Raman spectroscopy and principal component analysis (PCA). Biochemical changes in cancer cells were monitored following BV treatment; the results for different concentrations and treatment durations differed markedly. Significantly decreased Raman vibrations for DNA and proteins were observed for cells treated with 3.0 ug/mL BV for 48 h compared with those of control cells. These results suggest denaturation and degradation of proteins and DNA fragmentation (all cell death-related processes). The Raman spectroscopy results agreed with those of atomic force microscopy and conventional biological tests such as viability, TUNEL, and western blot assays. Therefore, Raman spectroscopy, with PCA, provides a noninvasive, label-free tool for assessment of cellular changes on the anti-cancer effect of BV. PMID- 30460158 TI - Small separation diffuse correlation spectroscopy for measurement of cerebral blood flow in rodents. AB - Diffuse correlation spectroscopy (DCS) has shown promise as a means to non invasively measure cerebral blood flow in small animal models. Here, we characterize the validity of DCS at small source-detector reflectance separations needed for small animal measurements. Through Monte Carlo simulations and liquid phantom experiments, we show that DCS error increases as separation decreases, although error remains below 12% for separations > 0.2 cm. In mice, DCS measures of cerebral blood flow have excellent intra-user repeatability and strongly correlate with MRI measures of blood flow (R = 0.74, p<0.01). These results are generalizable to other DCS applications wherein short-separation reflectance geometries are desired. PMID- 30460159 TI - Nano-plasmonics and electronics co-integration in CMOS enabling a pill-sized multiplexed fluorescence microarray system. AB - The ultra-miniaturization of massively multiplexed fluorescence-based bio molecular sensing systems for proteins and nucleic acids into a chip-scale form, small enough to fit inside a pill (~ 0.1cm3), can revolutionize sensing modalities in-vitro and in-vivo. Prior miniaturization techniques have been limited to focusing on traditional optical components (multiple filter sets, lenses, photo-detectors, etc.) arranged in new packaging systems. Here, we report a method that eliminates all external optics and miniaturizes an entire multiplexed fluorescence system into a 2 * 1 mm2 chip through co-integration for the first time of massively scalable nano-plasmonic multi-functional optical elements and electronic processing circuitry realized in an industry standard complementary-metal-oxide semiconductor (CMOS) foundry process with absolutely 'no change' in fabrication or processing. The implemented nano-waveguide based filters operating in the visible and near-IR realized with the embedded sub wavelength multi-layer copper-based electronic interconnects inside the chip show for the first time a sub-wavelength surface plasmon polariton mode inside CMOS. This is the principle behind the angle-insensitive nature of the filtering that operates in the presence of uncollimated and scattering environments, enabling the first optics-free 96-sensor CMOS fluorescence sensing system. The chip demonstrates the surface sensitivity of zeptomoles of quantum dot-based labels, and volume sensitivities of ~ 100 fM for nucleic acids and ~ 5 pM for proteins that are comparable to, if not better, than commercial fluorescence readers. The ability to integrate multi-functional nano-optical structures in a commercial CMOS process, along with all the complex electronics, can have a transformative impact and enable a new class of miniaturized and scalable chip-sized optical sensors. PMID- 30460160 TI - Automatic segmentation of OCT retinal boundaries using recurrent neural networks and graph search. AB - The manual segmentation of individual retinal layers within optical coherence tomography (OCT) images is a time-consuming task and is prone to errors. The investigation into automatic segmentation methods that are both efficient and accurate has seen a variety of methods proposed. In particular, recent machine learning approaches have focused on the use of convolutional neural networks (CNNs). Traditionally applied to sequential data, recurrent neural networks (RNNs) have recently demonstrated success in the area of image analysis, primarily due to their usefulness to extract temporal features from sequences of images or volumetric data. However, their potential use in OCT retinal layer segmentation has not previously been reported, and their direct application for extracting spatial features from individual 2D images has been limited. This paper proposes the use of a recurrent neural network trained as a patch-based image classifier (retinal boundary classifier) with a graph search (RNN-GS) to segment seven retinal layer boundaries in OCT images from healthy children and three retinal layer boundaries in OCT images from patients with age-related macular degeneration (AMD). The optimal architecture configuration to maximize classification performance is explored. The results demonstrate that a RNN is a viable alternative to a CNN for image classification tasks in the case where the images exhibit a clear sequential structure. Compared to a CNN, the RNN showed a slightly superior average generalization classification accuracy. Secondly, in terms of segmentation, the RNN-GS performed competitively against a previously proposed CNN based method (CNN-GS) with respect to both accuracy and consistency. These findings apply to both normal and AMD data. Overall, the RNN-GS method yielded superior mean absolute errors in terms of the boundary position with an average error of 0.53 pixels (normal) and 1.17 pixels (AMD). The methodology and results described in this paper may assist the future investigation of techniques within the area of OCT retinal segmentation and highlight the potential of RNN methods for OCT image analysis. PMID- 30460161 TI - Hyperspectral index-based metric for burn depth assessment. AB - Burn depth objective classification is of paramount importance for decision making and treatment. Despite the wide variety of burn depth assessment methods tested so far, none of them have gained wide clinical application. Here, we introduce a new approach for burn depth assessment based on hyperspectral imaging combined with a spectral index-based technique that exploits specific spectral bands to map skin areas with different burn degrees. The spectral index amplifies the contrast between normal skin and areas with different degrees of burn, taking advantage of the differences in spectral amplitudes that occur as a result of the morphological and physiological changes occurring in burned skin. We demonstrate that by using the new measurable spectral index, it is possible to generate accurate burn classification maps showing spatial distribution of burn types in the affected body areas, facilitating the decision-making process and prognosis evaluation. The results highlight the potential of the new hyperspectral metric in the field of burn depth classification and its applicability in hospital settings seems promising. PMID- 30460163 TI - Fast-scanning photoacoustic microscopy with a side-looking fiber optic ultrasound sensor. AB - Optical-resolution photoacoustic microscopy (OR-PAM) images biological tissue with sub-cellular resolution and optical absorption contrast. OR-PAM is limited by the tradeoff among imaging speed, field of view, and sensitivity. In this work, we present an OR-PAM technique based on an unfocused side-looking fiber optic ultrasound (FOUS) sensor, which achieves high imaging speed, large field of view, and good sensitivity for in vivo imaging. The FOUS sensor is developed based on a dual-polarized fiber laser and read out with real-time frequency demodulation. Via minimizing the readout noise, the sensor offers a noise equivalent pressure of 43.6 Pa, enabling high detection sensitivity over a large field of view. High imaging speed is achieved via scanning the laser beam with a 2D galvo mirror in the ultrasound detection area. Microvascular imaging with a frame rate of 2 Hz over a 2 * 2 mm2 area has been demonstrated in the mouse ear. The new OR-PAM technique may be used in the visualization of biological and physiologic dynamics. PMID- 30460162 TI - Stable tissue-simulating phantoms with various water and lipid contents for diffuse optical spectroscopy. AB - We introduced a method for producing solid phantoms with various water-to-lipid ratios that can simulate the absorption, and to some extent the scattering characteristics of human breast tissue. We also achieved phantom stability for a minimum of one month by solidifying the emulsion phantoms. The characteristics of the phantoms were evaluated using the six-wavelength time-domain diffuse optical spectroscopy (TD-DOS) system we developed to measure water and lipid contents and hemoglobin concentration. The TD-DOS measurements were validated with a magnetic resonance imaging system. PMID- 30460164 TI - Morphological changes in the ovarian carcinoma cells of Wistar rats induced by chemotherapy with cisplatin and dioxadet. AB - The development of new express methods for the analysis of the efficacy of anti cancer therapy on the cellular level is highly desirable for the analysis of chemotherapeutic agent performance. In this paper we suggest the use of parameters of cell morphology determined by holographic microscopy and tomography for the effective label free quantitative analysis of cell viability under antitumor chemotherapy and thus of cytostatic agent efficacy. As shown, measured phase shifts and cell morphology change dramatically as a result of chemotherapy and depend strongly on the cell type and agent applied. Experimentally, a comparative analysis of the antitumor efficacy of the two cytostatics, cisplatin and dioxadet, that are commonly used for chemotherapy of disseminated ovarian carcinoma has been performed. The experiments were carried out on the Wistar rat model. An essential difference in the morphology of cells, both normal (erythrocytes) and cancerous, present in ascitic fluid taken from the non-treated group of rats and the groups treated with either dioxadet or cisplatin, has been observed. The results obtained can be interpreted as an indication of the antitumor performance of both cytostatics at the cellular level and as a demonstration of the higher efficacy of therapy with dioxadet as compared to that with cisplatin. Differences in cell morphology are suggested to be applied as quantitative markers of cell viability and cytostatic agent efficacy. The conclusions made are supported by a comparison with the results of recent experiments based on survival rates of laboratory animals treated with these agents.. PMID- 30460165 TI - Multispectral total-variation reconstruction applied to lens-free microscopy. AB - Lens-free microscopy multispectral acquisitions are processed with an inverse problem approach: a multispectral total variation criterion is defined and minimized with the conjugate gradients method. Reconstruction results show that the method is efficient to recover the phase image of densely packed cells. PMID- 30460166 TI - Importance evaluation of spectral lines in Laser-induced breakdown spectroscopy for classification of pathogenic bacteria. AB - The correct classification of pathogenic bacteria is significant for clinical diagnosis and treatment. Compared with the use of whole spectral data, using feature lines as the inputs of the classification model can improve the correct classification rate (CCR) and reduce the analyzing time. In order to select feature lines, we need to investigate the contribution to the CCR of each spectral line. In this paper, two algorithms, important weights based on principal component analysis (IW-PCA) and random forests (RF), were proposed to evaluate the importance of spectra lines. The laser-induced plasma spectra (LIBS) of six common clinical pathogenic bacteria species were measured and a support vector machine (SVM) classifier was used to classify the LIBS of bacteria species. In the proposed IW-PCA algorithm, the product of the loading of each line and the variance of the corresponding principal component were calculated. The maximum product of each line calculated from the first three PCs was used to represent the line's importance weight. In the RF algorithm, the Gini index reduction value of each line was considered as the line's importance weight. The experimental results demonstrated that the lines with high importance were more suitable for classification and can be chosen as feature lines. The optimal number of feature lines used in the SVM classifier can be determined by comparing the CCRs with a different number of feature lines. Importance weights evaluated by RF are more suitable for extracting feature lines using LIBS combined with an SVM classification mechanism than those evaluated by IW-PCA. Furthermore, the two methods mutually verified the importance of selected lines and the lines evaluated important by both IW-PCA and RF contributed more to the CCR. PMID- 30460168 TI - A Brief Synopsis on the Genetics of Alzheimer's Disease. PMID- 30460167 TI - Rodent retinal circulation organization and oxygen metabolism revealed by visible light optical coherence tomography. AB - Visible light optical coherence tomography (vis-OCT) is an emerging label-free and high-resolution 3-dimensional imaging technique that can provide retinal oximetry, angiography, and flowmetry in one modality. In this paper, we studied the organization of the arterial and venous retinal circulation in rats using vis OCT. Arterioles were found predominantly in the superficial vascular plexus whereas veins tended to drain capillaries from the deep capillary plexus. After that, we determined the oxygen metabolic rate supported by retinal microcirculation by combining retinal vessel oxygen saturation and blood flow measurements. The ability to visualize and monitor retinal circulation organization and oxygen metabolism by vis-OCT may provide new opportunities for understanding the pathology of ocular diseases. PMID- 30460169 TI - NH3?H2O: The Simplest Nitrogen-Containing Ligand for Selective Aerobic Alcohol Oxidation to Aldehydes or Nitriles in Neat Water. AB - Aqueous ammonia (NH3?H2O) has been shown to serve as the simplest nitrogen containing ligand to effectively promote copper-catalyzed selective alcohol oxidation under air in water. A series of alcohols with varying electronic and steric properties were selectively oxidized to aldehydes with up to 95 % yield. Notably, by increasing the amount of aqueous ammonia in neat water, the exclusive formation of aryl nitriles was also accomplished with good-to-excellent yields. Additionally, the catalytic system exhibits a high level of functional group tolerance with -OH, -NO2, esters, and heteroaryl groups all being amenable to the reaction conditions. This one-pot and green oxidation protocol provides an important synthetic route for the selective preparation of either aldehydes or nitriles from commercially available alcohols. PMID- 30460170 TI - Efficient Synthesis of the N-(buta-2,3-dienyl)carboxamide of Isopimaric Acid and the Potential of This Compound towards Heterocyclic Derivatives of Diterpenoids. AB - The N-(2,3-butadienyl)carboxamide of isopimaric acid, that is, compound 3, was prepared through a two-step synthetic procedure starting from the natural diterpene isopimaric acid. The Pd-catalyzed cross-coupling and subsequent cyclization of terpenoid allene 3 with several aryl iodides and aryl bromides gave access to optically active diterpenoid-oxazoline derivatives in good to excellent yields. The functional group tolerance in the aryl iodides was demonstrated by several examples, including substrates with additional N-tert butoxycarbonyl-protected amino, hydroxy, and carboxy substituents in the ortho position. The cross-coupling-cyclization reaction of those compounds with allene 3 proceeded selectively with the formation of cyclization products on the substituent in the aromatic ring. This transformation opens a potential route to the synthesis of hybrid compounds containing a tricyclic diterpenoid and several heterocycles. PMID- 30460171 TI - Structural Determination of Antioxidant and Anticancer Flavonoid Rutin in Solution through DFT Calculations of 1H NMR Chemical Shifts. AB - As the knowledge of the predominant molecular structure of antioxidant and anticancer flavonoid rutin in solution is very important for understanding the mechanism of action, a quantum chemical investigation of plausible rutin structures including solvent effects is of relevance. In this work, DFT calculations were performed to find possible minimum energy structures for the rutin molecule. 1H NMR chemical shift DFT calculations were carried out in DMSO solution using the polarizable continuum model (PCM) to simulate the solvent effect. Analysis of the experimental and theoretical 1H NMR chemical shift profiles offers a powerful fingerprint criterion to determine the predominant molecular structure in solution. Therefore, our aim is to find the best match between experimental (in DMSO-d) and theoretical (PCM-DMSO) 1H NMR spectrum profiles. Among 34 optimized structures located on the potential energy surface, we found that structure 32, with a B-ring deviated 30 degrees from a planar configuration (geometry usually assumed for polyphenols), showed an almost perfect agreement with experimental the 1H NMR pattern when compared to the corresponding fully optimized planar geometry. This structure is also predicted as the global minimum based on room-temperature Gibbs free energy calculations in solution and, therefore, should be experimentally observed. This is new and valuable structural information regarding structure-activity relationship studies, and such information is hard to obtain by experimentalists without the aid of the X-ray diffraction technique. PMID- 30460173 TI - Influenza and respiratory syncytial virus screening for the detection of asymptomatically infected patients in hematology and oncology. AB - Introduction: Respiratory syncytial virus (RSV) and influenza virus infections are a significant healthcare risk for immunocompromised patients. In addition to community onset, nosocomial acquisition and transmission may also occur. Detection of asymptomatic shedders (e.g., patients in the incubation period or immunosuppressed long term shedders) facilitates control of nosocomial transmission. Methods: To strengthen the existing infection control concept, a PCR-based screening for RSV and influenza virus was implemented for all patients lacking respiratory symptoms (asymptomatic patients) who were hospitalized on an adult and a pediatric hemato-oncological ward. Laboratory results of this screening were analyzed retrospectively. Results: 665 respiratory specimens were obtained for screening from 251 patients (26% were 18 years and younger) from December 2016 to April 2017. In 23 patients without respiratory symptoms, either influenza virus or RSV infection was found, resulting in a detection rate of about 9%. In 6 patients, the infection was presumably detected during the incubation period, because an increase of viral load was observed in subsequent specimens. Positive screening results facilitated timely implementation of adequate infection control precautions. Nosocomial clusters of RSV or influenza were not detected during the screening period on the two wards. Conclusion: The seasonal screening program expanded our existing infection control concept in terms of patients lacking respiratory symptoms who shed influenza virus or RSV. It enabled us to identify 23 RSV or influenza infections in patients lacking respiratory symptoms in a 4-month period and thus to rapidly take isolation precautions. PMID- 30460174 TI - A day in the life. PMID- 30460172 TI - Buruli Ulcer: a Review of the Current Knowledge. AB - Purpose of the Review: Buruli ulcer (BU) is a necrotizing and disabling cutaneous disease caused by Mycobacterium ulcerans, one of the skin-related neglected tropical diseases (skin NTDs). This article aims to review the current knowledge of this disease and challenges ahead. Recent Findings: Around 60,000 cases of BU have been reported from over 33 countries between 2002 and 2017. Encouraging findings for development of point-of-care tests for BU are being made, and its treatment is currently in the transition period from rifampicin plus streptomycin (injection) to all-oral regimen. A major recent advance in our understanding of its pathogenesis has been agreement on the mechanism of action of the major virulence toxin mycolactone in host cells, targeting the Sec61 translocon during a major step in protein biogenesis. Summary: BU is distributed mainly in West Africa, but cases are also found in other parts of the world. We may be underestimating its true disease burden, due to the limited awareness of this disease. More awareness and more understanding of BU will surely contribute in enhancing our fight against this skin NTD. PMID- 30460175 TI - An overarching approach for acute care delivery: extension of the acute care model to the entire inpatient admission. AB - The acute care model has been proposed as a framework for quality improvement in emergency care to improve care delivery and patient flow. There is currently an absence of an overarching model inclusive of other relevant care settings, such as the inpatient ward or the intensive care unit (ICU), involved in the care of an acute illness episode. This gap limits our ability to optimize patient outcomes, improve flow, and reduce waste through all stages of acute illness. We propose that a unified approach to improve quality of care for acute illness may be achieved by extending the acute care model to the inpatient care setting. PMID- 30460176 TI - Continuum of care in pediatric sepsis: a prototypical acute care delivery model. AB - Sepsis is a burdensome public health problem and a leading cause of infant and child morbidity and mortality across the world. Few proven therapies exist to treat septic shock and the mainstay of management remains judicious fluid resuscitation and timely antibiotics. In its most recent iteration, the American College of Critical Care Medicine (ACCM) guidelines on hemodynamic support in pediatric septic shock recommends an institutional approach to the management of septic shock rather than one aimed at the individual practitioner. The acute care delivery model has been proposed as a way to guide quality improvement in emergency care and to improve care delivery. In this review, we summarize current recommendations in the management of pediatric patients with septic shock, and highlight opportunities to provide seamless care by application of the acute care model. PMID- 30460177 TI - Disease prevention & health promotion: what's critical care got to do with it? AB - Health systems are increasingly investing in efforts to prevent disease and promote health for populations. By and large, these prevention-related interventions have not been inclusive of critical care and the intensive care unit (ICU). However, we suggest that there is value-to patients, families, health systems, and society at large-in extending this continuum into the ICU setting and including the ICU in disease prevention and health promotion efforts. Including the ICU in this continuum allows the critical care perspective to inform (I) advocacy for prevention; (II) efforts to improve disparities in health and health care; (III) mitigation of the negative effects of critical illness and injury as well as ICU exposure; and (IV) promotion of health and well-being in the community. As disease prevention and health promotion rise as priorities within health systems, critical care can and should join, even help lead, the effort. PMID- 30460178 TI - Making care better in the pediatric intensive care unit. AB - The relatively young field of pediatric critical care has seen a shift from an approach with little consideration for the complications and adverse effects resulting from the procedures and medications to a more cautious approach with careful concern for the associated risks. Many senior pediatric intensivists recall a time when nearly every patient had a central venous line and arterial line; and hospital acquired infections, pressure injuries, unplanned extubations, and venous thromboemboli were expected costs of aggressive care. In addition to the morbidity and mortality associated with many of the health care-acquired conditions (HACs) in children, the attributable cost due to these HACs contributes to the unsustainable health care financial crisis. The Centers for Medicare and Medicaid Services (CMS) often penalize hospitals for HACs, and also are beginning to reimburse in a bundled fashion such that complications become the institution's burden. In children, payors and patients' families are often saddling this burden of costs attributable to HACs. The direct attributable costs per event are staggering. Payors, families, patients, and health care teams now demand a circumspect approach to care: do no harm, but how? PMID- 30460180 TI - From the street to the ICU: a review of pediatric emergency medical services and critical care transport. AB - Emergency medical services and critical care transport teams are relatively new parts of the American healthcare delivery system. Although most healthcare providers regularly interact with these groups and rely upon their almost ubiquitous availability, few know how these services developed or what sort of infrastructure currently exists to maintain them. This article provides a focused overview of the history and present practices of both emergency medical services and critical care transport teams, with a concentrated look at the implementation of these services in the pediatric population. Within this context, we also consider current challenges and future opportunities for both groups and conclude with ways to become involved in the improvement of out-of-hospital pediatric critical care. PMID- 30460179 TI - Staffing and workforce issues in the pediatric intensive care unit. AB - The health care industry is in the midst of incredible change, and unfortunately, change is not easy. The intensive care unit (ICU) plays a critical role in the overall delivery of care to patients in the hospital. Care in the ICU is expensive. One of the best ways of improving the value of care delivered in the ICU is to focus greater attention on the needs of the critical care workforce. Herein, we highlight three major areas of concern-the changing model of care delivery outside of the traditional four walls of the ICU, the need for greater diversity in the pediatric critical care workforce, and the widespread problem of professional burnout and its impact on patient care. PMID- 30460181 TI - No more pediatric code blues on the floor: evolution of pediatric rapid response teams and situational awareness plans. AB - Reducing or eliminating code blues that occur on the inpatient, noncritical care units of children's hospitals is a challenging yet achievable goal. The mechanism to accomplish this involves several levels of effort. The implementation of effective pediatric rapid response teams is a well identified part of the process. Rapid response teams can allow for appropriate clinical interventions for deteriorating patients and may ultimately result in a reduction in hospital wide mortality as well as efficient transfer to the pediatric intensive care unit (PICU) when necessary. The timely deployment of rapid response teams is dependent upon the appropriate recognition of patients at risk for deterioration. This recognition can be optimized by relying on assessments as simple as utilization of parental intuition to those as complex as big data models which utilize multiple predictor variables extracted from the electronic medical record. Ultimately, the goal to proactively identify patients at risk of deterioration may allow for prevention of clinical decline via appropriate and timely interventions, and if unsuccessful at that level, may allow for improved outcomes via optimized resuscitation care in the PICU. PMID- 30460182 TI - Improving transitions of care between the operating room and intensive care unit. AB - Transitions of care between individual providers or teams of providers have a high potential for errors due to the incomplete transfer of critical information and the need for ongoing care. The transition from the operating room (OR) to the intensive care unit (ICU) is a particularly dangerous time for critically ill children. Hand-offs of care between the OR and ICU teams during this key transition period require detailed communication of complete and accurate patient information at a time when the patient is perhaps most vulnerable from a physiologic standpoint. Improving the safety of transitions from the OR to the ICU is an active area of investigation, though there are a few notable best practices that are commonly employed in a number of centers. These best practices include having the appropriate personnel at the bedside for the hand-off, the use of scripts and the "sterile cockpit rule", the use of checklists, double verification of post-operative orders, and maintaining an overall safety culture. PMID- 30460183 TI - Early mobilization in the pediatric intensive care unit. AB - Survivors of critical illness often experience multiple morbidities that start in the intensive care unit and impact their quality of life after discharge. Reduced physical function, cognitive decline, feeding disorders, and psychological stress are just a few of the potential complications. Many of these morbidities can lead to a reduced quality of life and lifelong impediments. Early mobilization, an intervention that is intended to maintain or restore musculoskeletal strength in the critically ill, has the potential to also yield positive psychological and cognitive benefits. In adults, early mobilization has been shown to be safe, decrease the incidence of delirium, and decrease length of stay. Early mobilization of the pediatric critically ill patient is still a novel topic with a growing body of research. This article will review the current literature on early mobilization of the pediatric critically ill patient. PMID- 30460184 TI - Going back to the ward-transitioning care back to the ward team. AB - Transition of care from the intensive care unit (ICU) to the ward is usually an indication of the patient's improving clinical status, but is also a time when patients are particularly vulnerable. The transition between care teams poses a higher risk of medical error, which can be mitigated by safe and complete patient handoff and medication reconciliation. ICU readmissions are associated with increased mortality as well as ICU and hospital length of stay (LOS); however tools to accurately predict ICU readmission risk are limited. While there are many mechanisms in place to carefully identify patients appropriate for transfer to the ward, the optimal timing of transfer can be affected by ICU strain, limited resources such as ICU beds, and overall hospital capacity and flow leading to suboptimal transfer times or delays in transfer. The patient and family perspectives should also be considered when planning for transfer from the ICU to the ward. During times of transition, families will meet a new care team, experience uncertainty of future care plans, and adjust to a different daily routine which can lead to increased stress and anxiety. Additionally, a subset of patients, such as those with new technology, require additional multidisciplinary support, education and care coordination which can contribute to longer hospital LOS if not addressed proactively early in the hospitalization while the patient remains in the ICU. In this review article, we describe key components of the transfer from ICU to the ward, discuss current strategies to optimize timing of patient transfers, explore strategies to partner with patients and families during the transfer process, highlight patient populations where additional considerations are needed, and identify future areas of exploration which could improve the care transition from the ICU to the ward. PMID- 30460185 TI - Pediatric palliative care in the intensive care unit and questions of quality: a review of the determinants and mechanisms of high-quality palliative care in the pediatric intensive care unit (PICU). AB - This article reviews the state and practice of pediatric palliative care (PC) within the pediatric intensive care unit (PICU) with specific consideration of quality issues. This includes defining PC and end of life (EOL) care. We will also describe PC as it pertains to alleviating children's suffering through the provision of "concurrent care" in the ICU environment. Modes of care, and attendant strengths, of both the consultant and integrated models will be presented. We will review salient issues related to the provision of PC in the PICU, barriers to optimal practice, parental, and staff perceptions. Opportunity areas for quality improvement and the role of initiatives and measures such as education, family-based initiatives, staff needs, symptom recognition, grief, and communication follow. To conclude, we will look to the literature for PC resources for pediatric intensivists and future directions of study. PMID- 30460186 TI - Always ready, always prepared-preparing for the next pandemic. AB - A future global pandemic is likely to occur and planning for the care of critically ill children is less robust than that for adults. This review covers the current state of federal and regional resources for pediatric care in pandemics, a strategy for pandemic preparation in pediatric intensive care units and regions focusing on stuff, space, staff and systems, considerations in developing surge capacity and triage protocols, special circumstances such as highly infectious and highly lethal pandemics, and a discussion of ethics in the setting of pediatric critical care in a pandemic. PMID- 30460187 TI - A new approach to risk stratification using fetal MRI to predict outcomes in congenital diaphragmatic hernia: the preliminary retrospective single institutional study. AB - Background: Congenital diaphragmatic hernia (CDH) is a condition with a wide range of severity. Prenatal diagnosis is essential to optimize postnatal management, especially for severe cases. The lung to head ratio (LHR) and liver herniation estimated by prenatal ultrasound has been used as prenatal predictors in CDH. However, reliability of these factors remains to be proven and prediction of outcome from prenatal imaging is still challenging. We propose our new stratification system using lung to liver signal intensity ratio (LLSIR) in fetal MRI, which has been shown to be related to pulmonary maturation. Methods: Retrospective chart review was conducted on 25 infants with CDH treated from 2009 through 2016 in our hospital. We stratified patients according to fetal T2 weighted MRI as Grade I, detectable ipsilateral lung at the apex; Grade II, undetectable ipsilateral lung at the apex and contralateral LLSR >=2.0; Grade III, undetectable ipsilateral lung at the apex and contralateral LLSR <2.0. To evaluate this stratification system, we analyzed survival, severity [inhaled nitric oxide (iNO) usage with or without extracorporeal membrane oxygenation (ECMO)], and requirement of patch closure. Results: All 15 patients survived in Grade I, while 2 out of 6 died in Grade II, and 3 out of 4 died in Grade III (P=0.003). Four were severe in Grade I, and all in Grade II and III who survived (P=0.007). One needed patch in Grade I, and all in Grade II and III (OR: 414,238,332; 95% CI, 0-infinity). Liver herniation was noted in five patients, and significantly associated with survival (P=0.04), however, neither with severity (P=1.00) nor with the requirement of patch closure (P=0.52). Conclusions: The risk stratification algorithm using contralateral LLSIR in fetal MRI could be useful and more reliable than liver herniation to predict survival, severity, and need of patch closure. Further investigation is warranted. PMID- 30460189 TI - Optimal exposure for closure of ventricular septal defects through the tricuspid valve. PMID- 30460188 TI - When is early septal myectomy in children with hypertrophic cardiomyopathy justified? PMID- 30460190 TI - An evidence-based standardized protocol for anticoagulation following congenital heart surgery. PMID- 30460192 TI - Corrigendum: Metabolic Reprogramming During Multidrug Resistance in Leukemias. AB - [This corrects the article DOI: 10.3389/fonc.2018.00090.]. PMID- 30460191 TI - Mass Action Kinetic Model of Apoptosis by TRAIL-Functionalized Leukocytes. AB - Background: Metastasis through the bloodstream contributes to poor prognosis in many types of cancer. A unique approach to target and kill colon, prostate, and other epithelial-type cancer cells in the blood has been recently developed that uses circulating leukocytes to present the cancer-specific, liposome-bound Tumor Necrosis Factor (TNF)-related apoptosis inducing ligand (TRAIL) on their surface along with E - selectin adhesion receptors. This approach, demonstrated both in vitro with human blood and in mice, mimics the cytotoxic activity of natural killer cells. The resulting liposomal TRAIL-coated leukocytes hold promise as an effective means to neutralize circulating tumor cells that enter the bloodstream with the potential to form new metastases. Methods: The computational biology study reported here examines the mechanism of this effective signal delivery, by considering the kinetics of the coupled reaction cascade, from TRAIL binding death receptor to eventual apoptosis. In this study, a collision of bound TRAIL with circulating tumor cells (CTCs) is considered and compared to a prolonged exposure of CTCs to soluble TRAIL. An existing computational model of soluble TRAIL treatment was modified to represent the kinetics from a diffusion-limited 3D reference frame into a 2D collision frame with advection and adhesion to mimic the E - selectin and membrane bound TRAIL treatment. Thus, the current model recreates the new approach of targeting cancer cells within the blood. The model was found to faithfully reproduce representative observations from experiments of liposomal TRAIL treatment under shear. Results: The model predicts apoptosis of CTCs within 2 h when treated with membrane bound TRAIL, while apoptosis in CTCs treated with soluble TRAIL proceeds much more slowly over the course of 10 h, consistent with previous experiments. Given the clearance rate of soluble TRAIL in vivo, this model predicts that the soluble TRAIL method would be rendered ineffective, as found in previous experiments. Conclusion: This study therefore indicates that the kinetics of the coupled reaction cascade of liposomal E - selectin and membrane bound TRAIL colliding with CTCs can explain why this new approach to target and kill cancer cells in blood is much more effective than its soluble counterpart. PMID- 30460193 TI - Deciphering the Role of Regulatory CD4 T Cells in Oral and Oropharyngeal Cancer: A Systematic Review. AB - Background: Recruiting regulatory CD4 T cells (Tregs) into the tumor microenvironment is an important tumor escape mechanism. Diminishing these suppressive cells is therefore one of the targets of cancer immunotherapy. Selective depletion of Tregs has proven successful in enhancing anti-tumor immunity and therapeutic efficacy in multiple tumor types. However, the role of Tregs in oral/oropharyngeal cancers is unclear with conflicting evidence regarding the effect of these suppressive cells on tumor prognosis. In this study, we sought to review the role of Tregs in oral/oropharyngeal cancer with the aim of deciphering the controversy regarding their effect on tumor progression and prognosis. Methods: A systematic review of the literature pertaining to the role of Tregs in oral/oropharyngeal cancer was performed using Scopus, Embase, and PubMed. Forty-five records were deemed eligible and data describing methodology of Treg detection, tumor type, and association with prognosis were extracted. Results: Of the 45 eligible manuscripts accepted for this systematic review, thirty-nine studies reported data from human subjects while the remaining studies focused on animal models. Sixteen studies were carried out using peripheral blood samples, while samples from the tumor site were analyzed in 18 studies and 11 studies assessed both blood and tumor samples. The transcriptional factor, Foxp3, was the most commonly used marker for Treg identification (38/45). The findings of 25 studies suggested that an increase in Tregs in the tumor microenvironment and/or peripheral blood was associated with poorer prognosis. These conclusions were attributed to the suppression of immune responses and the consequent tumor progression. Conversely, nine studies showed an increase in Tregs in peripheral blood and/or tumor microenvironment was related to a favorable prognosis, particularly in the presence of human papilloma virus (HPV), the status of which was only assessed in 11 studies. Conclusions: This review underlines the importance of host immunity in the behavior of oral/oropharyngeal cancer. Furthermore, we report an apparent lack of clarity regarding the true role Tregs play in oral/oropharyngeal cancer progression which could be attributed to inconsistent detection techniques of Tregs. Our results therefore highlight the need for clearer methodologies and more robust phenotyping when defining Tregs. PMID- 30460194 TI - Prognostic Significance of Sarcopenia With Inflammation in Patients With Head and Neck Cancer Who Underwent Definitive Chemoradiotherapy. AB - Purpose: With growing evidence that inflammation and low muscularity play a role in the survival of cancer patients, we evaluated the prognostic implications of sarcopenia with systemic inflammation in patients who underwent definitive chemoradiotherapy (CCRT) for locally advanced head and neck cancer. Materials and Methods: We analyzed 221 patients with head and neck cancer who received definitive CCRT between 2006 and 2015. The skeletal muscle area was measured using a single computed tomography image slice at the level of the third lumbar vertebra (L3). Sarcopenia was defined as an L3 muscle index of <49 cm2/m2 for men and <31 cm2/m2 for women. Results: Patients with sarcopenia (n = 106) exhibited higher neutrophil/lymphocyte ratios (NLRs) than those without (n = 115); the former also had an inferior 3-year overall survival (OS) rate (62%) than the latter (76%, p = 0.037). Among patients with sarcopenia, those who also had high NLRs (n = 51) showed significantly poorer OS and progression-free survival (PFS). In the multivariate analysis, sarcopenia plus a high NLR remained the most significant predictor of poor OS and PFS. Patients with sarcopenia required more frequent interruption of RT; patients whose RT was interrupted for >=5 days showed inferior disease control and OS. Conclusions: Sarcopenia accompanied by systemic inflammation at initial diagnosis is associated with significantly inferior OS and PFS. Additionally, patients with sarcopenia required RT interruption more frequently. Intensive nutritional support and additional treatment methods are required for these patients while undergoing RT. PMID- 30460195 TI - Gears-In-Motion: The Interplay of WW and PPIase Domains in Pin1. AB - Pin1 belongs to the family of the peptidyl-prolyl cis-trans isomerase (PPIase), which is a class of enzymes that catalyze the cis/trans isomerization of the Proline residue. Pin1 is unique and only catalyzes the phosphorylated Serine/Threonine-Proline (S/T-P) motifs of a subset of proteins. Since the discovery of Pin1 as a key protein in cell cycle regulation, it has been implicated in numerous diseases, ranging from cancer to neurodegenerative diseases. The main features of Pin1 lies in its two main domains: the WW (two conserved tryptophan) domain and the PPIase domain. Despite extensive studies trying to understand the mechanisms of Pin1 functions, how these two domains contribute to the biological roles of Pin1 in cellular signaling requires more investigations. The WW domain of Pin1 is known to have a higher affinity to its substrate than that of the PPIase domain. Yet, the WW domain seems to prefer the trans configuration of phosphorylated S/T-P motif, while the PPIase catalyzes the cis to trans isomerasion. Such contradicting information has generated much confusion as to the actual mechanism of Pin1 function. In addition, dynamic allostery has been suggested to be important for Pin1 function. Henceforth, in this review, we will be looking at the progress made in understanding the function of Pin1, and how these understandings can aid us in overcoming the diseases implicated by Pin1 such as cancer during drug development. PMID- 30460196 TI - Defining Early-Onset Colon and Rectal Cancers. AB - Background: Colorectal cancer (CRC) incidence is rising in the young, yet the age of those affected is not clearly defined. In this study, we identify such cohorts and define clinicopathological features of early-onset colon and rectal cancers. Methods: The Surveillance, Epidemiology and End Results Program (SEER) database was queried to compare clinicopathological characteristics of colon and rectal cancers diagnosed during 1973-1995 with those diagnosed during 1995-2014. Results: We identified 430,886 patients with colon and rectal cancers. From 1973 1995 to 1995-2014, colon cancer incidence increased in patients aged 20-44 years, while rectal cancer incidence increased in patients aged <=54 years. The percent change of cancer incidence was greatest for rectal cancer with a 41.5% (95% confidence interval (CI): 37.4-45.8%) increase compared to a 9.8% (CI: 6.2-13.6%) increase in colon cancer. Colon cancer has increased in tumors located in ascending, sigmoid, and rectosigmoid locations. Adenocarcinoma histology has increased in both colon and rectal cancers (P < 0.01), but mucinous and signet ring cell subtypes have not increased (P = 0.13 and 0.08, respectively). Incidence increases were race-specific, with rectal cancer seeing similar rises in white (38.4%, CI: 33.8-43.1%) and black populations (38.0%, CI: 26.2-51.2%), while colon cancer as a whole saw a rise in white (11.5%, CI: 7.2-15.9%) but not black populations (-6.8%, CI: -14.6-1.9%). Conclusions: Our study underscores the existence of key differences between early-onset colon (20-44 years) and rectal cancers (<=54 years) and provides evidence-based inclusion criteria for future investigations. We recommend that future research of CRC in the young should avoid investigating these cases as a single entity. PMID- 30460197 TI - Seneca Valley Virus Exploits TEM8, a Collagen Receptor Implicated in Tumor Growth. AB - Recent studies reveal that Seneca Valley Virus (SVV) exploits tumor endothelial marker 8 (TEM8) for cellular entry, the same surface receptor pirated by bacterial-derived anthrax toxin. This observation is particularly significant as SVV is a known oncolytic virus which selectively infects and kills tumor cells, particularly those of neuroendocrine origin. TEM8 is a transmembrane glycoprotein that is preferentially upregulated in some tumor cell and tumor-associated stromal cell populations. Both TEM8 and SVV have been evaluated for targeting of tumors of multiple origins, but the connection between the two was previously unknown. Here, we review currently understood interactions between TEM8 and SVV, anthrax protective antigen (PA), and collagen VI, a native binding partner of TEM8, with an emphasis on potential therapeutic directions moving forward. PMID- 30460199 TI - Identification of Novel Genes Involved in the Pathogenesis of an ACTH-Secreting Pituitary Carcinoma: A Case Report and Literature Review. AB - Pituitary carcinomas (PCs) is considerable uncommon entities with a poor prognosis that represents only 0. 1-0.2% of all pituitary tumors. There are fewer than 150 reported cases up to now. In addition, the molecular pathogenesis leading to malignant pituitary transformation remain unclear due to the rarity of PCs. Here we present an uncommon case of ACTH-secreting PCs and explore the gene mutation following pituitary adenoma transformation. Our detailed clinical, histopathological and molecular detection data suggest that novel genes of ATRX and PTEN were implicated in the pathogenesis of PCs by searching Pubmed and the Web of Science databases as well as Cosmic databank. To the best of our knowledge, this is the first documented rare PCs patient with novel gene mutations that included ATRX and PTEN in addition to TP53. Present finding may therefore provide significant information for targeted therapy of PCs. PMID- 30460198 TI - Vgamma9Vdelta2 T Cells as Strategic Weapons to Improve the Potency of Immune Checkpoint Blockade and Immune Interventions in Human Myeloma. AB - The advent of immune checkpoint (ICP) blockade has introduced an unprecedented paradigm shift in the treatment of cancer. Though very promising, there is still a substantial proportion of patients who do not respond or develop resistance to ICP blockade. In vitro and in vivo models are eagerly needed to identify mechanisms to maximize the immune potency of ICP blockade and overcome primary and acquired resistance to ICP blockade. Vgamma9Vdelta2 T cells isolated from the bone marrow (BM) from multiple myeloma (MM) are excellent tools to investigate the mechanisms of resistance to PD-1 blockade and to decipher the network of mutual interactions between PD-1 and the immune suppressive tumor microenvironment (TME). Vgamma9Vdelta2 T cells can easily be interrogated to dissect the progressive immune competence impairment generated in the TME by the long-lasting exposure to myeloma cellss. BM MM Vgamma9Vdelta2 T cells are PD-1+ and anergic to phosphoantigen (pAg) stimulation; notably, single agent PD-1 blockade is insufficient to fully recover their anti-tumor activity in vitro indicating that additional players are involved in the anergy of Vgamma9Vdelta2 T cells. In this mini-review we will discuss the value of Vgamma9Vdelta2 T cells as investigational tools to improve the potency of ICP blockade and immune interventions in MM. PMID- 30460201 TI - Corrigendum: Microenvironment Cell Contribution to Lymphoma Immunity. AB - [This corrects the article DOI: 10.3389/fonc.2018.00288.]. PMID- 30460200 TI - Editorial: Central Nervous System Metastases in Lung Cancer Patients: From Prevention to Diagnosis and Treatment. PMID- 30460202 TI - Editorial: Role of Iron in Bacterial Pathogenesis. PMID- 30460203 TI - Comparative Analysis of the Microbial Profiles in Supragingival Plaque Samples Obtained From Twins With Discordant Caries Phenotypes and Their Mothers. AB - Early childhood caries (ECC), the most frequent disease of oral cavity in preschool children, is the consequence of microbial, genetic, biochemical, socioeconomic, physical, environmental and health-influencing behavioral factors. To investigate the role of the oral microbiome and the impact of host and environmental factors in the occurrence and development of ECC, we studied the supragingival plaques of 14 twin pairs and a set of triplets with discordant caries phenotypes and 15 mothers, applying the Human Oral Microbe Identification using Next Generation Sequencing technique (HOMINGS). A total of 2,293,650 reads revealed 11 phyla, 116 genera, and 139 species of micromiome. Comparative analysis between the caries and caries-free group at species level revealed that the relative abundance of Streptococcus mutans, Lactobacillus fermentum, Actinomyces islaelii, Neisseria sica, and Veilonella dispar was much higher in caries group (P < 0.0001). Furthermore, monozygotic twins exhibited a higher degree of similarity than dizygotic twins. Finally, we analyzed the relationship between environmental factors and the oral microbiome, and our results indicat that the frequency of taking sweet food is associated with ECC. We conclude the following. First, the occurrence of Streptococcus mutans, Lactobacillus fermentum, Neisseria sica, and Veilonella dispar is strongly associated with the occurrence of ECC. Second, host genetic factors influence the oral microbiome composition, while environmental and behavioral factors like the frequency of taking sweet foods have an impact on the distribution of caries-related bacteria. PMID- 30460204 TI - pYR4 From a Norwegian Isolate of Yersinia ruckeri Is a Putative Virulence Plasmid Encoding Both a Type IV Pilus and a Type IV Secretion System. AB - Enteric redmouth disease caused by the pathogen Yersinia ruckeri is a significant problem for fish farming around the world. Despite its importance, only a few virulence factors of Y. ruckeri have been identified and studied in detail. Here, we report and analyze the complete DNA sequence of pYR4, a plasmid from a highly pathogenic Norwegian Y. ruckeri isolate, sequenced using PacBio SMRT technology. Like the well-known pYV plasmid of human pathogenic Yersiniae, pYR4 is a member of the IncFII family. Thirty-one percent of the pYR4 sequence is unique compared to other Y. ruckeri plasmids. The unique regions contain, among others genes, a large number of mobile genetic elements and two partitioning systems. The G+C content of pYR4 is higher than that of the Y. ruckeri NVH_3758 genome, indicating its relatively recent horizontal acquisition. pYR4, as well as the related plasmid pYR3, comprises operons that encode for type IV pili and for a conjugation system (tra). In contrast to other Yersinia plasmids, pYR4 cannot be cured at elevated temperatures. Our study highlights the power of PacBio sequencing technology for identifying mis-assembled segments of genomic sequences. Comparative analysis of pYR4 and other Y. ruckeri plasmids and genomes, which were sequenced by second and the third generation sequencing technologies, showed errors in second generation sequencing assemblies. Specifically, in the Y. ruckeri 150 and Y. ruckeri ATCC29473 genome assemblies, we mapped the entire pYR3 plasmid sequence. Placing plasmid sequences on the chromosome can result in erroneous biological conclusions. Thus, PacBio sequencing or similar long-read methods should always be preferred for de novo genome sequencing. As the tra operons of pYR3, although misplaced on the chromosome during the genome assembly process, were demonstrated to have an effect on virulence, and type IV pili are virulence factors in many bacteria, we suggest that pYR4 directly contributes to Y. ruckeri virulence. PMID- 30460206 TI - CitE Enzymes Are Essential for Mycobacterium tuberculosis to Establish Infection in Macrophages and Guinea Pigs. AB - Bacterial citrate lyase activity has been demonstrated in various eukaryotes, bacteria and archaea, underscoring their importance in energy metabolism of the cell. While the bacterial citrate lyase comprises of three different subunits, M. tuberculosis genome lacks CitD and CitF subunits of citrate lyase complex but encodes for 2 homologs of CitE subunits, Rv2498c and Rv3075c. Using temperature sensitive mycobacteriophages, we were able to generate both single and double citE mutant strains of M. tuberculosis. The survival experiments revealed increased susceptibility of the double mutant strain to oxidative stress in comparison to the parental strain. Also, simultaneous deletion of both citE1 and citE2 in M. tuberculosis genome resulted in impairment of intracellular replication in macrophages. The double mutant strain displayed reduced growth in lungs and spleens of guinea pigs. This is the first study demonstrating that M. tuberculosis critically requires CitE subunits of citrate lyase for pathogenesis. Taken together, these findings position these enzymes as potential targets for development of anti-tubercular small molecules. PMID- 30460205 TI - Discovering RNA-Based Regulatory Systems for Yersinia Virulence. AB - The genus Yersinia includes three human pathogenic species, Yersinia pestis, the causative agent of the bubonic and pneumonic plague, and enteric pathogens Y. enterocolitica and Y. pseudotuberculosis that cause a number of gut-associated diseases. Over the past years a large repertoire of RNA-based regulatory systems has been discovered in these pathogens using different RNA-seq based approaches. Among them are several conserved or species-specific RNA-binding proteins, regulatory and sensory RNAs as well as various RNA-degrading enzymes. Many of them were shown to control the expression of important virulence-relevant factors and have a very strong impact on Yersinia virulence. The precise targets, the molecular mechanism and their role for Yersinia pathogenicity is only known for a small subset of identified genus- or species-specific RNA-based control elements. However, the ongoing development of new RNA-seq based methods and data analysis methods to investigate the synthesis, composition, translation, decay, and modification of RNAs in the bacterial cell will help us to generate a more comprehensive view of Yersinia RNA biology in the near future. PMID- 30460207 TI - H5N1 Influenza a Virus Replicates Productively in Pancreatic Cells and Induces Apoptosis and Pro-Inflammatory Cytokine Response. AB - The inflammatory response and apoptosis have been proved to have a crucial role in the pathogenesis of the influenza A virus (IAV). Previous studies indicated that while IAV commonly causes pancreatitis and pancreatic damage in naturally and experimentally infected animals, the molecular mechanisms of the pathogenesis of IAV infection are less reported. In the present study, we showed for the first time that both avian-like (alpha-2,3-linked) and human-like (alpha-2,6-linked) sialic acid (SA) receptors were expressed by the mouse pancreatic cancer cell line PAN02 and the human pancreatic cancer cell line PANC-1. Using growth kinetics experiments, we also showed that PAN02 and PANC-1 cells supported the productive replication of the H5N1 highly pathogenic avian influenza while exhibited the limited replication of IAV subtypes H1N1 and H7N2 in vitro. The in vivo infection of H5N1 in pancreatic cells was confirmed by the histopathological and immunohistochemical staining of pancreas tissue from mice. Other than H1N1 and H7N2, severe damage and extensive positive signals were observed in pancreas of H5N1 infected mice. All three virus subtypes induced apoptosis but also triggered the infected PAN02 and PANC-1 cells to release pro-inflammatory cytokines and chemokines including interferon (IFN)-alpha, IFN-beta, IFN-gamma, chemokine (C-C motif) ligand 2 (CCL2), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6. Notably, the subtypes of H5N1 could significantly upregulate these cytokines and chemokines in both two cells when compared with H1N1 and H7N2. The present data provide further understanding of the pathogenesis of H5N1 IAV in pancreatic cells derived from humans and mammals and may also benefit the development of new treatment against H5N1 influenza virus infection. PMID- 30460208 TI - Quantitative Proteomics Reveals Antibiotics Resistance Function of Outer Membrane Proteins in Aeromonas hydrophila. AB - Outer membrane proteins (OMPs) play essential roles in antibiotic resistance, particularly in Gram-negative bacteria; however, they still have many unidentified functions regarding their behavior in response to antibiotic stress. In the current work, quantitative tandem mass tag labeling-based mass spectrometry was used to compare the outer membrane related proteins between an oxytetracycline-resistant (OXY-R) and its original control stain (OXY-O) in Aeromonas hydrophila. Consequently, a total of 261 commonly altered proteins in two biological repeats were identified including 29 proteins that increased and 28 that decreased. Gene ontology analysis showed that the expression of transport proteins was significantly reduced, and translation-related proteins were downregulated in the OXY-R strain. After using western blotting to validate selected altered proteins, eight OMP-related genes were knocked out and their roles in antibiotic resistance were further evaluated. The survival assays showed that some mutants such as DeltaAHA_4281, DeltaAHA_2766, DeltaAHA_2282, DeltaAHA_1181, and DeltaAHA_1280 affected the susceptibility of A. hydrophila to antimicrobials. Moreover, the minimum inhibitory concentration assay showed that these candidate mutants also respond differently to other types of antibiotics. Our results reveal several novel outer membrane related proteins of A. hydrophila that play important roles in antibiotic resistance, and as such, may be helpful for screening studies to identify novel drug targets. PMID- 30460209 TI - Targeting IL-13 as a Host-Directed Therapy Against Ulcerative Colitis. AB - The role of interleukin-13 in mediating ulcerative colitis remains under scrutiny. Compelling evidence from both man and mouse suggests that IL-13 not only contributes to the pathology associated with disease but is also involved in mediating the inflammatory response. These studies have led to the approach of targeting IL-13 as a promising treatment strategy in alleviating ulcerative colitis disease. Despite this evidence, recent clinical trial data suggests that specifically blocking the receptor through which IL-13 signals, IL-4 receptor alpha (IL-4Ralpha) in ulcerative colitis patients, is insufficient in protecting them from disease outcome. This challenges the importance of IL-13 as a therapeutic target. This review describes the role of IL-13 in ulcerative colitis and current treatment strategies that target IL-13. The potential role of IL-13 signaling independently of IL-4Ralpha in mediating ulcerative colitis is highlighted as an important consideration when targeting the signaling mechanisms of IL-13 for therapeutic approaches. PMID- 30460210 TI - Developing computational biology at meridian 23 degrees E, and a little eastwards. AB - Modern biology is experiencing a deep transformation by the expansion of molecular-level measurements at all scales, using omics technologies. A key element in this transformation is the field of bioinformatics, that has-in the meanwhile-permeated pretty much all of biological and biomedical research and is now emerging as a key inter-disciplinary area that connects the natural sciences, chemical and electrical engineering, science education and science policy, on a number of science and technology fronts. The strong tradition of open access for large volumes of raw data, collections of complex results and high-quality algorithm implementations in bioinformatics makes the field a unique, special case of open science. We report on our recent research activities, the development of training initiatives in the wider region during the past years, and the lessons learned regarding our efforts away from major epicenters, within the general context of open science. PMID- 30460211 TI - School Functioning in Adolescents With Chronic Fatigue Syndrome. AB - Background: It is well known that adolescents with chronic fatigue syndrome (CFS) experience greater school absenteeism compared to healthy adolescents. Less is known about other important aspects of school functioning including school participation, school connectedness, and academic performance in students with CFS. The aim of this study was to compare school functioning as a multifaceted construct in adolescents with CFS to healthy adolescent peers. We also explored whether illness factors were associated with school functioning in adolescents with CFS. Methods: Thirty-nine participants with CFS and 28 healthy controls (aged 13-17 years) completed a range of subjective and objective measures of school functioning, as well as measures of fatigue and emotional symptoms. Results: Adolescents with CFS demonstrated significantly higher rates of school absence, as well as poorer school-related quality of life, reduced school participation, poorer connectedness with school, and reduced academic performance. Fatigue severity and emotional symptoms were significantly associated with most aspects of school function. Conclusions: Adolescents with CFS are at increased risk for poor school functioning across a range of indicators which extend beyond school absenteeism. PMID- 30460212 TI - High Temperature-Short Time Pasteurization Has a Lower Impact on the Antiviral Properties of Human Milk Than Holder Pasteurization. AB - Holder pasteurization (62. 5 degrees C for 30 min) is recommended by all international human milk bank guidelines to prevent infections potentially transmitted by donor human milk. A drawback is that it affects some human milk bioactive and nutritive components. Recently, High Temperature-Short Time (HTST) pasteurization has been reported to be a valuable alternative technology to increase the retention of some biological features of human milk. Nevertheless, to date, few data are available about the impact of pasteurization methods other than Holder on the antiviral activity of human milk. The present study was aimed at evaluating the antiviral activity of human milk against a panel of viral pathogens common in newborns and children (i.e., herpes simplex virus 1 and 2, cytomegalovirus, respiratory syncytial virus, rotavirus, and rhinovirus), and at assessing the effect of Holder and HTST pasteurization on milk's antiviral properties. The results indicate that human milk is endowed with antiviral activity against all viruses tested, although to a different extent. Unlike the Holder pasteurization, HTST preserved the inhibitory activity against cytomegalovirus, respiratory syncytial virus, rotavirus and herpes simplex virus type 2. By contrast, both methods reduced significantly the antiviral activities against rhinovirus and herpes simplex virus type 1. Unexpectedly, Holder pasteurization improved milk's anti-rotavirus activity. In conclusion, this study contributes to the definition of the pasteurization method that allows the best compromise between microbiological safety and biological quality of the donor human milk: HTST pasteurization preserved milk antiviral activity better than Holder. PMID- 30460214 TI - Challenges in Managing EBV-Associated T- and NK-Cell Lymphoproliferative Diseases. PMID- 30460215 TI - The Development of the DePaul Symptom Questionnaire: Original, Expanded, Brief, and Pediatric Versions. AB - One of the key requirements of a reliable case definition is the use of standardized procedures for assessing symptoms. This article chronicles the development of the DePaul Symptom Questionnaire (DSQ) to assess symptoms of the major chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME) case definitions. The original questionnaire has been modified and expanded over time to more fully capture symptoms from various adult case definitions, and a brief as well as pediatric version have also been developed. The DSQ has demonstrated very good psychometric properties in terms of test-retest reliability and sensitivity/specificity, as well as construct, predictive, and discriminant validity. The DSQ allows for a clear characterization of a patient's illness and allows scientists and clinicians to improve diagnostic reliability and validity when employing case definitions of ME and CFS. PMID- 30460216 TI - Hematopoietic Stem Cell Transplantation for the Treatment of Epstein-Barr Virus Associated T- or NK-Cell Lymphoproliferative Diseases and Associated Disorders. AB - Chronic active Epstein-Barr virus infection (CAEBV) is a prototype of EBV associated T- and/or NK-cell (EBV+ T/NK-cell) lymphoproliferative disorders. Most subtypes of these are lethal. We established a unified treatment strategy composed of step 1 (immunochemotherapy: steroids, cyclosporine A, and etoposide), step 2 (multi-drug block chemotherapy), and step 3 (allogeneic hematopoietic stem cell transplantation; HSCT) for CAEBV and its related diseases. Allogeneic HSCT is the only cure for CAEBV with few exceptions. Primary-EBV infection-associated hemophagocytic lymphohistiocytosis (primary-EBV HLH) is also an EBV+ T/NK-cell lymphoproliferation. The nature of EBV+ T/NK cells in CAEBV and those in primary EBV HLH differ. In primary-EBV HLH, most patients need step 1 only and some require step 2 for the successful induction of apoptosis in EBV-infected T cells; however, some exceptional patients require HSCT. We herein present our single institutional experience of CAEBV and primary-EBV HLH, together with that of post transplant EBV+ T/NK-cell lymphoproliferative disease. We also discuss some practical points on HCST with a review of the literature. PMID- 30460217 TI - Safety of Patient-Controlled Analgesia After Surgery in Children And Adolescents: Concerns And Potential Solutions. AB - Patient-controlled analgesia (PCA) is common practice for acute postoperative pain management. Postoperative PCA use decreases pain intensity and improves patient satisfaction when compared to non-PCA routes of medication administration. Although PCA has several advantages regarding efficacy and safety, adverse events remain a concern. Programming errors and protocols, patient monitoring, and PCA by proxy or with continuous infusion are recurring silent dangers of PCA use in children and adolescents. Innovative considerations need to be emphasized for future improvement of PCA devices for elective surgical patients. With technology within the healthcare setting advancing at a fast pace, smart pump technology is something to look forward to. PMID- 30460218 TI - Physical Fitness and Locomotor Skills in Children With Esophageal Atresia-A Case Control Pilot Study. AB - Background: Patients with esophageal atresia (EA) often experience physical limitations. With increasing survival over the past decades, the focus in care shifted toward improving the long-term quality of life. We performed validated testing fitness and motor skills in children born with EA. Methods: Patients with EA were evaluated using the standardized Kinderturntest Plus/ Deutscher Motorik Test after caregiver's written consent. Test scores range from 1 to 5 (compared to an age- and gender matched standard population). Caregivers completed an online-questionnaire on patient history. Results: Seventeen patients (median age 7 [3-12] years) were included. Comorbidities were prematurity (54%), birth weight <1,500 g (23%), congenital heart disease (46%), developmental delay (38%), skeletal deformity (23%), and anorectal malformation (15%). The mean test score was significantly lower in children with EA (2.19) compared to a control group matched for age, gender, body weight, and -height, (2.75, p = 0.04), and the general population (3, p = 0.00). Distribution of patient scores was below the 41st performance percentile for gender and age in 54-63%. Caregivers identified notable deficits of strength and endurance. All but one patient complained about discomfort during physical exercise, most commonly respiratory distress (46%) and gastroesophageal reflux symptoms (31%). Notably, 93% of subjects participated in regular school physical education classes, and 86% participated regularly in additional organized sporting activities. Conclusions: Children after EA repair have decreased physical fitness and impaired locomotor function compared to the general population on a standardized test. Physical discomfort is frequent during exertion. To avoid demotivation, locomotor skill should be promoted at each individual's comfortable level. The study was registered at www.researchregistry.com (No. 3707). PMID- 30460213 TI - Compositional Dynamics of the Milk Fat Globule and Its Role in Infant Development. AB - Human milk is uniquely optimized for the needs of the developing infant. Its composition is complex and dynamic, driven primarily by maternal genetics, and to a lesser extent by diet and environment. One important component that is gaining attention is the milk fat globule (MFG). The MFG is composed of a triglyceride rich core surrounded by a tri-layer membrane, also known as the milk fat globule membrane (MFGM) that originates from mammary gland epithelia. The MFGM is enriched with glycerophospholipids, sphingolipids, cholesterol, and proteins, some of which are glycosylated, and are known to exert numerous biological roles. Mounting evidence suggests that the structure of the MFG and bioactive components of the MFGM may benefit the infant by aiding in the structural and functional maturation of the gut through the provision of essential nutrients and/or regulating various cellular events during infant growth and immune education. Further, antimicrobial peptides and surface carbohydrate moieties surrounding the MFG might have a pivotal role in shaping gut microbial populations, which in turn may promote protection against immune and inflammatory diseases early in life. This review seeks to: (1) understand the components of the MFG, as well as maternal factors including genetic and lifestyle factors that influence its characteristics; (2) examine the potential role of this milk component on the intestinal immune system; and (3) delineate the mechanistic roles of the MFG in infant intestinal maturation and establishment of the microbiota in the alimentary canal. PMID- 30460219 TI - Nutrition Support and Tight Glucose Control in Critically Ill Children: Food for Thought! AB - Numerous studies have examined the strategy of tight glucose control (TGC) with intensive insulin therapy (IIT) to improve clinical outcomes in critically ill adults and children. Although early studies of TGC with IIT demonstrated improved outcomes at the cost of elevated hypoglycemia rates, subsequent studies in both adults and children have not demonstrated any benefit from such a strategy. Differences in patient populations, variable glycemic targets, and glucose control protocols, inconsistency in attaining these targets, heterogeneous intermittent sampling, and measurement techniques, and variable expertise in protocol implementation are possible reasons for the contrasting results from these studies. Notably, differences in modes of nutrition support may have also contributed to these disparate results. In particular, combined use of early parenteral nutrition (PN) and a strategy of TGC with IIT may be associated with improved outcomes, while combined use of enteral nutrition (EN) and a strategy of TGC with IIT may be associated with equivocal or worse outcomes. This article critically examines published clinical trials that have employed a strategy of TGC with IIT in critically ill children to highlight the role of EN vs. PN in influencing clinical outcomes including efficacy of TGC, and adverse effects such as occurrence of hypoglycemia and hospital acquired infections. The perspective afforded by this article should help practitioners consider the potential importance of mode of nutrition support in impacting key clinical outcomes if they should choose to employ a strategy of TGC with IIT in critically ill children with hyperglycemia. PMID- 30460220 TI - Almost Everything We Need to Better Serve Children of the Opioid Crisis We Learned in the 80s and 90s. AB - Opioid use disorder impedes dependent parents' abilities to care for their children. In turn, children may languish in unpredictability and persistent chaos. Societal responses to these children are often guided by a belief that unless the drug dependent parent receives treatment, there is little help for the child. While a preponderance of the drug dependence research is adult-centric, a significant body of research demonstrates the importance of not only addressing the immediate well being of the children of drug dependent caregivers but preventing the continuing cycle of drug dependence. The present commentary demonstrates through a brief review of the US history of drug dependence crises and research from the 1980s and 1990s, a range of "tried and true" family, school, and community interventions centered on children. We already know that these children are at high risk of maladjustment and early onset of drug dependence; early intervention is critical; multiple risk factors are likely to occur simultaneously; comprehensive strategies are optimal; and multiple risk focused strategies are most protective. Where we need now to turn our efforts is on how to effectively implement and disseminate best practices, many of which we learned in the 1980s and 1990s. The greatest opportunity in both changing the nature of the opioid epidemic at scale and influencing rapid translation of existing research findings into policy and practice is not in asking what to do, but in asking how to do the right things well, and quickly. PMID- 30460221 TI - A New High Hydrostatic Pressure Process to Assure the Microbial Safety of Human Milk While Preserving the Biological Activity of Its Main Components. AB - Background: The main process used to pasteurize human milk is the low temperature, long-time Holder method. More recently, the high-temperature, short time method has been investigated. Both processes lead to the appropriate inactivation of vegetative bacterial forms but are ineffective against bacterial spores. Research Aims/Questions: We aimed to accomplish two main objectives: inactivation of all pathogens, including spores; and preservation of the activity of milk components. Design/Methods: Recently, a novel high-hydrostatic pressure process has been developed by HPBioTECH. Using the same raw human milk samples, we compared the effects of this method with those of the Holder method on vegetative and spore forms of pathogens and on bioactive components (lipase activity, immunoproteins). Results: Two main microbial strains were selected: Staphylococcus aureus (as a reference for vegetative forms) and Bacillus cereus (as a reference for spores). Use of the high-hydrostatic pressure process led to microbial decontamination of 6 log for both S. aureus and B. cereus. Additionally, the bioactivity of the main components of human milk was preserved, with activities of lipase, alpha-lactalbumin, casein, lysozyme, lactoferrin, and sIgA of ~80, 96-99, 98-100, 95-100, 93-97, and 63-64%, respectively. Conclusions: Use of this novel high-hydrostatic pressure process to generate microbiologically safe human milk may provide important benefits for preterm infants, including improved assimilation of human milk (leading increased weight gain) and improved resistance to infections. Because 10% of all human milk collected is contaminated by B. cereus, use of this method will also prevent waste. PMID- 30460222 TI - Mindfulness and Acceptance as Potential Protective Factors for Mothers of Children With Fragile X Syndrome. AB - Women with an FMR1 premutation may be at increased genetic risk for stress vulnerability. This increased vulnerability, when combined with stressful parenting that can result from raising children with fragile X syndrome (FXS), may result in negative physical and emotional outcomes. Mindfulness and acceptance have been found to be protective factors for parents of children with similar behavioral challenges, but these traits have not previously been explored among mothers with a child with FXS. This study explored the associations of child disability severity with maternal stress, anxiety, depression, and physical health symptoms in 155 biological mothers of children with FXS. Women completed an online survey using standardized measures of stress, mindfulness, and acceptance. General mindfulness, mindfulness in the parenting role, and general acceptance were explored as potential protective factors between the child disability severity and maternal outcomes. Trait mindfulness and acceptance were significant predictors of lower stress, anxiety, depression, and daily health symptoms, while mindful parenting was associated with lower stress, anxiety, and depression. Acceptance was found to attenuate the effects of child severity on maternal stress and depression. These findings suggest that interventions focused on improving mindfulness and acceptance may promote health and well-being for mothers of children with FXS and have important health implications for all individuals with an FMR1 premutation. PMID- 30460223 TI - A Simple SERS-Based Trace Sensing Platform Enabled by AuNPs-Analyte/AuNPs Double Decker Structure on Wax-Coated Hydrophobic Surface. AB - In this work, a simple and versatile SERS sensing platform enabled by AuNPs analyte/AuNPs double-decker structure on wax-coated hydrophobic surface was developed using a portable Raman spectrometer. Wax-coated silicon wafer served as a hydrophobic surface to induce both aggregation and concentration of aqueous phase AuNPs mixed with analyte of interest. After drying, another layer of AuNPs was drop-cast onto the layer of AuNPs-analyte on the substrate to form double decker structure, thus introducing more "hot spots" to further enhance the Raman signal. To validate the sensing platform, methyl parathion (pesticide), and melamine (a nitrogen-enrich compound illegally added to food products to increase their apparent protein content) were employed as two model compounds for trace sensing demonstration. The as-fabricated sensor showed high reproducibility and sensitivity toward both methyl parathion and melamine detection with the limit of detection at the nanomolar and sub-nanomolar concentration level, respectively. In addition, remarkable recoveries for methyl parathion spiked into lake water samples were obtained, while reasonably good recoveries for melamine spiked into milk samples were achieved. These results demonstrate that the as-developed SERS sensing platform holds great promise in detecting trace amount of hazardous chemicals for food safety and environment protection. PMID- 30460225 TI - Point-of-Care Blood Tests: Do Indian Villagers Have Cultural Objections? PMID- 30460224 TI - Rational Design of Self-Healing Tough Hydrogels: A Mini Review. AB - Hydrogels are three-dimensional cross-linked polymer networks which can absorb and retain large amount of water. As representative soft materials with tunable chemical, physical and biological properties, hydrogels with different functions have been developed and utilized in a broad range of applications, from tissue engineering to soft robotics. However, conventional hydrogels usually suffer from weak mechanical properties and they are easily deformed or damaged when they are subjected to mechanical forces. The accumulation of the damage may lead to the permanent structural change and the loss of the functional properties of the hydrogels. Therefore, it is important to develop mechanically robust hydrogels with autonomous self-healing property in order to extend their lifespan for various applications. In this mini review, we focus on the discussion about the appropriate molecular design of the hydrogel network for achieving self-healing and excellent mechanical properties, respectively as well as the corresponding self-healing and toughening mechanisms. We conclude with perspectives on the remaining challenges in the field as well as the recommendations for future development. PMID- 30460226 TI - Li2O-Reinforced Solid Electrolyte Interphase on Three-Dimensional Sponges for Dendrite-Free Lithium Deposition. AB - Lithium (Li) metal, with ultra-high theoretical capacity and low electrochemical potential, is the ultimate anode for next-generation Li metal batteries. However, the undesirable Li dendrite growth usually results in severe safety hazards and low Coulombic efficiency. In this work, we design a three-dimensional CuO@Cu submicron wire sponge current collector with high mechanical strength SEI layer dominated by Li2O during electrochemical reaction process. The 3D CuO@Cu current collector realizes an enhanced CE of above 91% for an ultrahigh current of 10 mA cm-2 after 100 cycles, and yields decent cycle stability at 5 C for the full cell. The exceptional performances of CuO@Cu submicron wire sponge current collector hold promise for further development of the next-generation metal-based batteries. PMID- 30460227 TI - Low-Loading of Pt Nanoparticles on 3D Carbon Foam Support for Highly Active and Stable Hydrogen Production. AB - Minimizing Pt loading is essential for designing cost-effective water electrolyzers and fuel cell systems. Recently, three-dimensional macroporous open pore electroactive supports have been widely regarded as promising architectures to lower loading amounts of Pt because of its large surface area, easy electrolyte access to Pt sites, and superior gas diffusion properties to accelerate diffusion of H2 bubbles from the Pt surface. However, studies to date have mainly focused on Pt loading on Ni-based 3D open pore supports which are prone to corrosion in highly acidic and alkaline conditions. Here, we investigate electrodeposition of Pt nanoparticles in low-loading amounts on commercially available, inexpensive, 3D carbon foam (CF) support and benchmark their activity and stability for electrolytic hydrogen production. We first elucidate the effect of deposition potential on the Pt nanoparticle size, density and subsequently its coverage on 3D CF. Analysis of the Pt deposit using scanning electron microscopy images reveal that for a given deposition charge density, the particle density increases (with cubic power) and particle size decreases (linearly) with deposition overpotential. A deposition potential of -0.4 V vs. standard calomel electrode (SCE) provided the highest Pt nanoparticle coverage on 3D CF surface. Different loading amounts of Pt (0.0075-0.1 mgPt/cm2) was then deposited on CF at -0.4 V vs. SCE and subsequently studied for its hydrogen evolution reaction (HER) activity in acidic 1M H2SO4 electrolyte. The Pt/CF catalyst with loading amounts as low as 0.06 mgPt/cm2 (10-fold lower than state-of-the-art commercial electrodes) demonstrated a mass activity of 2.6 ampere per milligram Pt at 200 mV overpotential, nearly 6-fold greater than the commercial Pt/C catalyst tested under similar conditions. The 3D architectured electrode also demonstrated excellent stability, showing <7% loss in activity after 60 h of constant current water electrolysis at 100 mA/cm2. PMID- 30460228 TI - Nano-Dispersed Ziegler-Natta Catalysts for 1 MUm-Sized Ultra-High Molecular Weight Polyethylene Particles. AB - A catalytic approach to synthesize microfine ultra-high molecular weight polyethylene (UHMWPE) particles was proposed based on the exploitation of nano sized catalysts. By utilizing MgO nanoparticles as a core material, a Ziegler Natta-type MgO/MgCl2/TiCl4 core-shell catalyst with the particle size in a nano range scale was prepared in a simple preparation step. The organic modification of MgO surfaces prior to catalyzation prevented agglomeration and facilitated the full dispersion of catalyst particles at a primary particle level for the first time. The nano-dispersed catalysts successfully afforded a direct access to UHMWPE having the particle size in the range of 1-2 MUm at a reasonable activity. Extremely fine polymer particles yielded several advantages, especially at a significantly lower fusion temperature in compression molding. PMID- 30460229 TI - Electrospun ZnO-SnO2 Composite Nanofibers and Enhanced Sensing Properties to SF6 Decomposition Byproduct H2S. AB - Hydrogen sulfide (H2S) is an important decomposition component of sulfur hexafluoride (SF6), which has been extensively used in gas-insulated switchgear (GIS) power equipment as insulating and arc-quenching medium. In this work, electrospun ZnO-SnO2 composite nanofibers as a promising sensing material for SF6 decomposition component H2S were proposed and prepared. The crystal structure and morphology of the electrospun ZnO-SnO2 samples were investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM), respectively. The composition of the sensitive materials was analyzed by energy dispersive X-ray spectrometers (EDS) and X-ray photoelectron spectroscopy (XPS). Side heated sensors were fabricated with the electrospun ZnO SnO2 nanofibers and the gas sensing behaviors to H2S gas were systematically investigated. The proposed ZnO-SnO2 composite nanofibers sensor showed lower optimal operating temperature, enhanced sensing response, quick response/recovery time and good long-term stability against H2S. The measured optimal operating temperature of the ZnO-SnO2 nanofibers sensor to 50 ppm H2S gas was about 250 degrees C with a response of 66.23, which was 6 times larger than pure SnO2 nanofibers sensor. The detection limit of the fabricated ZnO-SnO2 nanofibers sensor toward H2S gas can be as low as 0.5 ppm. Finally, a plausible sensing mechanism for the proposed ZnO-SnO2 composite nanofibers sensor to H2S was also discussed. PMID- 30460230 TI - Membrane-Modified Metal Triazole Complexes for the Electrocatalytic Reduction of Oxygen and Carbon Dioxide. AB - In this manuscript, an electrochemical architecture is designed that controls the kinetics of proton transfer to metal triazole complexes for electrocatalytic O2 and CO2 reduction. Self-assembled monolayers of these catalysts are attached to a glassy carbon electrode and covered with a lipid monolayer containing proton carriers, which acts as a proton-permeable membrane. The O2 reduction voltammograms on carbon are similar to those obtained on membrane-modified Au electrodes, which through the control of proton transfer rates, can be used to improve the selectivity of O2 reduction. The improved voltage stability of the carbon platforms allows for the investigation of a CO2 reduction catalyst inside a membrane. By controlling proton transfer kinetics across the lipid membrane, it is found that the relative rates of H2, CO, and HCOOH production can be modulated. It is envisioned that the use of these membrane-modified carbon electrodes will aid in understanding catalytic reactions involving the transfer of multiple protons and electrons. PMID- 30460231 TI - Make It Simple: (SR-A1+TLR7) Macrophage Targeted NANOarchaeosomes. AB - Hyperhalophilic archaebacteria exclusively produce sn2,3 diphytanylglycerol diether archaeolipids, unique structures absent in bacteria and eukaryotes. Nanovesicles made of archaeolipids known as nanoarchaeosomes (nanoARC), possess highly stable bilayers, some of them displaying specific targeting ability. Here we hypothesize that nanoARC made from Halorubrum tebenquichense archaebacteria, may constitute efficient carriers for the TLR7 agonist imiquimod (IMQ). NanoARC IMQ takes advantage of the intense interaction between IMQ and the highly disordered, poorly fluid branched archaeolipid bilayers, rich in archaeol analog of methyl ester of phosphatidylglycerophosphate (PGP-Me), a natural ligand of scavenger receptor A1 (SR-A1). This approach lacks complex manufacture steps required for bilayers labeling, enabling future analytical characterization, batch reproducibility, and adaptation to higher scale production. SR-A1 mediated internalization of particulate material is mostly targeted to macrophages and is extensive because it is not submitted to a negative feedback. A massive and selective intracellular delivery of IMQ may concentrate its effect specifically into the endosomes, where the TLR7 is expressed, magnifying its immunogenicity, at the same time reducing its systemic bioavailability, and therefore it's in vivo adverse effects. NanoARC-IMQ (600-900 nm diameter oligolamellar vesicles of ~-43 mV Z potential) were heavily loaded with IMQ at ~44 MUg IMQ/mg phospholipids [~20 folds higher than the non-SR-A1 ligand soyPC liposomes loaded with IMQ (LIPO IMQ)]. In vitro, nanoARC-IMQ induced higher TNF-alpha and IL-6 secretion by J774A1 macrophages compared to same dose of IMQ and same lipid dose of LIPO-IMQ. In vivo, 3 subcutaneous doses of nanoARC-IMQ+ 10 MUg total leishmania antigens (TLA) at 50 MUg IMQ per Balb/C mice, induced more pronounced DTH response, accompanied by a nearly 2 orders higher antigen-specific systemic IgG titers than IMQ+TLA and LIPO-IMQ. The isotype ratio of nanoARC-IMQ+TLA remained ~0.5 indicating, the same as IMQ+TLA, a Th2 biased response distinguished by a pronounced increase in antibody titers, without negative effects on splenocytes lymphoproliferation, with a potential CD8+LT induction 10 days after the last dose. Overall, this first approach showed that highly SR-A1 mediated internalization of heavily loaded nanoARC-IMQ, magnified the effect of IMQ on TLR7 expressing macrophages, leading to a more intense in vivo immune response. PMID- 30460232 TI - Renal ADAM10 and 17: Their Physiological and Medical Meanings. AB - A disintegrin and metalloproteinases (ADAMs) are a Zn2+-dependent transmembrane and secreted metalloprotease superfamily, so-called "molecular scissors," and they consist of an N-terminal signal sequence, a prodomain, zinc-binding metalloprotease domain, disintegrin domain, cysteine-rich domain, transmembrane domain and cytoplasmic tail. ADAMs perform proteolytic processing of the ectodomains of diverse transmembrane molecules into bioactive mediators. This review summarizes on their most well-known members, ADAM10 and 17, focusing on the kidneys. ADAM10 is expressed in renal tubular cells and affects the expression of specific brush border genes, and its activation is involved in some renal diseases. ADAM17 is weakly expressed in normal kidneys, but its expression is markedly induced in the tubules, capillaries, glomeruli, and mesangium, and it is involved in interstitial fibrosis and tubular atrophy. So far, the various substrates have been identified in the kidneys. Shedding fragments become released ligands, such as Notch and EGFR ligands, and act as the chemoattractant factors including CXCL16. Their ectodomain shedding is closely correlated with pathological factors, which include inflammation, interstitial fibrosis, and renal injury. Also, the substrates of both ADAMs contain the molecules that play important roles at the plasma membrane, such as meaprin, E-cadherin, Klotho, and CADM1. By being released into urine, the shedding products could be useful for biomarkers of renal diseases, but ADAM10 and 17 per se are also notable as biomarkers. Furthermore, ADAM10 and/or 17 inhibitions based on various strategies such as small molecules, antibodies, and their recombinant prodomains are valuable, because they potentially protect renal tissues and promote renal regeneration. Although temporal and spatial regulations of inhibitors are problems to be solved, their inhibitors could be useful for renal diseases. PMID- 30460234 TI - The Effects of Music Therapy-Singing Group on Quality of Life and Affect of Persons With Dementia: A Randomized Controlled Trial. AB - Dementia is a clinical syndrome that is progressive and degenerative, affecting memory, behavior, emotion, and personality. Persons with dementia often experience deterioration of cognitive ability, as well as various behavioral and psychological disturbances, which significantly contribute to reduced quality of life and emotional well-being. The demand for long-term care continues to rise rapidly and it is therefore critical to develop effective strategies and evidence based interventions to improve the quality of life for persons with dementia. Music therapy has drawn attention as a promising non-pharmacological approach for persons with dementia. A variety of music interventions including singing and listening to music have been widely applied for dementia care not only by music therapists, but also by other healthcare professionals. There are, however, little research studies that compare possible effects of music therapy interventions with those of music-based approaches on dementia care. The purpose of the current study was to compare the short-term effects of a music therapy singing group with those of a music medicine-listening group and a control-TV group, on quality of life and affect of persons with dementia at a long-term care facility. The music therapy-singing group was facilitated by a music therapist, whereas the music medicine-listening and the control-TV group were led by nursing home activity staff. Fifty-two participants, whose ages range from 67 to 99 years old, were randomly assigned to one of the three groups, and 37 participants completed the interventions. The participants in each group were engaged for a 40 min session twice a week for four consecutive weeks. Quality of life was measured at the baseline and after the last session and only the music therapy-singing group demonstrated significant improvements when compared to the other groups. Positive and negative affect were measured at three points, including pre and post the first, fourth and eighth sessions. Only the music therapy-singing group significantly increased positive affect scores and decreased negative affect scores. The findings of the current study suggest that music therapy with active group singing may be an effective non-pharmacological intervention in improving quality of life and affect of persons with dementia at long-term care settings. Clinical Trial Registration: http://www.germanctr.de/drks_web/, registration number DRKS00014934. PMID- 30460235 TI - Nitroglycerin and Iloprost Improve Mitochondrial Function in Colon Homogenate Without Altering the Barrier Integrity of Caco-2 Monolayers. AB - Locally applied nitroglycerin [nitric oxide (NO) donor] and iloprost (analog of prostacyclin PGI2) improve regional gastric oxygenation and nitroglycerin preserves gastric mucosal barrier integrity. This suggests direct effects of these substances on oxygenation and barrier function. The aim of this study was to analyze the effect of iloprost and nitroglycerin on intestinal mitochondrial function and on mucosal barrier function in vitro. Mitochondrial oxygen consumption (respirometry) was determined in colon homogenates from 16 healthy rats before (baseline) and 15 min after incubation with nitroglycerin (25 and 250 MUg/ml) and iloprost (0.1 and 1 MUg/ml). State 2 (substrate-dependent oxygen consumption) and state 3 respiration (ADP-dependent oxygen consumption) were assessed and ADP/O ratio (ADP added/oxygen consumed) for complex I and II were calculated. For permeability measurement we used the Caco-2 monolayer. Fluorescein sulfonic acid (FS) (200 MUg/ml) and the drugs were administered into the apical compartment of the transwell chamber. After 48 h, FS translocation was assessed as basolateral/apical FS. Both concentrations of nitroglycerin and iloprost reduced state 3 by stimulation via both complexes. Iloprost increased ADP/O ratio after stimulation via both complexes at both concentrations. Nitroglycerin increased ADP/O ratio at the higher concentration (250 MUg/ml) after stimulation via complex I and at the lower concentration (25 MUg/ml) via complex II. Neither nitroglycerin nor iloprost influenced FS translocation. Iloprost and nitroglycerin reduce the maximal mitochondrial respiration and improve the efficacy of oxidative phosphorylation in colon homogenates. Both drugs have no direct influence on mucosal barrier integrity of Caco-2 monolayers. PMID- 30460233 TI - The Vasoreparative Potential of Endothelial Colony Forming Cells: A Journey Through Pre-clinical Studies. AB - For over a decade various cell populations have been investigated for their vasoreparative potential. Cells with the capacity to promote blood vessel regeneration are commonly known as endothelial progenitor cells (EPCs); although such a definition is currently considered too simple for the complexity of cell populations involved in the reparative angiogenic process. A subset of EPCs called endothelial colony forming cells (ECFCs) have emerged as a suitable candidate for cytotherapy, primarily due to their clonogenic progenitor characteristics, unequivocal endothelial phenotype, and inherent ability to promote vasculogenesis. ECFCs can be readily isolated from human peripheral and cord blood, expanded ex vivo and used to revascularize ischemic tissues. These cells have demonstrated efficacy in several in vivo preclinical models such as the ischemic heart, retina, brain, limb, lung and kidney. This review will summarize the current pre-clinical evidence for ECFC cytotherapy and discuss their potential for clinical application. PMID- 30460236 TI - A Community-Based Music Therapy Support Group for People With Alzheimer's Disease and Their Caregivers: A Sustainable Partnership Model. AB - People with Alzheimer's and related dementias and their family caregivers who reside at home have unique strengths and needs. They have the strengths of being in a place with which they are familiar, with people whom they are in close relationship. Often it is the spouse who provides the primary care of their loved one, and as the disease progresses both members of the couple are at risk for depression, isolation, and decreased contact with peers and community networks that serve to help maintain sociocultural, intellectual, physical, sensory, and spiritual needs. The person with Alzheimer's Disease (AD) loses life skills and sense of self as their memory loss worsens, and the caregiver-loved one, whether they are the spouse, relative, or close companion, becomes increasingly burdened physically and emotionally. Meaningful support through a community-based peer group helps meet the needs of the person with dementia and their caregiver from the first symptoms to the later stages of AD, through a carefully designed music therapy program tailored to preferences, culture, and ability. The music therapist working in the community provides practical leadership in coordination with local agencies, understands the needs of the person with dementia and their caregiver from a cultural and psychosocial perspective, and is creatively equipped in all facets of musical engagement for health and wellness, and fosters cognitive/intellectual, socio-emotional, physical, and spiritual support. The MT support group was found to relieve some of the strain on caregivers by allowing for greater emotional support through relationships with peers and professionals, and through the increase of meaningful interactions with their loved one with dementia. Through enjoyment of shared, pleasurable music experiences that stimulate memories, movement, language, and socialization, the person with AD and their caregiver developed a deeper connection with each other, and gained support, creative expression, and comfort from their peer group, as well as practical networking and sharing of resources and information related to their specific health and wellness needs. The community-based MT support group has been replicated twice within the region, and is a promising model for other communities. Formal research is recommended to provide further evidence of the effectiveness of the approach, and to allow for greater accessibility for marginalized people to participate in a program such as this in their own community. PMID- 30460238 TI - Increasing Non-tuberculous Mycobacteria Infections in Veterans With COPD and Association With Increased Risk of Mortality. AB - Background: There are limited data on the epidemiology of Non-tuberculous mycobacteria (NTM) infections among patients with COPD, particularly in the veteran population. This study examined the prevalence, incidence, and mortality of pulmonary NTM infections among veterans with COPD population in the United States. Methods: We analyzed nationwide data from Veterans Affairs Hospitals from 2001 to 2015. First, we determined the incidence and prevalence rates and geographic distribution of NTM infections among veterans with COPD and then we evaluated the association between NTM infections with mortality among veterans with COPD. Pulmonary NTM and COPD diagnosis were defined based on charting claims for each condition on >=2 occasions and >=30 days apart. COPD diagnoses had to precede diagnosis of NTM. Cox Proportional-Hazards Regression was performed to determine the dependency of survival time of COPD patients with NTM. Results: The incidence and prevalence rates of NTM rose over the study period, with a sharp rise in incidence after 2012. The areas with the highest NTM period prevalence were Puerto Rico (370), followed by Florida (351) and District of Columbia (309) in 100,000 COPD population. Mortality registered for those patients with COPD Patients and NTM infection was 1.43 times higher compared to those that were uninfected. Conclusions: NTM rates have been increasing in veterans with COPD since 2012. NTM infection is associated with increased risk of mortality. This highlights the importance of identifying preventable risk factors associated with NTM infections in subjects with COPD. PMID- 30460237 TI - The Role of Melanoma Cell-Stroma Interaction in Cell Motility, Invasion, and Metastasis. AB - The importance of studying cancer cell invasion is highlighted by the fact that 90% of all cancer-related mortalities are due to metastatic disease. Melanoma metastasis is driven fundamentally by aberrant cell motility within three dimensional or confined environments. Within this realm of cell motility, cytokines, growth factors, and their receptors are crucial for engaging signaling pathways, which both mediate crosstalk between cancer, stromal, and immune cells in addition to interactions with the surrounding microenvironment. Recently, the study of the mechanical biology of tumor cells, stromal cells and the mechanics of the microenvironment have emerged as important themes in driving invasion and metastasis. While current anti-melanoma therapies target either the MAPK signaling pathway or immune checkpoints, there are no drugs available that specifically inhibit motility and thus invasion and dissemination of melanoma cells during metastasis. One of the reasons for the lack of so-called "migrastatics" is that, despite decades of research, the precise biology of metastatic disease is still not fully understood. Metastatic disease has been traditionally lumped into a single classification, however what is now emergent is that the biology of melanoma metastasis is highly diverse, heterogeneous and exceedingly dynamic-suggesting that not all cases are created equal. The following mini-review discusses melanoma heterogeneity in the context of the emergent theme of mechanobiology and how it influences the tumor-stroma crosstalk during metastasis. Thus, highlighting future therapeutic options for migrastatics and mechanomedicines in the prevention and treatment of metastatic melanoma. PMID- 30460239 TI - Complex Left Atrial Appendage Morphology Is an Independent Risk Factor for Cryptogenic Ischemic Stroke. AB - Importance: Ischemic strokes pose a significant health burden. However, the etiology of between 20 and 40% of these events remains unknown. Left atrial appendage morphology may influence the occurrence of thromboembolic events. Design: A retrospective cross-sectional study was conducted to investigate the role of LAA morphology in patients with atrial fibrillation (AF) and cardioembolic-associated stroke and patients with cryptogenic stroke without atrial fibrillation. LAA morphology is classified into two groups: (1) simple (chicken-wing) vs. (2) complex (non-chicken wing) based on transesophageal echocardiography (TEE) findings. In addition to the LAA morphology, left atrial parameters, including orifice diameter, depth, emptying velocity, and filling velocity, were collected for both groups. Mathematical, computational models were constructed to investigate flow velocities in chicken-wing and non-chicken wing morphological patterns to assess LAA function further. Findings: TEE values for volume, size, emptying, and filling velocities were similar between simple and complex LAA morphology groups. Patients with cryptogenic stroke without coexisting AF were noted to have significantly higher rates of complex LAA morphology. Chicken-wing LAA morphology was associated with four-fold higher flow rate (kg/s) in computational simulations. Conclusions: Complex LAA morphology may be an independent contributing factor for cryptogenic strokes. Further studies are warranted to investigate the mechanism involved in LAA morphology and thromboembolic events. PMID- 30460240 TI - Echocardiography Differentiates Lethally Irradiated Whole-Body From Partial-Body Exposed Rats. AB - Background: Acute radiation syndrome (ARS) affects morbidity and mortality dependent on the amount of body exposed. We propose the use of echocardiography (EC) to differentiate between survivors and non-survivors by measuring changes in cardiac function (CF) and pulmonary arterial function (PAF). We also investigate the role of rheology in our observed changes. Methods and Results: Rats were irradiated to the whole body (WB) or partial body with two-legs shielded (2LS) at a lethal dose of 7.5Gy. EC and magnetic resonance imaging were performed, and rheological measurements conducted. Only 2LS survived past 12-days post-exposure and their CF and PAR were not significantly different from baseline. WB was significantly different from both baseline and 2LS in stroke volume (P < 0.05), velocity time integral (VTI; P < 0.05) and pulmonary artery acceleration time (PAAT; P < 0.05). Differences were identified as early as six-days post-exposure, where VTI and PAAT were significantly (P < 0.05) decreased in WB versus baseline but only PAAT was different from 2LS. Blood viscosity was significantly lower in the WB versus baseline and 2LS (P < 0.0001). WB exhibited a significant rise in dense red blood cells versus baseline (P < 0.01) and 2LS (P < 0.01). Cell-free hemoglobin, a contributor to pulmonary artery hypertension and vasculopathy, was significantly elevated in WB vs. sham. Conclusions: Non-invasive and readily available imaging can be used to identify critically affected victims. Our findings point to heart failure as one possible cause of death in WB exposed animals, potentially exacerbated by rheological, hemolytic, and pulmonary factors, and the importance of developing radiomitigators against cardiac ARS mortality. PMID- 30460241 TI - Tyrosine Kinase Inhibitor Pazopanib Inhibits Platelet Procoagulant Activity in Renal Cell Carcinoma Patients. AB - Pazopanib is an angiostatic tyrosine kinase inhibitor (TKI) presently used for cancer treatment, particularly in patients with renal cell carcinoma (RCC). This treatment can be accompanied by mild bleeding as an adverse effect. Given the role of protein tyrosine kinases in platelet activation processes, we investigated whether and how pazopanib can affect platelet functions in purified systems and during treatment of advanced RCC patients. In isolated platelets from healthy volunteers, pazopanib dose-dependently reduced collagen-induced integrin activation and secretion, as well as platelet aggregation. Pazopanib addition diminished glycoprotein (GP) VI-dependent tyrosine phosphorylation of multiple platelet proteins, including the tyrosine kinase Syk. Furthermore, pazopanib inhibited GPVI-induced Ca2+ elevation, resulting in reduced exposure of the procoagulant phospholipid phosphatidylserine (PS). Upon perfusion of control blood over a collagen surface, pazopanib inhibited thrombus size as well as PS exposure. Blood samples from 10 RCC patients were also analyzed before and after 14 days of pazopanib treatment as monotherapy. This treatment caused an overall lowering in platelet count, with 3 out of 10 patients experiencing mild bleeding. Platelets isolated from pazopanib-treated patients showed a significant lowering of PS exposure upon activation. In addition, platelet procoagulant activity was inhibited in thrombi formed under flow conditions. Control experiments indicated that higher pazopanib concentrations were required to inhibit GPVI-mediated PS exposure in the presence of plasma. Together, these results indicated that pazopanib suppresses GPVI-induced platelet activation responses in a way partly antagonized by the presence of plasma. In treated cancer patients, pazopanib effects were confined to a reduction in GPVI-dependent PS exposure. Together with the reduced platelet count, this may explain the mild bleeding tendency observed in pazopanib-treated patients. PMID- 30460242 TI - Activation of Toll-Like Receptor 9 Impairs Blood Flow Recovery After Hind-Limb Ischemia. AB - Background: Peripheral artery disease causes significant functional disability and results in impaired quality of life. Ischemic tissue injury releases various endogenous ligands for Toll-like receptors (TLRs), suggesting the involvement of TLRs in blood flow recovery. However, the role of TLR9, which was originally known as a sensor for bacterial DNA, remains unknown. This study investigated the role of TLR9 in blood flow recovery in the ischemic limb using a mouse hind-limb ischemia model. Methods and Results: Unilateral femoral artery ligation was performed in TLR9-deficient (Tlr9 -/-) mice and wild-type mice. In wild-type mice, femoral artery ligation significantly increased mRNA expression of TLR9 in the ischemic limb (P < 0.001) and plasma levels of cell-free DNA (cfDNA) as determined by single-stranded DNA (ssDNA) (P < 0.05) and double-stranded DNA (dsDNA) (P < 0.01), which are endogenous ligands for TLR9, compared with the sham operated group. Laser Doppler perfusion imaging demonstrated significantly improved ratio of blood flow in the ischemic to non-ischemic limb in Tlr9 -/- mice compared with wild-type mice at 2 weeks after ligation (P < 0.05). Tlr9 -/- mice showed increased capillary density and reduced macrophage infiltration in ischemic limb. Genetic deletion of TLR9 reduced the expression of TNF-alpha, and attenuated NF-kappaB activation in ischemic muscle compared with wild-type mice (P < 0.05, respectively) at 3 days after the surgery. ODN1826, a synthetic agonistic oligonucleotide for TLR9, or plasma obtained from mice with ischemic muscle promoted the expression of TNF-alpha in wild-type macrophages (P < 0.05), but not in Tlr9 -/- macrophages. ODN1826 also activated NF-kappaB signaling as determined by the degradation of IkappaBalpha in wild-type macrophages (P < 0.05), but not in Tlr9 -/- macrophages. In vitro experiments using human umbilical vein endothelial cells demonstrated that TNF-alpha, or conditioned medium obtained from wild-type macrophages treated with ODN1826 accelerated cell death as determined by MTS assay (P < 0.05 and P < 0.01, respectively). Conclusion: Our results suggest that ischemic muscle releases cfDNA, which activates TLR9 and enhances inflammation, leading to impairment of blood flow recovery in the ischemic limb. cfDNA-TLR9 signaling may serve as a potential therapeutic target in ischemic limb disease. PMID- 30460243 TI - Long Noncoding RNA ANRIL: Lnc-ing Genetic Variation at the Chromosome 9p21 Locus to Molecular Mechanisms of Atherosclerosis. AB - Ever since the first genome-wide association studies (GWAS) on coronary artery disease (CAD), the Chr9p21 risk locus has emerged as a top signal in GWAS of atherosclerotic cardiovascular disease, including stroke and peripheral artery disease. The CAD risk SNPs on Chr9p21 lie within a stretch of 58 kilobases of non protein-coding DNA, containing the gene body of the long noncoding RNA (lncRNA) antisense non coding RNA in the INK4 locus (ANRIL). How risk is affected by the Chr9p21 locus in molecular detail is a matter of ongoing research. Here we will review recent advances in the understanding that ANRIL serves as a key risk effector molecule of atherogenesis at the locus. One focus of this review is the shift in understanding that genetic variation at Chr9p21 not only affects the abundance of ANRIL, and in some cases expression of the adjacent CDKN2A/B tumor suppressors, but also impacts ANRIL splicing, such that 3'-5'-linked circular noncoding ANRIL RNA species are produced. We describe how the balance of linear and circular ANRIL RNA, determined by the Chr9p21 genotype, regulates molecular pathways and cellular functions involved in atherogenesis. We end with an outlook on how manipulating circular ANRIL abundance may be exploited for therapeutic purposes. PMID- 30460244 TI - Exploring Coronary Artery Disease GWAs Targets With Functional Links to Immunometabolism. AB - Finding genetic variants that cause functional disruption or regulatory change among the many implicated GWAs variants remains a key challenge to translating the findings from GWAs to therapeutic treatments. Defining the causal mechanisms behind the variants require functional screening experiments that can be complex and costly. Prioritizing variants for functional characterization using techniques that capture important functional and regulatory elements can assist this. The genetic architecture of complex traits such as cardiovascular disease and type II diabetes comprise an enormously large number of variants of small effect contributing to heritability and spread throughout the genome. This makes it difficult to distinguish which variants or core genes are most relevant for prioritization and how they contribute to the regulatory networks that become dysregulated leading to disease. Despite these challenges, recent GWAs for CAD prioritized genes associated with lipid metabolism, coagulation and adhesion along with novel signals related to innate immunity, adipose tissue and, vascular function as important core drivers of risk. We focus on three examples of novel signals associated with CAD which affect risk through missense or UTR mutations indicating their potential for therapeutic modification. These variants play roles in adipose tissue function vascular function and innate immunity which form the cornerstones of immuno-metabolism. In addition we have explored the putative, but potentially important interactions between the environment, specifically food and nutrition, with respect to key processes. PMID- 30460246 TI - Electrophysiological Basis for Early Repolarization Syndrome. AB - During last centuries, Early Repolarization pattern has been interpreted as an ECG manifestation not linked to serious cardiovascular events. This view has been challenged on the basis of sporadic clinical observations that linked the J-wave with ventricular arrhythmias and sudden cardiac death. The particular role of this characteristic pattern in initiating ventricular fibrillation has been sustained by clinical descriptions of a marked and consistent J-wave elevation preceding the onset of the ventricular arrhythmia. Until now, Early Repolarization syndrome patients have been evaluated using ECG and theorizing different interpretations of the findings. Nonetheless, ECG analysis is not able to reveal all depolarization and repolarization properties and the explanation for this clinical events. Recent studies have characterized the epicardial substrate in these patients on the basis of high-resolution data, in an effort to provide insights into the substrate properties that support arrhythmogenicity in these patients. An overview for the current evidence supporting different theories explaining Early Repolarization Syndrome is provided in this review. Finally, future developments in the field directed toward individualized treatment strategies are examined. PMID- 30460245 TI - Cell Sources for Tissue Engineering Strategies to Treat Calcific Valve Disease. AB - Cardiovascular calcification is an independent risk factor and an established predictor of adverse cardiovascular events. Despite concomitant factors leading to atherosclerosis and heart valve disease (VHD), the latter has been identified as an independent pathological entity. Calcific aortic valve stenosis is the most common form of VDH resulting of either congenital malformations or senile "degeneration." About 2% of the population over 65 years is affected by aortic valve stenosis which represents a major cause of morbidity and mortality in the elderly. A multifactorial, complex and active heterotopic bone-like formation process, including extracellular matrix remodeling, osteogenesis and angiogenesis, drives heart valve "degeneration" and calcification, finally causing left ventricle outflow obstruction. Surgical heart valve replacement is the current therapeutic option for those patients diagnosed with severe VHD representing more than 20% of all cardiac surgeries nowadays. Tissue Engineering of Heart Valves (TEHV) is emerging as a valuable alternative for definitive treatment of VHD and promises to overcome either the chronic oral anticoagulation or the time-dependent deterioration and reintervention of current mechanical or biological prosthesis, respectively. Among the plethora of approaches and stablished techniques for TEHV, utilization of different cell sources may confer of additional properties, desirable and not, which need to be considered before moving from the bench to the bedside. This review aims to provide a critical appraisal of current knowledge about calcific VHD and to discuss the pros and cons of the main cell sources tested in studies addressing in vitro TEHV. PMID- 30460249 TI - Respiratory mechanics in mechanically ventilated patients: from physiology to clinical practice at the bedside. PMID- 30460248 TI - Modeling as a Decision Support Tool for Bovine TB Control Programs in Wildlife. AB - Computer modeling has a long history of association with epidemiology, and has improved our understanding of the theory of disease dynamics and provided insights into wildlife disease management. A summary of badger bovine TB models and their role in decision making is presented, from a simple initial SEI model, to SEIR (inclusion of a recovered category) and SEI1I2 (inclusion of two stages of disease progression) variants, and subsequent spatially-explicit individual based models used to assess historical badger management strategies. The integration of cattle into TB models allowed comparison of the predicted impacts of different badger management strategies on cattle herd breakdown rates, and provided an economic dimension to the outputs. Estimates of R0 for bovine TB in cattle and badgers are little higher than unity implying that the disease should be relatively easy to control, which is at odds with practical experience. A cohort of recent models have suggested that combined strategies, involving management of both host species and including vaccination may be most effective. Future models of badger vaccination will need to accommodate the partial protection from infection and likely duration of immunity conferred by the currently available vaccine (BCG). Descriptions of how models could better represent the ecological and epidemiological complexities of the badger-cattle TB system are presented, along with a wider discussion of the utility of modeling for bovine TB management interventions. This includes consideration of the information required to maximize the utility of the next generation of models. PMID- 30460250 TI - The basics of respiratory mechanics: ventilator-derived parameters. AB - Mechanical ventilation is a life-support system used to maintain adequate lung function in patients who are critically ill or undergoing general anesthesia. The benefits and harms of mechanical ventilation depend not only on the operator's setting of the machine (input), but also on their interpretation of ventilator derived parameters (outputs), which should guide ventilator strategies. Once the inputs-tidal volume (VT), positive end-expiratory pressure (PEEP), respiratory rate (RR), and inspiratory airflow (V')-have been adjusted, the following outputs should be measured: intrinsic PEEP, peak (Ppeak) and plateau (Pplat) pressures, driving pressure (DeltaP), transpulmonary pressure (PL), mechanical energy, mechanical power, and intensity. During assisted mechanical ventilation, in addition to these parameters, the pressure generated 100 ms after onset of inspiratory effort (P0.1) and the pressure-time product per minute (PTP/min) should also be evaluated. The aforementioned parameters should be seen as a set of outputs, all of which need to be strictly monitored at bedside in order to develop a personalized, case-by-case approach to mechanical ventilation. Additionally, more clinical research to evaluate the safe thresholds of each parameter in injured and uninjured lungs is required. PMID- 30460251 TI - Technical aspects of bedside respiratory monitoring of transpulmonary pressure. AB - Transpulmonary pressure, that is the difference between airway pressure (Paw) and pleural pressure, is considered one of the most important parameters to know in order to set a safe mechanical ventilation in acute respiratory distress syndrome (ARDS) patients but also in critically ill obese patients, in abdominal pathologies or in pathologies affecting the chest wall itself. Transpulmonary pressure should rely on the assessment of intrathoracic pleural pressure. Esophageal pressure (Pes) is considered the best surrogate of pleural pressure in critically ill patients, but concerns about its reliability exist. The aim of this article is to describe the technique of Pes measurement in mechanically ventilated patients: the catheter insertion, the proper balloon placement and filling, the validation test and specific procedures to remove the main artifacts will be discussed. PMID- 30460247 TI - The Genetic Regulation of Aortic Valve Development and Calcific Disease. AB - Heart valves are dynamic, highly organized structures required for unidirectional blood flow through the heart. Over an average lifetime, the valve leaflets or cusps open and close over a billion times, however in over 5 million Americans, leaflet function fails due to biomechanical insufficiency in response to wear-and tear or pathological stimulus. Calcific aortic valve disease (CAVD) is the most common valve pathology and leads to stiffening of the cusp and narrowing of the aortic orifice leading to stenosis and insufficiency. At the cellular level, CAVD is characterized by valve endothelial cell dysfunction and osteoblast-like differentiation of valve interstitial cells. These processes are associated with dysregulation of several molecular pathways important for valve development including Notch, Sox9, Tgfbeta, Bmp, Wnt, as well as additional epigenetic regulators. In this review, we discuss the multifactorial mechanisms that contribute to CAVD pathogenesis and the potential of targeting these for the development of novel, alternative therapeutics beyond surgical intervention. PMID- 30460252 TI - Ventilator-induced lung injury and lung mechanics. AB - Mechanical ventilation applies physical stresses to the tissues of the lung and thus may give rise to ventilator-induced lung injury (VILI), particular in patients with acute respiratory distress syndrome (ARDS). The most dire consequences of VILI result from injury to the blood-gas barrier. This allows plasma-derived fluid and proteins to leak into the airspaces where they flood some alveolar regions, while interfering with the functioning of pulmonary surfactant in those regions that remain open. These effects are reflected in commensurately increased values of dynamic lung elastance (EL ), a quantity that in principle is readily measured at the bedside. Recent mathematical/computational modeling studies have shown that the way in which EL varies as a function of both time and positive end-expiratory pressure (PEEP) reflects the nature and degree of lung injury, and can even be used to infer the separate contributions of volutrauma and atelectrauma to VILI. Interrogating such models for minimally injurious regimens of mechanical ventilation that apply to a particular lung may thus lead to personalized approaches to the ventilatory management of ARDS. PMID- 30460253 TI - Respiratory mechanics during general anaesthesia. AB - Intraoperative mechanical ventilation is mandatory during many surgical procedures. Knowledge in this field has been widely derived from the experience in the treatment of patients with acute respiratory distress syndrome in the intensive care unit. However, also in surgical patients without lung injury, mechanical ventilation settings affect the clinical outcome, and in particular the occurrence of postoperative pulmonary complications (PPCs). A deep understanding of respiratory physiology is mandatory for the clinician, in order to tailor ventilation settings based on the specific characteristics of each patient. In this paper we will discuss the basis of lung physiology applied to the mechanical ventilation in the operating room. The role of compliance, tidal volume, positive end-expiratory pressure (PEEP), plateau pressure, driving pressure, stress index, mechanical power and other ventilator-derived parameters will be discussed. The above-mentioned physiological parameters are easy to measure and can guide the clinician to assess and titrate mechanical ventilation parameters, but the clinical impact of guiding mechanical ventilation based on these parameters has yet to be determined. PMID- 30460254 TI - Mechanical ventilation management during cardiothoracic surgery: an open challenge. AB - Mechanical ventilation during surgery is a highly complex procedure, particularly in cardiothoracic surgery, where patients need to undergo substantial hemodynamic management, involving large fluid exchanges and pharmacological manipulation of vascular resistance, as well as direct manipulation of the lungs themselves. Cardiothoracic surgery is burdened by a high rate of postoperative pulmonary complication (PPC), comorbidity, and mortality. Recent trials have examined various techniques to preserve lung function, although consensus on best practice has yet to be reached. This might be due to the close relationship between the circulatory and pulmonary systems. The use of a technique designed to prevent pulmonary complication might negatively impact the hemodynamics of an already critical patient. Stress-induced lung injury can occur during surgery for various reasons, some of which have yet to be fully investigated. In cardiac surgery, this damage is mainly ascribed to two events: cardiopulmonary bypass (CPB) and sternotomy. In thoracic surgery, on the other hand, overdistention and permissive hyperoxia, both routinely used on one lung to compensate for the collapse of the other, are generally to blame for lung injury. In recent years "protective" ventilation strategies have been proposed to spare lung parenchyma from stress induced damage. Despite the growing interest in protective ventilation techniques, there are still no clear international guidelines for mechanical ventilation in cardiothoracic surgery. However, some recent progress has been made, with positive clinical outcomes. PMID- 30460255 TI - Management and weaning from mechanical ventilation in neurologic patients. AB - In the early phase following severe brain injury (BI), mechanical ventilation (MV) is often needed to prevent airway from aspiration, control PaCO2 and PaO2 and avoid secondary brain insults. Although patients with BI are frequently hospitalized in the intensive care unit (ICU) without respiratory problems, they display longer durations of MV and a challenging weaning process compared to other ICU populations. Historically, the MV settings of BI patients associated high tidal volume with low or no positive end-expiratory pressure (PEEP), for neurological reasons. The extensive data about the beneficial effects of protective ventilation in patients without acute respiratory distress syndrome, have questioned the consequences of such management in BI patients. Recent studies suggest that protective ventilation is safe and could even bear significant impact on morbidity in these patients. The MV weaning process is also challenging, since these patients display a high rate of extubation failure. Recently, new clinical scales of successful extubation have been highlighted combining airway and neurologic operators. A minimal level of arousal should be achieved before extubation, but the Glasgow Coma Score has been inconsistently associated with successful extubation, probably owing to the challenging quantification in intubated patients. Early tracheostomy seems to bear positive effects on morbidity in BI patients. Nonetheless the level of evidence remains poor and no strong recommendations can be made on this topic. Overall, the respiratory bundle of care in BI patients could be readapted with the new data available in the literature. Even if they bear positive impact on morbidity in ICU, their consequences on neurological recovery have yet to be adequately assessed. PMID- 30460256 TI - Respiratory mechanics in patients with acute respiratory distress syndrome. AB - Despite the recognition of its iatrogenic potential, mechanical ventilation remains the mainstay of respiratory support for patients with acute respiratory distress syndrome (ARDS). The low volume ventilation has been recognized as the only method to reduce mortality of ARDS patients and plateau pressure as the lighthouse for delivering safe ventilation. Recent investigations suggest that a ventilation based on lung mechanics (tidal ventilation tailored to the available lung volume able to receive it, i.e., driving pressure) is a successful approach to improve outcome. However, currently available bedside mechanical variables do not consider regional mechanical properties of ARDS affected lungs, which include the role of local stress risers at the boundaries of areas with different aeration. A unifying approach considers lung-related causes and ventilation related causes of lung injury. These last may be incorporated in the mechanical power (i.e., amount of mechanical energy transferred per unit of time). Ventilation-induced lung injury (which includes the self-inflicted lung injury of a spontaneously breathing patient) can therefore be prevented by the adoption of measures promoting an increase of ventilable lung and its homogeneity and by delivering lower levels of mechanical power. Prone position promotes lung homogeneity without increasing the delivered mechanical power. This review describes the recent developments on respiratory mechanics in ARDS patients, providing both bedside and research insights from the most updated evidence. PMID- 30460257 TI - Interpretation of the transpulmonary pressure in the critically ill patient. AB - Mechanical ventilation is a life-saving procedure, which takes over the function of the respiratory muscles while buying time for healing to take place. However, it can also promote or worsen lung injury, so that careful monitoring of respiratory mechanics is suggested to titrate the level of support and avoid injurious pressures and volumes to develop. Standard monitoring includes flow, volume and airway pressure (Paw). However, Paw represents the pressure acting on the respiratory system as a whole, and does not allow to differentiate the part of pressure that is spent di distend the chest wall. Moreover, if spontaneous breathing efforts are allowed, the Paw is the sum of that applied by the ventilator and that generated by the patient. As a consequence, monitoring of Paw has significant shortcomings. Assessment of esophageal pressure (Pes), as a surrogate for pleural pressure (Ppl), may allow the clinicians to discriminate between the elastic behaviour of the lung and the chest wall, and to calculate the degree of spontaneous respiratory effort. In the present review, the characteristics and limitations of airway and transpulmonary pressure monitoring will be presented; we will highlight the different assumptions underlying the various methods for measuring transpulmonary pressure (i.e., the elastance derived and the release-derived method, and the direct measurement), as well as the potential application of transpulmonary pressure assessment during both controlled and spontaneous/assisted mechanical ventilation in critically ill patients. PMID- 30460258 TI - Effects of patient positioning on respiratory mechanics in mechanically ventilated ICU patients. AB - Changes in the body position of patients receiving mechanical ventilation in intensive care unit are frequent. Contrary to healthy humans, little data has explored the physiological impact of position on respiratory mechanics. The objective of present paper is to review the available data on the effect of changing body position on respiratory mechanics in ICU patients receiving mechanical ventilation. Supine position (lying flat) or lateral position do not seem beneficial for critically ill patients in terms of respiratory mechanics. The sitting position (with thorax angulation >30 degrees from the horizontal plane) is associated with improvement of functional residual capacity (FRC), oxygenation and reduction of work of breathing. There is a critical angle of inclination in the seated position above which the increase in abdominal pressure contributes to increase chest wall elastance and offset the increase in FRC. The impact of prone position on respiratory mechanics is complex, but the increase in chest wall elastance is a central mechanism. To sum up, both sitting and prone positions provides beneficial impact on respiratory mechanics of mechanically ventilated patients as compared to supine position. PMID- 30460259 TI - Regional distribution of transpulmonary pressure. AB - The pressure across the lung, so-called transpulmonary pressure (PL), represents the main force acting toward to provide lung movement. During mechanical ventilation, PL is provided by respiratory system pressurization, using specific ventilator setting settled by the operator, such as: tidal volume (VT), positive end-expiratory pressure (PEEP), respiratory rate (RR), and inspiratory airway flow. Once PL is developed throughout the lungs, its distribution is heterogeneous, being explained by the elastic properties of the lungs and pleural pressure gradient. There are different methods of PL calculation, each one with importance and some limitations. Among the most known, it can be quoted: (I) direct measurement of PL; (II) elastance derived method at end-inspiration of PL; (III) transpulmonary driving pressure. Recent studies using pleural sensors in large animal models as also in human cadaver have added new and important information about PL heterogeneous distribution across the lungs. Due to this heterogeneous distribution, lung damage could happen in specific areas of the lung. In addition, it is widely accepted that high PL can cause lung damage, however the way it is delivered, whether it's compressible or tensile, may also further damage despite the values of PL achieved. According to heterogeneous distribution of PL across the lungs, the interstitium and lymphatic vessels may also interplay to disseminate lung inflammation toward peripheral organs through thoracic lymph tracts. Thus, it is conceivable that juxta-diaphragmatic area associated strong efforts leading to high values of PL may be a source of dissemination of inflammatory cells, large molecules, and plasma contents able to perpetuate inflammation in distal organs. PMID- 30460260 TI - Mechanical ventilation and respiratory monitoring during extracorporeal membrane oxygenation for respiratory support. AB - Over the past decade, the use of veno-venous extracorporeal membrane oxygenation (VV-ECMO) for respiratory support has widely expanded as a treatment strategy for patients with acute respiratory distress syndrome (ARDS). Despite considerable attention has been given to the indications, the timing and the management of patients undergoing ECMO for refractory respiratory hypoxemic failure, little is known regarding the management of mechanical ventilation (MV) in this group of patients. ECMO enables to minimize ventilatory induced lung injury (VILI) and it has been successfully used as rescue therapy in patients with ARDS when conventional ventilator strategies have failed. However, literature is lacking regarding the best strategies and MV settings, including positive end expiratory pressure (PEEP), tidal volume (VT), respiratory rate (RR) and plateau pressure (PPLAT). The aim of this review is to summarize current evidence, the rationale and provide recommendations about the best ventilator strategy to adopt in patients with ARDS undergoing VV-ECMO support. PMID- 30460262 TI - Dead space in acute respiratory distress syndrome. AB - Dead space is the portion of each tidal volume that does not take part in gas exchange and represents a good global index of the efficiency of the lung function. Dead space is not routinely measured in critical care practice, because the difficulties in in interpreting capnograms and the different methods of calculations. Different dead space indices can provide useful information in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) patients, where changes in microvasculature are the main determinants for the increase in dead space and consequently a worsening of the outcome. Lung recruitment is a dynamic process that combines recruitment manoeuvres (RMs) with positive end expiratory pressure (PEEP) and low Vt to recruit collapsed alveoli. Dead space guided recruitment allows avoiding regional overdistension or reduction in cardiac output in critical care patients with ALI or ARDS. Different patterns of ventilation affect also CO2 elimination; in fact, end-inspiratory pause prolongation reduces dead space, increasing respiratory system compliance; plateau pressure and consequently driving pressure increase accordingly. Dead space measurement is a reliable method that provides important clinical and prognostic information. Different capnographic indices can be useful to evaluate therapeutic interventions or setting mechanical ventilation. PMID- 30460261 TI - Assessing breathing effort in mechanical ventilation: physiology and clinical implications. AB - Recent studies have shown both beneficial and detrimental effects of patient breathing effort in mechanical ventilation. Quantification of breathing effort may allow the clinician to titrate ventilator support to physiological levels of respiratory muscle activity. In this review we will describe the physiological background and methodological issues of the most frequently used methods to quantify breathing effort, including esophageal pressure measurement, the work of breathing, the pressure-time-product, electromyography and ultrasound. We will also discuss the level of breathing effort that may be considered optimal during mechanical ventilation at different stages of critical illness. PMID- 30460263 TI - Should we titrate ventilation based on driving pressure? Maybe not in the way we would expect. AB - Mechanical ventilation maintains adequate gas exchange in patients during general anaesthesia, as well as in critically ill patients without and with acute respiratory distress syndrome (ARDS). Optimization of mechanical ventilation is important to minimize ventilator induced lung injury and improve outcome. Tidal volume (VT), positive end-expiratory pressure (PEEP), respiratory rate (RR), plateau pressures as well as inspiratory oxygen are the main parameters to set mechanical ventilation. Recently, the driving pressure (?P), i.e., the difference of the plateau pressure and end-expiratory pressure of the respiratory system or of the lung, has been proposed as a key role parameter to optimize mechanical ventilation parameters. The ?P depends on the VT as well as on the relative balance between the amount of aerated and/or overinflated lung at end-expiration and end-inspiration at different levels of PEEP. During surgery, higher ?P, mainly due to VT, was progressively associated with an increased risk to develop post-operative pulmonary complications; in two large randomized controlled trials the reduction in ?P by PEEP did not result in better outcome. In non-ARDS patients, ?P was not found even associated with morbidity and mortality. In ARDS patients, an association between ?P (higher than 13-15 cmH2O) and mortality has been reported. In several randomized controlled trials, when ?P was minimized by the use of higher PEEP with or without recruitment manoeuvres, this strategy resulted in equal or even higher mortality. No clear data are currently available about the interpretation and clinical use of ?P during assisted ventilation. In conclusion, ?P is an indicator of severity of the lung disease, is related to VT size and associated with complications and mortality. We advocate the use of ?P to optimize individually VT but not PEEP in mechanically ventilated patients with and without ARDS. PMID- 30460264 TI - Should we titrate peep based on end-expiratory transpulmonary pressure?-yes. AB - Ventilator management of patients with acute respiratory distress syndrome (ARDS) has been characterized by implementation of basic physiology principles by minimizing harmful distending pressures and preventing lung derecruitment. Such strategies have led to significant improvements in outcomes. Positive end expiratory pressure (PEEP) is an important part of a lung protective strategy but there is no standardized method to set PEEP level. With widely varying types of lung injury, body habitus and pulmonary mechanics, the use of esophageal manometry has become important for personalization and optimization of mechanical ventilation in patients with ARDS. Esophageal manometry estimates pleural pressures, and can be used to differentiate the chest wall and lung (transpulmonary) contributions to the total respiratory system mechanics. Elevated pleural pressures may result in negative transpulmonary pressures at end expiration, leading to lung collapse. Measuring the esophageal pressures and adjusting PEEP to make transpulmonary pressures positive can decrease atelectasis, derecruitment of lung, and cyclical opening and closing of airways and alveoli, thus optimizing lung mechanics and oxygenation. Although there is some spatial and positional artifact, esophageal pressures in numerous animal and human studies in healthy, obese and critically ill patients appear to be a good estimate for the "effective" pleural pressure. Multiple studies have illustrated the benefit of using esophageal pressures to titrate PEEP in patients with obesity and with ARDS. Esophageal pressure monitoring provides a window into the unique physiology of a patient and helps improve clinical decision making at the bedside. PMID- 30460265 TI - Should we titrate positive end-expiratory pressure based on an end-expiratory transpulmonary pressure? AB - Arguments continue to swirl regarding the need for and best method of positive end-expiratory pressure (PEEP) titration. An appropriately conducted decremental method that uses modest peak pressures for the recruiting maneuver (RM), a lung protective tidal excursion, relatively small PEEP increments and appropriate timing intervals is currently the most logical and attractive option, particularly when the esophageal balloon pressure (Pes) is used to calculate transpulmonary driving pressures relevant to the lung. The setting of PEEP by the Pes-guided end-expiratory pressure at the 'polarity transition' point of the transmural end-expiratory pressure is quite relevant to the locale of the esophageal balloon catheter. Its desirability, however, is limited by its tendency to encourage PEEP levels that are higher than most other PEEP titration methods. These Pes-set PEEP values promote higher mean airway pressures and are likely to be unnecessary when small tidal driving pressures are in use. Because high airway pressures increase global lung stress and risk hemodynamic compromise, the Pes-determined PEEP would seem associated with a relatively high hazard to benefit ratio for many patients. PMID- 30460266 TI - Can we estimate transpulmonary pressure without an esophageal balloon?-yes. AB - A protective ventilation strategy is based on separation of lung and chest wall mechanics and determination of transpulmonary pressure. So far, this has required esophageal pressure measurement, which is cumbersome, rarely used clinically and associated with lack of consensus on the interpretation of measurements. We have developed an alternative method based on a positive end expiratory pressure (PEEP) step procedure where the PEEP-induced change in end-expiratory lung volume is determined by the ventilator pneumotachograph. In pigs, lung healthy patients and acute lung injury (ALI) patients, it has been verified that the determinants of the change in end-expiratory lung volume following a PEEP change are the size of the PEEP step and the elastic properties of the lung, ?PEEP * Clung. As a consequence, lung compliance can be calculated as the change in end-expiratory lung volume divided by the change in PEEP and esophageal pressure measurements are not needed. When lung compliance is determined in this way, transpulmonary driving pressure can be calculated on a breath-by-breath basis. As the end expiratory transpulmonary pressure increases as much as PEEP is increased, it is also possible to determine the end-inspiratory transpulmonary pressure at any PEEP level. Thus, the most crucial factors of ventilator induced lung injury can be determined by a simple PEEP step procedure. The measurement procedure can be repeated with short intervals, which makes it possible to follow the course of the lung disease closely. By the PEEP step procedure we may also obtain information (decision support) on the mechanical consequences of changes in PEEP and tidal volume performed to improve oxygenation and/or carbon dioxide removal. PMID- 30460267 TI - Should we titrate mechanical ventilation based on driving pressure?-yes. AB - Recent reports revealed that lower respiratory driving pressure is associated with better ARDS patients survival during invasive mechanical ventilation and less pulmonary complications in surgical patients and at risk ICU patients without ARDS, makes the best understanding of this subject primordial for the future application of mechanical ventilatory support. PMID- 30460268 TI - Is mechanical power the final word on ventilator-induced lung injury?-no. AB - Despite being a promising idea that combines several variables related to ventilator-induced lung injury (VILI), the concept of mechanical power (MP) carries a number of limitations, leaves several open questions, lacks proper modelling of positive end-expiratory pressure (PEEP) effects and, more importantly, does not respect the amount of lung tissue subjected to MP. First, the assessment of MP as a measure for development of VILI would have the highest relevance when volume displacement and related pressure changes are measured directly within the lung. Thus, ideally the relationship between MP delivered to the total respiratory system, and that delivered to lung tissue is discerned. Second, MP as defined today relates to the inspiratory phase only, and it is very possible that the expiratory phase will also play a role. Third, the calculation of MP during spontaneous breathing is challenging as airway pressure, flow and esophageal pressure are affected counter-directionally and simultaneously overlapping by the action of the ventilator and the respiratory muscles. Fourth, in its current form, MP is modelled with a positive linear relationship with PEEP, which is based on incorrect mathematical modelling to integrate the role of PEEP into MP. Fifth, the present equation used to calculate MP is qualitatively in disagreement with clinical data on VILI. The reduction of MP to its elastic part, might not only result in a higher association with VILI, but also amplifies an indirect U-shaped relationship with PEEP. PMID- 30460269 TI - Is the mechanical power the final word on ventilator-induced lung injury?-we are not sure. PMID- 30460271 TI - Phytochemically Functionalized Cu and Ag Nanoparticles Embedded in MWCNTs for Enhanced Antimicrobial and Anticancer Properties. AB - Nanomedicine is an emerging field concerned with the use of precision engineered nanomaterials, which leads to the development of novel remedial and diagnostic modalities for human use. In this study, Cu(NO3)2 and AgNO3 precursors were reduced to copper nanoparticles (CuNPs) and silver nanoparticles (AgNPs) using Terminalia arjuna bark extracts under microwave irradiation in the presence of well-dispersed multi-walled carbon nanotubes (MWCNTs) in aqueous medium. The formation of CuNPs or AgNPs and their functionalization with MWCNTs via bioactive molecules of plant extract were evidenced from UV-Vis spectra, XRD, FTIR, FESEM, EDX, and TEM images. The phytochemically functionalized Cu-MWCNTs and Ag-MWCNTs nanomaterials showed enhanced biocide activity, and the inhibitory activity for bacteria was higher than that of fungus. Furthermore, these biohybrid nanomaterials are non-toxic to normal epithelial cells (Vero), whereas they are highly toxic for tested human cancer cells of MDA-MB-231, HeLa, SiHa, and Hep-G2. The cell viability was found to decrease with the increasing dose from 10 to 50 ug mL-1, as well as incubation time from 24 to 72 h. For instance, the cell viability was found to be ~91 % for normal Vero cells and ~76 % for cancer cells for lower dose of 10 ug mL-1. PMID- 30460270 TI - A Review on Graphene-Based Gas/Vapor Sensors with Unique Properties and Potential Applications. AB - Graphene-based gas/vapor sensors have attracted much attention in recent years due to their variety of structures, unique sensing performances, room-temperature working conditions, and tremendous application prospects, etc. Herein, we summarize recent advantages in graphene preparation, sensor construction, and sensing properties of various graphene-based gas/vapor sensors, such as NH3, NO2, H2, CO, SO2, H2S, as well as vapor of volatile organic compounds. The detection mechanisms pertaining to various gases are also discussed. In conclusion part, some existing problems which may hinder the sensor applications are presented. Several possible methods to solve these problems are proposed, for example, conceived solutions, hybrid nanostructures, multiple sensor arrays, and new recognition algorithm. PMID- 30460272 TI - Enhanced Electromagnetic Wave Absorption Properties of Poly(3,4 ethylenedioxythiophene) Nanofiber-Decorated Graphene Sheets by Non-covalent Interactions. AB - Graphene sheets (GNs) have high conductivity, but they exhibit weak electromagnetic (EM) wave absorption performance. Here, poly (3,4 ethylenedioxythiophene) (PEDOT) nanofibers were decorated on the surface of GNs in which the residual defects and groups act as the active sites and therefore are beneficial for the deposition of PEDOT nanofibers. The SEM images display that PEDOT nanofibers are successfully decorated on the surface of GNs through in situ polymerization. The diameter of the PEDOT nanofibers were ranged from 15 to 50 nm with hundreds of nanometers in length. The EM wave absorption properties of graphene, PEDOT, and GNs-PEDOT were also investigated. Compared to pure graphene and PEDOT, the EM wave absorption properties of GNs-PEDOT improved significantly. The maximum value of R L was up to -48.1 dB at 10.5 GHz with a thickness of only 2 mm. Meanwhile, the absorption bandwidth of R L values below -10 dB was 9.4 GHz (5.8-12.3, 12.9-15.8 GHz) in the thickness of 1.5-3 mm. The enhancement is attributed to the modification of PEDOT and the unique structure of nanofibers. On one hand, the deposition of PEDOT nanofibers on the surface of GNs decreases the conductivity of graphene, and makes impedance match better. On the other hand, the unique structure of PEDOT nanofibers results in relatively large specific surfaces areas, providing more active sites for reflection and scattering of EM waves. Therefore, our findings demonstrate that the deposition of conducting polymers on GNs by non-covalent bond is an efficient way to fabricate strong EM wave absorbers. PMID- 30460273 TI - A Facile Self-assembly Synthesis of Hexagonal ZnO Nanosheet Films and Their Photoelectrochemical Properties. AB - Here, large-scale and uniform hexagonal zinc oxide (ZnO) nanosheet films were deposited onto indium tin oxide (ITO)-coated transparent conducting glass substrates via a facile galvanic displacement deposition process. Compared with other commonly used solution methods, this process avoids high temperature and electric power as well as supporting agents to make it simple and cost-effective. The as-fabricated ZnO nanosheet films have uniform hexagonal wurtzite structure. The photoelectrochemical (PEC) cell based on ZnO nanosheet film/ITO photoelectrode was also fabricated and its performance was improved by optimizing the solution concentration. A higher photocurrent density of ~500 MUA cm-2 under AM 1.5 G simulated illumination of 100 mW cm-2 with zero bias potential (vs. Ag/AgCl electrode) was obtained, which may ascribe to the increased surface-to volume ratio of disordered ZnO nanosheet arrays. Our developed method may be used to deposit other oxide semiconductors, and the ZnO nanosheet film/ITO PEC cell can be used to design low-cost optoelectronic and photoelectrochemical devices. PMID- 30460274 TI - A Hybrid Electrode of Co3O4@PPy Core/Shell Nanosheet Arrays for High-Performance Supercapacitors. AB - Herein, combining solverthermal route and electrodeposition, we grew unique hybrid nanosheet arrays consisting of Co3O4 nanosheet as a core, PPy as a shell. Benefiting from the PPy as conducting polymer improving an electron transport rate as well as synergistic effects from such a core/shell structure, a hybrid electrode made of the Co3O4@PPy core/shell nanosheet arrays exhibits a large areal capacitance of 2.11 F cm-2 at the current density of 2 mA cm-2, a ~4-fold enhancement compared with the pristine Co3O4 electrode; furthermore, this hybrid electrode also displays good rate capability (~65 % retention of the initial capacitance from 2 to 20 mA cm-2) and superior cycling performance (~85.5 % capacitance retention after 5000 cycles). In addition, the equivalent series resistance value of the Co3O4@PPy hybrid electrode (0.238 Omega) is significantly lower than that of the pristine Co3O4 electrode (0.319 Omega). These results imply that the Co3O4@PPy hybrid composites have a potential for fabricating next generation energy storage and conversion devices. PMID- 30460275 TI - Pod-Like Supramicelles with Multicompartment Hydrophobic Cores Prepared by Self Assembly of Modified Chitosan. AB - In this paper, pod-like supramicelles with multicompartment hydrophobic cores were prepared by self-assembly of amphiphilic N-phthaloylchitosan-g-poly(N vinylcaprolactam) (PHCS-g-PNVCL) in aqueous medium. The employed biocompatible amphiphilic polymer was synthesized by grafting the carboxyl terminated poly(N vinylcaprolactam) (PNVCL-COOH) chains onto N-phthaloylchitosan (PHCS) backbone. 1H NMR and FTIR results confirmed the molecular structure of the copolymers. The morphology of the supramicelles assembled by PHCS-g-PNVCL was revealed by means of TEM and polarized light microscope. In solution, the supramicelles were very stable as monitored by DLS and zeta potential measurements. Temperature and pH presented significant influences on the size and size distribution of the supramicelles. These supramicelles with multicompartment hydrophobic cores should be ideal biomimetic systems with promising applications in drug delivery. PMID- 30460276 TI - Dual-Fuel-Driven Bactericidal Micromotor. AB - In this paper, we report fabrication of the bimetallic Janus microsphere, a magnesium microsphere with a silver surface coating, through thermal evaporation technique. Because of the Janus structure, this micromotor can be propelled in two different directions by the surface silver or magnesium 'engine' and hydrogen peroxide or water fuel. In addition, due to the bactericidal property of silver, this autonomous micromotor is capable of killing bacteria in solution. As compared to the static one, the micromotor is able to kill the bacteria at a much faster rate (about nine times of that of the static one), demonstrating the superiority of the motion one. We thus believe that the micromotor shown in the current study is potentially attractive for the environmental hygiene applications. PMID- 30460277 TI - A Facile and Template-Free One-Pot Synthesis of Mn3O4 Nanostructures as Electrochemical Supercapacitors. AB - In this paper, we report an effective, simple, and cost-effective strategy of electrochemical deposition to prepare hausmannite Mn3O4 thin films for the applications of supercapacitors. Various precursor concentrations and deposition durations were manipulated to tailor the surface morphologies of Mn3O4 nanostructures and to optimize their electrochemical performances. The Mn3O4 samples prepared at 0.05 M Mn(NO3)2 solution for 30 min delivered a large gravimetric specific capacitance of 210 F g-1 at a current density of 0.5 A g-1, and a good rate capability over other samples. This superior electrochemical performance may be attributed to the improved electrode conductivity with increased accessible area for electrolytes ions. Furthermore, a nanocomposite film based on Mn3O4/carbon foam was fabricated by utilizing the developed optimized conditions. The Mn3O4/carbon foam films exhibit an excellent specific capacitance with negligible degradation in retaining specific capacitance values up to 4000 cycles. These findings could further broaden the applications of hausmannite Mn3O4 in electrochemical energy storage electrodes. PMID- 30460278 TI - Facile Synthesis of Porous Zn-Sn-O Nanocubes and Their Electrochemical Performances. AB - Porous Zn-Sn-O nanocubes with a uniform size were synthesized through a facile aqueous solution route combined with subsequent thermal treatment. The chemical composition, morphology, and microstructure of Zn-Sn-O nanocubes, which have significant effects on the lithium storage performances, were easily tuned by adjusting the calcination temperature in preparation processes of ZnSn(OH)6 solid nanocubes. Further studies revealed that porous Zn-Sn-O nanocubes prepared at 600 degrees C exhibited a good rate capability and a high reversible capacity of 700 mAh g-1 at a current density of 200 mA g-1 after 50 cycles, which may be a great potential as anode materials in Lithium-ion batteries. PMID- 30460279 TI - AgCl/Ag/g-C3N4 Hybrid Composites: Preparation, Visible Light-Driven Photocatalytic Activity and Mechanism. AB - The ternary plasmonic AgCl/Ag/g-C3N4 photocatalysts were successfully fabricated by a modified deposition-precipitation method, through which Ag/AgCl nanoparticles (5-15 nm in size) were evenly dispersed on the surface of g-C3N4. The AgCl/Ag/g-C3N4 composites exhibited higher photocatalytic activity than Ag/AgCl and g-C3N4. The enhanced photocatalytic performance could be attributed to an efficient separation of electron-hole pairs through a Z-scheme mechanism, in which Ag nanoparticles acted as charge separation centers. PMID- 30460280 TI - Biomedical Perspective of Electrochemical Nanobiosensor. AB - Electrochemical biosensor holds great promise in the biomedical area due to its enhanced specificity, sensitivity, label-free nature and cost effectiveness for rapid point-of-care detection of diseases at bedside. In this review, we are focusing on the working principle of electrochemical biosensor and how it can be employed in detecting biomarkers of fatal diseases like cancer, AIDS, hepatitis and cardiovascular diseases. Recent advances in the development of implantable biosensors and exploration of nanomaterials in fabrication of electrodes with increasing the sensitivity of biosensor for quick and easy detection of biomolecules have been elucidated in detail. Electrochemical-based detection of heavy metal ions which cause harmful effect on human health has been discussed. Key challenges associated with the electrochemical sensor and its future perspectives are also addressed. PMID- 30460282 TI - A Bi-layer Composite Film Based on TiO2 Hollow Spheres, P25, and Multi-walled Carbon Nanotubes for Efficient Photoanode of Dye-sensitized Solar Cell. AB - Abstract: A bi-layer photoanode for dye-sensitized solar cell (DSSC) was fabricated, in which TiO2 hollow spheres (THSs) were designed as a scattering layer and P25/multi-walled carbon nanotubes (MWNTs) as an under-layer. The THSs were synthesized by a sacrifice template method and showed good light scattering ability as an over-layer of the photoanode. MWNTs were mixed with P25 to form an under-layer of the photoanode to improve the electron transmission ability of the photoanode. The power conversion efficiency of this kind of DSSC with bi-layer was enhanced to 5.13 %, which is 14.25 % higher than that of pure P25 DSSC. Graphical Abstract: A bi-layer composite photoanode based on P25/MWNTs-THSs with improved light scattering and electron transmission, which will provide a new insight into fabrication and structure design of highly efficient dye-sensitized solar cells. PMID- 30460281 TI - Microfluidics: Rapid Diagnosis for Breast Cancer. AB - Breast cancer affected 1.7 million people worldwide in 2012 and accounts for approximately 23.3 % of all cancers diagnosed in women. The disease is characterized by a genetic mutation, either inherited or resulting from environmental factors, that causes uncontrollable cellular growth of breast tissue or adjacent tissues. Current means of diagnosing this disease depend on the individual analyzing the results from bulky, highly technical, and expensive equipment that is not globally accessible. As a result, patients can go undiagnosed due to a lack of available equipment or be over-diagnosed due to human error. This review attempts to highlight current means of diagnosing breast cancer and critically analyze their effectiveness and usefulness in terms of patient survival. An alternative means based on microfluidics biomarker detection is then presented. This method can be considered as a primary screening tool for diagnosing breast cancer based on its robustness, high throughput, low energy requirements, and accessibility to the general public. PMID- 30460283 TI - Thermo-Electrochemical Cells Based on Carbon Nanotube Electrodes by Electrophoretic Deposition. AB - Drawbacks of low efficiency and high cost of the electrode materials have restricted the wide applications of the thermo-electrochemical cells (TECs). Due to high specific areas and electrical conductivities, the low cost multi-walled carbon nanotubes (MWNTs) are promising alternative electrode materials. In this work, the MWNT films of up to 16 cm2 were synthesized on stainless steel substrates by the electrophoretic deposition (EPD) to make the thermo electrochemical electrodes. MWNT electrodes based on TECs were characterized by cyclic voltammetry and the long-term stability tests with the potassium ferri/ferrocyanide electrolyte. The TECs reached the current density of 45.2 A m 2 and the maximum power density of 0.82 W m-2. The relative power conversion efficiency of the MWNT electrode is 50 % higher than that for the Pt electrode. Meanwhile, the TECs was operated continuously for 300 h without performance degradation. With the priorities of low cost and simple fabrication, EPD-based MWNT TECs may become commercially viable. PMID- 30460284 TI - High-Performance Photo-Modulated Thin-Film Transistor Based on Quantum dots/Reduced Graphene Oxide Fragment-Decorated ZnO Nanowires. AB - In this paper, a photo-modulated transistor based on the thin-film transistor structure was fabricated on the flexible substrate by spin-coating and magnetron sputtering. A novel hybrid material that composed of CdSe quantum dots and reduced graphene oxide (RGO) fragment-decorated ZnO nanowires was synthesized to overcome the narrow optical sensitive waveband and enhance the photo responsivity. Due to the enrichment of the interface and heterostructure by RGO fragments being utilized, the photo-responsivity of the transistor was improved to 2000 A W-1 and the photo-sensitive wavelength was extended from ultraviolet to visible. In addition, a positive back-gate voltage was employed to reduce the Schottky barrier width of RGO fragments and ZnO nanowires. As a result, the amount of carriers was increased by 10 folds via the modulation of back-gate voltage. With these inherent properties, such as integrated circuit capability and wide optical sensitive waveband, the transistor will manifest great potential in the future applications in photodetectors. PMID- 30460285 TI - Temperature-Responsive Tensile Actuator Based on Multi-walled Carbon Nanotube Yarn. AB - Many temperature indicators or sensors show color changes for materials used in food and medical fields. However, they are not helpful for a color-blind person or children who lack judgment. In this paper, we introduce simply fabricated and more useful low-temperature indicator (~30 degrees C) for devices that actuates using paraffin-infiltrated multi-walled carbon nanotube (MWCNT) coiled yarn. The density difference of MWCNT yarn provides large strain (~330 %) when heat causes the melted polymer to move. Furthermore, the MWCNT yarn decreases the melting point of paraffin. These properties allow control of the actuating temperature. In addition, mechanical strength was enhanced by MWCNT than previously reported temperature-responsive actuators based on shape memory polymers. This simply fabricated temperature indicator can be applied in latching devices for medical and biological fields. PMID- 30460286 TI - 5-Fluorouracil Loaded Chitosan-PVA/Na+MMT Nanocomposite Films for Drug Release and Antimicrobial Activity. AB - In the present study, chitosan and polyvinyl alcohol (PVA) were blended with different concentrations of sodium montmorillonite (Na+MMT) clay solution by a solvent casting method. X-ray diffraction and transition electron microscope results show that the film properties are related to the co-existence of Na+MMT intercalation/exfoliation in the blend and the interaction between chitosan-PVA and Na+MMT. 5-Fluorouracil (5-FU) was loaded with chitosan-PVA/Na+MMT nanocomposite films for in vitro drug delivery study. The antimicrobial activity of the chitosan-PVA/Na+MMT films showed significant effect against Salmonella (Gram-negative) and Staphylococcus aureus (Gram-positive), whereas 5-FU encapsulated chitosan-PVA/Na+MMT bio-nanocomposite films did not show any inhibition against bacteria. Our results indicate that combination of a flexible and soft polymeric material with high drug loading ability of a hard inorganic porous material can produce improved control over degradation and drug release. It will be an economically viable method for preparation of advanced drug delivery vehicles and biodegradable implants or scaffolds. PMID- 30460287 TI - Trapping and Driving Individual Charged Micro-particles in Fluid with an Electrostatic Device. AB - A variety of micro-tweezers techniques, such as optical tweezers, magnetic tweezers, and dielectrophoresis technique, have been applied intensively in precise characterization of micro/nanoparticles and bio-molecules. They have contributed remarkably in better understanding of working mechanisms of individual sub-cell organelles, proteins, and DNA. In this paper, we present a controllable electrostatic device embedded in a microchannel, which is capable of driving, trapping, and releasing charged micro-particles suspended in microfluid, demonstrating the basic concepts of electrostatic tweezers. Such a device is scalable to smaller size and offers an alternative to currently used micro tweezers for application in sorting, selecting, manipulating, and analyzing individual micro/nanoparticles. Furthermore, the system offers the potential in being combined with dielectrophoresis and other techniques to create hybrid micro manipulation systems. PMID- 30460288 TI - Surface Acoustic Wave Device with Reduced Insertion Loss by Electrospinning P(VDF TrFE)/ZnO Nanocomposites. AB - Surface acoustic wave (SAW) devices have been utilized for the sensing of chemical and biological phenomena in microscale for the past few decades. In this study, SAW device was fabricated by electrospinning poly(vinylidenefluoride-co trifluoroethylene) (P(VDF-TrFE)) incorporated with zinc oxide (ZnO) nanoparticles over the delay line area of the SAW device. The morphology, composition, and crystallinity of P(VDF-TrFE)/ZnO nanocomposites were investigated. After measurement of SAW frequency response, it was found that the insertion loss of the SAW devices incorporated with ZnO nanoparticles was much less than that of the neat polymer-deposited device. The fabricated device was expected to be used in acoustic biosensors to detect and quantify the cell proliferation in cell culture systems. PMID- 30460289 TI - A Short Review on Copper Calcium Titanate (CCTO) Electroceramic: Synthesis, Dielectric Properties, Film Deposition, and Sensing Application. AB - Electroceramic calcium copper titanates (CaCu3Ti4O12, CCTO), with high dielectric permittivities (epsilon) of approximately 105 and 104, respectively, for single crystal and bulk materials, are produced for a number of well-established and emerging applications such as resonator, capacitor, and sensor. These applications take advantage of the unique properties achieved through the structure and properties of CCTO. This review comprehensively focuses on the primary processing routes, effect of impurity, dielectric permittivity, and deposition technique used for the processing of electroceramics along with their chemical composition and micro and nanostructures. Emphasis is given to versatile and basic approaches that allow one to control the microstructural features that ultimately determine the properties of the CCTO ceramic. Despite the intensive research in this area, none of the studies available in the literature provides all the possible relevant information about CCTO fabrication, structure, the factors influencing its dielectric properties, CCTO immobilization, and sensing applications. PMID- 30460290 TI - Facile In Situ Fabrication of Nanostructured Graphene-CuO Hybrid with Hydrogen Sulfide Removal Capacity. AB - A simple and scalable synthetic approach for one-step synthesis of graphene-CuO (TRGC) nanocomposite by an in situ thermo-annealing method has been developed. Using graphene oxide (GO) and copper hydroxide as a precursors reagent, the reduction of GO and the uniform deposition of in situ formed CuO nanoparticles on graphene was simultaneously achieved. The method employed no solvents, toxic reducing agents, or organic modifiers. The resulting nanostructured hybrid exhibited improved H2S sorption capacity of 1.5 mmol H2S/g-sorbent (3 g S/100 g sorbent). Due to its highly dispersed sub-20 nm CuO nanoparticles and large specific surface area, TRGC nanocomposite exhibits tremendous potential for energy and environment applications. PMID- 30460291 TI - Rapid Seedless Synthesis of Gold Nanoplates with Microscaled Edge Length in a High Yield and Their Application in SERS. AB - We report a facile and reproducible approach toward rapid seedless synthesis of single crystalline gold nanoplates with edge length on the order of microns. The reaction is carried out by reducing gold ions with ascorbic acid in the presence of cetyltrimethylammonium bromide (CTAB). Reaction temperature and molar ratio of CTAB/Au are critical for the formation of gold nanoplates in a high yield, which are, respectively, optimized to be 85 degrees C and 6. The highest yield that can be achieved is 60 % at the optimized condition. The synthesis to achieve the microscaled gold nanoplates can be finished in less than 1 h under proper reaction conditions. Therefore, the reported synthesis approach is a time- and cost-effective one. The gold nanoplates were further employed as the surface enhanced Raman scattering substrates and investigated individually. Interestingly, only those adsorbed with gold nanoparticles exhibit pronounced Raman signals of probe molecules, where a maximum enhancement factor of 1.7 * 107 was obtained. The obtained Raman enhancement can be ascribed to the plasmon coupling between the gold nanoplate and the nanoparticle adsorbed onto it. PMID- 30460292 TI - Toward High Carrier Mobility and Low Contact Resistance: Laser Cleaning of PMMA Residues on Graphene Surfaces. AB - Abstract: Poly(methyl methacrylate) (PMMA) is widely used for graphene transfer and device fabrication. However, it inevitably leaves a thin layer of polymer residues after acetone rinsing and leads to dramatic degradation of device performance. How to eliminate contamination and restore clean surfaces of graphene is still highly demanded. In this paper, we present a reliable and position-controllable method to remove the polymer residues on graphene films by laser exposure. Under proper laser conditions, PMMA residues can be substantially reduced without introducing defects to the underlying graphene. Furthermore, by applying this laser cleaning technique to the channel and contacts of graphene field-effect transistors (GFETs), higher carrier mobility as well as lower contact resistance can be realized. This work opens a way for probing intrinsic properties of contaminant-free graphene and fabricating high-performance GFETs with both clean channel and intimate graphene/metal contact. Graphical Abstract: PMID- 30460293 TI - Effective Improvement of the Photovoltaic Performance of Carbon-Based Perovskite Solar Cells by Additional Solvents. AB - Abstract: A solvent-assisted methodology has been developed to synthesize CH3NH3PbI3 perovskite absorber layers. It involved the use of a mixed solvent of CH3NH3I, PbI2, gamma-butyrolactone, and dimethyl sulfoxide (DMSO) followed by the addition of chlorobenzene (CB). The method produced ultra-flat and dense perovskite capping layers atop mesoporous TiO2 films, enabling a remarkable improvement in the performance of free hole transport material (HTM) carbon electrode-based perovskite solar cells (PSCs). Toluene (TO) was also studied as an additional solvent for comparison. At the annealing temperature of 100 degrees C, the fabricated HTM-free PSCs based on drop-casting CB demonstrated power conversion efficiency (PCE) of 9.73 %, which is 36 and 71 % higher than those fabricated from the perovskite films using TO or without adding an extra solvent, respectively. The interaction between the PbI2-DMSO-CH3NH3I intermediate phase and the additional solvent was discussed. Furthermore, the influence of the annealing temperature on the absorber film formation, morphology, and crystalline structure was investigated and correlated with the photovoltaic performance. Highly efficient, simple, and stable HTM-free solar cells with a PCE of 11.44 % were prepared utilizing the optimum perovskite absorbers annealed at 120 degrees C. Graphical Abstract: PMID- 30460294 TI - Polymer Film Supported Bimetallic Au-Ag Catalysts for Electrocatalytic Oxidation of Ammonia Borane in Alkaline Media. AB - Abstract: Ammonia borane is widely used in most areas including fuel cell applications. The present paper describes electrochemical behavior of ammonia borane in alkaline media on the poly(p-aminophenol) film modified with Au and Ag bimetallic nanoparticles. The glassy carbon electrode was firstly covered with polymeric film electrochemically and then, Au, Ag, and Au-Ag nanoparticles were deposited on the polymeric film, respectively. The surface morphology and chemical composition of these electrodes were examined by scanning electron microscopy, transmission electron microscopy, electrochemical impedance spectroscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. It was found that alloyed Au-Ag bimetallic nanoparticles are formed. Electrochemical measurements indicate that the developed electrode modified by Au-Ag bimetallic nanoparticles exhibit the highest electrocatalytic activity for ammonia borane oxidation in alkaline media. The rotating disk electrode voltammetry demonstrates that the developed electrode can catalyze almost six-electron oxidation pathway of ammonia borane. Our results may be attractive for anode materials of ammonia borane fuel cells under alkaline conditions. Graphical Abstract: PMID- 30460295 TI - Self-Decoration of PtNi Alloy Nanoparticles on Multiwalled Carbon Nanotubes for Highly Efficient Methanol Electro-Oxidation. AB - Abstract: A simple one-pot method was developed to prepare PtNi alloy nanoparticles, which can be self-decorated on multiwalled carbon nanotubes in [BMIm][BF4] ionic liquid. The nanohybrids are targeting stable nanocatalysts for fuel cell applications. The sizes of the supported PtNi nanoparticles are uniform and as small as 1-2 nm. Pt-to-Ni ratio was controllable by simply selecting a PtNi alloy target. The alloy nanoparticles with Pt-to-Ni ratio of 1:1 show high catalytic activity and stability for methanol electro-oxidation. The performance is much higher compared with those of both Pt-only nanoparticles and commercial Pt/C catalyst. The electronic structure characterization on the PtNi nanoparticles demonstrates that the electrons are transferred from Ni to Pt, which can suppress the CO poisoning effect. Graphical Abstract: PMID- 30460296 TI - Electrochemical Synthesis of Novel Zn-Doped TiO2 Nanotube/ZnO Nanoflake Heterostructure with Enhanced DSSC Efficiency. AB - Abstract: The paper reports the fabrication of Zn-doped TiO2 nanotubes (Zn TONT)/ZnO nanoflakes heterostructure for the first time, which shows improved performance as a photoanode in dye-sensitized solar cell (DSSC). The layered structure of this novel nanoporous structure has been analyzed unambiguously by Rutherford backscattering spectroscopy, scanning electron microscopy, and X-ray diffractometer. The cell using the heterostructure as photoanode manifests an enhancement of about an order in the magnitude of the short circuit current and a seven-fold increase in efficiency, over pure TiO2 photoanodes. Characterizations further reveal that the Zn-TONT is preferentially oriented in [001] direction and there is a Ti metal-depleted interface layer which leads to better band alignment in DSSC. Graphical Abstract: PMID- 30460297 TI - Stable Superwetting Surface Prepared with Tilted Silicon Nanowires. AB - Abstract: Large-scale uniform nanostructured surface with superwettability is crucial in both fundamental research and engineering applications. A facile and controllable approach was employed to fabricate a superwetting tilted silicon nanowires (TSNWs) surface through metal-assisted chemical etching and modification with low-surface-energy material. The contact angle (CA) measurements of the nanostructured surface show a large range from the superhydrophilicity (the CA approximate to 0 degrees ) to superhydrophobicity (the CA up to 160 degrees ). The surface becomes antiadhesion to water upon nanostructuring with a measured sliding angle (alpha) close to 0 degrees . Moreover, the fluorinated TSNWs surface exhibits excellent stability and durability because strong chemical bonding has been formed on the surface. Graphical Abstract: PMID- 30460300 TI - Inorganic and Organic Solution-Processed Thin Film Devices. AB - Thin films and thin film devices have a ubiquitous presence in numerous conventional and emerging technologies. This is because of the recent advances in nanotechnology, the development of functional and smart materials, conducting polymers, molecular semiconductors, carbon nanotubes, and graphene, and the employment of unique properties of thin films and ultrathin films, such as high surface area, controlled nanostructure for effective charge transfer, and special physical and chemical properties, to develop new thin film devices. This paper is therefore intended to provide a concise critical review and research directions on most thin film devices, including thin film transistors, data storage memory, solar cells, organic light-emitting diodes, thermoelectric devices, smart materials, sensors, and actuators. The thin film devices may consist of organic, inorganic, and composite thin layers, and share similar functionality, properties, and fabrication routes. Therefore, due to the multidisciplinary nature of thin film devices, knowledge and advances already made in one area may be applicable to other similar areas. Owing to the importance of developing low cost, scalable, and vacuum-free fabrication routes, this paper focuses on thin film devices that may be processed and deposited from solution. PMID- 30460299 TI - Molybdenum Nanoscrews: A Novel Non-coinage-Metal Substrate for Surface-Enhanced Raman Scattering. AB - Abstract: For the first time, Mo nanoscrew was cultivated as a novel non-coinage metal substrate for surface-enhanced Raman scattering (SERS). It was found that the nanoscrew is composed of many small screw threads stacking along its length direction with small separations. Under external light excitation, strong electromagnetic coupling was initiated within the gaps, and many hot-spots formed on the surface of the nanoscrew, which was confirmed by high-resolution scanning near-field optical microscope measurements and numerical simulations using finite element method. These hot-spots are responsible for the observed SERS activity of the nanoscrews. Raman mapping characterizations further revealed the excellent reproducibility of the SERS activity. Our findings may pave the way for design of low-cost and stable SERS substrates. Graphical Abstract: Mo nanoscrews are for the first time cultivated as a novel type of SERS substrate. The SERS activity is originated from the electromagnetic field enhancements on the individual Mo nanoscrew, which is corroborated by single-particle optical characterizations. PMID- 30460298 TI - Fabrication and Applications of Micro/Nanostructured Devices for Tissue Engineering. AB - Nanotechnology allows the realization of new materials and devices with basic structural unit in the range of 1-100 nm and characterized by gaining control at the atomic, molecular, and supramolecular level. Reducing the dimensions of a material into the nanoscale range usually results in the change of its physiochemical properties such as reactivity, crystallinity, and solubility. This review treats the convergence of last research news at the interface of nanostructured biomaterials and tissue engineering for emerging biomedical technologies such as scaffolding and tissue regeneration. The present review is organized into three main sections. The introduction concerns an overview of the increasing utility of nanostructured materials in the field of tissue engineering. It elucidates how nanotechnology, by working in the submicron length scale, assures the realization of a biocompatible interface that is able to reproduce the physiological cell-matrix interaction. The second, more technical section, concerns the design and fabrication of biocompatible surface characterized by micro- and submicroscale features, using microfabrication, nanolithography, and miscellaneous nanolithographic techniques. In the last part, we review the ongoing tissue engineering application of nanostructured materials and scaffolds in different fields such as neurology, cardiology, orthopedics, and skin tissue regeneration. PMID- 30460301 TI - Surface-Renewable AgNPs/CNT/rGO Nanocomposites as Bifunctional Impedimetric Sensors. AB - Abstract: In this study, glassy carbon electrode modified by silver nanoparticles/carbon nanotube/reduced graphene oxide (AgNPs/CNT/rGO) composite has been utilized as a platform to immobilize cis-dioxomolybdenum (VI) salicylaldehyde-histidine (MoO2/Sal-His). The modified electrode shows two reversible redox couples for MoO2/Sal-His. Electrocatalytic oxidation of cysteine (CySH) and electrocatalytic reduction of iodate on the surface of the modified electrode were investigated with cyclic voltammetry and electrochemical impedance spectroscopy methods. The presence of MoO2/Sal-His on AgNPs/CNT/rGO shifted the catalytic current of iodate reduction to a more positive potential and the catalytic current of cysteine oxidation to a more negative potential. The change of interfacial charge transfer resistance (R ct) recorded by the modified electrode was monitored for sensitive quantitative detection of CySH and iodate. Moreover, the sensor has a good stability, and it can be renewed easily and repeatedly through a mechanical or electrochemical process. Graphical Abstract: PMID- 30460302 TI - Controllable Biosynthesis and Properties of Gold Nanoplates Using Yeast Extract. AB - Abstract: Biosynthesis of gold nanostructures has drawn increasing concerns because of its green and sustainable synthetic process. However, biosynthesis of gold nanoplates is still a challenge because of the expensive source and difficulties of controllable formation of morphology and size. Herein, one-pot biosynthesis of gold nanoplates is proposed, in which cheap yeast was extracted as a green precursor. The morphologies and sizes of the gold nanostructures can be controlled via varying the pH value of the biomedium. In acid condition, gold nanoplates with side length from 1300 +/- 200 to 300 +/- 100 nm and height from 18 to 15 nm were obtained by increasing the pH value. Whereas, in neutral or basic condition, only gold nanoflowers and nanoparticles were obtained. It was determined that organic molecules, such as succinic acid, lactic acid, malic acid, and glutathione, which are generated in metabolism process, played important role in the reduction of gold ions. Besides, it was found that the gold nanoplates exhibited plasmonic property with prominent dipole infrared resonance in near-infrared region, indicating their potential in surface plasmon-enhanced applications, such as bioimaging and photothermal therapy. Graphical Abstract: PMID- 30460303 TI - Novel Hybrid Nanoparticles of Vanadium Nitride/Porous Carbon as an Anode Material for Symmetrical Supercapacitor. AB - Abstract: Hybrid materials of vanadium nitride and porous carbon nanoparticles (VN/PCNPs) were fabricated by a facile pyrolysis process of vanadium pentoxide (V2O5) xerogel and melamine at relatively low temperature of 800 degrees C for supercapacitor application. The effects of the feed ratio of V2O5 to melamine (r), and nitrogen flow rate on the microstructure and electrochemical performance were also investigated. It was found that the size of the as-synthesized nanoparticles is about 20 nm. Both r value and N2 flow rate have enormous impacts on morphology and microstructure of the nanoparticle, which correspondingly determined the electrochemical performance of the material. The VN/C hybrid nanoparticles exhibited high capacitive properties, and a maximum specific capacitance of 255.0 F g-1 was achieved at a current density of 1.0 A g-1 in 2 M KOH aqueous electrolyte and the potential range from 0 to -1.15 V. In addition, symmetrical supercapacitor fabricated with the as-synthesized VN/PCNPs presents a high specific capacitance of 43.5 F g-1 at 0.5 A g-1 based on the entire cell, and an energy density of 8.0 Wh kg-1 when the power density was 575 W kg-1. Even when the power density increased to 2831.5 W kg-1, the energy density still remained 6.1 Wh kg-1. Graphical Abstract: PMID- 30460304 TI - Electrochemical Impedance Analysis of Biofunctionalized Conducting Polymer Modified Graphene-CNTs Nanocomposite for Protein Detection. AB - We report an electrodeposited poly(pyrrole-co-pyrrolepropylic acid) copolymer modified electroactive graphene-carbon nanotubes composite deposited on a glassy carbon electrode to detect the protein antigen (cTnI). The copolymer provides pendant carboxyl groups for the site-specific covalent immobilization of protein antibody, anti-troponin I. The hybrid nanocomposite was used as a transducer for biointerfacial impedance sensing for cTnI detection. The results show that the hybrid exhibits a pseudo capacitive behaviour with a maximum phase angle of 49 degrees near 1 Hz, which is due to the inhomogeneous and porous structure of the hybrid composition. The constant phase element of copolymer is 0.61 (n = 0.61), whereas, it is 0.88 (n = 0.88) for the hybrid composites, indicating a comparatively homogeneous microstructure after biomolecular functionalization. The transducer shows a linear change in charge transfer characteristic (R et) on cTnI immunoreaction for spiked human serum in the concentration range of 1.0 pg mL-1-10.0 ng mL-1. The sensitivity of the transducer is 167.8 +/- 14.2 Omega cm2 per decade, and it also exhibits high specificity and good reproducibility. PMID- 30460305 TI - Detection of Adhesion Molecules on Inflamed Macrophages at Early-Stage Using SERS Probe Gold Nanorods. AB - In recent years, it has been shown that inflammatory biomarkers can be used as an effective signal for disease diagnoses. The early detection of these signals provides useful information that could prevent the occurrence of severe diseases. Here, we employed surface-enhanced Raman scattering (SERS) probe gold nanorods (GNRs) as a tool for the early detection of inflammatory molecules in inflamed cells. A murine macrophage cell line (Raw264.7) stimulated with lipopolysaccharide (LPS) was used as a model in this study. The prepared SERS probe GNRs containing 4-mercaptobenzoic acid as a Raman reporter to generate SERS signals were used for detection of intracellular adhesion molecule-1 (ICAM-1) in macrophages after treatment with LPS for varying lengths of time. Our results show that SERS probe GNRs could detect significant differences in the expression of ICAM-1 molecules in LPS-treated macrophages compared to those in untreated macrophages after only 1 h of LPS treatment. In contrast, when using fluorescent labeling or enzyme-linked immunosorbent assays (ELISA) to detect ICAM-1, significant differences between inflamed and un-inflamed macrophages were not seen until the cells had been treated with LPS for 5 h. These results indicate that our SERS probe GNRs provide a higher sensitivity for detecting biomarker molecules in inflamed macrophages than the conventional fluorescence and ELISA techniques, and could therefore be useful as a potential diagnostic tool for managing disease risk. PMID- 30460306 TI - Extending the Frequency Range of Surface Plasmon Polariton Mode with Meta Material. AB - The frequency range that surface plasmon polariton (SPP) mode exists is mainly limited by the metal material. With high permittivity dielectrics above metal surface, the SPP mode at high frequency has extremely large loss or can be cutoff, which limits the potential applications of SPP in the field of optical interconnection, active SPP devices and so on. To extend the frequency range of SPP mode, the surface mode guided by metal/dielectric multilayers meta-material has been studied based on the theory of electromagnetic field. It is demonstrated that surface mode not only could be supported by the meta-material but also extends the frequency to where conventional metal SPP cannot exist. Meanwhile, the characteristics of this surface mode, such as dispersion relation, frequency range, propagation loss and skin depth in meta-material and dielectrics, are also studied. It is indicated that, by varying the structure parameters, the meta material guided SPP mode presents its advantages and flexibility over traditional metal one. PMID- 30460307 TI - Recent Advances to Understand Morphology Stability of Organic Photovoltaics. AB - Organic photovoltaic devices are on the verge of commercialization with power conversion efficiencies exceeding 10 % in laboratory cells and above 8.5 % in modules. However, one of the main limitations hindering their mass scale production is the debatable inferior stability of organic photovoltaic devices in comparison to other technologies. Adequate donor/acceptor morphology of the active layer is required to provide carrier separation and transport to the electrodes. Unfortunately, the beneficial morphology for device performance is usually a kinetically frozen state which has not reached thermodynamic equilibrium. During the last 5 years, special efforts have been dedicated to isolate the effects related to morphology changes taking place within the active layer and compare to those affecting the interfaces with the external electrodes. The current review discusses some of the factors affecting the donor/acceptor morphology evolution as one of the major intrinsic degradation pathways. Special attention is paid to factors in the nano- and microscale domain. For example, phase segregation of the polymer and fullerene domains due to Ostwald ripening is a major factor in the microscale domain and is affected by the presence of additives, glass transition temperature of the polymers or use of crosslinkers in the active layer. Alternatively, the role of vertical segregation profile toward the external electrodes is key for device operation, being a clear case of nanoscale morphology evolution. For example, donor and acceptor molecules actually present at the external interfaces will determine the leakage current of the device, energy-level alignment, and interfacial recombination processes. Different techniques have been developed over the last few years to understand its relationship with the device efficiency. Of special interest are those techniques which enable in situ analysis being non-destructive as they can be used to study accelerated degradation experiments and some will be discussed here. PMID- 30460308 TI - A Self-Powered Fast-Response Ultraviolet Detector of p-n Homojunction Assembled from Two ZnO-Based Nanowires. AB - Abstract: Nowadays, fabrication of micro/nano-scale electronic devices with bottom-up approach is paid much research attention. Here, we provide a novel micro/nano-assembling method, which is accurate and efficient, especially suitable for the fabrication of micro/nano-scale electronic devices. Using this method, a self-powered ZnO/Sb-doped ZnO nanowire p-n homojunction ultraviolet detector (UVD) was fabricated, and the detailed photoelectric properties were tested. At a reverse bias of -0.1 V under UV light illumination, the photoresponse sensitivity of the UVD was 26.5 and the rise/decay time of the UVD was as short as 30 ms. The micro/nano-assembling method has wide potential applications in the fabrication of specific micro/nano-scale electronic devices. Graphical Abstract: A self-powered ZnO/Sb-doped ZnO nanowire p-n homojunction ultraviolet detector (UVD) was fabricated by using a novel micro/nano-assembling method with bottom-up approach. At reverse bias of -0.1 V under UV light illumination, the photoresponse sensitivity of the UVD was 26.5, and the rise time and decay time of the UVD were as short as 30 ms. PMID- 30460309 TI - Investigation on the Formation Mechanism of Double-Layer Vertically Aligned Carbon Nanotube Arrays via Single-Step Chemical Vapour Deposition. AB - Abstract: The mechanism for the formation of double-layer vertically aligned carbon nanotube arrays (VACNTs) through single-step CVD growth is investigated. The evolution of the structures and defect concentration of the VACNTs are tracked by scanning electron microscopy (SEM) and Raman spectroscopy. During the growth, the catalyst particles are stayed constantly on the substrate. The precipitation of the second CNT layer happens at around 30 min as proved by SEM. During the growth of the first layer, catalyst nanoparticles are deactivated with the accumulation of amorphous carbon coatings on their surfaces, which leads to the termination of the growth of the first layer CNTs. Then, the catalyst particles are reactivated by the hydrogen in the gas flow, leading to the precipitation of the second CNT layer. The growth of the second CNT layer lifts the amorphous carbon coatings on catalyst particles and substrates. The release of mechanical energy by CNTs provides big enough energy to lift up amorphous carbon flakes on catalyst particles and substrates which finally stay at the interfaces of the two layers simulated by finite element analysis. This study sheds light on the termination mechanism of CNTs during CVD process. Graphical Abstract: The mechanism for the formation of double-layer vertically aligned carbon nanotube arrays (VACNTs) through single-step CVD growth was investigated. The growth of the second CNT layer lifts the amorphous carbon coatings on catalyst particles and substrates. PMID- 30460311 TI - BiVO4/TiO2(N2) Nanotubes Heterojunction Photoanode for Highly Efficient Photoelectrocatalytic Applications. AB - Abstract: We report the development of a novel visible response BiVO4/TiO2(N2) nanotubes photoanode for photoelectrocatalytic applications. The nitrogen-treated TiO2 nanotube shows a high carrier concentration rate, thus resulting in a high efficient charge transportation and low electron-hole recombination in the TiO2 BiVO4. Therefore, the BiVO4/TiO2(N2) NTs photoanode enabled with a significantly enhanced photocurrent of 2.73 mA cm-2 (at 1 V vs. Ag/AgCl) and a degradation efficiency in the oxidation of dyes under visible light. Field emission scanning electron microscopy, X-ray diffractometry, energy-dispersive X-ray spectrometer, and UV-Vis absorption spectrum were conducted to characterize the photoanode and demonstrated the presence of both metal oxides as a junction composite. Graphical Abstract: Visible-light response BiVO4/TiO2(N2) naontubes photoelectrode was fabricated for photoelectrochemical water splitting and organic degradation in this paper. PMID- 30460310 TI - Fast Growth of Highly Ordered TiO2 Nanotube Arrays on Si Substrate under High Field Anodization. AB - Abstract: Highly ordered TiO2 nanotube arrays (NTAs) on Si substrate possess broad applications due to its high surface-to-volume ratio and novel functionalities, however, there are still some challenges on facile synthesis. Here, we report a simple and cost-effective high-field (90-180 V) anodization method to grow highly ordered TiO2 NTAs on Si substrate, and investigate the effect of anodization time, voltage, and fluoride content on the formation of TiO2 NTAs. The current density-time curves, recorded during anodization processes, can be used to determine the optimum anodization time. It is found that the growth rate of TiO2 NTAs is improved significantly under high field, which is nearly 8 times faster than that under low fields (40-60 V). The length and growth rate of the nanotubes are further increased with the increase of fluoride content in the electrolyte. Graphical Abstract: Highly ordered TiO2 nanotube arrays (NTAs) on Si substrate have been fabricated by high-field anodization method. A high voltage (90-180 V) leads to a high growth rate of TiO2 NTAs (35-47 nm s-1), which is nearly 8 times faster than the growth rate under low fields (40-60 V). Furthermore, the current density-time curves recorded during the anodization provide a facial method to determine the optimal anodization parameters, leading to an easy obtaining of the desired nanotubes. PMID- 30460312 TI - Resistive Switching Memory of TiO2 Nanowire Networks Grown on Ti Foil by a Single Hydrothermal Method. AB - The resistive switching characteristics of TiO2 nanowire networks directly grown on Ti foil by a single-step hydrothermal technique are discussed in this paper. The Ti foil serves as the supply of Ti atoms for growth of the TiO2 nanowires, making the preparation straightforward. It also acts as a bottom electrode for the device. A top Al electrode was fabricated by e-beam evaporation process. The Al/TiO2 nanowire networks/Ti device fabricated in this way displayed a highly repeatable and electroforming-free bipolar resistive behavior with retention for more than 104 s and an OFF/ON ratio of approximately 70. The switching mechanism of this Al/TiO2 nanowire networks/Ti device is suggested to arise from the migration of oxygen vacancies under applied electric field. This provides a facile way to obtain metal oxide nanowire-based ReRAM device in the future. PMID- 30460313 TI - Preparation of Sandwich-like NiCo2O4/rGO/NiO Heterostructure on Nickel Foam for High-Performance Supercapacitor Electrodes. AB - Abstract: A kind of sandwich-like NiCo2O4/rGO/NiO heterostructure composite has been successfully anchored on nickel foam substrate via a three-step hydrothermal method with successive annealing treatment. The smart combination of NiCo2O4, reduced graphene oxide (rGO), and NiO nanostructure in the sandwich-like nano architecture shows a promising synergistic effect for supercapacitors with greatly enhanced electrochemical performance. For serving as supercapacitor electrode, the NiCo2O4/rGO/NiO heterostructure materials exhibit remarkable specific capacitance of 2644 mF cm-2 at current density of 1 mA cm-2, and excellent capacitance retentions of 97.5% after 3000 cycles. It is expected that the present heterostructure will be a promising electrode material for high performance supercapacitors. Graphical Abstract: PMID- 30460314 TI - In-Situ Hydrothermal Synthesis of Bi-Bi2O2CO3 Heterojunction Photocatalyst with Enhanced Visible Light Photocatalytic Activity. AB - Bismuth containing nanomaterials recently received increasing attention with respect to environmental applications because of their low cost, high stability and nontoxicity. In this work, Bi-Bi2O2CO3 heterojunctions were fabricated by in situ decoration of Bi nanoparticles on Bi2O2CO3 nanosheets via a simple hydrothermal synthesis approach. X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) were used to confirm the morphology of the nanosheet-like heterostructure of the Bi-Bi2O2CO3 composite. Detailed ultrafast electronic spectroscopy reveals that the in-situ decoration of Bi nanoparticles on Bi2O2CO3 nanosheets exhibit a dramatically enhanced electron-hole pair separation rate, which results in an extraordinarily high photocatalytic activity for the degradation of a model organic dye, methylene blue (MB) under visible light illumination. Cycling experiments revealed a good photochemical stability of the Bi-Bi2O2CO3 heterojunction under repeated irradiation. Photocurrent measurements further indicated that the heterojunction incredibly enhanced the charge generation and suppressed the charge recombination of photogenerated electron-hole pairs. PMID- 30460315 TI - Carbon-Based Flexible and All-Solid-State Micro-supercapacitors Fabricated by Inkjet Printing with Enhanced Performance. AB - Abstract: By means of inkjet printing technique, flexible and all-solid-state micro-supercapacitors (MSCs) were fabricated with carbon-based hybrid ink composed of graphene oxide (GO, 98.0 vol.%) ink and commercial pen ink (2.0 vol.%). A small amount of commercial pen ink was added to effectively reduce the agglomeration of the GO sheets during solvent evaporation and the following reduction processes in which the presence of graphite carbon nanoparticles served as nano-spacer to separate GO sheets. The printed device fabricated using the hybrid ink, combined with the binder-free microelectrodes and interdigital microelectrode configuration, exhibits nearly 780% enhancement in areal capacitance compared with that of pure GO ink. It also shows excellent flexibility and cycling stability with nearly 100% retention of the areal capacitance after 10,000 cycles. The all-solid-state device can be optionally connected in series or in parallel to meet the voltage and capacity requirements for a given application. This work demonstrates a promising future of the carbon based hybrid ink for directly large-scale inkjet printing MSCs for disposable energy storage devices. Graphical Abstract: PMID- 30460316 TI - A Facile Synthesis of ZnCo2O4 Nanocluster Particles and the Performance as Anode Materials for Lithium Ion Batteries. AB - Abstract: ZnCo2O4 nanocluster particles (NCPs) were prepared through a designed hydrothermal method, with the assistance of a surfactant, sodium dodecyl benzene sulfonate. The crystalline structure and surface morphology of ZnCo2O4 were investigated by XRD, XPS, SEM, TEM, and BET analyses. The results of SEM and TEM suggest a clear nanocluster particle structure of cubic ZnCo2O4 (~100 nm in diameter), which consists of aggregated primary nanoparticles (~10 nm in diameter), is achieved. The electrochemical behavior of synthesized ZnCo2O4 NCPs was investigated by galvanostatic discharge/charge measurements and cyclic voltammetry. The ZnCo2O4 NCPs exhibit a high reversible capacity of 700 mAh g-1 over 100 cycles under a current density of 100 mA g-1 with an excellent coulombic efficiency of 98.9% and a considerable cycling stability. This work demonstrates a facile technique designed to synthesize ZnCo2O4 NCPs which show great potential as anode materials for lithium ion batteries. Graphical Abstract: PMID- 30460317 TI - 3D Hierarchical Co-Al Layered Double Hydroxides with Long-Term Stabilities and High Rate Performances in Supercapacitors. AB - Three-dimensional (3D) flower-like Co-Al layered double hydroxide (Co-Al-LDH) architectures composed of atomically thin nanosheets were successfully synthesized via a hydrothermal method in a mixed solvent of water and butyl alcohol. Owing to the unique hierarchical structure and modification by butyl alcohol, the electrochemical stability and the charge/mass transport of the Co-Al LDHs was improved. When used in supercapacitors, the obtained Co-Al-LDHs deliver a high specific capacitance of 838 F g-1 at a current density of 1 A g-1 and excellent rate performance (753 F g-1 at 30 A g-1 and 677 F g-1 at 100 A g-1), as well as excellent cycling stability with 95% retention of the initial capacitance even after 20,000 cycles at a current density of 5 A g-1. This work provides a promising alternative strategy to enhance the electrochemical properties of supercapacitors. PMID- 30460318 TI - Research Progress in Improving the Cycling Stability of High-Voltage LiNi0.5Mn1.5O4 Cathode in Lithium-Ion Battery. AB - High-voltage lithium-ion batteries (HVLIBs) are considered as promising devices of energy storage for electric vehicle, hybrid electric vehicle, and other high power equipment. HVLIBs require their own platform voltages to be higher than 4.5 V on charge. Lithium nickel manganese spinel LiNi0.5Mn1.5O4 (LNMO) cathode is the most promising candidate among the 5 V cathode materials for HVLIBs due to its flat plateau at 4.7 V. However, the degradation of cyclic performance is very serious when LNMO cathode operates over 4.2 V. In this review, we summarize some methods for enhancing the cycling stability of LNMO cathodes in lithium-ion batteries, including doping, cathode surface coating, electrolyte modifying, and other methods. We also discuss the advantages and disadvantages of different methods. PMID- 30460319 TI - Improving the Performance of PbS Quantum Dot Solar Cells by Optimizing ZnO Window Layer. AB - Comparing with hot researches in absorber layer, window layer has attracted less attention in PbS quantum dot solar cells (QD SCs). Actually, the window layer plays a key role in exciton separation, charge drifting, and so on. Herein, ZnO window layer was systematically investigated for its roles in QD SCs performance. The physical mechanism of improved performance was also explored. It was found that the optimized ZnO films with appropriate thickness and doping concentration can balance the optical and electrical properties, and its energy band align well with the absorber layer for efficient charge extraction. Further characterizations demonstrated that the window layer optimization can help to reduce the surface defects, improve the heterojunction quality, as well as extend the depletion width. Compared with the control devices, the optimized devices have obtained an efficiency of 6.7% with an enhanced V oc of 18%, J sc of 21%, FF of 10%, and power conversion efficiency of 58%. The present work suggests a useful strategy to improve the device performance by optimizing the window layer besides the absorber layer. PMID- 30460321 TI - Bezlotoxumab Is Associated With a Reduction in Cumulative Inpatient-Days: Analysis of the Hospitalization Data From the MODIFY I and II Clinical Trials. AB - Background: Patients with recurrent Clostridium difficile infection (rCDI) are more likely to have a hospital readmission and spend increased time in inpatient settings compared with patients with primary CDI. MODIFY I and II demonstrated that bezlotoxumab significantly reduced rCDI vs placebo. A post hoc within-trial analysis assessed whether bezlotoxumab was associated with a reduction in cumulative inpatient-days. Methods: Data were pooled from the MODIFY trials to estimate the cumulative hospitalized days summed over the 84-day follow-up period. We adjusted inpatient use data from pooled MODIFY I and II for survival and censoring to estimate 84-day cumulative inpatient-days, overall and for subgroups. Treatment effects were obtained using recycled predictions based on trial protocol and rCDI risk, and 95% confidence intervals were obtained using 1000 bootstrap replicates. Results: Mean cumulative inpatient-days were greater in the placebo arm (14.1 days) vs the bezlotoxumab arm (12.1 days) in the overall population. The mean difference between treatment groups was 2.1 days (95% confidence interval, -0.4 to -3.7). This was consistent in participants with risk factors for rCDI: age >=65 years, compromised immunity, severe CDI, prior CDI, and ribotype 027/078/244 infection. As the number of risk factors increased, bezlotoxumab resulted in greater reductions in the number of inpatient-days compared with placebo (difference: -1.2 days, -2.3 days, -2.5 days, and -3.0 days for 0, 1, 2, and >=3 risk factors, respectively). Conclusions: Bezlotoxumab was associated with a reduction in cumulative inpatient-days, suggesting that treatment with bezlotoxumab may substantially reduce rCDI-associated health care resource use. Trial registrations. MODIFY I (MK-3415A-001, NCT01241552) and II (MK-3415A-002, NCT01513239). PMID- 30460320 TI - Long-term mental health outcomes after unintentional burns sustained during childhood: a retrospective cohort study. AB - Background: Burns are a devastating injury that can cause physical and psychological issues. Limited data exist on long-term mental health (MH) after unintentional burns sustained during childhood. This study assessed long-term MH admissions after paediatric burns. Methods: This retrospective cohort study included all children (< 18 years) hospitalised for a first burn (n = 11,967) in Western Australia, 1980-2012, and a frequency matched uninjured comparison cohort (n = 46,548). Linked hospital, MH and death data were examined. Multivariable negative binomial regression modelling was used to generate incidence rate ratios (IRR) and 95% confidence intervals (CI). Results: The burn cohort had a significantly higher adjusted rate of post-burn MH admissions compared to the uninjured cohort (IRR, 95% CI: 2.55, 2.07-3.15). Post-burn MH admission rates were twice as high for those younger than 5 years at index burn (IRR, 95% CI 2.06, 1.54-2.74), three times higher for those 5-9 years and 15-18 years (IRR, 95% CI: 3.21, 1.92-5.37 and 3.37, 2.13-5.33, respectively) and almost five times higher for those aged 10-14 (IRR, 95% CI: 4.90, 3.10-7.76), when compared with respective ages of uninjured children. The burn cohort had higher admission rates for mood and anxiety disorders (IRR, 95% CI: 2.79, 2.20-3.53), psychotic disorders (IRR, 95% CI: 2.82, 1.97-4.03) and mental and behavioural conditions relating to drug and alcohol abuse (IRR, 95% CI: 4.25, 3.39-5.32). Conclusions: Ongoing MH support is indicated for paediatric burn patients for a prolonged period after discharge to potentially prevent psychiatric morbidity and associated academic, social and psychological issues. PMID- 30460322 TI - Acute Toxoplasma Dissemination With Encephalitis in the Era of Biological Therapies. AB - We report the case of a 65-year-old patient with pseudolymphoma who developed acute toxoplasmosis following 6 cycles of rituximab and bendamustine therapy. Acute toxoplasmosis in the setting of biological response modifiers, rather than reactivation, is a unique unreported infection. The patient developed severe disease with multi-organ involvement, including retinitis, myocarditis, and myositis. We discuss the clinical findings, epidemiology, and laboratory diagnosis. PMID- 30460323 TI - Re-thinking preclinical models of cancer metastasis. PMID- 30460324 TI - Targeting PIM kinases to oppose hypoxia-mediated therapeutic resistance. PMID- 30460325 TI - Risks and chances of aberrant DNA repair in cancer. PMID- 30460326 TI - TP53 mutation status: emerging biomarker for precision radiation medicine? PMID- 30460327 TI - ETV4: an emerging target in pancreatic cancer. PMID- 30460328 TI - Reply to: Biological role of miR-204 and miR-211 in melanoma (published in Oncoscience, Vol 5 (7-8), July 2018). PMID- 30460329 TI - Regression of primary cardiac angiosarcoma and metastatic nodules following propranolol as a single agent treatment. AB - Angiosarcoma is the most common malignant cardiac tumor. Cardiac angiosarcoma is a highly lethal neoplasm that is largely resistant to conventional anti-cancer therapy. Mean survival of patients with cardiac angiosarcoma is only 4 months, and almost all patients will succumb to the disease within 1 year. The beta blocker propranolol is an emerging therapy against angiosarcoma. When combined with conventional therapies, propranolol increases progression free and overall survival in patients with this tumor type. It is currently unknown if propranolol is capable of showing anti-cancer efficacy as a single agent therapy. We report a case of a 61 year old woman diagnosed with primary cardiac angiosarcoma and liver and lung metastases. This patient chose to decline conventional therapy, and instead was prescribed the beta blocker propranolol as a single agent treatment. After 12 months, the mediastinal mass substantially debulked and decreased in size, and the metastatic nodules stabilized or resolved with no evidence of hyper metabolic activity on PET-CT. This is the first reported data showing long term efficacy of the beta blocker propranolol as a single agent therapy against angiosarcoma. PMID- 30460330 TI - Active and passive diffusion processes in complex networks. AB - Ideas, information, viruses: all of them, with their mechanisms, spread over the complex social information, viruses: all tissues described by our interpersonal relations. Usually, to simulate and understand the unfolding of such complex phenomena are used general mathematical models; these models act agnostically from the object of which they simulate the diffusion, thus considering spreading of virus, ideas and innovations alike. Indeed, such degree of abstraction makes it easier to define a standard set of tools that can be applied to heterogeneous contexts; however, it can also lead to biased, incorrect, simulation outcomes. In this work we introduce the concepts of active and passive diffusion to discriminate the degree in which individuals choice affect the overall spreading of content over a social graph. Moving from the analysis of a well-known passive diffusion schema, the Threshold model (that can be used to model peer-pressure related processes), we introduce two novel approaches whose aim is to provide active and mixed schemas applicable in the context of innovations/ideas diffusion simulation. Our analysis, performed both in synthetic and real-world data, underline that the adoption of exclusively passive/active models leads to conflicting results, thus highlighting the need of mixed approaches to capture the real complexity of the simulated system better. PMID- 30460332 TI - Trends and characteristics of enrolment in the National Health Insurance Scheme in Ghana: a quantitative analysis of longitudinal data. AB - Background: In 2004, Ghana started experimenting a National Health Insurance Scheme (NHIS) to reduce out-of-pocket payment for healthcare. Like many other social health insurance schemes in Africa, the NHIS is striving for universal health coverage (UHC). This paper examines trends and characteristics of enrolment in the scheme to inform policy decisions on attainment of UHC. Methods: We conducted trend analysis of longitudinal enrolment data of the NHIS for the period, 2010-2017. Descriptive statistics were used to examine trends and characteristics of enrolment by geographical region and member groups. Results: Over the 8-year period, the population enrolled in the scheme increased from 33% (8.2 million) to 41% (11.3 million) between 2010 and 2015 and dropped to 35% (10.3 million) in 2017. Members who renewed their membership increased from 44% to 75.4% between 2010 and 2013 and then dropped to 73% in 2017. On average, the urban regions had significantly higher number of new enrolments than the rural ones. Similarly, the urban and peri-urban regions recorded significantly higher number of renewals than the other regions. In addition, persons below the age of 18 years and the informal sector workers had significantly higher number of enrolment than any other member group. Conclusions: Enrolment in the NHIS is declining and there are significant differences among geographical regions and member groups. Managers of the NHIS need to enforce the mandatory enrolment provision in the Act governing the scheme, employ innovative strategies such as mobile phone application for registration and renewals and address delays in healthcare provider claims to improve enrolment. PMID- 30460333 TI - Effectively Addressing Human Immunodeficiency Virus Disparities Affecting US Black Women. AB - Black women have disproportionately higher rates of human immunodeficiency virus (HIV) infection, and low percentages being linked to care and becoming virally suppressed, compared with women of other races/ethnicities. To date, few evidence based HIV prevention and care interventions tailored for black women exist. We highlight three essential factors to consider in designing culturally and gender appropriate studies to address HIV-related disparities affecting black women: (1) social determinants of HIV risk, (2) determinants of equity, and (3) perceptions of black women's sexuality. Synergy between a strong evidence base and developing strong partnerships could accelerate progress toward HIV-related health equity for black women. PMID- 30460331 TI - Vascularization and Engraftment of Transplanted Human Cerebral Organoids in Mouse Cortex. AB - Neural stem cells (NSCs) hold great promise for neural repair in cases of CNS injury and neurodegeneration; however, conventional cell-based transplant methods face the challenges of poor survival and inadequate neuronal differentiation. Here, we report an alternative, tissue-based transplantation strategy whereby cerebral organoids derived from human pluripotent stem cells (PSCs) were grafted into lesioned mouse cortex. Cerebral organoid transplants exhibited enhanced survival and robust vascularization from host brain as compared to transplants of dissociated neural progenitor cells (NPCs). Engrafted cerebral organoids harbored a large NSC pool and displayed multilineage neurodifferentiation at two and four weeks after grafting. Cerebral organoids therefore represent a promising alternative source to NSCs or fetal tissues for transplantation, as they contain a large set of neuroprogenitors and differentiated neurons in a structured organization. Engrafted cerebral organoids may also offer a unique experimental paradigm for modeling human neurodevelopment and CNS diseases in the context of vascularized cortical tissue. PMID- 30460335 TI - Variables Reflecting the Mineralization of Bone Tissue From Fracturing Versus Nonfracturing Postmenopausal Nonosteoporotic Women. AB - Women with equivalent areal bone mineral densities may show a different fracture incidence due to differences in bone intrinsic quality. Previously, Fourier transform infrared spectroscopic imaging (FTIRI) on the same iliac bone biopsies reported here, showed that the only significantly different variable was the carbonate/phosphate ratio, which was decreased in the fracturing group. Nanoindentation showed that fracturing bone was less mechanically heterogeneous than nonfracturing bone and could propagate damage (microcracks) more easily. The hypothesis is that fracturing women have reduced mineralization of bone tissue compared to nonfracturing women. Transiliac bone biopsies were collected from fracturing (n = 60, 62.5 +/- 7.4 years old) and nonfracturing (n = 60, 62.3 +/- 7.3 years old) postmenopausal women, to assess the mineralization of bone tissue using digitized microradiography. The degree of mineralization of bone (DMB, g/cm3) and the heterogeneity index (HI, g/cm3) of the DMB were calculated for cancellous (canc), cortical (cort) and total bone. Results were compared to variables from nanoindentation, FTIRI, and histomorphometry. DMB and HI were not significantly different between fracturing and nonfracturing groups. In the nonfracturing group, cort and canc HI were weakly negatively associated with cort and canc DMB (r' = -0.388, p < 0.003; r' = -0.532, p < 0.0001, respectively). In the fracturing group, DMB and HI were negatively correlated only in canc (r' = 0.295, p = 0.024). DMB and HI were not associated with nanoindentation variables. Cort and canc DMB were positively associated with mineral-to-matrix ratio measured by FTIRI (ratio between mineral and organic matrix representing the relative mineralization of the collagen matrix), and negatively associated with carbonate/phosphate ratio. None of the DMB variables were strongly associated with any of the histomorphometric variables. In conclusion, bone mineralization was not significantly different between fracturing and nonfracturing postmenopausal women, suggesting that bone fragility could be partly due to other variables, such as changes in hydration of bone matrix or an increase of non enzymatic crosslinks in bone collagen. (c) 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. PMID- 30460336 TI - Comparative Characterization of Osteoclasts Derived From Murine Bone Marrow Macrophages and RAW 264.7 Cells Using Quantitative Proteomics. AB - Osteoclasts are bone-resorbing cells differentiated from macrophage/monocyte precursors in response to macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-kappaB ligand (RANKL). In vitro models are principally based on primary bone marrow macrophages (BMMs), but RAW 264.7 cells are frequently used because they are widely available, easy to culture, and more amenable to genetic manipulation than primary cells. Increasing evidence, however, has shown that the vastly different origins of these two cell types may have important effects on cell behavior. In particular, M-CSF is a prerequisite for the differentiation of BMMs, by promoting survival and proliferation and priming the cells for RANKL induction. RAW 264.7 cells readily form osteoclasts in the presence of RANKL, but M-CSF is not required. Based on these key differences, we sought to understand their functional implications and how it might affect osteoclast differentiation and related signaling pathways. Using a robust and high-throughput proteomics strategy, we quantified the global protein changes in osteoclasts derived from BMMs and RAW 264.7 cells at 1, 3, and 5 days of differentiation. Data are available via ProteomeXchange with the identifier PXD009610. Correlation analysis of the proteomes demonstrated low concordance between the two cell types (R2 ~ 0.13). Bioinformatics analysis indicate that RANKL-dependent signaling was intact in RAW 264.7 cells, but biological processes known to be dependent on M-CSF were significantly different, including cell cycle control, cytoskeletal organization, and apoptosis. RAW 264.7 cells exhibited constitutive activation of Erk and Akt that was dependent on the activity of Abelson tyrosine kinase, and the timing of Erk and Akt activation was significantly different between BMMs and RAW 264.7 cells. Our findings provide the first evidence for major discrepancies between BMMs and RAW 264.7 cells, indicating that careful consideration is needed when using the RAW 264.7 cell line for studying M-CSF-dependent signaling and functions. (c) 2018 American Society for Bone and Mineral Research. (c) 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. PMID- 30460337 TI - Mucin 1 (Muc1) Deficiency in Female Mice Leads to Temporal Skeletal Changes During Aging. AB - Mucin1 (MUC1) encodes a glycoprotein that has been demonstrated to have important roles in cell-cell interactions, cell-matrix interactions, cell signaling, modulating tumor progression and metastasis, and providing physical protection to cells against pathogens. In this study, we investigated the bone phenotype in female C57BL/6 Muc1 null mice and the impact of the loss of Muc1 on osteoblasts and osteoclasts. We found that deletion of Muc1 results in reduced trabecular bone volume in 8-week-old mice compared with wild-type controls, but the trabecular bone volume fraction normalizes with increasing age. In mature female mice (16 weeks old), Muc1 deletion results in stiffer femoral bones with fewer osteoblasts lining the trabecular surface but increased endosteal mineralized surface and bone formation rate. The latter remains higher compared with wild type females at age 52 weeks. No difference was found in osteoclast numbers in vivo and in bone marrow osteoblast or osteoclast differentiation capacity or activity in vitro. Taken together, these results suggest that Muc1 depletion causes a transiently reduced trabecular bone mass phenotype in young mice, and later in life reduced numbers of osteoblasts with increased endocortical mineralization activity coincides with unaffected total bone mass and increased stiffness. In conclusion, our results show, for the first time to our knowledge, a role for Muc1 in bone mass and mineralization in mice in a time-dependent manner. (c) 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. PMID- 30460334 TI - Rethinking Bone Disease in Kidney Disease. AB - Renal osteodystrophy (ROD) is the bone component of chronic kidney disease mineral and bone disorder (CKD-MBD). ROD affects bone quality and strength through the numerous hormonal and metabolic disturbances that occur in patients with kidney disease. Collectively these disorders in bone quality increase fracture risk in CKD patients compared with the general population. Fractures are a serious complication of kidney disease and are associated with higher morbidity and mortality compared with the general population. Furthermore, at a population level, fractures are at historically high levels in patients with end-stage kidney disease (ESKD), whereas in contrast the general population has experienced a steady decline in fracture incidence rates. Based on these findings, it is clear that a paradigm shift is needed in our approach to diagnosing and managing ROD. In clinical practice, our ability to diagnose ROD and initiate antifracture treatments is impeded by the lack of accurate noninvasive methods that identify ROD type. The past decade has seen advances in the noninvasive measurement of bone quality and strength that have been studied in kidney disease patients. Below we review the current literature pertaining to the epidemiology, pathology, diagnosis, and management of ROD. We aim to highlight the pressing need for a greater awareness of this condition and the need for the implementation of strategies that prevent fractures in kidney disease patients. Research is needed for more accurate noninvasive assessment of ROD type, clinical studies of existing osteoporosis therapies in patients across the spectrum of kidney disease, and the development of CKD-specific treatments. (c) 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research. PMID- 30460338 TI - Evidence That Rat Chondrocytes Can Differentiate Into Perichondrial Cells. AB - During early bone formation, mesenchymal cells condense and then differentiate into collagen type II-expressing chondrocytes that make up the cartilaginous bone anlagen. This anlage then becomes enclosed by the perichondrium. The mechanisms by which the perichondrium forms are not known. The purpose of this study was to determine whether epiphyseal chondrocytes can differentiate into perichondrial cells. Novel perichondrium markers were identified by expression microarray of microdissected rat perichondrium and growth plate cartilage. A dissection method that allowed for removal of contaminating perichondrium was developed and the absence was confirmed by histological examination and by expression of perichondrium markers. Perichondrium formation surrounding chondrocyte pellets was studied using histology, real-time PCR, and in situ hybridization for chondrocyte and perichondrium markers. Cultured chondrocyte pellets developed an exterior perichondrium-like layer. This surrounding tissue did not express chondrocyte markers, collagen-type II and type X, as assessed by in situ hybridization. Instead, perichondrium markers, periostin, Dickkopf 3 (Dkk3), roundabout 2, cadherin 2, L-galectin 1 (Lgals1), and thrombospondin 2 (Thbs2) were upregulated following formation of the perichondrium-like layer as assessed by real-time PCR. Interestingly, markers specific for the cambium layer, Dkk3, Thbs2, and Lgals1, but not for the fibrous layer, collagen-type XIV and decorin, were upregulated. The findings suggest that epiphyseal chondrocytes of postnatal animals retain the potential to differentiate into perichondrial cells, supporting the hypothesis that the perichondrium originates from collagen type II expressing chondrocytes at the periphery of the cartilaginous bone template. (c) 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. PMID- 30460339 TI - Dynamic Analyses of the Short-Term Effects of Different Bisphosphonates Using Intravital Two-Photon Microscopy. AB - Bisphosphonates are commonly used for the treatment of bone disorders such as osteoporosis; however, the mechanism by which they affect the dynamics of living mature osteoclasts in vivo remains unknown. Here, we describe the short-term effects of different bisphosphonates on controlling the bone resorptive activity of mature osteoclasts in living bone tissues of mice using intravital two-photon microscopy with a pH-sensing chemical fluorescent probe. Three types of nitrogen containing bisphosphonates, risedronate, alendronate, and minodronate, inhibited osteoclastic acidification during osteoporotic conditions just 12 hours after i.v. injection. Among the three types of drugs, risedronate was the most effective at increasing osteoclast motility and changing the localization of proton pumps, which led to an inhibition of bone resorption. Together, these results demonstrate that the intravital imaging system is a useful tool for evaluating the similarities and differences in currently used antibone resorptive drugs. (c) 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. PMID- 30460341 TI - Surgery: To what extent can we operate? PMID- 30460340 TI - The Free Hormone Hypothesis: Is Free Serum 25-Hydroxyvitamin D a Better Marker for Bone Mineral Density in Older Women? AB - It is presently unclear whether free serum 25-hydroxyvitamin D (S-25(OH)D) better reflects bone health than total S-25(OH)D. We have previously shown that summer total S-25(OH)D values are more useful to predict bone mineral density (BMD) than winter values. Our objective was therefore to compare the relative importance of free and total S-25(OH)D for BMD by season. BMD was measured by dual-energy X-ray absorptiometry (DXA) in 5002 Swedish women (mean age 68 years) randomly selected from a large population-based longitudinal cohort study. Free S-25(OH)D was analyzed by a commercial ELISA and total S-25(OH)D by HPLC-tandem mass spectrometry (MS/MS). Free and total S-25(OH)D co-varied with season, with 26% and 29% higher values in August compared with those in January-March (nadir). There were no differences in mean BMD between categories of free or total S 25(OH)D in samples collected during winter. Women with higher total S-25(OH)D measured during summer had higher BMD at the total hip. Compared with women who had total S-25(OH)D values above 80 nmol/L during summer, adjusted BMD at the total hip was 6% (95% CI, 1% to 11%) lower for S-25(OH)D concentrations between 30 and 40 mmol/L, and 11% (95% CI, 3% to 19%) lower for those with total S 25(OH)D <30 nmol/L. In contrast, free S-25(OH)D measured during summer was not associated with BMD. Compared with women who had highest free S-25(OH)D measured during summer (>8.8 pmol/L), those with intermediate (2.4-3.5 pmol/L) and lowest (<2.4 pmol/L) free S-25(OH)D during summer did not have lower total hip BMD values (3% [95% CI, -2% to 7%] and -2% [95% CI, -8% to 4%]). In addition, we found no added value for the prediction of BMD with the combined measurement of total and free S-25(OH)D during summer or winter. We conclude that vitamin D status assessed by direct measurements of free S-25(OH)D does not reflect BMD better than total S-25(OH)D. (c) 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. PMID- 30460342 TI - Recent updates in perioperative chemotherapy and recurrence pattern of gastric cancer. AB - Gastrectomy with D2 lymph node dissection has become the global standard procedure for locally advanced gastric cancer to maximally reduce locoregional recurrence. In East Asia, based on the evidence of the ACTS-GC and the CLASSIC trials, postadjuvant chemotherapy with S-1 monotherapy or capecitabine and oxaliplatin after curative D2 gastrectomy is the current standard strategy. However, approximately 20% to 30% of patients still develop distant recurrence even after these postadjuvant chemotherapies, especially in those with pathological stage III disease. This review summarizes recent (2008-2018) evidence on the benefits of adjuvant therapy for locally advanced gastric cancer. JACRO GC-07, a Phase III trial, recently showed a superior 3-year recurrence-free survival of the S-1 plus docetaxel regimen in comparison to S-1 monotherapy for patients with pathological stage III gastric cancer after curative D2 gastrectomy. With regard to recent new evidence on neoadjuvant strategy, JCOG0501, a Phase III trial, did not show any superiority in 3-year overall survival (OS) of additional neoadjuvant chemotherapy with S-1/cisplatin over postadjuvant S-1 monotherapy in scirrhous type gastric cancer. Further clinical trials of neoadjuvant chemotherapy are ongoing to improve the poor prognosis for gastric cancer with extensive lymph node metastases. These trials could lead to new evidence for improved treatment of gastric cancer in the near future. PMID- 30460343 TI - Robotic-assisted surgery for rectal cancer: Current state and future perspective. AB - Interest in minimally invasive surgery has increased in recent decades. Robotic assisted laparoscopic surgery (RALS) was introduced as the latest advance in minimally invasive surgery. RALS has the potential to provide better clinical outcomes in rectal cancer surgery, allowing for precise dissection in the narrow pelvic space. In addition, RALS represents an important advancement in surgical education with respect to use of the dual-console robotic surgery system. Because the public health insurance systems in Japan have covered the cost of RALS for rectal cancer since April 2018, RALS has been attracting increasingly more attention. Although no overall robust evidence has yet shown that RALS is superior to laparoscopic or open surgery, the current evidence supports the notion that technically demanding subgroups (patients with obesity, male patients, and patients treated by extended procedures) may benefit from RALS. Technological innovation is a constantly evolving field. Several companies have been developing new robotic systems that incorporate new technology. This competition among companies in the development of such systems is anticipated to lead to further improvements in patient outcomes as well as drive down the cost of RALS, which is one main concern of this new technique. PMID- 30460344 TI - Surgery for Pancreatic Cancer after neoadjuvant treatment. AB - Pancreatic ductal adenocarcinoma (PDAC) remains to be a therapeutic challenge as only 15%-20% of all patients present with resectable tumor stages by the time of diagnosis. In the remaining patients, either local tumor extension or systemic spread are obstacles for a surgical therapy as the only chance for long-term survival. With regard to local tumor extension, PDAC has been classified as resectable, borderline-resectable (BR) or locally advanced (LA). While there is currently no evidence for neoadjuvant therapy in resectable PDAC, this issue remains controversial in BR-PDAC. In the case of venous tumor involvement, guidelines mostly recommend upfront resection, when technically possible; whereas arterial involvement is regarded as an indication for chemotherapy or chemoradiotherapy first. Furthermore, in locally advanced PDAC, neoadjuvant treatment approaches have recently resulted in high rates of secondary resection, thus allowing "conversion" surgery in an otherwise palliative treatment situation. The present review gives an overview on the current literature of treatment concepts in these situations and additionally focuses of evaluation of resectability after neoadjuvant therapy as well as technical aspects in this specific situation. PMID- 30460345 TI - High-risk group of upper and middle mediastinal lymph node metastasis in patients with esophagogastric junction carcinoma. AB - Aim: The aim of the present study was to clarify esophagogastric junction (EGJ) carcinoma patients who are at high risk of upper and middle mediastinal lymph node (MLN) metastasis. Methods: This was a retrospective study and included 110 consecutive patients with EGJ carcinoma who underwent R0/R1 resection at Keio University Hospital between January 2000 and December 2013. Results: Of the 110 patients, 18 (16.3%) had MLN metastasis, and the number increased to 23 (20.9%) when recurrence cases were added (adenocarcinoma, N = 11; squamous cell carcinoma, N = 12). Patients whose tumor epicenter was located above the EGJ had a significantly higher incidence of MLN metastasis/recurrence (18/51 [35.3%]) than those whose tumor epicenter was located below the EGJ (5/59 [8.5%]). The MLN metastasis/recurrence rate was particularly high when the distance from the EGJ to the proximal edge of the primary tumor was >3 cm for the upper and middle mediastinum (18.8%). Patients in a selected group (>=T2 and tumor epicenter located above the EGJ or below the EGJ with >=3 cm esophageal invasion) showed 17.9% and 15.4% upper and middle MLN metastasis/recurrence rates, respectively. Therapeutic value of MLN dissection was relatively high (#105 + 106: 8.9, #110: 12.2). Conclusions: Therapeutic value of MLN dissection to treat EGJ carcinomas was relatively high in patients with MLN metastasis. Our algorithm could select patients at high risk for MLN metastasis. PMID- 30460346 TI - Long-term outcomes following restorative proctocolectomy ileal pouch-anal anastomosis in pediatric ulcerative colitis patients: Multicenter national study in Japan. AB - Background: Few studies have investigated surgical outcomes following a colectomy in pediatric patients with ulcerative colitis (UC). Purpose: This study aimed to determine long-term outcomes in a large cohort of pediatric patients who underwent proctocolectomy with ileal pouch-anal anastomosis (IPAA) for UC. Methods: Pediatric patients (<17 years old) who underwent surgery at 12 different hospitals in Japan between May 1979 and March 2015 were included in this study. Information was obtained by the use of a questionnaire survey. Results: There were 113 (53.3%) male and 99 (46.7%) female pediatric patients. The most common indication for elective surgery was failure of medical management, whereas emergency surgery was carried out for fulminant cases. A hand-sewn IPAA was used with a mucosectomy in 112 (52.8%), stapled anastomosis in 93 (43.9%), and not specified in 7 (3.3%) patients. Small bowel obstruction and surgical site infection were the most frequent early postoperative complications (POC), whereas pouchitis, small bowel obstruction, and perianal fistula were frequent late POC. The most common late POC was pouchitis, found in 38 (17.9%) of the patients, whereas pouch failure was noted in 11 patients at the latest follow-up examination. Cumulative pouch survival rate after 10 years was 91.7%. There were no significant differences regarding gender or anastomotic procedure in relation to cumulative pouch survival rate. Conclusion: To avoid pouch failure following an IPAA procedure, it is important to recognize that pouchitis or an anal fistula may lead to this condition in pediatric UC patients. PMID- 30460347 TI - Clinical significance of the globulin-to-albumin ratio for prediction of postoperative survival in patients with colorectal cancer. AB - Aim: A previous study has revealed that the albumin/globulin ratio (GAR) before treatment is a predictor of cancer-specific survival in patients with colorectal cancer (CRC). The aim of the present study was to investigate the clinical significance of GAR for prediction of postoperative survival in patients with CRC. Methods: Nine hundred and forty-one patients who had undergone elective CRC surgery were enrolled. Uni- and multivariate analysis models were performed to detect the clinical characteristics that were most closely associated with overall survival (OS). All recommended cutoff values were defined using receiver operating characteristic curve (ROC) analyses. Kaplan-Meier analysis was used to compare the OS curves between the high GAR (GAR > 0.83) and low GAR (GAR <= 0.83) groups. Results: Multivariate analysis using eight clinical characteristics selected by univariate analyses showed that the GAR was associated with OS (>0.83/<=0.83) (hazard ratio [HR], 1.979; 95% CI, 1.321-2.966; P = 0.001) along with carcinoembryonic antigen (CEA; >8.7/<=8.7, ng/mL; HR, 2.319; 95% CI, 1.569 3.428; P < 0.001), carbohydrate antigen 19-9 (CA19-9; >18.5/<=18.5, U/mL; HR, 1.727; 95% CI, 1.178-2.532; P = 0.005), and the neutrophil-to-lymphocyte ratio (NLR; >2.9/<=2.9; HR, 2.132; 95% CI, 1.454-3.126; P < 0.001), and the area under the ROC (AUROC) curve revealed that the GAR had the largest AUROC among these four clinical characteristics (GAR 0.711 > CEA 0.698 > CA19-9 0.676 > NLR 0.635). A significant difference in OS was observed between patients with low GAR and those with high GAR (P < 0.001). Conclusion: Globulin-to-albumin ratio is a useful predictor of postoperative survival in patients with CRC. PMID- 30460350 TI - Cancer-associated thrombosis: Role of direct oral anticoagulants. PMID- 30460348 TI - Dual-center randomized clinical trial exploring the optimal duration of antimicrobial prophylaxis in patients undergoing pancreaticoduodenectomy following biliary drainage. AB - Objectives: The aim of this dual-center randomized controlled trial was to determine the optimal duration of antimicrobial prophylaxis in patients treated with pancreaticoduodenectomy (PD) who underwent preoperative biliary drainage (PBD) but were without cholangitis. Background: Some reports showed that PBD in patients undergoing pancreatectomy increased the rate of perioperative complications. However, no clinical trial has evaluated the optimal duration of antimicrobial prophylaxis with a focus on patients who underwent PD following PBD. Methods: A total of 82 patients who underwent PD between March 2012 and December 2016 were randomly assigned to either a 1-day group (n = 40), in which cefozopran (CZOP) as antimicrobial prophylaxis was given only on the day of surgery, or a 5-day group (n = 42), in which CZOP was given for 5 consecutive days beginning on the day of surgery. We evaluated the incidence of infectious and other complications after PD. Results: Outcomes were significantly better in the 1-day group compared with the 5-day group (P < 0.05) in terms of the incidence of overall infectious complications (15% vs 36%, respectively), intra abdominal abscess (3% vs 21%, respectively), clinically relevant postoperative pancreatic fistula (8% vs 24%, respectively), and Clavien-Dindo grade III-V complications (10% vs 31%, respectively). Duration of postoperative hospital stay was significantly shorter in the 1-day group (10 days vs 15 days, P = 0.018). Anaerobic bacteria and methicillin-resistant cocci were isolated from the drainage fluid only among patients in the 5-day group. Conclusion: Single-day prophylactic use of CZOP is appropriate for patients who undergo PD following PBD without preoperative cholangitis. PMID- 30460351 TI - Editorial: Can we help smoking patients? How? PMID- 30460352 TI - White Spot Lesion Remineralisation Agents in Primary Teeth: A Systematic Review. AB - PURPOSE: To perform a systematic review of articles related to the clinical efficacy of topical fluoride varnishes/gels, casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), and other remineralisation agents of white spot lesions (WSL) in primary teeth. MATERIALS AND METHODS: Electronic and manual searches were conducted through diverse electronic databases. The search was limited to randomised, clinical, controlled trials, and quasi-experimental papers in full-text version. Suitable individual studies were evaluated through a previously reported quality system, their data extracted and carefully analysed. RESULTS: The search identified 298 citations, and 95 were chosen and reviewed in full text. Nine relevant citations met the eligibility criteria for inclusion in the systematic review. Pair comparisons were made between fluoride varnishes, CPP ACP, dental lasers, and control interventions. CONCLUSIONS: Clinicians are encouraged to discuss more high-quality studies in order to provide sufficient evidence and to confirm the clinical utility of remineralisation agents of WSL in primary teeth. PMID- 30460353 TI - Efficacy and Tolerability of Sodium Bicarbonate Toothpaste in Subjects with Gingivitis: A 6-Month Randomized Controlled Study. AB - PURPOSE: Sodium bicarbonate (NaHCO3) in toothpaste can enhance the removal of biofilms involved in the development of gingivitis. To examine this over an extended time period, this study compared the efficacy and tolerability of twice daily brushing for 24 weeks with 67% or 0% NaHCO3-containing toothpastes in subjects with moderate gingivitis. MATERIALS AND METHODS: 247 adults with bleeding after brushing and >= 20 gingival bleeding sites were randomized to twice-daily brushing with a 67% NaHCO3 or 0% NaHCO3 toothpaste. The primary efficacy variables were between-treatment differences in number of bleeding sites and the Modified Gingival Index (MGI) score after 24 weeks' use. Secondary efficacy variables included Bleeding Index (BI) and Turesky modification of Quigley-Hein Plaque Index (TPI) (overall and only interproximal sites). RESULTS: The 67% NaHCO3 toothpaste produced statistically significant improvements compared with the 0% NaHCO3 toothpaste in number of bleeding sites (-17.5; 95% CI -20.32, -14.66; p < 0.0001) and MGI score (-0.2; 95% CI -0.24, -0.17; p < 0.0001) at week 24. These significant differences were also found at 6 and 12 weeks for these measures and at 6, 12, and 24 weeks for BI and TPI scores (including at only interproximal sites) (all p < 0.0001). No treatment-related adverse events were reported. CONCLUSION: Twice-daily brushing with 67% NaHCO3 toothpaste was generally well tolerated and significantly improved indices of gingival bleeding and plaque compared with 0% NaHCO3 toothpaste in subjects with moderate gingivitis. PMID- 30460349 TI - Signal regulatory protein alpha blockade potentiates tumoricidal effects of macrophages on gastroenterological neoplastic cells in syngeneic immunocompetent mice. AB - Aim: Immunotherapies blocking the CD47-SIRPalpha pathway by targeting CD47 enhance macrophage phagocytosis of neoplastic cells in mouse models. As SIRPalpha exhibits relatively restricted tissue expression, SIRPalpha antagonists may be better tolerated than agents targeting CD47, which is ubiquitously expressed in many tissues. Here, we investigated the therapeutic impact of monoclonal antibodies (mAbs) against CD47 and/or SIRPalpha on gastroenterological tumors in syngeneic immunocompetent mouse models. Methods: We used in vitro and in vivo phagocytosis assays in C57BL/6J (B6) mice to investigate anti-CD47/SIRPalpha mAb effects on Hepa1-6 and CMT93 originating from B6 mice. The influence of these mAbs on macrophage transmigration was also assessed. To investigate anti SIRPalpha mAb therapy-induced inhibitory effects on sporadic colon cancer growth, we used a CDX2P9.5-NLS Cre;APC + /FLOX (CPC-APC) mouse model. Results: Systemic anti-SIRPalpha mAb administration significantly increased Hepa1-6 and CMT93 cell susceptibility to macrophage phagocytosis, both in vitro and in vivo. Conversely, similarly administered anti-CD47 mAb did not promote macrophage phagocytosis of target cells, whereas cells incubated with anti-CD47 mAb prior to inoculation were more susceptible to macrophage phagocytosis. In vitro cell migration assays revealed that binding with anti-CD47 mAb inhibited macrophage transmigration. Anti-SIRPalpha mAb treatment inhibited tumor progression in CPC-APC mice and significantly improved overall survival. Anti-CD47 mAb administration in vivo eliminated the phagocytosis-promoting CD47 blockade effect, probably by inhibiting macrophage transmigration/chemotaxis. In contrast, anti-SIRPalpha mAb exhibited enhanced macrophage phagocytic activity and marked anti-tumor effects against gastroenterological malignancies. Conclusion: SIRPalpha mAb augmentation of macrophage phagocytic activity may represent an effective treatment strategy for human gastrointestinal tumors. PMID- 30460354 TI - Microhardness and SEM-EDX Analysis of Permanent Enamel Surface Adjacent to Fluoride-releasing Restorative Materials Under Severe Cariogenic Challenges. AB - PURPOSE: In this study, the protective effects of restorative materials with fluoride content, resin-modified glass-ionomer cement (RMGIC), giomer, and glass carbomer against artificial initial caries lesions in a simulated highly cariogenic oral environment were evaluated. Considering the reported recharging abilities of these restorative materials, fluoridated toothpaste was applied to some groups, in which the anti-demineralising effect was also evaluated. MATERIALS AND METHODS: Two enamel blocks were produced from each of 60 sound permanent molars. Sixty specimens were used for microhardness analysis, and the rest were used for SEM-EDX analysis. Enamel specimens were randomly assigned to three groups according to the restorative material: A = resin-modified glass ionomer cement; B = giomer; C = glass carbomer. Artificial initial caries lesions were created using demineralising solutions, after which specimens were exposed to in vitro pH cycling simulating a highly cariogenic oral environment. Microhardness and mineral analyses were performed on the enamel surrounding the restorative materials at three different times during the experiment: at the beginning of the experiment, then after the creation of the artificial early caries lesions, and finally after pH cycling. RESULTS: Microhardness and SEM-EDX results mostly confirmed each other. RMGIC and glass carbomer groups with added fluoride toothpaste showed statitsically significantly better anti-demineralising effects in comparison to other groups. Neither of the giomer groups performed as well as RMGIC or glass carbomer. CONCLUSION: Because of the similarity between the demineralisation inhibitory activity of glass carbomer and RMGIC, glass carbomer may be preferred as a restorative material in paediatric dentistry. PMID- 30460355 TI - The Effect of Radiotherapy for Treatment of Head and Neck Cancer on Oral Flora and Saliva. AB - PURPOSE: Radiotherapy causes xerostomia in patients treated for head and neck cancer. This study investigated changes in quality and quantity of saliva after radiotherapy and possible associations between these changes and alterations in oral flora. MATERIALS AND METHODS: The study was a prospective cohort study of patients receiving radiotherapy for head and neck cancer. Suitable patients were recruited before treatment commenced, and informed consent was obtained. Patients were examined, and provided unstimulated and stimulated saliva samples. Quantity of saliva, buffering capacity and pH were measured. Oral flora was cultured from the saliva samples. Oral clearance of glucose and of lactose was measured. These interventions were repeated at intervals after radiotherapy had been completed. RESULTS: Eighteen patients were recruited. Stimulated and unstimulated saliva flow rates, glucose clearance, salivary pH and buffering capacity were significantly reduced after radiotherapy. Candida albicans counts were significantly increased. These increases were significantly correlated with reductions in stimulated and unstimulated salivary flow rates. Counts of lactobacilli, Streptococcus mutans and Bifidobacteriaceae increased, but not statistically significantly. CONCLUSIONS: Therapeutic radiotherapy significantly reduced the quality and quantity of saliva in head and neck cancer patients. These reductions were associated with increased C. albicans counts. PMID- 30460356 TI - Compomers Reinforced with Bioactive Glass and Hydroxyapatite Particles. AB - PURPOSE: To understand the effect of the addition of hydroxyapatite (HA) and bioactive glass (BAG) to compomer restorative materials on the remineralisation capacity of the material. MATERIALS AND METHODS: 1%, 2%, 3% and 4% w/w HA and BAG particles were added mechanically to the compomers. To examine the resistance to demineralisation, Class V cavities were prepared in extracted teeth and restored with experimental filling materials. Demineralised lesions were created in 72 enamel samples. Vickers microhardness measurements of samples were performed at three different areas including the margin of the restoration, the varnish protected enamel and the exposed enamel areas. Measurements performed on protected enamel were used as reference enamel values for each group. SEM was used to evaluate the surface texture of the specimens. The statistical analyses were performed by one-way ANOVA, Tukey's HDS and paired-samples t-tests. RESULTS: BAG and HA groups revealed higher microhardness values at the exposed enamel and exposed marginal enamel than did the control group (p = 0.001). 3% and 4% HA and BAG groups produced higher microhardness values than did 1% modified groups on exposed enamel (p = 0.001). 4% HA group revealed the highest microhardness values on marginal exposed enamel (p = 0.001). 2%, 3%, 4% and HA, as well as 3% and 4% BAG groups showed higher microhardness values than did the control group on marginal exposed enamel at 20 um depth (p = 0.001). SEM images revealed that HA and BAG particles were not distributed homogeneously and the particles seemed to be grouped in the matrix. CONCLUSIONS: Within the limits of this study, the addition of the BAG and HA into compomers improved the demineralisation resistance properties of enamel, depending on the amount of additive. PMID- 30460357 TI - Protection Against Discolouration by Two Over-the Counter Desensitising Products. AB - PURPOSE: To determine in vitro the protection potential against discolouration of two OTC (over-the-counter) desensitising products on enamel and dentin in comparison to a standard toothpaste and water by means of a spectrophotometer. MATERIALS AND METHODS: A total of 96 samples of bovine enamel-dentin complex and 48 of bovine dentin were alternatively immersed in red wine, tea, coffee or water after having been treated by a sodium monofluorophosphate- and calcium phosphate based product (Curodont Protect), an amine fluoride-based toothpaste (Elmex Red), a stannous chloride-based toothpaste (Elmex Protection Erosion) or distilled water (negative control). Initial (T0) and final colour (T1, after 4 weeks of immersion in staining solutions) of each specimen were assessed by a spectrophotometer. Statistical analysis was done by means of repeated measures ANOVA followed by Fisher's LSD post-hoc test. Differences between T0 and T1 were considered stastistically significant at p <= 0.05. RESULTS: When enamel samples were measured over a black background, DeltaE00 values (T0-T1) varied from 2.2 (SD 0.7) for amine fluoride-based product/water to 53.9 (SD 7.6) for amine fluoride-based-product/red wine. When dentin samples were measured over a black background, DeltaE00 values (T0-T1) varied from 5.4 (SD 0.9) stannous chloride based product/water to 61.6 (SD 3.7) amine fluoride-based product/red wine. CONCLUSION: Specifically, the application of the sodium monofluorophosphate was able to statistically significantly (p <= 0.05) reduce discolouration induced by the staining solutions tested only on the enamel-dentin complex, while distilled water and the stannous fluoride-based product were able to statistically significantly (p <= 0.05) reduce discolouration induced by the staining solutions tested in pure dentin samples. PMID- 30460358 TI - Isolation and Characterisation of Probiotics for Antagonising the Cariogenic Bacterium Streptococcus mutans and Preventing Biofilm Formation. AB - PURPOSE: Consumption of refined foods and beverages high in sugar make the teeth susceptible to the formation of biofilm and may lead to dental caries. The aim of the present study was to determine the ability of selected probiotics to inhibit growth and biofilm formation by the cariogenic bacterium Streptococcus mutans in vitro. MATERIALS AND METHODS: Strains of latic acid bacteria (LAB) (n = 120) from the Bioresources Collection and Research Center (BCRC), saliva of healthy adults and infant stool were screened. The antimicrobial activity of LAB in vitro was evaluated by agar spot culture and co-culture of the S. mutans strains. Antagonistic substances in the spent culture suspensions (SCS) of LAB were precipitated by extraction with ammonium sulphate and chloroform to characterise the protein and lipophilic fractions. RESULTS: Results of co-culturing show that the SCS of the three LAB strains (Lactobacillus pentosus 13-1, 13-4 and L. crispatus BCRC 14618) subjected to heat treatment showed statistically significantly higher antimicrobial activity. Substances produced by L. pentosus 13-4 which have the potential to exhibit antimicrobial properties might be lipophilic proteins. Additionally, microtiter plate biofilm assays indicated that in vitro biofilm formation by S. mutans is strongly modulated by L. pentosus 13-4 and L. crispatus BCRC 14618. CONCLUSION: It can be inferred that the mechanism of reducing biofilm formation by these two LAB strains is associated with sucrose dependent cell-cell adhesion and the gtfC level of glucosyltransferases in the biofilm. Therefore, it is suggested that L. pentosus 13-4 and L. crispatus BCRC 14618 may contribute to preventing dental caries, as they showed an inhibitory effect on the growth and biofilm formation of the cariogenic bacterium S. mutans in vitro. PMID- 30460359 TI - Plaque Accumulation and Inflammation Adjacent to Restorations of Amorphous Calcium Phosphate-containing Composite in Early Childhood Caries. AB - PURPOSE: To evaluate the clinical, biochemical, and microbiological reactions to nanocomposite containing amorphous calcium phosphate (ACP) in comparison to a traditional composite restorative material in early childhood caries. MATERIALS AND METHODS: Eighteen teeth were restored with the test material (ACP-containing resin) and 18 teeth were restored with the control material (traditional composite, TC) in fourteen paediatric patients using a split-mouth design. One caries- and restoration-free intact tooth in each patient was selected as the healthy control. Gingival crevicular fluid (GCF) and supragingival plaque samples were collected at baseline before the treatment and also on days 1, 7, 14 and 30 after treatment. Unstimulated whole saliva samples were obtained from each patient at baseline, and 1 and 6 months after restoration. GCF and saliva samples were assayed for IL-17A, IL-17F IL-17A/F, IL-17E, OPG and RANKL levels by ELISA, and plaque composition was assessed using RT-PCR. RESULTS: Clinical evaluation indicated no statistically significant differences between the two restorative materials according to the FDI criteria surface lustre, material retention and marginal adaptation properties. Pro-inflammatory IL-17 levels decreased statistically significantly at 6 months compared to baseline and 1-month values (p < 0.05). The baseline pro-inflammatory IL-17 cytokine levels in GCF samples around the carious teeth were higher than those obtained around the healthy teeth (p < 0.05), but similar in GCF from the ACP-test and TC teeth. Microbiological findings were similar in the ACP and T groups. CONCLUSION: It may be suggested that both ACP-containing and traditional resin composites show similar antimicrobial and biochemical effects in early childhood caries. PMID- 30460360 TI - Pufa Index and Related Factors Among 36- to 71-month-old Children in Turkey: A Cross-Sectional Study. AB - PURPOSE: To determine the clinical consequences of untreated dental caries among preschool children by using the pufa index (visible pulp, ulceration of the oral mucosa due to root fragments, a fistula or an abscess) and the incorporation of some risk factors. MATERIALS AND METHODS: Data were collected via structured, pre tested questionnaires from 729 parents in Turkey's capital, Ankara. Examinations were performed under field conditions by one examiner. The decayed teeth were scored according to the International Caries Detection and Assessment System (ICDAS) II criteria. The filled and missing teeth and surfaces were also recorded as dmft and dmfs, and the pufa index was used for the consequences of untreated caries. The associations were evaluated by univariate analysis and logistic regression. RESULTS: The means age of the study population was 58.8 +/- 8.6 months. 45% of the children were female and 55% were male. Mean dmft and dmfs were 4.8 +/- 4.7 and 8.3 +/- 10.2, respectively. 73.8% of the children had early childhood caries (ECC), while 51.0% had severe cases. Only 58 children (8.0%) had totally healthy primary teeth according to ICDAS II. Of the children with caries (n = 538), 17.5% had at least one pufa tooth. According to the logistic regression analysis, sex, having at least one sibling, extraction experience, and father's educational level were found to be the factors associated with the existence of pufa. CONCLUSION: Healthcare providers' attention must be drawn to both untreated carious lesions and the high ECC proportion among preschool children. PMID- 30460361 TI - Mechanism of phase transfer of uranyl ions: a vibrational sum frequency generation spectroscopy study on solvent extraction in nuclear reprocessing. AB - Mechanistic understanding of solvent extraction of uranyl ions (UO22+) by tributyl phosphate (TBP) will help improve the technology for the treatment and disposal of spent nuclear fuels. So far, it has been believed that uranyl ions in the aqueous phase are adsorbed to a TBP-enriched organic/aqueous interface, form complexes with TBP at the interface, and are extracted into the organic phase. Here we show that uranyl-TBP complex formation does not take place at the interface using vibrational sum frequency generation (VSFG) spectroscopy and propose an alternative extraction mechanism that uranyl nitrate, UO2(NO3)2, passes through the interface and forms the uranyl-TBP complex, UO2(NO3)2(TBP)2, in the organic phase. PMID- 30460362 TI - Quantifying cyanide in water and foodstuff using corrin-based CyanoKit technologies and a smartphone. AB - This paper describes the detection of endogenous cyanide using corrin-based CyanoKit technologies in combination with a smartphone readout device. When applied to the detection of cyanide in water, this method demonstrates high repeatability and discriminative power with a limit of blank of 0.074 ppm and an instrument limit of detection of 0.13 ppm. Quantification of endogenous cyanide in cassava and bitter almond extracts with the smartphone readout is in excellent agreement with independent analyses using traditional spectrophotometric detection. The prototype system objectively detects levels of cyanide with a high granularity at the point-of-need and does not depend on large, heavy and expensive instrumentation. The methodology has the potential to be easily adopted in resource limited situations and low-income countries. PMID- 30460363 TI - Eu(iii) and Tb(iii) complexes of 6-fold coordinating ligands showing high affinity for the hydrogen carbonate ion: a spectroscopic and thermodynamic study. AB - In the present contribution, four classes of Ln(iii) complexes (Ln = Eu and Tb) have been synthesized and characterized in aqueous solution. They differ by charge, Ln(bpcd)+ [bpcd2- = N,N'-bis(2-pyridylmethyl)-trans-1,2 diaminocyclohexane N,N'-diacetate] and Ln(bQcd)+ (bQcd2- = N,N'-bis(2 quinolinmethyl)-trans-1,2-diaminocyclohexane N,N'-diacetate) being positively charged and Ln(PyC3A) (PyC3A3- = N-picolyl-N,N',N'-trans-l,2 cyclohexylenediaminetriacetate) and Ln(QC3A) (QC3A3- = N-quinolyl-N,N',N'-trans l,2-cyclohexylenediaminetriacetate) being neutral. Combined DFT, spectrophotometric and potentiometric studies reveal the presence, under physiological conditions (pH 7.4), of a couple of equally and highly stable isomers differing by the stereochemistry of the ligands (trans-N,N and trans-O,O for bpcd2- and bQcd2-; trans-O,O and trans-N,O for PyC3A3- and QC3A3-). Their high log beta values (9.97 < log beta < 15.68), the presence of an efficient antenna effect and the strong increase of the Ln(iii) luminescence intensity as a function of the hydrogen carbonate concentration in physiological solution, render these complexes as very promising optical probes for a selective detection of HCO3-in cellulo or in extracellular fluid. This particularly applies to the cationic Eu(bpcd)+, Tb(bpcd)+ and Eu(bQcd)+ complexes, which are capable of guesting up to two hydrogen carbonate anions in the inner coordination sphere of the metal ion, so that they show an unprecedented affinity towards HCO3- (log K for the formation of the adduct in the 4.6-5.9 range). PMID- 30460364 TI - Hyperspectral analysis applied to micro-Brillouin maps of amyloid-beta plaques in Alzheimer's disease brains. AB - A recent investigation on the architecture and chemical composition of amyloid beta (Abeta) plaques in ex vivo histological sections of an Abeta-overexpressing transgenic mouse hippocampus has shed light on the infrared light signature of cell-activation related biomarkers of Alzheimer's disease. A correlation was highlighted between the biomechanical properties detected by Brillouin microscopy and the molecular make-up of Abeta plaques provided by FTIR spectroscopic imaging and Raman microscopy (with correlative immunofluorescence imaging) in this animal model of the disease. In the Brillouin spectra of heterogeneous materials such as biomedical samples, peaks are likely the result of multiple contributions, more or less overlaid on a spatial and spectral scale. The ability to disentangle these contributions is very important as it may give access to discrete components that would otherwise be buried within the Brillouin peak envelope. Here, we applied an unsupervised non-negative matrix factorization method to analyse the spontaneous Brillouin microscopy maps of Abeta plaques in transgenic mouse hippocampal sections. The method has already been proven successful in decomposing chemical images and is applied here for the first time to acoustic maps acquired with a Fabry-Perot Brillouin microscope. We extracted and visualised a decrease in tissue rigidity from the core through to the periphery of the plaque, with spatially distinct components that we assigned to specific entities. This work demonstrates that it is possible to reveal the structure and mechanical properties of Abeta plaques, with details visualized by the projection of the mechanical contrast into a few relevant channels. PMID- 30460366 TI - Combination of Surgery and Nd:YAG Laser Therapy for Recalcitrant Viral Warts: A Successful Therapeutic Approach for Immunosuppressed Patients. PMID- 30460365 TI - A lung/liver-on-a-chip platform for acute and chronic toxicity studies. AB - The merging of three-dimensional in vitro models with multi-organ-on-a-chip (MOC) technology has taken in vitro assessment of chemicals to an unprecedented level. By connecting multiple organotypic models, MOC allows for the crosstalk between different organs to be studied to evaluate a compound's safety and efficacy better than with single cultures. The technology could also improve the toxicological assessment of aerosols that have been implicated in the development of chronic obstructive pulmonary disease, asthma, or lung cancer. Here we report the development of a lung/liver-on-a-chip, connecting in a single circuit, normal human bronchial epithelial (NHBE) cells cultured at the air-liquid interface (ALI), and HepaRGTM liver spheroids. Maintenance of the individual tissues in the chip increased NHBE ALI tissue transepithelial electrical resistance and decreased HepaRGTM spheroid adenosine triphosphate content as well as cytochrome P450 (CYP) 1A1/1B1 inducibility. CYP inducibility was partly restored when HepaRGTM spheroids were cocultured with NHBE ALI tissues. Both tissues remained viable and functional for 28 days when cocultured in the chip. The capacity of the HepaRGTM spheroids to metabolize compounds present in the medium and to modulate their toxicity was proven using aflatoxin B1 (AFB1). AFB1 toxicity in NHBE ALI tissues decreased when HepaRGTM spheroids were present in the same chip circuit, proving that the HepaRGTM-mediated detoxification is protecting/decreasing from AFB1-mediated cytotoxicity. The lung/liver-on-a-chip platform presented here offers new opportunities to study the toxicity of inhaled aerosols or to demonstrate the safety and efficacy of new drug candidates targeting the human lung. PMID- 30460367 TI - A Case of Aplasia Cutis Congenita with Widespread Multifocal Skin Defects Without Extracutaneous Abnormalities. PMID- 30460368 TI - Use of Anti-transcriptional Intermediary Factor-1 Gamma Autoantibody in Identifying Adult Dermatomyositis Patients with Cancer: A Systematic Review and Meta-analysis. AB - Anti-transcriptional intermediary factor-1gamma (TIF-1gamma) autoantibody may be associated with cancer in adult patients with dermatomyositis. The aim of this study was to evaluate the risk of cancer in the presence of anti-TIF-1gamma autoantibody in adult dermatomyositis. A comprehensive database search of EMBASE, MEDLINE and the Cochrane Library up to May 2018 was performed using the main key words "dermatomyositis", ""myositis", "inflammatory myopathies" and "anti-TIF-1". Eighteen studies, with a total of 1,962 dermatomyositis, were included in the meta-analysis. The pooled prevalence of cancer-associated dermatomyositis in patients with anti-TIF-1gamma autoantibody was 0.41 (95% confidence interval (CI) 0.36-0.45). In the presence of anti-TIF-1gamma autoantibody, the overall diagnostic odds ratio of cancer was 9.37 (95% CI 5.37-16.34) with low heterogeneity (Cochran's Q: 14.88 (df = 17, p = 0.604); I2 = 0%). The results of this systematic review confirm that detection of anti-TIF-1gamma autoantibody is a valuable tool to identify a subset of adult dermatomyositis patients with higher risk of cancer. PMID- 30460369 TI - Changes in Lesional and Non-lesional Skin Microbiome During Treatment of Atopic Dermatitis. AB - The aim of this study was to evaluate changes in the skin surface microbiome in patients with atopic dermatitis during treatment. The effect of narrowband ultraviolet B phototherapy was also studied to determine the influence of exposure to ultraviolet. A total of 18 patients with atopic dermatitis were included in the study. Patients were divided into 2 groups based on treatment: 1 group treated with narrowband ultraviolet B phototherapy and topical corticosteroid, and the other group treated with topical corticosteroid only. Skin swabs and high-throughput sequencing of 16S ribosomal RNA bacterial genes were performed at 3 time-points. The microbial diversity of lesional skin increased greatly after treatment. The proportion of Staphylococcus aureus showed a significant positive correlation with eczema severity. In conclusion, a drastic increase in microbial diversity and decrease in S. aureus proportion were observed with eczema treatment. Narrowband ultraviolet B treatment did not exert additive effects on eczema improvement; however, it appeared to reduce the recurrence of eczema. PMID- 30460371 TI - Treatment-Induced Delusions of Infestation Associated with Increased Brain Dopamine Levels. PMID- 30460370 TI - Psoriasis as a Predictor of Cardiometabolic Comorbidity in Women: A Study Based on the Danish National Birth Cohort. AB - Psoriasis is associated with cardiometabolic comorbidity; however, whether this is due to common lifestyle-related risk factors is unclear. This study investigated the association between psoriasis and cardiometabolic comorbidity, taking body mass index and smoking into account. The population comprised expectant mothers in the Danish National Birth Cohort (established 1996-2002). During pregnancy, the women were asked about physician-diagnosed psoriasis. Any association with self-reported cardiometabolic comorbidity 11 years later was assessed using logistic regression. The cohort was also followed up for hospital diagnosed comorbidity, including cardiac death, until 31 December 2014, and the risk was assessed using Cox regression. A total of 2,435 women with psoriasis (2.90%) and 81,388 women without were identified. Psoriasis was significantly associated with self-reported hypercholesterolaemia (adjusted odds ratio 1.31; 1.01-1.70) and hospital-diagnosed hypertension (adjusted hazard ratio 1.33; 1.08 1.65). Women with psoriasis have an increased risk of developing cardiometabolic comorbidity in early adult life. PMID- 30460372 TI - Tazarotene 0.015% Cream as a Potential Topical Agent for Management of Ichthyosis in Dorfman-Chanarin Syndrome. PMID- 30460373 TI - Prevalence and Description of Hidradenitis Suppurativa in Down Syndrome: A Cross sectional Study of 783 Subjects. PMID- 30460374 TI - Antipruritic Effects of Janus Kinase Inhibitor Tofacitinib in a Mouse Model of Psoriasis. AB - The Janus kinase 1/3 inhibitor tofacitinib has demonstrated an antipruritic effect in two phase IotaIotaIota studies in psoriasis. However, the mechanisms behind this antipruritic effect are still unknown. We presently investigated whether tofacitinib affects spontaneous itch as well as expression of itch related cytokines and epidermal nerve fiber density (ENFD) in the imiquimod induced mouse model of psoriasis. Psoriasis-like skin lesions were produced by daily topical application of imiquimod to the back skin. Imiquimod treatment resulted in spontaneous scratching, which was significantly inhibited by tofacitinib treatment. Imiquimod treatment significantly increased mRNA expression of Il22, Il23, and Il31, reduced peptidergic ENFD, and increased nonpeptidergic ENFD compared to naive mice. Tofacitinib significantly decreased the expression of those cytokines and increased peptidergic ENFD without a significant effect on nonpeptidergic ENFD. Tofacitinib may inhibit psoriatic itch through inhibition of cytokine expression as well as modulation of epidermal innervation. PMID- 30460375 TI - Usefulness of Psychiatric Intervention in a Joint Consultation for the Treatment of Burning Mouth Syndrome: A Monocentric Retrospective Study. AB - Primary burning mouth syndrome is a term used for chronic oral mucosal pain with no identifiable organic cause. The aim of the study was to evaluate the usefulness of a psychiatric intervention for treating burning mouth syndrome based on a joint consultation with a psychiatrist and a dermatologist. The study was proposed to all patients who visited this consultation group between 2001 and 2017 for the treatment of primary burning mouth syndrome. The patients answered a questionnaire that was administered via mail. Of the 57 patients diagnosed with primary burning mouth syndrome, 38 were included. Seven patients (18.4%) no longer had pain; 8 (21.1%) estimated that the pain had decreased by greater than 50%; 11 (28.9%) estimated the decrease at between 30 and 50%, and 12 (31.6%) estimated a less than 30% decrease. Only 14 patients (36.8%) remained under treatment with antidepressants, as compared to 63.2% before the psychiatric intervention. This psychiatric intervention could be considered a valuable tool in the global burning mouth syndrome treatment strategy. PMID- 30460376 TI - Early detection value of 18F-FDG-PET/CT for drug-induced lung injury in lymphoma. AB - Recent studies have not only shown better prognosis of lymphoma with the advancement of therapeutic drug development, but also suggested more attention should be paid to drug-induced lung injury. Early diagnosis is critical for treatment of drug-induced lung injury. 18F-FDG-PET/CT, the standard imaging method for prognosis evaluation of Hodgkin's lymphoma and some non-Hodgkin's lymphoma, has also shown the potential for early detection of drug-induced lung injury in our study. A total of 579 lymphoma patients evaluated by 18F-FDG-PET/CT between June 2016 and March 2018 are studied retrospectively. Clinical and imaging characteristics are described in 32 patients (average age of 55), who were diagnosed with drug-induced lung injury. The incidence of drug-induced lung injury was 5.53% (32/579); most of the chemotherapy regimens include rituximab (90.63%, 29/32). Twelve patients demonstrated fever, cough, and dyspnea, and the other 20 had no significant symptoms. 18F-FDG-PET/CT showed multiple or diffused distribution of ground glass and patchy shadows, with increased FDG uptake in both lungs (SUVmax 2.28 +/- 1.13, standardized uptake ratio-blood pool, SUR-BP = 0.59-4.07, median SUR-BP 1.32). SUVmax and SUR-BP in patients with symptoms (SUVmax 3.03 +/- 1.33 and SUR-BP 2.12 +/- 1.06) were significantly higher than in those without symptoms (SUVmax 1.84 +/- 0.70 and SUR-BP 1.18 +/- 0.48) (P = 0.002 for both SUVmax and SUR-BP). After temporary drug withdrawal, changing chemotherapy regimens, and corticosteroid usage, the pulmonary lesions in all patients were relieved, confirmed with chest CT. Drug-induced lung injury can be a co-finding during 18F-FDG-PET/CT assessment of lymphoma. With positive correlation between FDG uptake and symptoms, 18F-FDG-PET/CT provided value in early detection of lung injury in asymptomatic patients. PMID- 30460377 TI - Downregulation of DAPK1 promotes the stemness of cancer stem cells and EMT process by activating ZEB1 in colorectal cancer. AB - Cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) play an important role in the metastasis and chemoresistance in the context of colorectal cancer (CRC). Downregulation of death associated protein kinase 1 (DAPK1) may promote metastasis and chemoresistance of cancer cells through various mechanisms. However, the association between DAPK1 and CSCs or EMT has not been explored. In this study, we demonstrated that DAPK1 was associated with elevated stemness of CSCs in patients with CRC. Silencing of DAPK1 in CRC cell lines promoted the metastasis and chemoresistance due to increased stemness of CSCs and enhanced mesenchymal phenotype, an effect that was mediated via activation of the transcription factor, zinc finger E-box binding homeobox 1 (ZEB1). Blockade of this signaling pathway attenuated the stemness of CSCs and rescued the EMT process. DAPK1-ZEB1 may lie at the interface of TGF-beta and WNT pathways and participate in both CSCs and EMT process. Targeted therapies aimed at DAPK1-ZEB1 pathway may inhibit the chemoresistance and metastasis of CRC. KEY MESSAGES: Downregulation of DAPK1 promotes chemoresistance and metastasis of CRC. Inhibition of DAPK1 promotes the stemness of cancer stem cells and EMT process. DAPK1-ZEB1 may lie at the interface of TGF-beta and WNT pathways. DAPK1-ZEB1 participates in both CSCs and EMT process. PMID- 30460378 TI - Risk factors for suicide in rural Italy: a case-control study. AB - PURPOSE: Increased frequency of suicide in rural areas of Tuscany has been described since the 1970s. A case-control study was conducted in 2014 and 2015. The objective of this study was to identify major individual risk factors related to suicides in six rural districts of Tuscany. METHODS: Cases were identified as all 128 suicides occurred in six rural districts between 2009 and 2013. Controls (three for each case) were matched for age, sex, and general practice. Information was collected from GPs using a structured questionnaire. Univariate and multivariate analyses were carried out to investigate the association between individual risk factors and suicide. RESULTS: Informants for 91 cases of the 128 identified cases were successfully interviewed (response rate 71.1%). About 40.5 65.9% suicide cases and 11.4-20.0% of controls had some psychiatric pathology, accordingly to different definitions. Univariate conditional regression analysis showed that living in isolated houses (OR 2.48), living alone (OR 2.97), not being married (OR 2.63), low income (OR 2.73), psychiatric pathology (OR 9.70), psychotropic medication (OR 5.58), problems with relatives (OR 14.78), psychiatric family history (OR 5.67), and suicidal ideation (OR 15.61) were all risk factors. Practising religion (OR 0.27) was the only protective factor identified. Multivariate regression identified two independently and significantly associated variables namely, psychiatric pathology (OR 8.87) and living alone (OR 2.30). CONCLUSIONS: Results of this study showed, similarly to recent research, that not all suicide events are the results of psychiatric pathology. Prevention strategies should, therefore, target both socio-economic and clinical risk factors. PMID- 30460379 TI - Controlled outcome of Hirschsprung's disease beyond adolescence: a single center experience. AB - PURPOSE: The aim of this study was to assess the function and quality of life of Hirschsprung's Disease (HD) beyond adolescence and relate it to matched controls. METHODS: All 203 patients diagnosed with HD at our department from 1961 to 1995 were identified. 21 had died, 43 had unclear diagnosis and 16 could not be traced. The remaining 123 patients were sent bowel function and SF-36 quality of life questionnaires. 69 patients (mean age 37.8, range 22-58, 13 female) responded and were matched with 138 age and sex-matched controls. RESULTS: Function: HD-patients had significantly higher number of bowel movements per week, higher incidence of soiling, urgency, permanent stomas, use of laxatives, enemas and loperamide. HD-patients also scored significantly lower in their satisfaction with their bowel function. There was, however, no significant difference in Miller Incontinence score. QOL: HD-patients reported a significantly higher incidence of negative impact by their bowel function on daily life, social interaction and ability to go on vacation. There were no significant differences in SF-36-scores. CONCLUSIONS: Bowel function has a lifelong negative impact on the lives of patients with HD. This strongly indicates a need for structured follow-up beyond adolescence. PMID- 30460380 TI - Cultural adaptation and validation of the Turkish CONTILIFE: a quality of life questionnaire for urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: The objective of the present study was to adapt the CONTILIFE, a quality-of-life questionnaire, into Turkish and to reveal its psychometric properties in women suffering from stress urinary incontinence (SUI). METHODS: Ninety-eight patients with a symptom of SUI participated in the study and filled out the Turkish CONTILIFE. Cronbach's alpha (alpha) and intraclass correlation coefficients (ICCs) were evaluated for the internal consistency and test-retest reliability, respectively. Exploratory factor analysis was performed to determine the underlying structure. Criterion validity was analyzed using the correlation coefficients between the total and subscale scores of the CONTILIFE and King's Health Questionnaire (KHQ), the Incontinence Impact Questionnaire-7 (IIQ-7), and the Urinary Distress Inventory-6 (UDI-6). RESULTS: Internal consistency was found to be strong to very strong (Cronbach's alpha: 0.90-0.96). Test-retest reliability was very strong (ICCs = 0.91-0.98, p < 0.001). Exploratory factor analysis revealed five significant factors, explained by 74% of the total variance. Total scores on the CONTILIFE were significantly correlated with the KHQ subscales (r = -0.43 - -0.81), IIQ-7 (r = -0.89), UDI-6 (r = -0.66), and ISI (r = -0.66); (p < 0.01). CONCLUSION: The Turkish CONTILIFE is a valid and reliable tool to determine the influence of SUI on health-related quality of life in Turkish women. PMID- 30460381 TI - Use of observed ureteric catheter movement to facilitate laparoscopic identification and dissection of the ureter in complex gynaecological procedures. AB - INTRODUCTION AND HYPOTHESIS: Ureteric injury is a serious complication in gynaecological surgery. Identification and dissection of the ureter is important to minimise the risk of injury. However, some pelvic pathologies and previous pelvic surgery can render laparoscopic identification and dissection of the ureter difficult and risky. This video demonstrates the use of observing ureteric catheter movement to facilitate identification and dissection of the ureter in complicated laparoscopic gynaecological procedures. MATERIALS: A 42-year-old woman with previous history of total abdominal hysterectomy underwent laparoscopic removal of her right ovary, which was plastered over the course of the ureter. A 5-F ureteric catheter was inserted, and observing its movement facilitated identification and dissection of the ureter from the ovary. RESULTS: The procedure was completed safely, and the patient was discharged the same day. CONCLUSIONS: This video demonstrates that moving the ureteric catheter laparoscopically to facilitate identification and dissection of the ureter in complex gynaecological procedures may be useful for urogynecologists when assisting ureteric dissection in complex cases. PMID- 30460382 TI - Long waiting time before tooth extraction may increase delayed wound healing in elderly Japanese. AB - : In osteoporosis patients receiving antiresorptive medications, stopping the drug and delaying tooth extraction has been suggested to reduce the risk of osteonecrosis of the jaw (ONJ). However, postponing tooth extraction for >= 2 months was associated with an increased risk of delayed wound healing beyond 8 weeks after extraction, a risk factor for developing ONJ. INTRODUCTION: A long waiting time before tooth extraction could result from concern about a potential increased risk of osteonecrosis of the jaw (ONJ) in osteoporosis patients. We clarified whether a long waiting time before tooth extraction during the past year may be associated with an increased risk of delayed wound healing beyond 8 weeks after tooth extraction, which may be a risk factor of ONJ. METHODS: Of 5639 patients aged >= 60 years who visited our 20 clinics or hospitals and answered a structured questionnaire, 426 patients (151 men, 275 women) aged 60-96 years comprised the final participants in this study. Self-reported kyphosis was used as a surrogate marker of vertebral fractures. Stepwise logistic regression analysis, adjusted for covariates, was used to calculate the odds ratio (OR) and the 95% confidence interval (CI) for the presence of delayed wound healing longer than 8 weeks after tooth extraction during the past year based on the duration before extraction. RESULTS: Subjects who had waited > 2 months for tooth extraction had a significantly higher risk of delayed wound healing compared with those whose tooth was extracted within 1 month (OR = 7.23; 95% CI = 2.19-23.85, p = 0.001) regardless if antiresorptive medications for osteoporosis were used. The presence of self-reported kyphosis was significantly associated with an increased risk of delayed wound healing (OR = 5.08; 95% CI = 1.11-23.32, p = 0.036). CONCLUSIONS: A long waiting time before tooth extraction may be a risk factor for delayed wound healing beyond 8 weeks after extraction in patients aged >= 60 years. PMID- 30460383 TI - Vertebral Compression Fracture as the Complication of Embolization by Direct Puncture with Transpedicular Approach in a Patient with Type II Endoleak After Endovascular Aortic Repair. PMID- 30460384 TI - Lymphangiography and Post-lymphangiographic Multidetector CT for Preclinical Lymphatic Interventions in a Rabbit Model. AB - PURPOSE: To describe the feasibility of lymphangiography and the visibility of the lymphatic system using post-lymphangiographic multidetector CT (MDCT) for preclinical lymphatic interventions in a rabbit model. MATERIALS AND METHODS: Lymphangiography via the popliteal lymph node or vessel after surgical exposure was performed, using six healthy female Japanese White rabbits. Lipiodol was manually injected for lymphangiography. Post-lymphangiographic MDCT examinations were performed in all rabbits. The dataset images were subjected to image processing analysis utilizing the three-dimensional maximum intensity projection technique. Three reviewers evaluated the degree of depiction of the lymphatic system using a four-point visual score (1, poor; 2, fair; 3, good; 4, excellent). The distance between the body surface and cisterna chyli was measured on post lymphangiographic MDCT axial image. RESULTS: Lymphangiography was successfully performed in all rabbits. The popliteal lymph node was detectable in 90%. The visualization of lymphatic system via the popliteal node was achieved in 89%. Mean visual scores of > 3.0 were realized by the right femoral lymphatic vessel, left femoral lymphatic vessel, left iliac lymphatic vessel, left lumbar lymphatic trunks and cisterna chyli, whereas mean visual scores of < 3.0 were yielded by the right iliac lymphatic vessel, right lumbar lymphatic trunks and thoracic duct. The distance between the body surface and cisterna chyli on post lymphangiographic MDCT axial images was 4.33 +/- 0.14 cm. CONCLUSION: Lymphangiography is feasible, and the visibility of the lymphatic system on post lymphangiographic MDCT in a rabbit model provides enough information for interventional radiologists to perform preclinical lymphatic interventions. PMID- 30460385 TI - Approach, Technical Success, Complications, and Stent Patency of Sharp Recanalization for the Treatment of Chronic Venous Occlusive Disease: Experience in 123 Patients. AB - PURPOSE: To report the technical success and complications following sharp recanalization of chronic venous occlusions. MATERIALS AND METHODS: A total of 123 patients, including 75 (61.0%) men and 48 (39.0%) women, with mean age of 50.5 +/- 17.5 years (range 19-90 years), underwent sharp recanalization of chronic venous occlusions. The etiologies of occlusion were chronic deep venous thrombosis (n = 43; 35.0%), prior central venous access (n = 39; 31.7%), indwelling cardiac leads (n = 21; 17.1%), and occluded venous stents (n = 20; 16.3%). The sites of venous occlusion included 59/123 (48.0%) thoracic central veins, 37 (30.1%) non-thoracic central veins, and 27 (22.0%) peripheral veins. Median length of occlusion was 3.2 +/- 1.4 cm (range 1.3-10.9 cm). RESULTS: Sharp recanalization was most commonly attempted with transseptal needles in 108/123 (87.8%), with a mean number of 1.2 +/- 0.4 crossing devices per patient (range 1 4 devices). Targeting devices included a loop snare (n = 92; 74.8%), partially deployed Wallstent (n = 21; 17.1%), partially deployed Amplatzer vascular plug (n = 8; 6.5%), and an angioplasty balloon (n = 3; 2.4%). Technical success was achieved in 111 (90.2%) patients. There were 3 (2.4%) severe, 1 (0.8%) moderate, and 7 (5.7%) minor adverse events. Severe adverse events included 1 case each of pericardial tamponade, hemothorax, and inferior vena cava filter occlusion. 88 (71.5%) patients had venous stents placed; at the last follow-up examination, 68/86 (79.0%) stents were patent. CONCLUSION: Sharp recanalization has a high technical success and low rate of adverse events in the recanalization of chronic venous occlusions. PMID- 30460386 TI - Cinnamaldehyde ameliorates STZ-induced rat diabetes through modulation of IRS1/PI3K/AKT2 pathway and AGEs/RAGE interaction. AB - Type 2 diabetes mellitus (T2D) is a chronic metabolic disorder considered to be the most predominant form of diabetes throughout the world. This study aimed to investigate the possible effects of cinnamaldehyde (CIN) on insulin signaling pathways in STZ-induced T2D rat model. T2D was originated by feeding rats with a high-fat diet (HFD) plus 25% fructose solution plus streptozotocin (STZ) (35 mg/kg, i.p.). CIN effects were investigated on fasting blood glucose, insulin, oral glucose tolerance test (OGTT), insulin tolerance test (ITT), liver biomarkers, lipid profile, oxidative stress biomarkers, serum advanced glycation end products (AGEs) and its receptors (RAGE) in the aorta, and histopathology of the liver and aorta. Additionally, the mRNA expression of hepatic insulin signaling pathway genes, phosphorylated AKT (serine 473) (P-AKT ser473) level, and aortic nitric oxide synthase3 (eNOS) and NADPH oxidase4 (NOX4) were determined. CIN treatment for 30 days significantly decreased OGTT, ITT, fasting blood glucose, insulin, and HOMA-IR and increased HOMA-beta index when compared to diabetic rats. CIN also improved lipid profile and decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, serum AGEs, and aortic RAGE. Additionally, CIN treatment significantly decreased hepatic malondialdehyde (MDA), increased hepatic and aortic glutathione (GSH) and superoxide dismutase (SOD), and decreased steatosis and inflammation observed in liver tissue of rats. Additionally, significant elevation in mRNA expression of insulin receptor substrate1 (IRS1), phosphatidylinositol 3-kinase regulatory subunit1 (PI3K-P85 subunit), and AKT serine/threonine kinase2 (AKT2); increased levels of P-AKT ser473 and aortic eNOS; and decrease in mRNA expression of NOX4 were detected in CIN-treated group when compared to diabetic group. This study suggests antidiabetic and antioxidant effects of CIN probably through upregulation of eNOS and IRS1/PI3K/AKT2 signaling pathway and alleviating AGEs, RAGE, and NOX4 elevation. PMID- 30460387 TI - Carboxyl Fe3O4 magnetic nanoparticle-based SPE and HPLC method for the determination of six tetracyclines in water. AB - A novel carboxyl Fe3O4 magnetic nanoparticle-based solid-phase extraction combined with high-performance liquid chromatography was developed for the analysis of oxytetracycline, tetracycline, demeclocycline, metacycline, chlortetracycline, and doxycycline in water samples. Driven by the electrostatic interaction and the strong chelation between tetracyclines and iron ions, tetracyclines in samples were adsorbed onto the adsorbents. The adsorbed analytes were subsequently eluted with oxalic acid and separated with a C18 column under gradient condition with a mobile phase consisting of methanol, acetonitrile, and oxalic acid at a flow rate of 0.5 mL/min. The detection was performed at variable ultraviolet wavelengths. Under optimized conditions, the developed method gave an enrichment factor of 33.3, linearity ranges of 5.00-1000 MUg/L, detection limits of (2.86-5.19) * 10-2 MUg/L, quantification limits of (9.54-17.3) * 10-2 MUg/L, recoveries of 76.2-98.0%, and intra- and inter-day RSDs of 0.132-15.5% and 2.28 14.5% for these tetracyclines. The established method was successfully applied for the determination of these six tetracyclines in tap water, river water, pond water, and lake water samples. Graphical abstract ?. PMID- 30460388 TI - Benchtop-compatible sample processing workflow for proteome profiling of < 100 mammalian cells. AB - Extending proteomics to smaller samples can enable the mapping of protein expression across tissues with high spatial resolution and can reveal sub-group heterogeneity. However, despite the continually improving sensitivity of LC-MS instrumentation, in-depth profiling of samples containing low-nanogram amounts of protein has remained challenging due to analyte losses incurred during preparation and analysis. To address this, we recently developed nanodroplet processing in one pot for trace samples (nanoPOTS), a robotic/microfluidic platform that generates ready-to-analyze peptides from cellular material in ~200 nL droplets with greatly reduced sample losses. In combination with ultrasensitive LC-MS, nanoPOTS has enabled >3000 proteins to be confidently identified from as few as 10 cultured human cells and ~700 proteins from single cells. However, the nanoPOTS platform requires a highly skilled operator and a costly in-house-built robotic nanopipetting instrument. In this work, we sought to evaluate the extent to which the benefits of nanodroplet processing could be preserved when upscaling reagent dispensing volumes by a factor of 10 to those addressable by commercial micropipette. We characterized the resulting platform, termed microdroplet processing in one pot for trace samples (MUPOTS), for the analysis of as few as ~25 cultured HeLa cells (4 ng total protein) or 50 MUm square mouse liver tissue thin sections and found that ~1800 and ~1200 unique proteins were respectively identified with high reproducibility. The reduced equipment requirements should facilitate broad dissemination of nanoproteomics workflows by obviating the need for a capital-intensive custom liquid handling system. PMID- 30460389 TI - Thread-based assay for quantitative small molecule analysis of mice tear fluid by capillary electrophoresis. AB - Tear fluid plays blood-like roles in the cornea, and changes in its chemical composition may be reflective of ocular surface disease pathogenesis. Studies of mice tears are limited by the small volume available for collection and difficulty in obtaining representative samples. Here, we establish a non-invasive assay for small volume analysis of small molecules in mice tears that requires no pre-treatment of mice. To the best of our knowledge, this is the first small molecule analysis of mice tears. Nanoliters of mice tears (70 +/- 25 nL) was collected via a single insertion of phenol red thread in the corner of the eye without anesthesia to prevent any tear production alteration. The processing and elution of tear samples were optimized for minimal sample handling and dilution while maintaining high separation resolution. A capillary electrophoresis separation with light-emitting diode-induced fluorescence detection was developed for the analysis of primary amine-containing small molecules. The levels of arginine, alanine, aspartate, and glutamate after elution were in the micromolar range as seen in human tears. However, taurine and histamine levels were decreased and increased, respectively, compared to human tears, which may be indicative of restraint-induced emotional stress. No significant differences were seen for any of the small molecules between 20-week-old ND4 Swiss Webster females and 12-week-old CD-1 males (N = 3). The developed assay represents a means to assess the chemical composition of tear fluid in mouse models of human disease, which could significantly improve our understanding of ocular surface diseases. Graphical abstract ?. PMID- 30460390 TI - Quantitative analysis of chemoresistance-inducing fatty acid in food supplements using UHPLC-ESI-MS/MS. AB - Polyunsaturated fatty acids are important signaling molecules. A recent study reported hexadeca-4Z,7Z,10Z,13Z-tetraenoic acid, 12-oxo-5Z,8E,10E heptadecatrienoic acid, and (12S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid as chemotherapy resistance-inducing factors when tumor cells were treated with cisplatin. Marine-based food supplements like fish oil or algae extracts are rich in polyunsaturated fatty acids and can contain large amounts of hexadeca 4Z,7Z,10Z,13Z-tetraenoic acid. Thus, it was concluded that oral uptake of hexadeca-4Z,7Z,10Z,13Z-tetraenoic acid might induce chemoresistance as shown in a mouse model. Cancer patients tend to consume food supplements containing polyunsaturated fatty acids on a regular basis. The uptake of hexadeca 4Z,7Z,10Z,13Z-tetraenoic acid and (12S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid should be controlled, because even low concentrations of 0.5 ng mL-1 showed chemoresistance-inducing effects in animal experiments. For accurate analysis of hexadeca-4Z,7Z,10Z,13Z-tetraenoic acid and (12S)-hydroxy-5Z,8E,10E heptadecatrienoic acid a validated method was developed by using ultrahigh performance liquid chromatography hyphenated to quadrupole time of flight mass spectrometry via electrospray ionization and sample preparation by solid-phase extraction (SPE) with 3-aminopropyl silica. A combined targeted/untargeted approach was utilized using MS/MS by data-independent acquisition with SWATH and applied to commercial food supplements (refined fish oil, fish oil capsules, algae oil capsules, and flaxseed capsules). Accurate quantification of hexadeca 4Z,7Z,10Z,13Z-tetraenoic acid and (12S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid on the MS/MS level with simultaneous untargeted fatty acid screening revealed additional information. The LODs for hexadeca-4Z,7Z,10Z,13Z-tetraenoic acid and (12S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid were 0.036 ng mL-1 and 0.054 ng mL 1, respectively. Since hexadeca-4Z,7Z,10Z,13Z-tetraenoic acid was present in the samples in large amounts and (12S)-hydroxy-5Z,8E,10E-heptadecatrienoic was not expected to be present in high concentrations, two calibration ranges, namely, 0.5-20 ng mL-1 and 5-200 ng mL-1, were validated. An untargeted screening identified 18-39 free fatty acids being present in the lipid extracts of the food supplement samples. Graphical abstract ?. PMID- 30460391 TI - Carcinogenesis: the cancer cell-mast cell connection. AB - BACKGROUND: In mammals, inflammation is required for wound repair and tumorigenesis. However, the events that lead to inflammation, particularly in non healing wounds and cancer, are only partly understood. FINDINGS: Mast cells, due to their great plasticity, could orchestrate the inflammatory responses inducing the expression of extraembryonic programs of normal and pathological tissue formation. This heterogeneity of mast cells could allow a microenvironment to be recreated similar to the extraembryonic structures, i.e., amnion and yolk sac, which are needed for embryonic development. Mast cells could provide a framework for understanding the connection between inflammation and tumor growth, invasion and metastasis. In this way, the mast cells could express inflammatory phenotypes, which would enable the cancer stem cells to develop. Thus, the cancer cell uses mast cells to express the extraembryonic functions that are needed to allow the cancer stem cell to proliferate and invade. If so, then by using this appropriate inflammatory interstitial microenvironment, a cancer stem cell can reach maximum levels of growth and invasion inside the host. CONCLUSION: Therefore, the comparison of tumors with wounds that do not heal would be supported since both pathological processes use extraembryonic mechanisms by mast cells. The adoption of these mechanisms warrants tumor survival in an embryonic like state. PMID- 30460392 TI - Quantitative analysis of multi-element synergy stabilizing performance: comparison of three methods with respect to their use in clinical studies. AB - A number of analyses associated with the uncontrolled manifold (UCM) hypothesis have been used recently to investigate stability of actions across populations. We explored whether some of those methods have an advantage for clinical studies because they require fewer trials to achieve consistent findings. We compared the number of trials needed for the analysis of inter-trial variance, analysis of motor equivalence, and analysis in the space of referent coordinates. Young healthy adults performed four-finger accurate force production tasks under visual feedback with the right (dominant) and left hand over three days. Three methods [analytical (M1), experimental (M2), and cumulative mean (M3) methods] were used to define the minimal number of trials required to reach certain statistical criteria. Two of these methods, M1 and M2, showed qualitatively similar results. Fewer trials (M1: 5-13, M2: 4-10) were needed for analysis of motor equivalence compared to inter-trial variance analysis (M1: 14-24, M2: 10-14). The third method (M3) showed no major differences among the outcome variables. The index of synergy in the inter-trial variance analysis required a very small number of trials (M1, M2: 2-4). Variables related to referent coordinates required only a few trials (under 3), whereas the synergy index in this analysis required the largest number of trials (M1: 24-34, M2: 12-16). This is the first study to quantify the number of trials needed for UCM-based methods of assessing motor coordination broadly used in clinical studies. Clinical studies can take advantage of specific recommendations based on the current data regarding the number of trials needed for each analysis thus allowing minimizing the test session duration without compromising data reliability. PMID- 30460393 TI - Biomechanical and neurocognitive performance outcomes of walking with transtibial limb loss while challenged by a concurrent task. AB - Individuals who have sustained loss of a lower limb may require adaptations in sensorimotor and control systems to effectively utilize a prosthesis, and the interaction of these systems during walking is not clearly understood for this patient population. The aim of this study was to concurrently evaluate temporospatial gait mechanics and cortical dynamics in a population with and without unilateral transtibial limb loss (TT). Utilizing motion capture and electroencephalography, these outcomes were simultaneously collected while participants with and without TT completed a concurrent task of varying difficulty (low- and high-demand) while seated and walking. All participants demonstrated a wider base of support and more stable gait pattern when walking and completing the high-demand concurrent task. The cortical dynamics were similarly modulated by the task demand for both groups, to include a decrease in the novelty-P3 component and increase in the frontal theta/parietal alpha ratio power when completing the high-demand task, although specific differences were also observed. These findings confirm and extend prior efforts indicating that dual-task walking can negatively affect walking mechanics and/or neurocognitive performance. However, there may be limited additional cognitive and/or biomechanical impact of utilizing a prosthesis in a stable, protected environment in TT who have acclimated to ambulating with a prosthesis. These results highlight the need for future work to evaluate interactions between these cognitive-motor control systems for individuals with more proximal levels of lower limb loss, and in more challenging (ecologically valid) environments. PMID- 30460394 TI - Short-term inhibition of spinal reflexes in multiple lower limb muscles after neuromuscular electrical stimulation of ankle plantar flexors. AB - Neuromuscular electrical stimulation (NMES) of lower limbs elicits muscle contractions through the activation of efferent fibers and concomitant recruitment of afferent fibers, which can modulate excitability of the central nervous system. However, neural mechanisms of NMES and how unilateral stimulation of the soleus affects spinal reflexes in multiple lower limb muscles bilaterally remains unknown. Twelve able-bodied participants were recruited, and spinal reflex excitability changes were tested after four interventions, each applied for 60 s, on the right plantar flexors: (1) motor-level NMES; (2) sensory-level NMES; (3) voluntary contraction; (4) rest. Spinal reflexes were elicited using single-pulse transcutaneous spinal cord stimulation applied on the lumbar level of the spinal cord to evoke bilateral responses in multiple lower limb muscles, while maximum motor response (Mmax) was tested in the soleus by stimulating the posterior tibial nerve. Spinal reflexes and Mmax before each intervention were compared to immediately after and every 5 min subsequently, for 15 min. Results showed that motor-level NMES inhibited spinal reflexes of the soleus and other studied muscles of the ipsilateral leg, but not the contralateral leg (except vastus medialis) for 15 min, while not affecting soleus muscle properties (Mmax). Voluntary contraction effect lasted less than 5 min, while sensory-level NMES and rest did not produce an effect. Short-term spinal reflex excitability was likely affected because antidromic impulses during motor-level NMES coincided in the spinal cord with afferent inputs to induce spinal neuroplasticity, whereas afferent input alone did not produce short-term effects. Such activation of muscles with NMES could reduce spasticity in individuals with neurological impairments. PMID- 30460395 TI - Different tool training induces specific effects on body metric representation. AB - Morphology and functional aspects of the tool have been proposed to be critical factors modulating tool use-induced plasticity. However, how these aspects contribute to changing body representation has been underinvestigated. In the arm bisection task, participants have to estimate the length of their own arm by indicating its midpoint, a paradigm used to investigate the representation of the metric properties of the body. We employed this paradigm to investigate the impact of different actions onto tool embodiment. Our findings suggest that a training requiring actions mostly with proximal (shoulder) or distal (wrist) parts induces a different shift in the perceived arm midpoint. This effect is independent of, but enhanced by, the use of the tool during the training and in part influenced by specific demands of the task. These results suggest that specific motor patterns required by the training can induce different changes of body representation, calling for rethinking the concept of tool embodiment, which would be characterized not simply by the morphology of the tools, but also by the actions required for their specific use. PMID- 30460396 TI - Anatomical rectangular tunnels identified with the arthroscopic landmarks result in excellent outcomes in ACL reconstruction with a BTB graft. AB - PURPOSE: To elucidate tunnel locations and clinical outcomes after anatomic rectangular tunnel (ART) anterior cruciate ligament reconstruction (ACLR) using a bone-patellar tendon-bone (BTB) graft. METHODS: Sixty-one patients with a primary unilateral ACL injury were included. Tunnels were created inside the ACL attachment areas after carefully removing the ACL remnant and clearly identifying the bony landmarks. Using 3-dimensional computed tomography (3-D CT) images, the proportion of the tunnel apertures to the anatomical attachment areas was evaluated at 3 weeks. The clinical outcomes were evaluated at 2 years postoperatively. RESULTS: Geographically, the 3-D CT evaluation showed the entire femoral tunnel aperture; at least 75% of the entire tibial tunnel aperture area was consistently located inside the anatomical attachment areas surrounded by the bony landmarks. In the International Knee Documentation Committee (IKDC) subjective assessment, all patients were classified as 'normal' or 'nearly normal'. The Lachman test and pivot-shift test were negative in 98.4% and 95.1% of patients, respectively. The mean side-to-side difference of the anterior laxity at the maximum manual force with a KT- 1000 Knee Arthrometer was 0.2 +/- 0.9 mm, with 95.1% of patients ranging from - 1 to + 2 mm. CONCLUSION: By identifying arthroscopic landmarks, the entire femoral tunnel aperture and at least 75% of the entire tibial tunnel aperture area were consistently located inside the anatomical attachment areas. With properly created tunnels inside the anatomical attachment areas, the ART ACLR using a BTB graft could provide satisfactory outcomes both subjectively and objectively in more than 95% of patients. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 30460397 TI - Molecular profiling of tumors of the brainstem by sequencing of CSF-derived circulating tumor DNA. AB - Brainstem gliomas are molecularly heterogeneous diseases, many of which are difficult to safely surgically resect and have limited treatment options due to their eloquent location. These constraints pose challenges to biopsy, which limits the use of routine molecular profiling and identification of personalized therapies. Here, we explored the potential of sequencing of circulating tumor DNA (ctDNA) isolated from the cerebrospinal fluid (CSF) of brainstem glioma patients as a less invasive approach for tumor molecular profiling. CSF was obtained from patients either intraoperatively (91.2%, 52/57), from ventricular-peritoneal shunt (3.5%, 2/57), or by lumbar puncture (5.3%, 3/57), all prior to surgical manipulation of the tumor. Deep sequencing of glioma-associated genes was performed on CSF-derived ctDNA and, where available, matched blood and tumor DNA from 57 patients, including nine medullary and 23 diffuse intrinsic pontine gliomas (DIPG). At least one tumor-specific mutation was detected in over 82.5% of CSF ctDNA samples (47/57). In cases with primary tumors harboring at least one mutation, alterations were identified in the CSF ctDNA of 97.3% of cases (36/37). In over 83% (31/37) of cases, all primary tumor alterations were detected in the CSF, and in 91.9% (34/37) of cases, at least half of the alterations were identified. Among ten patients found to have primary tumors negative for mutations, 30% (3/10) had detectable somatic alterations in the CSF. Finally, mutation detection using plasma ctDNA was less sensitive than sequencing the CSF ctDNA (38% vs. 100%, respectively). Our study indicates that deep sequencing of CSF ctDNA is a reliable technique for detecting tumor-specific alterations in brainstem tumors. This approach may offer an alternative approach to stereotactic biopsy for molecular profiling of brainstem tumors. PMID- 30460398 TI - An overview of the unique challenges facing African-American breast cancer survivors. AB - PURPOSE: The existence of cancer disparities is well known. Focus on alleviating such disparities centers on diagnosis, treatment, and mortality. This review surveyed current knowledge of health disparities that exist in the acute survivorship period (immediately following diagnosis and treatment) and their contributors, particularly for African-American breast cancer survivors (AA-BCS). METHODS: Utilizing the ASCO four components of survivorship care, we explore disparities in surveillance and effects of cancer and therapies that AA-BCS face within the acute survivorship period (the years immediately following diagnosis). A literature review of PUBMED, Scopus, and Cochrane databases was conducted to identify articles related to AA-BCS acute survivorship. The search yielded 97 articles. Of the 97 articles, 38 articles met inclusion criteria. RESULTS: AA-BCS experience disparate survivorship care, which negatively impacts quality of life and health outcomes. Challenges exist in surveillance, interventions for late effects (e.g., quality-of-life outcomes, cardiotoxicity, and cognitive changes), preventing recurrence with promotion of healthy living, and coordinating care among the healthcare team. CONCLUSIONS: This overview identified current knowledge on the challenges in survivorship among AA-BCS. Barriers to optimal survivorship care inhibit progress in eliminating breast cancer disparities. Research addressing best practices for survivorship care is needed for this population. Implementation of culturally tailored care may reduce breast cancer disparities among AA-BCS. PMID- 30460399 TI - Rasch model-based testing of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy (QLQ-CIPN20) using Alliance for Clinical Trials in Oncology (Alliance) A151408 study data. AB - PURPOSE: To test the psychometric properties of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy (QLQ-CIPN20) using Rasch-based methods. METHODS: A secondary data analysis was performed using pooled QLQ-CIPN20 data from patients (N = 1008) who had participated in any of four multi-site chemotherapy-induced peripheral neuropathy (CIPN) treatment and prevention trials. QLQ-CIPN20 responses were evaluated using a polytomous Rasch partial credit model. Data were assessed for person-item fit using the chi-square statistic, item scaling based on response proportions, threshold ordering using item characteristic curves and logit threshold locations, differential item response (DIF) (i.e., response bias) using likelihood ratio tests, and unidimensionality using cluster analysis. RESULTS: A statistically significant chi-square test indicated poor fit of the observed to the expected responses. More than 70% of the respondents reported a complete absence of six symptoms, reflecting significant floor effects and poor item scaling. Disordered/non ordinal or narrow response thresholds were found for 11 of the 20 items. Item responses were significantly different by gender (p < 0.0001) and chemotherapy type (p < 0.0001). Cluster analysis findings suggest that the QLQ-CIPN20 is a unidimensional scale due to the absence of item clusters. CONCLUSIONS: Rasch model testing revealed psychometric weaknesses that could be addressed by revising the QLQ-CIPN20's problematic items and response options. Alternatively, perhaps the new gold standard CIPN measurement approach in future intervention trials should involve use of only the best items, which would also allow comparisons across previous trials that utilized the QLQ-CIPN20. PMID- 30460400 TI - Buoy-bead flotation application for the harvesting of microalgae and mechanistic analysis of significant factors. AB - Harvesting technology has a significant influence on the microalgal biomass industry. This study develops a buoy-bead flotation method and analyzes the factors impacting flotation. Experimental results show that adding sodium borosilicate as an alternative microsphere material can result in 58.5% harvesting efficiency, a 25.65% increase over the foam flotation average. The Plackett-Burman design experimental results reveal that pH conditions, microsphere diameter, and the speed of agitation are the three most important factors affecting harvesting efficiency. The interaction between these three factors was all found to be significant, which indicates that the harvesting efficiency was affected by a combination of multiple factors. Analyses of the Extended Derjaguin-Landau-Vewey-Overbeek (XDLVO) theory show that the Van der Waals interactions are the key factor in the attachment of algae and microspheres. A harvesting efficiency of 89.9% can be achieved at pH 10, with 56 um dimeter microspheres and an agitation speed of 114 rpm. PMID- 30460401 TI - Transoral vestibule approach for thyroid disease: a systematic review. AB - OBJECTIVES: Transoral endoscopic/robotic thyroidectomy vestibule approach (TOETVA/TORTVA) is a novel technology that has been proposed for the treatment of thyroid disease. Its adoption has increased because of its satisfying cosmetic effects. The primary aim of this systematic review was to assess the feasibility and safety of this approach, and the secondary aim was to discuss the indications for this technology. MATERIALS AND METHODS: According to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines, we searched Pubmed, Embase and the Cochrane databases for published studies on the feasibility and safety of TOETVA or TORTVA. RESULTS: 11 articles containing 864 patients met the inclusion criteria after full-text screening, of which two were reports of randomized controlled trial (RCT), two were retrospective cohort studies and the remaining seven studies were case series. Only studies that evaluated the feasibility and safety of this approach were included. TOETVA/TORTVA was successfully performed in 857 out of the 864 cases (99.2%). The mean operative time ranged from 60.4 to 265.4 min. In most articles, blood loss was less than 50 mL and the mean hospital stay ranged from 1.1 to 8.2 days. The safety outcomes were presented in all articles. The total incidence of adverse events was 14.5%, of which the main complications were transient hypoparathyroidism (5.6%) and transient recurrent laryngeal nerve (RLN) injury (3.1%). CONCLUSIONS: This review preliminarily suggests that TOETVA or TORTVA could be an effective and safe treatment for thyroidectomy. Due to the small sample size and low level of evidence, further large-scale, well-designed RCTs are required to validate our findings. PMID- 30460402 TI - The impact of platelet-rich plasma therapy on short-term postoperative outcomes of pediatric tonsillectomy patients. AB - INTRODUCTION: To compare the short-term outcomes of pediatric patients who underwent tonsillectomy alone vs. tonsillectomy plus platelet-rich plasma (PRP) therapy in terms of postoperative pain, appetite status, analgesia requirement, and bleeding complications. MATERIALS AND METHODS: This study included a total of 80 pediatric tonsillectomy patients (53.8% female, 46.2% male, aged 4-16 years), who were randomly allocated into tonsillectomy alone (TA group; n = 40) and tonsillectomy plus PRP therapy (TPRP group, n = 40) groups. Patient demographic data (age, gender) and postoperative data of visual analog scale (VAS) pain scores (postoperative 2nd hour, 1-10 days), appetite scores (postoperative 1-7 days), and analgesia requirement (postoperative 1-10 days) and bleeding complications were recorded. RESULTS: A significant gradual decrease was noted in pain scores starting from the 3rd postoperative day reaching 0.0 +/- 0.0 and 0.50 +/- 0.88 on Day 10 in the TPRP and TA groups, respectively (p < 0.001 for each). Compared to the TA group, the TPRP group was associated with significantly lower pain scores (Day 1 to Day 10), better appetite scores (Day 1 to Day 6), a lower requirement for analgesia (Day1 to Day 10) and fewer common bleeding complications (1 vs. 4 patients) in the postoperative period (p < 0.001 for each). CONCLUSION: In conclusion, this study of pediatric tonsillectomy patients revealed the superiority of tonsillectomy with PRP over tonsillectomy alone in terms of effectiveness in reducing post-tonsillectomy pain and improving appetite status, together with a lower requirement for analgesia and a reduced risk of post-tonsillectomy bleeding during the first 10 postoperative days. PMID- 30460403 TI - Correction to: Purse-string approximation vs. primary closure with a drain for stoma reversal surgery: results of a randomized clinical trial. AB - In the original publication, surname of first author is misspelt as "Amamo". It should be "Amano" as given in this Correction. PMID- 30460404 TI - Natural variation of ZmHKT1 affects root morphology in maize at the seedling stage. AB - MAIN CONCLUSION: Eight variants in ZmHKT1 promoter were significantly associated with root diameter, four haplotypes based on these significant variants were found, and Hap2 has the largest root diameter. Roots play an important role in uptake of water, nutrients and plant anchorage. Identification of gene and corresponding SNPs associated with root traits would enable develop maize lines with better root traits that might help to improve capacity for absorbing nutrients and water acquisition. The genomic sequences of a salt tolerance gene ZmHKT1 was resequenced in 349 maize inbred lines, and the association between nucleotide polymorphisms and seedling root traits was detected. A total of 269 variants in ZmHKT1 were identified, including 226 single nucleotide polymorphisms and 43 insertions and deletions. The gene displayed high level of nucleotide diversity, especially in non-genic regions. A total of 19 variations in untranslated region of ZmHKT1 were found to be associated with six seedling traits. Eight variants in promoter region were significantly associated with average root diameter (ARD), four haplotypes were found based on these significant variants, and Hap2 has the largest ARD. Two SNPs in high-linkage disequilibrium (SNP-415 and SNP 2169) with pleiotropic effects were significantly associated with plant height, root surface area, root volume, and shoot dry weight. This result revealed that ZmHKT1 was an important contributor to the phenotypic variations of seedling root traits in maize, these significant variants could use to develop functional markers to improve root traits. PMID- 30460405 TI - Effects of fasting on warfarin sensitivity index in patients undergoing cardiovascular surgery. AB - PURPOSE: Warfarin shows large inter- and intra-individual variabilities in its pharmacokinetics and pharmacodynamics. Sufficient understanding of factors affecting the response to warfarin is necessary to achieve improved outcomes for warfarin therapy. In this study, we evaluated effects of fasting on the anticoagulant properties of warfarin. METHODS: We conducted a retrospective observational study involving a total of 58 patients, who received cardiovascular surgeries and subsequent warfarin therapy. The effect of dietary intake on the anticoagulant properties with warfarin was assessed by measurement of the international normalized ratio of prothrombin time (PT-INR): the anticoagulant activities of warfarin were expressed as the warfarin sensitivity index (WSI). Additionally, fluctuations in WSI during the study period were obtained as differences between the maximum and minimum WSI. RESULTS: The maximum PT-INR and WSI values were significantly higher for patients who were fasting for different reasons during the postoperative period than those in the group without reduced dietary intake. The differences between maximum and minimum WSI in the fasting group significantly increased compared with those in the groups with moderate or no reduced dietary intake. Meanwhile, effects of other markers of clinical conditions including the baseline Child-Pugh score and Charlson Comorbidity Index on WSI were not significant. CONCLUSIONS: Our results indicate that postoperative fasting was significantly associated with the anticoagulation activity of warfarin. In patients fasting for different reasons during the postoperative period, closer control of PT-INR values and warfarin adjustments may be required to avoid adverse effects such as bleeding in warfarin treatment. PMID- 30460406 TI - Correction to: The proliferation marker pKi-67 becomes masked to MIB-1 staining after expression of its tandem repeats. AB - In the PubMed citation records, the author's name shows. PMID- 30460407 TI - Incident reports versus direct observation to identify medication errors and risk factors in hospitalised newborns. AB - Newborns are often exposed to medication errors in hospitals. Identification and understanding the causes and risk factors associated with medication errors will help to improve the effectiveness of medication. We sought to compare voluntary incident reports and direct observation in the identification of medication errors. We also identified corresponding risk factors in order to establish measures to prevent medication errors. Medication errors identified by a clinical pharmacist and those recorded in our incident reporting system by caregivers were analysed. Main outcomes were rates, type and severity of medication error, and other variables related to medication errors. Ultimately, 383 medication errors were identified by the clinical pharmacist, and two medication errors were declared by caregivers. Prescription errors accounted for 38.4%, preparation errors for 16.2%, and administration errors for 45.4%. The two variables significantly related to the occurrence of medication errors were gestational age < 32.0 weeks (p = 0.04) and the number of drugs prescribed (p < 0.01).Conclusion: Caregivers underreported the true rate of medication errors. Most medication errors were caused by inattention and could have been limited by simplifying the medication process. Risk of medication errors is increased in newborns < 32.0 weeks and increases with the number of drugs prescribed to each patient. What is Known: * Newborns in hospitals are particularly susceptible to medication errors. * Identification and understanding the reasons for medication errors should help us to establish preventive measures to reduce the occurrence of such errors. What is New: * Direct observation of the medication process, though time consuming, is essential to accurately assess the frequency of medication errors, which are underreported by caregivers. Most medication errors are caused by inattention and could be limited by simplifying the medication process. * The risk of medication errors was significantly increased in very preterm newborns (< 32 weeks) and when the number of prescription per patient increased. PMID- 30460408 TI - ? PMID- 30460409 TI - Identifying potential distributions of 10 invasive alien trees: implications for conservation management of protected areas. AB - Tree invasion has the potential to negatively affect biodiversity and ecosystems, with invasive alien trees (IATs) expanding widely in protected areas (PAs) across different habitats. Thus, the effectiveness of PAs might be reduced. Investigation of the distributions of IAT is urgently required to improve the effective conservation management of PAs. We projected the potential distributions of 10 IATs, which included Acacia mearnsii, Ardisia elliptica, Cecropia peltata, Cinchona pubescens, Leucaena leucocephala, Melaleuca quinquenervia, Miconia calvescens, Morella faya, Prosopis glandulosa, and Spathodea campanulata, that have a serious influence on global biodiversity and assessed the distribution possibilities of these IATs in PAs based on the PA categories of the International Union for Conservation of Nature (IUCN). The overall potential distributions of these 10 IATs included Latin America, central and southern Africa, southeastern Asia, eastern Australia and New Zealand, and western Europe. Annual mean temperature, temperature seasonality, annual precipitation, and soil bulk density were found to be important environmental variables for the potential distributions of these IATs. Overall, A. mearnsii, A. elliptica, C. peltata, L. leucocephala, M. quinquenervia, M. calvescens, and S. campanulata were distributed mainly in the IUCN PA categories of national parks and PAs with sustainable use of natural resources. We proposed the following for conservation management of PAs: (1) completion of species inventories for PAs, (2) better understanding of factors driving invasions in PAs, (3) assessment of the efficiency of management within particular PAs, and (4) evaluation of changes in trends regarding plant invasions in PAs under climate change conditions. PMID- 30460410 TI - A magnetic knitting aromatic polymer as a new sorbent for use in solid-phase extraction of organics. AB - Magnetic knitting aromatic polymers (Fe3O4/KAPs) are introduced here as a new kind of sorbents. KAPs are hyper-cross-linked-polymers that were prepared via a Friedl-Crafts reaction from triphenylphosphine and benzene as building blocks. The Fe3O4/KAP composite was obtained by coprecipitation of KAP with magnetite nanoparticles. The resulting Fe3O4/KAP is shown to be a viable magnetic sorbent for various organic materials such as the phenylurea herbicides (PUHs), including metoxuron, monuron, chlortoluron, monolinuron and buturon, and also for various phthalates, polycyclic aromatic hydrocarbons and chlorophenols. The Fe3O4/KAP was characterized by means of Brunauer-Emmett-Teller surface area measurements, Fourier-transform infrared spectroscopy, thermogravimetry, X-ray diffraction, scanning electron microscopy and transmission electron microscopy. Following desorption with acetonitrile, the analytes were quantified by using HPLC with UV detection. The effects of adsorbent dosage, extraction time, sample pH, ionic strength, desorption solvent and desorption time were optimized for the PUHs. Under optimal conditions, response is linear from 0.5-1.0 up to 50 ng.mL-1 for the five PUHs. Lower limits of detection range between 0.05 and 0.30 ng.mL-1. Other figures of merit include (a) high enrichment factors (60-297), (b) good recoveries (91.8-106.5%), and (c) relative standard deviations of <8.4%. The method was successfully applied to analysis of the PUHs in real samples (bottled mixed juice, milk and soymilk). The results indicate that such Fe3O4/KAPs have a wide application scope as an adsorbent for use in magnetic solid phase extraction. Graphical abstract A magnetic knitting aromatic polymer based nanocomposite (Fe3O4/KAP) was prepared by a one-pot method and explored as an absorbent for magnetic solid-phase extraction (MSPE) of phenylurea herbicides (PUHs) from bottled mixed juice, milk and soymilk samples before quantitation by HPLC with UV detection. PMID- 30460411 TI - Surgical staging in endometrial cancer. AB - In several malignancies, it has been demonstrated that the lymph nodal status is the most important pathologic factor affecting prognosis and giving the indication to further adjuvant treatment. The surgical assessment of the lymph nodal status in endometrial cancer is debated since 30 years. Recently, the sentinel lymph node mapping is rapidly gaining clinical acceptance in endometrial cancer. The adoption of Indocyanine Green as a safe and user friendly tracer for sentinel lymph node mapping increased the speed to which this procedure is getting applied in clinical practice. As a consequence of this rapid growth, several fundamental questions have been raised and are still debatable. In this manuscript, we discuss the importance of a known pathological lymph nodal status, the technique of the sentinel lymph node mapping with the reported false negative rates and detection rates according to the different tracers adopted, and the clinical scenarios in which a sentinel lymph node mapping could be employed. PMID- 30460412 TI - Referral pattern for DXA scanning in a tertiary care centre from southern India. AB - : Referral patterns for bone mineral density testing by dual energy X-ray absorptiometry (DXA) scanning are seldom studied. In our study, the overall proportion of referrals from specialties remained low. This highlights the need for adequate utilisation of DXA by specialties treating subjects at risk for osteoporosis. PURPOSE/OBJECTIVES: The knowledge of referral patterns for DXA scanning (dual energy X-ray absorptiometry) for bone mineral density (BMD) measurement is relevant in a developing country like India. We studied the referral source and clinical and densitometric profile of patients referred for DXA scanning at a south Indian tertiary care centre. METHODS: We conducted a cross-sectional study over 3 months and included subjects referred during this period for BMD assessment (lumbar spine and femoral neck) by DXA scan. Details regarding referring departments and reasons for referral were collected. The number of patients seen in individual departments was obtained during the study period and respective proportions of patients referred were calculated. RESULTS: Of the 1932 subjects included in the study, we observed a definite female preponderance (90.2%), with a mean (SD) age of 51.6 (13.3) years. The greatest number of referrals came from the departments of rheumatology (37%; n = 724) and endocrinology (20%; n = 382). Overall, 36% were referred for inflammatory arthritis or systemic inflammatory disorders (n = 696) and 34% for postmenopausal state screening (n = 657). In relation to the individual outpatient strength, the departments who referred the highest proportion of their patients were rheumatology (6.8%), endocrinology (1.76%) and geriatrics (1.05%). A diagnosis of osteoporosis at any one site was made in 41% (448 of 1107) and the BMD was below the expected range for age in 37% (304 of 825) of the referrals. CONCLUSION: Most referrals for DXA scanning were from rheumatology. Among the referred patients, about two fifth had osteoporosis and over one third had BMD below expected range for age. Although referrals by rheumatology were relatively higher, overall referrals from all departments remained low. This underscores the need for adequate utilisation of DXA by specialties treating subjects at risk for osteoporosis. PMID- 30460413 TI - Artificial Intelligence Based Skin Classification Using GMM. AB - This study describes the usage of neural community based on the texture evaluation of pores and skin a variety of similarities in their signs, inclusive of Measles (rubella), German measles (rubella), and Chickenpox etc. In fashionable, these illnesses have similarities in sample of infection and symptoms along with redness and rash. Various skin problems have similar symptoms. For example, in German measles (rubella), Chicken pox and Measles (rubella) a similarity can be observed in skin rashes and redness. The prognosis of skin problems take a long time as the patient's previous medical records, physical examination report and the respective laboratory diagnostic reports have to be studied. The recognition and diagnosis get tough due to the complexity involved. Subsequently, a computer aided analysis and recognition gadget would be handy in such cases. Computer algorithm steps include image processing, picture characteristic extraction and categorize facts with the help of a classifier with Artificial Neural Network (ANN). The ANN can analyze the patterns of symptoms of a particular disease and present faster prognosis and reputation than a human doctor. For this reason, the patients can undergo the treatment for the pores and skin problems based totally on the symptoms detected. PMID- 30460415 TI - Can exposure to neem oil affect the spermatogenesis of predator Ceraeochrysa claveri? AB - Novel biological control methods and integrated pest management strategies are basic requirements for the development of sustainable agriculture. As a result, there is a growing demand for research on the use of plant extracts and natural enemies such as the green lacewing, Ceraeochrysa claveri, as natural pest control methods. Studies have shown that although natural compounds such as neem oil (Azadirachta indica) are effective as pest control strategies, they also cause sublethal effects on nontarget insects, such as C. claveri. The aim of this study was to examine the effects of neem oil on C. claveri testes. C. claveri larvae were fed Diatraea saccharalis eggs, which were pretreated with 0.5%, 1%, and 2% neem oil. Testes were collected from larvae, pupae, and adults and analyzed using light and electron (transmission and scanning) microscopy. Changes in cellular stress and possible cell death were also determined by TUNEL assay and the marker HSP-70. The results showed that neem oil affects the organization and distribution of cysts in the testes and the normal sequence of cyst development, causing a delay in spermatogenesis in the testes of treated insects. Tests for cellular stress and DNA fragmentation indicated there was no cellular alteration in the treated groups. Although neem oil does not induce cell death or changes in HSP-70 expression, this biopesticide negatively impacts the process of spermatogenesis and could decrease the perpetuation of this species in the agroecosystem, indicating that the use of neem oil in association with green lacewings as a biological control should be carefully evaluated. PMID- 30460414 TI - Ecotoxicity evaluation and human risk assessment of an agricultural polluted soil. AB - The present study aims to evaluate the nature and level of chemical pollution as well as the potential toxicity and ecotoxicity of an agricultural soil irrigated by the water of Litani River. Our findings showed that the soil was mainly contaminated by alkanes (hentriacontane, octadecane, hexadecane) and metal trace elements (nickel, vanadium, chromium, and manganese). Soil organic extracts showed high cytotoxicity against human hepatic (HepG2) and bronchial epithelial cells (Beas-2B). Soil ecotoxicity was revealed by seed germination inhibition of several plant species (wheat, clover, alfalfa, tall fescue, and ryegrass) ranging from 7 to 30% on the polluted soil compared to non-polluted one. In addition, significant decreases in telluric microbial biomasses (bacterial and fungal biomasses), quantified by phospholipid fatty acids (PLFA) analysis were observed in polluted soil compared to non-contaminated soils. The density of the arbuscular mycorrhizal fungal (AMF) spores isolated from the polluted soil was about 316 spores/100 g. Three main AMF species were identified as Funelliformis mosseae, Septoglomus constrictum, and Claroideoglomus lamellosum. Moreover, 16 indigenous plant species were inventoried with Silybum marianum L. as the dominant one. Plant biodiversity indices (Shannon, Simpson, Menhinick, and Margaleff) were lower than those found in other contaminated soils. Finally, it was found that all the present plant species on this polluted site were mycorrhized, suggesting a possible protection of these plants against encountered pollutants, and the possibility to use AMF-assisted phytoremediation to clean-up such a site. PMID- 30460416 TI - Herpes zoster and the risks of osteoporosis and fracture: a nationwide cohort study. AB - This study aimed to investigate the association between herpes zoster (HZ) and the risks of osteoporosis and fracture. We conducted a nationwide retrospective cohort study using the National Health Insurance Research Database of Taiwan. The study enrolled 63,786 patients: 31,893 diagnosed with HZ between 2000 and 2012 were included in the HZ cohort, and 31,893 matched controls without HZ were included in the non-HZ cohort, with 1:1 exact matching for age, sex, and index year. Hazard ratios (HRs) were calculated for the risks of osteoporosis and fracture according to the HZ status using the Cox proportional hazards regression models. During a mean follow-up period of 6.0 years, 5597 and 4639 patients in the HZ and non-HZ cohorts, respectively, developed osteoporosis or fractures (incidence rate: 29.8 vs. 23.8 per 1000 person-years). HZ diagnosis was significantly associated with an elevated risk of developing osteoporosis or fracture (adjusted HR [aHR] = 1.20, p < 0.001). On analyses for each individual event, the HZ cohort had significantly increased risks for all events, including osteoporosis (aHR = 1.32, p < 0.001), hip fracture (aHR = 1.34, p < 0.001), vertebral fracture (aHR = 1.38, p < 0.001), and other fractures (aHR = 1.10, p < 0.001) compared with the non-HZ cohort. Patients with postherpetic neuralgia had especially higher risks of osteoporosis and fracture. Age- and sex-stratified analyses also revealed similar patterns. In conclusion, HZ was independently associated with an increased risk of osteoporosis and fracture. Further studies are required to investigate its underlying mechanisms. PMID- 30460417 TI - Concentrated pineapple juice for visualisation of the oesophagus during magnetic resonance angiography before atrial fibrillation radiofrequency catheter ablation. AB - The purpose of this study was to compare in vitro pineapple juice and a solution of concentrated pineapple juice with a paramagnetic contrast agent in order to determine the feasibility of using the solution of concentrated pineapple juice in vivo for oesophagus visualisation at magnetic resonance angiography (MRA) before the radiofrequency catheter ablation procedure for atrial fibrillation. The pineapple juice was concentrated by a microwave heating evaporation process performed in a domestic microwave oven. Five grams of modified potato starch for every 40 mL of concentrated pineapple juice were added to the concentrated pineapple juice in order to thicken the solution. The solution resulted visually and quantitatively as hyperintense as the contrast agent in vitro (ratio = 1.02). in vivo, no technical difficulties were encountered during the MRA acquisition and a complete enhanced oesophagus was obtained in 37/38 patients (97.4%). The volumetric analysis and the three-dimensional reconstruction were feasible; the quality was rated as diagnostic in every patient. The intensified oesophagus was successfully merged into the electro-anatomical maps in all the patients. In summary, we demonstrated that this technique allows a feasible and safe oesophagus visualisation during MRA. PMID- 30460418 TI - Global carbon dioxide removal rates from forest landscape restoration activities. AB - BACKGROUND: Forest landscape restoration (FLR) has been adopted by governments and practitioners across the globe to mitigate and adapt to climate change and restore ecological functions across degraded landscapes. However, the extent to which these activities capture CO2 with associated climate mitigation impacts are poorly known, especially in geographies where data on biomass growth of restored forests are limited or do not exist. To fill this gap, we developed biomass accumulation rates for a set of FLR activities (natural regeneration, planted forests and woodlots, agroforestry, and mangrove restoration) across the globe and global CO2 removal rates with corresponding confidence intervals, grouped by FLR activity and region/climate. RESULTS: Planted forests and woodlots were found to have the highest CO2 removal rates, ranging from 4.5 to 40.7 t CO2 ha-1 year-1 during the first 20 years of growth. Mangrove tree restoration was the second most efficient FLR at removing CO2, with growth rates up to 23.1 t CO2 ha-1 year 1 the first 20 years post restoration. Natural regeneration removal rates were 9.1-18.8 t CO2 ha-1 year-1 during the first 20 years of forest regeneration, followed by agroforestry, the FLR category with the lowest and regionally broad removal rates (10.8-15.6 t CO2 ha-1 year-1). Biomass growth data was most abundant and widely distributed across the world for planted forests and natural regeneration, representing 45% and 32% of all the data points assessed, respectively. Agroforestry studies, were only found in Africa, Asia, and the Latin America and Caribbean regions. CONCLUSION: This study represents the most comprehensive review of published literature on tree growth and CO2 removals to date, which we operationalized by constructing removal rates for specific FLR activities across the globe. These rates can easily be applied by practitioners and decision-makers seeking to better understand the positive climate mitigation impacts of existing or planned FLR actions, or by countries making restoration pledges under the Bonn Challenge Commitments or fulfilling Nationally Determined Contributions to the UNFCCC, thereby helping boost FLR efforts world-wide. PMID- 30460419 TI - Serum histamine and acetylcholine variations as new noninvasive biochemical markers in staging of experimental hepatocellular carcinoma. AB - Angiogenesis is a major prerequisite for hepatocellular carcinoma (HCC) development and progression. The present study aims to assess the potential role of two endogenous regulators of angiogenesis histamine (His) and acetylcholine (Ach), as possible biochemical markers for staging of HCC. Five groups of rats were used in this study: a control healthy group (I), another 4 intoxicated groups used for the induction of HCC with a high dose of diethyl nitrosamine (DENA, 200 mg/kg, single I.P. dose), (II, III, IV, and V). Groups II, III, IV, and V were killed following 8, 16, 24, and 32 weeks after DENA injection, respectively. Serum level of His and Ach was estimated using high-performance liquid chromatography technique coupled with diode array detector (HPLC-DAD), and alpha-fetoprotein (AFP) was measured using ELISA technique along with liver histological examination for all groups. Progression of HCC was estimated by histopathological examination. The results exhibited prominent increase in serum His and Ach levels during the early stages of HCC in group II, III in comparison with the control, and then His serum level declined to the normal level during the last stage of HCC development (group V).However, Ach elevation continued. AFP serum level showed marked increase, till 32 weeks after hepatocarcinogenesis. The decreased histamine level, combined to elevated AFP, indicates an early stage, while continued elevation of Ach with decreased His levels indicates a later stage of HCC. The combination of these two neurotransmitters to AFP may contribute to a noninvasive biochemical staging for HCC. PMID- 30460420 TI - Effect of Post Thermal Annealing on the Optical Properties of InP/ZnS Quantum Dot Films. AB - The enhancement of optical properties via thermal annealing on InP/ZnS core/shell quantum dot (QD) film was investigated in this work. The increase of emission intensities of the QD films was observed after thermal annealing at 180 degrees C for 5 min. Through temperature dependence photoluminescence (TDPL) and power dependence photoluminescence (PL) measurement, the peak located at the low-energy shoulder was confirmed to be localized state emission and the high energy one comes from free-carrier emission. Moreover, from the TDPL spectra of the sample annealed at 180 degrees C for 5 min, the full width at half maximum (FWHM) of localization state emission was nearly the same before which is 250 K and then decreased with increasing temperature. However, the FWHM was decreased significantly when temperature increased in the untreated sample. We conclude that the escape of localization states with increasing temperature contributes to this anomaly phenomenon. Our studies have significance on the application of QDs in electroluminescence devices and down-conversion light-emitting devices. PMID- 30460422 TI - MicroRNAs in the diagnosis and prevention of drug-induced cardiotoxicity. AB - Drug-induced cardiotoxicity is a serious problem associated with the administration of many drugs. MicroRNAs (miRNAs) have been reported to be affected by drugs and other xenobiotics, and the potential of miRNAs as biomarkers and diagnostic tools has been considered. In recent years, an association of certain miRNAs with the cardiotoxicity of some drugs, namely anthracyclines, bevacizumab, cyclosporine A and isoprenaline, has already been found. This review article summarizes available information about the changes in miRNA levels induced by cardiotoxic drugs. Three aspects are discussed: the altered expression of miRNAs in the heart upon treatment with cardiotoxic drugs, circulating miRNAs as promising early biomarkers of cardiotoxicity, and the potential of miRNAs in the prevention and/or attenuation of drug-induced cardiotoxicity. The targeted changes in the level of certain miRNAs by antagomiRs and miRNA mimics are also described and evaluated. In addition, the cardioprotective mechanism of various natural compounds via their effect on miRNA levels are examined. PMID- 30460423 TI - 3D visualization of the biliary tree by X-ray phase-contrast computed tomography. PMID- 30460424 TI - The Screen for Child Anxiety Related Emotional Disorders (SCARED): Informant Discrepancy, Measurement Invariance, and Test-Retest Reliability. AB - The Screen for Child Anxiety Related Emotional Disorders (SCARED) is a measure widely used to assess childhood anxiety based on parent and child report. However, while the SCARED is a reliable, valid, and sensitive measure to screen for pediatric anxiety disorders, informant discrepancy can pose clinical and research challenges. The present study assesses informant discrepancy, measurement invariance, test-retest reliability, and external validity of the SCARED in 1092 anxious and healthy parent-child dyads. Our findings indicate that discrepancy does not vary systematically by the various clinical, demographic, and familial variables examined. There was support for strict measurement invariance, strong test-retest reliability, and adequate external validity with a clinician-rated measure of anxiety. These findings further support the utility of the SCARED in clinical and research settings, but low parent-child agreement highlights the need for further investigation of factors contributing to SCARED informant discrepancy. PMID- 30460425 TI - Reflection in medical education: intellectual humility, discovery, and know-how. AB - Reflection has been proclaimed as a means to help physicians deal with medicine's inherent complexity and remedy many of the shortcomings of medical education. Yet, there is little agreement on the nature of reflection nor on how it should be taught and practiced. Emerging neuroscientific concepts suggest that human thought processes are largely nonconscious, in part inaccessible to introspection. Our knowledge of the world is fraught with uncertainty, ignorance and indeterminacy, and influenced by emotion, biases and illusions, including the illusion of not having illusions. Neuroscience also documents that lifelong learning processes may hone nonconscious cognition to high levels of sophistication, allowing rapid and precise perceptions, judgments and actions in complex situations. We argue that knowledge of mechanisms underlying human thought may be useful in designing educational programs to foster desired attributes such as curiosity, critical self-awareness and intuitive acumen in medical professionals. The juxtaposition of neuroscientific insights with ideas from Kant on reflective judgement, van Manen on tact, and Aristotle on phronesis, supports a concept of reflection that manifests as wise practice. We suggest that reflection in medical education should be (a) an imperative for educators seeking to guide learners to manage the complexity and "messiness" of medical practice, and (b) a role-modelling mode of medical practice characterized by self correcting behaviors that culminate in good and right professional actions. An example illustrates reflective practice in the teaching and learning of physicianship. PMID- 30460421 TI - The c-MYC/NAMPT/SIRT1 feedback loop is activated in early classical and serrated route colorectal cancer and represents a therapeutic target. AB - We have recently identified a positive feedback loop in which c-MYC increases silent information regulator 1 (SIRT1) protein level and activity through transcriptional activation of nicotinamide phosphoribosyltransferase (NAMPT) and NAD+ increase. Here, we determined the relevance of the c-MYC-NAMPT-SIRT1 feedback loop, including the SIRT1 inhibitor deleted in breast cancer 1 (DBC1), for the development of conventional and serrated colorectal adenomas. Immunohistochemical analyses of 104 conventional adenomas with low- and high grade dysplasia and of 157 serrated lesions revealed that elevated expression of c-MYC, NAMPT, and SIRT1 characterized all conventional and serrated adenomas, whereas DBC1 was not differentially regulated. Analyzing publicly available pharmacogenomic databases from 43 colorectal cancer cell lines demonstrated that responsiveness towards a NAMPT inhibitor was significantly associated with alterations in PTEN and TGFBR2, while features such as BRAF or RNF43 alterations, or microsatellite instability typical for serrated route colorectal cancer, showed increased sensitivities for inhibition of NAMPT and SIRT1. Our findings suggest an activation of the c-MYC-NAMPT-SIRT1 feedback loop that may crucially contribute to initiation and development of both routes to colorectal cancer. Targeting of NAMPT or SIRT1 may represent novel therapeutic strategies with putative higher sensitivity of the serrated route colorectal cancer subtype. PMID- 30460426 TI - Improved understanding of aqueous solubility modeling through topological data analysis. AB - Topological data analysis is a family of recent mathematical techniques seeking to understand the 'shape' of data, and has been used to understand the structure of the descriptor space produced from a standard chemical informatics software from the point of view of solubility. We have used the mapper algorithm, a TDA method that creates low-dimensional representations of data, to create a network visualization of the solubility space. While descriptors with clear chemical implications are prominent features in this space, reflecting their importance to the chemical properties, an unexpected and interesting correlation between chlorine content and rings and their implication for solubility prediction is revealed. A parallel representation of the chemical space was generated using persistent homology applied to molecular graphs. Links between this chemical space and the descriptor space were shown to be in agreement with chemical heuristics. The use of persistent homology on molecular graphs, extended by the use of norms on the associated persistence landscapes allow the conversion of discrete shape descriptors to continuous ones, and a perspective of the application of these descriptors to quantitative structure property relations is presented. PMID- 30460427 TI - Spatial modeling applied to environmental monitoring: identifying sources of potentially toxic metals in aquatic system. AB - Aquatic contamination by potentially toxic metals is a problem that has been aggravated, especially due to the quantity and the diversity of sources. Locating these sources is not always an easy task, especially because of the wide variety of possibilities. In this context, the application of geostatistical methods may represent an excellent tool to find out sources of metal contaminants in aquatic systems. Thus, the objective of this work was to elaborate an approach to identify sources of potentially toxic metals (Zn, Ba, Pb, Cr, Mn and Fe), by relating their spatial-temporal variations with the local land use patterns, along a longitudinal profile of the Pirapora River, located in the State of Sao Paulo, Brazil. For this purpose, water samples were collected at different points, taking into consideration each specific land use pattern and quantifying the metals contents by microwave plasma atomic emission spectrometry. In this work, thirteen land use patterns have been identified: mining, forestry, abandoned pasture, water, urban area, human occupation, floodplain, bare soil, temporary crop, roads, forest, streets and pasture. The results revealed temporal variations for the metals Ba, Cr, Fe, and Pb and spatial for Zn and Mn, making possible to correlate the presence of these two latter metals with mining and forestry, the most proeminent activities in the region. Overall, this work proposes a model which brings together geoprocessing and analytical methods, in order to correlate spatial-temporal variations of potentially toxic metals with specific land use patterns of a determined region, aiming the environmental monitoring. PMID- 30460428 TI - PM10 and surface dust source characterization in Baguio City Central Business District (CBD), Philippines. AB - This study measured both PM10 and surface dust concentrations at roadside in the Central Business District of Baguio City. A total of 66 PM10 filters and 25 surface dust samples were analyzed for 14 metals (Na, Mg, Al, Ca, Cr, Mn, Co, Ni, Cu, Zn, As, Sr, Cd and Pb) using inductively coupled plasma mass spectrometer ICP MS to characterize sources of airborne particulate matter (APM). Calculation of enrichment factors indicated elements Zn, Cd, Pb and As to be enriched in both PM10 and surface dust samples. The compositional signature of local surface dust was found to be strongly correlated with that of PM10 particles. Enrichment Factor, Conditional Probability Function (CPF), Correlation Analysis and Principal component analysis were applied to determine sources affecting the Baguio CBD area, and results indicate three APM contributing sources (1) soil sources and (2) soil-road dust resuspension and vehicular emissions (3) vehicular emissions. The NE and SW wind sectors were dominant for most of the identified sources. PMID- 30460429 TI - APC-Cdh1 Regulates Neuronal Apoptosis Through Modulating Glycolysis and Pentose Phosphate Pathway After Oxygen-Glucose Deprivation and Reperfusion. AB - Anaphase-promoting complex (APC) with its coactivator Cdh1 is required to maintain the postmitotic state of neurons via degradation of Cyclin B1, which aims to prevent aberrant cell cycle entry that causes neuronal apoptosis. Interestingly, evidence is accumulating that apart from the cell cycle, APC-Cdh1 also involves in neuronal metabolism via modulating the glycolysis promoting enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3). Here, we showed that under oxygen-glucose deprivation and reperfusion (OGD/R), APC-Cdh1 was decreased in primary cortical neurons. Likewise, the neurons exhibited enhanced glycolysis when oxygen supply was reestablished during reperfusion, which was termed as the "neuronal Warburg effect." In particular, the reperfused neurons showed elevated PFKFB3 expression in addition to a reduction in glucose 6 phosphate dehydrogenase (G6PD). Such changes directed neuronal glucose metabolism from pentose-phosphate pathway (PPP) to aerobic glycolysis compared to the normal neurons, resulting in increased ROS production and apoptosis during reperfusion. Pretreatment of neurons with Cdh1 expressing lentivirus before OGD could reverse this metabolic shift and attenuated ROS-induced apoptosis. However, the metabolism regulation and neuroprotection by Cdh1 under OGD/R condition could be blocked when co-transfecting neurons with Ken box-mut-PFKFB3 (which is APC-Cdh1 insensitive). Based on these data, we suggest that the Warburg effect may contribute to apoptotic mechanisms in neurons under OGD/R insult, and targeting Cdh1 may be a potential therapeutic strategy as both glucose metabolic regulator and apoptosis suppressor of neurons in brain injuries. PMID- 30460430 TI - Development and testing of a deep learning-based strategy for scar segmentation on CMR-LGE images. AB - OBJECTIVE: The aim of this paper is to investigate the use of fully convolutional neural networks (FCNNs) to segment scar tissue in the left ventricle from cardiac magnetic resonance with late gadolinium enhancement (CMR-LGE) images. METHODS: A successful FCNN in the literature (the ENet) was modified and trained to provide scar-tissue segmentation. Two segmentation protocols (Protocol 1 and Protocol 2) were investigated, the latter limiting the scar-segmentation search area to the left ventricular myocardial tissue region. CMR-LGE from 30 patients with ischemic heart disease were retrospectively analyzed, for a total of 250 images, presenting high variability in terms of scar dimension and location. Segmentation results were assessed against manual scar-tissue tracing using one-patient-out cross validation. RESULTS: Protocol 2 outperformed Protocol 1 significantly (p value < 0.05), with median sensitivity and Dice similarity coefficient equal to 88.07% [inter-quartile range (IQR) 18.84%] and 71.25% (IQR 31.82%), respectively. DISCUSSION: Both segmentation protocols were able to detect scar tissues in the CMR-LGE images but higher performance was achieved when limiting the search area to the myocardial region. The findings of this paper represent an encouraging starting point for the use of FCNNs for the segmentation of nonviable scar tissue from CMR-LGE images. PMID- 30460431 TI - Short-acquisition-time JPRESS and its application to paediatric brain tumours. AB - OBJECTIVE: To develop and assess a short-duration JPRESS protocol for detection of overlapping metabolite biomarkers and its application to paediatric brain tumours at 3 Tesla. MATERIALS AND METHODS: The short-duration protocol (6 min) was optimised and compared for spectral quality to a high-resolution (38 min) JPRESS protocol in a phantom and five healthy volunteers. The 6-min JPRESS was acquired from four paediatric brain tumours and compared with short-TE PRESS. RESULTS: Metabolite identification between the 6- and 38-min protocols was comparable in phantom and volunteer data. For metabolites with Cramer-Rao lower bounds > 50%, interpretation of JPRESS increased confidence in assignment of lactate, myo-Inositol and scyllo-Inositol. JPRESS also showed promise for the detection of glycine and taurine in paediatric brain tumours when compared to short-TE MRS. CONCLUSION: A 6-min JPRESS protocol is well tolerated in paediatric brain tumour patients. Visual inspection of a 6-min JPRESS spectrum enables identification of a range of metabolite biomarkers of clinical interest. PMID- 30460432 TI - Quantification and evaluation of intra-urban heat-stress variability in Seoul, Korea. AB - This study quantifies heat-stress hazard (air temperature), vulnerability (heat vulnerability index and age score), and risk (heat-related mortality) on the district scale in Seoul, Korea, for a comprehensive heat-stress impact assessment. Moreover, the heat-stress impact assessment is evaluated by checking the spatial consistency between heat-stress hazard, vulnerability, and risk, which was rarely done before. We applied numerical and geo-empirical models to simulate the spatial pattern of heat-stress hazard. For heat-stress vulnerability, we used demographic and socioeconomic factors. Heat-related mortality was estimated based on an event-based heat-stress risk analysis. Results are that heat-stress hazard, vulnerability, and risk are spatially variable in Seoul. The highest heat-stress hazard was detected in the districts Mapo, Yeongdeungpo, and Yangcheon, the highest vulnerability in Jongno and the highest risk in Jongno and Yangcheon. The different components (heat-stress hazard, vulnerability, and risk) and variables (heat vulnerability index and percentage of seniors) showed different spatial patterns. Knowledge about the causes of higher heat-stress risk, either the hazard or vulnerability, is helpful to design tailored adaptation measures that focus on the reduction of thermal loads or on the preparation of the vulnerable population. The evaluation showed that heat-stress vulnerability and hazard explain the spatial pattern of risk only partly. This highlights the need to evaluate heat-stress impact assessment systems to produce reliable urban heat-stress maps. PMID- 30460433 TI - Yield potential definition of the chilling requirement reveals likely underestimation of the risk of climate change on winter chill accumulation. AB - Evaluation of chilling requirements of cultivars of temperate fruit trees provides key information to assess regional suitability, according to winter chill, for both industry expansion and ongoing profitability as climate change progresses. Traditional methods for calculating chilling requirements use climate controlled chambers and define chilling requirements (CR) using a fixed bud burst percentage, usually close to 50% (CR-50%). However, this CR-50% definition may estimate chilling requirements that lead to flowering percentages that are lower than required for orchards to be commercially viable. We used sweet cherry to analyse the traditional method for calculating chilling requirements (CR-50%) and compared the results with a more restrictive method, where the chilling requirement was defined by a 90% bud break level (CRm-90%). For sweet cherry, this higher requirement of flowering success (90% as opposed to 50%) better represents grower production needs as a greater number of flowers leads to greater potential yield. To investigate the future risk of insufficient chill based on alternate calculations of the chilling requirement, climate projections of winter chill suitability across Europe were calculated using CR-50% and CRm 90%. Regional suitability across the landscape was highly dependent on the method used to define chilling requirements, and differences were found for both cold and mild winter areas. Our results suggest that bud break percentage levels used in the assessment of chilling requirements for sweet cherry influence production risks of current and future production areas. The use of traditional methods to determine chilling requirements can result in an underestimation of productivity chilling requirements for tree crops like sweet cherry which rely on a high conversion of flowers to mature fruit to obtain profitable yields. This underestimation may have negative consequences for the fruit industry as climate change advances with climate risk underestimated. PMID- 30460434 TI - Effects of tetrabromobisphenol A on maize (Zea mays L.) physiological indexes, soil enzyme activity, and soil microbial biomass. AB - TetrabromobisphenolA (TBBPA) is the most widely used brominated flame retardant, and it has the characteristics of persistent organic pollutants (POPs), attracting considerable attention. Many studies mainly focus on TBBPA toxicological effects in aquatic animals and rodents, but the ecotoxicology data of TBBPA on plant-soil system are limited so far. In this study, we assessed the impacts of TBBPA on maize (Zea mays L.) physiological indexes, soil enzyme activity, and soil microbial biomass at different concentrations of TBBPA (0, 0.75, 3.75, 7.5, 15, 37.5 and 75 mg.kg-1) and explored their relationships. Results showed that the maize physiological indexes and chlorophyll contents were significantly decreased by TBBPA, the activities of anti-oxidative enzymes including catalase (CAT), peroxidase (POD) and polyphenol oxidase (PPO) and the contents of malondialdehyde (MDA) were remarkably enhanced. Meanwhile, TBBPA activated the CAT, POD and PPO activities in soil. The low concentrations TBBPA promoted the activities of soil urease (S-UE), neutral phosphatase (S-PE) and increased the soil microbial biomass carbon (SMBC) and nitrogen (SMBN) while the high concentrations TBBPA suppressed them. Notably, the data indicated microbial biomass had respectively a significant correlation with CAT, PPO and S-UE in soil in the presence of TBBPA, and maize chlorophyll contents were associated with SMBN, CAT, and PPO. Taken together, TBBPA caused soil pollution, affected soil enzyme activities and microbial biomass, and hindered maize growth under the current experimental condition, suggesting the interactions among maize growth, soil enzyme, soil microorganism in maize rhizosphere of TBBPA-polluted soils are very important aspects to comprehensively evaluate the ecotoxicological effects of TBBPA. PMID- 30460435 TI - Acute oil exposure reduces physiological process rates in Arctic phyto- and zooplankton. AB - Arctic shipping and oil exploration are expected to increase, as sea ice extent is reduced. This enhances the risk for accidental oil spills throughout the Arctic, which emphasises the need to quantify potential consequences to the marine ecosystem and to evaluate risk and choose appropriate remediation methods. This study investigated the sensitivity of Arctic marine plankton to the water accommodated fraction (WAF) of heavy fuel oil. Arctic marine phytoplankton and copepods (Calanus finmarchicus) were exposed to three WAF concentrations corresponding to total hydrocarbon contents of 0.07 mg l-1, 0.28 mg l-1 and 0.55 mg l-1. Additionally, the potential phototoxic effects of exposing the WAF to sunlight, including the UV spectrum, were tested. The study determined sub-lethal effects of WAF exposure on rates of key ecosystem processes: primary production of phytoplankton and grazing (faecal pellet production) of copepods. Both phytoplankton and copepods responded negatively to WAF exposure. Biomass specific primary production was reduced by 6, 52 and 73% and faecal pellet production by 18, 51 and 86% with increasing WAF concentrations compared to controls. The phototoxic effect reduced primary production in the two highest WAF concentration treatments by 71 and 91%, respectively. This experiment contributes to the limited knowledge of acute sub-lethal effects of potential oil spills to the Arctic pelagic food web. PMID- 30460436 TI - The Trajectory of Pseudoneglect in Adults: A Systematic Review. AB - Neurologically healthy adults tend to display a reliable leftward perceptual bias during visuospatial tasks, a phenomenon known as pseudoneglect. However, the phenomenon in older adults is not well understood, and a synthesis of research that examines pseudoneglect using the line bisection task, as well as other tasks, in the context of aging is lacking. The aim of the current systematic review is to integrate the available research on pseudoneglect in late adulthood, and to discuss the association between age and a bias to the left hemispace. The systematic search revealed that five different tasks have been used to examine pseudoneglect in younger and older adults, and that participants over 60 years of age have demonstrated inconsistent perceptual biases (e.g., enhanced leftward bias, suppressed leftward bias, and rightward bias). Based on current evidence, although some age-related trends in the perceptual bias can be identified within each task, no firm conclusions about the effects of age on pseudoneglect can be drawn. A number of recommendations for future research are outlined throughout the review, including use of smaller age ranges within age groups, differentiating between neurologically healthy participants and those with clinical diagnoses, continued examination of gender, and consistent use of stimuli and methods of analyses within each task to improve internal comparability. PMID- 30460438 TI - Correction to: Abstracts : 30th European Congress of Pathology. AB - The authors of PS-03-015 wish to clarify the Funding details related to their abstract. The abstract is included in full below - no changes have been made to the abstract beyond listing the Funding information. PMID- 30460439 TI - Differences in Calcium Metabolism and Thyroid Physiology After Sleeve Gastrectomy and Roux-En-Y Gastric Bypass. AB - INTRODUCTION: Bariatric surgery may modulate the hormones and elements which maintain thyroid and calcium homeostasis. These adaptations in hormonal and elemental aspects have previously been determined via some studies with variations in their findings. Thyroid volume and 24-h urinary calcium are two parameters which have not been investigated regarding whether they change during the bariatric postsurgical period. This study planned to examine the changes in calcium metabolism and thyroid gland functioning after sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). MATERIALS AND METHODS: Seventy-three morbidly obese patients with planned bariatric surgery were enrolled in the study. Before and 12 months after the operation, parathormone (PTH), 25-OH vitamin D3(25vitD3), TSH, free triiodothyronine (fT3), free thyroxine (fT4), calcium (Ca), 24-h urinary Ca and ultrasonography-guided thyroid volume were measured. RESULTS: In the beginning, 73 patients were examined and 12 months after surgery out of 25 patients continuing follow-up, 20 (80%) had undergone sleeve gastrectomy (SG) while five (20%) had undergone Roux-en-Y gastric bypass (RYGB). Accompanied by significant BMI decrease, 24-h urinary Ca and thyroid volume did not significantly increase in RYGB, SG, and the whole group after 12 months. The SG group showed a significant drop in TSH (p 0.03) level, while the RYGB group showed significant decreases in fT4 (p 0.00) and fT3 (p 0.00); and significant fT3 decrease (p 0.01) was recorded for the whole group. CONCLUSION: Bariatric surgery may modify Ca homeostasis and thyroid gland functional status. We documented that these were not statistically significant increases in 24-h urinary Ca level and thyroid volume after 1 year. Further studies are needed to understand the issue, enrolling more patients who underwent the same bariatric procedure and after accounting for the inhibition of supplementary vitamin and mineral effects. PMID- 30460440 TI - Low population genetic differentiation in two Tamarix species (Tamarix austromongolica and Tamarix chinensis) along the Yellow River. AB - Geological events have been shown to be the main factors affecting the distributions and population genetic structure of species. However, the impact of the Yellow River, the second longest river in China, on the distribution and genetic structure of the endemic flora remains largely unknown. Here, we used microsatellites to evaluate the genetic structure of Tamarix austromongolica and Tamarix chinensis (343 individuals in total), two endemic tree species widely distributed along the Yellow River, as well as the role of river drainages in shaping the structure. We found that frequent gene flow resulted in low genetic differentiation among populations within species (T. austromongolica: Fst = 0.144, Nm = 1.486; T. chinensis: Fst = 0.103, Nm = 2.177); and low levels of genetic differentiation were detected between populations within species on the north and south banks. Also, high gene flow was found between populations in the upper reaches and those in the middle reaches, and middle reaches and lower reaches of the Yellow River (T. austromongolica: Fst = 0.023, Nm = 10.619; T. chinensis: Fst = 0.045, Nm = 5.306). Additionally, discriminant analysis of principal components (DAPC) and Bayesian analysis revealed a weak population structure in T. austromongolica and T. chinensis. Therefore, the Yellow River does not act as a barrier to dispersal and gene flow for Tamarix. Our findings provide support for the role of the river in shaping the spatial distribution and the genetic structure of species. PMID- 30460441 TI - Oxygenic photosynthesis: EPR study of photosynthetic electron transport and oxygen-exchange, an overview. AB - In this review, we consider the applications of electron paramagnetic resonance (EPR) methods to the study of the relationships between the electron transport and oxygen-exchange processes in photosynthetic systems of oxygenic type. One of the purposes of this article is to encourage scientists to use the advantageous EPR oximetry approaches to study oxygen-related electron transport processes in photosynthetic systems. The structural organization of the photosynthetic electron transfer chain and the EPR approaches to the measurements of molecular oxygen (O2) with O2-sensitive species (nitroxide spin labels and solid paramagnetic particles) are briefly reviewed. In solution, the collision of O2 with spin probes causes the broadening of their EPR spectra and the reduction of their spin-lattice relaxation times. Based on these effects, tools for measuring O2 concentration and O2 diffusion in biological systems have been developed. These methods, named "spin-label oximetry," include not only nitroxide spin labels, but also other stable-free radicals with narrow EPR lines, as well as particulate probes with EPR spectra sensitive to molecular oxygen (lithium phthalocyanine, coals, and India ink). Applications of EPR approaches for measuring O2 evolution and consumption are illustrated using examples of photosynthetic systems of oxygenic type, chloroplasts in situ (green leaves), and cyanobacteria. PMID- 30460442 TI - Correction to: New clotting disorders that cast new light on blood coagulation and may play a role in clinical practice. AB - The original version of the article unfortunately contained few errors. PMID- 30460443 TI - Adjusted versus actual body weight dosing of 4-factor prothrombin complex concentrate in obese patients with warfarin-associated major bleeding. AB - The package insert of 4-factor prothrombin complex concentrate (4F-PCC) contains specific dosing recommendations stating to determine the patients dose based on their INR and weight, capping the weight at 100 kg. However, the mean body mass index (BMI) in the 4F-PCC U.S. approval study was 27 kg/m2, and there is a lack of literature identifying the ideal dosing strategy in obesity. We conducted a retrospective analysis of obese patients (BMI >= 30 kg/m2) who received 4F-PCC for warfarin associated emergent bleeding reversal. Treatment groups were those that received 4F-PCC on adjusted body weight (AdjBW) and those on actual body weight (ActBW). The primary outcome was the percent of patients achieving coagulopathy reversal, defined as a post-treatment INR < 1.4 for neurologic indications and < 1.5 for all others. A total of 78 obese patients were included (28 AdjBW and 50 ActBW). Baseline INR (3.1 vs. 2.8; p = 0.052) and BMI (33.6 vs. 33.6 kg/m2) were similar between groups. Achievement of goal INR was significantly lower in the AdjBW group (36% vs. 68%; p = 0.006). A majority of patients had intracranial hemorrhage (32% vs. 54%; p = 0.06), and the median dose of 4F-PCC was lower in the AdjBW group (2120 vs. 2500 units; p = 0.02). Dosing 4F PCC using adjusted body weight in obese patients resulted in a significantly lower rate of coagulopathy reversal. ActBW should be used to dose 4F-PCC in obese patients when the 100 kg dose cap is utilized per the package insert recommendations. PMID- 30460444 TI - Perfusion contrast-enhanced ultrasound to predict early lymph-node metastasis in breast cancer. AB - PURPOSE: To evaluate whether quantitative analysis of perfusion contrast-enhanced ultrasound (CE-US) could predict early lymph-node (LN) metastasis in clinically node-negative breast cancer. MATERIALS AND METHODS: In this prospective study, 64 breast cancer patients were selected for perfusion CE-US imaging. Regions of interest were placed where the strongest and weakest signal increases were found to obtain peak intensities (PIs; PImax and PImin, respectively) for time intensity curve analyzes. The PI difference and PI ratio were calculated as follows: PI difference = PImax-PImin; PI ratio = PImax/PImin. RESULTS: Forty seven cases were histologically diagnosed as negative for LN metastasis and 17 were positive. There was a significant difference in PImin and the PI ratio between the LN-negative and -positive metastasis groups (p = 0.0053 and 0.0082, respectively). Receiver-operating curve analysis revealed that the area under the curve of PImin and the PI ratio were 0.73 and 0.72, respectively. The most effective threshold for the PI ratio was 1.52, and the sensitivity, specificity, positive predictive value, and negative predictive value were 59% (10/17), 87% (41/47), 63% (10/16), and 85% (41/48), respectively. CONCLUSIONS: Parameters from the quantitative analysis of perfusion CE-US imaging showed significant differences between the LN-negative and -positive metastasis groups in clinically node-negative breast cancer. PMID- 30460446 TI - New rare genetic variants in multiple sclerosis. PMID- 30460445 TI - Needle and Syringe Programs and HIV-Related Risk Behaviors Among Men Who Inject Drugs: A Multilevel Analysis of Two Cities in Iran. AB - BACKGROUND: Many studies have found significant differences in HIV risk at the community and socioeconomic levels. However, few have considered variations in needle and syringe program (Jin et al., Oral Dis. 1;22(7):609-19) coverage and other community characteristics on HIV risk behaviors among people who inject drugs (PWIDs). Our objective was to study the relationship between individual factors and city-level characteristics (such as the city's coverage of harm reduction programs) on HIV risk behavior among PWID residing in two cities in Iran. METHODS: The study was conducted from March to August 2016 in Tehran and Kermanshah provinces. One thousand PWID were recruited by a convenience sampling recruitment at local NSP Drop-in Centers (DIC) and through "snowball sampling" (i.e., using peers to refer participants to the study). We first examined associations between individual-level variables and HIV risk behaviors in bivariate analysis using the chi-square or Fisher's exact tests, as appropriate. Next, multi-level models were constructed to determine the amount of variability in HIV risk behavior that could be accounted for by individual- and community level characteristics. Variables with p value < 0.2 were included in the multiple logistic regression model. RESULTS: The results of the multilevel modeling showed that 32% of the variability in HIV risk behaviors among PWID could be explained by factors that differed between the two cities. When individual factors including higher HIV knowledge, access to NSP, higher HIV risk perception, and methamphetamine use were all included in the final model, 22% of the variability in HIV risk behaviors could be explained to city-level variables. CONCLUSION: Findings suggest that expanding the accessibility (i.e., hours and venues) and community-level coverage of NSP services by establishing programs where PWID congregate might reduce HIV risk behavior among PWID. PMID- 30460447 TI - Quality of life in idiopathic dystonia: a systematic review. AB - OBJECTIVE: Dystonia is characterised by sustained muscular contractions frequently producing repetitive, twisting and patterned movements. The primary aim of this systematic review was to establish how quality of life (QoL) is affected in idiopathic focal, multifocal and segmental dystonia. This review aimed to evaluate variations in QoL between different subtypes of dystonia, identify the determinants of QoL and assess the effects of different treatments on QoL. METHODOLOGY: A systematic computer-based literature search was conducted using the PubMed database to search for papers on QoL in idiopathic focal, segmental, multifocal and generalized dystonia. We identified 75 studies meeting our inclusion criteria. Information was extracted regarding prevalence, demographics and response to treatment where indicated. RESULTS: This review revealed QoL to be a significant yet often overlooked issue in idiopathic dystonia. Data consistently showed that dystonia has a negative effect on QoL in patients compared to healthy controls, when measured using disease-specific and generic QoL measures. The majority of studies (n = 25) involved patients with cervical dystonia, followed by benign-essential blepharospasm (n = 10). Along with the beneficial effect to the dystonia symptoms, treatment using Botulinum Toxin and Deep Brain Stimulation is also effective in improving overall QoL across the majority of subtypes. CONCLUSION: The findings demonstrate that patients' QoL should routinely be assessed and monitored, as this may affect subsequent management. Further research will allow for more robust management of factors contributing to impaired QoL, aside from the physical defects found in dystonia. PMID- 30460448 TI - An update on advances in magnetic resonance imaging of multiple system atrophy. AB - In this review, we describe how different neuroimaging tools have been used to identify novel MSA biomarkers, highlighting their advantages and limitations. First, we describe the main structural MRI changes frequently associated with MSA including the 'hot cross-bun' and 'putaminal rim' signs as well as putaminal, pontine, and middle cerebellar peduncle (MCP) atrophy. We discuss the sensitivity and specificity of different supra- and infratentorial changes in differentiating MSA from other disorders, highlighting those that can improve diagnostic accuracy, including the MCP width and MCP/superior cerebellar peduncle (SCP) ratio on T1-weighted imaging, raised putaminal diffusivity on diffusion-weighted imaging, and increased T2* signal in the putamen, striatum, and substantia nigra on susceptibility-weighted imaging. Second, we focus on recent advances in structural and functional MRI techniques including diffusion tensor imaging (DTI), resting-state functional MRI (fMRI), and arterial spin labelling (ASL) imaging. Finally, we discuss new approaches for MSA research such as multimodal neuroimaging strategies and how such markers may be applied in clinical trials to provide crucial data for accurately selecting patients and to act as secondary outcome measures. PMID- 30460449 TI - Intrathecal administration of nusinersen in adolescent and adult SMA type 2 and 3 patients. AB - Spinal muscular atrophy is a genetic motor neuron disease that leads to progressive muscular atrophy and muscle weakness. In December 2016, the Food and Drug Administration, and in June 2017, the European Medicines Agency approved the antisense oligonucleotide nusinersen for treatment of spinal muscular atrophy. Nusinersen has to be repeatedly administered intrathecally. Due to the clinical features of SMA, the application of the ASO by lumbar puncture can be challenging in symptomatic patients considering the frequently observed scoliosis, previous spine fusion surgeries, joint contractures, and respiratory insufficiency. To evaluate safety and feasibility of the intrathecal treatment in adolescent and adult SMA type 2 and 3 patients, we analyzed 93 lumbar punctures, monitored number of lumbar puncture attempts, duration of the procedure, injection site, and needle length. Oxygen saturation during the intervention, medication for sedation and local anesthesia, adverse events related to lumbar punctures, and macroscopic analysis of CSF were recorded. Moreover, we analyzed the use of CT scans for performing lumbar punctures and its associated radiation exposure. Performing lumbar puncture for the intrathecal administration of nusinersen in adolescent and adult patients with later-onset SMA is feasible and safe, even in patients with complex spinal anatomies and respiratory insufficiency. To guarantee the quality of the procedure, we recommend establishing an experienced interdisciplinary team consisting of neurologists and/or neuropediatricians, anesthesiologists, orthopedic surgeons, and/or neuroradiologists. PMID- 30460450 TI - Isolated seizures are a common early feature of paraneoplastic anti-GABAB receptor encephalitis. AB - OBJECTIVE: To report the clinical features and long-term outcome of 22 newly diagnosed paraneoplastic patients with GABAB receptor antibodies (GABABR-Abs). METHODS: Retrospective clinical study of CSF-confirmed cases of GABABR-Abs encephalitis. RESULTS: We identified 22 patients (4 female) with GABABR-Abs, with a median age of 64 years (range 55-85). All were paraneoplastic: 20 small-cell lung cancer, one malignant thymoma, and one uncharacterized lung mass. The most frequent first symptom was the isolated recurrent seizures without cognitive inter-ictal impairment in 17 patients (77%). In the other, three presented the first behavioral disorders and two presented de novo status epilepticus (SE). After a median delay of 10 days (range 1-30), the recurrent seizures' phase was followed by an encephalitic phase characterized by confusion in 100% of cases and SE in 81% (n = 17), with 53% (n = 9) non-convulsive SE. Dysautonomic episodes were frequent (36%, n = 8, bradycardia and central apnea) and killed three patients. CSF study was abnormal in 95% of the cases (n = 21). At the encephalitic phase, MRI showed a temporal FLAIR hypersignal in 73% (n = 16) of the cases. First-line immunotherapy was initiated after a median delay of 26 days (range 6-65) from disease onset, and a partial response was observed in 10 out of 20 patients (50%). There was no complete response. Two years after onset, a massive anterograde amnesia affected all still alive patients. Nine patients died from cancer progression (median survival: 1.2 years). CONCLUSION: Paraneoplastic GABABR-Abs encephalitis is characterized by a stereotype presentation with an epilepsy phase before an encephalitic phase with dysautonomia. The functional prognosis is poor. PMID- 30460451 TI - Sez6l2-antibody-associated progressive cerebellar ataxia: a differential diagnosis of atypical parkinsonism. PMID- 30460453 TI - A remark on: do all the European surgeons perform the same D2? The need for D2 audit in Europe. PMID- 30460452 TI - Cardiac manifestations of Han Chinese patients with systemic lupus erythematosus: a retrospective study. AB - OBJECTIVE: To investigate cardiac manifestations and the risk factors in Han Chinese patients with systemic lupus erythematosus (SLE). METHODS: Seven hundred fifty SLE patients who were hospitalized at our department were recruited in the present study. The patients were divided into two groups-those with or without cardiac manifestations. Cardiac manifestations in those SLE patients, such as pericarditis, myocarditis, heart valve disease, arrhythmia, were analyzed. The risk and protective factors of cardiac diseases in patients with SLE, as well as the predictors of mortality, were assessed, respectively. RESULTS: In all 750 SLE patients, there were 339 (45.20%) patients suffered from one or more cardiac manifestations, involving pericarditis in 9.5%, myocarditis in 5.7%, heart valve disease in 15.6%, arrhythmia in 16.67%, and cardiovascular diseases (CVD) in 14%. 15.7% of SLE patients were accompanied with pulmonary arterial hypertension (PAH), of which 13.7% were mild, 1.2% were moderate, and 0.8% were severe. No significant differences were found between the two groups in age, disease duration, gender, antibody, and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). The incidence of pericarditis, heart valve disease, arrhythmia, and PAH was positively correlated with age. The incidence of arrhythmia, CVD, and PAH was correlated with SLEDAI. PAH and myocarditis were the risk factors of mortality in SLE patients with disease duration <= 10 years (P = 0.034 and 0.001, respectively). CONCLUSION: Cardiac involvement is common in Han Chinese SLE patients and associated with age and disease activity. PAH and myocarditis are the risk factors of mortality in SLE. PMID- 30460454 TI - The Biomechanics of Competitive Male Runners in Three Marathon Racing Shoes: A Randomized Crossover Study. AB - BACKGROUND: We have shown that a prototype marathon racing shoe reduced the metabolic cost of running for all 18 participants in our sample by an average of 4%, compared to two well-established racing shoes. Gross measures of biomechanics showed minor differences and could not explain the metabolic savings. OBJECTIVE: To explain the metabolic savings by comparing the mechanics of the shoes, leg, and foot joints during the stance phase of running. METHODS: Ten male competitive runners, who habitually rearfoot strike ran three 5-min trials in prototype shoes (NP) and two established marathon shoes, the Nike Zoom Streak 6 (NS) and the adidas adizero Adios BOOST 2 (AB), at 16 km/h. We measured ground reaction forces and 3D kinematics of the lower limbs. RESULTS: Hip and knee joint mechanics were similar between the shoes, but peak ankle extensor moment was smaller in NP versus AB shoes. Negative and positive work rates at the ankle were lower in NP shoes versus the other shoes. Dorsiflexion and negative work at the metatarsophalangeal (MTP) joint were reduced in the NP shoes versus the other shoes. Substantial mechanical energy was stored/returned in compressing the NP midsole foam, but not in bending the carbon-fiber plate. CONCLUSION: The metabolic savings of the NP shoes appear to be due to: (1) superior energy storage in the midsole foam, (2) the clever lever effects of the carbon-fiber plate on the ankle joint mechanics, and (3) the stiffening effects of the plate on the MTP joint. PMID- 30460455 TI - Model-Based and Model-Free Techniques for Amyotrophic Lateral Sclerosis Diagnostic Prediction and Patient Clustering. AB - Amyotrophic lateral sclerosis (ALS) is a complex progressive neurodegenerative disorder with an estimated prevalence of about 5 per 100,000 people in the United States. In this study, the ALS disease progression is measured by the change of Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) score over time. The study aims to provide clinical decision support for timely forecasting of the ALS trajectory as well as accurate and reproducible computable phenotypic clustering of participants. Patient data are extracted from DREAM-Phil Bowen ALS Prediction Prize4Life Challenge data, most of which are from the Pooled Resource Open-Access ALS Clinical Trials Database (PRO-ACT) archive. We employed model based and model-free machine-learning methods to predict the change of the ALSFRS score over time. Using training and testing data we quantified and compared the performance of different techniques. We also used unsupervised machine learning methods to cluster the patients into separate computable phenotypes and interpret the derived subcohorts. Direct prediction of univariate clinical outcomes based on model-based (linear models) or model-free (machine learning based techniques - random forest and Bayesian adaptive regression trees) was only moderately successful. The correlation coefficients between clinically observed changes in ALSFRS scores relative to the model-based/model-free predicted counterparts were 0.427 (random forest) and 0.545(BART). The reliability of these results were assessed using internal statistical cross validation and well as external data validation. Unsupervised clustering generated very reliable and consistent partitions of the patient cohort into four computable phenotypic subgroups. These clusters were explicated by identifying specific salient clinical features included in the PRO-ACT archive that discriminate between the derived subcohorts. There are differences between alternative analytical methods in forecasting specific clinical phenotypes. Although predicting univariate clinical outcomes may be challenging, our results suggest that modern data science strategies are useful in clustering patients and generating evidence-based ALS hypotheses about complex interactions of multivariate factors. Predicting univariate clinical outcomes using the PRO-ACT data yields only marginal accuracy (about 70%). However, unsupervised clustering of participants into sub-groups generates stable, reliable and consistent (exceeding 95%) computable phenotypes whose explication requires interpretation of multivariate sets of features. HIGHLIGHTS: * Used a large ALS data archive of 8,000 patients consisting of 3 million records, including 200 clinical features tracked over 12 months. * Employed model based and model-free methods to predict ALSFRS changes over time, cluster patients into cohorts, and derive computable phenotypes. * Research findings include stable, reliable, and consistent (95%) patient stratification into computable phenotypes. However, clinical explication of the results requires interpretation of multivariate information. Graphical Abstract ?. PMID- 30460456 TI - The Evolution of Selective Dorsal Rhizotomy for the Management of Spasticity. AB - Selective dorsal rhizotomy is a key technique in the surgical management of spasticity in patients with cerebral palsy. The technique evolved from the late 1800s when pioneers like Dana and Abbe performed dorsal rhizotomy in their treatment of refractory pain. These surgeons noted a reduction in muscle tone associated with the operation. When Sherrington then published his Nobel prize winning work on the corticospinal tract and its role in the neuromuscular system in the 1890s, the course was set for modifying spasticity by aiming surgery at the dorsal roots. This procedure underwent multiple modifications through the next century and today it is, arguably, the most commonly performed operation to treat cerebral palsy children with spasticity. Selective dorsal rhizotomy is a technique that still teaches us a great deal about neurophysiology on a daily basis and it is thanks to the pioneers, described in this article, that we have this tool in our armamentarium. PMID- 30460457 TI - Behavioral and Cognitive Improvement Induced by Novel Imidazoline I2 Receptor Ligands in Female SAMP8 Mice. AB - As populations increase their life expectancy, age-related neurodegenerative disorders such as Alzheimer's disease have become more common. I2-Imidazoline receptors (I2-IR) are widely distributed in the central nervous system, and dysregulation of I2-IR in patients with neurodegenerative diseases has been reported, suggesting their implication in cognitive impairment. This evidence indicates that high-affinity selective I2-IR ligands potentially contribute to the delay of neurodegeneration. In vivo studies in the female senescence accelerated mouse-prone 8 mice have shown that treatment with I2-IR ligands, MCR5 and MCR9, produce beneficial effects in behavior and cognition. Changes in molecular pathways implicated in oxidative stress, inflammation, synaptic plasticity, and apoptotic cell death were also studied. Furthermore, treatments with these I2-IR ligands diminished the amyloid precursor protein processing pathway and increased Abeta degrading enzymes in the hippocampus of SAMP8 mice. These results collectively demonstrate the neuroprotective role of these new I2 IR ligands in a mouse model of brain aging through specific pathways and suggest their potential as therapeutic agents in brain disorders and age-related neurodegenerative diseases. PMID- 30460459 TI - Precocious or early puberty in patients with combined pituitary hormone deficiency due to POU1F1 gene mutation: case report and review of possible mechanisms. AB - Central precocious puberty (CPP) or early puberty (EP) is a rare entity in combined pituitary hormone deficiency (CPHD), the latter caused by mutations in pituitary transcription factor genes. The early onset of puberty in two patients with CPHD with POU1F1 gene mutation was evaluated. A 3-month-old boy was diagnosed with central hypothyroidism, and L-thyroxine was commenced. He was referred for the evaluation of short stature at 20 months of age. Anthropometric evaluation revealed severe short stature (- 6.1 SDS), and growth hormone (GH) and prolactin deficiencies were diagnosed. Homozygous POU1F1 gene mutation (c.731T>G, p. I244S) was also detected. Testicular enlargement and high luteinizing hormone (LH) levels were observed at 7 years and 9 months of age while he was on GH and L thyroxine treatment. Due to rapid progression of puberty, gonadotropin-releasing hormone analogue (GnRHa) was initiated at 11.3 years of age. This patient recently turned 19.2 years old, and his final height was - 2.3 SDS. The second patient, a 6-month-old boy, was also referred for growth retardation. His height was - 2.7 SDS, and GH and thyroid-stimulating hormone (TSH) deficiencies were diagnosed. He also had homozygous (c.10C>T, p.Q4*) POU1F1 gene mutation. Onset of puberty was relatively early, at 10 years, with advanced bone age. He was on GnRHa treatment between 11.5 and 12.5 years of age. Recent evaluation of the patient was at 13.6 years of age, and he is still on levothyroxine and GH treatment. The relationship between the POU1F1 genotype and CPP or EP has not as yet been firmly established in humans. Animal studies have revealed that the Pou1f1 gene has a major effect on regulation of GnRH receptor function and the Gata2 gene. It has also been demonstrated that this gene controls gonadotrope evolution and prevents excess gonadotropin levels. Further studies are, however, needed to elucidate the relation between POU1F1 function and CPP. PMID- 30460458 TI - Polymerization and depolymerization of actin with nucleotide states at filament ends. AB - Polymerization induces hydrolysis of ATP bound to actin, followed by gamma phosphate release, which helps advance the disassembly of actin filaments into ADP-G-actin. Mechanical understanding of this correlation between actin assembly and ATP hydrolysis has been an object of intensive studies in biochemistry and structural biology for many decades. Although actin polymerization and depolymerization occur only at either the barbed or pointed ends and the kinetic and equilibrium properties are substantially different from each other, characterizing their properties is difficult to do by bulk assays, as these assays report the average of all actin filaments in solution and are therefore not able to discern the properties of individual actin filaments. Biochemical studies of actin polymerization and hydrolysis were hampered by these inherent properties of actin filaments. Total internal reflection fluorescence (TIRF) microscopy overcame this problem by observing single actin filaments. With TIRF, we now know not only that each end has distinct properties, but also that the rate of gamma-phosphate release is much faster from the terminals than from the interior of actin filaments. The rate of gamma-phosphate release from actin filament ends is even more accelerated when latrunculin A is bound. These findings highlight the importance of resolving structural differences between actin molecules in the interior of the filament and those at either filament end. This review provides a history of observing actin filaments under light microscopy, an overview of dynamic properties of ATP hydrolysis at the end of actin filament, and structural views of gamma-phosphate release. PMID- 30460460 TI - Clinical variability of children with anti-N-methyl-D-aspartate receptor encephalitis in southern Brazil: a cases series and review of the literature. AB - PURPOSE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an immune mediated disease of the central nervous system (CNS). The aim of this study was to describe the variability of clinical presentation in anti-NMDAR encephalitis, treatment and outcomes in a case series of children and adolescents. METHODS: Retrospectively analyse patients diagnosed with anti-NMDAR encephalitis, from 2010 to 2018. RESULTS: The study population consisted of nine children with anti NMDAR encephalitis from southern Brazil, six females and three males, aged 5 months to 16 years (mean 5 years). The time of follow-up varied between 1 and 7 years, with a mean of 3 years. The most frequent first manifestation consisted of seizures. All patients described had psychiatric symptoms and a wide spectrum of neurologic findings. Five patients had unilateral symptoms. Magnetic resonance imaging and electroencephalogram were normal in most patients. Cerebrospinal fluid pleocytosis occurred in five patients. All patients were administered immunoglobulin and/or steroids. Seven patients (78%) required cyclophosphamide and/or rituximab. Almost half of the patients fully recovered from all symptoms. CONCLUSIONS: A wide variety of symptoms were observed in this study and, although unilateral symptoms are rarely reported in the literature, a high frequency was observed among Brazilian children. Alternatives to first-line therapy should be considered in patients with clinical suspicion, even if they have not had a good response with first-line therapy. PMID- 30460461 TI - Exploring the binding properties of agonists interacting with glucocorticoid receptor: an in silico approach. AB - The glucocorticoid receptors (GR) are members of the nuclear receptor superfamily that regulate growth, development, and many of the biological functions, including metabolism and inflammation, in a ligand dependent behavior. Thus, GRs are vital as therapeutic targets with steroid hormones and steroidal analogues, especially including the glucocorticoids. Studying the molecular mechanism of binding between GR and ligands is fundamentally important to develop applications in the pharmacological industry. The present study was carried out via molecular docking and molecular dynamic (MD) simulations of three GR-ligand complexes formed between the ligand binding domain (LBD) of GR with cortisol (a natural steroid), dexamethasone (a well-known synthetic steroid drug), and chonemorphine (a steroid virtually screened from the "Sri Lankan Flora" web-based information system). The investigation was mainly carried out in terms of macroscopic properties of the ligand-protein interactions and conformational fluctuations of the protein. The results indicated greater stability and a similar behavior of the GR protein in the chonemorphine-GR complex, compared to the other two complexes, GR-dexamethasone and GR-cortisol, in an aqueous medium. The integrity of the protein-substrate complexes was preserved by strong hydrogen bonds formed between the amino acid residues of the binding site of the proteins and ligands. The findings revealed that chonemorphine is a promising agonist to GR and may produce a pharmacological effect like that produced by glucocorticoids. Thus, the obtained knowledge could lead to further investigations of the pharmaceutical potential of chonemorphine and biological functions of GR in vivo. PMID- 30460462 TI - Minimal under-correction gives better outcomes following total knee arthroplasty in severe varus knees-myth or reality?-analysis of one hundred sixty two knees with varus greater than fifteen degrees. AB - PURPOSE OF THE STUDY: To document and compare the functional outcome of neutral alignment and under-correction after total knee arthroplasty (TKA) in severe varus knees of more than 15 degrees at three and 12 months post-surgery. MATERIALS AND METHODS: One hundred twenty-four consecutive patients (163 TKAs) of an average age of 61.9 years (52-79) with a pre-operative varus more than 15 degrees were managed with jig-based TKA. Based on the post-operative mechanical femorotibial alignment (FTMA), they were categorised into three groups, namely neutral (180 + 3 degrees ), mild varus (173 degrees to 176 degrees ) and severe varus (172 degrees and below). The outcomes of these three groups were assessed at three and 12 months by the Oxford knee score and the WOMAC score were calculated and co-related to the extent of correction. RESULTS: At three months, knees in the mild varus group (n = 88) had the best results with an Oxford knee score of 41.76 + 1.44 and a WOMAC score of 19.29 + 2.93 compared to the severe varus group and the neutral alignment group which had Oxford knee scores (OKS) of 37.43 + 2.51 and 31.91 + 3.51 and WOMAC scores of 22.57 + 1.51 and 24.46 + 4.15 respectively. However at 12 months, knees in all the groups (neutral, mild varus, severe varus) had similar good functional outcomes with OKS of 39.08 + 1.68, 39.24 + 1.88, 39.29 + 1.11 and WOMAC scores of 17.42 + 2.15, 16.48 + 2.11, 16.14 + 1.21 respectively. A scatter plot done for post-operative FTMA and the functional outcome score for both scores showed a bell curve with the best outcome corresponding to a FTMA of 175 degrees at 3 months and equal distribution for both scores at 12 months. CONCLUSION: The results of our study showed that minimal under-correction gave superior functional outcomes at three months. But this advantage was temporary and both, under-correction and neutral alignment achieved equally good outcomes at one year. Considering the increased prosthesis longevity associated with neutral alignment, we propose that neutral alignment must be aimed for during TKA for knees with severe varus. STUDY DESIGN: Prospective study. PMID- 30460463 TI - Surgical medial patellofemoral ligament reconstruction versus non-surgical treatment of acute primary patellar dislocation: a prospective controlled trial. AB - PURPOSE: The acute primary (first-time) lateral patellar dislocation is associated with a high rate of functional disability. There is no consensus as to the choice of surgical or non-surgical treatment for these patients. The aim of this study is to compare the clinical results between the surgical (reconstruction of the medial patellofemoral ligament [MPFL]) and non-surgical treatments for acute primary patellar dislocations. METHODS: Sixty-nine skeletally mature patients (69 knees) were included in this prospective non randomized controlled trial. At least one predisposing factor for patellar dislocation (including patella alta, high lateral patellar tilt, trochlear dysplasia, and increased TT-TG distance) was identified in the included patients. Thirty patients were treated surgically with MPFL reconstruction, and the other 39 patients were treated non-surgically. The main outcome variable was patellar redislocation within a two year follow-up period. The Kujala questionnaire was applied for analyzing the pain and the quality of life. The additional surgeries due to patellofemoral problems were also recorded. RESULTS: Patellar redislocation occurred in eight patients in the non-surgical group, while no redislocation occurred in the surgical group (P < 0.05). Four patients in non surgical group underwent further surgery due to patellar redislocation and poor function during the follow-up period. The Kujala score and the percentage of "good/excellent" results on the Kujala score of the surgical group were significantly better than that of the non-surgical group (P < 0.05). CONCLUSIONS: The surgical MPFL reconstruction achieved better clinical outcomes compared with non-surgical treatment for the acute primary patellar dislocation in the skeletally mature patients with the presence of abnormal patellofemoral anatomy. Surgery should be considered as the better choice for these specific patients. PMID- 30460464 TI - Meta-analysis of upgrade rates in 3163 radial scars excised after needle core biopsy diagnosis. AB - BACKGROUND: Since concurrent malignancy may be associated with radial scars (RS) in up to 45% of RS diagnosed on core biopsy, surgical excision is usually advised. Recent very low upgrade rates have caused a re-evaluation of the need for routine surgery. We aimed to find subsets of RS at such low risk of upgrade, as to render imaging surveillance a plausible alternative to surgery. DESIGN: We performed a systematic review of the Pubmed, Cochrane and Embase databases, focusing on the following eligibility criteria: full papers, published after 1998, in English, included at least 5 RS, provided information on needle biopsy gauge and upgrade rates based on the excised lesion. For the meta-analysis, studies were grouped by the presence of histologic atypia and the core needle gauge. Study-specific and pooled upgrade rates were calculated for each subgroup. RESULTS: 49 studies that included 3163 RS with surgical outcomes are included. There were 217 upgrades to malignancies, 71 (32.7%) invasive and 144 (66.4%) DCIS. The random-effects pooled estimate was 7% (95% CI 5, 9%). Among the pre planned subgroups, in RS assessed by 14G NCB the upgrade rates were: without atypia - 5% (95% CI 3, 8%), mixed or presence of atypia not specified - 15% (95% CI 10, 20%), with atypia - 29% (95% CI 20, 38%). For RS assessed by a mix of 8 16G cores the respective upgrade rates were 2% (95% CI 1, 4%), 12% (95% CI 6, 18%) and 11% (95% CI 3, 23%) and for RS assessed by 8-11 vacuum assisted biopsies 1% (95% CI 0, 4%), 5% (95% CI 0, 11%) and 18% for the one study of RS with atypia assessed by VAB. Surgery after VAB excision showed no upgrades. The difference across all subgroups was statistically significant. CONCLUSION: When stratified by atypia and biopsy gauge, upgrade rates in RS are consistent and predictable. RS assessed by VABs and lacking atypia have a 1% (95% CI 0, 4%) upgrade rate to DCIS. Other groups have upgrade rates of 2-28%. This risk may be reduced by VAB excision. The results of this meta-analysis provide a decision aid and evidence based selection criteria for surgery after a needle biopsy diagnosis of RS. PMID- 30460466 TI - Synthesis, biological evaluation and corrosion inhibition studies of transition metal complexes of Schiff base. AB - BACKGROUND: The transition metal complexes formed from Schiff base is regarded as leading molecules in medicinal chemistry. Because of the preparative availability and diversity in the structure of central group, the transition metals are important in coordination chemistry. In the present work, we have designed and prepared Schiff base and its metal complexes (MC1-MC4) and screened them for antimicrobial, anticancer and corrosion inhibitory properties. METHODOLOGY: The synthesized metal complexes were characterized by physicochemical and spectral investigation (UV, IR, 1H and 13C-NMR) and were further evaluated for their antimicrobial (tube dilution) and anticancer (SRB assay) activities. In addition, the corrosion inhibition potential was determined by electrochemical impedance spectroscopy (EIS) technique. RESULTS AND DISCUSSION: Antimicrobial screening results found complexes (MC1-MC4) to exhibit less antibacterial activity against the tested bacterial species compared to ofloxacin while the complex MC1 exhibited greater antifungal activity than the fluconazole. The anticancer activity results found the synthesized Schiff base and its metal complexes to elicit poor cytotoxic activity than the standard drug (5-fluorouracil) against HCT116 cancer cell line. Metal complex MC2 showed more corrosion inhibition efficiency with high Rct values and low Cdl values. CONCLUSION: From the results, we can conclude that complexes MC1 and MC2 may be used as potent antimicrobial and anticorrosion agents, respectively. PMID- 30460465 TI - Sleep duration and risk of breast cancer: The JACC Study. AB - PURPOSE: The evidence on beneficial or adverse effects of sleep duration on risk of breast cancer remains controversial and limited, especially in Asia. METHODS: A prospective study of 34,350 women aged 40-79 years in whom sleep duration, and menstrual and reproductive histories were determined by a self-administered questionnaire. The follow-up period was from 1988 to 2009, and hazard ratios (HRs) with 95% confidence intervals (CIs) of breast cancer incidence were calculated for shorter sleep duration in reference to sleep duration of >= 8 h/day by Cox proportional hazard models. RESULTS: During 19.2-year median follow up (236 cases), we found a significant inverse association between sleep duration and risk of breast cancer, especially among postmenopausal women and women with low parity (nulliparous and women with < 3 children); the multivariable HRs (95% CIs) among postmenopausal women who reported 7 h/day and <= 6 h/day of sleep in reference to >= 8 h/day were 1.49 (0.81-2.76) and 1.98 (1.08-3.70) (P for trend = 0.028), respectively, and the corresponding values among women with low parity were 1.50 (0.96-2.35) and 1.76 (1.01-2.79) (P for trend = 0.018). CONCLUSIONS: Short sleep duration was associated with increased risk of incident breast cancer, especially among postmenopausal women and women with low parity. PMID- 30460467 TI - "Just do your job": technology, bureaucracy, and the eclipse of conscience in contemporary medicine. AB - Market metaphors have come to dominate discourse on medical practice. In this essay, we revisit Peter Berger and colleagues' analysis of modernization in their book The Homeless Mind and place that analysis in conversation with Max Weber's 1917 lecture "Science as a Vocation" to argue that the rise of market metaphors betokens the carry-over to medical practice of various features from the institutions of technological production and bureaucratic administration. We refer to this carry-over as the product presumption. The product presumption foregrounds accidental features of medicine while hiding its essential features. It thereby confounds the public understanding of medicine and impedes the professional achievement of the excellences most central to medical practice. In demonstrating this pattern, we focus on a recent article, "Physicians, Not Conscripts-Conscientious Objection in Health Care," in which Ronit Stahl and Ezekiel Emanuel decry conscientious refusals by medical practitioners. We demonstrate that Stahl and Emanuel's argument depends on the product presumption, ignoring and undermining central features of good medicine. We conclude by encouraging conscientious resistance to the product presumption and the language it engenders. PMID- 30460468 TI - Sequential nonarteritic anterior ischemic optic neuropathy in patient on chronic hemodialysis. AB - Nonarteritic anterior ischemic optic neuropathy (NAION) is a well acknowledged rare complication of chronic hemodialysis in patients with end-stage renal disease (ESRD). We present a unique case of a patient on chronic hemodialysis who presented with an NAION in the right eye, then 3 months later developed an NAION in the left eye followed in 1 month by second NAION episode in the left eye. Every episode of NAION was accompanied by intradialytic hypotension (drop in systolic blood pressure of over 20 mmHg) where visual loss was noticed at the end of the dialysis session. Clinicians should be aware of association between NAION and hemodialysis and that patients with dialysis-induced hypotension are at particularly increased risk of having NAION. Patients who had dialysis-associated NAION should be closely monitored to prevent occurrence of intra-dialytic hypotension as they are at the highest risk of sequential NAION and thus severe visual loss. PMID- 30460469 TI - Correction to: Propionate represses the dnaA gene via the methylcitrate pathway regulating transcription factor, PrpR, in Mycobacterium tuberculosis. AB - Subsequent to the publication of the above article, it has been noticed that data published in Figure 2A and Figure 2B of this article duplicate images previously published by this research group in the following paper. PMID- 30460470 TI - 19th International Meeting on Frankia and Actinorhizal Plants. AB - It has been 40 years since the first meeting dedicated to Frankia and actinorhizal plants, which was held at Petersham, Massachusetts (reported in Torrey and Tjepkema, 1979). Since then biennial meetings have been organised and held in different venues around the globe (Table 1). The most recent meeting, the "19th International Meeting on Frankia and Actinorhizal Plants", organised in Hammamet, Tunisia from 17th to 19th of March, 2018, gathered scientists from Algeria, Argentina, Belgium, China, Egypt, France, India, Portugal, Senegal, Sweden, UK, USA and Tunisia. The event was a stimulating opportunity for active researchers to share many advances since the previous meeting held in Montpellier, France (Franche et al. 2016) and to discuss new perspectives in this research field. PMID- 30460471 TI - Integrin-interacting protein Kindlin-2 induces mammary tumors in transgenic mice. AB - Kindlin-2, an integrin-interacting protein, regulates breast cancer progression. However, currently, no animal model to study the role of Kindlin-2 in the carcinogenesis of mammary gland is available. We established a Kindlin-2 transgenic mouse model using a mammary gland-specific promoter, mammary tumor virus (MMTV) long terminal repeat (LTR). Kindlin-2 was overexpressed in the epithelial cells of the transgenic mice. The mammary gland ductal trees were found to grow faster in MMTV-Kindlin-2 transgenic mice than in control mice during puberty. Kindlin-2 promoted mammary gland growth as indicated by more numerous duct branches and larger lumens, and more alveoli were formed in the mammary glands during pregnancy under Kindlin-2 overexpression. Importantly, mammary gland-specific expression of Kindlin-2 induced tumor formation at the age of 55 weeks on average. Additionally, the levels of estrogen receptor and progesterone receptor were decreased, whereas human epidermal growth factor receptor 2 and beta-catenin were upregulated in the Kindlin-2-induced mammary tumors. These findings demonstrated that Kindlin-2 induces mammary tumor formation via activation of the Wnt signaling pathway. PMID- 30460472 TI - Modeling elastin-associated vasculopathy with patient induced pluripotent stem cells and tissue engineering. AB - Elastin-associated vasculopathies are life-threatening conditions of blood vessel dysfunction. The extracellular matrix protein elastin endows the recoil and compliance required for physiologic arterial function, while disruption of function can lead to aberrant vascular smooth muscle cell proliferation manifesting through stenosis, aneurysm, or vessel dissection. Although research efforts have been informative, they remain incomplete as no viable therapies exist outside of a heart transplant. Induced pluripotent stem cell technology may be uniquely suited to address current obstacles as these present a replenishable supply of patient-specific material with which to study disease. The following review will cover the cutting edge in vascular smooth muscle cell modeling of elastin-associated vasculopathy, and aid in the development of human disease modeling and drug screening approaches to identify potential treatments. Vascular proliferative disease can affect up to 50% of the population throughout the world, making this a relevant and critical area of research for therapeutic development. PMID- 30460473 TI - Risk factors for early postoperative complications in patients with Crohn's disease after colorectal surgery other than ileocecal resection or right hemicolectomy. AB - PURPOSE: To evaluate risk factors for early postoperative complications in patients with Crohn's disease (CD) after extensive colorectal resection excluding mere ileocecal resection or right hemicolectomy at a university center. METHODS: A retrospective analysis of the prospectively maintained database for surgical patients with CD at our institution was performed. All consecutive patients operated between December 2009 and December 2017 were included. RESULTS: In total, 126 patients were eligible for this study. Most common types of operations performed were subtotal colectomy or proctocolectomy (37.3%) and resections of the rectum (34.1%) or the sigmoid colon (14.3%). Major postoperative complications occurred in 29 patients (23.0%). The rate of local septic complications (anastomotic leak, postoperative abscess) was 11.1%. In univariate analysis, low preoperative albumin, elevated preoperative C-reactive protein (CRP), and emergency surgery were factors associated with major postoperative complications. When multivariable analysis was performed, low preoperative albumin was the only independent risk factor for the occurrence of major postoperative complications (p = 0.0033; OR 0.899). The cut-off value for albumin was 32.6 g/L. CONCLUSIONS: In this large cohort of consecutive patients undergoing surgery of the colorectum in CD, the rate of major postoperative complications was considerably higher compared to our recently published data from patients with ileocecal resection or right hemicolectomy. Preoperative albumin is the only independent risk factor for the occurrence of major postoperative complications. Preoperative albumin levels > 32.6 g/L significantly reduce the risk for postoperative complications. PMID- 30460474 TI - Enhanced recovery protocols in colonic surgery: retrospective cohort analysis of economic impact from an institutional point of view. AB - BACKGROUND: Despite increasing evidence supporting the beneficial effects of enhanced recovery protocols (ERPs), their accurate economic impact on institutions remains lacking. The aim of this study was to analyze ERP economic impact in a French center in order to further encourage implementation. METHODS: All patients who underwent elective laparoscopic right or left colectomy for benign or malignant pathology from 2014 to 2017 in a single center were retrospectively reviewed. ERP according to national recommendations was effective starting November 2015. Perioperative data and all direct costs borne by the institution were collected for each patient. Patients who underwent colectomy before and after ERP implementation were compared. RESULTS: Overall, 288 patients were included of which 144 received conventional perioperative care (CC) and 144 received ERP. There were 161 (56%) men, median age was 71 (28-92) years, and 242 (84%) patients underwent surgery for malignant disease. Operative time, intraoperative blood loss, and severe postoperative complications were similar between both groups. ERP was associated with reduced Clavien-Dindo I-II postoperative complications (15% vs. 28%, p = 0.010) and overall in-hospital stay (6 vs. 7 days, p = 0.003). Overall institutional costs were lower in the ERP group although difference was not statistically significant (7022 vs. 7501 euros, p = 0.098). Estimated savings per patient reached a mean of 480 euros. CONCLUSIONS: In a tertiary French center, ERP was associated with reduced postoperative morbidity and in-hospital stay resulting in considerable cost savings. Although not significant, ERP resulted in positive economic impact even in an early implementation phase. PMID- 30460475 TI - Lipid accumulation in grass carp (Ctenopharyngodon idellus) fed faba beans (Vicia faba L.). AB - Feeding faba beans (Vicia faba L.) to grass carp (Ctenopharyngodon idellus) increases muscle compactness but decreases growth and motility. The lipid metabolism of grass carp was examined to assess potential effects of feeding faba beans on physiological properties using a total of 180 fish. The treatment group was fed faba beans for 120 days and a commercial diet for another 30 days. The control group received a commercial diet for 150 days. Fish were sampled every month. Weight gain was significantly lower in the treatment group than in the control. Hardness, springiness, chewiness, cohesiveness, and gumminess of the dorsal muscle increased significantly with the feeding faba beans from 30 to 120 days, which was not reversed by the subsequent feeding of commercial diet. Fat accumulation increased significantly in the treatment group as suggested by the condition factor, viscera index, hepatopancreatic index, and intraperitoneal fat index (IPFI), hepatopancreas, and muscle fat content but was not affected by subsequent feeding with the commercial diet. Serum triglyceride and total cholesterol levels were significantly reduced in the experimental diet group. In the hepatopancreas and intraperitoneal fat IPF, monounsaturated fatty acids showed significantly higher content in faba bean feeding fish, whereas polyunsaturated fatty acid content showed the reversed pattern. In the hepatopancreas, the activities of the lipogenic enzymes malate dehydrogenase and glucose 6-phosphate dehydrogenase were higher in the treatment than in the control group. Moreover, the treatment group showed lower mRNA levels of carnitine palmitoyltransferase-1. Overall, our results clearly demonstrate increasing lipid accumulation in the viscera of faba bean-fed grass carp. PMID- 30460476 TI - Evaluation of the depiction ability of similar subtraction images using digital chest radiographs of different patients. AB - The temporal subtraction (TS) technique requires the same patient's chest radiographs (CXRs) acquired on different dates, whereas the similar subtraction (SS) technique can be used in patients who have no previous CXR, using similar CXRs from different patients. This study aimed to examine the depiction ability of SS images with simulated nodules in comparison with that of TS images with 2- and 7-year acquisition intervals. One hundred patients were randomly selected from our image database. The most recently acquired images of the patients were used as target images for subtraction. The simulated nodule was superimposed on each target image to examine the usefulness of the SS technique. The most (Top 1) and ten most (Top 10) similar images for each target image were identified in the 24,254-image database using a template-matching technique, and used for the SS technique. SS and TS images were obtained using a previously developed nonlinear image-warping technique. The depiction ability of SS and TS images was evaluated using the contrast-to-noise ratio (CNR). The proportion of Top 1 SS images showing higher CNR than that of the TS images with 2- and 7-year acquisition intervals was 28% (28/100) and 33% (33/100), respectively. Moreover, the proportion of cases that had any of the Top 10 SS images with higher CNRs than those of TS images with 2- and 7-year acquisition intervals was 56% (56/100) and 72% (72/100), respectively. Our study indicates that the SS technique can potentially be used to detect lung nodules on CXRs. PMID- 30460477 TI - Air potato (Dioscorea bulbifera) plants displaying virus-like symptoms are co infected with a novel potyvirus and a novel ampelovirus. AB - Air potato (Dioscorea bulbifera) plants being grown at the Florida Department of Agriculture and Consumer Services Division of Plant Industry Biological Control Laboratory II in Alachua County, Florida were observed exhibiting foliar mosaic symptoms characteristic of virus infection. A double-stranded RNA library generated from a symptomatic plant underwent high-throughput sequencing to determine if viral pathogens were present. Sequence data revealed the presence of two viral genomes, one with properties congruent with members of the genus Potyvirus (family Potyviridae), and the other with members of the genus Ampelovirus (family Closteroviridae). Sequence comparisons and phylogenetic placement indicate that both viruses represent novel species. The names "dioscorea mosaic virus" and "air potato virus 1" are proposed for the potyvirus and ampelovirus, respectively. PMID- 30460478 TI - Contamination profile in allografts retrieved from multitissue donors: longitudinal analysis. AB - Microbiological contamination of retrieved tissues has become an issue of key importance and is a critical aspect of allograft safety, especially in the case of multi-tissue donations, which frequently become contaminated during retrieval and handling. We analysed contamination in 11,129 tissues with a longitudinal contamination profile for each individual tissue. Specifically, 10,035 musculoskeletal tissues and 1094 cardiovascular tissues were retrieved from a total of 763 multi-tissue donors, of whom 105 heart-beating organ donors and 658 deceased tissue donors. Of the 1955 tissues found to be contaminated after the first decontamination step, 1401 tissues (72%) were contaminated by the same species as the one(s) isolated at retrieval (Time1) and 554 (28%) by different species. Among the 113 tissues testing positive after the 2nd decontamination (Time3), 36 tissues (32%) were contaminated by the same species detected at Timel while the contaminating species differed from Time1 in 77 tissues (68%). The higher the number of contaminating species per tissue the higher the percentage of tissues in which contamination changed over time compared to Time1. The analysis revealed a 28% incidence of new species in tissues already testing positive after retrieval and of 3.5% of tissues becoming positive after admission to the tissue bank. Of these, coagulase-negative Staphylococcus accounted for over 70% of new contaminations. PMID- 30460479 TI - The incidence, indications and predictors of acute pacemaker implantation after ablation of persistent atrial fibrillation. AB - INTRODUCTION: Patients with persistent atrial fibrillation (AF) may additionally suffer from a concealed sinus node disease. We sought to determine the incidence, indications and predictors of acute pacemaker [PM] implantation within 1 week after the ablation of persistent AF. METHODS AND RESULTS: We performed a retrospective analysis of patients, who had had an ablation of persistent AF at our center. Between 01/2011 and 08/2016, 1234 patients (mean age 65 +/- 10 years, 66.7% male) without prior PM implantation underwent an ablation of persistent AF. Pulmonary vein isolation (PVI) was performed in 1158 (93.8%), the additional ablation of complex fractionated atrial electrograms (CFAE) in 1109 (89.9%) and linear ablation in 524 (42.5%) patients. Temporary cardiac pacing was necessary in 27 (2.2%) patients. The temporary PM was removed in 15 patients (1.2%) because sinus node recovered after a median of 1.0 (minimum 0.1-maximum 2.0) day. The remaining 12 (1.0%) patients required the implantation of a permanent PM. Another 13 (1.1%) patients required permanent PM implantation without prior temporary pacing. In a multivariable regression model, age [OR 1.07 (1.02-1.12), p = 0.006], sinus pauses prior to ablation [OR 7.97 (2.36-26.88), p = 0.001] and atria with low voltage [OR 2.83 (1.31-6.11), p = 0.008] were identified as significant predictors for acute cardiac pacing. CONCLUSION: Acute cardiac pacing within 1 week after the ablation of persistent AF was necessary in 40 (3.2%) patients. Age, sinus pauses in history prior to ablation and the existence of low voltage areas in the atria were identified as relevant risk factors. PMID- 30460481 TI - Global Aquaculture Productivity, Environmental Sustainability, and Climate Change Adaptability. AB - To meet the demand for food from a growing global population, aquaculture production is under great pressure to increase as capture fisheries have stagnated. However, aquaculture has raised a range of environmental concerns, and further increases in aquaculture production will face widespread environmental challenges. The effects of climate change will pose a further threat to global aquaculture production. Aquaculture is often at risk from a combination of climatic variables, including cyclone, drought, flood, global warming, ocean acidification, rainfall variation, salinity, and sea level rise. For aquaculture growth to be sustainable its environmental impacts must reduce significantly. Adaptation to climate change is also needed to produce more fish without environmental impacts. Some adaptation strategies including integrated aquaculture, recirculating aquaculture systems (RAS), and the expansion of seafood farming could increase aquaculture productivity, environmental sustainability, and climate change adaptability. PMID- 30460480 TI - A novel CRX variant (p.R98X) is identified in a Chinese family of Retinitis pigmentosa with atypical and mild manifestations. AB - BACKGROUND: Retinitis pigmentosa (RP) is the most common form of hereditary retinal degeneration that can cause inherited blindness. RP has extreme genetic and clinical heterogeneity, which brings a major obstacle to obtaining an accurate molecular diagnosis. OBJECTIVE: To analyze the genetic defect in a Chinese family of RP with a few atypical manifestations. METHODS: Whole-exome sequencing (WES) was applied to identify the disease-associated genes. Sanger sequencing was performed to validate the variants of candidate genes in the patient and his parents. In vitro expression analysis was further conducted to examine the potential biological function of the gene variant. RESULTS: A heterozygous nonsense variant c.292C > T (p.R98X) of CRX gene was identified to be present in the affected male. The c.292C > T variant of CRX was absent in all of the searched databases, including the 10,000 Chinese exome database. The nonsense variant was supposed to result in a truncated CRX protein with a destroyed homedomain (HD), which is essential for CRX translation. Interestingly, the following assay showed that the potential truncated protein was not detected, indicating that the variant may cause a loss-of-function mutation of CRX gene. CONCLUSION: We identified a novel heterozygous null mutation in the CRX gene which was the first evidence of a nonsense mutation in the HD domain of CRX. Our finding suggested that the haploinsufficiency mutation of CRX gene contributed to the atypical and mild manifestations of the autosomal dominant RP in the Chinese family. PMID- 30460482 TI - Value-driven attentional capture is modulated by the contents of working memory: An EEG study. AB - Attention and working memory (WM) have previously been shown to interact closely when sensory information is being maintained. However, when non-sensory information is maintained in WM, the relationship between WM and sensory attention may be less strong. In the current study, we used electroencephalography to evaluate whether value-driven attentional capture (i.e., allocation of attention to a task-irrelevant feature previously associated with a reward) and its effects on either sensory or non-sensory WM performance might be greater than the effects of salient, non-reward-associated stimuli. In a training phase, 19 participants learned to associate a color with reward. Then, participants were presented with squares and encoded their locations into WM. Participants were instructed to convert the spatial locations either to another type of sensory representation or to an abstract, relational type of representation. During the WM delay period, task-irrelevant distractors, either previously-rewarded or non-rewarded, were presented, with a novel color distractor in the other hemifield. The results revealed lower alpha power and larger N2pc amplitude over posterior electrode sides contralateral to the previously rewarded color, compared to ipsilateral. These effects were mainly found during relational WM, compared to sensory WM, and only for the previously rewarded distractor color, compared to a previous non-rewarded target color or novel color. These effects were associated with modulations of WM performance. These results appear to reflect less capture of attention during maintenance of specific location information, and suggest that value-driven attentional capture can be mitigated as a function of the type of information maintained in WM. PMID- 30460483 TI - Using emotion regulation strategies after sleep deprivation: ERP and behavioral findings. AB - Sleep deprivation is suggested to impact emotion regulation, but few studies have directly examined it. This study investigated the influence of sleep deprivation on three commonly used emotion regulation strategies (distraction, reappraisal, suppression) in Gross's (1998) process model of emotion regulation. Young healthy adults were randomly assigned to a sleep deprivation group (SD; n = 26, 13 males, age = 20.0 +/- 1.7) or a sleep control group (SC; n = 25, 13 males, age = 20.2 +/ 1.7). Following 24-h sleep deprivation or normal nighttime sleep, participants completed an emotion regulation task, in which they naturally viewed or applied a given emotion regulation strategy towards negative pictures, with electroencephalographic (EEG) recordings. A reduction in the centroparietal late positive potential (LPP) amplitudes towards negative pictures from the naturally viewing condition to a regulated condition was calculated as an index of regulatory effects. Comparisons between the two groups indicated that sleep deprivation significantly impaired the regulatory effects of distraction and reappraisal on LPP amplitudes. Suppression did not reduce LPP amplitudes in either group. In addition, habitual sleep quality moderated the effect of sleep deprivation on subjective perception of emotional stimuli, such that sleep deprivation only made good sleepers perceive negative pictures as more unpleasant and more arousing, but it had no significant effect on poor sleepers' perception of negative pictures. Altogether, this study provides the first evidence that sleep deprivation may impair the effectiveness of applying adaptive emotion regulation strategies (distraction and reappraisal), creating potentially undesirable consequences to emotional well-being. PMID- 30460484 TI - Socioeconomic disadvantage, brain morphometry, and attentional bias to threat in middle childhood. AB - Socioeconomic disadvantage is associated with higher rates of psychopathology as well as hippocampus, amygdala and prefrontal cortex structure. However, little is known about how variations in brain morphometry are associated with socio emotional risks for mood disorders in children growing up in families experiencing low income. In the current study, using structural magnetic resonance imaging, we examined the relationship between socioeconomic disadvantage and gray matter volume in the hippocampus, amygdala, and ventrolateral prefrontal cortex in a sample of children (n = 34) in middle childhood. Using an affective dot probe paradigm, we examined the association between gray matter volume in these regions and attentional bias to threat, a risk marker for mood disorders including anxiety disorders. We found that lower income-to-needs ratio was associated with lower bilateral hippocampal and right amygdala volume, but not prefrontal cortex volumes. Moreover, lower attentional bias to threat was associated with greater left hippocampal volume. We provide evidence of a relationship between income-related variations in brain structure and attentional bias to threat, a risk for mood disorders. Therefore, these findings support an environment-morphometry-behavior relationship that contributes to the understanding of income-related mental health disparities in childhood. PMID- 30460485 TI - Inactivation of the Ras/MAPK/PPARgamma signaling axis alleviates diabetic mellitus-induced erectile dysfunction through suppression of corpus cavernosal endothelial cell apoptosis by inhibiting HMGCS2 expression. AB - PURPOSE: Diabetic mellitus-induced erectile dysfunction (DMED) represents a significant complication associated with diabetes mellitus (DM) that greatly affects human life quality. Various reports have highlighted the involvement of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) in the regulation of mitochondrial fatty acid oxidation, which has also been linked with DM. Through bioinformatics analysis, HMGCS2 was determined to be a novel target among DM patients suffering from erectile dysfunction (ED), and enriched in the Ras/ERK/PPAR signaling axis. Owing to the fact that the key mechanism HMGCS2 involved in DM remains largely unknown, we set out to investigate the role of the Ras/MAPK/PPARgamma signaling axis and HMGCS2 in the corpus cavernosal endothelial cells (CCECs) of rats with DMED. METHODS: Firstly, bioinformatics analysis was used to screen out differentially expressed genes in DMED. Then, to investigate the influence of the Ras/MAPK/PPARgamma signaling axis and HMGCS2 on DMED, a rat model of DMED was established and injected with Simvastatin and si-Hmgcs2. The individual expression patterns of Ras, MAPK, PPARgamma and HMGCS2 were determined by RT-qPCR, immunohistochemistry and western blot analysis methods. Afterwards, to investigate the mechanism of Ras/MAPK/PPARgamma signaling axis and HMGCS2, CCECs were isolated from DMED rats and transfected with agonists and inhibitors of the Ras/MAPK/PPARgamma signaling axis and siRNA of HMGCS2, with their respective functions in apoptosis and impairment of CCECs evaluated using TUNEL staining and flow cytometry. RESULTS: Microarray analysis and KEGG pathway enrichment analysis revealed that Ras/ERK/PPAR signaling axis mediated HMGCS2 in DMED. Among the DMED rats, the Ras/MAPK/PPAR signaling axis was also activated while the expression of HMGCS2 was upregulated. The activation of Ras was determined to be capable of upregulating ERK expression which resulted in the inhibition of the transcription of PPARgamma and subsequent upregulation of HMGCS2 expression. The inhibited activation of the Ras/ERK/PPAR signaling axis and silencing HMGCS2 were observed to provide an alleviatory effect on the injury of DMED while acting to inhibit the apoptosis of CCECs. CONCLUSION: Collectively, the key findings suggested that suppression of the Ras/MAPK/PPARgamma signaling axis could downregulate expression of HMGCS2, so as to alleviate DMED. This study defines the potential treatment for DMED through inhibition of the Ras/MAPK/PPARgamma signaling axis and silencing HMGCS2. PMID- 30460486 TI - A Systematic Review on the Extent and Quality of Pharmacoeconomic Publications in Egypt. AB - BACKGROUND: Egypt faces many challenges when matching patient needs with available resources. Consequently, there has been an increasing interest in pharmacoeconomics as an aid tool in health decision-making to better allocate resources. OBJECTIVES: To review and evaluate the volume and the quality of published pharmacoeconomic studies in Egypt. METHODS: A literature search was conducted in August 2018 using PubMed, Google Scholar, and Cochrane library to identify published Egyptian pharmacoeconomic studies. Articles were included if they were original economic studies, written and published in English, and conducted in Egypt. Each article was assessed independently by two reviewers using the 100-point Quality of Health Evaluation Studies (QHES) scale. RESULTS: Fifteen studies published between 2002 and 2017 were included in the review. Most of them were cost-effectiveness analyses (60%). The minority used secondary data (33.3%) or adopted modeling techniques (40%). The mean QHES score of the included studies was 70.1 +/- 21.8, and approximately 40% of them had a QHES score of more than 80. CONCLUSION: Pharmacoeconomic evaluations in Egypt are still in their infancy. The Egyptian guidelines for economic evaluation should be adopted and the EQ-5D-5L value sets should be developed to increase the quality of economic research. PMID- 30460487 TI - Exploring the potential of Juglans regia-derived activated carbon for the removal of adsorbed fungicide Ethaboxam from soils. AB - The dearth of adsorption studies on aminothiazole carboxamide-based fungicide Ethaboxam has eventuated to its current investigation of sorption behavior on soil samples utilizing standard batch equilibrium method. Ethaboxam-based sorption studies have never been reported in the selected regions. Linear adsorption coefficient (Kd) ranged from 3.2 to 16.74 MUg mL-1. The highest value of Kd was observed for soil rich in organic matter. Low Gibbs free energy values indicated the weak interaction between soil particles and Ethaboxam resulting in physiosorption and an exothermic reaction. Statistical analysis expressed a negative correlation between soil pH and Kd (R2 = - 0.85 and p < 0.05) and positive correlation with organic matter (R2 = 0.94). The data was further analyzed by univariate ANOVA, and accuracy was checked by residual plots for investigating the statistical significance of the results. Cost effective Ethaboxam remediation from soils was performed by Juglans regia (walnut) shells derived activated carbon on different pesticide concentrations (5 ppm and 7.5 ppm) in soils. Consummate removal percentages were obtained in 5 ppm (99%) and 7.5 ppm concentrations (89%). The use of Juglans regia shells for the removal of Ethaboxam makes this method environmental friendly, economical, and easily applicable. PMID- 30460488 TI - Virus discovery reveals frequent infection by diverse novel members of the Flaviviridae in wild lemurs. AB - Lemurs are highly endangered mammals inhabiting the forests of Madagascar. In this study, we performed virus discovery on serum samples collected from 84 wild lemurs and identified viral sequence fragments from 4 novel viruses within the family Flaviviridae, including members of the genera Hepacivirus and Pegivirus. The sifaka hepacivirus (SifHV, two genotypes) and pegivirus (SifPgV, two genotypes) were discovered in the diademed sifaka (Propithecus diadema), while other pegiviral fragments were detected in samples from the indri (Indri indri, IndPgV) and the weasel sportive lemur (Lepilemur mustelinus, LepPgV). Although data are preliminary, each viral species appeared host species-specific and frequent infection was detected (18 of 84 individuals were positive for at least one virus). The complete coding sequence and partial 5' and 3' untranslated regions (UTRs) were obtained for SifHV and its genomic organization was consistent with that of other hepaciviruses, with one unique polyprotein and highly structured UTRs. Phylogenetic analyses showed the SifHV belonged to a clade that includes several viral species identified in rodents from Asia and North America, while SifPgV and IndPgV were more closely related to pegiviral species A and C, that include viruses found in humans as well as New- and Old World monkeys. Our results support the current proposed model of virus-host co divergence with frequent occurrence of cross-species transmission for these genera and highlight how the discovery of more members of the Flaviviridae can help clarify the ecology and evolutionary history of these viruses. Furthermore, this knowledge is important for conservation and captive management of lemurs. PMID- 30460489 TI - Metastatic or locally advanced breast cancer patients: towards an expert consensus on nab-paclitaxel treatment in HER2-negative tumours-the MACBETH project. AB - INTRODUCTION: Despite the large use of nab-paclitaxel as a treatment option in metastatic breast cancer (MBC) across different countries, no definitive data are available in particular clinical situations. AREAS COVERED: Efficacy, safety and schedule issues concerning available literature on nab-paclitaxel in advanced breast cancer and in specific subgroups of patients have been discussed and voted during an International Expert Meeting. Ten expert specialists in oncology, with extensive clinical experience on Nab-P and publications in the field of MBC have been identified. Six scientific areas of interest have been covered, generating 13 specific Statements for Nab-P, after literature review. For efficacy issues, a summary of research quality was performed adopting the GRADE algorithm for evidence scoring. The panel members were invited to express their opinion on the statements, in case of disagreement all the controversial opinions and the relative motivations have been made public. EXPERT OPINION: Consensus was reached in 30.8% of the Nab-P statements, mainly those regarding safety issues, whereas ones regarding efficacy and schedule still remain controversial areas, requiring further data originated by the literature. PMID- 30460490 TI - A computer vision technique for automated assessment of surgical performance using surgeons' console-feed videos. AB - PURPOSE: To develop and validate an automated assessment of surgical performance (AASP) system for objective and computerized assessment of pelvic lymph node dissection (PLND) as an integral part of robot-assisted radical cystectomy (RARC) using console-feed videos recorded during live surgery. METHODS: Video recordings of 20 PLNDs were included. The quality of lymph node clearance was assessed based on the features derived from the computer vision process which include: the number and cleared area of the vessels/nerve (N-Vs); image median color map; and mean entropy (measures the level of disorganization) in the video frame. The automated scores were compared to the validated pelvic lymphadenectomy appropriateness and completion evaluation (PLACE) scoring rated by a panel of expert surgeons. Logistic regression analysis was employed to compare automated scores versus PLACE scores. RESULTS: Fourteen procedures were used to develop the AASP algorithm. A logistic regression model was trained and validated using the aforementioned features with 30% holdout cross-validation. The model was tested on the remaining six procedures, and the accuracy of predicting the expert-based PLACE scores was 83.3%. CONCLUSIONS: To our knowledge, this is the first automated surgical skill assessment tool that provides an objective evaluation of surgical performance with high accuracy compared to expert surgeons' assessment that can be extended to any endoscopic or robotic video-enabled surgical procedure. PMID- 30460492 TI - Risk Perception Plays Minimal Role in Sun Exposure Behaviours. AB - Despite decades of public health campaigns, tanning and sunburn still occur at unacceptably high rates. Skin cancer prevention campaigns predominately focus on increasing awareness of the risk of excessive sun exposure. This study sought to assess the efficacy of this approach, by interrogating correlations between risk perception and sun exposure behaviour. A 31-item questionnaire assessing skin cancer risk factors, tanning attitudes, sunburn and tanning behaviour was undertaken by individuals who attended a workplace skin check. Validated questions were included to assess cognitive and affective risk perception and to frame risk as absolute, comparative and conditional. One hundred sixty-seven respondents completed the questionnaire. No aspects of risk perception (absolute cognitive, affective or conditional) significantly correlated with protective sun exposure behaviour, with the exception of perceived comparative severity of skin cancer. Instead, positive tanning attitudes were far more significantly correlated with sun exposure behaviour. Actual risk and risk perception have very limited impact on sun exposure behaviour. Instead, sun exposure behaviour was significantly linked with positive tanning attitudes. It is suggested, therefore, that campaigns focussing solely on education regarding risk factors appear to have been ineffective in behaviour mitigation, and innovative approaches, aimed at influencing tanning norms, might complement the existing educational campaigns. PMID- 30460491 TI - Environmental Water Pollution, Endocrine Interference and Ecotoxicity of 4-tert Octylphenol: A Review. AB - 4-tert-Octylphenol is a degradation product of non-ionic surfactants alkylphenol polyethoxylates as well as raw material for a number of industrial applications. It is a multimedia compound having been detected in all environmental compartments such as indoor air and surface waters. The pollutant is biodegradable, but certain degradation products are more toxic than the parent compound. Newer removal techniques from environmental waters have been presented, but they still require development for large-scale applications. Wastewater treatment by plant enzymes such as peroxidases offers promise in total removal of 4-tert-octylphenol leaving less toxic degradation products. The pollutant's endocrine interference has been well reported but more in oestrogens than in any other signalling pathways through which it is believed to exert toxicity on human and wildlife. In this paper we carried out a review of the activities of this pollutant in environmental waters, endocrine interference and relevance to its toxicities and concluded that inadequate knowledge of its endocrine activities impedes understanding of its toxicity which may frustrate current efforts at ridding the compound from the environment. PMID- 30460493 TI - Effect of Education on Awareness, Knowledge, and Willingness to Be Vaccinated in Females of Western India. AB - Cervical Cancer is the second most leading cause of death among Indian women. Infection by human papillomavirus (HPV) is one of the major causes of cervical cancer. Two prophylactic HPV vaccines approved and recommended for adolescents and young women in India. However, due to lack of appropriate knowledge, education, resources, and proper communication, these tools have little impact on disease burden. It is important to understand attitude, knowledge, and beliefs of females about HPV, cervical cancer, and HPV vaccine. Hence, the present study aimed to check awareness, educate females about cervical cancer and HPV vaccine, and evaluate the major hurdles in acceptability of HPV vaccine. Total 693 females of age 16 to 40 years of diverse background were enrolled in the study. Questionnaires were prepared to assess knowledge about cervical cancer and HPV vaccine before and after education and impact of knowledge on willingness to administer the vaccine. Education was given with the help of concern physicians. Final follow-up was done after 1 month to assess the attitude towards vaccination. The overall awareness before education was found to be 20.63%; maximum in females of medical (51.37%), and paramedical background (33.33%). Improvement after education was observed in terms of improved information about etiology, symptoms, precautions, and vaccination for cervical cancer. Acceptability of HPV vaccine was found to be poor (40.11% refused to undergo vaccination and 32.17% were in dilemma/unable to decide). Besides religious beliefs, high cost of the vaccine and unavailability of proper and convincing information about the vaccine would be the chief reasons for poor acceptability of HPV vaccine. PMID- 30460494 TI - Union Transitions and Fertility Within First Premarital Cohabitations in Canada: Diverging Patterns by Education? AB - Cohabitation has become increasingly accepted and normalized as part of the family system in Canada and has become the most common way to form a first union. The changing role of cohabitation in the family system is often understood as being driven by the ideational changes associated with the second demographic transition, but increasing international evidence indicates that this explanation is incomplete. Using nationally representative retrospective data from Canadians born between 1940 and 1979 from the 2011 General Social Survey, this study examines transitions out of first premarital cohabitation and fertility within these unions as two measures of the changing role of cohabitation. Across birth cohorts, Canadians are increasingly likely to use cohabitation as an alternative to marriage and less likely to use cohabitation as a short-lived prelude to marriage. These overall trends support the second demographic transition perspective. However, this study also finds that Canadians without a bachelor's degree are far more likely to experience a birth within cohabitation and that their likelihood of transitioning to marriage has declined steeply across birth cohorts. This educational gradient in childbearing in cohabitation and the increasing educational differences in union transitions over time provide support for the diverging destinies thesis in Canada. PMID- 30460495 TI - Cystatin C serum levels in healthy children are related to age, gender, and pubertal stage. AB - BACKGROUND: This study aims to establish age- and gender-specific cystatin C (CysC) reference values for healthy infants, children, and adolescents and to relate them to pubertal stage, height, weight, and body mass index (BMI). METHODS: Serum CysC and creatinine levels of 6217 fasting, morning venous blood samples from 2803 healthy participants of the LIFE Child study (age 3 months to 18 years) were analyzed by an immunoassay. Recruitment started in 2011; 1636 participants provided at least one follow-up measurement. Percentiles for CysC were calculated. Age- and gender-related effects of height, weight, BMI, and puberty status were assessed through linear regression models. RESULTS: Over the first 2 years of life, median CysC levels decrease depending on height (beta = - 0.010 mg/l/cm, p < 0.001) and weight (beta = - 0.033 mg/l/kg, p < 0.001) from 1.06 to 0.88 mg/l for males and from 1.04 to 0.87 mg/l for females. Following the second year of age, the levels remain stable for eight years. From 11 to 14 years of age, there is an increase of median CysC levels in males to 0.98 mg/l and a decrease in females to 0.86 mg/l. The change is associated with puberty (beta = 0.105 mg/l/Tanner stage, p < 0.001 in males and beta = - 0.093 mg/l/Tanner stage, p < 0.01 in females) and in males with height (beta = 0.003 mg/l/cm, p < 0.001). CONCLUSIONS: CysC levels depend on age, gender, and height, especially during infancy and puberty. We recommend the use of age- and gender-specific reference values for CysC serum levels for estimating kidney function in clinical practice. PMID- 30460496 TI - In Situ Synthesis of All-Solid-State Z-Scheme BiOBr0.3I0.7/Ag/AgI Photocatalysts with Enhanced Photocatalytic Activity Under Visible Light Irradiation. AB - A series of novel visible light driven all-solid-state Z-scheme BiOBr0.3I0.7/Ag/AgI photocatalysts were synthesized by facile in situ precipitation and photo-reduction methods. Under visible light irradiation, the BiOBr0.3I0.7/Ag/AgI samples exhibited enhanced photocatalytic activity compared to BiOBr0.3I0.7 and AgI in the degradation of methyl orange (MO). The optimal ratio of added elemental Ag was 15%, which degraded 89% of MO within 20 min. The enhanced photocatalytic activity of BiOBr0.3I0.7/Ag/AgI can be ascribed to the efficient separation of photo-generated electron-hole pairs through a Z-scheme charge-carrier migration pathway, in which Ag nanoparticles act as electron mediators. The mechanism study indicated that .O2- and h+ are active radicals for photocatalytic degradation and that a small amount of .OH also participates in the photocatalytic degradation process. PMID- 30460497 TI - Tracing Rhizophagus irregularis isolate IR27 in Ziziphus mauritiana roots under field conditions. AB - Arbuscular mycorrhizal fungi (AMF) play a major role as biofertilizer for sustainable agriculture. Nevertheless, it is still poorly documented whether inoculated AMF can successfully establish in field soils as exotic AMF and improve plant growth and productivity. Further, the fate of an exogenous inoculum is still poorly understood. Here, we pre-inoculated two cultivars (Tasset and Gola) of the fruit tree Ziziphus mauritiana (jujube) with the exotic AM fungus Rhizophagus irregularis isolate IR27 before transplantation in the field. In two experiments, tracking and quantification of R. irregularis IR27 were assessed in a 13-month-old jujube and an 18-month-old jujube in two fields located in Senegal. Our results showed that the inoculant R. irregularis IR27 was quantitatively traced and discriminated from native R. irregularis isolates in roots by using a qPCR assay targeting a fragment of the RNA polymerase II gene (RPB1), and that the inoculum represented only fractions ranging from 11 to 15% of the Rhizophagus genus in the two plantations 13 and 18 months after transplantation, respectively. This study validates the use of the RPB1 gene as marker for a relative quantification of a mycorrhizal inoculant fungus isolate in the field. PMID- 30460498 TI - A Case of Fulminant Type 1 Diabetes with Gastric and Urinary Retention. AB - Fulminant type 1 diabetes (fT1D) is a severe subtype of type 1 diabetes which progresses rapidly with islet cells destroyed almost completely within a short period of time. It is often characterized by flu-like or gastrointestinal symptoms at the onset with negative islet-associated autoantibodies, resulting in an absolute deficiency of endogenous insulin secretion. Poor prognosis can be caused by the significantly higher incidence of metabolic disorders (such as severe ion disorders and elevated serum pancreatic enzymes), acute and chronic complications if not diagnosed and treated in a timely manner. We herein describe an fT1D patient with gastric and urinary retention along with severe ion disturbance, whose laboratory tests revealed diabetic ketoacidosis, peripheral neuropathy, retinopathy, nephropathy, and hypoproteinemia. PMID- 30460499 TI - [Pseudarthrosis after bony avulsion fracture of the posterior cruciate ligament]. AB - BACKGROUND: Tibial bony avulsion fractures of the posterior cruciate ligament (PCL) are rare injuries and in certain cases a delayed healing or non-union can occur under conservative treatment. OBJECTIVE: Presentation of the clinical result of patients with pseudarthrosis who were secondarily operated on after bony avulsion of the PCL. MATERIAL AND METHODS: The study included all patients who were operated on since 2010 for reasons of delayed or non-union PCL avulsion fracture in this clinic. Standardized questionnaires and follow-up documentation, e.g. visual analog scale (VAS), International Knee Documentation Committee (IKDC), Lysholm and Tegner scores were used and a magnetic resonance imaging (MRI) monitoring of the injured knee was carried out. RESULTS: A total of 5 patients aged from 30 to 63 years (3 male, 2 female) were identified with mainly persisting flexion pain and instability under conservative treatment and secondary surgery of the knee. In the follow-up of 4 patients good results could be achieved (IKDC health condition 81/subjective assessment 76) after minimally invasive direct screw reduction with consolidation of the fracture zone; however, there was a slight residual dorsal instability. DISCUSSION: The secondary operative treatment of pseudarthrosis of bony PCL injuries led to good clinical results. Due to the detectable residual instability the authors are of the opinion that the indications for primary osteosynthesis in the acute phase should be generously considered. This must still be corroborated in studies with larger case numbers. CONCLUSION: The indications for MRI diagnostics should be generously considered, Smoking appears to be associated with an increased risk of pseudarthrosis. Good results can be achieved with a minimally invasive posterior screw approach, even after a delay. PMID- 30460500 TI - Will your patient benefit from palliative care? A multicenter exploratory survey about the acceptance of trigger factors for palliative care consultations among ICU physicians. PMID- 30460501 TI - Assessment of vocal cord movement by ultrasound in the ICU. AB - PURPOSE: Ultrasound can be used to non-invasively and rapidly examine airway conditions, but vocal cord visualization with the traditional approaches is poor. Our aim was to compare the accuracies of front-side transverse-axis ultrasound (FTU), lateral-side longitudinal-axis ultrasound (LLU), and the combination of both approaches for vocal cord movement disorder diagnoses (e.g., vocal cord paralysis or arytenoid cartilage dislocation). METHODS: We compared FTU, LLU, and the combination of both methods for patients in the intensive care unit (ICU). We used nasal fiber-optic endoscopy to confirm vocal cord injury. RESULTS: Among the 120 patients examined, 24 (20%) had vocal cord paralysis. The visualization rate of vocal cords for FTU was 71.7% (assessable, 86; non-assessable, 34), that for LLU was 88.3% (assessable, 106; non-assessable, 14), and that for the combined approach was 96.7% (assessable, 116; non-assessable, 4). The sensitivities and specificities were 58.3% (14/24) and 75% (72/96) for FTU, 91.7% (22/24) and 87.5% (84/96) for LLU, and 100% (24/24) and 95.8% (92/96) for the combined approach. Visualization rates for LLU were significantly higher than for FTU (P = 0.002); FTU + LLU rates were higher than those for FTU (P = 0.001). The difference between LLU and FTU + LLU was not statistically significant (P = 0.025). CONCLUSION: LLU can be used to evaluate arytenoid cartilage activity in ICUs, and the results are highly correlated with the diagnosis of nasal fiber-optic endoscopy. The combination of FTU and LLU shows promise as a rapid primary screening method for vocal cord injury. PMID- 30460502 TI - Laparoscopic versus open surgery for adhesional small bowel obstruction: a systematic review and meta-analysis of case-control studies. AB - BACKGROUND: Small bowel obstruction (SBO) due to adhesions is a common acute surgical presentation. Laparoscopic adhesiolysis is being performed more frequently. However, the clear benefits of laparoscopic adhesiolysis (LA) compared with traditional open adhesiolysis (OA) remain uncertain. The aim of this study was to compare the outcomes of LA versus OA for SBO due to adhesions. METHODS: A systemic literature review was conducted using PRISMA guidelines. A search was conducted using MEDLINE, EMBASE, PubMed and Cochrane Databases of all randomised controlled trials (RCT) and case-controlled studies (CCS) that compared LA with OA for SBO. Data were extracted using a standardised form and subsequently analysed. RESULTS: There were no RCT. Data from 18 CCS on 38,927 patients (LA = 5,729 and OA = 33,389) were analysed. A meta-analysis showed that LA for SBO has decreased overall mortality (LA = 1.6% vs. OA = 4.9%, p < 0.001) and morbidity (LA = 11.2% vs. OA = 30.9%, p < 0.001). Similarly, the incidences of specific complications are significantly lower in the LA group. There are significantly lower reoperation rate (LA = 4.5% vs. OA = 6.5%, p = 0.017), shorter average operating time (LA = 89 min vs. OA = 104 min, p < 0.001) and a shorter length of stay (LOS) (LA = 6.7 days vs. OA = 11.6 days, p < 0.001) in the LA group. In the CCS, there is likely to be a selection bias favouring less complex adhesions in the LA group that may contribute to the better outcomes in this group. CONCLUSIONS: Although there is a probable selection bias, these results suggest that LA for SBO in selected patients has a reduced mortality, morbidity, reoperation rate, average operating time and LOS compared with OA. LA should be considered in appropriately selected patients with acute SBO due to adhesions. PMID- 30460503 TI - Purse-string sutures using novel endoloops and repositionable clips for the closure of large iatrogenic duodenal perforations with single-channel endoscope: a multicenter study. AB - BACKGROUND: Serious complications due to perforation restrict the development of duodenal endoscopic treatment. The key stage for remediation is the successful endoscopic closure to prevent peritonitis and the need for surgical intervention. This report aimed to present a new simple method for the closure of large iatrogenic duodenal perforations with purse-string sutures using the novel endoloops and repositionable clips through a single-channel endoscope. METHODS: A total of 23 patients with iatrogenic duodenal perforations >= 1 cm were retrospectively studied who were presently treated by purse-string sutures using the novel endoloops and the repositionable hemostasis clips with the single channel endoscope at four institutes. During and after the procedure, a 20-gauge needle was used to relieve the pneumoperitoneum or subcutaneous emphysema. Finally, a gastroduodenal decompression tube was placed. RESULTS: The median maximum diameter of iatrogenic duodenal perforations was 1.65 cm (range 1.0-3.0 cm). Complete endoscopic closure of all 23 perforations was achieved. No patient had severe complications such as peritonitis. The wounds were healed and no obvious duodenal stricture was observed in all cases after 3 months. CONCLUSION: Purse-string sutures using the novel endoloops and repositionable endoclips through single-channel endoscope were feasible, effective and easy methods for the closure of large duodenal iatrogenic perforations. PMID- 30460504 TI - Laparoscopic Roux-en-Y Gastric Bypass Without Division of the Mesentery Reduces the Risk of Postoperative Complications. AB - BACKGROUND: Anastomotic complications after laparoscopic Roux-en-Y gastric bypass (LRYGB) including leaks, ulceration, and stenosis remain a significant cause of post-operative morbidity and mortality. Our objective was to compare two different surgical techniques regarding short-term anastomotic complications. METHODS: A retrospective analysis of all patients operated with a primary LRYGB from 2006 to June 2015 in one institution, where prospectively collected data from an internal quality registry and medical journals were analyzed. RESULTS: In total, 2420 patients were included in the analysis. 1016 were operated with a technique where the mesentery was divided during the creation of the Roux-limb (DM-LRYGB) and 1404 were operated with a method where the mesentery was left intact (IM-LRYGB). Leakage in the first 30 days [2.6% vs. 1.1% (p < 0.05)], and ulceration or stenosis occurring during the first 6 months after surgery [5.6% vs. 0.1% (p < 0.05)] was significantly higher in the DM-LRYGB group. Adjusted odds ratio for anastomotic leak was 0.46 (95% CI 0.24-0.87) and for stenosis/ulceration 0.01 (95% CI 0.002-0.09). CONCLUSION: IM-LRYGB seems to reduce the risk of complications at the anastomosis. A plausible explanation for this is that the blood supply to the anastomosis is compromised when the mesentery is divided. PMID- 30460506 TI - Efficient transposition of Tn4556 by alterations in inverted repeats using a delivery vector carrying a counter-selectable marker for Streptomyces. AB - A 6625-base pair transposon, Tn4556, was initially isolated from a Streptomyces strain and a sequence analysis was performed; however, its annotation data remain incomplete. At least three positions were identified as frameshift and base exchange errors by resequencing. The revised sequence revealed that Tn4556 contains four open reading frames that encode transposase, methyltransferase, isoprenyl diphosphate transferase, and resolvase, respectively. Thirty-eight-base pair inverted repeat (IR) sequences at both ends contained a 1-bp mismatch flanked by a target duplication site, and transposition efficiency was improved by the replacement of imperfectly matched IR-L to perfectly matched IR-L. The detection of Tn4556 transposition was markedly facilitated using a delivery vector carrying a strictly counter-selectable marker for Streptomyces strains. PMID- 30460505 TI - A phase I study of the safety and tolerability of VLX600, an Iron Chelator, in patients with refractory advanced solid tumors. AB - Introduction VLX600 is a novel iron chelator designed to interfere with intracellular iron metabolism, leading to inhibition of mitochondrial respiration and bioenergetic catastrophe and resultant tumor cell death. Methods We conducted a multicenter, phase 1, dose escalation study to determine the safety and adverse event profile and the maximum tolerated dose and recommended phase 2 dose of VLX600. Other endpoints included pharmacokinetics, and preliminary evidence of anti-cancer efficacy as assessed according to RECIST 1.1 criteria. VLX600 was administered intravenously on days 1, 8, and 15 of each 28-day treatment cycle. Results Nineteen patients were enrolled, and seventeen received at least one dose of VLX600. Dose increments were reduced to 50% after dose level 3 (40 mg) due to the occurrence of a grade 3 pulmonary embolism. The study was then closed early due to slow recruitment. No maximum tolerated dose (MTD) nor RP2D had been identified at the time of study closure. Overall, the drug was well tolerated and no DLTs were observed. Fourteen patients experienced drug-related adverse events of any grade. The most frequently reported drug-related AEs were fatigue, nausea, constipation, vomiting, increased alkaline phosphatase, anemia, and decreased appetite. No formal efficacy or survival analyses were performed. No objective responses were observed, though six patients (32%) had stable disease as best response. Conclusion VLX600 was reasonably well tolerated and, together with preclinical data, there is support for further efforts to explore its activity as single agent and in combination with drugs or radiation. PMID- 30460507 TI - Searching for potent and specific antibiotics against pathogenic Helicobacter and Campylobacter strains. AB - Menaquinone is an obligatory component of the electron-transfer pathway in microorganisms. Its biosynthetic pathway was established by pioneering studies with Escherichia coli and it was revealed to be derived from chorismate by Men enzymes. However, we identified an alternative pathway, the futalosine pathway, operating in some microorganisms including Helicobacter pylori and Campylobacter jejuni, which cause gastric carcinoma and diarrhea, respectively. Because some useful intestinal bacteria, such as lactobacilli, use the canonical pathway, the futalosine pathway is an attractive target for development of chemotherapeutics for the abovementioned pathogens. In this mini-review, we summarize compounds that inhibit Mqn enzymes involved in the futalosine pathway discovered to date. PMID- 30460508 TI - Robotic Morgagni hernia repair: an emerging approach to a congenital defect. AB - Morgagni hernia (MH) is a rare, congenital diaphragmatic hernia (CDH). The use of robotic surgery to repair MH in adults has recently been described in the literature, but only on two previous occasions. The objective of this report is to describe four cases of robotic repair of MH in adults performed by a single surgeon to better delineate an emerging approach to this rare condition. A retrospective review of patients who underwent robotic repair of MH by a single surgeon was performed. Four consecutive patients were identified and included. The median age of patients was 43 (range: 23-70). All patients had symptoms prior to diagnosis, including substernal chest pain (n = 3), dyspnea (n = 4), dysphagia (n = 1), and regurgitation (n = 1). All patients underwent hernia reduction, primary tissue repair, and mesh implant with minimal average estimated blood loss. All hernias were right sided, and the average length of surgery was 129.8 min. The average length of stay was 2 days. No intraoperative complications or 30 day postoperative complications were reported. Symptoms, including chest pain and dyspnea, resolved postoperatively for each patient. With this technique, robotic Morgagni hernia repair can be done with short operative time, few complications, and favorable length of stay. This operation takes advantage of the dexterity and wristed nature of the instruments; suturing of the diaphragmatic defect and mesh (performed on the "ceiling" of field) and incorporating pledgets into these sutures become straightforward endeavors when performed robotically. We have found the robotic platform useful for a transabdominal approach to Morgagni hernia repair. PMID- 30460509 TI - "The acid test"-validation of the ParaDNA(r) Body Fluid ID Test for routine forensic casework. AB - The identification of the cellular origin and composition of crime scene-related traces can provide crucial insight into a crime scene reconstruction. In the last decade, especially mRNA-based body fluid and tissue identification (BFI) has been vigorously examined. Besides capillary electrophoretic (CE) and real-time quantitative PCR (RT-qPCR)-based approaches for mRNA detection, melt curve analysis bears potential as a simple-to-use method for BFI. The ParaDNA(r) Body Fluid ID Test relies on HyBeacon(r) probes and was developed as a rapid test for mRNA-based BFI of six different body fluids: vaginal fluid, seminal fluid, sperm cells, saliva, menstrual, and peripheral blood. The herein presented work was performed as an "acid test" of the system and should clarify whether the approach matches the requirements of forensic routine casework in German police departments. Tested samples consisted of single source as well as of mixed samples. PMID- 30460510 TI - Evidence of proliferative activity in human Merkel cells: implications in the histogenesis of Merkel cell carcinoma. AB - The cellular origin of Merkel cell carcinoma (MCC) is controversial. We previously hypothesized that MCC originates from hair follicle stem cells or Merkel cell (MC) progenitors residing within the hair follicle bulge. Examination of three cases of combined MCC led to the unexpected discovery that numerous keratin 20 (CK20)-positive MCs within the squamous cell carcinoma (SCC) component of combined MCC appeared morphologically normal with dendritic and oval shapes. Moreover, one extremely rare case of combined SCC and MCC showed both intra epidermal and dermal MCCs. These three cases represent the first documentation of MC hyperplasia in MCC, besides various benign follicular neoplasms associated with MC hyperplasia. Therefore, to elucidate the proliferating potential of MCs and their histogenetic relationship with MCCs, we further investigated these cases based on pathological observations. We identified numerous cells co expressing CK20 and the proliferation marker Ki-67, identical to the morphological and immunohistochemical features of normal MCs. This finding indicated that MCs can no longer be considered as pure post-mitotic cells. Instead, they have proliferative potential under specific conditions in the diseased or wounded skin, or adjacent to various skin tumors, including MCC. Intimate co-existence of two malignant cell components composed of intradermal and intra-epidermal MCCs, with the proliferation of normal-appearing MCs in the same lesion, lends support to the hypothesis that MCs and MCC cells are derived from MC progenitors residing within the hair follicle bulge. Specifically, MCCs are derived from transformed MC progenitors with potential for dual-directional differentiation towards neuroendocrine and epithelial lineages. PMID- 30460511 TI - Podoplanin suppresses the cell adhesion of epidermal keratinocytes via functional regulation of beta1-integrin. AB - Epidermal stem cells adhere more efficiently to the extracellular matrix (ECM) than the less adhesive differentiating cells due to their high expression of cell adhesion molecules including beta1-integrin. Podoplanin is majorly expressed in the markedly proliferative and differentiating basal cells of the wounded and psoriatic epidermis. This study was designed to reveal podoplanin's function in human epidermal keratinocytes (HEK) focusing on its interaction with beta1 integrin. We analyzed the adhesion and differentiation of HEK in both podoplanin overexpressing and -knock-down cells, considering their beta1-integrin levels. The basal layer of IL-22-treated hyperproliferative reconstituted epidermis cells (simulating basal hyperproliferative psoriatic epidermal basal cells) expressed higher podoplanin levels than the untreated control cells. The adhesiveness of HaCaT cells, which do not express podoplanin, was reduced after the overexpression of podoplanin. HEK with podoplanin overexpression suppressed the cell adhesion to type I collagen (while downregulating beta1-integrin functions) and podoplanin silencing augmented it (by increasing active ECM-bound beta1 integrin). The increased cell adhesion to type I collagen induced by podoplanin silencing could be reversed by addition of P5D2, a neutralizing antibody against beta1-integrin. In the psoriatic epidermis, podoplanin expression was especially upregulated on the rete ridges of the basal cell layer. This expression pattern was inversely correlated with the total/ECM-bound active beta1-integrin expression, which was stronger at the basal cell layer covering the dermal papillae. Our results indicate that podoplanin inhibits the cell ECM attachment by suppressing beta1-integrin and initiating HEK differentiation. Podoplanin is presumably involved in the pathogenesis of psoriasis. PMID- 30460512 TI - Individuality in coo calls of adult male golden snub-nosed monkeys (Rhinopithecus roxellana) living in a multilevel society. AB - Vocal individuality is a prerequisite for individual recognition, especially when visual and chemical cues are not available or effective. Vocalizations encoding information of individual identity have been reported in many social animals and should be particularly adaptive for species living in large and complexly organized societies. Here, we examined the individuality in coo calls of adult male golden snub-nosed monkeys (Rhinopithecus roxellana) living in a large and multilevel society. Coo calls are one of the most frequently occurring call types in R. roxellana and likely serve as the signals for contact maintenance or advertisement in various contexts including group movement, foraging, and resting. From April to October 2016, April to July 2017, and September to October 2017, we recorded a total of 721 coo calls from six adult males in a provisioned, free-ranging group and one adult male in captivity in Shennongjia National Park, China. We selected 162 high-quality recordings to extract 14 acoustic parameters based on the source-filter theory. Results showed that each of all parameters significantly differed among individuals, while pairwise comparisons failed to detect any parameter that was different between all pairs. Furthermore, a discriminant function analysis indicated that the correct assignment rate was 80.2% (cross-validation: 67.3%), greater than expected by chance (14.3%). In conclusion, we found evidence that coo calls of adult male R. roxellana allowed the reliable accuracy of individual discrimination complementarily enhanced by multiple acoustic parameters. The results of our study point to the selective pressures acting on individual discrimination via vocal signals in a highly gregarious forest-living primate. PMID- 30460513 TI - Psychometric properties of the Quality of Life Inventory-Disability (QI Disability) measure. AB - PURPOSE: Children with intellectual disability encounter daily challenges beyond those captured in current quality of life measures. This study evaluated a new parent-report measure for children with intellectual disability, the Quality of Life Inventory-Disability (QI-Disability). METHODS: QI-Disability was administered to 253 primary caregivers of children (aged 5-18 years) with intellectual disability across four diagnostic groups: Rett syndrome, Down syndrome, cerebral palsy or autism spectrum disorder. Exploratory and confirmatory factor analyses were conducted and goodness of fit of the factor structure assessed. Associations between QI-Disability scores, and diagnostic and age groups were examined with linear regression. RESULTS: Six domains were identified: physical health, positive emotions, negative emotions, social interaction, leisure and the outdoors, and independence. Goodness-of-fit statistics were satisfactory and similar for the whole sample and when the sample was split by ability to walk or talk. On 100 point scales and compared to Rett syndrome, children with Down syndrome had higher leisure and the outdoors (coefficient 10.6, 95% CI 3.4,17.8) and independence (coefficient 29.7, 95% CI 22.9, 36.5) scores, whereas children with autism spectrum disorder had lower social interaction scores (coefficient - 12.8, 95% CI - 19.3, - 6.4). Scores for positive emotions (coefficient - 6.1, 95% CI - 10.7, - 1.6) and leisure and the outdoors (coefficient 5.4, 95% CI - 10.6, - 0.1) were lower for adolescents compared with children. CONCLUSIONS: Initial evaluation suggests that QI Disability is a reliable and valid measure of quality of life across the spectrum of intellectual disability. It has the potential to allow clearer identification of support needs and measure responsiveness to interventions. PMID- 30460514 TI - Uveitis: contrasting the approaches in Japan and the United States. AB - PURPOSE: To compare the approaches to uveitis in Japan and the United States. METHODS: This report is based on the author's personal experience, conversations with Japanese colleagues, and a literature search using the database of the US National Library of Medicine. RESULTS: The frequencies of specific forms of uveitis vary between the two countries. Options for therapy are affected by government regulations and the impact of insurance carriers. In both countries, there is a stepwise approach to therapy beginning with topical corticosteroids and ultimately advancing to biologics. Despite the differences, the goals for therapy, disease control with minimal toxicity, are the same. CONCLUSIONS: Genetic, environmental, and regulatory differences impact the approach to uveitis. Despite these factors, the goal for therapy is essentially the same. PMID- 30460515 TI - Cannabinoid-induced lower lip retraction in rats. AB - RATIONALE: Lower lip retraction (LLR) in rats has been described as a distinctive effect of 5-HT1A agonists. In the course of evaluating behavioral effects of cannabinoid agonists in rats, LLR effects were evident following injection of several cannabinoid agonists. OBJECTIVES: To pharmacologically characterize cannabinoid-induced LLR in rats. METHODS: Lower lip retraction was scored using a 3-point scale for up to 6 h after injection of the cannabinoid agonists Delta9 tetrahydrocannabinol (Delta9-THC, 1-10 mg/kg), AM7499 (0.01-1.0 mg/kg), or AM2389 (0.003-0.1 mg/kg), or, for comparison, the 5-HT1A agonist 8-OH-DPAT (0.01-0.3 mg/kg). Next, antagonist effects of rimonabant (1-10 mg/kg) and WAY100635 (0.3 mg/kg) on LLR produced by cannabinoid or 5-HT1A agonists were evaluated. Lastly, effects of 8-OH-DPAT were determined following pretreatment with AM2389 (0.003 0.01 mg/kg) or Delta9-THC (1 mg/kg). RESULTS: All three cannabinoid agonists produced LLR. Effects of AM2389 were attenuated by both rimonabant and WAY100635 whereas effects of 8-OH-DPAT were antagonized by WAY 100635 but not by rimonabant. Pretreatment with 1 mg/kg Delta9-THC or 0.01 mg/kg AM2389 shifted the 8-OH-DPAT dose-effect function for LLR to the left and isobolographic analysis of the data indicates CB1 and 5-HT1A interactions can be supraadditive. CONCLUSIONS: Cannabinoid agonists produce LLR in rats, an effect heretofore ascribed only to activity at 5-HT1A receptors, via CB1 receptor-mediated actions. Co administration of a cannabinoid agonist and the 5-HT1A agonist 8-OH-DPAT results in a synergistic effect on LLR. PMID- 30460517 TI - Acknowledgment to Referees. PMID- 30460516 TI - Second-generation antipsychotics and metabolism alterations: a systematic review of the role of the gut microbiome. AB - RATIONALE: Multiple drugs are known to induce metabolic malfunctions, among them second-generation antipsychotics (SGAs). The pathogenesis of such adverse effects is of multifactorial origin. OBJECTIVES: We investigated whether SGAs drive dysbiosis, assessed whether gut microbiota alterations affect body weight and metabolic outcomes, and looked for the possible mechanism of metabolic disturbances secondary to SGA treatment in animal and human studies. METHODS: A systematic literature search (PubMed/Medline/Embase/ClinicalTrials.gov/PsychInfo) was conducted from database inception until 03 July 2018 for studies that reported the microbiome and weight alterations in SGA-treated subjects. RESULTS: Seven articles reporting studies in mice (experiments = 8) and rats (experiments = 3) were included. Olanzapine was used in five and risperidone in six experiments. Only three articles (experiments = 4) in humans fit our criteria of using risperidone and mixed SGAs. The results confirmed microbiome alterations directly (rodent experiments = 5, human experiments = 4) or indirectly (rodent experiments = 4) with predominantly increased Firmicutes abundance relative to Bacteroidetes, as well as weight gain in rodents (experiments = 8) and humans (experiments = 4). Additionally, olanzapine administration was found to induce both metabolic alterations (adiposity, lipogenesis, plasma free fatty acid, and acetate levels increase) (experiments = 3) and inflammation (experiments = 2) in rodents, whereas risperidone suppressed the resting metabolic rate in rodents (experiments = 5) and elevated fasting blood glucose, triglycerides, LDL, hs-CRP, antioxidant superoxide dismutase, and HOMA-IR in humans (experiment = 1). One rodent study suggested a gender-dependent effect of dysbiosis on body weight. CONCLUSIONS: Antipsychotic treatment-related microbiome alterations potentially result in body weight gain and metabolic disturbances. Inflammation and resting metabolic rate suppression seem to play crucial roles in the development of metabolic disorders. PMID- 30460518 TI - Apixaban Levels in Octogenarian Patients with Non-valvular Atrial Fibrillation. AB - BACKGROUND: There is a paucity of data on apixaban levels among octogenarians with non-valvular atrial fibrillation (NVAF). We aimed to compare apixaban levels between octogenarians (with and without dose reduction) and younger patients, to assess the frequency of high and above-range drug levels. METHODS: A cross sectional, prospective study of 80 patients treated with apixaban for NVAF was conducted. Apixaban levels were compared among octogenarians treated with 5 mg twice daily (bid), octogenarians with appropriately reduced dose (2.5 mg bid), octogenarians with inappropriately reduced dose and younger patients (age < 70 years). Trough and peak levels were measured by a chromogenic assay calibrated for apixaban and compared to predicted manufacturer levels. RESULTS: A significant proportion of the cohort had above-range trough [n = 11 (13.8%)] and peak [n = 16 (20%)] levels, especially octogenarians with the 5-mg bid dosage [n = 6 (30%) for trough and n = 8 (40%) for peak]. No significant differences were found in the trough or peak geometric mean (GM) levels among the groups, apart from the peak GM levels between the 5-mg octogenarian group and the other two 2.5 mg bid octogenarian groups (p = 0.0004). The frequency of apixaban peak levels within the upper quartile was significantly higher in the 5-mg octogenarian group compared to the other groups [n = 12 (60%) of measurements, p = 0.019), whereas trough levels were comparable between groups. CONCLUSION: High and above-range peak apixaban steady-state levels are highly prevalent in octogenarians receiving the appropriate dosage of 5 mg bid for NVAF stroke prevention. Age above 80 strongly affects apixaban levels. TRIAL REGISTRATION: ClinicalTrials.gov Identifier number NCT02623049. PMID- 30460519 TI - Exploring the potential of iron to replace ruthenium in photosensitizers: a computational study. AB - In an effort to replace the widely used ruthenium metal complexes with low-cost, earth abundant iron complexes as photosensitizers for dye-sensitized solar cell (DSSC) applications, herein we report the computational design of heteroleptic iron complexes (FC1-3) coordinated with benzimidazole-phenylcarbene (C^N) ligands. DFT and TDDFT calculations predicted the stronger sigma-donating and pi accepting nature of phenyl carbene ligands substituted with electron-withdrawing CF3, donating -N(CH3)2, and benzothiazine annulation than the imidazole carbene ligands (FC4); consequently, the metal-ligand bond distances and interactions that influence the ordering of charge transfer states with respect to metal centered states are altered in FC1-3 complexes. Detailed analysis based on energy decomposition analysis, spin density distribution analysis, and ab initio ligand field theory parameters were enabled to understand the nature of heteroleptic ligand interactions with the rest of the metal complex. The results from the study shed light on the judicious choice of ligands, as the same non-innocent ligand that is experimentally proven as favorable for Ru-dyes (TC1) is found to be detrimental for Fe-dyes (FC1). Among the complexes studied, the FC3 complex is a promising sensitizer for DSSC with 1,3MLCT energy level well separated from 3,5MC, thereby preventing the deactivation of MLCT. The outcome of the study is therefore an important step toward the development of photosensitizers based on iron metal. Graphical abstract Potential photosensitzers based on earth-abundant, low cost iron metal have been designed for dye sensitized solar cell applications. PMID- 30460520 TI - Occurrence of ochratoxin A in typical salami produced in different regions of Italy. AB - A total of 172 different salamis were purchased from farms and small salami factories located in four Italian regions (Piedmont, Veneto, Calabria, and Sicily) and analyzed for the presence of ochratoxin A (OTA). Analysis was performed by high-performance liquid chromatography coupled to a fluorimetric detector (HPLC-FLD). The detection limit (LOD) for the method used was 0.05 MUg/kg, while the quantitation limit (LOQ) was 0.20 MUg/kg; the average recovery rate was 89.1%. OTA was detected in 22 salamis, and 3 samples exceeded the Italian guidance value for OTA in pork meat (1 MUg/kg). In particular, what emerges from this research is the high percentage of spicy salamis among positive samples (68.2%, 15 out of 22), although spicy salamis are only 27.3% of the total number of samples collected and analyzed. Red chili pepper contaminated by OTA could be responsible for the presence of the mycotoxin in these spicy salamis. It follow that, also the control of some ingredients used in the manufacture of these meat products, like spices, should not be neglected. PMID- 30460521 TI - Does low-level laser therapy on degenerated ovine testes improve post-thawed sperm characteristics? AB - Low-level laser therapy (LLLT) can modulate redox state of the cell which could be useful to treat testicular degeneration and also prevent injuries by sperm cryopreservation. The aim of this study was to evaluate the effects of LLLT treatment on semen cryopreservation from rams submitted or not to testicular degeneration by testicular insulation. Eleven White Dorper rams were divided into four groups: animals that were not insulated (Control) and not treated (No Laser) (n = 2); animals that were not insulated and treated with LLLT (n = 3); animals that were insulated and not treated with LLLT (n = 3), and animals that were insulated and treated with LLLT (n = 3). Testicular insulation was performed using scrotal insulation bags for 72 h. LLLT treatment was 28 J/cm2 energy, 808 nm of wavelength, and 30 mW of power output, irradiated on testis for 15 days with an interval of 48 h. Three ejaculates from each ram were collected: before insulation, 23, and 59 days after insulation bag removal. Cryopreservation was performed of the third ejaculate. Sperm evaluation was performed before and after cryopreservation considering sperm motility, morphology, acrosomal and plasma membrane integrity, mitochondrial potential, and oxidative stress. As expected, cryopreservation had a negative effect on several sperm motility characteristics and sperm membranes. LLLT treatment did not improve sperm quality from rams submitted to testicular insulation. Thus, testicular insulation and cryopreservation effects on spermatozoa were not attenuated by LLLT in this study. PMID- 30460522 TI - A Physiologically Based Pharmacokinetic Model for Optimally Profiling Lamotrigine Disposition and Drug-Drug Interactions. AB - BACKGROUND AND OBJECTIVES: Lamotrigine (Lamictal(r)) is a broad-spectrum antiepileptic drug available in both immediate-(IR) and extended-release (XR) formulations. Here, we present a new physiologically based pharmacokinetic (PBPK) model for IR and XR formulations of lamotrigine to predict disposition in adults and children, plus drug-drug interactions (DDIs). METHODS: Models for lamotrigine IR and XR formulations were constructed using a Simcyp(r) Simulator. Concentration-time profiles were simulated for lamotrigine IR single (SD) and steady-state (SS) doses ranging from 25 to 200 mg in adults, as well as 2 mg/kg (SD), and 7.7-9.4 mg/kg (SS) in children aged between 4 and 17 years. Lamotrigine XR profiles were simulated for SD and SS doses ranging from 250 to 400 mg. DDI prediction with lamotrigine was simulated in adults with enzyme-inducing drugs, rifampin (rifampicin) and ritonavir, as well as the enzyme inhibitor, valproic acid. RESULTS: The lamotrigine model predicted adult area-under-the-curve (AUC) and peak plasma concentration (Cmax) results for IR SD within 35% of observed data; lamotrigine IR SS dosing was within 10% and 30% of observed data, respectively. Pediatric lamotrigine IR SD AUC and Cmax values were within 10% and 15% of observed data, respectively. AUC and Cmax values for lamotrigine XR SD simulated in adults were within 20% of observed data; similarly lamotrigine XR SS parameters were within 10%. Concerning DDI simulation in adults, predicted-to observed lamotrigine AUC ratios [AUCDDI/AUCalone] were within 15% for ritonavir and rifampin, and 20% for valproic acid. CONCLUSIONS: Our developed PBPK lamotrigine profile accurately predicts DDIs and lamotrigine IR/XR formulation disposition in adults and children. This PBPK model will be helpful in designing future DDI studies for co-administration of lamotrigine with other drugs and in designing individualized patient dosing regimens. PMID- 30460523 TI - The impact of sarcopenia and myosteatosis on postoperative outcomes in patients with inflammatory bowel disease. AB - BACKGROUND: Inflammatory bowel disease (IBD) is a relatively common disorder with significant associated morbidity. Sarcopenia and myosteatosis are associated with adverse postoperative outcomes. This study investigated outcomes in IBD patients undergoing surgical resection relative to the presence of sarcopenia and myosteatosis. METHODS: A retrospective analysis of a prospectively maintained surgical database was conducted. All patients undergoing elective or emergency resection for IBD between 2011 and 2016, with a contemporaneous perioperative computed tomography (CT) scan, were included. Patient demographics, clinical and biochemical measurements were collected. Skeletal muscle index and attenuation were measured on perioperative CT scans using Osirix version 5.6.1. Univariate and multivariate regression analysis was used to identify risk factors for adverse postoperative outcomes. RESULTS: Seventy-seven patients (46 male, 31 female; mean age 42 years, range 20-80 years) were included. Thirty patients (30%) had sarcopenia and 26 (34%) had myosteatosis. Myosteatosis was significantly associated with increased hospital stay postoperatively (9 versus 13 days). Sarcopenia and myosteatosis were associated with hospital readmission within 30 days on univariate analysis. Multivariate regression analysis demonstrated an independent association between myosteatosis and hospital readmission. Sixteen patients (21%) had a clinically relevant postoperative complication, but an association with sarcopenia and myosteatosis was not observed. A neutrophil-lymphocyte ratio greater than 5 was predictive of clinically relevant postoperative complications on multivariate regression analysis. CONCLUSIONS: Myosteatosis was associated with increased hospital stay and increased 30-day hospital readmission rates on multivariate regression analysis. Sarcopenia and myosteatosis in IBD were not associated with clinically relevant postoperative complications. PMID- 30460525 TI - Heritable traits that contribute to nephrolithiasis. AB - Urinary stones tend to cluster in families. Of the known risk factors, evidence is strongest for heritability of urinary calcium excretion. Recent studies suggest that other stone risk factors may have heritable components including urinary pH, citrate and magnesium excretion, and circulating vitamin D concentration. Several risk factors assumed purely environmental may also have heritable components, including dietary intake and thirst. Thus, future studies may reveal that genetics plays an even stronger role in urinary stone pathogenesis than previously known. PMID- 30460524 TI - Intracerebroventricular injection of resveratrol ameliorated Abeta-induced learning and cognitive decline in mice. AB - Resveratrol (RSV) is a natural plant polyphenol compound which consists in red grape skins and wine in general. Plenty of previous studies have shown that resveratrol has neuroprotective effects. The primary object of this research was to study the effects of RSV on improving the cognitive function and neurodegeneration in the mouse model of Alzheimer's disease induced by Abeta1-42, and the possible mechanism about targeting on Sirt1, which results in attenuating inflammatory response and mitochondrial dysfunction. We established the AD model of intracerebroventricular (i.c.v.) injection of Abeta1-42 and it was observed that the significant decrease in alternately of Y Maze and the quadrant dwell time percentage of Morris water maze test. Furthermore, there were significant upregulations of AMPK/ PGC-1alpha and downregulations of NF-kappaB/ IL-1beta/ NLRP3 signaling pathways in the hippocampus and prefrontal cortex in AD mice. The treatments with RSV and Donepezil could significantly ameliorate all the behavioral and biochemical changes induced by Abeta1-42. It also noticeably improved the histopathological changes in the hippocampus and cortex. The results suggested that RSV might protect against cognitive deficits and neurodegeneration induced by Abeta1-42, and serve as a potential agent in treatment of AD. PMID- 30460526 TI - Precision medicine in renal stone-formers. AB - Here we define precision medicine approaches and discuss how these may be applied to renal stone-formers to optimise diagnosis and a management. Using the gene discovery of monogenic stone disorders as examples, we discuss the benefits of personalising therapies for renal stone-formers to provide improved prevention and treatment of these disorders. PMID- 30460527 TI - Nephrolithiasis secondary to inherited defects in the thick ascending loop of henle and connecting tubules. AB - Twin and genealogy studies suggest a strong genetic component of nephrolithiasis. Likewise, urinary traits associated with renal stone formation were found to be highly heritable, even after adjustment for demographic, anthropometric and dietary covariates. Recent high-throughput sequencing projects of phenotypically well-defined cohorts of stone formers and large genome-wide association studies led to the discovery of many new genes associated with kidney stones. The spectrum ranges from infrequent but highly penetrant variants (mutations) causing mendelian forms of nephrolithiasis (monogenic traits) to common but phenotypically mild variants associated with nephrolithiasis (polygenic traits). About two-thirds of the genes currently known to be associated with nephrolithiasis code for membrane proteins or enzymes involved in renal tubular transport. The thick ascending limb of Henle and connecting tubules are of paramount importance for renal water and electrolyte handling, urinary concentration and maintenance of acid-base homeostasis. In most instances, pathogenic variants in genes involved in thick ascending limb of Henle and connecting tubule function result in phenotypically severe disease, frequently accompanied by nephrocalcinosis with progressive CKD and to a variable degree by nephrolithiasis. The aim of this article is to review the current knowledge on kidney stone disease associated with inherited defects in the thick ascending loop of Henle and the connecting tubules. We also highlight recent advances in the field of kidney stone genetics that have implications beyond rare disease, offering new insights into the most common type of kidney stone disease, i.e., idiopathic calcium stone disease. PMID- 30460528 TI - Characteristics of missed prostate cancer lesions on 3T multiparametric-MRI in 518 patients: based on PI-RADSv2 and using whole-mount histopathology reference. AB - PURPOSE: To determine the characteristics of missed prostate cancer (PCa) lesions on 3T multiparametric-MRI (mpMRI) based on PI-RADSv2 with whole-mount histopathology (WMHP) correlation. MATERIALS AND METHODS: This IRB-approved, HIPAA-compliant study, included 614 consecutive men with 3T mpMRI prior to prostatectomy at a single tertiary center between 12/2009 and 4/2017. Clinical, mpMRI, and pathologic features were obtained. PI-RADSv2-based MRI detected lesions were matched with previously finalized WMHP by a genitourinary (GU) radiologist and a GU pathologist. Patients with no mpMRI detected PCa lesion, but with at least one lesion >= 1 cm on WMHP, were reviewed retrospectively and assigned a PI-RADSv2 score. Tumor characteristics were compared between missed and detected lesions. RESULT: The final cohort included 518 patients with 1085 WMHP lesions. 51.9% (563/1085) of lesions were missed on 3T mpMRI. 71.4% (402/563), 21.7% (122/563), 4.4% (25/563), and 2.5% (14/563) of the missed lesions were Gleason scores (GS) 3 + 3, 3 + 4, 4 + 3, and 8 - 10, respectively. Missed PCa lesions had significantly lower proportion of GS >= 7 (p < 0.001) and smaller size for overall (p < 0.001) and index subcohorts (p < 0.001), as compared to detected lesions. 34.5% (194) of overall and 71.2% (79) index missed lesions were larger than 1 cm. In 13.7% (71/518) of patients without MR detected PCa, 149 lesions were detected on WMHP, with 70 (47%) lesions >= 1 cm. In retrospective review of these lesions, 42.9% (30), 18.6% (13), 21.5% (15), 10% (7), and 7% (5) were PI-RADSv2 1, 2, 3, 4, and 5, respectively. CONCLUSION: 3T mpMRI has an excellent per patients diagnostic performance for PCa and majority of missed lesions are clinically nonsignificant. PMID- 30460529 TI - Deep transfer learning-based prostate cancer classification using 3 Tesla multi parametric MRI. AB - PURPOSE: The purpose of the study was to propose a deep transfer learning (DTL) based model to distinguish indolent from clinically significant prostate cancer (PCa) lesions and to compare the DTL-based model with a deep learning (DL) model without transfer learning and PIRADS v2 score on 3 Tesla multi-parametric MRI (3T mp-MRI) with whole-mount histopathology (WMHP) validation. METHODS: With IRB approval, 140 patients with 3T mp-MRI and WMHP comprised the study cohort. The DTL-based model was trained on 169 lesions in 110 arbitrarily selected patients and tested on the remaining 47 lesions in 30 patients. We compared the DTL-based model with the same DL model architecture trained from scratch and the classification based on PIRADS v2 score with a threshold of 4 using accuracy, sensitivity, specificity, and area under curve (AUC). Bootstrapping with 2000 resamples was performed to estimate the 95% confidence interval (CI) for AUC. RESULTS: After training on 169 lesions in 110 patients, the AUC of discriminating indolent from clinically significant PCa lesions of the DTL-based model, DL model without transfer learning and PIRADS v2 score >= 4 were 0.726 (CI [0.575, 0.876]), 0.687 (CI [0.532, 0.843]), and 0.711 (CI [0.575, 0.847]), respectively, in the testing set. The DTL-based model achieved higher AUC compared to the DL model without transfer learning and PIRADS v2 score >= 4 in discriminating clinically significant lesions in the testing set. CONCLUSION: The DeLong test indicated that the DTL-based model achieved comparable AUC compared to the classification based on PIRADS v2 score (p = 0.89). PMID- 30460530 TI - Radiofrequency ablation following artificial ascites and pleural effusion creation may improve outcomes for hepatocellular carcinoma in high-risk locations. AB - PURPOSE: To investigate the outcomes of radiofrequency ablation (RFA) following artificial ascites (AA) and artificial pleural effusion (AP) creation for hepatocellular carcinoma (HCC) in high-risk locations. MATERIALS AND METHODS: Eligible patients were divided into 2 study periods (non-AAAP and AAAP groups) with AAAP performed in the latter period. Local tumor progression, primary technique effectiveness and complications were compared between patients with and without AAAP. Cumulative probability of local tumor progression and overall survival were estimated with Kaplan-Meier curves. RESULTS: One hundred thirty eight patients with 195 tumors were evaluated. AAAP was performed in 48 patients with 76 tumors. Local tumor progression rates at 12 and 24 months were 9.3% and 22.2% in the non-AAAP group versus 5.5% and 9% in the AAAP group (p < 0.0001). Primary technique effectiveness was achieved in 76.5% of the non-AAAP group versus 89.5% of the AAAP group (p = 0.046). Night (7.6%) major complications occurred in the non-AAAP group and 2 (2.6%) cases occurred in the AAAP group. Therapy-oriented severity grading system after RFA was lower in the AAAP group (p = 0.02). Overall survival rates at 12 and 24 months were 85.6% and 77.7% in the non-AAAP group versus 97.2% and 89.7% in the AAAP group (p = 0.033). CONCLUSION: RFA following AA and AP for high-risk located HCC may improve outcomes. PMID- 30460531 TI - Influence of slice thickness on result of CT histogram analysis in indetermined adrenal masses. AB - PURPOSE: The aim was to determine the optimal slice thickness of CT images and the optimal threshold of negative voxels for CT histogram analysis to distinguish adrenal adenomas from non-adenomas with a mean attenuation more than 10 Hounsfield units (HU). METHODS: Volume CT histogram analysis of 83 lipid-poor adenomas and 80 non-adenomas was performed retrospectively. The volume of interest was extracted from each adrenal lesion, and the mean attenuation, standard deviation (SD), and percentage of voxels with a negative CT value were recorded using reconstructions with different slice thicknesses (5 mm, 2.5 mm, 1.25 mm). The percentage of negative voxels was correlated with SD as a measure of image noise and with the reference splenic tissue values. The sensitivity, specificity, and positive predictive value (PPV) for the identification of adenomas were calculated using reconstructions with different slice thicknesses and three different thresholds of negative voxels (1%, 5%, 10%). RESULTS: The percentage of negative voxels increased with a thinner slice thickness and correlated with increasing CT image noise in adenomas, non-adenomas, and spleen. Using a threshold of 10% negative voxels and a slice thickness of 5 mm, we reached a sensitivity of 53.0%, specificity of 98.8% and the highest PPV, and thus we propose this combination for clinical use. Other combinations achieved a clearly lower specificity and PPV as a result of the increasing noise in CT images. CONCLUSION: The CT slice thickness significantly affects the result and diagnostic value of histogram analysis. Thin CT slice reconstructions are inappropriate for histogram analysis. PMID- 30460532 TI - Magnetic resonance imaging features of pubic symphysis urinary fistula with pubic bone osteomyelitis in the treated prostate cancer patient. AB - INTRODUCTION: Pubic bone osteomyelitis with pubic symphysis urinary fistula represents a debilitating complication of radiation and ablative treatments for prostate cancer. The definitive radiographic diagnosis of this clinical entity is not described. In this study, we characterize the plain film and magnetic resonance imaging findings of pubic osteomyelitis. MATERIALS AND METHODS: We reviewed a database of prostate cancer survivors with diagnosed pubic osteomyelitis from 2011 to 2015. These patients underwent pelvic plain radiographs and magnetic resonance imaging with T1-weighted and fat-suppressed T2 weighted fast spin echo sequences. Intravenous gadolinium was utilized. The diagnosis was verified with extirpative surgery. 16 patients with diagnosed pubic osteomyelitis from 2011 to 2015 underwent imaging at our institution. RESULTS: All patients demonstrated increased signal on T2- weighted sequences and decreased signal on T1-weighted sequences along the pubic symphysis and the marrow of the involved pubic rami. Inflammatory myositis with diastasis of the pubic symphysis and cortical bone erosion were identified in the majority of patients. Fluid collections were identified in 75% of patients. 63% of conventional radiographs demonstrated no radiographic evidence of pubic osteomyelitis. CONCLUSION: Magnetic resonance imaging of pubic symphysis osteomyelitis in the prostate cancer survivor is characterized by high signal on T2-weighted images and low signal on T1-weighted images of the involved pubic rami, with the majority of patients demonstrating regional myositis. Imaging data combined with clinical assessment should prompt diagnosis and management of pubic osteomyelitis. Conventional radiography is generally insensitive to these findings. We consider magnetic resonance imaging to be the definitive diagnostic modality for this clinical entity. PMID- 30460533 TI - Bacterial tannases: classification and biochemical properties. AB - Tannin acyl hydrolases, also known as tannases, are a group of enzymes critical for the transformation of tannins. The study of these enzymes, which initially evolved in different organisms to detoxify and/or use these plant metabolites, has nowadays become relevant in microbial enzymology research due to their relevant role in food tannin transformation. Microorganisms, particularly bacteria, are major sources of tannase. Cloning and heterologous expression of bacterial tannase genes and structural studies have been performed in the last few years. However, a systematic compilation of the information related to all recombinant tannases, their classification, and characteristics is missing. In this review, we explore the diversity of heterologously produced bacterial tannases, describing their substrate specificity and biochemical characterization. Moreover, a new classification based on sequence similarity analysis is proposed. Finally, putative tannases have been identified in silico for each group of tannases taking advantage of the use of the "tannase" distinctive features previously proposed. PMID- 30460534 TI - Activity of gemini quaternary ammonium salts against microorganisms. AB - Quaternary ammonium salts (QAS), as the surface active compounds, are widely used in medicine and industry. Their common application is responsible for the development of microbial resistance to QAS. To overcome, this issue novel surfactants, including gemini-type ones, were developed. These unique compounds are built of two hydrophilic and two hydrophobic parts. The double-head double tail type of structure enhances their physicochemical properties (like surface activity) and biological activity and makes them a potential candidate for new drugs and disinfectants. Antimicrobial activity is mainly attributed to the biocidal action towards bacteria and fungi in their planktonic and biofilm forms, but the mode of action of gemini QAS is not yet fully understood. Moreover, gemini surfactants are of particular interest towards their application as gene carriers. Cationic charge of gemini QAS and their ability to form liposomes facilitate DNA compaction and transfection of the target cells. Multifunctional nature of gemini QAS is the reason of the long-standing research on mainly their structure-activity relationship. PMID- 30460535 TI - The role of mitochondria in angiogenesis. AB - Angiogenesis extends pre-existing blood vessels to improve oxygen and nutrient delivery to inflamed or otherwise hypoxic tissues. Mitochondria are integral in this process, controlling cellular metabolism to regulate the proliferation, migration, and survival of endothelial cells which comprise the inner lining of blood vessels. Mitochondrial Complex III senses hypoxic conditions and generates mitochondrial reactive oxygen species which stabilize hypoxia-inducible factor (HIF-1alpha) protein. HIF-1alpha induces the transcription of the vegfa gene, allowing the translation of vascular endothelial growth factor protein, which interacts with mature and precursor endothelial cells, mobilizing them to form new blood vessels. This cascade can be inhibited at specific points by means of gene knockdown, enzyme treatment, and introduction of naturally occurring small molecules, providing insight into the relationship between mitochondria and angiogenesis. This review focuses on current knowledge of the overall role of mitochondria in controlling angiogenesis and outlines known inhibitors that have been used to elucidate this pathway which may be useful in future research to control angiogenesis in vivo. PMID- 30460536 TI - Hypertension and longevity: role of genetic polymorphisms in renin-angiotensin aldosterone system and endothelial nitric oxide synthase. AB - Hypertension (HT), a common age-related disorder, is an important risk factor for cardiovascular disease. This study aims to identify the prevalence of HT in Portuguese centenarians and evaluate whether gene polymorphisms encoding key molecules in blood pressure (BP) regulation are associated with longevity. There were recruited 253 centenarians (100.26 +/- 1.98 years) and 268 control subjects (67.51 +/- 3.25 years). Hypertension (ESH/ESC2013 and JNC8) and diabetes (WHO) were evaluate. Genetic polymorphisms of renin-angiotensin-aldosterone system (RAAS) and NOS3 were determined. The prevalence of HT among centenarians was 64.4% and the majority (58.9%) were controlled, differing from control group both on frequency (P < 0.001) and on their control (P < 0.001). We found that HT is a risk factor for not achieving longevity (OR 2.531, 95% CI 1.688-3.793, P < 0.001), the same for diabetes (OR 5.669 95% CI 2.966-10.835, P < 0.001), and male gender (OR 2.196, 95% CI 1.493-3.29, P < 0.001). Hypertension, adjusted for gender and diabetes, was independent risk factor anti-longevity (OR 2.007, 95% CI 1320-3.052, P = 0.001). The ACE_D and NOS3_G alleles were more frequent in centenarians compared to controls (P < 0.001, both cases). ACE_II and NOS3_TT genotypes, adjusted for BP, gender and diabetes, increased risk in 3.748 (95% CI 1.887-7.444) and 2.533 (95% CI 1.483-4.327), respectively, in relation to ACE_DD (P < 0.001) and NOS3_GG (P = 0.001), against longevity. Our findings suggest that the prevalence of hypertension was lower in Portuguese centenarians than in the elderly, reinforcing the importance of better cardiovascular risk profiles to achieve longevity even in the presence of genetic condition. PMID- 30460537 TI - Baroreflex Control of Heart Rate in Mice Overexpressing Human SOD1: Functional Changes in Central and Vagal Efferent Components. AB - Excessive reactive oxygen species (ROS) (such as the superoxide radical) are commonly associated with cardiac autonomic dysfunctions. Though superoxide dismutase 1 (SOD1) overexpression may protect against ROS damage to the autonomic nervous system, superoxide radical reduction may change normal physiological functions. Previously, we demonstrated that human SOD1 (hSOD1) overexpression does not change baroreflex bradycardia and tachycardia but rather increases aortic depressor nerve activity in response to arterial pressure changes in C57B6SJL-Tg (SOD1)2 Gur/J mice. Since the baroreflex arc includes afferent, central, and efferent components, the objective of this study was to determine whether hSOD1 overexpression alters the central and vagal efferent mediation of heart rate (HR) responses. Our data indicate that SOD1 overexpression decreased the HR responses to vagal efferent nerve stimulation but did not change the HR responses to aortic depressor nerve (ADN) stimulation. Along with the previous study, we suggest that SOD1 overexpression preserves normal baroreflex function but may differentially alter the functions of the ADN, vagal efferents, and central components. While SOD1 overexpression likely enhanced ADN function and the central mediation of bradycardia, it decreased vagal efferent control of HR. PMID- 30460539 TI - The avian "hibernation" enigma: thermoregulatory patterns and roost choice of the common poorwill. AB - Compared to mammals, there are relatively few studies examining heterothermy in birds. In 13 bird families known to contain heterothermic species, the common poorwill (Phalaenoptilus nuttallii) is the only species that ostensibly hibernates. We used temperature-sensitive radio-transmitters to collect roost and skin temperature (Tskin) data, and winter roost preferences for free-ranging poorwills in southern Arizona. Further, to determine the effect of passive rewarming on torpor bout duration and active rewarming (i.e., the use of metabolic heat to increase Tskin), we experimentally shaded seven birds during winter to prevent them from passively rewarming via solar radiation. Poorwills selected winter roosts that were open to the south or southwest, facilitating passive solar warming in the late afternoon. Shaded birds actively rewarmed following at least 3 days of continuous torpor. Average torpor bout duration by shaded birds was 122 h and ranged from 91 to 164 h. Active rewarming by shaded birds occurred on significantly warmer days than those when poorwills remained torpid. One shaded bird remained inactive for 45 days, during which it spontaneously rewarmed actively on eight occasions. Our findings show that during winter poorwills exhibit physiological patterns and active rewarming similar to hibernating mammals. PMID- 30460538 TI - Apparent kleptoparasitism in fish-parasitic gnathiid isopods. AB - Gnathiid isopods are common external parasites/micropredators that feed on the blood of marine fishes. During the course of processing samples of gnathiid isopods collected from light traps in the central Philippines, we observed a gnathiid attached to and apparently feeding from the abdomen of another gnathiid. Because the abdomens of both gnathiids were enlarged, it was unclear whether one actually fed on the blood meal of the other. Introduction of unfed gnathiids with fed gnathiids revealed that one gnathiid could and did feed on the blood meal of another. This is the first observation of apparent conspecific kleptoparasitism reported for gnathiid isopods. PMID- 30460540 TI - Next-Generation Sequencing Identifies Novel RTK VUSs in Breast Cancer with an Emphasis on ROS1, ERBB4, ALK and NTRK3. PMID- 30460541 TI - Immunomodulatory Effect of Lentinan on Aberrant T Subsets and Cytokines Profile in Non-small Cell Lung Cancer Patients. AB - As a purified active component from traditional Chinese medicine, lentinan administration can be applied as beneficial chemo-immunotherapy for anti-tumor. In this study, the immunomodulatory effects of lentinan on aberrant T subsets and cytokines profile were evaluated for non-small cell lung cancer (NSCLC). Of all NSCLC patients treated with NP chemotherapeutic protocol (combination of vinorelbin and cisplatin), 73 cases were recruited in this retrospective cohort trial study, of which 38 cases received additional lentinan. The changes of aberrant T subsets and cytokines profile were compared between two groups (chemotherapy in combination with lentinan vs. conserved single chemotherapy) by flow cytometry and molecular biology. Higher subset ratio of CD3+CD8+ cytotoxic T cells was confirmed in the peripheral blood of NSCLC patients. Chemo immunotherapy of lentinan resulted in a significant increase of CD3 + CD56+ NKT cells (15.7 +/- 3.1%), compared with 8.6 +/- 1.4% of NKT cells in single chemotherapy group, and up-regulated CD3+CD8+ and CD3+CD4+ subsets as well, but caused the decrease of CD4+CD25+ Tregs induction, accompanied by significant alleviation of IL-10 and TGF-beta1, and elevation of IFN-gamma, TNF-alpha, and IL 12 (P < 0.05). It could be confirmed that lentinan could not only enhance the cellular immunity and promote the beneficial of anti-tumor by associated immunotherapy, but also had the ability to inhibit the expansion of immune suppressive Tregs in the NSCLC patients, in whom there was a raised Tregs induction compared to health control. Lentinan-based chemo-immunotherapy is a promising strategy for anti-tumor via enhancing the proliferation of cytotoxic T cells, followed by the elevation of inflammatory chemokines/cytokines. Meanwhile, the percentage of CD4+ CD25+ Tregs is down-regulated, leading to a shift in the inflammatory status from Th2 to Th1 in NSCLC patients treated with lentinan. PMID- 30460543 TI - Neocerebellar Crus I Abnormalities Associated with a Speech and Language Disorder Due to a Mutation in FOXP2. AB - Bilateral volume reduction in the caudate nucleus has been established as a prominent brain abnormality associated with a FOXP2 mutation in affected members of the 'KE family', who present with developmental orofacial and verbal dyspraxia in conjunction with pervasive language deficits. Despite the gene's early and prominent expression in the cerebellum and the evidence for reciprocal cerebellum basal ganglia connectivity, very little is known about cerebellar abnormalities in affected KE members. Using cerebellum-specific voxel-based morphometry (VBM) and volumetry, we provide converging evidence from subsets of affected KE members scanned at three time points for grey matter (GM) volume reduction bilaterally in neocerebellar lobule VIIa Crus I compared with unaffected members and unrelated controls. We also show that right Crus I volume correlates with left and total caudate nucleus volumes in affected KE members, and that right and total Crus I volumes predict the performance of affected members in non-word repetition and non-verbal orofacial praxis. Crus I also shows bilateral hypo-activation in functional MRI in the affected KE members relative to controls during non-word repetition. The association of Crus I with key aspects of the behavioural phenotype of this FOXP2 point mutation is consistent with recent evidence of cerebellar involvement in complex motor sequencing. For the first time, specific cerebello-basal ganglia loops are implicated in the execution of complex oromotor sequences needed for human speech. PMID- 30460544 TI - Delivery of a Genetically Marked Serratia AS1 to Medically Important Arthropods for Use in RNAi and Paratransgenic Control Strategies. AB - Understanding how arthropod vectors acquire their bacteria is essential for implementation of paratransgenic and RNAi strategies using genetically modified bacteria to control vector-borne diseases. In this study, a genetically marked Serratia AS1 strain expressing the mCherry fluorescent protein (mCherry-Serratia) was used to test various acquisition routes in six arthropod vectors including Anopheles stephensi, Culex pipiens, Cx. quinquefaciatus, Cx. theileri, Phlebotomus papatasi, and Hyalomma dromedarii. Depending on the species, the bacteria were delivered to (i) mosquito larval breeding water, (ii) host skin, (iii) sugar bait, and (iv) males (paratransgenic). The arthropods were screened for the bacteria in their guts or other tissues. All the hematophagous arthropods were able to take the bacteria from the skin of their hosts while taking blood meal. The mosquitoes were able to take up the bacteria from the water at larval stages and to transfer them transstadially to adults and finally to transfer them to the water they laid eggs in. The mosquitoes were also able to acquire the bacteria from male sperm. The level of bacterial acquisition was influenced by blood feeding time and strategies (pool or vessel feeding), dipping in water and resting time of newly emerged adult mosquitoes, and the disseminated tissue/organ. Transstadial, vertical, and venereal bacterial acquisition would increase the sustainability of the modified bacteria in vector populations and decrease the need for supplementary release experiments whereas release of paratransgenic males that do not bite has fewer ethical issues. Furthermore, this study is required to determine if the modified bacteria can be introduced to arthropods in the same routes in nature. PMID- 30460546 TI - Long-Term Safety, Tolerability, and Efficacy of Cannabidiol in Children with Refractory Epilepsy: Results from an Expanded Access Program in the US. AB - BACKGROUND: Purified cannabidiol is a new antiepileptic drug that has recently been approved for use in patients with Lennox-Gastaut and Dravet syndromes, but most published studies have not extended beyond 12-16 weeks. OBJECTIVE: The objective of this study was to evaluate the long-term safety, tolerability, and efficacy of cannabidiol in children with epilepsy. METHODS: Patients aged 1-17 years with refractory epilepsy were enrolled in an open-label prospective study through individual patient and expanded access programs between April 2013 and December 2014. Seizure types were video-electroencephalogram confirmed prior to enrollment. After a 28-day evaluation period, during which baseline seizure frequency was assessed, cannabidiol was given as add-on therapy at 5 mg/kg/day and titrated weekly by 5-mg/kg increments to a dose of 25 mg/kg/day. Blood tests were performed at baseline, after 1, 2, and 3 months, and every 3 months thereafter. Trough concentrations of concomitant antiepileptic drugs were measured at baseline, after 1, 2, and 3 months of therapy, and as clinically indicated afterwards. Concomitant antiepileptic drugs, ketogenic diet ratio, and vagal nerve stimulator settings remained unchanged during the baseline period and the first 3 months of treatment, unless there was a significant increase in plasma concentrations. Seizure frequency was reported daily in seizure diaries by parents or caregivers. Clinical assessments occurred after 15 days of treatment, at 1 month, at 3 months, and every 3 months thereafter. Diaries of seizure frequency and adverse events were reviewed at each visit. The primary efficacy outcome was a reduction in seizure frequency and responders were defined as those patients achieving a > 50% reduction in motor seizures. RESULTS: Twenty-six children were enrolled. Most had genetic epilepsies with daily or weekly seizures and multiple seizure types. All were refractory to prior antiepileptic drugs (range 4-11, mean 7), and were taking two antiepileptic drugs on average. Duration of therapy ranged from 4 to 53 months (mean 21 months). Adverse events were reported in 21 patients (80.8%), including reduced appetite in ten (38.4%), diarrhea in nine (34.6%), and weight loss in eight (30.7%). Four (15.4%) had changes in antiepileptic drug concentrations and three had elevated aspartate aminotransferase and alanine aminotransferase levels when cannabidiol was administered together with valproate. Serious adverse events, reported in six patients (23.1%), included status epilepticus in three, catatonia in two, and hypoalbuminemia in one. Fifteen patients (57.7%) discontinued cannabidiol for lack of efficacy, one because of status epilepticus, and one for severe weight loss. The retention rate declined rapidly in the first 6 months and more gradually thereafter. At 24 months, the number of patients continuing cannabidiol as adjunctive therapy was nine of the original 26 (34.6%). Of these patients, seven (26.9%) had a sustained > 50% reduction in motor seizures, including three (11.5%) who remain seizure free. CONCLUSION: Over a 4-year period, cannabidiol was effective in 26.9% of children with otherwise refractory epilepsy. It was well tolerated in about 20% of patients, but 80.8% had adverse events, including 23.1% with serious adverse events. Decreased appetite and diarrhea were frequent along with weight loss that became evident only later in the treatment. PMID- 30460542 TI - SACS variants are a relevant cause of autosomal recessive hereditary motor and sensory neuropathy. AB - Mutations in the SACS gene have been initially reported in a rare autosomal recessive cerebellar ataxia syndrome featuring prominent cerebellar atrophy, spasticity and peripheral neuropathy as well as retinal abnormalities in some cases (autosomal recessive spastic ataxia of Charlevoix-Saguenay, ARSACS). In the past few years, the phenotypic spectrum has broadened, mainly owing to the availability and application of high-throughput genetic testing methods. We identified nine patients (three sib pairs, three singleton cases) with isolated, non-syndromic hereditary motor and sensory neuropathy (HMSN) who carried pathogenic SACS mutations, either in the homozygous or compound heterozygous state. None of the patients displayed spasticity or pyramidal signs. Ataxia, which was noted in only three patients, was consistent with a sensory ataxia. Nerve conduction and nerve biopsy studies showed mixed demyelinating and axonal neuropathy. Brain MRI scans were either normal or revealed isolated upper vermis atrophy of the cerebellum. Our findings confirm the broad clinical spectrum associated with SACS mutations, including pure polyneuropathy without characteristic clinical and brain imaging manifestations of ARSACS. PMID- 30460547 TI - Bictegravir/Emtricitabine/Tenofovir Alafenamide: A Review in HIV-1 Infection. AB - Bictegravir is a new integrase strand transfer inhibitor (INSTI) with a high genetic barrier to the development of HIV-1 resistance. The drug is co-formulated with the nucleos(t)ide reverse transcriptase inhibitors emtricitabine and tenofovir alafenamide (AF) in a single-tablet regimen (STR) for the once-daily treatment of HIV-1 infection in adults (bictegravir/emtricitabine/tenofovir AF; Biktarvy(r)). In phase 3 trials, bictegravir/emtricitabine/tenofovir AF was noninferior to dolutegravir-based therapy (dolutegravir/abacavir/lamivudine or dolutegravir plus emtricitabine/tenofovir AF) in establishing virological suppression in treatment-naive adults through 96 weeks' treatment and, similarly, was noninferior to ongoing dolutegravir/abacavir/lamivudine or boosted elvitegravir- or protease inhibitor (PI)-based therapy in preventing virological rebound over 48 weeks in treatment-experienced patients. No resistance emerged to any of the antiretrovirals in the STR. Bictegravir/emtricitabine/tenofovir AF is generally well tolerated, requires no prior HLA-B*5701 testing (making it more suitable for 'rapid start' treatment), fulfils the antiretroviral regimen requirement for patients with hepatitis B virus (HBV) co-infection (i.e. contains tenofovir AF and emtricitabine, both of which are active against HBV) and can be used in renally impaired patients with creatinine clearance (CRCL) >= 30 mL/min. Thus, although cost-effectiveness analyses would be beneficial, current data indicate that bictegravir/emtricitabine/tenofovir AF is a convenient initial and subsequent treatment option for adults with HIV-1 infection, including those co infected with HBV, and provides the first non-pharmacologically boosted, INSTI based, triple-combination STR suitable for patients with CRCL 30-50 mL/min. PMID- 30460548 TI - Correction to: The Continuing Evolution of Molecular Functional Imaging in Clinical Oncology: The Road to Precision Medicine and Radiogenomics (Part II). AB - An Online First version of this article was made available online at http://link.springer.com/journal/40291/onlineFirst/page/1 on 01 Nov 2018. An error was subsequently identified in the article, and the following correction should be noted. PMID- 30460549 TI - Correction to: Genome-Wide Array Analysis Reveals Novel Genomic Regions and Candidate Gene for Intellectual Disability. AB - An Online First version of this article was made available online. PMID- 30460550 TI - A genetic linkage map for the salmon louse (Lepeophtheirus salmonis): evidence for high male:female and inter-familial recombination rate differences. AB - A salmon louse (Lepeophtheirus salmonis salmonis) genetic linkage map was constructed to serve as a genomic resource for future investigations into the biology of this important marine parasitic copepod species, and to provide insights into the inheritance patterns of genetic markers in this species. SNP genotyping of 8 families confirmed the presence of 15 linkage groups based upon the assignment of 93,773 markers. Progeny sample size weight adjusted map sizes in males (with the exception of SL12 and SL15) ranged in size from 96.50 cM (SL11) to 134.61 cM (SL06), and total combined map steps or bins ranged from 143 (SL09) to 203 (SL13). The SL12 male map was the smallest linkage group with a weight-averaged size of 3.05 cM with 6 recombination bins. Male:female specific recombination rate differences are 10.49:1 and represent one of the largest reported sex-specific differences for any animal species. Recombination ratio differences (M:F) ranged from 1.0 (SL12) to 29:1 (SL15). The number of markers exhibiting normal Mendelian segregation within the sex linkage group SL15 was extremely low (N = 80) in comparison to other linkage groups genotyped [range: 1459 (SL12)-10206 markers (SL05)]. Re-evaluation of Mendelian inheritance patterns of markers unassigned to any mapping parent according to hemizygous segregation patterns (models presented) identified matches for many of these markers to hemizygous patterns. The greatest proportion of these markers assigned to SL15 (N increased to 574). Inclusion of the hemizygous markers revised SL15 sex-specific recombination rate differences to 28:1. Recombination hot- and coldspots were identified across all linkage groups with all linkage groups possessing multiple peaks. Nine of 13 linkage groups evaluated possessed adjacent domains with hot-coldspot transitional zones. The most common pattern was for one end of the linkage to show elevated recombination in addition to internal regions. For SL01 and SL06, however, a terminal region with high recombination was not evident while a central domain possessing extremely high-recombination levels was present. High levels of recombination were weakly coupled to higher levels of SNP variation within domains, but this association was very strong for the central domains of SL01 and SL06. From the pooled paternal half-sib lots (several virgin females placed with 1 male), only 1 or two surviving family lots were obtained. Surviving families possessed parents where both the male and female possessed either inherently low or high recombination rates. This study provides insight into the organization of the sea louse genome, and describes large differences in recombination rate that exist among individuals of the same sex, and between the sexes. These differences in recombination rate may be coupled to the capabilities of this species to adapt to environmental and pharmaceutical treatments, given that family survivorship appears to be enhanced when parents have similar recombination levels. PMID- 30460551 TI - A population-based atlas of the human pyramidal tract in 410 healthy participants. AB - With the advances in diffusion MRI and tractography, numerous atlases of the human pyramidal tract (PyT) have been proposed, but the inherent limitation of tractography to resolve crossing bundles within the centrum semiovale has so far prevented the complete description of the most lateral PyT projections. Here, we combined a precise manual positioning of individual subcortical regions of interest along the descending pathway of the PyT with a new bundle-specific tractography algorithm. This later is based on anatomical priors to improve streamlines tracking in crossing areas. We then extracted both left and right PyT in a large cohort of 410 healthy participants and built a population-based atlas of the whole-fanning PyT with a complete description of its most corticolateral projections. Clinical applications are envisaged, the whole-fanning PyT atlas being likely a better marker of corticospinal integrity metrics than those currently used within the frame of prediction of poststroke motor recovery. The present population-based PyT, freely available, provides an interesting tool for clinical applications to locate specific PyT damage and its impact to the short- and long-term motor recovery after stroke. PMID- 30460552 TI - Regulatory roles of perineuronal nets and semaphorin 3A in the postnatal maturation of the central vestibular circuitry for graviceptive reflex. AB - Perineuronal nets (PN) restrict neuronal plasticity in the adult brain. We hypothesize that activity-dependent consolidation of PN is required for functional maturation of behavioral circuits. Using the postnatal maturation of brainstem vestibular nucleus (VN) circuits as a model system, we report a neonatal period in which consolidation of central vestibular circuitry for graviception is accompanied by activity-dependent consolidation of chondroitin sulfate (CS)-rich PN around GABAergic neurons in the VN. Postnatal onset of negative geotaxis was used as an indicator for functional maturation of vestibular circuits. Rats display negative geotaxis from postnatal day (P) 9, coinciding with the condensation of CS-rich PN around GABAergic interneurons in the VN. Delaying PN formation, by removal of primordial CS moieties on VN with chondroitinase ABC (ChABC) treatment at P6, postponed emergence of negative geotaxis to P13. Similar postponement was observed following inhibition of GABAergic transmission with bicuculline, in line with the reported role of PN in increasing excitability of parvalbumin neurons. We further reasoned that PN-CS restricts bioavailability of plasticity-inducing factors such as semaphorin 3A (Sema3A) to bring about circuit maturation. Treatment of VN explants with ChABC to liberate PN-bound Sema3A resulted in dendritic growth and arborization, implicating structural plasticity that delays synapse formation. Evidence is thus provided for the role of PN-CS-Sema3A in regulating structural and circuit plasticity at VN interneurons with impacts on the development of graviceptive postural control. PMID- 30460553 TI - Knockdown of calcium-binding calb2a and calb2b genes indicates the key regulator of the early development of the zebrafish, Danio rerio. AB - The present study initiates our investigation regarding the role of calb2a and calb2b genes that are expressed in the central nervous system, including the multiple tissues during early embryonic development of zebrafish. In this study, we have adopted individual and combined morpholino-mediated inactivation approach to investigate the functions of calb2a and calb2b in early development of the zebrafish. We have found that calb2a and calb2b morpholino alone failed to generate an obvious phenotype; however, morphological inspection in early developmental stages of calb2a and calb2b combined knockdown morphants show abnormal neural plate folding in midbrain-hindbrain region. In addition to this, combinatorial loss of these mRNA leads to severe hydrocephalus, axial curvature defect, and yolk sac edema in later developmental stages. Also, the combined knockdown of calb2a and calb2b are found to be associated with an impaired touchdown and swimming performance in the zebrafish. Co-injection of the calb2a and calb2b morpholino oligonucleotide cocktail with human CALB2 mRNA leads to the rescue of the strong phenotype. This study provided the first comprehensive analyses of the zebrafish Calb2a and Calb2b proteins; we have found that Calb2a and Calb2b are highly conserved across vertebrate species and originated from the same ancestral gene long back in the evolution. Homology modeling and docking with the similar structure and Ca2+ binding sites for both proteins provide the evidence that both the proteins may have similar function and one can compensate for the loss of other. Collectively, these findings confirm the unique and essential functions of calb2a and calb2b genes in the early development of the zebrafish. PMID- 30460554 TI - Somatotopy of corticospinal tract fibres of the intercostal muscles: report of a case and review of literature. AB - This study aimed at describing the first case of subcortical stimulation of the corticospinal tract leading to selective contraction of the intercostal muscles during surgery for removal of a tumour centred in the right central lobule/supplementary motor area. A 53-year-old male presented with partial motor seizures. Imaging demonstrated a low-grade glioma affecting the posterior aspect of the superior and middle frontal gyri and invading the precentral gyrus. Preoperative motor Transcranial Magnetic Stimulation and advanced diffusion tractography were performed to establish the relationship of the tumour with the motor cortex and corticospinal tract. Intraoperative motor mapping and monitoring were performed with monopolar stimulation ("train of 5" technique). At the posterior margin of resection, subcortical stimulation demonstrated a selective response from intercostal muscles, medial to responses from the lower limb and lateral to responses from the upper limb. PubMed literature search was performed to identify any case reporting similar findings. There were no cases previously reported in the literature. The location of the subcortical response for intercostal muscles confirms the somatotopy of the corticospinal tract. Intercostal muscles are controlled by selective fibres within the corticospinal tract. Damage to these fibres can lead to paralysis of voluntary respiratory muscles. Further studies are needed to define the cortico-subcortical network controlling voluntary respiratory muscles. PMID- 30460555 TI - An Introduction to Barley: The Crop and the Model. AB - Barley has a number of unique features among our crop plants. It was one of the earliest plants to be domesticated and continues to play an important role in modern agriculture today. It is a versatile crop, used both for human nutrition and for animal feed, and plays an important role as an experimental model plant allowing advances in plant genetics, plant physiology, plant pathology, plant biochemistry, and more recently in plant biotechnology. In this introductory chapter, the key features of barley as both crop and model plant are considered. PMID- 30460556 TI - Mutation Breeding in Barley: Historical Overview. AB - The discovery of radioactivity at the end of the nineteenth century played a key role in a series of historical landmarks that would lead to contemporary mutation breeding in agricultural crops. The aim of the earliest experiments was to test the effects of radiation on living organisms beginning with fruit flies. Exposure of plants to X-rays provided the first incontrovertible proof that phenotypic changes could be induced. Chemicals were a second type of mutagen tested from the 1940s and both forms are used today. This chapter is an overview of some of the historical developments that led to the use of mutagenesis in plants, with a focus on barley, a model species for mutation genetics and breeding as well as a major cereal crop. Perhaps the most well-known examples of mutant barley cultivars are Diamant, Golden Promise, and their hybrids. PMID- 30460557 TI - A Practical Guide to Barley Crossing. AB - Barley is naturally an inbreeding hermaphrodite plant so that each generation resembles its parental generation. New variation can be introduced by crossing parents that complement each other for desirable or target characteristics but requires human intervention to ensure that all the resulting seeds are hybrids of the two parents. That means that plants selected to be female parents have to be emasculated and are then fertilized with pollen from plants selected to be male parents. Here we describe how to emasculate and pollinate barley plants with a method that can be used either in the glasshouse or in the field. PMID- 30460559 TI - Isolated Microspore Culture in Barley. AB - Isolated microspore culture (IMC) is the most efficient way to produce large numbers of doubled-haploid (DH) barley plants in a short time. Yet, while IMC is more cost-efficient and less labor-intensive than anther culture, it is technically more complex and requires more experienced personnel if it is to yield its full potential. In part, this is because of multiple and important interactions that exist between factors at its many different phases, including genotype effects as well. When every phase is fine-tuned, the protocol that is presented below yields a useful number of DHs with almost all genotypes and can allow the production of up to 300 DH plants from a single F1 plant in just a few months. PMID- 30460558 TI - Barley Anther Culture. AB - The production of doubled haploid (DH) barley plants through anther culture is a very useful yet simple in vitro technique. DH plants derive from divisions of haploid microspores that have undergone a developmental switch under the appropriate conditions. The successive divisions lead to the formation of an embryo or callus rather than the formation of mature pollen grains. Plants that regenerate from these embryos are often either haploid, in which case their chromosome set can be doubled by treatment with colchicine, or spontaneous double haploids. The efficiency of DH plant production is highly variable depending on the genotype of the source material. Despite this limitation, DH plants have been widely used in breeding and research programs. Compared to conventional approaches, breeding strategies that makes use of DH plants achieve a homozygous state, allowing transgene or mutation stabilization in the genome, within a considerably shorter time, thus accelerating workflow or reducing work volume. PMID- 30460560 TI - TILLING in Barley. AB - TILLING (Targeting Induced Local Lesions IN Genomes), a popular reverse genetics approach in barley research, combines plant mutagenesis with efficient mutation detection for studying biological function of a specific gene. The high mutation frequency within a TILLING population principally enables the identification of induced variations in (almost) all genes of a given species (more precisely a given genotype of a species) of interest, which can be tested for their functional impact on morphological and/or physiological characteristics of the plant. Several TILLING populations induced by chemical mutagenesis were established for barley (Talame et al., Plant Biotechnol J 6:477-485, 2008; Gottwald et al., BMC Res Notes 2:258, 2009; Caldwell et al. Plant J 40:143-150, 2004) and showed the possibility for adapting protocols to develop further populations. This chapter describes a chemical mutagenesis protocol for barley seeds and two independent procedures for efficient single nucleotide polymorphism (SNP) detection in a large number of mutagenized plants either by slab-gel- or capillary gel-based electrophoreses on the LI-COR 4300 DNA Analyzer and the AdvanCE FS96 instruments, respectively. PMID- 30460561 TI - Virus-Induced Gene Silencing (VIGS) for Functional Characterization of Disease Resistance Genes in Barley Seedlings. AB - With the recent advances in sequencing technologies, many studies are generating lists of candidate genes associated with specific traits. The major bottleneck in functional genomics is the validation of gene function. This is achieved by analyzing the effect of either gene silencing or overexpression on a specific phenotypic or biochemical trait. This usually requires the generation of stable transgenic plants and this can take considerable time. Therefore any technique that expedites the validation of gene function is of particular benefit in cereals, including barley. One such technique is Virus-Induced Gene Silencing (VIGS), which evokes a natural antiviral defense mechanism in plants. VIGS can be used to downregulate gene expression in a transient manner, but long enough to determine its effects on a specific phenotype. It is particularly useful for screening candidate genes and selecting those with potential for disease control. VIGS based on Barley Stripe Mosaic Virus (BSMV) is a powerful and efficient tool for the analysis of gene function in cereals. Here we present a BSMV VIGS protocol for simple and robust gene silencing in barley and describe it to evaluate the role of the hormone receptor BRI1 (Brassinosteroid Insensitive 1) in barley leaf resistance to Fusarium infection. PMID- 30460562 TI - Agrobacterium-Mediated Transformation of Barley Immature Embryos. AB - Barley transformation is an essential tool for a range of functional genomics studies as well as for future crop improvement. The demand for efficient crop transformation systems continues to grow, with new genome editing technologies adding to that demand. Here we describe an efficient and routine transformation protocol for the spring barley Golden Promise, based on Agrobacterium-mediated inoculation of immature embryos. This protocol has been widely used for overexpression and RNAi applications and more recently for CRISPR/Cas9 mediated genome editing. Average transformation efficiencies of 25% can be easily achieved. PMID- 30460563 TI - Methods for the Simple and Reliable Assessment of Barley Sensitivity to Abiotic Stresses During Early Development. AB - Physiological assays that facilitate screening for various types of responses to abiotic stresses are well established for model plants such as Arabidopsis; however, there is a need to optimize similar tests for cereal crops, including barley. We have developed a set of stress assays to characterize the response of different barley lines during two stages of development-seed germination and seedling growth. The assays presented, including the response to osmotic, salt, oxidative stresses, and exogenously applied abscisic acid, can be used for forward screening of populations after mutagenesis as well as for phenotyping of already isolated mutants, cultivars, or breeding lines. As well as protocols for stress treatments, we also provide methods for plant stress response evaluation, such as chlorophyll a fluorescence (ChlF) and image analysis. PMID- 30460564 TI - Preparation of Barley Roots for Histological, Structural, and Immunolocalization Studies Using Light and Electron Microscopy. AB - Microscopic investigations of biological objects are an integral part in plant research and most fields of life sciences. They allow the description of morphological, histological, and structural aspects of individual cells or tissues. Based on various cell biological tools and methods it is possible to characterize different plant genotypes or study their adaptation to changing environmental conditions. In combination with antibodies raised against specific antigens and epitopes light and electron microscopy enable investigation of the function of single genes/proteins in plant growth and development or their role related to abiotic or biotic stresses.Here, we describe sample preparation of barley roots for cell biological investigations using light and electron microscopy, to characterize morphological, structural, and functional aspects on root sections and the root surface. PMID- 30460565 TI - Preparation of Barley Pollen Mother Cells for Confocal and Super Resolution Microscopy. AB - Recombination (crossover) drives the release of genetic diversity in plant breeding programs. However, in barley, recombination is skewed toward the telomeric ends of its seven chromosomes, restricting the re-assortment of about 30% of the genes located in the centromeric regions of its large 5.1 Gb genome. A better understanding of meiosis and recombination could provide ways of modulating crossover distribution and frequency in barley as well as in other grasses, including wheat. While most research on recombination has been carried out in the model plant Arabidopsis thaliana, recent studies in barley (Hordeum Vulgare) have provided new insights into the control of crossing over in large genome species. A major achievement in these studies has been the use of cytological procedures to follow meiotic events. This protocol provides detailed practical steps required to perform immunostaining of barley meiocytes (pollen mother cells) for confocal or structured illumination microscopy. PMID- 30460566 TI - Microarrays for High-Throughput Gene Expression Analysis of Barley. AB - Microarrays remain an extremely robust and cost-efficient technology for transcriptome analysis. A custom Agilent microarray has been designed from the predicted gene transcripts of the barley genome reference. Here, we describe total RNA extraction, fluorescent labeling, hybridization, and image analysis of barley arrays. Quality control measures are detailed, along with recommendations for downstream data analysis. PMID- 30460567 TI - Genome Engineering Using TALENs. AB - Genome engineering involves methods of genetic modification of cells at predefined genomic sites. Here, we used transcription activator-like effector nucleases (TALENs) for the site-directed mutagenesis in barley. Target gene specific TALEN-encoding expression units were designed and delivered to totipotent cells of either cultivated embryogenic pollen or immature embryos. The analysis of resulting transgenic plants revealed that the described approach allows for the generation of site-specific, heritable mutations at reasonable efficiency. PMID- 30460568 TI - Creating Targeted Gene Knockouts in Barley Using CRISPR/Cas9. AB - Knockout mutants are an invaluable reverse genetics tool which have not been well developed in crop species compared to models like Arabidopsis. However, the emergence of CRISPR/Cas9 has changed this situation making the generation of such mutants accessible to many crops including barley. A single T-DNA construct can be transformed into barley immature embryos and stable transgenic lines regenerated through tissue culture which contain targeted mutations. Mutations are detected in T0 plants and go on in subsequent T1 and T2 generations to segregate from T-DNA, leaving lines which are non-transgenic and carrying a variety of mutations at the target locus. These mutations can be targeted to a particular gene of interest in order to bring about a loss of function creating a knockout mutant. PMID- 30460569 TI - Genotyping-by-Sequencing on the Ion Torrent Platform in Barley. AB - The characterization of genetic polymorphism is a crucial step in both genetic studies and breeding programs. Genotyping-by-sequencing (GBS) constitutes one of the most attractive approaches for this purpose, especially in a genome as large as that of barley. The genome sequencing project undertaken by the International Barley Sequencing Consortium (IBSC) has produced a structured reference genome for the cultivar Morex [1] that can serve as an excellent resource for the analysis of GBS data. The genome assembly for this species [2] is thought to adequately capture the gene-rich portion of the genome (~80% of the entire genome). In this chapter, we describe the entire GBS process, from library preparation to the analysis of read data to produce a high-quality catalog of single nucleotide polymorphism (SNP) markers using the barley reference genome. PMID- 30460570 TI - DNA Methylation Analysis in Barley and Other Species with Large Genomes. AB - Detailed DNA methylation analyses in plant species with large and highly repetitive genomes can be challenging as well as costly. Here, we describe a complete protocol for a high-throughput DNA methylation changes analysis using Methylation-Sensitive Amplification Polymorphism Sequencing (MSAP-Seq; Chwialkowska et al., Front Plant Sci. 8: 2056 (2017)). This method allows detailed information about DNA methylation changes in large and complex genomes to be obtained at a relatively low cost. MSAP-Seq is based on conventional MSAP marker analysis and employs all its basic steps such as restriction cleavage with methylation-sensitive restriction enzyme, ligation of universal adapters, and PCR amplification. However, the traditional gel-based amplicon separation is replaced by direct, global sequencing with next-generation sequencing (NGS) methods. Consequently, MSAP-Seq allows for parallel analysis of hundreds of thousands of different CCGG sites and evaluation of their DNA methylation state. This technique especially targets to genic regions, so it is well suited for large genomes with low gene density, such as barley and other plants with large genomes. PMID- 30460571 TI - High-Resolution RT-PCR Analysis of Alternative Barley Transcripts. AB - Assembly of the barley genome and extensive use of RNA-seq has resulted in an abundance of gene expression data and the recognition of wide-scale production of alternatively spliced transcripts. Here, we describe in detail a high-resolution reverse transcription-PCR based panel (HR RT-PCR) that confirms the accuracy of alternatively spliced transcripts from RNA-seq and allows quantification of changes in the proportion of splice isoforms between different experimental conditions, time points, tissues, genotypes, ecotypes, and treatments. By validating a selection of barley genes, use of the panel gives confidence or otherwise to the genome-wide global changes in alternatively spliced transcripts reported by RNA-seq. This simple assay can readily be applied to perform detailed transcript isoform analysis for any gene in any species. PMID- 30460572 TI - Exome Capture for Variant Discovery and Analysis in Barley. AB - Exome capture is a reduced representation approach that selectively captures sequence from only the gene-bearing regions of a genome. It is based on probes targeted at these regions and, compared with whole genome shotgun sequencing, leads to a significant reduction in cost and data processing effort while still providing insights into the most relevant part of a genome. An exome capture array for barley was released in 2013 and this has opened the door to numerous studies that have put this technology to good use. In this chapter we detail the laboratory protocols required for enrichment and sequencing, and provide detailed step-by-step instructions for the bioinformatics analysis of the resulting data. PMID- 30460573 TI - Residual high intrapulmonary shunt fraction limits exercise capacity in patients treated with balloon pulmonary angioplasty. AB - Balloon pulmonary angioplasty (BPA) has emerged as a new treatment strategy for patients with chronic thromboembolic pulmonary hypertension (CTEPH). Improvements in hemodynamic parameters after BPA have been reported, but some patients continue to suffer from reduced exercise tolerance even after the normalization of hemodynamic parameters following BPA. As the amelioration of hemodynamic parameters is reportedly achieved via BPA, we hypothesized that the limiting factors for exercise tolerance in these patients are related to respiratory function. Therefore, we investigated the associations between respiratory function and exercise tolerance, and the mechanisms underlying respiratory dysfunction in patients after BPA. We analyzed 62 patients with CTEPH who underwent 1-year follow-up after BPA. Predictors for reduced exercise tolerance after BPA determined with six-minute walk test were sought from pulmonary hemodynamic and respiratory parameters using logistic regression analysis. After multivariate adjustments, high mean right atrium pressure (mRAP) and high alveolar-arterial oxygen gradient (A-aDO2) were significant predictors for reduced exercise tolerance. Next, we analyzed factors associated with high A aDO2. Among the pathophysiological causes of high A-aDO2, including ventilation, diffusing capacity, and low ventilation-perfusion ratio, only low ventilation perfusion ratio caused by high intrapulmonary shunt fraction was associated with high A-aDO2. Impaired oxygenation due to residual high intrapulmonary shunt fraction was associated with reduced exercise tolerance in patients with CTEPH, after receiving BPA. PMID- 30460574 TI - Relationship between non-osmotic arginine vasopressin secretion and hemoglobin A1c levels in adult patients with congenital heart disease. AB - Arginine vasopressin (AVP), which induces vasoconstriction and conserves solute free water when released during high plasma osmolality, is secreted through 2 mechanisms: osmoregulation and baroregulation. This study aims to clarify the mechanisms and influencing factors for non-osmotic AVP secretion in adult patients with congenital heart disease (CHD). AVP levels were measured in 74 adults with CHD. Non-osmotic AVP secretion was defined as excessive AVP secretion relative to the AVP level inferred from plasma osmolality. Accordingly, 10 patients (13.5%) demonstrated non-osmotic AVP secretion, with AVP levels higher than those in patients without non-osmotic AVP secretion (6.4 +/- 3.1 vs. 1.6 +/- 0.9 pg/ml; p < 0.0001). Non-osmotic AVP secretion was significantly correlated with diuretic use [odds ratio (OR) 7.227; confidence interval (CI) 1.743-29.962; p = 0.0006], HbA1c level (OR 11.812; CI 1.732-80.548; p = 0.012), and B-type natriuretic peptide (BNP) level (OR 1.007; CI 1.001-1.012; p = 0.022). Multiple logistic regression analysis revealed that there was a significant association between non-osmotic AVP secretion and HbA1c level (OR 9.958; 1.127-87.979; p = 0.0039), and a nearly significant relationship between non-osmotic AVP secretion and BNP (OR 1.006; CI 1.000-1.012; p = 0.056). In conclusion, this study showed that 13.5% of adult patients with CHD demonstrated non-osmotic AVP secretion, which could be correlated with heart failure and insulin resistance. The AVP system might be one of the mechanisms linking heart failure and the onset of type 2 diabetes mellitus in adults with CHD. PMID- 30460575 TI - Type 2 inositol 1,4,5-trisphosphate receptor inhibits the progression of pulmonary arterial hypertension via calcium signaling and apoptosis. AB - Pulmonary arterial hypertension (PAH) is a progressive disease associated with vasoconstriction and remodeling. Intracellular Ca2+ signaling regulates the contraction of pulmonary arteries and the proliferation of pulmonary arterial smooth muscle cells (PASMCs); however, it is not clear which molecules related to Ca2+ signaling contribute to the progression of PAH. In this study, we found the specific expression of type 2 inositol 1,4,5-trisphosphate receptor (IP3R2), which is an intracellular Ca2+ release channel, on the sarco/endoplasmic reticulum in mouse PASMCs, and demonstrated its inhibitory role in the progression of PAH using a chronic hypoxia-induced PAH mouse model. After chronic hypoxia exposure, IP3R2-/- mice exhibited the significant aggravation of PAH, as determined by echocardiography and right ventricular hypertrophy, with significantly greater medial wall thickness by immunohistochemistry than that of wild-type mice. In IP3R2-/- murine PASMCs with chronic hypoxia, a TUNEL assay revealed the significant suppression of apoptosis, whereas there was no significant change in proliferation. Thapsigargin-induced store-operated Ca2+ entry (SOCE) was significantly enhanced in IP3R2-/- PASMCs in both normoxia and hypoxia based on in vitro fluorescent Ca2+ imaging. Furthermore, the enhancement of SOCE in IP3R2-/- PASMCs was remarkably suppressed by the addition of DPB162 AE, an inhibitor of the stromal-interacting molecule (STIM)-Orai complex which is about 100 times more potent than 2-APB. Our results indicate that IP3R2 may inhibit the progression of PAH by promoting apoptosis and inhibiting SOCE via the STIM-Orai pathway in PASMCs. These findings suggest a previously undetermined role of IP3R in the development of PAH and may contribute to the development of targeted therapies. PMID- 30460576 TI - In the lab and in the wild: How distraction and mind wandering affect attention and memory. AB - The present study examined the impact that the environment has on the ability to remain attentive and retain information. Participants listened to an audiobook in either a controlled lab setting or in an uncontrolled natural setting. While listening to the audiobook, participants were randomly prompted to report their current attentional status (focused, mind wandering, or distracted). Participants performed a memory test on audiobook content at the end. Inattention (mind wandering and distraction) did not differ between the two settings. However, there was a setting by attentional state interaction: distraction rates were higher than mind wandering rates outside the lab, while inattention rates did not differ inside the lab. Memory test performance was poorer outside the lab, suggesting that increased distraction may compromise memory more than mind wandering. Collectively, the data suggest that mind wandering and distraction are distinct types of attentional failures and that past controlled lab investigations may have overestimated the role of mind wandering and underestimated the role of distraction in everyday cognition. PMID- 30460577 TI - Feasibility of PET/CT system performance harmonisation for quantitative multicentre 89Zr studies. AB - PURPOSE: The aim of this study was to investigate the variability in quantitative performance and feasibility of quantitative harmonisation in 89Zr PET/CT imaging. METHODS: Eight EANM EARL-accredited (Kaalep A et al., Eur J Nucl Med Mol Imaging 45:412-22, 2018) PET/CT systems were investigated using phantom acquisitions of uniform and NEMA NU2-2007 body phantoms. The phantoms were filled according to EANM EARL guidelines for [18F]FDG, but [18F]FDG solution was replaced by a 89Zr calibration mixture. For each system, standard uptake value (SUV) accuracy and recovery coefficients (RC) using SUVmean, SUVmax and SUVpeak metrics were determined. RESULTS: All eight investigated systems demonstrated similarly shaped RC curves, and five of them exhibited closely aligning recoveries when SUV bias correction was applied. From the evaluated metrics, SUVpeak was found to be least sensitive to noise and reconstruction differences among different systems. CONCLUSIONS: Harmonisation of PET/CT scanners for quantitative 89Zr studies is feasible when proper scanner-dose calibrator cross-calibration and harmonised image reconstruction procedures are followed. An accreditation programme for PET/CT scanners would facilitate multicentre 89Zr quantitative studies. PMID- 30460578 TI - Skin autofluorescence predicts incident type 2 diabetes, cardiovascular disease and mortality in the general population. AB - AIMS/HYPOTHESIS: Earlier studies have shown that skin autofluorescence measured with an AGE reader estimates the accumulation of AGEs in the skin, which increases with ageing and is associated with the metabolic syndrome and type 2 diabetes. In the present study, we examined whether the measurement of skin autofluorescence can predict 4 year risk of incident type 2 diabetes, cardiovascular disease (CVD) and mortality in the general population. METHODS: For this prospective analysis, we included 72,880 participants of the Dutch Lifelines Cohort Study, who underwent baseline investigations between 2007 and 2013, had validated baseline skin autofluorescence values available and were not known to have diabetes or CVD. Individuals were diagnosed with incident type 2 diabetes by self-report or by a fasting blood glucose >=7.0 mmol/l or HbA1c >=48 mmol/mol (>=6.5%) at follow-up. Participants were diagnosed as having incident CVD (myocardial infarction, coronary interventions, cerebrovascular accident, transient ischaemic attack, intermittent claudication or vascular surgery) by self-report. Mortality was ascertained using the Municipal Personal Records Database. RESULTS: After a median follow-up of 4 years (range 0.5-10 years), 1056 participants (1.4%) had developed type 2 diabetes, 1258 individuals (1.7%) were diagnosed with CVD, while 928 (1.3%) had died. Baseline skin autofluorescence was elevated in participants with incident type 2 diabetes and/or CVD and in those who had died (all p < 0.001), compared with individuals who survived and remained free of the two diseases. Skin autofluorescence predicted the development of type 2 diabetes, CVD and mortality, independent of several traditional risk factors, such as the metabolic syndrome, glucose and HbA1c. CONCLUSIONS/INTERPRETATION: The non-invasive skin autofluorescence measurement is of clinical value for screening for future risk of type 2 diabetes, CVD and mortality, independent of glycaemic measures and the metabolic syndrome. PMID- 30460579 TI - Mapping heterogeneity in glucose uptake in metastatic melanoma using quantitative 18F-FDG PET/CT analysis. AB - BACKGROUND: Metastatic melanoma patients can have durable responses to systemic therapy and even long-term survival. However, a large subgroup of patients does not benefit. Tumour metabolic alterations may well be involved in the efficacy of both targeted and immunotherapy. Knowledge on in vivo tumour glucose uptake and its heterogeneity in metastatic melanoma may aid in upfront patient selection for novel (concomitant) metabolically targeted therapies. The aim of this retrospective study was to provide insight into quantitative 18F fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) parameters and corresponding intra- and inter-patient heterogeneity in tumour 18F-FDG uptake among metastatic melanoma patients. Consecutive, newly diagnosed stage IV melanoma patients with a baseline 18F-FDG PET/CT scan performed between May 2014 and December 2015 and scheduled to start first-line systemic treatment were included. Volume of interests (VOIs) of all visible tumour lesions were delineated using a gradient-based contour method, and standardized uptake values (SUVs), metabolically active tumour volume (MATV) and total lesion glycolysis (TLG) were determined on a per-lesion and per-patient basis. Differences in quantitative PET parameters were explored between patient categories stratified by BRAFV600 and RAS mutational status, baseline serum lactate dehydrogenase (LDH) levels and tumour programmed death-ligand 1 (PD-L1) expression. RESULTS: In 64 patients, 1143 lesions >= 1 ml were delineated. Median number of lesions >= 1 ml was 6 (range 0-168), median maximum SUVpeak 9.5 (range 0-58), median total MATV 29 ml (range 0-2212) and median total TLG 209 (range 0 16,740). Per-patient analysis revealed considerable intra- and inter-patient heterogeneity. Maximum SUVs, MATV, number of lesions and TLG per patient did not differ when stratifying between BRAFV600 or RAS mutational status or PD-L1 expression status, but were higher in the patient group with elevated LDH levels (> 250 U/l) compared to the group with normal LDH levels (P < 0.001). A subset of patients with normal LDH levels also showed above median tumour 18F-FDG uptake. CONCLUSIONS: Baseline tumour 18F-FDG uptake in stage IV melanoma is heterogeneous, independent of mutational status and cannot be fully explained by LDH levels. Further investigation of the prognostic and predictive value of quantitative 18F-FDG PET parameters is of interest. PMID- 30460581 TI - Tissue-based markers of right ventricular dysfunction in ischemic mitral regurgitation assessed via stress cardiac magnetic resonance and three dimensional echocardiography. AB - Ischemic mitral regurgitation (iMR) augments risk for right ventricular dysfunction (RVDYS). Right and left ventricular (LV) function are linked via common coronary perfusion, but data is lacking regarding impact of LV ischemia and infarct transmurality-as well as altered preload and afterload-on RV performance. In this prospective multimodality imaging study, stress CMR and 3 dimensional echo (3D-echo) were performed concomitantly in patients with iMR. CMR provided a reference for RVDYS (RVEF < 50%), as well as LV function/remodeling, ischemia and infarction. Echo was used to test multiple RV performance indices, including linear (TAPSE, S'), strain (GLS), and volumetric (3D-echo) approaches. 90 iMR patients were studied; 32% had RVDYS. RVDYS patients had greater iMR, lower LVEF, larger global ischemic burden and inferior infarct size (all p < 0.05). Regarding injury pattern, RVDYS was associated with LV inferior ischemia and infarction (both p < 0.05); 80% of affected patients had substantial viable myocardium (< 50% infarct thickness) in ischemic inferior segments. Regarding RV function, CMR RVEF similarly correlated with 3D-echo and GLS (r = 0.81-0.87): GLS yielded high overall performance for CMR-evidenced RVDYS (AUC: 0.94), nearly equivalent to that of 3D-echo (AUC: 0.95). In multivariable regression, GLS was independently associated with RV volumetric dilation on CMR (OR - 0.90 [CI - 1.19 to - 0.61], p < 0.001) and 3D echo (OR - 0.43 [CI - 0.84 to - 0.02], p = 0.04). Among patients with iMR, RVDYS is associated with potentially reversible processes, including LV inferior ischemic but predominantly viable myocardium and strongly impacted by volumetric loading conditions. PMID- 30460582 TI - Drop-off in positivity rate of stress echocardiography based on regional wall motion abnormalities over the last three decades. AB - Previous studies have suggested a decline in positivity of stress cardiac imaging based on regional wall motion abnormalities (RWMA). To assess the rate of RWMA positivity of stress echocardiography (SE) over 3 decades in the same primary care SE lab. We retrospectively assessed the rate of SE positivity in 7626 SE tests (dipyridamole in 5053, dobutamine in 2496, exercise in 77) in consecutive patients with known or suspected coronary artery disease and /or heart failure who performed SE in a primary care referral center from April 1991 to May 2018. Starting April 2005, SE based on RWMA was complemented by assessment of coronary flow velocity reserve (CFVR) of the left anterior descending coronary artery. Starting October 2016, we added left ventricular contractile reserve (LVCR). Starting October 2016, we also added B-lines by lung ultrasound. There was a progressive decline over time in the rate of SE positivity based on RWMA from 24% (1991-1999) to 10% (2000-2009) down to 4% (2010-2018) (p < 0.0001). Positivity rate was 29% with CFVR, 16% with LVCR, and 12% with B-lines. Over three decades, we observed a dramatic decline in SE positivity rate based on classical RWMA. In the last decade, the positivity rate rose sharply thanks to the stepwise introduction of CFVR, LVCR and B-lines as additional positivity criteria in integrated quadruple SE. PMID- 30460580 TI - Association Between TG-to-HDL-C Ratio and In-Stent Stenosis Under Optical Coherence Tomography Guidance. AB - We determined the relevance between the TG-to-HDL-C ratio and stent restenosis. Ninety-nine patients with in-stent stenosis (ISR) who were admitted to An Zhen Hospital in Beijing between April 2014 and June 2017 were selected. At the same time, 122 patients with coronary stenosis <50% were selected. All patients were tested for TG, HDL-C, and TG/HDL-C ratio. Optical coherence tomography (OCT) can assess microscopic status in all ISR patients. The proportion of male and Diabetic patients were significantly higher for ISR. There were differences in the prevalence of cigarette smokers among the different tissue types, among which the layered tissue type accounted for the highest proportion. In logistic regression analysis the study showed that male, diabetes mellitus, and the TG/HDL C ratio are risk factors for ISR. The ISR ROC was 0.725 based on the TG/HDL-C ratio diagnosis. It is related to the degree of coronary stenosis and effective in diagnosing in-stent stenosis in ISR. PMID- 30460583 TI - The Relationships Between Perceived Discrimination and Utilization of Mental Health Services Among African Americans and Caribbean Blacks. AB - Although all ethnic/racial groups underutilize mental health services, only about one-third of African Americans and Caribbean Blacks in need utilize mental health services. An extensive literature review led us to examine if an association between perceived discrimination and mental health utilization exists. The National Survey of American Life 2001-2003 nationally representative dataset was analyzed. Variables including utilization of mental health services, perceived discrimination, and socio-demographic variables were assessed for their relationships. The study found that each of the following predictors statistically significant: being male, being employed, having household income higher than 100,000, perceiving no discrimination, being African American, or being Caribbean Black are less likely to utilize mental health services than their counterparts. This study contributes to the emerging body of evidence demonstrating that perceived discrimination has a strong connection with the utilization of mental health services. PMID- 30460584 TI - Predicting Posttraumatic Growth in Mothers and Fathers of Critically Ill Children: A Longitudinal Study. AB - Research on parental psychological effects related to a child's critical illness has focused on studying negative outcomes, while the possibility of posttraumatic growth (PTG), defined as the perception of positive changes after a traumatic event, has been overlooked. This study explores the degree of parental PTG after a child's hospitalization in a pediatric intensive care unit (PICU) and the role of resilience, emotions, perceived severity of the child's condition and stress in predicting PTG. In the first 48 h after their child's discharge from a PICU, N = 196 parents were assessed for resilience, emotions, perceived stress, and the degree to which they perceived their child's condition as severe. 6 months later N = 143 parents were assessed PTG. 6 months post discharge, 37.1% of parents reported PTG at least to a medium degree. Path analyses with latent variables showed that the psychological variables assessed at discharge predicted between 20 and 21% of the total variance in PTG. Resilience affected PTG indirectly, through the bias of positive emotions. PTG is a frequent phenomenon. Psychological interventions aimed at encouraging parental PTG after a child's critical admission should focus on boosting resilience and positive emotions. PMID- 30460585 TI - [Self-help support for chronic illness-societal challenges and current approaches]. AB - Community self-help in self-help groups is socially recognized as a form and culture of informal help. Knowledge is gathered and common strategies for coping with everyday life in chronic illness or disability are developed. Self-help clearinghouses at 300 locations in Germany significantly support the foundation and work of self-help groups. The increasing involvement of self-help in healthcare through participation rights and cooperation necessitate an expansion of the range of tasks of self-help clearinghouses. Likewise, societal framework conditions such as demographic development and digitalization make demands on the counseling competence of specialists in self-help support. The support of generational change in self-help groups and the acquisition of young people for a self-help commitment is a task for the future. Depending on the resources available, self-help clearinghouses manage to address development challenges and include them in a process of organizational and quality development. PMID- 30460586 TI - ["Decoratively figured blisters" on the whole integument in initially diagnosed ulcerative colitis]. AB - The rare case of a 61-year-old patient suffering from linear IgA dermatosis is presented. The patient was previously hospitalized with chronic inflammatory bowel disease. The correct diagnosis of the disease was based on clinical and histological findings. Serological methods, such as indirect immunofluorescence, ELISA and immunoblotting are suitable for identification of the autoantibodies. In this case the detection of IgA antibodies along the basal membrane was achieved by direct immunofluorescence. Other bullous dermatoses with similar symptoms, such as an IgG-mediated bullous pemphigoid have to be excluded. The therapy of linear IgA dermatosis is ensured by steroid-containing topical agents, alongside antiseptic measures as well as systemic dapsone p.o. PMID- 30460587 TI - The relationship between obstructive sleep apnea and recurrence of atrial fibrillation after pulmonary vein isolation using a contact force-sensing catheter. AB - PURPOSE: Our aim was to elucidate the relationship between obstructive sleep apnea (OSA) and atrial fibrillation (AF) recurrence after repeated pulmonary vein isolation (PVI). METHODS: We conducted a non-randomized observational study, with the data prospectively collected. One hundred patients (paroxysmal AF, n = 89) underwent PVI using a contact force-sensing catheter. All patients underwent an electrophysiological study and additional ablation for left atrium-pulmonary vein (PV) reconnection and non-PV foci, 6 months after the first treatment session, regardless of AF recurrence. Those with an apnea-hypopnea index >= 15 were diagnosed with OSA. Continuous positive air pressure (CPAP) therapy was initiated after the second treatment session, based on results of a sleep study. For analysis, patients were classified into the non-OSA (n = 66), treated OSA (OSA patients undergoing CPAP; n = 11), and untreated OSA (n = 23) groups, and between group differences evaluated. RESULTS: After the first session, AF recurrence was observed in 18.2% (12/66) and 14.7% (5/34) of patients without and with OSA, respectively (P = 0.678). After the second procedure, the rate of AF recurrence was 12.1% (8/66) in the non-OSA group, 9.1% (1/11) in the treated OSA group, and 8.7% (2/23) in the untreated OSA group (log-rank P = 0.944). CONCLUSIONS: The rate of AF recurrence might not be greater in patients with untreated OSA than in those without OSA and those with treated OSA after repeated PVI, using a contact force-sensing catheter, for patients with paroxysmal or short-term persistent AF. PMID- 30460588 TI - Pocket related complications following cardiac electronic device implantation in patients receiving anticoagulation and/or dual antiplatelet therapy: prospective evaluation of different preventive strategies. AB - PURPOSE: We sought to assess the safety and effectiveness of three different devices: (1) vacuum drainage system, (2) hemostatic gelatin sponge (Stypro(r)), and (3) compression device (Premofix(r)) compared to standard of care (control) in patients undergoing cardiac implantable electronic device (CIED) implantation receiving anticoagulation and/or dual antiplatelet therapy (DAPT). METHODS: We enrolled all consecutive patients admitted for first permanent CIED implantation receiving anticoagulation and/or DAPT into a prospective registry. The primary endpoint (1 degrees EP) was a composite of hematoma grade > 1 and pocket infection. RESULTS: We included 406 patients (median age 73 years, 71% male) of whom 103 (25%) received a vacuum drainage system, 99 (24%) received Stypro(r), 103 (25%) received Premofix(r), and 101 (25%) were in the control group. One hundred eighty patients (44%) were treated with anticoagulation (median INR 2.0), 176 (43%) received DAPT, and 50 (12%) both. The occurrence of the 1 degrees EP was reduced by Stypro(r) (hazard ratio (HR) 0.38 (95% confidence interval (CI) 0.16-0.94) and Premofix(r) (HR: 0.37 (95% CI 0.15-0.90)) compared to controls (p < 0.05 for both). The incidence of hematoma grade 2 or 3 was exclusively lowered by Premofix(r) compared to control (6% versus 15%; p < 0.05) and was not affected by the type of CIED, INR (>= 2.5 versus < 2.5), body mass index (>= 30 versus < 30), or CIED implantation under anticoagulation plus DAPT. The vacuum drainage system did not affect the 1 degrees EP or the incidence of hematoma. CONCLUSIONS: In patients receiving anticoagulation and/or DAPT undergoing CIED implantation, the use of Premofix(r) and Stypro(r) significantly lowered the 1 degrees EP occurrence compared to control. Premofix(r) additionally lowered the frequency of pocket hematomas >grade 1. PMID- 30460589 TI - Dynamics of Bone Cell Interactions and Differential Responses to PTH and Antibody Based Therapies. AB - We propose a mathematical model describing the dynamics of osteoblasts and osteoclasts in bone remodeling. The goal of this work is to develop an integrated modeling framework for bone remodeling and bone cell signaling dynamics that could be used to explore qualitatively combination treatments for osteoporosis in humans. The model has been calibrated using 57 checks from the literature. Specific global optimization methods based on qualitative objectives have been developed to perform the model calibration. We also added pharmacokinetics representations of three drugs to the model, which are teriparatide (PTH(1-34)), denosumab (a RANKL antibody) and romosozumab (a sclerostin antibody), achieving excellent goodness-of-fit of human clinical data. The model reproduces the paradoxical effects of PTH on the bone mass, where continuous administration of PTH results in bone loss but intermittent administration of PTH leads to bone gain, thus proposing an explanation of this phenomenon. We used the model to simulate different categories of osteoporosis. The main attributes of each disease are qualitatively well captured by the model, for example changes in bone turnover in the disease states. We explored dosing regimens for each disease based on the combination of denosumab and romosozumab, identifying adequate ratios and doses of both drugs for subpopulations of patients in function of categories of osteoporosis and the degree of severity of the disease. PMID- 30460590 TI - Clinical presentations, management outcomes, and diagnostic dilemma in Kocuria endophthalmitis. AB - AIM: To describe the clinical presentations and management outcomes of Kocuria endophthalmitis and discuss diagnostic dilemmas DESIGN: Retrospective interventional comparative case series INTERVENTION: Eight unilateral cases with culture-proven Kocuria endophthalmitis from January 2013 to December 2017 underwent vitrectomy/vitreous biopsy and intravitreal antibiotic with or without additional procedures. The undiluted vitreous was subjected to microbiologic evaluation. MAIN OUTCOME MEASURES: The mean age at presentation, etiology, number of interventions, interval between inciting event and presentation, type of intravitreal antibiotic used, and anatomic and functional outcomes were reported. A favorable anatomic outcome was defined as preservation of the globe, absence of hypotony, attached retina, and absence of active inflammation at the last visit. RESULTS: In the current series, there were five males and three females. The mean age at presentation was 31 +/- 17.44 years (median 30 years). The inciting event was open globe injury in five cases and one case each following cataract surgery, microbial keratitis, and endogenous cause. Visual acuity was >= 20/400 in one case at presentation and >= 20/400 in three cases at the last visit. The species identified by Vitek 2, included Kocuria kristinae in three, K. rosea in four and K. varians in one. Follow-up period was 8.25 +/- 8.24 months (median 6.5). Six cases (75%) had complete resolution of infection and inflammation at the last visit. Anatomic success was achieved in 75%. CONCLUSIONS: Kocuria is a relatively rare cause of endophthalmitis often misdiagnosed as Staphylococcal endophthalmitis. Clinical presentation can be variable but favorable antibiotic susceptibility and appropriate timely management can result in acceptable visual and anatomic outcomes. PMID- 30460591 TI - The Role of Youth Trainee-Trainer Alliance and Involvement in School-Based Prevention: A Moderated-Mediation Model of Student Gatekeeper Suicide Prevention Training. AB - This study examined the roles that youth involvement and youth trainee-trainer alliance play in school mental health prevention within the context of youth suicide gatekeeper training. Measures included youth involvement in programming, trainee-trainer alliance, and intentions to refer at-risk youth at pre- and post training. A moderated-mediation design was used to examine associations among these factors. Results show alliance mediating pre- and post-training referral intentions, and involvement moderating the relationship between alliance and post training intentions. On average, trainee intentions improved from pre- to post training, but trainees reporting high alliance endorsed higher post-training referral intentions regardless of involvement level. Low alliance resulted in lower than average post-training referral intentions, even with active involvement in programming, and those with both low alliance and involvement showed the lowest post-training referral intentions. Given these findings, fostering the youth trainee-trainer relationship may be an avenue to optimize prevention program effectiveness. PMID- 30460592 TI - Seeking Help for Mental Health Problems in Hong Kong: The Role of Family. AB - Family members, rather than mental health professionals, are often the first responders for emotional or mental problems, particularly in Chinese societies where family is regarded as the primary care unit. Using data from the third wave of a representative sample of Chinese adults in the Hong Kong Panel Study of Social Dynamics, we investigate how family, and particularly family functioning, is associated with individual mental health help seeking and perceived barriers to professional service use, and how the associations vary across different generations of immigrants and between individuals with high versus low psychological distress. Our results demonstrate that family is still the primary source of help sought for mental health problems. Stronger family functioning is particularly significant for second-generation immigrants when they consider seeking help from immediate family members. Seeking professional help is uncommon, and stronger family functioning is associated with a lower probability of seeking help from general health professionals and alternative services. A well-functioning family is related to certain structural and cultural barriers to seeking professional help, yet trust in professional mental health services does not diminish along with stronger family functioning, even among the high psychological distress subgroup. The findings indicate that family can facilitate mental illness prevention and service integration. It is recommended that appropriate family support and services be incorporated into mental health treatment according to clients' differential family circumstances. PMID- 30460593 TI - Possible reparative effect of low-intensity pulsed ultrasound (LIPUS) on injured meniscus. AB - Menisci are a pair of crescent-shaped fibrocartilages, particularly of which their inner region of meniscus is an avascular tissue. It has characteristics similar to those of articular cartilage, and hence is inferior in healing. We previously reported that low-intensity pulsed ultrasound (LIPUS) treatment stimulates the production of CCN2/CTGF, a protein involved in repairing articular cartilage, and the gene expression of major cartilage matrices such as type II collagen and aggrecan in cultured chondrocytes. Therefore, in this present study, we investigated whether LIPUS has also favorable effect on meniscus cells and tissues. LIPUS applied with a 60 mW/cm2 intensity for 20 min stimulated the gene expression and protein production of CCN2 via ERK and p38 signaling pathways, as well as gene expression of SOX9, aggrecan, and collagen type II in human inner meniscus cells in culture, and slightly stimulated the gene expression of CCN2 and promoted the migration in human outer meniscus cells in culture. LIPUS also induced the expression of Ccn2, Sox9, Col2a1, and Vegf in rat intact meniscus. Furthermore, histological evaluations showed that LIPUS treatment for 1 to 4 weeks promoted healing of rat injured lateral meniscus, as evidenced by better and earlier angiogenesis and extracellular matrix synthesis. The data presented indicate that LIPUS treatment might prevent meniscus from degenerative change and exert a reparative effect on injured meniscus via up-regulation of repairing factors such as CCN2 and that it might thus be useful for treatment of an injured meniscus as a non-invasive therapy. PMID- 30460594 TI - Outcomes of magnetic resonance imaging fusion-targeted biopsy of prostate imaging reporting and data system 3 lesions. AB - PURPOSE: To evaluate the characteristics and histological outcomes in patients with Prostate Imaging Reporting and Data System (PI-RADS) 3 lesions undergoing magnetic resonance imaging-guided fusion-targeted biopsy (MRIFTB). METHODS: We retrospectively reviewed 138 patients with PI-RADS category 3 lesions classified using multiparametric MRI who underwent MRIFTB between May 2016 and March 2018. The study population included biopsy-naive and patients with prior negative biopsy. Univariate and multivariate analyzes were performed to determine significant predictors of prostate cancer (PCa) and clinically significant prostate cancer (csPCa). The definition of csPCa was set at Gleason score >= 3 + 4. RESULTS: Overall, 114 (82.6%) biopsied lesions were benign and 24 (17.4%) were identified as prostate cancer. Of these 24 lesions, 14 (58.3%) harbored csPCa. Peripheral zone (PZ) lesions were more likely to be associated with malignant disease than transition zone lesions (13.7 vs. 6.2%). Multivariate logistic analysis revealed that age, PZ location, and prostate-specific antigen (PSA) density (P < 0.05) were independent predictors of both PCa and csPCa. CONCLUSIONS: A non-negligible number of PI-RADS 3 patients harbor csPCa. Moreover, age, lesion location, and PSA density could be potential clinical predictors of PCa and csPCa. Physicians should be aware of the cancer prevalence of PI-RADS 3 lesions, as the use of the aforementioned factors can help in the decision-making process for these patients. PMID- 30460595 TI - The use of buccal mucosa graft for correction of severe chordee and urethroplasty in proximal hypospadias repair. PMID- 30460596 TI - Pros and cons of mouse models for studying osteoarthritis. AB - Osteoarthritis (OA) is one of the most common chronic conditions in the world today. It results in breakdown of cartilage in joints and causes the patient to experience intense pain and even disability. The pathophysiology of OA is not fully understood; therefore, there is currently no cure for OA. Many researchers are investigating the pathophysiology of the disease and attempting to develop methods to alleviate the symptoms or cure the OA entirely using animal models. Most studies on OA use animal models; this is necessary as the disease develops very slowly in humans and presents differently in each patient. This makes it difficult to effectively study the progression of osteoarthritis. Animal models can be spontaneous, in which OA naturally occurs in the animal. Genetic modifications can be used to make the mice more susceptible to developing OA. Osteoarthritis can also be induced via surgery, chemical injections, or non invasive trauma. This review aims to describe animal models of inducing osteoarthritis with a focus on the models used on mice and their advantages and disadvantages that each model presents. PMID- 30460597 TI - Hotspots 2.0: Toward an integrated understanding of stressors and response options. AB - Integrated and transdisciplinary approaches are necessary in hotspots research where the intention is to influence policy and practice. Knowing that climate change will impact major ecosystem services and the sustainability of life support systems, a critical examination of the hotspot concept and approach is undertaken to pursue synergistic responses. Hotspots 2.0 embodies current thinking about planning towards multiple drivers of change and seeing human and natural systems as mutually inter-dependent and benefiting from integrated policy approaches. Such proposed adaptation interventions to inter-related stressors will complement biodiversity conservation, disaster risk reduction, and human well-being. Through a systematic review, we assess 114 relevant peer review cases to examine integrative responses to climatic and non-climatic vulnerabilities in various hotspot regions. Furthermore, we illustrate the utility of the Hotspots 2.0 approach using emerging insights from the 'Collaborative Adaptation Research Initiative in Africa and Asia' in semi-arid regions, deltas, and glacier-fed river basin hotspots. PMID- 30460598 TI - Early Manipulation of Arterial Blood Pressure in Acute Ischemic Stroke (MAPAS): Results of a Randomized Controlled Trial. AB - INTRODUCTION: There is uncertainty over the optimal level of systolic blood pressure (SBP) in the setting of acute ischemic stroke (AIS). The aim of this study was to determine the efficacy of the early manipulation of SBP in non thrombolised patients. The key hypothesis under investigation was that clinical outcomes vary across ranges of SBP in AIS. METHODS: 218 patients were randomized within 12 h of AIS to maintain the SBP during 24 h within three ranges: Group 1 140-160 mmHg, Group 2 161-180 mmHg or Group 3 181-200 mmHg. Vasoactive drugs and fluids were used to achieve these targets. Good outcome was defined as a modified Rankin score 0-2 at 90-days. RESULTS: The median SBP in the three groups in 24 h was: 153 mmHg, 163 mmHg, and 178 mmHg, respectively, P < 0.0001. Good clinical outcome did not differ among the different groups (51% vs 52% vs 39%, P = 0.27). Symptomatic intracranial hemorrhage (SICH) was more frequent in the higher SBP range (1% vs 2.7% vs 9.1%, P = 0.048) with similar mortality rates. No patient had acute neurological deterioration related to the SBP reduction in the first 24 h. In our logistic regression analysis, the odds of having good clinical outcome was higher in Group 2 (OR 2.83) after adjusting for important confounders. Regardless of the assigned group, the probability of good outcome was 47% in patients who were manipulated to increase the BP, 42% to decrease and 62% in non manipulated (P = 0.1). Adverse effects were limited to Group 2 (4%) and Group 3 (7.6%) and were associated with the use of norepinephrine (P = 0.05). CONCLUSIONS: Good outcome in 90 days was not significantly different among the 3 blood pressure ranges. After logistic regression analysis, the odds of having good outcome was greater in Group 2 (SBP 161-180 mmHg). SICH occurred more frequently in Group 3 (181-200 mmHg). PMID- 30460599 TI - GP2017: An Adalimumab Biosimilar. AB - GP2017 (adalimumab) is a biosimilar anti-TNF-alpha antibody. It is approved in the EU for use in all indications for which reference adalimumab is approved. GP2017 has similar physicochemical and functional properties to those of reference adalimumab, and the pharmacokinetic similarity of the agent has been shown in healthy male volunteers. GP2017 demonstrated clinical efficacy equivalent to that of reference adalimumab in patients with moderate to severe plaque psoriasis or rheumatoid arthritis; the tolerability, safety and immunogenicity profiles of the two agents were also similar. Multiple switching between GP2017 and reference adalimumab (up to four times) had no impact on efficacy, tolerability or immunogenicity. The role of reference adalimumab in the management of autoimmune inflammatory conditions is well established and GP2017 provides an effective biosimilar alternative for patients requiring adalimumab therapy. PMID- 30460600 TI - Laser speckle contrast imaging for quantitative assessment of facial flushing during mesenteric traction syndrome in upper gastrointestinal surgery. AB - The mesenteric traction syndrome (MTS) is associated with prostacyclin (PGI2) facilitated systemic vasodilatation during surgery and is identified by facial flushing. We hypothesized that severe facial flushing would be related to the highest concentrations of plasma PGI2 and accordingly to the highest levels of skin blood flow measured by laser speckle contrast imaging (LSCI). Patients scheduled for major upper abdominal surgery were consecutively included. Within the first hour of the procedure, facial flushing was scored according to a standardized scale, and skin blood flow (LSPU) was continuously measured on the forehead and the cheeks by LSCI. Arterial blood samples for 6-keto-PGF1alpha (stable metabolite of PGI2) and hemodynamic variables were obtained at defined time points. Overall, 66 patients were included. After 15 min of surgery, patients with severe flushing demonstrated the highest plasma 6-keto-PGF1alpha concentration and the most significant decrease in systemic vascular resistance. Accordingly, the skin blood flow on the forehead (238 [201-372] to 562 LSPU [433 729]) and the cheeks (341 [239-355] to 624 LSPU [468-917]) increased and were significantly higher than for patients with moderate or no flushing (both, P = 0.04). A cut-off value for skin blood flow could be defined for both the cheeks and the forehead for patients with severe flushing vs. no flushing (425/456 LSPU, sensitivity 75/76% and specificity 80/85%). MTS is linked to an increase in facial skin blood flow during upper gastrointestinal surgery. By applying LSCI, it is possible to quantitatively register facial blood flow, and thereby provide an objective tool for intraoperative verification of MTS. PMID- 30460601 TI - Classification of coronal imbalance in adult scoliosis and spine deformity: a treatment-oriented guideline. AB - INTRODUCTION: In adult spinal deformity (ASD), sagittal imbalance and sagittal malalignment have been extensively described in the literature during the past decade, whereas coronal imbalance and coronal malalignment (CM) have been given little attention. CM can cause severe impairment in adult scoliosis and ASD patients, as compensatory mechanisms are limited. The aim of this paper is to develop a comprehensive classification of coronal spinopelvic malalignment and to suggest a treatment algorithm for this condition. METHODS: This is an expert's opinion consensus based on a retrospective review of CM cases where different patterns of CM were identified, in addition to treatment modifiers. After the identification of the subgroups for each category, surgical planning for each subgroup could be specified. RESULTS: Two main CM patterns were defined: concave CM (type 1) and convex CM (type 2), and the following modifiers were identified as potentially influencing the choice of surgical strategy: stiffness of the main coronal curve, coronal mobility of the lumbosacral junction and degeneration of the lumbosacral junction. A surgical algorithm was proposed to deal with each situation combining the different patterns and their modifiers. CONCLUSION: Coronal malalignment is a frequent condition, usually associated to sagittal malalignment, but it is often misunderstood. Its classification should help the spine surgeon to better understand the full spinal alignment of ASD patients. In concave CM, the correction should be obtained at the apex of the main curve. In convex CM, the correction should be obtained at the lumbosacral junction. These slides can be retrieved under Electronic Supplementary Material. PMID- 30460602 TI - The extended posterior approach for resection of sacral tumours. AB - PURPOSE: The conventional posterior approach is mostly advocated for excision of sacral tumours below S2. We describe an operative technique of single-stage en bloc resection of sacral tumours, extending up to S1, through an extended posterior approach. METHOD: Nine patients, who had undergone resection of sacral tumours, by the described technique formed the basis of this study. Four patients had chordomas, whereas schwannoma, neurilemmoma, giant-cell tumour, malignant paraganglioma and recurrent Ewing's sarcoma were seen in one patient each. They were followed up at regular intervals with a mean follow-up of 45.4 months. Perioperative complications, their functional and oncological outcomes at final follow-up were analysed. RESULT: None of the patients had any perioperative complications like uncontrolled haemorrhage, injury to the rectum, deep vein thrombosis or pulmonary embolism. One patient had a superficial wound infection which subsided with regular dressing, and another patient developed a wound breakdown that required an additional flap procedure. At final follow-up, six patients were able to walk without any assistive devices, six patients had normal bladder function, and five patients had normal bowel function. Five patients did not have any recurrence at final follow-up, whereas two were alive with the disease and two had died. CONCLUSION: The reported technique allows en bloc resection of sacral tumours up to S1, through a posterior-only approach. It is less invasive with minimal morbidity. The functional and oncological outcomes are similar to those reported by other investigators. These slides can be retrieved from electronic supplementary material. PMID- 30460603 TI - Contributions of academic institutions in high income countries to anesthesia and surgical care in low- and middle-income countries: are they providing what is really needed? PMID- 30460604 TI - Data matters: implications for surgery and anesthesia in achieving universal health coverage. PMID- 30460605 TI - Potential gender remuneration gaps in anesthesiology. PMID- 30460606 TI - Re-Analysis of Modeling a Switch from a 13-Valent to 10-Valent Pneumococcal Conjugate Vaccine in Canada: Leveraging Real-World Experience from Belgium. PMID- 30460607 TI - Evidence from an In Vitro Study: Is Oxacillin Plus Vancomycin a Better Choice for Heteroresistant Vancomycin-Intermediate Staphylococcus aureus? AB - INTRODUCTION: Heteroresistant vancomycin-intermediate Staphylococcus aureus (hVISA) bacteremia may result in clinical failure of vancomycin therapy, together with prolonged infection and hospitalization. This clinical problem has resulted in a search for more effective treatment options. The current study was designed to further investigate the synergistic effect of oxacillin plus vancomycin against methicillin-resistant S. aureus (MRSA) and hVISA using checkerboard and time-kill assays. METHODS: Non-duplicate S. aureus isolates including hVISA (n = 29), MRSA (n = 10) and methicillin susceptible S. aureus (MSSA, n = 11) were used for combinational testing using checkerboard and time-kill assays. RESULTS: Twenty-one isolates, 15 hVISA and 6 MRSA, showed synergy between oxacillin and vancomycin by checkerboard assay with fractional inhibitory concentration indices of <= 0.5. The addition of oxacillin to vancomycin resulted in a reduction in baseline vancomycin MIC from 1-2 to 0.06-0.5 ug/ml against MRSA and hVISA isolates. In the time-kill assay, the combination of oxacillin and vancomycin resulted in synergistic activity against hVISA (n = 23) and MRSA (n = 7) isolates. Regrowth was observed in six hVISA isolates exposed to combination in the time-kill assay, but none of them reached the original inoculum density at 24 h. All re-growth isolates showed a onefold increase in vancomycin MIC (from 1 to 2 ug/ml) and were re-confirmed as hVISA using the population-analysis profile experiment. Overall, for hVISA and MRSA, the combination of oxacillin plus vancomycin had greater antibacterial effect than each individual drug alone. CONCLUSION: The present study showed the potential activity of vancomycin plus oxacillin combination against hVISA and MRSA isolates. Further, continued evaluation of this combination is warranted and may have therapeutic benefits in treating complicated MRSA infections. PMID- 30460608 TI - Circular RNAs: Functions and Prospects in Glioma. AB - Improving the survival rate of patients with glioma, a malignant tumor of the human brain has become increasingly important. In recent years, the function of circular RNAs (circRNAs) in different diseases and the pathophysiological mechanisms involved have been elucidated. In the pathophysiological mechanism, the primary function of circRNAs is to act as microRNA sponges. An increasing number of studies have found that circRNAs are differentially expressed in gliomas and regulate the occurrence, proliferation, and invasion of glioma and thus may be potential markers for the diagnosis of gliomas. Additionally, some circRNAs have been associated with glioma staging and may be useful in determining prognosis. Based on the stability and high conservation of circRNAs, we believe that circRNAs may have molecular targets that are useful for the treatment of glioma. In this review, we summarize the current research regarding the role of circRNAs in gliomas, discuss the potential value and role of circRNAs in gliomas, and provide new perspectives for future research. PMID- 30460609 TI - Effects of vitamin D supplementation on androgens in men with low testosterone levels: a randomized controlled trial. AB - PURPOSE: It has been hypothesized that vitamin D is associated with androgen levels in men. We, therefore, aimed to evaluate whether vitamin D supplementation increases serum total testosterone (TT) levels in men with low TT levels at baseline. METHODS: The Graz Vitamin D&TT-RCT is a single-center, double-blind, randomized placebo-controlled trial conducted between March 2013 and November 2017 at the endocrine outpatient clinic at the Medical University of Graz, Austria. One-hundred healthy men with serum TT levels < 10.4 nmol/l and 25 hydroxyvitamin D [25(OH)D] levels < 75 nmol/l participated in the trial. Subjects were randomized to receive 20,000 IU of vitamin D3/week (n = 50) or placebo (n = 50) for 12 weeks. Primary outcome was TT measured using mass spectrometry. Secondary outcomes were free testosterone, free androgen index, sex hormone binding globulin, estradiol, follicle-stimulating hormone, luteinizing hormone, metabolic characteristics, and body composition. RESULTS: Ninety-four men [mean age and 25(OH)D: 47 (+/- 12) years and 56.3 (+/- 18.3) nmol/l, respectively] completed the study. We found no significant treatment effect on serum TT or on the remaining secondary outcome variables. CONCLUSION: Vitamin D treatment had no effect on serum TT levels in middle-aged healthy men with low TT levels. PMID- 30460610 TI - Hydroxytyrosol inhibits cancer stem cells and the metastatic capacity of triple negative breast cancer cell lines by the simultaneous targeting of epithelial-to mesenchymal transition, Wnt/beta-catenin and TGFbeta signaling pathways. AB - PURPOSE: This study was aimed to determine the impact of hydroxytyrosol (HT), a minor compound found in olive oil, on breast cancer stem cells (BCSCs) and the migration capacity of triple-negative breast cancer (TNBC) cell lines through the alteration of epithelial-to-mesenchymal transition (EMT) and embryonic signaling pathways. METHODS: BCSCs self-renewal was determined by the mammosphere-forming efficiency in SUM159PT, BT549, MDA-MB-231 and Hs578T TNBC cell lines. Flow cytometric analysis of CD44+/CD24-/low and aldehyde dehydrogenase positive (ALDH+) subpopulations, migration by the "wound healing assay", invasion and Western blot of EMT markers and TGFbeta signaling were investigated in SUM159PT, BT549 and MDA-MB-231 cell lines. Wnt/beta-catenin signaling was assessed by Western blot in BT549 cells expressing WNT1 and MDA-MB-231 cells. Changes in TGFbeta activity was determined by SMAD Binding Element (SBE) reporter assay. RESULTS: HT reduced BCSCs self-renewal, ALDH+ (aldehyde dehydrogenase) and CD44+/CD24-/low subpopulations, tumor cell migration and invasion. Consistently, HT suppressed Wnt/beta-catenin signaling by decreasing p-LRP6, LRP6, beta-catenin and cyclin D1 protein expression and the EMT markers SLUG, ZEB1, SNAIL and VIMENTIN. Finally, HT inhibited p-SMAD2/3 and SMAD2/3 in SUM159PT, BT549 and MDA MB-231 cells, what was correlated with a less TGFbeta activity. CONCLUSION: In conclusion, we report for the first time the inhibitory role of HT on BCSCs and tumor cell migration by targeting EMT, Wnt/beta-catenin and TGFbeta signaling pathways. Our findings highlight the importance of the chemopreventive compound HT as a novel candidate to be investigated as an alternative targeted therapy for TNBC. PMID- 30460611 TI - Impact of endometriosis on risk of ovarian, endometrial and cervical cancers: a meta-analysis. AB - PURPOSE: The risks of gynecologic cancer have not been well established in women with endometriosis. The objective of the present study was to investigate the influence of endometriosis on the risk for three gynecologic cancer (ovarian cancer, endometrial cancer and cervical cancer). METHODS: We gathered updated evidence about the risk relationship between endometriosis and gynecologic cancers by conducting a comprehensive search of several medical literature electronic databases, including PubMed, Embase and the Cochrane Library. The design and quality of all studies were evaluated using the Newcastle-Ottawa Scale (NOS), and a random-effects model was used to calculate pooled risk ratio (RR). RESULTS: Of the 8538 articles our search produced, we selected 25 qualified studies, including 16 cohort studies and 9 case-control studies. Patients with endometriosis had both an increased risk of ovarian cancer [RR 1.964; 95% CI (1.685, 2.290)]. The risk of endometrial cancer (EC) is not necessarily higher in patients with endometriosis [RR 1.176, 95% CI (0.878, 1.575)]. Endometriosis was not associated with an increased risk for cervical cancer (CC) [RR 0.670, 95% CI (0.537, 0.838)]. CONCLUSIONS: Patients with endometriosis need to be closely observed and rechecked regularly to prevent malignant changes. PMID- 30460612 TI - "Freshman effect" in gynecologic surgery at a teaching hospital. AB - PURPOSE: The purpose of this study was to determine the existence of the freshman effect in patients who underwent gynecologic surgery at a teaching hospital by comparing surgical outcomes and morbidity rates between the first academic quarter and other quarters. METHODS: All data were collected prospectively. Between January 2015 and March 2018, patients who underwent gynecologic surgeries during the first academic quarter (March, April, and May in Korea) were retrospectively compared with patients who underwent gynecologic surgeries during other academic quarters (June through February). The primary outcome measure was the incidence of operative complication. Secondary outcomes were the operative time, operative blood loss, and length of hospital stay. RESULTS: Among 1241 patients who underwent gynecologic surgery during the study period of 39 months, 1136 patients were analyzed for this study and divided into groups according to the first academic quarter (n = 335) and other academic quarters (n = 801). The baseline characteristics were not different between the groups. No significant difference in operative complications was found between the first and other academic quarters (1.5% versus 3.0%; P = 0.143). Moreover, there was no significant difference in operative time, operative blood loss, and length of hospital stay between the groups. CONCLUSIONS: This study did not demonstrate the existence of a "freshman effect", i.e., an increase in morbidity, at a Korean teaching hospital providing gynecologic surgical care. Patients undergoing gynecologic surgery can be reassured of their safety during the first academic quarter. PMID- 30460613 TI - The participation rate of migrant women in gestational diabetes screening in Austria: a retrospective analysis of 3293 births. AB - PURPOSE: This study evaluated the extent to which migrant women participate in the mandatory oral glucose tolerance test (OGTT) for gestational diabetes mellitus (GDM) screening in Austria. METHODS: A retrospective data analysis was carried out of births at an obstetrics unit in a university hospital between January 2013 and December 2015. The inclusion criteria were singleton pregnancies, live births, birth weight >= 3500, and no preexisting diabetes mellitus. The patient's extramurally obtained OGTT values and history of GDM were checked. If the mother's country of birth was not Austria, the woman was classified as a migrant. Three groups were defined: group 1-women with normal OGTT; group 2-women with pathological OGTT; and group 3-women without OGTT or with an incomplete OGTT. MAIN OUTCOME MEASURES: Numbers of complete and incomplete OGTTs and rate of women with pathological OGTTs not treated in accordance with the guidelines among mothers born in Austria or migrants. The groups were compared using the t-test, chi-squared test, or Fisher's exact test. RESULTS: A total of 3293 births met the inclusion criteria, and 43.52% of all mothers were migrants; 16.8% of all women had pathological OGTT findings. Only 60.1% of the latter received treatment in accordance with the guidelines. The proportion of mothers born in Austria who did not have OGTTs, or only incomplete ones, was 5.4%. In the group of migrant women, the corresponding figure was 10.5% (P < 0.01). CONCLUSIONS: Migrant women have significantly lower rates of participation in GDM screening. PMID- 30460614 TI - Accuracy and efficacy of embryo transfer based on the previous measurement of cervical length and total uterine length. AB - PURPOSE: Aim of the study was to examine the accuracy of embryo transfer based on the previous measurement of cervical length and total uterine length. METHODS: The study has taken place in an academic-assisted reproduction clinic. 248 patients with infertility requiring IVF/ICSI treatment have been included. All patients underwent IVF/ICSI cycles with antagonist protocol and were treated with controlled ovarian stimulation using recombinant FSH (100-400 IU/day). On the day of oocyte retrieval, all patients were given vaginally natural micronized progesterone in a dose of 200 mg/tds. All patients had transvaginal ultrasound measurement of cervical length and endometrial cavity length prior to embryo transfer and measurement of embryo distance (intrauterine air bubbles) from fundal surface of uterine cavity and internal cervical os immediately after embryo transfer. Embryo transfer was performed on days 2-3. Primary outcome was to estimate the accuracy of embryo transfer based on the measurement of the embryo distance from middle of uterine cavity after embryo transfer and secondary outcome was to assess the effect of embryo distance from uterine fundus and internal cervical os to clinical pregnancy rate. RESULTS: The clinical pregnancy rate was 42.7%. The mean embryo distance from the middle of endometrial cavity was 0.48 +/- 0.02 cm, the mean embryo distance from the uterine fundus was 0.88 +/- 0.32 cm, and from the internal cervical os was 1.67 +/- 0.45 cm. Multiple regression analysis showed that the embryo distance from middle of cavity was related to endometrial cavity length and to the embryo distance from the fundus and it was not related to Cx length, total uterine length, embryo distance from internal Cx os, and embryo transfer length. CONCLUSIONS: Embryo transfer with the previous measurement of total uterine length and estimation of embryo transfer length can be performed with very good accuracy by a single operator. PMID- 30460616 TI - Amyloid beta1-42-Induced Rapid Zn2+ Influx into Dentate Granule Cells Attenuates Maintained LTP Followed by Retrograde Amnesia. AB - On the basis of the evidence that amyloid beta1-42 (Abeta1-42)-induced Zn2+ influx affects memory acquisition via attenuated long-term potentiation (LTP) induction, here we tested whether Abeta1-42-induced Zn2+ influx affects maintained LTP in freely moving rats, resulting in retrograde amnesia. Both maintained LTP and space memory were impaired by local injection of 250 MUM ZnCl2 (2 MUl) into the dentate gyrus, while maintained LTP was impaired by injection of either Abeta1-40 or Abeta1-42 (25 MUM, 2 MUl) into the dentate gyrus. Abeta1-40 induced impairment of maintained LTP was rescued by co-injection of CaEDTA, an extracellular Zn2+ chelator, but not by co-injection of ZnAF-2DA, an intracellular Zn2+ chelator, suggesting that maintained LTP is impaired by Abeta1 40 via a mechanism that may involve extracellular Zn2+. In contrast, Abeta1-42 induced impairments of maintained LTP and space memory were rescued by co injection of either CaEDTA or ZnAF-2DA. Intracellular Zn2+ in dentate granule cells was rapidly increased by Abeta1-42 injection into the dentate gyrus, but not by Abeta1-40 injection. The block of Abeta1-42-induced increase in intracellular Zn2+ by pretreatment with dexamethasone, a metallothionein inducer also rescued Abeta1-42-induced impairment of maintained LTP. The present study indicates that Abeta1-42-induced Zn2+ influx into dentate granule cells, which more readily occurs than free Zn2+-induced Zn2+ influx, attenuates maintained LTP followed by retrograde amnesia. It is likely that controlling Abeta1-42-induced intracellular Zn2+ dysregulation is a strategy for defending AD pathogenesis. PMID- 30460615 TI - Local Application of Autologous Platelet-Rich Fibrin Patch (PRF-P) Suppresses Regulatory T Cell Recruitment in a Murine Glioma Model. AB - The immunosuppressive microenvironment is one of the major factors promoting the growth of glioblastoma multiforme (GBM). Infiltration of CD4+CD25+Foxp3+ regulatory T cells (Tregs) into the tumor microenvironment plays a significant role in the suppression of the anti-tumor immunity and portends a dismal prognosis for patients. Glioma-mediated secretion of chemo-attractant C-C motif ligand 2 and 22 (CCL2/22) has previously been shown by our group to promote Treg migration in vitro. In this study, we show that a local implantation of platelet rich fibrin patch (PRF-P) into the brain of GL261 glioma-bearing mice prolonged the survival of affected animals by 42.85% (p = 0.0011). Analysis performed on brain tumor tissue harvested from PRF-P-treated mice revealed a specific decrease in intra-tumoral lymphocytes with a preferential depletion of immunosuppressive Tregs. Importantly, co-culture of GL261 or chemo-attractants (CCL2/22) with PRF-P abrogated Treg migration. Pharmacological blockade of the CCL2/22 interaction with their receptors potentiated the inhibitory effect of PRF-P on Tregs recruitment in culture. Moreover, our findings revealed the soluble CD40 ligand (sCD40L) as a major Treg inhibitory player produced by activated platelets entrapped within the fibrin matrix of the PRF-P. Blockade of sCD40L restored the migratory capacity of Tregs, emphasizing the role of PRF-P in preventing the Treg migration to glioma tissue. Our findings highlight autologous PRF-P as a personalized, Treg-selective suppression platform that can potentially supplement and enhance the efficacy of glioma therapies. PMID- 30460617 TI - Differential Role of Hypothalamic AMPKalpha Isoforms in Fish: an Evolutive Perspective. AB - In mammals, hypothalamic AMP-activated protein kinase (AMPK) alpha1 and alpha2 isoforms mainly relate to regulation of thermogenesis/liver metabolism and food intake, respectively. Since both isoforms are present in fish, which do not thermoregulate, we assessed their role(s) in hypothalamus regarding control of food intake and energy homeostasis. Since many fish species are carnivorous and mostly mammals are omnivorous, assessing if the role of hypothalamic AMPK is different is also an open question. Using the rainbow trout as a fish model, we first observed that food deprivation for 5 days did not significantly increase phosphorylation status of AMPKalpha in hypothalamus. Then, we administered adenoviral vectors that express dominant negative (DN) AMPKalpha1 or AMPKalpha2 isoforms. The inhibition of AMPKalpha2 (but not AMPKalpha1) led to decreased food intake. The central inhibition of AMPKalpha2 resulted in liver with decreased capacity of use and synthesis of glucose, lipids, and amino acids suggesting that a signal of nutrient abundance flows from hypothalamus to the liver, thus suggesting a role for central AMPKalpha2 in the regulation of peripheral metabolism in fishes. The central inhibition of AMPKalpha1 induced comparable changes in liver metabolism though at a lower extent. From an evolutionary point of view, it is of interest that the function of central AMPKalpha2 remained similar throughout the vertebrate lineage. In contrast, the function of central AMPKalpha1 in fish relates to modulation of liver metabolism whereas in mammals modulates not only liver metabolism but also brown adipose tissue and thermogenesis. PMID- 30460618 TI - Detecting medical prescriptions suspected of fraud using an unsupervised data mining algorithm. AB - Nowadays, health insurance companies face various types of fraud, like phantom billing, up-coding, and identity theft. Detecting such frauds is thus of vital importance to reduce and eliminate corresponding financial losses. We used an unsupervised data mining algorithm and implemented an outlier detection model to assist the experts in detecting medical prescriptions suspected of fraud. The implementation ran medicine code, patients' sex, and patients' age variables through three successive screening steps. The proposed model is capable of detecting 25% to 100% of cases violating the standards for some medicines that are not supposed to be prescribed at the same time in one single prescription. This model can also detect medical prescriptions suspected of fraud with a sensitivity of 62.16%, specificity of 55.11%, and accuracy of 57.2%. This paper shows that data mining can help detecting potential fraud cases in medical prescriptions more quickly and accurately than by the manual inspection as well as reducing the number of medical prescriptions to be checked which will result in reducing investigators heavy workload. The results of the proposed model can also help policymakers to plan for fighting against fraudulent activities. Graphical Abstract Detecting Medical Prescriptions Suspected of Fraud Using an Unsupervised Data Mining Algorithm. PMID- 30460619 TI - Laparoscopy reduces iatrogenic splenic injuries during colorectal surgery. AB - BACKGROUND: Splenic injury can occur during colorectal surgery especially in cases, where the splenic flexure is mobilized. The aim of this study was to analyze whether the operative approach (laparoscopic vs. open) was associated with an increased risk for splenic injury during colorectal surgery and to compare the outcomes of different management options. METHODS: All accidental injuries that occurred during colorectal resections performed in our department between January 2010 and June 2013 were identified from an administrative database. All patients with iatrogenic splenic injuries were classified into two groups according to the operative approach. Only procedures that required splenic flexure mobilization were included. Splenic injury management options and outcomes were compared. RESULTS: There were 2336 colorectal resections (1520 open, 816 laparoscopic) performed during the study period. There were 25 (1.1%) iatrogenic splenic injuries. 23 out of 25 splenic injuries occurred during open colorectal surgery. Overall, 16 (64%) patients were managed with topical hemostatic methods, 5 (20%) with splenectomy, and 4 (16%) with splenorrhaphy. It was possible to salvage the spleen in both laparoscopic patients. The laparoscopic approach was associated with a lower splenic injury rate (0.25% vs. 1.5%, p = 0.005) and a lower need for splenectomy/splenorrhaphy (p = 0.03). CONCLUSIONS: Our data suggest that laparoscopic colorectal surgery may be associated with a lower risk of iatrogenic splenic injury, and that most splenic injuries can be managed with spleen-preserving approaches. PMID- 30460620 TI - Perforated sigmoid diverticulitis: Hartmann's procedure or resection with primary anastomosis. PMID- 30460621 TI - Unpacking multi-trophic herbivore-grass-endophyte interactions: feedbacks across different scales in vegetation responses to Soay sheep herbivory. AB - Grazing can induce changes in both plant productivity and nutritional quality, which may subsequently influence herbivore carrying capacity. While research on Soay sheep (Ovis aries L.) dynamics on Hirta Island in the St. Kilda archipelago has elucidated the complexity of population drivers, including parasites, the role of herbivore-generated feedbacks as an intrinsic regulating factor remains unclear. The sheep lack large predators and every 3-9 years undergo population crashes (overcompensatory mortality). We investigated the effects of grazing on (1) sward productivity and (2) quality (toxicity) of the primary forage species, red fescue (Festuca rubra L.), which is highly infected by an alkaloid synthesizing fungal endophyte. Grazing had a negative impact on both forage quantity and quality. At higher sheep densities, impacts on sward growth were magnified, resulting in a nonlinear relationship with plant productivity. Simultaneously, endophyte hyphal load (and by inference, toxicity) peaked close to the time of a crash. A greenhouse experiment showed that alkaloid concentration in F. rubra increased in response to artificial defoliation. We conclude that at high sheep densities, grazing-mediated reductions in productivity, together with sustained alkaloid production, are likely to influence sheep dynamics. Future research should consider the interactive effects of forage toxicity, quantity, and nutritional content. PMID- 30460622 TI - Authors' Reply to Angelis and Kanavos: "Does MCDA Trump CEA?" PMID- 30460623 TI - Patient-specific simulation of transcatheter aortic valve replacement: impact of deployment options on paravalvular leakage. AB - Transcatheter aortic valve replacement (TAVR) has emerged as an effective alternative to conventional surgical valve replacement in high-risk patients afflicted by severe aortic stenosis. Despite newer-generation devices enhancements, post-procedural complications such as paravalvular leakage (PVL) and related thromboembolic events have been hindering TAVR expansion into lower risk patients. Computational methods can be used to build and simulate patient specific deployment of transcatheter aortic valves (TAVs) and help predict the occurrence and degree of PVL. In this study finite element analysis and computational fluid dynamics were used to investigate the influence of procedural parameters on post-deployment hemodynamics on three retrospective clinical cases affected by PVL. Specifically, TAV implantation depth and balloon inflation volume effects on stent anchorage, degree of paravalvular regurgitation and thrombogenic potential were analyzed for cases in which Edwards SAPIEN and Medtronic CoreValve were employed. CFD results were in good agreement with corresponding echocardiography data measured in patients in terms of the PVL jets locations and overall PVL degree. Furthermore, parametric analyses demonstrated that positioning and balloon over-expansion may have a direct impact on the post deployment TAVR performance, achieving as high as 47% in PVL volume reduction. While the model predicted very well clinical data, further validation on a larger cohort of patients is needed to verify the level of the model's predictions in various patient-specific conditions. This study demonstrated that rigorous and realistic patient-specific numerical models could potentially serve as a valuable tool to assist physicians in pre-operative TAVR planning and TAV selection to ultimately reduce the risk of clinical complications. PMID- 30460624 TI - Recommendations for Reviewers of Biomedical Imaging Grant Applications. AB - This commentary provides recommendations about how to interpret procedures and scoring criteria when reviewing grant applications and how to efficiently perform reviews. This guidance is especially designed for new grant reviewers and especially for reviewers of biomedical imaging grant applications. Recommendations are included about how to start the review process; how to review the Specific Aims page; how to consider Significance, Investigators, Innovation, Research Approach, and Environment; how to improve interactions at the review meeting; and other aspects of the review process. These recommendations are intended to improve the quality of the review process, which ultimately depends on the quality of the reviewers. PMID- 30460625 TI - Preclinical SPECT Imaging of Choroidal Neovascularization in Mice Using Integrin Binding [99mTc]IDA-D-[c(RGDfK)]2. AB - PURPOSE: Integrin alphavbeta3, an adhesion molecule overexpressed in neovascular endothelial cells, is involved in ocular angiogenesis. Integrin alphavbeta3 binding arginine-glycine-aspartic acid (RGD) peptide has been used to target and visualize new vessels. We explored the use of integrin alphavbeta3-targeted RGD peptide ([99mTc]IDA-D-[c(RGDfK)]2) for in vivo molecular imaging of choroidal neovascularization (CNV). PROCEDURES: To induce CNV in animals, the right eyes of C57BL/6 mice were treated with retinal argon laser photocoagulation. CNV formation was confirmed on immunohistopathological examination of retinal and choroidal tissues. To explore the association of integrin with angiogenesis, integrin mRNA expression in the retinal and choroidal tissues was measured using real-time reverse transcriptase-polymerase chain reaction. For in vivo imaging, mice were intravenously injected with [99mTc]IDA-D-[c(RGDfK)]2 and single-photon emission computed tomography (SPECT) images of [99mTc]IDA-D-[c(RGDfK)]2 were obtained before laser induction (baseline) and at 1, 3, 7, and 14 days post induction. CNV-induced regional alterations were measured using radiotracer uptake count. RESULTS: Immunohistopathological examination revealed that CNV lesions showed intense fluorescein isothiocyanate (FITC)-D-[c(RGDfK)]2 immunofluorescence, in contrast to the normal retina and choroid. Retinal integrin mRNA expression peaked at day 1 following CNV induction. On SPECT images using [99mTc]IDA-D-[c(RGDfK)]2, the radio-uptake count in eyes with CNV was significantly higher than in normal controls on days 1-7 (all p < 0.05), with a peak at day 3 representing the highest angiogenic activity. Our preclinical data demonstrated that [99mTc]IDA-D-[c(RGDfK)]2 can detect CNV and its associated angiogenesis in an animal model of CNV. CONCLUSIONS: SPECT imaging using an integrin alphavbeta3-targeted RGD peptide radiotracer may be a useful tool for in vivo functional molecular imaging of CNV. PMID- 30460626 TI - Quantification of [18F]UCB-H Binding in the Rat Brain: From Kinetic Modelling to Standardised Uptake Value. AB - PURPOSE: [18F]UCB-H is a specific positron emission tomography (PET) biomarker for the Synaptic Vesicle protein 2A (SV2A), the binding site of the antiepileptic drug levetiracetam. With a view to optimising acquisition time and simplifying data analysis with this radiotracer, we compared two parameters: the distribution volume (Vt) obtained from Logan graphical analysis using a Population-Based Input Function, and the Standardised Uptake Value (SUV). PROCEDURES: Twelve Sprague Dawley male rats, pre-treated with three different doses of levetiracetam were employed to develop the methodology. Three additional kainic acid (KA) treated rats (temporal lobe epilepsy model) were also used to test the procedure. Image analyses focused on: (i) length of the dynamic acquisition (90 versus 60 min); (ii) correlations between Vt and SUV over 20-min consecutive time-frames; (iii) and (iv) evaluation of differences between groups using the Vt and the SUV; and (v) preliminary evaluation of the methodology in the KA epilepsy model. RESULTS: A large correlation between the Vt issued from 60 to 90-min acquisitions was observed. Further analyses highlighted a large correlation (r > 0.8) between the Vt and the SUV. Equivalent differences between groups were detected for both parameters, especially in the 20-40 and 40-60-min time-frames. The same results were also obtained with the epilepsy model. CONCLUSIONS: Our results enable the acquisition setting to be changed from a 90-min dynamic to a 20-min static PET acquisition. According to a better image quality, the 20-40-min time-frame appears optimal. Due to its equivalence to the Vt, the SUV parameter can be considered in order to quantify [18F]UCB-H uptake in the rat brain. This work, therefore, establishes a starting point for the simplification of SV2A in vivo quantification with [18F]UCB-H, and represents a step forward to the clinical application of this PET radiotracer. PMID- 30460627 TI - Variation in management of spinal gliobastoma multiforme: results from a national cancer registry. AB - PURPOSE: Primary glioblastoma of the spinal cord (spinal GBM) is a rare central nervous system tumor, relative to its cranial counterpart (cranial GBM). Our current knowledge of spinal GBM epidemiology, tumor characteristics and treatment are insufficient and mostly based on single-institution case series. METHODS: All patients diagnosed with grade-4 GBM from 2004 to 2014 were queried from the National Cancer Database. Chi square analysis was used to compare presenting characteristics while Kaplan-Meier and Cox regression analyses were employed for survival analyses. RESULTS: Total 103,496 patients with cranial GBM and 190 patients with spinal GBM were analyzed. Median survival for spinal GBM was found to be higher compared to cranial GBM (p = 0.07). Spinal GBM patients had significant better survival in 18 to 65 years age group than < 18 years and > 65 years age group (p = 0.003). Overall survival time for 95 spinal GBM patients with available treatment data was not statistically different among the four treatment modalities (radiation with or without chemotherapy, surgery alone, surgery with adjuvant therapy, and palliative therapy; p = 0.28).On multivariable analysis, < 18 years age group was associated with improved survival (HR 0.50, 95% CI 0.23-1.00, p = 0.046), while tumor extension was associated with poor survival (HR 2.71, 95% CI 1.04-6.22, p = 0.041). Interestingly surgery with adjuvant therapy was unable to show increase survival compared to other treatment modalities. CONCLUSIONS: Our study adds to the growing literature on spinal GBM with a focus on comparative trends with cranial GBM and outcomes with different treatment modalities. PMID- 30460628 TI - Clinical factors associated with mortality within three months after radiosurgery of asymptomatic brain metastases from non-small cell lung cancer. AB - PURPOSE: Routine brain MRI surveillance frequently diagnoses small, asymptomatic brain metastases from non-small cell lung cancer (NSCLC) that are effectively treated with stereotactic radiosurgery (SRS). A subset of patients, however, may die prior to the onset of symptoms. This study identifies clinical features that distinguish neurologically-asymptomatic NSCLC brain metastases patients that die prior to routine 3 month follow-up after SRS. METHODS: Retrospective chart review from 2007 to 2017 identified 18 patients with neurologically-asymptomatic NSCLC brain metastases who died < 3 months after SRS. Twenty-eight additional patients meeting criteria and surviving > 6 months after SRS were identified. Clinical factors were examined to determine characteristics correlated with survival using cox proportional hazards and nominal logistic regression models. Logistic regression models using salient factors were trained with 10-fold cross validation and compared to the graded prognostic assessment (GPA) and score index of radiosurgery (SIR) using the AUC from receiver operant characteristic curves. RESULTS: The median survival following SRS was 1.4 and 9.2 months for the < 3 months and > 6 months groups, respectively. Age, number of brain metastases, and Karnofsky performance status were associated with overall survival while gender and interval between primary cancer and first brain metastasis diagnoses were associated with < 3 months and > 6 months survival, respectively. Models using GPA and SIR performed poorly compared to preliminary metrics generated in this study for prognosis of both < 3 months and > 6 months survival. CONCLUSION: Physicians require data to provide high-value, cost-conscious health care. Clinical metrics can screen patients with asymptomatic NSCLC brain metastases likely to die prior to the standard screening interval and observation could be considered. PMID- 30460630 TI - Carnosic acid potentiates the anticancer effect of temozolomide by inducing apoptosis and autophagy in glioma. AB - OBJECTIVE: Malignant glioma is a lethal brain tumor with a low survival rate and poor prognosis. New strategies are urgently needed to augment the chemotherapeutic effects of temozolomide (TMZ), the standard drug in glioma treatment. Carnosic acid (CA) has been reported to have anticancer, antioxidant and anti-infectious properties. In this study, we aimed to investigate the anticancer effects and the underlying mechanisms of CA in combination with TMZ in glioma cancer cells. METHODS: The glioma cancer cells were treated with TMZ, CA, or TMZ + CA. We evaluated cell survival by CCK-8 assay, cell anchorage independent survival by colony formation assay, cell migration by wound-healing assay, cell cycle and cell apoptosis by flow cytometry, and protein expression by western blot. RESULTS: CA enhanced the cytotoxic effect of TMZ in glioma cancer cells. CA enhanced TMZ-induced inhibition of colony formation and cell migration and enhanced TMZ-induced cell cycle arrest and cellular apoptosis. Immunofluorescence suggested that CA in combination with TMZ triggered autophagy. Furthermore, CA promoted TMZ-induced cell cycle arrest and cellular apoptosis by Cyclin B1 inhibition and activation of PARP and Caspase-3, while CA promoted TMZ induced cellular autophagy by p-AKT inhibition, p62 downregulation and LC3-I to LC3-II transition. CONCLUSION: These data suggest that the combination therapy of CA and TMZ strengthens the anticancer effect of TMZ by enhancing apoptosis and autophagy. PMID- 30460629 TI - The impact of traveling distance and hospital volume on post-surgical outcomes for patients with glioblastoma. AB - BACKGROUND: High-volume hospitals are associated with improved outcomes in glioblastoma (GBM). However, the impact of travel burden to high-volume centers is poorly understood. We examined post-operative outcomes between GBM patients that underwent treatment at local, low-volume hospitals with those that traveled long distances to high-volume hospitals. METHODS: The National Cancer Database was queried for GBM patients that underwent surgery (2010-2014). We established two cohorts: patients in the lowest quartile of travel distance and volume (Short travel/Low-Volume: STLV) and patients in the highest quartile of travel and volume (Long-travel/High-Volume: LTHV). Outcomes analyzed were 30-day, 90-day mortality, overall survival, 30-day readmission, and hospital length of stay. RESULTS: Of 35,529 cases, STLV patients (n = 3414) traveled a median of 3 miles (Interquartile range [IQR] 1.8-4.2) to low-volume centers (5 [3-7] annual cases) and LTHV patients (n = 3808) traveled a median of 62 miles [44.1-111.3] to high volume centers (48 [42-71]). LTHV patients were younger, had lower Charlson scores, largely received care at academic centers (84.4% vs 11.9%), were less likely to be minorities (8.1% vs 17.1%) or underinsured (6.9% vs 12.1), and were more likely to receive trimodality therapy (75.6% vs 69.2%; all p < 0.001). On adjusted analysis, LTHV predicted improved overall survival (HR 0.87, p = 0.002), decreased 90-day mortality (OR 0.72, p = 0.019), lower 30-day readmission (OR 0.42, p < 0.001), and shorter hospitalizations (RR 0.79, p < 0.001). CONCLUSIONS: Glioblastoma patients who travel farther to high-volume centers have superior post-operative outcomes compared to patients who receive treatment locally at low volume centers. Strategies that facilitate patient travel to high-volume hospitals may improve outcomes. PMID- 30460631 TI - Characterization of iPSCs derived from low grade gliomas revealed early regional chromosomal amplifications during gliomagenesis. AB - INTRODUCTION: IDH1 mutation has been identified as an early genetic event driving low grade gliomas (LGGs) and it has been proven to exerts a powerful epigenetic effect. Cells containing IDH1 mutation are refractory to epigenetical reprogramming to iPSC induced by expression of Yamanaka transcription factors, a feature that we employed to study early genetic amplifications or deletions in gliomagenesis. METHODS: We made iPSC clones from freshly surgically resected IDH1 mutant LGGs by forced expression of Yamanaka transcription factors. We sequenced the IDH locus and analyzed the genetic composition of multiple iPSC clones by array-based comparative genomic hybridization (aCGH). RESULTS: We hypothesize that the primary cell pool isolated from LGG tumor contains a heterogeneous population consisting tumor cells at various stages of tumor progression including cells with early genetic lesions if any prior to acquisition of IDH1 mutation. Because cells containing IDH1 mutation are refractory to reprogramming, we predict that iPSC clones should originate only from LGG cells without IDH1 mutation, i.e. cells prior to acquisition of IDH1 mutation. As expected, we found that none of the iPSC clones contains IDH1 mutation. Further analysis by aCGH of the iPSC clones reveals that they contain regional chromosomal amplifications which are also present in the primary LGG cells. CONCLUSIONS: These results indicate that there exists a subpopulation of cells harboring gene amplification but without IDH1 mutation in the LGG primary cell pool. Further analysis of TCGA LGG database demonstrates that these regional chromosomal amplifications are also present in some cases of low grade gliomas indicating they are reoccurring lesions in glioma albeit at a low frequency. Taken together, these data suggest that regional chromosomal alterations may exist prior to the acquisition of IDH mutations in at least some cases of LGGs. PMID- 30460632 TI - Neurocognitive function, performance status, and quality of life in pediatric intracranial germ cell tumor survivors. AB - BACKGROUND: Intracranial germ cell tumors (GCT) are more common in Asia than in the West, accounting for about 15% of brain tumors in Asian children. The survival rate for intracranial GCT is excellent, but there are concerns about the effects of radiotherapy on neuropsychological function and quality of life of patients. METHODS: Intracranial germ cell tumors (GCT) are more common in Asia than in the West, accounting for about 15% of brain tumors in Asian children. The survival rate for intracranial GCT is excellent, but there are concerns about the effects of radiotherapy on neuropsychological function and quality of life of patients. Intracranial GCT survivors in Hong Kong aged >= 6 years who received cranial irradiation in the past 15 years were recruited. Neurocognitive function and performance status were assessed by the Hong Kong Wechsler Intelligence scale and Karnofsky/Lansky performance scales (KPS), respectively. Quality of life was assessed using the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales. A chart review was performed for tumor characteristics and complications related to the tumor and its treatment. RESULTS: Twenty-five intracranial GCT survivors were recruited. Longer length of time since treatment was associated with lower IQ scores. Larger tumor size was associated with lower KPS scores. Hemiparesis, poor manual dexterity, and complications with multi-organ involvement were associated with significantly lower KPS scores. Higher irradiation dosage was associated with lower PedsQL physical scores. CONCLUSIONS: The majority of GCT survivors had average intellectual functioning, satisfactory performance status and relatively good quality of life, except in the physical aspect. Comprehensive evaluation and long-term follow-up of GCT survivors are essential to provide timely support and improve long-term outcomes. PMID- 30460633 TI - Transcriptome profiling reveals PDZ binding kinase as a novel biomarker in peritumoral brain zone of glioblastoma. AB - PURPOSE: Peritumoural brain zone (PT) of glioblastoma (GBM) is the area where tumour recurrence is often observed. We aimed to identify differentially regulated genes between tumour core (TC) and PT to understand the underlying molecular characteristics of infiltrating tumour cells in PT. METHODS: 17 each histologically characterised TC and PT tissues of GBM along with eight control tissues were subjected to cDNA Microarray. PT tissues contained 25-30% infiltrating tumour cells. Data was analysed using R Bioconductor software. Shortlisted genes were validated using qRT-PCR. Expression of one selected candidate gene, PDZ Binding Kinase (PBK) was correlated with patient survival, tumour recurrence and functionally characterized in vitro using gene knock-down approach. RESULTS: Unsupervised hierarchical clustering showed that TC and PT have distinct gene expression profiles compared to controls. Further, comparing TC with PT, we observed a significant overlap in gene expression profile in both, despite PT having fewer infiltrating tumour cells. qRT-PCR for 13 selected genes validated the microarray data. Expression of PBK was higher in PT as compared to TC and recurrent when compared to newly diagnosed GBM tumours. PBK knock-down showed a significant reduction in cell proliferation, migration and invasion with increase in sensitivity to radiation and Temozolomide treatment. CONCLUSIONS: We show that several genes of TC are expressed even in PT contributing to the vulnerability of PT for tumour recurrence. PBK is identified as a novel gene up regulated in PT of GBM with a strong role in conferring aggressiveness, including radio-chemoresistance, thus contributing to recurrence in GBM tumours. PMID- 30460634 TI - Infusion of 5-Azacytidine (5-AZA) into the fourth ventricle or resection cavity in children with recurrent posterior Fossa Ependymoma: a pilot clinical trial. AB - BACKGROUND: DNA methylation inhibitors are logical therapeutic candidates for ependymomas originating in the posterior fossa of the brain. Our objective was to test the safety of infusing 5-Azacytidine (5-AZA), a DNA methylation inhibitor, directly into cerebrospinal fluid (CSF) spaces of the fourth ventricle or tumor resection cavity in children with recurrent ependymoma originating in the posterior fossa. MATERIALS AND METHODS: In patients with recurrent ependymoma whose disease originated in the posterior fossa, a maximal safe subtotal tumor resection was performed. At the conclusion of the tumor resection, a catheter was surgically placed into the fourth ventricle or tumor resection cavity and attached to a ventricular access device. CSF flow from the posterior fossa to the sacrum was confirmed by CINE phase contrast magnetic resonance imaging (MRI) postoperatively. 12 consecutive weekly 10 milligram (mg) infusions of 5 Azacytidine (AZA) were planned. Disease response was monitored with MRI scans and CSF cytology. RESULTS: Six patients were enrolled. One patient was withdrawn prior to planned 5-AZA infusions due to surgical complications after tumor resection. The remaining five patients received 8, 12, 12, 12, and 12 infusions, respectively. There were no serious adverse events or new neurological deficits attributed to 5-AZA infusions. All five patients with ependymoma who received 5 AZA infusions had progressive disease. Two of the five patients, however, were noted to have decrease in the size of at least one intraventricular lesion. CONCLUSION: 5-AZA can be infused into the fourth ventricle or posterior fossa tumor resection cavity without causing neurological toxicity. Future studies with higher doses and/or increased dosing frequency are warranted. PMID- 30460635 TI - A need to reduce premature CV mortality in the developing world: How could appropriate use of non-invasive imaging help? AB - We discuss premature deaths due to coronary heart disease (CHD) in developing countries and the importance of a comprehensive approach, involving clinical judgement, prevention, appropriate use of technology to diagnose and guide CHD treatment. Healthcare policies and levels of knowledge vary tremendously resulting heterogeneous utilization of diagnostic strategies and treatments worldwide. Many countries with high mortality have low utilization of non invasive cardiac imaging. Appropriate use coupled with guideline-based management could help to improve care in the developing world and potentially result in better life expectancy already experienced by most high-income countries. In a scenario of increasing costs, a rational utilization of resources is imperative for all nations. A stepwise approach to suspected CHD is necessary, starting from good judgement, adding tests only as needed, preferably filtering patients who might benefit from advanced imaging. In stable patients, non-invasive tests should be used as filters to invasive procedure, preventing stable patients from undergoing revascularizations of questionable benefit. In this article, we review the relative role of exercise testing, myocardial perfusion imaging, and coronary computed tomography angiography to evaluate CHD and how these can be utilized as ways to help guide management that could impact premature mortality in developing nations. PMID- 30460636 TI - Shifting breast attenuation artifact mimicking ischemia: Resolved with attenuation correction. PMID- 30460637 TI - Multimodality imaging: Bird's eye view from The European Society of Cardiology Congress 2018 Munich, August 25-29, 2018. AB - At the European Society of Cardiology (ESC) congress of this year 2018, held in Munich from August 25th to 29th, 4594 abstracts were presented. Of those, 423 (10.8%) belonged to an imaging category. Experts in echocardiography (VD), cardiovascular magnetic resonance (CMR) (CBD), nuclear imaging (OG), and cardiac computed tomography (CT) (PMH) have selected the abstracts in their areas of expertise that were of most interest to them and are summarized in this bird's eye view from this ESC meeting. These abstracts were integrated by one of the Editors of the Journal (JB). PMID- 30460638 TI - Phosphoglycerate Mutase 1 Promotes Cell Proliferation and Neuroblast Differentiation in the Dentate Gyrus by Facilitating the Phosphorylation of cAMP Response Element-Binding Protein. AB - In a previous study, we observed a significant increase in phosphoglycerate mutase 1 (PGAM1) levels after pyridoxine treatment. In the present study, we investigated the effects of PGAM1 on novel object recognition, cell proliferation, and neuroblast differentiation in the dentate gyrus. We generated a Tat-PGAM1 fusion protein to cross the blood-brain barrier and neuronal plasma membrane. We administered the Tat peptide, control-PGAM1, or Tat-PGAM1 fusion protein to 8-week-old mice once a day for 3 weeks and tested novel object recognition memory. The mice were then euthanized to conduct western blot analysis for polyhistidine expression and immunohistochemical analysis for Ki67, doublecortin, and phosphorylated cAMP response element-binding protein. Mice treated with Tat peptide showed similar exploration times for familiar and new objects and the discrimination index was significantly lower in this group than in the control group. Tat-PGAM1 moderately increased the exploration time of new objects when compared to familiar objects, while the discrimination index was significantly higher in the Tat-PGAM1-treated group, but not in the control-PGAM1 treated group, when compared with the control group. Higher PGAM1 protein expression was observed in the hippocampus of Tat-PGAM1-treated mice when compared with the hippocampi of control, Tat peptide-, and control-PGAM1-treated mice, using western blot analysis. In addition, the numbers of proliferating cells and differentiated neuroblasts were significantly lower in the Tat peptide treated group than in the control group. In contrast, the numbers of proliferating cells and differentiated neuroblasts in the dentate gyrus were higher in the Tat-PGAM1-treated group than in the control group. Administration of Tat-PGAM1 significantly facilitated the phosphorylation of cAMP response element-binding protein in the dentate gyrus. Administration of control-PGAM1 did not show any significant effects on novel object recognition, cell proliferation, and neuroblast differentiation in the dentate gyrus. These results suggest that PGAM1 plays a role in cell proliferation and neuroblast differentiation in the dentate gyrus via the phosphorylation of cAMP response element-binding protein in the hippocampus. PMID- 30460639 TI - Food For Thought: Short-Term Fasting Upregulates Glucose Transporters in Neurons and Endothelial Cells, But Not in Astrocytes. AB - Our group previously reported that 6-h fasting increased both insulin II mRNA expression and insulin level in rat hypothalamus. Given that insulin effects on central glucose metabolism are insufficiently understood, we wanted to examine if the centrally produced insulin affects expression and/or regional distribution of glucose transporters, and glycogen stores in the hypothalamus during short-term fasting. In addition to determining the amount of total and activated insulin receptor, glucose transporters, and glycogen, we also studied distribution of insulin receptors and glucose transporters within the hypothalamus. We found that short-term fasting did not affect the astrocytic 45 kDa GLUT1 isoform, but it significantly increased the amount of endothelial 55 kDa GLUT1, and neuronal GLUT3 in the membrane fractions of hypothalamic proteins. The level of GLUT2 whose presence was detected in neurons, ependymocytes and tanycytes was also elevated. Unlike hepatic glycogen which was decreased, hypothalamic glycogen content was not changed after 6-h fasting. Our findings suggest that neurons may be given a priority over astrocytes in terms of glucose supply even during the initial phase of metabolic response to fasting. Namely, increase in glucose influx into the brain extracellular fluid and neurons by increasing the translocation of GLUT1, and GLUT3 in the cell membrane may represent the first line of defense in times of scarcity. The absence of co-localization of these membrane transporters with the activated insulin receptor suggests this process takes place in an insulin-independent manner. PMID- 30460640 TI - Impaired Cerebellar Development in Mice Overexpressing VGF. AB - VGF nerve growth factor inducible (VGF) is a neuropeptide precursor induced by brain-derived neurotrophic factor and nerve growth factor. VGF is increased in the prefrontal cortex and cerebrospinal fluid in schizophrenia patients. In our previous study, VGF-overexpressing mice exhibited schizophrenia-like behaviors and smaller brain weights. Brain developmental abnormality is one cause of mental illness. Research on brain development is important for discovery of pathogenesis of mental disorders. In the present study, we investigated the role of VGF on cerebellar development. We performed a histological analysis with cerebellar sections of adult and postnatal day 3 mice by Nissl staining. To investigate cerebellar development, we performed immunostaining with antibodies of immature and mature granule cell markers. To understand the mechanism underlying these histological changes, we examined MAPK, Wnt, and sonic hedgehog signaling by Western blot. Finally, we performed rotarod and footprint tests using adult mice to investigate motor function. VGF-overexpressing adult mice exhibited smaller cerebellar sagittal section area. In postnatal day 3 mice, a cerebellar sagittal section area reduction of the whole cerebellum and external granule layer and a decrease in the number of mature granule cells were found in VGF-overexpressing mice. Additionally, the number of proliferative granule cell precursors was lower in VGF-overexpressing mice. Phosphorylation of Trk and Erk1 were increased in the cerebellum of postnatal day 3 VGF-overexpressing mice. Adult VGF-overexpressing mice exhibited motor disability. All together, these findings implicate VGF in the development of cerebellar granule cells via promoting MAPK signaling and motor function in the adult stage. PMID- 30460641 TI - Sevoflurane Postconditioning Inhibits Autophagy Through Activation of the Extracellular Signal-Regulated Kinase Cascade, Alleviating Hypoxic-Ischemic Brain Injury in Neonatal Rats. AB - Hypoxic-ischemic brain injury (HIBI) in neonates is one of the major contributors of newborn death and cognitive impairment. Numerous animal studies have demonstrated that autophagy is substantially increased in HIBI and that sevoflurane postconditioning (SPC) can attenuate HIBI. However, if SPC-induced neuroprotection inhibits autophagy in HIBI remains unknown. To investigate if cerebral protection induced by SPC is related to decreased autophagy in the setting of HIBI. Postnatal rats at day 7 (P7) were randomly assigned to 7 different groups: Sham, HIBI, SPC-HIBI, HIBI + rapamycin, SPC-HIBI + rapamycin, HIBI + p-extracellular signal-regulated kinase (p-ERK) inhibitor, and SPC-HIBI + p-ERK inhibitor. To induce HIBI, neonatal rats underwent left common carotid artery ligation, followed by 2 h of hypoxia (8% O2). Rats in the SPC groups were treated with 1 minimum alveolar concentration ([MAC], 2.4%) SPC for 30 min after HIBI induction. Markers of autophagy and expression of ERK cascade components were measured in the rat brains after 24 h. Spatial learning and memory function were examined 29-34 days after administration of an autophagy agonist or a p-ERK inhibitor. The expression of microtubule-associated proteins 1A/1B, light chain 3B II (LC3-II) and tuberous sclerosis complex 2 (TSC2) were decreased in the SPC HIBI group compared to the HIBI group. Expression of the p62 sequestosome 1 (P62/SQSTM1) protein, p-ERK/ERK, phospho-mammalian target of rapamycin (p-mTOR) and phospho-p70S6 were increased in SPC-HIBI group. Rats within the SPC-HIBI groups that also received the p-ERK inhibitor or autophagy inhibitor demonstrated reduced cross platform times and increased escape latency. Approximately 30 min of 2.4% SPC treatment in the P7 rat HIBI model attenuated excessive autophagy in the brain by elevating the ERK cascade. This finding provides additional insight into HIBI and identifies new targets for therapeutic approaches to treat HIBI. PMID- 30460643 TI - Changes in occlusal bite force following placement of preformed metal crowns on primary molars in 4-6 years old children: a 6 months' follow-up pilot study. AB - AIM: To evaluate the occlusal bite force (OBF) changes 6 months after placement of preformed metal crowns PMCs on primary molars in children. METHOD: Twenty-two subjects (aged 5.08 +/- 0.92 years) participated and completed OBF records. Each patient received eight PMCs on their primary molars. OBF was recorded using a battery-operated portable type of OBF gauge at different time intervals: before placement, 1 week-, 1 month-, 2 months-, 3 months-, and 6 months after PMCs placement (T0-T5). A second group consisted of 22 caries-free children matched for age and gender were selected as a control sample and received no dental treatment. OBF was recorded in these subjects at T0 and T5 (6 months after). RESULTS: OBF was reduced the first week after placement of PMCs. However, the OBF was restored and reached its original value at T4. At the 6-month recall visit (T5), maximum occlusal bite force (MOBF) was 148% and 136% of pre-treatment value on right and left sides, respectively. The mean MOBF difference between T5 and T0 was statistically significant (70.83N and 54.67N on the right and left sides respectively, p < 0.000). CONCLUSION: OBF decreased 1 week after placement of PMC restoration and started to increase after 1 month reaching 136-140% of its original value after 6 months. PMID- 30460642 TI - Probing the Dissociation of Protein Complexes by Means of Gas-Phase H/D Exchange Mass Spectrometry. AB - Gas-phase hydrogen/deuterium exchange measured by mass spectrometry (gas-phase HDX-MS) is a fast method to probe the conformation of protein ions. The use of gas-phase HDX-MS to investigate the structure and interactions of protein complexes is however mostly unharnessed. Ionizing proteins under conditions that maximize preservation of their native structure (native MS) enables the study of solution-like conformation for milliseconds after electrospray ionization (ESI), which enables the use of ND3-gas inside the mass spectrometer to rapidly deuterate heteroatom-bound non-amide hydrogens. Here, we explored the utility of gas-phase HDX-MS to examine protein-protein complexes and inform on their binding surface and the structural consequences of gas-phase dissociation. Protein complexes ranging from 24 kDa dimers to 395 kDa 24mers were analyzed by gas-phase HDX-MS with subsequent collision-induced dissociation (CID). The number of exchangeable sites involved in complex formation could, therefore, be estimated. For instance, dimers of cytochrome c or alpha-lactalbumin incorporated less deuterium/subunit than their unbound monomer counterparts, providing a measure of the number of heteroatom-bound side-chain hydrogens involved in complex formation. We furthermore studied if asymmetric charge-partitioning upon dissociation of protein complexes caused intermolecular H/D migration. In larger multimeric protein complexes, the dissociated monomer showed a significant increase in deuterium. This indicates that intermolecular H/D migration occurs as part of the asymmetric partitioning of charge during CID. We discuss several models that may explain this increase deuterium content and find that a model where only deuterium involved in migrating charge can account for most of the deuterium enrichment observed on the ejected monomer. In summary, the deuterium content of the ejected subunit can be used to estimate that of the intact complex with deviations observed for large complexes accounted for by charge migration. Graphical abstract ?. PMID- 30460644 TI - ? PMID- 30460645 TI - Spatiotemporal variation of atmospheric nitrated polycyclic aromatic hydrocarbons in semi-arid and petrochemical industrialized Lanzhou City, Northwest China. AB - Polyurethane foam-based passive air sampler (PUF-PAS) and passive dry deposition sampler (PAS-DD) were adopted, for the first time ever in China, to investigate the atmospheric levels and spatial-temporal distributions of air burdens and dry deposition fluxes of 12 nitrated polycyclic aromatic hydrocarbons (NPAHs) during winter and summer seasons in a multiple site field campaign in a petrochemical industrialized capital city in Northwest China. The results showed that the highest air concentration and dry deposition fluxes of ?12NPAHs occurred at a heavy traffic site among 18 sampling sites in both winter and summer season. The lowest air concentration and dry deposition fluxes were observed at the background site. The mean concentrations of ?12NPAHs in the ambient air were 8.6 +/- 8.1 ng m-3 in winter and 15 +/- 11 ng m-3 in summer. The mean dry deposition fluxes of ?12NPAHs were 1.8 * 103 +/- 1.9 * 103 ng (m2 day)-1 in winter and 1.4 * 103 +/- 1.3 * 103 ng (m2 day)-1 in summer, respectively. The total concentration of 12 NPAHs was mainly dominated by 1-nitro-naphthalene (1N-NAP) and 2-nitro naphthalene(2N-NAP) in air, accounting for 32% in winter and 45% in summer of ?12NPAHs. 7-Nitro-benzo [a] anthracene (7N-BaA) made the largest contribution to dry deposition fluxes of ?12NPAHs, accounting for 28% in winter and 24% in summer. The ratios of ?12NPAHs/?15pPAHs (parent polycyclic aromatic hydrocarbons) were calculated to identify potential sources of NPAHs across the city. The results revealed that the main atmospheric air concentration and dry deposition fluxes of 12 NPAHs could be attributed to the primary emissions in winter and the secondary reaction formation in summer. The sources of primary emissions could be traced back to petrochemical, steel mills, as well as aluminum industries in winter and vehicle exhaust in summer. Higher ?12NPAH/?15pPAH concentration ratios in summer indicated that the oxidation of pPAHs contributed to the secondary formation of NPAHs via atmospheric chemical reactions in this petrochemical industrialized mountain-valley city. PMID- 30460646 TI - Concentrations and emissions of particulate matter and ammonia from extensive livestock farm in South China. AB - Atmospheric particulate matter (PM) and ammonia pollution from livestock feeding have gradually become the environmental concerns due to the spring up of livestock farms in worldwide. However, researches about the formation of atmospheric particulate matter related to ammonia are still limited. Therefore, a study to survey the total suspended particles (TSP), PM with the diameter less than 10 MUm (PM10), PM4, PM2.5, PM1, and ammonia was conducted at four types of hog houses distinguished by its building design as well as manure handling methods in South China. Four hog houses were monitored during three fattening periods from 2016 to 2017. The emissions of NH3 per hog house averaged 210.42 MUg s-1. The emissions of PM per hog house averaged 2.017 MUg h-1 for PM1, 2.149 MUg h-1 for PM2.5, 2.305 MUg h-1 for PM4, 3.950 MUg h-1 for PM10, and 9.317 MUg h-1 for TSP. The emissions of PM per hog house average 2.017 MUg h-1, 2.149 MUg h-1, 2.305 MUg h-1, 3.950 MUg h-1, and 9.317 MUg h-1, respectively for PM1, PM2.5, PM4, PM10, and PM10. In each hog house, while the quantity of manure determined the concentration of NH3, biological fermentation bed was able to control the ammonia volatilization compared with other three manure handling methods. The largest percentage of fine PM (< 10 MUm) is produced by the manual waterless method for manure handling. When it came to the manual waterless method, largest amount of fine PM (< 10 MUm) was founded to form. Among various contributions of secondary inorganic PM to PM1, the NH3 was a dominant factor. Based on our experiment, the absolute concentration of NH3 was inversely proportional to the concentration of PM1 when the background influence was removed. PMID- 30460647 TI - Fabrication of phosphonium bamboo cellulose by triphenylphosphine: preparation, characterization, and adsorption of Acid Black 24. AB - Cellulose from bamboo shavings (BC) separated and modified by grafting triphenylphosphine, which was used as an adsorbent for the removal of Acid Black 24 from aqueous solution. The quaternary phosphonium-based bamboo cellulose (PBC) was characterized by FTIR and SEM measurements. The FTIR studies showed that the quaternary phosphonium group was successfully grafted onto the BC molecular structure. The effects of PBC dosage, contact time, initial dye concentration, temperature, and pH on the adsorption performance were studied. The nonlinear fitting kinetics and isotherms models were also conducted. The pseudo-second order, intra-particle diffusion and Langmuir models were more suitable for analyzing the adsorption behavior of PBC for Acid Black 24 dye. The adsorption activation energy was lower than 40 kJ mol-1, and the DeltaH0 value was in the range of 20~80 kJ mol-1, indicating that PBC played a dominant role in the physical purification of dye. The results of thermodynamic analysis indicated that the adsorption was a spontaneous endothermic purification process. Adsorbents had a good reusability and high adsorption performance for dye removal. The adsorbents PBC had a good reusability and could effectively remove residual Acid Black 24 dye with good development prospects in the field of biomass adsorbent materials. PMID- 30460649 TI - An insight into the cytotoxicity, genotoxicity, and mutagenicity of smoked cigarette butt leachate by using Allium cepa as test system. AB - Smoked cigarette butt (SCB) discharged in the environment became an issue of unknown consequences for plants. Thus, we aim at assessing the impact of water containing SBC leachate on the meristem cells of Allium cepa roots. We defined the following experimental groups: negative control (water), positive control (cyclophosphamide); water with SCB leachate at environmental concentration (1.9 MUg/L of nicotine) (EC1* group) and water with SCB leachate concentration 1000 times higher than EC1 (EC1000* group). Mitotic index, total number of abnormal cells, index of abnormal cells per mitotic/phase, relative growth index, and inhibition index were calculated after 48 exposure hours. Root meristems were used to prepare slides in order to investigate chromosomal and nuclear abnormalities. According to our data, plants exposed to SCB leachate presented low relative growth index, high inhibition index, large number of abnormal cells, and high abnormality frequency at metaphase/anaphase. The exposed A. cepa recorded a wide variety of abnormalities such as diagonal metaphase/anaphase, metaphase/anaphase presenting chromosome fragments, binucleated cells, displaced nucleus, chromosome bridges, micronuclei, necrotic cells, stick metaphase, chromosome adherence, notched nucleus, among other cell disturbances. The chemicals in the SBC leachate had aneugenic and clastogenic effect on the genetic material of the tested plants, either when they acted individually, synergistically, or additively. Thus, our study is a pioneer in reporting that the mere disposal of cigarette butts in the environment can have cytotoxic, genotoxic, and mutagenic effects on plants. PMID- 30460648 TI - Evaluation of hematological, biochemical parameters and thiol enzyme activity in chrome plating workers. AB - The most commonly used solution in chrome plating bath is chromic acid (hexavalent Cr), and a considerable amount of mists is released into the air and consequently produce hazards to workers. Thus, the aim of this study was to evaluate whether the biomarker of exposure to metals, specially Cr levels, presents associations with hematological and biochemical parameters and if they can alter the activity of enzymes that contain thiol groups such as pyruvate kinase, creatine kinase, adenylate kinase, and delta-aminolevulinate dehydratase. Fifty male chrome plating workers were used for exposed group and 50 male non exposed workers for control group. For that, biological monitoring was performed through quantification of metals on total blood and urine by inductively coupled plasma mass spectrometry (ICP-MS) and enzyme activity was performed by spectrometry in erythrocytes. In addition, chromium levels in water was quantified and ecotoxicology assay was performed with Allium cepa test. The results demonstrated that blood and urinary chromium levels in exposed group were higher than the control group (p < 0.0001). Furthermore, decreased activity of enzymes was found in those that contain thiol groups from exposed group when compared with the control group (p < 0.001). The water analysis did not present a statistical difference between control and exposed groups (p > 0.05), demonstrating that water did not seem to be the source of contamination. In summary, our findings indicated some toxicology effects observed in the exposed group, such as thiol enzyme inhibition, mainly associated with occupational exposure in chrome plating and besides the presence of other metals, and Cr demonstrated to influence the activity of the enzymes analyzed in this research. PMID- 30460650 TI - PM2.5 mapping using integrated geographically temporally weighted regression (GTWR) and random sample consensus (RANSAC) models. AB - An uncertainty in the relationship between aerosol optical depth (AOD) and fine particulate matter (PM2.5) comes from the uncertainty of AOD by aerosol models and the estimated surface reflectance, a mismatch in spatiotemporal resolution, integration of AOD and PM2.5 data, and data modeling. In this study, an integrated geographically temporally weighted regression (GTWR) and RANdom SAmple Consensus (RANSAC) models, which provide fine goodness-of-fit between observed PM2.5 and AOD data, were used for mapping of PM2.5 over Taiwan for the year 2014. For this, dark target (DT) AOD observations at 3-km resolution (DT3K) only for high-quality assurance flag (QA = 3) were obtained from the scientific data set (SDS) "Optical_Depth_Land_And_Ocean". AOD observations were also obtained from the merged DT and DB (deep blue) product (DTB3K) which was generated using the simplified merge scheme (SMS), i.e., using an average of the DT and DB highest quality AOD retrievals or the available one. The GTWR model integrated with RANSAC can use the effective sampling and fitting to overcome the estimation problem of AOD-PM2.5 with the uncertainty and outliers of observation data. Results showed that the model dealing with spatiotemporal heterogeneity and uncertainty is a powerful tool to infer patterns of PM2.5 from a RANSAC subset samples. Moreover, spatial variability and hotspot analysis were applied after PM2.5 mapping. The hotspot and spatial variability of PM2.5 maps can give us a summary of the spatiotemporal patterns of PM2.5 variations. PMID- 30460651 TI - The size-dependent genotoxicity and oxidative stress of silica nanoparticles on endothelial cells. AB - Concerns over the health risk of the widely distributed, commonly used silica nanoparticles (SiNPs) are increasing worldwide. Yet, up to now, there are still many major knowledge gaps over the potential adverse effects of SiNP exposure on human cardiovascular health and the underlying mechanisms. In this study, comet assay and micronucleus test were employed to determine the genotoxic potentials of four sizes (10, 25, 50, 100 nm) of SiNPs to human umbilical vein endothelial cells (HUVECs) in culture. The intracellular redox statuses were explored through the determination of the levels of reactive oxygen species (ROS) and reduced glutathione (GSH) with kits, respectively. The protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) were also detected by Western blot. The results showed that at the administrative levels (1, 5, 25 MUg/mL), all the four sizes of SiNPs could induce an increase of both DNA damages and MN frequencies in HUVECs in culture, with a positive dose- and negative size-dependent effect relationship (S100 < S50 < S25 < S10). Also, significantly enhanced levels of intracellular ROS, but decreased levels of GSH, were observed in the SiNP-treated groups. Interestingly, a very similar manner of dose- and size-dependent effect relationship was observed between the ROS test and both comet assay and MN test, but contrary to that of GSH assay. Correspondingly, the levels of Nrf2 protein were also enhanced in the SiNP-treated HUVECs, with a negative size-dependent effect relationship. These results implicated that induction of oxidative stress and subsequent genotoxicity may be an important biological mechanism by which SiNP exposure may affect human cardiovascular health. PMID- 30460652 TI - Candy consumption may add to the body burden of lead and cadmium of children in Nigeria. AB - The affordability of candies and chocolates makes their consumption common especially in children. Heavy metal contamination of these candies is well known. This study has estimated health risks associated with heavy metals (HM; Pb, Cd, Cr, Ni, and Zn) in commonly consumed candies in Nigeria. Fifty candies/sweets and chocolates/chewing gums bought from different stores in Port Harcourt and Uyo in Niger Delta, Nigeria, were processed and digested in perchloric acid. The filtrate was analyzed for these heavy metals using atomic absorption spectroscopy (AAS). Pb/Zn and Cd/Zn ratios were calculated. Daily intake, the target hazard quotient (THQ), the hazard index (HI), and the cancer risk were estimated for children. About 80% of the samples exceeded the 0.1 mg/kg permissible lead level in candies. Milk sweet had the highest Pb:Zn and Cd:Zn ratios of 0.99 and 0.40 respectively. For chocolates, the Emperor had the highest Pb:Zn (0.50) ratios and Trident had the highest Cd:Zn (0.57) ratios. The calculated percentage provisional tolerable weekly intake (%PTWI) of cadmium from consumption of chocolates and candies was higher than the Joint Expert Committee for Food Additives (JECFA) standard, and the cancer risk of lead, cadmium, and chromium ranged between 10-7 and 10-3. Consumption of some candies by children in Nigeria may pose significant health risks. PMID- 30460653 TI - A study of "cancer villages" in Jiangsu Province of China. AB - China's economic boom has created many environmental and health challenges, including so-called cancer villages. This study, the first to use the lens of "cancer villages" at provincial level, examines the correlation between changes in Jiangsu cancer villages and economic and environmental quality indicators identified as being relevant, and hence to highlight environmental issues that should be mitigated to protect public health. Since 2001, 25 cancer villages have been reported in Jiangsu. The distribution pattern of these villages is of a cluster whose mean centre had moved from Suzhou city in 2001 to Taizhou in 2006 and 2011. By applying the buffer analysis tool of ArcGIS10.2.2 using 3-km and 5 km radius buffer, to examine the relationship between these cancer villages and the surrounding rivers, it was revealed that 76% of the villages fall within the 3-km buffer zone, and 88% are within the 5-km buffer zone. A fairly strong correlation between the cancer villages and annual GDP, as well as pollutant discharge, was found, with correlation coefficients of 0.94 for Jiangsu, 0.89 for Northern Jiangsu, 0.93 for Central Jiangsu, 0.83 for Southern Jiangsu and 0.64 for city level. The change of newly added cancer villages is significantly influenced by the discharge of sewage water (raising COD) and SO2, and the peak of newly added cancer villages, as well as discharge of COD and SO2 all occurred in 2005. For four cities, the total sewage water discharge and SO2 emissions are consistent with the order of the distribution density of the villages. The phenomenon of cancer villages in China will gradually be resolved as the government takes effective measures to tackle environmental issues coupled with people's increasing environmental and health awareness. PMID- 30460654 TI - Relationship between cadmium content in semen and male infertility: a meta analysis. AB - Meta-analysis with high-quality studies can provide superior evidence. In this paper, we use meta-analysis to analyze the relationship between cadmium (Cd) content in semen and male infertility, and then objectively evaluate the effect of Cd on sperm quality. The objectives of this study were to update our understanding of infertility and to provide evidence to treat and prevent the infertility. We searched potentially relevant studies that were published from establishing database data to April 2018. Articles came from the databases of CNKI, Wanfang, VIP, PubMed, CMCI, and EMBASE. A total of 11 articles were included. We gathered the mean and variance of the infertility group and the control group to compare the Cd content in two groups. In total, the 11 studies include 1707 subjects, 1093 of which were in the infertility group and 614 of which were in the control group. We can get some information from this meta analysis: SMD = 0.50 (95% Cl 0.39-0.61), Z = 8.92, P < 0.05; the funnel plot of the meta-analysis shows incomplete symmetry, which may have the publication bias. Therefore, the high content of Cd in semen is a causative factor of infertility. The Cd content in semen can be used as an indicator of sperm quality. PMID- 30460655 TI - Novel approach for controlling resistant Listeria monocytogenes to antimicrobials using different disinfectants types loaded on silver nanoparticles (AgNPs). AB - A combined use of silver nanoparticles (AgNPs) with different types of disinfectants as antimicrobial might be useful in mitigating the problem of development of bacterial resistance with a strong enhancement of the biocidal effect of disinfectants. To evaluate the biocidal activity of silver nanoparticles and its loaded forms, five commercial disinfectants (quaternary ammonium compounds (benzalkonium chloride (BC) and TH4+), Virkon(r)S, sodium hypochlorite, and hydrogen peroxide (H2O2)) were used against Listeria monocytogenes (L. monocytogenes) isolates at different concentrations and exposure times to reveal intra-species variability and the percentage of resistance to antimicrobial agents used. Therefore, a total of 260 specimens from animal and human stool as well as environmental samples from dairy cattle farms were cultured for isolation of L. monocytogenes. Thereafter, bacterial isolates were identified using PCR. Silver nanoparticle was synthesized using chemical reduction. Both silver nanoparticles and its loaded forms were characterized by transmission electron microscopy (TEM). The sensitivity test of 60 strains of L. monocytogenes bacteria to AgNPs and its loaded forms was evaluated using broth macrodilution method. Virkon(r)S/AgNPs 2.0% exhibited the highest bactericidal effect (100%) against L. monocytogenes strains followed by H2O2/AgNPs 5.0% and TH4+/AgNPs 1.0% (90% each). Furthermore, the percentage of resistance of L. monocytogenes was 0.0% to both H2O2/AgNPs 5.0% and Virkon(r)S/AgNPs 2.0%. In conclusion, monitoring the main source of contamination with Listeria monocytogenes in dairy cattle farms is an essential factor to achieve an efficient control. Moreover, the use of the disinfectants, Virkon(r)S 2.0%, H2O2 5.0%, and TH4+1.0%, loaded on silver nanoparticles composite had the strong bactericidal effect against L. monocytogenes. PMID- 30460656 TI - Insights into the effect of chemical treatment on the physicochemical characteristics and adsorption behavior of pig manure-derived biochars. AB - Chemical treatment could improve the adsorption performance of biochars (BC). In order to deal with Pb(II) pollution, four types of biochars including unmodified, acid-treated, alkali-treated, and magnetic-treated pig manure-derived biochars (PBCs) were prepared. The effect of chemical treatment on the physical property, chemical composition, and the adsorption behavior of biochars was compared. Magnetic and alkali treatment improved pore volume and specific surface areas, and the adsorption capacity and rates were enhanced. In contrast, the adsorption capacity of acid-treated BC decreased due to the significant decrease of ash content. The magnetic samples displayed the satisfactory absorption performance, which could achieve 99.8% removal efficiency within 15 min at a Pb(II) concentration of 50 mg/L. Considering its properties of excellent adsorption performance, fast reaction rate, and convenient recovery by an external magnetic field, magnetic biochar based on pig manure may provide an effective way to remove heavy metals and decrease the pig manure solid waste. PMID- 30460657 TI - Effects of in vivo exposure to tritium: a multi-biomarker approach using the fathead minnow, Pimephales promelas. AB - Tritium (3H) is a radioactive isotope of hydrogen. In the environment, the most common form of tritium is tritiated water (HTO). However, tritium can also be incorporated into organic molecules, forming organically bound tritium (OBT). The present study characterized the effects of tritium on the health of the fathead minnow, Pimephales promelas. Fish were exposed to a gradient of HTO (activity concentrations of 12,000, 25,000, and 180,000 Bq/L) and OBT using food spiked with tritiated amino acids (OBT only, with an activity concentration of 27,000 Bq/L). A combined exposure condition where fish were placed in 25,000 Bq/L water and received OBT through feed was also studied. Fish were exposed for 60 days, followed by a 60-day depuration period. A battery of health biomarkers were measured in fish tissues at seven time points throughout the 120 days required to complete the exposure and depuration phases. HTO and OBT were also measured in fish tissues at the same time points. Results showed effects of increasing tritium activity concentrations in water after 60 days of exposure. The internal dose rates of tritium, estimated from the tissue free-water tritium (TFWT) and OBT activity concentrations, reached a maximum of 0.65 MUGy/h, which is relatively low considering background levels. No effects were observed on survival, fish condition, and metabolic indices (gonado-, hepato-, and spleno somatic indexes (GSI, HSI, SSI), RNA/DNA and proteins/DNA ratios). Multivariate analyses showed that several biomarkers (DNA damages, micronucleus frequency, brain acetylcholinesterase, lysosomal membrane integrity, phagocytosis activity, and reactive oxygen species production) were exclusively correlated with fish tritium internal dose rate, showing that tritium induced genotoxicity, as well as neural and immune responses. The results were compared with another study on the same fish species where fish were exposed to tritium and other contaminants in natural environments. Together with the field study, the present work provides useful data to identify biomarkers for tritium exposure and better understand modes of action of tritium on the fathead minnow. PMID- 30460658 TI - Effect of tea plantation age on the distribution of glomalin-related soil protein in soil water-stable aggregates in southwestern China. AB - Glomalin-related soil protein (GRSP) is crucial for the accumulation of soil organic carbon (SOC), and contributes to the formation of soil aggregates. However, it remains unclear whether GRSP is involved in altering the stability of soil aggregates in the long-term tea planting process. The relationship between the distribution of GRSP and soil aggregates in tea plantations is poorly studied. We compared the distribution of SOC and GRSP in aggregates in tea plantations of different ages (18, 25, 33, and 55 years) and those in an abandoned land and investigated their potential contribution to the soil aggregate stability. Tea plantation was found to be beneficial for the accumulation of SOC and GRSP compared to the abandoned land. The content of SOC significantly increased after tea plantation, especially in surface soil (0-20 cm), and the increase range was 21.79%-46.51%, due to the centralized management of tea plantations. The content of total glomalin-related soil protein (T-GRSP) and easily extractable glomalin-related soil protein (EE-GRSP) varied with the increasing tea plantation age. The T-GRSP content was higher in 25-year-old tea plantation, while EE-GRSP was gradually decreased with the increasing age of the tea plantation, and T-GRSP had better correlation with SOC than EE-GRSP. Long term tea plantation (after 33 years) was not conducive to the preservation of GRSP. The distribution of GRSP in the tea plantation soils differed greatly among the aggregates, with the 0.25-1-mm aggregate having less GRSP, which might be related to the distribution of soil fungi in the aggregates. There was a significant correlation between T-GRSP and mean weight diameter (MWD; P < 0.05) in the whole soil, whereas EE-GRSP had no correlation with the MWD of the aggregates. The T-GRSP content was correlated closely with the stability of soil aggregates in the tea plantations, and their relationship was dependent on the aggregate scale. Our results show that the T-GRSP content in the tea plantation soils has important effects on the formation and stability of aggregates in this region, which was one of the factors affecting the structure and quality of tea plantation soil. Improving GRSP is an effective way for the both SOC sequestration and soil health after long-term tea plantation. PMID- 30460659 TI - Efficiency of rice husk ash to adsorb chromium(VI) using the Allium cepa toxicity test. AB - Adsorption is widely used in the treatment of effluents and contaminated water. However, the removal of the pollutant alone does not ensure that the effluent can be safely discharged in the environment. Controlling effluent toxicity may become an important tool to ensure that the quality of the treated effluent is compatible with that of the receiving water body. In this sense, this study evaluated the efficiency of rice husk ash (RHA) to adsorb chromium(VI) using the Allium cepa toxicity test. Adsorption was assessed based on the variables adsorption time, initial concentration, and pH. The data obtained were fitted the pseudo-second-order and the pseudo-first-order models, and the Langmuir and Freundlich isotherms. Kinetic analysis indicated removal rates between 43 and 100%. All data were best fitted by the pseudo-second-order model. Also, pH 1 and pH 2 data were best fitted by the Freundlich and Langmuir isotherms, respectively. In the Allium cepa test, pH 2 solutions were toxic. At pH 7, the Alium cepa test confirmed the efficiency of chromium(VI) adsorption by RHA, ensuring acceptable germination index values. PMID- 30460660 TI - Levels of organochlorine pesticide residues in fresh water fishes of three bird sanctuaries in Tamil Nadu, India. AB - Organochlorine pesticide (OCP) residues were determined in nine species of fresh water fishes caught from three bird sanctuaries in Tamil Nadu, India. A total of 302 fishes were analyzed for various types of OCPS. OCPs, namely hexachlorocyclohexane (HCH), dichloro diphenyl trichloroethane (DDT), heptachlor epoxide, endosulfan, and dieldrin were detected among various species of fishes. Among the various OCPs analyzed, HCH was the most frequently detected pesticides. Among the HCH isomers, beta HCH contributed more than 50% to the Sigma HCH. p,p' DDT, the metabolites of DDT, had high percentage of occurrence. Among the cyclodiene insecticide residues, endosulfan was detected in more than 60% of the fishes. Varying levels of SigmaOCPs (a sum of Sigma HCH, Sigma DDT, Sigma endosulfan, heptachlor epoxide, and dieldrin) were detected in various fish species, although it was not significant (p > 0.05). However, significant variations in OCPs were observed among location and between seasons (p < 0.05). However, continuous monitoring is recommended to facilitate the early identification of risks not only to the fishes, but also to fish-eating birds breeding in these sanctuaries. PMID- 30460661 TI - Correction to: China's provincial CO2 emissions and interprovincial transfer caused by investment demand. AB - The original publication of this paper contains a mistake. The correct image of figure 4 is shown in this paper. The original article has been corrected. PMID- 30460662 TI - Impact of Age, Comorbidity, and FIGO Stage on Treatment Choice and Mortality in Older Danish Patients with Gynecological Cancer: A Retrospective Register-Based Cohort Study. AB - BACKGROUND: The number of older patients with cancer is increasing in general, and ovarian and endometrial cancer are to a large extent cancers of the elderly. Older patients with cancer have a high prevalence of comorbidity. Comorbidity and age may be predictive of treatment choice and mortality in older patients with cancer along with stage and performance status. OBJECTIVES: The aim of this study was to describe comorbidity in a population of older Danish patients with gynecological cancer, and to evaluate the predictive value of comorbidity and age on treatment choice and cancer-specific and all-cause mortality. MATERIALS AND METHODS: In this retrospective study, we included 459 patients aged >= 70 years. Patients were diagnosed with cervical, endometrial, or ovarian cancer from 1 January, 2007 to 31 December, 2011 and were evaluated and/or treated at Odense University Hospital. Comorbidity was assessed using the Charlson Comorbidity Index. Treatment was classified as curative intended, palliative intended, or no treatment. RESULTS: Age, International Federation of Gynecology and Obstetrics (FIGO) stage, and performance status were found to be significant predictors of treatment choice, while comorbidity was not. Multivariate analyses showed that both cancer-specific and all-cause mortality were significantly associated with treatment choice, FIGO stage, and performance status. Age was not associated with mortality, with the exception of ovarian cancer, where age was associated with all-cause mortality. Comorbidity was not an independent predictor of treatment choice or mortality. CONCLUSIONS: In our population of older Danish patients with gynecological cancer, age, FIGO stage, and performance status were predictors of treatment choice, while comorbidity was not. Treatment choice, FIGO stage, and performance status were significantly associated with both cancer-specific and all-cause mortality. Age was only associated with mortality in ovarian cancer, while comorbidity was not associated with mortality. PMID- 30460663 TI - A method for obtaining three-dimensional measurements of HDR brachytherapy dose distributions using Fricke gel dosimeters and optical computed tomography. AB - This study aimed to develop a method for performing accurate, high-resolution, three-dimensional (3D) Fricke gel dosimetry measurements of high dose rate (HDR) brachytherapy dose distributions using optical computed tomography (CT). A multi needle brachytherapy gel phantom was purpose-built to contain four stainless steel brachytherapy needles and a sample of Fricke Xylenol gel. A Paris-style HDR brachytherapy treatment was planned and delivered to the gel, which was then read out using a novel optical CT scanning method; all the brachytherapy needles were removed prior to scanning and replaced with a refractive index matched fluid. The removal of the stainless-steel needles during pre- and post-irradiation scanning minimised the potential for artefacts caused by missing ray-sum data. Results showed good agreement between measured and calculated doses (within 1%) at all positions greater than 0.1 cm from each needle. This study demonstrated that 3D Fricke gel phantoms may be valuable tools in verifying HDR brachytherapy treatments. The phantom construction and optical CT scanning method proposed in this work has the potential to enable routine quality assurance measurements of complex HDR brachytherapy treatment deliveries via accurate and detailed three dimensional dose measurements. PMID- 30460664 TI - Dual Unsafe Injection and Sexual Behaviors for HIV Infection Among People Who Inject Drugs in Iran. AB - We used two national surveys (2010: N = 1597; 2013: N = 1057) of people who inject drugs (PWID) in past-month to assess the prevalence and population size of PWID with either safe or unsafe injection and sex behaviors, overall and by HIV status. In 2013, only 27.0% (vs. 32.3% in 2010) had safe injection and sex, 24.6% (vs. 23.3% in 2010) had unsafe injection and sex, 26.4% (vs. 26.5% in 2010) had only unsafe injection, and 22.0% (vs. 18.0% in 2010) had unsafe sex only. Among HIV-positive PWID in 2013, only 22.1% (~ 2200 persons) had safe injection and sex, 14.2% (~ 1400 persons) had unsafe injection and sex, 53.1% (~ 5200 persons) had unsafe injection, and 10.6% had unsafe sex (~ 1100 persons). Among HIV negative PWID in 2013, only 27.5% (~ 22,200 persons) had safe injection and sex, 25.9% (~ 20,900 PWID) had unsafe injection and sex, 23.2% (~ 18,700 persons) had unsafe injection, and 23.3% (~ 18,800 persons) had unsafe sex. HIV-positive and negative PWID in Iran continue to be at risk of HIV acquisition or transmission which calls for targeted preventions services. PMID- 30460665 TI - Clinical outcomes of high-pressure balloon angioplasty for common femoral artery disease in contemporary practice. AB - In recent years, improvements in endovascular equipment and the technical skills of operators have led to an increasing number of percutaneous common femoral artery (CFA) interventions. However, there are few reports of the detailed treatment strategy for CFA intervention and its subsequent clinical outcomes. We evaluated the safety and efficacy of endovascular therapy (EVT) with a high pressure balloon for CFA disease. Fifty-five consecutive patients (59 lesions) who underwent EVT with high-pressure ballooning were analyzed retrospectively. The primary endpoint was clinically driven target lesion revascularization (TLR). The median follow-up was 34.0 months. The mean age was 68.0 +/- 10.1 years, and 70.1% were men. The procedural success rate was 98.3%. All patients underwent high-pressure balloon angioplasty (mean pressure 17.7 atm). Clinically driven TLR free rates at 2, 3, and 4 years were 88.7%, 77.9%, and 74.2%, respectively. Endovascular interventions with high-pressure ballooning for CFA showed an acceptable mid-term freedom rate from TLR. PMID- 30460667 TI - Noli me tangere: how to defibrillate without touching the heart. PMID- 30460666 TI - Evaluation of the cut-off value for the instantaneous wave-free ratio of patients with aortic valve stenosis. AB - The aim of this study was to examine the clinical value of iFR for AS patients. Functional evaluation of coronary stenosis in patients with aortic valve stenosis (AS) is challenging because the stress-induced test is often thought to be a contraindication. AS patients have a unique coronary flow pattern dependent on the diastolic phase. The instantaneous wave-free ratio (iFR) is a vasodilator free, invasive pressure wire index of the functional severity of coronary stenosis and is calculated under resting conditions. And iFR calculated during a specific period of diastole may have the potential benefit to assess the functional severity of coronary stenosis in AS patients. We examined 158 consecutive patients (217 stenoses) whose iFR and fractional flow reserve (FFR) were measured simultaneously. Among the 158 patients, AS was observed in 13 (8.2%). The iFR showed good correlation with FFR in AS patients. The best cut-off value of iFR for the receiver-operator curve analysis to predict FFR of 0.8 was 0.9 for non-AS patients. However, it was 0.73 for AS patients. The present study demonstrated good correlation between iFR and FFR for AS patients. Vasodilator free assessment using iFR may provide potential benefits when evaluating coronary stenosis in patients with AS. In AS patients, the best cut-off of iFR value predicting FFR value of 0.8 was lower than 0.9 that is the standard predictive value of iFR. PMID- 30460668 TI - Socioeconomic status, cardiovascular disease and health care services: highlighting the gender gap. PMID- 30460669 TI - Stent delivery failure: a new indication for rotational atherectomy? PMID- 30460670 TI - Multiple fusiform cerebral aneurysms detected after atrial myxoma resection: a report of two cases. AB - N/A. PMID- 30460671 TI - Cryoablation of pulmonary veins for the treatment of paroxysmal atrial fibrillation coexisting with isolated persistent left superior vena cava. PMID- 30460672 TI - A cautionary tale of carotid sinus massage for narrow QRS tachycardia. PMID- 30460673 TI - Complication of transvenous lead extraction: migration of the broken helix of an implantable cardioverter-defibrillator lead to the hepatic vein. PMID- 30460674 TI - Echocardiographic guidance of pulmonary vein isolation catheter ablation procedure for recurrent atrial fibrillation in partial cor triatriatum. PMID- 30460675 TI - Rotational atherectomy in everyday clinical practice. Association of Cardiovascular Interventions of the Polish Society of Cardiology (Asocjacja Interwencji Sercowo-Naczyniowych Polskiego Towarzystwa Kardiologicznego - AISN PTK): Expert opinion. AB - The common use of stents, including antiproliferative drug-eluting stents, has been a major breakthrough in invasive cardiology. Nowadays, a change in the clinical presentation of patients treated with percutaneous coronary intervention (PCI) is observed. The typical clinical characteristics now include advanced age, diabetes, chronic kidney disease, heart failure, and multilevel atherosclerosis. Age, diabetes, and chronic kidney disease are the main predictors of coronary artery calcifications. Severe coronary artery calcifications are the main factor limiting the efficacy of PCI. Successful stent implantation is challenging in the presence of calcifications, because it is difficult to achieve full stent expansion and proper stent apposition. Therefore, it is necessary to adequately prepare the lesion before stent implantation. This document presents the technique of rotational atherectomy (rotablation) as well as indications for and contraindications to the procedure, along with its possible complications and their prevention. Training in rotablation for operators as well as reimbursement policy for the procedure in Poland are also discussed. PMID- 30460676 TI - In vitro fermentation of oligosaccharides obtained from enzymatic hydrolysis of Opuntia streptacantha mucilage. AB - BACKGROUND: Among Cactaceae, the genus Opuntia is widely known for the use of its biomass as cattle fodder and in human nutrition (for example, species such as O. ficus indica and O. streptacantha). In particular, O. streptacantha (OS) produces abundant mucilage, and hence, characterization of its properties and nutritional value is important. Therefore, determination of the dietary fiber content of the OS mucilage and the fermentability of its hydrolysis products (oligosaccharides, OLI) is important for developing new uses of the crop as a functional food. RESULTS: The values for insoluble dietary fiber (IDF) and soluble dietary fiber (SDF) in the mucilage were 204.6 g kg-1 and 371.6 g kg-1 , respectively. After hydrolysis of OS mucilage with alpha-amylase, three purified fractions of OLI were evaluated (OLI-A, OLI-B, and OLI-C). OLI (1% w/v) stimulated the growth of the commercial probiotic strains (Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium animalis subsp. lactis) in vitro, showing behaviors similar to those of commercial inulin. The production of short chain fatty acids (SCFAs) in the fermentation broth was also determined. The final pH of the fermentation broth as well as the identification and concentrations of SCFA depended on the type of OLI and probiotic used. CONCLUSION: The OS mucilage is an unconventional fiber source and can be used to produce non-digestible oligosaccharides (NDO) as functional compounds. This knowledge will be useful for proposing new sustainable ways of processing cacti crops for food and industrial purposes. This article is protected by copyright. All rights reserved. PMID- 30460677 TI - Spontaneous remission in a Diamond-Blackfan anaemia patient due to a revertant uniparental disomy ablating a de novo RPS19 mutation. PMID- 30460678 TI - A novel nonsense homozygous variant in the NLGN1 gene found in a pair of monozygotic twin brothers with intellectual disability and autism. PMID- 30460680 TI - Detailed molecular analysis and evaluation of prognosis in cases with high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements. PMID- 30460679 TI - Paternal methyl donor deficient diets during development affect male offspring behavior and memory-related gene expression in mice. AB - It has become increasingly evident that the methylation of DNA, known as an epigenetic marker, affects behavior in animals. In our previous study, a methyl donors (folate, methionine, and choline)-deficient (FMCD) diet during the juvenile period could be shown to affect anxiety-like behavior and fear memory, accompanied by alteration in some gene expression and their methylations in the hippocampus. One question is whether the fear memory of a parent affects the fear responses of offspring. To explore this question in the present study, C57BL/6 J male (F0) mice were given a FMCD diet from 3 to 12 weeks of age. After confirming the effect of the FMCD diet on the behavior and gene expression of F0 mice, their male offspring (F1-FMCD mice) were examined using the same behavioral batteries and genetic analysis. F0 diet-based differences in F1 behavior were observed, accompanied by the differences in the expression of memory-related genes (Camk2alpha and PP1) and promoter methylation of the PP1 gene in the hippocampus. Our results add evidence that behavior and gene expression of the F1 generation could be altered due to differences in the father's intake of methyl-donor nutrients. PMID- 30460681 TI - Interchangeability of Generics-Experiences and Outlook Toward Pharmacokinetics Variability and Generic-Generic Substitution. PMID- 30460682 TI - Low risk of Pneumocystis jirovecii pneumonia and invasive aspergillosis in patients with Waldenstrom macroglobulinaemia on ibrutinib. PMID- 30460683 TI - Global Challenges in Regulatory Capacity and Capability Building: Extrapolating Lessons Learned From the HSA. PMID- 30460684 TI - Phase 2 study of all-oral ixazomib, cyclophosphamide and low-dose dexamethasone for relapsed/refractory multiple myeloma. AB - There is a need for efficacious, convenient treatments with long-term tolerability for patients with relapsed/refractory multiple myeloma (RRMM). This phase 2 study evaluated the all-oral combination of ixazomib, cyclophosphamide and dexamethasone (ICd). Patients with RRMM received ixazomib 4 mg and cyclophosphamide 300 mg/m2 on days 1, 8 and 15, and dexamethasone 40 mg on days 1, 8, 15 and 22 in 28-day cycles. The primary endpoint was overall response rate (ORR). Seventy-eight patients were enrolled (median age 63.5 years). At data cut off, patients had received a median of 12 treatment cycles; 31% remained on treatment. ORR was 48% [16% very good partial response or better (>=VGPR)]. ORR was 64% and 32% in patients aged >=65 and <65 years (25% and 16% >=VGPR), respectively. At a median follow-up of 15.2 months, median progression-free survival (PFS) was 14.2 months, with a trend towards better PFS in patients aged >=65 years vs. <65 years (median 18.7 months vs. 12.0 months; hazard ratio 0.62, P = 0.14). ICd was well tolerated. The most common treatment-emergent adverse events were diarrhoea (33%), nausea (24%), upper respiratory tract infection (24%), and thrombocytopenia (22%); 10 patients (13%) had peripheral neuropathy (one grade 3). This study is registered at ClinicalTrials.gov (NCT02046070). PMID- 30460685 TI - Genetic Risk Score modifies the effect of APOE on risk and age onset of Alzheimer's disease. AB - Single nucleotide polymorphism (SNP)-based genetic risk score (GRS) and APOE genotype are both important in risk prediction of Alzheimer's disease (AD); however, the interaction between GRS and APOE has not been extensively investigated. Our objective was to determine whether GRS modifies the APOE effect on AD risk and age at onset (AAO). The study included 774 AD cases and 767 controls of European descent. Population standardized GRS was calculated based on 17 previously implicated AD risk-associated SNPs. Association was analyzed using logistic regression, Cox proportional hazards model and Kaplan-Meier curve. We found that GRS was significantly associated with AD risk and the association was stronger among APOE epsilon4 carriers. Compared to epsilon4 non-carriers, the Odds Ratio (OR) for AD was 8.09 (95% Confidence Interval [CI]: 4.98-13.63) for epsilon4 carriers with high-GRS (>=1.5). In contrast, the OR was 2.55 (95% CI: 1.46-4.49) for epsilon4 carriers with low-GRS (<0.6). In conclusion, these results suggest SNP-based GRS may supplement APOE for better assessment of inherited risk and age of onset of AD. This article is protected by copyright. All rights reserved. PMID- 30460686 TI - Effects of different nitrogen fertiliser levels on growth and active compounds of rhubarb from Qinghai plateau. AB - BACKGROUND: Rheum tanguticum Maxim. ex Balf is one of the plants generically known as rhubarb, a culinary vegetable that has long been used as a herbal remedy both in China and Europe. Increasing demand for rhubarb has triggered the overexploitation of Rh. tanguticum. Therefore, cultivation is necessary for both quality control and protection of wild resources. Nitrogen fertiliser plays an important role in cultivation. This study was set to explore how nitrogen fertiliser affect growth and quality of rhubarb in Qinghai-Tibetan plateau. RESULTS: Nitrogen fertiliser promoted growth but had no significant influence on the active compounds of Rh. tanguticum. Generally, the N2 (150 kg/ha) and N3 (225 kg/ha) levels showed the most improved growth indexes, with no significant differences between them. The growth index and the amounts of eight of the nine studied active compounds in Rh. tanguticum increased from each year to the next and differed among growth stages. The contents of the active compounds were higher at the green stage and lower at the growth stage, which was the opposite trend to the root dry matter ratio. Gallic acid levels decreased with the growth of the plant. CONCLUSION: The N2 level (150 kg/ha) was set as the recommended nitrogen fertiliser level in this study. It was revealed that season changes rather than nitrogen fertiliser influenced active compounds in root of Rh. tanguticum. Results in this study made senses in cultivation of this plant. This article is protected by copyright. All rights reserved. PMID- 30460687 TI - A novel mutation in MYORG causes primary familial brain calcification with central neuropathic pain. PMID- 30460688 TI - In Memoriam: Kenji Tadokoro, MD, PhD: 1947 - 2018. PMID- 30460689 TI - In Memoriam: Celso Bianco MD: 1941-2018. PMID- 30460691 TI - Accumulation, mobilization and transformation of selenium in rice grain provided with foliar sodium selenite. AB - BACKGROUND: Selenium is an indispensable trace element for humans and its deficiency can lead to serious health complications. Nearly 70% of the geographical region in China faces selenium deficiency. To deal with this problem, selenium-enriched rice has been increasingly incorporated in everyday diet. However, there is a lack of in-depth study about absorption, translocation and transformation of selenium in the distinct parts of the rice plant, when sprayed with sodium selenite. RESULTS: The results revealed that foliar sodium selenite applied at critical growth stages could significantly improve the total and organic selenium contents of the plant. Application of 10 mg L-1 sodium selenite disclosed most organic selenium (0.03 mg kg-1 ) in polished rice. Association studies between sodium selenite applied at leaves and other plant parts (brown rice and glume) uncovered positive relation for total selenium accretion in the order; glume>rice bran>polished rice>embryo, but behaviour of the organic selenium differed in a pattern such as; polished rice>embryo>rice bran>glume. In addition, 75-85% of the Se found in polished rice and embryo was organic in nature. CONCLUSIONS: Altogether, we propose that 10 mg L-1 sodium selenite could be recommended as an appropriate rate of foliar fertilizer for organic selenium biofortification of Se-free rice This article is protected by copyright. All rights reserved. PMID- 30460692 TI - Effects of high temperature on starch fine structure during grain-filling stages in rice: mathematical modeling and integrated enzymatic analysis. AB - BACKGROUND: High temperature during the grain-filling stage is an important factor that can affect grain quality by altering the composition and structure of starch in rice. Therefore, it is important to study the regulatory mechanism of high temperature on rice starch biosynthesis. RESULTS: Two japonica cultivars, the waxy rice Taihunuo and non-waxy Nangeng 5055 were used to examine the effect of high temperature during the grain-filling stage on starch fine structure. Analysis of starch chain length distribution indicated that exposure to a high temperature increased the content of starch with medium-long chains and decreased the starch with short chains in both rice varieties. The differences of amylopectin synthesis responding to high temperature between waxy and non-waxy rice can shed light on the interactions of amylose and amylopectin synthesis under high temperature conditions. In non-waxy variety, the amylose biosynthesis may affect the short and medium-long amylopectin biosynthesis under high temperature. A mathematical fitting model was used to interpret the fine structure of amylopectin and a series of parameters with enzymatical significance (beta and gamma) were obtained. The fitting results showed that the waxy and non waxy rice had similar responses to high temperature. The variations of the parameter response to high temperature was more remarkable in Taihunuo. Activity analysis of starch synthesis-related enzymes during the grain-filling stage demonstrated the reliability of model fitting results. CONCLUSION: The influences of high temperature on starch fine structure are similar between waxy and non waxy rice. Amylose biosynthesis may affect amylopectin biosynthesis under high temperature. This article is protected by copyright. All rights reserved. PMID- 30460693 TI - Aplastic anaemia in pregnancy - a single centre, North American series. AB - Aplastic anaemia (AA) is infrequently observed in pregnancy. We describe 19 pregnancies in 9 women at a tertiary care centre over a period of 30 years. Spontaneous resolution of AA did not occur postpartum in the five pregnancies where AA was first diagnosed in pregnancy. In the remaining pregnancies, although haematological indices declined and transfusion support was needed in 35% of pregnancies, relapses were not observed. There were no deaths, but complications occurred in 79% of pregnancies. Preterm delivery and postpartum haemorrhage were observed in 21% and 26% of pregnancies, respectively. PMID- 30460694 TI - Connection between gut microbiome and brain development in preterm infants. AB - Dysbiosis of the gut microbiome in preterm infants predisposes the neonate to various major morbidities including neonatal necrotizing enterocolitis and sepsis in the neonatal intensive care unit, and adverse neurological outcomes later in life. There are parallel early developmental windows for the gut microbiota and the nervous system during prenatal to postnatal of life. Therefore, preterm infants represent a unique population in which optimization of initial colonization and microbiota development can affect brain development and enhance neurological outcomes. In this review, we will first discuss the factors affecting the assembly of neonatal gut microbiota and the contribution of dysbiosis in preterm infants to neuroinflammation and neurodevelopmental disorders. We then will discuss the emerging pathways connecting the gut microbiome and brain development. Further we will discuss the significance of current models for alteration of the gut microbiome (including humanized gnotobiotic models and exposure to antibiotics) to brain development and functions. Understanding the role of early optimization of the microbiome in brain development is of paramount importance for developing microbiome-targeted therapies and protecting infants from prematurity-related neurodevelopmental diseases. PMID- 30460695 TI - Current considerations in AYA Hodgkin lymphoma. AB - Hodgkin lymphoma (HL) commonly occurs in adolescents and young adults (AYA), defined by the National Cancer Institute as people diagnosed with cancer between the ages of 15 and 39 years. Despite therapeutic advances, the AYA population has derived less incremental benefit compared to both paediatric and adult counterparts. Although the exact aetiology is unclear, contributing factors probably include differences in disease biology, delayed diagnosis, decreased participation in clinical trials and treatment adherence secondary to complex social factors. As such, while HL remains highly curable, there is not a clear consensus regarding the management of patients within this age range, specifically whether paediatric or adult regimens are preferred or how best to incorporate emerging therapeutic advancements. Ongoing clinical trials, as well as continued collaborative efforts are required to address the needs of this population, investigate the potential for unique biological factors and allow for optimization of treatment. Here we review current prognostic and treatment strategies for paediatric and adult patients with HL and highlight complexities around the management of this patient population. PMID- 30460696 TI - Bortezomib consolidation post-ASCT as frontline therapy for multiple myeloma deepens disease response and MRD-negative rate whilst maintaining QOL and response to re-treatment at relapse. PMID- 30460697 TI - Phytosphingosine Increases Biosynthesis of Phytoceramide by Uniquely Stimulating the Expression of Dihydroceramide C4-desaturase (DES2) in Cultured Human Keratinocytes. AB - Ceramide NP is known to be the most abundant class of 12 ceramide (CER) families that form a permeability barrier in the human skin barrier. However, not many studies have been reported on the regulation of the biosynthesis of ceramide NP. Recently, it has been reported that phytosphingosine (PHS) treatment in the cultured keratinocytes (KC) notably increased the content of ceramide NP. However, the mechanism behind the PHS-induced enhancement of ceramide NP has not been elucidated. In this study, we investigated the effects of PHS on the expression of several essential genes for the biosynthesis of CER. Also, we determined the molecular mechanism behind the unique enhancement of ceramide NP upon treatment of PHS in the cultured KC. The expressions of all of the three genes (SPT, ceramide synthase 3 [CERS3], and ELOVL4) and their respective proteins were markedly increased in PHS-treated KC. In addition, the expression of the dihydroceramide C4-desaturase (DES2) responsible for conversion of dihydroceramide into ceramide NP was uniquely enhanced only by PHS treatment. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed that more than 20-fold increase of ceramide NP by PHS was observed while no significant enhancement of ceramide NS and NDS was observed. This study demonstrates that PHS plays a fundamental role in strengthening the epidermal permeability barrier by stimulating the overall processes of biosynthesis of all classes of CER in epidermis. The dramatic increase of ceramide NP upon PHS treatment seemed to be the outcome of transformation of dihydroceramide and/or ceramide NS by C4-hydroxylase activity. PMID- 30460698 TI - Anandamide Induces Platelet Nitric Oxide Synthase through AMP-Activated Protein Kinase. AB - The objective of this study was to determine whether adenosine 5' monophosphate (AMP)-activated protein kinase (AMPK) is activated by anandamide (AEA) and is involved in endothelial nitric oxide synthase (eNOS) activation. We found that AEA stimulates and activates AMPKalpha through a Ca2+ -dependent/Calmodulin (CaM) dependent pathway as the specific inhibitor of the Ca2+ /Calmodulin kinase kinase beta (CaMKKbeta) STO-609 abolishes the AMPK phosphorylation/activation. The same inhibiting effect is shown in platelets pretreated with LY294002, an inhibitor of phosphatidylinositol 3 kinase (PI3K), or with MK2206, an inhibitor of protein kinase B (AKT), suggesting that AMPK is downstream of the PI3K/AKT pathway. Moreover, the AEA-induced eNOS activation and the consequent nitric oxide (NO) and guanosine 3'-5' cyclic monophosphate (cGMP) increase are mediated by the CaMKKbeta/AMPKalpha pathway as STO-609 significantly inhibits these parameters. In contrast, liver kinase B1 (LKB1) seems to be very poorly involved. One crucial effect of NO and cGMP elevation is the activation of protein kinase G that can phosphorylate the vasodilator-stimulated phosphoprotein (VASP). We have demonstrated that AEA stimulates VASP phosphorylation on both thr278 and ser239 that is strongly inhibited by STO-609, LY294002, and MK2206. Finally, AMPK phosphorylation/activation and VASP phosphorylation are significantly reduced by SR141716, the specific inhibitor of type 1 cannabinoid receptor (CB1). SR144528, an antagonist of type 2 cannabinoid receptor (CB2), has a less-potent effect, suggesting that the CB1 receptor is overall involved in the AEA effect. In conclusion, we show that the CaMKKbeta/AMPKalpha pathway, downstream of the PI3K/AKT pathway, is activated by AEA in human platelets and leads to increase NO levels producing beneficial effects during ischemic conditions and contributing to extend platelet survival. PMID- 30460699 TI - Unsaturated Fatty Acids Increase the Expression of Hepassocin through a Signal Transducer and Activator of Transcription 3-Dependent Pathway in HepG2 Cells. AB - Hepassocin (HPS) is a hepatokine that regulates hepatocyte proliferation. It is known that HPS plays an important role in the development of nonalcoholic fatty liver diseases (NAFLD). Fatty acids, such as oleic acid (OLA), exhibit the ability to activate the signal transducer and activator of transcription-3 (STAT3), and the binding site of STAT3 is found in the promoter region of HPS. However, the regulation of HPS by fatty acids is still obscure. To clarify the regulation of HPS, we detected the expression of HPS by western blots. In addition, a hepatic steatosis cell culture model was established by treatment of different fatty acids, including linoleic acid (LNA), oleic acid, palmitic acid, and stearic acid. The intracellular lipid accumulation was confirmed by oil red O staining. Blocking of STAT3 activity was achieved by the pretreatment of the STAT3 inhibitor, stattic. We found that activation of STAT3 by interleukin-6 (IL 6) was mediated in the regulation of HPS expression. Treatment of unsaturated fatty acids significantly induced intracellular lipid accumulation in HepG2 cells. Moreover, the expressions of HPS were increased in unsaturated fatty acid treated HepG2 cells, as compared with saturated fatty acid-treated groups. Also, the expression of HPS induced by OLA was blocked by the inhibition of STAT3 activity. Furthermore, we found that deletion of HPS by small interfering ribonucleic acid transfection decreased the protective effect of OLA on cell viability. Taken together, we provided evidence that STAT3 plays an important role in the regulation of OLA-induced HPS expression and the increased HPS may further participate in the development of NAFLD. In addition, the increase of HPS might be involved in the protective effect of OLA on cell viability. PMID- 30460700 TI - Lipopolysaccharide Alters Thermogenic and Inflammatory Genes in White Adipose Tissue in Mice Fed Diets with Distinct 18-Carbon Fatty-Acid Composition. AB - Fatty acids are involved in the regulation of inflammatory responses in obesity. However, despite being the largest dietary fatty-acid class, effects of 18-carbon fatty acids with different degrees of saturation on inflammatory, metabolic, and thermogenic markers have not been well studied. Therefore, the objective of this study was to test if diets with different 18-carbon fatty-acid profiles differentially regulate inflammatory and metabolic genes. Male C57BL/6 mice were fed one of the four different diets: a control diet (CON) containing 5.6% kcal fat from lard and 4.4% kcal fat from soybean oil (CON) or three high-fat diets (HFD) containing 25% kcal fat from lard and 20% kcal fat from either shea butter oil (saturated fatty-acid-rich fat; shea butter [SHB]), olive oil (monounsaturated fatty-acid-rich fat; olive oil [OO]), or soybean oil (polyunsaturated fatty-acid-rich fat; soybean oil [SBO]) ad libitum for 4 weeks with or without a terminal 4-h lipopolysaccharide (LPS) treatment. Compared to CON, HFD-fed mice had higher weight gain and fat accumulation. The OO group had the highest brown adipose tissue (BAT) mass while the SBO group had higher Il6 and lower Cpt1a expression in white adipose tissue (WAT) than other HFD groups. Treatment with LPS upregulated expression of proinflammatory cytokines, and this was associated with downregulation of thermogenic gene expression. However, the diets did not have differential effects on inflammatory response to LPS. These data indicate that the saturation degree of 18-C fatty acids is not an important factor on response to LPS with regard to metabolic and inflammatory indicators. PMID- 30460701 TI - Anthropomorphism, social understanding, and imaginary companions. AB - In two studies, we investigated the correlates of anthropomorphism, the attribution of unobservable mental states to inanimate entities and non-human animals. In Study 1, we investigated the relations between anthropomorphism, social understanding, empathy, prosocial attitudes, and history of childhood imaginary companions in a college sample (N = 264; Mage = 19 years, 2 months). In Study 2, we explored the relations between two different measures of anthropomorphism, theory of mind, imaginary companions, and social preferences in 73 children (Mage = 5 years, 5 months). Anthropomorphism was not strongly correlated with social understanding in adults or with theory of mind in children. There was, however, some evidence for links between anthropomorphism and reports of having imaginary companions and social preferences. Moreover, the two measures of anthropomorphism were not correlated with each other and yielded different patterns of results in Study 2, a finding that is discussed in relation to different forms of anthropomorphism. Statement of contribution What is already known on this subject? There are individual differences in anthropomorphism in both adults and children. There are two different methods to assess anthropomorphism: self-reports and narration of movies of geometric shapes. The two different methods that are used to assess anthropomorphism yield different developmental patterns. What does this study add? Individual differences in social understanding or theory of mind are not associated with individual differences in anthropomorphism. Having a childhood imaginary companion is linked with a tendency to anthropomorphize in both children and adults. Two measures of anthropomorphism are not correlated in children, consistent with the view that there are different forms of anthropomorphism. PMID- 30460703 TI - Ingenol mebutate for the treatment of anogenital condylomata acuminata. PMID- 30460702 TI - Uninterrupted Anticoagulation with Non-Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation Catheter Ablation: Lessons Learned from Randomized Trials. AB - Catheter ablation has been established as a rhythm control strategy in select patients with atrial fibrillation (AF) who have failed or wish to avoid anti arrhythmic drugs. Uninterrupted oral anticoagulation with vitamin K antagonists (VKAs) peri-ablation is associated with a lower risk of thromboembolic and bleeding complications as compared to interrupted oral anticoagulation and bridging heparin. However, a substantial portion of patients with AF are treated with non-vitamin K antagonist oral anticoagulants (NOACs). Herein, we perform an in-depth review and comparison of three recent randomized trials of uninterrupted oral anticoagulation with NOACs vs. VKAs in patients undergoing AF catheter ablation. Further, we report pooled results of these randomized trials. The pooled incidence of major bleeding was significantly lower with NOACs as compared to VKAs (2% vs. 4.9%, respectively; OR 0.40; 95% CI 0.16-0.99). Similarly, cardiac tamponade was also reduced in the NOAC group (0.4% vs. 1.5%; OR 0.27; 95% CI 0.07-0.97). Thromboembolic complications were not significantly different between groups. Overall, these findings support the 2017 HRS/EHRA/ECAS/ APHRS/SOLAECE expert consensus statement's class I recommendation for uninterrupted NOAC use in patients undergoing AF catheter ablation. PMID- 30460704 TI - Habermasian communication pathologies in do-not-resuscitate discussions at the end of life: manipulation as an unintended consequence of an ideology of patient autonomy. AB - The focus on patient autonomy in American and increasingly British medicine highlights the importance of choice. However, to truly honour patient autonomy, there must be both understanding and non-control. Fifty-eight semi-structured in depth interviews were conducted with internal medicine physicians at three hospitals in the US and one in the UK. At hospitals where autonomy was prioritised, trainees equated autonomy with giving a menu of choices and felt uncomfortable giving a recommendation based on clinical knowledge as they worried that that would infringe upon patient autonomy. Employing Habermas's Theory of Communicative Action, this paper explores how physician trainees' communication practices of using purposefully graphic descriptions of resuscitation to discourage that choice prevent greater understanding and compromise non-control. Central to this problem are also issues of colonisation of the life-world by the system. Physicians are fully inculcated in their respect for autonomy but unintentionally resort to strategic forms of communication that prevent patients from adequately understanding their situation because trainees feel constrained against making recommendations. However, if the ideal of autonomy is to be realised, physicians might have to move towards practices that embrace a more authentic autonomy that fosters open communication that allows for co-creation of consensus between doctors and patients. PMID- 30460705 TI - A new semiparametric transformation approach to disease diagnosis with multiple biomarkers. AB - When multiple biomarkers are available for disease diagnosis, it is desirable to efficiently combine them to form a single index. Making use of the Neyman-Pearson paradigm, we propose a new combination/transformation approach to disease diagnosis that efficiently combines multiple biomarkers. The proposed method does not require that the biomarkers be jointly normally distributed or the covariance matrices for the diseased and the nondiseased are nondifferential. An R package is developed to implement the proposed method. Simulations and two real data examples demonstrate advantages of the new method over existing ones. PMID- 30460706 TI - Study of the cytotoxic and genotoxic potential of the carbonyl ruthenium(II) compound, ct-[RuCl(CO)(dppb)(bipy)]PF6 [dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2'-bipyridine], by in vitro and in vivo assays. AB - Considering the promising previous results of ct-[RuCl(CO)(dppb)(bipy)]PF6 (where dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2'-bipyridine) as an antitumor agent, novel biological assays evaluating its toxicogenic potential were performed. The genotoxicity of the compound was evaluated by the in vitro micronucleus test (V79, Chinese hamster lung fibroblasts; HepG2, hepatocellular carcinoma cells), in vivo bone marrow micronucleus test and comet assay in hepatocytes (Swiss mice). The animals were treated with 0.63, 1.25, 2.5 and 5.0 mg/kg body weight (bw) of the compound. Negative (water) and positive (cisplatin, 1.5 mg/kg bw; methyl methanesulfonate, 40 mg/kg bw) controls were included. The parameters considered in the comet assay were the percentage of tail DNA, tail moment and tail length. The results of the in vitro micronucleus tests showed the absence of genotoxicity in V79 cells, while the compound was genotoxic in HepG2 cells at a concentration of 1.25 MUm. In the in vivo micronucleus test, the compound was not genotoxic at the different doses evaluated. In the comet assay, only the dose of 5.0 mg/kg bw resulted in a significant increase in the frequency of DNA damage in hepatocytes when compared to the negative control. The genotoxic effect observed in HepG2 cells and in the liver comet assay indicates that the compound was metabolized by hepatic cells. PMID- 30460707 TI - The non-steroidal anti-inflammatory drug diclofenac sodium induces abnormal embryogenesis and delayed lethal effects in early life stage zebrafish (Danio rerio). AB - Diclofenac sodium, a non-steroidal anti-inflammatory drug widely used in both human and veterinary medicine, has been detected in aquatic environments; therefore, its ecotoxicological effects on aquatic organisms need to be clarified. Recently, toxicity testing using zebrafish (Danio rerio) embryos has been recommended from the point of view of animal welfare; therefore, we investigated the suitability of using sub-lethal endpoints observed during embryogenesis for predicting lethal effects in early life stage zebrafish exposed to diclofenac sodium. After exposure to diclofenac sodium (0.4-7.0 mg/L) from 2 hours post-fertilization to 30 days post-hatching, abnormal embryogenesis, characterized by the presence of edema and body curvature, was observed in the 7.0 mg/L exposure group but not in any other groups including controls. The body curvature was found to be the result of abnormal development of the spine. All abnormal embryos hatched without delay, but died within 1 week after hatching, suggesting that the combination of the sub-lethal endpoints of edema and abnormal development of the spine during embryogenesis may predict lethal effects in early life stage zebrafish exposed to diclofenac sodium. Further investigations to verify these findings are needed. The value of the no observed effect concentrations for the embryogenesis, survival and growth endpoints were 3.5, 1.8 and >3.5 mg/L, respectively. PMID- 30460708 TI - Cobalt content of a convenience sample of leather shoes and gloves in Denmark. AB - Chromium is a well-known allergen in leather products, however, cobalt has not historically been associated with leather exposure. Cobalt allergic contact dermatitis (ACD) from leather in furniture upholstery has been reported in Denmark,1,2 and leather furniture samples obtained in the United States also were found to contain cobalt.3 However, no clear cases of cobalt ACD from leather gloves or shoes have been reported. In this study we examined cobalt content in a convenience sample of shoes and gloves. PMID- 30460709 TI - A comment on "clinical experience with sex chromosome aneuploidies detected by noninvasive prenatal testing (NIPT): Accuracy and patient decision-making". PMID- 30460710 TI - 'Treat them into the grave': cancer physicians' attitudes towards the use of high cost cancer medicines at the end of life. AB - The prescribing of high-cost cancer medicines at the end of life has become a focus of criticism, due primarily to concerns about the safety, efficacy and cost effectiveness of these medicines in this clinical context. In response to these concerns, a number of interventions have been proposed - frequently focused on improving physician-patient communication at the end of life. Underpinning these strategies is the assumption that the prescribing of high-cost cancer medicines at the end of life is primarily the result of poor communication on the part of cancer physicians. In this paper, we explore the factors perceived by cancer physicians to be driving the use of high-cost cancer medicines at the end of life. Drawing on semi-structured interviews with 16 Australian oncologists and haematologists, we demonstrate that these physicians believe that the use of high cost medicines at the end of life is driven by multiple factors - including individual, interpersonal, socio-cultural and public policy influences. We conclude that these factors, and their interactions, need to be taken into account in the development of public policy and clinical interventions to address the use of high-cost medicines at the end of life. PMID- 30460711 TI - A powerful and data-adaptive test for rare-variant-based gene-environment interaction analysis. AB - As whole-exome/genome sequencing data become increasingly available in genetic epidemiology research consortia, there is emerging interest in testing the interactions between rare genetic variants and environmental exposures that modify the risk of complex diseases. However, testing rare-variant-based gene-by environment interactions (GxE) is more challenging than testing the genetic main effects due to the difficulty in correctly estimating the latter under the null hypothesis of no GxE effects and the presence of neutral variants. In response, we have developed a family of powerful and data-adaptive GxE tests, called "aGE" tests, in the framework of the adaptive powered score test, originally proposed for testing the genetic main effects. Using extensive simulations, we show that aGE tests can control the type I error rate in the presence of a large number of neutral variants or a nonlinear environmental main effect, and the power is more resilient to the inclusion of neutral variants than that of existing methods. We demonstrate the performance of the proposed aGE tests using Pancreatic Cancer Case-Control Consortium Exome Chip data. An R package "aGE" is available at http://github.com/ytzhong/projects/. PMID- 30460712 TI - Modeling a bivariate residential-workplace neighborhood effect when estimating the effect of proximity to fast-food establishments on body mass index. AB - Hierarchical modeling is the preferred approach of modeling neighborhood effects. When both residential and workplace neighborhoods are known, a bivariate (residential-workplace) neighborhood random effect that quantifies the extent that a neighborhood's residential and workplace effects are correlated may be modeled. However, standard statistical software for hierarchical models does not easily allow correlations between the random effects of distinct clustering variables to be incorporated. To overcome this challenge, we develop a Bayesian model and an accompanying estimation procedure that allows for correlated bivariate neighborhood effects and allows individuals to reside or work in multiple neighborhoods, cross-sectional and longitudinal heterogeneity between individuals, and serial correlation between repeated observations over time. Simulation studies that vary key model parameters evaluate how well each aspect of the model is identified by the data. We apply the model to the motivating Framingham Heart Study linked food establishment data to examine whether (i) proximity to fast-food establishments is associated with body mass index, (ii) workplace neighborhood exposure associations are larger than those for residential neighborhood exposure, and (iii) residential neighborhood exposure associations correlate with workplace neighborhood exposure. Comparisons of the full model to models with restricted versions of the covariance structure illustrate the impact of including each feature of the covariance structure. PMID- 30460713 TI - One-sample aggregate data meta-analysis of medians. AB - An aggregate data meta-analysis is a statistical method that pools the summary statistics of several selected studies to estimate the outcome of interest. When considering a continuous outcome, typically each study must report the same measure of the outcome variable and its spread (eg, the sample mean and its standard error). However, some studies may instead report the median along with various measures of spread. Recently, the task of incorporating medians in meta analysis has been achieved by estimating the sample mean and its standard error from each study that reports a median in order to meta-analyze the means. In this paper, we propose two alternative approaches to meta-analyze data that instead rely on medians. We systematically compare these approaches via simulation study to each other and to methods that transform the study-specific medians and spread into sample means and their standard errors. We demonstrate that the proposed median-based approaches perform better than the transformation-based approaches, especially when applied to skewed data and data with high inter-study variance. Finally, we illustrate these approaches in a meta-analysis of patient delay in tuberculosis diagnosis. PMID- 30460714 TI - Household collectives: resituating health promotion and physical activity. AB - In this article, we situate the practices of health and physical activity in household collectives, and conceptualise everyday health 'behaviour' and lifestyle as complex, collective practices. Based on an ethnographic study on everyday family life and health practices, we provide a framework for understanding the household as a collective, where the household collective may take precedence over individual preferences, and individual behaviour has collective implications. We describe the household as a node for practices, gathered by the activities that draw together and align actors in collective practices of everyday life. In the everyday efforts of the households to live up to ideals and balance conflicting practices, healthy living is about more than simple, individual choices about whether to follow health recommendations or not. It is also dependent on pragmatic negotiations, the distribution of roles and tasks and conflicts between ideals and what is feasible in the everyday management and maintaining of the household. We suggest that engaging with these collectives could serve as a useful point of departure for health promotion activities, situating health promotion in the here and now of collectives, tinkering with their specific constellations, values and identities in the entangledness of multiple household practices. PMID- 30460715 TI - Association of pyoderma gangrenosum, erythema nodosum and aseptic liver abscess without significant underlying disease. PMID- 30460716 TI - Late-onset naevus of Ota: a case series of six patients. PMID- 30460717 TI - Simplifying the language of fetal monitoring. AB - BACKGROUND: Health professionals in Australia and New Zealand have used various intrapartum fetal surveillance (IFS) guidelines, with clear differences in how these guidelines present information. Based on clinician feedback, the 2015 Queensland Clinical Guideline on IFS structured the prose-based Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) IFS Guidelines as a traffic-light matrix and represented the categorical terms of unlikely, maybe, possible and likely fetal compromise, as the colours GREEN, BLUE, AMBER, and RED, respectively. AIMS: To determine whether the interpretation of the RANZCOG IFS Guidelines in Table Format is more accurate and quicker compared to the current presentation of the RANZCOG Guideline in prose format. MATERIALS AND METHOD: Twenty-nine clinicians, naive to the use of the RANZCOG IFS Guidelines, interpreted ten cardiotocographs (CTGs) using one format and then the alternative format (totalling 580 CTG interpretations). Accuracy and time to decision were recorded as well as a participant questionnaire. A repeated measures analysis of variance was used to compare differences. RESULTS: Compared to prose format, clinicians interpreted CTGs quicker using the table format (P < 0.01), especially CTGs representative of unlikely and maybe fetal compromise. There was a trend toward more accurate interpretation for table format for all clinicians, with significance among medical officers (P = 0.02). Participants responded more favourably to the table format regarding questions about ease of use, determining actions required, and desire to use the system in the future (P < 0.01). CONCLUSIONS: Presenting the RANZCOG IFS Guideline in table format as opposed to prose format improved the speed and accuracy of CTG interpretation and is preferred by clinicians. PMID- 30460718 TI - Influence of idebenone on ram semen quality stored at 4 degrees C. AB - The current study was designed to investigate the effect of idebenone (Id), an antioxidant on ram semen quality. Semen samples were collected, pooled, and diluted in a Tris-based extender supplemented with 0, 1, 2, 4 and 8 MUM idebenone. Computer-assisted sperm analysis was used to evaluate spermatozoa kinematics. Sperm viability and membrane functionality were assessed respectively, by eosin-nigrosin staining and HOS test. Biochemical assays were carried out to measure different metabolites in spermatozoa and medium at 0, 24, 48 and 72h. Total and forward progressive motility were greater in 1, 2 and 4 MUM idebenone treated groups compared to control at 24, 48 and 72h time points (P < 0.05). Semen supplementation with Id, significantly increased viability and functionality of spermatozoa membrane during storage (P < 0.05). Lower amounts of lipid hydroperoxides in medium and spermatozoa were observed in Id treated groups compared to control one at 24 and 48h of storage (P < 0.05). Medium and spermatozoa amounts of malondialdehyde and nitric oxide were less in Id 4 MUM group compared to the control at 72h (P < 0.05). Total antioxidant capacity values and superoxide dismutase activity of spermatozoa and medium were greater in 2 and 4 MUM idebenone treated groups in comparison with the control at 72h (P < 0.05). Results of the current study indicated that ram semen supplementation with Id at 4 MUM level improved quality by ameliorating nitrosative and peroxidative stress, hence could be considered as an antioxidant additive during storage at 4 degrees C. This article is protected by copyright. All rights reserved. PMID- 30460719 TI - The role of different mechanical circulatory support devices and their timing of implantation on myocardial damage and mid-term recovery in acute myocardial infarction related cardiogenic shock. AB - OBJECTIVES: Aim of the study was to assess in-hospital survival rate and the degree of myocardial recovery after MCS treatment (IABP or IMPELLA) at discharge and at 6 months in patients with AMI-CS and planned early percutaneous revascularization. BACKGROUND: All studies on MCS for acute myocardial infarction related cardiogenic shock (AMI-CS) focused on its impact on in-hospital mortality; however, few data about its role on myocardial recovery are available. METHODS: Retrospective study on 64 patients: 36 patients (56%) received IABP and 28 (44%) Impella 2.5/CP. RESULTS: Patients treated with Impella were sicker compared to those treated with IABP as shown by a higher need of catecholamines (93% Impella vs 57% IABP, P = 0.002) and higher inotropic score before procedure: 8 (5-15) versus 4.5 (0-9), P = 0.02. In-hospital survival and MCS-related complications were comparable; hemolysis was more frequent in the Impella group (32% vs 0%, P < 0.0001). Myocardial damage was lower in those patients who were implanted with IMPELLA before PCI: lower troponin peak [3831 ng/dL (1441-8436) vs 16 581 (7802-23 675), P = 0.004] and lower CPK peak [893 UI/L (584-4082) vs 5797 (2483-9292) P = 0.04]. Impella patients had higher LVEF at 6 months [45 (38-52) vs 40 (33-45)%, P = 0.04]. LVEF increase at 6 months was statistically significant in both groups (P < 0.0001), with higher myocardial recovery in patients supported with Impella (absolute delta-LVEF increase 20% vs 10% P = 0.005). CONCLUSIONS: Cardiac unloading with IMPELLA in ACS-CS, especially if implanted before PCI, might provide lower myocardial damage and improved myocardial recovery which translates into significantly higher LVEF at 6 months. PMID- 30460720 TI - Psychometric properties of the Dynamic Risk Outcome Scales (DROS) for individuals with mild intellectual disability or borderline intellectual functioning and externalizing behaviour problems. AB - BACKGROUND: The present study examined the psychometric properties of the Dynamic Risk Outcome Scales (DROS), an instrument developed to measure dynamic risk factors in individuals with mild intellectual disabilities or borderline intellectual functioning (MID-BIF) and externalizing (including offending-like) behaviour problems. METHOD: The sample consisted of 606 clients (86% male) from inpatient treatment wards at a facility for individuals with MID-BIF and externalizing behaviour problems. RESULTS: The DROS showed an acceptable factor structure, good internal consistency, significant test-retest reliability and fair to excellent inter-rater reliabilities for most subscales and total score. Compared to the Adult Behavior Checklist (ABCL; Achenbach & Rescorla, 2003 Manual for the ASEBA adult forms and profiles. Burlington, VT: University of Vermont, Research Center for Children, Youth, & Families), the DROS showed convergent and divergent validity, concurrent and longitudinal validity. CONCLUSIONS: The DROS is a reliable and valid instrument to measure dynamic risk factors in clients with MID-BIF. Future research on the DROS will focus on the assessment of recidivism and the inclusion of internalizing problems. PMID- 30460721 TI - On the Theory of Electrolytic Dissociation, the Greenhouse Effect, and Activation Energy in (Electro)Catalysis: A Tribute to Svante Augustus Arrhenius. AB - There are powerful lessons to take from Svante August Arrhenius' journey leading to a Nobel laureate as there are from his tremendous contributions to chemistry and science in general, including climate science, immunochemistry and cosmology. The theory of electrolytic dissociation for which Arrhenius received the 1903 Nobel Prize in Chemistry has had a profound impact on our understanding of the chemistry of solutions, chemical reactivity, mechanisms underlying chemical transformations as well as physiological processes. As a tribute to Arrhenius, we present a brief historical perspective and present status of the theory of electrolytic dissociation, its relevance and role to the development of electrochemistry, as well as some perspectives on the possible role of the theory to future advancements in electroanalysis, electrocatalysis and electrochemical energy storage. The review briefly highlights Arrhenius' contribution to climate science owing to his studies on the potential effects of increased anthropogenic CO2 emissions on the global climate. These studies were far ahead of their time and revealed a daunting global dilemma, global warming, that we are faced with today. Efforts to abate or reverse CO2 accumulation constitute one of the most pressing scientific problems of our time, "man's urgent strive to save self from the adverse effects of his self-orchestrated change on the climate". Finally, we review the application of the Arrhenius equation that correlates reaction rate constants (k) and temperature (T); k=A e^(Ea/RT), in determining reaction barriers in catalysis with a particular focus on recent modifications of the equation to account for reactions exhibiting non-linear Arrhenius behavior with concave curvature due to prevalence of quantum mechanical tunneling, as well as infrequent convexity of Arrhenius plots due to decrease of the microcanonical rate coefficient with energy as observed for some enzyme catalyzed reactions. PMID- 30460722 TI - beta-carotene attenuates lipopolysaccharide-induced inflammation via inhibition of the NF-kappaB, JAK2/STAT3 and JNK/p38 MAPK signaling pathways in macrophages. AB - beta-carotene is one of the most abundant carotenoids, has potential anti inflammatory effect, it has been reported that beta-carotene could suppress LPS induced inflammatory responses by inhibiting nuclear factor kappa B (NF-kappaB) translocation, but the more detailed molecular mechanisms underlying the anti inflammatory action of beta-carotene remain to be fully understood. In this study, we investigated the influence of beta-carotene on the activation of JAK2/STAT3, MAPK, and NF-kappaB signaling pathway induced by LPS in RAW264.7 cells and peritoneal macrophages. Cells were treated with different concentrations of beta-carotene for 3 hr after LPS treatment for 24 hr. The mRNA expression and the release of IL-1beta, IL-6, and TNF-alpha were evaluated by RT PCR and ELISA, and the level of signaling proteins of JAK2/STAT3, MAPK, and NF kappaB signaling pathway were detected by Western blot. The results showed that beta-carotene significantly suppressed (p < 0.05) LPS-induced release of IL 1beta, IL-6, and TNF-alpha and their mRNA expression. LPS-induced JAK2/STAT3, IkappaB/NF-kappaB p65, JNK/p38 MAPK signal activation were significantly attenuated (p < 0.05) by beta-carotene in a dose-dependent manner. In conclusion, beta-carotene could attenuate LPS-induced inflammation via inhibition of the NF kappaB, JAK2/STAT3, and JNK/p38 MAPK signaling pathways in macrophages. PMID- 30460723 TI - Simulation and Experimental Characterization of Lateral Imaging Resolution of Ultrasound Systems and Assessment of System Suitability for Acoustic Optic Nerve Sheath Diameter Measurement. AB - BACKGROUND AND PURPOSE: Optic nerve sheath diameter (ONSD) is used for the estimation of intracranial pressure (ICP). But there are still doubts about the quality of the images and the lateral resolution. Our aim is to investigate the system suitability and best lateral resolution of different ultrasound systems for acoustic ONSD measurement. METHODS: First, we calculated the theoretically lateral imaging resolution at increasing frequencies: 6.6, 10, and 15 MHz using two different ultrasound systems. Second, we created two phantoms consisting of copper wires or polyvinylchloride (PVC) strips and tested the best lateral resolution at different frequencies with the two ultrasound systems. Using the same ultrasound systems, we evaluated the anatomy of optic nerve at increasing transmission frequencies. Finally, the two probes were tested in two patients with different neurological conditions affected by an increase of ICP. RESULTS: Theoretical resolutions were .63, .43, and .41 mm, respectively, with a frequency of 6.6, 10, and 15 MHz. We found a similar lateral resolution in both phantoms: copper wire; .56 mm at 6.6 MHz, .46 mm at 10 MHz, and .44 mm at 15 MHz; and PVC strips .6 mm at 6.6 MHz, .47 mm at 10 MHz, and .40 mm at 15 MHz in accordance with experimental resolution. The ONSD thickening could be clearly displayed at frequencies higher than 7.5 MHz using the two linear probes and the two patients with an increase of ICP showed thickening of ONSD. CONCLUSION: According to our study, both systems are suitable for ultrasound OSND measurement. PMID- 30460724 TI - Effects of antenatal azithromycin for Ureaplasma spp. on neonatal outcomes. AB - BACKGROUND: Ureaplasma spp. in the maternal genitourinary tract has come to the attention for is becoming more evident as a cause of preterm labor, spontaneous abortion, chorioamnionitis and adverse outcomes. However, a few controversies still remain, namely, whether it should be treated aggressively or not. The aim of this study was to evaluate the effects of maternal azithromycin (AZ) treatment for Ureaplasma colonization on neonatal morbidities including bronchopulmonary dysplasia (BPD). METHODS: A retrospective case-control study of preterm babies delivered at <=30 weeks of gestational age (GA) from 2012 to 2016 was conducted. Infants whose mothers were treated with AZ with confirmed colonization (m-AZ, cases) were matched by GA to control subjects without colonization. A subgroup analysis according to neonatal respiratory Ureaplasma colonization status (nUU) was also performed. RESULTS: Fifty-five control subjects were matched to 110 case subjects. The incidence of preterm premature rupture of membranes (P=0.003) and moderate-to-severe BPD (P=0.010) was significantly higher in the m-AZ group. By analyzing and comparing subgroups [i.e., m-AZ with nUU colonization (I, n=55) vs. m-AZ without colonization (II, n=55) vs. controls (n=55)], post hoc analysis showed the following significant differences in the incidences of moderate-to severe BPD: 26% (I) vs. 22% (II) vs. 7% (controls), (P=0.033). CONCLUSIONS: Maternal Ureaplasma colonization was associated with moderate-to-severe BPD even though AZ treatment was performed. In addition, if the neonatal respiratory tract was colonized, then moderate-to-severe BPD developed even with maternal AZ treatment. Hence, selective antenatal and postnatal treatment of Ureaplasma colonization may be considered to control BPD development. This article is protected by copyright. All rights reserved. PMID- 30460725 TI - Determination and analysis of volatile components from Thymus kotschyanus Boiss with a new solid-phase microextraction fibre and microwave-assisted hydrodistillation by periodic mesoporous organosilica based on alkylimidazolium ionic liquid. AB - INTRODUCTION: Research on the volatile oil composition of Thymus kotschyanus Boiss was conducted by applying mesoporous organosilica based on alkylimidazolium ionic liquid (PMO-IL) as a fibre coating material via a method referred to as microwave-assisted headspace solid-phase microextraction (MA-HS-SPME). METHODOLOGY: This technique entails microwave irradiation of the sample and collection of the volatile sample components. These components are further introduced into a gas chromatography-mass spectrometry (GC-MS) injection port for further analysis. A simplex method was used for the optimisation of three different parameters affecting the efficiency of the extraction. CONCLUSION: The MA-HS-SPME method proved to be the most suitable technique in oil determination and extraction from Thymus kotschyanus owing to its advantageous aspects of cost effectiveness, simplicity and solvent independence. PMID- 30460726 TI - Methadone maintenance treatment as social control: Analyzing patient experiences. AB - Methadone maintenance treatment (MMT) is a harm reduction approach for persons who wish to stop using opioids and is rather effective if used for a minimum of 12 months. Notably, research demonstrates that many persons enrolled in MMT programs discontinue care before this time, limiting its effects. To better understand this process, we undertook an exploratory descriptive qualitative study and interviewed 12 men and women who were using MMT. Using the theoretical work of Foucault and Hardt and Negri, the interview data highlighted that MMT continues to be strongly stigmatized, and that it is a system of care that involves rewards and penalties, based on if patients behave according to prescribed norms. These results suggest that MMT is a disciplinary mechanism, albeit one that impedes its own access. We consequently recommend that healthcare providers work to facilitate access to MMT, which means altering care delivery. PMID- 30460728 TI - Health consequences of androgenic anabolic steroid use. AB - BACKGROUND: The lifetime prevalence of androgenic anabolic steroid abuse is estimated to be around 6% for men, but there is limited knowledge about the side effects of these drugs. OBJECTIVE: To investigate mortality and morbidity amongst users of androgenic anabolic steroids (AAS). METHODS: In this retrospective matched cohort study, 545 male subjects tested positive for AAS in Danish fitness centres during the period 3 January 2006 to 1 March 2018. Subjects were matched with 5450 male controls. In addition, 644 men who were sanctioned because they refused to submit to a doping test and 6440 controls were included as a replication cohort. RESULTS: Mortality was three times higher amongst users of AAS than amongst nonuser controls (hazard ratio 3.0, 95% CI 1.3-7.0). The median annual number of hospital contacts was 0.81 in the cohort of AAS users and 0.36 in the control cohort (P < 0.0001). Acne, gynaecomastia and erectile dysfunction affected more than 10% of the androgenic anabolic steroid users, and the prevalence of these disorders was significantly higher than in the control group (P < 0.0001). The results could be replicated in a similar cohort. CONCLUSION: Androgenic anabolic steroid users have an increased risk of dying and significantly more hospital admissions than their nonuser peers. Side effects of AAS and their metabolites were highly prevalent. Given the high rate of androgenic anabolic steroid abuse, these side effects are of public health concern. PMID- 30460727 TI - Effects of methionine on muscle protein synthesis and degradation pathways in broilers. AB - This study investigated the hypothesis that supplementation of methionine (Met) to broiler diets increases muscle growth due to regulation of molecular pathways related to protein synthesis and degradation depending on the Met source. Day-old male Cobb-500 broilers (n = 240) were phase-fed three different wheat-soya bean meal-based basal diets during days 1-10, 11-21 and 22-35. Basal diets (Met- group, Met + Cys concentration 15% below NRC recommendations) were supplemented with 0.10% or 0.40% Met either as DL-Met (DLM) or DL-2-hydroxy-4-(methylthio) butanoic acid (DL-HMTBA) (equimolar comparison). Breast muscle weights were lower in the Met- group compared to all Met-supplemented groups and were lower in broilers supplemented with 0.10% of DL-HMTBA compared to the other groups fed Met supplemented diets. However, the expression of genes or relative phosphorylation and thus activation state of proteins involved in the somatotropic axis, the mammalian target of rapamycin (mTOR) pathway of protein synthesis, the ubiquitin proteasome pathway (UPP) and autophagy-lysosomal pathway of protein degradation, the GCN2/eIF2a pathway involved in the inhibition of protein synthesis and in the myostatin-Smad2/3 pathway involved in myogenesis were not affected by Met source. Feeding diets with suboptimum Met + Cys concentrations, however, decreased expression of GHR and IGF1 in liver and muscle and increased that of MURF1 involved in the UPP in the broiler's muscle at day 10 and 21, while that of FOXO and atrogin-1 and FOXO phosphorylation remained unaffected. Additionally, suboptimum dietary Met concentrations increased expression of the autophagy related genes ATG5 and BECN1 at day 35. Met supplementation neither affected gene expression nor phosphorylation of proteins involved in the GNC2/eIF2a and mTOR pathways. These data indicate that protein synthesis was not affected on the molecular level, while protein degradation was marginally affected by dietary Met dosage. PMID- 30460729 TI - Multi-professional simulation and risk perception of health care workers caring for Ebola-infected patients. AB - INTRODUCTION: Treatment of infections that require high-level isolation can cause anxiety and fear among health care workers. Adequate and complete multi professional simulation-based training could reduce those feelings and improve patient care. OBJECTIVE: The purpose of this study was to assess the impact of multi-professional simulation-based training on the risk perception and preparedness of health care workers (registered nurses, doctors and ancillary staff) who care for patients assessed to be at risk or confirmed to have Ebola, level 3-4 biohazard. METHODS: A prospective before-after study was designed. Health care workers who participated in a multi-professional simulation training course to improve the care of patients potentially infected with Level 3 and 4 biohazards were evaluated about their risk perception. The training was based on clinical scenarios. The evaluation was conducted using questionnaire based on Likert scale. After the training, a satisfaction survey about the most important aspects of the course was also conducted. RESULTS: Fifty-eight health care workers participated in the training course, 22 of whom were registered nurses. Participants presented positive changes after the training, increasing their sense of security, predisposition and confidence (p < 0.000001 for all). CONCLUSION: Multi-professional simulation-based training significantly improves the perception of safety and preparedness of health care workers regarding the care of patients potentially infected with Ebola virus and other Level 3-4 biohazards. RELEVANCE TO CLINICAL PRACTICE: The implementation of educational training strategies - such as simulations - is beneficial in improving the capacity of response and coping, as well as in reducing feelings of fear and insecurity. PMID- 30460731 TI - Warm ischemic time as a critical risk factor of graft failure from donors after cardiac death: A single-center experience over three decades in the Kidney Donor Profile Index/Kidney Donor Risk Index era in Japan. AB - OBJECTIVES: To evaluate the prognostic value of the warm ischemic time and the validity of the Kidney Donor Profile Index/Kidney Donor Risk Index for predicting the survival of donors after cardiac death grafts. METHODS: We retrospectively assessed 315 kidneys retrieved from donors after cardiac death at Fujita Health University Hospital, Toyoake, Aichi, Japan. The Kidney Donor Profile Index/Kidney Donor Risk Index was calculated and the grafts were enrolled. RESULTS: The median follow-up period was 11.9 years. The Kidney Donor Profile Index had a markedly asymmetric distribution (median 94%), and the Kidney Donor Risk Index had high index rates (0.79-2.94, median 1.70). The overall 5-, 10- and 15-year graft survival rates were 67.5%, 52.1% and 38.9%, respectively. The Kidney Donor Profile Index correlated with graft survival. The 5-, 10- and 15-year graft survival rates for the Kidney Donor Profile Index <1.2 were 87.7%, 73.5% and 59.2%; those for the Kidney Donor Risk Index >2.0 were 55.0%, 34.7% and 22.1%, respectively. A Cox multivariate analysis identified the Kidney Donor Risk Index (hazard ratio 2.06, 95% confidence interval 1.48-2.86, P < 0.0001) and warm ischemic time (hazard ratio 1.21, 95% confidence interval 1.09-1.34, P = 0.0010) as independent risk factors for graft loss. The addition of warm ischemic time >30 min had a significant effect, as measured by the C-index (0.708-0.731, P = 0.032), improving the net reclassification improvement score (0.256, P = 0.0039) and integrated discrimination improvement score (0.042, P = 0.0022). CONCLUSIONS: The Kidney Donor Profile Index/Kidney Donor Risk Index is a good prognostic tool for determining the outcomes of donors after cardiac death grafts. However, the warm ischemic time should also be included in the allocation system for donors after cardiac death grafts. PMID- 30460730 TI - Helicobacter pylori antimicrobial resistance during a 5-year period (2013-2017) in northern Spain and its relationship with the eradication therapies. AB - BACKGROUND: Antibiotic resistance is the main cause for Helicobacter pylori therapy failure. Frequently, empirical regimens have been recommended in patients with various H. pylori eradication failures. In patients with H. pylori-resistant to various families of antibiotics, the treatment guided by antimicrobial susceptibility testing allows the achievement of good eradication rates. AIM: To evaluate the effectiveness of susceptibility-guided antimicrobial treatment for H. pylori infection in patients with resistance to one or various families of antibiotics. METHODS: A total of 3170 consecutive patients infected by H. pylori during 2013-2017 were tested for antimicrobial susceptibility. 66.6% patients showed resistance to one antimicrobial, 18.9% to two, and 2.4% to three families of antibiotics. A cohort of 162 H. pylori-positive patients were enrolled in this study. Forty-three with single H. pylori resistance to clarithromycin (CLR) were treated with omeprazole (PPI), amoxicillin (AMX), and levofloxacin (LVX)-OAL (31 subjects) or omeprazole, AMX, and metronidazole (MTZ)-OAM (12 patients) and 77 patients with dual H. pylori resistance (51 to CLR and MTZ, 12 to CLR plus LVX, and 14 to MTZ plus LVX) received OAL or OBTM (PPI, bismuth subcitrate, tetracycline, and MTZ), OAM, and OAC, respectively. Other 42 patients with triple H. pylori resistance (CLR, LVX, and MTZ) were treated with PPI, AMX, and rifabutin-OAR (18 subjects), PPI, AMX, and doxycycline-OAD (8), OADB (7), OBTM (6), and ODBR (3). All subjects received standard doses for 10 days. Eradication rate was confirmed by 13 C-UBT. Adverse events were assessed by a questionnaire. RESULTS: Intention-to-treat analysis demonstrates that eradication rates using triple therapies in patients with H. pylori resistance to one and to two families of antibiotics were 93% and 94.8%, respectively. In subjects with H. pylori resistant to three families of antibiotics, cure rate was higher in naive patients treated with OAR-10 days compared to those treated with bismuth containing quadruple therapies (90% vs 75%). Adverse events were limited (18 of 162, 11.1%), all of them mild-moderate. CONCLUSIONS: The implementation of susceptibility-guided triple therapy for 10 days leads to eradication rate >=95% in naive patients with H. pylori resistance to one or two families of antimicrobials. In naive patients with H. pylori resistance to three families, OAR treatment achieved a 90% of eradication. PMID- 30460732 TI - Systematic review of fertility-related psychological distress in cancer patients: Informing on an improved model of care. AB - OBJECTIVE: Cancer patients experience reproductive concerns from diagnosis through to survivorship. However, research has yet to investigate the degree of fertility-related psychological distress at different treatment time points: diagnosis, treatment, and survivorship. Currently, cancer patients are offered fertility counselling at the time of diagnosis, to assist fertility preservation decision making. A systematic review of the short-term and long-term psychological impact of infertility in cancer patients would inform on an improved, longitudinal model of psychological care. METHODS: A systematic review of the literature was conducted in January 2018 utilising electronic databases Medline, EMBASE, PSYCH Info, Web of Science, and SCOPUS. An initial search identified 708 potentially relevant studies. Literature was assessed that reported on fertility-related psychological distress experienced by male and female cancer patients of reproductive age (<45 years) across oncology treatment time points. RESULTS: A total of 47 papers were included within the final review. Fertility-related psychological distress persists from diagnosis through to survivorship, with cancer patients reporting a range of negative emotional experiences brought about by threatened infertility. In survivorship, reproductive concerns, unfulfilled desire for a child, nulliparous status, and early menopause were linked to higher rates of mental health disorders and psychological distress. CONCLUSIONS: Fertility-related psychological distress is prevalent and persistent in cancer patients and survivors. As such, patients and survivors would greatly benefit from fertility-related psychological support implemented into standard practice from diagnosis through to survivorship. A revised model of care is proposed. PMID- 30460733 TI - New Member of Gromochytriales (Chytridiomycetes) - Apiochytrium granulosporum nov. gen. et sp. AB - Molecular phylogenetic analysis of 18S rRNA gene sequences of nearly any species of Chytridiomycota has typically challenged traditional classification and triggered taxonomic revision. This has often led to the establishment of new taxa which, normally, appear well supported by zoospore ultrastructure, which provides diagnostic characters. To construct a meaningful and comprehensive classification of Chytridiomycota, the combination of molecular phylogenies and morphological studies of traditionally defined chytrid species is needed. In this work, we have studied morphological and ultrastructural features based on light and transmission electron microscopy as well as molecular phylogenetic analysis of a parasite (strain X-124 CCPP ZIN RAS) morphologically similar to Rhizophydium granulosporum living on the yellow-green alga Tribonema gayanum. Phylogenetic analysis of the 18S rRNA gene sequence of this strain supports that it represents a new genus and species affiliated to the recently established order Gromochytriales. The ultrastructure of X-124 confirms its phylogenetic position sister to Gromochytrium and serves as the basis for the description of the new genus and species Apiochytrium granulosporum. The 18S rRNA gene of A. granulosporum contains S943 intron carries a homing endonuclease pseudogene. This article is protected by copyright. All rights reserved. PMID- 30460734 TI - The Experience Sampling Method-Evaluation of treatment effect of escitalopram in IBS with comorbid panic disorder. AB - BACKGROUND: Confirming treatment response in clinical trials for irritable bowel syndrome (IBS) is challenging, due to the lack of biomarkers and limitations of the currently available symptom assessment tools. The Experience Sampling Method (ESM) might overcome these limitations by collecting digital assessments randomly and repeatedly during daily life. This study evaluated differences in change in abdominal pain between real-time (ie, ESM) and retrospective (ie, Gastrointestinal Symptom Rating Scale [GSRS] and an end-of-day symptom diary) measurements, using data of an RCT on escitalopram vs placebo in patients with IBS and comorbid panic disorder. METHODS: Twenty-nine IBS patients with comorbid panic disorder were included in a 6-month RCT. The GSRS, diary, and ESM were completed at baseline (t = 0) and after 3 (t = 3) and 6 months (t = 6). Linear mixed models were used. KEY RESULTS: Experience Sampling Method analyses revealed a significant interaction between escitalopram and time, and ESM abdominal pain scores were 1.4 points lower in the escitalopram group compared to placebo at t = 6 (on a 1-to-7 scale; P = 0.021). When including the interaction with momentary anxiety, the reduction in abdominal pain scores in escitalopram vs placebo was even more pronounced for higher levels of anxiety. Average GSRS- and end-of-day abdominal pain scores were not significantly different between escitalopram and placebo at t = 3 and 6. CONCLUSIONS & INFERENCES: Real-time ESM has the potential to capture treatment response more sensitively compared to a retrospective end-of day GI symptom diary and the GSRS, by taking into account day-to-day symptom variability as well as momentary factors that might moderate treatment effect, such as anxiety. PMID- 30460735 TI - Patch testing with alkyl glucosides: concomitant reactions are common but not ubiquitous. AB - BACKGROUND: Alkyl glucosides are a family of mild surfactants that are increasingly used in a wide range of cosmetics and household products. Contact allergy to alkyl glucosides may be more frequent than previously suspected, especially in atopic patients. OBJECTIVES: To investigate the frequency of contact allergy to alkyl glucosides and to identify concomitant reactivity. PATIENTS/METHODS: We retrospectively reviewed all cases of suspected allergic contact dermatitis (ACD) in which patients were either patch tested with a cosmetic series that includes five alkyl glucosides (decyl glucoside, lauryl glucoside, coco glucoside, cetearyl glucoside, caprylyl/capryl glucoside) or a specific alkyl glucoside series from November 2013 to April 2017 in two UK centres. RESULTS: A total of 5775 patients were patch tested across the two centres. Twenty-nine (1.04%) of the 2796 patients tested to the cosmetic/alkyl glucoside series had a positive patch test reaction to at least one of the alkyl glucosides. Twenty three (79.3%) were sensitised to multiple alkyl glucosides; 21 patients (72.4%) were female. The mean age was 43.5 years. Twelve patients (41.4%) had a background of atopic dermatitis. CONCLUSIONS: The prevalence of alkyl glucoside-induced ACD is relatively high and there are frequent concomitant reactions between different alkyl glucosides. We recommend the inclusion of alkyl glucosides in all cosmetic series. PMID- 30460736 TI - Facilitation promotes invasions in plant-associated microbial communities. AB - While several studies have established a positive correlation between community diversity and invasion resistance, it is less clear how species interactions within resident communities shape this process. Here, we experimentally tested how antagonistic and facilitative pairwise interactions within resident model microbial communities predict invasion by the plant-pathogenic bacterium Ralstonia solanacearum. We found that facilitative resident community interactions promoted and antagonistic interactions suppressed invasions both in the lab and in the tomato plant rhizosphere. Crucially, pairwise interactions reliably explained observed invasion outcomes also in multispecies communities, and mechanistically, this was linked to direct inhibition of the invader by antagonistic communities (antibiosis), and to a lesser degree by resource competition between members of the resident community and the invader. Together, our findings suggest that the type and strength of pairwise interactions can reliably predict the outcome of invasions in more complex multispecies communities. PMID- 30460737 TI - Low glycaemic index diets as an intervention for obesity: a systematic review and meta-analysis. AB - OBJECTIVES: Low glycaemic index (GI) diets may aid in weight loss by reducing postprandial blood glucose excursions, leading to more stable blood glucose concentrations and therefore a reduction in hunger. To test this hypothesis, we conducted a systematic review and meta-analysis of randomized controlled trials comparing low GI diets with other diet types. METHODS: We included 101 studies involving 109 study arms and 8,527 participants. We meta-analysed the studies using a random-effects model and conducted subgroup analyses and meta-regression based on control diet, blood glucose control, baseline BMI and dietary GI. RESULTS: Low GI diets resulted in small but significant improvements in body weight, BMI, LDL and total cholesterol overall, although no individual control diet was significantly different from low GI diets. Studies in people with normal blood glucose who achieved a difference in GI of 20 points or more resulted in a larger reduction in body weight (SMD = -0.26; 95% CIs [-0.43, -0.09]), and total cholesterol (SMD = -0.24; 95% CIs [-0.42, -0.05]) than studies that only achieved a smaller reduction in GI. CONCLUSIONS: Low GI diets, especially diets achieving a substantial decrease in GI, were moderately effective in lowering body weight. However, efforts should be made to increase compliance with low GI diets, in order for them to be effective in people with overweight and obesity. PMID- 30460738 TI - Invasive plants differentially affect soil biota through litter and rhizosphere pathways: a meta-analysis. AB - Invasive plants affect soil biota through litter and rhizosphere inputs, but the direction and magnitude of these effects are variable. We conducted a meta analysis to examine the different effects of litter and rhizosphere of invasive plants on soil communities and nutrient cycling. Our results showed that invasive plants increased bacterial biomass by 16%, detritivore abundance by 119% and microbivore abundance by 89% through litter pathway. In the rhizosphere, invasive plants reduced bacterial biomass by 12%, herbivore abundance by 55% and predator abundance by 52%, but increased AM fungal biomass by 36%. Moreover, CO2 efflux, N mineralisation rate and enzyme activities were all higher in invasive than native rhizosphere soils. These findings indicate that invasive plants may support more decomposers that in turn stimulate nutrient release via litter effect, and enhance nutrient uptake by reducing root grazing but forming more symbioses in the rhizosphere. Thus, we hypothesise that litter- and root-based loops are probably linked to generate positive feedback of invaders on soil systems through stimulating nutrient cycling, consequently facilitating plant invasion. Our findings from limited cases with diverse contexts suggest that more studies are needed to differentiate litter and rhizosphere effects within single systems to better understand invasive plant-soil interactions. PMID- 30460739 TI - The use of fat grafting and platelet-rich plasma for wound healing: A review of the current evidence. AB - Fat grafting is becoming a common procedure in regenerative medicine because of its high content of growth factors and adipose derived stem cells (ADSCs) and the ease of harvest, safety, and low cost. The high concentration of ADSCs found in fat has the potential to differentiate into a wide range of wound-healing cells including fibroblasts and keratinocytes as well as demonstrating proangiogenic qualities. This suggests that fat could play an important role in wound healing. However retention rates of fat grafts are highly variable due in part to inconsistent vascularisation of the transplanted fat. Furthermore, conditions such as diabetes, which have a high prevalence of chronic wounds, reduce the potency and regenerative potential of ADSCs. Platelet-rich plasma (PRP) is an autologous blood product rich in growth factors, cell adhesion molecules, and cytokines. It has been hypothesised that PRP may have a positive effect on the survival and retention of fat grafts because of improved proliferation and differentiations of ADSCs, reduced inflammation, and improved vascularisation. There is also increasing interest in a possible synergistic effect that PRP may have on the healing potential of fat, although the evidence for this is very limited. In this review, we evaluate the evidence in both in vitro and animal studies on the mechanistic relationship between fat and PRP and how this translates to a benefit in wound healing. We also discuss future directions for both research and clinical practice on how to enhance the regenerative potential of the combination of PRP and fat. PMID- 30460740 TI - Using a muscle pump activator device to stimulate healing for non-healing lower leg wounds in long-term care residents. AB - Chronic non-healing wounds are a burden in the Long-Term Care (LTC) sector, increasing costs, morbidity, and mortality and causing pain and suffering. The objective of this LTC Innovation pilot was to test the value of a promising new neuromuscular stimulation device in elevating the experience and satisfaction of the residents, engaging and empowering the nursing staff, and improving healing and/or reducing costs. Small, wireless, and worn at the knee, this muscle pump activator is self-contained, wearable, and battery-powered to increase lower-leg blood circulation (up to 60% of that achieved by walking). It has no wires, weighs just 10 g, and is easy to use. Nurses in four LTC homes identified residents with non-healing lower leg wounds. Consent was obtained, and on-site training was delivered. Eleven residents were recruited. Only seven met the inclusion criteria for venous/mixed or diabetic foot ulcers. Of the seven who met the criteria and were adherent with best practices and the muscle pump activator, four healed 100%, and one healed 90%. Two patients with other aetiologies, who were also adherent, healed. All adherent residents had an average weekly decrease in wound size of 9.75% and were extremely happy with the results. Three residents who were non-adherent had a 9.25% increase in wound size per week. One patient with diabetic foot ulcers developed skin changes at the end of life and passed away. Nursing staff and cognisant residents can easily adjust the pulse of muscle pump activator, and application and removal are simple. Most residents feel engaged with the therapy "because they feel it working". The LTC corporation feels that it is a great adjunctive solution for many types of lower-leg wounds (venous, mixed, diabetic, pressure) in addition to best practices in the LTC and Retirement home sectors. PMID- 30460741 TI - A further change of the guard. PMID- 30460743 TI - Design and synthesis of selective acetylcholinesterase inhibitors: arylisoxazole phenylpiperazine derivatives. AB - In this work, a novel series of arylisoxazole-phenylpiperazines 5a-k were designed, synthesized, and evaluated toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Our results revealed that (5-(2 chlorophenyl)isoxazol-3-yl)(4-phenylpiperazin-1-yl)methanone (5c) was the most potent AChE inhibitor with IC50 of 21.85 uM. It should be noted that most of synthesized compounds showed no BChE inhibitory activity and (5-phenylisoxazol-3 yl)(4-phenylpiperazin-1-yl)methanone (5a) was the most active anti-BChE derivative (IC50 = 51.66 uM). Also, kinetic studies for the AChE and BChE inhibitory activity of compounds 5c and 5a confirmed that they have simultaneously bound to the catalytic site (CS) and peripheral anionic site (PAS) of both AChE and BChE. Furthermore, docking study of compound 5c showed desired interactions of that compound with amino acid residues located in the active and peripheral anionic sites. Compound 5c was also evaluated for its BACE1 inhibitory activity and demonstrated IC50 = 76.78 uM. Finally, neuroprotectivity of compound 5c on Abeta-treated neurotoxicity in PC12 cells depicted low activity. PMID- 30460744 TI - Age-associated changes in the blood-brain barrier: comparative studies in human and mouse. PMID- 30460745 TI - Design and Catalytic Asymmetric Construction of Axially Chiral 3,3'-Bisindole Skeletons. AB - The first catalytic asymmetric construction of 3,3'-bisindole skeletons bearing both axial and central chirality has been established via organocatalytic asymmetric addition reactions of 2-substituted 3,3'-bisindoles with 3 indolylmethanols (up to 98% yield, all >95:5 dr, >99% ee). This reaction also represents the first highly enantioselective construction of axially chiral 3,3' bisindole skeletons, which utilized the strategy of introducing a bulky group to the ortho-position of prochiral 3,3'-bisindoles. This reaction not only provides a good example for simultaneously controlling the axial chirality and the central chirality in one operation, but also serves as a new strategy for catalytic enantioselective construction of axially chiral 3,3'-bisindole backbones from prochiral substrates. PMID- 30460746 TI - Risk factors for high myopia: a 22-year follow-up study from childhood to adulthood. AB - PURPOSE: To determine the effect of the definition of high myopia on its prevalence and risk factors for high myopia. METHODS: A total of 240 myopic schoolchildren (119 boys and 121 girls) at the mean age of 10.9 years (range 8.8 12.8 years) were recruited to a randomized clinical trial of myopia treatment among children from 3rd- and 5th grades of school referred for an eye examination due to poor distant vision and having no previous spectacles. Clinical follow ups, including refraction with cycloplegia, were conducted annually at 3 years [third follow-up here = clinical follow-up 1, (n = 237)], and thereafter twice at approximately 10-year intervals [clinical follow-ups 2 (n = 179) and 3, (n = 134)]. Additional refraction values between follow-ups 2 and 3 were received from ophthalmologists and opticians' prescriptions and records. The most recent adulthood refraction measure available was taken as the final refraction value for 204 (85%) of the original cohort [mean follow-up time (+/-standard deviation) 22.1 (+/-3.9) years]. Parental myopia, time spent on reading and close work, watching TV and outdoor activities were assessed with a questionnaire at the clinical follow-ups. The influence of different definitions of high myopia on its prevalence was analysed. The associations of different factors with high myopia were investigated. RESULTS: Mean spherical equivalent (SE) at baseline was -1.43 (+/-0.60) D, ranging from -0.38 D to -3.00 D. At follow-up end, mean SE of the more myopic eye was -5.29 (+/-1.95) D, ranging from -1.00 D to -11.25 D. High myopia prevalence with the definitions SE < -6.00 D in the right eye and SE <= 6.00 D or <=-5.00 D in either eye was 24%, 32% and 52%, respectively. In this study, high myopia was defined as spherical equivalent (SE) <= -6.00 D in either eye. If both parents were myopic, the odds ratio (OR) of having high myopia was 3.9 (95% CI: 1.5-10.4). Younger age at baseline predicted higher prevalence of high myopia; baseline ages between 8.8 and 9.7 and between 11.9 and 12.8 years gave prevalences 65% and 7%. Higher myopia at baseline, higher myopic progression between the first follow-ups and more time spent on reading and close work as compared with time spent outdoors were associated with high myopia. CONCLUSION: About 32% of the children receiving first spectacles for myopia between ages of 8.8-12.8 years had high myopia (SE <= -6.00 D in either eye) in adulthood. Different definitions of high myopia ranging between -5 D and -6 D lead to large differences in prevalence. A generally accepted definition of high myopia is thus needed. Parental myopia, age at baseline, myopic progression during the first post onset year, and more time spent on reading and close work and less on outdoor activities in childhood were associated with adulthood high myopia. PMID- 30460747 TI - Results from a person-centered music intervention for individuals living with dementia. AB - AIM: Dementia is a chronic, costly disease affecting millions of people worldwide. Effective, affordable person-centered interventions are required to improve the lived experiences of individuals with dementia and their caregivers in various care settings. The present study examined the effects of a person centered music listening intervention on mood, agitation and social engagement for individuals living with dementia. METHODS: This quasi-experimental study was carried out with participants at five community-based adult day health centers (n = 51). Standardized instruments were used to measure mood and agitation, and in person and video-recorded observations of participant behavior were used to analyze changes before, during and after the intervention across four domains: mood, agitation, connecting to music and engaging socially. Within-person differences were examined using the Wilcoxon signed rank test, and between-group differences were examined using the Mann-Whitney U-test. RESULTS: Although standardized instruments did not yield statistically significant results, the behavioral observations showed a positive change in mood and a decrease in agitation. From pre- to post-intervention, there were statistically significant increases in joy, eye contact, eye movement, being engaged and talkativeness, and a decrease in sleeping and moving or dancing. CONCLUSIONS: Behavioral observations show the positive impact a person-centered music listening intervention might have on individuals living with dementia and attending adult day health centers. This affordable intervention provides a useful tool for caregivers that might improve the day-to-day experience of individuals living with dementia. Geriatr Gerontol Int 2018; **: **-**. PMID- 30460748 TI - Recent Updates In Curcumin Pyrazole and Isoxazole Derivatives: Synthesis and Biological Application. AB - Curcumin is a admired, plant-derived compound that has been extensively investigated for diverse range of biological activities, but the use of this polyphenol is limited due to its instability. Chemical modifications in curcumin is reported to seize this limitation, such efforts are intensively performed to discover molecules with similar but improved stability and better properties. Focal point of these review are synthesis of stable pyrazole and isoxazole analogs of curcumin and application in various biological systems. This review aims to emphasize the latest evidence of curcumin pyrazole analogs as a privileged scaffold in medicinal chemistry. Manifold features of curcumin pyrazole analogs will be summarized herein, including the synthesis of novel curcumin pyrazole analogs and the evaluation of their biological properties. This review is expected to be a complete, trustworthy, and critical review of the curcumin pyrazole analogs template to the medicinal chemistry community. PMID- 30460749 TI - Hepatitis B and Renal Function: A Matched Study Comparing Non-Hepatitis B, Untreated, Treated and Cirrhotic Hepatitis Patients. AB - BACKGROUND/AIM: Renal impairment is associated with chronic hepatitis B (CHB). To overcome prior study design differences, we used propensity score matching to balance the non- CHB and CHB cohorts and generalized linear modeling (GLM, models using probit and logit linking functions for complex models) to evaluate the effect of CHB, treatment, and cirrhosis on renal function. METHODS: A retrospective cohort (1996-2017) from one U.S. university medical center. Included patients had >=12 months of serial creatinine labs and a baseline estimated glomerular filtration rate (eGFR, by the Modification of Diet in Renal Disease Study equation) >=60 mL/min/1.73 m2 . Propensity score matching was performed using age, sex, ethnicity, diabetes, hypertension, and baseline eGFR. GLM was performed to generate adjusted mean eGFR over time. RESULTS: Adjusted mean eGFR was significantly higher for non-CHB vs. untreated CHB patients (eGFR 87.4 vs. 85.6, p=0.004, n=580, median follow-up=82 months). A significant difference in adjusted mean eGFR between untreated vs. entecavir (ETV)-treated CHB patients (eGFR 85.1 vs. 83.5, p=0.02, n=340, median follow-up=70 months) was found among non-cirrhotic CHB. Among treated CHB, there was no difference in adjusted mean eGFR between non-cirrhotic vs. cirrhotic patients (eGFR 77.0 vs. 76.5; p=0.66, n=112, median follow-up=58 months). CONCLUSION: After PSM and GLM, the significant predictors for worsening renal function were age, hypertension, and diabetes mellitus but not CHB, ETV, or cirrhosis. However, given small sample size, data regarding the use of ETV in patients with cirrhosis should be interpreted with caution and requires additional investigation. This article is protected by copyright. All rights reserved. PMID- 30460750 TI - Interruption points in the wing gene regulatory network underlying wing polyphenism evolved independently in male and female morphs in Cardiocondyla ants. AB - Wing polyphenism in ants, which produces a winged female queen caste and a wingless female worker caste, evolved approximately 150 million years ago and has been key to the remarkable success of ants. Approximately 20 million years ago, the myrmicine ant genus Cardiocondyla evolved an additional wing polyphenism among males producing two male morphs: wingless males that fight to enhance mating success and winged males that disperse. Here we show that interruption of rudimentary wing-disc development in larvae of the ant Cardiocondyla obscurior occurs further downstream in the network in wingless males as compared with wingless female workers. This pattern is corroborated in C. kagutsuchi, a species from a different clade within the genus, indicating that late interruption of wing development in males is conserved across Cardiocondyla. Therefore, our results show that the novel male wing polyphenism was not developmentally constrained by the pre-existing female wing polyphenism and evolved through independent alteration of interruption points in the wing gene network. Furthermore, a comparison of adult morphological characters in C. obscurior reveals that developmental trajectories lead to similar morphological trait integration between winged and wingless females, but dramatically different integration between winged and wingless males. This suggests that the alternative sex-specific developmental routes to achieve winglessness in the genus Cardiocondyla may have evolved through different selection regimes acting on wingless males and females. PMID- 30460751 TI - A Convergent Synthetic Strategy towards Oligosaccharides containing 2,3,6 Trideoxypyranoglycosides. AB - A de novo synthetic strategy for the production of oligosaccharides containing 2,3,6-trideoxypyranoglycoside is reported. The key event is the Pd-catalyzed asymmetric diastereoselective hydroalkoxylation of ene-alkoxyallene-linked glycosidic fragments. The utility of this approach was demonstrated by the activation-free, stereodivergent, and convergent synthesis of various 2 deoxyoligosaccharides, as well as their aglycon conjugates. PMID- 30460752 TI - Simulation as a learning method in public health nurse education. AB - OBJECTIVE: To view simulation as a learning method in the light of learning theories and to describe the student's reflections and experiences of simulating anaphylaxis during vaccination. DESIGN AND SAMPLE: Public health nursing students at a university in Norway simulated scenarios related to anaphylaxis during vaccination of an infant. The aim of the intervention was to facilitate the competence of public health nurses to handle unforeseen events associated with vaccinations. The students wrote reflection notes about their experiences after the simulation. The reflection notes were analyzed using qualitative content analysis. RESULTS: The students experienced simulation as a realistic educational method with feelings of stress in an acute situation. They discovered the importance of cooperation and communication to avoid misunderstandings that could lead to serious failure in the treatment. The students emphasized that simulation gave them a preparation for practice to handle anaphylaxis associated with vaccines. CONCLUSION: The public health nurse students experienced simulation as a realistic and effective educational method. Simulation made them reflect on the public health nurse's area of responsibility. Kolb's learning theory and Schon's theory of knowledge-in-action, may explain how simulation as a didactic method develops competence to act in a concrete situation of anaphylaxis by vaccination of children. PMID- 30460753 TI - Corrigendum. PMID- 30460754 TI - Echocardiographic diastolic function evolution in patients with an anterior Q wave myocardial infarction: insights from the REVE-2 study. AB - AIMS: Myocardial fibrosis plays a key role in the development of adverse left ventricular remodelling after myocardial infarction (MI). This study aimed to determine whether the circulating levels of BNP, collagen peptides, and galectin 3 are associated with diastolic function evolution (both deterioration and improvement) at 1 year after an anterior MI. METHODS AND RESULTS: The REVE-2 is a prospective multicentre study including 246 patients with a first anterior Q-wave MI. Echocardiographic assessment was performed at hospital discharge and +/-1 year after MI. BNP, galectin-3, and collagen peptides were measured +/-1 month after MI. Left ventricular diastolic dysfunction (DD) was defined according to the presence of at least two criteria of echocardiographic parameters: septal e' < 8 cm/s, lateral e' < 10 cm/s, and left atrial volume >= 34 mL/m2 . At baseline, 87 (35.4%) patients had normal diastolic function and 159 (64.6%) patients had DD. Follow-up of 61 patients among the 87 patients with normal diastolic function at baseline showed that 22 patients (36%) developed DD at 1 year post-MI. The circulating levels of amino-terminal propeptide of type III procollagen > 6 mg/L [odds ratio (OR) = 5.29; 95% confidence interval (CI) = 1.05-26.66; P = 0.044], galectin-3 > 13 MUg/L (OR = 5.99; 95% CI = 1.18-30.45; P = 0.031), and BNP > 82 ng/L (OR = 10.25; 95% CI = 2.36-44.50; P = 0.002) quantified at 1 month post-MI were independently associated with 1 year DD. Follow-up of the 137 patients with DD at baseline among the 159 patients showed that 36 patients (26%) had a normalized diastolic function at 1 year post-MI. Patients with a BNP > 82 ng/L were less likely to improve diastolic function (OR = 0.06; 95% CI = 0.01-0.28; P = 0.0003). CONCLUSIONS: The present study suggests that circulating levels of amino-terminal propeptide of type III procollagen, galectin-3, and BNP may be independently associated with new-onset DD in post-MI patients. PMID- 30460755 TI - A comparative study: tongue muscle performance in weightlifters and runners. AB - Exercise mode (i.e., resistance training, endurance training) is known to yield mode-specific effects on strength and endurance of muscles that are directly targeted during the exercise. Such mode-specific effects can also be observed in indirectly involved (i.e., nontargeted) muscles. Mode-specific muscle performance changes of nontargeted muscles, however, have only been investigated within the skeletal system. Therefore, as a first step, this study aimed to determine if bulbar muscle performance (tongue strength [TS], tongue endurance [TE]) differs between weightlifters and runners and if group differences are tongue region specific. The Iowa Oral Performance Instrument (IOPI) was used to measure TS and TE of the anterior and posterior tongue regions in 21 weightlifters and 23 runners. In weightlifters anterior TS was significantly greater than posterior TS (P = 0.008), whereas in runners anterior and posterior TS were comparable. Furthermore, weightlifters produced significantly greater anterior TS than runners (P = 0.001). Finally, TE was overall significantly greater in runners than in weightlifters (P = 0.001). Findings suggest that exercise mode may differentially impact performance patterns of nontargeted bulbar muscles. More research is warranted to better understand the mechanisms underlying tongue muscle performance differences between weightlifters and runners. PMID- 30460757 TI - CD47 agonist peptide pkhb1 induces immunogenic cell death in T-cell acute lymphoblastic leukemia cells. AB - T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis derived from its genetic heterogeneity, which translates to a high chemoresistance. Recently, our workgroup designed TSP1-derived CD47 agonist peptides and demonstrated their ability to induce cell death in chronic lymphocytic leukemia. Encouraged by these promising results, we evaluated cell death induced by PKHB1 (the first-described serum-stable CD47-agonist peptide) on CEM and MOLT-4 human cell lines (T-ALL) and on one T-murine tumor lymphoblast cell-line (L5178Y-R), also assessing caspase and calcium dependency and mitochondrial membrane potential. Additionally, we evaluated selectivity for cancer cell lines by analyzing cell death and viability of human and murine non-tumor cells after CD47 activation. In vivo, we determined that PKHB1-treatment in mice bearing L5178Y-R cell line, increased leukocyte cell count in peripheral blood and lymphoid organs while recruiting leukocytes to the tumor site. To analyze if CD47 activation induced immunogenic cell death (ICD), we evaluated damage-associated molecular patterns (DAMPs) exposure (Calreticulin, CRT) and release (ATP, HSP70, HSP90, HMGB1, CRT). Furthermore, we administered a prophylactic antitumor vaccination, determining immunologic memory. Our data indicate that PKHB1 induces caspase-independent and calcium-dependent cell death in leukemic cells while sparing non-tumor murine and human cells. Moreover, our results show that PKHB1 can induce ICD in leukemic cells as it induces CRT exposure and DAMPs release in vitro, and prophylactic vaccinations inhibit tumor establishment in vivo. Altogether our results improve the knowledge of CD47 agonist peptides potential as therapeutic tools to treat leukemia. This article is protected by copyright. All rights reserved. PMID- 30460756 TI - Reliability and validity of the Dutch Anxiety, Depression And Mood Scale in adults aged <50 years with intellectual disabilities. AB - BACKGROUND: Reliable and valid screening instruments for depression and anxiety are needed for adults with intellectual disabilities. METHODS: Internal consistency (n = 198), inter-rater reliability (n = 41), test-retest reliability (n = 37) and criterion validity (n = 43) were studied in adults aged between 18 and 49 years. Internal consistency was also studied in a sample with epilepsy (n = 98). RESULTS: Internal consistencies of the Dutch ADAMS total scale and subscales were satisfactory to good (alpha = 0.76-0.92), as well as in the subgroup with epilepsy (alpha = 0.74-0.88). Inter-rater reliability and test retest reliability were fair to excellent for the total scale (ICC's: 0.57-0.84) and subscales (ICC's: 0.43-0.86). The criterion validity of the Dutch ADAMS Depressive Mood subscale was good with a sensitivity of 88% (95% CI: 53%-98%) and a specificity of 80% (95% CI: 64%-90%). CONCLUSIONS: Our study shows that the Dutch ADAMS is a reliable and valid instrument for adults aged between 18 and 49 years with intellectual disabilities (and comorbid epilepsy). PMID- 30460758 TI - Nano-Cu-mediated multi-sites approach for growing ultrafine MoO2 nanoparticles on PDDA-rGO as a robust hydrogen evolution electrocatalyst. AB - The catalyst with high atom utilization efficiency accompanied by improved reactivity and durability is highly desired. Metallic MoO2 with small size is easy to agglomerate, making it difficult to water splitting for hydrogen by electrolysis. Here, the nano-Cu-mediated multi-sites method is proposed for the first time to prepare ultrafine MoO2 nanoparticles (NPs) dispersed on poly (diallyldimethylammonium chloride) decorated-reduced graphene oxide (denoted as MoO2/PDDA-rGO). The introduction of Cu NPs increases the number of growing sites for MoO2 on PDDA-rGO and simultaneously promotes the growing rate of MoO2 on PDDA rGO. As a consequence, the resulting size of MoO2 NPs is only 2 nm and evenly disperse on PDDA-rGO. Significantly, the optimized catalyst possesses an onset potential low to -42 mV vs. reversible hydrogen electrode (RHE), a calculated Tafel slope only 42 mV dec-1 and good cycling stability more than 40 h. This favored hydrogen evolution reaction (HER) activity is aroused by the synergistic effect of MoO2 and PDDA-rGO, rapid charge transport and sufficient exposed active sites of MoO2/PDDA-rGO. PMID- 30460759 TI - Rabbit syndrome as a side effect triggered by amisulpride. PMID- 30460760 TI - The impact of genetic variants in IL1R2 on cervical cancer risk among Uygur females from China: A case-control study. AB - BACKGROUND: Disordered inflammation and immune response is an acknowledged risk factor for cervical cancer development. Interleukin-1 receptor type 2 (IL1R2) is a decoy receptor for IL-1 cytokines and involved in host inflammatory and immune progression which could lead to the lesion and neoplasia of cervix. In this study, we aimed to evaluate the relationships between IL1R2 polymorphisms and cervical cancer risk in Uygur females from China. METHODS: In this case-control study, genotypes of six selected variants (rs11674595, rs4851527, rs719250, rs3218896, rs3218977, and rs2072472) distributed in IL1R2 were detected among 247 cervical cancer patients and 286 healthy controls with the usage of an Agena MassARRY method. Furthermore, Genetic models and haplotype analyses were conducted to estimate the associations of IL1R2 polymorphisms with cervical cancer risk. RESULTS: After statistical analyses, rs719250 (odd ratio [OR] = 1.436, 95% confidence interval [95% CI] = 1.079-1.911, p = 0.013) and rs3218896 (OR = 1.552, 95% CI = 1.080-2.229, p = 0.017) showed obvious evidence in correlation to cervical cancer susceptibility owing to the surviving significant differences between cases and controls in allele model. Genetic model analyses also revealed significant associations of rs719250 and rs3218896 with cervical cancer risk in the codominant model, the dominant model and the log-additive model even after adjustment for age (p < 0.05). Moreover, haplotype "T/A" of rs11674595/rs4851527 (adjusted OR = 0.73, 95% CI = 0.54-0.98, p = 0.037) and "T/C" of rs719250/rs3218896 (adjusted OR = 1.61, 95% CI = 1.10-2.36, p = 0.015) exhibited protective and risky effects for Uygur individuals on cervical cancer development, respectively. CONCLUSION: Our data first shed the new light on the associations of IL1R2 polymorphisms with cervical cancer susceptibility among Uygur females. These results are supposed to facilitate the tumorigenesis genetic research among Chinese minorities. PMID- 30460761 TI - Retinal oximetry and systemic arterial oxygen levels. AB - PURPOSE: Continuous peripheral pulse oximetry for monitoring adequacy of oxygenation is probably the most important technological advance for patients' monitoring and safety in the last decades. Pulse oximetry has the disadvantage of measuring the peripheral circulation, and the only mean to measure oxygen content of the central circulation is by invasive technology. Determination of blood oxyhaemoglobin saturation in the retinal vessels of the eye can be achieved noninvasively through spectrophotometric retinal oximetry which provides access to the central nervous system circulation. The aim of the thesis was to determine whether retinal oximetry technique can be applied for estimation of the central nervous system circulation which until now has only been possible invasively. This was achieved by measuring oxyhaemoglobin saturation in three adult subject study groups: in people with central retinal vein occlusion (CRVO) to observe local tissue hypoxia, in patients with severe chronic obstructive pulmonary disease (COPD) on long-term oxygen therapy to observe systemic hypoxaemia and in healthy subjects during hyperoxic breathing to observe systemic hyperoxemia. In addition, the fourth study that is mentioned was performed to test whether retinal oximetry is feasible for neonates. METHODS: Retinal oximetry in central retinal vein occlusion: Sixteen subjects with central retinal vein occlusion participated in the study. The oxyhaemoglobin saturation of the central retinal vein occlusion affected eye was compared with the fellow unaffected eye. Retinal oximetry in healthy people under hyperoxia: Thirty healthy subjects participated in the study, and the oxyhaemoglobin saturation of retinal arterioles and venules was compared between normoxic and hyperoxic breathing. Retinal oximetry in severe chronic obstructive pulmonary disease: Eleven patients with severe chronic obstructive pulmonary disease participated in the study. Retinal oximetry measurements were made with and without their daily supplemental oxygen therapy. Retinal arteriolar oxyhaemoglobin saturation when inspiring ambient air was compared with blood samples from the radial artery and finger pulse oximetry and healthy controls. The healthy control group was assembled from our database for comparison of oxyhaemoglobin saturation of retinal arterioles and venules during the ambient air breathing. The retinal oximeter is based on a conventional fundus camera and a specialized software. A beam splitter coupled with two high resolution digital cameras allows for simultaneous acquisition of retinal images at separative wavelengths for calculation of oxyhaemoglobin saturation. In addition, retinal images of 28 full-term healthy neonates were obtained with scanning laser ophthalmoscope combined with modified Oxymap analysis software for calculation of the optical density ratio and vessel diameter RESULTS: Retinal oximetry in central retinal vein occlusion: Mean retinal venous oxyhaemoglobin saturation was 31 +/- 12% in CRVO eyes and 52 +/- 11% in unaffected fellow eyes (mean +/- SD, n = 14, p < 0.0001). The arteriovenous oxygen difference (AV difference) was 63 +/- 11% in CRVO eyes and 43 +/- 7% in fellow eyes (p < 0.0001). The variability of retinal venous oxyhaemoglobin saturation was considerable within and between eyes affected by CRVO. There was no difference in oxyhaemoglobin saturation of retinal arterioles between the CRVO eyes and the unaffected eyes (p = 0.49). Retinal oximetry in healthy people under hyperoxia: During hyperoxic breathing, the oxyhaemoglobin saturation in retinal arterioles increased to 94.5 +/- 3.8% as compared with 92.0 +/- 3.7% at baseline (n = 30, p < 0.0001). In venules, the mean oxyhaemoglobin saturation increased to 76.2 +/- 8.0% from 51.3 +/- 5.6% (p < 0.0001) at baseline. The AV-difference was markedly lower during hyperoxic breathing as compared with the normoxic breathing (18.3 +/ 9.0% versus 40.7 +/- 5.7%, p < 0.0001). Retinal oximetry in severe chronic obstructive pulmonary disease: During ambient air breathing, chronic obstructive pulmonary disease subjects had significantly lower oxyhaemoglobin saturation than healthy controls in both retinal arterioles (87.2 +/- 4.9% versus 93.4 +/- 4.3%, p = 0.02, n = 11) and venules (45.0 +/- 10.3% versus 55.2 +/- 5.5%, p = 0.01) but the AV-difference was not markedly different (p = 0.17). Administration of their prescribed oxygen therapy significantly increased the oxyhaemoglobin saturation in retinal arterioles (87.2 +/- 4.9% to 89.5 +/- 6.0%, p = 0.02) but not in venules (45.0 +/- 10.3% to 46.7 +/- 12.8%, p = 0.3). Retinal oximetry values were slightly lower than finger pulse oximetry (mean percentage points difference = 3.1 +/- 5.5) and radial artery blood values (-5.0 +/- 5.4). Retinal oximetry study in neonates: The modified version of the retinal oximetry instrument estimated the optical density ratio in retinal arterioles to be 0.256 +/- 0.041 that was significantly different from the 0.421 +/- 0.089 in venules (n = 28, p < 0.001, paired t-test). The vascular diameter of retinal arterioles was markedly narrower than of venules (14.1 +/- 2.7 and 19.7 +/- 3.7 pixels, p < 0.001). CONCLUSION: The results of this thesis indicate that spectrophotometric retinal oximetry is sensitive to both local and systemic changes in oxyhaemoglobin saturation. Retinal oxyhaemoglobin saturation values are slightly lower than radial artery blood sample and finger pulse oximetry values. The discrepancies between the different modalities are expected to derive from countercurrent exchange between central retinal artery and vein within the optic nerve but calibration issues cannot be excluded as contributing to this difference. Despite these differences, the findings indicate the potential of retinal oximetry for noninvasive real-time measurements of oxyhaemoglobin saturation in central nervous system vessels. Following calibration upgrade and technological improvement, verification retinal oximetry may potentially be applied to critically ill and anaesthesia care patients. The study on combined scanning laser ophthalmoscope and retinal oximetry supports the feasibility of the technique for oximetry analysis in newly born babies. PMID- 30460762 TI - Expression pattern and histone acetylation of energy metabolic genes in Xenopus laevis liver in response to diet statuses. AB - Amphibians can survive without food for relatively longer periods by reducing the locomotor activity and metabolic rate and can recover quickly with refeeding from a dormant state. To clarify the molecular mechanism underlying this survival strategy, we investigated serum biochemical parameters, the transcript levels of energy metabolic genes, and global and gene-specific histone modifications in the liver of adult male Xenopus laevis, which were fed, fasted, or refed after fasting. Glucose, triglyceride, cholesterol, and free fatty-acid levels in sera decreased with fasting for 22 days, with only glucose levels recovered with 1 day of refeeding. The transcript levels of two-thirds of energy metabolic genes tested decreased with fasting for 22 days and partially recovered with 1 day of refeeding. The transcript levels of gluconeogenesis and lipid catabolism genes did not increase with fasting for 22 days. The Western blot analysis revealed no significant differences in the amounts of acetylated and methylated histones in the liver among the three groups on Day 22. The amounts of acetylated histone H4 did not change in diet-response genes, although the transcript levels of these genes quickly responded to fasting and refeeding. Our results indicate that Xenopus liver may respond to fasting toward an overall decrease in transcriptional activity and to refeeding toward quick recovery, despite no significant changes in histone acetylation level. This unusual unresponsiveness of histone acetylation to diet conditions may serve as an effective adaptation strategy to minimize energy demands during fasting and to quickly respond to refeeding. PMID- 30460763 TI - Giardia duodenalis in small animals and their owners in Germany: A pilot study. AB - Giardia duodenalis is a relevant gastrointestinal protozoan pathogen of humans and animals. This species complex consists of eight genetically different assemblages. Assemblages A and B are pathogenic to humans and pets, thus confer zoonotic potential. The risk of zoonotic transmission has been controversially discussed. The aim of this monocentric cross-sectional pilot study was to investigate G. duodenalis assemblages in humans and pets living in common households in Berlin/Brandenburg (Germany). Samples from dogs, cats and humans sharing the same households were screened for Giardia infection by antigen detecting assays. All human samples were additionally analysed by a Giardia specific qPCR. Cyst quantification and sequences of different gene loci (triosephosphate isomerase (tpi), glutamate dehydrogenase (gdh), beta-giardin (bg) and for dogs SSUrDNA) were analysed. A total of 38 households (31 households with dogs and seven with cats) with 69 human individuals participated in the study. Initial antigen-detecting assays revealed Giardia-positive results for 13 (39%) canine, one (14%) feline and one human sample. Reanalysis of the human samples by qPCR revealed two more positive specimens (4%). Two of these three samples were identified as assemblage B at all tested loci. Success rate of assemblage typing for pet samples was generally low and comprised mainly the SSUrDNA locus only. Overall, six of 13 Giardia-positive canine samples were typable (2* A, 1* co-infection: A and B, 1* C; 2* D). One pair of samples (dog and human) from the same household had a similar but not identical assemblage B sequence at tpi locus. Assemblage A was also detected in the dog specimen, which hampered sequence analysis. In conclusion, although exhibiting limitations due to the sample size, our study highlights the need for better and standardized typing tools to distinguish G. duodenalis strains with higher resolution in order to perform proper case-control studies for a realistic estimation of zoonotic risk. PMID- 30460765 TI - Increased Biobutanol Production by Mediator-Less Electro-Fermentation. AB - A future bio-economy should not only be based on renewable raw materials but also in the raise of carbon yields of existing production routes. Microbial electrochemical technologies are gaining increased attention for this purpose. In this study, the electro-fermentative production of biobutanol with C. acetobutylicum without the use of exogenous mediators is investigated regarding the medium composition and the reactor design. It is shown that the use of an optimized synthetic culture medium allows higher product concentrations, increased biofilm formation, and higher conductivities compared to a synthetic medium supplemented with yeast extract. Moreover, the optimization of the reactor system results in a doubling of the maximum product concentrations for fermentation products. When a working electrode is polarized at -600 mV vs. Ag/AgCl, a shift from butyrate to acetone and butanol production is induced. This leads to an increased final solvent yield of YABE = 0.202 g g-1 (control 0.103 g g-1 ), which is also reflected in a higher carbon efficiency of 37.6% compared to 23.3% (control) as well as a fourfold decrease in simplified E-factor to 0.43. The results are promising for further development of biobutanol production in bioelectrochemical systems in order to fulfil the principles of Green Chemistry. PMID- 30460764 TI - The relationship between computed tomography-derived body composition, systemic inflammatory response, and survival in patients undergoing surgery for colorectal cancer. AB - INTRODUCTION: Colorectal cancer is the fourth leading cause of cancer mortality in developed countries. There is evidence supporting a disproportionate loss of skeletal muscle as an independent prognostic factor. The importance of the systemic inflammatory response as a unifying mechanism for specific loss of skeletal muscle mass in patients with cancer is increasingly recognized. The aim of the present study was to delineate the relationship between the systemic inflammatory response, skeletal muscle index (SMI), skeletal muscle density (SMD), and overall survival in patients with colorectal cancer. MATERIALS AND METHODS: The study included 650 patients with primary operable colorectal cancer. Computed tomography scans were used to define the presence of visceral obesity, sarcopenia (low SMI), and myosteatosis (low SMD). Tumour and patient characteristics were recorded. Survival analysis was carried out using univariate and multivariate Cox regression. RESULTS: A total of 650 patients (354 men and 296 women) were included. The majority of patients were over 65 years of age (64%) and overweight or obese (68%). On univariate survival analysis, age, ASA, TNM stage, modified Glasgow Prognostic Score (mGPS), body mass index, subcutaneous fat index, visceral obesity, SMI, and SMD were significantly associated with overall survival (all P < 0.05). A low SMI and SMD were significantly associated with an elevated mGPS (<0.05). On multivariate analysis, SMI (Martin) [hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.04-2.18, P = 0.031], SMD (Xiao) (HR 1.42, 95% CI 0.98-2.05, P = 0.061), and mGPS (HR 1.44, 95% CI 1.15-1.79, P = 0.001) were independently associated with overall survival. SMD but not SMI was significantly associated with ASA (P < 0.001). CONCLUSIONS: This study delineates the relationship between the loss of quantity and quality of skeletal muscle mass, the systemic inflammatory response, and survival in patients with operable colorectal cancer. PMID- 30460766 TI - Ustekinumab use in patients with severe psoriasis co-infected with hepatitis B and/or C. AB - Exacerbation or reactivation of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) in persons infected with psoriasis during treatment with biologics is a documented concern with use of tumor necrosis factor (TNF) inhibitors. Much less is known, however, about these risks in relation to newer biologic drugs including ustekinumab (interleukin (IL)-12/23 inhibition). This article is protected by copyright. All rights reserved. PMID- 30460768 TI - The impact of post-traumatic stress disorder on dental and gingival status of children during syrian crisis: A preliminary study. AB - AIM: Most children in war zone countries often experience post-traumatic stress disorder (PTSD). This turns the war into a health issue of great importance. The aim was to evaluate dental and gingival status of children suffering from PTSD. METHODS: A case control study, which included 60 children (30 diagnosed with PTSD and 30 healthy controls) between 9 and 14 years, was undertaken. Dental status was assessed using decayed, missing, and filled teeth (DMFT) for permanent and decayed, missing and filled teeth (dmft) for primary. Gingival status was examined using plaque (PI) and gingival (GI) indices. Child PTSD reaction index (CPTSD-RI) was used to evaluate the severity of PTSD. RESULTS: There was no significant difference in DMFT and dmft indices between the PTSD children and the controls. However, PTSD children had more decay in permanent (DT) and primary teeth (dt), more primary missing teeth mt and less filled teeth in their permanent (FT) and primary (ft) dentition. Significant difference was found between PTSD children and controls regarding PI (P < 0.00001) and GI (P < 0.0001). CPTSD-RI was positively correlated with DMFT (P = 0.002), PI (P = 0.038), and GI (P = 0.007). CONCLUSION: PTSD children had poor dental and gingival status than matched controls and they were affected by PTSD severity. PMID- 30460767 TI - A smartphone-based teleconsultation system for the management of chronic pressure injuries. AB - We investigated the accuracy of pressure injury evaluation using tele-devices and examined the concordance between automatically generated recommendations and primary manual recommendations. Caregivers took photos and videos of pressure injuries using smartphones with built-in cameras and uploaded the media to the application. The wound team evaluated the wound using a specially modified version of the Pressure Sore Status Tool. This was compared with the Pressure Sore Status Tool score assessed during the actual examination of the patient. We developed an automatic algorithm for dressing based on the Pressure Sore Status Tool score, checking for consistency between this and the primary manual recommendation. A total of 60 patients diagnosed with pressure injuries were included. The kappa coefficients indicated substantial agreement for wound size and total score, and excellent for all other items. We found that the overall concordance rates were statistically significant for all items (p < 0.001). For the primary dressing, the kappa coefficient for the concordance rate of automatic algorithm and manual recommendation was 0.771, while that of teleconsultation system and manual recommendation was 0.971. For the secondary dressing, the figures were 0.798 and 0.989, respectively. All values were statistically significant (p < 0.001). We presented strong evidence documenting the utilization of a smartphone, patient-driven system, and demonstrated that the measurements obtained were comparable to the ones obtained by a trained, on-site, wound team. Furthermore, we confirmed agreement between automatically generated recommendations and primary manual recommendations. PMID- 30460769 TI - How different helmet fixing options could affect patients' pain experience during helmet-continuous positive airway pressure. AB - BACKGROUND: Prolonged application time of helmet continuous positive airway pressure (CPAP) leads to better outcomes, but its timing can be influenced by the patient's tolerance. AIMS AND OBJECTIVES: To investigate patients' pain and tolerance experience related to different options of helmet fixing system: 'armpits strap' versus 'counterweights system'. DESIGN: This was a non-randomized crossover study performed in a 10-bed intensive care unit and referral extra corporeal membrane oxigenation (ECMO) centre of an Italian university hospital. RESULTS: Twenty patients were enrolled. For helmet-CPAP cycles performed with the armpit straps option, the mean pain numerical rate on a 0-10 scale was: 0.5 +/- 1.4 at T0 (baseline), 1.5 +/- 2.0 at T1 (after 1 h) and 2.6 +/- 2.5 at T2 (end of cycle) (p = 0.023). The same analysis was performed for the counterweights fixing option. The mean score was 0.3 +/- 0.6 at T0 , 0.3 +/- 0.2 at T1 and 0.5 +/- 0.7 at T2 (p = 0.069). The mean duration for CPAP cycles performed with armpits strap and counterweights system was 3.0 +/- 1.0 and 3.9 +/- 2.3 h, respectively (p < 0.001). The mean section of the Basilic vein that was investigated before wearing the helmet was equal to 0.23 +/- 0.20 cm2 . After 1 h of therapy with the counterweight option and armpit straps, the mean increase of the vein's section was 0.27 +/- 0.21(p = 0.099) and 0.30 +/- 0.25, respectively (p = 0.080). CONCLUSIONS: The fixing system options in use to anchor the helmet during CPAP could worsen the pain experience level and cause device-related pressure ulcers. When compared with the armpit straps option, the counterweights system appears to be a suitable approach to minimize the risks of pressure sores and pain during the treatment. RELEVANCE TO PRACTICE: The helmet CPAP is a reliable therapy to manage acute respiratory failure. Major improvements regarding pulmonary alveolar recruitment and oxygen levels are strictly related to a prolonged time of helmet CPAP cycles. Using a counterweight fixing system, where the armpits straps are not necessary, could be helpful in reducing patients' pain experience. PMID- 30460771 TI - Corrigendum. PMID- 30460770 TI - Probiotics in irritable bowel syndrome: Where are we? AB - We have only recently begun to understand how alterations of the intestinal microbial ecosystem lead to the disruption of host-microbial interactions and are associated with diseases, including functional gastrointestinal disorders such as irritable bowel syndrome (IBS). Although we are still far from understanding the human microbiome, gut microbiota is already a therapeutic target. Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit to the host and may represent a therapeutic option for diseases characterized by dysbiosis such as IBS. Meta-analyses suggest that probiotics provide a therapeutic gain over placebo on global symptoms with a high safety profile in IBS patients. However, the mechanisms by which they provide benefit in IBS remain virtually unknown. In this issue of Neurogastroenterology and Motility, BIO-25, a multispecies probiotic, did not significantly modify the composition of the fecal microbiota, but interestingly, patients with specific basal features of the intestinal microbial ecosystem improved with treatment. Based on these data, it is tantalizing to speculate that microbiota composition serves as a predictor of the response to probiotic intervention. This mini-review addresses unresolved issues related to mechanisms through which probiotics may exert their beneficial effects, the biological, as well as clinical predictors of favorable outcomes in IBS and finally considers possible new directions for future studies. PMID- 30460772 TI - Deciphering the molecular effects of romidepsin on germ cell tumours: DHRS2 is involved in cell cycle arrest but not apoptosis or induction of romidepsin effectors. AB - Testicular germ cell tumours (GCTs) mostly affect young men at age 17-40. Although high cure rates can be achieved by orchiectomy and chemotherapy, GCTs can still be a lethal threat to young patients with metastases or therapy resistance. Thus, alternative treatment options are needed. Based on studies utilising GCT cell lines, the histone deacetylase inhibitor romidepsin is a promising therapeutic option, showing high toxicity at very low doses towards cisplatin-resistant GCT cells, but not fibroblasts or Sertoli cells. In this study, we extended our analysis of the molecular effects of romidepsin to deepen our understanding of the underlying mechanisms. Patients will benefit from these analyses, since detailed knowledge of the romidepsin effects allows for a better risk and side-effect assessment. We screened for changes in histone acetylation of specific lysine residues and analysed changes in the DNA methylation landscape after romidepsin treatment of the GCT cell lines TCam-2, 2102EP, NCCIT and JAR, while human fibroblasts were used as controls. In addition, we focused on the role of the dehydrogenase/reductase DHRS2, which was strongly up-regulated in romidepsin treated cells, by generating DHRS2-deficient TCam-2 cells using CRISPR/Cas9 gene editing. We show that DHRS2 is dispensable for up-regulation of romidepsin effectors (GADD45B, DUSP1, ZFP36, ATF3, FOS, CDKN1A, ID2) but contributes to induction of cell cycle arrest. Finally, we show that a combinatory treatment of romidepsin plus the gluccocorticoid dexamethasone further boosts expression of the romidepsin effectors and reduces viability of GCT cells more strongly than under single agent treatment. Thus, romidepsin and dexamethasone might represent a new combinatorial approach for treatment of GCT. PMID- 30460773 TI - Heterogeneity in Obesity: More Research Needed to Improve Precision Weight Loss Treatment. PMID- 30460774 TI - Genetic Susceptibility for Childhood BMI has no Impact on Weight Loss Following Lifestyle Intervention in Danish Children. AB - OBJECTIVE: This study aimed to investigate the effect of a genetic risk score (GRS) comprising 15 single-nucleotide polymorphisms, previously shown to associate with childhood BMI, on the baseline cardiometabolic traits and the response to a lifestyle intervention in Danish children and adolescents. METHODS: Children and adolescents with overweight or obesity (n = 920) and a population based control sample (n = 698) were recruited. Anthropometric and biochemical measures were obtained at baseline and in a subgroup of children and adolescents with overweight or obesity again after 6 to 24 months of lifestyle intervention (n = 754). The effects of the GRS were examined by multiple linear regressions using additive genetic models. RESULTS: At baseline, the GRS associated with BMI standard deviation score (SDS) both in children and adolescents with overweight or obesity (beta = 0.033 [SE = 0.01]; P = 0.001) and in the population-based sample (beta = 0.065 [SE = 0.02]; P = 0.001). No associations were observed for cardiometabolic traits. The GRS did not influence changes in BMI SDS or cardiometabolic traits following lifestyle intervention. CONCLUSIONS: A GRS for childhood BMI was associated with BMI SDS but not with other cardiometabolic traits in Danish children and adolescents. The GRS did not influence treatment response following lifestyle intervention. PMID- 30460776 TI - Genetic Predictors of Behavioral Weight Loss: Current Status and Future Directions. PMID- 30460775 TI - Hypothalamic Gliosis by MRI and Visceral Fat Mass Negatively Correlate with Plasma Testosterone Concentrations in Healthy Men. AB - OBJECTIVE: This study aimed to determine whether a relationship was evident between gliosis in the mediobasal hypothalamus (MBH) and plasma testosterone concentrations in men. METHODS: A total of 41 adult men (aged 18-50 years) from 23 twin pairs underwent fasting morning blood draw and brain magnetic resonance imaging. T2 relaxation time was used to quantify gliosis in the MBH and control areas in the putamen and amygdala. Plasma concentrations of testosterone and 17beta-estradiol were measured by liquid chromatography-tandem mass spectrometry. Body composition including visceral adiposity was measured by dual x-ray absorptiometry. RESULTS: A negative association was found between MBH T2 relaxation time and plasma concentrations of both free and total testosterone (r = -0.29, P < 0.05 and r = -0.37, P < 0.01, respectively). Visceral adiposity exhibited a negative correlation with plasma total testosterone concentration (r = -0.45, P = 0.001) but a positive correlation with MBH T2 relaxation time (r = 0.24, P = 0.03). The negative correlation between plasma total testosterone and MBH T2 relaxation time remained significant after adjustment for visceral adiposity, age, BMI, and insulin resistance. CONCLUSIONS: In healthy men across a range of BMIs, MBH gliosis was associated with higher visceral adiposity but lower endogenous testosterone. These findings suggest that MBH gliosis could provide novel mechanistic insights into gonadal dysfunction in men with obesity. PMID- 30460777 TI - Negative pressure wound therapy: A systematic review of randomized controlled trials from 2000 to 2017. AB - BACKGROUND: Negative pressure wound therapy (NPWT) proposes to provide better wound healing than standard wound management. Evidence quality of randomized controlled trials (RCTs) varies. METHODS: We included participants with any kind of wounds and commercial as well as the homemade NPWT system. Comparators were any other wound dressing including variant NPWTs. We included RCTs randomizing patients or wounds in parallel or crossover designs. We searched PubMed and Cochrane Library on January 03, 2018. We assessed the risk of bias according to Cochrane and appropriateness of clinical endpoints according to the Food and Drug Administration (FDA). RESULTS: We included 93 RCTs originating in 30 countries, 70 studies on open wounds and 23 studies on closed wounds. With respect to random sequence generation, we judged an unclear or high risk of bias in 50% (47 of 93) studies. With respect to allocation concealment, we judged an unclear or high risk of bias in 90% (84 of 93). We identified 41% (38 of 93) studies that based their conclusion on not appropriate endpoints. CONCLUSIONS: High risk of bias concerning random sequence generation and allocation concealment limited the credibility of the majority of 93 included RCTs on NPWT. A low risk of bias can and should be achieved with both items, and we recommend to align future RCTs to Cochrane. Many primary clinical endpoints were deemed not valid for making inferences on the efficacy of NPWT. We recommend using patient-centered endpoints as requested by the FDA and suggested in the present systematic review. PMID- 30460778 TI - Inhibiting transforming growth factor-beta signaling regulates in vitro maintenance and differentiation of bovine bone marrow mesenchymal stem cells. AB - Bovine bone marrow mesenchymal stem cells (bBMSC) are potential stem cell source which can be used for multipurpose. However, their application is limited because the in vitro maintenance of these cells is usually accompanied by aging and multipotency losing. Considering transforming growth factor-beta (TGF-beta) pathway inhibitor Repsox is beneficial for cell reprogramming, here we investigated its impacts on the maintenance and differentiation of bBMSC. The bBMSC were enriched and characterized by morphology, immunofluorescent staining, flow cytometry, and multilineage differentiation. The impacts of Repsox on their proliferation, apoptosis, cell cycle, multipotency, and differentiation were examined by Cell Counting Kit-8 (CCK-8), real-time polymerase chain reaction, induced differentiation and specific staining. The results showed that highly purified cluster of diffrentiation 73+ (CD73 + )/CD90 + /CD105 + /CD34 - /CD45 - bBMSC with adipogenic, osteogenic, and chondrogenic differentiation capacities were enriched. Repsox treatments (5 MUM, 48 hr) enhanced the messenger RNA mRNA levels of the proliferation gene (telomerase reverse transcriptase [ TERT]; basic fibroblast growth factor [ bFGF]), apoptosis-related gene ( bax and Bcl2), antiapoptosis ratio ( Bcl2/bax), and pluripotency marker gene ( Oct4, Sox2, and Nanog), instead of changing the cell cycle, in bBMSC. Repsox treatments also enhanced the osteogenic differentiation but attenuated the chondrogenic differentiation of bBMSC, concomitant with decreased Smad2 and increased Smad3/4 expressions in TGF-beta pathway. Collectively, inhibiting TGF-beta/Smad signaling by Repsox regulates the in vitro maintenance and differentiation of bBMSC. PMID- 30460780 TI - Long-term efficacy of repeated sodium hyaluronate injections in adult patients with Kashin-Beck disease of the knee. AB - AIM: To prospectively evaluate the long-term efficacy and safety of repeated sodium hyaluronate injections for the treatment of knee pain due to Kashin-Beck disease (KBD). METHODS: A total of 85 patients with KBD-based knee pain were treated with two cycles of a 5-week course of sodium hyaluronate and received clinical assessments with a follow-up period of 24 months after the first cycle. The primary efficacy measure was the visual analogue scale (VAS) pain score. The second efficacy measure included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores; and the patients' and physicians' global assessments. Tolerability was evaluated based on adverse events (AEs). RESULTS: Seventy-one patients (83.5%) completed the final study. The VAS was significantly reduced from 65.06 +/- 12.21 mm (mean +/- standard deviation [SD]) at baseline to 30.17 +/- 11.92 mm at 6 months and was maintained for 24 months (35.79 +/- 7.92 mm, P < 0.01 vs baseline). This finding was supported by the secondary variables (the WOMAC A, B and C scores; the total WOMAC scores; and the global assessments of the patients and their physicians at months 6, 12, 18 and 24). The overall incidence of AEs during the first and second cycles was 8 (9.4%) and 7 patients (8.2%), respectively. No serious AEs were reported. CONCLUSIONS: Repeated once yearly cycles of intra-articular sodium hyaluronate injections may improve knee KBD symptoms during the inbetween cycle period as well as exert a significant carry-over effect for at least 1 year after the repeated cycle. Other randomized double-blind studies are needed to confirm the findings from our study. PMID- 30460779 TI - Lleida Bat Lyssavirus isolation in Miniopterus schreibersii in France. AB - Bat rabies cases are attributed in Europe to five different Lyssavirus species of 16 recognized Lyssavirus species causing rabies. One of the most genetically divergent Lyssavirus spp. has been detected in a dead Miniopterus schreibersii bat in France. Brain samples were found positive for the presence of antigen, infectious virus and viral RNA by classical virological methods and molecular methods respectively. The complete genome sequence was determined by next generation sequencing. The analysis of the complete genome sequence confirmed the presence of Lleida bat lyssavirus (LLEBV) in bats in France with 99.7% of nucleotide identity with the Spanish LLEBV strain (KY006983). PMID- 30460781 TI - Treatment of opioid dependence with buprenorphine/naloxone sublingual tablets: A phase 3 randomized, double-blind, placebo-controlled trial. AB - INTRODUCTION: The purpose of the study is to evaluate the efficacy and safety of buprenorphine/naloxone sublingual tablets for the treatment of opioid dependence in Chinese adults. METHODS: This multicenter, double-blind, placebo-controlled study included four periods: induction (3-5 days), stabilization (7-21 days), randomization/treatment (6 weeks), and postmedication follow-up (1 week). A total of 442 participants with opioid dependence were enrolled; 260 were randomized to buprenorphine/naloxone or placebo. The primary outcome was retention in treatment, defined as the time from randomization to treatment completion or treatment failure. Secondary outcomes included maximum consecutive days of abstinence from opioids, self-reported craving and opioid withdrawal symptoms, and urine drug screen results. Safety assessments included adverse event reporting, electrocardiograms, clinical laboratory tests, vital signs, and prior/concomitant medications. RESULTS: The median treatment retention time (95% confidence internal) with buprenorphine/naloxone was 32 days (26-38) versus 6 days (5-8) for placebo, with a Cox hazard ratio of 0.28 (95% confidence interval, 0.21-0.38; P < 0.0001). The median maximum consecutive days of abstinence (95% confidence interval) was: buprenorphine/naloxone, 21 days (26-38); placebo, 5 days (5-8) with a Cox hazard ratio of 0.38 (95% confidence interval, 0.25-0.60; P < 0.0001). Withdrawal and craving symptoms were significantly milder with buprenorphine/naloxone versus placebo (P < 0.001). Urine drug screen results indicated significantly lower opioid usage in the buprenorphine/naloxone group compared with placebo (P < 0.001). The most commonly reported adverse events in the buprenorphine/naloxone group during treatment were aspartate aminotransferase increased and nasopharyngitis. DISCUSSION: Efficacy and safety results from this clinical trial support a positive benefit-risk ratio for buprenorphine/naloxone sublingual tablet use in the treatment of an opioid-dependent Chinese population. PMID- 30460782 TI - Double-chambered left ventricle: A rare case in a child. AB - Double-chambered left ventricle (DCLV) is an extremely rare congenital heart disease. In this condition, the left ventricle is divided into two chambers by a septum or muscle fiber with abnormal proliferation. A symptomatic boy was diagnosed with DCLV at our hospital. The patient was admitted with the major complaint of 8 years of cardiac murmur, which was discovered through physical examination, and 5 years of palpitations and shortness of breath. He has been followed up without treatment. PMID- 30460783 TI - Skin ionocyte remodeling in the amphibious mangrove rivulus fish (Kryptolebias marmoratus). AB - Amphibious fishes have evolved a variety of physiological modifications allowing them to survive in water and air. In air, the amphibious mangrove rivulus, Kryptolebias marmoratus, uses its skin as a site of ionoregulation. Skin ionocytes actively transport ions into/out of the body; however, it is unclear if there are specific morphological or functional changes occurring in skin ionocytes during air exposure. We used two microscopy techniques to describe skin ionocyte morphology and to investigate their plasticity after salinity challenges and air exposure. Immunohistochemical staining in air-exposed fish revealed ionocytes with Na + /K + ATPase (NKA), Na + /H + exchanger (NHE3b) and cystic fibrosis transmembrane conductance regulator (CFTR) immunoreactivity, whereas ionocytes from aquatic fish had only NKA (freshwater) or NKA and CFTR (brackish and hypersaline water). Following salinity challenges, we noted increases in the number and area of ionocyte apical surfaces, indicating that skin ionocyte activity increased in high salinity environments compared with control conditions. Furthermore, we show increased ionocyte area during air exposure suggesting increased ionocyte activity in all salinity conditions. Using energy dispersive X-ray spectroscopy to analyze the skin surface, we report decreases in magnesium, phosphorous, and sulfur after 7 days in air compared with fish in water, suggesting ionic movement in the skin surface during air exposure. Our study highlights morphological and functional features of skin ionocytes that are involved in ionoregulation in an air-exposed amphibious fish. PMID- 30460784 TI - A novel nomogram for predicting ECE of prostate cancer. PMID- 30460785 TI - Ureteroscopy vs miniaturized percutaneous nephrolithotomy: what and who are we comparing? PMID- 30460786 TI - Mental imagery: 'You can observe a lot by watching!' PMID- 30460787 TI - Predicting progression in T1 non-muscle-invasive bladder cancer: back to histology. PMID- 30460789 TI - Science, technology and artificial intelligence. PMID- 30460788 TI - Urinary incontinence and the causality dilemma. PMID- 30460790 TI - A picture is worth a thousand words... but does it add utility to a nomogram to predict extraprostatic extension? PMID- 30460791 TI - Previous incarceration impacts access to hepatitis C virus (HCV) treatment among HIV-HCV co-infected patients in Canada. AB - INTRODUCTION: The prevalence of hepatitis C virus (HCV) is far higher in prison settings than in the general population; thus, micro-elimination strategies must target people in prison to eliminate HCV. We aimed to examine incarceration patterns and determine whether incarceration impacts HCV treatment uptake among Canadian HIV-HCV co-infected individuals in the direct-acting antiviral (DAA) era. METHODS: The Canadian Co-Infection Cohort prospectively follows HIV-HCV co infected people from 18 centres. HCV RNA-positive participants with available baseline information on incarceration history were included and followed from 21 November 2013 (when second-generation DAAs were approved by Health Canada) until 30 June 2017. A Cox proportional hazards model was used to assess the effect of time-updated incarceration status on time to treatment uptake, adjusting for patient-level characteristics known to be associated with treatment uptake in the DAA era. RESULTS: Overall, 1433 participants (1032/72% men) were included; 67% had a history of incarceration and 39% were re-incarcerated at least once. Compared to those never incarcerated, previously incarcerated participants were more likely to be Indigenous, earn <$1500 CAD/month, report current or past injection drug use and have poorly controlled HIV. There were 339 second generation DAA treatment initiations during follow-up (18/100 person-years). Overall, 48% of participants never incarcerated were treated (27/100 person years) compared to only 31% of previously incarcerated participants (15/100 person-years). Sustained virologic response (SVR) rates at 12 weeks were 95% and 92% respectively. After adjusting for other factors, participants with a history of incarceration (adjusted hazard ratio (aHR): 0.7, 95% CI: 0.5 to 0.9) were less likely to initiate treatment, as were those with a monthly income <$1500 (aHR: 0.7, 95% CI: 0.5 to 0.9) or who reported current injection drug use (aHR: 0.7, 95% CI: 0.4 to 1.0). Participants with undetectable HIV RNA (aHR: 2.1, 95% CI: 1.6 to 2.9) or significant fibrosis (aHR: 1.5, 95% CI: 1.2 to 1.9) were more likely to initiate treatment. CONCLUSIONS: The majority of HIV-HCV co-infected persons had a history of incarceration. Those previously incarcerated were 30% less likely to access treatment in the DAA era even after accounting for several patient-level characteristics. With SVR rates above 90%, HCV elimination may be possible if treatment is expanded for this vulnerable and neglected group. PMID- 30460793 TI - The current state and future perspectives of cannabinoids in cancer biology. PMID- 30460792 TI - Subtype-specific epidemiology of lymphoid malignancies in Taiwan compared to Japan and the United States, 2002-2012. AB - BACKGROUND: There are many unrevealed parts regarding lymphoma etiology. Previous studies suggested differences in lymphoma epidemiology among countries existed; however, some were one-center studies that were not enough to represent the whole population. OBJECTIVE: To provide epidemiological information on lymphoma within Taiwanese and to compare the data with that in Japan and the United States. METHODS: We used Taiwan Cancer Registry Database as our data source. Patients with lymphoma were identified through the ICD-O-3 codes and those with non Hodgkin lymphoma (NHL) were categorized into three major types and 13 subtypes according to 2008 WHO classification. Incidence of lymphoma was adjusted according to the 2000 world standard population. RESULTS: During 2002-2012, 21 929 cases were diagnosed with four major types of lymphoma in Taiwan. Aggressive B-cell lymphoma (52.21%, N = 11 450) was the most common type of NHL. Median age at diagnosis of aggressive B-cell lymphoma was the eldest (63.0-65.0 years). Male excess in T/NK-cell lymphoma was the most obvious (sex ratio: 1.39-2.07). The incidence of NK/T-cell lymphoma, nasal type, was higher (male: 0.16-0.34 per 100 000, female: 0.06-0.16 per 100 000) in Taiwan than that in the United States and Japan. CONCLUSION: This is the first population-based study in Taiwan to investigate subtype-specific epidemiology of lymphoma. The incidence rates of lymphoma in Taiwan are mostly lower than those in the United States and higher or comparable to those in Japan except for NK/T-cell lymphoma, nasal type, whose age adjusted incidence in Taiwan is the highest. PMID- 30460794 TI - Quantitative analysis of in vivo high-resolution microendoscopic images for the detection of neoplastic colorectal polyps. AB - Colonoscopy is routinely performed for colorectal cancer screening but lacks the capability to accurately characterize precursor lesions and early cancers. High resolution microendoscopy (HRME) is a low-cost imaging tool to visualize colorectal polyps with subcellular resolution. We present a computer-aided algorithm to evaluate HRME images of colorectal polyps and classify neoplastic from benign lesions. Using histopathology as the gold standard, clinically relevant features based on luminal morphology and texture are quantified to build the classification algorithm. We demonstrate that adenomatous polyps can be identified with a sensitivity and specificity of 100% and 80% using a two-feature linear discriminant model in a pilot test set. The classification algorithm presented here offers an objective framework to detect adenomatous lesions in the colon with high accuracy and can potentially improve real-time assessment of colorectal polyps. PMID- 30460795 TI - Use of acupuncture in the management of pain. AB - Nurses practising in almost any area of healthcare may encounter individuals who are considering acupuncture, particularly those caring for people who are experiencing chronic pain. Acupuncture is a complex intervention and in traditional practice is not simply the insertion of needles, as some people believe. This article provides a historical understanding of acupuncture, outlining some of the differences between styles of practice that may be relevant when selecting an acupuncturist. It also examines the issues that should be considered when assessing the evidence base for acupuncture. PMID- 30460796 TI - [Effects of canopy on the redistribution of potassium and sodium ions in rainfall in Quercus acutissima and Camptotheca acuminata mixed plantation of the rainy area of western China]. AB - The role of canopy in redistributing rainwater K+ and Na+ at different phenological stages (leafless stage, leaf expanding stage, frondent leaf stage and senesced leaf stage) was investigated in Quercus acutissima and Camptotheca acuminata mixed plantation in Mt. Lingyan of Dujiangyan city from December 2016 to November 2017. The concentrations of K+ and Na+ were 1.87 and 1.46 mg.L-1 in the rainfall, respectively, and 5.78 and 1.39 mg.L-1 in the throughfall, respectively. The highest and lowest K+ concentrations in the rainwater were found at leaf expanding stage and frondent leaf stage, respectively. Meanwhile, higher Na+ concentration in rainwater was found at leafless stage and leaf expanding stage, and lower concentration at frondent leaf stage and senesced leaf stage. The inputs of K+ and Na+ through rainfall were 25.47 and 21.60 kg.hm-2.a 1, respectively. The leaching flux of K+ was 13.64 kg.hm-2.a-1 from canopy by rainfall, with the flux of 1.67, 6.23, 2.28 and 3.46 kg.hm-2 at the leafless stage, leaf expanding stage, frondent leaf stage and senesced leaf stage, respectively. On the contrary, the canopy intercepted 11.26 kg Na+.hm-2.a-1, with the interception rate being 32.6%, 18.0%, 44.9% and 31.5% at leafless stage, leaf expanding stage, frondent leaf stage, and senesced leaf stage, respectively. In conclusion, the redistribution of K+ and Na+ in the rainfall affected by Q. acutissima and C. acuminata mixed plantation canopy varied greatly with phenological stages. The results could provide basic data for further understanding of the cycles of K+ and Na+ in the forest ecosystem in the rainy area of western China. PMID- 30460797 TI - [Changes of non-structural carbohydrates of Pinus sylvestris var. mongolica seedlings in the process of drought-induced mortality]. AB - To understand the distribution of non-structural carbohydrates (NSC) and adaptive mechanism in the process of drought-induced mortality, two-year-old Pinus sylvestris var. mongolica seedlings were grown under continuous natural drought condition. Needle water potential and the contents of soluble sugar, starch and total NSC in different organs (current-year-old needles, one-year-old needles, stems, coarse roots and fine roots) of the seedlings were measured when soil water content decreased to 60%, 40%, 30%, 20% and 15% of the soil field water capacity (SFC). The results showed that when the soil water content decreased from 40% SFC to 15% SFC, there was no significant change in needle water potential at predawn and midday. When soil water content decreased from 60% SFC to 30% SFC, the contents of soluble sugar, starch, total NSC and the ratio of soluble sugar and starch first decreased and then increased in all organs. When soil water content dropped from 30% SFC to 20% SFC, the soluble sugar, starch and total NSC contents decreased in the current-year-old needles, one-year-old needles, stems and fine roots. The soluble sugar content increased, but the starch and total NSC contents decreased in the coarse roots. When soil water content decreased from 20% SFC to 15% SFC, the contents of soluble sugar, starch and total NSC decreased in the current-year-old needles, one-year-old needles and stems, and the soluble sugar and total NSC contents decreased, but the starch content increased in the coarse roots, the soluble sugar content decreased, but the starch and total NSC contents increased in fine roots. The results indicated that NSC content in different organs of P. sylvestris var. mongolica seedlings varied in their adaptation to different degrees of drought. The contents of soluble sugar and total NSC in seedlings decreased under less than 30% of the soil field water capacity, with the starch being accumulated in the coarse roots and fine roots. The seedlings might be died due to carbon depletion. PMID- 30460798 TI - [Relationships between plant community and soil chemical factors in coastal saline area of Shandong, China]. AB - To reveal the correlation between plant communities and soil chemical factors (pH, the total amount of soil soluble salt, TN, TP, SOM, K+, Na+, Ca2+, Mg2+, Cl , SO42-, HCO3-) in Shandong coastal saline area, a field investigation of 81 samples was carried out and the chemical properties of the soil were analyzed. The results showed that a total of 85 species, 67 genera and 30 families of salt tolerant plants were recorded. The top three dominant families were Compositae, Gramineae and Chenopodiaceae. The community could be divided into four types: Phragmites aus-tralis - Imperata cylindrical + Artemisia capillaris, Suaeda salsa + P. australis - A. capillaris + Kochia scoparia, P. australis - Typha orientalis + Apocynum venetum, P. australis - A. venetum. The CCA sequencing results showed that the soil total soluble salt and water-soluble ions were the key chemical factors affecting the distribution of salt-tolerant vegetation, followed by total nitrogen content. The community of P. australis - I. cylindrical + A. capillaris had richest species diversity among the four community types, and the resources of salt-tolerant plants were abundant. The species diversity of plant community showed a significant negative correlation with soil total soluble salts and water soluble salt ions content. The plant community diversity index would be reduced by the high saline soil. PMID- 30460799 TI - [Response of radial growth to climate change in Pinus koraiensis with different diameter classes]. AB - Dendrochronological techniques were used to study the response of radial growth of Pinus koraiensis with different diameter classes to climate change throughout the natural range of broad-leaved Korean pine forests, including Baishilazi Nature Reserve (40.9 degrees N), Changbai Mountain Nature Reserve (42.4 degrees N), Liangshui Nature Reserve (47.2 degrees N), and Shengshan Nature Reserve (49.4 degrees N). We investigated the similarities and differences of growth responses of different diameter classes to climate factors and clarified the key climate factors affecting the growth of P. koraiensis at different latitude sites. We explored the dynamic changes of the radial growth of P. koraiensis from the latitudinal gradient over the past 40 years. The results showed many similarities in the response of two diameter classes to local climate factors. Small diameter (diameter at breast height of 10-20 cm) trees were more sensitive to the changes of average minimum temperature of the current growing season and the meteorological factors of the previous year, whereas large diameter (diameter at breast height >40 cm) trees were more sensitive to the changes of average maximum temperature and average relative humidity of the current growing season. The key meteorological factors that affecting radial growth of P. koraiensis differed along the latitude gradient. In Baishilazi Nature Reserve, the southernmost plot, the key climate factors were the average maximum temperature and the average maximum temperature in the current growing season. In Shengshan Nature Reserve, the northernmost sample plot, the key climate factors were low temperature factors, such as the minimum temperature in all seasons, the average maximum temperature in winter, the average temperature of all seasons except for the end of previous growing season and the current growing season. The Palmer drought severity index (PDSI) in the current growth season and the end of the current growth season and the precipitation in the current growth season were the key climate factors in Changbai Mountain Nature Reserve. The average temperature of the current growing season was the key climate factor of Liangshui Nature Reserve. In recent four decades, with the rising of temperature, the radial growth of P. koraiensis of two diameter classes significantly decreased in the southernmost point, significantly increased in the northernmost point, and had no significant variation in middle latitudes. PMID- 30460800 TI - [Self-healing properties of lateral-root branches of three shrub species after fracture force injure in semi-arid mining area]. AB - To clarify the sustainable soil reinforcement capacity of the lateral root branches of shrubs after injury by fracture force in a semi-arid coal mining subsidence region of Shendong, we analyzed the ultimate anti-fracture mechanical characteristics of three shrub species, Caragana microphylla, Salix cheilophila, and Hippophae rhamnoides, as well as the self-healing ability of their growth indices and mechanical characteristics after injury by fracture force. The results showed that the anti-fracture force and its strength had significant difference among the three shrub species in their late-ral root branches in the early stage of growing season, with the order of C. microphylla > S. cheilophila > H. rhamnoides. The anti-fracture strengths of C. microphylla and S. cheilophila were positively correlated with the contents of cellulose, lignin and holocellulose, while that of H. rhamnoides was significantly negatively correlated with cellulose and lignin contents, but significantly positively correlated with holocellulose content. The fracture force damage caused by activity in the subsidence area significantly reduced the normal growth and mechanical properties of lateral root branches, which could not return to control levels even after three months of self-healing. For the shrubs, stronger self healing ability of growth indicators resulted in a higher degree of self-healing of anti-fracture forces. Self-healing ability of growth indicators was in the order of H. rhamnoides (91.2%) > S. cheilophila (82.0%) > C. microphylla (73.9%), and self-healing degree of anti-fracture forces was in the order of H. rhamnoides (41.4%) > S. cheilophila (37.1%) > C. microphylla (30.0%). Sustainable soil reinforcement indices of the shrubs' lateral root branches were in the order of C. microphylla (2.2084) > S. cheilophila (0.2009) > H. rhamnoides (-2.4093). Our results indicated that C. microphylla was the best, S. cheilophila was intermediate, and H. rhamnoides was the least in soil reinforcement in semi-arid coal mining subsidence areas. PMID- 30460801 TI - [Effects of deficit irrigation on water-radiation use and yield of Coffea arabica under different shade cultivation modes in dry-hot region]. AB - The yield and quality of Coffea arabica cannot be guaranteed due to irrational irrigation and light management in dry-hot region. To investigate the best coupling mode of irrigation and shade cultivation of C. arabica in dry-hot region, a field experiment was carried out with different irrigation levels and shade cultivation modes. Three levels of irrigation, i.e., full irrigation, light deficit irrigation and severe deficit irrigation, and four modes of shade cultivation, i.e., no shade cultivation (C. arabica monoculture), light shade cultivation (intercropping of four-line C. arabica and a line banana), moderate shade cultivation (intercropping of three-line C. arabica and a line banana) and severe shade cultivation (intercropping of two-line C. arabica and a line banana) were designed to examine the effects of deficit irrigation on growth, photosynthetic characteristics of lea-ves, water-radiation use and yield of C. arabica under the shade of banana trees. The results showed that net photosynthesis rate (Pn), transpiration rate (Tr), stomatal conductance (gs), leaf water use efficiency (LWUE), leaf radiation use efficiency (LRUE) increased with the increases of irrigation amount, while the intercellular CO2 concentration (Ci) decreased with the increases of irrigation amount. Compared with full irrigation, light deficit irrigation decreased dry bean yield by 9.4%, severe deficit irrigation decreased dry bean yield and water use efficiency (WUE) by 36.7% and 16.9%, respectively. Pn, Tr, gs, LWUE first increased and then decreased with the increases of shading degree, with moderate shade cultivation having the maximum increment. Compared with no shade cultivation, light shade cultivation increased dry bean yield and WUE by 13.0% and 12.9%, respectively; moderate shade cultivation increased dry bean yield and WUE by 23.1% and 23.4%, respectively. The dry bean yield, WUE, volume and fresh mass of 100-bean of C. arabica increased in different degrees with the increases of irrigation amount and shading degree, with the largest enhancement of dry bean yield and WUE occurring in full irrigation under moderate shade cultivation. Soil water content in the same soil depth decreased with the increases of shading degree. Soil water content in the same place increased first and then decreased with the increases of soil la-yer depth in 0-50 cm soil layer. Results of regression analysis showed that LRUE had a significantly negative exponential relation or Logistic-curve variation with photosynthetically active radiation. Therefore, the suitable combination of irrigation treatment and banana shade cultivation mode for C. arabica was full irrigation and moderate shade cultivation, considering the comprehensive benefit of superior quality and high production and high efficiency water-radiation use. PMID- 30460802 TI - [Composition and niche of the existing herbaceous plants in the water-level fluctuating zone of the Three Gorges Reservoir Area, China]. AB - To understand the usages of available resource by dominant plants, their niches and the mechanisms of inter-specific competition and co-existence in the water level fluctuation zone, we studied the spatial distributions and niche characteristics of existing dominant herbaceous species at a typical water-level fluctuation site of the Three Gorges Reservoir Area, Zigui. The results showed that there were 39 herb species in total, which belonged to 18 families and 32 genera. Gramineae, Compositae, Polygonaceae and Euphorbiaceae were the dominant families. Cynodon dactylon, Setaria viridis, Bidentis tripartitae and Digitaria chrysoblephara were the dominant species, with high importance value and niche breadth. In addition, at 145-155 m, 155-165 m and 165-175 m altitude section, the three major species, expressing the highest ecological niche breadth, which were in order of C. dactylon > Polygonum lapathifolium > S. viridis, S. viridis > D. chrysoblephara > C. dactylon, and S. viridis > B. tripartitae > P. orientale, respectively. The niche overlap of the species between the different altitudes zone was relatively high. The species which had a broad niche could co-exist with those occupying narrow niche. The niche overlap could not be determined by niche breadth lonely. Furthermore, after seven times of water level fluctuations, most of the species were annual herbs, and the degree of niche differentiation was low in the area. Due to scarce resources and unstable habitats, the inter-specific competition was strong, and the vegetation was at the primary successional stage. PMID- 30460803 TI - [Physiological integration of growth, carbohydrates, and soluble protein of Zoysia japonica clonal ramets under nutrient heterogeneity]. AB - This study was carried out to analyze the changes of growth, the contents of carbohydrates and soluble protein of Zoysia japonica clonal ramets under nutrient heterogeneity, where the connected and disconnected ramets were treated with different nutrient levels. The results indicated that under the nutrient heterogeneity the parent ramets in middle or high nutrient levels improved the aboveground biomass, belowground biomass, and total biomass, with the enhancement of 32.5%, 22.1% and 24.8% at high nutrient level, respectively, reduced the root/shoot ratio, the contents of soluble sugar and non-structural carbohydrates (NSC), with the reduction of 7.7%, 15.2% and 13.1% in high nutrient level, respectively, but had no significant impacts on the contents of starch, cellulous, and soluble protein of the connected daughter ramets. The daughter ramets in middle and high nutrient levels had no significant impacts on the growth and the contents of carbohydrates and soluble protein of the connected parent ramets. There was a significant physiological integration effects from parent to the daughter ramets on the biomass, root/shoot, the contents of soluble sugar and NSC. The intensity of physiological integration was proportional to the nutrient gradient of ramets, but had no significant physiological integration effects on the contents of starch, cellulous and soluble protein. The daughter ramets had no physiological integration for any indicator of the parent ramets. There was a unidirectional physiological integration between parent and daughter ramets of Z. japonica. PMID- 30460804 TI - [Spatial heterogeneity of soil water content under introduced shrub (Caragana korshinskii) in desert grassland of the eastern Ningxia, China]. AB - Combined with geographic information system (GIS) data, the spatial heterogeneity of soil water in the 0-200 cm soil layer of the desert steppe with the introduction of the shrub Caragana korshinskii in eastern Ningxia was studied by classical statistical and geostatistical methods. It was found that the soil water content of each soil layer in the 0-200 cm profile was relatively low, ranging from 0.6% to 19.0% (averaged 4.4%). The coefficient of soil water content variation ranged from 49.5% to 86.3%, which indicated moderate spatial heterogeneity. The variation of soil water content at the 0-60 cm and 80-120 cm soil layers fitted the spherical model, while that at the 60-80 cm soil layer fitted the exponential model and that at the 120-200 cm soil layer fitted the Gaussian model. Soil water content at different soil layers showed different degrees of spatial autocorrelation. The nugget/sill [C0/(C0+C)] of soil water content in the 0-40, 60-80, and 120-200 cm soil layers ranged from 26.1% to 49.9%, with moderate spatial correlations. The nugget/sill of soil water content in the 40-60 cm, 80-100 cm, and 100-120 cm soil layers ranged from 15.5% to 22.1%, with strong spatial correlations. The scale of spatial heterogeneity in soil water content (A0) varied among soil layers. The A0 was relatively large in the 0-20 and 20-40 cm soil layers (37.10-45.18 km) and small in the 40-200 cm soil layers (3.58-8.66 km). The results indicated that the introduction of C. korshinskii shrubs into desert grassland for vegetation recovery in recent decades have depleted soil water and accelerated the depletion of soil water in the deep layer (40-200 cm), leading to spatial heterogeneity and fragmentation of soil water (0-200 cm) with stronger effects at deep soil layer. PMID- 30460805 TI - [Prezygotic reproductive isolation of two sympatric species of Ligularia weeds in eastern Qinghai-Tibet Plateau, China]. AB - Reproductive isolation, the key process to prevent interspecific hybridization and keep the completeness and independence of species, is crucial to the formation and maintenance of biodiversity. The forming steps, methods and intensities of reproductive isolation between different species are not completely the same. Literatures on reproductive isolation between species provide valuable evidence for speciation and its maintenance. Flowering phenology, flowering-visiting insects, and pollen-stigma compatibility were observed for Ligularia virgaurea and L. sagitta, two species of weeds sympatrically distributed in eastern Qinghai-Tibet Plateau. The characteristics of reproductive isolation mechanism of both species and its role in reproductive isolation were also studied. The results showed that the flowering period of L. virgaurea was 20 d earlier than that of L. sagitta. Although the full-blooming period separated, there was a roughly 10 d overlap between the two species. Meanwhile, the pollens and stigmas of the two species were both viability in the overlapped 10 d. L. virgaurea and L. sagitta shared the same types of pollinating insects, which was a generalized pollination type. Besides, the flower-visiting behavior towards the two species from the pollinators was similar, along with the interleaved access between the two species. There was no complete time isolation and no complete pollinator isolation between the two species, but the stigma had poor compatibility towards heterogenic pollen. The germination of pollen on stigma and growth of the pollen tube was hampered. Furthermore, the rejection of pollen-stigma was likely to be an important prezygotic reproductive isolation between L. virgaurea and L. sagitta, thus avoiding the natural hybridization and maintaining the diversity and genetic stability of the two species. PMID- 30460806 TI - [Photosynthetic mechanism of tea yield and quality affected by different habitats]. AB - To understand photosynthetic mechanism of tea yield and quality, an experiment was conducted with four different typical habitats, including three intercropping patterns (S1:Osmanthus-Tea, S2:Michelia-Tea, S3:Osmanthus-Michelia-Tea) and a control (CK) at Changsha Agricutural Observation Station of Chinese Academy of Sciences. The photosynthetic physiological and ecological characteristics of tea yield and quality were examined. The results showed that the habitats S1, S2, S3 reduced the leaf temperature (TL), photosynthesis active radiation flux (PAR), net photosynthetic rate (Pn), transpiration rate (Tr), and stomatal conductance (gs), as well as the tea polyphenol content. Habitats S1, S2, S3 significantly increased leaf relative humidity (RHS), total amino-acid content of tea, and the yield and quality of tea, with a pattern of S3>S1>S2>CK. The leaves in habitats S1 and S3 could be made into high-grade green tea and famous green tea respectively. Comprehensive indicators showed that habitat S3 is an ideal intercropping pattern for high quality and high yield of tea garden. PMID- 30460807 TI - [Ecological and biological effects of biodegradable film on cotton in Hexi area of Gansu, Northwest China]. AB - To examine the effects of biodegradable film on preservation of soil temperature, moisture, growth and yield of cotton fields in Hexi area of Gansu, the trials were conducted with four treatments of DA (biodegradable film A with thickness of 0.012 mm), DB (biodegradable film B with thickness of 0.008 mm), common plastic film and unmulching were used to analyze the changes of degradation property, soil temperature, moisture, weeds control, and yield in 2016 and 2017. The results showed that the induction period of DB was three to five days earlier than that of the DA and the degradation rate was higher than DA. The mass loss rate of DA and DB could reach 95.6% and 94.5% respectively under 180 days landfill treatment. The DA showed good performance in water retention, soil warming in seedling stage, with no significant difference with the common plastic film. Due to the high degradation rate, water retention property, and insulation of DB were significantly lower than that of common plastic film. The growth period of cotton prolonged by biodegradable film compared with common plastic film, but with no significant difference of the emergence rate, boll number per plant, boll mass and lint percentage. However, the pre-frost yield and weeds control effects significantly decreased. There was no significant difference of cotton yield of DA compared with common film, but significantly increased by 73.1% and 59.9% compared with unmulching. The cotton yield of DB was significantly decreased by 11.8% and 7.1% compared with common film. In summary, DA played good performance on the preservation of soil temperature, moisture and the yield increasing effect, which could be applied in Hexi agricultural area of Gansu. PMID- 30460808 TI - [Differences in light and heat utilization efficiency and yield of soybean in two ecological zones and their response to chemical control regulators]. AB - The field experiment was conducted at two farms at Jiusan in Heihe (the fourth accumulated temperature zone) and at Lindian County of Daqing (the second accumulated temperature zone), both sites located in Heilongjiang Province, China. With soybean Kenfeng 41 as the test material, uniconazole (S3307, 50 mg.L 1) and 2-N, N- diethylamino ethyl caproate (DTA-6, 50 mg.L-1) were sprayed on leaves in the early flowering period of soybean. Through grey correlation analysis, the main factors affecting soybean yield were examined, and the differences of the light and heat utilization efficiency and soybean yield in two ecological conditions were compared. The regulation effects of chemical control technology on the light and heat utilization efficiency of soybean were explored. The results showed that the total surface radiation and >=10 C effective accumulated temperature were the main factors affecting soybean yield in both areas compared with rainfall and sunshine hours. The light and heat utilization efficiency from sowing to flowering period was significantly positively correlated with dry matter accumulation, and that from flowering to podding period was significantly positively correlated with dry matter accumulation per plant. There was a significant positive correlation between yield and dry matter accumulation, grain number per plant, grain mass per plant and 100-grain mass at seedling stage to podding stage. S3307 and DTA-6 could significantly improve light and heat utilization efficiency and soybean yield in both areas. S3307 showed the better regulation function to impact the light and heat utilization efficiency and yield than DTA-6 in both sites. In the two ecological areas of Jiusan and Lindian, spraying S3307 increased light utilization efficiency by 13.6% and 17.1%, and increased heat utilization efficiency by 14.1% and 17.2%, respectively. The yield by spraying S3307 was increased by 14.1% and 17.3% separately in Jiusan and Lindian. Therefore, it is the effective way to enhance resources utilization and achieve high-yield by using the reasonable chemical control technology. PMID- 30460809 TI - [Effects of micro-sprinkling hose irrigation with different hose lengths on soil water distribution, dry matter accumulation, and grain yield of wheat fields]. AB - To explore the optimal hose length of micro-sprinkling hose irrigation in wheat fields, a field trial taking JiMai 22 as test material was carried out in two growing seasons (2015-2016 and 2016-2017). Three lengths of micro-sprinkling hoses with 80-mm width were used, including 60 m (T1), 80 m (T2) and 100 m (T3). The length of trial plot was equal to the hose length. The trial plots were divided to different sample sections every 20-m length along the irrigation direction, which were named as A, B, C, D and E sections, respectively, to examine the effects of micro-sprinkling hose irrigations with different hose lengths on soil water distribution, dry matter accumulation and grain yield of wheat fields. The results showed that: 1) After irrigation at the jointing and anthesis stages in the two growing seasons, the relative soil water content in the 0-40 cm soil layer showed T1T2, T3 in the C section and T2>T3 in the D section. The CV of relative soil water content in different sections in the same treatment showed T1T2, T3 in the C section and T2>T3 in the D section. Leaf area index and rate of canopy photosynthesis active radiation interception at 20 d and 30 d after anthesis and dry matter accumulation amount after anthesis showed T1, T2>T3, and dry matter accumulation amount at the maturity stage showed T1> T2>T3. 3) In the two growing seasons, grain yield in the A and B sections had no significant differences among different treatments, and that showed T1>T2, T3 in the C section and T2>T3 in the D section. Grain yield of each treatment showed T1, T2>T3. 4) The grain yield and water use efficiency showed T1> T2>T3, and the irrigation water use efficiency showed T1>T2>T3 among different treatments in the two growing seasons. Considering grain yield and water use efficiency, hose irrigation with micro-sprinkling hose at 80-mm width and 60-m length was optimal treatment for water-saving and high-yield irrigation, and the suboptimal length was 80 m under this condition. The results could provide theoretical basis for water-saving and high-yield irrigation with micro-sprinkling hose in wheat fields in Shandong Province. PMID- 30460810 TI - [Effects of irrigation regimes on the variation of soil water and salt and yield of mechanically harvested cotton in Southern Xinjiang, China]. AB - The expansion of soil salinization area is a threat to cotton production in Southern Xinjiang. How to control soil salt accumulation by developing precise irrigation strategy is currently a hot topic for the film mulching drip-irrigated cotton field. With aims for soil quality improvement and high yield, we investigated the effects of irrigation regimes on soil water and salt distribution, yield and fiber quality in major cotton production area of Southern Xinjiang. Results showed that the increase of irrigation amount contributed to a higher cotton photosynthetic product accumulation, but had no significant effect on the ratio of reproductive organs to total biomass. The degree of soil desa lination had a positive correlation with the irrigation quotas. When the seasonal total irrigation amount exceeded 2577.83 m3.hm-2, soil salinization would not deteriorate. Irrigation amount had significant effect on WUEI, but had no effect on fiber quality. With the increasing of irrigation amount, cotton yield increased first and then decreased. In conclusion, applying 4200 m3.hm-2 seasonal irrigation amount in total and 7 d and 5 d irrigation interval for the budding and flowering stage respectively could be a suitable irrigation regime for mechanically-harvested cotton in the arid area of Southern Xinjiang. PMID- 30460811 TI - [Effects of straw returning on maize yield and root system spatial distribution under water stress]. AB - To investigate the effects of straw amendments on the yield and root spatial distribution of maize under water stress, an experiment with rainproof shelter was conducted in the field experimental station of Shenyang Agricultural University in 2016 and 2017. The drip irrigation facilities were used to perform water stress treatments. Straw burying (T1) and straw incorporation (T2) as two approaches of straw amendments were conducted combined with three depths of 15 cm (D1), 30 cm (D2), and 45 cm (D3) for straw returning, ploughing tillage at above three depths without straw presence as control in this study. During seedling and silking stages of maize, drought and water logging stresses were introduced respectively to the plants. Our results showed that the yield of maize under S1T1D2 treatment in 2016 was significantly increased by 5.7%-7.1%. Compared with all the rest treatments, the dry weights of lateral roots and deep roots under S1T1D2 treatment were increased by 67.3%-149.9% and 17.9%-116.4%, respectively. The dry matter accumulation in shoot of maize observed from S1T1D2 treatment was significantly lower than those under other treatments, with 2.1%-35.8% reduction. Our results indicated that S1T1D2 could significantly promote the growth and spatial distribution of maize root, accounting to release water stress and keep yield stabilization or promotion. Therefore, 30 cm of straw burying could be used as a suitable approach of straw returning for maize production in northeastern China, where the climate is with a pattern of drought first and waterlogging in later stage. PMID- 30460812 TI - [Effects of light quality ratio on photosynthetic characteristics and quality of purple lettuce]. AB - To explore the effects of different light quality ratios on the growth and development of purple lettuce, we used LED intelligent light control console as light source to study the effects of adding different proportions of red and blue light (1:1, 2:1, 4:1 and 1:2) to the white light on photosynthetic characteristics and commercial quality of purple lettuce (Lactuca sativa L. cv 'Zhongshu Purple Lettuce'). The results showed that when the ratio of red to blue light was 4:1, the chlorophyll content, RuBP carboxylase activity, electron transport efficiency of photosynthesis, net photosynthetic rate and growth were all significantly higher than that in control and other treatments, whereas the nitrate content was the lowest. When the ratio of red to blue light was 1:2, the contents of soluble protein, vitamin C, secondary metabolites such as anthocyanins, flavonoids, total phenolic compounds, and the contents of antioxidant capacity were significantly higher than those in the control and other treatments. We concluded that adding appropriate ratios of red to blue light to the white light could increase photosynthesis and improve commercial quality of purple lettuce. PMID- 30460813 TI - [Emergy analysis, water-heat utilization, and carbon emission of typical cropping patterns in the oasis irrigation area.] AB - Reasonable cropping pattern can improve resource utilization efficiency, reduce environmental risks in agricultural production, and achieve the goal of resource saving coupled with high production and efficiency. We evaluated the production effects of typical cropping patterns in an arid irrigation region from several aspects, including resource utilization, carbon emissions, economic benefit, emergy self-sufficiency ratio and net emergy yield ratio, with the method of emergy theory, to provide theoretical and practical basis for the establishment of efficient cropping with lower resource investment and carbon emissions but higher yield and resource utilization efficiency combined with the sustainability of agricultural production. The results showed that, high-efficient wheat-maize intercropping production pattern (integration of no tillage with 25 to 30 cm height of wheat straw covering in the wheat strip and two-year plastic mulching in the maize strip, NTSI) had the best performance in grain yield boosting, with the yields 13.5% to 16.9% and 13.8% to 17.1% higher than that in local traditional production patterns (i.e., wheat-maize intercropping, CTI, and monoculture maize, CTM), respectively. Moreover, NTSI increased water use efficiency and solar energy use efficiency by 12.4% to 17.2% and 6.1% to 8.1%, compared to CTI, respectively. Compared to CTI and CTM, NTSI improved the effect on carbon emission reduction by decreasing total soil CO2 emission by 618 to 895 kg.hm-2 and 1804 to 2002 kg.hm-2 with the ratio of 12.1% to 16.4% and 28.6% to 31.0%, but increased carbon emission efficiency by 29.3% to 40.1% and 58.9 to 71.4%, respectively. Meanwhile, the NTSI pattern had obvious resources saving potential. Compared with CTI and CTM, NTSI reduced total input by 1424 to 1431 yuan.hm-2 and 501 to 1547 yuan.hm-2, with the proportional reduction being 12.6% to 13.6% and 4.9% to 14.6%; however, increased total output by 4309 to 4603 yuan.hm-2 and 8439 to 11057 yuan.hm-2, the increased ratio was 11.2% to 11.8% and 24.4% to 36.3%; also, increased net return by 5740 to 6027 yuan.hm-2 and 9544 to 11558 yuan.hm-2, and the improved percentage was 19.6% to 22.4% and 40.1% to 57.7%, respectively. Therefore, the high-efficient NTSI pattern had greater input output ratio by 27.9% to 29.0% and 40.5% to 45.6% than CTI and CTM, respectively, similarly, greater benefit per cubic meter of water by 19.9% to 23.2% and 27.7% to 39.3%, respectively. The emergy self-sufficiency ratio of NTSI pattern was 57.2%, being 4.0% and 12.2% higher than CTI and CTM, respectively. NTSI pattern's net emergy yield ratio was 0.173, being 10.0% greater than CTI but 11.7% lower than CTM. With respect to resource utilization, carbon emission reduction, economic benefits and the sustainable development of high-efficient intercropping pattern, the integration of no tillage with straw covering and two-year plastic film mulching measures had higher economic activity, better function of agricultural system, greater production efficiency, and higher returns on energy value. We concluded that NTSI could be a high-efficiency farming system pattern on resources saving, carbon emission reduction, high yield and efficiency in arid oasis irrigation areas. PMID- 30460814 TI - [Dynamic of carbon footprint and its composition for double rice production in Southern China during 2004-2014]. AB - The area of rice production in Southern China is one of the most important farming regions in China, due to its great contribution to national food security. To assess the differences in carbon footprints (CF) of double rice production will benefit the achievement of low carbon agriculture. Base on the statistical data of crop yield and farmland investment of double rice production from 2004 to 2014, the spatiotemporal dynamics of CF and its composition of double rice in Southern China was estimated using the theory of CF and life cycle assessment method. The results showed that the CF of early and late rice in each province tended to increase, with the CF of early rice being higher than that of late rice. CF of early and late rice in Anhui were the highest (1000 kg CO2-eq.hm 2), and those in Fujian, Hubei and Hunan were the lowest (750 kg CO2-eq.hm-2). The highest component of CF in double rice was the production, transportation and utilization of fertilizers (60%), followed with the consumption of diesel. Progressive regression analysis showed that CF of double rice from 2004 to 2014 was mainly affected by diesel, compound fertilizer and K2O fertilizer. The analysis of net profit income showed that Hubei was a province with low-emission and high-yield, which was conducive to the sustainable development of low carbon agriculture. Given to the large transfer of rural labor from agricultural to non agricultural sections and the development of mechanization, diesel and other mechanical inputs would increase rapidly in the future. Therefore, improving fertilizer utilization, mechanical and irrigation efficiencies in crop production would be the main approach to promote low-carbon agriculture in rice production of southern China. PMID- 30460815 TI - [Radical variation of main wood properties and its relationship to climatic factors of Machilus pauhoi plantation]. AB - To provide a theoretical foundation for forecasting wood properties, rotation selection and efficient use of timber, wood properties of 17 year-old Machilus pauhoi plantation were examined using SilviScanTM fast detection technology. The radical variation mode of anatomical traits, wood density, modulus of elasticity and their responses to climate change were analyzed. We also analyzed the relationship between growth ring width, growth ring age and wood property parameters. The results showed that the radical variation patterns of all the wood properties were different, with 7-11th growth ring being the turning point of the variation curves. Growth ring width had no significant correlation with wood density and cell wall to cavity ratio. Growth rate and growth ring age imposed significant impacts on most wood properties. Different climatic factors had different impacts on different wood properties. Relative humidity was the main factor affecting wood properties. The responses of microfibril angle and modulus of elasticity to climate change were more sensitive than other wood properties. PMID- 30460816 TI - [Additive aboveground biomass equations based on different predictors for natural Tilia Linn]. AB - Biomass is a basic quantitative character of forest ecosystem. Biomass data are foundation of researching many forestry and ecology problems. Accurate quantification of tree biomass is critical and essential for calculating carbon storage, as well as for studying climate change, forest health, forest productivity, nutrient cycling, etc. Constructing biomass models is considered a good approach to estimate forest biomass. Based on biomass data of 97 sampling trees of natural Tilia Linn. in Xiaoxing'an Mountains and Zhangguangcai ranges, three additive systems of individual tree biomass equations were developed: based on tree diameter at breast height (D) only, based on tree diameter at breast height and height (H), and based on the best models. The nonlinear seemly unrelated regression was used to estimate the parameters in the additive system of biomass equations. The heteroscedasticity in model residuals was addressed by applying a unique weight function to each equation. The individual tree biomass model validation was accomplished by Jackknifing technique. The results showed that three additive systems of individual tree biomass equations could fit and predict the biomass of Tilia Linn. well (adjusted coefficient of determination Ra2>0.84, mean predicted error percentage MPE<8.5%, mean absolute error MAE<16.3 kg,mean standard error percentage MPSE<28.5%). The biomass equations of stem and aboveground were better than biomass equations of branch, foliage and crown. Adding total tree height and crown factor in the additive systems of biomass equations could significantly improve model fitting performance and predicting precision (Ra2 improved from 0.01 to 0.04, MAE decreased from 0.01 to 4.55 kg), narrow the confidence interval of the predicted value and the biomass of stem, foliage and aboveground were increased more than the biomass of branch and crown. In general, the equations of the additive system based on the best models produced the best model fitting, followed by that of the additive system based on D and H, and that based on D. It was essential to develop biomass model by adding total tree height and crown factor. PMID- 30460817 TI - [Potential geographical distribution of Pyrus calleryana under different climate change scena-rios based on the MaxEnt model]. AB - To resovle the problems of in-situ conservation and resource utilization of Pyrus caller-yana, maximum entropy model (MaxEnt) and geographic information system (GIS) were used to predict the global ecological suitable region of P. calleryana in different climate scenarios based on 236 distribution data and 19 ecological factors. The results showed that the ecological suitable regions of P. calleryana were mainly concentrated in North America, Asia and other regions, with a total area of 1.6*107 km2. In China, the regions with high ecological suitability were Hunan, Hubei, Anhui, Jiangxi, Jiangsu, Zhejiang and Fujian provinces. The main factors affecting the geographical distribution of P. calleryana were mean annual temperature and mean annual precipitation, followed by the seasonality of temperature. The model simulations indicated that P. calleryana would have different suitable habitat areas and marginally suitable habitat areas in different climate scenarios. In terms of the spatial distribution of the potential habitat area, both the distributional range and the center of distribution of suitable and marginally suitable habitat area would shift from east to west. The suitable habitat area in North America and marginally suitable habitat areas in Europe would increase rapidly. PMID- 30460818 TI - [Hydrological effects of vegetation restoration and the threshold for its response to annual precipitation in Pengchongjian small watershed, Jiangxi, China]. AB - To examine the change of runoff and its reason is an important scientific issue in forest hydrology. In this study, we performed the trend and inflection analysis on the time series of daily precipitation and runoff in the Pengchongjian small watershed from 1983 to 2014 by Mann-Kendall test method, a site with abundant precipitation . Using the empirical statistics method, we analyzed the effects of precipitation variation and vegetation restoration on the runoff and its contribution rates. Furthermore, we calculated the critical value of the hydrological effect of vegetation restoration on the annual precipitation. The results showed that the year 2003 was a consistent abrupt point for annual precipitation and runoff. Compared to the baseline period (1983-2003), annual precipitation and the depth of runoff in the changing period (2004-2014) decreased by 8.7% and 29.2%, with the averaged annual decrease of 12.7 and 22.1 mm, respectively. The averaged depth of runoff in spring, summer, autumn, winter, and in the whole year decreased by 100.2, 105.8, 25.2, 23.4, and 243.0 mm, respectively. The contribution rates of the depth of runoff to precipitation varia-tion were 58.9%, 71.6%, 65.5%, 35.0%, and 57.1%, respectively, while the contribution rates of vegetation restoration were 41.1%, 28.4%, 34.5%, 65.0%, and 42.9%, respectively. The hydrological effect of vegetation restoration was attributed to the annual precipitation, with a critical value of 1181 mm. Vegetation restoration increased annual depth of runoff when annual precipitation was less than the critical value, and increased that when annual precipitation was higher than the critical value. Therefore, the critical value might help to explain the difference in contribution rates of vegetation restoration to runoff in different watersheds and serve as one of the important reasons for the debate and divergence of forest restoration impacts on runoff. PMID- 30460819 TI - [Simulating the post-fire net primary production restoration and its affecting factors by using MTCLIM and 3PGS model in Genhe forest region, Northeast China]. AB - Fire is a major disturbance factor in Daxing'anling region, with important impacts on carbon balance of forest ecosystems. Fire severity and the distinction of microclimates induced by different topography are the primary factors driving the restoration of post-fire net primary productivity (NPP). In this study, we examined the influence of fire severity and topographic factors on the restoration of forest NPP in the Genhe forest region. The spatial and temporal restoration process of post-fire NPP were simulated by combining with MTCLIM and 3PGS model based on multiyear Landsat TM satellite (2008-2012) and climate (1980 2010) data. The results showed that the 3PGS-MTCLIM model could precisely estimate the spatial distribution of NPP at small scales, with a good correlation between simulated and observed values (R2=0.828). The percentage of declined NPP in the year following the fire ranged 43%-80%, and the average NPP recovery period for this region was about 10 years by comparing pre- and post-fire NPP. Fire severity had significant impacts on post-fire recovery. The stronger the fire intensity, the longer the recovery period was needed. The NPP recovered relatively slower after a period of fast-speed recovery. Among the three topographic factors, elevation was the strongest one affecting forest NPP restoration, followed by slope and aspect. PMID- 30460820 TI - [Coupling analysis of landscape pattern and thermal fields after the afforestation in Beijing plain area]. AB - Under the positive human land use regulation (e.g. afforestation), understanding the impacts of landscape pattern changes on urban and rural thermal fields can provide reference data for future construction and optimization of urban afforestation projects and bring new insights for future landscape patterns and thermal fields environment related research. Under the context of "One Million Mu Plain Afforestation Project" in Beijing plain area, we applied remote sensing technology and geographic information system and used transfer-matrix method and coupling analysis to evaluate the impacts of plain afforestation on thermal field environment and to explore the correlation between changes in landscape patterns resulted from urban afforestation projects and urban land surface temperature. Our results showed that the percentage of landscape (PLAND) of forests and parks increased by 7.6% and 0.5% after the afforestation project in Beijing plain area, respectively. The heat island intensity decreased by 19.2% of entire plain area, and by 23.3% of suburban area, however, it increased by 23.5% of city area. Spanning urban to urban-rural interface, the PLAND of forests and parks, the mean patch size (MPS) of forests and wetlands were significantly negatively correlated with the changes in landscape surface temperature (LST). In city area, the area weighted mean shape index (AWMSI) of forests was significantly positively correlated with the changes of LST. In suburban area, the MPS and AWMSI of forests showed significantly negative correlation with changes of LST, which was contrary to parks. After the implementation of afforestation project in Beijing plain area, the increased urban forests and urban parks had mitigated thermal fields to some extent. The scale of mitigation was limited and most areas with decreased heat island intensity were concentrated in newly planted sites in suburban area. The more connected the forests and wetlands, the better the relief of the thermal fields in the plain area. Impacted by the grain size, time, topography, human activities and other factors, the change in landscape patterns caused by the control of land use structure showed non-linear correlation with the change of LST. PMID- 30460821 TI - [Temporal and spatial changes of urban impervious surface and its influence on urban ecolo-gical quality: A comparison between Shanghai and New York]. AB - The urban spatial expansion has led to the considerable substitution of natural vegetation-dominated land surfaces by impervious surfaces, especially in large cities, with great impacts on urban ecological quality. Two most heavily populated cities, Shanghai of China and New York of USA, were chosen as the study cases. Based on Landsat images obtained in 1989, 2002, 2015 in Shanghai and in 1991, 2001, 2015 in New York, normalized difference impervious surface index (NDISI) was used to extract impervious surface (IS) information. The remote sensing based ecolo-gical index (RSEI) was then applied to evaluate the changes of urban ecological quality caused by the increased impervious surface. Furthermore, landscape pattern indices were used to analyze the differences of spatial structure of impervious surface between Shanghai and New York and their influences on urban ecological quality. The results showed a significant difference in urban expansion rate and pattern between Shanghai and New York from the early 1990s to 2015. The IS expansion area in Shanghai was 17.4 times as much as that in New York. The annual IS increase rate of Shanghai was 62.2 times as much as that of New York. Shanghai had experienced an expansion from urban center to the surrounding countryside in a concentric ring pattern, whereas New York showed no much expansion but had IS increase mainly within the inner city through space filling pattern. These differences in IS change rate and spatial distribution pattern had resulted in the difference in urban ecological quality of the two cities. The mean RSEI in Shanghai dropped from 0.717 in 1989 to 0.453 in 2015, with a decrease of 36.8%. In contrast, the RSEI of New York had a decline of 6.9% from 0.552 in 1991 to 0.514 in 2015. The poor ecological condition urban area tended to have large IS patches that were well connected and aggregated. PMID- 30460822 TI - [Non-monetary accounting on forest ecosystem services value: Case study of forests in Beijing-Tianjin-Hebei Region]. AB - Forest ecosystem has significant functions and services. The accounting on forest ecosystem services valuation (ESV) is one of the key prerequisites to forest ESV pricing, ecosystems protection, and the implementation of that "Lucid waters and lush mountains are invaluable assets". We first reviewed the advantages and limitations of current forest ESV counting methods, and then established the non monetary accounting method on forest ESV based on emergy method. Further, we used forests in Beijing-Tianjin-Hebei area to test this accounting method. In addition, we modified the ESV accounting results based on normalized differential vegetation index (NDVI). Meanwhile, considering the uncertainty of data source, we conducted the uncertainty analysis on the accounting results. The results showed that the order of forest ESV in the different areas of Beijing-Tianjin Hebei was Chengde > Beijing > Baoding > Zhangjiakou > Shijiazhuang > Qinhuangdao > Tianjin > Tangshan > Xingtai > Langfang > Hengshui >Cangzhou. The ESV order of different forest types was deciduous broad-leaved forest > evergreen coniferous forest > deciduous coniferous forest. In terms of different ecosystem services subtypes, the largest type of the ESV per unit area in Beijing-Tianjin-Hebei was climate regulation, accounting for around 60% of the total ESV per unit area, following by net primary productivity (NPP) increase and carbon sequestration, accounting for around 23%, and the proportion of other subtypes were small. The forest ESV in Hebei Province contributed most to local GDP, followed by Beijing and Tianjin. The non-monetary forest ESV accounting method established here could overcome the limitations of previous methods, including double counting, failure to establish ESV from donor side and the improper use or replacement of emergy transformities. We systematically assessed the forest ESV and could provide more effective optimization and decision-making basis on forest ecosystem services pricing, eco-compensation establishment and ecological civilization promotion. PMID- 30460823 TI - [Multidimensional poverty measurement of poverty-stricken counties in China's 14 conti-guous destitute areas considering ecological environment]. AB - As an important part of the national poverty alleviation strategy in China, monitoring of poverty-stricken counties is the precondition and guarantee for implementing national precise poverty reduction strategies. Taking 724 poverty stricken counties in 14 contiguous destitute areas as the study area, we designed a county-level multidimensional poverty measurement index system that reflected the economic state (poverty appearance), social state (living guarantee ability) and ecological environment state (potential capacity of regional development) in fully consideration of the interdependent relationship between ecological vulnerability and economic poverty, and analyzed the poverty degree, poverty type, causes of poverty and the spatial distribution characteristics in multi scale and multi-angle levels. The results showed that the distribution of poverty level of different counties represented a geometrically olive-shaped pattern that was larger in lower and moderate impoverished counties and smaller in low and high poverty-stricken counties. As far as the distribution of poverty-stricken counties was concerned, the distribution was spatially heterogeneous, presenting a typical stepped structure that was "west-high vs. east-low", where different levels of dotted poverty kernels were scattered. The multidimensional characteristics of poverty-stricken counties represented a wholely strong spatial dependence; however, both High-High areas and Low-Low areas were distributed intensively while both High-Low areas and Low-High areas were distributed discretely. The characteristics of poverty distribution on both sides of the "Hu Line" were obviously different. The number of seven-factor comprehensive poverty stricken counties was the most, while the location advantages, terrain conditions and poverty alleviation performance were the significant factors affecting the development of poverty reduction. Ecological poverty caused by deterioration of ecological environment and natural endowments is a regional characteristic in most poverty areas of China. PMID- 30460824 TI - [Molecular weight fractionated characterization of dissolved organic matter and its correlation with water quality in the Bahe River Basin, Northwest China]. AB - Dissolved organic matter (DOM) is one of the core carriers of organic matter decomposition and nutrient regeneration in water. It is an important link of biogeochemical cycle of carbon and nitrogen, and the key content of water environmental science research. We used liquid chromatography-organic carbon detection-organic nitrogen detection (LC-OCD-OND) to investigate the molecular weight distribution of riverine DOM in the Bahe River of Xi'an City and further analyzed its correlation with water quality. The results showed that riverine DOM was composed of biopolymers, humic substances, humus degradation products, and low molecular-weight neutrals, with the ave-rage concentration of 0.15, 1.75, 0.48, 0.36 and 0.002 mg.L-1, respectively. The DOM along the river was in order of urban> town> river source. The humic substances with molecular weight of 1000 20000 Da accounted for 49.0% of total DOM which followed the order of town> waste water treatment plants (WWTPs) effluents>river estuary> river source. The biopolymers with the molecular weight of >20000Da accounted for 5.1% of total DOM, with the sequence of WWTPs effluents>river estuary>river source>town. The allochthonous (terrigenous) DOM produced by WWTPs effluents had the greatest contribution to the riverine DOM. The fractions of DOM with different molecular weights had significant correlations with water quality parameters. The results showed that the molecular weight fractions and abundance of DOM based on LC-OCD OND could be used as a comprehensive index for water quality monitoring, to characterize the spatial heterogeneity of river water quality, and used for quantitative identification and source apportionment of pollutant components. PMID- 30460825 TI - [Microbial biodiversity in rhizospheric soil of Torreya grandis 'Merrillii' relative to cultivation history]. AB - To examine the effects of different cultivation history (5 a,10 a, and 15 a) on soil microbial communities, we used Illumina sequencing to investigate the diversity and structure of soil bacterial and fungal communities from Torreya grandis 'Merrillii' fields. The results showed that bacterial Shannon index, the richness estimators Chao1 and ACE were lower in soil in 15 year-old stand than those in other cultivation histories, while Simpson index showed no significant variation. Results from bacterial community NMDS showed that cultivation history played a vital role in driving the changes of soil bacteria communitiy structure. The bacterial communities in 5 and 10 year-old stand had the similar composition. The variations of bacterial richness and diversity as well as community structure (comprised basically of Proteobacteria, Actinobacteria, Acidobacteria, and Chloroflexi) were significantly correlated with soil organic matters, soil C/N, and total nitrogen. The fungi richness estimators of Chao1 and ACE were significantly decreased with increasing cultivation history. Shannon and Simpson indices were significantly higher in soil with 10 year-old stand than soils with other cultivation history. Fungal NMDS could be clustered in the same era. Fungal communities were comprosed of Ascomycota, Basidiomycota and Zygomycota. Changes in fungal richness/diversity and community structure were mainly controlled by the variation of soil organic matter. In conclusion, the predominant factors affecting soil microbial communities were the cultivation history, soil C/N, total nitrogen and organic matter, respectively. PMID- 30460826 TI - [Relationship between soil bacterial community and environmental factors in the degraded alpine grassland of eastern Qilian Mountains, China]. AB - To explore the distribution of bacterial community and its relationship with soil environmental factors in degraded alpine grasslands in the eastern Qilian Mountains, we analyzed the changes of bacterial community structure and diversity across lightly, moderately and severely degraded grasslands by using high throughput sequencing technology. Redundancy analysis (RDA) was performed to analyze the relationship between soil bacterial communities and soil environmental factors by using CANOCO 4.5 software. The results showed that there were significant differences in soil physicochemical properties among different degraded alpine grasslands. There were 257125 effective sequences, 180826 high quality sequences and 4790 OTUs. The Chao1 index was lightly degraded grassland > moderately degraded grassland > severely degraded grassland; Shannon index was lightly degraded grassland > severely degraded grassland > moderately degraded grassland. Phylogenetic analysis indicated that the soil bacterial groups of each plot belonged to 33 phyla, with Actinomycetes, Proteobacteria and Firmicutes being the dominant groups in the three grasslands. From analysis of the proportion of soil bacteria in different degraded grassland, we found that the Actinomycetes, Acidobacteria and Proteobacteria increased first and then decreased with the degree of degradation, and the Firmicutes showed an opposite trend. The results of RDA analysis showed that the dominant groups of bacteria were significantly correlated with invertase, cellulase, phosphatas, pH, electronic conductivity, available nitrogen and available potassium. It was concluded that there were significant differences in soil bacterial communities among different degraded alpine grasslands in the eastern Qilian Mountains, and the soil environmental factors were the important factors driving the distribution of soil bacterial communities. PMID- 30460827 TI - [Comparison on fungal molecular ecological networks of agricultural soils with different latitudes in the black soil region of Northeast China]. AB - To investigate the differences of fungal network structures and interaction among fungal species of in black soil region of Northeast China, Illumina MiSeq sequencing was used to reveal the fungal communities in the three long-term fertilization experimental fields. Fungal molecular ecological networks were constructed based on random matrix theory (RMT). The results demonstrated that Ascomycota, Basidiomycota and Zygomycota were the dominant phyla and Hypocreales, Pleosporales and Sordariales were the dominant order, but the relative abundance of some dominant taxa significantly varied in different locations. Fungal molecular ecological network structures in three locations showed significant difference, with more complex fungal network being observed in north location with more competitive relations among species. The fungal network in south location was more easily disturbed by environmental perturbations with less stability. Only seven shared nodes were detected among three fungal molecular ecological networks. There were large differences in connectivity of shared nodes within individual fungal network. The subnetwork of Hypocreales was gradual complex from south to north location while subnetwork of Pleosporales presented reversed trend. The key species of south, middle and north locations were Chaetomiaceae, Pleosporales and Penicillium coralligerum, respectively. Soil pH and total N content were the main soil properties simultaneously influencing three fungal networks. PMID- 30460828 TI - [Colonization with arbuscular mycorrhizal fungus Funneliformis mosseae enhanced the responses of tomato plants to mechanical wounding]. AB - Insect herbivore feeding causes mechanical damage to plants, which can activate plant defense responses. Whether symbiosis with beneficial microorganisms can enhance the responses of plants to mechanical damage is of importance for plant anti-herbivore resistance. In this study, defense responses of tomato (Lycopersicon esculentum) plants to mechanical wounding was investigated after the tomato roots being infected by arbuscular mycorrhizal fungus (AMF) Funneliformis mosseae. The results showed that in response to leaf mechanical wounding, the activities of phenylalanine ammonia-lyase (PAL), superoxide dismutase (SOD), peroxidase (POD), polyphenol oxidase (PPO) and catalase (CAT) in the leaves of tomato pre-inoculated with AMF (FD), as well as transcript levels of genes encoding phenylalanine ammonia lyase (PAL) and beta-1,3-glucanase (PR2) in the leaves and roots were significantly higher in relative to sole mechanical wounding (D), sole mycorrhizal inoculation (F), and control without mechanical wounding and mycorrhizal inoculation (CK). Although the activities of protective enzyme and transcript levels of the two defense-related genes were induced in the plants of sole mechanical wounding (D) and sole mycorrhizal inoculation (F), the induction was faster and stronger in the plants with leaf mechanical wounding and mycorrhizal pre-inoculation (FD). Our findings indicated that arbuscular mycorrhizal colonization could prime quicker and stronger defense responses of tomato plants to mechanical damage. PMID- 30460829 TI - [Root promoting effect and its regulation mechanisms of endophytic Bacillus amyloliquefaciens YTB1407 in sweet potato]. AB - We isolated the endophytic Bacillus amyloliquefaciens YTB1407 from the root of Panax quinquefolium, which has both biological control and growth promoting effects. To investigate its potential applications, a pot experiment of sweet potato was tested to assess the capacity of endophytic colonization of YTB1407 and the selection of its optimum concentration by investigating the performance of root characteristics on three time points in the whole early growth phase after irrigating with different concentrations of bacterial suspensions with treatment of sterile water as control. The activities of endogenous hormone IAA, ZR, t-ZR and IAA oxidase (IAAO, PPO, POD) were analyzed. The results showed that YTB1407 promoted the specific colonization of root system, the elongation of adventitious root and branch roots, and root activity in the early growth stage of sweet potato. At later growth stage, it formed greater fresh mass of absorption root and lower aboveground/root system mass ratio. YTB1407 suspensions with OD600 of 0.50 (T0.50) had more significant effect, which induced the highest fresh tuber mass and the largest effective tuber numbers of per plant at top cover stage. YTB1407 promoted the differentiation of adventitious roots into tubers at initial point of tuberization by increasing IAA content and the ratio of (t-ZR+ZR)/IAA, decreasing IAAO activity and enhancing PPO activity. Moreover, it promoted the differentiated roots into tubers at tuberization stage by keeping the higher content of IAA, lower ratio of (t-ZR+ZR)/IAA, and decreasing IAAO and PPO activities. PMID- 30460830 TI - [Effects of long-term different fertilization regimes on the abundance and community structure of ammonia oxidizers in paddy soils]. AB - Ammonia oxidation, driven by the ammonia oxidizers, is the rate-limiting step of nitrification and plays a key role in soil nitrogen cycling. In this study, real time PCR and Illumina MiSeq sequencing approaches were used to investigate the effects of long-term different fertilization regimes on the abundance and community structure of ammonia oxidizers, targeting the amoA genes, in a 30-year located experimental paddy soil in Ningxiang County, Hunan Province. Four treatments were compared, including control without fertilizer (CK), fertilizers NPK (CF), 70% NPK plus 30% manure (CFM1), and 40% NPK plus 60% manure (CFM2). The results showed that the abundance of amoA genes in AOA and AOB was in the range of 3.09*107-8.37*107 and 1.04*107-7.03*107 copies.g-1 dry soil, respectively. Fertilization significantly increased the AOA and AOB abundances. However, no significant difference was observed in AOB abundance between CFM2 and CK. Manure fertilization rate greatly affected the alpha diversity index of AOB rather than AOA. The Shannon index of AOA and ACE and Chao1 indexes of AOB observed in CFM1 were significantly higher than that in CK, respectively. Thaumarchaeota and Crenarchaeota were the predominant AOA phyla and Nitrosospira, environmental_samples_norank, Bacteria_unclassified and Nitrosomonadales_unclassified were the main AOB genus groups which accounted for 83.4% and 97.8% of the total AOA and AOB amoA gene reads, respectively. Venn diagram indicated that manure fertilization rate had a stronger effect on the OTU number of AOB amoA gene than that of AOA in different treatments, but it slightly altered the proportion of shared AOA and AOB amoA gene reads. Furthermore, there were pronounced differences in the community structure of AOB among different treatments than that of AOA. These results suggested that manure fertilization rate significantly affected the abundance, diversity and community structure of AOA and AOB. The Shannon index of AOA and the abundance and ACE and Chao1 indexes of AOB in CFM1 were significantly higher than that in the rest treatments, respectively. Our results provided basis for further exploring the response mechanism of ammonia oxidizers to different fertilization strategies and the roles of ammonia oxidizers in nitrogen transformation in agricultural systems. PMID- 30460831 TI - [Behavioral responses of Holotrichia oblita larvae to root exudates from three host plants]. AB - The larva of Holotrichia oblita is a serious soil pest that feed with plant roots in north China. To explore the effects of host root exudates on the larva could provide theoretical basis for the development of green prevention and control methods. In order to elucidate the behavioral responses of Holotrichia oblita larva to the roots of peanut, soybean and maize, an experiment was conducted using the Y-olfactometers with the air as control. The constituents of the root exudates from the three host plants were identified by the gas chromatography mass spectrometer (GC-MS). The olfactory responses of H. oblita larvae to the main components were tested. The results showed that H. oblita larvae had a significant behavioral preference toward the roots of peanut, soybean and maize than the control. The GC-MS analysis showed that the main components of volatile compounds in the three plants had more than twenty compounds, with only three shared ones, which was glycerol, dodecanol, ethyl benzene. The results of the Y olfactometers showed that at low concentrations (40 to 80 MUg.mL-1), the number of insects attracted by compound 2-butenoic acid, methylsuccinic acid, myristic acid, acetic acid and phthalate was significantly higher than that of control. At the concentrations of 100 MUg.mL-1, 200 MUg.mL-1, compound tetradecane and hexadecane were more attractive to the larvae than the control. The compounds p xylene, o-xylene, and palmitic acid glycerol were found to significantly induce the larva at the concentration of 300 MUg.mL-1 and 500 MUg.mL-1. In summary, the main components of plant root exudates had a significant luring effect on H. oblita larvae. PMID- 30460832 TI - [Contamination status and speciation for the sediment nutrients in Panjiakou Daheiting Reservoir]. AB - As the source of the "Luanhe-Tianjin Diversion Project", water environment status in the Panjiakou-Daheiting Reservoir directly affects drinking water safety in the water receiving area, and therefore plays important role in the development of the Beijing-Tianjin-Hebei region. Field survey was carried out in July 2016 to examine the pollution status of the sediment nitrogen, phospho-rus and organic matter. The results showed that total nitrogen (TN) content of surface sediments in Panjiakou-Daheiting Reservoir ranged from 1175.41 to 2415.67 mg.kg-1 with a mean of 1648.71 mg.kg-1. Total phosphorus (TP) ranged from 1773.25 to 3471.70 mg.kg-1 with a mean of 2790.89 mg.kg-1. Organic matter (OM) ranged from 6.0% to 25.3% with a mean of 12.5%. Daheiting Reservoir which located downstream of Panjiakou Reservoir had higher value in TP content, while had similar TN content. Results from speciation analysis showed that sediment nitrogen was mainly composed of organic nitrogen and phosphorus mainly consisted of calcium phosphorus which belonged to inorganic phosphorus. The value of C/N ratio indicated that OM mainly originated from exogenous substances. The pollution assessment results demonstrated that the sediment Panjiakou-Daheiting Reservoir was in a severe pollution status, and might have potential effect to the water environment improvement through the nutrient exchange at the sediment-water interface. PMID- 30460833 TI - [Community structure of Chironomid larvae and their indicative significance for water quality in streams of Xianju National Park, China]. AB - In August 2016, 59 sites of 13 streams in Xianju National Park were surveyed to explore the community structure of Chironomid larvae and their indicative significance for water quality. Water quality of the streams was evaluated based on Hilsenhoff biological index. The results showed that there were 37 clean sites, 19 mild polluted sites and three moderated polluted sites in Xianju National Park. We identified a total of 86 species of Chironomid larvae, belonging to 51 genera and four subfamilies, including 37 species in 19 genera of Chironominae; 35 species in 21 genera of Orthcladiinae; 12 species in 9 genera of Tanypodinae, two species in two genera of Diamesinae. Chironominae accounted for 40.3% of Chironomid larval density. Tanypodinae and Orthcladiinae were almost similar in Chironomid larval density, respectively accounted for 30% and 29.4% of the total. Diamesinae accounted for 0.3% of total Chironomid larval density. Conchapelopia sp. was the overwhelming dominant species and Polypedilum flavum, Rheocricotopus sp., Cricotupus vierriensis, Rheotanytarsus muscicola and Corynoneura carriana were the dominant species of Chironomid larvae. The result of indicator species analysis showed that Cricotupus vierriensis, Nanocladius dichromus, Tanytarsus formosanus, Tanytarsus mendex were indicator species of moderated pollution water, and that Rheocricotopus sp. was the indicator species of clean state water. PMID- 30460834 TI - [Niche and interspecific associations of major nekton in northern coastal waters in Yuhuan, Taizhou, China]. AB - Base on the data from fishery resources survey carried out in northern coastal waters in Yuhuan in November 2016 (autumn) and April 2017 (spring), we examined the niche and interspecific associations of major nekton by the methods of index of relative importance (IRI), niche breadth, niche overlap, the variance ratio (VR), X2-test, association coefficient (AC), Jaccard index (JI), point correlation coefficient (Phi) and Spearman rank correlation index. The ecological niche breadth of Portunus trituberculatus was the largest, with the absolute competitive advantage. The niche breadths of the important economic species Coilia nasus and Octopus variabilis were the smallest, which was at a weak competitive position. The niche overlap of the major nekton species in this area was uneven, possibly caused by the diversity of local environments. Overall interspecific associations indicated that insignificant negative correlation existed among major nekton species. All results of the X2-test, association coefficient (AC) and Jaccard index (JI) were consistent with that of overall interspecific associations, which indicated the independent trend among species. The correlation coefficients (Phi) and the Spearman rank correlation index revealed that the positive coupling pairs were more than the negative ones. It was due to the positive association among the other 14 species, caused by the spatial exclusion from large captured individuals of Muraenesox cinereus. According to the Spearman rank correlation and cluster analysis, 15 species could be divided into five ecological groups. The species within one ecological group had similar ecologically adaptable requirements of habitat, while the species from different ecological groups had different living habits and different ecological requirements. PMID- 30460835 TI - [Jasmonates: From induced plant anti-herbivore defensive reaction to growth defense tradeoffs]. AB - Jasmonates (JAs), which can exogenously induce anti-herbivore defensive reaction in plants, are important in the field of plant physiology and plant protection. We summarized the ecological effects of exogenous JAs applied on 40 species of plants on various herbivores (such as Lepidoptera and Hemipteran) and their natural enemies in the past 20 years. We systematically genera-lized the research status about the direct and indirect antiherbivore defense induced by JAs, induced systemic defense, induction methods, induced performance in field, and the application status of JAs. Moreover, combining with the latest literatures, we reviewed the effects of JAs on plant growth-defense trade-offs from the cross talk between phytohormone signaling pathways, and the regulation of nodes in the JA signaling pathway. Finally, we proposed the future directions and key aspects of the research on the plant anti-herbivore defense induced by exogenous JAs, which would promote the development of the related research and the application of JAs in field. PMID- 30460836 TI - The Italian law on informed consent and advance directives: its impact on intensive care units and the European legal framework. AB - The Italian Parliament has recently approved a law on informed consent, advance directives and advance care planning. The law also deals with health care proxyand health care decisions for minors and adults who are not able to give consent. The Italian law arrived quite late in comparison with other European countries. After several years of debate on the need to approve such a law, the focus has now shifted to the assessment of the legislative provisions and their impact on clinical practice. In this article, the authors firstly offer an overview of the findings from the empirical research regarding the use of the different legal tools in the field of intensive care medicine; secondly, they present the tools now provided by law no. 219/2017 particularly with regardto the decision-making processes in the Intensive Care Unit (ICU); thirdly, the authors offer a comparison between the new Italian law and other European legal orders, with special referenceto France, Spain, Germany and England. The aim of the article is to assess the degree of innovation of the law vis-a-vis the previous framework. PMID- 30460837 TI - Biomimetic Photocurable 3D Printed Nerve Guidance Channels with Aligned Cryomatrix Lumen for Peripheral Nerve Regeneration. AB - Repair and regeneration of the critically injured peripheral nerves is one of the most challenging reconstructive surgeries. Currently available and FDA approved nerve guidance channels (NGCs) are suitable for small gap injuries, and their biological performance is inferior to that of autografts. Development of biomimetic NGCs with clinically relevant geometrical and biological characteristics such as topographical, biochemical and haptotactic cues could offer better regeneration of the long gap complex nerve injuries. Here, in this study, we present the development and preclinical analysis of a 3D printed aligned cryomatrix filled NGCs along with nerve growth factor (NGF) (aCG+NGF) for peripheral nerve regeneration. We demonstrated the application of these aCG+NGF NGCs in the enhanced and successful regeneration of a critically injured rat sciatic nerve in comparison to random cryogel filled NGCs, multichannel, and clinically preferred hollow conduits as well as gold standard autografts. Our results indicated viz-a-viz similar effect of aCG+NGF NGCs to that of autografts, and not only enhanced the overall regenerated nerve physiology, but could also mimic the cellular aspects of regeneration. This study emphasizes the paradigm that these biomimetic 3D printed NGCs will lead to a better functional regenerative outcome under clinical settings. PMID- 30460838 TI - Ratiometric Luminescent Sensor of Picric Acid based on the Dual-Emission Mixed Lanthanide Coordination Polymer. AB - Powerful explosive sensor plays a key role in public security and environmental protection. Herein we report a series of isostructural lanthanide metal-organic frameworks [Ln2L1.5(NMP)2]n (LnL, Ln = Eu , Gd, Tb, Dy, Ho and Er, NMP = N-methyl 2-pyrrolidone) and mixed-Ln LnL (EuxTb1-xL, EuxGd1-xL, TbxGd1-xL and EuxTb0.02 xGd0.98L), which were synthesized by using [1,1':4',1"-terphenyl]-2',4,4",5' tetracarboxylic acid (H4L). Luminescence studies show that both H4L and GdL emit strong fluorescence and phosphorescence at 77 K while only fluorescence at room temperature, and TbL exhibits strong Tb3+ characteristic emission though the energy difference between the triplet excited state of H4L (20661 cm-1) and the 5D4 energy level of Tb3+ (20500 cm-1) is very small. By doping Eu3+ and Tb3+ into GdL, we obtained EuxTb0.02-xGd0.98L emitting warm white light. For Tb0.01Gd0.99L showing the dual-emission, the Tb3+ emission decreases slowly, however, the ligand emission is sharply quenched upon increasing the concentration of PA from 0 to 60 MUM, rendering Tb0.01Gd0.99L an excellent mixed-lanthanide MOF ratiometric luminescent PA sensor. PMID- 30460839 TI - Coaxial Triboelectric Nanogenerator and Supercapacitor Fiber Based Self-Charging Power Fabric. AB - To meet the urgent demand for rapid advancement of wearable electronics, challenges are still remained in developing wearable and sustainable power sources with simple fabrication and low cost. In this work, we demonstrate a flexible and coaxial fiber by fabricating one dimensional triboelectric nanogenerator (TENG) outside and supercapacitor (SC) inside, which can not only harvest mechanical energy but also store energy in all-in-one fiber. In such coaxial fiber, carbon fiber bundles are utilized as the electrode material for TENG as well as the active and electrode material for SC. Meanwhile, silicone rubber is served as the separator between the SC and TENG, the triboelectric material of the TENG, and the encapsulation material for the whole fiber as well. Moreover, both of the SC and TENG exhibit good performance and stability, which ensures its long-term use in daily life. Due to the flexibility and durability of carbon fiber and silicone rubber, the proposed coaxial fibers show great flexibility, which could be further knitted as cloth to sustainably power wearable electronic devices. This work provides a promising platform for the wearable electronics as well as smart textile. PMID- 30460840 TI - Assembly of DNA probes into Superstructures for Dramatically Enhancing Enzymatic Stability and Signal-to-Background Ratio. AB - DNA fluorescent probes are versatile tools that are widely used for biological detection in tubes. Using DNA probes in living systems, however, represents a significant challenge due to the endogenous nuclease-induced DNA degradation and strong background fluo-rescence in complex biological environments. Here, we show that assembling DNA probes into core-satellite gold nanoparticle (AuNP) superstructures could unprecedentedly enhance enzymatic stability and reduce background interference. The embedded DNA probes are protected from interaction with nuclease, eliminating the enzymatic degradation. In the meantime, the AuNP superstructures show extremely high quenching efficiency (> 98%) towards the embedded DNA probes, whose fluorescence can be instantly turned on by the target binding, resulting in high signal-to-background ratio. To demonstrate these distinct properties, we made use of the assembled nanoprobes to monitor the ATP levels under different stimuli in living cells. The assembly strategy leads to a new oppor-tunity for accurately sensing targets in living systems. PMID- 30460841 TI - Nanomaterials in Skin-Inspired Electronics: Toward Soft and Robust Skin-like Electronic Nanosystems. AB - Skin-inspired wearable electronic/biomedical systems based on functional nanomaterials with exceptional electrical and mechanical properties have revolutionized wearable applications, such as portable Internet of Things, personalized healthcare monitors, human-machine interfaces, and even always connected precise medicine systems. Despite these advancements, including the ability to predict and to control nanolevel phenomena of functional nanomaterials precisely and strategies for integrating nanomaterials onto desired substrates without performance losses, skin-inspired electronic nanosystems are not yet feasible beyond proof-of-concept devices. In this Perspective, we provide an outlook on skin-like electronics through the review of several recent reports on various materials strategies and integration methodologies of stretchable conducting and semiconducting nanomaterials, which are used as electrodes and active layers in stretchable sensors, transistors, multiplexed arrays, and integrated circuits. To overcome the challenge of realizing robust electronic nanosystems, we discuss using nanomaterials in dynamically cross-linked polymer matrices, focusing on the latest innovations in stretchable self-healing electronics, which could change the paradigm of wearable electronics. PMID- 30460842 TI - Application of Sequential Palladium Catalysis for the Discovery of Janus Kinase Inhibitors in the Benzo[ c]pyrrolo[2,3- h][1,6]naphthyridin-5-one (BPN) Series. AB - The present account describes the discovery and development of a new benzo[ c]pyrrolo[2,3- h][1,6]naphthyridin-5-one (BPN) JAK inhibitory chemotype that has produced selective JAK inhibitors. Sequential palladium chemistry was optimized for the rapid access to a focused library of derivatives to explore the structure activity relationships of the new scaffold. Several compounds from the series displayed potencies in the low nanomolar range against the four members of the JAK family with various selectivity profiles. Compound 20a, with an azetidine amide side chain, showed the best selectivity for JAK1 kinase vs JAK2, JAK3, and TYK2, with low nanomolar potency (IC50 = 3.4 nM). On the other hand, BPNs 17b and 18 had good general activity against the JAK family with excellent kinome selectivity profiles. Many of the new BPNs inhibited JAK3-mediated STAT-5 phosphorylation, the production of inflammatory cytokines, and the proliferation of primary T cells. Moreover, BPN 17b showed very similar in vivo results to tofacitinib in a rheumatoid arthritis animal model. PMID- 30460843 TI - Impact of Cultivation Method and Cultivar Selection on Soluble Carbohydrates and Pungent Principles in Onions ( Allium cepa L.). AB - The composition of soluble carbohydrates such as fructooligosaccharides (FOS) in onions ( Allium cepa L.) plays a role regarding their digestibility, long-term storability, and processability. Qualitative and quantitative profiles of soluble carbohydrates were determined in 23 different onion samples comprising 20 cultivars grown at two different locations in 2014 and 2015. FOS concentrations were 1.1-fold higher in set grown onions than in seed grown onions ( p = 0.001). FOS levels of dehydrator cultivars were higher (overall average: 130.8 +/- 42.4 g/L FOS) than those of common set and seed (61.8 +/- 20.0 and 29.4 +/- 14.7 g/L FOS) grown cultivars. Consequently, cultivation method (seed vs. set planting) and cultivar selection were crucial when aiming at onions with defined FOS contents. Besides FOS and other carbohydrate-related parameters, levels of alk(en)yl cysteine sulfoxides, indicating onion oil yield and pungency of onions, were determined to be different in dehydrator onions (13.1 +/- 2.6 MUmol/mL), seed (8.4 +/- 1.3 MUmol/mL), and set grown onions (7.5 +/- 1.6 MUmol/mL). PMID- 30460844 TI - Isotopic Labeling Studies Reveal the Patulin Detoxification Pathway by the Biocontrol Yeast Rhodotorula kratochvilovae LS11. AB - Patulin (1) is a mycotoxin contaminant in fruit and vegetable products worldwide. Biocontrol agents, such as the yeast Rhodotorula kratochvilovae strain LS11, can reduce patulin (1) contamination in food. R. kratochvilovae LS11 converts patulin (1) into desoxypatulinic acid (DPA) (5), which is less cytotoxic than the mycotoxin (1) to in vitro human lymphocytes. In the present study, we report our investigations into the pathway of degradation of patulin (1) to DPA (5) by R. kratochvilovae. Isotopic labeling experiments revealed that 5 derives from patulin (1) through the hydrolysis of the gamma-lactone ring and subsequent enzymatic modifications. The ability of patulin (1) and DPA (5) to cause genetic damage was also investigated by the cytokinesis-block micronucleus cytome assay on in vitro human lymphocytes. Patulin (1) was demonstrated to cause much higher chromosomal damage than DPA (5). PMID- 30460845 TI - Solvent-Engineered Stress in Nanoscale Materials. AB - Nanoscale materials are frequently coated with surface stabilisation layers during growth that prevent flocculation in solution and facilitate processing technologies such ink-jet device printing. Here, we show that few-nanometer thick stabilisation layers typically used swell in the presence of certain solvents and impart significant stresses into the nanomaterial that remains even after the solvent has evaporated. Solvent-swelling of the surface layer dramatically enhances nanomaterial-substrate adhesion via the collapse of the stabilisation layer during solvent evaporation, preventing stress relaxation. We demonstrate stress modulation of Ag, Au and Si nanowires functionalised with surface polymers and surfactant layers and detect strain levels of between 0.1% and 0.6% using AFM mechanical measurement and Raman spectroscopy. Dry-transferred nanowires exhibit poor adhesion and show no evidence of incorporated stress but become stressed immediately following solvent exposure. Strain engineering is demonstrated by coating nanowires with few nanometer thick solvent-responsive polymer layers. PMID- 30460846 TI - Synthesis of Fmoc-Protected ( S, S)- trans-Cyclopentane Diamine Monomers Enables the Preparation and Study of Conformationally Restricted Peptide Nucleic Acids. AB - An efficient synthesis of Fmoc-protected ( S, S)- trans-cyclopentane PNA ( tcypPNA) monomers starting from mono-Boc-protected ( S, S)-1,2 cyclopentanediamine is reported. A general synthetic strategy was developed so that tcypPNA monomers with each nucleobase can be made in sufficient quantity and purity for use in solid-phase peptide synthesis (SPPS). The newly synthesized monomers were then successfully incorporated into 10-residue PNA oligomers using standard Fmoc chemistry for SPPS. The different tcypPNAs allow different positions in the sequence to be conformationally constrained with ( S, S)- trans cyclopentane to determine the effects on binding to complementary DNA. PMID- 30460847 TI - Alloy Clusters: Precise Synthesis and Mixing Effects. AB - Metal alloys exhibit functionalities unlike those of single metals. Such alloying has drawn considerable research interest, particularly for nanoscale particles (metal clusters/nanoparticles), from the viewpoint of creating new functional nanomaterials. In gas phase cluster research, generated alloy clusters can be spatially separated with atomic precision in vacuum. Thus, the influences of increases or decreases in each element on the overall electronic structure of the cluster can be elucidated. However, to further understand the related mixing and synergistic effects, alloy clusters need to be produced on a large scale and characterized by various techniques. Because alloy clusters protected by thiolate (SR) can be synthesized by chemical methods and are stable in both solution and the solid state, these clusters are ideal study materials to better understand the mixing and synergistic effects. Moreover, the alloy clusters thus created have potential applications as functional materials. Therefore, since 2008, we have been working on establishing a precise synthesis method for SR-protected alloy clusters and elucidating their mixing and synergistic effects. Early research focused on the precise synthesis of alloy clusters wherein some of the Au in the stable SR-protected gold clusters ([Au25(SR)18]- and [Au38(SR)24]0) is replaced by Pd, Ag, or Cu. These studies have shown that Pd, Ag, or Cu substitute at different metal sites. We also have examined the as-synthesized alloy clusters to clarify the effect of substitution by each element on the physical and chemical properties of the clusters. However, in early studies, the number of substitutions could not be controlled with atomic accuracy for [Au25- xM x(SR)18] (M = Ag or Cu). Then, in following research, methods have been established to obtain alloy clusters with control over the composition. We have succeeded in developing a method for controlling the number of Ag substitutions with atomic precision and thereby elucidating the effect of Ag substitution on the electronic structure of clusters with atomic precision. Concurrently, we also studied alloy clusters containing multiple heteroelements with different preferential substitution sites. These results revealed that the effects of substitution of each element can be superimposed on the cluster by combining multiple elemental substitutions at different sites. In addition, we successfully developed methods to synthesize alloy clusters with heterometal core. These findings are expected to lead to clear design guidelines for developing new functional nanomaterials. PMID- 30460848 TI - Development of an in vitro autocatalytic self-replication system for biosensing application. AB - Molecular self-replication is a fundamental function of all living organisms with the capability of templating and catalysing its own synthesis, and it plays important roles in prebiotic chemical evolution and effective synthetic machineries. However, the construc-tion of self-replication system in vitro remains a great challenge and its application for biosensing is rare. Here, we demonstrate for the first time the construction of an in vitro enzymatic nucleic acid self-replication system and its application for amplified sensing of human 8 oxoguanine DNA glycosylase (hOGG1) based on autocatalytic self-replicating-driven cascaded recycling amplification. In this strategy, hOGG1 excises 8-oxoguanine (8 oxoG) to unfold the hairpin substrate, activating autonomous biocatalytic process with molecular beacons (MBs) as both the fuels for producing nucleic acid templates and the generators for signal output, leading to the continuously replication of biocatalytic nucleic acid templates and the repeatedly cleavage of MBs for an enhanced fluorescence signal. This strategy exhibits an extremely low detection limit of 4.3 * 10-7 U/MUL and a large dynamic range of 5 orders of magnitude from 1 * 10-6 to 0.05 U/MUL. Importantly, it can be applied for the detection of enzyme kinetic parameters, the screening of hOGG1 inhibitors, and the quantification of hOGG1 activity in even 1 single lung cancer cell, providing a new approach for biomedical re-search and clinical diagnosis. PMID- 30460849 TI - Photocyclization of Tetra- and Pentapeptides Containing Adamantylphthalimide and Phenylalanines: Reaction Efficiency and Diastereoselectivity. AB - A series of tetrapeptides and pentapeptides was synthesized bearing a phthalimide chromophore at the N-terminus. The C-terminus of the peptides was strategically substituted with an amino acid, Phe, Phe(OMe), or Phe(OMe)2 characterized by different oxidation potentials. The photochemical reactivity of the peptides was investigated by preparative irradiation and isolation of photoproducts, as well as with laser flash photolysis. Upon photoexcitation, the peptides undergo photoinduced electron transfer (PET) and decarboxylation, followed by diastereoselective cyclization with the retention of configuration for tetrapeptides or inversion of configuration for pentapeptides. Molecular dynamics (MD) simulations and NOE experiments enabled assignment of the stereochemistry of the cyclic peptides. MD simulations of the linear peptides disclosed conformational reasons for the observed diastereoselectivity, being due to the peptide backbone spatial orientation imposed by the Phe amino acids. The photochemical efficiency for the decarboxylation and cyclization is not dependent on the peptide length, but it depends on the oxidation potential of the amino acid at the C-terminus. The results described herein are particularly important for the rational design of efficient photochemical reactions for the preparation of cyclic peptides with the desired selectivity. PMID- 30460850 TI - Shutting Down Shigella Secretion: Characterizing Small Molecule Type Three Secretion System ATPase Inhibitors. AB - Many important human pathogens rely on one or more type three secretion systems (T3SS) to inject bacterial effector proteins directly into the host cell cytoplasm. Protein secretion through the needle-like type three secretion apparatus (T3SA) is essential for pathogen virulence and relies on a highly conserved ATPase at the base of the apparatus, making it an attractive target for anti-infective therapeutics. Here, we leveraged the ability to purify an active oligomeric Shigella T3SS ATPase to provide kinetic analyses of three T3SS ATPase inhibitors of Spa47. In agreement with in silico docking simulations, the inhibitors displayed non-competitive inhibition profiles and efficiently reduced Spa47 ATPase activity with IC50s as low as 52 +/- 3 MUM. Two of the inhibitors functioned well in vivo, nearly abolishing effector protein secretion without significantly affecting Shigella growth phenotype or HeLa cell viability. Furthermore, characterization of Spa47 complexes in vitro and Shigella T3SA formation in vivo showed that the inhibitors do not function through disruption of Spa47 oligomers or by preventing T3SA formation. Together, these findings suggest that inhibitors targeting Spa47 may be an effective means of combating Shigella infection by shutting down type three secretion without preventing presentation of the highly antigenic T3SA tip proteins that aid in clearing the infection and developing pan- Shigella immunological memory. In summary, this is the first report of Shigella T3SS ATPase inhibitors and one of only a small number of studies characterizing T3SS ATPase inhibition in general. The work presented here provides much-needed insight into T3SS ATPase inhibition mechanisms and provides a strong platform for developing and evaluating non antibiotic therapeutics targeting Spa47 and other T3SS ATPases. PMID- 30460852 TI - Measuring Bone Biomarker Alkaline phosphatase with Wafer-scale Nanowell array Electrodes. AB - Biosensors that can analyze a single drop of biological fluid can overcome the limitation such as extraction volume from humans or animals, ethical problems, time and cost. In this work, we have developed a highly sensitive electrochemical biosensor based on a nanowell array (NWA) for the detection of alkaline phosphatase (ALP), a serum indicator of bone formation. The size of electrode is 2 * 1 mm2 and has over ten million nanowells (400 nm diameter) arranged uniformly on the electrode surface. For detecting ALP, Anti-ALP was immobilized and oriented on the NWA surface using a self-assembled monolayer and protein G. Electrochemical impedance spectroscopy (EIS) was used to determine the amount of ALP in 10 uL of sample. The impedance was calibrated with ALP concentration. The NWA has a linear dynamic range from 1 pg/mL to 100 ng/mL with a limit of detection (LOD) at 12 pg/mL. We used the sensor to measure the ALP in real mouse serum from 4, 10, and 20 weeks old mice and compared the results to the standard photometric assay. This work demonstrates the potential of electrochemical NWA sensors to analyze a single drop of real body fluid sample and can be developed for broad applications. PMID- 30460851 TI - Reconnaissance of Mixed Organic and Inorganic Chemicals in Private and Public Supply Tapwaters at Selected Residential and Workplace Sites in the United States. AB - Safe drinking water at the point-of-use (tapwater, TW) is a United States public health priority. Multiple lines of evidence were used to evaluate potential human health concerns of 482 organics and 19 inorganics in TW from 13 (7 public supply, 6 private well self-supply) home and 12 (public supply) workplace locations in 11 states. Only uranium (61.9 MUg L-1, private well) exceeded a National Primary Drinking Water Regulation maximum contaminant level (MCL: 30 MUg L-1). Lead was detected in 23 samples (MCL goal: zero). Seventy-five organics were detected at least once, with median detections of 5 and 17 compounds in self-supply and public supply samples, respectively (corresponding maxima: 12 and 29). Disinfection byproducts predominated in public supply samples, comprising 21% of all detected and 6 of the 10 most frequently detected. Chemicals designed to be bioactive (26 pesticides, 10 pharmaceuticals) comprised 48% of detected organics. Site-specific cumulative exposure-activity ratios (?EAR) were calculated for the 36 detected organics with ToxCast data. Because these detections are fractional indicators of a largely uncharacterized contaminant space, ?EAR in excess of 0.001 and 0.01 in 74 and 26% of public supply samples, respectively, provide an argument for prioritized assessment of cumulative effects to vulnerable populations from trace-level TW exposures. PMID- 30460853 TI - Active Delivery of Single DNA Molecules into a Plasmonic Nanopore for Label-Free Optical Sensing. AB - Plasmon resonance biosensors provide ultimate sensitivity at the single-molecule level. This sensitivity is, however, associated with a nanometer-sized confined hotspot, and molecular transport toward the sensor relies on inefficient diffusion. Here, we combine a plasmonic nanoantenna with a solid-state nanopore and demonstrate that single DNA molecules can be efficiently delivered to the plasmonic hotspots and detected in a label-free manner at submillisecond acquisition rates by monitoring the backscattered light intensity from the plasmonic nanoantennas. Our method realizes a better than 200 MUs temporal resolution together with a down to subsecond waiting time, which is orders of magnitude better than traditional single-molecule plasmonic resonance sensing methods. Furthermore, the electric field applied to the nanopore can actively drive biomolecules away from the hotspot, preventing molecules to permanently bind to the gold sensor surface and allowing efficient reuse of the sensor. Our plasmonic nanopore sensor thus significantly outperforms conventional plasmon resonance sensors and provides great opportunities for high-throughput optical single-molecule-sensing assays. PMID- 30460854 TI - Transition-Metal-Free Sulfuration/Annulation of Alkenes: Economical Access to Thiophenes Enabled by the Cleavage of Multiple C-H Bonds. AB - A novel, atom economical, and transition-metal-free strategy for the synthesis of thiophenes from substituted buta-1-enes with potassium sulfide has been presented. The reaction achieves double C-S bond formations via cleavage of multiple C-H bonds and provides an efficient approach to access various functionalized thiophenes. Moreover, the strategy can also be used for the synthesis of thiophenes from 1,4-diaryl-1,3-dienes. Mechanistically, DMSO plays a role of oxidant and S3*- in situ generated from K2S is involved. PMID- 30460855 TI - Pd/TiO2-Photocatalyzed Self-Condensation of Primary Amines To Afford Secondary Amines at Ambient Temperature. AB - Symmetric secondary amines were synthesized by the self-condensation of primary amines over a palladium-loaded titanium dioxide (Pd/TiO2) photocatalyst. The reactions afforded a series of secondary amines in moderate to excellent isolated yields at ambient temperature (30 degrees C, in cyclopentyl methyl ether). Applicability for one-pot pharmaceutical synthesis was demonstrated by a photocatalytic reaction sequence of self-condensation of an amine followed by N alkylation of the resulting secondary amine with an alcohol. PMID- 30460856 TI - Family caregivers' perspectives on medication adherence challenges in older people with dementia: a qualitative study. AB - OBJECTIVES: To achieve a better understanding of medication non-adherence determinants in older people with dementia from caregivers' perspectives and possible management solutions to improve medication adherence. METHOD: Semi structured telephone interviews were conducted with 20 caregivers of older people with dementia living in the community. Data was analyzed using an inductive thematic analysis based on Braun and Clarke's method. FINDINGS: Four themes emerged: dementia symptoms influence medication adherence, medication increases caregiver burden, lack of self-efficacy, medication aids and technology to enhance medication adherence. Caregivers' lack of knowledge reduces their self efficacy in managing medications and increases their burden of care. The majority of caregivers used technology and welcomed its use to assist them with their role. CONCLUSION: Caregivers require knowledge and support such as a multifaceted technology based intervention to assist with medication adherence. PMID- 30460857 TI - Clinical feasibility of pinhole glasses in presbyopia. AB - PURPOSE:: To investigate the ocular physiologic changes and subjective symptoms of wearing multiple-pinhole glasses in subjects with presbyopia. METHODS:: This prospective study included 32 eligible subjects with presbyopia. Objective ocular functions and a survey of ocular discomfort were performed at baseline. All participants underwent the same examinations after reading while wearing the pinhole glasses and not wearing these glasses at a 1-week interval in random order. RESULTS:: The pinhole glasses improved uncorrected distance and near visual acuity in presbyopia. These glasses also required 15% less accommodative power over the near stimulus of 25 cm than did eyes without pinholes. Compared to reading without pinhole glasses, reading with pinhole glasses led to the following changes: increase in monocular near point of accommodation from 4.39 +/ 0.78 diopter (D) to 5.19 +/- 1.12 D, increase in depth of focus from 1.42 +/- 0.44 D to 2.00 +/- 0.33 D, and increase in amplitude of fusional convergence from 13.38 +/- 6.88 prism D to 21.62 +/- 10.00 prism D. In contrast, the reading speed decreased, inter-blink interval increased, tear break-up time shortened, and subjective ophthalmic symptoms worsened with pinhole glasses compared to without. CONCLUSION:: In presbyopia, pinhole glasses improve visual acuity and accommodation-related parameters by pseudo-accommodation and the pinhole effect. However, the low legibility, increased inter-blink interval, and shortened break up time of pinhole glasses cause an uncomfortable feeling and excessive eye fatigue. Pinhole glasses have strengths and limitations that must be considered to provide appropriate guidance in patients with presbyopia. Clinical trial registration was done at www.ClinicalTrials.gov (identifier: NCT02722291). PMID- 30460858 TI - Comparison of the persistence and adherence between fixed-dose combinations and two-pill combinations in Japanese patients with type 2 diabetes. AB - OBJECTIVE: To explore treatment patterns, persistence and adherence between fixed dose combinations (FDC) and two-pill combinations (TPC) of oral antidiabetic drug (OAD) classes in Japanese patients with type 2 diabetes mellitus (T2DM) using administrative claims databases (Japan Medical Data Center [JMDC] and Medical Data Vision [MDV]). METHODS: This was a retrospective, longitudinal cohort analysis conducted between 2011 and 2015, in patients with T2DM receiving OADs as FDC or TPC. Outcomes included prescribing patterns, treatment persistence and adherence. RESULTS: Data from 3,474 and 3,066 patients receiving FDC, and 4,325 and 5,192 patients receiving TPC from the JMDC and MDV databases, respectively, were extracted. The most common OAD combination received by over half of all patients was dipeptidyl peptidase-4 inhibitor (DPP-4i) + thiazolidinediones (TZD) (64.1% [JMDC] and 70.5% [MDV]). Overall, 12-month persistence rates were higher in patients receiving FDC compared with TPC (70.4 vs 66.2% [JMDC], 75.6 vs 55.7% [MDV]). In the JMDC population receiving FDC or TPC, persistence rates were highest with DPP-4i schedules (67.5-83.5%). Median time to discontinuation was significantly longer with biguanide + TZD, and DPP-4i + TZD FDC schedules (p < 0.05) than TPC; adherence rates were >=80% across all antidiabetic drug classes in both database populations. CONCLUSIONS: Persistence and adherence to OADs in Japanese patients with T2DM were greater with FDC compared with TPC, which may suggest increased patient satisfaction due to reduced treatment burden. Further studies are warranted to investigate the impact of adherence and persistence of FDC of OADs on glycaemic control. PMID- 30460859 TI - Epidemiology of community-acquired sepsis in the Faroe Islands - a prospective observational study. AB - INTRODUCTION: The aim of the study was to gather nation-wide epidemiological and clinical data in order to characterize community-acquired sepsis in the Faroe Islands, and to compare these data with epidemiological studies performed in other geographical areas. METHODS: A prospective, observational study conducted from October 2013 until April 2015 to characterize sepsis, and to calculate incidence rates for community-acquired sepsis of any severity, community-acquired severe sepsis, community-acquired septic shock and community-acquired sepsis without community-acquired severe sepsis or community-acquired septic shock. RESULTS: Of 5279 admissions, 583 cases fulfilled the criteria for community acquired sepsis of any severity. The mean age of all cases was 67.6 +/- 18.3 years. Men accounted for 298 (51.5%) admissions. Charlson comorbidity index was greater than 2 in 247 (42.4%) cases. The incidence of community-acquired sepsis of any severity was 1414/100,000 person-years at risk (95% CI, 1374-1440). The incidence rate for community-acquired sepsis without community-acquired severe sepsis and community-acquired septic shock was 719/100,000 person-years at risk (95% CI, 695-742), for community-acquired severe sepsis 644/100,000 person-years at risk (95% CI, 623-668), for community-acquired septic shock 51/100,000 person years at risk (95% CI, 45-58). The highest incidence was seen in elderly patients. CONCLUSION: The incidence rates were slightly higher in men and increased with age, especially in those older than 85 years. Incidence rates of sepsis of any severity were higher than previously published from other countries. PMID- 30460860 TI - Pilot Assessment of Immersive Virtual-Reality Renal Models as an Educational and Preoperative Planning Tool for Percutaneous Nephrolithotomy. AB - BACKGROUND: Percutaneous nephrolithotomy (PCNL) requires the urologist to have detailed knowledge of the stone and its relationship to the renal anatomy. Immersive virtual reality (iVR) provides patient-specific 3D models that might be beneficial in this regard. Our objective is to present the initial experience with immersive VR in surgeon planning and patient preoperative education for PCNL. MATERIALS AND METHODS: From 2017-2018 four surgeons, each of whom had expertise in PCNL, used immersive VR (iVR) models to acquaint themselves with the renal anatomy prior to PCNL among 25 patients. iVR renderings were also viewed by patients using the same head-mounted Oculus rift display. Surgeons rated their understanding of the anatomy with CT alone and then after CT+iVR; patients also recorded their experience with iVR. To assess the impact on outcomes, the 25 iVR study patients were compared to 25 retrospectively matched-paired non-iVR patients. Student's t-test (Microsoft Excel) was used to analyze collected data. RESULTS: iVR improved surgeons' understanding of the optimal calyx of entry and the stone's location, size, and orientation (p<0.01). iVR altered the surgical approach in 10 (40%) cases. Patients strongly agreed that iVR improved their understanding of their stone disease and reduced their preoperative anxiety. In the retrospective matched-paired analysis, the iVR group had a statistically significant decrease in fluoroscopy time and blood loss as well as a trend toward fewer nephrostomy tracts and a higher stone-free rate. CONCLUSIONS: iVR improved urologists' understanding of the renal anatomy and, altered the operative approach in 40% of cases. In addition, iVR improved patient comprehension of their surgery. Clinically, iVR had benefits with regard to decreased fluoroscopy time and less blood loss along with a trend toward fewer access tracts and higher stone free rates. PMID- 30460861 TI - "I Thought I Was Dying:" (Un)Supportive Communication Surrounding Early Menstruation Experiences. AB - Menstruation is a salient, and sometimes scary, communication topic for young women. The present study reports on the early communication experiences about menstruation from 165 women using open-ended survey data. Through the framework of supportive communication, findings reveal that a discrepancy occurs between the health and practical information and needs to which young people who menstruate desire access, and their social and emotional needs. The present study indicates an inadequacy of both aspects of menstruation communication from important others in childhood and adolescence. Themes of boundary management, impersonal, silence, and accidents also characterize early communication experiences about menstruation. Our participants identified a desire for conversations that normalize menstruation as typical and acceptable, validate period pain and prescribe management tactics, and describe the existence of feminine hygiene products other than pads and tampons. Limitations and directions for future research are discussed. PMID- 30460862 TI - Endovascular management of endotension by graft reinforcement followed by direct sac embolization. AB - PURPOSE: To assess the efficacy of graft reinforcement followed by percutaneous direct sac embolization (PDSE) for the treatment of endotension after endovascular abdominal aortic aneurysm repair (EVAR). MATERIALS AND METHODS: A total of 290 patients underwent elective EVAR. All patients regularly underwent scheduled surveillance with contrast-enhanced computed tomography (CT). Two hundred thirty-five patients were followed for >=24 months after EVAR. Aneurysmal sac expansion of >=10 mm was observed in 20 patients. The patients with sac expansion of >=10 mm with no evidence of endoleak were treated with graft reinforcement. Graft reinforcement consisted of graft extension and graft relining. The patients with sac expansion at 6 months after graft reinforcement received PDSE using metallic coils and n-butyl cyanoacrylate-Lipiodol mixture. The aneurysm diameter was measured by CT performed 6 months and every year after the final intervention. RESULTS: Seven patients (7 men, 0 women; mean age, 69.1 +/- 4.2 years, Zenith(r):5/Excluder(r):1/Powerlink(r):1) underwent graft reinforcement. Two patients underwent graft reinforcement alone, and five patients underwent PDSE after graft reinforcement. Mean follow-up time after the final intervention was 21.1 months. The sac diameter stabilized after the final intervention in all patients. CONCLUSION: Graft reinforcement followed by complementary PDSE could be a useful treatment strategy for endotension. PMID- 30460863 TI - Mechanism of TangGanJian on nonalcoholic fatty liver disease with type 2 diabetes mellitus. AB - CONTEXT: TangGanJian (TGJ) has a curative effect in the clinical treatment of nonalcoholic fatty liver disease (NAFLD) with type 2 diabetes mellitus (T2DM), while the mechanism involved in the treatment process remains unclear. OBJECTIVE: This study details the mechanism of TGJ on the treatment of NAFLD with T2DM. MATERIALS AND METHODS: NAFLD was induced in T2DM rat model. Male Wistar rats were assigned into six groups: Group I (control), Group II (model), Group III (pioglitazone, 0.5 mg/kg), Group IV (high dose of TGJ, 24.8 g/kg), Group V (middle dose of TGJ, 12.4 g/kg) and Group VI (low dose of TGJ, 6.2 g/kg). All rats in each group were treated with the corresponding drugs by gavage for 8 weeks. Haematoxylin and eosin analysis was conducted. The indicators of inflammatory and oxidative stress were analysed utilizing one-way ANOVA. RESULTS: The contents of TNF-alpha (15.794 +/- 3.302 pg/mL), IL-6 (76.801 +/- 8.491 pg/mL), IL-1beta (100.101 +/- 13.150 pg/mL), CRP (1.052 +/- 0.079 pg/mL) and MDA (3.972 +/- 0.159 pg/mL) were obviously elevated in NAFLD with T2DM rats compared to controls. Except for the IL-6, the levels of other markers declined in a dose dependent manner after treatment with TGJ. The SOD (14.139 +/- 1.479 U/mgprot) and GSH-PX (81.511 +/- 5.276 U/mgprot) levels significantly decreased in NAFLD with T2DM rats, while the levels of these indicators increased after treatment with TGJ. CONCLUSIONS: TGJ may be a therapy for the NAFLD with T2DM rats by modulating the inflammatory response and the oxidative stress capacity. PMID- 30460864 TI - Outcomes of bilateral lateral rectus recession in treatment of recurrent exotropia after bilateral medial rectus resection. AB - PURPOSE:: To report the results of bilateral lateral rectus muscle recession for recurrent exotropia in cases where the primary surgery was a bilateral medial rectus resection. METHODS:: Retrospective chart review of 15 subjects who completed 6 months of follow-up. Data collected included patients' demographics and pre- and post-operative measurements of ocular alignment and motility. Surgical nomogram used was the same nomogram we use for primary cases of exotropia. RESULTS:: At 6-month follow-up, 73.3% of cases had a successful surgical outcome (defined as 8 PD of esotropia to 10 PD of exotropia). In addition, recession of lateral rectus muscles against the previously resected medial recti did not result in a significant increase in the limitation of abduction. CONCLUSION:: Bilateral lateral rectus recession using standard surgical tables is a safe and effective method for treating recurrent exotropia following bilateral medial rectus resection. Even large primary resections up to 12 mm do not seem to affect the results of bilateral lateral rectus recession. PMID- 30460865 TI - Simultaneous double arm automated blood pressure measurement for the screening of subjects with potential vascular disease: a community study. AB - PURPOSE: Hypertension guidelines recommend measuring blood pressure (BP) on both arms, since an abnormal inter-arm difference (IAD) in BP is associated with an increased risk of vascular abnormalities and cardiovascular (CV) disease. We tested whether an automatic oscillometric BP monitor allowing simultaneous both arm BP measurement might be effective for screening of subjects with potential vascular disease. MATERIALS AND METHODS: 220 consecutive subjects from an unselected sample of individuals of a small Italian community were screened using an automated upper-arm electronic BP monitor (Microlife WatchBP Office). Seated BP was measured in triplicate at 1 min interval. Demographic and clinical data were collected prior to any BP measurement. An average IAD difference >20 mmHg for systolic (S) and/or >10 mmHg for diastolic (D) BP was considered abnormal. RESULTS: In 9 subjects (4.1%) an abnormal IAD was found, with lower BPs measured in the non-dominant arm (147 +/- 28/78 +/- 9 vs. 154 +/- 15/92 +/- 11 mmHg dominant, p<.01). Subjects with a significant IAD were significantly older (71 +/ 8 vs. 57 +/- 15 years, p=.005), had a greater body mass index (BMI: 32 +/- 7 vs. 25 +/- 4 kg/m2, p=.0001), higher BP levels (154 +/- 15/92 +/- 11 vs. 133 +/- 18/80 +/- 10 mmHg, p=.001) and were more likely to report obesity (56 vs. 13%, p=.001), a history of hypertension (67 vs. 35%, p=.044) or cardiovascular disease (33 vs. 10%, p=.034) than subjects with normal IAD. In a multivariate analysis, a higher BMI [odds ratio (95% confidence interval): 1.29 (1.11, 1.51)] and SBP [1.06 (1.01, 1.10)] were significantly associated with a larger risk of an abnormal IAD (p=.001 and p=.012, respectively). CONCLUSIONS: An abnormal IAD in BP is associated with a larger prevalence of CV risk factors and CV disease. Our study confirms that simultaneous both arm BP measurement must always be accomplished in subjects at risk for or with established CV disease. PMID- 30460866 TI - Resveratrol mitigates the oxidative stress mediated by hypoxic-ischemic brain injury in neonatal rats via Nrf2/HO-1 pathway. AB - CONTEXT: Hypoxic-ischemic encephalopathy (HIE) has a high morbidity and mortality rate. Resveratrol possesses numerous biological properties including antioxidant, anti-inflammatory and neuroprotective activities. OBJECTIVE: The current experiment investigates the neuroprotective efficacy of resveratrol (RESV) against HIE by modulating Nrf2/HO-1 pathway in neonatal rats. MATERIALS AND METHODS: Seven-day-old pups (n = 48) were divided into four groups. Group-I rats receiving 2% DMSO saline (sham), group-II rats underwent unilateral carotid artery ligation and hypoxia (92% N2 and 8% O2) for 2.5 h (hypoxia-ischemia; HI), group-III and IV rats received 20 (RESV 20 + HI) or 40 mg/kg (RESV 40 + HI; group IV) of RESV via intraperitoneal injection (ip), respectively, for 7 days prior to HI induction. RESULTS: Pre-treatment with RESV (20 or 40) markedly reduced (p < 0.01) the cerebral oedema (86.23-71.26 or 65.24%), infarct area (33.85-19.81 or 14.30%), lipid peroxidation products, inflammatory markers [IL-1beta 186-110 or 82; IL-6 255-146 or 103; TNF-alpha 310-204 or 137; NF-kappaB 205-115 or 91) p65 subunit] and significantly restored (p < 0.01) the antioxidative status by enhancing the activities of glutathione peroxidase (GPx) 5.22-6.49 or 7.78; catalase (CAT) 51-55 or 59, superoxide dismutase (SOD) 2.5-3.05 or 3.25; through marked upregulation (p < 0.01) of heme oxygenase 1 (HO-1) 0.65-0.69 or 0.73; and nuclear factor erythroid 2 related factor 2 (Nrf2) 0.73-0.86 or 0.91. DISCUSSION AND CONCLUSIONS: RESV displays its neurotherapeutic potential via upregulating the protein expression of Nrf2 and HO-1 signalling pathway and thereby attenuates oxidative stress and inflammatory response in HI-induced neonatal rats. PMID- 30460867 TI - One 'knows': self-rated health and telomere length among ex-prisoners of war. AB - OBJECTIVE: Ill-health and early mortality are amongst the most significant ramifications of trauma. Furthermore, trauma alters the subjective perception and experience of the body. The aim of this study is to examine the extent to which deteriorations in perceived health among traumatised individuals are associated with cellular health as manifested in telomere length. METHODS: Specifically, 88 former prisoners of war (ex-POWs) evaluated their health (self-rated health; SRH) at 18 (T1), 35 (T2) and 42 (T3) years after the war, and were assessed for telomere length at T3. Health behaviour, BMI, morbidity and PTSD were also examined at T3. RESULTS: The findings demonstrated that SRH was cross-sectionally correlated with telomere length. Furthermore, a significant sequential indirect effect was found, in which worse SRH in T1 was associated with shorter telomere length at T3, through worse SRH at T2 and at T3. CONCLUSIONS: These findings demonstrate that long-term deteriorations in the subjective evaluations of health are implicated in actual cellular health among individuals exposed to trauma. PMID- 30460868 TI - Limiting ventilator-associated complications in ICU intubated subjects: strategies to prevent ventilator-associated events and improve outcomes. AB - INTRODUCTION: Intubation is required to maintain the airways in comatose patients and enhance oxygenation in hypoxemic or ventilation in hypercapnic subjects. Recently, the Centers of Disease Control (CDC) created new surveillance definitions designed to identify complications associated with poor outcomes. Areas covered: The new framework proposed by CDC, Ventilator-Associated Events (VAE), has a range of definitions encompassing Ventilator-Associated Conditions (VAC), Infection-related Ventilator-Associated Complications (IVAC), or Possible Ventilator-Associated Pneumonia - suggesting replacing the traditional definitions of Ventilator-Associated Tracheobronchitis (VAT) and Ventilator Associated Pneumonia (VAP). They focused more on oxygenation variations than on Chest-X rays or inflammatory biomarkers. This article will review the spectrum of infectious (VAP & VAT) complications, as well as the main non-infectious complications, namely pulmonary edema, acute respiratory distress syndrome (ARDS) and atelectasis. Strategies to limit these complications and improve outcomes will be presented. Expert commentary: Improving outcomes should be the objective of implementing bundles of prevention, based on risk factors amenable of intervention. Promotion of measures that reduce the exposition or duration of intubation should be a priority. PMID- 30460869 TI - Optical coherence tomography angiography (OCTA) flow speed mapping technology for retinal diseases. AB - INTRODUCTION: Optical coherence tomography angiography (OCTA) is a noninvasive imaging modality for depth-resolved visualization of retinal vasculature. Angiographic data couples with structural data to generate a cube scan, from which en-face images of vasculature can be obtained at various axial positions. OCTA has expanded understanding of retinal vascular disorders and has primarily been used for qualitative analysis. Areas covered: Recent studies have explored the quantitative properties of OCTA, which would allow for objective assessment and follow-up of retinal pathologies. Various quantitative metrics have been developed, such as foveal avascular zone area and vessel density. However, quantitative assessment of the characteristics of retinal blood flow remains limited, as OCTA provides an image depicting either the presence or absence of flow at a particular region without information of relative velocities. The development of variable interscan time analysis (VISTA) overcomes this limitation. The VISTA algorithm generates a color-coded map of relative blood flow speeds. VISTA has already demonstrated utility in furthering our understanding of various retinal pathologies, such as geographic atrophy, choroidal neovascularization, aneurysmal type 1 neovascularization, and diabetic retinopathy. Expert commentary: VISTA, an OCTA flow speed mapping technique, may have a role in developing the utility of OCTA as a screening tool. PMID- 30460870 TI - Partners' adjustment to older workers' retirement: testing the role of preretirement expectations in a 10-year panel study. AB - OBJECTIVES: Retirement is not only an important later-life transition for the retiring individual, but also for his or her life partner. This study aims to improve our understanding of the partner's adjustment to the retirement of the older worker, by paying attention to the multidimensional nature of adjustment, and by examining to what extent preretirement expectations are predictive of postretirement experiences. Well-established adjustment predictors - i.e. preretirement resources and characteristics of the work and retirement context - are also taken into account. METHOD: Analyses are based on Dutch three-wave multi actor panel data, collected between 2001 and 2011 among 724 partners of older workers who transitioned into retirement during the course of the study. RESULTS: Only a minority of the partners reported adjustment difficulties to the retirement of the employee. About 20 percent reported at least some financial problems, 8 percent reported relationship problems, and 10 percent reported problems with shared leisure time. Expected problems in all three domains were predictive of experienced problems in the same domain. For expected financial problems, a cross-over effect was observed: expected financial problems were also predictive of experienced adjustment difficulties with regards to shared leisure activities. CONCLUSION: Not only the older worker, but also the partner develops expectations on different dimensions about the shared postretirement future, and these expectations are related to postretirement experiences. Retirement counseling may therefore not only be relevant for older workers, but also for their partners, and needs to take the multidimensional character of retirement processes into account. PMID- 30460871 TI - Liver safety parameters of ulipristal acetate for the treatment of uterine fibroids: a comprehensive review of the clinical development program. AB - INTRODUCTION: Uterine fibroids are benign tumors within the uterine wall affecting women. Ulipristal acetate 5 mg was first authorized in the European Union on 23 February 2012, with a post-marketing exposure estimated to be more than 765,000 patients so far. During the post-marketing experience, sporadic cases of liver injury and hepatic failure were reported. A detailed review of the clinical trials carried out in the development of ulipristal acetate 5 mg was undertaken to further assess the liver safety data reported during the clinical trials. Areas covered: A detailed review of clinical data from Phase I to Phase III of patients exposed to ulipristal acetate at any investigated dose levels and for any treatment duration was conducted and the liver function test values are presented. In addition, a literature review on drug-induced liver injury is provided Expert opinion: The experts present an evaluation of the liver safety findings observed during the clinical development and their views on the role of these findings in predicting the occurrence of drug-induced liver injury, the benefits of the treatment, the safety and the implications to the current clinical practice. PMID- 30460872 TI - Consumer Engagement with Prescription Medicine Decisions: Influences of Health Beliefs and Health Communication Sources. AB - Consumers' prescription drug decisions are affected by a number of structural, psychological, and health communication source variables. To provide a theoretically sound and comprehensive prescription medication decision engagement framework, this study integrated Andersen's Health Service Use Model to address contextual and structural factors, the Health Belief Model (HBM) to examine psychological factors, and extant research on the influence of various health communication sources to explain the prescription drug decision engagement mechanisms of health information-seeking intention, prescription drug-seeking intent, and prescription-seeking behavior. Employing survey methodology, the framework was tested using a sample of U.S. adult consumers (N = 370). Results demonstrated the utility of the integrated model for explaining consumers' participation in their prescription decisions. Specifically, consumers' assessment of target health behaviors and the use of various health communication sources significantly improved the explanatory power of the decision engagement model beyond structural factors. The results impart valuable theoretical contributions and have the potential to guide public health interventions related to consumers' prescription drug decisions. PMID- 30460873 TI - Keratinocytes derived from embryonic stem cells induce wound healing in mice. AB - The skin plays an important role in defending the body against the environment. Treatments for burns and skin injuries that use autologous or allogenic skin grafts derived from adult or embryonic stem cells are promising. Embryonic stem cells are candidates for regenerative and reparative medicine. We investigated the utility of keratinocyte-like cells, which are differentiated from mouse embryonic stem cells, for wound healing using a mouse surgical wound model. Mice were allocated to the following groups: experimental, in which dressing and differentiated cells were applied after the surgical wound was created; control, in which only the surgical wound was created; sham, in which only the dressing was applied after the surgical wound was created; and untreated animal controls with healthy skin. Biopsies were taken from each group on days 3, 5 and 7 after cell transfer. Samples were fixed in formalin, then stained with Masson's trichrome and primary antibodies to interleukin-8 (IL-8), fibroblast growth factor-2 (FGF-2), monocyte chemoattractant protein-1 (MCP-1), collagen-1 and epidermal growth factor (EGF) using the indirect immunoperoxidase technique for light microscopy. Wound healing was faster in the experimental group compared to the sham and control groups. The experimental group exhibited increased expression of IL-8, FGF-2 and MCP-1 during early stages of wound healing (inflammation) and collagen-1 and EGF expression during late stages of wound healing (proliferation and remodeling). Keratinocytes derived from embryonic stem cells improved wound healing and influenced the wound healing stages. PMID- 30460874 TI - Is it safe to stop oral anticoagulation after catheter ablation for atrial fibrillation? AB - INTRODUCTION: Atrial fibrillation is the most common arrhythmia worldwide. Its increasing prevalence has made the use of oral anticoagulants for stroke prevention routine, however the use of them after the blanking period of catheter ablation remains uncertain. Areas covered: This review outlines the pros and cons of stopping oral anticoagulation after catheter ablation. Major databases such as Pubmed or Embase were used. The most relevant articles published were used along with major recommendations of society guidelines. Authors will also discuss different proposed mechanisms of atrial fibrillation and more importantly future directions in this topic. Expert commentary: The use of oral anticoagulants after catheter ablation for atrial fibrillation is debatable, however based on current guidelines we support the use of oral anticoagulants after the blanking period of catheter ablation. Noteworthy, is that although the risk of bleeding can be fatal in some cases, it does not outweigh the risk of a disabling stroke. PMID- 30460875 TI - N-methylcarbamate pesticides and their phenolic degradation products: hydrolytic decay, sequestration and metal complexation studies. AB - We report on the rates of decomposition of a group of N-methylcarbamate (NMC) pesticides (carbaryl, carbofuran and propoxur) under pre-determined tropical field conditions. Rates of decomposition for three NMCs were determined at pH 7.08 and T = 20 degrees C and pH 7.70 and T = 33 degrees C respectively, as follows: carbaryl (78 days and 69 days); carbofuran (143 days and 83 days) and propoxur (116 days and 79 days). Investigation on methods for removal of NMCs and their phenolic decomposition products shows that activated charcoal outperforms zeolite, alumina, diatomaceous earth, cellulose and montmorillonite clay in the removal of both NMCs and phenols from aqueous solution. Furthermore, metal complexation studies on the NMCs and phenols showed that Fe (III) forms a complex with isopropoxyphenol (IPP) within which the Fe:IPP ratio is 1:3, indicative of the formation of a metal chelate complex with the formula Fe(IPP)3. PMID- 30460876 TI - Cardiovascular risk factors and incident giant cell arteritis: a population-based cohort study. AB - OBJECTIVE: To assess the strength of the effect of cardiovascular risk factors on the incidence of giant cell arteritis (GCA) in a general population context. METHOD: Data from the Reykjavik Study (RS), a population-based cohort study focusing on cardiovascular disease, were used. Everyone born in 1907-1935 living in Reykjavik, Iceland, or adjacent communities on 1 December 1967 were invited to participate. Subjects attended a study visit in 1967-1996 and information on cardiovascular risk factors [smoking habits, blood pressure, diabetes, body mass index (BMI), and serum cholesterol] was obtained. All temporal artery biopsies obtained from members of the RS cohort were re-examined by a single pathologist with expertise in vascular pathology. Effects of risk factors on GCA occurrence are expressed as incidence rate ratios (IRRs) with 95% confidence intervals (CIs). RESULTS: Altogether, 19 241 subjects contributed a median of 23.1 (interquartile range 17.6-29.4) years after the age of 50 to this analysis. During 444 126 person-years of follow-up, 194 subjects developed GCA, corresponding to an incidence rate of 43.6 (95% CI 37.8-50.2) per 100 000 person years. Being overweight or obese were inversely associated with GCA, especially in women [IRRs 0.70 (0.48-1.02) and 0.31 (0.14-0.71), respectively]. There was a weaker association between BMI and incident GCA in men. Smoking was inversely associated with GCA in men [IRR 0.47 (0.27-0.81)], but not in women. CONCLUSIONS: The incidence of GCA in Iceland is very high. High BMI protects against the occurrence of GCA, and smoking may protect against GCA in men. PMID- 30460877 TI - Impediment of selenite-induced cataract in rats by combinatorial drug laden liposomal preparation. AB - Cataract is the leading cause of blindness globally with surgery being the only form of treatment. But cataract surgery is accompanied by complications, chiefly intra-ocular infections. Hence, preventive nanoformulations may be extremely beneficial. In the present study, novel chitosan-coated liposomal formulations encapsulating a combination of drugs, lanosterol and hesperetin were prepared and characterized. The combinatorial liposomes were prepared by thin film evaporation active extrusion method. The characterization of liposomes was done by transmission electron microscopy, zeta potential, encapsulation efficiency, stability, cytotoxicity and in vitro release studies. The main difference between the chitosan-coated and uncoated combinatorial liposomes is the release of drugs as indicated by the in vitro release studies. The slow and sustained release of the drugs from chitosan-coated ones as against the burst release from uncoated indicates an increased retention time for combinatorial drugs in cornea. This leads to a delay in progression of cataract as seen from in vivo studies. Cytotoxicity studies indicate no cell toxicity of the coating of chitosan or the combination of drugs. Stability studies indicate that there were almost no changes in size, zeta potential and polydispersity index values of the combinatorial liposomes upon storage at room temperature for 60 days. Another important study is the estimation of antioxidant defense system. The estimated values of glutathione reductase, malondialdehyde and chief antioxidant enzymes point toward an upregulation of antioxidant defense system. From the results, it may be concluded that novel chitosan-coated combinatorial liposomes are effective in delaying or preventing of cataract. PMID- 30460878 TI - Dissipation, residues, and risk assessment of imidacloprid in Zizania latifolia and purple sweet potato under field conditions using LC-MS/MS. AB - A shortened version of Quick, Easy, Cheap, Effective, Rugged, and Safe method (QuEChERS) for determining the dissipation and residue of imidacloprid present in Zizania latifolia and purple sweet potato was established by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The average recoveries of imidacloprid in the two crops ranged from 82.12 to 113.79%, with relative standard deviation (RSD) of <7.32%. The dissipation dynamics of imidacloprid in Z. latifolia plants and purple sweet potato plants followed first-order kinetics, with half-lives of 3.2-5.5 days in each of sampling locations. The terminal imidacloprid residues in Z. latifolia and purple sweet potato at each of location were <0.005-0.120 mg kg-1. According to the risk assessment results, both the acute dietary risk quotient and chronic dietary risk quotient values were <1, indicating that imidacloprid is unlikely to pose health risks to humans with normal recommended use. The present study may serve as a valuable reference for the safe and reasonable use of imidacloprid in Z. latifolia and purple sweet potato fields. PMID- 30460879 TI - The effect of a reduced first step width on starting block and first stance power and impulses during an athletic sprint start. AB - This study investigated how manipulating first step width affects 3D external force production, centre of mass (CoM) motion and performance in athletic sprinting. Eight male and 2 female competitive sprinters (100m PB: 11.03 +/- 0.36 s male and 11.6 +/- 0.45 s female) performed 10 maximal effort block starts. External force and three-dimensional kinematics were recorded in both the block and first stance phases. Five trials were performed with the athletes performing their preferred technique (Skating) and five trials with the athletes running inside a 0.3 m lane (Narrow). By reducing step width from a mean of 0.31 +/- 0.06 m (Skating) to 0.19 +/- 0.03 m (Narrow), reductions were found between the two styles in medial block and medial 1st stance impulses, 1st stance anterior toe off velocity and mediolateral motion of the CoM. No differences were found in block time, step length, stance time, average net resultant force vector, net anteroposterior impulse nor normalised external power. Step width correlated positively with medial impulse but not with braking nor net anteroposterior impulse. Despite less medially directed forces and less mediolateral motion of the CoM in the Narrow trials, no immediate improvement to performance was found by restricting step width. PMID- 30460880 TI - Intravenous magnesium sulphate infusion as first-line therapy in the control of spasms and muscular rigidity in childhood tetanus. AB - BACKGROUND: Reports suggest that, in tetanus, magnesium sulphate (MgSO4) alone may control muscle spasms, thereby avoiding sedation and mechanical ventilation. AIM: To study the efficacy and safety of intravenous MgSO4 in controlling spasms and rigidity in children with tetanus. METHODS: All children with tetanus consecutively admitted over a 2-year period in a tertiary-care teaching hospital were recruited. In addition to human tetanus immunoglobulin and parenteral metronidazole, patients received MgSO4 100 mg/kg intravenously followed by infusion at 40 mg/kg/hr. The infusion rate was increased by 5 mg/kg/hr every 6 h until cessation of spasms or abolition of the patellar tendon reflex. Efficacy was determined by control of spasms. Time to commencement of feeds, frequency of autonomic instability, the need for ventilatory support, duration of hospitalisation and mortality were also recorded. RESULTS: Twenty-seven children with tetanus aged between 18 months and 10 years were recruited. A contaminated wound was the most common portal of entry of tetanus spores. The incidences of severity were: grade I, 3; grade II, 7; grades IIIa and b, 17. Rigidity and spasms were controlled by magnesium therapy alone in 14 patients. Additional sedation was required for 13 patients (grade II, 1; grade III, 12). Feeding could be commenced early in five patients. Mechanical ventilation was required in eight patients. The mean (SD) duration of hospitalisation was 26.5 (12.0) days. Five patients died (18.5%). Asymptomatic hypocalcaemia was a universal finding and was treated with calcium supplements. CONCLUSION: MgSO4 alone is effective in mild-to moderate tetanus but not when it is severe. PMID- 30460881 TI - Many model thinking in systems ergonomics: a case study in road safety. AB - In complexity science, the many models thinking philosophy argues for a multi method approach to complex problems. This article investigates whether the use of multiple systems ergonomics methods to examine the same problem is useful, or whether using different approaches creates incompatible analyses. Five systems ergonomics analyses of road trauma are examined and their key insights extracted. The extent to which these insights are compatible with one another and can be integrated when attempting to reduce road trauma is assessed. The findings indicate that applying several systems ergonomics methods to the same problem is useful, as multiple insights are developed and deficiencies in one approach are countered by the others. Importantly, the analysis demonstrates that the insights gained are compatible and support the development of holistic systems thinking based interventions. In conclusion it is recommended that a many systems ergonomics model thinking approach be adopted by ergonomists working in complex problem spaces. PMID- 30460882 TI - Heritability of phenotypic udder traits to improve resilience to mastitis in Texel ewes. AB - There are no estimates of the heritability of phenotypic udder traits in suckler sheep, which produce meat lambs, and whether these are associated with resilience to mastitis. Mastitis is a common disease which damages the mammary gland and reduces productivity. The aims of this study were to investigate the feasibility of collecting udder phenotypes, their heritability and their association with mastitis in suckler ewes. Udder and teat conformation, teat lesions, intramammary masses (IMM) and litter size were recorded from 10 Texel flocks in Great Britain between 2012 and 2014; 968 records were collected. Pedigree data were obtained from an online pedigree recording system. Univariate quantitative genetic parameters were estimated using animal and sire models. Linear mixed models were used to analyse continuous traits and generalised linear mixed models were used to analyse binary traits. Continuous traits had higher heritabilities than binary with teat placement and teat length heritability (h 2) highest at 0.35 (SD 0.04) and 0.42 (SD 0.04), respectively. Udder width, drop and separation heritabilities were lower and varied with udder volume. The heritabilities of IMM and teat lesions (sire model) were 0.18 (SD 0.12) and 0.17 (SD 0.11), respectively. All heritabilities were sufficiently high to be in a selection programme to increase resilience to mastitis in the population of Texel sheep. Further studies are required to investigate genetic relationships between traits and to determine whether udder traits predict IMM, and the potential benefits from including traits in a selection programme to increase resilience to chronic mastitis. PMID- 30460883 TI - Low-risk and high-risk groups matter in suicide risk. PMID- 30460884 TI - Systematic review and exploratory meta-analysis of the efficacy, safety, and biological effects of psychostimulants and atomoxetine in patients with schizophrenia or schizoaffective disorder. AB - OBJECTIVE: Our aim was to summarize the efficacy and safety of atomoxetine, amphetamines, and methylphenidate in schizophrenia. METHODS: We undertook a systematic review, searching PubMed/Scopus/Clinicaltrials.gov for double-blind, randomized, placebo-controlled studies of psychostimulants or atomoxetine in schizophrenia published up to 1 January 2017. A meta-analysis of outcomes reported in two or more studies is presented. RESULTS: We included 22 studies investigating therapeutic effects of stimulants (k=14) or measuring symptomatic worsening/relapse prediction after stimulant challenge (k=6). Six studies of these two groups plus one additional study investigated biological effects of psychostimulants or atomoxetine. No effect resulted from interventional studies on weight loss (k=1), smoking cessation (k=1), and positive symptoms (k=12), and no improvement was reported with atomoxetine (k=3) for negative symptoms, with equivocal findings for negative (k=6) and mood symptoms (k=2) with amphetamines. Attention, processing speed, working memory, problem solving, and executive functions, among others, showed from no to some improvement with atomoxetine (k=3) or amphetamines (k=6). Meta-analysis did not confirm any effect of stimulants in any symptom domain, including negative symptoms, apart from atomoxetine improving problem solving (k=2, standardized mean difference (SMD)=0.73, 95% CI=0.10-1.36, p=0.02, I2=0%), and trending toward significant improvement in executive functions with amphetamines (k=2, SMD=0.80, 95% CI=-1.68 to +0.08, p=0.08, I2=66%). In challenge studies, amphetamines (k=1) did not worsen symptoms, and methylphenidate (k=5) consistently worsened or predicted relapse. Biological effects of atomoxetine (k=1) and amphetamines (k=1) were cortical activation, without change in beta-endorphin (k=1), improved response to antipsychotics after amphetamine challenge (k=2), and an increase of growth hormone-mediated psychosis with methylphenidate (k=2). No major side effects were reported (k=6). CONCLUSIONS: No efficacy for stimulants or atomoxetine on negative symptoms is proven. Atomoxetine or amphetamines may improve cognitive symptoms, while methylphenidate should be avoided in patients with schizophrenia. Insufficient evidence is available to draw firm conclusions. PMID- 30460885 TI - Outcomes and emergency medical services resource utilization among patients with syncope arriving to the emergency department by ambulance. AB - CLINICIAN'S CAPSULEWhat is known about the topic?A majority of syncope patients are transported to the emergency department by emergency medical services (EMS), yet only a small proportion are admitted or suffer serious adverse events (SAE).What did this study ask?What proportion of EMS syncope patient transports are at low risk (i.e., absence of EMS interventions, hospitalization, and SAE)?What did this study find?This prospective cohort study found that 40% of syncope transports are at low risk.Why does this study matter to clinicians?This group of patients represents potentially avoidable transports once a clinical decision tool is developed with a substantial opportunity cost for EMS systems. PMID- 30460886 TI - Influence of follicle-stimulating hormone concentrations on the integrity and development of bovine follicles cultured in vitro. AB - SummaryThis study investigated the in vitro culture of bovine follicles included in ovarian tissue for 2 or 6 days (D2 or D6), with the addition of different concentrations of follicle-stimulating hormone (FSH) (0, 10, 50, 100 or 200 ng/ml). Data were compared for follicular development, morphological integrity and diameter of follicles and oocytes. Ovaries (n = 10) from Nelore cows (n = 5) were divided into fragments (n = 11 per ovary) and were immediately fixed in Bouin's solution (D0) or were individually cultured for 2 or 6 days in one of the described concentrations of FSH and then processed for histology. Compared with the rates of follicular development at D2 for minimal essential medium (MEM) (75.0%) and 50 ng/ml of FSH (71.1%), the best rates of follicular development at D2 were obtained with 10 (84.7%), 100 (87.5%) and 200 ng/ml of FSH (85.0%; P<0.05). After 6 days of cultivation, there were no differences among treatments regarding follicular growth. The morphological integrity of preantral follicles was better maintained by 100 ng/ml FSH for 2 and 6 days of cultivation (51.2 and 40.4%, respectively; P<0.05) than that for MEM (D2: 30.9%, D6: 20.8%), 10 (D2: 39.2%, D6: 22.8%), 50 (D2: 30.4%, D6: 28.8%) and 200 ng/ml FSH (D2: 45.2%, D6: 36.8%). FSH at 100 ng/ml provided the highest mean diameter averages: 34.5+/-10.8 um at D2 and 33.2+/-12.5 um at D6 (P<0.05). We concluded that the medium supplemented with 100 ng/ml FSH during in vitro culture provided appropriate conditions for the development and morphological integrity of preantral follicles in cattle. PMID- 30460887 TI - Infection prevention in long-term care: re-evaluating the system using a human factors engineering approach. AB - The emergence and spread of extensively multidrug-resistant organisms is a public health crisis, and long-term care settings have been identified as a reservoir for the cultivation of these organisms. Long-term care settings are now taking on increasingly ill residents with complicated medical problems, indwelling devices, and significant healthcare exposure, all of which are considered risk factors selecting for resistant organisms. Despite this, guidelines addressing infection prevention procedures in long-term care remain vague, and implementation of these guidelines is challenging, largely due to staff turnover, limited resources, knowledge gaps, and lack of organizational support. Human factors engineering approaches have emerged as an important innovation to address patient safety issues and develop interventions in the healthcare work system (ie, tools and technologies, tasks, organization, physical environment) that support human performance, which, in turn, lead to improvements in processes (eg, compliance with infection prevention guidelines) and outcomes (eg, reduced infection rates). We propose the concept of using the methods and approaches from the scientific field of human factors engineering to address the unique challenges of implementing infection prevention in the long-term care setting. PMID- 30460888 TI - Risk of non-affective psychotic disorder or bipolar disorder in autism spectrum disorder: a longitudinal register-based study in the Netherlands. AB - BACKGROUND: Individuals with autism spectrum disorder (ASD) appear to be at increased risk of non-affective psychotic disorder (NAPD) and bipolar disorder (BD). However, most previous studies examined the co-occurrence of ASD and NAPD or BD, ignoring possible diagnostic bias and selection bias. We used longitudinal data from Dutch psychiatric case registers to assess the risk of NAPD or BD among individuals with ASD, and compared the results to those obtained for the Dutch population in earlier studies. METHODS: Individuals with ASD (n = 17 234) were followed up between 16 and 35 years of age. Kaplan-Meier estimates were used to calculate the risk of NAPD or BD. We conducted separate analyses to reduce possible bias, including an analysis among individuals diagnosed with ASD before age 16 years (n = 8337). RESULTS: Of the individuals with ASD, 23.50% (95% confidence interval 21.87-25.22) were diagnosed with NAPD and 3.79% (3.06-4.69) with BD before age 35 years. The corresponding figures for the general population were 0.91% (0.63-1.28) and 0.13% (0.08-0.20). Risk estimates were substantially lower, but still higher than general population estimates, when we restricted our analyses to individuals diagnosed with ASD before age 16, with 1.87% (1.33-2.61) being diagnosed with NAPD and 0.57% (0.21-1.53) with BD before age 25 years. The corresponding figures for the general population were 0.63% (0.44-0.86) and 0.08% (0.05-0.12). CONCLUSIONS: Individuals with ASD are at increased risk of NAPD or BD. This is likely not the result of diagnostic or selection bias. PMID- 30460889 TI - Effects of transportation on cattle health and production: a review. AB - The goal of this review is to present a concise and critical assessment of the literature related to physiologic responses in cattle that are subjected to transportation. Over two-thirds of US cattle are transported. Understanding trends in circulating physiologic parameters is an important part of mitigating the negative effects of transportation. For the producer, linking these effects after transportation to morbidity outcomes within the first 45 days on feed (i.e. especially development of bovine respiratory disease) is critical. Physiologic parameters in circulation are of primary importance and may have value for prediction of bovine respiratory disease on arrival and for the understanding of disease pathogenesis. The results of our literature survey indicated that post transportation immune function, increased acute phase proteins, glucocorticoids, and inflammation are a pivotal starting point for understanding disease. These potential biomarkers may have utility in identifying disease for targeted therapeutics so that traditional protocols that rely heavily on metaphylaxis can be avoided. Additional research is needed to develop strategies for physiological marker identification, treatment methods, or predictive behaviors to prevent respiratory disease before and after transport. This review examines the significant deleterious effects of transportation handling and stress, and current immune system translation and non-antimicrobial mitigation strategies. PMID- 30460890 TI - Equivalence testing: reversed hypotheses, margins, and the need for controlling researcher allegiance. PMID- 30460891 TI - Frontostriatal functional connectivity and striatal dopamine synthesis capacity in schizophrenia in terms of antipsychotic responsiveness: an [18F]DOPA PET and fMRI study. AB - BACKGROUND: Given that only a subgroup of patients with schizophrenia responds to first-line antipsychotic drugs, a key clinical question is what underlies treatment response. Observations that prefrontal activity correlates with striatal dopaminergic function, have led to the hypothesis that disrupted frontostriatal functional connectivity (FC) could be associated with altered dopaminergic function. Thus, the aim of this study was to investigate the relationship between frontostriatal FC and striatal dopamine synthesis capacity in patients with schizophrenia who had responded to first-line antipsychotic drug compared with those who had failed but responded to clozapine. METHODS: Twenty four symptomatically stable patients with schizophrenia were recruited from Seoul National University Hospital, 12 of which responded to first-line antipsychotic drugs (first-line AP group) and 12 under clozapine (clozapine group), along with 12 matched healthy controls. All participants underwent resting-state functional magnetic resonance imaging and [18F]DOPA PET scans. RESULTS: No significant difference was found in the total PANSS score between the patient groups. Voxel based analysis showed a significant correlation between frontal FC to the associative striatum and the influx rate constant of [18F]DOPA in the corresponding region in the first-line AP group. Region-of-interest analysis confirmed the result (control group: R2 = 0.019, p = 0.665; first-line AP group: R2 = 0.675, p < 0.001; clozapine group: R2 = 0.324, p = 0.054) and the correlation coefficients were significantly different between the groups. CONCLUSIONS: The relationship between striatal dopamine synthesis capacity and frontostriatal FC is different between responders to first-line treatment and clozapine treatment in schizophrenia, indicating that a different pathophysiology could underlie schizophrenia in patients who respond to first-line treatments relative to those who do not. PMID- 30460892 TI - Atom Probe Reconstruction With a Locally Varying Emitter Shape. AB - An improved reconstruction method for atom probe tomography is presented. In this approach, the curvature of the field emitter is variable, in contrast to the conventional reconstruction technique. The information about the tip shape at different stages of the reconstruction is directly extracted from the local density of events on the detector. To this end, the detector and the tip surface are split into different segments. According to the density distribution of events observed on the detector, the size of the corresponding segment on the tip surface is calculated, yielding an emitter profile which is not necessarily spherical. The new approach is demonstrated for emitter structures with radial symmetry that contain a spherical precipitate with a substantially lower or higher evaporation field compared to the surrounding matrix. A comparison to the conventional point projection approach is made. PMID- 30460893 TI - Lung Involvement in Chronic Schistosomiasis with Bladder Squamous Cell Carcinoma. AB - We report a case of chronic Schistosoma haematobium infection with pseudometastatic pulmonary nodules and high-grade squamous cell carcinoma in a 30 year-old man in Mali. Lung biopsies revealed chronic pulmonary involvement of S. haematobium and ruled out lung metastases. PMID- 30460894 TI - Rotavirus VP3 targets MAVS for degradation to inhibit type III interferon expression in intestinal epithelial cells. AB - Rotaviruses (RVs), a leading cause of severe diarrhea in young children1 and many mammalian species, have evolved multiple strategies to counteract the host innate immunity, specifically interferon (IFN) signaling through RV non-structural protein 1 (NSP1)2. However, whether RV structural components also subvert antiviral response remains under-studied. Here, we found that MAVS, critical for the host RNA sensing pathway upstream of IFN induction3, is degraded by the RV RNA methyl- and guanylyl-transferase (VP3) in a host-range-restricted manner. Mechanistically, VP3 localizes to the mitochondria and mediates the phosphorylation of a previously unidentified SPLTSS motif within the MAVS proline rich region, leading to its proteasomal degradation and blockade of IFN-lambda production in RV-infected intestinal epithelial cells. Importantly, VP3 inhibition of MAVS activity contributes to enhanced RV replication and to viral pathogenesis in vivo. Collectively, our findings establish RV VP3 as a viral antagonist of MAVS function in mammals and uncover a novel pathogen-mediated inhibitory mechanism of MAVS signaling. PMID- 30460895 TI - The CryoEM structure of the Saccharomyces cerevisiae ribosome maturation factor Rea1. AB - The biogenesis of 60S ribosomal subunits is initiated in the nucleus where rRNAs and proteins form pre-60S particles. These pre-60S particles mature by transiently interacting with various assembly factors. The ~5000 amino-acid AAA+ ATPase Rea1 (or Midasin) generates force to mechanically remove assembly factors from pre-60S particles, which promotes their export to the cytosol. Here we present three Rea1 cryoEM structures. We visualise the Rea1 engine, a hexameric ring of AAA+ domains, and identify an alpha-helical bundle of AAA2 as a major ATPase activity regulator. The alpha-helical bundle interferes with nucleotide induced conformational changes that create a docking site for the substrate binding MIDAS domain on the AAA +ring. Furthermore, we reveal the architecture of the Rea1 linker, which is involved in force generation and extends from the AAA+ ring. The data presented here provide insights into the mechanism of one of the most complex ribosome maturation factors. PMID- 30460896 TI - Adverse factors responsible for below-normal platelet count after laparoscopic splenectomy and azygoportal disconnection. AB - BACKGROUND/AIMS: Splenectomy is regarded as an effective curative treatment for thrombocytopenia caused by hypersplenism in patients with cirrhosis. However, in clinical practice, thrombocytopenia is not resolved by splenectomy in all patients. This study aimed to evaluate the adverse factors responsible for platelet (PLT) counts below the normal lower limit following laparoscopic splenectomy and azygoportal disconnection (LSD). MATERIALS AND METHODS: We retrospectively evaluated the outcomes of 123 cirrhotic patients with portal hypertensive bleeding and secondary hypersplenism, who underwent LSD and who had PLT counts <125*109/L (non-normal group) or >=125*109/L (normal group) at the postoperative month (POM) 3, between April 2014 and March 2017. RESULTS: Sixteen patients (13.01%) had PLT counts <125*109/L at POM 3 after LSD, while the remaining 107 patients had normal counts. We analyzed 25 perioperative variables in both groups. A logistic multivariate regression identified age (relative risk [RR] 1.082, 95% confidence interval [CI] 1.018-1.150) and longitudinal spleen diameter (RR 0.977, 95% CI 0.955-1.000) as significant independent factors for the PLT count <125*109/L at POM 3. Bivariate correlation analysis showed that age >50 years and longitudinal spleen diameter <=160 mm were threshold values for an increased risk of the PLT count <125*109/L at POM 3 after LSD. CONCLUSION: Age was an independent positive predictor and longitudinal spleen diameter an independent negative predictor of PLT count <125*109/L at POM 3 after LSD. PMID- 30460897 TI - Colorectal cancer and dysplasia risk of ulcerative colitis patients in a tertiary referral center in Turkey. AB - BACKGROUND/AIMS: Patients with ulcerative colitis (UC) are at increased risk of colorectal cancer (CRC). High-grade dysplasia (HGD) and low-grade dysplasia (LGD) are premalignant conditions. The aim of this study is to evaluate the risk of CRC/dysplasia in patients with UC, and the related risk factors. MATERIALS AND METHODS: Medical records of 1659 patients dating between 1993 and 2016 were scanned from an inflammatory bowel disease database. A total of 801 patients with UC who underwent at least one colonoscopic procedure with at least 1-year follow up period were included in the study. Clinical, endoscopic, and histopathological data were assessed. RESULTS: The mean disease duration was 6.7+/-6.6 years. The total disease duration was 5334 person-years duration (pyd), and 34% of patients had the disease for 8 years or longer. The prevalence of UC-associated CRC was 0.7%, and the prevalence of dysplasia was 0.85%. The overall incidence of CRC was determined to be 1.1/1000 pyd. The cumulative risk of CRC was 0.3% at 10 years, 1.3% at 20 years, and 5.9% at 30 years. The Cox regression analysis indicated that primary sclerosing cholangitis (HR:13.677, 95% CI:2.6-70.8, p = 0.012) was an independent risk factor for developing UC-associated CRC. CONCLUSION: This study underlined the low risk of CRC and dysplasia in patients with UC in a tertiary referral center in the western part of Turkey. Primary sclerosing cholangitis was found to be the most important risk factor for the development of CRC in patients with UC. Identification of risk factors is important to categorize patients into subgroups to know which patients will require frequent surveillance. PMID- 30460898 TI - Neostigmine treatment protocols applied in acute colonic pseudo-obstruction disease: A retrospective comparative study. AB - BACKGROUND/AIMS: When conservative methods fail, neostigmine is recommended in the pharmacological treatment of acute colonic pseudo-obstruction (ACPO). The objective of this study was to analyze the response of patients to different neostigmine protocols. MATERIALS AND METHODS: Patients diagnosed with ACPO in the intensive care unit between January 2015 and September 2017 were retrospectively studied. Either of the two neostigmine protocols, the bolus dose (BD) or continuous infusion (CI), was applied to the ACPO patients who were unresponsive to conservative treatments, and the results were analyzed. RESULTS: In 79 of 122 (64%) patients, the resolution of symptoms was observed with conservative treatments. Of 43 patients who did not respond to conservative treatments, 20 were applied neostigmine as BD, and 23 were applied by CI. A total of 55% of patients in the BD group and 60.9% patients in the CI group responded to neostigmine therapy after the first dose. The group-specific protocols were reapplied in patients unresponsive to the first dose. A total of 25% in the BD group and 8.7% in the CI group responded to the second dose treatment. As a result, 80% of patients from the BD group and 69.6% from the CI group responded to neostigmine therapy. Although an overall response rate was higher in the BD group, there was no significant difference between groups (P=0.322). Colonic complications were observed in 2 patients, 1 from each group. There were no major side effects requiring treatment cessation. CONCLUSION: The safety and effectiveness of both neostigmine protocols applied to ACPO patients were similar. Clinical and radiological responses were obtained without serious side effects with CI. PMID- 30460899 TI - Simultaneous osteosarcoma and adenocarcinoma of the gallbladder: A rare case report and literature review. PMID- 30460900 TI - Successful treatment of chronic hepatitis C virus infection with 22-day ledipasvir plus sofosbuvir therapy in a patient with renal transplantation. PMID- 30460901 TI - Metastatic small bowel occlusion as initial presentation of squamous cell carcinoma of the lung. PMID- 30460903 TI - Gastrointestinal stromal tumors (gist) of the anus: A single institution experience. PMID- 30460902 TI - A rare case of incidental mucinous adenocarcinoma with osseous metaplasia associated with cysts of the presacral space. PMID- 30460904 TI - Endovascular treatment of the superior mesenteric arteriovenous fistula complicated by gastrointestinal bleeding. PMID- 30460905 TI - Endoscopic resection using argon plasma coagulation for treating esophageal mucosal bridge in a patient with acquired immunodeficiency syndrome. PMID- 30460906 TI - A rare case of Wild-Type GIST of descending colon with GANT characteristics. PMID- 30460907 TI - Intramural duodenal hematoma related to antivitamin K overdose, an unusual cause of acute pancreatitis: Three case presentations. PMID- 30460908 TI - Is Ozone (O3) Treatment Effective in Atrophic Rhinitis? Experimental Animal Study. AB - INTRODUCTION: Atrophic rhinitis (AR) is a disease characterized by atrophy of the mucosa, submucosa, bone tissue due to an unknown cause and excessive nasal cavity enlargement. The disease still has no complete treatment, and the treatment of the functional loss of atrophic cells in AR is still a matter to be investigated. Ozone (O3) therapy has been shown to enhance cell metabolism, angiogenesis, fibroblast activity, and collagen synthesis. AIM: To determine whether ozone treatment affects the disease histopathologically, in experimentally created AR. Material - Method: Twelve Wistar Hanover strain albino male rats were included in the study. Atrophic rhinitis was induced in animals by administering Pasteurella multocida toxin diluted with saline for 21 days to both nasal cavities. A total of 12 animals included in the study were divided into 2 groups as control and study. Ozone gas (60 MUg/mL) was administered rectally to the study group for 21 days. After 2 weeks, the rats were decapitated, the nasal cavities were removed as a block, and atrophic rhinitis parameters (epithelial hyperplasia, goblet cell loss, cilia loss, inflammatory infiltration, and vascular ectasia) were evaluated under light microscopy by histopathological examination and statistically interpreted. RESULT: The incidence of vascular ectasia was significantly lower in the ozone group compared to the control group (p<0.05). There was no significant difference between the groups regarding other histopathologic findings. CONCLUSION: Ozone treatment was moderate at the histopathological level. We concluded that ozone therapy has no or very limited effect on atrophic rhinitis. PMID- 30460909 TI - Bacterial lysates in the prevention of respiratory tract infections. AB - Bacterial lysates stimulate the general immunity of the body in a non-specific way. They act on non-specific defense mechanisms, leading to an increase in type A antibody in mucous membranes, phagocytic activity and INF-y production. They can also stimulate the production of specific antibodies against the bacterial antigens that make up the preparation. The oral immunomodulatory preparations with the best documented clinical efficacy available on the Polish market are Ismigen, Broncho-Vaxom, Ribomunyl and Luivac. They are all lysates of bacterial strains that most often cause respiratory tract infections. In many clinical trials, oral bacterial lysates have been shown to minimize the risk of recurrent respiratory infections in children and adults and reduce the need for antibiotics. PMID- 30460910 TI - Obstructive sleep disordered breathing in children - an important problem in the light of current European guidelines. AB - Obstructive sleep-disordered breathing (SDB) is a common clinical problem. An unrecognized and untreated SDB is a serious threat for an intensively developing organism of a child. The consequences of SDB include cardiovascular and neurological complications, growth disorders and enuresis. Therefore, SDB in children becomes an important subject of many scientific investigations, publications, and congresses. In 2015 the European Respiratory Society Task Force published a document concerning the conclusions about the diagnostics and treatment of SDB in children and youth from 2 to 18 years of age (Fig. 1). The scientific data from 362 publications were presented in a condensed form of "seven steps", very useful in diagnosing and treatment planning (1). The authors underline the limited number of reliable evidence about SDB: prospective studies, randomized double-blinded studies with placebo. The presented evidence was categorized depending on their quality according to the classification of the American Academy of Neurology (ANN) into classes I - IV. Previously, in 2012, the guidelines of the American Academy of Pediatrics on obstructive sleep apnea syndrome (OSAS) in children with tonsillar hypertrophy and/or obesity were published (2, 3) and they were a valuable diagnostic and therapeutic compendium. The European guidelines discussed in this article result from the progress of knowledge in recent years, they cover the subject broadly, consider rare and difficult cases and present the spectrum of potential therapeutic actions. The aim of the guidelines is a better recognition of SDB, a systematization of diagnosis and treatment at every stage of medical care, including the causes of this disorder and its complications. PMID- 30460911 TI - Objectification of vocal folds mucosal wave. AB - The work assessed the clinical utility of open quotients measured during laryngovideostroboscopy and electroglottography. Values of the parameters were analyzed according to clinical diagnosis. An algorithm based on direct and indirect mucosal wave measurement is presented, which allows for differentiation of voice disorders. The method developed for the objectification of glottal functions in various voice pathologies is characterized by high sensitivity and specificity. PMID- 30460912 TI - Narrow band imaging in transoral laser microsurgery (TLM) in moderately advanced (T2, T3) glottic cancer. AB - INTRODUCTION: Treatment planning in T2, T3 laryngeal carcinoma is based on clinical assessment and radiological imaging. However, to delineate precise mucosal margins for transoral laser microsurgery (TLM), a high class, sophisticated endoscopy is indispensable. Narrowband imaging (NBI) which is an optical filter technology, seems to be a useful adjunctive tool in marking superficial margins. MATERIALS AND METHODS: A total of 98 patients diagnosed with HNSCC underwent cordectomies and were enrolled in the evaluation. T2 and T3 stage cancer were diagnosed in 90 and 8 patients, respectively. Intraoperatively, prior to the first laser shot, all anatomical sites were endoscopically evaluated by WL and NBI. RESULTS: In 10/98 patients (10.2%), 10 samples were taken based only on NBI findings to guarantee better delineation of superficial margins. The result of histology revealed moderate dysplasia in 4 cases (40%), severe dysplasia in 2 (20%), carcinoma in situ in 3 (30%) and hyperkeratosis in 1 (10%). Based on presented results, combined NBI/WL endoscopy reached the sensitivity of 100%, specificity 98.88%, positive predictive value 90%, negative predictive value 100% and accuracy 98.98%. All patients had clear margins according to definitive histology results. DISCUSSION: In this paper, we aimed to assess the usefulness of NBI in intraoperative imaging of laryngeal mucosa and delineation of superficial margins in patients with selected T2 and T3 laryngeal cancer treated with TLM. We proved in our study that with the support of NBI endoscopy, it is possible to increase the accuracy of superficial resection margins in patients with moderately advanced laryngeal cancer (T2, T3). PMID- 30460913 TI - Endonasal Triangular Technique for nasal valve rhinoplasty: a ten year review. AB - INTRODUCTION: The nasal valve is the main regulator of airflow in the nose. Consequently, the collapse of the nasal valve has a significant impact on nasal obstruction and hence quality-of-life of patients. Several nasal valve rhinoplasty techniques are being used, from cartilage grafts to endonasal resection of the upper lateral cartilage. We describe a new endonasal approach to nasal valve rhinoplasty, the Triangular Technique, and assess its efficacy and complication rate over ten years. MATERIALS AND METHODS: A retrospective study of patients who underwent nasal valve rhinoplasty at three regional hospitals from Jan 2004 to May 2014 was conducted. Subjective reports were used to assess the improvement of nasal obstruction. 24 patients were included. RESULTS: 3 months postoperatively, 19 patients reported improvement in nasal obstruction. 4 patients required revision surgery. 2 of these 4 patients had substantial symptom resolution post revision surgery. 10 patients were followed up for more than 5 years (range: 5.8 to 10.3 years), 9 of who reported continued satisfaction and none or minimal nasal obstruction after nasal valve rhinoplasty compared to before surgery. There were no reported complications. DISCUSSION: The Triangular Technique is a straightforward endonasal technique to address collapsed nasal valves with minimal associated co-morbidities. PMID- 30460914 TI - Transnasal microscopic approach for juvenile nasopharyngeal angiofibroma. AB - INTRODUCTION: Juvenile nasopharyngeal angiofibroma (JNA) is a rare, benign, vascular tumor originating in the nasopharynx. The treatment of choice for JNA is surgical excision. In recent years, surgical management has been greatly influenced by the use of the transnasal endoscopic technique. THE AIM: The aim of the study was to present our experience with the transnasal microscopic removal of JNA. MATERIAL AND METHODS: Ten patients with JNA aged 12-17 underwent diagnostics imaging and transnasal microscopic tumor excision. Medical records of patients were retrospectively reviewed. The main outcome measures were complications and recurrences. Preoperative embolization of feeding vessels was performed in 7 patients. RESULTS: According to Andrews' classification, the group included 2 stage I patients, 6 stage II patients and 2 stage IIIA patients with the extensive occupation of the infratemporal fossa. 9 patients had no recurrence in 6-11 years follow up. One stage IIIA patient had a recurrence posteriorly to the pterygopalatine process and it was completely removed. No complications during or after surgery occurred. CONCLUSION: Transnasal microscopic excision is an effective approach to resect stage I-IIIA JNA. PMID- 30460915 TI - Brucella pinnipedialis in lungworms Parafilaroides sp. and Pacific harbor seals Phoca vitulina richardsi: proposed pathogenesis. AB - Brucella spp. were first isolated from marine mammals in 1994 and since have been described in numerous pinniped and cetacean species with nearly global distribution. Microscopic, electron microscopic, or culture results have shown lungworms in harbor seals to be infected with brucellae, suggesting that the lungworms may serve a role in this infection. In this study, we reviewed archived and more recent case material from 5 Pacific harbor seals from Washington State (USA) with evidence of B. pinnipedialis infection in the lungworm Parafilaroides sp. Twenty-two sections of lung containing approximately 220 Parafilaroides sp., stained with an immunohistochemical technique using antibody to B. abortus, showed approximately 80 (36%) infected nematodes. A few brucellae were also present in lung parenchyma in proximity to nematodes. Infection was present in the first- and fourth-stage larvae in the seal lung and intestines, as well as in the male and female reproductive organs of adult nematodes. Infected sperm deposits in the nematode uterus were suggestive of venereal transmission between lungworms. Massive infection of some degenerate adult lungworms and evidence of degeneration of some developing larvae in utero were observed. Based on these observations, we suggest that Parafilaroides sp., rather than the Pacific harbor seal Phoca vitulina richardsi, is the preferred host of B. pinnipedialis infection. PMID- 30460916 TI - Pathology of the skeleton of Indo-Pacific bottlenose dolphins Tursiops aduncus: a comparison of adjacent gulfs in South Australia. AB - Studies of skeletal pathology of marine mammals can contribute to conservation measures, yet few have focused on causative factors. Museums hold vast collections of skeletons relevant to this knowledge gap. Indo-Pacific bottlenose dolphin Tursiops aduncus carcasses (n = 162) were collected from Gulf St Vincent (GSV) and Spencer Gulf (SG), South Australia (SA), between 1988 and 2013, and post-mortem examinations were carried out. After preparing skeletons, their gross pathology was classified into 4 categories: lytic lesions, degenerative lesions, fractures and malformations. Comparisons were made between gulfs based on pathology type, relative age, period of collection and cause of death (anthropogenic vs. non-anthropogenic). Pathology prevalence (76%) was higher than reported in other studies but observed pathologies were similar. More than one pathology was observed in 88% of dolphins that had pathology. Vertebrae were often the site of pathology. Prevalence of lesions were: fractures (82%), lytic lesions (75%) including spondylo-osteomyelitis and osteomyelitis, degenerative lesions (57%) including spondylosis deformans, and malformations (17%). Prevalence of pathology increased with dolphin relative age, and GSV dolphins had more pathology than those in SG. In SG, anthropogenic cases had more pathology than non-anthropogenic cases, and dolphins collected after 2000 had more degenerative lesions than those collected before 2000. There were more malformations in SG dolphins than those from GSV, although this was not statistically significant. In one anomalous case, an individual was found with 5 detached transverse processes on 4 lumbar vertebrae. Heavy metal toxicity reported for T. aduncus from SG may be related to the malformations reported in this study. PMID- 30460917 TI - Age- and size-dependent resistance to chytridiomycosis in the invasive cane toad Rhinella marina. AB - In Australia, the cane toad Rhinella marina and chytrid fungus Batrachochytrium dendrobatidis (Bd) are examples of invasive species that have had dramatic impacts on native fauna. However, little is known about the interaction between Bd and cane toads. We aimed to explore the interaction of these 2 species in 3 parts. First, we collated data from the literature on Bd infection in wild cane toads. Second, we tested the susceptibility of recently metamorphosed cane toads to Bd infection. Finally, we modelled the distribution of the 2 species in Australia to identify where they overlap and, therefore, might interact. Through our data collation, we found that adult cane toads are infrequently infected and do not carry high infection burdens; however, our infection experiment showed that metamorphs are highly susceptible to infection and disease, but resistance appears to increase with increasing toad size. Niche modelling revealed overlapping distributions and the potential for cane toads to be affected by chytridiomycosis in the wild. While Bd can cause mortality in small juveniles in the laboratory, warm microhabitats used by wild toads likely prevent infection, and furthermore, high mortality of juveniles is unlikely to affect the adult populations because they are highly fecund. However, to demonstrate the impact of Bd on wild cane toad populations, targeted field studies are required to assess (1) the overall impact of chytridiomycosis on recruitment especially in cooler areas more favourable for Bd and (2) whether cane toad juveniles can amplify Bd exposure of native amphibian species in these areas. PMID- 30460918 TI - Pseudocapillaria tomentosa in laboratory zebrafish Danio rerio: patterns of infection and dose response. AB - Parasites in wild populations almost always exhibit aggregation (overdispersion), in which relatively few hosts are infected with high numbers of the parasites. This pattern of infection has also been observed in laboratory studies, where many of the sources of natural variation are removed. Pseudocapillaria tomentosa (Nematoda) is common in zebrafish (Danio rerio) facilities. We describe here patterns of infections in zebrafish experimentally infected with larvated P. tomentosa eggs in various trials with defined numbers of eggs. One trial with eggs delivered in a gelatin diet is also included. Fish were exposed at 25, 75, and 200 eggs fish-1, and the minimal infectious dose was estimated to be 1.5 eggs fish-1. The ID50 (50% infective dose) was calculated to be 17.5 eggs fish-1. We also included data from a trial and 2 previously published experiments with undefined doses in which zebrafish were exposed to infectious water and detritus from a tank that previously contained infected fish. All doses resulted in a high prevalence of infection (>70%), except at the 25 eggs fish-1 dose, where the prevalence was 43-46%. Mean abundance of worms corresponded to dose, from 0.57 worms fish-1 at 25 eggs fish-1 to 7 worms fish-1 at 200 eggs fish-1. Variance to mean ratios (V/M) and the k parameters showed aggregation across the 8 separate trials, including the gelatin diet. Aggregation increased with increased parasite abundance. Given the consistent observation of aggregation across our experiments, the zebrafish/P. tomentosa system provides a potentially robust, high-throughput model to investigate factors that influence differences in host susceptibility within defined populations. PMID- 30460919 TI - Parasites of amberjacks from the archipelago of Madeira, Eastern Atlantic. AB - Amberjacks, Seriola spp., are a group of carangid fishes of economic importance for fisheries and aquaculture worldwide. A survey of the parasites of greater amberjack S. dumerili and almaco jack or longfin yellowtail S. rivoliana from the Madeira archipelago (including the Madeira and Selvagens Islands) was carried out. This work is the first parasitological study of these 2 species in the Eastern Atlantic. A total of 14 parasite taxa were detected in the 47 fish analysed: Allencotyla mcintoshi, Stephanostomum petimba, Rhadinorhynchus sp. and Caligus aesopus (in both Seriola spp.); Dionchus agassizi, Zeuxapta seriolae, Tormopsolus orientalis, Didymocystis sp. and Anisakis sp. (in S. rivoliana); Tetrochetus coryphaenae, Stephanostomum sp., S. ditrematis, Oncophora melanocephala and Hysterothylacium seriolae (in Seriola dumerili). The monogenean Dionchus agassizi and the nematode O. melanocephala constitute new host records for the genus Seriola, and the species Allencotyla mcintoshi, Z. seriolae, Tormopsolus orientalis, H. seriolae, and C. aesopus are reported in the region of Madeira for the first time. Some of the parasites detected, in particular Z. seriolae and C. aesopus, could constitute a threat to amberjack aquaculture, and measures should be taken to prevent their introduction into sea cages. PMID- 30460920 TI - Simultaneous occurrence of two new myxosporean species infecting the central nervous system of Hypopygus lepturus from Brazil. AB - This paper describes 2 new myxosporean species, Henneguya lepturus sp. nov. and Thelohanellus lepturus sp. nov., simultaneously infecting the brain and spinal cord of Hypopygus lepturus Hoedeman, 1962 (Teleostei, Hypopomidae) from the Brazilian Amazon (Roraima State). Several spherical cysts of varying dimensions (up to 135 um) were microscopically observed. The myxospores of H. lepturus sp. nov. measured 25.8 um in total length, having an ellipsoidal body (12.4 * 6.4 * 2.2 um) and 2 equal tapering tails (13.4 um in length). Each of the 2 pyriform polar capsules measured 4.4 * 1.6 um and possessed a polar filament coiled in 8-9 turns. The myxospores of T. lepturus sp. nov. were pyriform, formed by 2 equal valves (17.7 * 9.1 * 4.3 um) surrounding a single polar capsule (10.9 * 3.5 um) that had a coiled polar filament with 13-16 turns and a binucleated sporoplasm that contained several circular sporoplasmosomes. Molecular analysis of the small subunit (SSU) rRNA gene sequences of these 2 species were in agreement with the taxonomic classification derived from the ultrastructure of the myxospores. Histopathology of the host tissue showed degradation of the myelinated axons surrounding the cysts of both species, with the hosts displaying behavioural changes and erratic movements when observed in an aquarium. PMID- 30460921 TI - Sodium chloride treatment effects on rainbow trout suffering from proliferative kidney disease caused by Tetracapsuloides bryosalmonae. AB - The aim of the present study was to evaluate the effect of a long-term sodium chloride bath on rainbow trout Oncorhynchus mykiss naturally infected by Tetracapsuloides bryosalmonae. A total of 106 infected fish were divided into 2 groups. One group was left untreated and the other was treated with sodium chloride in increasing doses up a concentration of 0.8%. After 14 d, treatment was stopped and for a further 7 d the fish response to the sodium chloride bath was observed. Cumulative mortality was significantly lower in the treated group (19.2%) compared to the untreated group (31.5%) after 21 d. This corresponded to the lower but non-significant parasite intensity in kidney and spleen in the treated group after 14 d of treatment. However, lower prevalence of parasites in both tissues was recorded in the untreated group after 21 d of treatment, but a significant difference was observed only in spleen tissue. Furthermore, significant increases in leukocytes, hemoglobin, haematocrit, ferric reducing ability of plasma, and ceruloplasmin, and significant decreases in alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase activities were noticed in the treated group compared to the untreated group. In contrast, significant decreases in lysozyme concentration in the mucus and phagocyte oxidative burst in the blood were observed in the treated group. Histopathological examination revealed proliferative and reparative changes in parenchymatous tissues in the treated group. The 14- and 21-d salt bath used in rainbow trout with proliferative kidney disease was associated with a reduction in mortality and enhanced the reparative phase in the treated group. PMID- 30460922 TI - NMR diagnosis of pseudo-scalar superconductivity in 3D Dirac materials. AB - Recently observed 4pi periodic Andreev bound states in 3D Dirac materials are attributed to conventional superconducting pairing. Our alternative explanation in terms of a novel form of parity breaking pseudo-scalar superconducting order can be sharply diagnosed by nuclear magnetic resonance relaxation rate. The left right symmetry breaking of the pseudo-scalar superconductivity can be directly probed as an anti-peak structure below T C in sharp contrast to the conventional Hebel-Slichter peak. PMID- 30460923 TI - Magnetotransport studies of optimally doped Sr(Fe1-x Co x )2As2. AB - We report magnetotransport measurements and their scaling analysis for the optimally electron-doped Sr(Fe0.88Co[Formula: see text]As2 system. We observe that both the Kohler's and modified Kohler's scalings are violated. Interestingly, the Hall angle displays a quadratic temperature dependence (cot[Formula: see text] [Formula: see text] T 2) similar to many cuprates and heavy fermion systems. The fact that this T 2 dependence is seen in spite of the violation of modified Kohler's scaling suggests that the Hall angle and magnetoresistance are not governed by the same scattering mechanism. We also observe a linear magnetoresistance in this system, which does not harbor a spin density wave ground state. Implications of our observations are discussed in the context of existing models for the magnetotransport of these strongly correlated electron systems. PMID- 30460924 TI - On the work function of the surface Mo(0 0 1) and its temperature dependence: an ab initio molecular dynamics study. AB - Ab initio molecular dynamics simulations in NVT ensemble have been performed to investigate the finite temperature structure of the Mo(0 0 1) surface and its effect on work function (phi). In accord with previous experimental and theoretical work, our simulations predict that a termination with a stable reconstruction pattern is formed at T = 123 K. This pattern vanishes when temperature is increased to 423 K or 623 K and a disordered surface phase is formed whose time average corresponds to a bulk-like termination. Our results demonstrate that the surface relaxation is an important factor contributing to thermal variation of phi. At the lowest temperature, at which a stable reconstruction pattern is formed, the work function is found to increase by ~0.23 eV compared to relaxed unreconstructed surface. The disappearance of stable reconstruction pattern at elevated temperatures leads to a decrease of phi by ~0.07 eV. In contrast, the values computed for a non-reconstructing surface Mo(1 1 0) at T = 123 K, 423 K and 623 K are found to be nearly identical to the zero temperature value, which is a consequence of restricted atomic motion due to high packing density in this surface. PMID- 30460925 TI - Characteristics of flexible and transparent Eu2O3 resistive switching memory at high bending condition. AB - The characteristics of ITO/Eu2O3/ITO/PET transparent and flexible resistive switching memory are studied. The device exhibits superior characteristics such as device area-independent and forming-free resistive switching behavior with a resistance on/off ratio of 104, good retention of >104 s and high AC endurance of >107 cycles. The conduction mechanism of the high-resistance state is the Poole Frenkel mechanism, while that of the low-resistance state is ohmic conduction. The electrical characteristics of the flexible device have shown excellent results up to 5 mm bending radius, at which a degradation in the on/off ratio of the memory window is observed, due to the change in the dielectric layer resistance. The resistive switching characteristics can be improved during bending up to the radius of 2 mm by the incorporation of an aluminum-doped zinc oxide layer in the device as the bottom electrode, proving its application in future flexible and transparent memory devices. PMID- 30460926 TI - Construction of noble-metal-free TiO2 nanobelt/ZnIn2S4 nanosheet heterojunction nanocomposite for highly efficient photocatalytic hydrogen evolution. AB - A binary nanocomposite composed of two-dimensional (2D) ultrathin ZnIn2S4 nanosheets and one-dimension (1D) TiO2 nanobelts was prepared and applied as a noble-metal-free photocatalyst for hydrogen evolution under solar-light irradiation. The TiO2 nanobelt/ZnIn2S4 nanosheet heterojunction nanocomposites show higher light absorption capacity, larger surface area and higher separation of charge carriers in comparison to pristine TiO2 and ZnIn2S4. As a result, the hydrogen production over the TiO2/ZnIn2S4 nanocomposite with 15 wt% TiO2 can reach up to 348.21 MUmol . g-1 . h-1, even without noble metals, which is about 26 and 2.3 times higher than the pristine TiO2 and ZnIn2S4, respectively. Meanwhile, a possible photocatalytic mechanism of TiO2/ZnIn2S4 heterojunction nanocomposites was proposed and corroborated by photoluminescence (PL) spectroscopy and photoelectrochemical (PEC) results. This work paves a way for developing low-cost and high-efficiency noble-metal-free photocatalytic systems for solar-to-hydrogen evolution. PMID- 30460927 TI - Correlation between composition, microstructure, and emission properties in Nd doped Si-rich Si oxynitride films: investigation into the nature of the sensitizer. AB - Rare earth (RE) ions doped in Si-based materials, compatible with Si technology, are promising compounds with regards to optical communication and energy conversion. In this article, we show the emission properties of Nd-doped Si-rich Si oxynitride (Nd-SRSON) films, and their dependence on the dangling bond density and the nature of the sensitizer. These films were prepared by reactive magnetron sputtering and post-annealing. The film composition, microstructure, and emission properties were investigated as a function of deposition parameters and annealing temperatures. Both Fourier transform infrared (FTIR) and ellipsometry spectroscopy measurements have confirmed that the sample composition (Si/N ratio) can be carefully tuned by varying the ratio of reactive nitrogen to argon in the sputtering plasma. Moreover, FTIR and x-ray photoelectron spectroscopy measurements demonstrate the existence of both nitrogen and oxygen dangling bonds (N. and O.) in as-deposited samples. These dangling bonds were passivated during annealing. Under non-resonant excitation at 488 nm, the films exhibit a significant photoluminescence (PL) signal from Nd3+ ions demonstrating the occurrence of an effective sensitization of Nd3+ ions in the host matrix. Both PL excitation and ellipsometry results (the energy band gap from new amorphous model) exclude the sensitization by an exciton with energy over the band gap, whereas the presence of Si agglomerates, at the atomic scale, have been identified as effective sensitizers towards Nd3+ ions. This work not only provides knowledge to optimize Si-based materials for favorable emission properties, but also, presents a universal methodology to investigate the nature of sensitizers for RE emitters. This allows one to find correlations between composition, microstructure, and emission properties. PMID- 30460928 TI - Controlling disorder in two-dimensional networks. AB - Two-dimensional networks are constructed by reference to a distribution of ring sizes and a parameter (alpha) which controls the preferred nearest-neighbour spatial correlations, and allows network topologies to be varied in a systematic manner. Our method efficiently utilizes the dual lattice and allows the range of physically-realisable configurations to be established and compared to networks observed for a wide range of real and model systems. Three different ring distributions are considered; a system containing five-, six- and seven-membered rings only (a proxy for amorphous graphene), the configuration proposed by Zachariasen in 1932, and a configuration observed experimentally for thin (near 2D) films of SiO2. The system energies are investigated as a function of the network topologies and the range of physically-realisable structures established and compared to known experimental results. The limits on the parameter alpha are discussed and compared to previous results. The evolution of the network structure as a function of topology is discussed in terms of the ring-ring pair distribution functions. PMID- 30460929 TI - Everything is in the name: Macular hyperpigmentation of uncertain etiology or acquired dermal macular hyperpigmentation of varied etiologies? PMID- 30460930 TI - End of the road for terbinafine? Think of compliance to treatment. PMID- 30460931 TI - Separate Chinese lines for prostate cancer? PMID- 30460933 TI - Enzalutamide: a new indication for nonmetastatic castration-resistant prostate cancer. PMID- 30460932 TI - Psychological burden prediction based on demographic variables among infertile men with sexual dysfunction. AB - There has been increasing interest in the psycho-socio-relational and sexual disorders of infertility, as the risk of psychological burden among infertile men with sexual dysfunctions is significant. The purpose of this study was to develop and to validate a predictive model to estimate individual psychological burden among infertile men with sexual dysfunction and study the association between them. Comprehensive data were collected for infertile men (n = 480) who sought treatment for infertility in a reproductive medicine center between June 2012 and December 2013. Using independent predictors of psychological burden from the least absolute shrinkage and selection operator, univariable and multivariable analyses were developed into two models. Predictive accuracy was compared between the models. We explored the association between sexual dysfunction and psychological burden. A total of 480 patients were analyzed using 10-fold cross validation. Independent predictors of psychological burden were incorporated into a model to measure anxiety (corrected-area under curve (AUC): 77.3%) and a model to measure depression (corrected-AUC: 70.2%). Anxiety and depression were both associated with erectile dysfunction (P < 0.05), with anxiety demonstrating the strongest association. Only anxiety was associated with premature ejaculation (P < 0.05). Premature ejaculation was not found to be associated with depression (P > 0.05). Predictive models for psychological burden among infertile men with sexual dysfunction are presented, and we found that there is an association between psychological burden and sexual dysfunction. According to the models, proper counseling and treatment of sexual dysfunction in infertile men may reduce the psychological burden, help attain natural pregnancy, and improve the quality of life. PMID- 30460934 TI - A novel rat model of seminal vesiculitis. AB - We aimed to establish a novel rat model of seminal vesiculitis that would provide an effective approach to investigate the pathogenesis of this disease in the future. Eight male rats received the same operation, during which the root of one of the two seminal vesicles was partly ligatured with sutures and the other vesicle was left intact. The samples of seminal vesicles were harvested on the 8th day following the operation. Hematoxylin and eosin and Masson's trichrome stains were used to observe the histopathology and the presence of fibrous tissue in seminal vesicles, respectively. Immunoblotting and immunohistochemistry were applied to determine the tumor necrosis factor-alpha and cyclooxygenase-2 levels in seminal vesicle tissues. Real-time fluorescence quantitative polymerase chain reaction was performed to measure the gene expression levels of proinflammatory cytokines. H2O2levelsin the seminal plasma from the seminal vesicle were also measured. Hematoxylin and eosin staining suggested that there was inflammatory cell infiltration into the seminal vesicles treated by partial root ligation. The tumor necrosis factor-alpha and cyclooxygenase-2 proteins were significantly upregulated in the treated seminal vesicles. The tumor necrosis factor-alpha, cyclooxygenase, interleukin 6, and inducible nitric oxide synthase mRNA expression levels were also upregulated in the treated seminal vesicles. The H2O2 levels in the seminal plasma from seminal vesicles with partial root ligation were significantly elevated compared with those from vesicle left intact. In conclusion, partially ligating the root of the seminal vesicle via sutures in rats is an effective method to establish a seminal vesiculitis rat model. PMID- 30460935 TI - Outcomes of men aged <=50 years treated with radical prostatectomy: a retrospective analysis. AB - Previous studies investigating prostate cancer (PCa) features in younger men have reported conflicting findings. This study aimed to investigate pathologic outcomes and biochemical recurrence (BCR) status in younger men who underwent radical prostatectomy (RP) for PCa. Records of 2057 patients who underwent RP at Seoul National University Bundang Hospital (Seongnam, Korea) between 2006 and 2015 were reviewed; patients were divided according to age into the younger and older groups (men aged <=50 and >50 years, respectively). Postoperative BCR status and functional outcomes and clinicopathologic features were compared between both groups. All analyses were repeated after propensity score matching. Younger men were more likely to have low-risk disease (P < 0.001), lower pathologic Gleason score (P < 0.001) and pathologic stages (P < 0.001) than older men. The pathologic Gleason score (P = 0.002) and rates of extracapsular extension (P = 0.004) were lower in younger men after propensity score matching. In multivariate analysis, age at RP was not an independent predictor of BCR-free survival after RP (P = 0.669). Moreover, at 1 year after RP, younger men with preoperative 5-item International Index of Erectile Function score >=22 (n = 228) showed more favorable results for urinary continence (defined as nonuse of pads daily) (99.4% vs 95%, P = 0.009) and erections sufficient for vaginal intercourse (81.8% vs 55.5%, P = 0.001). Younger men had more favorable clinicopathologic features at RP than their older counterparts. Although age was not an independent predictor of BCR status outcome, younger men had better functional outcomes following RP. PMID- 30460936 TI - A Modified Strategy Using Barbed Sutures for Wound Closure in Total Joint Arthroplasty: A Prospective, Randomized, Double-Blind, Self-Controlled Clinical Trial. AB - BACKGROUND Barbed suture has reported time-saving and safety benefits for wound closure in total joint arthroplasty (TJA). However, this technique requires further investigation. The aim of this study was to use a prospective, randomized, self-controlled study to further determine the efficiency and safety of this technology and to introduce our modified suturing method through a randomized, self-controlled trial. MATERIAL AND METHODS From August 2015 to December 2016, 84 patients (hip 46, knee 38) who had undergone primary simultaneous bilateral total knee or hip arthroplasties were enrolled in this study. Barbed sutures were randomized and used on one side, and traditional sutures (Vicryl) were used on the other side. RESULTS Closure time was shorter with the barbed sutures: 6.25 min (12.00 min vs. 18.25 min, p=0.000) for hip and 5.54 min (13.18 min vs. 18.71 min, p=0.000) for knee. There was no difference in the complication rate for the 2 groups. The total cost of our suturing strategy (Quill) was 872.3 RMB, which is 375.1 RMB higher than the total cost of the standard suture method (Vicryl). However, the traditional barbed suturing method (Quill) cost 2195.6 RMB. CONCLUSIONS Barbed suturing was a fast and safe method for wound closure in TJA. We also recommend our modified suturing strategy, especially in countries where operation cost was not associated with operation time. PMID- 30460937 TI - A pH-responsive hydrogel with potent antibacterial activity against both aerobic and anaerobic pathogens. AB - Aminoglycosides are a family of antibiotics with a wide-spread antibacterial spectrum and high antibacterial activity. However, they are less effective against anaerobic pathogens due to the requirement of aerobic respiration to exert their antibacterial functions. Here, we prepared a pH-responsive hydrogel with potent antibacterial activities against both aerobic and anaerobic pathogens. The hydrogel was prepared by reacting oxidized dextran with aminoglycoside and an ornidazole analogue via an acid-labile Schiff base linkage. The prepared hydrogel was injectable, self-healing, biocompatible, and showed a pH-responsive drug release behavior. More importantly, the gel was efficient in killing both aerobic and anaerobic pathogens. This study provides a facile strategy to expand the antibacterial spectrum of aminoglycoside hydrogels. PMID- 30460938 TI - Integration of FexS electrocatalysts and simultaneously generated interfacial oxygen vacancies to synergistically boost photoelectrochemical water splitting of Fe2O3 photoanodes. AB - Integration of FexS electrocatalysts and simultaneously generated interfacial oxygen vacancies (VO) was designed to promote the water splitting performance of Fe2O3 photoanodes, in which a synergistic effect remarkably reduces the carrier recombination, increases the number of active sites, and facilitates the photogenerated holes to participate in water oxidation. PMID- 30460939 TI - A nanozyme tag enabled chemiluminescence imaging immunoassay for multiplexed cytokine monitoring. AB - We report a new concept of a chemiluminescence imaging nanozyme immunoassay (CINIA), in which nanozymes are exploited as catalytic tags for simultaneous multiplex detection of cytokines. The CINIA provides a novel and universal nanozyme-labeled multiplex immunoassay strategy for high-throughput detection of relevant biomarkers and further disease diagnosis. PMID- 30460940 TI - Impact of pore size, interconnections, and dynamic conductivity on the electrochemistry of vanadium pentoxide in well defined porous structures. AB - Considering the tortuous, random porous nanostructures existing in many battery electrodes, it is essential to understand electronic and ionic behaviors in such a confined nanoscale porous geometry in which electron and ion transports can change dynamically. Here, we have carefully designed three dimensional (3D) interconnected porous electrode structures and performed experiments to probe how the ion and electron transport is impacted within these controlled geometries. By using anodized aluminum oxide as a template, we were able to fabricate both 1D array electrodes and 3D electrodes with varying numbers of interconnections, utilizing vanadium oxide (V2O5) as the active material. We demonstrate that the inherent properties of the electrode material in combination with the structural properties of the electrodes can both positively and negatively impact electrochemical characteristics. Most notably, electrodes with seven interconnecting layers in their structure had 19.7% less capacity at 25C than electrodes with zero interconnecting layers, demonstrating the negative effect of interconnections combined with poor electronic conductivity of V2O5 upon lithiation beyond one Li insertion. These results indicate that a careful consideration of the material and structural properties is needed for the design of high performance battery systems. PMID- 30460941 TI - Accurate calculation of optically induced birefringences in chiral systems using efficient polarized basis sets. AB - Using state-of-the-art ab initio methodology, we evaluate universal molecular parameters entering the expressions for various optically induced birefringences in chiral fluids. For this, we use the single and double excitation coupled cluster (CCSD) theory together with Dunning's augmented correlation consistent polarized basis sets of increasing size. As this is the first time these parameters are evaluated for chiral molecules using the CCSD approach, we choose possibly small test systems: a model asymmetric methane molecule, and (R)-fluoro oxirane. With this choice, the convergence of the molecular parameters with the increase of the basis set size is investigated in detail. The results are compared to those obtained with the LPol-n (n = ds, dl, fs) and the ORP basis sets, and to the corresponding Density Functional Theory (DFT) counterparts. We can conclude that the DFT medium constant values are considerably far from coupled cluster, and therefore, aware of the known excellent performance of the CCSD method in the evaluation of various dynamic responses, we do not recommend the former methodology for accurate evaluation of the present properties. Regarding basis set convergence, the performace of the LPol-ds basis set is more efficient than that of the d-aug-cc-pVDZ set, and therefore, the former basis set can be a good choice when dealing with the study of larger systems. PMID- 30460942 TI - Impact of copper and iron binding properties on the anticancer activity of 8 hydroxyquinoline derived Mannich bases. AB - The anticancer activity of 8-hydroxyquinolines relies on complex formation with redox active copper and iron ions. Here we employ UV-visible spectrophotometry and EPR spectroscopy to compare proton dissociation and complex formation processes of the reference compound 8-hydroxyquinoline (Q-1) and three related Mannich bases to reveal possible correlations with biological activity. The studied derivatives harbor a CH2-N moiety at position 7 linked to morpholine (Q 2), piperidine (Q-3), and chlorine and fluorobenzylamino (Q-4) substituents. Solid phase structures of Q-3, Q-4.HCl.H2O, [(Cu(HQ-2)2)2].(CH3OH)2.Cl4.(H2O)2, [Cu(Q-3)2].Cl2 and [Cu(HQ-4)2(CH3OH)].ZnCl4.CH3OH were characterized by single crystal X-ray diffraction analysis. In addition, the redox properties of the copper and iron complexes were studied by cyclic voltammetry, and the direct reaction with physiologically relevant reductants (glutathione and ascorbic acid) was monitored. In vitro cytotoxicity studies conducted with the human uterine sarcoma MES-SA/Dx5 cell line reveal the significant cytotoxicity of Q-2, Q-3, and Q-4 in the sub- to low micromolar range (IC50 values 0.2-3.3 MUM). Correlation analysis of the anticancer activity and the metal binding properties of the compound series indicates that, at physiological pH, weaker copper(ii) and iron(iii) binding results in elevated toxicity (e.g.Q4: pCu = 13.0, pFe = 6.8, IC50 = 0.2 MUM vs.Q1: pCu = 15.1, pFe = 13.0 IC50 = 2.5 MUM). Although the studied 8-hydroxyquinolines preferentially bind copper(ii) over iron(iii), the cyclic voltammetry data revealed that the more cytotoxic ligands preferentially stabilize the lower oxidation state of the metal ions. A linear relationship between the pKa (OH) and IC50 values of the studied 8-hydroxyquinolines was found. In summary, we identify Q-4 as a potent and selective anticancer candidate with significant toxicity in drug resistant cells. PMID- 30460944 TI - Imaging H abstraction dynamics in crossed molecular beams: O(3P) + propanol isomers. AB - The crossed beam reaction dynamics of ground state O(3P) atoms with propanol isomers (1-propanol and 2-propanol) have been studied for the first time using the velocity map imaging technique. The hydroxypropyl radical products, generated from H-abstraction of the secondary and tertiary C-H groups of propanol isomers, were detected via single photon ionization at 157 nm under single collision conditions with collision energies of 8 and 10 kcal mol-1. Direct rebound dynamics were suggested by the angular distributions, which show overall sideways backward scattering but more pronounced backward scattering for both isomer reactions under all collision energies studied here. All the translational energy distributions peak at low energy, on average 20-40% of the total available energy. This indicates high internal excitation in the products that is treated by various models of energy release. We infer that most of the total available energy is partitioned into rotational excitation due to the long-rang dipole dipole interaction between the dipolar OH and hydroxypropyl radicals. PMID- 30460945 TI - An open-framework silicogermanate regularly constructed from natrolite zeolite chains and Ge9O18(OH)4 clusters. AB - Here we describe the synthesis and structure of PST-18, a novel open-framework silicogermanate with Si/Ge ~ 0.6, which contains a three-dimensional pore system consisting of large cuboid-shaped cavities with 8-ring windows, as well as with 7 rings interrupted by one OH group. Synchrotron single-crystal X-ray diffraction reveals that the structure of PST-18, synthesized using only tetramethylammonium fluoride as a structure-directing agent, is built up of natrolite zeolite chains and Ge9O18(OH)4 clusters in a fully ordered manner. The discovery of such a hybrid structure of zeolitic building units and non-zeolitic oxide clusters provides a new direction for expanding the structural regime of inorganic microporous crystalline materials. PMID- 30460950 TI - A new synthetic route to 5,6,11,12-tetraarylethynyltetracenes. AB - A new synthetic route to 5,6,11,12-tetrakis(arylethynyl)tetracenes, pi-extended rubrenes, was developed via [4 + 2] cycloadditions of dialkynylisobenzofuran and 1,4-naphthoquinone. Introduction of arylethynyl groups by double nucleophilic additions to tetracenequinone gave sterically congested (arylethynyl)tetracenes after reductive aromatization. The photophysical properties of the newly prepared pi-conjugated molecules are also evaluated. PMID- 30460951 TI - Mechanistic insights into HCO2H dehydrogenation and CO2 hydrogenation catalyzed by Ir(Cp*) containing tetrahydroxy bipyrimidine ligand: the role of sodium and proton shuttle. AB - The mechanism of HCO2H dehydrogenation catalyzed by [IrCp*(H2O)(bpymO4H4)]2+ (bpymO4H4 = 2,2',6,6'-tetrahydroxy-4,4'-bipyrimidine) was investigated using density functional theory. The relative free energy profiles at various protonation states corrected to pH 3.5 and pH 7.6 suggested that Na+ together with the ortho-oxyanion of bipyrimidine facilitates the Ir-HCO2 formation, subsequent hydride transfer, and H2 formation. HCO2H was found to be a more effective proton shuttle than H2O for H2 formation. Under experimental conditions, the highest catalytic reactivity was found at pH 3.5-4.0, where both HCO2Na and HCO2H were present. At lower pH and low formate concentration, HCO2H dehydrogenation tends to proceed via a Na+ independent pathway, involving a higher energy barrier. At higher pH, although Na+ can mediate hydride transfer and H2 formation, the low amount of HCO2H results in H2O as the proton shuttle, which involves a higher energy barrier than that for HCO2H proton shuttle. In other words, the catalytic activity of HCO2H dehydrogenation by the proton responsive Ir complexes at different pH values is influenced by the protonation state, involvement of Na+, and the availability of HCO2H as a proton shuttle. For the hydrogenation of CO2 at pH 8.3, the rate determining step is the heterolytic cleavage of H2 mediated by Na+via a HCO3- proton shuttle. Our results demonstrate the importance of alkali metal ions in the design of catalysts for efficient, reversible, CO2 conversion. PMID- 30460952 TI - A temperature-triggered triplex bistable switch in a hybrid multifunctional material: [(CH2)4N(CH2)4]2[MnBr4]. AB - Bistable optical-electrical duplex switches represent a class of highly desirable intelligent materials because of their potential applications in the fields of next-generation flexible devices. However, controllable photoelectric switchable materials with high-performance dielectric-switching and optical-switching properties are still scarce, with triplex bistable switches being rarely reported. Herein, a novel optoelectronic triple-functional organic-inorganic material, 5-azonia-spiro[4,4]nonane tetrabromomanganese (1, [ASN]2[MnBr4], ASN = (CH2)4N(CH2)4), which undergoes a reversible solid-state phase transition around 327 K and exhibits a recognizable second harmonic generation (SHG) effect between SHG-on and SHG-off states, has been successfully synthesized and grown as block crystals. Intriguingly, the bromine-doped crystal can exhibit intense green luminescence with a high quantum yield of 13.07% under UV excitation, extending its application in the field of photoelectric seamless integration and/or flexible multifunctional devices. PMID- 30460953 TI - New aspects of iron-copper crosstalk uncovered by transcriptomic characterization of Col-0 and the copper uptake mutant spl7 in Arabidopsis thaliana. AB - Iron (Fe) and copper (Cu) are essential micronutrients for energy metabolism and reactive oxygen species (ROS) scavenging. Some Cu-containing proteins can be substituted with Fe-containing proteins, and vice versa, while several Arabidopsis genes are regulated by both metals. Few details of how plants coordinate Fe-Cu crosstalk are known. Gene expression was measured in the roots and rosettes of Fe, Cu, and simultaneously Fe and Cu deficient WT plants and a mutant of the Cu-uptake transcription factor SPL7. The spl7 mutant accumulated excess Fe under normal conditions, and lower Fe supply rescued the growth phenotype and normalized the Fe : Cu ratios. Most Fe regulated genes were expressed similarly in the WT and spl7 mutant, although at higher fold-change levels in spl7 mutants. Expression patterns indicated that both SPL7 and the FIT Fe uptake transcription factor influenced the expression of many key Fe uptake genes. Most notably, the newly discovered IMA/FEP genes and the subgroup Ib bHLH genes, which are upstream of Fe uptake responses, were repressed in the WT under Cu deficiency. Several AP2/ethylene response factor (AP2/ERF) genes and other redox homeostasis network genes were derepressed in spl7 mutants. Together, we present new information about Fe-Cu crosstalk in plants that could be applied for developing abiotic stress tolerant crops. PMID- 30460954 TI - Imino-stabilised phosphinidene (or azaphosphole?) and some of its derivatives. AB - Diiminophenyl (dimph) proved to be an excellent ligand platform to stabilise a low-valent phosphorus centre. The resultant compound dimphP (3), which can be rationalized as an imino-stabilised phosphinidene or benzoazaphosphole, shows remarkable chemical stability: it withstands treatment with water and oxidizers (O2 and pyridine oxide) and only reacts with excess strong acid (e.g. HCl) to generate the P(iii) chloride (dimHph)PCl (7), where dimHph stands for a diiminophenyl group hydrogenated at one imine position. Surprisingly, substitution of the chloride under some nucleophilic (KOBut) and electrophilic conditions (Me3SiOTf) regenerates the parent compound 3, by proton removal from the weakly acidic CH2N position. A related species (dimH2ph)P (14), where dimH2ph stands for diiminophenyl hydrogenated to imino(aminomethyl)phenyl, is produced upon thermal rearrangement of the hydride (dimHph)PH (13). X-ray structures of compounds 3, 14, and (dimHph)PO2CH (17) are also discussed. PMID- 30460955 TI - Construction of uniform Co-Sn-X (X = S, Se, Te) nanocages with enhanced photovoltaic and oxygen evolution properties via anion exchange reaction. AB - The development of highly efficient electrocatalysts has attracted increasing attention in the field of electrochemical energy conversion. Therefore, we report a simple self-template method to construct Co-Sn-X (X = S, Se, Te) nanocages through the anion exchange reaction of CoSn(OH)6 nanocubes with chalcogenide ions under mild solvothermal conditions. Benefiting from advantageous compositional features and well-designed architectures, the obtained Co-Sn-X (X = S, Se, Te) nanocages display enhanced electrocatalytic activity for dye-sensitized solar cells (DSSCs) and the oxygen evolution reaction (OER) in an alkaline electrolyte. Remarkably, the Co-Sn-Se nanocages as the counter electrode (CE) catalyst deliver a prominent power conversion efficiency (PCE) of 9.25% for DSSCs compared with Pt CE (8.19%). Furthermore, when used as an OER catalyst, the Co-Sn-Se nanocages also exhibit outstanding electrocatalytic activity in terms of their low overpotential of 304 mV at the current density of 10 mA cm-2 and long-term stability in 1.0 M KOH solution. This work provides wide prospects for the rational design and synthesis of high-performance transition metal chalcogenide based electrocatalysts for future energy conversion systems. PMID- 30460956 TI - Boosting the photocatalytic hydrogen evolution activity of g-C3N4 nanosheets by Cu2(OH)2CO3-modification and dye-sensitization. AB - Considering the cleanness and renewability of the solar H2-production system, photocatalytic H2-production from water splitting with the assistance of nonprecious and Earth-abundant cocatalysts has become a research hotspot. Herein, robust Cu2(OH)2CO3 nanoparticles were successfully anchored onto the surface of g C3N4 nanosheets through a mild precipitation route in which Cu2(OH)2CO3 serves as an effectively nonprecious metal-based cocatalyst for boosting hydrogen generation. The results demonstrated that the as-prepared hybrid Cu2(OH)2CO3/g C3N4 nanocomposite photocatalyst with an optimum 3 wt% loading amount of Cu2(OH)2CO3 exhibited a noticeable improvement of photocatalytic H2-evolution performance under visible light illumination. The boosted H2-evolution activity was associated with the formation of active Cu species during the photocatalytic process, which could promote the interfacial charge separation and simultaneously reduce the overpotential of hydrogen generation, thus boosting the H2-evolution activity over the hybrid photocatalyst. More importantly, by introducing an optimum amount of fluorescein dye molecules into the photocatalytic system, the maximum photocatalytic H2-production rate over the binary Cu2(OH)2CO3/g-C3N4 photocatalyst could be further improved to be 22.6 MUmol h-1, 19.3 and 3.8 times higher than those of pristine g-C3N4 and the corresponding binary catalyst without the assistance of fluorescein. These results could be ascribed to the positively cooperative effects of Cu2(OH)2CO3, fluorescein dye molecules and g C3N4, which lead to the increasing light absorption ability, fast charge mobility and efficient charge separation of the fluorescein-sensitized Cu2(OH)2CO3/g-C3N4 hybrid photocatalyst, thus ultimately boosting the photocatalytic H2-production activity. This study may pave a new way for engineering a low-cost, high efficiency, noble-metal-free and dye-sensitized cocatalyst/semiconductor system for solar-to-fuel conversion. PMID- 30460957 TI - Superelectrophilic activation of 1-nitronaphthalene in the presence of aluminum chloride. Reactions with benzene and cyclohexane. AB - 1-Nitronaphthalene smoothly reacts with benzene and undergoes selective reduction with cyclohexane in the presence of aluminum chloride to give 2,4,4-triphenyl-3,4 dihydronaphthalen-1(2H)-one oxime and 5,6,7,8-tetrahydro-1-naphthylamine, respectively. The mechanistic aspects of these and related reactions are discussed on the basis of DFT, providing insight into the protonation behavior of 1-nitronaphthalene coordinated to AlCl3. PMID- 30460958 TI - Unveiling reactive metal sites in a Pd pincer MOF: insights into Lewis acid and pore selective catalysis. AB - A porous Zr metal-organic framework, 1-PdBF4 [Zr6O4(OH)4(OAc)2.4{(PNNNP)Pd(MeCN)}2.4(BF4)2.4; PNNNP = 2,6-(HNPAr2)2C5H3N; Ar = p-C6H4CO2-], has been synthesized via postsynthetic oxidative I-/BF4- ligand exchange using NOBF4. 1-PdBF4 enjoys markedly superior catalytic activity and recyclability to its trifluoracetate-exchanged analogue, 1-PdTFA, for the intramolecular cyclization of o-alkynyl anilines and the carbonyl-ene cyclization of citronellal. Moreover, 1-PdBF4 demonstrates a rare example of pore selective catalysis for the cyclization of 2-ethynyl aniline. PMID- 30460959 TI - Network elasticity of a model hydrogel as a function of swelling ratio: from shrinking to extreme swelling states. AB - In this work, we intended to investigate the relationship between the swelling ratio Q and Young's modulus E of hydrogels from their contracted state to extreme swelling state and elucidate the underlining molecular mechanism. For this purpose, we used tetra-poly(ethylene glycol) (tetra-PEG) gel, whose network parameters are well known, as the polymer backbone, and we succeeded in tuning the swelling of the gel by a factor of 1500 times while maintaining the topological structure of the network unchanged, using an approach combining a molecular stent method and a PEG dehydration method. A master curve of Q-E, independent of the method of obtaining Q, was obtained. Using the worm-like chain model, the experimentally determined master curve can be well reproduced. We also observed that the uniaxial stress-strain curve of the hydrogel can be well predicted by the worm-like chain model using the structure parameters determined from the fitting of the Q-E experimental curve. PMID- 30460960 TI - Mechanics of an adhesive tape in a zero degree peel test: effect of large deformation and material nonlinearity. AB - The common pressure sensitive adhesive (PSA) tape is a composite consisting of a stiff backing layer and a soft adhesive layer. A simple and common way to test how adhesive tapes respond to large shear deformations is the zero degree peel test. Because the backing is very stiff compared to the adhesive layer, the region where the adhesive layer is subjected to large shear can be hundreds of times its thickness. We use a large deformation hyperelastic model to study the stress and deformation fields in the adhesive layer in this test. We present a closed-form solution for the stress field in the adhesive layer and use this solution to determine how load is transferred from the backing layer to the adhesive. Our analytical model is then compared with finite element results, and except for a small region near the peel front, the predicted stress and deformation agree well with the finite element model. Interestingly, we find very different results from the classical linear theory established by Kaelble. In particular for large deformations, our analysis shows that the lateral stresses (parallel to the rigid substrate) are much larger than the shear stress in the adhesive layer. The discrepancy in the stress state and the deformation state with the linear theory is particularly large near the peel front, which we study with a finite element model. These new results will be very useful to interpret experiments and in particular to identify the high stress regions where failure is likely to initiate in zero-degree peel tests also called shear resistance tests in the PSA industry. PMID- 30460961 TI - Single-stranded DNA oligomer brush structure is dominated by intramolecular interactions mediated by the ion environment. AB - Single-stranded DNA (ssDNA) brushes, in which ssDNA oligomers are tethered to surfaces in dense monolayers, are being investigated for potential biosensing applications. The structure of the brush can affect the selectivity and the hybridization efficiency of the device. The structure is commonly thought to result from the balance of intramolecular interactions, intermolecular interactions within the monolayer, and molecule-surface interactions. Here, we test the hypothesis that ssDNA oligomer brush structure is dominated by intramolecular interactions. We use AFM to measure the height of an ssDNA brush and molecular dynamics to simulate the end-to-end distance, both as a function of ionic strength of the surrounding solution. The brush height and the molecule end to-end distance match quantitatively, providing evidence that the brush structure is dominated by intramolecular interactions (mediated by ions). The physical basis of the intramolecular interactions is elucidated by the simulations. PMID- 30460962 TI - Selective hydrosiloxane synthesis via dehydrogenative coupling of silanols with hydrosilanes catalysed by Fe complexes bearing a tetradentate PNNP ligand. AB - A well-defined iron complex system was established using PNNP-R (R = Ph and Cy) as a strong sigma-donating ligand with a rigid meridional tetradentate structure. Reactive Fe(0) complexes [{Fe(PNNP-R)}2(MU-N2)] were synthesized by a reaction of the corresponding iron dihalide with NaBEt3H and structurally characterized. The reaction proceeded via the iron dihydride intermediate [Fe(H)2(PNNP-R)], which underwent H2 reductive elimination, supporting the hemilabile behavior of PNNP-R. [{Fe(PNNP-R)}2(MU-N2)] catalyzed the dehydrogenative coupling of silanols with silanes to selectively form various hydrosiloxanes, which are important building blocks for the synthesis of a range of siloxane compounds. This system exhibited higher catalytic efficiency than the previously reported precious-metal-catalyzed systems. PMID- 30460963 TI - Cardioprotection and natural polyphenols: an update of clinical and experimental studies. AB - Myocardial ischemia is the leading cause of death worldwide. Despite better outcomes with early coronary artery reperfusion strategies, morbidity and mortality remain significant. The principal myocardial hallmark of myocardial ischemia is cell death and the associated impairment of cardiac contractility. In this way, the use of extracts from medicinal plants versus synthetic drugs to mitigate post-ischemic damage constitutes an alternative. Despite their proven beneficial effects in cardiovascular disorders, the use of many plants is questioned. Our aim is to update the clinical and experimental studies about the actions of medicinal plants and polyphenol-enriched extracts against ischemia reperfusion injury and the involved mechanisms. A review of the recent scientific literature (last ten years) on cardioprotective medicinal plants was developed using the following bibliographic databases: PubMed, Scopus, Web of Knowledge and Google Scholar. Herein, the clinical and experimental studies on medicinal plants and their phenolic compounds have been reviewed. The second part of this review was centered on the search for medicinal plant extracts and natural products isolated from them as potential cardioprotective agents. The botanical names of the cited plants have been authenticated by searching the Plant List and Royal Botanical Garden, Kew databases. The data collected show that treatment with natural products diminishes post-ischemic damage through an improvement of the mitochondrial functionality mainly mediated by enhanced nitric oxide bioavailability. Despite these results, further studies must be carried out to validate their use to prevent or mitigate ischemia-reperfusion injury in the clinical setting. PMID- 30460964 TI - Selective synthesis of iridium(iii) end-capped polyynes by oxidative addition of 1-iodopolyynes to Vaska's complex. AB - The reaction of bis(triphenylphosphine)iridium(i) carbonyl chloride (Vaska's complex) with a series of 1-iodopolyynes (1-CnI and 2-CnI) gave sigma-polyynyl iridium(iii) complexes with general formula R(C[triple bond, length as m dash]C)nIr(PPh3)2(Cl)(I)(CO). The use of acetonitrile as a solvent appeared crucial and allowed selectively obtaining only one from a few possible isomers. The X-ray single crystal diffraction experiment for 2-C4[Ir]I allowed the determination of the exact structure of this complex. Further spectroscopic measurements, especially 31P NMR, confirmed the formation of the same type of isomers with trans coordinated phosphines in each case. All complexes were fully characterized with the use of NMR (1H, 13C and 31P), IR, UV/Vis, cyclic voltammetry and (ESI)HRMS techniques. Moreover, DFT calculations were performed for all the resulting species. The complexes with a linear carbon chain from butadiyne to decapentayne are the longest iridium end-capped polyynes known to date since only compounds with a (C[triple bond, length as m-dash]C)2 structural motif have been reported so far. Moreover, we confirmed that the synthetic approach, first used for palladium(ii) end-capped polyynes, may be also applied for the synthesis of other structurally new organometallic polyynes. PMID- 30460965 TI - Isolation of reactive Ln(ii) complexes with C5H4Me ligands (CpMe) using inverse sandwich countercations: synthesis and structure of [(18-crown-6)K(MU-CpMe)K(18 crown-6)][CpMe3LnII] (Ln = Tb, Ho). AB - Although attempts to make the Y(ii) complex, (CpMe3Y)1- (CpMe = C5H4Me), by reduction of CpMe3Y with potassium were unsuccessful and the products of potassium reduction of CpMe3Ln for Ln = La and Pr led to ring-opening reduction of THF, we report that crystallographically-characterizable Ln(ii) complexes of Tb and Ho can be isolated by reducing CpMe3Ln(THF) with KC8 in THF in the presence of 18-crown-6 (18-c-6). X-ray crystallography revealed that these complexes are isolated with a methylcyclopentadienide inverse sandwich countercation: [(18-c-6)K(MU-CpMe)K(18-c-6)][CpMe3Ln] (Ln = Tb, Ho). Although reduction of CpMe3Ln with potassium in the presence of the 2.2.2-cryptand (crypt) chelate has not generally provided fully-characterizable, crystalline products, in the case of Dy, crystals of [K(crypt)][CpMe3Dy] could be isolated. PMID- 30460966 TI - Climate Change and Infectious Diseases: The Next 50 Years. PMID- 30460967 TI - Antenatal Anxiety: Prevalence and Patterns in a Routine Obstetric Population. AB - INTRODUCTION: Expectant mothers may appear anxious even during healthy pregnancies. Unfortunately, little is known about antenatal anxiety, and affected women may remain undetected and untreated. This study aimed to examine the prevalence, incidence, course and associations of high state anxiety in routine obstetric care. MATERIALS AND METHODS: This was an observational prospective cohort study at a large maternity unit. Obstetric outpatients with low-risk singleton pregnancies were recruited during first trimester consultations. Participants provided sociodemographic data and completed the State-Trait Anxiety Inventory (STAI) and Edinburgh Postnatal Depression Scale. The STAI was re administered at each subsequent trimester. RESULTS: Prevalence and incidence of high state anxiety among 634 completers were 29.5% (95% CI 25.6%-33.6%) and 13.9% (95% CI 9.9%-18.0%), respectively. Anxiety was persistent in 17.0% (95% CI 14.3% 20.2%) and transient in 26.3% (95% CI 23.1%-29.9%). Only persistently anxious participants had high mean second trimester state anxiety scores. Odds for anxiety of greater persistence increased by 29% (95% CI 24%-35%) per 1-point increase in first trimester depression scores, and decreased by 36% (95% CI 7% 56%) with tertiary education. CONCLUSION: Antenatal anxiety symptoms are common even in normal pregnancies, especially among women with depression and lower education. Our study indicates value in exploring diagnostic criteria and quantitative measures for antenatal anxiety. PMID- 30460968 TI - Five-Year Review of Patients Presenting with Non-Accidental Injury to a Children's Emergency Unit in Singapore. AB - INTRODUCTION: There is an increasing trend of physical child abuse cases reported in Singapore. Children presenting to the Emergency Department with injuries require a high index of suspicion for clinicians to distinguish those that are abusive in nature. MATERIALS AND METHODS: A retrospective study of children with diagnosis of NAI presenting to KK Women's and Children's Hospital (KKH) from June 2011 to May 2016 was conducted. RESULTS: There were 1917 cases reported from 1730 subjects, of which: 8.8% of subjects had repeat visits; 55.2% of cases were male; and mean age was 7.69 years. Racial demographics were: Chinese 45.5%, Malay 33.4%, Indian 15.4% and Others 5.9%. The most frequent injuries sustained were head and neck (50.8%), limbs (32.2%), and chest (5.7%). Of the type of injuries, 55% had contusions, 21% had cane marks, 16% had lacerations, 4.4% had burn marks and 1% sustained fractures. Males were more likely to be caned (P <0.001); 54.9% of cases were admitted and 38.9% were discharged. Cases that presented without a parent (P <0.001), were known to Child Protective Service (P <0.001), or had a history of parental substance abuse (P = 0.038), mental illness in caregiver (P = 0.021), or domestic violence (P <0.001) were more likely to require admission. CONCLUSION: Analysing these factors provide a better understanding of the presentation of NAI cases, including 'red flags' and vulnerable groups who should have better protection. PMID- 30460969 TI - Periorbital Cellulitis in Paediatric Emergency Medicine Department Patients. PMID- 30460970 TI - Bicycle-Related Injuries in Paediatric Patients. PMID- 30460971 TI - Papular Purpuric Glove and Socks Syndrome with Evolution into Pemphigus Vulgaris. PMID- 30460972 TI - Patient-Surrogate Agreement in Advance Care Planning: Who Are the Surrogates and Are They Making the Right Decisions? PMID- 30460973 TI - Pulmonary thromboendarterectomy in a combined thrombophilia patient. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is a potentially correctable cause of secondary pulmonary hypertension. Surgical treatment remains the primary treatment for patients with CTEPH. Pulmonary thromboendarterectomy (PEA) with deep hypothermic circulatory arrest is the standard and recommended surgical technique for the treatment of these patients. The prevalence of CTEPH after an acute pulmonary thromboembolism (PTE) has been found in various studies to be between 0.6 and 8.8%. Mortality rates in elective PEA cases with CTEPH are reported to be between 1.9 and 4.5%. We report on a 50-year-old female patient with combined inherited thrombophilia, including protein C and protein S deficiencies, who was diagnosed with CTEPH and was successfully treated with pulmonary thromboendarterectomy. PMID- 30460974 TI - Intracoronary or intravenous abciximab after aspiration thrombectomy in patients with STEMI undergoing primary percutaneous coronary intervention. AB - OBJECTIVE: To test whether aspiration thrombectomy with intracoronary (IC) instead of intravenous (IV) administration of abciximab could reduce the no reflow phenomenon in patients undergoing primary percutaneous intervention (PCI) for ST-elevation myocardial infarction (STEMI). BACKGROUND: Despite recanalisation with PCI, failure to restore microvascular flow may affect the prognosis of patients with STEMI. A combination of aspiration thrombectomy with IC abciximab may improve distal perfusion. METHODS: After aspiration thrombectomy during primary PCI for STEMI, 160 patients were randomly assigned to either an IV or IC abciximab bolus delivered through the aspiration catheter, both followed by a 12-hour IV abciximab infusion. RESULTS: ST-segment resolution >= 70% was achieved in 36 of 78 patients with IC versus 30 of 82 patients with IV abciximab (46.1 vs 36.6%, p = 0.368), and partial resolution in 28 of 78 versus 31 of 82 patients (35.9 vs 37.8%, p = 0.368). Postprocedural myocardial blush grade (MBG) 3 was obtained in 62.8 vs 63.4% (p = 0.235) and MBG >= 2 in 89.7 vs 81.7% (p = 0.148) of patients given IC and IV abciximab, respectively. There were three deaths in each group (3.8%). Major adverse cardiac events occurred in six of 78 patients given the IC and seven of 82 patients given the IV abciximab bolus (7.6 vs 8.5%, p = 0.410). One stroke occurred in each group, and two patients in the IC and nine in the IV group developed renal failure (2.5 vs 10.9%, p = 0.414). CONCLUSIONS: IC versus IV abciximab did not enhance myocardial reperfusion in non selected patients with STEMI undergoing primary PCI after aspiration thrombectomy had successfully been performed. PMID- 30460975 TI - Functional Trajectories of Persons with Cardiovascular Disease in Late Life. AB - OBJECTIVES: Physical function declines with aging and is accelerated for persons with cardiovascular disease (CVD). While CVD increases the risk of functional decline in late life, little is known about differences in trajectories of functional decline. To determine whether there is more than 1 trajectory of functional decline in Americans with cardiovascular disease (CVD) who are functionally independent. DESIGN: Secondary analysis of National Health and Aging Trends Study (NHATS). Latent class growth modeling was used to estimate trajectories of function over 4 years of follow-up. SETTING: Annual structured in home interviews. PARTICIPANTS: Americans aged 65 and older with CVD who were functionally independent at baseline (N = 392). MEASUREMENTS: We compared trajectories of function in individuals with CVD with trajectories of those without and examined the association between risk factors (sex, age at baseline, education level, comorbidity) and trajectory group membership. Function was measured using the Short Physical Performance Battery. RESULTS: Three functional trajectories emerged: rapid functional decline (23.8%), gradual functional decline (44.2%), and stable function (32.0%). Similar trajectories were seen for those without CVD, with a smaller proportion in the rapid functional decline group (16.2%). Women, older participants, and those with less education and greater comorbidity were less likely to be in the stable function group than the rapid functional decline group. CONCLUSION: Although function declines in late life for independently functioning persons with CVD, some individuals remain stable, and others decline gradually or rapidly. Persons with CVD were more likely to experience rapid functional decline than those without, suggesting that CVD increases the risk of rapid functional decline. Risk factors predicted functional trajectory group membership, not just overall decline. PMID- 30460976 TI - The 11-item and 14-item versions of the Altman Self-Rating Mania Scale (ASRM). AB - The Altman Self-Rating Mania Scale (ASRM) was originally published in 1997 as a self-rated measure aimed at assessing the severity of manic symptoms [1]. The published ASRM consists of the following five symptom items: i) elevated mood, ii) Increased self-esteem, iii) decreased need for sleep, iv) pressured speech, and v) psychomotor agitation, which are rated by the patients via endorsement of one of five statements ranging from 0 (symptom not present) to 4 (symptom present in severe degree) [1]. This article is protected by copyright. All rights reserved. PMID- 30460977 TI - Effect of renin-angiotensin-aldosterone system blocking agents on progression of glomerulopathy in sickle cell disease. AB - Although renin-angiotensin-aldosterone system (RAAS) blocking agents decrease albuminuria in short-term studies, there is no evidence confirming their long term efficacy in sickle cell disease (SCD). In a single-centre, retrospective study, we evaluated the long-term effect of RAAS blocking agents on proteinuria and declining estimated glomerular filtration rates (eGFR). Eighty-six patients on RAAS blocking agents for proteinuria, followed for a median of 2.28 years, were compared with 68 patients with proteinuria followed for 2.24 years who were not receiving such treatment. The log odds of proteinuria decreased over time in patients on RAAS blocking agents (beta: -0.23, P = 0.03) and in the non-treatment group (beta: -0.54, P < 0.0001), but was not statistically different between both groups (beta: 0.31, P = 0.063). The eGFR declined over time in patients on RAAS blocking agents (beta: -2.78, P < 0.0001) and in those not on such treatment (beta: -4.7, P < 0.0001), and was statistically different between both groups (beta: 1.9, P = 0.0002). Baseline eGFR was associated with mortality (Hazard rato: 0.97, P < 0.0001), but RAAS blocking agents had no significant effect on mortality. These data suggest that RAAS blockade may slow the loss of kidney function in SCD. PMID- 30460978 TI - Independent Association Between Cardio-Ankle Vascular Index and Sarcopenia in Older U.K. Adults. AB - OBJECTIVES: To investigate the correlation between sarcopenia and arterial stiffness in Caucasians, centering on the relationship between skeletal mass index (SMI) and the cardio-ankle vascular index (CAVI) to assess the use of CAVI in predicting sarcopenia. DESIGN CROSS-SECTIONAL SETTING: United Kingdom. PARTICIPANTS: UK adults aged 45 years and over (N = 366, n = 177 male, n = 189 female). MEASUREMENTS: Bioimpedance analysis was used to derive SMI. CAVI score was calculated using a vascular screening system. Handgrip strength was measured using a standard dynamometer. RESULTS: Average CAVI was significantly correlated with SMI (correlation coefficient (r) = -0.285, p < .001), with higher correlation in women (r = -0.416, p < .001) than men (r = -0.214, p = .01). CAVI had the highest correlation with SMI from appendicular muscle (fat-free mass in men, r = -0.253, p = .002; predicted muscle mass in women, r = -0.436, p < .001). There was a significant difference in average CAVI between groups, with participants who were not sarcopenic having lower CAVI (8.98) than those who were sarcopenic (9.80) (p < .001, t-test). Linear regression was performed using SMI as the dependent variable. After adjustment for age, average CAVI was a significant predictor of SMI in women (beta = -0.332, p < .001) but not men. CONCLUSION: Indices of sarcopenia are independently associated with a higher CAVI, with greater correlation in women than men. The CAVI can be used to assess overall vascular compliance and may be a useful operator-independent tool that can be used to measure sarcopenia and its cardiovascular implications in older adults. PMID- 30460979 TI - Risk factors affecting outcome of unrelated cord blood transplantation for children with familial haemophagocytic lymphohistiocytosis. AB - Allogeneic haematopoietic stem cell transplantation is still the only available curative option for Familial Haemophagocytic Lymphohistiocytosis (FHLH). Most studies report outcomes after bone marrow or peripheral blood stem cell transplantation. We analysed the outcomes of 118 children with FHLH undergoing single-unit umbilical cord blood transplantation performed from 1996 to 2014. Myeloablative conditioning regimen was given to 90% of the patients, and was mostly busulfan-based (n = 81, 76%), including anti-thymocyte globulin or alemtuzumab (n = 102, 86%). The cumulative incidence of Day 60 neutrophil engraftment was 85%; and that of non-relapse mortality and acute graft-versus host disease (GvHD) was 21% and 33% at 100 days, respectively. The 6-year cumulative incidence of chronic GvHD was 17% and the 6-year probability of overall survival was 55%. In multivariate analysis, children receiving a graft with a total nucleated cell dose greater than 9.9 * 107 /kg had a better overall survival (hazard ratio [HR]: 0.49, 95% CI: 0.27-0.88, P = 0.02). Degree of human leucocyte antigen (HLA) matching was associated with improved disease-free survival (5/6 vs. 6/6 HR: 2.11, 95% confidence interval [CI]: 1.01-4.4, P = 0.05 and <=4/6 vs. 6/6, HR: 2.82, CI: 1.27-6.23, P = 0.01). Umbilical cord blood transplantation with a high cell dose and good HLA match is a suitable alternative option to haematopoietic stem cell transplantation in children with FHLH who lack a HLA-matched donor. PMID- 30460980 TI - Outcome of patients aged 80 years or older treated for chronic lymphocytic leukaemia. AB - Clinical management of chronic lymphocytic leukaemia (CLL) in patients aged >=80 years is based on limited evidence due to the lack of published information. Therefore, we analysed CLL patients aged >=80 years using data from seven phase III clinical trials of the German CLL Study Group. Among 3552 participants, 152 were >=80 years old at initiation of first-line study treatment. Median age was 82 years (range 80-90). Concomitant diseases were present in 99% of the patients, with a median cumulative illness rating scale score of 8 (0-18). Chemoimmunotherapy with chlorambucil-obinutuzumab (CLB-OB) or chlorambucil rituximab (CLB-R) was administered to 61 (40%) and 56 (37%) patients. The remaining patients received CLB (n = 19) or fludarabine (F, n = 10), F/cyclophosphamide (FC, n = 1), FC/rituximab (FCR, n = 2) or bendamustine/rituximab (BR, n = 3). Rates of grade 3 or 4 neutropenia and infections were 35% and 13%. Overall response rate was 77% with 13% complete remissions. Median progression-free survival and treatment-free survival were 17.2 and 32.3 months, respectively. Median overall survival was 48.3 months; adverse events (22%) and progressive CLL (16.4%) were the most frequent causes of death. These findings suggest that anti-leukaemic treatment including chemoimmunotherapy is feasible and efficacious in >=80-year-old CLL patients. However, this group of patients lives for a shorter time than age-matched controls of the general population. PMID- 30460982 TI - Airway management research: a systematic review. AB - Recent controversy regarding the ethics of conducting airway research in patients led to disagreements concerning the value and frequency of manikin-based investigation. However, no formal examination of the methodology of airway research has been undertaken. We, therefore, performed a systematic bibliometric review of airway management research to describe the conduct, quantify the subjects (patient vs. manikin vs. other), assess the reported outcomes and map global trends. We retrieved 1505 relevant studies published between 2006 and 2017, together recruiting 359,648 subjects, of which 341,233 were patients, the remaining being volunteers or subjects managing manikins, human cadavers, animals or bench models. There were 701 randomised controlled clinical trials (46.6%), 83 non-randomised experimental clinical trials (5.5%), 298 observational studies (19.8%) and 423 non-patient studies (28.1%). A total of 1082 studies (71.9%) were patient studies and 322 were manikin studies (21.4%). The total annual number of airway management studies increased over time, as did the annual number of patient studies, but there was no significant increase in the annual number of manikin studies over time. Of the patient studies, subject baseline characteristics were most likely to be ASA status 1-2 (n = 531, 49.1%), populations were most often elective surgical patients (n = 918, 84.8%) and the most common interventions studied were tracheal intubation (n = 820, 54.4%) or supraglottic airway device insertion (n = 257, 17.1%). There was a total of 77 different primary outcomes used in the included studies, the most commonly reported being success rate and procedure time. By understanding how and what has been previously studied these data can be used to form the basis for future priority setting exercises, core outcome set development, and could inform strategy on the future directions of airway management research. PMID- 30460983 TI - Glomulin gene c.157_161del mutation in a family with multiple glomuvenous malformations. PMID- 30460981 TI - Preventing Postoperative Delirium After Major Noncardiac Thoracic Surgery-A Randomized Clinical Trial. AB - OBJECTIVES: To assess the efficacy of haloperidol in reducing postoperative delirium in individuals undergoing thoracic surgery. DESIGN: Randomized double blind placebo-controlled trial. SETTING: Surgical intensive care unit (ICU) of tertiary care center. PARTICIPANTS: Individuals undergoing thoracic surgery (N=135). INTERVENTION: Low-dose intravenous haloperidol (0.5 mg three times daily for a total of 11 doses) administered postoperatively. MEASUREMENTS: The primary outcome was delirium incidence during hospitalization. Secondary outcomes were time to delirium, delirium duration, delirium severity, and ICU and hospital length of stay. Delirium was assessed using the Confusion Assessment Method for the ICU and delirium severity using the Delirium Rating Scale-Revised. RESULTS: Sixty-eight participants were randomized to receive haloperidol and 67 placebo. No significant differences were observed between those receiving haloperidol and those receiving placebo in incident delirium (n=15 (22.1%) vs n=19 (28.4%); p = .43), time to delirium (p = .43), delirium duration (median 1 day, interquartile range (IQR) 1-2 days vs median 1 day, IQR 1-2 days; p = .71), delirium severity, ICU length of stay (median 2.2 days, IQR 1-3.3 days vs median 2.3 days, IQR 1-4 days; p = .29), or hospital length of stay (median 10 days, IQR 8-11.5 days vs median 10 days, IQR 8-12 days; p = .41). In the esophagectomy subgroup (n = 84), the haloperidol group was less likely to experience incident delirium (n=10 (23.8%) vs n=17 (40.5%); p = .16). There were no differences in time to delirium (p = .14), delirium duration (median 1 day, IQR 1-2 days vs median 1 day, IQR 1-2 days; p = .71), delirium severity, or hospital length of stay (median 11 days, IQR 10-12 days vs median days 11, IQR 10-15 days; p = .26). ICU length of stay was significantly shorter in the haloperidol group (median 2.8 days, IQR 1.1-3.8 days vs median 3.1 days, IQR 2.1-5.1 days; p = .03). Safety events were comparable between the groups. CONCLUSION: Low-dose postoperative haloperidol did not reduce delirium in individuals undergoing thoracic surgery but may be efficacious in those undergoing esophagectomy. PMID- 30460984 TI - Exogenous IL-19 attenuates acute ischemic injury and improves survival in male mice with myocardial infarction. AB - BACKGROUND AND PURPOSE: Myocardial infarction (MI) is one of the leading causes of death in China and often results in the development of heart failure. In this work, we tested the therapeutic role of Interleukin-19 (IL-19) in mice with MI and investigated the underlying molecular mechanism. EXPERIMENTAL APPROACH AND KEY RESULTS: Protein expression of IL-19 and its receptor in myocardium were upregulated 24 hrs post-MI in male mice. Male mice were injected i.p. with 10ng/g murine recombinant IL-19 immediately after surgery of MI, and it was found that IL-19 treatment decreased infarct and apoptosis in myocardium, accompanied by enhanced heme oxygenase-1 (HO-1) activities and reduced malondialdehyde (MDA) formation. Pretreatment with IL-19 upregulated HO-1 expression in cultured neonatal mouse ventricular myocytes and attenuated oxygen-glucose deprivation (OGD)-induced injuries in vitro. Furthermore, IL-19 preserved cardiac function and improved survival of mice with MI. IL-19 reduced inflammatory infiltrates and suppressed formation of TNF-alpha, IL-1beta, and IL-6. More importantly, IL-19 inhibited polarization toward proinflammatory M1 macrophages and stimulated M2 macrophage polarization in myocardium of mice with MI. IL-19 enhanced protein levels of vascular endothelial growth factor (VEGF) and promoted angiogenesis in myocardium of mice with MI. In addition, IL-19 treatment increased DNA-binding activity of activator of transcription 3 (STAT3) in myocardium of mice with MI. CONCLUSIONS AND IMPLICATIONS: IL-19 attenuated acute ischemic injury and improved survival of mice with MI, and the mechanisms involved induction of HO-1, M2 macrophage polarization, angiogenesis, and STAT3 activation. PMID- 30460985 TI - A retrospective review of patients with Kaposi's sarcoma in Botswana. AB - BACKGROUND: Despite widespread antiretroviral coverage in Botswana, Kaposi's sarcoma (KS) remains among the most common malignancies. To date, adult KS in Botswana is not well characterized. The diagnosis relies on clinical suspicion that is often confirmed by histopathology given the implications of treatment; however, this poses a significant resource burden. METHODS: We conducted a retrospective review of the cohort of patients biopsied for possible KS at Princess Marina Hospital, the main dermatology referral site in Botswana, from September 2008 through June 2015 to describe the demographics, human immunodeficiency virus (HIV) characteristics, and clinical presentations of these patients. Histopathologic diagnoses were reviewed, and positive predictive value (PPV) was used to characterize the accuracy of clinical suspicion of KS. RESULTS: A total of 441 patients received 450 biopsies where KS was on the differential diagnosis, and 239 patients (54%) were ultimately diagnosed with KS. The KS cohort was more likely to be male (58% vs. 37%, P < 0.001), HIV positive (94% vs. 85%, P < 0.05), and have lower CD4 counts at the time of biopsy (274 cells/MUl vs. 362 cells/MUl, P < 0.05). The PPV of clinical suspicion of KS was 58%. When KS was not histopathologically diagnosed, clinically benign diseases were found in 17%, medically significant conditions requiring alternative therapies in 78%, and life-threatening diseases in 5%. DISCUSSION: Our study reinforces the risk factors in development of KS. The poor PPV supports the important role of histology in KS diagnosis to both ensure appropriate treatment and prevent overtreatment. Improved accessibility to biopsy and augmentation of local dermatopathologic services would likely improve diagnostic accuracy and treatment. PMID- 30460986 TI - The role of the Histamine H4 receptor in atopic dermatitis and psoriasis. AB - Atopic dermatitis (AD) and psoriasis are common skin diseases with a high negative impact on patients' quality of life. Both diseases are mediated by a pro inflammatory infiltrate consisting of various cell types like T cells, antigen presenting cells and granulocytes and display disturbed keratinocyte differentiation. Given the fact that histamine levels are also highly elevated in inflamed skin, it is likely that histamine plays a relevant role in disease pathology. However, antagonists blocking histamine H1 receptor (HRH1) and HRH2 are largely ineffective in reducing chronic symptoms in AD and psoriasis. Over the last years a lot of research was undertaken to shed light into the mode of action of the latest discovered HRH4. Thereby it could be shown that HRH4 antagonists display anti-pruritic as well as anti-inflammatory effects not only in mouse models but also in first human clinical trials and therefore the HRH4 might present a novel therapeutic target. In this review we summarize the impact of the HRH4 on different cell types, mouse models as well as clinical studies in regard to AD and psoriasis, respectively. PMID- 30460987 TI - Agency of internal transnationalism in social memory. AB - The article examines the limitations of methodological nationalism in the studies of social memory through a case study of memory of Stalinist repression in Belarus. It analyses how various social agencies - national and local activists, religious organisations, and international foundations - use the memory of repression for constructing post-Soviet Belarusian identity by embedding their national representations in larger transnational frameworks. Drawing on the concept of 'internal globalisation', this article develops the idea of 'internal transnationalism' that suggests the importance of wider transnational configurations for the definition of nation. Internalized transnationalism does not make a national memory concept less nation-centred, but it affects the choice of its cultural, political and civilizational framing. In contrast to methodological cosmopolitanism that implies rediscovering of the national as an internalized global, methodological transnationalism emphasizes the multiplicity of co-existing transnational networks that can be invoked by social actors in their national mnemonic agenda. Using the case of the Kurapaty memorial site the article analyses how multiple framings of memory representations - the Belarusian national memory, liberal anti-communist memory, contesting memories, such as Polish, Baltic and Jewish - compete and juxtapose in the space of social memory of political repression. PMID- 30460988 TI - Drugs with a stigma: thoughts regarding a recent publication, "One of the Best Treatments for Alopecia Areata Remains Unpublished". PMID- 30460989 TI - Superficial granulomatous pyoderma in a patient with ulcerative colitis successfully treated with cyclosporine A. PMID- 30460990 TI - A dynamic and multifunctional account of middle-range theories. AB - This article develops a novel account of middle-range theories for combining theoretical and empirical analysis in explanatory sociology. I first revisit Robert K. Merton's original ideas on middle-range theories and identify a tension between his developmental approach to middle-range theorizing that recognizes multiple functions of theories in sociological research and his static definition of the concept of middle-range theory that focuses only on empirical testing of theories. Drawing on Merton's ideas on theorizing and recent discussions on mechanism-based explanations, I argue that this tension can be resolved by decomposing a middle-range theory into three interrelated and evolving components that perform different functions in sociological research: (i) a conceptual framework about social phenomena that is a set of interrelated concepts that evolve in close connection with empirical analysis; (ii) a mechanism schema that is an abstract and incomplete description of a social mechanism; and (iii) a cluster of all mechanism-based explanations of social phenomena that are based on the particular mechanism schema. I show how these components develop over time and how they serve different functions in sociological theorizing and research. Finally, I illustrate these ideas by discussing Merton's theory of the Matthew effect in science and its more recent applications in sociology. PMID- 30460991 TI - A sequence conserved between CD5 and CD6 binds a FERM domain and exerts a restraint on T cell activation. AB - CD5 and CD6 are related surface receptors which limit and promote T cell responses. Costimulatory effects of CD6 depend on binding a cell surface ligand, CD166 and recruitment of intracellular adaptor proteins GADS and SLP-76 by C terminal phosphotyrosines. We have continued to identify interactions of CD5 and CD6 to understand their roles in T cell activation. In a screen to identify binding partners for peptides containing a cytoplasmic sequence, SDSDY conserved between CD5 and CD6, we identified ezrin radixin moesin (ERM) proteins which link plasma membrane proteins to actin. Purified radixin FERM domain bound directly to CD5 and CD6 SDSDY peptides in a phosphorylation dependent manner (KD =0.5-2 MUM) at 370 C. In human T cell blasts, mutation of the CD6 SDSDY sequence enhanced CD69 expression in response to CD3 mAb. In this proximal readout, interactions of the SDSDY sequence were dominant compared with the C-terminal tyrosines of CD6. In contrast, in a more downstream readout, Il-2 expression, in response to immobilised CD3 and CD6 mAbs, the C-terminal tyrosines were dominant. The data suggest that varying functional effects of CD6 and potentially, CD5 depend on interactions of different cytoplasmic regions with the cytoskeleton and which alter depending on the stimuli. This article is protected by copyright. All rights reserved. PMID- 30460992 TI - Paediatric anthracycline-induced cardiotoxicity: mechanisms, pharmacogenomics and pluripotent stem cell modelling. AB - Anthracycline-induced cardiotoxicity (ACT) is a severe adverse drug reaction for a subset of children treated with anthracyclines as part of chemotherapy protocols. The identification of genetic markers associated with increased ACT susceptibility has clinical significance towards improving patient care and our understanding of the molecular mechanisms involved in ACT. Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) represent a novel approach to determine the pharmacogenomics of ACT and guide the development of genetic screening tests. This article is protected by copyright. All rights reserved. PMID- 30460993 TI - The importance of the Neutral Theory in 1968 and 50 years on: a response to Kern and Hahn 2018. AB - A recent article reassessing the Neutral Theory of Molecular Evolution claims that it is no longer as important as is widely believed. The authors argue that "the neutral theory was supported by unreliable theoretical and empirical evidence from the beginning, and that in light of modern, genome-scale data, we can firmly reject its universality." Claiming that "the neutral theory has been overwhelmingly rejected," they propose instead that natural selection is the major force shaping both between-species divergence and within-species variation. Although this is probably a minority view, it is important to evaluate such claims carefully in the context of current knowledge, as inaccuracies can sometimes morph into an accepted narrative for those not familiar with the underlying science. We here critically examine and ultimately reject Kern and Hahn's arguments and assessment, and instead propose that it is now abundantly clear that the foundational ideas presented five decades ago by Kimura and Ohta are indeed correct. PMID- 30460994 TI - Myiasis incidences reported in and around central province of Sri Lanka. AB - BACKGROUND: Myiasis, or the invasion of living tissues of humans and other mammals by dipterous larvae, is considered the world's fourth most common travel associated skin disease after cutaneous larval migrants, pyodermas, and pruritic arthropod-reactive dermatitis. METHOD: The present study recorded the cause, anatomical position, and severity of the wounds of myiasis patients admitted to 11 hospitals located in the central region of Sri Lanka from February 2016 to July 2017. RESULTS: Altogether, 28 myiasis incidences were noted within the study period. Of the total identified myiasis patients, nine were female while the remainder were male. The greatest number of patients was recorded from the Mawanella Base Hospital and Peradeniya Teaching Hospital (seven patients each). The ages of recorded patients ranged between 30 and 92 years with the average being 59.4 years. The greatest number of myiasis cases was diagnosed in wounds located in lower limbs (24). In addition, scalp, urogenital, and umbilical infestations were recorded. Eighteen out of the total patients had diabetes mellitus, and two patients suffered from filarial lymphedema. Psychiatric illnesses were a predisposing factor of larval infestation of six patients including the recorded scalp and two urogenital myiasis patients. Of the 28 myiasis cases, 27 were caused by the old world screwworm, Chrysomya bezziana Villeneuve (Diptera: Calliphoridae), and one by the blowfly, Chrysomya megacephala Fabricius (Diptera: Calliphoridae). CONCLUSION: The awareness of patients with ulcers about this disease helps to decrease further risk of being infected by fly larvae. PMID- 30460995 TI - Prevalence of skin diseases among hospitals in the public healthcare system of a developing country. AB - BACKGROUND: Skin diseases in the population are universal, common, and can cause significant economic burden. The impact of skin diseases in the national public healthcare system is complex and poorly studied. This study analyzes the prevalence of skin diseases in a hospital setting within the National Public Health System of Mexico and describes the main associated characteristics. METHODS: Information was obtained from the 2015 hospital discharge database of the public healthcare system of Mexico. Pathologies that result in a direct dermatological condition were included according to chapter XII of the Tenth Revision of the International Statistical Classification of Diseases and Related Health Problems (ICD - 10) and grouped according to the classification of the report, The burden of skin diseases in the United States. RESULTS: In 2015, a total of 9,230,968 hospital discharges were registered nationwide, of which 170,917 discharges (1.85%) reported a dermatological disease as the main diagnosis; five states account for 40.79% of the cases reported in Mexico. Half of all the cases corresponded to skin infections (32.08%, n = 54,843) and non cancerous skin growths (27.80%, n = 47,515), and 59.71% were adult patients between 18 and 65 years of age. CONCLUSIONS: Understanding of the configuration of skin diseases in a hospital setting and public healthcare system is warranted to develop effective public policies and research for the development of effective, safe, high-quality care processes for the main groups of identified diseases. PMID- 30460996 TI - Bioequivalance and therapeutic equivalence of generic and brand bupropion in adults with major depression: A randomized clinical trial. AB - Controversy persists about bupropion XL300mg generic equivalence to brand product. A prospective, randomized, double-blinded, crossover in 70 adults with major depression in stable remission taking any bupropion XL300mg tested bioequivalence and therapeutic equivalence of available XL300mg products. After 4 week lead-in on patients' existing bupropion, four 6-week phases evaluated brand and three generics. Patients were uninformed of switching. Drug overencapsulation ensured blinding. There were no differences between any generic and brand, or between generics, in plasma Cmax and AUC0-24 for racemic bupropion or major metabolites. All generics met formal bioequivalence criteria for bupropion and metabolites. There were no differences between generics and brand, or between generics, in depression symptoms or side effects, assessed by every 3-week in person interviews and daily smartphone-based self-report. There were no differences in patients' perceptions of bupropion products. Results show three bupropion XL300mg generic products both bioequivalent and not therapeutically different from brand drug and each other. This article is protected by copyright. All rights reserved. PMID- 30460997 TI - Identifiability of biologicals in adverse drug reaction reports received from European clinical practice. AB - Biologicals are established treatment options that require pharmacovigilance adapted to their specific nature, including the need for products to be identifiable up to the specific manufacturer in reports of adverse drug reactions (ADRs). This study explored the identifiability of ten classes of similar and related biologicals up to the level of the manufacturer in ADR reports received from European clinical practice between 2011 and June 2016. Adequate identifiers were reported for 96.7% of the suspected biologicals, ranging from 89.5% for filgrastim to 99.8% for interferon beta-1a. The product identifiability remained consistently high over time for classes of biologicals for which biosimilars were introduced during follow-up. The overall batch traceability was however only ensured for 20.5% of the suspected biologicals and needs further improvement. This study shows that the EU system for identification of ADRs to the level of the manufacturer is robust, allowing for the timely detection of potential product-specific safety signals for biologicals. This article is protected by copyright. All rights reserved. PMID- 30460998 TI - The convergent evolution of snake-like forms by divergent evolutionary pathways in squamate reptiles. AB - Convergent evolution of phenotypes is considered evidence that evolution is deterministic. Establishing if such convergent phenotypes arose through convergent evolutionary pathways is a stronger test of determinism. We studied the evolution of snake-like body shapes in six clades of lizards, each containing species ranging from short-bodied and pentadactyl to long-bodied and limbless. We tested whether body shapes that evolved in each clade were convergent, and whether clades evolved snake-like body shapes following convergent evolutionary pathways. Our analyses showed that indeed species with the same numbers of digits in each clade evolved convergent body shapes. We then compared evolutionary pathways among clades by considering patterns of evolutionary integration and shape of relationship among body parts, patterns of vertebral evolution, and models of digit evolution. We found that all clades elongated their bodies through the addition, not elongation, of vertebrae, and had similar patterns of integration. However, patterns of integration, the body parts that were related by a linear or a threshold model, and patterns of digit evolution differed among clades. These results showed that clades followed different evolutionary pathways. This suggests an important role of historical contingency as opposed to determinism in the convergent evolution of snake-like body shapes. PMID- 30461000 TI - Snapshot quiz. PMID- 30460999 TI - Sex differences in faecal occult blood test screening for colorectal cancer. AB - BACKGROUND: This analysis of patients in a randomized population-based health services study was done to determine the effects of faecal occult blood test (FOBT) screening of colorectal cancer (CRC) in outcomes beyond mortality, and to obtain explanations for potential sex differences in screening effectiveness. METHODS: In the Finnish FOBT screening programme (2004-2011), people aged 60-69 years were randomized into the screening and control arms. Differences in incidence, symptoms, tumour location, TNM categories, non-vital outcomes and survival in the screening and control arms were analysed. RESULTS: From 321 311 individuals randomized, 743 patients with screening-detected tumours and 617 control patients with CRC were analysed. CRC was less common in women than in men (0.34 versus 0.50 per cent; risk ratio (RR) 0.82, 95 per cent c.i. 0.74 to 0.91) and women were less often asymptomatic (16.7 versus 22.0 per cent; RR 0.76, 0.61 to 0.93). Women more often had right-sided tumours (32.0 versus 21.3 per cent; RR 1.51, 1.26 to 1.80). Among men with left-sided tumours, those in the screening arm had lower N (RR 1.23, 1.02 to 1.48) and M (RR 1.57, 1.14 to 2.17) categories, as well as a higher overall survival rate than those in the control arm. Furthermore among men with left-sided tumours, non-radical resections (26.2 versus 15.7 per cent; RR 1.67, 1.22 to 2.30) and postoperative chemotherapy sessions (61.6 versus 48.2 per cent; RR 1.28, 1.10 to 1.48) were more frequent in the control arm. Similar benefits of screening were not detected in men with right-sided tumours or in women. CONCLUSION: Biennial FOBT screening seems to be effective in terms of improving several different outcomes in men, but not in women. Differences in incidence, symptoms and tumour location may explain the differences in screening efficacy between sexes. PMID- 30461001 TI - Snapshot quiz. PMID- 30461002 TI - Scientific Surgery August 2018 BJS. PMID- 30461004 TI - Corrigenda. PMID- 30461003 TI - Optimizing medical management in peripheral artery disease. PMID- 30461005 TI - Corrigenda. PMID- 30461008 TI - Corrigenda. PMID- 30461009 TI - Preconceptions and awareness of good glycemic control, pregnancy contraindications, and maternal and fetal adverse events in Sudan. AB - OBJECTIVE: to investigate the preconception awareness and attitude of pregnant women with gestational diabetes about glycemic control and complication of diabetes in pregnancy in Sudan. METHOD: A cross-sectional hospital based study was conducted among 119 pregnant women with gestational diabetes at 1st, 2nd and 3rd trimester who had received pregnancy care services at Omdurman Maternity Hospital, Khartoum, Sudan, between January 2016 and June 2017. RESULTS: A total of 119 ladies were enrolled, (49.6%) of the ladies their BMI were between (25 29), Most of the patient had diabetes for 1-5 years (74.4%), women with GDM were (46%), and women with pre-existing DM were (54%). Diabetic women who use insulin were (51%). About (82%) of participants do not know the signs of hypoglycemia. (85%) do not know the effect of diabetes on maternal and fetal outcome. (72%) of participants know well about their insulin dose, and (69%) had no plan to reduce their weight. (73%) of the participants with DM had no regular medical follow up out of pregnancy, (39.4%) of participants had had co-existing disorders in their previous pregnancy other than DM. CONCLUSION: the knowledge among the diabetic Sudanese women about GDM and its complication was low. This article is protected by copyright. All rights reserved. PMID- 30461007 TI - Value of risk scores in the decision to palliate patients with ruptured abdominal aortic aneurysm. AB - BACKGROUND: The aim of this study was to develop a 48-h mortality risk score, which included morphology data, for patients with ruptured abdominal aortic aneurysm presenting to an emergency department, and to assess its predictive accuracy and clinical effectiveness in triaging patients to immediate aneurysm repair, transfer or palliative care. METHODS: Data from patients in the IMPROVE (Immediate Management of the Patient With Ruptured Aneurysm: Open Versus Endovascular Repair) randomized trial were used to develop the risk score. Variables considered included age, sex, haemodynamic markers and aortic morphology. Backwards selection was used to identify relevant predictors. Predictive performance was assessed using calibration plots and the C-statistic. Validation of the newly developed and other previously published scores was conducted in four external populations. The net benefit of treating patients based on a risk threshold compared with treating none was quantified. RESULTS: Data from 536 patients in the IMPROVE trial were included. The final variables retained were age, sex, haemoglobin level, serum creatinine level, systolic BP, aortic neck length and angle, and acute myocardial ischaemia. The discrimination of the score for 48-h mortality in the IMPROVE data was reasonable (C-statistic 0.710, 95 per cent c.i. 0.659 to 0.760), but varied in external populations (from 0.652 to 0.761). The new score outperformed other published risk scores in some, but not all, populations. An 8 (95 per cent c.i. 5 to 11) per cent improvement in the C-statistic was estimated compared with using age alone. CONCLUSION: The assessed risk scores did not have sufficient accuracy to enable potentially life saving decisions to be made regarding intervention. Focus should therefore shift to offering repair to more patients and reducing non-intervention rates, while respecting the wishes of the patient and family. PMID- 30461010 TI - Teaching a perspective-taking component skill to children with autism in the natural environment. AB - We evaluated procedures for teaching three children diagnosed with autism spectrum disorder the perspective-taking component skill of tacting what others are sensing across all five senses: see, taste, feel, hear, and smell. Using a multiple baseline across participants design, we evaluated a training package consisting of multiple exemplar training, reinforcement, and error correction. The treatment package was implemented in the natural environment and was effective for teaching participants to tact what others sensed. Generalization across untrained stimuli and people was observed from baseline to posttraining for all participants. We discuss how this component skill may be related to teaching further skills related to perspective taking such as tacting what others know, predicting future behavior based upon one's beliefs, and creating false beliefs in others for the purpose of adaptive deceptive behaviors such as keeping secrets, surprises, and bluffing during games. PMID- 30461011 TI - Maternal serum vitamin D levels and preterm delivery among low-risk parturients in Lagos, Nigeria. AB - OBJECTIVE: To determine the association between low maternal vitamin D levels and preterm delivery among parturients in Lagos, Nigeria. METHODS: The present study was analytical cross-sectional study of women with preterm deliveries (defined as <37 weeks) and women with term deliveries (defined as >=37 weeks) at the labor unit of Lagos University Teaching Hospital between December 2015 and October 2016. Relevant information was obtained via a proforma, and maternal venous samples were collected immediately after delivery. Serum 25-hydroxy vitamin D was determined by a vitamin D enzyme-linked immunoassay kit. RESULTS: The study enrolled 103 women in each group. The overall prevalence of vitamin D deficiency was 14.1% (29/206). Twenty-four (23.3%) women with preterm delivery had low serum vitamin D (<30 ng/mL) as compared with only 5 (4.9%) women with term delivery (P<0.001). As compared with normal serum vitamin D levels, low maternal vitamin D had an approximately nine-fold higher likelihood of preterm delivery (adjusted odds ratio 9.41, 95% confidence interval 2.42-36.54; P<0.001). CONCLUSION: The prevalence of serum vitamin D deficiency was higher among women with preterm delivery than among those with term delivery. The potential role of prenatal vitamin D supplementation in the prevention of preterm delivery should be further investigated. This article is protected by copyright. All rights reserved. PMID- 30461012 TI - Upregulation of transient receptor potential melastatin 6 channel expression by rosiglitazone and all-trans-retinoic acid in erlotinib-treated renal tubular epithelial cells. AB - Anti-epidermal growth factor receptor (EGFR) drugs including erlotinib cause a side effect of hypomagnesemia. In lung adenocarcinoma A549 cells, anticancer agents such as cisplatin and doxorubicin dose-dependently increased toxicity, but the effects were significantly suppressed by culturing the cells in low Mg2+ containing media. To obtain the maximum effect in cancer chemotherapy, it should be necessary to prevent the reduction of body Mg 2+ content. Anti-EGFR drugs inhibit EGF-induced elevation of transient receptor potential melastatin 6 (TRPM6) Mg 2+ channel in renal tubular epithelial NRK-52E cells. Here, we found that rosiglitazone, an antidiabetic drug, and all- trans-retinoic acid (ATRA), a vitamin A derivative, increase the messenger RNA (mRNA) level of TRPM6 in the presence of erlotinib. The rosiglitazone- and ATRA-induced elevation of mRNA level, Mg 2+ influx, and promoter activity of TRPM6 were inhibited by GW-9662, a potent antagonist of peroxisome proliferator-activated receptor (PPAR)gamma, and LE135, a retinoic acid receptor (RAR) antagonist, respectively. Rosiglitazone increased the phosphorylation and nuclear localization levels of PPARgamma, which were inhibited by GW-9662. In contrast, RAR was mainly distributed in the nuclei under control conditions, which was unchanged by ATRA and LE135. The promoter activity of TRPM6 was inhibited by a mutation in the peroxisome proliferator hormone response element (PPRE). A chromatin immunoprecipitation assay revealed that PPARgamma and RAR bind to the PPRE, which was blocked by GW-9662 and LE135, respectively. These results suggest that rosiglitazone and ATRA reverse the reduction in Mg 2+ reabsorption caused by anti-EGFR drugs. PMID- 30461013 TI - Hypericum perforatum in the treatment of psychiatric and neurodegenerative disorders: Current evidence and potential mechanisms of action. AB - BACKGROUND: Psychiatric disorders are substantially associated with reduced quality of life and increased mortality. Depression and anxiety are two of the most common psychiatric disorders that often co-occur with each other as well as with other mental health conditions. Because of the limitations of currently available antidepressant therapies, there is a need for agents with improved efficacy and less adverse effects. Hypericum perforatum, widely known as St. John's wort, is a perennial herbaceous plant most well known for its antidepressant properties. METHODS: We reviewed the available in vitro, in vivo, and clinical evidence on the efficacy, safety, and mechanisms of action of St. John's wort and its active constituents in the treatment of psychiatric and neurodegenerative disorders. RESULTS: Several interesting data have been reported about the antidepressant properties of H. perforatum in clinical trials with different designs. In particular, a number of antidepressant-controlled trials demonstrated that H. perforatum and its active ingredients, hypericin and hyperforin, possess antidepressant properties similar to those of tricyclic antidepressants and selective serotonin reuptake inhibitors but with fewer and milder side effects. CONCLUSION: St. John's wort may exert potent antidepressant effects and represents an efficacious and safe treatment. However, the current clinical evidence regarding the efficacy of H. perforatum in other psychiatric and neurodegenerative disorders is not sufficient to draw a robust conclusion. PMID- 30461014 TI - Specific knockdown of WNT8b expression protects against phosphate-induced calcification in vascular smooth muscle cells by inhibiting the Wnt-beta-catenin signaling pathway. AB - In the last 10 years, the prevalence, significance, and regulatory mechanisms of vascular calcification (VC) have gained increasing recognition. The aim of this study is to explore the action of WNT8b in the development of phosphate-induced VC through its effect on vascular smooth muscle cells (VSMCs) in vitro by inactivating the Wnt-beta-catenin signaling pathway. To explore the effect of WNT8b on the Wnt-beta-catenin signaling pathway and VC in vitro, beta glycerophosphate (GP)-induced T/G HA-VSMCs were treated with small interfering RNA against WNT8b (Si-WNT8b), Wnt-beta-catenin signaling pathway activator (LiCl) and both, respectively. Reverse transcription quantitative polymerase chain reaction and western blot analysis were used to determine the messenger RNA and protein levels of WNT8b, alpha-smooth muscle actin (alpha-SMA), calcification associated molecules, and molecules related to the Wnt signaling pathway. The TOP/FOP-Flash reporter assay was performed to detect the transcription activity mediated by beta-catenin. Si-WNT8b reduced calcium deposition and the activity of alkaline phosphatase (ALP), increased the alpha-SMA level, and decreased bone morphogenetic protein 2, Pit1, MSX2, and Runt-related transcription factor 2 levels, whereas stimulation of LiCl worsened beta-GP-induced calcium deposition, increased the activity of ALP, and reduced the alpha-SMA expression level. Si WNT8b reduced the levels of WNT8b, frizzled-4, beta-catenin, phospho-GSK-3beta (p GSK-3beta), and cyclin-D, whereas it increased the levels of p-beta-catenin and GSK-3beta, indicating that si-WNT8b could alter the Wnt-beta-catenin signaling pathway and thus hamper the VC in T/G HA-VSMC, which was further demonstrated by the TOP/FOP-Flash assay and detection of the beta-catenin expression level in the nucleus. Altogether, we conclude that WNT8b knockdown terminates phosphate induced VC in VSMCs by inhibiting the Wnt-beta-catenin signaling pathway. PMID- 30461015 TI - Over-under versus medial tympanoplasty: Comparison of benefit, success, and hearing results. AB - OBJECTIVES/HYPOTHESIS: A hybrid variation of a tympanoplasty technique, termed over-under tympanoplasty (OUT), was evaluated to demonstrate the long-term outcomes and complications compared to medial tympanoplasty. STUDY DESIGN: Retrospective review. METHODS: Patients who underwent a tympanoplasty between 2010 and 2015 were included. Primary outcome measures included graft healing at 18 months, change in air-bone gap (ABG), and change in high-frequency hearing at 8 kHz. The Shapiro-Wilk test, Student t test, and nonparametric Mann-Whitney test were used to compare results. Univariate logistic regression analysis was used to identify potential predictors of surgical success. RESULTS: One hundred eleven patients were included; 84 underwent the over-under technique and 27 underwent medial tympanoplasty. At the 18-month follow-up, 100% of patients in the medial tympanoplasty group had closure of the TM perforation compared to 84% (71/84) in the over-under group. In the over-under group, 12% of patients developed small or pinpoint perforations, and 4% developed larger, recurrent perforations. Mean improvement in ABG was similar between the two groups (11.6 dB for the medial group vs. 11.9 dB for the over-under group, P < .001). No hearing loss was noted in either group. No lateralization of the graft or anterior blunting was noted. CONCLUSIONS: In this series, the OUT technique had a high success rate with TM perforations, including anterior, near total, and total perforations. Hearing loss from dissection on the malleus was not found. This approach blends the advantages and minimizes the disadvantages of the classic techniques and is well suited for all types of tympanic membrane perforations. LEVEL OF EVIDENCE: 3b Laryngoscope, 2018. PMID- 30461016 TI - Significance of keratinized mucosa/gingiva on peri-implant and adjacent periodontal conditions in erratic maintenance compliers. AB - BACKGROUND: Given the fact that most patients are not regular compliers in supportive peri-implant maintenance programs, it is of interest to examine the significance of the peri-implant soft tissue characteristics in relationship to the onset of peri-implant diseases. METHODS: Based on an a priori statistical power calculation, a cross-sectional study was conducted on erratic peri-implant maintenance compliers (<2 times/year) to examine the significance of keratinized mucosa (KM) and gingival tissue (KT) on peri-implant and adjacent periodontal conditions in implants restored >=3 years. Seven clinical parameters were recorded around implants and the adjacent buccal sites. Radiographic assessment was performed using periapical X-rays. In addition, a visual analog scale (VAS) was used to evaluate the impact of KM upon brushing comfort. The case definition used for peri-implant diseases was in accordance with the 2017 World Workshop on the classification of periodontal and peri-implant diseases and conditions. RESULTS: Overall, 37 patients with 45 edentulous gaps restored with 66 implants and 90 adjacent teeth were analyzed. On comparing a KM band of <2 mm versus >=2 mm, with the exception of suppuration (P = 0.6), all the clinical and radiographic parameters were significantly increased when the KM band was <2 mm (P < 0.001). A significant correlation was observed between KM and KT (r = 0.55), though a lack of KM did not condition a lack of KT. In the presence of peri implantitis, only bleeding on probing at the adjacent dentate sites was identified to be increased. CONCLUSIONS: The presence of <2 mm of KM around dental implants in erratic maintenance compliers seems to be associated with peri implantitis diseases. The lack of KM constitutes a site-specific phenomenon independent of the keratinized tissue present in the adjacent dentition (NCT03501537). PMID- 30461017 TI - LSD1, EDS1 and PAD4-dependent conditional correlation among salicylic acid, hydrogen peroxide, water use efficiency, and seed yield in Arabidopsis thaliana. AB - In Arabidopsis thaliana, LESION SIMULATING DISEASE 1 (LSD1), ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1), and PHYTOALEXIN DEFICIENT 4 (PAD4) proteins are regulators of cell death in response to abiotic and biotic stresses. Hormones, such as salicylic acid (SA), and reactive oxygen species, such as hydrogen peroxide (H2 O2 ), are key signaling molecules involved in plant cell death. The proposed mathematical model presented in this study suggests that LSD1, EDS1 and PAD4 together with SA and H2 O2 are involved in the regulation of plant water use efficiency (WUE), vegetative growth, and generative development. The analysis of Arabidopsis wild-type and single mutants lsd1, eds1, and pad4, as well as double mutants eds1/lsd1 and pad4/lsd1, demonstrated the strong conditional correlation between SA/H2 O2 and WUE that is dependent on LSD1, EDS1 and PAD4 proteins. Furthermore, we showed that WUE, vegetative biomass accumulation, and seed yield differ significantly in analyzed genotypes depending on the growing conditions, and therefore cannot be described by the same mathematical equation. However, we found a strong correlation between the SA/H2 O2 homeostasis of 4-week-old Arabidopsis leaves and total seed yield of 9-week-old plants. Altogether, our results prove that SA and H2 O2 are conditionally regulated by LSD1/EDS/PAD4 to govern WUE, biomass accumulation, and seed yield. Conditional correlation and the proposed model presented in this study can be used as the starting points in the creation of a plant breeding algorithm that would allow to estimate the seed yield at the initial stage of plant growth, based on WUE, SA, and H2 O2 content. This article is protected by copyright. All rights reserved. PMID- 30461018 TI - A domestication-associated reduction in K+ -preferring HKT transporter activity underlies maize shoot K+ accumulation and salt tolerance. AB - Maize was domesticated from balsas teosinte c. 10000 yr ago. Previous studies have suggested that increased tolerance to environmental stresses have occurred during maize domestication. However, the underlying genetic basis remains largely unknown. We here employ a maize(W22)-teosinte recombinant inbred line (RIL) population to investigate the salt-tolerance aspects of maize domestication. We revealed that ZmHKT2 is a major QTL regulating K+ homeostasis in saline soils. Whilst ZmHKT2 encodes a K+ -preferring HKT family transporter and likely reduces shoot K+ content by removing K+ ions from root-to-shoot flowing xylem sap, ZmHKT2 deficiency increases xylem sap and shoot K+ concentrations, and increases salt tolerance. A coding sequence polymorphism in the ZmHKT2W22 allele (SNP389-G) confers an amino acid variant ZmHKT2 that increases xylem sap K+ concentration, thus increasing shoot K+ content and salt tolerance. Additional analyses showed that SNP389-G first existed in teosinte (allele frequency 56% in assayed accessions), then swept through the maize population (allele frequency 98%), and that SNP389-G likely undergoes positive selection during maize domestication. We conclude that a domestication-associated reduction in K+ transport activity of ZmHKT2 underlies maize shoot K+ content and salt tolerance, and propose that CRISPR-based editing of ZmHKT2 might provide a feasible strategy of improving maize salt tolerance. This article is protected by copyright. All rights reserved. PMID- 30461019 TI - Biologically guided implant therapy: A diagnostic and therapeutic strategy of conservation and preservation based on periodontal staging and grading. AB - Biologically guided implant therapy is based on the new periodontitis classification system recently released by the American Academy of Periodontology and the European Federation of Periodontology that uses Staging and Grading for the diagnosis of periodontitis. This paper proposes that periodontitis Staging and Grading should be used in dental implant therapy as a means to ensure maximum conservation of teeth and maximum preservation of alveolar bone. These biologic principles should guide the treatment planning process and supersede a mechanically based, restoratively driven rationale that should be secondary to the biologic principles of conservation and preservation but part of the collaborative treatment planning process. And treatment alternatives throughout the patient's lifetime should be provided for in case of prosthesis loss due to peri-implantitis. The use of Grading will help with recognition of systemic aspects that can have a negative impact. PMID- 30461020 TI - Dependent scheduling and evidence for melioration. PMID- 30461021 TI - Cash Transfers, Early Marriage, and Fertility in Malawi and Zambia. AB - There is increasing interest in the ability of cash transfers to facilitate safe transitions to adulthood in low-income settings; however, evidence from scaled-up government programming demonstrating this potential is scarce. Using two experimental evaluations of unconditional cash transfers targeted to ultra-poor and labor-constrained households over approximately three years in Malawi and Zambia, we examine whether cash transfers delayed early marriage and pregnancy among youth aged 14 to 21 years at baseline. Although we find strong impacts on poverty and schooling, two main pathways hypothesized in the literature, we find limited impacts on safe transition outcomes for both males and females. In addition, despite hypotheses that social norms may constrain potential impacts of cash transfer programs, we show suggestive evidence that pre-program variation in social norms across communities does not significantly affect program impact. We conclude with policy implications and suggestions for future research. PMID- 30461022 TI - Effect of Partial Hydrolysis with Papain on the Characteristics of Transglutaminase-Crosslinked Tofu Gel. AB - The effects of partial enzymatic hydrolysis of soymilk on the characteristics of transglutaminase (TG)-crosslinked tofu gel were studied. SDS-PAGE showed that the molecular weight of the partially hydrolyzed soybean protein was reduced to that of a digested peptide (less than 43.0 kDa) when papain was added at more than 50 MUL/100 mL soymilk. The content of free sulfhydryls, beta-sheets, and random coils in papain-treated soymilk increased. When TG was added to soy milk after papain treatment and tofu gel was formed, its storage modulus increased from 957.44 to 1241.39 Pa. The gel strength, water-holding capacity, and nonfreezing water content of the tofu gel were greater than those without enzyme treatment. Scanning electron microscopy revealed that limited papain hydrolysis stimulated TG-catalyzed cross-linking of soymilk to form a dense gel network structure, whereas an extended enzymatic hydrolysis of soymilk did not promote crosslinking by TG. PRACTICAL APPLICATION: This work investigated the effect of partial hydrolysis on TG cross-linked tofu gel. Partial hydrolysis of soybean protein with papain can promote TG cross-linking reaction, thus form a dense network structure, increase gel strength, and water-holding capacity. Therefore, it can be used to produce a good gel product with higher gel strength, springiness, water-holding capacity, and a more dense microstructure. PMID- 30461023 TI - Reduction of Phytic Acid in Soymilk by Immobilized Phytase System. AB - In this study, three carriers (glass microsphere, cellulose beads and AlgNa/PVA beads) were evaluated as phytase solid carriers for reduction of phytic acid within soymilk. Phytase was covalently immobilized onto or entrapped within carriers for repeated use. Glass microsphere was chosen due to its high catalytic efficiency. Optimal operating condition (pH 6.0, 60 degrees C) was determined using 4-Nitrophenyl phosphate disodium salt hexahydrate as an indicator. Operational reusability was confirmed for more than seven batch reactions and the storage stability was capable of sustaining 70% of its catalytic activity for 40 days. The kinetic parameters including rate constant (K), time (tau50 ) in which 50% of phytic acid hydrolysis was reached, and time (taucomplete ) required to achieve complete phytic acid hydrolysis, were 0.023 min-1 , 35.7 min, 110 min. The current procedure provides a cheap as well as an easy way to carry out the reduction of phytic acid in soymilk, which has great potential in practical application. PMID- 30461024 TI - Latency of skin conductance responses across stimulus modalities. AB - Reproducibility and methodological robustness are of major concern in research today, also with respect to autonomic measures. Quantification of skin conductance responses (SCRs), for instance, relies on response characteristics such as response onset (i.e., latency), which were established more than four decades ago by using paper-pencil methods. Since then, data acquisition has advanced to digital methods, improving sampling rates up to 100,000 samples/second and thereby improving resolution and accuracy. Here, SCR latency as a major characteristic for defining an appropriate response window is revisited by using state-of-the-art equipment. Furthermore, SCR latencies are investigated across different stimulus modalities (tactile, auditory, visual) and with respect to their temporal dynamics over the course of a learning experiment (i.e., fear conditioning). The established response latency criteria were largely confirmed even though results did suggest an even narrower and potential stimulus modality-specific latency criterion. Exploratory analyses investigating individual differences in SCR latencies provided first evidence for a role of sex and cognitive effects (i.e., contingency awareness) while dispositional negativity as well as other personality traits did not affect SCR latencies. Consequently, SCR latencies might have an informative and discriminative value beyond a solely criterial function for defining response windows. The current findings may help to improve the rigor of using SCRs and suggest that SCR latency as a descriptive measure warrants further investigation. PMID- 30461025 TI - Washing or filtering of blood products does not improve outcome in a rat model of trauma and multiple transfusion. AB - BACKGROUND: Transfusion is associated with organ failure and nosocomial infection in trauma patients, which may be mediated by soluble bioactive substances in blood products, including extracellular vesicles (EVs). We hypothesize that removing EVs, by washing or filtering of blood products, reduces organ failure and improves host immune response. MATERIALS AND METHODS: Blood products were prepared from syngeneic rat blood. EVs were removed from RBCs and platelets by washing. Plasma was filtered through a 0.22-MUm filter. Rats were traumatized by crush injury to the intestines and liver, and a femur was fractured. Rats were hemorrhaged until a mean arterial pressure of 40 mm Hg and randomized to receive resuscitation with standard or washed/filtered blood products, in a 1:1:1 ratio. Sham controls were not resuscitated. Ex vivo whole blood stimulation tests were performed and histopathology was done. RESULTS: Washing of blood products improved quality metrics compared to standard products. Also, EV levels reduced by 12% to 77%. The coagulation status, as assessed by thromboelastometry, was deranged in both groups and normalized during transfusion, without significant differences. Use of washed/filtered products did not reduce organ failure, as assessed by histopathologic score and biochemical measurements. Immune response ex vivo was decreased following transfusion compared to sham but did not differ between transfusion groups. CONCLUSION: Filtering or washing of blood products improved biochemical properties and reduced EV counts, while maintaining coagulation abilities. However, in this trauma and transfusion model, the use of optimized blood components did not attenuate organ injury or immune suppression. PMID- 30461026 TI - The argument(s) for lowering the US minimum required content of apheresis platelet components. PMID- 30461027 TI - Fixed drug eruption caused by fulvestrant confirmed by skin tests: First case. PMID- 30461028 TI - Where did inaction go? Towards a broader and more refined perspective on collective actions. AB - While injustice is widespread, collective action against it appears to be rare. This paper argues that this may be because research often focuses on a narrow range of outgroup-oriented actions, such as demonstrating, signing petitions, that are symbolic of a collective response to injustice. The present work takes a bottom-up approach to study a broad range of collective and individual actions that people undertake in response to collective injustice. Participants indicated actions they felt they could take (Study 1) and, via interviews, actually had taken (Study 2) in response to human-induced earthquakes. These studies revealed a broad range of actions, many of which are collective but ingroup- (e.g., helping ingroup members) rather than outgroup-oriented. Study 3 further conceptualized these collective and individual actions by including quantitative measures thereof in an assessment of responses to stressful life events that were collective or individual. Results revealed that, while traditional forms of collective action are rare, ingroup-oriented and individual level (e.g., social support) responses form distinct dimensions in response to both individual and collective events. This work extends our understanding of responses to collective injustice and suggests the need to broaden the scope of collective action research. PMID- 30461029 TI - Gene-edited plants: What is happening now? PMID- 30461030 TI - Retraction. PMID- 30461031 TI - Right atrial position of a return electrode for bipolar ablation of the left posterosuperior process ventricular tachycardia. AB - INTRODUCTION: Radiofrequency catheter ablation (RFCA) of ventricular tachycardia (VT) is an effective method of treatment. However, when arrhythmia has ischemic etiology and originates from the posterosuperior process (PSP) of the left ventricular (LV) base, ablation performed with conventional unipolar energy sources may be challenging or impossible. METHOD AND RESULT: A 67-year-old male after six unsuccessful RFCA for highly symptomatic VT originating from PSP of LV base underwent successful RFCA using multiple bipolar RF applications delivered between two electrodes located at LV endocardium and adjacent right atrial sites. CONCLUSION: This case report shows that bipolar RFCA can be used for safe and successful treatment of VT originating from deep PSP of LV base. This article is protected by copyright. All rights reserved. PMID- 30461032 TI - Activation of Nrf2/ARE pathway alleviates the cognitive deficits in PS1V97L-Tg mouse model of Alzheimer's disease through modulation of oxidative stress. AB - Oxidative stress refers to an imbalance between oxidative and antioxidative systems due to environmental factors. Although oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD), its precise role is not yet understood. We aimed to investigate the pathogenic mechanisms of the oxidative stress by using in vitro cultured neurons and in vivo AD models of PS1V97L transgenic (Tg) mice. Our results showed that when oxidative stress became increasingly evident, the endogenous protective pathway of nuclear factor E2 related factor 2 (Nrf2)/antioxidant response element (ARE) decreased in 10-month old PS1V97L-Tg mice. Activating the Nrf2/ARE pathway suppressed oxidative stress, decreased amyloid-beta (Abeta), and improved the cognitive function of the PS1V97L-Tg mice. In contrast, blocking the Nrf2/ARE pathway augmented oxidative injury and decreased the cell viability of PS1V97L-Tg neurons. Our results highlight the role of the Nrf2/ARE pathway in regulating oxidative stress of the PS1V97L-Tg mice and may indicate a potential therapeutic avenue for AD treatment. PMID- 30461033 TI - Synthesis, molecular modeling studies, and anticonvulsant evaluation of novel 1 ((2-hydroxyethyl)(aryl)amino)-N-substituted cycloalkanecarboxamides and their acetate esters. AB - A series of 1-((2-hydroxyethyl)(aryl)amino)-N-substituted cycloalkanecarboxamides IXa-l and their acetate esters Xa-l were designed and synthesized as new anticovulsant agents. The evaluation of the anticonvulsant effect was performed in vivo by subcutaneous pentylenetetrazole (scPTZ) and maximal electroshock (MES) tests in mice. Further, neurotoxicity, hepatotoxicity, and acute toxicity were determined. All the new candidates displayed 100% anticonvulsant activity in the scPTZ screen in the dose range of 0.0057-0.283 mmol/kg. The most potent compounds in the scPTZ screen were Xh (ED50 = 0.0012 mmol/kg), Xd (ED50 = 0.002 mmol/kg), Xf (ED50 = 0.004 mmol/kg), IXj (ED50 = 0.0047 mmol/kg), Xl (ED50 = 0.0076 mmol/kg), and Xi (ED50 = 0.008 mmol/kg). They exhibited higher fold activity in the anticonvulsant potential than the gold standards, phenobarbital and ethosuximide. Compound Xf was active in both scPTZ and MES screens. It showed ED50 of 0.016 mmol/kg in MES screen. In the neurotoxicity screens, none of the test compounds displayed any minimal motor impairment at the maximum administered dose. The 3D pharmacophore model using Biova 1 Discovery Studio 2016 programs exhibited high fit value. The anticonvulsant evaluation results were compatible with the molecular modeling study. PMID- 30461034 TI - HEartLight guided - PUre Pulmonary Vein Isolation Regardless of Concomitant Atrial Substrate: HEURECA Study. AB - BACKGROUND: It remains unclear whether left atrial low-voltage area (LALVA) affects atrial tachyarrhythmia recurrence after laser balloon pulmonary vein isolation (PVI) for atrial fibrillation (AF). We prospectively evaluated the outcome of laser balloon PVI in patients with and without LALVA (<= 0.5 mV) together with surface/intracardiac electrophysiological criteria. METHODS: One hundred consecutive paroxysmal/persistent AF patients underwent laser balloon PVI. The relative extent of LALVA (extent of LALVA/left atrial surface area * 100 [%]: rLALVA), total p-wave duration in lead II (PWD), and time interval from the beginning of p-wave to the local activation in left atrial appendage (TTLAA) were assessed. Patients were divided into patients with LALVA (group A: 23 patients) and those without LALVA (group B: 77 patients). The primary endpoint was freedom from atrial tachyarrhythmia after the blanking periods. RESULTS: Complete PVI was achieved in 99/100 (99%) patients. PWD and TTLAA were longer in group A (both, P < 0.001). During 12 months' follow-up, survival free from atrial tachyarrhythmia recurrence was lower in group A (12/23 [52%] patients vs 67/77 [87%] patients, P < 0.001). Multivariate analysis identified rLALVA as the only independent predictor of atrial tachyarrhythmia recurrence. rLALVA correlated with PWD and TTLAA (r = 0.41, P < 0.001 and r = 0.60, P < 0.001, respectively). Receiver operating characteristic curve for rLALVA revealed PWD of 122 ms and TTLAA of 92 ms as the optimal cut-off value. CONCLUSION: LALVA was associated with poorer outcome after laser balloon PVI. Patients may be identified by longer PWD and TTLAA. PMID- 30461035 TI - Tocotrienol-rich fraction supplementation prevents foetal loss in females mated with corticosterone-treated male Sprague-Dawley rats. AB - This study examined whether tocotrienol supplementation to corticosterone-treated male rats could prevent foetal loss in females upon their mating. Epididymides of adult male Sprague-Dawley (SD) rats with proven fertility were surgically separated at the testis-caput junction. Twenty-four hours post-surgery, these animals received for 7 days either: tocopherol-stripped corn oil (Control), corticosterone 25 mg/kg s.c. (CORT), CORT 25 mg/kg s.c. and tocotrienol-rich fraction (TRF) 100 mg/kg orally (CORT + TRF) or TRF 100 mg/kg orally (TRF). On day 8, males were cohabited with proestrus females. A spermatozoa-positive vaginal smear indicated pregnancy. Males were euthanised for analysis of testosterone and antioxidant activities. Reproductive organs were weighed. On day 8 of pregnancy, females were laparotomised to count the number of implantation sites. Pregnancy was continued until term. Number of pups delivered and their weights were determined. Data were analysed using ANOVA. Malondialdehyde levels were significantly lower in CORT + TRF group compared with CORT group. Enzymatic antioxidant activities, testosterone level and reproductive organ weights were significantly higher in CORT + TRF group compared with CORT group. Number of implantation sites and live pups delivered, and their birth weights from females mated with CORT + TRF males were significantly higher compared to CORT group. Therefore, TRF prevents foetal loss in females mated with CORT + TRF-treated males. PMID- 30461036 TI - Texture as an Imaging Biomarker for Disease Severity in Golden Retriever Muscular Dystrophy. AB - INTRODUCTION: Golden retriever muscular dystrophy (GRMD), an X-linked recessive disorder, causes similar phenotypic features to Duchenne muscular dystrophy (DMD). There is currently a need for a quantitative and reproducible monitoring of disease progression for GRMD and DMD. METHODS: To assess severity in the GRMD, we analyzed texture features extracted from multi-parametric MRI (T1w, T2w, T1m, T2m, and Dixon images) using five feature extraction methods and classified using support vector machines. RESULTS: A single feature from qualitative images can provide 89% maximal accuracy. Furthermore, two features from T1w, T2m, or Dixon images provided highest accuracy. When considering a tradeoff between scan-time and computational complexity, T2m images provided good accuracy at a lower acquisition and processing time and effort. DISCUSSION: The combination of MRI texture features improved the classification accuracy for assessment of disease progression in GRMD with evaluation of the heterogenous nature of skeletal muscles as reflection of the histopathological changes. This article is protected by copyright. All rights reserved. PMID- 30461037 TI - Effect of cytomegalovirus infection and leukocyte immunoglobulin like receptor B1 polymorphisms on receptor expression in peripheral blood mononuclear cells. AB - Leukocyte immunoglobulin like receptor B1 (LILRB1) is a receptor with a significant role in several infectious, autoimmune, cardiovascular, and oncologic disorders. LILRB1 expression varies between individuals and may be associated to polymorphisms on the regulatory region of the LILRB1 gene, as well as to previous cytomegalovirus infection. We analyzed the contribution of these two factors to LILRB1 expression in peripheral blood mononuclear cells of healthy young adults. LILRB1 expression in NK cells, T cells, B cells, and monocytes was significantly higher in subjects with previous cytomegalovirus infection than in those without infection (P < 0.001, P < 0.001, P < 0.01, and P < 0.001, respectively). Overall, no differences in LILRB1 expression were observed between individuals with and without GAA haplotypes of the LILRB1 regulatory region. However, when analyzed according to cytomegalovirus infection status, significant differences in LILRB1+ NK cells were observed: a higher proportion of LILRB1-positive cells was found in GAA+ individuals compared to GAA- individuals in the absence of infection (P < 0.01), but GAA- individuals showed a larger proportion of LILRB1-positive cells than GAA+ subjects in cytomegalovirus positive individuals (P < 0.01). In conclusion, cytomegalovirus infection is a major factor affecting LILRB1 expression in NK and other mononuclear cells, while polymorphisms in the LILRB1 regulatory region appear to have a modulatory influence over this effect. PMID- 30461038 TI - The Final Frontier: Primary Muscle Dysfunction in ALS. PMID- 30461039 TI - The use of diffusion-weighted MR imaging in the functional assessment of the testes of patients with clinical varicocele. AB - We aimed to evaluate the use of diffusion-weighted imaging (DWI) in the assessment of the varicocele effect on testicular parenchyma and spermatogenesis, with estimation of apparent diffusion coefficient (ADC) value changes in the testicular parenchyma. We prospectively evaluated 30 consecutive patients (18 patients with bilateral varicocele and 12 patients with unilateral varicocele) and 10 healthy controls. US and DWI were performed to all patients. A total of 80 testes were included, which divided into three groups: group A: testes ipsilateral to the varicocele (n = 48, 60%); group B: testes contralateral to the varicocele (n = 12, 15%); and group C: normal testes of the control (n = 20, 25%). There was a statistically significant difference in mean ADC value between all groups (p-value < 0.001). In groups A and B, there was a negative correlation between mean ADC values and varicocele grade as well as pampiniformis venous diameter. In group A, there was a significant positive correlation between mean ADC value and sperm count (p-value = 0.01, r-value = 0.48) as well as sperm motility (p-value = 0.04, r-value = 0.33). DWI sequence can be used to evaluate the sequel of varicocele, with decreased ADC values that are significantly correlated with abnormal semen parameters. Thus, ADC values may be considered as an ancillary indicator of testicular parenchyma changes. PMID- 30461040 TI - Skull variation in a shovel-headed amphisbaenian genus, inferred from the geometric morphometric analysis of five South American Leposternon species. AB - Amphisabenia is a group of squamates adapted for a fossorial lifestyle. The skull is the animal's the main digging tool, and can present one of four principal shapes. The shovel-headed shape is considered to be the most specialized for digging. The South American genus Leposternon presents a shovel-headed morphotype, and is widely distributed on this continent. The general shovel headed skull pattern may vary considerably, even within the same genus, and we hypothesized that this variation may be influenced primarily by body size and geographical factors. This study investigated the variation in skull size and shape among five Leposternon species, and examined the potential relationship between this variation and the size of the specimens and bioclimatic variables, through a geometric morphometric approach. Significant morphological variation was found among the species, and was also related systematically to body size and the geographical distribution of the specimens. As even subtle differences in the skull size or shape may represent significant modification in bite force and digging capacity and digging speed, the cranial variation found among the Leposternon species and specimens may have a direct influence on their diet and locomotor performance. Our results, together with direct observations of some of these species, suggest that shovel-headed amphisbaenians may be able to penetrate different soil types under a range of climatic conditions, especially considering the ample, but often sympatric distribution of the species studied here. PMID- 30461041 TI - Oxidative stress-mediated alterations on sperm parameters in male Wistar rats exposed to 3G mobile phone radiation. AB - In recent years, there has been significant increase in mobile phone users. With this, health concerns associated with the exposure to electromagnetic radiation are also increasing. Continuous exposure to electromagnetic (EM) radiation generated from mobile phone is one of the probable reasons behind increasing male infertility. EM radiations induce oxidative stress that leads to numerous changes in reproductive parameters. With this hypothesis, we studied the effect of 3G mobile phone radiations on the reproductive system of male Wistar rats. Adult rats were divided into two groups: control and radio frequency-exposed. The animals were exposed to 3G mobile phone radiation for 45 days (2 hr/day) in specially designed exposure setup under standard conditions. Various biochemical and physiological parameters such as sperm count, sperm morphology, mitochondrial activity, lipid peroxidation, reactive oxygen species level and histopathological analysis were studied. Histopathological examination revealed a reduction in spermatogenic cells and alterations in sperm membrane. Significant increase in ROS and lipid peroxidation level with simultaneously decrease in sperm count, alterations in sperm tail morphology were observed in the exposed group. In conclusion, exposure to mobile phone radiations induces oxidative stress in male Wistar rats which may lead to alteration in sperm parameters and affects their fertility. PMID- 30461042 TI - A burden from birth? Non-invasive prenatal testing and the stigmatization of people with disabilities. AB - The notion of being a burden to others is mostly discussed in the context of care intensive diseases or end-of-life decisions. But the notion is also crucial in decision-making at the beginning of life, namely regarding prenatal testing. Ever more sophisticated testing methods, especially non-invasive prenatal testing (NIPT), allow the detection of genetic traits in the unborn child that may cause disabilities. A positive result often influences the decision of the pregnant women towards a termination of the pregnancy. Thus, critics claim that these testing methods send a negative message to people with disabilities. At the core of this is what we call the burden assumption. This assumption claims that children with disabilities are necessarily a burden to others, especially to their parents and other family members. In this paper, we discuss what being a burden to others means in this context and how such an attitude can be avoided without restraining reproductive autonomy. A closer examination shows that the burden assumption is mostly based on misinformation and a false model of disability. Empirical studies as well as narrative evidence from parents who raise a child with disabilities show that the burden assumption is wrong. Raising a child with disabilities does not necessarily mean a decrease in the quality of life. We show how the burden assumption can be challenged through an advanced genetic counselling that combines empirical evidence with narratives from a first person perspective. PMID- 30461043 TI - Kanamycin induces free radicals formation in melanocytes: An important factor for aminoglycosides ototoxicity. AB - Ototoxicity is well-documented but not fully understood undesirable side effect of aminoglycoside antibiotic, kanamycin. Kanamycin is capable of binding to melanin biopolymers-natural pigments of the skin, hair, and eyes. Melanin producing cells, melanocytes, are also present in the inner ear and are known to be necessary for normal hearing. It was considered that melanin content in the inner ear may influence aminoglycoside-induced ototoxic effect. The impact of kanamycin on melanocytes homeostasis may thus play role in the antibiotic-induced ototoxic effect. Previously, we demonstrated that kanamycin disturbs homeostasis in light-pigmented melanocytes. To investigate if/how melanization contributes to this phenomenon, the study using in vitro model of dark-pigmented melanocytes is required. Spectrophotometric measurements and electron paramagnetic resonance (EPR) spectroscopy analysis were performed. Kanamycin induced a concentration dependent loss in HEMn-DP melanocytes viability. The value of IC 50 was estimated to be 5.0 mM. Modulation of the activity of analyzed antioxidant enzymes and increased production of free radicals as well as the decrease of the melanin content were observed. Our results confirmed that kanamycin generates oxidative stress in melanocytes. The increased level of free radicals caused by kanamycin may be responsible for the imbalance of antioxidant defense and the reduction of melanin content in melanocytes. The role of melanin in the mechanism of kanamycin induced hearing impairment was discussed and the obtained results were compared with the previously demonstrated data concerning light-pigmented melanocytes. PMID- 30461044 TI - Diagnosing atopic dermatitis in infancy: Questionnaire reports vs criteria-based assessment. AB - BACKGROUND: Persisting atopic dermatitis (AD) is known to be associated with more serious allergic diseases at later ages; however, making an accurate diagnosis during infancy is challenging. We assessed the diagnostic performance of questionnaire-based AD measures with criteria-based in-person clinical assessments at age 1 year and evaluated the ability of these diagnostic methods to predict asthma, allergic rhinitis and food allergies at age 5 years. METHODS: Data relate to 3014 children participating in the Canadian Healthy Infant Longitudinal Development (CHILD) Study who were directly observed in a clinical assessment by an experienced healthcare professional using the UK Working Party criteria. The majority (2221; 73.7%) of these children also provided multiple other methods of AD ascertainment: a parent reporting a characteristic rash on a questionnaire, a parent reporting the diagnosis provided by an external physician and a combination of these two reports. RESULTS: Relative to the direct clinical assessment, the area under the Receiver Operating Characteristic curve for a parental report of a characteristic rash, reported physician diagnosis and a combination of both were, respectively, 0.60, 0.69 and 0.70. The strongest predictor of asthma at 5 years was AD determined by criteria-based in-person clinical assessment followed by the combination of parental and physician report. CONCLUSIONS: These findings suggest that questionnaire data cannot accurately substitute for assessment by experienced healthcare professionals using validated criteria for diagnosis of atopic dermatitis. Combining the parental report with diagnosis by a family physician might sometimes be appropriate (eg to avoid costs of a clinical assessment). PMID- 30461045 TI - Help-seeking Behavior in Socially Conservative and Christian Suicide Decedents. AB - OBJECTIVE: The purpose of this study was to examine the relationship between religious affiliation, political beliefs, and lifetime mental health help-seeking behavior in a sample of suicide decedents. We hypothesized that Christian decedents would be less likely to have sought help than non-Christians, and socially conservative individuals would be less likely to have sought help than socially liberal or moderate individuals. METHOD: Smaller samples (N = 147 for political analyses, N = 218 for religion analyses) were drawn from a larger sample of 267 suicide decedents, for whom data were collected from loss survivors. RESULTS: Logistic regression analyses showed that Christian and non Christian individuals did not differ significantly in help-seeking behavior prior to death by suicide. Individuals who identified as socially liberal were significantly more likely to have sought mental health care than were individuals who identified as socially conservative. CONCLUSIONS: This is the first study to examine the association between social conservatism and a lack of help-seeking behavior. These findings show the importance of implementing interventions to increase help-seeking behavior for suicidality within demographic groups that stigmatize help-seeking behavior, specifically socially conservative individuals. They also stress the importance of suicide prevention tactics that do not require disclosing suicidal intent within these groups. PMID- 30461046 TI - A review and illustrated description of Musca crassirostris, one of the most neglected haematophagous livestock flies. AB - Tabanids, stomoxyine flies, hippoboscids and tsetse flies are the most well-known brachyceran biting flies of livestock. Only a few other higher Diptera have developed the unique mouthparts required for blood feeding. These neglected blood feeders can also have direct effects on hosts through blood loss, and are likely to contribute to the transmission of pathogens. Musca crassirostris (Diptera: Muscidae) is one of the most abundant of the muscid flies with this haematophagous lifestyle; it is widespread in the Palaearctic, Afrotropical and Oriental regions. The present study reviews and summarizes the biology and morphology of this species, and its potential for impact on animals and humans. The study also provides a fully illustrated description of the fly to facilitate its identification, and reviews information on abundance, with a focus on recent trapping surveys in Thailand. When sampled using traps designed for other biting flies, M. crassirostris appears to be four and 45 times more abundant than stomoxyines and tabanids, respectively. High numbers of M. crassirostris in the vicinity of livestock have also been associated with outbreaks of disease, such as that of a fatal plague in bovine farms in Egypt. This calls for a reconsideration of its potential impacts on livestock economics and health, and thus the development of suitable control methods. PMID- 30461047 TI - Multiple oral ulcers caused by incorrect use of oral bisphosphonate in a patient with dementia: A case report. AB - It is not widely known that incorrect use of oral bisphosphonates (BPs), such as chewing the medication, can cause oral ulcers. An 83-year-old woman with dementia was referred to our clinic with multiple oral ulcers. Blood and histopathological examinations were inconclusive. Further questioning revealed that the patient chewed the oral BP, resulting in oral ulceration. Patients with loss of cognitive function, such as dementia, are at risk of oral ulcers caused by incorrect use of BPs. PMID- 30461048 TI - Polycystins in disease mechanobiology. AB - Distorted mechanotransduction represents the molecular hallmark of disease mechanobiology and is displayed with common features during the development of various pathophysiologies. Polycystins constitute a family of mechanosensitive proteins that facilitate pathogenic signal transduction mechanisms. The main representatives of the family are polycystin-1 (PC1) and polycystin-2 (PC2), which function as a mechano-induced membrane receptor and a calcium-permeable ion channel, respectively. PC1 and PC2 mediate extracellular mechanical stimulation, induce intracellular molecular signaling and evoke corresponding gene transcription. Recent reports reveal that polycystin-mediated signaling does not occur in polycystic kidney disease only, where it is most prominently studied. It is also present during the development of clinical entities such as endothelial dysfunction and atheromatosis, deregulation of osteoblast differentiation, cancer development, and psoriasis. In this study, we highlight emerging data that support the overall contribution of polycystins to disease mechanobiology and suggest further exploration of this protein family in diseases generated from force-bearing tissue structures. PMID- 30461049 TI - Bank accounts for public primary health care facilities: Reflections on implementation from three districts in Tanzania. AB - Health care financing reforms are gaining popularity in a number of African countries to increase financial resources and promote financial autonomy, particularly at peripheral health care facilities. The paper explores the establishment of facility bank accounts at public primary facilities in Tanzania, with the intention of informing other countries embarking on such reform of the lessons learned from its implementation process. A case study approach was used, in which three district councils were purposively sampled. A total of 34 focus group discussions and 14 in-depth interviews were conducted. Thematic content analysis was used during analysis. The study revealed that the main use of bank account revenue was for the purchase of drugs, medical supplies, and minor facility needs. To ensure accountability for funds, health care facilities had to submit monthly reports of expenditures incurred. District managers also undertook quality control of facility infrastructure, which had been renovated using facility resources and purchases of facility needs. Facility autonomy in the use of revenue retained in their accounts would improve the availability of drugs and service delivery. The experienced process of opening facility bank accounts, managing, and using the funds highlights the need to strengthen the capacity of staff and health-governing committees. PMID- 30461050 TI - Histopathological evaluation of oral membranous substance in bedridden elderly persons without oral intake in Japan. AB - OBJECTIVES: The aim of this study was to clarify by histopathological examination the origin of oral membranous substances deposited on the palate, tongue, buccal mucosa and teeth. BACKGROUND: Several investigators have reported membranous substances deposited in the mouths of bedridden elderly persons requiring nursing care without oral intake. However, the precise nature and origin of the substances are poorly understood. METHODS: Sixty-nine specimens were taken from the oral cavity of bedridden patients, that is, the palate, dorsum of the tongue, the cheek and teeth. Sections were stained with haematoxylin and eosin stain, alcian-blue and periodic acid-Schiff stain (AB-PAS) and antibodies for pankeratin (AE1AE3) and leukocyte common antigen (LCA). RESULTS: All specimens showed a film like nature coloured from tan to white, accompanied by a mucous substance. Histologically, specimens of all sites had a similar feature of the combination of basophilic amorphous and eosinophilic lamellar features. The basophilic substance was positive for AB-PAS, and PAS-positive glycogen granules were also noted in the lamellar structure. Immunochemistry revealed various degrees of pankeratin positive substance and LCA-positive inflammatory cell infiltration. CONCLUSION: The oral membranous substance was composed of keratin and mucin with inflammation. These results suggest that the deposition of the oral membranous substance is a pathological condition or oral mucositis caused by dry mouth. PMID- 30461051 TI - Heterocyclic electrophiles as new MurA inhibitors. AB - An electrophilic fragment library of small heterocycles was developed and characterized in the surrogate GSH-reactivity assay and aqueous stability test that revealed their potential as covalent warheads. Screening the library against MurA from Staphylococcus aureus (MurASA ) and Escherichia coli (MurAEC ) identified heterocyclic fragments with significant inhibitory potency. The validated heterocyclic warhead library might be useful for developing targeted covalent inhibitors for other targets of interest with a new design strategy incorporating heterocyclic electrophiles as warheads. PMID- 30461052 TI - The relationship between platelet indices and ABO blood groups in healthy adults. AB - BACKGROUND: ABO blood groups have been suggested to have a high correlation with cardiovascular diseases (CVDs). It has also been postulated that platelet indices, including mean platelet volume (MPV) and platelet distribution width (PDW), are very important in the development and progression of CVDs. However, despite these common associations with CVDs, as far as we know, there are no studies investigating platelet indices in ABO blood groups. Thus, the aim of this study was to investigate whether platelet indices are associated with ABO blood groups. METHODS: The study included 301 healthy volunteers (99 women and 202 men; mean age: 32.59 +/- 7.52 years) whose blood groups were determined by the gel column method using agglutination techniques. Platelet indices were studied by an automated blood counter. RESULTS: No considerable differences in age, gender, or Rh factors were observed among ABO blood groups. MPV was detected to be considerably lower in O and A blood group subjects than in AB and B blood group subjects. Similarly, PDW was significantly lower in O and A blood group subjects than in B blood group subjects. Additionally, MPV in the O blood group subjects was significantly lower than in the non-O blood group subjects. CONCLUSIONS: Because MPV and PDW are used as markers of CVDs, individuals with O and A blood groups in this study may be considered to have a lower risk of CVDs than AB and B blood group subjects. However, prospective cohort studies involving a greater number of volunteers are needed to elucidate these relationships. PMID- 30461053 TI - Algorithm for predicting threshold retinopathy of prematurity is insufficient and fundus examinations are still needed before 31 weeks. AB - AIM: We evaluated the weight, insulin-like growth factor-1, neonatal, retinopathy of prematurity (WINROP) algorithm for very premature infants. METHOD: Infants born before 32 weeks who had undergone fundus examinations in the neonatal intensive care unit at the University Hospital of Nancy were included in this French retrospective cohort study from July 2012 to July 2016. We evaluated how well the WINROP software predicted threshold retinopathy of prematurity (ROP). RESULTS: We studied 570 infants with a mean gestational age of 28.7 +/-1.8 weeks and a mean birth weight of 1,110 +/-297 grams: 28.1% had ROP and 1.2% had threshold ROP. The overall WINROP sensitivity was 57.1%, specificity was 46.0%, predictive positive value was 1.3% and predictive negative value was 98.9%. At more than 30 weeks of gestation or 1,250 grams, these figures rose to a respective specificity of 100% and 95.7% and respective predictive negative value of 100% and 100%. There were independent associations between the severity of ROP and the Apgar Score at five minutes, the duration of oxygen therapy and non invasive ventilation. CONCLUSION: WINROP worked better on preterm infants born from 31 weeks onwards or weighing over 1,250g. Fundus examinations remain necessary for infants born earlier or lighter. This article is protected by copyright. All rights reserved. PMID- 30461054 TI - Direct detection from clinical sputum samples to differentiate live and dead Mycobacterium Tuberculosis. AB - BACKGROUND: In this study, we aimed to optimize the condition of propidium monoazide (PMA) treatment for direct detection of Mycobacterium tuberculosis (MTB) from clinical specimens. METHODS: The light exposure time, dark incubation time, bacterial load, and PMA concentration were varied to determine the optimal condition of PMA treatment. RESULTS: Overall, the maximum DeltaCq value was observed in the group receiving a light exposure time of 20 minutes, which was significantly higher than the others (P < 0.05). The prolongation of dark incubation time seemed more likely to result in greater DeltaCq value, and the DeltaCq values were 2.0, 4.1, 6.5, 10.1, and 12.7 cycles under dark incubation time of 10, 20, 40, 60, and 120 minutes, respectively. Alternatively, the 4+ samples exhibited favorable detection results at the application of 104 -fold dilution by PMA assay with Cq values higher than 35 cycles. Further evaluation revealed that the PMA assay showed an accordance rate of 98.0% (98/100) among clinical sputa. CONCLUSIONS: we develop an acceptable method to directly identify the live bacteria from sputum samples. Our data demonstrate that the dark incubation plays a crucial role in the efficacy of PMA treatment for MTB. PMID- 30461055 TI - NIRS cerebral patterns in healthy late preterm and term infants are gender- and gestational age-dependent. AB - AIM: Near infrared spectroscopy (NIRS) has been proposed to provide reliable information concerning brain oximetry and tissue activation level in the perinatal period. We aimed to investigate whether NIRS brain patterns in healthy preterm and term infants were gender- and gestational age-dependent. METHODS: We conducted an observational study in 74 newborns, from consecutive singleton pregnancies, of whom 37 were born at term (male: n=19 female: n=18) and 37 (male: n=18 female: n=19) were preterm. Cerebral oximetry (crSO2 ) and fractional tissue oxygen extraction (cFTOE), were recorded on the 5th day from birth. RESULTS: crSO2 was significantly higher and cFTOE lower (P<0.001, for both) in the preterm female than male group. At term crSO2 was significantly higher and cFTOE lower (P<0.001, for both) in males. crSO2 (male: R=0.84, P<0.001; female: R=0.74, P= P<0.001) and cFTOE (male: R=0.72, P<0.001; female: R=0.72, P<0.001) in male and female groups correlated positively with gestational age at recording. CONCLUSION: Different brain oximetry between males and females in preterm and term gestational ages, may suggest that in the perinatal period brain development is gender- and time-dependent. Data support the use of NIRS as a feasible tool for non-invasive cerebral monitoring. This article is protected by copyright. All rights reserved. PMID- 30461056 TI - Improving collaboration in the implementation of global biodiversity conventions. AB - Eight conventions make up the biodiversity cluster of Multilateral Environmental Agreements (MEAs) which provide the critical international legal framework for the conservation and sustainable use of nature. However, concerns about the rate of implementation of the conventions at the national level have triggered discussions about the effectiveness of these MEAs in halting the loss of biodiversity. Two main concerns have emerged, lack of capacity and resources, and lack of coherence in implementing multiple conventions. Here we focus on the latter, outlining the mechanisms by which international conventions are translated into national policy, specifically the role of the 'Strategic Plan for Biodiversity 2011-2020' and the associated Aichi Biodiversity Targets as a unifying grand plan for biodiversity conservation. This strategic plan has been used to coordinate and align targets to promote and enable more effective implementation across all biodiversity-related conventions. However, a survey of 139 key stakeholders from 88 countries suggested opportunities to further improve cooperation among the biodiversity-related conventions. The roadmap for improving synergies among conventions agreed at the 13th Convention on Biological Diversity's Conference of Parties in Cancun, Mexico in 2016 can help to address these concerns. Further, we suggest ways that the scientific community can actively engage and contribute to the policy process by: 1) establishing a science-policy platform to address key knowledge gaps, 2) improving data gathering, reporting and monitoring, 3) developing indicators that adequately support implementation of national plans and strategies, and 4) providing evidence-based recommendations to policy makers. This will be particularly important as 2020 approaches and work to develop a new biodiversity agenda for the next decade is beginning. This article is protected by copyright. All rights reserved. PMID- 30461057 TI - Prevalence of food-allergen and aeroallergen sensitization among people in Sichuan, Western China: An 8-year observational study. AB - BACKGROUND: Identifying the distribution of allergens is invaluable to effective diagnosis and treatment of allergic disease. The present study aims to analyze the epidemiology of allergens in Sichuan, Western China. METHODS: A total of 14 030 participants including 8031 men and 5999 women were enrolled in this study during 2007-2014 in West China Hospital. An assay testing for the presence of allergen-specific IgE was used to identify highly immunogenic allergens. RESULTS: Of the 14 030 total participants, 3470 (24.72%) were sensitive to at least one of tested allergens. The most immunogenic allergens were mite mix (1876, 13.38%), crab (876, 6.24%), sea-fish mix (865, 6.16%), house dust (355, 2.54%), and cockroach (292, 2.08%). The differences between population of participants who were sensitive to food allergens and aeroallergens were statistically significant in 0 to 10, 11 to 20, 21 to 30, 41 to 50, and 51 to 60 year-old age-groups (all P < 0.05). Distributions of three food allergens and two aeroallergens were significantly different between male and female participants. There was also an increase in sensitization to cow's milk, mutton, sea-fish, and mould that was observed in the 71 to 90 year-old group. CONCLUSION: The most common allergens presented in Sichuan were observed to be mites, crab, sea-fish, and house dust. There was an observable difference in sensitivity to five allergens between males and females. Additionally, aeroallergens appeared to have a greater immunogenic effect in younger populations while the elderly presented with increased sensitization to specific allergens, suggesting that specific allergens' immunogenicity was age-dependent. PMID- 30461058 TI - Evaluation of biological variation of glycated hemoglobin and glycated albumin in healthy Chinese subjects. AB - BACKGROUND: Glycated hemoglobin (HbA1c) and glycated serum albumin (GSA) are used to evaluate the mean blood glucose levels. To ensure safe clinical application of HbA1c and GSA, reliable biological variation (BV) data are required. The aim of this research was to define the BV of HbA1c and GSA employing stringent rules. METHODS: Blood samples were drawn from 19 healthy subjects (10 females, nine males) once per week for 5 weeks. All samples were analyzed using enzymatic method for GSA and HPLC for HbA1c. The data were assessed for outliers, normality and variance homogeneity, and coefficient of variation (by ANOVA) for BV. Sex stratified BV including within-subject (CVI ) and between-subject (CVG ) was defined for HbA1c and GSA. RESULTS: The following estimates for BV values for CVI and CVG , respectively, were GSA: 1.23% and 4.67%, Alb: 0.75% and 3.18%, and HbA1c: 0.12% and 2.91%. The RCV of GSA was 3.61%, and HbA1c was 1.41%. And the II was 0.26 for GSA, and 0.07 for HbA1c, both of them less than 0.6. According to the 95% CI, the CVI of HbA1c was statistically different between females and males. And both the CVG of HbA1c and GSA were statistically different between females and males. CONCLUSION: All CVI and CVG estimates were lower than those reported in the online BV database. And there is a significant difference between males and females. Analytical performance specifications derived from BV of this research can be applied internationally. PMID- 30461059 TI - A low cost and input tailing method of quality control on multiple annealing, and looping-based amplification cycles-based whole-genome amplification products. AB - BACKGROUND: Single-cell whole-genome sequencing provides novel insights into the nature of genetic heterogeneity in normal and diseased cells. However, amplification of formalin-fixed tissues with low cell numbers is still problematic and multiple annealing, and looping-based amplification cycles (MALBAC) is a commonly used whole-genome amplification (WGA) method with low cell numbers. METHODS: We developed a low-input tailing method to evaluate the MALBAC based WGA from sub-nanogram or less quantities of input DNA. The tailing method uses 2100 BioAnalyzer to evaluate the size distribution of MALBAC products, and comparing the tailing with 10380 bp. RESULTS: Compared with a 22 loci qPCR panel, the tailing method provided a similar WGA evaluation efficiency in 13 samples on one set of study, with lower input, cheaper cost, shorter manual time, and a clear filtering cut off. Later, we demonstrated a strong correlation between tailing size and coverage breadth in another 29 samples on two sets of assays. As a result, the tailing method showed that it could predict whether a sequence breadth achieved 70% or not with 100% accuracy on these three sets of assays. Although further studies are needed, this tailing method is expected to be used as an excellent tool to select high-quality WGA products before library construction. CONCLUSIONS: Our tailing method can provide a new WGA quality test to evaluate the WGA efficiency with 100% accuracy (42/42). Compared with qPCR panel, our tailing method needs lower input, cheaper cost, shorter manual time, a clear filtering cut off, and extendable high throughput as well as the same sensitivity. PMID- 30461060 TI - Preliminary study of the relationship between promoter methylation of the ANGPTL2 gene and coronary heart disease. AB - BACKGROUND: Coronary heart disease (CHD) is primarily caused by atherosclerosis of coronary arteries. It is largely an inflammatory disease of the vascular wall. The inflammation is related to DNA methylation. Angiopoietin-like protein 2 (ANGPTL2) has various functions in several chronic inflammatory diseases. Macrophage-derived ANGPTL2 was reported to accelerate CHD development. It is reported that DNA hypomethylation in the promoter region of ANGPTL2 gene was associated with acute coronary syndrome (ACS), a type of CHD. Our objective was to explore the correlation between promoter methylation of the ANGPTL2 gene and CHD, and to investigate the association between methylation status and clinical characteristics of CHD patients. METHODS: Firstly, we collected 122 CHD patients and 58 non-CHD participants from Han Chinese population and purified the peripheral blood DNA. The purified DNA was subjected to bisulfite modification. After bisulfite conversion, the target DNA locus was amplified using polymerase chain reaction (PCR), and the PCR products were measured by pyrosequencing. Finally, the methylation level was calculated according to the sequencing result, and the data were analyzed using xx software. RESULTS: CHD patients had a relatively lower methylation levels (P50: 7.67% [P25: 6.22%, P75: 10.43%]) in the ANGPTL2 promoter region than did controls (P50: 8.25% [P25: 5.46%, P75: 17.98%], P = 0.001), indicating an association between ANGPTL2 promoter methylation and CHD (OR: 0.890; 95% CI, 0.832-0.953; adjusted P = 0.001). A breakdown analysis by gender showed that ANGPTL2 promoter methylation was associated with CHD in females (adjusted P = 0.002) but not in males (adjusted P = 0.404). We found no correlation between gene methylation and other clinical characteristics. CONCLUSIONS: The present work provides evidence to support an association between ANGPTL2 promoter DNA methylation status and the risk profile of CHD in females. Our data indicated that in females, promoter DNA hypomethylation of the ANGPTL2 gene is associated with an increased risk of CHD. PMID- 30461061 TI - Current status of treatment of type 2 diabetes mellitus in Ningbo, China. AB - BACKGROUND: The treatment status of type 2 diabetes mellitus (T2DM) in Ningbo has not been reported in the past. To evaluate the current status of T2DM in Ningbo and provide evidence to formulate more policies, a multicenter investigation was needed. METHODS: The Ningbo Clinical Research Group of Diabetes constituted nine hospitals. Participants included 3015 patients who visited the nine hospitals from June to December 2016. General characteristics, the medication situation, the laboratory indexes in nearly 3 months consisting of glycosylated hemoglobin level (HbA1c), low-density lipoprotein cholesterol (LDL-C), and fasting blood glucose (FBG), and the results of ophthalmologic examination were investigated. The evaluation criteria were defined based on 2013 China guideline for T2DM. RESULTS: The 3015 subjects included 1685 men and 1330 women. The average age was 63.3 +/- 13.0 years. The prevalence of hypertension and dyslipidemia was 58.7% and 56.7%, respectively. In the examinees, nephropathy appeared in 11.6% and retinopathy in 14.5%. More than half (50.9%) of the subjects were overweight. The achievement rate of blood pressure (BP) was 39.6% (<140/80 mm Hg), FBG was 46.0% (4.4-7.0 mmol/L), HbA1c was 41.7% (<7.0%), and LDL-C was 51.7% (<1.8 mmol/L; and if accompanied by CHD, <2.6). CONCLUSION: Ningbo City T2DM status is not optimistic, and there is a big gap with the indicators. PMID- 30461062 TI - Association of VDR-FokI and VDBP-Thr420Lys polymorphisms with cervical spondylotic myelopathy: A case-control study in the population of China. AB - BACKGROUND: Cervical spondylotic myelopathy (CSM), a common degenerative disorder, is characterized by chronic progressive compression of the cervical spinal cord. The present case-control study aimed to explore the potential role of VDR-FokI and VDBP-Thr420Lys polymorphisms in the susceptibility to CSM in the Chinese population. METHODS: The study enrolled 318 CSM patients and 282 healthy individuals whose clinical data were retrospectively analyzed. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was used to genotype VDR-FokI and VDBP-Thr420Lys polymorphisms. The severity of CSM was assessed using the Japanese Orthopaedic Association (JOA) score with magnetic resonance imaging (MRI) of cervical vertebra. A nonconditional binary logistic regression model was conducted for assessing the risk factors of CSM. RESULTS: Patients in the CSM group had longer time duration to bend over desk working than the control group. The ff genotype and f allele frequency of VDR-FokI were elevated in CSM patients. Elevated Ff + ff genotype and f allele frequency of VDR FokI might increase the risk of CSM. The VDR-FokI polymorphism was associated with nucleus pulposus capillary invasion, necrosis, hyaline degeneration and fibrosis, genesis and hyperplasia of cartilage-like cells, and fibrocyst in the fibrous ring. The VDR-FokI and VDBP-Thr420Lys genotypes conformed to Hardy Weinberg equilibrium which showed that VDR-FokI and VDBP-Thr420Lys had group representation characteristics. CONCLUSION: Binary logistic regression analysis confirmed that VDR-FokI polymorphism and the time to bend over desk working were risk factors of CSM. Our results indicate that VDR-FokI polymorphism may be closely associated with the risk of CSM. PMID- 30461063 TI - Comparison of non-invasive tests with invasive tests in the diagnosis of celiac disease. AB - BACKGROUND/AIMS: Today, invasive diagnostic tests are necessary for definite diagnosis of adult celiac disease (CD). However, in selected children patients, the need for invasive tests is ceased. In this study, we evaluated adult patients according to the ESPGHAN (European Pediatric Gastroenterology Hepatology and Nutrition Society) criteria. METHODS: Thirty-nine patients (aged 17-66) with symptoms of CD were included. Serum samples were tested for total IgA, tTG-IgA (antitissue transglutaminase), tTG-IgG, DGP-IgA (antideamidated gliadin peptide), DGP-IgG, and EMA (endomysial antibodies). HLA-DQ typing was studied with PCR-SSP (sequence-specific primers) method. Biopsy samples were evaluated according to Marsh scoring. RESULTS: In CD patients, 71.4% (15/21) of the patients were diagnosed without biopsy according to the EPSGHAN criteria but when ESPGHAN's IgA tTG threshold value for children was taken into consideration (>200 IU/mL), the sensitivity decreased to 81%. Celiac disease diagnosed and control groups were compared in terms of HLA tissue types. DQ2.5 homozygous or DQ2.5/DQ2.2 was significantly higher in CD group, and DQ2- or DQ8-negative HLA tissue type was significantly higher in control group. CONCLUSION: When serological tests, HLA typing, and clinical symptoms are all in favor of CD, biopsy may not be performed in selected adult CD patients. PMID- 30461064 TI - Circulating CEA-dNLR score predicts clinical outcome of metastatic gallbladder cancer patient. AB - BACKGROUND: Cancer-related inflammation promotes gallbladder tumorigenesis and metastasis of gallbladder cancer (mGBC). The levels of circulating inflammatory related cell and protein as well as the ratios of them may imply the severity of chronic inflammation in GBC patients, and all of them are candidate prognostic biomarkers for mGBC. MATERIALS AND METHODS: In our study, pre-treatment circulating immune cell, fibrinogen (Fib), albumin (Alb), and pre-albumin (pAlb) were detected in 220 mGBC patients, and we calculated neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), lymphocyte-to monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), Alb-to-Fib ratio (AFR), and Fib-to-pAlb ratio (FPR) replying on the detection. Three years' follow-up was carried out in those patients, and we investigated the possible associations between those biomarkers and three years' overall survival (OS) of these patients using X-tile software, Kaplan-Meier curve, Cox regression, and time-dependent receiver operating characteristics (ROC). RESULTS: Our results showed that OS of the patients with high pAlb and LMR was significantly superior to the cases with the low biomarkers, respectively. However, survival of the cases with high CEA, dNLR, and FPR was significantly inferior to the patients with low levels of those biomarkers. Area under the curve (AUC) of time-dependent ROC of CEA and dNLR was higher than pAlb, LMR, and FPR, respectively. Additionally, higher CEA-dNLR score (adjusted HR = 3.09, 95% CI = 1.01-4.51 for the score one; adjusted HR = 4.99, 95% CI = 2.32-7.21 for the score two) was significantly associated with reduced survival of the patients, and AUC of the score for predicting clinical outcome of mGBC patients was 0.756, and it was significantly higher than the single CEA and dNLR, respectively. CONCLUSION: Our findings implied that pretreatment CEA-dNLR score was superior to the other biomarkers to predict OS of mGBC patients, and it was an independent prognostic factor for the disease. PMID- 30461065 TI - Effects of life history and reproduction on recruitment time lags in reintroductions of rare plants. AB - Reintroductions are important components of conservation and recovery programs with rare plant species, but their long-term success rates are poorly understood. Previous reviews of plant reintroductions focused on short-term (e.g., <= 3 years) survival and flowering of founder individuals rather than on benchmarks of intergenerational persistence, such as seedling recruitment. However, short-term metrics may obscure outcomes since the unique demographic properties of reintroductions, including small size and unstable stage structure, could create lags in population growth. Here, we used time-to-event analysis on a database of unusually well-monitored and long-term (4 - 28 years) reintroductions of 27 rare plant species to test whether life-history traits and population characteristics of reintroductions create time-lagged responses in seedling recruitment (i.e., recruitment time lags), an important benchmark of success and indicator of persistence in reintroduced populations. Recruitment time lags (RTLs) were highly variable among reintroductions, ranging from <1 to 17 years after installation. Recruitment patterns matched predictions from life-history theory with short lived species (fast species) exhibiting consistently shorter and less variable RTLs than long-lived species (slow species). Long RTLs occurred in long-lived herbs, especially in grasslands, whereas short RTLs occurred in short-lived subtropical woody plants and annual herbs. Across plant life-histories, as reproductive adult abundance increased, RTLs decreased. Highly variable RTLs were observed in species with multiple reintroduction events suggesting local processes are just as important as life-history strategy in determining reintroduction outcomes. Time-lags in restoration outcomes highlight the need to scale success benchmarks in reintroduction monitoring programs with plant life history strategies and the unique demographic properties of restored populations. Drawing conclusions on the long-term success of plant reintroduction programs is premature given that demographic processes in species with slow life-histories take decades to unfold. This article is protected by copyright. All rights reserved. PMID- 30461066 TI - Characteristics of Self-Reported Sleep and the Risk of Falls and Fractures: The Women's Health Initiative (WHI). AB - Sleep disturbances are common and may influence falls and fracture directly by influencing bone turnover and muscle strength or indirectly through high comorbidity or poor physical function. To investigate the association between self-reported sleep and falls and fractures, we prospectively studied 157,306 women in the Women's Health Initiative (WHI) using information on sleep quality, sleep duration, and insomnia from questionnaires. Annual self-report of falling two or more times (ie, "recurrent falling") during each year of follow-up was modeled with repeated measures logistic regression models fit by generalized estimating equations. Cox proportional hazards models were used to investigate sleep disturbance and time to first fracture. We examined the risks of recurrent falls and fracture by sleep duration with 7 hours as referent. We examined the risks across categories of sleep disturbance, insomnia status, and sleep quality. The average follow-up time was 7.6 years for falls and 12.0 years for fractures. In multivariable adjusted models, including adjustment for comorbidity, medications, and physical function, women who were short (<=5 hours) and long (>=10 hours) sleepers had increased odds of recurrent falls (odds ratio [OR] 1.28; 95% confidence interval [CI], 1.23 to 1.34 and OR 1.25; 95% CI, 1.09 to 1.43, respectively). Poor sleep quality, insomnia, and more sleep disturbances were also associated with an increased odds of recurrent falls. Short sleep was associated with an increased risk of all fractures, and upper limb, lower limb, and central body fractures, but not hip fractures, with hazard ratios ranging from 1.10 to 1.13 (p < 0.05). There was little association between other sleep characteristics and fracture. In conclusion, short and long sleep duration and poor sleep quality were independently associated with increased odds of recurrent falls. Short sleep was associated with modest increase in fractures. Future long term trials of sleep interventions should include falls and fractures as endpoints. (c) 2018 American Society for Bone and Mineral Research. PMID- 30461067 TI - Insignificant interference of Elevit in pregnant women serum samples with HBsAg immunoassay on Sysmex. AB - BACKGROUND: The pregnant women often take Elevit as the multivitamin supplement which has a substantial amount of biotin that might potentially interfere with the HBsAg immunoassay performed by the prevalent Sysmex system in clinical laboratories. We therefore wanted to determine this, so that the therapeutic intervention on the hepatitis B virus infection during pregnancy and birth would not be missed. METHODS: Elevit was both serially diluted in vitro and orally taken by healthy volunteers whose blood samples were then taken at different time points. All samples were added to a serum sample with a known result of HBsAg and then measured by Sysmex. The Abbott immunoassay system was used as the control as it involves no streptavidin-biotin binding in the reagent set. Besides, the HBsAg results were compared between the pregnant women taking or not taking Elevit. RESULTS: Biotin at 25 ng/mL in the Elevit started to suppress the HBsAg and reached about 50% suppression at 100 ng/mL on Sysmex. In the volunteers, biotin reached the peak concentration at 2 hours. However, their blood samples showed no suppression on the HBsAg detection by Sysmex. In samples from pregnant women who took Elevit, the HBsAg results by Sysmex were highly correlated with those by Abbott (R2 = 0.96). Comparison of the results from Sysmex between the age- and pregnancy-matched females with and without Elevit intake showed no difference. CONCLUSION: Elevit intake in pregnant women shows no significant interference with HBsAg immunoassay on Sysmex. PMID- 30461068 TI - Region-specific control of microglia by adenosine A2A receptors: uncoupling anxiety and associated cognitive deficits in female rats. AB - Epidemiologic studies have provided compelling evidence that prenatal stress, through excessive maternal glucocorticoids exposure, is associated with psychiatric disorders later in life. We have recently reported that anxiety associated with prenatal exposure to dexamethasone (DEX, a synthetic glucocorticoid) correlates with a gender-specific remodeling of microglia in the medial prefrontal cortex (mPFC), a core brain region in anxiety-related disorders. Gender differences in microglia morphology, the higher prevalence of anxiety in women and the negative impact of anxiety in cognition, led us to specifically evaluate cognitive behavior and associated circuits (namely mPFC dorsal hippocampus, dHIP), as well as microglia morphology in female rats prenatally exposed to dexamethasone (in utero DEX, iuDEX). We report that iuDEX impaired recognition memory and deteriorated neuronal synchronization between mPFC and dHIP. These functional deficits are paralleled by microglia hyper ramification in the dHIP and decreased ramification in the mPFC, showing a heterogeneous remodeling of microglia morphology, both postnatally and at adulthood in different brain regions, that differently affect mood and cognition. The chronic blockade of adenosine A2A receptors (A2A R), which are core regulators of microglia morphology and physiology, ameliorated the cognitive deficits, but not the anxiety-like behavior. Notably, A2A R blockade rectified both microglia morphology in the dHIP and the lack of mPFC-dHIP synchronization, further heralding their role in cognitive function. PMID- 30461069 TI - Attention Deficit Hyperactivity Disorder and Risk of Posttraumatic Stress and Related Disorders: A Prospective Longitudinal Evaluation in U.S. Army Soldiers. AB - Cross-sectional associations between attention deficit hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) have been observed, but longitudinal studies assessing this association are lacking. This prospective study evaluated the association between predeployment ADHD and postdeployment PTSD among U.S. Army soldiers. Soldiers who deployed to Afghanistan were surveyed before deployment (T0) and approximately 1 month (T1), 3 months (T2), and 9 months (T3) after their return. Logistic regression was performed to estimate the association between predeployment ADHD and postdeployment (T2 or T3) PTSD among 4,612 soldiers with data at all waves and no record of stimulant medication treatment during the study. To evaluate specificity of the ADHD-PTSD association, we examined associations among predeployment ADHD, postdeployment major depressive episode (MDE), generalized anxiety disorder (GAD), and suicidal ideation. Weighted prevalence of ADHD predeployment was 6.1% (SE = 0.4%). Adjusting for other risk factors, predeployment ADHD was associated with risk of postdeployment PTSD, adjusted odds ratio (AOR) = 2.13, 95% CI [1.51, 3.00], p < .001, including incidence among soldiers with no predeployment history of PTSD, AOR = 2.50, 95% CI [1.69, 3.69], p < .001. ADHD was associated with postdeployment MDE, AOR = 2.80, 95% CI [2.01, 3.91], p < .001, and GAD, AOR = 3.04, 95% CI [2.10, 4.42], p < .001, but not suicidal ideation. Recognition of associations between predeployment ADHD and postdeployment PTSD, MDE, and GAD may inform targeted prevention efforts. Future research should examine whether treatment of ADHD is protective against PTSD and related disorders in trauma exposed individuals. PMID- 30461070 TI - Sympathetic overactivity in dialysis patients-Underappreciated and clinically consequential. AB - Cardiovascular morbidity and mortality remain frustratingly common in dialysis patients. A dearth of established evidence-based treatment calls for alternative therapeutic avenues to be embraced. Sympathetic hyperactivity, predominantly due to afferent nerve signaling from the diseased native kidneys, has been established to be prognostic in the dialysis population for over 15 years. Despite this, tangible therapeutic interventions have, to date, been unsuccessful and the outlook for patients remains poor. This narrative review summarizes established experimental and clinical data, highlighting recent developments, and proposes why interventions to ameliorate sympathetic hyperactivity may well be beneficial for this high-risk population. PMID- 30461071 TI - Portal vein variants associated with right hepatectomy: an analysis of abdominal CT angiography with 3D reconstruction. AB - BACKGROUND: Glissonian approach has been described as a selective vascular clamping procedure during hepatectomy based on external anatomical landmarks. Anatomical variations of the right Glissonian pedicle have been identified with an increased risk of clamping failure during Glissonian approach. The objective of this study was to characterize the anatomical variations of the right Glissonian pedicle at risk of clamping failure during right hepatectomy. MATERIAL: This was a retrospective analysis of abdominal multiphasic CT and routine 3D reconstruction (n=346). Anatomical variations at risk of clamping failure were type 1 to 3 (Madoff's classification) and an angle of less than 50 degrees between the portal vein and the left portal vein. Primary objective was the risk of right Glissonian pedicle clamping failure. Secondary objectives were the rate of normal anatomy, the rate of variations, and the rate of incomplete or extended clamping. RESULTS: Normal anatomy was found in 245 patients (71%). Anatomical variations were as follows: type 1: 11%, type 2: 17%, type 3: 0.8%, type 4: 0%. Angle variation less than 50 degrees was observed in 4.5%. The risk of selective clamping failure was 34%. Extension of clamping was observed in 16%, while incomplete clamping was observed in 17.8%. CONCLUSION: Failure of right Glissonian pedicle clamping was predictable in 34% of cases while 71% of patients presented normal portal vein anatomy. This article is protected by copyright. All rights reserved. PMID- 30461072 TI - Effectiveness of ureteroscope-assisted renal puncture for endoscopic combined intrarenal surgery. PMID- 30461073 TI - Robot-Assisted Laparoscopic Versus Laparoscopic Donor Nephrectomy in Renal Transplantation: A Meta-Analysis. AB - BACKGROUND: Currently, the robot-assisted laparoscopic donor nephrectomy (RDN) technique is used for live donor nephrectomy. Does it provide sufficient safety and benefits for living donors? We conducted a meta-analysis to assess the safety and efficacy of RDN compared with the laparoscopic donor nephrectomy (LDN). MATERIAL AND METHODS: Eligible studies were retrieved and screened from electronic databases from 1999 onward: PubMed, Cochrane Library and Web of Science. Relevant parameters were explored using Review Manager V5.3 and included operative time, warm ischemia time, estimated blood loss, and length of hospital stay. RESULTS: Compared with RDN, LDN had shorter operative time (min; weighted mean difference (WMD): -0.53; 95% CI: [-0.85, 0.20]; P=0.001) and warm ischemia time (second; WMD: -55.01; 95% CI: [-71.56, 38.45]; P<0.00001) and less estimated blood loss (ml; WMD: -28.30, 95% CI: [-46.37, 10.24], P=0.002). The pooled analysis of postoperative pain showed lower visual analogue scale (VAS) scores for RDN compared with LDN (WMD:1.28, P<0.00001). We also observed that length of hospital stay, postoperative serum creatinine (SCr) in donors, postoperative estimated glomerular filtration rate (eGFR) of recipients and postoperative complications for donors were not significantly different between groups. CONCLUSION: As long as RDN is practiced proficiently, it is believed that RDN is a feasible alternative to LDN. This article is protected by copyright. All rights reserved. PMID- 30461074 TI - Circulating miRNA-150-5p is associated with immune-mediated early beta-cell loss in a humanized mouse model. AB - BACKGROUND: Aberrant microRNA (miRNA) expression levels are associated with various graft rejections. We used our humanized mouse model with transplanted human islets to identify miRNAs in islet grafts related to xenograft rejection and circulating miRNAs associated with xenograft rejection-mediated beta-cell loss. METHODS: Diabetic immunodeficient NOD.scid mice were transplanted with human islets and subsequently achieved stable normoglycemia. Lymphocytes from NOD mice were then adoptively transferred to the humanized mice to induce human beta cell destruction. Islet graft and plasma were collected immediately once blood glucose reached >200 mg/dL. miRNAs in the islet grafts and in the plasma with or without adoptive lymphocyte transfer (ALT) were measured using NanoString nCounter(r) miRNA Expression Assay and qPCR. RESULTS: A set of immune-related miRNAs was significantly increased in human islet grafts of ALT-treated mice compared to control mice. Of these miRNAs, miR-150-5p was significantly increased in the circulation of ALT-treated mice at tissue collection and the increase was a result of immune activation rather than simply the presence of lymphocytes in circulation. Furthermore, miR-150-5p was significantly increased in human islet graft and circulation prior to the development of hyperglycemia in the ALT treated mice. CONCLUSIONS: Our data demonstrated that immune-related miRNAs are associated with human islet xenograft rejection in mice. miR-150-5p is increased in human islet graft and in the circulation during islet xenograft rejection and beta-cell destruction prior to hyperglycemia and may be an early biomarker for islet xenograft rejection. PMID- 30461075 TI - Optimal Axis for Lumbosacral Interbody Fusion: Prospective Finite Element Analysis and Retrospective 3D-CT Measurement. AB - INTRODUCTION: A feasible and optimal axis of biomechanical and anatomic significance in axial lumbosacral interbody fusion (AxiaLIF) was designed. MATERIALS AND METHODS: Using the image data set of an adult volunteer, two groups of finite element models of the AxiaLIF, lumbosacral anterior column fixation (ACF) models and middle column fixation (MCF) models with different bone graft fusion degrees, were prospectively established, and their biomechanical differences were comparatively predicted. In addition, 3D reconstruction was performed by retrospectively collecting CT data from pelvises in 60 adult cases. Their anatomic parameters relating to two groups of models were digitally measured and statistically compared. RESULTS: Numerical analysis revealed that the load and the maximum stress on the screw as well as the maximum stress difference between the screw and peripheral tissues in the MCF model were reduced compared with the ACF model. These indices of both models all decreased markedly in response to the increase in the disc fusion degree. Statistical analysis revealed that the effective fixed length of the sacrum in the MCF model was increased compared with the ACF model (P<0.05). The surgical dissection distance of presacral vessels and nerves from the axis to sacrum of the MCF model was reduced compared with the ACF model (P<0.05). CONCLUSIONS: The feasible and optimal axis of biomechanical and anatomic significance of the AxiaLIF is similar to the axis of the MCF model. Disc bone graft fusions plus axial screw fixations of middle column could strengthen the biomechanical stability of the AxiaLIF model. This article is protected by copyright. All rights reserved. PMID- 30461076 TI - Detection rate of clinically significant prostate cancer in magnetic resonance imaging and ultrasonography-fusion transperineal targeted biopsy for lesions with a prostate imaging reporting and data system version 2 score of 3-5. AB - OBJECTIVES: To evaluate the detection rates of clinically significant prostate cancer classified according to the prostate imaging reporting and data system scoring system using magnetic resonance imaging/ultrasound rigid fusion targeted biopsy. METHODS: A total of 339 patients underwent transperineal magnetic resonance imaging/ultrasound rigid fusion targeted biopsy in our institution between January 2015 and July 2017. Patients with prostate imaging reporting and data system category 1 or 2 and those with a pre-biopsy prostate-specific antigen value of >30 ng/mL were excluded from this study. Finally, 310 patients were recruited. RESULTS: The detection rates of clinically significant prostate cancer with prostate imaging reporting and data system category 3, 4, and 5 were 1.0% (1/98), 35.1% (47/134) and 73.1% (57/78), respectively. The factors affecting the detection of clinically significant prostate cancer with prostate imaging reporting and data system categories 4 and 5 were: (i) prostate imaging reporting and data system category 5; (ii) prostate volume <40 cc; (iii) no previous biopsy; (iv) lesion located in the peripheral zone; and (v) prostate-specific antigen density >0.35 ng/mL/mL. CONCLUSIONS: The detection rate of clinically significant prostate cancer on magnetic resonance imaging/ultrasound rigid fusion targeted biopsy is very low in patients with prostate imaging reporting and data system category 3; therefore, patients with this classification should not undergo targeted biopsy. Prostate-specific antigen density, prostate volume, locations of suspected cancer and history of biopsy should be considered to predict the detection rate of clinically significant prostate cancer with prostate imaging reporting and data system categories 4 and 5. PMID- 30461077 TI - Hsa_circ_0000467 promotes cancer progression and serves as a diagnostic and prognostic biomarker for gastric cancer. AB - BACKGROUND: Emerging evidence indicates that dysregulation of circular RNAs (circRNAs) is implicated in the development of malignancies. However, the diagnostic value and functional role of circRNAs in gastric cancer (GC) remain largely elusive. METHODS: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to detect the expression of hsa_circ_0000467 in tissues, cell lines, and plasma. A receiver operating characteristic (ROC) curve was constructed to estimate the diagnostic value of hsa_circ_0000467. The association between the expression level of hsa_circ_0000467 and the clinicopathological features was analyzed. Moreover, cell functional assays were performed. RESULTS: Hsa_circ_0000467 was significantly upregulated in GC tissue compared to adjacent nontumor tissue (n = 51, P < 0.05). Similar results were detected in the HGC-27, MGC-803, AGS, NUGC-3, GES-1 cell lines (n = 15, P < 0.001), and in the plasma samples from GC patients (n = 20, P < 0.05). The area under the ROC curve of hsa_circ_0000467 was 0.790, which is superior to commonly used biomarkers including CEA and CA-724. We found that the expression levels of hsa_circ_0000467 in the same patient were significantly lower after surgery (n = 20, P < 0.05). Moreover, the hsa_circ_0000467 expression level is closely associated with TNM stage. Additionally, Cox multivariate analysis showed that hsa_circ_0000467 is a novel independent prognostic factor. Furthermore, in vitro experiments demonstrated that knockdown of hsa_circ_0000467 markedly inhibited the proliferation, migration, and invasion of GC cells. Moreover, hsa_circ_0000467 silencing increased tumor apoptosis in vitro. CONCLUSION: Hsa_circ_0000467 can act as a novel noninvasive biomarker for the diagnosis and prognosis of GC and may be a potential therapeutic target for GC. PMID- 30461078 TI - Teledermatology diagnosis of the first Italian patient affected with restrictive dermopathy due to ZMPSTE24 homozygous mutation. PMID- 30461079 TI - Deep learning enables automatic quantitative assessment of the puborectalis muscle and the urogenital hiatus in the plane of minimal hiatal dimensions. AB - OBJECTIVES: Measuring the length, width and area of the urogenital hiatus (UH), and the length and mean echo intensity (MEP) of the Puborectalis muscle (PRM) automatically and observer independently in the plane of minimal hiatal dimensions from transperineal ultrasound (TPUS) images by automatic segmentation of the UH and the PRM using deep learning. METHODS: In 1318 3D/4D TPUS volume datasets, images of the plane of minimal hiatal dimensions were manually obtained and the UH and the PRM were manually segmented. Those images were obtained from 253 nulliparae at 12 and 36 weeks pregnancy with the PRM at rest, contraction and Valsalva. A total of 713 images were used to train a convolutional neural network (CNN) to automatically segment the UH and the PRM in the plane of minimal hiatal dimensions. In the remaining dataset (test set 1, TS1, 601 images, 4 images were excluded), the performance of the CNN was evaluated and compared to the manual segmentations. The performance of the CNN was also tested on 119 images of an independent dataset of 40 nulliparae at 12 weeks pregnancy. This dataset was acquired and manually segmented by another different observer (TS2, 2 images were excluded). For these segmentations, the segmentation success was manually scored. Based on the CNN segmentations the following clinically relevant parameters were measured; the length, width and area of the UH, and the length and mean echo intensity of the PRM. The overlap (Dice similarity index (DSI)), surface distance (mean absolute distance (MAD) and Hausdorff distance(HDD)) between manual and CNN segmentations were measured to investigate the similarity of both segmentations. For the measured clinically relevant parameters, the intraclass correlation coefficients (ICC) between manual and CNN results were determined. RESULTS: Fully automatic CNN segmentation was successful in 99.0% and 93.2% for TS1 and TS2, respectively. DSI, MAD and HDD showed good overlap and distance between manual and CNN segmentations in both test sets. This was reflected in the ICC values of the length (0.96 resp. 0.95), width (0.77 resp. 0.87) and area (0.96 resp. 0.91) of the UH and the length of the PRM (0.87 resp. 0.73) and the MEP (0.95 resp. 0.97), which showed a good to very good agreement. CONCLUSION: Deep learning can be used to automatically and reliably segment the PRM and UH in 2D, in the plane of minimal hiatal dimensions, of the nulliparous female pelvic floor. These segmentations can be used to reliably measure the parameters; hiatal dimensions, PRM length and MEP. This article is protected by copyright. All rights reserved. PMID- 30461080 TI - Systemic and local hepcidin as emerging and important peptides in renal homeostasis and pathology. AB - Recent data suggest that the importance of hepcidin goes beyond its classical role in controlling systemic iron metabolism. Local hepcidins are emerging as important peptides for organ homeostasis in the brain, heart, blood vessels, and in cancer as well. Similarly, accumulating data indicate that hepcidin does seem to be an important factor in renal homeostasis. This review encompasses present knowledge concerning the role of hepcidin in renoprotection and its use as a biomarker of kidney diseases. Understanding the role of hepcidin in kidneys is important due to its relevance for kidney physiology and its potential therapeutic application in kidney pathologies. (c) 2018 BioFactors, 2018. PMID- 30461081 TI - Prognostic significance of risk stratification in CHAARTED and LATITUDE studies among Japanese men with de novo metastatic prostate cancer. PMID- 30461082 TI - Award Winners and Abstracts of the 32nd Annual Symposium of The Protein Society; Boston, MA, July 9-12, 2018. PMID- 30461083 TI - Genetic association between different criteria to define sexual precocious heifers with growth, carcass, reproductive and feed efficiency indicator traits in Nellore cattle using genomic information. AB - The aim of this study was to estimate genetic parameters for different precocious calving criteria and their relationship with reproductive, growth, carcass and feed efficiency in Nellore cattle using the single-step genomic BLUP. The reproductive traits used were probability of precocious calving (PPC) at 24 (PPC24), 26 (PPC26), 28 (PPC28) and 30 (PPC30) months of age, stayability (STAY) and scrotal circumference at 455 days of age (SC455). Growth traits such as weights at 240 (W240) and 455 (W455) days of age and adult weight (AW) were used. Rib eye area (REA), subcutaneous fat thickness (SFT), rump fat thickness (RFT) and residual feed intake (RFI) were included in the analyses. The estimation of genetic parameters was performed using a bi-trait threshold model including genomic information in a single-step approach. Heritability for PPC traits was moderate to high (0.29-0.56) with highest estimates for PPC24 (0.56) and PPC26 (0.50). Genetic correlation estimates between PPC and STAY weakened as a function of calving age. Correlation with SC455, growth and carcass traits were low (0.25 0.31; -0.22 to 0.04; -0.09 to 0.18, respectively), the same occurs with RFI ( 0.09 to 0.08), this suggests independence between female sexual precocity and feed efficiency traits. The results of this study encourage the use of PPC traits in Nellore cattle because the selection for such trait would not have a negative impact on reproductive, growth, carcass and feed efficiency indicator traits. Stayability for sexual precocious heifers (PPC24 and PPC26) must be redefined to avoid incorrectly phenotype assignment. PMID- 30461084 TI - Aging-associated perifollicular changes and calcium deposition in poodles. AB - BACKGROUND: It is commonly accepted that canine dystrophic mineralization of the hair follicle glassy membrane can be seen in hyperadrenocorticism and as a senile change in poodles. Pathology textbooks define this change as deposition of calcium salts in the form of basophilic, amorphous, granular material along collagen fibrils. HYPOTHESIS/OBJECTIVES: The aim was to evaluate whether the incidence of the lesion is specific to poodles and if it is always associated with calcium deposition. ANIMALS: One hundred and forty-seven dogs divided into three groups: (i) 91 normal poodles; (ii) 40 dogs of other breeds; and (iii) 16 dogs with clinical/histopathological diagnosis of hyperadrenocorticism. METHODS AND MATERIALS: Retrospective study; with haematoxylin and eosin, and von Kossa staining. RESULTS: Our findings demonstrate that perifollicular changes of the hair follicle glassy membrane of poodles are not always associated with calcium deposition. CONCLUSIONS AND CLINICAL IMPORTANCE: A specific staining is needed to identify true calcium deposition when performing histological examination of the skin of poodles. PMID- 30461085 TI - Curcumin promotes burn wound healing in mice by upregulating caveolin-1 in epidermal stem cells. AB - We aimed to explore the effect of curcumin on epidermal stem cells (ESCs) in regulating wound healing and the underlying molecular mechanism. We treated mouse ESCs isolated from skin tissues with curcumin, and then assessed the proliferation ability of cells induced by epidermal growth factor using cell counting kit-8 assay. The pluripotency of ESCs was evaluated as well through examination of Nanog expression in ESCs. Further, mice with skin burns were treated with ESCs with or without curcumin pretreatments. Histological evaluations were then preformed to determine wound scores, cell proliferation, reepithelialization, and capillary density in wounds. Curcumin treatment promoted the proliferative ability of ESCs and conditioned medium from curcumin-treated ESCs enhanced human umbilical vein endothelial cell (HUVEC) tube formation. We also found curcumin treatment elevated caveolin-1 expression in ESCs, which was required for the beneficial effect of curcumin on ESC proliferation and HUVEC tube formation. Next, using a mouse model of burn wound healing, curcumin-treated ESCs exhibited enhanced wound closure, which also required caveolin-1 expression. Our current study demonstrates the beneficial effect of curcumin on burn wound healing in mice, which is mediated by upregulating caveolin-1 in ESCs, and supports the potential therapeutic role of curcumin in ESC-based treatment against skin wound healing. PMID- 30461086 TI - Water Adsorption and Transport on Oxidized Two-dimensional Carbon Materials. AB - Studies on the adsorption and transport of water molecules with oxidized two dimensional (2D) carbon materials have attracted increasing interest due to their wide applications, such as sensing, energy conversion and membrane separation. In this concept, we discuss the interaction between water molecules and oxidized 2D carbon materials (i.e., graphene oxide and graphdiyne oxide), present the influence of water adsorption and transport on the physicochemical properties of 2D carbon materials, and highlight the recent progress on oxidized 2D carbon materials-based proton conduction, electricity generation, water transport, and humidity sensing. Moreover, the opportunities and challenges in these research fields are discussed, especially the structural stability and chemical modification of 2D carbon materials. PMID- 30461087 TI - Magnetoelectric Radical Hydrocarbons. AB - The molecular radicals, systems with unpaired electrons of open-shell electronic structures, set the stage for a multidisciplinary science frontier relevant to the cooperative magnetic exchange interaction and magnetoelectric effect. Here ferroelectricity together with magnetic spin exchange coupling in molecular radical hydrocarbon solids is reported, representing a new class of magnetoelectrics. Electronic correlation through radical-radical interactions plays a decisive role in the coupling between magnetic and charge orders. A substantial photoconductance and visible-light photovoltaic effect are found in radical hydrocarbons. The ability to simultaneously control and retrieve the changes in magnetic and electrical responses opens up a new breadth of applications, such as radical magnetoelectrics, magnets, and optoelectronics. PMID- 30461088 TI - Excitonic Aharonov-Bohm Oscillations in Core-Shell Nanowires. AB - Phase coherence in nanostructures is at the heart of a wide range of quantum effects such as Josephson oscillations between exciton-polariton condensates in microcavities, conductance quantization in 1D ballistic transport, or the optical (excitonic) Aharonov-Bohm effect in semiconductor quantum rings. These effects only occur in structures of the highest perfection. The 2D semiconductor heterostructures required for the observation of Aharonov-Bohm oscillations have proved to be particularly demanding, since interface roughness or alloy fluctuations cause a loss of the spatial phase coherence of excitons, and ultimately induce exciton localization. Experimental work in this field has so far relied on either self-assembled ring structures with very limited control of shape and dimension or on lithographically defined nanorings that suffer from the detrimental effects of free surfaces. Here, it is demonstrated that nanowires are an ideal platform for studies of the Aharonov-Bohm effect of neutral and charged excitons, as they facilitate the controlled fabrication of nearly ideal quantum rings by combining all-binary radial heterostructures with axial crystal-phase quantum structures. Thanks to the atomically flat interfaces and the absence of alloy disorder, excitonic phase coherence is preserved even in rings with circumferences as large as 200 nm. PMID- 30461089 TI - Impact of Parental Asthma, Prenatal Maternal Asthma Control and Vitamin D Status on Risk of Asthma and Recurrent Wheeze in 3-Year Old Children. AB - BACKGROUND: While familial clustering of asthma is known, few studies have reported on the relative roles of paternal and maternal asthma, and the role of maternal asthma control in pregnancy on the risk for asthma in the child. OBJECTIVE: We aimed to investigate the relative roles of paternal asthma, maternal asthma, and maternal asthma control during pregnancy on the risk of asthma or recurrent wheeze in 3-year old children how prenatal and cord blood vitamin D status might affect this risk. METHODS: Data from 806 women, their partners (biologic fathers of the infant), and their children participated in the Vitamin D Antenatal Asthma Reduction Trail (VDAART, clinicaltrialsgov identification number NCT00920621) were used for this cohort analysis. The parental report of physician-diagnosed asthma or recurrent wheeze in offspring was the main outcome. Weibull regression models for interval-censored event times were used to estimate the main variables of interests and additional covariates on the outcome. RESULTS: The highest risk was observed among children with both parents being asthmatic relative to non-asthmatic parents (aHR=2.30, 95%CI: 1.35 3.84), and less so if only the mother was asthmatic (aHR=1.70, 95%CI: 1.17-2.40). In the subset of children born to asthmatic mothers, the risk for asthma was higher in those who were born to mothers whose asthma was uncontrolled (aHR=1.60, 95%CI: 1.02-2.54). Children whose mothers had sufficient vitamin D status (25Hydroxyvitamin D>=30 ng/mL) at early and late pregnancy and had cord blood vitamin D sufficiency demonstrated a lower risk of asthma/recurrent wheeze than children who had insufficient vitamin D status at birth (aHR=0.47, 95%CI: 0.27 0.83). CONCLUSION AND CLINICAL RELEVANCE: Careful attention to maternal asthma control, monitoring vitamin D status and correcting insufficiency at early pregnancy and maintaining the sufficiency status throughout pregnancy have potential preventive roles in offspring asthma or recurrent wheeze. This article is protected by copyright. All rights reserved. PMID- 30461090 TI - Truly Concomitant and Independently Expressed Short- and Long-Term Plasticity in a Bi2 O2 Se-Based Three-Terminal Memristor. AB - Concomitance of diverse synaptic plasticity across different timescales produces complex cognitive processes. To achieve comparable cognitive complexity in memristive neuromorphic systems, devices that are capable of emulating short-term (STP) and long-term plasticity (LTP) concomitantly are essential. In existing memristors, however, STP and LTP can only be induced selectively because of the inability to be decoupled using different loci and mechanisms. In this work, the first demonstration of truly concomitant STP and LTP is reported in a three terminal memristor that uses independent physical phenomena to represent each form of plasticity. The emerging layered material Bi2 O2 Se is used for memristors for the first time, opening up the prospects for ultrathin, high speed, and low-power neuromorphic devices. The concerted action of STP and LTP allows full-range modulation of the transient synaptic efficacy, from depression to facilitation, by stimulus frequency or intensity, providing a versatile device platform for neuromorphic function implementation. A heuristic recurrent neural circuitry model is developed to simulate the intricate "sleep-wake cycle autoregulation" process, in which the concomitance of STP and LTP is posited as a key factor in enabling this neural homeostasis. This work sheds new light on the development of generic memristor platforms for highly dynamic neuromorphic computing. PMID- 30461091 TI - Crystal structure of human Vaccinia-related kinase 1 (VRK1) in complex with AMP PNP, a non-hydrolysable ATP analog. AB - Vaccinia-related kinase 1 (VRK1), a serine/threonine mitotic kinase, is widely over-expressed in dividing cells and regarded as a cancer drug target primarily due to its function as an early response gene in cell proliferation. However, the mechanism of VRK1 phosphorylation and substrate activation is not well understood. More importantly even the molecular basis of VRK1 interaction with its cofactor, adenosine triphosphate (ATP), is unavailable to-date. As designing specific inhibitors remains to be the major challenge in kinase research, such a molecular understanding will enable us to design ATP-competitive specific inhibitors of VRK1. Here we report the molecular characterization of VRK1 in complex with AMP-PNP, a non-hydrolysable ATP-analog, using NMR titration followed by the co-crystal structure determined at 2.07A resolution. We also carried out the structural comparison of the AMP-PNP bound-form with its apo and inhibitor bound counterparts, which has enabled us to present our rationale toward designing VRK1 specific inhibitors. This article is protected by copyright. All rights reserved. PMID- 30461092 TI - Quasi-Hodgkin-Huxley Neurons with Leaky Integrate-and-Fire Functions Physically Realized with Memristive Devices. AB - Artificial neurons with functions such as leaky integrate-and-fire (LIF) and spike output are essential for brain-inspired computation with high efficiency. However, previously implemented artificial neurons, e.g., Hodgkin-Huxley (HH) neurons, integrate-and-fire (IF) neurons, and LIF neurons, only achieve partial functionality of a biological neuron. In this work, quasi-HH neurons with leaky integrate-and-fire functions are physically demonstrated with a volatile memristive device, W/WO3 /poly(3,4-ethylenedioxythiophene): polystyrene sulfonate/Pt. The resistive switching behavior of the device can be attributed to the migration of protons, unlike the migration of oxygen ions normally involved in oxide-based memristors. With multifunctions similar to their biological counterparts, quasi-HH neurons are advantageous over the reported HH and LIF neurons, demonstrating their potential for neuromorphic computing applications. PMID- 30461093 TI - Echogenicity of the puborectalis muscle, the cervix and the vastus lateralis muscle in pregnancy in relation to mode of delivery. AB - OBJECTIVES: The primary objective of this study was to confirm our previous observation that hiatal dimensions and mean echogenicity of the puborectalis muscle (MEP) were statistically significant different at 12 weeks gestation in women who delivered by a caesarean section (CS) due to failure to progress (FTP), compared to women who delivered vaginally. The secondary objective was to assess the association between the echogenicity of the cervix and the vastus lateralis muscle and mode of delivery. METHODS: In this multicenter study 306 nulliparous women with a singleton pregnancy received ultrasound assessments of the pelvic floor at rest, contraction and on Valsalva maneuver, of the cervix and of the vastus lateralis muscle at 12 weeks' gestation. Dimensions of the levator hiatus and mean echogenicity of the puborectalis muscle, cervix and vastus lateralis muscle were measured. RESULTS: Two hundred forty-seven women were eligible for analyses. We were unable to confirm our previous finding that the MEP and hiatal transverse diameter and area at 12 weeks gestation are significantly associated with the mode of delivery. In addition, we could not demonstrate a significant association between the echogenicity of the cervix and vastus lateralis muscle and mode of delivery. Furthermore, no significant differences between the levator hiatal dimensions and the modes of delivery are found. Overall, we noticed a mean 20 points lower MEP in all women in the new database as compared to the previous study, despite the use of the same ultrasound equipment. CONCLUSION: In a second, independent multicenter dataset we were unable to confirm our previous finding that the hiatal dimensions and MEP on contraction were statistically significant associated with the mode of delivery. The overall lower MEP in all women was caused by to a higher depth in all ultrasound images of the current study. This article is protected by copyright. All rights reserved. PMID- 30461094 TI - Redox Proteins. PMID- 30461095 TI - Carbon-Based Metal-Free Catalysts for Key Reactions Involved in Energy Conversion and Storage. AB - Electrocatalysts are key for renewable energy technologies and other important industrial processes. Currently, noble metals and metal oxides are the most widely used catalysts for electrocatalysis. However, metal-based catalysts often suffer from multiple disadvantages, including high cost, low selectivity, poor durability, impurity poisoning and fuel crossover effects, and detrimental effects on the environment. Therefore, carbon-based metal-free catalysts have received increasing interest as promising electrocatalysts for advanced energy conversion and storage. Recently, tremendous progress has been achieved in the development of low-cost, efficient carbon-based metal-free catalysts for renewable energy technologies and beyond. Here, a concise, but comprehensive and critical, review of recent advances in the field of carbon-based metal-free catalysts is provided. A brief overview of various reactions involved in renewable energy conversion and storage, including the oxygen reduction reaction, hydrogen evolution reaction, oxygen evolution reaction, carbon dioxide reduction reaction, nitrogen reduction reaction, and bifunctional/multifunctional electrocatalysis, along with some challenges and opportunities, is presented. PMID- 30461096 TI - Structural versatility that serves the function of the HRD motif in the catalytic loop of protein tyrosine kinase, Src. AB - Site-directed mutagenesis is a traditional approach for structure-function analysis of protein tyrosine kinases, and it requires the generation, expression, purification, and analysis of each mutant enzyme. In this study, we report a versatile high throughput bacterial screening system that can identify functional kinase mutants by immunological detection of tyrosine phosphorylation. Two key features of this screening system are noteworthy. First, instead of blotting bacterial colonies directly from Agar plates to nitrocellulose membrane, the colonies were cultured in 96-well plates, and then spotted in duplicate onto the membrane with appropriate controls. This made the screening much more reliable compared to direct colony blotting transfer. A second feature is the parallel use of a protein tyrosine phosphatase (PTP)-expressing host and a non-PTP-expressing host. Because high activity Src mutants are toxic to the host, the PTP system allowed the identification of Src mutants with high activity, while the non-PTP system identified Src mutants with low activity. This approach was applied to Src mutant libraries randomized in the highly conserved HRD motif in the catalytic loop, and revealed that structurally diverse residues can replace the His and Arg residues, while the Asp residue is irreplaceable for catalytic activity. This article is protected by copyright. All rights reserved. PMID- 30461097 TI - A Qualitative Exploration of Social and Environmental Factors Affecting Diet and Activity in Knee Replacement Patients. AB - AIMS AND OBJECTIVES: This study examined perceived social and environmental barriers and facilitators for healthy eating and activity before and after knee replacement. BACKGROUND: Many patients undergoing knee replacement surgery are overweight or obese. While obesity treatment guidelines encourage diet and activity modifications, gaps exist in understanding social and environmental determinants of these behaviors for knee replacement patients. Identifying these determinants is critical for treatment, as they are likely amplified due to patients' mobility limitations, the nature of surgery, and reliance on others during recovery. DESIGN: This qualitative study utilized semi-structured interviews. METHODS: Twenty patients (M= 64.7+/-9.8 years, 45% female, 90% Caucasian, BMI 30.8+/-5.5 kg/m2 ) who were scheduled for or had recently undergone knee replacement were interviewed. Participants were asked to identify social and environmental factors that made it easier or harder to engage in healthy eating or physical activity. Deidentified transcripts were analyzed via constant comparative analysis to identify barriers and facilitators to healthy eating and activity. This paper was written in accordance with COREQ standards. RESULTS: Identified social and environmental healthy eating barriers included availability of unhealthy food and attending social gatherings; facilitators included availability of healthy food, keeping unhealthy options 'out of sight,' and social support. Weather was the primary activity barrier, while facilitators included access to physical activity opportunities and social support. CONCLUSIONS: Results provide salient factors for consideration by clinicians and behavioral programs targeting diet, activity, and weight management, and patient variables to consider when tailoring interventions. RELEVANCE TO CLINICAL PRACTICE: Practitioners treating knee replacement patients would be aided by an understanding of patients' perceived social and environmental factors that impede or facilitate surgical progress. Particularly for those directly interacting with patients, like nurses, physiotherapists, or other professionals, support from health professionals appears to be a strong facilitator of adherence to diet and increased activity. This article is protected by copyright. All rights reserved. PMID- 30461098 TI - N domain of the Lon AAA+ protease controls assembly and substrate choice. AB - The protein quality control network (pQC) plays critical roles in maintaining protein and cellular homeostasis, especially during stress. Lon is a major pQC AAA+ protease, conserved from bacteria to human mitochondria. It is the principal enzyme that degrades most unfolded or damaged proteins. Degradation by Lon also controls cellular levels of several key regulatory proteins. Recently, our group determined that E. coli Lon, previously thought to be an obligate homo-hexamer, also forms a dodecamer. This larger assembly has decreased ATPase activity and displays substrate-specific alterations in degradation compared to the hexamer. Here we experimentally probe the physical hexamer-hexamer interactions and the biological roles of the Lon dodecamer. Using structure prediction methods coupled with mutagenesis, we identified a key interface and specific residues within the Lon N domain that participate in an intermolecular coiled coil unique to the dodecamer. With this knowledge, we made a Lon variant (LonVQ ) that forms a dodecamer with increased stability, as determined by analytical ultracentrifugation and electron microscopy. Using this altered Lon, we characterize the Lon dodecamer's activities using a panel of substrates. Lon dodecamers are clearly functional, and complement critical lon- phenotypes but also exhibit altered substrate specificity. For example the small heat shock proteins IbpA and IbpB are only efficiently degraded well by the hexamer. Thus, by elucidating the intermolecular contacts connecting the hexamers, we are starting to illuminate how dodecamer formation versus disassembly can alter Lon function under conditions where controlling specific activities and substrate preferences of this key protease may be advantageous. PMID- 30461099 TI - Risk of exposure to air pollution among British children with and without intellectual disabilities. AB - BACKGROUND: Exposure to outdoor air pollution is a well-established risk factor for a range of adverse health conditions. No previous study has quantified the extent to which children with intellectual disability (ID) may be exposed to outdoor air pollution. METHODS: Secondary analysis of data extracted from the UK's Millennium Cohort Study, a nationally representative sample of over 18 000 UK children born 2000-2002. RESULTS: Averaging across ages, children with IDs were 33% more likely to live in areas with high levels of diesel particulate matter, 30% more likely to live in areas with high levels of nitrogen dioxide, 30% more likely to live in areas with high levels of carbon monoxide and 17% more likely to live in areas with high levels of sulphur dioxide. CONCLUSIONS: Levels of exposure to outdoor air pollution among children with ID are significantly higher than those of families of children without ID. Exposure to outdoor air pollution may be one of the pathways that contributes to the health inequities experienced by people with IDs. PMID- 30461100 TI - A rodent cage change insomnia model disrupts memory consolidation. AB - Insomnia involves disruption of sleep initiation, maintenance and/or overall quality, and may interfere with cognition. Here, we evaluated memory impairment produced by rodent mild (acute) insomnia models. Insomnia models consisted of either single or repeated exposure to cages previously occupied (dirtied) by an unfamiliar rat for 5-7 days. Rats were trained in the Morris water maze to remember the platform location (acquisition), and were then exposed to: (a) 6 hr of undisturbed baseline; (b) dirty cage change-induced insomnia (animal placed into a cage dirtied by another rat for 6 hr); or (c) double-dirty cage change induced insomnia (animal placed into a cage dirtied by another rat for 3 hr, and then another dirty cage 3 hr later). The animal's memory for the platform location was then evaluated in a probe trial. Double-dirty cage change-induced insomnia significantly disrupted sleep, although the effects of dirty cage change induced insomnia were overall not significant. In the fourth hour of double-dirty cage change-induced insomnia (following the second cage change), sleep episode number and duration alterations indicated sleep fragmentation. Furthermore, power spectral analysis revealed diminished wake and, to a lesser extent, rapid eye movement theta power (indicated by trend difference) in the last 3 hr of exposure. Significant deficits were noted for measures of water maze performance following double-dirty cage change-induced insomnia, indicating impaired memory. In summary, one variant of the rodent insomnia model, double-dirty cage change induced insomnia, disrupted sleep and attenuated memory consolidation, indicating this paradigm may be useful to evaluate the effects of hypnotics on memory consolidation. PMID- 30461101 TI - Lived experiences and quality of life after gynaecological cancer - an integrative review. AB - AIM AND OBJECTIVES: To review the literature on Nordic women's lived experiences and quality of life (QoL) after gynaecological cancer treatment. BACKGROUND: While incidence and survival are increasing in all groups of gynaecological cancers in the Nordic countries, inpatient hospitalization has become shorter in relation to treatment. This has increased the need for follow-up and rehabilitation. DESIGN: Integrative literature review using the Equator PRISMA guidelines. METHODS: The review was selected, allowing inclusion of both experimental and non-experimental research. The search included peer-reviewed articles published 1995-2017. To frame the search strategy, we applied the concept of rehabilitation, which holds a holistic perspective on health. RESULTS: Fifty-five articles were included and were contextualized within three themes. Physical wellbeing in a changed body encompasses bodily changes comprising menopausal symptoms, a changed sexual life, complications in bowels, urinary tract, lymphedema and pain, bodily-based preparedness and fear of recurrence. Mental wellbeing as a woman deal with questioned womanliness, the experience of revitalized values in life, and challenges of how to come to terms with oneself after cancer treatment. Psychosocial wellbeing and interaction deal with the importance of having a partner or close person in the process of coming to terms with oneself after cancer. Furthermore, the women needed conversations with health professionals around the process of coping with changes and late effects, including intimate and sensitive issues. CONCLUSION: Years after gynaecological cancer women have to deal with fundamental changes and challenges concerning their physical, mental and psychosocial wellbeing. Future research should focus on how follow-up programs can be organized to target the multidimensional aspects of women's QoL. Research collaboration across Nordic countries on rehabilitation needs and intervention is timely and welcomed. RELEVANCE TO CLINICAL PRACTICE: To ensure that all aspects of cancer rehabilitation are being addressed, we suggest that the individual woman is offered an active role in her follow-up. This article is protected by copyright. All rights reserved. PMID- 30461102 TI - Physiological effects of cold-dry versus heated-humidified partial amniotic carbon dioxide insufflation in sheep. AB - OBJECTIVES: Partial amniotic carbon dioxide (CO2 ) insufflation (PACI) is used to improve visualisation and enable complex fetoscopic surgery. However, concerns exist about fetal hypercapnic acidosis and post-operative fetal membrane inflammation. We assessed whether heated-humidified CO2 would reduce the impact of PACI on the fetus and fetal membranes in sheep. METHODS: Fetal lambs 105 days gestation (term=145 days) were partially delivered through a caesarean section and instrumented with arterial catheters and flow probes. Fetuses were returned to the uterus which was then closed and insufflated with cold-dry (22o C at 0-5% humidity, n=7) or heated-humidified CO2 (40o C at 100% humidity, n=5) at 15mmHg for 180 minutes. Fetal membranes were collected immediately after insufflation for histological analysis. Physiological data and membrane cell counts are presented as mean+/-SEM and median [IQR] as appropriate. RESULTS: After 180 minutes, fetal survival was 0% with cold-dry PACI, and 60% with heated humidified. Compared to cold-dry, heated-humidified PACI reduced fetal hypercapnia (170.5 +/-28.5 vs. 82.7 +/-9.1mmHg, p<0.01), lactate accumulation (8.5 +/-0.9 vs. 1.4 +/-0.4mmol/L, p<0.01) and subsequent acidosis (pH 6.75 +/ 0.04 vs. 7.10 +/-0.04, p<0.01). Heated-humidified PACI also maintained arterial pressures (46.8+/-1.2 vs. 12.3 +/-8.5mmHg, p=0.22) and significantly reduced the number of leukocytes in the chorion (0.7x10-5 [0.5x10-5 ] vs. 3.2x10-5 [1.8x10-5 ] cells per square micron, p=0.02). CONCLUSIONS: Cold-dry PACI caused fetal hypercapnia, acidosis, hypotension and fetal membrane inflammation in sheep raising potential concerns for use in humans. Heated-humidified PACI partially mitigated these effects and may be a suitable alternative that reduces the risk of fetal acid base disturbances and fetal membrane inflammation following complex fetoscopic surgery. This article is protected by copyright. All rights reserved. PMID- 30461103 TI - Experiences of living with varicose veins: a systematic review of qualitative research. AB - AIM: To identify the symptoms and quality of life impacts that are important from the perspective of patients with varicose veins, and to compare identified themes to items in varicose vein Patient Reported Outcome Measures (PROMs). BACKGROUND: Varicose veins are common worldwide, and are considered a chronic condition with implications for quality of life. Treatment is predominantly conservative, therefore understanding patients' experiences' of living with varicose veins is important to inform the provision of clinical care. PROMs are often used to collect data about patients' quality of life. DESIGN: Thematic synthesis of qualitative research reported according to ENTREQ guidelines. METHODS: Multiple electronic databases, including MEDLINE and CINAHL, were systematically searched to identify qualitative research examining experiences of adults with varicose veins. Thematic synthesis was then conducted on the included studies. RESULTS: Three studies met the inclusion criteria; the quality of the studies was high. The range and intensity of reported symptoms and participant's experiences of living with varicose veins were varied. Five overarching themes were identified; physical, psychological and social impact of varicose veins, adapting to varicose veins and reasons for seeking treatment. The overall key theme to emerge was adaptation, with patients' demonstrating how they adapted to the various impacts. CONCLUSION: This review demonstrates that varicose veins have a wide range of symptoms, and may have a significant impact on quality of life; people made significant adaptations to enable them to live their lives as fully as possible. RELEVANCE TO CLINICAL PRACTICE: Healthcare professionals need to be aware of the range of symptoms, and their impact on quality of life. The use of PROMs to gather information about quality of life and symptoms is well established globally; however, PROMs currently used may not capture the full extent of the impact on patient's quality of life. This article is protected by copyright. All rights reserved. PMID- 30461104 TI - Dysregulation of TDP-43 Intracellular Localization and Early-Onset ALS are Associated with a TARDBP S375G Variant. AB - We investigated the CNS and skeletal muscle tissue from a woman clinically diagnosed with amyotrophic lateral sclerosis (ALS) at the age of 22. Neuropathologic evaluation showed upper and lower motor neuron loss, corticospinal tract degeneration, and skeletal muscle denervation.Analysis of the patient's DNA revealed a AGT>GGT change resulting in a S375G substitution in the C-terminal region of TDP-43. This variant was previously reported as being benign. Considering the early onset and severity of the disease in this patient, we tested the effects of this genetic variant on TDP-43 localization, pre-mRNA splicing activity, and toxicity, in parallel with the effects on known neighboring disease-associated mutations. In cell lines, expressed in culture, S375G TDP-43 appeared to be more significantly localized in the nucleus and to exert higher toxicity than wild-type TDP-43. Strikingly, a phosphomimic mutant at the same residue (S375E) showed a strong tendency to accumulate in the cytoplasm, especially under stress conditions, and molecular dynamics simulations suggest that phosphorylation of this residue can disrupt TDP-43 intermolecular interactions. The results of the current study highlight the importance of phosphorylation and regulation of TDP-43 nuclear-cytoplasmic shuttling/redistribution, in relation to the pathogenetic mechanisms involved in different forms of ALS. This article is protected by copyright. All rights reserved. PMID- 30461105 TI - Resource use and cost of annual health checks in primary care for people with intellectual disabilities. AB - BACKGROUND: The annual health check (AHC) programme, as part of a Directed Enhanced Service, offers an incentive to general practitioners in England to conduct health checks for people with intellectual disabilities (IDs). The aim of this analysis was to estimate the impact on health care costs of AHCs in primary care to the National Health Service in England by comparing adults with ID who did or did not have AHCs using data obtained from The Health Improvement Network. METHODS: Two hundred eight records of people with ID from The Health Improvement Network database were analysed. Baseline health care resource use was captured at the time the first AHC was recorded (i.e. index date), or the earliest date after 1 April 2008 for those without an AHC. We examined the volume of resource use and associated costs that occurred at the time AHCs were performed, as well as before and after the index date. We then estimated the impact of AHCs on health care costs. RESULTS: The average cost of AHC was estimated at L142.57 (95%CI L135.41 to L149.74). Primary, community and secondary health care costs increased significantly after the index date in the no AHC group owing to higher increase in resource utilisation. Regression analysis showed that the expected health care cost for those who have an AHC is 56% higher than for those who did not have an AHC. Age and gender were also associated with increase in expected health care cost. CONCLUSION: The level of resource utilisation increased in both (AHC and no AHC) groups after the index date. Although the level of resource use before index date was lower in the no AHC group, it increased after the index date up to almost reaching the level of resource utilisation in the AHC group. Further research is needed to explore if the AHCs are effective in reducing health inequalities. PMID- 30461106 TI - Diffusion Tensor Imaging of the Superior Thalamic Radiation and Cerebrospinal Fluid Distribution in Idiopathic Normal Pressure Hydrocephalus. AB - BACKGROUND AND PURPOSE: Ventricular enlargement in elderly raises a challenging differential diagnosis to physicians. While Alzheimer's disease is the most common form of dementia, idiopathic normal pressure hydrocephalus (iNPH) constitutes a potentially reversible syndrome. iNPH has a unique pathophysiology pertaining to cerebrospinal fluid (CSF) dynamics and periventricular white matter. We aimed to determine the effects of iNPH on periventricular white matter bundles and to further characterize its ventricular and sulcal CSF distribution by using diffusion tensor tractography (DTT) and CSF volumetrics on high resolution T1-weighted magnetic resonance imaging data. METHODS: Deterministic DTT and validated volumetric parcellation were performed on 20 healthy elderly, 13 Alzheimer's disease (AD), and 9 iNPH patients. The superior thalamic radiation, corticospinal tract, and dentatorubrothalamic tract were traced and quantified using DTI studio software. Cloud-based volumetric parcellation was also performed on 138 healthy subjects across the lifespan, 13 AD, and 9 iNPH patients. Ventricular and sulcal CSF volumes in the three groups were compared. RESULTS: Combining increased mean diffusivity of the superior thalamic radiation with ventricular volume resulted in clear separation of iNPH from the AD and age matched healthy subject groups. Additionally, ventricular to sulcal CSF ratio, utilizing fully automated methods, was significantly greater in the iNPH patients compared to AD and healthy age-matched controls. CONCLUSIONS: Combined microstructural (DTT) and macrostructural (ventricular volume) changes is a promising radiological approach in studying ventriculomegaly. Automated estimation of the disproportionate ventricular and sulcal CSF ratio in patients presenting with ventriculomegaly may be important as radiologic markers in differentiating iNPH from other causes of ventriculomegaly. PMID- 30461107 TI - Releasing small ejaculates slowly increases per-gamete fertilization success in an external fertilizer: Galeolaria caespitosa (Polychaeta: Serpulidae). AB - The idea that male reproductive strategies evolve primarily in response to sperm competition is almost axiomatic in evolutionary biology. However, externally fertilizing species, especially broadcast spawners, represent a large and taxonomically diverse group that have long challenged predictions from sperm competition theory - broadcast spawning males often release sperm slowly, with weak resource-dependent allocation to ejaculates despite massive investment in gonads. One possible explanation for these counterintuitive patterns is that male broadcast spawners experience strong natural selection from the external environment during sperm dispersal. Using a manipulative experiment, we examine how male reproductive success in the absence of sperm competition varies with ejaculate size and rate of sperm release, in the broadcast spawning marine invertebrate Galeolaria caespitosa (Polychaeta: Serpulidae). We find that the benefits of fast or slow sperm release depend strongly on ejaculate size, but also that the per-gamete fertilization rate decreases precipitously with ejaculate size. Overall, these results suggest that, if males can facultatively adjust ejaculate size, they should slowly release small amounts of sperm. Recent theory for broadcast spawners predicts that sperm competition can also select for slow release rates. Taken together our results and theory suggest selection for slow release rates regardless of whether males experience sperm competition or not. This article is protected by copyright. All rights reserved. PMID- 30461108 TI - Correlates of early cognition in infants with Down syndrome. AB - BACKGROUND: While delays in cognitive development are detectable during early development in Down syndrome, the neuropsychological and biomedical underpinnings of cognitive skill acquisition in this population remain poorly understood. METHOD: To explore this issue, 38 infants with Down syndrome [mean chronological age = 9.65 months; SD = 3.64] completed the Bayley Scales of Infant Development III and a set of laboratory tasks that measured sustained attention (duration of visual attention during a 1-min object exploration task), attention shifting (mean latency to shift attention on an alternating object presentation task) and visual short-term memory (dishabituation to a novel object on a change preference task). RESULTS: Latency to shift attention was negatively associated with Bayley Cognitive Scale raw scores, even when controlling for the effects of chronological age, r (33) = -.41, P = .02. In addition, prematurity status was associated with latency to shift attention. CONCLUSIONS: Early attention shifting may be an important factor that facilitates overall cognitive skill acquisition in infants with Down syndrome, and premature birth may be a risk factor for difficulties on this dimension. PMID- 30461109 TI - The prevalence of temporal bone fractures is high in horses with severe temporohyoid osteoarthropathy. AB - Temporohyoid osteoarthropathy is a well-recognized cause of equine neurologic disease. Temporal bone fractures associated with temporohyoid osteoarthropathy have been recognized with CT, however, little information is available regarding these fractures. The aims of this retrospective analytical study were to assess the prevalence of these fractures and to describe the specific configurations and associated imaging and clinical features. Fracture of the temporal bone was identified with CT in 16 of 39 included horses. All fractures were unilateral, minimally displaced and extended through the temporal bone in a rostrodorsal to caudoventral orientation. Two fracture configurations were identified: in nine cases, the fracture extended the full width of the petrous pyramid into the cranial vault and in seven cases, the fracture only extended through the lateral part of the petrous temporal bone, not involving the cranial vault. Fusion of the temporohyoid joint was present in 13 of the 16 fracture cases. Quarter Horses were over-represented in the fractured population (14/16). All horses with fractures had ipsilateral neurologic deficits. Patient outcomes were not significantly different between temporohyoid osteoarthropathy horses with and without temporal bone fractures (P = 0.68). However, six of the nine patients with cranial vault involvement did not return to their previous use. Findings support previous studies indicating that temporal bones should be carefully assessed for concurrent fractures when temporohyoid osteoarthropathy is identified in CT images, especially when there is fusion of the temporohyoid joint. An improved awareness of specific fracture configurations will help with detection of these fractures. PMID- 30461110 TI - Early Phase PIB-PET as a Surrogate for Global and Regional Cerebral Blood Flow Measures. AB - BACKGROUND AND PURPOSE: To explore the potential for simplified measures of [11 C]PIB uptake to serve as a surrogate for cerebral blood flow (CBF) measures, thereby, providing both pathological and functional information in the same scan. METHODS: Participants (N = 24, 16 M, 8 F, 57-87 years) underwent quantitative [15 O]water imaging and dynamic [11 C]PIB imaging. Time-activity curves were created for each participant's regional [11 C]PIB data scaled in standardized uptake values (SUVs). The frame in which maximal uptake occurred was defined for each subject (ie, "peak"). The concentration (SUV) for each region at the individual's peak, during the 3.5-4 minute time interval and for the initial 6 minute sum, was determined. R1 (ie, relative delivery using cerebellum as reference tissue) from the simplified reference tissue model 2 was determined for each region. PIB SUVs were compared to the absolute CBF global and regional values (in mL/minute/100 mL) and the R1 values were compared to the cerebellar-normalized rCBF. RESULTS: Significant linear relationships were found for all SUV measures with measures of absolute global and regional CBF that were comparable to the relationship between normalized CBF and R1. The individual SUVpeak exhibited the strongest relationship both regionally and globally. All individuals and all regions had highly significant regression slopes. Age, gender, or amyloid burden did not influence the relationship. CONCLUSION: Early PIB uptake has the potential to effectively serve as a surrogate for global and regional CBF measures. The simple and readily obtainable individual's SUVpeak value was the strongest predictor regionally and globally of CBF. PMID- 30461111 TI - Self-wise, Other-wise, Streetwise (SOS) training, an intervention to prevent victimization in dual diagnosis patients: results from a randomized clinical trial. AB - BACKGROUND AND AIMS: Patients with co-occurring substance use and other mental disorders are vulnerable to crime victimization, yet no evidence based preventive interventions exist. Our aim was to test the efficacy of a new intervention, Self wise, Other-wise, Streetwise training (SOS-training), to prevent victimization in these dual diagnosis patients as an add-on to care as usual. DESIGN: Multi-site single-blind parallel randomized controlled trial. SETTING: Three sites within one psychiatric service in Amsterdam, the Netherlands. PARTICIPANTS: Adult inpatients and outpatients with dual diagnosis (n=250), who were predominantly male (70.4%), on average 42.1 years old, and diagnosed with 3.7 DSM-IV disorders. INTERVENTION AND COMPARATOR: Care as usual, consisting of pharmacotherapy combined with individual psychotherapy, group psychotherapy and/or supportive counselling (n=125) was compared with care as usual plus SOS-training: a 6-week, 12-session manualized group training focused on enhancing emotion regulation skills, conflict resolution skills, and street skills (n=125). MEASUREMENTS: Victimization was assessed with the Safety Monitor, the Dutch equivalent of the International Crime Victims Survey, in a face-to-face assessment. The primary outcome measure was treatment response (yes/no), with yes defined as reporting at least a 50% reduction in the number of past year victimization incidents at the 14-month follow-up compared with baseline. Analyses were performed according to the intention-to-treat principle. FINDINGS: The proportion of participants achieving treatment response for total victimization was 54.0% in the control group and 67.6% in the experimental group, a significant difference [odds ratio (OR)= 1.78, 95% confidence interval (CI)= 1.02-3.11, P= .042]. Treatment response for violent victimization was achieved by 68.7% of the control group and 79.3% of the experimental group (OR= 1.75, 95% CI= 0.91-3.34, P= .092). With a Bayes factor of 2.26, this result was inconclusive. CONCLUSIONS: Among dual diagnosis patients, care as usual plus Self-wise, Other-wise, Streetwise (SOS) training was more effective in preventing victimization than care as usual alone. PMID- 30461112 TI - Association between 12-hr shifts and nursing resource use in an acute hospital: Longitudinal study. AB - AIM: To evaluate whether >=12-hr shifts are associated with a decrease in resource use, in terms of care hours per patient day and staffing costs per patient day. BACKGROUND: Nurses working long shifts may become less productive and no research has investigated whether potential cost savings are realized. METHOD: A retrospective longitudinal study using routinely collected data from 32 wards within an English hospital across 3 years (1 April 2012-31 March 2015). There were 24,005 ward-days. Hierarchical linear mixed models measured the association between the proportion of >=12-hr shifts worked on a ward-day, care hours per patient day and staffing costs per patient day. RESULTS: Compared with days with no >=12-hr shifts, days with between 50% and 75% >=12-hr shifts had more care hours per patient day and higher costs (estimate for care hours per patient day: 0.32; 95% CI: 0.28-0.36; estimate for staffing costs per patient day: L8.86; 95% CI: 7.59-10.12). CONCLUSIONS: We did not find reductions in total care hours and costs associated with the use of >=12-hr shifts. The reason why mixed shift patterns are associated with increased cost needs further exploration. IMPLICATIONS FOR NURSING MANAGEMENT: Increases in resource use could result in additional costs or loss of productivity for hospitals. Implementation of long shifts should be questioned. PMID- 30461113 TI - Double ventricular capture by a single atrial extrastimulus during slow-fast atrioventricular reentrant tachycardia. AB - A 49-year-old woman underwent catheter ablation of slow-fast atrioventricular nodal reentrant tachycardia (AVNRT) targeting the antegrade slow pathway (SP). After a successful SP modification, another slower tachycardia with a tachycardia cycle length of 522ms was induced during an isoproterenol infusion. This article is protected by copyright. All rights reserved. PMID- 30461114 TI - Dying Alone: The Sad Irrelevance of Naloxone in the Context of Solitary Opiate Use. PMID- 30461115 TI - Changes over time in marijuana use, deviant behavior and preference for risky behavior among U.S. adolescents from 2002-2014: Testing the moderating effect of gender and age. AB - BACKGROUND AND AIMS: Among adolescents, risk preference and deviant behaviors are associated with marijuana use, which exhibit substantial historical trends. We examined 1) trends, 2) effect modification by sex and age, 3) associations of marijuana use with deviant behaviors and risk preferences, and 4) differences by sex, age, and year. DESIGN: Adjusted logistic and relative risk regression models, using data from the 2002-2014 National Survey on Drug Use and Health, annual cross-sectional surveys of U.S. households. SETTING: U.S. PARTICIPANTS: A nationally representative sample of adolescents 12-17 years-old (n=230,452). MEASUREMENTS: We estimated associations between past-year marijuana use (self reported using CAPI/ACASI), deviant behavior (i.e., selling drugs; stealing; attacking someone), and risk preference (i.e., getting a kick; testing oneself). FINDINGS: Marijuana use, deviant behaviors, and risk preferences declined among adolescents from 2002-2014. There were no significant sex or age differences in the decline of marijuana use over time. There were sex (sold drugs: beta=0.90, 95% CI: 0.75, 1.04) and age (attacked someone: beta=0.32, 95% CI: 0.22, 0.42) differences in the prevalence of deviant behaviors, and trends over time differed by sex and age for attacking someone. CONCLUSIONS: While marijuana use, deviant behavior, and risk preferences among U.S. adolescents declined from 2002 to 2014, associations have remained stable, with marijuana use positively associated with deviant behavoirs and risk preferences. PMID- 30461116 TI - Long non-coding RNA expression profiling in cancer: challenges and opportunities. AB - In recent years, technological advances in transcriptome profiling revealed that the repertoire of human RNA molecules is more diverse and extended than originally thought. This diversity and complexity mainly derives from a large ensemble of non-coding RNAs. Because of their key roles in cellular processes important for normal development and physiology, disruption of non-coding RNA expression is intrinsically linked to human disease, including cancer. Therefore, studying the non-coding portion of the transcriptome offers the prospect of identifying novel therapeutic and diagnostic targets. While evidence of the relevance of non-coding RNAs in cancer is accumulating, we still face many challenges when it comes to accurately profiling their expression levels. Some of these challenges are inherent to the technologies employed, while others are associated with characteristics of the non-coding RNAs themselves. In this review, we discuss the challenges related to long non-coding RNA expression profiling, highlight how cancer long non-coding RNAs provide new opportunities for cancer diagnosis and treatment, and reflect on future developments. This article is protected by copyright. All rights reserved. PMID- 30461117 TI - Machine-Learning Prediction of Adolescent Alcohol Use: A Cross-Study, Cross Cultural Validation. AB - BACKGROUND AND AIMS: The experience of alcohol use among adolescents is complex, with international differences in age of purchase and individual differences in consumption and consequences. This latter underlines the importance of prediction modeling of adolescent alcohol use. The current study a) compared the performance of seven machine-learning algorithms to predict different levels of alcohol use in mid-adolescence and b) used a cross-cultural cross-study scheme in the training-validation-test process to display the predictive power of the best performing machine-learning algorithm. DESIGN: A comparison of seven machine learning algorithms: Logistic Regression, Support Vector Machines, Random Forest, Neural Network, Lasso Regression, Ridge Regression, and Elastic-net. SETTING: Canada and Australia PARTICIPANTS: The Canadian sample is part of a 4-year follow up (2012-2016) of the Co-Venture cohort (N=3826, baseline age 12.8+/-0.4, 49.2% girls). The Australian sample is part of a 3-year follow-up (2012-2015) of the Climate Schools and Preventure (CAP) cohort (N=2190, baseline age 13.3+/-0.3, 43.7% girls). MEASUREMENTS: The algorithms used several prediction indices such as F1 prediction score, accuracy, precision, recall, negative predictive value, and area under the curve. FINDINGS: Based on prediction indices, the elastic-net machine-learning algorithm showed the best predictive performance in both Canadian (AUC=0.869+/-0.066) and Australian (AUC=0.855+/-0.072) samples. Domain contribution analysis showed that the highest prediction accuracy indices yielded from models with only psychopathology (AUC=0.816+/-0.044/0.790+/-0.071 in Canada/Australia) and only personality clusters (AUC=0.776+/-0.063/0.796+/-0.066 in Canada/Australia). Likewise, regardless of the level of alcohol use, in both samples, externalizing psychopathologies, alcohol use at baseline, and the sensation seeking personality profile contributed to the prediction. CONCLUSIONS: Computerized screening software shows promise in predicting the risk of alcohol use among adolescents. PMID- 30461118 TI - US state cigarette tax increases and smoke-free legislation in relation to cigarette expenditure across household socioeconomic circumstances: a quasi experimental study. AB - BACKGROUND AND AIMS: While research has focused on outcomes of tobacco control policies, less is known about the mechanisms by which policies may affect tobacco use. We estimated the associations of changes in cigarette taxes and smoke-free legislation with 1) any household cigarette expenditure and 2) the level of household expenditure on cigarettes, as well as 3) tested interactions with socioeconomic circumstances. DESIGN: Difference-in-differences regression models to estimate the associations between changes in US state cigarette taxes and smoke-free legislation with changes in household expenditure on cigarettes. SETTING: 40 US states and District of Columbia. PARTICIPANTS: From annual, cross sectional surveys (with a longitudinal component) between 2000-2014, 128,138 households interviewed quarterly in the Consumer Expenditure Survey. MEASUREMENTS: Dependent measures included any household cigarette expenditure, expenditure in real dollars, and budget share of cigarette expenditure. Policy measures included state cigarette taxes and 100% smoke-free legislation. Covariates included respondent age, race/ethnicity, sex; household education; poverty level; family structure; and number of children and adults. FINDINGS: Every $1.00 cigarette tax increase was associated with a 1.5 percentage point ( 0.028, -0.002) reduction in any cigarette expenditure, and an increase of 0.1% (0.1%, 0.1%) budget share and $10.11 ($8.38, $11.84) absolute expenditure. The association with absolute expenditure was stronger among smoking households above poverty level ($10.73; $8.94, $12.51) than below ($4.72; $2.37, $7.07). The enactment of smoke-free legislation was associated with $2.33 (-$4.56, -$0.10) less expenditure, but not with any expenditure (0.1%; -1.6%, 1.8%) or budget share (-0.1%; -0.1%, 0.1%). The association with absolute expenditure was stronger among households above poverty level (-$2.62; -$4.95, -$0.29) than below (-$0.34; -$4.27, $3.58). CONCLUSION: Cigarette tax increases in the US between 2000 and 2014 may have reduced smoking prevalence due to an absolute and relative increase in household tobacco expenditure while smoke-free policies appear to have led to a reduction in expenditure. Although tax increases had a stronger impact on absolute expenditure among households above the poverty level, impact on relative expenditure was similar, and consequences for socioeconomic inequalities in smoking will vary based on the broader financial situation of households. PMID- 30461119 TI - T1 rho and T2 mapping for the determination of articular cartilage denaturalization with osteonecrosis of the femoral head: A prospective controlled trial. AB - BACKGROUND: In the future, biochemical MRI might provide a valuable noninvasive quantitative analysis of the biochemical composition of cartilage in osteonecrosis of the femoral head (ONFH). PURPOSE: To investigate the diagnostic performance of T1 rho and T2 mapping in cartilage denaturalization with ONFH and to determine the correlation between T1 rho and T2 mapping and the Association Research Circulation Osseous (ARCO) stage. STUDY TYPE: Prospective. SUBJECTS: Forty-seven patients with ONFH (stage I to III according to the ARCO criteria) and 24 volunteers (control group) were recruited for the prospective study. SEQUENCE: Conventional MRI, multiple echo recalled gradient echo (MERGE), and T1 rho and T2 mapping sequences. ASSESSMENT: Pseudocolor images and MERGE images were combined in the AW4.5 workstation. The region of interest (ROI) of the hip cartilage was 4-6 mm2. The sagittal T1 rho and T2 mapping values were calculated by the two first authors. STATISTICAL TESTS: One-way analysis of variance (ANOVA), LSD t-tests, Pearson correlation analysis, and receiver operator characteristic (ROC) curves. The significance level was set at P < 0.05. RESULTS: The T1 rho and T2 mapping values of the ONFH group were significantly higher than the values of the control group (P = 0.000). Regarding the assessment of the severity of ARCO staging, both T1 rho (r = 0.66, P = 0.004) and T2 mapping (r = 0.501, P = 0.002) were positively associated with disease severity. The T1 rho values were positively correlated with the T2 mapping values (r = 0.381, P = 0.000). The areas under the curve (AUC) for the T1 rho and T2 mapping values were 0.822 and 0.791, respectively. The diagnostic sensitivity and specificity were 72.34% and 70.83% for T1 rho mapping and 72.34% and 58.33%, respectively, for T2 mapping. DATA CONCLUSION: Both T1 rho and T2 mapping performed well in diagnosing the cartilage denaturalization in ARCO stage I-III ONFH patients. T1 rho mapping had a higher diagnostic sensitivity and specificity than T2 mapping. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30461120 TI - Compliance with Ecological Momentary Assessment Protocols in Substance Users: a Meta-Analysis. AB - BACKGROUND AND AIMS: Whilst there are considerable benefits to Ecological Momentary Assessment (EMA), poor compliance with assessment protocols has been identified as a limitation, particularly in substance users. Our aim was to identify the pooled compliance rate of EMA studies in substance users and examine variables that may influence compliance with EMA protocols; such as the length and frequency of assessments. DESIGN: A meta-analysis and meta-regression of all possible studies (randomised controlled trials and longitudinal) which incorporated EMA protocols, examining substance use. SETTING: Studies took place from 1998 to 2017, in numerous countries worldwide. PARTICIPANTS: One-hundred and twenty six studies were identified, contributing a total of 19431 participants (52.31% male, mean age 28.86). MEASUREMENTS: Compliance data, the proportion of responses to the study protocol, were extracted from each study alongside prompt frequency, total length of assessment period, substance use population and device used to administer EMA prompts. FINDINGS: The pooled compliance rate across all studies was 75.06% (95% CI 72.37%, 77.65%). There was no evidence that compliance rates were significantly associated with prompt frequency (Q(3) = 7.35, p = .061), length of assessment period (Q(2) = 2.40, p = .301), substance type (Q(3) = 6.30, p = .098) or device administration (Q(4) = 4.28, p =.369). However, dependent samples (69.80%) had lower compliance rates than non-dependent samples (76.02%; Q(1) = 4.13, p = .042). CONCLUSIONS: The pooled compliance rate for Ecological Momentary Assessment studies in substance-using populations from 1998 to 2017 was lower than the recommended rate of 80%, and was not associated with frequency or duration of assessments. PMID- 30461121 TI - MARSHALL bundles elimination, Pulmonary veins isolation and Lines completion for ANatomical ablation of persistent atrial fibrillation: MARSHALL-PLAN case series. AB - INTRODUCTION: Beyond pulmonary veins (PV) isolation, the ablation strategy for persistent atrial fibrillation (AF) remains controversial. Substrate ablation may provide high termination rate, but at the cost of impaired atrial physiology and recurrent complex reentries. To overcome these pitfalls, we investigated a new lesion set based on important anatomical considerations. METHODS AND RESULTS: The case series included 10 consecutive patients with persistent AF. Three atrial structures were successively targeted: 1) coronary sinus and vein of Marshall (CS VOM) musculature elimination; 2) PVs isolation; and 3) anatomical isthmuses block. The lesion set completion was the procedural endpoint. Step 1: VOM ethanol infusion was feasible in all cases (mean time of 33.4 +/- 9.4 minutes), mean RF time for CS-VOM bundles was 14.4 +/- 6.9 minutes. Step 2: mean RF time for PV isolation was 27.7 +/- 9.3 minutes. Step 3: mean RF time for mitral, roof and cavotricuspid lines was 5.7 +/- 2.3, 8.1 +/- 4.3 and 5.9 +/- 1.9 minutes, respectively. The lesion set was achieved in all patients. Mean procedure time was 270 +/- 29.9 minutes. AF termination and non-inducibility were respectively obtained in 50% and 90% of the patients. After a 6-month follow-up, all patients were free from arrhythmia recurrence. CONCLUSION: The present case series reports a new ablation strategy systematically targeting anatomical structures previously identified as possibly involved in the fibrillatory process and the recurrent tachycardias. The resulting lesion set provides good short-terms outcomes. Although promising, these preliminary results need to be confirmed in larger prospective study. This article is protected by copyright. All rights reserved. PMID- 30461122 TI - Mutational and Phenotypic Spectra of KCNE1 deficiency in Jervell and Lange Nielsen Syndrome and Romano-Ward Syndrome. AB - KCNE1 encodes a regulatory subunit of the KCNQ1 potassium channel-complex. Both KCNE1 and KCNQ1 are necessary for normal hearing and cardiac ventricular repolarization. Recessive variants in these genes are associated with Jervell and Lange-Nielson syndrome (JLNS1 and JLNS2), a cardio-auditory syndrome characterized by congenital profound sensorineural deafness and a prolonged QT interval that can cause ventricular arrhythmias and sudden cardiac death. Some normal-hearing carriers of heterozygous missense variants of KCNE1 and KCNQ1 have prolonged QT intervals, a dominantly inherited phenotype designated Romano-Ward syndrome (RWS), which is also associated with arrhythmias and elevated risk of sudden death. Co-assembly of certain mutant KCNE1 monomers with wild-type KCNQ1 subunits results in RWS by a dominant negative mechanism. This Mutation Update reviews variants of KCNE1 and their associated phenotypes, including biallelic truncating null variants of KCNE1 that have not been previously reported. We describe three homozygous nonsense mutations of KCNE1 segregating in families ascertained ostensibly for nonsyndromic deafness: c.50G>A (p.Trp17*), c.51G>A (p.Trp17*), and c.138C>A (p.Tyr46*). Some individuals carrying missense variants of KCNE1 have RWS. However, heterozygotes for loss of function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2, indicating a complex genotype-phenotype spectrum for KCNE1 variants. This article is protected by copyright. All rights reserved. PMID- 30461123 TI - Blunted stress reactivity reveals vulnerability to early life adversity in young adults with a family history of alcoholism. AB - BACKGROUND AND AIMS: Persons with blunted stress reactivity have poor impulse control and also show increased risk for alcoholism. Exposure to early life adversity (ELA) contributes to blunted reactivity, but individual differences in susceptibility to ELA are not well understood. This study aimed to determine whether exposure to ELA has a greater impact on stress reactivity in young adults with a family history of alcoholism (FH+) compared with young adults with no family history of alcoholism (FH-). DESIGN: Observational study using linear modelling. SETTING: Oklahoma, USA. PARTICIPANTS: 709 young adults (398 females) recruited through community advertisement. MEASUREMENTS: We obtained heart rates and cortisol levels in subjects while undergoing public speaking and mental arithmetic stress compared with a resting control day (1418 test sessions). ELA was quantified as 0, 1, or > 1 adverse events experienced by age 15 yr. FH+ persons had 1 or 2 parents with an alcohol use disorder, and FH- controls had no such history for 2 generations. FINDINGS: Increasing levels of ELA predicted progressive blunting of cortisol and heart rate reactivity for the whole sample (F >= 4.6, p < .01), but examination by FH status showed that the effect of ELA was significant only among FH+ (Fs >= 3.5, ps < .05) and absent in FH- (ps > .40). This difference in ELA impact was not explained by the cortisol diurnal cycle or subjective evaluation of the stressors. CONCLUSIONS: People with a family history of alcoholism appear to be vulnerable, in terms of changes to physiological stress response, to the impact of exposure to early life adversity (ELA) while people with no family history of alcoholism appear to be resilient. Blunted stress reactivity may reflect differential vulnerability to ELA in young adults with a family history of alcoholism. PMID- 30461124 TI - EPCAM mutation update: Variants associated with congenital tufting enteropathy and Lynch syndrome. AB - The epithelial cell adhesion molecule gene (EPCAM, previously known as TACSTD1 or TROP1) encodes a membrane-bound protein that is localized to the basolateral membrane of epithelial cells and is overexpressed in some tumors. Biallelic mutations in EPCAM cause congenital tufting enteropathy (CTE), which is a rare chronic diarrheal disorder presenting in infancy. Monoallelic deletions of the 3' end of EPCAM that silence the downstream gene, MSH2, cause a form of Lynch syndrome, which is a cancer predisposition syndrome associated with loss of DNA mismatch repair. Here, we report 13 novel EPCAM mutations from 17 CTE patients from two separate centers, review EPCAM mutations associated with CTE and Lynch syndrome, and structurally model pathogenic missense mutations. Statistical analyses indicate that the c.499dupC (previously reported as c.498insC) frameshift mutation was associated with more severe treatment regimens and greater mortality in CTE, whereas the c.556-14A>G and c.491+1G>A splice site mutations were not correlated with treatments or outcomes significantly different than random simulation. These findings suggest that genotype-phenotype correlations may be useful in contributing to management decisions of CTE patients. Depending on the type and nature of EPCAM mutation, one of two unrelated diseases may occur, CTE or Lynch syndrome. PMID- 30461125 TI - Direct 3D Printing of Flexible Nasal Prosthesis: Optimized Digital Workflow from Scan to Fit. AB - A maxillofacial prosthesis is a successful treatment modality to restore missing facial parts. Digital technologies and 3D printing are employed in constructing facial prostheses such as ears; however, their application is still partial, and final prostheses are usually manufactured conventionally using stone molds. This report aims to introduce a complete digital workflow to construct a nasal prosthesis and compare it to the conventional workflow of a patient requiring a nasal prosthesis. A computer tomography scan showing the defect was exported to specialized software to create 3D reconstructions of the patient's face and underlying bone. The nose was digitally designed restoring facial esthetics, anatomy, shape, and skin color. Different skin tones were digitally matched to skin tissues adjacent to the defect area using the Spectromatch system. The design was 3D printed in flexible and colorful material at 16 MUm resolution using a 3D printer. External color pigmentations were applied to the nose for optimum esthetics, and the prosthetic nose was sealed in silicone and left to heat polymerize for 15 minutes. The prosthetic nose was retained in place using biomedical adhesive, and the patient was pleased with it. This report proposes a complete digital workflow to directly design and fabricate a prosthetic nose of acceptable esthetics. Such a workflow can lead to enhanced prosthesis reproducibility and acceptability and may become an effective treatment option for treatment of patients with facial defects. PMID- 30461126 TI - Vaccines for Preventing Influenza in Healthy Individuals. AB - Influenza is an acute respiratory infection that imposes a heavy burden on society. The illness itself usually lasts a few days but the residual symptoms of cough and malaise can last for weeks. In addition, it can cause complications such as otitis media, pneumonia, secondary bacterial pneumonia, exacerbations of chronic respiratory disease, bronchiolitis, febrile seizures, Reye's syndrome, and myocarditis.1 Vaccines have been developed in attempt to minimize the effects of influenza. However, given the yearly antigenic changes of the virus, a new vaccine has to be developed, produced, and administered to the population every year.2 The Cochrane review discussed here assesses the efficacy of vaccines in preventing influenza in healthy adults including pregnant women. This article is protected by copyright. All rights reserved. PMID- 30461127 TI - Executive Summary: The 2018 Academic Emergency Medicine Consensus Conference: Aligning the Pediatric Emergency Medicine Research Agenda to Reduce Health Outcome Gaps. AB - Emergency care providers share a compelling interest in developing an effective patient-centered, outcomes-based research agenda that can decrease variability in pediatric outcomes. The 2018 Academic Emergency Medicine Consensus Conference "Aligning the Pediatric Emergency Medicine Research Agenda to Reduce Health Outcome Gaps (AEMCC)" aimed to fulfill this role. This conference convened major thought leaders and stakeholders to introduce a research, scholarship, and innovation agenda for pediatric emergency care specifically to reduce health outcome gaps. Planning committee and conference participants included emergency physicians, pediatric emergency physicians, pediatricians, and researchers with expertise in research dissemination and translation, as well as comparative effectiveness, in collaboration with patients, patient and family advocates from national advocacy organizations, and trainees. Topics that were explored and deliberated through subcommittee breakout sessions led by content experts included 1) pediatric emergency medical services research, 2) pediatric emergency medicine (PEM) research network collaboration, 3) PEM education for emergency medicine providers, 4) workforce development for PEM, and 5) enhancing collaboration across emergency departments (PEM practice in non-children's hospitals). The work product of this conference is a research agenda that aims to identify areas of future research, innovation, and scholarship in PEM. PMID- 30461128 TI - Incidence of and risk factors for development of oral mucositis in outpatients undergoing cancer chemotherapy. AB - AIM: The aims of the study are to determine the incidence of oral mucositis, the stage of the condition, risk factors, and other oral complications in patients receiving outpatient chemotherapy and to evaluate the factors that have an impact on these. METHODS: The study included 147 patients undergoing outpatient cancer chemotherapy at the Chemotherapy Unit of a University Hospital between February and April 2015. We used a questionnaire and the World Health Organization "Mucositis Grading Scale". Chi-squared tests were used to determine the relationships between factors, and multiple logistic regression analysis was employed to explore predictive factors. RESULTS: The frequency of oral mucositis was 51.7%. The most common oral problems were mouth dryness (55.1%), a reduced/changed sense of taste (52.4%), and a lack of appetite (47.6%). Logistic regression analysis showed that the risk factors for oral mucositis were advanced age, a lack of appetite, and the duration of chemotherapy. CONCLUSIONS: As a result, half of all patients undergoing outpatient cancer chemotherapy developed oral mucositis. Patients are unable to adequately prevent oral mucositis and carry out oral care. It is recommended that more studies be conducted in outpatient units to evaluate predictive factors for oral mucositis. PMID- 30461129 TI - Evaluating the frequency of upgrade to malignancy following surgical excision of high-risk breast lesions and ductal carcinoma in situ identified by core needle biopsy. AB - Excision of high-risk breast lesions (HRL) continues to be standard of care. Previous studies have shown that HRLs can be upgraded to carcinoma in situ (CIS) or invasive carcinoma (IC) upon excision. A single institution retrospective review was conducted to determine the rate of upgrade of HRLs and ductal carcinoma in situ (DCIS) identified on image-guided biopsy upon excision. Eight hundred and fifty-seven patients who underwent core needle biopsy (CNB) following the detection of suspicious lesions (BI-RADS IV) on mammograms were identified. HRLs and DCIS warranting subsequent surgical excision were found in 129 of 857 patients (15.1%). Overall, 19.6% (10/51) of DCIS, 52.4% (11/21) of ADH, and 17.6% (3/17) of papillomas were upgraded on surgical excision. A statistically significant difference was found between the concordant and discordant groups regarding the number of cores obtained (P = 0.01) and the needle size used to retrieve specimens on CNB (P = 0.01). This study reveals an upgrade rate of 26.7% of HRLs and DCIS diagnosed by CNB on surgical excision and emphasizes the continued use of large bore needles with an adequate number of core specimens when investigating a suspicious breast lesion. PMID- 30461130 TI - Extracellular matrix remodeling effects of serum amyloid A1 in the human amnion: implications for fetal membrane rupture. AB - PROBLEM: Rupture of fetal membranes is a crucial event at parturition, which is preceded by extensive extracellular matrix (ECM) remodeling. Our recent studies have demonstrated that the human fetal membranes are capable of de novo synthesis of serum amyloid A1 (SAA1), an acute phase protein, and the abundance of SAA1 in the amnion was increased at parturition. However, the exact role of SAA1 in human parturition remains to be established. METHOD OF STUDY: The effects of SAA1 on the abundance of collagenases and lysyl oxidase, the enzyme that cross-links collagens, were investigated in culture primary human amnion fibroblasts and tissue explants with an aim to examine the involvement of SAA1 in the ECM remodeling in the amnion. RESULTS: SAA1 time- and dose-dependently increased the abundance of collagenases MMP-1, -8 and -13, while decreased the abundance of lysyl oxidase-like 1 (LOXL1). These effects of SAA1 were attenuated by siRNA mediated knockdown of the toll-like receptor (TLR) 4 and its antagonist CLI-095, but not by siRNA-mediated knockdown of TLR2. Furthermore, the inhibitors for NFkappaB (JSH-23) and mitogen-activated protein kinases (MAPKs) p38 (SB203580) and JNK (SP600125) could also attenuate the effects of SAA1, while the inhibitor for MAPK ERK1/2 (PD 98059) could block the effects of SAA1 only on MMP-1, -8 and LOXL1 but not on MMP-13. CONCLUSIONS: These data highlight a possible role for SAA1 in ECM remodeling preceding membrane rupture by regulating the expression of collagenases MMP-1, -8, -13 and LOXL1 through TLR4-mediated activation of the NFkappaB and MAPK pathways in amnion fibroblasts. This article is protected by copyright. All rights reserved. PMID- 30461131 TI - Atypical ductal hyperplasia on core needle biopsy: Development of a predictive model stratifying carcinoma upgrade risk on excision. AB - BACKGROUND: Although the rate of carcinoma upgrade for atypical ductal hyperplasia (ADH) diagnosed on core needle biopsy (CNB) is variable, current standard treatment consists of surgical excision (SE) for all ADH CNB diagnoses. Our objective was to identify features of ADH on CNB that may stratify carcinoma upgrade risk on SE. METHODS: We retrospectively analyzed cases diagnosed as ADH on CNB. An independent slide review and detailed analysis of radiological and clinical data was performed. Statistical analyses were used to identify predictors for upgrade. Using variables predictive of upgrade, a model to stratify the probability of upgrade of ADH diagnosed on CNB was constructed. RESULTS: We identified 124 ADH cases with subsequent SE. Of these, 62 cases (50%) were upgraded to carcinoma. Features predictive of upgrade were as follows: diagnosis of "At least ADH", percentage of cores involved by ADH, radiologic lesion size, presence of ipsilateral carcinoma, and patient age. A 4-tiered predictive model using percentage of cores involved by ADH, histologic extent of ADH, radiologic lesion size, and patient age was constructed. This predictive model has a fair accuracy, with an area under the ROC curve of 0.76. CONCLUSION: We have identified several predictors of carcinoma upgrade for ADH diagnosed on CNB. Our predictive model may be used to stratify the risk of carcinoma upgrade on SE. PMID- 30461132 TI - Dental students' perceptions of learning communication skills in a forum theatre style teaching session on breaking bad news. AB - INTRODUCTION: Communication skills are an integral component of dental undergraduate education. Due to the complex nature of these skills, didactic teaching methods used in other educational contexts can be limited. Interactive and participative methods rooted in modern adult learning theories, such as Forum Theatre, may be more effective in the teaching of communication skills. AIM: To explore the usefulness of Forum Theatre in teaching clinical undergraduate dental students how to break bad news to their patients. METHODS: A purposive sample of 4th-year undergraduate dental students was invited to participate. An evaluation questionnaire was given to the students and collected after the Forum Theatre interactive session. Participants were asked to provide self-reported accounts on the most and least useful parts of the session, as well as the most important learning outcome. Usefulness of the session in clinical work, increasing confidence and ability in breaking bad news, were evaluated via a 5-point Likert scale type question. Qualitative data were analysed using Framework Analysis to explore the themes found in the open-text component. Descriptive statistics were used to analyse the Likert-scale items. RESULTS: One hundred and fifteen completed questionnaires were collected from the 2015 and 2016 classes. Most students gave the Forum Theatre session a rating of 3 or above on a 5-point Likert scale; indicating that they found it useful. Qualitative results also showed that most participants liked the teaching session thanks to its interactive nature, the use of actors and the input of the facilitators. The majority of students showed preference towards smaller groups which give everyone equal opportunity to participate without unnecessary repetition. CONCLUSION: The results seem to confirm previous findings. Students rated their learning experience involving Forum Theatre favourably. Smaller groups and trained facilitators are required for the success of this teaching method. Further research is needed to assess the long-term educational benefits of Forum Theatre. PMID- 30461133 TI - Intravenous immunoglobulin in patients with acquired Von Willebrand syndrome: A single referral centre experience. PMID- 30461134 TI - Utility valuation of health states for haemophilia and related complications in Europe and in the United States. AB - INTRODUCTION: There is currently a paucity of health utility data describing the consequences of haemophilia and related complications. AIM: To quantify the impact of distinct stages of severity of haemophilia and disease-related complications on health-related quality of life, expressed as health utilities in Europe and the United States. METHODS: Nine health state descriptions were developed based on literature review and interviews with haematologists and haemophilia patients. Three descriptions characterized the impact of mild, moderate and severe haemophilia without inhibitors. Six descriptions characterized disease-related complications added to the moderate haemophilia description (arthroscopic synovectomy, prosthetic joint replacement, chronic pain, spontaneous bleed, traumatic bleed and end-stage joint disease). Time trade off (TTO) interviews were conducted with 100 adults from the general public in the UK, France, Germany, Italy, Sweden and the United States. Mean TTO-derived utility values were expressed on a scale from 0 (death) to 1 (full health). RESULTS: Utility values obtained for the health states corresponding to mild (0.73-0.86), moderate (0.68-0.76) and severe (0.64-0.71) haemophilia followed the increase in severity. The addition of a complication to the "moderate" state leads to a decrease in the associated utility value. The most severe disutility (0.23-0.36) across all countries was associated with the burden of end-stage joint disease. CONCLUSIONS: This study underlines the value that the French, Italian, German, Swedish, United States and UK populations ascribe to the avoidance of disease progression in haemophilia without inhibitors. Improved treatment options hold a potential for important benefits to haemophilia patients. PMID- 30461135 TI - Samuel Armstrong Lane's first successful treatment of haemophilia with blood transfusion in 1840: Could this also be the first successful bypassing therapy? PMID- 30461136 TI - A unifying framework for improving health care. AB - The quality health care around world is suboptimal. To improve the quality of contemporary health care delivery, advocates have proposed a number of scientific and technical initiatives. All these initiatives, however, have arisen and continue to operate in siloes, resulting in confusion and incommensurability among those concerned with health care improvement. Participants in the quality improvement (QI) space typically stress their own, often narrow, perspective, failing to place QI in context or to acknowledge other approaches. In order to improve delivery of health care, the following is required: Provide a unifying framework for improving health care. We argue this is best done under a Health System Science (HSS) framework but with full understanding that the fundamental principles of HSS are rooted in evidence-based medicine (EBM) and decision sciences. Understand that QI initiatives are fundamentally local activities. Hence, incentivizing bottom-up, local QI initiatives would improve health care delivery to a far greater extent than the current top-down initiatives undertaken in a response to various regulatory mandates. Akin to the "Choosing Wisely" initiative, which challenged professional societies, each institution should identify (a) the extent to which its practices are evidence-based and (b) the top 5 health care practices or interventions that, at a given institution, represent overuse, underuse, or misuse/error or undermine clinicians' efforts to deliver kind and empathic care. Providing a framework that can unify the current patchwork of the initiatives would help create a common basis to help align all the existing QI efforts. In addition, thinking small (at local level) may lead to health care quality improvements that national initiatives (thinking big), focused on regulation, competition, or legal requirements, have failed to achieve. PMID- 30461137 TI - Salutogenesis and beyond. AB - In this hypothesis paper on paradoxes in preventive medicine, which also deals with the indocility of biological functions, the following issues will be addressed. First, a definition of salutogenesis will be given, providing the origin of this notion of health preservation and disease prevention. Then four paradoxes of the biology of health will be discussed. The first deals with the biomarkers of aging. The second addresses the good and bad of the much praised anti-oxidants. The third details how the mTOR (mammalian transporter of rapamycin) pathway plays a discreet but fundamental role. The fourth explores the yin and yang effects of the secretory profile of senescent cells. In conclusion, the need for a new paradigm in preventive medicine will be proposed. This article is protected by copyright. All rights reserved. PMID- 30461138 TI - Narrative review of methods and findings of recent studies on the carriage of meningococci and other Neisseria species in the African Meningitis Belt. AB - OBJECTIVE: To review the findings of studies of pharyngeal carriage of Neisseria meningitidis and related species conducted in the African meningitis belt since a previous review published in 2007. METHODS: PubMed and Web of Science were searched in July 2018 using the terms 'meningococcal OR Neisseria meningitidis OR lactamica AND carriage AND Africa', with the search limited to papers published on or after 1st January 2007. We conducted a narrative review of these publications. RESULTS: One hundred and thirteen papers were identified using the search terms described above, 20 of which reported new data from surveys conducted in an African meningitis belt country. These papers described 40 surveys conducted before the introduction of the group A meningococcal conjugate vaccine (MenAfriVacR ) during which 66 707 pharyngeal swabs were obtained. Carriage prevalence of N. meningitidis varied substantially by time and place, ranging from <1% to 24%. The mean pharyngeal carriage prevalence of N. meningitidis across all surveys was 4.5% [95% CI: 3.4%, 6.8%] and that of capsulated N. meningitidis was 2.8% [95% CI: 1.9%; 5.2%]. A study of households provided strong evidence for meningococcal transmission within and outside households. The introduction of MenAfriVac(r) led to marked reductions in carriage of the serogroup A meningococcus in Burkina Faso and Chad. CONCLUSIONS: Recent studies employing standardised methods confirm the findings of older studies that carriage of N. meningitidis in the African meningitis belt is highly variable over time and place, but generally occurs with a lower prevalence and shorter duration than reported from industrialised countries. PMID- 30461139 TI - Influence of contextual factors on quality of primary care in children with asthma. AB - OBJECTIVE: Asthma is a common chronic disease among children, quality assurance is thus important. Adherence to pre-specified quality indicators of practice guidelines could be used to assess the quality of asthma care. The aim was to estimate which contextual factors that had an influence on the primary health care centres (PHCs) adherence to the quality indicators as stated in the practice guidelines. METHOD: A pragmatic cross-sectional study was performed comprising 14 PHCs in Sweden. Included contextual factors were socio-demographic characteristics, organizational characteristics, and indicators regarding engagement in asthma care. Documentation on adherence to the quality indicators was retrieved from the medical health care records. Quality indicators included documentation of history of allergy and risk factors, diagnostics and patient support performed, and pharmacological treatment. To score adherence, a composite quality indicator (CQI) was computed for each PHC. A multivariable regression analysis was performed by orthogonal projection to latent structures (OPLS). By this analysis, the relationship between the result variable (CQI) and 26 pre specified contextual factors was assessed. RESULTS: There was a wide variation of CQI between the PHCs. The OPLS analysis identified that 10 of the contextual factors influenced CQI. The most pronounced influences were found in more time scheduled for asthma care, a lower age-limit for performing spirometry, a lower duty-grade for general practitioners, and a higher activity at asthma educational seminars. We found no influence of socio-demographic contextual factors. CONCLUSION: We found that some of the contextual factors at the PHCs influenced the quality of performed care. Evidence-based care in paediatric asthma may thus be presumed to be facilitated by allocating time, by improving interprofessional collaboration, and by creating structures and opportunities for commitment to asthma care. PMID- 30461140 TI - Examining the implementation of clinical practice guidelines for the management of adult cancers: A mixed methods study. AB - RATIONALE, AIMS, AND OBJECTIVES: Focusing on the implementation of clinical practice guidelines (CPGs) for the management of adult cancers, the objectives of this study were to (a) describe the intrinsic elements known to influence CPG use; (b) identify the ways in which CPGs are implemented; and (c) explore how CPG characteristics and contextual factors influence implementation and use. METHODS: We conducted a sequential mixed methods study. First, we performed a content analysis of all CPGs developed and approved for the management of adult cancers in Nova Scotia, Canada, from 2005 to 2015. CPGs were examined for the presence of 22 elements known to influence CPG use. Next, we conducted semistructured interviews with CPG developers and end users. Participants were purposively sampled, based on the findings of the content analysis. All interviews were audiotaped and transcribed verbatim. Data were analysed by two researchers using the Framework Method. RESULTS: CPGs (n = 20) demonstrated large variation with respect to elements shown to influence CPG use. For example, 85% included content related to individualization and objectives. Yet no CPGs (0%) had journal or patient versions; discussed the education, training, or competencies needed to deliver recommendations; contained an explicit statement on anticipated work changes, or on potential direct or productivity costs; or identified barriers or facilitators that might influence CPG adoption. Interview data from CPG developers (n = 4) and users (n = 6) revealed five themes related to CPG implementation and use: (a) lack of consistency in CPG development; (b) timing and nature of stakeholder engagement; (c) credibility of the CPG development process and final CPGs; (d) limited understanding of implementation as an active process; and (e) factors at organizational and system levels influence CPG implementation and use. CONCLUSIONS: This mixed methods study provides complementary data that may help inform more effective CPG implementation efforts and optimize their use in practice. PMID- 30461141 TI - NiFe Hydroxide Lattice Tensile Strain Enhances Adsorption of Oxygenated Intermediates for Efficient Water Oxidation Catalysis. AB - Binding strength of reactive intermediates with catalytically active sites plays a crucial role in governing catalytic performance of electrocatalysts. NiFe hydroxide offers efficient oxygen evolution reaction (OER) catalysis in alkaline electrolyte, however weak binding of oxygenated intermediates on NiFe hydroxide still badly limits its catalytic activity. Herein, we developed a facile ball milling method to enhance binding strength of NiFe hydroxide to oxygenated intermediates via generating tensile strain, which reduced the anti-bonding filling states in the d orbital and thus facilitated oxygenated intermediates adsorption. The NiFe hydroxide with tensile strain increasing after ball-milling exhibits an OER onset potential as low as 1.44 V (vs. reversible hydrogen electrode) and requires only a 270 mV overpotential to reach a water oxidation current density of 10 mA cm-2. PMID- 30461142 TI - Plant growth-promoting archaea trigger induced systemic resistance in Arabidopsis thaliana against Pectobacterium carotovorum and Pseudomonas syringae. AB - Archaea have inhabited the earth for a long period of time, and are ubiquitously distributed in diverse environments. However, few studies have focused on the interactions of archaea with other organisms, including eukaryotes such as plants, since it is difficult to cultivate sufficient numbers of archaeal cells for analysis. In this study, we investigated the interaction between soil archaea and Arabidopsis thaliana. We demonstrate for the first time that soil archaea promote plant growth and trigger induced systemic resistance (ISR) against the necrotrophic bacterium Pectobacterium carotovorum subsp. carotovorum SCC1 and biotrophic bacterium Pseudomonas syringae pv. tomato DC3000. Ammonia-oxidizing archaeon Nitrosocosmicus oleophilus MY3 cells clearly colonized the root surface of Arabidopsis plants, and increased resistance against both pathogenic species via the salicylic acid-independent signaling pathway. This mechanism of bacterial resistance resembles that underlying soil bacteria- and fungi-mediated ISR signaling. Additionally, volatile emissions from N. oleophilus MY3 were identified as major archaeal determinants that elicit ISR. Our results lay a foundation for archaea-plant interactions as a new field of research. This article is protected by copyright. All rights reserved. PMID- 30461143 TI - Intercepting the Disilene-Silylsilylene Equilibrium. AB - The equilibrium between disilenes (R2Si=SiR2) and their silylsilylene (R3Si-SiR) isomers has previously been inferred but not directly observed, except in the case of the parent system H2Si=SiH2. Here, we report a new method to prepare base coordinated disilenes with hydride substituents. By varying the bulk of the coordinating base and other silicon substituents, we have been able to control the rearrangement of disilene adducts to their silylsilylene tautomers. Remarkably, 1,2 migration of a trimethylsilyl group is preferred over hydrogen migration. A DFT study of the reaction mechanism provides a rationale for the observed reactivity and detailed information on the bonding situation in base stabilized disilenes. PMID- 30461144 TI - Multicolor emission from non-conjugated polymers based on a single switchable boron chromophore. AB - Multicolor emissive and responsive materials are highly attractive due to their potential applications in various fields, and polymers are preferred for their good processability and high stability. Herein, we report a series of new polymers based on a methacrylate monomer containing a switchable boron chromophore. In spite of the unconjugated nature, interestingly, the homopolymers from this monomer display rare multicolor fluorescence in solution that is highly dependent on the degree of polymerization (DP). With an ascending DP, the local concentration of the chromophore increases, leading to a higher propensity for switching the blue emitting tricoordinate boron chromophore to the red emitting tetracoordinate one. The homopolymers also display temperature and solvent dependent emission colour change. Furthermore, pure white-light emission could be achieved in various solvents by precisely tuning the homopolymer molecular weight, or in films/solid state by copolymerizing the emissive boron monomer with non-emissive monomers in an appropriate ratio. PMID- 30461145 TI - A Nitrogen-Rich 2D sp2 Carbon-Linked Conjugated Polymer Framework as a High Performance Cathode for Lithium-ion Batteries. AB - In this work, we report a novel two-dimensional (2D) sp2 carbon-linked conjugated polymer framework (2D CCP-HATN) with a nitrogen-doped skeleton, a periodical dual pore structure and high chemical stability. The chemical identity of the polymer backbone consisting of hexaazatrinaphthalene (HATN) and cyanovinylene units linked entirely by carbon-carbon double bonds is verified by FT-IR, Raman and solid-state 13C cross-polarization magic-angle spinning (CP-MAS) NMR spectroscopies. In stacked form, together with the imine-linked covalent organic framework analogue 2D C=N HATN, the interior framework architecture of the crystalline 2D CCP-HATN is unambiguously demonstrated by powder X-ray diffraction and N2 adsorption-desorption measurements. Profiting from the shape-persistent framework of 2D CCP-HATN integrated with the electrochemical redox-active HATN and the robust sp2 carbon-carbon linkage, 2D CCP-HATN hybridized with carbon nanotubes shows an excellent capacity of 116 mA h/g, with high utilization of its redox-active sites and superb cycling stability (91% after 1000 cycles) and rate capability (82%, 1.0 A/g vs 0.1 A/g) as an organic cathode material for lithium ion batteries. PMID- 30461146 TI - Precise Synthesis of Poly(thioester)s with Diverse Structures by Copolymerization of Cyclic Thioanhydrides and Episulfides Mediated by Organic Ammonium Salts. AB - Precise synthesis of poly(thioester)s with diverse structures is still a significant challenge in the polymeric materials field. Herein, we report a novel approach to the synthesis of well-defined poly(thioester)s by the controlled alternating copolymerization of cyclic thioanhydrides and episulfides induced by simple organic ammonium salts. Both the cation and anion have strong effects on the copolymerization. [PPN]OAc ([PPN] = bis(triphenylphosphine)iminium) with a bulky cation was proven to be efficient in initiating this polymerization, yielding poly(thioester)s with completely alternating structure, controlled molecular weight, and narrow polydispersity. The poly(thioester) obtained from succinic thioanhydride and propylene sulfide is a typical semi-crystalline material, possessing a high refractive index of up to 1.78. Because it uses readily available monomers, this method is expected to open up a new route to poly(thioester)s with diverse structures and properties. PMID- 30461147 TI - Spontaneous Single-Crystal-to-Single-Crystal Evolution of Two Cross-Laminated Polymers. AB - Two cases of spontaneous evolution of monomers to linear polymers having novel cross-laminated topology are reported. We synthesized two peptide monomers N3 Gly-Gly-NH-CH2 -CCH and N3 -Gly-Gly-Gly-CH2 -CCH and solved their crystal structures by single-crystal X-ray diffraction. They adopt H-bonded crisscrossed layered packing in their crystals such that: (a) the monomers are aligned head-to tail in 1D-chain-like arrays and parallel arrangement of such arrays forms a layer; (b) the proximally placed azide and alkyne motifs are in an orientation apt for their regiospecific cycloaddition; (c) each monomer having x peptide bonds is H-bonded with 2x monomers disposed in intersecting arrangement, which pre-organize 1D-chain-like arrays in adjacent layers in perpendicular orientation. These crystals underwent spontaneous single-crystal-to-single crystal (SCSC) polymerization via azide-alkyne cycloaddition reaction to form triazolyl-polyglycines, at room temperature. The crisscrossed arrangement of monomers in adjacent layers ensured the formation of cross-laminated polymers. PMID- 30461148 TI - Indirect CO2 Methanation: Hydrogenolysis of Cyclic Carbonates Catalyzed by Ru Modified Zeolite Produces Methane and Diols. AB - We report a ruthenium-modified zeolite which efficiently transforms propylene carbonate to propylene glycol and methane, under solvent-free conditions. The catalyst achieved high product selectivity and no significant ageing effect was observed after multiple cycles. The resulting liquid product (water-containing glycol) can be directly used as anti-freeze solution and the gas phase can directly be used as an energy carrier in the form of H2 -enriched methane. This process efficiently bridges energy storage and an important chemical synthesis under sustainable (CO2 consuming) conditions. PMID- 30461149 TI - Prevalence and determinants of resistance mutations in HIV-1-infected patients exposed to integrase inhibitors in a large Italian cohort. AB - OBJECTIVES: The aim of the study was to analyse the prevalence of integrase resistance mutations in integrase strand transfer inhibitor (INSTI)-experienced HIV-1-infected patients and its predictors. METHODS: We selected HIV-1 integrase sequences from the Antiviral Response Cohort Analysis (ARCA) database, derived from INSTI-experienced patients between 2008 and 2017. Differences in the prevalence of resistance to raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG) were assessed by chi2 test and predictors of resistance were analysed by logistic regression. RESULTS: We included 462 genotypes from INSTI exposed individuals: 356 'INSTI-failing' patients and 106 'previously INSTI exposed' patients (obtained a median of 42 weeks after INSTI discontinuation [interquartile range (IQR) 17-110 weeks]). Overall, at least low-level resistance (LLR) to any INSTI (Stanford 8.5 algorithm) was detected in 198 (42.9%) cases. The most frequent INSTI resistance mutation was N155H, followed by Q148H/K/R, G140A/C/S, E138A/K/T and Y143C/H/R. Y143R and E138A were more prevalent in viral subtype B versus non-B [5.2 versus 1.5%, respectively (P = 0.04), and 3.1 versus 0%, respectively (P = 0.02)]. Overall, the Q148H/K/R plus G140A/C/S and/or E138A/K/T pattern, defining an intermediate level of resistance to DTG, was detected in 70 (15%) cases. Independent predictors of at least LLR to any INSTI were current use versus past use of INSTIs, a lower genotypic sensitivity score (GSS) for contemporary antiretroviral drugs used, and having an integrase sequence obtained in calendar year 2016 as compared to 2008-2009. CONCLUSIONS: The results support integrase resistance testing in INSTI-experienced patients. Emergence of INSTI resistance is facilitated by the reduced genetic barrier of the regimen as a consequence of resistance to companion drugs. However, INSTI resistance may become undetectable by standard population sequencing upon INSTI discontinuation. PMID- 30461150 TI - Giant Star-shaped Nitrogen-doped Nanographenes. AB - Star-shaped nanographenes are large monodisperse polycyclic aromatic hydrocarbons that extend in size beyond the nanometer and have shown a lot of promise in a wide range of applications including electronics, energy conversion and sensing. Herein we report a new family of giant star-shaped N-doped nanographenes with diameters up to 6.5 nm. Furthermore, the high solubility of this SNG family in neutral organic solvents at room temperature allowed a complete structural, optoelectronic and electrochemical characterisation, which together with charge transport studies illustrate their n-type semiconducting character. PMID- 30461151 TI - Reflections on 40 years of IVF. AB - For many practitioners of in vitro fertilisation (IVF) today, it must be hard to comprehend the disdain and disgust with which the introduction of IVF as therapy for infertility was greeted. The ethical and legal wrangling about human reproductive cloning and the current debate over trans-generational (germline) genome editing gives a small flavour of how IVF was seen then. What was regarded as an irrelevant, disruptive and unethical practice is now effectively mainstream treatment in most countries of the world. This article is protected by copyright. All rights reserved. PMID- 30461152 TI - Second victims need emotional support after adverse events: even in a just safety culture. PMID- 30461153 TI - Increased incidence of obstetric complications in women carrying mitochondrial DNA mutations: a retrospective cohort study in a single tertiary centre. AB - OBJECTIVE: To investigate the obstetric outcome of women carriers of OXPHOS disorders mutation. DESIGN: A retrospective cohort study in a single tertiary centre SETTING: A review of obstetric history of women referred for prenatal screening of a mitochondrial disorder was performed. POPULATION: Women were divided into three groups: 1) women carrying mitochondrial DNA (mtDNA) mutations 2) healthy women with a family history of mtDNA-related OXPHOS disorder, 3) healthy women carrying heterozygote nuclear DNA (nDNA) mutations. METHODS: Obstetric history and pregnancy complications were evaluated separately in the three groups and compared to the control group. RESULTS: Seventy-five women were included with 287 cumulative pregnancies. Groups 1 and 3 had a significantly greater proportion of termination of pregnancy (TOP, 20% and 13% vs 0.8%, p<0.001) and less percentage of live births (52% and 72% vs 87%, p=0.001) compared to controls. Apart this, the rate of obstetric complications in group 3 did not differ from the controls. Obstetric history of women in group 1 was marked by a greater rate of early miscarriages (26% vs 11% p=0.004), gestational diabetes (14% vs 3%, p=0.02), intra-uterine growth retardation (IUGR, 10% vs 1%, p=0.008) and postpartum haemorrhage than in controls (12% vs 2%, p=0.01). CONCLUSIONS: Women heteroplasmic for OXPHOS mutations have a higher incidence of pregnancy losses, gestational diabetes, IUGR and post postpartum haemorrhage. This article is protected by copyright. All rights reserved. PMID- 30461154 TI - Addressing knowledge gaps in long term outcomes following embryo freezing. AB - Cryopreservation of embryos following in vitro fertilisation (IVF) has been a major advance in assisted reproductive technology (ART), facilitating single embryo transfer and thereby reducing multiple births. Compared with fresh embryo cycles, cryopreservation is also associated with improved pregnancy rates and reductions in preterm birth, small for gestational age and low birth weight (Maheshwari et al Hum Reprod Update 2018;24(1):35-58). However, emerging adverse health impacts include increased risks of hypertensive disease in pregnancy and macrosomia (Maheshwari et al Hum Reprod Update 2018;24(1):35-58). This article is protected by copyright. All rights reserved. PMID- 30461155 TI - Absorbable subcuticular staples versus suture for caesarean section closure: a randomised clinical trial. AB - OBJECTIVE: To compare outcomes of efficiency, safety, patient, and surgeon satisfaction between absorbable subcuticular staples and subcuticular suture for caesarean section skin closure. DESIGN: A prospective, randomised, non-blinded, parallel-group trial. SETTING: Mayo Clinic Family Birth Center in Rochester, MN, USA. POPULATION: At least 18 years old and 24 weeks' gestation, undergoing caesarean section. Exclusion criteria were body mass index >50, chorioamnionitis, intrauterine fetal death, and multifetal gestation. METHODS: Patients were stratified by prior caesarean section, body mass index, and surgeon level and randomised to absorbable subcuticular staples or subcuticular suture. Electronic medical records and surveys were used. MAIN OUTCOME MEASURES: Primary outcomes were total operating time, from incision start to close. Secondary outcomes included subcuticular skin closure time, patient and surgeon satisfaction, percutaneous injuries, pain (analgesic use), cosmesis, and wound complications. RESULTS: Of 220 randomised patients, 206 were included in the final analysis (103 per group). Baseline characteristics were similar. The primary outcome of total operative time was not significantly different between groups [54.0 (44.9-63.6) versus 58.0 (50.4-68.2) minutes, P = 0.053]. The subcuticular staple group had shorter subcuticular skin closure time [median 2.6 (1.8-4.0) versus 8.5 (6.2 10.5) minutes, P < 0.001]. There were no differences in analgesic use, wound complications, cosmesis or patient satisfaction. One needlestick injury occurred with suture. Surgeons were more likely to recommend (97% versus 85%, P = 0.004) and use (98% versus 82%, P < 0.001) absorbable subcuticular staples. CONCLUSION: For caesarean section skin closure, absorbable subcuticular staples did not result in significantly different total operative times compared with sutures. Analgesic use, wound complications, and cosmesis were comparable. Patient and surgeon satisfaction were high with both methods. TWEETABLE ABSTRACT: Absorbable subcuticular staples associated with a similar total operative time compared with suture. PMID- 30461156 TI - External Cephalic Version is Associated with a Low Complication Rate. AB - When conducted for an established medical indication, caesarean section is a surgical procedure that is effective in preventing severe fetal and maternal morbidity and mortality. However despite the 1985 WHO claim that "there is no justification for any region to have a rate higher than 10-15%" (WHO, Lancet 1985; 326:436-7) caesarean section rates, particularly in middle and high income countries, are much higher and continue to rise. This article is protected by copyright. All rights reserved. PMID- 30461157 TI - Elevated pCO2 Alters Marine Heterotrophic Bacterial Community Composition and Metabolic Potential in Response to a Pulse of Phytoplankton Organic Matter. AB - Factors that affect the respiration of organic carbon by marine bacteria can alter the extent to which the oceans act as a sink of atmospheric carbon dioxide. We designed seawater dilution experiments to assess the effect of pCO2 enrichment on heterotrophic bacterial community composition and metabolic potential in response to a pulse of phytoplankton-derived organic carbon. Experiments included treatments of elevated (1000 ppm) and low (250 ppm) pCO2 , amended with 10 MUmol L-1 dissolved organic carbon from Emiliana huxleyi lysates, and were conducted using surface-seawater collected from the South Pacific Subtropical Gyre. To assess differences in community composition and metabolic potential, shotgun metagenomic libraries were sequenced from low and elevated pCO2 treatments collected at the start of the experiment and following exponential growth. Our results indicate bacterial communities changed markedly in response to the organic matter pulse over time and was significantly affected by pCO2 enrichment. Elevated pCO2 also had disproportionate effects on the abundance of sequences related to proton pumps, carbohydrate metabolism, modifications of the phospholipid bilayer, resistance to toxic compounds and conjugative transfer. These results contribute to a growing understanding of the effects of elevated pCO2 on bacteria-mediated carbon cycling during phytoplankton bloom conditions in the marine environment. This article is protected by copyright. All rights reserved. PMID- 30461159 TI - Re: Uterine Transplantation in Transgender Women: Medical, Legal and Ethical Considerations. AB - We read with interest the mini-commentary by Hammond-Browning on the medical, legal and ethical considerations associated with uterine transplantation (UTx) in transgender women. Whilst the manuscript adds value and context to this emerging area, the legal implications to which she alludes deserve further discussion. She states that male to female (M2F) transgender women would be unable to undergo embryo transfer, as under current legislation it would be illegal. Whilst the legislation cited is unclear, even upon the strictest interpretation to which she refers, it is highly vulnerable to challenge. This article is protected by copyright. All rights reserved. PMID- 30461160 TI - Outcomes in prevention and management of miscarriage trials: a systematic review. AB - BACKGROUND: There is a substantial body of research evaluating ways to prevent and manage miscarriage, but studies do not report on the same outcomes. OBJECTIVE: To systematically review outcomes reported in existing miscarriage trials. SEARCH STRATEGY: MEDLINE, Embase, CINAHL and Cochrane were searched from inception until January 2017. SELECTION CRITERIA: Randomised controlled trials (RCTs) reporting prevention or management of miscarriage. Miscarriage was defined as a pregnancy loss in the first trimester. DATA COLLECTION AND ANALYSIS: Data about the study characteristics, primary and secondary outcomes were extracted. MAIN RESULTS: We retrieved 1,553 titles and abstracts, from which 208 RCTs were included. For prevention of miscarriage the most commonly reported primary outcome was live birth and the top four reported outcomes were pregnancy loss/stillbirth (n=112), gestation of birth (n=68), birth dimensions (n=65) and live birth (n=49). For these four outcomes, 58 specific measures were used for evaluation. For management of miscarriage the most commonly reported primary outcome was efficacy of treatment. The top four reported outcomes were bleeding (n=186), efficacy of miscarriage treatment (n=105), infection (n=97) and quality of life (n=90). For these outcomes, 130 specific measures were used for evaluation. CONCLUSIONS: Our review found considerable variation in the reporting of primary and secondary outcomes along with the measures used to assess them. There is a need for standardised patient-centred clinical outcomes through the development of a core outcome set; the work from this systematic review will form the foundation of the core outcome set for miscarriage. This article is protected by copyright. All rights reserved. PMID- 30461158 TI - Evolution of major non-HIV-related comorbidities in HIV-infected patients in the Italian Cohort of Individuals, Naive for Antiretrovirals (ICONA) Foundation Study cohort in the period 2004-2014. AB - OBJECTIVES: The management of HIV disease is complicated by the incidence of a new spectrum of comorbid noncommunicable diseases (NCDs). It is important to document changes in the prevalence of NCDs over time. The aim of the study was to describe the impact of ageing on HIV markers and on the prevalence of NCDs in people living with HIV (PLWHIV) in the Italian Cohort of Individuals, Naive for Antiretrovirals (ICONA) seen for care in 2004-2014. METHODS: Analyses were conducted separately for a closed cohort (same people seen at both times) and an open cohort (all people under follow-up). We used the chi2 test for categorical factors and the Wilcoxon test for quantitative factors to compare profiles over time. RESULTS: The closed cohort included 1517 participants and the open cohort 3668 under follow-up in 2004 and 6679 in 2014. The median age of the open cohort was 41 [interquartile range (IQR) 37-46] years in 2004 and 44 (IQR 36-52) years in 2014. Analysis of the closed cohort showed an increase in the prevalence of some NCDs [the prevalence of dyslipidaemia increased from 75% in 2004 to 91% in 2014, that of hypertension from 67 to 84%, and that of cardiovascular disease (CVD) from 18 to 32%] and a decrease in renal function (5% with eGFR < 60 mL/min per 1.73 m2 in 2004 versus 30% in 2014); the percentage of people in the high risk group for the Framingham CHD score more than tripled (from 13 to 45%). Results in the open cohort were similar. CONCLUSIONS: The burden of NCDs in our PLWHIV population markedly worsened over a 10-year time-span, which is likely to be a result of the effects of both ageing and HIV infection as well as their interaction. Special attention must be given to the management and prevention of NCDs. PMID- 30461161 TI - Trends in caesarean section rates between 2007 and 2013 in obstetric risk groups inspired by the Robson classification: results from population-based surveys in a low-resource setting. AB - OBJECTIVE: To describe caesarean section rates and neonatal mortality to assess change in access to life-saving interventions in a rural low-resource setting between 2007 and 2013. DESIGN: Population-based cross-sectional study. SETTING: Southern Tanzania. POPULATION: A total of 34 063 women from 384 549 households who gave birth in the previous year. METHODS: Using data collected in two geo referenced household surveys conducted in 2007 and 2013 in the context of two cluster-randomized controlled trials, we describe trends in caesarean section and neonatal mortality in obstetric risk groups inspired by the 10-group Robson classification. MAIN OUTCOME MEASURES: Rates of self-reported birth by caesarean section and neonatal mortality. RESULTS: Population-based caesarean section rates increased from 4.0% in 2007 to 6.4% in 2013. In 2013, the lowest caesarean section rate was found in multipara whose labour was not induced or augmented [4.4%, 95% confidence interval (CI) 3.9-4.9], a group that showed a rate increase of over 50% from 2007 [adjusted prevalence ratio 1.57 (95% CI 1.34-1.82)]. Nullipara whose labour was not induced or augmented had rates of 6.2% in 2007 and 8.5% in 2013. Caesarean rates in multiple pregnancies were low at 8.1% (95% CI 5.6-10.5) in 2007, and 14.6% (95% CI 9.4-19.8) in 2013. Overall neonatal mortality was high: 3.5% in 2007 and 3.2% in 2013, with rates being lowest in multiparous women whose labour was not induced or augmented: 2.4% (95% CI 2.2 2.7) and 1.7% (95% CI 1.4-2.0) in 2007 and 2013, respectively. CONCLUSION: Although use of caesarean section remains insufficient, and higher rates do not necessarily imply better quality of care, our analysis highlights improvements in reaching women with caesarean section. Rates in multiple birth remained low compared with high-income settings. TWEETABLE ABSTRACT: In Southern Tanzania caesarean section rates increased over time, but the rate in high-risk births remained alarmingly low. PMID- 30461162 TI - Re: Plasma concentrations of etonogestrel in obese women using oral desogestrel before and after Roux-en-Y gastric bypass surgery (RYGB): a pharmacokinetic study. AB - Up to eighty percent of patients who undergo bariatric surgery (BS) are women of childbearing age. The issue of efficient contraception is of paramount importance after BS, not only among those who do not wish to conceive, but also among those who wish to become pregnant as the most recent practice guidelines suggest delaying pregnancy for 12-24 months after surgery, ensuring that pregnancy does not occur during the rapid catabolic weight loss period, which may theoretically lead to impaired fetal growth. This article is protected by copyright. All rights reserved. PMID- 30461163 TI - Counselling and Treatment for Synthetic Mid-Urethral Slings. AB - Female stress urinary incontinence (SUI) is a condition that affects women worldwide. While treatment options span behavioral therapy, pelvic floor physical therapy, continent devices and surgery, many patients turn to surgical options due to longevity and efficacy. The modern midurethral sling (MUS) with synthetic mesh was popularized in the 1990s and has become the gold standard for surgical treatment for SUI since then. Ford, et al's 2017 Cochrane review concluded that MUS have a good safety profile and are highly effective. While there are multiple studies looking at efficacy of these slings, the urogynecological world finds itself at a crossroads (once again) as popular culture has targeted mesh safety (once again) for midurethral surgeries. This article is protected by copyright. All rights reserved. PMID- 30461164 TI - Edwards Sapien 3 transcatheter aortic valve implantation for management of severe aortic regurgitation in a teenage patient with corrected atrioventricular septal defect and progressive left ventricular dysfunction. AB - Transcatheter aortic valve replacement is mostly performed in elderly patients with severely calcified aortic valves. There are few reports about its use for pure aortic regurgitation, few reports about its use in adolescent patients and to the best of our knowledge no report about the use of an Edwards Sapien valve in the aortic position in an underage patient after surgically corrected congenital heart disease (CHD). Decompensation of a complex CHD can be difficult to manage and may require unusual solutions. We report a case of a teenage patient presenting with progressive aortic regurgitation and deterioration of left ventricular function after multiple surgical procedures for an atrioventricular septal defect (AVSD). As "bridge-to-transplant," we performed a transcatheter aortic valve implantation using a balloon-expandable Sapien 3 prosthesis. At 6 month follow-up, the patient remained clinically stable with no rehospitalization due to heart failure. PMID- 30461165 TI - Staged revascularization in patients with acute coronary syndromes due to saphenous vein graft failure and chronic total occlusion of the native vessel: A novel concept. AB - Percutaneous coronary intervention of saphenous vein graft (SVG) lesions can be challenging due to high risk for acute and long-term complications. Treating the corresponding native coronary artery lesion(s) is preferable, but may not be feasible in the acute setting, due to high technical difficulty, especially when the native coronary lesion is a chronic total occlusion (CTO). We describe a novel concept of "staged revascularization" in patients presenting with an acute coronary syndrome due to SVG failure, whose native coronary artery supplied by the SVG has a CTO. In the first stage, the culprit SVG lesion is treated restoring flow to the supplied myocardium and minimizing the extent of myocardial injury. During the second stage (typically few weeks later), revascularization of the corresponding native coronary artery lesion(s) is performed, often using the initially treated SVG for retrograde crossing of the native coronary artery CTO. We describe two cases of non-ST segment elevation acute myocardial infarction due to SVG failure that were treated with "staged revascularization": the culprit SVG was initially treated followed by staged revascularization of the corresponding native coronary artery CTO. Staged revascularization of SVG lesions causing acute coronary syndromes may allow optimization of both acute and long-term outcomes. PMID- 30461166 TI - Computerised analysis of intrapartum fetal heart rate patterns and adverse outcomes in the INFANT trial. AB - OBJECTIVE: To assess if a computerised decision support system reliably identified abnormal fetal heart rate (FHR) patterns in fetuses with adverse neonatal outcomes in the INFANT trial, and whether its use reduced substandard care. DESIGN: Prospective cohort study within a randomised controlled trial. SETTING: Twenty-four maternity units in the UK and Ireland. POPULATION OR SAMPLE: A total of 46 614 labours between January 6th 2010 and August 31 2013 in the INFANT trial. METHODS: Panel review of intrapartum and neonatal care in infants with adverse outcome, and an assessment of the effectiveness of computerised interpretation of fetal heart rate in reducing substandard care. Descriptive analysis of other factors associated with adverse outcome. MAIN OUTCOME MEASURES: Incidence and detection rate of abnormal fetal heart rate patterns, other characteristics associated with perinatal adverse outcome, and frequency of substandard care. RESULTS: Computer interpretation of FHR patterns was deemed to be completely valid in only 24 of 71 (33.8%) cases of adverse outcome. On a scale of 0-10 (completely invalid to completely valid), 28 cases (39.4%) had a score of 6 or less, mainly due to lack of recognition of decelerations (15 cases), or reduced variability (seven cases), or failure to recognise tachysystole (five cases). There were multiple associated factors that modified the clinical assessment of FHR patterns. There was substandard care in 45/71 cases (63%). CONCLUSION: A significant proportion of abnormal fetal heart rate patterns were not detected accurately by computer analysis, and its use did not reduce the incidence of substandard care. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme (project number 06.38.01). TWEETABLE ABSTRACT: Improved recognition of abnormal fetal heart rate patterns is insufficient to reduce the incidence of substandard care. PMID- 30461167 TI - Long-term outcomes of melody valve-in-valve implantation for bioprosthetic mitral valve dysfunction. AB - OBJECTIVES: This study reports long-term outcomes percutaneous Melody valve (Medtronic, Minneapolis, Minnesota) valve-in-valve therapy in patients with prosthetic valve dysfunction. BACKGROUND: Repeat valve surgery is associated with high morbidity and mortality. Transcatheter mitral valve-in-valve is a promising alternative in patients at high-risk for cardiac surgery. METHODS: We conducted a retrospective cohort analysis of 13 patients who underwent Melody valve-in-valve for bioprosthetic dysfunction from July 2011 to October 2013. RESULTS: Mean age was 74.4 years, 46% male, and STS score 13.5 +/- 6.8%. All patients had NYHA class 3 or 4 symptoms with improvement to class 1 or 2 in 82% post procedure. Median follow-up was 4.5 years with longest follow-up of 5.5 years. Thirty-day mortality was 15.4% with 1-year mortality of 25% and no other reported deaths until 4.5 years. 76.9% of patients had mitral gradient of 5 mmHg or less immediately postprocedure. One patient required repeat valve procedure for structural deterioration at 4.4 years. At 1, 3, and 5 year follow-ups 75% of patients were NYHA class 1 or 2, mean gradients were 4.5 +/- 0.6, 6.8 +/- 0.5, and 7.5 +/- 0.7, respectively. Using 4-point scale, mitral regurgitation postprocedure was 0.8 +/- 0.6. At 1, 3, and 5 years this increased to 1.0 +/- 1.1, 1.3 +/- 1.3, and 2.5 +/- 2.1, respectively. CONCLUSIONS: Melody valve-in valve therapy was effective with 1-year symptomatic improvement. Prosthesis deterioration requiring repeat intervention was observed in one patient. Larger cohorts with multicenter registries are needed to determine the role of this percutaneous valve-in-valve therapy as valve technology and procedural techniques improve. PMID- 30461168 TI - Author's reply re: Uterine Transplantation in Transgender Women: Medical, Legal and Ethical Considerations. AB - I thank you for the opportunity to respond to the letter submitted in response to my mini-commentary on uterine transplantation in transgender women. I agree with Jones, Alghrani and Smith that current legislation is not well equipped to govern the rapidly developing field of uterus transplantation (UTx). UTx straddles transplant and reproductive medicine, law, and ethics, with current legislation brought into force before UTx was contemplated as a reproductive possibility in the UK. This article is protected by copyright. All rights reserved. PMID- 30461169 TI - Breastfeeding and long-term maternal metabolic health in the HUNT Study: a longitudinal population-based cohort study. AB - OBJECTIVE: Breastfeeding (BF) is reported to improve long-term maternal metabolic health in observational studies, but not in the randomized-controlled PROBIT Study. Research also suggests that maternal pre-pregnant metabolic health may affect BF. We aimed to disentangle effects of BF on long-term maternal metabolic health, from effects of pre-pregnant metabolic health on both BF-duration and long-term metabolic health. DESIGN: Longitudinal population-based cohort study. SETTING: Nord-Trondelag county, Norway. POPULATION: Women with a first live-born baby (1987-2008) participating in the Nord-Trondelag Health Study (HUNT). METHODS: Odds ratios (ORs) for short BF-duration (<3 months) by pre-pregnant body mass index (BMI), waist circumference (WCF), blood pressures (BPs) and heart rate (HR) were adjusted for age and smoking using logistic regression. Mixed linear models were used to estimate effects of BF-duration (<3, 3-6, >6 months) on mean values of metabolic health-parameters from baseline to follow-up. MAIN OUTCOME MEASURES: Mean change in BMI, WCF, BPs, HR, serum-glucose and serum-lipids from baseline to follow-up by BF-duration categories. RESULTS: 1403 women with median follow-up of 12 years (inter-quartile range 11-22) were analyzed. Pre-pregnant WCF and HR correlated inversely with BF-duration. Pre-pregnant BMI had a u-shaped correlation-pattern with BF-duration. We observed similar between-group differences in metabolic health-parameters at baseline and at follow-up. I.e., mean change in metabolic alth-parameters was similar across BF-groups. Those women who started out with best health had longest BF-duration and ended up with best health, and those women who started out with poorest health had shortest BF duration and ended up with poorest health. CONCLUSIONS: Our results do not support a causal relationship between long BF-duration and improved metabolic health. It is more likely that pre-pregnant metabolic health affects both BF duration and long-term metabolic health. Reverse causality can explain previously observed improved long-term metabolic health after BF. This article is protected by copyright. All rights reserved. PMID- 30461170 TI - Continence, quality of life, and depression following surgical repair of obstetric vesicovaginal fistula: a cohort study. AB - OBJECTIVE: We evaluated residual incontinence, depression, and quality of life among Malawian women who had undergone vesicovaginal fistula (VVF) repair 12 or more months ago. DESIGN: Prospective cohort study. SETTING: Fistula Care Centre in Lilongwe, Malawi. POPULATION: Women who had undergone VVF repair in Lilongwe, Malawi at least 12 months prior to enrollment. METHODS: Self-report of urinary leakage was used to evaluate for residual urinary incontinence; depression was evaluated with the Patient health Questionnaire-9; quality of life was evaluated with the King's Health Questionnaire. MAIN OUTCOME MEASURES: Prevalence and predictors of residual incontinence, quality of life scores, and prevalence of depression and suicidal ideation. RESULTS: Fifty-six women (19.3%) reported residual urinary incontinence. In multivariable analyses, predictors of residual urinary incontinence included: pre-operative Goh type 3 (aRR=2.82; 95% CI:1.61, 5.27) or 4 (aRR=3.10; 95% CI:1.48, 6.50) VVF, more than one prior surgery (aRR=1.74; 95% CI:1.08, 2.78), positive post-operative cough stress test (aRR=2.42; 95% CI 1.24, 4.71) and the one-hour post-operative pad test (aRR=2.20; 95% CI:1.08, 4.48). Women with Goh types 3 and 4 VVF reported lower quality of life scores. Depressive symptoms were reported in 3.5% of women; all reported residual urinary incontinence. CONCLUSIONS: While the majority of women reported improved outcomes in the years following surgical VVF repair, those with residual urinary incontinence had a poorer quality of life. Services are needed to identify and treat this at-risk group. This article is protected by copyright. All rights reserved. PMID- 30461171 TI - Extraperitoneal uterosacral suspension technique for post hysterectomy apical prolapse in 472 women: results from a longitudinal clinical study. AB - OBJECTIVES: The study aims to evaluate the long-term results of the extraperitoneal uterosacral ligament suspension (bilateral) in women with apical prolapse following hysterectomy. DESIGN: Longitudinal clinical follow up conducted between June 2002 and December 2017. SETTING: Tertiary urogynaecology centre in Melbourne Australia. POPULATION: 472 women with symptomatic vault prolapse who underwent bilateral extraperitoneal uterosacral ligament suspension (EPUSLS). 61%(287/ 472) of these patients had previously had a procedure for pelvic organ prolapse(POP). METHODS: Follow up using structured, standardized questionnaires and examination by POP-Q and Baden -Walker system pre-and post operatively. MAIN OUTCOME MEASURES: Objective and subjective outcome measures for pelvic organ prolapse were functional and anatomical results and surgical complications. RESULTS: Mean follow up duration was approximately 5 years. The objective success rate at vaginal cuff support was 89% (420/472). Only 4% needed revision surgery for vault recurrence. There was improvement in bladder, bowel and sexual symptoms after the procedure. Mesh exposure rate was 17% (of the 138 having mesh augmentation) with the majority of cases managed conservatively or with minor interventions. The ureteric injury rate was 1% and mainly occurred in earlier cases. No women had buttock pain. CONCLUSION: EPUSLS is an effective, suture based procedure for vault prolapse with few complications even on long term follow up. This technique avoids the need to open the peritoneum vaginally and has a low risk of ureteric injury and gluteal pain. This article is protected by copyright. All rights reserved. PMID- 30461172 TI - The influence of the introduction of national guidelines on preterm birth prevention practice: UK experience. AB - OBJECTIVE: To identify the current status of specialist preterm labour (PTL) clinics and identify changes in management trends over the last 5 years following release of the NICE preterm birth (PTB) guidance. DESIGN: Postal Survey of Clinical Practice. SETTING: UK. POPULATION: All consultant-led obstetric units. METHODS: A questionnaire was sent by post to all 187 NHS consultant-led obstetric units. Units with specialist PTL clinic were asked to complete a further 6 questions defining their protocol for risk stratification and management. MAIN OUTCOME MEASURES: Current practice in specialist PTL clinics. Changes in treatment trends over 5 years. RESULTS: Thirty-three PTL prevention clinics were identified, with 73% running weekly. NHS staff (84%) have replaced university staff as the lead clinicians (from 69% in 2012 to 21% in 2017) suggesting this clinic has become increasingly integrated with standard care for women at the highest risk for PTB. There has been a large shift from nearly half of clinics offering cerclage as primary treatment for short cervix to offering more choice (30%) between at least two of cerclage, vaginal progesterone or pessary and combinations of primary treatments (18%) demonstrating more equipoise amongst clinicians regarding therapies for short cervix. CONCLUSIONS: Over 5 years there has been a 44% increase in the number of specialist PTL clinics in the UK. Although there is a better consensus over the target high risk population, there is increasing heterogeneity among first line treatments for short cervix. This article is protected by copyright. All rights reserved. PMID- 30461173 TI - How to close the calcium gap. PMID- 30461174 TI - Authors' reply re: Plasma concentrations of etonogestrel in obese women using oral desogestrel before and after Roux-en-Y gastric bypass surgery (RYGB): a pharmacokinetic study. AB - We read the comments of Rottenstreich and co-workers with great interest. We realize that we to a large extent agree with the authors opinions. The aim of our study was to evaluate the effects of Roux-en-Y gastric bypass (RYGB) on the pharmacokinetics of etonogestrel. We are aware of that the sample size of our study was limited and that the lack of sample size calculation limits the ability to draw conclusions regarding change in the present recommendations for contraception after RYGB. This article is protected by copyright. All rights reserved. PMID- 30461175 TI - Percutaneous patent foramen ovale closure using the Occlutech Figulla device: More than 1,300 patient-years of follow up. AB - OBJECTIVE: To evaluate the safety and efficacy of the Occlutech patent foramen ovale (PFO) device at long-term follow-up (FU). BACKGROUND: The Occlutech device has been proven safe and effective six-months after percutaneous PFO closure. We describe the safety and efficacy after more than 1,300 patient-years of FU. METHODS: All consecutive patients who underwent PFO closure between October 2008 and December 2015 were included. All complications were registered. Residual right-to-left shunt (RLS) was diagnosed using contrast transthoracic echocardiography and graded as minimal, moderate, or severe. RESULTS: In total, 250 patients (mean age 53.5 +/- 10.7 years, 46.8% female) underwent percutaneous PFO closure using the Occlutech device. Mean FU was 5.9 +/- 1.8 years, a total of 1,345 patient-years. Transient ischemic attack (TIA) or stroke was the main indication for closure (89.6%). Implantation was successful in 100%, no major complications occurred. Minor complications were inguinal hematoma in 16 patients (6.4%), pericardial effusion without the need for intervention in one patient (0.4%) and a supraventricular tachycardia in one patient (0.4%). A moderate or large shunt at one-year follow up was present in 5.9%. A cerebrovascular vascular event occurred in 2.0% at 1-year FU (four TIA, one stroke) and in 7.4% at long term FU (nine TIA, eight stroke). The total cerebrovascular event rate (TIA and CVA) was 0.02% per patient-year of FU, with a stroke rate of 0.01%. CONCLUSION: The Occlutech device appears to be safe at long-term FU with a very low annual cerebrovascular event rate and a low moderate to large shunt rate at 1-year FU. PMID- 30461176 TI - Physical activity in pregnancy and offspring weight: what we know and what we don't. AB - In this issue of the journal a remote federated individual level meta-analysis evaluates the association between maternal exercise during pregnancy and infant birth weight (BJOG xxxx). The findings are interesting since the authors conclude that physical activity in late, but not early, pregnancy is consistently associated with modestly lower risk of large-for-gestational-age (LGA) and macrosomia, but not small-for-gestational-age (SGA). As with any study though, it is important to understand that the generalizability of the results is determined by the type of population analysed. In this study, >70% of the sample size is contributed by the Danish National Birth Cohort (DNBC) which means that the outcomes of the meta-analysis will be, in most cases, significantly affected by the DNBC findings. This article is protected by copyright. All rights reserved. PMID- 30461178 TI - Falling stillbirth and neonatal mortality rates in twin gestation: not a reason for complacency. AB - The rate of twin pregnancies has been increasing globally and stabilized to 32 per 1000 births in the USA in 2006 (Chauhan SP et al; Am J Obstet Gynecol. 2010;203:305-15)and 16 per 1000 in the UK in 2015 (Khalil A. Ultrasound Obstet Gynecol. 2018; Epub Ahead of print). The significance of twin pregnancies is illustrated by a thirteenfold increase in rates of stillbirth in monochorionic and a fivefold increase in dichorionic twins compared with singleton pregnancies (Russo FM et al; Eur J Obstet Gynecol Reprod Biol 2013;170:131-6.). This article is protected by copyright. All rights reserved. PMID- 30461177 TI - Cytotoxic and morphological effects of microcystin-LR, cylindrospermopsin, and their combinations on the human hepatic cell line HepG2. AB - Cylindrospermopsin (CYN) and Microcystin-LR (MC-LR) are toxins produced by different cyanobacterial species, which are found mainly in freshwater reservoirs. Both of them can induce, separately, toxic effects in humans and wildlife. However, little is known about the toxic effects of the combined exposure, which could likely happen, taking into account the concomitant occurrence of the producers. As both cyanotoxins are well known to induce hepatic damage, the human hepatocellular HepG2 cell line was selected for the present study. Thus, the cytotoxicity of both pure cyanotoxins alone (0-5 MUg/mL CYN and 0-120 MUg/mL MC-LR) and in combination for 24 and 48 h was assayed, as long as the cytotoxicity of extracts from CYN-producing and nonproducing cyanobacterial species. The potential interaction of the combination was evaluated by the isobologram or Chou-Talalay's method, which provides a combination index as a quantitative measure of the two cyanotoxins interaction's degree. Moreover, a morphological study of the individual pure toxins and their combinations was also performed. Results showed that CYN was the most toxic pure cyanotoxin, being the mean effective concentrations obtained ~4 and 90 MUg/mL for CYN and MC-LR, respectively after 24 h. However, the simultaneous exposure showed an antagonistic effect. Morphologically, autophagy, at low concentrations, and apoptosis, at high concentrations were observed, with affectation of the rough endoplasmic reticulum and mitochondria. These effects were more pronounced with the combination. Therefore, it is important to assess the toxicological profile of cyanotoxins combinations in order to perform more realistic risk evaluations. PMID- 30461180 TI - Interventricular vessel of the heart and diuretics. PMID- 30461179 TI - Prognosis of the co-twin following spontaneous single intrauterine fetal death in twin pregnancies: a systematic review and meta-analysis. AB - BACKGROUND: Single intrauterine fetal death affects approximately 6% of twin pregnancies and can have serious sequelae for the surviving co-twin. OBJECTIVES: Determine the prognosis of the surviving co-twin following spontaneous single intrauterine fetal death to aid counselling patients and highlight future research areas. SEARCH STRATEGY: Medline, Embase, Web of Science, and Cochrane Library, from 1980 to June 2017. SELECTION CRITERIA: Studies of five or more cases of spontaneous single intrauterine fetal death after 14 weeks gestation, in diamniotic twin pregnancies. DATA COLLECTION AND ANALYSIS: Summary event rates were calculated and stratified by chorionicity. Monochorionic and dichorionic twins, and sub-groups, were compared by odds ratios. MAIN RESULTS: In monochorionic twins, when single intrauterine fetal death occurred at less than 28 weeks' gestation, this significantly increased the rate of co-twin intrauterine fetal death [odds ratio (OR) 2.31, 95% confidence interval (CI) 1.02 5.25, I2 = 0.0%, 12 studies, 184 pregnancies] and neonatal death (OR 2.84, 95% CI 1.18-6.77, I2 = 0.0%, 10 studies, 117 pregnancies) compared with when the single intrauterine fetal death occurred at more than 28 weeks' gestation. Neonatal death in monochorionic twins was significantly higher if the pregnancy was complicated by fetal growth restriction (OR 4.83, 95% CI 1.14-20.47, I2 = 0.0%, six studies, 60 pregnancies) or preterm birth (OR 4.95, 95% CI 1.71-14.30, I2 = 0.0%, 11 studies, 124 pregnancies). Abnormal antenatal brain imaging was reported in 20.0% (95% CI 12.8-31.1, I2 = 21.9%, six studies, 116 pregnancies) of surviving monochorionic co-twins. The studies included in the meta-analysis demonstrated small study effects and possible selection bias. CONCLUSIONS: Preterm birth was the commonest adverse outcome affecting 58.5 and 53.7% of monochorionic and dichorionic twin pregnancies. Outcomes regarding brain imaging and neurodevelopmental comorbidity are an important area for future research, but meta-analysis may be limited due to different methods of assessment. TWEETABLE ABSTRACT: Preterm birth is the highest risk in single co-twin death. Abnormal antenatal brain imaging was found in 1/5 surviving MC twins. PMID- 30461181 TI - Route of hysterectomy: a retrospective, cohort study in English NHS Hospitals from 2011-2017. AB - OBJECTIVE: To assess variation in the route of hysterectomy over 7-years and to assess regional variation in practice. DESIGN: Retrospective cohort study. SETTING: EnglishaNHSaHospitalsa2011-2017. POPULATION: 230,876 patients having a hysterectomy for six diagnostic categories (endometrial cancer, endometriosis and pain, menstrual disorders, fibroids, benign adnexal masses and 'other') identified from Hospital Episode Statistics. METHODS: The proportion of hysterectomies carried out by each route was calculated for each year overall and for each primary diagnosis by year. Comparisons between 2011 and 2017 were via Chi-squared test. Rank correlation coefficients were calculated to assess trends over the study period. Analysis of regional variation in practice was restricted to 2017. A multivariable logistic regression was performed to obtain crude and adjusted odds of having a minimal access hysterectomy. MAIN OUTCOME MEASURES: The proportion of abdominal, vaginal, laparoscopic and failed laparoscopic procedures for each primary diagnosis by study year. Odds of a minimal access hysterectomy in 2017. RESULTS: The proportion of hysterectomies performed laparoscopically increased from 16.5% in 2011 to 47.2% in 2017, as did the proportion of failed laparoscopic procedures; 1.3% in 2011 to 2.8% in 2017. The proportion of abdominal hysterectomies decreased from 73.4% in 2011 to 46.5% in 2017. There was a smaller decrease in vaginal procedures from 8.8% in 2011 to 3.5% in 2017. Regional variation in the route of hysterectomy was demonstrated in 2017, which persisted when adjusted for confounding factors. CONCLUSIONS: The proportion of laparoscopic procedures has increased, and it was the commonest route of hysterectomy for this cohort in 2017. There were significant regional differences in route of hysterectomy in 2017. This article is protected by copyright. All rights reserved. PMID- 30461182 TI - The associations of lipids and lipid ratios with stroke: A prospective cohort study. AB - Lipids and lipid ratios have been proven to be associated with cardiovascular disease; however, their relationships with stroke and stroke subtypes had not been fully understood. This study aims to assess the associations of lipids and lipid ratios with type-specific stroke and compare their predictive capacities for stroke occurrence. In this prospective cohort study, a total of 42 005 Chinese participants aged 20 to 80 who were free of stroke at baseline were included and selected into subgroups of stroke subtypes (ischemic, hemorrhagic, and total). Total stroke outcome included a combination of ischemic and hemorrhagic stroke. Over an average follow-up of 3.6 years, 781 participants developed stroke (623 ischemic and 158 hemorrhagic). In men, the highest TC/HDL-C quartile was significantly associated with increased ischemic stroke risk (multivariable-adjusted hazard ratio [HR], 1.52, 95% confidence interval [CI], 1.14-2.03) and total stroke risk (HR, 1.45, 95% CI, 1.12-1.87), and TC/HDL-C had the highest area under the receiver operating characteristic curve (AUC) for predicting ischemic (AUC, 0.868) and total stroke (AUC, 0.874). In women, the highest TG quartile was significantly associated with increased risk of ischemic (HR, 1.99, 95% CI, 1.11-3.59) and total stroke (HR, 1.85, 95% CI, 1.07-3.20), with AUCs of 0.850 and 0.861, respectively. No lipid variables were significantly associated with hemorrhagic stroke in both sex. In conclusion, TC/HDL-C ratio may better predict stroke risk in men, whereas TG was more valuable in predicting stroke risk in women. TC/HDL-C and TG may help to discriminate high stroke risk individuals and serve as potential targets for stroke prevention. PMID- 30461183 TI - A dosimetric analysis of a spine SBRT specific treatment planning system. AB - PURPOSE: The Brainlab Elements treatment planning system utilizes distinct modules for treatment planning specific to stereotactic treatment sites including single or multiple brain lesions as well as spine. This work investigates the hypothesis that an optimization tailored specifically to spine can in fact create dosimetrically superior plans to those created in more general use treatment planning systems (TPS). METHODS: Ten spine patients at our institution were replanned in Brainlab Elements, Phillips Pinnacle3 , and Elekta Monaco. The planning target volume (PTV) included the vertebral body (in either the thoracic or lumbar spine), pedicles, and transverse processes. In all plans, the target was prescribed 20 Gy to 95% of the PTV. Objectives for the study included D5%<25 Gy and spinal cord D0.035cc < 14 Gy. Plans were evaluated by the satisfaction of the objectives as well total monitor units (MU), gradient index (GI), conformity index (CI), and dose gradient (distance between 100% and 50% isodose lines) in a selected slice between the vertebral body and spinal cord. RESULTS: All TPS produced clinically acceptable plans. The sharpest dose gradient was achieved with Elements (mean 3.3 +/- 0.2 mm). This resulted in lowest spinal cord maximum point doses (6.6 +/- 1.0 Gy). Gradient indices were also the smallest for Elements (3.6 +/- 0.5). Further improvement in gradient index and spinal cord sparing were not performed due to the subsequent violation of the PTV D5% < 25 Gy constraint or the loss of conformity due to the loss of coverage at the PTV spinal canal interface. CONCLUSIONS: Brainlab Elements planning which relies on arc duplication to specifically optimize for spine anatomy did result in dosimetrically superior plans while holding prescription levels constant. While any planning system can improve upon specific dosimetric objectives, the simultaneous satisfaction of all constraints was best achieved with Brainlab Elements. PMID- 30461184 TI - Repellence of Myzus persicae (Sulzer): evidence of two modes of action of volatiles from selected living aromatic plants. AB - BACKGROUND: Intercropping companion plants (CPs) with horticultural crops could be an eco-friendly strategy to optimize pest management. In this research, volatile organic compounds (VOCs) emitted by some CPs were investigated for their repellent properties towards the green peach aphid (Myzus persicae Sulzer). The aim of this study was to understand the modes of action involved: direct effects on the aphid and/or indirect effects via the host plant (pepper, Capsicum annuum L.). RESULTS: We identified two promising repellent CPs species: the volatile blend from basil (Ocimum basilicum, direct repellent effect) and the mixture of (or previously intercropped) C. annuum plants with Tagetes patula cv. Nana (indirect effect). This effect was cultivar-dependent and linked to the volatile bouquet. For the 16 compounds present in the O. basilicum or T. patula bouquets tested individually, (E)-beta-farnesene and eugenol reported good repellent properties against M. persicae. Other compounds were repellent at medium and/or at highest concentrations. Thus, the presence of repellent VOCs in a mixture does not mean that it had a repellent propriety. CONCLUSION: We identified two promising repellent CPs species towards M. persicae, with a likely effect of one CPs' VOCs on the host plant repellency and highlighted the specific effectiveness of VOC blends. This article is protected by copyright. All rights reserved. PMID- 30461185 TI - Screening, isolation and evaluation of a nematicidal compound from actinomycetes against the pine wood nematode, Bursaphelenchus xylophilus. AB - BACKGROUND: Bursaphelenchus xylophilus is a migratory endoparasitic nematode known to cause severe environmental damage and economic losses in pine forest ecosystems. This present study investigated the nematicidal metabolites of actinomycetes in vitro and evaluated the disease control efficacy of the active compound and metabolites under greenhouse and field conditions. RESULTS: Five thousand types of actinobacteria from Korean forest soil samples were screened to identify novel nematicidal agents against the pine wood nematode. Streptomyces sp. AN091965 showed the strongest nematicidal activity. One active compound, spectinabilin, was obtained by nematicidal asssy-directed fractionation, and it showed significant nematicidal activity against B. xylophilus, with an LC50 value of 0.84 MUg mL-1 . Spectinabilin effectively suppressed the development of pine wilt disease in 5-year-old Pinus densiflora trees, even at 0.9 mg per tree under greenhouse conditions. Moreover, the acetone extract of the active strain's mycelia efficiently suppressed the development of pine wilt disease under field conditions. CONCLUSION: To the best of our knowledge, this the first report to describe the nematicidal activity of spectinabilin against B. xylophilus. The cell extracts described herein merit further field studies as potential nematicides against the pine wood nematode. This article is protected by copyright. All rights reserved. PMID- 30461186 TI - Para-tertiary butyl catechol (PTBC), an industrial antioxidant induces human platelet apoptosis. AB - The catecholic derivative para-tertiary butyl catechol (PTBC) is a conventional antioxidant and polymerization inhibitor, which exhibits melanocytotoxic effects and contact dermatitis often leading to occupational leucoderma or vitiligo. Although numerous industrial workers will be in constant exposure to PTBC and its chances of getting entry into blood are most expected, its effect on blood components is still undisclosed. As platelets play a prominent role in dermatitis, inflammation, and immunity, in this study we have evaluated the effect of PTBC on human platelets in vitro. Exposure of platelets to PTBC showed increased reactive oxygen species (ROS), intracellular calcium, cardiolipin oxidation, mitochondrial permeability transition pore (MPTP) formation, activation of caspases, phosphatidylserine (PS) externalization and decreased mitochondrial membrane potential. In addition, there was a significant decrease in cellular glutathione level, increased gamma-glutamyltransferase (GGT) activity and cell death. These findings demonstrate that PTBC could induce toxic effects on blood components, which is often ignored field of research. Since dermal exposure of humans to toxic chemicals covers an important issue in various industries, there is a need of such work to understand and update the long-term toxicities induced by PTBC usage in industrial sectors and public domain. PMID- 30461187 TI - Insight on patient specific computer modeling of transcatheter aortic valve implantation in patients with bicuspid aortic valve disease. AB - OBJECTIVE: The aim of this study was to describe the early use of dedicated patient specific computer modeling in patients with bicuspid aortic valve (BAV) undergoing transcatheter aortic valve implantation (TAVI), in predicting procedure feasibility and patient related outcome. BACKGROUND: Dedicated patient specific computer modeling, used for optimizing TAVI procedures, is currently validated for the prediction of contact pressure, valve morphology and paravalvular leakage (PVL). The simulation of TAVI procedures is increasingly used in patients with tricuspid aortic valve stenosis. Currently, BAV disease is considered as a relative contra-indication for TAVI due to its specific anatomical characteristics. METHODS: This single center study consisted of seven patients with BAV undergoing TAVI. A patient specific computer simulation was performed based on multislice computer tomography images. The model advised the best fitting prosthetic valve size or sizes and simulated this valve on different implantation depths with the corresponding presence and severity of PVL and prosthetic valve morphology. The simulation results were compared with the procedural outcomes using transesophageal echocardiography (TEE) and fluoroscopy. RESULTS: The patient specific computer modeling predicted accurately the outcome (PVL and valve morphology) of TAVI in all cases. In one case, the TAVI procedure was unsuccessful and retrospectively not suitable for TAVI, which was correctly predicted by the model. CONCLUSION: The patient specific computer modeling adequately predicts feasibility and outcome of TAVI in patients with BAV disease and may extend the applicability of TAVI. Moreover, it improves decision-making and therefore individual procedural outcomes in this difficult patient population. PMID- 30461188 TI - Hydrophilic interaction chromatography (HILIC) for the analysis of biopharmaceutical drugs and therapeutic peptides: A review based on the separation characteristics of the HILIC phases. AB - Applications of hydrophilic interaction chromatography (HILIC) for the analysis of biopharmaceutical drugs, i.e., glycosylated proteins represented by monoclonal antibodies are discussed in the manner of glycoproteomics. They can be analyzed using HILIC in five different stages as (1) their intact forms, (2) their subunits, (3) N- and O-glycopeptides digested by proteases, (4) N- and O-glycans released from the glycoproteins or glycopeptides, and (5) monosaccharides. HILIC is a more useful tool in the order of the (1) to (5). At the stages (4) and (5), quantitation of glycans and saccharides are also reported. HILIC is employed not only for analytical uses, but also pre-treatment items as solid phase extraction, followed by RPLC separations. Comprehensive search results of these application of HILIC are summarized in tables to show what kind of HILIC columns are suitable for each step of analysis.Relationship of favored and less favored HILIC columns and their separation characteristics such as hydrophilicity, and selectivity for structural difference, is also discussed. Analysis of the therapeutic peptides (not glycosylated) using HILIC is summarized, too. This article is protected by copyright. All rights reserved. PMID- 30461189 TI - Target regulation of both VECs and VSMCs by dual-loading miRNA-126 and miRNA-145 in the bilayered electrospun membrane for small-diameter vascular regeneration. AB - Clinical utility of small-diameter vascular grafts is still challenging in blood vessel regeneration owing to thrombosis and intimal hyperplasia. To cope with the issues, modulation of gene expression via microRNAs (miRNAs) could be a feasible approach by rational regulating physiological activities of both vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). Our previous studies demonstrated that individually loaded miRNA-126 (miR-126) or miRNA-145 (miR-145) in the electrospun membranes showed the tendency to promote vascular regeneration. In this work, the bilayered electrospun graft in 1.5-mm diameter was developed by emulsion electrospinning to dual-load miR-126 and miR-145 for target regulation of both VECs and VSMCs, respectively. Accelerated release of miR-126 was achieved by introducing poly(ethylene glycol) in the inner electrospun poly(ethylene glycol)-b-poly(l-lactide-co-caprolactone) ultrafine fibrous membrane, reaching 61.3 +/- 1.2% of the cumulative release in the initial 10 days, whereas the outer electrospun poly(l-lactide-co-glycolide) membrane composed of microfibers fulfilled prolonged release of miR-145 for about 56 days. In vivo tests suggested that dual-loading with miR-126 and miR-145 in the bilayered electrospun membranes could modulate both VECs and VSMCs for rapid endothelialization and hyperplasia inhibition as well. It is reasonably expected that dual target-delivery of miR-126 and miR-145 in the electrospun vascular grafts has effective potential for small-diameter vascular regeneration. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 2018. PMID- 30461190 TI - Cadherin-7 mediates proper neural crest cell-placodal neuron interactions during trigeminal ganglion assembly. AB - The cranial trigeminal ganglia play a vital role in the peripheral nervous system through their relay of sensory information from the vertebrate head to the brain. These ganglia are generated from the intermixing and coalescence of two distinct cell populations: cranial neural crest cells and placodal neurons. Trigeminal ganglion assembly requires the formation of cadherin-based adherens junctions within the neural crest cell and placodal neuron populations; however, the molecular composition of these adherens junctions is still unknown. Herein, we aimed to define the spatio-temporal expression pattern and function of Cadherin-7 during early chick trigeminal ganglion formation. Our data reveal that Cadherin-7 is expressed exclusively in migratory cranial neural crest cells and is absent from trigeminal neurons. Using molecular perturbation experiments, we demonstrate that modulation of Cadherin-7 in neural crest cells influences trigeminal ganglion assembly, including the organization of neural crest cells and placodal neurons within the ganglionic anlage. Moreover, alterations in Cadherin-7 levels lead to changes in the morphology of trigeminal neurons. Taken together, these findings provide additional insight into the role of cadherin-based adhesion in trigeminal ganglion formation, and, more broadly, the molecular mechanisms that orchestrate the cellular interactions essential for cranial gangliogenesis. This article is protected by copyright. All rights reserved. PMID- 30461191 TI - Suppression of ovarian follicle development by nano TiO2 is associated with TGF beta-mediated signaling pathways. AB - Nanoparticulate titanium dioxide (nano TiO2 ) is extensively applied in biological tissue engineering materials, food additives, cosmetics, and sunscreens. Numerous studies to date have demonstrated that nano TiO2 penetrates through the digestive system and possibly the blood circulation, leading to accumulation in the ovary and consequent reproductive toxicity. However, the mechanisms underlying the toxic effects of nano TiO2 on the female reproductive system remain to be established. In this study, female mice were exposed to different doses of nano TiO2 (1.25, 2.5, or 5 mg/kg body weight) via intragastric administration for 60 consecutive days, followed by investigation of follicular development, regulation of TGF-beta-mediated signaling pathways, and expression of the pathway components. Subchronic exposure to nano TiO2 induced a decrease in the number of primordial, secondary, and antral follicles and corpus luteum and concomitant increase in atretic follicles. Furthermore, follicular development disorder induced by nano TiO2 was associated with upregulation of TGF-beta1, TGF betaR1, PTEN, and Foxo3a involved in cell growth and apoptosis and downregulation of several growth factors (PI3K, AKT, p-mTOR, p70S6K, p-p70S6K1, rpS6, p-rpS6, TSC1, and TSC2) in mouse ovaries. Our data collectively implied that suppression of ovarian follicle development by nano TiO2 was triggered by dysfunction of the TGF-beta, PI3K/AKT/mTOR, and AKT/p70S6K-rpS6/TSC/mTOR pathways. The adverse effects of nano TiO2 on follicular development highlights the necessity for caution in the use of nanomaterials in the food industry. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 2018. PMID- 30461192 TI - Towards development of generic inhibitors against the 3C proteases of picornaviruses. AB - Development of novel antivirals, which requires knowledge of the viral life cycle in molecular detail, is a daunting task, involving extensive investments, and frequently resulting in failure. As there exist significant commonalities among virus families in the manner of host interaction, identifying and targeting common rather than specific features may lead to the development of broadly useful antivirals. Here, we have targeted the 3C protease of Hepatitis A Virus (HAV), a faeco-orally transmitted virus of the family Picornaviridae, for identification of potential antivirals. The 3C protease is a viable drug target as it is required by HAV, as well as by other picornaviruses, for post translational proteolysis of viral polyproteins and for inhibiting host innate immune pathways. Computational screening, followed by chemical synthesis and experimental validation resulted in identification of a few compounds which, at low micromolar concentrations, could inhibit HAV 3C activity. These compounds were further tested experimentally against the 3C protease of Human Rhinovirus, another member of the Picornaviridae family, with comparable results. Computational studies on 3C proteases from other members of the picornavirus family has indicated that the compounds identified could potentially be generic inhibitors for picornavirus 3C proteases. This article is protected by copyright. All rights reserved. PMID- 30461193 TI - Targeting PRMT5/Akt signalling axis prevents human lung cancer cell growth. AB - The emerging evidence reveals that protein arginine methyltransferase 5 (PRMT5) is involved in regulation of tumour cell proliferation and cancer development. Nevertheless, the exact role of PRMT5 in human lung cancer cell proliferation and the underlying molecular mechanism remains largely obscure. Here, we showed that PRMT5 was highly expressed in human lung cancer cells and lung cancer tissues. Furthermore, we generated PRMT5 stable knockdown cell lines (A549 and H1299 cells) and explored the functions of PRMT5 in lung cancer cell proliferation. We found that the down-regulation of PRMT5 by shRNA or the inhibition of PRMT5 by specific inhibitor GSK591 dramatically suppressed cyclin E1 and cyclin D1 expression and cell proliferation. Moreover, we uncovered that PRMT5 promoted lung cancer cell proliferation via regulation of Akt activation. PRMT5 was directly co-localized and interacted with Akt, but not PTEN and mTOR. Down regulation or inhibition of PRMT5 markedly reduced Akt phosphorylation at Thr308 and Ser473, whereas the expression of PTEN and mTOR phosphorylation was unchanged, indicating that PRMT5 was an important upstream regulator of Akt and induced lung cancer cell proliferation. Altogether, our results indicate that PRMT5 promotes human lung cancer cell proliferation through direct interaction with Akt and regulation of Akt activity. Our findings also suggest that targeting PRMT5 may have therapeutic potential for treatment of human lung cancer. PMID- 30461194 TI - Small molecule nAS-E targeting cAMP response element binding protein (CREB) and CREB-binding protein interaction inhibits breast cancer bone metastasis. AB - Bone is the most common metastatic site for breast cancer. The excessive osteoclast activity in the metastatic bone lesions often produces osteolysis. The cyclic-AMP (cAMP)-response element binding protein (CREB) serves a variety of biological functions including the transformation and immortalization of breast cancer cells. In addition, evidence has shown that CREB plays a key role in osteoclastgenesis and bone resorption. Small organic molecules with good pharmacokinetic properties and specificity, targeting CREB-CBP (CREB-binding protein) interaction to inhibit CREB-mediated gene transcription have attracted more considerations as cancer therapeutics. We recently identified naphthol AS-E (nAS-E) as a cell-permeable inhibitor of CREB-mediated gene transcription through inhibiting CREB-CBP interaction. In this study, we tested the effect of nAS-E on breast cancer cell proliferation, survival, migration as well as osteoclast formation and bone resorption in vitro for the first time. Our results demonstrated that nAS-E inhibited breast cancer cell proliferation, migration, survival and suppressed osteoclast differentiation as well as bone resorption through inhibiting CREB-CBP interaction. In addition, the in vivo effect of nAS-E in protecting against breast cancer-induced osteolysis was evaluated. Our results indicated that nAS-E could reverse bone loss induced by MDA-MB-231 tumour. These results suggest that small molecules targeting CREB-CBP interaction to inhibit CREB-mediated gene transcription might be a potential approach for the treatment of breast cancer bone metastasis. PMID- 30461195 TI - VEGF-A regulates angiogenesis during osseointegration of Ti implants via paracrine/autocrine regulation of osteoblast response to hierarchical microstructure of the surface. AB - Establishment of a patent vasculature at the bone-implant interface plays a significant role in determining overall success of orthopedic and dental implants. Osteoblasts produce vascular endothelial growth factor-A (VEGF-A), an important regulator of angiogenesis during bone formation and healing, and the amount secreted is sensitive to titanium (Ti) surface microtopography and surface energy. The purpose of this study was to determine if surface properties modulate cellular response to VEGF-A. MG63 osteoblast-like cells were transfected with shRNA targeting VEGF-A at >80% knockdown. Cells stably silenced for VEGF-A secreted reduced levels of osteocalcin, osteoprotegerin, FGF-2, and angiopoietin 1 when cultured on grit-blasted/acid-etched (SLA) and hydrophilic SLA (modSLA) Ti surfaces and conditioned media from these cultures caused reduced angiogenesis in an endothelial tubule formation assay. Treatment of MG63 cells with 20 ng/mL rhVEGF-A165 rescued production in silenced cells and increased production of osteocalcin, osteoprotegerin, FGF-2, and angiopoietin-1, with greatest effects on control cells cultured on modSLA. Addition of a neutralization antibody against VEGF receptor 2 (VEGFR2; Flk-1) resulted in a significant increase in VEGF-A production. Overall, this study indicates that VEGF-A has two roles in osseointegration: enhanced angiogenesis and an autocrine/paracrine role in maturation of osteoblast-like cells in response to Ti surface properties. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 2018. PMID- 30461196 TI - Preparative separation of the flavonoid fractions from Periploca forrestii Schltr. ethanol extracts using macroporous resin combined with HPLC analysis and evaluation of their biological activities. AB - A preparative separation method using macroporous absorptive resin coupled with high-performance liquid chromatography (HPLC) was developed for the separation of six fractions of an 80% ethanol extract of Periploca forrestii Schltr. The six obtained 5-95% ethanol fractions (A, B, C, D, E, and F) were carefully analyzed to locate the corresponding peaks in the HPLC chromatogram of the total extract, which was established in a previous study. Furthermore, the biological activities, including antioxidant activities, acetyl cholinesterase inhibitory capacities, antihyaluronidase activities and anti-inflammatory effects, were evaluated in MH7A cells. The results demonstrated that fraction E could significantly prevent oxidation and inhibit hyaluronidase and acetyl cholinesterase. Finally, the main flavonoids in fractions A and E from Periploca forrestii Schltr. were purified, and the compounds were identified as chlorogenic acid, quercetin-3-O-alpha-L-arabinopyranoside and quercetin-7-O-beta-D glucopyranoside. The chemical structures were confirmed by MS and nuclear magnetic resonance spectroscopy. Furthermore, the inhibitory effects of these compounds against complete Freund's adjuvant-induced secondary immune arthritis in rats were evaluated. This article is protected by copyright. All rights reserved. PMID- 30461197 TI - Novel peptide dermaseptin-PS1 exhibits anticancer activity via induction of intrinsic apoptosis signalling. AB - Antimicrobial peptides (AMP) secreted by the granular glands of frog skin have been widely reported to exhibit strong bacteriostatic and bactericidal activities. Many of them have been documented with potent antiproliferative effects on multiple cancer cells, many studies also suggested that AMPs exert their functions via disrupting cell membranes. However, whether and how other cell death induction mechanism is involved in mammalian cancer cells has rarely been investigated. In this study, a novel AMP named Dermaseptin-PS1 was isolated and identified from Phyllomedusa sauvagei, it showed strong antimicrobial activities against three types of microorganisms. In vitro antiproliferative studies on human glioblastoma U-251 MG cells indicated that Dermaseptin-PS1 disrupted cell membranes at the concentrations of 10-5 M and above, while the cell membrane integrity was not affected when concentrations were decreased to 10 6 M or lower. Further examinations revealed that, at the relatively low concentration (10-6 M), Dermaseptin-PS1 induced apoptosis through mitochondrial related signal pathway in U-251 MG cells. Thus, for the first time, we report a novel frog skin derived AMP with anticancer property by distinct mechanisms, which largely depends on its concentration. Together, our study provides new insights into the mechanism-illustrated drug design and the optimisation of dose control for cancer treatment in clinic. PMID- 30461198 TI - Pancreatic fibroblast growth factor 21 protects against type 2 diabetes in mice by promoting insulin expression and secretion in a PI3K/Akt signaling-dependent manner. AB - Fibroblast growth factor 21 (FGF21) is important in glucose, lipid homeostasis and insulin sensitivity. However, it remains unknown whether FGF21 is involved in insulin expression and secretion that are dysregulated in type 2 diabetes mellitus (T2DM). In this study, we found that FGF21 was down-regulated in pancreatic islets of db/db mice, a mouse model of T2DM, along with decreased insulin expression, suggesting the possible involvement of FGF21 in maintaining insulin homeostasis and islet beta-cell function. Importantly, FGF21 knockout exacerbated palmitate-induced islet beta-cell failure and suppression of glucose stimulated insulin secretion (GSIS). Pancreatic FGF21 overexpression significantly increased insulin expression, enhanced GSIS, improved islet morphology and reduced beta-cell apoptosis in db/db mice. Mechanistically, FGF21 promoted expression of insulin gene transcription factors and soluble N ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, the major regulators of insulin secretion, as well as activating phosphatidylinositol 3-kinase (PI3K)/Akt signaling in islets of db/db mice. In addition, pharmaceutical inhibition of PI3K/Akt signaling effectively suppressed FGF21 induced expression of insulin gene transcription factors and SNARE proteins, suggesting an essential role of PI3K/Akt signaling in FGF21-induced insulin expression and secretion. Taken together, our results demonstrate a protective role of pancreatic FGF21 in T2DM mice through inducing PI3K/Akt signaling dependent insulin expression and secretion. PMID- 30461199 TI - Bioinspired Photonic Barcodes with Graphene Oxide Encapsulation for Multiplexed MicroRNA Quantification. AB - Multiplexed microRNA (miRNA) quantification has a demonstrated value in clinical diagnosis. In this paper, novel mussel-inspired photonic crystal (PhC) barcodes with graphene oxide (GO) encapsulation for multiplexed miRNA detection are presented. Using the excellent adhesion capability of polydopamine, the dispersed GO particles can be immobilized on the surfaces of the PhC barcodes to form an additional functional layer. The GO-decorated PhC barcodes have constant characteristic reflection peaks because the GO immobilization process not only maintains their periodic microstructure but also enhances their stability and anti-incoherent light-scattering capability. The immobilized GO particles are shown to enable high-sensitivity miRNA screening on the surface of the PhC barcodes by integration with a hybridization chain reaction amplification strategy. Because the PhC barcodes have stable encoding reflection peaks, multiplexed low-abundance miRNA quantification can also be achieved rapidly, accurately, and reproducibly by employing different GO-decorated PhC barcodes. These features should make GO-encapsulated PhC barcodes ideal for many practical applications. PMID- 30461200 TI - The variant at TGFBRAP1 is significantly associated with type 2 diabetes mellitus and affects diabetes-related miRNA expression. AB - While the transforming growth factor-beta1 (TGF-beta1) regulates the growth and proliferation of pancreatic beta-cells, its receptors trigger the activation of Smad network and subsequently induce the insulin resistance. A case-control was conducted to evaluate the associations of the polymorphisms of TGF-beta1 receptor associated protein 1 (TGFBRAP1) and TGF-beta1 receptor 2 (TGFBR2) with type 2 diabetes mellitus (T2DM), and its genetic effects on diabetes-related miRNA expression. miRNA microarray chip was used to screen T2DM-related miRNA and 15 differential expressed miRNAs were further validated in 75 T2DM and 75 normal glucose tolerance (NGT). The variation of rs2241797 (T/C) at TGFBRAP1 showed significant association with T2DM in case-control study, and the OR (95% CI) of dominant model for cumulative effects was 1.204 (1.060-1.370), Bonferroni corrected P < 0.05. Significant differences in the fast glucose and HOMA-beta indices were observed amongst the genotypes of rs2241797. The expression of has miR-30b-5p and has-miR-93-5p was linearly increased across TT, TC, and CC genotypes of rs2241797 in NGT, Ptrend values were 0.024 and 0.016, respectively. Our findings suggest that genetic polymorphisms of TGFBRAP1 may contribute to the genetic susceptibility of T2DM by mediating diabetes-related miRNA expression. PMID- 30461201 TI - Cartilage/bone interface fabricated under perfusion: Spatially organized commitment of adipose-derived stem cells without medium supplementation. AB - Tissue engineering of an osteochondral interface demands for a gradual transition of chondrocyte- to osteoblast-prevailing tissue. If stem cells are used as a single cell source, an appropriate cue to trigger the desired differentiation is the use of composite materials with different amounts of calcium phosphate. Electrospun meshes of poly-lactic-co-glycolic acid and amorphous calcium phosphate nanoparticles (PLGA/aCaP) in weight ratios of 100:0; 90:10, 80:20, and 70:30 were seeded with human adipose-derived stem cells (ASCs) and cultured in DMEM without chemical supplementation. After 2 weeks of static cultivation, they were either further cultivated statically for another 2 weeks (group 1), or placed in a Bose(r) bioreactor with a flow rate per area of 0.16 mL cm-2 min-1 (group 2). Markers for stem cell criteria, chondrogenesis, osteogenesis, adipogenesis and angiogenesis were analyzed by quantitative real-time PCR. Cell distribution, Sox9 protein expression and proteoglycans were assessed by histology. In group 2 (perfusion culture), chondrogenic Sox9 was upregulated toward the cartilage-mimicking side compared to pure PLGA. On the bone-mimicking side, Sox9 experienced a downregulation, which was confirmed on the protein level. Vice versa, expression of osteocalcin was upregulated on the bone mimicking side, while it was unchanged on the cartilage-mimicking side. In group 1 (static culture), CD31 was upregulated in the presence of aCaP compared to pure PLGA, whereas Sox9 and osteocalcin expression were not affected. aCaP nanoparticles incorporated in electrospun PLGA drive the differentiation behavior of human ASCs in a dose-dependent manner. Discrete gradients of aCaP may act as promising osteochondral interfaces. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res B Part B: Appl Biomater, 2018. PMID- 30461202 TI - Perceived stress mediates the relationship between mindfulness and negative affect variability: A randomized controlled trial among middle-aged to older adults. AB - Despite the interest in mindfulness over the past 20 years, studies have only recently begun to examine mindfulness in older adults. The primary aim of this study was to evaluate pretreatment to post-treatment change in negative affect variability (NAV) following a mindfulness training among 134 mildly stressed, middle-aged to older adults. The secondary aim was to assess if the effects of mindfulness training on NAV would be partially explained by pretreatment to post treatment reductions in perceived stress, a trend that would be congruent with several stress models. In this randomized control trial, participants were assigned to either a 6-week mindfulness meditation training programme or to a wait list control. Ecological momentary assessment, a data capturing technique that queries about present moment experiences in real time, captured NAV. Mixed model ANOVAs and a path analysis were conducted. Participants in the mindfulness meditation training significantly reduced NAV when compared with wait list control participants. Further, there was a significant indirect group effect on reductions in NAV through change in perceived stress. Few studies have tested mechanisms of action, which connect changes that occur during mindfulness training with psychological outcomes in older adults. Understanding the mechanisms by which mindfulness enhances well-being may optimize interventions. PMID- 30461203 TI - Predicting how evolution will beat us. AB - In this Crystal Ball article, we look ahead to the possibility of model and tools that can predict the accumulation of mutations that inactivate engineered plasmids. PMID- 30461204 TI - Prevalence of pulp stones: A systematic review and meta-analysis. AB - OBJECTIVE: During the last years, different prevalences of dental pulps had been reported from different parts of the world. Combining these original estimates will provide useful information for policymaking in the field of health, treatment and research. This study aims to estimate the global prevalence of pulp stones. METHODS: Electronic databanks such as PubMed, Scopus, Science direct, Cochrane, and also Google scholar motor engine were searched by 2 researchers using related keywords. The heterogeneity between the results was assessed using Cochrane and I2 indices. The initial estimates were represented by forest plot and were combined according to random effects models. Factors responsible for heterogeneity were investigated using meta-regression models, and studies responsible for heterogeneity were assessed following sensitivity analysis. RESULTS: Prevalence of pulp stones had been reported in 16 studies including 14 093 subjects. The pooled prevalence (95% confidence interval) of pulp stones among the total population, men and women were estimated as of 36.53% (27.17 45.88), 32.58% (24-41.15), and 39.23% (28.73-49.73), respectively. In addition, of 193 687 teeth investigated during the primary studies, 9.57% (95% confidence interval: 7.05-12.08) were affected by pulp stones. CONCLUSION: Our meta-analysis shows a considerable prevalence of pulp stones, especially among women. PMID- 30461205 TI - Engineering Pseudomonas protegens Pf-5 to improve its antifungal activity and nitrogen fixation. AB - In agricultural production, sustainability is currently one of the most significant concerns. The genetic modification of plant growth-promoting rhizobacteria may provide a novel way to use natural bacteria as microbial inoculants. In this study, the root-colonizing strain Pseudomonas protegens Pf-5 was genetically modified to act as a biocontrol agent and biofertilizer with biological nitrogen fixation activity. Genetic inactivation of retS enhanced the production of 2,4-diacetylphloroglucinol, which contributed for the enhanced antifungal activity. Then, the entire nitrogenase island with native promoter from Pseudomonas stutzeri DSM4166 was introduced into a retS mutant strain for expression. Root colonization patterns assessed via confocal laser scanning microscopy confirmed that GFP-tagged bacterial were mainly located on root surfaces and at the junctions between epidermal root cells. Moreover, under pathogen and N-limited double treatment conditions, the fresh weights of seedlings inoculated with the recombinant retS mutant-nif strain were increased compared with those of the control. In conclusion, this study has innovatively developed an eco-friendly alternative to the agrochemicals that will benefit global plant production significantly. PMID- 30461206 TI - Engineered cell-to-cell signalling within growing bacterial cellulose pellicles. AB - Bacterial cellulose is a strong and flexible biomaterial produced at high yields by Acetobacter species and has applications in health care, biotechnology and electronics. Naturally, bacterial cellulose grows as a large unstructured polymer network around the bacteria that produce it, and tools to enable these bacteria to respond to different locations are required to grow more complex structured materials. Here, we introduce engineered cell-to-cell communication into a bacterial cellulose-producing strain of Komagataeibacter rhaeticus to enable different cells to detect their proximity within growing material and trigger differential gene expression in response. Using synthetic biology tools, we engineer Sender and Receiver strains of K. rhaeticus to produce and respond to the diffusible signalling molecule, acyl-homoserine lactone. We demonstrate that communication can occur both within and between growing pellicles and use this in a boundary detection experiment, where spliced and joined pellicles sense and reveal their original boundary. This work sets the basis for synthetic cell-to cell communication within bacterial cellulose and is an important step forward for pattern formation within engineered living materials. PMID- 30461207 TI - Randomized double-blind trial of amifostine versus placebo for radiation-induced xerostomia in patients with head and neck cancer. AB - INTRODUCTION: The role of the radioprotector amifostine in ameliorating radiotherapy side effects in head and neck squamous cell carcinoma (HNSCC) is controversial. This trial aimed to determine whether pretreatment with amifostine reduced the incidence of Radiation Therapy Oncology Group grade >=2 acute and late xerostomia in patients receiving definitive or adjuvant radiotherapy for HNSCC, without reducing tumour control or survival. METHODS: Between 14 September 2001 and 8 November 2004, 44 Royal Adelaide Hospital patients were randomized double-blind to receive amifostine (200 mg/m2 IV) or placebo (normal saline IV) 5 days/week, prior to standard radiotherapy (60-70 Gy), each having >=75% of the parotids treated to >=40 Gy. Side effects were assessed weekly during treatment, at 3 and 5 months after radiotherapy, then every 6 months until disease progression or death. RESULTS: The accrual target was 200 patients over 4-5 years, but the trial closed prematurely when only 44 patients had been randomized after 3 years. Of 41 evaluable patients, 80% (16/20) in the amifostine arm had grade >=2 acute radiation salivary toxicity versus 76% (16/21) in the placebo arm (P = 1.00). The rate of grade >=2 late radiation salivary toxicity at 12 months was 66% in the amifostine arm and 82% in the placebo arm (estimated hazard ratio 1.61, 95% confidence interval 0.74-3.49, P = 0.22). Other toxicities tended to be worse in the amifostine arm: acute grade 3-4 skin 35% vs 5% and mucous membrane 40% vs 5%; grade >=2 vomiting 35% vs 5%, hypocalcaemia 25% vs 5% and fatigue 85% vs 33%, with only the latter retaining statistical significance after adjusting for multiple comparisons. There were no significant differences in failure-free (P = 0.70) or overall survival (P = 0.86), with estimated 4-year rates of 48% vs 54% and 49% vs 59% for the amifostine vs placebo arms respectively. CONCLUSION: There was no clear evidence that pretreatment with amifostine made any difference to the incidence of grade >=2 acute or late xerostomia. Other toxicity tended to be more severe with amifostine. There was no effect on failure-free or overall survival. Acknowledging the low statistical power, these results do not support the use of IV amifostine pre-radiotherapy in HNSCC. PMID- 30461208 TI - The Synthetic Microbiology Caucus: from abstract ideas to turning microbes into cellular machines and back. PMID- 30461209 TI - Objective assessment of robotic suturing skills with a new computerized system: A step forward in the training of robotic surgeons. AB - INTRODUCTION: The purpose of this study was to assess robot-assisted suturing skills on a laparoscopic intestinal anastomosis model by using a novel computerized objective assessment system. METHODS: This study compared the suturing skills of 13 surgically naive participants on an artificial intestinal anastomosis model that mimics real tissue. Each examinee sutured using da Vinci robot assistance under 2-D and 3-D visualization and with conventional laparoscopy (CL). Pressure-measuring and image-processing devices were employed to quantitatively evaluate suturing skills. Five unique criteria were used to evaluate the skills of participants. RESULTS: Suturing under 3-D visualization (P < 0.01) and with CL (P < 0.05) were significantly faster than under 2-D visualization. Sutures placed under 3-D (P < 0.05) and 2-D (P < 0.01) visualization had significantly better suture tension than those placed with CL, which did not meet acceptable values for suture tension. Sutures placed with CL had significantly better air pressure leakage than those placed under 2-D visualization (P < 0.05), which did not meet acceptable values for air pressure leakage and wound opening area. One participants failed to achieve full-thickness sutures with 2-D, two participants with CL, and one participant with 3-D. CONCLUSION: Using 3-D vision is necessary for complex maneuvering during robot assisted minimally invasive surgery. Our quantitative assessment system is useful for evaluating the skill acquisition of surgeon-trainees undergoing robotic surgery training. PMID- 30461210 TI - A potential mechanism of the onset of acute eosinophilic pneumonia triggered by an anti-PD-1 immune checkpoint antibody in a lung cancer patient. AB - INTRODUCTION: The impact of immune checkpoint blockade on immunity in cancer patients is not completely elucidated due to the complexity of the immune network. Recent studies have revealed a significant role of programed cell death ligand 2 (PD-L2) in negatively controlling the production of CD4+ T helper type 2 (Th2) cytokines and airway hypersensitiveness, suggesting hypo-responsive Th2 cells via the PD-1/PD-L2 inhibitory pathway in lung could be reawaken by PD-1 blockade therapy. METHODS: We describe the first report of acute eosinophilic pneumonia (AEP), which is known as Th2-associated pulmonary disease, triggered by nivolumab, an anti-PD-1 antibody, in an advanced non-small cell lung cancer patient. Based on the current case report and literature, the present study proposes a potential mechanism of the onset of AEP as an immune-related adverse event (irAE). RESULTS: A 62-year-old man was diagnosed with lung adenocarcinoma and nivolumab was selected as the third-line regimen. After three cycles of nivolumab treatment, chest computed tomography revealed pulmonary infiltrates in both lungs. The patient was diagnosed with AEP based on the diagnostic criteria for AEP. Nivolumab was suspended and the patient was started on oral prednisolone. His symptoms and radiological findings had rapidly improved. CONCLUSIONS: Given the increasing frequency of the use of anti-PD-1 antibodies, clinicians should be aware of the risk of AEP as a potential irAE. This study may improve our understanding of the pathophysiology underlying Th2-associated irAEs and AEP. PMID- 30461211 TI - Wound-healing effect of adipose stem cell-derived extracellular matrix sheet on full-thickness skin defect rat model: Histological and immunohistochemical study. AB - The potential use of extracellular matrix (ECM) as a source of wound dressing material has recently received much attention. The ECM is an intricate network of various combinations of elastin, collagens, laminin, fibronectin, and proteoglycans that play a key role in stimulating cell proliferation and differentiation. We evaluated the efficacy of an ECM sheet derived from human adipose tissue as a wound dressing material to enhance healing. We prepared a novel porous ECM sheet dressing scaffold from human adipose tissue. in vitro analysis of the ECM sheets showed efficient decellularisation; absence of immunostimulatory components; and the presence of a wide number of angiogenic and bioactive factors, including collagen, elastin, and proteoglycans. To evaluate in vivo efficacy, full-thickness excisional wounds were created on the dorsal skin of a rat, and the ECM sheets; secondary healing foam wound dressing, Healoderm; or a conventional dressing were applied to each wound site. Photographs were taken every other day, and the degree of reepithelialisation of the wounds was determined. Application of an ECM sheet dressing enhanced the macroscopic wound healing rate on days 4, 7, and 10 compared with that in the control group. Microscopic analysis indicated that the reepithelialisation rate of the wound was higher in the ECM group compared with that in the control group; the reepithelialisation rate was better than that of the secondary healing foam wound dressing. Moreover, a denser and more organised granulation tissue was formed in the ECM sheet group compared with that in the secondary healing foam wound dressing and control groups. The ECM sheet also showed the highest microvessel density compared with the secondary healing foam wound dressing and control groups. Based on these data, we suggest that a bioactive ECM sheet dressing derived from human adipose can provide therapeutic proteins for wound healing. PMID- 30461212 TI - Direct growth of MoO2/reduced graphene oxide hollow spheres composites as advanced anode materials for potassium-ion batteries. AB - Hollow MoO2/reduced graphene oxide (MoO2/rGO) submicro-spheres composites have been successfully fabricated through a simple hydrothermal approach followed by a heat treatment process. When employed as an anode material for potassium-ion batteries, the as-synthesized MoO2/rGO composite can deliver an initial charge specific capacity of 367.2 mAh g-1 at 50 mA g-1, and its reversible capacity is 218.9 mAh g-1 after 200 cycles. Even when cycled at 500 mA g-1, a high charge specific capacity of 104.2 mAh g-1 is achieved after 500 cycles. The excellent cycling capability and rate performance may be ascribed to the synergistic effects of the reduced graphene oxide and the hollow MoO2 spheres, which can increase the electrical conductivity of the composite, as well as resisting the strain arose from the repeated discharge/charge processes. These results indicate that the MoO2/rGO hollow spheres composites are promising negative electrode materials for potassium-ion batteries. PMID- 30461213 TI - Updates on the pathogenesis of advanced lung cancer-induced cachexia. AB - Advanced lung cancer is becoming a chronic disease threatening human life and health. Cachexia has been recognized as the most common problem associated with advanced lung cancer. Lung cancer-induced cachexia seriously affects patients' quality of life. The present article summarizes the pathogenesis of advanced lung cancer-induced cachexia from three aspects: anorexia, cytokines, and energy and metabolic abnormalities. In addition, the present article proposes corresponding nursing measures based on cachexia pathogenesis to improve the quality of life and survival rate of cachectic patients with advanced lung cancer by combining continuously advancing treatment regimens and effective nursing. The present article also provides references for healthcare professionals when administering related treatments and nursing care. PMID- 30461214 TI - The PPARalpha agonist fenofibrate attenuates disruption of dopamine function in a maternal immune activation rat model of schizophrenia. AB - AIMS: Prenatal maternal immune activation (MIA) is associated with a risk to develop schizophrenia and affects dopamine systems in the ventral tegmental area (VTA), key region in the neurobiology of psychoses. Considering the well described sex differences in schizophrenia, we investigated whether sex affects MIA impact on dopamine system and on schizophrenia-related behavioral phenotype. Furthermore, considering peroxisome proliferator-activated receptor-alpha (PPARalpha) expression in the CNS as well as its anti-inflammatory and neuroprotective properties, we tested if PPARalpha activation by prenatal treatment with a clinically available fibrate (fenofibrate) may mitigate MIA related effects. METHODS: We induced MIA in rat dams with polyriboinosinic polyribocytidylic acid (Poly I:C) and assessed prepulse inhibition and dopamine neuron activity in the VTA by means of electrophysiological recordings in male and female preweaned and adult offspring. RESULTS: Poly I:C-treated males displayed prepulse inhibition deficits, reduced number and firing rate of VTA dopamine neurons, and paired-pulse facilitation of inhibitory and excitatory synapses. Prenatal fenofibrate administration attenuated detrimental effects induced by MIA on both the schizophrenia-like behavioral phenotype and dopamine transmission in male offspring. CONCLUSION: Our study confirms previous evidence that females are less susceptible to MIA and highlights PPARalpha as a potential target for treatments in schizophrenia. PMID- 30461215 TI - The regulation of CIRBP by transforming growth factor beta during heat shock induced testicular injury. AB - BACKGROUND: Cold-inducible RNA-binding protein (CIRBP) is associated with cell stress. However, its upstream regulatory factors are still largely unknown. OBJECTIVES: This study investigated whether CIRBP expression was regulated by transforming growth factor beta (TGF-beta) during the process of heat-induced testicular damage. MATERIALS AND METHODS: Ten male adult ICR mice were allocated to heat treatment (scrotal hyperthermia at 43 degrees C for 30 min, n = 5) and control group (n = 5); CIRBP and TGF-beta1, TGF-beta2, and TGF-beta3 expression levels in the testis in mRNA and protein were analyzed. Then, we conducted in vivo and in vitro studies to investigate the regulatory effects of TGF-beta on CIRBP. In the in vivo study, male adult ICR mice were subjected to testicular hyperthermia followed by a local testicular injection of TGF-beta antagonist (non selective TGF-beta I/II receptor inhibitor, 5 MUg or 10 MUg). In the in vitro study, GC2-spd cells were cultured under 43 degrees C for 30 min or with different TGF-beta isoforms (10 ng/mL), and CIRBP expression levels in the testis and GC2-spd cells were analyzed 24 and 48 h, respectively, after treatment. RESULTS: As a result, heat treatment significantly downregulated the relative CIRBP mRNA and protein expression (p = 0.006 and 0.011), and significantly upregulated TGF-beta2 and TGF-beta3 expression levels (p = 0.022 and 0.04, for mRNA, and p = 0.001 for both protein levels). Local testicular injection of 10 MUg TGF-beta antagonist significantly attenuated heat-induced histological damage to the testes and CIRBP downregulation (p = 0.038). Furthermore, TGF-beta2 and TGF-beta3 significantly downregulated CIRBP mRNA and protein expression in GC2 spd cells (all p < 0.01), exerting a similar effect to heat treatment. DISCUSSION AND CONCLUSION: Our in vivo and in vitro experiments demonstrated that heat induced CIRBP downregulation in the testes was mediated by the upregulation of TGF-beta. Further studies are needed to clarify the molecular mechanisms underlying these processes. PMID- 30461216 TI - Galactocele of adult male breast: A cytopathologist's perspective. AB - Galactocele, although a common cytological diagnosis in females, is not previously reported as a cause of breast enlargement in adult males. Hyperprolactinemia is the principal cause of galactocele in male breast. Besides drug induced hyperprolactinemia, other anatomical lesions of hypothalamo pituitary region and different medical conditions like cirrhosis and chronic kidney disease are to be considered along with a full evaluation of features revealing hypogonadism in case of galactocele. Aspirated milk from the male breast is the primary clue for this detailed investigation process. Here we are presenting the first case of galactocele of the male breast due to hypogonadotropic hypogonadism with idiopathic hyperprolactinemia. PMID- 30461217 TI - Smear cytological features of large cell neuroendocrine carcinoma of the uterine cervix in pregnancy: A case report and review of the literature. AB - Large-cell neuroendocrine carcinoma (LCNEC) of the uterine cervix is a rare aggressive tumor. The examination of a cervicovaginal smear from a 31-year-old patient diagnosed with LCNEC after a cervical polypectomy during the 32nd week of pregnancy was carried out. The observed atypical cells had large cytoplasm, increased nucleus: cytoplasm ratio with the nucleus containing coarse, dispersed chromatin, and were arranged in a pseudorosette formation, which all confirmed the diagnosis. In addition, adenocarcinoma in situ (AIS) was determined in the histopathological examination of the subsequent hysterectomy material. Given the rarity of this condition, we present and discuss the case herein. PMID- 30461219 TI - Central Obesity Increases the Risk of Gestational Diabetes Partially Through Increasing Insulin Resistance. AB - OBJECTIVE: This study examined the associations of central obesity measures, waist to hip ratio (WHR) and waist circumference (WC), in early pregnancy with subsequent risk of gestational diabetes mellitus (GDM) and evaluated the potential mediating role of insulin resistance markers. METHODS: Within the prospective Pregnancy Environment and Lifestyle Study cohort of 1,750 women, WC and hip circumference were measured at gestational weeks 10 to 13. In a nested case-control study within the cohort, 115 GDM cases and 230 controls had fasting serum insulin, homeostatic model assessment of insulin resistance (HOMA-IR), and adiponectin measurements at gestational weeks 16 to 19. Poisson and conditional logistic regression models were used, adjusting for established risk factors for GDM, including prepregnancy overweight or obesity. RESULTS: For women with WHR < 0.85, one or more established risk factors increased GDM risk 1.99-fold (95% CI: 0.99-4.02). For women with WHR >= 0.85 but no established risk factors, GDM risk increased 2.41-fold (95% CI: 1.14-5.06), and in those with established risk factors it increased 6.22-fold (95% CI: 3.49-11.10). Similar but attenuated results were observed for WC >= 88 cm. Insulin, HOMA-IR, and adiponectin levels mediated the WHR-GDM association by 9% to 11%; corresponding mediation proportions for the WC-GDM association were 35% to 41% (all P < 0.04). CONCLUSIONS: Central obesity in early pregnancy represented a high-risk phenotype for GDM independent of other risk factors, including overweight or obesity, and may inform early screening and prevention strategies. PMID- 30461218 TI - Target oxygen saturation and development of pulmonary hypertension and increased pulmonary vascular resistance in preterm infants. AB - OBJECTIVE: Determine whether higher targeted oxygen levels are associated with reduced incidence of pulmonary hypertension (PH) and elevated pulmonary vascular resistance (PVR) in extremely premature infants. STUDY DESIGN: Retrospective chart review of 252 extremely preterm infants (<29 weeks), who underwent echocardiogram prior to discharge. PH rates were compared during periods (June 2012-May 2015 and June 2015-April 2016) when lower (88-92%) or higher (90-95%) oxygen saturation targets were used. PH was determined on echocardiography. The ratio of pulmonary artery acceleration time to right ventricular ejection time was computed, with values <0.31 indicative of elevated PVR. Survival analysis compared the effects of oxygen saturation group on development/resolution of PH and elevated PVR. RESULTS: The higher saturation group had significantly lower risk of developing PH (hazard ratio (HR) = 0.50, 95%CI 0.26-0.95; P = 0.03) or elevated PVR (HR = 0.55, 95%CI 0.38-0.81; P = 0.002), compared to the lower oxygen saturation group. Median time to PH development was significantly shorter in the lower saturation group than in the higher saturation group (5 days vs 12 days; P = 0.02), as was time to development of elevated PVR (4 days vs 6 days; P < 0.001). Duration of PH (P = 0.12) and elevated PVR (P = 0.86) did not differ significantly between groups. Cumulative incidence of PH (P = 0.04) and elevated PVR (P = 0.01) at 36 weeks post-menstrual age was significantly lower in the high saturation group compared to the lower saturation group. CONCLUSION: Higher targeted oxygen saturation was associated with reduced risk of PH or elevated PVR in extremely preterm infants compared to lower oxygen saturation target. PMID- 30461221 TI - Effects of Canagliflozin on Body Composition and Hepatic Fat Content in Type 2 Diabetes Patients with Non-alcoholic Fatty Liver Disease. AB - AIMS: Non-alcoholic fatty liver disease (NAFLD) is frequently associated with type 2 diabetes (T2D) and constitutes an important risk factor for the development of hepatic fibrosis and hepatocellular carcinoma. Because there remains no effective drug therapy for NAFLD associated with T2D, we evaluated the efficacy of sodium-glucose cotransporter 2 inhibitor (SGLT2i). METHODS AND MATERIALS: In this pilot, prospective non-randomized open-label single-arm study, we evaluated the effect of 100 mg canagliflozin administered once daily for 12 months on serological markers, body composition measured by bioelectrical impedance analysis method, and hepatic fat fraction (HFF) measured by magnetic resonance imaging, in T2D with NAFLD. This study was registered with the UMIN Clinical Trial Registry (UMIN000020615). RESULTS: Canagliflozin significantly reduced body and fat mass while induced slight decrease in lean body or muscle mass that did not reach significance at 6 and 12 months. Reductions in fat mass in each body segment (trunk, arms, and legs) were evident, while those in lean body mass were not. HFF was reduced from a baseline of 17.6 +/- 7.5% to 12.0 +/- 4.6% after 6 months and 12.1 +/- 6.1% after 12 months (p<0.0005 and p<0.005), while serum liver enzymes and type IV collagen concentrations improved. From a mean baseline HbA1c of 8.7 +/- 1.4%, canagliflozin significantly reduced HbA1c after 6 and 12 months to 7.3 +/- 0.6% and 7.7 +/- 0.7% (p<0.0005 and p<0.01). CONCLUSIONS: Canagliflozin reduced body mass, fat mass, and hepatic fat content, without significantly reducing muscle mass. This article is protected by copyright. All rights reserved. PMID- 30461222 TI - Label-Free Electrophoretic Mobility Shift Assay (EMSA) for Measuring Dissociation Constants of Protein-RNA Complexes. AB - The electrophoretic mobility shift assay (EMSA) is a well-established method to detect formation of complexes between proteins and nucleic acids and to determine, among other parameters, equilibrium constants for the interaction. Mixtures of protein and nucleic acid solutions of various ratios are analyzed via polyacrylamide gel electrophoresis (PAGE) under native conditions. In general, protein-nucleic acid complexes will migrate more slowly than the free nucleic acid. From the distributions of the nucleic acid components in the observed bands in individual gel lanes, quantitative parameters such as the dissociation constant (Kd ) of the interaction can be measured. This article describes a simple and rapid EMSA that relies either on precast commercial or handcast polyacrylamide gels and uses unlabeled protein and nucleic acid. Nucleic acids are instead detected with SYBR Gold stain and band intensities established with a standard gel imaging system. We used this protocol specifically to determine Kd values for complexes between the PAZ domain of Argonaute 2 (Ago2) enzyme and native and chemically modified RNA oligonucleotides. EMSA-based equilibrium constants are compared to those determined with isothermal titration calorimetry (ITC). Advantages and limitations of this simple EMSA are discussed by comparing it to other techniques used for determination of equilibrium constants of protein RNA interactions, and a troubleshooting guide is provided. (c) 2018 by John Wiley & Sons, Inc. PMID- 30461220 TI - Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole-body homeostasis. AB - BACKGROUND: The protein kinase mechanistic target of rapamycin (mTOR) controls cellular growth and metabolism. Although balanced mTOR signalling is required for proper muscle homeostasis, partial mTOR inhibition by rapamycin has beneficial effects on various muscle disorders and age-related pathologies. Besides, more potent mTOR inhibitors targeting mTOR catalytic activity have been developed and are in clinical trials. However, the physiological impact of loss of mTOR catalytic activity in skeletal muscle is currently unknown. METHODS: We have generated the mTORmKOKI mouse model in which conditional loss of mTOR is concomitant with expression of kinase inactive mTOR in skeletal muscle. We performed a comparative phenotypic and biochemical analysis of mTORmKOKI mutant animals with muscle-specific mTOR knockout (mTORmKO) littermates. RESULTS: In striking contrast with mTORmKO littermates, mTORmKOKI mice developed an early onset rapidly progressive myopathy causing juvenile lethality. More than 50% mTORmKOKI mice died before 8 weeks of age, and none survived more than 12 weeks, while mTORmKO mice died around 7 months of age. The growth rate of mTORmKOKI mice declined beyond 1 week of age, and the animals showed profound alterations in body composition at 4 weeks of age. At this age, their body weight was 64% that of mTORmKO mice (P < 0.001) due to significant reduction in lean and fat mass. The mass of isolated muscles from mTORmKOKI mice was remarkably decreased by 38 56% (P < 0.001) as compared with that from mTORmKO mice. Histopathological analysis further revealed exacerbated dystrophic features and metabolic alterations in both slow/oxidative and fast/glycolytic muscles from mTORmKOKI mice. We show that the severity of the mTORmKOKI as compared with the mild mTORmKO phenotype is due to more robust suppression of muscle mTORC1 signalling leading to stronger alterations in protein synthesis, oxidative metabolism, and autophagy. This was accompanied with stronger feedback activation of PKB/Akt and dramatic down-regulation of glycogen phosphorylase expression (0.16-fold in tibialis anterior muscle, P < 0.01), thus causing features of glycogen storage disease type V. CONCLUSIONS: Our study demonstrates a critical role for muscle mTOR catalytic activity in the regulation of whole-body growth and homeostasis. We suggest that skeletal muscle targeting with mTOR catalytic inhibitors may have detrimental effects. The mTORmKOKI mutant mouse provides an animal model for the pathophysiological understanding of muscle mTOR activity inhibition as well as for mechanistic investigation of the influence of skeletal muscle perturbations on whole-body homeostasis. PMID- 30461223 TI - Clinical approach to cardiac pauses in congenital central hypoventilation syndrome. AB - Congenital central hypoventilation syndrome (CCHS) patients may have heart rhythm disorders related to autonomic nervous system dysfunction such as, sinus bradycardia and transient asystole with potentially dramatic syncopal events. The diagnosis of these cardiac alterations may be challenging with conventional periodical Holter monitoring. The case shows how continuous heart rhythm monitoring provided by the implantable cardiac monitor (ICM) may play a crucial role for their early diagnosis and the choice of the appropriate therapeutic intervention. PMID- 30461224 TI - Infertility in a man with oligoasthenozoospermia associated with mosaic chromosome 22q11 deletion. AB - BACKGROUND: A 30-year-old oligoasthenozoospermia man was found to have unbalance mosaic translocation between chromosome 22 and four other chromosomes (5, 6, 13, and 15) during the investigations for a couple with infertility for 3 years, which is a rare event in human pathology. METHODS: Classical cytogenetics analysis, fluorescence in situ hybridization (FISH), and chromosome microarray analyses (CMA) were performed on peripheral blood lymphocytes; copy number variation sequencing (CNV-Seq) analysis was performed on sperm DNA. RESULTS: Classical cytogenetics analysis showed the presence of six cell lines on peripheral blood lymphocytes: 45, XY, der (13) t(13;22),-22[10]/46, XY, t(13;22)[6]/45, XY, der(15)t(15;22),-22[4]/46, XY, t(13;22)[1]/45, XY, der(5)t(5;22),-22[1]/45, XY, der(6)t(6;22)[1]. FISH and CMA performed on peripheral blood cells showed the presence of a 6.9 Mb mosaic 22q11 deletion (approximately 50% of cells); it is unexpected that the phenotypes of this man were merely oligoasthenozoospermia, mild bradycardia, and mild tricuspid regurgitation. CNV-Seq analysis performed on sperm DNA revealed the rate of 22q11 deletion cells was obviously lower compared with peripheral blood cells. And the frequency of gametes exhibiting a normal or balance chromosomal equipment was above 80% in sperm samples. CONCLUSION: To the best of our knowledge, this report is the first case of a de novo gonosomal mosaic of chromosome 22q11 deletion just associated with male infertility. PMID- 30461225 TI - Trabecular Bone Fraction Variation in Modern Humans, Fossil Hominins and other Primates. AB - Evidence suggests that recent modern humans (Holocene) have low trabecular bone density (i.e., trabecular bone fraction, TBF) compared with other extant primates and fossil hominins. However, the extent to which TBF in recent humans with varying subsistence strategies differs from that of fossil hominins, and in turn, how hominins differ from various extant catarrhines is unclear. This study tests the hypotheses that first, populations with subsistence strategies demanding high physical activity exhibit greater TBF than sedentary populations and are more similar to fossil Homo. Secondly, that, australopiths have TBF that is more similar to nonhuman primates because of the greater mechanical loading on their skeletons. The study quantifies TBF in the limb epiphyses of recent humans, hominoids, cercopithecines, and fossil hominins. The results show overall a significant decrease in TBF among recent humans, whereas hominins, hominoids, and cercopithecines have similar, high TBF values. In addition, active human populations display TBF that is more similar to fossil Homo. The results suggest that this TBF decline reflects a reduction in activity levels among sedentary populations, although a systemic decline cannot be ruled out. These findings support the recent evolution of low trabecular density because of a decline in activity levels and underscore the utility of comparing multiple skeletal elements across a diverse set of recent modern humans when drawing conclusions about changes in trabecular bone in the human skeleton. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30461226 TI - Microbial degradation of agricultural chemicals: An annotated selection of World Wide Web sites relevant to the topics in environmental microbiology. PMID- 30461227 TI - The diagnostic value of parathyroid hormone washout in primary hyperparathyroidism patients with negative or equivocal 99 m Tc-MIBI results. AB - BACKGROUND AND OBJECTIVES: The accurate identification of hyper functioning parathyroid gland is needed for definitive surgical treatment in primary hyperparathyroidism. Ultrasonography and 99mTechnetium sestamibi scintigraphy are the two most used methods with varying sensitivities. This study aimed to assess the value of parathyroid hormone (PTH) assay in preoperative ultrasound guided fine needle aspiration (FNA)-PTH washout fluid to verify the correct localisation of lesions with negative or inconclusive scintigraphy results. METHODS: We evaluated data of 28 lesions in 21 patients who underwent US-guided parathyroid fine-needle aspiration (FNA) with PTH washout, retrospectively. The PTH washout results and the reports of parathyroid surgery and imaging studies were reviewed. RESULTS: Of operated 28 lesions 23 had positive and 5 had negative washout results. The median FNA-PTH washout was 2315.5 pg/ ml (min-max: 12.3-6978 pg/ ml). The calculated sensitivity of FNA-PTH washout was 85.7% and the specifity was 28.6%. The positive and negative predictive values were 78.3% and 40.0%, respectively. CONCLUSIONS: FNA-PTH can be used to establish the nature of the lesion, discriminate parathyroid gland from thyroid lesions or cervical lymph nodes, improving the surgical outcomes. It can be used to localise parathyroid lesions preoperatively when negative or discordant ultrasound and scintigraphy findings are obtained. PMID- 30461229 TI - Toxicology of caffine. PMID- 30461228 TI - Pediatric patients with home mechanical ventilation: The health services landscape. AB - OBJECTIVE: Children with invasive home mechanical ventilation (HMV) are a growing population with complex health service needs. Single institution studies provide insight into successful program structures and outcomes. Our study objectives were to assess health service structures, providers, and programs caring for this population throughout the U.S., and to understand barriers to high-quality care. DESIGN: Using purposeful sampling with capture-recapture and snowball sampling methods, we identified key informants for care of the U.S. pediatric HMV population. Informants received web-based surveys with two reminders. Survey domains included respondent characteristics, HMV team composition, and barriers to care. RESULTS: Survey response was 71% with 101 completed. Respondents caring for patients in 45 states included physicians (61%), nurses (20%), therapists (12%), case managers (4%), and social workers (2%). Half (53%) of physicians were fellowship trained, most commonly pulmonology (22%) and critical care medicine (13%). The majority (65%) of providers described a dedicated HMV service. The majority (61%) of respondents from a HMV service provided both inpatient and outpatient care. Nearly all respondents (96%) described an inadequate supply of home nurses and 88% reported inadequate respite facilities. CONCLUSIONS: Children with HMV assistance receive care from a diverse group of providers with varied team structure. Heterogeneity may reflect patient diversity and provider interest, increasing efficacy but challenging standardization nationwide. Despite team structure variability, similar home care difficulties were universally experienced. Data suggest that the home nursing shortage is a national impediment to quality and efficient discharge with limited community-based support for this vulnerable population. PMID- 30461230 TI - Current state of caffeine intoxication. PMID- 30461231 TI - Caffeine poisoning in Japan. PMID- 30461232 TI - A case of suicide by helium gas. AB - Helium is a colorless, tasteless, and odorless gas that is used as a lifting gas for air balloons and small airships due to its high level of safety. In recent years, it has become easy to search the Internet for methods to commit suicide, and the use of helium gas for this purpose has recently been garnering attention. We report a case of a male in his 30's in which helium gas was used to commit suicide. He was found unconscious on a bed with a plastic bag covering his head. When emergency personnel arrived at the scene, he was in cardiac arrest and remained in cardiac arrest at the time of his arrival at the hospital. Continued cardiopulmonary resuscitation resulted in a return of spontaneous circulation. Head computed tomography showed the corticomedullary border was indistinct. Fifteen hours at the hospital, the patient died. Recently, there has been an increasing trend for suicide being performed according to methods obtained through the Internet or mass media. Although there are only a few cases of suicide by helium gas in Japan, attention must be paid to this issue as the number of such cases may increase in the future. PMID- 30461233 TI - Acute onset of a tonic seizure in a phenytoin-overdosed patient who had taken phenytoin and levetiracetam daily. AB - The 42-year-old woman who had been taking 300 mg phenytoin and 2,000 mg levetiracetam daily took 28.6 g of phenytoin and was transferred to our critical care center. The blood phenytoin concentration was 67.9 MUg/mL on admission and decreased to 53.4 MUg/mL on hospital day 2. Tonic seizures occurred several times on hospital day 2; thus, we resumed levetiracetam via a nasogastric tube. Thereafter, no further seizures were observed. We thought the seizure to have been caused by temporary withdrawal of levetiracetam because it did not occur on the day when the blood phenytoin concentration peaked and stopped altogether after resumption of levetiracetam. We considered that to treat the convulsion attack resulting from an overdose of the other antiepileptic drug with a different action mechanism, it was necessary to promptly restart the administration of the antiepileptic drug, which the patient was usually administered. PMID- 30461234 TI - Topical thermotherapy for extended numbness and pain after Cheiracanthium japonicum bite. PMID- 30461236 TI - Management of convulsive seizures induced by intoxicating substances. PMID- 30461235 TI - A Case of child abuse disguised as drug intoxication: Abuse should suspected in cases of accidental drug ingestion. AB - A 2-year-old boy presented to the emergency room of abuse to the child guidance office in the relevant public our hospital with disturbance of consciousness. His mother health center. Additionally, we reported 5 cases of neglect reported that he ingested flunitrazepam, which his mother that led to accidental ingestion of chemical substances to had been using and had given him in order to put him to the child guidance office. sleep. He was hospitalized due to disturbance of conscious- Cases of accidental drug ingestion by children should be ness, and was discharged from the hospital the next day dealt with taking into account the possibility of child abuse. with improved symptoms. We reported this case of child abuse to the child guidance office in the relevant public health center. Additionally, we reported 5 cases of neglect that led to accidental ingestion of chemical substances to the child guidance office. Cases of accidental drug ingestion by children should be dealt with taking into account the possibility of child abuse. PMID- 30461238 TI - Translational toxicology from basic sciences to clinical toxicology Toxicological significance of heme oxygenase-1 induction, the enzyme of carbon monoxide production. PMID- 30461237 TI - Pralidoxime. PMID- 30461239 TI - Practical analysis of toxic substances useful for clinical toxicology: From sample preparation to screening Basics of gas chromatography-tandem mass spectrometry (GC/MS/MS) and its applications to toxicological analysis. PMID- 30461240 TI - The progress of Japan Poison Information Center during 30 years. PMID- 30461241 TI - Japan Poison Information Center (JPIC) and Japanese Society for Clinical Toxicology (JSCT). PMID- 30461243 TI - [A report of the 30th anniversary of the Japan Poison Information Center celebration.] PMID- 30461242 TI - [A close relationship between the Japan Poison Infromation Center and the Japanese Journal of Clinical toxicology.] PMID- 30461244 TI - [Accidental ingestion of smokeless tabacco products.] PMID- 30461245 TI - Reward signals downstream of dopamine D1 receptors. AB - It-is well known that dopamine is necessary for motor function, reward-motivated behaviors. The principal target of dopamine is medium spiny neurons (MSNs), which are a special type of GABAergic inhibitory cell that represents,90% of the neurons within the striatum, including the nucleus accumbens (NAc). There is a distinct class of spatially intermixed MSNs that express dopamine type 1 or 2 receptors (DlR-MSNs or D2R-MSNs, respectively). The D1R-MSN and D2R-MSN pathways control the dynamic balance in the basal ganglia circuit. D1R is coupled -to adenylate cyclase through Golf to activate protein kinase A (PKA), whereas D2R inhibits adenylate cyclase through Gi. Although PKA has been implicated in reward signals downstream of D1Rs by pharmacological approaches, there is no direct evidence indicating that PKA in DlR-MSNs regulates neuronal excitability and reward-related behaviors. We have established the system in which enzymatic activity can be manipulated in the NAc under the control of specific promoters for DlR-MSNs using adeno-associated virus (AAV)-mediated conditional'transgenic techniques. We have also found novel PKA substrates in dopamine receptor signaling using phosphoproteomic approach. This review article focuses on the PKA and its substrates to understand dopamine-related signals in the MSNs. We discuss phosphoproteomic approaches for' comprehensively screening of dopamine signaling. Finally, we highlight RapI pathway as a novel reward signal in vivo. PMID- 30461246 TI - The potential of e-Health for treatment and prevention for drug dependence process of development and revision of web-based relapse prevention program "e SMARPP". AB - e-Health is the use of information and communication technologies for health, such as in patient-treatment programs, education for health care professionals, and monitoring public health. Web-/Internet-based programs, mobile applications, and wearable devices have been developed and adapted to various diseases and are now increasingly used to promote individual self-care of health. In the field of addiction, there has been a gap between potential treatment needs and available treatment services, and as such, it is necessary to develop new treatments that- are flexible and accessible. The authors developed a web-based relapse prevention program prototype dalled -"e-SMARPP" for drug users in Japan and assessed usability. Qualitative comments from pilot study participants were assessed in detail.-The authors found areas for improvement based on participant comments and revised e-SMARPP. The main areas identified for improvement included: 1) simplify video content regarding prelease prevention sessions, 2) refine the self monitoring calendar to monitor various health-related conditions, and 3) revise glitches that occurred when used with a smartphone. In developing an e-health program, it is important to consider commeits from targeted users to make the program user-friendly and effective. PMID- 30461247 TI - Dependence/addiction/use disorder from a therapeutic perspective -A preliminary study of preference for terms describing the condition. AB - This study focused on patients receiving specialized outpatient (n=26) care to improve addiction behavior (mainly patients with alcohol dependency) and investigated their preferences for terms that describe the relationship between a patient and the object of his or her addiction and how those preferences correlated with the patient's current stage of recovery. The results showed a correlation between a preference for the term "dependence" and a stagnated recovery and a correlation between a preference for the term "overindulgence" and recovery progress (p<0.05). This was a correlation study, so it did not reveal the existence of a causal relationship. It did, however, suggest that terms implying self-directedness, such as "overindulgence" or "addiction," are preferable to the term "dependence" when providing treatment, because they allow.the patient to have a more autonomous self-image. However, the words "use disorder" and "habit" are safe in the sense that they are neutral, so these words are useful when beginning treatment, etc., in a patient-centered care setting, such as one that utilizes Shared Decision Making (SDM). PMID- 30461248 TI - Alteration of Breath Hydrogen and Methane in Ethanol-Fed Rats. AB - Chronic alcohol consumption can cause dysbiosis, but it is difficult to determine the effect of alcohol on the structure and activity of gastrointestinal tract microbiota. We therefore designed a noninvasive hydrogen breath test (HBT) to investigate the alteration in the chemical profile of gut microbiota in ethanol fed rats. Thirteen F344/DuCri rats were fed on a commercial mash food with 16% ethanol solution drinking fluid from 4 weeks of age. HBTs were carried out on six 8-week-old and seven 24-week-old ethanol-fed rats. As controls, HBTs were carried out on sixteen 8-week-old, six 24-week-old, and five 48-week-old male rats. Six 24-week- old male rats were examined twice at 1-week intervals. HBTs were performed after fasting for 24 hr. Rats were orally administrated 4 mL/kg of 65% lactulose solution and housed in an animal chamber. The expired air was collected in a breath-sampling bag at 10-min intervals for 180 min. The hydrogen (H2) and methane (CH4) levels in the breath sample were measured using a breath analyzer and were expressed.as parts- per million (ppm). Elevated H2 and CH4 levels were more frequent in male rats. Maximal values of H2 and CH4 were highest in 8-week- old rats, followed by 48-week-old and 24-week-old rats. No ethanol-fed rat exhaled more than 2 ppm of H2 or CH4 until 180 min after the oral administration of lactulose, unlike the controls. This alteration was more obvious than that of aging or gender differentiation. We conclude that there is a close association between chronic ethanol consumption and H2 and CH4 production. An asymptomatic heavy drinker might have dysbiosis that involves gut microbiota with lower fermentation performance. PMID- 30461249 TI - Effectiveness evaluation of Serigaya Methamphetamine Relapse Prevention Program in drug addiction rehabilitation center. AB - The Serigaya Methamphetamine Relapse Prevention Program (SMARPP) cognitive behavioral therapy was implemented among 38 substance. abusers in 12-Step Program Treatment Centers operated by:the Drug Addiction Rehabilitation Center (DARC). Tochigi DARC members (20 patients) started SMARPP after attending daily programs in the treatment centers for an extended time (mean period, 17.4 months). Chiba and Tateyama DARC members (18 patients) started SMARPP soon after initiation of treatment (mean period, 1.2 months). We provided SMARPP for approximately 70 days in the treatment centers, in addition to the regular programs, and examined changes in the participants before and after SMARPP. The results showed that the Tochigi DARC members improved significantly after 70 days based on scores from the "taking steps" subscale of the Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES) (Wilcoxon rank sum test, p=0.041) and the "tension anxiety" subscale of the Profile of Mood States (POMS) (Wilcoxon rank sum test, p=0.004). However, the Chiba and Tateyama DARC members did not improve. In the 12 Step Program Treatment Centers, cognitive behavioral therapy-such as SMARPP seems to be more effective if it is implemented later rather immediately after regular programs. PMID- 30461250 TI - Medicare Program: Changes to Hospital Outpatient Prospective Payment and Ambulatory Surgical Center Payment Systems and Quality Reporting Programs. Final rule with comment period. AB - This final rule with comment period revises the Medicare hospital outpatient prospective payment system (OPPS) and the Medicare ambulatory surgical center (ASC) payment system for CY 2019 to implement changes arising from our continuing experience with these systems. In this final rule with comment period, we describe the changes to the amounts and factors used to determine the payment rates for Medicare services paid under the OPPS and those paid under the ASC payment system. In addition, this final rule with comment period updates and refines the requirements for the Hospital Outpatient Quality Reporting (OQR) Program and the ASC Quality Reporting (ASCQR) Program. In addition, we are updating the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) Survey measure under the Hospital Inpatient Quality Reporting (IQR) Program by removing the Communication about Pain questions; and retaining two measures that were proposed for removal, the Catheter-Associated Urinary Tract Infection (CAUTI) Outcome Measure and Central Line-Associated Bloodstream Infection (CLABSI) Outcome Measure, in the PPS-Exempt Cancer Hospital Quality Reporting (PCHQR) Program beginning with the FY 2021 program year. PMID- 30461251 TI - [Morpho-densitometric researches of cell nuclei at atypical hyperplasia and initial breast cancer]. AB - There were performed researches on morphometric (the nuclear area, perimeter, the maximum and minimum diameters) and densitometric (optical density, integrated optical density) parameters of nuclei of cells on the cytologic smears received from 28 patients with atypical hyperplasia and an initial breast cancer. Significant reduction of measured nuclei parameters was noted among: moderately - and high-grade ductal carcinoma in situ, atypical ductal hyperplasia, lobular carcinoma in situ, an invasive papillary cancer, intraductal papilloma. The lowest value of the measured parameters was noted at love-grade ductal carcinoma in situ and intraductal papillary cancer. It was established that morphometric and densitometric indicators at atypical hyperplasia of an epithelium and an initial breast cancer in some cases overlap each other that is at the bottom of difficulties of differential cytomorphological diagnostics and quite often forces to formulate the cytologic conclusion in the presumable form. PMID- 30461252 TI - [Determination of receptor and HER2 status of breast cancer using tissue matrix technology. Validation of the method]. AB - We studied ability of TMA technique as alternative to analysis of whole sections (WS) for breast carcinomas. The study included 229 patients with breast carcinoma T1-2 N0 M0 treated within 2000-2009 years. After whole slide scanning were constructed TMA blocks using 2mm punches and TMA master device (3DHistech, Budapest). TMA results of immunohistochemistry of HER2 were compared retrospectively with the results of WS. General distribution of HER2 status for WS was: negative (0+1) 85,5%, unequal (2+) 6,07%, positive (3+) - 8.41%, for TMA cores negative (0+1) 82,6%, unequal (2+) 7,04%, positive (3+) - 10,33%. When we compared each cases for HER2 there was moderate agreement with negative (score 0) and positive(score 3+) case around 70% and poor agreement in HER2 (1+2+ category) - only 50% 25% including both false negative and false positive estimations. We thought such kind disagreement in individual group was due to using different primary antibodies (all not FDA-approved) in previous years compared with PATHWAY(r) rmAb 4B5 (Ventana) antibody which was used for TMA slides. For breast cancer TMAs could be reasonable alternative to WS. Especially for Her2 testing, should be used only FDA approved systems and this technique allow reduce time, reagent and finally cost of such type of analysis. PMID- 30461253 TI - Evidence for Fast Lithium-Ion Diffusion and Charge-Transfer Reactions in Amorphous TiO x Nanotubes: Insights for High-Rate Electrochemical Energy Storage. AB - The charge-storage kinetics of amorphous TiO x nanotube electrodes formed by anodizing three-dimensional porous Ti scaffolds are reported. The resultant electrodes demonstrated not only superior storage capacities and rate capability to anatase TiO x nanotube electrodes but also improved areal capacities (324 MUAh cm-2 at 50 MUA cm-2 and 182 MUAh cm-2 at 5 mA cm-2) and cycling stability (over 2000 cycles) over previously reported TiO x nanotube electrodes using planar current collectors. Amorphous TiO x exhibits very different electrochemical storage behavior from its anatase counterpart as the majority of its storage capacity can be attributed to capacitive-like processes with more than 74 and 95% relative contributions being attained at 0.05 and 1 mV s-1, respectively. The kinetic analysis revealed that the insertion/extraction process of Li+ in amorphous TiO x is significantly faster than in anatase structure and controlled by both solid-state diffusion and interfacial charge-transfer kinetics. It is concluded that the large capacitive contribution in amorphous TiO x originates from its highly defective and loosely packed structure and lack of long-range ordering, which facilitate not only a significantly faster Li+ diffusion process (diffusion coefficients of 2 * 10-14 to 3 * 10-13 cm2 s-1) but also more facile interfacial charge-transfer kinetics than anatase TiO x. PMID- 30461254 TI - Microscopic Behavior of Active Materials inside a TCNQ-based Lithium Ion Rechargeable Battery by in-situ 2D ESR Measurements. AB - Real-time spectroscopic measurements in rechargeable batteries are important to understand the electrochemistry of the batteries at the molecular level and improve relevant functionalities. We have applied in-situ two-dimensional (2D) ESR spectroscopy to a well-known organic lithium ion battery, which is composed of 7,7,8,8-tetracyanoquinodimethane (TCNQ) as the cathode-active material and a lithium metal anode electrode. The TCNQ rechargeable battery is suitable for investigating electrochemistry in the battery in terms of behavior of electron spin at microscopic levels on both the cathode and anode electrodes. We have discussed two-stage oxidation/reduction reactions of TCNQ, Li deposited/stripped process and their resulting dendritic and/or mossy microstructures, clearly elucidating the cause of the cell capacity degradation upon the charge-discharge cycles. The observed in-situ ESR spectra showed that the degradation of the cell capacity was due to the elution of the active molecules, which caused the increase of ion-conductivity by the substitution of the electrolyte solution for the adsorbed active materials on the conductive carbon surface. In order to discriminate paramagnetic species during the charge-discharge process, the generalized 2D correlation spectroscopy has been applied to characterize time dependent in-situ ESR spectra. The correlation analysis with in-situ ESR helps us identify the paramagnetic species occurring in the battery cell in a straightforward manner. PMID- 30461255 TI - In Situ Atmospheric Deposition of Ultrasmooth Nickel Oxide for Efficient Perovskite Solar Cells. AB - Organic-inorganic perovskite solar cells have attracted significant attention due to their remarkable performance. The use of alternative metal-oxide charge transport layers is a strategy to improving device reliability for large-scale fabrication and long-term applications. Here, we report solution-processed perovskite solar cells employing nickel oxide hole-extraction layers produced in situ using an atmospheric pressure spatial atomic-layer deposition system, which is compatible with high-throughput processing of electronic devices from solution. Our sub-nanometer smooth (average roughness of <=0.6 nm) oxide films enable the efficient collection of holes and the formation of perovskite absorbers with high electronic quality. Initial solar-cell experiments show a power-conversion efficiency of 17.1%, near-unity ideality factors, and a fill factor of >80% with negligible hysteresis. Transient measurements reveal that a key contributor to this performance is the reduced luminescence quenching trap density in the perovskite/nickel oxide structure. PMID- 30461256 TI - One-dimensional Porous Hybrid Structure of Mo2C-CoP Encapsulated in N-doped Carbon Derived from MOF as An Efficient Electrocatalyst for Hydrogen Evolution Reaction over the Entire pH Range. AB - The development of the outstanding noble-metal-free electrocatalysts for the hydrogen evolution reaction (HER) has attracted the broad interest. Herein, a novel one-dimensional (1D) HER hybrid catalyst consisted of cobalt phosphide (CoP) and molybdenum carbide (Mo2C) nanoparticles wrapped by the nitrogen-doped graphitic carbon (called as CoP/Mo2C-NC) was successfully fabricated by a facile continuous flow method and a simple two-step annealing process. During these processes, the successful synthesis of the MoO3 nanorods coated by cobalt zeolitic imidazolate frameworks (Co-ZIF-67) (Co-ZIF-67@MoO3) through the continuous flow method plays a key step. As-synthesized CoP/Mo2C-NC hybrid electrocatalyst exhibits a significantly enhanced HER electrocatalytic activity over the entire pH range relative to the control material CoP, Mo2C-NC, and the physically mixed CoP and Mo2C-NC. The outstanding HER catalytic performance mainly due to the fact that the electron cloud transfers from Co to Mo in CoP/Mo2C-NC through the Co-P-Mo bond, resulting in the formation of high valence state for Co3+ species and the lower valence states for Mo (i.e., Mo2+, Mo3+) species, providing the abundant HER active sites. Moreover, the Gibbs free energy (?GH*) of CoP/Mo2C-NC obtained by the density function theory calculations indicate a good balance between Volmer and Heyrovsky/Tafel steps in HER kinetics. Such as a cobalt zeolitic imidazolate framework mediated strategy depicted in this work offers an interesting perspective for developing highly efficient noble metal-free electrocatalyst for hydrogen production. PMID- 30461257 TI - Honeycomb-like hard carbon derived from pine pollen as high-performance anode material for sodium-ion battery. AB - Sodium ions batteries (SIBs) was regarded as one of the most promising energy storage systems, but the choice of anode material was still facing great challenges. Biomass carbon materials were explored for their low cost and wide range of sources. Here, a hard carbon material with a "honeycomb" structure using pine pollen as a precursor was successfully prepared and applied as an anode. The initial discharge capacity can reach to 370 mA h g-1 at a current density of 0.1 A g-1. After cycling 200 times, the reversible capacity also stabled at 203.3 mA h g-1 with the retention rate of 98%. We further studied the sodium storage mechanism by different methods, especially the Na+ diffusivity coefficient (DNa+) calculated by galvanostatic intermittent titration technique (GITT), it was more accurate. Interestingly, the trend of DNa+ coincides with cyclic voltammetry (CV) curves. Carbonized pine pollen (CPP) exhibited excellent electrochemical properties due to its three-dimensional structure and larger layer spacing (~ 0.41 nm), which reduces the resistance of sodium ions to intercalation and deintercalation. PMID- 30461258 TI - Investigation of Human Neutrophil Elastase Inhibition by Staphylococcus aureus EapH1: The Key Role Played by Arginine 89. AB - Staphylococcus aureus secretes a family of potent, noncovalent inhibitory proteins that selectively target the neutrophil serine proteases neutrophil elastase, cathepsin-G, and proteinase-3. A majority of our understanding of these so-called EAP domain proteins has come from structure/function studies on EapH1 and its effects on human neutrophil elastase (hNE). Inspection of the EapH1/hNE cocrystal structure suggested that EapH1 residues R89, E94, and K95 are positioned near the EapH1/hNE interface and might contribute to the potent inhibition of hNE by EapH1. In this study, we used site directed mutagenesis, kinetic evaluation, and surface plasmon resonance to probe the individual contributions of R89, E94, and K95 to EapH1 function. We found that the wild-type EapH1/hNE complex is characterized by a fast association rate (2.0 * 106 M-1 s-1) and a very slow dissociation rate (4.3 * 10-5 s-1), yielding an apparent inhibition constant of 21 pM. The slow dissociation rate of EapH1 from hNE resulted in a time-dependent inhibition pattern. Although conservative mutants E94Q and K95M, as well as the E94Q/K95M double mutant, had on- and off-rates comparable to wild-type EapH1, mutation of R89 to methionine resulted in a 15,000 fold decrease in inhibition (321 nM) and loss of the time-dependent inhibition characteristic. The double mutants R89M/E94Q and R89M/K95M, as well as the triple mutant R89M/E94Q/K95M were similarly perturbed. Mutation of R89 to lysine restored a portion of the inhibition of hNE (27 nM). Given these observations, we conclude that R89 is a primary contributor to EapH1 function vis-a-vis time dependent inhibition of hNE. PMID- 30461259 TI - Reversible Control of Spacing in Charged Lamellar Membrane Hydrogels by Hydrophobically Mediated Tethering with Symmetric and Asymmetric Double-End Anchored Poly(ethylene glycol)s. AB - Complex materials often achieve their remarkable functional properties by hierarchical assembly of building blocks via competing and/or synergistic interactions. Here, we describe the properties of new double-end-anchored poly (ethylene glycol)s (DEA-PEGs), macromolecules designed to impart hydrophobically mediated tethering attractions between charged lipid membranes. We synthesized DEA-PEGs (MW 2000 (2K) and 4.6K) with two double-tail (symmetric) or a double tail and a single-tail (asymmetric) hydrophobic end anchors and characterized their equilibrium and kinetic properties using small-angle X-ray scattering. Control multilayer membranes without and with PEG-lipid (i.e. single-end-anchored PEG) swelled continuously with the interlayer spacing increasing between 30wt% and 90wt% water content, due to electrostatic as well as, in the case of PEG lipid, steric repulsion. In contrast, interlayer spacings in lamellar membrane hydrogels containing DEA-PEGs expanded over a limited water dilution range and reached a "locked" state, which displayed a near constant membrane wall-to-wall spacing (deltaw) with further increases in water content. Remarkably, the locked state displays a simple relation to the PEG radius of gyration deltaw ~ 1.6 RG for both 2K and 4.6K PEG. Nevertheless, deltaw being considerably less than the physical size of PEG (2(5/3)1/2RG) is highly unexpected and implies that, compared to free PEG, anchoring of the PEG tether at both ends leads to a considerable distortion of the PEG conformation confined between layers. Significantly, the lamellar hydrogel may be designed to reversibly transition from a locked to an unlocked (membrane unbinding) state by variations in the DEA PEG concentration controlling the strength of the interlayer attractions due to bridging conformations. The findings with DEA-PEGs have broad implications for hydrophobic-mediated assembly of lipid- or surfactant- coated building blocks with distinct shape and size, at predictable spacing, in aqueous environments. PMID- 30461260 TI - Leaf Vein-Inspired Hierarchical Wedge-Shaped Tracks on Flexible Substrate for Enhanced Directional Water Collection. AB - Water collection has been extensively researched due to its potential for mitigating the water scarcity in arid and semiarid regions. Numerous structures mimicking the fog-harvesting strategy of organisms have been fabricated for improving water-collecting efficiency. In this contribution, we demonstrate four level wedge-shaped tracks inspired by leaf vein for enhancing directional water collection. Superhydrophilic Cu(OH)2 nanowires are introduced and prepared on flexible hydrophobic polyethylene terephthalate (PET) substrates by alkali assisted surface oxidation at room temperature. They provide abundant capillary paths for promoting droplet absorption and forming water film tracks. Then, the hierarchical wedge-shaped tracks enable the water to be transported to a certain accumulation region spontaneously owing to the continuous Young-Laplace pressure difference. As a result, the four-level wedge-shaped tracks on PET substrate achieve the highest water-collecting efficiency, increasing by nearly 1150 and 510% compared to the bare PET and Cu(OH)2 nanowires on PET, respectively. After being bent for 105 cycles at a radius of 10 mm, the samples can still preserve high efficiency, indicating that the synthetic structures possess outstanding durability. Our approach provides a novel strategy for water collection and paves ways for directional liquid transportation and microfluidic devices. PMID- 30461261 TI - Insight of Enhanced Redox Chemistry for Porous MoO2 Carbon-Derived Framework as Polysulfide Reservoir in Lithium-Sulfur Batteries. AB - As a promising energy-storage system, lithium-sulfur batteries (LSBs) with a high energy density suffer from the polysulfide shuttle effect and sluggish reaction kinetics, which have been studied for a few decades. Incorporation of polar metal oxides is an efficient addition for LSBs to suppress the dissolution of soluble polysulfides, increase the utilization of sulfur, and improve cycling stability. Herein, a model (MoO2/C-NCs) based on a porous octahedral carbon framework decorated with MoO2 nanoparticles (MoO2 NPs) as a sulfur host is proposed. Adsorption experiments of lithium polysulfides (LiPSs) to MoO2/C-NCs and cyclic voltammetry analysis showed that the MoO2 NPs facilitate interfacial charge transfer and provide numerous active sites for the electrochemical redox reactions of LiPSs. Density functional theory calculations further reveal that LiPSs are diffused and strongly adsorbed on the surface of MoO2 NPs because of the powerful van der Waals forces via Mo-S and Li-O bonds, which helps achieve a stable long-term cycling performance. As a result, the fabricated LSBs display a high initial specific capacity of 1317 mA h g-1 at 0.2C and a promising capacity of 602 mA h g-1 and a capacity retention of 65.6% at 1C when proceeding to 500 cycles. PMID- 30461262 TI - A Sample-to-Targeted Gene Analysis Biochip for Nanofluidic Manipulation of Solid Phase Circulating Tumor Nucleic Acid Amplification in Liquid Biopsies. AB - The use of circulating tumor nucleic acids (ctNA) in patient liquid biopsies for targeted genetic analysis is rapidly increasing in clinical oncology. Still, the call for an integrated methodology that is both rapid and sensitive for analyzing trace ctNA amount in liquid biopsies, has unfortunately not been fully realized. Herein, we performed complex liquid biopsy sample-to-targeted genetic analysis on a biochip with 50 copies-detection limit within 30 min. Our biochip uniquely integrated: 1) electrical lysis and release of cellular targets with minimal processing; 2) nanofluidic manipulation to accelerate molecular kinetics of solid phase isothermal amplification; 3) single-step capture and amplification of multiple NA targets prior to nanozyme-mediated electrochemical detection. Using prostate cancer liquid biopsies, we successfully demonstrated multifunctionality for cancer risk prediction; correlation of serum and urine analyses; and cancer relapse monitoring. PMID- 30461263 TI - Previously uncharacterized v-ATPase binding site discovered from structurally similar compounds with distinct mechanisms of action. AB - Using a comprehensive chemical genetics approach, we identified a member of the lignan natural product family, HTP-013, which exhibited significant cytotoxicity across various cancer cell lines. Correlation of compound activity across a panel of reporter gene assays suggested the vacuolar-type ATPase (v-ATPase) as a potential target for this compound. Additional cellular studies and a yeast haploinsufficiency screen strongly supported this finding. Competitive photoaffinity labeling experiments demonstrated that the ATP6V0A2 subunit of the v-ATPase complex binds directly to HTP-013, and further mutagenesis library screening identified resistance-conferring mutations in ATP6V0A2. The positions of these mutations suggest the molecule binds a novel pocket within the domain of the v-ATPase complex responsible for proton translocation. While other mechanisms of v-ATPase regulation have been described, such as dissociation of the complex, or inhibition by natural products including Bafilomycin A1 and Concanamycin, this work provides detailed insight into a distinct binding pocket within the v-ATPase complex. PMID- 30461264 TI - Rotation-Assisted Hydrothermal Synthesis of Thermally Stable Multiwalled Titanate Nanotubes and Their Application to Selective Catalytic Reduction of NO with NH3. AB - Titanate nanotubes are widely applied in various fields, including photocatalysts and electronic devices, but their weak thermal stability limits their application for catalyst support. Here, we found that titanate nanotubes with a thick multiwalled structure of 15 layers or more can be prepared by using rotation assisted hydrothermal synthesis. The porous structure of conventional nanotubes synthesized without rotation collapsed easily after thermal treatment, whereas the nanotubes having a thick multiwalled structure retained their pore structure and the specific surface area (~300 m2/g) even after calcination at 400 degrees C in air. Systematic variation of rotation speed suggested that rotation in the synthesis process accelerated the stacking of layered titanate nanosheets, which are known to be intermediates of nanotubes. Thus, the rapid assembly of titanate nanosheets facilitated by rotation led to the formation of nanotubes with a multiwalled structure. Overly fast rotation, however, caused excessive stacking and created a thicker structure that cannot be easily wrapped into nanotubes. Therefore, it is essential to maintain the optimum rotation speed to obtain both the nanotube morphology and the thick multiwalled structure. Vanadium-tungsten oxide catalyst supported on the multiwalled titanate nanotubes was used in NH3 selective catalytic reduction, which showed stable NO x reduction performance with high selectivity to N2, which may originate from the suppressed sintering of VO x on multiwalled nanotubes. This study demonstrates that the morphology of nanotubes can be tuned by controlling the degree of interaction supplied by external forces. PMID- 30461265 TI - Lithium and silver co-doped nickel oxide hole-transporting layer boosting the efficiency and stability of inverted planar perovskite solar cells. AB - In this work, a lithium and silver co-doping strategy has been successfully implied to prepare NiOx films for high performance inverted planar PSCs. Compared to the pristine and single-doped NiOx, the Li and Ag co-doping approach exhibits the synergistic effect and can endow NiOx films with higher electrical conductivity, higher hole mobility and better interface energy band alignment with perovskite active layers. Moreover, the perovskite film with enhanced crystallinity can be obtained induced by the Li,Ag:NiOx film. The PSC with Li,Ag:NiOx HTL shows a high power conversion efficiency (PCE) up to 19.24% and less hysteresis effect, which outperforms the devices with the pristine NiOx or single-doped NiOx HTLs. Meanwhile, the Li,Ag:NiOx device can retain 95% of its initial PCE after storage at the relative humidity of 30 +/- 2% in 30 days without encapsulation. Our work demonstrates that lithium and silver co-doping is a promising route for realizing efficient p-type NiOx HTL, which provides a simple way to boost the efficient and stable of inverted planar PSCs. PMID- 30461266 TI - Discovery and Characterization of a Naturally Occurring, Turn-On Yellow Fluorescent Protein Sensor for Chloride. AB - Fluorescent proteins have been extensively engineered and applied as optical indicators for chloride in a variety of biological contexts. Surprisingly, given the biodiversity of fluorescent proteins, a naturally occurring chloride sensor has not been reported to date. Here, we present the identification and spectroscopic characterization of the yellow fluorescent protein from the jellyfish Phialidium sp . (phiYFP), a rare example of a naturally occurring, excitation ratiometric, and turn-on fluorescent protein sensor for chloride. Our results show that chloride binding tunes the p Ka of the chromophore Y66 and shifts the equilibrium from the fluorescent phenolate form to the weakly fluorescent phenol form. The latter likely undergoes excited-state proton transfer to generate a turn-on fluorescence response that is pH-dependent. Moreover, anion selectivity and mutagenesis in the chloride binding pocket provide additional evidence for the proposed chloride sensing mechanism. Given these properties, we anticipate that phiYFP, with further engineering, could be a new tool for imaging cellular chloride dynamics. PMID- 30461267 TI - A High-Performance P2-Na0.70Mn0.80Co0.15Zr0.05O2 Cathode for Sodium-Ion Batteries. AB - Room-temperature sodium-ion batteries (NIBs) using manganese-based layered cathode has been considered promising candidates for grid-scale energy storage applications. However, manganese-based materials suffer from seriously Jahn Teller distortion, phase transition and unstable interface, resulting in severe structure degradation, sluggish sodium diffusion kinetics, and poor cycle, respectively. Herein, we demonstrate a Zr-doped Na0.70Mn0.80Co0.15Zr0.05O2 material with much improved specific capacity and rate capability compared with Zr-free Na0.70Mn0.85Co0.15O2 when used as cathode materials for NIBs. The material delivers a reversible capacity of 173 mA h g-1 at 0.1 C rate, corresponding to approximately 72% of the theoretical capacity (239 mA h g-1) based on a single-electron redox process, and a capacity retention of 88% after 50 cycles was obtained. Additionally, a homogenous solid-state interphase film revealed directly by high-resolution transmission electron microscopy in Zr-doped material after battery cycling. Electrochemical impedance spectroscopy prove that the formation of SEI film provides the Zr-doped material with special chemical/electrochemical stability. These results here give clear evidence of the utility of Zr-doping to improve the surface and environmental stability, the sodium diffusion kinetics, and electrochemical performance of P2-type layered structure, promising advanced sodium ion batteries with higher energy density, higher surface stability, and longer cycle life compared with the commonly used magnesium-doping method in electrode materials. PMID- 30461269 TI - Semisynthesis of Platensimycin Derivatives with Antibiotic Activities in Mice via Suzuki-Miyaura Cross-Coupling Reactions. AB - Platensimycin (PTM), originally isolated from soil bacteria Streptomyces platensis, is a potent FabF inhibitor against many gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. However, the further clinical development of PTM is hampered by its poor pharmacokinetic properties. In this study, twenty PTM derivatives were prepared by Suzuki-Miyaura cross-coupling reactions catalyzed by Pd (0)/C. Compared to PTM, 6-pyrenyl PTM (6t) showed improved antibacterial activity against MRSA in a mouse peritonitis model. Our results support the strategy to target the essential fatty acid synthases in major pathogens, in order to discover and develop new generations of antibiotics. PMID- 30461268 TI - Magnetic Bistability in Crystalline Organic Radicals: The Interplay of H-bonding, Pancake Bonding, and Electrostatics in 4-(2'-Benzimidazolyl)-1,2,3,5 dithiadiazolyl. AB - The neutral radical 4-(2'-benzimidazolyl)-1,2,3,5-dithiadiazolyl (HbimDTDA) exhibits a first order phase transition around 270 K without symmetry breaking, preserving its orthorhombic Pbca space group between 340 and 100 K. Associated with this reversible single-crystal-to-single-crystal phase transition, thermal hysteresis of the magnetic susceptibility is observed. The low temperature (LT) phase is diamagnetic owing to pancake bonding between the pi-radicals. In the paramagnetic high temperature (HT) phase, the pancake bonds are broken, and new electrostatic contacts are apparent. As a result of the dense 3D network of supramolecular contacts, which includes H-bonds, the HbimDTDA system provides the first example of magnetic bistability for a DTDA radical. PMID- 30461270 TI - Regio- and Diastereo-selective Synthesis of Dihydropyrans and Pyrano-Pyrans via Oxonium-ene Reaction of beta-allenols and Aldehydes. AB - Bismuth trifluoromethanesulfonate (Bi(OTf)3) can be efficiently used for the preparation of dihydropyrans from beta-allenols and aldehydes by oxonium-ene reaction in good yields. The reaction is highly regioselective. On the other hand, the same reaction with trimethylsilyl trifluoromethanesulfonate (TMSOTf) at -45 oC affords hexahydropyrano[4,3-b]pyran skeleton in moderate yields. PMID- 30461271 TI - Subtle Changes in Lipid Environment Have Profound Effects on Membrane Oxidation Chemistry. AB - Nature carefully designs the components of amphiphile-composed monolayer and bilayer membranes to deliver specific functions. The compositions of these interfacial layered structures are so delicate that minute modifications can result in huge changes in function. Great efforts have been expended to understand membrane physical properties, with only minimum attention given to associated chemical properties. Here we report the first examples of the delicate chemistry associated with membrane amphiphilic components by studying OH mediated oxidation of six different unsaturated li-pids/surfactants and their mixtures at the air-water interface using field-induced droplet ionization mass spectrometry (FIDI-MS). When the packing is loose or perturbed to be loose by other components or prior chemical modification, the double bond is oxidized without cleavage by adding oxygen functionality. In contrast, compact packing results in double bond cleavage through a Criegee intermediate mechanism. We postulate that constrained environments imposed by lipid packing limit the conformations of the reaction intermediates, controlling reaction pathways. PMID- 30461272 TI - Total Synthesis, Biological Evaluation, and Target Identification of Rare Abies Sesquiterpenoids. AB - Abiespiroside A (1), beshanzuenone C (2), and beshanzuenone D (3) belong to the Abies sesquiterpenoid family. Beshanzue-nones C (2) and D (3) are isolated from the critically endangered Chinese fir tree species Abies beshanzuensis and demon strated weak inhibiting activity against protein tyrosine phosphatase 1B (PTP1B). We describe herein the first total synthe-ses of these Abies sesquiterpenoids relying on the sustainable and inexpensive chiral pool molecule (+)-carvone. The synthe-ses feature a palladium-catalyzed hydrocarbonylative lactonization to install the 6,6-fused bicyclic ring system and a Dreiding-Schmidt reaction to build the oxaspirolactone moiety of these target molecules. Our chemical total syntheses of these Abies sesquiterpenoids have enabled (i) the validation of beshanzuenone C's weak PTP1B inhibiting potency, (ii) iden-tification of new synthetic analogs with promising and selective protein tyrosine phosphatase SHP2 inhibiting potency, and (iii) preparation of azide-tagged probe molecules for target identification via a chemoproteomic approach. The latter has re-sulted in the identification and evaluation of DNA polymerase epsilon subunit 3 (POLE3) as one of the novel cellular targets of these Abies sesquiterpenoids and their analogs. More importantly, via POLE3 inactivation by probe molecule 29 and knockdown experiment, we further demonstrated that targeting POLE3 with small molecules may be a novel strategy for chemosensitization to DNA damaging drugs such as etoposide in cancer. PMID- 30461273 TI - Restoration of Myoglobin Native Fold from Its Initial State of Amyloid Formation by Trehalose. AB - Organisms having tolerances against extreme environments produce and accumulate stress proteins and/or sugars in cells against the extreme environment such as high or low temperature, drying, and so forth. Sugars and/or polyols are known to prevent protein denaturation and enzyme deactivation. In particular, trehalose has received considerable attention because of its association with cryptobiosis and anhydrobiosis. This study focuses on the restoration of acid-denatured amyloid transition of myoglobin by trehalose. Myoglobin is known to proceed amyloidogenic reaction under denaturation conditions. We found that acid denatured myoglobin at an initial process of amyloidogenic reaction (helix-to sheet transition followed by oligomerization) at 25 degrees C was substantially restored to its native structure by trehalose. This action was prominent during the early stage of amyloid formation. Recent results showed that sugars are preferentially excluded from the protein surface to preserve its hydration shell and stabilize the protein structure against chemical and thermal denaturation. Therefore, the present results suggest that trehalose will restore the tightly bound water molecules around the hotspot (G-helix) of myoglobin on the amyloid transition by its intrinsic preservative action of the native hydration shell against denaturation. The present finding on the restorative action by trehalose could provide new insights into protein folding and amyloidosis. PMID- 30461274 TI - Catalytic asymmetric cycloadditions between aldehydes and enolizable anhydrides: cis-selective dihydroisocoumarin formation. AB - In the presence of a trityl-substituted cinchona alkaloid-based catalyst, homophthalic-, aryl succinic- and glutaconic anhydride derivatives reacted with aromatic and aliphatic aldehydes to produce cis-lactones in up to 90:10 dr and 99% ee. A DFT study has shown how the catalyst is uniquely able to bring about the opposite sense of diastereocontrol to that usually observed. PMID- 30461275 TI - Chemical Insights into PbSe-x%HgSe: High Power Factor and Improved Thermoelectric Performance by Alloying with Discordant Atoms. AB - Thermoelectric generators can convert heat directly into usable electric power but suffer from low efficiencies and high costs, which has hindered wide-scale applications. Accordingly, an important goal in the field of thermoelectricity is to develop new high performance materials that are composed of more earth abundant elements. The best systems for mid-temperature power generation rely on heavily doped PbTe, but the Te in these materials is scarce in the Earth's crust. PbSe is emerging as a less expensive alternative to PbTe, although it displays inferior performance due to a considerably smaller power factor S2sigma, where S is the Seebeck coefficient and sigma is electrical conductivity. Here, we present a new p-type PbSe system, Pb0.98Na0.02Se-x%HgSe, which yields a very high power factor of ~ 20 uW?cm-1?K-2 at 963 K when x = 2, a 15 % improvement over the best performing PbSe-x%MSe materials. The enhancement is attributed to a combination of high carrier mobility and the early onset of band convergence in the Hg alloyed samples (~ 550 K), which results in a significant increase in the Seebeck coefficient. Interestingly, we find that the Hg2+ cations sit at an off-centered position within the PbSe lattice, and we dub the displaced Hg atoms 'discordant'. DFT calculations indicate that this feature plays a role in lowering thermal conductivity, and we believe that this insight may inspire new design criteria for engineering high performance thermoelectric materials. The high power factor combined with a decrease in thermal conductivity gives a high figure of merit ZT of 1.7 at 970 K, the highest value reported for PbSe to date. PMID- 30461276 TI - Molecular Simulation and Analysis of Sorption Process Toward Theoretical Prediction for Liquid Permeation Through Membranes. AB - The need to understand and describe permeation through membranes has driven the development of many well-established transport models. The modelling parameters such as solubility, diffusivity and permeability represent the intrinsic nature of molecular interactions between membrane and permeants. In this study, we report a simulation and analysis methodology for liquid permeation. Based on a single simulation of liquid sorption process into a membrane, the solubility and diffusivity are estimated simultaneously, then the permeability is predicted by the solution-diffusion model. The methodology is applied to water permeation through two representative membranes: a polymer of intrinsic microporosity (PIM 1) and a zeolitic imidazolate framework (ZIF-96). For amorphous PIM-1 membrane, the predicted water permeability agrees perfectly with simulation. For crystalline ZIF-96 membrane, water permeability is fairly well predicted. Furthermore, water dynamics in the membranes is analysed by simulation trajectories and water structure is characterized by hydrogen-bonds. Together with these microscopic insights, this study provides a simple theoretical approach to quantitatively describe water sorption, diffusion and permeation, and it can be further applied to other liquid permeation (e.g., organic solvent nanofiltration). PMID- 30461277 TI - N-O Bond Activation and Cleavage Reactions of the Nitrosyl-Bridged Complexes [M2Cp2(MU-PCy2)(MU-NO)(NO)2] (M = Mo, W). AB - The title complexes (1a,b) were prepared in two steps by first reacting the hydrides [M2Cp2(MU-H)(MU-PCy2)(CO)4] with [NO](BF4) in the presence of Na2CO3 to give dinitrosyls [M2Cp2(MU-PCy2)(CO)2(NO)2](BF4), which were then fully decarbonylated upon reaction with NaNO2 at 323 K. An isomer of the Mo2 complex having a cisoid arrangement of the terminal ligands ( cis-1a) was prepared upon irradiation of toluene solutions of 1a with visible-UV light at 288 K. The structure of these trinitrosyl complexes was investigated using X-ray diffraction and density functional theory (DFT) calculations, these revealing a genuine pyramidalization of the bridging NO that might be associated in part to an increase of charge at the N atom and anticipated a weakening of the N-O bond upon reaction with bases or reducing reagents. Complexes 1a,b reacted with [FeCp2](BF4) to give first the radicals [M2Cp2(MU-PCy2)(MU-NO)(NO)2](BF4) according to CV experiments, which then underwent H-abstraction to yield the nitroxyl-bridged complexes [M2Cp2(MU-PCy2)(MU-kappa1:eta2-HNO)(NO)2](BF4), alternatively prepared upon protonation with HBF4.OEt2. The novel coordination mode of the nitroxyl ligand in these products was thermodynamically favored over its tautomeric hydroximido form, according to DFT calculations, and similar nitrosomethane-bridged cations [M2Cp2(MU-PCy2)( MU-kappa1:eta2-MeNO)(NO)2]+ were prepared by reacting 1a,b with CF3SO3Me or [Me3O]BF4. Complexes 1 reacted with M(Hg) (M = Zn, Na) in tetrahydrofuran to give the amido-bridged derivatives [M2Cp2(MU-PCy2)(MU-NH2)(NO)2] with retention of stereochemistry, a transformation also induced by using mild O atom scavengers such as CO and phosphites in the presence of water. In the absence of water, phosphites accomplished a deoxygenation of the bridging NO of the Mo2 complexes to yield the phosphoraniminato-bridged derivatives [Mo2Cp2(MU-PCy2){MU-NP(OR)3}(NO)2] (R = Et, Ph), also with retention of stereochemistry. PMID- 30461278 TI - Free Energy of Classical Molecular Crystals by Thermodynamic Integration from a Harmonic Reference. AB - We develop an algorithm for calculating the normal modes of vibration of mechanical systems with constraints, particularly of molecules with rigid bonds and models of rigid molecules, and use it to obtain the harmonic free energy of a crystal. The anharmonic correction is then calculated by the conventional thermodynamic integration over temperature in the NVT ensemble. Attention is paid to finite-size errors, tail corrections, thermostat choice, ergodicity, and other sources of inaccuracies. The calculated free energy of ice XIV modeled by the TIP4P/2005 potential agrees with the previously reported value and is by one order more accurate. PMID- 30461279 TI - Water is a cagey liquid. AB - Liquid water is considered poorly understood. How are water's physical properties encoded in its molecular structure? We introduce a statistical mechanical model (CageWater) of water's hydrogen bonding (HB) and Lennard-Jones (LJ) interactions. It predicts the energetic and volumetric and anomalous properties accurately. Yet, because the model is analytical, it is essentially instantaneous to compute. This model advances our understanding beyond current molecular simulations and experiments. Water has long been regarded as a ?2-density liquid"; a dense LJ liquid and a looser HB one. Instead, we fnd here a different antagonism underlying water structure-property relations: HBs in water-water pairs drive density while HBs in cooperative cages drive openness. The balance shifts strongly with temperature and pressure. This model interprets the molecular structures underlying the liquid-liquid phase transition in supercooled water. It may have value in geophysics, biomolecular modeling, and the engineering of materials for water purification and green chemistry. PMID- 30461280 TI - Interrogation of Antigen Display on Individual Vaccine Nanoparticles for Achieving Neutralizing Antibody Responses against Hepatitis C Virus. AB - Elicitation of neutralizing antibody responses against hepatitis C virus (HCV) has been a challenging goal. While the E2 subunit of the HCV envelope glycoprotein complex is a promising target for generating cross-genotype neutralizing antibodies, vaccinations with soluble E2 immunogens generally induce weak neutralizing antibody responses. Here, E2 immunogens (i.e., E2.661 and E2c.661) were loaded into lipid-based nanovaccines and examined for induction of neutralizing antibody responses. Compared with soluble E2 immunogens, E2 nanoparticles elicited 6- to 20-fold higher E2-specific serum IgG titers in mice. Importantly, E2 vaccine nanoparticles analyzed at a single particle level with a flow cytometry-based method revealed interesting dynamics between epitope display on the surfaces of nanoparticles in vitro and induction of neutralizing antibody responses in vivo. E2c.661 nanoparticles that are preferentially bound by a broadly neutralizing antibody, HCV1, in vitro elicit neutralizing antibody responses against both autologous and heterologous HCV virions in vivo. In stark contrast, E2.661 nanoparticles with reduced HCV1-antibody binding in vitro mainly induce autologous neutralizing antibody responses in vivo. These results show that rationale antigen design coupled with interrogation of epitope display on vaccine nanoparticles at a single particle level may aid in vaccine development toward achieving neutralizing antibody responses in vivo. PMID- 30461281 TI - Cultivar-dependent accumulation and translocation of perfluorooctane sulfonate (PFOS) among lettuce (Lactuca sativa L.) cultivars grown on PFOS-contaminated soil. AB - Perfluorooctane sulfonate (PFOS) is a toxic and persistent organic pollutant that can be widely detected in agricultural soils. In this study, two lettuce cultivars with low PFOS accumulation were screened out to reduce the exposure of PFOS to the human body via vegetable consumption. The screened low-PFOS cultivars may help to ensure food safety, despite plantation in highly PFOS-polluted soils (1.0 mg/kg), due to their high tolerance to PFOS and 4.4-5.7 times lower shoot PFOS concentration than the high-PFOS cultivars. Protein content and protein mediated transpiration played key roles in regulating PFOS accumulation in the lettuce cultivars tested. Lower protein content, lower stomatal conductance, and lower transpiration rate resulted in low PFOS accumulation. This study reveals the mechanism of forming low-PFOS accumulation of lettuce cultivars at physiological and biochemical levels and lays a foundation for developing a cost effective and safe approach to grow vegetables in PFOS-polluted soils. PMID- 30461283 TI - Iron-Catalyzed Three-Component Reaction: Synthesis of Fluoroalkylated 2 H Azirines. AB - A convenient route for the synthesis of fluoroalkylated 2 H-azirines has been developed, involving an iron-catalyzed azidoperfluoroalkylation of alkynes with perfluoroalkyl iodides and trimethylsilyl azide. This novel alkyne difunctionalization reaction produces versatile fluoroalkylated 2 H-azirines, paving the way for further modifications into various heterocycles. PMID- 30461282 TI - Reentrant Phase Behavior in Protein Solutions Induced by Multivalent Salts: Strong Effect of Anions Cl- Versus NO3. AB - In this work, the effects of the two anions Cl- and NO3- on the phase behavior of bovine serum albumin (BSA) in solution with trivalent salts are compared systematically. In the presence of trivalent metal salts, negatively charged proteins such as BSA in solution undergo a reentrant condensation (RC) phase behavior, which has been established for several proteins with chlorides of trivalent salts. Here, we show that replacing Cl- by NO3- leads to a marked change in the phase behavior. The effect is investigated for the two different cations Y3+ and La3+. The salts are thus YCl3, Y(NO3)3, LaCl3, and La(NO3)3. The experimental phase behavior shows that while the chloride salts induce both liquid-liquid phase separation (LLPS) and RC, the nitrate salts also induce LLPS, but RC becomes partial with La(NO3)3 and disappears with Y(NO3)3. The observed phase behavior is rationalized by effective protein-protein interactions which are characterized using small-angle X-ray scattering. The results based on the reduced second virial coefficients B2/ B2HS and 1/ I( q -> 0) demonstrate that the NO3- salts induce a stronger attraction than the Cl- salts. Overall, the effective attraction, the width of the condensed regime in the RC phase diagram, and the nature of LLPS follow the order LaCl3 < YCl3 < La(NO3)3 < Y(NO3)3. Despite the decisive role of cations in RC phase behavior, isothermal titration calorimetry measurements indicate that replacing anions does not significantly influence the cation binding to proteins. The experimental results observed are discussed based on an "enhanced Hofmeister effect" including electrostatic and hydrophobic interactions between protein-cation complexes. PMID- 30461284 TI - Effect of Moving Contact Line's Curvature on Dynamic Wetting of non-Newtonian Fluids. AB - The curvature of the contact line is always changing with the dynamic wetting condition. Using a modified Wilhelmy plate method and the sessile drop method, this study experimentally investigated the dynamic wetting process of several kinds of Newtonian and non-Newtonian fluids. The results show that the curvature of the moving contact line strongly affects the relationship thetaD = f( U) for non-Newtonian fluids but has no effect on Newtonian fluids. The effect is more obvious with the stronger non-Newtonian fluids. The theoretical relationship derived from the Navier-Stokes equations established for spontaneous spreading indicates that the moving contact line curvature affects the relationship thetaD = f( U) for shear-thinning fluids and shear-thickening fluids in a different way, which agrees with the forced wetting experimental results for shear-thinning fluids in both this work and the previous one on the fluid showing shear thickening rheology. A force balance relation of the braking force and driving force for the moving contact line is used to explain the internal mechanism about how the curvature of the contact line affects thetaD during wetting process. PMID- 30461285 TI - Self-retraction of Surfactant Droplets on a Superhydrophilic Surface. AB - In the present work, an interesting droplet self-retraction phenomenon of C14TAB solution on the superhydrophilic mica surface was observed. The self-retraction could only occur within a concentration range from 0.01 to 16 cmc. The maximum variation of contact angle (from 24.99 degrees to 76.85 degrees ) was observed in droplets with a concentration of 0.1 cmc. The self-retraction mechanism was studied based on high-speed photography, surface analyses, surface energy calculation, and model fitting. It was proved that there was a monolayer of C14TAB molecules adsorbed on the mica surface, which formed through the electrostatic interaction between the negative mica and positive charged headgroups. The formation of this monolayer took only a short time of <67 ms since the droplet touched the surface, and the monolayer was well distributed and hydrophobic with a surface free energy of 76.041 mJ/m2 (20% of mica's surface free energy). The reduction of surface tension led to an imbalance at the borderline of the droplet, causing self-retraction. A dynamic model was established to simulate the self-retraction process and it agreed with the experimental data well. This study has significant implication in understanding the surface modification caused by surfactant molecules. PMID- 30461286 TI - Electrochemical Oxidation with Lewis-Acid Catalysis Leads to Trifluoromethylative Difunctionalization of Alkenes Using CF3SO2Na. AB - The directly external oxidant-free oxytrifluoromethylation and aminotrifluoromethylation of alkenes have been developed through the constant current electrolysis synergizing with a Lewis-acid catalysis protocol. By using sodium trifluoromethanesulfinate as the trifluoromethyl source, the method enabled difunctionalization of C-C double bonds of a wide range of styrene derivatives. PMID- 30461287 TI - Genetically Encoding Albumin Binding into Chemotherapeutic-loaded Polypeptide Nanoparticles Enhances Their Antitumor Efficacy. AB - We report the development of drug-encapsulating nanoparticles that bind endogenous albumin upon intravenous injection and evaluate their in vivo performance in a murine as well as canine animal model. The gene encoding a protein-G derived albumin binding domain (ABD) was fused to that of a chimeric polypeptide (CP), and the ABD-CP fusion was recombinantly synthesized by bacterial expression of the gene. Doxorubicin (DOX) was conjugated to the C terminus of the ABD-CP fusion, and conjugation of multiple copies of the drug to one end of the ABD-CP triggered its self-assembly into ~100 nm diameter spherical micelles. ABD-decorated micelles exhibited submicromolar binding affinity for albumin and also preserved their spherical morphology in the presence of albumin. In a murine model, albumin-binding micelles exhibited dose-independent pharmacokinetics, whereas naked micelles exhibited dose-dependent pharmacokinetics. In addition, in a canine model, albumin binding micelles resulted in a 3-fold increase in plasma half-life and 6-fold increase in plasma exposure as defined by the area under the curve (AUC) of the drug, compared with naked micelles. Furthermore, in a murine colon carcinoma model, albumin-binding nanoparticles demonstrated lower uptake by the reticuloendothelial system (RES) system organs, the liver and spleen, that are the main target organs of toxicity for nanoparticulate delivery systems and higher uptake by the tumor than naked micelles. The increased uptake by s.c. C26 colon carcinoma tumors in mice translated to a wider therapeutic window of doses ranging from 20 to 60 mg equivalent of DOX per kg body weight (mg DOX equiv.kg-1 BW) for albumin-binding ABD-CP-DOX micelles, as compared to naked micelles that were only effective at their maximum tolerated dose of 40 mg DOX equiv.kg-1 BW. PMID- 30461288 TI - BPIFA1 Regulates Lung Neutrophil Recruitment and Interferon Signaling During Acute Inflammation. AB - Bpifa1 (BPI-fold containing group A member 1) is an airway host-protective protein with immunomodulatory properties that binds to LPS and is regulated by infectious and inflammatory signals. Differential expression of Bpifa1 has been widely reported in lung disease, yet the biological significance of this observation is unclear. We sought to understand the role of Bpifa1 fluctuations in modulating lung inflammation. We treated WT and Bpifa1-/- mice with intranasal LPS and performed immunological and transcriptomic analyses of lung tissue to determine the immune effects of Bpifa1 deficiency. We show that neutrophil (PMN) lung recruitment and transmigration to the airways in response to LPS is impaired in Bpifa1-/- mice. Transcriptomic analysis revealed a signature of 379 genes that differentiated Bpifa1-/- mice from WT. During acute lung inflammation, the most downregulated genes in Bpifa1-/- mice were Cxcl9 and Cxcl10. Bpifa1-/- mice had lower BAL concentrations of Cxcl10 and Cxcl9, Interferon-inducible PMN chemokines. This was consistent with lower expression of IFN-gamma, IFN-lambda, downstream IFN-stimulated genes (ISG) and IFN-regulatory factors (IRF) which are important for the innate immune response. Administration of Cxcl10 before LPS treatment restored the inflammatory response in Bpifa1-/- mice. Our results identify a novel role for Bpifa1 in the regulation of Cxcl10-mediated PMN recruitment to the lungs via IFN-gamma and -lambda signaling during acute inflammation. PMID- 30461289 TI - Tissue-Informed Engineering Strategies for Modeling Human Pulmonary Diseases. AB - Chronic pulmonary diseases, including idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD), account for staggering morbidity and mortality worldwide but have limited clinical management options available. While great progress has been made to elucidate the cellular and molecular pathways underlying these diseases, there remains a significant disparity between basic research endeavors and clinical outcomes. This discrepancy is due in part to the failure of many current disease models to recapitulate the dynamic changes that occur during pathogenesis in vivo. As a result, pulmonary medicine has recently experienced a rapid expansion in the application of engineering principles to characterize changes in human tissues in vivo and model the resulting pathogenic alterations in vitro. We envision that engineering strategies using precision biomaterials and advanced biomanufacturing will revolutionize current approaches to disease modeling and accelerate the development and validation of personalized therapies . This review highlights how advances in lung tissue characterization reveal dynamic changes in the structure, mechanics and composition of the extracellular matrix in chronic pulmonary diseases, and how this information paves the way for tissue-informed engineering of more organotypic models of human pathology. Current translational challenges are discussed as well as opportunities to overcome these barriers with precision biomaterial design and advanced biomanufacturing techniques that embody the principles of personalized medicine to facilitate the rapid development of novel therapeutics for this devastating group of chronic diseases. PMID- 30461290 TI - Prevalence of Diabetic Neuropathy in Young Adults with Type 1 Diabetes and the Association with Insulin Pump Therapy. AB - AIMS: The aim was to investigate the prevalence of diabetic sensorimotor polyneuropathy (DSPN) and cardiovascular autonomic neuropathy (CAN) in a Danish population of young adults with type 1 diabetes (T1D) using both established and novel measuring modalities. Furthermore, to investigate the association between continuous subcutaneous insulin infusion (CSII) treatment and these complications. MATERIALS AND METHODS: CAN was assessed by cardiovascular autonomic reflex tests. DSPN was assessed not only by perception of light touch and pain, vibration perception threshold (VPT), Brief Pain Inventory (BPI), and Michigan Neuropathy Screening Instrument questionnaires but also by novel modalities: electrochemical skin conductance (ESC), sural nerve conduction velocity (SNCV), and sural nerve amplitude potential (SNAP). RESULTS: The study comprised 156 young adults with a mean age of 22 years (standard deviation 1.6). The prevalence of CAN and early CAN was 9% and 28.1%, respectively. Subclinical DSPN was 55.1% and confirmed DSPN was 2.6%. Prevalence of abnormal SNAP was 23.8%, SNCV was 37.1%, ESC on the hands and feet was 4% and 8%, respectively, VPT was 1.3%, and BPI questionnaire was 1.9%. No association was found between CSII treatment and the measures of DSPN and CAN. CONCLUSION: DSPN and CAN are prevalent in young adults with T1D with no association found with CSII treatment. The use of novel measuring modalities identified a higher number of subjects with DSPN compared with established measures. Screening for diabetic neuropathy in young adults may be beneficial to detect and prevent nerve damages at early stages. PMID- 30461291 TI - Displaced Dental Materials in the Maxillary Sinus: An Original Series. Analysis and Definition of a Surgical Decision-Making Process. AB - OBJECTIVES:: Displacement of dental materials into the maxillary sinus occurs in daily dental practice; dental implants have become a new common foreign body (FB), as implantation has become routine. The main goal of the present study was to analyze an original series of patients consecutively treated for maxillary sinus FBs. A secondary goal was to propose a decision-making flowchart on the basis of the authors' experience and a critical analysis of literature to select the most appropriate surgical approach. METHODS:: Eleven consecutive patients evaluated for maxillary sinus FBs consisting of dental material were considered. RESULTS:: For removal of the FBs, a nasal endoscopic approach was preferred in 5 cases, a nasal combined approach in 2 cases, an oronasal combined approach in 2 cases, and a lateral window approach in 2 cases. In 2 of 11 cases, complications were reported. A decision-making flowchart to select the best surgical approach is reported. CONCLUSIONS:: The correct choice and application of FB removal techniques allow minimization of unfavorable outcomes and creation of an appropriate environment for new dental treatment. Prospective, large series-based studies will be necessary to confirm the safety and clinical efficacy of the proposed decision-making flowchart. PMID- 30461292 TI - ADAMTS13 protects mice against renal ischemia/reperfusion injury by reducing inflammation and improving endothelial function. AB - Acute kidney injury (AKI) is a serious condition without efficient therapeutic options. Recent studies have indicated that recombinant human a disintegrin and metalloprotease with thrombospondin motifs 13 (rhADAMTS13) provides protection against inflammation. Therefore, we hypothesized that ADAMTS13 might protect against AKI by reducing inflammation. Bilateral renal ischemia/reperfusion injury (IR) was used as AKI models in this study. Prophylactic infusion of rhADAMTS13 was employed to investigate potential mechanisms of renal protection. Renal function, inflammation and microvascular endothelial function were assessed after 24 hours of reperfusion. Our results showed that IR mice increased plasma von Willebrand factor (VWF) levels but decreased ADAMTS13 expression. Administration of rhADAMTS13 to IR mice recovered renal function, histological injury, and apoptosis. Renal inflammation was reduced by rhADAMTS13, accompanied with the down-regulation of p38/ERK phosphorylation and COX-2 expression. rhADAMTS13 restored vasodilation in afferent arterioles in IR mice. Furthermore, rhADAMTS13 treatment enhanced phosphorylation of Akt at Ser473 and eNOS at Ser1177. Administration of the Akt pathway inhibitor wortmannin reduced the protective effect of rhADAMTS13. Our conclusions are that treatment with rhADAMTS13 ameliorates renal ischemia/reperfusion injury by reducing inflammation, tubular cell apoptosis and improving microvascular endothelial dysfunction. rhADAMTS13 could be a promising strategy to treat AKI in clinical settings. PMID- 30461293 TI - Special Section: Articles from Annual Biobank China 2017. PMID- 30461294 TI - Athletic Trainers' Effect on Population Health: Improving Access to and Quality of Care. AB - CONTEXT: The scope of athletic training practice combined with the magnitude of scholastic athletic injuries means that the scholastic athletic trainer (AT) is uniquely positioned to positively affect the overall health care of this population. The AT is equipped to serve in the prevention and primary management of injuries and return to activity of scholastic athletes. However, to optimize the musculoskeletal health of all athletes within a given setting, the gaps in clinical care must be continuously evaluated. Quality improvement (QI) approaches are often used to establish a framework for delivering care that promotes the best health status of the targeted population. OBJECTIVE: To describe the creation, implementation, and early results of a QI initiative aimed at advancing the health of the scholastic athletes served in the Greenville County, South Carolina, school district. DESIGN: Cohort study. PATIENTS OR OTHER PARTICIPANTS: A total of 49 793 athletes. MAIN OUTCOME MEASURE(S): The QI framework consisted of a process that documented the magnitude of athletic injuries, established risk factors for injury, defined intervention steps for at-risk athletes, and evaluated the QI process before and after implementation. The results were regularly reported to participating stakeholders, including ATs, athletic directors, coaches, parents, and athletes. RESULTS: After the QI process, injury rates decreased (absolute risk difference between the 2011-2012 and 2016-2017 academic years = 22%) and resources were more strategically allocated, which resulted in a decrease in health care costs of more than 50%. CONCLUSIONS: Collectively, the QI framework as described provides a systematic process for empowering the AT as the foundation of the scholastic sports medicine team. PMID- 30461295 TI - Application of Mitra(r) microsampling for pharmacokinetic bioanalysis of monoclonal antibodies in rats. AB - AIM: Volumetric absorptive microsampling (VAM) is being increasingly applied in nonclinical pharmacokinetic studies. Although there are published results for VAM use in small molecule pharmacokinetics (PK) studies, there is limited data on the utility of VAM for protein therapeutics. RESULTS: We describe the use of Mitra(r) microsampler for blood sampling, ELISA quantitation and PK analysis of two marketed therapeutic monoclonal antibodies administered to rat. Results generated for these monoclonal antibodies using Mitra(r) were compared with both serum and whole blood sampling methods in the same study. CONCLUSION: The low relative standard deviation among the three sets of PK data suggest that Mitra(r) microsampler could be useful in early nonclinical PK studies for protein therapeutics where reduction and refinement of animal use is desirable. PMID- 30461296 TI - Increased Substance P Immunoreactivity in Ipsilateral Knee Cartilage of Rats Exposed to Lumbar Spine Injury. AB - OBJECTIVE: The present study aimed to investigate whether experimentally induced lumbar facet-joint OA lead to degenerative changes and enhanced SP expression within the ipsilateral neurosegmentally linked tibiofemoral cartilage. METHODS: Adult male Sprague-Dawley rats were assigned to left side L5-L6 facet mechanical compression injury (surgery) ( n = 6), L5-L6 facet exposure with no compression (sham) ( n = 5), or naive (no surgery) ( n = 4) groups. The morphology of the tibiofemoral articular cartilage was assessed using a modified Mankin scoring system. Immunohistochemistry was used to examine the density of chondrocytes stained positive for SP (cells/cm2) in the ipsilateral tibiofemoral cartilage at 28 days postintervention. RESULTS: Tibiofemoral cartilage in the surgery group showed consistent loss of superficial zone chondrocytes, mild roughening of the articular surface and occasional chondrocyte clusters as well as a greater density of SP mainly in the superficial cartilage zone compared with sham and naive groups, although they also had a basic SP-expression. CONCLUSION: Our results support the hypothesis that neurogenic mechanisms may mediate the spread of SP to neurosegmentally linked heterologous joints affecting the distal cartilage homeostasis. These findings contribute additional insight into the potential role of neurogenic inflammation with implications in the pathophysiology of chronic inflammatory joint disease and OA. PMID- 30461297 TI - In Vitro Antibacterial Activity and Mechanism of Monocaprylin against Escherichia coli and Staphylococcus aureus. AB - In the present study, the antibacterial activity of monocaprylin in comparison with sodium benzoate and potassium sorbate against Staphylococcus aureus and Escherichia coli was assessed by measuring MIC, MBC, effect of pH on MIC, and incubation temperature on bactericidal efficacy. Results showed that monocaprylin exhibited an excellent antibacterial activity against both strains, with the lowest MIC and MBC of 1.28 mg/mL. A MIC of monocaprylin remained unchanged despite the pH values of culture medium, ranging from 5 to 9, unlike that of potassium sorbate or sodium benzoate. Furthermore, monocaprylin at MBC effectively reduced the population of E. coli and S. aureus by >5.5 log CFU/mL at 25 degrees C within 6 h and decreased E. coli by approximately 5.0 log CFU/mL and S. aureus by 2.9 log CFU/mL at 12 h. The underlying mechanism of monocaprylin was then investigated by measuring beta-galactosidase activity, membrane potential, release of cellular contents, scanning electron microscopy, and transmission electron microscopy observations. Results indicated that monocaprylin killed E. coli by the rapid change in permeability and integrity of cell membrane, leading to decline of membrane potential, leakage of nucleic acids and proteins, and ultimately cell membrane disintegration and lysis. On the other hand, monocaprylin might exert its antibacterial activity against S. aureus mainly by diffusing across the cell wall, collapsing the cell membrane, and disturbing the order of intracellular contents. These findings indicated that monocaprylin had better antibacterial ability compared with traditional synthetic preservatives and might be a potential antibacterial additive independent of pH. PMID- 30461298 TI - Associations Between Patient-Reported Outcome Measures of Asthma Control and Psychosocial Symptoms. AB - There is growing emphasis on using patient-reported outcome measures to enhance clinical practice. This study was a retrospective review of scores on the Childhood Asthma Control Test (C-ACT) and the Pediatric Symptom Checklist-17 (PSC 17) at a pediatric primary care center in Boston, Massachusetts. A total of 218 patients were selected at random using billing codes for well-child (WC) care and asthma, excluding complex medical conditions. Cutoff scores were used to identify uncontrolled asthma (C-ACT ?19) and clinically significant psychosocial symptoms (+PSC-17). Multiple logistic regression was used to measure associations between C-ACT ?19 and +PSC-17, adjusting for covariates. In multivariable analysis, C-ACT ?19 at WC visits was associated with +PSC-17 at WC visits (adjusted odds ratio = 3.2 [95% confidence interval = 1.3-8.6]). C-ACT ?19 at non-WC visits was also associated with +PSC-17 at WC visits (adjusted odds ratio = 3.1 [95% confidence interval = 1.2-8.9]). Patient-reported outcome measures of asthma control and psychosocial symptoms were positively correlated in this sample. PMID- 30461299 TI - Turned Inside Out: Will Myelin-Protective Therapies Become the Next-Generation Anti-Inflammatories? AB - The earliest and most proximal triggers of inflammatory demyelination in multiple sclerosis (MS) remain an open question. In this DNACB review we address experimental and clinical evidence consistent with subtle perturbations of the axo-myelinic compartment of central nervous system white matter as initiation sites of secondary autoimmune demyelination in MS. Strengthened by experimental evidence that by inhibiting myelinopathy one can prevent inflammatory demyelination, myelin-protective therapies may represent a new class of anti inflammatory medications for combating myelin autoimmunity. PMID- 30461300 TI - Microbial exposure to dairy farmers' dwellings and COPD occurrence. AB - Dairy farming is a risk factor for chronic obstructive pulmonary disease (COPD). The aim was to determine predictive markers either in blood samples or in dwelling dust samples by comparing COPD and healthy controls with or without farming activity. Dust was collected and analyzed by real-time quantitative PCR. ELISA and DELFIA(r) were performed to assay the level of specific IgG and IgE of 10 targeted microorganisms. The dwelling exposure of farmers was higher than in the non-farmers (Especially Eurotium amstelodami and Lichtheimia corymbifera). The IgG response against Wallemia sebi and Saccharopolyspora rectivirgula was more often higher in the farmers than the non-farmers. However, exposure and sensitization to the microorganisms tested cannot explain the occurrence of COPD in the dairy farmers' population. COPD development is probably caused by multiple factors associated with exposure over a period of several years. PMID- 30461301 TI - A step closer to improving cardiac homing of adipose-derived mesenchymal stem cells. PMID- 30461302 TI - Synergy Between Sacubitril and Valsartan Leads to Hemodynamic, Antifibrotic, and Exercise Tolerance Benefits in Rats with Preexisting Heart Failure. AB - BACKGROUND: Simultaneous neprilysin inhibition (NEPi) and angiotensin receptor blockade (ARB) with sacubitril/valsartan improves cardiac function and exercise tolerance in patients with heart failure (HF). However, it is not known if these therapeutic benefits are primarily due to NEPi with sacubitril or ARB with valsartan, or their combination. Therefore, the aim of this study was to investigate the potential contribution of sacubitril and valsartan to the benefits of the combination therapy on left ventricular (LV) function and exercise tolerance. METHODS: HF was induced by volume-overload via partial disruption of the aortic valve in rats. Therapy began 4 weeks after valve disruption and lasted through 8 weeks. Drugs were administered daily via oral gavage (sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), sacubitril (31 mg/kg). Hemodynamic assessments were conducted using MillarTM technology, and an exercise tolerance test was conducted using a rodent treadmill. RESULTS: Therapy with sacubitril/valsartan improved load dependent indices of left ventricular contractility (dP/dtmax) and relaxation (dP/dtmin), exercise tolerance, and mitigated myocardial fibrosis, while monotherapies with valsartan, or sacubitril did not. Both sacubitril/valsartan and valsartan similarly improved a load independent index of contractility (Ees). Sacubitril did not improve Ees. CONCLUSIONS: 1) Synergy of NEPi with sacubitril and ARB with valsartan leads to the improvement of load dependent LV contractility and relaxation, exercise tolerance, and reduction of myocardial collagen content. 2) Improvement in load independent LV contractility with sacubitril/valsartan appears to be solely due to ARB with valsartan constituent. PMID- 30461303 TI - DISRUPTION OF CARDIAC MED1 INHIBITS RNA POLYMERASE-II PROMOTER OCCUPANCY AND PROMOTES CHROMATIN REMODELING. AB - The Mediator co-activator complex directs gene specific expression by binding distal enhancer-bound transcription factors through its Med1 subunit while bridging to RNA Polymerase-II (Pol-II) at gene promoters. In addition, Mediator scaffolds epigenetic modifying enzymes that determine local DNA accessibility. We previously found that deletion of Med1 in cardiomyocytes deregulates more than 5000 genes and promotes acute heart failure. We therefore hypothesize Med1 deficiency disrupts enhancer-promoter coupling. Using chromatin immunoprecipitation coupled deep sequencing (ChIP-seq, n=3 per ChIP assay) we find Pol-II pausing index is increased in Med1 knockout versus floxed control mouse hearts primarily due to a decrease in Pol-II occupancy at the majority of transcriptional start sites without a corresponding increase in elongating species. Parallel ChIP-seq assays reveal Med1-dependent gene expression correlates strongly with histone H3 K27 acetylation indicative of open and active chromatin at transcriptional start sites while H3 K27 tri-methylated levels, representing condensed and repressed DNA, are broadly increased and inversely correlate with absolute expression levels. Furthermore, Med1 deletion leads to dynamic changes in acetyl-K27 associated super-enhancer regions and their enriched transcription factor binding motifs that are consistent with altered gene expression. Our findings suggest that Med1 is important in establishing enhancer-promoter coupling in the heart and supports the proposed role of Mediator in establishing pre-initiation complex formation. We also find Med1 determines chromatin accessibility within genes and enhancer regions and propose the composition of transcription factors associated with super-enhancers changes in order to direct gene-specific expression. PMID- 30461304 TI - Na/Ca exchanger overexpression in smooth muscle augments cytosolic Ca2+ in femoral arteries of living mice. AB - The plasma membrane Na/Ca exchanger-1 (NCX1) helps regulate the cytosolic Ca2+ concentration ([Ca2+]CYT) in arterial myocytes. NCX1 mediates both Ca2+ entry and exit, and tends to promote net Ca2+ entry in partially-constricted arteries. Mean BP (telemetry) is elevated by ~10 mm Hg in transgenic (TG) mice that overexpress NCX1 specifically in smooth muscle. We tested the hypothesis that NCX1 overexpression mediates Ca2+ gain and elevated [Ca2+]CYT in exposed femoral arteries that also express the Ca2+ biosensor, exMLCK. [Ca2+]CYT and the NCX1 dependent (SEA0400-sensitive) component, ~15% of total basal constriction in controls, were increased in TG arteries, but constrictions to phenylephrine (PE) and angiotensin II (Ang II) were comparable in TGs and controls. Normalized PE dose-response curve and constriction to 30 and 300 ng/kg iv Ang II were virtually identical in control and TG arteries. Ang II-evoked constrictions, superimposed on elevated basal tone, accounts for the larger BP responses to Ang II in the TGs. TG and control mouse arteries fit the same pCa-constriction relationship over a wide range of pCa (~125-500 nM). Vasodilation to acetylcholine (ACh), normalized to passive diameter (PD), also was comparable in TGs and controls, implying normal endothelial function. TG artery Na+ nitroprusside (SNP, an NO donor)-induced dilations were, however, shifted to lower SNP concentrations, indicating that TG myocyte vasodilator mechanisms were augmented. Maximum arterial dilation was comparable in TG and control mice although PD was ~6-7% smaller in TGs. The changes in TG arteries were apparently largely functional rather than structural despite the congenital hypertension. PMID- 30461305 TI - B lymphoma Mo-MLV insertion region 1 homolog (BMI1): The Janus-faced polycomb protein that will break your heart. PMID- 30461306 TI - JAVELIN Head and Neck 100: a Phase III trial of avelumab and chemoradiation for locally advanced head and neck cancer. AB - Chemoradiotherapy (CRT) is the standard of care for locoregionally advanced squamous cell carcinomas of the head and neck (HNSCC). The immune checkpoint inhibitors nivolumab and pembrolizumab were recently approved by the US FDA for treatment of recurrent or metastatic HNSCC that are refractory to platinum chemotherapy. However, prospective studies incorporating immune checkpoint inhibitors in the definitive management of poor prognosis, nonmetastatic, locoregionally advanced HNSCC are lacking. The JAVELIN Head and Neck 100 study is a multinational, Phase III, double-blind, placebo-controlled, randomized clinical trial assessing the efficacy of avelumab, a PD-L1 inhibitor, in combination with CRT compared with placebo in combination with CRT for high-risk HNSCC. Trial registration: Javelin Head and Neck 100; NCT 02952586. PMID- 30461307 TI - A Pilot Study of Use of a Software Platform for the Collection, Integration, and Visualization of Diabetes Device Data by Health Care Providers in a Multidisciplinary Pediatric Setting. AB - BACKGROUND: Diabetes devices provide data for health care providers (HCPs) and people with type 1 diabetes to make management decisions. Extracting and viewing the data require separate, proprietary software applications for each device. In this pilot study, we examined the feasibility of using a single software platform (Tidepool) that integrates data from multiple devices. MATERIALS AND METHODS: Participating HCPs (n = 15) used the software with compatible devices in all patient visits for 6 months. Samples of registration desk activity and office visits were observed before and after introducing the software, and HCPs provided feedback by survey and focus groups. RESULTS: The time required to upload data and the length of the office visit did not change. However, the number of times the HCP referred to the device data with patients increased from a mean of 2.8 (+/-1.2) to 6.1 (+/-3.1) times per visit (P = 0.0002). A significantly larger proportion of children looked at the device data with the new application (baseline: 61% vs. study end: 94%, P = 0.015). HCPs liked the web-based user interface, integration of the data from multiple devices, the ability to remotely access data, and use of the application to initiate patient education. Challenges included the need for automated data upload and integration with electronic medical records. CONCLUSIONS: The software did not add to the time needed to upload data or the length of clinic visits and promoted discussions with patients about data. Future studies of HCP use of the application will evaluate clinical outcomes and effects on patient engagement and self-management. PMID- 30461308 TI - Dual Role of a C-Terminally Truncated Isoform of Large Tumor Suppressor Kinase 1 in the Regulation of Hippo Signaling and Tissue Growth. AB - The considerable amount of experimental evidence has defined the Hippo pathway as a tumor suppressive pathway and increased expression and/or activity of its oncogenic effectors is frequently observed in cancer. However, clinical studies have failed to attribute cancer development and progression to mutations in the pathway. In explaining this conundrum, we investigated the expression and functions of a C-terminally truncated isoform of large tumor suppressor kinase 1 (LATS1) called short LATS1 (sLATS1) in human cell lines and Drosophila. Intriguingly, through overexpression of sLATS1, we demonstrated that sLATS1 either activates or suppresses the activity of Yes-associated protein (YAP), one of the effectors of the Hippo pathway, in a cell type-specific manner. The activation is mediated through inhibition of full-length LATS1, whereas suppression of YAP is accomplished through sLATS1-YAP interaction. In HEK293T cells, the former mechanism may affect the cellular response more dominantly, whereas in U2OS cells and developing tissues in Drosophila, the latter mechanism may be solely carried out. Finally, to find the clinical relevance of this molecule, we examined the expression of sLATS1 in breast cancer patients. The transcriptome analysis showed that the ratio of sLATS1 to LATS1 was increased in tumor tissues comparing to their adjacent normal tissues. PMID- 30461309 TI - Recalibrating the molecular clock for Arctic marine invertebrates based on DNA barcodes. AB - Divergence times for species assemblages of Arctic marine invertebrates have often been estimated using a standard rate (1.4%/MY) of molecular evolution calibrated using a single sister pair of tropical crustaceans. Because rates of molecular evolution vary among taxa and environments, it is essential to obtain clock calibrations from northern lineages. The recurrent opening and closure of the Bering Strait provide an exceptional opportunity for clock calibration. Here, we apply the iterative calibration approach to investigate patterns of molecular divergence among lineages of northern marine molluscs and arthropods using publicly available sequences of the cytochrome c oxidase subunit I (COI) gene and compare these results with previous estimates of trans-Bering divergences for echinoderms and polychaetes. The wide range of Kimura two-parameter (K2P) divergences among 73 trans-Bering sister pairs (0.12%-16.89%) supports multiple pulses of migration through the Strait. Overall, the results indicate a rate of K2P divergence of 3.2%/MY in molluscs, 5%-5.2%/MY in arthropods, and 3.5%-4.7%/MY in polychaetes. While these rates are considerably higher than the often-adopted 1.4%/MY rate, they are similar to calibrations (3%-5%/MY) in several other studies of marine invertebrates. This upward revision in rates means there is a need both to reevaluate the evolutionary history of marine lineages and to reexamine the impact of prior climatic changes upon the diversification of marine life. PMID- 30461310 TI - The antioxidant power of horseradish, Armoracia rusticana, underlies antimicrobial and antiradical effects, exerted in vitro. AB - Armoracia rusticana (AR) was tested for antimicrobial and antioxidants power. The compound demonstrated to inhibit fish pathogens such as Vibrio anguillarum, V. harvey, V. alginolyticus, Aeromonas hydrophila, A. salmonicida, Photobacterium damselae subspecie piscicida, Tenacibaculum marinum and Pseudomonas anguilliseptica,. The total phenolic content and the reducing power resulted higher in the water extract of AR, respect to the hydroalcoolic. In vitro test demonstrated that AR significantly protect cells against death, induced by oxidative stress. PMID- 30461311 TI - Molecular Diagnosis of Rare Autosomal Recessive Escobar Syndrome in a Consanguineous Pakistani Family. AB - BACKGROUND: Escobar syndrome, a nonlethal variant of multiple pterygium syndromes (MPS), is a rare autosomal recessive disorder characterized by pterygia and multiple joint contractures along with other anomalies. Variants in cholinergic receptor nicotinic gamma subunit (CHRNG) have been previously reported in patients with Escobar syndrome. OBJECTIVE: We studied a consanguineous Pakistani family affected with Escobar syndrome to identify the underlying genetic defect through short tandem repeat (STR) genotyping and direct DNA sequencing. RESULTS: Genotyping with microsatellite markers (D2S427, D2S2344, and D2S206) revealed linkage of the disease phenotype in the family to the CHRNG locus. Using Sanger sequencing, we identified a homozygous nonsense CHRNG variant c.136C>T (p.R46*), predicted to produce a truncated protein that leads to acetylcholine receptor deficiency, causing MPS. The unaffected parents and siblings in the family were heterozygous carriers of this disease-causing variant. CONCLUSION: We report the identification of a nonsense CHRNG variant in a consanguineous Pakistani family affected with Escobar syndrome. PMID- 30461312 TI - Causal explanations for lack of pregnancy applying the common sense model of illness representation to the fertility context. AB - OBJECTIVES: The current study explored causal explanations for lack of pregnancy and association with help-seeking behaviour. Differences based on gender and country Human Development Index were examined. DESIGN: A mixed method design was used. MAIN OUTCOME MEASURES: Data were drawn from the International Fertility Decision-Making Study, a cross-sectional study of 10,045 individuals (1690 men; 8355 women) from 79 countries. Respondents rated to what extent they believed their lack of pregnancy was due to something they or their partner had done/not done or other factors and described their reasons for making this rating. RESULTS: Respondents were aged 18-50 (M = 31.83) years, partnered and had been trying to achieve a pregnancy/father a child for over six months (M = 2.8 years). Men and women primarily believed their lack of pregnancy was due to medical problems or chance/bad luck. Thematic analysis of textual responses from 29.7% of the sample found that respondents focused on their personal experience or a salient life event when describing the cause of their lack of pregnancy. Women expressed more regret and helplessness about causes than men. Significant country differences were observed. CONCLUSIONS: Individuals may develop inaccurate causal explanations based on their personal experiences. Access to accurate information is necessary to facilitate timely help-seeking. PMID- 30461313 TI - Psychological Distress Transmission in Same-sex and Different-sex Marriages. AB - Ample work stresses the interdependence of spouses' psychological distress and that women are more influenced by their spouse's distress than men. Yet previous studies have focused primarily on heterosexual couples, raising questions about whether and how this gendered pattern might unfold for men and women in same-sex marriages. We analyze 10 days of diary data from a purposive sample of men and women in same-sex and different-sex marriages (n = 756 individuals from 378 couples) to examine psychological distress transmission between spouses and how this process may differ for men and women in same-sex and different-sex marriages. We find that women are more strongly influenced by their partners' distress than men, regardless of whether they are married to a man or a woman, and that this relationship is particularly strong for women with male spouses. PMID- 30461314 TI - Mortality, length of stay, and costs associated with acute graft-versus-host disease during hospitalization for allogeneic hematopoietic stem cell transplantation. AB - OBJECTIVE: Acute graft-versus-host disease (aGVHD) is a common and life threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The extent to which aGVHD increases inpatient costs associated with allo-HSCT has not been thoroughly evaluated. In this analysis, mortality, hospital length of stay (LOS), and costs associated with aGVHD during allo-HSCT admissions are evaluated. METHODS: This is a retrospective analysis of discharge records from the National Inpatient Sample database for patients receiving allo HSCT between January 1, 2009, and December 31, 2013. Allo-HSCT discharges with an aGVHD diagnosis were included in the aGVHD group and those without any graft versus-host disease (GVHD) diagnosis comprised the non-GVHD group. Mortality, LOS, and costs were compared between the two groups, as well as within subgroups, including age (<18 vs >=18 years) and survival status (alive vs deceased) at discharge. RESULTS: Overall, mortality (16.2% vs 5.3%; P < 0.01), median hospital LOS (42.0 vs 26.0 days; P < 0.01), and median total costs ($173,144 vs $98,982; P < 0.01) were significantly increased in patients with aGVHD versus those without GVHD during hospitalizations for allo-HSCT, irrespective of age group. Patients with aGVHD who were <18 years of age had a lower mortality rate but greater hospital LOS and total costs versus patients aged >=18 years. Patients who died during allo-HSCT hospitalization had longer LOS and incurred greater costs than those who survived in both the aGVHD and non-GVHD groups. CONCLUSION: Occurrence of aGVHD during allo-HSCT admissions resulted in a tripling of the mortality rate and a near doubling of hospital LOS and total costs. In addition, death during allo-HSCT hospitalizations was associated with greater healthcare utilization and costs. Effectively mitigating aGVHD may improve survival and substantially reduce hospital LOS and costs for allo-HSCT. PMID- 30461315 TI - Effects of Cognitive Behavioral Therapy for Insomnia on Sleep, Symptoms, Stress, and Autonomic Function Among Patients With Heart Failure. AB - BACKGROUND: Insomnia is common among patients with stable heart failure (HF) and associated with inflammation and altered autonomic function. PURPOSE: The purposes of this study were to examine the effects of cognitive behavioral therapy for insomnia (CBT-I) on the Hypothalamic Pituitary (HPA) Axis, autonomic function, inflammation, and circadian rhythmicity and the associations between these biomarkers and insomnia, sleep characteristics, symptoms, functional performance, and sleep-related cognitions. METHODS: We conducted a subanalysis of a pilot randomized controlled trial (RCT, NCT02827799) whose primary aim was to test the effects of CBT-I on insomnia. We randomized 51 patients with stable Class II-IV HF to CBT-I (n = 30) or attention control (n = 21). Participants completed wrist actigraphy and self-reported insomnia severity, sleep characteristics, sleep-related cognitions, daytime symptoms, and functional performance. We measured day and nighttime urinary free cortisol, melatonin sulfate, epinephrine, and norepinephrine at baseline, and two weeks after CBT-I and computed general linear models and partial correlations. RESULTS: CBT-I had no effects on the biomarkers, but there were statistically significant negative cross-sectional correlations between the ratio of day and night urinary free cortisol and sleep disturbance, anxiety, fatigue, depression, and negative sleep cognitions. Increases in the ratio between day and night cortisol were associated with statistically significant improvements in fatigue, depression, sleep duration, and sleep-related cognitions. CONCLUSIONS: Biomarkers of stress and autonomic function are associated with sleep, sleep-related symptoms, and cognitions among people with chronic HF. Future studies are needed to identify potential causal relationships and the impact of sleep interventions. PMID- 30461317 TI - Correction. PMID- 30461316 TI - Interpreting Patient-Reported Outcome Results: Is One Minimum Clinically Important Difference Really Enough? AB - BACKGROUND: Patient-reported outcomes (PROs) are the gold standard for reporting clinical outcomes in research. A crucial component of interpreting PROs is the minimum clinically important difference (MCID). Patient-Rated Wrist Evaluation (PRWE) is a disease-specific PRO tool developed for use in distal radius fractures. The purpose of this study was to determine the influence of injury characteristics, treatment modality, and calculation methodology on the PRWE MCID in distal radius fractures. We hypothesize the MCID would be significantly influenced by each of these factors. METHODS: From 2014 to 2016, 197 patients with a distal radius fracture were treated at a single level I trauma center. Each patient was asked to complete a PRWE survey at preoperative baseline, 6-week postoperative, and 12-week postoperative dates. The MCID was derived utilizing 2 distinct strategies, anchor and distribution. Anchor questions involved overall health anchor and mental and emotional health anchor. Patient variables regarding demographics, injury characteristics, and treatment modality were collected. RESULTS: The MCID was unique between analytical methods at all time points. The distribution MCID presented commonality across assessed variables. However, the anchor MCID was unique by AO/OTA fracture classifications, treatment modality, and time points. CONCLUSIONS: Our study found the MCID was heavily influenced by assessment time points, analytical method, treatment modality, and fracture classification. These results suggest that to accurately interpret PRO data in clinical trials, an anchor question should be included so that the MCID can be determined for the specific patient population included in the study. PMID- 30461318 TI - Does EEG activity during painful stimulation mirror more closely the noxious stimulus intensity or the subjective pain sensation? AB - BACKGROUND: Many researchers have tried to investigate pain by studying brain responses. One method used to investigate pain-related brain responses is continuous electroencephalography (EEG). The objective of the current study is to add on to our understanding of EEG responses during pain, by differentiation between EEG patterns indicative of (i) the noxious stimulus intensity and (ii) the subjective pain sensation. METHODS: EEG was recorded during the administration of tonic experimental pain, consisting of six minutes of contact heat applied to the leg via a thermode. Two stimuli above pain threshold, one at pain threshold and two non-painful stimuli were administered. Thirty-six healthy participants provided a subjective pain rating during thermal stimulation. Relative EEG power was calculated for the frequency bands alpha1, alpha2, beta1, beta2, delta, and theta. RESULTS: Whereas EEG activity could not be predicted by stimulus intensity (except in one frequency band), subjective pain sensation could significantly predict differences in EEG activity in several frequency bands. An increase in the subjective pain sensation was associated with a decrease in alpha2, beta1, beta2 as well as in theta activity across the midline electrodes. CONCLUSION: The subjective experience of pain seems to capture unique variance in EEG activity above and beyond what is captured by noxious stimulus intensity. PMID- 30461319 TI - A Prospective, Randomized Trial Comparing Open and Endoscopic Carpal Tunnel Release Within the Same Patient. AB - BACKGROUND: Surgical management of carpal tunnel syndrome includes performing an endoscopic (ECTR) or open (OCTR) carpal tunnel release. Several studies have shown less postoperative pain and improvement in grip and pinch strength with the endoscopic technique. The goal of this study was to prospectively examine outcomes, patient satisfaction, and complications after both ECTR and OCTR in the opposite hands of the same patient. METHODS: This was a prospective study in which patients with bilateral carpal tunnel syndrome underwent surgical release with both techniques, with initial operative approach randomized in the more symptomatic hand. Demographic data and functional outcomes were recorded, including the pain score, 2-point discrimination, Semmes-Weinstein monofilament testing, thenar strength testing, grip strength, carpal tunnel syndrome functional status score, carpal tunnel syndrome symptom severity score, and overall satisfaction. RESULTS: Thirty patients completed the study; there were no significant differences in any measure at any of the postoperative time points. Symptom severity and functional status scores were not significantly different between groups at any evaluation. Subjectively, 24 of 30 patients did state they preferred the ECTR, mostly citing less pain as their primary reason, although pain scores were not significantly different. Differences in overall satisfaction were also not significant. CONCLUSIONS: Both techniques are well tolerated with no differences in outcomes. With the added cost and equipment associated with ECTR, and no added benefit, the usefulness of ECTR is questionable. PMID- 30461320 TI - Screening of AIP Gene Variations in a Cohort of Turkish Patients with Young-Onset Sporadic Hormone-Secreting Pituitary Adenomas. AB - AIMS: Aryl hydrocarbon receptor-interacting protein (AIP) gene mutations have long been associated with apparently sporadic pituitary adenomas (PAs) with a prevalence range of 0-12%. The aim of this study was to evaluate the frequency of germline AIP variations in a large cohort of apparently sporadic PAs diagnosed before the age of 40 years, who did not exhibit hypercalcemia and/or MEN1 syndrome components during long-term follow-up. MATERIALS AND METHODS: A total of 97 patients, diagnosed with functional PAs <=40 years old, composed of somatotropinoma (n = 55), prolactinoma (n = 25), and corticotrophinoma (n = 17), were recruited for this study. Fifty-one of these patients [somatotropinoma (n = 30), prolactinoma (n = 15), and corticotrophinoma (n = 11)] were previously reported as AIP mutation-negative by Sanger sequencing. The entire coding sequence of the AIP gene, along with exon/intron boundaries and the untranslated regions of 41 newly recruited patients, were sequenced for germline variations. In addition, all patients were subjected to multiplex ligation-dependent probe amplification to detect copy number variations in the AIP gene. RESULTS: The AIP c.911G>A: p.Arg304Gln (rs104894190) variant was detected in only two patients with functional PA: one with somatotropinoma [in 1/55 (1.8%)] and one with prolactinoma [in 1/25 (4%)]. None of the corticotrophinomas revealed AIP gene alterations. Thus, the overall prevalence of AIP variation was 2.1% in our cohort. CONCLUSIONS: Germline AIP gene variations among Turkish patients with apparently sporadic PAs are relatively rare among patients <=40 years old. None of the patients in our cohort revealed any obviously pathogenic AIP variants. PMID- 30461321 TI - Insilico and in vivo analysis to identify the antidiabetic activity of beta sitosterol in adipose tissue of high fat diet and sucrose induced type-2 diabetic experimental rats. AB - Adipose tissue is the primary site of storage for excess energy as triglyceride and it helps in synthesizing a number of biologically active compounds that regulate metabolic homeostasis. Consumption of high dietary fat increases stored fat mass and is considered as a main risk factor for metabolic diseases. Beta sitosterol (beta-sitosterol) is a plant sterol. It has the similar chemical structure like cholesterol. Clinical and experimental studies have shown that beta-sitosterol has anti-diabetic, hypolipidemic, anti-cancer, anti-arthritic and hepatoprotective role. However, effect of beta-sitosterol on insulin signaling molecules and glucose oxidation has not been explored. Hence in the present study we aimed to discover the protective role of beta-sitosterol on the expression of insulin signaling molecules in the adipose tissue of high-fat diet and sucrose induced type-2 diabetic experimental rats. Effect dose of beta-sitosterol (20mg/kg b.wt, orally for 30 days) was given to high fat diet and sucrose-induced type-2 diabetic rats to study its anti-diabetic activity. Results of the study showed that the treatment with beta-sitosterol to diabetes-induced rats normalized the altered levels of blood glucose, serum insulin and testosterone, lipid profile, oxidative stress markers, antioxidant enzymes, insulin receptor (IR) and glucose transporter 4 (GLUT4) proteins. Our present findings indicate that beta-sitosterol improves glycemic control through activation of IR and GLUT4 in the adipose tissue of high fat and sucrose-induced type-2 diabetic rats. Insilico analysis also coincides with invivo results. Hence it is very clear that beta-sitosterol can act as potent antidiabetic agent. PMID- 30461323 TI - Correction. PMID- 30461322 TI - Drug delivery to tumours using a novel 5-FU derivative encapsulated into lipid nanocapsules. AB - In this work, a novel lipophilic 5-fluorouracil (5-FU) derivative was synthesised and encapsulated into lipid nanocapsules (LNC). 5-FU was modified with lauric acid to give a lipophilic mono-lauroyl-derivative (5-FU-C12, MW of about 342 g/mol, yield of reaction 70%). 5-FU-C12 obtained was efficiently encapsulated into LNC (encapsulation efficiency above 90%) without altering the physico chemical characteristics of LNC. The encapsulation of 5-FU-C12 led to an increased stability of the drug when in contact with plasma being the drug detectable until 3 h following incubation. Cytotoxicity assay carried out using MTS on 2D cell culture showed that 5-FU-C12-loaded LNC had an enhanced cytotoxic effect on glioma (9L) and human colorectal (HTC-116) cancer cell line in comparison with 5-FU or 5-FU-C12. Then, HCT-116 tumour spheroids were cultivated and the reduction of spheroid volume was measured following treatment with drug loaded LNC and drugs alone. Similar reduction on spheroids volume was observed following the treatment with drug-loaded LNC, 5-FU-C12 and 5-FU alone, while blank LNC displayed a reduction in cell viability only at high concentration. Globally, our data suggest that the encapsulation increased the activity of the 5 FU-C12. However, in-depth evaluations of LNC permeability into spheroids are needed to disclose the potential of these nanosystems for cancer treatment. PMID- 30461324 TI - Intraoperative Vaginal Perforation During Various Mid-Urethral Sling Procedures Treating Female Stress Urinary Incontinence. AB - BACKGROUND: Incidence of intraoperative vaginal perforation is generally considered to be low but varies among different procedures. Vaginal perforation could not only prolong the surgeries and aggravate surgical trauma but also result in postoperative discomfort or even a second surgery. METHOD: Vaginal perforation, vaginal epithelial perforation, vaginal wall perforation, vaginal penetration, urinary incontinence were searched in PubMed, Cochrane, Embase database to identify the qualified clinical trial and relevant literature sources were also searched. RESULTS: A total of 9223 cases of from 33 trials from literatures and 387 cases from our own trail were analyzed, which provided detailed data on intraoperative vaginal perforation. Incidence of intraoperative vaginal perforation during mid-urethral sling surgery treating stress urinary incontinence was generally low, which was 1.56%. Incidence of intraoperative vaginal perforation during transobturator (TOR) procedure was higher than that during retropubic (RPR) procedure, which were 2.11% and 0.89% respectively. Incidence of intraoperative vaginal perforation during outside-to-inside TOR procedure like TOT and MONARC was higher than that during inside-to-outside TOR procedure like TVT-O, which were 2.74% and 1.52%, respectively. Incidence of intraoperative vaginal perforation during single-incision surgery like H-type TVT SECUR reached 1.97%, while no report on U-type TVT-SECUR surgeries. CONCLUSION: The incidence of intraoperative vaginal during mid-urethral sling procedures for female stress urinary incontinence is fairly high. Vaginal perforation was more common in trans-obturator route (TOR) than retropubic route (RPR). In TOR route, it was less frequent in inside-to-outside procedure than outside-to-inside procedure. Surgery proficiency could also have an impact on this complication. PMID- 30461325 TI - Acute Cardiac Events in Patients With Severe Limb Infection. AB - Recent studies have shown an association between infections, such as influenza, pneumonia, or bacteremia, and acute cardiac events. We studied the association between foot infection and myocardial infarction, arrhythmia, and/or congestive heart failure. We analyzed the records of 318 consecutive episodes of deep soft tissue infection, gangrene, and/or osteomyelitis in 274 patients referred to a vascular surgery service at a tertiary center. We identified 24 acute cardiac events in 21 of 318 (6.6%) episodes of foot infection or foot gangrene. These 24 events included 11 new myocardial infarctions (3.5%), 8 episodes of new onset or worsening congestive heart failure (2.5%), and 5 new arrhythmias (1.6%). Tachycardia and systemic inflammatory response syndrome were associated with acute cardiac events ( P < .05 for each). The 1-year survival of patients with acute cardiac events was 50.4%, significantly lower than the 91.7% 1-year survival of patients without acute cardiac events ( P < .0015). Acute cardiac complications are not uncommon among patients presenting with severe foot infection and are associated with a high 1-year mortality. Primary care physicians, cardiologists, and vascular and orthopedic surgeons must keep a high index of suspicion for the occurrence of an acute cardiac event. PMID- 30461326 TI - Intravenous Regional Anesthesia Using a Forearm Tourniquet: A Safe and Effective Technique for Outpatient Hand Procedures. AB - BACKGROUND: Bier block provides anesthesia of an entire extremity distal to the tourniquet without necessitating direct injection at the surgical site. This avoids obscuring anatomy with local anesthetic and anesthetizes a wide area, allowing for multiple procedures and incisions. We hypothesize that a low-volume Bier block with forearm tourniquet, rather than a traditional brachial tourniquet, is a safe, well-tolerated, and effective anesthesia technique. METHODS: All cases in which adult patients underwent hand procedures using Bier block anesthesia by a single surgeon over a 4-year period were reviewed. Data collected included patient demographics, procedure(s) performed, complications, tourniquet time and settings, procedure and in-room time, and supplemental medications administered. RESULTS: In all, 319 patients were included, 103 from a university hospital and 216 from an ambulatory surgery center. The most commonly performed procedures were carpal tunnel release (205 cases) and trigger digit release (83 cases). Most patients received a 125-mg dose of lidocaine for the Bier block; many also received additional sedatives. Twenty-three patients received no additional medications. No patients required conversion to general anesthesia. One complication (0.3%) occurred, with paresthesias and tinnitus that resolved without intervention. The average tourniquet time was 24 minutes (SD = 4.3 minutes). Patients were discharged at a median of 49 minutes postoperatively, and 9.1% of patients received supplemental analgesics prior to discharge. CONCLUSIONS: Regional anesthesia achieved with a forearm tourniquet and intravenous local anesthetic provides adequate pain control, permits timely discharge home, and has a low complication rate. It should be considered for use in outpatient hand procedures. PMID- 30461327 TI - Differential effects of hypothermia on neurovascular unit determine protective or toxic results: Toward optimized therapeutic hypothermia. AB - Therapeutic hypothermia (TH) benefits survivors of cardiac arrest and neonatal hypoxic-ischemic injury and may benefit stroke patients. Large TH clinical trials, however, have shown mixed results. Given the substantial pre-clinical literature supporting TH, we explored possible mechanisms for clinical trial variability. Using a standard rodent stroke model ( n = 20 per group), we found smaller infarctions after 2 h pre- or post-reperfusion TH compared to 4 h. To explore the mechanism of this discrepancy, we used primary cell cultures of rodent neurons, astrocytes, or endothelial cells subjected to oxygen-glucose deprivation (OGD). Then, cells were randomly assigned to 33C, 35C or 37C for varying durations after varying delay times. Both 33 and 35C TH effectively preserved all cell types, although 33C was superior. Longer cooling durations overcame moderate delays to cooling initiation. In contrast, TH interfered with astrocyte paracrine protection of neurons in a temperature-dependent manner. These findings suggest that longer TH is needed to overcome delays to TH onset, but shorter TH durations may be superior to longer, perhaps due to suppression of astrocytic paracrine support of neurons during injury. We propose a scheme for optimizing TH after cerebral injury to stimulate further studies of cardiac arrest and stroke. PMID- 30461328 TI - A specific immunoassay for detection of feline kidney injury molecule 1. AB - OBJECTIVES: The aim of this study was to design and carry out a preliminary evaluation of a urine point-of-care test for kidney injury molecule 1( KIM-1) in healthy and diseased cats. METHODS: Part of the feline KIM-1 gene was amplified, ligated into a plasmid with a signal peptide and monomeric human IgGFc, and transfected into a mammalian cell line. Supernatant was purified and tested for the fusion protein by gel electrophoresis and Western blot. Mice were immunized three times with purified proteins, and hybridomas were generated from splenocytes. Antibodies were tested by ELISA for detection of recombinant KIM-1 and naturally occurring KIM-1 in disease-state urine. Next, a lateral flow assay (LFA) with capture and detection antibodies was constructed, and tested with 34 urine samples from healthy and diseased cats. Antibodies were also tested for reactivity with formalin-fixed paraffin-embedded kidney tissue. RESULTS: Three antibodies were assessed. Antibodies detected between 0.4 and 60 ng/ml feline KIM 1 fusion protein in the LFA. Urine samples from healthy cats yielded faint bands in the LFA corresponding to optical density (OD) values of 4.8-8.8. Samples from cats with suspected or confirmed acute kidney injury (AKI) had OD values ranging from 1.6-20.5. Urine KIM-1 varied over multiple days in cats with sepsis or urethral obstruction despite normalizing serum creatinine concentration. In tissue sections, KIM-1 antibodies labeled tubular cells with morphological features of injury. CONCLUSIONS AND RELEVANCE: A practical patient-side assay for detection of KIM-1 in feline urine has been developed. Preliminary results show marked though transient increases in cats with sepsis and urethral obstruction associated AKI, and expression in injured tubules. Although initial data indicating that the LFA is sensitive and specific for KIM-1 in cats with AKI are promising, values associated with different types of injury, urine collection, urine storage and specific gravity need to be investigated. PMID- 30461329 TI - Association Between Cigarette Smoking and Diabetic Foot Healing: A Systematic Review and Meta-Analysis. AB - The role of smoking for wound healing in patients with diabetic foot has been unclear. This meta-analysis examined the relationship between cigarette smoking and diabetic foot wound healing. Observational studies for the association between smoking and diabetic foot wound healing of patients were systematically searched through PubMed and Wanfang Data, published up to June 2018. Healing rates of wounds were recognized as outcomes. Meta-analysis models were chosen by heterogeneity. A total of 3388 eligible studies were identified, of which 18 met all our inclusion criteria. In the smoking group, healing rate had an average of 62.1%, ranging from 20.0% to 89.6%; in the nonsmoking group, healing rate had an average of 71.5%, ranging from 40.2% to 93.8%. A significant association was found between smoking and the healing of diabetic foot wounds ( z = 3.08; P = .002), with an odds ratio (OR) of 0.70 (95% CI = 0.56-0.88), based on a random effects model. Meta-regression analyses indicated that the heterogeneity did not come from publication year ( t = -0.50, P = .622) or overall healing rate ( t = 0.16, P = .872). The leave-one-out sensitivity analysis was robust; sensitivity analysis for pooled estimate of adjusted ORs had an OR of 0.20 (95% CI = 0.07 0.56; z = 3.08; P = .002). Subgroup analysis had an OR of 0.62 (95% CI = 0.41 0.95; z = 2.21; P = .027) in retrospective cohort studies and had an OR of 0.75 (95% CI = 0.57-0.99; z = 2.02; P = .043) in prospective cohort studies. Our meta analysis indicated that smoking had an overall negative effect on the wound healing of diabetic foot individuals. This study provides evidence for the harm of smoking to diabetic foot and may help reduce the medical and economic burden on poor healing of diabetic foot. PMID- 30461330 TI - A cost-effectiveness analysis comparing the originator follitropin alfa to its biosimilars in patients undergoing a medically assisted reproduction program from a French perspective. AB - OBJECTIVE: To assess the cost-effectiveness (CE) of the originator follitropin alpha (Gonal-F) in patients undergoing a medically assisted reproduction (MAR) program in comparison to its biosimilars Bemfola and Ovaleap in a French context. METHODS: A CE model was developed for France with a National Health Service (NHS) perspective. Clinical, safety, and dosage data were derived from pivotal clinical trials that compared Gonal-F to Ovaleap and Bemfola. Costs pertaining to drugs, hospitalizations, specialist visits, and examinations were retrieved from the French Programme de Medicalisation des Systemes d'Information (PMSI) hospital database, literature review, and French clinical experts using 2017 Euro tariffs. In order to test the robustness of results, deterministic one-way sensitivity analyses were carried out on the main variables to assess the impact of treatment cost, probability of birth, ovarian hyperstimulation syndrome (OHSS) rates, and dosage. RESULTS: The average incremental cost per live birth with OHSS and without OHSS was ?259.56 and ?278.39, respectively for Gonal-F compared to the pooled biosimilars (i.e., Ovaleap and Bemfola). GONAL-F had an incremental efficacy of 0.06 over the pooled biosimilars. The incremental cost-effectiveness ratio for Gonal-F with OHSS ranged from ?3,274.80 to ?4,877.76 compared to the pooled biosimilars, owing to the additional live births reported with Gonal-F. Sensitivity analyses also supported results from the base case analyses, with Gonal-F being cost-effective or the dominant strategy in most cases. CONCLUSION: Gonal-F seems to be a cost-effective strategy compared to its biosimilars Ovaleap and Bemfola, irrespective of the incidence of OHSS events, but further data are needed to confirm these results. PMID- 30461331 TI - Does the duration of motor imagery affect the excitability of spinal anterior horn cells? AB - PURPOSE: Motor imagery, the process of imagining a physical action, has been shown to facilitate the excitability of spinal anterior horn cells. In the acute phase after a stroke, the excitability of spinal anterior horn cells is significantly reduced, which leads to motor deficits. This loss of movement can be prevented by increasing the excitability of spinal anterior horn cells immediately following an injury. Motor imagery is an effective method for facilitating the excitability of spinal anterior horn cells in patients with impaired movement; however, the optimal duration for motor imagery is unclear. MATERIALS AND METHODS: To investigate time-dependent changes in spinal anterior horn cell excitability during motor imagery, healthy adult participants were recruited to measure the F-wave, an indicator of anterior horn cell excitability. F-waves were measured from participants at baseline, during motor imagery, and post-motor imagery. During motor imagery, participants imagined isometric thenar muscle activity at 50% maximum voluntary contraction for 5 min. F-waves were measured at 1, 3, and 5 min after beginning motor imagery and analysed for persistence and F/M amplitude ratio. RESULTS: Persistence and F/M amplitude ratios at 1- and 3-min after motor imagery initiation were significantly greater than at baseline. The persistence and F/M amplitude ratio at 5-min after motor imagery initiation, however, was comparable to baseline levels. CONCLUSION: Therefore, 1 to 3 min of motor imagery is likely sufficient to facilitate the excitability of spinal anterior horn cells. PMID- 30461332 TI - Toxicity of ZnO nanoparticles (NPs) to THP-1 macrophages: interactions with saturated or unsaturated free fatty acids. AB - In a biological microenvironment, free fatty acids (FFA) as ubiquitous biological molecules might interact with nanoparticles (NPs) and consequently change the toxicological responses. However, whether the chemical structures of FFA could influence their interactios with NPs remains unknown. This study investigated the interactions between ZnO NPs and saturated or unsaturated FFA (complexed to BSA), namely stearic acid (SA, C18:0), oleic acid (OA, C18:1), and alpha-linolenic acid (ALA, C18:3). It was shown that BSA, SA, OA and ALA increased the atomic force microscope (AFM) heights as well the the polydispersity index (PDI) of ZnO NPs. BSA modestly protected THP-1 macrophages from ZnO NP exposure, whereas OA and ALA led to relatively less cyto-protective effects of BSA. Moreover, only co-exposure to ZnO NPs and SA significantly promoted the release of interleukin-8 (IL-8). BSA, SA, OA and ALA equally changed intracellular ROS and Zn ions associated with ZnO exposure, but co-exposure to ZnO NPs and OA/ALA particularly activated the expression of ER stress-apoptosis genes. In combination, these results showed that FFA could influence the colloidal aspects and toxicological signaling pathway of ZnO NPs, which is dependent on the number of unsaturated bonds of FFA. PMID- 30461334 TI - Repeated transhepatic tunnelled catheter insertion for dialysis access. PMID- 30461333 TI - Long non-coding RNA MEG3 suppresses the development of bladder urothelial carcinoma by regulating miR-96 and TPM1. AB - We aimed at investigating effects of long non-coding RNA maternally expressed 3 (MEG3) on the proliferation, cell cycle and apoptosis of bladder urothelial carcinoma cells and regulatory relationships among lncRNA MEG3, miR-96 and alpha tropomyosin 1 (TPM1). Human clinical data from The Cancer Genome Atlas (TCGA) which contains bladder urothelial carcinoma tissues and adjacent tissues were used for analysis. The expression profiles of MEG3, miR-96, TPM1, cell cycle related genes and apoptosis-related genes were examined by real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. Regulating relationship among MEG3, miR-96 and TPM1 was confirmed by dual luciferase reporter assay. MTT assay and flow cytometry were performed to observe cell proliferation, cell cycle and apoptosis. The effects of lncRNA MEG3 on bladder urothelial carcinoma were confirmed both in vivo and in vitro. The mRNA expression and protein expression of MEG3, TPM1 were down-regulated in carcinoma tissues, whereas miR-96 expression was up-regulated. MEG3 overexpression resulted in miR-96 downregulation along with TPM1 upregulation, which inhibited cell proliferation and cell cycle but promoted cell apoptosis of bladder urothelial carcinoma cells in vitro, and at the same time inhibited tumor growth in vivo. In this process, expressions of apoptosis-related protein BCL2 associated X (Bax), cleaved-caspase 3 was up regulated, whereas apoptosis regulator protein (Bcl-2) expression was suppressed when MEG3 was overexpressed, and cell cycle-related protein Cyclin D1 was down regulated. LncRNA MEG3 low-expression promotes the proliferation and inhibits apoptosis of bladder urothelial carcinoma cells by regulating miR-96 along with TPM1. PMID- 30461335 TI - A Chemical Approach to Optimizing Bioactive Glass Dental Composites. AB - The chemical microenvironment surrounding dental composites plays a crucial role in controlling the bacteria grown on these specialized surfaces. In this study, we report a scanning electrochemical microscopy (SECM)-based analytic technique to design and optimize metal ion-releasing bioactive glass (BAG) composites, which showed a significant reduction in biofilm growth. SECM allows positioning of the probe without touching the substrate while mapping the chemical parameters in 3-dimensional space above the substrate. Using SECM and a solid-state H+ and Ca2+ ion-selective microprobe, we determined that the local Ca2+ concentration released by different composites was 10 to 224 uM for a BAG particle size of <5 to 150 um in the presence of artificial saliva at pH 4.5. The local pH was constant above the composites in the same saliva solution. The released amount of Ca2+ was determined to be maximal for particles <38 um and a BAG volume fraction of 0.32. This optimized BAG-resin composite also showed significant inhibition of biofilm growth (24 +/- 5 um) in comparison with resin-only composites (53 +/- 6 um) after Streptococcus mutans bacteria were grown for 3 d in a basal medium mucin solution. Biofilm morphology and its subsequent volume, as determined by the SECM imaging technique, was (0.59 +/- 0.38) * 107 um3 for BAG-resin composites and (1.29 +/- 0.53) * 107 um3 for resin-only composites. This study thus lays the foundation for a new analytic technique for designing dental composites that are based on the chemical microenvironment created by biomaterials to which bacteria have been exposed. PMID- 30461336 TI - Subcutaneous bleeding from arteriovenous fistula cannulation causes skin complication mimicking compartment syndrome. PMID- 30461337 TI - Dienogest for Treatment of Endometriosis in Women: A 28-Week, Open-Label, Extension Study. AB - BACKGROUND: Dienogest provided significantly greater reduction in endometriosis associated pelvic pain (EAPP) than placebo in a 24-week, randomized, double-blind study of Chinese women with endometriosis. The current open-label extension study investigated the efficacy and safety of dienogest for 28 additional weeks in this population. PATIENTS AND METHODS: Women with endometriosis were eligible to enroll at completion of the 24-week, placebo-controlled study (n = 220). All women, regardless of prior study treatment, received dienogest 2 mg once daily for up to 28 weeks. Absolute change in EAPP from baseline on a 1-100 mm visual analog scale (VAS), bleeding pattern, adverse events (AEs), laboratory parameters, and bone mineral density (BMD) were evaluated. RESULTS: The open label study was completed by 203 (92.3%) women. At the end of open-label study, mean (SD) change from baseline in EAPP score on VAS was -43.1 mm (26.54 mm) and 39.8 mm (31.15 mm) in the prior-dienogest and prior-placebo groups, respectively. Other assessments confirmed that dienogest maintained or enhanced efficacy after 28 weeks of additional treatment. Dienogest initiation was associated with longer, but fewer, spotting/bleeding episodes. Bleeding frequency and intensity decreased progressively during continued treatment. Treatment-emergent AEs, generally mild or moderate, led to withdrawal in 2 (0.9%) patients during the open-label study. Dienogest had no effect on BMD. CONCLUSIONS: Dienogest 2 mg once daily is effective and safe in the long-term management of EAPP in Chinese women with endometriosis, with progressive decreases in EAPP and bleeding irregularities during continued treatment. Efficacy and safety results of this study were consistent with previous studies in Caucasian patients. PMID- 30461338 TI - Sulfur-Functionalized Fullerene Nanoparticle as an Inhibitor and Eliminator Agent on Pseudomonas aeruginosa Biofilm and Expression of toxA Gene. AB - Over the last decade, nanotechnology-based therapeutic platforms have been directed toward developing nanoparticles with unique properties to combat biofilms. In this study, we evaluated the antibiofilm activity of the sulfur functionalized fullerene nanoparticles (SFF Nps) against Pseudomonas aeruginosa and also analyzed the effect of this nanoparticle on the expression of exotoxin A (toxA) gene. The functionalized fullerenes were prepared by chemical vapor deposition method. We assessed the potential of SFF Nps to inhibit biofilm formation and eradicate preformed biofilms. Also, the effect of this nanoparticle on the expression of toxA gene was investigated by real-time PCR. The minimum biofilm inhibitory concentration of SFF Nps was 1 mg/mL. The minimum biofilm eradication concentration of SFF Nps on the young (24- and 48-hr old) and older (72- and 96-hr old) biofilms was 2 and 4 mg/mL, respectively. Field emission electron scanning microscopy images confirmed the potent ability of SFF Nps to eradicate biofilm of P. aeruginosa. The expression of toxA was downregulated in the presence of SFF Nps. In conclusion, considering the ability of SFF Nps to kill P. aeruginosa biofilm and downregulate the expression of exotoxin A, this nanoparticle can be used for treatment of both chronic and acute P. aeruginosa infections. PMID- 30461339 TI - Stress and Coping Profiles and Cardiometabolic Risk in Low-Income African American Women. AB - BACKGROUND: The complex interplay of psychological stress appraisal, biology, chronically stressful environments, and individual coping mechanisms can impact and tax physiological adaptive processes. This can result in increased cardiometabolic risk (CMR), type 2 diabetes, and cardiovascular disease. Underlying mechanisms are not entirely clear and appear to differ significantly based on age, sex, race, and ethnicity. PURPOSE: This cross-sectional descriptive study explored stress profiles of psychological and behavioral adjustment to determine the extent to which patterns of stressors, coping, and CMR differentiated these profiles. MATERIALS AND METHODS: African American (AA) women (N = 110; M age = 38.61 years, SD = 6.94 years) were recruited from low-income communities and participated in two home visits to complete stress and coping and cardiovascular risk measures. RESULTS: Three distinct stress and coping adjustment profiles were associated with differences in CMR. The "holding steady" profile had less insulin resistance (IR) and substance use compared to "high substance users" and "high internalizers" profiles. Women who were "holding steady" used less avoidant coping than "high internalizers." CONCLUSIONS: Less favorable adjustment processes were associated with IR, as well as significantly higher levels of avoidant coping and substance use. In AA women, awareness of and attention to stress and coping patterns may help attenuate CMR. PMID- 30461340 TI - The Importance of Design Validation in Global Health Surgical Innovation. AB - INTRODUCTION: Medical technology development requires an understanding of user needs and environmental requirements. Accurately capturing market requirements, user needs, and design specifications are multifactorial and challenging. On-site observation and design validation may lead to development of more effective solutions to improve health care. This study was designed to evaluate the value of design validation for medical devices developed to address global medical needs. METHODS: Observational comparative analysis and survey studies were used to collect data involving multiple stakeholder viewpoints. User needs, market requirements, and design inputs were created using standard operating procedures in accordance with US FDA-21 CFR 820. Design requirements included user needs, product description, regulatory standards, functional requirements, performance and physical requirements, use environment, human-system interfacing, conceptual designs, and market analysis. A random population-based cohort sample in India was used to conduct a semi-longitudinal assessment of exposure-outcome relations from device prototype use and design validation. Seventy-two subjects were observed for a 4-week duration. After validation, each component of the traceability matrix was either marked "no change," "significant change," or "new addition" as defined in the methods section. RESULTS: A total of 198 design requirements and specifications were evaluated for each device. Eleven percent of the final design requirements and specifications were "new additions" and 12% were "significant changes." CONCLUSION: Assessment of design requirements and specifications in the global environment improves medical device design quality and safety. This study validates environmental immersion in the target use environment early to ensure validation of user needs and design specifications during design conception. PMID- 30461341 TI - Individual, Environmental, and Early Life Factors Associated With Client Perpetrated Violence Among Women Who Exchange Sex in New York City, 2016. AB - Women who exchange sex are at an increased risk of violence from both clients and nonpaying intimate partners. This study utilizes data from the 2016 New York City National HIV Behavioral Surveillance Study cycle focused on high-risk women to examine factors associated with experiencing client-perpetrated violence (CPV). Women who exchanged sex for money or drugs ( n = 330) were recruited via respondent-driven sampling. Adjusted log-linked Poisson regression was used to analyze individual, environmental, and early-life factors associated with experiencing CPV in the past 12 months. Compared with women who did not experience CPV, women who experienced CPV were more likely to have a household income of <$10,000 (adjusted prevalence ratio [aPR]: 2.15; 95% confidence interval [CI]: [1.29, 3.57]), have a same-sex partnership (aPR: 2.31; 95% CI: [1.23, 4.33]), have > 2 male exchange sex partners (aPR: 2.76; 95% CI: [1.28, 5.99]), find clients on the street (aPR: 2.10; 95% CI: [1.05, 3.99]), have been refused help from or avoided the police due to exchange sex (aPR: 1.88; 95% CI: [1.06, 3.32]) and to have experienced sexual violence as a minor (aPR: 2.16; 95% CI: [1.29, 3.30]). Multilevel approaches to violence prevention among women who exchange sex, particularly those who find clients on the street, should be considered. PMID- 30461342 TI - Percutaneous retrieval of a fractured HeRO graft venous outflow component with endobronchial forceps. PMID- 30461343 TI - Impact of inoculum acclimation on energy recovery and investigation of microbial community changes during anaerobic digestion of the chicken manure. AB - The aim of this study was to assess the effect of inoculum adaptation on biogas recovery from two identical lab-scale semi-continuous anaerobic digesters (AD) treating chicken waste (i.e., TS and VS contents of ca. 6.2% and 2.9%, respectively) at mesophilic condition (35 degrees C). For the first two months; one of the AD was run with adapted whereas the second AD was run with unadapted granular sludge to chicken manure which was further operated for about 100 more days. In this scope, qPCR analysis and Illumina sequencing were also used to detect microbial community changes inside anaerobic reactors. Molecular analyzes revealed that the number of archaea was significantly higher than that of overall archaea compared to the values obtained at the start-up time and methanogens also increased as operation continued. On the other hand, although average daily biogas production was about 25% higher in adapted AD compared to unadapted AD (i.e., biogas yields were ca. 0.6 and 0.7 m3/kg VSfeed, respectively), there was not meaningful change in archaea numbers at the end of operation. These suggest that changes in the structure of a microbial community lead to changes in biogas production and controlling ultimate methanogenic archaeal community may promote successful methane production in anaerobic reactors. PMID- 30461344 TI - Problematic Pornography Use and Physical and Sexual Intimate Partner Violence Perpetration Among Men in Batterer Intervention Programs. AB - Recent decades witnessed a surge in pornography use, contributing to what some researchers referred to as problematic pornography use (PPU; excessive, compulsive, and uncontrollable pornography use). Informed by cognitive scripts theory, cross-sectional, longitudinal, and experimental research spanning several decades documented a positive association between men's pornography use and physical and sexual violence perpetration. However, there is a paucity of research investigating pornography use broadly, and PPU specifically, among men who perpetrate intimate partner violence (IPV). The present cross-sectional study investigated the association between self-reported PPU and physical and sexual IPV perpetration among 273 men in batterer intervention programs. After accounting for psychiatric symptomology and substance use and problems, results revealed a positive association between PPU and both physical and sexual IPV perpetration. Findings highlighted the need for continued investigation of the function of pornography use for violent men, particularly as it relates to physical and sexual IPV perpetration. PMID- 30461345 TI - Laparoscopic Redo Pull-Through for Hirschsprung Disease Due to Innervation Disorders. AB - BACKGROUND: Reoperations in Hirschsprung disease (HD) may be required due to pathological problems. We conducted this retrospective study to determine the incidence and outcomes of innervation disorders among HD patients following pull through operation. MATERIALS AND METHODS: We retrospectively reviewed the data of patients who underwent pull-through procedure from 2005 to 2017. Only patients who underwent reoperation due to histological disorders were analyzed. Patients with mechanical obstruction that caused recurrent constipation were excluded. RESULTS: There were 836 patients who got treated for HD in our department during the study period, and of these, 72 (8.6%) had redo operation. Thirty-one out of the 72 patients (43.1%) showed abnormal histological findings on full-thickness biopsies. Primary operations included totally transanal endorectal pull-through (18), laparoscopic-assisted Duhamel (5) and Soave (8) techniques. The full thickness biopsies before the reoperation showed aganglionosis (n = 8, 1 was residual resulted from false-positive intraoperative frozen sections and 7 were acquired aganglionosis), transition-zone (3), intestinal neuronal dysplasia B (IND B, n = 15), and hypoganglionosis (5). The final diagnoses according to the resection specimens of the initial and second operations were HD (11), Hirschsprung-associated IND B (15), and Hirschsprung-associated hypoganglionosis (5). Reoperation consisted of laparoscopic-assisted Duhamel (14) and Soave procedures (17). In these patients, 77.4% had excellent/good bowel function, 16.1% were fair, and 6.5% were poor. CONCLUSIONS: Innervation disorders are still the underlying causes of recurrent constipation in almost half of all HD patients requiring redo pull-through operation. Most patients have a satisfactory outcome after redoing laparoscopic-assisted Duhamel or Soave operation. PMID- 30461346 TI - Recipes for Prevention: An Analysis of Intimate Partner Violence Messages on Pinterest. AB - Social media platforms such as Pinterest are often used as venues for discussing relationships, making them ideal channels for promoting healthy relationships and preventing intimate partner violence (IPV). This is particularly relevant for IPV, which has been historically understood as a personal issue and lacked support as a significant public health issue. To explore its potential as a platform for prevention, this study examines the ways in which IPV messages on Pinterest reflect public health understandings of, and approaches to, prevention, and how Pinterest users engage with these posts. We analyzed 750 Pinterest posts about IPV using the Social Ecological Model as a theoretical framework for conceptualizing framing devices. The majority of pins (82.9%) used contextually focused thematic framing, while only 8.0% used individually focused episodic framing, and 4.4% used both. The predominance of thematic framing is contrary to findings in examinations of traditional media portrayals of IPV and is likely to facilitate sharing information and education about IPV. However, posts that mention individual causal attribution and individual solution responsibility elicit more engagement than pins that do not. Overall, the Pinterest sample was more reflective of the range of IPV experiences than previous, older analyses of traditional media content, possibly indicating that the public health approach to this issue is gaining momentum. Encouragingly, the study showed increased engagement with posts that discuss psychological abuse, indicating a potentially promising transition from an emphasis on physical abuse to the neglect of psychological abuse. Although Pinterest does still show some stereotypical portrayals of IPV similar to traditional media stories, it also shows much promise for shifting the narrative around IPV in line with the current public health approach and public health professionals should be encouraged to enter the dialogue on IPV on Pinterest. PMID- 30461347 TI - Developing a Research Agenda for Adult Palliative Care: A Modified Delphi Study. AB - BACKGROUND: Little is known about research priorities in adult palliative care. Identifying research priorities for adult palliative care will help in increasing research quality and translation. OBJECTIVE: The aim was to identify the views of health professionals' research priorities in adult palliative care that lead to development of a palliative care research agenda in Australia. DESIGN: A modified three-round Delphi survey. SETTING/SUBJECTS: Palliative care researchers and clinicians in Australia were invited to participate. RESULTS: A total of 25 panelists completed round 1, 14 completed round 2, and 13 completed round 3. Round 1 resulted in 90 research priorities in 13 categories. Round 2 showed consensus agreement on 19/90 research priorities. Round 3 resulted in the top 10 research priorities of the 19 achieving consensus in round 2. Panelists agreed that research is needed on the transition to palliative care; improving communication about prognosis; increasing access to palliative care for indigenous communities, people who wish to remain at home, and people in aged care; addressing family caregivers' needs; promoting patients' and families' decision making; improving cross-cultural aspects of palliative care; determining the effects of assisted dying legislation; and improving bereavement care in rural, remote, and Aboriginal populations. CONCLUSIONS: The expert panelists identified the top 10 research priorities for adult palliative care. These identified research priorities are the most urgent topics requiring attention to increase the quality of life of patients requiring palliative care and their family members. PMID- 30461348 TI - Use of an Interdisciplinary Student Medical Innovation and Entrepreneurship Program to Create Affordable Global Health Care Solutions. AB - BACKGROUND: Bench to Bedside is a 7-month-long medical innovation and entrepreneurship program at the University of Utah in which teams comprising students from various disciplines work together to identify health care problems and develop novel technology solutions. Student teams are provided a small prototyping budget, access to device development workshops, prototyping facilities, and expert faculty and industry mentors. Teams then compete for seed funding at the Bench to Bedside competition at the end of the program. In 2014, we created global health-specific resources, mentorship, guidance, and award incentives as a means to drive global health technology development in the program and then studied our impact after 6 years. METHODS: We reviewed program data collected continuously between 2011 and 2018 to evaluate the impact of global health incentive initiatives on the development of global health-related technologies. We quantified the number of global health teams based on both team declared data and objective evaluation of each competing technology. RESULTS: The initiation of global health technology incentives was associated with an annual overall doubling of teams pursuing the development of global health-related technologies from an average of 11.4% to 24.8% ( P = .003). CONCLUSIONS: A student medical technology innovation program designed to address global health needs is an effective means of generating new solutions to improve global health care. The use of global health-specific awards and mentors raised awareness of the need for affordable global solutions and incentivized teams to pursue development. PMID- 30461349 TI - Stability and structure of Penicillium chrysogenum lipase in the presence of organic solvents. AB - The present work describes the enzymatic properties of Penicillium chrysogenum lipase and its behavior in the presence of organic solvents. The temperature and pH optima of the purified lipase was found to be 55 degrees C and pH 8.0 respectively. The lipase displayed remarkable stability in both polar and non polar solvents upto 50% (v/v) concentrations for 72 h. A structural perspective of the purified lipase in different organic solvents was gained by using circular dichroism and intrinsic fluorescence spectroscopy. The native lipase consisted of a predominant alpha-helix structure which was maintained in both polar and non polar solvents with the exception of ethyl butyrate where the activity was decreased and the structure was disrupted. The quenching of fluorescence intensity in the presence of organic solvents indicated the transformation of the lipase microenviroment P. chrysogenum lipase offers an interesting system for understanding the solvent stability mechanisms which could be used for rationale designing of engineered lipase biocatalysts for application in organic synthesis in non-aqueous media. PMID- 30461350 TI - Current status of Fusarium oxysporum formae speciales and races. AB - The Fusarium oxysporum species complex includes both plant pathogenic and non pathogenic strains, which are commonly found in soils. F. oxysporum has received considerable attention from plant pathologists for more than a century owing to its broad host range and the economic losses it causes. The narrow host specificity of pathogenic strains has led to the concept of formae speciales, each forma specialis grouping strains with the same host range. Initially restricted to one plant species, this host range was later found to be broader for many formae speciales. In addition, races were identified in some formae speciales, generally with cultivar-level specialization. In 1981, Armstrong and Armstrong listed 79 F. oxysporum formae speciales and mentioned races in 16 of them. Since then, the known host range of F. oxysporum has considerably increased, and many new formae speciales and races have been identified. We carried out a comprehensive search of the literature to propose this review of F. oxysporum formae speciales and races. We recorded 106 well-characterized formae speciales, together with 37 insufficiently documented ones, and updated knowledge on races and host ranges. We also recorded 58 plant species/genera susceptible to F. oxysporum but for which a forma specialis has not been characterized yet. This review raises issues regarding the nomenclature and the description of F. oxysporum formae speciales and races. PMID- 30461351 TI - Ciprofloxacin Promoted qnrD Expression and Phylogenetic Analysis of qnrD Harboring Plasmids. AB - Morganella morganii SE10MM harboring quinolone resistance determinant qnrD was investigated in our study. An entirely sequenced novel 2,662 bp qnrD-plasmid pSE10MM was identified and deposited at GenBank under accession number KU160530. Nucleic acid sequence of pSE10MM showed 94-97% similarity to previously detected qnrD-plasmids of Proteus mirabilis strains. Phylogenetic analysis by Geneious 9.0.5 showed clusters of plasmids with possible common origin. Initial expression of qnrD gene was found 12.5 normalized to rpoB housekeeping gene. Subsequently, a sub-minimum inhibitory concentration (1 mg/L) ciprofloxacin exposure resulted in a fold change of 30.06 at 24 hours. In contrast, qnrD-plasmid pSE10MM copy number increased in time from 1.1 to 6.63. Chromosomal mutations of gyrA with S83I, gyrB with S463A, and parC with S80I amino acid substitutions were detected, but no other mutations have occurred as a consequence of ciprofloxacin exposure. Elevated expression of qnrD correlated with that of recA in M. morganii during ciprofloxacin exposure, which indicates SOS-dependent regulation of qnrD. Protective effect of QnrD plays a role in fluoroquinolone-resistant strain even in the presence of chromosomal mutations in gyrase and topoisomerase IV. PMID- 30461352 TI - Histologically Verified Biliary Invasion was Associated with Impaired Liver Recurrence-Free Survival in Resected Colorectal Cancer Liver Metastases. AB - BACKGROUND AND AIMS:: The impact of biliary invasion on recurrence and survival, after resection of colorectal cancer liver metastases, is not well known as publications are limited to small patient series. The aim was to investigate if biliary invasion in liver resected patients associated with liver relapses and recurrence-free survival. Secondary endpoints included association with other prognostic factors, disease-free survival and overall survival. MATERIALS AND METHODS:: All patients with histologically verified biliary invasion (n = 31, 9%) were identified among 344 patients with liver resection between January 2009 and March 2015. Controls (n = 78) were selected from the same time period and matched for, among others, size and number of colorectal cancer liver metastasis. RESULTS:: Median liver recurrence-free survival was significantly shorter in patients with biliary invasion than in controls (15.3 months versus not reached; p = 0.031) and more relapses were noted in the liver (61.3% versus 33.3%; p = 0.010), respectively. In univariate analyses for liver recurrence-free survival, biliary invasion was the only significant prognostic factor; p = 0.034. There were no statistical differences in disease-free and overall survival between the groups. CONCLUSION:: Biliary invasion was associated with higher liver recurrence rates and shorter liver recurrence-free survival in patients with resected colorectal cancer liver metastasis. PMID- 30461353 TI - Discrimination of epileptogenic lesions and perilesional white matter using diffusion tensor magnetic resonance imaging. AB - The aim of this study was to evaluate whether ganglioglioma (GGL), dysembryoplastic neuroepithelial tumour (DNET) and FCD (focal cortical dysplasia) are distinguishable through diffusion tensor imaging. Additionally, it was investigated whether the diffusion measures differed in the perilesional (pNAWM) and in the contralateral normal appearing white matter (cNAWM). Six GGLs, eight DNETs and seven FCDs were included in this study. Quantitative diffusion measures, that is, axial, radial and mean diffusivity and fractional anisotropy, were determined in the lesion identified on isotropic T2 or FLAIR-weighted images and in pNAWM and cNAWM, respectively. DNET differed from FCD in mean diffusivity, and GGL from FCD in radial diffusivity. Both types of glioneuronal tumours were different from pNAWM in fractional anisotropy and radial diffusivity. For identifying the tumour edges, threshold values for tumour-free tissue were investigated with receiver operating characteristic analyses: tumour could be separated from pNAWM at a threshold <= 0.32 (fractional anisotropy) or >= 0.56 (radial diffusivity) *10-3 mm2/s (area under the curve 0.995 and 0.990 respectively). While diffusion parameters of FCDs differed from cNAWM (radial diffusivity (*10-3 mm/s2): 0.74 +/- 0.19 vs. 0.43 +/- 0.05; corrected p-value < 0.001), the pNAWM could not be differentiated from the FCD. PMID- 30461354 TI - Shooting soldiers: civil war medical photography by R.B. Bontecou. PMID- 30461355 TI - A backward glance at 50. PMID- 30461356 TI - Historic gallery: a look back at some early gallery highlights. PMID- 30461357 TI - MSc medical visualisation and human anatomy. PMID- 30461358 TI - Children's Participation in Household Tasks: Caregiver Importance and Satisfaction. AB - Attribution of importance and satisfaction with performance are key dimensions contributing to engagement in occupations. This study explored caregiver satisfaction with and importance attributed to the participation of their children and adolescents in household tasks. Participants included 109 caregivers of children and adolescents of both sexes, aged 6 to 14 years, from various socioeconomic levels. They were interviewed with two questions of the Children Helping Out: Responsibilities, Expectations and Supports (CHORES), with ratings of importance and satisfaction on Likert-type scales, and asked to explain their ratings. We examined the association between the two dimensions. Results showed no correlation between caregivers' ratings of satisfaction and importance ( rs = .04; p = .699). The majority of caregivers evaluated their children's participation in domestic care as very important, explaining in terms of the need for children's autonomy in adulthood. Caregivers' satisfaction was attributed to children's attitudes. The expressed ideal of children's future autonomy by caregivers is not converted to current engagement in household task. PMID- 30461359 TI - Managing Stigma: Young People, Asthma, and the Politics of Chronic Illness. AB - In this article, we explore the relationship between asthma and stigma, drawing on 31 interviews with young people (aged 5-17) in Ireland. Participants with mild to moderate asthma were recruited from Traveller and middle-class settled communities. Themes derived from an abductive approach to data analysis and a critical appreciation of Goffmanesque sociology include asthma as a discreditable stigma, negative social reactions (real, imagined, and anticipated), and stigma management. Going beyond a personal tragedy model, we reflect upon macro-social structures (e.g., ethnicity, class, gender) which underlie stigma and the management of a potentially spoiled identity. This raises issues about the politics of chronic illness, embodying health identities and efforts to tackle stigma in neoliberal times. PMID- 30461360 TI - Contribution of Vaccination to Human Health. PMID- 30461361 TI - A comparative study of the bispecific monoclonal antibody, blinatumomab expression in CHO cells and E. coli. AB - The "bispecifics" market improved over the past decade due to the development of many technological platforms including bispecific T cell engagers (BiTEs). The approval of blinatumomab, the most advanced bispecific T-cell engager (BiTE) in clinical trials, can be a significant milestone in the development of bispecific antibodies. Both Chinese hamster ovary (CHO) cells and E. coli strain are considered as the most widely used hosts for the large-scale production of therapeutic monoclonal antibodies. Since both of the economic and qualitative aspects of protein production are important in industry, selection of a suitable protein expression system is very critical. The BsAb gene was cloned into the expression vectors FC550A-1, pcDNA3.1 (+), and PET22b and 6 * His-tagged BsAb then purified on a Ni-NTA chromatography column. Both SDS-PAGE and Western blotting analysis of the purified protein demonstrated that blinatumomab was successfully expressed as a 55 kDa in both expression systems. The antigen binding properties of blinatumomab were compared in the mammalian system versus Escherichia coli. The results showed that the purified antibody from a mammalian expression system has better binding activity than the one from E. coli host. PMID- 30461362 TI - Co-localization of Distinct NMDA Receptor Subtypes at Excitatory Synapses in the Entorhinal Cortex. AB - The subunit composition of N-methyl-D-aspartate receptors (NMDARs) at synaptic inputs onto a neuron can either vary or be uniform depending on the type of neuron and/or brain region. Excitatory pyramidal neurons in the frontal and somatosensory cortices (L5), for example, show pathway-specific differences in NMDAR subunit composition in contrast with the entorhinal cortex (L3) where we now show co-localization of NMDARs with distinct subunit compositions at individual synaptic inputs onto these neurons. Subunit composition was deduced electrophysiologically based on alterations of current-voltage relationship ( I V) profiles, amplitudes, and decay kinetics of minimally-evoked, pharmacologically isolated, NMDAR-mediated EPSCs by known subunit-preferring antagonists. The I-Vs were outwardly rectifying in a majority of neurons assayed (~80%), indicating expression of GluN1/GluN2/GluN3-containing triheteromeric NMDARs ( t-NMDARs), and of the conventional type, reversing close to 0 mV with prominent regions of negative slope, in rest of the neurons sampled (~20%), indicating expression of GluN1/GluN2-containing diheteromeric NMDARs ( d-NMDARs). Blocking t-NMDARs in neurons with outwardly rectifying I-Vs pharmacologically unmasked d-NMDARs, with all responses antagonized using D-AP5. Co immunoprecipitation assays of membrane bound protein complexes isolated from the medial entorhinal area using subunit-selective antibodies corroborated stoichiometry and together suggested the co-expression of t- and d-NMDARs at these synapses. Co-localization of functionally distinct NMDAR subtypes at individual synaptic inputs likely enhances the repertoire of pyramidal neurons for information processing and plasticity within the entorhinal cortex. PMID- 30461363 TI - The noradrenergic and serotonergic contributions to Diffuse Noxious Inhibitory Controls over the course of the monoiodoacetate model of Osteoarthritis. AB - Osteoarthritis (OA) is a debilitating conditioning with pain as the major clinical symptom. Understanding the mechanisms that drive OA-associated chronic pain is crucial for developing the most effective analgesics. Although the degradation of the joint is the initial trigger for the development of chronic pain, the discordance between radiographic joint damage and the reported pain experience in patients, coupled with clinical features that cannot be explained by purely peripheral mechanisms, suggest there are often other factors at play. Therefore, this study considers the central contributions of chronic pain, using a monoiodoacetate model of OA. Particularly, this study explores the functionality of descending controls over the course of the model through assessing Diffuse Noxious Inhibitory Controls (DNIC). Early phase MIA animals have a functional DNIC system, while DNIC are abolished in late phase MIA animals, indicating a dysregulation in descending modulation over the course of the model. In early phase animals, blocking the actions of spinal alpha2 adrenergic receptors completely abolishes DNIC, while blocking the actions of spinal 5-HT7 receptors only partially decreases the magnitude of DNIC. However, activating the spinal alpha2-adrenergic or 5-HT7 receptors in late phase MIA animals restored DNIC-induced neuronal inhibition. This study confirms that descending noradrenergic signaling is crucial for DNIC expression. Furthermore, we suggest a compensatory increase in descending serotonergic inhibition acting at 5-HT7 receptors as the model progresses, such that receptor activation is sufficient to override the imbalance in descending controls and mediate neuronal inhibition. PMID- 30461364 TI - Intersegmental coordination patterns are differently affected in Parkinson's disease and cerebellar ataxia. AB - The law of intersegmental coordination (Borghese et al. 1996) may be altered in pathological conditions. Here we investigated the contribution of the basal ganglia (BG) and the cerebellum to lower limb intersegmental coordination by inspecting the plane's orientation and other parameters pertinent to this law in patients with idiopathic Parkinson's disease (PD) or cerebellar ataxia (CA). We also applied a mathematical model that successfully accounts for the intersegmental law of coordination observed in control subjects (Barliya et al . 2009). In the present study, we compared the Planarity Index (PI), covariation plane (CVP) orientation and CVP orientation predicted by the model in 11 PD patients, 8 CA patients and two groups of healthy subjects matched for age, height, weight and gender to each patient group (Ctrl_PD and Ctrl_CA). Controls were instructed to alter their gait speed to match those of their respective patient group. PD patients were examined after overnight withdrawal of anti parkinsonian medications (PD-off-med) and then on medication (PD-on-med). PI was above 96% in all gait conditions in all groups suggesting that the law of intersegmental coordination is preserved in both BG and cerebellar pathology. However, the measured and predicted CVP orientations rotated in PD-on-med and PD off-med compared to Ctrl_PD and in CA versus Ctrl_CA. These rotations caused by PD and CA were in opposite directions suggesting differences in the roles of the BG and cerebellum in intersegmental coordination during human locomotion. PMID- 30461365 TI - Dentate spikes and learning: Disrupting hippocampal function during memory consolidation can improve pattern separation. AB - Hippocampal dentate spikes (DSs) are short-duration, large-amplitude fluctuations in hilar local-field potentials and take place while resting and sleeping. During DSs, dentate gyrus (DG) granule cells increase firing while CA1 pyramidal cells decrease firing. Recent findings suggest DSs play a significant role in memory consolidation after training on a hippocampus-dependent, non-spatial associative learning task. Here, we aimed to find out if DSs are important in other types of hippocampus-dependent learning tasks as well. To this end, we trained adult male Sprague-Dawley rats in a spatial reference memory task, a fixed interval task and in a pattern separation task. During a rest period immediately after each training session, we either let neural activity to take place as usual, timed electrical stimulation of the ventral hippocampal commissure (vHC) to immediately follow DSs, or applied the vHC stimulation during a random neural state. We found no effect of vHC stimulation on performance in the spatial reference memory task or in the fixed interval task. Surprisingly, vHC stimulation, especially contingent on DSs, improved performance in the pattern separation task. In conclusion, the behavioral relevance of hippocampal processing and DSs seems to depend on the task at hand. It could be that in an intact brain, offline memory consolidation by default involves associating neural representations of temporally separate but related events. In some cases this might be beneficial for adaptive behavior in the future (associative learning), while in other cases it might not (pattern separation). PMID- 30461366 TI - Response properties of single neurons in higher-level auditory cortex of adult songbirds. AB - The caudo-medial nidopallium (NCM) is a higher-level region of auditory cortex in songbirds that has been implicated in encoding learned vocalizations and mediating perception of complex sounds. We made cell-attached recordings in awake adult male zebra finches ( Taeniopygia guttata) to characterize responses of single NCM neurons to playback of tones and songs. Neurons fell into two broad classes: narrow fast-spiking cells and broad sparsely-firing cells. Virtually all narrow-spiking cells responded to playback of pure tones, compared to approximately half of broad-spiking cells. In addition, narrow-spiking cells tended to have lower thresholds and faster, less variable spike onset latencies than did broad-spiking cells, as well as higher firing rates. Tonal responses of narrow-spiking cells also showed broader ranges for both frequency and amplitude compared to broad-spiking neurons, and were more apt to have V-shaped tuning curves compared to broad-spiking neurons, which tended to have complex (discontinuous), columnar, or O-shaped frequency response areas. In response to playback of conspecific songs, narrow-spiking neurons showed high firing rates and low levels of selectivity whereas broad-spiking neurons responded sparsely and selectively. Broad-spiking neurons in which tones failed to evoke a response showed greater song selectivity compared to those with a clear tuning curve. These results are consistent with the idea that narrow-spiking neurons represent putative fast-spiking interneurons, which may provide a source of intrinsic inhibition that contributes to the more selective tuning in broad-spiking cells. PMID- 30461367 TI - Temporal and spatial asymmetries during stationary cycling cause different feedforward and feedback modifications in the muscular control of the lower limbs. AB - Motor adaptations are useful for studying the way in which the lower limbs are controlled by the brain. However, motor adaptation paradigms for the lower limbs are typically based on locomotion tasks, where the necessity of maintaining postural stability is the main driver of adaptation and could possibly mask other underlying processes. In this study we investigated whether small temporal or spatial asymmetries can trigger motor adaptations during stationary cycling, where stability is not directly compromised. Fourteen healthy individuals participated in two experiments: in one of the experiments the angle between the crank arms of the pedals was altered by 10 degrees to induce a temporal asymmetry; in the other the length of the right pedal was shortened by 2.4 cm to induce a spatial asymmetry. We recorded the acceleration of the crank arms and the EMG signals of 16 muscles (8 per leg). The analysis of the accelerometer data was used to investigate the presence of motor adaptations. Muscle synergy analysis was performed on each side to quantify changes in neuromuscular control. We found that motor adaptations are present in response to temporal asymmetries and are obtained by progressively shifting the activation patterns of two synergies on the right leg. Spatial asymmetries, on the other hand, appear to trigger a feedback-driven response that does not present an aftereffect. This response is characterized by a step-like decrease in activity in the right gastrocnemius when the asymmetry is present and likely reflects the altered task demands. PMID- 30461368 TI - Neuromuscular junction abnormalities in a zebrafish loss-of-function model of TDP 43. AB - Almost 90% of ALS cases are characterized by the presence of aggregates of insoluble, misfolded cytoplasmic TAR DNA binding protein of 43 kDa (TDP-43). Distal axonopathy with impaired neuromuscular junctions (NMJs) prior to motor neuron degeneration or clinical onset of symptoms has been hypothesized as an early pathology in ALS. However, synaptic defects at the NMJ caused by TDP-43 mutations have not been characterized. In this study, we examined a previously reported zebrafish line expressing the tardbpY220X/Y220X variant, which results in an unstable and degraded protein. These tardbp-/- larvae, however, mature normally due to the upregulated expression of an alternative splice variant of the tardbp paralog tardbp-like, or tardbpl. We generated a mutant line with a CRISPR/Cas9-mediated 5 base pair deletion encompassing the ATG start codon of tardbpl and in-crossed these with tardbp-/- mutants to obtain tardbp-/- and tardbpl-/- double mutants herein, referred to as hom/hom. We subsequently characterized morphological, coiling, locomotor, synaptic and NMJ structural abnormalities in the hom/hom mutants and in their genotypic controls. We observed that hom/hom mutants displayed gross morphological defects, early lethality, reduced locomotor function, aberrant quantal transmission and perturbed synapse architecture at the NMJ. We further employed pharmacological manipulations in an effort to rescue phenotypic defects and observed that tardbp+/-; tardbpl-/- (herein referred to as het/hom) mutants, but not hom/hom mutants, were sensitive to chronic treatments of Bay K 8644, an L-type calcium channel agonist. This result highlights the importance of partial vs complete loss of allelic functions of TDP-43. PMID- 30461369 TI - Causal inference for spatial constancy across whole-body motion. AB - The brain uses self-motion information to internally update egocentric representations of locations of remembered world-fixed visual objects. If a discrepancy is observed between this internal update and reafferent visual feedback, this could be due to either an inaccurate update or because the object has moved during the motion. To optimally infer the object's location it is therefore critical for the brain to estimate the probabilities of these two causal structures and accordingly integrate and/or segregate the internal and sensory estimates. To test this hypothesis, we designed a spatial updating task involving passive whole-body translation. Participants, seated on a vestibular sled, had to remember the world-fixed position of a visual target. Immediately after the translation, the reafferent visual feedback was provided by flashing a second target around the estimated "updated" target location, and participants had to report the initial target location. We found that the participants' responses were systematically biased toward the position of the second target position for relatively small but not for large differences between the "updated" and the second target location. This pattern was better captured by a Bayesian causal inference model than by alternative models that would always either integrate or segregate the internally-updated target location and the visual feedback. Our results suggest that the brain implicitly represents the posterior probability that the internally updated estimate and the visual feedback come from a common cause, and use this probability to weigh the two sources of information in mediating spatial constancy across whole-body motion. PMID- 30461370 TI - Functional brainstem circuits for control of nose motion. AB - Rodents shift their nose from side to side when they actively explore and lateralize odors in the space. This motor action is driven by a pair of muscles, the deflector nasi. Here we study the premotor control of this motion. We use replication competent rabies virus to transsynaptically label inputs to deflector nasi. muscle and find putative premotor labeling throughout the parvocellular, intermediate, and gigantocellular reticular formations, the trigeminal nuclei, pontine reticular formation, midbrain reticular formation, red nucleus, and superior colliculus. Two areas with extensive labeling were analyzed for their impact on nose movement. One area is in the reticular formation caudal to the facial motor nucleus and is denoted the nose retrofacial area. The second is in the caudal part of the intermediate reticular region near the oscillator for whisking and denoted the nose IRt. Functionally, we find that optogenetic activation of glutamatergic cells in both areas drives deflection of the nose. Ablation of cells in the nose retrofacial area, but not the nose IRt, impairs movement of the nose in response to the presentation of odorants but otherwise leaves movement unaffected. These data suggest that the nose retrofacial area is a conduit for a sensory-driven orofacial motor action. Further, we find pre2motor labeling in the preBotzinger complex that presumably synchronizes a small, rhythmic component of nose motion to breathing. PMID- 30461371 TI - Interaction between TRPV1-expressing neurons in the hypothalamus. AB - Transient receptor potential vanilloid type 1 (TRPV1) is a ligand-gated ion channel expressed in the peripheral and central nervous system. TRPV1-dependent mechanisms take part in a wide range of physiological and pathophysiological pathways including the regulation of homeostatic functions. TRPV1 expression in the hypothalamus has been described as well as evidence that TRPV1-dependent excitatory inputs to hypothalamic preautonomic neurons are diminished in diabetic conditions. Here, we aimed to determine the functional expression of TRPV1 in two hypothalamic nuclei known to be involved in the central control of metabolism and test the hypothesis that TRPV1-expressing neurons receive TRPV1-expressing inputs. A mouse model (TRPV1Cre/tdTom) was generated to identify TRPV1-expressing cells and determine the cellular properties of TRPV1-expressing neurons in adult mice. Our study demonstrated the functional expression of TRPV1 in the dorsomedial hypothalamic nucleus (DMH) and paraventricular nucleus (PVN) in adult mice. Our findings revealed that a subset of TRPV1Cre/TdTom neurons receive TRPV1 expressing excitatory inputs indicating direct interaction between TRPV1 expressing neurons. In addition, astrocytes likely play a role in the modulation of TRPV1-expressing neurons. In summary, this study identified specific hypothalamic regions where TRPV1 is expressed and functional in adult mice, and the existence of direct connections between TRPV1Cre/tdTom neurons. PMID- 30461372 TI - Affective and emotional dysregulation as pre-dementia risk markers: exploring the mild behavioral impairment symptoms of depression, anxiety, irritability, and euphoria - CORRIGENDUM. AB - "Affective and emotional dysregulation as pre-dementia risk markers: exploring the mild behavioral impairment symptoms of depression, anxiety, irritability, and euphoria" by Ismail et al. published with an incorrect author's name, appearing as "Marc Chantillon". PMID- 30461373 TI - The resistomes of six carbapenem-resistant pathogens - a critical genotype phenotype analysis. AB - Carbapenem resistance is a rapidly growing threat to our ability to treat refractory bacterial infections. To understand how carbapenem resistance is mobilized and spread between pathogens, it is important to study the genetic context of the underlying resistance mechanisms. In this study, the resistomes of six clinical carbapenem-resistant isolates of five different species - Acinetobacter baumannii, Escherichia coli, two Klebsiella pneumoniae, Proteus mirabilis and Pseudomonas aeruginosa - were characterized using whole genome sequencing. All Enterobacteriaceae isolates and the A. baumannii isolate had acquired a large number of antimicrobial resistance genes (7-18 different genes per isolate), including the following encoding carbapenemases: blaKPC-2, blaOXA 48, blaOXA-72, blaNDM-1, blaNDM-7 and blaVIM-1. In addition, a novel version of blaSHV was discovered. Four new resistance plasmids were identified and their fully assembled sequences were verified using optical DNA mapping. Most of the resistance genes were co-localized on these and other plasmids, suggesting a risk for co-selection. In contrast, five out of six carbapenemase genes were present on plasmids with no or few other resistance genes. The expected level of resistance - based on acquired resistance determinants - was concordant with measured levels in most cases. There were, however, several important discrepancies for four of the six isolates concerning multiple classes of antibiotics. In conclusion, our results further elucidate the diversity of carbapenemases, their mechanisms of horizontal transfer and possible patterns of co-selection. The study also emphasizes the difficulty of using whole genome sequencing for antimicrobial susceptibility testing of pathogens with complex genotypes. PMID- 30461374 TI - Infection of covert mortality nodavirus in Japanese flounder reveals host jump of the emerging alphanodavirus. AB - Interspecies transmission of viruses, where a pathogen crosses species barriers and jumps from its original host into a novel species, has been receiving increasing attention. Viral covert mortality disease, caused by covert mortality nodavirus (CMNV), is an emerging disease that has recently had a substantial impact on shrimp aquaculture in Southeast Asia and Latin America. While investigating the host range of CMNV, we found that this virus is also capable of infecting populations of the farmed Japanese flounder Paralichthys olivaceus, a vertebrate host. The infected fish were being raised in aquaculture facilities that were also producing marine shrimp. Through RT-nPCR, targeting the RNA dependent RNA polymerase (RdRp) gene of CMNV, we found that 29 % of the fish sampled were positive. The amplicons were sequenced and aligned to the RdRp gene of shrimp CMNV and were found to have 98 % identity. Histopathological examination indicated that CMNV-positive fish showed vacuolation of nervous tissue in the eye and brain, as well as extensive necrosis of cardiac muscle. In situ hybridization showed positive reactions in tissues of the eye, brain, heart, liver, spleen and kidney of infected fish. Transmission electron microscopy showed the presence of CMNV-like particles in all of the above-mentioned tissues, except for brain. The novel finding of a shrimp alphanodavirus that can also infect farmed P. olivaceus indicates that this virus is capable of naturally crossing the species barrier and infecting another vertebrate. This finding will contribute to the development of efficient strategies for disease management in aquaculture. PMID- 30461375 TI - Resolving the complex Bordetella pertussis genome using barcoded nanopore sequencing. AB - The genome of Bordetella pertussis is complex, with high G+C content and many repeats, each longer than 1000 bp. Long-read sequencing offers the opportunity to produce single-contig B. pertussis assemblies using sequencing reads which are longer than the repetitive sections, with the potential to reveal genomic features which were previously unobservable in multi-contig assemblies produced by short-read sequencing alone. We used an R9.4 MinION flow cell and barcoding to sequence five B. pertussis strains in a single sequencing run. We then trialled combinations of the many nanopore user community-built long-read analysis tools to establish the current optimal assembly pipeline for B. pertussis genome sequences. This pipeline produced closed genome sequences for four strains, allowing visualization of inter-strain genomic rearrangement. Read mapping to the Tohama I reference genome suggests that the remaining strain contains an ultra long duplicated region (almost 200 kbp), which was not resolved by our pipeline; further investigation also revealed that a second strain that was seemingly resolved by our pipeline may contain an even longer duplication, albeit in a small subset of cells. We have therefore demonstrated the ability to resolve the structure of several B. pertussis strains per single barcoded nanopore flow cell, but the genomes with highest complexity (e.g. very large duplicated regions) remain only partially resolved using the standard library preparation and will require an alternative library preparation method. For full strain characterization, we recommend hybrid assembly of long and short reads together; for comparison of genome arrangement, assembly using long reads alone is sufficient. PMID- 30461376 TI - Paenibacillus flagellatus sp. nov., isolated from selenium mineral soil. AB - Strain DXL2T, a Gram-stain-negative, rod-shaped, endospore-forming, motile, aerobic bacterium, was isolated from selenium mineral soil. DXL2T had the highest 16S rRNA gene sequence similarities with those of Paenibacillus ginsengarviGsoil 139T (96.8 %), Paenibacillushemerocallicola DLE-12T (95.5 %) and Paenibacillus hodogayensisSGT (95.4 %). The genome size of DXL2T was 7.24 Mb, containing 6243 predicted protein-coding genes, with a DNA G+C content of 60.2 mol%. DXL2T contained meso-diaminopimelic acid in the cell-wall peptidoglycan. The major cellular fatty acids were anteiso-C15 : 0, iso-C16 : 0 and iso-C15 : 0. The major quinone was menaquinone 7. The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, two aminophospholipids, an unidentified aminolipid, phosphatidylmethylethanolamine, an unidentified glycolipid and an unidentified phospholipid. Compared with the other strains, DXL2T had a specific phospholipid and a specific aminolipid, it hydrolyzed Tween 40 and could not assimilate potassium gluconate. On the basis of the phenotypic, chemotaxonomic and phylogenetic results, strain DXL2T represents a novel species within the genus Paenibacillus, for which the name Paenibacillusflagellatus sp. nov. is proposed. The type strain is DXL2T (=KCTC 33976T=CCTCC AB 2018054T). PMID- 30461377 TI - Genome-based reclassification of Paenibacillus dauci as a later heterotypic synonym of Paenibacillus shenyangensis. AB - Paenibacillus shenyangensis and Paenibacillus dauci are Gram-stain-positive, rod shaped and endospore-forming bacteria originally isolated from soil and carrot samples, respectively, in China. Preliminary comparative genomic analysis showed that these bacteria could constitute a single species. Therefore, in this study, their taxonomic statuses were clarified through distinct genomic metrics and phylogenetic analyses. Paenibacillus shenyangensis A9T and P. dauci H9T presented values of average nucleotide identity (ANI) and its derivative metrics (gANI and OrthoANI) ranging from 97.88 to 98.08 %, and digital DNA-DNA hybridization equal to 89.08 %. Furthermore, the identities of 16S rRNA, gyrB, rpoB, recA and recN genes were all equal or higher than 98.7 %. Phylogenies of these marker genes and the concatenated core proteome were congruent in the sense that P. shenyangensis A9T and P. dauci H9T are the closest type-strains of the genus Paenibacillus. A review of their profiles revealed that these strains do not present pronounced differences at the phenotypic and chemotaxonomic levels. Considering phylogenetic, genomic, phenotypic and chemotaxonomic data, P. dauci should be reclassified as a later heterotypic synonym of P. shenyangensis. PMID- 30461378 TI - Bacillus safensis subsp. osmophilus subsp. nov., isolated from condensed milk, and description of Bacillus safensis subsp. safensis subsp. nov. AB - A bacterial strain, designated BC09T, was isolated from a contaminated sample of condensed milk. Phylogenetic analyses based on 16S rRNA gene sequences placed strain BC09T into the genus Bacillus with its closest relatives being Bacillus safensis and Bacillus australimaris with 100 and 99.9 % similarity, respectively. Analysis of the gyrB gene confirmed the closeness of strain BC09T with respect to the species B. safensis since it presented 97.8 and 95.2 % similarity values, respectively, to the type strains of B. safensis and B. australimaris. DNA-DNA hybridization confirmed these results showing averages of 67 and 56 %, respectively, between strain BC09T and the type strains of B. safensis and B. australimaris. Average nucleotide identity blast values obtained for BC09T compared to the closest relative type strains were 95.7 and 67.6 %, respectively, and predicted DNA-DNA hybridization values were 93.1 and 51.9 %, respectively. However, strain BC09T differs from the type strains of its closest relatives in several phenotypic characteristics. MK-7 was the only menaquinone detected and iso-C15:0 and anteiso-C15:0 were the major fatty acids. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol, two unidentified phospholipids, two unidentifed glycolipids, three unidentified lipids and one unidentifed phosphoglycolipid. Meso-diaminopimelic acid was detected in the peptidoglycan. The G+C content was 40.9 mol%. Phylogenetic, chemotaxonomic and phenotypic analyses showed that strain BC09T represents a new subspecies of B. safensis, for which the name Bacillus safensis subsp. osmophilus subsp. nov. is proposed. The type strain is BC09T (=LMG 30124T, =CECT 9344T). PMID- 30461379 TI - The safety and efficacy of transurethral microwave therapy in highrisk catheter dependent men. AB - OBJECTIVE: Previous studies have demonstrated the efficacy of transurethral microwave therapy (TUMT) in the management of high-risk catheter-dependent men, although few have assessed safety in high-risk patients, including those continuing anticoagulation therapy during treatment. Our goal was to assess the safety and effectiveness of TUMT in a population of high-risk catheter-dependent men. MATERIAL AND METHODS: A retrospective analysis of patients who underwent TUMT at a single Veterans Affairs facility for the treatment of benign prostatic hyperplasia was completed. The primary outcome was 30-day postprocedural complications by Clavien-Dindo grade, including bleeding events. The secondary outcome was success in catheter removal. RESULTS: We performed TUMT in 157 men, 105 of whom had urinary retention-requiring an indwelling urethral catheter or clean intermittent catheterization. Overall, 86% of patients underwent TUMT while on anticoagulant therapy and 25% were treated while taking warfarin. The median age of the patients was 76.9 years (95% CI 74.9-78.8) median ASA-score was 3, and median follow-up was 26 months (range 1-65). Only two men experienced hematuria requiring treatment postoperatively and no transfusions were required. Only two patients (1.9%) required readmission within 30 days after treatment. There were 24 (22.9%) Clavien-Dindo grade I-II complications without grade III or higher complications. Urinary retention resolved in 63.7% of men after treatment. CONCLUSION: Our results suggest that TUMT is a safe and reasonably effective treatment for high-risk catheter-dependent men. Furthermore, the low incidence of adverse bleeding events suggests that TUMT is a safe treatment modality for men requiring uninterrupted anticoagulation. PMID- 30461380 TI - Is active surveillance an appropriate approach to manage prostate cancer patients with Gleason Score 3+3 who met the criteria for active surveillance? AB - OBJECTIVE: Prostate cancer is one of the common malignant tumors in men worldwide. Nowadays it seems that Gleason Score 3+3 may not need definite treatment and some of the experts even ignore it as a cancer but we should be aware that in some patients with Gleason Score 3+3 there is a higher risk for harboring higher-grade cancer. We had done this study to evaluate patients with prostate cancer with Gleason Score 3+3 to determine the value of tumor volume in these cases. MATERIAL AND METHODS: From September 2010 to October 2017, radical prostatectomy was done for 123 sequential patients with localized prostate cancer in two referral centers of Shahid Beheshti Medical University, Tehran, Iran, and 42 cases with Gleason Scores 3+3 which who were candidates for active surveillance were included in the study. RESULTS: We interestingly found that 30 of 42 (71.4%) patients had significant tumor volumes (>=0/5 cm3). We concluded that when tumor volume was less than 0.5 cm3, none of the patients had extra prostatic tumor extension. In patients with tumor volume greater than 0.5 cm3, two cases (6.6%) had extra prostatic extension, 4 cases (13.3%) had positive margins, four cases (13.3%) reactive lymph nodes and 16 cases (53.3%) perineural invasion. CONCLUSION: Authors suggest that some patients with Gleason Score 3+3 have tumor volume >0.5 cm3 who are considered having significant cancer pathology and active surveillance may not be appropriate approach to manage all cases with Gleason Score 3+3. PMID- 30461381 TI - Do AB0 blood groups affect lower urinary tract symptoms? AB - OBJECTIVE: The aim of this study is to investigate whether there is a correlation between AB0 blood group antigens and Rhesus factor and lower urinary tract symptoms (LUTS). MATERIAL AND METHODS: A total of 556 male patients applying to our clinic with LUTS complaints from April 2012-2015 and complying with the study criteria were included in the study. The patients were divided into two groups as those with (Group 1; n=283) and without LUTS (Group 2; n=273) complaints. The effect of blood groups on LUTS complaints was compared using univariate logistic regression analyzes. RESULTS: According to AB0 blood groups, blood groups A (56.7%) and AB (56.9%) were most common in the LUTS group. But 0 blood group (44.1%) was the least common. According to rhesus factor, the incidence of LUTS in Rh (+), and Rh (-) groups were 48.9%, and 66.7%, respectively. Compared to 0 blood group, the LUTS incidence was 1.65, and 1.66 times higher for individuals with blood groups A, and AB, respectively. The same risk increased 2.09 times for individuals with Rhesus factor negative. CONCLUSION: This study identified a correlation between AB0 blood group and Rhesus factor and LUTS. The risk of LUTS risk increased in individuals with blood group A Rh (). Additionally there was a clear risk increase observed for AB blood group, though this did not reach statistical significance. PMID- 30461382 TI - The effect of coenzyme Q and selenium on kidney in rats with partial unilateral ureteral obstruction. AB - OBJECTIVE: In this study, we aimed to investigate the antioxidant effects of selenium and coenzyme Q on renal damage in a partial unilateral ureteral obstruction (PUUO) in a rat model. MATERIAL AND METHODS: A total of 24 Sprague Dawley rats were divided into four groups as Group 1 Control Group, Group 2, PUUO Group, Group 3 PUUO + coenzyme Q group, Group 4 PUUO + selenium group. Paraoxonase (PON), total antioxidant capacity (TAC), and total oxidant levels (TOS) were analyzed biochemically from tissue and blood samples. Tissue samples were examined histopathologically. RESULTS: The TAC in the tissues was found to be statistically significantly increased in Groups 3 and 4, compared to Group 2. Tissue TOS was found to be significantly reduced in Groups 3 and 4, compared to Group 2. Serum PON levels were significantly increased in Group 3 and 4, compared to Group 1 and 2. Histopathological examination showed that interstitial inflammation and congestion were lesser in the coenzyme Q and selenium groups than in the PUUO group. A more significant decrease was found in the selenium group than in the coenzyme Q group. CONCLUSION: Our study results showed that coenzyme Q and selenium reduced the oxidation and the damage in tissue in PUUO in rats. PMID- 30461383 TI - The Effects of Manufacturer's Prefit and Real-Ear Fitting on the Predicted Speech Perception of Children with Severe to Profound Hearing Loss. AB - BACKGROUND: The use of probe microphone measures in hearing aid verification is often neglected or not fully used by practitioners. Some practitioners rely on simulated gain and output provided by manufacturer's fitting software to verify hearing aids. PURPOSE: This study aims to evaluate the effectiveness of manufacturer's prefit procedure in matching the prescribed real-ear targets. It also aims to study its correlated impact on the predicted speech perception in children with severe and profound hearing loss. RESEARCH DESIGN: This cross sectional experiment was carried out by measuring the output of hearing aids based on prefit versus real-ear at low-, moderate-, and high-input levels. The predicted speech perception for different hearing aid fittings was determined based on the Speech Intelligibility Index (SII). STUDY SAMPLE: Sixteen children (28 ears) aged between 4 and 7 yr, with severe to profound sensorineural hearing loss took part in the study. METHOD: Two different types of hearing aids (Phonak and Unitron) were programmed based on their respective manufacturers' Desired Sensation Levels (DSL) v5 Child procedure. The hearing aids were then verified using coupler-based measurements and individual real-ear-to-coupler differences. The prefit outputs were compared with the DSL v5 Child-prescribed outputs at low , moderate-, and high-input levels. The hearing aids were then adjusted to closely match the prescribed output. The SIIs were calculated for the fittings before and after adjustment. DATA COLLECTION AND ANALYSIS: Sixty four percent of fittings that were based on the prefit procedure achieved the optimal fit-to targets, with less than 5-dB RMS deviations from the DSL v5 Child targets. After adjusting the hearing aids to attempt to meet the DSL v5 Child targets, 75% of the ears tested achieved the optimal fit-to-targets. On average, hearing aid outputs generated by the manufacturer's prefit procedure had good and reasonable agreement with the DSL v5 Child-prescribed outputs at low- and mid-frequencies. Nonetheless, at 4000 Hz, the hearing aid output mostly fell below the DSL v5 Child-prescribed outputs. This was still the case even after the hearing aid was adjusted to attempt to match with the targets. At low input level, some prefit outputs were found to be higher than the prescribed outputs. The deviations of prefit outputs from the prescribed outputs were dependent on the type of hearing aid and input levels. There was no significant difference between the SII calculated for fittings based on the prefit and adjusted fit. CONCLUSIONS: Prefit procedure tends to produce outputs that were below the DSL v5 Child-prescribed outputs, with the largest mean difference at 4000 Hz. Even though the hearing aid gains were adjusted to attempt to match with the targets, the outputs were still below the targets. The limitations of hearing aids to match the DSL v5 Child targets at high-frequency region have resulted in no improvement in the children's predicted speech perception. PMID- 30461384 TI - The Effects of Nonlinear Frequency Compression and Digital Noise Reduction on Word Recognition and Satisfaction Ratings in Noise in Adult Hearing Aid Users. AB - BACKGROUND: Nonlinear frequency compression (NLFC) and digital noise reduction (DNR) are hearing aid features often used simultaneously in the adult population with hearing loss. Although each feature has been studied extensively in isolation, the effects of using them in combination are unclear. PURPOSE: The effects of NLFC and DNR in noise on word recognition and satisfaction ratings in noise in adult hearing aid users were evaluated. RESEARCH DESIGN: A repeated measures design was used. STUDY SAMPLE: Two females and 13 males between the ages of 55 and 83 yr who were experienced hearing aid users participated. Thirteen were experienced with NLFC and all were experienced with DNR. Each participant was fit with Phonak Bolero Q90-P hearing instruments using their specific audiometric data and the Desired Sensation Level v5.0 (adult) fitting strategy. Fittings were verified with probe microphone measurements using speech at 65-dB sound pressure level (SPL). NLFC verification was performed using the Protocol for the Provision of Amplification, Version 2014.01. DATA COLLECTION AND ANALYSIS: All testing was conducted in a double-walled sound booth. Four hearing aid conditions were used for all testing: Baseline (NLFC off, DNR off), NLFC only, DNR only, and Combination (NLFC on, DNR on). A modified version of the Pascoe's High-Frequency Word List was presented at 65-dB SPL with speech spectrum noise at 6-dB signal-to-noise ratio (SNR) and 1-dB SNR for each hearing aid condition. Listener satisfaction ratings were obtained after each listening condition in terms of word comfort, word clarity, and average satisfaction. Two way repeated measures analyses of variance were conducted to assess listener performance. Pairwise comparisons were then completed for significant main effects. RESULTS: Word recognition results indicated a significant SNR effect only (6 dB SNR > 1 dB SNR). Satisfaction ratings results indicated a significant SNR and hearing aid condition effect for clarity, comfort, and average satisfaction. Clarity ratings were significantly higher for DNR and Combination than NLFC. Comfort ratings were significantly higher for DNR than NLFC. Average satisfaction was significantly higher for DNR and Combination than for NLFC. Also, average ratings were significantly higher for Combination than Baseline. CONCLUSIONS: Activating NLFC or DNR in isolation or in combination did not significantly impact word recognition in noise. Activating NLFC in isolation reduced satisfaction ratings relative to the DNR or Combination conditions. The isolated use of DNR significantly improved all satisfaction ratings when compared with the isolated use of NLFC. These findings suggest NLFC should not be used in isolation and should be coupled with DNR for best results. Future research should include a field trial as this was a limitation of the study. PMID- 30461385 TI - Enhancing Screening Systems to Facilitate Hearing-Healthcare Access: A Qualitative Study. AB - BACKGROUND: Although hearing loss is a common health issue, hearing healthcare (HHC) is poorly accessed. Screening to identify hearing loss is an important part of HHC access, specifically for those who screen positive for hearing loss and would benefit from seeing a HHC provider. New technologies can be automated to provide information and recommendations that are tailored to the needs of individual users, potentially enhancing rates of HHC access after positive screens. A greater understanding of the facilitators of postscreening HHC access that could be leveraged in such systems is needed. PURPOSE: The purpose of this project was to identify facilitators of postscreening HHC access that can be used in automated screening systems. RESEARCH DESIGN: This qualitative study used focus groups (FGs) to understand perceived barriers, perceived benefits, and potential cues to action, as informed by the Health Belief Model, for accessing HHC after use of automated hearing screening systems. STUDY SAMPLE: Fifty individuals participated in one of seven FGs. FGs were conducted separately with three types of stakeholders: four FGs included adults who reported some degree of perceived hearing loss and had recently completed a hearing screening; two FGs included adults who had recently sought HHC for the first time because of hearing loss; and one FG involved significant others/family members of individuals with hearing loss. DATA COLLECTION AND ANALYSIS: FGs were 60-90 minutes in length and were led by a trained facilitator following a discussion guide. A research audiologist was present at each FG and served as a notetaker. FGs were recorded and transcribed by research team members, and transcripts were then coded in an iterative process by multiple team members. Qualitative content analysis was used to reduce data and to identify salient themes and subthemes, following an inductive approach. We focused on identifying themes that were related to facilitators of HHC access after positive screens for hearing loss and, separately, potential enhancements to automated hearing screening systems that would leverage these facilitators to improve HHC access. RESULTS: We identified five key themes related to HHC access after a positive screen for hearing loss, along with ideas for enhancing automated hearing screening systems based on these themes. The themes included knowledge, trust, access, quality of life, and interpersonal influence. CONCLUSIONS: The results of our work help inform the development of innovative hearing screening systems that can be automated to leverage individual facilitators of HHC access. PMID- 30461386 TI - The Task-Evoked Pupil Response in Divided Auditory Attention Tasks. AB - BACKGROUND: Successful processing of complex auditory information relies on the interplay between low-level sensory processing and higher-level cognitive processing. However, the extent to which specific auditory processing tasks rely on cognitive processing as opposed to lower-level sensory processing is unclear. The task-evoked pupil response (TEPR) can quantify the cognitive load that complex listening tasks elicit. Previous research by Koelewijn et al (2014) indicated that dividing attention across two sentences presented dichotically resulted in larger pupil dilation (indicative of greater cognitive load) compared with selectively attending to one. However, it was unclear whether the larger pupil dilation measured during the divided attention task were the result of dividing attention or were due to the increased memory demand inherent to that task. PURPOSE: The first aim of the current study was to address the above issue of memory demand by comparing pupil dilation between divided and selective auditory attention tasks, while keeping memory and response load constant. The second aim was to further clarify the influence of memory demands on TEPRs in these auditory tasks by comparing the pupil dilation recorded to measures of participants' digit memory capacity. RESEARCH DESIGN: A repeated measures design was used. Each participant undertook two selective and three divided auditory attention tasks, generated by varying the specific instructions before each condition of the dichotic digits test (DDT). In addition, participants completed forward and reverse digit span (DS) tasks. STUDY SAMPLE: Thirty-one otologically healthy adults (aged 18-40 years) participated in this study. DATA COLLECTION AND ANALYSIS: A repeated measures analysis of variance was used to compare mean and peak pupil dilation between the selective and divided attention tasks. Spearman correlation analyses were used to examine potential relationships between DS scores and mean and peak pupil dilation elicited by the DDT conditions. RESULTS: Participants demonstrated larger mean and peak pupil dilation (indicative of greater cognitive load) when they were required to divide their attention across both ears than when they were required to selectively attend to input in one ear. DS scores were not significantly correlated with mean or peak pupil dilation measures. CONCLUSIONS: Auditory divided attention tasks involve significantly greater cognitive load than auditory selective attention tasks, even when memory demands are equal. In addition, mean and peak pupil dilation generated during the DDT are not significantly associated with digit memory capacity. The findings indicate that poor performance on tasks involving divided attention may be due to a cognitive deficit as opposed to an auditory processing deficit. Clinicians should consider this when using divided attention tasks in auditory processing assessments. PMID- 30461388 TI - Sentence Recognition in Steady-State Speech-Shaped Noise versus Four-Talker Babble. AB - BACKGROUND: Speech recognition in noise (SRN) evaluations reveal information about listening ability that is unavailable from pure-tone thresholds. Unfortunately, SRN evaluations are not commonly used in the clinic. A lack of standardization may be an explanation for the lack of widespread acceptance of SRN testing. Arguments have been made for the utilization of steady-state speech shaped noise vs. multi-talker babble. Previous investigations into the effect of masker type have used a monaural presentation of the stimuli. However, results of monaural SRN tests cannot be generalized to binaural listening conditions. PURPOSE: The purpose of this study was to investigate the effect of masker type on SRN thresholds under binaural listening conditions. RESEARCH DESIGN: The Hearing in Noise Test (HINT) protocol was selected in order to measure SRN thresholds in steady-state speech-shaped noise (HINT noise) and four-talker babble with and without the spatial separation of the target speech and masker stimuli. STUDY SAMPLE: Fifty native speakers of English with normal pure-tone thresholds (<= 25 dB HL, 250-4000 Hz) participated in the study. The mean age was 20.5 years (SD 1.01). DATA COLLECTION AND ANALYSIS: All participants were tested using the standard protocol for the HINT in a simulated soundfield environment under TDH-50P headphones. Thresholds were measured for the Noise Front, Noise Left, and Noise Right listening conditions with HINT noise and four-talker babble. The HINT composite score was determined for each noise condition. The spatial advantage was calculated from the HINT thresholds. Pure-tone threshold data were collected using the modified Hughson-Westlake procedure. Statistical analyses include descriptive statistics, effect size, correlations, and repeated measures ANOVA followed by matched-pairs t-tests. RESULTS: Repeated measures ANOVA was conducted to investigate the effects of masker type and noise location on HINT thresholds. Both main effects and their interaction were statistically significant (p < 0.01). No significant differences were found between masker conditions for the Noise Front thresholds. However, for the Noise Side conditions the four-talker babble thresholds were significantly better than the HINT noise thresholds. Overall, greater spatial advantage was found for the four-talker babble as opposed to the HINT noise conditions (p < 0.01). Pearson correlation analysis revealed no significant relationships between four-talker babble and HINT noise speech recognition performances for the Noise Front, Noise Right conditions, and the spatial advantage measures. Significant relationships (p < 0.05) were found between masking noise performances for the Noise Left condition and the Noise Composite scores. CONCLUSIONS: One cannot assume that a patient who performs within normal limits on a speech in four-talker babble test will also perform within normal limits on a speech in steady-state speech-shaped noise test, and vice-versa. Additionally, performances for the Noise Front condition cannot be used to predict performances for the Noise Side conditions. The utilization of both HINT noise and four-talker babble maskers, with and without the spatial separation of the stimuli, may be useful when determining the range of speech recognition in noise abilities found in everyday listening conditions. PMID- 30461387 TI - Influence of Instantaneous Compression on Recognition of Speech in Noise with Temporal Dips. AB - BACKGROUND: In listening environments with background noise that fluctuates in level, listeners with normal hearing can "glimpse" speech during dips in the noise, resulting in better speech recognition in fluctuating noise than in steady noise at the same overall level (referred to as masking release). Listeners with sensorineural hearing loss show less masking release. Amplification can improve masking release but not to the same extent that it does for listeners with normal hearing. PURPOSE: The purpose of this study was to compare masking release for listeners with sensorineural hearing loss obtained with an experimental hearing aid signal-processing algorithm with instantaneous compression (referred to as a suppression hearing aid, SHA) to masking release obtained with fast compression. The suppression hearing aid mimics effects of normal cochlear suppression, i.e., the reduction in the response to one sound by the simultaneous presentation of another sound. RESEARCH DESIGN: A within-participant design with repeated measures across test conditions was used. STUDY SAMPLE: Participants included 29 adults with mild-to-moderate sensorineural hearing loss and 21 adults with normal hearing. INTERVENTION: Participants with sensorineural hearing loss were fitted with simulators for SHA and a generic hearing aid (GHA) with fast (but not instantaneous) compression (5 ms attack and 50 ms release times) and no suppression. Gain was prescribed using either an experimental method based on categorical loudness scaling (CLS) or the Desired Sensation Level (DSL) algorithm version 5a, resulting in a total of four processing conditions: CLS-GHA, CLS-SHA, DSL-GHA, and DSL-SHA. DATA COLLECTION: All participants listened to consonant vowel-consonant nonwords in the presence of temporally-modulated and steady noise. An adaptive-tracking procedure was used to determine the signal-to-noise ratio required to obtain 29% and 71% correct. Measurements were made with amplification for participants with sensorineural hearing loss and without amplification for participants with normal hearing. ANALYSIS: Repeated-measures analysis of variance was used to determine the influence of within-participant factors of noise type and, for participants with sensorineural hearing loss, processing condition on masking release. Pearson correlational analysis was used to assess the effect of age on masking release for participants with sensorineural hearing loss. RESULTS: Statistically significant masking release was observed for listeners with sensorineural hearing loss for 29% correct, but not for 71% correct. However, the amount of masking release was less than masking release for participants with normal hearing. There were no significant differences among the amplification conditions for participants with sensorineural hearing loss. CONCLUSIONS: The results suggest that amplification with either instantaneous or fast compression resulted in similar masking release for listeners with sensorineural hearing loss. However, the masking release was less for participants with hearing loss than it was for those with normal hearing. PMID- 30461389 TI - A Comparison of Two Recording Montages for Ocular Vestibular Evoked Myogenic Potentials in Patients with Superior Canal Dehiscence Syndrome. AB - OBJECTIVE: The purpose of this investigation was to evaluate the sensitivity and specificity of the ocular vestibular evoked myogenic potential (oVEMP) using two electrode montages in patients with confirmed unilateral superior semicircular canal dehiscence syndrome (SCDS). STUDY DESIGN: This study evaluated oVEMP response characteristics measured using two different electrode montages from 12 unilateral SCDS ears and 36 age-matched control ears (age range = 23-66). The oVEMP responses were elicited using 500 Hz tone-burst air conduction stimuli presented at an intensity of 95 dB nHL and a rate of 5.1/sec. The two electrode montages used are described as an "infraorbital" montage and a "belly-tendon" montage. SETTING: Balance function laboratory embedded in a large, tertiary care otology clinic. RESULTS: The belly-tendon electrode montage resulted in significantly larger amplitude responses than the infraorbital electrode montage for the ears with SCDS and the normal control ears. For both electrode montages the ear with SCDS exhibited a significantly larger amplitude response, ~50% larger than the response amplitude from the normal control ear. The belly-tendon montage additionally produced larger median increases in amplitude compared with the infraorbital montage. Specifically, the median increase in oVEMP N1-P1 amplitudes using the belly-tendon montage was 39% greater in control ears, 76% greater in the SCDS ears, and 17% greater in the contralateral SCDS ears. CONCLUSIONS: The belly-tendon electrode montage yields significantly larger oVEMP amplitude responses for participants with SCDS and normal control participants. PMID- 30461390 TI - Pitch and Duration Pattern Sequence Tests in 7- to 11-Year-Old Children: Results Depend on Response Mode. AB - BACKGROUND: Pitch pattern sequence (PPS) and duration pattern sequence (DPS) tests are frequently used in the assessment of auditory processing disorder. Current recommendations suggest alternate, interchangeable modes for responding to stimuli. PURPOSE: The objective of the study is to evaluate the influence of response mode (i.e., humming, pointing, and labeling) and age on PPS and DPS performance of 7- to 11-year-old children. RESEARCH DESIGN: Laboratory-based testing of school children. Cross-sectional comparison of age, with repeated measures of age, test, ear, and response mode. STUDY SAMPLE: From 452 children recruited, 228 right-handed children (109 girls) aged 7 years to 11 years 11 months (mean age 9 years 4 months) completed at least one test (PPS: 211, DPS: 198), and 181 children completed both tests. Audiology inclusion criteria include normal hearing thresholds (<=15 dB HL at octave frequencies 250-8000 Hz); word recognition in quiet >=92%; tympanogram peak compensated static acoustic compliance 0.4-1.6 mmhos; and tympanometric peak pressure -100 to +50 daPa, all in both ears. Other inclusion criteria were Portuguese as first language; right handed; no musical training; no related, known, or observed phonological, learning, neurologic, psychiatric, or behavioral disorder; otologic history; and delayed neuropsychomotor or language development. DATA COLLECTION AND ANALYSIS: PPS: 30 trials per ear and response condition of three consecutive 500 msec duration intermixed high (1430 Hz) or low (880 Hz) frequency tones presented monaurally at 50 dB HL. The first response condition was humming followed by labeling (naming: high or low). DPS: As per PPS except 1000 Hz tones of intermixed 500 (long) and 250 msec (short) duration. First response was pointing (at a symbolic object) followed by labeling. Trends across age and between tests were assessed using repeated measures generalized linear mixed models. Correlation coefficients were calculated to assess relations among test scores. The two-sided significance level was 0.05. RESULTS: Older children performed better than younger children in all tasks. Humming the tone pattern (PPS humming) produced generally better performance than either articulating the attributes of the tones (labeling) or pointing to objects representing tone duration. PPS humming produced ceiling performance for many children of all ages. For both labeling tasks and DPS pointing, performance was better on the PPS than on the DPS, for stimulation of the right than the left ear, and in boys than girls. Individual performance on the two tasks was highly correlated. CONCLUSIONS: Response mode does matter in the PPS and DPS. Results from humming should not be combined with or be a substitute for results obtained from a labeling response. Tasks that rely on labeling a tonal stimulus should be avoided in testing hearing in children or other special populations. PMID- 30461391 TI - Quality and Readability of English-Language Internet Information for Tinnitus. AB - BACKGROUND: Because of the wealth of information available on the internet and increasing numbers of individuals relying on websites as a primary source of information for health-related questions, it is important that the readability of their content is within the comprehension level of most readers. OBJECTIVE: The study evaluated the quality and readability of English-language Internet information for tinnitus. RESEARCH DESIGN: Analysis of Internet websites on tinnitus. STUDY SAMPLE: A total of 134 websites with tinnitus information. DATA COLLECTION AND ANALYSIS: Three key words (i.e., tinnitus, ringing in the ear, and buzzing in the ear) were entered in five country-specific versions of the most commonly used internet search engine in August 2016. For each of the 15 searches, the first 20 relevant websites were examined. After removing duplicates, a total of 134 websites were assessed. Their origin (commercial, nonprofit organization, government, personal, or university), quality (Health On the Net [HON] certification and DISCERN scores), and readability (Flesch Reading Ease score, Flesch-Kincaid Reading Grade Level Formula, and Simple Measure of Gobbledygook) were assessed. RESULTS: Most websites were of commercial (49.3%) or nonprofit organization (38.8%) origin. Their quality and readability was highly variable. Only 13.5% of websites had HON certification. chi2 analysis showed that there was significant association between website origin and HON certification [chi2(4) = 132.9, p < 0.0001]. The mean DISCERN scores were 2.39. No association between DISCERN scores and website origin was found. Readability measures showed that on average, only people with at least 10-12 yr of education could read and understand the internet information for tinnitus in websites. Almost all the websites exceeded the most stringent reading level recommended for health information. CONCLUSIONS: The results highlight great variability in the quality and readability of health information, specifically for tinnitus in the internet. These findings underscores the need for stakeholders (e.g., web-developers, clinicians) to be aware of this and to develop more user-friendly health information on websites to make it more accessible for people with low literacy. PMID- 30461392 TI - Counseling in Pediatric Audiology: Audiologists' Perceptions, Confidence, and Training. AB - BACKGROUND: Pediatric audiologists are an important source of support for parents when a child is identified with hearing loss. As parents learn how to manage their child's hearing loss they often need help navigating challenges that arise; however, audiologists may experience a variety of barriers implementing effective counseling strategies. Many internal and external barriers experienced by parents can be appropriately supported and navigated within audiology services. PURPOSE: To investigate audiologists' perceptions, training, and confidence related to counseling and to explore the influence of years practicing audiology and taking a counseling course on perceptions and confidence. RESEARCH DESIGN: A cross sectional, population-based survey. STUDY SAMPLE: Three hundred and fifty surveys were analyzed from pediatric audiologists across the U.S. Responses were received from 26 states and one U.S. territory. DATA COLLECTION AND ANALYSIS: Data were collected through the mail and online. Descriptive and comparative statistics were used to analyze the information. Content analysis was performed to identify emergent themes from the responses to open-ended questions. RESULTS: Pediatric audiologists reported their perceptions about importance of counseling skills, challenges they encounter, their confidence in counseling, and how often they use the skills when needed in practice. Most audiologists (>=75%) felt it was very or extremely important to talk with parents about nine of the ten items (e.g., their [parents'] expectations). Three-fourth of the audiologists reported experiencing a moderate challenge or greater in knowing how to assess the presence of psychosocial challenges and in having enough time to address emotional needs. Many of the audiologists felt very or extremely confident in guiding parents in the development of an action plan (62%) and determining if parents have external barriers (60%). Approximately one-third or less of the participants reported performing any of the skills (e.g., determining if parent has external or internal barriers) >=75% of the time, and a statistically significant difference was found with participants practicing <=10 yr using the skills more frequently than participants practicing for >=11 yr. In addition, there was a statistically significant difference between participants who had taken an audiology-specific counseling course and those who had not; those who had reported being more confident and using counseling skills more often than audiologists did not have a counseling course. CONCLUSIONS: This study found strong support for audiologist perceived importance of counseling; however, fewer audiologists reported confidence in their counseling skills and in using counseling skills. Counseling training was variable; audiologists would benefit from a more systematic approach to counseling instruction within graduate training. PMID- 30461393 TI - Adult Children's Perspectives on Their Role in Their Parent's Hearing Healthcare Processes. AB - BACKGROUND: Communication partners play an important role in the hearing healthcare (HHC) process of the person with hearing impairment (HI). However, present research focuses mainly on the role of the spouse; the role of the adult child is often overlooked or understated. PURPOSE: The aim of the study was to describe the role of the adult child in the HHC process of a parent with HI. RESEARCH DESIGN: Using a qualitative study design, participants described their role in their parents' HHC process and the impact of a parent's HI on their relationship and communication in individual semi-structured interviews. STUDY SAMPLE: Twelve adult children of ten parents with HI participated; two sets of siblings were included to gain different perspectives on the HHC process within the same family. DATA COLLECTION AND ANALYSIS: Thematic analysis, a qualitative method to explore participant's perceptions and viewpoints, was used as the method of analysis. RESULTS: The superordinate theme discussed most frequently by participants, communication management, was bolstered by three ideas or pillars: facilitating HHC, communication strategies, and encouraging hearing aid use. Adult children saw themselves as advocates or supporters of their parent's HHC by taking an ongoing and active role in promoting successful communication rather than a role in directing their parent's HHC actions. Within each pillar of communication management, participants' perceptions and actions were modulated by the varying levels of effort and a desire to ask questions to better understand how to help their parent, which in turn influenced their awareness of the HI and HHC options, often resulting in the adult child putting forth new effort. CONCLUSIONS: Whereas the patient journey is often presented to the patient as a linear process, the adult children instead viewed the process of communication management as an ongoing and continuous cycle. The audiologist should be encouraged to involve adult children in the HHC process, as adult children play an important role in everyday communication management. PMID- 30461394 TI - Interregional Newborn Hearing Screening via Telehealth in Ghana. AB - BACKGROUND: Newborn hearing screening is a vital aspect of the Early Hearing Detection and Intervention program, aimed at detecting hearing loss in children for prompt treatment. In Ghana, this kind of pediatric hearing service is available at only one health care facility located in the Greater Accra Region. The current practice in effect has virtually cut-off infants in the other regions from accessing hearing screening and other pediatric audiological services. This has prompted a study into alternative methodologies to expand the reach of such services in Ghana. The present study was designed to assess the feasibility of using telehealth to deliver newborn hearing screening across Ghana. PURPOSE: To assess the feasibility of using telehealth to extend newborn hearing screening services across the ten regions of Ghana. RESEARCH DESIGN: A correlational study was designed to determine the extent of association between test results of telehealth and the conventional on-site methods (COMs) for conducting newborn hearing screening. The design also allowed for testing duration between the two methods to be compared. STUDY SAMPLE: Fifty infants from the Brong-Ahafo Regional Hospital (BARH) were enrolled. The infants aged between 2 and 90 days were selected through convenience sampling. There were 30 males and 20 females. PROCEDURE: Newborn hearing screening using distortion product otoacoustic emissions were performed via telehealth. By adopting the synchronous telehealth model, an audiologist located at the Korle-Bu Teaching Hospital conducted real time hearing screening tests over the internet on infants who were at the BARH. The former and latter hospitals are located in the Greater Accra and the Brong Ahafo Regions, respectively. As a control, similar hearing screening tests were conducted on the same infants at BARH using the conventional face-to-face on-site hearing screening method. DATA COLLECTION AND ANALYSIS: The test results and testing duration of the telehealth method and the conventional on-site approach were compared and subjected to statistical analysis. Here, the Spearman's correlation coefficient (rs) was used to determine the level of correlation between the test results, whereas the paired t-test statistic was used to test the level of significance between the testing duration of the two methods. RESULTS: Analysis of the test results showed a significantly high positive correlation between the telehealth and the COMs (rs = 0.778, 0.878, 0.857, 0.823, p < 0.05 @ 2.0, 3.0, 4.0, and 5.0 kHz respectively). Also, the difference in testing duration of the two methods was not statistically significant [t(99) = 1.309, p > 0.05]. The mean testing duration (in seconds) of telehealth was 27.287 (standard deviation = 27.373) and that of the COM was 24.689 (standard deviation = 27.169). CONCLUSION: The study showed the feasibility of establishing an interregional network of newborn hearing screening services across Ghana using telehealth. It is more efficient to deploy telehealth for pediatric hearing services than to have patients travel many hours to the Greater Accra Region for similar services. Poor road network, high transportation costs, and bad weather conditions are a few of the reasons for avoiding long distance travel in Ghana. PMID- 30461395 TI - Benefits of Compression Amplification in Telephone Bluetooth-Assistive Listening Devices for People with Hearing Loss. AB - BACKGROUND: Telephone conversation is one of the main scenarios where people with hearing loss require assistive listening devices (ALDs). Such people experience the greatest degree of difficulty during phone conversations in noisy environments. PURPOSE: This study compared the benefits of a linear scheme with a compression amplification scheme fitted with a prescription for sloping-type hearing loss implemented in a Bluetooth ALD in quiet and noisy environments. RESEARCH DESIGN: Word recognition scores (WRSs) for the Mandarin monosyllable recognition test (MMRT) and participants' satisfaction ratings were measured to serve as objective and subjective results, respectively. STUDY SAMPLE: Twelve native Mandarin speakers aged 27-68 yr with mild to moderate sensorineural hearing loss participated in this study. INTERVENTION: A compression amplification scheme with a prescription in maximizing speech intelligibility for sloping-type hearing loss was implemented in a Bluetooth ALD. DATA COLLECTION AND ANALYSIS: The MMRT WRSs of participants wearing the Bluetooth ALD were collected. Each test was conducted in a soundproof booth under quiet and 65-dBA speech noise environments. Each participant completed a satisfaction questionnaire administered by an audiologist. The collected WRSs were examined using analyses of variance and the satisfaction ratings were analyzed using Wilcoxon signed rank tests. RESULTS: The mean MMRT WRSs of the compression amplification scheme were significantly higher than those of the linear scheme (57% and 53% higher in quiet and noisy environments, respectively). The mean satisfaction ratings of both schemes were between neutral and satisfied in the quiet environment, whereas in the noisy environment, the participants were more satisfied with the compression scheme than the linear scheme. CONCLUSIONS: The results demonstrate the effective benefits of the compression amplification scheme fitted with a prescription in maximizing speech intelligibility for sloping-type hearing loss implemented in a Bluetooth ALD for people with mild to moderate hearing loss. PMID- 30461396 TI - Reliability of the Home Hearing Test: Implications for Public Health. AB - BACKGROUND: The projected increase in the aging population raises concerns about how to manage the health-care needs in a cost-effective way. Within hearing health care, there are presently too few audiologists to meet the expected demand, and training more professionals may not be a feasible way of addressing this problem. For this reason, there is a need to develop different ways of assessing hearing sensitivity that can be conducted accurately and inexpensively when a certified audiologist and/or sound-attenuated booth is unavailable. More specifically, there is a need to determine if the Etymotic Home Hearing Test (HHT) can yield accurate and reliable data from older adults with varying degrees of hearing loss. PURPOSE: To compare audiometric thresholds obtained using the HHT, an automated pure-tone air-conduction test, to those obtained using manual audiometry (MA), among older adults with varying degrees of hearing loss. STUDY SAMPLE: Participants were 112 English-speaking adults (58% Female), aged 60 yr and older. Participants were excluded from this study if otoscopy revealed cerumen impaction and/or suspected ear pathology. INTERVENTION: All participants completed the HHT on tablet computers in a carpeted classroom and MA in a double walled sound-attenuated booth using insert earphones for both measures. Both measures were completed in the same test session, and the order of testing (MA versus HHT) was counterbalanced. DATA COLLECTION AND ANALYSIS: Absolute differences in threshold measurements (in dB HL) were calculated across all ears (n = 224 ears) and for all frequencies (octave frequencies from 0.5 to 8 kHz). Correlation and multiple linear regression analyses were conducted to determine if thresholds obtained using the HHT significantly correlated with thresholds using MA. Mean thresholds for each method (HHT and MA) were compared using correlation analyses for each test frequency. Multiple linear regression analysis was used to examine the relationship between the four-frequency pure-tone average (PTA) (average threshold at 0.5, 1, 2, and 4 kHz) in the better-hearing ear measured using the HHT and a set of seven independent factors: four-frequency PTA in the better-hearing ear measured via MA, treatment group (HHT versus MA), age, gender, and degree of hearing loss (mild, moderate, and >moderate). RESULTS: Correlation analyses revealed significant frequency-specific correlations, ranging from 0.91 to 0.97 (p < 0.001), for air-conduction thresholds obtained using the HHT and MA. Mean HHT thresholds were significantly correlated with mean MA thresholds in both ears across the frequency range. This relationship held true across different degrees of hearing loss. The regression model accounted for a significant amount of variance in the HHT better-ear PTA, with MA better-ear PTA being the only significant predictor in our final model, with no effect of degree of loss, age, or gender. CONCLUSIONS: The HHT is an accurate and cost effective method of establishing pure-tone air-conduction thresholds, when compared with MA. Therefore, the HHT can be used as a tool to acquire accurate air-conduction hearing thresholds from older adults, in-group settings, without the use of a sound-attenuated booth or a certified audiologist. PMID- 30461397 TI - Bilingualism and Speech Understanding in Noise: Auditory and Linguistic Factors. AB - BACKGROUND: Bilingual speakers often have difficulty understanding speech in noisy and acoustically degraded conditions. PURPOSE: The first aim was to examine the potential source(s) of the difficulties that English-proficient bilingual listeners experience when hearing English speech in noise. The second aim was to assess how bilingual listeners perform on a battery of central auditory processing tests. RESEARCH DESIGN: A mixed design was used in this study. STUDY SAMPLE: Normal-hearing college students (n = 24) participated in this study. The bilingual participants (n = 12) self-reported that they learned a second language before age 9 and the monolingual participants reported that they only knew American English. All participants considered themselves to be native speakers of American English. DATA COLLECTION AND ANALYSIS: Participants were administered the Revised Speech Perception in Noise (R-SPIN) test to assess whether bilingual listeners' speech understanding in noise reflects auditory factors, linguistic factors, or a combination of the two. To minimize the influence of short-term memory and motor movements, only the final word of a sentence is repeated for this test. Sentence-final words were presented in two linguistic contexts: in the high-predictability condition, the final word can be deduced from the context created by the preceding words, and in the low-predictability condition, it cannot. The R-SPIN test was administered at two signal-to-noise ratios (SNRs) (0 and 3 dB). In addition, the participants were given a reading comprehension test to measure their ability to use context when linguistic stimuli are delivered to the visual, not auditory, modality. The central auditory test battery consisted of three tests: Competing Sentences, Dichotic Digits, and NU-6 Time-Compressed Speech with Reverberation. All test materials were given in American English. RESULTS: The bilingual and monolingual groups performed similarly in the low context condition of the R-SPIN test. However, in comparison to the age-matched monolingual group, the bilingual group did not derive the same level of benefit from contextual cues, as seen by a smaller improvement in performance between the low- and high-predictability R-SPIN conditions. The bilingual and monolingual groups showed a similar decrement in performance when the SNR dropped. In addition, bilingual individuals underperformed on the Competing Sentences test when instructed to attend to the left ear. However, the bilingual and monolingual groups performed equally well on the reading comprehension test, as well as on the Time-Compressed Speech with Reverberation and Dichotic Digits tests. CONCLUSIONS: We show that individuals who are exposed to two languages from an early age, and self-report as having a high level of proficiency in English, perform like their monolingual counterparts in acoustically degraded conditions where context is not facilitative, but they underperform in conditions where sentence-level linguistic context is facilitative to understanding. We conclude that deficits observed in noise are likely not due to a perceptual deficit or a lack of linguistic competence, but instead reflect a linguistic system that performs inefficiently in noise. In addition, we do not find evidence of an auditory processing weakness or advantage in our bilingual cohort; however, the use of speech materials to assess auditory processing is a confound. PMID- 30461398 TI - Parent Report of Amplification Use in Children with Mild Bilateral or Unilateral Hearing Loss. AB - BACKGROUND: Amplification is considered to be one of the most important interventions for children with hearing loss. However, achieving consistent use of hearing technology in young children is an important problem, particularly when hearing loss is of mild degree. Little information is available about amplification use specifically for children with mild bilateral or unilateral hearing loss when such losses are targeted and identified early because of the availability of newborn hearing screening. PURPOSE: We examined amplification use in a contemporary cohort of early-identified children with mild bilateral and unilateral hearing loss. RESEARCH DESIGN: As part of the Mild and Unilateral Hearing Loss in Children Study, we collected parent reports on their child's use of amplification during the preschool years. STUDY SAMPLE: A total of 69 children (38 unilateral and 31 bilateral mild) enrolled in the study from 2010 to 2015. Children entered the study at various ages between 12 and 36 mo of age and were followed up to age 48 mo. The median age of the children at enrollment was 16.5 mo (interquartile range [IQR] = 9.5, 26.8). Hearing loss was confirmed in these children at a median age of 3.6 mo (IQR = 2.4, 5.7). DATA COLLECTION AND ANALYSIS: Baseline characteristics related to the child and family were collected through an intake form at study enrollment. Data on amplification fitting and use were collected via parent questionnaires at each assessment interval. Information from parent questionnaires was summarized descriptively and amplification use was grouped into categories. Through logistic regression, we examined the relationship between amplification use and laterality of hearing loss, sex, and maternal education. RESULTS: Amplification was recommended for 59 (85.5%) children at a median age of 6.5 mo (IQR = 3.6, 21.2) and children were fitted at a median age of 10.9 mo (IQR = 6.0, 22.1). Based on parent report, hearing aid use was consistent for 39 (66.1%) of 59 children who had amplification recommended. Parent questionnaires showed very little change in use for most of the children over the study period. More children with bilateral hearing loss used their amplification consistently than those with unilateral hearing loss. After adjusting for maternal education and sex of the child, the odds for consistent use in children with mild bilateral loss was almost seven times higher (odds ratio = 6.75; 95% confidence interval = 1.84, 24.8) than for those with unilateral loss. CONCLUSIONS: Although 85.5% of children with mild bilateral or unilateral hearing loss received amplification recommendations, only two-thirds achieved consistent use by age 3-4 yr based on parent report. Children with mild bilateral loss were more likely to use amplification during the preschool years than those with unilateral loss. PMID- 30461400 TI - The Effect of Test, Electrode, and Rate on Electrocochleography Measures. AB - BACKGROUND: Electrocochleography (ECochG) is the measurement of stimulus-related cochlear potentials and the compound action potential (AP). Its primary clinical application is with the assessment of inner ear disorders. There are few studies examining the variability of ECochG measures. PURPOSE: The objective of the study was to examine the effect of test (i.e., initial versus retest), electrode (i.e., extratympanic versus tympanic), and stimulus rate (i.e., 7.7 versus 77.7/sec) on ECochG indices (i.e., summating potential [SP] amplitude, AP latency, AP amplitude, SP/AP amplitude ratio, and SP/AP area ratio). RESEARCH DESIGN: Correlational and three-factor repeated measures designs were employed. STUDY SAMPLE: Eighteen normal-hearing young adults participated. DATA COLLECTION AND ANALYSIS: ECochG responses were obtained with 90 dB nHL click stimuli for an initial test and retest at two stimulus rates with a commercially available extratympanic (TIPtrodeTM) and tympanic (Lilly TM-Wick) electrode. Separate repeated measures linear mixed-model analysis of variance examined the effect of test, electrode, and rate for all ECochG indices. Test-retest variability was also examined with correlation analyses; an examination of mean test-retest differences and their 95% confidence intervals (CI); and construction of Bland Altman plots. RESULTS: The presence of SP and AP responses varied across experimental conditions. Electrode and rate were statistically significant predictors (p < 0.05) of SP and AP responses: SP and AP responses were more likely to be present with the tympanic electrode and at the slow rate. Statistically significant correlations (p < 0.05) were found between initial tests and retests with all ECochG indices with both electrodes with the exception of SP amplitude with the TIPtrodeTM electrode. There were no significant main effects of test (initial versus retest) or interactions of test and electrode or rate for any of the ECochG indices (p > 0.05). The 95% CI of the mean test-retest differences contained 0 confirming that the effect of test was not statistically significant. There was a statistically significant main effect of electrode (p < 0.05) on three ECochG measures. The Lilly TM-Wick electrode produced larger SP amplitudes, AP amplitudes, and SP/AP area ratios than TIPtrodeTM electrodes. A statistically significant main effect of rate (p < 0.05) was identified for all ECochG measures. The effect of rate on AP latency and amplitude was expected. Increasing the stimulus rate prolonged the AP latency and decreased AP amplitude. SP amplitude was larger for the faster rate. CONCLUSIONS: There was no difference between electrodes with regard to test-retest measures. However, considering the higher likelihood of ECochG SP and AP responses and larger SP amplitude, SP/AP amplitude ratio, and SP/AP area ratio indices, the tympanic electrode placement is recommended for clinical practice. The addition of a fast stimulus rate may be considered for enhanced SP amplitude, SP/AP amplitude ratio, and SP/AP area ratio albeit with the consideration of the loss of SP and AP responses in some individuals. PMID- 30461399 TI - An Epidemiologic Study of the Association between Free Recall Dichotic Digits Test Performance and Vascular Health. AB - BACKGROUND: Associations between vascular health-related factors and hearing loss defined using audiometric pure-tone thresholds have been found. Studies have not focused on a potential relationship between vascular health-related factors and central auditory processing. PURPOSE: The aim of this study was to evaluate, on a population level, the relationship of vascular health-related factors with central auditory function. RESEARCH DESIGN: A cross-sectional, population study. STUDY SAMPLE: Subjects were participants in the Epidemiology of Hearing Loss Study (EHLS) or the Beaver Dam Offspring Study (BOSS)-prospective studies of aging and sensory loss. BOSS participants were the adult offspring of participants in the EHLS. Participants who completed the Dichotic Digits Test (DDT) during the fourth examination period of the EHLS (2008-2010) or the second examination period of the BOSS (2010-2013) were included (n = 3,655, mean age = 61.1 years). DATA COLLECTION AND ANALYSIS: The DDT-free recall test was conducted using 25 sets of triple-digit pairs at a 70 dB HL presentation level. The total number of correctly repeated digits from the right and left ears was converted to a percentage correct and used as an outcome. The percentage correct in the left ear was subtracted from the percentage correct in the right ear and used as an outcome. Vascular health-related measures obtained during the examination included blood pressure, mean carotid intima-media thickness, femoral pulse wave velocity (PWV), hemoglobin A1C, and non-high-density lipoprotein (HDL) cholesterol, and, in the EHLS participants, C-reactive protein and interleukin-6. Information on vascular health-related history and behaviors was self-reported. General linear modeling produced estimates of the age- and sex-adjusted least squares means for each vascular factor, and multiple linear regression was used for multivariable modeling of each outcome. RESULTS: After multivariable adjustment, participants with diabetes had a significantly lower (worse) mean DDT free recall total score (-2.08 percentage points, p < 0.001) than those without diabetes. Participants who exercised at least once per week had a significantly higher (better) mean DDT-free recall total score (+1.07 percentage points, p < 0.01) than those who did not exercise at least once per week. Alcohol consumption was associated with a higher DDT-free recall total score (+0.15 percentage points per +25 g ethanol, p < 0.01). In multivariable modeling of the right-left ear difference in DDT-free recall scores, participants with a history of cardiovascular disease (CVD) or higher PWV demonstrated significantly larger differences (CVD: +3.11 percentage points, p = 0.02; PWV: +0.36 percentage points per 1 m/sec, p < 0.01). Higher levels of non-HDL cholesterol were associated with smaller right-left ear differences (-0.22 percentage points per 10 mg/dL, p = 0.01). Adjustment for handedness did not affect the results. CONCLUSIONS: Vascular health-related factors may play a role in central auditory function. PMID- 30461401 TI - Verification Protocol for Signal Transparency Using the Cochlear Mini-Microphone 2+ and Digital Modulation Transmitter and Receiver with Cochlear Implants. AB - BACKGROUND: Guidelines established by the American Academy of Audiology (AAA) currently recommend behavioral testing when fitting frequency-modulated (FM) systems to individuals with cochlear implants (CIs). A protocol for completing electroacoustic measures on CI sound processors has not yet been established or validated when fitting either FM or digital-modulated (DM) systems, mini microphones, or mini microphones coupled to DM systems. In response, professionals have used or altered the AAA (2008) electroacoustic verification steps for fitting FM systems to hearing aids when fitting FM/DM systems, mini microphones, or mini microphones coupled to FM/DM systems to CI sound processors. PURPOSE: The purpose of this research is to determine if the electroacoustic verification guidelines established by AAA (2008) for fitting FM systems to hearing aids are feasible and verifiable when fitting mini microphones and mini microphones coupled to DM systems to CI sound processors. RESEARCH DESIGN: Electroacoustic measures were conducted on 51 Cochlear Nucleus 6/CP910 sound processors, one Cochlear Wireless Mini Microphone 2+ (MM2+), and one Phonak DM System (one Roger Inspiro transmitter and one Roger X receiver) using an adapted AAA (2008) protocol (Nair et al, 2017). Phonak's recommended default receiver gain setting was used with the Roger X receiver and adjusted if necessary to achieve transparency. Transparency refers to when the signal output of the device is the same when coupled and when not coupled to remote microphone technology. STUDY SAMPLE: Electroacoustic measures were conducted on 51 Cochlear Nucleus 6/CP910 sound processors. In this study, the 51 Cochlear Nucleus 6/CP910 sound processors were either streaming to the Cochlear MM2+ or streaming to the MM2+ coupled to a Phonak DM system. DATA COLLECTION AND ANALYSIS: In a clinical setting, using the AAA (2008) protocol for electroacoustic measurements when fitting FM systems to hearing aids, electroacoustic measurements using various equipment (MM2+ and Phonak DM system) were performed on 51 Cochlear Nucleus 6/CP910 sound processors using the Audioscan Verifit to determine transparency and verify DM advantage, comparing speech inputs (65 dB SPL) in an effort to achieve equal outputs. If transparency was not achieved when the CI sound processor was streaming to the MM2+ coupled to the Phonak DM system at the default receiver gain, adjustments were made to the Roger X receiver's gain. The integrity of the signal was monitored with the manufacturer's monitor earphones. RESULTS: Using the AAA (2008) hearing aid protocol, when the Cochlear Nucleus 6/CP910 sound processor was streaming to the Cochlear MM2+, transparency was achieved for 50 of 51 CI sound processors. Again, using the AAA (2008) protocol when the Cochlear Nucleus 6/CP910 sound processor was streaming to the Cochlear MM2+ coupled to the Phonak DM system at Phonak's recommended default receiver gain, 28 sound processors achieved transparency. After the receiver gain was adjusted, the remaining 23 sound processors met transparency. CONCLUSION: Electroacoustic measurements and transparency can be achieved for CI sound processors coupled to either a MM2+ only or to a MM2+ and a DM system by adapting the AAA (2008) guidelines. PMID- 30461402 TI - Levels of Music Played by Caucasian and Filipino Musicians with and without Conventional and Musicians' Earplugs. AB - BACKGROUND: Some musicians may play the music louder while using earplugs thus reducing the effectiveness of the hearing protection offered by earplugs. In addition, the dynamic range (DR) of the music may be altered because of the use of earplugs with negative impact on perceived quality of music. There are some cultural differences in attitudes toward loudness, which may lead to differences in the loudness of music played by musicians from different cultures. PURPOSE: To investigate the effect of the use of two different types of earplugs on the loudness and DR of music played by musicians of Caucasian and Filipino origins. RESEARCH DESIGN: Quasi-experimental repeated measures design. STUDY SAMPLE: Thirty six musicians with normal hearing within the age range of 18-49 yr. Fifteen were of Caucasian (eight men and 7 women) origin and 21 were of the Filipino (nine men and 12 women) origin. INTERVENTION: All participants received a brief educational session, which included information on music-induced hearing loss, the benefit of using earplugs, and the correct procedures for inserting and removing earplugs. They played music in five different conditions (three min each): Trial 1 of conventional and musicians' earplugs in random order, no earplug, and trial 2 of conventional and musicians' earplugs in random order. DATA COLLECTION AND ANALYSIS: Maximum, minimum, average (average sound level measured over the measurement period; LAVG), and peak levels were recorded using a dosimeter while playing music in each of the five conditions. The DR was derived by subtracting the minimum values from the maximum values. A different measure of the dynamic range 2 (DR2) was derived by subtracting the LAVG value from the peak value. Mixed analyses of variance (ANOVA) (Cultural origin and Gender as nonrepeated variables) was performed on LAVG, DR, and DR2. RESULTS: Based on the LAVG levels yielded by them, 42-61% of the musicians may be at risk for hearing loss. The mixed ANOVA revealed some main effects of culture and some significant interactions involving cultural origin, the plug conditions, type of earplugs, and trial number. CONCLUSIONS: Use of earplugs may vary the overall loudness of music, the DR, or the DR2 in some musicians depending on the type of earplugs and cultural origin, and the effect may change with practice. PMID- 30461403 TI - Monitoring Hearing in an Infectious Disease Clinic with mHealth Technologies. AB - BACKGROUND: Decentralized detection and monitoring of hearing loss can be supported by new mobile health technologies using automated testing that can be facilitated by minimally trained persons. These may prove particularly useful in an infectious disease (ID) clinic setting where the risk of hearing loss is high. PURPOSE: To evaluate the clinical utility of mobile and automated audiometry hearing health technology in an ID clinic setting. RESEARCH DESIGN: Smartphone automated pure-tone audiometry (PTA) (hearTestTM) and speech-in-noise testing (SA English digits-in-noise [DIN] test) were compared with manual audiometry (2, 4, and 8 kHz). Smartphone-automated PTA and the DIN test were repeated to determine the test-retest reliability. STUDY SAMPLE: Two hundred subjects (73% female and 27% male) were enrolled. Fifty participants were retested with the smartphone applications. Participants ranged from an age of 18 to 55 years with a mean age of 44.4 (8.7 standard deviation). DATA ANALYSIS: Threshold comparisons were made between smartphone audiometry testing and manual audiometry. Smartphone-automated PTA, manual audiometry, and test-retest measures were compared (Wilcoxon signed ranked test). Spearman rank correlation test was used to determine the relationship between the smartphone applications and manual audiometry, as well as for test-retest reliability. RESULTS: Within all participants, 88.2% of thresholds corresponded within 10 dB or less between smartphone audiometry and manual audiometry. There was a significant difference (p < 0.05) between the right ear at 4 and 8 kHz and in the left ear at 2 and 4 kHz between smartphone and manual audiometry, respectively. No significant difference was noted (p < 0.05) between test and retest measures of smartphone technology. CONCLUSIONS: Smartphone audiometry with calibrated headphones provides reliable results in an ID clinic setting and can be used as a baseline and monitoring tool at ID clinics. PMID- 30461404 TI - Hearing Screening in the Community. AB - BACKGROUND: Adults typically wait 7-10 yr after noticing hearing problems before seeking help, possibly because they are unaware of the extent of their impairment. Hearing screenings, frequently conducted at health fairs, community events, and retirement centers can increase this awareness. To our knowledge, there are no published studies in which testing conditions and outcomes have been examined for multiple "typical screening events." PURPOSE: The purpose of this article is to report hearing screening outcomes for pure tones and self-report screening tests and to examine their relationship with ambient noise levels in various screening environments. STUDY SAMPLE: One thousand nine hundred fifty four individuals who completed a hearing screening at one of 191 community-based screening events that took place in the Portland, OR, and Tampa, FL, metro areas. DATA COLLECTION AND ANALYSIS: The data were collected during the recruitment phase of a large multisite study. All participants received a hearing screening that consisted of otoscopy, pure-tone screening, and completion of the Hearing Handicap Inventory-Screening Version (HHI-S). In addition, ambient sound pressure levels were measured just before pure-tone testing. RESULTS: Many more individuals failed the pure-tone screening (n = 1,238) and then failed the HHI-S (n = 796). The percentage of individuals who failed the pure-tone screening increased linearly with age from <20% for ages <45 yr to almost 100% for individuals aged >=85 yr. On the other hand, the percentage of individuals who failed the HHI-S remained unchanged at approximately 40% for individuals aged >=55 yr. Ambient noise levels varied considerably across the hearing screening locations. They impacted the pure-tone screen failure rate but not the HHI-S failure rate. CONCLUSIONS: It is important to select screening locations with a quiet space for pure-tone screening, use headphones with good passive attenuation, measure sound levels regularly during hearing screening events, halt testing if ambient noise levels are high, and/or alert individuals to the possibility of a false-positive screening failure. The data substantiate prior findings that the relationship between pure-tone sensitivity and reported hearing loss changes with age. Although it might be possible to develop age-specific HHI S failure criteria to adjust for this, such an endeavor is not recommended because perceived difficulties are the best predictor of hearing health behaviors. Instead, it is proposed that a public health focus on education about hearing and hearing loss would be more effective. PMID- 30461405 TI - Difference in Speech Recognition between a Default and Programmed Telecoil Program. AB - BACKGROUND: Hearing loss can lead to isolation and social withdrawal. The telephone oftentimes connects persons with hearing loss to society; however, telephone use is impeded by narrow bandwidth, loss of visual cues, electromagnetic interference, and inherent phone-line noise. In the past, research assessing telephone communication has consistently reported that switching from the microphone to a telecoil will typically result in the acoustic signal being discernibly softer. Properly used telecoils improve the signal-to noise ratio (SNR), decrease the chance for acoustic feedback, and overcome the impact of distance and reverberation creating an opportunity for clearer telephone communication. Little research, however, has examined matching the telecoil frequency response to the prescribed target of the microphone frequency response (National Acoustics Laboratories, Non-Linear, version 1 [NAL-NL1]). PURPOSE: The primary goal of this study was to determine if differences exist in speech recognition for sentences (AZ-BIO) and consonant-vowel nucleus-consonant monosyllabic words (CNC) between two telecoil conditions (default and programmed). A secondary goal was to determine if differences exist in speech recognition for sentences between male and female talkers. RESEARCH DESIGN: A single-blinded randomized controlled trial. STUDY SAMPLE: Twenty experienced adult hearing aid users with bilateral symmetric slight to severe sensorineural hearing loss were recruited from Washington University in St. Louis School of Medicine. In addition, ten normal-hearing participants were recruited to determine the presentation level of the speech stimuli for the hearing aid participants. DATA COLLECTION AND ANALYSIS: Participants underwent real-ear measures to program the microphone frequency response of a receiver-in-the-canal hearing aid to NAL-NL1. Using the manufacturer software, one telecoil program remained as the manufacturer default and a second telecoil program was programmed so the sound pressure level for an inductive telephone simulator frequency response matching the microphone's frequency response to obtain as close to a 0 dB relative simulated equivalent telephone sensitivity value as possible. Participants then completed speech recognition measures including AZ-BIO sentences (male and female talkers) and CNC monosyllabic words and phonemes, using both telecoil programs. A mixed model analysis was performed to examine if significant differences in speech recognition exist between the two conditions and speech stimuli. RESULTS: Results revealed significant improvement in overall speech recognition for the programmed telecoil performance compared with default telecoil performance (p < 0.001). Also, improved performance in the programmed telecoil was reported with a male talker (p < 0.001) and performance for sentences compared with monosyllabic words (p < 0.001) or phonemes (p < 0.001). CONCLUSIONS: The programmed telecoil condition revealed significant improvement in speech recognition for all speech stimuli conditions compared with the default telecoil (sentences, monosyllables, and phonemes). Additional improvement was observed in both telecoil conditions when the talker was male. PMID- 30461406 TI - An Evaluation of Hearing Aid Beamforming Microphone Arrays in a Noisy Laboratory Setting. AB - BACKGROUND: People with hearing loss experience difficulty understanding speech in noisy environments. Beamforming microphone arrays in hearing aids can improve the signal-to-noise ratio (SNR) and thus also speech recognition and subjective ratings. Unilateral beamformer arrays, also known as directional microphones, accomplish this improvement using two microphones in one hearing aid. Bilateral beamformer arrays, which combine information across four microphones in a bilateral fitting, further improve the SNR. Early bilateral beamformers were static with fixed attenuation patterns. Recently adaptive, bilateral beamformers have been introduced in commercial hearing aids. PURPOSE: The purpose of this article was to evaluate the potential benefits of adaptive unilateral and bilateral beamformers for improving sentence recognition and subjective ratings in a laboratory setting. A secondary purpose was to identify potential participant factors that explain some of the variability in beamformer benefit. RESEARCH DESIGN: Participants were fitted with study hearing aids equipped with commercially available adaptive unilateral and bilateral beamformers. Participants completed sentence recognition testing in background noise using three hearing aid settings (omnidirectional, unilateral beamformer, bilateral beamformer) and two noise source configurations (surround, side). After each condition, participants made subjective ratings of their perceived work, desire to control the situation, willingness to give up, and tiredness. STUDY SAMPLE: Eighteen adults (50-80 yr, M = 66.2, sigma = 8.6) with symmetrical mild sloping to severe hearing loss participated. DATA COLLECTION AND ANALYSIS: Sentence recognition scores and subjective ratings were analyzed separately using generalized linear models with two within-subject factors (hearing aid microphone and noise configuration). Two benefit scores were calculated: (1) unilateral beamformer benefit (relative to performance with omnidirectional) and (2) additional bilateral beamformer benefit (relative to performance with unilateral beamformer). Hierarchical multiple linear regression was used to determine if beamformer benefit was associated with participant factors (age, degree of hearing loss, unaided speech in noise ability, spatial release from masking, and performance in omnidirectional). RESULTS: Sentence recognition and subjective ratings of work, control, and tiredness were better with both types of beamformers relative to the omnidirectional conditions. In addition, the bilateral beamformer offered small additional improvements relative to the unilateral beamformer in terms of sentence recognition and subjective ratings of tiredness. Speech recognition performance and subjective ratings were generally independent of noise configuration. Performance in the omnidirectional setting and pure-tone average were independently related to unilateral beamformer benefits. Those with the lowest performance or the largest degree of hearing loss benefited the most. No factors were significantly related to additional bilateral beamformer benefit. CONCLUSIONS: Adaptive bilateral beamformers offer additional advantages over adaptive unilateral beamformers in hearing aids. The small additional advantages with the adaptive beamformer are comparable to those reported in the literature with static beamformers. Although the additional benefits are small, they positively affected subjective ratings of tiredness. These data suggest that adaptive bilateral beamformers have the potential to improve listening in difficult situations for hearing aid users. In addition, patients who struggle the most without beamforming microphones may also benefit the most from the technology. PMID- 30461407 TI - Hormones and Hearing: Central Auditory Processing in Women. AB - BACKGROUND: Estrogen has been identified as playing a key role in many organ systems. Recently, estrogen has been found to be produced in the human brain and is believed contribute to central auditory processing. After menopause, a low estrogen state, many women report hearing loss but demonstrate no deficits in peripheral hearing sensitivity, which support the notion that estrogen plays an effect on central auditory processing. Although animal research on estrogen and hearing loss is extensive, there is little in the literature on the human model. PURPOSE: The aim of this study was to evaluate relationships between hormonal changes and hearing as it relates to higher auditory function in pre- and postmenopausal (Post-M) females. RESEARCH DESIGN: A prospective, group comparison study. STUDY SAMPLE: Twenty eight women between the ages of 18 and 70 at the University of Kentucky were recruited. DATA COLLECTION AND ANALYSIS: Participants were separated into premenopausal and peri-/Post-M groups. Participants had normal peripheral hearing sensitivity and underwent a behavioral auditory processing battery and electrophysiological evaluation. An analysis of variance was performed to address the aims of the study. RESULTS: Results from the study demonstrated statistically significant difference between groups, where Post-M females had difficulties in spatial hearing abilities as reflected on the Listening in Spatialized Noise Test-Sentences test. In addition, measures on the auditory brainstem response and the middle latency response reflected statistically significant differences between groups with Post-M females having longer latencies. CONCLUSIONS: Results from the present study demonstrated significant differences between groups, particularly listening in noise. Females who present with auditory complaints in spite of normal hearing thresholds should have a more extensive audiological evaluation to further evaluate possible central deficits. PMID- 30461408 TI - The Impact of Tinnitus on N-Back Performance in Normal Hearing Individuals. AB - BACKGROUND: Tinnitus sufferers commonly report concentration difficulties. Despite several previous studies investigating this, the underlying cause and the role of hearing status remains unclear. PURPOSE: To investigate whether there are any differences between normal hearing individuals with and without tinnitus in terms of working memory capacity, and whether working memory capacity correlates with high-frequency hearing thresholds. RESEARCH DESIGN: Participants had their hearing thresholds measured (0.125-16 kHz) and performed a visual n-back test. All participants completed the Hospital Anxiety and Depression Scale, in addition tinnitus participants filled out the Tinnitus Questionnaire. STUDY SAMPLE: Sixty two individuals participated, 31 had tinnitus (tinnitus group) and 31 did not have tinnitus (control group). Groups were age- and sex matched, and all participants had normal hearing thresholds (20 dB HL or better at 0.125-8 kHz). DATA ANALYSIS: Friedman test of differences among repeated measures was conducted on the collected data of n-back performance, and Mann-Whitney U-test was used to compare groups. Age-corrected correlations were calculated for high-frequency hearing and each n-back condition. RESULTS: We found no significant differences between the groups in terms of n-back task performances, except for the 2-back condition where the tinnitus group performed significantly better than the controls (p = 0.007). Furthermore, we found high-frequency hearing thresholds of the best ear (10-16 kHz) to correlate with performances at more demanding n-back conditions (p = 0.029 for 1-back and p = 0.015 for 2-back). CONCLUSION: This suggests that presence of tinnitus might not imply poorer working memory capacity and that deteriorated high-frequency hearing thresholds. PMID- 30461409 TI - Tracking of Noise Tolerance to Predict Hearing Aid Satisfaction in Loud Noisy Environments. AB - BACKGROUND: A method that tracked tolerable noise level (TNL) over time while maintaining subjective speech intelligibility was reported previously. Although this method was reliable and efficacious as a research tool, its clinical efficacy and predictive ability of real-life hearing aid satisfaction were not measured. PURPOSE: The study evaluated an adaptive method to estimate TNL using slope and variance of tracked noise level as criteria in a clinical setting. The relationship between TNL and subjective hearing aid satisfaction in noisy environments was also investigated. RESEARCH DESIGN: A single-blinded, repeated measures design. STUDY SAMPLE: Seventeen experienced hearing aid wearers with bilateral mild-to-moderately-severe sensorineural hearing loss. DATA COLLECTION AND ANALYSIS: Participants listened to 82-dB SPL continuous speech and tracked the background noise level that they could "put up with" while subjectively understanding >90% of the speech material. Two trials with each babble noise and continuous speech-shaped noise were measured in a single session. All four trials were completed aided using the participants' own hearing aids. The stimuli were presented in the sound field with speech from 0 degrees and noise from the 180 degrees azimuth. The instantaneous tolerable noise level was measured using a custom program and scored in two ways; the averaged TNL (aTNL) over the 2-min trial and the estimated TNL (eTNL) as soon as the listeners reached a stable noise estimate. Correlation between TNL and proportion of satisfied noisy environments was examined using the MarkeTrak questionnaire. RESULTS: All listeners completed the tracking of noise tolerance procedure within 2 min with good reliability. Sixty-five percent of the listeners yielded a stable noise estimate after 59.9 sec of actual test time. The eTNL for all trials was 78.6 dB SPL (standard deviation [SD] = 4.4 dB). The aTNL for all trials was 78.0 dB SPL (SD = 3.3 dB) after 120 sec. The aTNL was 79.2 dB SPL (SD = 5.4 dB) for babble noise and 77.0 dB SPL (SD = 5.9 dB) for speech-shaped noise. High within-session test-retest reliability was evident. The 95% confidence interval was 1.5 dB for babble noise and 2.8 dB for continuous speech-shaped noise. No significant correlation was measured between overall hearing aid satisfaction and the aTNL (rho = 0.20 for both noises); however, a significant relationship between aTNL and proportion of satisfied noisy situations was evident (rho = 0.48 for babble noise and rho = 0.55 for speech-shaped noise). CONCLUSION: The eTNL scoring method yielded similar results as the aTNL method although requiring only half the time for 65% of the listeners. This time efficiency, along with its reliability and the potential relationship between TNL and hearing aid satisfaction in noisy listening situations suggests that this procedure may be a good clinical tool to evaluate whether specific features on a hearing aid would improve noise tolerance and predict wearer satisfaction with the selected hearing aid in real-life loud noisy situations. A larger sample of hearing aid wearers is needed to further validate these potential uses. PMID- 30461410 TI - Knowledge of Hearing Loss among University Students Pursuing Careers in Health Care. AB - BACKGROUND: Albeit limited, research suggests that students pursuing careers in health care receive limited training on the provision of services for people with hearing loss. As the incidence of hearing loss continues to increase among Americans, it is critical that medical professionals understand how hearing loss among patients may affect the manner in which they can provide services most effectively. PURPOSE: The aim of this project is to assess the amount of experience and confidence that preprofessional health-care students at one university obtain during the course of their training and whether these students would be interested in additional information related to hearing health. RESEARCH DESIGN: Preprofessional health-care students in terminal degree programs at one university completed a survey regarding the provision of services for individuals with hearing loss. Students were asked to quantify their prior training on topics related to hearing loss, report their perceptions of the benefits and barriers to screening hearing, and report their self-efficacy in providing services for individuals with hearing loss. Additional survey items investigated students' interest in receiving further training on these topics. STUDY SAMPLE: Participants (n = 95; 16.2% response rate) were students at a mid-sized, Midwestern university who were pursuing the following terminal degrees: medicine, physician assistant, nursing, pharmacy, physical therapy, occupational therapy, speech-language pathology, and respiratory therapy (bachelor's degree in respiratory care). Participants were selected based on membership in an interdisciplinary education training program. All students in this program received an invitation to participate in the study. Of the participants, 68 (71.6%) were Caucasian and 86 (90.5%) were female. DATA COLLECTION AND ANALYSIS: A 28-item online survey on various topics related to hearing loss was used to document student responses. All students enrolled in a university's interdisciplinary professional education course (n = 586) received an online link to the survey via an initial email, which contained a brief introduction to the study, the assurance of response anonymity, and a statement regarding implied consent. A second email was sent to students, which reminded participants of the request to complete the survey. RESULTS: Overall, 60% of participants reported an interest in receiving additional information on hearing health and 66.3% of respondents indicated that they wished to receive training via an in-service or internet workshop facilitated by their university program. Most of the participants reported that they had not received training and did not feel confident identifying the signs and symptoms of hearing loss and making an appropriate referral, which led to the request for additional information. CONCLUSIONS: The results of this study suggest that preprofessional health-care students have an interest in receiving additional education on various topics related to hearing loss including a better understanding of how hearing loss impacts the quality of life in affected individuals. These findings provide an incentive to provide additional training related to hearing loss identification and management for preprofessional health-care students to foster increased competency and improved patient care. PMID- 30461411 TI - Can Self-Reported Personal Audio System Volume Predict Actual Listening Levels in Young Adults? AB - BACKGROUND: Most young adults report using personal audio systems (PAS) with earphones as part of their daily activities. PAS exposure is intermittent and research examining the levels these young adults are listening to is increasing. On average, preferred listening levels are below what would be considered at risk in an occupational setting. PURPOSE: The purpose of this study was to evaluate how two questions predicted preferred listening level in young adults with normal hearing; specifically, whether these young adults could identify if they listen at a high level or not. STUDY SAMPLE: One hundred and sixty young adults (111 women, 49 men) with normal hearing completed a questionnaire that had questions about PAS listening habits and then had preferred listening level assessed using a probe microphone system while listening to 1 hour of music through earphones. DATA COLLECTION AND ANALYSIS: Otoscopy, tympanometry, and pure-tone thresholds were completed in a randomly determined test ear. As part of the Risk Factors Survey, two closed-set questions were completed. First, "For a typical day, what is the most common volume used during this day?" with the following response options "Low," "Medium/Comfortable," "Loud," or "Very Loud." And second, "Do you listen to your personal music system at a volume where you..." with the following response options "Easily hear people," "Have a little trouble hearing people," "Have a lot of trouble hearing people," or "Cannot hear people." Using a probe microphone, chosen listening level (A-weighted, diffuse-field correction and a conversion to free-field equivalent [LDFeq]) was calculated over 1 hour while the participant listened to music with earphones. Sensitivity and specificity were determined to see how well young adults could identify themselves as listening at a high level (>85 dBA) or not. Linear regression analyses were performed to determine the amount of variance explained by the two survey questions as predictors of measured LDFeq. RESULTS: Almost half of the participants reported a longest single use of a PAS as <1 hour daily and more than half reported listening at a medium/comfortable volume and had a little trouble hearing people. Mean LDFeq was 72.5 dBA, with young adult men having a significantly higher mean LDFeq (76.5 dBA) compared with young adult women (70.8 dBA). Sensitivity was 88.9% and specificity was 70.6% for the question asking about volume on a typical day. For the question asking about being able to hear other people while listening to music sensitivity was 83.3% and specificity was 82.5%. Two variables, listening volume on a typical day and sex, accounted for 28.4% of the variability associated with LDFeq; the answer to the question asking about being able to hear others and sex accounted for 22.8% of the variability associated with LDFeq. CONCLUSIONS: About 11% of young adults in the present study listen to a PAS with earphones at a high level (>85 dBA) while in a quiet background. The participants who do report listening at a high level, however, do well at self reporting this risk behavior in survey questions. PMID- 30461412 TI - Face and Content Validity of a Probe Tube Placement Training Simulator. AB - BACKGROUND: Probe tube placement is an important skill audiologists must learn to make real-ear measurements in an audiology clinic. With current evidence-based guidelines recommending insertion of the probe tube within 5 mm of the tympanic membrane (TM) for proper acoustical measurements, students must be well trained to ensure they are capable to perform this placement in clinical practice. This is not always the case as it has been found that real-ear measurements are not performed in a clinic as often as required. To address this, a simulator consisting of a 3D-printed ear model and an optical tracking system was developed to provide a training system for students to practice probe tube placement and to provide a method to evaluate competency before starting clinical practicum placements. Two simulators were developed, an adult model and a pediatric model. PURPOSE: To assess the face and content validity of the two probe tube placement simulators (adult and pediatric) and define barriers and facilitators to implementing this system into an educational setting. RESEARCH DESIGN: Participants followed the setup and operating instructions designed to guide them through each functionality of the simulator. A questionnaire was used to assess face and content validity, applicability to an educational setting, and to determine perceived barriers and facilitators to using the probe tube simulators for training purposes. Five additional probe tube placements with each simulator were performed in which distance-to-TM was recorded. STUDY SAMPLE: Twelve participants with significant probe tube placement experience. DATA COLLECTION AND ANALYSIS: Participants rated each question in the questionnaire from 0% to 100% depending on their level of agreement. Averages and standard deviations (SDs) were compiled and presented for each section (face validity, content validity, and applicability to an educational setting). Final facilitators and barriers for the simulator were compiled and the top answers of each are presented. The five quantitative probe tube placement measurements for each participant were averaged, SDs were calculated, and contacts with the TM while placing the probe tube were recorded. RESULTS: The average face validity score over all questions for the adult model was 65% (SD = 18.2) whereas the pediatric model received a score of 64% (16.4). The overall content validity average score was 78.7% (17) and applicability to an educational setting had an average score of 80% (5.33). The average distance-to-TM across all trials and participants was 3.74 mm (1.82) for the adult model and 2.77 mm (0.94) for the pediatric model with only one participant exceeding the recommended maximum of 5 mm. Listed shortcomings of the current simulator included realism of the 3D-printed ear, ease of insertion of an otoscope tip into the ear, ability to visualize the ear canal "landmarks" and the TM, and foam tip insertion experience. CONCLUSIONS: Results were generally very positive for the simulator, and future iterations will look to improve the flexibility and texture of the ear, as well as the otoscopic view of the ear canal and TM. PMID- 30461413 TI - Contralateral Routing of Signal Yields Significant Speech in Noise Benefit for Unilateral Cochlear Implant Recipients. AB - BACKGROUND: Bilateral cochlear implantation is the standard of care for individuals with moderate sloping-to-profound sensorineural hearing loss who do not receive benefit from appropriately fit hearing aids. Because of financial, insurance, or medical reasons, some unilateral cochlear implant (CI) recipients are unable to obtain a second CI. Here, we evaluated the first clinically available solution for individuals who have been unilaterally implanted and who do not or cannot use technology (e.g., hearing aid or CI) on the non-implanted ear. PURPOSE: We aimed to investigate how the addition of a contralateral routing of signal (CROS) device could provide objective and/or subjective benefit to adult CI recipients with moderate-to-profound hearing loss in the non-implanted ear. RESEARCH DESIGN: Single-center prospective study using a within-subjects repeated-measures design. STUDY SAMPLE: Participants included ten experienced unilateral CI recipients with severe-to-profound (n = 9) or moderate-to-profound (n = 1) sensorineural hearing loss in the non-implanted ear. At the time of study enrollment, participants did not use any technology on the non-implanted ear. No other exclusion criteria were used. INTERVENTION: Individuals were tested with and without a CROS device worn on the non-implanted ear. DATA COLLECTION AND ANALYSIS: We obtained measures of speech understanding in quiet (50 and 65 dBA) and in noise (+5-dB signal-to-noise ratio with a 65-dBA speech signal) both with and without the CROS device in an acute listening condition. Subjective benefit was assessed via the Speech, Spatial and Qualities 12-item questionnaire before CROS fitting and after two weeks of continuous use. A mixed-model, repeated measures analysis of variance was completed with three talker locations and three presentation levels included as within-subjects factors and the presence or absence of a CROS device as a between-subjects factor. RESULTS: There was an 11% improvement in speech understanding in noise with the addition of the CROS device when speech was located at 0 degrees azimuth. Subjective benefit in the speech domain of the SSQ was also observed. CONCLUSIONS: Use of CROS provided both subjective and objective speech recognition benefit for unilateral CI recipients who do not have access to bilateral cochlear implantation. PMID- 30461414 TI - Negative Side Effects Associated with Hearing Aid Use in Adults with Hearing Loss. AB - BACKGROUND: The low uptake of hearing aids in the United States has been attributed to a number of reasons, including low perceived hearing disability, limited perceived benefit and cost. Another possible reason may be related to negative side effects associated with hearing aid use. PURPOSE: The present study was aimed at determining and classifying the negative side effects associated with hearing aid use in adults with hearing loss. RESEARCH DESIGN: The study used a cross-sectional survey design. STUDY SAMPLE: Five hundred and twelve participants completed an electronic survey. DATA COLLECTION AND ANALYSIS: The data was collected using the negative side effects of hearing aids (NSE-HAs) questionnaire. Data were analyzed using Chi square analysis, principal components analysis, and calculation of Cronbach's alpha. RESULTS: Some individuals reported negative side effects for all 32 items. However, careful examination of results suggests that, as a whole, reported negative side effects tend to be mild with mean scores falling close to the lower quartile of the total scores. Chi square test results suggest that the variables of age, gender, duration of hearing loss, self-reported hearing disability, and duration of hearing aid use seem to be significantly associated with the reported negative side effects. The NSE-HAs questionnaire was found to have a complex structure as indicated by the principal components analysis. However, good internal consistency was found in both the full scale and subscales. CONCLUSIONS: The present study suggests that, although a large number of adults with hearing loss who use hearing aids experience some degree of negative side effects, those effects tend to be mild. PMID- 30461415 TI - Early Indices of Reduced Cochlear Function in Young Adults with Type-1 Diabetes Revealed by DPOAE Fine Structure. AB - BACKGROUND: The relationship between type-1 diabetes mellitus (DM) and cochlear dysfunction remains inconclusive. PURPOSE: The purpose of this study was to examine otoacoustic emissions (OAEs) in normal-hearing young adults with type-1 DM as compared with matched controls and identify potential covariates influencing OAE findings. RESEARCH DESIGN: Cross-sectional study. STUDY SAMPLE: N = 40 young adults aged 18-28 years including individuals with type-1 DM (n = 20) and age-gender matched controls (n = 20) with normal hearing sensitivity. DATA COLLECTION AND ANALYSIS: Measures of pure-tone threshold sensitivity and OAEs, including distortion product otoacoustic emissions (DPOAEs), transient evoked OAEs, and DPOAE fine structure, were compared between groups. Covariates such as noise exposure and DM-related factors (e.g., duration of disease, glycated hemoglobin levels) were considered. Statistical analysis included analysis of variance and linear regression. RESULTS: Measures of hearing sensitivity and auditory function in both groups were comparable for all assays, except DPOAE fine structure. A reduced number of fine structure peaks and component amplitudes were found in the type-1 diabetes DM group with the primary difference in the reflection component. CONCLUSIONS: The results indicate that reduced cochlear function in young adults with type-1 DM can be revealed using DPOAE fine structure, suggesting potential clinical applications of DPOAE fine structure in early identification of cochlear pathology. Potential factors underlying these findings are discussed. PMID- 30461416 TI - Extended High-Frequency Smartphone Audiometry: Validity and Reliability. AB - BACKGROUND: Extended high-frequency (EHF) audiometry (8-16 kHz) has an important role in audiological assessments such as ototoxicity monitoring, and for speech recognition and localization. Accurate and reliable EHF testing with smartphone technologies has the potential to provide more affordable and accessible hearing care services, especially in underserved contexts. PURPOSE: To determine the accuracy and test-retest reliability of EHF audiometry with a smartphone application, using calibrated headphones. RESEARCH DESIGN: Air-conduction thresholds (8-16 kHz) and test-retest reproducibility, recorded with conventional audiometry (CA) and smartphone audiometry (SA), using audiometric (Sennheiser HDA 300 circumaural) and nonstandard audiometric (Sennheiser HD202 II supra-aural) headphones, were compared in a repeated-measures design. STUDY SAMPLE: A total of 61 participants (122 ears) were included in the study. Of these, 24 were adults attending a tuberculosis clinic (mean age = 36.8, standard deviation [SD] = 14.2 yr; 48% female) and 37 were adolescents and young adults recruited from a prospective students program (mean age = 17.6, SD = 3.2 yr; 76% female). Of these, 22.3% (n = 326) of EHF thresholds were >=25 dB HL. DATA ANALYSIS: Threshold comparisons were made between CA and SA, with audiometric headphones and nonstandard audiometric headphones. A paired samples t-test was used for comparison of threshold correspondence between conventional and smartphone thresholds, and test-retest reproducibility of smartphone thresholds. RESULTS: Conventional thresholds corresponded with smartphone thresholds at the lowest intensity (10 dB HL), using audiometric and nonstandard audiometric headphones in 59.4% and 57.6% of cases, respectively. Conventional thresholds (exceeding 10 dB HL) corresponded within 10 dB or less, with smartphone thresholds in 82.9% of cases using audiometric headphones and 84.1% of cases using nonstandard audiometric headphones. There was no significant difference between CA and SA, using audiometric headphones across all frequencies (p > 0.05). Test-retest comparison also showed no significant differences between conditions (p > 0.05). Smartphone test-retest thresholds corresponded within 10 dB or less in 86.7% and 93.4% of cases using audiometric and nonstandard audiometric headphones, respectively. CONCLUSIONS: EHF smartphone testing with calibrated headphones can provide an accurate and reliable option for affordable mobile audiometry. The validity of EHF smartphone testing outside a sound booth as a cost-effective and readily available option to detect high-frequency hearing loss in community-based settings should be established. PMID- 30461417 TI - A Client Oriented Scale of Improvement in Tinnitus for Therapy Goal Planning and Assessing Outcomes. AB - BACKGROUND: There is a need to develop methods to help clinicians work with clients to select and personalize tinnitus therapies. The use of validated measures to determine treatment success is also essential for research and clinical practice. A goal planning method widely used in audiologic rehabilitation is the client oriented scale of improvement (COSI). A modified version of the COSI has been used to identify tinnitus treatment goals and outcomes (client oriented scale of improvement in tinnitus [COSIT]). PURPOSE: The aims of this study were to identify treatment goals in a clinic sample and ascertain the convergent validity of the COSIT to three widely used standardized questionnaires. RESEARCH DESIGN: A retrospective evaluation of client treatment goals using thematic analysis and correlational analysis of secondary research data comparing the COSIT to tinnitus handicap questionnaire (THQ), tinnitus handicap inventory (THI), and tinnitus functional index (TFI). STUDY SAMPLE: One hundred and twenty-two adult patients and research participants attending the University of Auckland Hearing and Tinnitus Clinic. RESULTS: Specific treatment goals were categorized into 11 themes. The most common treatment goals (>10% of responses) were: (1) Reducing tinnitus' effects on Hearing. (2) Improved wellbeing and being less depressed. (3) Coping with or controlling the tinnitus. (4) Managing the effect of the environment (context) on tinnitus. (5) Improving sleep. (6) Understanding tinnitus. Individuals differed in their complaints and priorities for treatment. The COSIT showed moderate convergent validity with the THQ, THI, and TFI indicating that the total scores measured similar constructs. CONCLUSIONS: The COSIT is a pragmatic method for determining tinnitus treatment goals and priorities in a format that should be familiar to audiologists. PMID- 30461418 TI - Psychometric Comparison of the Hearing in Noise Test and the American English Matrix Test. AB - BACKGROUND: The hearing in noise test (HINT) is the most popular adaptive test used to evaluate speech in noise performance, especially in context of hearing aid features. However, the number of conditions that can be tested on the HINT is limited by a small speech corpus. The American English Matrix test (AEMT) is a new alternative adaptive speech in noise test with a larger speech corpus. The study examined the relationships between the performance of hearing aid wearers on the HINT and the AEMT. PURPOSE: To examine whether there was a difference in performance of hearing aid wearers on the HINT and the AEMT. A secondary purpose, given the AEMT's steep performance-intensity function, was to determine whether the AEMT is more sensitive to changes in speech recognition resulting from directional (DIR) microphone processing in hearing aids. RESEARCH DESIGN: A repeated measures design was used in this study. Multiple measurements were made on each subject. Each measurement involved a different experimental condition. STUDY SAMPLE: Ten adults with hearing loss participated in this study. DATA COLLECTION AND ANALYSIS: All participants completed the AEMT and HINT, using adaptive and fixed test formats while wearing hearing aids. Speech recognition was assessed in two hearing aid microphone settings-omnidirectional and fixed DIR. All testing was conducted via sound field presentation. Performance on HINT and AEMT were systematically compared across all test conditions using a linear model with repeated measures. RESULTS: The results of this study revealed that adult hearing aid users perform differently on the HINT and AEMT, with adaptive AEMT testing yielding significantly better (more negative) thresholds than the HINT. Slopes of performance intensity functions obtained by testing at multiple fixed signal-to-noise ratios, revealed a somewhat steeper slope for the HINT compared with the AEMT. Despite this steeper slope, the benefit provided by DIR microphones was not significantly different between the two speech tests. CONCLUSIONS: The observation of similar DIR benefits of the HINT and AEMT suggests that the HINT and AEMT are equally sensitive to changes in speech recognition thresholds following intervention. Therefore, the decision to use the AEMT or the HINT will depend on the purpose of the study and/or the technology being investigated. Other test related factors such as available sentence corpus, learning effects and test time will also influence test selection. PMID- 30461419 TI - Random-sequence genetic oligomer pools display an innate potential for ligation and recombination. AB - Recombination, the exchange of information between different genetic polymer strands, is of fundamental importance in biology for genome maintenance and genetic diversification mediated by dedicated recombinase enzymes. Here, we describe a pervasive non-enzymatic capacity for recombination (and ligation) in random-sequence genetic oligomer pools. Specifically, we examine random and semi random eicosamer (N20) pools of RNA, DNA and the unnatural genetic polymers ANA (arabino-), HNA (hexitol-) and AtNA (altritol-nucleic acids). While DNA, ANA and HNA pools proved inert, RNA and AtNA pools displayed diverse modes of spontaneous intermolecular recombination, connecting recombination mechanistically to the vicinal ring cis-diol configuration shared by RNA and AtNA. Thus, the chemical constitution that renders both susceptible to hydrolysis emerges as the fundamental determinant of an innate capacity for recombination, which is shown to enable a concomitant increase in compositional, informational and structural pool complexity and hence evolutionary potential. PMID- 30461421 TI - Proliferating Neurocristic Hamartoma Arising in a Giant Congenital Nevus: Comparative Genomic Hybridization Findings. AB - Neurocristic cutaneous hamartomas (NCHs) are rarely reported tumors with divergent differentiation derived from persistently active pluripotent cells from the neural crest. They result from aberrant development of the neuromesenchyme, and they can express fibrogenic, melanocytic, and/or neurosustentacular differentiation. Thus, congenital melanocytic nevus also represents a neurocristic dysplasia of the skin in which cells are melanogenic cells arrested in development located in the reticular dermis, and nodular proliferative neurocristic hamartoma may arise within a congenital melanocytic nevus. The real importance of NCHs is that, although few cases have been reported in the literature, some cases have shown development of melanoma. Moreover, the only previously reported case of a similar "proliferative neurocristic nodule" analyzed with comparative genomic hybridization showed an aberration pattern similar to melanoma. We present a rare case of NCH associated with a congenital nevus in a 7-year-old boy, with classical histological and immunohistochemical features suggesting a "proliferative neurocristic hamartoma". Comparative genomic hybridization assay showed that chromosomal aberrations were absent in the congenital nevus, whereas, interestingly, the proliferative neurocristic proliferation had an aberration pattern similar to proliferative nodules with gains or losses of entire chromosomes only, similar to typical proliferative nodules and supporting the benign behavior of this lesion. PMID- 30461422 TI - Utility of Skin Biopsy and Culture in the Diagnosis and Classification of Chronic Ulcers: A Single-Institution, Retrospective Study. AB - In the United States, chronic ulcers affect 6.5 million people, with a cost of ~$20 million annually. The most common etiology of chronic ulcers in the United States is venous stasis, followed by arterial insufficiency and neuropathic ulcers. Less common causes of chronic ulcers include infection, inflammatory etiologies such as vasculitis and pyoderma gangrenosum, and neoplastic causes. Obtaining skin biopsy and tissue culture can be helpful in diagnosing unusual causes of chronic ulcers; however, there are little data on the diagnostic utility of skin biopsy in rendering a definitive diagnosis of the etiology of chronic ulcers. A retrospective study of all skin ulcers biopsied during a 10 year period at the University of Washington was undertaken. Re-excisions and surgical wounds were excluded. A total of 270 ulcer biopsy specimens were included. In 48% of cases, no specific diagnosis could be rendered histologically. 44.8% of chronic ulcers biopsied were due to atypical causes, with neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma, and cutaneous T-cell lymphoma) being the most common. Vasculitis and pyoderma gangrenosum each represented 1.5% of rendered diagnoses. Concomitant skin culture was performed in 28.9% of cases, and special stains [acid-fast bacilli, Brown and Brenn (B&B), Grocott's methenamine silver, and periodic acid-Schiff stains] were performed in 34.0%. Although more than half (49 of 78) of tissue cultures were positive, only 6.8% (12 of 175) of special stains on tissue sections were positive. We conclude that although the etiology of many ulcers cannot be determined by routine histology alone, skin biopsy of ulcers remains a critical part of the workup given that when a specific cause can be determined, atypical etiologies, including neoplasms, represent a significant proportion of chronic ulcers. Limitations of our study include referral bias. Our results also confirm the higher diagnostic yield of conventional tissue culture compared with special tissue stain biopsies of skin ulcers. PMID- 30461420 TI - Expanded genetic screening in Caenorhabditis elegans identifies new regulators and an inhibitory role for NAD+ in axon regeneration. AB - The mechanisms underlying axon regeneration in mature neurons are relevant to the understanding of normal nervous system maintenance and for developing therapeutic strategies for injury. Here, we report novel pathways in axon regeneration, identified by extending our previous function-based screen using the C. elegans mechanosensory neuron axotomy model. We identify an unexpected role of the nicotinamide adenine dinucleotide (NAD+) synthesizing enzyme, NMAT-2/NMNAT, in axon regeneration. NMAT-2 inhibits axon regrowth via cell-autonomous and non autonomous mechanisms. NMAT-2 enzymatic activity is required to repress regrowth. Further, we find differential requirements for proteins in membrane contact site, components and regulators of the extracellular matrix, membrane trafficking, microtubule and actin cytoskeleton, the conserved Kelch-domain protein IVNS-1, and the orphan transporter MFSD-6 in axon regrowth. Identification of these new pathways expands our understanding of the molecular basis of axonal injury response and regeneration. PMID- 30461423 TI - Concurrent Metastatic Merkel Cell Carcinoma and Cutaneous Squamous Cell Carcinoma in the Same Lymph Node. AB - The coexistence of Merkel cell carcinoma (MCC) and squamous cell carcinoma (SCC) in the same cutaneous lesion is well known. The pathogenesis is believed to be distinct from conventional polyomavirus-related MCC, and it has a more aggressive course. Metastasis of MCC and SCC to the same lymph node is exceedingly rare with only one previously reported case in the English literature. To the best of our knowledge, this is the second case of MCC and SCC with metastasis to the same lymph node. Our case demonstrates the aggressive nature of the combined MCC and SCC in the setting of immunosuppression. PMID- 30461424 TI - Linear IgA Bullous Dermatosis Preceding the Diagnosis of Primary Sclerosing Cholangitis and Ulcerative Colitis: A Case Report. AB - Linear IgA bullous dermatosis (LABD) is a rare autoimmune blistering disorder seen in the pediatric and adult populations that is often linked to a medication, infection, or underlying gastrointestinal, hepatobiliary, or autoimmune disease. In this study, we describe the case of a 23-year-old white man whose presentation and diagnosis of LABD ultimately led to the discovery of underlying primary sclerosing cholangitis (PSC) and ulcerative colitis (UC). His dermatitis resolved with topical steroids and dapsone, and he is undergoing systemic treatment for his UC and PSC. This exceptional case further validates the association between LABD with UC, strengthens that with PSC, and underscores the importance of alerting clinicians to consider conducting a systemic workup in addition to thorough medication history on making the diagnosis of LABD. PMID- 30461425 TI - Late-Onset Nevus Comedonicus With Follicular Epidermolytic Hyperkeratosis-Case Report and Review of the Literature. AB - Nevus comedonicus is a rare cutaneous follicular hamartoma, characterized by the clustering of papules with firm, blackened horny buffers. It is usually present at birth or during childhood, although few cases of late-onset disease have been described. We present a case of postmenopausal-onset nevus comedonicus in a 55 year-old white woman without relevant medical history. Skin biopsy showed the typical features of several cyst-dilated follicular structures occupied by keratotic material and the peculiar finding of epidermolytic hyperkeratosis of the follicular epithelial walls. A brief review of the clinical and histological features of other similar cases published in the literature is performed. PMID- 30461426 TI - Positive Antinucleolar Antibodies on Direct Immunofluorescence of Lesional Skin of a Patient With Limited Systemic Sclerosis. PMID- 30461427 TI - Proinflammatory and anti-inflammatory biomarkers in schizophrenia and influence of simvastatin on the interleukin-6. AB - The present study sought to assess biomarkers of inflammation in stable patients with schizophrenia (SZ) on clozapine therapy. We recruited 60 outpatients with SZ and 60 healthy controls, matched for sex and age. Compared with controls, patients had significantly increased concentrations of interleukin-6 and tumor necrosis factor-alpha. Interestingly, patients on simvastatin had lower interleukin-6 levels compared with patients not on simvastatin and controls. This study corroborated previous evidence for increased inflammatory biomarkers in SZ and detected a potential anti-inflammatory action of simvastatin in patients with a clinical diagnosis of SZ on clozapine therapy. PMID- 30461428 TI - The Effect of Catheterization on Susceptibility of Uropathogens After Pelvic Reconstructive Surgery. AB - OBJECTIVE: The aim of this study was to determine whether bacterial uropathogens from positive urine cultures and uropathogen antibiotic susceptibility differ between catheterized (C) and noncatheterized (NC) patients after pelvic reconstructive surgery. METHODS: This is a retrospective cohort study of patients with a positive urine culture within 1 year of pelvic reconstructive surgery. Patients were categorized as having an indwelling catheter placed for urinary retention or voiding dysfunction within 48 hours of specimen collection versus no catheter. Microbiology reports provided uropathogens and antibiotic susceptibility for each culture. Student t test, chi, and logistic regression were used to compare rates of non-Escherichia coli uropathogens and susceptibility to first-line antibiotics between C and NC groups. RESULTS: A total of 427 positive urine cultures from 317 unique patients were identified. Positive urine cultures from C patients were less likely to contain E. coli (47.1% NC vs 29.2% C; P = 0.0009), with enterococcus being the most common non-E. coli uropathogen. The odds of non-E. coli uropathogens increased with age (adjusted odds ratio, 4.25; 95% confidence interval, 1.95-9.28; P = 0.0003 for the oldest patients). Cultures from C patients were more likely to have a uropathogen not susceptible to sulfamethoxazole/trimethoprim (20.5% NC vs 32.1% C; P = 0.03), nitrofurantoin (19.2% NC vs 34.6% C; P = 0.002), and cefazolin (18.1% NC vs 49.4% C; P < 0.0001). CONCLUSIONS: After pelvic reconstructive surgery, patients with a positive urine culture who have undergone catheterization within 48 hours of specimen collection are more likely to have non-E. coli uropathogens, with 1 in 3 cultures being not susceptible to common first-line antibiotics. This highlights the importance of performing susceptibility testing rather than treating empirically after pelvic reconstructive surgery. PMID- 30461429 TI - Intractable Central Pain in a Patient with Diffuse Glioma: Case Report. AB - Central neuropathic pain can be difficult to treat and, subsequently, cause a great amount of disability and distress to patients, which limits quality of life. Common etiologies include: stroke, spinal cord injury, multiple sclerosis, infection, vasculitis, and malignancy. This case is a description of an 18-year old male patient diagnosed with a grade IV diffuse glioma who experienced severe neuropathic pain refractory to first-line treatment options including: gabapentinoids, tricyclic antidepressants, and selective serotonin and norepinephrine reuptake inhibitors. The patient remained on high-dose oral gabapentin as well as methadone and high-dose oxycodone for pain control at the time of submission. The purpose of this case report is to review the nociceptive pathways as well as explore the role of opioids in central neuropathic pain secondary to neoplasm as a better understanding of these topics can aid in physiatrists better taking care of these patients and improving function and quality of life. PMID- 30461430 TI - Elbow Myositis Ossificans: Radiographic Evolution with Histologic Correlation. PMID- 30461431 TI - Ultrasound-guided 5-in-1 injection: trigger point injections and nerve hydrodissections for non-specific upper back pain. PMID- 30461432 TI - Microdialysis to quantify inflammatory cytokines in the glenohumeral joint: A brief methods report. AB - Microdialysis quantifies in vivo soft-tissue biochemical concentrations via passive diffusion of interstitial molecules through a porous membrane into a dialysate. The purpose of this pilot study was to evaluate a technique to measure inflammatory cytokines associated with rotator cuff tendinopathy by inserting a microdialysis catheter into the posterior glenohumeral joint (GHJ). The technique was tested in a convenience sample of six pain-free, able-bodied Veterans. Complete dialysate samples were collected in two participants. Two participants' sample volumes were smaller than what was required for analysis (30MUL) and thus were diluted. Catheter failures in two participants prevented collection altogether. Three cytokine concentrations were quantified: interleukin-1 receptor antagonist (IL-1RA), IL-8, and Regulated on Activation, Normal T-cell Expressed and Secreted (RANTES). Microdialysis is not recommended for use in the GHJ, yet quantification of GHJ cytokines could yield valuable information to better understand pathophysiology of the joint and its surrounding tissues. Another technique, such as joint lavage, may be a more attractive alternative to overcome the limitations of microdialysis in the GHJ. PMID- 30461433 TI - Comparative Effectiveness and Safety of Rivaroxaban in Adults With Nonvalvular Atrial Fibrillation. AB - BACKGROUND: All evidence regarding benefits and harms of rivaroxaban for stroke prevention has not been appraised yet. STUDY QUESTION: What are the comparative effectiveness and safety of rivaroxaban in adults with nonvalvular atrial fibrillation? DATA SOURCES: Randomized controlled trials (RCTs), meta-analyses, and observational studies were identified in several databases in October 2018. STUDY DESIGN: Rapid review with evidence appraisal using the Grading of Recommendations Assessment, Development and Evaluation working group approach. RESULTS: Two direct RCTs (23,021 patients) suggest that rivaroxaban is noninferior to warfarin in the prevention of stroke and systemic embolism (pooled relative risk [RR] 0.73, 95% confidence interval [CI], 0.43-1.24), reduces risk of hemorrhagic stroke (RR 0.59, 95% CI, 0.38-0.92), fatal bleeding (RR 0.49, 95% CI, 0.31-0.76), and cardiac arrest (RR 0.45, 95% CI, 0.25-0.82, 2 RCTs), but increases risk of major gastrointestinal bleeding (RR 1.46, 95% CI, 1.19-1.78). In observational studies, rivaroxaban is associated with lower risk of ischemic stroke (RR 0.87, 95% CI, 0.77-0.99, 222,750 patients), acute myocardial infarction (RR 0.61, 95% CI, 0.48-0.78, 73,739 patients), and intracranial hemorrhage (RR 0.64, 95% CI, 0.45-0.92, 197,506 patients) but higher risk of gastrointestinal bleeding (RR 1.30, 95% CI, 1.19-1.42, 188,968 patients) and higher risk of mortality when compared with warfarin in European studies (RR 1.19, 103,270 patients in the UK; RR 2.02, 22,358 patients in Denmark) but lower risk of mortality in Taiwan (RR 0.58, 40,000 patients). Network meta-analyses and observational studies suggest that rivaroxaban is associated with higher risk of bleeding when compared with apixaban (RR 2.14, 72,586 patients), dabigatran (RR 1.24, 67,102 patients), and edoxaban (RR 1.32, 71,683 patients). CONCLUSIONS: Research on the long-term comparative effectiveness, safety, and effects on quality of life between rivaroxaban and other novel oral anticoagulants is urgently needed. PMID- 30461434 TI - Toward stimulating apoptosis in human lung adenocarcinoma cells by novel nano carmofur compound treatment. AB - Lung cancer is one of the common and most fatal diseases worldwide. It has a high incidence in both men and women, in Turkey. Current antineoplastic drugs are reported to have limitations such as narrow therapeutic index and selectivity, toxicity, and antiproliferative effects on cancer cells. Thus, this study was aimed to investigate the potential cytotoxic, antiproliferative and apoptosis triggering effects of a newly developed SLN-Carmofur compound on human lung adenocarcinoma A549 cells. The results of this study have shown that SLN-Carmofur significantly decreased the viability of A549 cells in a dose-dependent manner by short-time application. The IC50 value of the agent caused chromatin condensation, fragmentation of the nuclei, and holes on cytoskeleton; moreover, it altered the ultrastructure of the exposed cells with clear signs of apoptosis. Taken all our results together, it is indicated that SLN-Carmofur may be proposed for further research for drug development for cancer therapy, depending on the valuable potential in stimulating apoptosis in cancer cells. PMID- 30461435 TI - Bone Marrow-Derived Cellular Therapies in Orthopaedics: Part I: Recommendations for Bone Marrow Aspiration Technique and Safety. PMID- 30461436 TI - Bone Marrow-Derived Cellular Therapies in Orthopaedics: Part II: Recommendations for Reporting the Quality of Bone Marrow-Derived Cell Populations. PMID- 30461437 TI - High-Resolution Chest Computed Tomography Imaging of the Lungs: Impact of 1024 Matrix Reconstruction and Photon-Counting Detector Computed Tomography. AB - OBJECTIVES: The aim of this study was to evaluate if a high-resolution photon counting detector computed tomography (PCD-CT) system with a 1024*1024 matrix reconstruction can improve the visualization of fine structures in the lungs compared with conventional high-resolution CT (HRCT). MATERIALS AND METHODS: Twenty-two adult patients referred for clinical chest HRCT (mean CTDI vol, 13.58 mGy) underwent additional dose-matched PCD-CT (mean volume CT dose index, 13.37 mGy) after written informed consent. Computed tomography images were reconstructed at a slice thickness of 1.5 mm and an image increment of 1 mm with our routine HRCT reconstruction kernels (B46 and Bv49) at 512 and 1024 matrix sizes for conventional energy-integrating detector (EID) CT scans. For PCD-CT, routine B46 kernel and an additional sharp kernel (Q65, unavailable for EID) images were reconstructed at 1024 matrix size. Two thoracic radiologists compared images from EID and PCD-CT noting the highest level bronchus clearly identified in each lobe of the right lung, and rating bronchial wall conspicuity of third- and fourth-order bronchi. Lung nodules were also compared with the B46/EID/512 images using a 5-point Likert scale. Statistical analysis was performed using a Wilcoxon signed rank test with a P < 0.05 considered significant. RESULTS: Compared with B46/EID/512, readers detected higher-order bronchi using B46/PCD/1024 and Q65/PCD/1024 images for every lung lobe (P < 0.0015), but in only the right middle lobe for B46/EID/1024 (P = 0.007). Readers were able to better identify bronchial walls of the third- and fourth-order bronchi better using the Q65/PCD/1024 images (mean Likert scores of 1.1 and 1.5), which was significantly higher compared with B46/EID/1024 or B46/PCD/1024 images (mean difference, 0.8; P < 0.0001). The Q65/PCD/1024 images had a mean nodule score of 1 +/- 1.3 for reader 1, and -0.1 (0.9) for reader 2, with one reader having improved nodule evaluation scores for both PCD kernels (P < 0.001), and the other reader not identifying any increased advantage over B46/EID/1024 (P = 1.0). CONCLUSIONS: High-resolution lung PCD-CT with 1024 image matrix reconstruction increased radiologists' ability to visualize higher-order bronchi and bronchial walls without compromising nodule evaluation compared with current chest CT, creating an opportunity for radiologists to better evaluate airway pathology. PMID- 30461438 TI - The Influence of Type 2 Diabetes Mellitus on the Osseointegration of Titanium Implants With Different Surface Modifications-A Histomorphometric Study in High Fat Diet/Low-Dose Streptozotocin-Treated Rats. AB - OBJECTIVES: Type 2 diabetes mellitus (T2DM) is a systemic disease that also compromises the bone healing capacity. In healthy individuals, surface modifications of dental implants are proven to increase bone response and implant success. The aim of this study was to clarify if the surface modifications also improve osseointegration in a setting with diabetes mellitus. METHODS: T2DM was induced in 7 rats by a high-fat diet/low-dose streptozotocin injection. All animals received a hydroxyapatite (HA) implant, a sandblasted and acid-etched (SLA) implant, and a standard machined titanium implant for control in the tibia. After 4 weeks, thin-ground sections were produced, and the volume of new bone formation (nBV/TV) and bone-to-implant contact (nB.I/Im.I) were histomorphometrically analyzed. RESULTS: Both surface modifications led to an increase of osseointegration compared with the machined surface implant in rats with T2DM. nBV/TV was highest in the SLA implants, whereas nB.I/Im.I was highest in the HA group. Regardless of the surface modification, a superordinate regional pattern of new bone formation over the length of the implant was observed. CONCLUSIONS: Implants with HA coating and SLA surface modifications seem to have the potential to increase osseointegration also in T2DM rats when compared with a conventional machined surface. PMID- 30461439 TI - Comparison of Xenogeneic Collagen Matrix vs. Free Gingival Grafts to Increase the Zone of Keratinized Mucosa Around Functioning Implants. AB - PURPOSE: To evaluate the effectiveness of collagen matrix (CM) grafts as an alternative to free gingival grafts (FGGs) in increasing the zone of keratinized tissue (KT) around dental implants. METHODS: Thirty subjects with 2 contralateral implants were recruited. The test group (n = 30) received CM grafts. The control group (n = 30) received FGGs. Clinical variables were plaque index, gingival index, probing depths, bleeding on probing (BOP), and mucosal recession (MR). Subjects were followed at 1 and 2 weeks and 1, 3, and 6 months. RESULTS: FGGs resulted in mean gains (3.73 +/- 1.93 mm) in KT for 28 of 30 implants (93% success rate). CM grafts resulted in mean gains (3.23 +/- 1.52 mm) in KT for 29 of the 30 implants (97% success rate). Mean change in pocket depth around implants grafted with FGG was -0.24 +/- 1.02 mm and with CM was -0.25 +/- 0.80 mm. Mean change in BOP around implants grafted with FGG was 0.03 +/- 0.49 and with CM was 0.13 +/- 0.57. CONCLUSION: CM grafts achieved results comparable to those of FGGs in augmented tissue. They do not negatively affect probing depths, MR, or bleeding on probing. PMID- 30461440 TI - The many ages of man: diverse approaches to assessing ageing-related biological and psychological measures and their relationship to chronological age. AB - PURPOSE OF REVIEW: Chronological age is a crude measure and may not be the best indicator of the ageing process. Establishing valid and reliable biomarkers to understand the true effect of ageing is of great interest. We provide an overview of biological and psychological characteristics that change with age and can potentially serve as markers of the ageing process, and discuss if an integration of these characteristics may more accurately measure the true age of a person. We also describe the clinicopathological continuum of these ageing-related changes. RECENT FINDINGS: Ageing-related changes in the biological and psychological systems of the body have been studied to varying degrees and with differing emphases. Despite the development of ageing indices, there is no single indicator that can holistically estimate the ageing process. Differential ageing of bodily systems remains poorly understood, and valid methods have not been developed for composite markers of biological and psychological processes. SUMMARY: The ageing process is complex and heterogeneous. Incorporating biological and psychological measures may improve accuracy in reflecting an individual's 'true age,' and elucidate why some people age successfully, whereas others show ageing-related decline and disease. PMID- 30461441 TI - Drug Use-Related Normative Misperceptions and Behaviors Among Persons Seeking Heroin Withdrawal Management. AB - OBJECTIVE: Normative perceptions about substance use are well-established predictors of substance use risk behaviors, yet no research to date has examined how people who use heroin perceive the drug use behaviors and their association with personal behaviors. In a sample of persons seeking heroin withdrawal, we compared normative beliefs (descriptive norms) about others' drug use behaviors, and examined the association between normative beliefs and behaviors. METHOD: Participants (n = 241) were patients undergoing short-term inpatient heroin withdrawal management in Massachusetts. t-Tests were used to compare participants' perceptions about various substance use behaviors among both US adults and persons seeking heroin withdrawal at the same site. We also examined associations between participants' normative beliefs and personal substance use behaviors. RESULTS: Participants significantly overestimated drug-related risk behaviors of adults nationally; overall, participants estimated that 44.7% had tried heroin, 37.6% had injected drugs in the past year, and 63.2% had smoked marijuana in the past month when actual national rates are 2.0%, 0.3%, and 5.5%, respectively. Participants also held significant misperceptions about contemporaneous patients in the heroin withdrawal program; behaviors about sharing works, diverting buprenorphine or methadone, and exchanging sex for drugs or money were most substantially overestimated. Normative perceptions were associated with a range of personal drug-using behaviors (eg, injection drug use, exchanging sex for drugs or money). CONCLUSIONS: Consistent with existing substance use norms research, participants in the current sample tended to overestimate others' engagement in risky substance use, and these normative perceptions were associated with increased personal risk. Leveraging norms in heroin harm reduction interventions may hold substantial promise. PMID- 30461442 TI - Impact of Nicotine and Other Stimulants on Sleep in Young Adults. AB - OBJECTIVES: Sleep problems can have long-term negative consequences. This study explored the relationship of commonly used stimulant substances to poor sleep quality in young adults. METHODS: We surveyed 498 participants, aged 18 to 25, who reported recent alcohol or marijuana use. Stimulant substances measured included coffee, energy drinks, nonmedical prescription stimulants (NPS), cocaine, and nicotine. Sleep outcomes were measured using the Pittsburgh Sleep Quality Index (PSQI) and its components. RESULTS: Participants averaged 21.3 (+/ 2.07) years of age, 47.8% male, 65.5% non-Latino white, 10.8% African-American, 12.3% Latino, and 11.5% other ethnic origins. In the past 30 days, 24.9% had used cigarettes, 48.1% energy drinks, 17.3% NPS, 79.3% coffee, and 7.9% cocaine. Mean PSQI global score was 6.21 (+/-3.66, median = 5). After adjusting for background characteristics, PSQI global scores were positively and significantly associated with number of cigarettes/day (b = 0.16, 95% confidence interval 0.07 to 0.25, P < 0.001) and days of NPS (b = 0.10, 95% confidence interval 0.01 to 0.18, P = 0.030). CONCLUSIONS: NPS negatively affects sleep, but nicotine is particularly deleterious to sleep quality. Addressing smoking cessation to improve sleep may be a novel way to motivate young adult smokers to quit. PMID- 30461443 TI - Receipt of Substance Use Disorder Treatment Among Patients Visiting Psychiatrists. PMID- 30461444 TI - A New Speech, Spatial, and Qualities of Hearing Scale Short-Form: Factor, Cluster, and Comparative Analyses. AB - OBJECTIVES: The objective of this work was to build a 15-item short-form of the Speech Spatial and Qualities of Hearing Scale (SSQ) that maintains the three factor structure of the full form, using a data-driven approach consistent with internationally recognized procedures for short-form building. This included the validation of the new short-form on an independent sample and an in-depth, comparative analysis of all existing, full and short SSQ forms. DESIGN: Data from a previous study involving 98 normal-hearing (NH) individuals and 196 people with hearing impairments (HI), non hearing aid wearers, along with results from several other published SSQ studies, were used for developing the short-form. Data from a new and independent sample of 35 NH and 88 HI hearing aid wearers were used to validate the new short-form. Factor and hierarchical cluster analyses were used to check the factor structure and internal consistency of the new short-form. In addition, the new short-form was compared with all other SSQ forms, including the full SSQ, the German SSQ15, the SSQ12, and the SSQ5. Construct validity was further assessed by testing statistical relationships between scores and audiometric factors, including pure-tone threshold averages (PTAs) and left/right PTA asymmetry. Receiver-operating characteristic analyses were used to compare the ability of different SSQ forms to discriminate between NH and HI (HI non hearing aid wearers and HI hearing aid wearers) individuals. RESULTS: Compared all other SSQ forms, including the full SSQ, the new short-form showed negligible cross-loading across the three main subscales and greater discriminatory power between NH and HI subjects (as indicated by a larger area under the receiver-operating characteristic curve), as well as between the main subscales (especially Speech and Qualities). Moreover, the new, 5-item Spatial subscale showed increased sensitivity to left/right PTA asymmetry. Very good internal consistency and homogeneity and high correlations with the SSQ were obtained for all short-forms. CONCLUSIONS: While maintaining the three-factor structure of the full SSQ, and exceeding the latter in terms of construct validity and sensitivity to audiometric variables, the new 15-item SSQ affords a substantial reduction in the number of items and, thus, in test time. Based on overall scores, Speech subscores, or Spatial subscores, but not Qualities subscores, the 15-item SSQ appears to be more sensitive to differences in self evaluated hearing abilities between NH and HI subjects than the full SSQ. PMID- 30461445 TI - The Influence of Stimulus Repetition Rate on Tone-Evoked Post-Auricular Muscle Response (PAMR) Threshold. AB - OBJECTIVES: Post-auricular muscle response (PAMR) is a large myogenic potential that can be useful in estimating behavioral hearing thresholds when the recording protocol is optimal. The main aim of the present study was to determine the influence of stimulus repetition rate on PAMR threshold. DESIGN: In this repeated measures study, 20 normally hearing adults aged between 18 and 30 years were recruited. Tone bursts (500, 1000, 2000, and 4000 Hz) were used to record PAMR thresholds at 3 different stimulus repetition rates (6.1/s, 11.1/s, and 17.1/s). RESULTS: Statistically higher PAMR thresholds were found for the faster stimulus rate (17.1/s) compared with the slower stimulus rate (6.1/s) (p < 0.05). For all stimulus rates and frequencies, significant correlations were found between PAMR and pure-tone audiometry thresholds (r = 0.62 to 0.82). CONCLUSIONS: Even though the stimulus rate effect was significant at most of the tested frequencies, the differences in PAMR thresholds between the rates were small (<5 dB). Nevertheless, based on the correlation results, we suggest the use of 11.1/s stimulus rate when recording PAMR thresholds. PMID- 30461446 TI - Upgrading the Diagnostic Assessment in Primary Pulmonary Carcinoids: The Tumor infiltrating Lymphocytes (TILs). PMID- 30461447 TI - Efficacy of axillary versus infraclavicular brachial plexus block in preventing tourniquet pain: A randomised trial. AB - BACKGROUND: Axillary and infraclavicular brachial plexus blocks are commonly used for upper limb surgery. Clinicians require information on the relative benefits of each to make a rational selection for specific patients and procedures. OBJECTIVES: The main objective of the study was to compare axillary and infraclavicular brachial plexus block in terms of the incidence and severity of tourniquet pain. DESIGN: Single blinded, randomised trial. SETTING: University affiliated hospital, level-1 trauma centre. PATIENTS: Age more than 18 years, ASAI-III patients undergoing orthopaedic surgery distal to the elbow, with an anticipated tourniquet duration of more than 45 min were recruited. INTERVENTIONS: Patients underwent either ultrasound guided axillary brachial plexus block or infraclavicular block (ICB). MAIN OUTCOME MEASURES: Incidence of tourniquet pain (onset, severity, associated haemodynamic changes) and block characteristics (block performance/onset times, distribution, incidence of adverse events, patient satisfaction) were recorded. RESULTS: Eighty two patients (40 in the axillary block and 42 in the ICB group) were recruited. The incidence (5/36 and 3/35; P = 0.71), onset time (73.0 +/- 14.8 and 86.6 +/- 5.7 min; P = 0.18) and severity (mild/moderate; 4/1 and 1/2; P = 0.51) of tourniquet pain were similar in the two groups. The incidence of paraesthesia during block performance, and block performance time were greater in the axillary block group (P = 0.0054 and 0.012, respectively). The volume of local anaesthetic administered was greater in the ICB group (P < 0.01). ICB was associated with a greater degree of sensory block in the distributions of both the axillary nerve and the medial cutaneous brachial nerve (P < 0.01). Overall patient satisfaction and incidence of inadvertent vascular puncture were similar in the two groups. CONCLUSION: For surgical procedures which are of moderate duration, infraclavicular and axillary blocks are associated with similar incidences of tourniquet pain. Other factors appear to differentiate between these two blocks, namely block performance time, incidence of paraesthesia and dose of local anaesthetic. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02714738. PMID- 30461448 TI - Cysteine-derived hydrogen sulfide and gut health: a matter of endogenous or bacterial origin. AB - PURPOSE OF REVIEW: Hydrogen sulfide (H2S) is produced in the gut from cysteine by epithelial cells and by the intestinal microbiota. Initially considered as a toxic gas, the pleiotropic effects of H2S are now recognized, especially in the colonic mucosa. The aim of this review is to present new experimental data indicating that cysteine-derived H2S is emerging as a key regulator of gut health. RECENT FINDINGS: Cysteine degradation by the microbiota emerged as a dominant pathway for H2S production. Among bacteria producing H2S from cysteine, Fusobacterium appears as a pivotal genus associated with digestive diseases. H2S promotes or alleviates mucosal inflammation, mostly according to its high (high micromolar to millimolar) or low (nanomolar to low micromolar) concentration, respectively. H2S maintains the integrity of the mucus layer when derived from endogenous metabolism but is detrimental for this parameter when produced in excess by gut microbes. In inflammatory bowel diseases, an upregulation of H2S production from cysteine by the gut microbiota is observed concomitantly with a downregulation of enzymes implicated in its mucosal detoxification. In colorectal cancer patients, an upregulation of both endogenous and microbial H2S production from cysteine are observed at tumor site that might contribute to disease progression. SUMMARY: H2S is a double-edge sword for the intestinal epithelium. This is related to the bell-shaped effects of H2S, with protective effect at low concentration but deleterious effects at higher concentrations. As the gut microbiota produces much more H2S from cysteine than endogenous metabolism, we consider that the bacterial or epithelial source of H2S is a major determinant of its effects for intestinal health. PMID- 30461449 TI - Contraction and nutrition interaction promotes anabolism in cachectic muscle. AB - PURPOSE OF REVIEW: Cachexia is a disease-related multifactorial syndrome characterized by inflammation, massive muscle protein catabolism and carbohydrate and lipid metabolism disorder.Several studies tried to define the impact of either nutrition or physical exercise (single approach strategy) or their combination (multimodal approach strategy) on prevention and/or treatment of muscle wasting in cachectic patients. RECENT FINDINGS: Single approach strategies (i.e. nutrition or physical exercise) have the potential of preventing and improving features of the cachexia syndrome possibly with a differential impact according to the underlying disease. Limited information is available on the beneficial effect of multimodal approach strategies. SUMMARY: Multimodal approaches appear to be more effective than those based on single interventions in physiological condition and in cachectic patients with COPD or chronic kidney disease. Further studies, however, are required in cachexia induced by heart failure, cancer and critical illness. PMID- 30461450 TI - Glutamine and type 1 diabetes mellitus: is there a role in glycemic control? AB - PURPOSE OF REVIEW: Recent literature suggests dietary glutamine supplementation may lower blood glucose in patients with type 1 diabetes (T1D), who have no residual insulin secretion. The mechanisms and potential relevance to the care of T1D remain unclear. RECENT FINDINGS: Glutamine is involved in multiple pathways including gluconeogenesis, lipolysis, antioxidant defense, the production of nitric oxide, the secretion of peptides (e.g., glucagon-like peptide 1, GLP-1), or neuromediators (e.g., [Latin Small Letter Gamma]-aminobutyric acid), all processes that may impact insulin sensitivity and/or glucose homeostasis. The article reviews potential mechanisms and literature evidence suggesting a role in improving glucose tolerance in patients with illness associated with insulin resistance, as well as the preliminary evidence for the increased incidence of postexercise hypoglycemia in T1D after oral glutamine. SUMMARY: Further studies are warranted to determine whether the lowering effect of glutamine on blood glucose is sustained over time. If so, long-term randomized trials would be warranted to determine whether there is a role for glutamine as an adjunct dietary supplement to improve glucose control in patients with T1D. PMID- 30461451 TI - Sarcopenia and obesity. AB - PURPOSE OF REVIEW: Together with age-related body composition changes, the increased prevalence of obesity observed in the past few decades in older individuals has led to a condition called sarcopenic obesity, characterized by a mismatch between muscle mass and fat mass. The operative definition of sarcopenic obesity is still under discussion and creates difficulties in clinical practice. Muscle weakness, rather than low muscle mass, was previously proposed as an alternative criterion and, more recently, the dynapenic abdominal obese phenotype is of increasing interest because of its unfavorable health consequences and usability in clinical practice. RECENT FINDINGS: This review focuses on the most recent findings of pathogenic inter-relationships between adipose tissue and muscle. Recent studies on health consequences of sarcopenic obesity and dynapenic abdominal obesity are also examined. Despite the lack of consensus on a definition for sarcopenic obesity, progress has been made in the delineation of the treatment principles for this condition. SUMMARY: Further research is needed to compare different definitions of sarcopenic/dynapenic obesity to clarify the relationship between obesity and the most important adverse outcomes in the elderly. The next step will be the definition of best possible therapeutic approaches for this condition. PMID- 30461452 TI - Scaling up pre-exposure prophylaxis in sub-Saharan Africa. AB - PURPOSE OF REVIEW: Pre-exposure prophylaxis (PrEP) is highly efficacious for preventing HIV. Demonstrations worldwide show growing acceptability with nonoral formulations in the pipeline. Despite these successes, oral PrEP scale-up in sub Saharan Africa (SSA), the region hardest hit by HIV, remains sub-optimal. This review details emerging practises and addresses challenges in PrEP scale-up and delivery within SSA. RECENT FINDINGS: PrEP scale-up varies across SSA. Some countries face implementation challenges, whereas most have not applied for or received regulatory approval. As governments balance treatment and prevention costs, PrEP advocacy is growing. Demand has been slow, because of low-risk perception, HIV treatment conflation or poor information. Challenges in SSA are markedly different than elsewhere, as delivery is targeted to generalized heterosexuals, rather than only key populations. SSA requires public sector engagement and innovative delivery platforms. SUMMARY: PrEP scale-up in SSA is sub-optimal, hindered by regulatory processes, implementation challenges, poor community engagement and inadequate funding. Approaches that acknowledge overburdened, under-resourced health sectors, and seek opportunities to integrate, task-shift, decentralize and even de-medicalize, with a tailored approach, while campaigning to educate and stimulate demand are most likely to work. Solutions to oral PrEP scale-up will apply to other formulations, opening new avenues for ARV (microbicides and injectables) and non-ARV-based (future vaccine) biomedical prevention provision. PMID- 30461453 TI - Optimizing antiretroviral regimens in chronic kidney disease. AB - PURPOSE OF THE REVIEW: To identify recent data that inform the management of individuals with HIV and chronic kidney disease. RECENT FINDINGS: Several nonnucleoside reverse transcriptase, protease, and integrase strand transfer inhibitors inhibit tubular creatinine secretion resulting in stable reductions in creatinine clearance of 5-20 ml/min in the absence of other manifestations of kidney injury. Progressive renal tubular dysfunction is observed with tenofovir disoproxil fumarate in clinical trials, and more rapid decline in estimated glomerular filtration rate in cohort studies of tenofovir disoproxil fumarate and atazanavir, with stabilization, improvement or recovery of kidney function upon discontinuation. Results from clinical trials of tenofovir alafenamide (TAF) in individuals with chronic kidney disease suggest that TAF is well tolerated in those with mild to moderate renal impairment (creatinine clearance >30 ml/min) but results in very high tenofovir exposures in those on haemodialysis. SUMMARY: Standard antiretroviral regimens remain appropriate for individuals with normal and/or stable, mildly impaired kidney function. In those with chronic kidney disease or progressive decline in estimated glomerular filtration rate, antiretrovirals with nephrotoxic potential should be avoided or discontinued. Although TAF provides a tenofovir formulation for individuals with impaired kidney function, TAF is best avoided in those with severe or end-stage kidney disease. PMID- 30461454 TI - Assessing inflammation and its role in comorbidities among persons living with HIV. AB - PURPOSE OF REVIEW: This article describes the use of biomarkers in expanding our understanding of chronic non-AIDS comorbidities among persons living with HIV (PLWH) receiving antiretroviral therapy (ART). RECENT FINDINGS: We review current evidence that biomarkers of chronic immune activation and inflammation associate with a broad spectrum of end-organ diseases in PLWH. We discuss how ART may impact inflammation associated with HIV infection and the degree to which inflammation persists despite effective suppression of viral replication in plasma. We then discuss the limitations of the current literature, which lacks evidence of causality and disproportionately involves a few protein biomarkers that are unable to disentangle complex and overlapping biological pathways. SUMMARY: Premature end-organ disease among PLWH has been repeatedly associated with higher levels of blood biomarkers reflecting inflammation and immune activation, which, despite viral suppression and CD4 T-cell increases after ART treatment, remain elevated relative to uninfected persons. There remain important unanswered questions with implications for the development of anti-inflammatory treatment strategies aimed at mitigating excess risk for end-organ comorbidities among PLWH. PMID- 30461455 TI - Aesthetic Durable Forehead Contouring in Asians With Fat Grafting and Botulinum Toxin. AB - BACKGROUND: Augmentative forehead contouring to create a full rounded smooth forehead is increasingly popular worldwide especially in East Asia where a flat and/or concave irregular forehead is considered unaesthetic. We present our outcomes performing fat transfer to the forehead in combination with botulinum toxin (Botox) corrugator-frontalis injection where indicated in East Asians. METHODS: From 2013 to 2017, 62 consecutive patients with flat and/or concave irregular unaesthetic foreheads underwent forehead fat transfer using a microautologous fat transplantation gun. Concomitant Botox injection to minimize corrugator and frontalis contraction-mediated fat displacement was indicated in 23 patients (thin forehead skin and/or excessive forehead animation or rhytides) to prevent forehead vertical crease formation. Thirty-nine subjects with a mean follow-up of 16 months (range = 3-44 months) had their pregraft and postgraft forehead contours assessed on an aesthetic grading scale. Of these 39, 17 completed forehead fat graft volumetric analysis using preoperative and postoperative 3D photography. RESULTS: Aesthetic results were durable at latest follow-up, and all patients were satisfied with their final appearance. The mean amount of fat transferred was 7.72 mL (range = 1.5-33 mL). One subject required a repeat fat grafting (with Botox) because of vertical crease formation after the index procedure (without Botox). Another 12 needed a second fat-grafting session to optimize the contour. All who received Botox did not develop vertical creases. The mean +/- SD forehead contour grade improved from 2.29 +/- 0.77 to 3.24 +/- 0.67 (P < 0.001). The percentage mean +/- SD retention of grafted fat was 46.71% +/- 5.77% with Botox versus 39.12% +/- 5.24% without Botox (P = 0.006). CONCLUSIONS: Fat grafting to the forehead using our technique with selective Botox administration is an effective, simple, fast, inexpensive, and safe strategy for aesthetic forehead contouring especially for flat and/or concave foreheads. Forehead fat survival rate is objectively improved with simultaneous Botox injection. There is minimum downtime and long-lasting results with high patient satisfaction rates. PMID- 30461456 TI - Lateral Toe Pulp Flap Used in Reconstruction of Distal Dorsal Toe Defect: Case Report and Review of the Literature. AB - BACKGROUND: When the distal dorsal part of the great toe is injured, especially with exposure of a tendon, bone, or joint, applying a free or local flap is difficult because of the lack of locally available tissue for reconstruction. Management of the distal dorsal part of a great toe soft tissue defect can be challenging for plastic surgeons. PATIENT AND METHOD: An 18-year-old woman presented with an injury to the dorsal aspect of her right great toe caused by a cobra bite. After fasciotomy, the wound showed exposure of the extensor hallucis longus tendon. After demarcation and infection control, the wound was reconstructed using a lateral toe pulp flap of approximately 3.5 * 1.0 cm. The flap was transposed to the defect, and the donor site was closed primarily. Toe pulp flaps are mainly used to reconstruct finger pulp defects and are useful because they provide a glabrous skin flap suitable for resurfacing fingertip injuries. A lateral toe pulp flap uses a homodigital adjacent skin flap, which is transposed to cover the soft tissue defect. Using a quick and straightforward procedure, we designed this flap to reconstruct a distal dorsal defect of the great toe, with minimal morbidity at the donor site. RESULTS: The flap initially showed mild congestion but survived completely. CONCLUSIONS: Applying a lateral toe pulp flap is a quick, simple, and reliable 1-stage procedure. It may be an effective option in reconstructing distal dorsal defects of the great toe. PMID- 30461457 TI - Application of Computer-Assisted Navigation System in Acute Zygomatic Fractures. AB - OBJECTIVE: To compare the surgical results of early treatment of zygomatic fractures with and without the use of the computer-assisted navigation system. METHODS: All patients with unilateral traumatic zygomatic fractures treated within 30 days after the injury at a single center between June 2012 and May 2017 were studied retrospectively. Primary outcome was defined by the displacement at 5 junctional sutures of zygomatic bone, the change at each point before and after the reconstruction, and the patient's subjective scoring of their appearance. Secondary outcome included the length of the operation and hospital stay, the number of incisional approaches, the fixation points, the maximal mouth opening, and the sequelae upon follow-up. RESULTS: Twenty-eight patients were enrolled in this study. Fourteen of them received surgery with the help of a computer assisted navigation system (navigation group), and 14 patients were treated without its assistance (control group). Before the surgery, the mean displacement of each junctional suture and the mean total displacement between both groups were comparable. Postoperative computed tomography showed that the mean total displacement was significantly less for the navigation group than the control group (0.53 vs 2.93 mm, P = 0.001), and the displacement of zygomaticosphenoid suture was smaller (0 vs 0.9 mm, P = 0.009). Patients in the navigation group underwent surgery via the single buccal-gingival approach without the need for longer operation time. There were no significant differences in the length of hospital stay, maximal mouth opening, or cheek numbness. All patients recovered without major complications and were comparatively satisfied with their final appearance. CONCLUSIONS: The navigation system has been demonstrated to be a useful tool for improving the symmetry in delayed or secondary reconstruction of zygomatic fractures. This study showed its effectiveness and safety in cases of early treatment as well, achieving a more accurate correction in a less invasive manner. PMID- 30461458 TI - Transposition of Duplicated Thumb for Reconstruction of Asymmetric Radial Polydactyly. AB - BACKGROUND: In this study, we present the long-term functional and aesthetic outcomes in patients with complicated asymmetric radial polydactyly treated with this surgical technique involving the transposition of a duplicated thumb. METHODS: We evaluated 6 thumbs in 6 patients who underwent radial polydactyly reconstruction using the transposition of duplicated thumb procedure between 2001 and 2017. The procedure was used when one of the thumbs was not obviously dominant over the other, with one having a better proximal portion and the other having a better distal portion. The average age at the time of surgery was 35 months, and at the final follow-up, average age was 86.5 months. Objective outcome values were obtained, and the Japanese Society for Surgery of the Hand evaluation form was adopted to assess functional and cosmetic outcomes. RESULTS: Neither soft tissue loss nor nonunion of the osteotomy was noted. No patients reported pain or difficulties in their activities. Mean flexion-extension arc for the metacarpophalangeal joint was 72.9 degrees (range, 8.8 degrees extension to 64.1 degrees flexion), and that for the interphalangeal joint was 44.0 degrees (range, 5.7 degrees extension to 38.3 degrees flexion). Mean key pinch, tip pinch, and grip strength of unaffected thumb were 75.1%, 68.7%, and 81.9%, respectively. Total scores using the Japanese Society for Surgery of the Hand scoring system averaged 18.2 points, and the results were excellent in 1 case and good in 5. CONCLUSIONS: Transposition of duplicated thumb can provide durable functional and cosmetic results for Rotterdam types IV and VI with asymmetric radial polydactyly in which neither thumb has adequate distal and proximal components. PMID- 30461459 TI - Madelung Disease: Analysis of Clinicopathological Experience in Taipei Veterans General Hospital. AB - BACKGROUND: The main feature of Madelung disease (MD), a rare condition, is the growth of adipose tissue without a capsule. Usually, this disease is known for its prominent features with fat deposition around the neck, shoulder, back, or chest wall. Clinically, the patient is likely to exhibit alcohol, neuropathy, and metabolic disorders; however, no clear cause has been confirmed. AIMS: The aim of this study was to analyze the morphological, pathophysiological, and various treatment methods of MD. We have presented and discussed 16 cases of treatment of this disease at our hospital and reviewed the literature on this subject. METHODS: We carried out a retrospective chart review of 16 consecutive patients with MD treated from 1989 through 2017. Patient demographic data, tumor size and location, and follow-up data were evaluated. Patients usually seek treatment because of the disfigured appearance, restricted range of the motion of the head and neck, inconvenience in daily activity such as eating or speaking, and worry about the mass effect. All patients underwent surgical resection and/or combined liposuction. RESULTS: Among the patients, 14 were men, aged 38 to 80 years, with a history of disease ranging from 6 months to 7 years. The mean duration from symptoms to diagnosis of MD was 4.4 years. The mean duration of follow-up was 82.8 months (range, 5-192 months). Three patients died of coronary artery disease at follow-up of 27, 78, and 141 months. The functional results were satisfactory in all patients. Severe complications were not observed. CONCLUSIONS: According to our experience, surgical resection is the main method of improving the appearance, ensuring eradication of the tumor, and reducing the possibility of recurrence. In addition, we have a case in which atypical changes were confirmed by histological examination in fractional surgery. A long follow-up period is recommended considering the high propensity and mean time to recurrence. Although malignant transformation of MD is rare occurrence, it occurred in 1 of the 16 patients. PMID- 30461460 TI - Endovenous Photocoagulation Using a Diode Laser for Complicated Varicose Veins Related to Stasis Ulcers. AB - BACKGROUND: The objective of this study was to assess the efficacy and safety of endovenous laser photocoagulation (EVLP) at a wavelength of 810 nm for treating complicated venous insufficiency associated with venous ulcers. MATERIALS AND METHODS: A retrospective review of 110 patients with 180 legs having chronic venous insufficiencies associated with varicose veins treated over an 8-year period was conducted. Patients ranged from 16 to 80 years of age and included 85 women and 25 men. Of the 110 patients, 32 (29.10%) patients with 40 legs having varicose veins were defined as having complicated varicose veins associated with venous ulcers. All 32 patients received EVLP treatment using a diode laser. Complications were evaluated at 3 weeks (early), 6 weeks (late), and 6 months (final) after EVLP treatment. The primary efficacy and final outcome measurement were determined through quantitative assessment using Hach's and clinical, etiological, anatomical, and pathophysiological classification. Safety was evaluated for each treatment group by monitoring adverse effects. RESULTS: Early complications were swelling, local paresthesia, pigmentation, minor superficial thermal injury, superficial phlebitis, and localized hematomas. All complications and ulcerations resolved completely within 2 weeks. No recurrence occurred after the study's 6-month follow-up period. Based on paired t test analysis, clinically significant differences in severity scores were discovered, which were based on Hach's classification before and after EVLP treatment at a wavelength of 810 nm. All patients achieved improvement from clinical, etiological, anatomical, and pathophysiological class C6 to C5. Permanent adverse effects were not observed. CONCLUSIONS: Endovenous laser photocoagulation at the wavelength of 810 nm permitted the use of appropriate light doses for treating complicated varicose veins associated with venous ulcers and resulted in significant improvement in lesions. PMID- 30461461 TI - Adjuvant Radiotherapy After Keloid Excision: Preliminary Experience in Taiwan. AB - BACKGROUND: Surgical excision with adjuvant radiotherapy has gained attention as an effective treatment of keloid. The Asian population is challenged with a high incidence of keloid occurrence with a specific genetic predominance. The annual reported incidence of new keloid cases in Taiwan is around 30,000, but the disease control rate and effectiveness by means of surgical excision with adjuvant radiotherapy is not yet clear. METHODS: A retrospective chart review of the included consecutive keloid patients receiving surgical excision and radiotherapy was performed from 2013 to 2016 in a single institute. The reported risk factors were collected to investigate according to the outcome analysis. The Vancouver Scar Scale and the Japan Scar Workshop (JSW) Scar Scale were used to evaluate the correlation with keloid recurrence. RESULTS: In this series, the overall recurrence rate was 32%, reported with an average follow-up of 28 months. Independent risk factors varied according to the different outcome variables. Only JSW classification score independently predicted the risk of keloid recurrence (odds ratio, 1.305; P = 0.02). Both the Vancouver Scar Scale and the JSW system showed a good correlation with keloid recurrence (correlation efficiency, 0.529 and 0.54; P = 0.0437 and 0.0165, respectively). CONCLUSIONS: This preliminary report revealed convincing evidence of feasibility and effectiveness of applying adjuvant radiotherapy after keloid excision in the Taiwanese population. A more delicate biological equivalent dose of radiotherapy with an effective local control should be considered to improve the final outcome. PMID- 30461462 TI - Thalamocortical network: a core structure for integrative multimodal vestibular functions. AB - PURPOSE OF REVIEW: To apply the concept of nonreflexive sensorimotor and cognitive vestibular functions and disturbances to the current view of separate right and left thalamocortical systems. RECENT FINDINGS: The neuronal modules for sensorimotor and cognitive functions are organized in so-called provincial hubs with intracommunity connections that interact task-dependently via connector hubs. Thalamic subnuclei may serve not only as provincial hubs but also in higher order nuclei as connector hubs. Thus, in addition to its function as a cortical relay station of sensory input, the human thalamus can be seen as an integrative hub for brain networks of higher multisensory vestibular function. Imaging studies on the functional connectivity have revealed a dominance of the right side in right-handers at the upper brainstem and thalamus. A connectivity-based parcellation study has confirmed the asymmetrical organization (i.e., cortical dominance) of the parieto-insular vestibular cortex, an area surrounded by other vestibular cortical areas with symmetrical (nondominant) organization. Notably, imaging techniques have shown that there are no crossings of the vestibular pathways in between the thalamic nuclei complexes. Central vestibular syndromes caused by lesions within the thalamocortical network rarely manifest with rotational vertigo. This can be explained and mathematically simulated by the specific coding of unilateral vestibular dysfunction within different cell systems, the angular velocity cell system (rotational vertigo in lower brainstem lesions) in contrast to the head direction cell system (directional disorientation and swaying vertigo in thalamocortical lesions). SUMMARY: The structural and functional separation of the two thalamic nuclei complexes allowed a lateralization of the right and left hemispheric functions to develop. Furthermore, it made possible the simultaneous performance of sensorimotor and cognitive tasks, which require different spatial reference systems in opposite hemispheres, for example, egocentric manipulation of objects (handedness) and allocentric orientation of the self in the environment by the multisensory vestibular system. PMID- 30461463 TI - New concepts on acute ocular ischemia. AB - PURPOSE OF REVIEW: To review recent advances in the management of acute ocular ischemic events, including: transient monocular vision loss, central and branch retinal artery occlusions, and nonarteritic anterior ischemic optic neuropathy. RECENT FINDINGS: Transient monocular vision loss and acute retinal arterial occlusions require immediate diagnosis and management, with recognition of these events as transient ischemic attack or stroke equivalents, respectively. Patients should undergo an immediate stroke workup in a stroke center, similar to patients with acute cerebral ischemia. The treatment of central retinal artery occlusions remains limited despite the growing use of thrombolytic treatments. The indication for these treatments remains under debate. No quality evidence exists to support any therapy, including corticosteroids, in the treatment of nonarteritic anterior ischemic optic neuropathy. The highest priority in management is to rule-out giant cell arteritis. SUMMARY: Effective therapies for the treatment of ischemic events of the retina and optic nerve remain elusive. Clinicians should focus on the prompt recognition of these events as ocular emergencies and immediately refer patients with vascular transient visual loss and acute central and branch retinal arterial occlusions to the nearest stroke center. PMID- 30461464 TI - Is intravenous thrombolysis still necessary in patients who undergo mechanical thrombectomy? AB - PURPOSE OF REVIEW: To summarize available evidence on the potential utility of pretreatment with intravenous thrombolysis (IVT) using recombinant tissue plasminogen activator (rt-PA) in acute ischemic stroke (AIS) patients with large vessel occlusions (LVO) who are treated with mechanical thrombectomy. RECENT FINDINGS: Despite theoretical concerns of a higher bleeding risk with IVT pretreatment, there are no data showing increased risk of symptomatic intracerebral hemorrhage (sICH) in patients with LVO receiving bridging therapy (IVT and mechanical thrombectomy) compared with direct mechanical thrombectomy (dMT). Additionally, evidence from observational studies suggest lower rates of infarctions in previously unaffected territories and higher rates of successful reperfusion, with lower number of device passes, in patients receiving bridging therapy. There are substantial discrepancies in studies comparing clinical outcomes between dMT and bridging therapy that are directly related to the inclusion of patients with contraindications to IVT in the dMT group. Ongoing clinical trials will provide definitive answers on the potential additional benefit of IVT in LVO patients receiving mechanical thrombectomy. SUMMARY: IVT and mechanical thrombectomy are two effective reperfusion therapies that should be used in a swift and noncompeting fashion in AIS patients. AIS patients with LVO and no contraindications for IVT should receive promptly rt-PA bolus followed by immediate initiation of mechanical thrombectomy as indicated by current international recommendations, unless future randomized controlled trials provide evidence to proceed differently. PMID- 30461465 TI - Vestibular rehabilitation: advances in peripheral and central vestibular disorders. AB - PURPOSE OF REVIEW: Rehabilitation for persons with vertigo and balance disorders is becoming commonplace and the literature is expanding rapidly. The present review highlights recent findings of both peripheral and central vestibular disorders and provides insight into evidence related to new rehabilitative interventions. Risk factors will be reviewed to create a better understanding of patient and clinical characteristics that may effect recovery among persons with vestibular disorders. RECENT FINDINGS: Clinical practice guidelines have recently been developed for peripheral vestibular hypofunction and updated for benign paroxysmal positional vertigo. Diagnoses such as persistent postural-perceptual dizziness (PPPD) and vestibular migraine are now defined, and there is growing literature supporting the effectiveness of vestibular rehabilitation as a treatment option. As technology advances, virtual reality and other technologies are being used more frequently to augment vestibular rehabilitation. Clinicians now have a better understanding of rehabilitation expectations and whom to refer based on evidence in order to improve functional outcomes for persons living with peripheral and central vestibular disorders. SUMMARY: An up-to-date understanding of the evidence related to vestibular rehabilitation can assist the practicing clinician in making better clinical decisions for their patient and hopefully result in optimal functional recovery. PMID- 30461466 TI - Outcomes, Satisfaction, and Costs of a Rheumatology Telemedicine Program: A Longitudinal Evaluation. AB - OBJECTIVES: Rural veterans with inflammatory arthritis (IA) lack access because of geographic barriers. Telemedicine (TM) holds great promise in relieving these disparities. We have prospectively measured patient-centered data surrounding a TM care program at a federal health system and compared these with usual care (UC). METHODS: Veterans with previously established IA were enrolled in TM follow up. Data collected longitudinally before and after entering the program included Routine Assessment of Patient Index Data 3 (RAPID-3), out-of-pocket visit costs and distances traveled, and patient satisfaction instruments. Demographics were recorded. Similar data were collected on a convenience sample of concurrent IA patients receiving UC. RESULTS: Eighty-five patients were observed, including 25 receiving TM care and 60 receiving UC. No differences in demographics, satisfaction scores, or RAPID-3 were noted at baseline between groups. Univariate linear regression of cross-sectional baseline data suggests satisfaction instrument scores were predicted by RAPID-3 (beta = -0.64/10 points, P = 0.01), as well as distance (beta = -0.19/100 miles, P = 0.02) and cost (beta = 0.37/$100, P = 0.05). A multivariate model indicates both distance (beta = 0.17/100 miles, P = 0.02) and RAPID-3 (beta = -0.47/10 points, P < 0.03) were predictors for visit satisfaction. In longitudinal follow-up via TM, satisfaction (Delta = 0.03, P = 0.94) and RAPID-3 (Delta = 0.27, P = 0.89) remained similar to baseline among TM patients, whereas distance traveled (Delta = -384.8 miles/visit, P < 0.01) and visit costs (Delta = -$113.8/visit, P < 0.01) were reduced. CONCLUSIONS: Patient-reported outcomes for care delivered via TM were similar to UC, with significant cost and distance savings. Patient-centered factors such as distance to care should be considered in design care delivery models, as they appear to drive patient satisfaction in conjunction with disease control. PMID- 30461467 TI - Trends in Deep Vein Thrombosis Prophylaxis and Deep Vein Thrombosis Rates After Total Hip and Knee Arthroplasty: Erratum. PMID- 30461468 TI - Finding a Peaceful Place. AB - Year-end is a good time for reflection. PMID- 30461469 TI - Workplace Violence. PMID- 30461470 TI - Rural Maternal Mortality. PMID- 30461471 TI - Medication And Fall Prevention. PMID- 30461472 TI - The Ethics of Slow Codes and the Implications for Nurses. AB - Timely, open communication with patients or their surrogates about prognosis is crucial. PMID- 30461473 TI - The American Pregnancy: A Tale of Race, Class-and Zip Code. AB - One state-California-is defying the system. PMID- 30461474 TI - 2018 Flu Vaccine Recommendations for Adults and Children. AB - New guidance for the intranasal vaccine and for those allergic to eggs. PMID- 30461475 TI - NewsCAP: Nearly half of pediatric ED visits for adverse drug events are antibiotic related. PMID- 30461477 TI - First Guidelines for Diagnosing and Managing Concussion in Kids. AB - The CDC addresses a common and significant health concern. PMID- 30461476 TI - NewsCAP: Poor-quality health care causes 8.4 million deaths in low- and middle income countries. PMID- 30461478 TI - NewsCAP: Tracking people with dementia or autism who wander. PMID- 30461479 TI - NewsCAP: The AAP updates child passenger safety policy. PMID- 30461480 TI - Do State Regulations on Nurse Staffing Make a Difference in ICU Outcomes? AB - A new study questions the effect on patient outcomes but is narrow in scope. PMID- 30461481 TI - NewsCAP: U.S. syphilis, gonorrhea, and chlamydia rates reach a record high. PMID- 30461482 TI - What Nurses Need to Know About Cybersecurity. AB - It's all part of protecting patients, and vigilance is key. PMID- 30461485 TI - Infant Safe Sleep Practices in the United States. AB - Risk of sleep-related infant deaths can be reduced by improving safe sleep practices. PMID- 30461486 TI - The Analgesic Efficacy of Opioids in Cancer Pain. AB - Editor's note: This is a summary of a nursing care-related systematic review from the Cochrane Library. For more information, see http://nursingcare.cochrane.org. PMID- 30461487 TI - Risk of Rare, Serious Genital Infection from some Diabetes Drugs. PMID- 30461488 TI - First Generic Epipen Approved. PMID- 30461489 TI - The Tenkara Way. PMID- 30461490 TI - 1 CE Test Hour: Original Research: Advance Care Planning: An Exploration of the Beliefs, Self-Efficacy, Education, and Practices of RNs and LPNs. PMID- 30461491 TI - 1 CE Test Hour: Managing Movement Disorders: A Clinical Review. PMID- 30461492 TI - Creating a Culture of Mobility: Using Real-Time Assessment to Drive Outcomes. AB - : : Background: Recent studies have demonstrated the safety and feasibility of early mobilization of patients in the hospital setting. Promoting early mobility improves patients' ability to perform daily activities and attend to basic needs. It also preserves patients' dignity and independence. We implemented a culture of mobility program to promote awareness of the importance of early mobility among health care providers, patients, and family caregivers on an inpatient orthopedic unit. PURPOSE: The goal of the program was to empower clinical RNs, physical therapists (PTs), and occupational therapists to conduct dynamic, ongoing assessment of a patient's functional status so the plan of care could be modified in real time to promote functional independence and prevent immobility-associated complications. METHODS: Nursing and therapy professionals used three mobility assessments to estimate the degree and type of activities a patient could safely perform during a hospital stay: the Johns Hopkins Highest Level of Mobility (JH HLM) scale, the Physical Therapy Mobility Assessment (PTMA) scale, and the Occupational Therapy Assistance Assessment (OTAA) scale. The three assessment tools were incorporated into the electronic health record. To evaluate their performance, we retrospectively collected patient data before (baseline) and after (intervention) their implementation. There were 61 patients in the baseline group and 59 in the intervention group. RESULTS: The clinical characteristics of patients in the two groups were comparable, including demographics, diagnoses, and activity orders. The JH-HLM and PTMA scores correlated significantly with the maximum distance patients ambulated as measured independently by RNs and PTs, suggesting the tools worked as expected to estimate the actual activity patients performed. Importantly, we found that the intervention improved patient mobility, as evidenced by significant increases in the maximum distances and the number of times patients ambulated. Further, the initial scores on the JH-HLM, PTMA, and OTAA scales correlated significantly with the length of stay (LOS), an important outcome variable. This suggests that the mobility assessments can also be used to predict LOS and thus optimize hospital bed management. CONCLUSIONS: Nursing and therapy professionals successfully implemented three new mobility assessment tools on an inpatient orthopedic unit. The tools captured real-time information about patients' functional ability that was used to encourage patients' mobility. PMID- 30461493 TI - Delegating as a New Nurse. AB - This column is designed to help new nurses in their first year at the bedside-a time of insecurity, growth, and constant challenges-and to offer advice as they learn what it means to be a nurse. This article offers strategies new nurses can use and specific steps they can take to help them succeed in delegating tasks to LPNs/LVNs and unlicensed assistive personnel. PMID- 30461494 TI - The Choosing Wisely Campaign for Nursing. AB - Ongoing efforts to identify and reduce the use of unnecessary tests and procedures. PMID- 30461495 TI - Get on Board with Being on a Board. AB - Why should nurses serve, what are the barriers, and how can they be overcome? PMID- 30461496 TI - Breaking the Cycle of Human Trafficking. AB - Resources to help nurses identify, assess, and care for victims. PMID- 30461497 TI - Seeking Good Nurses with a Story to Tell. AB - Updated several times a week with posts by a wide variety of authors, AJN's blog Off the Charts allows us to provide more timely-and often more personal perspectives on professional, policy, and clinical issues. Best of the Blog will be a regular column to draw the attention of AJN readers to posts we think deserve a wider audience. To read more, please visit: www.ajnoffthecharts.com. PMID- 30461498 TI - Epinephrine in Out-Of-Hospital Cardiac Arrest. AB - According to this study. PMID- 30461499 TI - Initial Laryngeal Tube Insertion in Out-Of-Hospital Cardiac Arrest. AB - According to this study. PMID- 30461500 TI - Study Doesn't Support Widespread Use of Statins in Elderly Patients. AB - According to this study. PMID- 30461501 TI - High LDL-C, Non-HDL-C Levels Associated with Higher CVD Death Risk, Even in Those at Low CVD Risk. AB - According to this study. PMID- 30461502 TI - Department of Public Health Nursing. AB - Editor's note: From its first issue in 1900 through to the present day, AJN has unparalleled archives detailing nurses' work and lives over more than a century. These articles not only chronicle nursing's growth as a profession within the context of the events of the day, but they also reveal prevailing societal attitudes about women, health care, and human rights. Today's nursing school curricula rarely include nursing's history, but it's a history worth knowing. To this end, From the AJN Archives highlights articles selected to fit today's topics and times.This month we remember the influenza pandemic of 1918-19, which peaked in the United States during the fall of 1918. In AJN's December 1918 issue, public health nursing leader Edna L. Foley reported on home nursing activities in Chicago that fall. She describes how the Visiting Nurse Association (VNA), the city's Tuberculosis Nurses, and the Red Cross managed the deployment of nurses, aides, and supplies as well as food, coal, and clean bedding for families. The VNA's daily case-load increased more than 400% from September to October. Face masks were in short supply, so the nurses replaced cloth masks, which had to be boiled and dried daily, with disposable gauze masks, "which were tied over the face or pinned to the hair."Death notices of nurses were a regular feature of AJN in its early years, and the December 1918 issue included a special, poignant section on "Deaths Resulting from Influenza." It filled four pages. To access Foley's full AJN article, go to http://links.lww.com/AJN/A127. PMID- 30461504 TI - No Illusion of Forever. AB - A mother and nurse expertly cares for her dangerously immunocompromised sons while making every day count. PMID- 30461505 TI - Incorporating risk factors in the development of the screening programme for developmental dysplasia of the hips. AB - In a 12-year cohort study, all newborns with suspected developmental dysplasia of the hips (DDHs) were scheduled for hip ultrasound at the sixth week of life. Female sex is the only isolated risk factor with a positive likelihood ratio predictive of DDH [1.26; 95% confidence interval (CI): 1.04-1.54]. In combination, the presence of two or more risk factors was predictive of DDH (positive likelihood ratio 1.10; 95% CI: 1.00-1.20). The sensitivity and specificity of two or more risk factors for the prediction of DDH were 93.6% (95% CI: 86.6-97.6) and 14.5% (95% CI: 8.70-22.2), respectively. The level of evidence for the cohort study is II. PMID- 30461506 TI - Family-Centered Care During Constraint-Induced Therapy After Chronic Stroke: A Feasibility Study. AB - PURPOSE: This feasibility study evaluated a theory-based intervention (CARE-CITE) designed to engage carepartners (CPs) in supporting stroke survivor upper extremity rehabilitation. DESIGN: The study was a one-group design with pre- and posttest and 1 month follow-up (N = 7 dyads). METHODS: Feasibility was determined by participant retention, CP and stroke survivor intervention adherence, and CP acceptability of the intervention (exit interview). Measures of CP depressive symptoms, fatigue, and family conflict around stroke recovery and stroke survivor upper extremity function are reported. Data were analyzed using descriptive statistics. FINDINGS: All participants completed the study and adhered to the intervention, and CPs found CARE-CITE helpful. Descriptively, better scores were observed for CP's mental health, family conflict, stroke survivor confidence, and upper extremity tasks performed. CONCLUSION: These results provide initial evidence that CARE-CITE is feasible after chronic stroke and that CPs and stroke survivors may benefit from family-centered care. CLINICAL RELEVANCE: Improving CP skills in supporting rehabilitation activities may improve stroke survivor upper extremity function. PMID- 30461507 TI - Nursing Interventions Improve Continuous Positive Airway Pressure Adherence in Obstructive Sleep Apnea With Excessive Daytime Sleepiness: A Systematic Review. AB - PURPOSE: The purpose of this systematic review was to summarize the effectiveness of interventions in the literature to improve adherence to continuous positive airway pressure (CPAP) treatment in patients with excessive daytime sleepiness. METHODS: In this review, we considered only randomized controlled trials that included interventions to improve CPAP adherence in adult obstructive sleep apnea (OSA) patients with high daytime sleepiness. FINDINGS: Eight trials were included in this review. The types of interventions to improve adherence to CPAP can be grouped into educational, technological, pharmacological, and multidimensional interventions. CONCLUSIONS AND CLINICAL RELEVANCE: Educational programs can increase CPAP adherence in OSA patients. As nurses are the main clinicians responsible for device use for patients, the therapeutic strategies to improve CPAP adherence are important in their clinical setting. Therefore, the nursing work related to the use of CPAP has a great impact on the quality of life and mortality of patients with OSA.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30461508 TI - Treatment of fever in neutropenia in pediatric oncology patients. AB - PURPOSE OF REVIEW: Fever during neutropenia is a common occurrence in children with cancer. A number of studies have recently been performed to refine algorithms regarding initiation, modification, and termination of antimicrobial treatment and are the basis for international pediatric-specific guidelines for the treatment of fever and neutropenia in children with cancer. RECENT FINDINGS: Although hospitalization and prompt initiation of intravenous broad-spectrum antibiotics remains the mainstay in the treatment of febrile neutropenic children with cancer, recent research has addressed a number of questions to optimize the management of these patients. Risk prediction rules have been evaluated to allow for individualized treatment intensity and to evaluate the safety of early discontinuation of empirical antibiotic therapy. In addition, the use of preemptive antifungal therapy has been evaluated to decrease the use of antifungal agents. SUMMARY: Based on the results of studies in children, pediatric-specific guidelines have been established and are regularly updated. PMID- 30461509 TI - Septic arthritis of the pediatric hip: update on diagnosis and treatment. AB - PURPOSE OF REVIEW: To review the clinical diagnosis, management and natural history of septic arthritis of the hip (SAH) in the pediatric patient, and to highlight new information that may improve the management of these patients. RECENT FINDINGS: The basics of management of possible pediatric SAH have remained largely unchanged for generations. New questions have been raised regarding the role and timing of advanced imaging (MRI) in the evaluation of patients with possible SAH. Published criteria have been derived to guide the need for MRI studies in these patients. Validation of these guidelines continues. Recent reviews have highlighted the possibility of Lyme disease as a potential cause of monoarticular pediatric hip pain. The role of PCR technology in the diagnosis and management of SAH remains unclear at this time. SUMMARY: The child with a limp remains a common and urgent clinical concern. There may be expanded roles for MRI and PCR to better diagnose and treat the involved joint itself, as well as any associated nonarticular area of infection. Lyme disease should remain on the list of possible differential diagnoses in this population, particularly in geographic areas where the disease vector is known to be endemic. PMID- 30461510 TI - Paediatric medial humeral epicondyle fracture management: 2019 approach. AB - PURPOSE OF REVIEW: The management of displaced medial humeral epicondyle fractures in children remains controversial. The indications for surgery, the ideal surgical strategy and the implications of a painful nonunion remain unclear. RECENT FINDINGS: This article describes the state of the evidence and the art in the management of medial humeral epicondyle fractures concentrating on recent research and current opinion. Treatment of paediatric medial epicondylar fractures of the elbow remains the domain of expert opinion and subject to great variance. Anatomical, biomechanical and computer simulation models suggest great importance should be given to the medial epicondyle and the structures, which insert onto it. However, this does not correlate with outcomes as reported by patients, parents and surgeons. SUMMARY: The question of which paediatric medial humeral epicondylar fractures benefit from operative fixation remains unanswered. A large randomized prospective trial is required. PMID- 30461511 TI - Evidence-based update on the surgical treatment of pediatric tibial shaft fractures. AB - PURPOSE OF REVIEW: To describe surgical treatment options for pediatric tibial shaft fractures which are the third most common pediatric long bone fracture. Management of these injuries is dictated by fracture location, fracture pattern, associated injuries, skeletal maturity, and other patient-specific factors. Although most pediatric tibial shaft fractures can be treated nonoperatively, this review provides an update on surgical treatment options when operative intervention is indicated. RECENT FINDINGS: Advances in surgical implants and techniques affords a wide range of options for the surgical treatment of pediatric tibial shaft fractures. Flexible intramedullary nailing is gaining wide adoption for acute surgical treatment. Recent studies support cross-sectional imaging for further evaluation and scrutiny of fracture patterns suspicious for intraphyseal or intra-articular extension. Grade I open tibial shaft fractures may be safely treated with irrigation and debridement in the emergency department; however, no high-level comparative studies have been performed to make any definitive conclusions regarding the effectiveness of this treatment strategy. SUMMARY: Tibial shaft fractures are common injuries in pediatric patients. Management is dictated by fracture location, fracture pattern, associated injuries, patient age, and other patient-specific factors. Surgical intervention is indicated for fractures that are open, irreducible, have failed nonoperative management, are associated with compartment syndrome, or in the multiply injured patient. Surgical treatment options include flexible intramedullary nailing, plate osteosynthesis, external fixation, and rigid intramedullary nailing. Recent literature has shown increased rates of flexible intramedullary nailing. All operative and nonoperative management options can result in complications including compartment syndrome, infection, delayed union, nonunion, malunion, limb length discrepancy, and symptomatic hardware. Most pediatric patients go on to uneventful union with excellent final outcomes and return to full activities. PMID- 30461512 TI - Adolescent idiopathic scoliosis for the primary care physician: frequently asked questions. AB - PURPOSE OF REVIEW: Provide primary care physicians with the best available evidence to support answers to frequently asked questions by caregivers of patients with adolescent idiopathic scoliosis (AIS). RECENT FINDINGS: A review of best available evidence shows that schoolbag design and weight are not associated with higher odds of developing AIS. However, patients with AIS are more prone to balance problems with asymmetric backpack carrying and with rising weights. In patients with AIS, the backpack should be worn in a symmetric way and should never exceed 10% of the child's body weight. Although no relationship was found between systematic exercising in general and development of AIS, classical ballet and professional swimming in skeletally immature adolescents were associated to higher odds of having AIS. Since AIS affects adolescent girls mainly, women health issues are of paramount importance in this disease. Except for limited sexual activity and higher need for infertility treatment, patients with AIS perform similar to controls in marriage rates, age at first pregnancy, gestational age, offspring, labor and delivery. Best available evidence shows that adults with AIS diagnosed during adolescence have similar physical activity level compared with controls. In patients with AIS, adults with surgically treated idiopathic scoliosis have slightly lower physical activity level than previously braced and untreated patients. SUMMARY: Although schoolbag weight isn't associated with higher odds of developing AIS, classical ballet and professional swimming in adolescents are. Except for limited sexual activity, patients with AIS perform similar to controls in remaining women health issues. Adults with AIS diagnosed during adolescence have similar physical activity level compared with controls. PMID- 30461513 TI - Does Tourniquet Use in TKA Increase Postoperative Pain? A Systematic Review and Meta-analysis. AB - BACKGROUND: Although tourniquets are commonly used during TKA, that practice has long been surrounded by controversy. Quantifying the case for or against tourniquet use in TKA, in terms of patient-reported outcomes such as postoperative pain, is a priority. QUESTIONS/PURPOSES: The purpose of this study was to meta-analyze the available randomized trials on tourniquet use during TKA to determine whether use of a tourniquet during TKA (either for the entire procedure or some portion of it) is associated with (1) increased postoperative pain; (2) decreased ROM; and (3) longer lengths of hospital stay (LOS) compared with TKAs performed without a tourniquet. METHODS: We completed a systematic review and meta-analysis using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines to assess the impact of tourniquet use on patients after TKA. We searched the following databases from inception to February 1, 2015, for randomized controlled trials meeting prespecified inclusion criteria: PubMed, Embase, and Cochrane Central Register of Controlled Trials. Postoperative pain was the primary outcome. Secondary outcomes were postoperative ROM and LOS. The initial search yielded 218 studies, of which 14 met the inclusion criteria. For our primary analysis on pain and ROM, a total of eight studies (221 patients in the tourniquet group, 219 patients in the no tourniquet group) were meta-analyzed. We also performed a subgroup meta-analysis on two studies that used the tourniquet only for a portion of the procedure (from osteotomy until the leg was wrapped with bandages) and defined this as half course tourniquet use (n = 62 in this analysis). The Jadad scale was used to ascertain methodological quality, which ranged from 3 to 5 with a maximum possible score of 5. Statistical heterogeneity was tested with I and chi-square tests. A fixed-effects (inverse variance) model was used when the effects were homogenous, which was only the case for postoperative pain; the other endpoints had moderate or high levels of heterogeneity. Publication bias was assessed using a funnel plot, and postoperative pain showed no evidence of publication bias, but the endpoint of LOS may have suffered from publication bias or poor methodological quality. We defined the minimum clinically important difference (MCID) in pain as 20 mm on the 100-mm visual analog scale (VAS). RESULTS: We found no clinically important difference in mean pain scores between patients treated with a tourniquet and those treated without one (5.23 +/- 1.94 cm versus 3.78 +/- 1.61 cm; standardized [STD] mean difference 0.88 cm; 95% confidence interval [CI], 0.54-1.23; p < 0.001). None of the studies met the MCID of 20 mm in VAS pain scores. There was also no clinically important difference in ROM based on degrees of flexion between the two groups (49 +/- 21 versus 56 +/- 22; STD mean difference 0.8; 95% CI, 0.4-1.1; p < 0.001). Similarly, we found no difference in mean LOS between groups (5.8 +/- 4.4 versus 5.9 +/- 4.6; STD mean difference -0.2; 95% CI, -0.4 to 0.1; p = 0.25). A subgroup meta-analysis also showed no clinically important difference in pain between the full-course and half-course tourniquet groups (5.17 +/- 0.98 cm versus 4.09 +/- 1.08 cm; STD mean difference 1.31 cm; 95% CI, -0.16 to 2.78; p = 0.08). CONCLUSIONS: We found no clinically important differences in pain or ROM between patients treated with and without tourniquets during TKA and no differences between the groups in terms of LOS. In the absence of short-term benefits of avoiding tourniquets, long-term harms must be considered; it is possible that use of a tourniquet improves a surgeon's visualization of the operative field and the quality of the cement technique, either of which may improve the long-term survivorship or patient function, but those endpoints could not be assessed here. We recommend that the randomized trials discussed in this meta-analysis follow patients from the original series to determine if there might be any long-term differences in pain or ROM after tourniquet use. LEVEL OF EVIDENCE: Level I, therapeutic study. PMID- 30461515 TI - Virtue Ethics in a Value-driven World: Can I Respect Autonomy Without Respecting the Person? PMID- 30461514 TI - Structured-mentorship Program for Periacetabular Osteotomy Resulted in Few Complications for a Low-volume Pelvic Surgeon. AB - BACKGROUND: The Bernese periacetabular osteotomy (PAO) is a complex surgical procedure with a substantial learning curve. Although larger hospital and surgeon procedure volumes have recently been associated with a lower risk of complications, in geographically isolated regions, some complex operations such as PAO will inevitably be performed in low volume. A continuous structured program of distant mentoring may offer benefits when low numbers of PAOs are undertaken, but this has not been tested. We sought to examine a structured, distant-mentorship program of a low-volume surgeon in a geographically remote setting. QUESTIONS/PURPOSES: The purposes of this study were (1) to identify the clinical results of PAO performed in a remote-mentorship program, as determined by patient-reported outcome measures and complications of the surgery; (2) to determine radiographic results, specifically postoperative angular corrections, hip congruity, and progression of osteoarthritis; and (3) to determine worst-case analysis of PAO survivorship, defined as nonconversion to THA, in a regionally isolated cohort of patients with a high rate of followup. METHODS: Between August 1992 and August 2016, 85 PAOs were undertaken in 72 patients under a structured, distant-mentorship program. The patients were followed for a median of 5 years (range, 2-25 years). There were 18 males (21 hips) and 54 females (64 hips). The median age of the patients at the time of surgery was 26 years (range, 14-45 years). One patient was lost to followup (two PAOs) and one patient died as a result of an unrelated event. Patient-reported outcome measures and complications were collected through completion of patient and doctor questionnaires and clinical examination. Radiographic assessment of angular correction, joint congruity, and osteoarthritis was undertaken using standard radiology software. PAO survivorship was defined as nonconversion to THA and is presented using worst case analysis. The loss-to-followup quotient-number of patients lost to followup divided by the number of a patients converted to THA-was calculated to determine quality of followup and reliability of survivorship data. RESULTS: The median preoperative Harris hip scores of 58 (range, 20-96) improved postoperatively to 78 (range, 33-100), 86 (range, 44-100), 87 (range, 55-97), and 80 (range, 41-97) at 1, 5, 10, and 14 years, respectively. Sink Grade III complications at 12 months included four relating to the PAO and one relating to the concomitant femoral procedure. The median lateral center-edge angle correction achieved was 22 degrees (range, 3 degrees -50 degrees ) and the median correction of acetabular index was 19 degrees (range, 3 degrees -37 degrees ). Osteoarthritis progressed from a preoperative mean Tonnis grade of 0.6 (median, 1; range, 0-2) to a postoperative mean of 0.9 (median, 1; range, 0-3). Six hips underwent conversion to THA: five for progression of osteoarthritis and one for impingement. At 12-year followup, survivorship of PAO was 94% (95% confidence interval [CI], 85%-98%) and survivorship with worst-case analysis was 90% (95% CI, 79%-96%). The loss-to-followup quotient for this study was low, calculated to be 0.3. CONCLUSIONS: When PAO is performed using a structured process of mentoring under the guidance of an expert, one low-volume surgeon in a geographically isolated region achieved good patient-reported outcomes, a low incidence of complications at 12 months, satisfactory radiographic outcomes, and high survivorship. A structured distant-mentorship program may be a suitable method for initially learning and continuing to perform low-volume complex surgery in a geographically isolated region. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 30461516 TI - Does Patellar Tendon Repair With Gastrocnemius Flap Augmentation Effectively Restore Active Extension After Proximal Tibial Sarcoma Resection? AB - BACKGROUND: A rotational gastrocnemius flap is often used for soft tissue reconstruction after proximal tibia sarcoma resection. However, little is known about the frequency and severity of complications and the recovery of extensor function after this procedure. QUESTIONS/PURPOSES: After gastrocnemius flap reconstruction with split-thickness skin grafting (STSG) to augment the extensor mechanism repair after proximal tibial resection for sarcoma, we asked: (1) What ROM was achieved (including extensor lag and active flexion)? (2) How often did complications and reoperations occur and what caused them? METHODS: Between 1991 and 2014, one surgeon treated 26 patients with proximal tibial resections for primary bone sarcoma. Of these, 18 were reconstructed with the preferred approach: resecting the proximal tibia leaving the patellar tendon in continuity with the tibialis anterior fascia whenever possible (10), cementing a stemmed proximal tibial endoprosthesis, suturing the patellar tendon to the implant, rotating a medial (16) or lateral (two) gastrocnemius flap over the tendon and prosthesis to augment the repair, and covering the flap with STSG. Alternative methods were used when this was technically impossible (one patient), when there was no advantage to secondary soft tissue coverage (two patients), or when the limb could not be salvaged (five patients). Of the 18 treated with gastrocnemius flaps, two were lost to followup or died of disease before the 24-month minimum and excluded; the median followup of the remaining 16 was 6 years (mean, 9.9 years; range, 2.3-21.7 years); three patients died of disease, and four have not been seen within the last 5 years. We reviewed medical records for passive and active extension, maximum flexion achieved, and complications requiring reoperation. ROM in patients with successful limb salvage was graded as excellent (flexion >= 110 degrees and no lag), good (flexion 90 degrees -110 degrees and lag <= 10 degrees ), fair (one function limited: either flexion < 90 degrees or lag > 10 degrees ), or poor (both functions limited: flexion < 90 degrees and lag > 10 degrees ). RESULTS: At latest followup, three patients had undergone amputation for deep infection. Of those remaining, median active flexion was 110 degrees (mean, 104 degrees ; range, 60 degrees -120 degrees ) and extensor lag was 0 degrees (mean, 4 degrees ; range, 0 degrees -10 degrees ). ROM was excellent in nine patients, good in three, fair in one, and poor in none. We observed 18 complications requiring reoperation in 12 patients, including deep infection (four), patellar tendon avulsion/attenuation (three), and flap necrosis (one). Survivorship free from revision or loss of the gastrocnemius flap was 74% (95% confidence interval [CI], 5.6-95.8) at 2, 5, and 10 years. Survivorship free from reoperation for any cause was 74% (95% CI, 52.0-96.0) at 2 years, 52% (95% CI, 25.8-77.8) at 5 years, and 35% (95% CI, 0-61.5) at 10 years using Kaplan Meier analysis. CONCLUSIONS: Although most patients regained functional ROM including active extension, 12 required reoperation for complications including infection and early extensor mechanism failures. Despite the observed risks, we believe the gastrocnemius flap with STSG should be considered a suitable approach to provide active extension and soft tissue coverage given the paucity of good surgical options for extensor mechanism reconstruction in this challenging clinical setting. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 30461517 TI - Three Different Databases, Three Different Complication Rates for Knee and Hip Arthroplasty: Comparing the National Inpatient Sample, National Hospital Discharge Survey, and National Surgical Quality Improvement Program, 2006 to 2010. AB - BACKGROUND: National databases are increasingly used to research complication rates, risk factors, and the role of comorbidities. Three commonly used databases are the Healthcare Cost and Utilization Program's National Inpatient Sample (NIS), the National Hospital Discharge Survey (NHDS), and the American College of Surgeons National Surgical Quality Improvement Program (NSQIP). Despite many publications, the accuracy of results from these databases remains unclear. METHODS: We compared demographics and complication rates of primary total hip arthroplasty (THA) and primary total knee arthroplasty (TKA) across three national databases from 2006 to 2010. Using International Classification of Diseases, Ninth Revision, Clinical Modification and Current Procedural Terminology codes to identify cases, we calculated postoperative inpatient complication rates in all three databases and 30-day complication rates in the NSQIP. RESULTS: We identified a total of 607,322 TKAs and 279,428 THAs. Overall complication rates varied greatly between the databases. For TKA, the overall complication rates were the highest in the NIS (17.3% [16.6 to 18.0]), followed by the NHDS (14.9% [14.0 to 15.8]), and then the NSQIP 30 days (10.20% [9.73 to 10.70]) and the NSQIP until discharge (7.34% [6.95 to 7.75]). Similarly, for THA, the NIS was the highest (24.09% [23.05 to 25.16]), and then the NHDS (21.5% [19.8 to 23.2]), followed by the NSQIP 30 days (12.00% [11.31 to 12.72]), and the NSQIP until discharge (9.25% [8.64 to 9.90]). Breakdown and comparison of individual adverse events further revealed different complication rates. CONCLUSION: The estimated complication rates from THA and TKA depend on which data source is used because of differences in data collection and sampling methodology. Similar differences may exist in other publications that use such secondary data sources. PMID- 30461518 TI - Effect of Obesity on the Development, Management, and Outcomes of Spinal Disorders. AB - Obesity is a major public health issue in the United States, and rates of obesity continue to increase across the population. The association of obesity with degenerative spinal pathology underlies the observation that a substantial number of patients undergoing spine surgery are either overweight or obese. Obesity is a notable independent risk factor for both surgical and medical complications in the perioperative period and an important consideration in preoperative planning, intraoperative strategies, and postoperative management. Despite these increased risks, surgery in obese patients for a variety of degenerative conditions results in improvement in outcomes. Although obese patients may undergo gains that are absolutely lower than their nonobese counterparts, they still experience a positive treatment effect with surgery appropriate for their condition. An evidence-based approach to both preoperative and perioperative management of patients with obesity is not well established. The purpose of this article is to review the effect of obesity on the development, management, and outcomes of patients with spinal disorders and to provide data that may guide an evidence based approach to care in this expanding patient population. PMID- 30461519 TI - Mortality After Periprosthetic Femur Fractures During and After Primary and Revision Total Hip Arthroplasty. AB - INTRODUCTION: We determined mortality rates after intraoperative and postoperative periprosthetic femur fractures in primary and revision total hip arthroplasty (THA). METHODS: The study population comprised 522 intraoperative and 480 postoperative femur fractures in 26,250 primary THA patients and 590 intraoperative and 224 postoperative femur fractures in 4,532 revision THA patients. The risk of death was examined using Cox regression models. RESULTS: In primary THA, intraoperative periprosthetic femur fractures were not associated with excess risk of death (hazard ratio, 1.03; 95% confidence interval, 0.86 to 1.22). The risk of death was slightly elevated among primary THA patients with postoperative femur fractures (hazard ratio, 1.19; 95% confidence interval, 1.08 to 1.43), but the excess risk was only confined to patients with comorbid orthopaedic conditions. In revision THA, neither intraoperative nor postoperative periprosthetic femur fractures were associated with excess risk of death. CONCLUSION: Periprosthetic femur fractures are not associated with excess mortality among primary osteoarthritis patients. LEVEL OF EVIDENCE: Level III. PMID- 30461520 TI - Musculoskeletal-based Patient-reported Outcome Performance Measures, Where Have We Been-Where Are We Going. AB - While health care evolves from volume to value, there is increasing interest by payors to use patient-reported outcomes (PROs) to determine value and more specifically, quality from the patient's perspective. This article reviews the current state of PROs and discusses future directions. Specifically, this article will review the current history and background of PROs; it will highlight the perspective of the National Quality Forum and review the efforts of the musculoskeletal community related to PROs. Goals, positive aspects, limitations, and barriers related to PROs will be discussed. Additionally, development considerations and strategies will be highlighted. Finally, development recommendations from the American Academy of Orthopaedic Surgery position statement "principles for musculoskeletal based PRO performance measurement development" will be introduced. PMID- 30461521 TI - The Nepean Dyspepsia Index is a valid instrument for measuring quality-of-life in functional dyspepsia. AB - BACKGROUND: The Nepean Dyspepsia Index (NDI) has been in widespread use since its publication in 1999 and the addition of a short form in 2001. The NDI was one of the first disease-specific quality-of-life instruments created for functional dyspepsia (FD). However, its psychometric properties have never been validated in an independent sample. AIM: This study aimed to evaluate the validity and reliability of the NDI in an a-priori driven approach in an independent population. PATIENTS AND METHODS: In 289 individuals who fulfilled the Rome criteria for FD enrolled in a randomized placebo-controlled trial (FD treatment trial), we examined construct validity, convergent validity, and internal consistency. RESULTS: Construct validity was supported in its 25-item unweighted and weighted forms as well as the 10-item short form. All items in the 25-item form yielded considerable (>0.5) standardized loadings on their respective latent variables and all reached statistical significance (P<0.0001), supporting their relationships with the hypothesized domains. Convergent validity was strongly supported, with every domain being correlated with multiple external instruments; the majority of correlations were in the range 0.3-0.5 (in absolute values). The items comprising each domain showed good internal consistency, with the lowest value of Chronbach alpha at 0.80. Scores based on the short form (10-item) version of the NDI correlated strongly with the full 25-item form (tension rho=0.88, interference rho=0.94, eat/drink rho=0.95, knowledge rho=0.84 and work/study rho=0.97; all P<0.0001). CONCLUSION: The NDI is a valid instrument that can be used to measure the disease-specific impact of FD on quality of life. PMID- 30461522 TI - Long-term follow-up after cure from chronic hepatitis C virus infection shows occult hepatitis and a risk of hepatocellular carcinoma in noncirrhotic patients. AB - OBJECTIVES: Curing hepatitis C virus (HCV) infection primarily aims to prevent severe liver complications. Our objectives were to investigate the long-term presence and impact of occult HCV infection (OCI) and to study the outcomes in terms of liver disease after virological cure. PATIENTS AND METHODS: A total of 97 patients with achieved sustained virological response (SVR) during 1990-2005 were followed either by a clinical follow-up (FU) visit with blood sampling and liver elastography (n=54) or through national registries for outcomes (n=43). To diagnose OCI among patients with SVR, a highly sensitive method was used to detect HCV-RNA traces in whole blood. The FU duration was a median of 10.5 years, with samples up to 21.5 years after the end of treatment (EOT). RESULTS: The majority of patients [52 (96%)] were HCV-RNA negative at FU, and regression of fibrosis was statistically significant. OCI was found in two (4%) of them at 8 and 9 years after EOT. These patients had F1 and F2 fibrosis before treatment and F2 at FU, but no other abnormal findings. Three previously noncirrhotic men were diagnosed with hepatocellular carcinoma 8-11 years after EOT. CONCLUSION: Occult infection could be detected many years after the achievement of SVR but was not associated with the serious liver disease. The majority had persistent viral eradication and regression of fibrosis after SVR. However, an increased risk of hepatocellular carcinoma may persist in the long term after SVR even in noncirrhotic patients. Further studies with FU after direct-acting antiviral therapy and on the long-term impact after cure are needed. PMID- 30461523 TI - Response to letter: 'Proton pump inhibitors therapy and the risk of major osteoporotic nonhip fractures in older adults in Taiwan'. PMID- 30461524 TI - Evidence-Based Practice Curriculum Development for Undergraduate Nursing Students: The Preliminary Results of an Action Research Study in Taiwan. AB - BACKGROUND: Equipping undergraduate nursing students with sufficient competence in evidence-based practice (EBP) is essential to meeting future practice needs. Integrating necessary EBP knowledge and skills systematically into the formal curriculum allows students to obtain better learning experience and outcomes. However, in Taiwan, a systematic nursing curriculum that integrates EBP concepts across the 4-year nursing baccalaureate program has not yet been developed. Moreover, engaging students in the clinical application of evidence remains a key challenge facing nursing education. PURPOSE: This study aimed to construct an EBP undergraduate nursing curriculum and develop clinical scenarios that support EBP teaching. METHODS: Three cycles of action research, incorporating both focus group interviews and questionnaire surveys, were applied to construct and evaluate the appropriateness and feasibility of the EBP nursing curriculum and relevant teaching strategies. RESULTS: An EBP nursing curriculum was constructed that integrates the three levels of learning objectives and corresponding learning outcomes, teaching content, and learning activities. Scenario activities were developed to familiarize students with the EBP process and to maximize their learning with regard to the clinical application of evidence. Next, a preliminary evaluation showed the appropriateness and feasibility of the developed curriculum, which was shown to foster the EBP competency of students and increase their confidence and positive attitudes toward EBP. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: A systematic EBP bachelor nursing curriculum with effective pedagogical strategies was developed. The associated process and the elicited information may offer a valuable reference for other nursing schools. PMID- 30461525 TI - Application of Ultrasonic Bone Aspirator for Decompression of the Internal Auditory Canal via the Middle Cranial Fossa Approach. AB - OBJECTIVE: Evaluate the safety and efficacy of the ultrasonic bone aspirator (UBA) during middle cranial fossa (MCF) approach to vestibular schwannoma (VS). STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center. PATIENTS: Charts of 192 consecutive VS patients over 18 years of age were reviewed to identify 65 patients who underwent MCF approach to VS resection between 2006 and 2017. A combination of UBA and high-speed drill (HSD) was used to decompress the internal auditory canal (IAC) in 25 patients and HSD alone was used in the other 40 patients. INTERVENTION(S): Use of UBA during vestibular schwannoma surgery via MCF approach for decompression of the IAC. MAIN OUTCOME MEASURE(S): Postoperative facial nerve outcomes assessed by the House-Brackmann (HB) facial nerve grading scale. Rates of gross total resection (GTR) and cerebrospinal fluid (CSF) leak. RESULTS: There were no significant differences in postoperative facial nerve function, in rate of GTR of tumor, or in rate of CSF leak. In the UBA group 24/25 (96%) had postoperative HB grade I-II compared with 36/40 (90%) in the HSD group (p-value = 0.66). GTR was achieved in 25/25 (100%) in the UBA group compared with 38/40 (95%) in the HSD group (p-value = 1). In the UBA group, there were 0/25 (0%) cases of CSF leak compared with 1/40 (2.5%) in the HSD group (p-value = 1). CONCLUSIONS: UBA use is a safe and effective alternative or adjunct to HSD during MCF approach to expose the IAC contents. This surgical tool allows for bone removal with low risk of injury to adjacent structures. PMID- 30461526 TI - Utility of Postoperative Magnetic Resonance Imaging in Patients Who Fail Superior Canal Dehiscence Surgery. AB - OBJECTIVE: The etiology of symptoms following primary repair of superior canal dehiscence (SCD) may be due to a persistent third window. However, the extent of surgery cannot be seen on postoperative computed tomography (CT) since most repair materials are not radiopaque. We hypothesize that the extent of superior semicircular canal (SSC) occlusion following primary repair can be quantified based on postoperative magnetic resonance imaging (MRI) data. STUDY DESIGN: Retrospective series. SETTING: Tertiary care center. PATIENTS: Adult patients with a history of SCD syndrome who 1) report persistent symptoms following primary SCD repair and 2) underwent heavily T2-weighted MRI postoperatively. INTERVENTIONS: Analysis of SSC using 3D-reconstruction of CT co-registered with MRI data. MAIN OUTCOME MEASURES: Arc length of fluid void on MRI and quantification of persistent SCD based on CT/MRI co-registration. RESULTS: We identified 9 revision cases from a cohort of 145 SCD repairs at our institution (2002-2017) with CT/MRI data. A fluid void on postoperative MRI (indicating occlusion of the SSC) was observed in all cases (anterior limb: 50.1 degrees [+/ 21.8 SD] and posterior limb 48.1 degrees [+/-28.5 SD]). Co-registration of CT/MRI revealed a residual defect that was most commonly found along the posterior limb in most patients with persistent symptoms. CONCLUSIONS: The extent of SCD repair can be determined using reformatted or direct T2-weighted MRI sequences in the plane of Poschl. Co-registration of CT/MRI may be useful to determine the location of a residual superior canal defect and when present was found most commonly along the posterior limb. PMID- 30461527 TI - Increased risk of inflammatory bowel disease in families with tonsillectomy: A Danish national cohort study. AB - BACKGROUND: The possible etiologic link between tonsillectomy and inflammatory bowel diseases remains unclear. To investigate the hereditary component, we assessed the risk of inflammatory bowel disease after own tonsillectomy as well as after tonsillectomy among family members. METHODS: A nationwide Danish cohort of 7,045,288 individuals was established and linked to comprehensive national registers with data on kinship, tonsillectomy surgery, and diagnosis of inflammatory bowel disease from all health sectors. We used Poisson regression models to estimate hospital contact rate ratios (RR) for Crohn's disease and ulcerative colitis, with 95% confidence intervals (CI), between individuals with or without tonsillectomy, as well as between individuals with or without tonsillectomized relatives. RESULTS: During 189 million person-years of follow-up between 1977 and 2014, 276,673 individuals were tonsillectomized, 22,015 developed Crohn's disease, and 49,550 developed ulcerative colitis. Rates of inflammatory bowel disease were elevated up to 20 years after own tonsillectomy (Crohn's disease: RR 1.52 (95% CI, 1.43-1.61); ulcerative colitis: RR 1.24 (95% CI, 1.18-1.29)). RRs for Crohn's disease was 1.22 (95% CI, 1.17-1.27) after 1 degree relatives' tonsillectomy, 1.14 (95% CI, 1.08-1.19) after 2 degree relatives' tonsillectomy, and 1.08 (95% CI, 1.01-1.15 after 3 degree relatives' tonsillectomy. Corresponding RRs for ulcerative colitis were 1.10 (95% CI, 1.07 1.13), 1.05 (95% CI, 1.01-1.08), and 1.03 (95% CI, 0.98-1.09). CONCLUSIONS: Even individuals with tonsillectomized family members were at increased risk of inflammatory bowel disease. These findings call into question a direct influence of tonsillectomy on gastrointestinal inflammation and point instead towards shared hereditary or environmental factors. PMID- 30461528 TI - Comparison of methods for algorithmic classification of dementia status in the Health and Retirement Study. AB - BACKGROUND: Dementia ascertainment is time-consuming and costly. Several algorithms use existing data from the U.S.-representative Health and Retirement Study (HRS) to algorithmically identify dementia. However, relative performance of these algorithms remains unknown. METHODS: We compared performance across five algorithms (Herzog-Wallace, Langa-Kabeto-Weir, Crimmins, Hurd, Wu) overall and within sociodemographic subgroups in participants in HRS and Wave A of the Aging, Demographics, and Memory Study (ADAMS, 2000-2002), an HRS sub-study including in person dementia ascertainment. We then compared algorithmic performance in an internal (time-split) validation dataset including participants of HRS and ADAMS Waves B, C, and/or D (2002-2009). RESULTS: In the unweighted training data, sensitivity ranged from 53% to 90%, specificity ranged from 79% to 97%, and overall accuracy ranged from 81% to 87%. Though sensitivity was lower in the unweighted validation data (range: 18% to 62%), overall accuracy was similar (range: 79% to 88%) due to higher specificities (range: 82% to 98%). In analyses weighted to represent the age-eligible US population, accuracy ranged from 91% to 94% in the training data and 87% to 94% in the validation data. Using a 0.5 probability cutoff, Crimmins maximized sensitivity, Herzog-Wallace maximized specificity, and Wu and Hurd maximized accuracy. Accuracy was higher among younger, highly-educated, and non-Hispanic white participants versus their complements in both weighted and unweighted analyses. CONCLUSIONS: Algorithmic diagnoses provide a cost-effective way to conduct dementia research. However, naive use of existing algorithms in disparities or risk-factor research may induce non-conservative bias. Algorithms with more comparable performance across relevant subgroups are needed.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30461529 TI - Accuracy of Self-Reported Abnormal Pap Smears among Reproductive-Age African American Women. AB - BACKGROUND: Self-reported history of abnormal Pap smear is used in large public health surveys. However, literature on the accuracy of this reporting is limited. We sought to assess the validity of self-reported abnormal Pap history in a community-based sample of African-American women ages 24-37 in the Detroit, Michigan area, recruited from 2010 to 2012. METHODS: We compared self-reported data on 2-year history of abnormal Pap smear to medical Pap record data (the gold standard) obtained from eligible participants. Sensitivity and specificity were evaluated to summarize the accuracy of the self-reported data. We also explored the sensitivity by severity of abnormality. RESULTS: We identified 345 participants with 480 eligible Pap records. Thirty-five percent of abnormal Pap results were not identified by self-report (sensitivity/specificity: 65%/91%; kappa=0.54). The sensitivity of reporting an abnormal Pap tended to be higher for those with a more severe abnormality. CONCLUSIONS: A large proportion of abnormal Pap smears were not identified by self-report in this sample of African-American women. Public health studies utilizing self-reported abnormal Pap information should be interpreted with caution. PMID- 30461530 TI - Oral corticosteroid-dependent asthma: current knowledge and future needs. AB - PURPOSE OF REVIEW: To discuss the current use of oral corticosteroids (OCS) as a chronic treatment in patients with severe asthma and as a rescue treatment for patients presenting with acute exacerbations. RECENT FINDINGS: Airways disease is responsible for the bulk of OCS use in the community and considerable OCS associated morbidity. I speculate that the key mechanism leading to a beneficial effect in these situations is depletion of circulating eosinophils resulting in a reduced response to potentially inhaled corticosteroid unresponsive recruitment signals to the airway mucosa. This effect is shared by anti-IL-5 biological agents, which have emerged as highly effective OCS-sparing agents. Mitigation of the adverse effects of OCS might also result from a better appreciation of features associated with a response to OCS and targeted, biomarker-directed use. SUMMARY: Longer term, there are real prospects that chronic and acute OCS use in asthma will be replaced by biological agents targeting eosinophilic airway inflammation more specifically and safely. PMID- 30461531 TI - Bronchiectasis in severe asthma: a distinct phenotype? AB - PURPOSE OF REVIEW: The presence of bronchiectasis has been described in about 30% of severe asthma patients. The coexistence of these two respiratory conditions poses new challenges from both clinical and research perspectives. We will review the available literature on this topic to discuss the existance of a specific clinical phenotype of asthma. RECENT FINDINGS: Despite the paucity of literature, the presence of bronchiectasis with severe asthma is associated with older age, chronic bronchial expectoration, rhinosinusitis, more frequent and severe exacerbations, neutrophilic airway inflammation and poor response to usual treatment. Conversely, asthma features are also described in bronchiectasis patients even in the absence of an appropriate diagnosis of asthma. In both cases, there is some evidence supporting the use of bronchodilators, macrolides and respiratory physiotherapy, while the use of inhaled corticosteroids and antibiotics is controversial. SUMMARY: Based on available evidence on the association between (severe) asthma and bronchiectasis, its pathophysiology, certain clinical aspects and prognosis are largely unclear. Although specific management appears to be required in most cases, in our opinion there is still insufficient evidence to consider it a distinct phenotype of severe asthma. Hopefully, future research will shed more light on this topic and define the best therapeutic approach. PMID- 30461532 TI - The many faces of asthma-chronic obstructive pulmonary disease overlap. AB - PURPOSE OF REVIEW: Asthma and chronic obstructive pulmonary disease (COPD) are common diseases that often overlap. The term asthma-COPD overlap (ACO) has been used to define this entity but there remain several speculations on its exact definition, impact, pathophysiology, clinical features, and management. We reviewed recent publications on ACO to obtain more insight of current knowledge and outline future needs. RECENT FINDINGS: Criteria for ACO vary from one publication to another and the many variable features of these patients underline the need to reconsider the evaluation and approach of patients with overlapping features based on clinical traits and underlying biological mechanisms. Epidemiological studies reveal that ACO patients have generally an increased burden of illness and healthcare use in addition to poorer quality of life (QoL) compared with asthma and higher or equal to COPD. However, their long-term outcome seems better than patients with COPD alone. Various methods have been proposed to evaluate these patients but their usefulness compared to 'classical' investigation of obstructive lung diseases remains speculative and needs further evaluation. Furthermore, there are no formal studies that examined and compared the different treatment strategies of well-characterized patients with ACO as such patients are usually excluded from clinical trials. SUMMARY: ACO is a common condition with variable features and a high burden of disease. There is no consensus on its definition, diagnostic, and clinical features and more research should be done on its optimal management and long-term outcomes. PMID- 30461533 TI - Initiating drug therapy in early stage chronic obstructive pulmonary disease: does it impact the course and outcome? AB - PURPOSE OF REVIEW: Early chronic obstructive pulmonary disease (COPD) is emerging in importance for the clinical and research settings. This review will highlight a proposed definition of early COPD, examine early and midlife factors that lead to development of early COPD and review the literature pertaining to the treatment of mild COPD to gain insight into potential therapeutic approaches for early disease. RECENT FINDINGS: Early COPD can be defined as disease occurring in patients younger than 50 years in age with a 10-pack-year or more smoking history and abnormal spirometry, imaging or lung function decline. Childhood exposures (maternal smoking and recurrent respiratory infections), childhood and adult asthma, and smoking affect middle-age lung function. Multiple studies of long acting muscarinic antagonists (LAMAs) in mild COPD have shown improvements in lung function and symptoms scores. Smoking cessation also has a beneficial effect on longitudinal lung function. SUMMARY: Early COPD is an important manifestation of COPD, with a newly proposed definition and associated risk factors identified. Inferring from studies on mild COPD cohorts, LAMAs and smoking cessation may have a positive effect on longitudinal lung function and symptomatic improvement. PMID- 30461534 TI - Wildfire smoke exposure under climate change: impact on respiratory health of affected communities. AB - PURPOSE OF REVIEW: In this review, we describe the current status of the literature regarding respiratory health related to wildfire smoke exposure, anticipated future impacts under a changing climate, and strategies to reduce respiratory health impacts of wildfire smoke. RECENT FINDINGS: Recent findings confirm associations between wildfire smoke exposure and respiratory health outcomes, with the clearest evidence for exacerbations of asthma. Although previous evidence showed a clear association between wildfire smoke and chronic obstructive pulmonary disease, findings from recent studies are more mixed. Current evidence in support of an association between respiratory infections and wildfire smoke exposure is also mixed. Only one study has investigated long-term respiratory health impacts of wildfire smoke, and few studies have estimated future health impacts of wildfires under likely climate change scenarios. SUMMARY: Wildfire activity has been increasing over the past several decades and is likely to continue to do so as climate change progresses, which, combined with a growing population, means that population exposure to and respiratory health impacts of wildfire smoke is likely to grow in the future. More research is needed to understand which population subgroups are most vulnerable to wildfire smoke exposure and the long-term respiratory health impacts of these high pollution events. PMID- 30461535 TI - Wrong inhalation technique is associated to poor asthma clinical outcomes. Is there room for improvement? AB - PURPOSE OF REVIEW: The long-term goals of asthma management are to control symptoms and to reduce the risk of exacerbations. Inhaled medication is the cornerstone of pharmacological treatment for asthma; therefore, good inhalation technique is the key for asthma management. However, up to 70% of asthma patients do not use their inhalers correctly. There is evidence on how poor inhalation technique is associated to poor asthma control. The purpose of this review is to present the most recent research in this field to help clinicians understand the importance of proper inhalers use and the possible interventions to optimize patients' inhalation technique. RECENT FINDINGS: New evidence on how poor inhaler technique and specific critical errors are significantly associated to poor asthma control and exacerbations and how this negative impact could be improved by optimizing device selection, enhancing shared decision-making and giving more importance to education, both for patients and healthcare professionals. New devices and additional tools might help patients to achieve the correct inhaler technique and could form the basis of simplified educational interventions. SUMMARY: There is an urgent need for specific interventions including new educational strategies to minimize the negative effects of wrong inhalation technique in asthma clinical outcomes. PMID- 30461536 TI - Respiratory symptoms in smokers with normal spirometry: clinical significance and management considerations. AB - PURPOSE OF REVIEW: Current respiratory society guidelines recommend confirming the diagnosis of chronic obstructive pulmonary disease (COPD) with demonstration of airflow obstruction on spirometry. However, multiple recent studies have demonstrated that smokers without overt airflow obstruction on spirometry, termed symptomatic smokers, have evidence of structural lung disease on imaging, have a substantial symptom burden, and also suffer respiratory exacerbations. In this review, we provide an overview of the epidemiology of symptomatic smokers, and address issues of screening and diagnosis, evaluation, and management considerations. RECENT FINDINGS: Two large prospective cohorts of adults with and at risk for COPD quantified the respiratory morbidity of symptomatic smokers. These studies demonstrated that approximately half of smokers without spirometrically defined airflow obstruction have increased respiratory symptoms, poor quality of life, low functional capacity, and suffer from respiratory exacerbations. Symptomatic smokers also have evidence of structural lung disease on imaging, and are at risk for faster lung function decline compared with those without respiratory symptoms. Several methods have been proposed to detect smoking-related lung damage among symptomatic smokers with normal forced expired volume in 1 second (FEV1)/forced vital capacity (FVC) ratio. Novel spirometry measures have been reported to diagnose disease before detection using traditional spirometry thresholds. Small airway involvement can be detected earlier using impulse oscillometry and metrics on multiple breath nitrogen washout tests. Imaging biomarkers have been developed that are associated with respiratory morbidity and lung function decline in symptomatic smokers. The translation of novel methods for COPD disease detection into more timely introduction of therapeutics and a consequent reduction in long-term morbidity and mortality has not yet been observed. SUMMARY: A better understanding of the pathobiologic basis of disease in smokers without overt airflow limitation, and earlier recognition of lung disease, while also appropriately evaluating for comorbidities that may account for the symptoms, will enhance the management of symptomatic smokers with preserved lung function. PMID- 30461537 TI - Transnasal Humidified Rapid-Insufflation Ventilatory Exchange During Electroconvulsive Therapy: A Feasibility Study. AB - BACKGROUND: In electroconvulsive therapy (ECT), a generalized seizure is provoked under general anesthesia. Standard airway management is done by face mask ventilation, but this is difficult during generalized seizure. Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) is a method to increase apnea tolerance and permit apnea oxygenation. We hypothesize that THRIVE can oxygenate the patient during ECT and that it is comfortable for patients. METHODS: In this single-center feasibility study, 13 patients with a pharmacotherapy-resistant depressive disorder underwent 20 ECT sessions with the use of THRIVE. They received general anesthesia under standard monitoring and transcutaneous carbon dioxide monitoring. Afterward, they completed a survey comparing their prior experience with face mask oxygenation. RESULTS: There were no desaturations during the procedure, and patient comfort showed no difference in comparison to face mask. Compared with data from earlier ECT with face mask ventilation in the same patient, THRIVE did not seem to shorten seizure duration. CONCLUSIONS: THRIVE is a novel, safe oxygenation method during ECT. PMID- 30461538 TI - Racial Disparities in the Administration of ECT in Texas, 1998-2013. AB - OBJECTIVE: Electroconvulsive therapy (ECT) is a treatment of choice for severe depression but has been underutilized among black patients. This study investigates racial disparities in the administration of ECT in the state of Texas between 1998 and 2013 using population data. DESIGN: Data from the Texas Department of State Health Services were obtained corresponding to the use for all ECT conducted in nonfederal settings during the period from January 2, 1998, to August 30, 2013. The data set comprised quarterly reports generated for each patient, totaling 27,931 patient quarters. Using year-by-year intercensal population estimates for the state of Texas, ECT treatments per capita were compared among black, white, Latina/Latino, and other individuals during this time period. RESULTS: Significantly more white patients were treated each quarter than minority patients (P < 0.001), with Latina/Latino patients recording fewer treatment quarters than any other racial group (P < 0.005). Large discrepancies in diagnosis by race were observed. Black patients were less likely than white and Latina/Latino patients to be diagnosed with depression and 4 times as likely as white patients to carry a diagnosis of schizophrenia. CONCLUSIONS: Concordant with previous data, large racial disparities in the administration of ECT were found in this Texas data set. Despite the limited nature of this data set, these results suggest that continued investigation is required to determine factors responsible for these disparities. PMID- 30461539 TI - Diagnostic and Therapeutic Challenges. PMID- 30461541 TI - The role of complement in antineutrophil cytoplasmic antibody-associated vasculitis. AB - PURPOSE OF REVIEW: To provide a comprehensive overview of the current insight into the role of complement activation in antineutrophil cytoplasmic antibody associated vasculitis (AAV). In addition, the therapeutic options targeting the complement system in AAV are discussed. RECENT FINDINGS: It has become increasingly clear that complement, and more specifically signalling through the C5a receptor, contributes to the immunopathology of AAV. This has led to the design of clinical trials with a C5a receptor blocker. The first results show a reduction in tissue damage and a favourable safety profile, as other parts of the complement defence system are left intact. SUMMARY: Although AAV was initially regarded as a pauci-immune disease, it is now well established that, in addition to autoantibodies, complement plays an essential role in the disease process. Animal models delivered the first insight, but the effective therapeutic interventions using complement inhibitors provided the proof that indeed complement activation contributes to disease activity and tissue damage in human AAV. PMID- 30461542 TI - Management of large-vessel vasculitis. AB - PURPOSE OF REVIEW: Glucocorticoids are the mainstay of therapy for large-vessel vasculitis, but potential toxicity and frequent relapses led to studies with nonbiologic and biologic glucocorticoid-sparing agents. The aim of this review is to discuss the recent evidence for the management of giant cell arteritis (GCA) and Takayasu arteritis (TAK). RECENT FINDINGS: Tocilizumab proved to be a powerful glucocorticoid-sparing agent for GCA in a randomized placebo-controlled trial, whereas the trials with tocilizumab and abatacept failed to show a significant difference from placebo in relapse-free survival rate in TAK. Further trials are awaiting for establishing the role of abatacept and ustekinumab for GCA, and rituximab and tumor necrosis factor inhibitors, including certolizumab for TAK, as well as nonbiologic agents for both indications. SUMMARY: Despite recent randomized controlled trials with biologic agents, management of large vessel vasculitis largely depends on observational studies. Well designed controlled trials using validated outcome measures in large number of patients, identification of biologic markers that could guide the choice of targeted treatments, and standardization of disease assessment including imaging modalities are unmet needs for the management of large-vessel vasculitis. PMID- 30461543 TI - Vasculitis and peripheral neuropathy. AB - PURPOSE OF REVIEW: Vasculitis of medium-sized and small vessels commonly affects peripheral nerves and can occur in context of a systemic vasculitis with multiorgan involvement or a nonsystemic vasculitis limited to the peripheral nervous system. This review summarizes the clinical and pathological features of systemic and nonsystemic vasculitis of the peripheral nervous system. RECENT FINDINGS: Vasculitis of peripheral nerves is a diffuse process that affects the vasa nervorum along the entire length of affected nerves but appears to cause injury primarily in a zone in the proximal-middle of the nerve that is particularly susceptible to ischemic injury. Nerve biopsy can help establish the diagnosis of a systemic vasculitis, particularly when other organ involvement is not clinically apparent, and is required for diagnosis of nonsystemic vasculitic neuropathy. Observational studies suggest that nonsystemic vasculitic neuropathy responds to immunosuppressive therapy but conclusive data are lacking. SUMMARY: The current review summarizes the clinical and pathological features of both systemic and nonsystemic vasculitis of the peripheral nervous system so that clinicians can better recognize, make a more timely diagnosis, and thus treat this condition more effectively in their patients. PMID- 30461544 TI - Molecular taxonomy of osteoarthritis for patient stratification, disease management and drug development: biochemical markers associated with emerging clinical phenotypes and molecular endotypes. AB - PURPOSE OF REVIEW: This review focuses on the molecular taxonomy of osteoarthritis from the perspective of molecular biomarkers. We discuss how wet biochemical markers may be used to understand disease pathogenesis and progression and define molecular endotypes of osteoarthritis and how these correspond to clinical phenotypes. RECENT FINDINGS: Emerging evidence suggests that osteoarthritis is a heterogeneous and multifaceted disease with multiple causes, molecular endotypes and corresponding clinical phenotypes. Biomarkers may be employed as tools for patient stratification in clinical trials, enhanced disease management in the primary care centres of the future and for directing more rational and targeted osteoarthritis drug development. Proximal molecular biomarkers (e.g synovial fluid) are more likely to distinguish between molecular endotypes because there is less interference from systemic sources of biomarker noise, including comorbidities. SUMMARY: In this review, we have focused on the molecular biomarkers of four distinct osteoarthritis subtypes including inflammatory, subchondral bone remodelling, metabolic syndrome and senescent age related endotypes, which have corresponding phenotypes. Progress in the field of osteoarthritis endotype and phenotype research requires a better understanding of molecular biomarkers that may be used in conjunction with imaging, pain and functional assessments for the design of more effective, stratified and individualized osteoarthritis treatments. PMID- 30461546 TI - Concordant Evidence-Based Interventions in Cardiac and Pulmonary Rehabilitation Guidelines. AB - Chronic conditions such as chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) contribute to a significant burden to patients and many experience a reduction in physical functioning, psychological health, and quality of life. The sentinel symptom for COPD and CVD is breathlessness. Rehabilitation programs have been proven to reduce disease symptoms and increase levels of physical and psychological wellness. Pulmonary and cardiac rehabilitation programs have been recommended in international and national guidelines for managing COPD and CVD. Given that these programs seek to reduce breathlessness and improve the physical and psychological functioning of people with COPD and CVD, this review examines the concordant evidence-based interventions in rehabilitation guidelines. The findings of this review indicate that there was concordance in the program design, location of programs, types of health professionals involved in program delivery, assessments of patient at commencement and completion of program, and the delivery of educational topics with minor deviations that were related to disease-specific topics. Apart from disease-specific recommendations, the main divergence from rehabilitation guidelines was found to be dietary screening, inspiratory muscle training, and psychological assessments in evidence-based recommendations for cardiac and pulmonary programs. PMID- 30461545 TI - Psychological Therapy for Centralized Pain: An Integrative Assessment and Treatment Model. AB - OBJECTIVE: Chronic pain is a significant health problem that is increasing in prevalence, and advances in treatment are needed. METHODS: We briefly review the leading evidence-based psychological therapies for chronic pain-cognitive behavioral and acceptance / mindfulness-based therapies-and examine several limitations and missing perspectives of these approaches. We review six lesser known interventions that address these limitations, and we describe our integrative model for psychological assessment and treatment of centralized pain. We present a typical patient and describe how we apply this approach, along with challenges to its implementation and possible solutions to these challenges. RESULTS: Greater pain treatment efficacy may be possible if clinicians: a) distinguish patients with primarily centralized (i.e., somatoform or nociplastic) pain from those with primarily peripheral (nociceptive, inflammatory, or neuropathic) pain; b) acknowledge the capacity of the brain not only to modulate pain but also generate as well as attenuate or eliminate centralized pain; c) consider the powerful role that adverse life experiences and psychological conflicts play in centralized pain; and d) integrate emotional processing and interpersonal changes into treatment. Our integrative treatment involves delivering a progression of interventions, as needed, to achieve pain reduction: tailored pain neuroscience education, cognitive and mindfulness skills to decrease the pain danger alarm mechanism, behavioral engagement in avoided painful and other feared activities, emotional awareness and expression to reverse emotional avoidance and overcome trauma or psychological conflict, and adaptive communication to decrease interpersonal stress. CONCLUSIONS: This integrative assessment and treatment model has the potential to substantially reduce and sometimes eliminate centralized pain by changing the cognitive, behavioral, emotional, and interpersonal processes that trigger and maintain centralized pain. PMID- 30461547 TI - Patient Perception of How Smoking Status Influences Cardiac Rehabilitation Attendance After an Acute Cardiac Hospitalization. AB - PURPOSE: Patients hospitalized with a cardiac condition are less likely to attend cardiac rehabilitation (CR) if they are smokers despite the benefits of doing so. The present study sought to investigate how, if at all, a patient's decision to attend CR was influenced by his or her tobacco use post-discharge. METHODS: We surveyed smokers during their hospitalization for a cardiac condition. Four to 8 wk after discharge, a follow-up survey assessed self-reported CR attendance, smoking cessation (SC), and patient opinion of how their smoking status influenced CR attendance. RESULTS: Of the 81 patients who completed the baseline survey (68% male, 57 +/- 10 y), 62 (77%) completed the follow-up survey. Consistent with prior findings, there was a substantial correlation between SC and CR attendance (OR: 16.0, P < .001) with 36 (44%) patients attending CR overall and 38 (47%) abstaining from smoking. Patients reported a wide variety of reasons for not attending CR, but most patients (n = 39, 63%) reported that their smoking status did not influence their decision to attend CR. However, 5 patients (8%) reported attending CR because they successfully quit smoking, and 5 (8%) attended CR anticipating support with SC. CONCLUSION: A strong relationship exists between SC and CR attendance following a cardiac hospitalization; however, most patients did not feel that their smoking status was a factor in their decision to attend CR. Regardless of the reason, it appears that success with one behavior may be related to the other and that both SC and CR attendance should be encouraged. PMID- 30461548 TI - Episcleral Venous Fluid Wave in the Living Human Eye Adjacent to Microinvasive Glaucoma Surgery (MIGS) Supports Laboratory Research: Outflow is Limited Circumferentially, Conserved Distally, and Favored Inferonasally. AB - PURPOSE: The purpose of this study was to describe downstream patterns of outflow with the episcleral venous fluid wave (EVFW) in the living human eye adjacent to microinvasive glaucoma surgery (MIGS) and determine if the EVFW supports existing ex-vivo laboratory outflow research. DESIGN: Retrospective, noncomparative case series. PATIENTS: A total of 10 eyes of 10 patients who underwent phaco Trabectome and 10 eyes of 10 patients who underwent phaco-iStent consecutively at Glaucoma Associates of Texas for cataract and uncontrolled glaucoma who demonstrated an episcleral wave. METHODS: The EVFW was visualized and recorded during irrigation and aspiration. To describe the hydrodynamic properties of the fluid wave, its degrees, extent, and characteristics were measured with a protractor in Photoshop. RESULTS: The incised Trabectome arc produced adjacent episcleral blanching of 134+/-11 degrees (range, 112 to 150 degrees) with an additional 54 degrees of marginal recruitment (41 degrees inferonasal plus 13 degrees superonasal) adjacent to the ends of the Trabectome incision. The mean episcleral blanch for the iStent was 51+/-19 degrees (range, 19 to 90 degrees), comprised of 29 degrees inferonasal plus 22 degrees superonasal. CONCLUSIONS: Downstream episcleral flow in the living human eye adjacent to the iStent is variable and mainly confined to 2 clock hours indicating a lack of significant circumferential flow in glaucomatous eyes. Flow distal to the Trabectome site encompasses the Trabectome incisional arc with an additional 2 clock hours of lateral fluid wave favoring the inferonasal over superonasal quadrant 3 to 1. These in-vivo findings made visible with MIGS, corroborate recent in-vivo and long-standing ex-vivo laboratory research that outflow is largely segmented, favored inferonasally and conserved distally. PMID- 30461549 TI - Adult-onset Buphthalmos in Down Syndrome. AB - PURPOSE: To report a peculiar case of adult-onset buphthalmos. METHODS: Review of the medical record of a 24-year-old patient with Down syndrome who developed buphthalmos in the left eye after corneal transplantation for keratoconus. RESULTS: In the next 2 years after surgery, the operated eye evolved with chronic anterior uveitis that led to progressive peripheral synechiae, oscillating intraocular pressure, cataract, graft failure, and buphthalmos. CONCLUSIONS: The finding of buphthalmos of adult-onset in Down syndrome raises important issues concerning the classification of this eye condition and the responsibility for detecting and monitoring eyes with glaucoma in individuals with chromosome 21 trisomy. PMID- 30461550 TI - Clinical Presentation and Management Outcomes of Coexistent Congenital Glaucoma and Retinopathy of Prematurity. AB - PURPOSE: The purpose of this study was to report presentation and outcomes of coexisting congenital glaucoma with retinopathy of prematurity (ROP) in "Indian Twin cities ROP study (ITCROPS)." METHODS: Children with ROP and congenital glaucoma were identified from ITCROPS (prospective digital database) between 1997 and 2016. The presentation, interventions, and outcomes for glaucoma and ROP were evaluated. RESULTS: Out of 15,000 premature-infants database, 3000 children had ROP, of these 87 eyes of 64 premature children had glaucoma. Five eyes (5.7%) of 3 children in the entire ROP cohort had coexisting congenital glaucoma (before any ROP intervention), 3 eyes of 2 children had primary congenital glaucoma and 2 eyes of one child had glaucoma with microspherophakia. The mean age at surgery was 2.7+/-0.6 months. At presentation, all eyes had corneal edema, mean corneal diameter was 10.3+/-0.75 mm and IOP was 20.4+/-1.67 mm Hg. Three eyes had stage-2 ROP and two eyes had stage-3 ROP. Four eyes received intravitreal Bevacizumab. All eyes underwent combined trabeculotomy with trabeculectomy. Post glaucoma surgery, 2 eyes underwent laser for ROP and 1 eye with stage-2 ROP was observed with no treatment. ROP regressed without any sequalae in all 5 eyes. Two eyes with microspherophakia and one eye with lens coloboma underwent lensectomy. One eye postlensectomy needed Ahmed glaucoma valve implant for IOP control. The mean IOP at last follow-up was 13.6+/-1.67 mm Hg and all eyes needed topical antiglaucoma medications for IOP control. CONCLUSIONS: Congenital glaucoma coexisting with ROP is a medical emergency. Intravitreal therapy can help tide over the vision-threatening fulminant phase of ROP while awaiting the effect of glaucoma surgery on corneal clarity. The need for medications even after glaucoma surgery suggests severe glaucoma phenotype. Close coordination between subspecialties is needed for best outcomes. PMID- 30461551 TI - Cigarette Smoking on Severity of Primary Angle Closure Glaucoma in Malay Patients. AB - PURPOSE: The purpose of this study was to determine the association between cigarette smoking and the severity of primary angle closure glaucoma (PACG) in Malay patients residing in Malaysia. METHODS: A cross-sectional study was conducted involving 150 Malay PACG patients between April 2014 and August 2016. Ocular examination was performed including Humphrey visual field (HVF) 24-2 analysis assessment. On the basis of the 2 consecutive reliable HVFs, the severity of glaucoma was scored according to modified Advanced Glaucoma Intervention Study (AGIS) by 2 masked investigators and classified as mild, moderate, and severe. Those with retinal diseases, neurological diseases, memory problem, and myopia >=4 diopters were excluded. Their smoking status and details were obtained by validated questionnaire from Singapore Malay Eye Study (SiMES). The duration of smoking, number of cigarettes per day, and pack/year was also documented. Multiple linear regression analysis was conducted. RESULTS: There was a significant association between education level and severity of PACG (P=0.001). However, there was no significant association between cigarette smoking and severity of glaucoma (P=0.080). On the basis of multivariate analysis, a linear association was identified between cigarette smoked per day (adjusted b=0.73; 95% CI: 0.54, 1.45; P<0.001) and body mass index (adjusted b=0.32; 95% CI: 0.07, 1.35; P=0.032) with AGIS score. CONCLUSIONS: There was no significant association between cigarette smoking and severity of PACG. Cigarette smoked per day among the smokers was associated with severity of PACG. However, because of the detrimental effect of smoking, cessation of smoking should be advocated to PACG patients. PMID- 30461552 TI - Vection Responses in Patients With Early Glaucoma. AB - PURPOSE: Our lab has previously shown that patients with early glaucoma have longer vection latencies than controls. We attempted to explain this finding using a combined index of structure and function (CSFI), as proposed by Medeiros and colleagues. The CSFI estimates the proportion of retinal ganglion cell loss. METHODS: Roll and circular vection were evoked using a back-projected screen (experiment 1) and the Oculus Rift system (experiment 2). Vection latency and duration were measured using a button response box. In experiment 1, tilt angles were measured with a tilt sensor, whereas subjective tilt was determined using a joystick attached to a protractor. In experiment 2, subjective vection strength was rated on a 1 to 10 scale. These measurements were compared with the CSFI, which utilizes visual field and optical coherence tomography data. RESULTS: For experiment 1 we tested 22 patients (mean age, 70.3+/-6 y) with glaucoma and 18 controls (mean age, 54.6+/-9 y); and for experiment 2 we tested 24 patients (mean age, 71.1 +/-5 y) and 23 controls (mean age 61.4+/-10 y), but not all patients experienced vection. In both experiments, vection latency was significantly longer for patients than for controls (smallest P=0.02). The CSFI was not related to vection latency, duration, or objective and subjective measures of vection strength (smallest P=0.06) in either experiment. CONCLUSIONS: Two experiments have replicated the finding that vection responses are longer in patients with glaucoma than in controls; however, the CSFI is not related to vection responses. PMID- 30461553 TI - Optical Coherence Tomography Angiography of Optic Disc and Macula Vessel Density in Glaucoma and Healthy Eyes. AB - AIM: To study the microvascular density of the macular and optic nerve head in healthy and glaucoma subjects using optical coherence tomography angiography. METHODOLOGY: We performed a cross-sectional cohort study on healthy subjects and patients with glaucoma. The AngioVue Enhanced Microvascular Imaging System was used to capture the optic nerve head and macula images during one visit. En face segment images of the macular and optic disc were studied in layers. Microvascular density of the optic nerve head and macula were quantified by the number of pixels measured by a novel in-house developed software. Areas under the receiver operating characteristic curves (AUROC) were used to determine the accuracy of differentiating between glaucoma and healthy subjects. RESULTS: A total of 24 (32 eyes) glaucoma subjects (57.5+/-9.5-y old) and 29 (58 eyes) age matched controls (51.17+/-13.5-y old) were recruited. Optic disc and macula scans were performed showing a greater mean vessel density (VD) in healthy compared with glaucoma subjects. The control group had higher VD than the glaucoma group at the en face segmented layers of the optic disc (optic nerve head: 0.209+/-0.05 vs. 0.110+/-0.048, P<0.001; vitreoretinal interface: 0.086+/-0.045 vs. 0.052+/ 0.034, P=0.001; radial peripapillary capillary: 0.146+/-0.040 vs. 0.053+/-0.036, P<0.001; and choroid: 0.228+/-0.074 vs. 0.165+/-0.062, P<0.001). Similarly, the VD at the macula was also greater in controls than glaucoma patients (superficial retina capillary plexus: 0.115+/-0.016 vs. 0.088+/-0.027, P<0.001; deep retina capillary plexus: 0.233+/-0.027 vs. 0.136+/-0.073, P<0.001; outer retinal capillary plexus: 0.190+/-0.057 vs. 0.136+/-0.105, P=0.036; and choriocapillaris: 0.225+/-0.053 vs. 0.153+/-0.068, P<0.001. The AUROC was highest for optic disc radial peripapillary capillary (0.96), followed by nerve head (0.92) and optic disc choroid (0.76). At the macula, the AUROC was highest for deep retina (0.86), followed by choroid (0.84), superficial retina (0.81), and outer retina (0.72). CONCLUSIONS: Microvascular density of the optic disc and macula in glaucoma patients was reduced compared with healthy controls. VD of both optic disc and macula had a high diagnostic ability in differentiating healthy and glaucoma eyes. PMID- 30461554 TI - Sonographic Assessment of Optic Disc Cupping and its Diagnostic Performance in Glaucoma. AB - PURPOSE: The purpose of this study was to assess the optic cup diameter sonographically in glaucoma patients and in the normal population and correlate it with their photographic parameters to propose a cut-off value as a predictive index of glaucoma. METHODS: A total of 95/50 primary open-angle glaucoma and 87/44 control patients with clear media underwent visual field assessment, fundus photography, and B-scan ultrasound. Photographic vertical cup diameter (PVCD) of cases and controls were recorded after magnification correction using the Bengtsson formula. Sonographic vertical cup diameter (SVCD) was measured in the vertical transverse position. RESULTS: The mean SVCD was 1.13+/-0.23 mm in glaucoma and 0.72+/-0.25 mm in controls (P=0.001). The mean PVCD was 1.024+/ 0.199 mm in glaucoma and 0.636+/-0.217 mm in controls (P=0.001). A strong correlation between PVCD and SVCD in both groups was found (correlation coefficient r=0.857; P=0.001; glaucoma and r=0.795; P=0.001; control). SVCD had a positive correlation with vertical cup disc ratio (r=0.675; P=0.001 in glaucoma patients) and (r=0.797; P=0.001 in controls) cup area (r=0.798; P=0.001; glaucoma) and (r=0.727, P=0.001; control) a negative correlation with vertical neuroretinal rim diameter (r=-0.5187; P=0.000; glaucoma patients) and (r=-0.699; P=0.001; controls). No correlation of SVCD was found with severity of field grade changes. The receiving operative curve analysis was performed, and Youden's optimal cut-off method was used to find a cut-off value for SVCD, which came out to be 1.06, with 65.3% (95% confidence interval, 54.8-74.7) sensitivity and 94.3% (95% confidence interval, 87.1-97.1) specificity. CONCLUSIONS: The sonographic evaluation of the optic cup is a reliable noninvasive procedure and a potentially useful tool in the assessment of nonviewable suspected glaucomatous cups. PMID- 30461555 TI - A Retrospective Study of 199 Xen45 Stent Implantations From 2014 to 2016. AB - PURPOSE: The aim of this study is to determine the postoperative course after Xen45 Gel Stent implantation at the Medical University of Graz from 2014-2016. METHODS: Single-center, retrospective study. All patients with Xen implantation between 2014 and 2016 were included. Clinical records and reports received from supervising ophthalmologists were used for evaluations. Investigated parameters were intraocular pressure (IOP), the number of medications, visual acuity, and the number of previous operations, IOP-follow-up, intraoperative and postoperative complications, the rate of interventions (needling), and additionally performed surgeries. RESULTS: Xen was implanted in 199 eyes of 160 patients. Mean preoperative IOP was 22.8+/-6.9 mm Hg on 2.9+/-1.0 IOP-lowering medication. After 12 months follow-up, mean IOP was 17.1+/-5.9 mm Hg (n=89, P<0.0001; mean reduction of 22.7%) on 1.8+/-1.4 (n=87; P<0.0001) IOP-lowering medications. There were no intraoperative complications and in two cases (1.0%) severe postoperative adverse events occurred (aqueous misdirection and late-onset endophthalmitis). Postoperative needling was indicated in 44 cases (22.1%), while in 28 cases (14.1%) an additional glaucoma surgery was performed. CONCLUSIONS: Our results indicate that Xen implantation is an effective surgical intervention leading to a significant reduction of IOP and number of medications with a low rate of complications. An attentive postoperative management seems to be mandatory. PMID- 30461556 TI - Decreasing menopausal symptoms of Asian American breast cancer survivors through a technology-based information and coaching/support program. AB - OBJECTIVE: One of the most prevalent and distressing symptoms after breast cancer treatment is menopausal symptoms. Asian American breast cancer survivors have lower quality of life and often receive inadequate management of menopausal symptoms compared to other racial/ethnic groups. Technology-based programs could be a solution to fill the gap in care. The purpose of this study was to test the efficacy of a technology-based information and coaching/support program on menopausal symptoms of Asian American breast cancer survivors. METHODS: This study adopted a randomized pretest/post-test group design among 91 Asian American breast cancer survivors (42 in an intervention group who used the program and the American Cancer Society Web site and 49 in a control group who used only the American Cancer Society Web site). The intervention was a theory-driven and culturally tailored intervention program that aimed to provide information and coaching/support using computers and mobile devices. Multiple instruments were used to measure background characteristics and menopausal symptoms at pretest, post 1-month, and post 3 months. An intent-to-treat linear mixed-model growth curve analysis was used to analyze the data. RESULTS: The intervention group showed a significant decrease in the distress scores of menopausal symptoms over time: physical (beta = -0.07, P = 0.08), psychological (beta = -0.13, P = 0.05), psychosomatic (beta = -0.17, P = 0.06), and total symptoms (beta = -0.19, P = 0.01). Theory-based variables including attitudes, social influences, and self efficacy partially mediated the impact of the intervention on the distress scores of menopausal symptoms (P < 0.10). CONCLUSIONS: The program was effective in alleviating menopausal symptoms of Asian American breast cancer survivors. PMID- 30461557 TI - Long-term weight loss maintenance, sex steroid hormones, and sex hormone-binding globulin. AB - OBJECTIVE: We tested the effects of weight loss on serum estradiol, estrone, testosterone, and sex hormone-binding globulin (SHBG) in overweight/obese women 18 months after completing a year-long, 4-arm, randomized-controlled dietary weight loss and/or exercise trial. METHODS: From 2005 to 2008, 439 overweight/obese, postmenopausal women (BMI >25 kg/m), 50 to 75 years, were randomized to a year-long intervention: diet (reduced calorie, 10% weight loss, N = 118), exercise (225 min/wk moderate-to-vigorous activity, N = 117), combined diet + exercise (N = 117), or control (N = 87). At 12 months, 399 women provided blood; of these, 156 returned at 30 months and gave a blood sample. Hormones and SHBG were measured by immunoassay. Changes were compared using generalized estimating equations, adjusting for confounders. RESULTS: At 30 months, participants randomized to the diet + exercise intervention had statistically significant increases in SHBG levels versus controls (P = 0.001). There was no statistically significant change in SHBG in the exercise or diet intervention arms. Hormone levels did not vary by intervention arm from baseline to 30 months. Participants who maintained weight loss at 30 months had statistically significantly greater decreases in free estradiol and free testosterone (Ptrend = 0.02 and Ptrend = 0.04, respectively) and increases in SHBG (Ptrend < 0.0001) versus those who did not have sustained weight loss. Levels of other analytes did not vary by weight loss at 30 months. CONCLUSIONS: Sustained weight loss results in reductions in free estradiol and testosterone and increases in SHBG 18-month post-intervention. PMID- 30461559 TI - Immediate Loop Electrode Excisional Procedure for High-Grade Cervical Cytology: One Size Fits All? PMID- 30461558 TI - Manual therapy prevents onset of nociceptor activity, sensorimotor dysfunction, and neural fibrosis induced by a volitional repetitive task. AB - Painful and disabling musculoskeletal disorders remain prevalent. In rats trained to perform repetitive tasks leading to signs and dysfunction similar to those in humans, we tested whether manual therapy would prevent the development of the pathologies and symptoms. We collected behavioral, electrophysiological, and histological data from control rats, rats that trained for 5 weeks before performing a high repetition high force task (HRHF) for 3 weeks untreated, and trained rats that performed the task for 3 weeks while being treated 3x/week using modeled manual therapy (MMT) to the forearm (HRHF+MMT). The MMT included bilateral mobilization, skin rolling, and long axis stretching of the entire upper limb. HRHF rats showed decreased performance of the operant HRHF task and increased discomfort-related behaviors, starting after training. HRHF+MMT rats showed improved task performance and decreased discomfort related behaviors compared to untreated HRHF rats. Subsets of rats were assayed for presence or absence of ongoing activity in C- and slow Adelta- neurons in their median nerves. Neurons from HRHF rats had a heightened proportion of ongoing activity and altered conduction velocities compared to control and MMT-treated rats. Median nerve branches in HRHF rats contained increased numbers of CD68+ macrophages and degraded myelin basic protein, and showed increased extraneural collagen deposition, compared to the other groups. We conclude that the performance of the task for 3 weeks leads to increased ongoing activity in nociceptors, in parallel with behavioral and histological signs of neuritis and nerve injury, and that these pathophysiologies are reduced by MMT. PMID- 30461560 TI - Regional and sex-dependent alterations in Purkinje cell density in the valproate mouse model of autism. AB - Neuropathological and neuroimaging studies indicate a decrease in Purkinje cell (PC) density in the cerebellum of autistic patients and rodent models of autism. Autism is far more prevalent in males than females, and sex-specific properties of PCs have been reported recently. We investigated the differential sensitivity of PCs in the valproate acid (VPA) mouse model of autism by estimating the linear density of PCs immununolabelled with calbindin in the cerebellum of males and females. Whereas prenatal VPA treatment surprisingly increased PC linear density in both sexes 13 days after birth (P13), it significantly reduced the linear density of PCs in the cerebellum of 40-day-old (P40) males, but not females. In males, PC loss was more pronounced in the posterior part of the cerebellum and was significant in the VIth, VIIth, IXth and paramedian lobules. In females, PC loss was restricted to the paramedian lobule. These results suggest that this sex specific sensitivity of PCs to VPA may contribute towards the motor disturbances and behavioural abnormalities observed in autism. PMID- 30461562 TI - Re: Prediction of traumatic carotid-cavernous sinus fistula via noncontrast computed tomography by fracture pattern and abnormality of venous system. PMID- 30461563 TI - Re: Indication and survival bias: Threats to Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) outcomes research. PMID- 30461564 TI - Re: Cervical spine MRI in blunt cervical trauma patients. PMID- 30461565 TI - Re: Clinical features of 27 shark attack cases on La Reunion island. PMID- 30461566 TI - Re: Rib fractures fixation: Always worthwhile? PMID- 30461567 TI - Mesenchymal stem cell-derived extracellular vesicles attenuate pulmonary vascular permeability and lung injury induced by hemorrhagic shock and trauma: Erratum. PMID- 30461568 TI - Featured Articles for CME Credit December 2018. PMID- 30461570 TI - Arthroscopic Treatment of Lateral Elbow Pain Mimicking Lateral Epicondylitis: Long-term Follow-up of a Unique Surgical Protocol. AB - HYPOTHESIS AND/OR BACKGROUND: The failure rate of extensor carpi radialis brevis debridement for refractory lateral epicondylitis is reported around 15%. Our novel arthroscopic treatment is predicated on the hypothesis that lateral epicondylitis is an intra-articular problem related to a variation of the capsule meniscal anatomy that impinges on the radiocapitellar joint. We report long-term outcomes of 35 patients treated with a novel arthroscopic resection of their capsulosynovial fringe. METHODS: All patients failed nonoperative treatment but had temporary improvement with an intra-articular injection. Arthroscopic treatment involved resecting the meniscus and the proximal edge of the orbicular ligament, followed by a tendon-sparing anterolateral capsulectomy. 35 patients underwent evaluation on average 9.2 years after surgery. Outcome measures included VAS, DASH, and questions on return to sports, satisfaction, and perceived benefit of surgery. RESULTS: Median pain scores improved from 8 of 10 preoperatively to 0 of 10 postoperatively. This change was clinically and statistically significant, with 1 patient still requiring pain medication. Median DASH score at final follow-up was 1. Overall, 30 patients rated their postoperative outcome as much better, 5 rated it as better, and 0 reported their symptoms to be unchanged or worsened. All 35 patients stated they were happy they underwent the procedure and perceived a benefit. Totally, 4 of 35 patients had postoperative complications (2 with ulnar nerve symptoms, 2 with persistent pain), with one requiring revision surgery for persistent pain. DISCUSSION AND/OR CONCLUSIONS: We report promising long-term clinical and functional results of a novel arthroscopic resection of the capsulosynovial complex in lateral epicondylitis. PMID- 30461571 TI - Palmar Capsuloligamentous Plication in Dorsal Capitolunate Instability: Technique and Preliminary Results. AB - Midcarpal instability (MCI) is a form of the carpal instability nondissociative pattern and can be differentiated into dorsal, palmar, or extrinsic MCI. Dorsal MCI can frequently be observed in adolescent or adult patients due to trauma or hyperlaxity of the palmar intrinsic carpal ligaments. Clinical stress tests and cinematography are capable to depict the ligamentous instability centered around the capitolunate area. We describe a novel technique which aims to address palmar ligamentous hyperlaxity by plication of the radioscaphocapitate, radiolunotriquetral, and arcuate ligaments, thus closing the so-called space of Poirier. This palmar technique has been used in several cases in isolated form or in conjunction with other concomitant procedures. After the floor of the carpal tunnel and thus the palmar ligaments are exposed and the weak spot meticulously verified, 2 or rarely 3 deep FibreWire pulley sutures are used for capsuloligamentous plication. Among 11 patients, 4 cases (5 operated wrists) with isolated capitolunate capsuloligamentous plication were followed at an average of 2.6 years after surgery. The results were excellent with a mean postoperative Disabilities of the Arm, Shoulder and Hand Score of 9.7 (range, 6.9 to 15.0), mean numerical rating scale of 0 at rest and 1 (range, 0 to 2) during stress. All cases stated that they were very satisfied with the result and all would definitely elect to choose the surgery again. Palmar capsuloligamentous plication has been shown to be a quick, relatively easy and reliable procedure to reduce dorsal MCI in our patient cohort. PMID- 30461572 TI - Report of Resistant Varicella Zoster infection treated with Donor Lymphocyte Infusion in a Pediatric Oncology Patient. AB - We report an 8 year old boy with disseminated, life-threatening, drug treatment resistant varicella zoster infection occurring during standard treatment for neuroblastoma in whom viral clearance and cure was effected by donor Lymphocyte infusion from his HLA-identical twin sibling. PMID- 30461573 TI - Hemophagocytic Lymphohistiocytosis and Infections: An update. PMID- 30461574 TI - Maternal Perinatal HIV Infection is Associated with Increased Infectious Morbidity in HIV-Exposed Uninfected Infants. AB - More women with perinatally-acquired HIV are giving birth. We evaluated infectious cause hospitalizations (ICH) in HIV-uninfected infants of perinatally HIV-infected (HEU-P), non-perinatally HIV-infected (HEU-N), and HIV-uninfected women (HUU) through 12 months-of-life at an urban tertiary heath center. HEU-P infants experienced higher ICH risk compared to HEU-N and HUU infants. Identification of biological and structural drivers of differences are needed. PMID- 30461575 TI - 2018 Reviewer Acknowledgment. PMID- 30461576 TI - Self-Reported Fatigue in Children Following Intensive Care Treatment. AB - OBJECTIVES: Adults report high levels of fatigue after intensive care, but little is known about pediatric survivors. This study aimed to explore rates of self reported fatigue in children after critical illness. DESIGN: Prospective cohort study. SETTING: Tertiary children's hospital. PATIENTS: Ninety-seven children aged 7-17 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children completed the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale 3 months after discharge from PICU. Comparisons with normative data (n = 209) showed that PICU survivors reported similar mean (SD) total fatigue scores to their healthy peers (79.6 [16.3] vs 81.8 [12.5]; p = 0.239), but greater cognitive fatigue (77.4 [21.9] vs 82.4 [16.4]; p = 0.048). Also children who had sustained a traumatic brain injury reported "less" sleep/rest fatigue (84.6 [15.0] vs 76.8 [16.3]; p = 0.006). Baseline indices of severity of illness were not associated with fatigue. CONCLUSIONS: The Pediatric Quality of Life Inventory Multidimensional Fatigue Scale appears to be a promising tool for use in outcomes research with PICU survivors. These results highlight the need to bear in mind the heterogeneity of PICU patients and the multidimensional nature of fatigue symptoms. PMID- 30461577 TI - Outcomes of Children With Critical Bronchiolitis Meeting at Risk for Pediatric Acute Respiratory Distress Syndrome Criteria. AB - OBJECTIVES: New definitions of pediatric acute respiratory distress syndrome include criteria to identify a subset of children "at risk for pediatric acute respiratory distress syndrome." We hypothesized that, among PICU patients with bronchiolitis not immediately requiring invasive mechanical ventilation, those meeting at risk for pediatric acute respiratory distress syndrome criteria would have worse clinical outcomes, including higher rates of pediatric acute respiratory distress syndrome development. DESIGN: Single-center, retrospective chart review. SETTING: Mixed medical-surgical PICU within a tertiary academic children's hospital. PATIENTS: Children 24 months old or younger admitted to the PICU with a primary diagnosis of bronchiolitis from September 2013 to April 2014. Children intubated before PICU arrival were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Collected data included demographics, respiratory support, oxygen saturation, and chest radiograph interpretation by staff radiologist. Oxygen flow (calculated as FIO2 * flow rate [L/min]) was calculated when oxygen saturation was 88-97%. The median age of 115 subjects was 5 months (2 11 mo). Median PICU length of stay was 2.8 days (1.5-4.8 d), and median hospital length of stay was 5 days (3-10 d). The criteria for at risk for pediatric acute respiratory distress syndrome was met in 47 of 115 subjects (40.9%). Children who were at risk for pediatric acute respiratory distress syndrome were more likely to develop pediatric acute respiratory distress syndrome (15/47 [31.9%] vs 1/68 [1.5%]; p < 0.001), had longer PICU length of stay (4.6 d [2.8-10.2 d] vs 1.9 d [1.0-3.1 d]; p < 0.001) and hospital length of stay (8 d [5-16 d] vs 4 d [2-6 d]; p < 0.001), and increased need for invasive mechanical ventilation (16/47 [34.0%] vs 2/68 [2.9%]; p < 0.001), compared with those children who did not meet at risk for pediatric acute respiratory distress syndrome criteria. CONCLUSIONS: Our data suggest that the recent definition of at risk for pediatric acute respiratory distress syndrome can successfully identify children with critical bronchiolitis who have relatively unfavorable clinical courses. PMID- 30461578 TI - Does Tracheal Lidocaine Instillation Reduce Intracranial Pressure Changes After Tracheal Suctioning in Severe Head Trauma? A Prospective, Randomized Crossover Study. AB - OBJECTIVES: Tracheal suctioning is a routine procedure in mechanically ventilated children, however, in severe head-injured patients it can result in potential deleterious increase in intracranial pressure. We aimed to assess the effect of tracheal lidocaine administration on intracranial pressure during tracheal suctioning. DESIGN: Prospective randomized controlled crossover study. SETTING: PICU of a tertiary hospital. PATIENTS: Eleven patients with severe head trauma (Glasgow Coma Scale score 4-8) INTERVENTIONS:: Lidocaine (1.5 mg/kg) or saline solution was endotracheally instilled before a standardized tracheal suctioning maneuver. Each patient received both treatments in a crossover design. Cerebral hemodynamic and systemic and ventilatory effects were assessed at four time points: in baseline (T0), within 2 minutes (T1), 5 minutes (T2), and 15 minutes after tracheal instillation (T3). The 2-minute time interval around tracheal suctioning was used to assess each treatment efficacy MEASUREMENTS AND MAIN RESULTS:: The time course of intracranial pressure was different throughout the study in both treatment groups, with a significant increase of intracranial pressure from 14.82 +/- 3.48 to 23.27 +/- 9.06 with lidocaine (p = 0.003) and from 14.73 +/- 2.41 to 30.45 +/- 13.14 with saline (p = 0.02). The mean variation in intracranial pressure immediately after tracheal suctioning was smaller with lidocaine instillation than saline (8.45 vs 15.72 mm Hg; p = 0.006). Patients treated with lidocaine returned to baseline intracranial pressure value at 5 minutes after tracheal suctioning whereas those receiving saline solution returned to baseline intracranial pressure value at 15 minutes. Although patients treated with lidocaine had no significant hemodynamic changes, patients receiving saline solution experienced a higher mean value of mean arterial pressure (99.36 vs 81.73 mm Hg; p = 0.004) at T1. CONCLUSIONS: This preliminary study showed that tracheal lidocaine instillation can attenuate increase in intracranial pressure induced by tracheal suctioning and favor a faster return to the intracranial pressure baseline levels without significant hemodynamic and ventilatory changes. PMID- 30461579 TI - Protocol-Driven Management of Convulsive Status Epilepticus at a Tertiary Children's Hospital: A Quality Improvement Initiative. AB - OBJECTIVES: Convulsive status epilepticus is a medical emergency. Prompt treatment has been shown to decrease progression to refractory convulsive status epilepticus. We aimed to reduce time to second-line anti-seizure medication through implementation of a standardized treatment protocol. DESIGN: Quality improvement project. We constructed a multidisciplinary team and completed Plan Do-Study-Act cycles to achieve the project aim. SETTING: A tertiary care children's hospital. PATIENTS: Patients presenting to the Children's Hospital at Montefiore emergency department with convulsive status epilepticus or new-onset seizures during admission to Children's Hospital at Montefiore. INTERVENTIONS: Implementation of a standardized treatment protocol, uploading the protocol to the hospital's intranet, adding anti-seizure medications to the hospital's Pyxis system, and creating a standardized convulsive status epilepticus order set in the electronic medical record. The primary outcome measure was time from order to administration of second-line anti-seizure medication, and secondary outcome was total seizure time. MEASUREMENTS AND MAIN RESULTS: Seventy-eight patients were analyzed, including 41 from the baseline period (January 2014 through June 2015) and 37 from the postintervention period (July 2015 through December 2016). The median time to administration of second-line anti-seizure medication decreased from 52 to 21 minutes (p = 0.001) and total seizure time from 65 to 31 minutes (p = 0.09). CONCLUSIONS: A standardized treatment protocol for convulsive status epilepticus decreased time to administration of second-line therapy by 60%, but there was no statistically significant decrease in total seizure time. PMID- 30461580 TI - Feasibility and Perceptions of PICU Diaries. AB - OBJECTIVES: To determine the feasibility of implementing an ICU diary in the pediatric critical care setting and to understand the perceptions held by family members who receive the diaries after PICU discharge. DESIGN: Observational pilot study. SETTING: PICU in a tertiary academic hospital in the United States. PARTICIPANTS: Critically ill pediatric patients admitted to the PICU and their families. INTERVENTIONS: The addition of a PICU diary to a patient's routine care. MEASUREMENTS AND MAIN RESULTS: Twenty families of critically ill children admitted to the PICU were enrolled in the PICU diary pilot study between May 2017 and March 2018. Patients who had an anticipated length of stay of at least 3 days and whose families were English-speaking were included. The median age of patients was 6 years, ranging from newborns to 18 years old, and the median length of stay was 11.5 days (interquartile range, 8.5-41 d). A total of 453 diary entries were written in 19 diaries over 433 PICU days, the majority of which were composed by bedsides nurses (63%). Follow-up surveys sent to parents 2 weeks after PICU discharge revealed that of the parents who had contributed to the diary, most enjoyed doing so (7/8). Nine of 12 parents had reviewed the diary at least once since discharge, and all parent respondents found the diary to be a beneficial aspect of their experience after PICU discharge. CONCLUSIONS: The use of ICU diaries in the PICU setting is feasible and perceived as beneficial by families of critically ill children. Future studies are needed to better understand if PICU diaries may objectively improve psychologic outcomes of patients and family members after PICU admission. PMID- 30461581 TI - Emergency Department and Primary Care Use in Massachusetts 5 Years After Health Reform. AB - OBJECTIVE: Conceptually, access to primary care (through insurance) should reduce emergency department (ED) visits for primary care sensitive (PCS) conditions. We sought to identify characteristics of insured Massachusetts residents associated with PCS ED use, and compare such use for public versus private insurees. POPULATION AND SETTING: People under age 65 in the Massachusetts All-Payer Claims Data, 2011-2012. STUDY DESIGN: Retrospective, observational analysis of PCS ED use with nonurgent, urgent/primary care treatable, and urgent/potentially avoidable visits being considered PCS. We predicted utilization in 2012 using multivariable regression models and data available in 2011 administrative records. PRINCIPAL FINDINGS: Among 2,269,475 nonelderly Massachusetts residents, 40% had public insurance. Among public insurees, PCS ED use was higher than for private (mean, 36.5 vs. 9.0 per 100 persons; adjusted risk ratio, 2.53; 95% confidence limits, 2.49-2.56), while having any primary care visit was less common (70% vs. 83%), as was having any visit to one's own (attributed) primary care provider (38% vs. 44%). CONCLUSIONS: Public insurance was associated with less access to primary care and more PCS ED use; statewide labor shortages and low reimbursement rates from public insurance may have provided inadequate access to care that might otherwise have helped reduce PCS ED use. PMID- 30461582 TI - Identification of Cross-sector Service Utilization Patterns Among Urban Medicaid Expansion Enrollees. AB - BACKGROUND: The expansion of Medicaid as part of the Affordable Care Act opened new opportunities to provide health coverage to low-income adults who may be involved in other public sectors. OBJECTIVE: The main objective of this study was to describe cross-sector utilization patterns among urban Medicaid expansion enrollees. RESEARCH DESIGN: We merged data from 4 public sectors (health care, human services, housing, and criminal justice) for 98,282 Medicaid expansion enrollees in Hennepin County, MN. We fit a latent class model to indicators of cross-sector involvement. MEASURES: Indicator variables described involvement levels within each sector from March 2011 through December 2014. Demographic and chronic condition indicators were included post hoc to characterize classes. RESULTS: We found 6 archetypes of cross-sector involvement: The "Low Contact" class (33.9%) had little involvement in any public sector; "Primary Care" (26.3%) had moderate, stable health care utilization; "Health and Human Services" (15.3%) had high rates of health care and cash assistance utilization; "Minimal Criminal History" (11.0%) had less serious criminal justice involvement; "Cross-sector" (7.8%) had elevated emergency department use, involvement in all 4 sectors, and the highest prevalence of behavioral health conditions; "Extensive Criminal History" (5.7%) had serious criminal justice involvement. The 3 most expensive classes (Health and Human Services, Cross-sector, and Extensive Criminal History) had the highest rates of behavioral health conditions. Together, they comprised 29% of enrollees and 70% of total public costs. CONCLUSIONS: Medicaid expansion enrollees with behavioral health conditions deserve focus due to the high cost reduction potential across public sectors. Cross-sector collaboration is a plausible path to reduce costs and improve outcomes. PMID- 30461583 TI - Sexual Orientation Disparities in Physical Activity: Results From Insured Adults in California. AB - BACKGROUND: The majority of adults in the United States fail to meet the Centers for Disease Control and Prevention (CDC) physical activity (PA) guideline recommendations for health promotion. Despite evidence of disparities by sexual orientation in adverse health outcomes related to PA, little is known about whether PA patterns and the likelihood of meeting these guidelines differ between heterosexual and sexual minority (SM) men and women. METHODS: In 2018, we pooled unweighted respondent data from Kaiser Permanente Northern California Member Health Surveys conducted in 2008, 2011, and 2014/15 (N=42,534) to compare PA patterns among heterosexual and SM men and women. RESULTS: In total, 38.8% of heterosexual men, 43.4% of SM men, 32.9% of heterosexual women, and 40.0% of SM women meet the CDC PA guidelines, yet there was no statistically significant difference in the adjusted odds of meeting these guidelines. Compared with heterosexual women, SM women engage in PA more frequently [odds ratio=0.81; 95% confidence interval (CI), 0.74-0.89], for more minutes per week on average (12.71; 95% CI, 4.85-20.57), and at higher levels of intensity (relative risk ratio=1.26; 95% CI, 1.02-1.56). Compared with heterosexual men, SM men engage in PA more frequently (OR=0.85; 95% CI, 0.74-0.98), for fewer minutes per week on average (-12.89; 95% CI, -25.84 to 0.06), and at lower levels of intensity (relative risk ratio=0.83; 95% CI, 0.67-0.99). CONCLUSIONS: We find that SMs get more frequent PA than their heterosexual peers, which suggests that the higher prevalence of obesity and other PA-related adverse health outcomes among SMs may be due to factors other than PA patterns. PMID- 30461584 TI - Trends, Causes, and Outcomes of Hospitalizations for Homeless Individuals: A Retrospective Cohort Study. AB - OBJECTIVES: In the United States, an estimated 553,000 people are homeless on any given night. Few data provide large-scale, contemporary insight with regard to recent patterns of acute illness in this vulnerable population. We evaluated patterns, causes, and outcomes of acute hospitalization among homeless persons compared with a demographics-standardized and risk-standardized nonhomeless cohort. METHODS: Retrospective study comparing 185,292 hospitalizations for homeless individuals and 32,322,569 hospitalizations for demographics standardized nonhomeless individuals between 2007 and 2013 in Massachusetts, Florida, and California. Annual hospitalization rates for homeless persons were calculated and causes of hospitalization were compared with a demographics standardized nonhomeless cohort. Logistic and linear regression models were used to estimate risk-standardized outcomes. RESULTS: From 2007 to 2013, hospitalizations for the homeless increased in Massachusetts (294 to 420 hospitalizations per 1000 homeless residents), Florida (161 to 240/1000), and California (133 to 164/1000). Homeless patients were on average 46 years of age, often male (76.1%), white (62%), and either uninsured (41.9%) or insured by Medicaid (31.7%). Hospitalizations for homeless persons, compared with demographics-standardized nonhomeless, were more frequently for mental illness and substance use disorder (52% vs. 18%, P<0.001). Homeless compared with risk standardized nonhomeless individuals had lower in-hospital mortality rates (0.9% vs. 1.2%, P<0.001), longer mean length of stay (6.5 vs. 5.9 d, P<0.001), and lower mean costs per day ($1,535 vs. $1,834, P<0.001). CONCLUSIONS: Hospitalizations among homeless persons are rising. Despite greater policy and public health focus over the last few decades, mental illness and substance use remain primary drivers of acute hospitalization among homeless adults. Policy efforts should address barriers to the use of ambulatory care services, and behavioral health services in particular, to help reduce acute care use and improve the long-term health of homeless individuals. PMID- 30461585 TI - Physicians in Kentucky Perceive Physician Assistants to Be Competent Health Care Providers. AB - PURPOSE: The use of certified physician assistants (PA) has increased throughout the US health care system. The purpose of this study was to objectively evaluate physicians' perceptions of PAs' mastery of specific skills. It is important to understand stakeholders' perceptions of PAs' capabilities to support future changes in policies for better utilization of PAs in our health care system. METHODS: From 2014 to 2015, randomly chosen "active" physicians listed with the Kentucky Board of Medical Licensure were surveyed about their perceptions of competencies of certified PAs. Six competency domains (medical knowledge, interpersonal and communication skills, patient care, professionalism, practice based learning, and improvement and systems-based practice) were rated using a Likert scale. Each competency-derived skill-based question was ranked by the number of physicians giving the highest scores on the Likert scale (a score of 4 or 5) and by effect size. Cronbach's alpha for the survey was calculated. RESULTS: An overwhelming majority of the physicians perceived certified PAs to be competent (n >= 161, >= 60%) for specific skills. The survey had internal consistency with Cronbach's alpha ranging from 0.75 to 0.87 for competency domains. Effect size ranged from 0.44 to 0.98 for scores given by physicians with, versus without, experience with PAs. CONCLUSIONS: For the first time, there is objective evidence of physicians' perceptions of PAs' mastery of specific competency-derived PA skill sets. This study will help guide effective utilization of PAs throughout the health care system and future PA education. PMID- 30461586 TI - Citation and Characteristic Analysis of Physician Assistant Programs Placed on Accreditation-Probation, 2015-2017. AB - PURPOSE: The Accreditation Review Commission on Education for the Physician Assistant (ARC-PA) is responsible for accrediting the current 236 entry-level physician assistant (PA) programs in the United States. This study analyzes citations levied against PA programs by the ARC-PA and how those citations relate to the commission's ultimate accreditation decisions; in addition, this study compares PA program characteristics and assesses those characteristics as they relate to recent accreditation outcomes. METHODS: This study used citations for specific violations of ARC-PA Standards to analyze the ARC-PA's accreditation decisions from September 2015 through September 2017. The institutional characteristics of programs that received an accreditation-probation decision were compared with those that received an accreditation-continued or accreditation-provisional decision. Where possible, outcome decisions were benchmarked using national data obtained from publications distributed by the Physician Assistant Education Association. RESULTS: On average, programs that were placed on accreditation-probation during the time frame of this study had received their initial accreditation 16 years before being placed on probation. Altogether, 393 citations were levied against those programs (range: 2-60 citations; median: 13.5 citations). Physician assistant programs that were awarded provisional or continued accreditation were cited for slightly different Standards violations than PA programs that were placed on probation. The average 5-year pass rate for students taking the Physician Assistant National Certifying Examination for the first time was not very different for students from PA programs that were placed on probation and all other programs. CONCLUSIONS: Faculty members, institutions, and entities that support PA program development can use this information to compare PA programs. The results of this study can help PA programs identify areas of frequent noncompliance with the ARC-PA's Standards; provide context that PA programs can use to assess their performance against other programs in the accreditation process; and help PA programs identify areas in need of priority attention nationwide. PMID- 30461587 TI - Filling the Gaps: Predicting Physician Assistant Students' Interest in Practicing in Medically Underserved Areas. AB - PURPOSE: Physician assistants (PAs) are well situated to provide much-needed care in medically underserved areas (MUAs). Therefore, it is critical to understand the factors that make PA students want to practice in MUAs. The current study investigated how 3 student characteristics-underrepresented minority (URM) status, geographic origin, and family socioeconomic status-were associated with PA students' interest in practicing in MUAs after graduation. METHODS: Upon their matriculation in 2016, 4329 PA students provided key demographic information (ie, gender, age, race, ethnicity, geographic origin, and an indicator of family socioeconomic status) and reported their interest in working in an MUA after graduation. Multiple linear regression was used to predict students' level of interest in practicing in an MUA, and multiple logistic regression was used to predict students' likelihood of expressing interest in practicing in an MUA. All analyses controlled for students' gender and age at matriculation. RESULTS: All 3 student characteristics were independently associated with interest in practicing in an MUA, such that URM students, students from rural backgrounds, and less affluent students expressed greater interest in practicing in an MUA after graduation compared with their non-URM, suburban, and more affluent counterparts. CONCLUSION: Demographic commonalities may drive PA students' interest in practicing in an MUA after graduation. PMID- 30461588 TI - Veterans Health Administration's Physician Assistant Primary Care Residency: An Evaluation of the First 3 Years. AB - PURPOSE: Results from an evaluation of a 12-month postgraduate Veterans Health Administration (VHA) residency in primary care for physician assistants (PAs). METHODS: Descriptive and open-ended data were collected to describe the experience of faculty and trainees participating in the first 3 years of this pilot residency. Quantitative data were summarized using descriptive statistics. Text data were transcribed and reviewed for common themes across residency sites and respondents. Data were collected at 2 time points-the end of the first year and the beginning of year 4. RESULTS: In the first 3 years of the program, 18 residents were enrolled at 6 sites, with 89% completing the residency. At the second time point, 8 more residents were enrolled. Residents were primarily female (69%). Of the residents completing the program, 56% obtained VHA employment, and 75% of the current residents planned to work for the VHA upon completing the program. Program infrastructure, such as written curriculum, a dedicated administrative staff, and written evaluations for trainees, was more common at the second time point. Recurring themes included the importance of establishing relationships with potential applicants, preceptors, medical center leadership, and trainees to support the program and the importance of securing resources such as space and protected time for faculty. CONCLUSIONS: Although postgraduate residency programs are less common for PAs than for some other health professions, our data suggest that a one-year residency can provide training for new graduates to help solidify their clinical experience and facilitate their transition to practice. PMID- 30461589 TI - Influence of Health Educators in Clinical Settings: Addressing Social Determinants of Health. PMID- 30461590 TI - Bioethics Mediation: A Practical Approach to Physician Assistant Ethics Education. PMID- 30461591 TI - It Takes a Village: A Physician Assistant Student's Experience in Early Educator Mentorship and Faculty Development. PMID- 30461592 TI - Focal Electrographic Seizures in a Patient With Autism Spectrum Disorder and Speech Delay. AB - CASE: A 6-year-old boy with a diagnosis of autism spectrum disorder (ASD) presented to primary care for a new-patient, transfer-of-care evaluation. At the initial encounter, the patient used a maximum of 60 words and was receiving speech and language therapy (SLT) through school. Family history was positive for seizures in the father and paternal grandfather as well as ASD in an older brother. Referrals to genetics, private SLT, and an autism specialist were offered, although the latter was declined by family. The subsequent genetics evaluation resulted in discovery of a small gain on chromosome 1q42.2 and associated partial duplication of the DISC1 gene. The assay could not determine the exact clinical significance of the abnormality, but similarly sized and located abnormalities involving the DISC1 gene are reported in some patients with ASD and developmental delay. During a follow-up pediatrics appointment, the father expressed his wish for further evaluation of causes of autism spectrum disorder (ASD) and requested an electroencephalography (EEG) evaluation. The family concomitantly reported slow improvement in speech with therapy, the use of up to 200 words, and the ability to count to 10. The primary care physician reiterated that EEG and imaging studies are not indicated for an isolated ASD diagnosis with no supporting history or physical examination indications. The clinician discussed ASD-recommended therapies with the family. Neurology referral was made per parental request. The patient subsequently presented to neurology at the age of 7 years. The parents reiterated during the initial neurologic developmental history that the patient had shown some improvement with speech and language therapy in the past 18 months, knew as many as 200 to 300 words, and could put some words together into simple sentences. Gross and fine motor development were felt to be within the normal range for age. The parents also reported some scripting, and mild echolalia was noted on examination. Notably, there was no history of language regression. Apart from language delay, the neurologic examination was otherwise normal at initial evaluation. Given this clinical picture, ASD treatment options were again discussed. Despite education, parents continued to request for EEG evaluation as a workup for the etiology of the patient's ASD. Electroencephalography was ultimately ordered owing to the strong and repeated paternal request despite denial of any seizure-like episodes in the patient. EEG unexpectedly showed extremely frequent, almost constant focal electrographic seizures arising from the T3/T5 electrodes in the speech area of the left temporal lobe, prompting the initiation of oxcarbazepine maintenance therapy. Because of the noted abnormalities on EEG, magnetic resonance imaging (MRI) was obtained. Mild abnormalities were noted on MRI study including possible minimal inferior cerebellar vermian hypoplasia, mildly prominent bodies of the lateral ventricles, and nonspecific, nonenhancing punctate T2 hyperintensities in the subcortical white matter. These findings were not felt to be clinically relevant to the patient's presentation or seizure evaluation. No repeat imaging was ordered. Hindsight is always 20/20. As a clinician evaluating the patient initially, would you have pursued further workup sooner? PMID- 30461593 TI - A Pilot Project Using Pediatricians as Initial Diagnosticians in Multidisciplinary Autism Evaluations for Young Children. AB - OBJECTIVES: Wait times for autism spectrum disorder (ASD) evaluations are long, thereby delaying access to ASD-specific services. We asked how our traditional care model (requiring all patients to see psychologists for ASD diagnostic decisions) compared to an alternative model that better utilizes the available clinicians, including initial evaluation by speech, audiology, and pediatrics (trained in Level 2 autism screening tools). Pediatricians could diagnose immediately if certain about diagnosis but could refer uncertain cases to psychology. Accuracy and time to diagnosis, charges, and parent satisfaction were our main outcome measures. METHODS: Data were gathered through record extraction (n = 244) and parent questionnaire (n = 57). We compared time to diagnosis, charges, and parent satisfaction between traditional and alternative models. Agreement between pediatrician and psychologist diagnoses was examined for a subset (n = 18). RESULTS: The alternative model's time to diagnosis was 44% faster (85 vs 152 d) and 33% less costly overall. Diagnostic agreement was 93% for children with ASD diagnoses and 100% for children without ASD diagnoses. Pediatricians expressed higher diagnostic certainty about children with higher levels of ASD symptoms. Parents reported no differences in high satisfaction with experiences, family-centered care, and shared decision making. CONCLUSION: Efficient use of available clinicians with additional training in Level 2 autism screening resulted in improvements in time to diagnosis and reduced charges for families. Coordination of multidisciplinary teams makes this possible, with strategic sequencing of patients through workflow. Flexibility was key to not only allowing pediatricians to refer uncertain cases to psychology for diagnosis but also allowing for diagnosis by a pediatrician when symptomatic presentation clearly met diagnostic criteria. PMID- 30461594 TI - Prevalence of syphilis and related risk behaviors among women in five distinct indigenous populations in Paraguay. AB - BACKGROUND: The objective of this study was to measure the prevalence of syphilis among women of reproductive age from five distinct indigenous populations in Paraguay. We also sought to identify the demographic profile and behaviors of women with elevated prevalence of syphilis. METHODS: We conducted a population based, cross-sectional survey among women age 15 to 49 years old from five distinct language families in Paraguay in 2016. The five language families were Guarani, Maskoy, Mataco, Guaicuru, and Zamuco, sampled through a probability based, multi-stage cluster design. Participants completed a questionnaire on demographic characteristics and risk-related behavior. Blood samples were drawn for rapid testing for syphilis with confirmation and titers. Participants provided written informed consent; minors had written parental consent and provided their own assent. RESULTS: A total of 1,732 indigenous women were enrolled. Overall syphilis prevalence was 6.8% (95% confidence interval [CI] 5.6 8.0). Syphilis prevalence varied by language family/ethnic group (p=0.010), with Mataco having the highest prevalence (8.2%, 95% CI 5.3-11.9) and Maskoy having the lowest (2.5%, 95% CI 1.1-4.7). Women reporting multiple partners (11.3%, 95% CI 6.9-17.1, p=0.031) and transactional sex in the last year (18.7%, 95% CI 7.2 36.4, p=0.010) had higher prevalence of syphilis. CONCLUSIONS: Our survey found high prevalence of syphilis in indigenous women in Paraguay, in association with transactional sex and multiple partners. Interventions to reduce sexual behaviors associated with an increased risk of sexually transmitted infections in indigenous women must be carried out with programs aimed at addressing transactional sex, appropriately framed to respect interculturality and an indigenous worldview. PMID- 30461595 TI - Human papillomavirus vaccination and anogenital warts: A systematic review of impact and effectiveness in the United States. AB - BACKGROUND: Assessing the impact and effectiveness of HPV vaccines on anogenital warts in the United States can provide early indication of the success of vaccination programs as well as identify potential areas for improvement. METHODS: Articles were identified from the PubMed, Medline, and Embase databases. Exclusion criteria were applied, and remaining studies were then classified as impact or effectiveness studies. RESULTS: Eight eligible studies published through March 2018 were included. Population-based impact studies examining trends in diagnoses reported consistent declines in females ages 25 years and younger after 2006 when routine female vaccination began in the United States. Declines in males ages 25 years and younger were also seen; however, these declines were lower than those in females and more evident after routine male vaccination began in 2011. Among females and males older than 25 years, little to no change has been seen in the trends of anogenital warts since 2006. Studies that included the pre-vaccine era (before 2006) reported increasing trends during this period. After vaccine introduction, a reversal in these trends was observed. Effectiveness studies that included individual-level vaccination histories consistently demonstrated a lower risk of anogenital warts for those receiving at least one dose of the vaccine compared to those unvaccinated. CONCLUSIONS: These findings suggest that the degree of HPV vaccine impact has varied substantially by age and sex. Achieving the full prevention potential of HPV vaccines will likely require greater coverage among both females and males. Post-licensure estimates of effectiveness demonstrate the real-world benefit of the vaccine. PMID- 30461596 TI - Increasing Syphilis Diagnoses Among Females Giving Birth in US Hospitals, 2010 2014. AB - BACKGROUND: National trends in syphilis rates among females delivering newborns are not well characterized. We assessed 2010-2014 trends in syphilis diagnoses documented on discharge records and associated factors among females who have given birth in US hospitals. METHODS: We calculated quarterly trends in syphilis rates (per 100,000 deliveries) by using ICD-9 codes on delivery discharge records from the National Inpatient Sample. Changes in trends were determined by using Joinpoint software. We estimated relative risks (RR) to assess the association of syphilis diagnoses with race/ethnicity, age, insurance status, household income, and census region. RESULTS: Overall, estimated syphilis rates decreased during 2010-2012 at 1.0% per quarter (P < .001) and increased afterwards at 1.8% (P < .001). The syphilis rate increase was statistically significant across all sociodemographic groups and all US regions, with substantial increases identified among whites (35.2% per quarter; P < .001) and Medicaid recipients (15.1%; P < .001). In 2014, the risk of syphilis diagnosis was greater among blacks (RR, 13.02; 95% confidence interval [CI], 9.46-17.92) or Hispanics (RR, 4.53; 95% CI, 3.19-6.42), compared with whites; Medicaid recipients (RR, 4.63; 95% CI, 3.38 6.33) or uninsured persons (RR, 2.84; 95% CI, 1.74-4.63), compared with privately insured patients; females with the lowest household income (RR, 5.32; 95% CI, 3.55-7.97), compared with the highest income; and females in the South (RR, 2.42; 95% CI, 1.66-3.53), compared with the West. CONCLUSIONS: Increasing syphilis rates among pregnant females of all backgrounds reinforce the importance of prenatal screening and treatment. PMID- 30461597 TI - Results of a Pilot Study of a Mail-Based HPV Self-Testing Program for Underscreened Women from Appalachian Ohio. AB - BACKGROUND: Human papillomavirus (HPV) self-testing is an emerging cervical cancer screening strategy, yet few mail-based HPV self-testing programs have been implemented in the United States. We report the results of a pilot study of a mail-based program, the Health Outcomes through Motivation and Education (HOME) Project. METHODS: In 2015-2016, we recruited 103 women from Appalachian Ohio who were ages 30-65 and had not received a Pap test in at least three years. Women were mailed an HPV self-test and randomized to receive either: a) self-test instructions developed by the device manufacturer and a standard information brochure about cervical cancer (control group); or b) self-test instructions developed by the HOME Project and a photo story information brochure about cervical cancer (intervention group). Logistic regression compared study arms on HPV self-test return and receipt of a Pap test. RESULTS: Overall, 80 (78%) women returned their HPV self-test. Return was similar among the intervention and control groups (78% vs. 77%; OR=1.09, 95% CI: 0.43-2.76). Among returners, 26% had an oncogenic HPV type detected in their sample. Women who returned their self test reported high levels of satisfaction and positive experiences with the self testing process. Few women overall received a Pap test (11%), and Pap testing was similar among the intervention and control groups (14% vs. 8%; OR=1.91, 95% CI: 0.52-6.97). CONCLUSIONS: Mail-based HPV self-testing programs are a potentially promising strategy for reaching underscreened women in Appalachia. Efforts are needed to better understand how to optimize the success of such programs. PMID- 30461598 TI - Establishment of a gonococcal antimicrobial surveillance programme (GASP), in accordance with WHO standards, in Cote d'Ivoire, Western Africa, 2014-2017. AB - BACKGROUND: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is compromising the treatment of gonorrhea globally. Recent AMR data are extremely limited in Africa, and mainly totally lacking in Western Africa including Cote d'Ivoire. This study i) established a quality-assured gonococcal antimicrobial surveillance programme (GASP), according to WHO quality criteria, ii) investigated the AMR to eight therapeutic antimicrobials in gonococcal isolates from 2014 to 2017, and iii) provided evidence for updating the national STD syndromic management guidelines in Cote d'Ivoire. METHODS: During 2014-2017, gonococcal isolates were obtained from sexually active symptomatic or asymptomatic males and females in 14 sites in Cote d'Ivoire. It was a special focus on symptomatic males, and their sexual partners, due to the higher culture positivity rates in symptomatic males. Patient metadata were collected, including age, gender, sexual orientation and symptoms. Minimum inhibitory concentrations (MICs) of eight antimicrobials were determined by Etest and interpreted using EUCAST breakpoints. beta-lactamase production was detected using cefinase disks. RESULTS: The level of resistance, examining 212 gonococcal isolates, was as follows: 84.9% to tetracycline, 68.9% to benzylpenicillin, 62.7% to ciprofloxacin, 6.1% to azithromycin, and 1.4% to gentamicin. All isolates were susceptible to ceftriaxone, cefixime and spectinomycin. CONCLUSION: We provide the first gonococcal AMR data, quality assured according to WHO standards, from Cote d'Ivoire since more than 20 years. The high ciprofloxacin resistance, which informed a revision of the national syndromic management guideline during study, and relatively high resistance to azithromycin demand an improved GASP and increased awareness when prescribing treatment in Cote d'Ivoire. PMID- 30461599 TI - Novel tp0548 sequence-type of Treponema pallidum identified in Barcelona, Spain. AB - A novel tp0548 sequence-type of Treponema pallidum has been identified in a genital ulcer sample collected from a patient diagnosed with primary syphilis at the Hospital Universitari Vall d'Hebron in Barcelona. Following the nomenclature used in the Enhanced CDC Typing methodology, letter "z" has been assigned to the new sequence-type. PMID- 30461600 TI - Treatment of chronic obstructive pulmonary disease in patients with different fractional exhaled nitric oxide levels. AB - Some patients with chronic obstructive pulmonary disease (COPD) have eosinophilic inflammation which may be evaluated via the measurement of fractional exhaled nitric oxide (FeNO) like asthma. The aim of this prospective study was to assess whether FeNO levels can be used to identify patients with COPD with eosinophilic inflammation who may respond to inhaled corticosteroid (ICS) therapy.This study included patients (N = 112) with COPD (age >18 years) who were divided into 4 groups depending upon whether they had high (>=25 parts per billion [ppb]) or low (<25 ppb) pretreatment (baseline) FeNO and if they were treated with either ICS plus long-acting beta-agonist (ICS + LABA) or a long-acting muscarinic antagonist (LAMA). The 4 groups were: high FeNO/ICS + LABA, high FeNO/LAMA, low FeNO/ICS + LABA, and low FeNO/LAMA. Outcomes assessed included FeNO, COPD assessment test (CAT), and pulmonary function.The high FeNO/ICS + LABA group had the greatest reduction from baseline in FeNO levels (-25.80 ppb +/- 27.14) compared with the high FeNO/LAMA, low FeNO/ICS + LABA, and low FeNO/LAMA groups (range, -4.45 to 1.31 ppb; P < .001). The high FeNO/ICS + LABA group also showed the greatest improvement in CAT (-7.20), which was statistically larger than the low FeNO/ICS + LABA and low FeNO/LAMA groups (-1.72 and -2.03, respectively). No difference in pulmonary function following treatment was observed across the 4 groups.This study found that patients with high FeNO showed the greatest reduction in FeNO and improvement in CAT with ICS + LABA therapy, supporting the use of FeNO to identify patients who would benefit from ICS use. PMID- 30461601 TI - Salvianolate injection in the treatment of acute cerebral infarction: A systematic review and a meta-analysis. AB - To evaluate the effectiveness and safety of Salvianolate injection (SI) in the treatment of acute cerebral infarction (ACI).We electronically searched databases including PubMed, The Cochrane Library, EMBASE, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, and WanFang Data to collect randomized controlled trials (RCTs) focused on SI treating ACI up to August 2017. Two reviewers independently screened literatures, extracted data, and assessed the risk of bias of included studies. Then, meta-analysis was performed using RevMan 5.3 software.A total of 39 RCTs involving 4516 patients were included. The results of meta-analysis showed that compared with the Western medicine (WM) therapies group [experimental group (EG)], the total effective rate of SI + WM [control group (CG)] was higher (relative risk = 1.29, 95% CI: 1.24-1.35, P < .00001) in 21 RCTs; SI could improve movement function evaluation scores, including National Institute of Health Stroke Scale, Barthel Index, activities of daily living (P < .00001). There was no significant difference in modified Rankin Scale scores between the 2 groups (P = .008) EG was better than CG in improving Montreal Cognitive Assessment scores (P = .001) and Mini-Mental State Examination scores (P < .00001). SI could improved not only the hemorheology indexes, including plasma viscosity, whole blood high-shear viscosity, whole blood low shear viscosity, fibrinogen (P < .00001), but also high-sensitivity C-reactive protein and C-reactive protein. EG could achieve a better effect on improving the neural deficit scores (P < .00001). There was no significant difference about adverse drug reactions/adverse drug events between the EG and CG (P = .73).Salvianolate can promote recovery of the motor and cognitive function of patients with ACI. However, due to the limited quality and quantity of included studies, more high-quality studies are needed to verify the above conclusion. PMID- 30461602 TI - Reduction of oxidative stress a key for enhanced postoperative recovery with fewer complications in esophageal surgery patients: Randomized control trial to investigate therapeutic impact of anesthesia management and usefulness of simple blood test for prediction of high-risk patients. AB - BACKGROUND: Oxidative stress may be an integral determinant of surgical stress severity. We examined whether the preoperative level of derivatives of reactive oxygen metabolites (d-ROMs), an oxidative stress biomarker based on total hydroperoxides in circulating blood, is predictive of increased risk of delayed recovery and complications after surgery, as well as the effects of anesthesia management on postoperative recovery in light of oxidative stress. METHODS: Patients (American Society of Anesthesiologists physical status I-II) scheduled for a radical esophagectomy (n = 186) were randomly selected to receive inhalational sevoflurane (n = 94) or intravenous propofol (n = 92) anesthesia. Preoperative blood d-ROMs level, as well as pre-and postoperative plasma ferric reducing ability, were analyzed to assess oxidative stress, with white blood cell (WBC) count, C-reactive protein (CRP) level, incidence of severe postoperative complications, and postoperative recovery process within 30 days after surgery also examined in a double-blind fashion. RESULTS: Postoperative normalization of WBC and CRP was extended in patients with elevated preoperative d-ROMs [WBC versus d-ROMs: correlation coefficient (r) = 0.58 P < .001; CRP versus d-ROMs: r = 0.46 P < .001]. Receiver operating characteristics analysis of d-ROMs in relation to incidence of severe postoperative complications revealed an optimum d ROMs threshold value of 410 UCarr and that patients with >=410 UCarr had a greater risk of complications as compared to those with lower values (odds ratio = 4.7). Plasma ferric-reducing ability was decreased by 61 +/- 185 mmol.l (P < .001) after surgery, demonstrating development of surgery-related oxidative stress, the magnitude of which was positively correlated with preoperative d-ROMs level (r = 0.16, P = .043). A comparison of the 2 anesthesia management protocols showed that patients who received propofol, an antioxidant anesthetic, had no postoperative decrease in ferric-reducing ability, lower incidence of severe postoperative complications (7 of 92 versus 18 of 94, P = .030, odds ratio = 0.35), and faster uneventful recovery time (WBC normalization days 7.1 +/- 5.2 versus 13.6 +/- 10.2, P < .001) as compared to those who received sevoflurane. CONCLUSIONS: Elevated preoperative blood d-ROMs predicts greater intraoperative oxidative stress and increased postoperative complications with prolonged recovery, thus is useful for identifying high-risk patients for delayed and complicated surgical recovery. Reduction of oxidative stress is vital for enhanced recovery, with control by antioxidants such as propofol a possible solution. PMID- 30461603 TI - Sotos syndrome: A case report of 1st genetically proven case from Saudi Arabia with a novel mutation in NSD1 gene. AB - RATIONALE: Sotos syndrome is a rare genetic disorder characterized by rapid growth during infancy and childhood; >=2 SD for height and head circumference; distinctive facial appearance and developmental delay.Ten clinically diagnosed cases have been reported from Saudi Arabia; none of them was genetically confirmed. PATIENT CONCERNS: A male Saudi patient, who had a birth length and head circumference above 97th centile, presented with abnormal rapid growth, delayed motor and mental milestones, aggressive behavior, obsession to close doors, nail biting, defective attention, and hyperactivity. DIAGNOSES: Sotos syndrome was suspected INTERVENTIONS:: Molecular genetic analysis for NSD1 gene was carried for the patient. OUTCOMES: A novel heterozygous deletion of all exons 1 to 23 of the NSD1 gene was detected. Genetic counseling was carried for the family with extended genetic testing for the parents and his siblings with normal results. LESSONS: Despite its worldwide distribution, Sotos syndrome may be under reported. Besides its characteristic clinical picture, molecular genetic testing is also extremely recommended. PMID- 30461604 TI - Efficacy of rational emotive digital storytelling intervention on knowledge and risk perception of HIV/AIDS among schoolchildren in Nigeria. AB - BACKGROUND: This investigation was aimed at determining the efficacy of a rational emotive digital storytelling (REDStory) therapy on knowledge and perception of risk of HIV/AIDS among schoolchildren in Enugu State, Nigeria. METHODS: The researchers adopted a group randomized controlled trial design involving a pretest, posttest, and follow-up design involving a treatment group and a waiting-list control group. Participants were 80 junior secondary schoolchildren attending public and private schools who met the criteria for inclusion in the sample of this study. The REDStory intervention program lasted for 8-week duration of REDStory therapy. The HIV Knowledge Questionnaire and the Perceived Risk of HIV Scale (PRHS) were used for data collection for this study. Repeated measures analysis of variance and t test were used for data analysis. RESULTS: The results revealed that REDStory therapy had a significant effect in increasing knowledge level and perceived risk of HIV among schoolchildren compared to those in waitlisted control group. Lastly, the positive benefits of this study were significantly sustained by the treatment group at the follow-up. CONCLUSION: The current study therefore suggests the use of REDStory therapy in increasing knowledge and perception of risk of HIV/AIDS among schoolchildren in Enugu, Nigeria. PMID- 30461606 TI - Is dynamic locking plate superior than other implants for intracapsular hip fracture: A meta-analysis. AB - BACKGROUND: We studied the safety and efficacy of dynamic locking plate vs. other implants (cannulated cancellous screws [CCS] or sliding hip screw [SHS]) in patients undergoing intracapsular hip fracture (ICHF). METHODS: We searched Pubmed, Embase, Web of Science, Cochrane library and Google database from inception to March 25, 2018. We selected any studies comparing dynamic locking plate for treatment ICHF. Non-union rate, osteonecrosis rate, cutout rate, revision rate, the replacement rate, and Harris hip scores were the outcomes. Stata 12.0 was used for meta-analysis. RESULTS: Four studies involving 419 patients (143 patients in the dynamic locking plate group and 276 patients in the other implants group) were finally included. Compared with CCS or SHS, dynamic locking plate was associated with a reduction of nonunion rate, revision rate, replacement rate (P <.05). Furthermore, dynamic locking plate was also associated with an increase of the Harris hip scores (P <.05). There was no significant difference between the osteonecrosis rate and cutout rate (P >.05). CONCLUSIONS: Current meta-analysis revealed that dynamic locking plate has a benefit role in improving postoperative clinical outcome than CCS or SHS in ICHF patients. Further high quality and large-scale randomized controlled trials (RCTs) are needed to further identify the efficacy of dynamic locking plate for ICHF. PMID- 30461605 TI - A meta-analysis and systematic review of percutaneous catheter drainage in treating infected pancreatitis necrosis. AB - BACKGROUND: In the current meta-analysis, we focus on the exploration of percutaneous catheter drainage (PCD) in terms of its overall safety as well as efficacy in the treatment of infected pancreatitis necrosis based on qualified studies. METHODS: The following electronic databases were searched to identify eligible studies through the use of index words updated to May 2018: PubMed, Cochrane, and Embase. Relative risk (RR) or mean difference (MD) along with 95% confidence interval (95% CI) were utilized for the main outcomes. RESULTS: A total of 622 patients in the PCD group and 650 patients in the control group from 13 studies were included in the present meta-analysis. The aggregated results indicated that the incidence of bleeding was decreased significantly (RR: 0.42, 95% CI: 0.25-0.70) in the PCD group as compared with the control group. In addition, PCD decreased the mortality (RR: 0.76, 95% CI: 0.41-1.42), hospital duration (SMD: -0.22, 95% CI: -0.77 to -0.33), duration in intensive care unit (ICU) (SMD: -0.13, 95% CI: -0.30 to -0.04), pancreatic fistula (RR: 0.73, 95% CI: 0.46-1.17), and organ failure (RR: 0.91, 95% CI: 0.45-1.82) in comparison with the control group, but without statistical significance. CONCLUSION: Our findings provide evidence for the treatment effect of PCD in the decrease of bleeding, mortality, duration in hospital and ICU, pancreatic fistula, organ failure as compared with the surgical treatment. In conclusion, further studies based on high-quality RCTs with larger sample size and long-term follow-ups are warranted for the confirmation of PCD efficacy in treating infected pancreatitis necrosis. PMID- 30461607 TI - Assessing the methodological and reporting quality of network meta-analyses in Chinese medicine. AB - BACKGROUND: An increasing number of network meta-analyses (NMAs) in traditional Chinese medicine (TCM) have been published recently, but the quality of them was lack of assessment. This study aims to evaluate the methodological and reporting quality of NMAs in TCM. METHODS: Six electronic databases, including PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, China National Knowledge Infrastructure (CNKI), Wanfang and Chinese Biomedical Literature Database (CBM) from inception to January 2018, were searched. NMAs of TCM were included. A measurement tool to assess the methodological quality of systematic reviews (AMSTAR) and the PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions (PRISMA NMA) were used to assess the methodological and reporting quality of the included NMAs. RESULTS: A total of 40 NMAs, including 2535 randomized controlled trials (RCTs), were included. They were published between December 2012 and November 2017. The median score and interquartile range of methodological and reporting quality was 7 (6-8) and 22 (19.1-27.1). Serious methodological flaws existed in the following aspects: the status of publication (22.5%), a list of studies provided (0%), assessment of publication bias (37.5%), and conflicts of interest (12.5%). Several items need to be improved in reporting, especially for Protocol and registration (2.5%), Data items (22.5%), Risk of bias across studies (Methods section) (37.5%), Results of individual studies (27.5%), Risk of bias across studies (Results section) (40%), Results of additional analyses (35%), and Funding (15%). CONCLUSIONS: The methodological and reporting quality of NMAs in TCM is moderate. Identified shortcomings of published NMAs should be taken into consideration in further trainings of authors and editors of NMAs in TCM. Future researchers should be encouraged to apply PRISMA-NMA, and a recognized tool for the assessment of NMA methodology was wanted. PMID- 30461608 TI - Improve the ethical review of clinical trials on traditional medicine: A cross sectional study of clinical trial registration, ethical review, and informed consent in clinical trials of Traditional Chinese Medicine. AB - Recently, there is an increasing number of clinical trials on Traditional Chinese medicine (TCM) published, but the implementation of Clinical Trial Registration (CTR), Ethical Review (ER), and Informed Consent (IC) in clinical trials of TCM is unclear. This study aims to investigate the status of CTR, ER, and IC in clinical trials of TCM.Clinical trials of TCM published in 10 high-quality Chinese journals in 2016 were selected as a sample. Information of clinical trial registration, ethical review, and informed consent of clinical trials was extracted for analysis. Two authors independently screened the literature and extracted the relevant information.A total of 659 clinical trials met the criteria and were included for analysis. Only 9 clinical trials reported information of clinical trial registration (1.4%). The number for ethical review and informed consent were 156 (23.7%) and 502 (76.2%).Trial registration, protocol approval, and informed consent were not well executed. Especially registration and ethical review of clinical trials in TCM should be carefully concerned by researchers, clinicians, and journal editors. Training on methodology of clinical trial should be strengthened. PMID- 30461609 TI - Lymphocyte hydrogen sulfide production predicts intravenous immunoglobulin resistance in children with Kawasaki disease: A preliminary, single-center, case control study. AB - The aim of the study was to identify whether lymphocyte hydrogen sulfide production is a potential biomarker to predict intravenous immunoglobulin (IVIG) resistance in children with Kawasaki disease (KD).This preliminary, single center, case-control study conducted between June 2016 and March 2018 in Shaanxi Provincial People's Hospital, 85 children (50 with KD and 35 healthy controls) were included. Laboratory biomarkers were collected from the medical records. All patients with KD received 1 g/kg/d IVIG for 2 days and 30-50 mg/kg/d oral aspirin. The aspirin dose was reduced from 3 to 5 mg/kg/d after body temperature normalized. Plasma hydrogen sulfide levels were detected using sulfide electrode. Lymphocyte hydrogen sulfide levels were detected using the human hydrogen sulfide ELISA kits at the acute stage.Of 50 patients with KD, 31 and 19 were diagnosed with complete KD (cKD) and incomplete KD (iKD), respectively. Eleven patients with KD were resistant to IVIG treatment. The laboratory biomarker findings and levels of plasma and lymphocyte hydrogen sulfide were significantly different between the patients with KD and control group (P < .001). Moreover, lymphocyte hydrogen sulfide production was significantly greater in IVIG-resistant patients than in the IVIG-responsive patients, both in cKD and iKD (P = .018 and P < .001 respectively). Receiver operating characteristic curve indicated that when the lymphocyte hydrogen sulfide production was >15.285 nmol/min/10 lymphocytes, the sensitivity and specificity for predicting IVIG resistance were 90.9% and 76.9%, respectively.Lymphocyte hydrogen sulfide production could serve as a predictor of the therapeutic efficacy of IVIG in children with KD. PMID- 30461610 TI - Comorbidities, risk, and socioeconomic factors of uninsured cancer survivors. AB - Cancer patients can be well-connected to resources during treatment but become lost to follow-up and subsequently may receive treatment in free clinics for chronic morbidities. Few studies have examined outcomes for uninsured patients with cancer histories in free clinics, but research examining socioeconomic determinants emphasizes poor cancer outcomes for patients with lower socioeconomic statuses (SES).Demographic data and chronic disease measures were extracted from medical charts of patients treated in 8 free clinics in 2016 in Tampa Bay. Descriptive statistics and Pearson correlation coefficients were used to demonstrate relationships between socioeconomic factors, cancer diagnoses, and comorbidities. Charlson Comorbidity Index (CCI) was used to assess mortality risk and severity of disease burden.The histories of 4804 uninsured patients were evaluated, identifying 86 (1.7%) as having had cancer. They were predominantly female (65.1%) and significantly older than those without cancer histories. Average duration from initial diagnosis was approximately 8.53 years (standard deviation [SD] 7.55). Overall, cancer patients had higher CCI scores (3.04 [1.928 SD] versus 0.90 [1.209 SD]; P <.001); thus reflecting more weighted comorbidities than patients without cancer (P <.001). Other factors of chronic disease including obesity and substance abuse correlated with cancer history.Among uninsured patients, those with cancer histories had greater mortality risk by CCI than those without. Chronic conditions such as diabetes, cerebrovascular disease, and chronic pulmonary disease existed in patients with cancer histories, affecting their mortality risk. Uninsured patients with a history of cancer are in greater need for chronic disease management and prevention. PMID- 30461611 TI - Interleukin-6 for early diagnosis of neonatal sepsis with premature rupture of the membranes: A meta-analysis. AB - BACKGROUND: Premature rupture of the membranes (PROM) is the principal risk factor for neonatal sepsis. Interleukin-6 (IL-6) has been investigated for early diagnosis of neonatal sepsis, but not for diagnosis of neonatal sepsis with PROM. The objective of this study is to investigate the early diagnostic value of IL-6 for neonatal sepsis with PROM. METHODS: The literature was searched using PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wan Fang, VIP, and CBM databases until March 2018. Each study was evaluated using Quality Assessment of Diagnostic Accuracy Studies tool-2. We used a bivariate diagnostic random-effects model. RESULTS: The overall pooled sensitivity, specificity, positive likelihood rate, negative likelihood rate, diagnostic odds ratio, and area under the summary receiver operating characteristic curve were 0.85 (95% confidence interval [CI]: 0.81-0.91), 0.88 (95% CI: 0.86-0.91), 9.94 (95% CI: 4.27-23.15), 0.14 (95% CI: 0.06-0.32), 79.26 (95% CI: 23.42-268.26), and 0.9473, respectively, which showed high accuracy in diagnosing neonatal sepsis with PROM. The types of sepsis might be connected with the source of heterogeneity (P = .0351). CONCLUSION: IL-6 is therefore a sensitive and specific diagnostic marker for the early diagnosis of neonatal sepsis with PROM. PMID- 30461613 TI - Three mutations of adult type 1 Gaucher disease found in a Chinese patient: A case report. AB - RATIONALE: Gaucher disease (GD), characterized by glucosylceramide accumulation in the macrophage-monocyte system, is caused by glucosidase b acid (GBA) gene mutations which lead to the deficiency of lysosomal enzyme glucocerebrosidase. The mutation spectrum of GBA in Chinese patients is quite different from those seen in Jewish and non-Jewish Caucasian patients. Thus, it is relatively hard to diagnose GD in Chinese. PATIENT CONCERNS: A 24-year-old Chinese female with intermittent abdominal distension and progressive decrease in strength but without neurologic symptoms was initially referred for femoral head necrosis on the right feet. Laboratory examinations results indicated panhematopenia. Bone marrow aspiration smear and biopsy specimen found typical "wrinkled" Gaucher cells. Molecular-genetic testing of GBA gene revealed 3 mutations including R159W (c. 475 C > T), V1230G (c. 689T > G), and G241A (c. 721G > A). DIAGNOSES: On the basis of these findings and clinical manifestations, the final diagnosis of type 1 GD was made. INTERVENTIONS: Enzyme replacement therapy (ERT) with velaglucerase alpha was carried out after the diagnosis of type 1 GD. OUTCOMES: The platelet and hemoglobin levels were restored by ERT. LESSONS: To our knowledge, this is the first report of GD patient carrying 3 mutations in Chinese. These mutations in GBA in the present case imply a potential pool of patients with GD with this mutation in Chinese. PMID- 30461612 TI - Efficacy and safety of alfacalcidol in Chinese postmenopausal women aged over 65 with osteoporosis or osteopenia: An open label, non-comparative, post marketing observational study. AB - This study aimed to explore the therapeutic efficacy and safety of alfacalcidol among Chinese postmenopausal women (age >65 years) with osteoporosis or osteopenia.A total of 62 postmenopausal women with osteoporosis or osteopenia (>65 years) were recruited from urban residential community of Beijing. The patients daily took oral calcium and alfacalcidol (Alpha D3, 1 MUg) for 9 months. Safety and efficacy assessments were performed at baseline and regular intervals. Alfacalcidol was adjusted to a daily dose of 0.5 MUg in case of hypercalcemia or hypercalciuria.A significant improvement in "timed up and go test" and "chair rising test" was achieved 3 months after treatment. Significant decreases in bone turnover markers were observed 3 months after the treatment and lasted throughout the study. Nineteen patients discontinued due to adverse events (17 hypercalciuria, 1 hydronephrosis, and 1 stomach ache), while alfacalcidol was adjusted to a daily dose of 0.5 MUg in 18 patients (29.0%). Increased serum creatinine was observed when compared to baseline (P <.001), but all the values were in normal range.The treatment with 1 MUg alfacalcidol can significantly improve muscle function and bone metabolism. Regular monitoring of urine calcium and timely dosage-adjustments are very important to guarantee the safety of alfacalcidol treatment in Chinese menopausal women. PMID- 30461614 TI - Comparison of the effect of postoperative radiotherapy with surgery alone for esophagus squamous cell carcinoma patients: A meta-analysis. AB - BACKGROUND: This meta-analysis was conducted to evaluate the effect of postoperative radiotherapy for patients having esophagus squamous cell carcinoma after radical surgery. METHODS: A comprehensive research was performed in Pubmed, Embase and Cochrane Library electronic databases from inception until December 10, 2017. We collected all published full articles about comparison of surgery plus postoperative radiotherapy with surgery alone. RESULTS: Four randomized controlled trials (RCTs) with 1050 participants and 8 non-randomized-controlled trials with 3248 participants were included and evaluated separately. The risk ratio rate and its 95% confidence interval (CI) were calculated. Both RCTs and non-randomized-controlled trials (NRCTs) groups showed a significant increase in 3-year overall survival (OS) rate (RRRCT = 0.89, 95% CI: 0.80-0.99; RRNRCT = 0.82, 95% CI: 0.76-0.88) and decrease locoregional recurrence rate (RRRCT = 0.53, 95% CI: 0.43-0.66; RRNRCT = 0.47, 95% CI: 0.32-0.69) after postoperative radiotherapy compared with surgery alone. The 5-year OS rate in the group of NRCTs was markedly enhanced (RR = 0.87, 95% CI: 0.82-0.92), while that of the RCTs group was not enhanced in a significant way (RR = 0.84, 95% CI: 0.70-1.02). Subgroup analysis based on pathological lymph node status revealed that postoperative radiotherapy could improve OS regardless of pathological lymph node status (pathological lymph node positive patients: RR5-year os-RCT = 0.81, 95% CI: 0.70-0.93; RR5-year os-NRCT = 0.87, 95% CI: 0.80-0.94; Pathological lymph node negative patients: RR3-year os-RCT = 0.76, 95% CI: 0.59-0.96; RR3-year os NRCT = 0.52, 95% CI: 0.30-0.89). No effect on distant recurrence rate was detected. Adverse effects induced by postoperative radiotherapy were comparatively modest and tolerable. CONCLUSION: Polled results yielded that postoperative radiotherapy was promising in improving OS and reducing the locoregional recurrence rate. More large-scale up-to-date RCTs are needed to further validate the use of postoperative radiotherapy in modern practice. PMID- 30461615 TI - Equipment failure of intravenous syringe pump detected by increase in Narcotrend stage: A case report. AB - RATIONALE: Awareness is the recovery of consciousness during general anesthesia. It occurs when patients under general anesthesia receive inadequate anesthetic medications to maintain unconsciousness during surgery. Equipment failure is a common cause of intraoperative awareness. PATIENT CONCERNS: A 16-year-old boy, 85 kg in weight, was admitted to our hospital for thyroglossal cystectomy under general anesthesia. Six minutes after the intubation, we noted that the Narcotrend index indicated a condition of light anesthesia and the patient was observed to be in tears. DIAGNOSIS: Improper positioning of the syringe fixing clamp on the CP700TCI infusion pump caused equipment failure and light anesthesia. INTERVENTIONS: Bolus of 50 mg propofol and 2 mg midazolam were administered manually by syringe, and inhalation of 2% sevoflurane was supplemented. Infusion pump was replaced. OUTCOMES: The Narcotrend index of the patient returned to state of deep anesthesia following manual administration of the anesthetic medications. Following the surgery, the patient had an uneventful recovery, and did not present with evidence of awareness. LESSONS: Users of the CP700TCI syringe pump should pay attention to the position of the syringe fixing clamp. Anesthesiologists should check all the equipment according to a defined checklist prior to anesthesia. Narcotrend monitor could help to detect light anesthesia and prevent potential awareness. PMID- 30461616 TI - Effects of motivational methods on oral hygiene of orthodontic patients: A systematic review and meta-analysis. AB - OBJECTIVE: The aim of our study was to qualitatively and quantitatively synthesize the evidence regarding ways to improve motivation of oral hygiene among orthodontic patients with fixed appliances and identify the effects of motivational methods via comparing the oral hygiene condition before and after the motivations. METHODS: An electronic search was conducted in PubMed, Ovid, Embase, and the Crochrane Library for relevant random controlled trials (RCT) and clinical controlled trial (CCT) published before May 1, 2017 with manual search in addition. Search and selection of studies, quality assessment, data extraction and synthesis was completed by 2 reviewers independently. Plaque index (PI) and gingival index (GI) at 1, 3, 6-month were pooled with Review Manager 5.3. Bias of included studies was evaluated. RESULTS: In total, 12 studies fulfilled the inclusion criteria of this systematic review, of which, 5 were included in the meta-analysis. Motivational methods had statistically significant advantage regarding PI in the experimental group over control group at 1, 3, 6-month, while GI was significantly better controlled in the study group at 3, 6-month. The quality of included studies was moderate. CONCLUSION: It is worthy for orthodontists to put in additional efforts to motivate patients to maintain good oral hygiene throughout the entire treatment process. PMID- 30461617 TI - Surgical correction of residual facial deformity following conservative excision of a giant maxillary ossifying fibroma: A case report. AB - RATIONALE: Ossifying fibroma (OF) is a benign fibro-osseous lesion that can develop in the oral and maxillofacial region. OF is more common in females and has a marked predilection for the mandible, occurring rarely in the maxilla. Lesions grow slowly and are usually asymptomatic until growth produces an obvious swelling, pain, paresthesia, and facial deformity. With low rates of recurrence, treatment is usually curettage or resection. Very large lesions that invade other organs and that cannot be completely removed should be excised conservatively. PATIENT CONCERNS: We present a case of a 46-year-old female with a very large fibro-osseous lesion arising from the maxilla who was more concerned about the facial appearance and requested conservative treatment for economic reasons. DIAGNOSES: The pathological results based on conservative excision of the lesion confirmed the diagnosis of OF. INTERVENTIONS: We chose conservative excision via the Weber-Ferguson approach and followed up every 6 months. Facial deformity correction was performed 2 years postoperatively and right lower eyelid ectropion correction 3 years after the primary excision. OUTCOMES: The ectropion deformity in the right lower eyelid improved dramatically with a better facial appearance and no obvious swelling. LESSONS: Treatment programs for OF should be individualized based on the size, growth rate, invasion, and interference with facial function and esthetics. If lesions grow slowly, we suppose that it is feasible to excise conservatively when reconstruction cannot be performed due to esthetic and functional problems. Also regular postoperative follow-up is necessary to detect recurrence, and to improve facial appearance as required. PMID- 30461618 TI - Cerebrospinal fluid rhinorrhea in a bilateral frontal decompressive craniectomy patient caused by strenuous activity: A case report. AB - RATIONALE: Iatrogenic cerebrospinal fluid (CSF) rhinorrhea in a bilateral frontal decompressive craniectomy patient triggered by strenuous sport is rare. To the best of our knowledge, no similar case has yet been reported. PATIENT CONCERNS: Herein, we report a case of CSF rhinorrhea in a 37-year-old man. He had previously suffered a traumatic brain injury in a traffic accident, and a subsequent bilateral frontal decompressive craniectomy operation was performed. Based on the frontal skull defect peculiarity, strenuous exercise may have caused drastic CSF pressure waves to tear the dura mater of the anterior skull base, resulting in CSF rhinorrhea. DIAGNOSES: The thin-slice computerized tomography (CT) images revealed a frontal skull defect and the open frontal sinus. In addition, in the opened frontal sinus, low-density liquid-filled areas were visible. INTERVENTIONS: During surgery, the torn dura was carefully repaired, and the frontal sinus was filled with temporal muscle, fascia, and fibrin glue. A simultaneous cranioplasty was performed. OUTCOMES: The patient was followed-up postoperatively for 12 months to date without rhinorrhea recurrence. Recovery was uneventful. LESSONS: Patients with skull defects should avoid strenuous sports, and cranioplasty should be performed as early as possible in order to decrease the likelihood of a dural tear and prevent the occurrence of CSF leakage. After cranioplasty, the skull should be restored to a closed state to reduce the damaging effects of CSF waves during movement. It is important to maintain normal intracranial pressure to reduce the recurrence rate of CSF rhinorrhea. PMID- 30461619 TI - Medullary thyroid carcinoma with breast metastasis: Two case reports. AB - RATIONALE: Medullary thyroid carcinoma (MTC) is an aggressive subtype of thyroid cancer with frequent hematogenous metastasis. While its metastasis is usually observed in the lung, liver, or bone, it rarely migrates to the breast. PATIENT CONCERNS: Here we report 2 cases with a complaint of breast lump after initial treatment of MTC. DIAGNOSES: In both patients, the MTC characteristics of breast nodules were confirmed by pathologic analysis of biopsy specimens. INTERVENTIONS: The genetic mutations within the metastatic breast lesion were evaluated. Wide local excision was thus performed to 1st case, while no therapeutic intervention for another patient due to the wide-spread presence of the disease. OUTCOMES: No sign of relapse or metastasis was found in 1st case during a 14-month follow-up. For 2nd case, the breast nodule grew to 14 mm within 3 months before remaining stable for 10 months. LESSONS: MTC can be a very indolent disease despite its aggressiveness. Reoperation should be considered for patients with local recurrence or resectable distant metastasis of MTC. The findings for both cases supported serum calcitonin as an important marker for the evaluation of disease. Future studies are needed to advance our understanding of its molecular features and improve strategies for its diagnosis and treatment. PMID- 30461620 TI - Impact of a change in duration of prophylactic antibiotics on infectious complications after radical cystectomy with a neobladder. AB - A profound number of prophylactic antibiotics are used after radical cystectomy with an ileal orthotopic neobladder (RCIONB) despite a negative effect of infection control. We investigated the impact of short-term prophylactic antibiotic use on infectious complications after RCIONB.We retrospectively reviewed data from 287 patients who underwent RCIONB for bladder cancer between 2012 and 2016 at a tertiary hospital. The patients were divided into 2 groups according to the pattern of prophylactic antibiotics (185 patients in a long-term group, 25-day use of 3-staged multiple antibiotics versus 102 patients in a short term group, 24-hour use of cefotetan). The onset of complications, including bacteriuria, febrile urinary tract infection (FU), and bacteremia, and the microorganisms responsible for infections were compared between the groups. Of all 287 patients, bacteriuria, FU, and bacteremia were identified in 177 (61.7%), 85 (29.6%), and 18 (6.3%) patients, respectively. Bacteriuria was identified more frequently in the short-term group (49.2% vs 84.3%, P <.001). However, the rates of FU within 60 days of surgery were similar in both groups (28.6% vs 28.4%, P = .969). The rate of FU was not significantly different between the 2 groups. There was no significant difference in the rate of patients with bacteremia (5.4% vs 7.8%, P = .415). The most frequent microorganisms seen in bacteriuria were Enterococcus faecium and Enterococcus faecalis, in the long-term and short-term group, respectively. Antibiotic-resistant Enterococcus species were more frequently present in the long-term group.Short-term use of prophylactic antibiotics is effective for preventing urinary tract infections after RCIONB and decreasing colonization with multi-drug-resistant organisms. PMID- 30461621 TI - The effects of tonsillectomy by low-temperature plasma on the growth development and psychological behavior in children with obstructive sleep apnea hypopnea syndrome. AB - We investigated the effects of tonsillectomy by low-temperature plasma on the growth development and psychological behavior in children with obstructive sleep apnea hypopnea syndrome (OSAHS).This study included 72 moderate and severe OSAHS children with tonsils or adenoids hypertrophy, which were randomly assigned into either the study group (n = 36) or the control group (n = 36). Patients in study group underwent tonsillectomy by low-temperature plasma, while in the control group underwent tonsil-pecking, then the efficacy were compared.The time of surgery, VAS scores on postoperative day 1, 3, and 7 were significantly lower in the study group than in the control group, and the efficiency was significantly higher in the study group than the control group (P = .018). In the study group, the BMI was lower, the score of C-WISC (VIQ, PIQ, and FIQ) was higher, the score of CBCL social competence was higher and the score of behavioral questions was lower than that in the control group; differences were statistically significant (P = .022). The serum levels of IgA, IgG, and IgM, as well as the percentage of T lymphocytes, between the study group and the control group were not significantly different (P = .132).Tonsillectomy by low-temperature plasma was effective on the treatment of children with severe OSAHS, and could improve growth development and psychological behavior. PMID- 30461622 TI - Phenotypic and genotypic features of a pair of Chinese identical twins with congenital insensitivity to pain and anhidrosis: A case report. AB - RATIONALE: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive genetic disorder characterized by insensitivity to noxious stimulus and the absence of sweating. Fractures and joint destruction are common complications, but detailed studies on mineral and skeletal homeostasis are not available. Mental retardation is often reported, but detailed observations during childhood are lacking. PATIENT CONCERNS: A pair of 46-month-old Chinese identical twin brothers was presented at our hospital. The brothers had the typical manifestations of insensitivity to noxious stimulus, inability to sweat, and recurrent episodes of unexplained fever. Fortunately, they did not present common complications such as self-mutilation, trauma, bruise, and repeated bone fractures. DIAGNOSES: Two novel compound heterozygous variants of NTRK1 (c.632T > A and c.1253_1254delTC) were identified. INTERVENTIONS: The patients were subjected to routine and specialist clinical examinations. Daily care and symptomatic treatment were given. OUTCOME: X-ray films of proband 2 showed a fracture in the first metatarsal. Decreased bone mineral density (BMD) and mild to-moderate retardation of the Gesell developmental schedules (GDS), especially language and adaptability, were observed. Evaluation results for BMD and GDS in proband 2 were worse than those in his brother. LESSONS: The current findings expand our knowledge about the spectrum of phenotypic and genotypic features of CIPA, which will help facilitate future genotype-phenotype association studies. Daily care by parents promotes favorable outcomes in patients. PMID- 30461623 TI - Lymphomas diagnosed in an internal medicine department compared to lymphomas diagnosed in other departments: Clinical and outcome differences. AB - Lymphomas are common malignancies with highly variable clinical presentations and prognosis. Prognostic value of clinical presentation at onset is still questioned. The objective of this study was to compare the disease presentation and the outcome of lymphomas diagnosed in an Internal Medicine Department of a University Hospital to disease presentation and outcome of patients who were referred to the Hematology Department of the same institution by other departments or healthcare facilities.This retrospective monocentric observational study included 37 patients. They were matched to 73 patients, who were referred to the Hematology Department, according to age, histology, and Ann Arbor stage. The demographics, clinical and biological presentations, overall survival, and progression-free survival were compared.Patients diagnosed with lymphoma in the Internal Medicine Department were more likely to be febrile (67.5% vs 21.9%; P < .001) and have higher inflammatory markers (mean C-reactive protein 86.6 vs 56.3 mg/L; P = .02). The median overall survival of these patients was poorer (P < .001), even in the subset of patients treated with standard treatment, and remained shorter in multivariable analysis (P = .002). The specific treatment started earlier (20.2 vs 37.5 days; P = .006), but was more frequently palliative (37.8% vs 19.2%; P = .04). There was no significant difference in median progression-free survival.Lymphomas diagnosed in an Internal Medicine Department had aggressive clinical presentations and a poorer outcome, despite an early start of conventional treatment. PMID- 30461624 TI - The combination of Caprini risk assessment scale and thrombotic biomarkers to evaluate the risk of venous thromboembolism in critically ill patients. AB - To evaluate the correlation between the Caprini risk assessment scale and plasma thrombosis biomarkers and estimate the validity of this method in identifying critically ill patients at high risk of venous thromboembolism (VTE).Patients with VTE who were admitted to the intensive care unit (ICU) department of West China Hospital SiChuan University from October 2016 to October 2017 were enrolled in this case-control study. We retrieved relative clinical data and laboratory test results included in the Caprini risk assessment scale to calculate the Caprini score and compared thrombosis biomarkers between various risk stratifications (low, moderate, high, and highest).A total of 151 critically ill patients were enrolled in our research, including 47 VTE and 94 non-VTE patients. The differences in Caprini score and levels of thrombosis biomarkers between the VTE and control group were significant. Thrombomodulin (TM) was positively correlated with Caprini score (R-value was .451, P < .05). Based on the receiver operating characteristic analysis, TM, tissue plasminogen activator-inhibitor complexes, D-dimer, and fibrinogen degradation products had a certain diagnostic efficiency in distinguishing VTE from others (P < .05). Using the logistic regression model, we identified that 5 risk factors, namely drinking history, major surgery (>3 hours), swollen legs (current), TM, and D-dimer, were independent factors for the occurrence of VTE in critically ill patients admitted in the ICU.Thrombosis markers were positively correlated with Caprini risk stratification. The combination of plasma markers and Caprini risk assessment scale can further increase the predictive value in critically ill patients with VTE. PMID- 30461625 TI - Use of argatroban for extracorporeal life support in patients with nonheparin induced thrombocytopenia: Analysis of 10 consecutive patients. AB - Unfractionated heparin (UFH) is currently the standard anticoagulant used in extracorporeal life support (ECLS). However, severe thrombocytopenia occurs frequently during ECLS use and it may be difficult to determine whether this represents heparin-induced thrombocytopenia (HIT) or not. In this case, UFH cannot be continued. Because a confirmatory laboratory test requires time, argatroban is empirically used if HIT is suspected. However, many patients are not found to have HIT. In non-HIT patients, the effectiveness and safety of argatroban are unclear. Thus, we investigated whether argatroban was safe and useful in patients who were suspected of having HIT and were started on argatroban, but were ultimately found to have non-HIT.We retrospectively reviewed all patients on ECLS who received the anticoagulant argatroban as an alternative to UFH between January 2014 and July 2015. The pretest clinical score (4Ts) was calculated, and a score greater than 4 was considered an indication for argatroban. The target-activated clotting time or activated partial thromboplastin time was 1.5 times the patient's upper normal value. Of 191 patients on ECLS during the study period, 10 (5.2%) were treated with argatroban infusion.No patients were found to have antiplatelet factor 4/heparin antibodies. The average maintenance dose of argatroban was 0.1 MUg/kg/min. Platelet counts increased significantly following argatroban administration (P = .02). There were no anticoagulation-related complications such as bleeding or thrombosis.Our results suggest that argatroban is a safe alternative to UFH for patients with non-HIT on ECLS. Argatroban may have a more significant platelet-preserving effect than UFH, regardless of whether HIT is present. PMID- 30461626 TI - Coexistence of anti-HMGCR and anti-MDA5 identified by an unlabeled immunoprecipitation assay in a chinese patient cohort with myositis. AB - Myositis-specific autoantibodies are important diagnostic and prognostic markers. The aim of our study is to detect anti-3-hydroxy 3-methylutaryl coenzyme A reductase (anti-HMGCR) antibody using novel unlabeled immunoprecipitation (IP) assay and immunoblotting in Chinese patients with myositis and to clarify the features of anti-HMGCR-positive patients. In the present study, we established novel unlabeled IP assay and immunoblotting of HMGCR C-terminus for anti-HMGCR detection. The presence of anti-HMGCR was screened in 181 Chinese patients with myositis. The sera from 12 of 181 patients were positive for anti-HMGCR. The prevalence of anti-HMGCR autoantibody in our cohorts is about 6.6%. Unexpected, coexistence of anti-HMGCR and anti-melanoma differentiation-associated protein (anti-MDA5) were identified in 4 patients with characteristic rash and interstitial lung disease (ILD), but without myasthenia and elevated serum creatine kinase (CK) levels. Other anti-HMGCR positive patients without anti-MDA5 presented with severe proximal muscle weakness. Mean serum CK levels and lactate dehydrogenase (LDH) were significantly higher in anti-HMGCR-positive patients than in antibody-negative patients (P <.05). Muscle biopsies available from 6 anti-HMGCR-positive patients were characterized with prominent myofiber necrosis and regeneration, little or none of inflammatory cell infiltrates. None of anti HMGCR positive patients in our cohort was exposed to statins. Our data suggested that anti-HMGCR were found to coexist frequently with anti-MDA5 identified by the established unlabeled IP assay and statin exposure is rare in Chinese myositis patients with anti-HMGCR. PMID- 30461627 TI - Association of muscle strength with cardiovascular risk in Korean adults: Findings from the Korea National Health and Nutrition Examination Survey (KNHANES) VI to VII (2014-2016). AB - There are few existing studies that examine the association between muscle strength and cardiovascular disease (CVD) risk stratified by sex. Evaluation of the handgrip strength is a simple, quick, and inexpensive method to measure muscle strength. This study assessed the association of handgrip strength with the risk of CVD in the Korean general population.Data were derived from a subset of an ongoing nationally representative survey: the Korea National Health and Nutrition Examination Survey (KNHANES), 2014 to 2016, which included 8576 participants aged 40 to 79 years (men: 3807; women: 4769). Individual CVD risk was evaluated by calculating the atherosclerotic cardiovascular disease (ASCVD) risk score and the Framingham risk score (FRS) in subjects aged 40 to 79 years without prior CVD.Multivariate linear regression analysis revealed a significant inverse association (in both men and women) between relative handgrip strength and cardiovascular risk factors, including blood pressure, levels of fasting glucose and triglycerides, waist circumstance, FRS, high sensitivity C-reactive protein levels, and ASCVD risk. A significant positive association between relative handgrip and a low level of high density cholesterol levels in both men and women was identified. In both men and women, subjects in the lowest quartile of handgrip strength had an increased risk of CVD compared with those within the highest quartile (odds ratio range 2.05-3.03).The results of this study suggest that increased handgrip is associated with a lower degree of cardiovascular risk in both men and women. Longitudinal studies are needed to examine the association between muscle strength and cardiovascular risk. PMID- 30461628 TI - Does pigtail catheters relieve pneumothorax?: A PRISMA-compliant systematic review and meta-analysis. AB - BACKGROUND: Pigtail catheter drainage has been usually applied for the treatment of pleural effusion and pneumothorax. Our aim was to investigate the application and efficacy of pigtail catheters for pneumothorax. METHODS: We carried out a meta-analysis of retro- or pro-spective studies addressing the effect of pigtail catheters for pneumothorax. We presented success rates of pigtail catheter drainage as primary outcomes, and considered the duration of drainage, and complication rates as secondary outcomes. Pooled data were available using the fixed or random effects model. Heterogeneity, sensitivity, and subgroup analyses were performed. RESULTS: The meta-analysis was based on 16 articles with a total of 1067 patients. Our analyses showed that pooled success rates were 0.77 (0.71 0.82), )furthermore, duration of drainage was 5.61 (3.99-7.23), and complication rates 0.18 (0.09-0.27). Subgroup results according to causes of pneumothorax and patient characteristics were robust and all consistent with overall outcomes. CONCLUSION: These suggested that pigtail catheter insertion within radiological guidance may provide a safe and effective way for the treatment of pneumothorax. More large-scale and prospective studies were required to determine these findings. PMID- 30461629 TI - A comparison of shoulder muscular performance and lean mass between elite and recreational swimmers: Implications for talent identification and development. AB - This study compared the shoulder muscular performance and lean mass between elite and recreational swimmers.Thirty elite swimmers (mean age +/- standard deviation = 23.1 +/- 3.5 years) and 21 recreational swimmers (mean age +/- standard deviation = 20.8 +/- 2.1 years) participated in the study. Maximum muscle strength and time to maximum muscle strength of shoulder flexor, extensor, abductor, and adductor muscles were measured using a handheld dynamometer. Lean mass of the arms and body (excluding the head) were measured using dual-energy x ray absorptiometry (DXA).Results revealed that compared with recreational swimmers, elite swimmers had higher maximum muscle strength of the shoulder flexor, extensor, abductor, and adductor muscles (all P < .001). The time to reach maximum muscle strength of all shoulder muscles showed no significant difference between the 2 groups (P > .05). The lean mass values in the left arm (P = .037), right arm (P < .001), and whole body (P = .014) were higher in elite swimmers than recreational swimmers.Elite swimmers had greater shoulder maximum muscle strength compared with recreational swimmers though the time taken to reach maximum muscle strength was similar between the 2 groups. Elite swimmers also showed a higher lean mass in both arms and their entire body when compared with recreational swimmers. The results may be useful for recreational swimmers who intend to advance to professional level, and for talent identification and early development of elite swimmers. PMID- 30461630 TI - The combination of apatinib and S-1 for the treatment of advanced gastric cancer in China: A meta-analysis of randomized controlled trials. AB - BACKGROUND: Apatinib-targeted therapy is considered a promising treatment option for malignancies. This study systematically evaluated the efficacy and safety of the combination of apatinib and S-1 for the treatment of patients with advanced gastric cancer (GC). METHODS: Clinical trials were searched from the PubMed, Cochrane Library, Embase, CNKI, and Wanfang databases. Outcome measures including therapeutic efficacy, quality of life (QoL), and adverse events were extracted and evaluated. RESULTS: Data from 8 trials including 393 patients with advanced GC were included. The results indicated that, compared with S-1 alone, the combination of apatinib with S-1 significantly improved patient partial response rate (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.21-3.02, P = .005), overall response rate (ORR, OR = 2.40, 95% CI = 1.51-3.82, P = .0002), and disease control rate (DCR, OR = 2.78, 95% CI = 1.51-5.10, P = .0010), whereas the rates of complete response (CR, OR = 2.38, 95% CI = 0.93-6.12, P = .07) and stable disease (SD, OR = 0.99, 95% CI = 0.64-1.54, P = .97) and QoL (OR = 1.22, 95% CI = 0.51-2.92, P = .66) did not differ significantly. Moreover, the group receiving the combined therapy had higher rates of hand-foot syndrome (OR = 2.23, 95% CI = 1.19-4.17, P = .01), hypertension (OR = 8.85, 95% CI = 4.07-19.26, P < .00001), albuminuria (OR = 11.25, 95% CI = 3.32-38.06, P = .0001), and hemoglobin reduction (OR = 3.19, 95% CI = 1.32-7.67, P = .010), whereas analysis of other adverse events did not show significant differences (P > .05). CONCLUSION: The combination of apatinib and S-1 is more effective for GC treatment than S-1 alone. However, this combined treatment could lead to increased hand-foot syndrome, hypertension, albuminuria, and hemoglobin reduction. Therefore, the benefits and risks should be considered before treatment. PMID- 30461631 TI - Association of smoking with risk of stroke in middle-aged and older Chinese: Evidence from the China National Stroke Prevention Project. AB - Although the impacts of smoking on health are well established, it is unclear on how they affect the Chinese population aged >=40 years. This study aimed to investigate the association between smoking and risk of stroke in middle-aged and older Chinese adults, based on the data from the China National Stroke Prevention Project.A community-based cross-sectional study with 12,704 (5681 men, 7023 women) Chinese adults aged >=40 years was conducted to examine the association of smoking with stroke. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).Among the study population, a total of 524 stroke survivors were identified. The age-adjusted prevalence of stroke was 4.06% for both sexes, 2.95% for women, and 5.38% for men. The multivariate-adjusted ORs (95% CI) of stroke associated with current cigarette smoking and former cigarette smoking were 1.67 (1.24-2.25) and 1.93 (1.29-2.87), respectively. Compared with those who were never-smokers, the multivariate adjusted OR of stroke (95% CI) were 1.48 (0.96 to -2.29), 1.75 (1.20-2.56), and 2.37 (1.20 to -4.68) for those who smoked 1 to 10, 11 to 20, and >=21 cigarettes per day; and 0.51 (0.19 to -1.42), 1.90 (1.36 to -2.67), and 2.01 (1.17 to -3.46) for those who smoked 1 to 19, 20 to 39, and >=40 years, respectively (both P < .001 for linear trends). Among former smokers, the multivariable-adjusted ORs of stroke by duration of smoking cessation (compared with never smokers) for <5, 5 to 19, and >=20 years were 3.47 (1.42-8.49), 3.37 (1.95-5.80), and 0.95 (0.49 1.84), respectively (P = .009 for linear trend). The increased odds of stroke with smoking were more evident among participants who were men, >60 years old, or without family history of stroke than their counterparts.This study suggests the increased odds of stroke in current cigarette smokers with a graded increase in prevalent risk that depended on how many cigarettes and how many years were smoked. Moreover, quitting smoking appears to decrease this excess risk substantially. PMID- 30461632 TI - Associations between ERAP1 polymorphisms and susceptibility to ankylosing spondylitis: A meta-analysis of East Asian Population. AB - BACKGROUND: The genetic factor is importantly enrolled in the pathogenesis of ankylosing spondylitis (AS) and haplotype leukocyte antigen (HLA)-B27 is the most well-known. However, only 1% to 5% of B27-positive individuals will develop AS, and it confers only 20% to 30% of the overall genetic risks, indicating more genes other than HLA-B27 may play important roles in AS pathologies. The present study aims to investigate whether the polymorphisms of endoplasmic reticulum aminopeptidase 1 (ERAP1) is associated with increased risk of AS susceptibility. METHODS: The Cochrane library, Pubmed, and Embase databases were carefully searched for potential researches published before May 30, 2018. The title, abstract, and full text were assessed to determine whether the paper was suitable for inclusion. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were presented to assess the associations between ERAP1 polymorphisms and AS susceptibility. RESULTS: The study finally enrolled 10 papers, 4 matched single nucleotide polymorphisms (SNPs) of ERAP1 (rs27044, rs27434, rs30187, and rs27037), and a total of 30552 patients (12492 with AS and 18060 for control). No significant difference was found between the AS susceptibility and polymorphisms of rs27044 and rs27434. However, there was a significant association between ERAP1 polymorphisms rs30187 and rs27037 (T vs C, OR, 1.322, 95% CI = 1.240-10410, P <.05; T vs G, OR, 1.247, 95% CI = 1.149-1.353; P <.05; respectively) and AS susceptibility. CONCLUSION: There was a significant association between ERAP1 polymorphisms (rs30187 and rs27037) and increased risk of AS susceptibility. PMID- 30461633 TI - The association between statin use and endometrial cancer survival outcome: A meta-analysis. AB - BACKGROUND: Previous studies on the association between statin use and survival outcomes in gynecologic cancers have presented conflicting results. No independent studies to elucidate the association between statin use and survival outcomes of endometrial cancer (EC) have been conducted. METHODS: To gather updated evidence, we carried out an extensive literature search on Medline (PubMed and OvidSP), Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), wanfang data, and Vip network to identify all potential studies on the effect of statins on the prognosis of endometrial carcinoma. The design and quality of all studies were evaluated, and a fixed-effects model was used to calculate pooled hazard ratios (HRs) for overall survival (OS) and disease-specific survival (DSS). RESULTS: Of the 219 articles screened, 9 articles were eligible, including 8 articles and 1 abstract. A total of 5923 patients with endometrial cancer who used statins were identified. Statin use was related to increased overall survival (HR, 0.80; 95% confidence interval [CI], 0.66-0.95, without significant heterogeneity, I = 52%, P = .080). Statin users also had increased disease-specific survival (HR, 0.69; 95% CI, 0.61-0.79, I = 0.0%). CONCLUSION: Statins are beneficial to the survival outcome of patients with endometrial cancer. The selection of statins as a 1st-line agent seems justified for endometrial carcinoma. PMID- 30461634 TI - Diagnostic challenges and good treatment outcomes in pediatric paraganglioma of the abdomen: A case report. AB - RATIONALE: Paraganglioma is a catecholamine-producing neuroendocrine tumor. Management of paraganglioma including its diagnosis is difficult, because it has no characteristic symptoms and many diseases can manifest as headache and high blood pressure. Herein, we report a rare case of paraganglioma of the abdomen with headache and initial normal blood pressure. PATIENT CONCERNS: A 9-year-old Chinese girl was hospitalized because of intermittent headache persisting for more than 9 months and recurrent headache for 15 days, accompanied by weight loss, impaired heat tolerance, and otherwise normal blood pressure. DIAGNOSES: We eventually diagnosed paraganglioma. INTERVENTIONS: Her paroxysmal hypertension subsided over 1 month after surgical removal of the tumor. LESSONS: Intermittent headache and normal hypertension as the initial symptoms of paraganglioma can easily lead to misdiagnosis as another disease (e.g., renal artery stenosis, primary hyperaldosteronism, Takayasu's arteritis), and its differential diagnosis is difficult. When a patient presents with intermittent hypertension, clinicians should consider a diagnosis of paraganglioma. The comprehensive use of ultrasonography, computed tomography (including enhanced computed tomography and 3D reconstruction), magnetic resonance imaging, and plasma catecholamine measurement can aid the diagnosis of paraganglioma. PMID- 30461635 TI - Case report of dependent venous contrast pooling and layering in a patient without acute cardiogenic shock. AB - RATIONALE: We present a case of incidental venous contrast pooling and layering in a patient without sudden cardiac arrest or cardiogenic shock. PATIENT CONCERNS: The patient presented with only discrete symptoms and did not suffer fatal cessation of the cardiac pump function during or shortly after the scan. DIAGNOSIS: The patient showed stigmata of venous gravity-dependent pooling and layering of contrast medium, which has frequently been described as a sign of imminent cardiogenic shock and cardiac arrest. INTERVENTIONS: A cardiologic consultation including echocardiography was initiated. OUTCOMES: Echocardiography confirmed valvular heart disease and biventricular heart failure. A subsequent follow-up CT acquired 8 months after the incidental finding showed no signs of dependent contrast pooling. LESSONS: Pooling and layering of contrast medium can occur in patients not suffering acute fatal cessation of the cardiac pump function. Nonetheless, any signs of venous pooling observed in CT examinations, especially gravity-dependent layering of contrast medium, are indicative of severe heart dysfunction and should prompt immediate cardio-pulmonary monitoring and increased level of medical care. PMID- 30461636 TI - Novel exploration of customized 3D printed shoulder prosthesis in revision of total shoulder arthroplasty: A case report. AB - RATIONALE: This paper describes the application of individual customized 3 dimensional (3D) printed macro-porous Ti6Al4 V shoulder prosthesis in the revision of total shoulder arthroplasty (TSA) for the patient with severe bone defects. PATIENT CONCERNS: A 47-year-old male had been under proximal humeral resection and TSA due to shoulder chondrosarcoma 6 years ago, but a second surgery to insert a new prosthesis was then performed because the prosthesis became loose 2 months ago leaving severe bone defects which conventional prosthesis was not suitable for revision of TSA. American Shoulder and Elbow Surgeons' Form (ASES), Neer and Constant-Murley score were 36, 39, and 39, respectively. DIAGNOSES: The patient was diagnosed with shoulder bone defects and restriction of the shoulder movement. INTERVENTIONS: 3D printed shoulder model and computer-aided design (CAD) were used for prosthesis design and surgical simulation. The novel 3D printed titanium alloy shoulder prosthesis was customized subsequently to be used in the revision of TSA. The patient was followed up regularly after surgery. The ASES, Neer Shoulder score and Constant Murley Shoulder score were evaluated during pre-operation, post-operation, and follow-up. OUTCOMES: Prosthesis was successfully implanted to complete anatomic reconstruction intraoperatively. The scores of ASES, Neer, and Constant-Murley were gradually increased after the operation. According to the X-ray, the bone healed satisfactorily without change of prosthetic position at 3rd and 12th months after the operation. The function of shoulder could meet the requirements of daily activities. LESSONS: The application of customized 3D printed titanium alloy shoulder prosthesis in the revision of TSA achieves satisfactory results. It provides a novel method for the similar revision surgery with severe bone defects. PMID- 30461637 TI - Metastatic thymic carcinoid responds to chemoradiation and octreotide: A case report. AB - RATIONALE: Thymic carcinoids are a rare type of malignant neuroendocrine tumors which have a poor prognosis due to their distant metastasis, invasive behaviour, and postoperative recurrence. Surgical resection is still the fundamental mode for treating thymic carcinoids. Here, we report the rapid shrinkage of an atypical thymic carcinoid with multiple metastases following chemoradiation plus octreotide as a first-line therapy PATIENT CONCERNS:: A 39-year-old Chinese man presented with chest tightness, dyspnea with a history of lumbago and untreated malignant thymoma. DIAGNOSIS: Thoracic computed tomography (CT) scan revealed an anterior mediastinal mass with pulmonary and multiple bone metastases as well as bilateral pleural and pericardial effusions. Percutaneous needle biopsy was performed on the mediastinal mass and the pathological diagnosis was neuroendocrine carcinoma of moderately differentiation (atypical carcinoid) INTERVENTIONS:: The tumor was considered unresectable because of extensive invasion into the lung and various bones. The patient was started on paclitaxel and oxaliplatin per 21 days for 4 cycles, and on 20 mg of depot formulation of octreotide once per 21 days. After 2 cycles of chemotherapy, the patient received concurrently mediastinal radiotherapy (39.6 Gy * 22 fractions). OUTCOMES: A follow-up CT of the chest at the completion of his fourth chemotherapy regimen demonstrated, approximately 22% of tumor shrinkage. There were no signs of disease progression but the patient refused further chemoradiation treatment. The patient received monthly treatment of octreotide and zoledronate and his progression-free survival reached 18 months. Due to uncontrollable disease progression, the patient expired. LESSONS: Early diagnosis and radical surgery of thymic carcinoid are very important. However, radiotherapy (combined/noncombined chemotherapy) must be considered if radical resection is not performed. We believe that further study of chemoradiation and octreotide with the palliative intent of preparing tumors for shrinkage is warranted as a strategy to improve curative management of neuroendocrine tumors. PMID- 30461638 TI - Cord-derived mesenchymal stem cells therapy for liver cirrhosis in children with refractory Henoch-Schonlein purpura: A case report. AB - RATIONALE: To explore the curative effect of human umbilical cord-derived mesenchymal stem cell (ucMSC) therapy for patients with liver cirrhosis complicated with immune thrombocytopenia and refractory Henoch-Schonlein purpura (HSP). PATIENT CONCERNS: A 12-year-old boy presented to our hospital with an 11 month history of purpura on the skin of both lower limbs accompanied by thrombocytopenia. The patient had a history of repeated swelling and painful dorsum pedis, followed by skin redness. DIAGNOSIS: Bone marrow slides showed megakaryocyte maturation disorder. Based on the pathology and drug abuse history, he was diagnosed with nodular cirrhosis, secondary allergic purpura, and thrombocytopenia, etiologies related to his drugs and an immune dysfunction. INTERVENTIONS: ucMSC transplantation was performed, the liver damaging drugs were discontinued, and the appropriate liver immunosuppressive drugs were administered. ucMSCs were injected 8 times/wk in 2 months, with a median cell count of 5.65 * 10/L, ranging from 5.48 to 5.98 * 10/L. OUTCOMES: As the patient's skin rash resolved, his platelets gradually increased to >150 * 10/L and liver transaminase levels gradually decreased to a normal level. Ultrasonography of the abdomen indicated that the round nodules in the liver decreased in size and that the spleen thickness also decreased. LESSONS: This is a unique case of significant HSP with associated thrombocytopenia in a patient with liver cirrhosis. Long-term oral administration of excessive herbal medicine may cause liver damage. We believe that ucMSCs provide a novel approach for the treatment of liver cirrhosis. PMID- 30461639 TI - The multi-vessel and diffuse coronary spasm is a risk factor for persistent angina in patients received anti-angina medication. AB - Coronary artery spasm (CAS) is known to be a risk factor for cardiovascular events. However, there is limited data whether the multi-vessel and diffuse spasm (MVDS) is related to more adverse clinical outcomes compared to the Non-MVDS. The aim of this study is to evaluate the impact of the MVDS on clinical outcomes during a 3-year clinical follow-up period.A total 2797 patients underwent coronary angiography (CAG) with acetylcholine (ACH) provocation test from Nov 2004 to Oct 2010 were enrolled. It is a single-center, observational, prospective, all-comers registry designed to reflect the "real world" practic. The patients were divided into the 3 groups; the negative spasm (NS) group (n = 1188), the Non-MVDS group (n = 1081), and the MVDS group (n = 528). The incidence of major adverse cardiac events (MACE) and recurrent angina was evaluated up to 3 years. To minimize confounding factors, multivariable Cox-proportional hazards regression analysis was performed.In the 3-year clinical follow-up, the incidence of total death, myocardial infarction, de novo percutaneous coronary intervention (PCI), cerebrovascular accident and MACE were similar among the 3 groups. However, recurrent angina occurred more frequently in the MVDS group than in the NS group (hazard ratio [HR], 1.96; 95% confidence interval [CI], 1.27-3.02; P = .002). Recurrence angina between the MVDS group and the Non-MVDS group was not statistically significant (HR, 1.36; 95% CI, 0.91-2.03; P = .129).In this study, although the incidence of major adverse cardiovascular events were not different regardless of spasm type, the MVDS was associated with higher incidence of recurrent chest pain requiring repeat CAG during the 3-year follow-up period, suggesting more intensive optimal medical therapy with close clinical follow up would be necessary for this particular subset of patients. PMID- 30461640 TI - Primary diffuse large B-cell lymphoma as a chest-wall mass: A case report. AB - RATIONALE: Primary diffuse large B-cell lymphoma of the chest wall is extremely rare. A majority of the pleural lymphomas develop in patients with chronic tuberculous pyothorax. The underlying mechanism might be attributed to the sustained stimulation of chronic inflammation. Surgery followed by adjuvant chemotherapy can improve the outcome in some patients with lymphoma localized only in the chest wall. Thus, an early diagnosis of pyothorax-associated lymphoma is essential as it is a malignant, life-threatening condition. PATIENT CONCERNS: A 79-year-old male complained of left-side chest pain for more than 2 months, which was not alleviated with nitrates and aspirin. The patient presented an intermittent low fever, anorexia, and marasmus, accompanied by tuberculosis 40 years ago and chronic left-side pyothorax. Also, ANCA (antineutrophil cytoplasmic autoantibody)-associated vasculitis occurred for >3years. DIAGNOSIS: Computed tomography scan showed a solid mass in the left lateral chest wall. The patient underwent ultrasonic-guided biopsy of the lesion. A diagnosis of primary diffuse large B-cell lymphoma of the chest wall was established after histological examination. INTERVENTION: Due to advanced age and poor physical condition, the patient received CHOP chemotherapy at a reduced dose. OUTCOMES: The patient died 5 days after the first cycle of chemotherapy with severe dyspnea and high fever. LESSONS: The chronic inflammation stimulation might result in the development of lymphoma in the chest wall of patients with long-term pyothorax, vasculitis, or other autoimmune diseases associated with malignancies. The fever, chest pain, or other nonspecific clinical symptoms in these patients should be under intensive focus as it might indicate the development of malignant lymphoma. Thus, histological examination in these patients is essential for accurate early diagnosis. PMID- 30461641 TI - A body shape index and vascular structure and function in Spanish adults (MARK study): A cross-sectional study. AB - A body shape index (ABSI) has been introduced as a marker of the relationship between body composition and all-cause mortality. However, until now, the relationships between ABSI and vascular structure and function have not been evaluated. The aim of this study was to investigate the association of ABSI with vascular structure and function in Spanish adults with intermediate cardiovascular risk. This cross-sectional study analyzed the data of 2354 subjects [age, 35-74 years (median, 62.0 years [range, 56.0-67.0 years]), 61.9% men] enrolled into the MediAte Risk management (MARK) study. ABSI was calculated by using the following formula: ABSI = waist circumference (m)/[body mass index * height (m))]. Vascular function was assessed by measuring cardio-ankle vascular index (CAVI) with the VaSera device and brachial ankle pulse wave velocity (baPWV) by using a validated equation. Vascular structure was assessed by measuring carotid intima-media thickness (IMT) by ultrasonography. Median value of ABSI was 0.083 (range, 0.081-0.090), mean CAVI was (8.5 +/- 1.2), and median IMT was 0.727 (range, 0.672-0.799). The values of ABSI and CAVI were higher in men. After adjusting for confounders, ABSI was positively associated with CAVI, baPWV, and average mean IMT. Thus, for each unit increase in ABSI, CAVI increased by 0.16 units, baPWV by 0.25 m/s, and IMT by 0.033 mm. In the logistic regression analysis, the odds ratio of ABSI was > 1 for high CAVI >= 9, baPWV >= 15 m/s, and IMT >= 0.90 mm in the overall subject group, and in the sex- and age-specific (> 62 years, <= 62 years) subgroups, after adjusting for confounders. The area under the receiver-operating characteristic curve of the ABSI was 0.631 (95% confidence interval [CI], 0.608-0.654) for CAVI >= 9, and 0.617 (95% CI, 0.593-0.641) for high baPWV >= 15 m/s. ABSI showed a positive association with vascular structure and function, independent of other confounders that might influence weight and fat mass distribution in Spanish subjects at intermediate cardiovascular risk.Trial Registration: ClinicalTrials.gov Identifier: NCT01428934 (registered: September 2, 2011; last updated: September 8, 2016). PMID- 30461642 TI - Syphilis prevalence and risk factors among young men presenting to the Brazilian Army in 2016: Results from a national survey. AB - The Conscripts Survey has been conducted periodically by the Brazilian Department of Sexually Transmitted Infections (STIs), AIDS, and Viral Hepatitis (DIAHV) in collaboration with the Brazilian Ministry of Defense for over 2 decades. It aims to assess the syphilis prevalence and obtain data on knowledge regarding STIs and their risk factors among conscripts enlisted for the Brazilian Army.This cross sectional study was conducted among conscripts across Brazil aged 17 to 22 years from August to December 2016. It included a self-reported questionnaire and blood testing for syphilis, HIV, and hepatitis B and C.In total 38,247 conscripts were enrolled; after exclusion due to a lack of information, 37,282 (93.2%) conscripts were included. The estimated syphilis prevalence rates were: 1.63%, 1.09%, and 0.62% for screened, confirmed, and active syphilis, respectively. Among those with active syphilis, 81.1% reported not having syphilis infection in their lifetime. Higher confirmed syphilis prevalence rates were observed in the South region, followed by North and Southeast regions. Independent factors associated with confirmed syphilis infection were: self-reported STIs in one's lifetime (odds ratio [OR] = 7.24; P < .001), same-sex sexual relationships (OR = 3.43; P = .001), and having the 1st sexual intercourse encounter before 15 years of age (OR = 2.62; P = .04). The proportion of conscripts who reported having sex with other men (MSM) was 4.3%, and the estimated syphilis prevalence in this group was 5.23%, 4.61%, and 3.60% for screened, confirmed, and active syphilis, respectively. The sexual behaviors most frequently associated with confirmed syphilis were: sexual relationship with casual partners in the last year (P < .001), same-sex sexual relationships (P < .001), more than 10 partners (P = .006), and having sexual intercourse before 15 years of age (P = .003). Although not significant, only 25.4% of the conscripts who had a confirmed syphilis reported the use of condoms with steady partners, 32.4% with casual partner, and 24.3% with any partner.We found that syphilis is on the rise among the young Brazilian male population. The increase in its prevalence, particularly among MSM, highlights the need for urgent public health interventions, action plans, and implementation of risk reduction strategies aimed at this population. PMID- 30461643 TI - Suspended over length biliary stents versus conventional plastic biliary stents for the treatment of biliary stricture: A retrospective single-center study. AB - To compare patency between suspended over length biliary stents (SOBSs; made from nasobiliary tube) and conventional plastic biliary stents (CPBSs).We retrospectively analyzed 61 patients with extrahepatic biliary stricture who underwent SOBS placement (intrahepatic bile duct) and 74 patients who underwent CPBS placement. Stent patency and complications were compared.The SOBS group was slightly older and contained more females than the CPBS group but other baseline characteristics were similar. Malignant biliary obstruction accounted for 57.4% (SOBS group) and 45.9% (CPBS group) of cases. Technical success rate, hospital stay and post-procedure complications were similar between groups. Median patency in the CPBS and SOBS group was 116 (2-360) days and 175 (3-480) days, respectively (P <.001). The SOBS group had lower stent occlusion rates than the CPBS group at 3 months (9.8% vs 36.5%), 4 months (22.0% vs 55.4%), 5 months (35.6% vs 67.6%), and 6 months (39.3% vs 77.0%) (all P <.01). In Cox regression analysis, stent type (SOBS vs CPBS) was the only factor associated with patency (hazard ratio [HR]: 3.449; 95% CI: 1.973-6.028; P <.001).SOBS may have better medium-term patency than CPBS for benign/malignant biliary stricture. PMID- 30461644 TI - Reducing postoperative morbidity of mini-invasive percutaneous nephrolithotomy: Would it help if blood vessels are left unharmed during puncture? A CONSORT prospective randomized trial. AB - BACKGROUND: The aim of this study was to provide a randomized controlled trial comparing single B-mode ultrasound guidance and color doppler ultrasound guidance in minimally invasive percutaneous nephrolithotomy. METHODS: Three hundred patients with renal calculus were prospectively randomly assigned into 2 groups. In group 1 (150 patients), minimally invasive percutaneous nephrolithotomy (m PCNL) were managed with single B-mode ultrasound guidance; In group 2 (150 patients), m-PCNL were managed with color Doppler ultrasound guidance and a needle bracket in order to guide placement at a target location beneath the skin. The characteristics of patients, operation, complications and prognosis, including body temperature, urine culture, and hematologic tests after the operation were recorded and compared. RESULTS: Our vessel-sparing technique showed a statistically significant decrease in hemoglobin drop, postoperative procalcitonin values, the frequency of postoperative fever, systemic inflammatory response syndrome, and urosepsis (P < .05). CONCLUSION: Using color Doppler ultrasound in real time and a needle bracket to detect and avoid main renal blood vessels decreased incidences of hemorrhagic complications and postoperative infection. PMID- 30461645 TI - Dystrophic calcinosis in a patient with overlap syndrome (scleroderma and rheumatoid arthritis) treated by leflunomide: A case report. AB - RATIONALE: Dystrophic calcinosis occurs in chronically damaged tissue in patients with complicated autoimmune diseases. The therapeutic options are limited, and the treatment response rate is variable. Here, we describe a rare case of dystrophic calcinosis treated with leflunomide in a patient with overlap syndrome. PATIENT CONCERNS: A 53-year-old woman who was diagnosed with overlaps syndrome (systemic sclerosis [SSc] with rheumatoid arthritis [RA]), presented to our hospital with pain and swelling in both wrists, and underwent radiography, bone scan, and biopsy examination. DIAGNOSES: This patient was diagnosed with dystrophic calcinosis in overlaps syndrome. INTERVENTIONS: The conventional disease-modifying drugs were not effective. Hence, leflunomide was administered. OUTCOMES: Simple radiography and bone scan showed resolved mass-like dystrophic calcinosis on both wrists of the patient after the use of leflunomide. LESSONS: The control of underlying disease is important in the treatment of dystrophic calcinosis. The use of leflunomide maybe an option in treatment of dystrophic calcinosis combined with RA. PMID- 30461646 TI - Management of disseminated intravascular coagulation in a patient with hepatic angiosarcoma: A case report. AB - RATIONALE: Hepatic angiosarcoma is a rare endothelial cell tumor that may lead to concurrent consumptive coagulopathies including disseminated intravascular coagulation (DIC). This report details a multifaceted approach to managing DIC in a patient with advanced-stage hepatic angiosarcoma, which continued to progress after a brief response to taxane-based chemotherapy. PATIENT CONCERNS: A 55-year old man with a recent history of hemorrhoids and hemarthroses presented with acute rectal bleeding. He was found to have concurrent hepatomegaly, abnormal liver function tests, anemia, thrombocytopenia, and coagulopathy. DIAGNOSES: DIC in the setting of hepatic angiosarcoma. INTERVENTIONS: The patient's acute bleeding in the setting of DIC was controlled with a combination of antifibrinolytic agents to prevent clot breakdown, heparin products to prevent deposition of new clot, and romiplostim to increase platelet production. His angiosarcoma was treated with various combinations of chemotherapy, including taxane-based chemotherapy, doxorubicin, and pazopanib. OUTCOMES: The patient's DIC and acute bleeding on initial presentation improved following treatment with unfractionated heparin and low-molecular weight heparin maintenance therapy. It is unclear if the chemotherapy to treat the hepatic angiosarcoma played a significant role in the improvement of DIC. LESSONS: Laboratory measurement of prothrombin fragment 1.2, a byproduct of prothrombin conversion to thrombin, proved to be a useful way to monitor this patient's DIC over time. PMID- 30461647 TI - Effect of community-based extension clinics of methadone maintenance therapy for opiate-dependent clients: A prospective cohort study in Dehong Prefecture, Yunnan Province of China. AB - Methadone maintenance therapy (MMT) is effective in treatment of opiate dependents. However, there is a gap between the coverage of standard MMT clinics and the need of opiate dependents. Establishment of extension clinics of methadone maintenance therapy (EMMT) will increase the coverage and improve MMT accessibility. We implemented a prospective cohort study to understand the effects of establishment of community-based EMMT clinics comparing with MMT clinics in Yunnan Province.A total of 462 opiate-dependent clients were interviewed from the community-based EMMT clinics and standard MMT clinics located in 5 counties of Mangshi, Ruili, Longchuan, Yingjiang, and Lianghe in Yunnan Province. The information on the demographic characteristics, drug risk behaviors, quality of life (QOL), and urine testing results for morphine of the clients was collected and compared between the EMMT and MMT clinics. A survival analysis method was utilized to know the retention situation of the newly enrolled clients with Kaplan-Meier method during 9 months treatment.Among the EMMT clients, 96.9% were male; 31.4% were Han; 61.4% were married; 39.0% had primary school education; 95.5% lived with their family or relatives; 96.9% who arrived the clinic less than 15 min; 52.9% had used drugs for more than 10 years; and 16.7% injected drug. After 9 months therapy, there was no difference in the changes of life quality such as physical and psychological features, social relationships, environmental function, and total QOL and well-being between those of EMMT and MMT clinics. The positive detection rate of urine-morphine testing among newly enrolled clients of EMMT clinics decreased as the period of treatment lengthened. The average time of retention for newly enrolled EMMT clients who are still receiving the treatment was 175 days. And the average time from initiations to drop-out of treatment for newly enrolled EMMT clients was 122 days. The 9 month retention rates of the clients were 52.1% and 60.9% at EMMT and MMT clinics, respectively.The effect on EMMT retention was the same as that of MMT. Establishment of EMMT clinics was an effective strategy to expand the coverage of MMT and increase the retention of opiate dependents in the rural areas of the counties. PMID- 30461648 TI - Limited laminectomy and foraminal decompression combined with internal fixation for treating multi-segment cervical spondylotic myelopathy: Does it effectively improve neurological function and prevent C5 palsy? AB - Laminectomy is an effective surgical treatment for multi-segment cervical spondylotic myelopathy (M-CSM) but usually results in C5 palsy. Some surgical techniques to restore the spinal sequence, increase the intervertebral foramen diameter, and limit the spinal cord drift distance have been proposed; however, it is unclear whether these procedures can avoid this complication.To investigate the clinical efficacy of limited laminectomy and foraminal decompression with fixation (LLFDF) for improving neurological recovery and preventing C5 palsy.A total of 71 patients with M-CSM were retrospectively analyzed. Thirty-nine of them were treated with LLFDF (group A) and 32 with normal laminectomy with fixation (NLF; group B) after 3 months of formal conservative treatment. Pre- and postoperative neurological function, spinal cord drift distance, cervical curvature index (CCI), and number of C5 palsy cases were recorded and analyzed.There was no significant intergroup difference in the surgical time or intraoperative blood loss (P >.05). The laminectomy widths in groups A and B were 16.7 +/- 2.6 mm and 21.8 +/- 2.9 mm, respectively (P <.01), while the spinal cord drift distances were 2.3 +/- 0.4 mm and 3.6 +/- 0.7 mm, respectively (P <.01). The mean Japanese Orthopedic Association score of both groups increased significantly after surgery (P <.01), and no significant difference was noted at any observation time points (P >.05). Both groups demonstrated significant CCI improvements after surgery compared with those before surgery (P <.01). There were 2 cases of C5 palsy in group A (5.1%) and 8 cases in group B (25.0%), and the difference was significant (P <.05).LLFDF can relieve spinal compression and considerably promote neurological recovery. Moreover, it restricts excessive spinal cord back drifting and decreases the incidence of C5 palsy. PMID- 30461649 TI - Radiofrequency ablation in a patient with radiation enteritis: A case report. AB - RATIONALE: Radiation enteritis (RE) is one of the serious complications caused by the radiotherapy and it can occur in any segment of the intestine, including small intestine, colon, and rectum. It can cause a number of serious problems of the intestine, such as chronic ulcers, bleeding, intestinal stenosis, intestinal fistula, and perforation. At present, there is no standard treatment guideline for the RE. PATIENT CONCERNS: A 54-year-old male patient received surgery and chemotherapy for rectal cancer and radiofrequency ablation (RFA) for a single metastatic carcinoma of the liver. Three years later, he was diagnosed with recurrent lesion in the rectal anastomotic stoma and was treated with radiotherapy with a total dose of 70 Gy. Following this, he had persistent abdominal pain and diarrhea for 1 year. DIAGNOSES: Colonoscopy confirmed a diagnosis of RE. INTERVENTIONS: Since intestinal probiotics, intestinal mucosal protectants, antidiarrheal drugs, and other treatments were not effective; the patient was treated by RFA. OUTCOMES: Clinical symptoms of the patient were gradually decreased after the RFA. Colonoscopy examination was performed 3 months later and intestinal mucosa was found to have healed well. LESSONS: RFA is an effective treatment for patients with RE, and it is expected to be one of the standard treatments for the RE. PMID- 30461650 TI - Spontaneous adrenal hematoma in pregnancy: A case report. AB - RATIONAL: Spontaneous adrenal hematoma in pregnancy is a very rare condition. Herein we present an additional rare case of unilateral spontaneous adrenal hematoma in a pregnant woman, aiming to share this experience and summarize the signal characteristics of simple adrenal hematoma in magnetic resonance imaging (MRI). PATIENT CONCERNS: A 28-year old pregnant woman was referred to our hospital with a vague paroxysmal left-side back pain at 17 weeks of gestation. DIAGNOSIS: MR scan of the abdomen revealed an 8.1 * 7.7 * 6.8 cm round mass in the left adrenal region, which showed a rim of acute hemorrhage signal. Due to the stable condition of the patient and fetus, she was admitted for observation. Repeat MR scan was performed a month later, and it showed a stable mass with marginal subacute bleeding signal. INTERVENTIONS: Laparoscope excision of the hematoma was performed. OUTCOMES: Simple adrenal hematoma was confirmed by pathological examinations. And the patient was discharged 3 days later with normal renal and adrenal functions. LESSONS: The most important characteristic of adrenal hematoma is the high-signal rim on T1-weighted MR images, and the clinicians should make individualized treatment plan for every patient encountered in the future who might have different clinical conditions. PMID- 30461651 TI - Prevalence of the fabella and its association with pain in the posterolateral corner of the knee: A cross-sectional study in a Romanian population. AB - The functions and clinical consequences of the fabella, a sesamoid bone found in the posterolateral aspect of the knee joint, are still a reason of intense debate in the scientific literature. Its incidence was reported to range between 20% and 87% and its presence was usually associated with the persistent pain in the posterolateral region of the knee. The aim of our study was to measure the prevalence, anatomic and clinical features of the fabella within a cross sectional study, conducted in a Romanian orthopaedic center. Between 2015 and 2017, a consecutive series of 562 patients with knee injuries or persistent knee pain has been examined by radiographs and Magnetic Resonance Imaging and a set of anatomical and clinical parameters have been recorded. Collected data was evaluated with RadiANT DICOM Viewer and statistically analyzed with GraphPad Prism 7. The level of significance was set at P <.05. The incidence of the fabella in our study group was 16.93%, lower than previously reported for Caucasian populations. We found statistically significant differences regarding the possible association of the fabella with pain in the posterolateral corner of the knee (P = .04) and the 2 dimensions of the bone according to gender (P = .03 respectively P = .01), but the prevalence was not influenced by gender (P = .6). The anatomic characteristics could be important in differentiating this sesamoid bone from calcifications or loose bodies located in the knee joint region. Due to the high association with the posterolateral knee pain, the fabella should be recorded during knee examination as a differential diagnosis, before any surgical procedure. PMID- 30461652 TI - The time course of cervical alignment after cervical expansive laminoplasty: Determining optimal cut-off preoperative angle for predicting postoperative kyphosis. AB - Retrospective Cohort studyTo analyze cervical lordosis angle (CLA) change after cervical expansive laminoplasty (CEL) over time, and to determine optimal cut-off angle for predicting postoperative kyphosisPostoperative development of sagittal malalignment after laminoplasty is associated with neurological dysfunction and neck pain. However, there is no information on the serial CLA change over time and cut-off angle for predicting postoperative kyphosisThe Cobb angle between C2 and C7 in a series of lateral cervical X-rays in the neutral position was retrospectively reviewed for 36 months. And, the effect of time on CLA after CEL and the risk factors associated with postoperative cervical kyphosis (Cobb's angle <=0 degrees ) were analyzed. Also, the optimal cut-off angle for predicting postoperative kyphosis was determined.A total of 110 cases of CEL for cervical myelopathy were enrolled from February 2005 to May 2010. The mean cervical alignment changed from 12.3 +/- 10.4 degrees (mean +/- standard deviation [SD]) at the preoperative evaluation to 8.2 +/- 11.6 degrees , 10.6 +/- 10.1 degrees , 9.1 +/- 10.0 degrees , 8.4 +/- 11.2 degrees , 8.5 +/- 10.5 degrees , 8.1 +/- 9.9 degrees , and 8.7 +/- 10.1 degrees at 1, 3, 6, 12, 18, 24, and 36 postoperative months, respectively. The cervical lordosis showed statistically significant decreased at the 1st month, then the lordotic angle was partially restored at the 3rd, and 6th, and then no significant changes after the 6th. The only risk factor for kyphosis development was the preoperative CLA. The optimal cut-off preoperative angle for predicting postoperative kyphosis was 8.5 degrees .The decrease of CLA after expansive laminoplasty peaked in the 1st month. Some of the lordotic angles were restored in the 3rd and 6th months, before reaching a plateau after the 6th month. The optimal cut-off preoperative angle for predicting postoperative kyphosis was 8.5 degrees .Level of Evidence of their study: Level 4. PMID- 30461653 TI - Association between polymorphisms in estrogen metabolism genes and breast cancer development in Chinese women: A prospective case-control study. AB - We comprehensively identified polymorphisms in estrogen-metabolizing genes that may be associated with breast cancer initiation in Chinese women, via an ongoing prospective case-control study.An ongoing prospective case-control study of 427 female case patients diagnosed with breast cancer from August 2013 to March 2015 and 536 women (case controls) with no prior history of cancer or benign breast tumors was performed. Buccal cell specimens were obtained using the cotton swabbing method. DNA was extracted from the buccal cells using the phenol/chloroform method. Genotype was carried out for 5 single nucleotide polymorphisms (rs4646903, rs1056836, rs1695, rs4970737, and rs4680) using direct sequencing.The polymorphic genotypes of glutathione S-transferase (GSTP1) (P = .044) and catechol-O-methyltransferase (COMT) (P = .008) showed significantly different distributions, while that of cytochrome P450 (CYP1B1) (P = .051) showed a slight difference in distribution between healthy women and patients with breast cancer. Individuals with homozygous variant genotypes for GSTP1 or COMT exhibited a higher risk of developing breast cancer than those with wild-type genotypes; however, for CYP1B1, the homozygous variant genotype was associated with a lower risk, and the heterozygous genotype for these 3 genes was not associated with breast cancer development.An individual's risk of breast cancer is only influenced by the specific combination of risk-associated alleles of COMT and GSTP1, despite the protective effects of the homozygous CYP1B1 genotype revealed by univariate analysis. PMID- 30461654 TI - Efficacy and safety of recombinant human parathyroid hormone (1-34) are similar to those of alendronate in the treatment of postmenopausal osteoporosis. AB - The study evaluates efficacy and safety of recombinant human parathyroid hormone (1-34) [rhPTH (1-34)] and alendronate (ALN) in the treatment of postmenopausal osteoporosis.Totally 65 postmenopausal women with osteoporosis were divided into 2 groups. PTH group received daily subcutaneous injection of rhPTH (1-34), and ALN group were treated orally with ALN per week. Bone mineral density (BMD) of lumbar spine (1-4), femoral neck, and total hip, serum levels of calcium, phosphorus, total cholesterol, triglyceride, alkaline phosphatase (ALP), N terminal propeptide of type I collagen (PINP), and C-telopeptide of type I collagen (CTX) were tested before treatment and at week 24 and 48 after treatment. Serum levels of vascular endothelial growth factor (VEGF) and platelet derived growth factor-BB (PDGF-BB) were measured before treatment and at week 48 after treatment.The rhPTH (1-34) increased BMD of lumbar spine (1-4), but decreased BMD of femoral neck and total hip at week 48 after treatment. By contrast, ALN enhanced BMD of lumbar spine (1-4) and femoral neck, but reduced BMD of total hip at week 48 after treatment. In PTH group, serum levels of PINP, ALP, and beta-CTX were significantly elevated above baseline at week 24 and 48 after treatment. Treatment with ALN decreased levels of PINP, ALP, and beta-CTX compared with baseline at week 24 and 48 after treatment. rhPTH (1-34) and ALN significantly decreased levels of PDGF-BB, but not levels of VEGF. rhPTH (1-34) increased levels of calcium, phosphorus and triglyceride, but decreased levels of total cholesterol. ALN increased levels of calcium and triglyceride, but reduced levels of phosphorus and total cholesterol. rhPTH (1-34) and ALN were safe in the treatment of postmenopausal osteoporosis.The study demonstrates that efficacy of rhPTH (1-34) on BMD of lumbar spine (1-4) is similar to that of alendronate in the treatment of postmenopausal osteoporosis. The effect of rhPTH (1-34) on BMD of femoral neck or total hip is weaker than that of ALN. In addition, rhPTH (1 34) increases BMD of lumbar spine (1-4) maybe by raising serum levels of VEGF, but reduces BMD of femoral neck and total hip maybe by decreasing serum levels of PDGF-BB. PMID- 30461655 TI - The role of serum procalcitonin in the differential diagnosis of pneumonia from pulmonary edema among the patients with pulmonary infiltrates on chest radiography. AB - The aim of this study is to evaluate the usefulness of serum procalcitonin (PCT) as a diagnostic biomarker for distinguishing pneumonia from pulmonary edema in patients presenting with pulmonary infiltrates on chest radiography.A comparative study was performed retrospectively in a university-affiliated hospital, from May, 2013 to April, 2015. Adult patients (>=18 years) who showed pulmonary infiltrates on chest radiography and had blood tests with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), PCT, and N-terminal pro-b-type natriuretic peptide (NT-proBNP) on admission were included in the study. Clinical parameters collected on admission were compared between the case group (n = 143) with pneumonia and the control group (n = 88) with pulmonary edema alone.During the study period, a total of 1217 patients were identified. Of them, a total of 231 patients were included in analyses based on exclusion criteria. In the multivariate logistic regression analysis, PCT >=0.25 ng/mL, ESR >=35 mm/h, CRP >=18 mg/L, NT-proBNP <=200 pg/mL, underlying neurologic diseases, fever, sputum, absence of cardiomegaly, and a low Charlson comorbidity index were independently associated with pneumonia. For this model, the sensitivity, specificity, positive predictive value, and negative predictive value in distinguishing between the 2 groups were 90.2%, 79.6%, 87.8%, and 83.3%, respectively, with an area under the curve of 0.93.This study suggests that the practical use of PCT in conjunction with clinical data can be valuable in the differential diagnosis of pulmonary infiltrates and guidance for clinicians to prevent antibiotic misuse. PMID- 30461656 TI - Anatomical variants of dorsal scapular nerve in relation to the middle scalene muscle in Japanese population. AB - Dorsal scapular nerve (DSN) block is often performed in Japanese pain clinics to treat neck pain and katakori (a unique symptom in Japanese population characterized by myofascial pain syndromes such as shoulder girdle pain). However, to the best of our knowledge, there are only a few studies regarding anatomical variations in DSN paths around the middle scalene muscle (MSM) in Japanese population. Thus, we conducted a cadaveric study to examine anatomical variations in DSN paths around the MSM in Japanese population.DSN anatomies of 70 adult Japanese cadavers used for research and gross anatomy practice at the Tokai University School of Medicine between 2015 and 2016 were examined.In all cadavers, DSNs originated from the brachial plexus (BP) and innervated the rhomboid major, rhomboid minor, and levator scapulae muscles via the MSM. Two types of DSN paths were observed: piercing-type (piercing the MSM) and anterior type (running in front of the MSM). We surveyed all 140 sides in 70 Japanese cadavers; of these, 95 sides had piercing-type and 45 had anterior-type paths. Of the 70 cadavers, 42 had piercing-type and 17 had anterior-type paths on both the sides. In 9 cadavers, the left and right sides had piercing-type and anterior type paths, respectively. In the other 2 cadavers, the right and left sides had piercing-type and anterior-type paths, respectively.We found 2 distinct anatomical variants for DSN paths around the MSM in this Japanese cohort. Our results suggest that the rate of anterior-type DSN path is higher in Japanese population. Therefore, it is necessary to maintain caution while injecting anesthetic agents during a DSN block and the type of DSN should be considered. PMID- 30461657 TI - Exploring the use of single-port surgery in the conservative management of hepatic portal vein gas: A case report. AB - RATIONALE: Hepatic portal vein gas (HPVG) is known as a sign of a lethal condition resulting from bowel necrosis. Recently, the detection rate of non-life threatening cases of HPVG has increased due to the technological development of imaging, i.e., computed tomography (CT). However, it is difficult to determine accurately whether surgical treatment is necessary because of its lethal potential. PATIENT CONCERNS: A 74-year-old woman suddenly complained about lower abdominal pain and vomiting after an operation for cervical spondylosis myelopathy. Her vital signs were slightly unstable and she was perspiring and exhibited pallor. Muscular defense was not clear, though her abdomen was tender and slightly distended. DIAGNOSIS: CT results showed massive HPVG. However, laboratory investigation did not clearly indicate bowel necrosis. Also, a contrast-CT scan was not performed due to her chronic renal dysfunction and asthma. INTERVENTION: Exploration was performed by single-port surgery (SPS) instead of exploratory laparotomy. OUTCOME: This approach showed no ischemic bowel and so conservative therapies were undertaken with confidence. The HPVG disappeared 2 days later, and she recover completely from the illness. LESSONS: HPVG requires immediate and reliable decision for management. However, unnecessary exploratory laparotomy should be avoided. Hence, a novel strategy should be considered in light of innovative surgical procedures. Our experience suggested that SPS was useful as an exploratory tool for the management of HPVG. PMID- 30461658 TI - Giant sellar metastasis from renal cell carcinoma: A case report and literature review. AB - RATIONALE: Sellar metastasis is a rare and complex disease whose clinical features are strongly associated with the primary malignancy. Here, we present a rare case of giant sellar metastasis spread from renal cell carcinoma (RCC). PATIENT CONCERNS: A 30-year-old Chinese woman was admitted to our Hospital, reporting headache, nasal congestion, nausea, vomiting, and a sharp decline in her right eye vision. DIAGNOSES: Brain magnetic resonance imaging (MRI) revealed an invasive sellar mass with cavernous sinus and nasal cavity extension. Additionally, the patient had a medical history of right radical nephrectomy for clear-cell RCC. INTERVENTIONS: The patient underwent a successful subtotal resection of the tumor. Final pathological diagnosis confirmed sellar metastasis from RCC. After surgery, the patient was referred to our medical oncology department and received further systemic therapy. OUTCOMES: No light perception remained in her right eye even after prompt surgical decompression. Follow-up MRI showed subtotal resection of the giant sellar metastasis. LESSON: Sellar metastasis, although rare, should be particularly considered for elderly patients with deteriorating visual function and medical histories of cancer. PMID- 30461659 TI - Impact of carcinoid syndrome symptoms and long-term use of somatostatin analogs on quality of life in patients with carcinoid syndrome: A survey study. AB - To evaluate association of carcinoid syndrome (CS) symptom burden and somatostatin analog (SSA) duration with quality of life (QoL) using Functional Assessment of Cancer Therapy-General (FACT-G) and Patient-Reported Outcomes Measurement Information System (PROMIS-29) instruments.Adults who received treatment for CS symptoms in the US were recruited to participate in a cross sectional online survey (July-October, 2016). Demographic, clinical, and QoL questions (FACT-G, 29 CS-related supplemental questions, PROMIS-29) were included. Descriptive and multivariable regression analyses adjusting for demographic and clinical characteristics followed.Most (98%) of the 117 patients received SSAs in the prior month. Multivariable regression analysis showed >=4 bowel movements/day (vs <4) and each additional CS symptom was associated with 7.1 (P = .043) and 3.4 (P = .034) point FACT-G total score decreases, respectively. Requiring bed rest (vs normal activity) was associated with significant decreases in FACT-G total score (P < .001). There were similar associations for FACT-G subscales, supplemental questions, and PROMIS-29. After adjustment, FACT-G total score was significantly higher (11.3 points; P = .033) for patients treated with SSA >8 years versus <2.7 years.CS symptom burden was observed to be associated with lower QoL scores, measured by FACT-G. Patients with >8 years SSA treatment duration versus <2.7 years had higher QoL. PMID- 30461660 TI - Clinical features and outcomes of gastric neuroendocrine tumors after endoscopic diagnosis and treatment: A Digestive Endoscopy Society of Tawian (DEST) multicenter study: Erratum. PMID- 30461661 TI - Effect of 2% lidocaine continuous epidural infusion for thoracic or lumbar herpes zosterrelated pain: Erratum. PMID- 30461662 TI - The role of NLRP3 inflammasome in stroke and central poststroke pain: Erratum. PMID- 30461663 TI - Influence of an inconsistent appearance of antipsychotics on drug adherence in patients with schizophrenia: Erratum. PMID- 30461664 TI - Comparative study of MR mTI-ASL and DSC-PWI in evaluating cerebral hemodynamics of patients with Moyamoya disease: Erratum. PMID- 30461665 TI - Primary hyperparathyroidism characterized by diffuse homogeneous metastatic pulmonary calcification: A case report: Erratum. PMID- 30461666 TI - Effect of optimized collagenase digestion on isolated and cultured nucleus pulposus cells in degenerated intervertebral discs: Erratum. PMID- 30461667 TI - A stress management intervention for adults living with HIV in Nigerian community settings: An effects study: Erratum. PMID- 30461668 TI - Pediatric Transport Triage: Development and Assessment of an Objective Tool to Guide Transport Planning. AB - OBJECTIVES: We developed a Pediatric Transport Triage Tool (PT3) to objectively guide selection of team composition and transport mode, thereby standardizing transport planning. Previously, modified Pediatric Early Warning Score for transport has been used to assess illness severity but not to guide transport decision making. METHODS: The PT3 was created for pediatric transport by combining objective evaluations of neurologic, cardiovascular, and respiratory systems with a systems-based medical condition list to identify diagnoses requiring expedited transport and/or advanced team composition not captured by neurologic, cardiovascular, and respiratory systems alone. A scoring algorithm was developed to guide transport planning. Transport data (mode, team composition, time to dispatch, patient disposition, and complications) were collected before and after PT3 implementation at a single tertiary care center over an 18-month period. RESULTS: We reviewed 2237 inbound pediatric transports. Transport mode, patient disposition, and dispatch time were unchanged over the study period. Fewer calls using a transport nurse were noted after PT3 implementation (33.9% vs 30%, P = 0.05), with a trend toward fewer rotor-wing transports and transports requiring physicians. The majority of users, regardless of experience level, reported improved transport standardization with the tool. Need to upgrade team composition or mode during transport was not different during the study period. No adverse patient safety events occurred with PT3 use. CONCLUSIONS: The PT3 represents an objective triage tool to reduce variability in transport planning. The PT3 decreased resource utilization and was not associated with adverse outcomes. Teams with dynamic staffing models, various experience levels, and multiple transport modes may benefit from this standardized assessment tool. PMID- 30461669 TI - Exploratory Ingestions of Novel Anticoagulants and Antiplatelets: What Is the Risk? AB - BACKGROUND: Historically, anticoagulants and antiplatelet agents included warfarin and aspirin, respectively. In recent years, numerous novel anticoagulants (eg, direct thrombin inhibitors and factor Xa inhibitors) as well as the adenosine diphosphate receptor antagonists have increased significantly. Little information on the bleeding risk after exploratory ingestion of these agents is available. The primary purpose of this study is to evaluate the bleeding risk of these agents after an exploratory ingestion in children 6 years or younger. METHODS: This retrospective multicenter poison control center study was conducted on calls between 2005 and 2014. The following agents were included: apixaban, clopidogrel, dabigatran, edoxaban, prasugrel, rivaroxaban, or ticagrelor. Bleeding characteristics and treatment rendered were recorded. RESULTS: A total of 638 cases were identified. Most cases involved antiplatelet agents. No patient developed any bleeding complication. The administration of charcoal was independent of the amount of drug ingested. CONCLUSION: Accidental, exploratory ingestions of these agents seem well tolerated, with no patient developing bleeding complications. PMID- 30461670 TI - Chest Radiograph Alone Is Sufficient as the Foreign Body Survey for Children Presenting With Coin Ingestion. AB - OBJECTIVES: Radiographic survey of the entire aerodigestive tract (nares to anus) is common practice in children presenting to the emergency department following coin ingestion. The purpose of our study was to determine the optimal protocol for radiographic survey post-coin ingestion. We hypothesized that for children presenting with a clear history of coin ingestion a frontal chest radiograph including the entire esophagus is adequate to guide treatment. METHODS: We reviewed the clinical history and radiographic surveys of 134 patients presenting with suspected or witnessed coin ingestion to the emergency department of a tertiary care pediatric hospital between January 2012 and June 2016. Patient demographics, presenting symptoms, anatomic coverage of survey, type, number and location of radiopaque foreign bodies, intervention, and follow-up were recorded. RESULTS: Coins were identified on radiographic surveys in 109 of 134 patients; 25 of 134 patients had no coin. Of those with coins, none of 109 had coin(s) in the airway, 42 of 109 had coin(s) in the esophagus, and 67 of 109 had coin(s) distal to the esophagus. Of those with esophageal coins, 35 of 42 reported symptoms, 7 of 42 were asymptomatic, 40 of 42 underwent endoscopic coin removal, and 2 of 42 had no intervention. Of 92 of 134 surveyed patients with no coin or coin distal to the esophagus, 30 of 92 reported symptoms, 62 of 92 were asymptomatic, 90 of 92 had no further intervention, and 2 of 92 eventually underwent endoscopic coin removal for specific indications (abdominal pain, delayed passage). When there was no coin found in the esophagus, the negative predictive value for intervention was 97.8%. CONCLUSIONS: Following a clear history of coin ingestion, a frontal chest radiograph including the entire length of the esophagus provides sufficient information to direct patient management. PMID- 30461671 TI - Uncommon Presentation of Childhood Leukemia in Emergency Department: The Usefulness of an Early Multidisciplinary Approach. AB - Leukemia is the most common childhood malignancy, and it is often characterized by pallor, fatigue, cytopenia, and organomegaly; sometimes musculoskeletal symptoms, mainly characterized by diffuse bone pain in the lower extremities, are the onset clinical characteristics of the disease. In these cases, the disease may initially be misdiagnosed as reactive arthritis, osteomyelitis, or juvenile idiopathic arthritis delaying appropriate diagnosis and management. Even if leukopenia, thrombocytopenia, and a history of nighttime pain are reported to be the most important predictive factors for a pediatric leukemia, blood examinations can sometimes be subtle or within normal limits, and this represents a further diagnostic difficulty. Radiological findings of leukemic bone involvement are described in patients with musculoskeletal symptoms of acute lymphoblastic leukemia and often appear before hematologic anomalies, but they are not specific for the disease. However, they could be helpful to get the right diagnosis if integrated with other features; thus, it is important knowing them, and it is mandatory for the multidisciplinary comparison to talk about dubious cases even in an emergency setting. We describe 4 patients visited in the emergency department for musculoskeletal complaints and having radiological lesions and a final diagnosis of acute lymphoblastic leukemia, in whom the onset of the manifestations could mimic orthopedic/rheumatologic diseases. PMID- 30461672 TI - Florid Scurvy in an Autistic Child on a Ketogenic Diet. AB - Ketogenic diets used for treating various neurological disorders can have potentially serious adverse effects. Among these is scurvy, a rarely reported, yet potentially fatal adverse effect of the ketogenic diet caused by vitamin C deficiency. We report a case of a 5-year-old patient with autism, who presented with scurvy secondary to the dietary restrictions of a ketogenic diet. Our review of the literature showed a single previously reported case of vitamin C deficiency in a patient on ketogenic diet. We have also reviewed the clinical indications and adverse effects of ketogenic diets with special reference to scurvy. This case emphasizes the importance of vitamin supplements in patients consuming a special diet. PMID- 30461673 TI - Liposomal Bupivacaine Block at the Time of Cesarean Delivery to Decrease Postoperative Pain: A Randomized Controlled Trial. PMID- 30461674 TI - In Reply. PMID- 30461675 TI - Female Sexual Dysfunction and the Placebo Effect: A Meta-analysis. PMID- 30461676 TI - In Reply. PMID- 30461677 TI - ACOG Committee Opinion No. 739: The Late-Career Obstetrician-Gynecologist. PMID- 30461678 TI - In Reply. PMID- 30461679 TI - Nonobstetric Surgery During Pregnancy. PMID- 30461680 TI - In Reply. PMID- 30461682 TI - Risk of Severe Acute Maternal Morbidity According to Planned Mode of Delivery in Twin Pregnancies: Correction. PMID- 30461681 TI - The Current State of Residency Preparatory Courses in Obstetrics and Gynecology: Correction. PMID- 30461683 TI - Cervical Pessary Compared With Vaginal Progesterone for Preventing Early Preterm Birth: A Randomized Controlled Trial: Correction. PMID- 30461684 TI - Connect the Dots-October 2018: Correction. PMID- 30461685 TI - Long-Term Outcomes of Elagolix in Women With Endometriosis: Results From Two Extension Studies: Correction. PMID- 30461688 TI - ACOG publications: December 2018. PMID- 30461689 TI - ACOG Practice Bulletin No. 201 Summary: Pregestational Diabetes Mellitus. AB - Pregestational diabetes mellitus represents one of the most challenging medical complications of pregnancy because of the need for frequent monitoring and adjustment of medications as well as the potential for maternal and fetal complications. This document provides an overview of the current understanding of pregestational diabetes mellitus and suggests management guidelines during pregnancy. Because few well-designed studies have been performed, many of the guidelines are based on expert and consensus opinion. This document has been updated to reflect current data on pregestational diabetes. This Practice Bulletin is updated with summary information to counsel and manage women with pregestational diabetes before and during pregnancy; more recent literature reflecting experience with continuous subcutaneous insulin infusion during pregnancy; an expanded section on the role of oral hypoglycemic agents in pregnancy, and the option of long-acting reversible contraception during the postpartum period. PMID- 30461690 TI - ACOG Committee Opinion No. 760 Summary: Dysmenorrhea and Endometriosis in the Adolescent. AB - Dysmenorrhea, or menstrual pain, is the most common menstrual symptom among adolescent girls and young women. Most adolescents experiencing dysmenorrhea have primary dysmenorrhea, defined as painful menstruation in the absence of pelvic pathology. When the patient's history suggests primary dysmenorrhea, empiric treatment should be initiated. When a patient does not experience clinical improvement for her dysmenorrhea within 3-6 months of therapy initiation, her obstetrician-gynecologist should investigate for possible secondary causes and for treatment adherence. Secondary dysmenorrhea refers to painful menses due to pelvic pathology or a recognized medical condition. Endometriosis is the leading cause of secondary dysmenorrhea in adolescents. Endometriosis should be considered in patients with persistent, clinically significant dysmenorrhea despite treatment with hormonal agents and nonsteroidal antiinflammatory drugs, particularly if no other etiology for chronic pelvic pain or secondary dysmenorrhea has been identified based on history, physical examination, and pelvic ultrasonography. The appearance of endometriosis may be different in an adolescent than in an adult woman. In adolescents, endometriotic lesions are typically clear or red and can be difficult to identify for gynecologists unfamiliar with endometriosis in adolescents. Endometriosis in adolescents is considered a chronic disease with potential for progression if left untreated. The goals of therapy include symptom relief, suppression of disease progression, and protection of future fertility. Therapy must be individualized, and obstetrician-gynecologists should consider patient choice, the need for contraception, contraindications to hormone use, and potential adverse effects and counsel the adolescent and her family on treatment options. PMID- 30461691 TI - Obstetric Care Consensus No. 7 Summary: Placenta Accreta Spectrum. AB - Placenta accreta spectrum, formerly known as morbidly adherent placenta, refers to the range of pathologic adherence of the placenta, including placenta increta, placenta percreta, and placenta accreta. The most favored hypothesis regarding the etiology of placenta accreta spectrum is that a defect of the endometrial myometrial interface leads to a failure of normal decidualization in the area of a uterine scar, which allows abnormally deep placental anchoring villi and trophoblast infiltration. Maternal morbidity and mortality can occur because of severe and sometimes life-threatening hemorrhage, which often requires blood transfusion. Although ultrasound evaluation is important, the absence of ultrasound findings does not preclude a diagnosis of placenta accreta spectrum; thus, clinical risk factors remain equally important as predictors of placenta accreta spectrum by ultrasound findings. There are several risk factors for placenta accreta spectrum. The most common is a previous cesarean delivery, with the incidence of placenta accreta spectrum increasing with the number of prior cesarean deliveries. Antenatal diagnosis of placenta accreta spectrum is highly desirable because outcomes are optimized when delivery occurs at a level III or IV maternal care facility before the onset of labor or bleeding and with avoidance of placental disruption. The most generally accepted approach to placenta accreta spectrum is cesarean hysterectomy with the placenta left in situ after delivery of the fetus (attempts at placental removal are associated with significant risk of hemorrhage). Optimal management involves a standardized approach with a comprehensive multidisciplinary care team accustomed to management of placenta accreta spectrum. In addition, established infrastructure and strong nursing leadership accustomed to managing high-level postpartum hemorrhage should be in place, and access to a blood bank capable of employing massive transfusion protocols should help guide decisions about delivery location.(Table is included in full-text article.). PMID- 30461692 TI - Editorial Consultants. PMID- 30461693 TI - ACOG Practice Bulletin No. 201: Pregestational Diabetes Mellitus. AB - Pregestational diabetes mellitus represents one of the most challenging medical complications of pregnancy because of the need for frequent monitoring and adjustment of medications as well as the potential for maternal and fetal complications. This document provides an overview of the current understanding of pregestational diabetes mellitus and suggests management guidelines during pregnancy. Because few well-designed studies have been performed, many of the guidelines are based on expert and consensus opinion. This document has been updated to reflect current data on pregestational diabetes. This Practice Bulletin is updated with summary information to counsel and manage women with pregestational diabetes before and during pregnancy, more recent literature reflecting experience with continuous subcutaneous insulin infusion during pregnancy, an expanded section on the role of oral hypoglycemic agents in pregnancy, and the option of long-acting reversible contraception during the postpartum period. PMID- 30461694 TI - ACOG Committee Opinion No. 760: Dysmenorrhea and Endometriosis in the Adolescent. AB - Dysmenorrhea, or menstrual pain, is the most common menstrual symptom among adolescent girls and young women. Most adolescents experiencing dysmenorrhea have primary dysmenorrhea, defined as painful menstruation in the absence of pelvic pathology. When the patient's history suggests primary dysmenorrhea, empiric treatment should be initiated. When a patient does not experience clinical improvement for her dysmenorrhea within 3-6 months of therapy initiation, her obstetrician-gynecologist should investigate for possible secondary causes and for treatment adherence. Secondary dysmenorrhea refers to painful menses due to pelvic pathology or a recognized medical condition. Endometriosis is the leading cause of secondary dysmenorrhea in adolescents. Endometriosis should be considered in patients with persistent, clinically significant dysmenorrhea despite treatment with hormonal agents and nonsteroidal antiinflammatory drugs, particularly if no other etiology for chronic pelvic pain or secondary dysmenorrhea has been identified based on history, physical examination, and pelvic ultrasonography. The appearance of endometriosis may be different in an adolescent than in an adult woman. In adolescents, endometriotic lesions are typically clear or red and can be difficult to identify for gynecologists unfamiliar with endometriosis in adolescents. Endometriosis in adolescents is considered a chronic disease with potential for progression if left untreated. The goals of therapy include symptom relief, suppression of disease progression, and protection of future fertility. Therapy must be individualized, and obstetrician-gynecologists should consider patient choice, the need for contraception, contraindications to hormone use, and potential adverse effects and counsel the adolescent and her family on treatment options. PMID- 30461695 TI - Obstetric Care Consensus No. 7: Placenta Accreta Spectrum. AB - Placenta accreta spectrum, formerly known as morbidly adherent placenta, refers to the range of pathologic adherence of the placenta, including placenta increta, placenta percreta, and placenta accreta. The most favored hypothesis regarding the etiology of placenta accreta spectrum is that a defect of the endometrial myometrial interface leads to a failure of normal decidualization in the area of a uterine scar, which allows abnormally deep placental anchoring villi and trophoblast infiltration. Maternal morbidity and mortality can occur because of severe and sometimes life-threatening hemorrhage, which often requires blood transfusion. Although ultrasound evaluation is important, the absence of ultrasound findings does not preclude a diagnosis of placenta accreta spectrum; thus, clinical risk factors remain equally important as predictors of placenta accreta spectrum by ultrasound findings. There are several risk factors for placenta accreta spectrum. The most common is a previous cesarean delivery, with the incidence of placenta accreta spectrum increasing with the number of prior cesarean deliveries. Antenatal diagnosis of placenta accreta spectrum is highly desirable because outcomes are optimized when delivery occurs at a level III or IV maternal care facility before the onset of labor or bleeding and with avoidance of placental disruption. The most generally accepted approach to placenta accreta spectrum is cesarean hysterectomy with the placenta left in situ after delivery of the fetus (attempts at placental removal are associated with significant risk of hemorrhage). Optimal management involves a standardized approach with a comprehensive multidisciplinary care team accustomed to management of placenta accreta spectrum. In addition, established infrastructure and strong nursing leadership accustomed to managing high-level postpartum hemorrhage should be in place, and access to a blood bank capable of employing massive transfusion protocols should help guide decisions about delivery location. PMID- 30461696 TI - Assessment of therapeutic effects of statin on cardiac sympathetic nerve activity and cardiac events in patients with ischemic cardiomyopathy and mild to moderate heart failure. AB - INTRODUCTION: We determined whether statin therapy improved cardiac sympathetic nerve activity as evaluated using iodine-123-metaiodobenzylguanidine (I-MIBG) scintigraphy, and whether this therapy affects prognosis in patients with ischemic cardiomyopathy. PATIENTS AND METHODS: This study was a subanalysis of our previous report of the result that the serial I-MIBG scintigraphic studies were the most useful prognostic indicator in patients with heart failure. Patients with heart failure [left ventricular ejection fraction (LVEF) <45%] but no cardiac events for at least 5 months before the study were identified according to their history of decompensated acute heart failure requiring hospitalization. The patients underwent I-MIBG scintigraphy and echocardiography immediately before hospital discharge and after 6 months. The % denervation, heart/mediastinum count ratio, and washout rate were determined from the I-MIBG scintigraphy, and the left ventricular end-diastolic volume, left ventricular end systolic volume, and LVEF were also determined from echocardiography. We selected 76 patients with old myocardial infarction without active ischemia and used propensity score matching to compare patients who received oral statin (n=38) with those who did not (n=38). The patients were followed up for a median of 4.74 years, with the primary and secondary study end points defined as incidences of fatal cardiac events and major adverse cardiac events (MACEs), respectively. RESULTS: After treatment, the I-MIBG scintigraphic and echocardiographic parameters were improved in the statin and nonstatin groups. However, the extent of change in the % denervation was -12.3+/-10.3 and -6.2+/-9.6 (P<0.01), whereas that in the heart/mediastinum count ratio was 0.19+/-0.14 and 0.08+/-0.15 (P<0.01), and that in washout rate was -8.1+/-7.2 and -0.5+/-9.2% (P<0.01). The extent of change in left ventricular end-diastolic volume, left ventricular end systolic volume, and LVEF in the statin group tended to exceed than in the nonstatin group, but these changes were not statistically significant. Of the 76 patients, 18 experienced fatal cardiac events and 32 experienced MACEs during the study. Multivariate Cox regression analyses revealed that the nonstatin therapy was a significant predictor of both cardiac death and MACEs in our patients. On Kaplan-Meier analysis, the rates of freedom from cardiac death or MACEs were significantly higher in the statin group than those in the nonstatin group (all, P<0.05). CONCLUSION: Statin therapy improved cardiac sympathetic nerve activity in patients with ischemic cardiomyopathy and mild to moderate heart failure. Furthermore, statin is potentially effective for reducing cardiac events in these patients. PMID- 30461697 TI - The synthesis of a new macromolecule for the sentinel node detection: 99mTc-gly mannosyl-dextran. AB - OBJECTIVE: We aimed to design and synthesize a new macromolecule for sentinel node detection to improve the imaging quality and avoid possible adverse effect. BACKGROUND: The imaging of sentinel lymph node has been an important field in the nuclear medicine. A lot of imaging agents have been developed, including Tc sulfer colloid, Tc-labeled dextrans and the latest Tc-DTPA-mannosyl-dextran. With the technology advanced, the imaging ability of the agents has been better and better. However, there are still some drawbacks. MATERIALS AND METHODS: The new macromolecule agent was based on the dextran macromolecule backbone. Then the gly gly-gly and mannose molecules were conjugated onto the backbone proportionally by targeting two different reaction sites. Once the new macromolecule was labelled with Tc, its imaging ability was tested by single-photon emission computed tomography scanning with Tc-sulfur colloid as the comparison. RESULTS: The average numbers of gly-gyl-gyl and mannosyl groups on the dextran backbone are determined to be ~1: 2 per dextran. The average molecular diameter and molecular weight are measured to be 5.4+/-0.7 nm and 10 324 g/mol, respectively. The macromolecule is labelled by Tc with 93.2+/-2.4% radiochemical yield. The lymphatic imaging by single-photon emission computed tomography with the labeled compound showed no worse imaging ability but cost less time than the commercially available Tc-sulfur colloid. CONCLUSION: A new macromolecule imaging agent for sentinel node detection has been synthesized with better imaging ability and less imaging time cost. PMID- 30461698 TI - Influence of myocardial count on phase dyssynchrony analysis of gated myocardial perfusion single-photon emission computed tomography. AB - OBJECTIVES: Drugs and acquisition times for gated myocardial perfusion single photon emission computed tomography scintigraphy vary depending on the facility. Even if the same examination is performed in the same facility, the acquisition count differs for each examination because factors such as the patient's age, stress protocol of the patient, the biological half-life of the stress agent, and the patient's response are different. We aimed to evaluate the differences in acquisition counts on the effect of left ventricular function and phase analysis indices. MATERIALS AND METHODS: A gated myocardial perfusion phantom was used. The acquisition times acquired were varied (nine steps from 3 to 51 s per view). The myocardial average count per pixel of the left anterior oblique (LAO) of 45 degrees of projection data were 9.4, 17.8, 28.7, 47.1, 67.1, 97.7, 122.7, 174.4, and 254.0 counts per view. We used the count value of LAO of 45 degrees of projection data to find the lowest count that the left ventricular function and phase analysis indices can accurately calculate. The left ventricular function indices evaluated were the left ventricular ejection fraction (LVEF), end diastolic volume (EDV), and end-systolic volume (ESV). The bandwidth, phase SD, and entropy were evaluated as phase analysis indices. RESULTS: Functional analysis: LVEF and EDV showed constant values even when the collection count changed (%coefficient of variation (CV) of LVEF=2.1%, %CV of EDV=3.9%). The ESV value was large when the lowest count was obtained (9.4 counts per pixel per view), which caused %CV of ESV to be greater than that of LVEF and EDV (%CV of EDV=7.8%). Phase analysis indices: The difference between the highest and lowest values was that the bandwidth was 100.0%, phase SD was 62.0%, and entropy was 58.3%. Phase analysis indices declined as a function of increasing acquisition time. CONCLUSION: To accurately calculate left ventricular function, the myocardial counts of LAO of 45 degrees of projection data should be at least 17.8 average counts per pixel per view. To accurately calculate the phase analysis index, the myocardial counts of LAO of 45 degrees of projection data should be at least 67.1 average counts per pixel per view. PMID- 30461699 TI - Quantitative assessment of 18F-FDG PET in patients with Hodgkin lymphoma: is it significantly affected by contrast-enhanced computed tomography attenuation correction? AB - OBJECTIVE: The reliability of visual and quantitative response assessment may be impaired owing to inconsistent scanning protocols and image reconstruction methods of 2-deoxy-2-[F]fluoro-D-glucose (F-FDG) PET. Hence, this study investigates the effect of contrast-enhanced computed tomography (CT) attenuation correction in patients with Hodgkin lymphoma. PATIENTS AND METHODS: In 10 consecutive patients undergoing either staging or response assessment, F-FDG PET images were attenuation-corrected once on the basis of unenhanced CT and additionally using contrast-enhanced CT. Reconstruction was performed in both cases with ordered subset expectation maximization (OSEM) and ultra-high definition (UHD) algorithm. While maximum and peak standardized uptake value (SUV) were obtained from tumour tissue (lesionSUVmax and lesionSUVpeak), maximum and mean SUVs were determined within the background regions liver (liverSUVmax and liverSUVmean) and mediastinal blood pool (mbpSUVmax and mbpSUVmean). RESULTS: After switching to contrast-enhanced CT attenuation correction, lesionSUVmax and lesionSUVpeak increased on average by 2.55+/-3.24 (P=0.018) and 3.64+/-3.22% (P=0.008), respectively, with OSEM and by 4.59+/-5.49 (P=0.005) and 3.84+/-5.65% (P=0.005), respectively, with UHD reconstruction. LiverSUVmax and liverSUVmean showed a mean rise of 7.15+/-4.27 (P=0.005) and 6.97+/-2.18% (P=0.005), respectively, in the OSEM data sets and of 7.24+/-6.59 (P=0.017) and 6.29+/-2.83% (P=0.005), respectively, in the UHD images. The average increases of mbpSUVmax and mbpSUVmean were 10.82+/-4.89 (P=0.005) and 12.40+/-3.73% (P=0.005), respectively, after OSEM, compared with 13.11+/-14.93 (P=0.005) and 11.50+/ 12.19% (P=0.005), respectively, after UHD reconstruction. CONCLUSION: As the use of CT contrast fluids results in a stronger SUV increase within the liver and mediastinal blood pool than within lymphoma tissue, this may have clinical consequences regarding visual and quantitative response assessment. Ideally, CT scans for PET attenuation correction should therefore be performed in the absence of a contrast agent. PMID- 30461700 TI - Letters. PMID- 30461703 TI - Educational strategies for conflict management. PMID- 30461704 TI - Teaching the modified Valsalva maneuver to terminate SVT. PMID- 30461706 TI - Ventriculoperitoneal shunts: What nurses need to know. PMID- 30461707 TI - Confronting barriers to improve healthcare literacy and cultural competency in disparate populations. PMID- 30461709 TI - Looking for drug-free alternatives to control chronic back pain. PMID- 30461708 TI - Make connections by joining a professional nursing organization. AB - Although some may feel hesitant about joining a professional organization, induction is largely expected in the nursing community. This article offers insight to help nurses make informed decisions about membership. PMID- 30461710 TI - Understanding the role of speech language pathologists in managing dysphagia. AB - Collaboration between nurses and speech language pathologists is vital to the screening and management of dysphagia in acute care settings. This article examines each discipline's role in caring for patients with dysphagia. PMID- 30461711 TI - Removing epidural catheters: A guide for nurses. AB - Short-term epidural analgesia is effective for postoperative pain, procedural pain, trauma pain, and labor pain. This article describes the skills, procedures, and nursing care required for removing a short-term, temporary epidural catheter. PMID- 30461712 TI - Mass shootings: A call for nursing awareness and action. AB - Nurses everywhere may someday encounter the victims of a mass shooting, whether on the job or in their civilian lives. This article provides US mass shooting statistics, best practice recommendations for nurses, and lessons learned from the experiences of hospitals that have navigated this type of catastrophe. PMID- 30461713 TI - Perspective on cultural competency: A review of Chinese culture. AB - With an emphasis on Chinese seniors, this article raises awareness of the importance of cultural competency and how this can impact care delivery, as well as strategies healthcare professionals can use to improve cultural competency in their institution. PMID- 30461715 TI - Physician-nurse relationships after participation in a shadowing program. PMID- 30461714 TI - Take the initiative to reduce surgical site infections. PMID- 30461716 TI - Online resources about vaccination. PMID- 30461719 TI - Physical activity after solid organ transplantation: comprehensive guidance is needed to advance future research efforts. PMID- 30461718 TI - The effects of oxygenation on ex vivo kidneys undergoing Hypothermic Machine Perfusion. AB - BACKGROUND: Supplemental oxygenation of the standard Hypothermic Machine Perfusion (HMP) circuit has the potential to invoke favourable changes in metabolism, optimising cadaveric organs prior to transplantation. METHODS: Eight pairs of porcine kidneys underwent 18 hours of either oxygenated (HMP/O2) or aerated (HMP/Air) HMP in a paired DCD model of transplantation. Circulating perfusion fluid was supplemented with the metabolic tracer universally labelled glucose ([U-C] glucose).Perfusate, end-point renal cortex and medulla samples underwent metabolomic analysis using 1D and 2D NMR experiments in addition to GC MS. Analysis of C labelled metabolic products was combined with adenosine nucleotide levels and differences in tissue architecture. RESULTS: Metabolomic analysis revealed significantly higher concentrations of universally labelled lactate in the cortex of HMP/Air vs HMP/O2 kidneys (0.056 mM vs. 0.026 mM, p<0.05). Conversely, newly synthesised [4,5-C] glutamate concentrations were higher in the cortex of HMP/O2 kidneys inferring relative increases in tricarboxylic acid cycle activity vs HMP/Air kidneys (0.013 mmol/L vs. 0.003 mmol/L, p<0.05). This was associated with greater amounts of ATP in the cortex HMP/O2 vs HMP/Air kidneys (19.8 vs. 2.8 mmol/mg protein, p<0.05). Improved flow dynamics and favourable ultrastructural features were also observed in HMP/O2 kidneys. There were no differences in thiobarbituric acid reactive substances and reduced glutathione levels, tissue markers of oxidative stress, between groups. CONCLUSIONS: The supplementation of perfusion fluid with high concentration oxygen (95%) results in a greater degree of aerobic metabolism vs aeration (21%) in the non-physiological environment of HMP, with reciprocal changes in ATP levels. PMID- 30461720 TI - Correlates and Outcomes of Low Physical Activity Posttransplant: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Little is known about associations between low physical activity (PA) and its correlates and outcomes in solid organ transplant recipients. This systematic review with meta-analysis examined correlates and outcomes associated with low PA (i.e. not meeting individual study's definition of being physically active) following solid organ transplantation. METHODS: We searched PubMed, CINAHL, PsycINFO and EMBASE from inception to February 2016 to identify peer reviewed data-based articles. Articles published in English, German, Spanish, French, Italian, Portuguese, or Dutch that examined correlates or outcomes associated with low PA in adult single, solid organ transplant recipients were included. Studies' quality was assessed using a 14-item checklist. Pooled odds ratios and 95% confidence intervals were computed for correlates and outcomes examined in >= 5 studies. RESULTS: Of 7,401 publications screened, 34 studies met inclusion criteria and were included in the overall synthesis with 15 included in the meta-analysis. Most focused on renal transplantation (n=18, 53%) and used cross-sectional designs (n=26, 77%). Of 30 correlates examined, [condition related (n=11), social/economic-related (n=9), patient-related (n=4), healthcare system-related (n=3), and treatment-related (n=3)], only four were examined >=5 times and included in meta-analyses. None were significantly related to low PA. Of 19 outcomes assessed, only physical health-related quality of life was examined >= 5 times. Low PA was significantly associated with low physical health related quality of life (OR=0.172, 95% CI=0.08, 0.37). CONCLUSIONS: We found few studies examining most correlates and outcomes related to low PA despite growing evidence that improving PA might be an effective intervention in improving post transplant outcomes. PMID- 30461721 TI - Enrichment of cytomegalovirus-induced NKG2C+ Natural Killer cells in the lung allograft. AB - BACKGROUND: In lung transplant recipients, immunosuppressive medications result in impaired antiviral immunity and a propensity for cytomegalovirus (CMV) reactivation within the lung allograft. Natural Killer (NK) cells play a key role in immunity to CMV, with an increase in the proportion of NK cells expressing activating CD94-NKG2C receptors in the blood being a strong correlate of CMV infection. Whether a similar increase in NKG2C NK cells occurs in lung transplant recipients following CMV reactivation in the allograft and if such cells contribute to viral control, remains unclear. METHODS: In this pilot study, we longitudinally assessed the frequency and phenotype of NKG2C NK cells in the blood and bronchoalveolar lavage (BAL) of lung transplant recipients and stratified recipients based on their risk of developing CMV disease. RESULTS: We observed an increase in the proportion of NKG2C NK cells in the blood and BAL of CMV high-risk patients, coincident with both the cessation of anti-viral prophylaxis and subsequent detection of actively replicating CMV in the blood and/or lung allograft. Additionally, these NKG2C NK cells expressed killer-cell immunoglobulin-like receptors (KIR) distinct from those of other NK subsets and BAL NKG2C+ NK cells possessed an activated phenotype. Finally, the frequency of NKG2C+ NK cells in the BAL may be inversely correlated with CMV blood titers. CONCLUSIONS: Monitoring the phenotype of NK cells post-lung transplant may be a useful biomarker for monitoring patient levels of CMV immunity. PMID- 30461722 TI - At the bottom of Thomas Bayes' tea cup: Practical applications of lung transplant immunophenotyping. PMID- 30461723 TI - Report of the 24th Annual Congress of the International Liver Transplantation Society. AB - The 24 Joint Annual Congress of the International Liver Transplantation Society (ILTS) in association with European Liver and Intestine Transplant Association (ELITA) and Liver Intensive Care Group of Europe (LICAGE) was held in Lisbon, Portugal from May 23-26, 2018. More than 1200 participants from over 60 countries including surgeons, hepatologists, anesthesiologists and critical care intensivists, radiologists, pathologists, organ procurement personnel and research scientists, came together with the common aim of improving care and outcomes for liver transplant recipients. Over 600 scientific abstracts were presented. The principal themes were living donation, use of marginal liver donors, machine preservation, disease-specific immunosuppressive regimen, malignancies, and advances in pediatric liver transplantation and liver transplant anaesthesia. This report presents excerpts from invited lectures, and select abstracts from scientific sessions, which add to current knowledge, and will drive clinical practice and future research. PMID- 30461724 TI - Young people with biliary atresia requiring liver transplantation: a distinct population requiring specialist care. AB - BACKGROUND: Young people born with biliary atresia are an emerging population for adult hepatologists with 40-45% of children entering adolescence with their native liver intact. For those requiring liver transplantation during adolescence, disparity on the waiting list and post liver transplantation outcome for young adults compared to younger and older age groups has stimulated discussion regarding the optimal timing of listing. In this study we review our experience of young people with biliary atresia requiring liver transplantation during adolescence and young adulthood. METHODS: Retrospective, single centre review of patients with biliary atresia requiring liver transplantation > 11 years. RESULTS: Thirty-six young people (16 male) underwent liver transplantation between 1991-2014 at a median age of 16.6 (IQR 14.2,19.5) years. The commonest indications for listing were refractory cholangitis (31%), synthetic failure (25%) and variceal bleeding (14%). Patients listed by the adult team (n=14) waited longer than those listed by the paediatric team (10 (IQR 7.7,24.6) vs 5.8 (IQR 4.0,15.1) months (p<0.05)) and were more likely to require intensive care support at time of listing (29% vs 5%, p<0.05). Admission to intensive care unit at listing was associated with poorer patient and graft survival and support from a multidisciplinary liver transition service improved survival. Liver disease severity scores did not correlate with time on waiting list or outcome. CONCLUSIONS: Young people with biliary atresia require close monitoring by specialists familiar with their condition and timing for liver transplantation needs to be fine-tuned in order to avoid clinical decompensation and improve long term outcomes. PMID- 30461725 TI - Human Atrial Natriuretic Peptide in Cold Storage of Donation after Circulatory Death Rat Livers: An Old but New Agent for Protecting Vascular Endothelia? AB - BACKGROUND: Current critical shortage of donor organs has increased the use of donation after circulatory death (DCD) livers for transplantation, despite higher risk for primary non-function or ischemic cholangiopathy. Human atrial natriuretic peptide (hANP) is a cardiovascular hormone that possesses protective action to vascular endothelia. We aimed to clarify the therapeutic potential of hANP in cold storage of DCD livers. METHODS: Male Wistar rats were exposed to 30 minute warm ischemia in situ. Livers were then retrieved and cold-preserved for 6 hours with or without hANP supplementation. Functional and morphological integrity of the livers was evaluated by oxygenated ex vivo reperfusion at 37 degrees C. RESULTS: hANP supplementation resulted in significant reduction of portal venous pressure (12.2 +/- 0.5 vs. 22.5 +/- 3.5 mmHg, P <0.001). As underlying mechanisms, hANP supplementation significantly increased tissue adenosine concentration (P =0.008), followed by significant up-regulation of endothelial NOS and endothelin-1 down-regulation than in the controls (P =0.01 and P =0.004, respectively). Consequently, hANP significantly decreased transaminase release (P <0.001), and increased bile production (96.2 +/- 18.2 vs. 36.2 +/- 15.2 MUL/g-liver/hour, P <0.001). Morphologically, hepatocytes and sinusoidal endothelia were both better maintained by hANP (P =0.021). Electron microscopy also revealed that sinusoidal ultra-structures and microvilli formation in bile canaliculi were both better-preserved by hANP supplementation. Silver staining also demonstrated that hANP significantly preserved reticulin fibers in Disse space (P =0.017), representing significant protection of sinusoidal frameworks/architectures. CONCLUSIONS: Supplementation of hANP during cold storage significantly attenuated cold-ischemia/warm-reperfusion injury of DCD livers. PMID- 30461728 TI - Doris A. Taylor, PhD, Hon DSc: Director, Regenerative Medicine Research, Director, Center for Cell and Organ Biotechnology at Texas Heart Institute and Texas A&M University. PMID- 30461726 TI - Organ Donation in Wales: Time to Reflect. PMID- 30461729 TI - The Authors' Reply. PMID- 30461730 TI - [Olive Oil and Body Weight. Systematic Review and Meta-Analysis of Randomized Controlled Trials]. AB - BACKGROUND: Olive oil, as fundamental fat in the Mediterranean diet, has contributed to a decrease in obesity in several epidemiological studies. It is unknown whether olive oil itself can decrease the weight independently of the diet used. The objective of this work was to determine the efficacy of olive oil in reducing weight. METHODS: Systematic review of meta-analysis of randomized controlled trials (RCTs) of at least 12 weeks of intervention on adults without previous cardiovascular events to estimate the effect of an olive-enriched diet on weight, waist and body mass index. The search was performed in PubMed, Embase, Cochrane plus, Web of Science, Ovid, Scopus, Virtual Health Library (BVS), Theses and Dissertations Online (TDX) until December 2016. No language, gender or underlying pathology was restricted. We used Stata14 SE for data synthesis. RESULTS: 490 studies were identified, of which only 11 studies met the inclusion criteria. A diet enriched in olive oil reduced weight more than control diet: 0.92 kg, 95% CI (-1.16, -0.67), p heterogeneity = 0.1; decreased waist circumference in -0.60 cm, 95% CI (-1.17, -0.04), p heterogeneity = 0.6; and diminished BMI in -0.90, 95% CI (-0.91, -0.88), p heterogeneity < 0.001. The benefits were seen when olive oil was supplemented in its natural state and not when capsules were given. CONCLUSIONS: A diet enriched with olive oil can be an important weight control strategy in people without previous cardiovascular events. PMID- 30461731 TI - Linear-to-circular polarization transformation upon reflection by a transparent thin film on a transparent substrate: analytical determination of principal angles and principal azimuths. AB - The principal angles and principal azimuths at which incident linearly polarized light becomes circularly polarized upon external reflection by a transparent thin film on a transparent substrate are determined analytically. For a given principal angle, multiple solutions (two or four) are obtained for the required film thicknesses and the associated principal azimuths. Specific results are presented for the air-SiO2-Si (ambient-film-substrate) system at the near infrared wavelength lambda=1.55 MUm. PMID- 30461732 TI - On-orbit radiometric calibration of Suomi NPP VIIRS reflective solar bands using the Moon and solar diffuser. AB - Radiometric calibration of the Suomi National Polar-orbiting Partnership Visible Infrared Imaging Radiometer Suite (VIIRS) reflective solar bands relies mainly on the onboard solar diffuser (SD) observations. The SD reflectance degrades over time due to the exposure to solar ultraviolet radiation. The uncertainties embedded in characterizing the SD bidirectional reflectance distribution function (BRDF) directly affect the accuracy of sensor radiometric calibration coefficients, such as F-factors, which are proxies of detector gain. The Moon based radiometric calibration provides an independent way of validating and correcting the SD-based calibration. This study focuses on the comparison of the long-term SD F-factors with lunar F-factors by using two independent lunar irradiance models, i.e., Miller and Turner (MT) model and the Global Space-based Inter-Calibration System Implementation of ROLO (GIRO) model. To monitor the long term detector response changes, the lunar F-factor differences are matched to the SD F-factors by applying the best fit scaling factors. Overall, the two lunar F factors agree well, within 2% of one sigma standard deviation in the reflective solar bands compared to the SD F-factors. The lifetime standard deviations of difference between the GIRO-based lunar and SD F-factors show better long-term match than that of MT-based lunar F-factors. The GIRO-based lunar F-factors show increasing differences over time in comparison with the SD F-factors especially for bands M1 to M4, which indicates the underestimation of the VIIRS detector degradation by SD F-factors for these bands. Using standard SD calibration method and the GIRO-based lunar model, long-term difference between the lunar and SD F factors shows there are 1.6%, 1.3%, 1.0%, and 0.9% increases in lunar F-factor trend for bands M1 to M4 at the end of year 2015. To mitigate these time dependent biases, NOAA Ocean Color (OC) group and NASA VIIRS characterization support team (VCST) developed lunar correction methods and applied them to their specific products. However, the amounts of band-dependent lunar corrections are not consistent between these two teams, especially in the short-wavelength bands from M1 to M4, depending on the versions of lunar models and SD F-factor calculation algorithms. Using the standard SD F-factor algorithm and the multi agency endorsed GIRO model, we derived lunar correction factors based on the quadratic fits between the SD and lunar F-factors. The differences with the NOAA OC group and NASA VCST team are compared and described in this study. PMID- 30461733 TI - Periodic-trajectory-controlled, coherent-state-phase-switched, and wavelength tunable SU(2) geometric modes in a frequency-degenerate resonator. AB - We report a method to realize the periodic trajectory controlling, coherent-state phase switching, and wavelength tuning of SU(2) geometric modes (GMs) in a frequency-degenerate resonator (FDR). FDR is a resonator in which the ratio of transverse and longitude modes frequency spacing is a simple rational number, which would lead to a laser wave-packet in a SU(2) coherent state related to a periodic ray trajectory. We demonstrate that the periodic trajectory can be switched with coherent-state phase changing from 0 to pi (or pi to 0) by simply controlling the position of gain medium in the same FDR. For the period-of-four state, the geometries are switched between "W" and "M" shapes. For the period-of three state, those are switched between "IV" and "VI" shapes. Moreover, because a special crystal Yb:CALGO with extremely broad emission band is used as the gain medium, our SU(2) GMs have the wavelength-tunable property in contrast to the conventional single-frequency GMs. The center wavelength can be tuned with the range of about 10 nm by adjusting the pump power. These effects can further enrich the various applications of structured light manipulation. PMID- 30461734 TI - Efficient terahertz transmission modulation in plasmonic metallic slits by a graphene ribbon array. AB - Extraordinary optical transmission is the widely known phenomenon of enhanced transmission of waves through subwavelength periodic metallic apertures. Here, we propose efficient terahertz transmission modulation in subwavelength metallic slits by a graphene plasmonic ribbon array. The extraordinary optical transmission through the subwavelength metallic slits can be tuned by coupling with the plasmonic resonance of graphene ribbon array, resulting in a deep transmittance depression. Numerical simulations show that maximal transmission modulation depth of 98.99% can be obtained at 1.03 THz via this mechanism. PMID- 30461735 TI - Tunable terahertz metamaterial absorber based on Dirac semimetal films. AB - In this paper, the tunable properties of metamaterial absorbers based on 3D Dirac semimetal films (DSFs) in the terahertz (THz) regime are discussed in theory. We consider the absorbers with square-shaped, circular-patch, and cross-shaped resonators. These resonances are theoretically polarization-insensitive at normal incidence because of their 90 degrees rotational symmetry and can achieve perfect absorption in numerical simulation. We then introduce dual-band and broadband absorbers by combining two DSF-based square-shaped (or circular-patch) resonators into one unit cell with different sizes. Unlike with a conventional metal-based absorber, the absorption of a DSF-based absorber can be dynamically tuned by varying the Fermi energy instead of refabricating the structures. Moreover, the DSFs can be regarded as a "Salisbury screen" of an absorber to block the transmission at the THz frequencies, which can be more convenient than graphene in the application of a tunable absorber. Our designs have potential applications in various fields such as sensors, thermal detectors, and imagers. PMID- 30461736 TI - Dual-wavelength end-pumped Rb-Cs vapor lasers. AB - Diode-pumped alkali vapor lasers (DPALs) have been rapidly developed because of their excellent performances. However, there have been few reports about DPALs with multiple wavelengths until now. The effects of the output features on the waist size and position of both Rb and Cs pump beams were first theoretically investigated using a kinetic model for an end-pumped dual-wavelength Rb-Cs laser. Then, a continuous-wave (CW) laser was experimentally constructed. Finally, the hybrid CW-modulated output with two wavelengths was also successfully obtained for the first time in development of alkali lasers. The results might be helpful in applications for laser communication and ranging/radar in the future. PMID- 30461737 TI - Power balancing the multibeam OMEGA laser. AB - Multibeam lasers often require an output beam balance that specifies the degree of simultaneity of the laser output energy, instantaneous power, or instantaneous irradiance (power per unit area). This work describes the general problem of balancing a multibeam laser. Specific techniques used to balance the output power of the 60-beam pulsed OMEGA Laser System are discussed along with a measured reduction of beam-to-beam imbalance. In particular, the square-pulse distortion induced by a simple saturating amplifier operating with its output at some fraction of its saturation fluence is derived, and a method to exchange gain between saturated amplifiers in a single beam that have different saturation fluences to adjust balance is described. PMID- 30461738 TI - Dimming control scheme for VLC systems based on multilevel data transmission. AB - As an emerging wireless communications technology, visible light communications (VLC) have attracted much attention for synergistically providing both high-speed data transmission and high-quality illumination. To provide energy savings and ecological benefits, dimming control is an essential function in VLC systems where users can obtain the required illumination levels. However, the conventional binary-based dimming schemes are spectrally inefficient. In this paper, we propose a novel multilevel data transmission scheme for VLC systems that can achieve dimming control and communication functions simultaneously. Additionally, the encoding/decoding structure is provided where the specific symbol set can maintain the specific dimming level. Finally, simulation results show that the proposed multilevel transmission scheme can achieve increased spectral efficiency and better error performance. PMID- 30461739 TI - Three-axis attitude accuracy of better than 5 arcseconds obtained for the star sensor in a long-term on-ship dynamic experiment. AB - Carried on the deck of the satellite maritime tracking and control ship, Yuan Wang 6, we have conducted a long-term on-ship dynamic experiment for a star sensor in the South Pacific. Motion-blurred star images of the star sensor obtained under different dynamic conditions are processed by our previously proposed region confined restoration method method, after which the SNR of the motion-blurred star images and the identification rate of the star sensor have been improved remarkably. With the attitude-correlated frames approach, the random noise aroused by the motion of the ship is reduced further. As a result, considering the accuracy and star observation length of the ship-borne star sensor, we believe reported for the first time, a three-axis attitude accuracy of better than 5 arcseconds is obtained in our on-ship experiment. PMID- 30461740 TI - Analysis of a heterodyne detection system affected by irradiance and phase fluctuations in slant atmospheric turbulence. AB - A mathematical model considering the effects of amplitude and phase random fluctuations on the signal-to-noise ratio (SNR) of heterodyne detection was established, and the effects of irradiance and phase fluctuations on the performance of heterodyne detection were investigated. The results show that the inner scale of turbulence significantly affects the SNR. The first 20 Zernike modes have a greater effect on the SNR of the heterodyne detection system. The SNR is affected more significantly by phase fluctuations than by irradiance fluctuations. The SNR decreases by four orders of magnitude because of amplitude and phase fluctuations. PMID- 30461741 TI - Improved edge detection in computational ghost imaging by introducing orbital angular momentum. AB - The effect of orbital angular momentum (OAM) on computational ghost imaging (CGI) with a classical or thermal source is investigated. Application of the OAM on the phase of object light is shown to enhance edge formation in the constructed image. Ghost image (GI) formation by the correlation of object and reference beams with and without OAM is studied theoretically and experimentally. In both approaches, it is confirmed that employing OAM results in higher values for visibility and contrast-to-noise ratio. Despite lowered signal-to-noise ratios in the introduced method, edge detection shows considerable enhancement over that of CGI. Additionally, compared with the previous methods for edge detection in the GI, we also show that the introduced OAM method requires lower shot numbers for image construction. PMID- 30461742 TI - Estimation of spectral mismatch correction factor f1' indicated by radiometer responsivity toward phototherapic infant devices. AB - The main aim of this research is to assess the variation in phototherapy radiometer responsivities toward the optical power of the phototherapeutic devices and hence estimate the spectral mismatch correction factor f1'. Two conventional phototherapy devices were studied to verify their spectral irradiance and three different phototherapy radiometers were studied for their responsivity at the range 400-500 nm. The results show the dependence of total irradiance measurement of phototherapy sources on matching between phototherapy radiometer band responsivity and spectral irradiance of the phototherapy sources. The spectral mismatch values vary from 13% to 47% of the total measured irradiance for the three radiometers. These mismatch values could be added to the measured irradiance as a correction. PMID- 30461743 TI - Coherent phase transfer via fiber using heterodyne optical phase locking as optical amplification. AB - We demonstrate a coherent phase transfer via a 224 km cascaded fiber link comprising two 112 km links stabilized by two phase-locking loops, respectively. The optical signal is regenerated employing heterodyne optical phase locking (HOPL) after the first 112 km transfer. With a gain of more than 50 dB, the HOPL is capable of tracking the frequency of the incoming carrier with a fluctuation of 0.48 mHz and preserving the instability of the incoming laser to 6*10-20 at 1000 s. The phase noise cancellation of each span is investigated, and the out loop transfer instability of the 224 km link reaches 7.7*10-19 at 10,000 s. The relation between the transfer instability of each span and that of the whole link is also deduced in the paper, in agreement with experimental results of the 224 km link. PMID- 30461744 TI - Influence of the frequency response of the photodetector on the heterodyne interferometer-based sound pressure standards in water. AB - The heterodyne interferometer has been used to realize the sound pressure unit directly and absolutely for underwater acoustics and ultrasound, which is considered as the primary standard of the hydrophone calibration instead of the reciprocity method. The widely used demodulation methods are the zero-crossing method and the arctangent method. Recent studies show that the frequency response of the utilized photodetector (PD) in the heterodyne interferometer also significantly influences the results of the sound pressure realization using the two demodulation methods, especially for the high-intensity focused ultrasound application, which is investigated in this paper. Simulations are performed to obtain general conclusions using different types of low-pass filters to simulate the nonideal frequency responses of the PD. Also, experimental results of the frequency response of the utilized PD are then used to analyze the induced relative error of the demodulated acoustic particle velocity so as to evaluate the related measurement uncertainty of the sound pressure realization. The simulation method is useful to choose the required PDs and evaluate the related measurement uncertainty induced by their frequency responses for the optical sound pressure standards and other optical measurement applications. PMID- 30461745 TI - Wet-etching-assisted femtosecond laser holographic processing of a sapphire concave microlens array. AB - We report rapid and mask-free fabrication of a sapphire concave microlens array by a combined method of femtosecond laser holographic processing and wet etching. The method features high fabrication efficiency, as crater arrays can be created on sapphire through a parallel processing manner, and the subsequent wet etching facilitates the formation of microlens arrays with a smooth surface. More importantly, the size and spacing of the concave microlenses can be well tuned by varying the distance of craters and etching time. Two types of microlens arrays with a spacing of 25 and 40 MUm have been successfully fabricated, both of which showed good imaging performance. This method holds great promise for developing sapphire-based micro-optical components. PMID- 30461746 TI - Research of the three-dimensional tracking and registration method based on multiobjective constraints in an AR system. AB - To match the virtual image and actual environment in an augmented reality (AR) system, it is necessary to complete the task of three-dimensional (3D) tracking registration. This paper proposes a new method for 3D tracking registration. Previous methods extract feature points in images to realize tracking registration. In this paper, the objects are extracted from the deep convolution neural network in the scene, and the camera pose is estimated by establishing the constraint relation of the objects. Then, 3D tracking and registration of the virtual object are realized. We design an improved single-shot multibox detector semantic segmentation network to identify and segment the scene and extract the pixel classification results of the objects in the scene. The effect of classification with this method is better. The depth of the extracted object is estimated based on the data from the left and right cameras, and the 2D image is converted into a 3D point cloud. A camera pose estimation method, combined with multiobjective information, is proposed. The camera transformation matrix is directly estimated by establishing a mathematical model. This method avoids the effect on the accuracy of the camera pose estimation when the feature points are not sufficient. Moreover, by assigning different weights to the point clouds of different objects, errors caused by the model can be reduced. The experimental results showed that the 3D registration method proposed in this paper is less than 2.5 pixels in the application scene of an augmented reality head-up display. This method had a better effect compared with that of existing methods and also improved driving safety. PMID- 30461747 TI - Multiring pure-phase binary optical elements to extend depth of focus. AB - Multiring pure-phase binary optical elements (BOEs) are widely used to extend the depth of focus (DOF) in many optical applications. Although researchers have designed various BOEs to extend the DOF, few theories and experiments have been reported to validate the performances of different N-ring pure-phase BOEs to realize the DOF as long as possible. In this paper, aberration theory is used to obtain the simple and straightforward initial phase, and a novel modified Gerchberg-Saxton algorithm is presented for generating N-ring 0-pi-phase BOEs to optimally extend the DOF. Theoretical, numerical, and experimental results demonstrate that the DOF can be extended with increased N in the same NA. PMID- 30461748 TI - Stokes imaging polarimetry using a twisted hybrid aligned nematic liquid crystal cell. AB - We propose a Stokes polarimetry system containing a twisted hybrid aligned nematic (HAN) liquid crystal (LC) cell as a simple and compact polarimetry setup that can function without any mechanical movement of the optical components. We measured the Mueller matrix of the twisted HAN-LC cell and compared it with the Mueller matrix of an ordinary nontwisted HAN-LC cell with respect to practicability for the proposed LC polarimetry system. The basic measurement principle of LC polarimetry is presented after determining the best set of four driving voltages for maximizing measurement performance. Finally, we conducted some demonstrative experiments using two different birefringent samples to ensure the applicability of the proposed LC polarimetry system. PMID- 30461750 TI - Measurement of a true Brillouin grating distribution generated at mated fiber connectors with optical low coherence reflectometry coupled with dispersive Fourier spectroscopy. AB - We previously reported a reflectogram from mated fiber connectors that was measured at a spatial resolution of 100 MUm with Brillouin-gating-based optical low coherence reflectometry, and that agreed with a theoretical curve calculated by assuming that there was a step-like Brillouin grating distribution [Electron. Lett.53, 423 (2017)]. The agreement meant that the reflectogram was determined by the coherence function of the low coherence light and did not mean that we could observe the Brillouin grating distribution generated around the fiber connector joint. In this paper, we focused on increasing the spatial resolution to reveal the actual distribution by broadening the low coherence light, removing the erbium-doped fiber amplifier from the probe port of the interferometer to reduce the dispersion and phase fluctuations, and introducing dispersive Fourier spectroscopy to numerically and completely eliminate the residual dispersion. Although the signal-to-noise ratio (S/N) of a reflectogram obtained by a single translation of the stage was only 4, we succeeded in increasing the S/N 15-fold by averaging 200 samples acquired with repetitive measurements while maintaining a spatial resolution of 30 MUm. We were able to clearly observe 320 and 430 MUm wide transitions in a Brillouin grating distribution generated around the joint. PMID- 30461749 TI - Growth, spectral properties, and diode-pumped laser operation of a Nd3+-doped LaMgAl11O19 crystal. AB - A Nd3+-doped LaMgAl11O19 (Nd:LMA) crystal was grown by the Czochralski method. Room temperature polarized absorption spectra, fluorescence spectra, and fluorescence lifetime of the Nd:LMA crystal were measured and analyzed. The Judd Ofelt parameters Omega2,4,6 were calculated to be 1.21*10-20, 3.63*10-20, and 2.35*10-20 cm2, respectively. The absorption and emission cross sections were calculated. Using a 790-nm diode laser as pump source, continuous-wave laser operation of an a-cut Nd:LMA crystal has been demonstrated with a maximum output power of 1.71 W and slope efficiency of 40.4% for a 1055 nm laser. Low-gain laser operation at 1082 nm is also realized with a maximum output power of 1.46 W and slope efficiency of 34.5%. PMID- 30461751 TI - Remotely biasing the electro-optic response of an electric field sensing detection system using LiNbO3 asymmetric Mach-Zehnder optical retarders. AB - Lithium niobate (LiNbO3) electro-optic birefringent optical waveguides or electro optic Mach-Zehnder interferometers have been proposed as electric field sensors in recent years. Electrode-less sensing using LiNbO3 devices is an active research domain, as they do not perturb the measurands. Asymmetric LiNbO3 Mach Zehnder interferometers can be used as electrode-less electric field sensors. However, as an electrode-less sensor cannot be electrically adjusted in the linear region of its electro-optic transfer function, the measurand is imprinted anywhere on such a characteristic. With a view toward achieving a linear response of the sensing-detection process, a simple technique for remotely biasing the electro-optic response, based on two cascaded LiNbO3 AMZI optical retarders, is described in this paper. PMID- 30461753 TI - Optical single-channel color image cryptosystem based on vector decomposition and three-dimensional chaotic maps. AB - We propose an optical single-channel color image cryptosystem based on vector decomposition and three-dimensional (3D) chaotic maps. In the proposed cryptosystem, the color image is first decomposed into R, G, and B channels, and then the three channels are individually scrambled by a generalized Arnold transform. Subsequently, the scrambled channels are phase encoded and then synthesized into one vector. The synthesized vector is used as the input image of the double random phase encoding (DRPE) in the gyrator domain. The introduction of the vector decomposition enables the cryptosystem to realize single-channel color image encryption, and the first phase mask of DRPE acts as the main secret key when the input image is a non-negative amplitude-only map. In addition, the phase masks of DRPE are generated by a 3D logistic map, which can facilitate the update, management, and transmission of the phase keys. Numerical simulation results demonstrate that the proposed cryptosystem is robust against various attacks and outperforms the other relevant cryptosystems. Furthermore, the proposed cryptosystem can be directly extended to encrypt multiple color images. PMID- 30461752 TI - Simultaneous measurement of displacement and temperature using a PMF-based dual Mach-Zehnder interferometer. AB - A dual Mach-Zehnder interferometer (MZI) based on polarization-maintaining fiber (PMF) is described for simultaneous measurement of displacement and temperature. Two orthogonal polarization components of a beam are simultaneously transmitted in the interferometer. The sensing configuration contains a short PMF section, a lens, and a mirror. The lens can transmit the slow polarization component and reflect the fast polarization component. Each polarization component exhibits a unique phase shift in response to changes in displacement and temperature, forming a dual MZI. Experimental results show that the resolutions of displacement and temperature are 60 pm and 2*10-3 degrees C, respectively, and measurement ranges of displacement and temperature can reach 20 cm and 70 degrees C. The experimental result demonstrates that there is no crosstalk between displacement and temperature, and high repeatability is demonstrated experimentally. This sensor allows multiparameter measurement, high resolution, wide measurement range, and good repeatability, conferring good application potential. PMID- 30461754 TI - Practical implementation of the sine condition test. AB - The effectiveness and predictability of the sine condition test (SCTest) as an alignment technique is explored and demonstrated. This paper shows the experimental results of an alignment of a three-mirror telescope using the SCTest. We discuss the results of this alignment and compare the predicted behavior with the measured behavior. The experimental results match the predictions to within the expected errors in the process. This practical implementation shows that the SCTest is an effective tool for system alignment and that the results can be accurately predicted. PMID- 30461755 TI - Highly sensitive displacement sensor based on composite interference established within a balloon-shaped bent multimode fiber structure. AB - A novel optical fiber displacement sensor based on composite interference established within a balloon-shaped bent multimode (BSBM) fiber structure is described and experimentally demonstrated. The BSBM fiber structure is realized by bending a straight single-mode-multimode-single-mode (SMS) fiber structure into a balloon shape using a length of capillary tube to fix the shape of the structure. Owing to the bend in the multimode waveguide, the original undistorted multimode interference pattern is changed, and an extra Mach-Zehnder interferometer is effectively introduced within the multimode fiber (MMF) section at a suitable bending radius. This established composite interference greatly improves the displacement sensing performance of the SMS fiber structure. A maximum displacement sensitivity of 0.51 dB/MUm over the displacement range of 0 100 MUm at the operating wavelength of 1564.7 nm is achieved experimentally. Based on its easy fabrication process, low cost, and high measurement sensitivity, the sensor of this investigation could be a realistic candidate in the high-accuracy displacement measurement field. PMID- 30461756 TI - Vacuum-compatible low-loss Faraday isolator for efficient squeezed-light injection in laser-interferometer-based gravitational-wave detectors. AB - In this paper, we present, to the best of our knowledge, the first low-loss vacuum-compatible thermally controlled Faraday isolator able to retain a good isolation factor under high-vacuum working conditions. The throughput that can be obtained with the developed device is as high as 99%, retaining an isolation factor higher than 40 dB. That very high isolation ratio can be kept over long time periods independently from external temperature conditions with a few Celsius degrees of variation due to thermal active control. The mechanical and optical configuration is detailed, and the performances achieved with this device are presented. PMID- 30461757 TI - Fast decoding algorithm for Gourlay-Young coded apertures. AB - A fast decoding algorithm is described for the class of flexible coded-aperture designs introduced by Gourlay and Young [Appl. Opt.23, 4111 (1984)APOPAI0003 693510.1364/AO.23.004111]. The algorithm significantly reduces the number of mathematical operations required to perform the decoding of images produced using these apertures compared to currently known methods, such as direct decoding, and hence speeds up the image reconstruction. Experimental tests confirm the efficacy of the fast decoding algorithm, which offers a speed-up enabling a typical 120*120 element aperture to be decoded in around 1% of the time required for direct decoding. PMID- 30461758 TI - Optofluidic variable optical attenuator controlled by electricity. AB - An optofluidic variable optical attenuator (VOA) is proposed in this paper, where the microfluidic driving technology adopts the electrically controlled way. The proposed driving technology solves some problems of existing microfluidic driving technologies and introduces a simple structure, a small volume, high precision, and a quick response for the VOA. This VOA has some advantages over other VOAs, such as a wide wavelength band (from visible light to the near infrared), a wide adjustable attenuation range, a low wavelength-dependent loss, and a quick response. The experiment results indicate that the attenuation range of this VOA is more than 80 dB and the wavelength-dependent loss is 0.09 dB at an attenuation of 20 dB in the C-band. Most VOAs have millisecond-scale response times, whereas the response time here is about 155-180 MUs. Our work shows a new way to design miniaturized VOAs with good performance and can also promote optofluidics. PMID- 30461759 TI - Properties of unidirectional absorption in one-dimensional plasma photonic crystals with ultra-wideband. AB - In this paper, the properties of tunable unidirectional absorption in one dimensional (1D) plasma photonic crystals (PPCs) are theoretically investigated by the transfer matrix method. The PPCs are composed of dielectric layers and non magnetized and magnetized plasma layers. The simulated results show that a unidirectional ultra-wideband absorption region (absorption rate is larger than 0.9) whose relative bandwidth is 36.2% can be obtained in the proposed 1D PPCs. The effects of the parameters of such PPCs on the features of the unidirectional absorption region (UAR) are also studied. The computed results illustrate that the obtained UARs can be tuned by those parameters as mentioned above, and also show us an alternative way to realize the reconfigurable unidirectional applications in the 1D PPCs. PMID- 30461760 TI - Multiple off-axis fiber Bragg gratings for 3D shape sensing. AB - Point-by-point femtosecond laser processed fiber Bragg gratings are arranged around the edge of a standard single-mode optical fiber core. The relative amplitudes of at least three such fiber Bragg gratings are utilized to detect the central position of the mode field within the fiber core and calculate the local curvature of the fiber. An analytical approximation is given, and an experimental validation is performed. PMID- 30461761 TI - Adaptive correction of retardations with immunity to alignment errors for a channeled spectropolarimeter. AB - Retardation errors of high-order retarders will decrease the accuracy of a channeled spectropolarimeter. Taniguchi et al. have proposed a self-calibration method to calibrate the retardations [Opt. Lett.31, 3279 (2006)OPLEDP0146 959210.1364/OL.31.003279]; however, they do not take into account the inevitable alignment errors of high-order retarders. In this paper, an adaptive correction method with immunity to alignment errors is proposed to reduce the effects of temperature variation on retardations. By separating and analyzing the amplitude terms and phase terms contained in the measurement data, the phase terms are utilized to correct the retardations, which makes the effectiveness of this adaptive correction method immune to the inevitable alignment errors of high order retarders. The adaptive correction process can be accomplished in parallel to the measurement process without any auxiliary resources. The effectiveness and feasibility of this method is verified by simulations and experiments. The convenience and simplicity of the presented method make it extremely suitable for application on track. PMID- 30461762 TI - Using spherical harmonics to describe large-angle freeform lenses. AB - We propose the use of spherical harmonics for large-angle freeform lenses as a dramatic improvement over polynomials set on the disk and plane, such as Zernike and X-Y polynomials. This new representation enables fitting of surfaces designed in spherical coordinates, such as freeform illumination lenses that would be impossible to describe with respect to a plane. The proposed representation is validated through an extremely compact, high-performance design. PMID- 30461763 TI - Delay-disorder fiber Bragg grating recognition and calibration method for a Fourier domain mode-locked wavelength-swept laser-based interrogation system. AB - Fourier domain mode-locking has been used in fiber Bragg grating interrogation for high-speed and long-distance measurement. But the delays induced by long fiber between multisensors and interrogation systems result in nonneglected wavelength error in this high-speed wavelength-swept system. More seriously, the cross-sweep cycle and different distance delays may cause the delay-disorder problem which makes the system unable to determine the order of the delayed peaks and unable to address the location of sensors with corresponding wavelength encoding characteristics. This paper proposes a novel delayed-peak recognition and calibration method in which the laser works at four different scanning rates. We confirm the relationship between delayed peaks and sensors with recognition parameters at two low rates and eliminate wavelength error at two high rates. Experimental results show that this method recognizes the delayed peaks correctly and calibrates wavelength accurately with error below 10 pm. PMID- 30461764 TI - Fast and precise 6D pose estimation of textureless objects using the point cloud and gray image. AB - Pose estimation for textureless objects is a challenging task in robotics, due to the scanty information of surfaces. In this paper, we design a vision system for fast and precise position and orientation measurement of textureless objects with a depth camera and a CCD camera. The corresponding process includes two parts: object segmentation in the point cloud and pose measurement in the gray image. Considering the relation between the object and its fixed panel, we first extract the panel in the point cloud by combining a random sample consensus algorithm with local surface normal. We then coarsely segment the possible area of the object based on an oriented bounding box. Finally, we transform the point cloud coordinates into the image coordinate system, and measure the precise pose of the object with a view-based matching method. Two types of cameras are brought together to make their respective advantages play well. The downscale method and coarse-to-fine strategy are utilized sufficiently to increase efficiency. Experiments show that our vision system achieves high pose measurement precision and enough efficiency. The average error is less than 2 mm for x and y, less than 4 mm for z, and 1 degrees in orientation, meeting the requirements for our robotic grasping task. PMID- 30461765 TI - Tunable temperature-dependent THz photonic bandgaps and localization mode engineering in 1D periodic and quasi-periodic structures with graded-index materials and InSb. AB - We present the tunability of terahertz (THz) photonic bandgaps and localization modes in one-dimensional (1D) periodic and quasi-periodic structures based on alternating layers of graded-index materials and InSb. These configurations show that operation frequencies of photonic bands and localization modes can be tuned by controlling temperature, structural and grading parameters, grading profiles, and different quasi-periodic arrangements. The number of photonic bands and localization modes can also be modulated with layer thickness and quasi-periodic arrangements. Changes in the grouping of the materials considered also modulate the operation frequencies of photonic bands and localization modes in quasi periodic structures. Results can be implemented to design thermo-tunable THz filters, reflectors, sensors, etc. PMID- 30461766 TI - All-in-fiber method of generating orbital angular momentum with helically symmetric fibers. AB - An all-in-fiber method of generating orbital angular momentum (OAM) is proposed. A simple device composed with a section of helically symmetric fiber and another section of regular fiber is designed to convert input light to optical vortices. Finite element method calculation of first- and second-order OAM generation based on the coordinates transformation technique is taken to show that the eigenmodes of the helically symmetric fiber structures carry orbital and spin angular momentum. Simulation using the self-developed beam propagation method algorithm is also performed to verify the orbital angular momentum generation and evaluate the performance of the OAM generator. PMID- 30461767 TI - Properties of dynamic image displacements based on microstructure. AB - The superposition structure of dynamic moire images contains a layer of micropattern array and a corresponding layer of microlens array. Dynamic moire images can be observed without special eyeglasses and will shift with variation of the viewing angle. In this work, it is described as a presentation of a variety of the moire. We chiefly investigate the motion effects of dynamic moire images. Analytical models to describe the structures and methods to evaluate the displacement of dynamic moire images are proposed. Experiments are conducted to validate the formula of the displacement. The results of this study are helpful to design dynamic moire images, which can be applied for potential applications in anti-counterfeiting films, packaging, and authentication. PMID- 30461768 TI - Transient processes under excitation of ultrashort laser pulses in colloidal solutions of CdSe/ZnS quantum dots. AB - We present that in the case of picosecond durations, the limitation efficiency of laser radiation and absorption kinetics in CdSe/ZnS colloidal solutions is determined by Auger relaxation through the 1S(e) states. In the observed kinetics of a probe-pulse transmission, the "delayed limitation" effect has been detected. Numerical modeling has made it possible to identify the competition between the next two relaxation processes of highly excited states: relaxation through size quantization levels and phononless relaxation through traps states. PMID- 30461769 TI - Controlling Goos-Hanchen shifts due to the surface plasmon effect in a hybrid system. AB - We have theoretically studied the Goos-Hanchen (GH) shifts of both the reflected and transmitted probe beams emerging from a cavity consisting of a hybrid system of a coupled quantum dot (QD) nanostructure and a metallic nanoparticle (MNP). It is realized that the GH shifts in the transmitted and reflected light beams can be enhanced due to the surface plasmon effect in the MNP. Also, it is shown that by adjusting the distance between QD and MNP and polarization control between probe field and major axis of the hybrid system, the simultaneous negative and positive GH shifts in reflected and transmitted light beams can occur. Moreover, the effects of the intensity and detuning of the coupling light on the GH shift properties of the reflected and transmitted lights have been discussed. We have found that under different parametric conditions of the hybrid system, the GH shifts of the reflected and transmitted light beams can be adjusted by tuning the intensity and controlling the detuning of the coupling field. The results show that our proposed model may be used for future optical sensor devices based on MNP hybrid systems. PMID- 30461770 TI - Variable step size adaptive cuckoo search optimization algorithm for phase diversity. AB - The phase diversity (PD) algorithm will eventually be converted into a large scale nonlinear numerical optimization problem, so the selection of numerical optimization algorithm will directly determine the accuracy and speed of the algorithm settlement. In this paper, we introduce the cuckoo search optimization algorithm, which has the advantages of simple model, few parameters, and easy implementation, to the phase diversity algorithm. By improving the step size control factor in the original cuckoo search algorithm, we can make it have faster optimization speed for PD. In the simulation experiments, we further proved and gave a simple explanation in theory that in the case of large-scale wavefront sensing, compared to the traditional particle swarm algorithm, this improved algorithm has higher accuracy and faster convergence speed. Finally, we set up a simple experimental system and proved the effectiveness of the improved cuckoo search algorithm for PD. PMID- 30461771 TI - Measurement investigation of an off-axis aspheric surface via a hybrid compensation method. AB - To measure the profile of an off-axis aspheric surface with large asphericity or lateral displacement, a hybrid compensation method is employed to realize a null test. First, the hybrid compensation method is simulated in MATLAB by using a fold sphere mirror and a computer-generated hologram (CGH) to compensate for the primary aberration and residual high-order aberration, respectively. For contrast, the hybrid compensation method is also simulated in Zemax by using dummy glass. Through comparing the simulation results from MATLAB and Zemax, the test CGH fringe positions from the two results are well matched. Then, the fold sphere mirror and CGH optical elements are designed and fabricated for an actual hybrid compensation measurement system, and the auto-collimation method is also used to detect the same off-axis aspheric surface. To ensure the correctness of the experiment, the result of actual hybrid compensation testing is contrasted with that of the auto-collimation method. Experiments show that the results obtained by the two methods are consistent, which indicates that this kind of hybrid compensation is an effective and accurate method for measurement of off axis aspheric surfaces. PMID- 30461772 TI - Quantum efficiency measurement of an x-ray charge-coupled device by means of an x ray generator monochromatized over the 0.2-1.2 keV spectral region. AB - The Atomic Energy Commission has been developing an x-ray calibration laboratory for several years close to the Laser MegaJoule Facility mainly to calibrate x-ray cameras. Based on x-ray generators, great effort is being carried out to obtain x ray monochromatic sources over the 0.1-10 keV spectral range. Moreover, their routine availability is a prerequisite while getting reduced uncertainties. To achieve this purpose, two x-ray monochromators have been recently developed, the former running below 1.5 keV and the latter in the harder x-ray region. The work presented in this paper constitutes, to the best of our knowledge, the first radiometric calibration of an x-ray camera, namely, a charge-coupled device (CCD). The CCD is thin and back illuminated with a 1300*1340 pixel, 20 MUm*20 MUm area. It has been calibrated by means of our soft x-ray monochromator based on Rowland circle geometry. This apparatus is able to take on board simultaneously two detectors under vacuum: the CCD to be calibrated and a silicon drift spectrometer (SDD), which acts as a reference detector to obtain the x-ray monochromatic intensity. An internal specific vacuum manipulator allows putting successively each detector in front of the scanning exit slit. Quantum efficiency (QE) of the CCD has thus been measured over the 0.2-1.2 keV region, due to the reference SDD. The latter was previously calibrated on the same monochromator by cross-calibration with another SDD calibrated at the Physikalisch-Technische Bundesanstalt (PTB) Radiometry Laboratory, on the synchrotron radiation facility BESSY. QE measurements are then compared to the CCD manufacturer's model and with previous ones performed on the same camera by means of our hard x-ray monochromator (2-10 keV). Comparison of these results with further PTB efficiency calibration of the reference SDD used to calibrate the CCD is discussed and allows concluding definitively about the validity of measurements performed by our x-ray monochromators. PMID- 30461773 TI - Passive Q switching of Yb:CNGS lasers by Cr4+:YAG and V3+:YAG saturable absorbers. AB - Trigonal langasite-type ordered silicate crystal Yb:Ca3NbGa3Si2O14 (Yb:CNGS) is a promising material for efficient ~1 MUm lasers. We report on the first passively Q-switched Yb:CNGS laser using Cr4+:YAG and V3+:YAG saturable absorbers (SAs) with a 976 nm volume-Bragg-grating-stabilized diode as a pump source. The laser crystal was a c cut 3 at.% Yb:CNGS grown by the Czochralski method. It was placed in a compact microchip-type laser cavity. With a Cr4+:YAG SA, very stable 62.2 MUJ/4.4 ns pulses were achieved at a repetition rate of 22.5 kHz. The average output power was 1.40 W at 1015.3 nm, corresponding to a Q switching conversion efficiency of 90%. With the V3+:YAG SA, the pulse characteristics were 13.3 MUJ/11.1 ns at a higher repetition rate of 68.4 kHz. The performance of the Yb:CNGS/Cr4+:YAG was numerically modeled showing a good agreement with the experiment. PMID- 30461774 TI - Narrowband wavelength selective waveguide for see-through glasses. AB - See-through glasses are a new type of portable mobile device; however, most existing designs cannot balance the requirements of field of view (FOV), optical efficiency, and system volume at the same time. Here we propose a design for ultra-compact see-through glasses by using a waveguide with embedded narrowband minus filters as the optical combiner. The optical combiner demonstrates wavelength selectivity and optional narrowband(s) and is based on inorganic materials. Compelling advantages of our approach are high light efficiency, stray ray suppression, full-color capacity, good stability, and low cost. A detailed calculation model is provided for analysis of the optical properties of the waveguide, and a proof-of-concept prototype is demonstrated that can convey a horizontal FOV of 31.4 degrees . The FOV can be further enlarged by parameter adjustments. PMID- 30461775 TI - Deep learning-based object classification through multimode fiber via a CNN architecture SpeckleNet. AB - With the fast development of deep learning, its performance in image classification and object recognition has presented dramatic improvements. These promising results could also be applied to better understand speckle patterns in scattering media imaging. In this paper, a multimode fiber is used as the scattering media, and 4000 face and nonface original images are transmitted generating speckle patterns. A SpeckleNet is proposed and trained with these 3600 speckle patterns based on a convolutional neural network, and its output layer is activated for a support vector machine (SVM) classifier. The binary classification accuracy of the proposed CNN-architecture SpeckleNet for face and nonface speckle patterns classification tested on another 400 speckle patterns is about 96%, which has been improved compared with the accuracy of the pure SVM method. The promising results confirm that the combination with deep learning could lead to lower optical and computation costs in optical sensing and contribute to practical applications in optics. PMID- 30461776 TI - Design of a sensitive uncooled thermal imager based on a liquid crystal Fabry Perot interferometer. AB - Microbolometers are the dominant technology for uncooled thermal imaging; however, devices based on a direct retardation measurement of a liquid crystal (LC) transducer pixel have been shown to have comparable sensitivity. In this paper, an approach for increasing LC transducer sensitivity utilizing an etalon structure is considered. A detailed design for an LC resonant cavity between dielectric mirrors is proposed and the performance is evaluated numerically. The measured quantity is the transmission of a visible wavelength through the etalon, which requires no thermal contact with the IR sensor. Numerical and analytical calculations that consider a 470 nm thick LC pixel demonstrate that the change in transmitted intensity with temperature is 26 times greater in the device based on a resonant structure than in a device based on a direct retardation measurement. Finally, the paper discusses how the dielectric mirror materials, dimensions of the resonant cavity structure, and expected process tolerances affect the sensitivity of the device. PMID- 30461777 TI - Potential use of surface-assisted LIBS for determination of strontium in wines. AB - Laser-induced breakdown spectroscopy (LIBS) is a well-established technique for elemental analysis and has been widely used for qualitative and quantitative analysis of different solid samples. LIBS is also well-known for not requiring sample preparation, but the analysis of liquids is actually a great challenge. In the present work, a novel approach of elemental analysis of liquids with an organic matrix has been performed, to the best of our knowledge, making a liquid to-solid matrix conversion by drying wine samples on aluminum and silicon wafers, which have demonstrated an increase in the analytical performance of LIBS. A red wine from Slovakia (not blended with any other variety or wine from other regions or adulterants) was prepared according to the procedure consisting of drying 2 ml of wine dropped on a solid wafer having a flat surface area of about 25 cm2. Surface-assisted LIBS in combination with the conversion of liquid into solid avoids the difficulties and limitations of working with liquid samples by LIBS, improving the limit of detection (LOD), repeatability, and sensitivity. The quantification of strontium (Sr) has been realized by addition of the known concentration of SrCl2.6H2O in wine before the drying process. Sr is an important element among those usually used as markers for identification of the soils on which the vines grow. Two ionic (407.771 nm and 421.552 nm) and two neutral (460.733 nm and 481.188 nm) Sr lines were used to plot the calibration curves in order to study the LODs and the matrix effects for the analysis of Sr in the tested wines and for different wafer materials. This direct surface-assisted LIBS measuring method has been successfully applied for the determination of Sr in a red wine sample from Slovakia, and the obtained results with two kinds of substrates (Al and Si) were compared. Finally, a validation sample has been employed to test the accuracy of the established calibration curves. PMID- 30461778 TI - Lidar algorithms in 3D scanning for atmospheric layering and planetary boundary layer height retrieval: comparison with other techniques. AB - The planetary boundary layer height (PBLH), of great importance in meteorology and atmospheric physics, is strongly correlated with the geographical location, the solar irradiance, the seasonal variations, and the variability of the weather phenomena. So far, several lidar techniques have been developed to detect the PBLH, besides the radio soundings, sodars, or other techniques. In this work we propose new algorithms to provide the PBLH in near real time using a three dimensional lidar in vertical or slant pointing. We show that the proposed variable space-time and vertical decision algorithms are able to estimate the PBLH under various meteorological conditions of more than 80% of the cases studied. Furthermore, these algorithms are user friendly (user adjustable), and they work automatically at any location and period of the year for any vertically/slant pointing lidar system. These algorithms are extremely helpful for meteorologists, airport tower controllers, and atmospheric scientists and in general for the remote sensing community. PMID- 30461779 TI - Passively Q-switched Yb-doped dual-wavelength fiber laser based on a gold nanocage saturable absorber. AB - In this paper, we demonstrate a passively Q-switched Yb-doped dual-wavelength fiber laser using gold nanocages (GNCs) as a saturable absorber. The GNCs are prepared by the seed-mediated method with modulation depth of 5.3% and saturable intensity of 0.16 MW/cm2. A simultaneous dual-wavelength operation is achieved at 1059.9 and 1060.5 nm with 3 dB bandwidths of 0.05 and 0.04 nm, respectively. A maximum average output power of 6.03 mW with minimum pulse width of 2.06 MUs and maximum repetition rate of 134.9 kHz is obtained at a pump power of 385 mW, corresponding to optical-to-optical conversion efficiency of 1.57% and slope efficiency of 2.75%. PMID- 30461780 TI - SHADOWS: a spectro-gonio radiometer for bidirectional reflectance studies of dark meteorites and terrestrial analogs: design, calibrations, and performances on challenging surfaces. AB - We have developed a new spectro-gonio radiometer, SHADOWS, to study in the laboratory the bidirectional reflectance distribution function of dark and precious samples. The instrument operates over a wide spectral range from the visible to the near-infrared (350-5000 nm) and is installed in a cold room to operate at a temperature as low as -20 degrees C. The high flux monochromatic beam is focused on the sample, resulting in an illumination spot of about 5.2 mm in diameter. The reflected light is measured by two detectors with high sensitivity (down to 0.005% in reflectance) and absolute accuracy of 1%. The illumination and observations angles, including azimuth, can be varied over wide ranges. This paper presents the scientific and technical constraints of the spectro-gonio radiometer, its design and additional capabilities, as well as the performances and limitations of the instrument. PMID- 30461781 TI - Laser-induced breakdown spectroscopy assisted chemometric methods for rice geographic origin classification. AB - The problems of adulteration and mislabeling are very common in the food industry. Laser-induced breakdown spectroscopy (LIBS) coupled with chemometric methods has many intrinsic advantages on adulteration analysis of various materials. In this work, several chemometric algorithms, i.e., principal component analysis (PCA), decision tree (DT), random forest (RF), partial least squares discriminant analysis (PLS-DA), linear discriminant analysis (LDA), and support vector machine (SVM), were carried out assisted by LIBS technology to study the classification performances on rice geographic origins. A series of samples, including 20 kinds of rice samples from different geographic origins, was detected using LIBS with no pretreatment processes. For data analysis, PCA was employed to reduce the input variables, and to reduce the collinearity of LIBS spectral results as well. The results showed the classification accuracies of the mentioned chemometric algorithms of DT, RF, PLS-DA, LDA, and SVM with 89 input variables of 86.80%, 96.30%, 96.80%, 98.60%, and 99.20%, respectively. At the same time, the operation times of these algorithms were 3.81 s, 54.64 s, 3.63 s, 2.09 s, and 531.01 s, respectively. On the other hand, 30 principal components of input variables were also tested under the same conditions. The classification accuracies for the above algorithms were 81.60%, 98.00%, 95.70%, 98.40%, and 99.20%, respectively. The operation times were 2.01 s, 4.88 s, 3.67 s, 0.36 s, and 308.55 s, respectively. In addition, the five-fold cross-validation classification accuracies with 30 input variables for DT, RF, PLS-DA, LDA, and SVM were 83.75%, 97.95%, 94.75%, 98.35%, and 99.25%, respectively. As a result, LDA was demonstrated to be the best and most efficient tool for rice geographic origin classification assisted by LIBS with high accuracy and analytical speed, which has great potential for rapid identification of adulterated products in agriculture without use of any chemical reagent. PMID- 30461782 TI - Modeling method of a ladar scene projector based on physically based rendering technology. AB - The ladar scene projector is a key device in the hardware-in-the-loop (HWIL) simulation system. Ladar scene modeling is a fundamental work of developing a ladar scene projector. A modeling method based on physically based rendering technology and OpenGL is proposed in this paper. This modeling method can quickly generate delay, amplitude, and pulse width data for all return signals in a large array-scale ladar scene. A 100*100-array-sized ladar scene model with a distance range of 0-3 km is simulated. The average data generation time is only 5.31 ms. Distance resolution is 1.5 m, and the peak-valley error is less than 0.15 m. This method achieves efficient modeling and fast hardware update rates, which greatly improves the real-time performance of the ladar scene projector. It has strong practicality and can be directly applied in the HWIL simulation system. PMID- 30461783 TI - Experimental study of the turbulence effect on underwater optical wireless communications. AB - Underwater optical wireless communications (UOWC) performance is affected by turbulence. However, not much research has been carried out to estimate the probability density function (PDF) of the received optical power. In this paper, we investigate the effect of turbulence on the UOWC system using a new experimental setup with a variable link span in a water pool. Different turbulence levels are created by changing the temperature and the rate of an injected water flow in the pool water to obtain the PDF. Results show that lognormal distribution closely matches the measured PDF for a range of link spans. In UOWC systems, the link span is one of the main factors influencing fluctuations of the received optical power, and it has not been thoroughly investigated. In this work, the scintillation index and turbulence-induced power loss are obtained for a range of turbulence strengths and transmission link spans. Finally, we show that there is a good agreement between the experimental and simulated results. PMID- 30461784 TI - Effect of deviation from purely transverse and longitudinal polarization states of acoustic waves on the anisotropy of acousto-optic figure of merit: the case of Tl3AsS4 crystals. AB - We analyze the effect of acoustic wave (AW) polarization states deviation from purely longitudinal and transverse on the anisotropy of the acousto-optic (AO) figure of merit for the case of AO interactions occurring in the principal crystallographic planes. In particular, we obtain phenomenological relations that describe the effective elasto-optic coefficient for the six types of AO interactions, which exhaust all of the possible isotropic AO diffractions. These relations are compared for the alternative cases when the deviations of polarization of the AWs from purely longitudinal and transverse ones are either taken into consideration or completely neglected. Our analysis carried out on the example of Tl3AsS4 crystals reveals that the deviation of AW polarization from its pure states influences the anisotropy of the AO figure of merit only when the AO interactions with quasi-transverse AWs are dealt with. This fact is caused by the peculiar acoustic and elasto-optic properties of Tl3AsS4. On the other hand, the situation can become different for other crystalline materials, where the angular dependences of the AO figure of merit can differ significantly in cases in which the deviation angle increases. This holds true for the AO interactions with both quasi-transverse and quasi-longitudinal AWs. Under these conditions, non-orthogonality of the AWs (or deviation from their longitudinal polarization states) affects essentially the AO characteristics. Finally, we determine the geometries of AO interactions for which the highest AO figures of merit are reached for the Tl3AsS4 crystals. PMID- 30461786 TI - Simultaneous interrogation of multiple fiber Bragg grating temperature sensors using a microwave photonic approach. AB - In this paper, we demonstrate a microwave photonic (MWP) approach for interrogating multiple linearly chirped fiber Bragg grating (LCFBG) temperature sensors. The MWP interrogation system is based on an arrayed waveguide grating Sagnac interferometer, incorporating multiple LCFBG sensors, that is used to generate multiple chirped microwave waveforms whose characteristics are uniquely related to those of the LCFBGs. Compressing the generated microwave signals allows monitoring simultaneously and independently the shifts associated with applying temperature changes to each LCFBG in real time. PMID- 30461785 TI - Ultralong photonic nanojet formed by dielectric microtoroid structure. AB - A photonic nanojet (PNJ) is a highly confined light beam formed by a transparent particle under light wave illumination. Here, we propose and numerically investigate the PNJ formed by a dielectric circular toroid with micro dimensions and a homogenous refractive index. Three-dimensional finite-difference time domain (FDTD) simulations are conducted and demonstrate that ultralong PNJs can be formed by the doughnut-like structure. Besides, microtoroid structures can allow high-index materials (n=3.5) for PNJ generation. Various PNJ properties, including the focal distance, PNJ length, full width at half-maximum, and maximum intensity, can be flexibly tuned by modifying the geometry of the proposed structure. PMID- 30461787 TI - Highly sensitive electro-optic probe incorporating an ultra-high Q-factor LiNbO3 etalon. AB - A highly sensitive electro-optic (EO) probe has been proposed and realized by tethering an ultra-high-quality (Q)-factor LiNbO3 etalon to a single-mode fiber operating at around a 1550-nm wavelength. For the adopted EO etalon, the electric field-induced refractive index modification is deemed to shift its own spectral response. An electrical modulation signal is anticipated to be produced when a probe light beam with a fixed bias wavelength impinges upon the EO etalon. The EO etalon is particularly required to exhibit a remarkably steep spectral response and thus facilitate modulation efficiency. In aiming to scrutinize the performance in terms of sensitivity, two EO probes involving profoundly different Q-factors were prepared and applied to detect the electric field emitted from a microstrip device. It was confirmed that the sensitivity could be efficiently enhanced by as much as 28 dB by boosting the Q-factor 18 times when a probe light beam operating at =~1550 nm was properly collimated and polarized. Accordingly, the minimum detectable signal was successfully diminished. PMID- 30461788 TI - Highly sensitive dual-core photonic crystal fiber based on a surface plasmon resonance sensor with a silver nano-continuous grating. AB - Two kinds of photonic crystal fiber (PCF) sensors based on surface plasmon resonance (SPR) with silver nano-continuous gratings (i) and (ii) are designed. The coupling characteristics and sensing properties are analyzed numerically by the finite element method (FEM). The results show that the proposed sensor based on silver nano-continuous grating (i) can achieve better performance than that of the sensors based on silver nano-continuous grating (ii) and plane silver film structures. When the segmented number is 50 and segmented angle is 0.5 degrees , a wavelength sensitivity of the proposed sensor with silver nano-continuous grating (i) is obtained as high as 13,600 nm/RIU in the refractive index (RI) range from 1.330 to 1.365, corresponding to a maximum RI resolution of 7.35*10-6 RIU, which can have promising applications in medical and environmental monitoring and biochemical detection. PMID- 30461789 TI - Error characteristic analysis and experimental research on a fiber optic current transformer. AB - To solve the operation precision problem of a fiber optic current transformer (FOCT), we have established models of the polarization error based on the Jones matrix and a model of the temperature drift error taking into account the bending characteristics. The polarization study shows that a greater extinction ratio of the polarizer and analyzer and a smaller deviation of the polarization direction lead to a smaller output error. Temperature analysis suggests that greater intrinsic linear birefringence, a smaller bending radius, and more winding turns of the sensing fiber should exacerbate temperature drift and reduce the temperature range to meet an accuracy of class 0.2. Furthermore, we have constructed an experimental platform and performed current tests for different extinction ratios, polarization direction deviations, and temperature conditions. The experimental results confirm the effectiveness of the theoretical analysis. PMID- 30461790 TI - Determination of Pb in soils by double-pulse laser-induced breakdown spectroscopy assisted by continuum wave-diode laser-induced fluorescence. AB - Laser-induced breakdown spectroscopy (LIBS) has attracted a lot of attention due to its potential to rapidly identify and quantify any chemical element with minimal sample preparation. Despite continuous improvements, the sensitivity of this technique still remains a challenge. In order to increase LIBS intensity, a laser-induced fluorescence (LIF) system can be coupled with LIBS to re-excite a transition of the element in the plasma by employing very expensive optical parametric oscillators (OPO). In this work, a homemade tunable continuum wave diode laser (CW-DL) has been developed and coupled to a double pulse (DP) LIBS system to enhance the sensitivity of Pb detection in a soil sample at the transition 6s26p2-P32->6s26p7s-P31 at 405.78 nm. Before sample analysis, the production of no scattered light by the plasma was ascertained, and the optimal temperature of 10,000 K was estimated for this transition, feasible to be achieved in DP-LIBS systems. An increase of approximately 100% for the Pb I transition at 405.78 nm was obtained by DP-LIBS-CW-DL-LIF with respect to the DP LIBS system alone. This result opens a new promising line of research to improve LIBS sensitivity using the CW-DL approach. PMID- 30461791 TI - Analysis of 90 day operation of the GINGERINO gyroscope: publisher's note. AB - This publisher's note identifies a figure error in Appl. Opt.57, 5844 (2018)APOPAI0003-693510.1364/AO.57.005844. PMID- 30461792 TI - Optimization of a spatial light modulator driven by digital video interface graphics to generate holographic optical traps. AB - We propose a method to optimize spatial light modulators (SLMs) driven by digital video interface graphics in a holographic optical tweezers system. A method analogous to that used to optimize LCD televisions is used to optimize the properties of the graphics card through a diffraction-based experiment and develop a lookup table for the SLM. The optimization allows the SLM to function with its full phase modulation depth with improved diffraction efficiency. Further, we propose a simple and robust method to correct for the spatially varying phase response of the SLM to enhance its diffraction efficiency. The optimization results in an improvement of uniformity in the intensity and quality of the trap spots. PMID- 30461793 TI - Vision solution for an assisted puncture robotics system positioning. AB - Medical robotics and computer-assisted surgery are hotspots in the field of robotics and medicine, changing the essence of traditional surgery using a combination of robotic, image processing, and computer technologies. The present paper aimed to study the auxiliary puncture procedure using a robot based on binocular vision optical positioning technology that can be used in minimally invasive surgery for coordinate precision of skin markers. ZED binocular cameras were selected for image acquisition and a model was established based on Zhang's calibration. Moreover, a Hough circle detection algorithm was proposed for binocular stereo image feature extraction to obtain the marker points in three dimensional space coordinates. Accurate marker coordinate information for a human 3D bone model was obtained, laying the foundation for further research regarding robot-assisted precise positioning technology for use in puncture surgery. PMID- 30461794 TI - Optical modeling of the emission zone profile and optimal emitter position based on the internal field profile of the air mode in organic light-emitting diodes. AB - We propose a theoretical formulation to calculate the internal profile of the air mode in the organic light-emitting diode (OLED) on the combination of the transfer matrix method and source-term method. The spatial distributions of the air mode are calculated in a top-emitting OLED with respect to the light polarization, extraction angle, dipole orientation, and dipole position. Air modes are also calculated on the basis of the previously used external source model, where the input optical wave is injected from the air into the OLED multilayer. Comparison of the calculated air modes between two models checks the validity of the external source model. In addition, we propose an improved formula to determine the optimal emitter positions that maximize the two-beam interference of the micro-cavity effect. In the improved formula, a non-ideal reflection phase shift at a reflective metal anode is treated as the skin depth of the air mode. Finally, the effect of the dipole orientation on the air mode is investigated. Compared with the air mode emitted by the horizontally oriented dipole, the air mode generated by the vertically oriented dipole has relatively small intensity and shows the opposite dependence of the emitter position variation. The calculation results of the internal profile of the air mode within the emission layer are matched with the profile of the emission zone obtained by output radiant flux on the basis of the currently used point dipole model. PMID- 30461795 TI - Effect of submount thickness on near-field bowing of laser diode arrays. AB - Near-field bowing a laser diode bar (i.e., the "SMILE" effect) degrades the laser beam brightness, adversely affecting optical coupling and beam shaping. Due to thermally induced stress during the bonding process, the emitters in a laser diode array (LDA) are vertically displaced, which causes the SMILE effect. The mismatch between the coefficients of thermal expansion of an LDA (GaAs with 6.4 ppm/K) and a heat sink (Cu with 16.4 ppm/K) is a large obstacle in the LDA bonding process, because it provokes thermal stress and a large SMILE value, resulting in a larger divergence angle and a wider line after focusing and collimation. In this paper, the changes in stress and strain (SMILE value) and their effects on the laser bar as a function of the copper-tungsten (CuW) submount thickness were theoretically and experimentally studied. The finite element modeling simulations and experimental results show that the compression stress on the laser bar decreases with increasing CuW submount thickness because the CuW submount works as a buffer layer and can absorb stress. However, the laser bar out-of-plane strain (SMILE value) is approximately zero when the LDA is directly bonded onto the heat sink without a submount; the SMILE value is maximized when the CuW submount thickness is increased to approximately one half or 44% of the heat sink. Beyond that, the SMILE value decreases with increasing CuW submount thickness. PMID- 30461796 TI - High power picosecond parametric mid-IR source tunable between 1.7 and 2.6 MUm. AB - A high-average-power wavelength-tunable picosecond mid-IR source based on parametric downconversion has been developed. The conversion system consists of two stages, optical parametric generator and optical parametric amplifier (OPA), which are pumped by an Yb:YAG thin-disk laser operated at 77 kHz repetition rate, 1030 nm wavelength, and pulse duration down to 1.3 ps. The signal beam is amplified up to 9.2 W and the idler up to 5.4 W at OPA pumping of 43 W. Tunability between 1.70 and 1.95 MUm for the signal and between 2.2 and 2.6 MUm for the idler has been achieved. The system is rather simple and power scalable. PMID- 30461797 TI - Nonparaxial propagation of abruptly autofocusing circular Pearcey Gaussian beams. AB - We introduce a new class of abruptly autofocusing circular Pearcey Gaussian beams (AAFCPGBs) which tend to be abruptly autofocusing circular Pearcey beams with a small distribution factor, or Gaussian beams with a larger distribution factor. The nonparaxial propagation of the AAFCPGBs is investigated by numerical calculation. The radiation force of the AAFCPGBs exerted on a Rayleigh particle is analyzed in detail. PMID- 30461798 TI - Study on extended depth of field for a planar flow cytometric microimaging system. AB - A planar flow cytometric microimaging system is mainly used for cell recognition and classification in urinary sediment and gynecological secretion analysis. The depth of field (DOF) of the microscope seriously restricts its imaging range in the direction of the optical axis, rendering it incapable of imaging all the cells in the whole laminar thickness of the planar flow cytometric microimaging system. In this paper, the DOF is extended by using dual sensors with a common light path, and imaging of high-speed moving cells at a large DOF is realized, thus solving the difficulty that the multifocus super-depth technique can only be used in a static observation sample. A fusion algorithm based on saliency detection and multiscale image decomposition is developed to fuse the dual-depth of-field images. The multiscale image decomposition uses L0 smoothing for multiscale image decomposition. L0 smoothing is particularly effective in sharpening major edges by increasing the steepness of transition, while eliminating a manageable degree of low-amplitude structures. It can globally control the number of non-zero gradients that result in an approximately prominent structure in a sparsity-control approach; this does not depend on the local features, instead it locates important edges globally. Experimental results show that our approach can enlarge the DOF 1.89 times, and the dual-DOF fusion algorithm can fuse two images with different DOFs into one image with clear multiple targets. PMID- 30461799 TI - Optical properties of a Cr/4H-SiC photodetector in the spectral range from ultraviolet to extreme ultraviolet. AB - This work examines the electrical and radiometric characteristics of a photodiode based on a 4H-SiC semiconductor material with a semitransparent Cr Schottky barrier of about 7 nm thickness. The device had a photosensitive area 10 mm in diameter. The spectral responsivity was determined in the wavelength range from 40 nm to 400 nm, thus particularly extending the characterization into the vacuum and extreme ultraviolet spectral ranges. The photodiode showed a maximum quantum efficiency of 50% at 253 nm with a relative uniformity of 4% in the photosensitivity over its surface. The linearity of the photoresponse was measured at wavelengths of 70 nm and 265 nm for incident radiant powers from 2 nW to 800 nW, and no significant deviation from linearity was found. Regarding its electrical characteristics, the photodiode showed less than 10-13 A dark current at a reverse voltage of 10 V. PMID- 30461800 TI - Multiscale modeling of fiber optic gyroscope temperature drift based on improved ensemble empirical mode decomposition. AB - Temperature drift is a major error source of the fiber optic gyroscope (FOG), and the method of modeling is important in eliminating it. A method of multiscale modeling based on improved ensemble empirical mode decomposition (EEMD) is proposed in this paper. First, in order to improve the ability of eliminating mode mixing, the influence of the frequency of the masking signal on mode mixing is analyzed. Then we conclude that the frequency of the masking signal should be higher than that of the signal, and an improved EEMD is proposed based on the conclusion. Second, the temperature drift of FOG is filtered by applying the permutation entropy to the intrinsic mode functions (IMFs). Third, the IMFs are divided into several scales according to the mean value and the distribution of instantaneous frequency of IMFs. Finally, the algorithm of the support vector machine is used to model each scale, and the models are accumulated into a total model. The regression error after compensation of the proposed method (in the case of the mean squared error indicator) increased by more than two orders of magnitude compared to the original temperature drift. PMID- 30461801 TI - Trade study of aperture size, adaptive optics and multiple spatial modes for a polarization entanglement QKD system over a 30 km maritime channel. AB - Transmitting a beam through the atmosphere over long distances can be a challenging problem. Factors from the channel, such as atmospheric turbulence causing beam wander and distortions to the wavefront, or the optical design can change the loss induced in the channel. This work simulates a quantum key distribution system implementing the BB84 protocol with entangled photons operating over a 30 km maritime channel using one, four, and nine spatial modes. For the cases of multiple spatial modes, atmospheric turbulence increases the channel cross talk, resulting in an increase in the noise for each channel. To compensate for distortions in the wavefront, adaptive optics at the transmitter or receiver are used to pre- or post-correct the wavefront. PMID- 30461802 TI - Parallel superposition of phase holograms for multiple parameters identification. AB - A method to identify the azimuthal index of vortices and the radial parameter of axicons, as well as their associated spatial frequencies, is presented. These constructive parameters are employed to design parallel superimposed computer generated holograms (PSCGHs). The diffraction patterns are studied in correspondence with the constructive parameters of the PSCGH. Another diffractive structure serving as identification key is inserted in the entire beam emerging from the PSCGH. The method identifies the parameters set in the first and second diffraction orders. The robustness and sensitivity of the method were checked against parameter mismatches. This method can be exploited as an authentication tool for holographic stamps incorporating PSCGHs. PMID- 30461803 TI - VCSEL mode and polarization control by an elliptic dielectric mode filter. AB - In this paper, we demonstrate the effectiveness of polarization mode control in vertical-cavity surface-emitting lasers (VCSELs) with integrated elliptic dielectric mode filters. The single-mode single-polarization laser operation is obtained by an irregularly shaped oval dielectric mode filter, aimed at cost effective mass production. The orthogonal polarization suppression ratio was measured to be 16.7 dB, and the side-mode suppression ratio exceeded 30 dB. A single fundamental mode power of 0.55 mW was achieved at a bias current of 4 mA. We compared the spectra and near-field intensities of the dielectric mode filter VCSEL with a reference device. The comparison clearly indicates the effectiveness of our dielectric mode filter in controlling the transverse- and polarization mode properties of VCSELs. PMID- 30461804 TI - Enhanced and broadened fluorescence of ZnSe quantum dots enabled by the fluorescence energy transfer system of ZnSe quantum dots and gold nanoparticles. AB - The enhanced and broadened fluorescence of ZnSe quantum dots (QDs) were studied by using a fluorescence energy transfer system (FETS) of ZnSe QDs and gold nanoparticles (NPs). The FETS were prepared via uniformly dispersing the gold nanoparticles into ZnSe QD solution in the condition of magnetic stirring. Enhanced and broadened fluorescence was observed on the film of the FETS due to the transfer of photo-generated carriers between the ZnSe QDs and the gold NPs, instead of the surface plasma resonance effect. The excitonic and enhanced fluorescence on the FETS film depended on the competition of electron-hole recombination and electron transfer from the ZnSe QDs to the gold NPs. In addition, because of the excitonic fluorescence of the ZnSe QDs absorbed by the gold NPs, the electrons of the s-p band of the gold NPs were further increased to facilitate its energy level shift toward the conduction band of the ZnSe QDs in order to create a blueshift in the enhanced fluorescence. This enhanced and broadened fluorescence method can be applied for controlling fluorescence in photoelectric detection, photodiodes, lightshows, and sensor devices. PMID- 30461805 TI - Quarter-mode spoof plasmonic resonator for a microfluidic chemical sensor. AB - In this paper, we propose a microfluidic chemical sensor based on quarter-mode spoof plasmonic resonators with more compact overall size and higher sensitivity. First, a microfluidic channel engraved on polydimethylsiloxane is aligned to the upper part of the spoof plasmonic metal-insulator-metal (MIM) ring resonator where the strongest electric fields are observed at resonance. Although a resonant frequency shift of 270 MHz has been observed when the microfluidic channel is filled with pure ethanol, there is no resonant frequency shift when the ethanol concentration is changed from 40% to 60%. Then the spoof localized surface plasmons modes on the quarter corrugated MIM ring are analyzed, and a microfluidic sensor based on the quarter-mode spoof plasmonic resonator has been proposed. The proposed microfluidic sensor requires a very small amount (3.9 MUL) of liquid for testing. After infilling the microfluidic channel with pure ethanol, the resonant frequency shift of 940 MHz has been observed on account of the dielectric changes. It is observed that the resonant frequency of the proposed sensor shifts from 5.07 to 6.62 GHz when the ethanol concentration is varied from 10% to 90%. It has been demonstrated that such quarter-mode spoof plasmonic resonator is well suited to a highly sensitive and compact microfluidic chemical sensor. PMID- 30461806 TI - Research on the optimal optical attenuation in a laser radar using a Geiger-mode APD. AB - For a laser radar (LADAR) system using a Geiger-mode avalanche photodiode (GmAPD), attenuating echo and background noise simultaneously affect the original data output from the GmAPD and eventually affect detection performance. In this study, we established a model that applies to the GmAPD-based LADAR with optical attenuation and also applies to any typical single photon detector that has a dead time (e.g., the photomultiplier tube); thus, a comprehensive and fundamental study is performed for the mathematical expectation of the number of signal detections (ES), the mathematical expectation of the number of noise detections (EN), the signal-to-noise ratio (SNR), and the range bias (absolute error, Rb) and precision (standard deviation, Rp) under various attenuation levels with different dead times and signal noise conditions. We observed the following: on the one hand, there exists an optimum attenuation level at which ES and SNR are maximized; on the other hand, there exists another optimum attenuation level for shorter dead times, at which Rp is minimized. The phenomenon of the maximum ES, SNR, or minimum Rp disappears gradually as the echo or noise decreases from high levels (e.g., 10 photoelectrons/echo or an equivalent background noise of 10 photoelectrons/range gate). Further, higher attenuation, which shows advantages under strong echo or noise conditions, yields a larger improvement in ES for longer dead times; and, with the reduction of the dead time or the noise, the maximum ES gradually increases, and the corresponding optimum attenuation level becomes slighter. Additionally, we found that, as the optical attenuation increases, EN decreases to 0, Rb changes from a negative value to 0, and Rp is minimized, becomes slightly worse, and reaches a constant. Moreover, the shorter dead times, which show advantages when they are shorter than the end time of the echo, lead to a larger ES, better Rb, and slightly worse Rp than the longer ones. PMID- 30461807 TI - Characterization and optimization of a tapered amplifier by its spectra through a long multi-pass rubidium absorption cell. AB - We present a method to characterize and optimize a tapered-amplifier laser system (TALS) by its spectral quality through a long multi-pass rubidium absorption cell. A thermal vapor cell is used to measure the non-resonant spectrum of TALS, including the broadband amplified spontaneous emission (ASE), which is its main spectral noise. This method gives a simple quantified measurement to optimize various working parameters of a TA, including current and temperature online. It can as well be used to compare various TA chips based on their usage time during our precision measurement experiments. The results of this method are compared and found in sync with traditional methods of Fabry-Perot cavity and beat measurements. Such characterization and optimization are important for noise control in atom interferometers, atomic clocks, and other atomic manipulations. It can very well be used for investigating nonlinearity and ASE inside amplifying chips and can be utilized in other applications of ASE using bioimaging. PMID- 30461808 TI - Structural changes and electrical properties of nanowelded multiwalled carbon nanotube junctions. AB - This study proposes an efficient approach that uses a 1064 nm continuous fiber laser to achieve nanoscale welding of crossed multiwalled carbon nanotubes (MWCNTs). We investigate the effects of laser irradiation time (from 1 to 6 s) on the structure changes and the welding quality of crossed MWCNTs using a scanning electron microscope, transmission electron microscope, and Raman spectroscopy. The experimental results demonstrate that (1) after 2 or 3 s laser irradiation, moderate temperature of MWCNTs can be formed and can cause a higher degree of graphitization and (2) the degree of graphitization and effective contact of nanowelded MWCNT junctions strongly affects its electrical properties. PMID- 30461809 TI - Phase-matching properties of BaGa2GeSe6 for three-wave interactions in the 0.778 10.5910 MUm spectral range. AB - We present new experimental results for the phase-matching properties of the recently discovered BaGa2GeSe6 crystal for harmonic generation of a Nd:YAG laser pumped KTP OPO and a CO2 laser in the 0.778-10.5910 MUm spectral range. In addition, we present new Sellmeier equations that provide a good reproduction of the present experimental results as well as the published data points for SHG of a CO2 laser at 10.5910 MUm and a 1.85 MUm-pumped OPO in the 2.156-3.220 MUm and 4.348-13.035 MUm spectral ranges. PMID- 30461810 TI - Phase-dependent Fano-shape optomechanically induced transparency. AB - We present a detailed study of a three-mode-coupling cavity optomechanical system where one mechanical mode and two optical whispering-gallery modes are coupled together. We extend the earlier investigation of regular optomechanically induced transparency (OMIT) [Science330, 1520 (2010)SCIEAS0036 807510.1126/science.1195596] in a more general case. A complete analytical description of the present system is obtained, and quantitative analyses of the Fano-shape OMIT spectrum are provided. It is clearly shown that a sharp and asymmetric Fano-shape OMIT lineshape, which is decided by the phase difference between the probe field and the mechanical driving, can be observed from the probe output. PMID- 30461811 TI - Suppression of backscattering-induced noise by sideband locking based on high and low modulation frequencies in ROG. AB - Backscattering-induced noise is a dominant noise in a resonant optic gyroscope (ROG). This paper proposes a method to suppress the carrier and backscattering induced noise with a sideband locking technique. The resonant cavity can be taken as a band-pass filter, and the carrier frequency component can be located at the stop-band while one sideband is locked to the cavity resonance. Then, the carrier will be suppressed by the cavity itself, which will reduce the interference with carrier backscattering. For the adoption of different modulation frequencies in clockwise (CW) and counter-clockwise (CCW) directions, the first-order sidebands of CW and CCW have a frequency offset to each other. Therefore, the first-order sideband backscattering can be eliminated when the sideband is locked to the cavity resonance. Also, both high and low modulation frequencies are applied to the phase modulator, which will further suppress the carrier, and the demodulation of low frequency will reduce the sensitivity to phase fluctuation noise in the system. The method has low requirements for parameter accuracy or device performance. PMID- 30461812 TI - Adaptive beam control techniques for airborne free-space optical communication systems. AB - In this paper, we study two adaptive beam control techniques, where the beam divergence angle is adjusted at the transmitter to (i) maximize link availability or (ii) minimize transmitter power while maintaining target link availability. For this purpose, we provide closed-form expressions about the link availability and optimum beam divergence angle under the effect of generalized two-dimensional Gaussian distribution of the alignment error between the transmitter and receiver. These simple and closed-form expressions reduce the computational complexity for performance optimization. Thus, they can be used to (i) reduce the power consumption required for adaptive beam control and (ii) facilitate the fast operation of the control techniques. The results show that the adaptive beam control techniques can improve system performance under various scenarios. PMID- 30461813 TI - Optimizing cirrus optical depth retrievals over the ocean from collocated CALIPSO and AMSR-E observations. AB - Retrievals of particulate optical depths and extinction coefficients from the cloud-aerosol lidar with orthogonal polarization (CALIOP) instrument deployed on the CALIPSO satellite mainly rely on a single global mean extinction-to backscatter ratio, also known as the lidar ratio. However, the lidar ratio depends on the microphysical properties of particulates. An alternative approach is adopted to infer single-layer semi-transparent cirrus optical depths (CODs) over the open ocean that does not rely on an assumed lidar ratio. Instead, the COD is inferred directly from backscatter measurements obtained from the CALIOP lidar in conjunction with collocated sea surface wind speed data obtained from AMSR-E. This method is based on a Gram-Charlier ocean surface reflectance model relating wind-driven wave slope variances to sea surface wind speeds. To properly apply this method, the impact of multiple scattering between the sea surface and ice clouds should be taken into account. We take advantage of the 532 nm cross polarization feature of CALIOP and introduce an empirical method based on the depolarization change at the sea surface to correct for potential bias in sea surface backscatter caused by whitecaps, bubbles, foam, and multiple scattering. After the correction, the COD can be derived for individual CALIOP retrievals in a single cloud layer over the ocean with this method. The global mean COD was found to be roughly 14% higher than the current values determined by the Version 4 CALIOP extinction retrieval algorithm. This study is relevant to future improvements of CALIOP operational products and is expected to lead to more accurate COD retrievals. PMID- 30461814 TI - Determining the colorimetric attributes of multicolored materials based on a global correction and unsupervised image segmentation method. AB - Fast and accurate measurement of colors in multicolored prints using commercial instruments or existing computer vision systems remains a challenge due to limitations in image segmentation methods and the size and complexity of the colored patterns. To determine the colorimetric attributes (L*a*b*) of multicolored materials, an approach based on global color correction and an effective unsupervised image segmentation is presented. The colorimetric attributes of all patches in a ColorChecker chart were measured spectrophotometrically, and an image of the chart was also captured. Images were segmented using a modified Chan-Vese method, and the sRGB values of each patch were extracted and then transformed into L*a*b* values. In order to optimize the transformation process, the performance of 10 models was examined by minimizing the average color differences between measured and calculated colorimetric values. To assess the performance of the model, a set of printed samples was employed and the color differences between the predicted and measured L*a*b* values of samples were compared. The results show that the modified Chan-Vese method, with suitable settings, generates satisfactory segmentation of the printed images with mean and maximum DeltaE00 values of 2.43 and 4.28 between measured and calculated values. PMID- 30461815 TI - Interconnecting data based on vortex beams by adjusting the ellipticity of a ring core fiber. AB - In order to exchange data in a space-division multiplexing (SDM) system, a novel vortex-beam-based data interconnection concept, which is achieved by adjusting the ellipticity of a ring-core fiber, is proposed. A new ring-core fiber is also designed and fabricated for exchanging and propagating the data carried by first- or second-order vortex (orbital angular momentum) beams. The proposed scheme is not only analyzed and simulated in principle, but is also verified through experiments. The numerical results demonstrate that the vortex beams can be exchanged by appropriately adjusting the phase difference (with respect to the ellipticity of a ring-core fiber) between the even and odd vector modes. A new experimental platform is designed and established for the sake of investigating the feasibility of the proposed scheme. The experimental results are consistent with the results of the simulation, and demonstrate that the data carried by the first- or second-order vortex beams can be successfully switched with acceptable bit error rates (BERs) between the first-order vortex beams (L=1 or -1) or between the second-order vortex beams (L=2 or -2, left or right circular polarization), respectively. The measured BERs and constellation diagrams of 16 QAM are employed to evaluate the data exchange performance with respect to different cases (i.e., data exchange once or twice, and data exchange with or without crosstalk). The measured BERs and constellation diagrams also demonstrate that the performance degrades with increase in topological charge or crosstalk. The proposed scheme is flexible, simple, and reliable for data exchange in a SDM system. PMID- 30461816 TI - Energy calibration of integrated path differential absorption lidars. AB - The stringent requirements for energy reference measurement represent a challenging task for integrated path differential absorption lidars to measure greenhouse gas columns from satellite or aircraft. The coherence of the lidar transmitter gives rise to speckle effects that have to be considered for accurate monitoring of the energy ratio of outgoing on- and off-line pulses. Detailed investigations have been performed on various measurement concepts potentially suited for deployment within future satellite missions. PMID- 30461817 TI - Direct inscription and evaluation of fiber Bragg gratings in carbon-coated optical sensor glass fibers for harsh environment oil and gas applications. AB - In this research work, we show the successful inscription of fiber Bragg gratings into carbon-coated pure silica as well as germanium-doped glass fibers by applying the pulsed laser point-by-point manufacturing technique. First, the parameters used for the Ti:sapphire femtosecond laser process are demonstrated. Without removing the polymeric carbon coating, destruction-free formation of highly reflective Bragg gratings is performed with selected types of hermetically enclosed fibers. We demonstrate the advantage of the carbon coating by long-term exposure to a pure hydrogen atmosphere at an elevated temperature. Such harsh conditions exist in the oil and gas industry, which means there is high application potential for technologically advanced optical sensors. Compared to the also examined standard glass fibers with a distinct signal attenuation, carbon-coated fibers show no significant degradation. Finally, we analyze the mechanical stability of the processed fibers via standardized tensile tests. No substantial decrease in strength occurs among the sensor-integrated samples. PMID- 30461818 TI - Continuous-wavelet-transform-based automatic curve fitting method for laser induced breakdown spectroscopy. AB - In this work, an automatic curve fitting method based on a continuous-wavelet transform (CWT) is proposed to resolve overlapped peaks and to adaptively extract the major peaks in laser-induced breakdown spectroscopy (LIBS). From the local minimum of the second derivative of the LIBS spectrum calculated with CWT, the number of individual peaks is determined, and corresponding peak positions are estimated. The full width at half-maximums (FWHMs) of individual peaks are estimated from the separation of two maxima siding the minimum. A threshold is introduced to eliminate the small peaks and therefore reduce the number of fitting parameters and adaptively extract the major peaks with different spectral intensities. The Trust-Region algorithm is used for parameter optimization. The proposed method is used to analyze both simulated LIBS spectra and experimental overlapped peaks. Both simulated and experimental results show that the proposed method can resolve overlapped peaks even with a low separation degree, although the minimum resolvable separation degree depends on the FWHM ratio and strength ratio of individual peaks and the wavelet scale. In a LIBS calibration experiment of N2/SF6 gasses mixture, after resolving the overlapped peaks with the proposed method, better linear correlations between the concentration and intensity of F (with an adjusted R-squared value 0.9972), as well as between the concentration ratio and intensity ratio of nitrogen to fluorine (with adjusted R-squared values >0.98 and 0.99) are obtained. PMID- 30461819 TI - Single-shot large field of view imaging with scattering media by spatial demultiplexing. AB - Benefiting from the memory effect (ME) for speckle intensity correlations, only one single-shot speckle pattern can be used for the high-quality recovery of objects. However, ME gives a restriction to the field of view (FOV) for imaging with scattering media. Objects beyond the ME region cannot be recovered and produce unwanted speckle patterns, which cause reduction in the speckle contrast and recovery quality. Nevertheless, all the spatial information from a large object is embedded in a single speckle image. Here, we extract the spatial information from these unavoidable speckle patterns and enlarge the FOV of the imaging system with scattering media. Regional point spreading functions, which are fixed and only need to be recorded once for all-time use, are employed to recover corresponding spatial regions of an object by deconvolution. Then, an automatic weighted averaging in an iterative process is performed to obtain the object with significantly enlarged FOV. Our results present an important advancement of imaging techniques with strongly scattering media. PMID- 30461820 TI - Simple method for volumetric thickness measurement using a color camera. AB - A simple volumetric thickness measurement method for in-line high-speed inspection is proposed. With a color camera alone, spectrally resolved reflectance in a spatial domain is obtained: a Bayer filter spectrally resolves the reflected signal, and a CMOS sensor acquires three multi-spectral reflectances from RGB data at a single shot. To determine an accurate thickness, a modified reflectance is derived to convert a conventional spectral reflectance throughout a wavelength domain into an adequate form in an RGB domain by considering the characteristics of wide-band multi-spectral acquisition. The proposed method is validated by the measurement of a uniformly deposited SiO2 film and a tapered SiNx film. PMID- 30461821 TI - Method to determine the anisotropy parameter g of a turbid medium. AB - We present a method to determine the anisotropy parameter g of a scattering liquid medium. A simple experimental setup is used to measure the scattered light from turbid samples, and a calibration curve is used to determine g. The interaction coefficient of the medium is experimentally determined, and the calibration curve is obtained through Monte Carlo simulations. The method is tested for nonabsorbing solutions of polystyrene spheres, and the simulation results are found to agree with the experiments. PMID- 30461822 TI - Method to reduce motion artifacts of sequential imaging polarimetry: long enough exposures minimize polarization blurs of wavy water surfaces. AB - Researchers studying the polarization characteristics of the optical environment prefer to use sequential imaging polarimetry, because it is inexpensive and simple. This technique takes polarization pictures through polarizers in succession. Its main drawback is, however, that during sequential exposure of the polarization pictures, the target must not move, otherwise so-called motion artifacts are caused after evaluation of the polarization pictures. How could these disturbing motion artifacts be minimized? Taking inspiration from photography, our idea was to take the polarization pictures with an exposure that is long enough so that the changes of the moving/changing target can be averaged and, thus, motion artifacts are reduced, at least in a special case when the motion has a stable mean. In the laboratory, we demonstrated the performance of this method when the target was a wavy water surface. We found that the errors of the measured degree and angle of polarization of light reflected from the undulating water surface decreased with increasing exposure time (shutter speed) and converged to very low values. Although various simultaneous polarimeters (taking the polarization pictures at once) are available that do not suffer from motion artifacts, our method is much cheaper and performs very well, at least when the target is a wavy water surface. PMID- 30461823 TI - Calibration of an array projector used for high-speed three-dimensional shape measurements using a single camera. AB - Geometric calibration of digital light processing projectors in single-camera, fringe-projecting 3D measurement systems have been studied assuming the projector is inverse pinhole modeled. Conversely, a high-speed multi-aperture array projector (MAAP) projecting aperiodic fringes is not dependent on a digital mirror device and cannot be pinhole modeled. With MAAP projection, a stereo camera setup is required. This paper presents a model-less method to calibrate a MAAP by direct measurement of its illumination field and re-enables 3D measurements with a single camera even with surface discontinuities present. Experimental proof of principle and preliminary measurement performance are shown. PMID- 30461824 TI - Finite aperture correction for spectral cameras with integrated thin-film Fabry Perot filters. AB - Spectral cameras with integrated thin-film Fabry-Perot filters enable many different applications. Some applications require the detection of spectral features that are only visible at specific wavelengths, and some need to quantify small spectral differences that are undetectable with RGB color cameras. One factor that influences the central wavelength of thin-film filters is the angle of incidence. Therefore, when light is focused from an imaging lens onto the filter array, undesirable shifts in the measured spectra are observed. These shifts limit the use of the sensor in applications that require fast lenses or lenses with large chief ray angles. To increase flexibility and enable new applications, we derive an analytical model that explains and can correct the observed shifts in measured spectra. The model includes the size of the aperture and physical position of each filter on the sensor. We experimentally validate the model with two spectral cameras: one in the visible and near-infrared region and one in the short wave infrared region. PMID- 30461825 TI - High-resolution ex vacuo objective for cold atom experiments. AB - We present a versatile and cost-efficient objective with a five-lens configuration, which consists completely of commercial singlets. The home-built objective has a numerical aperture (NA) of 0.44 and a long working distance of 35.9 mm, making it suitable for ex vacuo utilization. A diffraction-limited resolution of 1.08 MUm and a field of view of about 210 MUm are achieved when a 780 nm light passes through a 5 mm thick vacuum window. Moreover, such a design can be well adapted to a broad range of laser wavelengths (560-1000 nm) and vacuum window thicknesses (0-6 mm) by simply modifying one lens spacing, while maintaining a NA of above 0.43. The characteristics of the objective are evaluated experimentally, which are in good agreement with the simulations. Also, the objective has been successfully used for single-atom trapping and detecting in experiments. We believe that it will find more applications in various cold atom experiments. PMID- 30461826 TI - Research on tunable distributed SPR sensor based on bimetal film. AB - In order to overcome the limitations in range of traditional prism structure surface plasmon resonance (SPR) single-point sensor measurement, a symmetric bimetallic film SPR multi-sensor structure is proposed. Based on this, the dual channel sensing attenuation mechanism of SPR in gold and silver composite film and the improvement of sensing characteristics were studied. By optimizing the characteristics such as material and thickness, a wider range of dual-channel distributed sensing is realized. Using a He-Ne laser (632.8 nm) as the reference light source, prism-excited symmetric SPR sensing was studied theoretically for a symmetrical metal-clad dielectric waveguide using thin-film optics theory. The influence of the angle of incidence of the light source and the thickness of the dielectric layer on the performance of SPR dual formant sensing is explained. The finite-difference time-domain method was used for the simulation calculation for various thicknesses and compositions of the symmetric combined layer, resulting in the choice of silver (30 nm) and gold (10 nm). When the incident angle was 78 deg, the quality factor reached 5960, showing an excellent resonance sensing effect. The sensitivity reached a maximum of 5.25*10-5 RIU when testing the water content of an aqueous solution of honey, which proves the feasibility and practicality of the structure design. The structure improves the theoretical basis for designing an SPR multi-channel distributed sensing system, which can greatly reduce the cost of biochemical detection and significantly increase the detection efficiency. PMID- 30461827 TI - Low voltage-defect quantum cascade lasers based on excited-states injection at lambda ~ 8.5 MUm. AB - A quantum cascade laser emitting at lambda~8.5 MUm based on the excited-state injection is presented. The operating voltage is reduced for a low-voltage defect in the excited-state design, compared with the conventional ground-state injection design. The threshold voltage and voltage defect are as low as 6.3 V and 54 mV for a 30-stage active region, respectively. Devices were fabricated through standard buried-heterostructure processing to decrease the heat accumulation. A continuous-wave optical power of 340 mW is obtained at 283 K with a threshold current density of 2.7 kA/cm2. Such a design has the potential to further improve the wall plug efficiency for increased voltage efficiency. PMID- 30461828 TI - Error performance of underwater wireless optical communications with spatial diversity under turbulence channels. AB - In underwater optical wireless communications (UOWC), absorption, scattering, and turbulence severely degrade the reliability and transmission rate of the UOWC link. In this paper, spatial diversity (SD) is exploited to improve the error performance of UOWC links, which involves the deployment of multiple transmit/receive apertures. Channel impulse responses for various configurations in a coastal ocean water link are obtained by Monte Carlo simulation. By using maximum-likelihood sequence detection depending on the Euclidean distance, the error probability of the SD UOWC is derived. We further present an efficient approximated closed-form expression with one-dimensional integral for the error probability of single-input multiple-output and multiple-input single-output systems. Our analytical derivations build upon an approximation to the sum of correlated log-normal random variables. Both the derived bit error probability expressions and simulations are used to quantify the effect of SD, and the performance of SD UOWC is compared with a single-input single-output link. Our numerical results indicate that SD combats the impairing effects of fading and considerably improves the UOWC system performance. PMID- 30461829 TI - Multi-depth three-dimensional image encryption based on the phase retrieval algorithm in the Fresnel and fractional Fourier transform domains. AB - We propose a multi-depth three-dimensional (3D) image cryptosystem by employing the phase retrieval algorithm in the Fresnel and fractional Fourier (Fr-FrF) domains. Encryption was realized by applying the phase retrieval algorithm based on the double-random-phase-encoding architecture in which two encryption keys will be incessantly updated in each iteration loop. The phase-only functions (POFs) are generated in two cascaded Fr-FrF transforms (Fr-FrFT), serving as decryption keys to efficiently reduce the speckle noise and crosstalk between encrypted 3D image depths. The use of Fr-FrFT position parameters and fractional order as decryption keys further extended the key space, enhancing the cryptosystem's security level. Numerical simulations demonstrated the feasibility and robustness of our proposed scheme. PMID- 30461830 TI - Dynamic compensation of gradient index rod lens aberrations by using liquid crystals. AB - An electrically variable liquid crystal lens is used to compensate the aberrations of commercial gradient index rod lenses used for deep brain endoscopy. This is achieved by the use of a weakly conductive layer in the so called "modal control" lens approach with a segmented peripheral electrode. The root mean square aberrations of the system are reduced by a factor of 4.3. The proposed solution can be used in many photonic applications using fixed optical components with high aberrations that have significant sample-to-sample variability. PMID- 30461831 TI - Full-color holographic 3D display with horizontal full viewing zone by spatiotemporal-division multiplexing. AB - A technical full-color reconstruction method is presented to develop our previous monochromatic holographic three-dimensional display with a horizontal full viewing zone. A digital micromirror device (DMD) is used as a high-speed spatial light modulator, and its modulation area is divided into three parts, which independently handle three sub-holograms corresponding to red, green, and blue components. The reconstructed images from a single frame of the DMD never form full-color images. However, given that this spatial division is combined with the time-division method for the full viewing zone, each monochromatic image is temporally mixed, and practically full-color images are reconstructed. After monochromatic reconstruction from a single frame was confirmed, full-color reconstruction with a horizontal full viewing zone was demonstrated. PMID- 30461832 TI - Photo-induced luminescence degradation in Ce, Yb co-doped yttrium aluminum garnet phosphors. AB - Photon-induced luminescence degradation of Ce, Yb co-doped yttrium aluminum garnet phosphors with different Yb concentrations under 457 nm irradiation is studied for the first time, to the best of our knowledge. The degradation behavior is more significant in nano-phosphors prepared via the solgel method, compared with bulkier samples prepared via solid-state reaction. Photoluminescence intensity of Ce3+ ions experiences a drop after initial illumination, due to photoionization of Ce3+ ions, whereas the down-converted luminescence of Yb3+ ions remains relatively stable. Co-doping Yb3+ contributes to the luminescence drop of Ce3+ with the excessive Yb3+ ions serving as additional electron traps. The results are in support of a charge transfer process. PMID- 30461833 TI - Ultrasound vibration measurements based on laser optical feedback imaging. AB - This paper examines the detection of ultrasound vibrations with nanometric amplitude by using a laser optical feedback imaging (LOFI) setup. By means of numerical simulations, we show typical examples of ultrasound vibrations having different temporal shapes (harmonic and transient), extracted from the laser output power modulation induced by the frequency-shifted optical feedback. Considering the laser quantum noise dynamic and the detection noise separately, we show that the simulated vibration noise is in good agreement with the theoretical prediction. Also, we demonstrate that ultra-high frequencies (in the gigahertz range) can be detected by using a usual LOFI setup with a low-power laser (few mW) and a conventional detection with a usual white noise level. Then we show how the noise of a short transient vibration can be reduced by the reconstruction of its wide vibration spectrum by concatenation. Finally, the experimental detection of transient-harmonics ultrasound vibrations propagating in water and detected at the air/water interface is presented. PMID- 30461834 TI - Adaptive turbulence compensation with a hybrid input-output algorithm in orbital angular momentum-based free-space optical communication. AB - Atmospheric turbulence is a major challenge for practical orbital angular momentum (OAM)-based free-space optical (FSO) communication systems that causes intermodal crosstalk and degrades the performance of the system. Herein, we propose a hybrid input-output algorithm (HIOA)-based adaptive optics (AO) system to compensate for distorted OAM beams. The principle and parameters of the HIOA based AO system in an OAM-based FSO system are analyzed, and the performance is discussed. The simulation results indicate that the HIOA-based AO system can effectively correct distorted OAM beams and that the HIOA improves the compensation performance and convergence speed compared to the traditional Gerchberg-Saxton algorithm. Moreover, we analyze the compensation performance based on different probe beams. Using an OAM beam with state l=1 as a probe beam can yield better correction effects than a Gaussian beam. This work verifies the feasibility of using an HIOA for adaptive turbulence compensation and provides new insights into OAM communication systems. PMID- 30461835 TI - Techniques for arbitrary sampling in two-dimensional Fourier transforms. AB - In this paper, we discuss two effective methods for computing optical propagations using two-dimensional (2D) discrete Fourier transforms: the matrix triple product (MTP) and the chirp z-transform (CZT) and analyze their performance both in theory and via benchmarks compared to the performance of a traditional padded fast Fourier transform (FFT). We show that, in many regimes of interest for phase-retrieval algorithms, the MTP or CZT is comparable to or better than the FFT in terms of run time while offering more flexible control over the sampling. We propose that for many applications, the CZT makes a robust general purpose alternative to the padded 2D FFT. PMID- 30461836 TI - Enhanced backscatter in LIDAR systems with retro-reflectors operating through a turbulent ocean. AB - The enhanced backscatter (EBS) effect is examined for light propagation through a weakly turbulent ocean in a monostatic channel with a retro-reflector. Using the second-order Rytov theory to account for the turbulent medium perturbations of the optical wave, we numerically predict the appearance of the EBS in the average intensity for the incident plane and spherical waves within the first several meters of the channel. The influence of the size of the retro-reflector on the EBS factor is also revealed for both types of waves. Our predictions are instrumental for the development of LIDARs in turbulent waters for communications, imaging, and sensing. PMID- 30461838 TI - A new topical editor for JOSA A: editorial. AB - Editor-in-Chief P. Scott Carney introduces the Journal's newest Topical Editor, Yangjian Cai. PMID- 30461837 TI - Learning Siamese networks for laser vision seam tracking. AB - To design a stable laser vision seam-tracking system, an advanced weld image processing algorithm based on Siamese networks is investigated and proposed to resist the interference of arc and spatter in the welding process. This specially designed neural network, combined with powerful feature expression capabilities of deep learning, takes two welding images with different sizes as inputs and generates a target confidence map in a single forward pass by using the cross correlation algorithm. To prevent the error accumulation and model drift, an online update strategy via local cosine similarity is developed. The use of metal inert-gas welding can realize real-time and precious tracking under the condition that the strong arc continuously shields the welding seam feature points. PMID- 30461839 TI - Three-way decision based reconstruction frame for fluorescence molecular tomography. AB - Fluorescence molecular tomography (FMT) has been a promising imaging tool because it allows an accurate localizaton and quantitative analysis of the fluorophore distribution in animals. It, however, is still a challenge since its reconstruction suffers from severe ill-posedness. This paper introduces a reconstruction frame based on three-way decisions (TWD) for the inverse problem of FMT. On the first stage, a reconstruction result on the whole region is obtained by a certain reconstruction algorithm. With TWD, the recovered result has been divided into three regions: fluorescent target region, boundary region, and background region. On the second stage, the boundary region and fluorescent target region have been combined into the permissible region of the target. Then a new reconstruction on the permissible region has been carried out and a new recovered result is obtained. With TWD again, the new result has been classified into three pairwise disjoint regions. And the new fluorescent target region is the final reconstructed result. Both numerical simulation experiments and a real mouse experiment are carried out to validate the feasibility and potential of the presented reconstruction frame. The results indicate that the proposed reconstuction strategy based on TWD can provide a good performance in FMT reconstruction. PMID- 30461840 TI - First-order nonparaxial scalar theory of surface and bulk scattering for high quality optical coatings. AB - A novel nonparaxial scalar theory is presented to calculate the angular scattering that is due to interface roughnesses or bulk inhomogeneities in a high quality optical coating. Based on the empirically modified Beckmann-Kirchhoff surface scatter model, this theory in surface scattering and bulk scattering predicts similar formulas for the angular scattered intensity, and at the same time provides new understanding and insight into multilayer scattering phenomena. It is worth noting that the derived expressions are in the same form as those given by the typical vector methods. Based on comparisons of the surface and bulk models with the corresponding typical models for several multilayer designs, the novel theory is demonstrated to be valid for multilayer coatings even with large incident and scattering angles. PMID- 30461841 TI - Improved broadband spectral selectivity of absorbers/emitters for solar thermophotovoltaics based on 2D photonic crystal heterostructures. AB - We propose a novel heterostructure based on 2D photonic crystals as broadband selective absorbers/emitters for solar thermophotovoltaics. Alternating hafnium oxide (HfO2) and titanium oxide (TiO2) filled cylinder cavities with tetragonal lattices are embedded into antireflection-coated tungsten (W) film. The simulated results show that the designed structures can obtain high solar collection efficiency etac of 87.9% as an absorber and great spectral emission efficiency etae of 81.6% as an emitter. Meanwhile, high average absorptivity of 84.5% under 45 degrees oblique incidence exhibits good performance of wide-angle absorption. This study provides a new way to acquire broadband spectral selective absorbers/emitters. PMID- 30461842 TI - Effects of anisotropic oceanic turbulence on the power of the bandwidth-limited OAM mode of partially coherent modified Bessel correlated vortex beams. AB - We study the impacts of anisotropic turbulence on the bandwidth-limited orbital angular momentum (OAM) mode of partially coherent modified Bessel correlated beam propagation in oceanic turbulence. In a paraxial link, a power model of the bandwidth-limited OAM mode is established. We find that small-scale eddies of turbulence are an important factor that affects the power of the bandwidth limited OAM mode transfer in a region of strong salinity fluctuation. By choosing the mode carrying lower OAM quantum number, we can transfer OAM information more efficiently, and by utilizing OAM modes with large energy level difference between modes, one can achieve multichannel communication. PMID- 30461843 TI - Partially coherent microscope imaging system in phase space: effect of defocus and phase reconstruction. AB - Explicit relationships between the defocused partially coherent cross-coefficient and phase space representations in the image plane are derived. Measurement of a phase space representation in the image plane in principle allows the complex image to be extracted. Implications for phase retrieval using the weak object transfer function or the transport of intensity equation are considered. The phase gradient transfer function, which determines the image for an object exhibiting a slowly varying phase gradient for a partially coherent microscope system, is derived. The effect of the effective source size and geometry on phase imaging with the transport of intensity equation is investigated. The primary consequence of source shape is a rescaling of the phase reconstruction. An annular source is found to give close to a linear response, while at the same time providing improved transverse resolution and an improved response to low spatial frequencies. PMID- 30461844 TI - Radiative transport in quasi-homogeneous random media. AB - We consider the theory of radiative transport in quasi-homogeneous random media. We derive the radiative transport equation that governs the propagation of light in such media. This result provides conditions under which it is justified to apply radiative transport theory to spatially inhomogeneous media. PMID- 30461845 TI - Reciprocity theorem and accuracy evaluation on scattering fields by dielectric gratings. AB - In the theory of gratings, a diffraction solution must satisfy the energy balance and the reciprocity. This paper examines the diffraction by multilayered dielectric gratings, including lossy layers of which the solutions do not satisfy the energy balance. Applying the shadow theory to the matrix eigenvalues method, the symmetry of scattering factors in the theory and that of diffraction efficiencies are shown in some formulae and then are validated numerically. In addition, the reciprocity errors for diffraction efficiencies and scattering factors are newly considered as an accuracy criterion. It is shown that, on numerical calculations, the reciprocity errors for diffraction efficiencies have only to be checked. PMID- 30461846 TI - X-ray tomography of extended objects: a comparison of data acquisition approaches. AB - The penetration power of x rays allows one to image large objects, while their short wavelength allows for high spatial resolution. As a result, with synchrotron sources, one has the potential to obtain tomographic images of centimeter-sized specimens with sub-micrometer pixel sizes. However, limitations on beam and detector size make it difficult to acquire such data of this sort in a single take, necessitating strategies for combining data from multiple regions. One strategy is to acquire a tiled set of local tomograms by rotating the specimen around each of the local tomogram center positions. Another strategy, sinogram oriented acquisition, involves the collection of projections at multiple offset positions from the rotation axis followed by data merging and reconstruction. We have carried out a simulation study to compare these two approaches in terms of radiation dose applied to the specimen, and reconstructed image quality. Local tomography acquisition involves an easier data alignment problem, and immediate viewing of subregions before the entire dataset has been acquired. Sinogram oriented acquisition involves a more difficult data assembly and alignment procedure, and it is more sensitive to accumulative registration error. However, sinogram oriented acquisition is more dose efficient, involves fewer translation motions of the object, and avoids certain artifacts of local tomography. PMID- 30461847 TI - Interferometry-based modal analysis with finite aperture effects. AB - We analyze the effects of aperture finiteness on interferograms recorded to unveil the modal content of optical beams in arbitrary bases using generalized interferometry. We develop a scheme for modal reconstruction from interferometric measurements that accounts for the ensuing clipping effects. Clipping-cognizant reconstruction is shown to yield significant performance gains over traditional schemes that overlook such effects that do arise in practice. PMID- 30461848 TI - Generalized quantification of three-dimensional resolution in optical diffraction tomography using the projection of maximal spatial bandwidths. AB - Optical diffraction tomography (ODT) is a three-dimensional (3D) quantitative phase imaging technique, which enables the reconstruction of the 3D refractive index (RI) distribution of a transparent sample. Due to its fast, non-invasive, and quantitative imaging capability, ODT has emerged as a powerful tool for various applications. However, the spatial resolution of ODT has only been quantified along the lateral and axial directions for limited conditions; it has not been investigated for arbitrary-oblique directions. In this paper, we systematically quantify the 3D spatial resolution of ODT by exploiting the spatial bandwidth of the reconstructed scattering potential. The 3D spatial resolution is calculated for various types of systems, including the illumination scanning, sample-rotation, and hybrid scanning-rotation methods. In particular, using the calculated 3D spatial resolution, we provide the spatial resolution as well as the arbitrary sliced angle. Furthermore, to validate the present method, the point spread function of an ODT system is experimentally obtained using the deconvolution of a 3D RI distribution of a microsphere and is compared with the calculated resolution. PMID- 30461849 TI - Twisted vortex Gaussian Schell-model beams. AB - We introduce a new class of partially coherent vortex beams in which the angular momentum of the beam is provided from two different sources: the underlying vortex of the random beam and the "twist" given to the ensemble of beams. The statistical and propagation properties of such beams are investigated, and their orbital angular momentum properties are analyzed. The combination of distinct orbital angular momentum sources allows unusual behaviors that were previously unobserved. PMID- 30461850 TI - Traffic sign recognition method for intelligent vehicles. AB - Traffic sign recognition is one of the main components of intelligent transportation systems (ITS). It improves safety by informing the driver of the current state of the road, e.g., warnings, prohibitions, restrictions, and other information useful for driving. This paper presents a new road sign recognition method that is achieved in three main steps. The first step maps the input image from the Cartesian coordinate system to the log-polar one. The second step computes the histogram of oriented gradients, local binary pattern, and local self-similarity characteristics from the image represented in the log-polar coordinate system. The third step performs classification on the basis of the random forest classifier and the features computed in the second step. The proposed method has been tested on the German Traffic Sign Recognition Benchmark dataset, and the results obtained are satisfactory when compared to the state-of the-art approaches. PMID- 30461851 TI - Generalization of the axicon shape: the gaxicon. AB - We generalize the shape of the traditional axicon by analytically finding the function of the output surface when the input surface is not flat but an arbitrary continuous function that possesses rotational symmetry. Several illustrative examples are presented and tested using ray tracing techniques without the paraxial approximation. PMID- 30461852 TI - Recording and erasure of photorefractive holograms in undoped BTO crystal at moderate to high intensities of 639.7 nm laser under action of 532 nm laser pre illumination. AB - We investigate recording and erasure of photorefractive holographic gratings in an undoped Bi12TiO20 crystal in a moderate to high intensity regime of the recording beams at 639.7 nm without and with the action of laser pre-illumination at 532 nm. The detected hologram without pre-illumination indicates the participation of two photorefractive electronic gratings in its recording process, and the diffracted signal by itself exhibits a fivefold enhancement when the total intensity increases from 38.4 to 214.5 mW/cm2. The dependence of the measured total diffraction efficiency on intensity was investigated and showed linear behavior. At least three gratings are present in the regime of pre illumination and participate in the writing and erasure of holographic mechanisms. Two of them are electronic, and one is hole-based, with a phase difference of Deltaphi between them. The theoretical approach used to analyze the total diffraction efficiency based upon the photorefractivity standard model, and considering the presence of the three gratings, showed good agreement with the holographic erasure experimental data and permitted us to compute Deltaphi, which exhibited strong and unusual dependence on the total intensity. PMID- 30461853 TI - All-optical DNA variant discovery utilizing extended DV-curve-based wavelength modulation. AB - This paper presents a novel optical processing approach for exploring genome sequences built upon an optical correlator for global alignment and the extended dual-vector-curve (DV-curve) method for local alignment. To overcome the problem of the traditional DV-curve method for presenting an accurate and simplified output, we propose the hybrid amplitude wavelength polarization optical DV-curve (HAWPOD) method, built upon the DV-curve method, to analyze genome sequences in three steps: DNA coding, alignment, and post-analysis. For this purpose, a tunable graphene-based color filter is designed for wavelength modulation of optical signals. Moreover, all-optical implementation of the HAWPOD method is developed, while its accuracy is validated through numerical simulations in LUMERICAL FDTD. The results express that the proposed method is much faster than its electrical counterparts. PMID- 30461854 TI - Leukocyte recognition in human fecal samples using texture features. AB - Unlike urine or blood samples with a single background, human fecal samples contain large amounts of food debris, amorphous particles, and undigested plant cells. It is difficult to segment such impurities when mixed with leukocytes. Cell degradation results in ambiguous nuclei, incompleteness of the cell membrane, and a changeable cell morphology, which are difficult to recognize. Aiming at the segmentation problem, a threshold segmentation method combining an inscribed circle and circumscribed circle is proposed to effectively remove the adhesion impurities with a segmentation accuracy reaching 97.6%. For the identification problem, five texture features (i.e., LBP-uniform, Gabor, HOG, GLCM, and Haar) were extracted and classified using four kinds of classifiers (support vector machine (SVM), artificial neural network, AdaBoost, and random forest). The experimental results show that using a histogram of oriented gradient features with an SVM classifier can achieve precision of 88.46% and recall of 88.72%. PMID- 30461855 TI - Design of an axisymmetrical refractive optical element generating required illuminance distribution and wavefront. AB - The design of an axisymmetrical refractive optical element transforming a given incident beam into an output beam with prescribed illuminance distribution and wavefront is considered. The wavefront of the output beam is represented by the eikonal function defined in a certain plane behind the optical element. The design of the optical element is reduced to the solution of two explicit ordinary differential equations of the first order. These equations can be easily integrated using conventional numerical methods. As examples, we consider the design of two optical elements transforming a spherical beam from a point Lambertian light source into the uniform-illuminance beams with a plane wavefront and with a complex wavefront providing the subsequent focusing into a line segment on the optical axis. PMID- 30461856 TI - Improved wide-field emmetropic human eye model based on ocular wavefront measurements and geometry-independent gradient index lens. AB - There is a need to better understand the peripheral optics of the human eye and their correction. Current eye models have some limitations to accurately predict the wavefront errors for the emmetropic eye over a wide field. The aim here was to develop an anatomically correct optical model of the human eye that closely reproduces the wavefront of an average Caucasian-only emmetropic eye across a wide visual field. Using an optical design program, a schematic eye was constructed based on ocular wavefront measurements of the right eyes of thirty healthy young emmetropic individuals over a wide visual field (from 40 degrees nasal to 40 degrees temporal and up to 20 degrees inferior field). Anatomical parameters, asymmetries, and dispersion properties of the eye's different optical components were taken into account. A geometry-independent gradient index model was employed to better represent the crystalline lens. The RMS wavefront error, wavefront shapes, dominant Zernike coefficients, nasal-temporal asymmetries, and dispersion properties of the developed schematic eye closely matched the corresponding measured values across the visual field. The developed model can help in the design of wide-field ophthalmic instruments and is useful in the study and simulations of the peripheral optics of the human eye. PMID- 30461857 TI - Manipulating far-zone scattered field by controlling distribution characteristics of a particulate medium. AB - Within the validity of the first-order Born approximation and far-field approximation, the possibility for producing scattered fields with various intensity distributions is discussed. It is shown that when light waves are scattered from a collection of particles with random distribution, the intensity distribution of the scattered field can be manipulated by properly controlling the distribution characteristics of particles in the collection. To illustrate this result, three special cases of a particulate medium are discussed to produce scattered spectral density with Gaussian distributions, circular flattened distributions, and ring-like distributions, respectively. PMID- 30461858 TI - Nonlinear wavefront reconstruction methods for pyramid sensors using Landweber and Landweber-Kaczmarz iterations. AB - Accurate and robust wavefront reconstruction methods for pyramid wavefront sensors are in high demand, as these sensors are planned to be part of many instruments currently under development for ground-based telescopes. The pyramid sensor relates the incoming wavefront and its measurements in a nonlinear way. Nevertheless, almost all existing reconstruction algorithms are based on a linearization of the model. The assumption of a linear pyramid sensor response is justifiable in closed-loop adaptive optics (AO) when the measured phase information is small, but, depending on the system, may not be feasible due to unpreventable errors such as non-common path aberrations. In order to solve the nonlinear inverse problem of wavefront reconstruction from pyramid sensor data, we introduce two new methods based on the nonlinear Landweber and Landweber Kaczmarz iterations. Using these algorithms, we experience high-quality wavefront estimation, especially for the non-modulated sensor, by still keeping the numerical effort feasible for large-scale AO systems. PMID- 30461859 TI - Immunosensing platform with large detection range using an excessively tilted fiber grating coated with graphene oxide. AB - We report an immunosensing platform with a large detection range using an excessively tilted fiber grating (ExTFG) coated with graphene oxide (GO). ExTFG was inscribed in standard single-mode fiber; GO film was coated on the fiber surface through hydrogen bond. The effectiveness and uniformity of GO deposited on the ExTFG surface were investigated by field emission scanning electron microscopy and energy spectrum method. Bovine serum albumin (BSA) monoclonal antibodies (MAbs) were used as biometric units to link the GO film through a covalent bond for the specific detection of BSA, so as to evaluate the performances of the proposed biosensor. The whole dynamic immobilization process of BSA MAbs and BSA detection were observed by the spectral evolution of the sensor. Experimental results show that the fabricated GO-coated ExTFG biosensor has a large detection range from 1.5 nM-75 nM and fast response for BSA antigen; the limit of detection is ~0.88 nM by using an optical spectrum analyzer with a resolution of 0.03 nm, and the dissociation constant KD and the affinity constant KA are calculated to be ~6.66*10-9 M and ~1.5*108 M-1, respectively. The proposed GO-coated ExTFG immunosensing platform could lay a foundation for the specific detection of other biomolecules. PMID- 30461860 TI - Rotation-as-fast-axis scanning-probe x-ray tomography: the importance of angular diversity for fly-scan modes. AB - We investigate the effects of angular diversity on image-reconstruction quality of scanning-probe x-ray tomography for both fly- and step-mode data collection. We propose probe-coverage maps as a tool for both visualizing and quantifying the distribution of probe interactions with the object. We show that data sampling with more angular diversity yields better tomographic image reconstruction as long as it does not come at the cost of not covering some voxels in the object. Therefore, for fly-mode data collection, rotation-as-fast-axis (RAFA) trajectories are superior to raster or other non-RAFA trajectories because they allow for the increasing of angular diversity without sacrificing spatial coverage uniformity. In contrast, for step-mode data collection and a fixed measurement budget, increasing angular diversity can come at the cost of not covering some voxels, and may not be desired. This study has implications for how scanning-probe microscopes should be collecting data in order to make the most of limited resources. PMID- 30461861 TI - Various large-energy soliton operations within an Er-doped fiber laser with bismuth selenide as a saturable absorber. AB - Different large-energy mode-locked operations were successfully obtained within a Bi2Se3-based Er-doped fiber laser. First, mode-locked operation with maximum pulse energy of 17.2 nJ and pulse width of 187 ns under a pulse repetition rate of 537.6 kHz was obtained under the pump power of 680 mW. In addition, the characteristics of dark solitons and soliton rains, which also exhibit large pulse energies, have been investigated experimentally. Our results fully proved that Bi2Se3 was an excellent candidate for investigating various mode-locked operations with large pulse energy due to its high nonlinear effect and high damage threshold. PMID- 30461862 TI - Pump-probe measurement of metastable state lifetime reduced by cooperative upconversion in a high-concentration erbium-doped fiber. AB - We report measurements of the metastable state lifetime in a high-concentration erbium-doped fiber. We use a single-wavelength pump-probe technique that allows us to measure the average lifetime over the entire fiber length. A reduction in the lifetime of approximately 20% caused by a cooperative upconversion effect is clearly observed when the input power is increased up to 10 mW. The input power dependence of the lifetime is analyzed using a simple model. The cooperative upconversion coefficient is determined based on this analysis. PMID- 30461863 TI - Cost-effective high-spatial-resolution photon-counting optical time-domain reflectometry at 850 nm. AB - Optical time-domain reflectometry (OTDR) is a widely employed instrument for monitoring the property of fiber links. Traditional OTDR always suffers from the trade-off between its spatial resolution and the sensitivity of light detection. Therefore, it cannot be applied in critical applications, such as in aviation, where OTDR with a high spatial resolution of several centimeters is required. In this paper, we develop a cost-effective photon-counting OTDR based on our homemade gain-switching pulsed laser at 850 nm. Thanks to the short pulse width of the laser and the relatively small time jitter of the photon detector, our photon-counting OTDR achieves a spatial resolution of less than 9 cm and satisfies the requirements for monitoring short fiber links in various types of airplanes. Finally, we realize a fully running system for monitoring an optical cable with 32 fiber channels on a plane. PMID- 30461864 TI - Effective wind and temperature retrieval from Doppler asymmetric spatial heterodyne spectrometer interferograms. AB - This paper presents a method for wind velocity and Doppler temperature retrieval from interferograms of a Doppler asymmetric spatial heterodyne spectrometer. This method is based on the analytic representation of the signal and the subsequent algorithms. It turns out to be more robust than the conventional Fourier transform method at low SNR. The influence of optical dispersion on the accuracy of the retrieved parameters is also characterized. The effective optical path difference is suggested for use in wind and temperature retrieval routines. Computer simulations are used to characterize the accuracy of the proposed method, in particular regarding the influence of optical dispersion. PMID- 30461865 TI - Transport-of-intensity holographic data storage based on a computer-generated hologram. AB - To increase the recording density of computer-generated-hologram (CGH)-based holographic data storage, a phase data page reconstruction method by the transport of intensity equation (TIE) is proposed. The TIE generally requires a scanning image sensor because the phase retrieval process needs at least two defocused intensity distributions. Although the TIE is applied, the proposed method enables detection of the distributions simultaneously by utilizing an extra conjugate component reconstructed from the CGH. Experimental results show that the proposed method allows reconstructing of a phase data page without any additional elements, which keeps the optical setup simple and low cost. PMID- 30461866 TI - Rapid identification of Huanlongbing-infected citrus plants using laser-induced breakdown spectroscopy of phloem samples. AB - Huanglongbing (HLB) is the most destructive disease of citrus worldwide. The disease is caused by the proto-bacteria Candidatus Liberibacter asiaticus and transmitted by the Asian citrus psyllid Diaphorina citri. HLB symptoms are slow to appear while the tree continues to be a source of inoculum. Monitoring tree health and rapid detection of HLB is critical for sustainable citrus production. Currently, scientists are working on developing new techniques for pre symptomatic detection of HLB, as there is no available method for real-time assessment of tree health. In this study, we demonstrate the rapid and efficient discrimination between healthy and HLB-affected citrus by laser-induced breakdown spectroscopy combined with chemometric analysis. Healthy and HLB-affected trees were differentiated with a high degree of precision. The novelty of this method lies in the fingerprinting of healthy and diseased plants based on their organic and inorganic constituents, and the use of a multi-pulse laser coupled with a microscope to take spectra of the plant phloem. PMID- 30461867 TI - Wavelength-spacing-controllable multi-wavelength fiber laser based on a Lyot Sagnac filter. AB - A wavelength-spacing-controllable multi-wavelength polarization-maintaining erbium-doped fiber laser (MW-PM-EDFL) in a linear cavity configuration is presented based on a Lyot-Sagnac filter and a nonlinear optical loop mirror (NOLM). Using a Lyot-Sagnac filter as the wavelength selective filter makes the wavelength spacing controllable by adjusting the effective length of polarization maintained fiber (PMF) segments. An NOLM inducing wavelength-dependent cavity loss can be used as an amplitude equalizer, which is employed to suppress the mode competition resulting from the homogeneous line broadening effect of the erbium-doped fiber in the cavity. Thus, a stable wavelength-spacing-controllable MW-PM-EDFL is realized. In this experiment, 20 stable lasing wavelengths are obtained with a pump power of 170 mW at 980 nm when the length of the PMF is 13 m. When the length of the PMF is 8 m, 10 stable lasing wavelengths are obtained at 185 mW pump power. The power fluctuations and wavelength shifts are less than 2 dB and 0.02 nm in 1 h at room temperature. The demonstrated multi-wavelength fiber laser has great potential for applications in optical communications and optical sensing systems. PMID- 30461868 TI - Binary code DOE optimization for speckle suppression in a laser display. AB - Using a laser light source in imaging devices provides a wide color gamut, high brightness, resolution, and efficiency. At the same time, it creates a speckle pattern that deteriorates the image quality. This paper is related to the application of the moving binary code diffractive optical element (DOE) for speckle suppression in a laser display. Analytical optimization of DOE parameters is made in this paper. The optimal DOE pitch is found analytically. Limitation of the DOE code length is shown, and the highest possible code length is estimated. Application of the compound Barker code for the DOE design is suggested. As an alternative, the M-sequence and minimum peak side-lobe codes are considered. The expected residual speckle contrast ratio after application of those codes is estimated for the number of codes. A comparison of the different codes is done, and recommendations for speckle suppression DOE design are provided. PMID- 30461869 TI - Optimization method of multilayer diffractive optical elements with consideration of ambient temperature. AB - A method for the optimal design of multilayer diffractive optical elements (MLDOEs) with consideration of ambient temperature is presented to improve the image quality over the entire temperature range. The relationship between diffraction efficiency and temperature is analyzed, and an optimization process of surface relief height for the MLDOEs is given. A practical 3-5 MUm athermal hybrid optical system with a double-layer diffractive optical element is designed in the temperature range from -20 degrees C to 60 degrees C, and the image quality of two hybrid optical systems with optimized MLDOE and original MLDOE is compared. The result shows that the comprehensive modulation transfer function is obviously improved in the whole working temperature range. This method can be used during the passive athermalization hybrid optical system design with MLDOEs. PMID- 30461870 TI - Polarization imaging using an anisotropic diffraction grating and liquid crystal retarders. AB - We present a simple yet versatile and practical polarization camera for imaging full Stokes parameters. The developed system consists of one anisotropic diffraction grating plate and two electro-switchable retarders and obtains in nearly real-time full Stokes images of the light scattered from the objects. The monochromatic S3 image is obtained by physically separating the right and left circularly polarized components with the aid of the anisotropic grating, and S1 and S2 images are obtained by fast electro-switching the retardation of each retarder. The simple polarization imaging system has possible applications in various types of imaging systems and especially should be incorporated into optical microscopes as well as imaging cameras in future work. PMID- 30461871 TI - Unilateral-shift-subtracting confocal microscopy with nanoscale axial focusing precision. AB - A novel unilateral-shift-subtracting confocal microscopy (USSCM) method with nanoscale axial focusing precision is proposed based on the optical arrangement of conventional confocal microscopy (CM). As the two segments of data on both sides of the confocal axial response curve are very sensitive to variations of the axial position, USSCM introduces an axial shift of S for one segment, to intersect it with the other segment. It then separately interpolates the two segments of intersecting data, subtracts the corresponding interpolated data, and selects the data that exhibit a good linearity from all of the subtracted data to fit a straight line. It calculates the zero position of the fitting line and offsets it by S/2, to precisely reveal the focus position of the confocal system, thereby achieving high-precision imaging of the three-dimensional sample's structure. Theoretical analyses and preliminary experiments indicate that, for excitation wavelength of lambda=405 nm, numerical aperture of NA=0.95, and normalized axial shift of S=5.21, USSCM achieves an axial resolution of 3 nm and a repetitive focusing precision of 1.5 nm, while it does not change the lateral resolution of CM. Furthermore, compared with conventional CM, under the same noise condition, USSCM is less affected by system aberration, which leads to higher focusing precision. These findings demonstrate that USSCM is a very efficient method for imaging. PMID- 30461872 TI - Volume hologram replication system for spectrum-splitting photovoltaic applications. AB - A system for replicating high-efficiency volume hologram arrays, which has potential for high-volume manufacturing, is proposed. The system can meet the fabrication requirements of spectrum-splitting photovoltaic systems that are based on transmission volume holographic lens arrays. While previous hologram replication systems are mostly based on variations of the contact-copy method, the new technique is based on diffraction of reference and object beams from a master hologram through a prism and does not require contact with the copy hologram. The replication system has a number of identified advantages over contact-copy systems. An experimental volume holographic lens arrays fabricated using the proposed system had high median diffraction efficiency and low variability (95.3%+/-0.9%). PMID- 30461873 TI - Tunable broadband, wide-angle, and polarization-dependent perfect infrared absorber based on planar structure containing phase-change material. AB - A multilayer absorber composed of SiO2, Fe, Ge2Sb2Te5 (GST), and Al is designed, and the absorptive properties are theoretically investigated based on the Fresnel coefficients method in the wavelength range of 300-2500 nm by changing the thickness and crystallization rate of GST, the incident angle, and the polarization. The results show that the thin Fe layer plays a key role in obtaining an ultra-broadband perfect absorption. The absorption properties are polarization-dependent, and the perfect absorption can be nearly realized for a p polarized wave at the incident angle smaller than 75 degrees with the bandwidth larger than 316 nm at 90% of max absorption value. The absorptive peak of this absorber can be tuned with the crystallization rate of GST by temperature, and the peak wavelength moves from 1433 nm in the amorphous phase to 2051 nm in the crystalline phase. This structure can provide a feasible route to design the tunable broadband, wide-angle, and polarization-dependent perfect absorber without lithographic patterns in the infrared band. PMID- 30461874 TI - Simple spectral reduction algorithm used for the echelle spectrometer. AB - The structure of the echelle spectrometer equipped with a prism cross-dispersion element is very complex because of the nonlinear interaction between the prism and the echelle grating, which makes it difficult to extract the wavelength information from the two-dimensional spectrogram. According to the dispersion equations of both the grating and the prism direction, a wavelength calibration model is derived, establishing a relationship between the pixel position and the wavelength. It is found that a calibration process is always needed in repeated experiments due to the slight change of the spectrometer parameters caused by the environment. To solve this problem and improve the accuracy of the reduction, a simple spectral reduction algorithm involving calibration and compensation is proposed, which combines the least-square method and the polynomial fitting method. The algorithm was implemented with LabVIEW software, and the result showed that the absolute error of each wavelength was less than 0.02 nm. PMID- 30461875 TI - Method for determining the footprint center of a satellite laser altimeter based on marked waveforms by CCRs. AB - To evaluate the data accuracy of a satellite laser altimeter, in situ verification should be performed periodically, and the laser footprint center should be precisely extracted and positioned. To date, two methods have been derived to determine the center of the laser footprint: using waveform matching when a laser is illuminated on complex surfaces or using an energy detector array to capture the laser footprint when illuminating a flat calibration site. A corner cube retroreflector (CCR) array is never used to calculate the footprint center. In this study, a new method is derived to determine the laser center by analyzing the return waveforms, which are marked with a designed CCR array above ground. First, the parameters of a single CCR are designed to compensate for the velocity aberration of a satellite. The footprint center is positioned based on a damped steepest decent method when at least four CCRs are hit, and the corresponding return waveforms are marked. Next, the layout scheme of the CCRs is designed, and the positioning accuracy is evaluated using this new method. The simulated results indicate that the positioning accuracy of the laser footprint centers will be approximately 2 m horizontal. In the future, this method will be used to determine laser footprint centers and will be integrated with the current method of energy detector array in the calibration site to provide basic data to accomplish in situ verification work for the China GF-7 satellite laser altimeter. PMID- 30461876 TI - Simultaneous measurement of mode dependent loss and mode coupling in few mode fibers by analyzing the Rayleigh backscattering amplitudes. AB - In this paper, we propose and experimentally demonstrate a nondestructive method for simultaneously measuring the mode-dependent loss (MDL) and mode coupling (MC) in few-mode fibers (FMFs). The method is based on analyzing the Rayleigh backscattering amplitudes obtained with an optical time domain reflectometer (OTDR). The experimental results show that, in about 4 km six-mode FMF, the MDL and MC values are 0.132 dB and -23.13 dB/km between LP01 and LP11a, 0.176 dB and -23.73 dB/km between LP01 and LP11b, 0.272 dB and -26.17 dB/km between LP01 and LP21a, 0.284 dB and -26.70 dB/km between LP01 and LP21b, and 0.380 dB and -20.21 dB/km between LP01 and LP02. And it also demonstrated that the proposed scheme can be scalable to measure MDL and MC between higher-order modes. The values of the MC and MDL obtained by the proposed method agree well with that by the conventional transmission method. However, the proposed method has the merits of simultaneous and single-end measurement of MDL and MC in the FMF and could be a good solution to the characterization of FMFs used in large-capacity mode division-multiplexing transmission systems. PMID- 30461877 TI - Analytical procedure to assess the performance characteristics of a non spectroscopic infrared optical sensor for discrimination of chemical vapors. AB - An optical-filter-based sensor that was designed to mimic human color vision was recently developed. This sensor uses three mid-infrared optical filters to discriminate between chemicals with similar, strongly overlapping mid-infrared absorption bands. This non-spectroscopic technique requires no spectral scanning. This paper defines the selectivity and specificity of this biomimetic sensor. Receiver operating characteristic curves are presented for each target chemical. These results demonstrate that the sensor is highly selective and can provide discrimination with no false positives for three similar target chemicals acetone, hexane, and fuel oil-while rejecting potential interferents. PMID- 30461878 TI - Optical elements containing semitransparent wavelike films: erratum. AB - This erratum corrects errors in Eqs. (12) and (19) of the original paper, Appl. Opt.56, 6146 (2017)APOPAI0003-693510.1364/AO.56.006146. PMID- 30461879 TI - Broadband, high-resolution Raman observations from a double-echelle spatial heterodyne Raman spectrometer. AB - A new broadband Raman spectrometer has been developed, to the best of our knowledge, using a double-echelle spatial heterodyne Raman spectrometer (DESHRS). The instrument is constructed by using two echelle gratings. Masks are used to remove the shadow ghosts caused by the different orders of the two echelle gratings. Raman spectra of inorganic solid targets and methanol are given, and Raman shifts of up to 3000 cm-1 are obtained by the DESHRS. The instrument has shown that a broadband coverage and high resolution can be achieved simultaneously to meet the requirements of Raman measurements, covering 3590 cm 1 with 1.21 cm-1 spectral resolution. PMID- 30461880 TI - Determination of antimony in soil using laser-induced breakdown spectroscopy assisted with laser-induced fluorescence. AB - Antimony (Sb) in soil is attracting attention in the research community due to its potential toxicity and carcinogenicity. Traditional methods of detecting Sb lack the ability of rapid and nondigestion analysis, which hinders their development and application. Moreover, it is still a challenge for laser-induced breakdown spectroscopy (LIBS) to detect Sb in soil due to the weak intensities and intense interference of spectral lines. Here, LIBS, assisted with laser induced fluorescence (LIBS-LIF), was used to selectively enhance the Sb's characteristic spectral lines under optimal parameters. The quantitative analysis performance was notably improved with a determination coefficient (R2) of 0.991, the limit of detection of 0.221 MUg/g, and root mean square error of cross validation of 3.592 MUg/g. These results demonstrate that LIBS-LIF has the potential to realize the rapid and accurate analysis of Sb in soil. PMID- 30461882 TI - Plasmon coupling between complex gold nanostructures and a dielectric substrate. AB - Intercoupling of an incident electric field in metal nanoparticles causes asymmetric distribution of surface charges, which eventuates in shifting of the surface plasmon resonance frequency. This feature can be used in tuning the surface plasmon resonance and controlling the light absorption in a desired wavelength. This work provides a theoretical study of the plasmonic properties of complex gold nanostructures on a dielectric substrate where the nanoparticles have different morphologies. For analysis, we have developed a discrete dipole approximation with surface interactions-z, which is the third version of the MATLAB-based DDA-SI toolbox. In this version, lower-upper decomposition of the interaction matrix is used as a preconditioning of the LSQR iterative solver. This method accelerates the DDA-SI calculations by decreasing the total number of iteration steps and decreases the relative residual to achieve more accurate results. In the analysis, nanostructures are assumed to be gold dimers, trimers, and quadrumers with different sizes and elongations of cubical or spherical geometries on a BK7 substrate. The results show that absorption spectra exhibit both red- and blueshifted plasmon resonances in array, depending on the particle shape and elongation. The cubic structure of gold array provides the highest absorption efficiency, while the spherical structures give wider bandwidth; the combination of these structures could be used to design a system with intended features. We demonstrate that the geometrical symmetry plays an important role in the plasmon resonance of gold arrays, and it is shifted when the symmetry of the array is broken. PMID- 30461881 TI - Fourier spectrometer built by a permanent magnet cylinder falling uniformly in a conductive tube. AB - The possibility of constructing a Fourier transform spectrometer by uniform motion of a permanent magnet cylinder falling in an upright conductive tube was researched. Two identical permanent magnet cylinders were reversely connected to two ends of a non-magnetic rod, making a compound permanent magnet cylinder, to reduce the lateral swing of a single permanent magnet cylinder as it falls. Falling velocity fluctuation of the compound permanent magnet cylinder was measured by laser diode self-mixing interferometry. Spectral lines with a frequency interval of about 9 GHz could be clearly distinguished on a cosine transform spectrum of the self-mixing interference signal under a weak feedback situation. PMID- 30461883 TI - Combined reflectance spectroscopy and coherent light backscattering measurement differentiate cervical cancer from normal epithelial tissue in a xenograft mouse model. AB - Cervical cancer is a type of slow-growing cancer associated with high mortality rates. Early detection can enable lifesaving early intervention. Current cervical premalignant lesion detection methods suffer from both high miss rates and excessive referrals for unnecessary biopsies. Herein, coherent light backscatter and modifications in reflected white-light spectra were measured to specifically discriminate between cervical tumors and normal squamous epithelial tissues resected from a mouse xenograft model. The combined measurements resulted in 92% sensitivity and 93% specificity in discrimination between the two tissues. These methods can be used to develop a noninvasive portable optical probe for sensitive and objective detection of precancer and cancer epithelial lesions in the cervix and other accessible epithelial tissues. PMID- 30461884 TI - Tunable leaky-wave radiation by graphene-covered corrugated surfaces. AB - In this paper, we propose a graphene-covered subwavelength metallic grating where the Fermi level of graphene is sinusoidally modulated as a leaky-wave antenna at terahertz frequencies. This structure can convert spoof surface plasmon guided waves to free-space radiation due to the tunability of graphene. Analysis and design of the proposed leaky-wave antenna are discussed based on sinusoidally modulated surface impedance. The surface impedance is obtained by an analytical circuit model. The sinusoidal surface impedance is realized using modulation of the conductivity of graphene by applying a bias voltage. The proposed leaky-wave antenna is capable of electronic beam scanning with an almost constant gain and low sidelobe level by tuning the graphene Fermi level. In addition, a mode converting section is proposed that drastically improves the return loss of the antenna. PMID- 30461885 TI - Prescription of wavelength-dependent spot size relations of a broadband laser diode in the context of uniformly maximum lens excitation of WDM signals. AB - We prescribe an empirical relationship between spot size and emitted wavelength for a semiconductor laser diode generating a broad spectrum of light in the near infrared range of 1.5-1.6 MUm. Then, we establish uniformly maximum launch optics employing these relations in the case of hyperbolic microlens lens excitation of a step index single-mode fiber using this source. Subsequently, we explain the necessity of this source in the context of wavelength-division multiplexing (WDM) and dense WDM signal transmission with guidelines inviting its fabrication. PMID- 30461886 TI - Multi-spectral image shift-estimation error calculations using simulated phenomenology. AB - Registration of multi-spectral imagery is a critical pre-processing step for applications such as image fusion, but phenomenological differences between spectral bands can lead to significant estimation errors. To develop credible requirements for multi-spectral imaging systems, it is critical to characterize errors, both algorithmic and fundamental, associated with estimating registration parameters; however, attempting to quantify error using archival data sets poses a number of problems. In this paper, we demonstrate the use of commercially available graphics software and available optical property measurements to create fully synthetic, multi-spectral imagery with high-fidelity representations of emissive and reflective phenomenology. We discuss and demonstrate techniques needed to quantify error for both area- and feature-based algorithms. We further show that such synthetic data sets can be used to quantify both the Fisher information and sample errors associated with estimation of the shift between images acquired in different spectral bands and, by extension, estimation of registration model parameters. With the flexibility offered by synthetic data, such characterization can be obtained for robust domains of image brightness, sensor parameters, and differences in image phenomenology. PMID- 30461887 TI - Propagation properties of a twisted rectangular multi-Gaussian Schell-model beam in free space and oceanic turbulence. AB - With the paraxial approximation, we derive the analytical formulas for the propagation of a twisted rectangular multi-Gaussian Schell-model (TRMGSM) beam in free space and oceanic turbulence. The spectral density and degree of coherence of the TRMGSM beam both in free space and oceanic turbulence are investigated. We found that the oceanic turbulence barely had any influence on the rotation effect both of the spectral density and degree of coherence. In addition, we found that the spot could degenerate into a Gaussian profile caused by a turbulence medium. Furthermore, for stronger turbulence, the beam spot spreads more rapidly, and the coherence region decreases faster. In this paper, we also study the effect of the twisted factor on the propagating properties. PMID- 30461888 TI - Joint digital-optical design of complex lenses using a surrogate image quality criterion adapted to commercial optical design software. AB - Like classical optical design, joint digital-optical design of complex lenses requires a skilled optical designer helped by powerful optical design software. Consequently, if optimization criteria have to be modified to take into account digital post-processing, the convenient optimization environment provided by commercial optical design software needs to be preserved. For that purpose, we define a joint-design criterion based on a merit function that contains terms classically implemented in optical design software but used in a non-standard way. After validation on a simple design problem, the proposed method is applied to the design of a very fast (f/0.75) complex lens. The obtained joint-designed lens is shown to be superior to a classically designed one in terms of weight and image quality in the field. PMID- 30461889 TI - Crystallization-sapphire-derived-fiber-based Fabry-Perot interferometer for refractive index and high-temperature measurement. AB - A crystallization-sapphire-derived-fiber (CSDF)-based Fabry-Perot interferometer (FPI) for refractive index (RI) and high-temperature measurement is proposed and demonstrated. The FPI is formed by splicing sapphire-derived fiber (SDF) to the end face of a well-cleaved single-mode fiber (SMF). CSDF is generated hundreds of micrometers away from the fusion joint resulting from arc discharge and then cuts the SDF to the edge of the CSDF. The FPI consists of two cavities, one of which is formed by CSDF, and the other is SDF, between the SMF and CSDF. The fringe contrast of the reflection spectrum varying with the RI changes of the external environment is used for RI sensing, while the wavelength shifting is for the ambient temperature sensing. In the experiment, the refractive index and temperature sensitivities are about 233.8 dB/RIU in the RI range of 1.333-1.363 and 13.571 pm/ degrees C in the temperature range of 20 degrees C-1000 degrees C. PMID- 30461890 TI - Praseodymium ion doped K+-Na+ thermal ion-exchangeable waveguide-adaptive aluminum germanate glasses. AB - Intense multi-peak red fluorescence and effective near-infrared (NIR) ultra broadband emission have been observed in Pr3+ doped ion-exchangeable aluminum germanate (NMAG) glasses. The maximum emission cross section for P03->F23 red emission is up to 100.58*10-21 cm2, and the NIR emission corresponding to D21 >G41 transition possesses a full-width at half-maximum (FWHM) of 210 nm. Although the obvious cross-relaxation (CR) process at high concentration causes a decrease of the quantum efficiency, the CR broadens the spectral FWHM effectively from another perspective. The admirable red fluorescence trace and the NIR single-mode transmission confirm that Pr3+ doped NMAG glass planar waveguides can support the generation of visible fluorescence and the amplification of infrared signal. For a waveguide channel ion-exchanged in molten KNO3 for 2 h, the single-mode field diameters at 1.55 MUm are identified to be 10.4 MUm in the horizontal direction and 6.5 MUm in the vertical direction, implying an acceptable overlap with a standard single-mode fiber. Effective red fluorescence and broad NIR emission demonstrate that Pr3+ doped NMAG glasses are a promising substrate in developing irradiative luminescence sources and ultra-broadband waveguide amplifiers, especially operating at the entire S-, C-, and L- bands. PMID- 30461891 TI - High-intensity x-ray microbeam for macromolecular crystallography using silicon kinoform diffractive lenses. AB - Macromolecular crystallography often requires focused high-intensity x-ray beams for solving challenging protein structures from micrometer-sized crystals using current synchrotron radiation sources. The design of optical focusing schemes for hard x-rays showing high efficiency and flexibility in beam size is therefore continuously pursued. Here, we present an innovative solution based on a two stage demagnification of the undulator source for photon energies from 6 keV to 19 keV, commissioned at the X10SA beamline of the Swiss Light Source, where a secondary source is imaged by two crossed silicon kinoform x-ray diffractive lenses with 75 nm outermost zone width. A source-size limited spot with a size of 4.8 MUm*1.7 MUm(h*v,FWHM) and flux of 7.5*1010 photons/s at 12.4 keV is demonstrated at the sample position. PMID- 30461892 TI - Tunable reflective color filters based on asymmetric Fabry-Perot cavities employing ultrathin Ge2Sb2Te5 as a broadband absorber. AB - We demonstrated a tunable structural color filter based on an asymmetric Fabry Perot cavity employing germanium antimony tellurium alloy Ge2Sb2Te5 (GST) as a switchable ultrathin lossy layer. The color tunability and switch mechanism of our designed structure were investigated by both simulation and analytical approaches. Both numerical simulations and analytical results show that the tunable reflective colors can be generated through the reversible phase transition of GST from amorphous to crystalline. Additionally, the generated colors possess high brightness, high saturation, and a wide gamut. Our designed structure will inspire phase-transition-based systems' potential applications in colorimetric sensing, smart windows, full-color printing and displays, anti counterfeiting, and data encryption. PMID- 30461893 TI - Simple and fast approach to exploit the spectral reflection properties of liquid media. AB - Bidirectional reflectance distribution functions (BRDFs) are of importance for their wide applications. In this study, we presented a simple and fast approach to measure the spectral BRDF of both solid and liquid samples. Based on this approach, we fabricated a prototype and measured the BRDF value of some liquid samples such as water and NaCl solution at different wavelengths. According to the experimental data, we discussed the trend of the BRDF value of the NaCl solution of different concentrations. Then, the experimental data of the different NaCl solution at 637 nm were used to invert the parameters of a five parameter model. Additionally, we fitted the parameters as a polynomial. PMID- 30461895 TI - Reconstruction method of axisymmetric refractive index fields with background oriented schlieren. AB - A refractive index field can be quantitatively visualized by using a background oriented schlieren (BOS) technique to measure the displacements of background dot patterns of a 2D image captured by a camera. In BOS, the displacement is caused by the deflection of the light ray passing through the refractive index field. However, obtaining depth information of refractive index fields is often difficult because dot-pattern displacement results from deflection of light rays integrated over their path. A method of reconstructing depth information of the refractive index field using an inverse matrix method with the BOS technique is proposed here under the assumption of an axisymmetric refractive index field. A field, generated by laser irradiation inside a glass, is reconstructed by the proposed method and is also theoretically calculated using the heat diffusion equation and thermal stress theory. The reconstructed field agrees well with the theoretically calculated one, which validates the proposed method. The proposed method is a promising candidate for measuring axisymmetric refractive index fields of various media. PMID- 30461894 TI - Lyapunov exponent analysis for the evaluation of hybrid laser double-arc welding process stability. AB - Hybrid laser double-arc welding is a complicated process with many random and uncertain influencing factors because of the interactions of energy, forces, and fields. The wire spacing is one of the main factors affecting the coupling behavior of laser and arc plasma and the stability of welding process. However, it is difficult to establish a precise mathematical model for evaluation of welding stability. In this paper, the largest Lyapunov exponent (LLE) of characteristic currents during the welding process under different wire-wire distances were numerically evaluated by the phase space reconstruction technique. Synchronous high-speed photography was adopted to observe arc shape and droplet transfer. The experimental and calculated results indicate that hybrid laser double-pulsed arc welding is a complex process of chaos. The LLE can provide a criterion for welding stability and can agree well with the observation of electrical signal, arc shape, and droplet transfer. Research results are needed to understand the welding process and to guarantee a stable and safe joining. PMID- 30461896 TI - Flexible control of transmitting terahertz beams based on multilayer encoding metasurfaces. AB - The concept of encoding metasurfaces makes a connection between the physical metamaterial particles and the digital code so the digital coding can be performed on the coding surface for signal processing to achieve unusual physical phenomena. Here, a complete 2pi transmission phase with high efficiency at the target frequency can be manipulated by a multilayer metasurface structure. Different period sequence codes are designed to obtain the deflection angles, and then a new sequence is obtained through a four-bit system operation sequence according to the Fourier convolution principle. This study shows that Fourier calculation provides an efficient way to optimize the coding to achieve a pre designed transmitted beam. The advantage of this method over previous solutions in generating an anomalous single transmission beam is its flexibility and continuous control of arbitrary directions, and it is possible to transmit a normally incident terahertz beam to an abnormal arbitrary direction with cross polarization. This work opens up a new digital perspective on the new approach to metamaterials, predicting the possibility of combining electromagnetic wave operations with the convolution theorems in digital signal processing and the transcoding surface. PMID- 30461897 TI - Extending a set of well-focused beams described by gamma and gamma-coupled functions. AB - A set of rotationally symmetric, paraxial gamma and gamma-coupled beams [introduced in Appl. Opt.57, 3653 (2018)APOPAI0003-693510.1364/AO.57.003653] is extended with other well-focused higher-order beams described by the gamma and gamma-coupled functions with extra free parameters. A computer simulation of the propagation characteristics of some new parametrically optimized higher-order beams with a sharp central peak demonstrates that, in relation to the previous gamma and gamma-coupled beams, most of the new beams have elevated levels of sidelobes in the waist plane. At the same time, the new beams have far more propagation stability over an extended depth of field. In relation to similar Bessel-Gauss beams, these beams have a much better spatial localization of their energy. PMID- 30461898 TI - Direct absorption spectroscopy baseline fitting for blended absorption features. AB - A method for determining the gas concentration from blended absorption features using direct absorption spectroscopy is developed. Blended spectra occur when multiple absorption lines are in close proximity in a laser scan and/or when pressures begin to increase. The blended-feature baseline fitting method estimates the baseline by coupling measured data with simulated fractional transmission at the peaks between absorption features. The method is first validated with synthetically created data. The method is then demonstrated using the absorption lines of CO2(P41e,P42f,P34e,P43e) and H2O in the nu1+nu3 combination band (3683.5 cm-1 to 3686.5 cm-1) in a heated static test cell. Results from the fitting method and wavelength modulation spectroscopy measurements agree within 1%. The method is finally applied to measurements of flue gas emissions from a practical combustion system (wood boiler) and compared to measurements from a hand-held gas analyzer. The mean percent difference of the blended-feature baseline fitting and the wavelength modulation spectroscopy is 2.8% and 5.8% for XCO2 and XH2O, respectively, indicating that this method of direct absorption data analysis can be used for spectra with moderate feature blending, which is useful for scan ranges with multiple closely spaced absorption lines and moderate pressures. PMID- 30461899 TI - Influence of ambient temperature on the modulation transfer function of an infrared membrane diffraction optical system. AB - In this paper, we present a model that analyzes the influence of the temperature on the modulation transfer function (MTF) of an infrared membrane diffraction optical system. Based on the physical imaging mechanism of diffractive optical systems, the imaging characteristics of the diffraction optical system are characterized by using diffraction efficiency. Then we establish the corresponding calculation model and MTF analysis model based on scalar diffraction theory. In particular, considering the material properties of flexible membrane optical elements and thermal environment effect, the Zernike polynomials are used to establish the thickness distribution model of the membrane diffractive optical components combined with the finite element analysis. After that, we modify the MTF calculation model of diffraction optical system and accordingly propose the model of the infrared membrane diffraction optical system. Finally, we present some experimental results for a 2-m infrared membrane diffraction optical system. The results show that when the temperature is -40 degrees C and wavelength band is 80 nm at the center field of view, the diffraction efficiency is reduced to 81%, and MTF at 75 l p/mm is reduced to 0.12. And when the temperature is -40 degrees C at edge field of view, the efficiency at center wavelength is reduced to 71%, and MTF at 75 l p/mm is reduced to 0.02. The established model and method can be used to estimate the imaging performance of a space infrared membrane diffractive telescope and provide theoretical guidance for the processing algorithm and imaging system design. PMID- 30461900 TI - Polymer-based diffractive optical elements for rear end automotive applications: design and fabrication process. AB - Advances in illumination technology in the automotive industry are heading toward the use of coherent sources for adaptable and high-resolution head lamps as well as interior and rear-end lights. We present a cost-effective method to fabricate and design laser-based lighting systems for the rear end in automobiles and other vehicles. The design relies on using binary gratings to generate a desired intensity distribution. For cost-effective fabrication, an optical maskless UV lithography system that employs a spatial light modulator (SLM) for projection of the desired structure onto photoresist is introduced. To replicate the structures onto polymers like poly(methyl methacrylate) (PMMA), we use polydimethylsiloxane soft stamps and a hot embossing system. The experimental results show that the proposed design and fabrication process is promising for high-resolution rear-end lights that might be employed to project symbols or information to guide road users in future. PMID- 30461901 TI - Finite-element reconstruction of 2D circular scanning photoacoustic tomography with detectors in far-field condition. AB - The finite-element method (FEM) has been a powerful numerical tool for the reconstruction of 2D circular scanning-based photoacoustic tomography (PAT) for its unrivaled ability to accommodate complex boundary conditions, quantitatively reconstruct different physical parameters, and enable low sampling frequency and fewer detector numbers. To reduce the computation cost, a smaller image domain is commonly used instead of the region surrounded by the transducer scanning trace. Then, the pressure data used for the reconstruction that is defined on the boundary of the image domain is usually obtained by directly time delaying the actual measured data. In this case, distortions will be aroused for targets that are away from the rotation center. In this work, we put forward a new data preprocessing method to overcome this problem with a virtual detector concept, in which the measured data for the virtual point detectors on the boundary of the reconstruction domain are generated by a summation of the signals from nearby true detectors. The complete removal of the distortions using our proposed algorithm was proven with experimental reconstruction results. PMID- 30461903 TI - Rigorous electromagnetic theory for waveguide evanescent field fluorescence microscopy. AB - Recently, waveguide evanescent field fluorescence (WEFF) microscopy was introduced and used to image and analyze cell-substrate contacts. Here, we establish a comprehensive electromagnetic theory in a seven-layer structure as a model for a typical waveguide-cell structure appropriate for WEFF microscopy and apply it to quantify cell-waveguide separation distances. First, electromagnetic fields at the various layers of a model waveguide-cell system are derived. Then, we obtain the dispersion relation or characteristic equation for TE modes with a stratified media as a cover. Waveguides supporting a defined number of modes are theoretically designed for conventional, reverse, and symmetric waveguide structures and then various waveguide parameters and the penetration depths of the evanescent fields are obtained. We show that the penetration depth of the evanescent field in a three-layer waveguide-cell structure is always lower than that of a seven-layer structure. Using the derived electromagnetic fields, the background and the excited fluorescence in the waveguide-cell gap, filled with water-soluble fluorophores, are analytically formulated. The effect of the waveguide structures on the fluorescence and the background are investigated for various modes. Numerical results are presented for the background and the stimulated fluorescence as functions of the water gap width for various waveguide structures, which can be used to find the water gap width. The results indicate that the background and excited fluorescence increase by increasing the penetration depth of the evanescent field. In addition, we show that for various guided modes of a conventional waveguide, the electric fields in the cell membrane and the cytoplasm are evanescent and they do not depend on the waveguide structure and the mode number. However, for the reverse symmetry and symmetric waveguide structures, the waves are sinusoidal in the cell membrane and the cytoplasm for the highest-order modes. PMID- 30461902 TI - Thermal dephasing in an enhanced cavity based high-power second harmonic generation. AB - We report on the performance of an enhanced-cavity (EC) designed for obtaining high-power and efficiency second-harmonic generation (SHG). This is performed by numerical simulation of SHG coupled equations in the presence of a thermal dephasing effect that is effectively intensified through embedding the periodically poled LiNbO3 crystal by an oven-surrounded scheme. It is found that by setting the PPLN temperature at an optimum value, adjusting the mirror reflectively, and pumping power at certain values, gaining SHG efficiency of more than 90% is possible. We further realized that by an ECSHG device SHG efficiency can be improved by about 15%-50%. Moreover, compared to a single-pass SHG scheme, the EC-based SHG device is shown to be a very promising candidate to reduce and suppress the effect of thermal dephasing on the stability and efficiency of SHG radiation. PMID- 30461904 TI - Performance evaluation of perfect optical vortices transmission in an underwater optical communication system. AB - In this paper, we experimentally evaluated the performance of underwater optical communications using 1 Mbit/s on-off keying signals of perfect optical vortices. Perfect optical vortices generated by Fourier transformation of the Bessel Gaussian beam are propagated through a 2.6 m underwater medium and affected by various water conditions such as stagnant water, water flow, temperature difference, and air bubbles, so beam wander and fluctuation of the signal are studied. Air bubbles have the maximum effect on signal fluctuations and beam wanders. Measurement of the system bit error rate (BER) based on the signal-to noise ratio (SNR) for these situations matches the results of wandering and fluctuations. The system BER is studied for different values of SNR, and its value is more degraded due to the air bubbles. PMID- 30461905 TI - Reciprocity and Babinet's principles applied to the enhancement of the electric and magnetic local density of states in integrated plasmonics on silicon photonics. AB - Here, reciprocity and Babinet's principles were applied to the design of integrated plasmonic structures on silicon photonic waveguides. Numerical analyses and near-field optical microscopy observations show that one of the hybrid photonic-plasmonic structures exhibits high confinement and enhancement of the electric field, and, through Babinet's principle, the magnetic field of its complementary structure is confined and enhanced as well. Reciprocally, due to the modification of the electric and magnetic local density of states, enhanced emission of electric and magnetic dipoles by Purcell effect were obtained into specific silicon photonic modes. Such structures can be advantageously implemented for on-chip integrated single-photon sources. PMID- 30461906 TI - Generation of an optical frequency comb based on two cascaded dual-parallel polarization modulators. AB - Generation of an optical frequency comb (OFC) based on two cascaded dual-parallel polarization modulators (DPPolMs) is proposed for the first time, to the best of our knowledge. The proposed method offers superior spectral flatness and improved side-comb suppression ratio (SCSR), and requires low radio frequency drive voltage compared to two cascaded polarization modulators based on OFC generation found elsewhere in the literature. Detailed investigation is carried out through theory and simulation for 25, 49, 81, and 121 comb lines generated with the proposed two-stage OFC generator. Theoretically obtained parameters are used in the simulation to obtain the desired results. In particular, for 49 lines of OFC generation, 1 dB power fluctuation in amplitude and 16.5 dB SCSR are obtained at a comb frequency spacing of 3.5 GHz, which outperforms any polarization modulator based OFC generator. PMID- 30461908 TI - Synthesis of one-dimensional calcium silicate nanowires as effective broadband optical limiters. AB - Synthesis of inorganic nanostructures with novel morphologies has attracted increasing attention from chemistry and materials science researchers. Calcium silicate nanowires (CaSiO3 NWs) were successfully prepared using a water-ethanol mixture solution system via hydrothermal synthesis. The resulting CaSiO3 NWs were uniform, with widths averaging 10-20 nm and lengths up to several micrometers. The synthesized silicate NWs were highly crystalline and mainly constituted of SiO4 tetrahedra. The nanosecond optical limiting (OL) effects were characterized using an open-aperture (OA) Z-scan technique with 4 ns laser pulses at 532 and 1064 nm. These CaSiO3 NWs exhibited excellent OL performance, superior to that of carbon nanotubes, which are a benchmark optical limiter. Input-fluence-dependent scattering measurements suggested that nonlinear scattering played an important role in the observed OL behavior in the CaSiO3 NWs at 532 and 1064 nm. This study provides new insights into the silicate nanowires, which will help in the design and preparation of 1D materials with improved nonlinear optical properties. PMID- 30461909 TI - Single-cell Raman spectroscopy reveals microsporidia spore heterogeneity in various insect hosts. AB - Single-cell Raman spectroscopy was used to analyze the spore heterogeneity of 16 microsporidia strains from various insect hosts in order to better understand the basic biology of microsporidia. The Raman spectrum of a single spore revealed basic spore composition, and microsporidia spores in various hosts were found to be rich in trehalose. Principal component analysis and Raman intensity showed obvious heterogeneity in the trehalose, nucleic acid, and protein content of various spores; however, there was no correlation between various spore groups and host type. Trehalose content correlated with spore infectivity on Bombyx mori. Raman spectroscopy is an excellent tool for label-free investigation of intercellular molecular constituents, providing insight into the heterogeneity of microsporidia spores. PMID- 30461907 TI - High-speed three-dimensional measurement technique for object surface with a large range of reflectivity variations. AB - It is a challenge for any optical method to measure object surfaces with a large range of reflectivity variations. Dark or saturated regions on fringe images may lead to phase and measurement errors. At present, the main defect of the existing methods is the low measurement efficiency. This paper presents a high-speed three dimensional (3D) measurement for object surfaces with a large range of reflectivity variations. First, we set the intensity of the projected fringes to the maximum, which ensures a better signal-to-noise ratio (SNR) of fringe images compared to the traditional methods. Second, in order to achieve high-speed projection, we transform 12 fringes with 256 gray-value cosine variations to binary fringes and defocus the digital light procession to filter out the higher harmonics. Third, since manually adjusting the camera lens or exposure time is much more time-consuming and not conducive to improving the SNR, we use the color light projection of the projector itself to get multiple groups of fringe sequences with different brightnesses. Finally, the final group of fringe images, used for 3D reconstruction, are formed by choosing the brightest but unsaturated corresponding pixels from multiple groups of fringe images. Experiments verified that the proposed method has the advantages of high-speed measurement, low cost in hardware, high measurement accuracy, a simple algorithm, and ease of extending to several applications. PMID- 30461910 TI - Three-component homovibrational vector hydrophone based on fiber Bragg grating F P interferometry. AB - A fiber optic vector hydrophone is an interesting topic for many applications. Using a fiber Bragg grating (FBG) as a reflection unit, the vector hydrophone combines the advantages of miniaturization, high reliability, and low cost. In this paper, the interferometric vector sensing, multiplexing design, and cross talk suppression of a fiber optic vector hydrophone based on FBG-based Fabry Perot interferometry are discussed and validated. The average cross talk of the channels is reduced by 20 dB than that of a high-reflectivity grating by using 1% reflectivity fiber gratings. A three-component homovibrational vector hydrophone with a low-reflection FBG was developed and tested. The working band of the hydrophone is extended to 20 Hz, and the sensitivity of each vector channel is about -132.5 dB at 500 Hz and its directivity index is more than 30 dB at 100 Hz. PMID- 30461911 TI - Limits on field of view for Risley prisms. AB - The constraints on directions of incoming and outgoing rays of Risley prisms, caused by total internal reflection and surface tilt, are investigated for the four typical configurations. After applying a nonparaxial ray-tracing method based on the vector form Snell's law, the incident angles at prisms' surfaces are calculated and compared with the critical angle. On this basis, the direction limitations of incoming and outgoing rays are investigated. The permissible incoming directions as well as the achievable outgoing directions depend on prisms' orientation. Their ranges over which the rays can pass through the system at any prism orientation are defined as the angular aperture and angular field of view (FOV). The effects of the prisms' refractive index, opening angle, and arrangement on angular aperture/FOV are discussed. It is shown that there exists a direct trade-off between the deviation power and the angular aperture/FOV for Risley prisms, that is, high refractive index and large opening angle yield a smaller angle aperture/FOV. Large angular aperture can be achieved by employing the 2121 configuration, while it is desirable to adopt a 1212 configuration to obtain large angular FOV. The research can afford guidance for prism material, geometry choices, and configuration setting in the design of a Risley prism system for wide-angle beam steering or imaging adjustment. PMID- 30461912 TI - Study on the backscattering disturbance in duplex underwater wireless optical communication systems. AB - Backscattering affects the performance of receivers in duplex underwater wireless optical communication (UWOC) systems. In this work, we study this issue using the Monte Carlo method. We show that with an increase of transmitter divergence angle, backscattering light power changes little while communication signal and optical signal-to-noise ratio (OSNR) are reduced dramatically at the receiver. With an increase of receiver field angle, backscattering light power becomes higher, communication signal is nearly unchanged, and OSNR is reduced greatly. With an increase of the separated distance between receiver and transmitter in each terminal, backscattering light power decreases quickly, communication signal is unchanged, and OSNR increases rapidly. With an increase of communication distance, backscattering light power is almost unchanged while both the communication signal and OSNR are reduced drastically. We demonstrate that, to reduce the impact of backscattering disturbance, the transmitter and receiver in each terminal should be placed at a greater distance and the latter should be with a smaller field angle. When the transmitting optical power or receiving sensitivity is too high, such disturbance is hard to suppress effectively. In this case, the system should work in half-duplex mode. These results will be useful for duplex UWOC system design. PMID- 30461913 TI - Sensitivity improvement by optimized optical switching and curve fitting in a cavity ring-down spectrometer. AB - We presented methods for the improvement of the sensitivity of a cavity ring-down spectrometer other than modifying the cavity length and the mirrors. As for the light switching, a fast driving scheme was proposed to address the slow switching speed of the boost optical amplifier, which makes it have only half of the switching time of that for the common acoustic-optical modulators and electro optical modulators, as well as have higher extinction ratios. This effectively suppressed the distortions of the ring-down signals. We further adopted a realistic non-exponential curve-fitting method, taking into account the switching speed and the delayed triggering of the optical switch. These methods help accurately determine the ring-down time constants, which in turn reduced the Allan variance of the measurement results and increased the sensitivity. We performed tests at different repetition rates and all of them revealed more than 30% sensitivity improvement. At a rate of 16 kHz, we increased the minimal detectable absorption of 9.1*10-11 cm-1 to 5.7*10-11 cm-1. The effectiveness of these upgrades could benefit many spectroscopic applications of the cavity ring down spectroscopy, especially for frontier research that requires sensitive measurement and high-quality spectral data. PMID- 30461914 TI - Design of a retina-like transmitting system based on a curved lens array. AB - In order to reduce data redundancy and improve scanning efficiency in three dimensional imaging, a retina-like transmitting optical system based on a curved lens array (CLA) is proposed. The mathematical model for the transmitting system is developed, and associated parameters for the space-variant CLA are studied. Model testing validates that the transmitting system bears flexible scanning field of view and achieves scanning efficiency up to 80%. Imaging simulations show that the proposed scanning method utilizing the logarithmic-polar imaging characteristics efficiently detects secondary targets. Furthermore, simulation results show that the parameters of the single lens in the lens array are not fixed, but flexible, which facilitates the corresponding structural design. PMID- 30461915 TI - Plasmonic topological edge states in ring-structure gate graphene. AB - Topological photonic states exhibit unique robustness against defects, facilitating fault-tolerant photonic device applications. However, existing proposals either involve a sophisticated and bulky structure or can only operate in the microwave regime. We show a theoretical demonstration for highly confined topologically protected plasmonic states to be realized at infrared frequencies in monolayer graphene with a ring-structure gate. With a suitable bias voltage, the combined gate-graphene structure is shown to produce sufficiently strong Bragg scattering of graphene surface plasmons and to impart them with nontrivial topological properties. Our design is compact and could pave the way for dynamically reconfigurable, robust, nanoscale, integrated photonic devices. PMID- 30461916 TI - Real-time layer-based computer-generated hologram calculation for the Fourier transform optical system. AB - With the growing interest for augmented reality devices, holography is often considered as a promising technology to overcome the focus issues of conventional stereoscopic displays. To enlarge the field of view of holographic head-mounted displays, a Fourier transform optical system (FTOS) has been proposed. However, since the scene geometry is distorted by the FTOS, it is necessary to compensate the position of each scene point during the hologram computation, resulting in long calculation times. In this paper, we propose a real-time computer-generated hologram calculation method for the FTOS. Whereas previously proposed methods used a ray-tracing approach to compensate the distortion induced by the FTOS, our proposed method relies on a layer-based approach. Experimental results show that our method is able to compute holograms of resolution (3840*2160) in real time at 24 frames per second, enabling its use in augmented reality applications. PMID- 30461917 TI - Bendable large-mode-area fiber with a non-circular core: publisher's note. AB - This publisher's note amends the spelling of the second author's name in Appl. Opt.57, 6388 (2018)APOPAI0003-693510.1364/AO.57.006388. PMID- 30461918 TI - Hardware and software improvements to a low-cost horizontal parallax holographic video monitor: publisher's note. AB - This publisher's note corrects a trademark concern in Appl. Opt.57, A122 (2018)APOPAI0003-693510.1364/AO.57.00A122. PMID- 30461919 TI - Polarization evolution in single-ring antiresonant hollow-core fibers. AB - Understanding polarization in waveguides is of fundamental importance for any photonic device and is particularly relevant within the scope of fiber optics. Here, we investigate the dependence of the geometry-induced polarization behavior of single-ring antiresonant hollow-core fibers on various parameters from the experimental perspective, showing that structural deviations from an ideal polygonal shape impose birefringence and polarization-dependent loss, confirmed by a toy model. The minimal output ellipticity was found at the wavelength of lowest loss near the center of the transmission band, whereas birefringence substantially increases toward the resonances. The analysis that qualitatively also applies to other kinds of hollow-core fibers showed that maximizing the amount of linearly polarized light at the fiber output demands both operating at the wavelength of lowest loss, as well as carefully choosing the relative orientation of input polarization. This should correspond to the situation in which the difference of the core extent along the two corresponding orthogonal polarization directions is minimal. Due to their practical relevance, we expect our findings to be very important in fields such as nonlinear photonics or metrology. PMID- 30461920 TI - Intensity enhancement in off-axis integrated cavity output spectroscopy. AB - In the field of laser-based absorption spectroscopy, off-axis integrated cavity output spectroscopy is considered to be a sensitive and robust method, employing a simple optical design. However, one of the major drawbacks of non-mode-matched cavities combined with highly reflective mirrors (>99.98%) is its low output intensity. Here, we systematically investigate the increase in cavity output intensity, using a third re-injection mirror before the absorption cavity. The presented design not only enables high transmission power but also retains a long effective path length. To investigate the intensity enhancement, we used a CO2 absorption line in the near-IR wavelength region at 6240.10 cm-1. In agreement with our simulation model, we achieved an intensity enhancement factor of 38. We achieved a noise equivalent absorption sensitivity to 1.6*10-8 cm-1 Hz-1/2, which is no longer limited by the detectivity of the detector. PMID- 30461921 TI - Integrated all-optical wavelength and polarization conversion of orbital angular momentum carrying modes. AB - Wavelength division multiplexing (WDM) using higher-order spatial modes such as orbital angular momentum (OAM) through a channelized bandwidth provides enhanced capacity communication systems. An all-optical wavelength converter is a key function in implemented WDM networks to overcome the wavelength contentions. In addition, a polarization converter provides efficient control on the state of polarization for encoded data channels in the optical networks. This paper proposes a novel versatile-designed integrated optical device with Ycut ridge lithium niobate photonic wire configuration that acts as a wavelength or polarization converter for data modulated on OAM. It is schemed in such a way that generates decomposed guided modes with a new wavelength and polarization via cascaded second harmonic generation/difference frequency generation (cSHG/DFG) and type-II DFG nonlinear interactions, respectively, where their desired relative phase is achieved by a linear electro-optical effect in the successive phase shifter part. The low loss <=0.09 dB/cm, high purity (>=94%), and low voltage (<=4 V) of the high-speed proposed modulator enable its compatible operation in commercial wireless and fiber-based polarization-multiplexed WDM communication systems. PMID- 30461922 TI - Polarization properties of reflected light with natural light incidence and elimination of angle of incidence ambiguity. AB - Polarization imaging technology provides information about not only the irradiance of a target but also the degree of polarization and angle of polarization, which indicate extensive application potential in the field of ocean remote sensing. Natural light can be converted into partially polarized light by the reflection from an interface, and the Fresnel equations can describe the quantitative relationship between the angle of incidence and the degree of polarization of the reflected light. However, the relationship between the angle of polarization and angle of incidence has rarely been studied. In this study, we investigate the polarization state model of reflected light and establish the relationship between the angle of polarization and angle of incidence. This is verified using polarization imaging experiments on a glass plate and calm water surface. The results indicate that the theoretical model agrees well with the experimental results. A method to eliminate the ambiguity of the angle of incidence is proposed based on the model, and its effectiveness and feasibility are verified. It lays the theoretical foundation for imaging detection based on the polarization imaging of transparent media surfaces and sea surface ripples. PMID- 30461923 TI - Direct binary search for improved coherent beam shaping and optical differentiation wavefront sensing. AB - Spatially dithered distributions of binary amplitude pixels are optimized using a full direct binary search, taking into account the experimental configuration for amplitude modulation of coherent waves. This design process is shown to yield a significant reduction of the noise induced by binarization and pixelation over the region of interest. We demonstrate this approach for beam shaping and optical differentiation wavefront sensing, where the region of interest is in an image plane of the pixel distribution, and in the far field of the pixel distribution, respectively. The observed reduction in error compared to a standard error diffusion algorithm is significant for both applications because it improves performance without the tighter fabrication tolerance and cost associated with smaller pixels. PMID- 30461924 TI - Method for estimating the Stark splitting of rare-earth ions from the measured cross-section spectra. AB - A method to estimate the Stark levels of the rare-earth ions doped in a laser medium from the measured emission and absorption cross-sections is proposed. The method is based on the McCumber theory, which can calculate the emission/absorption cross-sections from the given Stark levels. By fitting the calculated emission/absorption spectra to the measured ones through a numerical optimization process, the Stark levels of the RE ions can be determined. As examples, the Stark levels of the laser-emission-related manifolds of Er3+ and Yb3+ ions in a gain fiber and two doped glasses have been determined by the proposed method. The data were then used to analyze the temperature-dependent population of the Stark levels. This method avoids the difficulties in direct measurement of the Stark levels in a cryogenic temperature environment. It is important to the evaluation of the thermal load, distribution, and design of the thermal management system of high-power fiber lasers and amplifiers. PMID- 30461925 TI - Electro-optic phase modulation with a symmetrical metal-cladding waveguide. AB - A bulk electro-optic (EO) modulator based on the ultrahigh-order guided modes, which are excited in a symmetrical metal-cladding waveguide (SMCW), has been exploited. This kind of mode in a SMCW has high sensitivity to phase shift by changing the refractive index of the guiding layer. Compared with phase modulation via the bulk EO modulator without a waveguide, the applied half-wave voltage is reduced for one magnitude. This work may have practical applications in optical information processes. PMID- 30461926 TI - Calibration of a three-dimensional laser Doppler velocimeter in a land integrated navigation system. AB - In the land navigation field, a laser Doppler velocimeter (LDV), which is able to measure the speed of a carrier, can be combined with a strapdown inertial navigation system (SINS) to form an integrated navigation system. To realize the integrated navigation positioning of a free motion carrier on the ground accurately, this paper introduces a split-reuse three-dimensional (3D) LDV. For the error parameters during application, a Kalman filtering calibration method with the assistance of a differential global positioning system (DGPS) is put forward in this paper. Two groups of integrated navigation experiments are designed to validate the effectiveness of this method and the universality of the obtained parameters. The experimental results show that the calibration method proposed in this paper is effective and the 3D LDV after compensation can greatly improve the positioning accuracy of the integrated navigation. The maximum horizontal position errors of the two experiments calculated by the dead reckoning of the 3D LDV and the gyroscopes are 4.2 m and 2.9 m, and the maximum altitude errors are 0.8 m and 0.9 m, respectively. PMID- 30461927 TI - Polarization-maintaining Yb-doped large-mode-area fully aperiodic large-pitch fibers. AB - Based on a special large-pitch architecture that has already proved its single mode single-polarization behavior in a passive configuration, two ytterbium-doped versions of such large-mode-area fibers have been fabricated and tested in both laser and amplification configurations for high-power laser source applications. Due to the high sensitivity of large-pitch fiber design to the active-core-to passive-cladding index mismatch, the realization of a single-polarization structure is highly challenging. However, we report on the preservation of a polarization-maintaining feature. A linear polarization with an extinction ratio of 17 dB is demonstrated for mode field diameters reaching up to 58 MUm as long as the single-modeness of the emitted signal is preserved. PMID- 30461928 TI - High cost-efficient and computational gigapixel video camera based on commercial lenses and CMOS chips. AB - The state-of-the-art commercial telephoto lens has already provided us almost one giga space-bandwidth product. Since the single-image sensor cannot take such sampling capacity, we implement a four-parallel-boresight imaging system by using four such lenses and use 64 image sensors to complete full field of view (FOV) imaging for achieving 0.8 gigapixel over 15.6 degrees *10.5 degrees . Multiple sensors mosaicking can make most online computation and data transfer in parallel, and help us to realize a gigapixel video camera. Meanwhile, according to the four-parallel-boresight configuration, the flat image plane simplifies the image registration and image stitching, and allows us to keep high imaging performance in full frame following geometric and optical calibration and correction. Furthermore, considering that working distance changes do bring additional x/y offsets between sensor arrays, we propose a computation-based method and introduce an eight-axis automatic motion mechanism into the system to perform the online active displacement. Our prototype camera using 16 sensors has been validated in 50 m indoor conditions and 145 m outdoor condition experiments, respectively. The effective angular resolution under the 0.2 giga 24 Hz video output is 18 MUrad, which is two times the lens instantaneous FOV. Compared with other gigapixel cameras, it is superior in terms of optical system simplicity and cost efficiency, which would potentially benefit numerous unmanned aerial vehicle photogrammetric applications that pursue high angular resolution over moderate FOV. PMID- 30461929 TI - Bandpass-sampling-based heterodyne interferometer signal acquisition for vibration measurements in primary vibration calibration. AB - Heterodyne interferometers have been widely used for primary vibration calibration in recent years. Primary vibration calibration performance depends on the precision and real-time nature of vibration measurements, factors determined by the acquisition and demodulation of the heterodyne interferometer signal. This signal is commonly collected using the Nyquist sampling method, requiring devices with high sampling rates and large memories, or a sampling method using a mixer and low-pass filter-analog devices which may create time delays. This study proposes a novel bandpass sampling method that reduces sampling rate and storage capacity without generating time delays. To improve vibration measurement precision, an optimal sampling rate is designed to collect the heterodyne interferometer signal, and the collected signal is demodulated using the phase unwrapping sine approximation method. The proposed method is compared with existing methods through simulated and experimental data. Experimental results show that the proposed method avoids time delays and high sampling rates, while providing high-precision vibration measurements. PMID- 30461930 TI - Terahertz communication windows and their point-to-point transmission verification: publisher's note. AB - This publisher's note amends the author affiliations in Appl. Opt.57, 7673 (2018)APOPAI0003-693510.1364/AO.57.007673. PMID- 30461931 TI - Experimental analysis of the dynamic north-finding method based on a fiber optic gyroscope: erratum. AB - The correction to the funding in Appl. Opt.56, 6504 (2017)APOPAI0003 693510.1364/AO.56.006504 is presented in this erratum. PMID- 30461932 TI - Design of an acousto-optic tunable filter based on momentum mismatching together with the rotatory property. AB - Basing on the momentum mismatching together with the crystal rotatory property, we investigate the diffraction performance of an acousto-optic tunable filter (AOTF). The relationship between diffraction efficiency, momentum mismatching, incident optical wave vector, and ultrasound wave vector is analyzed. The correlation between the frequency tuning relation and the incident angle of light is demonstrated, which is usually ignored in the AOTF design. The diffracted wavelength can be decided by a particular acoustic frequency only when the incident angle of light is fixed. Theoretical and experimental analysis indicates that we can acquire a narrowband spectrum and big angular aperture with a proper incident angle. PMID- 30461933 TI - Easily implemented approach for the calibration of alignment and retardation errors in a channeled spectropolarimeter. AB - Calibration of the channeled spectropolarimeter is significant for the quantitative application of this instrument. In current calibration methods for a channeled spectropolarimeter, an absolute angle between the coordinate system of an auxiliary polarizer and the global coordinate system of the instrument is usually indispensable. The effectiveness of calibration depends on the precision of the absolute angle, while it is usually difficult to achieve in a practical calibration process. This paper presents an easily implemented method to simultaneously calibrate the alignment and retardation errors of high-order retarders for a channeled spectropolarimeter. In the presented method, the requirement of an absolute angle between the coordinate system of an auxiliary polarizer and the global coordinate system of the instrument is replaced by only rotating a relative angle in the coordinate system of the auxiliary polarizer itself. First, we theoretically derive the modified reconstruction model considering the alignment errors of high-order retarders. By analyzing and summarizing the modified reconstruction model, the calibration and compensation models of the alignment and retardation errors are further proposed. Then, two linearly polarized beams with a relative angle of 45 degrees between them are utilized to determine the alignment and retardation errors. Based on these results, the alignment and retardation errors can be compensated by a software correction algorithm without any precise mechanical adjustments. The effectiveness and feasibility of the presented method are verified by numerical simulations and experiments. The advantage of easy implementation makes this calibration method more suitable to apply in the laboratory and to be on track for correcting the channeled spectropolarimeter. PMID- 30461934 TI - Halo in the box: a macroscopic crystal arrangement to project mosaic halos. AB - We describe a three-dimensional halo demonstration experiment. A volumetric arrangement of crystals is used to project a mosaic halo display upon illumination. The demonstration can be used to convey the collective scattering aspect of the natural halo mechanism and at the same time vividly portray the concept of orientation classes in the context of halo theory. PMID- 30461935 TI - Quantification of tomographic PIV uncertainty using controlled experimental measurements: erratum. AB - This erratum corrects information regarding the author listing in Appl. Opt.57, 420 (2018)APOPAI0003-693510.1364/AO.56.00420. PMID- 30461936 TI - Optically reconfigurable gate array using a colored configuration. AB - This paper presents a proposal of an optically reconfigurable gate array using a colored configuration. The optically reconfigurable gate array consists of a very large-scale integration (VLSI), a holographic memory, and four lasers with different wavelengths. The optically reconfigurable gate array VLSI includes a fine-grained programmable gate array as well as field programmable gate arrays. Four configuration contexts can be stored on the holographic memory and can be programmed onto the programmable gate array VLSI addressed by the four lasers. This paper presents the demonstration of the optically reconfigurable gate array using a colored configuration. PMID- 30461937 TI - Transformation optics based on unitary vectors and Fermat's principle for arbitrary spatial transformation design. AB - A methodology of designing an arbitrary transformation using transformation optics (TO) based on unitary vectors and Fermat's principle is presented. The TO equation is derived in terms of grid coordinates. The geometry of the transformed space is stored in the grid coordinates rather than the transformation functions. This allows the crafting of an arbitrary transformation by combining several transformation templates together. The touch interface is employed to intuitively apply the transformations. The resulting material parameters are calculated from the proposed method and verified using the anisotropic finite-difference frequency-domain method. Five examples are presented to demonstrate the capability of this method. PMID- 30461938 TI - Theoretical study of multilayer coatingreflection taking into account third-order optical nonlinearities. AB - A theoretical approach is presented that allows calculating the reflectance of dielectric multilayer coatings taking third-order optical nonlinearities into account. The description is based on third-order optical susceptibility so that nonlinear refraction and two-photon absorption processes are automatically considered in terms of the real and imaginary parts of the susceptibility. Two model systems are calculated in order to demonstrate the physical validity of the approach: a mirror that is optimized for maximum reflectance at a given wavelength and a given incident intensity and a mirror that provides a rather flat dependence of the reflected intensity on the incident one. Model calculations are performed for laser wavelength values of 1064 nm, 800 nm, and 532 nm. PMID- 30461939 TI - Experimental ray-tracing with point diffraction interferometry and its application in focal length measurement. AB - A novel method that could experimentally trace the ray propagation of an optical system based on point diffraction interferometry (PDI) is presented. The ray represented by the line connecting two point light sources (PLS) intersects with two parallel photographic planes, which are separated at a distance. The intersections of the ray defined by the PLSs with the planes occur where the optical path difference is a maximum and can be determined from interferograms on the photographic planes. The ray is determined by connecting the two intersections. Using fibers as the PLSs and CCD arrays as the photographic planes, we demonstrate its principle and its application in focal length measurement through experiments. PMID- 30461940 TI - Active lens for thermal aberration compensation in lithography lens. AB - High laser absorption and strong resolution enhancement technology make thermal aberration control of lithography lenses more challenging. We present an active lens that uses four bellows actuators to generate astigmatism (Z5) on the lens surface. The apparatus utilizes optical path difference to compensate the system wavefront. In order to assess the specifications of the compensator, the finite element method and experimental analyses are carried out to obtain and validate the general properties of the apparatus. The results show that the Z5 deformation quantity of lens's upper surface exceeds 600 nm; further, Z5 coefficient accuracy is better than +/-1 nm. The apparatus can be an efficient compensator for thermal aberration compensation, especially aberration caused by the dipole illumination. PMID- 30461941 TI - Optical interconnects based on high-contrast all-dielectric nano-post arrays. AB - In this paper, we present a compact solution for optical interconnects in optoelectronic integrated neural networks using high-contrast all-dielectric nano post arrays. The nano-post arrays are made of amorphous silicon, which has a high refractive index and high transmittance in the near infrared. The radius of each post is changed to generate different phase delays. Deflection and convergence of the light are realized by proper design of the phase profile of the nano-post array. Connection efficiencies are calculated by numerical simulations and compared with those of zone plate interconnects. Simulation results show that the proposed nano-post arrays can have superior performance over zone plates in applications that require short focal length and high efficiency. PMID- 30461942 TI - Assessing surface characteristics of eroded dentine with optical coherence tomography: a preliminary in vitro validation study. AB - We conducted the first pilot study to investigate the use of the attenuation coefficient from an optical coherence tomography (OCT) backscattered signal as a measure of surface roughness changes in eroded dentine at an early stage of the erosion process. Ten human premolar root samples were subjected to citric acid treatment before scanning by OCT. The extracted relative attenuation coefficient (MUR) from backscattered OCT signals was shown to increase with the duration of acid challenge. Validated against roughness measurements (rSa) from scanning electron microscopy scans, MUR is significantly correlated with rSa indicative of severity of erosion (p<0.01, r=0.9195). We conclude that the OCT attenuation coefficient of the immediate subsurface in eroded dentine is a potential surrogate measure for its surface roughness. However, further work should be performed to study how it relates to the surface and immediate subsurface changes effected by other mechanical wear before it could unequivocally be used as a surrogate measurement for surface roughness. PMID- 30461943 TI - High-power sampled-grating-based master oscillator power amplifier system with 23.5 nm wavelength tuning around 970 nm. AB - Tunable high-power diode lasers are key components in various established and emerging applications. In this work, we present a compact hybrid master oscillator power amplifier (MOPA) laser system. The system utilizes a tunable GaAs-based sampled-grating (SG) distributed Bragg reflector (DBR) laser as the master oscillator (MO), which emits around a wavelength of 970 nm in a single longitudinal mode with a spectral width below 20 pm. The SG-DBR laser consists of two SGs, each of which can be thermally tuned with microheaters. By tuning one of the two SGs, a discrete wavelength tuning of 21.1 nm can be obtained with a Vernier mode spacing of about 2.3 nm. By tuning both SGs, 23.5 nm of quasi continuous tuning is obtained, with a mode spacing of about 115 pm. The coupling of the beam emitted by the MO into a tapered power amplifier provides an amplified output power in the watt range having a nearly diffraction-limited beam with a propagation factor of M1/e22=1.6. The combination of high power and wide wavelength tuning in a compact system makes this light source ideal for, among other things, nonlinear frequency conversion. PMID- 30461944 TI - Design of uniformly collimating light-emitting diode lenses of multiple freeform and Fresnel surfaces with different inter-surface mapping orders. AB - In this work, we propose a design method of composite freeform collimating lenses that integrates freeform reflection, refraction, and Fresnel surfaces to realize highly collimated and uniformed light output in a single lens element. The algorithm is designed considering a consistent combination of different surfaces, so the light rays reaching the Fresnel surface through refraction and reflection should generate the same luminous intensity. The Fresnel rings can be designed in two different ways, depending on the sequence of light rays propagating between the reflection and the Fresnel surfaces. The lighting effects of the lenses are analyzed in a 3D simulation, and the light output of both schemes reaches a high level of collimation and uniformity, agreeing well with design expectations. The obtained lenses have the advantages of a compact volume, high light extraction efficiency, and variable geometry by changing the combination form of the freeform surfaces. PMID- 30461945 TI - Angular resolved power spectral density analysis for improving mirror manufacturing. AB - Ultra-precise diamond turning is the method of choice for manufacturing freeform optics. Analyzing surface errors in different spatial frequency ranges has mainly been performed in a one-dimensional representation of the power spectral density function. However, the advanced machine dynamics at the fabrication of freeform mirrors result in highly anisotropic surfaces with regular ripples in different orientations. To properly analyze the entire surface in the frequency regime, a new way of representing the two-dimensional power spectral density is introduced in this paper. This novel tool is utilized for the evaluation of an example freeform mirror. PMID- 30461946 TI - Measurement of the refractive index profile of waveguides using defocusing microscopy. AB - Defocusing microscopy (DM) is a bright-field optical microscopy technique often used to obtain structural parameters of objects with low difference in refractive index in relation to the surrounding medium (phase objects). We show a use of this technique to measure the refractive index (n) profile of waveguides produced by femtosecond laser micromachining inside the bulk of a sodalime glass. The results are used to analyze the influence of production parameters on n. The methodology requires only a bright-field optical microscope and has proved to be easily applied. Results provide important insights on the waveguide microfabrication process, since translation speed, rather than intensity, has shown to be more important for achieving greater variations in refractive indices. Index of refraction differences between the waveguide and the substrate of the order of 10-4 were measured for a series of straight waveguides fabricated with different parameters. Low sample scan speeds and pulse energies near 1.20 MUJ used for fabrication showed the highest values of refractive index change for waveguides in sodalime glasses. PMID- 30461947 TI - Full-field optical coherence tomography in a balanced detection mode. AB - We discuss balanced time-domain full-field optical coherence tomography (FF-OCT) realized in a Mach-Zehnder configuration. The balanced detection scheme and spatial phase shifting allow single-shot acquisition and reconstruction in FF OCT. Combined with a 2D quadrature signal-based demodulation technique applying the Riesz transform, previously illustrated for a dual-shot temporal phase shifting in FF-OCT, we demonstrate the concept for single-shot spatial phase shifting. The monitoring of dynamic processes by time-domain FF-OCT is enabled by this approach. The advantage of single-shot acquisition consists of having no failure due to phase changes over time. However, it demands an accurate registration of both spatially shifted interferograms. PMID- 30461948 TI - Passive compensation of intensity and polarization-induced noise by a quadrature demodulation technique in a resonator optic gyroscope. AB - Polarization-induced noise is a dominant noise that seriously hinders the progress of resonator optic gyroscopes. Many countermeasures have been developed but showed insufficient performance. In this paper, we propose a quadrature demodulation technique (QDT) that adopts references of both sine and cosine to demodulate the signal. Theoretical analyses of the polarization effect and QDT are shown, and experimental results are listed and compared. Experimental results are consistent with theoretical analyses. QDT shows great performance in suppressing environment- and polarization-induced phase fluctuation of signal. We also demodulate the intensity-dependent coefficient of 2Omegat term, which is demonstrated effective for compensating polarization-induced intensity noise together with QDT. The scheme shows significant progress in improving long-term stability. PMID- 30461949 TI - Off-axis eight-pass neodymium glass laser amplifier with high efficiency and excellent energy stability. AB - A new relay-imaged off-axial eight-pass laser amplifier with several joules energy and 1 Hz repetition rate was demonstrated. The extraction efficiency and pulse-to-pulse energy stability were greatly improved. Under the single-pass small-signal gain of 3.6, a net gain of 900 and an effective extraction efficiency of 42.4% in the beam aperture were realized. Pulse-to-pulse energy stability of 0.83% (peak-valley) and 0.17% (root-mean-square) was achieved by the significant saturation of eight-pass amplification, which, to the best of our knowledge, is the best energy stability in several-joules-class amplifiers. The far-field quality was 2.52 times the diffraction limit, and the near-field modulation of the 90% beam aperture was 1.28. No parasitic oscillations or pencil beams were observed. Moreover, another key feature of the proposed amplifier was the ability to remarkably improve the pulse contrast with a unique design. PMID- 30461950 TI - 2 W single-frequency, low-noise 509 nm laser via single-pass frequency doubling of an ECDL-seeded Yb fiber amplifier. AB - A single-frequency low-noise green laser at 509 nm is developed for the study of cesium Rydberg atoms. The laser is generated by single-pass second-harmonic generation of a Yb fiber amplifier seeded with an external cavity diode laser (ECDL) at 1018 nm in a periodically poled MgO-doped lithium-niobate crystal. An up to 2.03 W, 509 nm laser is obtained from a 10.04 W incident 1018 nm laser with a conversion efficiency of 20.2%. The linewidth of the 509 nm laser is estimated to be 40 kHz according to the measured linewidth of 20 kHz of the 1018 nm fundamental laser. The relative intensity noise is 0.038% rms integrated from 10 Hz to 10 MHz. PMID- 30461951 TI - Graphene-based metasurface for a tunable broadband terahertz cross-polarization converter over a wide angle of incidence. AB - In this paper, using a graphene-based metasurface, we demonstrate a unique design to develop a highly efficient, broadband, mid-infrared cross-polarization converter. The proposed graphene-based metasurface structure comprises periodical phi-shaped graphene on the top surface of a noble-metal-backed dielectric silicon dioxide (SiO2). The reported structure converts the incident linearly polarized wave into cross-polarized components with a peak polarization conversion ratio of more than 0.9 over a large band. Furthermore, the metasurface structure exhibits the full width at half-maximum bandwidth of 41.98% with respect to its center frequency of 5.98 THz. The physical insights behind electromagnetic polarization conversion are supported by field distributions and retrieved electromagnetic parameters. The structure works as a broadband cross-polarization converter up to 40 degrees incident angle for both TE and TM polarizations. In addition, the structure is found to be as thin as ~lambda/6 with respect to lowermost frequency of the polarization conversion. The period of the unit cell is ~lambda/24 to support the fact that the structure can be treated as a metasurface. PMID- 30461952 TI - Identification of Huanglongbing-infected navel oranges based on laser-induced breakdown spectroscopy combined with different chemometric methods. AB - In order to realize rapid identification of Gannan navel oranges infected by Huanglongbing (HLB), a full optical diagnostic method of laser-induced breakdown spectroscopy (LIBS) was proposed. All navel oranges were collected from Ganzhou, Jiangxi, China, and samples contain healthy and HLB-infected navel oranges. The LIBS spectra of the plasma plume were collected directly from the epidermis of these navel oranges. The navel orange LIBS spectra in the wavelength range of 200 1050 nm were pretreated with smoothing and multiple scatter correction; on the basis of 10*10-fold cross validation, a random forest (RF) model based on continuous wavelet transform (CWT) and principal component analysis (PCA) were analyzed to identify the navel orange of HLB. The results showed that the PCA-RF and CWT-RF models coupled with suitable methods in preprocessing data can identify HLB-infected navel oranges. The average accuracy obtained from the CWT RF model was 96.86% in the training set and 97.45% in the test set; the average accuracy by the PCA-RF model was 97.64% in the training set and 97.89% in the test set. The overall results demonstrate that LIBS combined with CWT-RF or PCA RF, as a valuable analytical tool, could be used for HLB-infected navel orange identification. PMID- 30461953 TI - Temperature-dependent terahertz spectroscopy and refractive index measurements of aqua-soluble and plastic explosives. AB - The paper reports the temperature-dependent time domain terahertz spectroscopy of premium aqua-soluble and plastic explosives such as NH4NO3, TNT, and RDX between 0.1 and 2.2 THz. Tunable terahertz radiation was generated using ZnTe crystal as a source, and a photoconductive antenna was used as a detector. The temperature dependent study was carried out between 30 degrees C and 200 degrees C in a specially designed oven. The signature peaks of RDX and TNT present at 0.82 and 1.60 THz, respectively, show a strong redshift, whereas the NH4NO3 molecule shows a comparatively small shift. The high-temperature-based redshift phenomenon is just the opposite of the blueshift recorded at low temperatures. In addition, the temperature-dependent absorption coefficient data of these molecules support the change in the concentration of the NO2 molecule. We have also ascertained the temperature-dependent refractive indices of these molecules between 0.1 and 2.0 THz, which confirms the effect of temperature on the refractive indices. Finally, the signature peak of RDX with respect to the reduction in the weight concentration of RDX in the Teflon matrix was studied at 0.82 THz. PMID- 30461954 TI - Suprathreshold gray scale is implied by thresholds. AB - The inverse of the threshold just noticeable difference (i.e., 1/JND) is proportional to the slope (derivative with respect to visual stimulus luminance) of the suprathreshold gray scale at any stimulus and background luminances. Specifically, the inverse threshold and the gray-scale slope share 81% of their variance over six log units of target luminance; in log-log coordinates, 92% of their variance is shared. The strength of the connection improves when negative or positive contrasts are considered separately. Scientific literature is cited, empirical evidence is presented, results of theoretical calculations are discussed, and applications are described. For instance, suprathreshold gray scale appearance is important in medical imaging, video rendering, industrial process displays, public information displays (e.g., at airports), military situation displays, heads-up displays, multispectral and other abstract scientific imaging, artistic lighting design (e.g., equal-appearing steps of gray scale), and color coding of text, image segments, or symbols for rapid reliable visual search. PMID- 30461955 TI - Method to improve the resolution of a non-parallel Fabry-Perot etalon. AB - A new method to improve the resolution of a slightly non-parallel solid etalon is proposed. The method is aimed to reduce the spectrum broadening caused by non parallel surfaces; it contains a theoretical formula for adjusting image distances, and an algorithm for processing the corresponding fringe patterns. Theoretical consideration, computer simulation, experimental results, and application demonstration are given. The fringe patterns captured by a CCD showed good agreement with the computer simulation, and the resolution of a lambda/10 wavefront-error etalon was improved from 3.1 GHz to 0.51 GHz. In comparison with other methods, this new method is convenient and economical. PMID- 30461956 TI - Coating stress analysis and compensation for iridium-based x-ray mirrors. AB - Iridium-based coatings for mirrors of x-ray telescopes are studied. In particular, stress-induced deformation is characterized and shown to be compressive and equal to -1786 MPa. Two methods for stress compensation are then studied. One relies on the deposition of silica on the back surface of the substrate and a second one relies on the deposition of a chromium sublayer. Advantages and drawbacks of each of these techniques are presented. PMID- 30461957 TI - Efficient point cloud lossless data compression method based on an embedded Gray code structured light pattern sequence. AB - Despite the benefits derived from the development of 3D techniques to improve the acceleration and accuracy of 3D scanning operations over the past two decades and its wide range applications in various industries (e.g., quality control and inspection, reverse engineering, robotics), there are restrictions on data transfer, data storage, and even the development of real-time scanning methods due to the enlarging data size (point cloud). According to the importance of maintaining all the output data of the scanner in instrumentation engineering, the need to apply minimum loss or lossless data compression algorithms is more than ever evident. In this regard, this paper presents a novel method in point cloud lossless data compression, using a Gray code structured light pattern sequence and image-based compression. The empirical evaluation and results of the proposed method demonstrate that this idea is reliable and practical to achieve a distinct compression ratio among other lossless point cloud compression methods. PMID- 30461958 TI - Modeling of transmission characteristics in step-index polymer optical fiber using the matrix exponential method. AB - In this paper, we propose to calculate the impulse and frequency response of step index polymer optical fiber in the presence of mode coupling using the matrix exponential method. The computation time in this method is independent of the fiber length and is typically 2 orders of magnitude shortened compared with the standard numerical procedures involving finite difference methods. Results obtained with our method are compared with those of known cases, where an analytical solution for the time-dependent power flow equation exists, and with a finite difference method. We also investigate the impact of mode coupling and differential modal attenuation on impulse response duration and shape. PMID- 30461959 TI - Band enhanced ultra-broadband terahertz absorber based on a high-impedance surface and cavity resonance. AB - This paper demonstrates a band enhanced ultra-broadband terahertz absorber (UBTA) based on a high-impedance surface and cavity resonance; the absorber consists of a high-impedance surface and a metallic plate spaced by a dielectric spacing layer. Simulations indicate that ultra-broadband absorption over 90% from 4.65 to 8.86 THz is realized by the high-impedance surface. It is noted that the absorption is further broadened by inserting air cylinders (ACs), thus showing that the absorption rate exceeds 90% from 5.35 to 13.08 THz. The simulations also demonstrate that the UBTA can achieve high absorption under wider incident angles. Moreover, surface current, electric field distribution, and power loss density are simulated to expound the physical mechanism. PMID- 30461960 TI - Determination of the refractive indices of ionic liquids by ellipsometry, and their application as immersion liquids. AB - In principle, ionic liquids (ILs) can serve as stable and less harmful high refractive-index liquids (n>1.60). However, detailed information on their complex refractive indices and dispersions is rare. Therefore, we determined the optical constants of six commercially available low-index ILs (n ca. 1.4) and two high index ILs (n max. 2.38) synthesized by us utilizing spectroscopic ellipsometry. Furthermore, we tested the ILs as immersion liquids for different photonic crystals. Analysis of the optical properties of these photonic crystals after infiltration demonstrates potential applications of ILs in optofluidics and as index-matching liquids. PMID- 30461961 TI - Systematic study of the cross polarization introduced by broadband antireflection layers at microwave frequencies. AB - Implementation of antireflection layers using structured materials is of common use in millimeter- and submillimeter-wave refractive optic systems. In this work we have systematically studied the effect of such structures in the optical propagation with special emphasis on the cross polarization they introduce. We have performed extensive simulations and experimental verification of several commonly used structures: concentric grooves, parallel grooves, an array of boxes, an array of cylinders, and rectangular- versus triangular-shaped grooves. As a result, we propose optimal structures for demanding applications in terms of polarization and return losses over large fractional bandwidths. PMID- 30461962 TI - Gold-aluminum-based surface plasmon resonance sensor with a high quality factor and figure of merit for the detection of hemoglobin. AB - A gold (Au) and aluminum (Al)-based surface plasmon resonance (SPR) sensor, with a high-quality factor and figure of merit, for the detection of hemoglobin concentration in human blood is proposed. The sensing performance of a bimetallic Au grating over an Al film-based sensor depends on the thickness of the Al film. The sensor's performance is closely analyzed in terms of well-defined performance parameters: sensitivity, FWHM, and depth of SPR dips in order to optimize the thickness of Al film. With optimized thickness, we could achieve quality factor and figure of merit values of 286.2 RIU-1 and 0.97 deg-1, respectively. Al is chemically unstable, and, to address the oxidation problem, we analyzed the sensor with an ultrathin protective Au layer between the Au grating and Al film. We show that the introduction of an ultrathin Au layer gives stability to the sensor without much affecting the performance of the sensor. The obtained values of quality factor and figure of merit of the proposed sensor are 245.2 RIU-1 and 0.86 deg-1, respectively. We also discuss the potential of hemoglobin detection of the proposed sensor in the near-infrared region. Reported sensitivity of the sensor is 0.62 degrees /dgL-1. PMID- 30461963 TI - All-in-fiber method of generating orbital angular momentum with helically symmetric fibers: publisher's note. AB - This publisher's note amends a figure caption in Appl. Opt.57, 8182 (2018)APOPAI0003-693510.1364/AO.57.008182. PMID- 30461964 TI - Suppression of stray light based on energy information mining. AB - The star tracker plays a critical role in precision aerospace missions due to its high accuracy, absolute attitude output, and low power consumption. For an optical sensor, the problem of stray light is always an important research issue. A star energy information mining method for stray light suppression is proposed in this study. The gray-level co-occurrence matrix and k-nearest neighbor algorithm are adopted to identify the types of stray light that enter the optical system. Effective recognition of the stray light types is an important premise for the following steps. Then the parameters are optimized during background estimation. When star spots are extracted, the local differential encoding combined with Levenshtein distance filtering is conducted to eliminate the interference noise spots. The proposed algorithm can achieve accurate star spot extraction even when stray light exists in real night sky observation experiments. PMID- 30461965 TI - Design of a two-dimensional stray-light-free geometrical waveguide head-up display. AB - Stray light is one of the factors exerting negative influences on the image quality of the head-up display based on the geometrical waveguide. Particularly, compared with the architecture used to expand a one-dimensional pupil, the geometrical waveguide expanding the two-dimensional pupil makes it difficult to remove the stray light due to the combined effect from two orthogonal directions. To overcome it, causes of stray light in the two-dimensional geometrical waveguide are analyzed based on the detailed calculation of the parameters that determine the geometry; the corresponding approach is put forward to decrease the percentage of the stray light across the eye box to below 0.1%. The relationship between the resultant combined waveguide and the projection optics is also clarified to obtain the pupil matching. The head-up display integrating the combined waveguide and the designed projection optics achieves the field of 24 degrees *15 degrees and the eye box of 80 mm*80 mm. PMID- 30461966 TI - High-speed stereo-digital image correlation using a single color high-speed camera. AB - A simple and practical high-speed stereo-digital image correlation (stereo-DIC) technique using a single off-the-shelf high-speed color CMOS camera is described in this work. By using the high-speed color CMOS camera and suitable optical filters, the recorded color images can be directly separated into red and blue channel sub-images with negligible color cross-talk between sub-channel images, which offers evident efficiency and accuracy advantages over the existing technique we proposed recently [Opt. Lasers Eng.95, 17 (2017)OLENDN0143 816610.1016/j.optlaseng.2017.03.009]. These separated sub-channel images can then be processed by regular stereo-DIC to retrieve the desired kinematic fields on the test object surface. The accuracy and precision of the established high-speed stereo-DIC system were characterized by measuring the displacements of a stationary object, and the results show good agreement with theoretical predications. To show the broad utility and practicality of the proposed method, three typical experiments, involving (i) transient displacement and velocity measurement of a rotating fan; (ii) full-field vibration measurement of a rectangular aluminum panel; and (iii) transient 3D surface shape, displacement, and strain fields measurement of a balloon during the whole explosion procedure, were carried out. The results show that, by using a proper high-speed color camera, high-speed 3D shape, displacement and deformation measurements can be realized in a cost-effective and easy-to-implement manner. The proposed technique demonstrates great potential in impact engineering, explosion, and vibration tests. PMID- 30461967 TI - Multiwavelength Er-doped fiber laser using an all-fiber Lyot filter. AB - We experimentally demonstrated a multiwavelength Er-doped fiber ring laser system by employing an all-fiber Lyot filter (AFLF) and a highly nonlinear fiber (HNLF). The AFLF was employed as a polarizing filter to generate a nonlinear polarization rotation effect and the highly dense and narrow bandwidth comb-like channels. A 1 km-long HNLF was used to enhance the nonlinearity of the laser cavity and suppress the mode competition for multiwavelength operation. In the experiment, 97 laser output channels within a 3 dB bandwidth simultaneously were excited under 224 mW pump power. The power fluctuation of lasing channels was less than 0.182 dB, and the wavelength shift was less than 0.04 nm in 100 min, after treating the AFLF in a thermostatic ice bath. Meanwhile, the output laser was highly polarized with a degree of polarization up to 99.9%. PMID- 30461968 TI - Improved small moving target detection method in infrared sequences under a rotational background. AB - The infrared image sequence contains both the rotational background and a moving target, causing great difficulties in target detection and the occurrence of massive false alarm rates. This paper proposes an improved method using an optical flow field, which can estimate and compensate for the rotational motion background, thus detecting a small moving target. First of all, we select the Shi Tomasi angular points for image detection and represent the background rotation with the sparse optical flow field of a complete image. Then we use the least squares method to estimate the parameters of the perspective model of background rotation so as to reconstruct the background motion vector field and compensate for background rotation. Finally we detect the small moving target with the differential method and the morphological treatment. The experimental results verify that this method can accurately detect a small moving target against the violently rotational background and provide an idea for the target interception algorithm under the condition that an infrared imaging seeker is overlooking. PMID- 30461969 TI - Random and pseudo-random phase modulations for FM-to-AM reduction in high power lasers. AB - Frequency modulation to amplitude modulation (FM-to-AM) conversion is an important issue that can prevent fusion ignition with high power lasers such as with the Laser Megajoule (LMJ). A way to reduce FM-to-AM conversion is to change the phase modulation (currently sinusoidal). In this paper, we study the case of random phase modulation. We show, with numerical simulation modeling, FM-to-AM conversion induced by different transfer functions, in which such a modulation format, in some cases, may significantly reduce FM-to-AM conversion, particularly in the case of amplitude filtering. Phase filtering may create high overshoots, but the occurence probability is low, and, on average, random phase modulation is advantageous compared with sinusoidal modulation. We also demonstrate an equivalent smoothing efficiency with the LMJ facility with an important reduction of FM-to-AM conversion compared with the current solution. Taking particular random draws (pseudo-random modulation), we exhibit optimal performance. PMID- 30461970 TI - Novel technology for microlenses for imaging applications. AB - Microlenses are an important functional element of a modern imaging device. Typically, they are fabricated from organic materials on top of individual pixels. Though they are widely used, they do exhibit a number of limitations. These are, but not limited to, thermal stability, radiation sensitivity, outgassing properties, additional topography, and difficulty in manufacturing asymmetrical, noncircular microlens designs using conventional manufacturing techniques. In this paper, we present a novel approach for the fabrication of microlenses. We report on the design, manufacturing, and characterization of microlenses fabricated from classical dielectric materials used in the manufacturing of CMOS semiconductor devices. These microlenses rely on a Fresnel optical design, provide functionality similar to the classical microlenses, and do not suffer from their limitations. We subjected these microlenses to several environmental reliability stress conditions, including pressure, temperature, humidity, and their variation. Moreover, we test their sensitivity to gamma rays and protons. PMID- 30461971 TI - Sample orientation in corona-poled multilayer silica structures. AB - The impact of sample orientation on the poling of single-sided multilayer silica structures is studied. The results show that the presence of a multilayer stack near the cathode creates a nonlinear region where it otherwise would not have formed. It is shown that field orientation impacts the location and magnitude of the induced nonlinearity. A nonlinearity is always present in the stack independent of whether the stack is on the anode or cathode side of the sample unlike the nonlinearity in bulk silica, which is always located on the anode side. PMID- 30461972 TI - Color temperature tunable phosphor-coated white LEDs with excellent photometric and colorimetric performances. AB - The optimization model for the luminous efficacy (LE) of a correlated color temperature (CCT) tunable phosphor-coated white LED (pc-WLED) was developed. The optimal pc-WLEDs with green (498.7 nm, 70.0 nm), yellow (569.2 nm, 83.4 nm), and red (638.7 nm, 70.0 nm) phosphors excited by a blue chip (442.4 nm, 35.0 nm) could achieve a color fidelity index (Rf) of 97 and LEs of 118-127 lm/W at CCTs of 2700-6500 K for a radiant efficiency of the blue chip of 60% and a quantum efficiency of a phosphor layer of 90%. Compared to quantum dot WLEDs (QD-WLEDs), the LEs of the optimal pc-WLEDs are lower only by 2.7%-4.8% than the optimal QD WLEDs at CCTs of 2700-6500 K, so that QD-WLEDs have only a slight advantage in terms of luminous efficacy for excellent color rendition. Four real pc-WLEDs with Rfs of 96-97 and LEs of 93-106 lm/W at CCTs of 3037 K, 4081 K, 4951 K, and 6443 K were demonstrated. PMID- 30461973 TI - Fabry-Perot etalon-based ultraviolet trifrequency high-spectral-resolution lidar for wind, temperature, and aerosol measurements from 0.2 to 35 km altitude. AB - A novel ultraviolet trifrequency high-spectral-resolution lidar (HSRL) based on a triple Fabry-Perot etalon (FPE) and polarization discrimination technique is proposed, to the best of our knowledge, for measuring atmospheric wind, temperature, and aerosol optical properties simultaneously from the troposphere to low stratosphere. The measurement principle of wind speed, temperature, and aerosol is analyzed, and the structure of the proposed HSRL is designed. The parameters of the triple FPE are optimized. The multiparameter inversion method based on the nonlinear iterative approach and cubic spline interpolation method is also discussed, and the specific iteration steps are given. Finally, the detection performance of the proposed HSRL is simulated. The simulation results show that for 0.3 WSr-1 m-2 nm-1 at 355 nm sky brightness, by using a 350 mJ pulse energy, a 50 Hz repetition frequency laser, and a 0.45 m aperture telescope, the measurement errors of temperature, aerosol backscattering ratio and vertical wind speed are below 2.1 K, 2.5*10-3, and 2.2 m/s in nighttime and below 3.2 K, 3.4*10-3, and 2.6 m/s in daytime from 0.2 to 35 km with a temporal resolution of 5 min for temperature and aerosol, 1 min for vertical wind, and a vertical resolution of 30 m at 0.2-10 km, 100 m at 10-20 km, 200 m at 20-35 km; the measurement error of two other orthogonal line-of-sight wind speeds with a fixed zenith angle of 30 degrees is below 2.9 m/s in nighttime and 3.9 m/s in daytime in the range of +/-50 m/s from 0.2 to 35 km with a temporal resolution of 1 min and a vertical resolution of 26 m at 0.2-8.6 km, 87 m at 8.6-17.3 km, and 173 m at 17.3-35 km. Compared with the traditional double-edge wind-detection technique with the same complete instrumental parameters including those of the FPEs and FPE-based high-spectral-resolution temperature-detection technique with the optimal parameter values of FPEs for the same laser power and telescope aperture, the wind accuracy of the proposed technique improved by 1.5 times at night and by 1.5-1.9 times during the day, and the temperature accuracy of the proposed technique improved by 2.2-2.6 times at night and by 1.7-2.6 times during the day. PMID- 30461974 TI - Collinear heterodyne interferometer technique for measuring Goos-Hanchen shift. AB - Directly measuring the difference of the lateral Goos-Hanchen shift between TM and TE polarized lights under total internal reflection using what we believe is a new approach is introduced. This approach is based on the heterodyne interferometer system with two acousto-optic modulators driven at different frequencies combined with an analyzer with a high extinction ratio, two polarization beam splitters, an isosceles glass prism with two base angles of a critical angle, and a position-sensitive detector with high resolution. This approach compared to a 45 degrees right-angle prism used to obtain the Goos Hanchen shift on the total internal reflection has the advantages of reducing angle-modulated noise caused by small angle error of a rotary stage, the measurement of the absolute GH shifts of TE or TM polarized light, respectively, by means of the aluminum coating deposited on parallel plate glass, and the potential to simultaneously measure the phase changes and the GH shift at surface plasmon resonance in a Kretschmann-Raether configuration. PMID- 30461975 TI - Energy attenuations in single microfiber and double-loop cavity supported by optical substrate. AB - We report on the characterization of energy losses in single-silica microfiber and double-loop microcavity deposited on MgF2 substrate. When the bending radius is less than ~37 MUm, the bending loss rate of a 1.4 MUm diameter microfiber exceeds its propagation loss (~0.039 dB/MUm), which becomes the main source of energy attenuation. Furthermore, we measured the transmission energy losses during the assembling process of a double-loop cavity. The transmission loss in a double-loop cavity varies by adjusting the shape of the cavity. It is also found that a ~30 MUm radius cavity has a similar bending loss to that of a curved microfiber with the two bending radii of ~60 MUm, which demonstrates that the cavity can provide a more compact structure than a curved microfiber in integrated photonic circuits. By further bending the input end of a cavity, the output energy can be greatly attenuated, which indicates that the double-loop cavity is no longer suitable for integration. PMID- 30461976 TI - Producing uniform illumination within a rectangular area by using a nonimaging optic. AB - This paper proposes a new design method to create a novel optical element to generate uniform illumination within a rectangular area. Based on this model, an illuminated area is irradiated by two sets of rays; the first one irradiates the target plane after refraction from the top section of the lens, and the second one irradiates from the reflection at the side profile of the lens and then from refraction at the top part of the lens. The results show that a uniformity of over 90% can be achieved. PMID- 30461977 TI - Optical properties of surface states in two-dimensional topological insulators. AB - We present a simple and tractable approach to investigate the optical properties of surface states in two-dimensional (2D) topological insulators (TIs). The analytic expression of optical conductivity of surface states in 2D TIs are obtained based on the kinetic equations. It is found that universal optical conductance can be observed in the high frequency region, which does not depend on the temperature, the chemical potential, or the bandgap of the systems. This universal optical conductance is similar to that in graphene. However, the optical absorption edge of such surface states strongly depend on the chemical potential and the bandgap of the systems. There are obvious optical absorption peaks at low temperature in the low frequency region, which are very different from that in graphene. The bandgaps in surface states can be accurately experimentally measured by the optical absorption edges or the peaks. We expect that our theoretical results offer transparent understandings for the experimental results and applications of 2D TIs. PMID- 30461978 TI - Space-qualified fast steering mirror for an image stabilization system of space astronomical telescopes. AB - A space-qualified fast steering mirror (SQ-FSM) was designed, built, and tested at the National Astronomical Observatories of the Chinese Academy of Sciences for an image stabilization system of space astronomical telescopes, which is used for the tip-tilt correction of small jitter of the satellite platform; this achieved image stability in a closed-loop manner. Its design primarily faces four challenges involving (1) sustaining the specified sine and random vibration without launch lock, as well as shock response spectrum experiments; (2) surface form error of a clear aperture of phi120 mm less than 1/50lambda root mean square (RMS, lambda=632.8 nm) with a relatively rigid mirror support; (3) resonance frequency of at least 800 Hz and as high as possible; (4) minimum reaction force and torque in order to decrease its unfavorable influence on the satellite platform. To achieve these goals, the global optimizations and compromises have to be made throughout the design process. The study reviews the detailed design of the SQ-FSM with respect to the four challenges, mainly by keeping the mirror and its support lightweight, mirror bonding and solidification, actuator and its stiffness, flexure support of the mirror and its holder, material optimization for weight, stiffness, and coefficient of thermal expansion, as well as finite element analysis on statics and dynamics. The performances are also measured and expatiated, including the surface form, resonant frequency, tip-tilt stroke, vibration and shock response spectrum experiments, etc., which validate the performances of the SQ-FSM. PMID- 30461979 TI - Full-depth compressive sensing spectral-domain optical coherence tomography based on a compressive dispersion encoding method. AB - By combining the advantages of compressive sensing optical coherence tomography (OCT) and full-depth OCT in terms of imaging time and imaging depth, we demonstrate how compressive sampling and dispersion encoding can be simultaneously used to reconstruct a full-depth OCT image. Moreover, by considering the image processing speed, we propose a two-step compressive dispersion encoding (TCDE) method, in which a large dispersion imbalance is introduced between the reference arm and the sample arm and two iterations are performed. The first iteration selects the signals with higher intensity and then removes their conjugate items and incoherent aliasing artifacts caused by undersampling based on the least squares method. The second iteration selects the signals with lower intensity. Experimental results show that nearly the same conjugate inhibition ratio can be obtained with 50% sampled data and 100% sampled data using the TCDE method. Full-depth images of a glass slide, an onion, and a live fish eye are obtained from 50% and 100% sampled data using the TCDE method. For a 1.4 mm*3.6 mm fish eye image, the conjugate items are reduced by 33.2 and 31.7 dB using 50% sampled data and 100% sampled data, respectively. PMID- 30461980 TI - Design of modified InGaAs/InP one-sided junction photodiodes with improved response at high light intensity. AB - A modified InGaAs/InP one-sided junction photodiode (MOSJ-PD) is presented for the first time. The MOSJ-PD is proposed from the one-sided junction photodiode by inserting a cliff layer into the absorption layer. Compared to the modified uni traveling carrier photodiode, the MOSJ-PD has the advantages of simpler epitaxial layer structure and lower junction capacitance. In the MOSJ-PD, the space charge effect at high light intensity can be suppressed. Thus, both 3-dB bandwidth and output current can be improved simultaneously. The performance characteristics of the MOSJ-PD, including energy band diagram, internal electric field, frequency response, photocurrent, and responsivity, are carefully studied. PMID- 30461981 TI - General formula for bi-aspheric singlet lens design free of spherical aberration. AB - In this paper, we present a rigorous analytical solution for the bi-aspheric singlet lens design problem. The input of the general formula presented here is the first surface of the singlet lens; this surface must be continuous and such that the rays inside the lens do not cross each other. The output is the correcting second surface of the singlet; the second surface is such that the singlet is free of spherical aberration. PMID- 30461982 TI - Computational ghost imaging with designed low spatial frequency masks. AB - Minimally invasive imaging using weak illumination is required in the biomedical field. Computational ghost imaging (CGI) achieves imaging under illumination. However, CGI requires a large number of measurements to obtain an image. The number of measurements increases as illumination weakens. In this paper, decreasing the number of measurements of CGI with designed low spatial frequency masks is proposed. The proposed method allows us to image an object with a smaller number of measurements than with the conventional method. Numerical simulations and experiments confirm the feasibility of the proposed method. PMID- 30461983 TI - Dynamics of the laser fragmentation/laser-induced fluorescence process in nitrobenzene vapors. AB - The paper presents the results of an experimental study of the dynamic characteristics of the laser fragmentation/laser-induced fluorescence (LF/LIF) effects in nitrobenzene vapors under the separate initiation of processes of photofragmentation and fluorescence of fragments by nanosecond laser pulses. It is shown that, due to the inertia of the dissociation mechanism of nitrobenzene molecules, the process of the fragments' formation continues even after letup of excitation. The highest concentration of fragments is reached in a time several times greater than the standard fragmentation pulse duration of 10 ns. A kinetic model is presented that allows one to trace the temporal dynamics of the LF/LIF process of nitrobenzene vapors under separate excitation. A good agreement between the experimental data and the results of calculation indicates the adequacy of application of the developed kinetic model for describing the LF/LIF process. The information obtained in the experiment made it possible to clarify the values of the rate constants of the nitrobenzene dissociation. PMID- 30461984 TI - Ultrahigh-resolution interrogation of a fiber Bragg grating sensor based on higher order four-wave mixing. AB - The performance of a highly sensitive strain sensor based on nonlinear four-wave mixing (FWM) using a fiber Bragg grating (FBG) is investigated. The power change due to the wavelength shift induced by very small strain over the FBG is significantly magnified by a higher order FWM process. Strain sensitivity of 5.547 dBm/MUepsilon is achieved and minimum wavelength shift of 2.18*10-6 nm (which corresponds to a strain of 1.80*10-3 MUepsilon) is detected with uniform FBG, whereas in case of chirped FBG (CFBG) strain sensitivity of 0.3 dBm/MUepsilon with minimum detectable wavelength shift of 4*10-5 nm (which corresponds to a strain of 0.033 MUepsilon) is obtained. PMID- 30461985 TI - Misalignment measurement of membrane diffractive telescope segments by means of edge sensors with form closure. AB - The membrane diffractive telescope is an alternative to future 10-meter class space telescopes due to its possible lower cost of manufacturing and launching. To actively control the misalignment, the edge sensor network is utilized to measure the relative in-plane motions as well as out-of-plane motions of neighboring segments. The measurement is vulnerable to noise and malfunction of sensors. We first model the segment kinematics, which is used to simulate the propagation of sensor error to the segment configuration error. Monte Carlo simulation results show that the sensor error is considerably accumulated in the configuration error, which follows approximately normal distribution. On the other hand, the ring-arranged segments imply the form closure with redundancy of edge sensors. It is employed to judge whether there are abnormal sensor readings and then to identify the malfunctioning sensors. A better estimation can further be obtained as correction to the abnormal readings. Simulation results show that without sensor error, the algorithm in most cases can identify two malfunctioning in-plane sensors and two malfunctioning out-of-plane sensors. While considering the sensor error, only one malfunctioning in-plane sensor and one malfunctioning out-of-plane sensor can be identified with a sufficiently big ratio of abnormal reading to the normal sensor error. PMID- 30461986 TI - Reversible and irreversible alterations of the optical thickness of PQ/PMMA volume recording media samples. Part 2: mathematical modeling. AB - A theoretical study of phenanthrenequinone-doped polymethyl methacrylate (PQ/PMMA) samples parameter changes during irradiation is presented. The research has been carried out on the basis of the experimental study (Part 1, [Appl. Opt.56, 7351 (2017)APOPAI0003-693510.1364/AO.56.007351]) and a mathematical model that describes space-time reversible and irreversible light-induced changes of the PQ/PMMA sample parameters during exposition. Based on the numerical modeling results and the use of analytical dependencies, a number of practically important characteristics of the PQ/PMMA sample-exposure process are considered: conversion induction period of phenanthrenequinone into a photoproduct, Deltatind; bleaching time of a sample, tbl; and thermal nonlocality of photoresponse, deltalT. It is shown that the values Deltatind and tbl are on the order of tens and hundreds of seconds, respectively, and can be comparable to the exposure time. It is established that temperature increase leads to deltalT value change by hundreds of nanometers and can cause considerable deformation of the interference structure under recording. The sample heating during exposition is considered in detail, and an algorithm for estimation of the maximum temperature increase to be used in experiments is proposed. Recommendations are made for the reduction of negative influence of sample heating on the parameters of recorded holograms. PMID- 30461987 TI - Two-photon induced polarization spectroscopy of xenon 7p[1/2]0. AB - A novel experimental setup for two-photon induced polarization spectroscopy of xenon using a single dye laser is demonstrated. The experimental setup for probing this two-photon xenon transition using this technique has been developed in the High Enthalpy Flow Diagnostics Group of the Institute of Space Systems. The characterization of the setup is achieved through a polarization lineshape modelling approach accounting for absorption, dispersion, and imperfections in the alignment of the analyzing polarizer for asymmetrical polarization profiles. It is demonstrated that the lineshape modelling approach yields consistent results for measurements with pronounced asymmetrical lineshape properties as well as for those with symmetrical lineshapes. For the first time, data on pressure broadening and pressure dependent redshift of the absorption center wavelength of xenon 7p[1/2]0 is presented. The results show a pressure broadening of 1.475 pm/bar full width at half maximum and a redshift of 0.8425 pm/bar. PMID- 30461988 TI - Three-dimensional imaging system with both improved lateral resolution and depth of field considering non-uniform system parameters. AB - In this paper, we propose a new 3D passive image sensing and visualization technique to improve lateral resolution and depth of field (DoF) of integral imaging simultaneously. There is a resolution trade-off between lateral resolution and DoF in integral imaging. To overcome this issue, a large aperture and a small aperture can be used to record the elemental images to reduce the diffraction effect and extend the DoF, respectively. Therefore, in this paper, we utilize these two pickup concepts with a non-uniform camera array. To show the feasibility of our proposed method, we implement an optical experiment. For comparison in details, we calculate the peak signal-to-noise ratio (PSNR) as the performance metric. PMID- 30461989 TI - Flexible TWDM-RoF system with good dispersion tolerance for downlink and uplink based on additional SCS. AB - A high-efficiency full-duplex radio-over-fiber (RoF) system incorporating time- and wavelength-division multiplexing technology is proposed in this paper, which is more flexible for the wavelength assignment based on an additional subcentral station (SCS). The periodic power fading effect resulting from a radio frequency signal transmitted over an optical fiber is effectively eliminated for the downlink and uplink. Colorless base stations are achieved by a centralized allocation strategy of upstream light sources. At the SCS, an optical cross connect unit is employed to enhance the utilization of light sources and the flexibility of the proposed RoF system. Simultaneously, the requirements of high bandwidth modulators and photodetectors are significantly reduced with a centralized optical carrier suppressed modulation and an all-optical frequency downconversion at the SCS. On the basis of the additional SCS, a 26 GHz full duplex experiment system is demonstrated, and two 1.25 Gbps baseband data signals for downlink and uplink are successfully transmitted over a 40 km standard single mode fiber. PMID- 30461990 TI - Optical bistability, amplification, and transparency in a one-dimensional photonic crystal with a nonlinear central layer. AB - In this paper, we investigate optical properties of a multilayer one-dimensional photonic crystal, where the central layer is doped with one of different kinds of three-level atomic systems, e.g., Vee, Lambda, upper coupling ladder, and lower coupling ladder. Then, the control of optical bistability properties of the photonic crystal, by Rabi frequency of the coupling field, spontaneously generated coherence, and probe detuning, is studied. We discuss the advantages and disadvantages of different systems' optical properties. It is shown that the investigated photonic crystals have a bistability property as well as full transparency. Also, the photonic crystals show some amplification in transmission and even reflection of the probe field. PMID- 30461991 TI - Nanoscale, tunable, and highly sensitive biosensor utilizing hyperbolic metamaterials in the near-infrared range. AB - A plethora of research in recent years has been reported on biosensing in the surface plasmon resonant systems. However, very little research has reported a tunable and highly sensitive biosensor in a nanoscale platform. In this regard, we propose a nanoscale hyperbolic metamaterial (HMM)-based prism coupled waveguide sensor (PCWS) in the near-infrared range. The HMM layer makes up one of the constituents of the PCWS-comprised of a periodically arranged assembly of silver nanostrips. The structure is numerically simulated by the finite difference time domain method. It is demonstrated that the sensitivity of the reflected light can be tuned through the refractive index (RI) of the solution. Moreover, the effects of alteration of constituents of PCWS on the sensitivity have been analyzed. Results show that the sensitivity of PCWS can be harnessed by altering the thickness, slant angle of HMM layer, volume fraction (f) of metal in the HMM layer, and the incidence angle of light. For this purpose, the structure is numerically simulated by the finite difference time domain method. In the optimum design of the proposed sensor, the maximum value of sensitivity is achieved as high as S=3450 nm/refractive index unit with theta=10 degrees and phi=10 degrees and a metamaterial thickness of 250 nm. Moreover, the structure has a nanoscale footprint of 600 nm*400 nm*200 nm. PMID- 30461992 TI - Simple and compact grating-based heterodyne interferometer with the Littrow configuration for high-accuracy and long-range measurement of two-dimensional displacement. AB - We propose a simple and compact reading head with the Littrow configuration that will increase measurement range and reduce the complexity of a two-dimensional grating-based interferometer. The reading head contains only a beam splitter, two polarizing beam splitter modules, and two mirrors. The theoretical resolutions in two directions are 0.27 nm and 0.18 nm, respectively. In comparison with a dual frequency laser interferometer, the proposed interferometer can measure displacement from 3 nm to 10 mm with high accuracy. The 3sigma values in two directions for the difference are 1.67 nm and 1.35 nm for a displacement of 9 nm. Repeatability for a displacement of 1 MUm is better than 2 nm. PMID- 30461993 TI - Transparent intersatellite optical wireless communication link with double sideband-suppressed carrier modulation and coherent homodyne detection. AB - In this paper, we present an intersatellite optical wireless communication (IsOWC) link with double sideband-suppressed carrier (DSB-SC) modulation and coherent homodyne detection (CD), which enables transparent transport of multiband radio frequency (RF) signals. The performance of transparent multiband IsOWC link employing DSB-SC/CD and phase modulation with CD (PM/CD) is investigated. The theoretical model considers the finite extinction ratio (ER) of a Mach-Zehnder modulator (MZM) and the saturation property of an optical booster amplifier. The expressions of RF gain, noise figure (NF) and third-order spurious free dynamic range (SFDR) are derived considering the third-order intermodulation product and amplifier spontaneous emission noise for both architectures. Numerical results for RF gain, NF, and third-order SFDR are given for demonstration. Results indicate that DSB-SC/CD can provide higher linearity and better sensitivity than PM/CD. The performance of the DSB-SC/CD scheme is obviously influenced by the ER of MZM. The gain of the optical preamplifier and the power of a local oscillator optical signal should be optimized to obtain satisfactory performance. PMID- 30461994 TI - Lensing properties of rotational gas flow. AB - A negative lens comprising a gas in steady axisymmetric flow is demonstrated experimentally and analyzed. The lens has potential applications in high intensity laser optics and presents the possibility of adjusting the focusing properties on a submillisecond time scale. It can be operated in environments where conventional optical elements are vulnerable. PMID- 30461995 TI - Simulation and assessment of solar background noise for spaceborne lidar. AB - The properties for six typical land cover types and three sky conditions were derived in this paper, which allows to make seasonal upper estimations of solar background radiation for a given atmospheric scenario. Solar background noise can be derived from the estimations for a spaceborne lidar based on optical parameters. Comparisons among simulated solar background noise and measurements of Cloud-Aerosol Lidar with Orthogonal Polarization (CALIOP) and a Moderate Resolution Imaging Spectroradiometer (MODIS) demonstrate the feasibility of this method. The upper estimates of solar background radiation can be used for lidar engineers to assess the upper estimates of solar background noise for given atmospheric scenarios, which would be a step forward in comparison with using the worst-case scenario everywhere. PMID- 30461996 TI - Logistic-function-based nonlinear companding transform for asymmetrical hybrid optical orthogonal frequency division multiplexing visible light communications systems. AB - In this paper, a logistic-function-based nonlinear companding transform (LNCT) is proposed to reduce the peak-to-average power ratio of asymmetrical hybrid optical orthogonal frequency division multiplexing (AHO-OFDM) signals in visible light communications (VLC). First, the positive and negative amplitudes of the bipolar AHO-OFDM signal are divided into two groups as the positive and nonnegative groups. Then, a peak detection is employed frame-by-frame to locate the group where the maximum peak occurs. Finally, the piecewise companding transform consisting of the nonlinear logistic function and a linear function is performed on the amplitude groups with and without the maximum peak, respectively. The simulation results show that the proposed LNCT scheme outperforms the classical linear nonsymmetrical transform method in terms of the complementary cumulative distribution function with a competing bit error rate performance, thus demonstrating its application potential in AHO-OFDM-based VLC systems. PMID- 30461997 TI - Numerical modeling of nominal and stray waves in birefringent interferometers: application to large-field-of-view imaging Fourier transform spectrometers. AB - Birefringent interferometers are often used for compact static Fourier transform spectrometers. In such devices, several uniaxial birefringent parallel or prismatic plates are stacked, with their optical axes set so that there is an efficient coupling from ordinary to extraordinary and extraordinary to ordinary eigenmodes of two successive plates. Such coupling, aside from few particular cases, is, however, not perfect, an effect that may adversely affect performance. In order to help the design and the tolerancing of these interferometers, we have developed a numerical modeling based on the propagation of plane waves inside and through the interface of birefringent media. This tool evaluates the traveled optical path length and the amplitude of the different polarization modes, enabling prediction of both the optical path differences on the interferometer outputs and the unwanted coupling strengths and related stray wave amplitudes. The tool behavior is illustrated on Savart and double-Wollaston interferometers and compared with experimental characterization of a calcite double-Wollaston prism. PMID- 30461998 TI - Accurate deduction of infrared imaging features of subpixel targets based on the conversion of radiation fields of measured area targets. AB - The accurate generation of infrared (IR) imaging features of subpixel targets plays a very important role in the demonstration, verification, and optimization of system design schemes as well as in research into detection algorithms for small targets in the development of remote IR early warning systems. Based on the generation mechanism of target full-link IR imaging features, this study theoretically considers target radiation characteristics, the working environment, and the spatial response and energy-conversion characteristics of IR sensors, and an accurate deduction model of IR imaging features of subpixel targets is proposed and established. First, the surface-radiation field distribution of the target and background are inverted based on the measured data and the model of radiation calibration; then, the accurate simulation of IR imaging features of subpixel targets is realized by considering the geometric transformation of the spatial imaging, the aperiodic transfer function, scale registration of spatial sampling, and radiation coupling. Finally, the accuracy of the proposed model is verified by using the outfield experiment data. The experimental results show that the IR imaging-diffusion features of subpixel targets with different duty cycles are in good agreement with the prediction results of the model. The results obtained provide data support for the demonstration, verification, and optimization of the system design scheme, as well as for research into detection algorithms of small targets in the development of remote IR early warning systems. PMID- 30461999 TI - Why not use thermal radiation for nanothermometry? AB - The measurement of temperature with nanoscale spatial resolution is an emerging new technology, and it has an important impact in various fields. An ideal nanothermometer should not only be accurate, but also applicable over a wide temperature range and under diverse conditions. Furthermore, the measurement time should be short enough to follow the evolution of the system. However, many of the existing techniques are limited by drawbacks such as low sensitivity and fluctuations of fluorescence. Therefore, Planck's law offers an appealing relation between the absolute temperature of the system under interrogation and the thermal spectrum. Despite this, thermal radiation spectroscopy is unsuitable for far-field nanothermometry, primarily because of the power loss in the near surroundings and a poor spatial resolution. PMID- 30462000 TI - Design of a compact wide-spectrum double-channel prism imaging spectrometer with freeform surface. AB - A double-channel prism imaging spectrometer that includes visible-near-infrared (VNIR) and shortwave-infrared (SWIR) spectra is presented. Double slits divide a wide spectral band into two independent channels for VNIR and SWIR, guaranteeing their independent spectral resolution. A beam splitter splits the band into two, one detected by the SWIR and the other by the VNIR detector. The freeform surface, as a mirror, compensates for astigmatism across a wide spectral band. An imaging spectrometer with 30 degrees field of view and a measured spectrum from 400 nm to 2500 nm is designed. This compact, cost-effective spectrometer with high performance and small spectral distortion has a huge potential for broadband space exploration. PMID- 30462001 TI - Droplet sizing with a wavelength modulated laser. AB - The light scattered by spherical droplets much larger than the wavelength may be modeled with rays associated with scattering orders that follow the laws of geometrical optics. These rays travel different paths as they are reflected and refracted by the droplet. Therefore, there is an optical pathlength difference (OPD) between these rays as they arrive on the detector. By illuminating the droplet with a frequency or wavelength modulated laser, the OPD of any pair of rays can be measured from the beat frequency that results when the rays interfere on the detector. Sweep wavelength lasers are well suited for this application given their rapid sweep rate and broad sweep wavelength band. PMID- 30462002 TI - Study of an image autofocus method based on power threshold function wavelet reconstruction and a quality evaluation algorithm. AB - As a key component in optical microscopy imaging systems, autofocus technology has a significant effect on imaging quality. In this paper, an optical microscopy autofocus method that includes a wavelet denoising algorithm based on a power threshold function and a Brenner image quality evaluation algorithm is presented. Experimental results show that the power threshold function wavelet denoising algorithm, which can be adopted to obtain more realistic optical images, is superior to the traditional soft, hard, hyperbolic, and exponential threshold functions in terms of peak signal-to-noise ratio, signal-to-noise ratio, mean squared error, and histogram indicators; moreover, compared to the Roberts, sum modulus difference (SMD), and energy gradient functions, the Brenner image quality evaluation algorithm can be used to quickly and accurately lock onto the focal plane. By integrating and applying these two core algorithms in the autofocus image acquisition system of a microscope, the image sharpness and focusing quality are greatly improved, which benefits the further evaluation of images. PMID- 30462003 TI - Method of thickness measurement for transparent specimens with chromatic confocal microscopy. AB - In this paper, a new method for measuring the thickness of transparent specimens using chromatic confocal microscopy (CCM) is presented. The conventional CCM thickness measurement model relies on capturing the focal points on the upper and lower surfaces of a transparent specimen. This model has strict specimen placement tolerance and a limited measurement range. In order to overcome these limitations, a new thickness measurement model was developed by adding an auxiliary reflector below the specimen. The thickness of the specimen can be determined by comparing the wavelengths of light focused on the auxiliary reflector before and after placing the measurement specimen. Theoretical analysis and simulation showed that the proposed method has twice the measurement range of the conventional model. In order to verify the proposed CCM measurement model, a laboratory thickness measurement system was developed by the authors' team. A commercial laser scanning confocal microscope (Carl Zeiss LSM780) was used as the reference system. A set of quartz glasses was measured using both the proposed system and the reference system. Experimental comparison showed that the proposed method was able to achieve a measurement accuracy of 0.25 MUm. In addition, repeated measurements conducted at different heights showed negligible variation. Thus, it can be concluded that the specimen placement tolerance was improved significantly compared with the conventional model. PMID- 30462004 TI - Backscattering Raman spectroscopy using multi-grating spatial heterodyne Raman spectrometer. AB - Spatial heterodyne Raman spectrometry (SHRS) is a spectral analysis technique used to study material structures and compositions. We propose a multi-grating SHRS system that uses a multi-grating module rather than the single grating used to terminate each arm in traditional spatial heterodyne spectrometry (SHS). The proposed system not only retains the advantages of traditional SHS but also resolves the mutual limitation between system spectral range and resolution. The increased spectral range and resolution that can be achieved in detection are dependent on the number of sub-gratings used in the module. A verification system was built using 130 gr/mm and 150 gr/mm sub-gratings and calibrated. Under different experimental conditions (including laser power, integration time, container material and thickness, pure and mixed samples, and standoff experiments), the backscattered Raman spectra of different types of targets (including organic solutions, inorganic powders, and minerals) were tested. The multi-grating SHRS shows good performance for broad spectral range and high resolution Raman detection. PMID- 30462005 TI - Method of selecting independent components for defect detection in carbon fiber reinforced polymer sheets via pulsed thermography. AB - Carbon fiber-reinforced polymer (CFRP) is increasingly used by large industries because its characteristics are more favorable than those of traditional materials. However, due to mechanical stresses, or even manufacturing defects, CFRP tends to have internal defects, thus lowering the quality of the industrial processes in which it is used and compromising safety. A method for the early detection of internal defects in these materials, applicable to active pulsed thermography experiments, is presented herein. This method aims to select the most relevant components identified via the independent component analysis of sequences of thermographic images (thermograms) generated from the inspection of CFRP sheets to acquire a synthesis image that highlights the defects in the material. An application of this methodology to a CFRP sheet detects at least 20 of the 23 defects considered. PMID- 30462006 TI - Hydrogen sulfide sensor based on tapered fiber sandwiched between two molybdenum disulfide/citric acid composite membrane coated long-period fiber gratings. AB - In this work, a novel hydrogen sulfide detection scheme based on tapered fiber seeded in two long-period fiber gratings (LPGs) coated by a molybdenum disulfide/citric acid composite membrane is proposed and fabricated. The input light of a broadband source is coupled twice by passing through two LPGs with identical parameters, from which a Mach-Zehnder interferometer can be formed. The composite sensitive membrane was prepared with molybdenum disulfide and citric acid, which was coated on the surface of the two LPGs. The experimental results show that in the range of 0-70 ppm of hydrogen sulfide, with the increase of gas concentrations the interference spectra appear to blueshift. In addition, a high sensitivity of 16.65 pm/ppm, an excellent linear relationship (R2=0.97721), and high selectivity for hydrogen sulfide are achieved. The effect of temperature is also discussed. The sensor has the advantages of low cost and small volume, and can be used for detection applications at sites where hydrogen sulfide is produced, such as natural gas plants, areas of magmatic activity, coal mines, etc. PMID- 30462007 TI - Controlling TW-laser pulse long-range filamentation in air by a deformable mirror. AB - The results of experiments and theoretical modeling of the multiple filamentation of terawatt-power femtosecond laser pulses on a 137 m long air path are presented. We use a multielement optical setup consisting of a Galilean telescope and a deformable bimorph mirror, which allows construction for the desired pulse wavefront at the optical path entrance. By introducing controlled aberrations of the pulse phase profile, we demonstrate the wide-ranging manipulations on the position and spatial structure of the filamentation region. For the first time, to the best of our knowledge, the stable wide-aperture (5 cm in diameter) ring shaped spatial lattice of high-intense light channels is experimentally realized, which can persist over hundreds of meters in air. PMID- 30462008 TI - Pump fluence dependence of ultrafast carrier dynamics in InSb measured by optical pump-terahertz probe spectroscopy. AB - Ultrafast carrier dynamics in intrinsic and n-doped InSb crystals were studied by time-resolved terahertz spectroscopy using an optical pump-terahertz probe setup with pump fluence from 32 MUJ/cm2 to 1910 MUJ/cm2. With photoexcitation at 800 nm, the ultrafast photoinduced absorption and carrier recovery process of intrinsic and n-doped InSb showed strong pump fluence dependence. It was found that the magnitude of photoinduced absorption first increased and then decreased with pump fluence. The carrier recovery process could be well fitted with a single exponential curve at low pump fluence, but could be well fitted with a biexponential curve at high pump fluence when a fast photocarrier relaxation appeared. The magnitude of photoinduced absorption increased gradually at low pump fluence due to the increase of the carrier at the bottom of the conduction band by impact ionization. The magnitude of photoinduced absorption decreased gradually at high pump fluence, possibly due to the efficiency of transient Auger recombination greater than the rate of carriers generated in the impact ionization process. The fast decay process appearing at high pump fluence was thought to be dominated by transient Auger recombination. PMID- 30462009 TI - Wavelength-sensitive PIT-like double-layer graphene-based metal-dielectric-metal waveguide. AB - A wavelength-sensitive plasmonically induced transparency-like (PIT-like) device consisting of a double-layer graphene-based metal-dielectric-metal (MDM) waveguide is proposed. We initially investigate monolayer graphene sandwiched in the MDM waveguide and utilize the phase-matching equation to explain the reflected resonant wavelength of the transmission spectra. The PIT-like windows in the transmission spectra of double-layer graphene can be achieved by tuning the applied bias voltage on the graphene layer and the distance between the graphene layer and metal substrate. We can obtain the high-performance PIT-like devices with a flexible on-off-on effect. We use a finite element method to do all related simulations. PMID- 30462010 TI - Moire fringes of higher-order harmonics versus higher-order moire patterns. AB - This work presents a very simple and comprehensive approach for classification of the combinational spatial frequencies of the superimposed periodic or quasi periodic structures. The reciprocal vectors of the structures are used to express their respective spectral components, and a unique reciprocal vectors equation is introduced for presenting the corresponding combinational frequencies. By the aid of the reciprocal vectors equation we classify moire patterns of combinational frequencies into four classes: the conventional moire pattern, moire fringes of higher-order harmonics, higher-order moire patterns, and pseudo-moire patterns. The difference between the moire fringes of higher-order harmonics and higher order moire patterns is expressed in the formulas. By some typical examples, conditions for simultaneous formation of moire patterns of different harmonics of the superimposed gratings are investigated. We show that in the superimposition of two gratings, where at least one has a varying period and another has a non sinusoidal profile, different moire patterns are formed over different parts of the superimposed area, where a distinct pair of spatial frequencies of the superimposed structures contributes to the formation of each of the patterns. We use the same procedure in the analysis of simultaneously produced defected moire patterns in the superimposition of a linear grating and a zone plate, where one or both consist of some topological defects at specific locations and at least one of the gratings has a non-sinusoidal profile. The topological defects of resulting moire fringes are similar to those appearing in the interference patterns of optical vortices. It is shown that the defect number of resulting moire fringes depends on the defect numbers and order of frequency harmonics of the gratings. The dependency of the defect number of the moire fringes and its sign to the defect numbers of the gratings and their contributed frequency harmonics is derived for both additive and subtractive terms of moire fringes, and the results are verified with several examples based on computational simulations. PMID- 30462011 TI - Dual concave grating anastigmatic spectrometer with high spectral resolution for remote sensing. AB - A dual concave grating imaging spectrometer with anastigmatic imaging has been presented for remote sensing. The optimal arrangements of the gratings and the addition of a cylindrical lens have been determined based on different aberrations and the major corresponding parameter analysis. The advanced Wadsworth mounting can eliminate coma and astigmatism and realize high spectral resolution with low ruling density gratings. The design presents excellent optical performance: the spectral resolution is 0.6 nm, and spatial resolution is 1 mrad/pixel over the waveband of 400 nm centered at 600 nm with NA 0.1. The manufacture and testing of the prototype prove the principle of design and the engineering practicality. PMID- 30462012 TI - Performance evaluation of perfect optical vortices transmission in an underwater optical communication system: publisher's note. AB - This publisher's note identifies an error in the paper title of Appl. Opt.57, 9148 (2018)APOPAI0003-693510.1364/AO.57.009148. PMID- 30462013 TI - 302 nm continuous wave generation by intracavity frequency doubling of a diode pumped Pr:YLF laser. AB - In this paper, we report on the intracavity frequency doubling of the Pr:YLF laser with a LiB3O5 (LBO) crystal, which was pumped by a combined 1.4 W blue laser diode at 444 nm and 1.5 W blue laser diode at 469 nm. By optimizing the design of the resonator, using a 5-mm-long LBO crystal, the maximum output power of 5 mW at 302 nm was achieved with respect to the total pump power. PMID- 30462014 TI - Fourier conjugate adaptive optics for deep-tissue large field of view imaging. AB - Light microscopy enables multifunctional imaging of biological specimens at unprecedented depths and resolutions. However, the performance of all optical methods degrades with the imaging depth due to sample-induced aberrations. Methods of adaptive optics (AO), which are aimed at pre-compensation of these distortions, still suffer from a limited field of view and imaging depth as well as inconvenient microscope design. Here, I propose and investigate a new approach to overcome these limitations: Fourier image plane conjugate AO. Two experimental designs of the new approach are carefully studied, and an accurate comparison between different methods of AO is presented. Fourier conjugate AO provides a larger field of view, which can only be limited by the angular memory effect, and allows the optimal use of the spatial light modulator. Moreover, theoretically possible imaging depth of Fourier conjugate AO is limited only by the working distance of the objective and not by the microscope design. PMID- 30462015 TI - Low-power total internal reflection thermo-optic switch based on hybrid SiON polymer X-junction waveguides. AB - We propose and demonstrate a low-power 2*2 total internal reflection thermo-optic switch based on an X-junction configuration formed with a silicon oxynitride (SiON) core and polymer cladding. Unlike X-junctions reported thus far, our proposed configuration features a slot formed on the center of the X-junction and filled with polymer cladding. With such a configuration, the opposite thermo optic characteristics of SiON and polymer and, hence, heat utilization efficiency can be fully utilized. Our fabricated proof-of-principle switch shows extinction ratios of larger than 15.34 dB and switching powers of less than ~59.6 mW. The rise time and fall time of switching are 1.42 and 0.85 ms, respectively. The insertion losses are less than 10.6 dB for all channels, and the polarization dependent loss is ~0.3 dB. PMID- 30462016 TI - Calibration method of overlay measurement error caused by asymmetric mark. AB - With the process nodes extending to sub-10-nm in advanced semiconductor manufacturing, the overlay requirements keep progressively scaling down, which makes it very important to measure overlay precisely for monitoring on-product performance. The overlay mark being asymmetrical when generated via the lithography process, this asymmetry will be slightly variated even in the same process or same lot, and it will bring overlay measurement error. In general, the wafer alignment data are used for correcting this overlay measurement error, utilizing its wavelengths and polarizations dependence. However, there is a residual error that cannot be removed because the structures of the wafer alignment mark and overlay mark are different and are affected by the process differently. In this paper, a new method is proposed for calibrating the overlay measurement error introduced by the asymmetric mark, which is based on the relationship between measurement data of the overlay mark and the single layer mark. The validity is verified by simulation with different types of asymmetric mark. It is very useful for improving overlay measurement accuracy and for understanding how the overlay measurement error is affected by the asymmetric mark. PMID- 30462017 TI - Photonic crystal elliptical-hole tapered low-index-mode nanobeam cavities for sensing. AB - A one-dimensional photonic crystal elliptical-hole tapered low-index-mode nanobeam cavity sensor fully encapsulated in a water environment is proposed. In the proposed structure, to confine the light in the low-index region and enhance the light-matter interaction, a tapered major axis of the elliptical hole away from the nanobeam cavities center is optimized. Through a three-dimensional finite-difference time-domain simulation, the results show that the low-index mode of the middle geometry cell is confined in the photonic bandgap of two-sided cells. The highest quality factor of 6.04*105 is achieved when 13 tapered segments and 5 mirror segments are placed at both sides of the host waveguide. The proposed nanobeam structure theoretically possesses a sensitivity of 244.7 nm/RIU (refractive index unit) in a water environment. Moreover, an ultra-compact footprint of 6.4 MUm*0.85 MUm is achieved, which is only half of the size compared to the best value reported for the nanobeam structure. The results indicate that it is a promising sensor for excellent on-chip sensing with respect to the very small footprint. PMID- 30462018 TI - Inverse problem based on the fast alternating direction method of multipliers algorithm in multiangle total internal reflection fluorescence microscopy. AB - Multiangle total internal reflection fluorescence microscopy (TIRFM) has become one of the most important techniques for achieving axial superresolution. The key process in this technique is solving the inverse problem. This paper applies an improved alternating direction method of multipliers algorithm to solve the inverse problem and validates the accuracy of the algorithm by reconstructing simulated microtubule structures in multiangle TIRFM images. The reconstruction times for different algorithms and the convergence speeds of the improved and original algorithms are compared. Experimental results show that the improved algorithm can achieve an axial resolution of 40 nm, reduce the influence of the penalty parameter on convergence, and improve the convergence speed of the iterative process while ensuring image reconstruction quality. Based on the algorithm, a three-dimensional image with the depth information of microtubules and mitochondria is reconstructed. PMID- 30462019 TI - Coupling ultrafast laser pulses into few-mode optical fibers: a numerical study of the spatiotemporal field coupling efficiency. AB - Few-mode optical fibers have been widely used in applications such as data transmission and laser amplification. The coupling of laser beams into such fibers is important because it determines the fiber mode contents, which influence the beam quality, laser amplification efficiency, and appropriate distortion control methods. Ultrafast lasers, as a widely used type of laser source for intense-field applications, can generate pulses with broad spectra and varying phases, adding complexity to the fiber mode coupling problem. In this paper, we numerically study the coupling performance of ultrafast laser pulses into few-mode fibers, investigating the mode coupling efficiency under different launching field conditions. Certain modes can be optimized with their coupling efficiencies in the presence of pulse spatiotemporal couplings, which provides a new perspective toward generating complex waveforms and studying laser matter interactions. PMID- 30462020 TI - Evaluation of image matching techniques for optical fiber specklegram sensor analysis. AB - A quantitative study of image matching techniques applied to fiber specklegram sensor analysis is presented. The fiber status is modulated by a microbending transducer, so the output speckle field can be correlated to the input displacements. Once acquired and preprocessed, the specklegrams' variations were evaluated according to seven approaches. Although the average intensity did not provide reliable information per se, the correlation and sum of differences methods yielded ~11 mm-1 and ~14 mm-1 sensitivities, respectively, within a ~0.06 mm range and low linearity and hysteresis errors, with enhancement possibility by intensity level cancellation. Moreover, the phase-only correlation and the mutual information metrics provided very high sensitivities (22 mm-1 and 120 mm-1, respectively) for a <0.02 mm range, making these techniques suitable for detecting subtle variations in the fiber status due to physical or chemical stimuli. PMID- 30462021 TI - Object plane detection and phase retrieval from single-shot holograms using multi wavelength in-line holography. AB - Phase retrieval and the twin-image problem in digital in-line holographic microscopy can be resolved by iterative reconstruction routines. However, recovering the phase properties of an object in a hologram requires an object plane to be chosen correctly for reconstruction. In this work, we present a novel multi-wavelength iterative algorithm to determine the object plane using single shot holograms recorded at multiple wavelengths in an in-line holographic microscope. Using micro-sized objects, we verify the object positioning capabilities of the method for various shapes and derive the phase information using synthetic and experimental data. Experimentally, we built a compact digital in-line holographic microscopy setup around a standard optical microscope with a regular RGB-CCD camera and acquired holograms of micro-spheres, E. coli, and red blood cells, which are illuminated using three lasers operating at 491 nm, 532 nm, and 633 nm, respectively. We demonstrate that our method provides accurate object plane detection and phase retrieval under noisy conditions, e.g., using low-contrast holograms with an inhomogeneous background. This method allows for automatic positioning and phase retrieval suitable for holographic particle velocimetry, and object tracking in biophysical or colloidal research. PMID- 30462022 TI - Simple precision measurements of optical beam sizes. AB - We present a simple high-precision method to quickly and accurately measure the diameters of Gaussian beams, Airy spots, and central peaks of Bessel beams ranging from sub-millimeter to many centimeters without specialized equipment. By simply moving a wire through the beam and recording the relative losses using an optical power meter, one can easily measure the beam diameters with a precision of 1%. The accuracy of this method has been experimentally verified for Gaussian beams down to the limit of a commercial slit-based beam profiler (3%). PMID- 30462023 TI - Research on high-resolution imaging technology based on light field manipulation for a lenslet-based plenoptic camera. AB - In this paper, an aberration correction method for an extended target is proposed to solve the problem of the lenslet-based plenoptic camera not imaging clearly under the influence of aberrations. We propose a light field manipulation method to improve performance of the light field imaging system. The principle of this method is that the sub-aperture images extracted from the raw light field image are offset when the light field imaging system is affected by aberrations, and the symmetrical arrangement of the sub-aperture image array is destroyed. By repairing the symmetrical arrangement of the sub-aperture image array, the influence of phase aberrations on the imaging system can be eliminated, and the resolution of the plenoptic camera can be improved. We use an image correlation algorithm to process the sub-aperture images of the plenoptic camera, calculate and compensate each sub-aperture image's displacement caused by aberrations, and restore the symmetrical arrangement of the sub-aperture image array; then, a corrected high-resolution refocused image can be generated. In particular, this method uses only the raw light field information obtained by the plenoptic camera in a single exposure, without adding other hardware devices. Furthermore, it takes the extended target itself as the reference image, so the ideal position need not be calibrated in advance. Also, the parallax information of the sub aperture images is retained, and the method is simple and easy to use. Numerical simulation and experimental results show that the technology proposed in this paper can work well for high-resolution imaging of a plenoptic camera with phase aberrations. This method can be potentially applied to analyze lens aberration, media-induced image distortion such as water turbulence in underwater imaging, and atmospheric turbulence in remote imaging. It may have important application prospects in the fields of astronomical object detection, remote sensing, etc. PMID- 30462024 TI - Three-dimensional thermal model of a high-power diode laser bar. AB - An analytical, three-dimensional, steady-state thermal model of a high-power diode laser bar is presented in this paper. The heat spreading angle in a laser bar heat sink, subjected to several convective conditions on the bottom-side, was calculated with this model. Thermal design curves for the heat sink and submount are also presented. Special discussion is presented for two kinds of our conduction-cooled laser bars. Finite element simulation and experimental results based on the wavelength shift method are compared with this analytical solution. The familiar 45 degrees angle in thermal design for a commercial hard solder conduction-cooled laser bar was found to lead to a 12% increase in thermal resistance relative to a free lateral diffusion heat sink. PMID- 30462025 TI - On the development of an effective image acquisition system for diamond quality grading. AB - In this paper, an effective diamond image acquisition system is proposed for capturing images of the diamond sample under inspection separately with transmitted and reflected light. The proposed system consists of two parts: a lighting system and an imaging system. The lighting system is a newly designed integrating sphere that can control the light distribution in the image plane and provide uniform illumination to the diamond sample while it is being inspected under white LED lamps with a specific spectral power distribution. The imaging system comprises industrial-grade lenses, cameras, and a sample loading plate. One set of lenses and a camera is installed at the port of the lower hemisphere. This arrangement ensures that all light rays illuminated to the image plane are transmitted light. On the other hand, all light captured by the other set of lenses and a camera installed on the upper hemisphere is reflected light. The proposed design utilizes the ray tracing processing method based on the physical properties of materials and adjusts the parameters of each optical component. When properly designed, the signal-to-noise ratio of captured diamond images is significantly improved, so that imperfections inside the diamond or on its surface can be clearly distinguished. The proposed image acquisition system is cost-effective and compact. The experimental results agree well with the theoretical analysis and verify the effectiveness of the proposed image acquisition system. The proposed system will facilitate, improve, and simplify automated diamond quality grading. PMID- 30462026 TI - M2 factor of controllable dark-hollow beams through a multi-apertured ABCD optical system. AB - Under an optical system with multiple hard-edged apertures in a cylindrical coordinate system, the recurrence propagation expression is derived for the controllable dark-hollow beams (CDHBs) by expanding the hard-aperture function into a finite sum of complex Gaussian functions. Given the recurrence propagation expression, we deduce the approximate analytical expressions of the beam propagation factor M2 in terms of the generalized truncated second-order moments. This provides a fast algorithm for the evaluation of the beam propagation quality for CDHBs through complicated optical trains with a series of apertures. The propagation of CDHBs through a two-aperture-lens ABCD optical system serves as the special case of multi-apertured ABCD optical systems. Our numerical results suggest that a one-aperture-lens optical system reduces the beam propagation quality of CDHBs, and a two-aperture-lens optical system improves the beam propagation quality of CDHBs by selecting appropriate beam parameters and aperture parameters. PMID- 30462028 TI - Hyperspectral imaging system based on a single-pixel camera design for detecting differences in tissue properties. AB - Optical spectroscopy can be used to distinguish between healthy and diseased tissue. In this study, the design and testing of a single-pixel hyperspectral imaging (HSI) system that uses autofluorescence emission from collagen (400 nm) and nicotinamide adenine dinucleotide phosphate (475 nm) along with differences in the optical reflectance spectra to differentiate between healthy and thermally damaged tissue is discussed. The changes in protein autofluorescence and reflectance due to thermal damage are studied in ex vivo porcine tissue models. Thermal lesions were created in porcine skin (n=12) and liver (n=15) samples using an IR laser. The damaged regions were clearly visible in the hyperspectral images. Sizes of the thermally damaged regions as measured via HSI are compared to sizes of these regions as measured in white-light images and via physical measurement. Good agreement between the sizes measured in the hyperspectral images, white-light imaging, and physical measurements were found. The HSI system can differentiate between healthy and damaged tissue. Possible applications of this imaging system include determination of tumor margins during surgery/biopsy and cancer diagnosis and staging. PMID- 30462027 TI - Speckle noise reduction in digital speckle pattern interferometric fringes by nonlocal means and its related adaptive kernel-based methods. AB - Digital speckle pattern interferometry (DSPI) is widely used in many scientific and industrial applications. Besides its several advantages, one of the basic problems encountered in DSPI is the undesired speckle noise existing in the fringe pattern. In this paper, we demonstrate the performance of nonlocal means (NLM) and its related adaptive kernel-based filtering methods for speckle noise reduction in DSPI fringes. The NLM filter and its related kernel-based filters such as NLM-average, NLM-local polynomial regression, and NLM-shape adaptive patches are implemented first on simulated DSPI fringes, and their performances are quantified on the basis of peak signal-to-noise ratio (PSNR), mean square error (MSE), and quality index (Q). Further, their effectiveness and abilities in reducing speckle noise are compared with other speckle denoising methods. These filtering methods are then employed on experimental DSPI fringes. The obtained results reveal that these filtering methods have the ability to improve the PSNR and Q of the DSPI fringes and provide better visual and quantitative results. It is also observed that the proposed filtering methods preserve the edge information of the DSPI fringes, which is evaluated on the basis of the edge preservation index of the resultant filtered images. PMID- 30462029 TI - Double D-shaped hole optical fiber coated with graphene as a polarizer. AB - A double D-shaped hole optical fiber coated with graphene is proposed as a polarizer at the wavelength of 1.55 MUm. As the planar surfaces of D-shaped holes are both coated with graphene, the interaction between the core and graphene can be doubled. Moreover, the interaction can be further improved by introducing functional materials into the holes. The proposed fiber provides a high extinction ratio (ER) and low insertion loss, and it operates in the single polarization mode. The ER of 42.5 dB with a 2.5-mm-long optical fiber can be achieved for a transverse-electric-pass polarizer, and the insertion loss is approximately 1.08 dB. Specifically, the proposed fiber can achieve simultaneously dual-band polarization at 1.55 MUm and 1.31 MUm. The proposed fiber is feasible for seamless integration in existing fiber systems. We hope our work benefits high-efficiency polarizers, and we believe that the proposed fiber has some potential applications in photonic integrated circuits. PMID- 30462030 TI - Terahertz communication windows and their point-to-point transmission verification. AB - Terahertz communication is recognized as a transformational technology that can meet the future demands of point-to-point communication. The study of terahertz atmospheric transmission characteristics is important for guiding the terahertz communication window selection process. In this report, based on the modified ITU R P.676-10 model, we determined that the terahertz communication windows above 100 GHz were located at the bands at approximately 140, 220, 340, 410, and 460 GHz, which is verified by recent experiments. We also verified the feasibility of indoor point-to-point communication by the 110 m transmission experiment through the communication window around 460 GHz. PMID- 30462031 TI - Bidirectional reflectance characteristics of the sea surface based on midinfrared measured data. AB - In order to establish a more realistic radiation model of the sea surface, the effects of solar radiation, sky radiation, and atmospheric thermal radiation on sea surface radiation are taken into consideration, on the basis of which the infrared radiative transfer equation of the sea surface is deduced in this paper. A method for calculating the bidirectional reflection characteristics of the sea surface based on measured data is proposed according to the projection imaging of beam propagation. Based on the measurements of sea surface temperature, incident sky radiation, incident solar radiation, and radiance of sea crests at different times, the radiative transfer equation is used to retrieve the bidirectional reflectance of a midwave infrared sea surface. Meanwhile, the results of the method mentioned above are compared with the calculated results of Cox-Munk, Mermelstein, Wu, and Beckmann bidirectional reflection characteristics models. Research shows that the bidirectional reflectance at the wave crest of a sea surface increases gradually, when the solar incident zenith angle changes from 56.39 degrees to 76.02 degrees as well as the direction of observation remaining constant (thetar=80.0 degrees ; phir=73.0 degrees ). The reflection ability at the wave crest of the sea surface is strongest when the incident direction of the sun is close to the observation direction, which is in accordance with the law of reflection. The Cox-Munk model and Wu model are closer to our values when the solar incidence zenith angle is small (thetai<=65.93 degrees ). On the other hand, the calculated values of the Mermelstein and Wu models are closer to the values in this paper when the solar incidence zenith angle is large (thetai<=65.93 degrees ). In general, the error of the Beckmann model is a little greater than that of the other three models. PMID- 30462032 TI - In-flight characterization of the lunar orbiter laser altimeter instrument pointing and far-field pattern. AB - The Lunar Orbiter Laser Altimeter (LOLA) aboard the Lunar Reconnaissance Orbiter (LRO) has collected nearly seven billion measurements of surface height on the Moon with an absolute accuracy of ~1 m and a precision of ~10 cm. Converting time-of-flight laser altimeter measurements to topographic elevations requires accurate knowledge of the laser pointing with respect to the spacecraft body fixed coordinate system. To that end, we have utilized altimetric crossovers from LOLA, as well as bidirectional observations of the LOLA laser and receiver boresight via an Earth-based laser tracking ground station. Based on a sample of ~780,000 globally distributed crossovers from the circular-orbit phase of LRO's mission (~27 months), we derive corrections to the LOLA laser boresight. These corrections improve the cross-track and along-track agreement of the crossovers by 24% and 33%, respectively, yielding RMS residuals of ~10 m. Since early in the LRO mission, the bidirectional laser tracking experiments have confirmed a pointing anomaly when the LOLA instrument is facing toward deep space or the night side of the Moon and have allowed the reconstruction of the laser far-field pattern and receiver telescope pointing. By conducting such experiments shortly after launch and nearly eight years later, we have directly measured changes in the laser characteristics and obtained critical data to understand the laser behavior and refine the instrument pointing model. The methods and results presented here are also relevant to the design, fabrication, and operation of future planetary laser altimeters and their long-term behavior in the space environment. PMID- 30462033 TI - Giant Goos-Hanchen shift in two different enantiomers' chiral molecules via quantum coherence. AB - The Goos and Hanchen (GH) shifts in reflected and transmitted probe light through a cavity mixture of left- and right-handed chiral molecules into two enantiomer states are investigated. Due to the broken mirror symmetry of the left- and right handed chiral molecules in the presence of cyclic population transfer, such quantum systems can be selectively excited because of the coexistence of one- and two-photon transitions. With the help of coupling Rabi frequency and damping effects due to scattering processes, the generated GH shifts accompanied by simultaneously negative and positive lateral shifts in reflected and transmitted probe lights are greatly enhanced. It is found that the large negative and positive GH shifts are available in the presence of multiphoton resonance and off resonance conditions for two different enantiomers' chiral molecules. Moreover, the switching between superluminal and subluminal light propagation is extremely dependent on choosing the left- and right-handed chiral molecules. Furthermore, the effects of pulse shape and mode of Laguerre-Gaussian probe light on the GH shifts that lead to a switch between negative and positive shift are also studied. The negative and positive GH shifts in a reflected and transmitted probe beam for an incident Gaussian and different mode of Laguerre-Gaussian shaped beam with various widths by the use of two different enantiomers' chiral molecules are also discussed. PMID- 30462034 TI - UAV-based hyperspectral analysis and spectral indices constructing for quantitatively monitoring leaf nitrogen content of winter wheat. AB - In flag leaf and flowering stages of winter wheat, unmanned aerial vehicle (UAV) based and ground-measured hyperspectral data were collected simultaneously, and leaf nitrogen content (LNC) data were then measured in a laboratory. First, the accuracy of UAV-based hyperspectral data was analyzed using ground-measured hyperspectral data, and the analysis showed that the effectiveness and spectrum sampling precision of the UAV-based hyperspectral data are reliable. Hyperspectral characteristic analysis of winter wheat canopies of different LNCs was also conducted. Second, representative spectrum bands that are sensitive to the LNC of winter wheat were extracted through first-order differential spectral, continuum-removed reflectance, and band correlation prediction threshold methods. The optimal band combination that is sensitive to the LNC of winter wheat was obtained by comparing and analyzing the representative spectrum band results. Thus, several LNC spectral indices (LNCSI) were established through ratio, difference, and normalization methods, and linear regression statistical models for quantitatively simulating LNCs were established using the LNCSIs. Finally, comprehensive and comparative analyses of the LNCSIs and the inversion values of the LNC using the LNCSIs confirmed that the LNCSIs are effective in quantitatively inversing the LNC of winter wheat. PMID- 30462035 TI - Analyzing the performance of pseudo-random single photon counting ranging Lidar. AB - The detection principle and performance of the pseudo-random single photon counting ranging (PSPCR) Lidar system are investigated. The detection probability and single photon detection efficiency (SPDE) of the macro code for the PSPCR Lidar system are derived based on statistical theory. The effects of the echo primary electrons number and the dead time on the detection probability and SPDE are analyzed. The detection probability increases with the increase of the primary electron number and tends toward saturation. The change of dead time length has little effect on the detection probability of the macro code, especially when the number of echo primary electrons is large. However, the length of dead time is inversely proportional to the number of detected codes. The longer the dead time, the fewer the number of detected codes, and the worse the ranging performance. The signal-to-noise ratio (SNR) of the PSPCR Lidar is analyzed based on the cross-correlation function. The Monte Carlo simulation results show that the PSPCR Lidar has a satisfactory SNR even in a high noise level. As the number of signal primary electrons increases, the SNR gradually increases and tends to be saturated. As the noise increases, the SNR gradually decreases, and the greater the noise, the more severe the SNR decreases. At the same time, based on the assumption that the power of the single code in Gaussian distribution and the time resolution of the photon counting module are less than the code width, the theoretical formula of the range error is deduced. The effects of the echo signal primary electron number and code width on the range error are analyzed. The results show that the fewer the primary electron numbers or the narrower the code width, the smaller the range error of the PSPCR Lidar system. The range error of the PSPCR Lidar system is verified by Monte Carlo simulation. The simulation results are in good agreement with the theoretical analysis. PMID- 30462036 TI - Parametric study on photoluminescence enhancement of high-quality zinc oxide single-crystal capping with dielectric microsphere array. AB - A dielectric microsphere is a multifunctional platform to manipulate light in microscale by nanofocusing, optical whispering gallery resonance, and unidirectional antenna. Dielectric microsphere arrays (MSAs) have demonstrated the capability for photoluminescence (PL) and Raman enhancement without plasmonics. In this work, we investigate the effects of excitation power, tilting angle, and temperature on PL enhancement of high-quality zinc oxide (ZnO) single crystal capping with fused silica MSAs. The microsphere diameter is optimized to 3.5-5.5 MUm, achieving the maximum UV-PL enhancement ratio of intensity (ERI) up to tenfold by strong focusing and unidirectional antenna effects. Under the excitation power <0.2 mW, the incident light focused by the MSA increases the localized exciton state density for a higher ERI of ~15-fold. The angle-sensitive PL intensity from the MSA enhancer provides a simple approach achieving unidirectional UV emission from planar ZnO. The 16-fold enhancement for UV-PL near 130 degrees C is also demonstrated, for the first time, owing to thermal ionization of hydrogen-related donor that increases free-exciton concentration. The high temperature stability and reproducibility of PL enhancement up to 400 degrees C promote the nonplasmonic MSAs superior to surface plasmon-related metal nanostructures for ZnO-based highly efficient luminescence and highly sensitive photon detection above room temperature. PMID- 30462037 TI - Polarization-modulated three-dimensional imaging using a large-aperture electro optic modulator. AB - To implement high-resolution and low-light sensitive three-dimensional (3D) imaging for long-range applications while simplifying data collection and reducing collection time, a polarization-modulated 3D imaging structure, using a large-aperture electro-optic modulator (EOM) and electron-multiplying CCD (EMCCD), is proposed in this paper. As the EMCCD camera itself has no ability of time resolution and high-speed gating due to the time integration mechanism, large-aperture EOMs are used to provide time resolution and high-speed shutter simultaneously for the EMCCD cameras to obtain the polarization-modulated images from which a 3D image can be reconstructed. A narrow field of view was designed to match the divergence of laser beam for long-range imaging, and therefore through the receiver, the incident angle on the EOM would still be limited to within a small angle, which would not degrade the modulation performance significantly during electro-optic modulation. Ultimately, we found that the polarization-modulated 3D imaging lidar showed very promising performance on time resolved imaging in a field of view of 0.9 mrad. PMID- 30462038 TI - Research on the degradation of lightweight mirror surface accuracy. AB - The vibration test is one of many tests that space telescopes endure to ensure that functionality is not impaired by severe launch. Telescopes undergo detailed measurements, including mirror surface accuracy measurements. Due to the design shortcomings, degradation of lightweight mirror surface accuracy may exceed the design error budget at times. In this paper, we demonstrate a method to determine the cause of the degradation. By using inertia relief, the influence functions were obtained, and structural deformation was derived from finite element analysis. Based on the structural deformation, we found that the back frame of the telescope had insufficient torsional and bending stiffness. With the indicated need for higher stiffness, the rigidity of the back frame was improved. In addition, high- and low-temperature cycling was used to reduce residual stresses that cause high-frequency distortion. The new vibration test verified the mechanical safety and optical stability of the improved structure. The surface accuracy measured by an optical interferometer was maintained at 0.015 wave within the design error budget. PMID- 30462039 TI - Ritchey-Common sparse-aperture testing of the Giant Steerable Science Mirror. AB - The Giant Steerable Science Mirror (GSSM) is the tertiary mirror of the future large telescope, the Thirty Meter Telescope. However, the mirror is too large to be tested using only one aperture, and using many apertures will increase the cost of testing. To accomplish testing at a low cost, the number of apertures should be reduced. The Ritchey-Common (R-C) testing method, commonly used for testing large flat surfaces, uses only a reference spherical mirror and avoids the use of large planar interferometers. Additionally, only the low-spatial frequency mirror figure is relevant in the system assembly and alignment. Hence, the applicability of sparse-aperture testing is investigated in this paper. Sparse-aperture testing and the R-C method were combined to lower the cost. Using this method and the normalized point source sensitivity (PSSn), the mirror figure can be specified in a simple and accurate manner. Moreover, as fewer subapertures are under test, the efficiency can be improved. An error analysis is conducted, focusing on the shifting error, irregularity error, tipping error, tangential/sagittal error, and seeing. For the testing of the GSSM prototype, the error analysis showed the total error in PSSn is 0.9701. PMID- 30462040 TI - Performance of a flat-field grating spectrometer for tender x-ray emission spectroscopy. AB - A flat-field grating spectrometer for tender x-ray emission spectroscopy has been developed. The grating has been coated with an aperiodic Ni/C multilayer that improves the diffraction efficiency in the range 1-3.5 keV at a constant angle of incidence. The aperiodic layer structure originates from the topmost bilayer with a larger thickness compared to other Ni/C bilayers. The performance of the spectrometer has been evaluated by measuring characteristic x rays such as the L series emitted from a Cu(In,Ga)Se2-based thin-film solar cell specimen. It is shown that the Lalpha1,2 x-ray emission spectra of Cu, In, Ga, and Se can be clearly simultaneously observed in the range from 0.9 to 3.3 keV, and the linewidths are 4.9, 26.1, 4.6, and 6.1 eV, respectively, corresponding to a spectral resolution of 100-300. PMID- 30462041 TI - Active optical modulator based on a metasurface in the terahertz region. AB - The characteristics of the electromagnetically induced transparency (EIT) analog exposed under different illumination powers have been investigated theoretically and experimentally. The EIT analog is composed of a fixed aluminum structure fabricated on the silicon substrate. It was found that the resonance degree of the transparent window displayed a decreasing trend, and a blueshift phenomenon emerged by increasing the powers of the laser. Similarly, the properties of the time delay under different illumination powers have also been researched. The realization of the tuning effect may provide a possible choice for the modulation of the slow light devices. PMID- 30462042 TI - Experimental characterization and physics-based modeling of the temperature dependent diffuse reflectance of plasma-sprayed Nd2Zr2O7 in the near to short wave infrared. AB - Supercontinuum-laser illumination in conjunction with CO2-laser heating has been implemented to measure the near to short-wave infrared (970-1660 nm) diffuse reflectance of plasma-sprayed Nd2Zr2O7 as a function of temperature. Owing to the broadband nature of this experimental technique, the diffuse reflectance of plasma-sprayed Nd2Zr2O7 has been measured at many wavelengths and has been shown to decrease with increasing temperature. A physics-based model for diffuse reflectance predicated on the crystal/electronic band structure of highly scattering semiconductor materials has been constructed to interpret the results of these measurements. Baseline materials characterization has also been performed to assist in the development of crystal/electronic band structure optical property relationships that could be useful for the design of next generation environmental barrier coatings. This characterization has included ambient and non-ambient x-ray diffraction as well as room-temperature, integrating-sphere diffuse reflectance spectroscopy. PMID- 30462043 TI - Spectral characteristics of a guided mode resonant filter with planes of incidence. AB - Spectral responses of the guided mode resonant filter under different planes of incidence are comprehensively investigated in this paper. Commercially available software based on the rigorous coupled wave analysis method is used to perform the reflectance spectra. For normal incidence, there exists a pair of resonance bands, whose diffraction efficiencies can be tuned from 3.5% to 100% and 3.2% to 100% without shifting the resonant location as the plane of incidence (POI) angle ranges from 0 degrees to 90 degrees , whereas the resonances split into two branches as the POI angle decreases from 90 degrees to 0 degrees for oblique incidence. There exists a crossing point between the split bands that is proved to be polarization independent. Moreover, the physical mechanism of the above spectral characteristics is analyzed in detail by means of the wave vectors. The intensity-tunable feature under normal incidence can be used in the field of bioactive fluorescent protein dyes, displays, and signal processing. And the split characteristic under oblique incidence is applied to seek the polarization independent wavelength, which has potential applications in the field of dense wavelength division multiplexing and laser devices. PMID- 30462044 TI - Design of a plasmonic sensor based on a square array of nanorods and two slot cavities with a high figure of merit for glucose concentration monitoring. AB - In this paper, a plasmonic nanosensor, by using a nanorod array in a square resonator coupled with two slot cavities, with properties for the detection of glucose concentration in water, is proposed and analyzed. We investigated the sensing feature by changing the concentration of the glucose from 0 to 60%. Obtained results show that, by placing different water samples in a square resonator and two cavities, resonance wavelengths can be changed. These resonances demonstrate different dependence on the glucose concentration of water samples. Further, varying the physical parameters of the configuration can also change the resonance wavelength and can be simply tuned. These features recommend flexibility to propose the structure. Simulation results show that the values of sensitivity and figure of merit can be obtained as 892 nm/RIU and 3.5*106 RIU-1, respectively, which can help researchers to discover applications in the plasmonic sensor domain. PMID- 30462045 TI - Analysis of crosstalk-free conditions for a cross-shift multiplexing method in holographic data recording. AB - There are various multiplexing methods in holographic data recording. A larger storage capacity is anticipated when combining two different multiplexing methods and then ensuring crosstalk-free recording. We have proposed a cross-shift multiplexing method that combines shift multiplexing and peristrophic multiplexing. Crosstalk-free conditions for shift multiplexing and peristrophic multiplexing were separately clarified. However, these conditions cannot be individually applied to cross-shift multiplexing. Then, we deduced the analytic formula of crosstalk for cross-shift multiplexing and verified its validity by comparing the theoretical and experimental results. Using this analytic formula, the shift pitch and rotation angle that attain crosstalk-free multiplexing can be determined. PMID- 30462046 TI - Retargeting of forbidden-dense-alternate structures for lithography capability improvement in advanced nodes. AB - In advanced semiconductor technology nodes, the forbidden pitch effect induced by the destructive interference between neighboring features always leads to poor printing quality. This effect becomes more prominent when the forbidden pitch structure combines with dense pitch structures, which is called the forbidden dense-alternate (FDA) structure. To overcome its influence on lithographic performance, the design rules can be revised at the cost of design tolerance. Another method is to optimize the source map with the risk of bringing the performance attenuation onto other patterns. This work demonstrates a retargeting method on the weak point in FDA structures. This method can improve the lithographic performance of FDA structures and allow more tolerance to the source mask optimization and design rules. As a result, more process tuning margin can be reserved for other modules, such as optical proximity correction and process integration, in order to improve the yield. PMID- 30462047 TI - Reduced distortion in high-index microsphere imaging by partial immersion. AB - We experimentally demonstrate that pincushion distortion is obvious when using a BaTiO3 glass (BTG) microsphere fully immersed in ethanol or SU-8 2002 resist to image a Blu-ray disk with sub-diffraction features. The distortion is related to the layer thickness of the immersing medium. For a BTG microsphere partially immersed in the SU-8 resist where the SU-8 thickness is around 4/5 the diameter of the microsphere, its distortion decreases dramatically, but it can still clearly resolve the Blu-ray disk. For such a partially immersed microsphere, the calculated position of the photonic nanojet is outside the microsphere and close to the object, indicating the microsphere has a super-resolution imaging property, and the distortion simulated by ZEMAX is decreased. PMID- 30462048 TI - Planar tunable graphene based low-pass filter in the terahertz band. AB - In this paper, design and analysis of planar graphene-based low-pass filters in the terahertz band are proposed. Using the proposed approach, it is possible to design plasmonic low-pass filters with the desired properties in the form of open stubs. The transfer matrix method is used based on the transmission line model for analyzing filters. The propagation constant and characteristic impedance required for this method are obtained according to the electrostatic scaling law and power-current approach, respectively. A typical fifth-degree low-pass filter is designed and analyzed according to the mentioned process. The frequency response of the low-pass filter indicates insertion loss of less than 2 dB, roll off rate of 17 dB/THz, return loss higher than 10 dB, and constant group delay of 0.3 ps. The results of the full-wave simulation confirm the analytical ones. Also, the theory of graphene equivalent circuit variation to the different chemical potentials is expressed so the filter frequency response can be explicitly predicted for any bias value. These filters, due to their compact structure and integrated electrical and physical shape, are the suitable choice for use in full-integrated planar circuits of terahertz systems. PMID- 30462049 TI - Investigating the reduction of cross-polarized Gaussian beam scattering from a PEMC buried cylinder coated with a topological insulator. AB - An investigation is presented for the reduction of cross-polarized Gaussian beam scattering from a perfect electromagnetic conducting (PEMC) cylinder coated with topological insulator (TI) material and buried in a semi-infinite medium. To calculate the successive reflections of the scattered field from the interface, cylindrical wave functions are written into the spectrum of plane waves. The scattered reflected field is calculated for each plane wave of the spectrum. Near and far-zone scattered fields are reported for time-reversal symmetry and symmetry-broken TI coating. It is observed that the near-zone scattered field is very helpful to understand why the scattering width (SW) of a cylinder coated with time-reversal symmetry TI material is different from the SW of a cylinder coated with symmetry-broken TI material. The effect of spot size of the Gaussian beam on the scattering pattern is investigated, while the result for a plane wave is served as a reference. It is observed that cross-polarized scattering can be reduced by increasing the thickness of the coating layer. It also decreases as admittance of the PEMC core increases. Moreover, the cross-polarized scattered field becomes significantly small when time-reversal symmetry is broken, irrespective of PEMC or perfect electric conductor (PEC) core. PMID- 30462050 TI - Determination of the optical turbulence parameters from the adaptive optics telemetry: critical analysis and on-sky validation. AB - It has been demonstrated by several authors that the optical turbulence parameters associated with a given adaptive optics (AO) run-the seeing angle and outer scale-can be determined from a statistical analysis of the commands of the system's deformable mirror (DM). The higher the accuracy on these parameters, the more we can make use of them, allowing for instance a better estimation of the seeing statistics at the telescope location or a more accurate assessment of the performance of the AO system. In the context of a point spread function reconstruction project (PSF-R) for the W. M. Keck observatory AO system, we decided to identify, in the most exhaustive way, all the sources of systematic and random errors affecting the determination of the seeing angle and outer scale from the DM telemetry, and find ways to compensate/mitigate these errors to keep them under 10%. The seeing estimated using our improved DM-seeing method was compared with more than 70 nearly simultaneous seeing measurements from open-loop PSFs on the same optical axis, and with independent seeing-monitor measurements acquired at the same time but far from the telescope (DIMM/MASS): the correlation with the open-loop PSF is very good (the error is about 10%), validating the DM seeing method for accurate seeing determination, while it is weak and sometimes completely uncorrelated with the DIMM/MASS seeing monitor data. We concluded that DM-based seeing can be very accurate if all the error terms are considered in the DM data processing, but that seeing taken from non-collocated seeing monitors is of no use even when moderate accuracy is required. PMID- 30462051 TI - Self-correction of alignment errors and retardations for a channeled spectropolarimeter. AB - Alignment errors of birefringent retarders and retardation errors introduced by environmental perturbations can cause significant influences on reconstructed Stokes parameters for the channeled spectropolarimeter. In this paper, we propose what we believe is a novel self-correction model that is independent of input polarization parameters to reduce the effects of alignment errors and environmental perturbations. This self-correction method can realize calibration and compensation of alignment errors and retardations simultaneously by measuring the target light in orbit. Simulation results show that alignment errors and retardations can be calibrated accurately, and the reconstructed Stokes parameters by using the presented method are more precise than by using the traditional method. The validity and feasibility of the presented method are further confirmed through experiments in the presence of alignment errors and environmental perturbations. PMID- 30462052 TI - Analysis of false alarm in heterodyne coherence accumulation based on sequence shifting and the genetic algorithm. AB - As a new method, coherent accumulation based on sequence shifting and the genetic algorithm (GA) has been proposed to detect a weak heterodyne signal. The excellent performance of the new method was proved by an experiment in previous studies. In this paper, the phenomenon of false alarm caused by the method is revealed through numerical simulation. It is found that, when only noise exists or signal-to-noise ratio (SNR) is low, the false alarm will occur with a high probability. Based on the statistical property of the false alarm, a solution approach using multiple GA modules is proposed to avoid the false alarm. According to the approach, only when all search results of the modules are the same, can one determine that there is an actual heterodyne signal in the detection; otherwise, the inputs of the modules will be judged as noise. Thus, the false alarm can be eliminated completely even if the SNR is quite low. The studies of this paper promote the practical application of the new coherent accumulation method. PMID- 30462053 TI - Role of temperature in de-mixing absorbance spectra composed of compound electrolyte solutions. AB - This work is focused on the role of temperature in the de-mixing of absorbance spectra measured in mixed aqueous Na2SO4 and NaNO3 solutions. First, the influence of temperature on the absorbance spectrum of demineralized water was determined. Second, the absorbance spectra of five separate electrolytes (NaNO2, NaNO3, CaCl2, K2CO3, and NaOH) at three temperatures (4 degrees C, 25 degrees C, and 50 degrees C) for concentrations ranging from 0.0625 M to 0.5 M were examined. These five electrolytes show similar temperature dependencies. Finally, absorbance spectra of mixed solutions were investigated at temperatures of 5 degrees C, 15 degrees C, 25 degrees C, 35 degrees C, and 45 degrees C for concentrations ranging from 0.0625 M to 0.5 M per electrolyte in the mixture. The spectral window from 650 to 1100 nm was utilized to observe the ionic and temperature influences on the vibrational modes of the OH bond in the solvent molecules. The effects of dissolving Na2SO4 and NaNO3 are nonlinearly cumulative at lower temperatures indicating extended alteration of the water structure beyond the first hydration shell. A similar trend was observed for a mixture of Na2CO3 and NaCl. Furthermore, it was found that higher temperatures are better for recovering the separate component absorption signatures of an electrolyte mixture. The near-infrared spectral regime is well suited for integrated sensing, and therefore these results can help in designing an integrated sensor to identify inorganic species in water. PMID- 30462054 TI - Pixellated circle. AB - For applications in optical systems it is often necessary to represent a circular aperture in a pixellated form. An objective parameter is introduced that is a measure of how well an approximate circle can be generated from a small array of square pixels. Both filled circles (disks) and rings are considered. Arrays with a width given by an even number of pixels can also be used to generate quadrants of a circle. Rings with outer and inner profiles given by optimum circles or quadrants can be summed to fill a complete circle or quadrant. PMID- 30462055 TI - High numerical aperture multifocal metalens based on Pancharatnam-Berry phase optical elements. AB - A high numerical aperture multifocal metalens was proposed based on well-designed Pancharatnam-Berry phase optical elements. Both circularly and linearly polarized incident lights could be tightly focused into diffraction-limited focal spots. Right and left circularly polarized focal spots could be realized simultaneously by illuminating a linearly polarized beam. The highest numerical aperture reached to 0.84 with full width at half-maximum of 263 nm. Moreover, we also presented a metalens whose optical elements are hybrid arranged and the metalens can realize spin-independent focusing with a numerical aperture of 0.8. The presented metalens has significant potential applications in particles manipulation and high-resolution imaging. PMID- 30462056 TI - Broadband infrared Mueller-matrix ellipsometry for studies of structured surfaces and thin films. AB - We present a high-optical-throughput infrared Mueller-matrix (MM) ellipsometer for the characterization of structured surfaces and ultrathin films. Its unprecedented sensitivity of about 10-4 in the normalized MM elements enables studies of the complex vibrational fingerprint of thin organic films under different ambient conditions. The ellipsometer acquires quadruples of MM elements within a few 10 s to min, rendering it interesting for process and in-line monitoring. It uses retractable achromatic retarders for increased signal to noise, and tandem wire-grid polarizers for improved polarization control. We demonstrate several scientific and industry-related applications. First, we determine the 3D profile of MUm-sized trapezoidal SiO2 gratings on Si from azimuth-dependent MM measurements. Data modeling based on rigorous coupled-wave analysis is employed to quantify grating structure and orientation. We then monitor polymer relaxation processes with a time resolution of 47 s. Measurements of polymer films as thin as 7.7 nm illustrate the sensitivity of the device. We finally couple a liquid flow cell to the ellipsometer, highlighting the prospects for in situ infrared MM studies of thin films at solid-liquid interfaces. PMID- 30462057 TI - Fiber Bragg grating-based sensor for torque and angle measurement in a series elastic actuator's spring. AB - Conventional technologies to monitor torque feedback and angle in exoskeleton actuators are bulky and sensitive to misalignments, and do not allow for multiplexed operation. Fiber Bragg grating (FBG)-based sensors are a robust sensing approach that are desirable for multi-parametric monitoring. Temperature, strain, torque, and angle are widely studied in human-robot interaction. In order to acquire the torque and angle of deflection in the torsional spring of a series elastic actuator, an experimental setup with the spring and an array of three FBGs is submitted to repeated torques and angles. This paper presents the characterization and validation of the FBG-based sensor for measuring by torque and angle variations. Temperature cross-sensitivity is derived by the use of a non-strain FBG. The developed sensor presented high linearity and small error for torque and angle measurements. PMID- 30462058 TI - Realizing a terahertz far-field sub-diffraction optical needle with sub wavelength concentric ring structure array. AB - The terahertz (THz) lens is an essential and strategic element of THz optical systems, while a conventional THz lens cannot even reach high resolution due to the diffraction limit. Optical super-oscillation paves a way to generate sub diffraction hotspots in the far field, and demonstrates the capacity for resolution improvement of microscopic imaging in the visible range. However, there are few demonstrations of THz lenses for focusing hotspots or needles based on super-oscillation. We propose and experimentally demonstrate a far-field sub diffraction focusing planar lens, consisting of a sub-wavelength concentric ring structure array, for a wavelength of 118.8 MUm with focal length 420lambda and radius 160lambda. Utilizing the silicon-etching process, a sub-diffraction focusing lens is fabricated. The experimental results show that the planar lens can generate a sub-diffraction needle with length 19.7lambda in the focal region along the optic axis. Moreover, the smallest focal spot, with a transverse size of 1.212lambda, is smaller than the diffraction limit of 1.476lambda. The proposed sub-diffraction optical needle planar lens can substitute for its traditional counterpart, and it has great potential in super-resolution tomography THz imaging systems. PMID- 30462059 TI - Thermal conductivity determination of erbium-doped crystals measured by spatially resolved confocal luminescence. AB - Thermal conductivity of Er3+-doped yttrium aluminum perovskite has been obtained by the use of laser induced temperature distribution and time-independent heat propagation equations. By using the spatially resolved microluminescence technique, the fluorescence spectra on the sample surface were mapped during the laser focused heating process, and the local temperature was measured at different spots on the sample surface with micrometric resolution. Significant information about the temperature profile was obtained following the maximum temperature of the laser spot and the behavior of the heat diffusion on the surface of the irradiation side. These data were finally used to feed the heat propagation equations from where the thermal conductivity was evaluated. PMID- 30462060 TI - Homodyne coherent optical receiver for intersatellite communication. AB - For increasing the data rate and reducing the power consumption in satellite communication systems, free-space optical communication technology has been verified as an attractive alternative to traditional radiofrequency communication systems. In this study, a high-sensitivity homodyne coherent optical receiver was demonstrated. A sensitivity of -59.2 dBm was achieved with an unencoded bit error rate below 10-3 at a bit rate of 1 Gbps (9.4 photons/bit does not include any overhead for forward error correction). To achieve homodyne detection, a modified decision-driven Costas optical phase-locked loop and a digital control algorithm were used to suppress the phase error and track the Doppler shift. Test experiments show that the receiver sensitivity penalty caused by the phase error is approximately 1 dB and that the receiver can track a Doppler shift at the speed of 100 MHz/s. Test experiments demonstrate that the receiver has a robust adaptive capacity to received-power fluctuation. The theoretical analysis and experimental results are presented in this paper. PMID- 30462061 TI - Fabrication of three-dimensional zinc oxide nanoflowers for high-sensitivity fiber-optic ammonia gas sensors. AB - ZnO is identified as one of the promising coating materials in optical fiber for ammonia gas sensors. In this work, three-dimensional ZnO nanoflowers are fabricated via a facile hydrothermal method and used as sensitive coating materials for optical fiber ammonia gas sensors. Results show that the sensor with ZnO nanoflowers exhibits a high sensitivity of 5.75 pm/(MUg.L-1) for ammonia concentration ranging from 0 to 5460 MUg.L-1, which is more than 2.6 times higher than that of the sensor with a coating of ZnO microspheres [2.2 pm/(MUg.L-1)]. PMID- 30462062 TI - Compact dual-fiber surface-enhanced Raman scattering sensor with monolayer gold nanoparticles self-assembled on optical fiber. AB - Employing a self-assembly method and dual-fiber structure, a compact, low-cost, highly sensitive, fast surface-enhanced Raman scattering (SERS) optical fiber sensor was realized. Through detecting a SERS signal of 10 ppm rhodamine B analyte, sensor parameters such as coupling angle, fiber types, and corresponding glass substrate structure were optimized. The ratio of the SERS signal intensity to excitation light residual peak intensity was used as a significant parameter during the optimization process. Sensor characteristics such as the SERS signal dependence on excitation power, stability related to excitation time, and reusability were studied. Its compatibility in size with microfluidic structure would make it a prospective candidate for integrating into a microfluidic chip. PMID- 30462063 TI - Full density fluorescence molecular tomography (FD-FMT) based on a dichroic mirror. AB - We present a novel method called full density fluorescence molecular tomography (FD-FMT) that can considerably improve the performance of conventional FMT. By converting each source (or detector) to a detector (or source) through the use of a dichroic mirror, FD-FMT not only increases the amount of optical projections by more than fourfold (compared to conventional FMT) to achieve high-resolution image reconstruction, but also offers the possibility to realize miniaturized FMT systems. PMID- 30462064 TI - Simple empirical master-slave dual-source configuration within the diffusion approximation enhances modeling of spatially resolved diffuse reflectance at short-path and with low-scattering from a semi-infinite homogeneous medium: erratum. AB - We correct one typographical error of three equations in Appl. Opt.56, 1447 (2017)APOPAI0003-693510.1364/AO.56.001447. PMID- 30462065 TI - Ultra-low-loss double-cladding laser fiber fabricated by optimized chelate gas phase deposition technique. AB - By applying an optimized chelate gas phase deposition technique, a Yb/Ce codoped aluminosilicate fiber with ultra-low loss of 1.55 dB/km was successfully fabricated and reported. The fiber showed homogenous distribution of the refractive index and dopant concentration devoid of central dip and clustering. Using the fiber as the amplifier stage, it delivered 1023 W near-single-mode laser output (M2=1.35) with a high slope efficiency of 85.1%, and the fiber temperature was less than 24.2 degrees C, primarily benefiting from the ultra-low background loss. The fiber also exhibited low photodarkening-induced loss, illustrating its outstanding photodarkening resistance. These results indicate that the ultra-low-loss Yb/Ce codoped aluminosilicate fiber is a prospective candidate for stable and reliable fiber laser applications. PMID- 30462066 TI - Interferometric sensor with a PGC-AD-DSM demodulation algorithm insensitive to phase modulation depth and light intensity disturbance. AB - An interferometric sensor with asymmetric division and a differential-self multiplication phase-generated carrier (PGC-AD-DSM) demodulation algorithm based on fundamental frequency mixing is proposed and experimentally demonstrated. The effect of carrier modulation depth C on the demodulation result is eliminated via DSM. The influence of light intensity disturbance on the demodulation result is also eliminated by asymmetric division. In experiment, the proposed algorithm eliminates the influence of C on the demodulation result. The signal-to-noise and distortion ratio of the sensor with the proposed algorithm achieves a gain of 7.77 dB over the PGC-Arctan algorithm and 9.48 dB over the PGC-DCM algorithm. PMID- 30462067 TI - Optimization of a quantum weak measurement system with digital filtering technology. AB - In this paper, we propose a post-Gaussian filtering theory for weak measurement in the frequency domain, and propose a highly deformed digital filtering technique that can be used to optimize sensors based on weak-frequency measurement techniques. We completed the experimental verification based on the weak measurement total internal reflection sensor. The experimental results show that digital filtering technology can optimize the system in the working range, sensitivity, and resolution of the frequency domain weak measurement system, so that it can reach 0.210 rad, 3210.9 nm/RIU, and 7.12*10-7 RIU, respectively. PMID- 30462068 TI - Evanescent resonant mode for a T-shaped cavity in a terahertz parallel-plate waveguide. AB - The evanescent resonant modes are proposed for a T-shaped cavity in a terahertz (THz) parallel-plate waveguide (PPWG) to understand the essence of the resonant phenomenon. The theoretical modal field and the resonant frequency of the TE2 like evanescent resonant mode show agreement with the simulated ones through the whole THz region. The modal field consists of three evanescent fields outside the cross region and one propagation field inside the cross region. When the TE2-like mode is excited, the input THz wave is reflected. The resonance frequency of the TE2-like mode depends closely on the geometrical parameters of the T-shaped cavity. In particular, the separation of the PPWG must be twice larger than the width of the groove to avoid the non-evanescent electric field in the groove. In addition, the electric field of the TE1-like mode is localized in the T-shaped cavity. These results have potential applications in field enhancement, sensors, and filters. PMID- 30462069 TI - The VIS-SWIR spectrum of skylight polarization. AB - The skylight degree of linear polarization (DoLP) was previously shown to vary primarily with aerosol optical depth and underlying surface reflectance for visible-to-near-infrared (VNIR) wavelengths. This paper extends the study of skylight polarization to 2.5 MUm in the short-wave infrared (SWIR). A successive orders-of-scattering radiative transfer code was used to model skylight polarization with measured inputs that included aerosol properties retrieved from a ground-based solar radiometer (extrapolated into the SWIR) and spectral surface reflectance from a handheld spectrometer. The modeled DoLP depended heavily on the aerosol size distribution at SWIR wavelengths and on the aerosol optical depth at VNIR wavelengths. Once the aerosol optical depth became greater than the Rayleigh optical depth, the predicted polarization deviated significantly from Rayleigh scattering theory. The SWIR polarization spectrum generally decreased at wavelengths beyond 1 MUm at a rate dependent on the aerosol size distribution. The surface reflectance affected the polarization in the same manner throughout the visible (VIS)-SWIR spectrum, with higher reflectance decreasing the skylight polarization. Validation measurements of SWIR skylight polarization in a 1.5-1.8 MUm band are also shown. These measurements were made on clean and smoky days using a SWIR imaging polarimeter. In both simulations and measurements, the SWIR skylight polarization was greater in the smoky atmosphere than in the clean atmosphere. PMID- 30462070 TI - Optimized channel allocation scheme for jointly reducing four-wave mixing and Raman scattering in the DWDM-QKD system. AB - Conducting quantum key distribution (QKD) through existing optical fibers together with conventional communication signals is a viable way to expand its practical application, but weak quantum signals can be severely disrupted by co propagating classical signals. In this paper, the suppression of four-wave mixing (FWM) noise and Raman noise is considered simultaneously for the first time, to the best of our knowledge, and the joint optimized channel allocation (JOCA) scheme is proposed. In the JOCA scheme, the quantum channels and classical channels are interleaved with each other to avoid FWM noise and optimal quantum channel positions are chosen in variable conditions according to the Raman scattering spectrum. Experimental measurements of the noise photons show that the JOCA scheme can effectively reduce the impairments on quantum signals compared with the single-target schemes. Additionally, simulation results verify that the JOCA scheme can increase the secure key generation rate and transmission distance, and that it also enables the DWDM-QKD system to tolerate higher-power classical signals and more classical channels, which improve the compatibility with a high-capacity communication system. PMID- 30462071 TI - All-optical wireless wavelength multiplexing and demultiplexing using resonant cavity. AB - The potential capability of wireless wavelength multiplexing and demultiplexing can enable the next development of smaller photonic counterparts for network architectures. This paper numerically represents a new design of a wireless transmission in C-band infrared wavelengths within two identical resonant cavities between photonic chips. This system consists of an H1 rod-type two dimensional photonic crystal (PhC) microcavity, which can be operated as both a transmitter and a receiver without interfering with the signal in each PhC waveguide. By using the point-to-point oscillatory light-field exchange between resonant cavities, two independent photonic circuits are linked with each other. The obtained results show that the multi-resonance wavelengths in one chip can be transferred to another chip located far away by ten times the highest resonance wavelength. Such a device can be useful for integrated optical circuit interconnect and small-scale sensors between photonic chips. PMID- 30462072 TI - Interband cascade laser absorption sensor for real-time monitoring of formaldehyde filtration by a nanofiber membrane. AB - It is important to reduce the indoor formaldehyde (H2CO) level to improve indoor air quality. To investigate the H2CO filtration by a novel nanofiber membrane made from metal-organic frameworks (MOFs), we developed a laser absorption gas sensor for real-time H2CO monitoring using a room-temperature interband cascade laser (ICL) emitting at 3.6 um. Wavelength modulation spectroscopy combined with a multipass gas cell (36 m path length) was implemented to achieve a detection sensitivity of 3 ppb H2CO at 1-s averaging time. We custom-designed a permeation H2CO generator that produces reference H2CO/N2 mixtures with an uncertainty of 6.4% in concentration. With the time-resolved continuous measurements, we observed a high filtration efficiency of 83% for the MOF filter, which, however, decreases linearly to 30% after operating for 3 h. Hence, the ICL-based gas sensor has proved to be a promising technique to assess novel nanomaterials for indoor air purification and pollutant control applications. PMID- 30462073 TI - Broadband single-polarization filter of D-shaped photonic crystal fiber with a micro-opening based on surface plasmon resonance. AB - In this paper, a D-shaped photonic crystal fiber is designed to achieve a single polarization filter that has a broadband filtering property. The D-shaped structure is a triangular array of air holes, forming a micro-opening on the side polished surface and plating a gold layer thereon. The investigation of the polarization filter is based on the finite element method; its principle is surface plasmon resonance. The single-polarization filter in the y direction is realized by adjusting parameters such as the apertures of the fiber, the thickness of the gold layer, and the polishing depth. The confinement loss of the core mode in y polarization reaches to a high value of 376.31 dB/cm at 1.55 MUm, and that of the x polarization is 0.17 dB/cm; the former is 2225.35 times the latter. When the fiber length L is 1 mm, the crosstalk reaches a peak value of 326.7 dB at 1.55 MUm, and the bandwidth of crosstalk higher than 20 dB is 480 nm. In addition, the external gold coating operation is more conducive to application in the manufacturing process. This filter will be an effective application of the optical communication window near 1.55 MUm. PMID- 30462074 TI - Principles of compensation of optical rays' rotation and multi-channel optical rotary connectors. AB - This paper deals with some theoretical issues concerning the methods of compensation of optical beams' rotation as well as the ways to design multi channel optical rotary connectors (ORCs) operating on the compensation principle. A theoretical foundation is given for a general method of compensation of optical beams' rotation that is based on stage-by-stage transformation of beam rotation angular velocity by using a set of optical transducers mounted sequentially along the light rays. The compensation process is described in general form by some mathematical equations. One of its solutions opens the possibility to make ORCs (based on the compensation principle of operation) without any geared mechanisms. They are much smaller than their analogues and provide high reliability and long term operation at high rotation velocities. An example of the technical realization of an ORC based on two fiber-optic transducers of the original design is adduced. The construction of an ORC including a pioneering fiber-optic compensator (FOC) of high quality that can invert the beam rotation direction is described in detail. This FOC is made as a hollow fiber cylinder. The technological issues of manufacturing this compensator are briefly considered. Besides, the ORC construction with a compensator based on a triangular prism and two light guide bundles to transfer the images is described and analyzed theoretically. These bundles are optically coupled by one butt via the above prism, while their other butts are mounted along the rotation axis. An ORC facility with this compensator can be successfully used to transfer analog signals since it has potentially low rotational oscillations of optical signal amplitude at a level of several percent. PMID- 30462075 TI - Optimization design of a stereo-photographic system based on achromatic double prism arrays. AB - We present an optimization design for a stereo-photographic system where achromatic double-prism arrays are used in front of the camera lens to reduce chromatic aberration and distortion. Due to the optical properties of the prism, the image formed by a single-prism array exhibits large chromatic aberration and distortion. The chromatic aberration and distortion for both single-prism array and double-prism array stereo-photographic systems were analyzed by the CODE V software. The double-prism arrays have larger distortion, but the chromatic aberration is small. The distortion arising from the double-prism arrays can be compensated by the camera lens design. The design results show that the maximum spot size is reduced from 17.7 MUm to 8.8 MUm after optimization. The proposed stereo-photographic system has high-quality stereo images. PMID- 30462076 TI - Fast numerical Fourier analysis of moire pattern induced by a periodic metallic array on top of the microscopically patterned red-green-blue light sources. AB - An accurate and fast moire pattern analysis algorithm is proposed for a periodic metallic array placed adjacent to a patterned red-green-blue (RGB) light source with a microscopic gap utilizing Fourier transform along with the human eye contrast sensitivity function. We analyzed how the moire pattern evolved varying tilt angles and metal array periodicities placed on the top of RGB light sources, which have their own spatial periodicities. Based on multiplicative model, moire patterns were numerically generated and the influences of 70 tilt angles and 60 periodicities on the moire standard deviation were thoroughly analyzed to minimize moire visibility. Our numerical results were compared to a prior analytical approach to obtain a good agreement, and the proposed scheme can be further applied to larger scale display systems with sophisticated touch screen metal arrays. PMID- 30462077 TI - High-sensitivity fiber optic hydrogen sensor in air by optimizing a self referenced demodulating method. AB - Self-referenced demodulating methods of fiber optic hydrogen sensors based on WO3 Pd2Pt-Pt composite film are studied in this paper. By employing the proper baseline intensity as sensing parameters, fluctuations of the sensing signal of the hydrogen sensor can be obviously depressed, and sensitivity can be greatly improved. Experimental results show that the resolution of the hydrogen sensor can reach 3 parts per million (ppm) when the hydrogen concentration is lower than 1000 ppm. Additionally, the hydrogen sensor shows better sensitivity toward lower concentrations of hydrogen, enabling a hydrogen threshold down to 10 ppm in air at room temperature. To the best of our knowledge, this is the lowest threshold reported for an optical hydrogen sensor operated at room temperature in air. Moreover, the sensor has good repeatability during hydrogen response. This work proposes a simple and novel method to improve the performance of fiber optic hydrogen sensors, which can greatly promote their potential application in various fields. PMID- 30462078 TI - Optical differential temperature measurement with beat frequency phase fluorometry. AB - We present, to the best of our knowledge, a new method for differential temperature measurement based on thermal sensitivity of the fluorescence lifetime of thermographic phosphors. Pairs of thermographic phosphors are excited with intensity-modulated light at frequencies omega and omega+Deltaomega. The phase shift Deltatheta of the summary fluorescence intensity beat signal envelope is measured. A prototype of a fluorometric differential temperature sensor is developed, and feasibility of the method is experimentally demonstrated with a Sm2+:SrFCl crystal and the D15->F70 transition for high thermal sensitivity. The observed linear dependence between envelope phase shift Deltatheta and temperature difference DeltaT agrees with the theoretical prediction. Sensitivity of S=-0.97 degrees / degrees C was achieved. This method could also be applied to differential measurements of any parameter affecting fluorescence lifetime. PMID- 30462079 TI - High-quantum-efficiency ultraviolet solar-blind AlGaN photocathode detector with a sharp spectral sensitivity threshold at 300 nm. AB - At present, most of the existing practical ultraviolet (UV) solar-blind detectors are based on Te-Cs photocathode image intensifiers. However, limited by their photoemission characteristics, it is difficult for the Te-Cs-based photocathodes to achieve both high quantum efficiency in the application band and high cutoff ratio in the non-applied band simultaneously. In this paper, a high-quantum efficiency UV solar-blind detector based on AlGaN photocathodes with a sharp spectral sensitivity threshold at 300 nm is reported. The proposed AlGaN photocathode has extremely high quantum efficiency (i.e., 20%) in the 210-275 nm band, while the efficiency curve steeply reduces to 2% at 300 nm, showing obviously superior performance than the existing Te-Cs photocathodes. PMID- 30462080 TI - Determination of vibration amplitudes from binary phase patterns obtained by phase-shifting time-averaged speckle shearing interferometry. AB - Speckle shearing interferometry (shearography) is a full-field strain measurement technique that can be used in vibration analysis. In our case, we apply a method that combines the time-averaging and phase-shifting techniques. It produces binary phase patterns, where the phase changes are related to the zeroes of a Bessel J0 function, typical of time-averaging. However, the contrast and resolution are better compared to traditional time-averaging. In a previous paper, we have shown that this is particularly useful in vibration testing performed under industrial conditions, because fringe patterns are noisier than in quiet laboratory environments. This paper goes a step further in proposing a processing method for estimating the vibration amplitude, for helping non-experts to identify vibration modes. Since shearography measures the spatial derivative of displacement, spatial integration is required. Prior to that, different processes like denoising, binarization, automated nodal line detection, and amplitude assignment are applied. We analyze the performance of the method on synthetic and experimental data, in the function of noise level and fringes density. Results on data acquired in an industrial environment illustrate the good performances of the proposed method. PMID- 30462081 TI - Comparison of detection performance of near-, mid-, and far-infrared laser fuzes in clouds. AB - To compare the detection performance of near-, mid-, and far-infrared laser fuzes in clouds, we built a laser fuze detection model in a cloud environment based on the Monte Carlo method, and simulated the echoes of near- (0.86 MUm), mid- (4.6 MUm), and far-infrared (10 MUm) pulsed laser fuzes in clouds under two scenarios: the cloud backscattering echo in the absence of a target in clouds and the target echo in the presence of a target in clouds. The echoes of laser fuzes at different wave bands under two scenarios were compared, and the results show that the mid- and far-infrared laser fuzes have comparable detection performance in clouds, while presenting respective advantages and disadvantages compared to the fuze in the near-infrared wave band. With presentation of the detection performance comparison results between the near-, mid-, and far-infrared laser fuzes in clouds, this paper can provide guidance and reference for the application of mid- and far-infrared lasers in the laser fuze field. PMID- 30462082 TI - Zoomable telescope by rotation of toroidal lenses. AB - A novel type of a continuously zoomable telescope is based on two pairs of adjacent toroidal lenses ("saddle lenses") in combination with standard optical components. Its variable magnification is adjusted by a mere rotation of the four saddle lenses around the optical axis. This avoids the necessity of classical zoom systems to shift multiple lenses along the longitudinal axis of the setup. A rotationally tunable pair of saddle lenses consists of two individual saddle lenses (also known as quadrupole lenses, or biconic lenses), which are arranged directly behind each other, acting as a "combi-saddle lens." The transmission function of such a combi-saddle lens corresponds to that of a single saddle lens, but with an adjustable optical power which depends on the mutual rotation angle between its two components. The optical system contains two of these combi-saddle lenses, and acts as a cylindrical Kepler telescope in one plane, and as a cylindrical Galilei telescope in the orthogonal plane. The two orthogonal Kepler/Galilei telescopes stay aligned and change their magnification factors in the same way when the telescope is zoomed by adjusting the optical powers of the two combi-saddle lenses. Altogether this produces a sharp image, which is mirrored with respect to the axis of the Kepler telescope. Thus, in addition to the zooming capabilities of the telescope, it is also possible to rotate the resulting image by a rotation of the whole telescope, or of all included saddle lenses. The operation principle of the telescope will be explained in both a ray optical and a wave-optical description. PMID- 30462083 TI - Fabrication of a lightweight Al alloy mirror through 3D printing and replication methods. AB - In order to realize rapid fabrication of a lightweight mirror, an AlSi10Mg alloy mirror was made through 3D printing and replication methods. The mechanical, thermal, and physical properties, the surface accuracy, and the dimensional stability were investigated. Through a selective laser melting method, an Al alloy mirror was printed and exhibited a low areal density of 28.4 kg/m2. Through replication, the mirror surface accuracy was improved to 0.033lambda (root mean square, lambda=632.8 nm); surface roughness was 1.3 nm (Ra). The stability test result indicated that the 3D printed mirror presented good dimensional stability in air for a long time and in a temperature changing environment. PMID- 30462084 TI - Efficient middle-infrared ZGP-OPO pumped by a Q-switched Ho:LuAG laser with the orthogonally polarized pump recycling scheme. AB - We describe an efficient middle-infrared laser source based on the Tm:YLF-Ho:LuAG ZnGeP2 system in this paper. A new orthogonally polarized recycling pump scheme with a simple thin-film polarizer and a half-wave plate are used in a Ho:LuAG laser. Under an incident pump power of 63.8 W, we achieve a maximum continuous wave output power of 35.7 W in the Ho:LuAG laser, corresponding to a slope efficiency of 60.4% and an optical-to-optical efficiency of 56.0%. With the Q switched mode, maximum average output powers of 34.1 W, 34.9 W, and 35.2 W were achieved in the Ho:LuAG laser with pulse repetition frequencies of 10 kHz, 15 kHz, and 20 kHz, respectively. With a Ho pump power of 34.1 W, maximum average output powers of 16.7 W, 15.3 W, and 12.6 W were achieved in a middle-infrared zinc germanium phosphide optical parametric oscillator (ZGP-OPO) under pulse repetition frequencies of 10 kHz, 15 kHz, and 20 kHz, respectively. The evaluated beam quality factor M2 of the ZGP-OPO was 2.2 for the signal and 1.9 for the idler. To the authors' best knowledge, this is the best performance reported for a middle-infrared ZGP-OPO pumped by a Ho:LuAG laser. PMID- 30462085 TI - External versus induced and free versus bound electric currents and related fundamental questions of the classical electrodynamics of continuous media: discussion. AB - Standard textbooks on classical electrodynamics frequently operate with the notions of free and bound currents (charges). Alternative terminology of external and induced currents also exists. However, a clear physical definition of these physical objects is rarely given. The term "free current" can refer in some cases to the conductivity current, which is subject to constitutive relations in a material sample. In other cases, free current refers to the current that is completely extrinsic to a given material sample and is assumed to be known a priori or manipulated by the experimentalist at will. Although one can argue that all currents flowing in material media are subject to some constitutive relations, there is a clear distinction in the construction of the classical electrodynamics between the external and induced currents. The aim of this paper is to clarify this distinction while pointing out that the traditional distinction between free and bound currents is arbitrary and can be abandoned. In addition, the paper considers some relevant fundamental questions of classical electrodynamics, including the derivation of macroscopic Maxwell's equations, the properties of the external currents, and the physical interpretation of some auxiliary fields such as the field of polarization P. PMID- 30462086 TI - Laboratory calibration of star sensors using a global refining method. AB - Laboratory calibration is critical to ensure the precise attitude determination of star sensors. Existing laboratory star sensor calibration methods exhibit disadvantages for large-field-of-view star sensors and large amounts of calibration data. Inspired by the least-squares method and Li's method, a global refining method is proposed to overcome the inherent disadvantages by simultaneously obtaining all of the star sensor's parameters. It first employs the maximum likelihood estimation method to optimize the initial estimation of the principal point and focal length. Next, a linear least-squares solution is used to initially estimate the star sensor distortion. Taking the installation error into account, we conduct a maximum likelihood estimation to estimate the installation angles from the estimated parameters of the first two steps. Finally, we determine a globally optimal solution to refine the star sensor parameters. Compared with the traditional method and Li's method under the same conditions, both the simulation and real data results demonstrate that the proposed method is more robust and can achieve high precision. In addition, the experimental results show that the calibration method can satisfy the precision requirements for large-field-of-view star sensors. PMID- 30462087 TI - Self-plagiarism and conference papers: editorial. AB - Editor-in-Chief P. Scott Carney and Topical Editor Samuel T. Thurman discuss self plagiarism and conference papers. PMID- 30462088 TI - Isotropic wavevector domain image filters by a photonic crystal slab device. AB - We show that several types of isotropic image filters in the wavevector domain can be implemented with a single photonic crystal slab device. Such a slab is designed so that the guided resonance near the Gamma point exhibits an isotropic band structure. Depending on the light frequency and the choice of transmission or reflection mode, the device realizes isotropic high-pass, low-pass, band reject, and band-pass filtering in wavevector space. These filter functions are important for various image processing tasks, including edge detection, smoothing, white noise suppression, and suppression or extraction of periodic noises. We numerically demonstrate these filter functionalities by simulations of a slab structure that is designed to operate in the visible wavelength range. Our work expands the application of nanophotonics-based optical analog computing for image processing. PMID- 30462089 TI - Modified photon sieve as a high-performance bifocal and trifocal diffractive optical element. AB - We demonstrate that by dividing a Fresnel zone plate into a few regions having different periods in the s=r2 coordinate, then replacing the clear zones by a given distribution of pinholes, a so-called modified photon sieve is constructed. The first feature of the element is to increase its diameter without worrying about its feature size as the limiting factor in the fabrication zone plate. Moreover, it is shown that the number of the zones included in each region is an important parameter that has a great impact on handling the number of foci. So, by choosing a suitable relation between the number of the Fresnel zones of the regions, one gets a high-efficiency unifocal or bifocal or even multifocal element depending on the number of the regions and zones. This technique is detailed by making unifocal, bifocal, as well as trifocal modified photon sieves and surveying their focusing properties. Simulation studies are followed by the corresponding experiments to verify them. PMID- 30462090 TI - Non-near-field sub-diffraction focusing in the visible wavelength range by a Fibonacci subwavelength circular grating. AB - This study proposes a Fibonacci subwavelength circular grating (FiSCG) arranged with Au concentric annuli. The numerical results show that, when illuminated by radially polarized light with a wavelength of 632.8 nm, four foci can be observed in the non-near-field with full width at half-maximum (FWHM) of 0.378lambda, 0.421lambda, 0.520lambda, and 0.496lambda, respectively. These possess low sidelobe intensity. Moreover, FiSCG achieves non-near-field sub-diffraction focusing in the visible wavelength range by varying the widths of the air slit and the Au ring. The ratio of the widths and the incident wavelength is about 0.4. This finding provides a wider applied range for FiSCG and a reference for the research on Fibonacci-arranged structures. PMID- 30462091 TI - Correcting flat mirrors with surface stress: analytical stress fields. AB - Thin mirrors, important for next-generation space telescopes, are difficult to accurately fabricate. One approach is to fabricate a mirror using traditional methods, then to bend the mirror using surface stress to correct residual height errors. We present two surface stress fields that correct any height error field in thin flat plates. For round plates, we represent these as linear combinations of Zernike polynomials. We show that equibiaxial stress, a common and easy-to generate state of stress, cannot generally be used to make exact corrections. All three components of the surface stress are needed for exact corrections. We describe a process to design an equibiaxial stress field to make approximate corrections in round plates. Finally, we apply the three stress fields to simulate flattening of a measured glass wafer with 3.64 MUm root-mean-squared (RMS) height error. Using our chosen equibiaxial stress field, the residual error is 0.34 MUm RMS. In comparison, using all three stress components, the correction is exact and the required RMS stress is about 2.5* smaller than when using equibiaxial stress only. We compare the deformation with a finite element model and find agreement within 10 nm RMS in all three cases. PMID- 30462092 TI - Fresnel diffraction analysis of Ronchi and reverse Hartmann tests. AB - This paper presents a Fresnel diffraction analysis of classical Ronchi and reverse Hartmann tests. Simplified analytical expressions of the intensity patterns observed by the camera are established, allowing quantitative measurements of the wavefront slopes of the tested optical system. The wavefronts are then reconstructed from their slopes using a double Fourier transform algorithm. The optimization of the operational parameters of the system is discussed in view of different quality criteria, including relative pupil shear and contrast factors in both monochromatic and polychromatic light. Practical examples of applications are studied with the help of numerical simulations, demonstrating that measurement accuracies better than lambda/100 RMS are achievable on properly dimensioned systems. Finally, the technique is also applicable to wavefront sensing in adaptive optics systems. PMID- 30462093 TI - Rsp ratio approach for evaluation of scotopic/photopic ratios of light source performance at varying CCTs. AB - Scotopic/photopic ratio (S/P ratio, or Rsp) is an absolute measure of a light source's performance under the mesopic vision state. However, there is more potential for a light source to reach higher mesopic performance at higher correlated color temperatures (CCTs), and these cannot be evaluated. We proposed an Rsp ratio metric to examine relative performance of the S/P ratio at a corresponding CCT. Based on examination of a large set of light sources, we established the Rsp-CCT and Rsp ratio-CCT relations of different light source types. On investigating previously reported high S/P ratio light sources with the proposed metric, it shows high effectiveness in evaluating relative mesopic performance when considering CCT issues. PMID- 30462094 TI - Maggi-Rubinowicz integral for Fraunhofer diffraction by hexagonal particles: application to cirrus ice crystals. AB - This paper is devoted to Fraunhofer diffraction by hexagonal ice crystals like those that can be encountered in cirrus clouds. Such crystals are important, for they are the basic building elements of crystals of more complex shape. A new alternative based on the Maggi-Rubinowicz transformation is proposed. This technique, whose basic formula is a line integral version of the Kirchhoff integral, is very easy to implement and is not time consuming. Diffraction patterns of hexagonal ice crystals with (i) fixed arbitrary orientation, (ii) random orientation, and (iii) preferred orientation are given. The topic is of importance since the radiative impact of cirrus clouds, which depends directly on ice crystal optical properties, is still a challenging problem in climate research. PMID- 30462095 TI - Photon efficiency of computational ghost imaging with single-photon detection. AB - Photon-limited imaging has significant application under extreme environments, in which the photon efficiency is an important parameter. In this paper, we investigate the photon efficiency of computational ghost imaging with single photon detection. By exploiting the Poisson statistical characteristics of single photon counting, the relationships between the photon efficiency and the signal to-noise ratio of the retrieved image are theoretically obtained, and both are closely related to the distribution characteristics of target and spatial modulation in the ghost imaging framework. To verify the availability of the built theoretical model for the photon efficiency, a specific computational ghost imaging with a binary object and the first-photon imaging algorithm is rigorously demonstrated in theory and in experiment. Our investigation paves the way for optimization of photon-limited ghost imaging. PMID- 30462096 TI - Multiresolution-based weighted regularization for denoised image interpolation from scattered samples with application to confocal microscopy. AB - The problem of reconstructing an image from nonuniformly spaced, spatial point measurements is frequently encountered in bioimaging and other scientific disciplines. The most successful class of methods in handling this problem uses the regularization approach involving the minimization of a derivative-based roughness functional. It has been well demonstrated, in the presence of noise, that nonquadratic roughness functionals such as l1 measure yield better performance compared to the quadratic ones in inverse problems in general and in deconvolution in particular. However, for the present problem, all well-evaluated methods use quadratic roughness measures; indeed, l1 performs worse than the quadratic roughness when the sampling density is low. This is due to the fact that the mutual incoherence between the measurement operator (dirac-delta) and the regularization operator (derivative) is low in the present problem. Here we develop a new multiresolution-based roughness functional that performs better than l1 and quadratic functionals under a wide range of sampling densities. We also propose an efficient iterative method for minimizing the resulting cost function. We demonstrate the superiority of the proposed regularization functional in the context of reconstructing full images from nonuniformly undersampled data obtained from a confocal microscope. PMID- 30462097 TI - Multiple invisibility regions induced by symmetry breaking in a trimer of subwavelength graphene-coated nanowires. AB - Electromagnetic response is studied for clusters of subwavelength graphene-coated nanowires illuminated by a linearly polarized plane wave in the terahertz frequency range. The solution of the scattering problem is obtained with the Lorenz-Mie theory and multiple cylinder scattering formalism. The results show that normalized scattering cross-sections of nanowire clusters can be drastically changed by the symmetry breaking introduced into the cluster's design. This effect is due to excitation of dark modes and is observed only for the incident wave of TE polarization. PMID- 30462098 TI - Observation of Mie ripples in the synchrotron Fourier transform infrared spectra of spheroidal pollen grains. AB - Conceptually, biological cells are dielectric, photonic resonators that are expected to show a rich variety of shape resonances when exposed to electromagnetic radiation. For spheroidal cells, these shape resonances may be predicted and analyzed using the Mie theory of dielectric spheres, which predicts that a special class of resonances, i.e., whispering gallery modes (WGMs), causes ripples in the absorbance spectra of spheroidal cells. Indeed, the first tentative indication of the presence of Mie ripples in the synchrotron Fourier transform infrared (SFTIR) absorbance spectra of Juniperus chinensis pollen has already been reported [Analyst140, 3273 (2015)ANLYAG0365-488510.1039/C5AN00401B]. To show that this observation is no isolated incidence, but a generic spectral feature that can be expected to occur in all spheroidal biological cells, we measured and analyzed the SFTIR absorbance spectra of Cunninghamia lanceolata, Juniperus chinensis, Juniperus communis, and Juniperus excelsa. All four pollen species show Mie ripples. Since the WGMs causing the ripples are surface modes, we propose ripple spectroscopy as a powerful tool for studying the surface properties of spheroidal biological cells. In addition, our paper draws attention to the fact that shape resonances need to be taken into account when analyzing (S)FTIR spectra of isolated biological cells since shape resonances may distort the shape or mimic the presence of chemical absorption bands. PMID- 30462099 TI - Cone and melanopsin contributions to human brightness estimation: comment. AB - A recent study of large-field subjective brightness perception under different narrowband spectra and different luminances revealed distinct contributions of cone photoreceptors and intrinsically photosensitive retinal ganglion cells containing the photopigment melanopsin. The data from this study were analyzed with a recently published model of spectral sensitivity for full-field brightness incorporating three primary channels: a luminance (achromatic) channel, a blue yellow opponent color channel, and a melanopsin channel. There was good agreement between predictions based on this model and the recently published brightness perception data. PMID- 30462100 TI - Cone and melanopsin contributions to human brightness estimation: reply. AB - Our analytical description of full-field brightness perception data [J. Opt. Soc. Am. A35, B19 (2018)JOAOD60740-323210.1364/JOSAA.35.000B19] with contributions from cone luminance and melanopsin expressing intrinsically photosensitive retinal ganglion cells has been extended [J. Opt. Soc. Am. A35, 1780 (2018)JOAOD60740-323210.1364/JOSAA.35.001780] to include S-cones through a blue yellow opponent channel. We welcome this reanalysis and provide a few remarks on the approach. PMID- 30462101 TI - Diazachlorin and diazabacteriochlorin for one- and two-photon photodynamic therapy. AB - Diazachlorin and diazabacteriochlorin have been prepared through reduction of diazaporphyrin and their in vitro and in vivo activity in photodynamic therapy has been investigated. PMID- 30462102 TI - Degradable redox-responsive disulfide-based nanogel drug carriers via dithiol oxidation polymerization. AB - Stimuli-responsive nanogels are important drug and gene carriers that mediate the controlled release of therapeutic molecules. Herein, we report the synthesis of fully degradable disulfide cross-linked nanogel drug carriers formed by oxidative radical polymerization of 2,2'-(ethylenedioxy)diethanethiol (EDDET) as a monomer with different cross-linkers, including pentaerythritol tetramercaptoacetate (PETMA). Because the poly(EDDET) backbone repeat structure and cross-linking junctions are composed entirely of disulfide bonds, these nanogels specifically degrade to small molecule dithiols intracellularly in response to the reducing agent glutathione present inside of cells. Cross-linked nanogels were synthesized using controlled microfluidic mixing in the presence of a nonionic Pluronic surfactant PLU-127 to increase the nanogel stability. Adjusting the monomer to cross-linker ratio from 5 : 1 to 100 : 1 (mol/mol) tuned the cross-linking density, resulting in swelling ratios from 1.65 to >3. Increasing the amount of stabilizing Pluronic surfactant resulted in a decrease of nanogel diameter, as expected due to increased surface area of the resulting nanogels. The monomer to cross-linker ratio in the feed had no effect on the formed nanogel diameter, providing a way to control cross-linking density with constant nanogel size but tunable drug release kinetics. Nanogels exhibited an entrapment efficiency of up to 75% for loading of Rhodamine B dye. In vitro studies showed low cytotoxicity, quick uptake, and fast degradation kinetics. Due to the ease of synthesis, rapid gelation times, and tunable functionality, these non-toxic and fully degradable nanogels offer potential for use in a variety of drug delivery applications. PMID- 30462103 TI - A C3-substituted cyclotriveratrylene derivative with 8-quinolinyl groups as a fluorescence-enhanced probe for the sensing of Cu2+ ions. AB - C 3-Substituted cyclotriveratrylene (CTV) derivatives were considered suitable candidates for recognition compounds due to their unique structures. In this study, a C3-substituted CTV derivative with three fluorogenic 8-quinolinyl groups (1) was designed and prepared as a fluorescent probe. The synthesized CTV derivative 1 exhibited a selective response of fluorescence enhancement toward Cu2+ ions among the examined cations. The sensing ability of CTV derivative 1 toward Cu2+ ions was superior to that of the previously reported C3-substituted CTV derivative with three 2-quinolinyl groups (2). It is, thus, suggested that the CTV structure plays an important role in selective sensing ability toward Cu2+ ions since the mono-quinoline compound 5 showed fluorescence properties toward the Cr3+, Fe2+ and Fe3+ ions in addition to Cu2+ ions. In other words, the high Cu2+ ion-selectivity of CTV derivative 1 was demonstrated even in the presence of other co-existing examined cations. Moreover, it was found that CTV derivative 1 could work as a reversible fluorescence-enhanced probe toward Cu2+ ions by the simple addition of Et3N. PMID- 30462104 TI - A pH-driven ring translocation switch against cancer cells. AB - A molecular switch built with cucurbit[7]uril and a 3-station viologen-phenylene imidazole compound exhibited pH actuated ring translocation with high fatigue resistance (up to 102 cycles). The switch movement was harnessed toward selectively masking the toxicity of the viologen fragment at neutral pH near non cancerous cells, while exposing it at acid pH near cancer cells. PMID- 30462105 TI - Application of ion pair chromatography coupled with mass spectrometry to assess antisense oligonucleotides concentrations in living cells. AB - Antisense oligonucleotides (ASOs) are synthetic bioactive compounds used as therapeutic agents in clinical trials. They act by binding to complementary sequences of the targeted nucleic acids in cells. Assessing the efficiency of ASO delivery to cells or tissues and the stability of these compounds in different biological systems is important. To answer these questions, we developed a new, quick and reliable method to determine the concentrations of different types of ASOs in treated cells. Ultra-high performance liquid chromatography coupled with mass spectrometry was used for the first time for the separation and determination of the studied compounds in total RNA extracts. To develop a method with the highest possible sensitivity, a central composite design was used to comprehensively optimize the MS parameters. Moreover, the effects of the type and concentration of the ion pair reagent on sensitivity were also examined. Finally, a mobile phase containing methanol, hexafluoroisopropanol and N,N dimethylbutylamine was selected. The optimized method allowed good linearity, accuracy, precision and sensitivity of ASO detection. Next, these compounds were delivered into cells via transfection at a concentration of 25 nM or 125 nM in 1 mL of cell culture medium. After 48 hours, total RNA was isolated from the treated cells and analyzed with the use of the newly developed method. For the cells treated with a higher concentration of ASO composed of phosphorothioate 2' O-methyl RNA units, the concentration in solution was 0.96 +/- 0.06 MUM, while in the case of shorter ASO composed of locked nucleic acid units, it was 0.72 +/- 0.06 MUM in the total RNA extract. PMID- 30462106 TI - Understanding the interactions of imidazolium-based ionic liquids with cell membrane models. AB - Cell membrane models have been used to evaluate the interactions of various imidazolium-based ionic liquids (ILs) with Langmuir monolayers of two types of phospholipids and cholesterol. Data from surface pressure isotherms, Brewster angle microscopy (BAM) and polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS) pointed to significant effects on the monolayers of 1,2 dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol, used to mimic the membranes of eukaryotic cells, for ILs containing more than 6 carbon atoms in the alkyl chain (i.e. n > 6). For ILs with less hydrophobic tails (n <= 6) and low concentrations, the effects were almost negligible, therefore, such ILs should not be toxic to eukaryotic cells. The hydrophobicity of the anion was also proved to be relevant, with larger impact from ILs containing tetrafluoroborate ([BF4]-) than chloride (Cl-). Molecular dynamics simulations for DPPC monolayers at the surface of aqueous solutions of alkylimidazolium chloride ([Cnmim]Cl) confirm the penetration of the IL cations with longer alkyl chains into the phospholid monolayer and provide information on their location and orientation within the monolayer. For monolayers of dipalmitoylphosphatidyl glycerol (DPPG), which is negatively charged like bacteria cell membranes, the ILs induced much larger effects. Similarly to the results for DPPC and cholesterol, effects increased with the number of carbon atoms in the alkyl chain and with a more hydrophobic anion [BF4]-. Overall, the approach used can provide relevant information of molecular-level interactions behind the toxicity mechanisms and support the design of (quantitative) structure-activity relationship models, which may help design more efficient and environmentally friendly ILs. PMID- 30462107 TI - Molecular dynamics study of coil-to-globule transition in a thermo-responsive oligomer bound to various surfaces: hydrophilic surfaces stabilize the coil form. AB - The structural and dynamical properties of 40-mer of thermo-responsive polymer PNIPAM covalently bound to different surfaces have been studied, at different temperatures, by means of molecular dynamics simulations. Evolution of the radius of gyration, Rg, of the polymer chain and radial distribution functions (RDFs) calculated for the carbon atoms of the PNIPAM backbone with water oxygens and for the hydrogen atom of the amide groups with water oxygens indicate that functionalized surfaces affect the coil-to-globule transition of PNIPAM, by means of electrostatic interactions, increasing the lower critical solution temperature (LCST) of the polymer. Such interactions, mainly represented by a H-bond, hinder the transition in the globular form while hydrophobic groups on the surface, such as -OCH3, contribute to the globular collapse. A significant alteration in the arrangement of water molecules around the polymer is testified by: (i) the absence of the second peak in the RDF between the C atoms of the PNIPAM backbone and the O atoms of water at the same temperature at which the radius of gyration decreases; (ii) the height of both the first and the second peak of the RDF between the H atom of the amide groups and water O atoms decreases when the temperature increases above the LCST. Finally, the H-bond autocorrelation function indicates that: (i) hydrogen bonds between the bound-to-surface PNIPAM acceptor groups (O[double bond, length as m-dash]C[double bond splayed right]) and the H atoms of water molecules are less persistent than H-bonds formed between the free PNIPAM acceptor groups and water; (ii) H-bonds between the PNIPAM acceptor groups and hydroxyl groups on the quartz surface are longer lived than those formed on graphene oxide. PMID- 30462108 TI - Comment on "Negative effective Li transference numbers in Li salt/ionic liquid mixtures: does Li drift in the "Wrong" direction?" by M. Gouverneur, F. Schmidt and M. Schonhoff, Phys. Chem. Chem. Phys., 2018, 20, 7470. AB - Gouverneur et al. have recently reported "effective transport numbers" for mixtures of lithium and 1-ethyl-3-methylimidazolium salts with common (fluorinated) anions using 7Li, 1H and 19F and electrophoretic NMR to determine the electrophoretic mobilities of all three ionic species. The "effective transport number" for lithium is small, but negative. From this they deduce that the Li+ ions are each associated with two or more anions to form negatively charged complexes. However this interpretation may be incorrect: only a single independent transport number can be measured in such a system as the three ion fluxes are not independent. One ion flow must define the reference frame and then the transport numbers for the other two ions must sum to unity. Electrophoretic NMR appears to produce what are called "external" ion mobilities and transport numbers in the notation used by Klemm and Haase for molten salts. These are defined in the laboratory frame of reference and can depend on the boundary conditions of the experiment. Simple relations exist for their conversion to "internal" transport numbers where ion mobilities for two ions are given relative to that of the third, analogous to the more familiar Hittorf transport numbers of ions in electrolyte solutions which are given in the "solvent-fixed" frame of reference, i.e. relative to the flow of solvent. It is not unusual for a cation external transport number to be negative in molten salt mixtures, e.g. (LiNO3 + AgNO3) in a Hittorf experiment employing nitrate electrodes whereas true ion association would produce negative internal transport numbers. In the examples studied by Gouverneur et al. the cation internal transport numbers are both positive. Those for Li+ are also very small, and close to zero within experimental error. This may simply reflect that the mixtures employed are dilute in lithium ions. PMID- 30462109 TI - A dual-responsive hyperbranched supramolecular polymer constructed by cooperative host-guest recognition and hydrogen-bond interactions. AB - A homotritopic pillar[5]arene (H3) containing adenine units was synthesized and employed to interact with a uracil derivative (6-(2,4-dioxo-3,4-dihydropyrimidin 1(2H)-yl)hexanenitrile, G) to form a hyperbranched supramolecular polymer. The hyperbranched supramolecular polymer showed a dual stimulus response both to heat and acid/base. The cooperative host-guest binding and hydrogen-bond interactions play a key role in the supramolecular polymerization. PMID- 30462110 TI - Reply to the 'Comment on "Negative effective Li transference numbers in Li salt/ionic liquid mixtures: does Li drift in the "Wrong" direction?"' by K. R. Harris, Phys. Chem. Chem. Phys., 2018, 20, DOI: 10.1039/C8CP02595A. AB - We have recently directly measured the electrophoretic mobilities of the three species in "Li salt in-ionic liquid" electrolytes with a common anion by electrophoretic NMR. From the mobilities of the three species, we deduced the transference numbers and found a negative value for Li. We attributed this to a vehicle mechanism of 7Li transport, where Li is drifting in net negatively charged Li-anion clusters. In our work, as also in previous eNMR studies, ion drift velocities and thus electrophoretic mobilities are determined in the laboratory frame of reference. In his comment, Harris claims that in this frame conclusions on ion correlations are not deducable, but rather an internal reference frame, defined by the drift of one of the ions, needs to be used and that in such a reference frame no negative transference numbers would occur. While agreeing with Harris on the general relevance of reference frames in eNMR, we argue here that a reference frame of one of the ions leads to loss of information. We propose to use the reference frame of the center of mass of the electrolyte if an internal frame is required. An interesting observation is that the center of mass of an ionic liquid is drifting during the application of the short electric field pulse in eNMR. To account for this drift, we convert our data, determined from drift velocities in the laboratory frame into the center of mass frame. The results show that, independent of the reference frame chosen, using either a laboratory frame as an external frame or a center-of-mass frame as an internal frame, drift velocities of 7Li and anions are identical within error, such that the interpretation of a correlated motion of Li and anions holds. PMID- 30462111 TI - In silico assessment and structural characterization of antioxidant peptides from major yolk protein of sea urchin Strongylocentrotus nudus. AB - Sea urchin gonads have been demonstrated to contain major yolk protein (MYP), which can be hydrolyzed by enzymes to release biologically active peptides. The in silico analysis of the MYP sequence in the BIOPEP database showed the presence of fragments with antioxidant activity. The sequence was hydrolyzed by 21 kinds of proteases and 23 antioxidant peptides were obtained. Eight peptides, including Leu-Trp (LW), Arg-Trp (RW), Ala-Trp (AW), Thr-Trp (TW), Ala-Asp-Phe (ADF), Leu Trp-Lys (LWK), Ser-Asp-Phe (SDF) and Leu-Tyr (LY), were screened and a score over 0.5 was obtained using PeptideRanker. The peptides LW, TW and LWK showed a stronger antioxidant capacity with IC50 values of 8.85, 9.59 and 9.62 mmol L-1, respectively, compared to that of glutathione (10.81 mmol L-1). Furthermore, AW, LW and LY showed Trolox equivalent antioxidant capacity (TEAC) values of 3.07, 1.87 and 1.52 mmol TE per mmol peptide, respectively. These results suggest that the MYP from sea urchin (S. nudus) gonads is a good source of antioxidant peptides with abundant tryptophan. PMID- 30462112 TI - Combatting antibiotic-resistant bacteria using nanomaterials. AB - The dramatic increase in antimicrobial resistance for pathogenic bacteria constitutes a key threat to human health. The Centers for Disease Control and Prevention has recently stated that the world is on the verge of entering the "post-antibiotic era", one where more people will die from bacterial infections than from cancer. Recently, nanoparticles (NPs) have emerged as new tools that can be used to combat deadly bacterial infections. Nanoparticle-based strategies can overcome the barriers faced by traditional antimicrobials, including antibiotic resistance. In this tutorial review, we have highlighted multiple nanoparticle-based approaches to eliminate bacterial infections, providing crucial insight into the design of elements that play critical roles in creating antimicrobial nanotherapeutics. In particular, we have focused on the pivotal role played by NP-surface functionality in designing nanomaterials as self therapeutic agents and delivery vehicles for antimicrobial cargo. PMID- 30462113 TI - Broadband near-IR absorbing Au-dithiolene complexes bearing redox-active oligothiophene ligands. AB - A series of three homoleptic, monoanionic gold dithiolene complexes of oligothiophene ligands which coordinate via a central thiophene-3,4-dithiolate chelate are presented. The oligomer chains are three, five and seven thiophenes long and the complexes display hybrid optoelectronic properties featuring characteristics of both the oligothiophene chains and the delocalised metal dithiolene centre. The properties of the complexes have been characterised using a variety of spectroscopic and electrochemical methods complemented by computational studies. Solid state spectroelectrochemistry has revealed that upon oxidation these complexes display intense and broad absorption across the visible spectrum. In attempting to produce nickel analogues of these materials a single crystal of a photo-oxidised nickel dithiolene complex has also been isolated. PMID- 30462114 TI - Polarized absorbance and Davydov splitting in bulk and thin-film pentacene polymorphs. AB - Pentacene is one of the most studied organic materials and in particular its optical properties have been the subject of intense research during the last two decades. In spite of such a widespread interest and of the extensive knowledge achieved so far, a number of issues are still debated. One of the most relevant questions concerns the role of polymorphism and how it affects the lowest-energy exciton, which appears in the visible region and is subject to a sizable Davydov splitting. We address this problem in a combined theoretical and experimental work, where the optical absorption properties of three pentacene polymorphs are investigated within the whole energy range of visible light. Optical spectra computed from first principles in the framework of many-body perturbation theory are directly compared with the polarization-resolved absorbance, measured for three different pentacene phases (the two bulk polymorphs and the thin-film phase). In this way, we unambiguously identify the two Davydov components of the first exciton and the optical fingerprints of each considered phase. With very good agreement between theory and experiment, we show that all polymorphs exhibit common features at the absorption onset, while phase-dependent characteristics appear only above 2 eV. We discuss the character of the lowest-lying singlet and triplet excitons, including dark ones, highlighting the contributions from the electronic bands and the role of the electron-hole interaction and of the local field effects. PMID- 30462115 TI - Dye-embedded YAG:Ce3+@SiO2 composite phosphors toward warm wLEDs through radiative energy transfer: preparation, characterization and luminescence properties. AB - The most common yellow phosphor for wLEDs, Y3Al5O12:Ce3+ (YAG:Ce3+), suffers from a deficiency of red in its spectral content of light. In this paper, a new strategy is provided to tailor the Ce3+ spectral profile through surface-located dye molecules of ATTO-Rho101, which feature intense, broad absorption in the green-yellow spectral region of Ce3+ emission as well as bright red emission. Sphere-shaped and highly dispersed micrometer and nanometer-sized YAG:Ce3+ (micro/nano-YAG:Ce3+) was synthesized through a modified solvothermal method. Surface SiO2 coating and simultaneous dye embedding were performed on the solvothermally derived YAG:Ce3+, heat-treated micro-YAG:Ce3+ and commercial phosphors. Efficient radiative transfer/reabsorption from Ce3+ in the inner core of YAG to the dye molecules in the SiO2 outer shell, irrespective of the size of the phosphors, was demonstrated in the accumulated YAG:Ce3+@SiO2 + dye powder upon blue light excitation; this enhanced its red emission. Fluorescence microscopy was demonstrated to be a powerful tool to identify the reabsorption phenomenon of the powdered materials. Packaging the heat-treated micro YAG:Ce3+@SiO2 + dye phosphors on blue LED chips yielded a warm wLED (Ra~ 93), but an Ra of only ~79 was obtained for the wLED with commercial YAG:Ce3+@(SiO2 + dye)5 due to the low concentration of phosphors dispersed in the epoxy resin and the resulting decreased reabsorption by dye molecules. Surface-protonated amine species were found to induce Ce3+-> Ce4+ oxidation upon activation by heating or photoirradiation and then quench the photoluminescence (PL) of micro-YAG:Ce3+ even after surface modification by SiO2, YAG or being embedded in an epoxy resin matrix. High calcination temperatures greatly improved the PL stability of micro YAG:Ce3+ through the removal of surface-capped species. The dye in the silica matrix showed high stability against heating and irradiation due to the so-called "caging effects"; however, decreased photo-stability was found in commercial YAG:Ce3+@(SiO2 + dye)5 due to the incomplete and/or loose SiO2 layer grown during multiple surface modifications. PMID- 30462116 TI - Slow magnetization dynamics in Co(ii)/Co(iii) triethanolamine/pivalate complexes. AB - We report the synthesis, structural characterization and a combined computational and experimental study of the magnetic properties of two pivalate cobalt complexes, a mononuclear Co(ii) one and a tetranuclear Co(ii)3Co(iii) mixed valence polynuclear one. The latter shows SMM behaviour revealed under an applied DC field with a thermal barrier of ca. 30 cm-1 competing with direct and Raman relaxation processes. The Orbach thermal barrier can be understood from the doublets energy ladder arising from the anisotropic exchange interaction among ground Seff = 1/2 of each Co(ii) sites. The strong local zero-field splitting of the S = 3/2 Co(ii) states affords these well isolated ground Kramers doublets. DC and AC magnetic susceptibility measurements as well as HF-EPR spectra support this interpretation. CASSCF quantum chemical computations have been also performed in order to aid the overall comprehension of the magnetic behaviour in the reported complexes. PMID- 30462117 TI - Resveratrol alleviates motor and cognitive deficits and neuropathology in the A53T alpha-synuclein mouse model of Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by Lewy pathology and progressive loss of dopaminergic neurons in the substantia nigra. Lewy pathology mainly consists of abnormal aggregates of alpha-synuclein, which play a pivotal role in PD pathophysiology. However, the complexity of PD leads to clinical challenges, and there are still no treatments to halt or slow the neurodegenerative process. Resveratrol (RV) is a natural polyphenol compound with multiple biological activities, which has been reported to exert neuroprotective effects on several neurological diseases. Here we first provided evidence that RV treatment alleviated motor and cognitive deficits in the A53T alpha-synuclein mouse model of PD in a dose-dependent manner. The beneficial effects of RV against PD resulted from inhibiting alpha-synuclein aggregation and cytotoxicity, lowering the levels of total alpha-synuclein and oligomers, reducing neuroinflammation and oxidative stress. These findings suggest that RV has promising therapeutic potential for PD and other synucleinopathies. PMID- 30462118 TI - Elucidating the morphological aspects and proton dynamics in a hybrid perfluorosulfonic acid membrane for medium-temperature fuel cell applications. AB - A perfluorosulfonic acid (PFSA) membrane, i.e. Nafion(r) 117, was doped with the heteropoly salts (HPS) Cs3PW12O40, Rb3PW12O40, and (NH4)3PW12O40. Also, composite membranes with CsxH3-xPW12O40 (x = 1, 2, and 3) as dopants were investigated, which were rendered insoluble by substituting protons with larger cations. Morphological assessment and a detailed analysis of the hopping events via SAXS measurement and analysis of the hydrogen bond networks were performed using classical and quantum hopping molecular dynamics simulation. The phase segregation decreased by increasing the extent proton substitution in HPA. HPS containing cations with a larger ionic radius induced smaller phase segregation in the membrane, as confirmed by the RDF plots. SAXS simulation revealed that the hydrophilic phase domains in the HPS-doped Nafion(r) membrane were spaced further apart than that in the HPA-doped membrane. Although there was a greater number of isolated clusters for the Cs3PW12O40-doped Nafion(r), the average number of cluster decreased with an increase in the substitution cation/proton ratio and ionic radius of the cation. The analysis of the H-bond network stability revealed that the proton hops slower when the membrane contains HPS particles and the mean residence time of a proton on water molecules increases with an increase in the extent of proton substitution in H3PW12O40. Indeed, for the HPA-doped membrane, the diffusion of water molecules is lower than that in the HPS-doped system. PMID- 30462119 TI - Interfacial premelting of ice in nano composite materials. AB - The interfacial premelting in ice/clay nano composites was studied by high energy X-ray diffraction. Below the melting point of bulk water, the formation of liquid water was observed for the ice/vermiculite and ice/kaolin systems. The liquid fraction is gradually increasing with temperature. For both minerals, similar effective premelting layer thicknesses of 2-3 nm are reached 3 K below the bulk melting point. For the quantitative description of the molten water fraction in wet clay minerals we developed a continuum model for short range interactions and arbitrary pore size distributions. This model quantitatively describes the experimental data over the entire temperature range. Model parameters were obtained by fitting using a maximum entropy (MaxEnt) approach. Pronounced differences in the deviation from Antonow's rule relating interfacial free energy between ice, water, and clay are observed for the charged vermiculite and uncharged kaolin minerals. The resultant parameters are discussed in terms of their ice nucleation efficiency. Using well defined and characterized ice/clay nano composite samples, this work bridges the gap between studies on single crystalline ice/solid model interfaces and naturally occurring soils and permafrost. PMID- 30462120 TI - Lycopene attenuates AFB1-induced renal injury with the activation of the Nrf2 antioxidant signaling pathway in mice. AB - Oxidative stress is an important molecular mechanism for kidney injury in aflatoxin B1 (AFB1) nephrotoxicity. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master transcription factor for regulating the cellular oxidative stress response, which has been confirmed in animal models. Lycopene (LYC), a natural carotenoid, has received extensive attention due to its antioxidant effect with the activation of Nrf2. However, the role of LYC in protecting against AFB1-induced renal injury is unknown. To evaluate the chemoprotective effect of LYC on AFB1-induced renal injury, forty-eight male mice were randomly divided into 4 groups and treated with LYC (5 mg per kg of bodyweight) and/or AFB1 (0.75 mg per kg of bodyweight) by intragastric administration for 30 days. AFB1 and LYC were respectively dissolved in olive oil. We found that AFB1 exposure significantly increased the serum concentrations of blood urea nitrogen (BUN) and serum creatinine (SCR), and caused damage to the renal structure. Notably, LYC potentially alleviated AFB1-induced kidney lesions through attenuating AFB1-induced oxidative stress. Renal nuclear factor-erythroid 2 related factor 2 (Nrf2) and its downstream target gene (CAT, NQO1, SOD1, GSS, GCLM and GCLC) translation and protein expression were ameliorated by pretreatment with LYC in AFB1-exposed mice. These results suggested that LYC potentially alleviates AFB1-induced renal injury. This effect may be attributed to the enhancement of renal antioxidant capacity with the activation of the Nrf2 antioxidant signaling pathway. PMID- 30462121 TI - The anti-inflammatory activity of peptides from simulated gastrointestinal digestion of preserved egg white in DSS-induced mouse colitis. AB - Peptides DEDTQAMPFR (DR-10), MLGATSL (ML-7), SLSFASR (SR-7), and MSYSAGF (MF-7) derived from simulated gastrointestinal digestion of preserved egg white (SGD PEW) exerted anti-inflammatory effects on Caco-2 cells. Here, we aimed to evaluate the anti-inflammatory effects of these peptides derived from SGD-PEW in a mouse model of dextran sodium sulfate (DSS)-induced colitis. The results showed that DR-10, ML-7, SR-7 and MF-7 significantly ameliorated the clinical symptoms of DSS-induced mice colitis, such as weight loss, disease activity index (DAI), colon shortening, spleen hypertrophy and histological scores. Treatment with DR 10, ML-7, SR-7 and MF-7 also significantly inhibited the local secretion of pro inflammatory cytokines TNF-alpha and IL-6 and markedly decreased the gene expression of pro-inflammatory cytokines, including TNF-alpha, IL-6, IL-17, IL 1beta, IFN-gamma and MCP-1, in DSS-induced mice colitis. Overall, MF-7 showed the best effect of alleviating DSS-induced colitis among the four peptides. These results suggested that MF-7, DR-10, ML-7 and SR-7 may be a potential promising candidate for the treatment of inflammatory bowel disease (IBD). PMID- 30462122 TI - The influence of ZnII coordination sphere and chemical structure over the reactivity of metallo-beta-lactamase model compounds. AB - A systematic study of the influence of the first coordination sphere over the reactivity and structure of metallo-beta-lactamase (MbetaL) monozinc model complexes is reported. Three ZnII complexes with tripodal ligands forming the series [Zn(N-NNN)], [Zn(N-NNS)], and [Zn(N-NNO)] where N-NNX represents the tripodal donor atoms were investigated regarding their ability to mimic MbetaL. The tripodal series was inspired by MbetaL active sites in the respective subclasses, representing the (His, His, His) Zn1 site present in B1 and B3 subclasses, (His, His, Asp) present in the B3 subclass site and the thiolate present in B1 and B2 sites. The results were supported by electronic structure calculations. XAS analysis demonstrated that the ZnII electronic deficiency significantly changes in the order [Zn(N-NNS)] < [Zn(N-NNN)] < [Zn(N-NNO)]. This effect directly affects the reactivity over nitrocefin and amoxicillin, observed by the hydrolysis kinetics, which follows the same trend. NMR spectroscopy revealed the coordination of the carboxylic group in the substrate to the metal changes accordingly, affecting the hydrolysis kinetics. Our results also demonstrated that not only the Lewis acidity is changed by the ligand system but also the softness of the metal. [Zn(N-NNS)] is softened by the thiolate, promoting the ligand substitution reaction with solvents and favoring a secondary interaction with substrates, not observed for [Zn(N-NNO)]. XRD of the models reveals their similar geometric aspects in comparison to the crystal structure of GOB MbetaL. The present work demonstrates that the ZnII electronic details must be considered in the design of new MbetaL models that will further aid in the design of clinically useful inhibitors. PMID- 30462123 TI - Quantum-classical dynamics of the capture of neon atoms by superfluid helium nanodroplets. AB - The capture of a Ne atom by a superfluid helium nanodroplet, Ne + (4He)N -> Ne@(4He)N' + (N - N') 4He, was studied using a hybrid quantum (helium)-classical (Ne) approach and taking into account the angular momentum. The atom is captured by (4He)N and follows elliptical rotating trajectories, and large energy and angular momentum transfer from the atom to the nanodroplet occur. Evaporation of helium atoms from (4He)N allows removal of the excess energy and angular momentum of the doped nanodroplet. The behaviours observed for angular momentum different from zero are similar to the zero angular momentum case. The angular momentum of the Ne atom can induce vortex nucleation for high enough initial angular momentum values (~176.3-220.3 h). Vortices arise from collapse of the surface excitations (ripplons) and are long-lived under some initial conditions. Comparison with our own previous quantum dynamics study at zero angular momentum shows that quantum effects are not important under the initial conditions examined here. Besides, a comparison with the scarce information available on other systems has been performed, showing the rich variety of behaviours that can be observed in the solvation of impurities by superfluid helium. More efforts are welcome in order to obtain a deeper insight into the dynamics of the capture process, especially in the vortex formation context. PMID- 30462124 TI - Mechanisms of multiphase reactive flow using biogenically calcite-functionalized micromodels. AB - Dissolution of carbonate minerals in porous media is important to many instances of subsurface flow, including geological carbon dioxide (CO2) sequestration, karst formation, and crude-oil reservoir stimulation and acidizing. Of particular interest, geological CO2 storage in deep carbonate reservoirs presents a significant long-term opportunity to mitigate atmospheric carbon emissions. The reactivity of carbonate reservoirs, however, may negatively impact storage formation integrity and hence jeopardize sequestered CO2 storage security. In this work, we develop a novel biogenically calcite-functionalized microvisual device to study the fundamental pore-scale reactive transport dynamics in carbonate formations. Importantly, we discover a new microscale mechanism that dictates the overall behavior of the reactive transport phenomenon, where the reaction product, CO2, due to carbonate rock dissolution forms a separate, protective phase that engulfs the carbonate rock grain and reduces further dissolution. The presence of the separate, protective CO2 phase determines overall dissolution patterns in the storage reservoir and leads to formation of preferential leakage paths. We scale these results using nondimensional numbers to demonstrate their influence on industrial CO2 storage security, safety, and capacity. PMID- 30462126 TI - Syntheses and in vitro biological evaluation of S1PR1 ligands and PET studies of four F-18 labeled radiotracers in the brain of nonhuman primates. AB - A series of seventeen hydroxyl-containing sphingosine 1-phosphate receptor 1 (S1PR1) ligands were designed and synthesized. Their in vitro binding potencies were determined using [32P]S1P competitive binding assays. Compounds 10a, 17a, 17b, and 24 exhibited high S1PR1 binding potencies with IC50 values ranging from 3.9 to 15.4 nM and also displayed high selectivity for S1PR1 over other S1P receptor subtypes (IC50 > 1000 nM for S1PR2-5). The most potent compounds 10a, 17a, 17b, and 24 were subsequently radiolabeled with F-18 in high yields and purities. MicroPET studies in cynomolgus macaque showed that [18F]10a, [18F]17a, and [18F]17b but not [18F]24 crossed the blood brain barrier and had high initial brain uptake. Further validation of [18F]10a, [18F]17a, and [18F]17b in preclinical models of neuroinflammation is warranted to identify a suitable PET radioligand to quantify S1PR1 expression in vivo as a metric of an inflammatory response. PMID- 30462128 TI - Multicomponent dipolar cycloadditions: efficient synthesis of polycyclic fused pyrrolizidines via azomethine ylides. AB - An efficient multicomponent dipolar cycloaddition for the synthesis of polycyclic fused pyrrolizidines was developed using N-aromatic zwitterions, aldehydes, and amino acids. The developed reactions proceed through azomethine ylides generated in situ from the decarboxylated reactions of aldehydes and amino acids followed by the [3 + 2] cycloaddition of N-aromatic zwitterions under mild reaction conditions. PMID- 30462131 TI - Formation of a supramolecular charge-transfer complex. Ultrafast excited state dynamics and quantum-chemical calculations. AB - The formation of a supramolecular complex of bis(18-crown-6)stilbene (1) and 4,4' bipyridine with two ammoniopropyl N-substituents (3) and the substitution reaction between 1.3 and alkali and alkaline-earth metal perchlorates have been studied using absorption, steady-state fluorescence, and femtosecond transient absorption spectroscopy. The formation of 1.(Mn+)2 complexes in acetonitrile was demonstrated. The weak long-wavelength charge-transfer absorption band of 1.3 completely vanishes upon complexation with metal cations because of disruption of the pseudocyclic structure. The spectroscopic and luminescence parameters, stability and substitution constants were calculated. The relaxation scheme of the 1.3 singlet state excited by a 25 fs laser pulse was proposed. It includes very fast vibrational relaxation and direct (tauCT-d = 0.32 ps) and back (tauCT-b = 0.51 ps) electron transfer resulting in complete fluorescence quenching. The quantum-chemistry calculations revealed the species taking part in the ET process and elucidated the mechanism of relaxation of the excited complex. PMID- 30462132 TI - Rapidly tunable and highly reversible bio-inspired dry adhesion for transfer printing in air and a vacuum. AB - Tunable and reversible dry adhesion has attracted much attention in academia and industry due to its wide applications ranging from releasable joints to stamps for transfer printing. Here, a simple yet robust magnetically actuated, aphid inspired design of an elastomeric surface that provides rapidly tunable and highly reversible adhesion strength is reported. The magnetically actuated adhesive features open reservoirs filled with magnetic particles and encapsulated by a thin surface membrane, which can be deformed in a controlled manner via the magnetic field, thus, to tune the adhesion. The combination of the rate dependent effect and magnetic actuation of the thin surface membrane offers continuously tunable adhesion with a great switchability and a quick response. Experimental and theoretical studies reveal the underlying physics and provide design guidelines to optimize geometries for the broad control of adhesion. Demonstrations of this concept in stamps for transfer printing of silicon wafers in air and in a vacuum with a selective and programmable mode illustrate the capabilities for deterministic assembly and the potential in the semiconductor industry. PMID- 30462134 TI - Fabrication and design of mechanically stable and free-standing polymeric membrane with two-level apertures. AB - Herein, we report the fabrication process and the investigation of mechanically stable, flexible and free-standing polymeric membranes with two-level apertures. By using overlapped oxygen inhibition layers (OILs) with variation in diameters of the micro-sized supporting layer, we successfully fabricated the mechanically stable and free-standing polymeric membrane with micro/nano two-level apertures. The nano aperture membrane was stably sustained on the micro aperture membrane with a diameter of 50 MUm and 100 MUm, but was torn off in the case of 300 MUm and 500 MUm sized supporting layers. To analyze the results, we propose a simple model to set the criteria of the geometrical features which are mechanically stable during the demolding process. It is worth noting that an appropriate material modulus, length, and thickness of the membrane are required for designing and achieving the robust free-standing hierarchical polymeric membrane. PMID- 30462135 TI - The stabilization of primitive bicontinuous cubic phases with tunable swelling over a wide composition range. AB - In this paper we investigate the pseudo-ternary phase diagram of glycerol monooleate (GMO), a cationic lipid (DOTAP - 1,2-dioleoyl-3-trimethylammonium propane), and a "PEGylated" lipid (DOPE-PEG - 1,2-dioleoyl-sn-glycero-3 phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000 kDa]) in excess water. We use small angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (Cryo-EM) to map out a phase diagram in a regime of low DOPE-PEG content (1-5 mol%), which is pertinent for the application of lipid systems as carriers of biomolecular cargo to cells. Pure GMO is known to self-assemble into bicontinuous cubic phases of the gyroid type at low water content and of the diamond type in excess water. These complex structures have numerous advantages reaching beyond drug delivery, e.g. as protein crystallization matrices, but their formulation is challenging as very small contents of guest molecules can shift the phase behavior towards other geometries such as the lamellar phase. In this work, we show that the ternary GMO/DOTAP/DOPE-PEG system allows the stabilization of bicontinuous cubic phases in excess water over a wide composition range. The symmetry of the phase can be tuned by varying the amount of PEGylated lipid, with the primitive type dominating at low DOPE-PEG content (1 3 mol%) and the diamond phase arising at 5 mol% DOPE-PEG. In addition, we found that the diamond phase is virtually non-responsive to electrostatic swelling. In contrast, primitive bicontinuous cubic lattice dimensions swell up in equilibrium to 650 A with increased cationic lipid content. PMID- 30462136 TI - A differentially selective probe for trivalent chemosensor upon single excitation with cell imaging application: potential applications in combinatorial logic circuit and memory devices. AB - A new rhodamine 6G-benzylamine-based sensor (L1), having only hydrocarbon skeletons in the extended part, was synthesized and characterized by single crystal X-ray crystallographic study. It exhibited excellent selective and sensitive recognition of trivalent metal ions M3+ (M = Fe, Al and Cr) over mono- and di-valent and other trivalent metal ions. A large enhancement of the fluorescence intensity for Fe3+ (41-fold), Al3+ (31-fold) and Cr3+ (26-fold) was observed upon the addition of 3.0 equivalent of these metal ions into the probe in H2O/CH3CN (4 : 1, v/v, pH 7.2) with naked eye detection. The corresponding Kf values were evaluated to be 9.4 * 103 M-1 (Fe3+), 1.34 * 104 M-1 (Al3+) and 8.7 * 103 M-1 (Cr3+). Quantum yields of the L1, [L1-Fe3+], [L1-Al3+] and [L1-Cr3+] complexes in H2O/CH3CN (4 : 1, v/v, pH 7.2) were found to be 0.012, 0.489, 0.376 and 0.310, respectively, using rhodamine-6G as standard. LODs for Fe3+, Al3+ and Cr3+ were determined by 3sigma methods and found to be 1.28, 1.34 and 2.28 MUM, respectively. Cyanide ion scavenged Fe3+ from the [Fe3+-L1] complex and quenched its fluorescence via its ring-closed spirolactam form. Advanced level molecular logic devices using different inputs (2 and 4 inputs) as advanced level logic gates and memory devices were constructed. The large enhancement in fluorescence emission of L1 upon complexation with M3+ metal ions makes the probe suitable for the bio-imaging of M3+ (M = Fe, Al and Cr) in living cells. PMID- 30462137 TI - On measuring the acoustic state changes in lipid membranes using fluorescent probes. AB - Ultrasound is increasingly being used to modulate the properties of biological membranes for applications in drug delivery and neuromodulation. While various studies have investigated the mechanical aspects of the interaction such as acoustic absorption and membrane deformation, it is not clear how these effects transduce into biological functions, for example, changes in the permeability or the enzymatic activity of the membrane. A critical aspect of the activity of an enzyme is the thermal fluctuations of its solvation or hydration shell. Thermal fluctuations are also known to be directly related to membrane permeability. Here solvation shell changes of lipid membranes subject to an acoustic impulse were investigated using a fluorescence probe, Laurdan. Laurdan was embedded in multi lamellar lipid vesicles in water, which were exposed to broadband pressure impulses of the order of 1 MPa peak amplitude and 10 us pulse duration. An instrument was developed to monitor changes in the emission spectrum of the dye at two wavelengths with sub-microsecond temporal resolution. The experiments show that changes in the emission spectrum, and hence the fluctuations of the solvation shell, are related to the changes in the thermodynamic state of the membrane and correlated with the compression and rarefaction of the incident sound wave. The results suggest that acoustic fields affect the state of a lipid membrane and therefore can potentially modulate the kinetics of channels and enzymes embedded in the membrane. PMID- 30462141 TI - The electronic transitions of analogs of red wine pyranoanthocyanin pigments. AB - There is increasing interest in using natural colorants like anthocyanins in cosmetics, food and pharmaceuticals as replacements for synthetic colorants. During the maturation of red wines, the anthocyanin pigments contained in grapes are transformed via reaction with copigments and metabolic products into pyranoanthocyanins, responsible in part for the final color of the wine. In order to understand structural effects on the absorption spectra of pyranoanthocyanins, the calculated excited state energies and spectroscopic states of a series of substitued pyranoflavylium cation analogs of pyranoanthocyanins have been compared to experimental spectroscopic data for these compounds. The vertical excitation energies, calculated by using the ADC(2) approach, gave excellent agreement with the experimental UV-Vis spectra and the nature of the lowest excited state correlates with the observed photophysical behavior in solution. The present results thus provide a basis for the design of new pyranoflavylium chromophores with the desired colors and photophysics, as well as for understanding the analogous properties of natural pyranoanthocyanin pigments in red wine. PMID- 30462143 TI - A retrospective review of right-sided hearts at a South African tertiary hospital. AB - BACKGROUND: A right-sided heart (RSH) has three main causes: dextrocardia, dextroposition and dextroversion. It may be associated with cardiac malformation, extra-cardiac abnormalities and adverse patient outcomes. The aim of this study was to determine the prevalence, demographics, associated cardiac malformations (ACM) and outcome of paediatric patients diagnosed with a RSH at a South African tertiary hospital. METHODS: A retrospective review was performed over a 22-year period. RESULTS: RSH comprised 1% of the paediatric cardiology referrals. Dextrocardia was the most frequent cause (58.1%) and the majority of these patients had ACM (81.5%). More than a third (40.9%) were diagnosed with dextroposition, secondary to extra-cardiac factors. Dextroversion was the least common cause (1.1%). Over a quarter of all patients were confirmed dead at the time of the study; most had been diagnosed with dextrocardia. Two-thirds of the patients were lost to follow up. CONCLUSIONS: A RSH is an unusual occurrence. Dextrocardia, the most common cause, is frequently associated with ACM and extra cardiac abnormalities. It is therefore important to timeously elucidate the cause of a RSH. PMID- 30462144 TI - A comprehensive review of computational prediction of genome-wide features. AB - There are significant correlations among different types of genetic, genomic and epigenomic features within the genome. These correlations make the in silico feature prediction possible through statistical or machine learning models. With the accumulation of a vast amount of high-throughput data, feature prediction has gained significant interest lately, and a plethora of papers have been published in the past few years. Here we provide a comprehensive review on these published works, categorized by the prediction targets, including protein binding site, enhancer, DNA methylation, chromatin structure and gene expression. We also provide discussions on some important points and possible future directions. PMID- 30462145 TI - BulkVis: a graphical viewer for Oxford nanopore bulk FAST5 files. AB - Motivation: The Oxford Nanopore Technologies (ONT) MinION is used for sequencing a wide variety of sample types with diverse methods of sample extraction. Nanopore sequencers output FAST5 files containing signal data subsequently base called to FASTQ format. Optionally, ONT devices can collect data from all sequencing channels simultaneously in a bulk FAST5 file enabling inspection of signal in any channel at any point. We sought to visualize this signal to inspect challenging or difficult to sequence samples. Results: The BulkVis tool can load a bulk FAST5 file and overlays MinKNOW (the software that controls ONT sequencers) classifications on the signal trace and can show mappings to a reference. Users can navigate to a channel and time or, given a FASTQ header from a read, jump to its specific position. BulkVis can export regions as Nanopore base caller compatible reads. Using BulkVis, we find long reads can be incorrectly divided by MinKNOW resulting in single DNA molecules being split into two or more reads. The longest seen to date is 2 272 580 bases in length and reported in eleven consecutive reads. We provide helper scripts that identify and reconstruct split reads given a sequencing summary file and alignment to a reference. We note that incorrect read splitting appears to vary according to input sample type and is more common in 'ultra-long' read preparations. Availability and implementation: The software is available freely under an MIT license at https://github.com/LooseLab/bulkvis. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30462146 TI - Directional allelic imbalance profiling and visualization from multi-sample data with RECUR. AB - Motivation: Genetic analyses of cancer regularly include two or more samples from the same patient. Somatic copy number alterations leading to allelic imbalance (AI) play a critical role in cancer initiation and progression. Directional analysis and visualization of the alleles in imbalance in multi-sample settings allow for inference of recurrent mutations, providing insights into mutation rates, clonality and the genomic architecture and etiology of cancer. Results: The REpeat Chromosomal changes Uncovered by Reflection (RECUR) is an R application for the comparative analysis of AI profiles derived from SNP array and next-generation sequencing data. The algorithm accepts genotype calls and "B allele" frequencies (BAFs) from at least 2 samples derived from the same individual. For a predefined set of genomic regions with AI, RECUR compares BAF values among samples. In the presence of AI, the expected value of a BAF can shift in two possible directions, reflecting an increased or decreased abundance of the maternal haplotype, relative to the paternal. The phenomenon of opposite haplotype shifts, or "mirrored subclonal allelic imbalance", is a form of heterogeneity, and has been linked to clinico-pathological features of cancer. RECUR detects such genomic segments of opposite haplotypes in imbalance and plots BAF values for all samples, using a two-color scheme for intuitive visualization. Availability and Implementation: RECUR is available as an R application. Source code and documentation are available at scheet.org. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30462147 TI - Application of machine learning techniques to tuberculosis drug resistance analysis. AB - Motivation: Timely identification of Mycobacterium tuberculosis (MTB) resistance to existing drugs is vital to decrease mortality and prevent the amplification of existing antibiotic resistance. Machine learning methods have been widely applied for timely predicting resistance of MTB given a specific drug and identifying resistance markers. However, they have been not validated on a large cohort of MTB samples from multi-centers across the world in terms of resistance prediction and resistance marker identification. Summary: Several machine learning classifiers and linear dimension reduction techniques were developed and compared for a cohort of 13402 isolates collected from 16 countries across six continents and tested 11 drugs. Results: Compared to conventional molecular diagnostic test, area under curve (AUC) of the best machine learning classifier increased for all drugs especially by 23.11%, 15.22%, and 10.14% for pyrazinamide (PZA), ciprofloxacin (CIP), and ofloxacin (OFX) respectively (p < 0.01). Logistic regression (LR) and gradient tree boosting (GBT) found to perform better than other techniques. Moreover, LR/GBT with a sparse principal component analysis/non negative matrix factorisation step compared with the classifier alone enhanced the best performance in terms of F1-score by 12.54%, 4.61%, 7.45%, and 9.58% for amikacin (AK), moxifloxacin (MOX), OFX, and capreomycin (CAP) respectively, as well increasing AUC for AK and CAP. Results provided a comprehensive comparison of various techniques and confirmed the application of machine learning for better prediction of the large diverse TB data. Furthermore, mutation ranking showed the possibility of finding new resistance/susceptible markers. Availability: The source code can be found at http://www.robots.ox.ac.uk/~davidc/code.php. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30462148 TI - A novel mutation in 5'-UTR of Makorin ring finger 3 gene associated with the familial precocious puberty. PMID- 30462149 TI - Exaggerated Functional Impairment due to Malingered Neurocognitive Dysfunction Following Mild Traumatic Brain Injury. AB - Objective: Functional impairment associated with Neurocognitive Disorder is often claimed in medico-legal settings after mild Traumatic Brain Injury (mTBI). This case-control study examined self-reported functional impairment and the plausibility of chronic disability claims following uncomplicated mTBI. Method: Independent Medical Evaluations included a battery of performance and symptom validity tests, along with self-reports of physical or emotional complaints and functional impairment. Slick and colleagues' (Slick, D. J., Sherman, E. M., & Iverson, G. L. (1999). Diagnostic criteria for malingered neurocognitive dysfunction: Proposed standards for clinical practice and research. The Clinical Neuropsychologist, 13, 545-561.) criteria ruled out probable malingering in 21 mTBI cases without psychiatric comorbidity and their self-reports were compared to those of seven non-malingering cases with a psychiatric comorbidity, 17 who were probable malingerers, and 31 orthopedic pain sufferers. Coherence Analysis of medical documentation corroborated assignment of mTBI cases to non-malingering versus probable malingering groups. Results: Probable malingerers reported more postconcussion symptoms than non-malingerers (d = 0.79) but they did not differ significantly on tests of neurocognitive performance. Probable malingerers and orthopedic pain patients gave significantly higher ratings of functional impairment (d = 1.28 and 1.26) than non-malingerers. Orthopedic pain patients reported more disability due to pain than non-malingerers (d = 1.03), but pain catastrophizing was rated more highly by the probable malingerers (d = 1.21) as well as by the orthopedic pain patients (d = 0.98). The non-malingerers reported lower emotional distress than the other three groups, but only the probable malingerers reported elevated depression symptoms compared to the non-malingerers (d = 1.01). Conclusions: The combined evaluation of performance validity, function, and coherence analysis would appear to enhance the difficult clinical evaluation of postconcussion symptoms in the medical-legal setting. PMID- 30462150 TI - Association Between the Decline in Pneumococcal Disease in Unimmunized Adults and Vaccine-Derived Protection Against Colonization in Toddlers and Preschool-Aged Children. AB - Vaccinating children with pneumococcal conjugate vaccine (PCV) disrupts transmission, reducing disease rates in unvaccinated adults. When considering changes in vaccine dosing strategies (e.g., removing doses), it is critical to understand which groups of children contribute most to transmission to adults. We used data from Israel (2009-2016) to evaluate how the buildup of vaccine associated immunity in children was associated with declines in invasive pneumococcal disease (IPD) due to vaccine-targeted serotypes in unimmunized adults. Data on vaccine uptake and prevalence of colonization with PCV-targeted serotypes were obtained from children visiting an emergency department in southern Israel and from surveys of colonization from central Israel. Data on IPD in adults were obtained from a nationwide surveillance study carried out in Israel. We compared the trajectory of decline of IPD due to PCV-targeted serotypes in adults with the decline of colonization prevalence and increase in vaccine-derived protection against pneumococcal carriage among different age groupings of children. The declines in IPD in adults were most closely associated with the declines in colonization and increased vaccination coverage among children in the age range of 36-59 months. This suggests that preschool-aged children, rather than infants, are responsible for maintaining the indirect benefits of PCVs. PMID- 30462151 TI - Silent Synapse Unsilencing in Hippocampal CA1 Neurons for Associative Fear Memory Storage. AB - Clarifying learning-induced synaptic plasticity in hippocampal circuits is critical for understanding hippocampal mechanisms of memory acquisition and storage. Many in vitro studies have demonstrated learning-associated plasticity at hippocampal synapses. However, as a neural basis of memory encoding, the nature of synaptic plasticity underlying hippocampal neuronal responses to memorized stimulation remains elusive. Using in vivo whole-cell recording in anaesthetized adult rats and mice, we investigated synaptic activity of hippocampal CA1 pyramidal cells (PCs) in response to a flash of visual stimulation as the conditioned stimulus (CS) in associative fear conditioning. We found that shortly (<3 days) after conditioning, excitatory synaptic responses and spiking responses to the flash CS emerged in a large number (~70%) of CA1 PCs, a neuronal population previously unresponsive to the flash before conditioning. The learning-induced CA1 excitatory responsiveness was further indicated to result from postsynaptic unsilencing at flash-associated silent synapses, with NMDA receptor-gated responses we recently reported in naive animals. Our findings suggest that associative fear learning can induce excitatory responsiveness to the memorized CS in a large population of CA1 neurons, via a process of postsynaptic unsilencing at CA1 silent synapses, which may be critical for hippocampal acquisition and storage of associative memory. PMID- 30462152 TI - Can luteolin be a therapeutic molecule for both colon cancer and diabetes? AB - Diabetes and colon cancer are the leading cause of mortality worldwide. According to World Health Organization, the number of patients with diabetes and cancer is going to be elevated by 50% in 2020. However, several flavonoids have been known to be useful in reducing the chance of cancer/diabetes but the hunt of a single biomolecule that can act as therapeutic and preventive molecules for future epidemic continues. In this review, we aim to perform an illustration of all researches done that target molecular signaling using luteolin in cancer/diabetes and predicted target protein using PharmMapper. The search confirms that luteolin can be a remedial molecule for both cancer and diabetes via acting on variety of signaling pathway. Furthermore, we also intend to illustrate/compare the predicted and verified molecular modes of action of luteolin. Fluorescence in situ hybridization analysis confirms the expression of CCND1 in colon cancer while immunofluorescence analysis confirms the CDK4 in diabetes. Finally, an effort has been made to map docking of marker protein-luteolin at a particular site using docking software. This review gives a holistic overview about luteolin as a therapeutic molecule for cancer/diabetes via acting on multiple signaling cascade such as p53, Wnt, eNOS, iNOS, SOD and MMP9, with especial emphasis on the cyclin-CDK pathway. Altogether, the review concludes that luteolin can be a molecule for the therapy of both cancer and diabetes by acting on broad signaling pathway. PMID- 30462153 TI - Speckle Tracking Echocardiographic Layer-specific Strain Analysis on Subclinical Left Ventricular Dysfunction in Patients with Primary Aldosteronism. AB - Background: Primary aldosteronism (PA) may cause myocardial injury. We investigated myocardial dysfunction using speckle tracking echocardiographic (STE) layer-specific strain in patients with PA. Methods: Our study included 62 patients with PA (33 aldosterone-producing adenoma [APA] and 29 idiopathic hyperaldosteronism [IHA]) and 30 patients with primary hypertension. STE was acquired using the GE Vivid E9 equipment. The longitudinal (LS) and circumferential (CS) layer-specific strains of the endocardium, mid-myocardium and epicardium (LSendo, LSmid, LSepi, CSendo, CSmid and CSepi) were obtained using the EchoPAC BT13 workstation. Results: Patients with APA, compared to those with primary hypertension and IHA had a significantly (P<0.001) lower serum potassium concentration and plasma renin activity, and higher 24-h urinary aldosterone, plasma aldosterone concentration and aldosterone-to-renin ratio. Left ventricular ejection fraction was normal in all patients (58% to 60%). Layer specific strain showed decreasing gradient from the endocardium to epicardium in all three groups (P<0.01). However, LSendo and CSendo were lowest in APA (-20.2+/ 2.3% and -33.3+/-3.2%), intermediate in IHA (-22.1+/-1.9% and -35.7+/-2.8%) and highest in primary hypertension (-24.1+/-2.1% and -38.9+/-3.1%, P<0.001). Similar trends were observed for LSmid, LSepi, CSmid and CSepi, but statistical significance was only reached for the comparison between APA and primary hypertension (P<0.001), but not others (P>0.05). Layer-specific strain was significantly corelated with plasma aldosterone concentration for all echocardiographic parameters (r-0.69 to -0.53, P<0.001) in all three groups. Conclusions: Patients with PA, especially APA, had impaired regional systolic function with myocardial deformation changes at similar levels of blood pressure, probably because of elevated plasma aldosterone concentration. PMID- 30462154 TI - The bioinformatics tools for the genome assembly and analysis based on third generation sequencing. AB - The application of third-generation sequencing (TGS) technology in genetics and genomics have provided opportunities to categorize and explore the individual genomic landscapes and mutations relevant for diagnosis and therapy using whole genome sequencing and de novo genome assembly. In general, the emerging TGS technology can produce high quality long reads for the determination of overlapping reads and transcript isoforms. However, this technology still faces challenges such as the accuracy for the identification of nucleotide bases and high error rates. Here, we surveyed 39 TGS-related tools for de novo assembly and genome analysis to identify the differences among their characteristics, such as the required input, the interaction with the user, sequencing platforms, type of reads, error models, the possibility of introducing coverage bias, the simulation of genomic variants and outputs provided. The decision trees are summarized to help researchers to find out the most suitable tools to analyze the TGS data. Our comprehensive survey and evaluation of computational features of existing methods for TGS may provide a valuable guideline for researchers. PMID- 30462156 TI - Dreams can come true: The first steps towards a peripheral blood screening test for the early detection of tumors have been taken. PMID- 30462155 TI - Comprehensive and critical evaluation of individualized pathway activity measurement tools on pan-cancer data. AB - Motivation: : Biological pathways are extensively used for the analysis of transcriptome data to characterize biological mechanisms underlying various phenotypes. There are a number of computational tools that summarize transcriptome data at the pathway level. However, there is no comparative study on how well these tools produce useful information at the cohort level, enabling comparison of many samples or patients. Results: : In this study, we systematically compared and evaluated 13 different pathway activity inference tools based on 5 comparison criteria using pan-cancer data set. This study has two major contributions. First, our study provides a comprehensive survey on computational techniques used by existing pathway activity inference tools. The tools use different strategies and assume different requirements on data: input transformation, use of labels, necessity of cohort-level input data, use of gene relations and scoring metric. Second, we performed extensive evaluations on the performance of these tools. Because different tools use different methods to map samples to the pathway dimension, the tools are evaluated at the pathway level using five comparison criteria. Starting from measuring how well a tool maintains the characteristics of original gene expression values, robustness was also investigated by adding noise into gene expression data. Classification tasks on three clinical variables (tumor versus normal, survival and cancer subtypes) were performed to evaluate the utility of tools for their clinical applications. In addition, the inferred activity values were compared between the tools to see how similar they are along with the scoring schemes they use. PMID- 30462157 TI - Dating admixture events is unsolved problem in multi-way admixed populations. AB - Advances in human sequencing technologies, coupled with statistical and computational tools, have fostered the development of methods for dating admixture events. These methods have merits and drawbacks in estimating admixture events in multi-way admixed populations. Here, we first provide a comprehensive review and comparison of current methods pertinent to dating admixture events. Second, we assess various admixture dating tools. We do so by performing various simulations. Third, we apply the top two assessed methods to real data of a uniquely admixed population from South Africa. Results reveal that current dating admixture models are not sufficiently equipped to estimate ancient admixtures events and to identify multi-faceted admixture events in complex multi-way admixed populations. We conclude with a discussion of research areas where further work on dating admixture-based methods is needed. PMID- 30462158 TI - The application of Hadoop in structural bioinformatics. AB - The paper reviews the use of the Hadoop platform in structural bioinformatics applications. For structural bioinformatics, Hadoop provides a new framework to analyse large fractions of the Protein Data Bank that is key for high-throughput studies of, for example, protein-ligand docking, clustering of protein-ligand complexes and structural alignment. Specifically we review in the literature a number of implementations using Hadoop of high-throughput analyses and their scalability. We find that these deployments for the most part use known executables called from MapReduce rather than rewriting the algorithms. The scalability exhibits a variable behaviour in comparison with other batch schedulers, particularly as direct comparisons on the same platform are generally not available. Direct comparisons of Hadoop with batch schedulers are absent in the literature but we note there is some evidence that Message Passing Interface implementations scale better than Hadoop. A significant barrier to the use of the Hadoop ecosystem is the difficulty of the interface and configuration of a resource to use Hadoop. This will improve over time as interfaces to Hadoop, e.g. Spark improve, usage of cloud platforms (e.g. Azure and Amazon Web Services (AWS)) increases and standardised approaches such as Workflow Languages (i.e. Workflow Definition Language, Common Workflow Language and Nextflow) are taken up. PMID- 30462159 TI - Inhibition by Ethanol of Shear Stress-Induced Formation of Platelet Thrombi in Whole Blood. AB - Aims: The risk of thromboatherosclerotic disease is lower in moderate drinkers than in non-drinkers. We investigated the effects of ethanol on platelet aggregation under a condition with shear stress. Short summary: Shear stress induced formation of platelet thrombi is inhibited by ethanol at its attainable concentrations after drinking. This effect is prominent at the early stage of thrombus formation, being in agreement with inhibitory actions of ethanol on the initial steps of platelet activation such as Ca2+ entry and phospholipase A2 activation. Methods: Platelet aggregation was evaluated by using a total thrombus formation analysis system, and shear rates of 1000 s-1 (low), 1500 s-1 (middle) and 2000 s-1 (high) were loaded to whole blood. The times required to generate increases in flow pressure of 10 kPa (T10), 30 kPa (T30) and 50 kPa (T50) in microchips containing the blood, which depend on the degree of thrombus generation, were recorded. Results: Under the conditions of the low-grade and middle-grade shear rates, T10 and T30 were significantly longer in the presence of ethanol at 0.25-1% than in the absence of ethanol. T10 under the condition of the low-grade shear rate and T30 under the conditions of the low-grade and middle grade shear rates were also significantly longer in the presence of ethanol at 0.125% than in the absence of ethanol. On the other hand, T50 under the conditions of the low-grade and middle-grade shear rates was not significantly different in the absence and presence of ethanol at 0.125, 0.25 and 0.5%. Under the condition of the high-grade shear rate, T10, T30 and T50 were not significantly different in the absence and presence of ethanol at its lower concentrations. Conclusions: Ethanol at attainable concentrations inhibits platelet thrombus formation induced by shear stress, and the inhibitory effect of ethanol is prominent at the early stage of thrombus formation. PMID- 30462161 TI - Weighing false hope in population anti-cancer drug decision-making. PMID- 30462160 TI - Anti-EGFR Resistant Clones Decay Exponentially After Progression: Implications for Anti-EGFR Re-challenge. AB - Background: Colorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to EGFR inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay, however the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy. Patients and Methods: We present the post progression circulating tumor DNA (ctDNA) profiles of 135 patients with RAS/BRAF wild-type metastatic CRC treated with anti-EGFR who acquired RAS and/or EGFR mutations during therapy. Our validation cohort consisted of an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling. A separate retrospective cohort of 80 patients was used to evaluate overall response rate and progression free survival during re-challenge therapies. Results: Our analysis showed that RAS and EGFR relative mutant allele frequency (rMAF) decays exponentially (r2=0.93 for RAS; r2=0.94 for EGFR) with a cumulative half-life of 4.4 months. We validated our findings using an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling, confirming exponential decay with an estimated half life of 4.3 months. A separate retrospective cohort of 80 patients showed that patients had a higher overall response rate during re-challenge therapies after increasing time intervals, as predicted by our model. Conclusion: These results provide scientific support for anti-EGFR re-challenge and guide the optimal timing of re-challenge initiation. PMID- 30462162 TI - Effects of exercise and nutrition supplementation in community-dwelling older Chinese people with sarcopenia: a randomized controlled trial. AB - Background: Limited trials examining the effect of exercise and nutrition supplementation in older people with sarcopenia are available. Objectives: to assess the impact of resistance exercise program targeting muscle strength and power with and without nutrition supplementation on gait speed, body composition, physical function and quality of life. Methods: this trial randomized 113 community-dwelling older Chinese adults aged >=65 and with sarcopenia defined using the Asian Criteria into one of the three groups: exercise program alone, combined-exercise program and nutrition supplement or waitlist control. The exercise program consisted of 90-min group training twice weekly and one-home session weekly for 12 weeks. Participants in the combined group were additionally asked to consume nutrition supplement twice daily for 12 weeks. Both groups were encouraged to keep home exercise after intervention period for another 12 weeks to detect sustained effect. The primary outcome was gait speed. Results: at 12 and 24 weeks, gait speed did not differ significantly between groups. Significant improvement in leg extension, and five-chair stand test occurred in both intervention groups that persisted to 24 weeks. Physical Activity Scale for the Elderly improved in both intervention groups that persisted until 24 weeks only in the combined group. Lower limb muscle and appendicular skeletal muscle mass increased significantly in the combined group but the increase was not sustained to 24 weeks. Conclusion: the exercise program with and without nutrition supplementation had no significant effect on the primary outcome of gait speed but improved the secondary outcomes of strength and the five-chair stand test in community-dwelling Chinese sarcopenic older adults. ClinicalTrials.gov identifier: NCT02374268. PMID- 30462163 TI - Immune Biomarkers of Response to Immune-Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma. AB - Anti-PD-1 agents have become the standard of care for platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma and are currently being evaluated in various disease settings. However, despite the gain in overall survival seen in some of the clinical trials, the majority of patients display primary resistance and do not benefit from these agents. Taking into consideration the potentially severe immune-related toxicities and their high cost, the search for predictive biomarkers of response is crucial. Besides PD-L1 expression, other biomarkers such as immune infiltration, tumor mutational burden or immune gene expression profiling have been explored, but none of them has been validated in this disease. Among these, the microbiota has recently garnered tremendous interest since it has proven to influence the efficacy of PD-1 blockade in some tumor types. With the accumulating evidence on the effect of the microbiota in HNSCC tumorigenesis and progression, the study of its potential role as a predictive immune biomarker is warranted. This review will examine the available evidence on emerging immune predictive biomarkers of response to anti PD-1/PD-L1 therapy in HNSCC, introducing the microbiome and its potential use as a predictive immune biomarker in this disease. PMID- 30462164 TI - Harmonizing semantic annotations for computational models in biology. AB - Life science researchers use computational models to articulate and test hypotheses about the behavior of biological systems. Semantic annotation is a critical component for enhancing the interoperability and reusability of such models as well as for the integration of the data needed for model parameterization and validation. Encoded as machine-readable links to knowledge resource terms, semantic annotations describe the computational or biological meaning of what models and data represent. These annotations help researchers find and repurpose models, accelerate model composition and enable knowledge integration across model repositories and experimental data stores. However, realizing the potential benefits of semantic annotation requires the development of model annotation standards that adhere to a community-based annotation protocol. Without such standards, tool developers must account for a variety of annotation formats and approaches, a situation that can become prohibitively cumbersome and which can defeat the purpose of linking model elements to controlled knowledge resource terms. Currently, no consensus protocol for semantic annotation exists among the larger biological modeling community. Here, we report on the landscape of current annotation practices among the COmputational Modeling in BIology NEtwork community and provide a set of recommendations for building a consensus approach to semantic annotation. PMID- 30462165 TI - Evaluation and application of RNA-Seq by MinION. AB - The current RNA-Seq method analyses fragments of mRNAs, from which it is occasionally difficult to reconstruct the entire transcript structure. Here, we performed and evaluated the recent procedure for full-length cDNA sequencing using the Nanopore sequencer MinION. We applied MinION RNA-Seq for various applications, which would not always be easy using the usual RNA-Seq by Illumina. First, we examined and found that even though the sequencing accuracy was still limited to 92.3%, practically useful RNA-Seq analysis is possible. Particularly, taking advantage of the long-read nature of MinION, we demonstrate the identification of splicing patterns and their combinations as a form of full length cDNAs without losing precise information concerning their expression levels. Transcripts of fusion genes in cancer cells can also be identified and characterized. Furthermore, the full-length cDNA information can be used for phasing of the SNPs detected by WES on the transcripts, providing essential information to identify allele-specific transcriptional events. We constructed a catalogue of full-length cDNAs in seven major organs for two particular individuals and identified allele-specific transcription and splicing. Finally, we demonstrate that single-cell sequencing is also possible. RNA-Seq on the MinION platform should provide a novel approach that is complementary to the current RNA-Seq. PMID- 30462166 TI - The Concurrence of Cortical Surface Area Expansion and White Matter Myelination in Human Brain Development. AB - The human brain undergoes dramatic structural changes during childhood that co occur with behavioral development. These age-related changes are documented for the brain's gray matter and white matter. However, their interrelation is largely unknown. In this study, we investigated age-related effects in cortical thickness (CT) and in cortical surface area (SA) as parts of the gray matter volume as well as age effects in T1 relaxation times in the white matter. Data from N = 170 children between the ages of 3 and 7 years contributed to the sample. We found a high spatial overlap of age-related correlations between SA and T1 relaxation times of the corresponding white matter connections, but no such relation between SA and CT. These results indicate that during childhood the developmental expansion of the cortical surface goes hand-in-hand with age-related increase of white matter fiber connections terminating in the cortical surface. PMID- 30462167 TI - Natriuretic Protein Receptors and Atrial Selective Fibrosis: Potential Role in Atrial Fibrillation. PMID- 30462168 TI - The Microbiome Modeling Toolbox: from microbial interactions to personalized microbial communities. AB - Motivation: The application of constraint-based modeling to functionally analyze metagenomic data has been limited so far, partially due to the absence of suitable toolboxes. Results: To address this gap, we created a comprehensive toolbox to model i) microbe-microbe and host-microbe metabolic interactions, and ii) microbial communities using microbial genome-scale metabolic reconstructions and metagenomic data. The Microbiome Modeling Toolbox extends the functionality of the COBRA Toolbox. Availability: The Microbiome Modeling Toolbox and the tutorials at https://git.io/microbiomeModelingToolbox. PMID- 30462169 TI - TAIJI: Approaching Experimental Replicates-Level Accuracy for Drug Synergy Prediction. AB - Motivation: Combination therapy is widely used in cancer treatment to overcome drug resistance. High-throughput drug screening is the standard approach to study the drug combination effects, yet it becomes impractical when the number of drugs under consideration is large. Therefore, accurate and fast computational tools for predicting drug synergistic effects are needed to guide experimental design for developing candidate drug pairs. Results: Here, we present TAIJI, a high performance software for fast and accurate prediction of drug synergism. It is based on the winning algorithm in the AstraZeneca-Sanger Drug Combination Prediction DREAM Challenge, which is a unique platform to unbiasedly evaluate the performance of current state-of-the-art methods, and includes 160 team-based submission methods. When tested across a broad spectrum of 85 different cancer cell lines and 1089 drug combinations, TAIJI achieved a high prediction correlation (0.53), approaching the accuracy level of experimental replicates (0.56). The runtime is at the scale of minutes to achieve this state-of-the-field performance. Availability: TAIJI is freely available on GitHub (https://github.com/GuanLab/TAIJI). It is functional with built-in Perl and Python. Supplementary information: Supplementary Data are available at Bioinformatics online. PMID- 30462170 TI - Evolution of programmatic definitions used in tuberculosis prevention and care. PMID- 30462171 TI - DeepCrystal: A Deep Learning Framework for Sequence-based Protein Crystallization Prediction. AB - Motivation: Protein structure determination has primarily been performed using X ray crystallography. To overcome the expensive cost, high attrition rate and series of trial-and-error settings, many in-silico methods have been developed to predict crystallization propensities of proteins based on their sequences. However, the majority of these methods build their predictors by extracting features from protein sequences, which is computationally expensive and can explode the feature space. We propose DeepCrystal, a deep learning framework for sequence-based protein crystallization prediction. It uses deep learning to identify proteins which can produce diffraction quality crystals without the need to manually engineer additional biochemical and structural features from sequence. Our model is based on Convolutional Neural Networks (CNNs), which can exploit frequently occurring k-mers and sets of k-mers from the protein sequences to distinguish proteins that will result in diffraction quality crystals from those that will not. Results: Our model surpasses previous sequence-based protein crystallization predictors in terms of recall, F-score, accuracy and MCC on three independent test sets. DeepCrystal achieves an average improvement of 1.4%, 12.1% in recall, when compared to its closest competitors, Crysalis II and Crysf respectively. In addition, DeepCrystal attains an average improvement of 2.1%, 6.0% for F-score, 1.9%, 3.9% for accuracy and 3.8%, 7.0% for MCC w.r.t. Crysalis II and Crysf on independent test sets. Availability: The standalone source code and models are available at https://github.com/elbasir/DeepCrystal and a web server is also available at https://deeplearning-protein.qcri.org. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30462172 TI - Impact of the 13-valent pneumococcal conjugate vaccine on incidence of all-cause pneumonia in adults aged >= 60 years - a population-based retrospective cohort study. AB - In this population-based study evaluating the effectiveness of the 13-valent pneumococcal conjugate vaccine (2012-2016) to prevent all-cause pneumonia in adults >= 60 years, we found a significant 0.63% absolute and 11.9% relative risk reduction on three-year (2014-2016) all-cause pneumonia cumulative incidence after PCV-13 vaccination (NNV to prevent one pneumonia, 159). PMID- 30462173 TI - circtools - a one-stop software solution for circular RNA research. AB - Motivation: Circular RNAs (circRNAs) originate through back-splicing events from linear primary transcripts, are resistant to exonucleases, are not polyadenylated, and have been shown to be highly specific for cell type and developmental stage. CircRNA detection starts from high-throughput sequencing data and is a multi-stage bioinformatics process yielding sets of potential circRNA candidates that require further analyses. While a number of tools for the prediction process already exist, publicly available analysis tools for further characterization are rare. Our work provides researchers with a harmonized workflow that covers different stages of in silico circRNA analyses, from prediction to first functional insights. Results: Here, we present circtools, a modular, Python-based framework for computational circRNA analyses. The software includes modules for circRNA detection, internal sequence reconstruction, quality checking, statistical testing, RNA binding protein enrichment screenings, differential exon RNase R resistance, and circRNA-specific primer design. Circtools supports researchers with visualization options and data export into commonly used formats. Availability: Circtools is available via github.com/dieterich-lab/circtools and circ.tools under GPLv3.0. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30462174 TI - Intravascular lithotripsy for treatment of stent underexpansion secondary to severe coronary calcification. PMID- 30462176 TI - A Novel, 5-Transcript, Whole-blood Gene-expression Signature for Tuberculosis Screening Among People Living With Human Immunodeficiency Virus. AB - Background: Gene-expression profiles have been reported to distinguish between patients with and without active tuberculosis (TB), but no prior study has been conducted in the context of TB screening. Methods: We included all the patients (n = 40) with culture-confirmed TB and time-matched controls (n = 80) enrolled between July 2013 and April 2015 in a TB screening study among people living with human immunodeficiency virus (PLHIV) in Kampala, Uganda. We randomly split the patients into training (n = 80) and test (n = 40) datasets. We used the training dataset to derive candidate signatures that consisted of 1 to 5 differentially expressed transcripts (P <= .10) and compared the performance of our candidate signatures with 4 published TB gene-expression signatures, both on the independent test dataset and in 2 external datasets. Results: We identified a novel, 5-transcript signature that met the accuracy thresholds recommended for a TB screening test. On the independent test dataset, our signature had an area under the curve (AUC) of 0.87 (95% confidence interval [CI] 0.72-0.98), with sensitivity of 94% and specificity of 75%. None of the 4 published TB signatures achieved desired accuracy thresholds. Our novel signature performed well in external datasets from both high (AUC 0.81, 95% CI 0.74-0.88) and low (0.81, 95% CI 0.77-0.85) TB burden settings. Conclusions: We identified the first gene expression signature for TB screening. Our signature has the potential to be translated into a point-of-care test to facilitate systematic TB screening among PLHIV and other high-risk populations. PMID- 30462177 TI - Systematic Review of Tools and Methods to Measure Appetite in Undernourished Children in the Context of Low- and Middle-Income Countries. AB - Child undernutrition has multifactorial causes, ranging from food insecurity to etiologies refractory to conventional nutritional approaches, such as infections, environmental enteric dysfunction, and other conditions that lead to systemic inflammation. Poor appetite may be an important symptom of these causes and may be a useful marker of an undernourished child's ability to recover. We conducted a systematic review to characterize the methods and tools to measure appetite among children <5 y old in low- and middle-income countries. A systematic search of 8 databases identified 23 eligible studies published since 1995. Thirteen described methods based on direct feeding observation or quantification of nutrient intake from caregiver report, 16 described tools that assessed caregiver perceptions of appetite, and 6 reported assessments in both categories. Four studies that gauged caregiver perceptions assessed multiple appetite domains, whereas 12 assessed 1 domain-often with a single question. Only 6 studies reported validation processes, the most common of which compared an observed test meal with daily energy intake. No studies reported the use of a method or tool that was validated in multiple cultural or linguistic contexts. Although dietary intake measures and observed feeding tests have shown validity in some contexts, they are resource intensive. Subjective caregiver questionnaires may offer a more efficient appetite evaluation method, but they have been evaluated less consistently. A rigorously developed and validated tool to rapidly assess child appetite is needed and could be best addressed by a questionnaire that leverages the multiple domains of appetite. The application of interventions that target causes of undernutrition that are not amenable to food-based interventions in clinical or research contexts could be facilitated by an efficient appetite screening tool to identify appetite-related causes of undernutrition and to monitor children's response to such interventions. PMID- 30462175 TI - The search for pain biomarkers in the human brain. AB - Non-invasive functional brain imaging is used more than ever to investigate pain in health and disease, with the prospect of finding new means to alleviate pain and improve patient wellbeing. The observation that several brain areas are activated by transient painful stimuli, and that the magnitude of this activity is often graded with pain intensity, has prompted researchers to extract features of brain activity that could serve as biomarkers to measure pain objectively. However, most of the brain responses observed when pain is present can also be observed when pain is absent. For example, similar brain responses can be elicited by salient but non-painful auditory, tactile and visual stimuli, and such responses can even be recorded in patients with congenital analgesia. Thus, as argued in this review, there is still disagreement on the degree to which current measures of brain activity exactly relate to pain. Furthermore, whether more recent analysis techniques can be used to identify distributed patterns of brain activity specific for pain can be only warranted using carefully designed control conditions. On a more general level, the clinical utility of current pain biomarkers derived from human functional neuroimaging appears to be overstated, and evidence for their efficacy in real-life clinical conditions is scarce. Rather than searching for biomarkers of pain perception, several researchers are developing biomarkers to achieve mechanism-based stratification of pain conditions, predict response to medication and offer personalized treatments. Initial results with promising clinical perspectives need to be further tested for replicability and generalizability. PMID- 30462178 TI - Nutrient Profile Models with Applications in Government-Led Nutrition Policies Aimed at Health Promotion and Noncommunicable Disease Prevention: A Systematic Review. AB - Nutrient profile (NP) models, tools used to rate or evaluate the nutritional quality of foods, are increasingly used by government bodies worldwide to underpin nutrition-related policies. An up-to-date and accessible list of existing NP models is currently unavailable to support their adoption or adaptation in different jurisdictions. This study used a systematic approach to develop a global resource that summarizes key characteristics of NP models with applications in government-led nutrition policies. NP models were identified from an unpublished WHO catalog of NP models last updated in 2012 and from searches conducted in different databases of the peer-reviewed (n = 3; e.g., PubMed) and gray literature (n = 15). Included models had to meet the following inclusion criteria (selected) as of 22 December 2016: 1) developed or endorsed by governmental or intergovernmental organizations, 2) allow for the evaluation of individual food items, and 3) have publicly available nutritional criteria. A total of 387 potential NP models were identified, including n = 361 from the full text assessment of >600 publications and n = 26 exclusively from the catalog. Seventy-eight models were included. Most (73%) were introduced within the past 10 y, and 44% represent adaptations of >=1 previously built model. Models were primarily built for school food standards or guidelines (n = 27), food labeling (e.g., front-of-pack; n = 12), and restriction of the marketing of food products to children (n = 10). All models consider nutrients to limit, with sodium, saturated fatty acids, and total sugars being included most frequently; and 86% also consider >=1 nutrient to encourage (e.g., fiber). No information on validity testing could be identified for 58% of the models. Given the proliferation of NP models worldwide, this new resource will be highly valuable for assisting health professionals and policymakers in the selection of an appropriate model when the establishment of nutrition-related policies requires the use of nutrient profiling. PMID- 30462179 TI - The Effect of Nutrients and Dietary Supplements on Sperm Quality Parameters: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. AB - Infertility, which affects ~15% of the world's population, is a global public health issue recognized by the WHO. Therefore, it is of major clinical and public health importance to investigate whether modifiable lifestyle factors-such as stress, drug use, smoking, alcohol intake, and diet-may influence human fertility. A systematic review and meta-analysis of randomized clinical trials (RCTs) from the MEDLINE-PubMed database was conducted to assess the effect of nutrients, dietary supplements, or food on sperm quality parameters. In total, 28 articles were included for qualitative analysis and 15 for quantitative meta analysis. Total sperm concentrations [expressed as mean differences (MDs); 95% CIs, in spermatozoa (spz)/mL] were increased by selenium (3.91 * 106 spz/mL; 3.08, 4.73 spz/mL), zinc (1.48 * 106 spz/mL; 0.69, 2.27 spz/mL), omega-3 (n-3) fatty acids (10.98 * 106 spz/mL; 10.25, 11.72 spz/mL), and coenzyme Q10 (CoQ10) (5.93 * 106 spz/mL; 5.36, 6.51 spz/mL). Sperm counts were increased by omega-3 fatty acids (18.70 * 106 spz/mL; 16.89, 20.51 spz/mL) and CoQ10 supplementation (10.15 * 106 spz/mL; 8.34, 11.97 spz/mL). Sperm total motility was increased by selenium (3.30%; 2.95%, 3.65%), zinc (7.03%; 6.03%, 8.03%), omega-3 fatty acids (7.55%; 7.09%, 8.01%), CoQ10 (5.30%; 4.98%, 5.62%), and carnitines (7.84%; 6.54%, 9.13%), whereas sperm progressive motility was increased only after supplementation with carnitines (7.45%; 6.24%, 8.67%). Finally, sperm morphology was enhanced by selenium (1.87%; 1.50%, 2.24%), omega-3 fatty acid (0.91%; 0.69%, 1.13%), CoQ10 (1.06%; 0.72%, 1.41%), and carnitine (4.91%; 3.68%, 6.15%) supplementation. This meta-analysis of RCTs suggests that some dietary supplements could beneficially modulate sperm quality parameters and affect male fertility. However, results must be cautiously interpreted due to the limited sample size of the meta-analyzed studies and the considerable observed interstudy heterogeneity.The present study and the corresponding search protocol were registered at the PROSPERO registry at http://www.crd.york.ac.uk/PROSPERO as CRD42017058380. PMID- 30462181 TI - Consultation for presumed Lyme borreliosis: the need for a multidisciplinary management. PMID- 30462180 TI - Associations between Phytoestrogens, Glucose Homeostasis, and Risk of Diabetes in Women: A Systematic Review and Meta-Analysis. AB - Phytoestrogens might have advantageous effects on diabetes in women. We performed a systematic review and meta-analysis to determine the effect of phytoestrogens on glucose homeostasis and the risk of type 2 diabetes (T2D) among women. Randomized controlled trials (RCTs) and prospective observational studies that assessed associations of phytoestrogens (supplementation, dietary intake, or biomarkers) with fasting glucose or insulin, homeostatic model assessment of insulin resistance (HOMA-IR), or with the risk of T2D were included. We identified 18 RCTs (n = 1687 individuals) investigating the effect of phytoestrogen supplementation on glucose homeostasis and 9 prospective population based studies (n = 212,796 individuals) examining the association between phytoestrogen intake and the risk of T2D. Compared with placebo, phytoestrogen supplementation resulted in improvements in fasting glucose and HOMA-IR: the pooled mean differences of changes were -0.12 mmol/L (95% CI: -0.20, -0.03 mmol/L) and -0.24 mmol/L (95% CI: -0.45, -0.03 mmol/L), respectively. Although there was no significant decrease in insulin concentrations with overall phytoestrogen supplementation, the pooled mean difference in changes was -0.99 pmol/L (95% CI: -4.65, 2.68 pmol/L). However, the results of RCTs varied by type of phytoestrogens: soy-derived isoflavones and genistein improved glucose homeostasis, whereas isoflavone mix and daidzein had no effect or were associated with an adverse glycemic profile. Higher dietary phytoestrogen intake was associated with a 10% lower risk of developing T2D in observational studies (pooled RR: 0.90; 95% CI: 0.85, 0.96; for the highest compared with the lowest quantiles). Results were similar when the analyses were restricted to only medium and high-quality studies. Overall, phytoestrogens may have a positive influence on glycemia and could be used for diabetes prevention in women. However, for some individual types of phytoestrogens, such as mixed isoflavones, caution is needed in recommending their use in women, because their use could lead to an adverse glycemic profile in women. PMID- 30462182 TI - Treatment outcomes of colistin and carbapenem-resistant Acinetobacter baumannii infections: an exploratory subgroup analysis of a randomized clinical trial. AB - Background: We aimed to evaluate the association between mortality and colistin resistance in infections caused by Acinetobacter baumannii and the interaction with antibiotic therapy. Methods: This is a secondary analysis of a randomized controlled trial of patients with carbapenem-resistant Gram-negative bacterial infections treated with colistin or colistin-meropenem combination. We evaluated patients with infection caused by carbapenem-resistant A. baumannii (CRAB) initially found to be colistin-susceptible (CoS) at the time of treatment and compared patients in which the isolate was confirmed to be colistin-susceptible with those whose isolates were retrospectively found to be colistin-resistant (CoR) when tested by broth microdilution (BMD). The primary outcome was 28-day mortality. Results: Data were available for 266 patients with CRAB; 214 colistin susceptible and 52 colistin-resistant isolates. Patients with CoR isolates had higher baseline functional capacity and lower rates of mechanical ventilation than patients with CoS isolates. All-cause 28-day mortality was 42.3% (22/52) among patients with CoR strains and 52.8% (113/214) among patients with CoS isolates (p=0.174). After adjusting for variables associated with mortality, the mortality rate was significantly lower among patients with CoR isolates (OR 0.285, 95%CI 0.118-0.686). This difference was associated with treatment arm: mortality rates among patients with CoR isolates were higher in those randomized to colistin-meropenem combination compared to colistin monotherapy (OR 3.065, 95%CI 1.021-9.202). Conclusions: Colistin resistance as determined by BMD was associated with significantly lower mortality among patients with severe CRAB infections. Among patients with CoR isolates, colistin monotherapy was associated with a better outcome compared to colistin-meropenem combination therapy. PMID- 30462184 TI - The Impact of Antibiotic Stewardship Program Resources on Infection Prevention Programs. AB - Doernberg and colleagues describe the role and resourcing of the Infectious Disease (ID) physician for an effective hospital-based antibiotic stewardship program (ASP) (1). There are similar resource requirements for the ID physician leader in an effective Infection Prevention (IP) program. This ID physician partnership is supported by professional organizations and predates the imperative of ID physician leadership in ASP. There are regulatory requirements for established IP programs, but don't specify leadership structure to the same degree as ASP regulations. The Centers for Medicare and Medicaid (CMS) and The Joint Commission (TJC) have specified the inclusion an ID trained physician leader in ASP, and this has led to the development of curriculum to train more ASP physicians (2). More robust advocacy may ensure a similar regulatory mandate supporting the participation of ID trained physicians in IP programs. This may encourage the development of a curriculum to meet the workforce. PMID- 30462185 TI - The Relative Impact of Community and Hospital Antibiotic Use on the Selection of Extended-Spectrum Beta-lactamase-Producing Escherichia coli. AB - Antibiotic stewardship programs have traditionally focused on reducing antibiotic use in hospital. However, reducing community antibiotic prescribing could have substantial impacts in both the hospital and community settings. We developed a deterministic model of transmission of ESBL-producing Escherichia coli in the community and hospital. We fit the model to existing national-level antibiotic use and resistance prevalence data from Sweden. Across a range of conditions, a given relative change in antibiotic use in the community had a greater impact on resistance prevalence in the community AND the hospital than an equivalent relative change in hospital use. However, on a per prescription basis, changes in antibiotic use in the hospital had the greatest impact. The magnitude of changes in prevalence were modest even with large changes in antimicrobial use. These data support expansion of stewardship programs/interventions beyond the walls of healthcare institutions, but also suggest that such efforts would benefit institutions themselves. PMID- 30462183 TI - Microglial phenotypes in the human epileptic temporal lobe. AB - Microglia, the immune cells of the brain, are highly plastic and possess multiple functional phenotypes. Differences in phenotype in different regions and different states of epileptic human brain have been little studied. Here we use transcriptomics, anatomy, imaging of living cells and ELISA measurements of cytokine release to examine microglia from patients with temporal lobe epilepsies. Two distinct microglial phenotypes were explored. First we asked how microglial phenotype differs between regions of high and low neuronal loss in the same brain. Second, we asked how microglial phenotype is changed by a recent seizure. In sclerotic areas with few neurons, microglia have an amoeboid rather than ramified shape, express activation markers and respond faster to purinergic stimuli. The repairing interleukin, IL-10, regulates the basal phenotype of microglia in the CA1 and CA3 regions with neuronal loss and gliosis. To understand changes in phenotype induced by a seizure, we estimated the delay from the last seizure until tissue collection from changes in reads for immediate early gene transcripts. Pseudotime ordering of these data was validated by comparison with results from kainate-treated mice. It revealed a local and transient phenotype in which microglia secrete the human interleukin CXCL8, IL-1B and other cytokines. This secretory response is mediated in part via the NRLP3 inflammasome. PMID- 30462186 TI - Voluntary Wheel Running Exercise Evoked by Food-Restriction Stress Exacerbates Weight Loss of Adolescent Female Rats But Also Promotes Resilience by Enhancing GABAergic Inhibition of Pyramidal Neurons in the Dorsal Hippocampus. AB - Adolescence is marked by increased vulnerability to mental disorders and maladaptive behaviors, including anorexia nervosa. Food-restriction (FR) stress evokes foraging, which translates to increased wheel running exercise (EX) for caged rodents, a maladaptive behavior, since it does not improve food access and exacerbates weight loss. While almost all adolescent rodents increase EX following FR, some then become resilient by suppressing EX by the second-fourth FR day, which minimizes weight loss. We asked whether GABAergic plasticity in the hippocampus may underlie this gain in resilience. In vitro slice physiology revealed doubling of pyramidal neurons' GABA response in the dorsal hippocampus of food-restricted animals with wheel access (FR + EX for 4 days), but without increase of mIPSC amplitudes. mIPSC frequency increased by 46%, but electron microscopy revealed no increase in axosomatic GABAergic synapse number onto pyramidal cells and only a modest increase (26%) of GABAergic synapse lengths. These changes suggest increase of vesicular release probability and extrasynaptic GABAA receptors and unsilencing of GABAergic synapses. GABAergic synapse lengths correlated with individual's suppression of wheel running and weight loss. These analyses indicate that EX can have dual roles-exacerbate weight loss but also promote resilience to some by dampening hippocampal excitability. PMID- 30462187 TI - Bias in the Intervention in Prediction Measure in Random Forests: Illustrations and Recommendations. AB - Motivation: Random forests (RF) are fast, flexible and have become a standard tool in bioinformatics, particularly because they provide variable importance measures (VIM), which can be used to identify relevant features or perform variable selection. A recent study uses RF original implementation to propose a new VIM in order to identify relevant Gene Ontology terms and compares them to another recently proposed VIM called intervention in prediction measure (IPM) as a strong baseline. However, theres is still little knowledge on how the IPM performs, especially in high-dimensional scenarios. Simulations show that the IPM can produce results as biased as the Gini impurity VIM and can produce spurious results. The bias can be reduced if RF are build using more recent and unbiased splitting criteria. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30462188 TI - Persistent low level viremia predicts subsequent virologic failure. Is it time to change the 3rd 90? AB - Background: World Health Organization (WHO) guidelines identify HIV viral load less than 1000 copies/mL as the goal of antiretroviral therapy (ART). However, the clinical implications of viremia below this threshold are unclear in the African context. We examined factors associated with persistent low level viremia (pLLV) and quantified the risk of subsequent virologic failure among participants with pLLV. Methods: The African Cohort Study enrolled HIV-infected adults at clinics in Uganda, Kenya, Tanzania, and Nigeria, with assessments every six months. We evaluated participants prescribed ART for at least six months without virologic failure for pLLV. We used multinomial logistic regression clustered on participant to evaluate associations between pre-specified factors of interest and three levels of pLLV (<200, 200-499, and 500-999 copies/mL). We used Anderson Gill extended Cox proportional hazards to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for viremia category associations with time to failure, adjusting for key confounders. Results: We included 1,511 participants with 4,382 person years of follow-up. PLLV <200 copies/mL was observed at 20% of visits while 2% of visits had pLLV 200-499 and 500-999 copies/mL each, with substantial variation by site. Protease inhibitor-containing ART was associated with increased risk of pLLV. Compared to undetectable viral load, pLLV >=200 copies/mL doubled the risk of developing virologic failure (HR: pLLV 200-499: 11.81, 95% CI: 1.08,3.02); pLLV 500-999: 22.36, 95% CI: 1.5252, 3.67). Conclusions: Participants with pLLV >=200 copies/mL were at increased risk of subsequent virologic failure. Optimized HIV care in this setting should target viral suppression <200 copies/mL. PMID- 30462189 TI - Holistic or Dedicated Approach in Lyme Disease? PMID- 30462190 TI - ProteomicsBrowser: MS/Proteomics Data Visualization and Investigation. AB - Summary: Large-scale, quantitative proteomics data are being generated at ever increasing rates by high-throughput, mass spectrometry technologies. However, due to the complexity of these large datasets as well as the increasing numbers of post-translational modifications (PTMs) that are being identified, developing effective methods for proteomic visualization has been challenging. ProteomicsBrowser was designed to meet this need for comprehensive data visualization. Using peptide information files exported from mass spectrometry search engines or quantitative tools as input, the peptide sequences are aligned to an internal protein database such as UniProtKB. Each identified peptide ion including those with PTMs are then visualized along the parent protein in the Browser. A unique property of ProteomicsBrowser is the ability to combine overlapping peptides in different ways to focus analysis of sequence coverage, charge state, or PTMs. ProteomicsBrowser includes other useful functions, such as a data filtering tool and basic statistical analyses to qualify quantitative data. Availability and implementation: ProteomicsBrowser is implemented in Java8 and is available at https://medicine.yale.edu/keck/nida/proteomicsbrowser.aspx and https://github.com/peng-gang/ProteomicsBrowser. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30462192 TI - Mistakes should be corrected.... PMID- 30462191 TI - High Prevalence of Active and Latent Tuberculosis in Children and Adolescents in Tibetan Schools in India: The Zero TB Kids Initiative in Tibetan Refugee Children. AB - Background: Tuberculosis prevalence is high among Tibetan refugees in India, with almost half of cases occurring in congregate facilities, including schools. A comprehensive program of tuberculosis case-finding, and diagnosis and treatment of TB infection (TBI) was undertaken in schools for Tibetan refugee children. Methods: Under the Zero TB Kids program, schoolchildren and staff in Tibetan schools in Himachal Pradesh, India, were screened for tuberculosis with an algorithm using symptom criteria, chest radiography, molecular diagnostics, and tuberculin skin tests. Individuals with active TB were treated and those with TBI were offered isoniazid-rifampicin preventive therapy for 3 months. Findings: From April 2017-March 2018, 5391 schoolchildren (median age: 13 years) and 786 staff in 11 Tibetan schools-7 boarding- and 4 day-schools-were screened for TB. Forty six TB cases, including one multidrug resistant, were found in schoolchildren, for a prevalence of 853/100,000. Extensively drug resistant-TB was diagnosed in one staff member. The majority of cases (66%) were subclinical. TBI was detected in 930/5234 (18%) schoolchildren and 334/634 (53%) staff who completed testing. Children in boarding-schools had a higher prevalence of TBI than children in day schools [915/5020 (18%) vs 15/371 (4%), p<0.01]. Preventive therapy was provided to 799 of 930 (86%) schoolchildren and 101 of 334 (30%) staff with TBI; 857 (95%) people successfully completed therapy. Interpretation: TB prevalence is extremely high among Tibetan schoolchildren. Active case finding using radiography, skin testing, and molecular diagnostics is effective. A high uptake and completion of preventive therapy for children was achieved. With leadership and community mobilization, TB control is implementable on a population level. PMID- 30462193 TI - Genome sequence of the non-conventional wine yeast Hanseniaspora guilliermondii UTAD222 unveils relevant traits of this species and of the Hanseniaspora genus in the context of wine fermentation. AB - Hanseanispora species, including H. guilliermondii, are long known to be abundant in wine grape-musts and to play a critical role in vinification by modulating, among other aspects, the wine sensory profile. Despite this, the genetics and physiology of Hanseniaspora species remains poorly understood. The first genomic sequence of a H. guilliermondii strain (UTAD222) and the discussion of its potential significance are presented in this work. Metabolic reconstruction revealed that H. guilliermondii is not equipped with a functional gluconeogenesis or glyoxylate cycle, nor does it harbours key enzymes for glycerol or galactose catabolism or for biosynthesis of biotin and thiamine. Also, no fructose-specific transporter could also be predicted from the analysis of H. guilliermondii genome leaving open the mechanisms underlying the fructophilic character of this yeast. Comparative analysis involving H. guilliermondii, H. uvarum, H. opuntiae and S. cerevisiae revealed 14 H. guilliermondii-specific genes (including five viral proteins and one beta-glucosidase). Furthermore, 870 proteins were only found within the Hanseniaspora proteomes including several beta-glucosidases and decarboxylases required for catabolism of biogenic amines. The release of H. guilliermondii genomic sequence and the comparative genomics/proteomics analyses performed, is expected to accelerate research focused on Hanseniaspora species and to broaden their application in the wine industry and in other bio-industries in which they could be explored as cell factories. PMID- 30462194 TI - Endoscopic dilatation improves long-term dysphagia following head and neck cancer therapies: a randomized control trial. AB - Long-term pharyngeal dysphagia is a common complication following head and neck cancer (HNC) therapies. High-level evidence for pharyngoesophageal junction (POJ) dilatation as a treatment in this population is lacking. We aimed to evaluate the safety and efficacy of POJ dilatation in dysphagic HNC survivors. This single center, single-blind, placebo-controlled trial (St George Hospital, Sydney, Australia) randomly assigned (1:1) HNC survivors with long-term dysphagia (>=12 months postcompleted HNC therapies) to receive either graded endoscopic dilatations or sham dilatation (placebo). Patients were blinded to intervention types. Two strata were used for permuted randomization: (1) HNC therapies (total laryngectomy vs. chemoradiation alone); (2) Prior POJ dilatation (nil vs. previous dilatation). The primary endpoint was a short-term clinical response in swallowing function (3 months), defined as (1) a decrease in Sydney Swallow Questionnaire score by >=200 or a score <= ULN; and (2) satisfactory global clinical assessment. The secondary endpoints were dysphagia relapse and serious adverse events. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617000707369). Between 13 January 2013 and 16 January 2017, 41 patients were randomly assigned to endoscopic dilatation (n = 21) or placebo (n = 20). The short-term response rate in the endoscopic dilatation group was 76% (n = 16), compared with 5% (n = 1) in the placebo group (P < 0.001). There were no serious adverse events. The finding of a mucosal tear postdilatation was associated strongly with clinical response (OR 13.4, 95% CI [2.4, 74.9], P = 0.003). Kaplan-Meier estimate of dysphagia relapse is 50% by 9.6 months (95% CI [6.0, 19.2]) from completion of dilatation. Endoscopic dilatation of the POJ is a safe and efficacious therapy for the treatment of long-term dysphagia in HNC survivors. Close follow-up and repeat dilatation are necessary given the high dysphagia relapse rate. PMID- 30462195 TI - Electroanatomical delimitation of recipient atrium in heart transplantation. PMID- 30462196 TI - Cardiovascular magnetic resonance can be undertaken in pregnancy and guide clinical decision-making in this patient population. AB - Aims: Cardiovascular disease is the leading cause of maternal morbidity and mortality, frequently requiring cardiac imaging for diagnosis, and follow-up. This need does not change pregnancy; however, many centres do not offer cardiovascular magnetic resonance (CMR) to pregnant patients. This paper explores current practice of CMR in pregnancy in four large volume centres, its safety and its impact on patient management. Methods and results: Between 2008 and 2017, we collected consecutive pregnant patients between four centres. Guidelines and local standard operating procedures were followed and outcomes recorded modelled on the EuroCMR registry. Eighty-three women had diagnostic CMR without immediate complications. The commonest indication was vascular or congenital disease (48%), followed by cardiomyopathy/myocarditis (43%). Nineteen percent received contrast, and CMR changed management in 35% and in 50% of patients who received contrast. Conclusion: In this largest cohort to date describing CMR in pregnancy, we found that results frequently change management, thus adding valuable guidance for patient care. We conclude that CMR should be offered to pregnant women when indicated, including the administration of contrast as per current guidelines. PMID- 30462197 TI - Suppression of prolactin secretion partially explains the anti-diabetic effect of bromocriptine in ob/ob mice. AB - Previous studies have shown that bromocriptine mesylate (Bromo) lowers blood glucose levels in adults with type 2 diabetes mellitus. However, the mechanism of action of the anti-diabetic effects of Bromo is unclear. As a dopamine receptor agonist, Bromo can alter brain dopamine activity affecting glucose control. However, Bromo also suppresses prolactin (Prl) secretion, and Prl levels modulate glucose homeostasis. Thus, the objective of the present study was to investigate whether Bromo improves insulin sensitivity via inhibition of Prl secretion. Male and female ob/ob animals (a mouse model of obesity and insulin resistance) were treated with Bromo and/or Prl. Bromo-treated ob/ob mice exhibited lower serum Prl concentration, improved glucose and insulin tolerance, as well as increased insulin sensitivity in the liver and skeletal muscle, compared to vehicle-treated mice. Prl replacement in Bromo-treated mice normalized serum Prl concentration without inducing hyperprolactinemia. Importantly, Prl replacement partially reversed the improvements in glucose homeostasis caused by Bromo treatment. The effects of the Prl receptor antagonist G129R-hPrl on glucose homeostasis were also investigated. We found that central G129R-hPrl infusion increased insulin tolerance of male ob/ob mice. In summary, our findings indicate that part of Bromo effects on glucose homeostasis are associated with decrease in serum Prl levels. Since G129R-hPrl treatment also improved the insulin sensitivity of ob/ob mice, pharmacological compounds that inhibit Prl signaling may represent a promising and novel therapeutic approach to control blood glucose levels in individuals with insulin resistance. PMID- 30462198 TI - Cryoablation with an 8-mm tip catheter cryoablation in the treatment of atrioventricular nodal re-entrant tachycardia: results from a randomized controlled trial (CRYOABLATE). AB - Aims: This was a randomized controlled study performed to compare 8 mm-tip catheter cryoablation (CRYO) with radiofrequency ablation (RFA) in treating atrioventricular nodal re-entrant tachycardia (AVNRT). Methods and results: A total of 158 patients (103 women, mean age 48.9 +/- 14.1) with symptomatic AVNRT (140 typical; 18 atypical) were randomized to undergo CRYO with an 8 mm-tip catheter (n = 80) or RFA (n = 78). The primary endpoint was a composite of acute procedural failure, inadvertent permanent atrioventricular block (AVB) and recurrence at 12 months. No significant difference was observed between CRYO and RFA groups in primary endpoint (7.5 vs. 11.5%; P = 0.764), 12-month recurrence rate (3.8 vs. 1.3%; P = 0.358), inadvertent permanent AVB (0 vs. 1.3%; P = 0.307), and acute procedural failure (3.7 vs. 9%; P = 0.128). In patients with acute procedure failure, success was achieved in 5 of 7 patients (71.4%) in RFA group and 2 of 3 patients (66.7%) in CRYO group on cross-over. There was no significant difference in procedural duration between CRYO and RFA groups (72.4 +/- 41.6 vs. 63.7 +/- 29.8 min; P = 0.13), but fluoroscopic duration in CRYO group was significantly shorter (3.4 +/- 6.3 vs. 6.7 +/- 7.4 min; P = 0.005). Patient pain score (2.7 +/- 2.7 vs. 4.6 +/- 2.7; P < 0.001) and operator stress score (2.3 +/- 1.3 vs. 4.9 +/- 2; P < 0.001) were significantly lower in CRYO group. Conclusions: Cryoablation with an 8 mm-tip catheter is shown to be comparable to RFA in treating AVNRT in terms of efficacy and safety. Additional advantages in CRYO include shorter fluoroscopic time, lower patient pain perception, and operator stress level. PMID- 30462199 TI - Detecting and correcting for bias in Mendelian randomization analyses using Gene by-Environment interactions. AB - Background: Mendelian randomization (MR) has developed into an established method for strengthening causal inference and estimating causal effects, largely due to the proliferation of genome-wide association studies. However, genetic instruments remain controversial, as horizontal pleiotropic effects can introduce bias into causal estimates. Recent work has highlighted the potential of gene environment interactions in detecting and correcting for pleiotropic bias in MR analyses. Methods: We introduce MR using Gene-by-Environment interactions (MRGxE) as a framework capable of identifying and correcting for pleiotropic bias. If an instrument-covariate interaction induces variation in the association between a genetic instrument and exposure, it is possible to identify and correct for pleiotropic effects. The interpretation of MRGxE is similar to conventional summary MR approaches, with a particular advantage of MRGxE being the ability to assess the validity of an individual instrument. Results: We investigate the effect of adiposity, measured using body mass index (BMI), upon systolic blood pressure (SBP) using data from the UK Biobank and a single weighted allelic score informed by data from the GIANT consortium. We find MRGxE produces findings in agreement with two-sample summary MR approaches. Further, we perform simulations highlighting the utility of the approach even when the MRGxE assumptions are violated. Conclusions: By utilizing instrument-covariate interactions in MR analyses implemented within a linear-regression framework, it is possible to identify and correct for horizontal pleiotropic bias, provided the average magnitude of pleiotropy is constant across interaction-covariate subgroups. PMID- 30462200 TI - No heart is an island: hypertrophic cardiomyopathy, diabetes, and the test of time. PMID- 30462201 TI - TL1A Aggravates Cytokine-Induced Acute Gut Inflammation and Potentiates Infiltration of Intraepithelial Natural Killer Cells in Mice. AB - Background: The tumor necrosis factor alpha (TNFalpha)-homologous cytokine TL1A is emerging as a major player in intestinal inflammation. From in vitro experiments on human lymphocytes, TNF-like molecule 1A (TL1A) is known to activate a highly inflammatory lymphoid response in synergy with interleukin (IL) 12 and IL-18. Carriers of specific genetic polymorphisms associated with IL-12, IL-18, or TL1A signaling have increased Crohn's disease risk, and all 3 cytokines are upregulated during active disease. The study aim was to investigate whether the type 1-polarizing cytokines IL-12 and IL-18 could directly initiate intestinal pathology in mice and how TL1A would influence the resulting inflammatory response. Methods: Conventional barrier-bred and germ-free mice were randomly allocated to different groups and injected twice with different combinations of IL-12, IL-18, and TL1A, and killed 3 days after the first injection. All treatment groups were co-housed and fed a piroxicam-supplemented chow diet. Results: Intestinal pathology was evident in IL-12- and IL-18-treated mice and highly exacerbated by TL1A in both the colon and ileum. The cytokine induced intestinal inflammation was characterized by epithelial damage, increased colonic levels of TNFalpha, IL-1beta, IFN-gamma, and IL-6, and various chemokines along with gut microbiota alterations exhibiting high abundance of Enterobacteriaceae. Furthermore, the inflamed ileum and colon exhibited a TL1A specific increased infiltration of intraepithelial natural killer cells co expressing NKG2D and IL-18Ra and a higher frequency of unconventional T cells in the colonic epithelium. Upon cytokine injection, germ-free mice exhibited similar intraepithelial lymphoid infiltration and increased colonic levels of IFNgamma and TNFalpha. Conclusions: This study demonstrates that TL1A aggravates IL-12- and IL-18-induced intestinal inflammation in the presence and absence of microbiota. PMID- 30462202 TI - Choosing Wisely Italy: online survey on opinions and behaviors of 1006 people and 355 volunteers of healthcare advocacy associations. AB - Background: In the framework of 'Doing more does not mean doing better - Choosing Wisely Italy' health professionals, general population and healthcare advocacy associations are widely involved. PartecipaSalute-Mario Negri IRCCS and Altronconsumo organized a survey in order to assess the opinions and behaviors of people toward unnecessary tests and drugs. Methods: An online survey was distributed by Altroconsumo to a voluntary panel of 6304 Italian citizens covering the whole of the country and by PartecipaSalute-Mario Negri IRCCS through the PartecipaSalute website, e-mail lists, website articles, lay journals and Facebook. Results: In all 1006 people reached by Altroconsumo, and 355 volunteers of healthcare advocacy associations reached by PartecipaSalute responded. Respondents usually decides on their treatment together with the physician, respectively 50% for general population and 64% for volunteers of healthcare advocacy associations. The respondents are aware of the question of over-use of drugs and tests (80%), more often among the volunteers of healthcare advocacy associations (86%). Over-use is considered a problem mostly for economic reasons among the general population, while in the advocacy associations the risks for patients' health is considered more important. Conclusion: These findings suggest that patients do not always ask for more, especially if they receive an answer to their questions and clarifications about unnecessary treatments. There is a need for further understanding of the factors influencing decision-making aimed at achieving good care. Engaging the public and patients at all levels of healthcare is essential for a valuable use of health resources. PMID- 30462203 TI - A widely compatible expression system for the production of highly O-GlcNAcylated recombinant protein in Escherichia coli. AB - O-GlcNAcylation is a ubiquitous and dynamic post-translational modification on serine/threonine residues of nucleocytoplasmic proteins in metazoa, which plays a critical role in numerous physiological and pathological processes. But the O GlcNAcylation on most proteins is often substoichiometric, which hinders the functional study of the O-GlcNAcylation. This study aimed to improve the production of highly O-GlcNAcylated recombinant proteins in Escherichia coli (E. coli). To achieve this goal, we constructed a bacterial artificial chromosome based chloramphenicol-resistant expression vector co-expressing O-GlcNAc transferase (OGT) and key enzymes (phosphoglucose mutase, GlmM and N acetylglucosamine-1-phosphate uridyltransferase, GlmU) of the uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) synthesis pathway in E. coli, which can effectively increase the O-GlcNAcylation of the OGT target protein expressed by another vector. The results revealed that the expression of GlmM and GlmU increases the cellular concentration of UDP-GlcNAc in E. coli, which markedly enhanced the activity of the co-expressed OGT to its target proteins, such as H2B, p53 and TAB1. Altogether, we established a widely compatible E. coli expression system for producing highly O-GlcNAcylated protein, which could be used for modifying OGT target proteins expressed by almost any commercial expression vectors in E. coli. This new expression system provides possibility for investigating the roles of O-GlcNAcylation in the enzymatic activity, protein protein interaction and structure of OGT target proteins. PMID- 30462205 TI - Person-Based Brain Morphometric Similarity is Heritable and Correlates With Biological Features. AB - The characterization of the functional significance of interindividual variation in brain morphometry is a core aim of cognitive neuroscience. Prior research has focused on interindividual variation at the level of regional brain measures thus overlooking the fact that each individual brain is a person-specific ensemble of interdependent regions. To expand this line of inquiry we introduce the person based similarity index (PBSI) for brain morphometry. The conceptual unit of the PBSI is the individual person's brain structural profile which considers all relevant morphometric measures as features of a single vector. In 2 independent cohorts (total of 1756 healthy participants), we demonstrate the foundational validity of this approach by affirming that the PBSI scores for subcortical volume and cortical thickness in healthy individuals differ between men and women, are heritable, and robust to variation in neuroimaging parameters, sample composition, and regional brain morphometry. Moreover, the PBSI scores correlate with age, body mass index, and fluid intelligence. Collectively, these results suggest that the person-based measures of brain morphometry are biologically and functionally meaningful and have the potential to advance the study of human variation in multivariate brain imaging phenotypes in healthy and clinical populations. PMID- 30462206 TI - Angiopoietin like-4 as a novel vascular mediator in capillary cerebral amyloid angiopathy. AB - Increasing evidence suggests that vascular dysfunction in the brain is associated with early stages of Alzheimer's disease. Amyloid-beta deposition in the microvasculature of the brain, a process referred to as capillary cerebral amyloid angiopathy (capillary CAA), propagates vascular remodelling, which results in impaired function of the blood-brain barrier, reduced cerebral perfusion and increased hypoxia. While improving vascular function may be an attractive new way to fight capillary CAA, the underlying factors that mediate vascular alterations in Alzheimer's disease and capillary CAA pathogenesis remain largely unknown. Here we provide first evidence that angiopoietin like-4 (ANGPTL4), a hypoxia-induced factor, is highly expressed by reactive astrocytes in well characterized post-mortem tissues of patients with capillary CAA. Our in vitro studies reveal that ANGPTL4 is upregulated and secreted by human cortical astrocytes under hypoxic conditions and in turn stimulates endothelial cell migration and sprouting in a 3D spheroid model of human brain endothelial cells. Interestingly, plasma levels of ANGPTL4 are significantly increased in patients with vascular dementia compared to patients with subjective memory complaints. Overall, our data suggest that ANGPTL4 contributes to pathological vascular remodelling in capillary CAA and that detection of ANGPTL4 levels may improve current diagnostics. Ways of counteracting the detrimental effects of ANGPTL4 and thus promoting cerebral vascular function may provide novel treatment regimens to halt the progression of Alzheimer's disease. PMID- 30462207 TI - Comparison of electrocardiogram characteristics and pacing parameters between left bundle branch pacing and right ventricular pacing in patients receiving pacemaker therapy. AB - Aims: This study explores the feasibility of left bundle branch pacing (LBBP) and characterizes electrocardiogram (ECG) patterns during the pacing in comparison with conventional right ventricular pacing (RVP). Methods and results: Forty pacing-indicated patients were prospectively enrolled. Twenty patients underwent LBBP (the LBBP group), and 20 patients underwent RVP (the RVP group). Left bundle branch pacing was achieved by transseptal method in the basal ventricular septum. Electrocardiogram characteristics, pacing parameters, pacing sites, and safety events were assessed at implantation and 3-month follow-up. In the LBBP group, the pacing lead was successfully placed near the endocardium of the left side of the septum. Electrocardiogram pattern during LBBP showed right bundle branch conduction delay. Left bundle branch block (LBBB) in two patients was corrected by LBBP. Post-implantation 3D echocardiography confirmed the pacing location. In the RVP group, ECG showed LBBB pattern. The paced QRS duration was 111.85 +/- 10.77 ms in LBBP group and 160.15 +/- 15.04 ms in the RVP group (P < 0.001). Pacing thresholds (at implantation: 0.73 +/- 0.20 V in the LBBP group and 0.61 +/ 0.23 V in the RVP group) remained low and stable at 3-month follow-up. No adverse event was observed during 3-month follow-up. Conclusion: This study demonstrates the clinical feasibility of LBBP. Left bundle branch pacing that has a low pacing threshold and produces narrow ECG QRS duration may be a new pacing strategy for patients in need of ventricular pacing. PMID- 30462208 TI - Atrial fibrillation burden, progression, and the risk of death: a case-crossover analysis in patients with cardiac implantable electronic devices. AB - Aims: Atrial fibrillation (AF) is associated with increased mortality, but the temporal relationship between AF burden (AFB) and death among patients with cardiac implanted electronic devices is unknown. We sought to characterize the timing and progression of AFB before death. Methods and results: Using Merlin.netTM remote monitoring (RM) data, we analysed weekly AFB in patients age >=55 years implanted with dual-chamber pacemaker, implantable cardioverter defibrillator, or cardiac resynchronization therapy devices whose death was verified in the Social Security Death Index and who had continuous RM from 1 year to 4 weeks preceding death. Atrial fibrillation burden was defined as amount of time per week atrial rate exceeded a set threshold of 180 b.p.m. Case-crossover analysis was used to compare the AFB at every week to 6 control weeks at the start of the year before death. There were 3131 patients meeting analysis criteria (age at death 76 +/- 8 years, 70% men). Weekly increase in AFB >6 h was associated with increased odds of death, which was greatest at 4 weeks before death [odds ratio (OR) 2.30, 95% confidence interval (CI) 2.09-2.53; P < 0.001]. Atrial fibrillation progression week-to-week >24 h was associated with the greatest odds of death (OR 12.95, 95% 8.72-19.22; P < 0.001). A combination of AFB >6 h per week and activity <0.5 h per day was associated with an increased odds of death. Conclusion: In this large patient cohort, AFB progression accelerated in the weeks leading to death. Continuous monitoring of AFB may help identify device patients who may be at risk for adverse outcomes, including death. PMID- 30462209 TI - Adipocyte-specific GH receptor null (AdGHRKO) mice have enhanced insulin sensitivity with reduced liver triglycerides. AB - Global GH receptor null or "knockout" (GHRKO) mice have been extensively studied due to their unique phenotype (dwarf and obese but remarkably insulin sensitive and long-lived). To better understand the influence of adipose tissue (AT) on the GHRKO phenotype, we previously generated Fat-specific GHRKO (FaGHRKO) mice using the aP2 promoter driving Cre expression. Unlike global GHRKO mice, FaGHRKO mice are larger than control mice and have an increase in white AT (WAT) mass and adipocyte size as well as an increase in brown AT (BAT) mass. FaGHRKO mice also have an unexpected increase in IGF-1, decrease in adiponectin, no change in insulin sensitivity or liver triglyceride content, and a decreased lifespan. Extensive analysis of the aP2 promoter/enhancer by multiple laboratories has revealed expression in non-adipose tissues, confounding interpretation of results. In the current study, we used the adiponectin promoter/enhancer to drive Cre expression, which better targets mature adipocytes and generated a new line of adipocyte-specific GHRKO (AdGHRKO) mice. AdGHRKO mice have an increase in adipocyte size and WAT depot mass in all depots except male perigonadal, a WAT accumulation pattern similar to FaGHRKO mice. Likewise, adiponectin levels and WAT fibrosis are decreased in both tissue-specific mouse lines. However, unlike FaGHRKO mice, AdGHRKO mice have no change in IGF-1 levels, improved glucose homeostasis, and reduced liver triglycerides. Thus, AdGHRKO mice should be valuable for future studies assessing the contribution of adipocyte GHR signaling in long-term health and lifespan. PMID- 30462210 TI - Dangerous encounters: triggers of fatal ventricular arrhythmias and safety of interventional treatment strategies. PMID- 30462211 TI - One hundred and fifty years ago Charcot reported multiple sclerosis as a new neurological disease. PMID- 30462212 TI - Perceptions of Seasonal Influenza and Pneumococcal Vaccines Among Older Chinese Adults. AB - Background and Objectives: Seasonal influenza can lead to pneumonia. In Hong Kong, deaths from pneumonia increased steadily from 2001 to 2015, and pneumonia was the second most common cause of death between 2012 and 2015. The seasonal influenza vaccine and pneumococcal vaccine have been clinically proven as effective measures against these two diseases among older adults, who are at particularly high risk. Despite the availability of vaccine subsidies, however, more than 60% of older adults in Hong Kong remain unvaccinated against pneumococcal diseases and seasonal influenza. The objective of this study was to investigate the perceptions and barriers associated with the seasonal influenza and pneumococcal vaccinations among older adults in Hong Kong. Research Design and Methods: A qualitative approach of individual semistructured interviews was adopted; 40 adults aged 65 years and older were interviewed between September and November 2016. Results: The intersecting influences of belief of vaccines as harmful, low perceived risk of contracting the diseases, negative rumors about the vaccines, lack of promotion by health care providers, the perceived risk posed by the vaccinating locations, and the preference of using traditional Chinese medicine were discovered to prevent the participants from receiving the two vaccinations. Discussion and Implications: Perceptions and cultural factors should be considered in future vaccination promotion among older adults. This study found that, in particular, the participants' cultural associations and stereotypes of hospitals and clinics and health care providers' lack of perceived need to vaccinate older adults contributed to low vaccine acceptance among the participants. PMID- 30462213 TI - Association of hypertension cut-off values with 10-year cardiovascular mortality and clinical consequences: a real-world perspective from the prospective MONICA/KORA study. AB - Aims: To investigate the clinical value of a lower blood pressure (BP) cut-off for Stage 1 (S1) hypertension (130-139 mmHg systolic or 80-89 mmHg diastolic) in comparison to the currently established Stage 2 (S2) cut-off (>=140/90 mmHg) in a population-based cohort. Methods and results: We assessed the hypertension prevalence and associated cardiovascular disease (CVD) events in a sample of 11 603 participants (52% men, 48% women; mean 47.6 years) from the MONICA/KORA prospective study. The implementation of the new S1 cut-off increased the prevalence of hypertension from 34% to 63%. Only 24% of S2 hypertension patients were under treatment. Within a follow-up period of 10 years (70 148 person years), 370 fatal CVD events were observed. The adjusted CVD-specific mortality rate per 1000 persons was 1.61 [95% confidence interval (CI) 1.10-2.25] cases in S2 and 1.07 (95% CI 0.71-1.64) cases in S1 hypertension in comparison to normal BP. Cox proportional regression models were significant for the association of S2 and CVD mortality (1.54, 95% CI 1.04-2.28, P = 0.03), also in the presence of competing risks (1.47, P = 0.05). However, statistical significance for S1 hypertension was not reached (0.93, 95% CI 0.61-1.44, P = 0.76). Among S2 participants, there was a significantly higher prevalence of depressed-mood in treated patients (47%) in comparison to non-treated patients (33%) (P < 0.0001). Conclusion: The lower BP cut-off substantially increased hypertension prevalence, while capturing a population with lower CVD mortality. Additionally, participants under treatment were more likely to have depressed-mood in comparison to non treated participants, which might reflect a negative labelling effect. PMID- 30462214 TI - Atrial fibrillation in heart failure syndromes: does it matter more in some than in others? PMID- 30462215 TI - Respiratory syncytial virus F and G proteins core fragments fused to HBsAg binding protein (SBP) induce Th1 dominant immune response without vaccine enhanced disease. AB - The induction of a dominant Th2-type response is the main cause of harmful inflammation in respiratory syncytial virus (RSV) vaccines trials. A balanced Th1 versus Th2 immune response is needed for a safe and effective RSV vaccine. In this study, we evaluated the potential of a recombinant protein SBP-FG as vaccine candidate with main focus on shifting the harmful Th2 response to Th1 response. SBP-FG consists of epitopes from RSV fusion (F) and attachment (G) proteins conjugated to the N-terminal of HBsAg-binding protein (SBP). SBP-FG induced significantly stronger immune responses assessed at the level of total IgG, IgA and neutralizing antibodies as compared to formalin inactivated-RSV (FI-RSV) and live RSV. Analysis of IgG isotypes, lungs cytokines and T helper cells showed that SBP-FG induced dominant Th1-type response. Further, SBP-FG immunized mice showed significantly reduced lungs eosinophilia, reduced viral replication in lungs after challenge infection and provided protection against RSV infection. These results suggest that SBP-FG can be developed into a safe and effective vaccine against RSV. However, more studies are required to further evaluate SBP FG as a potent vaccine candidate against RSV. PMID- 30462216 TI - Quantification of Trace Elements in Different Dokha and Shisha Tobacco Products using EDXRF. AB - The present study aims to quantify trace metals in different dokha (medwakh) and shisha tobacco products available in local markets. Recent research has shown that these products have higher amounts of nicotine and tar compared to various other tobacco products. No specific data are available on the concentration of trace elements in dokha (medwakh) and shisha tobacco products in the Middle East and North Africa (MENA) region. Harmful health effects due to the toxicity of these elements in tobacco and its smoke have not been adequately emphasized. Concentrations of trace elements were extensively studied using HORIBA XGT-7200 EDXRF fluorescence absorption spectroscopy. The mean concentrations of aluminum, calcium, chromium, copper, iron, magnesium, manganese, nickel, potassium, strontium and zinc in 13 dokha products in MUg/g were 406.92 +/- 41.72, 14703.27 +/- 271.73, 11.73 +/- 2.12, 25.58 +/- 2.63, 753.85 +/- 14.87, 5306.54 +/- 134.94, 82.31 +/- 4.55, 25.58 +/- 2.50, 2212.12 +/- 39.04, 816.92 +/- 15.26 and 35.96 +/- 2.63, respectively; and those in the three shisha products in MUg/g were 244.83 +/- 25.11, 8235.77 +/- 144.51, 3.40 +/- 0.38, 22.77 +/- 4.50, 569.13 +/- 10.22, 2096.20 +/- 130.69, 72.13 +/- 7.13, 27.67 +/- 5.31, 4467.50 +/- 168.06, 320.20 +/ 6.03 and 36.40 +/- 3.57, respectively. In our study, the quantified trace metal concentrations in dokha and shisha tobacco using the EDXRF method were ten times higher than the LODs. The percentage of RSD was <10%, validating the precision of the method. Tobacco smoking is a major source of consumption of toxic elements, not only in the smoker but also in non-smokers through passive smoking. In dokha (medwakh) and shisha tobacco products, compared with cigarettes, Ni levels were significantly higher, Cr, Cu and Zn levels were higher, and Fe levels were similar, while Al and Mn levels were lower. The dokha and shisha tobacco products have no filters; many toxic metals can quickly enter the lungs and cause different pulmonary diseases and oral infections. Tobacco smoking causes lung and oral cancers, chronic obstructive pulmonary disease and cardiovascular diseases. PMID- 30462217 TI - Dynamic transcriptomic analysis reveals suppression of PGC1alpha/ERRalpha drives perturbed myogenesis in facioscapulohumeral muscular dystrophy. AB - Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable myopathy, linked to epigenetic de-repression of D4Z4 repeats on chromosome 4q, leading to ectopic DUX4 expression. FSHD patient myoblasts have defective myogenic differentiation, forming smaller myotubes with reduced myosin content. However, molecular mechanisms driving such disrupted myogenesis in FSHD are poorly understood. We performed high-throughput morphological analysis describing FSHD and control myogenesis, revealing altered myogenic differentiation results in hypotrophic myotubes. Employing polynomial models and an empirical Bayes approach, we established eight critical time-points during which human healthy and FSHD myogenesis differ. RNA-sequencing at these eight nodal time-points in triplicate, provided temporal depth for a multivariate regression analysis, allowing assessment of interaction between progression of differentiation and FSHD disease status. Importantly, the unique size and structure of our data permitted identification of many novel FSHD pathomechanisms undetectable by previous approaches. Selected for further analysis here, were pathways that control mitochondria: of interest considering known alterations in mitochondrial structure and function in FSHD muscle, and sensitivity of FSHD cells to oxidative stress. Notably, we identified suppression of mitochondrial biogenesis, in particular via PGC1alpha, the co-factor and activator of ERRalpha. PGC1alpha knock-down caused hypotrophic myotubes to form from healthy myoblasts. Known ERRalpha agonists and safe food supplements Biochanin A, Genistein or Daidzein, each rescued the hypotrophic FSHD myotube phenotype. Together our work describes transcriptomic changes in high resolution that occur during myogenesis in FSHD ex vivo, identifying suppression of the PGC1alpha-ERRalpha axis leading to perturbed myogenic differentiation, which can effectively be rescued by readily-available food supplements. PMID- 30462218 TI - Poor mothers, unhealthy children: the transmission of health inequalities in the INMA study, Spain. AB - Background: The health of pregnant women and their fetuses are especially sensitive to socioeconomic conditions. This study analyzes the impact of maternal socioeconomic status (SES), evaluated by occupation and maternal education level, in preterm births (PTBs) and in small for gestational age (SGA) fetuses, considering the effect of the potential mediating factors on the SES and birth outcomes. Methods: A total of 2497 mother/newborn dyads from the INMA-Spain project were studied. We examined maternal occupation and education in relation to PTB and SGA along with covariate data, using logistic regression analysis. Adjusted models for each of the outcome variables in relation to SES indicators were estimated, considering potential mediating factors. Results: About 4.7% of babies were PTB and 9.7% SGA. Full adjusted logistic regression models showed similar odds ratio (OR) for SGA in both SES indicators. Manual working women or without university studies had higher risk of SGA than their counterpart groups (OR = 1.39% CI = 1.03-1.88 and OR = 1.39% CI = 1.00-2.00, respectively). Likewise, mothers with a manual occupation were at more risk of PTB than those with a non-manual occupation (OR = 1.74 95% CI = 1.13-2.74), but there was no association between education and PTB. Smoking, pre-pregnancy BMI and underweight gain during pregnancy were significantly associated to SGA births. The mother's age, presence of complications and overweight gain during pregnancy were related to PTB. Conclusion: The mother's socioeconomic disadvantage was consistently associated with birth outcomes giving rise to intergenerational transmission of health inequalities. Reducing inequalities requires eliminating the upstream causes of poverty itself. PMID- 30462219 TI - Feeding distillers grains to cattle may affect beef tenderness early postmortem. AB - The objective of this study was to evaluate the effects of dietary fat source with modified distillers grains plus solubles (MDGS) on beef tenderness through examination of sarcoplasmic reticulum (SR) membrane fatty acid composition, changes in sarcoplasmic calcium concentration, Warner-Bratzler shear force (WBSF), sarcomere length, and proteolysis early postmortem. Steers (n=256) were fed for 134 d on either corn, or a diet containing 40% full-fat MDGS, 40% de oiled MDGS, or 38% de-oiled MDGS plus 2% corn oil. Twenty-four USDA Choice carcasses (3 carcasses/pen; 8 pens/treatment) were selected within each dietary treatment and strip loins were collected and aged for 2, 9, 16, or 23 d postmortem and subject to retail display (RD) for an additional 7 d. Feeding MDGS increased (P < 0.05) concentrations of linoleic acid (18:2) and tended to increase (P = 0.06) total polyunsaturated fatty acids (PUFA) in the SR membrane. Steaks from cattle fed MDGS had greater sarcoplasmic calcium concentration than steaks from cattle fed corn at d 2 postmortem (P = 0.05). Steaks from steers fed de-oiled MDGS and de-oiled MDGS plus corn oil tended to have lower WBSF values (P = 0.08) than steaks from cattle fed corn at 2 d of aging with 0 d of RD. There were no differences among dietary treatments for sarcomere length (P = 0.92) and troponin-T degradation at 2 d postmortem (P = 0.60). Results suggest that feeding MDGS may increase early-postmortem release of calcium into the sarcoplasm due to increased 18:2 and PUFA concentration in the SR membrane, which could result in increased beef tenderness early-postmortem. PMID- 30462220 TI - Edoxaban and implantable cardiac device interventions: insights from the ENGAGE AF-TIMI 48 trial. AB - Aims: Pacemaker, implantable cardioverter-defibrillator, and cardiac resynchronization therapy device implantations and generator changes are frequently performed in patients receiving direct oral anticoagulants. In an exploratory analysis, we investigated the outcome of patients undergoing such device procedures in the ENGAGE AF-TIMI 48 trial. Methods and results: During the trial, 1217 device procedures were performed in 1145 patients, with intervention dates available for 1203 procedures. Two hundred and twenty-five procedures (in 212 patients) were performed >30 days after study drug was stopped and are not included in the event analysis. For most interventions (n = 728, 74%), study drug was interrupted >3 days (median for the entire cohort: 5 days, interquartile range 0-11 days); 250 interventions were performed with <=3 days study drug interruption. During the first 30 days after the procedure, six strokes/systemic embolic events (SEEs) (three each in the lower-dose edoxaban and warfarin arm) and one major bleeding event (in the lower-dose edoxaban arm) occurred; no stroke/SEEs or major bleeds occurred around the 295 device procedures in the higher-dose edoxaban arm. Two ischaemic and one major bleeding event occurred after the 288 device procedures performed with <=3 days periprocedural interruption of study drug. Conclusion: In this first experience of patients undergoing device surgery with edoxaban, a low risk of ischaemic and bleeding events was observed during the first 30 days post-procedure. Our data are in line with current recommendations of no or only brief interruption of non-vitamin K antagonist oral anticoagulants prior to cardiac device surgery. PMID- 30462221 TI - How does managed competition affect hospital prices in a social health insurance system? The Colombian case. AB - This paper studies the effect on hospital service prices of a health system reform that allows managed selective contracting and regulation as a means for efficiency and price competition. Cross-sectional data about prices and market structure were analysed from a pool of 20 markets which includes 15 million Colombians. A multilevel regression method comparing three different market settings was performed. The analysis evaluates the effects of insurer choice, hospital quality and market characteristics using a nationwide health services transactional database. A Hirshmann-Herfindahl index was applied to evaluate the markets concentration. Among the results, bilateral monopolies were made evident, both in insurance and hospital markets. Insurer selective contracting policy has the greatest impact on pricing with hospital monopoly heavy effect on health service prices. Colombian government has a challenge in regulating managed competition in order to maintain competition and access to healthcare. Health reforms using market competition as a mechanism for efficiency should follow closely health services market evolution in order to introduce effective regulatory policies. PMID- 30462222 TI - The value of echocardiographic examination in predicting right ventricular heart failure in patients after the implantation of continuous-flow left ventricular assist devices. AB - The number of implanted left ventricular assist devices is increasing systematically. Novel systems are being introduced and survival rates are improving, but complications, such as heart failure, leading to high early and late mortality still exist. Echocardiography is the preferred method for assessing the anatomy and function of the right ventricle (RV). In spite of the many methods available for use, including 2- and 3-dimensional techniques, assessment of the RV remains challenging. In this review, we present echocardiographic parameters that are most often used to assess right ventricular anatomy and function, and analyse their ability to predict right heart failure after the implantation of a left ventricular assist device. PMID- 30462223 TI - Comparison of Temperature-Dependent Survivorship and Wood-Consumption Rate Among Two Invasive Subterranean Termite Species (Blattodea: Rhinotermitidae: Coptotermes) and Their Hybrids. AB - Two invasive subterranean termite species, Coptotermes formosanus Shiraki and Coptotermes gestroi Wasmann (Blattodea: Rhinotermitidae), established in South Florida have the potential to hybridize owing to their sympatric distribution, overlapping dispersal flight seasons, and interspecies mating behavior. This study examined the effects of temperature on survivorship and wood-consumption rate (WCR) to determine the potential of such hybrid termites as structural pests. Temperature tolerance was tested using groups of termites from incipient colonies established in the laboratory with four mating types (?C. gestroi * ?C. gestroi, ?C. formosanus * ?C. formosanus, ?C. gestroi * ?C. formosanus, ?C. formosanus * ?C. gestroi) in glass screw-top jars placed in incubators at 10, 15, 22, 28, and 35 degrees C in constant darkness for 28 d. Results showed that hybrid termites have a temperature tolerance covering those of both parental species and survived at 15-35 degrees C. WCR was not significantly different among the four mating types, but the WCR in the temperature range of 22-35 degrees C was significantly higher than at temperatures ranging from 10 to 15 degrees C for all mating types. Our results suggest that the potential distribution of the hybrid populations may cover most of the range of both parental species, i.e., 32.5 degrees N and 23.5 degrees S, and they can be as damaging as their parental species, the two most destructive termite pests, C. formosanus and C. gestroi. PMID- 30462224 TI - Response: Mechanism of intermittent PQ prolongation. PMID- 30462225 TI - A Liquid-Chromatography High-Resolution Mass Spectrometry Method for Non-FDA Approved Benzodiazepines. AB - Benzodiazepines (BZDs) are widely used for treatment of anxiety and insomnia, however, this class of drugs is also commonly abused. Many different BZDs and analogs have been produced that are not FDA-approved. We tested 15 of these with the ThermoFisher CEDIA(r) BZD-immunoassay. With the exception of ketazolam, all compounds showed significant reactivity, highlighting the need for mass spectrometry confirmation assays. We developed a liquid-chromatography high resolution mass spectrometry method for the detection of these 15 non-FDA approved BZDs. The limit of detection for most compounds ranged from 1 to 50 ng/mL, with mostly positive matrix effects observed in urine and negative matrix effects in serum. In a clinical research case, clonazolam and etizolam were detected in serum at 10.2 and 281 ng/mL, with an apparent elimination half-life of 3.6 and 4.8 hours, respectively. Although we did not detect non-FDA approved BZDs in 211 urine samples that were previously determined to be BZD-positive by immunoassay, abuse of these drugs is on the rise and clinical and forensic toxicology laboratories should consider developing methods to detect them. PMID- 30462227 TI - Determination of chemical composition, energy content and amino acid digestibility in different wheat cultivars fed to growing pigs. AB - This study was conducted to determine the DE, ME, and apparent (AID) and standardized ileal digestibility (SID) of AA in different wheat cultivars fed to growing pigs. In Exp. 1, twelve crossbred growing barrows were allotted to a replicated 6 * 6 Latin square designs to determine the DE and ME contents of 12 different wheat cultivars. In Exp. 2, twelve growing barrows with a simple T cannula were used to determine the AID and SID of AA in 10 different wheat cultivars. Pigs were randomly allotted to a replicated 6 * 6 Latin square design and fed one nitrogen-free diets and 10 different cultivars of wheat diets. Among different wheat cultivars, the concentrations of GE, CP, NDF, ADF, and starch ranged from 4,385 to 4,458 kcal/kg, 12.95 to 18.14%, 9.16 to 13.89%, 1.93 to 2.92% and 60.81 to 70.77%, respectively (DM basis). There were significant differences (P < 0.05) in the DE, ME values, and the ATTD of GE in 12 different cultivars of wheat in Exp. 1. The DE and ME contents and the ATTD of GE ranged (P < 0.05) from 3,922 to 4,067 kcal/kg DM, 3,759 to 3,941 kcal/kg DM and 88.14 to 90.31%, respectively. The best prediction equations of DE and ME for different cultivars of wheat cultivars were DE = - 2,738 - (40.8 * % ADF) + (1.7 * GE) - (51.5 * % Xylans) - (95.7 * % Ash) + (22.3 * % EE), R2= 0.98, and ME = -2,990 + (1.7 * GE) - (50.2 * % Xylans) - (87.6 * % Ash), R2= 0.88, respectively. There were also differences (P < 0.05) in the AID and SID of CP and indispensable AA, expect for His, in 10 wheat cultivars in Exp. 2. The AID and SID of CP, Lys, and Met ranged (P < 0.05) from 82.02 to 89.46%, 74.13 to 84.73%, 87.35 to 92.49% and 87.56 to 94.04%, 80.56 to 89.89%, 89.56 to 94.45%, respectively. In conclusion, the chemical composition, energy contents, and most AA digestibility in different cultivars of wheat varied widely. PMID- 30462226 TI - Pheochromocytoma Characteristics and Behavior Differ Depending on Method of Discovery. AB - Context: Modern pheochromocytomas (PHEO) are often discovered by incidental finding on cross-sectional imaging or mutation-based genetic case detection testing. Little information is known about how these PHEO behave. Objective: To describe the characteristics and behavior of PHEO discovered incidentally on imaging or through mutation-based genetic case detection testing. Design: Retrospective study. Setting: Referral center. Patients: Consecutive patients with pathology-confirmed PHEO, treated from 2005-2016. Main outcome measure(s): tumor size, plasma/urine fractionated metanephrines and catecholamines, pre operative management. Results: 271 patients (52% women, median age 52.0 years) presented with a 296 PHEOS. Discovery method was most often incidental finding on cross section imaging (61%) rather than PHEO-related symptoms (27%) or mutation based case detection testing (12%). Patients with incidentally discovered PHEO were older than symptomatic and mutation-based case detection testing patients (median age 56.6 vs. 43 vs. 35 years, P<.0001.) Mutation-based case detection PHEOs were smaller than those discovered due to symptoms (median size 29.0 vs. 50.5 mm, P=.0027). Patients with PHEO discovered due to symptoms had the highest median concentration of 24-hour urinary metanephrines and total plasma metanephrines (P<.0001). These patients required a higher cumulative phenoxybenzamine dose than patients with incidental or case detection PHEO (median 450 vs. 375 vs. 270 mg, P=.029). Conclusions: PHEO are primarily discovered due to incidental finding on cross-sectional imaging rather than PHEO related symptoms. PHEO discovered due to mutation-based genetic case detection testing were smaller and required less alpha-adrenergic blockade pre-operatively compared to PHEO found due to symptoms, which supports routine case detection testing for patients genetically pre-disposed for PHEO. PMID- 30462228 TI - Biomarkers of Exposure to Pyrimethanil After Controlled Human Experiments. AB - Pyrimethanil (PYM) is a fungicide used pre- and post-harvest on many crops. It has a low acute toxicity but is of toxicological concern because of its antiandrogenic properties. The aim of the current work was to investigate some metabolism and estimate elimination kinetics of PYM in humans after experimental oral and dermal exposure. A liquid chromatography triple quadrupole mass spectrometry (LC-MS-MS) method was developed and validated for the analysis of PYM and its metabolite 4-hydroxypyrimethanil (OH-PYM) in human urine. The method was applied to analyze urine obtained from two volunteers experimentally exposed to PYM. The elimination of OH-PYM seemed to follow first-order kinetics and a two phase excretion. After the oral exposure, the elimination half-life of OH-PYM in the rapid phase was 5 and 3 h for the female and male volunteer, respectively. In the slower phase, it was 15 h in both volunteers. After the dermal exposure, the half-life in the rapid phase was 8 h in both volunteers. In the slower phase, it was 30 and 20 h, respectively. About 80% of the oral dose was recovered as urinary OH-PYM in both volunteers. The dermal dose recovered as urinary OH-PYM was 9.4% and 19%, in the female and male volunteer, respectively. OH-PYM was mainly found as a conjugate of sulfonate and glucuronic acid. No free PYM was found. The analytical method showed good within-run, between-run and between batch precision with a coefficient of variation between 6% and 12%. A limit of detection of 0.1 ng/mL and a limit of quantification of 0.4 ng/mL were achieved for both the analytes. The method was applied to biomonitor PYM exposure in populations in Sweden. OH-PYM was detected in nearly 50% and 96% of samples from the environmentally and occupationally exposed populations, respectively. PMID- 30462229 TI - Determination of Fentanyl Analog Exposure Using Dried Blood Spots with LC-MS-MS. AB - Fentanyl, and the numerous drugs derived from it, are contributing to the opioid overdose epidemic currently underway in the USA. To identify human exposure to these growing public health threats, an LC-MS-MS method for 5 MUL dried blood spots (DBS) was developed. This method was developed to detect exposure to 3 methylfentanyl, alfentanil, alpha-methylfentanyl, carfentanil, fentanyl, lofentanil, sufentanil, norcarfentanil, norfentanyl, norlofentanil, norsufentanil, and using a separate LC-MS-MS injection, cyclopropylfentanyl, acrylfentanyl, 2-furanylfentanyl, isobutyrylfentanyl, ocfentanil and methoxyacetylfentanyl. Preparation of materials into groups of compounds was used to accommodate an ever increasing need to incorporate newly identified fentanyls. This protocol was validated within a linear range of 1.00-100 ng/mL, with precision <=12% CV and accuracy >=93%, as reported for the pooled blood QC samples, and limits of detection as low as 0.10 ng/mL. The use of DBS to assess fentanyl analog exposures can facilitate rapid sample collection, transport, and preparation for analysis that could enhance surveillance and response efforts in the ongoing opioid overdose epidemic. PMID- 30462231 TI - Development and Validation of a Novel All-Inclusive LC-MS-MS Designer Drug Method. AB - Designer drugs including synthetic cannabinoids and synthetic cathinones are an increasing problem due to the ease of access to these compounds. They present analytical challenges inasmuch as the compound structures are numerous and growing within each class. Typically each class of designer compounds is analyzed separately due to differences in chemistry, desired cut-offs or other reasons. Physicians treating "high-risk" patients typically order tests for all "illicit" substances which can span several test classes. Despite that multiple classes of designer drugs are ordered together, there has not been a comprehensive confirmatory test developed to date. Presented here is a novel comprehensive designer drug LC-MS-MS method that combines synthetic cannabinoids and synthetic cathinones, etizolam, a designer benzodiazepine and mitragynine (kratom), a natural product analgesic. This method improves laboratory throughput with a cycle time of ~4.5 min which affords resolution of crucial isomers, such as ethylone and butylone. Development of this method also provided an opportunity to update the list of compounds within the method. Analytes with fewer than five positive specimens in a year of testing with previous separate methods were removed as old and not current. New analytes were added based on reports from NMS Laboratories and the US Drug Enforcement Administration testing and drug seizures, which included etizolam, its major metabolite alpha-hydroxyetizolam as well as newer synthetic cannabinoids (5-fluoro ADB metabolite 7, AB-FUBINACA metabolite 3, AB-FUBINACA metabolite 4 and MDMB-FUBINACA metabolite M1) and synthetic cathinones (N-ethyl pentylone). Finally, the impact of the new analytes and cut-off changes are discussed in context with patient results from the first 4 months of testing after implementation of the method in the lab. PMID- 30462230 TI - Evaluation of Sensitivity Toward Storage Mites and House Dust Mites Among Nasobronchial Allergic Patients of Kolkata, India. AB - House dust mites (HDMs) are the major constituents of house dust (HD). HD and HDM sensitization is well documented worldwide. Storage mite (SM) sensitization is presently lacking from India. The present study evaluated the sensitization of both HDM and SM among 372 allergic rhinitis patients reported to the Allergy and Asthma Research Center of Kolkata metropolitan, India. HD samples were collected from the patients' home and analyzed for the major constituent mites. HD and six constituent mites Dermatophagoides pteronyssinus (DP), Dermatophagoides farina Hughes (Acari: Pyroglyphidae) (DF), Blomia tropicalis (BT), Acarus siro Linnaeus (Acari: Acaridae) (AS), Lepidoglyphus destructor (LD), and Tyrophagus putrescentiae (Schrank) (Acari: Acaridae) (TP) are tested for the allergenic potential through Skin Prick Test (SPT). Three SMs, namely AS, LD, and TP, were newly included in the mite SPT extract for the first time in Kolkata. In total, 330 patients showed significant positive SPT toward any one allergen tested. HD was the major elicitor exhibiting 92.42% response. Individuals of age group 15-40 were the worst sufferers. DF showed the highest sensitization (87.87%) among the dust mites. The SMs also contributed significantly to prove their sensitizing potential. SPT rates for AS, LD, and TP were 33, 25, and 18%, respectively. SPT grades and total Immunoglobulin E (IgE) were positively correlated for each of the allergens. Most of the patients were multi-sensitized (95%) and represented markedly high total IgE levels (>500 IU/ml). Three SMs proved to be significant allergens for the studied population. The sensitization toward these SMs is first time reported from India and can be recommended for inclusion of routine SPT for better outcome in the future. PMID- 30462232 TI - Macro-environmental sensitivity for growth rate in Danish Duroc pigs is under genetic control. AB - The aim of this study was to examine (i) the genetic variation in macro environmental sensitivity (macro-ES) for ADG in Danish Duroc pigs, (ii) the genetic heterogeneity among sexes, and (iii) residual variance heterogeneity among herds. Record of ADG for 32,297 boars (19 herds) and 42,724 gilts (16 herds) was used for analysis. The data were provided by the National Danish Pig Research Centre. The analysis was performed by fitting univariate reaction norm models with the herd-year-month on test (HYM) effect as environmental covariates and herd-specific residual variance for boars and gilts separately under a Bayesian setting. The environmental covariate was inferred simultaneously with other parameters of the model. Gibbs sampling was used to sample model dispersion and location parameters. The posterior means and highest posterior density intervals of the additive genetic variance, genetic correlations for ADG, and heritability were calculated over the continuous environmental range of -3sigmah to +3sigmah (SD of the HYM effect). The coheritability of ADG at the average environmental level and ADG in the environments along the -3sigmah to +3sigmah environmental gradient were also calculated. The analysis showed significant variation in macro-ES, revealing genotype by environment interactions (G * E) for ADG. The presence of G * E resulted in changes in additive genetic variance and heritability across the -3sigmah to +3sigmah range. The genetic correlations were high and positive between ADG in environments differing by 1sigmah units or less and decreased to moderately positive between ADG in the extreme environments in both sexes. The coheritability of ADG in the environment at the average level and the -3sigmah environment for boars were greater than the heritability in the environment at the average level, while it was less for gilts. The coheritability of ADG in the environment at the average level and the +3sigmah environment for boars was less than heritability in the environment at the average level, while it was either the same or greater for gilts, depending on the residual variance. Boars had larger additive genetic and residual variances than gilts. Heterogeneity of residual variances across herds was shown for both sexes. In conclusion, this study shows the presence of macro-ES, genetic variance heterogeneity among sexes for ADG in pigs, and residual variance heterogeneity across herds. PMID- 30462233 TI - Association between atrial fibrillation and patient-important outcomes in heart failure patients with implantable cardioverter-defibrillators. A systematic review and meta-analysis. AB - Aims: To assess the association between atrial fibrillation (AF) and all-cause mortality and implantable cardioverter defibrillators (ICD) therapies in heart failure (HF) patients with reduced ejection fraction and an ICD implanted. Methods and Results: A systematic MEDLINE search performed from inception through November 2016, supplemented by hand searching of reference lists, identified 62 eligible studies (227,998 patients) reporting on the association between AF and outcomes in HF patients; 36 studies included data on all-cause mortality, 30 on appropriate and 17 on inappropriate ICD interventions. Hazard Ratio, Risk Ratio, or Odds Ratio estimates were used based on data availability. Effect estimates were synthesized under a random-effects model. ICD-implanted HF patients with a history of AF had a 42% [combined effect estimate (cEE) 1.42 (95% CI: 1.28-1.57)] higher risk of all-cause mortality compared to patients with no AF history. Furthermore, AF patients had a higher risk of appropriate [cEE 1.44 (95% CI: 1.27 1.64)] and inappropriate ICD interventions [cEE 2.05 (95% CI 1.75-2.44)]. Conclusions: AF history is statistically significantly associated with adverse major clinical outcomes in ICD-implanted HF patients. Patients with AF have a higher risk of all-cause mortality, appropriate and inappropriate ICD interventions compared to patients with no AF history. Whether AF may have an independent deleterious effect on HF prognosis or may simply be a marker of HF severity should be further investigated. PMID- 30462235 TI - The HIV-1 reverse transcriptase E138A natural polymorphism decreases the genetic barrier to resistance to etravirine in vitro. AB - Objectives: The HIV-1 reverse transcriptase (RT) natural polymorphism E138A is included among the mutations with a minor impact on response to etravirine. However, the interpretation of E138A on etravirine susceptibility is not consistent across different genotypic resistance algorithms. The aim of the study was to investigate the effect of E138A on the genetic barrier to resistance to etravirine in vitro. Methods: A panel of 20 clinically derived recombinant viruses (10 with WT 138E and 10 with 138A, all without any other resistance mutation) were cultured in the presence of increasing etravirine concentrations and analysed for genotypic changes at virus breakthrough. Parallel experiments were conducted with 138E/A/G/K/Q NL4-3-based clones. Results: In the NL4-3 background, codon 138 changes increased etravirine resistance in the following order: Q > K > A > G > E. The 138A viruses were less susceptible to etravirine compared with the 138E viruses [median (IQR) fold change, 1.8 (1.5-2.8) versus 1.3 (0.8-1.8); P = 0.026], overcame etravirine pressure earlier [HR (95% CI) for viral outgrowth with 138A, 5.48 (2.95-28.24); P < 0.001] and grew at higher drug concentrations [median (IQR), 1350 (1350-1350) versus 0 (0-1350) nM; P = 0.005]. A variety of etravirine resistance-related mutations and changes in the RT connection and RNase H domains accumulated without any consistent pattern depending on baseline codon 138. Conclusions: E138A can contribute to reduced response to etravirine through a decreased genetic barrier to resistance. In vitro drug resistance selection is a valuable complement to define the full potential of low-level resistance mutations. PMID- 30462236 TI - How Can We Assess "Complete Healing" Beyond Endoscopic Remission? PMID- 30462234 TI - Exploring causality of the association between smoking and Parkinson's disease. AB - Background: The aim of this paper is to investigate the causality of the inverse association between cigarette smoking and Parkinson's disease (PD). The main suggested alternatives include a delaying effect of smoking, reverse causality or an unmeasured confounding related to a low-risk-taking personality trait. Methods: A total of 715 incident PD cases were ascertained in a cohort of 220 494 individuals from NeuroEPIC4PD, a prospective European population-based cohort study including 13 centres in eight countries. Smoking habits were recorded at recruitment. We analysed smoking status, duration, and intensity and exposure to passive smoking in relation to PD onset. Results: Former smokers had a 20% decreased risk and current smokers a halved risk of developing PD compared with never smokers. Strong dose-response relationships with smoking intensity and duration were found. Hazard ratios (HRs) for smoking <20 years were 0.84 [95% confidence interval (CI) 0.67-1.07], 20-29 years 0.73 (95% CI 0.56-0.96) and >30 years 0.54 (95% CI 0.43-0.36) compared with never smokers. The proportional hazard assumption was verified, showing no change of risk over time, arguing against a delaying effect. Reverse causality was disproved by the consistency of dose-response relationships among former and current smokers. The inverse association between passive smoking and PD, HR 0.70 (95% CI 0.49-0.99) ruled out the effect of unmeasured confounding. Conclusions: These results are highly suggestive of a true causal link between smoking and PD, although it is not clear which is the chemical compound in cigarette smoking responsible for the biological effect. PMID- 30462237 TI - Intravenous catheter-related adverse events exceed drug-related adverse events in outpatient parenteral antimicrobial therapy. AB - Background: Drug-related adverse events (AEs) are reported to be common amongst patients receiving outpatient parenteral antimicrobial therapy (OPAT). However, comparative data regarding intravenous (iv) catheter-related AEs are lacking. Objectives: To compare drug- and iv catheter-related AEs from a large UK OPAT centre. Patients and methods: We reviewed 544 OPAT episodes [median (IQR) age: 57 (39-71) years, 60% male, 13% with diabetes] with a median (IQR) duration of 7 (2 18) days. Clinically significant drug- and iv catheter-related AEs were calculated as a percentage of OPAT episodes with an AE and also as AEs per 1000 iv drug/catheter days. Results: Drug-related AEs complicated 13 (2.4%) OPAT episodes at 1.7 (95% CI 0.9-2.9) per 1000 drug days. Catheter-related AEs occurred more frequently, complicating 32 (5.9%) episodes at 5.7 (95% CI 4.2-7.9) per 1000 iv catheter days (chi2 test for difference in AE rate: P < 0.001). Non radiologically guided midline catheters were associated with the most frequent AEs (n = 23) at 15.6 (95% CI 10.3-23.4) per 1000 iv catheter days compared with other types of iv catheters (HR 8.4, 95% CI 2.4-51.9, P < 0.004), and self administration was associated with a higher rate of catheter-related AEs at 12.0 (95% CI 6.0-23.9) per 1000 iv catheter days (HR 4.15, 95% CI 1.7-9.1, P = 0.007). Conclusions: Clinically significant iv catheter-related AEs occurred more frequently than drug-related AEs, especially when using non-radiologically guided midline catheters. Regular review of the need for iv therapy and switching to oral antimicrobials when appropriate is likely to minimize OPAT-related AEs. PMID- 30462239 TI - Commentary: Methods and Designs for T1 Translation in Pediatric Psychology. PMID- 30462238 TI - DLK1 is a novel link between reproduction and metabolism. AB - Background: Delta-like homolog 1 (DLK1), also called preadipocyte factor 1, prevents adipocyte differentiation and has been considered a molecular gatekeeper of adipogenesis. A DLK1 complex genomic defect was identified in five women from a single family with central precocious puberty (CPP) and increased body fat percentage. Methods: We studied 60 female patients with a diagnosis of CPP or history of precocious menarche. Thirty-one of them reported a family history of precocious puberty. DLK1 DNA sequencing was performed in all patients. Serum DLK1 concentrations were measured using an ELISA assay in selected cases. Metabolic and reproductive profiles of adult women with CPP caused by DLK1 defects were compared with 20 women with idiopathic CPP. Results: We identified three novel frameshift mutations of DLK1 (p.Gly199Alafs*11, p.Val271Cysfs*14 and p.Pro160Leufs*50) in five women from three families with CPP. Segregation analysis was consistent with the maternal imprinting of DLK1. Serum DLK1 concentrations were undetectable in three affected women. Metabolic abnormalities, such as overweight/obesity, early onset glucose intolerance/type 2 diabetes and hyperlipidemia were more prevalent in the DLK1 mutated women compared to the idiopathic CPP group. Notably, the human metabolic alterations were similar to the previously described Dlk1-null mice phenotype. Two sisters who carried the p.Gly199Alafs*11 mutation also exhibited polycystic ovary syndrome and infertility. Conclusions: Loss-of-function mutations of DLK1 are a definitive cause of familial CPP. The high prevalence of metabolic alterations in adult women who experienced CPP due to DLK1 defects suggests that this antiadipogenic factor represents a novel link between reproduction and metabolism. PMID- 30462240 TI - BEEF SPECIES- RUMINANT NUTRITION CACTUS BEEF SYMPOSIUM: Influence of management decisions during heifer development on enhancing reproductive success and cow longevity. AB - Profitability of beef cattle producers can be directly tied to the productive lifespan of a cow. Management decisions influencing heifer nutrition and reproduction play a key role in establishing heifer fertility and longevity. Altering feeding strategies to utilize compensatory growth has been reported to have a positive influence on fertility during the first breeding season; however, there are discrepancies in the literature as to the impact this strategy may have on the proportion of heifers attaining puberty prior to entering their first breeding season. Ultimately, this may affect lifetime productivity as heifers born early in the calving season produce more kilograms of weaned calf over their first 6 calves, as well as, remain in the herd longer than those animals born later in the calving season. Thus, incorporation of reproductive technologies to identify fertile animals or aid in improving conception earlier in the breeding season may improve heifer reproductive performance and longevity. Reproductive tract scores have been utilized to identify animals which are more reproductively mature, increasing the likelihood of successful artificial insemination. Antral follicle counts (AFC), which predict the number of follicles in the ovarian reserve, have not only been reported to have a moderate to high heritability, but have also been used to identify animals with greater reproductive potential. Beef heifers classified as high AFC have greater pregnancy rates and longevity than low AFC heifers. Additionally, maternal diet may play a role in influencing reproductive success and ultimately cow longevity. Improving maternal plane of nutrition has been reported to increase female offspring pregnancy rates. Overall, recent research has provided producers with a variety of methods to optimize animal performance while enhancing reproductive success and longevity to ensure profitability. PMID- 30462241 TI - The molecular evolution of C4 photosynthesis: opportunities for understanding and improving the world's most productive plants. AB - C4 photosynthesis is a convergent evolutionary trait that enhances photosynthetic efficiency in a variety of environmental conditions. It has evolved repeatedly following a fall in atmospheric CO2 concentration such that there is up to 30 million years difference in the amount of time that natural selection has had to improve C4 function between the oldest and youngest C4 lineages. This large difference in time, coupled with the phylogenetic distance between lineages, has resulted in a large disparity in anatomy, physiology, and biochemistry between extant C4 species. This review summarises the myriad of molecular sequence changes that have been linked to the evolution of C4 photosynthesis. These range from single nucleotide changes to duplication of entire genes, and provide a roadmap for how natural selection has adapted enzymes and pathways for enhanced C4 function. Finally, this review discusses how this molecular diversity can provide opportunities for understanding and improving photosynthesis for multiple important C4 food, feed, and bioenergy crops. PMID- 30462242 TI - Beyond the H&E: Advanced Technologies for in situ Tissue Biomarker Imaging. AB - For decades, histopathology with routine hematoxylin and eosin staining has been and remains the gold standard for reaching a morphologic diagnosis in tissue samples from humans and veterinary species. However, within the past decade, there has been exponential growth in advanced techniques for in situ tissue biomarker imaging that bridge the divide between anatomic and molecular pathology. It is now possible to simultaneously observe localization and expression magnitude of multiple protein, nucleic acid, and molecular targets in tissue sections and apply machine learning to synthesize vast, image-derived datasets. As these technologies become more sophisticated and widely available, a team-science approach involving subspecialists with medical, engineering, and physics backgrounds is critical to upholding quality and validity in studies generating these data. The purpose of this manuscript is to detail the scientific premise, tools and training, quality control, and data collection and analysis considerations needed for the most prominent advanced imaging technologies currently applied in tissue sections: immunofluorescence, in situ hybridization, laser capture microdissection, matrix-assisted laser desorption ionization imaging mass spectrometry, and spectroscopic/optical methods. We conclude with a brief overview of future directions for ex vivo and in vivo imaging techniques. PMID- 30462243 TI - Influence of outdoor temperature and relative humidity on incidence and etiology of hyponatremia. AB - CONTEXT: Hyponatremia is the most common electrolyte disturbance in hospitalized patients. Known risk factors are heart or renal failure, excessive drinking or the use of diuretics. The incidence of hyponatremia may also be influenced by climate. OBJECTIVE: Analyzing the influence of outdoor temperature and relative humidity on the incidence and etiology of hyponatremia. DESIGN: Cohort A: cross sectional study from January 2011 to December 2016. Cohort B: prospective observational from June 2011 to August 2013. SETTING: Emergency department of two tertiary centers. PATIENTS: Cohort A: patients with plasma sodium <=145mmol/l (n=222,217). Cohort B: consecutive patients (n=294) with profound hyponatremia (plasma sodium <=125mmol/l). MAIN OUTCOME MEASURE: Association of outdoor temperature and relative humidity on the incidence of mild (sodium 126-134mmol/l) and profound hyponatremia (sodium <=125mmol/l) were investigated using logistic regression models. Association of outdoor temperature and relative humidity on hyponatremia etiology was evaluated. RESULTS: Cohort A: 222,217 patients (median age 58 (IQR:40-75) years; 48% female) were included in this study, 9.9% had mild and 1.08% had profound hyponatremia. Outdoor temperature was significantly associated with the incidence of profound but not mild hyponatremia (p-value <0.01, p-value 0.3). Relative humidity was not associated with the incidence of hyponatremia. Cohort B: Diuretic-induced hyponatremia occurred more frequently with higher outdoor temperatures, whereas other etiologies showed no clear variation with outdoor temperature nor relative humidity. CONCLUSIONS: Higher outdoor temperature, but not relative humidity, seems to be associated with the incidence of profound hyponatremia. Our data suggest that diuretics should be used with caution during hot weather. PMID- 30462244 TI - Phthalates exposure as determinant of albuminuria in type 2 diabetes subjects: a cross-sectional study. AB - Context: Recent epidemiological observations have reported an association among phthalates exposure and insulin resistance, obesity and diabetes, but no studies have so far related the exposure to these environmental pollutants with microvascular complications of diabetes. Objective: Exploring the relationship between phthalates and renal function in diabetic subjects. Design: Cross sectional, case-only study. Concentrations of three urinary metabolites of di-2 ethylhexylphthalate were quantified in a spot morning urine sample, normalized for creatinine urinary excretion and related to clinical parameters and phenotype, adjusting for confounders. Setting: Santa Chiara Hospital, Pisa, outpatient diabetes clinic. Patients or Other Participants: 209 diabetic patients consecutively referring to our clinic. Main Outcome Measures(s): Relationship between phthalates and renal function (evaluated with estimated glomerular filtration rate (eGFR) and albuminuria). Results: Creatinine-adjusted urinary concentrations of mono 2-ethylhexyl phthalate (MEHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), mono 2-ethyl-5-hydroxyhexyl phthalate (MEHHP) were 7.53 [4.84 12.60] ug/g, 3.04 [1.03-5.14] ug/g and 10.70 [7.02-17.40] ug/g. Age, sex, BMI, diabetes duration, smoking, blood pressure, HBA1c, eGFR did not influence their levels. Exposure to MEHP and MEOHP was higher in micro/macroalbuminuric individuals (MEHP, p=0.0173; MEOHP, p=0.0306); 4th vs 1st quartile showed higher risk of albuminuria (MEHP: OR 4.83 [CI 1.45-16.06], p=0.0297; MEOHP: OR 3.29 [CI 1.08-10.04], p=0.0352). MEOHP was higher (p=0.034) in subjects with cardiovascular events, MEHP showed a positive trend (p=0.061). Conclusion: Our findings reveal for the first time an association between exposure to di-2 ethylhexylphthalate metabolites and degree of albuminuria in diabetic subjects; the lack of relation with eGFR suggests their urinary levels to be independent of renal function. PMID- 30462245 TI - Corrigendum. PMID- 30462246 TI - Prospectively identifying older adults at risk for potentially avoidable hospitalizations in Korea using population-based data. AB - Objective: The purpose of this study is to develop and validate a prediction model to identify older adults at risk for potentially avoidable hospitalizations (PAHs) using variables readily available in routinely collected health administrative data. Design: Population-based, retrospective observational study using National Health Insurance Service-National Sample Cohort (NHIS-NSC) data. Setting: Primary care settings in South Korea. Participants: The sample includes 113 612 older NHI beneficiaries in the year 2011, among which 2856 had one or more PAHs in 2012. Methods: We examined multi-dimensional risk factors of PAHs in the base year and developed and validated prediction models of hospitalization risk using the following year. The predictive power of the developed models was examined with samples generated by the bootstrap method. The performance of the final model was evaluated with further test statistics at different risk thresholds. Main Outcome Measure: Predicting PAHs. Results: The c-statistic of the final predictive model was 0.784 (CI: 0.769-0.799). The final model including all selected predictors showed the greatest marginal improvement (integrated discrimination improvement of 365%) compared to the base model. The positive predictive value was good. Conclusions: Our prediction model based on health administrative data can assist the insurer and practitioners to proactively identify and intervene with older adults at risk for a PAH. PMID- 30462247 TI - Detection of Fentanyl Analogs and Synthetic Opioids in Real Hair Samples. AB - Novel synthetic opioids include various analogs of fentanyl and emerging non fentanyl compounds with different chemical structures, such as AH-7921, MT-45 and U-47700. In recent years, these drugs have rapidly emerged on the drug market, and their abuse has been increasing worldwide. The motivations for use of these new compounds include their legal status, ready availability, low cost, users' curiosity or preference for their particular pharmacological properties and the intention to avoid detection. Furthermore, more common drugs like heroin are now increasingly being replaced or cut with fentanyl or new designer opioids; thus, many drug users are unintentionally or unknowingly using synthetic fentanyl analogs. In this scenario, the detection of new psychoactive substances in hair can provide insight into their current diffusion among the population and social characteristics of these synthetic drug users. In this manuscript, we describe a simple, fast, specific and sensitive UHPLC-MS-MS method able to detect 13 synthetic opioids (including fentanyl analogs) and metabolites in hair samples. Furthermore, the method includes the detection of 4-anilino-N-phenethyl piperidine (4-ANPP), which is considered both a precursor and a metabolite of several fentanyl analogs. The method was applied to 34 real hair samples collected in New York City from subjects who had reported past-year non-medical opioid and/or heroin use. In total, 17 samples tested positive for at least one target analyte, with oxycodone (nine samples) and tramadol (eight samples) being the most common. Among these, the method was able to quantify furanyl-fentanyl and fentanyl in the pg/mg range in two samples. Simultaneously, also 4-ANPP was detected, giving evidence for the first time that this compound can be selected as a marker of fentanyl analogs use via hair testing. In conclusion, this study confirmed the increasing diffusion of new synthetic opioids and "fentalogs" with high potency among non-medical opioid users. PMID- 30462248 TI - Species boundaries in the Trichophyton mentagrophytes / T. interdigitale species complex. AB - The fungi Trichophyton mentagrophytes and T. interdigitale are closely related species, causing superficial infections in humans and other mammals. The status of these taxa is a field of long-lasting debates. To clarify their phylogenetic relationships within the genus Trichophyton and sharpen the species boundaries, we performed sequencing of four T. mentagrophytes genomes and also evaluated three previously published multilocus data sets. We performed computational species delimitation analysis on all available in GenBank internal transcribed spacer region (ITS) sequences of Trichophyton spp. Phylogenomic data, phylogenetic network, and species delimitation analyses implied that T. mentagrophytes and T. interdigitale belong to the same phylogenetic species. However, we argue that taxonomic status quo should be retained, from the perspective of epidemiological data and the principle of taxonomic stability. Since there is a correlation between ITS genotype and epidemiological source of an isolate, restriction of T. interdigitale to purely anthropophilic ITS genotypes seems to be reasonable. PMID- 30462249 TI - Ten yearly yellow fever booster vaccinations may still be justified. PMID- 30462250 TI - Smoking counts: experience of implementing questions on smoking on official death certification systems. AB - We describe our experience in several settings, following a suggestion in 1983 to add questions on the smoking status of the deceased on the UK death certificate as an effective way to monitor the evolution of the smoking epidemic. In South Africa in 1997 and in Tianjin Municipality, China, in 2010, questions about the smoking habits of the deceased were inserted on the official death certificates. In both places a system now exists to routinely collect information on smoking status in relation to causes of death. Results from two million South African and 300 000 Chinese deceased individuals have been reported, and the sample size in both places continues to grow. An unsuccessful attempt was made in 2008 to insert smoking questions on the Australian death notification forms but comments and concerns from the registrars of births, marriages and deaths have international applicability. In both China and South Africa, inserting questions on smoking on the death notification forms was not a trivial task-in each it required, as a minimum, significant commitment from several government agencies. Benefits, however, include a better local understanding of the smoking epidemic and allowing for planning and monitoring of tobacco control programmes. Documenting the varied experiences of collecting information on smoking on death notification forms is useful to those wishing to introduce such questions in their own settings. This is pertinent especially at a time when vital registration systems are being improved, with an aim to monitoring sustainable development goals. PMID- 30462251 TI - Adoption of Evidence-Based Medicine in Clinical Laboratory Science: A Survey of the Prevalence of Systematic and Narrative Reviews. AB - Background: Systematic reviews (SRs) play a critical role in evidence-based medicine. Objective: To determine the publication trends of SRs in clinical laboratory science (CLS). Methods: We searched Scopus to identify all reviews published in the top 20 CLS journals during the past 10 years (2008-2017). We determined year of publication, review type (systematic vs narrative), citations, and whether the review was accompanied by a meta-analysis (MA). Results: We identified 2934 reviews. Of these, 2833 (96.6%) were narrative reviews, and 98 (3.3%) were SRs. A total of 67 (66.3%) of the SRs were accompanied by a MA. Three journals accounted for 68 of 98 (69.4%) SRs. The percentage of SRs (relative to all reviews) has increased during the past decade (P = .01). SRs were more frequently published in high-impact journals (P <.001). Conclusion: The publication rate of SRs in CLS journals has increased during the past decade. PMID- 30462252 TI - Urological Manifestation of Cryptic Severe Psychiatric Illness. AB - Penile cellulitis has rarely been reported in the literature and never secondary to self-injury with subsequent sexual activity. It presents a challenging diagnostic situation in that the patient will likely be less than forthcoming about the etiology of his symptoms despite his willingness to seek formal medical attention. We present a case of penile cellulitis secondary to dermatitis artefacta in a severely depressed new submarine sailor. Initial studies for a more serious etiology were negative and he was treated with PO antibiotics for "syphilis" by the local civilian emergency department. After responding well to antibiotics, he subsequently presented back to medical in order to offer up the etiology of his penile wounds. In this report, we review the published literature on penile cellulitis and genital dermatitis artefacta. This case shows that military providers should always have psychiatric causes in their differential and not hesitate to ask about genital abnormalities. Recognition of underlying psychiatric etiology may play a key role in helping the patient get the care he or she needs. PMID- 30462253 TI - Fecal microbiota transplantation: what is the role in travelers' diarrhea? PMID- 30462254 TI - The overexpression of Bax inhibitor-1 in common bean roots highlights its dual role in the legume-rhizobia symbiosis. AB - Bax-inhibitor 1 (BI-1) is a cell death suppressor conserved in all eukaryotes that modulates cell death in response to abiotic stress and pathogen attack in plants. Thus far nothing is known about its role in the establishment of symbiotic interactions. Here, we demonstrate the functional relevance of an Arabidopsisthaliana BI-1 homolog (PvBI-1a) to symbiosis between the common bean (Phaseolus vulgaris) and Rhizobium tropici. We show that the PvBI-1a expression changes observed during early symbiosis resemble those of some defence-response related proteins. By using gain- and loss-of-function approaches, we demonstrate that the overexpression of PvBI-1a in the roots of common bean increases the number of rhizobial infection events (and therefore the final number of nodules per root), but induces the premature death of nodule cells, thus affecting their nitrogen fixation efficiency. Nodule morphological alterations are known to be associated with changes in the expression of genes tied to defence, autophagy, and vesicular trafficking. Results obtained in the present work suggest that BI-1 has a dual role in the regulation of programmed cell death during symbiosis, thus extending our understanding about its critical function in the modulation of host immunity while responding to by beneficial microbes. PMID- 30462255 TI - Nontraditional Laboratory Animal Species (Cephalopods, Fish, Amphibians, Reptiles, and Birds). AB - Aquatic vertebrates and cephalopods, amphibians, reptiles, and birds offer unique safety and occupational health challenges for laboratory animal personnel. This paper discusses environmental, handling, and zoonotic concerns associated with these species. PMID- 30462256 TI - NINJA-Associated ERF19 Negatively Regulates Arabidopsis Pattern-Triggered Immunity. AB - Recognition of microbe-associated molecular patterns (MAMPs) derived from invading pathogens by plant pattern-recognition receptors (PRRs) initiates a subset of defense responses known as pattern-triggered immunity (PTI). Transcription factors (TFs) orchestrate the onset of PTI through complex signaling networks. Here, we characterized the function of ERF19, a member of the Arabidopsis thaliana ethylene response factor (ERF) family. ERF19 was found to act as a negative regulator of PTI against Botrytis cinerea and Pseudomonas syringae. Notably, overexpression of ERF19 increased plant susceptibility to these pathogens and repressed MAMP-induced PTI outputs. In contrast, expression of the chimeric dominant repressor ERF19-SRDX boosted PTI activation, conferred increased resistance to the fungus B. cinerea, and enhanced elf18-triggered immunity against bacteria. Consistent with a negative role of ERF19 in PTI, MAMP mediated growth inhibition was weakened or augmented in lines overexpressing ERF19 or expressing ERF19-SRDX, respectively. Using biochemical and genetic approaches, we further show that the transcriptional co-repressor Novel INteractor of JAZ (NINJA) associates with and represses the function of ERF19. Our work reveals ERF19 as a novel player in the mitigation of PTI, and highlights a potential role for NINJA in fine-tuning ERF19-mediated regulation of Arabidopsis innate immunity. PMID- 30462257 TI - Plant RNases T2, but not Dicer-like proteins, are major players of tRNA-derived fragments biogenesis. AB - RNA fragments deriving from tRNAs (tRFs) exist in all branches of life and the repertoire of their biological functions regularly increases. Paradoxically, their biogenesis remains unclear. The human RNase A, Angiogenin, and the yeast RNase T2, Rny1p, generate long tRFs after cleavage in the anticodon region. The production of short tRFs after cleavage in the D or T regions is still enigmatic. Here, we show that the Arabidopsis Dicer-like proteins, DCL1-4, do not play a major role in the production of tRFs. Rather, we demonstrate that the Arabidopsis RNases T2, called RNS, are key players of both long and short tRFs biogenesis. Arabidopsis RNS show specific expression profiles. In particular, RNS1 and RNS3 are mainly found in the outer tissues of senescing seeds where they are the main endoribonucleases responsible of tRNA cleavage activity for tRFs production. In plants grown under phosphate starvation conditions, the induction of RNS1 is correlated with the accumulation of specific tRFs. Beyond plants, we also provide evidence that short tRFs can be produced by the yeast Rny1p and that, in vitro, human RNase T2 is also able to generate long and short tRFs. Our data suggest an evolutionary conserved feature of these enzymes in eukaryotes. PMID- 30462258 TI - Monitoring Insecticide Resistance Profiles of Aedes aegypti (Diptera: Culicidae) in the Sunda Islands of Indonesia Based on Diagnostic Doses of Larvicides. AB - This study was conducted to monitor the susceptibility status of Aedes aegypti (Linnaeus) larvae in the Sunda Islands of Indonesia against various organophosphates and organochlorines. Larval bioassay was performed in accordance with the World Health Organization standard protocol. Field-collected and reference strains of Ae. aegypti larvae were tested against diagnostic doses of eight larvicides belonging to organophosphates and organochlorines, namely bromophos (0.050 mg/liter), chlopyrifos (0.002 mg/liter), fenitrothion (0.020 mg/liter), fenthion (0.025 mg/liter), malathion (0.125 mg/liter), temephos (0.012 mg/liter), DDT (0.012 mg/liter), and dieldrin (0.025 mg/liter). Mortality rates of larvae were recorded at 24-h posttreatment. This study showed that Ae. aegypti larvae from Padang, Samarinda, Manggarai Barat, and South Central Timor were susceptible to both fenitrothion and dieldrin (mortality rates >= 98%). About 6 out of 10 field strains of Ae. aegypti larvae were resistant (<80% mortality rates) against fenthion, whereas Ae. aegypti larvae from Kuningan, Samarinda, Sumba, and South Central Timor exhibited some degrees of resistance (mortality rates 80-98%). All field-collected Ae. aegypti larvae were resistant against diagnostic doses of chlorpyrifos, malathion, temephos, and DDT with mortality rates ranging from 0 to 74.67%. Continued insecticide susceptibility studies are essential to identify the efficacy of insecticides for an improved dengue vector control and to delay the development of insecticide resistance. PMID- 30462260 TI - Rifamycin SV-MMX(r) for treatment of travelers' diarrhea: equally effective as ciprofloxacin and not associated with the acquisition of multi-drug resistant bacteria. AB - Background: The novel oral antibiotic formulation Rifamycin SV-MMX(r), with a targeted delivery to the distal small bowel and colon, was superior to placebo in treating travelers' diarrhea (TD) in previous study. Thus, a study was designed to compare this poorly absorbed antibiotic to the systemic agent ciprofloxacin. Methods: In a randomized, double-blind phase 3 study (ERASE) the efficacy and safety of Rifamycin SV-MMX(r) 400 mg twice daily (RIF-MMX) was compared to ciprofloxacin 500 mg twice daily in the oral treatment of TD. Overall, 835 international visitors to India, Guatemala or Ecuador with acute TD were randomized to receive a 3-day treatment with RIF-MMX (n = 420) or ciprofloxacin (n = 415). Primary endpoint was time to last unformed stool (TLUS), after which clinical cure was declared. Stools samples for microbiological evaluation were collected at the baseline visit and the end of treatment visit. Results: Median TLUS in the RIF-MMX group was 42.8 h vs. 36.8 h in the ciprofloxacin group indicating non-inferiority of RIF-MMX to ciprofloxacin (p = 0.0035). Secondary efficacy endpoint results including clinical cure rate, treatment failure rate, requirement of rescue therapy as well as microbiological eradication rate confirmed those of the primary analysis indicating equal efficacy for both compounds. While patients receiving ciprofloxacin showed a significant increase of Extended Spectrum Beta Lactamase Producing - Escherichia coli (ESBL-E. Coli) colonization rates after three days treatment (6.9%), rates did not increase in patients receiving RIF-MMX (-0.3%). Both drugs were well tolerated and safe. Conclusion: The novel multi-matrix formulation of the broad-spectrum, poorly absorbed antibiotic Rifamycin SV was found non-inferior to the systemic antibiotic ciprofloxacin in the oral treatment of non-dysenteric TD with the advantage of a lower risk of ESBL-E. Coli acquisition. PMID- 30462259 TI - Randomized evaluation of fibrinogen versus placebo in complex cardiovascular surgery: post hoc analysis and interpretation of phase III results. AB - OBJECTIVES: In a multicentre, randomized-controlled, phase III trial in complex cardiovascular surgery (Randomized Evaluation of Fibrinogen vs Placebo in Complex Cardiovascular Surgery: REPLACE), single-dose human fibrinogen concentrate (FCH) was associated with the transfusion of increased allogeneic blood products (ABPs) versus placebo. Post hoc analyses were performed to identify possible reasons for this result. METHODS: We stratified REPLACE results by adherence to the transfusion algorithm, pretreatment fibrinogen level (<=2 g/l vs >2 g/l) and whether patients were among the first 3 treated at their centre. RESULTS: Patients whose treatment was adherent with the transfusion algorithm [FCH, n = 47 (60.3%); placebo, n = 57 (77.0%); P = 0.036] received smaller quantities of ABPs than those with non-adherent treatment (P < 0.001). Among treatment-adherent patients with pretreatment plasma fibrinogen <=2 g/l, greater reduction in 5-min bleeding mass was seen with FCH versus placebo (median -22.5 g vs -15.5 g; P = 0.071). Considering patients with the above conditions and not among the first 3 treated at their centre (FCH, n = 15; placebo, n = 22), FCH was associated with trends towards reduced transfusion of ABPs (median 2.0 vs 4.0 units; P = 0.573) and greater reduction in 5-min bleeding mass (median -21.0 g vs -9.5 g; P = 0.173). Differences from a preceding single-centre phase II study with positive outcomes included more patients with pretreatment fibrinogen >2 g/l and fewer patients undergoing thoracoabdominal aortic aneurysm repair. CONCLUSIONS: None of the patient stratifications provided a clear explanation for the lack of efficacy seen for FCH in the REPLACE trial versus the positive phase II outcomes. However, together, the 3 factors demonstrated trends favouring FCH. Less familiarity with the protocol and procedures and unavoidable differences in the study populations may explain the differences seen between the phase II study and REPLACE. Clinical trial registration: NCT01475669 https://clinicaltrials.gov/ct2/show/NCT01475669; EudraCT trial no: 2011-002685-20. PMID- 30462261 TI - Effect of Fungicide on Pollen Foraging by Honeybees (Hymenoptera: Apidae) in Cranberry Differs by Fungicide Type. AB - Honeybees (Apis mellifera Linnaeus) (Hymenoptera: Apidae) play a major role in the pollination of cranberry (Vaccinium macrocarpon; Ericaceae). However, fungicide applications during cranberry bloom may affect bees foraging behavior. This research reports the amount of cranberry and noncranberry pollen brought back to hives immediately before and after two types of fungicide applications. The amount of cranberry pollen decreased while the amount of noncranberry pollen increased following a fungicide application. However, this relationship differed depending on the type of fungicide applied. Understanding how different fungicides specifically impact bee behavior is essential to minimizing bee exposure to potentially harmful chemicals. PMID- 30462262 TI - Midturbinate Swabs Are Comparable to Nasopharyngeal Swabs for Quantitative Detection of Respiratory Syncytial Virus in Infants. AB - Nasopharyngeal (NP) swabs are generally used to detect respiratory syncytial virus (RSV) in infants. However, midturbinate (MT) swabs may provide comparable results. In this study, we enrolled hospitalized infants aged <24 months with RSV and collected NP and MT swabs. The resulting viral loads measured by real-time reverse-transcription quantitative polymerase chain reaction were similar. Most parents preferred MT swabs over NP swabs. PMID- 30462264 TI - Characteristics of Intracranial Group A Streptococcal Infections in US Children, 1997-2014. AB - Background: Few data on intracranial group A Streptococcus (GAS) infection in children are available. Here, we describe the demographic, clinical, and diagnostic characteristics of 91 children with intracranial GAS infection. Methods: Cases of intracranial GAS infection in persons <=18 years of age reported between 1997 and 2014 were identified by the Centers for Disease Control and Prevention's population- and laboratory-based Active Bacterial Core surveillance (ABCs) system. Medical charts were abstracted using a active, standardized case report form. All available isolates were emm typed. US census data were used to calculate rates. Results: ABCs identified 2596 children with invasive GAS infection over an 18-year period; 91 (3.5%) had an intracranial infection. Intracranial infections were most frequent during the winter months and among children aged <1 year. The average annual incidence was 0.07 cases per 100000 children. For 83 patients for whom information for further classification was available, the principal clinical presentations included meningitis (35 [42%]), intracranial infection after otitis media, mastoiditis, or sinusitis (34 [41%]), and ventriculoperitoneal shunt infection (14 [17%]). Seven (8%) of these infections progressed to streptococcal toxic shock syndrome. The overall case fatality rate was 15%. GAS emm types 1 (31% of available isolates) and 12 (13% of available isolates) were most common. Conclusions: Pediatric intracranial (GAS) infections are uncommon but often severe. Risk factors for intracranial GAS infection include the presence of a ventriculoperitoneal shunt and contiguous infections in the middle ear or sinuses. PMID- 30462263 TI - How can we improve oncofertility care for patients? A systematic scoping review of current international practice and models of care. AB - BACKGROUND: Fertility preservation (FP) is an important quality of life issue for cancer survivors of reproductive age. Despite the existence of broad international guidelines, the delivery of oncofertility care, particularly amongst paediatric, adolescent and young adult patients, remains a challenge for healthcare professionals (HCPs). The quality of oncofertility care is variable and the uptake and utilization of FP remains low. Available guidelines fall short in providing adequate detail on how oncofertility models of care (MOC) allow for the real-world application of guidelines by HCPs. OBJECTIVE AND RATIONALE: The aim of this study was to systematically review the literature on the components of oncofertility care as defined by patient and clinician representatives, and identify the barriers, facilitators and challenges, so as to improve the implementation of oncofertility services. SEARCH METHODS: A systematic scoping review was conducted on oncofertility MOC literature published in English between 2007 and 2016, relating to 10 domains of care identified through consumer research: communication, oncofertility decision aids, age-appropriate care, referral pathways, documentation, training, supportive care during treatment, reproductive care after cancer treatment, psychosocial support and ethical practice of oncofertility care. A wide range of electronic databases (CINAHL, Embase, PsycINFO, PubMed, AEIPT, Education Research Complete, ProQuest and VOCED) were searched in order to synthesize the evidence around delivery of oncofertility care. Related citations and reference lists were searched. The review was undertaken following registration (International prospective register of systematic reviews (PROSPERO) registration number CRD42017055837) and guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). OUTCOMES: A total of 846 potentially relevant studies were identified after the removal of duplicates. All titles and abstracts were screened by a single reviewer and the final 147 papers were screened by two reviewers. Ten papers on established MOC were identified amongst the included papers. Data were extracted from each paper and quality scores were then summarized in the oncofertility MOC summary matrix. The results identified a number of themes for improving MOC in each domain, which included: the importance of patients receiving communication that is of a higher quality and in different formats on their fertility risk and FP options; improving provision of oncofertility care in a timely manner; improving access to age-appropriate care; defining the role and scope of practice of all HCPs; and improving communication between different HCPs. Different forms of decision aids were found useful for assisting patients to understand FP options and weigh up choices. WIDER IMPLICATIONS: This analysis identifies core components for delivery of oncofertility MOC. The provision of oncofertility services requires planning to ensure services have safe and reliable referral pathways and that they are age-appropriate and include medical and psychological oncofertility care into the survivorship period. In order for this to happen, collaboration needs to occur between clinicians, allied HCPs and executives within paediatric and adult hospitals, as well as fertility clinics across both public and private services. Training of both cancer and non-cancer HCPs is needed to improve the knowledge of HCPs, the quality of care provided and the confidence of HCPs with these consultations. PMID- 30462265 TI - Split-Night Polysomnography Overestimates Apnea-Hypopnea Index in High-Risk Professions. AB - Introduction: According to the American Academy of Sleep Medicine (AASM) guidelines, split-night polysomnography (SN-PSG) is an acceptable alternative to full-night PSG (FN-PSG) and may be considered in patients with an apnea-hypopnea index (AHI) >=20/hr within the first 2 hours of the study. While SN-PSGs are an accurate approximation of moderate-to-severe obstructive sleep apnea (OSA), there remains the potential to misclassify the severity of sleep disordered breathing. Risks associated with the misclassification of OSA severity may be significant in high-risk professions such as active duty service members (ADSMs). The purpose of our study was to determine the accuracy of split-night polysomnography (SN-PSG) in a cohort of ADSMs. Materials and Methods: We conducted a retrospective review of ADSMs undergoing FN-PSG with approval by our institution's Department of Clinical Investigation. FN-PSG data were processed using t-test, ANOVA, Chi Squared, and logistical regression using JMP v12.0 to obtain partial-night data for the first 2 and 3 hours of recording. Significance was established with p value less than 0.05. OSA severity was determined by calculating the AHI of each subject's FN-PSG and SN-PSG. Results: Three-hundred patients were included in the study. Overall 79% were male with a mean age of 37.6 +/- 8.4 years and mean BMI of 28.5 +/- 3.3 kg/m2. Of our cohort, 112 patients (37%) would have qualified for a SN-PSG, of which 94 (84%) were appropriately classified and 18 patients (16%) were misclassified. Conclusions: In the relatively young, non-obese ADSM population, the majority did not qualify for a SN-PSG. The 3-hour SN-PSG accurately determined OSA severity in those with moderate-severe OSA; however, some patients with mild OSA would have been misclassified which can result in unnecessary duty limitations. A SN-PSG may not be ideal for this population. PMID- 30462266 TI - Structure guided fluorescence labeling reveals a two-step binding mechanism of neomycin to its RNA aptamer. AB - The ability of the cytidine analog Cmf to act as a position specific reporter of RNA-dynamics was spectroscopically evaluated. Cmf-labeled single- and double stranded RNAs differ in their fluorescence lifetimes, quantum yields and anisotropies. These observables were also influenced by the nucleobases flanking Cmf. This conformation and position specificity allowed to investigate the binding dynamics and mechanism of neomycin to its aptamer N1 by independently incorporating Cmf at four different positions within the aptamer. Remarkably fast binding kinetics of neomycin binding was observed with stopped-flow measurements, which could be satisfactorily explained with a two-step binding. Conformational selection was identified as the dominant mechanism. PMID- 30462267 TI - Novel Compound Heterozygote Mutation in IL10RA in a Patient With Very Early-Onset Inflammatory Bowel Disease. AB - Background: Very early-onset inflammatory bowel disease (VEO-IBD) is often associated with monogenetic disorders. IL-10RA deficiency is one of the major causal mutations in VEO-IBD. Here, we aimed to identify the causal mutation associated with severe IBD in a 1-year-old patient, validate the pathogenicity of the mutation, and characterize the mutant protein. Methods: To identify the causal mutation, targeted exome sequencing (ES) was performed using the genomic DNA from the patient. To validate the pathogenicity, IL-10RA functional tests were performed using the patient's peripheral blood mononuclear cells (PBMCs). Additionally, flow cytometry analysis, confocal microscopy on overexpressed green fluorescent protein-fused mutants, and computational analysis on the structures of IL-10RA proteins were performed. Results: We identified a novel compound heterozygote mutation p.[Tyr91Cys];[Pro146Alafs*40] in the IL10RA gene of the patient. The missense variant p.Tyr91Cys was previously identified but not functionally tested, and a frameshift variant, p.Pro146Alafs*40, is novel and nonfunctional. PBMCs from the patient showed defective signal transducer and activator of transcription 3 activation. The p.Tyr91Cys mutant protein failed to properly localize on the plasma membrane. The p.Tyr91Cys mutation seems to disrupt the hydrophobic core structure surrounding the tyrosine 91 residue, causing structural instability. Conclusions: Targeted ES and linkage analysis identified novel compound heterozygous mutations p.[Tyr91Cys];[Pro146Alafs*40] in the IL10RA gene of a child with severe VEO-IBD. p.Tyr91Cys proteins were functionally defective in IL-10RA signaling and failed to properly localize on the plasma membrane, probably due to its structural instability. PMID- 30462268 TI - Auranofin/Vitamin C: A Novel Drug Combination Targeting Triple-Negative Breast Cancer. AB - Background: Cancer cells from different origins exhibit various basal redox statuses and thus respond differently to intrinsic or extrinsic oxidative stress. These intricate characteristics condition the success of redox-based anticancer therapies that capitalize on the ability of reactive oxygen species to achieve selective and efficient cancer cell killing. Methods: Redox biology methods, stable isotope labeling by amino acids in cell culture (SILAC)-based proteomics, and bioinformatics pattern comparisons were used to decipher the underlying mechanisms for differential response of lung and breast cancer cell models to redox-modulating molecule auranofin (AUF) and to combinations of AUF and vitamin C (VC). The in vivo effect of AUF, VC, and two AUF/VC combinations on mice bearing MDA-MB-231 xenografts (n = 5 mice per group) was also evaluated. All statistical tests were two-sided. Results: AUF targeted simultaneously the thioredoxin and glutathione antioxidant systems. AUF/VC combinations exerted a synergistic and hydrogen peroxide (H2O2)-mediated cytotoxicity toward MDA-MB-231 cells and other breast cancer cell lines. The anticancer potential of AUF/VC combinations was validated in vivo on MDA-MB-231 xenografts in mice without notable side effects. On day 14 of treatments, mean (SD) tumor volumes for the vehicle-treated control group and the two AUF/VC combination-treated groups (A/V1 and A/V2) were 197.67 (24.28) mm3, 15.66 (10.90) mm3, and 10.23 (7.30)mm3, respectively; adjusted P values of the differences between mean tumor volumes of vehicle vs A/V1 groups and vehicle vs A/V2 groups were both less than .001. SILAC proteomics, bioinformatics analysis, and functional experiments linked prostaglandin reductase 1 (PTGR1) expression levels with breast cancer cell sensitivity to AUF/VC combinations. Conclusion: The combination of AUF and VC, two commonly available drugs, could be efficient against triple-negative breast cancer and potentially other cancers with similar redox properties and PTGR1 expression levels. The redox-based anticancer activity of this combination and the discriminatory potential of PTGR1 expression are worth further assessment in preclinical and clinical studies. PMID- 30462269 TI - Standards of travel health services by Canadian pharmacists. PMID- 30462270 TI - Start-Stop Assembly: a functionally scarless DNA assembly system optimized for metabolic engineering. AB - DNA assembly allows individual DNA constructs or libraries to be assembled quickly and reliably. Most methods are either: (i) Modular, easily scalable and suitable for combinatorial assembly, but leave undesirable 'scar' sequences; or (ii) bespoke (non-modular), scarless but less suitable for construction of combinatorial libraries. Both have limitations for metabolic engineering. To overcome this trade-off we devised Start-Stop Assembly, a multi-part, modular DNA assembly method which is both functionally scarless and suitable for combinatorial assembly. Crucially, 3 bp overhangs corresponding to start and stop codons are used to assemble coding sequences into expression units, avoiding scars at sensitive coding sequence boundaries. Building on this concept, a complete DNA assembly framework was designed and implemented, allowing assembly of up to 15 genes from up to 60 parts (or mixtures); monocistronic, operon-based or hybrid configurations; and a new streamlined assembly hierarchy minimizing the number of vectors. Only one destination vector is required per organism, reflecting our optimization of the system for metabolic engineering in diverse organisms. Metabolic engineering using Start-Stop Assembly was demonstrated by combinatorial assembly of carotenoid pathways in Escherichia coli resulting in a wide range of carotenoid production and colony size phenotypes indicating the intended exploration of design space. PMID- 30462271 TI - Potassium iodide and miltefosine inhibit biofilms of Sporothrix schenckii species complex in yeast and filamentous forms. AB - This study aimed to evaluate the yeast biofilm growth kinetics and ultrastructure of Sporothrix schenckii complex and assess their mature biofilm susceptibility in filamentous and yeast forms to potassium iodide (KI) and miltefosine (MIL). Yeast biofilms were evaluated by crystal violet staining, XTT reduction assay and microscopic techniques. Susceptibility of planktonic and sessile cells was analyzed by broth microdilution. S. schenckii complex in yeast form produced biofilms, with an optimum maturation at 96 h, showing multilayered blastoconidia embedded in extracellular matrix. KI and MIL minimum inhibitory concentration (MIC) ranges against planktonic cells were 62,500-250,000 MUg/ml and 0.125-4 MUg/ml, respectively. KI and MIL reduced biofilm metabolic activity by 75.4% and 67.7% for filamentous form and 55.1% and 51.6% for yeast form, respectively. This study demonstrated that S. schenckii complex forms biofilms in vitro, and potassium iodide and miltefosine inhibit Sporothrix spp. biofilms in both filamentous and yeast forms. PMID- 30462272 TI - Aminocyclopropane-1-Aarboxylic Acid (ACC) is a key regulator of Guard Mother Cell (GMC) Terminal Division in Arabidopsis thaliana. AB - Stomata function in gas and water vapor exchange between plants and their environment. Stomatal development is under rigorous control of many regulators. The last step of stomatal development is the terminal division of guard mother cells (GMC) into two guard cells (GC). It is still unclear how the symmetric division of GMCs is regulated. Here, we show that ethylene precursor, Aminocyclopropane-1-Aarboxylic Acid (ACC) is required for the symmetric division of GMCs into GCs in Arabidopsis. Exogenous application of ACC biosynthesis inhibitor aminoethoxyvinylglycine (AVG) induced the formation of single guard cells (SGC). Correspondingly, an acs octuple mutant with extremely low endogenous ACC developed SGCs, and exogenous ACC dramatically decreased the number of SGCs in this mutant whereas exogenous ethephon (which is gradually converted into ethylene) had no effect. Furthermore, neither block of endogenous ethylene synthesis nor disruption of ethylene signaling transduction could induce the production of SGCs. Further investigation indicated that ACC promoted the division of GMCs in the fama-1 and flp-1myb88 mutants whereas AVG inhibited. Moreover, ACC positively regulated the expression of CDKB1;1 and CYCA2;3 in the fama-1 and flp-1myb88 mutants. The SGC number was not affected by ACC or AVG in the cdkb1;11;2 and cyca2;234 mutants. The present study demonstrates that ACC itself, but not ethylene, positively modulates the symmetric division of GMCs in a CDKB1s and CYCA2s dependent manner. PMID- 30462273 TI - Degenerate minigene library analysis enables identification of altered branch point utilization by mutant splicing factor 3B1 (SF3B1). AB - Cancer-associated mutations of the core splicing factor 3 B1 (SF3B1) result in selection of novel 3' splice sites (3'SS), but precise molecular mechanisms of oncogenesis remain unclear. SF3B1 stabilizes the interaction between U2 snRNP and branch point (BP) on the pre-mRNA. It has hence been speculated that a change in BP selection is the basis for novel 3'SS selection. Direct quantitative determination of BP utilization is however technically challenging. To define BP utilization by SF3B1-mutant spliceosomes, we used an overexpression approach in human cells as well as a complementary strategy using isogenic murine embryonic stem cells with monoallelic K700E mutations constructed via CRISPR/Cas9-based genome editing and a dual vector homology-directed repair methodology. A synthetic minigene library with degenerate regions in 3' intronic regions (3.4 million individual minigenes) was used to compare BP usage of SF3B1K700E and SF3B1WT. Using this model, we show that SF3B1K700E spliceosomes utilize non canonical sequence variants (at position -1 relative to BP adenosine) more frequently than wild-type spliceosomes. These predictions were confirmed using minigene splicing assays. Our results suggest a model of BP utilization by mutant SF3B1 wherein it is able to utilize non-consensus alternative BP sequences by stabilizing weaker U2-BP interactions. PMID- 30462274 TI - Evaluation of a Systems-Based Tobacco Cessation Program Using Bedside Volunteers. AB - Introduction: Hospitalization and post-discharge provides an opportune time for tobacco cessation. This study tested the feasibility, uptake, and cessation outcomes of a hospital-based tobacco cessation program, delivered by volunteers to the bedside with post-discharge referral to Quitline services. Patient characteristics associated with Quitline uptake and cessation were assessed. Methods: Between February and November 2016, trained hospital volunteers approached inpatient tobacco users on six pilot units. Volunteers shared a cessation brochure and used the ASK-ADVISE-CONNECT model to connect ready-to-quit patients to the Delaware Quitline via fax-referral. Volunteers administered a follow-up survey to all admitted tobacco users via telephone or email at 3-months post-discharge. Results: Of the 743 admitted tobacco users, 531 (72%) were visited by a volunteer, and 97% (531/547) of those approached, accepted the visit. Over one third (201/531; 38%) were ready-to-quit and fax-referred to the Quitline, and 36% of those referred accepted Quitline services. At 3-months post discharge, 37% (135/368) reported not using tobacco in the last 30 days; intent to-treat cessation rate was 18% (135/743). In a multivariable regression model of Quitline fax-referral completion, receiving NRT during hospitalization was the strongest predictor (OR: 1.97; 95% CI: 1.34-2.90). In a model of 3-month cessation, receiving Quitline services (OR: 3.21, 95%CI: 1.35-7.68) and having coronary artery disease (OR: 2.28; 95% CI: 1.11-4.68) were associated with tobacco cessation, but a volunteer visit was not. Conclusions: An "opt-out" tobacco cessation service using trained volunteers is feasible for connecting patients to Quitline services. PMID- 30462275 TI - Exploring Chiropractic Services in the Canadian Forces Health Services - Perceptions of Facilitators and Barriers Among Key Informants. AB - Introduction: Musculoskeletal (MSK) conditions have a significant impact on the health and operational readiness of military members. The Canadian Forces Health Services (CFHS) provides a spectrum of health services in managing Canadian Armed Forces (CAF) personnel health care needs with on-base and off-base services provided by civilian and uniformed health care professionals, including chiropractors. Although chiropractic services are available in US DoD and VA systems, little is known about the facilitators and barriers to integrating on base chiropractic services within the CFHS. This study explored key informants' perceptions of facilitators and barriers to the integration of on-base chiropractic services within the CFHS. Methods: We conducted a qualitative study to describe and understand how an integrated chiropractic service could be designed, implemented, and evaluated within the current interdisciplinary CFHS. Telephone interviews were conducted, using a semi-structured interview guide, to explore key informants' perceptions and experiences of chiropractic care within the CFHS. In total, we invited 27 individuals across Canada to participate; 15 were identified through purposeful sampling, 12 through a snowball sampling technique, and 2 declined. The 25 participants included military personnel (52%), public servants and contractors employed by the Department of Defense (24%), as well as civilian health care providers (24%). All participants were health care providers [physicians (MD) (7), physiotherapists (PT) (13), chiropractors (DC) (5)]. Interviews were audio-recorded and transcribed verbatim. Transcripts were prepared and analyzed using an interpretivist approach that explored key informants' perceptions and experiences. Results: Qualitative analysis revealed numerous facilitators and barriers to chiropractic services in the CFHS. These were categorized under three broad themes: base-to-base variations, variable gatekeeper roles, and referral processes. Barriers to integrating chiropractic services included: lack of clarity about a chiropractor's clinical knowledge and skills; CFHS team members' negative prior experiences with chiropractors (e.g., inappropriate patient-focused communication, clinical management that was not evidence-based, ignorance of military culture); suboptimal bi-directional communication between CAF personnel and DCs across bases; and wide-ranging perspectives pertaining to duplication of services offered by PTs and DCs in managing MSK conditions. Facilitators associated with the integration of chiropractic services within a collaborative and interdisciplinary CAF environment included: patient benefits associated with multiple approaches utilized by different providers; adoption of up-to-date, high-quality evidence and guidelines to standardize care and curtail "dependency" between patient and providers; and co-location of providers to strengthen existing interprofessional communication and relationships. Key informants called for patient care that is collaborative, integrated and patient-centered, rather than "patient-driven" care; civilian providers understanding and respecting military culture rather than assuming transferability of patient management processes from the public civilian sector; standardization of communication protocols and measures to evaluate outcomes of care; and the need to move slowly and respectfully within the current CAF health care system if planning the on-base implementation of chiropractic services. Conclusion: This study illuminated many opportunities and barriers, in complex and diverse domains, related to introducing collaborative chiropractic services in the CFHS. The findings are relevant to increasing understanding and strengthening interprofessional collaborative care within the unique CAF health care delivery system. PMID- 30462276 TI - Neonatal Conjunctivitis Caused by Neisseria cinerea: A Case of Mistaken Identity. AB - We report a case of a 3-day-old boy with Neisseria cinerea conjunctivitis, originally misidentified as Neisseria gonorrhoeae conjunctivitis. Neonates are at increased risk for disseminated gonococcal infection, and physicians should be cognizant of N cinerea and its potential to be mistaken for N gonorrhoeae. PMID- 30462277 TI - scFTD-seq: freeze-thaw lysis based, portable approach toward highly distributed single-cell 3' mRNA profiling. AB - Cellular barcoding of 3' mRNAs enabled massively parallel profiling of single cell gene expression and has been implemented in droplet and microwell based platforms. The latter further adds the value for compatibility with low input samples, optical imaging, scalability, and portability. However, cell lysis in microwells remains challenging despite the recently developed sophisticated solutions. Here, we present scFTD-seq, a microchip platform for performing single cell freeze-thaw lysis directly toward 3' mRNA sequencing. It offers format flexibility with a simplified, widely adoptable workflow that reduces the number of preparation steps and hands-on time, with the quality of data and cost per sample matching that of the state-of-the-art scRNA-seq platforms. Freeze-thaw, known as an unfavorable lysis method resulting in possible RNA fragmentation, turns out to be fully compatible with 3' scRNA-seq. We applied it to the profiling of circulating follicular helper T cells implicated in systemic lupus erythematosus pathogenesis. Our results delineate the heterogeneity in the transcriptional programs and effector functions of these rare pathogenic T cells. As scFTD-seq decouples on-chip cell isolation and library preparation, we envision it to allow sampling at the distributed sites including point-of-care settings and downstream processing at centralized facilities, which should enable wide-spread adoption beyond academic laboratories. PMID- 30462278 TI - Quantitative fluorescence imaging determines the absolute number of locked nucleic acid oligonucleotides needed for suppression of target gene expression. AB - Locked nucleic acid based antisense oligonucleotides (LNA-ASOs) can reach their intracellular RNA targets without delivery modules. Functional cellular uptake involves vesicular accumulation followed by translocation to the cytosol and nucleus. However, it is yet unknown how many LNA-ASO molecules need to be delivered to achieve target knock down. Here we show by quantitative fluorescence imaging combined with LNA-ASO microinjection into the cytosol or unassisted uptake that ~105 molecules produce >50% knock down of their targets, indicating that a substantial amount of LNA-ASO escapes from endosomes. Microinjected LNA ASOs redistributed within minutes from the cytosol to the nucleus and remained bound to nuclear components. Together with the fact that RNA levels for a given target are several orders of magnitude lower than the amounts of LNA-ASO, our data indicate that only a minor fraction is available for RNase H1 mediated reduction of target RNA. When non-specific binding sites were blocked by co administration of non-related LNA-ASOs, the amount of target LNA-ASO required was reduced by an order of magnitude. Therefore, dynamic processes within the nucleus appear to influence the distribution and activity of LNA-ASOs and may represent important parameters for improving their efficacy and potency. PMID- 30462280 TI - The Year in Cardiology at ESC Congress. PMID- 30462281 TI - The NHS and healthcare in Europe. PMID- 30462279 TI - Continued vs. interrupted direct oral anticoagulants at the time of device surgery, in patients with moderate to high risk of arterial thrombo-embolic events (BRUISE CONTROL-2). AB - Aims: Guidelines recommend warfarin continuation rather than heparin bridging for pacemaker and defibrillator surgery, after the BRUISE CONTROL trial demonstrated an 80% reduction in device pocket haematoma with this approach. However, direct oral anticoagulants (DOACs) are now used to treat the majority of patients with atrial fibrillation. We sought to understand the best strategy to manage the DOACs at the time of device surgery and specifically hypothesized that performing device surgery without DOAC interruption would result in a reduced haematoma rate. Methods and results: We randomly assigned patients with atrial fibrillation and CHA2DS2-VASc score >=2, to continued vs. interrupted DOAC (dabigatran, rivaroxaban, or apixaban). The primary outcome was blindly evaluated, clinically significant device pocket haematoma: resulting in re-operation, interruption of anticoagulation, or prolonging hospital stay. In the continued arm, the median time between pre- and post-operative DOAC doses was 12 h; in the interrupted arm the median time was 72 h. Clinically significant haematoma occurred in of 7 of 328 (2.1%; 95% CI 0.9-4.3) patients in the continued DOAC arm and 7 of 334 (2.1%; 95% CI 0.9-4.3) patients in the interrupted DOAC arm (P = 0.97). Complications were uncommon, and included one stroke and one symptomatic pericardial effusion in each arm. Conclusions: These results suggest that, dependent on the clinical scenario, either management strategy (continued DOAC or interrupted DOAC) might be reasonable, at least for patients similar to those enrolled in our trial. PMID- 30462282 TI - Biological defibrillation. PMID- 30462284 TI - How good is the NHS of the UK. PMID- 30462283 TI - The NHS of the UK at 70 years. PMID- 30462285 TI - Control of Cockroaches (Blattaria) in Sewers: A Practical Approach Systematic Review. AB - Periplaneta americana (L.) (Blattaria: Blattidae), the American cockroach, is the most important invasive urban pest of sewer environments colonizing there with high significance of human public health and household allergens need to be controlled. Therefore this practical approach systematic review perform internationally to highlight and provide a detailed P. americana control in sewers. Of the 474 papers, 129 papers were selected to become this practical approach systematic review study of cockroach control in sewers. To control the American cockroaches, many studies have been conducted in various fields describing from an angle. The results were classified and discussed in getting cockroaches from sewers into buildings and their elimination, insecticide susceptibility, application of dust, bait and Inesfly paint insecticide formulations, biocontrol, and futuristic action categories. A recommending manner to achieve a successful P. americana cockroach control in sewers is using a combination of Integrated Pest Management (IPM) strategies resulted in significant reductions of cockroach infestations and asthma health outcomes. Use of P. americana breeding thelytoky, push-pull strategies and an automated sewer robot, and integrating health into the future buildings may be new approaches of P. americana control strategies. PMID- 30462286 TI - Public Health Accreditation of Army Preventive Medicine Departments: Improving Military Medical Treatment Facility Practice to Impact Force Readiness. PMID- 30462287 TI - Endoscopic and Histological Normalization as a Target to Prevent Clinical Relapse in Ulcerative Colitis Patients. PMID- 30462288 TI - The utility of real-time polymerase chain reaction in detecting Coccidioides immitis among clinical specimens in the Central California San Joaquin Valley. AB - Coccidioidomycosis, the fungal infection caused by dimorphic Coccidioides species, is typically diagnosed by histopathologic identification of spherules, by culture, or by serology. These tests are reliable but time-intensive, delaying diagnosis and treatment. Rapid real-time polymerase chain reaction (RT-PCR) can be performed and was validated to identify Coccidioides immitis using an in-house developed assay for the Becton Dickinson molecular instrument (BD MAXTM). These studies were performed using patient samples that had been shown to be positive on previously set up fungal cultures. To evaluate this new RT-PCR test in the clinical setting, we conducted a retrospective chart review of patients (N = 1160) who underwent Coccidioides PCR (Cocci PCR) on clinical samples between March 1, 2014, and Dec 31, 2016. We abstracted clinical, microbiologic, serologic, radiographic, treatment, and follow-up data. Specimens of cerebrospinal fluid (CSF), bronchioalveolar lavage fluid (BAL), lung tissue biopsy (LTB), sputum, and pleural fluid were evaluated to determine sensitivity and specificity. Of the 113 specimens that tested positive for Cocci PCR, all had clinical disease defined by traditional clinical criteria, yielding 100% specificity. Overall sensitivity was 74% versus 46% for fungal culture and was available in 4 hours rather than 1-2 weeks. Sensitivities varied by source material and clinical setting. CSF had a sensitivity of 59%, BAL for acute pneumonia 91%, sputum for acute pneumonia 94%, pleural fluid 86%, but LTB for lung nodules only 44%. Overall positive predictive value (PPV) was 100%, while negative predictive value (NPV) was 96%, but again this varied by specimen and clinical setting. Our experience with clinical testing of >1160 specimens over 2 3 years shows we can utilize this technology to improve our ability to diagnose disease but that the sensitivity varies by specimen source and clinical setting. PMID- 30462289 TI - E. coli gene regulatory networks are inconsistent with gene expression data. AB - Gene regulatory networks (GRNs) and gene expression data form a core element of systems biology-based phenotyping. Changes in the expression of transcription factors are commonly believed to have a causal effect on the expression of their targets. Here we evaluated in the best researched model organism, Escherichia coli, the consistency between a GRN and a large gene expression compendium. Surprisingly, a modest correlation was observed between the expression of transcription factors and their targets and, most noteworthy, both activating and repressing interactions were associated with positive correlation. When evaluated using a sign consistency model we found the regulatory network was not more consistent with measured expression than random network models. We conclude that, at least in E. coli, one cannot expect a causal relationship between the expression of transcription and factors their targets, and that the current static GRN does not adequately explain transcriptional regulation. The implications of this are profound as they question what we consider established knowledge of the systemic biology of cells and point to methodological limitations with respect to single omics analysis, static networks and temporality. PMID- 30462290 TI - Finely tuned conformational dynamics regulate the protective function of the lncRNA MALAT1 triple helix. AB - Nucleic acid triplexes may regulate many important biological processes. Persistent accumulation of the oncogenic 7-kb long noncoding RNA MALAT1 is dependent on an unusually long intramolecular triple helix. This triplex structure is positioned within a conserved ENE (element for nuclear expression) motif at the lncRNA 3' terminus and protects the entire transcript from degradation in a polyA-independent manner. A requisite 3' maturation step leads to triplex formation though the precise mechanism of triplex folding remains unclear. Furthermore, the contributions of several peripheral structural elements to triplex formation and protective function have not been determined. We evaluated the stability, conformational fluctuations, and function of this MALAT1 ENE triple helix (M1TH) protective element using in vitro mutational analyses coupled with biochemical and biophysical characterizations. Using fluorescence and UV melts, FRET, and an exonucleolytic decay assay we define a concerted mechanism for triplex formation and uncover a metastable, dynamic triplex population under near-physiological conditions. Structural elements surrounding the triplex regulate the dynamic M1TH conformational variability, but increased triplex dynamics lead to M1TH degradation. Taken together, we suggest that finely tuned dynamics may be a general mechanism regulating triplex-mediated functions. PMID- 30462291 TI - Inosine induces context-dependent recoding and translational stalling. AB - RNA modifications are present in all classes of RNAs. They control the fate of mRNAs by affecting their processing, translation, or stability. Inosine is a particularly widespread modification in metazoan mRNA arising from deamination of adenosine catalyzed by the RNA-targeting adenosine deaminases ADAR1 or ADAR2. Inosine is commonly thought to be interpreted as guanosine by cellular machines and during translation. Here, we systematically test ribosomal decoding using mass spectrometry. We show that while inosine is primarily interpreted as guanosine it can also be decoded as adenosine, and rarely even as uracil. Decoding of inosine as adenosine and uracil is context-dependent. In addition, mass spectrometry analysis indicates that inosine causes ribosome stalling especially when multiple inosines are present in the codon. Indeed, ribosome profiling data from human tissues confirm inosine-dependent ribosome stalling in vivo. To our knowledge this is the first study where decoding of inosine is tested in a comprehensive and unbiased way. Thus, our study shows novel, unanticipated functions for inosines in mRNAs, further expanding coding potential and affecting translational efficiency. PMID- 30462292 TI - Structural basis for acceptor RNA substrate selectivity of the 3' terminal uridylyl transferase Tailor. AB - Non-templated 3'-uridylation of RNAs has emerged as an important mechanism for regulating the processing, stability and biological function of eukaryotic transcripts. In Drosophila, oligouridine tailing by the terminal uridylyl transferase (TUTase) Tailor of numerous RNAs induces their degradation by the exonuclease Dis3L2, which serves functional roles in RNA surveillance and mirtron RNA biogenesis. Tailor preferentially uridylates RNAs terminating in guanosine or uridine nucleotides but the structural basis underpinning its RNA substrate selectivity is unknown. Here, we report crystal structures of Tailor bound to a donor substrate analog or mono- and oligouridylated RNA products. These structures reveal specific amino acid residues involved in donor and acceptor substrate recognition, and complementary biochemical assays confirm the critical role of an active site arginine in conferring selectivity toward 3'-guanosine terminated RNAs. Notably, conservation of these active site features suggests that other eukaryotic TUTases, including mammalian TUT4 and TUT7, might exhibit similar, hitherto unknown, substrate selectivity. Together, these studies provide critical insights into the specificity of 3'-uridylation in eukaryotic post transcriptional gene regulation. PMID- 30462293 TI - Autocidal Gravid Ovitrap Incorporation with Attractants for Control of Gravid and Host-Seeking Aedes aegypti (Diptera: Culicidae). AB - Aedes aegypti Linnaeus (Diptera: Culicidae) is a primary vector of multiple arboviruses including Zika, dengue, chikungunya, and yellow fever. After incorporating BG lure or BG lure + octenol, the CDC's Autocidal Gravid Ovitrap (AGO) was more effective at collecting and controlling host-seeking female Ae. aegypti than gravid female mosquitoes. The addition of octenol to the AGO did not increase the number of female mosquitoes captured by the AGO, compared with the AGO alone. The AGO baited with the BG lure captured a significant number of host seeking female Ae. aegypti. This finding indicates that the combination of AGO with BG lure could enable the trap to control female Ae. aegypti mosquitoes representing either host-seeking or gravid physiological states. PMID- 30462294 TI - Genome-wide mapping of 8-oxo-7,8-dihydro-2'-deoxyguanosine reveals accumulation of oxidatively-generated damage at DNA replication origins within transcribed long genes of mammalian cells. AB - 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) is one of the major DNA modifications and a potent pre-mutagenic lesion prone to mispair with 2' deoxyadenosine (dA). Several thousand residues of 8-oxodG are constitutively generated in the genome of mammalian cells, but their genomic distribution has not yet been fully characterized. Here, by using OxiDIP-Seq, a highly sensitive methodology that uses immuno-precipitation with efficient anti-8-oxodG antibodies combined with high-throughput sequencing, we report the genome-wide distribution of 8-oxodG in human non-tumorigenic epithelial breast cells (MCF10A), and mouse embryonic fibroblasts (MEFs). OxiDIP-Seq revealed sites of 8-oxodG accumulation overlapping with gammaH2AX ChIP-Seq signals within the gene body of transcribed long genes, particularly at the DNA replication origins contained therein. We propose that the presence of persistent single-stranded DNA, as a consequence of transcription-replication clashes at these sites, determines local vulnerability to DNA oxidation and/or its slow repair. This oxidatively-generated damage, likely in combination with other kinds of lesion, might contribute to the formation of DNA double strand breaks and activation of DNA damage response. PMID- 30462295 TI - A genetic screen pinpoints ribonucleotide reductase residues that sustain dNTP homeostasis and specifies a highly mutagenic type of dNTP imbalance. AB - The balance and the overall concentration of intracellular deoxyribonucleoside triphosphates (dNTPs) are important determinants of faithful DNA replication. Despite the established fact that changes in dNTP pools negatively influence DNA replication fidelity, it is not clear why certain dNTP pool alterations are more mutagenic than others. As intracellular dNTP pools are mainly controlled by ribonucleotide reductase (RNR), and given the limited number of eukaryotic RNR mutations characterized so far, we screened for RNR1 mutations causing mutator phenotypes in Saccharomyces cerevisiae. We identified 24 rnr1 mutant alleles resulting in diverse mutator phenotypes linked in most cases to imbalanced dNTPs. Among the identified rnr1 alleles the strongest mutators presented a dNTP imbalance in which three out of the four dNTPs were elevated (dCTP, dTTP and dGTP), particularly if dGTP levels were highly increased. These rnr1 alleles caused growth defects/lethality in DNA replication fidelity-compromised backgrounds, and caused strong mutator phenotypes even in the presence of functional DNA polymerases and mismatch repair. In summary, this study pinpoints key residues that contribute to allosteric regulation of RNR's overall activity or substrate specificity. We propose a model that distinguishes between different dNTP pool alterations and provides a mechanistic explanation why certain dNTP imbalances are particularly detrimental. PMID- 30462296 TI - Oncolytic virus therapy in Japan: progress in clinical trials and future perspectives. AB - Oncolytic virus therapy is a promising new option for cancer. It utilizes genetically engineered or naturally occurring viruses that selectively replicate in and kill cancer cells without harming normal cells. T-VEC (talimogene laherparepvec), a second-generation oncolytic herpes simplex virus type 1, was approved by the US Food and Drug Administration for the treatment of inoperable melanoma in 2015 and subsequently approved in Europe in 2016. Other oncolytic viruses using different parental viruses have also been tested in Phase III clinical trials and are ready for drug approval: Pexa-Vec (pexastimogene devacirepvec), an oncolytic vaccinia virus, CG0070, an oncolytic adenovirus, and REOLYSIN (pelareorep), an oncolytic reovirus. In Japan, as of May 2018, several oncolytic viruses have been developed, and some have already proceeded to clinical trials. In this review, we summarize clinical trials assessing oncolytic virus therapy that were conducted or are currently ongoing in Japan, specifically, T-VEC, the abovementioned oncolytic herpes simplex virus type 1, G47Delta, a third-generation oncolytic herpes simplex virus type 1, HF10, a naturally attenuated oncolytic herpes simplex virus type 1, Telomelysin, an oncolytic adenovirus, Surv.m-CRA, another oncolytic adenovirus, and Sendai virus particle. In the near future, oncolytic virus therapy may become an important and major treatment option for cancer in Japan. PMID- 30462297 TI - Structural identification of conserved RNA binding sites in herpesvirus ORF57 homologs: implications for PAN RNA recognition. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) transcribes a long noncoding polyadenylated nuclear (PAN) RNA, which promotes the latent to lytic transition by repressing host genes involved in antiviral responses as well as viral proteins that support the latent state. KSHV also expresses several early proteins including ORF57 (Mta), a member of the conserved multifunctional ICP27 protein family, which is essential for productive replication. ORF57/Mta interacts with PAN RNA via a region termed the Mta responsive element (MRE), stabilizing the transcript and supporting nuclear accumulation. Here, using a close homolog of KSHV ORF57 from herpesvirus saimiri (HVS), we determined the crystal structure of the globular domain in complex with a PAN RNA MRE, revealing a uracil specific binding site that is also conserved in KSHV. Using solution NMR, RNA binding was also mapped within the disordered N-terminal domain of KSHV ORF57, and showed specificity for an RNA fragment containing a GAAGRG motif previously known to bind a homologous region in HVS ORF57. Together these data located novel differential RNA recognition sites within neighboring domains of herpesvirus ORF57 homologs, and revealed high-resolution details of their interactions with PAN RNA, thus providing insight into interactions crucial to viral function. PMID- 30462298 TI - Effects of Insecticides Used in Organic Agriculture on Anastatus reduvii (Hymenoptera: Eupelmidae) and Telenomus podisi (Hymenoptera: Scelionidae), Egg Parasitoids of Pestivorous Stink Bugs. AB - Lethal and sublethal effects of insecticides used in organic agriculture were tested against Anastatus reduvii and Telenomus podisi, native North American hymenopteran egg parasitoids of the native Euschistus servus Say (Hemiptera: Pentatomidae) and the invasive Halyomorpha halys Stal. Entrust (spinosad), PyGanic (pyrethrin), Neemix (azadirachtin), and Azera (pyrethrin + azadirachtin) were tested at equivalent field rates of 1*, 0.5*, and 0.1*. Bioassays included insecticide exposure to parasitoids through residue on substrate, parasitized host eggs, and their food source. When exposed to dried residues, Entrust caused 100% mortality at the 0.5* rate to both species; PyGanic, Neemix, and Azera exhibited low toxicity. Exposure of parasitized host eggs to Entrust 1* during the egg stage of parasitoid development reduced parasitoid emergence compared to all other treatments in both species. Anastatus reduvii emergence was also reduced by PyGanic at 0.5* and 1*. Parasitoid emergence from host eggs exposed during the pupal stage was more variable than egg stage exposure; emergence of both species was reduced in 0.5* and 1* rates of PyGanic, and A. reduvii was reduced in the 0.5* rate of Entrust compared to controls. Longevity of emerged parasitoids surviving exposure within host eggs showed that Entrust was more deleterious than Neemix or PyGanic. When A. reduvii was fed insecticide-laced honey, all treatments except Neemix at 0.1* reduced adult longevity compared to the control. These studies demonstrated that insecticides commonly used in organic agriculture can negatively affect two common parasitoids of stink bugs; specifically, negative effects were most pronounced with Entrust, and variable with Neemix and Pyganic. PMID- 30462299 TI - Still Perfecting Radioiodine in Thyroid Cancer, After All These Years. PMID- 30462300 TI - Synthetic switch to minimize CRISPR off-target effects by self-restricting Cas9 transcription and translation. AB - CRISPR/Cas9 is a powerful genome editing system but uncontrolled Cas9 nuclease expression triggers off-target effects and even in vivo immune responses. Inspired by synthetic biology, here we built a synthetic switch that self regulates Cas9 expression not only in the transcription step by guide RNA-aided self-cleavage of cas9 gene, but also in the translation step by L7Ae:K-turn repression system. We showed that the synthetic switch enabled simultaneous transcriptional and translational repression, hence stringently attenuating the Cas9 expression. The restricted Cas9 expression induced high efficiency on-target indel mutation while minimizing the off-target effects. Furthermore, we unveiled the correlation between Cas9 expression kinetics and on-target/off-target mutagenesis. The synthetic switch conferred detectable Cas9 expression and concomitant high frequency on-target mutagenesis at as early as 6 h, and restricted the Cas9 expression and off-target effects to minimal levels through 72 h. The synthetic switch is compact enough to be incorporated into viral vectors for self-regulation of Cas9 expression, thereby providing a novel 'hit and run' strategy for in vivo genome editing. PMID- 30462301 TI - Structural insights into chromosome attachment to the nuclear envelope by an inner nuclear membrane protein Bqt4 in fission yeast. AB - The dynamic association of chromosomes with the nuclear envelope (NE) is essential for chromosome maintenance. Schizosaccharomyces pombe inner nuclear membrane protein Bqt4 plays a critical role in connecting telomeres to the NE, mainly through a direct interaction with the telomeric protein Rap1. Bqt4 also interacts with Lem2 for pericentric heterochromatin maintenance. How Bqt4 coordinates the interactions with different proteins to exert their functions is unclear. Here, we report the crystal structures of the N-terminal domain of Bqt4 in complexes with Bqt4-binding motifs from Rap1, Lem2, and Sad1. The structural, biochemical and cellular analyses reveal that the N-terminal domain of Bqt4 is a protein-interaction module that recognizes a consensus motif and plays essential roles in telomere-NE association and meiosis progression. Phosphorylation of Bqt4 interacting proteins may act as a switch to regulate these interactions during cell cycles. Our studies provide structural insights into the identification and regulation of Bqt4-mediated interactions. PMID- 30462302 TI - MBGD update 2018: microbial genome database based on hierarchical orthology relations covering closely related and distantly related comparisons. AB - The Microbial Genome Database for Comparative Analysis (MBGD) is a database for comparative genomics based on comprehensive orthology analysis of bacteria, archaea and unicellular eukaryotes. MBGD now contains 6318 genomes. To utilize the database for both closely related and distantly related genomes, MBGD previously provided two types of ortholog tables: the standard ortholog table containing one representative genome from each genus covering the entire taxonomic range and the taxon specific ortholog tables for each taxon. However, this approach has a drawback in that the standard ortholog table contains only genes that are conserved in the representative genomes. To address this problem, we developed a stepwise procedure to construct ortholog tables hierarchically in a bottom-up manner. By using this approach, the new standard ortholog table now covers the entire gene repertoire stored in MBGD. In addition, we have enhanced several functionalities, including rapid and flexible keyword searching, profile based sequence searching for orthology assignment to a user query sequence, and displaying a phylogenetic tree of each taxon based on the concatenated core gene sequences. For integrative database searching, the core data in MBGD are represented in Resource Description Framework (RDF) and a SPARQL interface is provided to search them. MBGD is available at http://mbgd.genome.ad.jp/. PMID- 30462303 TI - Open Targets Platform: new developments and updates two years on. AB - The Open Targets Platform integrates evidence from genetics, genomics, transcriptomics, drugs, animal models and scientific literature to score and rank target-disease associations for drug target identification. The associations are displayed in an intuitive user interface (https://www.targetvalidation.org), and are available through a REST-API (https://api.opentargets.io/v3/platform/docs/swagger-ui) and a bulk download (https://www.targetvalidation.org/downloads/data). In addition to target-disease associations, we also aggregate and display data at the target and disease levels to aid target prioritisation. Since our first publication two years ago, we have made eight releases, added new data sources for target-disease associations, started including causal genetic variants from non genome-wide targeted arrays, added new target and disease annotations, launched new visualisations and improved existing ones and released a new web tool for batch search of up to 200 targets. We have a new URL for the Open Targets Platform REST-API, new REST endpoints and also removed the need for authorisation for API fair use. Here, we present the latest developments of the Open Targets Platform, expanding the evidence and target-disease associations with new and improved data sources, refining data quality, enhancing website usability, and increasing our user base with our training workshops, user support, social media and bioinformatics forum engagement. PMID- 30462304 TI - Pol III-dependent cabbage BoNR8 long ncRNA affects seed germination and growth in Arabidopsis. AB - Long ncRNAs (lncRNAs) are non-protein-coding transcripts longer than 200 nt that are distributed widely in organisms and play many physiological roles. The BoNR8 lncRNA is a 272 nt long transcript yielded by Pol III in cabbage that was identified as an closest homologues of the AtR8 lncRNA in Arabidopsis. The BoNR8 lncRNA was expressed extensively in the epidermal tissue in the root elongation zone of germinated seeds, and its accumulation was induced by abiotic stresses, auxins and ABA. To investigate the correlation between the BoNR8 lncRNA and germination, BoNR8-overexpressing Arabidopsis plants (BoNR8-AtOX) were prepared. Three independent BoNR8-AtOX lines showed less primary root elongation, incomplete silique development and decreased germination rates. The germination efficiencies were affected strongly by ABA and slightly by salt stress, and ABA related gene expression was changed in the BoNR8-AtOX lines. PMID- 30462305 TI - Sexually Acquired Hepatitis C Infection in HIV-uninfected Men Who Have Sex with Men Using Pre-exposure Prophylaxis Against HIV. AB - Sexually-acquired HCV infections among HIV-uninfected men who have sex with men (MSM) have been rare. With the introduction of pre-exposure prophylaxis (PrEP) against HIV, we hypothesized that these infections would increase. Between 2013 and 2018 we diagnosed 15 likely sexually-acquired HCV infections among 14 MSM using PrEP. Most (87%) were asymptomatic, detected by routine ALT or HCV monitoring. Half reported increasing sex partners and drug use after starting PrEP; 5 reported injection of methamphetamine. Interventions are needed to prevent sexually-acquired HCV infections by MSM using PrEP. CDC guidelines for monitoring during PrEP should include regular ALT and HCV testing. PMID- 30462306 TI - Uncritical Publication of a Biased Study Leads to Misleading Media Reports. PMID- 30462307 TI - Stem-loops direct precise processing of 3' UTR-derived small RNA MicL. AB - Increasing numbers of 3'UTR-derived small, regulatory RNAs (sRNAs) are being discovered in bacteria, most generated by cleavage from longer transcripts. The enzyme required for these cleavages has been reported to be RNase E, the major endoribonuclease in enterica bacteria. Previous studies investigating RNase E have come to a range of different conclusions regarding the determinants for RNase E processing. To better understand the sequence and structure determinants for the precise processing of a 3' UTR-derived sRNA, we examined the cleavage of multiple mutant and chimeric derivatives of the 3' UTR-derived MicL sRNA in vivo and in vitro. Our results revealed that tandem stem-loops 3' to the cleavage site define optimal, correctly-positioned cleavage of MicL and probably other sRNAs. Moreover, our assays of MicL, ArcZ and CpxQ showed that sRNAs exhibit differential sensitivity to RNase E, likely a consequence of a hierarchy of sRNA features recognized by the endonuclease. PMID- 30462308 TI - ERASE: a novel surface reconditioning strategy for single-molecule experiments. AB - While surface-based single-molecule experiments have revolutionized our understanding of biology and biomolecules, the workflow in preparing for such experiments, especially surface cleaning and functionalization, remains labor intensive and time-consuming. Even worse, meticulously assembled flow channels can be used only once for most experiments. A reusable surface would thus dramatically increase productivity and efficiency of single-molecule experiments. In this paper, we report a novel surface reconditioning strategy termed ERASE (Epitaxial Removal Aided by Strand Exchange) that allows a single flow cell to be used for vast repetition of single-molecule experiments. In this method, biomolecules immobilized to the surface through a nucleic acid duplex are liberated when a competing DNA strand disrupts the duplex via toehold-mediated strand displacement. We demonstrate the wide-range applicability of this method with various common surface preparation techniques, fluorescent dyes, and biomolecules including the bacterial ribosome. Beyond time and cost savings, we also show ERASE can assort molecules based on a nucleic acid barcode sequence, thus allowing experiments on different molecules in parallel. Our method increases the utility of prepared surfaces and is a significant improvement to the current single-use paradigm. PMID- 30462309 TI - Direct interaction between the PRDM3 and PRDM16 tumor suppressors and the NuRD chromatin remodeling complex. AB - Aberrant isoform expression of chromatin-associated proteins can induce epigenetic programs related to disease. The MDS1 and EVI1 complex locus (MECOM) encodes PRDM3, a protein with an N-terminal PR-SET domain, as well as a shorter isoform, EVI1, lacking the N-terminus containing the PR-SET domain (DeltaPR). Imbalanced expression of MECOM isoforms is observed in multiple malignancies, implicating EVI1 as an oncogene, while PRDM3 has been suggested to function as a tumor suppressor through an unknown mechanism. To elucidate functional characteristics of these N-terminal residues, we compared the protein interactomes of the full-length and DeltaPR isoforms of PRDM3 and its closely related paralog, PRDM16. Unlike the DeltaPR isoforms, both full-length isoforms exhibited a significantly enriched association with components of the NuRD chromatin remodeling complex, especially RBBP4. Typically, RBBP4 facilitates chromatin association of the NuRD complex by binding to histone H3 tails. We show that RBBP4 binds to the N-terminal amino acid residues of PRDM3 and PRDM16, with a dissociation constant of 3.0 MUM, as measured by isothermal titration calorimetry. Furthermore, high-resolution X-ray crystal structures of PRDM3 and PRDM16 N-terminal peptides in complex with RBBP4 revealed binding to RBBP4 within the conserved histone H3-binding groove. These data support a mechanism of isoform-specific interaction of PRDM3 and PRDM16 with the NuRD chromatin remodeling complex. PMID- 30462310 TI - Regulation of FUSCA3 expression during seed development in Arabidopsis. AB - FUSCA3 (FUS3) is a master regulator of seed development important in establishing and maintaining embryonic identity whose expression is tightly regulated at genetic and epigenetic levels. Despite this prominent role, the control of FUS3 expression remains poorly understood. Promoter and functional complementation analyses provided insight into the regulation of FUS3. W-boxes present in the promoter proximal to the start of transcription are recognised by WRKY type-1 factors which are necessary for the activation of FUS3 expression. The RY motif, binding site of B3 factors, is important for the activation of FUS3 in the embryo proper but not in the suspensor. The loss of a negative regulatory region (NRS) leads to preferential expression of FUS3 in the vasculature of vegetative tissues. Since the NRS includes the RY motif, mechanisms of activation and repression target adjacent or overlapping regions. These findings discriminate the regulation of FUS3 from that of LEAFY COTYLEDON2 by the control exerted by WRKY factors and by the presence of the RY motif, yet also confirm conservation of certain regulatory elements thereby implicating potential regulation by BASIC PENTACYSTEINE (BPC) factors and POLYCOMB REPRESSIVE COMPLEX2 (PRC2). PMID- 30462311 TI - Family members and their individual roles: an Arabidopsis arogenate dehydratase ADT2 and its role in seed development. PMID- 30462312 TI - Kinesiophobia Is Associated with Migraine. AB - Objective: The aim of this study was to assess kinesiophobia in patients with migraine and to determine its association and correlation with cutaneous allodynia and clinical manifestations of migraine. Design: A cross-sectional study. Setting: A headache clinic of a university-based hospital. Subjects: Eighty-nine patients diagnosed with migraine by a neurologist specialized in headache. Methods: Patients completed the Tampa Scale for Kinesiophobia (TSK) and the 12-item Allodynia Symptom Checklist (ASC-12) and described the frequency, duration, and intensity of migraine attacks, as well as number of years with migraine. Results: The prevalence of kinesiophobia was 53%, and it was associated with the classification of severe cutaneous allodynia (X2= 9.96, P = 0.02) but not with its presence (X2= 3.11, P = 0.07). Kinesiophobia and clinical migraine features were not significantly associated (P > 0.05), nor were TSK score, ASC-12 score, or clinical migraine features (r < 0.21, P > 0.05). Subjects with migraine, with or without kinesiophobia, believed that physical activity could not help to control or relieve their pain, and those with kinesiophobia, furthermore, believed that exercise may be harmful. Conclusions: Kinesiophobia is present in about half of migraineurs. It was associated with worsened cutaneous allodynia severity, but not with its presence, in patients with migraine. Education strategies should be implemented as negative beliefs related to exercise are present despite its evidence of benefit in migraine treatment. PMID- 30462313 TI - Cistrome Data Browser: expanded datasets and new tools for gene regulatory analysis. AB - The Cistrome Data Browser (DB) is a resource of human and mouse cis-regulatory information derived from ChIP-seq, DNase-seq and ATAC-seq chromatin profiling assays, which map the genome-wide locations of transcription factor binding sites, histone post-translational modifications and regions of chromatin accessible to endonuclease activity. Currently, the Cistrome DB contains approximately 47,000 human and mouse samples with about 24,000 newly collected datasets compared to the previous release two years ago. Furthermore, the Cistrome DB has a new Toolkit module with several features that allow users to better utilize the large-scale ChIP-seq, DNase-seq, and ATAC-seq data. First, users can query the factors which are likely to regulate a specific gene of interest. Second, the Cistrome DB Toolkit facilitates searches for factor binding, histone modifications, and chromatin accessibility in any given genomic interval shorter than 2Mb. Third, the Toolkit can determine the most similar ChIP seq, DNase-seq, and ATAC-seq samples in terms of genomic interval overlaps with user-provided genomic interval sets. The Cistrome DB is a user-friendly, up-to date, and well maintained resource, and the new tools will greatly benefit the biomedical research community. The database is freely available at http://cistrome.org/db, and the Toolkit is at http://dbtoolkit.cistrome.org. PMID- 30462314 TI - Design of highly active double-pseudoknotted ribozymes: a combined computational and experimental study. AB - Design of RNA sequences that adopt functional folds establishes principles of RNA folding and applications in biotechnology. Inverse folding for RNAs, which allows computational design of sequences that adopt specific structures, can be utilized for unveiling RNA functions and developing genetic tools in synthetic biology. Although many algorithms for inverse RNA folding have been developed, the pseudoknot, which plays a key role in folding of ribozymes and riboswitches, is not addressed in most algorithms. For the few algorithms that attempt to predict pseudoknot-containing ribozymes, self-cleavage activity has not been tested. Herein, we design double-pseudoknot HDV ribozymes using an inverse RNA folding algorithm and test their kinetic mechanisms experimentally. More than 90% of the positively designed ribozymes possess self-cleaving activity, whereas more than 70% of negative control ribozymes, which are predicted to fold to the necessary structure but with low fidelity, do not possess it. Kinetic and mutation analyses reveal that these RNAs cleave site-specifically and with the same mechanism as the WT ribozyme. Most ribozymes react just 50- to 80-fold slower than the WT ribozyme, and this rate can be improved to near WT by modification of a junction. Thus, fast-cleaving functional ribozymes with multiple pseudoknots can be designed computationally. PMID- 30462315 TI - Corrigendum. PMID- 30462316 TI - Black spruce assimilates nitrate in boreal winter. AB - Winter has long been considered a dormant season in boreal forests regarding plant physiological activity such as nutrient acquisition. However, biogeochemical data clearly show that soil can remain unfrozen with substantial rates of nutrient transformation for several weeks following autumn snowfall. Here we examined nitrate (NO3--N) assimilation by black spruce (Picea mariana (Mill.) Britton, Sterns and Poggenb.) during summer and winter in Interior Alaska to test our hypothesis that this boreal species is able to assimilate NO3--N, even at the very low temperatures typical of early winter. Nitrate reductase activity (NRA) was measured in current year needles and fine roots of black spruce as an indicator of NO3--N assimilation in the summer and winter at two boreal forest sites. Nitrate concentration in the needles and roots were also measured to determine whether NO3--N was available in plant tissue for the enzyme. Nitrate reductase activity and NO3--N were detected in needles and roots in the winter as well as the summer. The results of a generalized linear mixed model showed that season had minimal effects on NRA and NO3--N concentration in this species. Additionally, the effect of incubation temperature for the NRA assays was tested at 30 degrees C and -3 degrees C for samples collected in the winter. Substantial enzyme activity was detected in winter-collected samples, even in incubations conducted at -3 degrees C. These results indicate that this dominant tree species in the boreal forests of Interior Alaska, black spruce, has the capacity to assimilate NO3--N below freezing temperatures, suggesting that the physiological activity required for nitrogen (N) resource acquisition may extend beyond the typical growing season. Our findings coupled to biogeochemical evidence for high microbial activity under the snow also indicate that winter N acquisition should be taken into account when estimating the annual N budgets of boreal forest ecosystems. PMID- 30462317 TI - Quantifying the Impact of Excluding Insecticide Classes From Cotton Integrated Pest Management Programs in the U.S. Mid-South. AB - Current assessments from the U.S. Environmental Protection Agency suggest that some current insecticides may be lost or severely restricted in the near future. An experiment was conducted from 2014 to 2015 at two locations in Mississippi to determine the impact of losses of insecticide classes on integrated pest management of insect pests in cotton. The treatments included cotton treated with all available classes of insecticides, cotton treated with all classes except neonicotinoids, cotton treated with all classes except pyrethroids, cotton treated with all classes except carbamates and organophosphates, and an untreated control. Plots were scouted weekly and insecticide applications were made with the most efficacious and economical insecticides for each treatment when that treatment reached threshold for a particular insect pest(s). The primary insects at both locations were tobacco thrips and tarnished plant bugs. Thrips pressure was similar at both locations and generally showed that all insecticide treatments provided a similar level of protection compared with the untreated control. At the Stoneville location where tarnished plant bug pressure was greatest, cotton yields and economic returns differed between plots where all classes of insecticides were applied compared with the untreated control and where neonicotinoids were excluded. However, in Starkville where tarnished plant bug pressure was less, there were no differences among treatments. Although yield and economic returns were similar in high tarnished plant bug pressure areas when using all classes compared with managing without pyrethroids or organophosphates, a rotation among all insecticide classes should be beneficial for resistance management in Mid-South cotton production. PMID- 30462318 TI - The Association Between Acupuncture Training and Opioid Prescribing Practices. PMID- 30462319 TI - Analysis of a Military Parachutist Injury - A Retrospective Review of Over 37,000 Landings?. AB - Introduction: Parachute jumps are an indispensable element of military tactics of Air Cavalry. Parachute jumps, however, are characterized by high injury rate, which may impair the effectiveness of military strategies. The objective of this study is to analyze the circumstances and characteristics of injuries sustained by air cavalry brigade soldiers over a 7-year period. Materials and Methods: Retrospective analysis involved 37,467 parachute jumps done in the Air Cavalry Brigade between 2000 and 2006. The study group comprised 87 males aged 19-55, who suffered 84 injuries during jumps. The frequency and anatomic location of injuries, years of service, number of performed jumps, frequency and kind of injuries, the subunits involved in the study, number of injuries and age group, fitness test grade and injury risk during a parachute jump, season of year, meteorological conditions and injury risk, landing site and injury risk, jump altitude and frequency and kind of injuries, type of airship and parachute and injury occurrence, frequency of injuries depending on season, month and day of the week were analyzed. Results: The average rate of injuries among military parachutists ranged from 1.48 to 3.76 per 1,000 jumps. Younger and less experienced soldiers were more prone for injuries. Round parachute, lower altitude jumps, cloudy weather, and helicopter jumps were found to be risk factors for injury. The most frequent were ankle and knee sprains followed by shaft fractures (70% of all trauma). Conclusions: The material has revealed a significant relationship among physical fitness, number of parachute jumps, soldier's age, and traumatism. Ankle sprain is the most frequent parachute injury. Compared to the soldiers of other types of military forces, soldiers - parachutists run a higher risk for military disqualification in the aftermath of sustained injury. PMID- 30462320 TI - COXPRESdb v7: a gene coexpression database for 11 animal species supported by 23 coexpression platforms for technical evaluation and evolutionary inference. AB - The advent of RNA-sequencing and microarray technologies has led to rapid growth of transcriptome data generated for a wide range of organisms, under various cellular, organ and individual conditions. Since the number of possible combinations of intercellular and extracellular conditions is almost unlimited, cataloging all transcriptome conditions would be an immeasurable challenge. Gene coexpression refers to the similarity of gene expression patterns under various conditions, such as disease states, tissue types, and developmental stages. Since the quality of gene coexpression data depends on the quality and quantity of transcriptome data, timely usage of the growing data is key to promoting individual research in molecular biology. COXPRESdb (http://coxpresdb.jp) is a database providing coexpression information for 11 animal species. One characteristic feature of COXPRESdb is its ability to compare multiple coexpression data derived from different transcriptomics technologies and different species, which strongly reduces false positive relationships in individual gene coexpression data. Here, we summarized the current version of this database, including 23 coexpression platforms with the highest-level quality till date. Using various functionalities in COXPRESdb, the new coexpression data would support a broader area of research from molecular biology to medical sciences. PMID- 30462321 TI - heZEB2, a master regulator of the epithelial-mesenchymal transition, mediates trophoblast differentiation. AB - STUDY QUESTION: Does the upregulation of the zinc finger E-box binding homeobox 2 (ZEB2) transcription factor in human trophoblast cells lead to alterations in gene expression consistent with an epithelial-mesenchymal transition (EMT) and a consequent increase in invasiveness? SUMMARY ANSWER: Overexpression of ZEB2 results in an epithelial-mesenchymal shift in gene expression accompanied by a substantial increase in invasive capacity of human trophoblast cells. WHAT IS KNOWN ALREADY: In-vivo results have shown that cytotrophoblast differentiation into extravillous trophoblast involves an epithelial-mesenchymal transition. The only EMT master regulatory factor which shows changes consistent with extravillous trophoblast EMT status and invasive capacity is the ZEB2 transcription factor. STUDY DESIGN?SIZE, DURATION: This study is a mechanistic investigation of the role of ZEB2 in trophoblast differentiation. We generated stable ZEB2 overexpression clones using the epithelial, BeWo and JEG3 choriocarcinoma lines. Using these clones, we investigated the effects of ZEB2 overexpression on the expression of EMT-associated genes and proteins, cell morphology and invasive capability. PARTICIPANTS/MATERIALS, SETTING, METHODS: We used lentiviral transduction to overexpress ZEB2 in BeWo and JEG3 cells. Stable clones were selected based on ZEB2 expression and morphology. A PCR array of EMT associated genes was used to probe gene expression. Protein measurements were performed by Western blotting. Gain-of-function was assessed by quantitatively measuring cell invasion rates using a Transwell assay, a 3D bioprinted placenta model and the xCelligenceTM platform. MAIN RESULTS AND THE ROLE OF CHANCE: The four selected clones (2 x BeWo, 2 x JEG3, based on ZEB2 expression and morphology) all showed gene expression changes indicative of an EMT. The two clones (1 x BeWo, 1 x JEG3) showing > 40-fold increase in ZEB2 expression also displayed increased ZEB2 protein; the others, with increases in ZEB2 expression < 14-fold did not. The two high ZEB2-expressing clones demonstrated robust increases in invasive capacity, as assessed by three types of invasion assay. These data identify ZEB2-mediated transcription as a key mechanism transforming the epithelial-like trophoblast into cells with a mesenchymal, invasive phenotype. LARGE SCALE DATA: PCR array data have been deposited in the GEO database under accession number GSE116532. LIMITATIONS REASONS FOR CAUTION: These are in-vitro studies using choriocarcinoma cells and so the results should be interpreted in view of these limitations. Nevertheless, the data are consistent with in-vivo findings and are replicated in two different cell lines. WIDER IMPLICATIONS OF THE FINDINGS: The combination of these data with the in-vivo findings clearly identify ZEB2-mediated EMT as the mechanism for cytotrophoblast differentiation into extravillous trophoblast. Having characterized these cellular mechanisms, it will now be possible to identify the intracellular and extracellular regulatory components which control ZEB2 and trophoblast differentiation. It will also be possible to identify the aberrant factors which alter differentiation in invasive pathologies such as preeclampsia ? and abnormally invasive placenta (AKA accreta, increta, percreta). STUDY FUNDING AND COMPETING INTEREST(S): Funding was provided by the Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine and Surgery at Hackensack Meridian Health, Hackensack, NJ. The 3D bioprinted placental model work done in Drs. Kim and Fisher's labs was supported by the Children's National Medical Center. The xCELLigence work done in Dr. Birge's lab was supported by NIH CA165077. The authors declare no competing interests. PMID- 30462322 TI - Whole-genome multilocus sequence typing of closely related broiler chicken meat origin Campylobacter jejuni ST-5 isolates. AB - Broiler chicken meat is considered as the main source of foodborne Campylobacter infection. Campylobacter jejuni multilocus sequence type ST-5 has been previously identified as predominant among Latvian and Lithuanian broiler chicken meat products and is often isolated from Lithuanian patients with Campylobacter enteric infection. The market share of Lithuanian and Latvian origin fresh broiler chicken meat sold at Estonian retail is estimated close to 50%. In this study, we used the whole-genome sequences of Latvian and Lithuanian origin C. jejuni ST-5 broiler chicken meat isolates obtained from Estonian retail. Applied genome-by-genome whole-genome MLST revealed high similarity of investigated isolates with 1589 shared alleles, of which 218 loci were polymorphic. Latvian and Lithuanian isolates had 199 to 205 intergroup differences in shared alleles, whereas intragroup isolates differed by 27 to 31 alleles. Allele differences divided the isolates into 2 distinct groups based on the country of origin, which was supported by sequence-based phylogenetic tree. The resulting geographic separation of the isolates found in this study should be carefully interpreted taking into account the small sample size. PMID- 30462323 TI - Letter from the Executive Director November/December 2018. PMID- 30462324 TI - Comparative genetic characterization of third-generation cephalosporin-resistant Escherichia coli isolated from a layer operation system in Korea. AB - The layer operation system has a pyramidal structure in which the grandparent stock (GPS) is at the top, followed by the parent stock (PS), and commercial chickens (CC) that produce eggs at the bottom of the pyramid. Unfortunately, this vertical integration of the layer industry allows the transfer of Escherichia coli(E. coli) to the next step. The objective of this study was to genetically characterize and investigate the prevalence of third-generation cephalosporin resistant E. coli at all levels of the layer operation system in Korea. A total of 561 E. coli samples were tested in this study, and antimicrobial resistance to third-generation cephalosporin, cefotaxime, and ceftazidime gradually increased from GPS to CC. Fifty-one (9.1%) isolates produced beta-lactamase genes: GPS harbored blaTEM-1 (1 isolate) or blaCMY-2 (2 isolates) genes; PS harbored blaTEM 1 (7 isolates) or blaCMY-2 (6 isolates) genes; CC harbored blaCTX-M-1 (1 isolate), blaCTX-M-14 (1 isolate), blaTEM-1 (13 isolates), blaCTX-M-14+TEM-1 (7 isolates), or blaCMY-2 (4 isolates) genes; and eggs harbored blaCTX-M-1 (2 isolates), blaCTX-M-14 (1 isolate), blaTEM-1 (3 isolates), or blaCMY-2 (3 isolates) genes. Pulsed-field gel electrophoresis (PFGE) analysis was performed on the 51 beta-lactamase-producing E. coli isolates. In PFGE, E. coli included 7 PFGE patterns showing the same production stage and exhibited both beta-lactamase genes and the antimicrobial resistance pattern. Our findings suggest that there is a critical need for comprehensive surveillance of third-generation cephalosporin-resistant E. coli at all levels of the layer-production pyramid and provide important considerations for the control of infection in large-scale layer operations in Korea. PMID- 30462325 TI - A novel approach to candidemia? The potential role of checkpoint inhibition. AB - Infections with Candida spp. cause significant morbidity and mortality despite intensive treatment with antifungal agents. Novel treatment options are urgently needed. Predominately immunocompromised patients are affected. This warrants the conclusion that strengthening host immunity may have the potential to improve outcome. Recent studies imply a potential benefit of checkpoint inhibition reversing hyporesponsiveness of innate and adaptive immunity during invasive fungal infections and invasive candidiasis in particular. We here give a brief overview of first preclinical data in vitro and in vivo and clinical evidence in selected cases. PMID- 30462326 TI - A3-A3 Anastomosis in the Management of Complex Anterior Cerebral Artery Aneurysms: Experience With in Situ Bypass and Lessons Learned From Pseudoaneurysm Cases. AB - BACKGROUND: A3-A3 side-to-side bypass is an intracranial-to-intracranial (IC-IC) revascularization option when aneurysm treatment involves occlusion of one anterior cerebral artery (ACA). OBJECTIVE: To describe applications of A3-A3 side to-side bypass in the management of ACA true and pseudoaneurysms along with a review of pertinent literature. METHODS: Six consecutive patients undergoing an A3-A3 bypass as part of their aneurysm management, representing a single-surgeon experience in a 2-yr period, were included in this retrospective review of a prospectively collected database. RESULTS: Three male and three female patients with a median (range) age of 41.5 (11-69) years representing four ruptured and two unruptured aneurysms were included. Two of the aneurysms were communicating while four were postcommunicating from which three were pseudoaneurysms. Complete aneurysm obliteration was achieved in 5/6 cases. Bypass patency was evaluated in all cases intra- and postoperatively. Good outcomes (modified Rankin Scale score <= 2) at follow-up were observed in 4/6 patients. An improvement in mRS scores at the most recent follow-up as compared to preoperative status was achieved in three while scores remained the same in two patients. Ischemic complications related to aneurysm treatment were observed in two patients, both of which achieved good functional recovery upon follow-up. One patient deceased postoperatively due to progression of vasospasm-related infarcts. CONCLUSION: A3 A3 bypass in the management of true as well as pseudoaneurysms of the ACA can achieve good postoperative outcomes in selected patients. Prompt diagnosis and aggressive surgical treatment needs to be pursued if a vessel injury with pseudoaneurysm formation is suspected. 10.1093/ons/opy334Video Abstract10.1093.ons.opy3345969416742001. PMID- 30462327 TI - Preliminary Validation of a Two-Point Estimation Task for the Measurement of Sensory Dissociation in Patients with Chronic Low Back Pain. AB - Objectives: Sensory dissociation (SEDI), the discrepancy between perception and actual size or shape of a painful body part, is a frequently observed finding in patients with chronic low back pain. However, the current methods of evaluating SEDI have several limitations, such as a qualitative nature and weak evidence supporting their reliability. In the current study, the reliability of two versions (manual and verbal) of a novel test, a two-point estimation task (TPE), was investigated. Methods: To perform the manual version of the task, patients estimated the distance between two tactile stimuli delivered to their back using callipers, whereas in the verbal version they verbally reported the estimated distance. Results: The manual version of TPE showed greater interexaminer reliability than the verbal version, and the mean of the two repeated measurements was sufficient for reaching excellent reliability for the pain-free (intraclass correlation coefficient [ICC] = 0.91, 95% confidence interval [CI] = 0.77-0.97) and painful (ICC = 0.86, 95% CI = 0.65-0.94) sides. Intra-examiner reliability was moderate to excellent (ICC = 0.66-0.96) for the manual version performed at the pain-free and painful sides. Distribution, duration, and intensity of pain significantly predicted SEDI and accounted for 42% of the total variance (corrected R2 = 0.42, P < 0.01). Conclusions: TPE showed higher reliability coefficients compared with tools previously suggested in the literature and can therefore be used clinically and experimentally by one or more examiners. Further research is required to investigate the validity of this new test. PMID- 30462328 TI - Methyl cap binding protein 2: a key epigenetic protein in systemic sclerosis. AB - Objective: SSc is an autoimmune connective tissue disease that results in skin fibrosis and currently has no effective treatment. Epigenetic modifications have been described and these may be key in initiating and driving fibroblast activation. Among these epigenetic modifications methylation may be of central importance. The aim of this study was to examine the role of methyl cap binding protein-2 (MeCP2) in SSc fibrosis. Methods: We used healthy and SSc dermal fibroblasts to examine the role of MeCP2, using both small interfering RNA silencing and lentiviral overexpression to determine its effects. We also examined the expression of MeCP2 in SSc fibroblasts by immunoblotting. miRNA132 was quantified by Taqman real time PCR. Results: We demonstrated that TGF-beta1 induced the expression of MeCP2 in normal cells, and showed that SSc fibroblasts expressed high levels of MeCP2 under basal conditions. MeCP2 positively regulated the expression of extracellular matrix through epigenetic repression of the Wnt antagonist sFRP-1, leading to enhanced Wnt signalling. This mediated fibrosis through glycolysis, as the glycolysis inhibitor 2-deoxyglucose diminished the Wnt mediated collagen expression. MiR132 expression was reduced in SSc fibroblasts. Conclusion: The results suggest that an epigenetic loop exists mediating fibrosis. Targeting of MeCP2, as a key epigenetic regulator, may be a promising therapeutic approach, as would targeting the metabolic reprogramming that occurs through aerobic glycolysis. PMID- 30462329 TI - Fasudil, a ROCK inhibitor, recovers methylmercury-induced axonal degeneration by changing microglial phenotype in rats. AB - Methylmercury is an environmental neurotoxicant that induces neuropathological changes. In this study, we established chronic methylmercury-intoxicated rats. These rats survived, and sustained methylmercury-induced axonal degeneration, including the dorsal root nerve and the dorsal column of the spinal cord; these changes persisted 12 weeks after methylmercury withdrawal. We demonstrated for the first time the restorative effect of Fasudil, a specific inhibitor of Rho associated coiled coil-forming protein kinase, on axonal degeneration and corresponding neural dysfunction in the established chronic methylmercury intoxicated rats. To investigate the mechanism of this restorative effect, we focused on the expression of Rho protein families. This was supported by our previous study, which demonstrated that co-treatment with Fasudil prevented axonal degeneration by mitigating neurite extension/retraction incoordination caused by methylmercury-induced suppression of Rac1 in vitro and in subacute methylmercury-intoxicated rats. However, the mechanism of the restorative effect of Fasudil on axonal degeneration in chronic methylmercury-intoxicated rats differed from methylmercury-mediated neuritic extension/retraction incoordination. We found that the restorative effect of Fasudil was caused by the Fasudil-induced change of microglial phenotype, from pro-inflammatory to anti inflammatory; moreover, Fasudil suppressed Rho-associated coiled coil-forming protein kinase activity. Treatment with Fasudil decreased the expression of pro inflammatory factors, including tumor necrosis factor-alpha, inducible nitric oxide synthase, interleukin-1beta, and interleukin-6; furthermore, it inactivated the nuclear factor kappa-light-chain-enhancer of activated B cells pathway. Additionally, Fasudil treatment was associated with increased levels of anti inflammatory factors arginase-1 and interleukin-10. These results suggest that Rho-associated coiled coil-forming protein kinase inhibition may recover methylmercury-mediated axonal degeneration and neural dysfunction in chronic methylmercury intoxication. PMID- 30462330 TI - Binding of cellular nucleolin with the viral core RNA G-quadruplex structure suppresses HCV replication. AB - Hepatitis C virus (HCV) infection is a major cause of human chronic liver disease and hepatocellular carcinoma. G-quadruplex (G4) is an important four-stranded secondary structure of nucleic acids. Recently, we discovered that the core gene of HCV contains a G4 RNA structure; however, the interaction between the HCV core RNA G4 and host cellular proteins, and the roles of the HCV core RNA G4 in HCV infection and pathogenesis remain elusive. Here, we identified a cellular protein, nucleolin (NCL), which bound and stabilized the HCV core RNA G4 structure. We demonstrated the direct interaction and colocalization between NCL and wild-type core RNA G4 at both in vitro and in cell physiological conditions of the alive virus; however no significant interaction was found between NCL and G4-modified core RNA. NCL is also associated with HCV particles. HCV infection induced NCL mRNA and protein expression, while NCL suppressed wild-type viral replication and expression, but not G4-modified virus. Silencing of NCL greatly enhanced viral RNA replication. Our findings provide new insights that NCL may act as a host factor for anti-viral innate immunity, and binding of cellular NCL with the viral core RNA G4 structure is involved in suppressing HCV replication. PMID- 30462331 TI - Effect of salidroside on bone marrow haematopoiesis in a mouse model of myelosuppressed anaemia. AB - This study was designed to investigate the effect of salidroside (SAL) on bone marrow haematopoiesis in a mouse model of myelosuppressed anemia. After the mouse model was established by 60Co gamma irradiation and cyclophosphamide, pancytopenia and a sharp reduction in bone marrow stromal cells and bone marrow haematopoietic stem cells (lineage-Sca1+c-kit+) were observed. This was greatly alleviated by SAL (25 mg/kg, 50 mg/kg, 100 mg/kg) in a dose-dependent manner (50% effective dose value of 35.7 mg/kg and 61.2 mg/kg, respectively), followed by a distinct increment in anti-apoptotic protein Bcl-2. For cell culture in vitro, treatment with SAL resulted in a significant recovery of burst-forming unit erythroids, and colony-forming unit-granulocyte macrophages on Day 7, and colony forming unit-erythroids on Day 3, dose-dependently, but not of colony-forming unit-megakaryocyte macrophages. Inoculation of bone marrow cells derived from SAL administrated donor mice resulted in a 60% survival of recipient mice at the high dose of 100 mg/kg SAL at 2 months after surgery. SAL appeared to be able to stimulate the restoration of bone marrow haemopoietic regulation in myelosuppressed anemia. Based on the downregulation of Fas ligand associated with the expression of Caspase-3 at the protein level, it was suggested that SAL might have an anti-apoptotic effect on bone marrow cells in the Fas-apoptotic pathway of Fas/FasL-caspase-3. PMID- 30462332 TI - RPA resolves conflicting activities of accessory proteins during reconstitution of Dmc1-mediated meiotic recombination. AB - Dmc1 catalyzes homology search and strand exchange during meiotic recombination in budding yeast and many other organisms including humans. Here we reconstitute Dmc1 recombination in vitro using six purified proteins from budding yeast including Dmc1 and its accessory proteins RPA, Rad51, Rdh54/Tid1, Mei5-Sae3 and Hop2-Mnd1 to promote D-loop formation between ssDNA and dsDNA substrates. Each accessory protein contributed to Dmc1's activity, with the combination of all six proteins yielding optimal activity. The ssDNA binding protein RPA plays multiple roles in stimulating Dmc1's activity including by overcoming inhibitory effects of ssDNA secondary structure on D-loop reactions, and by elongating D-loops. In addition, we demonstrate that RPA limits inhibitory interactions of Hop2-Mnd1 and Rdh54/Tid1 that otherwise occur during assembly of Dmc1-ssDNA nucleoprotein filaments. Finally, we report interactions between the proteins employed in the biochemical reconstitution including a direct interaction between Rad51 and Dmc1 that is enhanced by Mei5-Sae3. PMID- 30462333 TI - Schizophrenia is Associated With an Aberrant Immune Response to Epstein-Barr Virus. AB - Background: Epstein-Barr virus (EBV) is a highly prevalent human herpesvirus capable of infecting the central nervous system and establishing persistent infection. Methods: We employed solid phase immunoassay techniques to measure immunoglobulin G (IgG) class antibodies to EBV virions and defined proteins in 432 individuals with schizophrenia and 311 individuals without a history of a psychiatric disorder. Western blot testing was performed to document reactivity to specific EBV proteins. Polygenic risk for schizophrenia was calculated from genome sequencing arrays. Levels of antibodies between the groups were compared by multivariate analyses incorporating clinical, genetic, and demographic measures. Results: Individuals with schizophrenia had marked elevations in the levels of antibodies to EBV virions as compared to the control population. Further analyses indicated increased levels of reactivity to EBV-viral capsid antibody (VCA) but not to EBV nuclear antigen-1 (EBNA-1) or to other human herpesviruses. Western blot analysis confirmed increased reactivity to VCA proteins in the group of individuals with schizophrenia and documented a lack of increased levels of antibodies to EBNA-1. Genetic analyses indicated an additive effect of increased levels of antibodies to EBV virions and genetic susceptibility to schizophrenia, with individuals with elevated levels of both type of markers having a greater than 8.5-fold odds of a schizophrenia diagnosis. Conclusions: Individuals with schizophrenia have increased levels of antibodies to some but not all EBV proteins indicating an aberrant response to EBV infection. This aberrant response may contribute to the immunopathology of schizophrenia and related disorders. PMID- 30462334 TI - In vitro culture and characterization of duck primordial germ cells. AB - This study aimed to isolate, culture, and characterize duck primordial germ cells (PGCs) and to compare these cells with chicken PGCs. We first cultured Muscovy duck (Cairina moschata) circulating PGCs and gonadal PGCs (gPGCs) in the modified serum-containing medium used to amplify chicken PGCs. gPGCs were found to proliferate better in serum-free chemically defined medium than in serum containing medium. Thereafter, gPGCs were similarly isolated from 2 other duck breeds, the Pekin duck (Anas platyrhynchos) and the hybrid mule duck (C. moschata * A. platyrhynchos), and amplified for a limited period of time in the chemically defined culture condition, but sufficiently to be characterized and transplanted. Cultured gPGCs of all 3 duck breeds were characterized by Periodic acid-Schiff staining, immunocytochemical staining, and expression analysis of germline specific and pluripotency genes. Cultured duck gPGCs colonized the gonads after being genetically labeled and injected into recipient embryos. Taken together, these results demonstrate that duck PGCs retain their germline characteristics after being isolated, expanded in vitro, and genetically modified. Further studies are required to establish the optimal conditions for long-term culture of duck PGCs, which may involve supplementing the culture medium with other growth factors or compounds. PMID- 30462335 TI - Acute Kidney Injury Secondary to Severe Hand, Foot and Mouth Disease Caused by Enterovirus-A71: Hypertension Is a Common. AB - Hand, foot and mouth disease (HFMD) is a common infectious disease among children, caused primarily by human enterovirus-A71 (EV-A71) and coxsackievirus A16 (CV-A16). To date, only two case reports mention that renal involvement can be secondary to or coexisting with CV-A16-associated HFMD. In the present report, we describe a 10-year-old girl who was infected with EV-A71 and subsequently developed a definite acute kidney injury (AKI), mainly based on the characteristic rash, virus isolation, eyelid edema, hypertension, decreased urine output, mild proteinuria and impaired renal function. She was treated with intravenous ribavirin, immunoglobulin, oral administration of nifedipine and ramipril. After 7 days of intensive observations, she recovered fully. Hypertension is a common feature in both HFMD and AKI. On one hand, hypertension serves as a risk factor for severe HFMD; on the other hand, hypertension induces AKI onset and is also deteriorated by AKI. PMID- 30462336 TI - T5 exonuclease-dependent assembly offers a low-cost method for efficient cloning and site-directed mutagenesis. AB - The assembly of DNA fragments with homologous arms is becoming popular in routine cloning. For an in vitro assembly reaction, a DNA polymerase is often used either alone for its 3'-5' exonuclease activity or together with a 5'-3' exonuclease for its DNA polymerase activity. Here, we present a 'T5 exonuclease DNA assembly' (TEDA) method that only uses a 5'-3' exonuclease. DNA fragments with short homologous ends were treated by T5 exonuclease and then transformed into Escherichia coli to produce clone colonies. The cloning efficiency was similar to that of the commercial In-Fusion method employing a proprietary DNA polymerase, but higher than that of the Gibson method utilizing T5 exonuclease, Phusion DNA polymerase, and DNA ligase. It also assembled multiple DNA fragments and did simultaneous site-directed mutagenesis at multiple sites. The reaction mixture was simple, and each reaction used 0.04 U of T5 exonuclease that cost 0.25 US cents. The simplicity, cost effectiveness, and cloning efficiency should promote its routine use, especially for labs with a budget constraint. TEDA may trigger further development of DNA assembly methods that employ single exonucleases. PMID- 30462337 TI - The Physician Shortage: A Red Herring in American Health Care Reform. AB - Although the USA spends more on health care than any other comparable nation, Americans are less healthy than citizens of high-income countries that spend far less. Over the past 12 years, the number of physicians per capita in the USA has been a concerning problem that may contribute to the disparity between health care costs and health status. Some have argued that remediating the shortage of primary care physicians will improve patient health. Others assert that the relationship between health care costs and health outcomes is more complex, influenced by a broad range of variables intrinsic to health care (i.e., provider availability, continuity, coordination); patient factors (ethnicity, socioeconomic status, health behaviors, health literacy, and other social factors); and systems factors (health information management, health information technology and health care measurement itself). This article contends that increasing the physician supply will not improve the health of Americans. Rather, solutions which lower health care costs while concomitantly improving health status will. Aside from community-level actions, health can improve at lower costs by increasing the prevalence of and proficiency in team-based care models, that address individual patient determinants of health, and poorly coordinated care. Future directions for this research and policy development are discussed. PMID- 30462338 TI - Person-Centricity: Promoting Self-Determination and Responsibility in Health and Health Care. AB - The transition from a system focused on the delivery of sickness and illness services to one with a heavy focus of helping people become and remain healthier requires a major shift in how we view the patient and person. The health care system attempts to magically transform us from persons to patients in a context of sickness and disease, in need of medical procedures and interventions. Those few hours we spend a year in formal medical and health care contexts do not define us in the broader life space. We contend that "person-centricity" is more reflective of the life space and as such better supports that shift than do models of consumer or patient empowerment, centeredness, engagement, or activation. "Person-centricity" represents the complexity of how individuals make decisions including health and health care decisions, within the broader context of their lives, and accurately addresses the needs and aspirations of people throughout their life journey. This is not simply a shift in semantics, but an entirely new paradigm that frees the individual from assuming and succumbing to the passive and subservient patient role and dramatically changes the way in which we view ourselves and interact with the health care system.The changes required to create a healthier America and affect costs associated with lifestyle related diseases need to happen on a personal level, coupled with a supportive infrastructure and public policies to promote and sustain them. This shift is critical to our transition from health care to a healthier way of living and of controlling avoidable costs. PMID- 30462339 TI - Developing the Next Generation of Physicians. AB - To improve health care, the USA needs to create a longitudinal medical education system that will develop physicians able to lead the transformation of health care toward a focus on the promotion of healthy behaviors aimed at preventing disease. The development of patient-centered care has been an important step in promoting healthy behaviors. However, to truly develop a meaningful relationship with a patient, a physician must first see them as a person, not as a list of diseases. Medical education should develop physicians able to provide person centered care - moving beyond patient-centered care to focus more broadly on the entirety of the person, for whom being a patient is merely one aspect of their personhood. Restructuring medical education begins with the admission process itself, followed by longitudinal changes at the undergraduate, graduate, and continuing professional development levels that will reinforce the attributes critical for future physicians. The authors view this longitudinal approach through the theoretical framework of situated cognition, exploring personal, environmental, and social factors leading to success; outline several key stages of medical education from matriculation through continuing professional development; and identify potential areas that merit longitudinal efforts to develop future physicians able to promote positive health behaviors. PMID- 30462340 TI - Toward a Contemporary Definition of Health. AB - Aristotle saw that the striving of humanity was toward being well - a physical, mental and spiritual state where life flourished. A contemporary definition of health recognizes that disease and disability can and often do co-exist with wellness. In this new conception, health is transformed from a state that requires the absence of disease to a state where the central theme is the fullness of life. Health becomes not a static state of being, but a dynamic quality of living where body, mind, and spirit are fully employed to make the most of each day. PMID- 30462341 TI - A Systems Approach to Person-Centric Health Economics. AB - The economics of health and the economics of health care are not the same, and in fact can be competitors for resources in some cases. Using a traditional supply/demand framework can clarify the forces at work in person-centric health economics. Use of cost-effectiveness analysis, employing a broader systems perspective that incorporates sectors other than health care, and nudging individuals to better health habits are three strategies that can help to drive a shift from health care to health. PMID- 30462342 TI - The Role of Incentives in Health - Closing the Gap. AB - Incentives motivate individuals to act in a certain way. Incentives are everywhere and in everything; they are woven into the very fabric of our lives. To address the issue of spiraling health care costs, incentive programs must be put into place to discourage the behaviors driving the growth of these costs. With nearly 75% of all health care costs associated with chronic diseases, most of which are preventable, the value of incentives must be recognized in policy and practice. Incentives can drive behavior, help realign the system, and improve the nation's health. Behavior change incentive programs have been successful for some large organizations in dramatically controlling health care costs when incorporated into an integrated plan redesign. It is necessary to both understand the types of incentives that are impactful and integrate these incentives into the plan design, the workplace environment, retail, education, and communities in order to impact the health of our nation. PMID- 30462343 TI - Toward a National Conversation on Health: The Transformative Power of Deregulated Markets and Market-Driven Innovation. AB - The U.S. health care system is broken. Unhealthy behaviors, misaligned incentives, excessive regulations, and a reactive care delivery system have created an unsustainable situation for the American people. Health care reform efforts to date have focused primarily on costs, insurance coverage, and policies and regulations in an attempt to increase access, improve quality and control costs. In addition, the Affordable Care Act has created so much complexity that it is nearly impossible to determine how elements in the health care system interact or impact health outcomes. Health care is more complex than ever, with a myriad of new government regulations that must be considered when designing new models of health.New care delivery models that increase consumer choice, encourage competition through free markets, and accelerate innovation are urgently needed. The longstanding fee-for-service model of health care, which is driven by government regulation and the insurance industry, must be abandoned. In its place, the authors provide examples of several emerging market-driven innovations that are currently being implemented and evaluated for viability, replicability, and scalability. They also recommend specific environments for piloting innovative, consumer-focused models of health care, and for helping the government define a process for eventually backing out of health care in order to create a truly deregulated system. PMID- 30462344 TI - Promoting and Sustaining Positive Personal Health Behaviors - Putting the Person First. AB - Amidst the national debate on the future of health care, there must be a focus on how individuals, communities, and the system need to change to promote and sustain health rather than reactively treat sickness and disability. To transition from a health care system to a "System for Health", we need to move from a patient-focused to a person-focused position. A system that focuses on improving personal decisions related to activity, nutrition, sleep, and tobacco free living could have a profound impact on health and well-being. The delivery of health, instead of just health care, entails more than just preventing sickness and disability; it requires focusing on building personal wellness, resilience, and endurance. Engaging the individual person to embrace a healthier lifestyle through education, incentives, and technology we can have a positive impact on reducing costs and improving health outcomes. The purpose of this commentary is three-fold: (1) to address the need to implement prescriptions for health, (2) advocate for the need for a person-centric model to help our health care system transition to a system for health, and (3) demonstrate how simple behavior changes can help drive the change to health. PMID- 30462345 TI - Toward a National Conversation on Health: Disruptive Intervention and the Transformation from Health Care to Health. AB - Over a century ago, Abraham Flexner's landmark report on medical education resulted in the most extensive reforms of medical training in history. They led to major advances in the diagnosis and treatment of disease and the relief of suffering. His prediction that "the physician's function is fast becoming social and preventive, rather than individual and curative," however, was never realized.Instead, with the rise of biomedical science, the scientific method and the American Medical Association, the health care system became increasingly distanced from a holistic approach to life that recognizes the critical role social determinants play in people's health. These developments created the beginning of the regulatory controls that have come to define and shape American health care - and our unhealthy obsession with illness, disease and curative medicine that has resulted in a system that has little to do with health.To realize Flexner's prediction, and to transform health care into a holistic system whose primary goals are focused on health outcomes, six disruptive interventions are proposed. First, health needs to be placed in the context of community. Second, the model of primary care needs to be revised. Third, big data need to be harnessed to provide personalized, consumable, and actionable health knowledge. Fourth, there needs to greater patient engagement, but with fewer face-to-face encounters.Fifth, we need revitalized, collaborative medical training for physicians. And finally, true transformation will require market-driven, not regulatory-constrained, innovation. The evolution from health care to health demands consumer-driven choices that only a deregulated, free market can provide. PMID- 30462347 TI - Intra-'cortical' activity during avian non-REM and REM sleep: variant and invariant traits between birds and mammals. AB - Several mammalian-based theories propose that the varying patterns of neuronal activity occurring in wakefulness and sleep reflect different modes of information processing. Neocortical slow-waves, hippocampal sharp-wave ripples, and thalamocortical spindles occurring during mammalian non-rapid eye-movement (NREM) sleep are proposed to play a role in systems level memory consolidation. Birds show similar NREM and REM (rapid eye-movement) sleep stages to mammals, however, it is unclear whether all neurophysiological rhythms implicated in mammalian memory consolidation are also present. Moreover, it is unknown whether the propagation of slow-waves described in the mammalian cortex occurs in the avian 'cortex' during natural NREM sleep. We used a 32-channel silicon probe connected to a transmitter to make intracerebral recordings of the visual hyperpallium and thalamus in naturally sleeping pigeons (Columba livia). As in the mammalian neocortex, slow-waves during NREM sleep propagated through the hyperpallium. Propagation primarily occurred in the thalamic input layers of the hyperpallium, regions which also showed the greatest slow-wave activity (SWA). Spindles were not detected in both the visual hyperpallium, including regions receiving thalamic input, and thalamus, using a recording method that readily detects spindles in mammals. Interestingly, during REM sleep fast gamma bursts in the hyperpallium (when present) were restricted to the thalamic input layers. Moreover, unlike mice, the decrease in SWA from NREM to REM sleep was the greatest in these layers. Taken together these variant and invariant neurophysiological aspects of avian and mammalian sleep, suggest that there may be associated mechanistic and functional similarities and differences between avian and mammalian sleep. PMID- 30462346 TI - Modulation of the microbiota by oral antibiotics treats immunoglobulin A nephropathy in humanized mice. AB - Background: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgA is mainly produced by the gut-associated lymphoid tissue (GALT). Both experimental and clinical data suggest a role of the gut microbiota in this disease. We aimed to determine if an intervention targeting the gut microbiota could impact the development of disease in a humanized mouse model of IgAN, the alpha1KI-CD89Tg mice. Methods: Four- and 12 week old mice were divided into two groups to receive either antibiotics or vehicle control. Faecal bacterial load and proteinuria were quantified both at the beginning and at the end of the experiment, when blood, kidneys and intestinal tissue were collected. Serum mouse immunoglobulin G (mIgG) and human immunoglobulin A1 (hIgA1)-containing complexes were quantified. Renal and intestinal tissue were analysed by optical microscopy after haematoxylin and eosin colouration and immunohistochemistry with anti-hIgA and anti-mouse CD11b antibodies. Results: Antibiotic treatment efficiently depleted the faecal microbiota, impaired GALT architecture and impacted mouse IgA production. However, while hIgA1 and mIgG serum levels were unchanged, the antibiotic treatment markedly prevented hIgA1 mesangial deposition, glomerular inflammation and the development of proteinuria. This was associated with a significant decrease in circulating hIgA1-mIgG complexes. Notably, final faecal bacterial load strongly correlated with critical clinical and pathophysiological features of IgAN such as proteinuria and hIgA1-mIgG complexes. In addition, treatment with broad-spectrum antibiotics reverted established disease. Conclusions: These data support an essential role of the gut microbiota in the generation of mucosa derived nephrotoxic IgA1 and in IgAN development, opening new avenues for therapeutic approaches in this disease. PMID- 30462348 TI - Characterization of PEGylated asparaginase: new opportunities from NMR analysis of large pegylated therapeutics. AB - Resonance assignment and structural characterization of pharmacologically relevant proteins promises to improve their understanding and safety by rational design. However, the PEG coating that is used to evade the immune system also causes these molecules to "evade" the standard structural biology methodologies. We here demonstrate that it is possible to obtain the resonance assignment and a reliable structural model of large PEGylated proteins through an integrated approach encompassing NMR and X-ray crystallography. PMID- 30462349 TI - The function of geophagy in Nepal gray langurs: Sodium acquisition rather than detoxification or prevention of acidosis. AB - OBJECTIVES: Geophagy has several hypothesized functions, among them (1) detoxification of plant secondary compounds, for example, tannins, (2) buffering stomach pH to alleviate acidosis caused by high sugar intake, and (3) supplementing the diet with mineral nutrients. We tested these hypotheses in Nepal gray langurs (Semnopithecus schistaceus), a foregut fermenter for which fruits and leaves dominate the diet at different times of the year. MATERIALS AND METHODS: We collected data on feeding time per food item for 21 unprovisioned adult langurs at Ramnagar, Nepal, for 1 year using instantaneous sampling (773 observation hours). We combined these data with relative sugar and tannin content of food items to estimate diet content. We collected rainfall data to distinguish the wet season (May-September) from the dry season (October-April). We collected soil samples from consumption and control sites to test for pH and sodium, potassium, magnesium, and calcium concentrations. RESULTS: Langurs consumed soil from two sources: termite structures (in almost all months) and river banks and beds (mainly in the dry season). Soil feeding was not positively correlated with dietary tannin or sugar content (GLMM). Soil pH was not high enough to buffer stomach contents. Only sodium was significantly higher in consumed soil. DISCUSSION: The most likely function of geophagy was the acquisition of sodium. This conclusion is consistent with reports for other animals. Buffering stomach pH, an often-suggested function for animals with ruminant-like digestion, was not supported. Detoxification, often proposed for animals with a diet high in secondary compounds, was also not supported. PMID- 30462350 TI - GARLEEK: Adding an extra flavor to ONIOM. AB - The ONIOM method, developed in the group of Keiji Morokuma, is one of the most successful examples of quantum mechanics/molecular mechanics (QM/MM) treatments, and of multilayer methods in general. Its implementation in the Gaussian program package is in particular widely used. This implementation has access to the wide variety of QM methods available in Gaussian, but is limited to only three specific force fields. The current article presents the GARLEEK interface, which expands the availability of molecular mechanics methods to the wide variety of force fields available in MM packages. The focus is in the simple installation and use. Two examples of the performance of the interface with selected systems are provided. GARLEEK is MIT-licensed and freely available at https://github.com/insilichem/garleek. (c) 2018 Wiley Periodicals, Inc. PMID- 30462351 TI - Trabecular bone functional adaptation and sexual dimorphism in the human foot. AB - OBJECTIVES: Trabecular bone adapts to the strains placed upon the skeleton during life. Anthropological research has largely focused on linking variation in primate trabecular bone to locomotor mode, to provide a context for interpreting fossil morphology. However, intraspecific variation and its underlying mechanisms are still poorly understood. Trabecular bone is influenced by a variety of factors including body mass, age, diet, temperature, genetics, sex, and behavior. Before trabecular structure can be used to infer habitual behavior in the past, the effects of these factors need to be understood. In this article, we examine variation in trabecular structure in the human foot in four archaeological groups in relation to inferred levels of terrestrial mobility and sex. MATERIALS AND METHODS: We use high-resolution MUCT scanning to examine variation in trabecular structure in the human calcaneus, talus, and first metatarsal in two relatively mobile and two relatively sedentary archaeological groups. RESULTS: The four population samples show similar patterns of trabecular variation throughout the foot, influenced by mechanical loading. Greater inferred terrestrial mobility is associated with greater bone volume fraction and thicker, more widely spaced, and less interconnected trabeculae. However, contrary to diaphyseal rigidity, only limited sexual dimorphism was found in trabecular structure. DISCUSSION: This work demonstrates that trabecular bone may serve as a useful proxy of habitual behavior in the fossil and archaeological record when other factors are carefully considered. However, the mechanisms underlying sexual dimorphism are not well understood. As such, inferring sex differences in habitual behavior is currently challenging. PMID- 30462352 TI - Metabolic remodeling of glucose, fatty acid and redox pathways in the heart of type 2 diabetic mice. AB - KEY POINTS: Hearts from type 2 diabetic animals display perturbations in excitation-contraction coupling, impairing myocyte contractility and delaying relaxation, along with altered substrate consumption patterns. Under high glucose and beta-adrenergic stimulation conditions, palmitate can, at least in part, offset left ventricle (LV) dysfunction in hearts from diabetic mice improving contractility and relaxation while restoring coronary perfusion pressure. Fluxome calculations of central catabolism in diabetic hearts show that, in presence of palmitate, there is a metabolic remodeling involving tricarboxylic acid cycle, polyol and pentose phosphate pathways, leading to improved redox balance in cytoplasmic and mitochondrial compartments. Under high glucose and increased energy demand, the metabolic/fluxomic re-direction leading to restored redox balance imparted by palmitate helps explain maintained LV function and may contribute to design novel therapeutic approaches to prevent cardiac dysfunction in diabetic patients. ABSTRACT: Type-2 diabetes (T2DM) leads to reduced myocardial performance, and eventually heart failure. Excessive accumulation of lipids and glucose are central to T2DM cardiomyopathy. Previous data showed that palmitate (Palm) or glutathione preserved heart mitochondrial energy/redox balance under excess glucose rescuing beta-adrenergic-stimulated cardiac excitation-contraction coupling. However, the mechanisms underlying the accompanying improved contractile performance have been largely ignored. Herein we explore in intact heart under substrate excess the metabolic remodeling associated with cardiac function in diabetic db/db mice subjected to stress given by beta-adrenergic stimulation with isoproterenol and high-glucose compared to their nondiabetic controls (+/+, WT) under euglycemic conditions. When perfused with Palm, T2DM hearts exhibit improved contractility/relaxation compared to WT, accompanied by extensive metabolic remodeling as demonstrated by metabolomics fluxomics combined with bioinformatics and computational modeling. The T2DM heart metabolome showed significant differences in the abundance of metabolites in pathways related to glucose, lipids, and redox metabolism. Using a validated computational model of heart's central catabolism, comprising glucose and fatty acid (FA) oxidation in cytoplasmic and mitochondrial compartments, we estimated that fluxes through glucose degradation pathways are ~2-fold lower in heart from T2DM vs. WT under all conditions studied. Palm addition elicits improvement of the redox status via enhanced beta-oxidation and decreased glucose uptake, leading to flux-redirection away from redox-consuming pathways (e.g., polyol) while maintaining the flux through redox-generating pathways together with glucose-FA "shared fueling" of oxidative phosphorylation. Thus, available FAs such as Palm may help improve function via enhanced redox balance in T2DM hearts during peaks of hyperglycemia and increased workload. Sonia Cortassa has a PhD in Chemical Sciences from the Universidad Nacional de Cordoba, Argentina, country where she held research and teaching positions at Universidad Nacional de Tucuman and Consejo Nacional Investigaciones Cientificas y Tecnicas (CONICET). In the United States of America, she continued her research at the Johns Hopkins University and, at present, at the Laboratory of Cardiovascular Sciences/National Institute on Aging/NIH. Her field of research is Physiology, Bioenergetics, with expertise in Computational modeling of metabolic networks. She believes that quantitative Systems Biology approaches represent a real opportunity to contribute to the understanding of human body function in health and disease. This article is protected by copyright. All rights reserved. PMID- 30462353 TI - Plasmacytoma of thyroid clinically and morphologically mimicking primary thyroid carcinoma. AB - Plasma cell neoplasms may have a spectrum of clinical presentation ranging from asymptomatic proliferation to single/multiple mass lesions in medullary/ extramedullary sites. Extramedullary plasmacytoma (EMP) is a rare tumor of the soft tissue without theinvolvement of bone marrow which most commonly affects the head and neck region and may precede multiple myeloma (MM) (1). Thyroid can rarely be a site for EMP or may be infiltrated by systemic multiple myeloma. These patients are predominantly males and are usually well beyond middle age. This article is protected by copyright. All rights reserved. PMID- 30462354 TI - Neandertal features of the deciduous and permanent teeth from Portel-Ouest Cave (Ariege, France). AB - OBJECTIVES: We describe 14 unpublished and nine published teeth from the Mousterian level of Portel-Ouest (Ariege, France), dated to 44 ka. In a comparative context, we explore the taxonomical affinities of those teeth with Neandertals and modern humans which are both known to exist at that time. We further make some paleobiological inferences about this human group. METHODS: The comparative analysis of Neandertals and modern humans is based on nonmetric traits at the outer enamel surface and the enamel-dentine junction, crown diameters and three-dimensional (3D) enamel thickness measurements of lower permanent teeth. The crown and roots are explored in detail based on the MUCT scan data to identify the multiple criteria involved in the paleobiological approach. RESULTS: Nonmetric traits and 3D enamel thickness tend to be more similar to Neandertals than modern humans, notably for C1 , P4 , and M2 (included in all analyses) as well as volume of the pulp cavity in roots of the anterior permanent teeth. The Portel-Ouest sample corresponds to a minimum of seven juveniles, one or two adolescents and one adult, which exhibit recurrent linear enamel hypoplasia (up to five events for one individual), the torsiversion of one anterior tooth and irregular oblique wear in some anterior deciduous teeth. DISCUSSION: This morphological study confirms that the remains from Portel-Ouest are Neandertals, associated with a Mousterian complex. Furthermore, we found the expected pattern of mortality and stress for a Neandertal group, that is, various age categories and developmental defects (nonexclusive to Neandertals), while adults are underrepresented and juveniles are overrepresented. Further excavations would contribute finding new remains and maybe complete this demographic profile. PMID- 30462355 TI - In Grateful Recognition of Our Editorial Board. PMID- 30462356 TI - Corrigendum Referring to: Getting the Message? Native Reactive Electrophiles Pass Two Out of Three Thresholds to be Bona Fide Signaling Mediators. PMID- 30462357 TI - On the State of Scientific English and How to Improve it - Part 12: Keeping it Simple When Under Time Pressure.... PMID- 30462358 TI - Allele frequency-free inference of close familial relationships from genotypes or low depth sequencing data. AB - Knowledge of how individuals are related is important in many areas of research and numerous methods for inferring pairwise relatedness from genetic data have been developed. However, the majority of these methods were not developed for situations where data is limited. Specifically, most methods rely on the availability of population allele frequencies, the relative genomic position of variants, and accurate genotype data. But in studies of non-model organisms or ancient human samples, such data is not always available. Motivated by this, we present a new method for pairwise relatedness inference, which requires neither allele frequency information nor information on genomic position. Furthermore, it can be applied not only to accurate genotype data but also to low-depth sequencing data from which genotypes cannot be accurately called. We evaluate it using data from a range of human populations and show that it can be used to infer close familial relationships with a similar accuracy as a widely used method that relies on population allele frequencies. Additionally, we show that our method is robust to SNP ascertainment and applicable to low-depth sequencing data generated using different strategies, including resequencing and RADseq, which is important for application to a diverse range of populations and species. This article is protected by copyright. All rights reserved. PMID- 30462360 TI - Metalo-Hydrogen Bonded Organic Frameworks (MHOFs) as New Class of Crystalline Materials for Protonic Conduction. AB - Recently, proton conduction has been a thread of high potential owing to its wide applications in fuel-cell technology. In search for new class of crystalline materials for protonic conductors three metalo-hydrogen bonded organic frameworks (MHOF) based on [Ni(IMDz)6]2+ and arene disulfonates (MHOF1 and MHOF2) or dicarboxylate (MHOF3) have been reported (IMDz = imidazole). The presence of ionic backbone with charge-assisted H-bonds coupled with amphiprotic imidazoles made these MHOFs as protonic conductors exhibiting conduction values 0.75 X 10-3, 3.5 X 10-4 and 0.97 X 10-3 S cm-1 respectively at 80 degrees C and 98% relative humidity, which are comparable among other crystalline MOFs, CPs, POMs, COFs, HOFs materials. This report initiates the usage of MHOF materials as new class of solid-state proton conductors. PMID- 30462359 TI - The bystander effect contributes to the accumulation of senescent cells in vivo. AB - Senescent cells accumulate with age in multiple tissues and may cause age associated disease and functional decline. In vitro, senescent cells induce senescence in bystander cells. To see how important this bystander effect may be for accumulation of senescent cells in vivo, we xenotransplanted senescent cells into skeletal muscle and skin of immunocompromised NSG mice. 3 weeks after the last transplantation, mouse dermal fibroblasts and myofibres displayed multiple senescence markers in the vicinity of transplanted senescent cells, but not where non-senescent or no cells were injected. Adjacent to injected senescent cells, the magnitude of the bystander effect was similar to the increase in senescence markers in myofibres between 8 and 32 months of age. The age-associated increase of senescence markers in muscle correlated with fibre thinning, a widely used marker of muscle aging and sarcopenia. Senescent cell transplantation resulted in borderline induction of centrally nucleated fibres and no significant thinning, suggesting that myofibre aging might be a delayed consequence of senescence-like signalling. To assess the relative importance of the bystander effect versus cell autonomous senescence, we compared senescent hepatocyte frequencies in livers of wild-type and NSG mice under ad libitum and dietary restricted feeding. This enabled us to approximate cell-autonomous and bystander-driven senescent cell accumulation as well as the impact of immunosurveillance separately. The results suggest a significant impact of the bystander effect for accumulation of senescent hepatocytes in liver and indicate that senostatic interventions like dietary restriction may act as senolytics in immunocompetent animals. PMID- 30462361 TI - Atypical presentation of pediatric BRAF RASopathy with acute encephalopathy. AB - We report a 9-year-old girl with hypotonia, severe motor delay, absent speech, and facial dysmorphism who developed acute encephalopathy with severe neurological outcome. Trio-based whole exome sequencing (WES) analysis detected a de novo heterozygous mutation in the BRAF gene leading to the diagnosis of an atypical presentation of cardiofaciocutaneous (CFC) syndrome. This is the second case of CFC syndrome complicated with acute encephalopathy reported in the literature and supports the hypothesis that acute encephalopathy might be one of the complications of the syndrome due to an intrinsic susceptibility to this acute event. The report furthermore highlights the role of WES in providing a fast diagnosis in patients in critical conditions with atypical presentation of rare genetic syndromes. PMID- 30462363 TI - Spanish translation section. PMID- 30462362 TI - Introducing national healthcare safety investigation bodies. PMID- 30462364 TI - Snapshot quiz. PMID- 30462365 TI - Reducing gender bias in surgery. PMID- 30462367 TI - Correction: An extremely severe phenotype attributed to WDR81 nonsense mutations. PMID- 30462368 TI - Emissive Iridium(III) Complexes with Phosphorous-Containing Ancillary. AB - Ir(III) metal complexes and related emitters bearing all kind of cyclometalated chromophoric chelates and non-chromophoric ancillary are extensively studied during the past three decades. Many of them have been found to display bright room temperature phosphorescence from triplet excited states in both solution and solid states, offering a possible application in contemporary optoelectronic technologies, including organic light emitting diodes, electrochemiluminescence, biological imaging and chemical sensing. Among reported materials, there are Ir(III) complexes with at least one phosphorus (P)-containing ligand and/or ancillary chelate, together with cyclometalates or equivalents that are in control of the actual emission energy. Particularly, possession of P-based donor can lead to divergent structural and photophysical properties compared to the traditional designs. This review aims to provide a literature overview as well as the authors' personal account to the development of relevant Ir(III) based phosphors bearing these P-donors. To the readers' convenience, the contents are subdivided into six sessions, according to whether or not they are charge natural, or with mono- or dianionic electronic character, and in accordance to their divergent bonding modes, i. e. monodentate, bidentate and tripodal coordination. In many cases, the P-based ancillaries offer an easy accessible route to the formation of efficient sky-blue and true-blue emitters due to their pi-accepting property, together with enlarged emission energy gap and destabilized upper lying quenching state. PMID- 30462369 TI - The Enhanced Catalytic Performance and Stability of Ordered Mesoporous Carbon Supported Nano-gold with High Structural Integrity for Glycerol Oxidation. AB - Ordered mesoporous carbon (OMC) supported gold nanoparticles of size 3-4 nm having uniform dispersion were synthesized by sol-immobilization method. OMCs such as CMK-3 and NCCR-56 with high surface area and uniform pore size were obtained, respectively, using ordered mesoporous silicas such as SBA-15 and IITM 56 as hard templates, respectively. The resulting OMC supported monodispersed nano-gold, i. e., Au/CMK-3 and Au/NCCR-56, exhibited excellent performance as mild-oxidizing catalysts for oxidation of glycerol with high hydrothermal stability. Further, unlike activated carbon supported nano-gold catalysts (Au/AC), the OMC supported nano-gold catalysts, i. e., Au/CMK-3 and Au/NCCR-56, show no aggregation of active species even after recycling. Thus, in the case of Au/CMK-3 and Au/NCCR-56, both the fresh and regenerated catalysts showed excellent performane for the chosen reaction owing to an enhanced textural integrity of the catalysts and that with remarkable selectivity towards glyceric acid. The significance of the OMC supports in maintaining the dispersion of gold nanoparticles is explicit from this study, and that the activity of Au/AC catalyst is considerably decreased (~50 %) upon recycling as a result of agglomeration of the active gold nanoparticles over the disordered amorphous carbon matrix. PMID- 30462370 TI - Development of Divide-and-Conquer Density-Functional Tight-Binding Method for Theoretical Research on Li-ion Battery. AB - The density-functional tight-binding (DFTB) method is one of the useful quantum chemical methods, which provides a good balance between accuracy and computational efficiency. In this account, we reviewed the basis of the DFTB method, the linear-scaling divide-and-conquer (DC) technique, as well as the parameterization process. We also provide some refinement, modifications, and extension of the existing parameters that can be applicable for lithium-ion battery systems. The diffusion constants of common electrolyte molecules and LiTFSA salt in solution have been estimated using DC-DFTB molecular dynamics simulation with our new parameters. The resulting diffusion constants have good agreement to the experimental diffusion constants. PMID- 30462371 TI - Assessment of students' external representations of mmCIF entries and their biochemical knowledge. AB - An assessment was developed using entries from the macromolecular Crystallographic Information File that was given to students in an upper level bioinformatics class at the end of the semester during a 21/2 hour time period. Although all students completed the same questions, they were assessed on an individual protein they had worked on during the semester in the situated learning of the classroom as they completed computer-based tutorials and exercises using internet sources. The students' difficulties with the external representation of their protein were: not following directions, not understanding how to use the computational software, or a lack of knowledge about their protein. The students also were required to answer questions that required biochemical knowledge. The difficulties they experienced during the assessment can be attributed to factors, such as, their reasoning ability, understanding of the concepts, and the external representations of their protein. (c) 2018 International Union of Biochemistry and Molecular Biology, 46(6):634-643, 2018. PMID- 30462372 TI - Idea to explore: The structure of the oxygen and iron ion. AB - Understanding diamagnetism of oxygenated and paramagnetism of deoxygenated hemoglobin, an important topic in (bio) chemistry for medical students, begins with the understanding of the detailed structure of the oxygen molecule. It continues with a short description of the structures of reactive oxygen species: the singlet form of oxygen, the superoxide, and peroxide anions. The article then describes the high spin and low spin form of the iron ion with its d-orbitals and explains why both forms with different diameters exist in the heme part. At the end, medical applications of the acquired knowledge are presented: the cooperative effect in hemoglobin and the principles of magnetic resonance imagining. (c) 2018 International Union of Biochemistry and Molecular Biology, 46(6):630-633, 2018. PMID- 30462373 TI - Analysis of lactase in lactose intolerance supplements. AB - Lactase is the enzyme responsible for the digestion of the disaccharide lactose, and deficiency in this enzyme causes the prevalent medical condition lactose intolerance. Management of lactose intolerance can be achieved through the administration of lactase supplements. Lactase is an appropriate platform for advanced enzymatic study because its medical application is a motivator for student learning. The following is an upper-level biochemistry laboratory sequence that integrates student inquiry and exposure to advanced laboratory techniques. Students investigate three different lactase supplements through experimentation that includes the Bradford assay, SDS-PAGE, continuous and discontinuous kinetic assays, and zymography. Upon completion of this project, students compile their results and conclusions in a scientifically formatted paper comparing supplement protein content and activity. This safe and inexpensive laboratory project enriches student understanding of key biochemical concepts while mirroring work performed in a realistic research setting. (c) 2018 International Union of Biochemistry and Molecular Biology, 46(6):652-662, 2018. PMID- 30462375 TI - Prehabilitation Prior to Kidney Transplantation: Results from a Pilot Study. AB - Prehabilitation is the process of enhancing pre-operative functional capacity to improve tolerance for the upcoming stressor; it was associated with improved post operative outcomes in a handful of studies, but never evaluated in transplantation. Kidney transplant (KT) candidates may be uniquely suited for prehabilitation because they experience a profound loss of functional capacity while waiting years on dialysis. To better understand the feasibility and effectiveness of prehabilitation in KT, we conducted a pilot study of center based prehabilitation for candidates; this intervention consisted of weekly physical therapy sessions at an outpatient center with at home exercises. We enrolled 24 participants; 18 participated in prehabilitation (75% of enrolled; 17% of eligible). 61% were male, 72% were African American, and mean age=52 (SD=12.9); 71% of participants had lower extremity impairment and 31% were frail. By 2 months of prehabilitation, participants improved their physical activity by 64% (p=0.004) based on accelerometry. Participants reported high satisfaction. Among 5 prehabilitation participants who received KT during the study, length of stay was shorter than for age, sex, and race-matched control (5 vs. 10 days; RR=0.69; 95%CI:0.50-0.94;P=0.02). These pilot study findings suggest that prehabilitation is feasible in pre-transplant patients and may potentially be a strategy to improve post-KT outcomes. This article is protected by copyright. All rights reserved. PMID- 30462376 TI - Unmasking familial CPX by WES and identification of novel clinical signs. AB - Mutations in the T-Box transcription factor gene TBX22 are found in X-linked Cleft Palate with or without Ankyloglossia syndrome (CPX syndrome). In addition to X-linked inheritance, ankyloglossia, present in the majority of CPX patients, is an important diagnostic marker, but it is frequently missed or unreported, as it is a "minor" feature. Other described anomalies include cleft lip, micro and/or hypodontia, and features of CHARGE syndrome. We conducted whole exome sequencing (WES) on 22 individuals from 17 "a priori" non-syndromic cleft lip and/or cleft palate (CL/P) families. We filtered the data for heterozygous pathogenic variants within a set of predefined candidate genes. Two canonical splice-site mutations were found in TBX22. Detailed re-phenotyping of the two probands and their families unravelled orofacial features previously not associated with the CPX phenotypic spectrum: choanal atresia, Pierre-Robin sequence, and overgrowths on the posterior edge of the hard palate, on each side of the palatal midline. This study emphasizes the importance of WES analysis in familial CLP cases, combined with deep (reverse) phenotyping in "a priori" non syndromic clefts. PMID- 30462377 TI - Independent associations of TOMM40 and APOE variants with body mass index. AB - The TOMM40-APOE variants are known for their strong, antagonistic associations with Alzheimer's disease and body weight. While a stronger role of the APOE than TOMM40 variants in Alzheimer's disease was suggested, comparative contribution of the TOMM40-APOE variants in the regulation of body weight remains elusive. We examined additive effects of rs2075650 and rs157580 TOMM40 variants and rs429358 and rs7412 APOE variants coding the epsilon2/epsilon3/epsilon4 polymorphism on body mass index (BMI) in age-aggregated and age-stratified cohort-specific and cohort-pooled analysis of 27,863 Caucasians aged 20-100 years from seven longitudinal studies. Minor alleles of rs2075650, rs429358, and rs7412 were individually associated with BMI (beta = -1.29, p = 3.97 * 10-9 ; beta = -1.38, p = 2.78 * 10-10 ; and beta = 0.58, p = 3.04 * 10-2 , respectively). Conditional analysis with rs2075650 and rs429358 identified independent BMI-lowering associations for minor alleles (beta = -0.63, p = 3.99 * 10-2 and beta = -0.94, p = 2.17 * 10-3 , respectively). Polygenic mega-analysis identified additive effects of the rs2075650 and rs429358 heterozygotes (beta = -1.68, p = 3.00 * 10 9 ), and the strongest BMI-lowering association for the rs2075650 heterozygous and rs429358 minor allele homozygous carriers (beta = -4.11, p = 2.78 * 10-3 ). Conditional analysis with four polymorphisms identified independent BMI-lowering (rs2075650, rs157580, and rs429358) and BMI-increasing (rs7412) associations of heterozygous genotypes with BMI. Age-stratified conditional analysis revealed well-powered support for a differential and independent association of the rs429358 heterozygote with BMI in younger and older individuals, beta = 0.58, 95% confidence interval (CI) = -1.18, 2.35, p = 5.18 * 10-1 for 3,068 individuals aged <=30 years and beta = -4.28, CI = -5.65, -2.92, p = 7.71 * 10-10 for 6,052 individuals aged >80 years. TOMM40 and APOE variants are independently and additively associated with BMI. The APOE epsilon4-coding rs429358 polymorphism is associated with BMI in older individuals but not in younger individuals. PMID- 30462378 TI - Secular trends in growth in the high-altitude district of Nunoa, Peru 1964-2015. AB - OBJECTIVES: Nunoa, Peru has been the site of anthropological research on human adaptability, growth, and health since the 1960s. Previous studies documented a nascent secular trend in growth between 1964 and 1984. However, no secular trend was evident when the population was re-examined in 1999, following an intervening period of sociopolitical upheaval. Subsequently, the region experienced considerable economic development reflected in secular increases in height. We seek to evaluate trends in growth and BMI among Nunoan children over 50 years. MATERIALS AND METHODS: Anthropometric data for 929 children collected in 2015 are compared with anthropometric data for 394 children from 1964, 912 children from 1984, and 292 children from 1999. The data were converted to z-scores using the WHO 2007 growth standards. anova is used to evaluate rates of stunting, underweight, overweight, and obesity across the study periods. RESULTS: We observe small increases in stature and weight between the 1960s and 1980s, almost no change between the 1980s and 1990s and statistically significant reductions in stunting and increases in height between the 1990s and 2015. DISCUSSION: There were relatively small differences in stature and weight and a high incidence of stunting between 1964 and 1999 attributed to extremely poor economic and health conditions. A large secular increase in height (7-8 cm on average) and consequent reduction in rates of stunting between 1999 and 2015 occurred due to improved social and economic conditions. In addition to political stabilization, enhanced infrastructure, social aid programs, improved healthcare, and economic expansion contribute to these trends. PMID- 30462379 TI - Japanese patient with Cole-carpenter syndrome with compound heterozygous variants of SEC24D. AB - Cole-Carpenter syndrome is a rare skeletal dysplasia associated with low-bone mass or an osteogenesis imperfecta (OI)-like syndrome. Only 3 and 6 variants in SEC24D have been reported in patients with Cole-Carpenter syndrome type 2 and autosomal recessive OI, respectively. We describe a 15-year-old Japanese boy with short stature of the short-trunk type and craniofacial abnormalities including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia. These features were consistent with a diagnosis of Cole-Carpenter syndrome. He had low-bone mineral density and basilar impression. Whole exome sequencing analysis identified biallelic variants in SEC24D (p.Arg484* and p.Arg313His) in the patient. We will report a patient with compound heterozygous variants of SEC24D causing Cole-Carpenter syndrome type 2. PMID- 30462380 TI - First reported adult patient with TARP syndrome: A case report. AB - TARP syndrome (talipes equinovarus, atrial septal defect, Robin sequence, and persistence of the left superior vena cava) is a rare X-linked syndrome often resulting in pre- or post-natal lethality in affected males. In 2010, RBM10 was identified as the disease-causing gene, and we describe the first adult patient with TARP syndrome at age 28 years, hereby expanding the phenotypic spectrum. Our patient had Robin sequence, atrial septal defect, intellectual disability, scoliosis, and other findings previously associated with TARP syndrome. In addition, he had a prominent nose and nasal bridge, esotropia, displacement of lacrimal points in the cranial direction, small teeth, and chin dimple, which are the findings that have not previously been associated with TARP syndrome. Our patient was found to carry a hemizygous c.273_283delinsA RBM10 mutation in exon 4, an exon skipped in three of five protein-coding transcripts, suggesting a possible explanation for our patient surviving to adulthood. Direct sequencing of maternal DNA indicated possible mosaicism, which was confirmed by massive parallel sequencing. One of two sisters were heterozygous for the mutation. Therefore, we recommend sisters of patients with TARP syndrome be carrier tested before family planning regardless of carrier testing results of the mother. Based on our patient and previously reported patients, we suggest TARP syndrome be considered as a possible diagnosis in males with severe or profound intellectual disability combined with septal heart defect, and Robin sequence, micrognathia, or cleft palate. PMID- 30462381 TI - Antidiabetic-like Effects of Naringenin-7-O-glucoside from Edible Chrysanthemum "Kotobuki" and Naringenin by Activation of the PI3K/Akt Pathway and PPARgamma. AB - Obesity is directly associated with type 2 diabetes, hypertension, cardiovascular injury, and cancer. To date, Yamamoto identified that hot water extracts of edible chrysanthemum (EC) induced cell size reduction, up-regulation of adiponectin expression, and glucose absorption inhibition in 3T3-L1 cells during adipogenesis. Furthermore, EC showed anti-diabetic effects such as improvement in insulin resistance and the down-regulation of the blood glucose level and liver lipid content in type 2 diabetes model mice. In the present study, we attempted to identify the antidiabetic components in EC. The methanol fraction from EC that showed relatively strong biological activity was purified by chromatography to obtain acacetin-7-O-glucoside, apigenin-7-O-glucoside, kaempferol-7-O-glucoside, and naringenin-7-O-glucoside. Among the isolated compounds and their aglycones, naringenin (NA) and naringenin-7-O-glucoside (NAG) up-regulated the intracellular lipid accumulation and secretion of adiponectin and down-regulated the diameter of 3T3-L1 cells during adipogenesis. Because the PPARgamma antagonist BADGE and PI3K/Akt inhibitors wortmannin and LY29004 inhibited the intracellular lipid accumulation by NA and NAG associated with adipogenesis, it was considered that NA and NAG showed the above-mentioned activities via the activation of PPARgamma as well as phosphorylation of the PI3K/Akt pathway. PMID- 30462382 TI - Factors affecting mortality in children requiring continuous renal replacement therapy in pediatric intensive care unit. AB - BACKGROUND: Acute kidney injury (AKI) occurs in up to 30% of pediatric intensive care unit (PICU) patients and is associated with a high mortality rate. OBJECTIVES: The objective of the study was to evaluate factors associated with the outcome and to identify the prognostic factors in children receiving continuous renal replacement therapy (CRRT). MATERIAL AND METHODS: This was a retrospective, single-center study, including 46 patients. RESULTS: Logistic regression analysis demonstrated significant effects on patient survival exerted by the percentage of fluid overload (FO%) (odds ratio (OR): 1.030; p = 0.044). In the group of patients with FO% < 25%, the mortality was 33.3%, and in the FO% >= 25% group, the mortality was 67.9% (p < 0.001). The probability of death without multi-organ failure (MOF) was 13%, while with MOF it was 74%. There was no difference in the duration of hospitalization between the CRRT patients (mean: 21.9 days) and the general population of children hospitalized in PICU in the same period (n = 3,255; mean: 25.4 days); however, a significant difference was noted in mortality between the 2 groups of patients (54% vs 6.5%; p < 0.001). CONCLUSIONS: The mortality of PICU CRRT patients is more than 8-fold higher than the mortality of the total PICU population. Coexisting MOF increases the mortality almost 6 times. The mortality of children with FO% >= 25% was more than 2-fold higher than the mortality of children with FO% < 25%. PMID- 30462383 TI - Current Status of Alcoholic Liver Disease in Japan and Therapeutic Strategy. AB - Alcoholism results in an estimated 3.3 million deaths annually worldwide, accounting for 5.9% of all mortality. Although per capita alcohol consumption in Japan, had been gradually decreasing since 1999, it has plateaued in the past 5 years. Alcoholic liver disease (ALD) is the most prevalent cause of advanced liver disease, and includes alcoholic fatty liver, alcoholic hepatitis (AH), alcoholic fibrosis, alcoholic liver cirrhosis (ALC), and alcoholic hepatocellular carcinoma (HCQ. Although alcohol consumption is the predominant etiological factor in the pathogenesis of ALD, there is marked variation in liver mortality rates among. different countries and over time within countries. Six national surveys of ALD in Japan were carried out by the Japanese ALD study groups. The first three studies reported that the prevalence of ALD increased in parallel with an increase in alcoholic beverage -intake and that the rise in ALD was one major- factor contributing to the increased prevalence of liver cirrhosis. However; recent epidemiological studies- showed that ALC continues to rise despite a gradual decrease in alcohol intake, indicating that there are other risk factors for the development of ALC. Our recent survey revealed that the prevalence of ALC has been rapidly increasing in Japan and that the prevalence of alcoholic HCC in ALC was higher in elderly male patients and younger patients with diabetes mellitus (DM). DM, female sex, and age were identified as risk factors for the development of ALC, while DM, male sex, and age were identified as significant risk factors for HCC in ALC. Severe alcoholic hepatitis (SAH) is an inflammatory response with multiple morbidity factors like leucocytosis, hepatomegay, and renal failure, and has a high mortality rate. We have created a new scoring system for AH (Japan Alcoholic Hepatitis Score [JAS]). Its ability to predict outcome was confirmed by examining the data of 59 patients with AH in 2011: 26 had moderate AH of whom 22 were alive and were dead, while 33 had SAH of whom 16 were alive and 17 were dead. There was no report of death in patients with mild AH (JAS was <= 7). The prevalence of renal failure, DIC and gastrointestinal bleeding was higher in patients who had died, while Cr and PT (INR) were higher in SAH patients who had died. These results suggest that JAS allows stratification of the risk of death and can help manage patients with AH. Our belief is that patients with elevated myeloid leucocytes benefit most from granulocytes/monocytes apheresis, while exchange appears to support patients with coagulation deficiency of high plasma bilirubin and hemodialysis is indicated for hit Cr. Liver transplantation is the ultimate therapy for ALD, but it has always been controversial. In Japan, most cases are living donor liver transplantations because the number of brain-dead donors are low. Although 6 months of abstinence is required for brain-dead donor liver transplantation in most countries, 18 months of proven abstinence is required in Japan. PMID- 30462384 TI - Neurofeedback therapy for alcohol use disorder. AB - Neurofeedback is a therapeutic learning process that provides visual and auditory feedback to an individual about his or her brainwaves in order to teach self regulation of brain func- tion. Currently, neurofeedback therapy has been attempted to apply to various psychiatric disorders and certain therapeutic effects have been shown. The advantage of incorporating neurofeedback therapy to the conventional treatments is 1) the action on the central nervous-system can be expected. by directly reinforcing EEG, 2) on the premise of neural plasticity, without ongoing intervention, long-term therapeutic effect can be expected, 3) except rare temporary headache, no significant side effects are reported, 4) compared to other psychotherapies, neurofeedback is expected to have a therapeutic effect within a relatively short period of time. The present paper outlines neurofeedback therapy in the treatment of alcohol dependence and points out the new direction and remaining issues in neurofeedback therapy. PMID- 30462385 TI - Estimating the economic effects of reduced drinking in Japan based on the methodologies of cost-of-illness studies on alcohol in Japan and overseas. AB - One of the alcohol-related goals in Japan's health promotion campaign called Health Japan 21 (secondary term) is to reduce the number of high-risk drinkers (20 years old or above) who consume 40g or more pure alcohol/day in men and 20g or more in women by year 2022. To achieve this goal, it is important for both the government and clinicians to understand the cost-of-illness associated with harmful drinking in Japan and .effectively reflect it into related poli- cies. In this study, direct and indirect costs attributable to alcohol based on conventional cost-of-illness study methodologies were estimated to be approximately 9.9 trillion yen using 2012 data. Furthermore, economic effects brought by achieving the goal of Health Japan 21 (seconda'ry term) were further analyzed by incorporating parameters such as employment rates, drinking volume and frequency by age group and gender. The authors.had previously estimated possible savings of as much as 381.3 billion yen, before subtracting associated intervention costs and decreased tax revenue from purchasing alcohol beverages. The scenario analysis in this study provided lower savings of approximately 158.4 194.6 billion yen. However, the estimates excluded high-risk drinkers in their 20s, early 30s and over 70, who account for a good part of high-risk drinkers in Japan. Furthermore, considerations of employment rates and average annual salaries into the calculations of economic loss due to premature mortality tend to ignore productivity loss (absenteeism and presentism) of high-risk drinkers and opportunity costs of home-makers or care-givers. Thus, possibly underestimated 158.4 billion yen was considered as realistic as possibly overestimated 381.3 billion yen. Despite such variations, economic effects brought by achieving reduced drinking among high-risk drinkers seemed to support related policies and disease management in Japan. PMID- 30462386 TI - Effects of solmach on alcohol hangover model in mice. AB - Alcohol hangover is an unpleasant state caused by acetaldehyde, which is produced by partial oxidation of ethanol. Treating hangover is important from the viewpoint of preventing excessive drinking. In the present study, we attempted to produce mouse model of alcohol hangover by intraperitoneal pretreatment with cyanamide at 12.5 mg/kg followed by oral ethanol at 1.6 g/kg. The mice showed decrease of spontaneous locomotor activity and food intake. Thus, it is suggested that the hangover model was successively established by co-administration of cyanamide and ethanol. Solmack, a product based on herbal medicine for stomach anda pproved as medical drug, recovered decrease of spontaneous locomotor activity and tended to recover decrease of food intake in the.hangover model mice. Other refreshing drinks did not show such effects, though they contain herbal medicine ingredients to some extent. Our model in mice might be useful to detect effective treatment for alcohol hangover. PMID- 30462387 TI - Common aspects of the lifestyles of high school students in Japan and their associations with drug abuse: Findings from an aggregate sample of the Japanese School Survey Project on Alcohol and Other Drugs in 2004, 2006, and 2009. AB - This study sought (1) to determine the significant associations between measures of drug abuse and lifestyle variables in high school students in Japan, and (2) to ascertain common lifestyle variables in relation to associations between lifestyle and eight measures of drug abuse. Four measures were use of an inhalant, marijuana, an amphetamine-type stimulant (ATS), or MDMA (ecstasy) over the past year, and four measures were use of those drugs over one's lifetime. Data were from a combined sample (aggregate sample) from the Japanese School Survey Project on Alcohol and Other Drugs (JSPAD). The aggregate sample consisted of 75, 726 1st-, 2nd-, and 3rd-year students (37,697 males and 38,029 females) at high schools nationwide who were selected by stratified, single-stage cluster sampling during surveys in 2004, 2006, and 2009. Eight measures of drug abuse were predicted with logistic regression analysis based on lifestyle variables. Six lifestyle variables jointly predicted those measures: "get- ting up at the same time every day," "eating breakfast," "enjoying school,'' "hours worked at a part-time job," "having close friends to hang out with", and "talking with one's parents about one's problems". The six lifestyle variables were associated with the measures of drug abuse in similar ways, regardless of which drug was abused. Those associations indicated that students whose parents were not at home had a markedly higher level of drug abuse. Students who lacked close friends to hang out with, students who did.not enjoy school, students who rarely ate breakfast, and students who did not get up at the same time every day had a higher level of drug abuse. Several indicators of associations yielded findings, and these findings could presumably help to determine if "individuals who abuse drugs display characteristics as a group" and if "individuals who abuse drugs tend to abuse multiple drugs". PMID- 30462388 TI - DSM-5 from the viewpoint of basic study of dependence and addiction. AB - In this review, current progress of neurobehavioral research using animal model of dependence and/or addiction is described in light of DSM-5. Although the terms "dependence" and "abuse" are deleted in DSM-5, the concept of dependence and the related animal experiments, drug self-administration, conditioned place preference, and drug discrimination are still useful to predict abuse liability of chemical substances. At the same time, it is necessary to model addictive nature of behavior in animals. Impulsivity, compulsivity, and comorbidity of addiction to other mental disorders are the major topics of such research area. At the same time, basic research aimed at treatment of dependence/addiction has been progressed. For example, a methamphetamine monoclonal antibody, a new chemical acting on DARPP-32 (dopamine and c-AMP-regulated phophoprotein-32), a galanin analogue, oxytocin, and others are included in such attempt. As DSM-5 mentioned the brain reward system as the major site of substance-related and addictive disorders, clinicians would be more interested in biological substrates of dependence/addiction. It is expected that the emergence of new diagnostic criteria promotes mutual communication between basic and clinical researchers. PMID- 30462389 TI - Survey of the relationship between internet addiction and social withdrawal (HIKIKOMORI) in Japan. AB - PURPOSE: The Internet was originally designed to facilitate communication and research activities.'However, there has been a dramatic increase in the use of the Internet in recent years for commerce, education, and entertainment, including video games. Internet addiction as.a phenomena has been described by researchers as excessive or compulsive use of computers that interferes with daily life. Hikikomori (social withdrawal) -has increasingly become a problem in Japan and has been hypothesized to be ,related to internet, addiction. Particularly amongst students, problematic internet use may be a major factor of social withdrawal. We conducted a survey of internet addiction. and social- withdrawal among college students and corhpany workers to examine this hypothesis. METHODS: Subjects were 63 university students and 56 company workers. To examine the relationship between internet addiction and social withdrawal, we administered the Internet Addiction Test (IAT) and the UCLA Loneliness Scale (ULS), a measure of social isolation, to all subjects. RESULTS: Students tended to score higher than workers on the IAT (Student u = 36.3, Worker u = 31.1, p<0.05). For students considered addictive internet users, we found a significant correlation between the ULS and the IAT (r=0.549,. p<0.05); suggesting that social isolation and internet addiction are associated with each other. Workers tended to score higher on the ULS than students (Worker p =40.4, Student u =37.5, p<0.05). For workers .who were not addictive internet users, we found a'mild, negative correlation between the ULS and the IAT (r=- 0.285, p<0.05), suggesting that use of the internet for workers was not a compensatory behavior. CONCLUSIONS: Based upon the IAT, we found that more students than workers reported problems with internet use. Based upon.the ULS, more workers reported feelings of loneliness than students. Workers' loneliness did not appear to be related to their use of the internet, but amongst students with internet addiction, loneliness appeared to be associated with internet use. PMID- 30462390 TI - Postmortem Computed Tomography Findings Associated with Sudden Death in Alcoholics. AB - Forensic pathologists.frequently encounter sudden natural.death of alcoholic in which fatty liver is the only pathological finding detected at autopsy, however, characteristics of postmortem CT (PMCT) of sudden death of alcoholic have not been reported so far. In this study, we investigated radiographic measurements of PMCT of the cases diagnosed as sudden death of alcoholic (ALC), and compared them with those of other causes of death (IHD; ischemic heart disease, SV; starvation), with reference to autopsy findings. The cardio-thoracic ratio, the cross-sectional area of the inferior vena cava and the radio density of the lungs of ALC on PMCT were significantly lower than those of IHD, and tended to be midway between IHD and SV. These findings were in parallel with the total heart blood volume at autopsy and the extent of lung edema on histopathological findings. In addition, the radiodensity of the liver of ALC was significantly lower than the other groups, which was in parallel with the extent of fatty deposit in the hepatocytes on histopathology. More than 60% of ALC cases showed BMI < 18.0, and acetone was detected in blood in 87.5% of ALC cases. The lower radiodensity of the liver, and lack of signs suggestive of significant pulmonary edema and congestion in the great vessels, on PMCT, are considered to mirror terminal pathophysiology of sudden death of alcoholic, such as severe fatty liver disease and metabolic disturbance (e.g., concomitant volume depletion with alcoholic ketoacidosis). Utilization of these findings on PMCT may serve to discern sudden death of alcoholic from other causes of death, in combination with detailed scene investigation, pathological, toxicological and biochemical analysis. PMID- 30462391 TI - The Alcohol Use Disorders. Identification Test (AUDIT) score is useful for predicting alcohol consumption. AB - It is important to screen for alcohol consumption and drinking customs by using a stan- dardized method. The aim of this study was to investigate whether standardized questionnaire was useful for predicting alcohol consumption. A cross sectional study using the Alcohol Use Disorders Identification Test (AUDIT) was conducted in 334 outpatients who consulted the Internal Medicine Department of Osaka City Juso Hospital. The patients completed self-reported questionnaires and underwent a diagnostic interview, physical examination, and laboratory testing. Forty (23%) male patients reported daily alcohol consumption 40 g, and 16 (10%) female patients reported consumption 20 g. The optimal cutoff values of hazardous drinking (all patients)/ drinker (male)/ drinker (female) were calculated using a 10-fold cross validation, resulting in an optimal AUDIT score cutoff of 8.2/ 7.2/ 6.1, with sensitivity of 95.5%/ 96.3%/ 88.9%, specificity of 87.0%/ 96.3%/ 88.9%, false positive rate of 13.0%/ 9.4%/6.6%, false negative rate of 4.5%/ 3.'%/ 11.1%, and area under the receiver operating characteristic curve of 0.97/ 0.98/ 0.99. In conclusion, this study showed that the AUDIT score was useful for predicting alcohol consumption. PMID- 30462392 TI - Reasons for alcohol consumption among Japanese high school students overall and by sex and year in school: An exploratory study. AB - This study sought to ascertain the association between alcohol consumption by Japanese high school students and their reasons for drinking. Monitoring the Future is a U.S. survey of substance abuse that features a core question that asks about reasons for drinking. This study translated that question into Japanese to survey 2,283 students (1,404 males and 879 females; 1,142 freshmen and 1,141 sophomores) at 3 Japanese high schools from November to December 2014. The original question had 15 possible answers, but 2 were eliminated and the answer "I don't drink" was added. Responses were analyzed overall and by sex and year. Results indicated that 9.4% of male students drank in the past 30 days, 28.4% drank in the past year, and 43.0% had drunk at some point in their lives. Similarly, 6.5% of female students drank in the past 30 days, 23.8% drank in the past year, and 36.7% had drunk at some point in their lives. Of the sample, 58.1% answered that they "don't drink. " Given reasons for drinking were "because it tastes good" (15.8%), "to-experiment-to see what it's like" (14.5%), "to have a good time with my friends" (14.1%), "to relax or relieve tension" (10.2%), "to feel good or get high" (7.9%), and "to fit in with a group I like" (5.2%). Respondents who drank in the past 30 days, in the past year, or at some point in their lives did so for different reasons. As alcohol consumption increased, respondents drank "because it tastes good" markedly more often. Reasons for drinking were ranked by frequency to compare Japanese high school students and U.S. 12th graders. Japanese students were more likely to drink "to fit in with a group I like" while U.S. students were more likely to drink "because of boredom, nothing else to do." PMID- 30462393 TI - Prevention of alcohol-induced hyperhomocysteinemia by suppression of SHP. AB - Chronic alcohol consumption is a major public health problem that frequently leads to the development of liver steatosis, fibrosis, and eventually cirrhosis and hepatocellular carcinoma. Hyperhomocysteinemia is a pathological consequence of alcoholic liver disease (ALD) and is attributed to hepatic endoplasmic reticulum (ER) stress and insulin resistance. However, the regulatory function of nuclear receptors in ALD associated with dysregulation of homocysteine metabolism remains largely unknown. Nuclear receptor small heterodimer partner (SHP, NROB2) is a pleiotropic transcriptional repressor involved in regulating various metabolic path-ways in the liver. This study investigated a critical role of SHP in alcohol-induced hyperhomocysteinemia. . The expression and enzymatic activities of betaine-homocysteine S-methyltransferase (BHMT) and cystathionine y -lyase (CTH) were significantly increased in the liver of SHP- knockout (SKO) mice as compared to the wild-type mice. The substrates of BHMT and CTH, such as betaine, choline and cystathionine, were decreased in SKO liver while their products including hydrogen sulfide and cysteine were increased. However, methionine and homocysteine were not altered by SHP- deficiency, suggesting that the methionine cycle is activated in SKO mice. Forkhead box A (FOXA)- binding site was identified in both the BHMT and CTH promoters. Luciferase assay demonstrated that FOXAI, but not FOXA2, activated both BHMT and CTH promoters through the FOXA-binding site. Overexpression of FOXA1 induced BHMT and CTH expression in Hepal-6 cells, which was inhibited by SHP coexpression. Consistently, alcohol-induced hyperhomocysteinemia, and homocysteine-induced hepatic ER stress and glucose intolerance were abrogated in SKO mice. These novel findings identified SHP and FOXA1 as important regulators of hepatic homocysteine metabolism. Because hyper-homocysteinemia is a risk factor for cardiovascular disease and insulin resistance, and is often associated with ALD and metabolic syndrome, SHP and FOXA1 could be used as potential targets for hyperhomocysteinemia and its related diseases. Taken together, these results shed light on the regulatory mechanism of homocysteine metabolism in the liver. PMID- 30462394 TI - Survey design and outcome measures to evaluate the effectiveness of relapse prevention guidance for drug-dependent inmates in-Japan: A review. AB - PURPOSE: . In the last-decade, the treatment of drug offenders in Japanese prisons has changed from severe punishment to a therapeutic approach. This study aimed to review studies that evaluated the effectiveness of relapse prevention guidance for drug- dependent inmates in Japan. METHODS: We searched three databases: Ichushi; the Japanese correctional library database; and- PubMed. The inclusion criteria were: 1) the guidance was conducted in prisons in Japan; 2) the participants were Japanese adult inmates; 3) the evaluations were reported in quanti- tative investigations and original articles in Ichushi and PubMed; and, 4) the evaluations were reported in quantitative investigations in the Japanese correctional library database. RESULTS: In total, we identified 13 studies. Three studies.used comparison groups, and two studies included follow-up after the inmates' : release. Two studies-used recidivism and one used treatment persistence as behavioral outcomes. Almost all of the studies used psychological scales. Self-efficacy measures were the most commonly used, and the second most common scale was the Stage of Change Readiness and Treatment Eagerness Scale (SOCRATES). CONCLUSION: Our findings indicate that SOCRATES is the most useful psychological outcome scale in assessing the effectiveness of. relapse prevention guidance for drug offenders in Japan. However, evidence is lacking, as most studies were before-and-after studies that only assessed psychological outcomes. More follow-up studies after release that include comparison groups and investigate behavioral outcomes are needed. PMID- 30462395 TI - ? PMID- 30462396 TI - [How to properly use beta-blockers ?] AB - Known since the 1950s, competitive beta-adrenergic receptor antagonists, namely beta-blockers (BB), constitute today a large and heterogeneous class of drugs with multiple clinical indications. Despite their daily use, can we choose the most appropriate BB for each of these indications? A better knowledge of the individual properties of BB (bioavailability, cardioselectivity, vasodilator and metabolic effects) could help to optimize their clinical benefits especially in polymorbid patients, frequently suffering from metabolic syndrome, peripheral arteriopathy or asthma/chronic obstructive pulmonary disease (COPD) supposed to be potential contraindications to their use. PMID- 30462397 TI - [The " Osler " group : a new opportunity to think about " becoming a physician "]. AB - Issues of professionalism and professional identity formation, particularly amongst young doctors, have been the object of increasing attention. This is explained in part by the evolution of the hospital environment (specialization, shorter stays), as well as by the prevalence of physician burnout and suicide. In this context, the CHUV implemented a pilot project within the department of internal medicine aiming to support its residents in the construction of their professional identity. The Osler group convened 10 residents led by an attending physician and a senior resident from the internal medicine department as well as an attending physician of the liaison psychiatry department. The experience has been a success, with residents describing clear benefits of the group. PMID- 30462398 TI - [Venous thromboembolism prophylaxis in internal medicine : for whom ?] AB - The incidence of thromboembolic events remains high in hospitalized medical patients, despite known risk factors and international recommendations regarding prevention of venous thromboembolism. Several studies have proven that the use of a thromboembolic prediction risk score, associated with an informatic alert system, improve the prescription of adequate thromboembolic prophylaxis and decrease the number of thromboembolic events. In this article, we present an overview of thromboembolic risk factors, thromboembolic prediction risk scores, and interventions that improve thromboembolic prophylaxis prescription. PMID- 30462399 TI - [Approach to the syndrome of inappropriate antidiuretic hormone secretion (SIADH)]. AB - The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is defined by euvolemic hyponatremia due to an inappropriate retention of free water under the effect of antidiuretic hormone. It is underdiagnosed despite well-defined criteria. Diagnosis involves a precise evaluation of volemia and the elimination of differential diagnoses. The etiologies are classified into four main groups : tumors, drugs, diseases of the central nervous system and lung diseases. In the case of a newly diagnosed SIADH, investigations depend on the clinical context and should at least include a chest radiograph or a chest CT-scan. Fluid restriction is the recommended first-line treatment for mild or moderate hyponatremia. However, only the etiologic treatment leads to the disappearance of SIADH. PMID- 30462400 TI - [Screening and management of malnutrition in internal medicine]. AB - Malnutrition is a common but underestimated condition in the hospital setting. Malnutrition increases in-hospital mortality and complications, and treatment costs. Simple screening tools such as the mini-nutritional assessment and the nutritional risk score allow identifying patients at risk of malnutrition and starting management. Malnutrition management is a multidisciplinary issue including dieticians, physiatrists, nurses, caregivers and doctors. Meal fractioning and oral nutritional supplements (ONS) should be provided. Frequently, micronutrient supplements are also needed. Particular care should be taken to ensure that the patient consumes the meals and ONS prescribed. Follow-up is based on weight and assessment of prealbumin. Malnutrition status should be systematically reported in the discharge letter. PMID- 30462401 TI - [The discharge summary in the transition between hospital and ambulatory care]. AB - The hospital discharge letter is an important tool for transmitting medical information during the transition from inpatient to outpatient care. It promotes continuity of care, as well as quality and safety of medical care. Nevertheless, several challenges exist within a university hospital department that may make it difficult to transmit these documents in a timely manner. In this article we describe a project to improve the quality and rapidity of the transmission of discharge letters in our internal medicine department, composed of organizational and formative measures. PMID- 30462403 TI - ? PMID- 30462402 TI - ? PMID- 30462404 TI - ? PMID- 30462405 TI - ? PMID- 30462406 TI - ? PMID- 30462407 TI - ? PMID- 30462408 TI - ? PMID- 30462409 TI - ? PMID- 30462411 TI - Gaming in the Classroom. PMID- 30462410 TI - Insight from a Nurse Leader on Board! PMID- 30462413 TI - Do you know what NAMI is? PMID- 30462412 TI - Stress vs. Mental and Physical Health. PMID- 30462414 TI - President's Message PMID- 30462416 TI - President's Message. PMID- 30462417 TI - A Case for the Nursing Informatics Executive. PMID- 30462418 TI - [Reconstructive plastic surgeries in patients with malignancies of tongue and floor of the mouth. Types of plastics]. AB - The problem of restoring tissue defects after radical surgery for malignant tumors of the head and neck remains relevant, as there is no standardized approach for solving this problem. This article describes the various options for plastics of combined through defects of the floor of the mouth, of angle of the mouth, of the upper and lower lips, of lateral parts of the neck. The use of a particular type of arterialized flap depended on the depth and character of the existing tissue defect. The use of this methodology allowed to reach satisfactory cosmetic and functional results, as well as improve the quality of patient's life. PMID- 30462419 TI - Mindfulness-Based Childbirth Parenting (MBCP) Program: Impact on anxiety and stress during labor. PMID- 30462420 TI - President's Message. PMID- 30462421 TI - Insight from a Nurse Leader on Board! PMID- 30462422 TI - Specialty Practice of Clinical Research Nursing Recognized. PMID- 30462423 TI - Fostering Children with Medical Needs. PMID- 30462424 TI - Tai Chi Moving for Better Balance: A Fall Prevention Program for Older Adults. PMID- 30462425 TI - Supporting women with perineal trauma. PMID- 30462426 TI - Promoting professional behavior in practice. AB - Becoming a midwife is the 16th series of 'Midwifery basics' targeted at practicing midwives and midwifery students. The aim of these articles is to provide information to raise awareness of the impact of professionalism on women's experience, consider the implications for midwives' practice and encourage midwives to seed further information through a series of activities relating to the topic. In this fourth article of the series, Jancis Shepherd discusses the issues of maintaining confidentiality, use of social media and veracity of students' practice assessment documents, to demonstrate the need to uphold the NMC Code (2015a) in clinical practice. PMID- 30462428 TI - Lifting the fog. AB - It is well established that maternal smoking can result in serious health consequences. Smoking cessation interventions for pregnant women can effectively reduce the rate of maternal smoking and consequently prevent perinatal morbidity. Although motivation is high for women in pregnancy to stop smoking, few achieve this status on their own. The support available varies throughout the country; this article describes the service available in Fife, Scotland. Support is provided by two specialist midwives and is funded by the Scottish Government. It is one of the few midwife-led services available in Scotland. Home visits are the foundation of its success, enabling engagement with women in areas of deprivation. Individualised care is provided and extended to partners and other family members who are interested in stopping smoking. PMID- 30462427 TI - Safeguarding children. AB - Safeguarding children is arguably one of the most challenging areas of the midwife's role. At a time when there is a national midwifery shortage and a rising birth rate, resources are stretched more than ever (Dabrowski 2016). Safeguarding is everyone's responsibility (Department for Education (DfE) 2015), but has become a much more significant part of the midwife's role and workload over recent years (Halsall and Marks-Moran 2014). Student midwives, newly qualified and experienced midwives alike must have the required level of understanding of the principles, processes and accompanying orders, to appropriately protect children (Griffiths 2009). This article explores safeguarding practice from a midwifery perspective, which includes looking again at the fundamental, basic principles of midwifery in order to advance practice further. PMID- 30462429 TI - Physiological breech birth. Evaluation of a training programme for birth professionals. AB - This article evaluates the results of physiological breech birth (PBB) study days provided by breech Birth Network (BBN). An expanded version of this article, with further details including the statistics and additional information about the content of the training, is available on our website. This paper reports an evaluation of the BBN PBB training programme, which has been developed out of consensus research, with highly experienced health professionals. The training was delivered in four National Health Service trust hospitals in the north and south of England throughout the spring and summer of 2016. The evaluation involved pre- and post-training surverys containing a mixture of open-ended and multiple-choice questions, and rating scales. Data were analysed descriptively. The results indicated that the training addressed the concernsof the participants and was rated highly in expected usefulness for practice. Significant improvements in self-reported confidence and objectively assessed knowledge were observed. Participants found discussions and hands-on practice accompanying videos helpful, and reported concerns about lack of support and involvement of obstetric colleagues both before and after the training. The package is an effectively designed and replicable programme for introducing PBB practice to health care professionals. PMID- 30462430 TI - MBRRACE-UK Report launch December 2016. AB - December 7th 2016 saw the launch of the third annual MBRRACE-UK Saving lives, improving mothers' care report; a report which provides us with a picture of maternal deaths in the UK between 2012-14 and information on the lessons learned from the UK and Ireland confidential enquiries into maternal deaths and morbidities between 2009-14. Globally, maternal deaths have fallen by over half since the introduction of the millennium development goals in 1990. Although short of the global target to reduce such maternal deaths by three quarters by the year 2015 (United Nations (UN) 2015), maternal deaths within the UK are, in fact, a rare event. This year's report calculates reduction in deaths from previous years to a rate 8.5 death per 100,00 maternities compared to last year's nine deaths per 100,000 maternities. Although not a statistically significant decrease, it is a promising reduction. Here, the key recommendations for practice outlined in the report are summarized in an attempt to further reduce such morbidity and mortality rates in the future. PMID- 30462432 TI - Matters of the mind. PMID- 30462433 TI - [The risk-adaptive strategies of Hodgkin's lymphoma therapy]. AB - Using of radiochemotherapy improves short-term and long-term results of treatment in patients with primary Hodgkin's lymphoma (HL) comparing with treatment by chemotherapy alone. The rates of 5-year, 10-year OS and DFS are 88%, 83% and 90%, 86% in case of radiochemotherapy, versus 73%, 66% and 72%, 68% using chemotherapy alone. The 5-year and 10-year OS, DFS estimates in treatment with ABVD are 84% and 83%, 75% and 74%; BEACOPP-baseline - 83% and 82%, 82% and 81% (p<0.05). At the same time ABVD chemotherapy develops less toxicity (p<0.001). The treatment with 6 cycles of ABVD is considered as the most appropriate in primary Hodgkin's lymphoma patients with extranodal lesions. Comparison of complications rate during chemotherapy with MOPP, ABVD, BEACOPP-baseline, BEACOPP-escalated reveals major hematologic toxicity and infectious complications rate in BEACOPP-escalated program (p<0,05). The age >=45 years, hemoglobin <105g/l, B symptoms, fibrinogen >5g/l, involvement of 3 and more areas of lymph nodes, liver involvement, inguinal lymph nodes are defined by the multiple-factor analysis as adverse prognostic factors of patients with primary Hodgkin's lymphoma (HL) with extranodal lesions (p<0.05). Allocation of group of high risk is proved by correlation between survival and the Prognostic Score (PS). The 5-year and 10 year DFS, OS for patients with PS-0-2 estimates are 88% and 86%, 89% and 83%, for patients with PS-3-4 - 78% and 69%, 80% and 77%, for patients with PS-5-6 - 43% and 42%, 60% and 38% respectively (p<0.001). PMID- 30462431 TI - [The first results of assessment of clinical efficacy of melatonin and metformin in patients with disseminated skin melanoma receiving dacarbazine as first-line systemic therapy]. AB - The aim of the study was to assess efficacy and safety of combined therapy with dacarbazine and melatonin or metformin in comparison with dacarbazine alone in the 1st line of therapy of cutaneous melanoma. Thirty-six patients with disseminated melanoma, therapy naive, were included between March 2014 and December 2015. Patients received DTIC 1000 mg/m2 in day 1 of 28-day cycle either as monotherapy (group 1) or in combination with melatonin 3 mg PO daily (group 2) or metformin 850 mg 2 times a day PO daily (group 3). Thirty-four patients were randomized (15-in group 1, 8 - in group 2, 13 - in group 3) and received 119 cycles of therapy. Response rate was 11% in groups 1 and 2, and 8,3% - in group 3 (p=0,57). Median time to progression was 52, 79 and 63 days, respectively in the 1st, 2nd and 3rd group (r=0,468). Two patients from the 2nd and 3rd group showed delayed response to therapy. No adverse events of grade 3-4 were seen. Thus, DTIC with melatonin or metformin was well tolerated. No meaningful increase of adverse event incidence was seen. No benefit of either combination was shown in this interim analysis. Delayed responses in melatonin and metformin combination groups were registered. This suggests immunologic effect of both drugs and warrants further study. PMID- 30462434 TI - Mothers in immigration detention: the most vulnerable and the hardest to reach. AB - Phoebe Pallotti and Morag Forbes are two experienced midwives who volunteered for a charity that works for the health rights of people in immigration detentions. They both have other experience of this client group and they both hold diplomas in Tropical Midwifery. Over more than three years, Phoebe and Morag have been visiting and calling on pregnant women in immigration detention, most often in the infamous detention centre, Yarl's Wood, in Bedfordshire, where a recent Channel Four documentary was secretly filmed. The centre has a small health care facility, but there are no midwifery staff employed there, though women were often referred to the local maternity unit. This article explores the situations of the pregnant women who are detained in the UK and considers how they may better be supported. PMID- 30462455 TI - Professionalism, public confidence and course application. AB - Becoming a midwife is the 16th series of 'Midwifery basics' targeted at practicing midwives and midwifery students. The aim of these articles is to provide information to raise awareness of the impact of professionalism on women's experience, consider the implications for midwives' practice and encourage midwives to seed further information through a series of activities relating to the topic. In this second article of the series, Jancis Sheperd considers why professionalism in an issue in maintaining public confidence, why midwives need to demonstrate good health and good character and how applicants are selected for midwifery courses to meet these attributes. PMID- 30462456 TI - [Modeling of the impact of chemotherapeutic agents on primary cultures of metastatic soft tissue sarcomas in the automated analytical system CELL-IQ]. AB - This work presents results of long-term phase-contrast microscopy research of proliferative potential of soft tissue sarcomas utilizing live-cell imaging technology Cell-IQ (Chip-Man Technologies Ltd, Finland). It was found that the machine vision technology allowed to obtained sufficient body of evidence about high-quality and quantitative changes of proliferative activity of the cells soft tissue sarcoma cultivated in static conditions. The present study demonstrates that modeling in time interval of maximum proliferative activity of soft tissue sarcoma cells increases information efficacy and reliability of the analysis of dividing cells patterns using Cell-IQ technology. The models of exponential growth of tumor cells soft sarcomas, describing their quantitative and dynamic changes of expansion potential to chemotherapeutic agents have been received. Modeling of maximum tumor cells proliferative activity in vitro can be applied for development of test-system of individual cell sensitivity to chemotherapy in vivo. PMID- 30462457 TI - Twins, postnatal depression and me. AB - I am a mother to four-year-old twin girls. Life since their birth has not been easy and postnatal depression has blighted our relationship. So, too, has it affected the relationship I have with friends, family, my husband, myself. My reasons for becoming a student midwife were numerous, but my experiences as a pregnant woman and a new mother were pivotal in that decision. Whilst screening tools are commended to detect postnatal depression, depression does not fit a scoring system neatly, and is experienced differently by everyone. In addition, women suffering may falsify results (I did) and may not consent to use of the tools. Women's subjective experience of pregnancy, birth and motherhood is crucial, and PND needs to be spoken about in the antenatal period in order to overcome the associated stigma and to encourage women's self-efficacy in reporting symptoms. PMID- 30462458 TI - [Processing of morphological material for molecular genetic tests]. AB - Molecular genetic analysis has become a mandatory component of cancer diagnostics. Preanalytical step for DNA and RNA analysis is a complex process requiring tight interaction between surgeons, pathologists and molecular geneticists. This article discusses key aspects of handling of the tissues before DNA- and RNA-testing. PMID- 30462459 TI - [Anxiety disorders diagnostic algorithm in cancer patients]. AB - The article defines the basic principles of anxiety disorders diagnosis (anxious phobic disorders, panic disorder, generalized anxiety disorder) in cancer patients in accordance with the evidence-based medicine. There are provided typical clinical manifestations, features and variants of courses of disease. There is proposed the anxiety-phobic disorders diagnosis algorithm. There are characterized clinical, experimental, psychological, laboratory methods and are highlighted stages of diagnostic process. PMID- 30462460 TI - Head start: cranial osteopathy for common baby problems. AB - Cranial osteopathy is the gentles form on osteopathy and is particularly suitable for babies where it is used to address a range of problems. It relies on gentle touch and manipulation for both working diagnosis and appropriate management of tension patterns in order to release stresses and tensions throughout the whole body. First we will look at the basic principles underlying the discipline, then at how it can be used in practice for managing conditions such as colic and generally unsettled babies, torticollis, feeding challenges and constipation. PMID- 30462461 TI - [Relationship between benign prostatic hyperplasia and prostate cancer: new opportunities for prostate cancer chemoprevention]. AB - In a review article the relationship between benign prostatic hyperplasia (BPH) and prostate cancer (PC) has been conducted. Epidemiological data on increasing the risk of PC in patients with BPH are presented. There are discussed common for BPH and PC constitutional, food, and life style etiologic factors and also common for the both diseases pathogenetic factors such as androgens, inflammation, metabolic syndrome. Pharmaceutical drugs and natural agents that have unidirectional therapeutic and preventive effect on BPH and PC are presented. Results of experimental studies of the authors to prove the link between BPH and PC are presented. It is concluded that BPH is a risk factor for PC and, ideally, drugs for the treatment of BPH should have a chemo preventive effect on PC. PMID- 30462462 TI - Hypnosis and hypnobirthing for labour - a critical selective narrative review. AB - The provision of woman-centred care is at the heart of midwifery practice, and there appear to be increasing numbers of women choosing alternative forms of support for their childbearing journey. Women are often fearful of the experience of labour and birth, and in particular express concern about pain and its management; the literature shows that fear of childbearing is associated with increased pain (Leeman et al 2003). Although there are many pharmacological and non-pharmacological approaches to managing the pain of labour, these depend on availability, women's preferences, and on the woman's perception of their efficacy. This literature review focuses on the use of hypnosis, including complex programmes of antenatal preparation known as hypnobirthing, as a means of coping with the experience of labour and birth. A key word search of the literature was carried out to identify published research and literature on this topic. The articles chosen for critical review will be evaluated and explored. PMID- 30462463 TI - Taking the plunge: the benefits of aquanatal exercise. AB - In this article, Anita Johnson carried out an interview with Cathy Charles, a midwife and aquanatal teacher in Wiltshire, to explore the benefits of aquanatal exercise in pregnancy and the postnatal period; this is particularly pertinent at a time when there is a focus on mental wellbeing and rising obesity and caesarean section rates. Anita wanted a first-hand account from a midwife trained in water based fitness and her experiences of delivering aquanatal classes to pregnant women. Following Anita's own experience of participating in the aquanatal class and Cathy's entertaining interview she hopes it may encourage midwives to promote this form of exercise and to pursue recognized training to deliver their own classes. PMID- 30462464 TI - Mindfulness and perinatal mental health: a systematic review. AB - Research unwrapped is a popular series to help readers make sense of published research by undertaking a detailed appraisal of an article in a careful and considered manner. In doing so we can advance our knowledge and understanding of a research topic and apply it to our practice. This process is designed to assess the usefulness of the evidence in terms of decision making and application to practice. The research being discussed here is a systematic review of articles which look at the implementation of mindfulness approaches and whether these can enhance or improve mental health and wellbeing in pregnancy and childbearing; it was evaluated using the critical appraisal skills programme (CASP) (2013) tool for assessing systematic reviews. PMID- 30462465 TI - The road to life. Neonatal transitions to extra-uterine life. AB - The onset of labour and birth initiates profound changes for infants. It is essential to understand these unique aspects of childbirth; doing so will equip midwives with the ability to detect deviations from expected trajectories, take appropriate actions, but most importantly support normal birth transitions. These transitions involve a complex cascade of physiological, anatomical and behavioural changes acting in concert. This article overviews essential knowledge about the early adaptive changes after birth and considers initial cardio-respiratory and metabolic responses to birth, together with how midwives can support the best possible start for infants. PMID- 30462466 TI - Global maternal health. 1. Traditions and birth in the Philippines. AB - This occasional series aims to share, discuss and promote midwifery in a global context. Midwifery is a truly global profession and even those of us who work solely in the UK will care for women from many different cultures; these articles reflect the experiences of midwives and students working in both the UK and in Asia, Australasia, Africa and Europe. The first few articles of the series have been developed by students undertaking a global maternity module at The University of Leeds. Each of these articles will be presented in a two-part format: a feature in print and an accompanying reflection hosted on our website. We encourage you to review both to support your full engagement with the series. PMID- 30462467 TI - 8. Becoming an accountable midwife. AB - Becoming a midwife is the 16th series of 'Midwifery basics' targeted at practicing midwives and midwifery students. The aims of these articles is to provide information to raise awareness of the impact of professionalism on women's experience, consider the implications for midwives' practice and encourage midwives to seek further information through a series of activities relating to the topic. In the final article of the series, Jancis Shepherd explores some of the challenges of becoming an accountable practitioner. PMID- 30462468 TI - The Midwifery Unit Network: creating a community of practice to enhance maternity services. AB - The Midwifery Unit Network (MUNet) is a community of practice which aims to promote and support the implementation and improvement of midwifery units (MUs) in the UK and internationally. It was launched in April 2016 and has been growing fast since its inception. In this article, three co-leads of MUNet describe why they set up the network and how they established it. The aim of the article is to inspire more midwives to consider establishing a community of practice, and to offer some guidance in doing so. PMID- 30462469 TI - Stand up and deliver: enhancing your presentation skills. AB - In this article I discuss the value and importance of presentation skills for midwives and offer recommendations for how to enhance these skills in practice. My aim is to support your development and confidence in delivering presentation. I include a series of practical tips to help you improve your preparation, content and delivery of future presentations, for greater personal confidence and impact. PMID- 30462470 TI - EMPOWER! Empowering mothers, providing options with education and relaxation. AB - Most women within their lifetime will experience pregnancy, birth and motherhood. Despite this almost universal experience, the process is far from uniform. Throughout the childbirth continuum, expectations and experiences of women are diverse and ever-changing (van Teijlingen et al 2017). THis article explores an innovative idea, well placed within this 'Shiny roads' edition of The Practising Midwife. It explores the birth of the EMPOWER project within a NHS trust. EMPOWER was developed to empower mothers and provide options, education and relaxation for pregnancy, birth and the postnatal period. PMID- 30462472 TI - New thinking on improving maternity care: international perspectives. PMID- 30462471 TI - The new Irish maternity strategy 2016-2026. AB - Report review runs alongside Guideline commentary and the other evidence series articles, examining local, national and international reports that have implications directly or indirectly for midwives. It helps readers to understand what reports mean for midwifery practice and to place report recommendations into context. As with all our evidence series articles, report reviews support you to critique recommendations and implications for your own practice. In 2016, Ireland launched its first ever maternity strategy (Department of Health (IDH) 2016). This followed many high-profile controversies, including maternal and neonatal deaths due to medical misadventure. This article reviews Ireland's history of maternity services, the new strategy and current perinatal mental health services. PMID- 30462473 TI - ALD-ZnxTiyO as window layer in Cu(In,Ga)Se2 solar cells. AB - We report on the application of ZnxTiyO deposited by atomic layer deposition (ALD) as buffer layer in thin film Cu(In,Ga)Se2 (CIGS) solar cells to improve the photovoltaic device performance. State-of-the-art CIGS devices employ a CdS/ZnO layer stack sandwiched between the absorber layer and the front contact. Replacing the sputter deposited ZnO with ALD-ZnxTiyO allowed a reduction of the CdS layer thickness without adversely affecting open-circuit voltage (VOC). This leads to an increased photocurrent density with a device efficiency of up to 20.8% by minimizing the parasitic absorption losses commonly observed for CdS. ALD was chosen as method to deposit homogeneous layers of ZnxTiyO with varying Ti content with a [Ti]/([Ti]+[Zn]) atomic fraction up to ~0.35 at a relatively low temperature of 373K. The Ti content influenced the absorption behavior of the ZnxTiyO layer by increasing the optical bandgap >3.5 eV in the investigated range. Temperature dependent current-voltage (I-V) measurements of solar cells were performed to investigate the photocurrent blocking behavior observed for high Ti content. Possible conduction band discontinuities introduced by ZnxTiyO are discussed based on x-ray photoelectron spectroscopy (XPS) measurements. PMID- 30462474 TI - Resveratrol Delivery from Porous Poly(lactide-co-glycolide) Scaffolds Promotes an Anti-inflammatory Environment within Visceral Adipose Tissue. AB - As biomaterial therapies emerge to address adipose tissue dysfunction that underlies metabolic disease, the immune response to these systems must be established. As a potential therapy, we are investigating resveratrol delivery from porous poly(lactide-co-glycolide) scaffolds designed to integrate with adipose tissue. Resveratrol was selected for its ability to protect mice and primates from high fat diet and broad anti-inflammatory properties. Herein, we report fabrication of scaffolds with high resveratrol loading that are stable and active for up to one year. In vitro release profiles indicate that drug release is biphasic with a burst release over three days followed by a plateau. Surprisingly, we find that PLG scaffold implant into adipose tissue of mice promotes an anti-inflammatory environment characterized by high arginase-1 and low TNF-alpha and IL-6 compared to naive unmanipulated fat. Resveratrol delivery from the scaffold augments this anti-inflammatory environment by decreasing monocyte and lymphocyte numbers at the implant site and increasing expression of IL-10 and IL-13, cytokines that promote healthy adipose tissue. In terms of therapeutic applications, implant of scaffolds designed to release resveratrol into the visceral fat decreases MCP-1 expression in mice fed a high fat diet, a molecule that drives both local and systemic inflammation during obesity. Taken together, resveratrol delivery to adipose tissue using poly(lactide-co-glycolide) scaffolds is a promising therapeutic strategy for the treatment of adipose tissue inflammation that drives metabolic disease. PMID- 30462475 TI - Wet NH3-Triggered NH2-MIL-125(Ti) Structural Switch for Visible Fluorescence Immunoassay Impregnated on Paper. AB - This work has looked to explore an innovative and powerful visible fluorescence immunoassay method through wet NH3-triggered structural change of NH2-MIL-125(Ti) impregnated on paper for the detection of carcinoembryonic antigen (CEA). Gold nanoparticles heavily functionalized with glutamate dehydrogenase (GDH) and secondary antibody were used for generation of wet NH3 with a sandwiched immunoassay format. Paper-based analytical device (PAD) coated with NH2-MIL 125(Ti) exhibited good visible fluorescence intensity through wet NH3-triggeried structural change with high accuracy and reproducibility. Moreover, NH2-MIL 125(Ti)-based PAD displayed two visual modes of fluorescence color and physical color with the naked eye and allowed the detection of CEA at a concentration as low as 0.041 ng mL-1. Importantly, the PAD-based assay provides promise for use in the mass production of miniaturized devices and opens new opportunities for protein diagnostics and biosecurity. PMID- 30462476 TI - Coaxial hydro-nanofibrils for self-assembly of cell sheets producing skin bilayers. AB - Bilayered skin sheets were fabricated with coaxial hydro-nanofibrils for three dimensional (3D) cultivation in a biomimetic environment. Polycaprolactone (PCL) was electrospun and hydrolyzed to release fragmented nanofibrils (NF) in an alkaline condition. Methacrylated gelatin (GelMA) was adsorbed and photo-tethered on the surface of the fibrils to prepare coaxial NF composed of hydrophilic shells and hydrophobic cores. GelMA layers on the NF were characterized by X-ray photoemission spectroscopy (XPS), Fourier-transform infrared spectroscopy (FT IR), and thermogravimetric analysis. The GelMA showed higher decoration level on NF compared to native gelatin. GelMA-decorated NF significantly enhanced cell proliferation rate and phenotypic expression of human dermal fibroblasts, when spontaneous formation of cell sheets was observed for seven days. HaCaT cells were layered on top of the fibroblast sheets and further cultivated in air-water interfaces to prepare bilayered skin sheets. After 21 days of incubation, the top layers of the bilayered sheets showed higher expression of pan-keratin and the dermal cells showed higher proliferation in GelMA-decorated NF. PMID- 30462477 TI - Adhesion between Hydrophobic Elastomer and Hydrogel through Hydrophilic Modification and Interfacial Segregation. AB - Recent progress in the printing of soft materials has made it possible to fabricate soft stretchable devices for a range of engineering applications. These devices tend to be heterogeneous systems and their reliability depends to a large extent on the integrity of the interfaces between the various materials in the system. Previous studies on the printing of hydrogels have highlighted the need to investigate the adhesion between extrusion printable dielectric elastomers and hydrogels. Here we consider polydimethylsiloxane (PDMS) and a polyacrylamide hydrogel that contains lithium chloride and a non-ionic rheological modifier. We show that the adhesion between oxygen plasma-treated PDMS and the hydrogel increases with time to reach a stable value of 15 J m-2 after approximately six days. During that time, the contact angle of water on the PDMS interface remains constant at approximately 30 degrees , suggesting that hydrophobic recovery of plasma-treated PDMS is suppressed by the presence of the hydrogel. It is further observed that a thin viscous layer develops at the interface between PDMS and hydrogel, which results in energy dissipation upon debonding and which allows full recovery of the adhesion after debonding and rejoining. This viscous layer develops only in the presence of the rheological modifier in the hydrogel and the hydrophilic surface treatment of the PDMS. PMID- 30462478 TI - Wood-Inspired Fabrication of Polyacrylonitrile Solid Foam with Superfast and High Absorption Capacity for Liquid Without Selectivity. AB - Inspired by the principles of natural capillary action, unidirectional freeze and low-temperature freeze-extraction methods are employed to replicate natural wood structure into aligned vertically oriented porous polyacryonitrile (PAN) foam (APPF), which show superfast absorption speed and high-efficiency absorption capacities for liquids, including organic pollutants (chloroform, soybean oil, and toluene). Foams with different absorption capacity and speed are prepared by adjusting the PAN concentration in the preparation. The mechanical properties of the APPFs with vertically oriented pores indicate that they have excellent strength and Young's modulus, which can help maintain the integrity of micropores. The prepared APPFs with aligned vertically oriented pores have immense potential in numerous applications, including wastewater treatment, cleaning, drug delivery, and hygiene products. PMID- 30462479 TI - Chemistry and Structure of Silver Molecular Nanoparticles. AB - Silver and gold molecular nanoparticles (mNPs) are a relatively new class of molecular materials of fundamental interest. They are high-nuclearity metal organic compounds, with ligated metal cores, where the different character of bonding in the ligand shell and metal core gives rise to many of the unique properties of these materials. Research has primarily focused on gold mNPs, due to their good stability and the ease with which they may be synthesized and processed. To understand these materials as a general class, however, it will be necessary to broaden research efforts to other metals. Gold and silver are isoelectronic and have the same atomic radius, making the comparison of gold and silver mNPs attractive. The optical and chemical differences of the two metals provide useful contrasts, however, as well as a means to access a wider range of properties. In this Account, we focus on the synthesis, structure, and reactivity of silver mNPs. First, we review the origins and history of the field, from the ill-defined gas-phase metal clusters of the 1980s to the precisely defined mNPs of 1996 and onward. Next, we discuss the role of silver as a complement to gold mNPs in the effort to generalize lessons learned from either material and extend them into new metals. The synthesis of silver mNPs is covered in some detail, noting the choices made as the chemistry and the materials were developed. The importance of coordinating solvents and thermodynamic stability are also noted. The need to reduce solvent use is discussed and a new approach to achieving this goal is presented. Next, the structures of silver mNPs are discussed, including the Ag44 and Ag17 archetypes, and focusing on the successful de novo structure prediction of the latter. Structure and prediction of ligand shell motifs are also discussed. Finally, the postsynthetic chemistry and reactivity of silver mNPs are presented, including some of the first efforts to elucidate reaction mechanisms, beginning in 2012. Silver nanoparticles are gaining in popularity, particularly compared with gold, as the potential for silver to make a technological and economic impact is recognized. The superior optical properties of silver already make it a valuable material for plasmonics, but this may also translate to molecular species for nonlinear optics, sensors, and optoelectronics. The higher reactivity may also lead to a greater diversity of chemistry for silver compared to gold, including as an important broad-spectrum antimicrobial. Conversely, the "ultrastability" of the Ag44 archetype has already enabled unprecedented scale up with molecular precision, and may lead to the first industrial-scale production of metal mNPs. Clearly, silver mNPs are one of the most promising and significant new materials being studied today. PMID- 30462480 TI - Residue-Specific Conformational Heterogeneity of Proline-Rich Sequences Uncovered via Infrared Spectroscopy. AB - Conformational heterogeneity is critical to understanding protein function but challenging to quantify. Experimental approaches that can provide sufficient temporal and spatial resolution to measure even rapidly interconverting states at specific locations in proteins are needed to fully elucidate the contribution of conformational heterogeneity and dynamics to function. Infrared spectroscopy in combination with the introduction of carbon deuterium bonds, which provide frequency-resolved probes of their environments, can uncover rapidly interconverting states with residue-specific detail. Using this approach, we quantify conformational heterogeneity of proline-rich peptides associated with different proline backbone conformations, as well as reveal their dependence on the sequence context. PMID- 30462481 TI - Ultrafast X-ray Transient Absorption Spectroscopy of Gas-Phase Photochemical Reactions: A New Universal Probe of Photoinduced Molecular Dynamics. AB - Time-resolved spectroscopic investigations of light-induced chemical reactions with universal detection capitalize recently on single-photon molecular probing using laser pulses in the extreme ultraviolet or X-ray regimes. Direct and simultaneous mappings of the time-evolving populations of ground-state reactants, Franck-Condon (FC) and transition state regions, excited-state intermediates and conical intersections (CI), and photoproducts in photochemical reactions utilize probe pulses that are broadband and energy-tunable. The limits on temporal resolution are set by the transit- or dwell-time of the photoexcited molecules at specific locations on the potential energy surface, typically ranging from a few femtoseconds to several hundred picoseconds. Femtosecond high-harmonic generation (HHG) meets the stringent demands for a universal spectroscopic probe of large regions of the intramolecular phase-space in unimolecular photochemical reactions. Extreme-ultraviolet and soft X-ray pulses generated in this manner with few-femtosecond or sub-femtosecond durations have enormous bandwidths, allowing the probing of many elements simultaneously through excitation or ionization of core-electrons, creating molecular movies that shed light on entire photochemical pathways. At free electron lasers (FELs), powerful investigations are also possible, recognizing their higher flux and tunability but more limited bandwidths. Femtosecond time-resolved X-ray transient absorption spectroscopy, in particular, is a valuable universal probe of reaction pathways that maps changes via the fingerprint core-to-valence resonances. The particular power of this method over valence-ionization probes lies in its unmatched element and chemical site specificities. The elements carbon, nitrogen, and oxygen constitute the fundamental building blocks of life; photochemical reactions involving these elements are ubiquitous, diverse, and manifold. However, table-top HHG sources in the "water-window" region (280-550 eV), which encompasses the 1s-absorption edges of carbon (284 eV), nitrogen (410 eV), and oxygen (543 eV), are far from abundant or trivial. Recent breakthroughs in the laboratory have embraced this region by using long driving-wavelength optical parametric amplifiers coupled with differentially pumped high-pressure gas source cells. This has opened avenues to study a host of photochemical reactions in organic molecules using femtosecond time-resolved transient absorption at the carbon K-edge. In this Account, we summarize recent efforts to deploy a table-top carbon K-edge source to obtain crucial chemical insights into ultrafast, ultraviolet-induced chemical reactions involving ring-opening, nonadiabatic excited-state relaxation, bond dissociation and radical formation. The X-ray probe provides a direct spectroscopic viewport into the electronic characters and configurations of the valence electronic states through spectroscopic core-level transitions into the frontier molecular orbitals of the photoexcited molecules, laying fertile ground for the real-time mapping of the evolving valence electronic structure. The profound detail and mechanistic insights emerging from the pioneering experiments at the carbon K edge are outlined here. Comparisons of the experimental methodology with other techniques employed to study similar reactions are drawn, where applicable and relevant. We show that femtosecond time-resolved X-ray transient absorption spectroscopy blazes a new trail in the study of nonadiabatic molecular dynamics. Despite table-top implementations being largely in their infancy, future chemical applications of the technique will set the stage for widely applicable, universal probes of photoinduced molecular dynamics with unprecedented temporal resolution. PMID- 30462482 TI - Resveratrol-Inspired Bridged Bicyclic Compounds: A New Compound Class for the Protection of Synaptic Function from Acute Oxidative Stress. AB - While resveratrol protects organisms from the deleterious effects of oxidative stress, its multifarious mechanism of action limits its potential as a selective medicinal agent. To address this shortcoming, we have designed a molecular scaffold that we have termed a resveramorph. The structure of this compound class possesses much of the functional group characteristics of resveratrol but in a nonplanar molecular arrangement, and, in the present work, we probe the neuroprotective activities of two resveramorph analogues. These novel compounds were found to protect neurotransmission from hydrogen peroxide-induced oxidative stress. Our findings demonstrate that, at a subnanomolar level, one analogue, resveramorph 1, protects synaptic transmission from acute oxidative stress at the Drosophila neuromuscular junction. These results position resveramorphs as potential lead compounds in the development of new drugs for neurodegenerative diseases. PMID- 30462483 TI - Polyethylene battery separator as a porous support for thin film composite organic solvent nanofiltration membranes. AB - Organic solvent nanofiltration (OSN) has made significant advances recently, and it is now possible to fabricate thin film composite (TFC) membranes with a selective layer thickness below 10 nm that gives ultrafast solvent permeance. However, such high permeance is inadvertently limited by the support membrane beneath the selective layer, and thus there is an urgent need to develop a suitable support to maximize TFC performance. In this work, we employed a commercially available polyethylene (PE) battery separator as a porous support to fabricate high performance TFC OSN membranes. To deposit a uniform polyamide selective layer onto the porous support via interfacial polymerization, the PE support was hydrophilized with O2 plasma and the reaction efficiency was optimized using a surfactant. Owing to the high surface porosity of the PE support and the high permselectivity of the PA layer, the PE-supported TFC membrane outperformed the previously-reported OSN membranes and its performance exceeded the current performance upperbound. A solvent activation step dramatically improved the solvent permeance by 5-fold while maintaining nano separation properties. In addition to the superior OSN performance, the commercial availability of the PE support and simplified TFC fabrication protocol would make the PE-supported OSN membranes commercially attractive. PMID- 30462484 TI - Ultratough Bioinspired Graphene Fiber via Sequential Toughening of Hydrogen and Ionic Bonding. AB - Graphene-based fibers synthesized under ambient temperature have not achieved excellent mechanical properties of high toughness or tensile strength compared with those synthesized by hydrothermal strategy or graphitization and annealing treatment. Inspired by the relationship between organic/inorganic hierarchical structure, interfacial interactions, and moderate growth temperature of natural nacre, we fabricate an ultratough graphene fiber via sequential toughening of hydrogen and ionic bonding through a wet-spinning method under ambient temperature. A slight amount of chitosan is introduced to form hydrogen bonding with graphene oxide nanosheets, and the ionic bonding is formed between graphene oxide nanosheets and divalent calcium ions. The optimized sequential toughening of hydrogen and ionic bonding results in an ultratough graphene fiber with toughness of 26.3 MJ/m3 and ultimate tensile strength of 743.6 MPa. Meanwhile, the electrical conductivity of the resultant graphene fiber is as high as 179.0 S/cm. This kind of multifunctional graphene fiber shows promising applications in photovoltaic wires, flexible supercapacitor electrodes, wearable electronic textiles, fiber motors, etc. Furthermore, the strategy of sequential toughening of hydrogen and ionic bonding interactions also offers an avenue for constructing high-performance graphene-based fibers in the near future. PMID- 30462485 TI - Genomic Deoxyxylulose Phosphate Reductoisomerase (DXR) Mutations Conferring Resistance to the Antimalarial Drug Fosmidomycin in E. coli. AB - Sequence to activity mapping technologies are rapidly developing, enabling the generation and isolation of mutations conferring novel phenotypes. Here we used the CRISPR EnAbled Trackable genome Engineering (CREATE) technology to investigate the inhibition of the essential ispC gene in its native genomic context in Escherichia coli. We created a full saturation library of 33 sites proximal to the ligand binding pocket and challenged this library with the antimalarial drug fosmidomycin, which targets the ispC gene product, DXR. This selection is especially challenging since it is a relatively weak in E. coli, with multiple naturally occurring pathways for resistance. We identified several previously unreported mutations that confer fosmidomycin resistance, in highly conserved sites that also exist in pathogens including the malaria-inducing Plasmodium falciparum. This approach may have implications for the isolation of resistance-conferring mutations and may affect the design of future generations of fosmidomycin-based drugs. PMID- 30462486 TI - Internal Standard Quantification Using Tandem Mass Spectrometry of a Tryptic Peptide in the Presence of an Isobaric Interference. AB - Model mixtures of isobaric peptides were studied to evaluate the possibility, using tandem mass spectrometry experiments, for internal standard quantification of a tryptic peptide in the presence of an isobaric interference. To this end, direct injection electrospray ionization-tandem mass spectrometry (ESI-MS/MS) experiments were performed on an ion trap instrument using a large mass-selection window (15 m/ z) encompassing the isobaric mixture and the internal standard; MS/MS experiments were carried out to remove completely the interference from the mixture by fragmenting it. This allowed for the correct intensity assignment for the protonated peptide peak and, thus, for the analyte to be quantified through the relative intensity estimate of this peak with respect to the internal standard. This was done by monitoring the 15 m/ z mass-selection window only and without the necessity for careful inspection of any fragment ions peaks. The interference removal was assessed by determining an excitation voltage large enough for the analyte/internal standard ratio to remain constant ensuring correct quantification despite isobaric contamination. A calibration curve was obtained to predict reference samples and compared to reference samples purposely spiked with the interference using the proposed methodology; internal standard quantification of the analyte was made possible with ~1% deviation despite the isobaric contamination. PMID- 30462487 TI - Endosomal escape and cytosolic penetration of macromolecules mediated by synthetic delivery agents. AB - Cell delivery reagents often exploit the endocytic pathway as a route of cell entry. Once endocytosed, these reagents must overcome endosomal entrapment to insure the release of their macromolecular cargos into the cytosol of cells. In this review, we describe several examples of prototypical synthetic reagents that are capable of endosomal escape and examine their mechanisms of action, their efficiencies, and effects on cells. Although these delivery systems are chemically distinct, some commonalities in how they interact with cellular membranes can be inferred. This, in turn, sheds some light on the process of endosomal escape, and may help guide the development and optimization of next generation delivery tools. PMID- 30462488 TI - Synergistic Nanozymetic Activity of Hybrid Gold Bipyramid- Molybdenum Disulfide Core@Shell Nanostructures for Two-Photon Imaging and Anticancer Therapy. AB - In recent years, the concept of combined therapy using gold hybrid nanomaterials has been broadly adopted to pioneer new anticancer treatments. However, their synergistic anticancer effects have yet to be thoroughly investigated. Herein, a hybrid gold nanobipyramid nanostructure coated with molybdenum disulfide (MoS2) semiconductor (AuNBPs@MoS2) was proposed as a smart nanozyme for anticancer therapy and two-photon bioimaging. The hybrid material showed dramatically enhanced localized surface plasmon resonance (LSPR) property under excitation owing to its anisotropic nature, coupled with the rich electron density in MoS2, resulting in the superior in situ photo-generation of reactive oxidative species (ROS - 1O2, OH). We demonstrated that the synergistic effect of enhanced photothermal conversion and generation of ROS could increase the anticancer effect of AuNBPs@MoS2. Two-photon imaging confirmed that AuNBPs@MoS2 was successfully internalized in cancer cells and that simultaneous anticancer treatments based on catalytic and photothermal therapy could be achieved. This study highlighted, for the first time, a novel approach of plasmon-mediated powerful anticancer therapy and imaging via the unprecedented combination of anisotropic AuNBPs and 2D MoS2 material. PMID- 30462489 TI - Site-specific integration by recruitment of a complex of PhiC31integrase and donor DNA to a target site by using a tandem, artificial zinc-finger protein. AB - To solve the problem of uncontrolled therapeutic gene integration, which is a critical drawback of retroviral vectors for gene therapy, the integration sites of exogenous genes should be precisely controlled not to perturb endogenous gene expression. To accomplish this, we explored the possibility of site-specific integration using two six-finger artificial zinc-finger proteins (AZPs) tandemly conjugated via a flexible peptide linker (designated "Tandem AZP"). A Tandem AZP in which two AZPs recognize specific 19-bp targets in a donor and acceptor DNA was expected to site-specifically recruit the donor DNA to the acceptor DNA. Thereafter, an exogenously added integrase was expected to integrate the donor DNA into a specific site in the acceptor DNA (as it might be in the human genome). We demonstrated in vitro that in the presence of Tandem AZP, PhiC31 integrase selectively integrated a donor plasmid into a target acceptor plasmid not only at 30 degrees C (the optimum temperature of the integrase), but also at 37 degrees C (for future application in humans). We expect that by further improving our current system, a combination of Tandem AZP with integrase/recombinase will enable site-specific integration in mammalian cells and provide safer gene therapy technology. PMID- 30462490 TI - CuATSM protects against the in vitro cytotoxicity of wild type-like SOD1 mutants but not mutants that disrupt metal binding. AB - Mutations in the SOD1 gene are associated with some forms of familial ALS (fALS). There are over 150 different mutations in the SOD1 gene which cause various effects to the SOD1 enzyme structure, including loss of metal binding and a decrease in dimer affinity. The copper-based therapeutic CuATSM has been proven to be effective at rescuing neuronal cells from SOD1 mutant toxicity, and has also increased the life expectancy of mice expressing the human transgenes SOD1G93A and SOD1G37R. Furthermore, CuATSM is currently the subject of a phase I/II clinical trial in Australia as a treatment for ALS. In order to determine if CuATSM protects against a broad variety of SOD1 mutations, we used a well established cell culture model of SOD1-fALS. NSC-34 cells expressing SOD1-EGFP constructs were treated with CuATSM and examined by time lapse microscopy. Our results show a concentration dependent protection of cells expressing mutant SOD1A4V over the experimental time period. We tested the efficacy of CuATSM on ten SOD1-fALS mutants and found that while protection was observed in cells expressing pathogenic wild type-like mutants, cells expressing a truncation mutant or metal binding region mutants were not. We also show that CuATSM rescue is associated with an increase in human SOD1 activity and a decrease in SOD1 aggregation in vitro. In conclusion, CuATSM has shown to be a promising therapeutic for SOD1-associated ALS, however, our in vitro results suggest that the protection afforded varies depending on the SOD1 variant, including negligible protection to mutants with deficient copper binding. PMID- 30462491 TI - Direct, transfer-free growth of large-area hexagonal boron nitride films by plasma-enhanced chemical film conversion (PECFC) of printable, solution-processed ammonia borane. AB - Synthesis of large-area hexagonal boron nitride (h-BN) films for two-dimensional (2D) electronic applications typically requires high temperatures (~1000 oC) and catalytic metal substrates which necessitate transfer. Here, analogous to plasma enhanced chemical vapor deposition, a non-thermal plasma is employed to create energetic and chemically-reactive states such as atomic hydrogen and convert a molecular precursor film to h-BN at temperatures as low as 500 oC directly on metal-free substrates - a process we term plasma-enhanced chemical film conversion (PECFC). Films containing ammonia borane as a precursor are prepared by a variety of solution processing methods including spray deposition, spin coating, and ink-jet printing, and reacted in a cold-wall reactor with a planar dielectric barrier discharge operated at atmospheric pressure in a background of argon or mixture of argon and hydrogen. Systematic characterization of the converted h-BN films by micro Raman spectroscopy shows that the minimum temperature for nucleation on silicon-based substrates can be lowered from 800 to 500 oC by the addition of a plasma. Furthermore, the crystalline domain size, as reflected by a decrease in the full-width-half-maximum, increased by more than 3 times (>40 cm-1 to ~13 cm-1). To demonstrate the potential of the h-BN films as a gate dielectric in 2D electronic devices, molybdenum disulfide field-effect transistors were fabricated and the field effect mobility was found to be improved by up to four times over silicon dioxide. Overall, PECFC allows h-BN films to be grown at lower temperatures and with improved crystallinity than CVD, directly on substrates suitable for electronic device fabrication. PMID- 30462492 TI - Chemodrug-Gated Biodegradable Hollow Mesoporous Organosilica Nanotheranostics for Multimodal Imaging-Guided Low-Temperature Photothermal Therapy/Chemotherapy of Cancer. AB - Non-invasive physical treatment with relatively low intensity stimulation and the development of highly efficient anticancer medical strategy are still desirable for cancer therapy. Herein, a versatile biodegradable hollow mesoporous organosilica nanocapsule (HMONs) nananoplatform that is capped by the gemcitabine (Gem) molecule through a pH-sensitive acetal covalent bond is designed. The fabricated nanocapsule exhibits desirable small molecule release at the tumor tissues/cell sites, shows a reduced potential for drug accumulation risk. After loading indocyanine green (ICG), the heat-shock protein 90 (Hsp 90) inhibitor, 17AAG and modification with polyethylene glycol (NH2-PEG), the resulting ICG 17AAG@HMONs-Gem-PEG exhibited a precisely controlled release of ICG and 17AAG and low-temperature photothermal therapy (PTT) (~41 degrees C) with excellent tumor destruction efficacy. In addition, ICG loaded conferring the nanoplatform with near-infrared fluorescence imaging (FL) and photoaccoustic (PA) imaging capability. In short, this work not only presents a smart drug self-controlled nanoplatform with pH-responsive payloads released and theranostic performance, but also provides an outstanding low-temperature PTT strategy, which is highly valid in inhibition of cancer cells with minimal damage to the organism. Therefore, this research provides a paradigm that has a chemodrug-gated HMONs based theranostic nanoplatform with intrinsic biodegradability, multimodal imaging capacity, high low-temperature PTT/chemotherapy efficacy and reduced systemic toxicity. PMID- 30462493 TI - Ultrathin Flexible Carbon Fiber Reinforced Hierarchical Metastructure for Broadband Microwave Absorption with Nano Lossy Composite and Multi-scale Optimization. AB - The implementation of thin structure for broadband microwave absorption is challenging due to requirement of impedance match across several frequency bands and poor mechanical properties. Herein, we demonstrate a carbon fiber (CF) reinforced flexible thin hierarchical metastructure (HM) composed of lossy materials including carbonyl iron (CI), multiwall carbon nanotube (MWCNT) and silicone rubber (SR) with thickness of 5mm and optimal concentration selected from twelve formulae. Optimization for the periodical unit size is applied and impacts of structural sizes on absorption performance is also investigated. An effective process combining the vacuum bag method and the hand lay-up technique is used to fabricate the HM. Experimental reflectivity of the absorber achieves broadband absorption below -10dB in 2-4GHz and 8-40GHz. Full band in 2-40GHz is covered below -8dB. Yielding stress of the HM is increased to 24MPa with attachment of CF while the fracture strain of the composite reaches 550%. The soft HM is suitable to adhere to curved surface of objects needed to be protected from microwave radiation detection and electromagnetic interference. Enhanced mechanical properties make it possible for further practical applications under harsh service environment such as ocean and machines with constant vibration. PMID- 30462494 TI - Lubrication and Wear Protection of Micro-Structured Hydrogels using Bioinspired Fluids. AB - We report the fabrication and the use of a bioinspired synovial fluid acting as a lubricant fluid and anti-wear agent at soft and porous chitosan hydrogel tribopairs. This synthetic synovial fluid is composed of sodium hyaluronate (HA) and a bottle-brush polymer (BB) having a polycationic attachment group and polyzwitterionic pendant chains. 2.5 %w/w chitosan hydrogel plugs are organized in a bilayered structure exposing a thin and dense superficial zone (SZ), covering a porous deep zone (DZ) and exhibiting microchannels perpendicularly aligned to the SZ. Using a low-load tribometer, the addition of HA lubricating solution at the hydrogel-hydrogel rubbing contact drastically decreased the coefficient of friction (CoF) from u = 0.20 +/- 0.01 to u = 0.04 +/- 0.01 on the DZ configuration and from u = 0.31 +/- 0.01 to u = 0.08 +/- 0.01 on the SZ surface when increasing HA concentration from 0 to 1000 ug/mL and its molecular mass from 10 to 1500 kDa, similar to what was found when using BB polymer alone. When combining the BB polymer and the 1500 kDa HA, the CoF remained stable at u = 0.04 +/- 0.01 for both studied contact configurations, highlighting the synergistic interaction of the two macromolecules independently of the gel surface topography. Hydrogel wear was characterized by assessing the final gel surface roughness by the means of an interferometer. Increasing HA concentration and molecular weight plus the addition of BB polymer lead to a dramatic surface wear protection with a final gel surface roughness of the hydrogels similar to the untested gels. In brief, BB polymer in combination with high molecular weight HA is a potential lubricating fluid as well as a wear resistant agent for soft materials lubrication and wear protection. PMID- 30462495 TI - Comment on "Application of Struvite Alters the Antibiotic Resistome in Soil, Rhizosphere, and Phyllosphere". PMID- 30462496 TI - Dynamic intermolecular interactions control adsorption from mixtures of natural organic matter and protein onto titanium dioxide nanoparticles. AB - Engineered nanoparticles (NPs) will obtain macromolecular coatings in environmental systems, changing their subsequent interactions. The matrix complexity inherent in natural waters and wastewaters greatly complicates prediction of the corona formation. Here, we investigate corona formation on titanium dioxide (TiO2) NPs from mixtures of natural organic matter (NOM) and a protein, bovine serum albumin (BSA), to thoroughly probe the role of mixture interactions in the adsorption process. Fundamentally different coronas were observed under different NP exposure conditions and time scales. In mixtures of NOM and protein, the corona composition was kinetically determined, and the species initially co-adsorbed but were ultimately limited to monolayers. On the contrary, sequential exposure of the NPs to pure solutions of NOM and protein resulted in extensive multilayer formation. The intermolecular complexation between NOM and BSA in solution and at the NP surface was the key mechanism controlling these distinctive adsorption behaviors, as determined by size exclusion chromatography (SEC) and in situ attenuated total reflectance - Fourier transform infrared (ATR-FTIR) spectroscopy. Overall, this study demonstrates that dynamic intermolecular interactions and the history of the NP surface must be considered together to predict corona formation on NPs in complex environmental media. PMID- 30462497 TI - Energy Decomposition Analysis for Metal Surface -- Adsorbate Interactions by Block Localized Wave Functions. AB - The energy decomposition analysis based on block localized wave functions (BLW EDA) allows to gain physical insight into the nature of chemical bonding, decomposing the interaction energy in (1) a "frozen" term, accounting for the attraction due to electrostatic and dispersion interactions, modulated by Pauli repulsion, (2) the variationally assessed polarization energy and (3) the charge transfer. This method has so far been applied to gas- and condensed-phase molecular systems. However, its standard version is not compatible with fractionally occupied orbitals (i.e. electronic smearing) and, as a consequence, cannot be applied to metallic surfaces. In this work, we propose a simple and practical extension of BLW-EDA to fractionally occupied orbitals, termed Ensemble BLW-EDA. As illustrative examples, we have applied the developed method to analyze the nature of the interaction of various adsorbates on Pt(111), ranging from physisorbed water to strongly chemisorbed ethylene. Our results show that polarization and charge-transfer both contribute significantly at the adsorption minimum for all studied systems. The energy decomposition analysis provides details with respect to competing adsorption sites (e.g., CO on atop, vs. hollow sites) and elucidates the respective importance of polarization and charge transfer for the increased adsorption energy of H2S compared to H2O. Our development will enable a deeper understanding of the impact of charge transfer on catalytic processes in general. PMID- 30462498 TI - Supramolecular Packing and Macroscopic Alignment Controls Actuation Speed in Macroscopic Strings of Molecular Motor Amphiphiles. AB - Three-dimensional organized unidirectionally aligned and responsive supramolecular structures have much potential in adaptive materials ranging from biomedical components to soft actuator systems. However, to control the supramolecular structure of these stimuli responsive, e.g., photoactive materials and control their actuation remains a major challenge. Towards the design of "artificial muscles", herein, we demonstrate an approach that allows hierarchical control of the supramolecular structure, and as a consequence its photoactuation function, by electrostatic interaction between motor amphiphiles (MA) and counter ions. Detailed insight into the effect of various ions on structural parameters for self-assembly from nano- to micro-meter scale in water including nanofiber formation and nanofiber aggregation as well as the packing structure, degree of alignment and actuation speed of the macroscopic MA strings prepared from various metal chlorides solution, as determined by electronic microscopy (SEM), X-ray diffraction (SAXS), and actuation speed measurements, is presented. Macroscopic MA strings prepared from calcium and magnesium ions provide a high degree of alignment and fast response photoactuation. By the selection of metal ions and chain length of MAs, the macroscopic MA string structure and function can be controlled demonstrating the potential of generating multiple photoresponsive supramolecular systems from an identical molecular structure. PMID- 30462499 TI - A single parameter for predicting the morphology of atmospheric black carbon. AB - Black carbon (BC) from fuel combustion is an effective light absorber that contributes significantly to direct climate forcing. The forcing is altered when BC combines with other substances, which modify its mixing state and morphology, making the evaluation of its atmospheric lifetime and climate impact a challenge. To elucidate the associated mechanisms, we exposed BC aerosol to supersaturated vapors of different chemicals to form thin coatings and measured the coating mass required to induce the restructuring of BC aggregates. We found that studied chemicals fall in two distinct groups based on a single dimensionless parameter, Chi, which depends on the diameter of BC monomer spheres and the coating material properties, including vapor supersaturation, molar volume, and surface tension. We show that when Chi is small (low-volatility chemicals), the highly supersaturated vapor condenses uniformly over aggregates, including convex monomers and concave junctions in between monomers, but when Chi is large (intermediate-volatility chemicals), junctions become preferred. The aggregates undergo prompt restructuring when condensation in the junctions dominates over condensation on monomer spheres. For a given monomer diameter, the coating distribution is mostly controlled by vapor supersaturation. The Chi factor can be incorporated straightforwardly into atmospheric models to improve simulations of BC aging. PMID- 30462500 TI - Structures and Reactivities of Sodiated Evans Enolates: Role of Solvation and Mixed Aggregation on the Stereochemistry and Mechanism of Alkylations. AB - Oxazolidinone-based sodiated enolates (Evans enolates) were generated using sodium diisopropylamide (NaDA) or sodium hexamethyldisilazide (NaHMDS) in the presence of N,N,N',N'-tetramethylethylenediamine (TMEDA), (R,R)-trans-N,N,N',N' tetramethylcyclohexanediamine [(R,R)-TMCDA], or (S,S)-TMCDA. 13C NMR spectroscopic analysis in conjunction with the method of continuous variations (MCV) and density functional theory (DFT) computations revealed the enolates to be octahedral bis-diamine-chelated monomers. Rate and computational studies of an alkylation with allyl bromide implicate a bis-diamine-chelated-monomer-based transition structure. The sodiated Evans enolates form mixed dimers with NaHMDS, NaDA, or sodium 2,6-di-tert-butylphenolate, the reactivities of which are examined. Stereoselective quaternizations, aldol additions, and azaaldol additions of sodiated Evans enolates are described. PMID- 30462501 TI - Chemically Induced Morphogenesis of P22 Virus like Particles by the Surfactant Sodium Dodecyl Sulfate. AB - In the infectious P22 bacteriophage the packaging of DNA into the initially formed procapsid triggers a remarkable morphological transformation where the capsid expands from 58 nm to 64 nm. Along with the increase in size, this maturation also provides greater stability to the capsid and initiates the release of scaffolding protein (SP).2, 4 In the P22 virus-like particle (VLP) this transformation can be mimicked in vitro by heating the procapsid particles to 65oC or by treatment with sodium dodecyl sulfate (SDS).5-6 Heating the P22 particles at 65 degrees C for 20 minutes is well established to trigger the transformation of P22 to the expanded (EX) P22 VLP but does not always result in a fully expanded population. Incubation with SDS resulted in a >80% expanded population for all P22 variants used in this work. This study elucidates the importance of the stoichiometric ratio between P22 subunits and SDS, the charge of the head group, and length of the carbon chain for the transformation. We propose a mechanism by which the expansion takes place, where both the negatively charged sulfate group and hydrophobic tail interact with the coat protein (CP) monomers within the capsid shell in a process that is facilitated by an internal osmotic pressure generated by an encapsulated macromolecular cargo. PMID- 30462502 TI - Structural insights of stereospecific inhibition of human acetylcholinesterase by VX and subsequent reactivation by HI-6. AB - Over 50 years ago, the toxicity of irreversible organophosphate inhibitors targeting human acetylcholinesterase (hAChE) were observed to be stereospecific. The therapeutic reversal of hAChE inhibition by reactivators has also been shown to depend on the stereochemistry of the inhibitor. To gain clarity on the mechanism of stereospecific inhibition, the X-ray crystallographic structures hAChE inhibited by a racemic mixture of VX (PR/S) and its enantiomers were obtained. Beyond identifying hAChE structural features that lend themselves to stereospecific inhibition, structures of the reactivator HI-6 bound to hAChEs inhibited by VX enantiomers of varying toxicity, or in its uninhibited state, were obtained. Comparison of hAChE in these pre-reactivation and post reactivation states along with enzymatic data reveals the potential influence of unproductive reactivator poses on the efficacy of these types of therapeutics. The recognition of structural features related to hAChE's stereospecificity towards VX shed light on the molecular influences of toxicity and their effect on reactivators. In addition to providing a better understanding of the innate issues with current reactivators, an avenue for improvement of reactivators is envisioned. PMID- 30462503 TI - Quadrupolar 14N NMR Relaxation from Force-Field and Ab-Initio Molecular Dynamics in Different Solvents. AB - Quadrupolar NMR spin relaxation rates and corresponding line widths were computed for the quadrupolar nucleus 14N for neat acetonitrile as well as for 1-methyl-1,3 imidazole and 1-methyl-1,3,4-triazole in different solvents. Molecular dynamics (MD) was performed with forces from Kohn-Sham (KS) theory (ab initio MD) and force-field molecular mechanics (classical MD), followed by KS electric field gradient (EFG) calculations. For acetonitrile the agreement of the 14N line width with experiment is nearly quantitative. Relative line widths for the azole nitrogens are improved over simpler approximations used previously in conjunction with single-point calculations at the multiconfigurational self-consistent field level. Overall, the NMR line widths are computed within a factor of two of the experimental values, giving access to reasonable estimates both of the dynamic EFG variance in the solvated systems as well as the associated correlation times that determine the relaxation rates. PMID- 30462504 TI - Fragment-to-Lead Medicinal Chemistry Publications in 2017. AB - This Miniperspective is the third in a series reviewing fragment-to-lead publications from a given year. Following our reviews for 2015 and 2016, this Miniperspective provides tabulated summaries of relevant articles published in 2017 along with some general observations. In addition, we discuss insights obtained from analysis of the combined data set of 85 examples from all three years of publications. PMID- 30462505 TI - Alignment-Free Molecular Shape Comparison Using Spectral Geometry. The Framework. AB - A framework is presented for the calculation of Snovel alignment-free descriptors of molecular shape. The methods are based on the technique of spectral geometry which has been developed in the field of computer vision where it has shown impressive performance for the comparison of deformable objects such as people and animals. Spectral geometry techniques encode shape by capturing the curvature of the surface of an object into a compact, information-rich representation that is alignment-free while also being invariant to isometric deformations, that is, changes that do not distort distances over the surface. Here we adapt the technique to the new domain of molecular shape representation. We describe a series of parameterisation steps aimed at optimizing the method for this new domain. Our focus here is on demonstrating that the basic approach is able to capture molecular shape into a compact and information-rich descriptor. We demonstrate improved performance in virtual screening over a more established alignment-free method and impressive performance compared to a more accurate, but much more computationally demanding, alignment-based approach. PMID- 30462506 TI - Citrus oil emulsions stabilized by citrus pectin: The influence mechanism of citrus variety and acid treatment. AB - Citrus pectin and citrus oil are the main functional components of citrus residuals in the processing industry. In this study, citrus oil emulsions were fabricated for the first time using 4 different citrus pectins (orange, mandarin, grapefruit and commercial citrus pectins) as the emulsifier. The influence mechanism of citrus variety and acid treatment (pH 1, 2, 3, 4, 5, 6 and 7) on the emulsifying capacity of citrus pectins were systematically investigated by understanding the relationship between molecular structure, solution property, interfacial property and emulsion property. The results suggest that citrus variety and acid treatment can significantly influence emulsifying capacity in relation to the molecular structure and molecular state of citrus pectins. Smaller molecular size of citrus pectin and lower pH between 2 and 7 produced a reduction in aggregate size, which improved interfacial capacity and emulsifying ability by promoting their distribution at interface. Although hydrolyzed citrus pectins at pH 1 with a lower molecular size exhibited better interfacial capacity, citrus oil emulsions were unstable due to electrostatic attraction caused by partially positive charged citrus pectins. Fine stable citrus oil emulsion was prepared using mandarin pectin with a relative high methyl ester content and small molecular size at pH 2. Our results provide a scientific basis for the fabrication of citrus oil emulsion based on citrus pectin and facilitate the application of citrus residuals in the food industry. PMID- 30462507 TI - Ag nanocrystals with nearly ideal optical quality: synthesis, growth mechanism, and characterizations. AB - Though Ag nanocrystals are predicted as the best material for localized surface plasmon resonances (LSPR) in the visible light region, realization of their ideal LSPR properties is hindered by the stringent requirement, i.e., simultaneous control of their size, shape, crystallinity, and surface structure. To achieve this goal, a synthetic scheme in non-polar solvent coupled with mild oxidative etching by H+ ions is established. With a trace amount of Cl- ions as catalysts, H+ ions (in the form of carboxylic acids) become active for selectively etching the nuclei (and small nanocrystals) with imperfect crystal structure, which results in a new growth mechanism for formation of monodisperse nanocrystals, namely "self-focusing of size/crystallinity distribution". H+ ions, ligands, and other reagents in the scheme are confirmed to possess negligible effects on the surface dielectric properties of Ag nanocrystals. To eliminate radiative damping of LSPR, single-crystalline and monodisperse spherical Ag nanocrystals in the size range between 7 and 20 nm are synthesized using this one-pot scheme. With excellent control of all related structural parameters, the full-width-at-half maximum of LSPR spectra of single-crystalline Ag nanocrystals match theoretical predictions in the entire size range, and the maximum quality factor (~20) of LSPR predicted by theory is realized. Raman enhancement factor of the single crystalline Ag nanocrystals for crystal violet (excitation at 514 nm) is 5 times higher than that of the typical multi-twinned ones with the same size. PMID- 30462508 TI - Thermally Induced Protonation of Conducting Polyaniline Film by Dibutyl Phosphite Conversion to Phosphate. AB - The blue thin polyaniline base film changes its color to green after immersion of the film into dibutyl phosphonate. The green color of the film converts to a greenish-blue after heating up to 200 degrees C in air which is characteristic for protonated conducting form of polyaniline. This is in the contrast to the "standard" polyaniline hydrochloride which is transformed into a crosslinked polyaniline base under such conditions. To explain this unexpected observation, the interaction of polyaniline base with dibutyl phosphonate at ambient conditions and after heating to 200 oC was studied using UV-visible, FTIR and Raman spectroscopies. Based on these studies, we propose that dibutyl phosphite tautomeric form of dibutyl phosphonate which interacts with polyaniline base at 20 degrees C converts to the oxidized form, dibutyl phosphate, at 200 degrees C and subsequently protonates the film. Quantum-chemical modelling of the interaction of polyaniline base with dibutyl phosphite and dibutyl phosphate supports this explanation. PMID- 30462510 TI - DNA Special Issue Editorial. AB - DNA Special Issue Editorial. PMID- 30462509 TI - Direct Sensing of Single Native RNA with a Single-Biomolecule Interface of Aerolysin Nanopore. AB - RNA sensing is of vital significance to advance our comprehension of gene expression and further benefits for medical diagnostic. Taking the advantage of the excellent sensing capability of the aerolysin nanopore as a single biomolecule interface, here, we for the first time achieved the direct characterization of single native RNA of Poly (A)4 and Poly (U)4. Poly (A)4 induces approximately 10% large blockade current amplitude than Poly (U)4. The statistical duration of Poly (A)4 is 18.83 +/- 1.08 ms, which is hundred times longer than that of Poly (U)4. Our results demonstrated that the capture of RNA homopolymers is restricted by the biased diffusion. The translocation of RNA need to overcome a lower free energy barrier than DNA. Moreover, the strong RNA interaction is attributed to the hydroxyl in pentose, which prolongs the translocation time. This study opens an avenue of aerolysin nanopores for achieving directly RNA sensing including discrimination of RNA epigenetic modification and selective detection of miRNA. PMID- 30462511 TI - Enhanced Efficiency of an Enzyme Cascade on DNA-Activated Silica Surfaces. AB - In nature, compartmentalized and spatially organized enzyme cascades are utilized to increase the efficiency of enzymatic reactions. From a technologically relevant perspective, synthetic enzyme systems have to be optimized with emphasis on enzyme activity, productivity, scalability, and ease of use. But the underlying principles and relevant parameters that lead to an enhancement of the activity of enzyme cascades through spatial organization are still under debate. Here, we report on the 10-fold activity enhancement of the GOx-HRP enzyme cascade for the oxidation of luminol, when the enzymes are colocalized on micron-scaled solid scaffolds. Both enzymes were initially assembled and concentrated on DNA origami rectangles and finally further concentrated on the surface of silica particles. We show that each particular component of the designed system contributes to the activity enhancement. Furthermore, we measured an influence of the silica particle length scale on the total productivity by a factor of 5-10, but to a lesser extent on the maximum enzyme activity. Our findings demonstrate that micrometer-sized scaffolds can be used to enhance the efficiency of enzyme cascades by at least a magnitude and that solid-phase scaffolds enable scalability for technological applications. PMID- 30462512 TI - Calculations of the pH-dependent onset potential for CO electro-oxidation on Au(111). AB - CO electro-oxidation on the Au(111) surface exhibits an onset potential that de- pends strongly on the pH of the electrolyte. In alkaline solution, the onset potential for CO electro-oxidation is found, experimentally, to be 0.5 V lower than in acidic media on the reversible hydrogen electrode scale. This phenomenon is explained here with density functional theory theory which is used to calculate adsorbate binding energies including the electric double layer of the Au(111)/aqueous interface. Our model con- sists of a charged Au(111) slab and implicit solvation for the electrolyte. The double reference method is used to determine the potential-dependent CO electro-oxidation reaction energetics. A microkinetic model, based upon the calculated reaction energet- ics, confirms the lower onset potential in alkaline media. Our results show that there are three factors contributing to the lower onset potential in base: (1) stronger CO ad- sorption, (2) attraction between adsorbed CO and OH- , and (3) the high concentration of OH- in base. PMID- 30462513 TI - RawTools: Rapid and Dynamic Interrogation of Orbitrap Data Files for Mass Spectrometer System Management. AB - Optimizing the quality of proteomics data collected from a mass spectrometer (MS) requires careful selection of acquisition parameters and proper assessment of instrument performance. Software tools capable of extracting a broad set of information from raw files, including meta, scan, quantification, and identification data are needed to provide guidance for MS system management. In this work, direct extraction and utilization of these data is demonstrated using RawTools, a standalone tool for extracting meta and scan data directly from raw MS files generated on Thermo Orbitrap instruments. RawTools generates summarized and detailed plain text outputs after parsing individual raw files, including scan rates and durations, duty cycle characteristics, precursor and reporter ion quantification, and chromatography performance. RawTools also contains a diagnostic module that includes an optional 'preview' database search for facilitating informed decision-making related to optimization of MS performance based on a variety of metrics. RawTools has been developed in C# and utilizes the Thermo RawFileReader library, and thus can process raw MS files with high speed and high efficiency on all major operating systems (Windows, MacOS, Linux). To demonstrate the utility of RawTools, extraction of meta and scan data from both individual and large collections of raw MS files was carried out to identify problematic characteristics of instrument performance. Taken together, the combined rich feature-set of RawTools with the capability for interrogation of MS and experiment performance makes this software a valuable tool for proteomics researchers. PMID- 30462514 TI - Theoretical Insights into Interfacial Electron Transfer between Zinc Phthalocyanine and Molybdenum Disulfide. AB - A comprehensive understanding of interfacial charge transfer dynamics is critical for improving the optoelectronic efficiency of organic-transition metal dichalcogenides heterostructures. In this work we have employed density functional theory (DFT) and developed nonadiabatic dynamics simulation approaches to study the photoinduced electron transfer dynamics at the interface of zinc phthalocyanine (ZnPc) and molybdenum disulfide (MoS2). Our present results show that ZnPc is adsorbed in a parallel orientation on MoS2 through weak van der Waals interaction. Photoirradiation excites an electron of ZnPc into its lowest unoccupied molecular orbital (LUMO), which is primarily located on ZnPc but has a remarkable tail on MoS2. This enhances the vibronic coupling between LUMO of ZnPc and adiabatic states of MoS2 thereby benefiting the interfacial electron transfer. The LUMO of ZnPc is also calculated to be 0.27 eV higher than the conduction band minimum (CBM) of MoS2 so that the electron transfer from ZnPc to MoS2 is thermodynamically favorable. Further nonadiabatic dynamics simulations verify such ultrafast electron transfer and estimate its time scale of ca. 10 fs. In this process, the low-frequency out-of-plane vibration of MoS2, and low- and high-frequency in-plane and out-of-plane vibrations of ZnPc are found to play an important role in regulating this interfacial electron transfer. In-depth analysis also reveals that atomic motion induced changes of adiabatic states is a dominant factor leading to such ultrafast interfacial electron transfer. These insights could be useful for understanding charge transfer processes at interfaces of heterostructures. PMID- 30462515 TI - Efficient Fog Harvesting Based on 1D Copper Wire Inspired by the Plant Pitaya. AB - The leaf of the plant pitaya shows excellent fog harvesting behavior through its 1D thorns with wire-like microstructures. The thorns of it cannot provide enough driving force for the droplet transportation by the special structure and chemistry gradient as the cactus thorns, but it showed efficient water supply which improved the fog harvesting greatly. The mechanism is studied based on 1D copper wire with similar 1D wire-like microstructure and wettability. This structure can significantly reduce the deviation of the fog-laden winds, and the surface intrinsic hydrophility makes water accumulate on it in the form of droplets, which endow it with an efficient water supply that is ~100 times faster than that on a 2D-flat surface. In addition, it can also enhance the fog capture and water removal. The 3D fog collector composed of 1D microcopper wires has been fabricated which show a high fog harvesting efficiency of ~13%. This work explains the role of 1D wire-like microstructure in efficient fog harvesting in a different view and provides new insight into the application of developing a more efficient fog collector. PMID- 30462516 TI - In Situ Scanning Electron Microscopy Detection of Carbide Nature of Dendrites in Li-Polymer Batteries. AB - Li metal batteries suffer from dendrite formation which causes short circuit of the battery. Therefore, it is important to understand the chemical composition and growth mechanism of dendrites that limit battery efficiency and cycle life. In this study, in situ scanning electron microscopy was employed to monitor the cycling behavior of all-solid Li metal batteries with LiFePO4 cathodes. Chemical analyses of the dendrites were conducted using a windowless energy dispersive spectroscopy detector, which showed that the dendrites are not metallic lithium as universally recognized. Our results revealed the carbide nature of the dendrites with a hollow morphology and hardness greater than that of pure lithium. These carbide-based dendrites were able to perforate through the polymer, which was confirmed by milling the polymer using focused ion beam. It was also shown that applying pressure on the battery can suppress growth of the dendrites. PMID- 30462517 TI - Synthesis of cis-/All- cis-Substituted Cyclopropanes through Stereocontrolled Metalation and Pd-Catalyzed Negishi Coupling. AB - We have developed a direct method for the synthesis of cis-substituted cyclopropanes from a cyclopropanecarboxamide through stereocontrolled metalation and Negishi coupling. Under the optimized reaction conditions, various substituents, including di/trisubstituted alkenes and aryl groups, were introduced in a stereoselective manner using a simple amide directing group that could subsequently be converted into an ester. Furthermore, this method was applicable to the synthesis of all- cis-substituted cyclopropanes bearing three different substituents, which are highly congested and strained molecules. PMID- 30462518 TI - Regulating Traditional Mexican Midwifery: Practices of Control, Strategies of Resistance. AB - The institutionalization of Mexican midwifery has a long history. Despite global recommendations moving away from training traditional midwives, training courses still continue. Based on fieldwork in the State of Chiapas, I argue that while ongoing trainings offered to traditional midwives in Mexico aim at teaching them best practices, they also limit midwives' autonomy and keep poor women's reproductive behaviors under control. I demonstrate how midwives and medical personnel mobilize discourses of reproductive risk, women's rights and indigenous cultural rights to reinforce or contest mechanisms of reproductive governance. PMID- 30462519 TI - Novel Imaging Modalities in Detection of Cardiovascular Involvement in Ankylosing Spondylitis. AB - OBJECTIVES: The diagnosis of cardiovascular involvement in ankylosing spondylitis (AS) is usually delayed since conventional echocardiography relies mainly on the morphological alterations. The aim of this study was to evaluate the role of echocardiographic methods such as tissue Doppler and strain imaging of left ventricle (LV) and proximal aorta; and concentrations of biomarkers of cardiac fibrosis such as galectin-3 (Gal-3) and soluble suppression-of-tumorogenicity-2 (sST2) in determining early cardiovascular impairment in AS. DESIGN: In this prospective study of 75 AS and 30 healthy subjects (mean age 41.7 +/- 10.1 years; 37.3% female), we determined layer-specific strain and strain rates in longitudinal, circumferential and radial axes for LV as well as transverse and longitudinal strains of proximal aorta; central pulse wave velocity(cPWV); plasma high sensitivity C-reactive protein(hsCRP), Gal-3 and sST2 levels. RESULTS: Patients with AS had increased levels of hsCRP and sST2 when compared to healthy controls. cPWV, E and e' velocities; longitudinal strain and strain rates at all myocardial layers; and transverse strains of both anterior and posterior aortic walls were reduced in AS patients. Gal-3 levels with strain and strain rates at circumferential and radial axes were similar between the groups. Among all echocardiographic and clinical parameters, AS was independently associated with LV dysfunction (expressed by longitudinal strain of LV) and aortic impairment (expressed by transverse strain of anterior wall). CONCLUSIONS: This study demonstrates that functional impairment in AS occurs early in the disease course and strain imaging is an effective tool in discriminating involvement. sST2 may represent the link between inflammation and fibrosis in AS. PMID- 30462520 TI - Role of N-glycosylation in the expression of human SLC26A2 and A3 anion transport membrane glycoproteins. AB - The human solute carrier 26 (SLC26) gene family of anion transporters consists of 10 members (SLC26A1-A11, A10 being a pseudogene) that encode membrane glycoproteins with 14 transmembrane (TM) segments and a C-terminal cytoplasmic sulfate transporter anti-sigma antagonist (STAS) domain. Thus far, mutations in eight members of the SLC26 family (A1 - A6, A8 and A9) have been linked to diseases in humans. Our goal is to characterize the role of N-glycosylation and the effect of mutations in SLC26A2 and A3 proteins on their functional expression in transfected HEK-293 cells. We found that certain mutants were retained in the ER via an interaction with the lectin chaperone, calnexin. Some could escape protein quality control and traffic to the cell surface upon removal of the N glycosylation sites. Furthermore, we found that loss of N-glycosylation reduced expression of SLC26A2 at the cell surface. Loss of N-glycosylation had no effect on the stability of SLC26A3, yet resulted in a profound decrease in transport activity. Thus, N-glycosylation plays three roles in the functional expression of SLC26 proteins: 1) to retain mis-folded proteins in the ER, 2) to stabilize the protein at the cell surface, and 3) to maintain the transport protein in a functional state. PMID- 30462521 TI - Evaluating the safety of emicizumab in patients with hemophilia A. AB - INTRODUCTION: Patients affected by hemophilia A often require frequent prophylactic and therapeutic self-infusion. For those who develop inhibitors, treatment options are limited and mortality is increased. Emicizumab, a bispecific antibody to Factors IXa and X that carries out the function of Factor VIII (FVIII), represents a novel therapeutic approach. Areas covered: We review the clinical trials and key laboratory assay research for emicizumab. Emicizumab reduced the annualized bleeding rate by 87% compared to placebo in patients with inhibitors. For patients without inhibitors, emicizumab reduced the annualized bleeding rate 96-97% compared to no prophylaxis and 68% compared to prior FVIII prophylaxis. Three patients developed a thrombotic microangiopathy (TMA) and two patients had thrombotic events while on emicizumab in combination with activated prothrombin complex concentration (aPCC) alone or concurrent with activated recombinant factor FVII (rFVIIa). Expert opinion: Emicizumab represents a much needed alternative approach to managing Factor VIII deficiency, especially for those with inhibitors or limited ability to self-infuse. For patients with inhibitors, thrombotic complications including TMA, not seen with other bypassing agents, raises concern about the use of emicizumab in combination with aPCC and how patients who have breakthrough bleeding can be safely managed. PMID- 30462522 TI - Distinct Roles of Histamine H1 and H2 Receptor Signaling Pathways in Inflammation Associated Colonic Tumorigenesis. AB - Inflammatory bowel disease (IBD) is a well-known risk factor for the development of colorectal cancer. Prior studies have demonstrated that microbial histamine can ameliorate intestinal inflammation in mice. We tested the hypothesis whether microbe-derived luminal histamine suppresses inflammation-associated colon cancer in Apcmin/+ mice. Mice were colonized with the human-derived Lactobacillus reuteri. Chronic inflammation was induced by repeated cycles of low-dose dextran sulfate sodium (DSS). Mice that were given histamine-producing L. reuteri via oral gavage developed fewer colonic tumors, despite the presence of a complex mouse gut microbiome. We further demonstrated that administration of a histamine H1 receptor (H1R) antagonist suppressed tumorigenesis, while administration of histamine H2 receptor (H2R) antagonist significantly increased both tumor number and size. The bimodal functions of histamine include pro-tumorigenic effects through H1R and anti-tumorigenic effects via H2R, and these results were supported by gene expression profiling studies on tumor specimens of patients with colorectal cancer. Greater ratios of gene expression of H2R ( HRH2) versus H1R ( HRH1) were correlated with improved overall survival outcomes in patients with colorectal cancer. Additionally, activation of H2R suppressed phosphorylation of mitogen-activated protein kinases (MAPKs) and inhibited chemokine gene expression induced by H1R activation in colorectal cancer cells. Moreover, the combination of a H1R antagonist and a H2R agonist yielded potent suppression of lipopolysaccharide (LPS) induced MAPK signaling in macrophages. Given the impact on intestinal epithelial and immune cells, simultaneous modulation of H1R and H2R signaling pathways may be a promising therapeutic target for the prevention and treatment of inflammation-associated colorectal cancer. PMID- 30462523 TI - The role of circulating free DNA in the management of NSCLC. AB - INTRODUCTION: Circulating cell-free DNA (cfDNA) testing has emerged as an alternative to tumor tissue analyses for the management of metastatic non-small cell lung cancer (NSCLC) patients. Analysis of cfDNA is a minimally invasive procedure that might better reflect tumor heterogeneity and allows repeated testing over the time. Areas covered: This review article covers the different applications of cfDNA testing in NSCLC: early diagnosis of the disease; detection of minimal residual disease in early lung cancer; identification of predictive and prognostic markers in advanced NSCLC patients; monitoring the response to therapy; assessment of tumor mutation burden. Expert commentary: The use of liquid biopsy is rapidly expanding to different applications. The combination of different circulating biomarkers (cfDNA, protein, miRNA) might improve the sensitivity and specificity of this approach in patients with low tumor burden. cfDNA testing is representing a valid source for molecular profiling in management of metastatic NSCLC patients and is providing important knowledge on tumor heterogeneity. Clinical trials are needed in order to transfer the information deriving from liquid biopsy testing in new therapeutic strategies. PMID- 30462524 TI - Glucagon and insulin secretion, insulin clearance and fasting glucose in GIP receptor and GLP-1 receptor knockout mice. AB - It is not known whether GIP receptor and GLP-1 receptor knockout (KO) mice have perturbations in glucagon secretion or insulin clearance, and studies on impact on fasting glycemia have previously been inconsistent in these mice. We therefore studied glucagon secretion after oral whey protein (60 mg) and intravenous arginine (6.25 mg), insulin clearance after intravenous glucose (0.35 g/kg) and fasting glucose, insulin and glucagon levels after standardized 5hr fasting in female GIP receptor and GLP-1 receptor KO mice and their wildtype (wt) littermates. Compared to wt controls, GIP receptor KO mice had normal glucagon responses to oral protein and intravenous arginine, except an enhanced 1 min response to arginine, whereas glucagon levels after oral protein and intravenous arginine were enhanced in GLP-1 receptor KO mice. Furthermore, the intravenous glucose test revealed normal insulin clearance in both GIP receptor and GLP-1 receptor KO mice, whereas beta-cell glucose sensitivity was enhanced in GIP receptor KO mice and reduced in GLP-1 receptor KO mice. Finally, GIP receptor KO mice had reduced fasting glucose (6.7+/-0.1, n=56, vs, 7.4+/-0.1 mmol/l, n=59, P=0.001), whereas GLP-1 receptor KO mice had increased fasting glucose (9.1+/ 0.2, n=44, vs. 7.7+/-0.1 mmol/l, n=41, P<0.001). We therefore suggest that GIP has a limited role for glucagon secretion in mice, whereas GLP-1 is of importance for glucagon regulation, that GIP and GLP-1 are of importance for the regulation of beta-cell function beyond their role as incretin hormones and that they are both of importance for fasting glucose. PMID- 30462525 TI - Effects of altered Pyruvate Dehydrogenase Activity on contracting skeletal muscle bioenergetics. AB - During aerobic exercise (>65% of VO2max) the primary source of acetyl-CoA to fuel oxidative ATP synthesis in muscle is the pyruvate dehydrogenase (PDH) reaction. This study investigated how regulation of PDH activity affects muscle energetics by determining whether activation of PDH with dichloroacetate (DCA) alters the dynamics of the phosphate potential of rat gastrocnemius muscle during contraction. Twitch contractions were induced in vivo over a broad range of intensities to sample submaximal and maximal aerobic workloads. Muscle phosphorus metabolites were measured in vivo before and after DCA treatment using phosphorus nuclear magnetic resonance spectroscopy. At rest, DCA increased PDH activation compared to control (90+/-12 vs 23+/-3%, p<0.05) with parallel decreases in inorganic phosphate (Pi) of 17% (1.4+/-0.2 vs 1.7+/-0.1 mM, p<0.05) and an increase in the free energy of ATP hydrolysis (DeltaGATP) (-66.2+/-0.3 vs -65.6+/ 0.2 kJ/mol, p<0.05). During stimulation DCA increased steady state phosphocreatine (PCr) and DeltaGATP with concomitant reduction in Pi and ADP concentrations. These effects were not due to kinetic alterations in PCr hydrolysis, resynthesis, or glycolytic ATP production and altered the flow force relationship between mitochondrial ATP synthesis rate (JMITO) and DeltaGATP. DCA had no significant effect at 1.0-2.0 Hz stimulation, because physiological mechanisms at these high stimulation levels cause maximal activation of PDH. These data support a role of PDH activation in the regulation of the energetic steady state by altering the thermodynamic set point of the phosphate potential (DeltaGATP) at rest and during contraction and do not support kinetic limitations to mitochondria as previously suggested. PMID- 30462526 TI - Tracking Autonomic Balance Using an Open-Loop Model of the Arterial Baroreflex. AB - Blood pressure control is vital for maintaining adequate perfusion of the brain and other organs in the body across varying physiological demands, and the arterial baroreceptor reflex (baroreflex) is the major short-term blood pressure control loop mediated by the autonomic nervous system (ANS). Accurate quantitative models of the baroreflex would provide physiological insight, and could allow for real-time tracking of ANS activity in clinical settings. In this work, we formulate a causal, parametric beat-to-beat model, relating systolic blood pressure (input) to heart rate (output). Model structure and parameterization are explicitly based on prior physiological insights of the response dynamics of the sympathetic and parasympathetic branches of the ANS. We analyze the model's ability to track changes in autonomic balance using data from fourteen nonsmoking adult males, without any history of cardiopulmonary disease, subject to both pharmacological blockade and postural changes. Our results show that the model parameters faithfully track expected changes in autonomic balance resulting from changing posture (p < 0.01) and sympathetic blockade (p < 0.05), and in many cases are more sensitive to changes in autonomic activity and balance than autonomic indices derived from the power spectral density of heart rate variability. Overall, the contributions of this work further the goal of obtaining real-time quantitative assessment of the ANS. PMID- 30462527 TI - Dopamine modulates excitatory transmission to orexin neurons in a receptor subtype-specific manner. AB - Dopamine (DA) can promote or inhibit consummatory and reward-related behaviors by activating different receptor subtypes in the lateral hypothalamus and perifornical area (LH/PF). Since orexin neurons are involved in reward and localized in the LH/PF, DA may modulate these neurons to influence reward-related behaviors. To determine the cellular mechanism underlying dopaminergic modulation of orexin neurons, the effect of DA on excitatory transmission to these neurons was investigated using in-vitro electrophysiology on rat brain slices. We found that low concentrations (0.1-1 uM) of DA increased evoked EPSC amplitude, while decreasing paired pulse ratio. In contrast, high concentrations (10-100 uM) of DA did the opposite. The excitatory effect of low DA was blocked by the D1 receptor antagonist SCH23390, while the inhibitory effect of high DA was blocked by the D2 receptor antagonist sulpiride. These results indicate distinct roles of D1 and D2 receptors in bidirectional presynaptic modulation of excitatory transmission. DA had stronger effects on isolated synaptic activity than repetitive ones, suggesting that sensitivity to dopaminergic modulation depends on the level of network activity. In orexin neurons from high-fat diet-fed rats, a high concentration of DA was less effective in suppressing repetitive synaptic activity compared to chow controls. Therefore, in diet-induced obesity, intense synaptic inputs may preferentially reach orexin neurons while intermittent signals are inhibited by high DA levels. In summary, our study provides a cellular mechanism by which DA may exert opposite behavioral effects in the LH/PF through bidirectional modulation of orexin neurons via different DA receptors. PMID- 30462528 TI - Ergosterol interacts with Sey1p to promote atlastin-mediated endoplasmic reticulum membrane fusion in Saccharomyces cerevisiae. AB - Sterols play critical roles in various membrane fusion events, including soluble NSF attachment protein receptor-mediated membrane fusion, mainly by modulating the physical properties of biologic membranes; however, it remains unclear whether they also function in atlastin-mediated endoplasmic reticulum (ER) membrane fusion. Although ergosterol, the major sterol in yeast, is essential for fusion of Sey1p (yeast atlastin)-containing liposomes with an ER-mimicking lipid composition, fusion of phosphatidylcholine/phosphatidylserine liposomes does not require sterols. Here, we examined whether sterols are important for Sey1p mediated ER fusion in Saccharomyces cerevisiae using an in vitro ER fusion assay with isolated yeast ER microsomes. Ergosterol-specific ligands inhibited microsome fusion, indicating that ergosterol is critical for ER fusion. However, microsomes isolated from yeast strains lacking genes that encode enzymes involved in synthesis of ergosterol from lanosterol still fused, suggesting that other sterols can replace ergosterol and support Sey1p-mediated ER fusion. Importantly, disruption of sterol-binding motifs in the transmembrane regions of Sey1p markedly reduced ER fusion. Sey1p physically interacted with Erg11p and Erg4p, which function in ergosterol biosynthesis, suggesting that Sey1p recruits ergosterol-synthesizing enzymes to fusion sites and thereby enriches ergosterol, which, in turn, may recruit more Sey1p. This positive feedback loop may facilitate ER membrane fusion by concentrating fusion factors at fusion sites. Lee, M., Moon, Y., Lee, S., Lee, C., Jun, Y. Ergosterol interacts with Sey1p to promote atlastin-mediated endoplasmic reticulum membrane fusion in Saccharomyces cerevisiae. PMID- 30462529 TI - Macrophage FABP4 is required for neutrophil recruitment and bacterial clearance in Pseudomonas aeruginosa pneumonia. AB - Fatty acid binding protein 4 (FABP4), an intracellular lipid chaperone and adipokine, is expressed by lung macrophages, but the function of macrophage-FABP4 remains elusive. We investigated the role of FABP4 in host defense in a murine model of Pseudomonas aeruginosa pneumonia. Compared with wild-type (WT) mice, FABP4-deficient (FABP4-/-) mice exhibited decreased bacterial clearance and increased mortality when challenged intranasally with P. aeruginosa. These findings in FABP4-/- mice were associated with a delayed neutrophil recruitment into the lungs and were followed by greater acute lung injury and inflammation. Among leukocytes, only macrophages expressed FABP4 in WT mice with P. aeruginosa pneumonia. Chimeric FABP4-/- mice with WT bone marrow were protected from increased mortality seen in chimeric WT mice with FABP4-/- bone marrow during P. aeruginosa pneumonia, thus confirming the role of macrophages as the main source of protective FABP4 against that infection. There was less production of C-X-C motif chemokine ligand 1 (CXCL1) in FABP4-/- alveolar macrophages and lower airway CXCL1 levels in FABP4-/- mice. Delivering recombinant CXCL1 to the airways protected FABP4-/- mice from increased susceptibility to P. aeruginosa pneumonia. Thus, macrophage-FABP4 has a novel role in pulmonary host defense against P. aeruginosa infection by facilitating crosstalk between macrophages and neutrophils via regulation of macrophage CXCL1 production.-Liang, X., Gupta, K., Rojas Quintero, J., Cernadas, M., Kobzik, L., Christou, H., Pier, G. B., Owen, C. A., Cataltepe, S. Macrophage FABP4 is required for neutrophil recruitment and bacterial clearance in Pseudomonas aeruginosa pneumonia. PMID- 30462530 TI - SCAP knockdown in vascular smooth muscle cells alleviates atherosclerosis plaque formation via up-regulating autophagy in ApoE-/- mice. AB - Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a cholesterol sensor that plays a critical role in regulating intracellular cholesterol levels, but the association between SCAP and foam cell formation in vascular smooth muscle cells (VSMCs) is poorly understood. Using tissue-specific SCAP knockdown in apolipoprotein E (ApoE)-/- mice, we sought to search the mechanism through which SCAP signaling affects VSMC foam cell development. VSMC-specific SCAP knockdown mice were generated by Cre/LoxP mediated gene targeting in ApoE-/- mice. Breeding SCAPflox/flox mice with SM22alpha-Cre mice resulted in no viable offspring with the homozygote SM22-Cre: SCAPflox/flox genotype due to embryonic lethality. We found that the heterozygote SM22alpha-Cre:SCAPflox/+:ApoE-/- mice fed a Western diet for 12 wk had significantly fewer atherosclerotic plaques in their aortas than the control mice due to reduced cholesterol uptake and synthesis. Furthermore, we found that autophagy in VSMCs was increased in SM22alpha-Cre:SCAPflox/+:ApoE-/- mice. Similarly, in vitro, SCAP knockdown in human coronary artery VSMCs by RNA interference reduced lipid accumulation and increased autophagy under LDL cholesterol loading. SCAP knockdown in VSMCs reduced oxidative stress and increased AMPK phosphorylation, which contributed to the up-regulation of autophagy in vivo and in vitro. VSMC-specific SCAP knockdown decreased the lipid accumulation and intracellular oxidative stress, increased excessive lipid clearance by enhancing lipid autophagy mediated by the reactive oxygen species/AMPK pathway in VSMCs, and consequently alleviated atherosclerosis plaque formation.-Li, D., Chen, A., Lan, T., Zou, Y., Zhao, L., Yang, P., Qu, H., Wei, L., Varghese, Z., Moorhead, J. F., Chen, Y., Ruan, X. Z. SCAP knockdown in vascular smooth muscle cells alleviates atherosclerosis plaque formation via up regulating autophagy in ApoE-/- mice. PMID- 30462531 TI - The protein synthesis inhibitor brusatol normalizes high-fat diet-induced glucose intolerance in male C57BL/6 mice: role of translation factor eIF5A hypusination. AB - The naturally occurring quassinoid compound brusatol improves the survival of insulin-producing cells when exposed to the proinflammatory cytokines IL-1beta and IFN-gamma in vitro. The aim of the present study was to investigate whether brusatol also promotes beneficial effects in mice fed a high-fat diet (HFD), and if so, to study the mechanisms by which brusatol acts. In vivo, we observed that the impaired glucose tolerance of HFD-fed male C57BL/6 mice was counteracted by a 2 wk treatment with brusatol. Brusatol treatment improved both beta-cell function and peripheral insulin sensitivity of HFD-fed mice. In vitro, brusatol inhibited beta-cell total protein and proinsulin biosynthesis, with an ED50 of ~40 nM. In line with this, brusatol blocked cytokine-induced iNOS protein expression via inhibition of iNOS mRNA translation. Brusatol may have affected protein synthesis, at least in part, via inhibition of eukaryotic initiation factor 5A (eIF5A) hypusination, as eIF5A spermidine association and hypusination in RIN-5AH cells was reduced in a dose- and time-dependent manner. The eIF5A hypusination inhibitor GC7 promoted a similar effect. Both brusatol and GC7 protected rat RIN 5AH cells against cytokine-induced cell death. Brusatol reduced eIF5A hypusination and cytokine-induced cell death in EndoC-betaH1 cells as well. Finally, hypusinated eIF5A was reduced in vivo by brusatol in islet endocrine and endothelial islet cells of mice fed a HFD. The results of the present study suggest that brusatol improves glucose intolerance in mice fed a HFD, possibly by inhibiting protein biosynthesis and eIF5A hypusination.-Turpaev, K., Krizhanovskii, C., Wang, X., Sargsyan, E., Bergsten, P., Welsh, N. The protein synthesis inhibitor brusatol normalizes high-fat diet-induced glucose intolerance in male C57BL/6 mice: role of translation factor eIF5A hypusination. PMID- 30462532 TI - Muller glia phagocytose dead photoreceptor cells in a mouse model of retinal degenerative disease. AB - Retinitis pigmentosa is a devastating, blinding disorder that affects 1 in 4000 people worldwide. During the progression of the disorder, phagocytic clearance of dead photoreceptor cell bodies has a protective role by preventing additional retinal damage from accumulation of cellular debris. However, the cells responsible for the clearance remain unidentified. Taking advantage of a mouse model of retinitis pigmentosa ( RhoP23H/P23H), we clarified the roles of Muller glia in the phagocytosis of rod photoreceptor cells. During the early stage of retinal degeneration, Muller glial cells participated in the phagocytosis of dying or dead rod photoreceptors throughout the outer nuclear layer. Nearly 50% of Muller glia engaged in phagocytosis. Among the Muller phagosomes, >90% matured into phagolysosomes. Those observations indicated that Muller glial cells are the primary contributor to phagocytosis. In contrast, macrophages migrate to the inner part of the outer nuclear layer during photoreceptor degeneration, participating in the phagocytosis of a limited population of dying or dead photoreceptor cells. In healthy retinas of wild-type mice, Muller glial cells phagocytosed cell bodies of dead rod photoreceptors albeit at a lower frequency. Taken together, the phagocytic function of Muller glia is responsible for retinal homeostasis and reorganization under normal and pathologic conditions.-Sakami, S., Imanishi, Y., Palczewski, K. Muller glia phagocytose dead photoreceptor cells in a mouse model of retinal degenerative disease. PMID- 30462533 TI - Early growth response protein 1 upregulates long noncoding RNA Arid2-IR to promote extracellular matrix production in diabetic kidney disease. AB - Diabetic kidney disease (DKD) has surpassed chronic glomerulonephritis as the leading cause of end-stage renal disease (ESRD). Previously, we showed that early growth response protein 1 (Egr1) plays a key role in DKD by enhancing mesangial cell proliferation and extracellular matrix (ECM) production. The long noncoding RNA Arid2-IR has been identified as a Smad3-associated lncRNA in unilateral ureteral obstructive (UUO) kidney disease. However, the effect of Egr1 on Arid2 IR in the development of DKD is still unknown. In this study, we found that Arid2 IR was increased in high-fat diet (HFD)-and streptozotocin (STZ)-induced type 2 diabetes mice and in mouse mesangial cells cultured with high glucose to mimic diabetes. Knockdown of Arid2-IR in mouse mesangial cells reduced the high expression of Col1a1 and alpha-SMA induced by high glucose. Furthermore, Arid2-IR expression changed the increased expression of Col1a1 and alpha-SMA caused by overexpression of Egr1. Overall, these data suggest that increased Arid2-IR likely contributes to ECM production in DKD and that Egr1 promotes ECM production in DKD partly by upregulating Arid2-IR. Thus, Arid2-IR may be a new target in the treatment of diabetic kidney disease. PMID- 30462534 TI - Anxa2 gene silencing attenuates obesity-induced insulin resistance by suppressing NF-kB signaling pathway. AB - Insulin resistance (IR) continues to pose a major threat to public health due to its role in the pathogenesis of metabolic syndrome, and its ever-increasing prevalence on a global scale. The aim of the current study was to investigate the efficacy of Anxa2 in obesity-induced IR through the mediation of the NF-kB signaling pathway. Microarray analysis was performed to screen differentially expressed genes associated with obesity. To verify whether Anxa2 was differentially expressed in IR triggered by obesity, IR mice models were established in connection with a high-fat diet (HFD). In the mouse IR model, the role of differentially expressed Anxa2 in glycometabolism and IR was subsequently detected. To investigate the effect of Anxa2 on IR and its correlation with inflammation, a palmitic acid (PA)-induced IR cell model was established, with the relationship between Anxa2 and the NF-kB signaling pathway investigated accordingly. Anxa2 was determined to be highly expressed in IR. Silencing Anxa2 was shown to inhibit IR triggered by obesity. When Anxa2 was knocked down, elevated expressions of p-IRS1, IRS1 and Pgc1a, glucose tolerance and insulin sensitivity along with 2DG uptake were detected, while decreased expressions of SOCS3, IL6, IL-1beta, TNF-alpha and p50 were observed. Taken together, the current study ultimately demonstrated that Anxa2 may be a novel drug strategy for IR disruption, indicating that Anxa2 gene silencing is capable of alleviating PA or HFD-induced IR and inflammation through its negative regulatory role in the process of p50 nuclear translocation of the NF-kappaB signaling pathway. PMID- 30462535 TI - Roles of integrins and extracellular matrix in stroke. AB - Ischemic stroke is a leading cause of death and disability in the United States, but recent advances in treatments (i.e. endovascular thrombectomy and tissue plasminogen activator (t-PA)) that target the stroke-causing blood clot, while improving overall stroke mortality rates, have had much less of an impact on overall stroke morbidity. This may in part be attributed to the lack of therapeutics targeting reperfusion induced injury after the blood clot has been removed, which, if left unchecked, can expand injury from its core into the surrounding at risk tissue (penumbra). This occurs in two phases of increased permeability of the blood-brain barrier, a physical barrier that under physiologic conditions regulates brain influx and efflux of substances and consists of tight junction forming endothelial cells (and transporter proteins), astrocytes, pericytes, extracellular matrix and their integrin cellular receptors. During, embryonic development, maturity, and following stroke reperfusion, cerebral vasculature undergoes significant changes including changes in expression of integrins and degradation of surrounding extracellular matrix. Integrins, heterodimers with alpha and beta subunits, and their extracellular matrix ligands, a collection of proteoglycans, glycoproteins, and collagens, have been modestly studied in the context of stroke compared to other diseases (e.g. cancer). In this review, we describe the affect that various integrins and extracellular matrix components have in embryonic brain development, and how this changes in both maturity and in the post-stroke environment, with particular focus on how these changes affect blood-brain barrier integrity and their potential as diagnostic and therapeutic targets for ischemic stroke. PMID- 30462536 TI - miR-429 and miR-424-5p inhibit cell proliferation and Ca2+ influx by downregulating CaSR in pulmonary artery smooth muscle cells. AB - Cytosolic free Ca2+ concentration is a key factor in pulmonary vasoconstriction and vascular remodeling of pulmonary artery smooth muscle cells (PASMC). These processes contribute to pulmonary arterial hypertension and are influenced by expression of calcium sensing receptor (CaSR). Although regulation of CaSR expression is precisely controlled, the contribution of microRNAs is incompletely understood. Here, we demonstrate that miR-429, miR-424-5p, miR-200b-3p, and miR 200c-3p regulate CaSR by targeting specific 3'-UTR, suggesting that these miRNAs function as CaSR inhibitors in PASMC. Moreover, miR-429 and miR-424-5p inhibit proliferation of PASMC by downregulating CaSR, resulting in reduced Ca2+ influx under both normoxia and hypoxia. These findings indicate miR-429 and miR-424-5p target CaSR and may function as Ca2+ influx suppressors in pulmonary arterial hypertension-associated diseases. PMID- 30462537 TI - Modulating GLUT1 expression in the RPE decreases glucose levels in the retina: Impact on photoreceptors and Muller glial cells. AB - The retina is one of the most metabolically active tissues in the body and utilizes glucose to produce energy and intermediates required for daily renewal of photoreceptor cell outer segments. GLUT1 facilitates glucose transport across outer blood retinal barrier (BRB) formed by the retinal pigment epithelium (RPE) and the inner BRB formed by the endothelium. We used conditional knockout mice to study the impact of reducing glucose transport across the RPE on photoreceptor and Muller glial cells. Transgenic mice expressing Cre recombinase under control of the Bestrophin1 ( Best1) promoter were bred with Glut1flox/flox mice to generate Tg-Best1-Cre:Glut1flox/flox mice ( RPEDeltaGlut1). The RPEDeltaGlut1 mice displayed a mosaic pattern of Cre expression within the RPE that allowed us to analyze mice with ~50% ( RPEDeltaGlut1m) recombination and mice with >70% ( RPEDeltaGlut1h) recombination separately. Deletion of GLUT1 from the RPE did not affect its carrier or barrier functions, indicating that the RPE utilizes other substrates to support its metabolic needs thereby sparing glucose for the outer retina. RPEDeltaGlut1m mice had normal retinal morphology, function and no cell death, however, where GLUT1 was absent from a span of RPE greater than 100 um, there was shortening of the photoreceptor cell outer segments. RPEDeltaGlut1h mice showed outer segment shortening, cell death of photoreceptors and activation of Muller glial cells. The severe phenotype seen in RPEDeltaGlut1h mice indicates that glucose transport via the GLUT1 transporter in the RPE is required to meet the anabolic and catabolic requirements of photoreceptors and maintain Muller glial cells in a quiescent state. PMID- 30462538 TI - The role of coagulation and platelets in colon cancer-associated thrombosis. AB - Cancer-associated thrombosis is a common first presenting sign of malignancy and is currently the second leading cause of death in cancer patients after their malignancy. Despite the high incidence of thrombosis in patients with malignancy however, the molecular mechanisms underlying cancer-associated thrombosis remain undefined. In this study, we aimed to develop a better understanding of how cancer cells affect the coagulation cascade and platelet activation to induce a prothrombotic phenotype. Our results show that colon cancer cells trigger platelet activation in a manner dependent on cancer cell tissue factor (TF) expression, thrombin generation, activation of the protease-activated receptor 4 (PAR4) on platelets and consequent release of ADP and TXA2. Platelet-colon cancer cell interactions potentiated the selective formation of platelet-derived extracellular vesicles (EVs) rather than cancer cell-derived EVs. Our data show that single colon cancer cells were capable of recruiting and activating platelets and generating fibrin in plasma under shear flow. Finally, in a retrospective analysis of colon cancer patients, we found that the number of venous thromboembolism events was 4.5 times higher in colon cancer patients than in a control population. In conclusion, our data suggest that platelet-cancer cell interactions and perhaps platelet procoagulant EVs may contribute to the prothrombotic phenotype of colon cancer patients. Our work may provide rationale for targeting platelet-cancer cell interactions with PAR-4 antagonists together with aspirin and/or ADP receptor antagonists as a potential intervention to limit cancer-associated thrombosis, balancing safety with efficacy. PMID- 30462539 TI - MicroRNA-146a-5p Enhances Radiosensitivity in Hepatocellular Carcinoma through Replication Protein A3 Induced Activation of the DNA Repair Pathway. AB - Hepatocellular carcinoma (HCC) is known for its high mortality rate worldwide. Based on intensive studies, microRNA (miRNA) expression functions in tumor suppression. Therefore, we aim at evaluating the contribution of miR-146a-5p to radiosensitivity in HCC through the activation of the DNA damage repair pathway by binding to Replication Protein A3 (RPA3). Firstly, the limma package of R was performed in order to differentially analyze HCC expression chip and regulative miRNA of RPA3 was predicted. Expressions of miR-146a-5p, RPA3 and DNA damage repair pathway-related factors in tissues and cells were determined. The effects of radiotherapy on the expression of miR-146a-5p and RPA3 as well as on cell radiosensitivity, proliferation, cell cycle and apoptosis were also assessed. The results showed that there exists a close correlation between miR-146a and the radiotherapy effect on HCC progression through regulation of RPA3 and DNA repair pathway. The positive rate of ATM, pCHK2 and Rad51 in HCC tissues was higher when compared to that of the paracancerous tissues. SMMC-7721 and HepG2 cell proliferation were significantly inhibited following 8 Gy 6Mv dose. MiR-146a-5p restrained the expression of RPA3 and promoted the expression of relative genes associated with the DNA repair pathway. In addition, miR-146a-5p overexpression suppresses cell proliferation and enhances radiosensitivity and cell apoptosis in HCC cells. In conclusion, the present study revealed that miR-146a-5p could lead to the restriction of proliferation and the promotion of radiosensitivity and apoptosis in HCC cells through activation of DNA repair pathway and inhibition of RPA3. PMID- 30462540 TI - GDE5 Inhibition Accumulates Intracellular Glycerophosphocholine and Suppresses Adipogenesis at a Mitotic Clonal Expansion Stage. AB - Mammalian glycerophosphodiesterases (GDEs) were recently shown to be involved in multiple cellular signaling pathways. This study showed that decreased GDE5 expression results in accumulation of intracellular glycerophosphocholine (GPC), showing that GDE5 is actively involved in GPC/choline metabolism in 3T3-L1 adipocytes. Using 3T3-L1 adipocytes, we further studied the biological significance of GPC/choline metabolism during adipocyte differentiation. Inhibition of GDE5 suppressed the formation of lipid droplets, which is accompanied by the decreased expression of adipocyte differentiation markers. We further showed that the decreased GDE5 expression suppressed mitotic clonal expansion (MCE) of preadipocytes. Decreased expression of CTP: phosphocholine cytidylyltransferase (CCTbeta), a rate-limiting enzyme for phosphatidylcholine (PC) synthesis, is similarly able to inhibit MCE and PC synthesis; however the decreased GDE5 expression resulted in accumulation of intracellular GPC but did not affect PC synthesis. Furthermore, we showed that mRNAs of proteoglycans and transporters for organic osmolytes are significantly up-regulated and that intracellular amino acids and urea levels are altered in response to GDE5 inhibition. Finally, we showed that reduction of GDE5 expression increased LDH release from preadipocytes. These observations indicate that decreased GDE5 expression can suppress adipocyte differentiation not through the PC pathway but possibly by intracellular GPC accumulation. These results provide insight into the roles of mammalian GDEs and their dependence upon osmotic regulation by altering intracellular GPC levels. PMID- 30462541 TI - Pathophysiology of stroke: what do cells of the neurovascular unit have to do with it? PMID- 30462542 TI - Appropriate Timing for Follow-Up CT Imaging for Stable Lung CT Screening Reporting and Data System Category 3 Lesions Identified at Baseline Low-Dose CT. PMID- 30462543 TI - Hallway Conversations in PhysicsWhat Should a Radiologist Know About Artificial Intelligence? PMID- 30462544 TI - Nonclassifiable Nodules in the Korean Society of Thyroid Radiology TIRADS and Size Threshold for Fine-Needle Aspiration. PMID- 30462545 TI - Reply to "Nonclassifiable Nodules in Korean Society of Thyroid Radiology TIRADS and Size Threshold of Fine-Needle Aspiration". PMID- 30462546 TI - Medicolegal-Malpractice and Ethical Issues in RadiologyShould I Settle My Malpractice Lawsuit or Insist on Defending It in a Jury Trial? PMID- 30462547 TI - Authorship Revisited: Part 3, From First Decision to Final Decision. PMID- 30462548 TI - Reply to "Appropriate Timing for Follow-Up CT Imaging for Stable Lung CT Screening Reporting and Data System Category 3 Lesions Identified at Baseline Low Dose CT". PMID- 30462549 TI - The PROFILE of assessment program for internal medicine internship of Sun Yat-Sen University. AB - OBJECTIVE: To reflectively look at the present methods by which the clinical competence of 5th-year medical students (i.e. interns) in Sun Yat-Sen University (SYSU) are assessed upon finishing internship rotation in internal medicine (IM). METHODS: Current procedures for the competence assessment of end-of-rotation IM interns in the First Affiliated Hospital of SYSU were reviewed, along with a point-by-point appraisal based on the PROFILE approach to structured assessment, and, whenever possible, suggestions for future improvement. RESULTS AND DISCUSSIONS: On a scale of 1-10, with 10 being the best or the most ideal, our marks for current methods to assess end-of-rotation IM interns in terms of being Programmatic, Real-World, Outcome-based, Formative, Impactful, Learner-engaged, and Evaluation-guaranteed were 7, 9, 3, 4, 6, 8, and 1, respectively. The strengths, weaknesses as well as potential solutions in each of the seven aspects are also discussed separately. CONCLUSIONS: Current assessment program for IM internship is strong in being programmatic, real-world, educationally impactful and learner engaged, and has room for further improvement in its time-based arrangements, relative shortage of feedback provision, as well as a systematic lack of quality control measures. PMID- 30462550 TI - Longer prehospital time was not associated with mortality in major trauma. A retrospective cohort study. AB - OBJECTIVE: To determine the association between prehospital time and outcomes in adult major trauma patients, transported by ambulance paramedics. METHODS: A retrospective cohort study of major trauma patients (Injury Severity Score >15) attended by St John Ambulance paramedics in Perth, Western Australia, who were transported to hospital between 1st January 2013 and 31st December 2016. Inverse probability of treatment weighting (IPTW) using the propensity score was performed to limit selection bias and confounding. The primary outcome was 30-day mortality and the secondary outcome was the length of hospital stay (LOS) for 30 day survivors. Multivariate logistic and log-linear regression analyses with IPTW were used to determine if prehospital time of more than the one hour (from receipt of the emergency call to arrival at hospital) or any individual prehospital time interval (response, on-scene, transport or total time) was associated with 30-day mortality or LOS. RESULTS: A total of 1,625 major trauma patients were included and 1,553 included in the IPTW sample. No significant association between prehospital time of one hour and 30-day mortality was found (adjusted odds ratio 1.10, 95% confidence interval (CI) 0.71-1.69). No association between any individual prehospital time interval and 30-day mortality was identified. In the 30-day survivors, one-minute increase of on-scene time was associated with 1.16 times (95% CI 1.03-1.31) longer LOS. CONCLUSION: Longer prehospital times were not associated with an increased likelihood of 30-day mortality in major trauma patients transported to hospital by ambulance paramedics. We found no evidence to support the hypothesis that prehospital time longer than one hour resulted in an increased risk of 30-day mortality. However, longer on-scene time was associated with longer hospital LOS (for 30-day survivors). Our recommendation is that prehospital care is delivered in a timely fashion and delivery of the patient to hospital is reasonably prompt. PMID- 30462551 TI - Price check on A(i)s(l)e 13: Investigation of interleukin-13 activity in cardiac regeneration. PMID- 30462552 TI - Downregulation of GATA6 in mTOR-inhibited human aortic endothelial cells: effects on TNFalpha-induced VCAM-1 expression and monocytic cell adhesion. AB - Increased expression of vascular cell adhesion molecule-1 (VCAM-1) on aortic endothelium is an early marker of atherogenesis, promoted in part by elevated inflammatory cytokines such as TNFalpha. Mammalian target of rapamycin (mTOR) is a ubiquitous signaling molecule that has been considered to contribute to diverse cellular processes through mTOR complex 1 (mTORC1) or complex 2 (mTORC2). This study aimed to elucidate the role of mTOR signaling in TNFalpha-induced VCAM-1 expression by arterial endothelium. Primary human aortic endothelial cells (HAEC) were treated with low-dose (0.1ng/mL) TNFalpha and VCAM-1 expression measured by real time quantitative PCR, Western blot, and flow cytometry. Inhibition of mTOR through siRNA-mediated depletion, or treatment with chemical inhibitors rapamycin or torin 1, suppressed VCAM1 transcription which translated to inhibition of VCAM 1 surface expression by HAEC and concomitant decreased adhesion of monocytes. A promoter luciferase assay and chromatin immunoprecipitation indicated that mTOR regulated VCAM1 transcription through a mechanism involving transcription factor GATA6. Activation of PKCalpha and an increase in microRNA(miRNA)-200a-3p expression, caused by mTOR inhibition but not disruption of mTORC1 or mTORC2 singly or together, decreased TNFalpha-induced GATA6 expression and its enrichment at the VCAM1 promoter. In conclusion, mTOR inhibition activates PKCalpha independently of disruption of mTORC1 and/or mTORC2, which challenges the conventional wisdom regarding mTOR signaling. Moreover, mTOR signals through transcriptional and post-transcriptional mechanisms to elicit maximal cytokine induced endothelial inflammation that precedes atherosclerosis. PMID- 30462553 TI - Inhibitory Effects of Growth Differentiation Factor 11 on Autophagy Deficiency induced Dedifferentiation of Arterial Smooth Muscle Cells. AB - Growth differentiation factor (GDF11) has been reported to reverse age-related cardiac hypertrophy in mice and cause youthful regeneration of cardiomyocytes. The present study attempted to test a hypothesis that GDF11 counteracts the pathologic dedifferentiation of mouse carotid arterial smooth muscle cells (CASMCs) due to deficient autophagy. By real-time RT-PCR and Western blot analysis, the exogenously administrated GDF11 was found to promote CASMCs differentiation with increased expression of various differentiation markers, alpha-SMA, myogenin, MyoD, and MyHC as well as decreased expression of dedifferentiation markers, vimentin and proliferating cell nuclear antigen (PCNA). Upregulation of the GDF11 gene by trichostatin A (TSA) or specific CRISPR cas9 activating plasmids also stimulated the differentiation of CASMCs. Either GDF11 or TSA treatment blocked 7-Ketocholesterol (7-Ket)-induced CASMC dedifferentiation and autophagosome accumulation and lysosome inhibitor bafilomycin (Baf)-induced dedifferentiation and autophagosome accumulation. Moreover, in CASMCs from mice lacking the CD38 gene (CD38-/-), an autophagy deficiency model in CASMCs, GDF11 also inhibited their phenotypic transition to dedifferentiation status. Correspondingly, TSA treatment was shown to decrease GDF11 expression and reverse CASMC dedifferentiation in the partial ligated carotid artery (PLCA) of mice. The inhibitory effects of TSA on dedifferentiation of CASMCs were accompanied by reduced autophagosome accumulation in the arterial wall, which was accompanied by attenuated neointima formation in PLCA. It is concluded that GDF11 promote CASMC differentiation and prevent the phenotypic transition of these cells induced by autophagosome accumulation during different pathological stimulations such as Western diet, lysosome function deficiency, and inflammation. PMID- 30462554 TI - Risankizumab for the treatment of moderate to severe psoriasis. AB - INTRODUCTION: Psoriasis is a chronic inflammatory skin disorder pathogenically mediated by multiple cytokines, including interleukin (IL)-23, IL-17, and TNF. An emerging class of therapeutics that selectively blocks IL-23 has been developed. Among these new agents, risankizumab is now being investigated in phase III clinical trials, and the preliminary data are promising in inducing an excellent clinical response. Areas covered: This review aims to describe the pathogenic role of IL-23 in psoriasis and to collect clinical data related to the efficacy and safety of risankizumab, an anti-IL-23p19 agent, in the treatment of psoriasis. Expert opinion: Risankizumab showed high response rates in reaching complete or almost complete clearance of psoriasis. When compared to other similarly effective drugs, it may show some advantages related to its mechanism of action (direct blockade of the main pathogenic pathway), safety (no impact on the immune surveillance against Candida infection), therapeutic regimen (every-12 week injections), and effectiveness in the treatment of immune-mediated psoriasis comorbid conditions, such as psoriatic arthritis and Crohn's disease. PMID- 30462555 TI - Cytokines: the yin and yang of vitiligo pathogenesis. AB - INTRODUCTION: Dysregulation of melanocyte function is associated with vitiligo, an idiopathic autoimmune hypopigmentary skin disorder, caused by the selective destruction of melanocytes. Cytokines, the key mediators of immune response, which are pivotal in maintaining immune homeostasis, are crucial in vitiligo pathogenesis. Several studies indicate that there is an imbalance between pro- and anti-inflammatory cytokines in the skin and serum of vitiligo patients. Areas covered: In this comprehensive review, we have summarized the correlation of cytokine imbalance and vitiligo pathogenesis, its role in melanocyte biology, and its impact on vitiligo treatment. We have integrated various published reports on the levels of major cytokines from skin and serum samples of vitiligo patients. We have also discussed the role of endoplasmic reticulum and oxidative stress on cytokine imbalance and vice versa leading to destruction of melanocytes. Expert commentary: The review reflects that dysregulation of cytokines is multifactorial, ranging from genetic predisposition to altered protein expression relevant to vitiligo pathogenesis. We emphasize that cytokine imbalance in systemic and skin microenvironment plays a crucial role in vitiligo pathogenesis and has promising potential as therapeutic targets for vitiligo. PMID- 30462556 TI - Fluoxetine oral treatment discloses 5-HT1D receptor as vagoinhibitor of the cardiac cholinergic neurotransmission in rat. AB - Although depression and cardiovascular diseases are related, the role of antidepressants, as fluoxetine (increasing serotonin levels), within cardiac regulation remains unclear. We aimed to determine whether fluoxetine modifies the pharmacological profile of serotonergic influence on vagal cardiac outflow. Rats were treated with fluoxetine (10 mg/kg.day; p.o.) for 14 days or equivalent volumes of drinking water (control group); then, they were pithed and prepared for vagal stimulation. Bradycardic responses were obtained by electrical stimulation of the vagal fibers (3, 6, and 9 Hz) or i.v. acetylcholine (ACh; 1, 5, and 10 ug/kg). i.v. administration of 5-hydroxytryptamine (5-HT; 10 and 50 ug/kg) inhibited the vagally-induced bradycardia. 5-CT (5-HT1/7 agonist) and L 694,247 (5-HT1D agonist) mimicked the serotonin inhibitory effect while alpha methyl-5-HT (5-HT2 agonist) was devoid of any action. SB269970 (5-HT7 antagonist) did not abolish 5-CT inhibitory action on the electrically induced bradycardia. Pretreatment with LY310762 (5-HT1D antagonist) blocked the effects induced by L 694,247 and 5-CT. 5-HT and 5-CT failed to modify the bradycardia induced by exogenous ACh. Our outcomes suggest that fluoxetine treatment modifies 5-HT modulation on heart parasympathetic neurotransmission in rats, evoking inhibition of the bradycardia via prejunctional 5-HT1D in pithed rats. PMID- 30462557 TI - Omalizumab treatment in a 12 year-old girl with chronic spontaneous urticaria. AB - Omalizumab is a recombinant humanized IgG monoclonal antibody, which binds the Fc region of free IgE prevent its binding to its high-affinity receptor (FcepsilonR1) on mast cells and basophils. Omalizumab was approved as add-on therapy for moderate-to-severe persistent allergic asthma and for patients with chronic spontaneous urticaria resistant to antihistamine treatment. This article reports effective and safe treatment of a 12 years old girl with add-on omalizumab. PMID- 30462558 TI - Crosstalk between TF/FVIIa and EGFR signaling in colorectal cancer cells. AB - TF/FVIIa (Tissue Factor/Active Coagulation factor VII) and EGFR (Epidermal Growth Factor Receptor) signaling both promote malignant progression of colorectal cancer. However, the crosstalk of these two signaling pathways in human colorectal cancer cells remains unclear. Here we detected the changes of mRNA profile in human colorectal cancer cell SW620 exposed to FVIIa. Microarray showed that mRNA levels of EGFR ligands were significantly upregulated. Western blot analysis confirmed the upregulation of EGFR ligands and the phosphorylation of EGFR at tyrosine-845 in colorectal cancer cells exposed to FVIIa. However, knockdown of TF by RNAi could block the upregulation of EGFR ligands induced by FVIIa stimulation. On the other hand, the expression of components of TF/FVIIa signaling was significantly upregulated in LoVo cells stimulated by EGF. However, the crosstalk between the two signaling pathways could not be detected in HT-29 colon cancer cells bearing wild-type KRAS. Taken together, our study suggest that the crosstalk between TF/FVIIa and EGFR signaling pathways in colon cancer cells depends on KRAS mutation. PMID- 30462559 TI - The Jakinibs in systemic lupus erythematosus: progress and prospects. AB - INTRODUCTION: Multiple pathways are involved in the pathogenesis of systemic lupus erythematosus (SLE). The Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway mediates the intracellular signals of more than 60 cytokines, growth factors and hormones from the type I/II cytokine receptors. Dysregulation of the cytokines is a hallmark of SLE; inhibition of downstream signaling mediated by the JAKs is an attractive therapeutic option. Areas covered: This article reviews the preliminary data concerning the efficacy of the JAK inhibitors (Jakinibs) in SLE. JAK inhibition has shown promise in murine lupus dermatitis and nephritis. Ex-vivo studies of human SLE have demonstrated the effect of JAK1/2 inhibition on the activation of the STAT proteins and autoantibody production from B cells. A Phase II trial reported modest efficacy of baricitinib in improving synovitis in SLE patients. Expert opinions: Inhibition of the JAK-STAT pathway is an attractive therapeutic option. The convenience of oral administration and lower production cost of the Jakinibs could replace the biological agents in the treatment hierarchy of autoimmune inflammatory diseases. Additional clinical data are needed; results of ongoing studies of the newer Jakinibs in cutaneous and non-life-threatening lupus are eagerly awaited. PMID- 30462560 TI - Chronic spontaneous urticaria treated with omalizumab: report of two cases. AB - Chronic spontaneous urticaria (CSU) is a relatively common skin disease whose etiopathogenesis, as well as other factors influencing disease manifestations, are not fully understood. Mast cell function is recognised as having a central role in CSU signs and symptoms. Therapeutic options are limited; a number of drugs, recommended by international guidelines for the management of urticaria, lack regulatory approval for CSU and are prescribed off label. Omalizumab, a recombinant humanized anti IgE antibody, has recently received the approval for CSU treatment in Europe after an appropriate clinical development. Two case reports, that describes our encouraging experience with this therapeutic option in a real-life setting are discussed and deeply investigate the different scenario for the omalizumab use. In both cases, a complete remission of CSU symptoms after omalizumab treatment are demonstrated. Moreover, 6 months therapy gave the better results, whit a relapse, in one subject, 1 month after discontinuing omalizumab. Accordingly, a better understanding of long-term safety and efficacy should be needed to allow long-term administration in responding patients through a changing in prescription rules. PMID- 30462561 TI - Assessing Sleep-Related Safety Behaviors: Adaptation and Validation of a French Version of the Sleep-Related Behaviors Questionnaire in a Nonclinical Sample. AB - OBJECTIVE/BACKGROUND: Safety behaviors play a prominent role in the development and maintenance of insomnia. The Sleep-Related Behaviors Questionnaire (SRBQ) is a self-report questionnaire designed to assess safety behaviors employed to cope with fatigue or to improve sleep. Despite its frequent use in insomnia, no systematic psychometric validation of the SRBQ has been conducted; its factor structure has never been explored. Furthermore, there is no French version of this scale. The goal of this study was to empirically validate a French version of the SRBQ. PARTICIPANTS/METHODS: A total of 539 French-speaking community dwelling participants from the general population completed a face-to-face clinical interview to determine insomnia disorder against DSM-5 criteria and several questionnaires including the French SRBQ. RESULTS: SRBQ items with poor psychometric properties were removed, thus leading to a 20-item version (SRBQ 20). Exploratory factor analysis and parallel analysis revealed three distinct factors with good internal consistency. The results supported the internal temporal stability of the SRBQ-20. The construct validity of that instrument was underpinned by correlations obtained with various measures of insomnia and related constructs. Adequate discriminative validity was established by comparing individuals with insomnia and individuals without insomnia. CONCLUSIONS: This study demonstrated that the French version of the SRBQ-20 has good psychometric properties. PMID- 30462562 TI - Dual-target MDM2/MDMX inhibitor increases the sensitization of doxorubicin and inhibits migration and invasion abilities of triple-negative breast cancer cells through activation of TAB1/TAK1/p38 MAPK pathway. AB - Triple-negative breast cancer (TNBC) has a poor prognosis mainly due to insensitivity or resistance to standard anthracycline- and taxane-based chemotherapy, urgently calling for new adjuvants to reverse drug resistance. Dual target murine double minute 2 (MDM2) and murine double minute X (MDMX) inhibitor has been proved to play a critical part against cancer, particularly focusing on the tremendous potential to enhance the efficacy of doxorubicin (DOX), however little was reported in TNBC. In the present study, we investigated the synergistic antitumor effect of the MDM2/MDMX inhibitor with DOX using three TNBC cell lines, two in situ transplantation tumor models and 214 clinical samples. We observed that the MDM2/MDMX inhibitor combined with DOX could not only inhibit cell vitality and migration and invasion abilities, but also highly inhibit tumor growth in TNBC nude mice. Besides, co-treatment of MDM2/MDMX inhibitor and DOX suppressed epithelial to mesenchymal transition (EMT) through increasing the TAK1 binding protein 1 (TAB1), transforming growth factor beta-activated kinase 1 (TAK1) and p38 mitogen-activated protein kinase (MAPK) expression. Small interfering RNA-mediated TAB1 knockdown induced the EMT, desensitized cells to DOX and enhanced the migration and invasion abilities. High MDM2/MDMX expression was positively associated with weak TAB1 expression in 214 TNBC tumor tissues confirmed by immumohistochemical staining and MDM2/MDMX/TAB1 expression was significantly related to TNBC patient survival. These findings indicate that dual target MDM2/MDMX inhibitor could increase the sensitization of doxorubicin and inhibit migration and invasion abilities in TNBC cells through p38 MAPK pathway activation caused EMT suppression and hence could be useful in TNBC treatments in future. PMID- 30462563 TI - Experience implementing a university-based mass immunization program in response to a Meningococcal B outbreak. AB - Neisseria meningitidis serogroup B (MenB) has caused several recent outbreaks of meningococcal disease on US college campuses. In January 2015, a case of MenB was reported at a university in Oregon, culminating in an outbreak with a total of 7 cases (including 1 fatality) identified over a 5-month period. In response to the outbreak, the university organized a mass immunization campaign with 4 "opt-in" immunization clinics. The preparation, challenges, and resources required for organization and implementation of a mass immunization program in response to an outbreak at a large public university are discussed herein. Based on the logistical challenges as well as resource expenditures associated with planning and executing a mass immunization effort, this experience illustrates that proactive, routine immunization of incoming students is the best strategy for MenB outbreak prevention. PMID- 30462564 TI - Successful treatment of a BRAF V600E-mutant extracranial metastatic anaplastic oligoastrocytoma with vemurafenib and everolimus. AB - BACKGROUND: Extracranial metastasis is a rare phenomenon of anaplastic oligoastrocytoma. When patients progress after comprehensive treatment, there is often no effective treatment. Rapid development of gene detection technology makes precision treatment of glioma possible. PATIENT AND METHODS: A 22-year-old girl was firstly diagnosed with anaplastic oligoastrocytoma WHO grade III-IV in 2014, and progressed rapidly after chemoradiotherapy in multiple extraneural lesions in 2016. She was expected to have a short life and Next-Generation Sequencing (NGS) was applied. RESULTS: Mutation of BRAF (V600E) was reported by 1st NGS and oral vemurafenib stabilized her disease for 6 months. PIK3CA was reported by 2nd NGS after her progression of vemurafenib. The oral administration of everolimus together with vemurafenib stabilized her disease for another 6 months. However, the patient died due to the rapid progression of the disease on 24 February 2018. CONCLUSION: We successfully treated a BRAF V600E-mutated anaplastic oligoastrocytoma with multiple extraneural metastases with vemurafenib and everolimus. For late-staged patients who have no clear and effective treatment plan, NGS may serve as an effective option. PMID- 30462565 TI - Preventing and treating kidney disease in patients with type 2 diabetes. AB - INTRODUCTION: Chronic kidney disease (CKD) represents a huge burden in patients with type 2 diabetes (T2DM). This review therefore has the aim of assessing the add-on value of new glucose-lowering agents compared or combined with inhibitors of the renin angiotensin aldosterone system (RAAS) on renal outcomes in T2DM patients. Areas covered: This article first summarizes the results reported with RAAS inhibitors, mainstay of nephroprotection in T2DM with albuminuria. Second, it describes the positive results with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and, even more impressive, sodium-glucose cotransporter type 2 inhibitors (SGLT2is). Third, besides the potential of combined therapies, it briefly considers some new approaches currently in development. Expert opinion: RAAS inhibitors exert renoprotective effects beyond their blood pressure lowering effects while SGLT2is, and possibly GLP-1RAs, exert nephroprotection independently of their glucose-lowering activity. These effects were demonstrated not only on surrogate endpoints such as albuminuria and estimated glomerular filtration rate decline, but also on hard endpoints, including progression to end stage renal disease requiring replacement therapy. The underlying mechanisms are different and potentially complementary on glomerular hemodynamics, arguing for combined therapies. Nevertheless, there is still room for new emerging drugs to tackle CKD in T2DM. PMID- 30462566 TI - Spleen reactivity during incremental ascent to altitude. AB - INTRODUCTION: The spleen contains a reservoir of red blood cells that are mobilized into circulation when under physiological stress. Despite the spleen having an established role in compensation to acute hypoxia, no previous work has assessed the role of the spleen during ascent to high altitude. METHODS: Twelve participants completed 2 minutes of handgrip exercise at 30% of maximal voluntary contraction at 1045m, 3440m, and 4240m. In a subset of eight participants, an infusion of phenylephrine hydrochloride was administered at a dosage of 30 ug/l of predicted blood volume at each altitude. The spleen was imaged by ultrasound via a 2-5.5 MHz curvilinear probe. Spleen volume was calculated by the prolate ellipsoid formula. Finger capillary blood samples were taken to measure hematocrit. Spleen images and hematocrit were taken both before and at the end of both handgrip and phenylephrine infusion. RESULTS: No changes in resting spleen volume were observed between altitudes. At low altitude, the spleen contracted in response to handgrip (272.8+/-102.3 vs 249.6+/-105.7 ml, p=0.009), leading to an increase in hematocrit (42.6+/-3.3% vs 44.3+/-3.3%, p=0.023) but did not contract nor increase hematocrit at the high-altitude locations. Infusion of phenylephrine led to spleen contraction at all altitudes, but only lead to an increase in hematocrit at low altitude. CONCLUSION: These data reveal that the human spleen may not contribute to acclimatization to chronic hypoxia, contrary to its response to acute sympathoexcitation. These results are explained by alterations in spleen reactivity to increased sympathetic activation at altitude. PMID- 30462567 TI - Curcumin Improves Exercise Performance of Mice with Coronary Artery Ligation Induced HFrEF: Nrf2 and Antioxidant Mechanisms in Skeletal Muscle. AB - A hallmark of chronic heart failure with low ejection fraction (HFrEF) is exercise intolerance. We hypothesized that reduced expression of nuclear factor E2-related factor 2 (Nrf2) in skeletal muscle contributes to impaired exercise performance. We further hypothesized that curcumin (Cur), a Nrf2 activator, would preserve or increase exercise capacity in HF. Experiments were carried out in mice with coronary artery ligation-induced HFrEF. Cur was deliveried by a subcutaneous osmotic minipump at a dose of 50 mg/kg/day for 8 weeks. In vivo, in situ, and in vitro experiments were employed to evaluate exercise capacity, muscle function, and molecular mechanisms. We found that: (1) the maximal speed, running distance to exhaustion, and limb grip force were significantly lower in HFrEF mice compared to sham. Cur-treated HF mice displayed enhanced exercise performance compared to vehicle-treated HF mice; (2) Both soleus (Sol) and extensor digitorum longus (EDL) muscles of HFrEF mice exhibited reduced force and rapid fatigue, which were ameliorated by Cur. (3) Protein expression of Nrf2, HO 1, SOD2, myogenin, and MyoD were significantly lower but total ubiquitinated proteins, MURF1, and Atrogen-1 were higher in Sol and EDL of HFrEF compared to sham mice, whereas these alterations in Nrf2 signaling and antioxidant defenses in HFrEF were attenuated by Cur. Cur had no effect on cardiac function per se in mice with severe HFrEF. These data suggest that impaired Nrf2 signaling intrinsic to skeletal muscle contributes to exercise intolerance in HFrEF. Skeletal muscle Nrf2 should be considered as a novel therapeutic target in severe HF. PMID- 30462568 TI - Intrinsic foot muscles contribute to elastic energy storage and return in the human foot. AB - The human foot is uniquely stiff to enable forward propulsion, yet also possesses sufficient elasticity to act as an energy store, recycling mechanical energy during locomotion. Historically this dichotomous function has been attributed to the passive contribution of the plantar aponeurosis. However, recent evidence highlights the potential for muscles to actively modulate the energetic function of the foot. Here we test the hypothesis that the central nervous system can actively control the foot's energetic function, via activation of the muscles within the foot's longitudinal arch. We used a custom-built loading apparatus to deliver cyclical loads to human feet in-vivo, in order to deform the arch in a manner similar to that observed in locomotion. We recorded foot motion and forces, alongside muscle activation and ultrasound images from flexor digitorum brevis (FDB), an intrinsic foot muscle that spans the arch. When active, the FDB muscle fascicles contracted in an isometric manner, facilitating elastic energy storage in the tendon, in addition to the energy stored within the plantar aponeurosis. We propose that the human foot is akin to an active suspension system for the human body, with mechanical and energetic properties that can be actively controlled by the central nervous system. PMID- 30462569 TI - Relationship between climate and hemodynamics according to echocardiography. AB - Studies performed in controlled laboratory conditions have shown that environmental thermal application may induce various circulatory changes. We aimed to demonstrate the effect of local climate on hemodynamics according to echocardiography . Echocardiographic studies conducted in ambulatory patients, 18 years of age or older, between January 2012 and July 2016 at our medical center were retrospectively included in case climate data on the day of the echocardiogram were available. Discomfort index, apparent temperature, temperature-humidity index, and thermal index were computed. Echocardiograms conducted in hotter months (June-November) were compared to those done in colder months (December-May). The cohort consisted of 11,348 individuals, 46.2% females, and mean age 57.9 (+/-18.1) years. Climate indices correlated directly with stroke volume (r=0.039) and e' (lateral r=0.047; septal r=0.038), and inversely with systolic pulmonary artery pressure (SPAP; r=-0.038) (all p-values<0.05). After adjustment for age and gender, echocardiograms conducted during June November had a lower chance to show e' septal<7cm/s (OR 0.88, 95% CI 0.78-0.98, p=0.017) and SPAP>40mmHg (OR 0.81, 95% CI 0.67-0.99, p=0.04) compared to those conducted in other months. Climate may affect hemodynamics according to echocardiographic assessment in ambulatory patients. PMID- 30462570 TI - A delayed HIV infection model with apoptosis and viral loss. AB - In this paper, a delayed human immunodeficiency virus (HIV) model with apoptosis of cells has been studied. Both immunological and intracellular delay have been incorporated to make the model more relevant. Firstly, the model has been investigated using local stability analysis. Next, the global stability analysis of steady states has been performed. The stability switch criteria taking the delay as the bifurcating parameter, leading to Hopf bifurcation has been studied. The transition of the system from order to chaos has been explored, and the analytical results have been verified by numerical simulations. The results thus can be used to describe the extensive dynamics exhibited by the model introduced in this article. The effects of apoptosis on viral load has been studied in the model numerically. PMID- 30462571 TI - Factors associated with time to breast cancer diagnosis and treatment in unscreened women in Portugal. AB - Delays in detection, diagnosis and treatment may lead to poorer prognosis in women with breast cancer. We quantified time intervals from first detection (FD) to diagnosis (D) and first treatment (FT) and identified associated factors. We studied 282 patients diagnosed with breast cancer during 2012 at the Breast Clinic of the Portuguese Institute of Oncology in Porto, Portugal using face-to face interview and medical records. Associations of sociodemographic and clinical characteristics with time intervals was computed using adjusted percentage differences (adjPD) after logarithmic transformation, odds ratios (adjOR) for comparing the highest and lowest thirds of the distribution and 95 percent confidence intervals (CI) for both measures, using linear and logistic regression, respectively. The median times between FD and D and FT were 31 and 44 days, respectively. Significantly longer periods between FD and D were found in symptomatic women (adjPD = 99.5, 95 percent CI: 37.1, 190.0; adjOR = 3.16, 95 percent CI: 1.57, 6.33). More advanced stage was associated with shorter intervals between D and FT (adjPD = -33.8, 95 percent CI: -44.2, -21.5; adjOR = 0.14, 95 percent CI: 0.05, 0.34). Although some differences according to clinical characteristics were observed, they did not seem to translate into inequities in access to public healthcare in this group of women. PMID- 30462572 TI - Effects of cardiomyopathy-linked mutations k15n and r21h in tropomyosin on thin filament regulation and pointed-end dynamics. AB - Missense mutations K15N and R21H in striated muscle tropomyosin are linked to dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), respectively. Tropomyosin, together with the troponin complex, regulates muscle contraction and, along with tropomodulin and leiomodin, controls the uniform thin filament lengths crucial for normal sarcomere structure and function. We used Forster resonance energy transfer to study effects of the tropomyosin mutations on the structure and kinetics of the cardiac troponin core domain associated with the Ca2+-dependent regulation of cardiac thin filaments. We found that the K15N mutation desensitizes thin filaments to Ca2+ and slows the kinetics of structural changes in troponin induced by Ca2+ dissociation from troponin, while the R21H mutation has almost no effect on these parameters. Expression of the K15N mutant in cardiomyocytes decreases leiomodin's thin filament pointed-end assembly but does not affect tropomodulin's assembly at the pointed end. Our in vitro assays show that the R21H mutation causes a two-fold decrease in tropomyosin's affinity for F-actin and affects leiomodin's function. We suggest that the K15N mutation causes DCM by altering Ca2+-dependent thin filament regulation, and that one of the possible HCM-causing mechanisms by the R21H mutation is through alteration of leiomodin's function. PMID- 30462573 TI - An endogenous chemorepellent directs cell movement by inhibiting pseudopods at one side of cells. AB - Eukaryotic chemoattraction signal transduction pathways, such as those used by Dictyostelium discoideum to move towards cAMP, use a G protein-coupled receptor to activate multiple conserved pathways such as PI3 kinase/Akt/PKB to induce actin polymerization and pseudopod formation at the front of a cell, and PTEN to localize myosin II to the rear of a cell. Relatively little is known about chemorepulsion. We previously found that AprA is a chemorepellent protein secreted by Dictyostelium cells. Here we used 29 cell lines with disruptions of cAMP and/or AprA signal transduction pathway components, and delineated the AprA chemorepulsion pathway. We find that AprA uses a subset of chemoattraction signal transduction pathways including Ras, protein kinase A, TOR, phospholipase A, and ERK1, but does not require the PI3 kinase/Akt/PKB and guanylyl cyclase pathways to induce chemorepulsion. Possibly as a result of not using the PI3 kinase/Akt/PKB pathway and guanylyl cyclases, AprA does not induce actin polymerization or increase the pseudopod formation rate, but rather appears to inhibit pseudopod formation at the side of cells closest to the source of AprA. PMID- 30462574 TI - Exercise effects on mood, and its associations with self-regulatory skills, self efficacy, and eating changes during the year following weight-loss treatment. AB - Maintaining weight loss beyond an initial year of behavioral treatment is of concern, and understanding interrelationships of theory-based psychosocial correlates is minimal. Although exercise is universally suggested, its indirect impacts on long-term nutritional changes are unclear. Data from women with obesity (N= 129), who participated in the treatment groups of two initial trials of a new social cognitive theory-based weight-loss protocol during 2016-2017, were incorporated. The intervention emphasized exercise adherence for two months prior to the next 12 months of biweekly meetings for nutritional change. Effects of exercise-induced changes in mood, and the role of self-regulatory skills in facilitating self-efficacy and improved eating 12-24 months after treatment initiation, were assessed. Change in mood significantly moderated changes in self regulation for controlled eating by exercise-related self-regulation. During Months 12 to 24, changes in both fruit/vegetable and sweets intake, by self regulation for eating change, was significantly mediated by change in self efficacy for controlled eating. Mood change from Months 12 to 24 was significantly associated with change in exercise, with indications that maintaining an equivalent of three days/week had critical value. Findings suggest the importance of bolstering self-regulatory skill usage beyond an initial year of treatment in women. PMID- 30462575 TI - Cellular tension encodes local Src-dependent differential beta1 and beta3 integrin mobility. AB - Integrins are transmembrane receptors that have a pivotal role in mechanotransduction processes by connecting the extracellular matrix to the cytoskeleton. Although it is well established that integrin activation/inhibition cycles are due to highly dynamic interactions, whether integrin mobility depends on local tension and cytoskeletal organization remains surprisingly unclear. Using an original approach combining micropatterning on glass substrates to induce standardized local mechanical constraints within a single cell with temporal image correlation spectroscopy (tICS), we measured the mechanosensitive response of integrin mobility at the whole cell level and in adhesion sites under different mechanical constraints. Contrary to beta1 integrins, high tension increases beta3 integrin residence time in adhesive regions. Chimeric integrins and structure-function studies revealed that the ability of beta3 integrins to specifically sense local tensional organization is mostly encoded by its cytoplasmic domain and is regulated by tuning the affinity of its NPXY domains through phosphorylation by Src family kinases (SFKs). PMID- 30462576 TI - Selective defects in gene expression control genome instability in yeast splicing mutants. AB - RNA processing mutants have been broadly implicated in genome stability but mechanistic links are often unclear. Two predominant models have emerged: one involving changes in gene expression that perturb other genome maintenance factors, and another in which genotoxic DNA:RNA hybrids, called R-loops, impair DNA replication. Here we characterize genome instability phenotypes in yeast splicing factor mutants and find that mitotic defects, and in some cases R-loop accumulation, are causes of genome instability. In both cases, alterations in gene expression, rather than direct cis effects are likely to contribute instability. Genome instability in splicing mutants is exacerbated by loss of the spindle-assembly checkpoint protein Mad1. Moreover, removal of the intron from the alpha-tubulin gene TUB1 restores genome integrity. Thus, differing penetrance and selective effects on the transcriptome can lead to a range of phenotypes in conditional mutants of the spliceosome, including multiple routes to genome instability. PMID- 30462577 TI - Interphase cohesin regulation ensures mitotic fidelity after genome reduplication. AB - To ensure faithful genome propagation, mitotic cells alternate one round of chromosome duplication with one round of chromosome separation. Chromosome separation failure thus causes genome reduplication, which alters mitotic chromosome structure. Such structural alterations are well-documented to impair mitotic fidelity following aberrant genome re-duplication, including in diseased states. In contrast, we recently showed that naturally occurring genome re duplication does not alter mitotic chromosome structure in Drosophila papillar cells. Our discovery raised the question of how a cell undergoing genome reduplication might regulate chromosome structure to prevent mitotic errors. Here, we show that papillar cells ensure mitotic fidelity through interphase cohesin regulation. We demonstrate a requirement for cohesins during programmed rounds of papillar genome reduplication known as endocycles. This interphase cohesin regulation relies on cohesin release but not cohesin cleavage, and depends on the conserved cohesin regulator Pds5. Our data suggest that a distinct form of interphase cohesin regulation ensures mitotic fidelity after genome reduplication. PMID- 30462578 TI - Enhanced shortcut nitrogen removal and metagenomic analysis of functional microbial communities in a double sludge system treating ammonium-rich wastewater. AB - Biological nitrogen removal processes based on partial nitrification are promising for ammonium-rich wastewater treatment. In this study, a partial nitrification-denitrification double sludge system was applied to treat synthetic ammonium-rich wastewater. Metagenomic analysis of functional genes and metabolic pathways was conducted, also with the evaluation of system performance and nitrous oxide (N2O) emission. In the nitrifying sequencing batch reactor (SBRPN), the removal percentage of ammonium nitrogen reached to 99.98% with a high nitritation efficiency of 93.24%, and the N2O emission factor was 0.88%. In the denitrifying sequencing batch reactor (SBRDN), there was almost no nitrate nitrogen and nitrite nitrogen in the effluent, and the maximum N2O emission was 0.078 mg N/L. The dominant ammonia oxidizing bacteria was Nitrosomonas in SBRPN (13.6%), and the main potential denitrifiers in SBRDN were Thauera (14.6%), an uncultured genus in the Comamonadaceae family (4.0%), an uncultured genus in Rhodocyclaceae family (2.4%) and Comamonas (1.1%). Metagenomic analysis revealed that amo mainly distributed in Nitrosomonas eutropha (38.3%), Nitrosomonas europaea (27.1%), Nitrosomonas sp. GH22 (20.5%) and Nitrosomonas sp. TK794 (15.0%), and Bacteroidetes had the N2O reduction potential in SBRPN. PMID- 30462579 TI - ErbB4 tyrosine kinase inhibition impairs neuromuscular development in zebrafish embryos. AB - Tyrosine kinase inhibitors are widely used in the clinic, but limited information is available about their toxicity in developing organisms. Here, we tested the effect of tyrosine kinase inhibitors targeting the ErbB receptors for their effects on developing zebrafish ( Danio rerio) embryos. Embryos treated with wide spectrum pan-ErbB inhibitors or erbb4a-targeting antisense oligonucleotides demonstrated reduced locomotion, reduced diameter of skeletal muscle fibers, reduced expression of muscle-specific genes, as well as reduced motoneuron length. The phenotypes in the skeletal muscle, as well as the defect in the motility, were rescued both by microinjection of human ERBB4 mRNA, and by transposon-mediated muscle-specific ERBB4 overexpression. The role of ErbB4 in regulating motility was further controlled by targeted mutation of the endogenous erbb4a locus in the zebrafish genome by CRISPR/Cas9. These observations demonstrate a potential for the ErbB tyrosine kinase inhibitors to induce neuromuscular toxicity in a developing organism via a mechanism involving inhibition of ErbB4 function. [Media: see text] [Media: see text]. PMID- 30462580 TI - Combinatorial processing of bacterial and host-derived innate immune stimuli at the single-cell level. AB - During the course of a bacterial infection, cells are exposed simultaneously to a range of bacterial and host factors, which converge on the central transcription factor nuclear factor (NF)-kappaB. How do single cells integrate and process these converging stimuli? Here, we tackle the question of how cells process combinatorial signals by making quantitative single-cell measurements of the NF kappaB response to combinations of bacterial lipopolysaccharide (LPS) and the stress cytokine Tumor Necrosis Factor (TNF). We found that cells encode the presence of both stimuli via the dynamics of NF-kappaB nuclear translocation in individual cells, suggesting the integration of NF-kappaB activity for these stimuli occurs at the molecular and pathway level. However, the gene expression and cytokine secretion response to combinatorial stimuli were more complex, suggesting that other factors in addition to NF-kappaB contribute to signal integration at downstream layers of the response. Taken together, our results support the theory that during innate immune threat assessment, a pathogen recognized as both foreign and harmful will recruit an enhanced immune response. Our work highlights the remarkable capacity of individual cells to process multiple input signals and suggests that a deeper understanding of signal integration mechanisms will facilitate efforts to control dysregulated immune responses. PMID- 30462581 TI - Prevalence of anemia and associated risk factors among pregnant women in Lahore, Pakistan. AB - Maternal anemia is a frequent problem during pregnancy, especially in developing countries, such as Pakistan. In this context, the present study was conducted to determine factors associated with maternal anemia prevalent among women of different age groups visiting different hospitals in Lahore from February to April 2017. The current study used a cross-sectional design involving 390 pregnant women. Data related to demographic area, maternal age, gestational age/period, educational and income level, as well as socioeconomic status of all the participants were collected. Also, hemoglobin levels of the participants were obtained for assessment of maternal anemia. A total of 57.7% of participants were anemic (34.4 % mild and 23.3% moderate anemia). Bivariate analysis showed that less education (p = 0.01), occupation as housewife (p = 0.03), lower income (p = 0.001), rural residence (p = 0.028), and greater number of house members (p = 0.04) were significantly associated with maternal anemia. Results of multivariable logistic regression showed that low income was the only significant factor independently associated with maternal anemia. These results suggest that interventions, such as the Nutrition Support Program, to improve nutritional status of pregnant women by providing free food supplements with focus on the poor and marginalized communities are recommended to prevent anemia. PMID- 30462582 TI - Decoding of Neural Data Using Cohomological Feature Extraction. AB - We introduce a novel data-driven approach to discover and decode features in the neural code coming from large population neural recordings with minimal assumptions, using cohomological feature extraction. We apply our approach to neural recordings of mice moving freely in a box, where we find a circular feature. We then observe that the decoded value corresponds well to the head direction of the mouse. Thus, we capture head direction cells and decode the head direction from the neural population activity without having to process the mouse's behavior. Interestingly, the decoded values convey more information about the neural activity than the tracked head direction does, with differences that have some spatial organization. Finally, we note that the residual population activity, after the head direction has been accounted for, retains some low dimensional structure that is correlated with the speed of the mouse. PMID- 30462583 TI - Fixed Points of Competitive Threshold-Linear Networks. AB - Threshold-linear networks (TLNs) are models of neural networks that consist of simple, perceptron-like neurons and exhibit nonlinear dynamics determined by the network's connectivity. The fixed points of a TLN, including both stable and unstable equilibria, play a critical role in shaping its emergent dynamics. In this work, we provide two novel characterizations for the set of fixed points of a competitive TLN: the first is in terms of a simple sign condition, while the second relies on the concept of domination. We apply these results to a special family of TLNs, called combinatorial threshold-linear networks (CTLNs), whose connectivity matrices are defined from directed graphs. This leads us to prove a series of graph rules that enable one to determine fixed points of a CTLN by analyzing the underlying graph. In addition, we study larger networks composed of smaller building block subnetworks and prove several theorems relating the fixed points of the full network to those of its components. Our results provide the foundation for a kind of graphical calculus to infer features of the dynamics from a network's connectivity. PMID- 30462584 TI - Dual Neural Network Method for Solving Multiple Definite Integrals. AB - This study, which examines a calculation method on the basis of a dual neural network for solving multiple definite integrals, addresses the problems of inefficiency, inaccuracy, and difficulty in finding solutions. First, the method offers a dual neural network method to construct a primitive function of the integral problem; it can approximate the primitive function of any given integrand with any precision. On this basis, a neural network calculation method that can solve multiple definite integrals whose upper and lower bounds are arbitrarily given is obtained with repeated applications of the dual neural network to construction of the primitive function. Example simulations indicate that compared with traditional methods, the proposed algorithm is more efficient and precise in obtaining solutions for multiple integrals with unknown integrand, except for the finite input-output data points. The advantages of the proposed method include the following: (1) integral multiplicity shows no influence and restriction on the employment of the method; (2) only a finite set of known sample points is required without the need to know the exact analytical expression of the integrand; and (3) high calculation accuracy is obtained for multiple definite integrals whose integrand is expressed by sample data points. PMID- 30462585 TI - Ten Simple Rules for Organizing and Running a Successful Intensive Two-Week Course. AB - Intensive summer schools often provide strong students with career-changing impact, teaching them the art of the trade, letting them understand the logical underbelly of a field, and connecting them with an elite circle of peers and field leaders. Indeed, many professors attribute considerable aspects of their growth as a scientist to such schools. Such summer schools are an essential service to the community. A well-run summer school combines many of the aspects that jointly define students overall success. Eight years of organizing the annual two-week Computational Sensory-Motor Neuroscience (CoSMo, http://www.compneurosci.com/CoSMo ) summer school has allowed us to experiment with different approaches and evaluate teaching outcomes, and we have seen rather clear patterns. Many new schools are started each year, only some move on to ongoing success, and the vast majority take a while until they reach very good ratings (our ratings are still increasing but approaching 10/10). Focusing on the student experience, we present a set of 10 simple rules to help you organize better summer schools that are more useful to students. PMID- 30462586 TI - Supervised Dimensionality Reduction on Grassmannian for Image Set Recognition. AB - Modeling videos and image sets by linear subspaces has achieved great success in various visual recognition tasks. However, subspaces constructed from visual data are always notoriously embedded in a high-dimensional ambient space, which limits the applicability of existing techniques. This letter explores the possibility of proposing a geometry-aware framework for constructing lower-dimensional subspaces with maximum discriminative power from high-dimensional subspaces in the supervised scenario. In particular, we make use of Riemannian geometry and optimization techniques on matrix manifolds to learn an orthogonal projection, which shows that the learning process can be formulated as an unconstrained optimization problem on a Grassmann manifold. With this natural geometry, any metric on the Grassmann manifold can theoretically be used in our model. Experimental evaluations on several data sets show that our approach results in significantly higher accuracy than other state-of-the-art algorithms. PMID- 30462587 TI - The Exact VC Dimension of the WiSARD n-Tuple Classifier. AB - The Wilkie, Stoneham, and Aleksander recognition device (WiSARD) [Formula: see text]-tuple classifier is a multiclass weightless neural network capable of learning a given pattern in a single step. Its architecture is determined by the number of classes it should discriminate. A target class is represented by a structure called a discriminator, which is composed of [Formula: see text] RAM nodes, each of them addressed by an [Formula: see text]-tuple. Previous studies were carried out in order to mitigate an important problem of the WiSARD [Formula: see text]-tuple classifier: having its RAM nodes saturated when trained by a large data set. Finding the VC dimension of the WiSARD [Formula: see text] tuple classifier was one of those studies. Although no exact value was found, tight bounds were discovered. Later, the bleaching technique was proposed as a means to avoid saturation. Recent empirical results with the bleaching extension showed that the WiSARD [Formula: see text]-tuple classifier can achieve high accuracies with low variance in a great range of tasks. Theoretical studies had not been conducted with that extension previously. This work presents the exact VC dimension of the basic two-class WiSARD [Formula: see text]-tuple classifier, which is linearly proportional to the number of RAM nodes belonging to a discriminator, and exponentially to their addressing tuple length, precisely [Formula: see text]. The exact VC dimension of the bleaching extension to the WiSARD [Formula: see text]-tuple classifier, whose value is the same as that of the basic model, is also produced. Such a result confirms that the bleaching technique is indeed an enhancement to the basic WiSARD [Formula: see text]-tuple classifier as it does no harm to the generalization capability of the original paradigm. PMID- 30462588 TI - Disease and Famine as Weapons of War in Yemen. PMID- 30462589 TI - Factors related to excessive sleepiness in patients with Parkinson's disease. AB - INTRODUCTION: Excessive sleepiness (ES) can affect up to 60% of Parkinson's disease (PD) patients, and it has a multifactorial etiology. It is related to the neurodegenerative processes affecting brain regions responsible for the sleep wake cycle, the effects of drugs acting on the central nervous system, and the excessive sleep fragmentation of this population. OBJECTIVES: To identify the factors associated with the presence of ES in patients with PD. METHODS: A cross sectional study was performed involving 88 consecutive patients with PD from an outpatient clinic. Participants underwent clinical interviews with neurologists and psychiatrist, assessment using standardized scales (Epworth Sleepiness Scale, Parkinson's disease Questionnaire, Pittsburgh Sleep Quality Index and, for individuals with a diagnosis of RLS/WED, International RLS/WED grading scale), and video-polysomnography. RESULTS: The complaint of ES was observed in 55.6% of the participants. The main related factors were: the presence of psychotic disorder, the presence of anxiety disorder, and the use of dopaminergic agonists. No higher prevalence of obstructive sleep apnea and any other sleep disorder was observed in PD group with ES in comparison with the group without ES. CONCLUSION: PD patients present a high prevalence of ES, and some factors, different from those observed in the general population, seem to have a greater impact in this group of patients. ABBREVIATIONS: RLS/ WED: Restless legs syndrome; Willis-Eckbom Disease ES: Excessive sleepiness. PMID- 30462590 TI - Reducing Protections for Noncitizen Children - Exacerbating Harm and Trauma. PMID- 30462591 TI - The Role of Social Worker in Promoting Immigrants' Integration. AB - The dramatic increase in migration in Italy represents a challenge for social workers involved in the integration services. The current study explores the Italian social work practice with immigrants within different working contexts through qualitative data consisting in interviews with social workers. The data were analyzed through T-LAB, a software for content analysis and text mining. Results showed that social workers suitably address immigrants' needs, approaching and understanding different cultures. We may conclude that social workers promote integration and individual empowerment, building a "relational bridge" between cultural diversities, immigrants' heritage, and the mainstream culture. Particularly, social workers have to meet and answer the essential needs of newcomers because the route to integration passes through the practical sphere of welfare provisions. PMID- 30462592 TI - Active caspase-3 upregulation is augmented in at-risk cerebellar Purkinje cells following inferior olive chemoablation in the shaker mutant rat: an immunofluorescence study. AB - OBJECTIVES: Mechanisms underlying Purkinje cell (PC) death, which leads to many diseases in humans, are still poorly elucidated. Progressive PC degeneration occurs in shaker mutant rat due to an X-linked recessive mutation leading to gait ataxia and total-body tremors. Chemoablation of the inferior olive (IO) and olivocerebellar deafferentation temporally accelerated PC death from the natural 6-8 week time-course to 1-2 weeks in the shaker mutant rat. The present study posits that IO chemoablation leads to the accelerated and augmented upregulation of the executioner active caspase-3 that triggers apoptosis of at-risk PCs throughout the ordinary phenotypic manifestation of the shaker mutation. METHODS: Immunofluorescence and double labeling for calbindin and active caspase-3 were used in vermal cerebellar sections from IO-chemoablated rats to demonstrate the effect of IO chemoablation on active caspase-3 expression in at-risk PCs. RESULTS: Active caspase-3 expression was enhanced in the anterior degeneration (ADC) and posterior degeneration (PDC) compartments to reach a peak in both degeneration compartments at 24 h following the injections for IO chemoablation. DISCUSSION: Consequently, it can be deduced that active caspase-3 expression in shaker mutant rats is modifiable suggesting the possibility of targeting it therapeutically in an attempt to rescue PCs from death. Abbreviation PC: Purkinje cell; IO: inferior olive; ADC: Anterior degeneration compartment; PDC: Posterior degeneration compartment; ISC: Intermediate survival compartment; FNSC: Flocculonodular survival compartment. PMID- 30462593 TI - Comparison of acetabulum posterior wall fractures and fracture dislocations: dislocation does not affect clinical and radiological outcomes. AB - The aim of this study was to compare radiological and clinical outcomes of posterior wall acetabulum fractures and posterior wall fracture dislocations. Data were including 52 acetabulum fractures and fracture dislocations. 26 patients (%50) had posterior acetabulum fractures and fracture dislocations who were operatively treated. Radiographic evaluations were performed before and after the operation and at the last follow up. Clinical outcome evaluation was performed at the last follow up. Clinical and radiological outcomes were evaluated including Merle D'aubigne clinical assessment score and Matta' s radiologic measurement score. Brooker classification was used to measure heterotopic ossification.Both Merle D'aubigne and Matta scores were found higher in the acetabulum posterior wall fracture group. But there wasn't significantly difference of clinical and radiological outcomes between two groups (p ? 0,05). Reduction quality and Matta radiologic scores were correlated significantly in 2 groups. Posterior dislocation may not negatively affect clinical and radiologic outcomes. PMID- 30462594 TI - A comparison of the InterTan nail and proximal femoral fail antirotation in the treatment of reverse intertrochanteric femoral fractures. AB - The aim of this study was to compare the clinical and radiological results of InterTan nail and proximal femoral nail antirotation (PFNA) in the treatment of reverse intertrochanteric fractures (AO/OTA 31-A3). The study included a total of consecutive patients who presented at trauma centre with a reverse intertrochanteric fracture between in the last 7 years. Treatment was applied with PFNA in 33 patients and with InterTan nail in 36. Evaluation was made from the radiographs taken on postoperative day 1 and at the final follow-up examination of changes in the femoral neck and shaft angulation, measurement of telescoping of blade and lag screws and reduction quality. The mean telescoping was measured as 7.21+/-7.13mm in the PFNA group and 4.18+/-4.32 mm in the InterTan group (p = 0.039). Mechanical failure was seen in 8 (24.2%) cases in the PFNA group and in one case of the InterTan group. Cut-out was observed in 4 cases of the PFNA group and in none of the InterTan group. No statistically significant difference was determined between the groups in respect of time to union and functional scores (p = 0.573 and p = 0.294). The use of InterTan nailing in the fixation of reverse intertrochanteric fractures provided better clinical and radiological results compared to PFNA in terms of less telescoping, less change in the neck shaft angle and lower complication rates. PMID- 30462595 TI - Retrograde dynamic locked intramedullary nailing for distal femoral aseptic nonunion associated with broken antegrade locked nail. AB - Techniques for treating distal femoral aseptic nonunions associated with antegrade locked nail breakage are controversial. Each technique has unique advantages and disadvantages. Retrograde dynamic locked nailing was used in such treatment. Twelve patients with the described disorders were treated with retrograde dynamic traditional femoral locked nails. The proximal segment of the broken nail was removed from the hip area with the patient in the lateral decubitus position. Consequently, the patient was changed to the supine position. The distal segment of the broken nail was removed from the intercondylar inlet and a dynamic locked nail was inserted in a retrograde fashion. Two staples were used for reinforcing rotational stability whenever necessary. Early ambulation with protected weight bearing was encouraged. All 12 patients with 12 nonunions were followed for an average of 2.9 years (range, 1.1-4.7 years). All nonunions healed with a union rate of 100%, and the average time to union was 4.2 months (range, 3.0-5.5 months). There were no complications of nonunions, malunions or deep infection. Satisfactory knee function among 12 patients improved from 42% pre-operatively to 100% at the latest follow-up (p = 0.002). All 12 patients could walk without aids. The described technique may be an excellent alternative for treating a distal femoral aseptic nonunion associated with antegrade locked nail breakage. The technique is not difficult and the union and satisfactory rates are high. PMID- 30462596 TI - Biomechanical and clinical comparison of single lateral plate and double plating of comminuted supracondylar femoral fractures. AB - This study was to compare the relative strength of fixation and clinical outcomes of single lateral plate and double plating of comminuted supracondylar femoral fractures. Eight matched pairs of embalmed cadaveric femurs were selected. A gap osteotomy was created to stimulate an AO/OTA A3 comminuted distal femoral fracture. One femur of each pair was fixed with a locking plate; the other, with a locking plate and a medial plate. Nondestructive axial compression and maximum load to failure test were performed. A total of 32 patients with comminuted supracondylar femoral fractures were identified and divided into single lateral plate group (SPG) and double plating group (DPG) randomly. Operative time, blood loss, time to union and complications were recorded. Visual analog score (VAS), range of motion (ROM) and Neer knee score were reviewed at one, three, 6, and 12 months postoperatively. Significantly greater axial displacement occurred with the SPG than with the DPG. In load-to-failure testing, the peak load was 2568 +/- 452 N, and 3822 +/- 567 N, respectively. The follow-ups lasted twelve months at least. The operative time was significantly lower in the SPG. However, there was no significant difference between the SPG and the DPG in terms of blood loss, time to union, complication rate, VAS, ROM and Neer knee score. Double plating proved stronger than single lateral plate in biomechanical testing; however, double plating was not superior to traditional lateral plating in clinical outcomes. Therefore, we do not recommend double plating as a routine fixation of comminuted supracondylar femoral fractures. PMID- 30462597 TI - Dual-mobility socket in challenging total hip arthroplasty: 2-6 years follow-up. AB - The success of dual-mobility sockets in achieving implant stability in primary hip replacement is already well established. However, stability cannot always be achieved, especially when dealing with more difficult indications. At our department, 104 dual-mobility sockets (92 uncemented and 12 cemented) were implanted for primary total hip arthroplasty in 97 patients between 2009 and 2013. Indications for hip arthroplasty included primary and secondary coxarthrosis, acetabular and subcapital fractures, avascular necrosis, tumor surgery and metastatic fractures. Although no loosenings were observed, 2 dislocations and 1 infection occurred shortly after surgery. In this challenging group of patients no fixation problems or intraprosthetic dislocations have been observed. The design therefore seems to be a valid alternative to constrained implants, especially in high-risk cases, although dislocation cannot be prevented at all times. Although the findings are very promising, long-term survival studies are mandatory to evaluate intraprosthetic stability and fixation longevity of dual-mobility sockets. PMID- 30462598 TI - The effectiveness of blood metal ions in identifying bilateral metal-on-metal total hip arthroplasty patients at risk of adverse reactions to metal debris. AB - We investigated whether blood metal ions could effectively identify bilateral metal-on-metal total hip arthroplasty (THA) patients at risk of adverse reactions to metal debris (ARMD). Whole blood metal ions were sampled in 50 patients with bilateral 36mm Corail-Pinnacle THAs. Patients were divided into ARMD (n=10) and non-ARMD groups (n=40), with optimal ion thresholds for identifying ARMD determined using receiver operating characteristic analysis. Maximum cobalt or chromium produced the highest area under the curve (71.8%). The optimal ion threshold for distinguishing between patients with and without ARMD was 4.0MUg/l (90.0%=sensitivity, 65.0%=specificity, 39.1%=positive predictive value, 96.3%=negative predictive value). Fixed regulatory authority thresholds missed more patients with ARMD (10%-12% missed) compared to our threshold (2% missed). Bilateral THA patients with blood metal ions below our threshold were at low-risk of ARMD. Compared to currently recommended fixed authority thresholds, our threshold appears preferable for managing patients with these particular implants. PMID- 30462599 TI - Leg power, pelvic movement and physical activity after periacetabular osteotomy. A prospective cohort study. AB - To investigate changes in leg power, pelvic movement and patient-reported outcome in patients with hip dysplasia one year after periacetabular osteotomy. Forty-one patients (7 males) with a mean age of 28.8 years scheduled for periacetabular osteotomy were tested before surgery, and 4 and 12 months after. Leg power, pelvic range of motion and the Hip and Groin Outcome Score (HAGOS) was collected. One year after surgery, power in the operated leg had improved (p = 0.004) and there was no significant difference between power in the operated leg and contralateral leg (p = 0.22). In the frontal plane, pelvic range of motion decreased significant during stair-climbing and stepping down. The same pattern was seen in the sagittal plane but the changes were non-significant. All subscales on the HAGOS improved significantly over time (p < 0.001). Leg power and pelvic range of motion in patients with symptomatic hip dysplasia improved 12 months after periacetabular. PMID- 30462600 TI - Long-term effects of intravenous iloprost therapy in patients with bone marrow oedema of the hip. AB - Bone marrow oedema (BMO) is a multifactorial condition. Various conservative treatment options include analgesic therapy, immobilisation of the affected joint and/or systemic intravenous iloprost or bisphosphonate therapy. Many studies confirm the positive effect of iloprost therapy in larger joints, e.g. the hip and knee joint, after short-term follow up. The objective of this study was to investigate that treatment with iloprost leads to positive long-term functional and radiological outcomes for BMO of the hip joint. Nineteen patients with BMO of the hip joint, ARCO stage 1-2, were included in this study. The Harris Hip Score, the SF-36, the WOMAC score and a visual analogue pain scale (VAS) were evaluated before and 29 +/- 11 months after Ilomedin therapy. All patients underwent MRI for radiological follow-up monitoring three months after treatment. Significant improvements were found in the WOMAC Index and the VAS. In 79% of patients, follow-up MRI after three months showed complete regression of the oedema. Based on the positive results of our study, we support treatment with iloprost for BMO of the hip joint at ARCO stage 1-2. PMID- 30462601 TI - The contribution of the medial retinaculum as a restraining factor to the patella dislocation. AB - The objective of this study was to evaluate the contribution of the medial retinaculum to the stability of the patella, for several angles of knee flexion. For six cadaveric knees, the patella and patella retinaculum were exposed, and the force required to dislocate the patella laterally by 5 mm was measured, in 0, 45 and 90 degrees of knee flexion, preserving and dissecting the medial retinaculum. Wilcoxon singed rank test (SPSS, version 23, Chicago, USA) was used for data analysis. A p value of < 0.05 was considered as statistically significant. The force required to displace the patella laterally is smaller with the medial retinaculum dissected than intact, in 0, 45 and 90 degrees (p = 0.028, p = 0.046, p = 0.027 respectively). The lateral displacement force is greater as the flexion angle increases, with medial retinaculum intact or dissected (p = 0.028). Thus, an intact medial retinaculum provides more stability against lateral displacement forces to the patella, especially in lower flexion angles. Consequently, surgical methods reinforcing the medial retinaculum combined or not with lateral retinaculum release, are of great importance in the plan of the orthopedic surgeons. The engagement of the bones during flexion of the knee contributes significantly to the stability of the patella. PMID- 30462602 TI - Total knee arthroplasty in patients with prior adjacent multi-organism osteomyelitis. AB - Joint degeneration may make a total knee replacement a requirement for pain relief and function, however the presence of adjacent osteomyelitis makes management extremely challenging. We describe a series of four patients with a mean age of 50 with multi-organism osteomyelitis who underwent single-stage total knee replacements at an average of 63 months following eradication. Three patients did well but had complications associated with poor skin and soft tissues, and abnormal bone anatomy. One patient developed an infection and following a re-revision had an arthrodesis. The final mean Knee Society Score and Oxford Knee Score was 62 (54-66) and 34 (29-38) respectively. We have highlighted that these are a difficult cohort of patients to manage and their care is optimised through a multi-disciplinary approach by a high volume surgeon. PMID- 30462603 TI - Are unilateral or staged bilateral total knee arthroplasty really safer than simultaneously bilateral TKA, or is it a myth? AB - The purpose is to evaluate feasibility of simultaneous TKA in comparison with staged and unilateral procedures. Number of patients included: 72 simultaneous bilateral, 61 staged bilateral and 222 unilateral TKAs were included. The mean age in the simultaneous group was lower than the other groups. Heart failure as comorbidity was observed less in the simultaneous TKA group than the other two groups. There was no significant difference between simultaneous and staged groups with respect to postoperative WOMAC and SF36 scores. Rates of thrombotic complications and mortality were not different. There was no significant difference in terms of wound healing, periprosthetic infection and TKA revision rates. Younger age and heart failure as a comorbidity were found to be decisive in the selection of simultaneous procedure. Thus, in the case of advanced bilateral knee osteoarthritis, simultaneous bilateral TKA should be performed after a proper preoperative risk assessment when there is a medical rationale, or the patient's personal preference. In the light of aforementioned conditions, hesitancy about simultaneous TKA seems unnecessary. PMID- 30462604 TI - Comparison of three posterior malleolar fixation methods in trimalleolar ankle fractures. AB - This study aimed to compare the results of AP screws, PA screws and posterior buttress plate used in posterior malleolar fixation of trimalleolar fractures. In this study, the data of 104 trimalleolar fracture cases treated surgically between October 2011 and January 2014 were extracted from hospital records. Patient demographics (age, gender, body mass index), the presence of syndesmotic injury, fracture type (according to the Lauge-Hansen classification), the size of posterior malleolar fragment (measured on lateral radiographs) were recorded. The patients requiring postoperative care for at least a year were invited to attend an evaluation of functional and radiological outcomes. At the final follow-up examination the functional evaluation was made by using AOFAS scores, VAS scores during walking, and dorsiflexion restrictions as compared with the unaffected side. As for the radiological evaluation, the patients were assessed according to the presence of a gap or step by the direct use of graphies following the fixation and with regard to the osteoarthritic development in alignment with the Bargon criteria. A total of 67 patients met the study inclusion criteria; 20 cases in the AP screw, 13 cases in the PA screw and 34 cases in the plate group. The mean follow-up period was 14.4 +/- 2.23 months in AP, 16.3 +/- 2.56 months in PA and 17.1 +/- 3.01 months in the plate group. Better AOFAS scores were obtained in the PA group and the plate group compared to the AP screw group (p < 0.001). No statistically significant difference was found between the groups in respect of VAS scores during walking and dorsiflexion restriction. Better radiological reduction was observed in the PA screw group and the plate group (p < 0.001). PMID- 30462605 TI - The proprioception of the knee joint following tibia plateau fractures. AB - Proprioception is a conscious and/or unconscious perception of position change in an extremity or joint in space. In our study our purpose was to evaluate whether the lower extremity proprioception in long term, is altered following tibia plateau fractures and to assess its relation with age and type of fracture. This retrospective study includes the evaluation of proprioception in 38 tibia plateau fracture patients (29 male, 9 female) of various types who were operated with open reduction and internal fixation (ORIF) technique in our clinic, by comparison of both operated knee and unaffected knee. The mean age of the patients were 38,8 (range, 20-60) and mean follow-up time was 56 months (range, 13-120 months). Proprioception measurements were assessed at 30 degrees and 60 degrees of knee flexion degrees both passively and actively. There were no significant difference between the operated knee and unaffected knee by mean absolute angular deviation values at passive (p = 0,22) or active 60 degrees (p = 0,22). Accordingly passive (p = 0,47) and active 30 degrees (p = 0,62) mean absolute angular deviation values showed no significant difference. Our study has indicated that proprioception at the operated extremity is not significantly different from the unaffected knee in tibia plateau fractures at long term follow up. PMID- 30462606 TI - Evaluation of intra-operative imaging during scarf osteotomy - an unnecessary cost or an essential prerequisite? AB - Scarf osteotomy is an effective surgical treatment option for hallux valgus. It can manipulate alignment in three planes, allowing accurate anatomical correction. The potential benefit of intra-operative image intensification (II) to gauge deformity correction during surgery however, has not been quantitatively reported. This study aims to compare the correction of hallux valgus by scarf osteotomy with and without intra-operative imaging. Retrospective analysis of a consecutive series of scarf osteotomy in 2 groups. Group A had intra-operative radiographic assessment and group B did not. Patient and surgical data was collected with a mean follow-up of 14 months. Of 99 scarf osteotomies there was no significant difference in age, gender or pre-operative deformity between the groups (p<0.05). No statistical difference was found between the radiographic corrections of the two groups (p<0.05), although operating time was less in group B. This series shows that intra-operative imaging does not improve accuracy of deformity correction, or implant position in scarf osteotomy. We suggest it is not required routinely during scarf osteotomy. PMID- 30462607 TI - The relation between ankle morphology and osteochondritis dissecans of talus. AB - The purpose of this study is to describe, if there is, any relation between ankle morphology and development of talus osteochondritis dissecans (OCD) using certain morphological parameters derived from high resolution magnetic resonance imaging (MRI). Study included a total of 93 patients: 26 patients with traumatic medial talus OCD, 30 patients with idiopathic medial talus OCD and 37 patients with normal ankle as the control group. Five MRI morphological parameters (Maximal Tibial Thickness (MTiTh), Malleolar Width (MalW), Length of Trochlea Tali Arc (TaL), Height of Trochlea Tali Arc (TaH) and Angle of Trochlea Tali Inclination (TaIA)) that are expected to be relevant to talus OCD formation are measured and compared for the three groups. Significant difference was found between the idiopathic and the traumatic group in terms of age and gender. Two of five morphologic parameters (MalW and TaL) also showed significant difference for the traumatic and idiopathic group compared to healthy volunteers. Two morphologic parameters that were found to be significantly different from healthy controls may suggest that ankle morphology be a possible factor for talus OCD. Age and gender difference between the traumatic and idiopathic group also may point out different underlying mechanisms for OCD formation. PMID- 30462608 TI - Importance of assistant intra-operative medial distraction technique for intraarticular calcaneus fractures. AB - To report the clinical efficacy of open reduction and internal fixation (ORIF) assisted by medial distraction for intra-articular calcaneus fractures. From September 2010 to November 2013, 151 patients with intra-articular calcaneus fractures were treated at our department by ORIF. They were 95 men and 56 women, 18 to 69 years of age. According to the Sanders classification, there were 24 cases of type II, 76 ones of type III and 51 ones of type IV. Medial distraction was used in 27 cases but not in 124 ones. The 2 groups were compatible, without significant differences in preoperative general data (p > 0.05). The two groups were compared in intraoperative indexes and follow-up radiological data. The mean duration of surgery in the distraction group (71.6 +/- 18.3 minutes) was significantly shorter than that in the non-distraction group (80.4+/-20.7 minutes), and the varus angle in the distraction group (5.3 degrees +/- 4.4 degrees ) was significantly smaller than that in the non-distraction group (10.6 degrees +/- 6.5 degrees ) (p < 0.05). There were no significant differences between the 2 groups in intraoperative bleeding, postoperative drainage, hospital stay, bone union time, follow-up duration, American Orthopaedic Foot & Ankle Society score, Bohler angle, Gissane angle, calcaneal axis, calcaneal horizontal length, tuberosity height, hillock calcaneal height, calcaneal width, or talar inclination angle (p > 0.05). ORIF assisted by medial distraction technique is effective for intra-articular calcaneal fractures, especially in correcting the calcaneal axis. PMID- 30462610 TI - The impact of steatosis on liver regeneration. AB - Alcoholic and non-alcoholic fatty liver diseases are the leading causes of cirrhosis in Western countries. These chronic liver diseases share common pathological features ranging from steatosis to steatohepatitis. Fatty liver is associated with primary liver graft dysfunction, a higher incidence of complications/mortality after surgery, in correlation with impaired liver regeneration. Liver regeneration is a multistep process including a priming phase under the control of cytokines followed by a growth factor receptor activation phase leading to hepatocyte proliferation. This process ends when the initial liver mass is restored. Deficiency in epidermal growth factor receptor (EGFR) liver expression, reduced expression of Wee1 and Myt1 kinases, oxidative stress and alteration in hepatocyte macroautophagy have been identified as mechanisms involved in the defective regeneration of fatty livers. Besides the mechanisms, we will also discuss in this review various treatments that have been investigated in the reversal of the regeneration defect, for example, omega-3 fatty acids, pioglitazone, fibroblast growth factor (FGF)19-based chimeric molecule or growth hormone (GH). Since dysbiosis impedes liver regeneration, targeting microbiota could also be an interesting therapeutic approach. PMID- 30462611 TI - Structural studies of carbons by neutron and x-ray scattering. AB - Carbon can have many different forms and the characterisation of structural features on a length scale of 1 A to 10 MUm is important in defining its physical and chemical properties for the various forms. The use of either electro-magnetic (x-ray) or particle (neutron) beams plays an important role in determining these characteristics. In this paper, we review the various techniques that are used to determine the structural features by experimental means and how the data are processed to give the required information in a suitable form for detailed analysis by computer simulation. Diffraction methods are used for studies of the atomic arrangement and small-angle scattering techniques are used for studies of microporosity in the sample materials. The experimental data obtained from a wide range of different carbon materials are considered and how these results can be used as a basis for modelling the structures in a quantitative manner is also considered. This information underpins their use as active components in a wide range of functional materials. PMID- 30462609 TI - Macro-connectomics and microstructure predict dynamic plasticity patterns in the non-human primate brain. AB - The brain displays a remarkable ability to adapt following injury by altering its connections through neural plasticity. Many of the biological mechanisms that underlie plasticity are known, but there is little knowledge as to when, or where in the brain plasticity will occur following injury. This knowledge could guide plasticity-promoting interventions and create a more accurate roadmap of the recovery process following injury. We causally investigated the time-course of plasticity after hippocampal lesions using multi-modal MRI in monkeys. We show that post-injury plasticity is highly dynamic, but also largely predictable on the basis of the functional connectivity of the lesioned region, gradients of cell densities across the cortex and the pre-lesion network structure of the brain. The ability to predict which brain areas will plastically adapt their functional connectivity following injury may allow us to decipher why some brain lesions lead to permanent loss of cognitive function, while others do not. PMID- 30462613 TI - Eugene L. Gottlieb, 1919-2018. PMID- 30462612 TI - Stochastic gravitational wave backgrounds. AB - A stochastic background of gravitational waves could be created by the superposition of a large number of independent sources. The physical processes occurring at the earliest moments of the universe certainly created a stochastic background that exists, at some level, today. This is analogous to the cosmic microwave background, which is an electromagnetic record of the early universe. The recent observations of gravitational waves by the Advanced LIGO and Advanced Virgo detectors imply that there is also a stochastic background that has been created by binary black hole and binary neutron star mergers over the history of the universe. Whether the stochastic background is observed directly, or upper limits placed on it in specific frequency bands, important astrophysical and cosmological statements about it can be made. This review will summarize the current state of research of the stochastic background, from the sources of these gravitational waves to the current methods used to observe them. PMID- 30462614 TI - Management of deeply impacted molars with the miniscrew-supported pole technique. PMID- 30462615 TI - Rapid palatal expansion with the Keles Keyless Expander. PMID- 30462616 TI - The biocreative strategy. Part 6: Class III Treatment. PMID- 30462618 TI - Nonsurgical correction of Class III malocclusion and anterior open bite with mini implant anchorage. PMID- 30462617 TI - CAD/CAM technology for digital indirect bonding. PMID- 30462619 TI - Closure of mandibular spaces during retention. PMID- 30462620 TI - A 2018 Reference Guide to the Banff Classification of Renal Allograft Pathology: Erratum. PMID- 30462621 TI - Neuromuscular blocking agents for adult patients with acute respiratory distress syndrome: A meta-analysis of randomized controlled trials. AB - BACKGROUND: To explore the effect of neuromuscular blocking agents (NMBAs) on adult patients with acute respiratory distress syndrome (ARDS) by meta-analysis. METHODS: Three databases including Cochrane central register of controlled trials, PubMed, and Wanfang Data were searched to find relevant articles. We included randomized controlled trials that evaluated NMBAs compared with placebo or usual treatment in adult patients with ARDS. RESULTS: Five trials totaling 551 patients were identified eligible for inclusion. All the five trials were protective ventilation strategies based. All patients (the ratio of partial pressure of arterial oxygen/fraction of inspired oxygen <= 200 mm Hg) met American-European Consensus Conference or the Berlin definition oxygenation criteria for ARDS. Neuromuscular blocking agents significantly reduced intensive care unit mortality (relative risk, 0.73; 95% confidence intervals [CI], 0.58 0.93; p = 0.009; I = 0.0%; 4 trials, 455 patients) and 21- to 28-day mortality (relative risk, 0.63; 95% CI, 0.49-0.82; p = 0.001; I = 0.0%; 4 trials, 527 patients). At 48 hours, NMBAs improved oxygenation (weighted mean differences [WMD], 27.98; 95% CI, 7.45-48.51; p = 0.008; I = 44.2%; 4 trials, 212 patients). However, NMBAs have no effect on reduction of oxygenation at 24 hours (WMD, 26.83; 95% CI, -5.89 to 59.55; p = 0.108; I = 82.4%; 4 trials, 447 patients), and plateau pressure (WMD, 0.43; 95% CI, -0.46 to 1.31; p = 0.345; 4 trials, 455 patients) as well as positive end expiratory pressure (WMD, 0.10; 95% CI, -0.47 to 0.67; p = 0.73; 4 trials, 455 patients) at 48 hours. CONCLUSION: Protective ventilation strategies based NMBAs treatment reduces mortality in patients with moderate to severe ARDS. LEVEL OF EVIDENCE: Systematic reviews & meta-analysis, level III. PMID- 30462622 TI - Organ injury scaling 2018 update: Spleen, liver, and kidney. PMID- 30462623 TI - Heeding the call: Military-civilian partnerships as a foundation for enhanced mass casualty care in the United States. PMID- 30462624 TI - Re: Neurosurgical activity by deployed military non-neurosurgeons: Is predeployment training enough? PMID- 30462625 TI - miR-339-5p Increases Radiosensitivity of Lung Cancer Cells by Targeting Phosphatases of Regenerating Liver-1 (PRL-1). AB - BACKGROUND Radiotherapy is the most effective non-surgical modality in lung cancer treatment, and microRNAs (miRNAs) have been suggested as key regulators in radiosensitization. Herein, we explored the specific function of miR-339-5p in the radiosensitivity of lung cancer cells. MATERIAL AND METHODS Radiosensitivity was assessed by cell viability (CCK-8 assay), cell apoptosis, and cell cycle changes (flow cytometry). qRT-PCR and subsequent Western blot assays were used to determine the expression of miR-339-5p and other related proteins. RESULTS We demonstrated that ionizing radiation (IR) exposure impaired lung cancer cell viability, and found that miR-339-5p is a novel IR-inducible miRNA. Overexpression of miR-339-5p enhanced radiosensitivity of A549 and H460 cells by inhibiting cell viability, increasing apoptosis, inducing cell cycle arrest, and suppressing cell proliferation. Further exploration validated that miR-339-5p can target phosphatases of regenerating liver-1 (PRL-1) in lung cancer cells. Restoration of PRL-1 partially reverses the enhanced radiosensitivity of lung cancer cells induced by miR-339-5p. CONCLUSIONS Our data support that miR-339-5p has potential therapeutic value by sensitizing lung cancer cells to radiation via targeting of PRL-1. PMID- 30462626 TI - Prevalence of Amyotrophic Lateral Sclerosis - United States, 2015. AB - Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a progressive and fatal neuromuscular disease; the majority of ALS patients die within 2-5 years of receiving a diagnosis (1). Familial ALS, a hereditary form of the disease, accounts for 5%-10% of cases, whereas the remaining cases have no clearly defined etiology (1). ALS affects persons of all races and ethnicities; however, whites, males, non-Hispanics, persons aged >=60 years, and those with a family history of ALS are more likely to develop the disease (2). No cure for ALS has yet been identified, and the lack of proven and effective therapeutic interventions is an ongoing challenge. Treatments currently available, Edaravone and Riluzole, do not cure ALS, but slow disease progression in certain patients (3,4). This report presents National ALS Registry findings regarding ALS prevalence in the United States for the period January 1-December 31, 2015. In 2015, the estimated prevalence of ALS cases was 5.2 per 100,000 population with a total of 16,583 cases identified. Overall, these findings are similar to the 2014 ALS prevalence and case count (5.0 per 100,000; 15,927 cases) (2). Prevalence rates by patient characteristics (most common in whites, males, and persons aged >=60 years) and U.S. Census regions are consistent with ALS demographics and have not changed from 2014 to 2015 calendar years. The algorithm used to identify cases from national administrative databases was updated from the International Classification of Diseases, Ninth Revision (ICD-9) to the ICD-10 codes for claims starting on October 1, 2015, with no apparent effect on case ascertainment. Data collected by the National ALS Registry are being used to better describe the epidemiology of ALS in the United States and to facilitate research on the genetics, potential biomarkers, environmental pollutants, and etiology for ALS. PMID- 30462627 TI - Correction and Republication: Abortion Surveillance - United States, 2014. AB - On November 24, 2017, MMWR published "Abortion Surveillance - United States, 2014" (1). On August 6, 2018, the authors informed MMWR about inadvertent errors in the data that resulted in publication of some erroneous numbers for gestational ages and abortion ratios throughout the report. The authors have corrected these errors and confirm that the interpretation or the conclusions of the original report have not changed. Additional text has been added to clarify how CDC adjusts gestational age data. In accordance with December 2017 guidance from the International Committee of Medical Journal Editors (2), MMWR is republishing the corrected report. The republished report has supplementary materials that include the original report with these corrections and additional text clearly marked (3). PMID- 30462628 TI - QuickStats: Percentage* of All Emergency Department (ED) Visits? Made by Patients with Diagnosed Depression,S by Sex and Age Group - National Hospital Ambulatory Medical Care Survey, United States, 2016. PMID- 30462629 TI - Self-Directed Walk With Ease Workplace Wellness Program - Montana, 2015-2017. AB - Arthritis occurs in 27% of adults in Montana, among whom 50% have activity limitations, 16% have social participation restrictions, and 23% have severe joint pain attributable to arthritis (1). Physical activity is beneficial in managing arthritis symptoms and in preventing other chronic diseases (2). Walk With Ease is a 6-week evidence-based physical activity program recommended by CDC to increase physical activity and help improve arthritis symptoms (3). In 2015, Walk With Ease was added to an ongoing workplace wellness program for Montana state employees; the results for five outcomes (minutes spent walking, engaging in other physical activity [including swimming, bicycling, other aerobic equipment use, and other aerobic exercise], stretching, pain, and fatigue) were analyzed by the Montana Department of Public Health and Human Services and CDC. Outcomes at baseline (pretest), 6 weeks after the program (posttest), and 6 months later (follow-up) were analyzed by self-reported arthritis status at the time the participant enrolled in the program. Significant increases (p<0.05) in the mean number of minutes spent per week walking and engaging in other physical activity were observed among participants with and without arthritis at the 6 week posttest. Time spent stretching did not change significantly at posttest for either group. Mean pain levels among participants without arthritis increased significantly both at the 6-week posttest and 6-month follow-up; however, pain and fatigue decreased significantly at posttest and follow-up for participants with or without arthritis who began the program with moderate or severe pain and fatigue levels. The data from these analyses suggest that, as a component of a workplace wellness program, self-directed Walk With Ease might be effective in increasing physical activity not only among adults with arthritis, but also among persons without arthritis. PMID- 30462630 TI - Lead in Spices, Herbal Remedies, and Ceremonial Powders Sampled from Home Investigations for Children with Elevated Blood Lead Levels - North Carolina, 2011-2018. AB - The number of pediatric cases of elevated blood lead levels (BLLs) are decreasing in North Carolina. However, one county reported an increase in the number of children with confirmed BLLs >=5 MUg/dL (CDC reference value, https://www.cdc.gov/nceh/lead/acclpp/blood_lead_levels.htm), from 27 in 2013 to 44 in 2017. Many children with elevated BLLs in this county lived in new housing, but samples of spices, herbal remedies, and ceremonial powders from their homes contained high levels of lead. Children with chronic lead exposure might suffer developmental delays and behavioral problems (https://www.cdc.gov/nceh/lead/). In 1978, lead was banned from house paint in the United States (1); however, children might consume spices and herbal remedies daily. To describe the problem of lead in spices, herbal remedies, and ceremonial powders, the North Carolina Childhood Lead Poisoning Prevention Program (NCCLPPP) retrospectively examined properties where spices, herbal remedies, and ceremonial powders were sampled that were investigated during January 2011-January 2018, in response to confirmed elevated BLLs among children. NCCLPPP identified 59 properties (6.0% of all 983 properties where home lead investigations had been conducted) that were investigated in response to elevated BLLs in 61 children. More than one fourth (28.8%) of the spices, herbal remedies, and ceremonial powders sampled from these homes contained >=1 mg/kg lead. NCCLPPP developed a survey to measure child specific consumption of these products and record product details for reporting to the Food and Drug Administration (FDA). Lead contamination of spices, herbal remedies, and ceremonial powders might represent an important route of childhood lead exposure, highlighting the need to increase product safety. Setting a national maximum allowable limit for lead in spices and herbal remedies might further reduce the risk for lead exposure from these substances. PMID- 30462631 TI - Abortion Surveillance - United States, 2014. AB - PROBLEM/CONDITION: Since 1969, CDC has conducted abortion surveillance to document the number and characteristics of women obtaining legal induced abortions in the United States. PERIOD COVERED: 2014. DESCRIPTION OF SYSTEM: Each year, CDC requests abortion data from the central health agencies of 52 reporting areas (the 50 states, the District of Columbia, and New York City). The reporting areas provide this information voluntarily. For 2014, data were received from 49 reporting areas. For trend analysis, abortion data were evaluated from 48 areas that reported data every year during 2005-2014. Census and natality data, respectively, were used to calculate abortion rates (number of abortions per 1,000 women aged 15-44 years) and ratios (number of abortions per 1,000 live births). RESULTS: A total of 652,639 abortions were reported to CDC for 2014. Of these abortions, 98.4% were from the 48 reporting areas that provided data every year during 2005-2014. Among these 48 reporting areas, the abortion rate for 2014 was 12.1 abortions per 1,000 women aged 15-44 years, and the abortion ratio was 193 abortions per 1,000 live births. From 2013 to 2014, the total number and rate of reported abortions decreased 2%, and the ratio decreased 3%. From 2005 to 2014, the total number, rate, and ratio of reported abortions decreased 21%, 22%, and 18%, respectively. In 2014, all three measures reached their lowest level for the entire period of analysis (2005-2014). In 2014 and throughout the period of analysis, women in their 20s accounted for the majority of abortions and had the highest abortion rates; women in their 30s and older accounted for a much smaller percentage of abortions and had lower abortion rates. In 2014, women aged 20-24 and 25-29 years accounted for 32.2% and 26.7% of all reported abortions, respectively, and had abortion rates of 21.3 and 18.4 abortions per 1,000 women aged 20-24 and 25-29 years, respectively. In contrast, women aged 30-34, 35-39, and >=40 years accounted for 17.1%, 9.7%, and 3.6% of all reported abortions, respectively, and had abortion rates of 11.9, 7.2, and 2.6 abortions per 1,000 women aged 30-34 years, 35-39 years, and >=40 years, respectively. From 2005 to 2014, the abortion rate decreased among women aged 20-24, 25-29, 30-34, and 35-39 years by 27%, 16%, 12%, and 5%, respectively, but increased 4% among women aged >=40 years. In 2014, adolescents aged <15 and 15-19 years accounted for 0.3% and 10.4% of all reported abortions, respectively, and had abortion rates of 0.5 and 7.5 abortions per 1,000 adolescents aged <15 and 15-19 years, respectively. From 2005 to 2014, the percentage of abortions accounted for by adolescents aged 15-19 years decreased 38%, and their abortion rate decreased 49%. These decreases were greater than the decreases for women in any older age group. In contrast to the percentage distribution of abortions and abortion rates by age, abortion ratios in 2014 and throughout the entire period of analysis were highest among adolescents and lowest among women aged 30-39 years. Abortion ratios decreased from 2005 to 2014 for women in all age groups. In 2014, the majority (64.9%) of abortions were performed at <=8 weeks' gestation, and nearly all (91.0%) were performed at <=13 weeks' gestation. Few abortions were performed between 14 and 20 weeks' gestation (7.7%) or at >=21 weeks' gestation (1.3%). During 2005-2014, the percentage of all abortions performed at <=13 weeks' gestation remained consistently high (>=90.9%). Among abortions performed at <=13 weeks' gestation, there was a shift toward earlier gestational ages, as the percentage performed at <=6 weeks' gestation increased 9%, and the percentage of all other gestational ages at <=13 weeks' gestation decreased 0%-12%. In 2014, among reporting areas that included medical (nonsurgical) abortion on their reporting form, 22.5% of all abortions were performed by early medical abortion (a nonsurgical abortion at <=8 weeks' gestation), 66.9% were performed by surgical abortion at <=13 weeks' gestation, and 9.1% were performed by surgical abortion at >13 weeks' gestation; all other methods were uncommon (<1.5%). Among abortions performed at <=8 weeks' gestation that were eligible for early medical abortion on the basis of gestational age, 33.3% were completed by this method. In 2014, women with one or more previous live births accounted for 59.5% of abortions, and women with no previous live births accounted for 40.4%. Women with one or more previous induced abortions accounted for 44.9% of abortions, and women with no previous abortion accounted for 55.1%. Women with three or more previous births accounted for 13.8% of abortions, and women with three or more previous abortions accounted for 8.6% of abortions. Deaths of women associated with complications from abortion for 2014 are being assessed as part of CDC's Pregnancy Mortality Surveillance System. In 2013, the most recent year for which data were available, four women were identified to have died as a result of complications from legal induced abortion. INTERPRETATION: Among the 48 areas that reported data every year during 2005 2014, the decreases in the total number, rate, and ratio of reported abortions that occurred during 2010-2013 continued from 2013 to 2014, resulting in historic lows for all three measures of abortion. PUBLIC HEALTH ACTION: The data in this report can help program planners and policymakers identify groups of women with the highest rates of abortion. Unintended pregnancy is the major contributor to induced abortion. Increasing access to and use of effective contraception can reduce unintended pregnancies and further reduce the number of abortions performed in the United States. PMID- 30462632 TI - Abortion Surveillance - United States, 2015. AB - PROBLEM/CONDITION: Since 1969, CDC has conducted abortion surveillance to document the number and characteristics of women obtaining legal induced abortions in the United States. PERIOD COVERED: 2015. DESCRIPTION OF SYSTEM: Each year, CDC requests abortion data from the central health agencies of 52 reporting areas (the 50 states, the District of Columbia, and New York City). The reporting areas provide this information voluntarily. For 2015, data were received from 49 reporting areas. Abortion data provided by these 49 reporting areas for each year during 2006-2015 were used in trend analyses. Census and natality data were used to calculate abortion rates (number of abortions per 1,000 women aged 15-44 years) and ratios (number of abortions per 1,000 live births), respectively. RESULTS: A total of 638,169 abortions for 2015 were reported to CDC from 49 reporting areas. Among these 49 reporting areas, the abortion rate for 2015 was 11.8 abortions per 1,000 women aged 15-44 years, and the abortion ratio was 188 abortions per 1,000 live births. From 2014 to 2015, the total number of reported abortions decreased 2% (from 652,639), the abortion rate decreased 2% (from 12.1 abortions per 1,000 women aged 15-44 years), and the abortion ratio decreased 2% (from 192 abortions per 1,000 live births). From 2006 to 2015, the total number of reported abortions decreased 24% (from 842,855), the abortion rate decreased 26% (from 15.9 abortions per 1,000 women aged 15-44 years), and the abortion ratio decreased 19% (from 233 abortions per 1,000 live births). In 2015, all three measures reached their lowest level for the entire period of analysis (2006 2015). In 2015 and throughout the period of analysis, women in their 20s accounted for the majority of abortions and had the highest abortion rates; women aged >=30 years accounted for a smaller percentage of abortions and had lower abortion rates. In 2015, women aged 20-24 and 25-29 years accounted for 31.1% and 27.6% of all reported abortions, respectively, and had abortion rates of 19.9 and 17.9 abortions per 1,000 women aged 20-24 and 25-29 years, respectively. In contrast, women aged 30-34, 35-39, and >=40 years accounted for 17.7%, 10.0%, and 3.5% of all reported abortions, respectively, and had abortion rates of 11.6, 7.0, and 2.5 abortions per 1,000 women aged 30-34, 35-39, and >=40 years, respectively. From 2006 to 2015, the abortion rate decreased among women in all age groups. In 2015, adolescents aged <15 and 15-19 years accounted for 0.3% and 9.8% of all reported abortions, respectively, and had abortion rates of 0.5 and 6.7 abortions per 1,000 adolescents aged <15 and 15-19 years, respectively. From 2006 to 2015, the percentage of abortions accounted for by adolescents aged 15-19 years decreased 41%, and their abortion rate decreased 54%. This decrease in abortion rate was greater than the decreases for women in any older age group. In contrast to the percentage distribution of abortions and abortion rates by age, abortion ratios in 2015 and throughout the entire period of analysis were highest among adolescents and lowest among women aged 25-39 years. Abortion ratios decreased from 2006 to 2015 for women in all age groups. In 2015, almost two thirds (65.4%) of abortions were performed at <=8 weeks' gestation, and nearly all (91.1%) were performed at <=13 weeks' gestation. Few abortions were performed between 14 and 20 weeks' gestation (7.6%) or at >=21 weeks' gestation (1.3%). During 2006-2015 the percentage of all abortions performed at >13 weeks' gestation remained consistently low (<=9.0%). Among abortions performed at <=13 weeks' gestation, a shift occurred toward earlier gestational ages, with the percentage performed at <=6 weeks' gestation increasing 11%. In 2015, 24.6% of all abortions were performed by early medical abortion (a nonsurgical abortion at <=8 weeks' gestation), 64.3% were performed by surgical abortion at <=13 weeks' gestation, and 8.8% were performed by surgical abortion at >13 weeks' gestation; all other methods were uncommon (<=2.2%). Among those that were eligible for early medical abortion on the basis of gestational age (i.e., performed at <=8 weeks' gestation), 35.8% were completed by this method. In 2015, women with one or more previous live births accounted for 59.3% of abortions, and women with no previous live births accounted for 40.7%. Women with one or more previous induced abortions accounted for 43.6% of abortions, and women with no previous abortion accounted for 56.3%. Women with three or more previous births accounted for 14.2% of abortions, and women with three or more previous abortions accounted for 8.2% of abortions. Deaths of women associated with complications from abortion for 2015 are being assessed as part of CDC's Pregnancy Mortality Surveillance System. In 2014, the most recent year for which data were available, six women were identified to have died as a result of complications from legal induced abortion. INTERPRETATION: Among the 49 areas that reported data every year during 2006 2015, decreases in the total number, rate, and ratio of reported abortions resulted in historic lows for the period of analysis for all three measures of abortion. PUBLIC HEALTH ACTION: The data in this report can help program planners and policymakers identify groups of women with the highest rates of abortion. Unintended pregnancy is the major contributor to induced abortion. Increasing access to and use of effective contraception can reduce unintended pregnancies and further reduce the number of abortions performed in the United States. PMID- 30462633 TI - TOR-autophagy branch signaling via Imp1 dictates plant-microbe biotrophic interface longevity. AB - Like other intracellular eukaryotic phytopathogens, the devastating rice blast fungus Magnaporthe (Pyricularia) oryzae first infects living host cells by elaborating invasive hyphae (IH) surrounded by a plant-derived membrane. This forms an extended biotrophic interface enclosing an apoplastic compartment into which fungal effectors can be deployed to evade host detection. M. oryzae also forms a focal, plant membrane-rich structure, the biotrophic interfacial complex (BIC), that accumulates cytoplasmic effectors for translocation into host cells. Molecular decision-making processes integrating fungal growth and metabolism in host cells with interface function and dynamics are unknown. Here, we report unanticipated roles for the M. oryzae Target-of-Rapamycin (TOR) nutrient signaling pathway in mediating plant-fungal biotrophic interface membrane integrity. Through a forward genetics screen for M. oryzae mutant strains resistant to the specific TOR kinase inhibitor rapamycin, we discovered IMP1 encoding a novel vacuolar protein required for membrane trafficking, V-ATPase assembly, organelle acidification and autophagy induction. During infection, Deltaimp1 deletants developed intracellular IH in the first infected rice cell following cuticle penetration. However, fluorescently labeled effector probes revealed that interface membrane integrity became compromised as biotrophy progressed, abolishing the BIC and releasing apoplastic effectors into host cytoplasm. Growth between rice cells was restricted. TOR-independent autophagy activation in Deltaimp1 deletants (following infection) remediated interface function and cell-to-cell growth. Autophagy inhibition in wild type (following infection) recapitulated Deltaimp1. In addition to vacuoles, Imp1GFP localized to IH membranes in an autophagy-dependent manner. Collectively, our results suggest TOR-Imp1-autophagy branch signaling mediates membrane homeostasis to prevent catastrophic erosion of the biotrophic interface, thus facilitating fungal growth in living rice cells. The significance of this work lays in elaborating a novel molecular mechanism of infection stressing the dominance of fungal metabolism and metabolic control in sustaining long-term plant-microbe interactions. This work also has implications for understanding the enigmatic biotrophy to necrotrophy transition. PMID- 30462634 TI - The many fates of tissue regeneration. PMID- 30462635 TI - Epidemiology of dengue and other arboviruses in a cohort of school children and their families in Yucatan, Mexico: Baseline and first year follow-up. AB - Dengue is the most prevalent mosquito-borne viral disease of humans and is caused by the four serotypes of dengue virus. To estimate the incidence of dengue and other arboviruses, we analyzed the baseline and first year follow-up of a prospective school-based cohort study and their families in three cities in the state of Yucatan, Mexico. Through enhanced surveillance activities, acute febrile illnesses in the participants were detected and yearly blood samples were collected to evaluate dengue infection incidence. A Cox model was fitted to identify hazard ratios of arboviral infections in the first year of follow-up of the cohort. The incidence of dengue symptomatic infections observed during the first year of follow-up (2015-2016) was 3.5 cases per 1,000 person-years (95% CI: 1.9, 5.9). The incidence of dengue infections was 33.9 infections per 1,000 person-years (95% CI: 31.7, 48.0). The majority of dengue infections and seroconversions were observed in the younger age groups (<= 14 years old). Other arboviruses were circulating in the state of Yucatan during the study period. The incidence of symptomatic chikungunya infections was 8.6 per 1,000 person-years (95% CI: 5.8, 12.3) and the incidence of symptomatic Zika infections was 2.3 per 1,000 person-years (95% CI: 0.9, 4.5). Our model shows that having a dengue infection during the first year of follow-up was significantly associated with being female, living in Ticul or Progreso, and being dengue naive at baseline. Age was not significantly associated with the outcome, it was confounded by prior immunity to dengue that increases with age. This is the first report of a cohort in Latin America that provides incidence estimates of the three arboviruses co circulating in all age groups. This study provides important information for understanding the epidemiology of dengue and other arboviruses and better informing public health policies. PMID- 30462636 TI - Ionizing radiation induces stem cell-like properties in a caspase-dependent manner in Drosophila. AB - Cancer treatments including ionizing radiation (IR) can induce cancer stem cell like properties in non-stem cancer cells, an outcome that can interfere with therapeutic success. Yet, we understand little about what consequences of IR induces stem cell like properties and why some cancer cells show this response but not others. In previous studies, we identified a pool of epithelial cells in Drosophila larval wing discs that display IR-induced stem cell-like properties. These cells are resistant to killing by IR and, after radiation damage, change fate and translocate to regenerate parts of the disc that suffered more cell death. Here, we report the identification of two new pools of cells with IR induced regenerative capability. We addressed how IR exposure results in the induction of stem cell-like behavior, and found a requirement for IR-induced caspase activity and for Zfh2, a transcription factor and an effector in the JAK/STAT pathway. Unexpectedly, the requirement for caspase activity was cell autonomous within cell populations that display regenerative behavior. We propose a model in which the requirement for caspase activity and Zfh2 can be explained by apoptotic and non-apoptotic functions of caspases in the induction of stem cell-like behavior. PMID- 30462637 TI - Aerosol exposure to intermediate size Nipah virus particles induces neurological disease in African green monkeys. AB - Nipah virus (NiV) infection can lead to severe respiratory or neurological disease in humans. Transmission of NiV has been shown to occur through contact with virus contaminated fomites or consumption of contaminated food. Previous results using the African green monkey (AGM) model of NiV infection identified aspects of infection that, while similar to humans, don't fully recapitulate disease. Previous studies also demonstrate near uniform lethality that is not consistent with human NiV infection. In these studies, aerosol exposure using an intermediate particle size (7MUm) was used to mimic potential human exposure by facilitating virus deposition in the upper respiratory tract. Computed tomography evaluation found some animals developed pulmonary parenchymal disease including consolidations, ground-glass opacities, and reactive adenopathy. Despite the lack of neurological signs, magnetic resonance imaging identified distinct brain lesions in three animals, similar to those previously reported in NiV-infected patients. Immunological characterization of tissues collected at necropsy suggested a local pulmonary inflammatory response with increased levels of macrophages in the lung, but a limited neurologic response. These data provide the first clear evidence of neurological involvement in the AGM that recapitulates human disease. With the development of a disease model that is more representative of human disease, these data suggest that NiV infection in the AGM may be appropriate for evaluating therapeutic countermeasures directed at virus induced neuropathogenesis. PMID- 30462638 TI - Bacterial group II introns generate genetic diversity by circularization and trans-splicing from a population of intron-invaded mRNAs. AB - Group II introns are ancient retroelements that significantly shaped the origin and evolution of contemporary eukaryotic genomes. These self-splicing ribozymes share a common ancestor with the telomerase enzyme, the spliceosome machinery as well as the highly abundant spliceosomal introns and non-LTR retroelements. More than half of the human genome thus consists of various elements that evolved from ancient group II introns, which altogether significantly contribute to key functions and genetic diversity in eukaryotes. Similarly, group II intron-related elements in bacteria such as abortive phage infection (Abi) retroelements, diversity generating retroelements (DGRs) and some CRISPR-Cas systems have evolved to confer important functions to their hosts. In sharp contrast, since bacterial group II introns are scarce, irregularly distributed and frequently spread by lateral transfer, they have mainly been considered as selfish retromobile elements with no beneficial function to their host. Here we unveil a new group II intron function that generates genetic diversity at the RNA level in bacterial cells. We demonstrate that Ll.LtrB, the model group II intron from Lactococcus lactis, recognizes specific sequence motifs within cellular mRNAs by base pairing, and invades them by reverse splicing. Subsequent splicing of ectopically inserted Ll.LtrB, through circularization, induces a novel trans splicing pathway that generates exon 1-mRNA and mRNA-mRNA intergenic chimeras. Our data also show that recognition of upstream alternative circularization sites on intron-interrupted mRNAs release Ll.LtrB circles harboring mRNA fragments of various lengths at their splice junction. Intergenic trans-splicing and alternative circularization both produce novel group II intron splicing products with potential new functions. Overall, this work describes new splicing pathways in bacteria that generate, similarly to the spliceosome in eukaryotes, genetic diversity at the RNA level while providing additional functional and evolutionary links between group II introns, spliceosomal introns and the spliceosome. PMID- 30462639 TI - Organization of oversight for integrated control of neglected tropical diseases within Ministries of Health. AB - BACKGROUND: Neglected tropical diseases (NTDs) are communicable diseases that impact approximately 1 billion people, but receive relatively little research, funding, and attention. Many NTDs have similar treatments, epidemiology, and geographic distribution, and as a result, the integration of control efforts can improve accountability, efficiency, and cost-effectiveness of programs. Here, we examine the landscape of efforts towards NTD integration across countries with the highest burden of disease, and review the administrative management of integration in order to identify approaches and pathways for integration. METHODOLOGY AND PRINCIPAL FINDINGS: We utilized a standardized system to score countries for NTD endemnicity to create a list of 25 countries with the highest overall burden of NTDs. We then conducted a literature review to characterize the NTD control programs in the focus countries. Six countries were selected for key informant interviews to validate literature review results and gather additional data on opportunities and obstacles to NTD integration, from an administrative perspective. The majority of countries included in the study were located in Africa, with the remainder from Asia, North America, and South America. Multiple models and pathways were observed for the integration of NTD programs, in combination with other NTD programs, other diseases, or other health programs. Substantial heterogeneity existed with respect to the NTD control programs, and no country had integrated all of their NTD control efforts into a single program. NTDs that can be treated with preventative chemotherapy were frequently integrated into a single program. Leprosy control was also frequently integrated with those of other communicable diseases, and notably tuberculosis. Barriers to NTD integration may result from internal administrative obstacles or external obstacles. CONCLUSIONS: Although many countries have begun to integrate NTD control efforts, additional work will be required to realize the full benefits of integration in most of the countries examined here. Moving forward, NTD integration efforts must ensure that administrative structures are designed to maximize the potential success of integrated programs and account for existing administrative processes. PMID- 30462640 TI - Backpack PCR: A point-of-collection diagnostic platform for the rapid detection of Brugia parasites in mosquitoes. AB - BACKGROUND: Currently, molecular xenomonitoring efforts for lymphatic filariasis rely on PCR or real-time PCR-based detection of Brugia malayi, Brugia timori and Wuchereria bancrofti in mosquito vectors. Most commonly, extraction of DNA from mosquitoes is performed using silica column-based technologies. However, such extractions are both time consuming and costly, and the diagnostic testing which follows typically requires expensive thermal cyclers or real-time PCR instruments. These expenses present significant challenges for laboratories in many endemic areas. Accordingly, in such locations, there exists a need for inexpensive, equipment-minimizing diagnostic options that can be transported to the field and implemented in minimal resource settings. Here we present a novel diagnostic approach for molecular xenomonitoring of filarial parasites in mosquitoes that uses a rapid, NaOH-based DNA extraction methodology coupled with a portable, battery powered PCR platform and a test strip-based DNA detection assay. While the research reported here serves as a proof-of-concept for the backpack PCR methodology for the detection of filarial parasites in mosquitoes, the platform should be easily adaptable to the detection of W. bancrofti and other mosquito-transmitted pathogens. METHODOLOGY/PRINCIPAL FINDINGS: Through comparisons with standard silica column-based DNA extraction techniques, we evaluated the performance of a rapid, NaOH-based methodology for the extraction of total DNA from pools of parasite-spiked vector mosquitoes. We also compared our novel test strip-based detection assay to real-time PCR and conventional PCR coupled with gel electrophoresis, and demonstrated that this method provides sensitive and genus-specific detection of parasite DNA from extracted mosquito pools. Finally, by comparing laboratory-based thermal cycling with a field friendly miniaturized PCR approach, we have demonstrated the potential for the point-of-collection-based use of this entire diagnostic platform that is compact enough to fit into a small backpack. CONCLUSIONS/SIGNIFICANCE: Because this point of-collection diagnostic platform eliminates reliance on expensive and bulky instrumentation without compromising sensitivity or specificity of detection, it provides an alternative to cost-prohibitive column-dependent DNA extractions that are typically coupled to detection methodologies requiring advanced laboratory infrastructure. In doing so, this field-ready system should increase the feasibility of molecular xenomonitoring within B. malayi-endemic locations. Of greater importance, this backpack PCR system also provides the proof-of-concept framework for the development of a parallel assay for the detection of W. bancrofti. PMID- 30462641 TI - The right to deworming: The case for girls and women of reproductive age. PMID- 30462643 TI - Hepatic gene body hypermethylation is a shared epigenetic signature of murine longevity. AB - Dietary, pharmacological and genetic interventions can extend health- and lifespan in diverse mammalian species. DNA methylation has been implicated in mediating the beneficial effects of these interventions; methylation patterns deteriorate during ageing, and this is prevented by lifespan-extending interventions. However, whether these interventions also actively shape the epigenome, and whether such epigenetic reprogramming contributes to improved health at old age, remains underexplored. We analysed published, whole-genome, BS seq data sets from mouse liver to explore DNA methylation patterns in aged mice in response to three lifespan-extending interventions: dietary restriction (DR), reduced TOR signaling (rapamycin), and reduced growth (Ames dwarf mice). Dwarf mice show enhanced DNA hypermethylation in the body of key genes in lipid biosynthesis, cell proliferation and somatotropic signaling, which strongly correlates with the pattern of transcriptional repression. Remarkably, DR causes a similar hypermethylation in lipid biosynthesis genes, while rapamycin treatment increases methylation signatures in genes coding for growth factor and growth hormone receptors. Shared changes of DNA methylation were restricted to hypermethylated regions, and they were not merely a consequence of slowed ageing, thus suggesting an active mechanism driving their formation. By comparing the overlap in ageing-independent hypermethylated patterns between all three interventions, we identified four regions, which, independent of genetic background or gender, may serve as novel biomarkers for longevity-extending interventions. In summary, we identified gene body hypermethylation as a novel and partly conserved signature of lifespan-extending interventions in mouse, highlighting epigenetic reprogramming as a possible intervention to improve health at old age. PMID- 30462642 TI - Root colonization and growth promotion of soybean, wheat and Chinese cabbage by Bacillus cereus YL6. AB - Although phosphate-solubilizing bacteria (PSBs) are used in agricultural production, comprehensive research on PSB that colonize the rhizosphere of different plants and promote plant growth is lacking. This study was conducted to examine the growth-promoting effects and colonizing capacity of strain YL6, a PSB. YL6 not only increased the biomass of soybean and wheat in pot experiments but also increased the yield and growth of Chinese cabbage under field conditions. The observed growth promotion was related to the capacity of YL6 to dissolve inorganic and organic phosphorus and to produce indole-3-acetic (IAA) and gibberellin (GA). After applying YL6 to soybean, wheat and Chinese cabbage, the rhizosphere soil available phosphorus (available P) content increased by 120.16%, 62.47% and 7.21%, respectively, and the plant total phosphorus content increased by 198.60%, 6.20% and 78.89%, respectively, compared with plants not treated with YL6. To examine plant colonization, YL6 labeled with green fluorescent protein (YL6-GFP) was inoculated into the plant rhizosphere and found to first colonize the root surface and hairs and then to penetrate into the intercellular spaces and vessels. Collectively, these results demonstrate that YL6 promotes the growth of three different crops and colonizes them in a similar manner. The findings therefore provide a solid foundation for probing the mechanisms by which PSB affect plant growth. PMID- 30462644 TI - Within-species phylogenetic relatedness of a common mycorrhizal fungus affects evenness in plant communities through effects on dominant species. AB - Arbuscular mycorrhizal fungi (AMF) have been shown to influence plant community structure and diversity. Studies based on single plant-single AMF isolate experiments show that within AMF species variation leads to large differential growth responses of different plant species. Because of these differential effects, genetic differences among isolates of an AMF species could potentially have strong effects on the structure of plant communities. We tested the hypothesis that within species variation in the AMF Rhizophagus irregularis significantly affects plant community structure and plant co-existence. We took advantage of a recent genetic characterization of several isolates using double digest restriction-site associated DNA sequencing (ddRADseq). This allowed us to test not only for the impact of within AMF species variation on plant community structure but also for the role of the R. irregularis phylogeny on plant community metrics. Nine isolates of R. irregularis, belonging to three different genetic groups (Gp1, Gp3 and Gp4), were used as either single inoculum or as mixed diversity inoculum. Plants in a mesocosm representing common species that naturally co-exist in European grasslands were inoculated with the different AMF treatments. We found that within-species differences in R. irregularis did not strongly influence the performance of individual plants or the structure of the overall plant community. However, the evenness of the plant community was affected by the phylogeny of the fungal isolates, where more closely-related AMF isolates were more likely to affect plant community evenness in a similar way compared to more genetically distant isolates. This study underlines the effect of within AMF species variability on plant community structure. While differential effects of the AMF isolates were not strong, a single AMF species had enough functional variability to change the equilibrium of a plant community in a way that is associated with the evolutionary history of the fungus. PMID- 30462645 TI - EAPB0503: An Imiquimod analog with potent in vitro activity against cutaneous leishmaniasis caused by Leishmania major and Leishmania tropica. AB - Cutaneous Leishmaniasis (CL) is a parasitic infection classified by the WHO as one of the most uncontrolled spreading neglected diseases. Syria is endemic for Leishmania tropica and Leishmania major, causing CL in the Eastern Mediterranean. The large-scale displacement of Syrian refugees exacerbated the spread of CL into neighboring countries. Therapeutic interventions against CL include local, systemic and physical treatments. The high risk for drug-resistance to current treatments stresses the need for new therapies. Imiquimod is an immunomodulatory drug with a tested efficacy against L. major species. Yet, Imiquimod efficacy against L. tropica and the molecular mechanisms dictating its potency are still underexplored. In this study, we characterized the effect of Imiquimod against L. tropica and L. major, and characterized the molecular mechanisms dictating its anti-leishmanial efficacy against both strains. We also investigated the potency and molecular mechanisms of an Imiquimod analog, EAPB0503, against these two strains. We have tested the effect of Imiquimod and EAPB0503 on macrophages infected with either L. major, L. tropica strains, or patient-derived freshly isolated L. tropica parasites. The anti-amastigote activity of either drugs was assessed by quantitative real time PCR (RT-PCR) using kinetoplast specific primers, confocal microscopy using the Glycoprotein 63 (Gp63) Leishmania amastigote antibody or by histology staining. The mechanism of action of either drugs on the canonical nuclear factor kappa- B (NF-kappaB) pathway was determined by western blot, and confocal microscopy. The immune production of cytokines upon treatment of infected macrophages with either drugs was assessed by ELISA. Both drugs reduced amastigote replication. EAPB0503 proved more potent, particularly on the wild type L. tropica amastigotes. Toll-Like Receptor-7 was upregulated, mainly by Imiquimod, and to a lesser extent by EAPB0503. Both drugs activated the NF-kappaB canonical pathway triggering an immune response and i-NOS upregulation in infected macrophages. Our findings establish Imiquimod as a strong candidate for treating L. tropica and show the higher potency of its analog EAPB0503 against CL. PMID- 30462646 TI - Salivary immunity and lower respiratory tract infections in non-elite marathon runners. AB - RATIONALE: Respiratory infections are common after strenuous exercise, when salivary immunity may be altered. We aim to investigate changes in salivary immunity after a marathon and its relationship with lower respiratory tract infections (LRTI) in healthy non-elite marathon runners. METHODS: Forty seven healthy marathon runners (28 males and 19 females) who completed the 42.195 km of the 2016 Barcelona marathon were studied. Saliva and blood samples were collected the day before the marathon and two days after the end of the race. Salivary IgA, antimicrobial proteins (lactoferrin, lysozyme) and chemokines (Groalpha, Grobeta, MCP-1) were determined using ELISA kits in saliva supernatant. Blood biochemistry and haemogram were analyzed in all participants. The presence of LRTI was considered in those runners who reported infectious lower respiratory tract symptoms during a minimum of 3 consecutive days in the 2 weeks after the race. RESULTS: Eight participants (17%) presented a LRTI during the 2 weeks of follow up. Higher lysozyme levels were detected after the race in runners with LRTI when compared with those without infection. A decrease in salivary lysozyme, Groalpha and Grobeta levels after the race were observed in those runners who did not develop a LRTI when compared to basal levels. Salivary Groalpha levels correlated with basophil blood counts, and salivary lysozyme levels correlated with leukocyte blood counts. CONCLUSIONS: LRTI are common after a marathon race in non elite healthy runners. Changes in salivary antimicrobial proteins and chemokines are related to the presence of LRTI and correlate with systemic defense cells, which suggest an important role of salivary immunity in the development of LRTI in non-elite marathon runners. PMID- 30462647 TI - Can mesenchymal stem cells and their conditioned medium assist inflammatory chondrocytes recovery? AB - Osteoarthritis (OA), one of the most common joint disease, affects more than 80% of the population aged 70 or over. Mesenchymal stem cells (MSCs) show multi potent differentiation and self-renewal capability, and, after exposure to an inflammatory environment, also exhibit immunosuppressive properties. In this study, we have used a model of lipopolysaccharide (LPS)-stimulated chondrocytes to evaluate MSC anti-inflammatory efficacy. The anti-inflammatory mechanism was tested in two cell-contained culture systems: (i) MSC-chondrocyte indirect contact system and (ii) MSC-chondrocyte direct contact system, and one cytokine only culture system: MSC-conditioned medium (CM) system. Results showed that MSCs reduced chondrocyte inflammation through both paracrine secretion and cell-to cell contact. The inflammation-associated, and free-radical-related genes were down-regulated significantly in the direct contact system on 24 h, however, the TNF-alpha. IL-6 were upregulated and aggrecan, COLII were downregulated on 72 h in direct contact system. Moreover, we found CM produced by MSC possess well therapeutic effect on inflammatory chondorcyte, and the 10-fold concentrated MSC conditioned medium could down-regulated chondorcyte synthesis inflammation associated, and free-radical-related genes, such as TNF-alpha, IL-1beta, IL-6 and iNOS even treated for 72 h. In conclusion, MSC-CM showed great potential for MSC based therapy for OA. PMID- 30462648 TI - The economic impact of non-communicable diseases among households in South Asia and their coping strategy: A systematic review. AB - BACKGROUND: Out of pocket payment (OOPP), is the major health financing mechanism in South Asia region. With the rising burden of non-communicable diseases (NCDs), the region is facing a high financial burden. However, the extent and nature of economic impact caused by treatment and management of NCDs at the household level is yet unknown. METHOD: We conducted a systematic review using Medline and Embase databases. Only peer-reviewed quantitative studies published between January 2000 to December 2016 assessing OOPP or catastrophic health expenditure or impoverishment or financial coping strategy due to at least one of the four major NCDs-cardiovascular diseases(CVDs), diabetes, cancer, chronic respiratory disease in South Asia region was included in the review. The review is registered in PROSPERO no: CRD42017059345. RESULTS: A total of 21 studies (of 2693 records identified) met the inclusion criteria. The economic impact was most frequently studied in CVDs and in terms of OOPP. The studies collectively indicated high OOPP, higher likelihood of catastrophic expenditure and impoverishment for inpatient care for these major NCDs which was visible in all income levels. Borrowing and selling off assets were the most common forms of coping strategies adopted and varied inconsistently between urban and rural households. The true extent of the economic impact, however, remains difficult to determine due to methodological heterogeneity regarding outcomes reported and measures employed for calculation of OOPP, catastrophic expenditure, and impoverishment across these four major NCDs and between nations. CONCLUSION: The economic impact due to treatment and management of CVDs, diabetes, cancer and chronic respiratory diseases among households in South Asia seems dire. Given the lack of sufficient evidence the review stresses the need for further research in the region to develop evidence-informed nationally tailored prepayment mechanisms covering NCDs to reduce economic vulnerability and standardization of tools measuring the economic impact for generating comparable estimates. PMID- 30462649 TI - Inter-observer agreement in athletes ECG interpretation using the recent international recommendations for ECG interpretation in athletes among observers with different levels of expertise. AB - INTRODUCTION: International criteria for the interpretation of the athlete's electrocardiogram (ECG) have been proposed. We aimed to evaluate the inter observer agreement among observers with different levels of expertise. METHODS: Consecutive ECGs of Swiss elite athletes (>=14 years), recorded during routine pre-participation screening between 2013 and 2016 at the Swiss Federal Institute of Sports were analysed. A medical student (A), a cardiology fellow (B) and an electrophysiologist (C) interpreted the ECG's independently according to the most recent criteria. The frequencies and percentages for each observer were calculated. An inter-observer reliability analysis using Cohen Kappa (kappa) statistics was used to determine consistency among observers. RESULTS: A total of 287 ECGs (64.1% males) were analysed. Mean age of the athletes was 20.4+/-4.9 years. The prevalence of abnormal ECG findings was 1.4%. Both, normal and borderline findings in athletes showed moderate to good agreement between all observers. kappa scores for abnormal findings resulted in excellent agreement (kappa 0.855 in observer A vs C and B vs C to kappa 1.000 in observer A vs B). Overall agreement ranged from moderate (kappa 0.539; 0.419-0.685 95% CI) between observer B vs C to good agreement (kappa 0.720; 0.681-0.821 95% CI) between observer A vs B. CONCLUSIONS: Our cohort of elite athletes had a low prevalence of abnormal ECGs. Agreement in abnormal ECG findings with the use of the recently published International recommendations for ECG interpretation in athletes among observers with different levels of expertise was excellent. ECG interpretation resulted in moderate to good overall agreement. PMID- 30462650 TI - Schema therapy for borderline personality disorder: A qualitative study of patients' perceptions. AB - Schema therapy (ST) has been found to be effective in the treatment of borderline personality disorder (BPD). However very little is known about how the therapy is experienced by individuals with BPD including which specific elements of ST are helpful or unhelpful from their perspectives. The aim of this study is to explore BPD patients' experiences of receiving ST, in intensive group or combined group individual format. Qualitative data were collected through semi-structured interviews with 36 individuals with a primary diagnosis of BPD (78% females) who received ST for at least 12 months. Participants were recruited as part of an international, multicenter randomized controlled trial (RCT). Interview data (11 Australian, 12 Dutch, 13 German) were analyzed following the procedures of qualitative content analysis. Patients' perceptions of the benefits gained in ST included improved self-understanding, and better awareness and management of their own emotional processes. While some aspects of ST, such as experiential techniques were perceived as emotionally confronting, patient narratives informed that this was necessary. Some recommendations for improved implementation of ST include the necessary adjunct of individual sessions to group ST and early discussion of therapy termination. Implications of the findings are also discussed, in particular the avenues for assessing the suitability of patients for group ST; management of group conflict and the optimal format for delivering treatment in the intensive group versus combined group-individual formats. PMID- 30462651 TI - A sport-specific wearable jump monitor for figure skating. AB - Advancements in wearable technology have facilitated performance monitoring in a number of sports. Figure skating may also benefit from this technology, but the inherent movements present some unique challenges. The purpose of this study was to evaluate the feasibility of using an inertial measurement unit (IMU) to monitor three aspects of figure skating jumping performance: jump count, jump height, and rotation speed. Seven competitive figure skaters, outfitted with a waist-mounted IMU, performed a total of 59 isolated multi-revolution jumps and their competition routines, which consisted of 41 multi-revolution jumps along with spins, footwork, and other skills. The isolated jumps were used to develop a jump identification algorithm, which was tested on the competition routines. Four algorithms to estimate jump height from flight time were then evaluated using calibrated video as a gold standard. The identification algorithm counted 39 of the 41 program jumps correctly, with one false positive. Flight time and jump height errors under 7% and 15% respectively were found using a peak-to-peak scaling algorithm. Rotation speeds up to 1,500 degrees /s were noted, with peak speeds occurring just over halfway between takeoff and landing. Overall, jump monitoring via IMUs may be an efficient aid for figure skaters training multi revolution jumps. PMID- 30462652 TI - Migration corridors of adult Golden Eagles originating in northwestern North America. AB - There has been increasing concern for Golden Eagle (Aquila chrysaetos) populations in North America due to current and future projections of mortality risk and habitat loss from anthropogenic sources. Identification of high-use movement corridors and bottlenecks for the migratory portion of the eagle population in western North America is an important first step to help habitat conservation and management efforts to reduce the risk of eagle mortality. We used dynamic Brownian Bridge movement models to estimate utilization distributions of adult eagles migrating across the western North America and identified high-use areas by calculating the overlap of individuals on population and regional levels. On a population level, the Rocky Mountain Front from east central British Columbia to central Montana and southwestern Yukon encompassed the most used migration corridors with our study extent for both spring and fall. Regional analysis on a 100 x 200 km scale revealed additional moderate and high level use corridors in the central British Columbia plateaus. Eagles were more dispersed in the spring until their routes converged in southern Alberta. High use fall corridors extended farther south into central Wyoming. Knowledge of these high-use areas can aid in conservation and site planning to help maintain and enhance migratory Golden Eagle populations in western North America. PMID- 30462653 TI - Bt eggplant (Solanum melongena L.) in Bangladesh: Fruit production and control of eggplant fruit and shoot borer (Leucinodes orbonalis Guenee), effects on non target arthropods and economic returns. AB - Eggplant or brinjal (Solanum melongena) is a popular vegetable grown throughout Asia where it is attacked by brinjal fruit and shoot borer (BFSB) (Leucinodes orbonalis). Yield losses in Bangladesh have been reported up to 86% and farmers rely primarily on frequent insecticide applications to reduce injury. Bangladesh has developed and released four brinjal varieties producing Cry1Ac (Bt brinjal) and is the first country to do so. We report on the first replicated field trials comparing four Bt brinjal varieties to their non-Bt isolines, with and without standard insecticide spray regimes. Results of the two-year study (2016-17) indicated Bt varieties had increased fruit production and minimal BFSB fruit infestation compared with their respective non-Bt isolines. Fruit infestation for Bt varieties varied from 0-2.27% in 2016, 0% in 2017, and was not significantly affected by the spray regime in either year. In contrast, fruit infestation in non-Bt lines reached 36.70% in 2016 and 45.51% in 2017, even with weekly spraying. An economic analysis revealed that all Bt lines had higher gross returns than their non-Bt isolines. The non-sprayed non-Bt isolines resulted in negative returns in most cases. Maximum fruit yield was obtained from sprayed plots compared to non-sprayed plots, indicating that other insects such as whiteflies, thrips and mites can reduce plant vigor and subsequent fruit weight. Statistically similar densities of non-target arthropods, including beneficial arthropods, were generally observed in both Bt and non-Bt varieties. An additional trial that focused on a single Bt variety and its isoline provided similar results on infestation levels, with and without sprays, and similarly demonstrated higher gross returns and no significant effects on non-target arthropods. Together, these studies indicate that the four Bt brinjal lines are extremely effective at controlling BFSB in Bangladesh without affecting other arthropods, and provide greater economic returns than their non-Bt isolines. PMID- 30462654 TI - Dengue seroprevalence in a cohort of schoolchildren and their siblings in Yucatan, Mexico (2015-2016). AB - BACKGROUND: The implementation of vector control interventions and potential introduction new tools requires baseline data to evaluate their direct and indirect effects. The objective of the study is to present the seroprevalence of dengue infection in a cohort of children 0 to 15 years old followed during 2015 to 2016, the risk factors and the role of enhanced surveillance strategies in three urban sites (Merida, Ticul and Progreso) in Yucatan, Mexico. METHODS: A cohort of school children and their family members was randomly selected in three urban areas with different demographic, social conditions and levels of transmission. We included results from 1,844 children aged 0 to 15 years. Serum samples were tested for IgG, NS1 and IgM. Enhanced surveillance strategies were established in schools (absenteeism) and cohort families (toll-free number). RESULTS: Seroprevalence in children 0 to 15 years old was 46.8 (CI 95% 44.1-49.6) with no difference by sex except in Ticul. Prevalence increased with age and was significantly lower in 0 to 5 years old (26.9%, 95% CI:18.4-35.4) compared with 6 to 8 years old (43.9%, 95% CI:40.1-47.7) and 9 to 15 years old (61.4%, 95% CI:58.0-64.8). Sharing the domestic space with other families increased the risk 1.7 times over the individual families that own or rented their house, while risk was significantly higher when kitchen and bathroom were outside. Complete protection with screens in doors and windows decreased risk of infection. Seroprevalence was significantly higher in the medium and high risk areas. CONCLUSIONS: The prevalence of antibodies in children 0 to 15 years in three urban settings in the state of Yucatan describe the high exposure and the heterogenous transmission of dengue virus by risk areas and between schools in the study sites. The enhanced surveillance strategy was useful to improve detection of dengue cases with the coincident transmission of chikungunya and Zika viruses. PMID- 30462655 TI - National character stereotypes mirror language use: A study of Canadian and American tweets. AB - National character stereotypes, or beliefs about the personality characteristics of the members of a nation, present a paradox. Such stereotypes have been argued to not be grounded in the actual personality traits of members of nations, yet they are also prolific and reliable. Stereotypes of Canadians and Americans exemplify the paradox; people in both nations strongly believe that the personality profiles of typical Canadians and Americans diverge, yet aggregated self-reports of personality profiles of Canadians and Americans show no reliable differences. We present evidence that the linguistic behavior of nations mirrors national character stereotypes. Utilizing 40 million tweets from the microblogging platform Twitter, in Study 1A we quantify the words and emojis diagnostic of Canadians and Americans. In Study 1B we explore the positivity of national language use. In Studies 2A and 2B, we present the 120 most nationally diagnostic words and emojis of each nation to naive participants, and ask them to assess personality of a hypothetical person who uses either diagnostically Canadian or American words and emojis. Personality profiles derived from the diagnostic words of each nation bear close resemblance to national character stereotypes. We therefore propose that national character stereotypes may be partially grounded in the collective linguistic behaviour of nations. PMID- 30462656 TI - Association of herpesviruses and stroke: Systematic review and meta-analysis. AB - BACKGROUND: Herpesviruses induce a range of inflammatory effects potentially contributing to an increased risk of stroke. OBJECTIVES: To investigate whether patients with infection, or reactivation of, human herpesviruses are at increased stroke risk, compared to those without human herpesviruses. DATA SOURCES: Six medical databases and grey literature sources from inception to January 2017. STUDY ELIGIBILITY CRITERIA: Studies where the exposure was any human herpesvirus and the outcome was stroke. We included randomised controlled trials, cohort, case-control, case-crossover and self-controlled case series designs. METHODS: Meta-analyses when sufficiently homogeneous studies were available. Quality of evidence across studies was assessed. RESULTS: We identified 5012 publications; 41 met the eligibility criteria. Across cohort and self-controlled case series studies, there was moderate quality evidence that varicella infection in children was associated with a short-term increased stroke risk. Zoster was associated with a 1.5-fold increased stroke risk four weeks following onset (summary estimate: 1.55, 95%CI 1.46-1.65), which resolved after one year. Subgroup analyses suggested post-zoster stroke risk was greater among ophthalmic zoster patients, younger individuals and those not prescribed antivirals. Recent infection/reactivation of cytomegalovirus and herpes simplex viruses, but not past infection, was associated with increased stroke risk; however the evidence across studies was mainly derived from small, very low quality case-control studies. CONCLUSIONS: Our review shows an increased stroke risk following zoster and suggests that recent infection or reactivation of other herpesviruses increases stroke risk, although better evidence is needed. Herpesviruses are common and potentially preventable; these findings may have implications for reducing stroke burden. PMID- 30462657 TI - RAMP1 in Kupffer cells is a critical regulator in immune-mediated hepatitis. AB - The significance of the relationship between the nervous and immune systems with respect to disease course is increasingly apparent. Immune cells in the liver and spleen are responsible for the development of acute liver injury, yet the regulatory mechanisms of the interactions remain elusive. Calcitonin gene-related peptide (CGRP), which is released from the sensory nervous system, regulates innate immune activation via receptor activity-modifying protein 1 (RAMP1), a subunit of the CGRP receptor. Here, we show that RAMP1 in Kupffer cells (KCs) plays a critical role in the etiology of immune-mediated hepatitis. RAMP1 deficient mice with concanavalin A (ConA)-mediated hepatitis, characterized by severe liver injury accompanied by infiltration of immune cells and increased secretion of pro-inflammatory cytokines by KCs and splenic T cells, showed poor survival. Removing KCs ameliorated liver damage, while depleting T cells or splenectomy led to partial amelioration. Adoptive transfer of splenic T cells from RAMP1-deficient mice led to a modest increase in liver injury. Co-culture of KCs with splenic T cells led to increased cytokine expression by both cells in a RAMP1-dependent manner. Thus, immune-mediated hepatitis develops via crosstalk between immune cells. RAMP1 in KCs is a key regulator of immune responses. PMID- 30462660 TI - Interaction of land management and araucaria trees in the maintenance of landscape diversity in the highlands of southern Brazil. AB - In the southern Brazilian highlands, pre-Columbian societies created domesticated landscapes through the use and management of forests, including nurse Araucaria angustifolia trees, a common conifer in these regions. Nowadays, local smallholders still use traditional practices, such as burning, to promote vegetation for cattle grazing in highland grasslands. Even though burning is normally of small extent and low frequency, such management can slow down natural forest expansion and contribute to the maintenance of grasslands, by opposing the facilitative effect of nurse araucaria trees. To comprehend the interplay between human cultural management, species interactions and the environment, it is important to better understand how these relations affect diversity and composition. Our goal was to investigate how land management, biotic interactions and abiotic factors affect saplings species richness, abundance and composition. We hypothesized that (1) land management would decrease sapling richness and abundance and change sapling composition, (2) nurse araucaria trees would increase species richness and abundance and change sapling composition, and (3) the interactive effect between land management and nurse araucaria trees would shape sapling richness, abundance and composition. Data were collected in unmanaged and managed conditions, both beneath araucaria crowns and in nearby treeless areas. Our results indicate that abundance and species composition are affected by land management and araucaria crown influence. The highest values of sapling abundance were found beneath crowns in unmanaged areas. Species composition changed between all assessed combinations of land management and crown influence. Our study demonstrates the major roles of land management and facilitation in structuring communities, despite the effects of rock and grass cover. Moreover, our results clarify patterns and processes that may emerge in natural highland grasslands, such as the conversion of grasslands into forests and the loss of cultural landscapes when the main local management actions are excluded. PMID- 30462659 TI - Epidemiology of severe acute respiratory infections from hospital-based surveillance in Madagascar, November 2010 to July 2013. AB - BACKGROUND: Few comprehensive data exist regarding the epidemiology of severe acute respiratory infections (SARI) in low income countries. This study aimed at identifying etiologies and describing clinical features of SARI-associated hospitalization in Madagascar. METHODS: It is a prospective surveillance of SARI in 2 hospitals for 3 years. Nasopharyngeal swabs, sputum, and blood were collected from SARI patients enrolled and tested for viruses and bacteria. Epidemiological and clinical information were obtained from case report forms. RESULTS: Overall, 876 patients were enrolled in the study, of which 83.1% (728/876) were tested positive for at least one pathogen. Viral and bacterial infections occurred in 76.1% (667/876) and 35.8% (314/876) of tested samples, respectively. Among all detected viruses, respiratory syncytial virus (RSV) was the most common (37.7%; 348/924) followed by influenza virus A (FLUA, 18.4%; 170/924), rhinovirus (RV, 13.5%; 125/924), and adenovirus (ADV, 8.3%; 77/924). Among bacteria, Streptococcus pneumoniae (S. pneumoniae, 50.3%, 189/370) was the most detected followed by Haemophilus influenzae type b (Hib, 21.4%; 79/370), and Klebsiella (4.6%; 17/370). Other Streptococcus species were found in 8.1% (30/370) of samples. Compared to patients aged less than 5 years, older age groups were significantly less infected with RSV. On the other hand, patients aged more than 64 years (OR = 3.66) were at higher risk to be infected with FLUA, while those aged 15-29 years (OR = 3.22) and 30-64 years (OR = 2.39) were more likely to be infected with FLUB (influenza virus B). CONCLUSION: The frequency of influenza viruses detected among SARI patients aged 65 years and more highlights the need for health authorities to develop strategies to reduce morbidity amongst at-risk population through vaccine recommendation. Amongst young children, the demonstrated burden of RSV should guide clinicians for a better case management of children. These findings reveal the need to develop point-of-care tests to avoid overuse of antibiotics and to promote vaccine that could reduce drastically the RSV hospitalizations. PMID- 30462658 TI - Cortical control of a tablet computer by people with paralysis. AB - General-purpose computers have become ubiquitous and important for everyday life, but they are difficult for people with paralysis to use. Specialized software and personalized input devices can improve access, but often provide only limited functionality. In this study, three research participants with tetraplegia who had multielectrode arrays implanted in motor cortex as part of the BrainGate2 clinical trial used an intracortical brain-computer interface (iBCI) to control an unmodified commercial tablet computer. Neural activity was decoded in real time as a point-and-click wireless Bluetooth mouse, allowing participants to use common and recreational applications (web browsing, email, chatting, playing music on a piano application, sending text messages, etc.). Two of the participants also used the iBCI to "chat" with each other in real time. This study demonstrates, for the first time, high-performance iBCI control of an unmodified, commercially available, general-purpose mobile computing device by people with tetraplegia. PMID- 30462661 TI - Giant flagellins form thick flagellar filaments in two species of marine gamma proteobacteria. AB - Flagella, the primary means of motility in bacteria, are helical filaments that function as microscopic propellers composed of thousands of copies of the protein flagellin. Here, we show that many bacteria encode "giant" flagellins, greater than a thousand amino acids in length, and that two species that encode giant flagellins, the marine gamma-proteobacteria Bermanella marisrubri and Oleibacter marinus, produce monopolar flagellar filaments considerably thicker than filaments composed of shorter flagellin monomers. We confirm that the flagellum from B. marisrubri is built from its giant flagellin. Phylogenetic analysis reveals that the mechanism of evolution of giant flagellins has followed a stepwise process involving an internal domain duplication followed by insertion of an additional novel insert. This work illustrates how "the" bacterial flagellum should not be seen as a single, idealised structure, but as a continuum of evolved machines adapted to a range of niches. PMID- 30462662 TI - A differential privacy protecting K-means clustering algorithm based on contour coefficients. AB - This paper, based on differential privacy protecting K-means clustering algorithm, realizes privacy protection by adding data-disturbing Laplace noise to cluster center point. In order to solve the problem of Laplace noise randomness which causes the center point to deviate, especially when poor availability of clustering results appears because of small privacy budget parameters, an improved differential privacy protecting K-means clustering algorithm was raised in this paper. The improved algorithm uses the contour coefficients to quantitatively evaluate the clustering effect of each iteration and add different noise to different clusters. In order to be adapted to the huge number of data, this paper provides an algorithm design in MapReduce Framework. Experimental finding shows that the new algorithm improves the availability of the algorithm clustering results under the condition of ensuring individual privacy without significantly increasing its operating time. PMID- 30462663 TI - Southern expansion of the invasive ant Wasmannia auropunctata within its native range and its relation with clonality and human activity. AB - The little fire ant Wasmannia auropunctata, native to the Neotropics, has become a serious pest worldwide over the past 100 years. It was originally distributed from Mexico to northern Argentina and new evidence suggests a recent southern range expansion during the last 60 years reaching central Argentina. This supercolonial ant species has a polymorphic reproductive system. Some populations, mostly found in undisturbed natural environments, are characterised by a classical sexual haplodiploid reproductive system. In other populations, which mainly occur in human-modified habitats, diploid queens and haploid males are produced clonally while workers are produced sexually. Here we studied the association between the recent southern range expansion of W. auropunctata in relation to human activity and clonality. We carried out an extensive survey within the southern limit of the species' native distribution and characterised the type of habitat where populations were found. Moreover, we genetically determined the type of reproductive system in 35 populations by genotyping at 12 microsatellite loci a total of 191 reproductive individuals (i.e. queens and/or males). Clonality was the most common reproductive system, occurring in 31 out of 35 populations analysed. All the populations found in the recently colonised area in central Argentina were clonal and established in human-modified habitats, suggesting that clonality together with human activity might have facilitated the southwards expansion of W. auropunctata. PMID- 30462664 TI - Establishing spatial and temporal patterns in Microcystis sediment seed stock viability and their relationship to subsequent bloom development in Western Lake Erie. AB - This study assessed the distribution, abundance, and viability of pre- and post overwintering Microcystis sediment seed stocks in Western Lake Erie and how these variables are potentially related to past and subsequent bloom formation. We conducted a two-year spatiotemporal survey of vegetative seed stocks in Western Lake Erie, the region where annual algal blooms generally develop. Sediment was collected from 16 sites covering an area of 375 km2 and water column depths ranging from 3-9 meters. Sample collection occurred in November 2014, April 2015, November 2015, and April 2016. The abundance of total and potentially-toxic Microcystis cell equivalents were determined using quantitative polymerase chain reaction. A series of laboratory experiments using lake sediment were conducted to assess the viability of Microcystis vegetative seed stocks. Across all sampling periods, the abundance of total Microcystis in the sediment ranged from 6.6 x 104 to 1.7 x 109 cell equivalents g-1, and potentially-toxic Microcystis ranged from 1.4 x 103 to 4.7 x 106 cell equivalents g-1. The percent potentially toxic Microcystis in the sediment ranged from <1% to 68% across all samples. Total Microcystis abundance diminished significantly over winter with densities in spring nearly 10 times less than the previous fall. However, despite cell loss from fall to spring, lab experiments demonstrated that remaining non-toxic and potentially-toxic cells were viable after the overwintering period. Further, lab grow-out experiments indicate that potentially-toxic strains recruited at a slightly higher rate than non-toxic strains, and may in part, contribute to the pattern of higher relative toxicity during early stages of the blooms. The abundance and distribution of overwintering cells did not correlate strongly to areas in the lake where subsequent summer blooms were most persistent. However, numerical analysis suggests that recruitment of benthic overwintering populations could help explain a portion of the initial rapid increase in bloom biomass and the spatial extent of this bloom initiation, particularly when recruitment is paired with subsequent growth in appropriate water column conditions. PMID- 30462665 TI - Estimation of neuronal firing rate using Bayesian Adaptive Kernel Smoother (BAKS). AB - Neurons use sequences of action potentials (spikes) to convey information across neuronal networks. In neurophysiology experiments, information about external stimuli or behavioral tasks has been frequently characterized in term of neuronal firing rate. The firing rate is conventionally estimated by averaging spiking responses across multiple similar experiments (or trials). However, there exist a number of applications in neuroscience research that require firing rate to be estimated on a single trial basis. Estimating firing rate from a single trial is a challenging problem and current state-of-the-art methods do not perform well. To address this issue, we develop a new method for estimating firing rate based on a kernel smoothing technique that considers the bandwidth as a random variable with prior distribution that is adaptively updated under an empirical Bayesian framework. By carefully selecting the prior distribution together with Gaussian kernel function, an analytical expression can be achieved for the kernel bandwidth. We refer to the proposed method as Bayesian Adaptive Kernel Smoother (BAKS). We evaluate the performance of BAKS using synthetic spike train data generated by biologically plausible models: inhomogeneous Gamma (IG) and inhomogeneous inverse Gaussian (IIG). We also apply BAKS to real spike train data from non-human primate (NHP) motor and visual cortex. We benchmark the proposed method against established and previously reported methods. These include: optimized kernel smoother (OKS), variable kernel smoother (VKS), local polynomial fit (Locfit), and Bayesian adaptive regression splines (BARS). Results using both synthetic and real data demonstrate that the proposed method achieves better performance compared to competing methods. This suggests that the proposed method could be useful for understanding the encoding mechanism of neurons in cognitive related tasks. The proposed method could also potentially improve the performance of brain-machine interface (BMI) decoder that relies on estimated firing rate as the input. PMID- 30462666 TI - An initial experience with the use of whole body MRI for cancer screening and regular health checks. AB - OBJECTIVES: We evaluated the utility of whole-body MRI (WB MRI) for cancer screening and other regular health evaluations. METHODS: This retrospective study included 229 patients who underwent whole-body MRI as part of a routine health examination and cancer screening. The WB MRIs and radiologic reports were evaluated by a musculoskeletal radiologist, a neuroradiologist, and an abdominal radiologist. The consensus of their findings was characterized into three categories, as follows: suspicion of malignancy (category I); need for follow-up (category II); and no need for follow-up (category III). Any correlations between the abnormal findings and each study group were evaluated using the Mann-Whitney U test and chi-square test. RESULTS: There were six category I lesions, among which two cases were found to involve malignancy. The most common category II findings were annular tears of the disc (14% of category II findings) and severe disc bulging or protrusion, followed by shoulder bursitis and uterine myoma. The most common category III finding was mild disc bulging or protrusion (47% of category III findings). CONCLUSIONS: WB MRI can be used in cancer screening and for regular health evaluations. WB MRI not only provides information about potential malignancy, but also provides information regarding nonmalignant abnormalities that require further evaluation. PMID- 30462667 TI - Episodic memory performance in a multi-ethnic longitudinal study of 13,037 elderly. AB - Age-related changes in memory are not uniform, even in the absence of dementia. Characterization of non-disease associated cognitive changes is crucial to gain a more complete understanding of brain aging. Episodic memory was investigated in 13,037 ethnically diverse elderly (ages 72 to 85 years) with two to 15 years of follow-up, and with known dementia status, age, sex, education, and APOE genotypes. Adjusted trajectories of episodic memory performance over time were estimated using Latent Class Mixed Models. Analysis was conducted using two samples at baseline evaluation: i) non-cognitively impaired individuals, and ii) all individuals regardless of dementia status. We calculated the age-specific annual incidence rates of dementia in the non-demented elderly (n = 10,220). Two major episodic memory trajectories were estimated: 1) Stable-consisting of individuals exhibiting a constant or improved memory function, and 2) Decliner consisting of individuals whose memory function declined. The majority of the study participants maintain their memory performance over time. Compared to those with Stable trajectory, individuals characterized as Decliners were more likely to have non-white ethnic background, fewer years of education, a higher frequency of epsilon4 allele at APOE gene and five times more likely to develop dementia. The steepest decline in episodic memory was observed in Caribbean-Hispanics compared to non-Hispanic whites (p = 4.3 x 10-15). The highest incident rates of dementia were observed in the oldest age group, among those of Caribbean Hispanics ancestry and among Decliners who exhibited rates five times higher than those with Stable trajectories (11 per 100 person-years versus 3 per 100 person years. Age, education, ethnic background and APOE genotype influence the maintenance of episodic memory. Declining memory is one of the strongest predictors of incident dementia. PMID- 30462669 TI - Video game loot boxes are linked to problem gambling: Results of a large-scale survey. AB - Loot boxes are items in video games that can be paid for with real-world money and contain randomised contents. In recent years, loot boxes have become increasingly common. There is concern in the research community that similarities between loot boxes and gambling may lead to increases in problem gambling amongst gamers. A large-scale survey of gamers (n = 7,422) found evidence for a link (eta2 = 0.054) between the amount that gamers spent on loot boxes and the severity of their problem gambling. This link was stronger than a link between problem gambling and buying other in-game items with real-world money (eta2 = 0.004), suggesting that the gambling-like features of loot boxes are specifically responsible for the observed relationship between problem gambling and spending on loot boxes. It is unclear from this study whether buying loot boxes acts as a gateway to problem gambling, or whether spending large amounts of money on loot boxes appeals more to problem gamblers. However, in either case these results suggest that there may be good reason to regulate loot boxes in games. PMID- 30462668 TI - Differential roles of gangliosides in malignant properties of melanomas. AB - Ganglioside GD3 is widely expressed in human malignant melanomas, and has been reported to be involved in the increased cell proliferation and invasion. In this study, we established GM3-, GM2-, GM1-, GD3-, or GD2-expressing melanoma cell lines by transfecting cDNAs of glyscosyltransferases, and effects of individual gangliosides on the cell phenotypes and signals were examined. The phenotypes of established ganglioside-expressing cells were quite different, i.e. cell growth increased as following order; GD2+, GD3+ > GM1+, GM2+, GM3+ cells. Cell invasion activity increased as GD3+ ? GM2+ > GM1+, GM3+, GD2+ cells. Intensity of cell adhesion to collagen I (CL-I) and spreading increased as GD2+ >> GD3+, GM1+ > GM2+, GM3+ cells. In particular, cell adhesion of GD2+ cells was markedly strong. As for cell migration velocity, GD2+ cells were slower than all other cells. The immunocytostaining revealed close localization of gangliosides and F-actin in lamellipodia. Immunoblotting of phosphorylated p130Cas and paxillin by serum treatment reveled that these phosphorylations were more increased in GD3+ cells than in GD2+ or GM3+ cells, while phosphorylation of Akt underwent similarly increased phosphorylation between GD3+ and GD2+ cells compared with GM3+ cells. While GD2 and GD3 enhanced cell growth, GD3 might also contribute in cell invasion. On the other hand, GD2 might contribute in the solid fixation of melanoma cells at metastasized sites. These results suggested that individual gangliosides exert distinct roles in the different aspects of melanomas by differentially regulating cytoskeletons and signaling molecules. PMID- 30462670 TI - Blue skies over China: The effect of pollution-control on solar power generation and revenues. AB - Air pollution is the single most important environmental health risk, causing about 7 million premature deaths annually worldwide. China is the world's largest emitter of anthropogenic air pollutants, which causes major negative health consequences. The Chinese government has implemented several policies to reduce air pollution, with success in some but far from all sectors. In addition to the health benefits, reducing air pollution will have side-benefits, such as an increase in the electricity generated by the solar photovoltaic panels via an increase in surface solar irradiance through a reduction of haze and aerosol impacted clouds. We use the global aerosol-climate model ECHAM6-HAM2 with the bottom-up emissions inventory from the Community Emission Data System and quantify the geographically specific increases in generation and economic revenue to the Chinese solar photovoltaic fleet as a result of reducing or eliminating air pollution from the energy, industrial, transport, and residential and commercial sectors. We find that by 2040, the gains will be substantial: the projected solar photovoltaic fleet would produce between 85-158 TWh/year of additional power in clean compared to polluted air, generating US$6.9-10.1 billion of additional annual revenues in the solar photovoltaic sector alone. Furthermore, we quantify the cost of adopting best-practice emission standards in all sectors and find that the revenue gains from the increased solar photovoltaic generation could offset up to about 13-17% of the costs of strong air pollution control measures designed to reach near-zero emissions in all sectors. Hence, reducing air pollution in China will not only have clear health benefits, but the side-effect of increased solar power generation would also offset a sizeable share of the costs of air pollution control measures. PMID- 30462671 TI - Clinical cascades as a novel way to assess physical readiness of facilities for the care of small and sick neonates in Kenya and Uganda. AB - BACKGROUND: Globally, there were 2.7 million neonatal deaths in 2015. Significant mortality reduction could be achieved by improving care in low- and middle-income countries (LMIC), where the majority of deaths occur. Determining the physical readiness of facilities to identify and manage complications is an essential component of strategies to reduce neonatal mortality. METHODS: We developed clinical cascades for 6 common neonatal conditions then utilized these to assess 23 health facilities in Kenya and Uganda at 2 time-points in 2016 and 2017. We calculated changes in resource availability over time by facility using McNemar's test. We estimated mean readiness and loss of readiness for the 6 conditions and 3 stages of care (identification, treatment, monitoring-modifying treatment). We estimated overall mean readiness and readiness loss across all conditions and stages. Finally, we compared readiness of facilities with a newborn special care unit (NSCU) to those without using the two-sample test of proportions. RESULTS: The cascade model estimated mean readiness of 26.3-26.6% across the 3 stages for all conditions. Mean readiness ranged from 11.6% (respiratory distress-apnea) to 47.8% (essential newborn care) across both time-points. The model estimated overall mean readiness loss of 30.4-31.9%. There was mild to moderate variability in the timing of readiness loss, with the majority occurring in the identification stage. Overall mean readiness was higher among facilities with a NSCU (36.8%) compared to those without (20.0%). CONCLUSION: The cascade model provides a novel approach to quantitatively assess physical readiness for neonatal care. Among 23 facilities in Kenya and Uganda, we identified a consistent pattern of 30-32% readiness loss across cascades and stages. This aggregate measure could be used to monitor and compare readiness at the facility , health system-, or national-level. Estimates of readiness and loss of readiness may help guide strategies to improve care, prioritize resources, and promote neonatal survival in LMICs. PMID- 30462672 TI - Effect of dose-delivery time for flattened and flattening filter-free photon beams based on microdosimetric kinetic model. AB - The effect of dose-delivery time with flattening filter (FF) and flattening filter-free (FFF) photon beams based on microdosimetric kinetic model (MKM) was investigated in this study. Monte Carlo simulation with the particle and heavy ion transport code system (PHITS) was performed to calculate the dose-mean lineal energy yD (keV/MUm) of FF and FFF 6 MV photon beams using the IAEA phase-space files of Varian TrueBeam linear accelerator. Human non-small cell lung cancer NCI H460 cells were used to determine the MKM parameters under the condition that dose-delivery times with continuous irradiation were 1, 5, 10, 30, and 60 min, and the adsorbed dose was 2, 4, and 8 Gy in this study. In addition, the relative biological effectiveness (RBE) of FF and FFF photon beams were calculated for evaluating the effect of dose delivery time. The RBE of FF decreased to 99.8% and 97.5% with 5 and 60 min for 2 Gy in comparison to 99.6% and 95.1% for 8 Gy, respectively. Meanwhile, that of FFF decreased to 99.5% and 94.9% with 5 and 60 min for 2 Gy in comparison to 99.5% and 94.9% for 8 Gy, respectively. Dose delivery time has an effect on the RBE with photon beams. In other words, the dose-delivery time should be considered during radiation therapy. Furthermore, FFF photon beams were an effective irradiation method compared to FF in dose delivery time on account of improving clinic throughput. PMID- 30462673 TI - Perspectives on the DNR decision process: A survey of nurses and physicians in hematology and oncology. AB - INTRODUCTION: In cancer care, do-not-resuscitate (DNR) decisions are made frequently; i.e., decisions not to start the heart in the event of a cardiac arrest. A DNR decision can be a complex process involving nurses and physicians with a wide variety of experiences and perspectives. Previous studies have shown different perceptions of the DNR decision process among nurses and physicians, e.g. concerning patient involvement and information. DNR decisions have also been reported to be unclear and documentation inconsistent. OBJECTIVE: The aim was to investigate how important and how likely to happen nurses and physicians considered various aspects of the DNR decision process, regarding participation, information and documentation, as well as which attributes they found most important in relation to DNR decisions. METHODS: A descriptive correlational study using a web survey was conducted, including 132 nurses and 84 physicians working in hematology and oncology. RESULTS: Almost half of the respondents reported it not likely that the patient would be involved in the decision on DNR, and 21% found it unimportant to inform patients of the DNR decision. Further, 57% reported that providing information to the patient was important, but only 21% stated that this was likely to happen. There were differences between nurses and physicians, especially regarding participation by and information to patients and relatives. The attributes deemed most important for both nurses and physicians pertained more to medical viewpoints than to ethical values, but a difference was found, as nurses chose patient autonomy as the most important value, while physicians rated non-maleficence as the most important value in relation to DNR decisions. CONCLUSION: Nurses and physicians need to be able to talk openly about their different perspectives on DNR decisions, so that they can develop a deeper understanding of the decisions, especially in cases where they disagree. They should also be aware that what they think is important is not always likely to happen. The organization needs to support such discussions through providing an environment that allows ethical discussions on regular basis. Patients and relatives will also benefit from receiving the same information from all caregivers. PMID- 30462675 TI - An empirical study on solving an integrated production and distribution problem with a hybrid strategy. AB - Coordination is essential for improving supply chain performance, and one of the most critical factors in achieving the coordination of a supply chain is the integrated research of production and distribution. In this paper, a novel two stage hybrid solution methodology is proposed. In the first stage, products are processed on the serial machines of multiple manufacturers located in two industrial parks. A fuzzy multi-objective scheduling optimization is performed using a modified non-dominated sorting genetic algorithm II (NSGA-II). The result obtained in the first stage is used in the second stage to optimize the distribution scheduling problem using a modified genetic annealing algorithm (GAA). Finally, simulation results verify both the feasibility and efficiency of the proposed solution methodology. PMID- 30462674 TI - Rates and determinants of neonatal mortality in two rural sub-districts of Sylhet, Bangladesh. AB - INTRODUCTION: Reducing neonatal mortality rate (NMR) is a challenge in many low- and middle-income countries including Bangladesh. In 2014, the estimated NMR in this country was 28 per 1,000 live births. This rate is higher in rural regions compared to the national average. Currently, Sylhet Division has the highest NMR in Bangladesh. Investigating rates and determinants of neonatal mortality in rural regions of this high-risk division is particularly important to implement evidence-based programs. This study examined rates and determinants of neonatal deaths in a large rural cohort in Sylhet Division. METHODS: We analyzed data from a multi-country cohort study, Aetiology of Neonatal Infections in South Asia. From November 2011 to December 2013, this study was conducted in two rural sub districts in Sylhet Division. Community health workers followed 28,960 pregnant women and their newborns up to two months postpartum and collected data on pregnancy outcomes and newborns' survival status. The NMR was obtained by dividing total number of neonatal deaths with all studied newborns. Logistic regression was employed to calculate adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for factors associated with neonatal mortality. Stata 14.0 was used for data analysis. RESULTS: This study analyzed data of 21,227 newborns. The NMR was 43.4 (95% CI: 39.3-48.0) per 1,000 live births (N = 922). Multivariable analysis showed that the odds of neonatal mortality were significantly higher among male newborns (AOR: 1.5, 95% CI: 1.2-1.8), babies born before 34 weeks of gestation (AOR: 5.0, 95% CI: 4.1-6.1), those who were twins or triplets (AOR: 6.2, 95% CI: 3.6-10.9), and first-born child (AOR: 2.9, 95% CI: 1.6-5.3). Additionally, maternal age 30-35 years (AOR: 1.4, 95% CI: 1.-1.8), history of child death (AOR: 1.6, 95% CI: 1.2-2.2), and delivery complications (AOR: 2.1, 95% CI: 1.6-2.6) had positive associations with neonatal deaths. CONCLUSION: Public health programs in Bangladesh need to adopt a comprehensive strategy to address the individual, maternal, and intrapartum factors associated with neonatal mortality in rural regions. Interventions should aim to prioritize managing pre-term deliveries, first-born child, and delivery complications among pregnant women. PMID- 30462676 TI - Scientific evidence for the management of dentin caries lesions in pediatric dentistry: A systematic review and network meta-analysis. AB - BACKGROUND: A systematic quantitative evaluation of the available evidence of the treatment for caries lesions in primary teeth that considers how different caries progressions lead to the need for distinct interventions might provide additional useful information for clinical evidence-based decision making. The aim of this systematic review and network meta-analysis was to verify the effect of the treatments on caries lesion arrestment (CLA) or the success rate (SR) of dentin caries lesion treatments in the primary teeth. METHODS: A search was conducted using the MEDLINE/PubMed, Web of Science and Scopus databases through December 2017. The primary search terms used in combination were primary teeth, caries lesion and restoration. The grey literature was also screened, as were the reference lists of eligible studies. A search of prospective studies with at least 12 months of follow up that compared different techniques was performed. The exclusion criteria were the absence of a comparison group; no evaluation of different restorative techniques; the evaluation of other outcomes unrelated to this review; and the recruitment of specific patient. The risk of bias was evaluated by the tools: the Cochrane Handbook for Systematic Reviews of Interventions and ROBINS-I. A network meta-analyses and meta-analyses were conducted considering CLA or SR as outcomes according to the surface involved and the depth of progression. RESULTS: Of the 1671 potentially eligible studies, 15 were included. For occlusal surfaces, only two studies presented data regarding the outer half of the dentin, with conventional restorative treatment (CRT) using composite resin showing superior results; five studies presented data regarding the depth of caries lesions, and CRT with compomer resulted in the best results. Seven studies considered occlusoproximal surfaces, and the Hall technique showed the best SR among the evaluated treatments. Finally, two annual applications of silver diamine fluoride showed the best nonrestorative approach to arrest caries lesions on occlusal and smooth surfaces. DISCUSSION/CONCLUSIONS: The treatments for dentin caries lesions in primary teeth depend on the depth of progression and the surface involved. However, few of the included studies provided evidence to strongly recommend the best treatment option. OTHER: Funding: FAPESP; Systematic review registration number-PROSPERO CRD42016037784. PMID- 30462677 TI - New insertion method of transnasal ileus tube for small bowel obstruction: Anterior balloon method. AB - BACKGROUND: Small bowel obstruction (SBO) is usually caused by postoperative adhesions and malignant disease, and decompression is effective for SBO. Our previous case report suggested that a new transnasal ileus tube insertion method, the anterior balloon method (ABM), could achieve decompression for adhesive SBO. AIMS: The study aimed to investigate the effectiveness of a new method for inserting transnasal ileus tubes in patients with SBO. METHODS: Altogether, 134 patients with small bowel obstruction treated from January 2011 to December 2017 were reviewed. The patients were categorized into two groups: those with the new method that inserts an anterior balloon (ABM group: 52 patients, 2014-2017) versus those with the ordinary insertion method (OIM group: 82 patients, 2011 2014). RESULTS: The patients' characteristics and symptoms on admission were similar in the ABM and OIM groups. Adhesions were the main cause of ileus in the two groups. The insertion time duration was significantly shorter in the ABM group than in OIM group (28.4 +/- 9.1 vs. 33.5 +/- 13.0 min; p = 0.01). The ABM group also had significantly longer tubes than OIM group (222.4 +/- 32.2 vs. 157.4 +/- 31.7 cm; p < 0.001), which resulted in a significantly shorter time until clinical symptoms were relieved in ABM group. There were no significant differences in adverse events between the two groups. CONCLUSIONS: The ABM group had shorter insertion duration and longer tubes than those of OIM group. The ABM might become a preferred therapeutic choice to achieve decompression in patients with SBO. PMID- 30462678 TI - Fecal virome composition of migratory wild duck species. AB - The fecal virome comprises a complex diversity of eukaryotic viruses, phages and viruses that infect the host. However, little is known about the intestinal community of viruses that is present in wild waterfowl, and the structure of this community in wild ducks has not yet been studied. The fecal virome compositions of six species of wild dabbling ducks and one species of wild diving duck were thus analyzed. Fecal samples were collected directly from the rectums of 60 ducks donated by hunters. DNA and RNA virus particles were purified and sequenced using the MiSeq Illumina platform. The reads obtained from the sequencing were analyzed and compared with sequences in the GenBank database. Viral-related sequences from the Herpesviridae, Alloherpesviridae, Adenoviridae, Retroviridae and Myoviridae viral families showed the highest overall abundances in the samples. The virome analysis identified viruses that had not been found in wild duck feces and revealed distinct virome profiles between different species and between samples of the same species. This study increases our understanding of viruses in wild ducks as possible viral reservoirs and provides a basis for further studying and monitoring the transmission of viruses from wild animals to humans and disease outbreaks in domestic animals. PMID- 30462679 TI - Benefits of global financial reporting models for developing markets: The case of Romania. AB - The paper explores the benefits of global financial reporting models for developing countries, discussing the case of Romania, which, at the recommendations of the World Bank and the International Monetary Fund, exceeded the minimum requirements of the European Union, by imposing the full adoption of the International Financial Reporting Standards (IFRS) in individual financial statements of listed companies. Using regression analysis and decomposition techniques, the paper explores the evolution in value relevance of financial variables based on pre-(2009-2012) and post-(2014-2016) adoption samples, showing that after IFRS adoption financial information becomes significantly more relevant for equity valuations. We also provide empirical evidence showing that the degree of relevance for stock valuation, as well as the IFRS impact varies across types of firms. Overall, our findings tend to indicate the success of the financial reporting reform, which could be relevant for other jurisdictions facing similar decisions. PMID- 30462680 TI - Drought increases the frequencies of fungal functional genes related to carbon and nitrogen acquisition. AB - Although water is a critical resource for organisms, microbially-mediated processes such as decomposition and nitrogen (N) transformations can endure within ecosystems even when water is scarce. To identify underlying mechanisms, we examined the genetic potential for fungi to contribute to specific aspects of carbon (C) and N cycling in a drought manipulation in Southern California grassland. In particular, we measured the frequency of fungal functional genes encoding enzymes that break down cellulose and chitin, and take up ammonium and amino acids, in decomposing litter. Furthermore, we used "microbial cages" to reciprocally transplant litter and microbes between control and drought plots. This approach allowed us to distinguish direct effects of drought in the plot environment versus indirect effects via shifts in the microbial community or changes in litter chemistry. For every fungal functional gene we examined, the frequency of that gene within the microbial community increased significantly in drought plots compared to control plots. In contrast, when plot environment was held constant, frequencies of these fungal functional genes did not differ significantly between control-derived microbes versus drought-derived microbes, or between control-derived litter versus drought-derived litter. It appears that drought directly selects for fungi with the genetic capacity to acquire these specific C- and N-containing compounds. This genetic trait may allow fungi to take advantage of ephemeral water supplies. Altogether, proliferation of fungi with the genetic capacity for C and N acquisition may contribute to the maintenance of biogeochemical cycling under drought. PMID- 30462681 TI - Human-like perceptual masking is difficult to observe in rats performing an orientation discrimination task. AB - Visual masking occurs when the perception of a brief target stimulus is affected by a preceding or succeeding mask. The uncoupling of the target and its perception allows an opportunity to investigate the neuronal mechanisms involved in sensory representation and visual perception. To determine whether rats are a suitable model for subsequent studies of the neuronal basis of visual masking, we first demonstrated that decoding of neuronal responses recorded in the primary visual cortex (V1) of anaesthetized rats predicted that orientation discrimination performance should decline when masking stimuli are presented immediately before or after oriented target stimuli. We then trained Long-Evans rats (n = 7) to discriminate between horizontal and vertical target Gabors or gratings. In some trials, a plaid mask was presented at varying stimulus onset asynchronies (SOAs) relative to the target. Spatially, the masks were presented either overlapping or surrounding the target location. In the absence of a mask, all animals could reliably discriminate orientation when stimulus durations were 16 ms or longer. In the presence of a mask, discrimination performance was impaired, but did not systematically vary with SOA as is typical of visual masking. In humans performing a similar task, we found visual masking impaired perception of the target at short SOAs regardless of the spatial or temporal configuration of stimuli. Our findings indicate that visual masking may be difficult to observe in rats as the stimulus parameters necessary to quantify masking will make the task so difficult that it prevents robust measurement of psychophysical performance. Thus, our results suggest that rats may not be an ideal model to investigate the effects of visual masking on perception. PMID- 30462682 TI - Extracting information from RNA SHAPE data: Kalman filtering approach. AB - RNA SHAPE experiments have become important and successful sources of information for RNA structure prediction. In such experiments, chemical reagents are used to probe RNA backbone flexibility at the nucleotide level, which in turn provides information on base pairing and therefore secondary structure. Little is known, however, about the statistics of such SHAPE data. In this work, we explore different representations of noise in SHAPE data and propose a statistically sound framework for extracting reliable reactivity information from multiple SHAPE replicates. Our analyses of RNA SHAPE experiments underscore that a normal noise model is not adequate to represent their data. We propose instead a log normal representation of noise and discuss its relevance. Under this assumption, we observe that processing simulated SHAPE data by directly averaging different replicates leads to bias. Such bias can be reduced by analyzing the data following a log transformation, either by log-averaging or Kalman filtering. Application of Kalman filtering has the additional advantage that a prior on the nucleotide reactivities can be introduced. We show that the performance of Kalman filtering is then directly dependent on the quality of that prior. We conclude the paper with guidelines on signal processing of RNA SHAPE data. PMID- 30462683 TI - Phylogeny and population genetic analyses reveals cryptic speciation in the Bombus fervidus species complex (Hymenoptera: Apidae). AB - Bumble bees (Bombus Latrielle) are significant pollinators of flowering plants due to their large body size, abundant setae, and generalist foraging strategies. However, shared setal coloration patterns among closely and distantly related bumble bee species makes identification notoriously difficult. The advent of molecular genetic techniques has increased our understanding of bumble bee evolution and taxonomy, and enables effective conservation policy and management. Individuals belonging to the North American Bombus fervidus species-complex (SC) are homogenous in body structure but exhibit significant body color phenotype variation across their geographic distribution. Given the uncertainty of the genealogical boundaries within the SC, some authors have synonymized all members of the B. fervidus SC within a single taxon, while others propose an alternative two taxa hypothesis. Operating under the phylogenetic species concept, our analysis supports the hypothesis that there are two independent lineages of bumble bees within the B. fervidus SC. With the current evidence, however, it is not possible to assign valid names to either of them, because both lineages include the color phenotypes found in the original species descriptions of B. fervidus and B. californicus. Cryptic speciation does not seem to be the product of Mullerian mimicry between the clades, because diverging coloration patterns are observed when the distribution of the clades overlaps. Furthermore, within each lineage there is evidence for strong population differentiation that is correlated with geographic distribution rather than color phenotype. In our study, we demonstrate the importance of obtaining a broad sample of multiple populations when conducting lower-level phylogenetic analyses. In addition to improving our knowledge of bumble bee diversification patterns, characterizing the evolutionary history of these pollinators provides the foundation needed to guide contemporary conservation assessments and management strategies. PMID- 30462684 TI - Local anesthesia underutilized for inguinal hernia repair in northern Ghana. AB - INTRODUCTION: Inguinal hernia repair is a common procedure and a priority for public health efforts in Ghana. It is essential that inguinal hernia repair be performed in a safe, efficient manner to justify its widespread use. Local anesthesia has many favorable properties and has been shown to be superior, compared to regional or general anesthesia, in terms of pain control, safety profile, cost-effectiveness, resources required, and time to discharge. Local anesthesia is recommended for open repair of reducible hernias, provided clinician experience, by multiple international guidelines. Regional anesthesia is associated with myocardial infarction and other complications, and its use is discouraged by multiple guidelines, especially in older patients. This study aims to assess the current state of anesthesia for inguinal hernia repair in the northern and transitional zone of Ghana. In addition we will assess the perceptions of different types of anesthesia along with understanding of evidence based guidelines among clinicians participating in inguinal hernia repair. METHODS: We performed a retrospective review of all inguinal hernia repairs for male patients, 18 and older, in over 90% of hospitals in northern Ghana. All 41 hospitals were visited and caselogs and patient charts were manually reviewed to extract data. Multivariate logistic regression was used to determine predictors of local anesthesia use. We designed a survey instrument to assess the perceptions of physicians and anesthetists regarding different types of anesthesia for inguinal hernia repair. The survey was designed by a Ghanaian surgeon, reviewed by all co-authors, and tested prior to implementation using a sample (n = 8) of clinicians having similar practices to those of the survey population. Of 70 clinicians, 66 responded, yielding a response rate of 94%. RESULTS: 8080 patients underwent hernia repair of which 37% were performed under local anesthesia, while the majority, 60%, were performed under regional anesthesia. Negative predictors of local anesthesia were emergent repair (OR = 0.258, p < 0.001), surgery performed at a teaching hospital (OR = 0.105, p < 0.001), and bilateral hernia repair (OR = 0.374, p < 0.001). 1,839 (22.8%) of IH repairs were done on patients age 65 or older and RA was most frequently used among the elderly population (57.8%), while local anesthesia was used 39.5% of the time. Sixty-six clinicians participated in the survey with the majority reporting that local anesthesia requires fewer staff, less equipment, has a shorter recovery, is more cost-effective, and might be safer for patients. However 66% were unfamiliar with or incorrectly perceived international guidelines. CONCLUSION: To our knowledge, this study is the largest assessment of anesthesia use for inguinal hernia repair in an LMIC. Although the selection of anesthetic technique should be guided by a patient's general health, the anatomy of the hernia, and clinician judgment, local anesthesia appears to be underutilized in northern Ghana. Survey responses demonstrate high rates of unfamiliarity or incorrectly perceived evidence-based guidelines. Future research should assess how education on the benefits and technique of local anesthesia administration may further increase rates for inguinal hernia repair, especially for older patients. PMID- 30462685 TI - BCT score predicts chemotherapy benefit in Asian patients with hormone receptor positive, HER2-negative, lymph node-negative breast cancer. AB - The Breast Cancer Test (BCT) score has been validated for its ability to predict the risk of distant metastasis in hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. This study aimed to examine the value of the BCT score for predicting the benefit of adjuvant chemotherapy for Korean women with hormone receptor-positive, HER2-negative, lymph node-negative breast cancer. The study included 346 patients treated with either hormone therapy alone (n = 203) or hormone therapy plus chemotherapy (n = 143), and compared patient survival between the two treatment groups. The effect of BCT score on patient survival by treatment group was assessed using Cox proportional hazards models. Based on the results, the BCT score was prognostic for distant metastasis-free survival and breast cancer-specific survival in the hormone therapy alone group. There was no significant difference between the treatment groups in terms of 10-year distant metastasis-free survival in the overall patient population. However, when patients were classified as low risk (n = 266) and high risk (n = 80) according to the BCT score, addition of adjuvant chemotherapy to hormone therapy for patients classified as BCT high-risk group led to a significant improvement in 10-year distant metastasis-free survival, from 65.4% to 91.9% (hazard ratio, 0.18; 95% confidence interval, 0.05-0.64; P = 0.003); in contrast, there was no benefit for the BCT low-risk group. The stratification of patients according to the BCT score also identified clinically high-risk patients who may not benefit from chemotherapy. Results were similar for breast cancer-specific survival. In conclusion, the BCT score was not only of prognostic value but was also a predictor of chemotherapy benefit for Korean patients with hormone receptor-positive, HER2-negative, lymph node-negative breast cancer. PMID- 30462686 TI - Refining a Nordmore-grid bycatch reduction device for the Spencer Gulf penaeid trawl fishery. AB - Incremental refinements were made to a generic Nordmore-grid to minimise bycatches of blue swimmer crabs Portunus armatus and giant cuttlefish Sepia apama, while maintaining catches of western king prawns Melicertus latisulcatus in the Spencer Gulf penaeid-trawl fishery. These refinements involved varying bar spaces, escape-exit areas and guiding-panel lengths, and were compared against a conventional trawl. Catches of teleosts and M. latisulcatus largely remained unaffected by the changes. Maximum reductions in P. armatus and S. apama bycatches (both ~90%) were achieved with a Nordmore-grid comprising 38-mm bar spaces, 0.81- or 1.05-m2 escape exits and a 2.7-m guiding panel. Catching fewer P. armatus should reduce abrasion and crushing of M. latisulcatus in the codend and so increase the value of this targeted species. While noting some unresolved operational concerns, these results demonstrate the potential improvements in selectivity in this fishery using a Nordmore-grid, primarily by mechanical separation. PMID- 30462687 TI - Risk of post-discharge fall-related injuries among adult patients with syncope: A nationwide cohort study. AB - BACKGROUND: Syncope could be related to high risk of falls and injury in adults, but documentation is sparse. We examined the association between syncope and subsequent fall-related injuries in a nationwide cohort. METHODS: By cross linkage of nationwide registers, all residents >=18 years with a first-time diagnosis of syncope were identified between 1997-2012. Syncope patients were matched 1:1 with individuals from the general population. The absolute one-year risk of fall-related injuries, defined as fractures and traumatic head injuries requiring hospitalization, was calculated using Aalen-Johansen estimator. Ratios of the absolute one-year risk of fall-related injuries (ARR) were assessed by absolute risk regression analysis. RESULTS: We identified 125,763 patients with syncope: median age 65 years (interquartile range 46-78). At one year, follow-up was complete for 99.8% where a total of 8394 (6.7%) patients sustained a fall related injury requiring hospitalization, of which 1606 (19.1%) suffered hip fracture. In the reference group, 4049 (3.2%) persons had a fall-related injury. The one-year ARR of a fall-related injury was 1.79 (95% confidence interval 1.72 1.87, P<0.001) in patients with syncope compared with the reference group; however, increased ARR was not exclusively in older patients. Factors independently associated with increased ARR of fall-related injuries in the syncope population were: injury in past 12 months, 2.39 (2.26-2.53, P<0.001), injury in relation to the syncope episode, 1.62 (1.49-1.77, P<0.001), and depression, 1.37 (1.30-1.45, P<0.001). CONCLUSION: Patients with syncope were at 80% increased risk of severe fall-related injuries within the year following discharge. Notably, increased risk was not exclusively in older patients. PMID- 30462689 TI - Non-foraging tool use in European Honey-buzzards: An experimental test. AB - Examples of tool-use behaviors by birds outside foraging contexts are scarce and limited to a handful of species. We report a field experiment aimed to test whether an observed suite of odd behaviors by European Honey-buzzards (Pernis apivorus) represents use of green twigs cut from trees and woody shrubs as a tool to attract ants for anting. Specifically, we tested whether buzzards are selective in their choice of twigs, under the assumption that birds would prefer easy-to-collect twigs from plants that effectively attract ants. Experimental results lend support to our hypothesis that European Honey-buzzards cut green twigs of Montpellier maple trees (Acer monspessulanum) and, to a lesser extent, of Pyrenean oaks (Quercus pyrenaica) for their immediate use as ant attractors. Fresh twigs of both tree species attracted large numbers of ants, suggesting that their preferential use in the reported behavior of Honey-buzzards is not a random selection of the available plant material. Maple twigs, however, were the easiest to break and oak twigs the hardest compared to other plants in the community. This suggests that the relative ease of cracking of maple twigs may account for the preference Honey-buzzards have for this plant species as compared with Pyrenean oak, whose twigs demand considerable more effort from the birds to break. Our results lend support to the inclusion of the reported behavioral sequence by this raptor species as a potential example of tool use in birds outside the usual foraging context. PMID- 30462688 TI - Gender disparities in depression severity and coping among people living with HIV/AIDS in Kolkata, India. AB - People living with HIV/AIDS (PLH) experience high rates of depression and related psychosocial risk factors that vary by gender. This study examines gender differences in depression severity among antiretroviral therapy (ART) patients (n = 362) from a large government ART clinic in Kolkata, India. Hypotheses for multiple linear regression models were guided by an integrated gendered stress process model focusing on variables reflecting social status (age, partner status), stressors (stigma), and resources (income, social support). Depressive symptoms were assessed with the Hospital Anxiety and Depression Scale (HADS); 22% of the sample reached the cutoff for severe depression, 56% moderate, and 13% mild depression. Compared to men, women reported lower income, education (50% no formal education vs. 20% men), availability of emotional and instrumental support, and were less likely to be married or cohabiting (53% women vs. 72% of men). However, more women had partners who were HIV-positive (78% women vs. 46% men). Overall, depression severity was negatively associated with availability of emotional support and self-distraction coping, and positively associated with internalized HIV/AIDS stigma, availability of instrumental support, and behavioral disengagement coping. Interactions for instrumental support by income and partner status by age varied significantly by gender. Analyses stratified by gender indicated that: 1) Frequently seeking instrumental support from others was protective for men at all income levels, but only for high-income women; and 2) having a partner was protective for men as they aged, but not for women. These results suggest that gender disparities in depression severity are created and maintained by women's lower social status and limited access to resources. The effect of stigma on depression severity did not vary by gender. These findings may inform the tailoring of future interventions to address mental health needs of PLH in India, particularly gender disparities in access to material and social resources for coping with HIV. Trial Registration: ClinicalTrials.gov registration #NCT02118454, registered April 2014. PMID- 30462690 TI - Palaeohistology and life history evolution in cave bears, Ursus spelaeus sensu lato. AB - The abundance of skeletal remains of cave bears in Pleistocene deposits can offer crucial information on the biology and life history of this megafaunal element. The histological study of 62 femora from 23 different European localities and comparisons with specimens of five extant ursid species revealed novel data on tissue types and growth patterns. Cave bear's femoral bone microstructure is characterized by a fibrolamellar complex with increasing amounts of parallel fibered and lamellar bone towards the outer cortex. Remodelling of the primary bone tissue initially occurs close to the perimedullary margin of the bone cortex around the linea aspera. Although similar histological traits can be observed in many extant bear species, the composition of the fibrolamellar complex can vary greatly. Cave bears reached skeletal maturity between the ages of 10 and 14, which is late compared to other bear species. There is a significant correlation between altitude and growth, which reflects the different body sizes of cave bears from different altitudes. PMID- 30462691 TI - EEG electrode digitization with commercial virtual reality hardware. AB - Accurate spatial co-registration of EEG electrode positions with individual head models is an important component for EEG source localization and imaging. Due to variations in head shape between individuals, this requires measurements of electrode locations in each individual. Existing hardware for digitization can be accurate, but also relatively expensive. With the goal of making digitization more accessible for a range of research laboratories, we have developed an open source software tool that can make use of less expensive consumer virtual reality hardware for EEG electrode digitization. Here we describe our developed VRDigitizer system and compare it to existing digitization solutions. Experimental evaluations were performed in a phantom head model and in 12 human subjects. In our comparison experiments, VRDigitizer was able to measure electrode positions with a mean error of 3.74 mm, compared to 1.73 mm and 2.98 mm for the commercial systems tested. PMID- 30462692 TI - Association between paternal smoking at the time of pregnancy and the semen quality in sons. AB - BACKGROUND: Maternal smoking during pregnancy has repeatedly been associated with decreased sperm counts in sons. Nevertheless, our team recently detected a lower total sperm count in the sons of smoking fathers as compared to sons of non smoking fathers. Since paternal and maternal tobacco smoking often coincide, it is difficult to discriminate whether effects are mediated paternally or maternally when using questionnaire- or register-based studies. Therefore, getting an objective measure of the maternal nicotine exposure level during pregnancy might help disentangling the impact of paternally and maternally derived exposure. OBJECTIVES: Our aim was to study how paternal smoking at the time of the pregnancy was associated with semen quality in the sons after adjusting for the maternal levels of nicotine exposure during pregnancy. METHODS: We recruited 104 men (17-20 years old) from the general Swedish population. The participants answered a questionnaire about paternal smoking. Associations between smoking and semen volume, total sperm count, sperm concentration, morphology and motility were adjusted for levels of the nicotine metabolite cotinine in stored maternal serum samples obtained from rubella screening between the 6th and 35th week of pregnancy. We additionally adjusted for the estimated socioeconomic status. RESULTS: After adjusting for the maternal cotinine, the men of smoking fathers had 41% lower sperm concentration and 51% lower total sperm count than the men of non-smoking fathers (p = 0.02 and 0.003, respectively). This was robust to the additional adjustment. CONCLUSIONS: Our results suggest a negative association between paternal smoking and sperm counts in the sons, independent of the level maternal nicotine exposure during the pregnancy. PMID- 30462693 TI - Functional analyses of heteromeric human PIEZO1 Channels. AB - PIEZO1 and PIEZO2 are mechanosensitive channels (MSCs) important for cellular function and mutations in them lead to human disorders. We examined how functional heteromers form between subunits of PIEZO1 using the mutants E2117K, E2117D, and E2117A. Homomers of E2117K do not conduct. E2117A homomers have low conductance with rapid inactivation, and those of E2117D have high conductance with slow inactivation. Pairing E2117K with E2117D or E2117A with E2117D gave rise to new channel species representing heteromers with distinct conductances. Whole-cell currents from co-expression of E2117A and E2117D fit well with a linear-combination model of homomeric channel currents suggesting that functional channels do not form from freely-diffusing, randomly-mixed monomers in-vitro. Whole-cell current from coexpressed PIEZO1/PIEZO2 also fit as a linear combination of homomer currents. High-resolution optical images of fluorescently tagged channels support this interpretation because coexpressed subunits segregate into discrete domains. PMID- 30462694 TI - Genetic diversity and population structure of Haloxylon salicornicum moq. in Kuwait by ISSR markers. AB - Haloxylon salicornicum moq. Bunge ex Boiss (Rimth) is one of the native plants of Kuwait, extensively depleting through the anthropogenic activities. It is important to conserve Haloxylon community in Kuwait as it can tolerate extreme adverse conditions of drought and salinity to be potentially used in the desert and urban revegetation and greenery national programs. Therefore, a set of 16 inter simple sequence repeat (ISSR) markers were used to assess genetic diversity and population structure of 108 genotypes from six locations in Kuwait. The ISSR primers produced 195 unambiguous and reproducible bands out of which 167 bands were polymorphic (86.5%) with a mean PIC value of 0.31. The overall average values of Nei's gene diversity (h') and Shannon's diversity index (I) were 0.254 and 0.375, respectively. Results of AMOVA revealed high genetic variations within populations (77.8%) and low among populations (22%). The values of Fixation index (FST = 0.22; P = 0.0), Genetic differentiation (GST = 0.262; G'ST = 0.327; D = 0.335 and Gene flow (NM = 0.880) were indicative of heterozygous populations. The results of STRUCTURE and split decomposition analysis suggested that the Rimth accessions of Kuwait can be grouped into five and six subpopulations, respectively. Principal coordinate analysis (PCoA) grouped them into three clusters. The pairwise Nei's genetic distances (DS) among populations demonstrated a narrow range from 0.047 to 0.187 (Scale-0.0 to 1.0). The Mantel's test revealed a weak correlation (r2- 0.188; P-0.013) between the genetic distance and geographic distances. Our results suggest that the narrowly distributed Haloxylon community in Kuwait demonstrated a high genetic diversity within the populations however the overall population structure was weak. PMID- 30462696 TI - Functional roles and redundancy of demersal Barents Sea fish: Ecological implications of environmental change. AB - When facing environmental change and intensified anthropogenic impact on marine ecosystems, extensive knowledge of how these systems are functioning is required in order to manage them properly. However, in high-latitude ecosystems, where climate change is expected to have substantial ecological impact, the ecosystem functions of biological species have received little attention, partly due to the limited biological knowledge of Arctic species. Functional traits address the ecosystem functions of member species, allowing the functionality of communities to be characterised and the degree of functional redundancy to be assessed. Ecosystems with higher functional redundancy are expected to be less affected by species loss, and therefore less sensitive to disturbance. Here we highlight and compare typical functional characteristics of Arctic and boreal fish in the Barents Sea and address the consequences of a community-wide reorganization driven by climate warming on functional redundancy and characterization. Based on trait and fish community composition data, we assessed functional redundancy of the Barents Sea fish community for the period 2004-2012, a period during which this northern region was characterized by rapidly warming water masses and declining sea ice coverage. We identified six functional groups, with distinct spatial distributions, that collectively provide a functional characterization of Barents Sea fish. The functional groups displayed different prevalence in boreal and Arctic water masses. Some functional groups displayed a spatial expansion towards the northeast during the study period, whereas other groups showed a general decline in functional redundancy. Presently, the observed patterns of functional redundancy would seem to provide sufficient scope for buffering against local loss in functional diversity only for the more speciose functional groups. Furthermore, the observed functional reconfiguration may affect future ecosystem functioning in the area. In a period of rapid environmental change, monitoring programs integrating functional traits will help inform management on ecosystem functioning and vulnerability. PMID- 30462695 TI - Does effective gaze behavior lead to enhanced performance in a complex error detection cockpit task? AB - The purpose of the current study was to examine the relationship between expertise, performance, and gaze behavior in a complex error-detection cockpit task. Twenty-four pilots and 26 non-pilots viewed video-clips from a pilot's viewpoint and were asked to detect malfunctions in the cockpit instrument panel. Compared to non-pilots, pilots detected more malfunctioning instruments, had shorter dwell times on the instruments, made more transitions, visited task relevant areas more often, and dwelled longer on the areas between the instruments. These results provide evidence for three theories that explain underlying processes for expert performance: The long-term working memory theory, the information-reduction hypothesis, and the holistic model of image perception. In addition, the results for generic attentional skills indicated a higher capability to switch between global and local information processing in pilots compared to non-pilots. Taken together, the results suggest that gaze behavior as well as other generic skills may provide important information concerning underlying processes that can explain successful performance during flight in expert pilots. PMID- 30462697 TI - Optimization of roadway layout in ultra-close coal seams: A case study. AB - Most coal mines in China are currently mining close coal seams. Roadways in close coal seams, especially ultra-close coal seams, confronted difficulties in maintaining, including large deformation of the roadway, roof caving, rib spalling and floor heaving. This is mainly caused by the complicated stress and geological conditions, shattered roof, improper layout and support. To explore the issues mentioned above, the theoretical analysis was used to build a mechanical model and study the stress distribution under coal pillars, and FLAC3D modelling was adopted to build numerical models with different staggered distances. The optimal roadway layout was brought forward combining the result of numerical simulation and coal recovery rate. The field practice was carried out in the tailgate of panel 25301 to investigate the effect of the layout scheme. The results of field monitoring show that the roadway's stability is well maintained in the mining process. PMID- 30462698 TI - Antibacterial properties of the pituitary adenylate cyclase-activating polypeptide: A new human antimicrobial peptide. AB - The Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), a polycationic, amphiphilic and helical neuropeptide, is well known for its neuroprotective actions and cell penetrating properties. In the present study, we evaluated the potent antibacterial property of PACAP38 and related analogs against various bacterial strains. Interestingly, PACAP38 and related analogs can inhibit the growth of various bacteria including Escherichia coli (JM109), Bacillus subtilis (PY79), and the pathogenic Burkholderia cenocepacia (J2315). Investigation of the mechanism of action suggested that a PACAP metabolite, identified as PACAP(9-38), might indeed be responsible for the observed PACAP38 antibacterial action. Surprisingly, PACAP(9-38), which does not induce haemolysis, exhibits an increased specificity toward Burkholderia cenocepacia J2315 compared to other tested bacteria. Finally, the predisposition of PACAP(9-38) to adopt a pi-helix conformation rather than an alpha-helical conformation like PACAP38 could explain this gain in specificity. Overall, this study has revealed a new function for PACAP38 and related derivatives that can be added to its pleiotropic biological activities. This innovative study could therefore pave the way toward the development of new therapeutic agents against multiresistant bacteria, and more specifically the Burkholderia cenocepacia complex. PMID- 30462699 TI - Is symptom-based diagnosis of lung cancer possible? A systematic review and meta analysis of symptomatic lung cancer prior to diagnosis for comparison with real time data from routine general practice. AB - BACKGROUND: Lung cancer is a good example of the potential benefit of symptom based diagnosis, as it is the commonest cancer worldwide, with the highest mortality from late diagnosis and poor symptom recognition. The diagnosis and risk assessment tools currently available have been shown to require further validation. In this study, we determine the symptoms associated with lung cancer prior to diagnosis and demonstrate that by separating prior risk based on factors such as smoking history and age, from presenting symptoms and combining them at the individual patient level, we can make greater use of this knowledge to create a practical framework for the symptomatic diagnosis of individual patients presenting in primary care. AIM: To provide an evidence-based analysis of symptoms observed in lung cancer patients prior to diagnosis. DESIGN AND SETTING: Systematic review and meta-analysis of primary and secondary care data. METHOD: Seven databases were searched (MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, Health Management Information Consortium, Web of Science, British Nursing Index and Cochrane Library). Thirteen studies were selected based on predetermined eligibility and quality criteria for diagnostic assessment to establish the value of symptom-based diagnosis using diagnosistic odds ratio (DOR) and summary receiver operating characteristic (SROC) curve. In addition, routinely collated real-time data from primary care electronic health records (EHR), TransHis, was analysed to compare with our findings. RESULTS: Haemoptysis was found to have the greatest diagnostic value for lung cancer, diagnostic odds ratio (DOR) 6.39 (3.32-12.28), followed by dyspnoea 2.73 (1.54 4.85) then cough 2.64 (1.24-5.64) and lastly chest pain 2.02 (0.88-4.60). The use of symptom-based diagnosis to accurately diagnose lung cancer cases from non cases was determined using the summary receiver operating characteristic (SROC) curve, the area under the curve (AUC) was consistently above 0.6 for each of the symptoms described, indicating reasonable discriminatory power. The positive predictive value (PPV) of diagnostic symptoms depends on an individual's prior risk of lung cancer, as well as their presenting symptom pattern. For at risk individuals we calculated prior risk using validated epidemiological models for risk factors such as age and smoking history, then combined with the calculated likelihood ratios for each symptom to establish posterior risk or positive predictive value (PPV). CONCLUSION: Our findings show that there is diagnostic value in the clinical symptoms associated with lung cancer and the potential benefit of characterising these symptoms using routine data studies to identify high-risk patients. PMID- 30462700 TI - Prescription and non-prescription antibiotic dispensing practices in part I and part II pharmacies in Moshi Municipality, Kilimanjaro Region in Tanzania: A simulated clients approach. AB - Antibiotic dispensing without a prescription poses a threat to public health as it leads to excessive antibiotic consumption. Inappropriate antibiotic availability to the community has been documented to be amongst drivers of antimicrobial resistance emergence. Community pharmacies are a source of antibiotics in low and middle-income countries (LMICs). We aimed at assessing antibiotic dispensing practices by community pharmacy retailers in Moshi urban, Kilimanjaro, Tanzania and recommend interventions to improve practice. Using a Simulated Client (SC) Method, an observational cross-sectional survey of antibiotic dispensing practices was conducted from 10th June to 10th July 2017. Data analysis was done using Stata 13 (StataCorp, College Station, TX, USA). A total of 82 pharmacies were visited. Part I pharmacies were 26 (31.71%) and 56 (68.29%) were part II. Overall 92.3% (95% CI 77.8-97.6) of retailers dispensed antibiotics without prescriptions. The antibiotics most commonly dispensed without a prescription were ampiclox for cough (3 encounters) and azithromycin for painful urination (3 encounters). An oral third generation cephalosporin (cefixime) was dispensed once for painful urination without prescription by a part I pharmacy retailer. Out of 21, 15(71.43%) prescriptions with incomplete doses were accepted and had antibiotics dispensed. Out of 68, 4(5.9%) retailers gave instructions for medicine use voluntarily. None of the retailers voluntarily explained drug side-effects. In Moshi pharmacies, a high proportion of antibiotics are sold and dispensed without prescriptions. Instructions for medicine use are rarely given and none of the retailers explain side effects. These findings support the need for a legislative enforcement of prescription only antibiotic dispensing rules and regulations. Initiation of clinician and community antibiotic stewardship and educational programs on proper antibiotic use to both pharmacists and public by the regulatory bodies are highly needed. PMID- 30462702 TI - An algorithm for fragment-aware virtual network reconfiguration. AB - In view of the fact that the current online virtual network embedding algorithms do not consider the fragment resources generated in the embedding process deeply enough, resulting in the problem that the acceptance ratio and the revenue to cost ratio are both low, a mathematical model for virtual network reconfiguration is constructed and a heuristic algorithm for fragment-aware virtual network reconfiguration (FA-VNR) is proposed. The FA-VNR algorithm selects the set of virtual nodes to be migrated according to the fragment degrees of the physical nodes, and selects the best virtual node migration scheme according to the reduction of the fragment degrees of the physical nodes as well as the reduction of the embedding cost of the embedded virtual networks. Extensive simulation results show that the proposed FA-VNR algorithm not only can obviously improve the acceptance ratio and the revenue to cost ratio of the current online virtual network embedding algorithm, but also has better optimization effect than the existing virtual network reconfiguration algorithm. PMID- 30462701 TI - Transcatheter aortic valve replacement (TAVR) leads to an increase in the subendocardial viability ratio assessed by pulse wave analysis. AB - BACKGROUND: Pulse wave analysis (PWA) is a useful tool for non-invasive assessment of central cardiac measures as subendocardial perfusion (Subendocardial Viability Ratio, SEVR) or contractility (dP/dtmax). The immediate influence of transcatheter aortic valve replacement (TAVR) on these indices has not been investigated yet. METHODS: We prospectively enrolled 40 patients presenting with severe aortic stenosis receiving TAVR. Central pressure curves were derived from radial and carotid sites using PWA up to 2 days before and 7 days after TAVR. Parameters were compared between peripheral measurement sites. Changes in SEVR, dP/dtmax and in indices of vascular stiffness were assessed. Additionally, association of these variables with clinical outcome was evaluated during a 12-month follow-up. RESULTS: Central waveform parameters were comparable between measurement sites. SEVR, but not dP/dtmax, augmentation Index (AIx) or augmentation pressure height (AGPH) correlated significantly with disease severity reflected by peak transvalvular velocity and mean transvalvular pressure gradient over the aortic valve (Vmax, DeltaPm) [r = -0.372,p = 0.029 for Vmax and r = -0.371,p = 0.021 for DeltaPm]. Vmax decreased from 4.5m/s (IQR:4.1-5.0) to 2.2m/s (IQR:1.9-2.7), (p<0.001). This resulted in a significant increase in SEVR [135.3%(IQR:115.5-150.8) vs. 140.3%(IQR:123.0-172.5),p = 0.039] and dP/dtmax [666mmHg(IQR:489-891) vs. 927mmHg(IQR:693-1092),p<0.001], and a reduction in AIx [154.8%(IQR:138.3-171.0) vs. 133.5%(IQR:128.3-151.8),p<0.001] and AGPH [34.1%(IQR:26.8-39.0) vs. 25.0%(IQR 21.8-33.7),p = 0.002], confirming the beneficial effects of replacing the stenotic valve. No association of these parameters could be revealed with outcome. CONCLUSIONS: PWA is suitable for assessing coronary microcirculation and contractility mirrored by SEVR and maxdP/dt in the setting of aortic stenosis. PWA parameters attributed to vascular properties should be interpreted with caution. PMID- 30462703 TI - Risk factors of colistin safety according to administration routes: Intravenous and aerosolized colistin. AB - BACKGROUND: Nephrotoxicity of intravenous (IV) colistin has impeded its clinical use; aerosolized (AS) colistin may be an alternative, but safety data are lacking. Therefore, this study aimed to evaluate the incidence of acute kidney injury (AKI) and risk factors associated with IV and AS colistin administration. METHODS: A retrospective study was performed in a tertiary referral hospital. Data were collected before and after colistin administration between October 2012 and April 2016. Exclusion criteria were as follows: age less than 18 years, previous colistin administration, concurrent use of IV and AS colistin, dialysis before colistin use, and colistin use for less than 3 days. We compared AKI incidence following administration of IV versus AS colistin and analyzed risk factors for colistin-associated nephrotoxicity. RESULTS: A total of 464 patients were enrolled (n = 311, IV group; n = 153, AS group). Incidence of AKI was significantly higher in the IV group (IV vs AS, 20.26% vs 7.84%, p-value < 0.001). Duration of colistin use (OR 1.033, 95% CI 1.009-1.058, p-value 0.008) and presence of chronic kidney disease (OR 2.710, 95% CI 1.348-5.448, p-value 0.005) were associated with nephrotoxicity. There were no significant risk factors associated with AS colistin. CONCLUSIONS: Although AS colistin was not associated with any significant risk factors for nephrotoxicity, duration of colistin use and baseline kidney function may affect AS colistin-associated nephrotoxicity. PMID- 30462704 TI - Utilizing the common sense model to explore African Americans' perception of type 2 diabetes: A qualitative study. AB - Illness perceptions, which are likely influenced by patients' cultural contexts, are associated with disease self-management and adherence. African American patients perceptions of type 2 diabetes is not well understood and no known studies has used a comprehensive evidence-based theoretical framework to explore what AAs with type 2 diabetes know, believe, and think about type 2 diabetes. Understanding perceptions of an illness shared by a group of people will be useful in developing culturally-appropriate interventions targeted to the needs of the community. The purpose of this study is to explore African Americans' perceptions of type 2 diabetes based on the common sense model of illness and self-regulation. Using a phenomenology qualitative approach and purposive sampling, 40 African American men and women, age 45-60 years old with diagnosed type 2 diabetes at least one year prior, and who took at least one prescription diabetes medication, participated in six semi-structured 90-minute focus groups conducted in a private space. Qualitative content analysis was conducted to explore African Americans beliefs about type 2 diabetes. Participants expressed that historical issues, e.g., slavery, healthcare providers, the government, and God influenced how they developed diabetes. Participants reported a loss of autonomy, a change of their identity as an employee, a social individual and sexual person, as well as anger and frustration due to having diabetes. Diabetes made the African American family bonding experience of eating difficult, and the disease diminished their cultural experiences. Concerns about diabetes ranged from fear of death and amputations to the inability to prevent the disease among their children/grandchildren. Participants perceived that medications, faith in God, and positive thinking about survival helped control diabetes. Conclusions: Improved diabetes self-management and medication adherence may depend on the meaning African Americans attach to diabetes, available psychosocial support for managing diabetes, and African Americans experience with diabetes. PMID- 30462705 TI - A radiomic approach for adaptive radiotherapy in non-small cell lung cancer patients. AB - The primary goal of precision medicine is to minimize side effects and optimize efficacy of treatments. Recent advances in medical imaging technology allow the use of more advanced image analysis methods beyond simple measurements of tumor size or radiotracer uptake metrics. The extraction of quantitative features from medical images to characterize tumor pathology or heterogeneity is an interesting process to investigate, in order to provide information that may be useful to guide the therapies and predict survival. This paper discusses the rationale supporting the concept of radiomics and the feasibility of its application to Non Small Cell Lung Cancer in the field of radiation oncology research. We studied 91 stage III patients treated with concurrent chemoradiation and adaptive approach in case of tumor reduction during treatment. We considered 12 statistics features and 230 textural features extracted from the CT images. In our study, we used an ensemble learning method to classify patients' data into either the adaptive or non-adaptive group during chemoradiation on the basis of the starting CT simulation. Our data supports the hypothesis that a specific signature can be identified (AUC 0.82). In our experience, a radiomic signature mixing semantic and image-based features has shown promising results for personalized adaptive radiotherapy in non-small cell lung cancer. PMID- 30462706 TI - Variability in monocular and binocular fixation during standard automated perimetry. AB - The aim of this cross-sectional study was to use standard automated perimetry to compare fixation variability among the dominant eye fixation, non-dominant eye fixation, and binocular fixation conditions. Thirty-five eyes of 35 healthy young participants underwent standard automated perimetry (Humphrey 24-2 SITA-Standard) in dominant eye fixation, non-dominant eye fixation, and binocular fixation conditions. Fixation variability during foveal threshold and visual field measurement, which was recorded using a wearable eye-tracking glass and calculated using the bivariate contour ellipse area (deg2), was compared among the three fixation conditions. Further, the association of bivariate contour ellipse area with ocular position and fusional amplitude during binocular fixation was analysed. There were no significant differences in bivariate contour ellipse area during foveal threshold measurement among the dominant eye fixation (1.75 deg2), non-dominant eye fixation (1.45 deg2), and binocular fixation (1.62 deg2) conditions. In contrast, the bivariate contour ellipse area during visual field measurement in binocular fixation (2.85 deg2) was significantly lower than the bivariate contour ellipse area in dominant eye fixation (4.62 deg2; p = 0.0227) and non-dominant eye fixation (5.24 deg2; p = 0.0006) conditions. There was no significant difference in bivariate contour ellipse area during visual field measurement between dominant eye fixation and non-dominant eye fixation conditions. There was no significant correlation between bivariate contour ellipse area and either ocular position or fusional amplitude during both foveal threshold and visual field measurements. Thus, fixation variability might be improved in binocular fixation conditions during a long-duration test, such as visual field measurement. PMID- 30462708 TI - Papillary Lesions of the Oral Cavity. PMID- 30462707 TI - Methods for assessing small-scale variation in the abundance of a generalist mesopredator. AB - Estimating animal abundance is essential for research, management and conservation purposes. Although reliable methods exist to estimate absolute density for populations with individually marked animals, robust relative abundance indices (RAIs) may allow to track changes in population size when individual identification is not possible. Their performance, however, needs be thoroughly evaluated. We investigated the relative performance of several common faeces-based and camera-based RAIs for estimating small-scale variation in red fox abundance, a mesopredator of high relevance for management, in two different study areas. We compared precision, cost and performance of the methods in capturing relationships with covariates of local abundance. Random transect-based RAIs had a low mean, a comparatively high coefficient of variation and a high proportion of zeros, prohibiting or impeding analysis in relation to environmental predictors. Rectangular scat plots and transects along linear landscape features had an intermediate amount of zeros while retaining a high precision, but were less sensitive to local variation in abundance related to environmental predictors and required a large field effort. Camera trap-based RAIs yielded low to intermediate precision, but were more sensitive to small scale variation in relative abundance than faeces-based methods. Camera traps were the most expensive methods for an initial monitoring session, but required the lowest field effort, were cheapest in the long run and were the least susceptible to observer bias and detection error under a robust sampling protocol. Generally, faeces count-based RAIs appear more suitable for studies that aim to compare local abundance between several study sites of equal landscape composition under constant detection probability. Camera traps provide more flexible data for studies that require accounting for influences of landscape composition on local abundance and are more cost-effective for long term or continuous monitoring and more suitable to achieve high replication. Accordingly, the choice of the most suitable method and plot design is context dependent. PMID- 30462709 TI - Association analysis of RTEL1 variants with risk of adult gliomas in a Korean population. AB - Previous studies have identified multiple loci for inherited susceptibility to glioma development, including the regulator of telomere elongation helicase 1 (RTEL1). However, the association between RTEL1 variants and risk of glioma has not been well understood. Therefore, we sought to comprehensively examine the genetic interaction between RTEL1 variants and risk of glioma with respect to defined histological and molecular subtypes. We employed a case-control study involving 250 adult glioma patients with previous molecular alterations and 375 population-based controls within Korean populations. Statistical analyses on the association between RTEL1 single nucleotide polymorphisms (SNPs) and glioma risk were conducted using unconditional logistic regression. Additional conditional and stepwise analyses were performed on significant RTEL1 SNPs. We detected significant associations (Bonferroni P < .05) between six SNPs (rs6089953, rs3848669, rs6010620, rs3787089, rs6062302, and rs115303435) and risk of glioma in the Korean subjects. The two coding variants, rs6062302 (D664D) and rs115303435 (A1059T), were plausibly causal variants and were independent among the significantly associated RTEL1 variants. The glioma subgroup analyses showed that the causal variants (rs6062302 and rs115303435) may be associated with increased risk of glioma regardless of histological grades and molecular alterations. This study provides a deeper understanding of relationships between RTEL1 variants and risk of glioma. Further studies are required to ascertain the impact of those variants on glioma susceptibility. PMID- 30462710 TI - Association between sleep-disordered breathing and breast cancer aggressiveness. AB - BACKGROUND: Sleep-disordered breathing (SDB) has been associated with cancer aggressiveness, but studies focused on specific tumors are lacking. In this pilot study we investigated whether SDB is associated with breast cancer (BC) aggressiveness. METHODS: 83 consecutive women <65 years diagnosed with primary BC underwent a home respiratory polygraphy. Markers of SDB severity included the apnea-hypopnea index (AHI) and the 4% oxygen desaturation index (ODI4). The Ki67 proliferation index, lack of hormone receptors (HR-), Nottingham Histological Grade (NHG), and tumor stage were used as markers of BC aggressiveness. The association between SDB and molecular subtypes of BC was also assessed. RESULTS: The mean (SD) age was 48.8 (8.8) years and body mass index was 27.4 (5.4) Kg/m2. 42 women (50.6%) were post-menopausal. The median (IQR) AHI was 5.1 (2-9.4), and ODI4 was 1.5 (0.5-5.8). The median (IQR) AHI did not differ between the groups with Ki67>28% and Ki67<29% [5.1 (2.6-8.3) vs 5.0 (1.5-10), p = 0.89)], HR- and HR+ [5.7 (1.6-12.4) vs 4.9 (2-9.4), p = 0.68], NHG (Grade3, Grade2, and Grade1; p = 0.86), tumor stage (stage III-IV, stage II, and stage I; p = 0.62), or molecular subtypes (Luminal A, Luminal B, HER2, and triple negative; p = 0.90). The prevalence of an AHI>=5 did not differ between the groups with Ki67>28% and Ki67<29% (51.2% vs 52.3%, p = 0.90), HR- and HR+ (58.3% vs 49.1%, p = 0.47), NHG categories (p = 0.89), different tumor stages (p = 0.71), or molecular subtypes (p = 0.73). These results did not change when the ODI4 was used instead of the AHI. CONCLUSION: Our results do not support an association between the presence or severity of SDB and BC aggressiveness. PMID- 30462711 TI - The differential effects of type and frequency of social participation on IADL declines of older people. AB - BACKGROUND: Although social participation (SP) is valid in active aging, it is vague which types and the frequency of SP are effective in maintaining instrumental activities of daily living (IADL). We conducted a community-based prospective cohort study and investigated the association of the types and frequency for SP with IADL decline in community-dwelling older adults. METHODS: The target population were all individuals aged >=65 living in a commuter town in Nara, Japan. A total of 6,013 participants with independent IADL at baseline were analyzed. IADL was assessed using the Tokyo Metropolitan Institute of Gerontology Index of Competence. Six SP types were assessed: volunteer groups, sports groups, hobby clubs, senior citizens' clubs, neighborhood community associations, and cultural clubs. The frequency of SP was categorized into frequent (i.e., weekly or more), moderate (i.e., monthly or yearly), and non-participation. Using multiple logistic regression models, the odds ratio (OR) and a 95% confidence interval (CI) for IADL decline were calculated. Covariates included age, marital status, education, subjective economic status, work status, body mass index, chronic medical conditions (i.e., hypertension, diabetes mellitus, heart disease, and cerebrovascular disease), lifestyle factors (i.e., alcohol, smoking, and exercise), self-rated health, depression, and cognitive functioning. To examine gender differences, stratified analyses by gender were performed. RESULTS: During the 33-month follow-up, 16.4% of men and 8.7% of women exhibited IADL decline. After adjustment for all covariates, compared to those who never participated, women with moderate participation had significantly lower odds of IADL decline in volunteer groups (OR = 0.53, 95% CI = 0.31-0.88), hobby clubs (OR = 0.55, 95% CI = 0.38-0.79), neighborhood community associations (OR = 0.58, 95% CI = 0.42 0.81), and cultural clubs (OR = 0.51, 95% CI = 0.31-0.82), and women with frequent participation had lower odds of IADL decline in hobby clubs (OR = 0.63, 95% CI = 0.43-0.93). In contrast, among men, the significant association between SP and less risk of IADL decline was limited to moderate participation in neighborhood community associations (OR = 0.79, 95% CI = 0.63-0.99), and there were no differences between frequent participation and non-participation in all types of SP. Regarding volunteer groups, compared to women with frequent participation, women with moderate participation had a significantly lower risk of IADL decline (OR = 0.37, 95% CI = 0.18-0.77). The results of additional stratified analyses by self-rated health, depression, and cognitive functioning showed that the associations of the type and frequency of SP with IADL decline varied according to physical and mental functioning. CONCLUSIONS: Several types of SP have a favorable effect on IADL through moderate participation rather than frequent participation, and women with moderate participation in volunteer groups have a more beneficial effect on IADL than women with frequent participation. When advising community-dwelling older adults on SP for IADL maintenance, health professionals may need to take into account plateau effects, gender differences, and physical and mental functioning. PMID- 30462712 TI - Pilot study for three-dimensional assessment of laminar pore structure in patients with glaucoma, as measured with swept source optical coherence tomography. AB - PURPOSE: To develop a method to quantify, based on swept-source optical coherence tomography (OCT), the 3D structure of the laminar pores in patients with glaucoma. METHODS: This retrospective study examined 160 laminar pores from 8 eyes of 8 cases: 4 normal subjects and 4 open-angle glaucoma (OAG) patients. We reconstructed 3D volume data for a 3 x 3 mm disc, using a method similar to OCT angiography, and segmented the structure of the lamina cribrosa. Then, we manually segmented each laminar pore in sequential C-scan images (>90 slices at 2.6-micron intervals) with VCAT5 (RIKEN, Japan). We compared the control and OAG subjects with the Mann-Whitney U test. Differences were considered significant at p < 0.05. RESULTS: We found that the laminar pores of the OAG patients had a significantly smaller average cross-sectional area, smaller 3D volume (adjusted to the average thickness of the lamina cribrosa), and higher true sphericity, and lower principal value (P1, 2, 3) of the 3D structure data (all: p < 0.0001). The topographic distribution of damaged laminar pores was consistent with the damaged area of the macular map. CONCLUSION: We successfully developed a method to quantify the 3D structure of the laminar pores; providing a useful tool to assess lamina cribrosa-associated risk factors for glaucoma. These findings promise to benefit future investigations into the pathomechanisms of glaucoma. PMID- 30462713 TI - Does motivation matter? - The relationship between teachers' self-efficacy and enthusiasm and students' performance. AB - Knowledge and motivation of a teacher are two unchallenged, essential characteristics for successful education. Whilst the relevance of teachers' professional knowledge for successful students' learning has been studied in a sophisticated manner for years, the meaning of teachers' motivational orientations for students' performance still lacks a differentiated consideration. This construct is conceptualized by three domains: (1) self efficacy, (2) subject-specific enthusiasm, and (3) enthusiasm for teaching the subject. Motivational orientations overall have shown to be relevant predictors of students' learning. However, there are several dimensions of motivation and their relative importance remains unclear. Our study goes beyond the available findings by considering in detail each of the three domains' relations to students' performance. Thus, we aim to further contribute to the clarification of the predictors of students' performance in school teaching. For this purpose, we conducted a study with 48 biology teachers and their 1036 students. To assess the three domains of teachers' motivational orientations, we applied paper and pencil tests. Concept maps and paper and pencil tests were used to measure students' performance. By specifying multilevel structural equation models, we examined the relationship between the domains of teachers' motivational orientations and the performance of the students. Our results reveal no relationship between teachers' self-efficacy and students' performance, but a significant positive relationship between the latter and teachers' subject-specific enthusiasm. Moreover, our results show a positive trend in the relationship between enthusiasm for teaching the subject and students' performance. The results provide a differentiated picture about the importance of motivational orientations for the characterisation of an effective teacher. We discuss our findings in terms of possible effect mechanisms and their relevance for further research on teacher motivation and the improvement of teacher education programmes. PMID- 30462714 TI - Societal determinants of HIV vulnerability among clients of female commercial sex workers in Indonesia. AB - This study aimed to explore societal determinants of HIV vulnerability among the clients of female commercial sex workers (FCSWs) in Belu and Malaka districts, Indonesia. A qualitative inquiry using in-depth interviews was employed to collect data from participants (n = 42) recruited using a purposive and snowball sampling technique. Data analysis was guided by a qualitative data analysis framework. The study results revealed several societal determinants that supported vulnerability to HIV infection among the participants. They included low education level and sexual health literacy including the lack of knowledge and information about HIV transmission and prevention. Additional determinants identified were limited source of HIV/AIDS-related information, availability of and ease of accessibility of brothels and FCSWs, peer influence, and high mobility of the study participants. Findings of this study indicate the needs and call for interventions that aim to protect both FCSWs and their clients, through provision of HIV/AIDS and sexual health education and information and improvement in the availability and accessibility of condoms. PMID- 30462715 TI - Molecular dynamics simulation of the follicle-stimulating hormone receptor. Understanding the conformational dynamics of receptor variants at positions N680 and D408 from in silico analysis. AB - Follicle-stimulating hormone receptor (FSHR) is a G-protein coupled receptor (GPCR) and a prototype of the glycoprotein hormone receptors subfamily of GPCRs. Structural data of the FSHR ectodomain in complex with follicle-stimulating hormone suggests a "pull and lift" activation mechanism that triggers a conformational change on the seven alpha-helix transmembrane domain (TMD). To analyze the conformational changes of the FSHR TMD resulting from sequence variants associated with reproductive impairment in humans, we set up a computational approach combining helix modeling and molecular simulation methods to generate conformational ensembles of the receptor at room (300 K) and physiological (310 K) temperatures. We examined the receptor dynamics in an explicit membrane environment of polyunsaturated phospholipids and solvent water molecules. The analysis of the conformational dynamics of the functional (N680 and S680) and dysfunctional (mutations at D408) variants of the FSHR allowed us to validate the FSHR-TMD model. Functional variants display a concerted motion of flexible intracellular regions at TMD helices 5 and 6. Disruption of side chain interactions and conformational dynamics were detected upon mutation at D408 when replaced with alanine, arginine, or tyrosine. Dynamical network analysis confirmed that TMD helices 2 and 5 may share communication pathways in the functional FSHR variants, whereas no connectivity was detected in the dysfunctional mutants, indicating that the global dynamics of the FSHR was sensitive to mutations at amino acid residue 408, a key position apparently linked to misfolding and variable cell surface plasma membrane expression of FSHRs with distinct mutations at this position. PMID- 30462716 TI - Xenogeneic Heterotopic Auxiliary Liver transplantation (XHALT) promotes native liver regeneration in a Post-Hepatectomy Liver failure model. AB - The liver's regenerative capacity is unique, but too small a segment can overwhelm its ability to simultaneously regenerate and support the host, resulting in liver dysfunction and death. Here we tested a temporary Xenogeneic Heterotopic Auxiliary Liver Transplant (XHALT) from Gal-KO miniature swine in a baboon model of Post-Hepatectomy Liver Failure (PHLF) by 90%- hepatectomy. Immunosuppression consisted of CVF, ATG, FK 506 and steroids. 90%-hepatectomized animals died within 4-5 days with the clinical picture of PHLF, (high LFTs and bilirubin, ascites, encephalopathy and coagulopathy). The 10% remnants had macroscopic and histological evidence of severe steatosis and absence of hepatocyte replication. In contrast, the addition of XHALT prolonged survival up to 11 days, with the cause of death being sepsis, rather than liver failure. The remnant liver appeared grossly normal, and on histology, there was no evidence of fatty infiltration, but there was pronounced Ki-67 staining. In conclusion, temporary auxiliary xenografts have the potential to support a small for size liver graft while it grows to adequate size or provide an opportunity for organ recovery in acute liver failure. PMID- 30462717 TI - Caring for the caregivers: Evaluation of the effect of an eight-week pilot mindful self-compassion (MSC) training program on nurses' compassion fatigue and resilience. AB - BACKGROUND: Nurses vicariously exposed to the suffering of those in their care are at risk of compassion fatigue. Emerging research suggests that self compassion interventions may provide protective factors and enhance resilience. This pilot study examined the effect of an eight-week Mindful Self-Compassion (MSC) training intervention on nurses' compassion fatigue and resilience and participants' lived experience of the effect of the training. METHODS: This observational mixed research pilot study adopted an evaluation design framework. It comprised of a single group and evaluated the effects of a pilot MSC intervention by analyzing the pre- and post-change scores in self-compassion, mindfulness, secondary trauma, burnout, compassion satisfaction, and resilience. The sample of the nurses' (N = 13) written responses to the question, "How did you experience the effect of this pilot MSC training?" were also analyzed. RESULTS: The Pre- to Post- scores of secondary trauma and burnout declined significantly and were negatively associated with self-compassion (r = -.62, p = .02) (r = -.55, p = .05) and mindfulness (r = -.54, p = .05). (r = -.60, p = .03), respectively. Resilience and compassion satisfaction scores increased. All variables demonstrated a large effect size: Mean (M) Cohen's d = 1.23. The qualitative emergent themes corroborated the quantitative findings and expanded the understanding about how MSC on the job practices enhanced nurses' coping. CONCLUSION: This is the first study to examine the effect of a pilot (MSC) training program on nurses' compassion fatigue and resilience in this new area of research. It provides some preliminary empirical evidence in support of the theorized benefits of self-compassion training for nurses. However, further research, such as a Randomized Control Trial (RCT) with a larger sample size and a longitudinal study, is required to see if the benefits of self-compassion training are sustainable. PMID- 30462718 TI - How does anonymous online peer communication affect prevention behavior? Evidence from a laboratory experiment. AB - While the importance of social networks for health behaviors is well-recognized, relatively little is known regarding the accuracy of anonymous online communication and its impact on health behavior. In 2012, we conducted a laboratory experiment in Boston, Massachusetts with 679 individuals to understand how anonymous online communication affects individual prevention decisions. Participants had to opt for or against investing in prevention over three sessions, each consisting of 15 experimental rounds. In the third session only, participants could share their experiences with a group of 1-3 other anonymous participants after each round. Groups exchanged an average of 16 messages over the 15 rounds of the third session. 70% of messages contained information about the subject's prevention decision and the resulting health outcome. Participants were more likely to communicate when they prevented than when they did not, with prevention failures resulting in the highest probability of sending a message. Nonetheless, receiving an additional message reporting prevention increased the odds a subject would prevent by 32 percent. We find that participants tend to adopt the prevention behavior reported by others, with less weight given to the reported outcomes of prevention, suggesting that social networks may influence behaviors through more than just information provision. PMID- 30462719 TI - Resilience as an emergent property of human-infrastructure dynamics: A multi agent simulation model for characterizing regime shifts and tipping point behaviors in infrastructure systems. AB - The objective of this study is to establish a framework for analyzing infrastructure dynamics affecting the long-term steady state, and hence resilience in civil infrastructure systems. To this end, a multi-agent simulation model was created to capture important phenomena affecting the dynamics of coupled human-infrastructure systems and model the long-term performance regimes of infrastructure. The proposed framework captures the following three factors that shape the dynamics of coupled human-infrastructure systems: (i) engineered physical infrastructure; (ii) human actors; and (iii) chronic and acute stressors. A complex system approach was adopted to examine the long-term resilience of infrastructure based on the understanding of performance regimes, as well as tipping points at which shifts in the performance regime of infrastructure occur under the impact of external stressors and/or change in internal dynamics. The application of the proposed framework is demonstrated in a case of urban water distribution infrastructure using the data from a numerical case study network. The developed multi-agent simulation model was then used in examining the system resilience over a 100-year horizon under stressors such as population change and funding constraints. The results identified the effects of internal dynamics and external stressors on the resilience landscape of infrastructure systems. Furthermore, the results also showed the capability of the framework in capturing and simulating the underlying mechanisms affecting human-infrastructure dynamics, as well as long-term regime shifts and tipping point behaviors. Therefore, the integrated framework proposed in this paper enables building complex system-based theories for a more advanced understanding of civil infrastructure resilience. PMID- 30462720 TI - Effect of gestational diabetes and insulin resistance on offspring's myocardial relaxation kinetics at three years of age. AB - PURPOSE: Scientific evidence on the long-term impact of gestational diabetes mellitus (GDM) on offspring's myocardial relaxation is scarce. Studies have linked GDM with transient ventricular hypertrophy in newborns resulting in diastolic dysfunction, but long-term assessment is lacking. The main objective of this study was to evaluate myocardial relaxation in 3-year-old children in relation to the degree of insulin resistance of their mother during pregnancy. METHODS: We prospectively assessed myocardial relaxation by echocardiography imaging on 106 children at 3 years of age. Subjects were divided into 3 groups [GDM, insulin resistance (IR) and normoglycemic (CTRL)], based on their mother's 75g-OGTT and HOMA-IR results at second trimester screening. We collected information on children adiposity and body size, maternal characteristics and maternal and cord blood measurement of C-peptide and insulin. RESULTS: The study population comprised 29 children from GDM mothers, 36 children from IR mothers and 41 CTRL children. Compared to the CTRL group, we found that a higher proportion of children in the IR group and the GDM group met the criteria for impaired myocardial relaxation, but this did not reach statistical significance (odds ratio adjusted for heart rate and body surface area of 1.4 [0.2-9.5] and 3.5 [0.6-20.6], respectively). CONCLUSION: We did not detect an increased risk of impaired myocardial relaxation at three years of age in children exposed in-utero to IR and GDM, compared to children from normoglycemic mothers. PMID- 30462721 TI - Do musicians learn a fine sequential hand motor skill differently than non musicians? AB - Do professional musicians learn a fine sequential hand motor skill more efficiently than non-musicians? Is this also the case when they perform motor imagery, which implies that they only mentally simulate these movements? Musicians and non-musicians performed a Go/NoGo discrete sequence production (DSP) task, which allows to separate sequence-specific from a-specific learning effects. In this task five stimuli, to be memorized during a preparation interval, signaled a response sequence. In a practice phase, different response sequences had to be either executed, imagined, or inhibited, which was indicated by different response cues. In a test phase, responses were required to familiar (previously executed, imagined, or inhibited) and unfamiliar sequences. In both phases, response times and response accuracy were measured while the electroencephalogram (EEG) was only registered during the practice phase to compare activity between motor imagery, motor execution, and motor inhibition for both groups. Results in the practice phase revealed that musicians learned the response sequences faster and more accurately than non-musicians although no difference in initiation time was found. EEG analyses revealed similar lateralized activity during learning a motor skill for both groups. Our results from the test phase showed better sequence-a-specific learning effects (i.e., faster response times and increased accuracy) for musicians than for non musicians. Moreover, we revealed that non-musicians benefit more from physical execution while learning a required motor sequence, whereas sequence-specific learning effects due to learning with motor imagery were very similar for musicians and non-musicians. PMID- 30462723 TI - Lactobacillus plantarum 299V improves the microbiological quality of legume sprouts and effectively survives in these carriers during cold storage and in vitro digestion. AB - Probiotics improve consumers' health and additionally may positively influence the microbiological and organoleptic quality of food. In the study, legume sprouts were inoculated with Lactobacilllus plantarum 299V to produce a new functional product ensuring the growth and survival of the probiotic and high microbiological quality of the final product. Legume sprouts, which are an excellent source of nutrients, were proposed as alternative carriers for the probiotic. The key factors influencing the production of probiotic-rich sprouts include the temperature (25 degrees C) of sprouting and methods of inoculation (soaking seeds in a suspension of probiotics). Compared to the control sprouts, the sprouts enriched with the probiotic were characterized by lower mesophilic bacterial counts. In the case of fresh and stored probiotic-rich sprouts, lactic acid bacteria (LAB) accounted for a majority of total microorganisms. The Lb. plantarum population was also stable during the cold storage. The high count of LAB observed in the digest confirmed the fact that the studied sprouts are effective carriers for probiotics and ensure their survival in the harmful conditions of the digestive tract in an in vitro model. Enrichment of legume sprouts with probiotics is a successful attempt and yields products for a new branch of functional foods. PMID- 30462722 TI - MicroRNA-451a overexpression induces accelerated neuronal differentiation of Ntera2/D1 cells and ablation affects neurogenesis in microRNA-451a-/- mice. AB - MiR-451a is best known for its role in erythropoiesis and for its tumour suppressor features. Here we show a role for miR-451a in neuronal differentiation through analysis of endogenous and ectopically expressed or silenced miR-451a in Ntera2/D1 cells during neuronal differentiation. Furthermore, we compared neuronal differentiation in the dentate gyrus of hippocampus of miR-451a-/- and wild type mice. MiR-451a overexpression in lentiviral transduced Ntera2/D1 cells was associated with a significant shifting of mRNA expression of the developmental markers Nestin, betaIII Tubulin, NF200, DCX and MAP2 to earlier developmental time points, compared to control vector transduced cells. In line with this, accelerated neuronal network formation in AB.G.miR-451a transduced cells, as well as an increase in neurite outgrowth both in number and length was observed. MiR-451a targets genes MIF, AKT1, CAB39, YWHAZ, RAB14, TSC1, OSR1, POU3F2, TNS4, PSMB8, CXCL16, CDKN2D and IL6R were, moreover, either constantly downregulated or exhibited shifted expression profiles in AB.G.miR-451a transduced cells. Lentiviral knockdown of endogenous miR-451a expression in Ntera2/D1 cells resulted in decelerated differentiation. Endogenous miR-451a expression was upregulated during development in the hippocampus of wildtype mice. In situ hybridization revealed intensively stained single cells in the subgranular zone and the hilus of the dentate gyrus of wild type mice, while genetic ablation of miR-451a was observed to promote an imbalance between proliferation and neuronal differentiation in neurogenic brain regions, suggested by Ki67 and DCX staining. Taken together, these results provide strong support for a role of miR-451a in neuronal maturation processes in vitro and in vivo. PMID- 30462724 TI - Transplant center assessment of the inequity in the kidney transplant process and outcomes for the Indigenous American patients. AB - BACKGROUND: The goal is to determine the delays and reduced rates of kidney transplant (KTx) for the Indigenous Americans and variables predictive of these outcomes at a large single transplant center. METHODS: 300 Indigenous Americans and 300 non-Hispanic white American patients presenting for KTx evaluation from 2012-2016 were studied. RESULTS: Compared to whites, the Indigenous Americans had the following: more diabetes, dialysis, physical limitation and worse socioeconomic characteristics(p<0.01); median difference of 20 day delay from referral to KTx evaluation, 17 day delay from approval to UNOS listing and 126.5 longer delay on the waitlist compared to whites(p<0.001). Of the Indigenous Americans listed, more died, were removed, or were still waiting than transplanted compared to whites (p<0.001). Variables predictive of delay from referral to transplant evaluation included: Indigenous race, distance from transplant center, coronary artery disease, and time on dialysis (p<0.05). Cumulative incidence of waitlisting and KTx was lower for Indigenous Americans (p<0.0001). Independent predictors of decreased likelihood of waitlisting included age, peripheral vascular disease, no caregiver, physical limitation, and illegal drug use history (p<0.05). Variables predictive of lower likelihood of KTx included Indigenous race, percentage of time inactive on the waitlist, no caregiver, and O blood type. CONCLUSIONS: Among patients referred and evaluated for KTx, the Indigenous American race was independently associated with significant delays in the KTx process after accounting for co-morbid and socioeconomic factors. Cardiovascular morbidity and physical limitation were identified as important determinants of delay and decreased likelihood of waitlisting. Further quantitative and qualitative work is needed to identify and intervene on modifiable barriers to improve access to KTx for the Indigenous Americans. PMID- 30462725 TI - Correction: Six minute walk distance and reference values in healthy Italian children: A cross-sectional study. AB - [This corrects the article DOI: 10.1371/journal.pone.0205792.]. PMID- 30462726 TI - An empirical analysis of post-work grocery shopping activity duration using modified accelerated failure time model to differentiate time-dependent and time independent covariates. AB - In this paper, the accelerated failure time (AFT) model is modified to analyze post-work grocery shopping activity duration. Much previous shopping duration analysis was conducted using the proportional hazard (PH) modeling approach. Once the proportionality assumption was violated, the traditional accelerated failure time (TAFT) model was usually selected as an alternative modeling approach. However, a TAFT model only has covariates with non-proportional and time dependent effects on the hazard overtime while a PH model only accommodates covariates with proportional and time-independent effects. Neither of them considers the possibility that some of covariates may have proportional and time independent effects and some may have non-proportional and time-dependent effects on the hazard value in one model. To address this issue, the paper generalizes the TAFT model and develops a modified accelerated failure time (MAFT) model to accommodate both time-dependent and time-independent covariates for activity duration analysis. Checking on the proportionality assumption indicates that the assumption is not valid in the post-work grocery shopping activity data extracted from the 2017 National Household Travel Survey (NHTS) conducted by the U.S. Department of Transportation (USDOT). Both TAFT and MAFT models are developed for comparisons and analysis. The empirical and statistical results show that there do exist two different types of covariates affecting shopping activity duration, including covariates only with proportional and time-independent effects (i.e. working duration, commute travel time) and those with non-proportional and time dependent effects. The MAFT model can capture the subtleties in various types of covariate effects and help better understand how those covariates affect activity duration overtime. This paper also shows the importance to develop a flexible duration model with both time-dependent and time-independent covariates for accurately evaluating travel demand management (TDM) policies, like flexible work hours. PMID- 30462727 TI - An assessment of the performance of the logistic mixed model for analyzing binary traits in maize and sorghum diversity panels. AB - The logistic mixed model (LMM) is well-suited for the genome-wide association study (GWAS) of binary agronomic traits because it can include fixed and random effects that account for spurious associations. The recent implementation of a computationally efficient model fitting and testing approach now makes it practical to use the LMM to search for markers associated with such binary traits on a genome-wide scale. Therefore, the purpose of this work was to assess the applicability of the LMM for GWAS in crop diversity panels. We dichotomized three publicly available quantitative traits in a maize diversity panel and two quantitative traits in a sorghum diversity panel, and them performed a GWAS using both the LMM and the unified mixed linear model (MLM) on these dichotomized traits. Our results suggest that the LMM is capable of identifying statistically significant marker-trait associations in the same genomic regions highlighted in previous studies, and this ability is consistent across both diversity panels. We also show how subpopulation structure in the maize diversity panel can underscore the LMM's superior control for spurious associations compared to the unified MLM. These results suggest that the LMM is a viable model to use for the GWAS of binary traits in crop diversity panels and we therefore encourage its broader implementation in the agronomic research community. PMID- 30462728 TI - Cervical human papillomavirus infection in women with preterm prelabor rupture of membranes. AB - OBJECTIVE: To evaluate the association between cervical human papillomavirus (HPV) infection at the time of admission and the presence of microbial invasion of the amniotic cavity (MIAC) and intra-amniotic inflammation (IAI) in women with preterm prelabor rupture of membranes (PPROM) and to determine the association between cervical HPV infection and short-term neonatal morbidity. METHODS: One hundred women with singleton pregnancies complicated by PPROM between the gestational ages of 24+0 and 36+6 weeks were included in the study. The presence of HPV DNA was evaluated in scraped cervical cells using polymerase chain reaction (PCR). Amniotic fluid samples were obtained by transabdominal amniocentesis. RESULTS: The rate of cervical HPV infection in women with PPROM was 24%. The rates of MIAC and IAI were not different between women with cervical HPV infection and those without cervical HPV infection [MIAC: with HPV: 21% (5/24) vs. without HPV: 22% (17/76), p = 1.00; IAI: with HPV: 21% (5/24) vs. without HPV: 18% (14/76), p = 0.77]. There were no differences in the selected aspects of short-term neonatal morbidity between women with and without cervical HPV infection. CONCLUSIONS: In women with PPROM, the presence of cervical HPV infection at the time of admission is not related to a higher risk of intra amniotic infection-related and inflammatory complications or worse short-term neonatal outcomes. PMID- 30462729 TI - Response to organic cultivation of heirloom Capsicum peppers: Variation in the level of bioactive compounds and effect of ripening. AB - Peppers (Capsicum spp.) are one of the most important vegetables and their double use (vegetable or spice) and two commercial stages (unripe and fully ripe) contributed to their use in many recipes and fast diffusion from America. Nowadays, Spain is a center of diversity for C. annuum, with many landraces, offering a great opportunity for adaptation to organic cultivation. Furthermore, Capsicum peppers contain many bioactive compounds, essential to provide high added-value to these cultivars, especially for organic markets, although knowledge about the effect of organic cultivation on Capsicum fruit quality is still scarce. Here, 37 accessions of Spanish landraces and foreign materials from C. annuum and other species were grown under organic and conventional conditions and evaluated for ascorbic acid (AAC), total phenolics (TP) and total red and yellow/orange carotenoids, considering both ripening stages. A large genotypic variation was found within each ripening stage and growing condition for the studied traits. Also, both stages showed high levels, although fully ripe fruits were the richest. Organic conditions enabled higher levels in fully ripe fruits of AAC and TP on average (135 vs 117 mg.100 g-1 and 232 vs 206 mg.100 g-1) and in most accessions, although the genotype*growing conditions interaction also contributed, but at lower extent, to the observed variation. Significant genotype*ripening stage and growing conditions*ripening stage interactions were also found, suggesting that the magnitude of the increase with ripening depends on the accession and growing conditions. By contrast, there were no differences between growing conditions for carotenoids and differences were mainly due to the genotype factor. Finally, the large genotypic variation and favourable organic conditions allowed identifying several materials from different types and uses with very high levels of bioactive compounds for organic cultivation, in both ripening stages but particularly at fully ripe stage (>500 mg.100 g-1). PMID- 30462730 TI - Necrostatin-1 promotes ectopic periodontal tissue like structure regeneration in LPS-treated PDLSCs. AB - Necroptosis is a programmed necrosis, regulated by receptor interacting protein kinase 1(RIP1) and receptor interacting protein kinase 3(RIP3), and could be inhibited by necrostatin-1(Nec-1) specifically. This study aims to evaluate the effect of Nec-1 on LPS-treated periodontal ligament stem cells (PDLSCs). In the research, three groups were established: normal cultured PDLSCs, Porphyromonas gingivalis (Pg)-LPS stimulated PDLSCs and Pg-LPS+Nec-1 treated PDLSCs. The expression of RIP1 and RIP3 and osteogenic differentiation of PDLSCs in three groups were analyzed. Then, we constructed cell aggregates (CA) using PDLSCs, then PDLSCs-CA were combined with Bio-Oss in three groups were transplanted subcutaneously in nude mice to assess their potentials of periodontal tissue regeneration. The results showed that RIP1 and RIP3 were fully expressed in Pg LPS stimulated PDLSCs and the level increased significantly. Nec-1 inhibited RIP1 RIP3 interaction, and further inhibited necroptosis of PDLSCs in inflammatory state. Moreover, Nec-1 pretreatment ameliorates the osteogenic differentiation of LPS-treated PDLSCs and can effectively promote the cementum like structure ectopic regenerative ability of PDLSCs in nude mice. These findings show RIP1/RIP3-mediated necroptosis is an important mechanism of cell death in PDLSCs. Nec-1 has a protective effect in reducing cell death and promotes ectopic periodontal tissue like structure regeneration by inhibiting necroptosis. Nec-1 is a hopeful therapeutic agent which protects cells from necroptosis and ameliorates functional outcome. PMID- 30462731 TI - Neddylation contributes to CD4+ T cell-mediated protective immunity against blood stage Plasmodium infection. AB - CD4+ T cells play predominant roles in protective immunity against blood-stage Plasmodium infection, both for IFN-gamma-dependent effector mechanisms and providing B cell helper signals. Neddylation, an ubiquitination-like process triggered by covalent conjugation of NEDD8 to specific targets, has emerged as a potential regulator of T cell activities to TCR engagement. However, its contribution to T cell-mediated immunity to blood-stage malaria remains unclear. Here using an experimental model induced by Plasmodium yoelii 17XNL, and conditional knockout mice with T cell-specific deficiency of crucial components of neddylation pathway, we demonstrate activation of neddylation in T cells during blood-stage Plasmodium infection is essential for parasite control and host survival. Mechanistically, we show that apart from promoting CD4+ T cell activation, proliferation, and development of protective T helper 1 (Th1) cell response as suggested previously, neddylation is also required for supporting CD4+ T cell survival, mainly through B-cell lymphoma-2 (Bcl-2) mediated suppression of the mitochondria-dependent apoptosis. Furthermore, we provide evidence that neddylation contributes to follicular helper T (Tfh) cell differentiation, probably via augmenting the ubiquitin ligase Itch activity and proteasomal degradation of FoxO1, thereby facilitating germinal center (GC) formation and parasite-specific antibody production. This study identifies neddylation as a positive regulator of anti-Plasmodium immunity and provides insight into an involvement of such pathway in host resistance to infectious diseases. PMID- 30462732 TI - Fucoidans inhibit the formation of post-operative abdominal adhesions in a rat model. AB - PURPOSE: Fibrin clot is essential for post-operative abdominal adhesion formation. Fucoidans, sulfated polysaccharides, inhibit fibrin clot formation. In addition, they inhibit inflammation and fibrosis, which also play important roles in adhesion formation. The purpose of this study was to evaluate fucoidans' potential for inhibiting post-operative abdominal adhesions and measure their effects on systemic coagulation parameters when administered intraperitoneally (IP). METHODS AND MATERIALS: Female Sprague Dawley rats were studied. A 2.5x2.5cm full thickness segment of abdominal wall was excised. The skin edges were approximated. This model induces extensive adhesions and allows objective quantitation. Three fucoidans were evaluated- Sigma Fucoidan Crude (SFC), Fucus vesiculosis 95% (Sigma) and, Peridan. One protocol involved continuous infusion into the abdomen from a subcutaneous osmotic pump. Alternatively, boluses of the solutions were injected IP at the end of the operation. Rats were sacrificed a week later. Adhesion extent was scored. Systemic coagulation effects of fucoidans were also evaluated. INR and aPTT were measured following IP injection of the fucoidan solutions and after 7 days of continuous infusion. RESULTS: Animals given a continuous infusion of either SFC or Peridan yielded adhesion reduction of 80 to 90% from control. Bolus Peridan had no discernable influence on adhesion formation, but a single bolus of SFC caused significant adhesion reductions. Peridan resulted in prompt aPTT elevations which fell to nearly normal by 5 hours. The maximum peak value after SFC injection was seen in 15 hours. The maximal INR elevations were around 2. Measurement of INR and aPTT after a week of continuous infusion of either Peridan or SFC, were always in the normal control range. The third agent, Sigma, frequently yielded intraperitoneal infection found at autopsy. CONCLUSIONS: These findings indicate that selected fucoidans infused intraperitoneally for a week after abdominal operations reduce adhesion extent by up to 90%. PMID- 30462733 TI - Tuberculosis burden on AIDS in Brazil: A study using linked databases. AB - OBJECTIVES: To estimate the burden of tuberculosis (TB) in reported AIDS cases, to compare the characteristics of TB/HIV subjects with those without TB and to evaluate survival with or without TB in Brazil. METHODS: The data source was the linked database between AIDS (2011-2014) and TB (2011-2014) databases from the Notifiable Diseases Information System (SINAN). The sociodemographic, clinical, laboratory results and use of antiretroviral therapy (ART) data were compared by TB occurrence or not. Survival probability was estimated using the Kaplan-Meier method and associated factors were sought using Cox regression. RESULTS: The proportion of TB diagnosed from 2011 to 2014 among AIDS cases reported between 2006 and 2014 was 6.3%. Subjects coinfected with TB were predominantly male, older, with lower schooling, with lower CD4 count, higher viral load, and higher proportion of ART initiation than those without TB. 57.5% were diagnosed with HIV before TB, 38.2% as concurrent TB/HIV and 4.3% with TB before HIV. 16,466 reported TB cases were not found in the AIDS database, although registered as HIV infected in the SINAN TB database between 2011 and 2014. Median survival for PLHIV was 581 days, with 582 for those without TB, significantly higher than 547 for those with TB (log-rank teste, p = 0,001). In the Cox multivariate analysis, male gender [aHR = 1.27 (CI 95% 1.22-1.33)], older age [aHR = 1.020 (CI 95% 1.019 1.022)] and TB coinfection [aHR = 1.97 (CI 95% 1.88-2.07)] were positively associated with adjusted hazard of death, whereas CD4 count 200-499 cells [aHR = 0.21 (CI 95% 0.20-0.22)] and receiving ART [aHR = 0.2 2(CI 95% 0.21-0.23)] reduced the risk of death. CONCLUSIONS: HIV-infected subjects should be screened for TB at care entry, to minimize diagnosis and treatment delays when active TB is present or to increase the odds of being offered latent TB infection therapy to prevent TB. On the other hand, TB cases should be promptly tested for HIV. All those will contribute to reduce mortality among people living with AIDS. PMID- 30462734 TI - High-throughput toxicity study of lubricant emulsions and their common ingredients using zebrafish. AB - Though lubricant emulsions have been widely used in many industrial processes, various human health hazards have been reported. Conducting a systematic toxicity study on emulsions is difficult since emulsions contain multiple chemical compounds, and hydrophobic compounds form complex emulsion particles via surfactants. For a quantitative toxicity study, we developed a high-throughput imaging system using zebrafish and conducted a large scale in vivo toxicity assay of lubricant emulsion and their common ingredients. By computing the locomotion activity of zebrafish from captured time-lapse images, we could quantify the degree of relative toxicity of 29 chemicals. The changes in the locomotion activity over time were observed to vary significantly depending on emulsions, indicating that the degree of toxicity of the commercial products was very diverse. We found that primary ethanolamines were more toxic than secondary or tertiary ethanolamines, and several factors, such as alkyl chain length, EO mole, test concentration, and emulsion particle size, affected toxicity. PMID- 30462735 TI - Correction: Syk Signaling in Dendritic Cells Orchestrates Innate Resistance to Systemic Fungal Infection. AB - [This corrects the article DOI: 10.1371/journal.ppat.1004276.]. PMID- 30462736 TI - Correction: Pre-Solutrean rock art in southernmost Europe: Evidence from Las Ventanas Cave (Andalusia, Spain). AB - [This corrects the article DOI: 10.1371/journal.pone.0204651.]. PMID- 30462737 TI - Correction: Behavioural traits of individual homing pigeons, Columba livia f. domestica, in their homing flights. AB - [This corrects the article DOI: 10.1371/journal.pone.0201291.]. PMID- 30462739 TI - Correction: Income disparities in smoking cessation and the diffusion of smoke free homes among U.S. smokers: Results from two longitudinal surveys. AB - [This corrects the article DOI: 10.1371/journal.pone.0201467.]. PMID- 30462738 TI - Preeclampsia and academic performance in children: A nationwide study from Iceland. AB - BACKGROUND: Hypertensive disorders complicate up to 10% of pregnancies. Evidence suggests a potential association between maternal hypertensive disorders during pregnancy, particularly preeclampsia, and adverse neurodevelopment in the offspring, but existing studies are subject to limitations. We aimed to assess whether in-utero exposure to preeclampsia/eclampsia negatively impacts academic performance at ages 9, 12 and 15 years. METHODS: Using individually linked, nationwide data from the Icelandic registries we followed all children born in 1989-2004 (N = 68,580), from birth until the end of 2014, thereof 63,014 (91.9%) took at least one standardized test. Using a stepwise, mixed-effects approach, we modelled the hypothesized relationship while adjusting for maternal, perinatal and childhood variables of interest. We compared test scores, measured on a normalized scale ranging from 0-60 with a mean of 30 and a standard deviation of 10, in the 4th, 7th, and 10th grades, between children exposed to preeclampsia or eclampsia in-utero versus children from normotensive pregnancies in the population. RESULTS: Children exposed to preeclampsia/eclampsia scored lower than those unexposed in mathematics across all grade levels, corresponding to a difference of 0.44 points (95% CI: 0.00, 0.89), 0.59 points (95% CI: 0.13, 1.06) and 0.59 points (95% CI: 0.08, 1.10), respectively. No differences were observed in the language arts. CONCLUSIONS: Our findings suggest a minimal effect of maternal preeclampsia/eclampsia on children's academic performance at ages 9, 12 and 15 years. The differences observed in mathematic scores between exposed and unexposed children were minimal, less than one tenth of a standard deviation per measurement occasion. PMID- 30462740 TI - Pulmonary isolation and clinical relevance of nontuberculous mycobacteria during nationwide survey in Serbia, 2010-2015. AB - The rates of pulmonary colonization and disease due to nontuberculous mycobacteria (NTM) appear to be increasing globally, but diversity of species recovered as well as clinical relevance of NTM isolates differ considerably by geographic region. The first nationwide study of isolation frequency and clinical significance of NTM in Serbia included all patients with respiratory specimens yielding a positive NTM culture over the six-year period, 2010-2015. We analyzed trends in annual NTM isolation and NTM pulmonary disease (PD) incidence rates, with NTM PD cases defined in accordance with microbiological criteria established by the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA). 777 pulmonary NTM isolates were collected from 565 patients, of whom 126 (22.3%) met the ATS/IDSA criteria. The annual NTM isolation and NTM PD incidence rates per 100,000 changed over 2010-2015 from 0.9 to 1.6 (p = 0.1746) and from 0.18 to 0.48 (p = f0.0040), respectively. Both isolation and disease rates increased considerably with age, while higher NTM PD rates were also associated with residence in urbanized areas. Diversity of NTM species isolated was shown to be region-specific, with M. xenopi as the most prevalent species (17.3%), and increasing isolation rates of rapid growing mycobacteria (RGM) (p = 0.0072). M. xenopi was also the most common cause of NTM PD (28.6%), followed by RGM (27.8%). With 73% clinically relevant isolates, M. abscessus was identified as the most clinically relevant NTM species. While NTM PD obviously remains a rare disease in Serbia, the overall results justify recognition of NTM as pathogens of rising importance, and require further characterization of their epidemiology in the country. PMID- 30462741 TI - Multiple-cluster detection test for purely temporal disease clustering: Integration of scan statistics and generalized linear models. AB - The spatial scan statistic is commonly used to detect spatial and/or temporal disease clusters in epidemiological studies. Although multiple clusters in the study space can be thus identified, current theoretical developments are mainly based on detecting a 'single' cluster. The standard scan statistic procedure enables the detection of multiple clusters, recursively identifying additional 'secondary' clusters. However, their p-values are calculated one at a time, as if each cluster is a primary one. Therefore, a new procedure that can accurately evaluate multiple clusters as a whole is needed. The present study focuses on purely temporal cases and then proposes a new test procedure that evaluates the p value for multiple clusters, combining generalized linear models with an information criterion approach. This framework encompasses the conventional, currently widely used detection procedure as a special case. An application study adopting the new framework is presented, analysing the Japanese daily incidence of out-of-hospital cardiac arrest cases. The analysis reveals that the number of the incident increases around New Year's Day in Japan. Further, simulation studies undertaken confirm that the proposed method possesses a consistency property that tends to select the correct number of clusters when the truth is known. PMID- 30462742 TI - Correction: Technical-efficiency analysis of end-of-life care in long-term care facilities within Europe: A cross-sectional study of deceased residents in 6 EU countries (PACE). AB - [This corrects the article DOI: 10.1371/journal.pone.0204120.]. PMID- 30462743 TI - High-density multi-population consensus genetic linkage map for peach. AB - Highly saturated genetic linkage maps are extremely helpful to breeders and are an essential prerequisite for many biological applications such as the identification of marker-trait associations, mapping quantitative trait loci (QTL), candidate gene identification, development of molecular markers for marker assisted selection (MAS) and comparative genetic studies. Several high-density genetic maps, constructed using the 9K SNP peach array, are available for peach. However, each of these maps is based on a single mapping population and has limited use for QTL discovery and comparative studies. A consensus genetic linkage map developed from multiple populations provides not only a higher marker density and a greater genome coverage when compared to the individual maps, but also serves as a valuable tool for estimating genetic positions of unmapped markers. In this study, a previously developed linkage map from the cross between two peach cultivars 'Zin Dai' and 'Crimson Lady' (ZC2) was improved by genotyping additional progenies. In addition, a peach consensus map was developed based on the combination of the improved ZC2 genetic linkage map with three existing high density genetic maps of peach and a reference map of Prunus. A total of 1,476 SNPs representing 351 unique marker positions were mapped across eight linkage groups on the ZC2 genetic map. The ZC2 linkage map spans 483.3 cM with an average distance between markers of 1.38 cM/marker. The MergeMap and LPmerge tools were used for the construction of a consensus map based on markers shared across five genetic linkage maps. The consensus linkage map contains a total of 3,092 molecular markers, consisting of 2,975 SNPs, 116 SSRs and 1 morphological marker associated with slow ripening in peach (SR). The consensus map provides valuable information on marker order and genetic position for QTL identification in peach and other genetic studies within Prunus and Rosaceae. PMID- 30462744 TI - Integrating spatial indicators in the surveillance of exploited marine ecosystems. AB - Spatial indicators are used to quantify the state of species and ecosystem status, that is the impacts of climate and anthropogenic changes, as well as to comprehend species ecology. These metrics are thus, determinant to the stakeholder's decisions on the conservation measures to be implemented. A detailed review of the literature (55 papers) showed that 18 spatial indicators were commonly used in marine ecology. Those indicators were than characterized and studied in detail, based on its application to empirical data (a time series of 35 marine species spatial distributions, sampled either with a random stratified survey or a regular transects surveys). The results suggest that the indicators can be grouped into three classes, that summarize the way the individuals occupy space: occupancy (the area occupied by a species), aggregation (spreading or concentration of species biomass) and quantity dependent (indicators correlated with biomass), whether these are spatially explicit (include the geographic coordinates, e.g. center of gravity) or not. Indicator's temporal variability was lower than between species variability and no clear effect was observed in relation to sampling design. Species were then classified accordingly to their indicators. One indicator was selected from each of the three categories of indicators, to represent the main axes of species spatial behavior and to interpret them in terms of occupancy-aggregation-quantity relationships. All species considered were then classified according to their relationships among those three axes, into species that under increasing abundancy, primarily increase occupancy or aggregation or both. We suggest to use these relationships along the three-axes as surveillance diagrams to follow the yearly evolution of species distributional patterns in the future. PMID- 30462745 TI - Machine learning model combining features from algorithms with different analytical methodologies to detect laboratory-event-related adverse drug reaction signals. AB - BACKGROUND: The importance of identifying and evaluating adverse drug reactions (ADRs) has been widely recognized. Many studies have developed algorithms for ADR signal detection using electronic health record (EHR) data. In this study, we propose a machine learning (ML) model that enables accurate ADR signal detection by integrating features from existing algorithms based on inpatient EHR laboratory results. MATERIALS AND METHODS: To construct an ADR reference dataset, we extracted known drug-laboratory event pairs represented by a laboratory test from the EU-SPC and SIDER databases. All possible drug-laboratory event pairs, except known ones, are considered unknown. To detect a known drug-laboratory event pair, three existing algorithms-CERT, CLEAR, and PACE-were applied to 21 year inpatient EHR data. We also constructed ML models (based on random forest, L1 regularized logistic regression, support vector machine, and a neural network) that use the intermediate products of the CERT, CLEAR, and PACE algorithms as inputs and determine whether a drug-laboratory event pair is associated. For performance comparison, we evaluated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), F1-measure, and area under receiver operating characteristic (AUROC). RESULTS: All measures of ML models outperformed those of existing algorithms with sensitivity of 0.593-0.793, specificity of 0.619-0.796, NPV of 0.645-0.727, PPV of 0.680-0.777, F1-measure of 0.629-0.709, and AUROC of 0.737-0.816. Features related to change or distribution of shape were considered important for detecting ADR signals. CONCLUSIONS: Improved performance of ML models indicated that applying our model to EHR data is feasible and promising for detecting more accurate and comprehensive ADR signals. PMID- 30462747 TI - Correction: Obligate development of Blastocrithidia papi (Trypanosomatidae) in the Malpighian tubules of Pyrrhocoris apterus (Hemiptera) and coordination of host-parasite life cycles. AB - [This corrects the article DOI: 10.1371/journal.pone.0204467.]. PMID- 30462746 TI - The KCNH3 inhibitor ASP2905 shows potential in the treatment of attention deficit/hyperactivity disorder. AB - N-(4-fluorophenyl)-N'-phenyl-N"-(pyrimidin-2-ylmethyl)-1,3,5-triazine-2,4,6 triamine [ASP2905] is a potent and selective inhibitor of the potassium voltage gated channel subfamily H member 3 (KCNH3) that was originally identified in our laboratory. KCNH3 is concentrated in the forebrain, and its overexpression in mice leads to cognitive deficits. In contrast, Kcnh3 knockout mice exhibit enhanced performance in cognitive tasks such as attention. These data suggest that KCNH3 plays important roles in cognition. Here we investigated the neurochemical and neurophysiological profiles of ASP2905 as well as its effects on cognitive function, focusing on attention. ASP2905 (0.0313 and 0.0625 mg/kg, po) improved the latent learning ability of mice, which reflects attention. Microdialysis assays in rats revealed that ASP2905 increased the efflux of dopamine and acetylcholine in the medial prefrontal cortex (0.03, 0.1 mg/kg, po; 0.1, 1 mg/kg, po, respectively). The activities of these neurotransmitters are closely associated with attention. We used a multiple-trial passive avoidance task to investigate the effects of ASP2905 on inattention and impulsivity in juvenile stroke-prone spontaneously hypertensive rats. ASP2905 (0.1 and 0.3 mg/kg, po) significantly prolonged cumulative latency as effectively as methylphenidate (0.1 and 0.3 mg/kg, sc), which is the gold standard for treating ADHD. Further, ASP2905, amphetamine, and methylphenidate significantly increased the alpha-band power of rats, suggesting that ASP2905 increases arousal, which is a pharmacologically important activity for treating ADHD. In contrast, atomoxetine and guanfacine did not significantly affect power. Together, these findings suggest that ASP2905, which acts through a novel mechanism, is as effective for treating ADHD as currently available drugs such as methylphenidate. PMID- 30462748 TI - Musical and temporal auditory skills in cochlear implant users after music therapy. AB - PURPOSE: Verify the performance of musical perception and temporal auditory resolution and ordering skills in pre- and post-music therapy patients with cochlear implants (CI). METHODS: Study participants were 11 postlingual CI users with mean age of 47.64 years. All individuals underwent 10 weekly music therapy sessions. Auditory assessment was conducted using the Montreal Battery of Evaluation of Amusia (MBEA) and the Frequency Pattern Test (FPT). All participants were submitted to a placebo condition prior to music therapy and were evaluated at three different times. RESULTS: Significant improvement was observed in the subtests of contour and melody memory after music therapy. No placebo effect or difference in the FPT was observed after music therapy. CONCLUSION: Music therapy is a useful tool to improve musical skills in adult postlingual users of CI. PMID- 30462749 TI - Efficacy of stem cells on bone consolidation of distraction osteogenesis in animal models: a systematic review. AB - Distraction osteogenesis (DO) relies on the recruitment and proliferation of mesenchymal stem cells (MSC) to the target site, where they differentiate into osteoblasts to promote bone formation. Nevertheless, MSC recruitment appears to be slow and limits bone formation in DO defects. Thus, this systematic review aims to evaluate the ability of locally applied MSC to enhance bone formation in DO preclinical models. Databases were searched for quantitative pre-clinical controlled studies that evaluated the effect of local administration of MSC on DO bone formation. Eligible studies were identified and data regarding study characteristics, outcome measures and quality were extracted. Nine studies met the inclusion criteria. Autogenous and xenogenous MSC were used to promote DO bone formation. These included bone marrow-derived MSC, adipose tissue-derived MSC and MSC derived from human exfoliated deciduous teeth. Meta-analysis was not possible due to heterogeneities in study designs. Local MSC implantation was not associated with adverse effects. In 4 out of the 5 studies, locally delivered undifferentiated bone-marrow MSC had a positive effect on DO bone formation. Few studies evaluated the therapeutic effects of MSC from other sources. The adjunct use of biologically active molecules or forced expression of key genes involved in osteogenesis further boosted the ability of bone-marrow MSC to promote DO bone formation. While risk of bias and heterogeneity limited the strength of this systematic review, our results suggest that the use of MSC is safe and may provide beneficial effects on DO bone formation. PMID- 30462750 TI - Light curing resin cements containing iodonium salts promote suitable apical bonding of posts to radicular dentin. AB - The aim of this study was to analyze the efficiency of experimental light-curing resin cements (ERCs) with a ternary photo-initiator system containing diphenyliodonium hexafluorphosphate (DPI) and different amines on retention of glass-fiber posts to dentin (GFP). ERCs formulations: a 1:1 mass ratio of 2,2 bis[4-(2-hydroxy-3-methacryloxypropoxy)phenylpropane and triethyleneglycol dimethacrylate. Camphorquinone was used as initiator. Six experimental groups were established according to the amine used: [ethyl-4-(dimethylamino)benzoate EDMAB or 2-(dimethylamino)ethyl methacrylate-DMAEMA] and the concentration of DPI (0, 0.5 mol%, 1 mol%). The resin cements Variolink II (dual- and light-cured versions) were used as commercial reference. Eighty recently extracted bovine incisors (n = 10) were selected for this study. The roots were prepared and the fiber posts were cemented with the resin cement specified for each experimental group. Specimens from coronal, middle, and apical thirds of the root were subjected to push-out bond strength test 24 hours after bonding. Data were subjected to split-plot ANOVA and the Tukey test (p = 0.05). ERCs containing DPI showed statistically significant higher bond strengths compared with ERCs without DPI. ERCs containing DPI were statistically similar to VARIOLINK II - dual-cured and superior to VARIOLINK II - light-cured (except for EDMAB - 1DPI in the medium third and DMAEMA - 1DPI in the coronal third). Different amines did not influence post retention. The apical root region showed the lowest bond strength for the groups EDAB-0DPI, DMAEMA-0DPI and VARIOLINK II light-cured. Light-cured ERCs containing DPI were efficient for GFP retention to radicular dentin, with similar behaviour to that of dual-curing commercial resin cement. PMID- 30462751 TI - Effectiveness of antiretroviral therapy in the single-tablet regimen era. AB - OBJECTIVE: To evaluate the effectiveness of antiretroviral therapy and the associated factors according to the type of regimen used: Single Tablet Regimen or Multiple Tablet Regimen. METHODS: Prospective cohort of 440 patients (male, 74.3%, median age, 36 years old) who initiated antiretroviral therapy between Jan/14 and Dec/15 at a referral service in Belo Horizonte. Efficacy was defined as viral suppression (viral load, VL < 50 copies/ml) and evaluated after six and twelve months of treatment. Sociodemographic, clinical and behavioral data were collected from clinical charts and from Information Systems. Multivariate analysis of overall effectiveness was performed by logistic regression. RESULTS: Most patients initiated Multiple Tablet Regimen antiretroviral therapy (n = 255, 58%). At six months, overall viral suppression was 74.6%, being higher among patients who used Single Tablet Regimen (80.6%, p = 0.04). At twelve months, 83.2% of patients reached viral suppression, with no difference between groups (p = 0.93). Factors independently associated with viral suppression at six and twelve months varied, being negatively associated with effectiveness: VL >= 100,000 copies/ml, symptoms of AIDS, longer interval time between diagnosis and initiation of antiretroviral therapy, antiretroviral switching, smoking or current illicit drugs usage (p < 0.05). Factors positively associated with viral suppression included adherence to antiretroviral therapy and category of risk/exposure of men who have sex with men (p < 0.05). Reaching viral suppression at six months was the main predictor of effectiveness at one year (OR = 8.96 and p < 0.01). CONCLUSIONS: Viral suppression was high and better results were achieved for patients who used Single Tablet Regimen regimens at six months. Clinical, behavioral, and antiretroviral therapy -related factors influence viral suppression and highlight the need for interventions to increase early diagnosis and initiation of antiretroviral therapy, patient's adherence, and to reduce illicit drugs and cigarette smoking in this population. PMID- 30462752 TI - Intrafamilial and extrafamilial sexual assault and its association with alcohol consumption. AB - OBJECTIVE: Analyze the prevalence of intrafamilial and extrafamilial sexual assault in adolescents of Peru and its association with alcohol consumption. METHODS: We used a two-step and stratified probabilistic sampling to select male and female students in secondary education from all over Peru. The study included data from 54,756 students with information on demographics, alcohol and drug use, and sexual assault. The statistical analysis considered the complex sampling and we conducted two independent analyses by type of sexual assault (intrafamilial and extrafamilial), stratified by the sex of the victim. RESULTS: The prevalence of life of intrafamilial sexual assaults (5.4%, 95%CI 5.0-5.8) was similar to that of extrafamilial sexual assaults (6.1%, 95%CI 5.6-6.6). Alcohol consumption in the past year was associated with intrafamilial and extrafamilial sexual assaults that occurred in the same period after adjusting for confounders. Alcohol consumption in the past year was associated with non-physical and physical forms of intrafamilial and extrafamilial sexual assaults in the disaggregated analysis by type of assault. Alcohol consumption in the past year was associated with extrafamilial rape only among females (ORa = 2.8; 95%CI 1.3 5.9). CONCLUSIONS: Sexual assault against adolescent males and females by family members is a frequent form of victimization that is associated with alcohol consumption in Peru. It is important to examine this form of victimization among adolescents, especially those who consume alcohol. PMID- 30462753 TI - NMR-based metabolomics to select a surgical method for treating papillary thyroid carcinoma. AB - OBJECTIVE: This study aims to investigate differences in the metabolomic profiles of patients who received different surgeries for papillary thyroid carcinoma (PTC). METHODS: Two surgical methods, i.e., unilateral and total thyroidectomy, were employed according to different disease conditions. Sera from patients who were treated with levothyroxine sodium tablets before and after surgery was analyzed with a Bruker 500 Hz nuclear magnetic resonance (NMR) spectrometer. Data were analyzed via principal component analysis (PCA) and partial least squares discriminate analysis (PLS-DA) with SIMCA-P+ 11.0 software, and metabolites were obtained and compared. The first and second principal components were selected from PCA, PLS-DA, and orthogonal partial least squares discriminate analysis (OPLS-DA). A p-value less than 0.05 was considered statistically significant. RESULTS: There were significant differences in serum metabolomics before and after surgery. Compared with unilateral thyroidectomy, total thyroidectomy reversed some highly increased metabolite levels (e.g., taurine and betaine). More significant variations in abnormal metabolites were noted after total thyroidectomy than after unilateral thyroidectomy (e.g., alanine, choline, hippurate, and formic acid). CONCLUSIONS: The choice of surgical method for PTC patients should be based not only on the tumor condition but also on the potential consequences of metabolic variations. Total thyroidectomy reversed some increased metabolite levels but led to accumulation of some other metabolites due to the loss of thyroid function; thus, metabolic disturbances caused by thyroid hormone deficiency should be prevented in advance. PMID- 30462754 TI - Passage of Borrelia burgdorferi through diverse Ixodid hard ticks causes distinct diseases: Lyme borreliosis and Baggio-Yoshinari syndrome. AB - Baggio-Yoshinari syndrome is an emerging, tick-borne, infectious disease recently discovered in Brazil. This syndrome is similar to Lyme disease, which is common in the United States of America, Europe and Asia; however, Brazilian borreliosis diverges from the disease observed in the Northern Hemisphere in its epidemiological, microbiological, laboratory and clinical characteristics. Polymerase chain reaction procedures showed that Baggio-Yoshinari syndrome is caused by the Borrelia burgdorferi sensu stricto spirochete. This bacterium has not yet been isolated or cultured in adequate culture media. In Brazil, this zoonosis is transmitted to humans through the bite of Amblyomma and Rhipicephalus genera ticks; these vectors do not belong to the usual Lyme disease transmitters, which are members of the Ixodes ricinus complex. The adaptation of Borrelia burgdorferi to Brazilian vectors and reservoirs probably originated from spirochetes with atypical morphologies (cysts or cell-wall-deficient bacteria) exhibiting genetic adjustments, such as gene suppression. These particularities could explain the protracted survival of these bacteria in hosts, beyond the induction of a weak immune response and the emergence of serious reactive symptoms. The aim of the present report is to note differences between Baggio Yoshinari syndrome and Lyme disease, to help health professionals recognize this exotic and neglected zoonosis. PMID- 30462755 TI - Assessment of suicidal behavior and factors associated with a diagnosis of prostate cancer. AB - OBJECTIVES: To determine the incidence of suicide risk in a group of patients who have been diagnosed with localized prostate cancer (PC) and to identify the factors that affect suicidal behavior. METHODS: Patients from a tertiary care oncology center in Sao Paulo, Brazil participated in this study and were interviewed after being diagnosed with low-risk or intermediate-risk PC, per the D'Amico risk classification, between September 2015 and March 2016. Patients underwent suicide risk assessment sessions using the Mini International Neuropsychiatric Interview (MINI), the Hospital Anxiety and Depression Scale (HADS), and the CAGE substance abuse screening tool before they started treatment and surveillance. Psychiatric treatment history, family history of suicidal behavior, and the use of psychotropic drugs were also examined. RESULTS: The prevalence of suicide risk among 250 patients who were recently diagnosed with low-risk or intermediate-risk PC was 4.8%. According to the HADS, 10.8% and 6.8% of patients had a positive score anxiety and for depression, respectively. Alcoholism was suspected in 2.8% of the group. Suicide risk was associated with anxiety (p=0.001); depression (p=0.005); being divorced, separated, widowed, or single (p=0.045); living alone (p=0.028); and prior psychological treatment (p=0.003). CONCLUSIONS: After being diagnosed with PC, patients who display risk factors for suicide should be monitored by a mental health team. PMID- 30462757 TI - Growth Dynamic of Allogeneic and Autogenous Bone Grafts in a Vertical Model. AB - Several techniques have been proposed for vertical bone regeneration, and many of them use bone autogenous and allogeneic grafts. The purpose of this study was to compare demineralised freeze-dried bone allografts (DFDBA), fresh-frozen (FF) allografts, autogenous bone grafts to find differences between volumetric and histological quantity of bone formation and vertical bone growth dynamic. A vertical tissue regeneration bone model was performed in rabbit calvarias under general anaesthesia. Four hollow cylinders of pure titanium were screwed onto external cortical bone calvarias in eight rabbits. Each one of the cylinders was randomly filled with one intervention: DFDBA, FF, autogenous bone, or left to be filled with blood clot (BC) as control. Allogeneic grafts were obtained from a ninth animal following international standardised protocols for the harvesting, processing, and cryopreservation of allografts. Autogenous graft was obtained from the host femur scraping before adapting hollow cylinders. Animals were euthanized at 13 weeks. Vertical volume was calculated after probe device measurements of the new formed tissue inside the cylinders and after titanium cylinders were removed. Histomorphometry and fluorochrome staining were used to analyse quantity and dynamic of bone formation, respectively. Results showed that DFDBA and fresh-frozen bone improved the velocity and the quantity of bone deposition in distant portions of the basal plane of grafting. Remaining material in allograft groups was more intense than in autogenous group. Both allografts can be indicated as reliable alternatives for volume gain and vertical bone augmentation. PMID- 30462756 TI - A prediction model for hypoxemia during routine sedation for gastrointestinal endoscopy. AB - OBJECTIVES: The current study was designed to assess the clinical predictors of hypoxemia and to develop a multivariable, predictive model for hypoxemia during routine gastrointestinal endoscopy. METHODS: In total, 308 patients were enrolled in the analysis. Demographic data, concurrent chronic disease information, anesthetic dose and Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores were collected and analyzed statistically. RESULTS: Multivariate logistic regression indicated that age (OR: 1.04; 95%CI 1.01-1.08), body mass index (BMI) (OR: 1.12; 95%CI: 1.02-1.21) and habitual snoring (OR: 3.71; 95%CI: 1.62-8.48) were independently associated with hypoxemia. A logistic regression function (LR model) was developed to predict hypoxemia considering the parameters of 7.73+0.04 age (years), +0.11 BMI, and +1.31 habitual snoring (yes or no). The area under the receiver operating characteristic (ROC) curve for the LR model was 0.76. CONCLUSIONS: The LR model, consisting of age, BMI and habitual snoring, was a useful predictor of hypoxemia during routine sedation for gastrointestinal endoscopy. PMID- 30462758 TI - Oval Versus Circular-Shaped Root Canals: Bond Strength Reached with Varying Post Techniques. AB - The aim of this study was to compare the bond strength (BS) of glass fiber posts (GFP) luted to oval and circular-shaped root canals rehabilitated using varying post techniques, at different intraradicular levels. Ninety 16-mm-long roots of human mandibular premolars, classified either as having oval or circular-shaped canals, were endodontically treated and prepared for restoration using one of three different post techniques (n=15): 1) single GFP; 2) resin-relined GFP; 3) main GFP associated with accessory posts. GFPs were luted with a dual polymerizing resin cement (RelyX ARC) after the canal had been treated with a 3 step etch-and-rinse adhesive system (Adper Scothbond Multipurpose). The samples were sectioned into three 1-mm-thick sections, which were differentiated by the root level (cervical, middle and apical) and tested for push-out BS. Assessment of failure mode was made under a stereomicroscope. Data were analyzed using repeated measures three-way ANOVA and Tukey's test. The root canal cross-section had a significant influence on BS (p<0.001), with the lowest values being observed in oval-shaped canals. The post technique also significantly affected the BS (p=0.018), with the resin-relined GFPs providing the highest BS values in both oval and circular-shaped canals. Irrespective of the cross-section of the root canal and post technique, there was no significant difference in BS in the cervical, middle and apical third of the root canal (p=0.084). In oval-shaped canals, the BS to intraradicular dentin at cervical, middle or apical level could be increased when the GFPs posts were relined. PMID- 30462759 TI - Vertical and Horizontal Misfit Analysis of 3-unit FDP Fabricated with Different Techniques and CAD/CAM Systems. AB - The aim of this is was evaluate the vertical and horizontal marginal adaptation of 3-unit fixed partial denture frameworks fabricated using different techniques and CAD/CAM systems. A total of 40 framework specimens were fabricated and divided into four groups as follows: lost-wax casting (G1); lost-wax casting with welding (G2); extraoral optical scanning of models (3S/DWOS) (G3); intraoral optical scanning (Cerec Bluecam/Sirona) (G4). A reference model was used to simulate a fixed partial denture with three elements (with a central pontic). The frameworks of G1 and G2 were cast in nickel-chromium (NiCr) alloy, whereas those of G3 and G4 were milled in zirconia. In all groups, vertical and horizontal marginal adaptation (over-contour and under-contour) was evaluated using a three dimensional optical microscope (Quick Scope, Mitutoyo). The results showed higher vertical marginal misfit in G1 than in the other groups (p<0.001). Regarding horizontal marginal misfit, higher over-contour values occurred in G3 than in the other groups (p<0.001). G3 did not show under-contour at all, whereas the other groups did not differ from each other in this regard (p>0.05). Within the limitations of this study, it can be concluded that lost-wax casting with welding is a viable alternative to the use of CAD/CAM systems to fabricate frameworks of three-unit FPDs, since the techniques yielded similar vertical misfit values. Extra-oral CAD/CAM systems showed the highest horizontal misfit (over-contour) compared to other groups. PMID- 30462760 TI - Characterization of Residual Stresses in Veneering Ceramics for Prostheses with Zirconia Framework. AB - The aim of this study was to evaluate the influence of the coefficient of thermal expansion (CTE or alpha) and glass transition temperature (Tg) of three veneering ceramics used with zirconia frameworks of full-arch fixed prostheses. The generation of residual stresses and linear contraction after the simulation of the cooling process and mechanical loading were measured. The analysis was based on the finite element method in three-dimensional model of a maxillary full-arch fixed prosthesis with zirconia framework (e.max ZirCAD) and veneer by felsdpathic ceramics (GEC - IPS e.max Ceram, GVM - Vita VM9 and GLC - Lava Ceram). The linear contraction simulation was performed by cooling the structures from the Tg of each veneer ceramic at room temperature (25 degrees C). A loading of 100 N on the occlusal region of the first molar was performed. The magnitude of the maximum principal stress (smax) and linear contraction were evaluated. The levels of CTE mismatch between veneering ceramics and framework showed no relevant influence on smax and linear contraction. The Tg values of the veneer ceramic showed to be directly proportional to amount of smax and linear contraction. The GEC presented the highest values of smax and linear contraction. The GVM and GLC did not present significant differences between them. In conclusion, GVM was similar to GLC, while GEC presented differences in relation to other veneer ceramics in terms of residual stress and linear contraction. PMID- 30462761 TI - In Vitro Antimicrobial Effect of Bioadhesive Oral Membrane with Chlorhexidine Gel. AB - This study aimed to evaluate in vitro the antimicrobial effect of a bioadhesive chitosan-based oral membrane with chlorhexidine for local treatment of infections in the oral tissues. Five oral membranes of different compositions were tested: 5% chitosan (G1); 5% chitosan +/- 0.2% chlorhexidine (G2), 5% chitosan +/- 0.6% chlorhexidine (G3), 5% chitosan +/- 1.0% chlorhexidine (G4), and 5% chitosan +/- 2.0% chlorhexidine (G5). Also, five gel types were tested according to the following compositions: 5% chitosan gel (G6), 0.2% chlorhexidine gel (G7), 2.0% chlorhexidine gel (G8), 5% chitosan gel +/- 0.2% chlorhexidine gel (G9), and 5% chitosan gel +/- 2.0% chlorhexidine gel (G10). The antimicrobial action of the samples was tested against Candida albicans and Streptococcus mutans through antibiogram by measuring the inhibition halos. Data were statistically analyzed by Kruskal-Wallis and one-way ANOVA followed by Tukey test (p<0.05). The 2.0% chlorhexidine membrane (G5) and the disks containing 2.0% chlorhexidine gel (G8) showed the greatest inhibition halos for both microorganisms, with statistically significant difference when compared to others tested groups (p=0.008) only for Candida albicans inhibitions results. All the other formulations of membranes and gels showed inhibition halos, but without statistically significant difference. The bioadhesive chitosan-based oral membrane with 2% chlorhexidine and 2% chlorhexidine gel were the most effective in inhibiting the tested microorganisms. PMID- 30462762 TI - Interactions between Terpinen-4-ol and Nystatin on biofilm of Candida albicans and Candida tropicalis. AB - The aim of this study was to evaluate the antifungal activity of Terpinen-4-ol associated with nystatin, on single and mixed species biofilms formed by Candida albicans and Candida tropicalis, as well as the effect of terpinen-4-ol on adhesion in oral cells and the enzymatic activity. The minimum inhibitory concentrations and minimum fungicide concentrations of terpinen-4-ol and nystatin on Candida albicans and Candida tropicalis were determined using the microdilution broth method, along with their synergistic activity ("checkerboard" method). Single and mixed species biofilms were prepared using the static microtiter plate model and quantified by colony forming units (CFU/mL). The effect of Terpinen-4-ol in adhesion of Candida albicans and Candida tropicalis in coculture with oral keratinocytes (NOK Si) was evaluated, as well as the enzymatic activity by measuring the size of the precipitation zone, after the growth agar to phospholipase, protease and hemolysin. Terpinen-4-ol (4.53 mg mL 1) and nystatin (0.008 mg mL-1) were able to inhibit biofilms growth, and a synergistic antifungal effect was showed with the drug association, reducing the inhibitory concentration of nystatin up to 8 times in single biofilm of Candida albicans, and 2 times in mixed species biofilm. A small decrease in the adhesion of Candida tropicalis in NOK Si cells was showed after treatment with terpinen-4 ol, and nystatin had a greater effect for both species. For enzymatic activity, the drugs showed no action. The effect potentiated by the combination of terpinen 4-ol and nystatin and the reduction of adhesion provide evidence of its potential as an anti-fungal agent. PMID- 30462763 TI - Effect of Breast Cancer Treatment on the Stomatognathic System. AB - Breast cancer is the most common cancer affecting women in the world and provides functional changes in the human body. Evaluate women submitted to unilateral mastectomy, through electromyographic activity (mandibular rest, right and left laterality, protrusion, maximum voluntary contraction with and without Parafilm, habitual and non-habitual mastication) and thickness (rest and maximum voluntary contraction) of the right temporal muscle (RT), left temporal (LT), right masseter (RM) and left masseter (LM), also the molar bite force (right and left) and compare the data with healthy women. Material and Methods: 32 women were divided into two groups: unilateral mastectomy group (MG), average +/- standard deviation 56.50+/-14.50 years (n=16) and without the disease group (CG), average +/- standard deviation 56.56+/-14.15 years (n=16). The normalized electromyographic data, muscle thickness and maximal molar bite force were tabulated and submitted to statistical analysis (SPSS 21.0; student t test, p<=0.05). Significant statistical differences between MG and CG were found in right laterality, for RM (p=0.02); left laterality, for LT (p=0.01); chewing with peanuts, for RM (p=0.04); chewing with raisins, for LM (p=0.04) and right molar bite force (p=0.03). There was no statistically significant difference between MG and CG for muscle thickness. The results of this study suggest that women undergoing unilateral mastectomy may present functional changes, with emphasis on muscular hyperactivity, lower masticatory efficiency and lower maxillary bite force. PMID- 30462764 TI - How Long does it Take to Examine Young Children with the Caries ICDAS System and how do they Respond? AB - A caries-epidemiological study using the ICDASepi-merged system was conducted in Colombian young children. This study aimed at associating the time needed for the clinical examination of caries and caries risk in 1 to 5-year-old children according to age and caries risk, and to assess behavior and child pain self perception during examination according to age. After IRB approval and given parents/caregivers' informed consent, seven trained examiners assessed 1 to 5 year olds in kindergartens under local field conditions. ICDASepi-merged caries experience (depiMEmf) was assessed as follows: Initial-depi (ICDAS 1/2 without air-drying); Moderate-dM (ICDAS 3,4); Extensive-dE (ICDAS 5,6) lesions; due-to caries fillings-f and missing-m surfaces/teeth. Caries risk was assessed with Cariogram(r). Child's behavior (Frankl-Behavior-Rating-Scale) and self-perceived pain (Visual-Analogue-Scale-of-Faces) during examination were evaluated. Clinical examination time was recorded with a stopwatch. A total of 592 children participated (1-yr.: n=31; 2-yrs.: n=96; 3-yrs.: n=155; 4-yrs.: n=209, 5-yrs.: n=101). The depiMEmfs prevalence was of 79.9% and the mean 8.4+/-10.4. Most were high-caries-risk children (68.9%). The majority (58.9%) showed >= positive behavior and <= light-pain self-perception (88.4%). Mean clinical examination time was around 3.5 minutes (216.9+/-133.9 seconds). For 5-yr. olds it corresponded to 4 minutes (240.4+/-145.0 seconds) vs. 2 minutes (122.8+/-80.1 seconds) for 1-yr. olds (Kruskal-Wallis; p=0.00). For high- and low-caries risk children it was around 4.3 minutes (255.7+/-118.5 seconds) and 3.3 minutes (201.3+/-129.4 seconds), respectively (ANOVA; p=0.01). This study demonstrates using the ICDAS system in young children is feasible, taking less than 4 minutes for the clinical examination without children behavior/pain self-perception issues. PMID- 30462765 TI - Family Religiosity and Oral Health Related Quality of Life: a Multilevel Analysis in Brazilian Schoolchildren. AB - Religiosity has been associated with a better dental condition and positive self perception of health, but there are no studies on the relationship between religious practice and oral health-related quality of life (OHRQoL), especially among schoolchildren. Thus, the aim of this study was to evaluate the association between family religiosity and OHRQoL in 12-year-old schoolchildren. We conducted a cross-sectional study in a representative sample of 12-year-old schoolchildren from Santa Maria, a city in southern Brazil. A total of 1,134 schoolchildren were assessed in a randomly selected in 20 public schools in the city. Participants were examined by 4 calibrated dentists (minimum Kappa-value for intra and inter examiner agreement were 0.79 and 0.77, respectively) according to dental caries (Decayed, Missed, Filled Teeth Index), and gingival bleeding (Community Periodontal Index criteria). OHRQoL was assessed by the Brazilian short version of Child Perceptions for Questionnaire (CPQ11-14). Parents or guardians answered a structured questionnaire regarding their socioeconomic status and religious practice. Data were analyzed using multilevel Poisson regression analysis to assess the association of religiosity and overall and domain-specific CPQ 11-14 scores. Religious practice less than once a week was associated with higher mean symptoms domain scores and higher mean CPQ 11-14 overall scores in schoolchildren. In conclusion, our findings demonstrate that family religiosity was positively associated with schoolchildren's OHRQoL. PMID- 30462766 TI - Preterm Birth, Pacifier use and Breastfeeding: is there a Relationship? AB - The immaturity of born to preterm infants may predispose to sucking difficulties. This research aimed to evaluate if pacifier use is associated with preterm birth and influenced in type of infant feeding. This comparative cross-sectional study was conducted in Belo Horizonte, Brazil and evaluated 250 children aged 3 to 5 years. As a sample, two groups were established: the normal term children group (n=125) was selected at a day-care centre and the group of preterm children (125) was identified at a public university hospital with a preterm care project from birth to seven years of age. To collect data, a pre-tested questionnaire regarding information on gestational age, infant development, infant feeding and non-nutritive sucking habits was used for both groups. Bivariate and multivariate Poisson regression was used for the statistical analysis. Pacifier use was more prevalent in the preterm group (PR=1.20, 95% CI=1.02-1.42) who used the bottle (PR=1.38, 95% CI=1.15-1.64) and were breastfed for less than six months (PR=1.19, 95% CI=1.01-1.41). The majority of breastfed infants were of normal term birth (PR=1.14, 95% CI=1.04-1.20) and had monthly family income greater than USD 450.28 (RP= 1.10, 95% CI=1.01-1.20). In this study, pacifier use was more prevalent among preterm infants and associated with less than six months of breastfeeding and used of bottle. Monthly family income was associated with a prevalence of breastfeeding. PMID- 30462767 TI - I've got Toothache, I need Antibiotics: a UK Perspective on Rational Antibiotic Prescribing by Dentists. AB - Antibiotics do not cure toothache. This headline message of the United Kingdom's (UK) Dental Antimicrobial Stewardship (AMS) toolkit's posters and leaflets is aimed at patients; clinicians are expected to know this already. Evidence based clinical guidelines exist to set clear standards for good clinical practice yet there are barriers to compliance. The national AMS audit tool is designed for clinicians to review their management of acute dental conditions, including but not limited to the prescription of antibiotics. In this article we aim to help dental teams protect their patients and themselves from adverse events related to antibiotic prescription. It explores the emergent problem of Clostridium difficile, antibiotic resistance and severe sepsis, and considers some of the barriers, which clinicians have suggested, contribute to the unjustified prescription of antibiotics. Dentists must weigh the risks against the benefits before prescribing any antibiotic. PMID- 30462768 TI - Melanotic Neuroectodermal Tumor of Infancy: a Clinicopathological Case Report. AB - Melanotic neuroectodermal tumor of infancy (MNTI) is a rare neoplasm that affects mainly children under 1 year of age. A 4-month-old boy was referred for evaluation of a lesion with 1 month of evolution. Intra-oral examination detected a firm upon palpation submucosal nodular mass, measuring 1.5 cm in diameter, affecting the anterior maxillary alveolar ridge and covered by a slightly blue mucosa with evident telangiectasia. The patient underwent an incisional biopsy and histological and immunohistochemical analyses revealed nests of AE1/AE3 positive epithelioid cells with abundant melanin pigmentation. Other cell types, resembling neuroblasts, were also present and positive for CD56, synaptophysin and enolase. The diagnosis of MNTI was established and the patient was referred for treatment. Conservative surgical resection was performed along with 3 adjacent teeth under general anesthesia. The patient is in follow-up for 1,5 year without recurrence. Conservative surgical management of MNTI may be an alternative to maxillectomy, contributing to the patient's quality of life. PMID- 30462769 TI - Familial history of hypertension-induced impairment on heart rate variability was not observed in strength-trained subjects. AB - Family history of hypertension is an important predictive factor for hypertension and is associated with hemodynamic and autonomic abnormalities. Previous studies reported that strength training might reduce arterial blood pressure (AP), as well as improve heart rate variability (HRV). However, the benefits of strength training in the offspring of hypertensive parents have not been fully evaluated. Here, we analyzed the impact of strength training on hemodynamics and autonomic parameters in offspring of hypertensive subjects. We performed a cross-sectional study with sedentary or physically active offspring of normotensives (S-ON and A ON) or hypertensives (S-OH and A-OH). We recorded RR interval for analysis of HRV. AP was similar between groups. Sedentary offspring of hypertensives presented impairment of total variance of RR interval, as well as an increase in cardiac sympathovagal balance (S-OH: 4.2+/-0.7 vs S-ON: 2.8+/-0.4 and A-ON: 2.4+/ 0.1). In contrast, the strength-trained group with a family history of hypertension did not show such dysfunctions. In conclusion, sedentary offspring of hypertensives, despite displaying no changes in AP, showed reduced HRV, reinforcing the hypothesis that autonomic dysfunctions have been associated with higher risk of hypertension onset. Our findings demonstrated that strength trained offspring of hypertensives did not present impaired HRV, thus reinforcing the benefits of an active lifestyle in the prevention of early dysfunctions associated with the onset of hypertension in predisposed populations. PMID- 30462770 TI - Participation of hepatic alpha/beta-adrenoceptors and AT1 receptors in glucose release and portal hypertensive response induced by adrenaline or angiotensin II. AB - It has been previously demonstrated that the hemodynamic effect induced by angiotensin II (AII) in the liver was completely abolished by losartan while glucose release was partially affected by losartan. Angiotensin II type 1 (AT1) and adrenergic (?1- and beta-) receptors (AR) belong to the G-proteins superfamily, which signaling promote glycogen breakdown and glucose release. Interactive relationship between AR and AT1-R was shown after blockade of these receptors with specific antagonists. The isolated perfused rat liver was used to study hemodynamic and metabolic responses induced by AII and adrenaline (Adr) in the presence of AT1 (losartan) and ?1-AR and beta-AR antagonists (prazosin and propranolol). All antagonists diminished the hemodynamic response induced by Adr. Losartan abolished hemodynamic response induced by AII, and AR antagonists had no effect when used alone. When combined, the antagonists caused a decrease in the hemodynamic response. The metabolic response induced by Adr was mainly mediated by ?1-AR. A significant decrease in the hemodynamic response induced by Adr caused by losartan confirmed the participation of AT1-R. The metabolic response induced by AII was impaired by propranolol, indicating the participation of beta AR. When both ARs were blocked, the hemodynamic and metabolic responses were impaired in a cumulative effect. These results suggested that both ARs might be responsible for AII effects. This possible cross-talk between beta-AR and AT1-R signaling in the hepatocytes has yet to be investigated and should be considered in the design of specific drugs. PMID- 30462771 TI - Oridonin induces growth inhibition and apoptosis in human gastric carcinoma cells by enhancement of p53 expression and function. AB - The tumor suppressive role of oridonin, an active compound extracted from Rabdosia rubescens, has been proven in several gastric cancer (GC) cell lines. The present study aimed to evaluate the effect of oridonin on another GC cell line, SNU-216, and explore the potential mechanisms. The viable cell numbers, cell migration, survival fraction, and cell viability were, respectively, evaluated by trypan blue exclusion assay, wound healing assay, clonogenic assay, and CCK-8 assay. Cell apoptosis was determined by flow cytometry assay and western blot. The expression of p53 was inhibited by transient transfection, and the efficiency was verified by western blot. qRT-PCR was performed to measure the mRNA expression of p53. Western blot was used to evaluate the protein expression of apoptosis, DNA damage and p53 function related factors. We found that oridonin significantly inhibited cell proliferation, migration, and survivability, and enhanced cell apoptosis in SNU-216 cells. However, it had no influence on HEK293 cell viability. Oridonin also remarkably enhanced the anti-tumor effect of cisplatin on SNU-216 cells, as it significantly increased apoptotic cells and decreased cell viability. Moreover, the mRNA and protein expression of p53 was significantly up-regulated in oridonin-treated cells, while Mdm2 expression was down-regulated. Furthermore, oridonin enhanced p53 function and induced DNA damage. Knockdown of p53 or employing the caspase inhibitor, Boc-D-FMK, reversed the effect of oridonin on cell viability and apoptosis-related protein expression. The present study demonstrated that oridonin exhibited an anti-tumor effect on GC SNU-216 cells through regulating p53 expression and function. PMID- 30462772 TI - Astragalus polysaccharides decrease proliferation, migration, and invasion but increase apoptosis of human osteosarcoma cells by up-regulation of microRNA-133a. AB - Osteosarcoma (OS) has a high incidence, malignity, and frequency of recurrence and metastasis. In this study, we aimed to explore the potential anti-cancer effects of Astragalus polysaccharides (APS) on human OS MG63 cells as well as underlying mechanisms. Viability of MG63 cells was assessed by CCK-8 assay to determine the adequate concentration of APS. Then, effects of APS on MG63 cell proliferation, cell cycle distribution, apoptosis, and migration and invasion were analyzed by BrdU incorporation, PI staining, flow cytometry, and transwell assays, respectively. The expression levels of proteins involved in these physiological processes were assessed by western blot analysis. Afterwards, miR 133a level in APS-treated cells was determined by qRT-PCR, and whether APS affected MG63 cells through regulation of miR-133a was determined. Finally, the activation of c-Jun N-terminal protein kinase (JNK) pathway was detected. We found that APS treatment suppressed the viability, proliferation, migration, and invasion of MG63 cells, as well as induced cell apoptosis. Moreover, APS enhanced the expression of miR-133a in MG63 cells. Knockdown of miR-133a reversed the APS treatment-induced MG63 cell proliferation, migration and invasion inhibition, as well as cell apoptosis. Furthermore, APS inactivated JNK pathway in MG63 cells. Knockdown of miR-133a reversed the APS treatment-induced inactivation of JNK pathway in MG63 cells. To conclude, APS repressed proliferation, migration, and invasion while induced apoptosis of OS MG63 cells by up-regulating miR-133a and then inactivating JNK pathway. PMID- 30462773 TI - Adiponectin is protective against endoplasmic reticulum stress-induced apoptosis of endothelial cells in sepsis. AB - Endoplasmic reticulum (ER) stress is a critical molecular mechanism involved in the pathogenesis of sepsis. Hence, strategies for alleviating this stress may be essential for preventing cardiovascular injuries under sepsis. Adiponectin is secreted by adipocytes and its levels are decreased in sepsis. The purpose of this study was to investigate the protective effects of adiponectin treatment on endothelial cells and its mechanism. Male Wistar rats underwent cecal ligation and puncture (CLP) before being treated with adiponectin (72 and 120 MUg/kg). The levels of malondialdehyde (MDA) in plasma, histological structure, and apoptosis of endothelial cells were evaluated. In vitro, human umbilical vein endothelial cells (HUVECs) were treated with adiponectin at 10 and 20 MUg/mL for 24 h after stimulation by lipopolysaccharide (LPS). The levels of reactive oxygen species (ROS), ultrastructure, rate of apoptosis, the expression of inositol-requiring enzyme 1alpha (IRE1alpha) protein, and its downstream molecules (78 kDa glucose regulated protein (GRP78), C/EBP homologous protein (CHOP), and caspase-12) were detected. The results showed that the levels of MDA and ROS induced by CLP or LPS stimulation were increased. Furthermore, endothelial cell apoptosis was increased under sepsis. The IRE1alpha pathway was initiated, as evidenced by activated IRE1alpha, increased GRP78, and up-regulated CHOP and caspase-12 in HUVECs. Following treatment with adiponectin, the number of apoptotic endothelial cells was markedly decreased. These findings demonstrated that treatment with adiponectin decreased apoptosis of endothelial cells caused by sepsis by attenuating the ER stress IRE1alpha pathway activated by oxidative stress. PMID- 30462774 TI - Hereditary angioedema with C1 inhibitor (C1-INH) deficit: the strength of recognition (51 cases). AB - Hereditary angioedema (HAE) is a rare autosomal dominant disease due to C1 esterase inhibitor deficiency (C1-INH). The disease is characterized by subcutaneous and submucosal edema in the absence of urticaria due to the accumulation of bradykinin. This descriptive study aimed to evaluate the clinical characteristics of patients with a confirmed diagnosis of HAE referred to our Outpatient Clinic between December 2009 and November 2017. Fifty-one patients (38 F, 13 M) with a mean age of 32 years (range: 7-70 y) were included. Family history of HAE was reported in 70% (36/51) of the cases; 33/46 patients became symptomatic by 18 years of age. The median time between onset of symptoms and diagnosis was 13 years (3 mo-50 y). The most frequent triggering factors for attacks were stress (74.4%), trauma (56.4%), and hormonal variations (56%). The main symptoms were subcutaneous edema in 93.5% (43/46) of patients, gastrointestinal symptoms in 84.8% (39/46), and obstruction in the upper airways in 34.8% (16/46). Hospitalization occurred in 65.2%, of whom 13.3% had to be transferred to the Intensive Care Unit. Prophylactic treatment was instituted in 87% (40/46) of patients, and 56.5% (26/46) required additional treatment to control attacks. Owing to our data collection over a period of 8 years, a significant number of patients were identified by this HAE reference center. Despite early recognition and prophylactic treatment, a high percentage of patients were hospitalized. HAE is still diagnosed late, reinforcing the need for more reference centers specialized in diagnosis and educational projects for health professionals. PMID- 30462775 TI - Interleukin-12 as a biomarker of the beneficial effects of food restriction in mice receiving high fat diet or high carbohydrate diet. AB - The impact of food restriction (FR) during 56 days on serum levels of cytokines in mice fed a high-fat diet (HFD) or high-carbohydrate diet (HCD) were evaluated. The amount of food was reduced 50% for HFD-FR and HCD-FR groups compared to mice receiving free access to HFD (HFD group) or HCD (HCD group). We quantified the serum levels of basic fibroblast growth factor, granulocyte-macrophage colony stimulating factor, inducible protein 10, interferon gamma, interleukin 1alpha (IL-1alpha), IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, keratinocyte chemoattractant, macrophage inflammatory protein-1alpha, monocyte chemotactic protein 1, monokine induced by IFN-gamma, and tumor necrosis factor alpha. Only IL-12 levels were lower (P<0.05), for both HFD-FR (HFD-FR vs HFD) and HCD-FR (HCD-FR vs HCD). Therefore, IL-12 levels could be considered a biological marker of the beneficial effects of FR. PMID- 30462776 TI - PSYCHOMETRIC PROPERTIES OF FUNCTIONAL CAPACITY TESTS IN CHILDREN AND ADOLESCENTS: SYSTEMATIC REVIEW. AB - OBJECTIVES: To identify studies that evaluated psychometric properties of functional capacity tests in children and adolescents, and to verify which of these have satisfactory properties of measurement. DATA SOURCES: Searches on MEDical Literature Analysis and Retrieval System Online (MEDLINE), Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Scientific Electronic Library Online (SciELO) databases without limiting period or language. Two investigators independently selected articles based on the following inclusion criteria: children and/or adolescent population (healthy or with cardiorespiratory diseases); and assessment of psychometric properties of functional capacity tests. Studies with (I) adult samples, (II) sample with neurological diseases, and (III) on reference values or prediction equations only were excluded. DATA SYNTHESIS: From the total of 677 articles identified, 11 were selected. These evaluated the psychometric properties of the following tests: 6 minute walk test (6MWT) (n=7); 6MWT and the 3-minute step test (3MST) (n=1); and Incremental Shuttle Walk Test (ISWT) (n=3). Reproducibility and reliability were good for 6MWT and ISWT, and moderate for 3MST. The ISWT showed high validity measures for both healthy children and children with chronic respiratory disease. The validity of 6MWT varied across studies, and should be analyzed according to the health conditions of test takers. The validity of 3MST is unclear, and further studies in pediatric population are required. CONCLUSIONS: Most studies investigated 6MWT measurement properties. Validity of 6MWT varied according to different pediatric populations. The use of 6MWT, ISWT and 3MST tests to measure clinically important changes in children and adolescents with cardiorespiratory diseases is still unclear. PMID- 30462777 TI - USE OF DRUGS IN CHILDREN AGED ZERO TO FIVE YEARS OLD IN TUBARAO, SANTA CATARINA, BRAZIL. AB - OBJECTIVE: To analyze the context of drug use in children aged zero to five years old. METHODS: Cross-sectional study based on interviews conducted at home with caregivers (parents, uncles or grandparents) of the children enrolled in ten Family Health Strategy units across different geographical points of the city of Tubarao, Santa Catarina, Brazil. RESULTS: A total of 350 caregivers were interviewed, whose children's mean age was 2.6 years. Of these, 56.9% had used at least one drug in the 15 days prior to the interview, 31.1% had been exposed to self-medication and 35.7% had used at least one medication obtained by current prescription. The use of medication was associated with the age range up to 24 months, periodic consultation with pediatricians and diagnosis of chronic and acute diseases. Among medicated children, 19.1% inappropriately had been exposed to at least one medication (considering dose, dose interval or period of treatment). Regarding medication storage, 55.2% of interviewees stored them in unsafe places that could be accessed by children and 32.0% in inappropriate places, with exposure to light, heat or humidity. Moreover, 45.2% of the interviewees stored drugs out of their packages, 38.9% without secondary packaging, and 1.6% of drugs had expired date. CONCLUSIONS: Drug use is high among children in this age range, and actions aimed at the safe and rational use of these substances in this population should be encouraged. PMID- 30462778 TI - INFLUENCE OF DILUTION, TIME, AND TEMPERATURE AFTER PREPARATION ON THE OSMOLALITY OF INFANT FORMULAS GIVEN TO NEWBORNS. AB - OBJECTIVE: To analyze the influence of dilution, time, and temperature after preparation on the osmolality of infant formulas given to newborns (NBs). METHODS: Experimental and descriptive study with samples of different neonatal formulas to verify the osmolality of the milk according to dilution, time, and temperature after preparation. We analyzed seven neonatal formulas in the following times after preparation: immediately (up to 5 minutes); 20 and 40 minutes; every hour up to 8 hours; and 12 and 24 hours. The samples were evaluated at room temperature and after refrigeration. Osmolality curves were designed with the mean of triplicate samples of each milk sample. The digital Osmometer A+, model 3320, from Advanced Instruments measured the osmolality. RESULTS: The time and temperature at which the milk was subjected after preparation did not cause the osmolality to exceed its safety cut-off point at a 1:30 dilution in any of the types of milk analyzed. At a 1:25 dilution, the formula with prebiotics in its composition went over the limit after 4 hours. CONCLUSIONS: The milk tested did not exceed the cut-off point of 450 mOsm/kg (approximately 400 mOsm/L), indicated as safe by the American Academy of Pediatrics (AAP) at a dilution recommended by manufacturers. It is important to know the factors that may or may not contribute to the rise of osmolality, in order to establish safe and quality practices for NBs, following protocols based on scientific evidence. PMID- 30462779 TI - OVERWEIGHT, PERCEIVED ENVIRONMENT, AND SOCIAL DEPRIVATION: A STUDY ON THE PERCEPTION OF PARENTS OR GUARDIANS. AB - OBJECTIVE: To investigate parents' or guardians' perception of their residential proximity to food retailers, leisure areas, and spaces for physical activity according to neighborhood social deprivation, and test associations between the perceived environment and their children's overweight. METHODS: Cross-sectional study conducted with 408 children and adolescents (6- to 15-year-olds) attending public schools in a medium-sized Brazilian city. Data were collected from 2011 to 2014. A telephone interview using a structured research tool determined the presence of overweight and the walking time between the participants' home and the places evaluated. The indicator of social deprivation adopted was the Health Vulnerability Index. Logistic regression models were constructed to predict the perception of proximity (social deprivation as an explanatory variable) and evaluate perceived environmental factors (explanatory variables) associated with overweight (outcome). RESULTS: Residents of areas with higher social vulnerability showed a probability of perceived proximity 50 to 71% lower to supermarkets, street/produce markets, parks, recreation areas/community centers, and gyms compared to residents of less vulnerable areas. The perceived proximity to parks reduced the chance of overweight in children and adolescents in 73%, with an odds ratio (OR) of 0.27 (95%CI 0.07-0.95; p<0.05). CONCLUSIONS: The perceived environment of the residential area infrastructure might be related to neighborhood social deprivation and the presence of overweight in children and adolescents. PMID- 30462780 TI - COMMUNICATION OF DEATH AND GRIEF SUPPORT TO THE WOMEN WHO HAVE LOST A NEWBORN CHILD. AB - OBJECTIVE: To analyze the communication of a child's death and the grief support provided to the women during puerperium. METHODS: This is a qualitative study performed at a capital of the Northeast region of Brazil. Semi-structured interviews were carried out with 15 women, whose children died from July 2012 to July 2014. The interviews contained questions about the child's death and the grieving process. The content analysis was performed with a thematic approach. RESULTS: The women expressed the suffering and the anguish of the loss of a child, sometimes aggravated by the way in which the news of death was delivered, and by the lack of support offered in the coping process. Two empirical categories were found: receiving the news of death and going back home empty handed. The health care teams are not prepared to deliver bad news, nor to give support to women who lose a newborn child. According to the women, the support received from the family and religion helped them in the grieving process. CONCLUSIONS: The results indicate the need for professional qualification for the delivery of bad news and for grief support. They also showed the need for institutional policies that offer support to the professionals. Besides, the articulation with the primary health care team is imperative for the continuity of care. PMID- 30462781 TI - Validation of instruments about family presence on invasive procedures and cardiopulmonary resuscitation in pediatrics. AB - OBJECTIVE: to develop and validate instruments to identify health professionals' beliefs related to the presence of the child's family in invasive procedures and in cardiopulmonary resuscitation. METHOD: study based on Psychometrics to conduct the theoretical, empirical and analytical stages, developed in a neonatal unit of a university hospital. The two instruments were constructed based on the literature and applied to 96 health professionals. RESULTS: the Cronbach's Alpha of the instrument related to the professionals' beliefson invasive procedures was 0.863 and the instrument on cardiopulmonary resuscitation was 0.882. In both instruments, the tests performed indicated a correlation between the items. From the factorial analysis, four factors were generated: (1) benefits of the presence of the family; (2) impairment for professional practice; (3) strategies for the inclusion of the family; and (4) limitation of learning and decision making by the professional. CONCLUSION: the instruments analyzed obtained a good internal consistency and are indicators of the professionals' beliefs with the potential to evaluate the quality of family care in this context. PMID- 30462782 TI - Occipital Neuralgia: a noninvasive therapeutic approach. AB - OBJECTIVE: to evaluate the application of a noninvasive intervention consisting of a postural modification using personalized models and osteopathy in people with occipital neuralgia. METHOD: retrospective study of the intervention performed in adult population with occipital neuralgia, consisting of postural modification using personalized plantar orthoses and osteopathy, in a study period of four years. The observed variables were: persistence of headache, alignment of the axes, plantar support, center of gravity and center of mass; medical interview data, visual analogue scale, Win-Track gait analysis system and Kinovea software for video analysis (clinical assessment instruments used). RESULTS: a total of 34 records of people with occipital neuralgia were studied. A fraction of 58.8% of the patients reported improvement after the intervention. The visual analogue scale data were provided for 64.7% of the records and significant differences (p <0.001) between the means before (8.4 +/- 1.7) and after the intervention (2.6 +/- 2.7) were found. CONCLUSION: postural modification using personalized orthoses and osteopathy substantially improves the symptomatology of patients with occipital neuralgia. PMID- 30462783 TI - Psychosocial aspects of work and minor psychic disorders in nursing: use of combined models. AB - OBJECTIVE: to analyze the combined use of models for the evaluation of work related psychosocial aspects and their association with the prevalence of Minor Psychics Disorders among nursing workers. METHOD: cross-sectional study with a sample of 285 nursing workers. Data collection was performed through the application of a structured sociodemographic and occupational questionnaire and the Demand-Control-Support, Effort-Reward Imbalance and Self-Reporting Questionnaire. Descriptive analysis and a multiple logistic regression were performed. RESULTS: the prevalence of suspicion of minor psychics disorders was 32.6%. The dimensions of both models were associated with mental health. The full Effort-Reward Imbalance and Demand-Control and Social Support models predict Minor Psychics Disorders to a greater extent than the combined use of partial models. CONCLUSION: it was found that the Effort-Reward Imbalance model captured better the magnitude of the Minor Psychics Disorders in this sample of workers compared to the Demand-Control and Social Support model. However, the concomitant use of the theoretical models revealed unique contributions in the evaluation of Minor Psychics Disorders. Considering the complexity of mental illnesses, it is important that different factors be evaluated. PMID- 30462784 TI - Pain in emergency units: correlation with risk classification categories. AB - OBJECTIVES: to correlate risk classification categories with the level of pain of patients in an emergency service. METHOD: cross-sectional study carried out in the Risk Classification of 611 patients. The variables studied were: age, gender, comorbidities, complaint duration, medical specialty, signs and symptoms, outcome, color attributed in the risk classification of and degree of pain. We used Analysis of Variance, a Chi-Square test and a Likelihood Ratio test. RESULTS: the average age was 42.1 years (17.8); 59.9% were women; the green (58.9%) and yellow (22.7%) risk classification prevailed and hypertension (18.3%) was the most common Comorbidity. The most frequent pain intensity was moderate (25.9%). In the red category, patients presented a higher percentage of absence of pain; in the blue, mild pain; and in the green, yellow and orange categories, there was a greater percentage of intense pain (p < 0.0001). CONCLUSION: among the patients who presented pain, the majority reported moderate intensity. Regarding risk categories, most patients in the red category did not report pain. Those who were classified as green, yellow and orange, reported mostly intense pain. On the other hand, patients in the blue category reported predominantly mild pain. PMID- 30462785 TI - Allostatic load and canine companionship: a comparative study using biomarkers in older adults. AB - OBJECTIVE: to compare the biomarkers and the allostatic load levels in a sample of older persons with and without canine companionship. METHOD: descriptive and comparative study. Data were collected using a sociodemographic questionnaire and a fasting blood sample. The allostatic load comprised 11 biomarkers that are primary and secondary stress mediators, which arise from the following systems: neuroendocrine, immune, metabolic, cardiovascular and anthropometric. RESULTS: a significant difference was found in two biomarkers: cortisol (t= -3.091, df=104, p=0.003) and total cholesterol (t= -2.566, df=104, p=0.012), in the allostatic load levels between older adults with and without a canine companionship (U= 1714.00, Z= 2.01, p=0.044). By associating the allostatic load level with the canine companionship, there was a higher frequency of older adults with low allostatic load among those who have canine companion, compared with those who do not have canine companionship. (chi2= 3.69, df=1, p= 0.043). CONCLUSION: canine companionship influences health in a positive way, as the allostatic load is lower in older adults who have a dog as companion, in addition to presenting lower levels of cortisol and total cholesterol. PMID- 30462786 TI - Translation and cross-cultural adaptation of the Hypertension Knowledge-Level Scale for use in Brazil. AB - OBJECTIVE: to make the translation, cross-cultural adaption and content and face validation of the Hypertension Knowledge-Level Scale for use in Brazil. METHODS: methodological research carried out in six stages: translation, synthesis, back translation, expert committee's assessment, pre-test and validation. Validation was performed through the Delphi technique in two rounds. The participants were two translators and two back-translators, eight professionals in the expert committee, 40 adult participants in the pre-test, 35 experts in the first validation round and 28 in the second validation round. Data analysis included Cronbach's alpha, content validity index and one-tailed t-test. RESULTS: the translation and cross-cultural adaptation allowed for language adjustments so that the items were comprehensible and suitable for use in Brazil. The content validity index of the Brazilian version of Hypertension Knowledge-Level Scale was 0.96 and Cronbach's alpha was 0.92. CONCLUSIONS: the scale was translated, cross culturally adapted to Brazilian Portuguese, had its content and face validated and proved reliable to evaluate the knowledge of adults about hypertension. PMID- 30462787 TI - The Joanna Briggs Institute approach for systematic reviews. PMID- 30462788 TI - Relationship of family management with sociodemographic aspects and children's physical dependence in neurological disorders. AB - OBJECTIVE: To investigate the relationship of family management with sociodemographic and physical dependence aspects of children and adolescents with neurological impairment. METHOD: Descriptive, cross-sectional study conducted at a child neurology center. A non-probabilistic sample was obtained from 141 family members who answered two instruments: a) Sociodemographic condition of families; b) Family Management Measure. In the statistical analysis, we used the Spearman Coefficient and the Mann Whitney Test. RESULTS: the longer the specialized care time, the lower the identity score (rs = - 0.209, p = 0.01); the higher the effort score (rs = 0.181, p = 0.03), the family difficulty score (rs = 0.239, p = 0.001) and the impact of the disease on family life (rs = 0.213, p = 0.01). The families of children and adolescents with physical dependence for activities of daily living presented a higher score in the following dimensions: management effort (<0.001), family difficulty (p = 0.004) and perception of disease impact (p = 0.001). CONCLUSION: There was evidence of a correlation between management with sociodemographic and child dependence aspects, with an association between management difficulty and longer time of child and adolescent care. PMID- 30462789 TI - Prevalence of bacterial vaginosis and factors associated among women who have sex with women. AB - OBJECTIVE: to describe the prevalence of bacterial vaginosis and factors associated among women who have sex with women. METHOD: cross-sectional, descriptive and analytical study with 150 women. The vaginal microbiota profile was analyzed by microscopic examination of vaginal swabs according to the Gram method. Endocervical samples were collected with cytobrush for the investigation of endocervicitis by Chlamydia trachomatis. The polymerase chain reaction was used to diagnosis Human Papillomavirus infection. Socio-demographic data, sexual behavior and clinical history were obtained through an interview. Logistic regression was performed to identify risk factors independently associated with bacterial vaginosis. RESULTS: among the 150 participants, 71 (47.3%) presented some alteration in the vaginal microbiota, 54 (36.0%) bacterial vaginosis and 12 (8.0%) Flora II. The variable independently associated with bacterial vaginosis was the use of sexual accessories [2.37(1.13-4.97), p=0.022]. CONCLUSION: the high prevalence of bacterial vaginosis among women who have sex with women indicates the need for screening this population and association between use of sexual accessories and this disease suggests the possibility of transmission of sexual fluids between the partners during the sexual act, which demonstrates the need for educational actions on sexual and reproductive health. PMID- 30462790 TI - Non-pharmacological interventions for sleep and quality of life: a randomized pilot study. AB - OBJECTIVE: to estimate the effects of non-pharmacological interventions to improve the quality of sleep and quality of life of patients with heart failure. METHOD: pilot study of a randomized controlled trial with 32 individuals assigned to four groups. Sleep was assessed using the Pittsburgh Sleep Quality Inventory, while health-related quality of life was assessed using the Minnesota Living with Heart Failure Questionnaire, at the baseline and at the 12th and 24th weeks. The means of the outcomes according to intervention groups were compared using analysis of covariance; effect sizes were calculated per group. RESULTS: all groups experienced improved quality of sleep and health-related quality of life at the end of the intervention (week 12) and at follow-up (week 24), though differences were not statistically significant (p between 0.22 and 0.40). The effects of the interventions at the 12th week ranged between -2.1 and -3.8 for the quality of sleep and between -0.8 and -1.7 for quality of life, with similar values at the 24th week. CONCLUSION: the effects found in this study provide information for sample size calculations and statistical power for confirmatory studies. Brazilian Clinical Trials Registry - RBR 7jd2mm. PMID- 30462791 TI - Anxiety of mothers of newborns with congenital malformations in the pre- and postnatal periods. AB - OBJECTIVE: to analyze the anxiety level of the mothers of newborns with congenital malformations who were diagnosed in prenatal and postnatal care. METHODS: a cross-sectional study with 115 mothers of 117 newborns with congenital malformation admitted to three neonatal units. A questionnaire containing maternal and neonatal variables was used, as well as the Trait-State Anxiety Inventory. Data were analyzed by Student's t-test and Kolmogorov-Sminorv test. The anxiety level was categorized as low (percentile <25), moderate (25-75) and high (> 75), with a significance level of 5%. RESULTS: most mothers had moderate levels of anxiety. Regarding the diagnosis of the malformation, 57% received the news in the prenatal and 43% in the postnatal period. The anxiety level of those who received the prenatal diagnosis was lower than those who received in the postnatal period, evaluated by the Trait Anxiety Inventory (p = 0.026). CONCLUSION: mothers of newborns with malformations presented moderate anxiety, and this was higher when the diagnosis was given in the postnatal period. The use of the Trait-State Anxiety Inventory can provide guidance to other studies and to clinical practice. PMID- 30462792 TI - Questionnaire on adaptation to type 1 diabetes among children and its relationship to psychological disorders. AB - OBJECTIVE: to study the psychometric properties of an adaptive disease response questionnaire for use with Spanish children with type 1 diabetes; to analyse this response in this sample and to observe the relationship between adaptive response and levels of anxiety-depression. METHOD: a total of 100 patients with type 1 diabetes aged between nine and 16 years (M=12.28, SD=1.78) participated in the study, of which 59% were children. Data was collected in public hospitals via interviews using the Adaptive Disease Response Questionnaire and Anxiety and Depression Scale. The data was analysed using Pearson correlations, multiple hierarchical linear regressions, Student's t Test for independent samples, and Cohen's d effect size to determine reliability and validity. RESULT: the instrument was shown to have adequate psychometric properties. Adaptive response was generally high. Adaptive response is negatively related to emotional distress, being a better predictor of depression than of anxiety. There was no association betwee adaptation and sex and age. CONCLUSION: promoting a better adaptive response appears to reduce emotional distress, especially in the case of depression, regardless of the age or gender of the patients. PMID- 30462794 TI - Approach to reflective practice: an epistemological redignification of the professional nurse. PMID- 30462793 TI - Cupping therapy and chronic back pain: systematic review and meta-analysis. AB - OBJECTIVES: to evaluate the evidence from the literature regarding the effects of cupping therapy on chronic back pain in adults, the most used outcomes to evaluate this condition, the protocol used to apply the intervention and to investigate the effectiveness of cupping therapy on the intensity of chronic back pain. METHOD: systematic review and meta-analysis carried out by two independent researchers in national and international databases. Reference lists of systematic reviews were also explored. The quality of evidence was assessed according to the Jadad scale. RESULTS: 611 studies were identified, of which 16 were included in the qualitative analysis and 10 in the quantitative analysis. Cupping therapy has shown positive results on chronic back pain. There is no standardization in the treatment protocol. The main assessed outcomes were pain intensity, physical incapacity, quality of life and nociceptive threshold before the mechanical stimulus. There was a significant reduction in the pain intensity score through the use of cupping therapy (p = 0.001). CONCLUSION: cupping therapy is a promising method for the treatment of chronic back pain in adults. There is the need to establish standardized application protocols for this intervention. PMID- 30462795 TI - Quality of life of Brazilian chronic hepatitis C patients treated with interferon free therapies. AB - Due to the severity of chronic hepatitis C, there are multiple factors that can negatively affect the quality of life of infected patients. The aim of this study was to evaluate changes in the health-related quality of life (HRQoL) in patients under second-generation direct-acting antiviral (DAA) (interferon-free) therapies and to assess treatment effectiveness. This was an observational study conducted in Curitiba (Brazil) using two instruments (a generic and a specific) for measuring the quality of life in patients with chronic hepatitis C, the Short Form-36 (SF-36) and the Chronic Liver Disease Questionnaire (CLDQ) for liver disease evaluation. The study included patients receiving any interferon-free therapy for hepatitis C treatment during 2016 and 2017. Data were collected before, during, and after treatment regarding the two questionnaires, effectiveness and safety. Fifty-six patients fulfilled all eligibility criteria and were included for analysis. Sustained virological response was obtained in 88% of the patients. They were mainly genotype 1, cirrhotic and treated with sofosbuvir combined with daclatasvir or sofosbuvir with simeprevir. Improvement in the quality of life was observed for several domains in both questionnaires (p < 0.05) in the comparison before and after treatment. Patients receiving sofosbuvir with daclatasvir had significantly lower scores compared to the group receiving sofosbuvir with simeprevir. Second-generation DAA therapies were effective and have considerably increased the HRQoL of patients with chronic hepatitis C virus. PMID- 30462796 TI - Renal dysfunction in Leishmaniasis and Chagas disease coinfection: a case report. AB - Visceral leishmaniasis (VL) is an endemic parasitic disease frequently found in Northeast Brazil and may cause acute kidney injury (AKI) and glomerulonephritis. After appropriate treatment, renal function recovery may occur. We describe the rare case of a patient with VL, who developed severe AKI requiring dialysis and was subsequently diagnosed with Chagas disease coinfection. After specific treatment for VL, there was partial recovery of the renal function, followed by the onset of Chagas disease cardiomyopathy. PMID- 30462797 TI - Chronic cavitary pneumonia by Rhodococcus equi in a highly prevalent tuberculosis country: a diagnosis challenge. AB - Rhodococcus equi is a facultative aerobic, intracellular, non-motile, non-spore forming, Gram-positive, weakly acid-fast coccobacillus belonging to the group of nocardioform actinomycetes. R. equi infections are rare opportunistic illnesses in patients with Acquired Immunodeficiency Syndrome (AIDS), associated with a high mortality rate. The most common clinical presentation of R. equi infections is a chronic cavitary pneumonia. Due to its acid-fastness, R. equi can be mistaken for others acid-fast organisms, as Mycobacterium tuberculosis. In turn, R. equi is also a gram-positive pleomorphic bacteria and can be mistaken for diphtheroids or Micrococcus organisms, being accidentally disregarded as oral contaminants in sputum cultures. Therefore, in Brazil, a highly prevalent tuberculosis (TB) country, pulmonary infections caused by R. equi may mimic pulmonary TB and represent a diagnostic challenge. Here, we report on a case of chronic cavitary pneumonia by R. equi in a Human Immunodeficiency Virus (HIV) infected patient, focusing on diagnostic aspects. PMID- 30462799 TI - Radioguided localization of recurrent lymph nodes in differentiated thyroid cancer - Where are we now? PMID- 30462798 TI - Coccidioidomycosis: first cases reported in Pernambuco, Brazil. AB - Coccidioidomycosis is a fungal infection caused by Coccidioides immitis or Coccidioides posadasii. These fungi are known to thrive in desert climate. Fungi produce infectious arthroconidia in soil, they are aerosolized in the air and when inhaled by humans, usually cause infections such as pneumonia. The first cases of coccidioidomycosis in Brazil were reported in 1978. Since then, there have been other reports mainly from desert regions of Northeastern Brazil. The present report describes three cases of coccidioidomycosis on male farmers from Serra Talhada county, Pernambuco State, who developed pneumonia and were subsequently diagnosed with pulmonary coccidioidomycosis. These three farmers were successfully treated with oral fluconazole. They reported having hunted armadillos in a rural and arid area of Pernambuco State. Armadillos are known to be carriers of Coccidioides. This is the first report of infection caused by Coccidioides in Pernambuco State, Brazil. PMID- 30462800 TI - Metabolomics of thyroid nodules and the future. PMID- 30462801 TI - Guided intraoperative scintigraphic tumor targeting of metastatic cervical lymph nodes in patients with differentiated thyroid cancer: a single-center report. AB - OBJECTIVE: Our aim was to present our experiences related to performing neck surgery using the guided intraoperative scintigraphic tumor targeting (GOSTT) procedure for patients who had locally recurrent or persistent differentiated thyroid cancer (DTC) and who had undergone previous thyroid surgery. SUBJECTS AND METHODS: We retrospectively evaluated 11 patients who had locally recurrent or persistent DTC, who had undergone previous surgery, and for whom reoperation was planned for metastatic cervical lymph nodes (LNs). We performed the neck surgery using the GOSTT procedure on all patients and at a single academic institution. RESULTS: The 11 patients had a total of 26 LNs, as marked with a radiotracer, and those LNs' mean size was 14.7 +/- 8.2 mm (range: 5-34 mm). Histopathological examinations revealed DTC metastasis in all 26 of the preoperatively marked LNs. Of the 11 patients, only one needed a reoperation in the neck; she had another successful surgery (also using the GOSTT procedure). In the evaluation of the patients' final status, all were disease-free in their necks. There also were no GOSTT-associated postoperative complications. CONCLUSION: The GOSTT procedure is a useful, successful, inexpensive, and comfortable procedure for marking and mapping metastatic LNs, especially in DTC patients who have undergone previous surgery. PMID- 30462802 TI - 3T magnetic resonance spectroscopy as a powerful diagnostic modality for assessment of thyroid nodules. AB - OBJECTIVE: Magnetic resonance spectroscopy (MRS) is a powerful tool for structural studies of chemical compounds and biomolecules and also documented promising findings as a potential imaging technology in thyroid oncology. This prospective study was to ascertain the clinical significance of 3 Tesla MRS in the evaluation of patients with thyroid nodules (TNs) as an ancillary diagnostic technique for thyroid carcinoma. MATERIALS AND METHODS: Magnetic resonance spectroscopy at 3T at echo- times (TEs) 136 and 270 ms was carried out on 15 patients with total number of 32 TNs larger than 1 cm3, which all were surgically resected. Choline (Chol) to creatine (Cr) ratio was assessed at 136 and 270 TEs on each nodule and a receiver operating characteristic (ROC) curve was used to determine optimal cut-off point. The findings were compared with histopathology of thyroid specimens. RESULTS: There were 23 benign and 9 malignant lesions (7 papillary and 2 follicular thyroid carcinomas). The mean values of Chol/Cr at 136 and 270 TEs was 2.28 +/- 3.65 and 1.52 +/- 1.67 respectively and the difference between benign and malignant nodules was only significant at 136 TEs. The study revealed that Chol/ Cr ratio cut-off point of 2.5 best correlates with histopathology results (sensitivity = 75%; specificity = 100%; PPV = 100%; NPV= 92%). CONCLUSION: This preliminary study showed that 3T magnetic resonance spectroscopy might be a specific modality for the evaluation of thyroid nodules in differentiation of benign from malignant thyroid tissue. However, a larger series would give much greater confidence that this state-of-the-art technology will worth pursuing in clinical practice. PMID- 30462803 TI - Is FGF-23 an early indicator of atherosclerosis and cardiac dysfunction in patients with gestational diabetes? AB - OBJECTIVE: Fibroblast growth factor 23 (FGF-23) is a phosphorus-regulating hormone and plays a role in the pathogenesis of myocardial hypertrophy. The aim of this study was to evaluate the association of FGF-23 levels with echocardiographic parameters and insulin resistance (IR) in patients with gestational diabetes. SUBJECTS AND METHODS: Fifty-four pregnant patients with gestational diabetes mellitus (GDM) (age, 31.12 +/- 5.72 years) and 33 healthy pregnant women (age, 29.51 +/- 4.92 years) were involved in the study. Fasting insulin, fasting plasma glucose (FPG), lipid profile, oral glucose tolerance test (OGTT), FGF23, echocardiographic parameters, and carotid artery intima-media thickness (CIMT) were evaluated in the two groups. RESULTS: The two groups were not significantly different in age, sex, body mass index, lipid profile, or blood pressure. Insulin, homeostatic model assessment-insulin resistance (HOMA-IR), FGF 23 levels, CIMT, left ventricular (LV) mass, LV mass index and myocardial performance index (MPI) were significantly higher in the GDM group. HOMA-IR was positively correlated with FGF-23, and insulin was positively correlated with FGF 23. Additionally, FGF-23 was positively correlated with CIMT, LV mass index, and MPI. CONCLUSION: Our findings suggest that monitoring serum FGF-23 may be useful as a non-invasive indicator of subclinical atherosclerosis in patients with GDM. PMID- 30462804 TI - Impact of an inpatient multidisciplinary glucose control management program. AB - OBJECTIVE: Glycemic control has been increasingly recognized as a critical element in inpatient care, but optimal management of blood glucose in the hospital setting remains challenging. The aims of this study were to describe and evaluate the impact of the implementation of an inpatient multidisciplinary glucose control management program on glucose control in hospitalized patients. MATERIALS AND METHODS: Retrospective analysis of medical records and glucose monitoring data obtained by point- of-care testing (POCT) in hospitalized patients before (May 2014) and after (June 2015 and May 2017) the implementation of the program. RESULTS: We analyzed 6888, 7290, and 7669 POCTs from 389, 545, and 475 patients in May 2014, June 2015, and May 2017, respectively. Hyperglycemia (>= 180 mg/ dL) occurred in 23.5%, 19.6%, and 19.3% POCTs in May 2014, June 2015, and May/2017, respectively (p < 0.001), while severe hyperglycemia (>= 300 mg/dL) was observed in 2.5%, 2.2%, and 1.8% of them, respectively (p = 0.003). Hyperglycemia (>= 180 mg/dL) reduced significantly from May 2014 to June 2015 (16.3%, p < 0.001) and from May 2014 to May 2017 (178%, p < 0.001). No significant changes occurred in hypoglycemic parameters. CONCLUSIONS: The implementation of an inpatient multidisciplinary glucose control management program led to significant reductions in hyperglycemic events. The key elements for this achievement were the development of institutional inpatient glycemic control protocols, establishment of a multidisciplinary team, and continuing educational programs for hospital personnel. Altogether, these actions resulted in improvements in care processes, patient safety, and clinical outcomes of hospitalized patients. PMID- 30462805 TI - ABSI is a poor predictor of insulin resistance in Chinese adults and elderly without diabetes. AB - OBJECTIVE: Recently, a new obesity index (A Body Shape Index, ABSI) based on waist circumference (WC) was developed, and high ABSI corresponds to a more central concentration of body volume. It is well known that central obesity is closely linked with insulin resistance (IR). Therefore, our study aimed to examine the discriminatory power of ABSI for IR in Chinese adults and elderly without diabetes. SUBJECTS AND METHODS: In 2007, a cross-sectional study was made. In this study, 570 individuals without diabetes were available for analysis (male: 56.1%, mean age: 62.3 +/- 6.5 years). Insulin resistance was assessed by homeostasis model assessment (HOMA-IR). Areas under the receiver operating characteristic (ROC) curves were determined to identify variables/models that could predict insulin resistance. RESULTS: ABSI was associated with IR, the cut off points was 0.0785 m11/6kg-2/3 to identifying IR and the area under the ROC (AUC) curve was 0.618 (95%CI: 0.561-0.675), which was not better than body mass index BMI (AUC = 0.753; 95%CI: 0.706-0.801), WC (AUC = 0.749; 95%CI: 0.700 0.797), and fasting plasma glucose (FPG, AUC = 0.752; 95%CI: 0.705-0.799). Furthermore, combination with ABSI could improve the discriminatory power of other variables for IR. The AUC curve increased from 0.753 to 0.771for BMI, 0.749 to 0.754 for WC, 0.752 to 0.769 for FPG, respectively. CONCLUSIONS: ABSI is associated with IR in the general Chinese adults and elderly without diabetes, but the discriminatory power for IR is poor. It is recommended that ABSI be used in combination with other variables. PMID- 30462806 TI - Exercise training improves quality of life in women with subclinical hypothyroidism: a randomized clinical trial. AB - OBJECTIVE: The aim was to evaluate the quality of life (HRQoL) in women with subclinical hypothyroidism (sHT) after 16 weeks of endurance training. SUBJECTS AND METHODS: In the first phase, a cross-sectional study was conducted in which 22 women with sHT (median age: 41.5 (interquartile range: 175) years, body mass index: 26.2 (8.7) kg/m2, thyroid stimulating hormone > 4.94 mIU/L and free thyroxine between 0.8 and 1.3 ng/dL were compared to a group of 33 euthyroid women concerned to HRQoL. In the second phase, a randomized clinical trial was conducted where only women with sHT were randomly divided into two groups: sHT-Tr (n = 10) - participants that performed an exercise program - and sHT-Sed (n = 10) - controls. Exercise training consisted of 60 minutes of aerobic activities (bike and treadmill), three times a week, for 16 weeks. The HRQoL was assessed by the SF-36 questionnaire in the early and at the end of four months. RESULTS: Women with sHT had lower scores on functional capacity domain in relation to the euthyroid ones (770 +/- 23.0 vs. 88.8 +/- 14.6; p = 0.020). The sHT-Tr group improved functional capacity, general health, emotional aspects, mental and physical component of HRQoL after training period, while the sHT-Sed group showed no significant changes. CONCLUSION: After 16 weeks of aerobic exercise training, there were remarkable improvements in HRQoL in women with sHT. PMID- 30462807 TI - Thyroid cancer burden and economic impact on the Brazilian public health system. AB - OBJECTIVE: Recent data indicates an increasing incidence of thyroid cancer not accompanied by a proportional increase in mortality, suggesting overdiagnosis, which may represent a big public health problem, particularly where resources are scarce. This article aims to describe and evaluate the procedures related to investigation of thyroid nodules and treatment and follow-up of thyroid cancer and the costs for the Brazilian public health system between 2008 and 2015. MATERIALS AND METHODS: Data on procedures related to investigation of thyroid nodules and treatment/follow-up of thyroid cancer between 2008 and 2015 in Brazil were collected from the Department of Informatics of the Brazilian Unified Health System (Datasus) website. RESULTS: A statistically significant increase in the use of procedures related to thyroid nodules investigation and thyroid cancer treatment and follow-up was observed in Brazil, though a reduction was noted for procedures related to the treatment of more aggressive thyroid cancer, such as total thyroidectomy with neck dissection and higher radioiodine activities such as 200 and 250 milicuries (mCi). The procedures related to thyroid nodules investigation costs increased by 91% for thyroid ultrasound (p = 0.0003) and 128% in thyroid nodule biopsy (p < 0.001). Costs related to treatment and follow-up related-procedures increased by 120%. CONCLUSION: The increase in the incidence of thyroid cancer in Brazil is directly associated with an increased use of diagnostic tools for thyroid nodules, which leads to an upsurge in thyroid cancer treatment and followup-related procedures. These data suggest that substantial resources are being used for diagnosis, treatment and follow-up of a potentially indolent condition. PMID- 30462808 TI - Evaluation of redox profiles in exogenous subclinical hyperthyroidism at two different levels of TSH suppression. AB - OBJECTIVE: Evaluate the relationship between exogenous subclinical hyperthyroidism and oxidative stress through the analysis of the redox profile of patients with subclinical hyperthyroidism exogenous (SCH) grade I (TSH = 0.1 to 0.4 IU/mL) and grade II (TSH < 0.1 IU/mL). SUBJECTS AND METHODS: We analyzed 46 patients with SCH due to the use of TSH suppressive therapy with LT4 after total thyroidectomy along with 6 control euthyroid individuals (3M and 3W). Patients were divided into two groups, G1 with TSH >= 0.1-0.4 IU/mL (n = 25; and 7M 14W) and G2 with TSH < 0.1 IU/mL (n = 25; and 4M 21W). Venous blood samples were collected to measure the levels of markers for oxidative damage (TBARS, FOX and protein carbonylation), muscle and liver damage (CK, AST, ALT, GGT) and antioxidants (GSH, GSSG and catalase). RESULTS: Individuals in G2 showed a GSH/GSSG ratio ~ 30% greater than those in G1 (p = 0.004) and a catalase activity that was 4 times higher (p = 0.005). For lipid peroxidation, the levels measured in G2 were higher than both control and G1 (p = 0.05). No differences were observed for both protein carbonyl markers. G1 and G2 presented with greater indications of cell injury markers than the control group. CONCLUSION: TSH suppression therapy with LT4 that results in subclinical hyperthyroidism can cause a redox imbalance. The greater antioxidant capacity observed in the more suppressed group was not sufficient to avoid lipid peroxidation and cellular damage. PMID- 30462809 TI - Lipid disorders among Black Africans non-users of lipid-lowering medication. AB - OBJECTIVE: Angola is a sub-Saharan African country where the population has scarce access to lipidlowering medication. We sought to determine the frequency of lipid disorders among Angolan nonusers of lipid-lowering medication. MATERIAL AND METHODS: A cross-sectional descriptive study was carried out in a sample of 604 workers from the public sector. Blood pressure and anthropometric data were measured along with biochemical parameters including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). LDL-C to HDL-C ratio (LDL-C/HDL-C) was obtained from LDL-C and HDL-C levels. RESULTS: High frequencies of elevated blood pressure (44.8%), metabolic syndrome (20.2%), increased TC (39.2%) and increased LDL-C (19.3%) were found. Low HDL-C was more frequent in women (62.4% vs. 36.1%, p < 0.001). Isolated hypercholesterolemia was more frequent in men (9.6% vs. 2.5%, p < 0.001). Among men TC, TG, LDL-C and LDL-C/HDL-C ratio were higher and HDL-C was lower in obese than in low-weight and normal-weight participants. Among women TC, TG, LDL-C and LDL-C/HDL-C ratio were higher in obese than in normal-weight participants. Significant linear trend of increasing TC and LDL-C levels as age increased was detected for both genders (p for trend < 0.05). CONCLUSION: The results of our study showed a high frequency of lipid disorders in Angolan non users of lipid-lowering medication. PMID- 30462810 TI - Congenital hyperinsulinism in two siblings with ABCC8 mutation: same genotype, different phenotypes. AB - Congenital hyperinsulinism (CHI) is a heterogenous disease caused by insulin secretion regulatory defects, being ABCC8/KCNJ11 the most commonly affected genes. Therapeutic options include diazoxide, somatostatin analogues and surgery, which is curative in focal CHI. We report the case of two siblings (born two years apart) that presented themselves with hypoketotic hyperinsulinemic persistent hypoglycemias during neonatal period. The diagnosis of diffuse CHI due to an ABCC8 compound mutation (c.3576delG and c.742C>T) was concluded. They did not benefit from diazoxide therapy (or pancreatectomy performed in patient number 1) yet responded to somatostatin analogues. Patient number 1 developed various neurological deficits (including epilepsy), however patient number 2 experienced an entirely normal neurodevelopment. We believe this case shows how previous knowledge of the firstborn sibling's disease contributed to a better and timelier medical care in patient number 2, which could potentially explain her better neurological outcome despite their same genotype. PMID- 30462811 TI - Insulin autoimmune syndrome in an occidental woman: a case report and literature review. AB - Insulin autoimmune syndrome (IAS, Hirata's disease) is a rare hypoglycemic disorder characterized by spontaneous hypoglycemia associated with extremely high circulating insulin levels and positive anti-insulin antibody results. Thus far, most cases have been reported in Asian countries, notably Japan, with few cases reported in western countries. As a possible cause, it is associated with the use of drugs containing sulfhydryl radicals, such as captopril. This report refers to a 63-year-old female Brazilian patient with a history of postprandial hypoglycemia. After extensive investigation and exclusion of other causes, her hyperinsulinemic hypoglycemia was considered to have likely been induced by captopril. Most cases of IAS are self-limiting. However, dietary management, corticosteroids, plasmapheresis, and rituximab have already been used to treat patients with IAS. In our case, after discontinuation of captopril, an initial decrease in insulin autoantibody levels was observed followed by improvement in episodes of hypoglycemia. Although it is a rare disease, IAS should be considered in the differential diagnosis of endogenous hyperinsulinemic hypoglycemia. Patients with suspected IAS must be screened for autoimmunity-related drugs for insulin. Initial clinical suspicion of IAS can avoid unnecessary costs associated with imaging examinations and/or invasive surgical procedures. PMID- 30462812 TI - Morphobiological, morphometric and ultrastructural characterization of sylvatic Trypanosoma cruzi isolates from Rio de Janeiro state, Brazil. AB - Triatoma vitticeps is a triatomine with geographic distribution restrict to Brazil, which exhibits high prevalence of Trypanosoma cruzi natural infection. Of special epidemiologic concern, this species often invades households in the states of Rio de Janeiro, Minas Gerais and Espirito Santo. The objective of this study was to evaluate morphological and ultrastructural parameters on three T. cruzi isolates obtained from wild T. vitticeps specimens. The growth and cell differentiation of the parasite was evaluated through epimastigote and trypomastigote forms obtained in the growth curves for three distinct isolates. The maximum growth showed differences at the 20th day of the curve. Our in vitro results show a heterogeneity, regarding these features for samples cultivated under the same conditions. Morphometric analyzes based on the shape of epimastigotes and trypomastigotes corroborated such differentiation. These results highlight the need of better understanding the meaning of this diversity under an eco-epidemiological perspective. PMID- 30462813 TI - Genotoxicity effects on Geophagus brasiliensis fish exposed to Doce River water after the environmental disaster in the city of Mariana, MG, Brazil. AB - The Doce River basin has suffered the largest environmental accident ever occurred in Brazil with the influx of tailings from Fundao and Santarem, belonging to Samarco mining company, due to the disaster in Mariana. A spill between 50 and 60 million m3 of tailings was estimated by the company. According to Samarco, the wastewater was composed mainly of clay, silt and heavy metals like iron, copper and manganese. Thereby, the objective of the present study was evaluated the genotoxic damage in juvenile of Geophagus brasiliensis (Quoy e Gaimard, 1824) exposed to Doce river water before (DRWBA - Doce River water before acident) and after (DRWAA - Doce River water after acident) the influx of tailings from the Germano and Santarem Dam disasters in Mariana, MG, Brazil. For this, 24 individuals of the species G. brasiliensis (obtained on IFES/ALEGRE fish culture) were submitted to a bioassay with three treatments and eight replicates. The treatments were: 1) Control water (water from the urban water supply system, filtered with a 0.45 um membrane), 2) DRBA and 3) DRAA. After 96 h, these fishes were anesthetized to remove blood for evaluation of genotoxic damage (micronucleus and comet). For the bioassay, a total of 80 L of The Doce River water were collected before the influx of tailings and after the influx and then submitted to metal quantification analysis. Fish exposed to DRWBA and DRWAA treatments showed a significant increase in both the number of erythrocyte micronuclei and the DNA damage index in relation to the control fish; however, they did not present any differences between the two treatments. The results demonstrate that the DRWBA treatment was already genotoxic for the fish, mainly due to dissolved Cu concentrations in the water. The DRWAA treatment probably presented genotoxicity due to the increase in the dissolved fraction and synergistic effects of several metals found in the tailings of the Mariana accident. PMID- 30462814 TI - Dynamics of vegetation structure in a fragmented landscape in Minas Gerais, Brazil. AB - Considering that area and edge effects are the most important factors that lead to landscape changes from the fragmentation of terrestrial communities, the present study aimed to analyze changes in the structure of vegetation classes of a fragmented landscape. The methodology employed was based on a model of patch dynamics for the years between 1979 and 2015. The analysis was performed with quantitative (area, shape and edge effect) and qualitative (low declivity of the terrain, fire resistance and tolerance to variation in light) variables of the classes of vegetation. Processes of retraction and expansion of the vegetation classes were identified, as well as the alteration of the structure of the fragments, which resulted in the intensification of the edge effect. PMID- 30462815 TI - Antibacterial and antiproliferative activities of the fresh leaf essential oil of Psidium guajava L. (Myrtaceae). AB - This study evaluated the antibacterial and antiproliferative activities of the essential oil of Psidium guajava leaves (PG-EO), traditionally used in folk medicine. The essential oil was obtained from fresh leaves by hydrodistillation, using a modified Clevenger apparatus. The major PG-EO chemical constituents were identified by GC-MS and GC-FID as being beta-caryophyllene (16.1%), alpha humulene (11.9%), aromadendrene oxide (14.7%), delta-selinene (13.6%), and selin 11-en-4alpha-ol (12.5%). The antibacterial activity of the essential oil of P. guajava leaves was determined in terms of its minimum inhibitory concentrations (MIC) using the broth microdilution method in 96-well microplates. PG-EO had moderate activity against Streptococcus mutans (MIC = 200 ug/mL), S. mitis (MIC = 200 ug/mL), S. sanguinis (MIC = 400 ug/mL), S. sobrinus (MIC = 100 ug/mL), and S. salivarius (MIC = 200 ug/mL). The antiproliferative activity was evaluated against different tumor cell lines: breast adenocarcinoma (MCF-7), human cervical adenocarcinoma (HeLa), and human gliobastoma (M059J). A normal human cell line (GM07492A, lung fibroblasts) was included. The antiproliferative activity was evaluated using the XTT assay and the results were expressed as IC50. The essential oil showed significantly lower IC50 values against MCF-7 and M059J lines than that obtained for the normal line, showing selectivity. Our results suggest that the essential oil of Psidium guajava L. has promising biological activities and can be considered a new source of bioactive compounds. PMID- 30462816 TI - First report of Crocidosema (Epinotia) cosmoptila Meyrick, 1917 (Lepidoptera: Tortricidae) in Brazil. PMID- 30462817 TI - Women and Science: a portrait of herpetology in the state of Piaui. PMID- 30462818 TI - Training in the nursing residency in Primary Care/Family Health from the perspective of the graduates. AB - OBJECTIVE: To understand the development of professional skills and competences from the training provided by the Nursing Residency in Primary Care/Family Health of a Brazilian public university from perspective of the graduates and analysis of the Pedagogical Project. METHOD: A qualitative case study carried out with 21 graduates of the Nursing Residency. The data were collected between December 2016 and July 2017, with individual interviews conducted with the graduates, recorded, transcribed and analyzed by the Content Thematic Analysis, with the support of ATLAS ti software and documentary analysis of the Pedagogical Project. RESULTS: Two categories emerged: "Professional profile for acquiring skills and abilities" and "Influential factors for the development of skills and abilities". FINAL CONSIDERATIONS: The graduates recognized the importance of the Residency in their training processes. However, they pointed to directives such as the improvement of interpersonal relations and the expansion of the development of the Administration/Management competency. PMID- 30462819 TI - The problem of invisibility and the eloquence of small things: reflections on the strengths of qualitative research. PMID- 30462820 TI - Occurrence of Ehrlichia canis and Hepatozoon canis and probable exposure to Rickettsia amblyommatis in dogs and cats in Natal, RN. AB - Occurrence of infection or exposure to Ehrlichia canis, Hepatozoon canis and Rickettsia spp. was detected in feral cats living in two fragments from Atlantic rainforest, in Natal, RN, Brazil, and in dogs living around the parks. While serum samples were collected from 155 animals (53 cats living in the parks; 29 dogs living in human homes around the parks; and 73 dogs living at an animal control center - ACC), spleen samples were collected from 20 dogs that were euthanized at ACC. Serum samples were analyzed to Rickettsia spp. and E. canis antibodies using the indirect immunofluorescence assay. Seventeen of the 102 dogs (17%) had E. canis antibodies and 13% (20/155) of all dogs and cats (i.e. 3% (3/102) of the dogs and 32% (17/53) of the cats) were seropositive for Rickettsia spp. antigens. The animals were therefore been exposed to R. amblyommatis or by a very closely related genotype. Among the 20 dog spleen samples analyzed, eight were PCR positive for E. canis and two for H. canis (GenBank accession number MG772657 and MG772658, respectively). In none of the spleen samples were obtained amplicons for Babesia spp. through PCR. This study provided the first evidence that Rickettsia of the spotted fever group is circulating among dogs and cats in Natal. PMID- 30462821 TI - Histopathological findings of Fasciola hepatica infection in non-native European hare (Lepus europaeus) in Southern Chile. AB - Fasciola hepatica is a parasite introduced in America from Europe, being considered of concern for public health and animal production, especially in countries with endemic areas as occur in Chile. In this country, the research has been focused mainly in domestic ruminants, with native and introduced wildlife being largely ignored. Thus, the aim of this study was to report the infection by Fasciola hepatica in an introduced mammal, the European hare, which is distributed along a vast area of the country. One in 42 hares hunted showed histological lesions compatible with F. hepatica, and harbored a parasitic load of 6 liver flukes. This is the first report of this lagomorph acting as host of this helminth in the country and the third in South America. Yet, we found no previous reports regard the pathology of this fluke in the species. Thus, we emphasize the importance of more studies regarding introduced mammals which could be acting as reservoirs for this important fluke. PMID- 30462822 TI - Molecular detection of vector borne pathogens in anemic and thrombocytopenic dogs in southern Brazil. AB - Arthropod-borne pathogens are medically important because of their ability to cause diseases in their hosts. The purpose of this study was to detect the occurrence of Ehrlichia spp., piroplasmids and Hepatozoon spp. in dogs with anemia and thrombocytopenia in southern Brazil. EDTA-whole blood was collected from 75 domestic dogs presenting anemia or/and thrombocytopenia from Guarapuava, state of Parana, Brazil. DNA samples were subjected to conventional PCR assays for Ehrlichia spp. (dsb), piroplasmids (18S rRNA) and Hepatozoon spp. (18S rRNA), followed by sequencing and phylogenetic analyses. Among the 75 dogs, one (1.33%) was positive for Hepatozoon sp. and six (8%) were positive for piroplasmids in 18S rRNA cPCR assays. None of the dogs showed positive results in Ehrlichia spp. cPCR targeting dsb gene. The phylogenetic analyses revealed that three piroplasm sequences were clustered with Rangellia vitalii, while one sequence was grouped with B. vogeli. The only sequence obtained from Hepatozoon spp.-PCR protocol was pooled with H. canis. Therefore, there is urgent need for differential molecular diagnosis of the two piroplasm species cited as etiological agents in clinical cases of canine hemoparasitic diseases, given the higher pathogenic potential of R. vitalii than of B. vogeli. PMID- 30462823 TI - Hemotropic mycoplasmas in naturally infected cats in Northeastern Brazil. AB - This study aimed to determine the prevalence, factors associated, laboratory findings (with and without coinfection by retroviruses) among naturally infected cats by hemoplasmas in northeastern Brazil. For convenience, 200 domesticated and healthy cats were selected. Blood samples were taken to perform complete blood counts, serum biochemical, immunochromatography tests and nPCR for FIV and FeLV, and PCR for hemoplasma recognition. An interview was conducted to determine the factors associated with hemoplasmas. A total of 71/200 (35.5%) cats were positive for at least one hemoplasma species. Isolated infections were observed in 12,5% for 'Candidatus Mycoplasma haemominutum', 12% for Mycoplasma haemofelis and 3% for 'Candidatus Mycoplasma turicensis'. Regarding copositivity, 2% of the animals were positive for M. haemofelis and 'Candidatus Mycoplasma haemominutum', 1.5% for M. haemofelis and 'Candidatus Mycoplasma turicensis', and 4.5% for ' Candidatus Mycoplasma haemominutum' and 'Candidatus Mycoplasma turicensis'. No clinical and laboratory changes were observed in the animals that were concomitantly positive for retroviruses and hemoplasmas. Periurban region cats were more likely to be infected by M. haemofelis, while contact with other cats and infection by ' Candidatus Mycoplasma turicensis' were associated with 'Candidatus Mycoplasma haemominutum'. This study indicates that infection by hemoplasmas is a common find in cats from northeastern Brazil. PMID- 30462824 TI - In vitro culture of Neoechinorhynchus buttnerae (Acanthocephala: Neoechinorhynchidae): Influence of temperature and culture media. AB - Infection by the acantocephalan Neoechinorhynchus buttnerae is considered one of most important concerns for tambaqui fish (Colossoma macropomum ) production. Treatment strategies have been the focus of several in vivo studies; however, few studies have been undertaken on in vitro protocols for parasite maintenance. The aim of the present study was to develop the best in vitro culture condition for N. buttnerae to ensure its survival and adaptation out of the host to allow for the testing of substances to be used to control the parasite. To achieve this, parasites were collected from naturally infected fish and distributed in 6-well culture plates under the following treatments in triplicate: 0.9% NaCl, sterile tank water, L-15 Leibovitz culture medium, L-15 Leibovitz + agar 2% culture medium, RPMI 1640 culture medium, and RPMI 1640 + agar 2% culture medium. The plates containing the parasites were maintained at 24 degrees C, 28 degrees C, and 32 degrees C. The RPMI 1640 + agar 2% culture medium showed the best survival of 24 days at 24 degrees C. No body alterations such as swollen parasites, body deformation, dehydration and hardening were observed in the RPMI 1640 + 2% culture medium. PMID- 30462825 TI - Predicting factors of postoperative complications in appendectomies. AB - OBJECTIVE: to evaluate the main risk factors for postoperative complications in patients undergoing appendectomy for acute appendicitis. METHODS: we retrospectively analyzed 1241 patients undergoing open or laparoscopic appendectomy. Patients were allocated to four groups: Group 1, without postoperative complications, and Groups 2, 3, and 4, with postoperative complications defined according to their severity, following Clavien-Dindo classification (I, II, and >=III, respectively). RESULTS: patients aged >=38.5 years had more severe complications (p<0.0001). Patients in Group 1, without postoperative complications, had, for the most part, a laparoscopic approach. Groups 2, 3, and 4 underwent, predominantly, to an open surgery (p<0.0001). In cases of acute appendicitis, the odds ratio (OR) for complications was 3.09, 3.04, and 12.41 for Groups 2, 3, and 4, respectively (p<0.0001). Anesthetic risk, duration of the procedure, and length of hospital stay were related to a higher risk and severity of complications. CONCLUSION: the main predicting factors of postoperative complications in patients operated for acute appendicitis were: age >=38.5 years, conventional or open surgical access, complicated appendicitis, ASA>=2, and surgical time >77 minutes. PMID- 30462826 TI - Transoral endoscopic thyroidectomy by vestibular approach (TOETVA): initial experience in Brazil. AB - OBJECTIVE: to present the initial experience in Brazil with transoral endoscopic thyroidectomy by vestibular approach (TOETVA). METHODS: prospective study of patients undergoing TOETVA in the Department of Head and Neck Surgery of Hospital Regional do Oeste, Chapeco, Santa Catarina. Patients between 18 and 65 years of age, ASA I and II, with maximum glandular volume of 35cm3 and nodules up to 4cm were candidates for the study. Data of the patients, nodules, surgical time, complications, and length of hospital stay were recorded. RESULTS: nine patients were operated between May 2017 and April 2018. All were women, aged 33-64 years. The size of the nodule ranged from 1cm to 4cm. Two patients had malignant neoplasia and total thyroidectomy was performed in eight cases. Seven patients were hospitalized for only one day. One patient had a minor complication on skin, but there were no lesions of the laryngeal recurrent nerves or definitive hypoparathyroidism. CONCLUSION: TOETVA is a safe technique for well-selected patients, with favorable conditions and special concern for aesthetic results. PMID- 30462829 TI - Detection and profiling of diarrheic marine biotoxins in shellfish by mRNA analysis of exposed Caco-2 cells using qRT-PCR and multiplex magnetic bead-based assays. AB - The mouse bioassay for the detection of marine biotoxins in shellfish products is 40 years old and still in use. A full ban or total replacement of this in vivo test has been postponed because of the fear that current chemical-based detection methods could miss a new emerging toxin. In order to fully replace the mouse bioassay, more efforts are needed on the search for functional assays with specific endpoints. Gene expression elicited by diarrheic shellfish poisons in Caco-2 cells allowed us to determine three 'DSP profiles', i.e. OA/DTX, AZA-YTX and PTX profiles. Twelve marker genes were selected to envision the three profiles. qRT-PCR is relatively cheap and easy, and although its multiplex capacity is limited to 5 genes, this turned out to be sufficient to show the three expected profiles. The use of the multiplex magnetic bead-based assay turned out to be even a slightly better alternative, allowing the use of all twelve selected marker genes and 2 reference genes, and resulting in clear profiles with for some genes even higher induction factors as obtained by qRT PCR. When analysing blank and contaminated shellfish samples with this multiplex magnetic bead-based assay, the contaminated samples could easily be distinguished from the blank samples, showing the expected profiles. This work is one step further on the final replacement of the mouse bioassay, e.g. by combining the neuro-2a bioassay for screening and detection with analytical chemical analyses and the multiplex magnetic bead-based assay for confirmation of known and unknown toxins respectively. PMID- 30462827 TI - Clinical, laboratory and densitometric comparison of patients with coxarthrosis and femoral neck fractures. AB - OBJECTIVE: to compare clinical, laboratory and densitometric data from patients with osteoarthrosis and femoral neck fractures. METHODS: we conducted a cross sectional study of patients with femoral neck fracture and hip osteoarthrosis submitted to hip arthroplasty. We collected clinical, laboratory and densitometric data. RESULTS: we included 53 patients, 22 with femoral neck fractures and 31 with osteoarthrosis. Patients with femoral neck fractures were older than patients with osteoarthrosis, with lower BMI values, bone mineral density and palmar grip strength (sarcopenic patients), being more neurologically impaired and presenting a worse ASA score. Among the various biochemical parameters analyzed, we found statistically significant differences in total serum calcium, ionized calcium, vitamin D, free thyroxine, erythrocytes, hemoglobin, hematocrit, total white blood cells, neutrophils, lymphocytes and creatinine between the two groups. Other hormones analyzed and biochemical parameters did not differ significantly, although they showed trends between the two groups. CONCLUSION: patients with femoral neck fractures are older than patients with osteoarthrosis, have a lower weight and BMI, are more debilitated, many with anemia and reduced bone mass, and have a significant decrease in total calcium, ionized calcium, vitamin D and creatinine and a significant increase in free thyroxine. PMID- 30462828 TI - Results of laparoscopic cholecystectomy in the elderly. AB - OBJECTIVE: to evaluate the results of laparoscopic cholecystectomy in the elderly compared with younger patients. METHODS: we retrospectively reviewed computerized medical records of all patients who underwent laparoscopic cholecystectomy for chronic or acute cholecystitis from January 1, 2011 to March 31, 2018 at a single teaching hospital. We stratified the patients into two groups: elderly (>=60 years of age) and younger (<60 years of age). RESULTS: of 1,645 patients subjected to laparoscopic cholecystectomy, 1,161 (70.3%) were younger and 484 (29.7%) were elderly. The rate of male was higher in the elderly (n=185; 38.2%) group than in the younger (n=355; 30.6) (p=0.003). Jaundice was more common in the elderly (p=0.004). The rate of prior abdominal operation was also higher in the elderly (p<0.001). The percentage of patients with ASA score II, III, and IV was higher in the elderly group (p<0.001 in score II and III and 0.294 in score IV). Operative time was longer in the elderly (71.68+/-31.27) than in the younger group (p=0.001). The following perioperative data were higher in the elderly: acute cholecystitis (p<0.001), conversion rate (p=0.028), postoperative complications (p=0.042), and mortality (p=0.026). CONCLUSION: the operative time is longer and the rate of acute cholecystitis, conversion to open cholecystectomy and postoperative complications are higher in the elderly patients submitted to laparoscopic cholecystectomy when compared with younger individuals. PMID- 30462830 TI - Analysis of Initial Nonresponders to Galcanezumab in Patients With Episodic or Chronic Migraine: Results From the EVOLVE-1, EVOLVE-2, and REGAIN Randomized, Double-Blind, Placebo-Controlled Studies. AB - OBJECTIVE: To examine the likelihood of response with continued galcanezumab treatment in patients with episodic or chronic migraine without initial clinical improvement. BACKGROUND: A percentage of patients with migraine may require additional time on pharmacotherapy but discontinue treatment prematurely. Additionally, recognizing when continued treatment is unlikely to provide improvement limits unnecessary exposure. METHODS: Post hoc analysis of response after continued galcanezumab treatment was conducted in a subset of patients with episodic (N = 879) and chronic (N = 555) migraine who did not achieve "good" early improvement (episodic, >=50% reduction in baseline migraine headache days [MHD] and chronic, >=30% reduction) after 1 month of dosing (NR-1; episodic, n = 450 and chronic, n = 306). This subset was categorized by level of reduction in MHD during 1 month of treatment: "modest" (>30% to <50% fewer MHD for episodic and >10% to <30% fewer MHD for chronic), "limited" (episodic only; >10% to <=30% fewer MHD), or "minimal/no" early improvement (<=10% fewer MHD to <=10% more MHD), or "worsening" (>10% more MHD). The percentages of patients having "better" (>=75% fewer MHD for episodic and >=50% for chronic), "good," or "little-to-no" (<=10% fewer MHD) response during the remaining treatment period were calculated for each category. Similarly, the subset of NR-1 patients who did not achieve "good" early improvement after 2 months of treatment (NR-2; episodic, n = 290 and chronic, n = 240) were categorized by level of their average monthly reduction across 1 and 2 months using similar categories. RESULTS: Of NR-1 patients with episodic migraine having "modest" early improvement, 62% (96/155) achieved "good" and 20% (31/155) achieved "better" responses with continued treatment. A percentage of patients with "limited" (43%; 46/108) or "minimal/no" (34%; 29/85) early improvement, or "worsening" (20%; 20/102) achieved a "good" response after continued treatment. A percentage of NR-1 patients with chronic migraine having "modest" early improvement achieved "good" (38%; 44/116) and "better" (13%; 15/116) responses with continued treatment. A "good" response was achieved for a percentage of patients with "minimal/no" early improvement (17%; 23/133). Similar patterns were observed for the NR-2 subset, though percentages were lower. CONCLUSIONS: Galcanezumab-treated patients with episodic or chronic migraine without response following 1 or 2 months of treatment appear to have a reasonable likelihood of continued improvement in months following initial treatment and this opportunity is more likely in patients showing greater early improvements. While a small percentage of patients with episodic or chronic migraine who experienced worsening in the number of MHD following initial treatment responded with continued treatment, most do not show substantial reduction in MHD. Overall benefit of therapy should be determined collaboratively between the patient and physician. PMID- 30462831 TI - Blueberry Pectin Extraction Methods Influence Physico-Chemical Properties. AB - Pectins from highbush blueberry powder were sequentially solubilized in water, chelator, and sodium carbonate solvents and precipitated (ADF.WSF, ADF.CSF, and ADF.NSF) or not precipitated in ethanol (DF.WSF, DF.CSF, and DF.NSF) before dialysis and freeze-drying. Alcohol precipitation more effectively removed bound anthocyanins and low molar mass pectins from water- and chelator soluble fractions than dialysis alone. Blueberry water soluble fractions were high methoxyl pectins, rich in neutral sugars (36 to 38 mol%), and had high molar mass (7.01 * 105 to 2.71 * 106 g/mol). Blueberry chelator soluble fractions were low methoxyl pectins and rich in uronic acids (90 to 92 mol%) which were more linear and less branched structure than other fractions or commercial citrus pectin. The molar mass ranged from 1.59 * 106 to 2.06 * 106 g/mol. Water- and chelator soluble fractions exhibited pseudoplastic behavior (n < 1) at 1% dispersion. Blueberry sodium carbonate soluble fractions were rich in protein (18%) and neutral sugars (42 to 28 mol%), and had low molar mass (1.08 * 105 to 1.27 * 105 g/mol). Blueberry pectins have desirable physico-chemical properties for use as functional ingredients in food or beverages. PRACTICAL APPLICATION: Alcohol precipitation effectively removed anthocyanins from the pectin. The characterization data provided the benefits of blueberry pectin as a functional ingredient. This study can be used by food or product developers who are interested in pectin from blueberries or other berry products. PMID- 30462832 TI - The magic of flowers or: speciation genes and where to find them. PMID- 30462833 TI - Machine Learning Methods as a Tool for Predicting Risk of Illness Applying Next Generation Sequencing Data. AB - Next-generation sequencing (NGS) data present an untapped potential to improve microbial risk assessment (MRA) through increased specificity and redefinition of the hazard. Most of the MRA models do not account for differences in survivability and virulence among strains. The potential of machine learning algorithms for predicting the risk/health burden at the population level while inputting large and complex NGS data was explored with Listeria monocytogenes as a case study. Listeria data consisted of a percentage similarity matrix from genome assemblies of 38 and 207 strains of clinical and food origin, respectively. Basic Local Alignment (BLAST) was used to align the assemblies against a database of 136 virulence and stress resistance genes. The outcome variable was frequency of illness, which is the percentage of reported cases associated with each strain. These frequency data were discretized into seven ordinal outcome categories and used for supervised machine learning and model selection from five ensemble algorithms. There was no significant difference in accuracy between the models, and support vector machine with linear kernel was chosen for further inference (accuracy of 89% [95% CI: 68%, 97%]). The virulence genes FAM002725, FAM002728, FAM002729, InlF, InlJ, Inlk, IisY, IisD, IisX, IisH, IisB, lmo2026, and FAM003296 were important predictors of higher frequency of illness. InlF was uniquely truncated in the sequence type 121 strains. Most important risk predictor genes occurred at highest prevalence among strains from ready-to-eat, dairy, and composite foods. We foresee that the findings and approaches described offer the potential for rethinking the current approaches in MRA. PMID- 30462834 TI - Functional Decline in Alzheimer's Disease: A Continuum. PMID- 30462835 TI - A Multimodal Fusion Approach for Bullet Identification Systems. AB - In the field of forensic science, bullet identification is based on the fact that firing the cartridge from a barrel leaves exclusive microscopic striation on the fired bullets as the fingerprint of the firearm. The bullet identification methods are categorized in 2-D and 3-D based on their image acquisition techniques. In this study, we focus on 2-D optical images using a multimodal technique and propose several distinct methods as its modalities. The proposed method uses a multimodal rule-based linear weighted fusion approach which combines the semantic level decisions from different modalities with a linear technique that its optimized modalities weights have been identified by the genetic algorithm. The proposed approach was applied on a dataset, which includes 180 2-D bullet images fired from 90 different AK-47 barrels. The experimentations showed that our approach attained better results compared to common methods in the field of bullet identification. PMID- 30462836 TI - Changing the Gel-Forming Properties of Myofibrillar Protein by Using a Gentle Broken Method. AB - Chopping and stirring methods were used to prepare surimi gels in a way that preserved their inherent characteristics while maintaining or improving their textural properties and microstructures. In samples with the same-salt levels, the stirring process led to a higher gel strength than the chopping process (P < 0.05), improved the gels' water holding capacity (WHC) and viscosity, and slightly decreased the amount of salt-soluble protein. Low-field nuclear magnetic resonance showed that the stirring method improved the WHC of the product more than the chopping method. Scanning electron microscopy revealed that the surimi gels produced by stirring with 3% salt had a denser and more uniform microstructure than those produced by chopping with 2% or 3% salt. Overall, the results indicated that the stirring method is comparatively more gentle than the chopping method and can produce high-quality surimi gels that retain their original properties. PRACTICAL APPLICATION: The study examines a gentle breaking method for improving the textural properties of surimi gels while remaining their original characteristics of fish. Stirring processing, as a low-intensity breaking method, can significantly increase the gel strength and slightly increase the WHC of surimi gels compared to chopping methods. The method produces high-quality products with nutritional value, which benefits both producers and customers. PMID- 30462837 TI - Working Memory Training in Alcohol Use Disorder: A Randomized Controlled Trial. AB - BACKGROUND: Alcohol use disorder (AUD) is associated with cognitive deficits such as impaired executive functions, which are hypothesized to contribute to the progression of the disease and worsen treatment outcome. Training of working memory (WM) to improve cognitive functions and thereby reduce alcohol use has been proposed as a novel treatment strategy. METHODS: Patients with AUD (n = 50) who were recruited to an outpatient addiction clinic were randomized to receive 5 weeks of active WM training or control training. Participants had weekly follow up visits, and all cognitive training sessions were done online at home. Primary outcomes were WM function and change in self-reported heavy drinking. Secondary outcomes were craving, other drinking outcomes, and performance on a range of neuropsychological tasks from the Cambridge Neuropsychological Test Automated Battery. RESULTS: The active training group demonstrated a significantly greater improvement in verbal WM compared with the control group. No statistically significant effect of training was found on the primary drinking outcome, but a trend was observed indicating that WM training reduces the number of drinks per drinking occasion. WM training had no statistically significant effect on any of the other neuropsychological tasks. CONCLUSIONS: Cognitive training can improve WM function in individuals with AUD, suggesting that such interventions are feasible to administer in this patient population. The results do not support an effect of WM training on heavy drinking or transfer effects to other cognitive domains. Future studies should evaluate WM training as an adjunct to evidence based treatments for AUD to assess potential synergistic effects. PMID- 30462838 TI - Severe Cardiac Rupture by Only One Blow to the Chest in a Young Boy: An Autopsy Case. AB - Cardiac rupture by blunt chest trauma is commonly seen after motor vehicle accidents and falls; however, it is rarely caused by a blow to the chest. We herein report an autopsy case of a high school boy who sustained severe right ventricular rupture by only one knee kick to the chest during a quarrel. He was hospitalized and developed cardiopulmonary arrest. Emergency surgery was performed, but the patient died. The autopsy revealed no external severe trauma or deformation, but the side wall of the right ventricle contained a large V shaped laceration. The other thoracic organs had no injuries. This case illustrates that severe cardiac rupture can occur by only one blow to the chest. Blunt cardiac injuries can occur even if no severe injuries are present on the body surface. We should consider the possibility of severe cardiac injuries regardless of the presence of external injuries. PMID- 30462839 TI - Analysis of risk factors and development of scoring system to predict severity of upper gastrointestinal bleeding in children. AB - BACKGROUND AND AIM: Upper gastrointestinal bleeding is a rare and potentially life-threatening condition in children. Herein, clinical features and risk factors in children with upper gastrointestinal bleeding were analyzed and a clinical scoring system was constructed to assess severity. METHODS: This retrospective cohort study involved 224 children hospitalized with upper gastrointestinal bleeding between January 2012 and April 2018. Demographic data, clinical information and laboratory test results on admission were statistically examined. RESULTS: Out of 224 upper gastrointestinal bleeding cases, 76 were diagnosed as severe and 148 as mild cases according to rate of blood loss and severity. Severe group was significantly different from mild group in 23 items including age, number of patients aged more than seven years old, etc (P < 0.01 or P < 0.05). Positive detection rate of bleeding etiology was gradually decreased (P < 0.01) in relation to delay in timing of endoscopy. Analysis of logistic regression evinced five independent risk factors for severe cases to be associated with poor consciousness, hemoglobin < 80 g/L, hemoglobin drop of > 20 g/L, hematochezia and anemic appearance (P < 0.01 or P < 0.05). Using these five parameters, a number of scoring models were tested. The most predictive resulted in a scoring system constructed with a total of 16 and a cutoff for intervention of 8. CONCLUSIONS: Amalgamation of risk factors with the scoring system plays an important role in assessing upper gastrointestinal bleeding severity in children. PMID- 30462840 TI - Simulation of P2X-mediated calcium signaling in microglia. AB - KEY POINTS SUMMARY: * A computational model of P2X channel activation in microglia was developed that includes downfield Ca2+ dependent signaling pathways. * This model provides quantitative insights into how diverse signaling pathways in microglia converge to control microglial function. ABSTRACT: Microglia function is orchestrated through highly-coupled signaling pathways that depend on calcium (Ca2+). In response to extracellular adeno- sine triphosphate (ATP), transient increases in intracellular Ca2+ driven through the activation of purinergic receptors, P2X and P2Y, are sufficient to promote cytokine synthesis. While steps comprising the pathways bridging purinergic receptor activation with transcriptional responses have been probed in great detail, a quantitative model for how these steps collectively control cytokine production has not been established. Here we developed a minimal computational model that quantitatively links extracellular stimulation of two prominent ionotropic purinergic receptors, P2 * 4 and P2 * 7, with the graded production of a gene product, namely the tumor necrosis factor alpha (TNFalpha) cytokine. In addition to Ca2+ handling mechanisms common to eukaryotic cells, our model includes microglia-specific processes including ATP-dependent P2 * 4 and P2 * 7 activation, activation of nuclear factor of activated T-cells (NFAT) transcription factors, and TNFalpha production. Parameters for this model were optimized to reproduce published data for these processes, where available. With this model, we determined the propensity for TNFalpha production in microglia, subject to a wide range of ATP exposure amplitudes, frequencies and durations that the cells could encounter in vivo. Furthermore, we have investigated the extent to which modulation of the signal transduction pathways influence TNFalpha production. Our results suggest that pulsatile stimulation of P2 * 4 via micromolar ATP may be sufficient to promote TNFalpha production, whereas high amplitude ATP exposure is necessary for production via P2 * 7. Further, under conditions that increase P2 * 4 expression, for instance the activation by pathogen associated molecular factors, P2 * 4 associated TNFalpha production is greatly enhanced. Given that Ca2+ homeostasis in microglia is profoundly important to its function, this computational model provides a quantitative framework to explore hypotheses pertaining to microglial physiology. This article is protected by copyright. All rights reserved. PMID- 30462841 TI - Cost-effectiveness of sofosbuvir plus ribavirin therapy for hepatitis C virus genotype 2 infection in South Korea. AB - BACKGROUND AND AIM: For genotype 2 chronic hepatitis C (CHC), the efficacy and safety of sofosbuvir plus ribavirin therapy (SOF+RBV) was better than pegylated interferon plus ribavirin therapy (PR) at a greater drug cost. This study investigated the cost-effectiveness of SOF+RBV compared to PR for treatment naive, genotype 2 CHC in South Korea. METHODS: Using a decision analytic Markov model, a cost-effectiveness analysis comparing SOF+RBV with PR or no treatment for treatment-naive genotype 2 CHC was performed with probabilistic and deterministic sensitivity analyses from the payer's perspective in 2017. Three cohorts of patients aged 40-49, 50-59, and 60-69 years were simulated to progress through the fibrosis stages F0-F4 to end-stage liver-disease, hepatocellular carcinoma or death. Published and calculated data on the clinical efficacy of the regimen, health-related quality-of-life, costs, and transition probabilities were used. RESULTS: While the incremental cost-effectiveness ratio (ICER) for PR was dominant over no treatment, the ICERs for SOF+RBV were $20,058 for the patients in their 40s, $19,662 for those in their 50s, and $22,278 for those in their 60s compared to PR. Probabilistic sensitivity analysis indicated a 89.0% probability for the SOF+RBV to be cost-effective at a willingness to pay of $29,754.4 (per capita GDP in 2017) for the patients in their 40s, and 94.1% and 89.1% for the patients in their 50s, and 60s, respectively. CONCLUSIONS: The SOF+RBV is a cost effective option for genotype 2 treatment-naive CHC patients, especially for the patients with liver cirrhosis in Korea. PMID- 30462842 TI - Care Maps and Care plans for Children with Medical Complexity. AB - INTRODUCTION: The support of families in the care of children with medical complexity (CMC) requires the integration of health care provider (HCP) medical knowledge and family experience. Care plans largely represent HCP information and care maps demonstrate the family experience. Understanding the intersection between a care plan and care map is critical, as it may provide solutions to the widely recognized tension between HCP-directed care and patient- and family centered care (PFCC). METHOD: This study used qualitative methods to explore the experience and usefulness of care maps. Parents of CMC who already had a care plan, created care maps (n=15). Subsequent interviews with parents (n=15) and HCPs (n=30) of CMC regarding both care maps and care plans were conducted and analyzed using thematic analysis. RESULTS: Data analysis exploring the relationship and utility of care plans and care maps revealed six primary themes related to using care plans and care maps that were grouped into two primary categories: 1) Utility of care plans and maps; and 2) Intersection of care plans and care maps. DISCUSSION: Care plans and care maps were identified as valuable complementary documents. Their integration offers context about family experience and respects the parents' experiential wisdom in a standard patient care document, thus promoting improved understanding and integration of the family experience into care decision making. PMID- 30462844 TI - Long non-coding RNA Linc00518 promotes paclitaxel resistance of the human prostate cancer by sequestering miR-216b-5p. AB - BACKGROUND INFORMATION: To characterise Linc00518 expression in prostate cancer and elucidate the potential mechanistic involvement in paclitaxel resistance, the relative expression of Linc00518 and miR-216b-5p was determined by real-time PCR. The regulatory effect of miR-216b-5p on either Linc00518 or GATA6 was interrogated with luciferase reporter assay. The endogenous GATA6 protein was analysed by Western blotting. The cell viability was measured by MTT assay and IC50 of paclitaxel was calculated through cell counting. RESULTS: Linc00518 was highly expressed in prostate tumour both in vivo and in vitro. High level of Linc00518 transcripts associated with paclitaxel resistance. Linc00518 competitively inhibited miR-216b-5p through sponging mechanism. Linc00518 deficiency compromised the paclitaxel resistance in the acquired resistance cell lines. CONCLUSIONS AND SIGNIFICANCE: We demonstrated that overexpression of Linc00518 contributed to the paclitaxel resistance in prostate cancer via sequestering miR-216b-5p. PMID- 30462843 TI - Association Between Functional Performance and Alzheimer's Disease Biomarkers in Individuals Without Dementia. AB - OBJECTIVES: To examine the cross-sectional association between functional performance and Alzheimer's disease (AD) neuroimaging biomarkers in individuals without dementia (cognitively unimpaired (CU), and those with mild cognitive impairment (MCI)). DESIGN: Cross-sectional. SETTING: Olmsted County, Minnesota. PARTICIPANTS: Population-based Mayo Clinic Study of Aging (MCSA) participants (aged >= 50, mean age 71.3 +/- 10.2; 53.4% male; 28.3% apolipoprotein (APO)E epsilon4 allele carriers, 1,578 CU, 204 MCI) who underwent 11 C-Pittsburgh compound B (11 C-PiB) positron emission tomography (PET) (N=1,782). MEASUREMENTS: We defined an abnormal (high) 11 C-PiB-PET retention ratio as a standardized uptake value ratio greater than 1.42 (high amyloid; A+), abnormal (reduced) AD signature cortical thickness (neurodegeneration; N+) as less than 2.67 mm (MRI measurement), and biomarker groups according to the combination of abnormality (or not) for amyloid accumulation (A+/A-) and neurodegeneration (N+/N-). Functional performance was assessed using the Clinical Dementia Rating (CDR) Sum of Boxes (SOB) for functional domains and the Functional Activities Questionnaire (FAQ). RESULTS: Participants with a CDR-SOB (functional) score greater than 0 were almost 4 times as likely to have N + (odds ratio (OR)=3.92, 95% confidence interval (CI)=1.77-8.67, adjusting for age, sex, education, global cognitive z score, and APOE epsilon4 allele status; p<.001) and those with a FAQ score greater than 0 were 1.5 times as likely to have A + (OR=1.48, 95% CI=1.04-2.11, p=.03). Higher FAQ scores were associated with greater odds of A+N + and A-N + in CU participants. CONCLUSION: The findings of this cross-sectional study supplement limited available information that supports an association between functional performance and AD neuroimaging biomarkers very early in the dementia pathophysiology. The associations should be validated in longitudinal studies. PMID- 30462845 TI - Tracing of Selected Viral, Bacterial, and Parasitic Agents on Vegetables and Herbs Originating from Farms and Markets. AB - Fresh vegetables and herbs are usually prepared and eaten raw without cooking or heating, which leads to a high risk of foodborne infection. The aim of the present study was to assess the contamination of raw vegetables, herbs, and the environment of food chains. Vegetable and herb samples originating both from the Czech Republic as well as from other countries were examined. The work was focused on the detection of commonly found, but also less frequently monitored foodborne pathogens, including viruses of the genus Norovirus (NoVs), hepatitis A virus (HAV), Listeria monocytogenes and Cronobacter spp. bacteria, and the parasites Cryptosporidium spp. and Giardia intestinalis. All samples were analyzed using individual RT-qPCR/qPCR assays; bacterial pathogens were also simultaneously detected using culture methods. The prevalence of the studied microorganisms in 623 samples ranged from 0.6% to 44.3% for individual pathogens. None of the samples were positive for the presence of HAV. Analysis of 157 environmental samples from 12 farms revealed the presence of NoVs in the environment of four farms. NoVs were detected in water samples as well as on the hands and gloves of workers. Escherichia coli was detected in all farms in the environmental samples and in eight farms in water samples. However, no sample of water exceeded the level of 100 CFU/mL for E. coli. None of the samples of water were positive for the presence of the studied parasites. Vegetables and herbs available from Czech markets and farms may pose a certain risk of foodborne disease, especially in the case of NoVs and parasites. PRACTICAL APPLICATION: This study provides valuable information on the microbiological quality of raw vegetables and herbs available from Czech markets and farms. Good hygienic practices aimed at reducing the incidence of pathogenic agents on fresh produce should not be neglected. Emphasis should be placed on the control of irrigation water, especially with respect to norovirus contamination. It is appropriate to combine culture methods and qPCR methods for the detection of bacterial agents. PMID- 30462847 TI - Editorial. PMID- 30462846 TI - The effects of electromagnetic fields on cultured human retinal pigment epithelial cells. AB - A great deal of evidence has confirmed that electromagnetic fields (EMFs) can affect the central nervous system. In this study, cultured neonatal human retinal pigment epithelial (hRPE) cells were exposed to pulsed EMF of 1 mT intensity and 50 Hz frequency 8 h daily for 3 days. In addition to cell proliferation and cell death assays, immunocytochemistry for RPE65, PAX6, nestin, and cytokeratin 8/18 proteins were performed. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) was performed for NES, PAX6, RPE65, and ACTA2 gene expression. Exposed hRPE cells did not demonstrate significant change in terms of cytomorphology, cell proliferation, or cell death. Protein expression of PAX6 was decreased in treated cells compared to controls and remained unchanged for RPE65, cytokeratin 8/18, and nestin. Gene expressions of NES, RPE65, and PAX6 were decreased in treated cells as compared to controls. Gene expression of ACTA2 did not significantly change. In conclusion, viability of cultivated neonatal hRPE cells did not change after short exposure to a safe dose of pulsed EMF albeit that both gene and protein expressions of retinal progenitor cell markers were reduced. Whether longer exposure durations that are being constantly produced by widely-used electronic devices may induce significant changes in these cells, needs further investigation. Bioelectromagnetics. 39:585-594, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30462849 TI - Clinical and pathological features of combined hepatocellular-cholangiocarcinoma compared with other liver cancers. AB - BACKGROUND AND AIM: Combined hepatocellular-cholangiocarcinoma (CHC) is a primary liver cancer containing both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) elements. Its reported clinicopathological features and prognoses have varied because of its low prevalence. This study aimed to clarify these aspects of CHC. METHODS: We enrolled 28 patients with CHC, 1050 with HCC, and 100 with ICC and compared the clinicopathological characteristics and prognosis of CHC with HCC and ICC. We also analyzed prognostic factors, recurrence patterns, and management in CHC patients. RESULTS: The incidences of hepatitis B virus (HBV), and high alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonists-II (PIVKAII) levels were significantly higher among CHC compared with ICC patients. Multiple tumors were more frequent in CHC compared with the other groups, while vascular invasion and lymph node metastasis were more frequent in the CHC than the HCC group. The 5-year overall (OS) and disease-free survival (DFS) rates for CHC were 25.1% and 22.6%, respectively. OS was significantly lower than for HCC (P<0.001) but not ICC (P=0.152), while DFS was significantly lower than for HCC and ICC (P=0.008 and P=0.005, respectively). Multivariate analysis identified carcinoembryonic antigen (CEA) levels and tumor size as independent predictors in patients with CHC. CONCLUSIONS: The clinical features of CHC, including sex, HBV infection, AFP and PIVKAII levels, were similar to HCC, while its prognosis and pathological features, including vascular invasion and lymph node metastasis, were similar to ICC. CEA levels and tumor size were independent prognostic factors in patients with CHC. PMID- 30462850 TI - Clinical validation of the '7x7' questionnaire for patients with functional gastrointestinal disorders. AB - BACKGROUND AND AIM: physicians use different scales and questionnaires to assess the severity of clinical symptoms in patients with functional gastrointestinal disorders. The current study aimed to validate the '7x7' questionnaire for assessment of severity of the symptoms as a tool for the efficacy of treatment of functional gastrointestinal disorders, using the Clinical Global Impressions scale as the reference standard. METHODS: fifty inpatients aged from 18 to 64 with a confirmed diagnosis of irritable bowel syndrome (26 patients, 52%), functional dyspepsia (15 patients, 30%) or both (9 patients, 18%) were prospectively enrolled in the study. We used both the '7x7' questionnaire and the Clinical Global Impressions scale before and after 28 days of stable treatment. RESULTS: our study revealed a significant correlation between the '7x7' questionnaire and the CGI scale results in assessment of severity of the clinical symptoms and their dynamics during treatment. The '7x7' questionnaire showed sensitivity of 74.5% and specificity of 54.1% for evaluating patients with mild to severe disease, 66.6% and 76% respectively for evaluating patients with moderate to severe disease. The Cronbach's alpha coefficient was 0,719. The intraclass correlation coefficient among participants in whom the condition remained the same was 0.973 (12 participants (24,5%)). CONCLUSIONS: the '7x7' questionnaire is a convenient, sensitive, and reliable tool for assessing the severity of symptoms and treatment efficacy in people with functional gastrointestinal disorders. PMID- 30462851 TI - Nasal High-flow During Neonatal and Infant Transport In Victoria, Australia. AB - The Paediatric Infant and Perinatal Emergency Retrieval (PIPER) service based in Melbourne, Victoria performs approximately 2800 transfers of neonates and young infants annually, of which >1100 are emergency transfers. Respiratory distress is common in this population, and treatment has traditionally been provided with nasal continuous positive airway pressure (CPAP), or endotracheal mechanical ventilation (MV). Heated, humidified nasal high-flow (nHF) treatment is increasingly popular in neonatal care,(1) including in tertiary and non-tertiary centres in Victoria. This article is protected by copyright. All rights reserved. PMID- 30462852 TI - 3-Bromopyruvate (3BP) as a Potent Anticancer Therapy in Honor and Memory of the Late Professor Andre Goffeau. AB - 3-bromopyruvate (3BP) is a small, highly reactive molecule formed by bromination of pyruvate. In the year 2000 the antitumor properties of 3BP were discovered. Studies using animal models proved its high efficacy for anti-cancer therapy with no apparent side effects. This was also found to be the case in a limited number of cancer patients treated with 3BP. Due to the 'Warburg effect' most tumor cells exhibit metabolic changes, e.g., increased glucose consumption and lactic acid production resulting from mitochondrial bound overexpressed hexokinase 2. Such alterations promote cell migration, immortality via inhibition of apoptosis, and less dependence on the availability of oxygen. Significantly, these attributes also make cancer cells more sensitive to agents, such as 3BP that inhibits energy production pathways without harming normal cells. This selectivity of 3BP is mainly due to overexpressed monocarboxylate transporters in cancer cells. Furthermore, 3BP is not a substrate for any pumps belonging to theATP-binding cassette superfamily which confers resistance to a variety of drugs. Also, 3BP has the capacity to induce multiple forms of cell death, by e.g. ATP depletion resulting from inactivation of both glycolytic and mitochondrial energy production pathways. In addition to its anticancer property, 3BP also exhibits antimicrobial activity. Various species of microorganisms are characterized by different susceptibility to 3BP inhibition. Among tested strains, the most sensitive was found to be the pathogenic yeast-like fungus Cryptococcus neoformans. Significantly, studies carried out in our laboratories have shown that 3BP exhibits a remarkable capacity to eradicate cancer cells, fungi, and algae. PMID- 30462853 TI - Development and therapeutic potential of autotaxin small molecule inhibitors: From bench to advanced clinical trials. AB - Several years after its isolation from melanoma cells, an increasing body of experimental evidence has established the involvement of Autotaxin (ATX) in the pathogenesis of several diseases. ATX, an extracellular enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) into the bioactive lipid lysophosphatidic acid (LPA), is overexpressed in a variety of human metastatic cancers and is strongly implicated in chronic inflammation and liver toxicity, fibrotic diseases, and thrombosis. Accordingly, the ATX-LPA signaling pathway is considered a tractable target for therapeutic intervention substantiated by the multitude of research campaigns that have been successful in identifying ATX inhibitors by both academia and industry. Furthermore, from a therapeutic standpoint, the entry and the so far promising results of the first ATX inhibitor in advanced clinical trials against idiopathic pulmonary fibrosis (IPF) lends support to the viability of this approach, bringing it to the forefront of drug discovery efforts. The present review article aims to provide a comprehensive overview of the most important series of ATX inhibitors developed so far. Special weight is lent to the design, structure activity relationship and mode of binding studies carried out, leading to the identification of advanced leads. The most significant in vitro and in vivo pharmacological results of these advanced leads are also summarized. Lastly, the development of the first ATX inhibitor entered in clinical trials accompanied by its phase 1 and 2a clinical trial data is disclosed. PMID- 30462854 TI - A propeller SGAP flap raised from a previous gluteus maximus myocutaneous flap to reconstruct a recurrent type IV sacral pressure ulcer. PMID- 30462855 TI - Implementation of a microsurgical breast reconstruction program in Mexico. PMID- 30462856 TI - Impact of family history of colorectal cancer on age-specific prevalence of colorectal neoplasia. AB - BACKGROUND: There are no established guidelines on screening strategies for persons with a family history of colorectal cancer (CRC) in Korea. We aimed to evaluate the age-specific risk of colorectal neoplasia according to family history of CRC. METHODS: Participants who underwent screening colonoscopy were included. Age-specific prevalence of non-advanced adenoma (NAA) and advanced colorectal neoplasia (ACRN) was calculated according to family history of CRC. RESULTS: Among 35,997 participants, 1,339 (3.7%) had a family history of CRC in first-degree relatives. A family history of CRC was an independent risk factor for NAA (adjusted odds ratio [AOR] 1.33, 95% confidence interval [CI] 1.16-1.52). In the subgroup analysis by age, family history of CRC was a risk factor for NAA in the 50-59 and >=60 years groups (AOR [95% CI]: 1.42 [1.04-1.91] and 2.33 [1.34 4.09], respectively), but not in the 30-39 and 40-49 years groups. In the curve of age-specific prevalence of NAA, the gap of the prevalence between the family history and non-family history groups began to widen after the mid-50s. In cases of ACRN, a family history of CRC was not a risk factor in the entire age group (AOR 1.16, 95% CI 0.75-1.70). In the curve of age-specific prevalence of ACRN, however, the gap of the prevalence between the family history and non-family history groups began to widen after the early 60s. CONCLUSION: Although a family history of CRC is a risk factor for NAA, it may affect NAA development from the mid-50s and ACRN development from the early 60s. PMID- 30462857 TI - Clinical Features of Idiopathic Portal Hypertension in China: A Retrospective Study of 338 Patients and Literature Review. AB - BACKGROUND AND AIM: Idiopathic portal hypertension (IPH) refers to a relatively rare condition characterized by intrahepatic portal hypertension in the absence of underlying disease such as liver cirrhosis. METHODS: We retrospectively reviewed 338 patients with IPH that were diagnosed at the pathological consultation center of our hospital. RESULTS: The ratio of male to female patients was 1:1. Mean age at onset was 35.1 +/- 16.5 years; male patients on average were 12 years younger than female patients at onset. The median duration from onset to IPH diagnosis was 12 months. In fifty patients, medication use may have been an etiological factor. The most common clinical manifestations were splenomegaly (91.3%) and hypersplenism (68.9%). 57.0% patients presented varicosis, while 25.1% patients had a history of variceal bleeding. Nodular regenerative hyperplasia was found in 22.2% liver biopsies. Among patients for whom laboratory data were available, 65.0%, 50.3%, and 71.4% patients presented leukopenia, anemia, and thrombocytopenia due to hypersplenism. Liver function was mostly in the compensated stage. Females showed worse leukopenia and anemia, while males were more likely to have abnormal serum transaminase and bilirubin levels. Sixty-seven patients received surgical or interventional treatment. CONCLUSIONS: High-quality liver biopsy, detailed clinical information, and expert pathologist are necessary for diagnosis of IPH. IPH can occur concurrently with other liver disease such as hepatitis and drug-induced liver injury. Medication appears to be an important etiological factor for IPH in China. Management approach was largely focused on treatment of portal hypertension and its complications. PMID- 30462858 TI - Factors Related to the Assessment of Resting Metabolic Rate in Critically Ill Patients. AB - BACKGROUND: Predicting resting metabolic rate (RMR) in mechanically ventilated, critically ill patients is an important part of the nutrition care in such patients. METHODS: RMR and associated clinical data from various studies of mechanically ventilated, critically ill patients were combined, and the impact of body size, age, reason for admission, and sedation level were analyzed along with prediction methods of RMR (the American Society for Parenteral and Enteral Nutrition [ASPEN] standards and the Penn State equation). RESULTS: Among 826 measurements, trauma patients had a higher RMR than surgical and medical patients (2077 +/- 290 vs 1987 +/- 282 kcal/d; P < .0001). RMR was not different in sedated vs unsedated patients. Wide ranges of weight (27-374 kg) and age (18-95 years) were captured. The relationships between weight and RMR and RMR and age were curvilinear. For weight-based ratio methods of RMR prediction, <50% of predictions were within the range in which they were designed to work. The accuracy of the Penn State equation was better in some weight categories than others. New equations based on a wider range of body weights and ages are presented. CONCLUSIONS: Curvilinear functions exist for weight and age in relation to RMR, but extraordinary levels of each are required for the curve to become apparent. The ASPEN energy standards (kcal/kg body weight) fail to predict RMR because the relationship is more complex than a simple ratio. The Penn State equations are better able to model these relationships. The new versions of the equation presented here await validation. PMID- 30462859 TI - Interaction between interferon regulatory factor 6 and glycine receptor beta shows a protective effect on developing nonsyndromic cleft lip with or without cleft palate in the Han Chinese population. AB - Single-nucleotide polymorphisms (SNPs) in protein-coding regions of genes which were previously reported to be associated with nonsyndromic cleft lip, with or without palate involvement (NSCL/P), were investigated. Twelve candidate loci [platelet-derived growth factor C (PDGFC), platelet-derived growth factor subunit A (PDGFA), platelet-derived growth factor receptor alpha (PDGFRA), glycine receptor alpha 2 (GLRA2), glycine receptor beta (GLRB), ATP binding cassette subfamily A member 4 (ABCA4), MAF bZIP transcription factor B (MAFB), interferon regulatory factor 6 (IRF6), CCDC26 long non-coding RNA (CCDC26), paired box 7 (PAX7), ventral anterior homeobox 1 (VAX1), and netrin 1 (NTN1)] covering 1.5 Mbp were sequenced in 136 NSCL/P patients and 54 healthy controls. Twenty-five genomic variants identified were further validated in another 400 NSCL/P and 200 controls. Two SNPs in IRF6 showed a protective effect against the development of NSCL/P (rs12405750, OR = 0.54, 95% CI: 0.41-0.69; and rs2235371, OR = 0.55, 95% CI: 0.43-0.71). The missense variant, rs2235371, alters the conserved amino acid valine to isoleucine at codon 274 (V274I). We observed that SNPs at IRF6 (rs2235371 and rs12405750) and GLRB (rs73856838 and rs72685584) show consistent interaction effects. The association between the missense SNP rs2235371 in gene IRF6 and NSCL/P suggests that this SNP may play an important role as a risk factor for NSCL/P in the Han Chinese populations. The marginal signal near 4q31 detected in previous genome-wide association studies might be caused by an interaction between the IRF6 and GLRB genes. This interaction needs to be further validated by experimentation in follow-up studies. PMID- 30462860 TI - Hardware Sequencing of Inflatable Nonlinear Actuators for Autonomous Soft Robots. AB - Soft robots are an interesting alternative for classic rigid robots in applications requiring interaction with organisms or delicate objects. Elastic inflatable actuators are one of the preferred actuation mechanisms for soft robots since they are intrinsically safe and soft. However, these pneumatic actuators each require a dedicated pressure supply and valve to drive and control their actuation sequence. Because of the relatively large size of pressure supplies and valves compared to electrical leads and electronic controllers, tethering pneumatic soft robots with multiple degrees of freedom is bulky and unpractical. Here, a new approach is described to embed hardware intelligence in soft robots where multiple actuators are attached to the same pressure supply, and their actuation sequence is programmed by the interaction between nonlinear actuators and passive flow restrictions. How to model this hardware sequencing is discussed, and it is demonstrated on an 8-degree-of-freedom walking robot where each limb comprises two actuators with a sequence embedded in their hardware. The robot is able to carry pay loads of 800 g in addition to its own weight and is able to walk at travel speeds of 3 body lengths per minute, without the need for complex on-board valves or bulky tethers. PMID- 30462861 TI - In Situ Solid Electrolyte Interphase from Spray Quenching on Molten Li: A New Way to Construct High-Performance Lithium-Metal Anodes. AB - Uncontrollable growth of Li dendrites and low utilization of active Li severely hinder its practical application. Construction of an artificial solid electrolyte interphase (SEI) on Li is demonstrated as one of the most effective ways to circumvent the above problems. Herein, a novel spray quenching method is developed in situ to fabricate an organic-inorganic composite SEI on Li metal. By spray quenching molten Li in a modified ether-based solution, a homogeneous and dense SEI consisting of organic matrix embedded with inorganic LiF and Li3 N nanocrystallines (denoted as OIFN) is constructed on Li metal. Arising from high ionic conductivity and strong mechanical stability, the OIFN can not only effectively minimize the corrosion reaction of Li, but also greatly suppresses the dendrite growth. Accordingly, the OIFN-Li anode presents prominent electrochemical performance with an enhanced Coulombic efficiency of 98.15% for 200 cycles and a small hysteresis of <450 mV even at ultrahigh current density up to 10 mA cm-2 . More importantly, during the full cell test with limited Li source, a high utilization of Li up to 40.5% is achieved for the OIFN-Li anode. The work provides a brand-new route to fabricate advanced SEI on alkali metal for high-performance alkali-metal batteries. PMID- 30462863 TI - Comment on 'Proton Pump Inhibitors. Risks and Rewards and Emerging Consequences to the Gut Microbiome'. PMID- 30462862 TI - Structurally Controlled Cellular Architectures for High-Performance Ultra Lightweight Materials. AB - The design and synthesis of cellular structured materials are of both scientific and technological importance since they can impart remarkably improved material properties such as low density, high mechanical strength, and adjustable surface functionality compared to their bulk counterparts. Although reducing the density of porous structures would generally result in reductions in mechanical properties, this challenge can be addressed by introducing a structural hierarchy and using mechanically reinforced constituent materials. Thus, precise control over several design factors in structuring, including the type of constituent, symmetry of architectures, and dimension of the unit cells, is extremely important for maximizing the targeted performance. The feasibility of lightweight materials for advanced applications is broadly explored due to recent advances in synthetic approaches for different types of cellular architectures. Here, an overview of the development of lightweight cellular materials according to the structural interconnectivity and randomness of the internal pores is provided. Starting from a fundamental study on how material density is associated with mechanical performance, the resulting structural and mechanical properties of cellular materials are investigated for potential applications such as energy/mass absorption and electrical and thermal management. Finally, current challenges and perspectives on high-performance ultra-lightweight materials potentially implementable by well-controlled cellular architectures are discussed. PMID- 30462864 TI - Molecular Magnets Based on Graphenes and Carbon Nanotubes. AB - Molecular magnets are demonstrated to provide a promising way to realize nanometer-scale structures with a stable spin orientation. Herein, first a description of conventional molecular magnets coupled with sp2 carbon materials, such as carbon nanotubes and graphenes, is given. Then, progress on ferromagnetism in sp2 carbon nanomaterials due to the existence of defects or topological structures as the spin units, which makes the sp2 materials themselves act as a novel class of molecular magnets, is reviewed, and a scheme of controllable synthesis of the molecular magnets at the sheared ends of carbon nanotubes is proposed. To conclude, remarks on some challenges and perspectives in the synthesis of carbon nanotube arrays with orderly sheared ends as integrated molecular magnets are provided. PMID- 30462865 TI - Experimental Insights into the Growth of Single Truncated Anatase Bipyramids. AB - Fluorine has been recognized to selectively stabilize anatase titanium dioxide (TiO2) crystal facets, however, resolving its physical location at the nanometer scale remains empirically elusive. Here, we provide direct experimental evidence to reveal the spatial distribution of fluorine on single truncated anatase bipyramids (TABs) using nanoscale secondary ion mass spectrometry (NanoSIMS). Fluorine was found to preferentially adsorb on the (001) facet compared to the (101) facet of TABs. Moreover, NanoSIMS depth profiling exhibited a significantly different fluorine distribution between these two facets in the near-surface region, illustrating the essential role of lattice-doped fluorine in the anisotropic crystal growth of TABs. PMID- 30462866 TI - Response to Comment on 'Proton Pump Inhibitors. Risks and Rewards and Emerging Consequences to the Gut Microbiome'. PMID- 30462867 TI - Synchronization and maintenance of circadian timing in the mammalian clockwork. AB - The hypothalamic suprachiasmatic nucleus (SCN) is the principal circadian pacemaker in mammals. Cells in the SCN contain cell-autonomous transcriptional translational feedback loops, which are synchronised to each other and thereby provide a coherent output to direct synchrony of peripheral clocks located in the brain and body. A major difference between these peripheral clocks and the SCN is the requirement for intercellular coupling mechanisms, which confer robustness, stability and amplitude to the system. There has been remarkable progress to our understanding of the intra- and inter-cellular mechanisms of the SCN circuitry over the last ~20 years, which has come hand-in-hand with the development of new technologies to measure and manipulate the clock. PMID- 30462869 TI - Continuous synthesis of nanominerals in supercritical water. AB - The synthesis of minerals has to play a crucial role in the development of new and advanced materials. Since 2016, a renewal of interest to enlarge the mineral synthesis towards industrial requirements is observed, especially thanks to three main recent papers. The innovative process exposed combines a continuous process with the use of supercritical water. In addition to curtail synthesis times, this process offers a control on the particle characteristics (size, crystallinity, structure...) and a capacity to be easily transferable at an industrial scale. This innovative concept is demonstrated with the synthesis of three minerals which are the talc (a phyllomineral), the xonotlite and the tobermorite (two inominerals). This paper proposes an overview of the possibilities to synthesize nanominerals in continuous for the development of advanced materials with promising industrial applications. PMID- 30462868 TI - An Electron/Ion Dual-Conductive Alloy Framework for High-Rate and High-Capacity Solid-State Lithium-Metal Batteries. AB - The solid-state Li battery is a promising energy-storage system that is both safe and features a high energy density. A main obstacle to its application is the poor interface contact between the solid electrodes and the ceramic electrolyte. Surface treatment methods have been proposed to improve the interface of the ceramic electrolytes, but they are generally limited to low-capacity or short term cycling. Herein, an electron/ion dual-conductive solid framework is proposed by partially dealloying the Li-Mg alloy anode on a garnet-type solid-state electrolyte. The Li-Mg alloy framework serves as a solid electron/ion dual conductive Li host during cell cycling, in which the Li metal can cycle as a Li rich or Li-deficient alloy anode, free from interface deterioration or volume collapse. Thus, the capacity, current density, and cycle life of the solid Li anode are improved. The cycle capability of this solid anode is demonstrated by cycling for 500 h at 1 mA cm-2 , followed by another 500 h at 2 mA cm-2 without short-circuiting, realizing a record high cumulative capacity of 750 mA h cm-2 for garnet-type all-solid-state Li batteries. This alloy framework with electron/ion dual-conductive pathways creates the possibility to realize high energy solid-state Li batteries with extended lifespans. PMID- 30462870 TI - Renewable Energy Special Issue: Going for Green! AB - Seeking sustainability: This Special Issue is dedicated to the topic of Renewable Energy. Within this collection of manuscripts are excellent contributions from leading scientists throughout the world who are committed to searching for ways to provide the world with cleaner and greener energy alternatives for a brighter tomorrow. PMID- 30462871 TI - A novel tool for time-locking study plans to results. AB - Often researchers wish to mark an objective line between study plans that were specified before data acquisition and decisions that were made following data exploration. Contrary to common perception, registering study plans to an online platform prior to data collection does not by itself provide such an objective distinction, even when the registration is time-stamped. Here we adapt a method from the field of cryptography to allow encoding of study plans and predictions within random aspects of the data acquisition process. Doing so introduces a causal link between the pre-registered content and objective attributes of the acquired data, such as the timing and location of brain activations. This guarantees that the pre-registered plans and predictions are indeed specified prior to data collection. Our time-locking system does not depend on any external party and can be performed entirely in-lab. We provide code for easy implementation and a detailed example from the field of functional Magnetic Resonance Imaging (fMRI). This article is protected by copyright. All rights reserved. PMID- 30462872 TI - Electrochemical Exfoliation of MoS2 Crystal for Hydrogen Electrogeneration. AB - Transition metal dichalcogenides (TMDs) have recently emerged within the group of 2D materials due to their electrical, catalytic and optical properties significantly enhanced and useful when down-sized to single layer. In particular, MoS2 has attracted much attention due to its semiconducting nature with a useful band gap when present as single layer, the enhanced photoluminescence, but also importantly the excellent catalytic properties towards the electrochemical hydrogen evolution. We present here the preparation of thin layers MoS2 nanosheets with enhanced catalytic properties towards the hydrogen evolution reaction by means of an easy and fast electrochemical top-down exfoliation procedure in aqueous solution from a naturally occurring MoS2 crystal. After structural and chemical characterization with STEM, AFM, XPS and Raman spectroscopy electrochemical investigations were performed to test catalytic properties in acidic solution for the electrogeneration of hydrogen and compare it to MoS2 nanosheets obtained through the widely employed chemical Li intercalation/exfoliation. Electrochemically exfoliated MoS2 shows lower Tafel slope than its counterpart obtained with chemical exfoliation. PMID- 30462873 TI - Mapping tissue water T1 in the liver using the MOLLI T1 method in the presence of fat, iron and B0 inhomogeneity. AB - Modified Look-Locker inversion recovery (MOLLI) T1 mapping sequences can be useful in cardiac and liver tissue characterization, but determining underlying water T1 is confounded by iron, fat and frequency offsets. This article proposes an algorithm that provides an independent water MOLLI T1 (referred to as on resonance water T1 ) that would have been measured if a subject had no fat and normal iron, and imaging had been done on resonance. Fifteen NiCl2 -doped agar phantoms with different peanut oil concentrations and 30 adults with various liver diseases, nineteen (63.3%) with liver steatosis, were scanned at 3 T using the shortened MOLLI (shMOLLI) T1 mapping, multiple-echo spoiled gradient-recalled echo and 1 H MR spectroscopy sequences. An algorithm based on Bloch equations was built in MATLAB, and water shMOLLI T1 values of both phantoms and human participants were determined. The quality of the algorithm's result was assessed by Pearson's correlation coefficient between shMOLLI T1 values and spectroscopically determined T1 values of the water, and by linear regression analysis. Correlation between shMOLLI and spectroscopy-based T1 values increased, from r = 0.910 (P < 0.001) to r = 0.998 (P < 0.001) in phantoms and from r = 0.493 (for iron-only correction; P = 0.005) to r = 0.771 (for iron, fat and off resonance correction; P < 0.001) in patients. Linear regression analysis revealed that the determined water shMOLLI T1 values in patients were independent of fat and iron. It can be concluded that determination of on-resonance water (sh)MOLLI T1 independent of fat, iron and macroscopic field inhomogeneities was possible in phantoms and human subjects. PMID- 30462874 TI - Organic farming at local and landscape scales fosters biological pest control in vineyards. AB - While organic farming practices, which are often promoted as models of ecological intensification, generally enhance biodiversity, their effects on the delivery of ecosystem services, such as biological pest control, are still unknown. Here, using a multi-scale hierarchical design in southwestern France, we examined the effects of organic farming and seminatural habitats at the local and landscape scales on biological control services of three pests, including weeds and insects, in 42 vineyards. Organic farming at the local and landscape scales was beneficial to the mean and temporal stability of biological control services, while the proportion of seminatural habitats in the landscape reduced the level of biological pest control potential. The effects of organic farming and seminatural habitats across spatial scales varied with the type of prey considered and with time. Egg moth removal rates were higher in fields under organic management compared to conventional management while weed seed removal rates increased with the proportion of organic farming in the landscape. Larval removal rates as well as seed removal rates were always more stable within time in organic fields than in conventional fields. Moreover, independently of farming system type, local variables describing the agricultural management intensity, such as pesticide use or crop productivity, were also found to be important variables explaining levels of biological control services. Pesticide use tended to reduce biological control potential, while crop productivity was associated with contrasting biological control responses depending on the pest type. Our study demonstrates the need to target multiple spatial scales and to consider farming practices, as well as the proportion of seminatural habitats, to design functional landscapes that optimize biological pest control services. PMID- 30462875 TI - Unmet supportive care needs in patients treated with total laryngectomy and its associated factors. AB - BACKGROUND: The purpose of this study was to investigate unmet supportive care needs in patients treated with total laryngectomy and its associated factors. METHODS: In this cross-sectional study, 283 patients who underwent total laryngectomy completed questions on supportive care needs (Supportive Care Needs Survey [SCNS]). Median time since total laryngectomy surgery was 7 years (range 0 37 years). The prevalence of unmet supportive care needs and its associated factors were investigated using logistic regression analyses. RESULTS: Unmet supportive care needs were highest for the head and neck cancer-specific functioning domain (53%), followed by the psychological (39%), physical and daily living (37%), health system, information, and patient support (35%), sexuality (23%), and lifestyle (5%) domains. Seventy-one percent reported at least one low, moderate, or high unmet need. Female sex, living alone, and having a voice prosthesis were positively associated with unmet needs on 1 domain (P < .05). A worse health-related quality of life was associated with unmet needs on all domains. CONCLUSION: The majority of patients who underwent total laryngectomy report at least one low, moderate, or high unmet supportive care need. PMID- 30462876 TI - Effect of increased inspiratory muscle work on blood flow to inactive and active limbs during submaximal dynamic exercise. AB - NEW FINDINGS: What is the central question of this study? Increased respiratory muscle activation is associated with neural and cardiovascular consequences via the respiratory muscle metaboreflex. Does increased sympathetic vasoconstriction originating from the respiratory musculature elicit a reduction in blood flow to an inactive limb in order to maintain blood flow to an active limb? What is the main finding and its importance? Arm blood flow was reduced while leg blood flow was preserved during mild leg exercise with inspiratory resistance. Blood flow to the active limb is maintained via sympathetic control of blood flow redistribution when the respiratory muscle-induced metaboreflex is activated. ABSTRACT: The purpose of this study was to elucidate the effect of increasing inspiratory muscle work on blood flow to inactive and active limbs. Healthy young men (n = 10, 20 +/- 2 yrs) performed two bilateral dynamic knee-extension and flexion exercise tests at 40% peak oxygen uptake for 10 min. The trials consisted of spontaneous breathing for 5 min followed by voluntary hyperventilation either with or without inspiratory resistance for 5 min (40% of maximal inspiratory mouth pressure, inspiratory duty cycle of 50% and a breathing frequency of 40 breaths/min). Mean arterial blood pressure (MAP) was acquired using finger photoplethysmography. Blood flow to the brachial artery (inactive limb) and in femoral artery (active limb) were monitored using Doppler ultrasound. MAP during exercise was higher (P < 0.05) with inspiratory resistance (121 +/- 7 mmHg) than without resistance (99 +/- 5 mmHg). Brachial artery blood flow increased during exercise without inspiratory resistance (120 +/- 31 ml/min) as compared with resting level, while it attenuated with inspiratory resistance (65 +/- 43 ml/min). Femoral artery blood flow increased at the onset of exercise and was maintained throughout exercise without inspiratory resistance (2576 +/- 640 ml/min) and was unchanged when inspiratory resistance was added (2634 +/- 659 ml/min) (P > 0.05). These results suggest that sympathetic control of blood redistribution to active limbs is facilitated, in part, by respiratory muscle induced metaboreflex. This article is protected by copyright. All rights reserved. PMID- 30462877 TI - Aerobic exercise training may improve nerve function in type 2 diabetes and pre diabetes: A systematic review. AB - Diabetic neuropathy is a major complication of type 2 diabetes. Emerging evidence also suggests that people with pre-diabetes may develop similar symptoms related to nerve dysfunction. While regular exercise provides many benefits to patients with diabetes, whether exercise influences nerve function has not been established. As such, the aim of this systematic review was to evaluate current evidence regarding the effect of exercise training on the progression and development of diabetic neuropathy. A systematic search of MEDLINE (Ovid), CINAHL, AMED, PEDro, the Cochrane Library, Embase, and Scopus databases identified a total of 12 studies that were eligible for inclusion in this systematic review. Quality rating and data extraction were performed by two independent reviewers. The 12 included studies examined people with pre-diabetes (n = 1) and with type 2 diabetes (n = 11). There was heterogeneity of study quality and exercise type and dosage among these studies. Eleven studies reported that exercise training had a positive influence on nerve function or neuropathy related symptoms; and only one study reported mild adverse events. Evidence from this systematic review suggests aerobic exercise training may positively influence nerve function among people with type 2 diabetes, with minimal risk of adverse events. Further research will be required to determine the optimal dosage of exercise training and the effect on nerve function in pre-diabetes and in women with previous gestational diabetes. This review is registered on PROSPERO (CRD42018088182). PMID- 30462878 TI - Lead and HTM free stable two-dimensional tin perovskites with suitable band gap for solar cell applications. AB - Organic-inorganic hybrid perovskites have attracted great attention over the last few years as potential light-harvesting materials for efficient and cost effective solar cells. However, the use of lead iodide in state-of-the-art perovskite devices may demonstrate an obstacle for future commercialization due to toxicity of lead. Herein we report on the synthesis and characterization of low dimensional tin-based perovskites. We found that the use of symmetrical imidazolium-based cations such as benzimidazolium (Bn) and benzodiimidazolium (Bdi) allow the formation of 2D perovskites with relatively narrow band gaps compared to traditional -NH3+ amino groups, with optical band gap values of 1.81 eV and 1.79 eV for Bn2SnI4 and BdiSnI4 respectively. Furthermore, we demonstrate that the optical properties in this class of perovskites can be tuned by formation of a quasi 2D perovskite with the formula Bn2FASn2I7. Additionally, we investigate the change in band gap in the mixed Sn/Pb solid solution Bn2SnxPbx 1I4. Devices fabricated with Bn2SnI4 show promising efficiencies of around 2.3%. PMID- 30462879 TI - Aliphatic Radical Relay Heck Reaction at Unactivated C(sp3)-H Sites of Alcohols. AB - The Mizoroki-Heck reaction is one of the most efficient methods for alkenylation of aryl, vinyl, and alkyl halides. Due to its innate nature, this protocol requires the employment of compounds possessing a halogen atom at the site of functionalization. However, the accessibility of organic molecules possessing a halogen atom at a particular site in aliphatic systems is extremely limited. Thus, a protocol that would allow a Heck reaction to occur at a specific non functionalized C(sp3)-H site would be highly desirable. Here, we report a radical relay Heck reaction which allows for a selective remote alkenylation of aliphatic alcohols at unactivated beta-, gamma- and delta-C(sp3)-H sites. The use of easily installable/removable Si-based auxiliary enables selective I-atom/radical translocation events at remote C-H sites followed by the Heck reaction. Notably, the reaction proceeds smoothly under mild visible light-mediated conditions at room temperature, producing highly modifiable and valuable alkenol products from readily available alcohols feedstocks. PMID- 30462880 TI - Design and Synthesis of Metabolically Stable t-RNA Synthetase Inhibitors derived from Cladosporin. AB - Selective and specific inhibitors of Plasmodium falciparum lysyl-tRNA synthetase represent promising therapeutic antimalarial avenues. Cladosporin was identified as a potent P. falciparum lysyl-tRNA synthetase inhibitor, with an activity against parasite lysyl-tRNA synthetase >100-fold more potent than the activity registered against the human enzyme. Despite its compelling activity, cladosporin exhibits poor oral bioavailability, a critical requirement for anti-malarial drugs. We thus entered the quest to develop metabolically stable cladosporin derived analogues, while retaining similar selectivity and potency as the natural compound. Chemogenomic profiling of our designed library allowed us to open the door to an entirely innovative SAR studies, shedding the light on a structural evidence of a privileged scaffold with a unique activity against tRNA synthetases. PMID- 30462881 TI - Unnecessary abdominal interventions in patients with hereditary angioedema. AB - BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disorder that leads to recurrent development of mucosal and dermal swelling. It is mediated by bradykinin, and can affect virtually any part of the human body, including the gastrointestinal tract, the extremities, and the laryngeal and pharyngeal regions. Safe and potent drugs are available for acute and prophylactic treatment of HAE. Owing to its unspecific symptoms and unique manifestations, HAE is often misdiagnosed and treated incorrectly. Abdominal edema in particular can resemble appendicitis or cholecystitis, and is therefore often treated with unnecessary surgical procedures. We performed a questionnaire study to quantify this issue. PATIENTS AND METHODS: We designed questionnaires for HAE patients and probands without HAE. The patient-control ratio was chosen at 1 : 2. RESULTS: Compared with the general population, HAE patients are subject to a significantly greater number of invasive diagnostic and therapeutic interventions. Our study showed that the HAE patients were 2.5 times more likely to undergo abdominal surgery (including gynecological and urological procedures) than the individuals without HAE (p = 0.007). The number of operations per patient correlated with the period (number of years) between the onset of symptoms and diagnosis (correlation coefficient 0.511; Spearman). Furthermore, twice as many appendectomies were performed on HAE patients (18.9 % vs. 37.7 %). Our results also showed that the HAE patients were 2.3 times more likely to undergo a gastroscopy than the control group without HAE (p = 0.003). CONCLUSIONS: Patients with rare diseases such as HAE not only suffer from the effects of the disease itself. The conditions are often misdiagnosed for years owing to the general lack of knowledge about such diseases and unspecific manifestations. This leads not only to erroneous and ineffective treatment, but also to needless invasive diagnostic and therapeutic medical procedures. It is therefore important to increase the general knowledge and awareness of orphan diseases such as HAE with a view to improving diagnosis and treatment, minimizing the patients' suffering and enhancing their quality of life. PMID- 30462883 TI - Investigating the ability of the microbial model Cunninghamella elegans for the metabolism of synthetic tryptamines. AB - Tryptamines can occur naturally in plants, mushrooms, microbes and amphibians and synthetic tryptamines have been sold as New Psychoactive Substances (NPS), due to their hallucinogenic effects. When it comes to NPS, metabolism studies are of crucial importance, due to the lack of pharmacological and toxicological data. In order to study in vitro and in vivo metabolism of xenobiotica, different approaches can be taken. The zygomycete fungus Cunninghamella elegans (C. elegans) can be used as a microbial model for the study of drug metabolism. The current study investigated the biotransformation of four natural occurring and synthetic tryptamines (N,N-Dimethyltryptamine (DMT), 4-hydroxy-N-methyl-N ethyltryptamine (4-HO-MET), N,N-di allyl-5-methoxy tryptamine (5-MeO-DALT) and 5 methoxy-N-methyl-N-isoporpoyltryptamine (5-MeO-MiPT)) in C. elegans after incubation for 72 hours. Metabolites were identified using liquid chromatography high resolution-tandem mass spectrometry (LC-HR-MS/MS) with a quadrupole time-of flight (QqToF) instrument. Results were compared to already published data on these substances. C. elegans was capable to produce all major biotransformation steps, hydroxylation, N-oxide formation, carboxylation, deamination and demethylation. On average 63 % of phase I metabolites found in literature could also be detected in C. elegans. Additionally, metabolites specific for C. elegans were identified. Therefore, C. elegans is a suitable complementary model to other in vitro or in vivo methods to study the metabolism of naturally occurring or synthetic tryptamines. PMID- 30462882 TI - Single Domain 10 nm Ferromagnetism Imprinted on Superparamagnetic Nanoparticles Using Chiral Molecules. AB - The rapid growth in demand for data and the emerging applications of Big Data require the increase of memory capacity. Magnetic memory devices are among the leading technologies for meeting this demand; however, they rely on the use of ferromagnets that creates size reduction limitations and poses complex materials requirements. Usually magnetic memory sizes are limited to 30-50 nm. Reducing the size even further, to the ~10-20 nm scale, destabilizes the magnetization and its magnetic orientation becomes susceptible to thermal fluctuations and stray magnetic fields. In the present work, it is shown that 10 nm single domain ferromagnetism can be achieved. Using asymmetric adsorption of chiral molecules, superparamagnetic iron oxide nanoparticles become ferromagnetic with an average coercive field of ~80 Oe. The asymmetric adsorption of molecules stabilizes the magnetization direction at room temperature and the orientation is found to depend on the handedness of the chiral molecules. These studies point to a novel method for the miniaturization of ferromagnets (down to ~10 nm) using established synthetic protocols. PMID- 30462884 TI - Short Communication: West Nile Fever imported from Austria to Germany. AB - This is the first report of West Nile virus infection imported by a traveler returning from a neighboring country to Germany (Austria). Physicians should be aware of the expansion of WNV endemic areas in Europe. This article is protected by copyright. All rights reserved. PMID- 30462885 TI - The mediating effect of sleep disturbance on the relationship between non malignant chronic pain and suicide death. AB - IMPORTANCE: Few studies have examined the relationship between non-malignant chronic pain (NMCP) and suicide death and even fewer have specifically explored what role sleep disturbance might play in the association between NMCP and suicide death. OBJECTIVE: To assess whether sleep disturbance mediates the relationship between NMCP and suicide death. DESIGN: This case-control study included 2,674 individuals who died by suicide between 2000-2013 (cases) and 267,400 matched individuals (controls). SETTING: Eight Mental Health Research Network (MHRN)-affiliated healthcare systems. PARTICIPANTS: All cases and matched controls were health plan members for at least 10 months during the year prior to the index date. MAIN OUTCOMES AND MEASURES: Sociodemographic data and diagnosis codes for NMCP and sleep disorders were extracted from the MHRN's Virtual Data Warehouse. Suicide mortality was identified using ICD-10 codes from official government mortality records matched to health system records. RESULTS: After accounting for covariates, there was a significant relationship between NMCP and sleep disturbance; those who were diagnosed with NMCP were more likely to develop subsequent sleep disturbance. Similarly, sleep disturbance was significantly associated with suicide death. Finally, a significant indirect effect of NMCP on suicide death, through sleep disturbance, and a non-significant direct effect of NMCP on suicide death provide support for a fully mediated model. CONCLUSIONS AND RELEVANCE: There is a need for clinicians to screen for both sleep disturbance and suicidal ideation in NMCP patients and for health systems to implement more widespread behavioral treatments that address comorbid sleep problems and NMCP. This article is protected by copyright. All rights reserved. PMID- 30462886 TI - Generation of monoclonal antibodies against foot-and-mouth disease virus SAT 2 and the development of a lateral flow strip test for virus detection. AB - Foot-and-mouth disease (FMD) remains a major economic concern for the livestock productivity in many developing countries and a continued threat to countries that are disease free because of its potential devastating impact on agricultural, food chain and tourism sectors. FMD virus (FMDV) is recognized as having seven serotypes: O, A, C, Asia 1, and South African Territories (SAT) 1, 2, 3, and multiple subtypes within each serotype. FMD outbreaks due to SAT 2 have been reported in many African countries. The development of a rapid and easily performed test for FMD detection is critical for controlling FMD outbreaks and containing its spread. The present project developed a lateral flow immunochromatographic (LFI) strip test for the rapid detection of FMDV SAT 2. A panel of monoclonal antibodies (mAbs) against FMDV serotype SAT 2 was produced and characterized. One mAb (#10) was selected as the capture mAb because it reacted to all 23 SAT 2 isolates archived at the National Center for Foreign Animal Disease. The LFI strip test was developed using biotin-conjugated mAb #10, and the colloid gold-conjugated FMDV serotype-independent mAb as the detection mAb. A generic RapidAssay Device (gRAD) with one test line and a control line was used for the test. The LFI strip test detected all 23 tested SAT 2 isolates and recent outbreak strains. The results indicated that the diagnostic specificity and sensitivity of the LFI strip test were greater than the double antibody sandwich (DAS) DAS ELISA. The ability of the LFI strip test to produce rapid diagnostic results will be useful for early on-site diagnosis during FMD outbreaks. This article is protected by copyright. All rights reserved. PMID- 30462887 TI - Development of an economic ultra-fast liquid chromatography with tandem mass spectrometry method for trace analysis of multi-class mycotoxins in Polygonum multiflorum. AB - Rapid, economic and highly-effective determination of multiple mycotoxins in complex matrices has given huge challenges for the analytical method. In this study, an economic analytical strategy based on sensitive and rapid ultra-fast liquid chromatography coupled to hybrid triple quadrupole/linear ion trap mass spectrometry technique was developed for the determination of seven mycotoxins of different chemical classes (aflatoxin B1 , B2 , G1 and G2 , ochratoxin A, T-2 toxin and HT-2 toxin) in Polygonum multiflorum. Target mycotoxins were completely extracted using a modified quick, easy, cheap effective, rugged and safe without additional clean-up steps. The types of extraction solvents and adsorbents for the extraction procedure were optimized to achieve high recoveries and reduce co extractives in the final extracts. Due to significant matrix effects for all analytes (<=68.9% and >=110.0%), matrix-matched calibration curves were introduced for reliable quantification, exploring excellent linearity for the seven mycotoxins with coefficients of determination > 0.9992. The method allowed high sensitivity with limit of detection in the range of 0.031-2.5 MUg/kg and limit of quantitation in the range of 0.078-6.25 MUg/kg, respectively, as well as satisfactory precision with relative standard deviations lower than 8%. Recovery rates were between 74.3% and 119.8% with relative standard deviations below 7.43%. The proposed method was successfully applied for 24 batches of Polygonum multiflorum samples, and 6 samples were found to be positive with aflatoxin B1 , B2 , G1 or ochratoxin A. The method with significant advantages including minimum analytical time, low time and solvent consumption, and high sensitivity would be a preferred candidate for economic analysis of multi-class mycotoxins in complex matrices. This article is protected by copyright. All rights reserved. PMID- 30462888 TI - A Study of the Interaction Between Cucurbit[8]uril and Alkyl-Substituted 4 Pyrrolidinopyridinium Salts. AB - The interaction between cucuribit[8]uril (Q[8]) and a series of 4 pyrrolidinopyridinium salts bearing aliphatic substituents at the pyridinium nitrogen, namely 4-(C4 H8 N)C5 H5 NRBr, where R=Et (g1), n-butyl (g2), n-pentyl (g3), n-hexyl (g4), n-octyl (g5), n-dodecyl (g6), has been studied in aqueous solution by 1 H NMR spectroscopy, electronic absorption spectroscopy, isothermal titration calorimetry and mass spectrometry. Single crystal X-ray diffraction revealed the structure of the host-guest complexes for g1, g2, g3, and g5. In each case, the Q[8] contains two guest molecules in a centrosymmetric dimer. The orientation of the guest molecule changes as the alkyl chain increases in length. Interestingly, in the solid state, the inclusion complexes identified are different from those observed in solution, and furthermore, in the case of g3, Q[8] exhibits two different interactions with the guest. In solution, the length of the alkyl chain plays a significant role in determining the type of host-guest interaction present. PMID- 30462891 TI - Employee Restrictive Covenants in the Practice of Dentistry. PMID- 30462889 TI - Calcium/calmodulin-dependent protein kinase 4 promotes GLUT1-dependent glycolysis in systemic lupus erythematosus. AB - OBJECTIVE: We sought to clarify the significance of immunometabolism in the pathological condition of systemic lupus erythematosus (SLE) and to determine the effect of calcium/calmodulin-dependent protein kinase 4 (CaMK4) on T-cell metabolism. METHODS: We performed metabolomic profiling using capillary electrophoresis mass spectrometry in naive T cells from MRL/lpr mice treated with anti-CD3/28 antibodies in the absence or presence of a CaMK4 inhibitor (KN-93). We examined the expression of GLUT1 and CaMK4 in CD4+ T cells from healthy controls (HCs: n=16), patients with inactive SLE (n=13), and patients with active SLE (n=14) by flowcytometry and quantitative PCR. We performed in vitro experiments to determine the effect of KN-93 on the expression of GLUT1 during Th17 differentiation in T cells from SLE patients. RESULTS: CaMK4 inhibition significantly decreased the levels of glycolytic intermediates such as glucose-6 phosphate, fructose-6-phosphate, fructose-1,6-diphosphate, pyruvate, and lactate, whereas it did not affect the levels of the pentose phosphate pathway intermediates such as 6-Phospho-D-gluconate, ribulose-5-phosphate, ribose-5 phosphate and phosphoribosyl pyrophosphate. The expressions of GLUT1 and CaMK4 in effector memory CD4+ T cells were significantly higher in active SLE patients compared to the HCs and inactive SLE patients. A functional analysis revealed that CaMK4 inhibition decreased the expression of GLUT1 during Th17 cell differentiation, followed by a reduction of IL-17 production. CONCLUSION: Our results indicate that (1) the activity of CaMK4 could be responsible for glycolysis, which contributes to the production of IL-17, and (2) CaMK4 may contribute to an aberrant expression of GLUT1 in T cells from active SLE patients. This article is protected by copyright. All rights reserved. PMID- 30462890 TI - Unilocular Radiolucency of the Anterior Mandible. PMID- 30462893 TI - Consistent Interpretation. Joint Commission Surveyors' Observations on R1.01.03.01, EP 13. PMID- 30462892 TI - Understanding Key Changes to the Life Safety Standards. PMID- 30462894 TI - Compliance Data for Deemed Psychiatric Hospitals Using SAFER Methodology. PMID- 30462895 TI - Posting: Spring E-dition for Accreditation and Certification Manuals. PMID- 30462896 TI - ESC Form Redesigned to Promote Successful Submission. PMID- 30462897 TI - Ordering and Implementing Medication Titration Orders Safely. PMID- 30462898 TI - Isolated pelvic perfusion in treatment for malignant tumors. AB - Rationale and feasibility of isolated pelvic perfusion (IPP) as a high-tech treatment modality for patients with pelvic malignancies was studied and analyzed based on the systematic review of the literature. Indications, techniques and regimens of IPP are reviewed. There is a focus on anticancer agents for IPP and methods of complete vascular isolation of the perfusated region. Data on the short- and long-term outcome of patients after IPP are presented. To the best of authors' knowledge this is the first Russian article regarding application of IPP in oncology practice. PMID- 30462899 TI - Suppressor cells - the basis of the immunopathogenesis of cancer. AB - There are numerous data in experimental and clinical medicine that convincing evidence on the leading role of the immune system in the pathogenesis of tumor diseases. Exactly immune cells such as cytotoxic T lymphocytes, NK cells, macrophages and dendritic cells have the ability to kill tumor cells. Under normal conditions the activity of these cells is a factor of inhibition proliferation and differentiation of tumor cells. An appearance of tumor itself, as uncontrolled cell growth and clinical manifestation, says that it was changed the cytotoxic activity of the cells causing tumor immunity. The main factor, if not the only reason for the decline of anti-tumor activity of the cells, is the formation of powerful extra- and inside-tumor suppressor mechanisms suppressing cytotoxic activity of anti-tumor immune-competent cells and allowing tumor cells to avoid surveillance by the immune system. It is showed that T and B cells, macrophages, and cells of myeloid origin suppressors possess these immunosuppressive properties. Therefore, in the future, methods to suppress functional activity of cells suppressors of various geneses can be the basis for immunotherapy of tumor growth. PMID- 30462900 TI - Possibilities of estimating the prognosis for development of preinvasive cervical neoplasia by the latest molecular biology methods. AB - Secondary prevention of cervical cancer is the identification and treatment for preinvasive forms of the disease, which include cervical intraepithelial neoplasia (CIN). The traditional method of identification of CIN is cytological however the sensitivity and specificity of this method is limited. The efficacy of a test for human papillomavirus as well as new molecular-biological methods for assessing the prognosis of development of dysplasia and choice of appropriate treatment tactics are still in the process of discussion. The article contains information about different possibilities of using molecular-biological methods for assessing the prognosis of development of CIN and cervical cancer. PMID- 30462902 TI - Radioprotector indralin at early and late manifestations of local radiation injuries. AB - Experimental model of acute local radiation injuries (LRI) was the degree of radiation skin burns of mouse paws, observed through the 10 day within 1 month after local gamma -60Co-irradiation at the doses of 20-45 Gy. For late local radiation injuries with a maximum of over 6 months after exposure to radiation, model was the contracture of animal paws and post-radiation amputation of limbs of the mouse. In the experiments on mice radioprotector indralin (B-190) IP as direct alpha1-adrenomimetic has a expressed protective effect on reducing acute and late LRI, equal in terms of dose reduction factor (DRF) 1.4 -1.5 that was comparable to their efficacy during radiation injuries of hematopoietic tissues. Indralin fully retain its radioprotective properties (DRF = 1.5-1.7) in the condition of repeated radioprotector administration through one day at total dose of 57 Gy (three times 19 Gy) of fractionated gamma -irradiation. The protective effect of indralin improved at parenteral administration in the place of local irradiation. The local topical application of indralin in the ointments or in solution of dimethylsulfoxide has radioprotective effect, equal in the term of DRF to 1.3 -1.5 at acute and late LRI. Indralin also possessed a expressed radioprotective properties (DRF = 1.5) in decrease radiation injuries of salivary glands during local irradiation of head of rats. PMID- 30462901 TI - Small heat shock proteins and the ubiquitin-proteasome system in malignant tumors. AB - It is necessary to maintain the safety of the cell proteome for the operation and adequate biological response of tumor cells to changing conditions, which is provided by chaperones and ATP-dependent proteases. Molecular chaperones, which include the small heat shock proteins, carry out folding, refolding and misfolding of proteins, support functional activity of intracellular proteins. Proteases, mainly proteasome, degrade abnormal, damaged and fulfilling its function proteins. The review presents modern data on the role of the proteasome and heat shock proteins in malignant tumors as well as the mechanism of interaction of these systems in the cell. PMID- 30462903 TI - Melatonin in complex treatment for colorectal cancer patients. AB - Colorectal cancer is closely related to changes in the immune status at all stages of the disease. The main method of treatment for colorectal cancer is surgery. Surgical intervention as any pathological impact on the body from the outside is leading to suppression of both humoral and cellular immunity. Melatonin can be used to stimulate the immune system acting as a protective agent. Currently melatonin is used in oncology practice rather modest - as part of a complex postoperative therapy. Melatonin in pharmaceutical concentrations acts as differentiation factor reducing infiltrative and metastatic potential by restoring the links between signaling molecules and inhibiting existing cell-cell contacts, which can be used in the preoperative therapy. PMID- 30462904 TI - Dynamics of morbidity, histological structure, contingents and survival of patients with malignant tumors of the lip (population-based study). AB - Introduction: Malignant tumors of the lip (C00) are rare tumor, and mainly affect men. Annually in Russia there are nearly 3000 new cases of malignant tumors of the lip (2011 - 2013). In 2000 there were registered more than 5000 cases. The positive dynamics of morbidity and mortality from this location was marked. Separately to analyze the dynamics of mortality from malignant tumors of the lip cannot be performed because the State Statistics Committee provides only aggregated data for all three-digit rubrics - malignant tumors of the lip, oral cavity and pharynx (S00-14). From 2000 to 2013 the number of deaths in this group according to both sexes increased from 8980 to 9445 or by 5.2%. According to the International Agency for Research on Cancer (IARC) the incidence rate of the population in various countries is also small (except Australia). Aims and objectives: To conduct a study of prevalence of malignant tumors of the lip at the population-based level and to estimate survival rates. Methods: For the first time in Russia there were estimated the rates of morbidity and survival of patients with malignant tumors of the lip by international standards. Paying attention to limited parameters that characterize malignant tumors of the lip in the state report, the main focus was aimed at database of Russia's first Population-based Cancer Registry of St. Petersburg working according to international standards. For the first time in Russia there is presented dynamics of a 5-year observed and relative survival of patients with malignant tumors of the lip. Results: For the first time in Russia there is provided the structure of morbidity of malignant tumors of the lip according to the 4th digits of ICD-10. There is underlined its stable distribution with decreasing of S00.9 rubrics (undefined parts of lips), showed a significant reduction in morbidity and average relative 5-year survival closed to the European rates. PMID- 30462905 TI - Breast cancer mortality in the Republic of Buryatia. AB - Breast cancer is the most common cause of cancer death in the Republic of Buryatia as a whole and among urban population (13.3 % and 16.0 %, respectively), and the second place belongs to rural population (11.8). Standardized mortality rates in the Republic of Buryatia (15.5+/-0.9) are 9.9% lower than the average for Russian Federation (17.0+/-0.1). The relationship between the national composition of the population of the municipal districts of Buryatia and breast cancer mortality rate has been found. Breast cancer mortality rates are higher for newcomers than for indigenous population (2.4 times higher among urban population and 2.3 times among rural population). Breast cancer mortality rate is expected to be decreased by 9.9% in the Republic as a whole, by 10.0% among urban population and also stability of mortality among rural population (2.3%). PMID- 30462906 TI - Pancreatic cancer (data of the Registry in Novosibirsk, risk factors, prevention options). AB - Dynamics of morbidity and mortality from pancreatic cancer in the population of Novosibirsk according to the Population-based Cancer Registry and the Registry of total mortality for 25 years (1988-2012) were analyzed. The morbidity and mortality for the studied period decreased slightly. Incidence rates in middle aged males are higher than in females but this difference is leveled after 75 years. Possible risk factors for pancreatic cancer as well as issues of screening and prevention are discussed. PMID- 30462907 TI - Technology of minimally invasive cryodestruction of recurrent tumors. AB - In oncology practice it has been introduced minimally invasive technology of puncture access for cryodestruction of tumors of various sites as well as obtained positive clinical results. PMID- 30462908 TI - Radical surgical treatment of elderly patients with gastric cancer. AB - To analyze the early results of radical surgery for gastric cancer in patients > 75 years. In the period between Jan. 2013 and June 2015 there were 25 radical operations in elderly (>= 75 years) patients with gastric cancer. The following outcomes are presented: bloodloss, duration of surgery, mortality and morbidiy according to Dindo-Clavien classification, length of stay. There were 12 total and 13 distal gastrectomies, including 8 laparoscopic procedures (2 - total laparoscopic gastrectomies), all with D2 lymph node dissection. Mean bloodloss constituted 50+/-64 ml (0-300 ml), mean duration of surgery 220+/-70 min (140-360 min). There was no in-hospital mortality, but one patient died 2 weeks after discharge because of an unclear intraluminal bleeding. Mild complications (Dindo Clavien I-II) were found in 6 patients, severe in 11 patients. In 6 patients repeated laparotomies were necessary. Mean length-of-stay constituted 13+/-17 (5 63) days. Radical gastric cancer surgery in the elderly patients is feasible. A prerequisite is a thorough pre-operative examination. This type of surgery shall be practiced in highly specialized centers after detailled control of patients' comorbidity. PMID- 30462909 TI - Efficacy of photodynamic therapy for basal cell carcinoma using photosensitizers of different classes. AB - The paper presented results of photodynamic therapy for 139 patients with basal cell carcinoma. We conducted a study of the efficacy and safety of four methods of photodynamic therapy. There were used the following photosensitizers: photohem, photosens, photolon and photodithazine. Photodynamic therapy using photosensitizers of chlorine series (photolon and photoditazin) provides a better long-term results improving disease-free 3-year survival rate to 90.4% and 92.3%, respectively compared to 54.7% and 71.1% in groups, in which treatment was restricted by photohem and photosens. PMID- 30462910 TI - Combined treatment for unresectable head and neck tumors using radiotherapy in combination with regional chemotherapy. AB - This article is concerned with treatment for unresectable epithelial tumors of the head and neck. It gives a detailed account of the experience of radiation therapy in combination with selective regional chemotherapy administration as a method of combined treatment. According to the study result the complete tumor responce was demonstrated in 5.3% cases; participal tumor responce - in 80.4%; stable disease - in10.7%; progression of the tumor proces - in 3.6%. The reported adveres events and their treatment details are described for all severity as per NCI-CTCAE. The performed analysis suggests the preliminary study treatment results and the advantages of the selected scheme. PMID- 30462911 TI - Features of contrast enhancement in different methods of multislice computed tomography. AB - The purpose of this study was a comparison of the X-ray density in certain organs and anatomical structures and the determination of the radiation exposure during venous-arterial MSCT scanning and classical two-phase CT of organs of the abdominal cavity. It has been established that the technique of venous-arterial MSCT scanning provided a significant reduction of radiation dose during CT of organs of the abdominal cavity and could be used as an alternative to two-phase examination in the process of dynamic monitoring of cancer patients. PMID- 30462912 TI - Effectiveness of cytological diagnosis of breast cancer metastases in regional lymph nodes. AB - Results are presented of preoperative and intraoperative cytological diagnosis of breast cancer metastases in regional lymph nodes in 84 patients. Of them in 42 there was studied material of fine-needle aspiration biopsy, in 42 - smears of sentinel lymph nodes. In all cases cytohistological comparisons were carried out. The effectiveness of cytological examination of material of fine-needle aspiration biopsy was 90.5%. Urgent cytology of smears of sentinel lymph nodes allowed revealing metastases in 5 of 10 patients. The use of immunohistochemical examination increases the likelihood of detection of micrometastases and isolated tumor cell clusters. PMID- 30462913 TI - THE STUDY OF POLYMORPHISMS OF XPD GENE A751C IN LUNG CANCER PATIENTS WITH DIFFERENT CLINICAL AND MORPHOLOGICAL CHARACTERISTICS OF TUMOR. AB - There were studied distribution of polymorphic variants of gene of repair of DNA XPD A751C in lung cancer depending on histological type of tumor (small cell / non-small cell lung cancer) and the prevalence of tumor process (with foci / without foci of metastasis). It was found a significant increase in the incidence of minor allele C, CC and AC genotypes of the polymorphic site of gene XPD A751C in patients with lung cancer. We estimated relative risks of lung cancer development in carriers of polymorphic variants of gene XPD A751C. The heterozygous genotype AC polymorphism of gene XPD A751C is characterized by the greatest risk of developing lung cancer with small cell histological type. Homozygous CC genotype of the polymorphic site of gene XPD A751C is associated with non-small cell lung cancer development. Statistically significant differences in the distribution of polymorphic variants of gene A751C XPD depending on spread of cancer were not received. PMID- 30462914 TI - Subungual melanoma. Features of clinic, diagnostics and treatment. AB - Subungual melanoma (SM) is a rare tumor and is 3-5% of all malignant skin melanoma. There was analyzed database of the Population-based Cancer Registry of the N.N.Petrov Research Institute of Oncology of St. Petersburg, the first in Russia, including information on more than 2,500 patients with malignant melanoma, of which for the period from 1986 to 2014 there were selected cases of acral lentiginous melanoma - 85 patients (3.4%). This group included 40 patients with SM (1.6%). More than half of patients were referred to a specialist in a year since the appearance of the first symptoms of the disease. Distribution of SM patients by Stages was as follows: 30% (n = 12) cases of the disease were identified in the Stage I, 40% (n = 16) - in the Stage II, 25% (n = 10) - in the Stage III and 5% (n = 2) - in the Stage IV. The most commonly misdiagnosed cases were considered as inflammation, fungal or other lesions of the nail phalanx. Histologically SM patients met all morphological types of melanoma. Over half of patients had Clark IV and V levels of invasion. The mean value of tumor by Breslow thickness was 5.5 mm. All patients with SM underwent radical surgery in the following volumes: 75% (30 cases) - amputation at the middle level (n = 16) and basic (n = 14) phalanges; 20% (8 cases) - disarticulation at the level of the proximal interphalangeal (n = 6) and metatarsusphalanx (n = 2) joints; 5% (n = 2) - resection metacarpal and metatarsal. Inguinal-femoral lymphadenectomy was performed in 8 patients with metastatic lesion of regional lymph nodes. PMID- 30462915 TI - Results of surgical treatment for stress urinary incontinence in prostate cancer patients after radical prostatectomy using modified version of transobturator synthetic sling. AB - Approximately 6-9% of prostate cancer patients suffering from incontinent of urine after radical prostatectomy are in need of surgical correction of this condition after failure of conservative treatment for 12 months. The study involved 65 patients who were divided into 2 groups of follow-up. Group No1 (n = 31) - patients with mild urinary incontinence, group No2 (n = 34) - patients with medium (moderate) urinary incontinence. Follow-up median of the group No1 was 36 months, an average of 39.5 (12-84) months. Follow-up median of the group No2 was 36 months, an average of 41.65 (12-84) months. The overall efficiency of surgery in both groups was 84% and 82.4%. PMID- 30462916 TI - Enhanced Electrochemical Stability of TiO2-Protected, Al-doped ZnO Transparent Conducting Oxide Synthesized by Atomic Layer Deposition. AB - Atomic layer deposition (ALD) is a convenient method for fabricating hierarchically structured materials as the basis for complex, three-dimensional electrode designs in electrocatalytic and photoelectrochemical applications. Transparent conducting oxides (TCOs) like Sn-doped In2O3 (ITO) and Al-doped ZnO (AZO) are useful as current collectors for semiconductors and electrocatalysts. While ITO and AZO can be grown by ALD, they are only stable in a narrow range of pH. To develop structured electrodes for use in the acidic and basic environments common for electrochemical applications like water splitting, it is important to identify methods for fabricating stable TCO layers by ALD. Ultra-thin coatings of stable materials can be used to protect otherwise unstable electrochemical interfaces while maintaining the desired function. Here, we describe experiments to characterize the chemical and electrochemical stability ALD-deposited AZO TCO thin films protected by 10nm TiO2 overlayer. The addition of a TiO2 protection layer is shown to improve the chemical stability of AZO by orders of magnitude compared to unprotected, yet otherwise identically prepared AZO films. The electrochemical stability is enhanced accordingly in both acidic and basic environments. We demonstrate that TiO2-protected AZO can be used as a TCO for both the cathodic hydrogen evolution (HER) and anodic water oxidation (OER) half reactions of electrochemical water splitting in base and for HER in acid when the appropriate electrocatalysts are added. As a result, we show that ALD can be used to synthesize a chemically stable TCO heterostructure, expanding the possible combinations of materials and electrochemical environments available for building complex photoelectrode architectures. PMID- 30462917 TI - ASSESSING AUTOMATED SAMPLE PREPARATION TECHNOLOGIES FOR HIGH-THROUGHPUT PROTEOMICS OF FROZEN WELL CHARACTERIZED TISSUES FROM SWEDISH BIOBANKS. AB - Large cohorts of carefully collected clinical tissue materials play a central role in acquiring sufficient depth and statistical power to discover disease related mechanisms and biomarkers of clinical significance. Manual preparation of such large sample cohorts requires experienced laboratory personnel. This carries other possible downsides such as low throughput, high risk of errors and low reproducibility. In this work, three automated technologies for high-throughput proteomics of frozen sectioned tissues were compared. The instruments evaluated included the Bioruptor for tissue disruption and protein extraction; the Barocycler, which is able to disrupt tissues and digest the proteins; and the AssayMAP Bravo, a micro-chromatography platform for protein digestion, peptide desalting and fractionation. Wide varieties of tissue samples from rat spleen, malignant melanoma and pancreatic tumors were used for the assessment. The three instruments displayed reproducible and consistent results, as was proven by high correlations and low coefficients of variation between technical replicates and even more importantly, between replicates that were processed in different batches or at different time points. The results from this study allowed us to integrate these technologies into an automated sample preparation workflow for large-scale proteomic studies that are currently ongoing. Data are available via ProteomeXchange with identifiers PXD010296 and PXD011295. PMID- 30462918 TI - Molecular Tunnel Junction-Controlled High-Order Charge Transfer Plasmon and Fano Resonances. AB - Quantum tunneling plays an important role in coupled plasmonic nanocavities with ultrasmall gap distances. It can lead to intriguing applications such as plasmon mode excitation, hot carrier generation, and construction of ultracompact electro optic devices. Molecular junctions bridging plasmonic nanocavities can provide a tunneling channel at moderate gap distances and therefore allow for the facile fabrication of quantum plasmonic devices. Herein we report on the large-scale bottom-up fabrication of molecular junction-bridged plasmonic nanocavities formed from Au nanoplate-Au nanosphere heterodimers. When the molecular junction turns from insulating to conductive, a distinct spectral change is observed, together with the emergence of a high-order charge transfer plasmon mode. The evolution of the electron tunneling-induced plasmon mode also greatly affects the Fano resonance feature in the scattering spectrum of the individual heterodimers. The molecular conductance at optical frequencies is estimated. The molecular junction assisted electron tunneling is further verified by the reduced surface-enhanced Raman intensities of the molecules in the plasmonic nanocavity. We believe that our results provide an interesting system that can boost the investigation on the use of molecular junctions to modulate quantum plasmon resonances and construct molecular plasmonic devices. PMID- 30462919 TI - Highly Photostable and Fluorescent Microporous Solids Prepared via Solid-State Entrapment of Boron Dipyrromethene Dyes in a Nascent Metal-Organic Framework. AB - We report a strategy to synthesize highly emissive, photostable, microporous materials by solid-state entrapment of boron dipyrromethene (BODIPY) fluorophores in a metal-organic framework. Solvent-free mechanochemistry or accelerated aging enabled quantitative capture and dispersal of the PM605 dye within the ZIF-8 framework starting from inexpensive, commercial materials. While the design of emissive BODIPY solids is normally challenged by quenching in a densely packed environment, herein reported PM605@ZIF-8 materials show excellent emissive properties and to the best of our knowledge an unprecedented ~10-fold enhancement of BODIPY photostability. Time-resolved and steady-state fluorescence studies of PM605@ZIF-8 show that interchromophore interactions are minimal at low dye loadings, but at higher ones lead to through-pore energy transfer between chromophores and to aggregate species. PMID- 30462920 TI - Tunable Metal-Organic Frameworks Enable High Efficiency Cascaded Adsorption Heat Pumps. AB - Rising global standards of living coupled with the recent agreement to eliminate hydrofluorocarbon refrigerants are creating intense pressure to develop more sustainable climate control systems. In this vein, the use of water as the refrigerant in adsorption heat pumps is highly attractive, but such adsorption systems are constrained to large size and poor efficiency by the characteristics of currently employed water sorbents. Here we demonstrate control of the relative humidity of water uptake by modulating the pore size in a family of isoreticular triazolate metal-organic frameworks. Using this method, we identify a pair of materials with stepped, non-overlapping water isotherms that can function in tandem to provide continuous cooling with a record ideal coefficient of performance of 1.63. Additionally, when used in a single-stage heat pump, the microporous Ni2Cl2BBTA has the largest working capacity of any material capable of generating a 25 degrees C difference between ambient and chiller output. PMID- 30462921 TI - Solvation Properties of Silver and Copper Ions in a Room Temperature Ionic Liquid: A First-Principles Study. AB - Understanding the behavior of metal ions in room temperature ionic liquids (ILs) is essential for predicting and optimizing performance for technologies like metal electrodeposition; however, many mechanistic details remain enigmatic, including the solvation properties of the ions in ILs and how they are governed by the intrinsic interaction between the ions and the liquid species. Here, we utilize first-principles molecular dynamics simulations to unravel and compare the key structural properties of Ag^{+} and Cu^{+} ions in a common room temperature ionic liquid, 1-ethyl-3-methylimidazolium trifluoromethanesulfonate. We find that, when compared to Cu^{+}, the larger Ag^{+} shows a more disordered and flexible solvation structure with more frequent exchange of the IL species between its solvation shells. In addition, our simulations reveal an interesting analog in the solvation behavior of the ions in the ionic liquid and aqueous environments, particularly in the effect of the ion electronic structures on their solvation properties. This work provides fundamental understanding of the intrinsic properties of the metal ions in the IL, while offering mechanistic understanding and strategy for future selection of ILs for metal electrodeposition processes. PMID- 30462922 TI - Dendronized Poly(2-oxazoline) Displays within only Five Monomer Repeat Units Liquid Quasicrystal, A15 and sigma Frank-Kasper Phases. AB - Liquid quasicrystals (LQC) have been discovered in self-assembling benzyl ether, biphenylmethyl ether, phenylpropyl ether, biphenylpropyl ether and some of their hybrid dendrons and subsequently in block copolymers, surfactants and other assemblies. These quasiperiodic arrays, which lack long-range translational periodicity, are approximated by two Frank-Kasper periodic arrays, Pm3 n cubic (Frank-Kasper A15) and P42/ mnm tetragonal (Frank-Kasper sigma), which have been discovered in complex soft matter in the same order and compounds. Poly(2 oxazoline)s dendronized with (3,4) nG1 minidendrons (where n denotes an alkyl chain, C nH2 n+1) self-organize into the Pm3 n cubic phase ( n = 14 and 15) and, as reported recently, the P42/ mnm tetragonal phase ( n = 16). However, no LQC of a poly(2-oxazoline) is yet known. Here we report the synthesis, structural and retrostructural analysis of a dendronized poly(2-oxazoline) with n = 17 which self-organizes not only into the LQC but also in the above two Frank-Kasper approximants. All three phases are observed from the same polymer within a very narrow range of degree of polymerization that corresponds to only five monomer repeat units (5 <= DP <= 10). The formation of the Pm3 n cubic, P42/ mnm tetragonal and LQC phases from a single polymer chain within such a narrow range of DP raises the questions of how and why each of these phases is self-organized. This system may provide a model for theoretical investigations into the self organization of soft matter into Frank-Kasper and related periodic and quasiperiodic arrays. PMID- 30462923 TI - Effectiveness of Secondary School Conceptual Physical Education: A 20-Year Longitudinal Study. AB - BACKGROUND: Previous research findings from Project Active Teen demonstrated the effectiveness of high school conceptual physical education (CPE) in promoting active lifestyles. METHOD: This study followed Project Active Teen participants 20 years after graduation from high school and 24 years after taking a CPE class. Physical activity behaviors were assessed using the same procedures as previous Project Active Teen studies. Activity patterns were compared with patterns while in high school and shortly after high school graduation. Activity patterns were also compared with a national sample of age-equivalent adults. RESULTS: Twenty years after high school graduation, former CPE students were less likely to be inactive and more likely to be moderately active than when in high school and were less likely to be inactive and more likely to be moderately active than national sample age-equivalent peers. They were typically not more vigorously physically active than comparison groups. CONCLUSION: Results support the long term effectiveness of CPE in reducing inactive behavior and promoting moderate physical activity later in life. PMID- 30462924 TI - Perspectives on the current and emerging chemical androgen receptor antagonists for the treatment of prostate cancer. AB - INTRODUCTION: Prostate cancer is the most common cancer in men. Regardless of the initial treatment of localized disease, almost all patients develop castration resistant prostate cancer (CRPC). A better understanding of the molecular mechanisms behind castration resistance has led to the approval of novel oral androgen receptor (AR) antagonists, such as enzalutamide and apalutamide. Indeed, research has accelerated with numerous agents being studied for the management of CRPC. Areas covered: Herein, the authors present currently used and emerging AR antagonists for the treatment of CRPC. Emerging agents include darolutamide, EZN-4176, AZD-3514, and AZD-5312, apatorsen, galeterone, ODM-2014, TRC-253, BMS-641988, and proxalutamide. Expert opinion: Further understanding of the mechanisms leading to castration resistance in prostate cancer can reveal potential targets for the development of novel AR antagonists. Current novel agents are associated with modest clinical and survival benefit, while acquired resistance and safety issues are under continuous evaluation. The combination of AR antagonists used and ideal sequencing strategies are key tasks ahead, along with the investigation of molecular biomarkers for future personalized targeted therapies. In the future, the challenge will be to determine an AR antagonist with the best combination of outcome and tolerability. PMID- 30462925 TI - Acute effect of taping on plantar pressure characteristics in athletes with exercise-induced leg pain: a description and comparison of groups. AB - OBJECTIVES: Foot pronation is considered as a potential risk factor of lower leg overuse injury. This study aimed to identify plantar pressure characteristics of elite athletes with exercise-induced leg pain in throwing athletic disciplines, and to verify the acute effect of taping for restricting foot pronation by analyzing the plantar pressure characteristics. METHODS: This study was designed as a description and comparison of throwing athletic athletes. Participants were divided into exercise-induced leg pain (ELP group, n = 17) and control groups (CON group, n = 14). Plantar pressure variables (contact area, maximum force, and peak pressure) at eight-foot regions in athletes' supporting leg were recorded during standing on one leg and a natural walk before and after applying anti pronation or sham taping techniques. RESULTS: There are significant difference of contact area, maximal force, and peak pressure in some regions of their foot between the ELP and CON groups. But the anti-pronation taping decreased only the peak pressure in lateral midfoot of CON group during a natural walk (p = 0.002). CONCLUSION: The anti-pronation taping technique may not be effective preventive strategy from the exercise-induced leg pain, such as shin splints. PMID- 30462926 TI - Roflumilast in patients with advanced chronic obstructive pulmonary disease: towards a better-targeted use. AB - INTRODUCTION: For patients with chronic obstructive pulmonary disease (COPD), one of the main goals in its management is to reduce the number of disease exacerbations. Roflumilast is an anti-inflammatory compound used in patients with advanced COPD and chronic bronchitis in order to fulfill this objective. However, this is not always easily achieved due to the heterogeneity of the population. Clinical trial data can allow more in-depth analysis in order to identify predictors for maximal efficacy in different patient populations. Areas covered: A post hoc pooled data analysis derived from two large-scale randomized controlled trials helped to better define the disease subsets in which roflumilast would exert the maximal therapeutic effect. These are represented by patients with prior hospitalizations for COPD exacerbations and by patients with higher values for eosinophil blood count. This analysis is the focus of our key paper evaluation. Expert opinion: This pooled data analysis suggests that a phenotype/endotype guided therapy has the potential to be impactful on overall survival by reducing the number of exacerbations and increase the life span of patients. PMID- 30462927 TI - On the Distinction Between Personal Standards Perfectionism and Excellencism: A Theory Elaboration and Research Agenda. AB - Research on perfectionism is flourishing, but the unspecified distinction between perfectionism and the pursuit of excellence is a lingering issue that urgently needs conceptual, theoretical, and empirical attention. In this article, excellence and perfection are defined as distinct goals that form the basis of two different but related constructs. To move this idea forward, the term excellencism is introduced. Perfectionism and excellencism are defined and their similarities and differences are illustrated using symbolic logic and adjectives from the English lexicon. A point is made to clearly indicate that excellencism is a required reference point for reassessing the healthiness or unhealthiness of personal standards perfectionism. Using the law of diminishing returns as an analogy, a theory-driven rationale is proposed, and three alternative hypotheses are formulated. Showing that personal standards perfectionism is associated with better, comparable, and worse outcomes compared with excellencism offers the needed and sufficient conditions for respectively supporting the hypothesis that perfectionism is a healthy, unneeded, or deleterious pursuit. The propositions advanced in this theoretical article are more than incremental, and their practical implications are far-reaching: If personal standards perfectionism yields no added value or deleterious outcomes over and above excellencism, then excellence rather than perfection should be promoted. PMID- 30462928 TI - Active Design Strategies and the Evolution of the WELL Building StandardTM. PMID- 30462929 TI - What "Moves" the Populations Most Likely to Be Physically Inactive-Women and Older Adults? Evidence From Mueller, a Mixed-Use Neighborhood in Austin, Texas. AB - BACKGROUND: Older age groups are less likely than their younger counterparts to be regularly active and women are even less active. Ecological models suggest that multiple levels of influence with each level influencing the next level impacts physical activity behaviors. METHODS: Hierarchical multiple regressions were used to determine factors within and across the ecological model that predicted both total physical activity and walking for recreation. FINDINGS: The overall predictors of total physical activity were different than those of walking for recreation, with the exception of dog ownership and perceived barriers. Gender and age were significant predictors of walking for recreation, but these associations were not present for total physical activity. Women and older adults walked more for recreation in a mixed-use community, Mueller, (and thus engaged in more total physical activity) compared with men and younger adults. CONCLUSION: Behavior-specific physical activity as well as total physical activity led to a better understanding of factors that may impact behavior among an overall aging population, especially women. This level of specificity is important in understanding specific factors that are associated with physical activity among vulnerable populations and can help guide the development of tailored, cost-effective, and efficient policies and interventions. PMID- 30462931 TI - Portal Venous Gas. PMID- 30462930 TI - Take It with a Grain of Salt. PMID- 30462932 TI - Probiotics for Children with Gastroenteritis. PMID- 30462933 TI - Case 36-2018: A 29-Year-Old Man with an Incidentally Discovered Renal Mass. PMID- 30462934 TI - Beyond Evidence-Based Medicine. PMID- 30462935 TI - Outcomes of Cardiac Screening in Adolescent Soccer Players. PMID- 30462936 TI - An Industry Experience with Data Sharing. PMID- 30462937 TI - Doctor Sahib. PMID- 30462938 TI - Lactobacillus rhamnosus GG versus Placebo for Acute Gastroenteritis in Children. AB - BACKGROUND: Acute gastroenteritis develops in millions of children in the United States every year, and treatment with probiotics is common. However, data to support the use of probiotics in this population are limited. METHODS: We conducted a prospective, randomized, double-blind trial involving children 3 months to 4 years of age with acute gastroenteritis who presented to one of 10 U.S. pediatric emergency departments. Participants received a 5-day course of Lactobacillus rhamnosus GG at a dose of 1*1010 colony-forming units twice daily or matching placebo. Follow-up surveys were conducted daily for 5 days and again 14 days after enrollment and 1 month after enrollment. The primary outcome was moderate-to-severe gastroenteritis, which was defined as an illness episode with a total score on the modified Vesikari scale of 9 or higher (scores range from 0 to 20, with higher scores indicating more severe disease), within 14 days after enrollment. Secondary outcomes included the duration and frequency of diarrhea and vomiting, the duration of day-care absenteeism, and the rate of household transmission (defined as the development of symptoms of gastroenteritis in previously asymptomatic household contacts). RESULTS: Among the 971 participants, 943 (97.1%) completed the trial. The median age was 1.4 years (interquartile range, 0.9 to 2.3), and 513 participants (52.9%) were male. The modified Vesikari scale score for the 14-day period after enrollment was 9 or higher in 55 of 468 participants (11.8%) in the L. rhamnosus GG group and in 60 of 475 participants (12.6%) in the placebo group (relative risk, 0.96; 95% confidence interval, 0.68 to 1.35; P=0.83). There were no significant differences between the L. rhamnosus GG group and the placebo group in the duration of diarrhea (median, 49.7 hours in the L. rhamnosus GG group and 50.9 hours in the placebo group; P=0.26), duration of vomiting (median, 0 hours in both groups; P=0.17), or day-care absenteeism (median, 2 days in both groups; P=0.67) or in the rate of household transmission (10.6% and 14.1% in the two groups, respectively; P=0.16). CONCLUSIONS: Among preschool children with acute gastroenteritis, those who received a 5-day course of L. rhamnosus GG did not have better outcomes than those who received placebo. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT01773967 .). PMID- 30462939 TI - Multicenter Trial of a Combination Probiotic for Children with Gastroenteritis. AB - BACKGROUND: Gastroenteritis accounts for approximately 1.7 million visits to the emergency department (ED) by children in the United States every year. Data to determine whether the use of probiotics improves outcomes in these children are lacking. METHODS: We conducted a randomized, double-blind trial involving 886 children 3 to 48 months of age with gastroenteritis who presented to six pediatric EDs in Canada. Participants received a 5-day course of a combination probiotic product containing Lactobacillus rhamnosus R0011 and L. helveticus R0052, at a dose of 4.0*109 colony-forming units twice daily or placebo. The primary outcome was moderate-to-severe gastroenteritis, which was defined according to a post-enrollment modified Vesikari scale symptom score of 9 or higher (scores range from 0 to 20, with higher scores indicating more severe disease). Secondary outcomes included the duration of diarrhea and vomiting, the percentage of children who had unscheduled physician visits, and the presence or absence of adverse events. RESULTS: Moderate-to-severe gastroenteritis within 14 days after enrollment occurred in 108 of 414 participants (26.1%) who were assigned to probiotics and 102 of 413 participants (24.7%) who were assigned to placebo (odds ratio, 1.06; 95% confidence interval [CI], 0.77 to 1.46; P=0.72). After adjustment for trial site, age, detection of rotavirus in stool, and frequency of diarrhea and vomiting before enrollment, trial-group assignment did not predict moderate-to-severe gastroenteritis (odds ratio, 1.06; 95% CI, 0.76 to 1.49; P=0.74). There were no significant differences between the probiotic group and the placebo group in the median duration of diarrhea (52.5 hours [interquartile range, 18.3 to 95.8] and 55.5 hours [interquartile range, 20.2 to 102.3], respectively; P=0.31) or vomiting (17.7 hours [interquartile range, 0 to 58.6] and 18.7 hours [interquartile range, 0 to 51.6], P=0.18), the percentages of participants with unscheduled visits to a health care provider (30.2% and 26.6%; odds ratio, 1.19; 95% CI, 0.87 to 1.62; P=0.27), and the percentage of participants who reported an adverse event (34.8% and 38.7%; odds ratio, 0.83; 95% CI, 0.62 to 1.11; P=0.21). CONCLUSIONS: In children who presented to the emergency department with gastroenteritis, twice-daily administration of a combined L. rhamnosus-L. helveticus probiotic did not prevent the development of moderate-to-severe gastroenteritis within 14 days after enrollment. (Funded by the Canadian Institutes of Health Research and others; PROGUT ClinicalTrials.gov number, NCT01853124 .). PMID- 30462940 TI - Iron Wars - The Host Strikes Back. PMID- 30462941 TI - Oligonucleotide Drugs for Transthyretin Amyloidosis. PMID- 30462942 TI - Fulfilling States' Duty to Evaluate Medicaid Waivers. PMID- 30462943 TI - Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer. PMID- 30462944 TI - Pneumococcal Bacteremia and Meningitis. PMID- 30462945 TI - Oral Tecovirimat for the Treatment of Smallpox. PMID- 30462947 TI - [Technical guidelines for seasonal influenza vaccination in China, 2018-2019]. AB - Seasonal influenza vaccination is the most effective way to prevent influenza virus infection and its complications. Currently, China has licensed trivalent (IIV3) and quadrivalent inactivated influenza vaccine (IIV4), including split virus influenza vaccine and subunit vaccine. In most parts of China, influenza vaccine is a category II vaccine, which means influenza vaccination is voluntary, and recipients need to pay for it. To strengthen the technical guidance for prevention and control of influenza and the operational research on influenza vaccination in China, the National Immunization Advisory Committee (NIAC), Influenza Vaccine Technical Working Group (TWG), updated the 2014 technical guidelines and compiled the "Technical guidelines for seasonal influenza vaccination in China (2018-2019)" , based on most recent existing scientific evidences. The main updates include: epidemiology and disease burden of influenza, types of influenza vaccines, northern hemisphere influenza vaccination composition for the 2018-2019 season, and, IIV3 and IIV4 vaccines'major immune responses, durability of immunity, immunogenicity, vaccine efficacy, effectiveness, safety, cost-effectiveness and cost-benefit. The recommendations include: Points of Vaccination clinics (PoVs) should provide influenza vaccination to all persons aged 6 months and above who are willing to be vaccinated and do not have contraindications. No preferential recommendation is made for any influenza vaccine product for persons who can accept >=1 licensed, recommended, and appropriate products. To decrease the risk of severe infections and complications due to influenza virus infection among high risk groups, the recommendations prioritize seasonal influenza vaccination for children aged 6-60 months, adults >=60 years of age, persons with specific chronic diseases, healthcare workers, the family members and caregivers of infants <6 months of age, and pregnant women or women who plan to pregnant during the influenza season. Children aged 6 months to 8 years old require 2 doses of influenza vaccine administered a minimum of 4 weeks apart during their first season of vaccination for optimal protection. If they were vaccinated in previous influenza season, 1 dose is recommended. People >= 9 years old require 1 dose of influenza vaccine. It is recommended that people receive their influenza vaccination by the end of October. Influenza vaccination should be offered as soon as the vaccination is available. Influenza vaccination should continue to be available for those unable to be vaccinated before the end of October during the whole season. Influenza vaccine is also recommended for use in pregnant women during any trimester. These guidelines are intended for CDC members who are working on influenza control and prevention, PoVs members, healthcare workers from the departments of pediatrics, internal medicine, and infectious diseases, and members of maternity and child care institutions at all levels. PMID- 30462948 TI - [Epidemiological characteristics of household fuel use in 10 areas of China]. AB - Objective: To describe the characteristics of cooking and heating fuel use in participants from the China Kadoorie Biobank (CKB) study. Methods: The CKB study recruited 512 891 adults from 10 areas in China during 2004-2008. Information on cooking fuel and heating fuel was collected using a questionnaire in baseline survey. The proportions of various fuels used in different areas, in different populations, and at different time points were calculated and compared. Results: Overall, 52.1% participants used solid fuel for cooking or heating. Rural areas had higher prevalence of solid fuel use than urban areas. The percentage of participants using solid fuel for cooking was 36.1% (coal 20.1%, wood/charcoal 16.0%); The percentage of participants using solid fuel for heating was 36.7% (coal 22.7%, wood/charcoal 14.0%). The prevalence of solid fuel use and the fuel type mainly used varied widely across 10 areas. The proportion of clean fuel use was lower in less-educated and lower-income people. Household coal and wood/charcoal use showed a declining trend, which was more remarkable in urban areas. Conclusion: There are still a large number of rural residents and people with low income relying on solid fuel in China, which is a serious public health concern. PMID- 30462949 TI - [Prevalence of alcohol drinking and influencing factors in female adults in China, 2010-2012]. AB - Objective: To understand the prevalence of alcohol drinking and influencing factors in female adults in China. Methods: At the 150 survey sites where 2010 2012 Chinese nutrition and health surveillance was conducted, a face to face questionnaire survey was conducted in female adults selected through multi-stage stratified cluster random sampling. Sample weights was assigned to each participant based on the study design by using national population census data in 2009. The complex sampling and unconditional multivariate logistics regression analysis was conducted to identify the influencing factors for the prevalence of alcohol drinking in the female adults. Results: A total of 75 518 participants were included in this study. The prevalence of drinking in female adults was 13.9% (95%CI: 11.7-16.2) in urban area and 13.3% (95%CI: 9.4-17.2) in rural area. The prevalence of frequent drinking was 13.9% (95%CI: 9.9-17.9) in women in urban area and 14.2% (95%CI: 10.8-17.6) in women in rural area. The prevalence of excessive drinking was 11.1% (95%CI: 7.5-14.8) in women in urban area and 12.8% (95%CI: 9.1-16.4) in women in rural area. The prevalence of wine drinking in women in urban area was significantly higher than in women in rural and had positive correlation with income and education levels. The social and economic factors influencing drinking behavior of the female adults included occupation, drinking behaviors of family members and smoking behavior. Those who were engaged in agriculture, production and transportation (OR=0.72, 95%CI: 0.56-0.94, P=0.016), housework (OR=0.59, 95%CI: 0.44-0.78, P<0.001) and other work (OR=0.61, 95%CI: 0.43-0.85, P=0.004) had lower drinking prevalence. Whereas those whose family members had drinking behavior (OR=2.66, 95%CI: 2.17-3.26, P<0.001) and those who were current smokers (OR=4.32, 95%CI: 2.95-6.34, P<0.01) had higher drinking prevalence. Conclusions: The prevalence of drinking, frequent alcohol drinking and excessive drinking were relatively low in female adults in China. Occupation, drinking behaviors of family members and smoking behavior were the main factors influencing the prevalence drinking behavior in female adults in China. PMID- 30462950 TI - [Survey on extramarital sexual behaviors and HIV infection in middle-aged and elderly people aged 50 and above in selected areas of Chongqing]. AB - Objective: To know the situation of extramarital sexual behaviors and HIV infection in middle-aged and elderly people in Chongqing, and provide reference for AIDS prevention and treatment. Methods: From October to December 2017, a multi-stage sampling method was used to recruit middleaged and elderly people aged >=50 years who lived in Dazu and Hechuan districts of Chongqing for at least one year, with a sample size of 410. Face-to-face questionnaires survey and HIV antibody test were conducted. Results: A total of 408 people were surveyed, including 313 males and 95 females aged 50-88 (64.93+/-9.03) years. The HIV infection rate was 1.47% (6/408), with the rate of 1.28% (4/313) in males and 2.11% (2/95) in females. The awareness rate of AIDS related knowledge was 37.50% (153/408). And 18.87% (77/408) of subjects surveyed reported extramarital sexual behaviors, 7.60% (31/408) reported extramarital sexual behaviors in the past half year, the constant condom use rate was 19.35% (6/31). The results of multivariate logistics model analysis on extramarital sexual behaviors showed that the prevalence in males were 39.51 times higher than that in females (OR=39.51, 95%CI: 5.03-310.30), 4.60 times higher in those who were unmarried, divorced or widowed than that in the married or cohabitants (OR=4.60, 95%CI: 1.50-14.05), 2.03 times higher in those with outside activities than those with individual activities (OR=2.03, 95%CI: 1.08-3.81) and 3.94 times higher in those with self evaluation of emptiness of living state than that in those with engaged life (OR=3.94, 95%CI: 1.86-8.36). Conclusions: The prevalence of extramarital sexual behavior in middle-aged and elderly people in some counties and districts in Chongqing is high. The factors such as gender, marital status, leisure activities, and self-evaluation of living state were related to the prevalence of extramarital sexual behaviors in this population. The condom use rate in extramarital sexual behavior was low. It is necessary to take effective interventions in this population. PMID- 30462952 TI - [Deaths attributed to ambient air pollution in China between 2006 and 2016]. AB - Objective: To analyze the deaths attributed to ambient air pollution in China between 2006 and 2016. Methods: The data were collected from the project of Global Burden of Disease in 2016 (GBD2016). The Data Integration Model for Air Quality were used to estimate exposure to particulate matter smaller than 2.5 MUm in aerodynamic diameter (PM(2.5)). The attributable death number was calculated based on the calculation of population attributable fraction (PAF), and the results were compared by gender, diseases and provinces. An average world population age structure was adopted to calculate age-standardized rates. Results: In 2016, a total of 1 075 000 deaths attributed to ambient air pollution occurred in China, accounting for 11.1% of the total deaths, and 57.6% of the deaths attributed to ambient air pollution were due to ischemic heart disease and stroke. The death number among men was 1.7 times higher than that in women, Compared with 2006, the proportion of ambient air pollution related deaths in total deaths decreased by 6.8%; the age- standardized death rate attributed to ambient air pollution decreased by 26.5% and the decrease rate of lower respiratory infections (37.6%) and chronic obstructive pulmonary disease (42.1%) were greater than ischemic heart disease (5.3%). The age-standardized rate of death attributed to ambient air pollution decreased both in men and in women, but the decrease rate was higher in women (34.8%) than that in men (20.4%). The PAFs varied among provinces, it was highest in Tianjin (13.9%), lowest in Tibet (6.1%), and it was relatively higher in Beijing, Hebei, Shandong, Henan and the three provinces in the northeast and relatively lower in Hong Kong, Macao, Fujian and Hainan etc.. The age-standardized rate of death attributed to ambient air pollution was highest in Xinjiang (120.1/100 000) and lowest in Hong Kong (30.9/100 000), and it was relatively higher in Qinghai, Guizhou, Henan and relatively lower in Macao, Shanghai and Fujian, etc.. Compared with 2006, the PAFs of 17 provinces decreased, the decrease rate ranged from 4.1% to 16.8%, whereas the PAF of Jilin (5.0%) and Heilongjiang (8.1%) increased, and the PAFs of other 14 provinces showed no significant change. The attributable age standardized death rate decreased in all provinces with the decrease rate ranging from 11.9% (Heilongjiang) to 43.2% (Fujian), and the decrease rate was relatively higher in Guangdong, Zhejiang and Guizhou, and lower in the three provinces in the northeast, Hubei and Hebei etc. Conclusions: In 2016, the disease burden attributable to PM(2.5) in China was heavy, but mitigated compared with 2006. The gender and area specific distributions of deaths attributed to ambient air pollution were observed. PMID- 30462951 TI - [Analysis on voluntary blood donation and associated factors in men who have sex with men in 3 cities in China]. AB - Objective: To assess the prevalence of blood donation and associated factors in men who have sex with men (MSM) in China. Methods: Our observational study was conducted between January and August, 2017 in 3 cities: Guangzhou, Shenzhen and Wuxi. Eligible participants were MSM (>=18 years old) who had either >=2 male sex partners or unprotected anal sex with casual partners, or had been diagnosed with STI in the past 6 months. A self-completed tablet-based questionnaire was used to collect the information about MSM's socio-demographic characteristics, sexual behaviors and blood donation history. Results: A total of 603 MSM were enrolled in our study, including 302 in Guangzhou, 152 in Shenzhen and 149 in Wuxi, with a mean age of 27.9 years (SD=7.8). Overall, 29.2% (176/603) of the MSM reported a history of blood donation, and 33.1% (100/302)in Guangzhou, 27.6% (42/152) in Shenzhen and 22.8% (34/149) in Wuxi, the differences were not significant (chi(2)=6.421, P=0.093). Multivariate logistic regression analysis indicated that MSM had ever tested for HIV for >=2 times in the past 12 months (vs. MSM tested for HIV one time, aOR=1.49, 95%CI: 1.08-2.19) or who had ever used gay dating app (vs. MSM who not used gay dating app, aOR=2.13, 95%CI: 1.12-4.44) were more likely to donate blood. Conclusions: Blood donation was common in MSM in China. Health education about blood donation in MSM should be strengthened to ensure the blood safety. PMID- 30462953 TI - [Influence of diurnal temperature range on influenza incidence in the elderly]. AB - Objective: To understand the influence of diurnal temperature range (DTR) on influenza incidence in the elderly in Beijing and to conduct a subgroup analysis. Methods: The incidence data of daily influenza cases in the elderly and daily meteorological data from 2014 to 2016 in Beijing were collected for this study. A generalized additive model (GAM) was used to explore whether the relationship between daily influenza cases and DTR is a linear one. A distributed lag non linear model (DLNM) was established to quantify the lagged effect of DTR on daily influenza incidence in the elderly. The model was also used to estimate the effects of DTR on daily influenza incidence among various subgroups. Results: A total of 4 097 influenza cases in the elderly were notified during study period. The mean DTR was 10.153 C. A linear relationship between daily influenza incidence and DTR was detected by using GAM. DTR was significantly associated with daily influenza incidence between lag0 and lag5 with a maximal effect at lag0. An 1 C increase of DTR was associated with a 2.0% increase in daily influenza incidence in the elderly (95%CI: 0.9%-3.0%). The RR values of males, females, people aged 60-69 years, people aged >=70 years were 1.018 (95%CI: 1.005 1.032), 1.021(95%CI: 1.007-1.035), 1.012 (95%CI: 1.002-1.022), 1.025 (95%CI: 1.012-1.039), respectively. The influencing time of DTR on females (lag6) was longer than males (lag2). Conclusions: DTR was associated with increased risk of influenza in the elderly in Beijing. It is necessary to take targeted measures in the elderly to control the incidence of influenza when DTR becomes greater. PMID- 30462954 TI - [Risk factors analysis and a new risk scoring system predicting hepatocarcinogenesis for chronic genotype C HBV infected patients]. AB - Objective: To investigate the effects of hepatitis B virus (HBV) genotype and mutations on the development of hepatocellular carcinoma (HCC) and to establish a new qualified HCC risk scores. Methods: A cohort study enrolling patients with chronic HBV infection was conducted. HBV genotypes were identified by nested multiplex PCR. HBV mutations in the basic core promoter region and PreS region were sequenced after PCR amplification. Scores on risk factors were set based on nomogram. Results: Totally, 1 525 patients were followed-up in this research. A total of 1 110 patients infected with genotype C were followed-up for 8.52 (Q(R): 5.36-11.68) years on average, of whom the incidence of HCC was 11.93/1 000 person years. In genotype C HBV infected patients, male gender, aged 40 years and over, and four DNA mutations (T1674CG, A1762T/G1764A, A3120T, and A2962G) can increase the risk of HCC (P<0.05); interferon therapy can reduce the risk of HCC (P<0.05). A new HCC predicting model was established according to the results. After validation, the predicted disease-free survival rate was consistent with the real one. Conclusions: Hepatitis B virus genotypes and mutations were closely associated with HCC. The new risk scoring system can well predict HCC occurrence in genotype C HBV infected patients. PMID- 30462955 TI - [Genetic characteristics of hemagglutinin and neuraminidase of avian influenza A (H7N9) virus in Guizhou province, 2014-2017]. AB - Objective: To understand the molecular characteristics of hemagglutinin (HA) and neuraminidase (NA) as well as the disease risk of influenza virus A H7N9 in Guizhou province. Methods: RNAs were extracted and sequenced from HA and NA genes of H7N9 virus strains obtained from 18 cases of human infection with H7N9 virus and 6 environmental swabs in Guizhou province during 2014-2017. Then the variation and the genetic evolution of the virus were analyzed by using a series of bioinformatics software package. Results: Homology analysis of HA and NA genes revealed that 2 strains detected during 2014-2015 shared 98.8%-99.2% and 99.2% similarities with vaccine strains A/Shanghai/2/2013 and A/Anhui/1/2013 recommended by WHO, respectively. Two strains detected in 2016 and 14 strains detected in 2017 shared 98.2%-99.3% and 97.6%-98.8% similarities with vaccine strain A/Hunan/02650/2016, respectively. Other 6 stains detected in 2017 shared 99.1%-99.4% and 98.9%-99.3% similarities with strain A/Guangdong/17SF003/2016, respectively. Phylogenetic analysis showed that all the strains were directly evolved in the Yangtze River Delta evolution branch, but they were derived from different small branch. PEVPKRKRTAR?GLF was found in 6 of 24 strains cleavage site sequences of HA protein, indicating the characteristic of highly pathogenic avian influenza virus. Mutations A134V, G186V and Q226L at the receptor binding sites were found in the HA. All the strains had a stalk deletion of 5 amino acid residue "QISNT" in NA protein, and drug resistance mutation R294K occurred in strain A/Guizhou-Danzhai/18980/2017. In addition, potential glycosylation motifs mutations NCS42NCT were found in the NA of 9 of 24 strains. Conclusions: HA and NA genes of avian influenza A (H7N9) virus showed genetic divergence in Guizhou province during 2014-2017. The mutations of key sites might enhance the virulence of the virus, human beings are more susceptible to it. Hence, the risk of infection is increasing. PMID- 30462956 TI - [Study on acute HIV-1 infection in men who have sex with men in Tianjin]. AB - Objective: To understand the immunological and virological characteristics of HIV 1 infected men who have sex with men (MSM) in the acute phase in Tianjin and evaluate the effects of the fourth generation HIV ELISA and the P24 ELISA for acute HIV-1 infected samples. Methods: From October 2015 to October 2016, MSM were recruited through the community-based organizations in Tianjin. All the participants received rapid HIV test, positive samples were confirmed by Western Blot and negative samples underwent pooled nucleic acid testing. The participants with HIV-1 RNA reactive result underwent testing for viral load and T-cell count after second blood collection. Acute HIV-1 infection was defined as negative rapid HIV test result and the positive results of two HIV RNA tests, then the sensitivity were compared between the fourth generation HIV ELISA and the P24 ELISA to detect the initial HIV-1 RNA positive samples. Results: Among 3 016 MSM screened, 193 were positive in rapid HIV test. Western blot testing indicated that 179 cases were HIV positive, 7 cases were HIV indeterminate and 7 cases were negative. Of 2 823 sero-negative cases, 17 were acute HIV-1 infections. The HIV-1 infection rate was 6.53% (197/3 016) and the acute HIV-1 infection rate was 0.56% (17/3 016), with an average viral load of (5.63+/-1.50) log(10) copies/ml, an average CD(4) count of (442.82+/-268.17) cells/MUl, an average CD(8) count of (1 069.65+/-668.22) cells/MUl and an average CD(4)/CD(8) ratio of (0.49+/-0.25). Higher viral load, CD(4) and CD(4)/CD(8) ratio were seen in the acute HIV-1 infection group compared with the chronic HIV-1 infection group (U=148, P<0.01; U=272, P=0.042 and t=3.147, P=0.005). Demographic characteristics were similar between two groups, except the occupation (chi(2)=11.016, P=0.026). The sensitivity of P24 ELISA was higher than the fourth generation HIV ELISA in the HIV-1 detection for acute infection (Fisher's exact test, P=0.017). Conclusions: MSM are at risk for acute HIV-1 infection. Screening for acute HIV-1 infection with P24 ELISA would increase the sensitivity of diagnosis and reduce HIV transmission in MSM. PMID- 30462958 TI - [Active and passive maternal smoking during pregnancy and risk of having a child with polydactyly: a case-control study]. AB - Objective: The number of children with polydactyly is increasing. In addition to genetic factors, an influence of maternal behavior or environmental effects during pregnancy is becoming increasingly apparent. However, epidemiological data on these effects are lacking. Methods: This hospital-based, case-control study enrolled 143 infants with polydactyly and 286 controls without genetic diseases to evaluate the association between active and passive maternal smoking during pregnancy and the likelihood of giving birth to a child with polydactyly. Results: Active and passive maternal smoking during pregnancy was associated with an increased risk of giving birth to a child with polydactyly (active smoking: OR=4.74, 95%CI: 1.43-15.65, P=0.011; passive smoking: OR=2.42, 95%CI: 1.32-4.44, P=0.004). After adjusting for confounders, smoking during pregnancy remained significant influence on polydactyly (active smoking: aOR=7.27, 95%CI: 1.72 30.72, P=0.007; passive smoking: aOR=2.41, 95%CI: 1.11-5.23, P=0.026). Conclusion: Active and passive maternal smoking during pregnancy appears to be a risk factor for polydactyly in newborns. PMID- 30462957 TI - [Seasonal distribution of patient hospitalization due to asthma exacerbation in 7 geographic areas in China]. AB - Objective: To understand the seasonal distribution of patient hospitalization due to asthma exacerbation in 7 geographic areas in China. Methods: This was a retrospective study which involved patients hospitalized for asthma exacerbation in 29 hospitals throughout 7 geographic areas in the mainland of China (northeast, north, central, east, south, northwest and southwest). The numbers of asthmatic patients and total inpatients of the respiratory department of each hospital were recorded. The monthly ratio of asthmatic patients to the total inpatients in every area was calculated and compared. Results: During the study period, 6 480 patients were admitted for asthma exacerbation, accounting for 3.14% of all the 206 135 patients admitted to the respiratory departments in the 29 hospitals. The ratio of asthmatic patients to total inpatients in the northeast area (5.61%) was highest, and the ratio in east area was lowest (1.97%). Statistical analysis showed that the difference among different areas was significant (P<0.000 1). In most areas, both the number and proportion of hospitalized asthmatic patients peaked in spring (February-April) and autumn (September-October). In the northeast area, east area and south area, the peaks in spring were more obvious, while in the north area and southwest area, the peaks in autumn were more obvious. In the northwest area the peaks occurred in winter (December-January) and summer (June-August), respectively. The differences in hospitalization due to asthma among different months were significant in the northeast, north, and southwest areas (P<0.005). Conclusion: The number of patients hospitalized for asthma exacerbation fluctuated with season in different areas in China. In most areas, more asthmatic patients were admitted to hospitals in spring and autumn. PMID- 30462959 TI - [Interaction between vaginal micro-environment alterations and HPV16 infection in cervical intraepithelial neoplasia]. AB - Objective: To explore the effect of vaginal micro-environment alterations and HPV16 infection and their interaction in the progression of cervical intraepithelial neoplasia. Methods: The participants of this study came from the cervical lesions study cohort in Shanxi province, including 623 women with normal cervical (NC), 303 patients with pathogenically diagnosed low-grade cervical intraepithelial neoplasia (CINI) and 93 patients with pathogenically diagnosed high-grade cervical intraepithelial neoplasia (CINII/III). The data of the demographic characteristics of the study subjects and factors related to cervical intraepithelial neoplasia were collected, and HPV16 infection were detected by using flow-through hybridization technology and H(2)O(2), beta-glucuronidase, clotting enzyme, neuraminidase and leucocyte esterase in vaginal secretions were detected by using the combined detection kit of aerobic vaginitis and bacterial vaginosis. pH value and vaginal cleanliness were also detected at the same time. The database was established and analyzed by SPSS statistical software (version 22.0). Results: The HPV16 infection rate (trend chi(2)=55.45, P<0.001) and the abnormal rates of H(2)O(2) (trend chi(2)=26.19, P<0.001), pH (trend chi(2)=5.06, P=0.024), vaginal cleanliness (trend chi(2)=19.55, P<0.001), beta-glucuronidase (trend chi(2)=17.52, P<0.001) and neuraminidase (trend chi(2)=14.90, P<0.001) increased gradually along with the severity of cervical intraepithelial neoplasia, but the abnormal rates of clotting enzyme and leucocyte esterase showed no same trend. The results of GMDR model analysis showed that there was interaction between HPV16 infection and abnormalities of H(2)O(2), beta glucuronidase, clotting enzyme and neuraminidase in CINI group, and the interaction between HPV16 infection and the abnormalities of vaginal cleanliness, H(2)O(2), beta-glucuronidase and neuraminidase in CIN II/III group. Conclusion: Our findings indicated that the vaginal micro-environment alterations and HPV16 infection could increase the risk of cervical intraepithelial neoplasia, and they might have an important synergistic effect in the progression of cervical intraepithelial neoplasia. PMID- 30462960 TI - [Diagnostic accuracy of line probe assays for drug-resistant tuberculosis: a Meta analysis]. AB - Objective: To evaluate the diagnostic accuracy of line probe assays for drug- resistant tuberculosis (TB) in China. Methods: Chinese databases (CNKI, Wanfang, SinoMed, VIP Information) and English databases (PubMed, Embase, Cochrane Library) were used to retrieve the literatures regarding the accuracy of line probe assays in the diagnosis of drug-resistant tuberculosis in China between January 1, 2000 and September 1, 2017. Quality Assessment of Diagnostic Accuracy Studies-2 was used to evaluate the quality of the included studies. Sensitivity and specificity in different studies (using drug sensitivity test or gene sequencing as gold standard) were combined by Meta-analysis using bivariate or univariate model. In addition, subgroup analysis (GenoType MTBDRplus, GenoType MTBDRsl and Reverse dot blot hybridization) and sensitivity analysis were also carried out. Results: A total of 24 literatures involving 82 studies were included in the final analysis. The sensitivity and specificity of line probe assays for rifampicin resistant TB were 0.91(0.88-0.94) and 0.98 (0.97-0.99), respectively. The sensitivity and specificity of line probe assays for isoniazid resistant TB were 0.80 (0.77-0.83) and 0.98 (0.96-0.99), respectively. The sensitivity and specificity of line probe assays for multidrug-resistant TB were 0.81 (0.76-0.85) and 0.99 (0.99-1.00), respectively. The sensitivity and specificity of line probe assays for quinolone resistant TB were 0.92(0.88-0.95) and 0.94 (0.91-0.97), respectively. The sensitivity and specificity of line probe assays for second-line injectable drug resistant TB (including kanamycin, Capreomycin, amikacin) were 0.79(0.58-0.91) and 0.98 (0.90-1.00), respectively. The sensitivity and specificity of line probe assays for extensively drug resistant TB were 0.46 (0.19-0.75) and 1.00 (0.98-1.00), respectively. Subgroup analysis showed that the overall diagnostic accuracy of GenoType MTBDRplus and GenoType MTBDRsl was higher than that of Reverse dot blot hybridization. According to the results of sensitivity analysis, the results of this study were robust. Conclusion: The diagnostic accuracy of line probe assays for drug resistant TB is high. PMID- 30462961 TI - [Establishment and role of national clonorchiasis surveillance system in China]. AB - Clonorchiasis is one key food-borne parasitic disease in China. Owing to several years'efforts and preparation, the national clonorchiasis surveillance system in China has been established preliminarily since 2016. In this article, the necessity to establish the national clonorchiasis surveillance system is explained. Then, the structure, content and corresponding methods of the surveillance system are briefly introduced. Key points in the surveillance are summarized and the development of surveillance in future is discussed. Furthermore, the contribution of clonorchiasis surveillance in China to the world is also analyzed. PMID- 30462962 TI - [Bibliometric analysis on research hotspots on HIV post-exposure prophylaxis related articles in the world, 2000-2017]. AB - Objective: To analyze and reveal the distribution, research hotspots and study trend of worldwide published articles correlated with HIV/AIDS post-exposure prophylaxis (PEP), and provide information for related studies in China. Methods: CiteSpace software 5.1 was used to visualize all related papers in the web of science database published during 2000-2017. Results: The average growth rate of international PEP-related papers was 10.78%,and number of published papers in 2016 was highest (n=34), relevant research hotspots have shifted from the prevention of occupational HIV exposure to the prevention of non-occupational HIV exposure in group at high risk, such as MSM, in recent years. Clustering analysis classified research hotspots into three categories, including risk reduction through enhanced intervention, current status of global HIV PEP and German Austrian Recommendation. Conclusions: Non-occupational HIV PEP in groups at high risk, especially MSM, has received increasing attention in recent years, the research of PEP mainly focus on improving the awareness and use of PEP in MSM and compliance in the course of medication. In the context of severe HIV epidemic in MSM without effective control in China, PEP should be strengthened to assess and explore the risk of HIV infection in MSM to provide reference for medical personnel and related departments to implement HIV non-occupation exposure blockade and formulate PEP medication. PMID- 30462963 TI - [Impact of the 90-90-90 goal and pre-exposure prophylaxis on HIV transmission and elimination in men who have sex with men in China: A mathematical modeling study]. AB - Objective: To establish a dynamic compartmental model to predict the impact of HIV testing and treatment and pre-exposure prophylaxis (PrEP) on the annual incidence of HIV infection in men who have sex with men (MSM) in China from 2018 to 2037. Methods: A dynamic compartmental model was developed to describe the HIV epidemic in MSM in China. The model was parameterized using data from the literature available. We used MATLAB 7.0 software for data simulation and graphics rendering. We analyzed HIV transmission among MSM and estimated the impact of expanded HIV testing and treatment and PrEP on HIV elimination in MSM. Results: Under the current policy, the number of new HIV infections would reach 770 000, the infection rate would reach 11.1% and the incidence rate would reach 0.72/100 person years in MSM in the next 20 years. Under the 90%-90%-90% goal, 440 000 new infections (57.7%) would be reduced, the HIV infection rate would decline to 5.7% and the incidence rate would decline to 0.24/100 person years in the next 20 years, but it is still unlikely to achieve the goal of HIV elimination. With 100% PrEP compliance, the required PrEP coverage rates for achieving HIV elimination in the next 10, 15 and 20 years would be 65%, 32% and 19%, respectively. Conclusion: It is necessary to strengthen the comprehensive intervention in MSM, continue to expand HIV testing and treatment, and improve PrEP adherence and coverage to further control and eliminate the epidemic of HIV/AIDS in MSM. PMID- 30462964 TI - [Progress in research of influence of gene polymorphisms on immune response]. AB - Genes play an important role in the immune system response, and different gene loci may result in different vaccine immune response rates. This review focuses on the correlation between gene polymorphisms and vaccine immune response in order to investigate the influence of gene polymorphisms on the immune response to vaccines. It discusses the effect of an individual's immune response after vaccination at genetic level and provides a scientific basis for individualized immune development strategies. It reveals that human leukocyte antigen genes, various cytokines and their receptor genes, and Toll-like receptor genes all affect the vaccine immune response. PMID- 30462965 TI - [Progress in research of bacillus calmette-guerin vaccination and repeated vaccination]. AB - Tuberculosis (TB) is a serious infectious diseases threating human health, bacillus balmette-guerin vaccine (BCG) is the only available TB vaccine now, neonatal vaccination can significantly reduce the incidence and death of tuberculosis. However, due to its limited protection period, one dose vaccination after birth does not have a protective effect for adolescents and adults. Therefore, how to reduce the prevalence of TB in adolescents and adults effectively is essential for TB prevention and control. In this paper, we reviewed the literature from PubMed, CNKI, and Wanfang database to analyze and summarize the characteristics of BCG vaccine, immune effects and immunity endurance, the effects of BCG vaccination and repeated BCG vaccination in adolescents adults and discuse the change of attitude and trends of BCG use in the three documents issued by the World Health Organization on position of BCG. PMID- 30462966 TI - [The status quo of service quality evaluation of pension institutions in China and research progress]. AB - With the accelerating process of population aging in China, social pension system has been rapidly developed, but its service quality remains poor. How to provide quality and efficient elderly care services has become a major livelihood issue of general public. The existing evaluation standards for service quality in the elderly care institutions vary greatly in terms of literature review and practice, and they have only single perspective and lack systematic review. Based on the three-dimensional theory of "structure-process-result" quality evaluation, this paper systematically compares and evaluates the evaluation index system and evaluation management mechanism of service quality of pension institutions in typical countries and regions, and provides an evidence-based basis for establishing an evaluation management system, which is in line with China's national conditions and covers evaluation principles, subject and object, regulation, rewards and punishments, and classifications. PMID- 30462967 TI - [Current status of surveillance for infectious diseases in Africa]. AB - The outbreak of infectious diseases is a major problem impacting the health of African people and global public health. It is important to establish a surveillance system and conduct continuous, appropriate and systemic surveillance for the prevention and control of infectious diseases. With the implementation of "The Belt and Road Initiative" , the communication and collaboration between China and Africa will be enhanced. Understanding and taking part in the surveillance, prevention and control of infectious diseases in Africa would be helpful for ensuring global public health and promoting economic and trade cooperation between China and Africa. This paper aims to introduce and analyze the current status of surveillance for infectious diseases in Africa from the aspect of whole Africa, partial Africa and some African countries to provide reference for the prevention and control of imported infectious diseases in China and implementation of international medical relief by China. PMID- 30462968 TI - [To further improve the diagnosis and treatment of stable coronary artery disease]. PMID- 30462969 TI - [Advances of vascular medical research on vascular homeostasis and reconstruction in China]. PMID- 30462970 TI - [To properly evaluate the genetic testing results]. PMID- 30462971 TI - [Is there to close the patent foramen ovale in time?] PMID- 30462972 TI - [Chinese expert consensus on clinical performance and quality measures for adults with acute ST-segment elevation myocardial infarction]. PMID- 30462973 TI - [Performance of interpreting the variants of long QT syndrome according ACMG guidelines by four clinical gene screening agencies from Beijing]. AB - Objective: To analyze the interpretation results on the pathogenic classification of KCNH2 variants and SCN5A variants of long QT syndrome (LQTS) based on American College of Medical Genetics and Genomics (ACMG) guidelines by 4 clinical gene screening agencies from Beijing. Methods: Pathogenic classification of 16 variants in KCNH2 and SCN5A was made by 4 clinical gene screening agencies from Beijing based on ACMG guideline. Krippendorff's alpha was used to assess the inter-agency variation consistency. Results: All 4 agencies made pathogenic assessment on all the variants and provided the interpretation results for the classification. For the eight variants from the patients with LQTS, the consistency of classification was only 1/8 and the alpha test value was - 0.01. For the eight variables from incidental findings, the consistency of classification was 4/8 and the alpha test value was 0.407. Evidence analysis of the 4 variants with large differences in classification among agencies showed that the main reasons for the discrepancies originated from the comprehensiveness of the literature search and the inconsistency of the subjective determination of the evidence grade. Conclusion: The consistency of the pathogenic classification of LQTS gene variants based on ACMG guidelines among clinical gene screening agencies from Beijing is poor, which will result in great impact on the clinical treatment strategies of the patients with LQTS. The standardization of pathogenic evaluation of variants in clinical gene screening agencies needs to be improved urgently. PMID- 30462974 TI - [Analysis of risk factors of ventricular arrhythmia in patients with Brugada syndrome]. AB - Objective: To investigate the risk factors of ventricular arrhythmias in patients with Brugada syndrome. Methods: Clinical data of 60 Brugada syndrome patients admitted in the department of cardiology of the First Affiliated Hospital of Nanjing Medical University from March 2003 to December 2016 were collected and retrospectively analyzed. The age at diagnosis was (43.2+/-13.1) years (0.6-83.0 years), 98.3% were males (n=59), and the patients were followed up to (92+/-41) months (12-169 months). The 12-lead surface electrocardiogram (ECG) recorded at the time of diagnosis and showing the highest type 1 ST elevation, either spontaneously or after provocative drug test, was used for the analysis. Patients were divided into ventricular arrhythmia (VA, n=12) group and non-ventricular arrhythmia (non-VA, n=48) group depending on the presence or absence of clinical VA event. The demographic data and ECG data of the 2 groups were compared, and the independent risk factors of VA events were analyzed by stepwise logistic regression. Results: Incidence of family history of sudden death (7/12 vs. 22.9% (11/48)) and percentage of type 1 ST elevation in the peripheral ECG leads (6/12 vs. 16.67% (8/48)) were significantly higher in VA group than in non-VA group (both P<0.05). Max Tpeak-Tend (Max-Tpe) interval ((144+/-53)ms vs. (110+/-16)ms) and dispersion of Tpe ((74+/-50)ms vs. (43+/-17)ms) were significantly higher in VA group than in non-VA group (both P<0.05). The area under receiver operating characteristic (ROC) curves for the Max-Tpe interval was 0.693 and Max-Tpe interval >=140 ms was determined as an optimized cutoff point with increased risk of VA event, which had a sensitivity of 50.0%, a specificity of 98.0%, a positive predictive value of 85.7%, and a negative predictive value of 88.7% for predicting VA event. The ROC curves for the dispersion of Tpe was 0.775 and dispersion of Tpe >=45 ms was determined as an optimized cutoff point for predicting VA event, which had a sensitivity of 91.7%, a specificity of 64.6%, a positive predictive value of 39.3%, and a negative predictive value of 96.9% for predicting VA event. In multivariate analysis, Max-Tpe interval >=140 ms (OR=27.53, 95%CI 1.07-706.77, P=0.045) and family history of sudden death (OR=24.63, 95%CI 2.05-295.38, P=0.011) were found to be the independent risk factors of arrhythmic events. Conclusions: Max-Tpe interval >=140 ms and family history of sudden death are risk factors of VA event in included patients with Brugada syndrome. PMID- 30462975 TI - [Analysis of the KCNQ1 gene mutation in 2 families with congenital long QT syndrome type 1 in Xinjiang Uygur Autonomous Region]. AB - Objective: Present study analyzed the association betwen the postassium voltage gated channel KQT-like subfamily member 1 gene (KCNQ1) mutation and the clinical and the electrocardiographic features in 2 pedigrees with congenital long QT syndrome type 1 (LQT1) in Xinjiang Uygur Autonomous Region. Methods: Three family members were diagnosed as LQT1 patients in 2 Uygur congenital LQT1 families, these 3 LQT1 patients served as long QT group, 24 Uygur healthy volunteers served as control group. Electrocardiogram (ECG) and the gene detection were applied to compare the ECG and molecular genetic features between the long QT group and control group, and to explore the relationship between the KCNQ1 gene mutation and the clinical and the electrocardiographic features in these 2 families with congenital long QT syndrome type 1. Results: The LQT1 was diagnosed in 3 cases of the 2 pedigrees. The common features of ECG were QTc>480 ms, prolonged ST segment, and delayed T wave. The gene test evidenced a polymorphism of KCNQ1 gene exon 13:47G?A(R16R). The mutation of 133G?A9(G45S) of exon 16 resulted in the change of the original glycine (G) to serine (s). The ECG of the control group were normal, and there were no KCNQ1 gene mutations in control group. Conclusion: The exon sequencing results of KCNQ1 gene in 2 Xinjiang Uygur congenital long LQT1 families showed that exon16 missense changes (133G to A (G45S)) can lead to amino acid mutation, this mutation may be a pathogenic mutation. Subsequent validation of the expanded sample will provide a reference for revealing the relationship between the KCNQ1 gene and the pathogenesis of LQT1. PMID- 30462976 TI - [Relationship between thrombolysis in myocardial infarction risk index and the severity of coronary artery lesions and long-term outcome in acute myocardial infarction patients undergoing percutaneous coronary intervention]. AB - Objective: To investigate the relationship between thrombolysis in myocardial infarction risk index(TRI) and the severity of coronary artery lesions and long term outcome in acute myocardial infarction(AMI) patients undergoing percutaneous coronary intervention(PCI). Methods: A total of 1 663 consecutive AMI patients undergoing PCI between January and December 2013 in Fuwai hospital were prospectively included in this study. The severity of coronary artery lesions was evaluated using the SYNTAX score. Receiver operating characteristic(ROC) curve was used to analyze the optimal cut-off value of TRI on predicting all-cause mortality at 2 years after PCI.The patients were divided into 2 groups based on the optimal cut-off value of TRI:high TRI group (TRI >= 23.05, 465 cases) and low TRI group(TRI<23.05, 1 198 cases). Multivariate logistic regression analyses were used for determining the relationship between TRI and SYNTAX scores>=33. A multivariate Cox regression analyses was used to identify the influence factors of long-term outcome after PCI. Results: SYNTAX score was higher in high TRI group than in low TRI group (13.00(7.00, 20.50) vs.10.25(7.00, 17.00), P<0.001). TRI was independently associated with SYNTAX score >= 33 (OR=1.09,95% CI 1.03 1.16, P=0.004). After the 2 years follow-up, rates of all-cause death (4.1% (19/465) vs. 0.3% (4/1 198) , P<0.001), cardiac death (2.6% (12/465) vs. 0.2% (2/1 198) , P< 0.001) and stent thrombosis (1.7% (8/465) vs. 0.5% (6/1 198) , P=0.015) were all significantly higher in high TRI group than in low TRI group. Multivariate Cox regression analyses showed that TRI>= 23.05 was an independent risk factor of all-cause death (HR=5.22, 95%CI 1.63-16.72, P=0.005), cardiac death (HR=8.48, 95%CI 1.75-41.07, P=0.008) and stent thrombosis(HR=3.87, 95%CI 1.32-11.41, P=0.014) at 2 years after PCI in AMI patients, but which was not the independent risk factor of major adverse cardiovascular and cerebrovascular events (HR=0.96, 95%CI 0.69-1.36, P=0.834) .The area under ROC curve of TRI >= 23.05 on predicting 2 years all-cause mortality in AMI patients undergoing PCI was 0.803(95%CI 0.711-0.894, P<0.001). Conclusions: TRI is independently associated with SYNTAX score >= 33. TRI is also an independent risk factor of 2 years all-cause death, cardiac death and stent thrombosis in AMI patients undergoing PCI. PMID- 30462977 TI - [Efficacy and outcome of transcatheter closure of patent foramen ovale in patients with cryptogenic stroke]. AB - Objective: To investigate the efficacy and outcome of transcatheter patent foramen ovale (PFO) closure in patients with cryptogenic stroke (CS). Methods: Sixty consecutive patients with cryptogenic stroke who undertook transcatheter PFO closure between May 2015 and September 2017 in Beijing Tiantan Hospital were enrolled in this prospective study.Transcranial Doppler (TCD) bubble test was performed and right-left shunt(RLS) was confirmed in all patients.Closure success rate,effective closure rate, complications, recurrence of ischemic stroke and new onset atrial fibrillation were evaluated. Results: A total of 60 patients (42 male,age range 24-68 (47+/-11)years) were included in the study.PFO size (motionless state) was (1.6+/-0.6)mm.RLS before closure was graded and 11 patients had moderate RLS and 48 patients had large RLS (include 41 patients who experienced shower or curtain effect).Closure success rate was 100% (60/60).No severe complications were observed.At 6 months,45 patients completed TCD bubble test.Of these, 4 patients suffered from moderate to large residual and thus effective closure rate was 91%(41/45).The mean follow-up period was 2-29 (median 12) months. During the follow-up, only 1 patient experienced recurrent cerebral infarction.New onset atrial fibrillation was not detected. Conclusion: Transcatheter PFO closure is effective,safe and related with a good outcome in reduction of recurrent CS for patients with PFO. PMID- 30462978 TI - [Gene screening and phenotype analysis in a pedigree with familial hypertrophic cardiomyopathy from Yunnan Province]. AB - Objective: To identify the disease-causing mutations in a pedigree with familial hypertrophic cardiomyopathy (HCM) from Yunnan province, and analyze the relationship between the genotype and the phenotype. Methods: The blood samples and the clinical data of the HCM family members were collected.The coding exons and their flanking intronic regions of 28 previously reported genes related to HCM were screened in the proband by high-throughput sequencing. The mutations in proband were confirmed and detected in all family members as well as in 159 healthy controls by Sanger sequencing.The relationship between the genotype and the phenotype was analyzed in this pedigree. Results: Two missense mutations of Arg1045His and Ala26Val in beta myosin heavy chain gene(MYH7) were identified. Genetic screening showed that the mother and brother of the proband carried Arg1045His mutation.Both mutations were absent in other family members and in 159 healthy controls.Disease onset age was less than 50 years old in this pedigree, chest pain, exertional dyspnea and syncope were the major symptoms, and all accompanied by severe left ventricular hypertrophy and left ventricular outflow tract stenosis.The grandma of the proband suffered sudden cardiac death. The proband had the worst symptoms and the earliest disease onset in this pedigree. Conclusions: We find a pedigree with familial HCM from Yunnan province carrying MYH7 Arg1045His and Ala26Val mutations. The study suggests that Arg1045His mutation in MYH7 gene caused HCM is malignant with early onset, severe ventricular hypertrophy and poor prognosis. Arg1045His and Ala26Val double-mutant might have dosage effects and aggravate the clinical phenotype of the patient. PMID- 30462980 TI - [Epicardial electrical ablation of ventricular fibrillation storm after implantable cardioverter defibrillor implantation in Brugada syndrome: a case report]. PMID- 30462979 TI - [CD137-CD137L interaction induced the calcification of mouse smooth muscle cells via P38 MAPK signaling]. AB - Objective: To explore whether CD137-CD137L interaction could induce mouse vascular smooth muscle cells(VSMCs) calcification via P38 MAPK signaling. Methods: (1) Mouse VSMCs obtained from 8-week old male C57 mice were cultured by using method of tissue piece inoculation.The cells from 3 to 8 passage were divided into 4 groups: control group, agonist-CD137 group(recombinant CD137L protein), anti-P38 group(agonist-CD137 group+P38 inhibitor), single anti-P38 group(P38 inhibitor). The calcification was induced by adding a mixture of 10 mmol/L beta-glycerophosphate+10(-8) mol/L dexamethasone+10(-7) mol/L insulin in the culture medium.Immunofluorescence was used to observe the changes of VSMCs markers(alpha-SMA and OPN).Real time-PCR was used to observe the mRNA expression of OPN and RUNX-2. Western blot was used to observe the protein expression of p P38, OPN and RUNX-2. The level of cell calcification was observed by detecting alkaline phosphatase activity and calcium concentration. (2) The degeree of local calcium deposition was also tested on Von Kossa staining and Alizarin red staining methods in following 5 mouse VSMCs groups: control group, agonist-CD137 group(recombinant CD137L protein), anti-P38 group (agonist-CD137 group+P38 inhibitor), anti-CD137 group (agonist-CD137 group+CD137 inhibitor),agonist-P38 group(anti-CD137 group+P38 agonist). Results: (1) Compared with the control group, the fluorescence intensity of alpha-SMA was lower in the agonist-CD137 group(2.79+/-0.25 vs. 5.42+/-0.47,P<0.05), while the fluorescence intensity of OPN was higher(4.91+/-0.23 vs. 1.63+/-0.26, P<0.05). The fluorescence intensity of alpha-SMA was partly recovered after adding P38 inhibitor(4.48+/-0.27 vs. 2.79+/-0.25,P<0.05),but it was still lower than the control group (4.48+/-0.27 vs. 5.42+/-0.47, P<0.05),the fluorescence intensity of OPN decreased(2.66+/-0.15 vs. 4.91+/-0.23,P<0.05),but it was still higher than that in the control group (2.66+/-0.15 vs. 1.63+/-0.26,P<0.05).The fluorescence intensity of alpha-SMA and OPN(5.32+/-0.67 vs. 5.42+/-0.47,1.82+/-0.30 vs.1.63+/-0.26,both P>0.05) was similar between the control group and single anti-P38 group.(2) Compared with the control group, the protein level of p-P38(4.15+/-0.24 vs. 3.48+/-0.26, P<0.05), OPN(2.43+/-0.21 vs. 1.53+/-0.08, P<0.05), RUNX-2(3.20+/-0.23 vs. 1.13+/-0.10, P<0.05) was significantly increased in agonist-CD137 group,the above effects were blocked by adding specific P38 inhibitor SB203580(1.16+/-0.12 vs. 4.15+/-0.24, 0.50+/-0.02 vs. 2.43+/-0.21,and 1.74+/-0.14 vs. 3.20+/-0.23,all P<0.05);the protein level of p-P38(2.93+/-0.60 vs. 3.48+/-0.26,P>0.05),OPN (1.4+/-0.64 vs. 1.53+/-0.08,P>0.05),RUNX-2(1.26+/-0.26 vs.1.13+/-0.10, P>0.05) was similar between single anti-P38 group and the control group. (3) Compared with the control group, the mRNA level of OPN (1.51+/-0.34 vs. 1, P<0.05) and RUNX 2(2.67+/-0.19 vs. 1, P<0.05) was significantly upregulated in agonist-CD137 group, and these effects were blocked by adding specific P38 inhibitor SB203580(0.33+/-0.14 vs. 1 and 0.45+/-0.03 vs. 1,P<0.05);the mRNA level of OPN (1.05+/-0.09 vs. 1, P>0.05) and RUNX-2(1.18+/-0.10 vs. 1, P>0.05) was similar between the single anti-P38 group and the control group.(4) Compared with the control group,the ALP activity and calcium concentration(2.40+/-0.25 vs. 1.40+/ 0.21,5.51+/-0.33 vs. 3.15+/-0.31,both P<0.05) were significantly increased in agonist-CD137 group,while the effects could be blocked by adding specific P38 inhibitor SB203580((1.99+/-0.07) king unit/gprot vs. (2.40+/-0.25) king unit/gprot, (3.74+/-0.20) mmol/gprot vs. (5.51+/-0.33) mmol/gprot, both P<0.05).The ALP activity and calcium concentration was similar between single anti-P38 group and the control group((1.60+/-0.25) king unit/gprot vs. (1.40+/ 0.21)king unit/gprot, (2.66+/-0.28) mmol/gprot vs. (3.15+/-0.31) mmol/gprot, both P>0.05). (5) Compared with the control group,the calcification of VSMCs in the agonist-CD137 group was significantly increased,while the calcification in the anti-P38 group was significantly reduced.Compared with the agonist-CD137 group,the level of calcification in the anti-CD137 group was obviously increased,and the calcification in the agonist-P38 group was significantly higher than that in the anti-CD137 group and the control group. Conclusion: These findings suggest that CD137-CD137L signaling may regulate VSMCs calcification via modulating P38 pathway. PMID- 30462981 TI - [A case of acute myocardial infarction and cardiac shock due to severe coronary arteryspasm]. PMID- 30462983 TI - [Research progress on predictive factors for sudden cardiac death in patients with non-ischemic cardiomyopathy]. PMID- 30462982 TI - [A case of acromegalic cardiomyopathy]. PMID- 30462984 TI - [Role of gut microbiota and trimethylamine N-oxide in atherothrombotic diseases]. PMID- 30462985 TI - Nicotine modulates the facial stimulation-evoked responses in cerebellar granule cell layer in vivo in mice. AB - Nicotinic acetylcholine receptors are cationic channels that mediate fast excitatory transmission in the central nervous system. Several nicotinic acetylcholine receptor subunits have been detected within cerebellar granule cell layer (GCL), and activation of these receptors may have a significant influence on neuronal synaptic transmission of the cerebellum. The aim of present study was to better understand the roles of nicotinic acetylcholine receptors during the sensory stimulation-evoked synaptic transmission in the cerebellar GCL. Our results showed that cerebellar surface perfusion of nicotine significantly facilitated the cerebellar GCL field potential responses evoked by air-puff stimulation of ipsilateral whisker pad, which exhibited increases in amplitude and area under the curve (AUC) of both stimulus onset responses (N1) and stimulus offset responses (N2). The nicotine-induced increase in AUC of facial stimulation evoked N1 was dose-dependent with a 50% effective concentration (EC50) of 32.6 MUM. Application of either a selective alpha4beta2 nicotinic acetylcholine receptors antagonist, DHbetaE (1 MUM) or a selective alpha7 nicotinic acetylcholine receptors antagonist, MLA (1 MUM) alone attenuated, but not completely abolished the nicotine-induced increases in the amplitude and AUC of the facial stimulation-evoked N1. However, simultaneous blockade of alpha7 and alpha4beta2 nicotinic acetylcholine receptor subunits abolished the nicotine induced increase in the amplitude of N1. These results indicate that nicotine activates alpha7 and alpha4beta2 nicotinic acetylcholine receptor subunits, resulting in an enhancement of facial stimulation-evoked responses in mouse cerebellar GCL. Our results suggest that nicotine modulates the sensory information processing in the cerebellar GCL through alpha7 and alpha4beta2 subunits nicotinic acetylcholine receptors. PMID- 30462986 TI - Porous magnetic resin-g-chitosan beads for adsorptive removal of phenolic compounds. AB - In this study, porous magnetic resin grafted chitosan (R-g-Ch) beads were prepared for removal of 4-chlorophenol and phenol from aqueous solutions. The R-g Ch beads were characterized by vibrating sample magnetometer, Fourier-transform infrared spectroscopy, scanning electron microscopy and thermogravimetry methods. The removal of the phenolic compounds was optimized by varying the experimental conditions. Results herein are well fitted to the pseudo-second order kinetic and Langmuir isotherm. The maximum adsorption capacity of phenol and 4-chlorophenol were found to be 188.6 and 99 mg/g, respectively. The thermodynamic studies suggested that the adsorption process was exothermic, irreversible and feasible within the range of 298-318 K. PMID- 30462987 TI - Anorexigenic effects of estradiol in the medial preoptic area occur through membrane-associated estrogen receptors and metabotropic glutamate receptors. AB - Activation of membrane-associated estrogen receptors (mER) decreases food and water intake in female rats. Additional studies suggest these effects are mediated, at least in part, by membrane-associated estrogen receptor alpha (ERalpha). Nevertheless, the critical site of action and the intracellular signaling required for the ingestive effects of ERalpha remain unclear. Estradiol given to the medial preoptic area (mPOA) decreases ingestive behaviors, and membrane-associated ERalpha has been shown to affect intracellular signaling through interactions with metabotropic glutamate receptor (mGluR) subtypes, but an involvement of this signaling pathway, in the mPOA, in ingestive behavior remains untested. To address these open questions, we first showed that activation of mER in the mPOA decreased both overnight food and water intake, and did so in a time course consistent with a genomic mechanism of action. Next, we tested the requirement of mGluR1a signaling in the mPOA for the anorexigenic and anti-dipsogenic effects of estradiol. As expected, estradiol in the mPOA decreased food intake, but only in the absence of an mGluR1a antagonist. The same was not true for estradiol effects on water intake, which were unaffected by an mGluR1a antagonist. These results suggest that estrogens require mGluR activation for at least some of their effects on ingestive behaviors, and indicate that the mPOA is a critical site of action. The results also reveal an interesting divergence in the estrogenic control of ingestive behavior by which mGluR signaling in the mPOA plays a role in the control of food intake, but not water intake. PMID- 30462988 TI - Effects of a novel partner and sexual satiety on the expression of male sexual behavior and brain aromatase activity in quail. AB - This study was designed to determine whether changes in sexual motivation acutely regulate brain estrogen synthesis by aromatase. Five experiments (Exp.1-5) were first conducted to determine the effect of recent mating and of the presentation of a new female (Coolidge effect) on sexual motivation. Exp.1-2 showed that 10 min or overnight access to copulation decreases measures of male sexual motivation when male subjects were visually exposed to the female they had copulated with and this effect is not counteracted by the view of a new female. Exp.3 showed that sexual motivation is revived by the view of a new female in previously unmated males only allowed to see another female for 10 min. After mating for 10 min (Exp.4) or overnight (Exp.5) with a female, males showed a decrease in copulatory behavior that was not reversed by access to a new female. Exp.6 and 7 confirmed that overnight copulation (Exp.6) and view of a novel female (Exp.7) respectively decreases and increases sexual behavior and motivation. Yet, these manipulations did not affect brain aromatase activity except in the tuberal hypothalamus. Together these data confirm that copulation or prolonged view of a female decrease sexual motivation but a reactivation of sexual motivation by a new female can only be obtained if males had only seen another female but not copulated with her, which is different in some degree from the Coolidge effect described in rodents. Moreover changes in brain aromatase do not simply reflect changes in motivation and more complex mechanisms must be considered. PMID- 30462989 TI - Kv4.3 expression abrogates and reverses norepinephrine-induced myocyte hypertrophy by CaMKII inhibition. AB - BACKGROUND: Down-regulation of Kv4.3 protein is a general feature of cardiac hypertrophy. Based on our recent studies, we propose that Kv4.3 reduction may be a hypertrophic stimulator. OBJECTIVE: We tested whether Kv4.3 expression can prevent or reverse cardiac hypertrophy induced by norepinephrine (NE). METHODS AND RESULTS: Incubation of 20 MUM NE in cultured neonatal rat ventricular myocytes (NRVMs) for 48 h and 96 h induced myocyte hypertrophy in a time dependent manner, characterized by progressive increase in cell size, protein/DNA ratio, ANP and BNP, along with an progressive increase in the activity of CaMKII and calcineurin and reduction of Kv4.3 mRNA and proteins. Interestingly, PKA dependent phosphorylation of phospholamban (PLB) at Ser16 was increased at 48 h but reduced to the basal level at 96 h NE incubation. CaMKII inhibitors KN93 and AIP blunted NE-induced hypertrophic response and caused regression of hypertrophy, which is associated with a reduction of CaMKII activity and calcineurin expression. Kv4.3 expression completely suppressed the development of NE-induced hypertrophy and led to a regression in the hypertrophic myocytes. These effects were accompanied by a reduction in CaMKII autophosphorylation, PLB phosphorylation at Thr-17 without changing PLB phosphorylation at Ser-16. NFATc3 was also reduced by Kv4.3 expression. CONCLUSIONS: Our results demonstrated that Kv4.3 reduction is an important mediator in cardiac hypertrophy development via excessive CaMKII activation and that Kv4.3 expression is likely a potential therapeutic strategy for prevention and reversion of adrenergic stress-induced cardiac hypertrophy. PMID- 30462990 TI - Monocyte-Derived Macrophages: The Missing Link in Organ Transplantation. AB - Successful organ transplantation requires an optimal innate immune response to avoid tissue injury. In this issue of Immunity, Braza et al. (2018) inhibit pro inflammatory activation of infiltrating graft macrophages using nanotechnology tools to promote immune tolerance, leading to long-term transplant acceptance in mouse models. PMID- 30462991 TI - Bonds Voyage! A Dissociative Model of TCR-CD3 Triggering Is Proposed. AB - How the T cell receptor (TCR)-CD3 complex activates T cells is debated. In this issue of Immunity, Brazin et al. (2018) propose that TCR engagement under force releases the CD3 signaling modules to disperse and adopt signaling active states. PMID- 30462992 TI - 23, 22 Calling the Microbiota to Control Atherosclerosis. AB - While the commensal microbiota is considered an important regulator of immunity and metabolism, the mechanisms controlling the interplay between diet, cytokine signaling, and the microbiota in atherosclerosis remains unknown. In this issue of Immunity, Fatkhullina et al. (2018) demonstrate that interlukin-23-22 axis regulates diet-induced atherosclerosis by repressing pro-atherogenic microbiota. PMID- 30462993 TI - Fc-Engineered Anti-4-1BB Antibodies Pack a One-Two Punch. AB - A key issue in immuno-oncology is how to optimize and combine antibody therapies for improved efficacy. In this issue of Immunity, Buchan et al. (2018) reveal the importance of antibody Fc region, Fc receptor availability, and sequence of administration for optimal cancer therapy with antibodies targeting the co stimulatory receptor 4-1BB. PMID- 30462994 TI - Seq-ing out the Killers of Mice and Men. AB - The diversity of natural killer cells between mouse and human is poorly understood. In this issue of Immunity, Crinier et al. (2018) utilize single-cell RNA-seq to profile splenic and blood NK cells from both organisms, uncovering both tissue- and species-specific transcriptomic signatures. PMID- 30462995 TI - Are Neuropeptide-Reactive T Cells behind Narcolepsy? AB - Researchers have previously hypothesized autoimmune origins for narcolepsy on the basis of its strong genetic association with an MHC class II allele. In a recent issue of Nature, Latorre et al. (2018) discovered that narcolepsy patients had autoreactive T cells specific to the neuronal antigen hypocretin, providing more evidence of the potential immune origin of the disease. PMID- 30462996 TI - Mets and NETs: The Awakening Force. AB - In a recent study published in Science, Albrengues et al. (2018) unveil an intriguing mechanism whereby the release of neutrophil extra-cellular traps during chronic lung inflammation awakens dormant malignant cells and contributes to cancer progression. PMID- 30462998 TI - Heart Regeneration in the Mexican Cavefish. AB - Although Astyanax mexicanus surface fish regenerate their hearts after injury, their Pachon cave-dwelling counterparts cannot and, instead, form a permanent fibrotic scar, similar to the human heart. Myocardial proliferation peaks at similar levels in both surface fish and Pachon 1 week after injury. However, in Pachon, this peak coincides with a strong scarring and immune response, and ultimately, cavefish cardiomyocytes fail to replace the scar. We identified lrrc10 to be upregulated in surface fish compared with Pachon after injury. Similar to cavefish, knockout of lrrc10 in zebrafish impairs heart regeneration without affecting wound cardiomyocyte proliferation. Furthermore, using quantitative trait locus (QTL) analysis, we have linked the degree of heart regeneration to three loci in the genome, identifying candidate genes fundamental to the difference between scarring and regeneration. Our study provides evidence that successful heart regeneration entails a delicate interplay between cardiomyocyte proliferation and scarring. PMID- 30462999 TI - Chiral Cilia Orientation in the Left-Right Organizer. AB - Chirality is a property of asymmetry between an object and its mirror image. Most biomolecules and many cell types are chiral. In the left-right organizer (LRO), cilia-driven flows transfer such chirality to the body scale. However, the existence of cellular chirality within tissues remains unknown. Here, we investigate this question in Kupffer's vesicle (KV), the zebrafish LRO. Quantitative live imaging reveals that cilia populating the KV display asymmetric orientation between the right and left sides, resulting in a chiral structure, which is different from the chiral cilia rotation. This KV chirality establishment is dynamic and depends on planar cell polarity. While its impact on left-right (LR) symmetry breaking remains unclear, we show that this asymmetry does not depend on the LR signaling pathway or flow. This work identifies a different type of tissue asymmetry and sheds light on chirality genesis in developing tissues. PMID- 30463000 TI - Synaptic Convergence Patterns onto Retinal Ganglion Cells Are Preserved despite Topographic Variation in Pre- and Postsynaptic Territories. AB - Sensory processing can be tuned by a neuron's integration area, the types of inputs, and the proportion and number of connections with those inputs. Integration areas often vary topographically to sample space differentially across regions. Here, we highlight two visual circuits in which topographic changes in the postsynaptic retinal ganglion cell (RGC) dendritic territories and their presynaptic bipolar cell (BC) axonal territories are either matched or unmatched. Despite this difference, in both circuits, the proportion of inputs from each BC type, i.e., synaptic convergence between specific BCs and RGCs, remained constant across varying dendritic territory sizes. Furthermore, synapse density between BCs and RGCs was invariant across topography. Our results demonstrate a wiring design, likely engaging homotypic axonal tiling of BCs, that ensures consistency in synaptic convergence between specific BC types onto their target RGCs while enabling independent regulation of pre- and postsynaptic territory sizes and synapse number between cell pairs. PMID- 30462997 TI - Modulation of Host Immunity by Helminths: The Expanding Repertoire of Parasite Effector Molecules. AB - Helminths are extraordinarily successful parasites due to their ability to modulate the host immune response. They have evolved a spectrum of immunomodulatory molecules that are now beginning to be defined, heralding a molecular revolution in parasite immunology. These discoveries have the potential both to transform our understanding of parasite adaptation to the host and to develop possible therapies for immune-mediated disease. In this review we will summarize the current state of the art in parasite immunomodulation and discuss perspectives on future areas for research and discovery. PMID- 30463001 TI - Secretion of Tau via an Unconventional Non-vesicular Mechanism. AB - Tauopathies are characterized by cerebral accumulation of Tau protein aggregates that appear to spread throughout the brain via a cell-to-cell transmission process that includes secretion and uptake of pathological Tau, followed by templated misfolding of normal Tau in recipient cells. Here, we show that phosphorylated, oligomeric Tau clusters at the plasma membrane in N2A cells and is secreted in vesicle-free form in an unconventional process sensitive to changes in membrane properties, particularly cholesterol and sphingomyelin content. Cell surface heparan sulfate proteoglycans support Tau secretion, possibly by facilitating its release after membrane penetration. Notably, secretion of endogenous Tau from primary cortical neurons is mediated, at least partially, by a similar mechanism. We suggest that Tau is released from cells by an unconventional secretory mechanism that involves its phosphorylation and oligomerization and that membrane interaction may help Tau to acquire properties that allow its escape from cells directly through the plasma membrane. PMID- 30463002 TI - Recruitment of Cytosolic J-Proteins by TOM Receptors Promotes Mitochondrial Protein Biogenesis. AB - Mitochondria possess elaborate machineries for the import of proteins from the cytosol. Cytosolic factors like Hsp70 chaperones and their co-chaperones, the J proteins, guide proteins to the mitochondrial surface. The translocase of the mitochondrial outer membrane (TOM) forms the entry gate for preproteins. How the proteins are delivered to mitochondrial preprotein receptors is poorly understood. We identify the cytosolic J-protein Xdj1 as a specific interaction partner of the central receptor Tom22. Tom22 recruits Xdj1 to the mitochondrial surface to promote import of preproteins and assembly of the TOM complex. Additionally, we find that the receptor Tom70 binds a different cytosolic J protein, Djp1. Our findings suggest that cytosolic J-proteins target distinct TOM receptors and promote the biogenesis of mitochondrial proteins. PMID- 30463003 TI - A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia. AB - Metabolic reprogramming has emerged as a crucial regulator of immune cell activation, but how systemic metabolism influences immune cell metabolism and function remains to be investigated. To investigate the effect of dyslipidemia on immune cell metabolism, we performed in-depth transcriptional, metabolic, and functional characterization of macrophages isolated from hypercholesterolemic mice. Systemic metabolic changes in such mice alter cellular macrophage metabolism and attenuate inflammatory macrophage responses. In addition to diminished maximal mitochondrial respiration, hypercholesterolemia reduces the LPS-mediated induction of the pentose phosphate pathway (PPP) and the Nrf2 mediated oxidative stress response. Our observation that suppression of the PPP diminishes LPS-induced cytokine secretion supports the notion that this pathway contributes to inflammatory macrophage responses. Overall, this study reveals that systemic and cellular metabolism are strongly interconnected, together dictating macrophage phenotype and function. PMID- 30463004 TI - PD-1 Is Involved in the Dysregulation of Type 2 Innate Lymphoid Cells in a Murine Model of Obesity. AB - Recent observations clearly highlight the critical role of type 2 innate lymphoid cells in maintaining the homeostasis of adipose tissues in humans and mice. This cell population promotes beiging and limits adiposity directly and indirectly by sustaining a Th2-prone environment enriched in eosinophils and alternatively activated macrophages. Accordingly, the number and function of type 2 innate lymphoid cells (ILC2s) are strongly impaired in obese individuals. In this work, we identify the PD-1-PD-L1 pathway as a factor leading to ILC2 destabilization upon high-fat feeding resulting in impaired tissue metabolism. Tumor necrosis factor (TNF) appears to play a central role, triggering interleukin-33 (IL-33) dependent PD-1 expression on ILC2s and recruiting and activating PD-L1hi M1 macrophages. PD-1 blockade partially restores the type 2 innate axis, raising the possibility of restoring tissue homeostasis. PMID- 30463005 TI - BET Inhibition Induces HEXIM1- and RAD51-Dependent Conflicts between Transcription and Replication. AB - BET bromodomain proteins are required for oncogenic transcription activities, and BET inhibitors have been rapidly advanced into clinical trials. Understanding the effects of BET inhibition on processes such as DNA replication will be important for future clinical applications. Here, we show that BET inhibition, and specifically inhibition of BRD4, causes replication stress through a rapid overall increase in RNA synthesis. We provide evidence that BET inhibition acts by releasing P-TEFb from its inhibitor HEXIM1, promoting interference between transcription and replication. Unusually, these transcription-replication conflicts do not activate the ATM/ATR-dependent DNA damage response but recruit the homologous recombination factor RAD51. Both HEXIM1 and RAD51 promote BET inhibitor-induced fork slowing but also prevent a DNA damage response. Our data suggest that BET inhibitors slow replication through concerted action of transcription and recombination machineries and shed light on the importance of replication stress in the action of this class of experimental cancer drugs. PMID- 30463006 TI - Purinergic-Dependent Glial Regulation of Synaptic Plasticity of Competing Terminals and Synapse Elimination at the Neuromuscular Junction. AB - The precise wiring of synaptic connections requires the elimination of supernumerary inputs competing for innervation of the same target cell. This competition is activity-dependent, strengthening some inputs whereas others are eliminated. Although glial cells are required for the elimination and clearance of terminals, their involvement in activity-dependent synaptic competition remains ill-defined. Here, we used the developing neuromuscular junctions of mice to show that perisynaptic glial cells, through 2Y1 purinergic receptors (P2Y1Rs), decode synaptic efficacy of competing terminals in a Ca2+-dependent manner. This glial activity induces long-lasting synaptic potentiation of strong but not weak terminals via presynaptic adenosine 2A receptors. Blockade of glial activity by intracellular Ca2+ chelation or blockade of P2Y1Rs prevents this plasticity. In addition, blockade of P2Y1Rs delays synapse elimination in vivo. Hence, P2Y1Rs drive glial cell regulation of strong synaptic inputs and influence synapse competition and elimination. PMID- 30463008 TI - Constitutive Activation of the Canonical NF-kappaB Pathway Leads to Bone Marrow Failure and Induction of Erythroid Signature in Hematopoietic Stem Cells. AB - Constitutive activation of the canonical NF-kappaB pathway has been associated with a variety of human pathologies. However, molecular mechanisms through which canonical NF-kappaB affects hematopoiesis remain elusive. Here, we demonstrate that deregulated canonical NF-kappaB signals in hematopoietic stem cells (HSCs) cause a complete depletion of HSC pool, pancytopenia, bone marrow failure, and premature death. Constitutive activation of IKK2 in HSCs leads to impaired quiescence and loss of function. Gene set enrichment analysis (GSEA) identified an induction of "erythroid signature" in HSCs with augmented NF-kappaB activity. Mechanistic studies indicated a reduction of thrombopoietin (TPO)-mediated signals and its downstream target p57 in HSCs, due to reduced c-Mpl expression in a cell-intrinsic manner. Molecular studies established Klf1 as a key suppressor of c-Mpl in HSPCs with increased NF-kappaB. In essence, these studies identified a previously unknown mechanism through which exaggerated canonical NF-kappaB signals affect HSCs and cause pathophysiology. PMID- 30463007 TI - The Molecular Signature of Megakaryocyte-Erythroid Progenitors Reveals a Role for the Cell Cycle in Fate Specification. AB - Megakaryocytic-erythroid progenitors (MEPs) give rise to the cells that produce red blood cells and platelets. Although the mechanisms underlying megakaryocytic (MK) and erythroid (E) maturation have been described, those controlling their specification from MEPs are unknown. Single-cell RNA sequencing of primary human MEPs, common myeloid progenitors (CMPs), megakaryocyte progenitors, and E progenitors revealed a distinct transitional MEP signature. Inferred regulatory transcription factors (TFs) were associated with differential expression of cell cycle regulators. Genetic manipulation of selected TFs validated their role in lineage specification and demonstrated coincident modulation of the cell cycle. Genetic and pharmacologic modulation demonstrated that cell cycle activation is sufficient to promote E versus MK specification. These findings, obtained from healthy human cells, lay a foundation to study the mechanisms underlying benign and malignant disease states of the megakaryocytic and E lineages. PMID- 30463009 TI - The NF-kappaB Factor Relish Regulates Atg1 Expression and Controls Autophagy. AB - Macroautophagy and cell death both contribute to innate immunity, but little is known about how these processes integrate. Drosophila larval salivary glands require autophagy for developmentally programmed cell death, and innate immune signaling factors increase in these dying cells. Here, we show that the nuclear factor kappaB (NF-kappaB) factor Relish, a component of the immune deficiency (Imd) pathway, is required for salivary gland degradation. Surprisingly, of the classic Imd pathway components, only Relish and the PGRP receptors were involved in salivary gland degradation. Significantly, Relish controls salivary gland degradation by regulating autophagy but not caspases. In addition, expression of either Relish or PGRP-LC causes premature autophagy induction and subsequent gland degradation. Relish controls autophagy by regulating the expression of Atg1, a core component and activator of the autophagy pathway. Together these findings demonstrate that a NF-kappaB pathway regulates autophagy during developmentally programmed cell death. PMID- 30463010 TI - Computational Design of Epitope-Specific Functional Antibodies. AB - The ultimate goal of protein design is to introduce new biological activity. We propose a computational approach for designing functional antibodies by focusing on functional epitopes, integrating large-scale statistical analysis with multiple structural models. Machine learning is used to analyze these models and predict specific residue-residue contacts. We use this approach to design a functional antibody to counter the proinflammatory effect of the cytokine interleukin-17A (IL-17A). X-ray crystallography confirms that the designed antibody binds the targeted epitope and the interaction is mediated by the designed contacts. Cell-based assays confirm that the antibody is functional. Importantly, this approach does not rely on a high-quality 3D model of the designed complex or even a solved structure of the target. As demonstrated here, this approach can be used to design biologically active antibodies, removing some of the main hurdles in antibody design and in drug discovery. PMID- 30463011 TI - A Dock-and-Lock Mechanism Clusters ADAM10 at Cell-Cell Junctions to Promote alpha Toxin Cytotoxicity. AB - We previously identified PLEKHA7 and other junctional proteins as host factors mediating death by S. aureus alpha-toxin, but the mechanism through which junctions promote toxicity was unclear. Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. ADAM10 is locked at junctions through binding of its cytoplasmic C terminus to afadin. Junctionally clustered ADAM10 supports the efficient formation of stable toxin pores. Instead, disruption of the PLEKHA7 PDZD11 complex inhibits ADAM10 and toxin junctional clustering. This promotes toxin pore removal from the cell surface through an actin- and macropinocytosis dependent process, resulting in cell recovery from initial injury and survival. These results uncover a dock-and-lock molecular mechanism to target ADAM10 to junctions and provide a paradigm for how junctions regulate transmembrane receptors through their clustering. PMID- 30463012 TI - Activation of miR-21-Regulated Pathways in Immune Aging Selects against Signatures Characteristic of Memory T Cells. AB - Induction of protective vaccine responses, governed by the successful generation of antigen-specific antibodies and long-lived memory T cells, is increasingly impaired with age. Regulation of the T cell proteome by a dynamic network of microRNAs is crucial to T cell responses. Here, we show that activation-induced upregulation of miR-21 biases the transcriptome of differentiating T cells away from memory T cells and toward inflammatory effector T cells. Such a transcriptome bias is also characteristic of T cell responses in older individuals who have increased miR-21 expression and is reversed by antagonizing miR-21. miR-21 targets negative feedback circuits in several signaling pathways. The concerted, sustained activity of these signaling pathways in miR-21high T cells disfavors the induction of transcription factor networks involved in memory cell differentiation. Our data suggest that curbing miR-21 upregulation or activity in older individuals may improve their ability to mount effective vaccine responses. PMID- 30463013 TI - AMPK Activation Regulates LTBP4-Dependent TGF-beta1 Secretion by Pro-inflammatory Macrophages and Controls Fibrosis in Duchenne Muscular Dystrophy. AB - Chronic inflammation and fibrosis characterize Duchenne muscular dystrophy (DMD). We show that pro-inflammatory macrophages are associated with fibrosis in mouse and human DMD muscle. DMD-derived Ly6Cpos macrophages exhibit a profibrotic activity by sustaining fibroblast production of collagen I. This is mediated by the high production of latent-TGF-beta1 due to the higher expression of LTBP4, for which polymorphisms are associated with the progression of fibrosis in DMD patients. Skewing macrophage phenotype via AMPK activation decreases ltbp4 expression by Ly6Cpos macrophages, blunts the production of latent-TGF-beta1, and eventually reduces fibrosis and improves DMD muscle force. Moreover, fibro adipogenic progenitors are the main providers of TGF-beta-activating enzymes in mouse and human DMD, leading to collagen production by fibroblasts. In vivo pharmacological inhibition of TGF-beta-activating enzymes improves the dystrophic phenotype. Thus, an AMPK-LTBP4 axis in inflammatory macrophages controls the production of TGF-beta1, which is further activated by and acts on fibroblastic cells, leading to fibrosis in DMD. PMID- 30463014 TI - Plasminogen Activator Inhibitor-1 Promotes the Recruitment and Polarization of Macrophages in Cancer. AB - Plasminogen activator inhibitor-1 (PAI-1) has a pro-tumorigenic function via its pro-angiogenic and anti-apoptotic activities. Here, we demonstrate that PAI-1 promotes the recruitment and M2 polarization of monocytes/macrophages through different structural domains. Its LRP1 interacting domain regulated macrophage migration, while its C-terminal uPA interacting domain promoted M2 macrophage polarization through activation of p38MAPK and nuclear factor kappaB (NF-kappaB) and induction of an autocrine interleukin (IL)-6/STAT3 activation pathway. We then show in several experiments in mice that expression of PAI-1 is associated with increased tumorigenicity, increased presence of M2 macrophages, higher levels of IL-6, and increased STAT3 phosphorylation in macrophages. Strong positive correlations between PAI-1, IL-6, and CD163 (M2 marker) expression were also found by meta-analysis of transcriptome data in many human cancers. Altogether, these data provide evidence for a mechanism explaining the paradoxical pro-tumorigenic function of PAI-1 in cancer. PMID- 30463015 TI - Janus Kinase 1 Plays a Critical Role in Mammary Cancer Progression. AB - Janus kinases (JAKs) and their downstream STAT proteins play key roles in cytokine signaling, tissue homeostasis, and cancer development. Using a breast cancer model that conditionally lacks Janus kinase 1, we show here that JAK1 is essential for IL-6-class inflammatory cytokine signaling and plays a critical role in metastatic cancer progression. JAK1 is indispensable for the oncogenic activation of STAT1, STAT3, and STAT6 in ERBB2-expressing cancer cells, suggesting that ERBB2 receptor tyrosine kinase complexes do not directly activate these STAT proteins in vivo. A genome-wide gene expression analysis revealed that JAK1 signaling has pleiotropic effects on several pathways associated with cancer progression. We established that FOS and MAP3K8 are targets of JAK1/STAT3 signaling, which promotes tumorsphere formation and cell migration. The results highlight the significance of JAK1 as a rational therapeutic target to block IL-6 class cytokines, which are master regulators of cancer-associated inflammation. PMID- 30463016 TI - Cellular Barcoding Identifies Clonal Substitution as a Hallmark of Local Recurrence in a Surgical Model of Head and Neck Squamous Cell Carcinoma. AB - Local recurrence after surgery for head and neck squamous cell carcinoma (HNSCC) remains a common event associated with a dismal prognosis. Improving this outcome requires a better understanding of cancer cell populations that expand from postsurgical minimal residual disease (MRD). Therefore, we assessed clonal dynamics in a surgical model of barcoded HNSCC growing in the submental region of immunodeficient mice. Clonal substitution and massive reduction of clonal heterogeneity emerged as hallmarks of local recurrence, as the clones dominating in less heterogeneous recurrences were scarce in their matched primary tumors. These lineages were selected by their ability to persist after surgery and competitively expand from MRD. Clones enriched in recurrences exhibited both private and shared genetic features and likely originated from ancestors shared with clones dominating in primary tumors. They demonstrated high invasiveness and epithelial-to-mesenchymal transition, eventually providing an attractive target for obtaining better local control for these tumors. PMID- 30463017 TI - Transmembrane Protease TMPRSS11B Promotes Lung Cancer Growth by Enhancing Lactate Export and Glycolytic Metabolism. AB - Pathways underlying metabolic reprogramming in cancer remain incompletely understood. We identify the transmembrane serine protease TMPRSS11B as a gene that promotes transformation of immortalized human bronchial epithelial cells (HBECs). TMPRSS11B is upregulated in human lung squamous cell carcinomas (LSCCs), and high expression is associated with poor survival of non-small cell lung cancer patients. TMPRSS11B inhibition in human LSCCs reduces transformation and tumor growth. Given that TMPRSS11B harbors an extracellular (EC) protease domain, we hypothesized that catalysis of a membrane-bound substrate modulates tumor progression. Interrogation of a set of soluble receptors revealed that TMPRSS11B promotes solubilization of Basigin, an obligate chaperone of the lactate monocarboxylate transporter MCT4. Basigin release mediated by TMPRSS11B enhances lactate export and glycolytic metabolism, thereby promoting tumorigenesis. These findings establish an oncogenic role for TMPRSS11B and provide support for the development of therapies that target this enzyme at the surface of cancer cells. PMID- 30463018 TI - Comparing the Effects of Low-Protein and High-Carbohydrate Diets and Caloric Restriction on Brain Aging in Mice. AB - Calorie restriction (CR) increases lifespan and improves brain health in mice. Ad libitum low-protein, high-carbohydrate (LPHC) diets also extend lifespan, but it is not known whether they are beneficial for brain health. We compared hippocampus biology and memory in mice subjected to 20% CR or provided ad libitum access to one of three LPHC diets or to a control diet. Patterns of RNA expression in the hippocampus of 15-month-old mice were similar between mice fed CR and LPHC diets when we looked at genes associated with longevity, cytokines, and dendrite morphogenesis. Nutrient-sensing proteins, including SIRT1, mTOR, and PGC1alpha, were also influenced by diet; however, the effects varied by sex. CR and LPHC diets were associated with increased dendritic spines in dentate gyrus neurons. Mice fed CR and LPHC diets had modest improvements in the Barnes maze and novel object recognition. LPHC diets recapitulate some of the benefits of CR on brain aging. PMID- 30463019 TI - A Metabolic Checkpoint for the Yeast-to-Hyphae Developmental Switch Regulated by Endogenous Nitric Oxide Signaling. AB - The yeast Candida albicans colonizes several sites in the human body and responds to metabolic signals in commensal and pathogenic states. The yeast-to-hyphae transition correlates with virulence, but how metabolic status is integrated with this transition is incompletely understood. We used the putative mitochondrial fission inhibitor mdivi-1 to probe the crosstalk between hyphal signaling and metabolism. Mdivi-1 repressed C. albicans hyphal morphogenesis, but the mechanism was independent of its presumed target, the mitochondrial fission GTPase Dnm1. Instead, mdivi-1 triggered extensive metabolic reprogramming, consistent with metabolic stress, and reduced endogenous nitric oxide (NO) levels. Limiting endogenous NO stabilized the transcriptional repressor Nrg1 and inhibited the yeast-to-hyphae transition. We establish a role for endogenous NO signaling in C. albicans hyphal morphogenesis and suggest that NO regulates a metabolic checkpoint for hyphal growth. Furthermore, identifying NO signaling as an mdivi-1 target could inform its therapeutic applications in human diseases. PMID- 30463020 TI - Chromatin Modifiers SET-25 and SET-32 Are Required for Establishment but Not Long Term Maintenance of Transgenerational Epigenetic Inheritance. AB - Some epigenetic modifications are inherited from one generation to the next, providing a potential mechanism for the inheritance of environmentally acquired traits. Transgenerational inheritance of RNAi phenotypes in Caenorhabditis elegans provides an excellent model to study this phenomenon, and although studies have implicated both chromatin modifications and small RNA pathways in heritable silencing, their relative contributions remain unclear. Here, we demonstrate that the putative histone methyltransferases SET-25 and SET-32 are required for establishment of a transgenerational silencing signal but not for long-term maintenance of this signal between subsequent generations, suggesting that transgenerational epigenetic inheritance is a multi-step process with distinct genetic requirements for establishment and maintenance of heritable silencing. Furthermore, small RNA sequencing reveals that the abundance of secondary siRNAs (thought to be the effector molecules of heritable silencing) does not correlate with silencing phenotypes. Together, our results suggest that the current mechanistic models of epigenetic inheritance are incomplete. PMID- 30463021 TI - C. elegans Heterochromatin Factor SET-32 Plays an Essential Role in Transgenerational Establishment of Nuclear RNAi-Mediated Epigenetic Silencing. AB - The dynamic process by which nuclear RNAi engages a transcriptionally active target, before the repressive state is stably established, remains largely a mystery. Here, we found that the onset of exogenous dsRNA-induced nuclear RNAi in C. elegans is a transgenerational process, and it requires a putative histone methyltransferase (HMT), SET-32. By developing a CRISPR-based genetic approach, we found that silencing establishment at the endogenous targets of germline nuclear RNAi also requires SET-32. Although SET-32 and two H3K9 HMTs, MET-2 and SET-25, are dispensable for the maintenance of silencing, they do contribute to transcriptional repression in mutants that lack the germline nuclear Argonaute protein HRDE-1, suggesting a conditional role of heterochromatin in the maintenance phase. Our study indicates that (1) establishment and maintenance of siRNA-guided transcriptional repression are two distinct processes with different genetic requirements and (2) the rate-limiting step of the establishment phase is a transgenerational, chromatin-based process. PMID- 30463022 TI - Single-Cell Transcriptome Analysis Reveals Estrogen Signaling Coordinately Augments One-Carbon, Polyamine, and Purine Synthesis in Breast Cancer. AB - Estrogen drives breast cancer (BCa) progression by directly activating estrogen receptor alpha (ERalpha). However, because of the stochastic nature of gene transcription, it is important to study the estrogen signaling pathway at the single-cell level to fully understand how ERalpha regulates transcription. Here, we performed single-cell transcriptome analysis on ERalpha-positive BCa cells following 17beta-estradiol stimulation and reconstructed the dynamic estrogen responsive transcriptional network from discrete time points into a pseudotemporal continuum. Notably, differentially expressed genes show an estrogen-stimulated metabolic switch that favors biosynthesis but reduces estrogen degradation. Moreover, folate-mediated one-carbon metabolism is reprogrammed through the mitochondrial folate pathway and polyamine and purine synthesis are upregulated coordinately. Finally, we show AZIN1 and PPAT are direct ERalpha targets that are essential for BCa cell survival and growth. In summary, our study highlights the dynamic transcriptional heterogeneity in ERalpha-positive BCa cells upon estrogen stimulation and uncovers a mechanism of estrogen-mediated metabolic switch. PMID- 30463023 TI - A novel Rhein derivative: Activation of Rac1/NADPH pathway enhances sensitivity of nasopharyngeal carcinoma cells to radiotherapy. AB - Radiation resistance and recurrent have become the major factors resulting in poor prognosis in the clinical treatment of patients with nasopharyngeal carcinoma (NPC). New strategies to enhance the efficacy of radiotherapy have been focused on the development of radiosensitizers and searching for directly targets that modulated tumor radiosensitivity. A novel potential radiosensitizer 1,8 Dihydroxy -3-(2'-(4"-methylpiperazin-1"-yl) ethyl-9,10-anthraquinone -3 carboxylate (RP-4) was designed and synthesized based on molecular docking technology, which was expected to regulate the radiosensitivity of tumor cells through targeting Rac1. In order to assess the radiosensitization activity of RP 4 on NPC cells, the highly differentiated CNE1 and poorly differentiated CNE2 cells NPC lines were employed. According to the results, RP-4 showed higher binding affinity toward the interaction with Rac1 than lead compounds. We found that RP-4 could inhibit cell viability and proliferation in CNE1 and CNE2 cells and significantly induced apoptosis after non-toxic concentration of RP-4 combined with 2Gy irradiation. RP-4 could effectively modulated the radiosensitivity both CNE1 cells and CNE2 cells through activating Rac1/NADPH signaling pathway and its downstream JNK/AP-1 pathway. What's more, Rac1/NADPH signaling pathway were significantly activated in Rac1-overexpressed CNE1 and CNE2 cells after treated with RP-4. Taken together, Rac1 and its downstream pathway may probably be the direct targets of RP-4 in regulating radiosensitivity of NPC cells, our finding provided a novel strategy for the development of therapeutic agents in response to tumorous radiation resistance. PMID- 30463024 TI - Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency. AB - Epidermolysis bullosa (EB), the paradigm of heritable skin fragility disorders, is associated with mutations in as many as 20 distinct genes. One of the clinical variants, recessive dystrophic EB (RDEB), demonstrates sub-lamina densa blistering accompanied by alterations in anchoring fibrils due to mutations in COL7A1. In this study, we characterized a patient with widespread connective tissue abnormalities including skin blistering similar to that in RDEB. Whole exome sequencing, combined with genome-wide homozygosity mapping, identified a homozygous missense mutation in PLOD3 encoding lysyl hydroxylase 3 (LH3). No mutations in COL7A1, the gene previously associated with RDEB, were detected. The level of LH3 was dramatically reduced in the skin and fibroblast cultures from the patient. The blistering in the skin occurred below the lamina densa and was associated with variable density and morphology of anchoring fibrils. The level of type VII collagen expression in the skin was markedly reduced. Analysis of hydroxylysine and its glycosylated derivatives (galactosyl-hydroxylysine and glucosyl-galactosyl-hydroxylysine) revealed marked reduction in glycosylated hydroxylysine. Collectively, these findings indicate that PLOD3 mutations can result in a dystrophic EB-like phenotype in the spectrum of connective tissue disorders and add it to the list of candidate genes associated with skin fragility. PMID- 30463025 TI - Estimation of brain functional connectivity from hypercapnia BOLD MRI data: Validation in a lifespan cohort of 170 subjects. AB - Functional connectivity MRI, based on Blood-Oxygenation-Level-Dependent (BOLD) signals, is typically performed while the subject is at rest. On the other hand, BOLD is also widely used in physiological imaging such as cerebrovascular reactivity (CVR) mapping using hypercapnia (HC) as a modulator. We therefore hypothesize that hypercapnia BOLD data can be used to extract FC metrics after factoring out the effects of the physiological modulation, which will allow simultaneous assessment of neural and vascular function and may be particularly important in populations such as aging and cerebrovascular diseases. The present work aims to systematically examine the feasibility of hypercapnia BOLD-based FC mapping using three commonly applied analysis methods, specifically dual regression Independent Component Analysis (ICA), region-based FC matrix analysis, and graph-theory based network analysis, in a large cohort of 170 healthy subjects ranging from 20 to 88 years old. To validate the hypercapnia BOLD results, we also compared these FC metrics with those obtained from conventional resting-state data. ICA analysis of the hypercapnia BOLD data revealed FC maps that strongly resembled those reported in the literature. FC matrix using region based analysis showed a correlation of 0.97 on the group-level and 0.54 +/- 0.10 on the individual-level, when comparing between hypercapnia and resting-state results. Although the correspondence on the individual-level was moderate, this was primarily attributed to variations intrinsic to FC mapping, because a corresponding resting-vs-resting comparison in a sub-cohort (N = 39) revealed a similar correlation of 0.57 +/- 0.09. Graph-theory computations were also feasible in hypercapnia BOLD data and indices of global efficiency, clustering coefficient, modularity, and segregation were successfully derived. Hypercapnia FC results revealed age-dependent differences in which within-network connections generally exhibited an age-dependent decrease while between-network connections showed an age-dependent increase. PMID- 30463026 TI - Mechanistic basis of vitamin B12 and cobinamide salvaging by the Vibrio species. AB - Biosynthesis of vitamin B12, which occurs through salvaging pathway or de novo synthesis, is essential for the survival and growth of bacteria. While the mechanism is known for many bacteria, it is elusive yet for diarrhea causing pathogenic bacteria Vibrio cholerae or the other Vibrio species. Sequence analysis using genome databases delineated that majority of the Vibrio species including V. cholerae contain genes required for salvaging cobalamin/cobinamide in aerobic pathway while lack the genes required for de novo synthesis of B12. Fluorescence quenching study showed that VcBtuF, the PBP of putative ABC transporter BtuF-CD of V. cholerae O395 binds cyanocobalamin and dicyanocobinamide with micromolar dissociation constants (Kd). Productive internalization of these nutrients has been established through growth assay. The crystal structure of cyanocobalamin bound VcBtuF has shown that although interactions between cyanocobalamin and VcBtuF are largely similar to E. coli BtuF, VcBtuF possesses a wider binding pocket. MD simulations indicated that in contrast to EcBtuF that executes 'open-close' movement, inter-lobe twisting is prevalent in VcBtuF. Although H70, located at the entrance of the substrate binding cleft of VcBtuF, executes swinging motion, it cannot act as 'closed gate' to retain cyanocobalamin or cobinamide in the pocket like corresponding residue W66 of EcBtuF. Rather, VcBtuF shows a distinctive phenomenon of heme binding with comparable affinity to B12. Soret shift of heme upon binding with VcBtuF pointed towards involvement of H70 in heme recognition. This may lead to a restricted B12 or cobinamide binding during abundance of heme in the periplasmic space. PMID- 30463027 TI - A neural network approach to analyze cross-sections of muscle fibers in pathological images. AB - Morphological characteristics of muscle fibers, such as their cross-sections, are important indicators of the health and function of the musculoskeletal system. However, manual analysis of muscle fiber morphology is a labor-intensive and time consuming process that is prone to errors. Overall, the procedure involves high inter- and intra-observer variability. Therefore, it is desirable for biologists to have a tool that can produce objective and reproducible analysis for muscle fiber images. In this work, we propose a deep convolutional neural network (DCNN) followed by post-processing for detecting and measuring the cross-sections of muscle fibers. We evaluate three segmentation networks for muscle boundary segmentation: (1) U-net, (2) FusionNet, and (3) a customized FusionNet. The customized FusionNet, which had the highest Dice coefficient on the test set, was used for subsequent morphological analysis of the muscle fibers. The proposed method was tested on microscopic images of the tibialis anterior muscles of a pre clinical model of muscular dystrophy. The dataset contained four mosaic images, totalling more than 3400 fibers. Because of the severity of muscle injury in this pre-clinical model, its muscle fiber images present a challenge for quantitative analysis for several reasons. First, the muscle fibers had inhomogeneous spatial distribution and very different sizes. Second, the membranes of the muscle fibers had uneven signal intensity due to the loss of a membrane protein. Third, the shapes of intact muscle fibers were very different. All these factors contributed to the difficulty of acquiring good training data in the first place. Despite these difficulties, we achieved an average muscle fiber overlay precision of 0.65 and an average recall of 0.49. In this context, overlaid fibers are defined as fibers that have one or more pixels overlaying in the manual and DCNN cross section segmentation. For the overlaid fibers, the proposed method achieved excellent segmentation accuracy of 94% +/- 10.26%, as measured by the Dice Sorensen coefficient. PMID- 30463028 TI - First report on global fallout 236U and uranium atom ratios in soils from Hunan Province, China. AB - More nuclear power plants continue to be built in China. Due to its long half life, radiotoxicity and potential application as an environmental tracer, 236U is one of the most important artificial radionuclides deserving more study since activity data are important for risk assessment. However, the ultra-trace activity of 236U and its dilution by natural uranium isotopes make it difficult to distinguish its sources and there are only limited global fallout 236U data for present in Chinese environmental samples. In order to understand the background levels for uranium isotopes, especially 236U, and clarify their sources, inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) was applied to analyze uranium isotopes in 48 soil samples from Hunan Province, China. The 234U, 235U, 238U and 236U concentrations were measured as 9.91-33.7, 0.312-1.43, 6.63-28.7 Bq kg-1 and (1.61-21.3) * 107 atoms g-1, while, the 236U/238U, 234U/238U and 235U/238U atom ratios were (0.470-4.91) * 10-8, (5.10 9.31) * 10-5, and (7.11-7.82) * 10-3, respectively. The uranium isotopic fractionation may be due to irrigation of the agricultural lands where the samples were collected. Considering the facts that neither previous nuclear tests nor nuclear accidents had occurred in Hunan Province and the present 236U/238U atom ratios were included in the range of global fallout values in other areas, it may be concluded that 236U in soils from Hunan Province is mainly from global fallout. To the best of the authors' knowledge, the presence of global fallout 236U in soil samples from China has been confirmed for the first time, and these values may be useful as background data for risk assessment in the future. PMID- 30463029 TI - Safety sensitivity to roadway characteristics: A comparison across highway classes. AB - This paper examined the accident risk factors associated with highway traffic and roadway design, for each of three highway classes in the United States using a bivariate modeling framework involving two levels of accident severity. With regard to the highest class (Interstates), the results suggest that, compared to no-casualty accidents, casualty accidents are more sensitive to traffic volume and average vertical grade, but less sensitive to the inside shoulder width and the median width. For US Roads, it was determined that, compared to no-casualty accidents, casualty accidents are more sensitive to traffic volume, outside shoulder width, pavement condition, and median width but less sensitive to the average vertical grade. For the relatively lowest-class roads (State Roads), it was determined that, compared to no-casualty accidents, casualty accidents are more sensitive to the traffic volume, lane width, outside shoulder width, and pavement condition. Compared to the relatively lower-class highways, accidents at higher-class highways are more sensitive to: changes in traffic volume, average vertical grade, median width, inside shoulder width, and the pavement condition (no-casualty accidents only); but less sensitive to changes in lane width, pavement condition (casualty accidents only), and the outside shoulder width. This variation in sensitivity across the different road classes could be attributed to the differences in road geometry standards across the road classes, as the results seem to support the hypothesis that these standards strongly influence accident occurrence. It is hoped that the developed bivariate negative binomial models can help highway engineers to evaluate their current design standards and policy, and to assess the safety consequences of changes in these standards in each road class. PMID- 30463030 TI - Lactobacillus and dietary sunflower meal supplementation in layer diets: Effects on specific serum content and hydrogen sulfide concentration in layer manure. AB - Studies show that in poultry houses, hydrogen sulfide (H2S) is present in a much higher concentration than its odor threshold of 10 ppb for humans and has a short lived deleterious effect on White Leghorns at concentrations of 0.2% H2S. A possible way to reduce H2S emissions (often exhausted into the environment) is to decrease its concentration in manure by adding high fiber byproducts and probiotics in diets. A combination of probiotics (Lactobaccillus paracasei, Lactobaccillus plantarum, and Lactobaccillus rhamnosus at 1.56 mL per 10 L (to provide 3.64 * 106 cfu/L of each species) in chlorinated drinking water and sunflower seed meal (SFM) were evaluated for their early effects on the H2S concentration in manure and specific measurements in serum. Sixty-four White Leghorn inbred crosses (65- to 74-week-old) were randomly allocated into two replicates of four treatments including a Control, Control + Probiotics, Control + Probiotics + 20% SFM, and Control + 20% SFM. After a 7-day acclimation period with different treatments, fecal matter was analyzed for total sulfur (TS), sulfate-sulfur (SO4-S), and H2S while blood serum was analyzed for amylase, calcium, phosphate, cholesterol, and triglycerides. Results indicated that probiotics significantly increased SO4-S, whereas 20% SFM decreased H2S, total sulfur, and increased sulfate sulfur. Dietary supplementation of SFM also significantly decreased serum amylase activity, calcium, and phosphorus. PMID- 30463031 TI - Special issue on 10th international conference of predictive modelling in foods: Towards a new paradigm in predictive microbiology. PMID- 30463032 TI - Endoplasmic reticulum calcium dictates the distribution of intracellular unesterified cholesterol. AB - Endoplasmic reticulum (ER) luminal Ca2+ influences many functions of this organelle, notably the synthesis and quality control of proteins and lipids. Cholesterol is an essential component of biological membranes and a precursor for many biologically important signaling molecules. The sterol regulatory element binding proteins (SREBPs) are key regulators of lipid metabolism. These transcription factors are synthesized as ER membrane-bound precursor proteins that are proteolytically processed in response to cellular cholesterol status. Recently, ER Ca2+ status was shown to be an important determinant of the basal sensitivity of the sterol sensing mechanism inherent to the SREBP processing pathway. This article discusses the emerging relationship between cellular Ca2+ and cholesterol metabolism. PMID- 30463033 TI - Compassion: Use it or lose it?: A study into the perceptions of novice nurses on compassion: A qualitative approach. AB - BACKGROUND: Nurses and patients believe compassion to be one of the most important professional values. However, it is not known which factors influence compassionate behaviour in practice. There is a need for insight whether or not compassion in nursing practice flourishes or falters. OBJECTIVES: This study aims to explore how Dutch novice nurses perceive compassion within nursing care and gain insight in their strategies of sustaining and developing compassionate care. DESIGN: This study used an exploratory design, employing a qualitative approach. DATA SOURCES: 14 in depth interviews with Dutch bachelor novice nurses with 0-5 years of practical experience took place. REVIEW METHODS: Thematic analysis and inductive coding was used. RESULTS: Four themes emerged from the data. First, participants perceive compassion to be a part of their professional identity. Balancing between positive and negative environmental influences and their own perceptions was shown as a second theme. Thirdly, various strategies such as rebellion and conforming to the ideas on the workplace helped nurses to do so in daily practice. If nurses succeeded in dealing positively with various influences, a professional development was perceived over time. The fourth theme described the increased awareness of compassion and professional identity if strategies were successful. If not; insecurity, job dissatisfaction and ultimately consideration of job-retention was described. CONCLUSION: Compassion is an essential value during the development of the professional identity of novice nurses. Dealing with meaningful emotions and experiences broadened nurses' personal awareness of compassionate care and stimulated a growth in their professional identity. Novices need support during their internships that builds empowerment and resilience in sustaining compassion. Furthermore, there is a need for role models and a corporative team spirit in order to coach novice nurses in compassionate behaviour. PMID- 30463034 TI - The influence of socio-demographic factors, resilience and stress reducing activities on academic outcomes of undergraduate nursing students: A cross sectional research study. AB - BACKGROUND: Nursing students who stop their education before obtaining their degree (dropout) is a common problem. Scientific studies on factors influencing academic outcomes amongst nursing students are sparse and difficult to transfer to undergraduate nursing students. OBJECTIVES: The objective of the present study was to explore in undergraduate nursing students the influence of socio demographic factors, resilience and stress reducing activities on the academic outcomes: intention to leave, academic success and dropout. DESIGN: A cross sectional design was used. PARTICIPANTS/SETTING: 554 participants form 6 nursing colleges in the Antwerp region in Belgium were included. METHODS: Data were collected using SurveyMonkey(r). In a second phase, these data were linked to the academic outcomes from the school administration. RESULTS: Lower resilience, more destructive and less positive stress reducing activities, having committed a suicide attempt in the past, studying in a densely populated area and starting as a regular student was significantly influenced with higher intentions to leave. Higher resilience significantly predicted academic success. Finally, students that dropped out showed a significantly lower resilience. CONCLUSION: Resilience was the only factor that significantly predicted the three academic outcomes: intention to leave, academic success and dropout. Known predictors of academic outcomes such as young age, gender, previous education, nationality and caring for family members were not confirmed in this study. To study in depth dropout within the undergraduate nursing course, conducting a cohort study might be recommended. PMID- 30463035 TI - Immunomodulatory effects of antipsychotic treatment on gene expression in first episode psychosis. AB - Previous studies suggest immunological alterations in patients with first-episode psychosis (FEP). Some studies show that antipsychotic compounds may cause immunomodulatory effects. To evaluate the immunological changes and the possible immunomodulatory effects in FEP, we recruited patients with FEP (n = 67) and matched controls (n = 38), aged 18-40 years, from the catchment area of the Helsinki University Hospital and the City of Helsinki, Finland. Fasting peripheral blood samples were collected between 8 and 10 a.m. in 10 ml PAXgene tubes. We applied the NanoString nCounter in-solution hybridization technology to determine gene expression levels of 147 candidate genes reflecting activation of the immune system. Cases had higher gene expression levels of BDKRB1 and SPP1/osteopontin compared with controls. Of the individual medications used as monotherapy, risperidone was associated with a statistically significant upregulation of 11 immune system genes, including cytokines and cytokine receptors (SPP1, IL1R1, IL1R2), pattern recognition molecules (TLR1, TLR2 and TLR6, dectin-1/CLEC7A), molecules involved in apoptosis (FAS), and some other molecules with functions in immune activation (BDKRB1, IGF1R, CR1). In conclusion, risperidone possessed strong immunomodulatory properties affecting mainly innate immune response in FEP patients, whereas the observed effects of quetiapine and olanzapine were only marginal. Our results further emphasize the importance of understanding the immunomodulatory mechanisms of antipsychotic treatment, especially in terms of specific compounds, doses and duration of medication in patients with severe mental illness. Future studies should evaluate the response pre- and post-treatment, and the possible role of this inflammatory activation for the progression of psychiatric and metabolic symptoms. PMID- 30463036 TI - The role of side tail fibers during the infection cycle of phage lambda. AB - Bacteriophage lambda has served as an important model for molecular biology and different cellular processes over the past few decades. In 1992, the phage strain used in most laboratories around the world, thought of as lambda wild type, was discovered to carry a mutation in the stf gene which encodes four side tail fibers. Up to now, the role of the side tail fibers during the infection cycle, especially at the single-cell level, remains largely unknown. Here we utilized fluorescent reporter systems to characterize the effect of the side tail fibers on phage infection. We found that the side tail fibers interfere with phage DNA ejection process, most likely through the binding with their receptors, OmpC, leading to a more frequent failed infection. However, the side tail fibers do not seem to affect the lysis-lysogeny decision-making or lysis time. PMID- 30463037 TI - Validity of the gait variability index for individuals after a stroke in a chronic stage of recovery. AB - BACKGROUND: Increased variability in spatiotemporal variables has been demonstrated in individuals after stroke. Gait Variability Index (GVI) has recently been proposed, potentially to be used as a standardized tool for quantifying gait impairment due to spatiotemporal variables. The experience with the GVI in patients after stroke is unknown. RESEARCH QUESTION: The aim of this study was to investigate the validity of the GVI as an outcome measure of gait disturbance after stroke. METHODS: 50 individuals (mean age 60.9 +/- 11.2 years) after stroke at a chronic phase of recovery were included. The control group comprised 50 healthy subjects without gait disorders, matched for age and gender. Data on functional mobility and spatiotemporal gait parameters (BTS Smart system) was collected. RESULTS: The results showed lower mean GVI (mGVI) scores (mean 78.53 +/- 6.12), lower GVI for the affected leg (mean 76.32 +/- 7.98) and for the unaffected leg (mean 80.74 +/- 4.68) in the individuals after stroke compared to the healthy subjects (mean 98.00 +/- 6.32). This was significantly different from the control group mean for both mGVI, affected and unaffected leg - p < 0.001. The GVI for the affected leg and unaffected leg as well as the mGVI were significantly correlated with all clinical measures of functional mobility (0.7<=R|<0.9, 0.5<=|R|<0.7, p < 0.001). SIGNIFICANCE: The validity of the GVI appears to be confirmed for individuals after stroke at a chronic stage of recovery. The GVI is lower in individuals after stroke compared to healthy controls. The GVI showed moderate to strong correlations with validated clinical measures of functional mobility. Application of the GVI in the clinical practice will significantly facilitate assessment of gait in individuals after stroke, in comparison to the necessity to interpret a large number of data from 3 dimensional gait analysis. CLINICAL TRIAL REGISTRATION: Data are parts of the following clinical trial: ACTRN12617000436370 (anzctr.org.au). PMID- 30463038 TI - The balance control of young children under different shod conditions in a naturalistic environment. AB - BACKGROUND: A primary function of footwear is to protect the feet from environmental conditions and possibly, to reduce the risk of injury. In addition, the use of footwear may be critical to improve the balance control of young children at their early years. Therefore, the objective of this study was to evaluate the performance of different balance tasks in young children under barefoot (unshod) and own covered footwear (shod) conditions. RESEARCH QUESTION: Does footwear affect the balance control of young children? METHODS: Twenty-three young children (n = 23, M age = 6.32 +/- 0.27 years, age range: 5-6 years) participated in this study. Three balance tasks, 1) One-leg stand, 2) Walking heels raised and 3) Jumping on mats were used to determine the balance proficiency of young children. RESULTS: The mean scores of the young children were significantly higher with a lower standard deviation under shod condition for the task of walking heels raised. SIGNIFICANCE: These results suggest that own covered footwear could aid in providing increased postural stability for complex and novel balance tasks which are highly unstable. PMID- 30463039 TI - Determination of adulterated gasoline using fluorescence emission-excitation matrices and multivariate calibration. AB - Methanol gasoline, known as a new energy, has a certain degree of damage to automobile. The aim of this work was to identify and quantify the methanol in methanol gasoline using three-dimensional fluorescence spectroscopy technique combined with second order chemometric methods. Parallel factor analysis (PARAFAC) and self-weighted alternating trilinear decomposition (SWATLD) methods were used to analyse artificial samples. However, the obtained results by PARAFAC were not satisfactory. On the other hand, excellent prediction results were obtained when SWATLD model was applied, with recovery rate between 98.7 and 102.8%, and between 97.4 and 101.9% for two and three factor respectively. In order to verify the accuracy of the method, four real samples were predicted using SWATLD model with RMSEP between 0.1 MUg/mL and 0.23 MUg/mL. PMID- 30463040 TI - Detection of adulteration with duck meat in minced lamb meat by using visible near-infrared hyperspectral imaging. AB - This paper described a rapid and non-destructive method based on visible near infrared (Vis-NIR) hyperspectral imaging system (400-1000 nm) for detection adulteration with duck meat in minced lamb. The multiple average of the reference spectral and a predicted relative spatial distribution coefficient were applied in this study to reduce the noise of the spectra. The PLSR model with selected wavelengths achieved better results than others with determination of coefficients (R2P) of 0.98, and standard error of prediction (RMSEP) of 2.51%. And the prediction map of the duck minced in lamb meat was generated by applying the prediction model. The results of this study indicate the great potential of the hyperspectral technology applying to rapidly and accurately detect the meat adulteration in minced lamb meat. PMID- 30463041 TI - Imputation of missing prostate cancer stage in English cancer registry data based on clinical assumptions. AB - BACKGROUND: Cancer stage can be missing in national cancer registry records. We explored whether missing prostate cancer stage can be imputed using specific clinical assumptions. METHODS: Prostate cancer patients diagnosed between 2010 and 2013 were identified in English cancer registry data and linked to administrative hospital and mortality data (n = 139,807). Missing staging items were imputed based on specific assumptions: men with recorded N-stage but missing M-stage have no distant metastases (M0); low/intermediate-risk men with missing N and/or M-stage have no nodal disease (N0) or metastases; and high-risk men with missing M-stage have no metastases. We tested these clinical assumptions by comparing 4-year survival in men with the same recorded and imputed cancer stage. Multi-variable Cox regression was used to test the validity of the clinical assumptions and multiple imputation. RESULTS: Survival was similar for men with recorded N-stage but missing M-stage and corresponding men with M0 (89.5% vs 89.6%); for low/intermediate-risk men with missing M-stage and corresponding men with M0 (92.0% vs 93.1%); and for low/intermediate-risk men with missing N-stage and corresponding men with N0 (90.9% vs 93.7%). However, survival was different for high-risk men with missing M-stage and corresponding men with M0. Imputation based on clinical imputation performs as well as statistical multiple imputation. CONCLUSION: Specific clinical assumptions can be used to impute missing information on nodal involvement and distant metastases in some patients with prostate cancer. PMID- 30463042 TI - Transcriptional responses to low-salinity stress in the gills of adult female Portunus trituberculatus. AB - The swimming crab (Portunus trituberculatus, Portunus) can tolerate low salinity, but the mechanism of its varied salinity adaptation at the molecular level remains unclear. In this study, we prepared four mRNA and microRNA (miRNA) libraries using the gills collected from four salinity groups and performed RNA sequencing (RNA-Seq) to identify the genes related to the low salinity. We set 25 ppt as the control group. A total of 659 genes were differentially expressed in at least one of the six comparison groups (25 ppt vs. 20 ppt, 25 ppt vs. 15 ppt, 25 ppt vs. 10 ppt, 20 ppt vs. 15 ppt, 20 ppt vs. 10 ppt and 15 ppt vs. 10 ppt). A total of 15 and 9 unigenes were downregulated and upregulated under low salinity compared with that in 25 ppt, respectively. Six genes, namely, aminopeptidase, centromere protein, cytochrome b5 reductase, bone morphogenetic protein, and two carbonic anhydrases, were selected for verification through quantitative real time PCR. The results were consistent with the RNA-Seq results. Furthermore, 95 conserved miRNAs and 16 novel miRNAs were differentially expressed in at least one of the six comparison groups. Analysis of the miRNA-mRNA interaction showed that miR-2 and miR-317 regulated >50 mRNA targets. In addition, let-7c was downregulated in all groups under low salinity compared with that in the control group. This study helped elucidate the adaptation mechanism of the swimming crab in low-saline environments. PMID- 30463043 TI - Comparison of the Malpighian tubules and fat body transcriptional profiles of Zophobas morio larvae (Coleoptera: Tenebrionidae). AB - The Malpighian tubules in insects play an essential role in osmoregulation, through the transport of ions during excretion, whereas the fat body is usually associated with the intermediary metabolism. The tubules also are involved in excretion of organic solutes and xenobiotics. However, with the exception of a preliminary transcriptional survey of the Zophobas morio (Tenebrionidae) larval tubules, there are no detailed transcriptional analysis of this organ in Coleoptera. A luciferase-like enzyme that displays weak luminescence activity in the presence of firefly D-luciferin and ATP was cloned from the tubules of Z. morio larvae. In order to better understand the molecular physiology of Malpighian tubules and fat body in Coleoptera larvae, and to investigate the occurrence and functions of AMP-CoA ligases in these tissues, we performed a comparative transcriptional analysis of these tissues using Z. morio giant mealworms. As expected, the tubules displayed organic and inorganic transporters, xenobiotic metabolism enzymes, V-ATPases, channels, and pumps. The fat body showed proteins that are synthesized in this tissue and secreted to the hemolymph, as well as enzymes involved in lipid and carbohydrate metabolism. These tissues are also involved in common pathways, such as nitrogen metabolism to degradation/excretion, eye pigments biosynthesis, immunity, and detoxification. The presence of coumarate-CoA ligase-like enzymes in these tissues suggest their involvement in the degradation of coumaric acid derivatives obtained from the diet, or alternatively, in the biosynthesis of compounds structurally related to coumaric acids such as eye pigments. Our results confirm to the physiological versatility of tubules and fat body in larval Coleoptera. PMID- 30463044 TI - Basal testosterone's relationship with dictator game decision-making depends on cortisol reactivity to acute stress: A dual-hormone perspective on dominant behavior during resource allocation. AB - The dual-hormone hypothesis proposes that testosterone's relationship with status seeking behavior is moderated by cortisol. However, research testing this hypothesis has focused on basal cortisol; the potential moderating effect of the acute cortisol response to stress has been largely overlooked. The present research investigated the moderating role of cortisol responses to an acute stressor on basal testosterone's link with dominant, status-relevant decision making. Also, given the multifaceted nature of the response to acute stress, cardiovascular and affective responses to the stressor were examined as alternative moderators of the testosterone-behavior relationship. Participants (N = 112; 56% female) were exposed to a social-evaluative stressor, and their stress responses were measured. Participants subsequently engaged in a one-shot dictator game, wherein they were asked to split money ($10) with a confederate counterpart. The amount of money participants decided to keep for themselves was treated as a metric of dominant status-seeking behavior. For individuals who demonstrated lower cortisol responses to the stressor, basal testosterone was positively associated with more dominant behavior (i.e., keeping more money for oneself), but for those who showed higher cortisol responses, the testosterone behavior relationship was suppressed. Moreover, other aspects of the stress response (i.e., cardiovascular and affective responses) did not moderate the relationship between basal testosterone and dictator game behavior. These results provide unique support for the dual-hormone hypothesis using markers of stress induced cortisol change. The findings also suggest that the antagonistic effects of stress on testosterone's role in motivating status-relevant behavior may be specific to cortisol's role in the acute stress response. PMID- 30463045 TI - Neuroprotective role of astaxanthin in hippocampal insulin resistance induced by Abeta peptides in animal model of Alzheimer's disease. AB - With the constant failure of the clinical trials continuous exploration of a therapeutic target against Alzheimer's disease (AD) is the utmost need. Numerous studies have supported the hypothesis that central insulin resistance plays a significant role in AD. Serine phosphorylation of Insulin Receptor Substarte-1 (IRS-1) has been found to be a contributing factor in neuronal insulin resistance. Astaxanthin (ASX) is xanthophyll carotenoid which has previously demonstrated significant antidiabetic and neuroprotective actions. In the present study, AD was induced by i.c.v administration of Amyloid-beta (1-42) peptides in Wistar rats. After 7 days of recovery, rats were treated with 0.5 mg/kg and 1 mg/kg of ASX orally for 28 days. Behavioral analysis was done in the last week of our experimental study. On the 36th day, rats were sacrificed and their hippocampus were separated from the whole brain, then homogenized and stored for biochemical estimations. ASX significantly and dose-dependently reversed the cognitive and memory impairment, assessed by Morris water maze test and Novel object Recognition test, Abeta (1-42) peptides infused Wistar rats. ASX also significantly attenuated soluble Abeta (1-42) level, IRS-S307 activity, GSK-3beta activity, TNF-alpha level, AChE level, nitrite level and oxidative stress in the hippocampus. Histopathological evaluation, done through H&E and Congo red staining, also demonstrated neuroprotective and anti-amyloidogenic effects of ASX in hippocampus. Our study concludes preventive action of Astaxanthin against hippocampal insulin resistance and Alzheimer's disease complications, supporting potential role of hippocampal insulin resistance targeting against AD. PMID- 30463046 TI - The preferences of physiotherapy clinical educators on a learning package for teaching musculoskeletal clinical prediction rules - A qualitative study. AB - BACKGROUND: There is a growing number of clinical prediction rules (CPRs) relevant to physiotherapy, particularly in the musculoskeletal area, but many students are not learning about them due to lack of awareness or understanding by clinical educators. An educational package specifically designed for physiotherapy clinical educators would aid their understanding of CPRs and ability to utilise them clinically, and also to be able to teach them to students. OBJECTIVES: To determine the desired content and preferred methods of delivery of an educational package for clinical educators on musculoskeletal CPRs. DESIGN: A qualitative descriptive approach using semi-structured group and individual interviews with clinical educators. METHOD: Educators working in the clinical area of musculoskeletal physiotherapy who had an awareness of or interest in CPRs were recruited and interviewed on their views regarding the content and delivery of an educational package on musculoskeletal CPRs. Audio files were transcribed and analysed using framework analysis to explore and develop themes and subthemes. FINDINGS: Content of an educational package should include general information on CPRs to improve familiarity and understanding, including a brief description, purpose, stages of development, application, limitations, and Information to dispel common myths and misunderstandings, as well as some specific examples of commonly-used CPRs. The package should be available in multiple formats to allow for different learning styles, both online via video, webinars, and podcasts, and face-to-face in practical sessions. CONCLUSIONS: Clinical educators would find an educational package useful in assisting them to learn about musculoskeletal CPRs and to teach them to students. PMID- 30463047 TI - Hearing loss, family status and mortality - Findings from the HUNT study, Norway. AB - Hearing loss as well as being single has been associated with an increased risk of all-cause mortality. The purpose of the study is to assess whether being single or childless moderates the elevated risk of mortality in hearing impaired. The Nord-Trondelag hearing Loss Study examined 50,462 persons above 20 years of age during 1996-1998. The Norwegian Cause of Death Registry was used to identify deaths until 2016. Data on marital status was obtained from the Norwegian Population Registry. Hearing loss was defined as the pure-tone average (0.5-4 kHz) of hearing thresholds greater than 25 dB hearing level (dB HL) in the better ear. Associations between hearing loss and mortality risk were estimated using Cox regression after an average follow-up of 17.6 years. Hearing loss was associated with increased risk of all-cause mortality before 75 years of age (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.2-1.4) and cardiovascular mortality (HR 1.8, 95% CI 1.5-2.1) but not with cancer mortality (HR 1.1, 95% CI 0.9-1.3) or mortality due to injuries (HR 1.4, 95% CI 0.9-2.3). Adjusting for socio-economic characteristics, cardiovascular risk-factors, diseases, and family status, reduced the associations for all-cause mortality (HR 1.1, 95% CI 1.0-1.2) and cardiovascular mortality (HR 1.4, 95% CI 1.2-1.6). The adjusted mortality risk was found to be significantly related to family status. Being divorced raised the mortality risk associated with hearing loss among those below 75 years of age. There was a similar tendency also for being childless, although this was only significant for females. There was also a trend for a lower mortality related to hearing loss in subjects with a well-hearing partner. More focus should be given to those who lack a family when having functional limitations such as hearing impairment. PMID- 30463048 TI - Effects of saturated and polyunsaturated fatty acids on interactions with cholesterol versus 7-ketocholesterol in Langmuir monolayers and their potential biological implications. AB - In this work the Langmuir monolayer technique was used to study interactions between cholesterol (chol) and 7-ketocholesterol (7-KC) with saturated (arachidic acid, AA) and polyunsaturated fatty acids (PUFAs) (omega-3 alpha-linolenic acid, alpha-LA,and omega-6 gamma- linolenic, gamma-LA) in order to get insight into their potential role in atherosclerosis. For this study, surface pressure (pi) area (A) isotherms, compressibility modulus (Cs-1) versus pi plots, Brewster angle microscopy (BAM) images and excess functions (Aexc and DeltaGexc) were analysed. Different behaviour has been observed. For cholesterol/AA mixed monolayers, components immiscibility occurs, whatever the surface pressure or the mixtures composition is, whereas for the 7-KC/AA mixed system, ideal behaviour was observed at low and high surface pressures for all the investigated compositions. However, the remaining mixed studied systems (sterol/PUFA) exhibit negative deviations from the ideality, although some differences do occurr. The magnitude of these deviations depend on the kind of a PUFA (for omega-3 PUFA greater than for omega-6) - attributed to the different geometry of their acyl chains- and the type of a sterol (for 7-KC greater than for cholesterol).The strength of attractive interactions followed the order: chol/ gamma-LA <7 KC/gamma-LA < chol/alpha-LA < 7-KC/ alpha-LA, postulating the formation of stable complexes of 1:2 stoichiometry for 7-KC/alpha-LA mixed monolayers and 1:1 stoichiometry for chol/alpha-LA mixed films. For 7-KC/gamma-LA system, the formation of a low stability complex of 2:1 stoichiometry was suggested. The existence of these complexes can play an important role in diminishing the circulating sterols in the blood stream, thus decreasing the probability of atherosclerotic plaques formation. PMID- 30463049 TI - Pharmacophore-based virtual screening for identification of potential selective inhibitors of human histone deacetylase 6. AB - Histone deacetylase (HDAC) 6 plays a role in oncogenic transformation and cancer metastasis via tubulin deacetylation, making it a critical target for anticancer drug design. However, lack of selectivity shown by many of the current HDAC6 inhibitors in clinical use and trials prompts the continuous search for selective inhibitors. Here, 10 pharmacophore hypotheses were developed based on the 3D common features of training set of 20 HDAC inhibitors in clinical use and trials. The hypotheses were validated using a test set of another 20 HDAC inhibitors along with 400 inactive (decoys) molecules based on Guner-Henry pharmacophore scoring method. Hypothesis 1 consisting of 1 H-bond donor, 1 H-bond acceptor and 2 hydrophobic features, was used to screen "DruglikeDiverse" database using Biovia Discovery Studio 4.5. The top 10 hit compounds were selected based on the pharmacophore fit values (>3.00). Their binding affinity against HDAC6 compared to class I HDACs (1, 2, 3 & 8) and a class IIa member (HDAC7), was calculated by molecular docking using AutoDock4. The stability of binding modes of 2 potential HDAC6-selective inhibitors (ENA501965 and IBS399024) was examined by 30 ns molecular dynamics (MD) simulation using nanoscale MD (NAMD) software. Both ligands showed potential stability in HDAC6 active site over time. Therefore, these may provide additional scaffolds for further optimization towards the design of safe, potent and selective HDAC6 inhibitors. PMID- 30463050 TI - Clinico-radiologic factors in paraclinoid aneurysms associated with aneurysm rupture: A CTA study. AB - BACKGROUND AND PURPOSE: Paraclinoid aneurysms are commonly noted as incidental findings by computed tomography angiography (CTA), and there exists disagreement in the literature as to which patient and aneurysm characteristics predict subsequent rupture. This question is of particular significance given the complex anatomy of the paraclinoid region and the associated risks of aneurysm treatment. The purpose of this study was to determine significant associated risk factors for paraclinoid aneurysm rupture. MATERIALS AND METHODS: Medical records and CTA imaging from 179 patients with 205 paraclinoid aneurysms. Patient and aneurysm characteristics including aneurysm size, morphology, and multiplicity were gathered for analysis of rupture risk. Factors influencing the decision to treat or observe unruptured aneurysms were also evaluated. A Cox regression analysis was used, and results were corrected for multiple comparisons using the Bonferroni method. RESULTS: Aneurysm size, diameter:neck ratio, and multilobularity were significantly associated with increased rupture risk; however, only multilobularity remained significant after Bonferroni correction for multiple comparisons. Intervention for unruptured aneurysms was significantly more likely to occur among younger patients and multilobulated aneurysms, or those having a larger diameter, height, height:neck ratio, or diameter:neck ratio. CONCLUSIONS: Multilobularity constitutes a significant associated risk factor for rupture among paraclinoid aneurysms. Younger age, larger size and multilobulated aneurysms are characteristics that favored treatment over observation in this cohort. PMID- 30463051 TI - Association of thirty-year alcohol consumption typologies and fatty liver: Findings from a large population cohort study. AB - OBJECTIVE: To evaluate the longitudinal relationship between repeated measures of alcohol consumption and risk of developing fatty liver. PATIENTS AND METHODS: This study includes 5407 men and women from a British population-based cohort, the Whitehall II study of civil servants, who self-reported alcohol consumption by questionnaire over approximately 30 years (1985-1989 through to 2012-2013). Drinking typologies during midlife were linked to measures of fatty liver (the fatty liver index, FLI) when participants were in older age (age range 60-84 years) and adjusted for age, socio-economic position, ethnicity, and smoking. RESULTS: Those who consistently drank heavily had two-fold higher odds of increased FLI compared to stable low-risk moderate drinkers after adjustment for covariates (men: OR = 2.04, 95%CI = 1.53-2.74; women: OR = 2.24, 95%CI = 1.08 4.55). Former drinkers also had an increased FLI compared to low-risk drinkers (men: OR = 2.09, 95%CI = 1.55-2.85; women: OR = 1.68, 95%CI = 1.08-2.67). There were non-significant differences in FLI between non-drinkers and stable low-risk drinkers. Among women, there was no increased risk for current heavy drinkers in cross sectional analyses. CONCLUSION: Drinking habits among adults during midlife affect the development of fatty liver, and sustained heavy drinking is associated with an increased FLI compared to stable low-risk drinkers. After the exclusion of former drinkers, there was no difference between non-drinkers and low-risk drinkers, which does not support a protective effect on fatty liver from low-risk drinking. Cross-sectional analyses among women did not find an increased risk of heavy drinking compared to low-risk drinkers, thus highlighting the need to take a longitudinal approach. PMID- 30463052 TI - Frequency of chromosomal aberrations in lymphocytes of peripheral blood in patients with solid tumors. AB - There was carried out a study to compare the frequency of spontaneous chromosomal aberrations (CA) in lymphocytes of peripheral blood between the group of cancer patients with different types of solid tumors and the group of healthy people of the same age. There was established a significant increase in the average frequency of CA in cancer patients. Analysis of the group of patients has revealed its heterogeneity: in the majority of patients the individual frequency of CA significantly exceeded the average frequency of CA in the control group, in some - did not differ from that. The first patients were described as the group with "generalized" genomic instability. Also this group differed by increased radiosensitivity of lymphocyte chromosomes during their irradiation in vivo. PMID- 30463053 TI - Age-related changes in the levels and kinetics of pulmonary cytokine and chemokine responses to Streptococcuspneumoniae in mouse pneumonia models. AB - Streptococcuspneumoniae is a major human pathogen at the extremes of age. The elderly are particularly vulnerable to S.pneumoniae, the most common causative agent of bacterial pneumonia in this population. Despite the availability of vaccines and antibiotics, mortality rates associated with pneumococcal pneumonia in this age group remain high. In light of globally increasing life-expectancy, a better understanding of the patho-mechanisms of elderly pneumococcal pneumonia, including alterations in innate immune responses, is needed to develop improved therapies. In this study we aimed at investigating how increased susceptibility to pneumococcal infection relates to inflammation kinetics in the aged mouse pneumonia model by determining pulmonary cytokine and chemokine levels and comparing these parameters to those measured in young adult mice. Firstly, we detected overall higher pulmonary cytokine and chemokine levels in aged mice. However, upon induction of pneumococcal pneumonia in aged mice, delayed production of certain analytes, such as IFN-gamma, MIG (CXCL9), IP-10 (CXCL10), MCP-1 (CCL2), TARC (CCL17) and MDC (CCL22) became apparent. In addition, aged mice were unable to control excess inflammatory responses: while young mice showed peak inflammatory responses at 20 h and subsequent resolution by 48 h post intranasal challenge, in aged mice increasing cytokine and chemokine levels were measured. These findings highlight the importance of considering multiple time points when delineating inflammatory responses to S.pneumoniae in an age-related context. Finally, correlation between pulmonary bacterial burden and cytokine or chemokine levels in young mice suggested that appropriately controlled inflammatory responses support the host to fight pneumococcal infection. PMID- 30463054 TI - Enhanced accumulation of alpha-linolenic acid rich lipids in indigenous freshwater microalga Desmodesmus sp.: The effect of low-temperature on nutrient replete, UV treated and nutrient stressed cultures. AB - The indigenous microalga, Desmodesmus sp. produced alpha-linolenic acid (ALA) rich lipids in response to low temperature and UV treatment. Incubation at 5 degrees C showed a 1.5 fold increase in lipid content (34% w/w) with 44% ALA fraction of total fatty acids. The UV treatment (UV 60 min) exhibited a 1.4 fold increase in biomass productivity and 1.6 fold increase in lipid content (37% w/w) with ALA fraction as 31% of total fatty acids. The nitrogen stress enhanced the lipid content (39% w/w) with a reduced ALA fraction (18%) of total fatty acids. The UV treated cultures (UV 40 and 60 min) on incubation at 5 degrees C showed maximum lipid accumulation (59 to 62% w/w) with ALA fraction of total fatty acids as 39 to 42%. The incubation of nutrient-replete and UV treated cultures at low temperature could therefore be used for the production of ALA-rich lipids in microalgae. PMID- 30463055 TI - Effect of feed glucose and acetic acid on continuous biohydrogen production by Thermotoga neapolitana. AB - This study focused on the effect of feed glucose and acetic acid on biohydrogen production by Thermotoga neapolitana under continuous-flow conditions. Increasing the feed glucose concentration from 11.1 to 41.6 mM decreased the hydrogen yield from 3.6 (+/-0.1) to 1.4 (+/-0.1) mol H2/mol glucose. The hydrogen production rate concomitantly increased until 27.8 mM of feed glucose but remained unaffected when feed glucose was further raised to 41.6 mM. Increasing the acetic acid concentration from 0 to 240 mM hampered dark fermentation in batch bioassays, diminishing the cumulative hydrogen production by 45% and the hydrogen production rate by 57%, but induced no negative effect during continuous operation. Indeed, throughout the continuous flow operation the process performance improved considerably, as indicated by the 47% increase of hydrogen yield up to 3.1 (+/-0.1) mol H2/mol glucose on day 110 at 27.8 mM feed glucose. PMID- 30463056 TI - miR-2954 Inhibits PI3K Signaling and Induces Autophagy and Apoptosis in Myocardium Selenium Deficiency. AB - BACKGROUND/AIMS: Selenium (Se) deficiency can lead to several cardiac diseases, including Keshan disease in humans, mulberry heart disease in pigs and cardiac injury in chickens. MicroRNAs have been a research focus in recent years and have been shown to participate in a new avenue of cell death-autophagy, which can play a significant role in several types of heart disease. METHODS: MicroRNAome analysis showed that the expression of miR-2954 was increased in the myocardium of selenium-deficient chickens, and PI3K was predicted to be the target gene. The target relationship between miR-2954 and PI3K was verified with a double fluorescence enzyme assay and RNA Protein Interaction Prediction and molecular docking software. qRT-PCR and western blotting were used to detect the expression of PI3K and related pathway components in selenium-deficient chickens and miR 2954 knockout/overexpression cardiomyocytes. RESULTS: In this study, we observed that miR-2954 overexpression led to inhibition of PI3K pathway in vivo and in vitroled to inhibition of the PI3K pathway in vivo and in vitro. CONCLUSION: The expression of miR-2954 was increased in selenium-deficient myocardium, whereas overexpression of miR-2954 led to autophagy and apoptosis of myocardial cells during cardiac injury through regulation of the PI3K pathway; whether this phenomenon is a self-protection mechanism of the organism or damage caused by miR 2954 requires further study. Our findings provides new insight apoptosis in cardiomyocytes; additionally, we aim to provide a new direction for the diagnosis and targeted treatment of myocardial diseases. PMID- 30463057 TI - Physical Activity, Physical Function, and Quadriceps Muscle Thickness in Male Patients with Sub-Acute Stroke during Hospitalization: A Pilot Study. AB - Increasing physical activity (PA) is an important rehabilitation target for patients with sub-acute stroke during hospitalization in order to recover physical function and prevent stroke recurrence. However, the characteristics of low PA in stroke patients during hospitalization who were targets for increased intervention have not been reported. The purpose of this study was to investigate the relationship between the daily number of steps and physical function and quadriceps muscle thickness (QMT) in patients with sub-acute stroke during hospitalization for convalescence rehabilitation. Twenty-nine patients with ischemic or haemorrhagic stroke (mean age, 69 +/- 11 years) hospitalized for inpatient convalescent rehabilitation were included. PA was measured using a three-dimensional accelerometer that calculates the daily number of steps taken. Physical function was measured by a short physical performance battery (SPPB; 0 12 points) and the leg motor selectivity score (6 motor stages defined by Brunnstrom), and the QMT of both legs was measured using ultrasonography. PA was significantly correlated with the SPPB score (r = 0.63, p = 0.0002), QMT on the paretic side (r = 0.41, p = 0.02), and QMT on non-paretic side (r = 0.56, p = 0.002). There were no significant effects of the leg motor selectivity score on daily PA (F = 1.37, p = 0.27). In the multiple regression analysis, only the SPPB score showed significant linear regression (beta = 0.44, p = 0.02). PA in male patients with sub-acute stroke during hospitalization was related to physical function and QMT and not with the severity of paresis. PMID- 30463058 TI - Development of Inflammatory Immune Response-Related Drugs Based on G Protein Coupled Receptor Kinase 2. AB - G protein-coupled receptor kinase 2 (GRK2), as a vital Ser/Thr kinase, is an important regulatory protein in the inflammatory immune response (IIR) by maintaining the balance between the function of inflammatory immune cells and non conventional inflammatory immune cells and regulating inflammatory immune cell infiltration, inflammatory cytokine secretion, and the signaling associated with endothelial function. However, the imbalance of GRK2 expression and activity plays an important role in the development of IIR-related diseases, such as hypertension, heart failure, Alzheimer's disease, type 2 diabetes mellitus, insulin resistance, rheumatoid arthritis, thyroid cancer, multiple sclerosis, and liver cancer. Small molecule GRK2 inhibitors, including balanol, Takeda inhibitors, paroxetine and derivatives, M119 and gallein, peptides, RNA aptamers, Raf kinase inhibitory protein, and microRNAs, that can directly inhibit GRK2 kinase activity have been identified by different strategies. This review discusses recent progress in one of the hallmark molecular abnormalities of GRK2 in IIR-related diseases and explores the soft regulation of IIR by innovative drugs reducing the excessive activity of GRK2 to basal levels, without damaging normal physiological function, to ameliorate inflammatory disorders. PMID- 30463059 TI - Evaluation of Intestinal Patency with the Patency Capsule: The Twenty-Four Hour Assessment Method. AB - INTRODUCTION: Confirmation of intestinal patency using the patency capsule (PC) in 30-33 h may result in a complex testing schedule. The aim of this study was to perform and evaluate a 24-h PC procedure for potential use as a simple and easy to-apply intestinal patency assessment method. SUBJECT AND METHODS: The study included 342 patients who were assessed 24 h after ingesting a PC for assessment of intestinal patency. The PC elimination rate and the distribution of elimination time were evaluated. RESULTS: Assessment of intestinal patency was conducted in 308 (90%) patients. Self-confirmed PC elimination within 24 h was possible in 104 (30.4%) patients. The PC was considered to have been already eliminated in 38 (11.1%) patients. Thus, the extracorporeal elimination rate was 41.5%. Among 200 patients with non-extracorporeal elimination, the PC reached the large intestine in 166 patients (48.5% of the total patients). Small-bowel capsule endoscopy (CE) was performed in all 308 patients, and the entire small bowel could be observed in 98.4%. Capsule retention was not observed in any of the patients. CONCLUSION: The 24-h assessment method, in which the PC can be ingested using the same procedure as that for CE capsule, can be handled more easily and is more useful clinically. PMID- 30463060 TI - MicroRNA Quantitation During Dendritic Cell Endocytosis Using Imaging Flow Cytometry: Key Factors and Requirements. AB - BACKGROUND/AIMS: MicroRNA (miRNA)-induced suppression of dendritic cells (DCs) has been implicated in many diseases. Therefore, accurate monitoring of miRNA endocytosis by DCs is important for understanding the role of miRNAs in many diseases. Recently, a method for measuring the co-localization of Argonaute 2 (AGO2)-associated miRNAs on laser-scanning confocal microscopy method was proposed to localize the miRNAs. But its definition was limited by the number of observed cells through its accuracy. METHODS: In this study, a method based on imaging flow cytometry was developed to localize miR-590-5p with fluorescent probes in DCs. miR-590-5p proven to play an important role in tumor immunity. This method enabled the quantification, visualization and localization of the fluorescence intensity in 30,000 individual cells. RESULTS: Using this method, the DCs with different endocytotic ability were distinguished. The behaviour of miR-590-5p during endocytosis under the stimulation of tumor antigen in DCs was observed, binding to its cognate target mRNA and degradation in DCs. CONCLUSION: This method based on imaging flow cytometry provide an additional method to study miRNA processing in DCs, which makes it a valuable addition to existing miRNA research techniques. PMID- 30463061 TI - Curcumin Protects an SH-SY5Y Cell Model of Parkinson's Disease Against Toxic Injury by Regulating HSP90. AB - BACKGROUND/AIMS: We aimed to explore the protective role of curcumin (Cur) in a cell model of Parkinson's disease (PD) and its underlying mechanism. METHODS: In this study, genes concerned with PD-related keywords were screened within DiGSeE database. The association network between Cur and selected genes was downloaded from STITCH, with the interactions analyzed by STRING. We built a mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+)-induced SH-SY5Y cell model of PD. Cell morphology was observed under an electron microscope. MTT assay was applied to detect cell proliferation rate. Western blot assay was conducted to determine the level of apoptotic markers, including cleaved caspase 3, Bcl-2-associated X protein (Bax) and B-cell lymphoma-extra-large (Bcl-xl). Tyrosine hydroxylase (TH), dopamine transporter (DAT) protein levels and dopamine (DA) concentration were identified as dopaminergic neuron markers and measured by western blotting or Enzyme-linked immunosorbent assay (ELISA). RESULTS: Cur rescued the toxicity effects of MPP+ on SH-SY5Y cells, by controlling morphological change, promoting cell proliferation and inhibiting apoptosis. Of all PD-related genes, HSP90 played an important role in Cur-gene network. HSP90 protein level was elevated by MPP+, whereas Cur could reverse this effect. Silencing of HSP90 significantly attenuated the curative effect introduced by Cur, while HSP90 overexpression enhanced the impact of Cur on PD. CONCLUSION: Cur can effectively inhibit the toxic effect of MPP+ on SH-SY5Y cells and significantly reduce the adverse effects of MPP+ on dopaminergic neurons via up-regulation of HSP90. PMID- 30463062 TI - The Association of Longitudinal Serum Uric Acid and All-Cause Mortality in Incident Peritoneal Dialysis Patients. AB - BACKGROUND: Time-averaged uric acid (TA-UA) value was calculated to investigate the association of longitudinal UA and all-cause mortality in incident peritoneal dialysis (PD) patients. METHODS: Three hundred PD patients were divided into 3 groups based on the serum TA-UA level (Group 1: < 6 mg/dL; Group 2: 6-8 mg/dL; Group 3: >=8 mg/dL). Hazards ratio (HR) of all-cause mortality was calculated. Logistic regression was conducted to identify the associated clinical factors of lower and higher TA-UA level. RESULTS: Increased HRs for death existed in Group 1 and Group 3 compared with Group 2 (HR 3.24, 95% CI 1.25-8.39, p = 0.016; HR 4.69, 95% CI 1.24-17.72, p = 0.023). Lower residual renal function, lower albumin, and higher high-density lipoprotein cholesterol were related to the lower serum TA UA. Higher body mass index and higher C-reactive protein were associated with higher serum TA-UA in PD patients. CONCLUSION: Both TA-UA < 6 and >=8 mg/dL increased the all-cause mortality in incident PD patients. PMID- 30463063 TI - Unique Case of Myeloproliferative Neoplasm with Two Rare Clonal Abnormalities: Rare JAK2 Exon 12 Mutation and Rare e14a3 (b3a3) BCR/ABL Fusion Transcript. AB - Myeloproliferative neoplasms (MPNs) are clonal disorders divided into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) or Ph chromosome-negative MPNs. Co-occurrence of these disease entities is very rare and typically involves presence of common p190 or p210 BCR/ABL fusion transcript (responsible for CML) along with JAK2V617F mutation (most common driver mutation in Ph-negative MPNs). Because of the rarity of such cases, it is not clear if the outcomes are any different in these patients. In this article, we report a unique patient with polycythemia vera driven by a rare complex in-frame deletion insertion mutation in JAK2 exon 12, and CML driven by uncommon p210 e14a3 (b3a3) BCR/ABL fusion transcript. We describe clinical and laboratory features, bone marrow pathology, treatment, and overall outcome. PMID- 30463064 TI - miRNA-1290 Promotes Aggressiveness in Pancreatic Ductal Adenocarcinoma by Targeting IKK1. AB - BACKGROUND/AIMS: MicroRNAs (miRNAs) are a group of non-coding RNAs that play diverse roles in pancreatic carcinogenesis. In pancreatic ductal adenocarcinoma (PDAC), NF-kB is constitutively activated in most patients and is linked to a mutation in KRAS via IkB kinase complex 1 (IKK1, also known as IKKa). We investigated the link between PDAC aggressiveness and miR-1290. METHODS: We used miRCURYTM LNA Array and in situ hybridization to investigate candidate miRNAs and validated the findings with PCR. The malignant behavior of cell lines was assessed with Cell Counting Kit-8, colony formation, and Transwell assays. A dual luciferase reporter assay was used to evaluate the interaction between miR-1290 and IKK1. Protein expression was observed by western blotting. RESULTS: In this study, 36 miRNAs were dysregulated in high-grade pancreatic intraepithelial neoplasia (PanIN) and PDAC tissues compared with low-grade PanIN tissues. The area under the curve values of miR-1290 and miR-31-5p were 0.829 and 0.848, respectively (95% confidence interval, 0.722-0.936 and 0.749-0.948, both P < 0.001). There was a significant correlation between miR-1290 and histological differentiation (P = 0.029), pT stage (P = 0.006), and lymph node metastasis (P = 0.001). In addition, the in vitro work showed that miR-1290 promoted PDAC cell proliferation, invasion, and migration. Western blotting and the dual-luciferase reporter assay showed that miR-1290 promoted cancer aggressiveness by directly targeting IKK1. The synergist effect of miR-1290 on the proliferation and metastasis of PDAC cells was attenuated and enhanced by IKK1 overexpression and knockdown, respectively. Consistent with the in vitro results, a subcutaneous tumor mouse model showed that miR-1290 functioned as a potent promoter of PDAC in vivo. CONCLUSION: MiR-1290 may act as an oncogene by directly targeting the 3' untranslated region of IKK1, and the miR-1290/IKK1 pathway may prove to be a novel diagnostic and therapeutic target for PDAC. PMID- 30463065 TI - MicroRNA-485 Modulates the TGF-beta/ Smads Signaling Pathway in Chronic Asthmatic Mice by Targeting Smurf2. AB - BACKGROUND/AIMS: Chronic respiratory conditions continue to plague millions of people worldwide. We aimed to elucidate the detailed mechanisms of microRNA-485 (miR-485) in airway smooth muscle cell (ASMC) proliferation and apoptosis in chronic asthmatic mice. METHODS: A mouse model of chronic asthma was established. Ovalbumin was used to induce chronic asthma in the mice. The levels of transforming growth factor beta (TGF-beta), interleukin (IL)-4, IL-5, IL-13 and IL-17 in bronchoalveolar lavage fluid in mice were measured by enzyme-linked immunoassays (ELISAs). ASMCs were transfected with miR-485 mimic, miR-485 inhibitor and siRNA-Smurf2. The reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analyses were applied to detect the mRNA and protein levels of Smurf2, alpha-SMA, TGF-beta1 and decapentaplegic homolog (Smads). The MTT assay was utilized for cell proliferation, while flow cytometry was conducted to assess cell cycle distribution and apoptosis. RESULTS: Lower expression of miR-485 and higher expression levels of TGF-beta1, IL-4, IL 5, IL-13 and IL-17 were detected in mice with chronic asthma. Smurf2 was identified as the target gene of miR-485. Upregulation of miR-485 mimic and downregulation of Smurf2 decreased expression levels of Smurf2, alpha-SMA, TGF beta1 and Smad3, inhibited cell proliferation and increased apoptosis, while contrary results were observed in ASMCs transfected with miR-485 inhibitor. CONCLUSION: Overexpressed miR-485 inhibits cell proliferation and promotes apoptosis of ASMCs through the Smurf2-mediated TGF-beta/Smads signaling pathway in mice with chronic asthma. PMID- 30463066 TI - Osteogenic Effect of Inducible Nitric Oxide Synthase (iNOS)-Loaded Mineralized Nanoparticles on Embryonic Stem Cells. AB - BACKGROUND/AIMS: This study investigated the effect of inducible nitric oxide synthase-loaded mineralized nanoparticles (iNOS-MNPs) on the osteogenic differentiation of mouse embryonic stem cells (ESCs). METHODS: We prepared iNOS MNPs using an anionic block copolymer template-mediated calcium carbonate (CaCO3) mineralization process in the presence of iNOS. iNOS-MNPs were spherical and had a narrow size distribution. iNOS was stably loaded within MNPs without denaturation. In order to confirm the successful introduction of iNOS-MNPs into the cytosol of ESCs, intracellular levels of nitric oxide (NO) was determined with a fluorometric analysis. A NO effector molecule, cyclic guanosine 3',5' monophosphate (cGMP) was also quantified with a competitive enzyme immunoassay. Cell viability in response to iNOS-MNP treatment was determined using the cell counting kit-8 (CCK-8) assay. Alkaline phosphatase (ALP) activity assay, intracellular calcium quantification assay, and Alizarin red S staining for matrix mineralization were performed to investigate osteogenic differentiation of ESCs. The protein levels of Runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), and osterix (OSX) as osteogenic-related factors were also assessed by immunofluorescence staining and Western blot analysis. The complex pathways associated with iNOS-MNP-derived osteogenic differentiation of ESCs were evaluated by network-based analysis. RESULTS: Cells with iNOS-MNPs displayed a significant increase in NO and cGMP concentration compared with the control group. When cells were exposed to iNOS-MNPs, there were no adverse effects on cell viability. Importantly, iNOS-MNP uptake promoted the osteogenic differentiation of ESCs. Using transcriptome profiling, we obtained 1,836 differentially-induced genes and performed functional enrichment analysis with ClueGO and KEGG. These analyses identified significantly enriched and interconnected molecular pathways such as protein kinase activity, estrogen receptor activity, bone morphogenetic protein (BMP) receptor binding, ligand gated ion channel activity, and phosphatidylinositol 3-phosphate binding. CONCLUSION: These findings suggest that iNOS-MNPs can induce osteogenic differentiation in ESCs by integrating complex signaling pathways. PMID- 30463067 TI - The Designer Antimicrobial Peptide A-hBD-2 Facilitates Skin Wound Healing by Stimulating Keratinocyte Migration and Proliferation. AB - BACKGROUND/AIMS: Antimicrobial peptides are effective promoters of wound healing but are susceptible to degradation. In this study, we replaced the GIGDP unit on the N-terminal of the endogenous human antimicrobial peptide hBD-2 with APKAM to produce A-hBD-2 and analyzed the effect on wound healing both in vitro and in vivo. METHODS: The effects of A-hBD-2 and hBD-2 on cytotoxicity and proliferation in keratinocytes were assessed by Cell Counting Kit-8 assay. The structural stability and antimicrobial activity of hBD-2 and A-hBD-2 were evaluated against Staphylococcus aureus. RNA and proteins levels were evaluated by real-time PCR and western blotting, respectively. Cell migration was evaluated using a transwell assay. Cell cycle analysis was performed by flow cytometry. Wound healing was assessed in Sprague-Dawley rats. Epidermal thickness was evaluated by hematoxylin and eosin staining. RESULTS: We found that hBD-2 exhibited cytotoxicity at high concentrations and decreased the structural stability in the presence of high sodium chloride concentrations. A-hBD-2 exhibited increased structural stability and antimicrobial activity, and had lower cytotoxicity in keratinocytes. A-hBD-2 increased the migration and proliferation of keratinocytes via phosphorylation of EGFR and STAT3 and suppressed terminal differentiation of keratinocytes. We also found that A-hBD-2 elicited mobilization of intracellular Ca2+ and stimulated keratinocytes to produce pro- and anti-inflammatory cytokines and chemokines via phospholipase C activation. Furthermore, A-hBD-2 promoted wound healing in vivo. CONCLUSION: Our data suggest that A-hBD-2 may be a promising candidate therapy for wound healing. PMID- 30463068 TI - Gastric Mammalian Target of Rapamycin Signaling Contributes to Inhibition of Ghrelin Expression Induced by Roux-En-Y Gastric Bypass. AB - BACKGROUND/AIMS: Roux-en-Y Gastric Bypass, RYGB, is the most effective strategy to control body weight in morbid obesity. RYGB leads to rapid improvement of glycemic status and weight loss, which are largely attributed to the alteration of gastrointestinal hormones including ghrelin. The current study examined potential mechanisms of altered ghrelin synthesis after RYGB. METHODS: Gastric mammalian target of rapamycin (mTOR) signaling, ghrelin synthesis and secretion were determined in lean or obese male mice with or without RYGB operation, as well as in obese patients pre- and post-RYGB surgery. Ghrelin expression and mTOR signaling were investigated by western blotting and immunohistochemistry. Ghrelin mRNA levels were detected by real-time PCR. Plasma ghrelin was measured by enzyme immunoassay. RESULTS: mTOR activity in the gastric fundus was significantly lower than in the forestomachs. Both of them were decreased after 24h fasting. A significant negative correlation was found between gastric levels of phospho-S6 (phospho-S6 ribosomal protein) and proghrelin during changes of energy status. mTOR activity was activated, whereas ghrelin expression was inhibited by Roux-en Y Gastric Bypass in both rodents and human beings. Increment of ghrelin synthesis and decline of mTOR signaling induced by rapamycin were significantly reversed by RYGB in both lean and obese mice. Administration of Ad-S6K1 (adenovirus-mediated p70 ribosomal protein subunit 6 kinase 1) from tail vein suppressed the expression of ghrelin in RYGB-operated mice relative to control animals. CONCLUSION: mTOR is therefore a gastric fuel sensor whose activity is linked to the regulation of ghrelin after Roux-en-Y Gastric Bypass. PMID- 30463069 TI - Potassium Iodide for Cutaneous Inflammatory Disorders: A Monocentric, Retrospective Study. AB - OBJECTIVES: Potassium iodide (KI) is a medication that has been used for decades in dermatology and it is mentioned as a treatment option in all major dermatology textbooks. Yet, there is little recent information on its efficacy. In our study, we wanted to retrospectively evaluate the therapy response to KI in our patients. METHODS: The hospital information system was searched for patients treated with KI at the Department of Dermatology (University Hospital Zurich) in the last 20 years (January 1, 1998 to December 31, 2017). A total of 52 patients were found and, subsequently, 35 patients were included in our study. RESULTS: KI was prescribed for the following skin conditions: erythema nodosum, disseminated granuloma anulare, necrobiosis lipoidica, nodular vasculitis, cutaneous sarcoidosis, and granulomatous perioral dermatitis/ rosacea. The median duration of KI intake was 5 +/- 7.7 weeks (range 1-26). The global assessment of efficacy by the treating physician showed an improvement of disease in about a third of all patients. No response was seen in 14 patients and 9 even had a progression of disease. An adverse event was documented in 16 cases. CONCLUSIONS: Our findings show that an improvement was reached in only about a third of all cases. High response rates with only mild side effects (in 16 out of 35 patients) were observed. PMID- 30463070 TI - Serum Myostatin Levels Are Higher in Fitter, More Active, and Non-Frail Long-Term Nursing Home Residents and Increase after a Physical Exercise Intervention. AB - BACKGROUND: Myostatin has been proposed as a candidate biomarker for frailty and sarcopenia. However, the relationship of myostatin with these conditions remains inconclusive. OBJECTIVE: To determine the association of serum myostatin concentration with body composition, physical fitness, physical activity level, and frailty in long-term nursing home residents. We also aimed to ascertain the effect of an exercise program on myostatin levels. METHODS: We obtained study data on 112 participants from long-term nursing homes. Participants were randomly assigned to a control or an intervention group and performed a 6-month multicomponent exercise program. Serum myostatin levels were analyzed by ELISA. Assessments also included body composition (anthropometry and bioelectrical impedance), physical fitness (Senior Fitness Test), physical activity level (accelerometry), and frailty (Fried frailty criteria, Clinical Frailty Scale, and Tilburg frailty indicator). RESULTS: The concentration of myostatin at baseline was positively correlated with: a leaner body composition (p < 0.05), and a higher number of steps per day and light and moderate-vigorous physical activity in women (p < 0.005); greater upper and lower limb strength, endurance, and poorer flexibility (p < 0.05) in men; and better performance (less time) in the 8 ft timed up-and-go test in both women (p < 0.01) and men (p < 0.005). We observed higher concentrations of serum myostatin in non-frail than in frail participants (p < 0.05). Additionally, we found that the implemented physical exercise intervention, which was effective to improve physical fitness, increased myostatin concentration in men (p < 0.05) but not in women. The improvements in physical condition were related with increases in serum myostatin only in men (p < 0.05-0.01). CONCLUSIONS: Higher serum levels of myostatin were found to be associated with better physical fitness. The improvements in physical fitness after the intervention were positively related to increases in myostatin concentrations in men. These results seem to rule out the idea that high serum myostatin levels are indicative of frailty in long-term nursing home residents. However, although the direction of association was opposite to that expected for the function of myostatin, the use of this protein as a biomarker for physical fitness, rather than frailty, merits further study. PMID- 30463071 TI - Decremental Responses to Repetitive Nerve Stimulation in Amyotrophic Lateral Sclerosis. AB - INTRODUCTION: To illuminate the mechanism of neuromuscular junction involvement by analyzing the features of a slow-rate repetitive nerve simulation (RNS) and EMG in amyotrophic lateral sclerosis (ALS) patients. METHODS: We retrospectively analyzed relationship between clinical features and the decremental response in RNS in 184 sporadic ALS patients. RESULTS: (1) 44.3 and 43.5% of compound muscle action potentials (CMAP) decrement were more than -10% in deltoid muscle (Del) and Trap; (2) ALS patients were divided into RNS positive (RNS+) and RNS negative (RNS-) group according to decremental percentage of RNS greater or less than 10%. The diagnostic delay time was shorter and ALSFRS-r score was lower in RNS+ than RNS- group (p < 0.05), progression rate had no difference. The incidence of RNS+ decrement was higher in cervical enlargement onset and definite diagnostic degrees (p < 0.05); (3) In EMG+ group, the CMAP amplitude was lower (Axillary: 3.1 +/- 1.91 vs. 5.92 +/- 2.896, p = 0.000; Accessory: 2.68 +/- 1.349 vs. 3.65 +/ 1.53, p = 0.002), decremental percentage of RNS was higher (Axillary: -10.85 +/- 7.508 vs. -5.43 +/- 8.425, p = 0.000; Accessory: -13.11 +/- 7.539 vs. -8.03 +/- 5.999, p = 0.000) compared with needle EMG- group whether in Del or Trap; (4) Decremental response of RNS was positively correlated with the CMAP amplitude in Axillary and Accessory nerves (R = 0.201, p < 0.0001; R = 0.103, p < 0.0001). CONCLUSIONS: Our clinical results support the mechanism of decremental phenomenon of RNS is immature sprouts and unstable conduction by the degenerating axons in ALS patients. The more serious the axon damage, the more significant the RNS decremental response. But decremental response dose not effect disease progression. PMID- 30463072 TI - Human Epidermal Growth Factor Receptor 2 in Non-Muscle Invasive Bladder Cancer: Issues in Assessment Methods and Its Role as Prognostic/Predictive Marker and Putative Therapeutic Target: A Comprehensive Review. AB - Although human epidermal growth factor receptor 2 (HER2) plays a prognostic and predictive role in breast and gastric cancer, its function in bladder cancer (BC) is still controversial. A comprehensive review of the literature has been carried out. An electronic search of databases from PubMed, Scopus, Google Scholar was implemented. The search terms were: "BC," "bladder carcinoma," "bladder neoplasm," "human epidermal growth factor 2," "HER2," "HER-2," "c-erbB-2," "c erbB2," "erbB-2," "erbB2," "neu," "marker," "biomarker," and "prognosis". Results of the review consented to (a) summarize the available data on HER2 a predictor of recurrence and/or progression free survival on univariate and multivariate analysis, (b) explore the related issues in assessing HER2 status on these tumor samples, since they may severely impair its predictive function, and (c) report the state-of-the art of HER2 as a putative therapeutic target in BC and especially non-muscle invasive BC. HER2 stands out for being a prognostic factor as well as a therapeutic target in various cancers. Data from the literature concerning its use in BC provide conflicting results, probably due to the inherent complexity of BC biology. Efforts should be made to establish a suitable tumor-specific scoring system, and to assess single drugs' efficacy in well designed clinical trials. PMID- 30463073 TI - Galectin-3- Mediated Transdifferentiation of Pulmonary Artery Endothelial Cells Contributes to Hypoxic Pulmonary Vascular Remodeling. AB - BACKGROUND/AIMS: Vascular muscularity is a key event in vessel remodeling during pulmonary artery hypertension (PAH). Endothelial-mesenchymal transdifferentiation (EndMT) has been increasingly reported to play a role in disease occurrence. Galectin-3, a carbohydrate-binding protein regulates cell proliferation, differentiation, migration and neovascularization. However, whether galectin-3 controls endothelial cell transdifferentiation during the development of PAH is unknown. METHODS: Rats were exposed to normoxic or hypoxic conditions (fraction of inspired O2 0.10) for 21 d to establish PAH models. Hemodynamic changes were evaluated through surgery of the right jugular vein and ultrasound biomicroscopy inviVue. And vessel pathological alterations were detected by H&E staining. Galectin-3 (Gal-3)-induced pulmonary artery endothelium cell (PAEC) dynamic alterations were measured by MTT assays, Cell immunofluorescence, Flow cytometry, Real-time PCR and Western blot. RESULTS: Our study demonstrated that Gal-3 was expressed in hypoxic pulmonary vascular adventitia and intima. The increased Gal 3 expression was responsible for hypoxic vessel remodeling and PAH development in vivo. Gal-3 was found to inhibit cell proliferation and apoptosis in cultured endothelial cells. Meanwhile endothelial cell morphology was altered and exhibited smooth muscle-like cell features as demonstrated by the expression of alpha-SMA after Gal-3 treatment. Gal-3 activated Jagged1/Notch1 pathways and induced MyoD and SRF. When MyoD or SRF were silenced with siRNAs, Gal-3-initiated transdifferentiation in endothelial cells was blocked as indicated by a lack of alpha-SMA. CONCLUSION: These results suggest that Gal-3 induces PAECs to acquire an alpha-SMA phenotype via a transdifferentiation process which depends on the activation of Jagged1/Notch1 pathways that mediate MyoD and SRF expression. PMID- 30463074 TI - A Pilot Study on Daily Intensive ECT over 8 Days Improved Positive and Negative Symptoms and General Psychopathology of Patients with Treatment-Resistant Schizophrenia up to 4 Weeks after Treatment. AB - OBJECTIVE: For patients with treatment-resistant schizophrenia (TRS) who do not respond to drug therapy, electroconvulsive therapy (ECT) is often employed as an additional treatment. The aims of the present study were to investigate to what extent an 8-day daily ECT treatment might reduce symptoms of schizophrenia among patients with TRS both in the short term (end of the treatment) and medium term, that is 4 and 12 weeks after the treatment. METHODS: Fourteen patients with TRS based on DSM-5 criteria took part in the present study. ECT consisted of daily sessions for 8 consecutive days. At baseline, at the end of the intervention, and 4 and 12 weeks after study completion, trained psychiatrists assessed the patients' disease severity (positive and negative symptoms; psychopathology) and cognitive functions. RESULTS: Disease symptoms (positive and negative symptoms; psychopathology) became reduced from baseline to the end of the intervention and to 4 weeks after treatment. Twelve weeks after the intervention symptoms again increased. Cognitive functions decreased from baseline to the end of the study and 4 weeks after treatment. However, by 12 weeks after the intervention, cognitive functions had returned to baseline levels. CONCLUSION: The pattern of results suggests that an intensive 8-day daily course of ECT reduced psychiatric symptoms (positive and negative symptoms, psychopathology) in both the short and medium term among patients with TRS. The increase in symptoms between 4 and 12 weeks following intervention suggests that booster sessions of ECT could be beneficial. PMID- 30463075 TI - Intravenous Thrombolysis in Middle Cerebral Artery Occlusion Associated with Transient Symptoms. PMID- 30463076 TI - Fiberoptic versus Digital: A Comparison of Durability and Cost Effectiveness of the Two Flexible Ureteroscopes. AB - AIMS: We aimed to evaluate the durability and cost effectiveness of the latest digital flexible ureterescope by comparing it with the conventional fiberoptic one. MATERIALS AND METHODS: Data of patients who underwent retrograde intrarenal surgery between January 2013 and December 2014 were collected. Fiberoptic Flex-X2 or digital Cobra vision flexible ureteroscopes were used for the procedures. The comparison of both ureteroscopes was performed in terms of patient and stone characteristics, operative outcomes, durability, and cost effectiveness. RESULTS: A total of 105 patients were evaluated for the study. The patient and stone characteristics and operative outcomes were similar between the groups. Overall, 54 and 51 procedures were performed using Flex-X2 and Cobra vision, respectively, before they were sent for renovation. The purchase prices were USD 29,500 for Flex-X2 and USD 58,000 for Cobra vision. Costs of per case were determined as USD 549.29 for Flex-X2 and as USD 1,137.25 for Cobra vision. Per minute working time costs were USD 772.04 and 1,471.33 for Flex-X2 and Cobra vision respectively. CONCLUSIONS: The digital Cobra vision has high costs without any difference in durability as compared to Flex-X2. Moreover, it has no benefit over Flex-X2 in terms of surgical outcomes. PMID- 30463077 TI - Front-of-Pack Labeling: Tool for Noncommunicable Diseases Prevention. PMID- 30463078 TI - Genome-Scale Single Nucleotide Resolution Analysis of DNA Methylation in Human Autosomal Dominant Polycystic Kidney Disease. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of fluid-filled cysts in the kidney and end stage renal disease by the fourth or fifth decade of life. Mutations in the PKD1 gene account for 85% of all cases of ADPKD. No curative therapy exists for patients affected by this disease and an underexplored avenue for the treatment of ADPKD is the targeting of epigenetic changes that occur during cystogenesis. Limited data exists on alterations in DNA methylation that are associated with ADPKD. Given the similarities between cyst growth and neoplasia, and the fact that 2 DNA methylation inhibitors are already Food and Drug Administration-approved for the treatment of myelodysplastic syndrome, we hypothesized that global DNA methylation patterns in ADPKD would parallel that observed in neoplasia, and which may provide an opportunity to treat ADPKD with epigenetic inhibitors. To address this hypothesis, we undertook a global DNA methylation analysis of human ADPKD kidney. METHODS: We generated single nucleotide resolution methylomes of cortical kidney tissue from individuals with ADPKD, and from non-ADPKD kidney tissue, using reduced representation bisulfite sequencing. Using quantitative reverse transcription polymerase chain reaction, we investigated expression of the PKD1 gene in both ADPKD and non-ADPKD kidney. RESULTS: We have shown that ADPKD-derived genomic DNA exhibits global hypomethylation when compared with non ADPKD kidney, a pattern commonly observed in DNA methylation studies of tumor derived tissue. We have also identified 13 discrete regions that are significantly differentially methylated in ADPKD compared to non-ADPKD, and 8 of these are gene specific. The PKD1 gene shows an increase in methylation at the 3' end of the gene body, but in contrast to previously published data, this is not associated with a decrease in PKD1 mRNA expression. CONCLUSION: This genome-scale single nucleotide resolution analysis of DNA methylation in human polycystic kidneys suggests that DNA methylation differences at specific loci are associated with ADPKD. Further exploration into the significance of these preliminary results may shed light on the disease process, and potentially reveal new therapeutic possibilities. PMID- 30463079 TI - Impact of Assisted Peritoneal Dialysis Modality on Outcomes: A Cohort Study of the French Language Peritoneal Dialysis Registry. AB - BACKGROUND: Patients on peritoneal dialysis (PD) can be assisted by a nurse or a family member and treated either by automated PD (APD) or continuous ambulatory PD (CAPD). The aim of this study was to evaluate the effect of PD modality and type of assistance on the risk of transfer to haemodialysis (HD) and on the peritonitis risk in assisted PD patients. METHOD: This was a retrospective study based on data from the French Language PD Registry. All adults starting assisted PD in France between 2006 and 2015 were included. Events of interest were transfer to HD, peritonitis and death. Cox regression models were used for statistical analysis. RESULTS: Among the 12,144 incident patients who started PD in France during the study period, 6,167 were assisted. There were 5,060 nurse assisted and 1,095 family-assisted PD patients. Overall, 5,171 were treated by CAPD and 996 by APD. In multivariate analysis, CAPD, compared to APD, was not associated with the risk of transfer to HD (cause specific hazard ratios [cs-HR] 0.96 [95% CI 0.84-1.09]). Patients on nurse-assisted PD had a lower risk of transfer to HD than family assisted PD patients (cs-HR 0.85 [95% CI 0.75-0.97]). Neither PD modality nor type of assistance were associated with peritonitis risk. CONCLUSIONS: In assisted PD, technique survival was not associated with PD modality. Nurse-assisted patients had a lower risk of transfer to HD than family assisted patients. Peritonitis risk was not influenced either by PD modality, or by type of assistance. Both APD and CAPD should be offered to assisted-PD patients. PMID- 30463080 TI - Refining the Prediction and Prevention of Emergency Operative Deliveries with the Fetal Reserve Index. AB - : Electronic fetal monitoring (EFM) is a poor predictor of outcomes attributable to delivery problems. Contextualizing EFM by adding maternal, obstetrical, and fetal risk-related information to create an index called the Fetal Reserve Index (FRI) improves the predictive capacity and facilitates the timing of interventions. Here, we test critical assumptions of FRI as a clinical tool. Our conceptualization implies that the earlier one reaches the red zone (FRI <=25) and the longer one spends in the red zone, the greater the likelihood of emergency operative deliveries (EOD). METHODS: We analyzed 1,402 patients using logistic regression predicting the probability of EOD and employed qualitative methodology techniques to refine predictive capabilities. RESULTS: Reaching the red zone early and staying there > 1 h increases the probability of EOD. When these risk factors are paired with intrauterine resuscitation (IR) in Stage 1, the reduction of EOD is substantial. CONCLUSION: FRI is a capable predictor of EOD because it accurately identifies the level of malleable risk. FRI analysis increases the risk of using IR in Stage 1. Matching risk and resources dramatically reduces the chances of EOD. Earlier IR improves the outcomes if the calculated risk is high. PMID- 30463081 TI - Integrated Transcriptome Sequencing Analysis Reveals Role of miR-138-5p/ TBL1X in Placenta from Gestational Diabetes Mellitus. AB - BACKGROUND/AIMS: The placenta has been suggested to play a crucial role in the pathology of gestational diabetes mellitus (GDM). Placenta-specific microRNAs (miRNAs) and the corresponding targeting genes involved in the pathology of GDM still remain to be elucidated. We aimed to identify the dysregulated miRNAs and the corresponding mRNA targets through an integrated miRNA and mRNA transcriptomic profiles analysis and investigate the role of differentially expressed miR-138-5p/TBL1X in GDM. METHODS: RNA sequencing (RNA-seq) was performed in 16 placentas from GDM and control group. Differentially expressed mRNAs and miRNAs in GDM were validated by quantitative PCR (qPCR). The wound healing assay and transwell migration assay were used to analyze cell migration ability. The cell proliferation was determined by CCK8 assay. Luciferase assay was used to confirm the direct binding of the targeted TBL1X with miR-138-5p. RESULTS: Totally, 281 mRNAs and 32 miRNAs were found to be differentially expressed in the GDM placentas. The biological relationships of the miRNA/mRNA pairs were related to cellular development and function and organ morphology. Among the aberrantly expressed molecules, we selected miR-138-5p from the bioinformatics analysis and found that miR-138-5p significantly inhibited the migration and proliferation of trophoblasts (HTR-8/SVneo) by targeting the 3'-UTR of TBL1X. Furthermore, the aberrant expression of miR-138-5p and TBL1X was significantly correlated with the weight of the placenta. CONCLUSION: We present the first integrative analysis of miRNA and mRNA expression profiles in GDM placenta and uncover a more detailed role for miR-138-5p, as well as its target TBL1X in the pathology of GDM. PMID- 30463082 TI - What are the Risk Factors for One-Year Mortality in Older Patients with Chronic Kidney Disease? An Analysis of the Cleveland Clinic CKD Registry. AB - BACKGROUND: Prognostic factors after dialysis initiation among older chronic kidney disease (CKD) patients are not well studied. In this study, we examined the risk factors associated with 1-year mortality after dialysis initiation among older CKD patients. METHODS: In this retrospective study, we included 621 CKD patients from an electronic medical record based CKD registry that was linked to the United States Renal Data System data. In terms of age, they were all >=65. We examined the associations of various demographic factors, comorbid conditions, relevant laboratory parameters, the presence of arteriovenous fistula, and inability to take care of oneself with 1-year mortality after dialysis initiation using Cox proportional hazards model. RESULTS: In our study cohort, 224 older patients died during the first year of dialysis initiation and the estimated survival at 1 year was 65% (95% CI 62-69). After adjusting for covariates, increasing age by each year (Hazard ratio 1.04 [95% CI 1.02-1.06]), congestive heart failure (CHF; 1.57 [1.13-2.18]), an absence of AVF (3.0 [1.7-5.1]) and lack of nephrology care prior to dialysis initiation (1.93 [1.39-2.70]) were associated with increased risk of 1-year mortality. Nearly 60% of deaths were due to non-cardiovascular (CV) causes including cancer. CONCLUSION: Risk factors portending high 1-year mortality in older CKD patients are increasing age, CHF, an absence of AVF, and lack of pre-dialysis nephrology care. Clinicians need to be aware of non-CV risks of high mortality in these patients. PMID- 30463083 TI - Cognitive Status and Functional Dexterity as Outcome Predictors Following Urinary Diversion: A Combined Retrospective and Prospective Observational Study. AB - PURPOSE: The study aimed to evaluate the impact of the validated functional dexterity test and the Mini-Mental Status test on subjective functional outcomes, medical care situation, and health-related quality of life (HRQoL) after urinary diversion (UD). PATIENTS AND METHODS: A total of 106 patients (n = 26 ileal conduits, n = 29 neobladders, and n = 51 ileocecal pouches) were included in this combined retrospective (n = 77) and prospective (n = 29) observational study. All patients performed the 2 tests mentioned above and filled out self-designed questionnaires with diversion and HRQoL items. In the prospective cohort, the tests were performed preoperatively and the questionnaires were filled out preoperatively as well as 3 and 6 months after surgery. RESULTS: Reduced dexterity and cognitive skills were significantly associated with increased patient age and subjective constraints in stoma care of ileal conduits, self catheterization in ileocecal pouches, and continence in neobladders. Overall HRQoL, however, was not affected by dexterity or cognitive measures. CONCLUSIONS: Assessing the cognitive status and functional dexterity of patients undergoing UD might provide a useful objective clinical tool to aid in decision-making regarding the type of UD and postoperative medical care situation. Further prospective data are needed to confirm these findings and further simplify the methods used here. PMID- 30463090 TI - [Development and status of personalized medicine in Germany]. PMID- 30463084 TI - Catestatin Enhances Neuropathic Pain Mediated by P2X4 Receptor of Dorsal Root Ganglia in a Rat Model of Chronic Constriction Injury. AB - BACKGROUND/AIMS: Neuropathic pain (NPP) is the consequence of a number of central nervous system injuries or diseases. Previous studies have shown that NPP is mediated by P2X4 receptors that are expressed on satellite glial cells (SGCs) of dorsal root ganglia (DRG). Catestatin (CST), a neuroendocrine multifunctional peptide, may be involved in the pathogenesis of NPP. Here, we studied the mechanism through which CST affects NPP. METHODS: We made rat models of chronic constriction injury (CCI) that simulate neuropathic pain. Rat behavioral changes were estimated by measuring the degree of hyperalgesia as assessed by the mechanical withdrawal threshold (MWT) and the thermal withdrawal latency (TWL). P2X4 mRNA expression was detected by quantitative real-time reverse transcription polymerase chain reaction. P2X4 protein level and related signal pathways were assessed by western blot. Additionally, double-labeled immunofluorescence was employed to visualize the correspondence between the P2X4 receptor and glial fibrillary acidic protein. An enzyme-linked immunosorbent assay was performed to determine the concentration of CST and inflammatory factors. RESULTS: CST led to lower MWT and TWL and increased P2X4 mRNA and protein expression on the SGCs of model rats. Further, CST upregulated the expression of phosphor-p38 and phosphor ERK 1/2 on the SGCs of CCI rats. However, the expression level of phosphor-JNK and phosphor-p65 did not obviously change. CONCLUSION: Taken together, CST might boost NPP by enhancing the sensitivity of P2X4 receptors in the DRG of rats, which would provide us a novel perspective and research direction to explore new therapeutic targets for NPP. PMID- 30463091 TI - Safranal Attenuates Excitotoxin-Induced Oxidative OLN-93 Cells Injury. AB - OBJECTIVES: Researches have been shown that glutamic acid (GA) or quinolinic acid (QA) can play role in neuroinflammatory and demyelinating diseases including multiple sclerosis (MS), mainly via oligodendrocytes activation and extreme free radicals generation. Recent studies have demonstrated that safranal, an active constituent of Crocus sativus, has several pharmacological effects such as antioxidant, anti-inflammatory and neuroprotective properties. Since there is no data about the impact of safranal on MS, this study was designed to investigate the protective effect of safranal on OLN-93 oligodendrocytes injury induced by GA or QA. MATERIALS AND METHODS: At first, the potential toxic effect of safranal on OLN-93 viability was evaluated. Also, the cells were pretreated with safranal (0.1, 1, 10, 50, 100 and 200 MUM) for 2 h and then subjected to GA (16 mM) or QA (8 mM) toxicity for 24 h, in which the same treatments were applied. The cell viability and parameters of redox status such as the levels of intracellular reactive oxygen species (ROS) and lipid peroxidation were measured. RESULTS: Safranal at concentration ranges of 1-800 MUM had no toxic effect on cell viability (p>0.05). Treatment with safranal significantly increased cell viability following GA or QA insults at concentrations higher than 1 MUM (p<0.01). The cytoprotective potential of safranal was also accompanied by decreased ROS accumulation (p<0.001) and malondialdehyde level (p<0.001) following GA or QA insults. CONCLUSION: The data suggests that safranal exhibits oligoprotection potential by means of inhibiting oxidative stress parameters. PMID- 30463092 TI - Effect of Flying at High Altitude on Early Exposure of Paracetamol in Humans. AB - Pharmacokinetics of paracetamol (APAP) was studied on-board during an air flight and compared to those on ground after 500 mg oral dose in 20 healthy human volunteer in parallel design study. Saliva samples were obtained every 15 min up to 2 h after dosing. Pharmacokinetic parameters were calculated by non compartmental analysis and one compartment models using Winnonlin program V5.2. Results have showed that on-board to ground ratios for area under curves AUC0->1, AUC0->2, time to reach maximum saliva concentration Tmax, absorption rate constant Ka and maximum saliva concentration Cmax were 0.62, 0.38, 1.01, 0.81 and 0.79 respectively. Effective membrane permeability coefficients were optimized by Nelder-Mead algorithm using Simcyp program V13. This showed similar rate of absorption and early exposure up to one hour, and lower bioavailability after 1 h on-board. This can be explained by the increased liver blood flow at high altitude that led to increased liver metabolism on-board. However, APAP elimination parameters were not calculated due to short sampling time. This suggests a need for dose adjustment on-board during long air flights, especially for narrow therapeutic index drugs with flow limited metabolism. PMID- 30463093 TI - Functional Classification of Paediatric Patients with Non-syndromic Delta-Storage Pool Deficiency. AB - Storage pool disease (SPD) covers a group of platelet defects in which alpha- and/or delta-granules are reduced or cannot be secreted adequately in response to agonists. The detection of delta-granule release defects is hampered by a lack of fast and feasible tests. We aimed to implement a flow cytometry-based kinetic mepacrine assay to better identify and subgroup childhood patients with a mild to moderate bleeding diathesis and compare our method to established laboratory tests. We analysed 50 children with suspected SPD whose initial parameters were re-assessed in a second site visit. Mepacrine uptake and release patterns were correlated with CD63 exposure, platelet ADP/ATP release and content, and the bleeding score ascertained by the ISTH-BAT. Mepacrine release was overall significantly reduced in investigated patients compared with controls. Summarizing, our time-resolved approach proved to be a quick and inexpensive tool that was additionally able to distinguish between mepacrine uptake, mepacrine release, and combined defects. Classification of patients using such a kinetic assay makes it feasible to sensitively detect frequently missed SPD and to group these patients for further analyses and clinical correlations. PMID- 30463094 TI - Self-Care Support for Patients with Gastrointestinal Cancer: iCancerHealth. AB - BACKGROUND: Patient-centered symptom assessment and management tools allow patients to perform self-assessments and engage in self-symptom management. Efficacious tools exist for reducing symptom distress; however, little is known about feature-specific use. OBJECTIVES: This article evaluates the feasibility of the iCancerHealth app as an adjunct to usual patient education regarding cancer symptoms and medication management. METHODS: We conducted a single-arm, pilot study grounded in the health outcomes model. Our evaluation included (1) enrollment rates, (2) 2-month utilization rates, (3) patient acceptability, and (4) clinician satisfaction with the provider-side application. English-speaking, adult patients receiving care in the gastrointestinal oncology service of a comprehensive cancer center were invited to participate. Research coordinators enrolled consenting participants who had a personal, Internet-connected device; participants registered and used the platform to complete the baseline symptom assessment in clinic. Participants were reminded weekly to use the app and to perform a symptom report 4 to 6 weeks later. RESULTS: A total of 64 patients were approached, of which 57 (89%; 95% exact confidence interval [CI], 79-96%) enrolled. About half were >= 60 years old and 40% were women. Fifty-three patients (93%; 95% exact CI, 85-99%) accessed at least one app feature, at least once, from home. The most frequently used (86%) feature was Health Tracker in which participants monitored and reported symptoms; followed by My Inbox (63%) and My Medications features (60%). The mean acceptability score was 24.8 (standard deviation = 4.2), indicating good acceptability. Clinicians reported that the app was most acceptable with regard to facilitating in-person interactions that occurred after app use. CONCLUSION: In a sample of adults with various stages of gastrointestinal malignancies, the iCancerHealth app was utilized at a high rate. Features that focused on symptoms and medication side effects plus communication with clinicians were used most frequently. This extends our understanding of preferences and specific feature use with patient centered technologies. PMID- 30463095 TI - The Impact of a Location-Sensing Electronic Health Record on Clinician Efficiency and Accuracy: A Pilot Simulation Study. AB - BACKGROUND: Through the Health Information Technology for Economic and Clinical Health Act of 2009, the federal government invested $26 billion in electronic health records (EHRs) to improve physician performance and patient safety; however, these systems have not met expectations. One of the cited issues with EHRs is the human-computer interaction, as exhibited by the excessive number of interactions with the interface, which reduces clinician efficiency. In contrast, real-time location systems (RTLS)-technologies that can track the location of people and objects-have been shown to increase clinician efficiency. RTLS can improve patient flow in part through the optimization of patient verification activities. However, the data collected by RTLS have not been effectively applied to optimize interaction with EHR systems. OBJECTIVES: We conducted a pilot study with the intention of improving the human-computer interaction of EHR systems by incorporating a RTLS. The aim of this study is to determine the impact of RTLS on process metrics (i.e., provider time, number of rooms searched to find a patient, and the number of interactions with the computer interface), and the outcome metric of patient identification accuracy METHODS: A pilot study was conducted in a simulated emergency department using a locally developed camera-based RTLS equipped EHR that detected the proximity of subjects to simulated patients and displayed patient information when subjects entered the exam rooms. Ten volunteers participated in 10 patient encounters with the RTLS activated (RTLS-A) and then deactivated (RTLS-D). Each volunteer was monitored and actions recorded by trained observers. We sought a 50% improvement in time to locate patients, number of rooms searched to locate patients, and the number of mouse clicks necessary to perform those tasks. RESULTS: The time required to locate patients (RTLS-A = 11.9 +/- 2.0 seconds vs. RTLS-D = 36.0 +/- 5.7 seconds, p < 0.001), rooms searched to find patient (RTLS-A = 1.0 +/- 1.06 vs. RTLS-D = 3.8 +/- 0.5, p < 0.001), and number of clicks to access patient data (RTLS-A = 1.0 +/- 0.06 vs. RTLS-D = 4.1 +/- 0.13, p < 0.001) were significantly reduced with RTLS-A relative to RTLS-D. There was no significant difference between RTLS-A and RTLS-D for patient identification accuracy. CONCLUSION: This pilot demonstrated in simulation that an EHR equipped with real-time location services improved performance in locating patients and reduced error compared with an EHR without RTLS. Furthermore, RTLS decreased the number of mouse clicks required to access information. This study suggests EHRs equipped with real-time location services that automates patient location and other repetitive tasks may improve physician efficiency, and ultimately, patient safety. PMID- 30463096 TI - [Health Economic Effects of Rehabilitation for Chronic Back Pain - An Observational Study with Combined Secondary Data from Statutory Health Insurance and German Pension Fund]. AB - BACKGROUND: Chronic back pain is the most common indication in medical rehabilitation. Numerous studies hint on positive effects of rehabilitation on health state. However, there is no evidence about the effectiveness of rehabilitation due to the lack of a valid comparison group. METHODS: Based on combined secondary data from German Pension Fund and statutory health insurance, a comparison group of insured persons was identified by their typical patient career that did not apply for rehabilitation for unclear reasons. Effectiveness was measured by direct and indirect costs of back pain between rehabilitants and non-rehabilitants. RESULTS: Costs of rehabilitation split in 2.742 ? direct costs and 2.597 ? indirect costs. In the 2 years following rehabilitation, rehabilitants were hospitalized less frequent and caused less indirect costs due to disability. Therefore, the benefit of rehabilitation was 727 ? in the first year after rehabilitation and additional 37 ? in the subsequent year. CONCLUSION: Rehabilitation for chronic back pain contributes to maintain the ability to work. Moreover, rehabilitation reduces duration of disability and healthcare utilization, hence direct and indirect costs of illness are lowered compared to a treatment without rehabilitation. Effects of rehabilitation by avoidance and delay of retirement are not yet recorded. PMID- 30463097 TI - [On Clinical Significance in German Clinical Rehabilitation Trials - An Inventory of Current Practice]. AB - OBJECTIVE: It is investigated whether and how the issue of clinical significance is treated in German rehabilitation trials. METHODS: Review of 64 articles published between 2012 and 2016, which report data on at least 2 measuring times and involve German scientists and rehabilitation facilities. RESULTS: Clinical significance is mentioned in 28% of the articles, defined by 19%, and 13% provide justification for the definition. Statistics suitable for determining clinical significance are reported by 70% but no more than 28% actually use these statistics for this purpose. The most commonly used statistics are measures of effect size (45%). They are interpreted schematically according to Cohen's categories without further reflection. CONCLUSION: Determining and discussing the clinical significance of results is recognizable in the majority of cases only to some extent or non-existing. PMID- 30463098 TI - Cucurbitacin B Induces Hypermethylation of Oncogenes in Breast Cancer Cells. AB - Breast cancer is a complex disease driven by multiple factors including both genetic and epigenetic alterations. Recent studies revealed that abnormal gene expression induced by epigenetic changes including aberrant promoter methylation plays a critical role in human breast carcinogenesis. Cucurbitacin B has antiproliferative activity against various human breast cancer cells, but the molecular mechanism is not completely understood. In this study, we explore the influence of cucurbitacin B from Trichosanthes cucumerina on the methylation status at the promoter of oncogenes c-Myc, cyclin D1, and survivin in breast cancer cell lines. Growth inhibitory effect of cucurbitacin B on breast cancer cells was assessed by MTT assay and colony formation assay. Methylation status of genomic DNA was determined by methylation-specific PCR. Gene and protein expression levels of all genes studied were analyzed by real-time RT-PCR and western blot. The results indicated that cucurbitacin B could inhibit cell growth in breast cancer cells. The oncogene promoters are usually hypomethylated in cancer cells. Upon cucurbitacin B treatment, upregulation of DNMT1 and obvious heavy methylation in the promoters of c-Myc, cyclin D1, and survivin, which consequently downregulated the expression of all these oncogenes, were observed. Hence, cucurbitacin B proved to be a potential cancer therapeutic agent, in part by inducing hypermethylation and silences the oncogenic activation. PMID- 30463099 TI - [Subjective Health and Unemployment in Germany: Analysis of 2005-2014 EU-SILC Data]. AB - BACKGROUND: This study aims to analyze self-perceived health and chronic illness in the working population and to explore disparities between social groups. METHODS: The annual EU-SILC Survey has been conducted in Germany since 2005. The reference population is defined as all private households. In the EU-SILC 2014, a random sample of 22,695 persons aged 16 years and older was interviewed in Germany (860 unemployed and 11,390 employed). RESULTS: In accordance to the EU SILC-Surveys 2005 until 2014, the self-perceived general health of the population has improved in Germany. 65.2% of the population (aged 16 years and older) in Germany assessed their health as very good or good in 2014 vs. 60.7% in 2005, despite an ageing population. However, there was an increase in health inequalities between employment status groups. In 2014, only 37.2% among unemployed persons vs. 77.1% of the employed perceived their general health as very good or good (53.8 vs. 73.2% in 2005). Multivariate logistic regression models revealed strong associations of subjective general health and chronic illness with age groups and social determinants on the EU-SILC-Survey 2014. Cross sectional analysis showed unemployed persons to be much less likely to have very good or good self-perceived health (OR=0.26) and more likely to have chronic illness (OR=3.99) compared to employed people after adjustment for sociodemographic characteristics. The probabilities of better health and lower chronic illness rose with the increasing disposable (net) income as well as educational levels. 78.8% of the household members in the highest income quintile vs. 51.7% of the household members in the lowest income quintile said they had very good or good health (OR=2.53). In all investigated age groups, members of the households at risk of poverty were more likely to have poor health on average. High educational level (ISCED 5-8) was associated with higher positive self-rated health (OR=1.78). CONCLUSION: The EU-SILC-Survey shows distinct health developments and inequalities in Germany. EU-SILC is useful as an annual general population survey to monitor public health targets and reduce health inequalities. PMID- 30463100 TI - [Evolving Epidemiology of Home Mechanical Ventilation: A Rapidly Growing Challenge for Patient Care]. AB - BACKGROUND: Home mechanical ventilation is dramatically evolving in Germany. Patients with non-invasive and invasive ventilation are increasingly treated at home. In-hospital treatment of these patients is also necessary either for control visits or the management of acute medical problems. However, the development of in-hospital patient care, morbidity and mortality of these patients is unknown. METHODS: All patients with long-term dependence on mechanical ventilation for more than three months requiring hospitalisation between 2006 and 2016 were analysed (data obtained from the Federal Statistical Office of Germany). RESULTS: There was an exponential increase in the number of in-patients with long-term dependence of mechanical ventilation. While 24 845 patients were treated in-hospital in 2006, 86 117 patients were treated in 2016. Correspondingly, mortality decreased from 13.2 % (2006) to 5.7 % (2016). In addition, in 2016 47 % of all patients were treated on the intensive care or high dependency care unit. Overall, patients had been severely ill, as there were plenty of medical and neurological co-morbidities. The most common diagnosis was COPD with 58 % of all cases, followed by several cardiology diagnosis. A high number of patients had an impairment of renal function (24 %), in part requiring dialysis. CONCLUSIONS: The rapid development of home mechanical ventilation substantially impacts on the development of the hospital landscape in Germany. The exponential increase of these care-intensive patients is challenging for the health care system and requires a discussion about its limits. PMID- 30463101 TI - Head Biometry in Fetuses with Isolated Congenital Heart Disease. AB - PURPOSE: Altered cerebral hemodynamics are involved in changes in head biometry in fetuses with congenital heart disease (CHD). We compared head growth in different CHD groups with published normative values and investigated whether CHD groups differ from each other in terms of head circumference (HC) development over gestational age (GA). MATERIALS AND METHODS: Retrospective cohort study consisting of 248 CHD fetuses. Subgroups were generated according to the expected ascending aorta oxygen saturation: Low placental blood content (BC) and therefore low oxygen delivery to the brain (group 1: n = 108), intermediate placental and systemic BC due to intracardiac mixing of blood (group 2: n = 103), high placental BC (group 3: n = 13) and low placental BC and low oxygen delivery to the brain without mixing of blood (group 4: n = 24). Furthermore, group 1 was divided into antegrade (n = 34) and retrograde (n = 74) flow through the aortic arch. Comparisons were made at a GA of 22, 30 and 38 weeks. RESULTS: Estimated values of zHC (z-score transformed) were not significantly different between the four CHD groups at the three time points in gestation (all p > 0.05). Within group 1 fetuses with retrograde aortic arch flow showed a significant negative association between HC and GA compared to reference values (b = - 0.054, p < 0.001) and had significantly lower zHC values at 38 weeks (- 0.836) compared to fetuses with antegrade flow (0.366, p = 0.009). CONCLUSION: Our data do not confirm that CHD fetuses in general have a significantly smaller HC. HC becomes smaller throughout gestation depending on the direction of aortic arch flow. PMID- 30463102 TI - High frequency of getting out of bed in patients with Alzheimer's disease monitored by non-wearable actigraphy. AB - AIM: Sleep disturbances in patients with Alzheimer's disease have not been systematically evaluated, because sleep monitoring has proved difficult. Our goal was to quantitatively characterize sleep disturbances in patients with Alzheimer's disease. METHODS: The present study was a cross-sectional descriptive study, carried out in dementia care units in Japan. Participants were 63 patients with Alzheimer's disease (mean age 77.6 +/- 8.0 years) with severe behavioral and psychological symptoms of dementia. A non-wearable actigraphy device placed under patient mattresses was used to measure sleep parameters: sleep time, time in bed, number of wakings and number of times they left the bed. Cut-off points for sleep parameters were based on the interquartile range of the data. RESULTS: Median nocturnal sleep time was 6.2 h (interquartile range 2.7 h). Median frequency of waking was eight times (5)/night. Median frequency of leaving the bed was five times (6), with a maximum of 31/night. We identified three types of sleep disturbance: frequent bed leaving, short sleep time and excessive sleep time. Multiple linear regression showed that duration of dementia was a significant predictor of frequent bed leaving at night (P = 0.042). CONCLUSIONS: Frequent bed leaving at night reflects severe sleep deprivation in patients with mild-to severe Alzheimer's disease. Safety measures are required to prevent accidents related to sleep disturbances, regardless of dementia severity. Geriatr Gerontol Int 2018; **: **-**. PMID- 30463103 TI - Language development and intelligence in midlife. AB - Individual differences in early language skills have been found to be associated with other cognitive outcomes in childhood and adolescence. However, research is limited on whether these associations persist into adulthood. In this study, we examined potential associations of the timing of early language milestones with cognitive ability in a prospective cohort study of 938 singletons from the Copenhagen Perinatal Cohort (CPC), who participated in a 50-year follow-up examination in 2009-2011. Later attainment of a number of milestones was associated with lower midlife IQ with the strongest associations found for 'Naming objects/animals in pictures', 'Forming a sentence', and 'Sharing experiences'. Milestones related to language explained 6.7% of the variance in midlife IQ, while milestones related to social interaction explained 3.1%. The study provides evidence that individual differences in language development during the first years of life are associated with intelligence in midlife. Statement of contribution What is already known on this subject? Differences in early language skills are associated with other cognitive skills in childhood and adolescence. No study has examined this association from childhood through midlife in a large community-based sample. What does this study add? Early language development is associated with intelligence in midlife. A total of 6.7% of the variance in midlife IQ is explained by milestones related to language. Adjustment for potentially confounding factors did not change the associations. PMID- 30463105 TI - Bartonella quintana Type IV secretion effector BepE induced selective autophagy by conjugation with K63 poly-ubiquitin chain. AB - Bartonella effector proteins (named Beps) are substrates of VirB type IV secretion system for translocation into host cells evolved in Bartonella spp. Among these, BepE has been shown to protect cells from fragmentation effects triggered by other Beps and to promote in vivo dissemination of bacteria from the dermal site of inoculation to the bloodstream. Bacterial pathogens secreted effectors to modulate the interplay with host autophagy, either to combat autophagy to escape its bactericidal effect, or to exploit autophagy to benefit intracellular replication. Here we reported a distinct phenotype that selective autophagy in host cells is activated as a countermeasure, to attack BepE via conjugation with K63 poly-ubiquitin chain on BepE. We found that ectopic expression of Bartonella quintana BepE specifically induced punctate structures that co-localized with an autophagy marker (LC3-II) in host cells, in addition to filopodia and membrane ruffle formation. Two tandemly arranged Bartonella Intracellular Delivery (BID) domains in the BepE C-terminus, where ubiquitination of sister pairs of lysine residues were confirmed, were essential to activate host cell autophagy. Multiple poly-ubiquitin chain linkages of K27, K29, K33 and K63 were found to be conjugated at sites of K222 and K365 on BepE, of which K63 polyubiquitination on BepE K365 determined the selective autophagy (p62/SQSTM1 positive autophagy) independent of the PI3K pathway. Co-localization of BepE with LAMP1 confirmed the maturation of BepE-induced autophagosomes in which BepE were targeted for degradation. Moreover, host cells employed selective autophagy to counterattack BepE to rescue cells from BepE-induced endocytosis deficiency. PMID- 30463104 TI - Specialisation and diversity of multiple trophic groups are promoted by different forest features. AB - While forest management strongly influences biodiversity, it remains unclear how the structural and compositional changes caused by management affect different community dimensions (e.g. richness, specialisation, abundance or completeness) and how this differs between taxa. We assessed the effects of nine forest features (representing stand structure, heterogeneity and tree composition) on thirteen above- and belowground trophic groups of plants, animals, fungi and bacteria in 150 temperate forest plots differing in their management type. Canopy cover decreased light resources, which increased community specialisation but reduced overall diversity and abundance. Features increasing resource types and diversifying microhabitats (admixing of oaks and conifers) were important and mostly affected richness. Belowground groups responded differently to those aboveground and had weaker responses to most forest features. Our results show that we need to consider forest features rather than broad management types and highlight the importance of considering several groups and community dimensions to better inform conservation. PMID- 30463106 TI - Activation of AKT of signaling pathway and the level of mTOR substrates in tumor of patients with kidney cancer, connection with prevalence of malignancy. AB - Activation of AKT signaling pathway and mTOR substrates of kidney tumor tissue occurs by improving AKT, its phosphorylated form, the serine / threonine proteinkinase m-TOR, the exchange regulator glycogen GSK-3-beta and also the inhibitor of 4E-BP1transcription. Increasing the size of primary tumor is followed by increasing the content of therein c-Raf and decreasing the content of phospho-m-TOR. The development of disseminated forms of the disease was associated with a reduction PTEN and phospho-AKT in tumor. PMID- 30463107 TI - Study of tumor-specific expression of some evolutionary new genes. AB - In this paper we have showed that evolutionary new genes DCD1(Dermicidin), LINC00309 (Long intergenic non-protein coding RNA 309) and CLLU1(Chronic lymphocytic leukemia up-regulated 1) have tumor-specific expression profile. Along with our previously published results this confirms the existence of the phenomenon of TSEEN (Tumor-Specifically Expressed, Evolutionarily Novel). PMID- 30463108 TI - Morphological study of benzofurocain correction of structure of rat small intestine microvasculature damaged by cyclophosphamide. AB - Experimental study results confirm morphologically usefulness of benzofurocain for correction of microcirculation changes manifested as a side-effect of cyclophosphamide on the small intestine tissue. The experiment was conducted on 63 white purebred rats. The morphological and morphometric analysis of small intestine tissue was carried out in the control group, the group that was injected intraperitoneally with cyclophosphamide and the group that was injected intraperitoneally with cyclophosphamide and benzofurocain. It was reliably proven that the structure of microcirculation damaged by cyclophosphamide morphologically and morphometrically rose up to values of control group on the third day. PMID- 30463109 TI - Polychromatic visible and infrared light (480-3400 nm) downregulates the growth of hepatoma MH22a in mice. AB - We studied the effect of polychromatic visible (380-750 nm) (VIS) and combined with the visible infrared (480-3400 nm) (VIS-IR) radiation on the growth of hepatoma in mice. In the first series of experiments on C3HA mice with subcutaneously transplanted syngeneic hepatoma MH22a it was shown 1.5-4 times inhibition of tumor volume after irradiation of tumor-bearing mice with VIS infrared light at a dose 4.8 J/ cm2. Mice irradiation at doses of 9.6 J/cm2 and 38.4 J/cm2 had no effect on the rate of tumor growth. Exposition to VIS and IR light in all doses we used an increase of the surviveness of animals in the 1.5 and 2 times respectively was observed. In a second series of experiments we investigated the effect VIS-IR radiation on tumor cells in vitro with subsequent inoculation to intact mice. After implantation in mice irradiated cells at a dose of 4.8 J/cm2 9.6 J/cm2 inhibition of tumor growth during the first 25 days at 3 12 times as compared to control and increased survival in mice 1.5-2 respectively was observed. The main results of this study consists in the fact that none of the doses used VIS and a IR-radiation has not been shown to stimulate tumor growth both in irradiated mice with tumors, and the irradiation of MH22a hepatoma cells under in vitro conditions prior to transplantation of intact mice. Furthermore it was detected dose range VIS-IR light (4.8-9.6 Joules/cm2) when the rate of growth of hepatoma MH22a decreased and increased surviveness of animals. PMID- 30463110 TI - RHAMM (receptor hyaluronan-mediated motility)-target peptides induce apoptosis in prostate cancer cells. AB - In this work the effect of RHAMM (receptor hyaluronan-mediated motility)-target peptides was investigated on the viability, apoptosis and necrosis of prostate cancer cells (PC3m-LN4). It has been established that RHAMM-target peptides inhibited on 90 % cell viability of PC3m-LN4 cells at a concentration of 10 ug / ml (2x10-7 M) for 48 h. It has shown that RHAMM-target peptides induced apoptosis and inhibited necrosis of tumor cells. RHAMM-target peptide had no effect on fibroblasts (non-tumor cells) and fibroblasts (RHAMM-/-). The studies also revealed that RHAMM-target peptides enhanced activity of caspase-3/7 in cancer cells. PMID- 30463111 TI - Associativity of microRnA levels in blood serum to quantity and functional activity of haemo - and lymphopoiesis cells in experimental breast cancer. AB - The work purpose was to reveal an existence of an associativity of the microRNA levels in blood serum to quantitative and functional indices of cells haemo - and lymphopoiesis at the experimental breast cancer induced by N -methyl - N- nitrosourea in the remote period after surgery and carrying out neoadjuvant polychemotherapy. At animals there were investigated levels of microRNA-21, microRNA-221, microRNA-222 and microRNA-429 in serum, also investigated quantitative and functional parameters of cells from bone marrow, from lymph of a chest channel and from spleen. Statistically significant distinctions on the microRNA level in blood serum and an existence of interrelations of microRNA levels with quantitative and functional indices of haemo- and lymphopoiesis cells were revealed. PMID- 30463112 TI - Possibilities of ultrasound examination with elastography in the diagnosis of recurrent rectal cancer. AB - The purpose of this study was to evaluate possibilities of complex ultrasound examination in the diagnosis of recurrent rectal cancer. The study included 40 patients with recurrent rectal cancer, 19 men and 21 women aged from 27 to 83 years, mean age was 60 +/- 7.9 years. In order to detect recurrence we performed ultrasound examination with elastography of possible sites of recurrences of rectal cancer. It was found that our study showed a high diagnostic efficiency of complex ultrasound examination with elastography in the early diagnosis of recurrences and the continued growth of rectal cancer. PMID- 30463113 TI - Prophylaxis and treatment of radiation oral cavity mucositis by hydrogel preparations in patients with oropharyngeal cancer. AB - Development of radiation mucositis in patients with oropharingeal cancer who are treated by radiation therapy leads to constrains breaks, decreases of the quality of life and makes the radiation dose in target insufficient. All above mentioned increases recurrence risk. Since 2010 there was developed and introduced the method of prophylaxis and treatment of radiation injuries of oral cavity in patients with oropharingeal cancer which gives an ability to improve radiation treatment outcomes and the quality of life of patients. PMID- 30463114 TI - Possibilities of intraoperative thermal chemotherapy in radical surgery for advanced gastric cancer pt4a-4bn0-3M0. AB - The paper evaluates results of randomized study of treatment of 135 patients for II-IIIB stage resectable gastric cancer (Borrmann type III and IV); of them 70 underwent intraoperative hyperthermic chemotherapy based on a technique adopted in the clinic. It has been noted the improvement of long-term results in particular the increase of dissemination-free survival (plog-rank=0,004) especially in patients with absence of metastases in regional lymph nodes (pN0) - (plog-rank=0,03). Application of an integrated technique appears to improve remote results thereby necessitating the need for further studies. PMID- 30463115 TI - Role of C-reactive protein concentration of blood plasma in assessment of the severity and the effectiveness of treatment in patients with squamous cell carcinoma of the oral cavity mucosa. AB - The purpose of this study was to determine the prognostic significance of dynamics of C-reactive protein concentration in blood plasma as a marker for the progression of squamous cell carcinoma of the oral cavity mucosa. From January 2014 to August 2014 there were under the observation 35 patients with squamous cell carcinoma of the oral cavity mucosa. All patients were divided into 2 groups: group 1 - primary patients who had been diagnosed with malignant lesions of the oral cavity mucosa for the first time (17 people); group 2 - patients with recurrent disease (18 people). All 17 patients of group 1 received induction polychemotherapy by PF scheme and 18 patients of group 2 - curative polychemotherapy by the following schemes: PF, DCF, TC. In all patients there was performed an assessment of the level of C-reactive protein in blood serum at the stage prior to drug treatment and before each subsequent cycle of chemotherapy. An assessment of the level of C-reactive protein before treatment showed that in 17 patients of group 1 its level was in the normal range. Patients of group 2 had an increased concentration of C-reactive protein in blood plasma. Analysis of obtained data allows concluding that the level of C-reactive protein may be effectively used as a prognostic marker in patients with this pathology. PMID- 30463116 TI - Cancer metastases in the pituitary gland. AB - Metastases to the pituitary gland is a rare complication of systemic cancer in adults (does not practically occur in children). In 1857 L.Benjamin was the first who described a case of metastasis to the pituitary gland at autopsy of a patient with disseminated melanoma. Metastases in the pituitary gland are marked in 0,14 28,1% of all metastases to the brain in several series of autopsies. Many researchers consider that metastases in the pituitary gland are met in 1% of patients who underwent transsphenoidal surgery and 5% of autopsies. PMID- 30463117 TI - Diagnosis and treatment of phylloides tumors of the breast. AB - Phylloides tumors (PT) are a rare and the least studied pathology of the breast. Data on physical examination and imaging methods of diagnostics in most cases do not allow accurate diagnosing at the preoperative stage as there are no clear characteristics that allow differentiating benign from malignant variants of PT or other benign breast diseases. Surgery is the main treatment of PT. Chemotherapy and radiation therapy of malignant variants of PT in the adjuvant setting do not significantly improve survival rates. In recurrent or metastatic forms of PT these methods can be effective in some cases. Currently there are identified molecular signaling pathways that play an important role in the pathogenesis of PT. Thus there are prerequisites for the study of the effectiveness of targeted therapies for this pathology. PMID- 30463118 TI - Activated petroleum waste sludge biochar for efficient catalytic ozonation of refinery wastewater. AB - Large quantities of hazardous activated petroleum waste sludge and wastewaters are generated from petroleum refining. The present disposal of the sludge via incineration or landfill may cause secondary pollution as well as additional costs. Treatment of petroleum refinery wastewater (PRW) by catalytic ozonation process (COP) remains a great challenge of developing low-cost and high efficiency catalysts. Use of waste sludge derived biochar as catalysts in COP of PRW not only solves the solid wastes and wastewaters problems but also improves profitability. The elements of carbon (C), silicon (Si) and metals originally found in activated petroleum waste sludge contribute to the formation of active sites during pyrolysis. The biochar contains functional C groups, SiO structures, and metallic oxides that promote oxidation through the formation of hydroxyl radicals (OHs) mineralizing petroleum contaminants. Catalytic ozonation of PRW using this sludge biochar (SBC) doubles the total organic carbon removal (53.5%) relative to single ozonation (26.9%). Oxygen (Ox)-, nitrogen (NOx)- and sulfur (OxS)-containing contaminants were decreased by 33.4% (989 vs 659), 58.2% (912 vs 384) and 12.5% (384 vs 336). The present study shows the potential of a "wastes treat-wastes" process for wastewater treatment. PMID- 30463119 TI - Impact of elevated CO2 on grain nutrient concentration varies with crops and soils - A long-term FACE study. AB - The impact of elevated CO2 (eCO2) on grain nutrient concentration is becoming a global concern in terms of future human nutrition. Previous research has shown that eCO2 can alter the availability and uptake of nutrients in crops. However, the interactive effects of long-term eCO2 and soil types on the concentrations of nutrients in grain are poorly understood. By understanding such effects, we are able to develop management practices that maintain grain nutritional quality while improving crop yield in response to future climatic conditions. We conducted a seven-year experiment of free air CO2 enrichment (FACE) with a rotation of wheat, field pea and canola grown in a Chromosol (Luvisol), Vertosol (Vertisol) and Calcarosol (Calcic Xerosol) under ambient CO2 (aCO2) (390 +/- 10 MUmol mol-1) or eCO2 (550 +/- 30 MUmol mol-1). The concentration and amount of five macro- and four micro-nutrients in grain over the seven years were determined. Compared to aCO2, the concentrations of N, P and Zn decreased by 6%, 5% and 10% under eCO2, respectively, irrespective of soil, crop and year. A greater decrease in N concentration was found in canola and wheat compared to field pea. The reduction in P and Mg concentration of canola was significant in Chromosol, but not in the Vertosol nor Calcarosol soils. The concentrations of K, Fe, Mn and Cu were not affected by eCO2 in any crop grown in the soils tested. Furthermore, eCO2 significantly decreased soil labile N and P and exchangeable Mg and Cu due to greater nutrient uptake, which was in part ascribed to the decreased nutrient accumulation in crop grains. It appears that eCO2 lowers the nutritional quality (nutrient concentration) in grains of non-legume crops, and that the extent of this decrease was greater in relatively fertile than infertile soils. PMID- 30463120 TI - Variability of subsurface structure and infiltration hydrology among surface coal mine valley fills. AB - Surface coal mining alters landscapes including creating waste-rock fills or dumps. In Appalachia USA, mines fill valleys with waste rock, constructing valley fills that affect water quality and aquatic ecology downstream. Total dissolved solids (TDS) in mine effluent are elevated from exposure of mineral surfaces to weathering. Understanding TDS variability requires understanding valley fill internal structure and its effect on hydrology, yet prior studies focused on point measurements or did not address patterns among fills. Here we investigated subsurface structure and hydrologic flowpaths in two dimensions within four valley fills using electrical resistivity imaging (ERI). We used artificial rainfall to investigate the location and transit time of preferential flowpaths through the fills. We corroborated our ERI interpretations using borehole logs, downhole video, and shallow soil excavation. ERI results indicated variability in substrate type and widespread presence of preferential flowpaths. We estimated an average preferential flowpath vertical length of 6.6 m, average transit time of water along the flowpath of 1.4 h, and average minimum water velocity of 5.1 m/h (0.14 cm/s). These rates are higher than typical for undisturbed lands, and resemble highly preferential flow in karst terrain. ERI successfully distinguished fills using conventional loose-dump construction from experimental controlled-material compacted-lift construction. Conventional fills exhibited finer particles that retain water at the surface, with larger rocks and larger voids at depth. Conventional fills had greater ranges of subsurface resistivity (i.e. substrate types) and greater interior accumulation of water during artificial rainfall, indicating more quick/deep preferential infiltration flowpaths. We show experimental construction significantly alters hydrologic response, which in combination with use of low-TDS waste rock, may affect downstream water quality relative to conventional loose-dump methods. Our soil boring and pits corroborated ERI interpretation, thus demonstrating ERI to be a robust non-invasive technique that provides reliable information on valley fill structure and hydrology. PMID- 30463121 TI - Topography controls post-fire changes in soil properties in a Chinese boreal forest. AB - Both topography and the occurrence of wildfire can strongly affect soil properties in forest successions. Although numerous studies have examined the effects of fire and topography, few have explored their shifting relative importance with time since fire. We measured physical, chemical, and biological soil properties in two topographic positions (north-facing and south-facing) in a Chinese boreal forest along a gradient of fire history. In the control site, topography strongly influenced soil properties, with north-facing slopes having higher soil moisture (SM), depth of organic matter layer (OML), total carbon and inorganic N concentrations, and lower pH, dissolved organic carbon (DOC) and nitrogen (DON). In the 1-year-post-fire site, wildfire erased topographic effects on soil variables, and greater changes in soil properties occurred on the north facing slopes. The wildfire significantly increased soil pH, DON, ammonium and nitrate, and decreased SM, OML, DOC and microbial biomass, while no significant differences in soil properties appeared between high- and low-severity plots. In the 11-year-post-fire site, most soil properties were similar to the control except for microbial biomass, OML and DOC; topography again became a significant factor in explaining variations in soil properties. Fire severity was highly correlated only with soil pH in the 1-year-post-fire site, whereas topographic factors were always correlated with some soil properties in the three sites. In the 1-year-post-fire site, wildfire explained almost five times more variance than topography for most soil properties, whereas in the 11-year-post-fire site, the proportion of variance explained by topography increased and even surpassed that by wildfire. These results demonstrate that the resilience of Larix gmelinii forest soils might be controlled by wildfires in the short term but by topography in the long term. PMID- 30463122 TI - Effects of Ciprofloxacin and Roundup on seed germination and root development of maize. AB - Their continuous release into the environment, associated with their inherent biological activity, has motivated investigations into the detrimental effects of antibiotics and herbicides in natural and agricultural ecosystems. In this study, the interactive effects of the antibiotic ciprofloxacin (Cipro) and the herbicide Roundup on seed germination and root development were investigated. Although both compounds act as inhibitors of the mitochondrial electron transport chain in seeds, neither Cipro nor Roundup disrupted germinability of maize seeds. However, Cipro accelerated germination by promoting ROS accumulation in seeds, while the stimulatory effect of Roundup on ROS-scavenging enzymes (catalase and ascorbate peroxidase) seems to prevent ROS-signaling, delaying the germination process. Roundup reduced root elongation, possibly due to its interference with auxin production, thereby preventing cell division, while Cipro stimulated root elongation by increasing root oxidative status. Cipro and Roundup showed antagonistic effects on maize seeds and root physiology. The presence of the antibiotic is likely not to disturb plant development; however, its stimulatory effects were not sufficient to overcome the deleterious effects of Roundup. According to our results, glyphosate-based herbicides must be carefully used during maize cropping and although antibiotics such as Cipro may not negatively impact agricultural production, their accumulation by crops must be investigated since this can be a pathway of antibiotic-insertion into the food chain. PMID- 30463123 TI - Characterization and source apportionment of marine aerosols over the East China Sea. AB - Awareness of the importance of marine atmosphere for accurately estimating global aerosol budget and climate impacts has arisen recently. However, studies are limited due to the difficulty and inconvenience in sampling as well as the diversity of sources. In this study, the Community Multiscale Air Quality (CMAQ) model was applied to investigate the fine particulate matter (PM2.5) and its chemical components over the East China Sea (ECS) and offshore regions. In spite of slight under-predictions, model predictions agree well with observations over the ECS and along the coast. PM2.5 and its major components in the mainland are higher than in marine area, suggesting Asian continent is a major emitter of marine aerosols. PM2.5 and its components in marine regions show higher abundance during daytime than nighttime, while it is opposite in continental regions. Aerosol phase SO42- is the most abundant component of PM2.5 over the ECS with an average concentration of 5.12 MUg m-3, followed by NH4+ (1.02 MUg m-3) and primary organic aerosol (POA) (0.92 MUg m-3). Industry and ship emissions are the top two contributors to primary (PPM) and total PM2.5 over the ECS, while industry and agriculture sectors are major sources for secondary inorganic aerosols (SIA), followed by ship emissions. For terrestrial regions, industry and agriculture are predominant sources of PM2.5 and SIA, while industry and residential activities are the top two contributors to PPM. This study improves the understanding of transport and accumulation of air pollutants over the ECS and adjacent regions, and provides useful information for designing efficient control strategies. PMID- 30463124 TI - Dynamic accounting of greenhouse gas emissions from cascading utilisation of wood waste. AB - Cascading utilisation of post-consumer wood waste has recently gained increasing attention in the European Union, aiming for a society in which the resource's properties are optimized through sequential uses. To date, material utilisation of wood waste has been limited to particleboard production, with additional niche alternatives being restricted by quality requirements for wood waste. In this consequential life cycle assessment focusing on post-consumer wood collected at Danish recycling centres, Global Warming Potential (GWP) impacts from quality driven choices for cascading management of wood waste were compared with those from handling mixed wood waste qualities. GWPs were modelled by considering the dynamic profile of greenhouse gas emissions (including biogenic carbon dioxide) for two time horizons (100 and 500 years). The robustness of the results was tested by varying modelling assumptions with respect to electricity system, wood sourcing and associated rotation period, and impacts from indirect land use changes. The results demonstrated that valuing quality over quantity in wood waste management can ensure larger GWP savings, especially if recycling applications have a long lifetime and/or substitute energy-intensive products; such results were confirmed under all scenario analyses. Inclusion of land use changes credited land-intensive products. More cascade steps of the wood waste resource ensured larger savings; however, assumptions on the electricity mix, on the source of the wood alongside the choice of the time horizon for GWP greatly influenced the results on cascading management. PMID- 30463125 TI - Delineation of contaminant sources and denitrification using isotopes of nitrate near a wastewater treatment plant in peri-urban settings. AB - Distinguishing sources of groundwater contamination in regions with multiple potential sources can be challenging using conventional markers. In this study, isotopes of nitrate (delta15NNO3 and delta18ONO3) were examined in conjunction with other hydrochemical parameters to better distinguish sources of groundwater contamination, where intensive agriculture occurs adjacent to a wastewater treatment plant (WWTP). High nitrate concentrations were found in groundwater both within the WWTP site and surrounding market garden farms (maximum of 99 mg/L and 78 mg/L nitrate as N, respectively). Ranges and median delta15NNO3 values showed clear differences between sample groups. In groundwater close to the WWTP, delta15NNO3 and delta18ONO3 values ranged from 10.4 to 41.20/00 and -0.5to 21.30/00, respectively, indicating predominantly sewage-sourced nitrate, while samples within market gardens showed evidence of mixed fertilizer (manure and synthetic) sourced nitrate, with delta15NNO3 and delta18ONO3 values between 7.2 and 29.80/00 and 0.4 to 15.10/00, respectively. Nitrate interpreted to be derived from the WWTP was also typically associated with elevated ammonia as N (median concentration of 17 mg/L) and SO4 (median concentration of 350 mg/L). These distinctive signatures allowed for clearer delineation of the extent and overlap between different contaminant plumes than otherwise possible. Geochemical conditions in groundwater surrounding the WWTP appear to promote denitrification, evident through enrichment in delta15NNO3 and delta18ONO3 and reduced nitrate concentrations between sampling rounds (locally). However, isotopic signatures in market garden areas showed no evidence of denitrification, and groundwater exhibited conditions likely to preserve nitrate (e.g. dissolved oxygen levels >2 mg/L). There is limited evidence of nitrate contamination currently impacting a nearby groundwater dependent ecosystem (Tootgarook Swamp), located down-gradient from the WWTP. This research demonstrates that a combination of hydrochemical and isotope data can help resolve sources of groundwater contamination and characterise nutrient degradation behaviour in settings with multiple inputs. PMID- 30463126 TI - Ground-based evaluation of MODIS snow cover product V6 across China: Implications for the selection of NDSI threshold. AB - The new MODIS daily NDSI snow cover product version 6 (V6) is released to replace V5 with significant revisions. This study evaluates, for the first time, the accuracy of product V6 across China based on daily snow-depth measurements during 2003-2013 from 279 and 252 stations for Terra and Aqua, respectively. Three schemes of selecting NDSI thresholds for Terra and Aqua were tested and compared including: (1) the locally optimal NDSI threshold, (2) the minimum valid NDSI of 0.1, and (3) the global reference NDSI threshold of 0.4. The mean Cohen's Kappa (CK) of the optimal, minimum and global reference thresholds for Terra (Aqua) are 0.80 (0.60), 0.77 (0.58), 0.72 (0.51), respectively, while snow depth >= 1 cm. The NDSI threshold of 0.1 is demonstrated to be more reasonable than the threshold of 0.4 for use in China. This is also supported by the accuracy comparison conducted for the clear-day snow-cover day calculation. Terra V6 and Terra V5 have comparable accuracies whereas Aqua V6 shows better accuracy than Aqua V5 does. The revised temperature screen algorithm employed in V6 is found to be problematic with large snow commission errors in high altitude stations. Regionally, product V6 presents low CKs of 0.61 and 0.35 for the optimal thresholds of Terra and Aqua in the Tibetan Plateau, which are attributed to its high elevation and relatively small snow depth. This study provides practical implications for use of MODIS snow cover production V6 in China. PMID- 30463127 TI - Characteristics of atmospheric bacterial and fungal communities in PM2.5 following biomass burning disturbance in a rural area of North China Plain. AB - Biomass burning (BB) in North China Plain has been urgent issue in recent years due to the severe environmental impaction. Bacteria and fungi are ubiquitous in particulate matter. Their taxonomic composition, concentration, ecophysiological functions have potentially important implications in atmospheric biochemical cycle and human health. However, current knowledge about airborne microbes during biomass burning period is scant. Here we investigated bacterial and fungal community composition, abundance and potential function in Yucheng, the center of the North China Plain during summer harvest season in 2014. Monthly field observation suggested serious pollution with high concentration of PM2.5 and water-soluble ions during biomass burning period. Elevated total bacterial and fungal concentration determined by real-time quantitative PCR was observed for samples during burning events. The predominant bacterial taxa were gram-negative, e.g. Acinetobacter, Cyanobacterium, Janthinobacterium, Massilia, Pseudomonas, accounted for 70.9% of total bacteria. The filamentous fungi Alternaria, Aspergillus, Cladosporium and Penicillium were predominant fungal genera. Metastats analysis showed significant disparity in terms of carbohydrate, amino acids metabolism, human and plant disease predicted by PICRUSt analysis between BB and non-BB events. Microbial community structure were mainly influenced by organic carbon and water-soluble ions (magnesium and potassium) suggested by redundancy analysis (RDA) and co-occurrence analysis. Our data yielded insights into microbial community dynamics following biomass burning disturbance. This study may provide potentially important reference for environmental, agricultural and health management. PMID- 30463128 TI - The hidden costs of living in a transformed habitat: Ecological and evolutionary consequences in a tripartite mutualistic system with a keystone mistletoe. AB - Land use change is one of the most important anthropogenic drivers of biodiversity loss. Nevertheless, the ecological and evolutionary consequences of habitat transformation remain less understood than those from habitat fragmentation. Transformed habitats are structurally simpler, altering species composition and their ecological interactions, potentially compromising gene flow and genetic diversity. We focused on a tripartite mutualistic system composed of a mistletoe (Tristerix corymbosus), its pollinator (Sephanoides sephaniodes) and its seed disperser (Dromiciops gliroides) to assess changes in their ecological and evolutionary dynamics as a result of habitat transformation. We used eight microsatellite markers to compare genetic diversity, relatedness and gene flow among five mistletoe groups inhabiting native and transformed habitats (abandoned Eucalyptus globulus plantations). We found that these groups were genetically structured, with greater allelic richness and genetic diversity in their native habitat. Also, we found higher relatedness among mistletoe individuals in transformed habitats, which varied as a function of the geographic distance among plants, probably as a result of larger resource availability, which influenced mutualist visitation rates. We did not find differences in the current migration patterns, which suggests that Tristerix corymbosus may be resilient to habitat transformation. Yet, its highly specialized interactions along with changes in its spatial configuration depict a more complex scenario, which probably impose a cost in terms of lower genetic diversity and increased relatedness that might compromise its long-term viability. PMID- 30463129 TI - Technology review and data analysis for cost assessment of water treatment systems. AB - A wide variety of water sources, treatment methods, and recycling options have created a myriad of water management options. For modeling of sustainable water treatment options, computationally efficient models may be required. This paper provides a comprehensive and comparative review of the water management systems and the associated economic, environmental, and performance metrics. The water management systems are represented as a network of sources, users, technologies, recycling options, and quality of water. Special attention is given to desalination systems. The two main technology categories currently used for desalination are thermal (e.g., Multistage Flash "MSF", Multi-Effect Distillation "MED", and Mechanical Vapor Compression "MVC") and membrane (e.g., seawater reverse osmosis "SWRO", brackish water reverse osmosis "BWRO"). The cost assessment includes a capital cost comparison (for which regression analysis has been used to account for the non-linear nature of the capacity-cost curves), an operating cost comparison, which includes energy requirements, labor costs, chemicals used, maintenance and repair costs, membrane replacement costs and a unit product cost ($/m3) breakdown, which combines the capital and operating costs. Numerous data were collected for the cost of desalination systems. Statistical methods were then used to analyze these collected data to establish deeper understanding of the relationship to capital cost, operating cost, capacity, constraints due to treatment method capabilities, requirements of the users. The paper also briefly discusses other cost considerations such as the water intake and distribution costs. The environmental impacts (concentrate disposal and CO2 footprint) have also been compared for the various technologies considered. Some integration strategies such as use of hybrid systems, cogeneration plants and use of renewable energy have shown reductions in cost associated due to energy consumption and thereby, reducing the unit product cost. Finally, the paper provides a selection guide suitable for various situations with consideration of the different factors affecting cost, environmental impact and energy demands. PMID- 30463130 TI - Characteristics of wood-derived biochars produced at different temperatures before and after deashing: Their different potential advantages in environmental applications. AB - Ash in biochar has great influence on the characteristics of biochars. This study systematically compared the differences in physico-chemical properties between pristine biochars (PBCs) and deashed biochars (DBCs) produced at different temperatures (300-900 degrees C), and specifically analyzed their different advantages in environmental applications. In terms of all the PBCs and DBCs, PBC of 900 degrees C and the corresponding DBC have the highest degree of graphitization that is recalcitrant in environment, they are benefit for carbon sequestration. PBC of 300 degrees C and the corresponding DBC have the highest content of O-containing functional groups and aliphaticity that is labile in environment, they are potential carbon source for the growth of soil organisms. PBCs of 300-400 degrees C have the greatest releasable PO43- content (0.418 0.441 mg/g), and PBCs of 700-900 degrees C have highest pH (9.28-9.59) and mineral elements content (11.58-12.64 mg/g), they are potential provision of P, and acid soil amendments with potential provision of mineral elements, respectively. DBCs of 300-400 degrees C possess less competitive cations including Ca, Mg, Al, Fe, and Zn (1.49-2.01 mg/g) and highest content of O containing functional groups, they are good sorbents for heavy metals, meanwhile these DBCs have the lowest pH (4.49-4.70) that are potential amendments for alkaline soil. Moreover, DBCs of 900 degrees C have the highest surface area (SA) (351 m2/g), the most developed porosity, and the highest releasable NH4+ content (0.052 mg/g), they are good sorbents for hydrophobic organic pollutants and potential provision of N. This study gives an effective guidance for selecting the suitable biochars-design (deashing or non-deashing) according to their applications in environment. PMID- 30463131 TI - Climate change will constrain the rapid urban expansion in drylands: A scenario analysis with the zoned Land Use Scenario Dynamics-urban model. AB - Evaluation of climate change impacts (CCIs) on urban expansion is important to improving the urban sustainability in drylands. Taking the agro-pastoral transitional zone of northern China (APTZNC) as an example, this study evaluates potential CCIs on urban expansion in 2015-2050. First, we set up six climate change scenarios (CCSs) based on the simulated results of global climate model and regional climate model under different representative concentration pathways. Then, we simulate regional urban expansion under the different CCSs using the zoned Land Use Scenario Dynamics-urban (LUSD-urban) model. We find that climate change will be a key factor that affects urban expansion in this region. The urban land affected by climate change in the entire region will increase from 20.24-26.48 km2 (2020) to 119.71-339.26 km2 (2050), an increase of 4.91-11.81 times. The CCIs on urban expansion will be the most significant in the mid western region. In 2050, the urban land potentially affected by climate change will be 98.70-213.88 km2, which is 42.26%-134.12% of the urban land in the entire region. To improve urban sustainability in the APTZNC, effective measures must be adopted to mitigate and adapt to CCIs on urban expansion. PMID- 30463132 TI - Exploring the potential of actinomycetes in improving soil fertility and grain quality of economically important cereals. AB - The search for environment-friendly, economical and healthy alternatives to agrochemicals tempted us to evaluate the potential of naturally occurring actinomycetes to improve soil properties, plant growth and photosynthesis, grain yield and chemical composition of economically important cereals (wheat, barley, oat, maize and sorghum). To this end, actinomycetes were isolated from soils of local cereals fields, then their biological activities, namely antibacterial, antiprotozoal, antioxidant, and phenolic and flavonoid contents were evaluated. The four most active isolates (9, 16, 24 and 26) were selected and used for enriching the soils until seed set. Each isolate was separately applied. Seeds of the selected cereals were grown in the actinomycete-enriched soils. The soils were analyzed for their electrical conductivity, pH values, total phenolics, organic matter and mineral content. At the vegetative stage, chlorophyll content and gas exchange rates were measured. Mature seeds were then harvested, the yield was evaluated and the seeds were analyzed for their primary and secondary metabolites. The selected isolates improved the grain yield in all tested cereals and most noticeably in barley and maize as compared to control counterparts. These positive effects were probably a result of increased carbon gain due to higher chlorophyll and photosynthetic rate. Isolate 26 showed the highest effect on grains composition profiles followed by the isolate 16. Phenolics and sugars of all grains increased by treatment with the tested isolates. Isolate 26 was the most effective in this regard. All isolates generally improved vitamins, amino acids and organic acids contents in grains. However, fatty acids profile showed a decrease in the content of all measured fatty acids by isolate 26 and an increase in the contents by isolate 16. These results emphasize the potential of actinomycete enrichment as an alternative to agrochemicals and strongly suggest that they can be used in organic farming. PMID- 30463133 TI - Linking oral bioaccessibility and solid phase distribution of potentially toxic elements in extractive waste and soil from an abandoned mine site: Case study in Campello Monti, NW Italy. AB - Oral bioaccessibility and solid phase distribution of potentially toxic elements (PTE) from extractive waste streams were investigated to assess the potential human health risk posed by abandoned mines. The solid phase distribution along with micro-X-ray fluorescence (micro-XRF) and scanning electron microscopy (SEM) analysis were also performed. The results showed that the total concentrations of PTE were higher in <250 MUm size fractions of waste rock and soil samples in comparison to the <2 mm size fractions. Mean value of total concentrations of chromium(Cr), copper (Cu), and nickel (Ni) in waste rocks (size fractions <250 MUm) were found to be 1299, 1570, and 4010 mg/kg respectively due to the parent material. However, only 11% of Ni in this sample was orally bioaccessible. Detailed analysis of the oral bioaccessible fraction (BAF, reported as the ratio of highest bioaccessible concentration compared with the total concentration from the 250 MUm fraction) across all samples showed that Cr, Cu, and Ni varied from 1 to 6%, 14 to 47%, and 5 to 21%, respectively. The variation can be attributed to the difference in pH, organic matter content and mineralogical composition of the samples. Non-specific sequential extraction showed that the non-mobile forms of PTE were associated with the clay and Fe oxide components of the environmental matrices. The present study demonstrates how oral bioaccessibility, solid phase distribution and mineralogical analysis can provide insights into the distribution, fate and behaviour of PTE in waste streams from abandoned mine sites and inform human health risk posed by such sites . PMID- 30463134 TI - Performance assessment of stormwater GI practices using artificial neural networks. AB - This study evaluates the performance of a suite of stormwater green infrastructure (GI) practices at the Belknap Campus, University of Louisville. In lack of instrumentation within individual GIs, and detailed drainage and sewer information, data mining procedures and artificial neural networks (ANN) were used. Two separate Back Propagation Neural Network Models (BPNNMs) were developed to estimate the reductions of flow volume and peak flow rates within the combined sewer system. The results from developed BPNNMs showed that following the construction of stormwater GIs at the Belknap campus, downstream wet-weather related flow decreased. The developed BPNNMs showed that the flow volume reduction and the peak flow attenuation rates had averages of approximately 33% and 61% per storm event, respectively. The flow reduction rates generally were lower for larger storms. Similarly, the peak flow rates decreased by increase of maximum intensity values per storm. However, further analysis indicated that even for large storm events, with long durations, the GIs had a positive impact on mitigation of combined sewer flows. Additionally, using rainfall data and downstream sewer flow in conjunction with artificial neural network modeling, was determined to be an effective technique for evaluating the combined hydrological performance of a suite of stormwater GIs. PMID- 30463135 TI - Disturbance of ecological habitat distribution driven by a chemical barrier of domestic and agricultural discharges: An experimental approach to test habitat fragmentation. AB - Contamination is an important factor for determining the pattern of habitat selection by organisms. Since many organisms are able to move from contaminated to more favorable habitats, we aimed to: (i) verify if the contamination along the river Guadalete (Spain) could generate a chemical barrier, restricting the displacement of freshwater shrimps (Atyaephyra desmarestii) and (ii) discriminate the role of the contaminants concerning the preference response by the shrimps. A. desmarestii was experimentally tested in a multi-compartmented, non-forced exposure system, simulating the spatial arrangement of the samples just like their distribution in the environment. Water and sediment samples were chemically characterized by analyses of 98 chemical compounds and 19 inorganic elements. Shrimps selected the less contaminated water and sediment samples, with two marked preference patterns: (i) upstream displacement avoiding the sample located at the point of pollutant discharges and those samples downstream from this point and (ii) fragmentation of the population with spatial isolation of the upstream and downstream populations. The preference was related to the avoidance of artificial sweeteners, flame retardants, fragrances, PAHs, PCBs, pesticides, UV filters and some inorganic elements. The threat of contamination was related to its potential to isolate populations due to the chemical fragmentation of their habitat. PMID- 30463136 TI - Exposure to naphthenic acids and the acid extractable organic fraction from oil sands process-affected water alters the subcellular structure and dynamics of plant cells. AB - Oil sands surface mining generates vast quantities of oil sands process-affected water (OSPW) as a by-product of bitumen extraction. The acid extractable organic (AEO) fraction of OSPW contains several contaminants, including naphthenic acids (NAs). While responses of living organisms to NA and AEO exposure have been described at the developmental, physiological, metabolic and gene expression levels, the effects of these compounds at the cellular and subcellular level are limited. Using live cell fluorescence microscopy and a suite of fluorescent marker proteins, we studied the intracellular responses of the plant cell cytoskeleton and several membrane-bound organelles to NA and AEO treatments. A rapid disassembly of cortical microtubules and a decrease in dynamics associated with actin filaments was observed in response to these treatments. Concomitantly, the integrity and dynamics of mitochondria, peroxisomes, Golgi stacks, and endoplasmic reticulum were also altered. AEO treatments were the most toxic to cells and resulted in the accumulation reactive oxygen species. This study provides foundational evidence for intracellular responses to NA and AEO exposure using two evolutionarily diverse model plant cell types. This cellular assay could be used to identify the most toxic components of AEO sub-fractions, and assist in determining the effectiveness of OSPW remediation efforts. PMID- 30463137 TI - H2O2-assisted photoelectrocatalytic degradation of Mitoxantrone using CuO nanostructured films: Identification of by-products and toxicity. AB - CuO nanostructured thin films supported on silicon with 6.5 cm2 area (geometric area greater than the studies reported in the literature) were synthesized by a chemical bath deposition technique. The electrodes were characterized by MEV, XRD, XPS, contact angle, cyclic voltammetry and electrochemical impedance spectroscopy analyses. To evaluate the photoelectrochemical properties of the CuO films, photocurrent-voltage measurements were performed using linear voltammetry. The catalytic activities of CuO nanostructures were evaluated by monitoring photodegradation of Mitoxantrone (MTX) under UV-A light irradiation. The method of photoelectrocatalysis (PEC), applying a voltage of 1.5 V and assisted by adding H2O2, was undertaken. To the best of our knowledge, no studies on the degradation of anticancer agents using PEC process have been found in the literature. For comparison purposes, experiments were performed under the same conditions by assisted photocatalysis (PC) with H2O2 and direct photolysis. CuO deposits consist of a needle-like morphology. The presence of CuO in the tenorite phase was evidenced by XRD and the XPS spectra showed the presence of copper(II) oxide. The increase in current under illumination shows that CuO exhibits photoactivity. The PEC system showed a 75% level of MTX degradation, while the level achieved using PC was 50%. Under UV-A light alone only 3% removal was obtained after 180 min. Up to 10 by-products were identified by chromatography mass spectrometry (LC-MS) with m/z values ranging between 521 and 285 and a plausible degradation route has been proposed. It is worth mentioning that 9 by products identified in this work, were not found in the literature in other studies of degradation or products generated as metabolites. The toxicity tests of MTX before and after PEC treatment with Artemia Salina and Allium cepa showed a decrease in the acute toxicity of the medium as the antineoplastic was degraded. PMID- 30463138 TI - Preparation of laccase-loaded magnetic nanoflowers and their recycling for efficient degradation of bisphenol A. AB - Bisphenol A (BPA) has been identified as one of the endocrine disrupting chemicals. However, the issue that BPA widely exists in various environments has puzzled people for decades. To develop highly efficient, easy separation, recyclable and reusable materials for BPA degradation in water, laccase-loaded magnetic nanoflowers (MNFs) were prepared by attaching amino-functionalized magnetic nanoparticles onto the laccase-inorganic hybrid nanoflowers. Characterization results showed that MNFs were spherical, porous and hierarchical structure with an average diameter of 15 MUm to which magnetic nanoparticles was successfully attached through electrostatic force. MNFs exhibited excellent catalytic activity on BPA degradation under room temperature in the presence of ABTS. Under optimized conditions, MNFs reached 100% BPA degradation for only 5 min. In addition, it still retained over 92% of its initial activity after 60 days of storage at 4 degrees C, indicating that its thermal and storage stabilities have been improved. When the MNFs was recycled and reused 5 cycles, only 5% decrease in degradation efficiency of BPA was observed. These results suggest that MNFs possess great efficiency and reusability in the treatment of aqueous solution containing BPA and is a novel promising material. PMID- 30463139 TI - Impacts of 1.5 degrees C and 2 degrees C global warming on winter snow depth in Central Asia. AB - Snow depth plays an essential role in the water and energy balance of the land surface. It is of special importance in arid and semi-arid regions of Central Asia. Owing to the limited availability of field observations, the spatial and temporal variations of snow depth are still poorly known. Using the Japanese 55 year (JRA-55) and the ERA-Interim reanalysis snow depth products, we considered four global climate models (GCMs) applied in the Inter-Sectoral Impact Model Intercomparison Project (ISI-MIP), examining how they represent snow depth in Central Asia during the period 1986-2005 in terms of spatial and temporal characteristics. We also investigated changes of winter (January-March) snow depth in Central Asia, at 1.5 degrees C and 2 degrees C global warming levels. Finally, the joint probabilistic behavior of winter temperature and precipitation at 1.5 degrees C and 2 degrees C global warming are investigated using the kernel density estimator (KDE). The result shows that the snow depth climatology of Central Asia is generally well simulated in both spatial pattern and temporal (inter-annual and inter-seasonal) pattern. All models approximately simulate the winter maximum and the summer minimum values of snow depth but tend to overestimate the amplitude during October-December. Only the trend in HadGEM2-ES matches fairly well to the JRA-55 reanalysis snow depth. When comparing the projections of spatial distribution of winter snow depth, distinctive spatial pattern is noted at both 1.5 degrees C and 2 degrees C global warming levels, when the snow depth is shown to increase in northeastern and to decrease in midwestern regions of Central Asia. According to the joint probability distributions of precipitation and temperature, Central Asia will tend to experience a warmer and wetter winter at both 1.5 degrees C and 2 degrees C global warming levels, which can be associated with an increase in snow depth in the northeastern regions. PMID- 30463140 TI - Soil and climate differently impact NDVI patterns according to the season and the stand type. AB - Several studies use satellite-based normalized difference vegetation index (NDVI) to monitor the impact of climate change on vegetation covers. Good understanding of the drivers of NDVI patterns is hindered by the difficulties in disentangling the effects of environmental factors from anthropogenic changes, by the limited number of environmental predictors studied, and by the diversity of responses according to periods and land covers. This study aims to improve our understanding of the different environmental drivers of NDVI spatial variations for different stand type characteristics of mountain and Mediterranean biomes. Using NDVI values extracted from MODIS Terra time series, we calculated Spring Greenness (SG) and annual Relative Greenness (RGRE) to depict spring and summer vegetation activity, respectively, in a contrasted area of 10,255 km2 located in the south of France. We modeled SG and RGRE at different scales, using 20 environmental predictors characterizing available energy, water supply, and nutrient supply calculated for different periods of the year. In spring, high minimum temperatures, good nitrogen availability, and acidic or neutral pH turned out to be determining for greenness, particularly for stand types located in altitude. In summer, an important soil water reserve and low temperatures promoted vegetation dynamics, particularly for stands located in areas with a Mediterranean climate. Our results show that NDVI dynamics was not only driven by climatic variability, and should not be studied using only mean temperature and rainfall. They highlight that different environmental factors act complementarily, and that soil parameters characterizing water stress and soil nutrition should be taken into account. While the factors limiting NDVI values varied according to the season and the position of the stands along the ecological gradients, we identified a global temperature and water-stress threshold when considering the whole vegetation. PMID- 30463141 TI - Does energy consumption follow asymmetric behavior? An assessment of Ghana's energy sector dynamics. AB - The study answered the following questions: First, does energy evolves in different regimes by transitioning over a finite set of unobserved states? Second, does energy consumption follow an asymmetric behavior over "energy boom" and energy scarcity? and, Third, are there unobserved factors underpinning energy crisis? We employed Markov-switching dynamic regression to examine the asymmetric effect, NIPALS regression to examine energy determinants and neural network analysis for prediction. The neural network model suggests a 99% prediction of energy consumption by the predictor variables. It was evident that energy consumption evolves in two states by transitioning over a finite set of unobserved states. The 11.6% growth in energy consumption is expected to occur in 4.1 years while energy crisis is expected to last for 3.7 years. Technological advancement and the development of green energy through foreign direct investment are essential to improve energy sector portfolio. PMID- 30463142 TI - Dam reservoir backwater as a field-scale laboratory of human-induced changes in river biogeomorphology: A review focused on gravel-bed rivers. AB - Only in the years 2007-2016 about 8000 large dams were constructed all over the world, adding to >50,000 previously built dams. These structures disturb abiotic and biotic components of rivers, but to date the knowledge of their impacts has been mainly derived from observations of downstream river reaches. Upstream from dams, however, backwater fluctuations induce sediment deposition, cause more frequent and higher valley-floor inundation, increase groundwater level, and change channel morphology and riparian vegetation. Little is known on the effects of these disturbances on the river biogeomorphological processes. In this review I synthesized knowledge on backwater effects on rivers into a model of backwater induced abiotic-biotic interactions in the fluvial system. This model is next used to propose new hypotheses and research tasks concerning the biogeomorphology of gravel-bed rivers in the temperate climatic zone. Implications for flow sediment-morphology-vegetation interactions and feedbacks are conceptualized in a river cross-section based on recent biogeomorphological insights and methodological approaches allowing to explore them in future studies. The model highlights that backwater-induced changes in abiotic and biotic components of river system trigger further feedbacks between them that additionally influence these components even without a direct backwater influence. Backwater-induced changes in hydrodynamics and sediment transport favour seed germination and growth of plants and decrease their mortality during floods, but also eliminate plants intolerant to prolonged inundation and intensive fine sediment deposition. These impacts may change the biogeomorphical structure of river system by modifying trajectories of biogeomorphic succession cycles and related zones of vegetation-hydromorphology interactions in the river corridor. Specifically, backwater effects may promote the development of more stable channel morphology and a less diverse mosaic of riparian vegetation and animals habitats, contrasting with those occurring in free-flowing rivers of the temperate zone. PMID- 30463143 TI - Toward creating an environment of cooperation between water, energy, and food stakeholders in San Antonio. AB - The San Antonio Region is home to a rapidly growing population with developing energy and agricultural sectors competing for water, land, and financial resources. Despite the tight interconnectedness between water, energy, and food challenges, little is known about the levels of communication and coordination among the various officials responsible for making the decisions that affect the management and planning of the three resource systems. It has been postulated that efficient communication is a prerequisite to developing resource allocation strategies that avoid potential unintended negative consequences that could result from inefficient allocation of natural resources and competing demands. Factors that may impact communication are identified and their potential roles are considered in improving existing levels of communication between San Antonio's water officials and those at other energy, food, and water institutions in the San Antonio Region. A questionnaire designed to gather information on stakeholder concerns, frequency of communication, and participation in engagement forums was sent to public water officials in the Region. Using social network analysis and bivariate Ordinary Least Square regression analysis, the authors conclude that while modest levels of communication exist among water institutions, a very low level of communication exists between water institutions and those responsible for food and energy. It was further concluded that the frequency of communication among officials at different water institutions is higher among those that participated in stakeholder engagement activities. However, there is insufficient evidence to suggest that participation in stakeholder engagement activities improves communication frequency between water stakeholders and those in the food and energy sectors. There is also insufficient evidence to conclude that people at water institutions in San Antonio would have a higher frequency of communication with other water, energy, and food stakeholder in correlation with a higher level of concern about future water availability in the Region. PMID- 30463144 TI - Trace elements in soil-vegetables interface: Translocation, bioaccumulation, toxicity and amelioration - A review. AB - The contamination of soil and vegetables with trace elements is one of the most severe ecological problems in developing industrialized countries. Trace elements are released into the environment from natural and anthropogenic activities and accumulated in soil and vegetables through various pathways which ultimately affects the human health. The present review aimed at 1) discussing the anthropogenic sources in detail, 2) describing the bioaccumulation, absorption, and transportation of trace elements, 3) exploring the options to reduce the health risk due to consumption of contaminated vegetables, 4) identifying the research and policy gaps related to soil and vegetables contamination with trace elements. Besides these objectives, the present review also detailed the several factors which affect the rate of accumulation, toxicity mechanism, and effects of trace elements on vegetables and humans. Various toxicity indices for health risk assessment have also been described. It is suggested to evaluate the trace metals concentration in irrigation water and soil prior to plant the vegetable to minimize the possible contamination. PMID- 30463145 TI - Risk assessment and source identification of heavy metal contamination by multivariate and hazard index analyses of a pipeline vandalised area in Lagos State, Nigeria. AB - Petroleum contamination is a significant contributor of elevated level of toxic heavy metals, which are of great concern to human health, due to their non biodegradable nature. Agaye community has experienced frequent gasoline spills due to pipeline vandalisation, resulting in the contamination of soil and water sources. The concentrations of metals (Cd, Cr, Cu, Mn, Ni, Pb, V and Zn) in groundwater, surface-water and soil were determined from a total of 216 samples acquired bi-monthly for two years by Inductively Coupled Plasma-Optical Emission Spectrometry (ICP-OES) to evaluate the impact of oil spills. Multivariate analyses using principal component analysis (PCA) and cluster analysis (CA) were also used to study the interactions between metals and identify the possible sources of contamination. The concentrations of heavy metals in soil and water samples (surface and groundwater) were in decreasing order of Mn > Ni > Zn > Cu > V > Cr > Pb > Cd and Ni > Zn > V > Cu > Mn > Pb > Cr > Cd respectively. Ni concentration ranged from 0.42-8.05 mg kg-1 and 0.10-2.85 mg L-1 for soil and groundwater respectively. Ni and V were more enhanced (P < 0.05) in soil samples. This study showed that there was significant relationship between elevated levels of Cr, Cu, Ni and Zn and oil spillage, due to petroleum spills and that residents were vulnerable to and at greater risk of non-carcinogenic hazards if they consumed groundwater. Multivariate analyses showed significant anthropogenic intrusions of two diagnostic heavy metals (Ni and V) for petroleum contamination in the soils and water sources. PMID- 30463146 TI - Determinants of pesticide safety behavior among Iranian rice farmers. AB - Safety behaviors in pesticide use are considered the most important determinants of the adverse health effects among farmers. In addition, the risk of pesticide exposure is strongly associated with farmers' behavior when working with pesticides. However, there is limited understanding of farmers' safety behavior and its determinants, particularly in developing countries like Iran. A field survey of 373 rice producers was conducted in Mazandaran Province of northern Iran to study determinants of farmers' safety behavior when working with pesticides. Although farmers' safety behavior varied depending on the type of safety measures adopted, few farmers showed safe behaviors in using personal protective equipment (PPE) (8.9%), in following appropriate practices in pesticide use (8.6%), in following hygiene practices after using pesticides (2.7%), and in avoiding health risks (2.4%). The mean scores of importance of all four components of safety behavior were higher than the mean scores of their current use, implying that perceptions of importance of various types of safety measures during pesticide application were not fully reflected in farmers' practices. Perceived barriers of using safety measures were the most reliable predictor of farmers' safety behavior in pesticide use. Perceived barriers of using safety measures and mean number of pesticide applications per cropping season had a negative impact on farmers' safety behaviors. By contrast, the variables education, level of self-consumed production in the household, experience of health risks related to working with pesticides, regular health check-ups, and perception of pesticide hazards promoted farmers' safety behaviors. The study not only presents a clear framework for better understanding and assessing farmers' safety behavior in pesticide use, but also provides valuable inputs for the design of effective interventions that could support farmers in the implementation of safety measures in Iran. PMID- 30463147 TI - Trace metal availability in soil horizons amended with various urban waste composts during 17 years - Monitoring and modelling. AB - Recycling organic residues in agrosystems presents several benefits but faces the question of contaminants, among them a few trace metals which eventually accumulate in soils following regular applications of organic waste products (OWP) and represent an ecological risk. The increase of total trace metal contents in amended topsoils can be predicted by a mass balance approach, but the evolution of their available fractions is a more intricate issue. We aimed at modelling this evolution by using the dataset of a long-term field experiment of OWP applications (manure and three urban waste composts). Two operationally defined fractions of 6 trace metals have been quantified in the OWP and amended topsoils between 2002 and 2015: the soluble and potentially available metals, extracted in 0.01 M CaCl2 and 0.05 M EDTA solutions, respectively. The potentially available metals have progressively increased in amended topsoils, at rates depending on elements and types of OWP. For Zn, these increases corresponded in average to inputs of potentially available Zn from OWP. But the soil stocks of potentially available Cu increased faster than from the inputs of EDTA-extractable Cu, showing linear regression slopes between 1.4 and 2.5, depending on OWP type. The influence of OWP has been provisionally interpreted in the light of their efficiency to increase soil organic matter and their inputs of reactive oxides. Soluble copper has increased with repeated amendments. But soluble cadmium, nickel and zinc have generally decreased, as they are influenced by changing soil variables such as pH and organic matter. Statistic models were used to unravel the relationships between soluble and EDTA-extractable metals and other soil variables. For Cu, the most satisfactory models just relate soluble and potentially available Cu. Developing such models could contribute to predict the long-term effects of a precise scenario of agricultural OWP recycling upon available trace metals in soils. PMID- 30463148 TI - Molecular structure-reactivity correlations of humic acid and humin fractions from a typical black soil for hexavalent chromium reduction. AB - Different soil humus fractions are structurally distinct from each other molecularly, however, the relationship between their microscopic molecular structures and the macroscopic reduction of Cr(VI) is still unknown, especially for the humin fraction. In this study, different humus fractions (HA, humic acid; HMi, humin linked to iron oxides; HMc, humin linked to clay; and HMr, humin residue) were sequentially extracted from a typical black soil and well characterized. It was found that HA, HMi and HMc were the same type of humus with similar molecular structures, while HMr was structurally different from the other fractions with a high cellulose content. The removal rate of Cr(VI) in solution decreased with progressive humus fractionation, namely, HA > HMi > HMc > HMr. Based on the two-dimensional correlation spectroscopic analysis (2DCOS) of the FTIR data, the changing functional groups of all humus fractions during reacting with Cr(VI) followed a similar order: carboxyl > phenol > hydroxyl > methyl > methylene. According to the correlation analysis, Cr(VI) reduction rates by different humus fractions were mainly determined by the content of phenol (R2 = 0.99) instead of carboxyl (R2 = 0.28). Except for HMr, the Cr(VI) reduction rates of different humus fractions were also positively correlated with surface and bulk polarity (R2 = 0.98 and 0.99) but not with aromaticity or aliphaticity (R2 = 0.21). PMID- 30463149 TI - Modelling eutrophication in lake ecosystems: A review. AB - Eutrophication is one of the main causes of the degradation of lake ecosystems. Its intensification during the last decades has led the stakeholders to seek for water management and restoration solutions, including those based on modelling approaches. This paper presents a review of lake eutrophication modelling, on the basis of a scientific appraisal performed by researchers for the French ministries of Environment and Agriculture. After a brief introduction presenting the scientific context, a bibliography analysis is presented. Then the main results obtained with process-based models are summarized. A synthesis of the scientist recommendations in order to improve the lake eutrophication modelling is finally given before the conclusion. PMID- 30463150 TI - Effects of sky conditions on net ecosystem productivity of a subtropical coniferous plantation vary from half-hourly to daily timescales. AB - The dynamic changes of solar radiation have received wide attention in global change studies, but there are controversies about the influence of diffuse radiation on ecosystem carbon sequestration. Using eddy covariance measurements from 2010 to 2012, the effects of sky conditions extracted from adjacent sunny, cloudy, and overcast days on net ecosystem productivity (NEP) of a subtropical coniferous plantation were examined from half-hourly to daily scales. Half-hourly NEP responded to the changing radiation more efficiently on overcast days compared to sunny days, but such response did not differ obviously between cloudy and sunny days. Compared with sunny conditions, apparent quantum yield (alpha) under overcast (cloudy) conditions changed 282.4% (41.7%) in spring, 140.3% ( 4.2%) in summer, 218.5% (38.9%) in autumn, and 146.2% (0.5%) in winter, respectively; annually, alpha under overcast (cloudy) conditions increased by 225.9% (19.8%) in 2010, 189.8% (6.0%) in 2011, and 159.5% (21.4%) in 2012, respectively. Moreover, the potential NEP at the light intensity of 150 and 750 W m-2 was improved due to increased diffuse fraction. However, both daytime NEP and daily NEP were significantly lower under overcast skies than under sunny and cloudy skies. Compared with sunny days, daily NEP on overcast days decreased by 127.7% in spring, 126.4% in summer, 121.8% in autumn, and 100.6% in winter, respectively; annually, daily NEP decreased by 122.5% in 2010, 141.7% in 2011, and 109.9% in 2012, respectively. Diurnal patterns of daily NEP were quite similar between sunny and cloudy days. Both path analysis and multiple regression showed that solar radiation, especially diffuse radiation, was responsible for the variations of NEP under different skies across seasons, but this effect may be weakened by seasonal droughts. This study implies that the effects of sky conditions on NEP are timescale dependent and should be paid more attention in ecosystem carbon cycle study. PMID- 30463151 TI - Urbanization and blood parasite infections affect the body condition of wild birds. AB - Human landscape transformation, especially urbanization, strongly affects ecosystems worldwide. Both urban stressors and parasites have negative effects on organism health, however the potential synergy between those factors has been poorly investigated. We analysed the body condition (i.e. body mass after controlling for wing chord) of 2043 house sparrows (adults and yearlings) captured in 45 localities along an urbanization gradient in relation to Plasmodium, Haemoproteus and Leucocytozoon infection status. Body condition was negatively related to urbanization level and to urbanized land coverage but only in yearling birds from urban habitats. In addition, bird body condition tended to increase in rural habitats, significantly in the case of yearlings. Infected individuals by Plasmodium or Haemoproteus had higher body condition than un infected birds, but this pattern could be due to a selective disappearance of infected individuals with lower body condition as suggested by the reduced variance in body condition in infected birds in urban habitats. These results provide support for a negative impact of urbanization on bird body condition, while Plasmodium and Haemoproteus may exert selection against individuals with lower body condition living in urban habitats, especially during earlier life stages, underlining the synergistic effects that urbanization and parasites may have on wild birds. PMID- 30463152 TI - Overcoming challenges in mainstream Anammox applications: Utilization of nanoscale zero valent iron (nZVI). AB - Although Anammox process is a proven technology for sidestream nitrogen removal, the process faces challenges for mainstream applications in sewage treatment plants (STPs). The aim of this study was to investigate the effect of zero valent iron nanoparticles (nZVI) on process performance to eliminate confronts for mainstream applications. An SBR (sequencing batch reactor) system was fed with various nZVI concentrations (0.04-5000 ppb) within 310 days of operation. Ammonium (NH4+-N) and nitrite (NO2--N) removal rates showed 58% increase in daily measurements and 73% increase in instant measurements. Specific Anammox Activity (SAA) was noticeably higher on the days the system was exposed to nZVI compared to the unexposed days. EPS secretion, which enhances granulation of Anammox bacteria was favored by nZVI. Despite lower sludge retention time (SRT) values, the fraction of Anammox bacteria in total bacteria reached to 91-92% implying a boosting effect of nZVI on growth rate of Anammox bacteria. High Resolution Melting (HRM) analyses showed that four distinct clades were present in the reactor. PMID- 30463153 TI - Current status of agricultural soil pollution by heavy metals in China: A meta analysis. AB - In the last decades, agricultural soil pollution by heavy metals has been extensively investigated in China. However, nearly all studies were field monitoring in small regions and/or with limited samples, which may not represent soil pollution situation at the national scale. In this paper, attempt was made to provide a comprehensive report about heavy metal pollution in China based on meta-analysis of reviewed data. Given the characteristics of field monitoring studies, the weighted mean values based on "sampling number", "study area", and "standard deviation" were calculated to represent national mean values. In addition, subgroup analysis and cumulative meta-analysis were applied to explore the spatial and temporal variations as well as the influence of cropping systems. 336 articles published from 2005 to 2017 were reviewed in the analysis. Eight heavy metals (cadmium (Cd), chromium (Cr), mercury (Hg), lead (Pb), arsenic (As), copper (Cu), zinc (Zn) and nickel (Ni)) were analyzed. The contents of Cd and Hg were increased compared to background values, while, other six elements showed no significant accumulation. Little pollution was found in normal farmland, which was far from obvious anthropogenic emissions, but Cd and Hg in mining & smelting areas and industrial areas continued to accumulate significantly. Moreover, the accumulation had slowed down or decreased since 2012, which might be due to reduced use of coals, non-ferrous metals and agro-chemicals. Heavy metal contents were generally higher in southwest and south coastal areas but lower in northwest regions, whereas vegetable and paddy fields had higher concentrations than upland and other land use. This study provides information on soil pollution caused by heavy metals and its affected regions and cropping systems on a national scale. It can be useful for developing heavy metal pollution control and management strategies in China. PMID- 30463154 TI - A novel model for hourly PM2.5 concentration prediction based on CART and EELM. AB - Hourly PM2.5 concentrations have multiple change patterns. For hourly PM2.5 concentration prediction, it is beneficial to split the whole dataset into several subsets with similar properties and to train a local prediction model for each subset. However, the methods based on local models need to solve the global local duality. In this study, a novel prediction model based on classification and regression tree (CART) and ensemble extreme learning machine (EELM) methods is developed to split the dataset into subsets in a hierarchical fashion and build a prediction model for each leaf. Firstly, CART is used to split the dataset by constructing a shallow hierarchical regression tree. Then at each node of the tree, EELM models are built using the training samples of the node, and hidden neuron numbers are selected to minimize validation errors respectively on the leaves of a sub-tree that takes the node as the root. Finally, for each leaf of the tree, a global and several local EELMs on the path from the root to the leaf are compared, and the one with the smallest validation error on the leaf is chosen. The meteorological data of Yancheng urban area and the air pollutant concentration data from City Monitoring Centre are used to evaluate the method developed. The experimental results demonstrate that the method developed addresses the global-local duality, having better performance than global models including random forest (RF), v-support vector regression (v-SVR) and EELM, and other local models based on season and k-means clustering. The new model has improved the capability of treating multiple change patterns. PMID- 30463155 TI - Interactive effects of hydrological conditions on soil respiration in China's Horqin sandy land: An example of dune-meadow cascade ecosystem. AB - Soil moisture (Ms) strongly influences dynamic changes in soil respiration (Rs) and is thus an important factor when predicting soil carbon emissions. However, the various sources of Ms (rainfall, groundwater, and condensation) exert complicated and uncertain effects on Rs. This study examined the growth seasonal variation (from April to October) of Rs and the diurnal variation in a cascade ecosystem consisting of sandy bare ground, a transitional artificial Populus forest, and a meadow Phragmites communis community in China's Horqin sandy land. Simultaneous measurements of the 0-10 cm depth soil temperature (Ts) and Ms, rainfall, the surface air relative humidity and the groundwater depth were collected. The results revealed that in sandy bare ground with Ms below field capacity, Ms had a greater impact on Rs than Ts, and rainfall could increase Rs. The effect of condensation on Rs during periods of continuous drought could not be ignored. In the meadowlands with Ms above field capacity, the groundwater affected Rs indirectly by regulating Ms and the relationship with Ts, and rainfall had an adverse effect on Rs. The effects of rainfall, Ms and Ts on Rs were minimum as Ms approached the saturation water content. In the transitional forest, Ms and Ts were the main factors controlling Rs. The most favorable Ms for Rs was close to the field capacity. The results emphasize that field capacity and saturation water content are the demarcation points of a soil carbon emissions prediction model, and the effect of different hydrological conditions and Ts on Rs at each segment are reconsidered accordingly. Ultimately, the carbon emission patterns of the cascade ecosystems in arid and semi-arid areas are extremely complicated and have to be considered specially for estimating terrestrial carbon emissions. PMID- 30463156 TI - Temporal controls on dissolved organic carbon biodegradation in subtropical rivers: Initial chemical composition versus stoichiometry. AB - Dissolved organic carbon (DOC) plays an indispensable role in biogeochemical cycles and ecosystem services in rivers. However, little is known about the seasonal variations of DOC biodegradation in subtropical rivers. Here, we investigated the concentrations of DOC, dissolved total nitrogen (DTN), and dissolved total phosphorus (DTP), humification index (HIX), fluorescence index (FI), and DOC biodegradation in 57 rivers in the dry and wet seasons in the Three Gorges Reservoir area, China, and the aims were to clarify the temporal changes in DOC biodegradation and its driving factors in these subtropical rivers. Compared with dry season, DTN and DTP concentrations, and HIX value were greater, and FI value was lower in the wet season. However, DOC biodegradation remained unchanged across the two sampling seasons. Further, DOC biodegradation negatively correlated with DOC:DTP ratio, DTN:DTP ratio, and FI in the dry season, but only with HIX in the wet season. These findings emphasis that, despite unchanged DOC biodegradation, the key factors driving DOC biodegradation shift from C:N:P stoichiometry in the dry season to initial chemical composition in the wet season in subtropical rivers. Our results regarding the temporal patterns of DOC biodegradation and the underlying mechanisms bear important implications for a better understanding of C dynamics in subtropical river ecosystems. PMID- 30463157 TI - Embryonic buoyancy control as a mechanism of ultraviolet radiation avoidance. AB - Pelagic fish have long been presumed to produce buoyant embryos which float and hatch at or near surface waters. Due to their transparency and rapid development, mahi embryos are thought to be especially vulnerable to stressors occurring in surface waters, such as ultraviolet radiation (UVR) and increased temperatures. In the present study, we suggest a possibly critical mechanism of UVR avoidance by pelagic fish embryos. Specifically, we provide evidence that mahi embryos are able to sense UVR and may alter buoyancy as a means of reducing exposure to the most harmful stressors occurring in the upper layers of the water column. Further, once the UVR exposure was terminated, embryos displayed fast recovery of positive buoyancy indicating this response is rapidly dynamic and not pathological. The mechanism behind buoyancy control is not known, but evidence from the current study suggests that ammonia sequestration, as seen in multiple other fish species, is not the primary control mechanism employed by embryonic mahi. Finally, expression of antioxidant and UV repair enzymes were investigated to elucidate possible involvement in observed buoyancy changes and to explore alternative methods of repairing UVR damage. PMID- 30463158 TI - Personal care products reconnaissance in EVROTAS river (Greece): Water-sediment partition and bioaccumulation in fish. AB - Twenty-six common ingredients of personal care products (PCPs) in water, sediment and fish from the Evrotas River (Greece) were investigated. Water sample analysis revealed the occurrence of twenty PCPs at concentrations ranging from 2.8 to 2031.0 ng l-1, the maximum corresponding to the endocrine disrupting UV filter benzophenone 3 (BP3). In sediment samples, six compounds were found to be adsorbed, the highest concentration being that of 4-methylbenzylidene camphor (4MBC, 1400.4 ng g-1 dw). Evrotas cyprinid fish (Squalius keadicus) showed a high accumulation potential for these chemicals, 100% detection frequency with maximum concentration that of benzophenone 2 (BP2, 41.9 ng g-1 dw). These data allowed estimating the distribution coefficients sediment-water (DCs-w) and the bioaccumulation factors (BAFs) of the pollutants investigated. Calculated rates revealed that benzophenone 1 (BP1), 4-hydroxybenzophenone (4HB) and ethyl-4 (dimethyl-amino)benzoate (EtPABA) have a strong tendency to adsorb onto the sediments, showing high DCs-w, i.e. 8.2E + 4 l g-1, 6.7E + 4 l g-1 and 5.7E + 3 l g-1, respectively. BFAs were only estimated for 5-methyl benzotriazole (MeBT), the compound having paired data from fish and water. The obtained values (range 2.0E + 2 l g-1-3.8E + 3 l g-1), indicated MeBT's strong bioaccumulation. Risk assessment of the investigated compounds for several aquatic organisms indicated a high ecological risk (HQ > 1) for BP3 and medium ecological risk (HQ ~ 0.5) for ODPABA. PMID- 30463159 TI - Mountain grassland restoration: Effects of sowing rate, climate and soil on plant density and cover. AB - Semi-natural grasslands are of great importance to European biodiversity. Their restoration in mountain regions often presents specific problems of raw soil stabilisation and difficult climatic conditions. Methods used to tackle these problems include increasing sowing density and fertilisation. However, past studies were performed at only one site or for a short time and do not clearly show how site traits and time affect restoration results. In six field experiments undertaken on raw soils in the Italian Alps, the effects of sowing density, fertilisation, soil, and climate on the development over time of plant density and cover were analysed over three to six years. The seed was collected from nearby grasslands and sown at rates of 335-21,410 seeds m-2. During the first one-two years, the percentage of seeds producing established plants at low seed rates was higher in stonier surfaces; however, at high rates a larger absolute plant number was recorded in finer soils. Two to five years after sowing, climatic conditions became more important. Full vegetation cover was achieved in all experiments. However, at high altitudes, individual plant cover became greater (and plant density decreased), probably because the grasses needed to accumulate more non-structural carbohydrates necessary to survive during the longer winter. Fertilisation accelerated the establishment of full vegetation cover by 1 to 3 years as it increased the mean cover per plant without affecting plant density. Grassland restoration is possible in mountain raw soils by using the seeds collected from nearby donor sites. High sowing densities are not required even in coarse or higher altitude soils because, in the short term, stones on the ground surface increase the percentage of seed producing established plants and, over the long term, plant density is not dependent on the sowing density. In low-fertile soils, fertilisation accelerates the establishment of full vegetation cover. PMID- 30463160 TI - Experimental sand burial and precipitation enhancement alter plant and soil carbon allocation in a semi-arid steppe in north China. AB - Sand burial is a common phenomenon in inland semi-arid and arid areas, affecting plant growth and even plant community structure. Precipitation regime, including the variation of precipitation intensity and frequency, also drives community structure and functions in such areas. However, few studies have focused on the combined effect of sand burial and changed precipitation regime on community function, specifically its role in carbon storage. A 2-yr field experiment with factorial treatments of precipitation (control, slight enhancement and strong enhancement) and sand addition (control and 5 cm sand addition) was conducted to test the responses of plant and soil carbon content in a semi-arid typical steppe in N China. Results showed that sand burial had no significant effect on plant carbon density, but significantly changed the allocation of plant carbon from aboveground to belowground; these responses differed among species and life forms in the community. Precipitation enhancement had no significant effects on plant carbon and its allocation, perhaps because effects of precipitation on plants are due more to precipitation frequency than to precipitation intensity per event. Sand burial and precipitation enhancement decreased soil carbon, especially soil organic carbon, and promoted soil carbon to be distributed deeper down the soil profile. These findings will help to understand how sand deposition affects plant and soil carbon storage and their allocation in plant communities under a changing precipitation regime, and more generally, to understand carbon storage dynamics in early-successional sandy ecosystems in the context of global change. PMID- 30463161 TI - Controlled sequential biocathodic denitrification for contaminated groundwater bioremediation. AB - Nitrate groundwater contamination is a worldwide concern. In this study, a novel 2-stage, sequential biocathodic denitrification system was tested to perform autotrophic denitrification of synthetic groundwater. The system was operated at different nitrate loading rates (66-301 gNO3--N m-3NCC d-1) at constant NO3--N concentration (40 mgNO3--N L-1), by varying hydraulic retention time (HRT) during different trials from about 14 to 3 h. The system was able to achieve almost complete removal of nitrate (>95%) and Total Nitrogen (TN) (>92%) at NO3- loading rates between 66 and 200 gNO3--N m-3NCC d-1. The first stage reactor achieved lower values of effluent nitrate and nitrite than WHO guidelines for drinking water quality (<11.3 mg NO3--N L-1, and 0.9 mgNO2--N L-1, respectively) up to a nitrate loading rate of 167 gNO3--N m-3NCC d-1; in these conditions the second stage acted mainly as polishing step. From a loading rate of 200 gNO3--N m-3NCC d 1 on, N2O accumulation was observed in the first stage reactor, afterwards successfully removed in the second stage. Maximum nitrate removal rate of the 2 step process was 259.83 gNO3--N m-3NCC at HRT of 3.19 h. The specific energy consumption of the system (SEC) decreased with decreasing HRT, both in terms of mass of nitrate removed (SECN) and volume treated (SECV). The described combination of two bioelectrochemical systems system hence proved to be effective for groundwater denitrification. PMID- 30463162 TI - Seasonal time-series reveal the impact and rapid recovery in richness, abundance and community structure of benthic macroinvertebrates following catchment wildfire. AB - Catchment wildfire can decimate freshwater benthos when burnt material washes through river channels. We conducted detailed seasonal surveys over the course of one-year at N = 9 sites following summer-time wildfire in 2009 and N = 3 sites following summer-time wildfire in 2010 (constituting one-year time-series of 9 * 5 and 3 * 5 samples, respectively). Basic one-year-on surveys were conducted at an additional 12 sites following 2009 wildfires (Sumpostfire:Sum+one.yr; N = 12 * 2). Burnt sites were compared with 6 reference sites surveyed seasonally between autumn and summer, 2009-2010 (N = 6 * 4), supplemented by 6 additional sites surveyed in summer 2004 (total reference samples: N = 6 * 5). While benthic macroinvertebrates were largely unaffected by the fire event, richness and abundance were decimated during the winter, yet recovered to initial survey levels by the following summer. The differential response of assemblages in the exceptionally wet winter of 2009-10 versus 2010-11 highlighted the catalytic role of rainfall as a driver of benthic disturbance. Ecological disturbance was proportionally greater for less abundant taxa with community evenness peaking at the time of maximum disturbance. Seasonal dynamics in fire-impacted and reference sites followed a similar pattern, implying that despite the major reduction in macroinvertebrate standing crop the general character of benthic processes was sustained. One year after the wildfire event community structure was similar to the immediate post-fire assemblages and generally indistinguishable from reference samples. The statistical importance of habitat parameters at the landscape and local scale (catchment size, landuse, slope, bank management and benthic substrate) were indicative of mechanistic processes underlying wildfire disturbance-recovery and define the scope for mitigation management. The remarkable resilience of community structure in these Mediterranean streams marks an emphatic contrast to the response of benthic macroinvertebrates to comparable disturbance processes in temperate regions. Given the increasing geographic scale and frequency of fires accompanying global warming wildfire-risk may become a leading issue for river management. PMID- 30463163 TI - Multiple methods for the identification of heavy metal sources in cropland soils from a resource-based region. AB - Examination of heavy metal sources in soils from a resource-based region is essential for source identification and implementation of restoration strategies regarding soil contamination. A total of 1069 samples were collected from cropland soils in the Baiyin District (Loess Plateau, Northwest China), a characteristically resource-based region to investigate the sources of arsenic (As), chromium (Cr), copper (Cu), manganese (Mn), nickel (Ni), lead (Pb), vanadium (V), and zinc (Zn). Source identification was analyzed by multiple methods including spatial deviation (SD), correlation analysis (CA), enrichment factor (EF), principal component analysis (PCA), geographic information system (GIS), and positive matrix factorization (PMF). The results showed the combined applications of PMF, GIS, and PCA were accurate, pragmatic, and effective for source apportionment. Three origins were identified and the contribution rates were calculated as follows: approximately 95% of As came from wastewater irrigation; 75, 88, 60, and 76% of Cr, Mn, Ni, and V were separately derived from natural origins; and 81, 93, and 70% of Cu, Pb, and Zn originated from industrial sources, respectively. Natural origins, industrial sources, and wastewater irrigation were the three main contributors of heavy metals to cropland soils in this region. PMID- 30463164 TI - Mass spectrometry-based metabolomics reveals the mechanism of ambient fine particulate matter and its components on energy metabolic reprogramming in BEAS 2B cells. AB - Exposure to airborne fine particulate matter (PM2.5) is associated with various adverse effects. However, the molecular mechanism involved in PM2.5-elicited energy metabolic reprogramming and the toxic chemical determinants within PM2.5 are not well elucidated. In this study, nontargeted and targeted metabolomics research were conducted to investigate the overall metabolic changes and relevant toxicological pathways caused by Taiyuan winter total PM2.5 and its water soluble and organic soluble fractions in human lung bronchial epithelial cells (BEAS-2B). The results showed that significant metabolome alterations in BEAS-2B cells were observed after the exposure of total PM2.5 and its organic soluble fraction. Purine metabolism, arginine and proline metabolism, glutathione (GSH) metabolism, tricarboxylic acid (TCA) cycle and glycolysis were mainly affected. Along with a significant increase of reactive oxygen species (ROS), malondialdehyde (MDA), nitric oxide (NO) and pro-inflammatory cytokines (TNF-alpha, IL-6 and IL-1beta), obvious metabolic phenotype remodeling from oxidative phosphorylation to glycolysis was found in BEAS-2B cells treated with total PM2.5 and its organic soluble fraction. Compared with water soluble fraction, organic soluble fraction was found to play the dominant role in PM2.5 toxicity. Our study provided novel insights into the mechanism of PM2.5-elicited toxicity. PMID- 30463165 TI - Risk assessment of biosolids-borne ciprofloxacin and azithromycin. AB - Ciprofloxacin (CIP) and azithromycin (AZ) are commonly prescribed antibiotics for various infections in humans and are frequently detected in biosolids. Ecological and human health risks from biosolids-borne CIP and AZ are not well understood, but necessary for formulating policies on safe use and management of biosolids. A tiered integrated risk assessment (IRA), based on the World Health Organization (WHO) framework and the USEPA Part 503 Biosolids Rule, was conducted to assess human and ecological health risks from biosolids-borne CIP and AZ. The IRA utilized the hazard quotient (HQ) approach to evaluate risks to various receptors of concern (including humans, animals, and birds) in sixteen exposure pathways and three conservative biosolids land application scenarios. The scenarios consisted of (i) single-heavy (100 Mg ha-1) land application of biosolids containing 95th percentile concentrations of CIP or AZ (USEPA, 2009), (ii) long term (annual for 40-y) land application of biosolids containing typical (median; USEPA, 2009) CIP or AZ concentrations, and (iii) long-term (annual for 40-y) land application of biosolids containing the 95th percentile concentrations of CIP or AZ. The unrealistically conservative screening level (Tier 1) assessment identified three pathways of potential concern: biosolids -> soil -> plant (CIP); biosolids -> soil -> soil organism (CIP and AZ); and biosolids -> soil -> soil organism -> predator (CIP and AZ). Subsequent tier (refined; more realistic) assessments and pollutant limits (calculated based on the USEPA Part 503 Biosolids Rule) suggested negligible human and ecological health risks from biosolids-borne CIP and AZ under real-world biosolids application scenarios. Pollutant concentration limits were 12 mg CIP kg-1 and 2.2 mg AZ kg-1; suggesting that pollutant load tracking is not needed for the majority (75% for CIP and 90% for AZ) of USA biosolids. Biosolids-borne antibiotic resistance (currently not addressed in any risk assessment model) is the principal uncertainty limiting risk assessment of biosolids-borne antibiotics including CIP and AZ. PMID- 30463166 TI - Impacts of rising temperature, carbon dioxide concentration and sea level on wheat production in North Nile delta. AB - Climate change poses a serious threat to arid and low elevation coastal zones. Kafrelsheikh governorate, as a large agricultural and coastal region on the Egyptian North Nile Delta, is one of the most vulnerable areas to higher temperature and global sea level rise. Two DSSAT wheat models (CERES and N-Wheat) were calibrated using a local cultivar (Misr3) grown under irrigated conditions in Egypt. Experimental data of two successive growing seasons during 2014/2015 and 2015/2016 were used for calibration using different treatments of irrigation, planting dates and fertilization. Both models simulated the phenology and wheat yield well, with root mean square deviation of <10%, and d-index > 0.80. Climate change sensitivity analysis showed that rising temperature by 1 degrees C to 4 degrees C decreased wheat yield by 17.6%. However, elevated atmospheric CO2 concentrations increased yield and could overtake some of the negative temperature responses. Sea level rise by 2.0 m will reduce the extent of agricultural land on the North Nile Delta of Egypt by ~60% creating an additional challenge to wheat production in this region. PMID- 30463167 TI - Spatial and temporal distribution of heavy metal concentrations and enrichment in the southern Gulf of Mexico. AB - Trace element (As, Co, Cr, Cu, Ni, Pb, V and Zn) enrichment trends during the past century, were assessed in thirteen 210Pb-dated sediment cores from the southern Gulf of Mexico, with the purpose to evaluate the impact on the environment, and potentially on public health, of the offshore oil industry and of oil spills such as that of the Ixtoc1 well blowout in 1979. The trace element composition was quite homogeneous among cores; and the pre-industrial concentrations of Ba, Cr, Cu and Ni are naturally high in the region, as to reach levels of potential ecological concern. The influence of multiple and simultaneous processes (e.g. industrial activities, natural seeps, fluvial discharges) on the trace element concentrations is difficult to disentangle. Some cores suggested long-term preservation of putative oil spill traces, although it was not possible to attribute their origin. The Al-normalized redox element ratios, and the crude oil contamination ratio, suggested that these events occurred along almost four decades, and that the traces attributed to the Ixtoc1 spill were comparable to background conditions, most likely owing to active natural oil seeps in the area. In most cases there was a trend towards a lowering in the supply of trace elements; this might be associated with environmental controls in the region since the 1980s. This study highlights the relevance of using dated environmental archives to reconstruct the historical trends of trace metal contamination in areas where long-term environmental studies are scarce. PMID- 30463168 TI - Microalgal biofilms: A further step over current microalgal cultivation techniques. AB - The scientific community has turned its interest to microalgae lately, because of their countless applications such as wastewater treatment and pharmaceutical industry. Nevertheless, so far applied cultivation methods are still prohibitive. Ordinary cultivation techniques in which microalgae are suspended in liquid medium suffer from many bottlenecks, such as low biomass productivities, difficulty in biomass harvesting and recovery, high installation and operating cost, high water requirements etc. Although, microalgal biofilms are known to be a nuisance because of surfaces fouling, they have emerged as an innovative technology with which microalgae are developed attached to a solid surface. This technique seems to be advantageous as compared to conventional cultivation systems. Microalgal biofilm systems could resolve the problematic aspects of ordinary cultivation techniques such as low biomass productivities, water management and biomass recovery. A detailed description of this technique with respect to the parameters affecting them is reviewed in this work. PMID- 30463169 TI - Opinion paper about organic trace pollutants in wastewater: Toxicity assessment in a European perspective. PMID- 30463170 TI - The accumulation dynamics, elimination and risk assessment of paralytic shellfish toxins in fish from a water supply reservoir. AB - Paralytic shellfish Toxins (PSTs) or saxitoxins are neurotoxins that block the neural transmission by binding to the voltage-gated sodium channels in the nerve cells. There are >50 analogues described, which could be biotransformed into a molecular form of greater or lesser toxicity. The Alagados Reservoir is used for water supply, and persistent cyanobacterial blooms as well as PSTs concentrations have been found in this water body since 2002. The aims of this study were to quantify the concentrations of PSTs in the water and fish samples from the Alagados Reservoir. In addition, we evaluated the elimination of PSTs for 90 days in fish and estimated the potential risk to human health. Water and fish samples were collected from the reservoir. For the water samples the phytoplankton and chemical analyses were carried out. Fish were divided into two sample times: Field Samples (FS) and Elimination Experiment Samples (EES), which were maintained for 90 days in filtered and dechlorinated water. For chemical analysis, the muscles of FS were collected on the fish sampling day and the muscles and feces of EES were collected at 7, 15, 30, 45, 60, 75 and 90 days. PSTs concentrations were present in water and fish samples, and they were estimated as a potential risk to humans; mainly for children. In addition, toxins were accumulated, biotransformed to other analogues and excreted by the fish. However, after 90 days, the toxins were still present in the water and fish muscle. Therefore, PSTs can remain for a long period in water, and fish can be a carrier of these neurotoxins. New approaches of monitoring and management are necessary in the actual global context of cyanobacteria and cyanotoxins. PMID- 30463171 TI - Two-way long-range atmospheric transport of organochlorine pesticides (OCPs) between the Yellow River source and the Sichuan Basin, Western China. AB - This study revealed a two-way long-range atmospheric transport of organochlorine pesticides (OCPs) rather than a single mode, in Western China. Soil and air samples were collected along a transect with length of ca. 1000 km between the Yellow River source in the Qinghai-Tibet Plateau and the Sichuan Basin. Concentrations of SigmaOCPs in soils and air were detected to be 175-69,229 (median 567) pg/g dry weight and 33.6-271 (median 98.3) pg/m3, respectively. HCB, HCHs, DDTs, and SULPHs (sum of Endosulfan-I, Endosulfan-II and Endosulfan sulfate) were dominant. Isomeric ratios suggested dominant weathered technical HCH, technical DDT and chlordane profile, and confirmed the current-use of Endosulfan along the transect. Furthermore, local fresh input of Lindane and possible illegal use of technical DDT might occur in the basin area. Based on isomeric and metabolic ratios, fractionation and principal component analysis, a two-way transport system was determined. One flowed from the Sichuan Basin to the Qinghai-Tibet Plateau comprising HCB, HCHs, and DDTs, while the other flowed reversely from the Qinghai-Tibet Plateau to the Sichuan Basin dominating by SULPHs and CHLs (including Heptachlor, Heptachlor epoxide, trans-chlordane, and cis-chlordane). Multiple linear regression analysis demonstrated greater average contributions of the Sichuan Basin sources onto the soil SigmaOCPs than that of the Qinghai-Tibet Plateau source. Distinct from the single long-range atmospheric transport, our results highlighted the different source-sink roles of the Qinghai Tibet Plateau and the Sichuan Basin for different OCP compounds. PMID- 30463172 TI - Landscape typology and ecological connectivity assessment to inform Greenway design. AB - European Greenway developments typically 'upcycle' disused transport corridors for multi-use, non-motorised public infrastructure. The linear and relatively undisturbed nature of these disused infrastructures means many currently function as high quality ecological corridors. Corridors providing connectivity among habitat patches can mitigate the effects of fragmentation on biodiversity, allowing species dispersal throughout the landscape matrix. The sustainable integration of Greenway infrastructure and ecological corridor functions requires consideration during design, development and maintenance stages, taking into account surrounding landscape composition and connectivity. This paper presents a method to characterise a proposed Greenway corridor landscape, focusing on habitat composition and ecosystems connectivity. Morphological Spatial Pattern Analysis (MSPA) was used to comprehensively describe the structural connectivity of linear and spatial habitats occurring within the study area. A subsequent multivariate classification of structural connectivity and habitat data determined six distinctive landscape characters. Interpretation of these landscape characters highlights the principal habitat compositions and connectivity conditions in terms of habitat core, links and potential linkages. For example one landscape was intensified, yet retained high woodland connectivity, while another diverse habitat landscape supported little connectivity for woodland and grasslands. The results of this study suggest significant opportunities exist to enhance European landscape connectivity through informed Greenway development. Crucial habitat linkages can be optimised along Greenway infrastructure, contributing towards the realisation of European Greenways as Green Infrastructure and true sustainable projects. PMID- 30463173 TI - Overview of known plastic packaging-associated chemicals and their hazards. AB - Global plastics production has reached 380 million metric tons in 2015, with around 40% used for packaging. Plastic packaging is diverse and made of multiple polymers and numerous additives, along with other components, such as adhesives or coatings. Further, packaging can contain residues from substances used during manufacturing, such as solvents, along with non-intentionally added substances (NIAS), such as impurities, oligomers, or degradation products. To characterize risks from chemicals potentially released during manufacturing, use, disposal, and/or recycling of packaging, comprehensive information on all chemicals involved is needed. Here, we present a database of Chemicals associated with Plastic Packaging (CPPdb), which includes chemicals used during manufacturing and/or present in final packaging articles. The CPPdb lists 906 chemicals likely associated with plastic packaging and 3377 substances that are possibly associated. Of the 906 chemicals likely associated with plastic packaging, 63 rank highest for human health hazards and 68 for environmental hazards according to the harmonized hazard classifications assigned by the European Chemicals Agency within the Classification, Labeling and Packaging (CLP) regulation implementing the United Nations' Globally Harmonized System (GHS). Further, 7 of the 906 substances are classified in the European Union as persistent, bioaccumulative, and toxic (PBT), or very persistent, very bioaccumulative (vPvB), and 15 as endocrine disrupting chemicals (EDC). Thirty-four of the 906 chemicals are also recognized as EDC or potential EDC in the recent EDC report by the United Nations Environment Programme. The identified hazardous chemicals are used in plastics as monomers, intermediates, solvents, surfactants, plasticizers, stabilizers, biocides, flame retardants, accelerators, and colorants, among other functions. Our work was challenged by a lack of transparency and incompleteness of publicly available information on both the use and toxicity of numerous substances. The most hazardous chemicals identified here should be assessed in detail as potential candidates for substitution. PMID- 30463174 TI - Characterization of Bacillus subtilis from gastrointestinal tract of hybrid Hulong grouper (Epinephelus fuscoguttatus * E. lanceolatus) and its effects as probiotic additives. AB - Probiotics are widely used for the improvement of animals' growth and health. However, few marine aquatic probiotics are applied and licensed in China. In this study, a Bacillus spp. strain was isolated from the Hulong grouper gastrointestinal tract, which was identified as a new strain of Bacillus subtilis and was named as 7k. B. subtilis 7k showed desirable capability of sporulation and resistance to heat, simulated gastric juice and simulated duodenum juice, indicating its potential as probiotics. Seven antimicrobial chemicals were found in the secretion of the B. subtilis 7k. B. subtilis 7k addition in diet promoted the growth rate of Hulong groupers. Moreover, B. subtilis 7k can inhibit infection by iridovirus, making B. subtilis 7k a suitable kind of probiotic for maintaining fishes' health. Our results also revealed that B. subtilis 7k induced non-specific immune response in Hulong grouper under virus infection. Hulong grouper fed by diets containing B. subtilis 7k at 108 and 1010 cfu g-1 for 4-8 weeks were significantly strengthened in serum lysozyme activity, serum alternative complement activity (ACH50), serum bactericidal activity, respiratory burst, superoxide dismutase activity (SOD), and phagocytic activity of head kidney leucocytes when compared with those fed by control diets. In conclusion, B. subtilis 7k was isolated and characterized to be a kind of process enduring, growth stimulating, immunity enhancing and health promoting probiotic using in grouper culture. PMID- 30463175 TI - Analysis of Hazardous Elements in Children Toys: Multi-Elemental Determination by Chromatography and Spectrometry Methods. AB - This paper presents the results of determination of hazardous metal (Cd, Cu, Cr, Hg, Mn, Ni, Pb, Zn) and metalloid (As, Sb) levels in toys available in the Polish market. Two independent sample preparation methods were used to determine the concentration and content of the metals and metalloids. The first one is defined by the guidelines of the EN-71 standard and undertook extraction in 0.07 mol/L HCl. This method was used to conduct speciation analysis of Cr(III) and Cr(VI), as well as for the determination of selected metals and metalloids. The second method conducted mineralization in a HNO3 and H2O2 mixture using microwave energy to determine the content of metals and metalloids. Determination of chromium forms was made using the high-performance liquid chromatography inductively coupled plasma mass spectrometry (HPLC-ICP-MS) method, while those of metals and metalloids were made using the ICP-MS technique. Additionally, in order to determine total content of chromium in toys, an energy dispersive X-ray fluorescence spectrometer (EDX) was used. The results of the analyses showed that Cr(VI) was not detected in the toys. In general, the content of heavy metals and metalloids in the studied samples was below the migration limit set by the norm EN-71. PMID- 30463176 TI - Pathogenesis of Rift Valley Fever Virus Aerosol Infection in STAT2 Knockout Hamsters. AB - Rift Valley fever virus (RVFV) is an emerging pathogen capable of causing severe disease in livestock and humans and can be transmitted by multiple routes including aerosol exposure. Several animal models have been developed to gain insight into the pathogenesis associated with aerosolized RVFV infection, but work with these models is restricted to high containment biosafety level (BSL) laboratories limiting their use for antiviral and vaccine development studies. Here, we report on a new RVFV inhalation infection model in STAT2 KO hamsters exposed to aerosolized MP-12 vaccine virus by nose-only inhalation that enables a more accurate delivery and measurement of exposure dose. RVFV was detected in hepatic and other tissues 4-5 days after challenge, consistent with virus-induced lesions in the liver, spleen and lung. Furthermore, assessment of blood chemistry and hematological parameters revealed alterations in several liver disease markers and white blood cell parameters. Our results indicate that STAT2 KO hamsters develop a disease course that shares features of disease observed in human cases and in other animal models of RVFV aerosol exposure, supporting the use of this BSL-2 infection model for countermeasure development efforts. PMID- 30463177 TI - Prediction of GluN2B-CT1290-1310/DAPK1 Interaction by Protein-Peptide Docking and Molecular Dynamics Simulation. AB - The interaction of death-associated protein kinase 1 (DAPK1) with the 2B subunit (GluN2B) C-terminus of N-methyl-D-aspartate receptor (NMDAR) plays a critical role in the pathophysiology of depression and is considered a potential target for the structure-based discovery of new antidepressants. However, the 3D structures of C-terminus residues 1290-1310 of GluN2B (GluN2B-CT1290-1310) remain elusive and the interaction between GluN2B-CT1290-1310 and DAPK1 is unknown. In this study, the mechanism of interaction between DAPK1 and GluN2B-CT1290-1310 was predicted by computational simulation methods including protein-peptide docking and molecular dynamics (MD) simulation. Based on the equilibrated MD trajectory, the total binding free energy between GluN2B-CT1290-1310 and DAPK1 was computed by the mechanics generalized born surface area (MM/GBSA) approach. The simulation results showed that hydrophobic, van der Waals, and electrostatic interactions are responsible for the binding of GluN2B-CT1290-1310/DAPK1. Moreover, through per-residue free energy decomposition and in silico alanine scanning analysis, hotspot residues between GluN2B-CT1290-1310 and DAPK1 interface were identified. In conclusion, this work predicted the binding mode and quantitatively characterized the protein-peptide interface, which will aid in the discovery of novel drugs targeting the GluN2B-CT1290-1310 and DAPK1 interface. PMID- 30463178 TI - Tail Tip Lesions in Mink (Neovison vison): Effects of an Additional Hammock in Multilevel Cages. AB - The occurrence of wounds in different anatomical regions, such as tail tip lesions, is an important welfare concern in farmed mink. This study investigated whether mechanical factors attributed to cage design in multilevel cages may be involved in the etiology of tail tip lesions. Specifically, effects of an additional hammock intended to reduce speed during transitions between cage levels and thereby assumed to lower the incidence and severity of tails hitting the wire mesh were investigated. Three mink farms and a total of 600 mink participated in the study. On each farm, brown female mink (n = 100) were either housed in multilevel cages equipped with plastic hammocks (placed either perpendicular or parallel to the sidewalls) or in standard multilevel cages without hammocks (n = 100). The study was conducted from December to March using singly housed females. Significant differences in the number of tail tip wounds were found between groups with a hammock installed in the cage vs. control groups in two of the farms (p = 0.029 and p = 0.031), with more wounds developing in cages without a hammock. Furthermore, there was a trend towards difference in the number of tail tip wounds in groups with hammocks installed perpendicular vs. groups with hammocks installed parallel to the cage sidewalls, but a potential farm effect cannot be ruled out. This study is the first to suggest that mechanical factors associated with cage design may play a role in the etiology of tail tip lesions in farmed mink. Further studies are needed to understand the causal relationship between cage design and tail tip lesions in mink. PMID- 30463179 TI - The Influence of pH, NaCl, and the Deacidifying Yeasts Debaryomyces hansenii and Kluyveromyces marxianus on the Production of Pigments by the Cheese-Ripening Bacteria Arthrobacter arilaitensis. AB - Arthrobacter arilaitensis is a food-related bacterial species under investigation for its involvement in the coloration of surface-ripened cheeses. Presently, information about this species in association with the development of appropriate cheese coloration is still lacking. This study was performed in order to investigate-with the use of spectrocolorimetry-the influence of pH, NaCl, and deacidifying yeasts on the pigmentation of Arthrobacter arilaitensis biofilms. Three types of cheese-based (curd) solid media were prepared by using different deacidification methods: (i) chemical deacidification by NaOH (CMNaOH); (ii) biological deacidification by the yeast strain Debaryomyces hansenii 304 (CMDh304); and (iii) biological deacidification by the yeast strain Kluyveromyces marxianus 44 (CMKm44). Each medium was prepared with initial pH values of 5.8, 7.0, and 7.5. After pasteurization, agar was incorporated and NaCl was added in varying concentrations (0%, 2%, 4%, and 8% (w/v)). A. arilaitensis Po102 was then inoculated on the so prepared "solid-curd" media, and incubated at 12 degrees C under light conditions for 28 days. According to the data obtained by spectrocolorimetry in the Compagnie Internationale de l'Eclairage (CIE) L*a*b* color system, all controlled factors appeared to affect the pigments produced by the A. arilaitensis strain. NaCl content in the media showed distinct inhibitory effects on the development of color by this strain when the initial pH was at 5.8. By contrast, when the initial pH of the media was higher (7.0, 7.5), only the highest concentration of NaCl (8%) had this effect, while the coloring capacity of this bacterial species was always higher when D. hansenii 304 was used for deacidification compared to K. marxianus 44. PMID- 30463180 TI - Factors Underlying Racial Disparities in Sepsis Management. AB - Sepsis, a syndrome characterized by systemic inflammation during infection, continues to be one of the most common causes of patient mortality in hospitals across the United States. While standardized treatment protocols have been implemented, a wide variability in clinical outcomes persists across racial groups. Specifically, black and Hispanic populations are frequently associated with higher rates of morbidity and mortality in sepsis compared to the white population. While this is often attributed to systemic bias against minority groups, a growing body of literature has found patient, community, and hospital based factors to be driving racial differences. In this article, we provide a focused review on some of the factors driving racial disparities in sepsis. We also suggest potential interventions aimed at reducing health disparities in the prevention, early identification, and clinical management of sepsis. PMID- 30463181 TI - Influence of Polymethylsilsesquioxane Content to the Thermal Stability of Meta Aramid Fiber Insulation Paper. AB - Polymethylsilsesquioxane (PMSQ) nanoparticles with mass percentages of 0, 2.5, 5.0, 7.2, 9.4 wt %, respectively, were constructed by molecular dynamics methods in this paper. Composite molecular models were established using PMSQ and MPIA (poly-metaphenylene isophthalamide) fiber. The influence of different PMSQ contents on the thermal stability of meta-aramid insulation paper was analyzed from the parameters of mechanical property, interaction energy, and mean square displacement. The results showed that the trend of mechanical properties decreased with the increase of PMSQ content. When the PMSQ content was 2.5 wt %, the mechanical properties of the composited model were the best, which was about 24% higher than that of the unmodified model. From an intermolecular bonding and nonbonding point of view, the energy parameters of composite model with the 2.5 wt % content was better than those of the composite model with other contents. Therefore, it is considered that MPIA can interact better with the 2.5 wt % content PMSQ composite model. When the PMSQ content is 2.5 wt %, the overall chain movement in the composite model is slower than that of the unmodified model, which can effectively inhibit the diffusion movement of the MPIA chain. In general, the thermal stability of composite molecular models MPIA and PMSQ (2.5 wt %) was better improved. PMID- 30463182 TI - A Novel Dual-Band Six-Phase Voltage-Control Oscillator. AB - The paper presents a novel dual-band six-phase voltage-control oscillator. The voltage-controlled oscillator (VCO) with a single-ended delay cell architecture has a lower power consumption, a smaller chip area, and a larger output swing than one with a differential delay cell architecture. However, the conventional even-phase outputs ring-type VCO cannot be implemented using single-ended delay cells. In other words, the VCO with single-ended delay cells meets most of the requirements of a sensor circuit system, except even-phase outputs function. This work presents a dual-band six-phase ring type VCO, which is implemented using the proposed single-ended delay cell. The proposed VCO both exhibits the advantages of single-ended delay cells and differential delay cells. The proposed delay cell has a band-switching function, which improves the jitter performance of a VCO in which it is used. The proposed VCO can be operated at 890-1080 MHz. The peak-to peak jitter and the root mean square jitter are the 35.5 ps and 2.8 ps (at 1 GHz), respectively. The maximal power consumption is approximately 6.4 mW at a supply voltage of 1.8 V in a United Microelectronics Corporation 0.18 MUm RF CMOS process. The area of the chip is 0.195 * 0.208 mm2. PMID- 30463183 TI - Nutritional Regulators of Bcl-xL in the Brain. AB - B-cell lymphoma-extra large (Bcl-xL) is an anti-apoptotic Bcl-2 protein found in the mitochondrial membrane. Bcl-xL is reported to support normal brain development and protects neurons against toxic stimulation during pathological process via its roles in regulation of mitochondrial functions. Despite promising evidence showing neuroprotective properties of Bcl-xL, commonly applied molecular approaches such as genetic manipulation may not be readily applicable for human subjects. Therefore, findings at the bench may be slow to be translated into treatments for disease. Currently, there is no FDA approved application that specifically targets Bcl-xL and treats brain-associated pathology in humans. In this review, we will discuss naturally occurring nutrients that may exhibit regulatory effects on Bcl-xL expression or activity, thus potentially providing affordable, readily-applicable, easy, and safe strategies to protect the brain. PMID- 30463184 TI - Implementation of a Single Quadrupole Mass Spectrometer for Fingerprint Analysis: Venenum bufonis as a Case Study. AB - The mass spectrometry (MS) has been widely used for profiling chemical components of traditional Chinese medicine (TCM). However, there are few studies reporting quality control of TCM based on mass spectrometry fingerprint (MSF) due to its complicated operation and high cost. The aim of this study was to extend the application of MSF for quality evaluation of TCM. In this study, an MSF based on single quadrupole mass spectrometry method was established, and was successfully used for the quality control of Venenum bufonis (VB), a famous TCM which was used clinically for cancer treatment in China. The results showed that the superiority of MSF for more chemical information exposure and the finding of more potential chemical markers (eight versus four) compared with the traditional photo-diode array (a kind of ultra violet detector, PDA). Besides, the performance of MSF was also validated by similarity and principle component analysis (PCA) of MS data acquired on two other mass spectrometry (low-resolution, triple quadrupole, QQQ, and high-resolution, quadruple time-of-flight, Q-TOF), showing high consistency with QQQ and Q-TOF, but robustness with few parameters' settings. Based on our study, MSF could be widely applied for the quality control of TCM. PMID- 30463185 TI - Identification, Classification, and Functional Analysis of AP2/ERF Family Genes in the Desert Moss Bryum argenteum. AB - Bryum argenteum is a desert moss which shows tolerance to the desert environment and is emerging as a good plant material for identification of stress-related genes. AP2/ERF transcription factor family plays important roles in plant responses to biotic and abiotic stresses. AP2/ERF genes have been identified and extensively studied in many plants, while they are rarely studied in moss. In the present study, we identified 83 AP2/ERF genes based on the comprehensive dehydrationrehydration transcriptomic atlas of B. argenteum. BaAP2/ERF genes can be classified into five families, including 11 AP2s, 43 DREBs, 26 ERFs, 1 RAV, and 2 Soloists. RNA-seq data showed that 83 BaAP2/ERFs exhibited elevated transcript abundances during dehydration-rehydration process. We used RT-qPCR to validate the expression profiles of 12 representative BaAP2/ERFs and confirmed the expression trends using RNA-seq data. Eight out of 12 BaAP2/ERFs demonstrated transactivation activities. Seven BaAP2/ERFs enhanced salt and osmotic stress tolerances of yeast. This is the first study to provide detailed information on the identification, classification, and functional analysis of the AP2/ERFs in B. argenteum. This study will lay the foundation for the further functional analysis of these genes in plants, as well as provide greater insights into the molecular mechanisms of abiotic stress tolerance of B. argenteum. PMID- 30463186 TI - Preparation of Assembled Carbon Soot Films and Hydrophobic Properties. AB - In this paper, a simple, inexpensive, and rapid method for the fabrication of controlled layer candle soot film has been reported by interface self-assembly and transferred method. The mechanism of candle soot self-assembly is explained and their morphology, elemental composition, optical, and wetting properties are characterized. The uniformity and thickness of prepared films especially depend on the concentration of candle soot mixed solution (alcohol and deionized water). The results show that the optimal concentration of candle soot solution is approximately ~0.2% wt/mL. In addition, the absorption spectra of the controlled layer candle soot films are determined by the number of layers and the surface morphology. The hydrophobic properties of candle soot films are closely related to their layer number. When these films reach to the fourth layer, the water contact angle and roll-off angle are measured as 142 degrees +/- 2 degrees and 6 degrees , respectively. The controlled assembly CS films have the potential application in photo/electrocatalysis, solar cells, lithium-ion batteries, and water splitting. PMID- 30463187 TI - Editorial for Special Issue on Flexible Electronics: Fabrication and Ubiquitous Integration. AB - Based on the premise "anything thin is flexible", the field of flexible electronics has been fueled from the ever-evolving advances in thin-film materials and devices. [...]. PMID- 30463188 TI - Model Establishment of a Co-Based Metal Matrix with Additives of WC and Ni by Discrete Element Method. AB - A metal matrix is an indispensable component of metal-bonded diamond tools. The composition design of a metal matrix involves a number of experiments, making costly in terms of time, labor, and expense. The discrete element method (DEM) is a potential way to relieve these costs. The aim of this work is to demonstrate a methodology for establishing and calibrating metal matrix's DEM model. A Co-based metal matrix with WC and Ni additives (CoX-WC-Ni) was used, in which the Co-based metal was Co-Cu-Sn metal (CoX). The skeletal substances in the metal matrix were treated as particles in the model, and the bonding substances were represented by the parallel bond between particles. To describe the elasticity of the metal matrix, a contact bond was also loaded between particles. A step-by-step calibration procedure with experimental tests of three-point bending and compression was proposed to calibrate all microcosmic parameters involved during the establishment of DEM models: first for the CoX matrix, then for the CoX-WC matrix and CoX-Ni matrix, and finally for the CoX-WC-Ni matrix. The CoX-WC-Ni DEM model was validated by the transverse rupture strength (TRS) of two new compositions and the results indicated that the model exhibited a satisfactory prediction ability with an error rate of less than 10%. PMID- 30463190 TI - TGF-beta Signaling and the Epithelial-Mesenchymal Transition during Palatal Fusion. AB - Signaling by transforming growth factor (TGF)-beta plays an important role in development, including in palatogenesis. The dynamic morphological process of palatal fusion occurs to achieve separation of the nasal and oral cavities. Critically and specifically important in palatal fusion are the medial edge epithelial (MEE) cells, which are initially present at the palatal midline seam and over the course of the palate fusion process are lost from the seam, due to cell migration, epithelial-mesenchymal transition (EMT), and/or programed cell death. In order to define the role of TGF-beta signaling during this process, several approaches have been utilized, including a small interfering RNA (siRNA) strategy targeting TGF-beta receptors in an organ culture context, the use of genetically engineered mice, such as Wnt1-cre/R26R double transgenic mice, and a cell fate tracing through utilization of cell lineage markers. These approaches have permitted investigators to distinguish some specific traits of well-defined cell populations throughout the palatogenic events. In this paper, we summarize the current understanding on the role of TGF-beta signaling, and specifically its association with MEE cell fate during palatal fusion. TGF-beta is highly regulated both temporally and spatially, with TGF-beta3 and Smad2 being the preferentially expressed signaling molecules in the critical cells of the fusion processes. Interestingly, the accessory receptor, TGF-beta type 3 receptor, is also critical for palatal fusion, with evidence for its significance provided by Cre-lox systems and siRNA approaches. This suggests the high demand of ligand for this fine-tuned signaling process. We discuss the new insights in the fate of MEE cells in the midline epithelial seam (MES) during the palate fusion process, with a particular focus on the role of TGF-beta signaling. PMID- 30463191 TI - Significant Sensitivity Improvement for Camera-Based Lateral Flow Immunoassay Readers. AB - Recent developments in smartphone-based strip readers have further improved the performances of lateral flow test kits. Most smartphone cameras encode an unaltered and nonlinear power-law transfer function that maps the light intensity to a pixel value; this poses some limitations for camera-based strip readers. For faint-color test lines which are almost as white such as with nitrocellulose pads, the slope of the transfer function is low. Therefore, it is difficult to differentiate between the faint test lines and the white background. We show that by manually setting the camera exposure time-instead of using the automatic settings-to the high-slope region of the transfer function, the reader's sensitivity can be improved. We found that the sensitivity and the limit of detection of the Acidovorax avenae subsp. citrulli (Aac) test kit were enhanced up to 3-fold and 5-fold, respectively, when using the readers at the optimal camera settings, compared to the automatic mode settings. This simple technique can be readily applied to any existing camera-based colorimetric strip reader to significantly improve its performance. PMID- 30463189 TI - Chitosan Oligosaccharides Improve Glucolipid Metabolism Disorder in Liver by Suppression of Obesity-Related Inflammation and Restoration of Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma). AB - Chitosan oligosaccharides (COS) display various biological activities. In this study, we aimed to explore the preventive effects of COS on glucolipid metabolism disorder using palmitic acid (PA)-induced HepG2 cells and high-fat diet (HFD)-fed C57BL/6J mice as experimental models in vitro and in vivo, respectively. The results showed that COS pretreatment for 12 h significantly ameliorated lipid accumulation in HepG2 cells exposed to PA for 24 h, accompanied by a reversing of the upregulated mRNA expression of proinflammatory cytokines (IL-6, MCP-1, TNF alpha) and glucolipid metabolism-related regulators (SCD-1, ACC1, PCK1-alpha). In addition, COS treatment alleviated glucolipid metabolism disorder in mice fed with HFD for five months, including reduction in body weight and fasting glucose, restoration of intraperitoneal glucose tolerance, and suppression of overexpression of proinflammatory cytokines and glucolipid metabolism-related regulators. Furthermore, our study found that COS pretreatment significantly reversed the downregulation of PPARgamma at transcriptional and translational levels in both PA-induced HepG2 cells and liver tissues of HFD-fed mice. In summary, the study suggests that COS can improve glucolipid metabolism disorder by suppressing inflammation and upregulating PPARgamma expression. This indicates a novel application of COS in preventing and treating glucolipid metabolism related diseases. PMID- 30463192 TI - Water Sustainability at the River Grande Basin, Brazil: An Approach Based on the Barometer of Sustainability. AB - Water resources are fundamental for the social and economic development of a country and sustainability is the best approach to treat water-related problems. Therefore, sustainability studies of water resources are deemed urgent. Sustainability analysis methods should enable space-temporal monitoring, decision making, and development of policies necessary for water governance. Furthermore, sustainability analysis methods should also integrate environment and socioeconomic variables into a single system. In this context, this study aimed to assess the water sustainability conditions of the River Grande Basin (BHRG), Brazil, before the implementation of the Integrated Water Resources Plan (IWRP), using the Barometer of Sustainability tool (BS). The River Grande basin was in an "almost unsustainable" condition and under high environmental stress. A significant imbalance between environmental and human well-being in the system was also observed. To achieve an acceptable sustainability condition, it is thus necessary to improve the environmental quality of the area. Among the priority thematic area, native vegetation recovery was the most urgent. Overall, the sustainability study based on the BS not only facilitates comprehension regarding environment and human interrelationships, but also provide references for policy formulations and water management. PMID- 30463194 TI - Mathematical Analysis and Treatment for a Delayed Hepatitis B Viral Infection Model with the Adaptive Immune Response and DNA-Containing Capsids. AB - We model the transmission of the hepatitis B virus (HBV) by six differential equations that represent the reactions between HBV with DNA-containing capsids, the hepatocytes, the antibodies and the cytotoxic T-lymphocyte (CTL) cells. The intracellular delay and treatment are integrated into the model. The existence of the optimal control pair is supported and the characterization of this pair is given by the Pontryagin's minimum principle. Note that one of them describes the effectiveness of medical treatment in restraining viral production, while the second stands for the success of drug treatment in blocking new infections. Using the finite difference approximation, the optimality system is derived and solved numerically. Finally, the numerical simulations are illustrated in order to determine the role of optimal treatment in preventing viral replication. PMID- 30463193 TI - Can Donkey Behavior and Cognition Be Used to Trace Back, Explain, or Forecast Moon Cycle and Weather Events? AB - Donkeys have been reported to be highly sensitive to environmental changes. Their 8900-8400-year-old evolution process made them interact with diverse environmental situations that were very distant from their harsh origins. These changing situations not only affect donkeys' short-term behavior but may also determine their long-term cognitive skills from birth. Thus, animal behavior becomes a useful tool to obtain past, present or predict information from the environmental situation of a particular area. We performed an operant conditioning test on 300 donkeys to assess their response type, mood, response intensity, and learning capabilities, while we simultaneously registered 14 categorical environmental factors. We quantified the effect power of such environmental factors on donkey behavior and cognition. We used principal component analysis (CATPCA) to reduce the number of factors affecting each behavioral variable and built categorical regression (CATREG) equations to model for the effects of potential factor combinations. Effect power ranged from 7.9% for the birth season on learning (p < 0.05) to 38.8% for birth moon phase on mood (p < 0.001). CATPCA suggests the percentage of variance explained by a four dimension-model (comprising the dimensions of response type, mood, response intensity and learning capabilities), is 75.9%. CATREG suggests environmental predictors explain 28.8% of the variability of response type, 37.0% of mood, and 37.5% of response intensity, and learning capabilities. PMID- 30463195 TI - The Use of Personal Protective Equipment: Finger Temperatures and Thermal Sensation of Workers' Exposure to Cold Environment. AB - This study analyzed the finger temperatures of poultry slaughterhouse workers and its association with personal and organizational variables, bodily discomfort perception, and cold thermal sensation. The study included 143 poultry slaughterhouse workers. A thermograph was used to measure finger temperature and an interview to collect worker data. There were two groups: workers who used a tool and those without. The binary logistic regression, Friedman and Wilcoxon tests were used (p <= 0.05). Most workers presented at least one finger with an average temperature <=15 degrees C (66.4%) and <=24 degrees C (99.3%), perceived their cold hands, and wore three overlapping gloves (57.3%). There were no associations between finger temperatures (<=15 degrees C) and the analyzed variables. The chance of feeling cold for a worker who used a tool was greater than for a worker who did not (OR = 3.19, 95% CI 1.46; 6.94). There was a difference between the finger temperatures of each hand on both surfaces and the analyzed groups (p < 0.01). The temperature of each finger with its respective contralateral was different in the little fingers (no tool), index, middle, ring, and little fingers (using a tool) (p < 0.05). The use of several overlapping gloves was not sufficient to promote thermal insulation of the hands. PMID- 30463196 TI - On Consensus-Based Distributed Blind Calibration of Sensor Networks. AB - This paper deals with recently proposed algorithms for real-time distributed blind macro-calibration of sensor networks based on consensus (synchronization). The algorithms are completely decentralized and do not require a fusion center. The goal is to consolidate all of the existing results on the subject, present them in a unified way, and provide additional important analysis of theoretical and practical issues that one can encounter when designing and applying the methodology. We first present the basic algorithm which estimates local calibration parameters by enforcing asymptotic consensus, in the mean-square sense and with probability one (w.p.1), on calibrated sensor gains and calibrated sensor offsets. For the more realistic case in which additive measurement noise, communication dropouts and additive communication noise are present, two algorithm modifications are discussed: one that uses a simple compensation term, and a more robust one based on an instrumental variable. The modified algorithms also achieve asymptotic agreement for calibrated sensor gains and offsets, in the mean-square sense and w.p.1. The convergence rate can be determined in terms of an upper bound on the mean-square error. The case when the communications between nodes is completely asynchronous, which is of substantial importance for real world applications, is also presented. Suggestions for design of a priori adjustable weights are given. We also present the results for the case in which the underlying sensor network has a subset of (precalibrated) reference sensors with fixed calibration parameters. Wide applicability and efficacy of these algorithms are illustrated on several simulation examples. Finally, important open questions and future research directions are discussed. PMID- 30463198 TI - The Feasibility of Using Pulsatile Electromagnetic Fields (PEMFs) to Enhance the Regenerative Ability of Dermal Biomaterial Scaffolds. AB - Degradable regenerative scaffolds usually require adjunctive treatment to meet the clinical healing performance requirements. This study was designed to look at pulsatile electromagnetic fields (PEMF) as an adjunctive therapy for these scaffolds in skin wounds; however, no scaffold was used in this study in order to isolate the effects of PEMF alone. In this study, New Zealand rabbits received four full-thickness defects with a size of 3 cm * 3 cm on the dorsolateral aspect. The rabbits in the treatment group were placed in a chamber and subjected to a PEMF at six different predetermined frequency and intensity combinations for 2 h a day for a 2-week period. At the end of the 2-week period, the animals were sacrificed and tissue samples were taken. Half of each tissue sample was used for histomorphometric analysis and the other half was for tensile testing. The study showed an increased healing response by all the PEMF treatments compared to that in the control, although different combinations led to increases in different aspects of the healing response. This suggests that although some treatments are better for the critical clinical parameter-healing rate, it might be beneficial to use treatments in the early stages to increase angiogenesis before the treatment is switched to the one best for the healing rate to get an even better haling rate. PMID- 30463197 TI - Comparison of Short-Term Clinical and Pathological Outcomes after Transanal versus Laparoscopic Total Mesorectal Excision for Low Anterior Rectal Resection Due to Rectal Cancer: A Systematic Review with Meta-Analysis. AB - BACKGROUND: Transanal total mesorectal excision (TaTME) is a new technique that is designed to overcome the limits of the open and laparoscopic approach for rectal resections. OBJECTIVE: This study is designed to compare TaTME with standard laparoscopic TME (LaTME). METHODS: We searched Medline, Embase, and Scopus databases covering a up to October 2018. Inclusion criteria for study enrolment: (1) study comparing laparoscopic resection of rectal cancer vs. TaTME for rectal malignancy, (2) reporting of overall morbidity, operative time, or major complications. RESULTS: Eleven non-randomized studies were eligible with a total of 778 patients. We found statistical significant differences in regard to major complications in favour of TaTME (RR = 0.55; 95% CI 0.31-0.97; p = 0.04). We did not found significant differences regarding overall complications intraoperative adverse effects, operative time, anastomotic leakage, intra abdominal abscess occurrence, Surgical Site Infection, reoperations, Length of stay, completeness of mesorectal excision, R0 resection rate, number of harvested lymph nodes, circumferential resection margin, and distal resection margin. CONCLUSIONS: This meta-analysis shows benefits of TaTME technique regarding major postoperative complications. Regarding clinicopathological features transanal approach is not superior to LaTME. Currently, the quality of the evidence on benefits of TaTME is low due to lack of randomized controlled trials, which needs to be taken into consideration in further evaluation of the technique. Further evaluation of TaTME require conducting large randomized control trials. PMID- 30463199 TI - Sensor Fusion for Recognition of Activities of Daily Living. AB - Activity of daily living (ADL) is a significant predictor of the independence and functional capabilities of an individual. Measurements of ADLs help to indicate one's health status and capabilities of quality living. Recently, the most common ways to capture ADL data are far from automation, including a costly 24/7 observation by a designated caregiver, self-reporting by the user laboriously, or filling out a written ADL survey. Fortunately, ubiquitous sensors exist in our surroundings and on electronic devices in the Internet of Things (IoT) era. We proposed the ADL Recognition System that utilizes the sensor data from a single point of contact, such as smartphones, and conducts time-series sensor fusion processing. Raw data is collected from the ADL Recorder App constantly running on a user's smartphone with multiple embedded sensors, including the microphone, Wi Fi scan module, heading orientation of the device, light proximity, step detector, accelerometer, gyroscope, magnetometer, etc. Key technologies in this research cover audio processing, Wi-Fi indoor positioning, proximity sensing localization, and time-series sensor data fusion. By merging the information of multiple sensors, with a time-series error correction technique, the ADL Recognition System is able to accurately profile a person's ADLs and discover his life patterns. This paper is particularly concerned with the care for the older adults who live independently. PMID- 30463200 TI - Effects of Strength Training Program and Infrared Thermography in Soccer Athletes Injuries. AB - The purpose of this investigation was to examine the effects of a periodized strength training program and the use of infrared thermography (IRT) in injuries mapping in under 20-year-old (U-20) soccer players. In this study, 26 professional soccer players participated in strength training (ST) twice a week and were tested with IRT consistently across the 1-year. Strength, vertical jump, heat differences and injuries were tracked and analyzed. Results: 69 injuries occurred during 12 months of tracking; most identified injuries were: contusions, sprains, strains to the thigh (n = 16), ankle (n = 15) and knee (n = 12). Differences (>7 degrees C) in IRT patterns were noted among injured and non injured athletes. Significant improvements in strength (p < 0.005) were found for vertical jump, bench press, front lat pull down, shoulder press, leg press, leg curl and squat. Number of injuries decreased from 23 (33.3%) to 14 (20.3%) when early year rates were compared to late year (p < 0.005). Combined ST and IRT represent useful strategies for reducing injuries among U-20 soccer players. PMID- 30463201 TI - Synthesis and Characterization of a Dual-Cation Organomontmorillonite Nanocomposite. AB - In this study, a novel dual-cation organomontmorillonites (OMt) nanocomposite was synthesized by two kinds of modifiers cetyltrimethylammonium chloride and cysteamine hydrochloride, and the adsorption behavior of modifiers into montmorillonite (Mt) has been investigated. The OMt were characterized by techniques, such as X-ray diffraction (XRD), Fourier Transform Infrared (FTIR) spectroscopy, and thermogravimetric and differential thermal (TG-DTA) analyses. The effects of temperature, contact time, the order of addition and the concentration of organic modifiers on the amounts of organics adsorbed were investigated. The adsorption amount of cetyltrimethylammonium chloride (CTAC) and cysteamine hydrochloride (CSH) increased with the increase of the added CTAC amount and contact time, while the addition order of modifiers and modification temperature had no significant effect on the actual adsorption amount of CTAC and CSH on Mt, as confirmed by the XRD patterns. The experimentally determined isotherms showed a good fit with the Langmuir adsorption models. The adsorption kinetics demonstrated that the adsorption of CTAC and CSH by Mt followed the pseudo-second-order model, and CTAC adsorption rate on Mt was faster than that of CSH. FTIR spectrum clearly revealed the incorporation of surfactant ions into the interlayer region. The TG-DTA analyses showed that the total mass losses of OMt strongly depended on the molecular volume of modifiers. PMID- 30463202 TI - Gas-Sensor Drift Counteraction with Adaptive Active Learning for an Electronic Nose. AB - Gas sensors are the key components of an electronic nose (E-nose) in violated odour analysis. Gas-sensor drift is a kind of physical change on a sensor surface once an E-nose works. The perturbation of gas-sensor responses caused by drift would deteriorate the performance of the E-nose system over time. In this study, we intend to explore a suitable approach to deal with the drift effect in an online situation. Considering that the conventional drift calibration is difficult to implement online, we use active learning (AL) to provide reliable labels for online instances. Common AL learning methods tend to select and label instances with low confidence or massive information. Although this action clarifies the ambiguity near the classification boundary, it is inadequate under the influence of gas-sensor drift. We still need the samples away from the classification plane to represent drift variations comprehensively in the entire data space. Thus, a novel drift counteraction method named AL on adaptive confidence rule (AL-ACR) is proposed to deal with online drift data dynamically. By contrast with conventional AL methods selecting instances near the classification boundary of a certain category, AL-ACR collects instances distributed evenly in different categories. This action implements on an adjustable rule according to the outputs of classifiers. Compared with other reference methods, we adopt two drift databases of E-noses to evaluate the performance of the proposed method. The experimental results indicate that the AL ACR reaches higher accuracy than references on two E-nose databases, respectively. Furthermore, the impact of the labelling number is discussed to show the trend of performance for the AL-type methods. Additionally, we define the labelling efficiency index (LEI) to assess the contribution of certain labelling numerically. According to the results of LEI, we believe AL-ACR can achieve the best effect with the lowest cost among the AL-type methods in this work. PMID- 30463203 TI - The Impact of 'Selfie' Tourism on the Behaviour and Welfare of Brown-Throated Three-Toed Sloths. AB - The use of wild animals as photo props is prevalent across the globe and is widely recognised to represent a potential animal welfare concern. However, detailed information regarding the specific impacts of such activity on wild animal behaviour is currently lacking. Herein, we investigated how brown-throated three-toed sloths (Bradypus variegatus) were handled by tourists, and how sloths behaved during wildlife 'selfies' taken in Manaus, Brazil and Puerto Alegria and Iquitos in Peru. In total, we observed 17 sloths (during 70 focal observations) that were provided for use in wildlife selfies on 34 different tours. We found that an average number of 5 people held each sloth during each focal observation. For 48.6% of the time the sloths were handled in a way which involved physical manipulation of the sloths' head and/or limbs and/or being held by the claws. From the eight different types of sloth behaviour observed, we found that the two types performed for the longest average duration of time were surveillance (55.3%) and limb stretching (12.6%). Our findings show that when being handled sloths were frequently held in ways that may compromise their welfare. Although to date the behaviour of sloths while being handled has not been reported in any published literature, in this study we document certain behaviours which may act as indicators of compromised welfare. We suggest that our data provides a potential baseline for future study into the behaviour and welfare of sloths. PMID- 30463204 TI - Molecular Characterization of Annexin B2, B3 and B12 in Taenia multiceps. AB - Coenurus cerebralis, the metacestode of Taenia multiceps, causes coenurosis, a disease severely affecting goat, sheep, cattle and yak farming and resulting in huge economic losses annually. Annexins bind calcium ions and play an important role in flatworm parasite development. To explore potential functions of annexins in T. multiceps, three homologous genes, namely, TmAnxB2, TmAnxB3 and TmAnxB12, were screened from the transcriptome dataset, amplified from C. cerebralis cDNA and subjected to bioinformatics analysis. Then, polyclonal antibodies recognizing the recombinant TmAnxB2 (rTmAnxB2) and rTmAnxB3 were prepared for localization of TmAnxB2 and TmAnxB3 in different tissues and developmental stages by immunofluorescence. The transcription of all three genes was also measured by relative fluorescent quantitative PCR. The sizes of rTmAnxB2, rTmAnxB3 and rTmAnxB12 were 58.00, 53.06 and 53.51 kDa, respectively, and rTmAnxB12 was unstable. Both rTmAnxB2 and rTmAnxB3 were recognized by goat-positive T. multiceps sera in Western blots. Immunofluorescence revealed that TmAnxB2 and TmAnxB3 were localized in the protoscolex and cyst wall and TmAnxB3 was also detected in adult cortex. TmAnxB2 and TmAnxB12 mRNA levels were determined to be highest in oncospheres and protoscolex, whereas transcription of TmAnxB3 was highest in scolex and immature segments. Taken together, these findings indicate that TmAnxB2 and TmAnxB12 may play critical roles in T. multiceps larvae, while TmAnxB3 may have important functions in adults. These results will lay the foundation for functional research of annexins in T. multiceps. PMID- 30463205 TI - A Set of Platforms with Combinatorial and High-Throughput Technique for Gas Sensing, from Material to Device and to System. AB - In a new E-nose development, the sensor array needs to be optimized to have enough sensitivity and selectivity for gas/odor classification in the application. The development process includes the preparation of gas sensitive materials, gas sensor fabrication, array optimization, sensor array package and E nose system integration, which would take a long time to complete. A set of platforms including a gas sensing film parallel synthesis platform, high throughput gas sensing unmanned testing platform and a handheld wireless E-nose system were presented in this paper to improve the efficiency of a new E-nose development. Inkjet printing was used to parallel synthesize sensor libraries (400 sensors can be prepared each time). For gas sensor selection and array optimization, a high-throughput unmanned testing platform was designed and fabricated for gas sensing measurements of more than 1000 materials synchronously. The structures of a handheld wireless E-nose system with low power were presented in detail. Using the proposed hardware platforms, a new E-nose development might only take one week. PMID- 30463206 TI - Pathobiological and Genomic Characterization of a Cold-Adapted Infectious Bronchitis Virus (BP-caKII). AB - We established a cold-adapted infectious bronchitis virus (BP-caKII) by passaging a field virus through specific pathogen-free embryonated eggs 20 times at 32 degrees C. We characterized its growth kinetics and pathogenicity in embryonated eggs, and its tropism and persistence in different tissues from chickens; then, we evaluated pathogenicity by using a new premature reproductive tract pathogenicity model. Furthermore, we determined the complete genomic sequence of BP-caKII to understand the genetic changes related to cold adaptation. According to our results, BP-caKII clustered with the KII genotype viruses K2 and KM91, and showed less pathogenicity than K2, a live attenuated vaccine strain. BP-caKII showed delayed viremia, resulting in its delayed dissemination to the kidneys and cecal tonsils compared to K2 and KM91, the latter of which is a pathogenic field strain. A comparative genomics study revealed similar nucleotide sequences between BP-caKII, K2 and KM91 but clearly showed different mutations among them. BP-caKII shared several mutations with K2 (nsp13, 14, 15 and 16) following embryo adaptation but acquired multiple additional mutations in nonstructural proteins (nsp3, 4 and 12), spike proteins and nucleocapsid proteins following cold adaptation. Thus, the establishment of BP-caKII and the identified mutations in this study may provide insight into the genetic background of embryo and cold adaptations, and the attenuation of coronaviruses. PMID- 30463207 TI - Preventive Effect of Lactobacillus fermentum CQPC03 on Activated Carbon-Induced Constipation in ICR Mice. AB - Background and objectives: Paocai (pickled cabbage), which is fermented by lactic acid bacteria, is a traditional Chinese food. The microorganisms of Paocai were isolated and identified, and the constipation inhibition effect of one of the isolated Lactobacillus was investigated. Materials and Methods: The 16S rDNA technology was used for microbial identification. A mouse constipation model was established using activated carbon. After intragastric administration of Lactobacillus (108 CFU/mL), the mice were dissected to prepare pathological sections of the small intestine. Serum indicators were detected using kits, and the expression of small intestine-related mRNAs was detected by qPCR assay. Results: One strain of Lactobacillus was identified and named Lactobacillus fermentum CQPC03 (LF-CQPC03). Body weight and activated carbon propulsion rate were all higher in mice intragastrically administered with LF-CQPC03 compared with the control group, while the time to the first black stool in treated mice was lower than that in the control group. Serum assays showed that gastrin (Gas), endothelin (ET), and acetylcholinesterase (AchE) levels were significantly higher in the LF-CQPC03-treated mice than in the control group, while somatostatin (SS) levels were significantly lower than in the control mice. Mouse small intestine tissue showed that c-Kit, stem cell factor (SCF), and glial cell-derived neurotrophic factor (GDNF) mRNA expression levels were significantly higher in the LF-CQPC03 treated mice than in control mice, while transient receptor potential cation channel subfamily V member 1 (TRPV1) and inducible nitric oxide synthase (iNOS) expression levels were significantly lower in the LF-CQPC03 treated mice than in control mice. Conclusions: There is a better effect with high-dose LF-CQPC03, compared to the lower dose (LF-CQPC03-L), showing good probiotic potential, as well as development and application value. PMID- 30463208 TI - A Regenerative Immunoaffinity Layer Based on the Outer Membrane of Z-Domains Autodisplaying E. coli for Immunoassays and Immunosensors. AB - Through orientation control of antibodies, Z-domains autodisplaying Escherichia coli outer cell membrane (OM) may be utilized to improve the sensitivity and limit of detection (LOD) of immunoassays and immunosensors. A regenerative immunoaffinity layer based on Z-domains autodisplaying E. coli OM was developed for the surface plasmon resonance (SPR) biosensor. Regeneration conditions for the Z-domains autodisplaying E. coli OM-based immunoassays and immunosensors were optimized by varying pH and detergent concentration. An E. coli cell-based HRP immunoassay was tested and validated in three sequential regenerative immunoassays under optimal conditions. The OM of Z-domains autodisplaying E. coli was isolated and coated on the two-dimensional substrate (microplate). The OM based HRP immunoassay was tested and validated in four regenerative immunoassays. This regenerative OM layer was applied to the SPR biosensor. Z-domains autodisplaying OM layered onto the gold surface of SPR biosensors was developed, and the OM-based regenerative immunoaffinity layer with orientation control was tested using CRP analyte. The SPR biosensor regenerative immunoaffinity layer demonstrated that CRP biosensing was repeated for five regeneration cycles with less than 2% signal difference. Therefore, the newly developed regenerative immunoaffinity layer with antibody orientation control may improve biosensing sensitivity and reduce the cost of medical diagnosis. PMID- 30463209 TI - A PB1-K577E Mutation in H9N2 Influenza Virus Increases Polymerase Activity and Pathogenicity in Mice. AB - H9N2 avian influenza viruses are present in poultry worldwide. These viruses are considered to have pandemic potential, because recent isolates can recognize human-type receptor and several sporadic human infections have been reported. In this study, we aimed to identify mutations related to mammalian adaptation of H9N2 influenza virus. We found that mouse-adapted viruses had several mutations in hemagglutinin (HA), PB2, PA, and PB1. Among the detected mutations, PB1-K577E was a novel mutation that had not been previously reported to involve mammalian adaptation. A recombinant H9N2 virus bearing only the PB1-K577E mutation showed enhanced pathogenicity in mice, with increased virus titers in nasal turbinates compared to that in mice infected with the wild-type virus. In addition, the PB1 K577E mutation increased virus polymerase activity in human cell culture at a lower temperature. These data suggest that the PB1-K577E mutation is a novel pathogenicity determinant of H9N2 virus in mice and could be a signature for mammalian adaptation. PMID- 30463210 TI - Ordering of Primary Carbonitrides in an Austenitic Steel Revealed by Transmission Electron Microscopy and Atom Probe Tomography. AB - We reveal for the first time an ordering phenomenon of a type of carbonitrides in a Super304H austenitic steel via the techniques of transmission electron microscopy and atom probe tomography. Solution-treated Super304H austenitic steel samples containing a few primary carbonitrides were aged at 923 K for 5000 h. The results show that the primary carbonitrides in the Super304H steel are non stoichiometric compounds enriched in Nb and with a NaCl-type structure. The crystal structure of the Nb-rich carbonitrides is in a disordered state in the solution-treated steel, while in an ordered state in the aged steel. This observation suggests the occurrence of a disorder-order structural transition in the primary carbonitrides during long-term aging. We found that such a disorder order structural transition is accompanied by carbon diffusion from the primary carbonitrides into the austenitic matrix. The ordering phenomenon is discussed based on the long-range ordering of structure vacancies in the non-metal lattice of the superstructure, providing new insights for the understanding of ordering in non-stoichiometric compounds. PMID- 30463211 TI - Needle-Free Immunization with Chitosan-Based Systems. AB - Despite successful use, needle-based immunizations have several issues such as the risk of injuries and infections from the reuse of needles and syringes and the low patient compliance due to pain and fear of needles during immunization. In contrast, needle-free immunizations have several advantages including ease of administration, high level of patient compliance and the possibility of mass vaccination. Thus, there is an increasing interest on developing effective needle free immunizations via cutaneous and mucosal approaches. Here, we discuss several methods of needle-free immunizations and provide insights into promising use of chitosan systems for successful immunization. PMID- 30463212 TI - Large Scale Phenotyping Provides Insight into the Diversity of Vegetative and Reproductive Organs in a Wide Collection of Wild and Domesticated Peppers (Capsicum spp.). AB - In the past years, the diversity of Capsicum has been mainly investigated through genetics and genomics approaches, fewer efforts have been made in the field of plant phenomics. Assessment of crop traits with high-throughput methodologies could enhance the knowledge of the plant phenome, giving at the same time a key contribution to the understanding of the function of many genes. In this study, a wide germplasm collection of 307 accessions retrieved from 48 world regions, and belonging to nine Capsicum species was characterized for 54 plant, leaf, flower and fruit traits. Conventional descriptors and semi-automated tools based on image analysis and colour coordinate detection were used. Significant differences were found among accessions, between species and between sweet and spicy cultivated types, revealing a large diversity. The results highlighted how the domestication process and the continued selection have increased the variability of fruit shape and colour. Hierarchical clustering based on conventional and fruit morphological descriptors reflected the separation of species on the basis of their phylogenetic relationships. These observations suggested that the flow between distinct gene pools could have contributed to determine the similarity of the species on the basis of morphological plant and fruit parameters. The approach used represents the first high-throughput phenotyping effort in Capsicum spp. aimed at broadening the knowledge of the diversity of domesticated and wild peppers. The data could help to select best the candidates for breeding and provide new insight into the understanding of the genetic base of the fruit shape of pepper. PMID- 30463213 TI - Decrease in Lipid Droplets in Adrenal Cortex of Male Wistar Rats after Chronic Exposure to Energy Drinks. AB - Background and objectives: Energy drinks are popular non-alcoholic beverages. They are consumed in large amounts, mainly by active, young people. Although they are easily accessible and marketed as safe, numerous cases of adverse effects have been published, including cardiac arrest, arrythmias, acute hepatitis, and renal failure. The aim of the current study is the assessment of energy drink influence on the histological structure of adrenal cortex in rats. Material and Methods: 15 male young Wistar rats were equally divided into three groups: control (C), experimental (E) and reversibility control (RC). C group received water and standard rodent food ad libitum while both E and RC groups had additionally unlimited access to energy drinks. C and E groups were decapitated after 8 weeks and RC was given another 8 weeks without energy drinks. Adrenal glands were embedded in paraffin blocks and 5 MUm slides were prepared and stained according to standard H&E and Masson's trichrome protocols. Additionally, immunohistochemical stainings against Ki-67, p53, CTGF and caspase-3 were prepared. Results: Decreased vacuolization and numerous pyknotic nuclei were noted in E and RC groups. Overexpression of caspase-3 was noted both subcapsular in zona glomerulosa and along sinusoids in zona fasciculata. Increased collagen deposition in zona glomerulosa and zona fasciculata of E and RC was observed. Insular and irregular overexpression of CTGF was noted. The overall picture of CTGF expression matched the Masson's trichrome. No significant difference was observed in Ki-67 expression. Conclusions: The results of the current study suggest that the stimulation is so intense that it causes significant damage to adrenal cortical cells, resulting in their apoptosis. It seems, however, that the observed effects are at least partially reversible. PMID- 30463214 TI - Multi-Objective Optimizations for Microinjection Molding Process Parameters of Biodegradable Polymer Stent. AB - Microinjection molding technology for degradable polymer stents has good development potential. However, there is a very complicated relationship between molding quality and process parameters of microinjection, and it is hard to determine the best combination of process parameters to optimize the molding quality of polymer stent. In this study, an adaptive optimization method based on the kriging surrogate model is proposed to reduce the residual stress and warpage of stent during its injection molding. Integrating design of experiment (DOE) methods with the kriging surrogate model can approximate the functional relationship between design goals and design variables, replacing the expensive reanalysis of the stent residual stress and warpage during the optimization process. In this proposed optimization algorithm, expected improvement (EI) is used to balance local and global search. The finite element method (FEM) is used to simulate the micro-injection molding process of polymer stent. As an example, a typical polymer vascular stent ART18Z was studied, where four key process parameters are selected to be the design variables. Numerical results demonstrate that the proposed adaptive optimization method can effectively decrease the residual stress and warpage during the stent injection molding process. PMID- 30463215 TI - Effects of Enhanced Hydrophilic Titanium Dioxide-Coated Hydroxyapatite on Bone Regeneration in Rabbit Calvarial Defects. AB - The regeneration of bone defects caused by periodontal disease or trauma is an important goal. Porous hydroxyapatite (HA) is an osteoconductive graft material. However, the hydrophobic properties of HA can be a disadvantage in the initial healing process. HA can be coated with TiO2 to improve its hydrophilicity, and ultraviolet irradiation (UV) can further increase the hydrophilicity by photofunctionalization. This study was designed to evaluate the effect of 5% TiO2 coated HA on rabbit calvarial defects and compare it with that of photofunctionalization on new bone in the early stage. The following four study groups were established, negative control, HA, TiO2-coated HA, and TiO2-coated HA with UV. The animals were sacrificed and the defects were assessed by radiography as well as histologic and histomorphometric analyses. At 2 and 8 weeks postoperatively, the TiO2-coated HA with UV group and TiO2-coated HA group showed significantly higher percentages of new bone than the control group (p < 0.05). UV irradiation increased the extent of new bone formation, and there was a significant difference between the TiO2-coated HA group and TiO2-coated HA with UV group. The combination of TiO2/HA and UV irradiation in bone regeneration appears to induce a favorable response. PMID- 30463216 TI - In Vitro Anti-Inflammatory Properties of Selected Green Leafy Vegetables. AB - The study investigated the anti-inflammatory activity of the hydro methanolic extract of six leafy vegetables, namely Cassia auriculata, Passiflora edulis, Sesbania grandiflora, Olax zeylanica, Gymnema lactiferum, and Centella asiatica. The anti-inflammatory activity of methanolic extracts of leafy vegetables was evaluated using four in vitro-based assays: hemolysis inhibition, proteinase inhibition, protein denaturation inhibition, and lipoxygenase inhibition. Results showed that the percent inhibition of hemolysis from these leaf extracts (25-100 ug/mL dry weight basis (DW)) was within the range from 5.4% to 14.9%, and the leaves of P. edulis and O. zeylanica showed a significantly higher (p < 0.05) inhibition levels. Percent inhibition of protein denaturation of these leafy types was within the range of 36.0-61.0%, and the leaf extract of C. auriculata has exhibited a significantly higher (p < 0.05) inhibition level. Proteinase inhibitory activity of these leaf extracts was within the range of 20.2-25.9%. The lipoxygenase inhibition was within the range of 3.7-36.0%, and the leaf extract of G. lactiferum showed an improved ability to inhibit lipoxygenase activity. In conclusion, results revealed that all the studied leaves possess anti-inflammatory properties at different levels, and this could be due to the differences in the composition and concentration of bioactive compounds. PMID- 30463217 TI - Coherent Diffraction Imaging in Transmission Electron Microscopy for Atomic Resolution Quantitative Studies of the Matter. AB - The paper focuses on the development of electron coherent diffraction imaging in transmission electron microscopy, made in the, approximately, last ten years in our collaborative research group, to study the properties of materials at atomic resolution, overcoming the limitations due to the aberrations of the electron lenses and obtaining atomic resolution images, in which the distribution of the maxima is directly related to the specimen atomic potentials projected onto the microscope image detector. Here, it is shown how augmented coherent diffraction imaging makes it possible to achieve quantitative atomic resolution maps of the specimen atomic species, even in the presence of low atomic number atoms within a crystal matrix containing heavy atoms. This aim is achieved by: (i) tailoring the experimental set-up, (ii) improving the experimental data by properly treating parasitic diffused intensities to maximize the measure of the significant information, (iii) developing efficient methods to merge the information acquired in both direct and reciprocal spaces, (iv) treating the dynamical diffused intensities to accurately measure the specimen projected potentials, (v) improving the phase retrieval algorithms to better explore the space of solutions. Finally, some of the future perspectives of coherent diffraction imaging in a transmission electron microscope are given. PMID- 30463218 TI - Design of Shape Memory Alloy Coil Spring Actuator for Improving Performance in Cyclic Actuation. AB - Performance of the shape memory alloy (SMA) coil spring actuator in cyclic actuation as an artificial muscle is strongly related to the mechanical design of the coil geometry. This paper proposes a practical design method for improving the frequency and efficiency of the SMA coil spring actuator; by designing the SMA coil spring to have large index (coil diameter/wire diameter) and pitch angle (LIP), cooling characteristics can be improved (increasing the actuation frequency) and large deformation can be obtained. The LIP design process is based on the two-state static model that describes the displacement-force relationship of the SMA coil spring in two states-a fully austenite phase and a fully martensite phase. The design process gives accurate design parameters of the SMA coil spring actuator that satisfy the required stroke and force. The model of the fully martensite phase of the SMA coil that includes the stress-induced detwinning enables the use of maximum shear strain of the SMA. The design method reduces the mass of an SMA without changing the stroke and increase the power density and efficiency. The cyclic actuation experiments demonstrate that the LIP design doubles the maximum frequency of SMA coil actuator with one-sixth the mass of the non-LIP design. PMID- 30463219 TI - Effect of Aminosilane Coupling Agents with Different Chain Lengths on Thermo Mechanical Properties of Cross-Linked Epoxy Resin. AB - In this paper, a molecular dynamics simulation method was used to study the thermo-mechanical properties of cross-linked epoxy resins doped with nano silica particles that were grafted with 3-aminopropyltriethoxysilane, N-(2-aminoethyl)-3 aminopropyltrimethoxysilane, and 3-[2-(2-aminoethylamino)ethylamino]-propyl trimethoxysilane with different chain lengths. Firstly, a set of pure epoxy resin models, and four sets of SiO2/EP composite models were established. Then, a reasonable structure was obtained through a series of optimizations using molecular dynamics calculations. Next, the mechanical properties, hydrogen bond statistics, glass transition temperature, free volume fraction, and chain spacing of the five models were studied comparatively. The results show that doped nano silica particles of surfaces grafted with 3-aminopropyltriethoxysilane, N-(2 aminoethyl)-3-aminopropyltrimethoxysilane, and 3-[2-(2 aminoethylamino)ethylamino]-propyl-trimethoxysilane with different chain lengths enhanced mechanical properties such as elastic modulus, shear modulus, and volume modulus obviously. The glass transition temperature increased by 15-16 K, 40-41 K, and 24-27 K, respectively. Finally, the data show that the cross-linked epoxy resin modified by nanoparticles grafted with N-(2-aminoethyl)-3-aminopropyl trimethoxysilane had better effects for improving thermo-mechanical properties by the comparatively studying the five groups of parameter models under the same conditions. PMID- 30463220 TI - Equivalent Properties of Transition Layer Based on Element Distribution in Laser Bending of 304 Stainless Steel/Q235 Carbon Steel Laminated Plate. AB - Compared with the single-component metal plate, there is a special transition layer on the joint interface between two kinds of materials in the stainless steel-carbon steel laminated plate (SCLP). In order to describe the finite element model of laser bending accurately, it is of great significance to determine material properties of the transition layer. Based on the element distribution, an equivalent method is adopted to calculate thermal conductivity, thermal expansion coefficient, elastic modulus, density, Poisson's ratio, and specific heat capacity of transition layer. The electron probe experiments show that the transition layer is formed by interfacial element diffusion with thickness of 7 MUm. Besides, the volume fraction of stainless steel (46.63%) and carbon steel (53.37%) in the transition layer is tested by energy dispersive spectrometer, respectively. Through the equivalent method, a laser bending model of SCLP is simulated by ANSYS software to predict the bending angle under different parameters. The experimental verification shows that the maximum of bending angle errors is 3.74%, which is lower than the maximum 4.93% of errors calculated by the mean value method. The analysis verifies that the laser bending model is feasible and contributes to improving the accuracy of modeling SCLP in the laser bending process. PMID- 30463221 TI - Structure-Activity Relationship Study of Newly Synthesized Iridium-III Complexes as Potential Series for Treating Thrombotic Diseases. AB - Platelets play a major role in hemostatic events and are associated with various pathological events, such as arterial thrombosis and atherosclerosis. Iridium (Ir) compounds are potential alternatives to platinum compounds, since they exert promising anticancer effects without cellular toxicity. Our recent studies found that Ir compounds show potent antiplatelet properties. In this study, we evaluated the in vitro antiplatelet, in vivo antithrombotic and structure activity relationship (SAR) of newly synthesized Ir complexes, Ir-1, Ir-2 and Ir 4, in agonists-induced human platelets. Among the tested compounds, Ir-1 was active in inhibiting platelet aggregation induced by collagen; however, Ir-2 and Ir-4 had no effects even at their maximum concentrations of 50 MUM against collagen and 500 MUM against U46619-induced aggregation. Similarly, Ir-1 was potently inhibiting of adenosine triphosphate (ATP) release, calcium mobilization ([Ca2+]i) and P-selectin expression induced by collagen-induced without cytotoxicity. Likewise, Ir-1 expressively suppressed collagen-induced Akt, PKC, p38MAPKs and JNK phosphorylation. Interestingly, Ir-2 and Ir-4 had no effect on platelet function analyzer (PFA-100) collagen-adenosine diphosphate (C-ADP) and collagen-epinephrine (C-EPI) induced closure times in mice, but Ir-1 caused a significant increase when using C-ADP stimulation. Other in vivo studies revealed that Ir-1 significantly prolonged the platelet plug formation, increased tail bleeding times and reduced the mortality of adenosine diphosphate (ADP)-induced acute pulmonary thromboembolism in mice. Ir-1 has no substitution on its phenyl group, a water molecule (like cisplatin) can replace its chloride ion and, hence, the rate of hydrolysis might be tuned by the substituent on the ligand system. These features might have played a role for the observed effects of Ir-1. These results indicate that Ir-1 may be a lead compound to design new antiplatelet drugs for the treatment of thromboembolic diseases. PMID- 30463222 TI - Assumption of Constraining Force to Explain Distortion in Laser Additive Manufacturing. AB - Distortion is a common but unrevealed problem in metal additive manufacturing, due to the rapid melting in metallurgy and the intricate thermal-mechanical processes involved. We explain the distortion mechanism and major influencing factors by assumption of constraining force, which is assumed between the added layer and substrate. The constraining force was set to act on the substrate in a static structural finite element analysis (FEA) model. The results were compared with those of a thermal-mechanical FEA model and experiments. The constraining force and the associated static structural FEA showed trends in distortion and stress distribution similar to those shown by thermal-mechanical FEA and experiments. It can be concluded that the constraining force acting on the substrate is a major contributory factor towards the distortion mechanism. The constraining force seems to be primarily related to the material properties, temperature, and cross-sectional area of the added layer. PMID- 30463223 TI - Deformation and Failure Behavior of Wooden Sandwich Composites with Taiji Honeycomb Core under a Three-Point Bending Test. AB - A new type of Taiji honeycomb structure bonded outside with wood-based laminates was characterized from a mechanical standpoint. Both theoretical and experimental methods were employed to analyze comprehensively the deformation behavior and failure mechanism under a three-point bending test. The analytical analysis reveals that a Taiji honeycomb has 3.5 times higher strength in compression and 3.44 times higher strength in shear compared with a traditional hexagonal honeycomb. Considering the strength-weight issue, the novel structure also displays an increase in compression strength of 1.75 times and shear strength of 1.72 times. Under a three-point bending test, indentation and core shear failure played the dominant role for the total failure of a wooden sandwich with Taiji honeycomb core. Typical face yield was not observed due to limited thickness-span ratio of specimens. Large spans weaken the loading level due to the contribution of global bending stress in the compressive skin to indentation failure. A set of analytical equations between mechanical properties and key structure parameters were developed to accurately predict the threshold stresses corresponding to the onset of those deformation events, which offer critical new knowledge for the rational structure design of wooden sandwich composites. PMID- 30463224 TI - Synthesis and Anticancer Activity Evaluation of Hydrolyzed Derivatives of Panaxnotoginseng Saponins. AB - To increase the antitumor activity of ginsenosides and acetylsalicylic acid, acid hydrolysis products of Panaxnotoginseng saponin were used as raw materials to be combined with salicylic acid to obtain ginsenoside salicylic acid derivatives. All derivatives were assessed for anti-cancer activity. A total of 20 target compounds were designed and synthesized. The cytotoxic activity on five cancer cell lines, including human colon cancer (HT-29), gastric cancer (BGC-823), cervical cancer (Hela), human breast cancer (MCF-7), human lung cancer cells (A549), and two normal cancer cell lines (human gastric epithelial cells (GES-1), and human ovarian epithelial cells (IOSE144)) was evaluated following treatment with the compounds. The results showed that all compounds inhibited the growth of cancer cells. Compounds 1a, 3a, 7a, 1b, 2b, 3b and 8b showed strong anticancer activity. For MCF-7 cells, compound 3b showed the strongest inhibitory activity, IC50 = 2.56 +/- 0.09 MUM. In the cytotoxicity test, all compounds showed low toxicity or no toxicity (IC50 > 100 MUM). In addition, a cell cycle distribution assay and wound healing assay demonstrated that compound 3b specifically inhibited MCF-7 proliferation and migration ability. Our results indicate that compound 3b represents a promising compound for further cancer studies. PMID- 30463225 TI - Intensified LOHC-Dehydrogenation Using Multi-Stage Microstructures and Pd-Based Membranes. AB - Liquid organic hydrogen carriers (LOHC) are able to store hydrogen stably and safely in liquid form. The carrier can be loaded or unloaded with hydrogen via catalytic reactions. However, the release reaction brings certain challenges. In addition to an enormous heat requirement, the released hydrogen is contaminated by traces of evaporated LOHC and by-products. Micro process engineering offers a promising approach to meet these challenges. In this paper, a micro-structured multi-stage reactor concept with an intermediate separation of hydrogen is presented for the application of perhydro-dibenzyltoluene dehydrogenation. Each reactor stage consists of a micro-structured radial flow reactor designed for multi-phase flow of LOHC and released hydrogen. The hydrogen is separated from the reactors' gas phase effluent via PdAg-membranes, which are integrated into a micro-structured environment. Separate experiments were carried out to describe the kinetics of the reaction and the separation ability of the membrane. A model was developed, which was fed with these data to demonstrate the influence of intermediate separation on the efficiency of LOHC dehydrogenation. PMID- 30463226 TI - Using Portable Force Plates to Assess Vertical Jump Performance: A Metrological Appraisal. AB - The purpose of this study was to verify the metrological properties of portable force plates that are used to assess countermovement jump performance. While 88 participants (38 males, 50 females) were included in the agreement analyses, 84 participants (37 males and 47 females) completed the reliability part of the study. This randomized crossover design suggests that portable force plates could be used interchangeably with a reference system. Indeed, the differences between both devices were all considered trivial (effect size (ES) < 0.20), and the mean bias was never greater than 3.41% in comparison to the reference system. In addition, the absolute and relative reliability parameters were found to be acceptable for clinical use, even when used on different floor surfaces. However, it was found that the ratio between flight time and contraction time (FTCT) showed questionable reliability when tests were conducted on different surfaces (intraclass correlation coefficient = 0.49; coefficient of variation = 26.72%). Therefore, practitioners should be careful when installing the portable device on different floor surfaces in order to optimize the reliability and the ability to detect real change in the context of a countermovement jump monitoring process. PMID- 30463227 TI - Cutting Forces Measurement for Milling Process by Using Working Tables with Integrated PVDF Thin-Film Sensors. AB - In the milling process, cutting forces contain key information about the machining process status in terms of workpiece quality and tool condition. On line cutting force measurement is key for machining condition monitoring and machined surface quality assurance. This paper presents a novel instrumented working table with integrated polyvinylidene fluoride (PVDF) thin-film sensors, thus enabling the dynamic milling force measurement with compact structures. To achieve this, PVDF thin-film sensors are integrated into the working table to sense forces in different directions and the dedicated cutting force decoupling model is derived. A prototype instrumented working table is developed and validated. The validation demonstrates that profiles of the forces measured from the developed instrumented working table prototype and the dynamometer match well. Furthermore, the milling experiment results convey that the instrumented working table prototype could also identify the tool runout due to tool manufacturing or assembly errors, and the force signal spectrum analysis indicates that the developed working table can capture the tool passing frequency correctly, therefore, is suitable for the milling force measurement. PMID- 30463228 TI - Revisiting Rab7 Functions in Mammalian Autophagy: Rab7 Knockout Studies. AB - Rab7 (or Ypt7 in yeast) is one of the well-characterized members of the Rab family small GTPases, which serve as master regulators of membrane trafficking in eukaryotes. It localizes to late endosomes and lysosomes and has multiple functions in the autophagic pathway as well as in the endocytic pathway. Because Rab7/Ypt7 has previously been shown to regulate the autophagosome-lysosome fusion step in yeast and fruit flies (i.e., autophagosome accumulation has been observed in both Ypt7-knockout [KO] yeast and Rab7-knockdown fruit flies), it is widely assumed that Rab7 regulates the autophagosome-lysosome fusion step in mammals. A recent analysis of Rab7-KO mammalian cultured cells, however, has revealed that Rab7 is essential for autolysosome maturation (i.e., autolysosome accumulation has been observed in Rab7-KO cells), but not for autophagosome-lysosome fusion, under nutrient-rich conditions. Thus, although Rab7/Ypt7 itself is essential for the proper progression of autophagy in eukaryotes, the function of Rab7/Ypt7 in autophagy in yeast/fruit flies and mammals must be different. In this review article, we describe novel roles of Rab7 in mammalian autophagy and discuss its functional diversification during evolution. PMID- 30463229 TI - Visfatin Promotes Wound Healing through the Activation of ERK1/2 and JNK1/2 Pathway. AB - Visfatin, a member of the adipokine family, plays an important role in many metabolic and stress responses. The mechanisms underlying the direct therapeutic effects of visfatin on wound healing have not been reported yet. In this study, we examined the effects of visfatin on wound healing in vitro and in vivo. Visfatin enhanced the proliferation and migration of human dermal fibroblasts (HDFs) and keratinocytes the expression of wound healing-related vascular endothelial growth factor (VEGF) in vitro and in vivo. Treatment of HDFs with visfatin induced activation of both extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinases 1 and 2 (JNK1/2) in a time-dependent manner. Inhibition of ERK1/2 and JNK1/2 led to a significant decrease in visfatin induced proliferation and migration of HDFs. Importantly, blocking VEGF with its neutralizing antibodies suppressed the visfatin-induced proliferation and migration of HDFs and human keratinocytes, indicating that visfatin induces the proliferation and migration of HDFs and human keratinocytes via increased VEGF expression. Moreover, visfatin effectively improved wound repair in vivo, which was comparable to the wound healing activity of epidermal growth factor (EGF). Taken together, we demonstrate that visfatin promotes the proliferation and migration of HDFs and human keratinocytes by inducing VEGF expression and can be used as a potential novel therapeutic agent for wound healing. PMID- 30463230 TI - Organophosphine-Catalyzed [4C+X] Annulations. AB - In recent years, there have been extraordinary developments of organophosphine catalyzed reactions. This includes progress in the area of [4C+X] annulations, which are of particular interest due to their potential for the rapid construction of 5-8-membered cyclic products. In this short overview, we summarize the remarkable progress, emphasizing reaction mechanisms and key intermediates involved in the processes. The discussion is classified according to the type of electrophilic reactants that acted as C4 synthons in the annulation process, in the order of alpha-alkyl allenoates, gamma-alkyl allenoates, alpha-methyl allene ketones, beta'-OAc allenoate, delta-OAc allenoate, activated dienes and cyclobutenones. PMID- 30463231 TI - Molecular Mechanism for the Regulation of ABA Homeostasis During Plant Development and Stress Responses. AB - The plant hormone abscisic acid (ABA) play essential roles in numerous physiological processes such as seed dormancy, seed germination, seeding growth and responses to biotic and abiotic stresses. Such biological processes are tightly controlled by a complicated regulatory network including ABA homoeostasis, signal transduction as well as cross-talking among other signaling pathways. It is known that ABA homoeostasis modulated by its production, inactivation, and transport pathways is considered to be of great importance for plant development and stress responses. Most of the enzymes and transporters involved in ABA homoeostasis have been largely characterized and they all work synergistically to maintain ABA level in plants. Increasing evidence have suggested that transcriptional regulation of the genes involved in either ABA production or ABA inactivation plays vital roles in ABA homoeostasis. In addition to transcription factors, such progress is also regulated by microRNAs and newly characterized root to shoot mobile peptide-receptor like kinase (RLKs) mediated long-distance signal transduction. Thus, ABA contents are always kept in a dynamic balance. In this review, we survey recent research on ABA production, inactivation and transport pathways, and summarize some latest findings about the mechanisms that regulate ABA homoeostasis. PMID- 30463232 TI - Detection of Alpha-Fetoprotein in Hepatocellular Carcinoma Patient Plasma with Graphene Field-Effect Transistor. AB - The detection of alpha-fetoprotein (AFP) in plasma is important in the diagnosis of hepatocellular carcinoma (HCC) in humans. We developed a biosensor to detect AFP in HCC patient plasma and in a phosphate buffer saline (PBS) solution using a graphene field-effect transistor (G-FET). The G-FET was functionalized with 1 pyrenebutyric acid N-hydroxysuccinimide ester (PBASE) for immobilization of an anti-AFP antibody. AFP was detected by assessing the shift in the voltage of the Dirac point (DeltaVDirac) after binding of AFP to the anti-AFP-immobilized G-FET channel surface. This anti-AFP-immobilized G-FET biosensor was able to detect AFP at a concentration of 0.1 ng mL-1 in PBS, and the detection sensitivity was 16.91 mV. In HCC patient plasma, the biosensor was able to detect AFP at a concentration of 12.9 ng mL-1, with a detection sensitivity of 5.68 mV. The sensitivity (DeltaVDirac) depended on the concentration of AFP in either PBS or HCC patient plasma. These data suggest that G-FET biosensors could have practical applications in diagnostics. PMID- 30463234 TI - Evaluating the Effect of Hydrophobic Nanosilica on the Viscoelasticity Property of Asphalt and Asphalt Mixture. AB - Viscoelasticity property of bitumen is closely related to the service life of bituminous pavement. This paper evaluated the impact of one of the most efficient and widely used nanomaterials in various industries called hydrophobic nanosilica on the viscoelasticity property of bitumen and asphalt mixture. In this paper, three hydrophobic nanosilica modified bitumens and asphalt mixtures were researched by conventional physical properties test, SEM test, FTIR test, DSC test, DSR test, static creep test and dynamic creep test. The results showed that the introduction of hydrophobic nanosilica could strengthen the viscosity of asphalt more effectively and had better dispersion than hydrophilic nanosilica in asphalt. From conventional physical properties test and rheological performance test, hydrophobic nanosilica could weaken the temperature susceptibility of bitumen observably. From DSR test, hydrophobic nanosilica modified asphalt had a lower sensitivity and dependence on temperature and frequency than hydrophilic nanosilica modified asphalt. The Cole-Cole diagrams indicated that hydrophobic nanosilica exhibited good compatibility with asphalt compared with hydrophilic nanosilica. Newly formed chemical bonds were found in the hydrophobic nanosilica modified asphalt and its mixture with stone according to SEM test, FTIR test, and DSC test, which is the biggest difference from the modification mechanism of hydrophilic nanosilica modified asphalt. Through static and dynamic creep test, it found that the addition of hydrophobic nanosilica can significantly reduce the creep strain at the same temperature. PMID- 30463233 TI - Effects of Different Grazing Intensities on Soil C, N, and P in an Alpine Meadow on the Qinghai-Tibetan Plateau, China. AB - Inappropriate grazing management is one of the most common causes of grassland degradation, and thus, an assessment of soil properties under different grazing intensities is critical for understanding its effects on ecosystem nutrient cycling and for formulating appropriate management strategies. However, the responses of certain main elements, including soil carbon, nitrogen, and phosphorus, to grazing in alpine meadow ecosystems remain insufficiently clarified. Here, we measured carbon, nitrogen, and phosphorus contents in the topmost 30 cm of soil in an alpine meadow under three grazing intensities (light, moderate, and heavy) and found clear differences in soil physical and chemical properties among different grazing intensities and soil layers. As grazing intensity increased, soil water content, carbon and nitrogen contents and stocks, and carbon to phosphorus and nitrogen to phosphorus ratios decreased, whereas soil bulk density increased. However, soil phosphorus and carbon to nitrogen ratio remained stable. Our findings highlight the negative impacts of heavy grazing intensity, in terms of soil carbon and nitrogen loss and phosphorus mineralization. Moreover, we emphasize that further related studies are necessary to gain a more comprehensive understanding of the effects of grazing on grassland ecosystems, and thereby provide information for sustainable management practices and eco-compensation policies. PMID- 30463235 TI - Association of Candidate Genes with Response to Heat and Newcastle Disease Virus. AB - Newcastle disease is considered the number one disease constraint to poultry production in low and middle-income countries, however poultry that is raised in resource-poor areas often experience multiple environmental challenges. Heat stress has a negative impact on production, and immune response to pathogens can be negatively modulated by heat stress. Candidate genes and regions chosen for this study were based on previously reported associations with response to immune stimulants, pathogens, or heat, including: TLR3, TLR7, MX, MHC-B (major histocompatibility complex, gene complex), IFI27L2, SLC5A1, HSPB1, HSPA2, HSPA8, IFRD1, IL18R1, IL1R1, AP2A2, and TOLLIP. Chickens of a commercial egg-laying line were infected with a lentogenic strain of NDV (Newcastle disease virus); half the birds were maintained at thermoneutral temperature and the other half were exposed to high ambient temperature before the NDV challenge and throughout the remainder of the study. Phenotypic responses to heat, to NDV, or to heat + NDV were measured. Selected SNPs (single nucleotide polymorphisms) within 14 target genes or regions were genotyped; and genotype effects on phenotypic responses to NDV or heat + NDV were tested in each individual treatment group and the combined groups. Seventeen significant haplotype effects, among seven genes and seven phenotypes, were detected for response to NDV or heat or NDV + heat. These findings identify specific genetic variants that are associated with response to heat and/or NDV which may be useful in the genetic improvement of chickens to perform favorably when faced with pathogens and heat stress. PMID- 30463237 TI - Hypoxia and Oxidative Stress Are Associated with Reduced Fetal Growth in Twin and Undernourished Sheep Pregnancies. AB - Low birth weight has profound implications for perinatal mortality and morbidity in lambs, causing higher mortality and lower growth potential. Low birth weight, as a consequence of fetal growth restriction, occurs in undernourished and multiple pregnancies, where hypoxia and oxidative stress could play a critical role. Our aim was to establish the effects of nutritional deprivation and pregnancy rank on fetal growth, oxygenation, and oxidative status in sheep pregnancies under extensive Patagonian conditions. At 30 days after mating, single- and twin-bearing ewes were offered only natural pasture (undernutrition group) or natural pasture plus concentrate supplementation (well-nourished group). At day 140 of gestation, blood gases and redox status were evaluated in venous cord blood, and fetal biometric characteristics were obtained after cesarean section. Both maternal undernutrition and twinning led to decreased oxygen supply to the fetuses (p = 0.016 and p = 0.050, respectively), which was associated with decreased intrauterine growth (r = 0.446, p < 0.01). Moreover, twinning increased oxidative stress in cord blood (p < 0.05), which might also contribute to fetal growth restriction. These results reinforce the importance of maternal nutrition, especially for those ewes bearing multiples, and opens new possibilities for nutritional or antioxidant interventions for preventing fetal hypoxia and oxidative stress. PMID- 30463236 TI - Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents. AB - Specific modifications of colchicine followed by synthesis of its analogues have been tested in vitro with the objective of lowering colchicine toxicity. Our previous studies have clearly shown the anticancer potential of double-modified colchicine derivatives in C-7 and C-10 positions. Here, a series of novel triple modified colchicine derivatives is reported. They have been obtained following a four-step strategy. In vitro cytotoxicity of these compounds has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo, and LoVo/DX). Additionally, the mode of binding of the synthesized compounds was evaluated in silico using molecular docking to a 3D structure of beta-tubulin based on crystallographic data from the Protein Data Bank and homology methodology. Binding free energy estimates, binding poses, and MlogP values of the compounds were obtained. All triple-modified colchicine derivatives were shown to be active at nanomolar concentrations against three of the investigated cancer cell lines (A549, MCF-7, LoVo). Four of them also showed higher potency against tumor cells over normal cells as confirmed by their high selectivity index values. A vast majority of the synthesized derivatives exhibited several times higher cytotoxicity than colchicine, doxorubicin, and cisplatin. PMID- 30463238 TI - pH-Sensitive Poly(beta-amino ester)s Nanocarriers Facilitate the Inhibition of Drug Resistance in Breast Cancer Cells. AB - Multidrug resistance (MDR) remains an unmet challenge in chemotherapy. Stimuli responsive nanocarriers emerge as a promising tool to overcome MDR. Herein, pH sensitive poly(beta-amino ester)s polymers (PHP)-based micellar nanoparticles were synthesized for enhanced doxorubicin (DOX) delivery in drug resistant breast cancer MCF-7/ADR cells. DOX-loaded PHP micelles showed rapid cell-internalization and lysosomal escape in MCF-7/ADR cells. The cytotoxicity assays showed relatively higher cell inhibition of DOX-loaded PHP micelles than that of free DOX against MCF-7/ADR cells. Further mechanistic studies showed that PHP micelles were able to inhibit P-glycoprotein (P-gp) activity by lowering mitochondrial membrane potentials and ATP levels. These results suggested that the enhanced antitumor effect might be attributed to PHP-mediated lysosomal escape and drug efflux inhibition. Therefore, PHP would be a promising pH-responsive nanocarrier for enhanced intracellular drug delivery and overcoming MDR in cancer cells. PMID- 30463239 TI - Mechanisms of TQ-6, a Novel Ruthenium-Derivative Compound, against Lipopolysaccharide-Induced In Vitro Macrophage Activation and Liver Injury in Experimental Mice: The Crucial Role of p38 MAPK and NF-kappaB Signaling. AB - Several studies have reported that metal complexes exhibit anti-inflammatory activities; however, the molecular mechanism is not well understood. In this study, we used a potent ruthenium (II)-derived compound, [Ru(eta6-cymene)2-(1H benzoimidazol-2-yl)-quinoline Cl]BF4 (TQ-6), to investigate the molecular mechanisms underlying the anti-inflammatory effects against lipopolysaccharide (LPS)-induced macrophage activation and liver injury in mice. Treating LPS stimulated RAW 264.7 cells with TQ-6 suppressed nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression in a concentration-dependent manner. The LPS-induced expression of tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) were reduced in TQ-6-treated cells. TQ-6 suppressed, LPS-stimulated p38 MAPK phosphorylation, IkappaBalpha degradation, and p65 nuclear translocation in cells. Consistent with the in vitro studies, TQ 6 also suppressed the expression of iNOS, TNF-alpha, and p65 in the mouse model with acute liver injury induced by LPS. The present study showed that TQ-6 could protect against LPS-induced in vitro inflammation in macrophage and in vivo liver injury in mice, and suggested that NF-kappaB could be a promising target for protecting against LPS-induced inflammation and liver injury by TQ-6. Therefore, TQ-6 can be a potential therapeutic agent for treating inflammatory diseases. PMID- 30463240 TI - Template-Based Step Detection with Inertial Measurement Units. AB - This article presents a method for step detection from accelerometer and gyrometer signals recorded with Inertial Measurement Units (IMUs). The principle of our step detection algorithm is to recognize the start and end times of the steps in the signal thanks to a predefined library of templates. The algorithm is tested on a database of 1020 recordings, composed of healthy subjects and patients with various neurological or orthopedic troubles. Simulations on more than 40,000 steps show that the template-based method achieves remarkable results with a 98% recall and a 98% precision. The method adapts well to pathological subjects and can be used in a medical context for robust step estimation and gait characterization. PMID- 30463241 TI - Optimization of Sample Preparation for Detection of 10 Phthalates in Non Alcoholic Beverages in Northern Vietnam. AB - A novel method was developed for the sensitive, cheap and fast quantitation of 10 phthalates in non-alcoholic beverages by liquid-liquid extraction (LLE) combined with gas chromatography tandem mass spectrometry (GC-MS/MS). The best results were obtained when n-hexane was used as extraction solvent. A central composite design (CCD) was applied to select the most appreciated operating condition. The method performance was evaluated according to the SANTE/11945/2015 guidelines and was linear in the 0.1 to 200 ug/L range for 10 phthalate compounds, with r2 > 0.996 and individual residuals <15%. Repeatability (RSDr), within-laboratory reproducibility (RSDwr), and the trueness range were from 2.7 to 9.1%, from 3.4 to 14.3% and from 91.5 to 118.1%, respectively. The limit of detection (LOD) was between 0.5 to 1.0 ng/L and the limit of quantitation (LOQ) was between 1.5 to 3.0 ng/L for all 10 compounds. The developed method was successfully applied to the analysis of non-alcoholic beverages. PMID- 30463243 TI - Multiclass Radio Frequency Interference Detection and Suppression for SAR Based on the Single Shot MultiBox Detector. AB - Radio frequency interference (RFI) is known to jam synthetic aperture radar (SAR) measurements, severely degrading the SAR imaging quality. The suppression of RFI in SAR echo signals is usually an underdetermined blind source separation problem. In this paper, we propose a novel method for multiclass RFI detection and suppression based on the single shot multibox detector (SSD). First, an echo interference dataset is established by randomly combining the target signal with various types of RFI in a simulation, and the time-frequency form of the dataset is obtained by utilizing the short-time Fourier transform (STFT). Next, the time frequency dataset acts as input data to train the SSD and obtain a network that is capable of detecting, identifying and estimating the interference. Finally, all of the interference signals are exactly reconstructed based on the prediction results of the SSD and mitigated by an adaptive filter. The proposed method can effectively increase the signal-to-interference-noise ratio (SINR) of RFI contaminated SAR echoes and improve the peak sidelobe ratio (PSLR) after pulse compression. The simulated experimental results validate the effectiveness of the proposed method. PMID- 30463242 TI - Association between Sleep Quality and Body Composition in Sedentary Middle-Aged Adults. AB - Background: Ageing is associated with sleep pattern changes and body composition changes, which are related to several diseases. Purpose: This study aimed to analyse the association between sleep quality and an extensive set of body composition parameters (waist-hip ratio, body mass index, bone mineral content, bone mineral density, lean mass, lean mass index, fat mass, fat mass percentage, fat mass index, visceral adipose tissue) and sleep quality in sedentary middle aged adults. We also aimed to evaluate whether the possible associations accord between subjective and objective measurements of sleep quality. Methods: 74 (39 women) middle-aged sedentary adults (40-65 years old) participated in the present study. The sleep quality was assessed using the Pittsburgh sleep quality index (PSQI) scale and accelerometers. A PSQI global score more than 5 indicates poor sleep quality. Weight, height, waist and hip circumferences were measured, and body mass index and waist-hip ratio were also calculated. Body composition was assessed with a dual-energy X-ray absorptiometry scanner. Results: The PSQI global score was negatively associated with bone mineral content, bone mineral density, lean mass, lean mass index and positively associated with fat mass percentage. No association was found between accelerometer parameters and body composition variables. Conclusion: We showed that a subjective poor sleep quality was negatively associated with bone mineral content (BMC), bone mineral density (BMD), lean mass and lean mass index (LMI) whereas was positively associated with fat mass percentage in middle-aged adults. We also observed that these associations did not accord with objective sleep quality measurements. PMID- 30463245 TI - A Comparison of Waste Stability Indices for Mechanical-Biological Waste Treatment and Composting Plants. AB - Achieving high efficiency of biological waste treatment in mechanical-biological treatment (MBT) plants requires reliable methods for measuring the degree of biodegradation of organic substances. For this purpose, several physical, chemical, and biological indices are used. This paper presents respirometric activity (AT4), biogas potential (GB21), total and dissolved organic carbon (TOC and DOC, respectively), and loss on ignition (LOI) values, as well as the correlations between the indices selected for stabilized waste produced in 18 MBT plants in Poland, which use various technologies for biological processing of the organic fraction of municipal solid waste. The study confirms that there is a linear relationship between AT4 and GB21 for stabilized waste produced in MBT plants, regardless of the waste treatment technology used. It has also been found that there is a linear relationship between AT4 and the concentration of dissolved carbon in water extract from stabilized waste. This indicates that DOC can be used for monitoring the organic matter stabilization process in mechanical biological waste treatment plants. Its advantage is a shorter time needed for measurements in comparison to AT4 and GB21 tests. PMID- 30463244 TI - Renal Cell Carcinoma Is Abrogated by p53 Stabilization through Transglutaminase 2 Inhibition. AB - In general, expression of transglutaminase 2 (TGase 2) is upregulated in renal cell carcinoma (RCC), resulting in p53 instability. Previous studies show that TGase 2 binds to p53 and transports it to the autophagosome. Knockdown or inhibition of TGase 2 in RCC induces p53-mediated apoptosis. Here, we screened a chemical library for TGase 2 inhibitors and identified streptonigrin as a potential therapeutic compound for RCC. Surface plasmon resonance and mass spectroscopy were used to measure streptonigrin binding to TGase 2. Mass spectrometry analysis revealed that streptonigrin binds to the N-terminus of TGase 2 (amino acids 95-116), which is associated with inhibition of TGase 2 activity in vitro and with p53 stabilization in RCC. The anti-cancer effects of streptonigrin on RCC cell lines were demonstrated in cell proliferation and cell death assays. In addition, a single dose of streptonigrin (0.2 mg/kg) showed marked anti-tumor effects in a preclinical RCC model by stabilizing p53. Inhibition of TGase 2 using streptonigrin increased p53 stability, which resulted in p53-mediated apoptosis of RCC. Thus, targeting TGase 2 may be a new therapeutic approach to RCC. PMID- 30463246 TI - Identification of Arenin, a Novel Kunitz-Like Polypeptide from the Skin Secretions of Dryophytes arenicolor. AB - Amphibian skin secretions are enriched with complex cocktails of bioactive molecules such as proteins, peptides, biogenic amines, alkaloids guanidine derivatives, steroids and other minor components spanning a wide spectrum of pharmacological actions exploited for centuries in folk medicine. This study presents evidence on the protein profile of the skin secretions of the canyon tree frog, Dryophytes arenicolor. At the same time, it presents the reverse-phase liquid chromatography isolation, mass spectrometry characterization and identification at mRNA level of a novel 58 amino acids Kunitz-like polypeptide from the skin secretions of Dryophytes arenicolor, arenin. Cell viability assays performed on HDFa, CaCo2 and MCF7 cells cultured with different concentrations of arenin showed a discrete effect at low concentrations (2, 4, 8 and 16 ug/mL) suggesting a multi-target interaction in a hormetic-like dose-response. Further work is required to investigate the mechanisms underlying the variable effect on cell viability produced by different concentrations of arenin. PMID- 30463247 TI - Atrial Fibrillation Predicts Long-Term Outcome after Transcatheter Edge-to-Edge Mitral Valve Repair by MitraClip Implantation. AB - Background: Atrial fibrillation is common in patients with mitral regurgitation (MR) and has a negative impact on the clinical outcome of patients with valvular heart disease. We aimed to evaluate the impact of pre-procedural atrial fibrillation on the long-term clinical outcomes of patients with MR undergoing transcatheter mitral valve repair by MitraClip implantation. Methods: We analysed 355 consecutive patients with and without atrial fibrillation with symptomatic, severe MR and inoperability or high surgical risk undergoing MitraClip implantation in a three-year follow-up. Results: In patients with pre-procedural atrial fibrillation undergoing MitraClip implantation, we found advanced age, higher baseline NT-pro-BNP levels, increased left atrial diameter, and higher rate of severe tricuspid regurgitation, compared to patients with sinus rhythm. In the three-year follow-up after MitraClip implantation, mortality and major adverse cardiovascular and cerebral events (MACCE) occur significantly more often in patients with atrial fibrillation, compared to patients without atrial fibrillation. Multivariate regression analysis confirmed atrial fibrillation (hazard ratio 2.39, 95%-confidence interval 1.06-5.41, p = 0.036) as an independent predictor for three-year-mortality after MitraClip implantation. Conclusions: Atrial fibrillation is an independent predictor for long-term mortality after MitraClip implantation. We demonstrate the association of atrial fibrillation with mortality and MACCE in the long-term follow-up of patients undergoing MitraClip implantation. PMID- 30463248 TI - Preparation of Polybenzimidazole Hollow-Fiber Membranes for Reverse Osmosis and Nanofiltration by Changing the Spinning Air Gap. AB - High-performance polybenzimidazole (PBI) hollow-fiber membranes (HFMs) were fabricated through a continuous dry-jet wet spinning process at SRI International. By adjusting the spinning air gap from 4" (10.2 cm) to 0.5" (1.3 cm), the HFM pore sizes were enlarged dramatically without any significant change of the fiber dimensional size and barrier layer thickness. When fabricated with an air gap of 2.5" (6.4 cm) and a surface modified by NaClO solution, the PBI HFM performance was comparable to that of a commercial reverse osmosis (RO) HFM product from Toyobo in terms of salt (NaCl) rejection and water permeability. The PBI RO HFM was positively surface charged in acidic conditions (pH < 7), which enhanced salt rejection via the Donnan effect. With an air gap of 1.5" (3.8 cm), the PBI HFM rejected MgSO4 and Na2SO4 above 95%, a result that compares favorably with that achieved by nanofiltration. In addition, the PBI HFM has a defect-free structure with an ultra-thin barrier layer and porous sublayer. We believe PBI HFMs are ideal for water purification and can be readily commercialized. PMID- 30463250 TI - Role of Synbiotics Containing d-Allulose in the Alteration of Body Fat and Hepatic Lipids in Diet-Induced Obese Mice. AB - The effects of allulose and two probiotic species on diet-induced obese (DIO) mice were investigated. Lactobacillus sakei LS03 (108 cfu/day) and Leuconostoc kimchii GJ2 (108 cfu/day) were used as probiotics, and allulose (AL) as a prebiotic. The synergistic effect of prebiotics and probiotics in improving obesity was evaluated. Orally fed Lactobacillus sakei LS03 (LS) or Leuconostoc kimchii GJ2 (GJ), significantly decreased hepatic triglyceride (TG) and fatty acid (FA) compared to the high-fat diet (HFD) control. AL markedly decreased visceral adiposity and pro-inflammatory adipokines (leptin and resistin) and cytokines (IL-6 and IL-1beta) as well as hepatic TG and FA. In addition, AL exerted synergic effects with probiotics (LS and/or GJ) on the reduction of visceral white adipose tissue (WAT), associated with a decreased leptin: adiponectin ratio. There was no significant differences between the AL-SL and AL group, allulose and GJ combination (AL-GJ) was more effective than allulose in improving dyslipidemia, and decreasing WAT weight and hepatic FA, suggesting allulose may act as a favorable prebiotic for GJ supplement than LS. Combination of allulose with LS and GJ supplementation (AL-LSGJ) was the most effective for improving obesity related complications among the synbiotics groups containing allulose. In conclusion, this study demonstrated that the synbiotic mixture with allulose was more effective in suppressing diet-induced obese (DIO) and its complications via the regulation of lipid metabolism, than the probiotics or allulose alone, suggesting allulose may act as a prebiotic for the two probiotics tested in the study. This new synbiotic mixture with allulose may help ameliorate the deleterious effects of diet-induced obesity and contribute to the growth of the food industry. PMID- 30463249 TI - New Hope in Brain Glioma Surgery: The Role of Intraoperative Ultrasound. A Review. AB - Maximal safe resection represents the gold standard for surgery of malignant brain tumors. As regards gross-total resection, accurate localization and precise delineation of the tumor margins are required. Intraoperative diagnostic imaging (Intra-Operative Magnetic Resonance-IOMR, Intra-Operative Computed Tomography IOCT, Intra-Operative Ultrasound-IOUS) and dyes (fluorescence) have become relevant in brain tumor surgery, allowing for a more radical and safer tumor resection. IOUS guidance for brain tumor surgery is accurate in distinguishing tumor from normal parenchyma, and it allows a real-time intraoperative visualization. We aim to evaluate the role of IOUS in gliomas surgery and to outline specific strategies to maximize its efficacy. We performed a literature research through the Pubmed database by selecting each article which was focused on the use of IOUS in brain tumor surgery, and in particular in glioma surgery, published in the last 15 years (from 2003 to 2018). We selected 39 papers concerning the use of IOUS in brain tumor surgery, including gliomas. IOUS exerts a notable attraction due to its low cost, minimal interruption of the operational flow, and lack of radiation exposure. Our literature review shows that increasing the use of ultrasound in brain tumors allows more radical resections, thus giving rise to increases in survival. PMID- 30463251 TI - Self-Renewal and Differentiation of Adipose-Derived Stem Cells (ADSCs) Stimulated by Multi-Axial Tensile Strain in a Pneumatic Microdevice. AB - Adipose-derived stem cells (ADSCs) were suggested for treating degenerative osteoarthritis, suppressing inflammatory responses, and repairing damaged soft tissues. Moreover, the ADSCs have the potential to undergo self-renewal and differentiate into bone, tendon, cartilage, and ligament. Recently, investigation of the self-renewal and differentiation of the ADSCs has become an attractive area. In this work, a pneumatic microdevice has been developed to study the gene expression of the ADSCs after the stimulation of multi-axial tensile strain. The ADSCs were cultured on the microdevice and experienced multi-axial tensile strain during a three-day culture course. Self-renewal and differentiation abilities were investigated by mRNA expressions of NANOG, sex determining region Y-box 2 (SOX2), octamer-binding transcription factor 4 (OCT4), sex determining region Y box9 (SOX9), peroxisome proliferator-activated receptor gamma (PPAR-gamma), and runt-related transcription factor 2 (RUNX2). The result showed that the genes related self-renewal were significantly up-regulated after the tensile stimulation. Higher proliferation ratio of the ADSCs was also shown by cell viability assay. The microdevice provides a promising platform for cell-based study under mechanical tensile stimulation. PMID- 30463253 TI - Cystine/Glutamate Antiporter and Aripiprazole Compensate NMDA Antagonist-Induced Dysfunction of Thalamocortical L-Glutamatergic Transmission. AB - To explore pathophysiology of schizophrenia, this study analyzed the regulation mechanisms that are associated with cystine/glutamate antiporter (Sxc), group-II (II-mGluR), and group-III (III-mGluR) metabotropic glutamate-receptors in thalamo cortical glutamatergic transmission of MK801-induced model using dual-probe microdialysis. L-glutamate release in medial pre-frontal cortex (mPFC) was increased by systemic- and local mediodorsal thalamic nucleus (MDTN) administrations of MK801, but was unaffected by local administration into mPFC. Perfusion into mPFC of activators of Sxc, II-mGluR, and III-mGluR, and into the MDTN of activators of Sxc, II-mGluR, and GABAA receptor inhibited MK801-evoked L glutamate release in mPFC. Perfusion of aripiprazole (APZ) into MDTN and mPFC also inhibited systemic MK801-evoked L-glutamate release in mPFC. Inhibition of II-mGluR in mPFC and MDTN blocked inhibitory effects of Sxc-activator and APZ on MK801-evoked L-glutamate release; however, their inhibitory effects were blocked by the inhibition of III-mGluR in mPFC but not in MDTN. These results indicate that reduced activation of the glutamate/NMDA receptor (NMDAR) in MDTN enhanced L glutamate release in mPFC possibly through GABAergic disinhibition in MDTN. Furthermore, MDTN-mPFC glutamatergic transmission receives inhibitory regulation of Sxc/II-mGluR/III-mGluR functional complex in mPFC and Sxc/II-mGluR complex in MDTN. Established antipsychotic, APZ inhibits MK801-evoked L-glutamate release through the activation of Sxc/mGluRs functional complexes in both MDTN and mPFC. PMID- 30463252 TI - Milk Other Than Breast Milk and the Development of Asthma in Children 3 Years of Age. A Birth Cohort Study (2006-2011). AB - Prevalence of asthma in Australian children is amongst the highest in the world. Although breastfeeding positively influences infant immunity, early introduction of Milk Other than Breast Milk (MOTBM) may also play an important role in the development of Asthma. The aim of this study was to investigate the association between the introduction of MOTBM in the first six months after birth and the development of reported persistent asthma in 3-year olds. A sample of 1121 children was extracted from the Environments for Healthy Living longitudinal birth cohort study. Introduction of MOTBM during the first six months after birth increased almost two-fold the risk of development of persistent asthma after adjusting for other covariates (Adjusted Relative Risk (ARR): 1.71, 95% CI: 1.03 2.83, p = 0.038). This study indicates that the introduction of MOTBM in the first six months of life is a risk factor for asthma incidence among 3-year old children. This result is important in explaining the benefits of breastfeeding as part of public health interventions to encourage mothers to increase breastfeeding initiation and duration, and avoid the introduction of MOTBM in the first six months after childbirth. PMID- 30463254 TI - Mycotoxins Contaminant in Kelp: A Neglected Dietary Exposure Pathway. AB - In order to investigated current occurrence of major mycotoxins in dietary kelp in Shandong Province in Northern China, a reliable, sensitive, and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous determination of the 7 most frequent mycotoxins, including 3-acetoxy deoxynivalenol (3AcDON), 15-acetoxy deoxynivalenol (15AcDON), Deoxynivalenol (DON), Fusarenon-X (F-X), Nivalenol (NIV), T-2 toxin (T-2), and Zearalenone (ZEA). Based on optimized pretreatment and chromatographic and mass spectrometry conditions, these target analytes could be monitored with mean recoveries from 72.59~107.34%, with intra-day RSD < 9.21%, inter-day RSD < 9.09%, LOD < 5.55 MUg kg-1, and LOQ < 18.5 MUg kg-1. Approximately 43 kelp samples were detected, 3AcDON/15AcDON ranged from 15.3 to 162.5 MUg kg-1 with positive rate of 86% in Shandong Province in Northern China. Considering there were no related investigations about mycotoxin contamination in kelp, the high contamination rate of 3AcDON/15AcDON in kelp showed a neglected mycotoxin exposure pathway, which might lead to high dietary exposure risk to consumers. PMID- 30463255 TI - Solar Light Induced Photon-Assisted Synthesis of TiO2 Supported Highly Dispersed Ru Nanoparticle Catalysts. AB - Ru/TiO2 are promising heterogeneous catalysts in different key-reactions taking place in the catalytic conversion of biomass towards fuel additives, biofuels, or biochemicals. TiO2 supported highly dispersed nanometric-size metallic Ru catalysts were prepared at room temperature via a solar light induced photon assisted one-step synthesis in liquid phase, far smaller Ru nanoparticles with sharper size distribution being synthesized when compared to the catalysts that were prepared by impregnation with thermal reduction in hydrogen. The underlying strategy is based on the redox photoactivity of the TiO2 semi-conductor support under solar light for allowing the reduction of metal ions pre-adsorbed at the host surface by photogenerated electrons from the conduction band of the semi conductor in order to get a fine control in terms of size distribution and dispersion, with no need of chemical reductant, final thermal treatment, or external hydrogen. Whether acetylacetonate or chloride was used as precursor, 0.6 nm sub-nanometric metallic Ru particles were synthesized on TiO2 with a sharp size distribution at a low loading of 0.5 wt.%. Using the chloride precursor was necessary for preparing Ru/TiO2 catalysts with a 0.8 nm sub-nanometric mean particle size at 5 wt.% loading, achieved in basic conditions for benefitting from the enhanced adsorption between the positively-charged chloro-complexes and the negatively-charged TiO2 surface. Remarkably, within the 0.5-5 wt.% range, the Ru content had only a slight influence on the sub-nanometric particle size distribution, thanks to the implementation of suitable photo-assisted synthesis conditions. We demonstrated further that a fine control of the metal Ru nanoparticle size on the TiO2 support was possible via a controlled nanocluster growth under irradiation, while the nanoparticles revealed a good resistance to thermal sintering. PMID- 30463256 TI - Endothelial Microsomal Prostaglandin E Synthetase-1 Upregulates Vascularity and Endothelial Interleukin-1beta in Deteriorative Progression of Experimental Autoimmune Encephalomyelitis. AB - Microsomal prostaglandin E synthetase-1 (mPGES-1) is an inducible terminal enzyme for the production of prostaglandin E2 (PGE2). In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, mPGES-1 is induced in vascular endothelial cells (VECs) around inflammatory foci and facilitates inflammation, demyelination, and paralysis. Therefore, we investigated the role of CD31-positive VECs in mPGES-1-mediated EAE aggravation using immunohistochemical analysis and imaging of wild-type (wt) and mPGES-1 deficient (mPGES-1-/-) mice. We demonstrated that EAE induction facilitated vascularity in inflammatory lesions in the spinal cord, and this was significantly higher in wt mice than in mPGES-1-/- mice. In addition, endothelial interleukin-1beta (IL-1beta) production was significantly higher in wt mice than in mPGES-1-/- mice. Moreover, endothelial PGE2 receptors (E-prostanoid (EP) receptors EP1-4) were expressed after EAE induction, and IL-1beta was induced in EP receptor-positive VECs. Furthermore, IL-1 receptor 1 expression on VECs was increased upon EAE induction. Thus, increased vascularity is one mechanism involved in EAE aggravation induced by mPGES-1. Furthermore, mPGES-1 facilitated the autocrine function of VECs upon EP receptor induction and IL-1beta production, modulating mPGES-1 induction in EAE. PMID- 30463257 TI - Comparative Characterization of the Complete Mitochondrial Genomes of the Three Apple Snails (Gastropoda: Ampullariidae) and the Phylogenetic Analyses. AB - The apple snails Pomacea canaliculata, Pomacea diffusa and Pomacea maculate (Gastropoda: Caenogastropoda: Ampullariidae) are invasive pests causing massive economic losses and ecological damage. We sequenced and characterized the complete mitochondrial genomes of these snails to conduct phylogenetic analyses based on comparisons with the mitochondrial protein coding sequences of 47 Caenogastropoda species. The gene arrangements, distribution and content were canonically identical and consistent with typical Mollusca except for the tRNA Gln absent in P. diffusa. An identifiable control region (d-loop) was absent. Bayesian phylogenetic analysis indicated that all the Ampullariidae species clustered on the same branch. The genus Pomacea clustered together and then with the genus Marisa. The orders Architaenioglossa and Sorbeoconcha clustered together and then with the order Hypsogastropoda. Furthermore, the intergenic and interspecific taxonomic positions were defined. Unexpectedly, Ceraesignum maximum, Dendropoma gregarium, Eualetes tulipa and Thylacodes squamigerus, traditionally classified in order Hypsogastropoda, were isolated from the order Hypsogastropoda in the most external branch of the Bayesian inference tree. The divergence times of the Caenogastropoda indicated that their evolutionary process covered four geological epochs that included the Quaternary, Neogene, Paleogene and Cretaceous periods. This study will facilitate further investigation of species identification to aid in the implementation of effective management and control strategies of these invasive species. PMID- 30463258 TI - Modulation of Enterohaemorrhagic Escherichia coli Survival and Virulence in the Human Gastrointestinal Tract. AB - Enterohaemorrhagic Escherichia coli (EHEC) is a major foodborne pathogen responsible for human diseases ranging from diarrhoea to life-threatening complications. Survival of the pathogen and modulation of virulence gene expression along the human gastrointestinal tract (GIT) are key features in bacterial pathogenesis, but remain poorly described, due to a paucity of relevant model systems. This review will provide an overview of the in vitro and in vivo studies investigating the effect of abiotic (e.g., gastric acid, bile, low oxygen concentration or fluid shear) and biotic (e.g., gut microbiota, short chain fatty acids or host hormones) parameters of the human gut on EHEC survival and/or virulence (especially in relation with motility, adhesion and toxin production). Despite their relevance, these studies display important limitations considering the complexity of the human digestive environment. These include the evaluation of only one single digestive parameter at a time, lack of dynamic flux and compartmentalization, and the absence of a complex human gut microbiota. In a last part of the review, we will discuss how dynamic multi-compartmental in vitro models of the human gut represent a novel platform for elucidating spatial and temporal modulation of EHEC survival and virulence along the GIT, and provide new insights into EHEC pathogenesis. PMID- 30463259 TI - Structural Damage Identification of Bridges from Passing Test Vehicles. AB - This paper presents two approaches for the structural damage identification of a bridge from the dynamic response recorded from a test vehicle during its passage over the bridge. Using the acceleration response recorded by the vibration sensors mounted on a test vehicle during its passage over the bridge, along with the computed displacement response, the bending stiffness of the bridge can be determined using either: (1) the frequency-domain method based on the improved directed stiffness method with the identified frequency and corresponding mode shape, or (2) the time-domain method based on the residual vector of the least squares method with a fourth-order displacement moment. By comparing the bending stiffness values identified from the vehicle-collected data for the bridge under the undamaged and damaged states that are monitored regularly by the test vehicle, the bridge damage location and severity can be identified. Through numerical simulations and field tests, the present approaches are shown to be effective and feasible. PMID- 30463260 TI - Conversion of Medium-Sized Lactams to alpha-Vinyl or alpha-Acetylenyl Azacycles via N,O-Acetal TMS Ethers. AB - alpha-Vinyl or alpha-acetylenyl azacycles were easily synthesized from 7- to 9 membered lactams and 6- to 9-membered lactams via N,O-acetal trimethylsilyl (TMS) ethers. Organocopper and organostannane reagents afforded reasonable yields for the respective N-acyliminium ion vinylation and acetylenylation intermediates generated from N,O-acetal TMS ethers in the presence of a Lewis acid. PMID- 30463261 TI - VINS-MKF:A Tightly-Coupled Multi-Keyframe Visual-Inertial Odometry for Accurate and Robust State Estimation. AB - State estimation is crucial for robot autonomy, visual odometry (VO) has received significant attention in the robotics field because it can provide accurate state estimation. However, the accuracy and robustness of most existing VO methods are degraded in complex conditions, due to the limited field of view (FOV) of the utilized camera. In this paper, we present a novel tightly-coupled multi-keyframe visual-inertial odometry (called VINS-MKF), which can provide an accurate and robust state estimation for robots in an indoor environment. We first modify the monocular ORBSLAM (Oriented FAST and Rotated BRIEF Simultaneous Localization and Mapping) to multiple fisheye cameras alongside an inertial measurement unit (IMU) to provide large FOV visual-inertial information. Then, a novel VO framework is proposed to ensure the efficiency of state estimation, by adopting a GPU (Graphics Processing Unit) based feature extraction method and parallelizing the feature extraction thread that is separated from the tracking thread with the mapping thread. Finally, a nonlinear optimization method is formulated for accurate state estimation, which is characterized as being multi-keyframe, tightly-coupled and visual-inertial. In addition, accurate initialization and a novel MultiCol-IMU camera model are coupled to further improve the performance of VINS-MKF. To the best of our knowledge, it's the first tightly-coupled multi keyframe visual-inertial odometry that joins measurements from multiple fisheye cameras and IMU. The performance of the VINS-MKF was validated by extensive experiments using home-made datasets, and it showed improved accuracy and robustness over the state-of-art VINS-Mono. PMID- 30463262 TI - Natural Killer Cell Dysfunction in Hepatocellular Carcinoma: Pathogenesis and Clinical Implications. AB - Hepatocellular carcinoma (HCC) is currently the third leading cause of malignancy related mortalities worldwide. Natural killer (NK) cells are involved in the critical role of first line immunological defense against cancer development. Defects in NK cell functions are recognized as important mechanisms for immune evasion of tumor cells. NK cell function appears to be attenuated in HCC, and many previous reports suggested that NK cells play a critical role in controlling HCC, suggesting that boosting the activity of dysfunctional NK cells can enhance tumor cell killing. However, the detailed mechanisms of NK cell dysfunction in tumor microenvironment of HCC remain largely unknown. A better understanding of the mechanisms of NK cell dysfunction in HCC will help in the NK cell-mediated eradication of cancer cells and prolong patient survival. In this review, we describe the various mechanisms underlying human NK cell dysfunction in HCC. Further, we summarize current advances in the approaches to enhance endogenous NK cell function and in adoptive NK cell therapies, to cure this difficult-to-treat cancer. PMID- 30463263 TI - Pencil Lead as a Material for Microfluidic 3D-Electrode Assemblies. AB - We present an electrochemical, microfluidic system with a working electrode based on an ordered 3D array of pencil leads. The electrode array was integrated into a plexiglass/PDMS channel. We tested the setup using a simple redox probe and compared the results with computer simulations. As a proof of concept application of the device we showed that the setup can be used for determination of dopamine concentration in physiological pH and ultrasensitive, although only qualitative, detection of p-nitrophenol with a limit of detection below 1 nmol L-1. The observed limit of detection for p-nitrophenol is not only much lower than achieved with similar methods but also sufficient for evaluation of exposure to pesticides such as methyl parathion through urinalysis. This low cost setup can be fabricated without the need for clean room facilities and in the future, due to the ordered structure of the electrode could be used to better understand the process of electroanalysis and electrode functionalization. To the best of our knowledge it is the first application of pencil leads as 3D electrochemical sensor in a microfluidic channel. PMID- 30463265 TI - Lactate Promotes Myoblast Differentiation and Myotube Hypertrophy via a Pathway Involving MyoD In Vitro and Enhances Muscle Regeneration In Vivo. AB - Lactate is a metabolic substrate mainly produced in muscles, especially during exercise. Recently, it was reported that lactate affects myoblast differentiation; however, the obtained results are inconsistent and the in vivo effect of lactate remains unclear. Our study thus aimed to evaluate the effects of lactate on myogenic differentiation and its underlying mechanism. The differentiation of C2C12 murine myogenic cells was accelerated in the presence of lactate and, consequently, myotube hypertrophy was achieved. Gene expression analysis of myogenic regulatory factors showed significantly increased myogenic determination protein (MyoD) gene expression in lactate-treated cells compared with that in untreated ones. Moreover, lactate enhanced gene and protein expression of myosin heavy chain (MHC). In particular, lactate increased gene expression of specific MHC isotypes, MHCIIb and IId/x, in a dose-dependent manner. Using a reporter assay, we showed that lactate increased promoter activity of the MHCIIb gene and that a MyoD binding site in the promoter region was necessary for the lactate-induced increase in activity. Finally, peritoneal injection of lactate in mice resulted in enhanced regeneration and fiber hypertrophy in glycerol-induced regenerating muscles. In conclusion, physiologically high lactate concentrations modulated muscle differentiation by regulating MyoD-associated networks, thereby enhancing MHC expression and myotube hypertrophy in vitro and, potentially, in vivo. PMID- 30463264 TI - Does Village Chicken-Keeping Contribute to Young Children's Diets and Growth? A Longitudinal Observational Study in Rural Tanzania. AB - There is substantial current interest in linkages between livestock-keeping and human nutrition in resource-poor settings. These may include benefits of improved diet quality, through animal-source food consumption and nutritious food purchases using livestock-derived income, and hazards of infectious disease or environmental enteric dysfunction associated with exposure to livestock feces. Particular concerns center on free-roaming chickens, given their proximity to children in rural settings, but findings to date have been inconclusive. This longitudinal study of 503 households with a child under 24 months at enrolment was conducted in villages of Manyoni District, Tanzania between May 2014, and May 2016. Questionnaires encompassed demographic characteristics, assets, livestock ownership, chicken housing practices, maternal education, water and sanitation, and dietary diversity. Twice-monthly household visits provided information on chicken numbers, breastfeeding and child diarrhea, and anthropometry was collected six-monthly. Multivariable mixed model analyses evaluated associations between demographic, socioeconomic and livestock-associated variables and (a) maternal and child diets, (b) children's height-for-age and (c) children's diarrhea frequency. Alongside modest contributions of chicken-keeping to some improved dietary outcomes, this study importantly (and of substantial practical significance if confirmed) found no indication of a heightened risk of stunting or greater frequency of diarrhea being associated with chicken-keeping or the practice of keeping chickens within human dwellings overnight. PMID- 30463266 TI - Body Mass Index and Helicobacter pylori among Obese and Non-Obese Patients in Najran, Saudi Arabia: A Case-Control Study. AB - Objective: We examine obese and non-obese patients with respect to Helicobacter pylori (H. pylori) positive-infection (HPPI) and associated factors, specifically body mass index (BMI). Methods: This study took place in the Department of Endoscopy of a central hospital in the Najran region of Saudi Arabia (SA). A total of 340 obese Saudi patients (BMI >= 30 kg/m2) who had undergone diagnostic upper endoscopy before sleeve gastrectomy, were compared with 340 age and gender matched control patients (BMI < 30 kg/m2) who had undergone diagnostic upper endoscopy for other reasons. Data collected included diagnosis of HPPI. Descriptive and multivariable binary logistic regression was conducted. Results: Mean patient age was 31.22 +/- 8.10 years, and 65% were males. The total prevalence of HPPI was 58% (95% CI = 54-61%) with obese patients presenting significantly more HPPI than non-obese patients (66% vs. 50%, OR = 1.98, 95% CI = 1.45-2.70, p < 0.0005). Age and gender did not associate significantly with HPPI (p = 0.659, 0.200, respectively) and increases in BMI associated significantly with increases in HPPI (p < 0.0005). BMI remained a significant factor in HPPI when modelled with both age and gender (OR = 1.022, 95% CI = 1.01-1.03, p < 0.0005). Conclusions: Within the limitations of this study, the significance of HPPI in obese Saudi patients residing in the Najran region in SA was demonstrated alongside the significance role of BMI in HPPI. PMID- 30463267 TI - Therapeutic Chemical Screen Identifies Phosphatase Inhibitors to Reconstitute PKB Phosphorylation and Cardiac Contractility in ILK-Deficient Zebrafish. AB - Patients with inherited dilated cardiomyopathy (DCM) often suffer from severe heart failure based on impaired cardiac contractility leading to increased morbidity and mortality. Integrin-linked kinase (ILK) as a part of the cardiac mechanical stretch sensor was found to be an essential genetic regulator of cardiac contractility. Integrin-linked kinase localizes to z-disks and costameres in vertebrate hearts and regulates the activity of the signaling molecule protein kinase B (PKB/Akt) by controlling its phosphorylation. Despite identification of several potential drug targets in the ILK signaling pathway, pharmacological treatment strategies to restore contractile function in ILK-dependent cardiomyopathies have not been established yet. In recent years, the zebrafish has emerged as a valuable experimental system to model human cardiomyopathies as well as a powerful tool for the straightforward high-throughput in vivo small compound screening of therapeutically active substances. Using the ILK deficient zebrafish heart failure mutant main squeeze (msq), which shows reduced PKB phosphorylation and thereby impaired cardiac contractile force, we identified here, in an automated small compound screen, the protein phosphatase inhibitors calyculin A and okadaic acid significantly restoring myocardial contractile function by reconstituting PKB phosphorylation in msq ILK-deficient zebrafish embryos. PMID- 30463268 TI - Bacterioneuston in Lake Baikal: Abundance, Spatial and Temporal Distribution. AB - An aquatic surface microlayer covers more than 70% of the world's surface. Our knowledge about the biology of the surface microlayer of Lake Baikal, the most ancient lake on Earth with a surface area of 31,500 km2, is still scarce. The total bacterial abundance, the number of cultured heterotrophic temporal bacteria, and the spatial distribution of bacteria in the surface microlayer and underlying waters of Lake Baikal were studied. For the first time, the chemical composition of the surface microlayer of Lake Baikal was determined. There were significant differences and a direct relationship between the total bacterial abundance in the surface microlayer and underlying waters of Lake Baikal, as well as between the number of cultured heterotrophic bacteria in studied water layers in the period of summer stratification. In the surface microlayer, the share of cultured heterotrophic bacteria was higher than in the underlying waters. The surface microlayer was characterized by enrichment with PO43-, total organic carbon and suspended particulate matter compared to underlying waters. A direct relationship was found between the number of bacteria in the surface microlayer and environmental factors, including temperature, total organic carbon and suspended particulate matter concentration. PMID- 30463269 TI - Identifying Stops and Moves in WiFi Tracking Data. AB - There are multiple methods for tracking individuals, but the classical ones such as using GPS or video surveillance systems do not scale or have large costs. The need for large-scale tracking, for thousands or even millions of individuals, over large areas such as cities, requires the use of alternative techniques. WiFi tracking is a scalable solution that has gained attention recently. This method permits unobtrusive tracking of large crowds, at a reduced cost. However, extracting knowledge from the data gathered through WiFi tracking is not simple, due to the low positional accuracy and the dependence on signals generated by the tracked device, which are irregular and sparse. To facilitate further data analysis, we can partition individual trajectories into periods of stops and moves. This abstraction level is fundamental, and it opens the way for answering complex questions about visited locations or even social behavior. Determining stops and movements has been previously addressed for tracking data gathered using GPS. GPS trajectories have higher positional accuracy at a fixed, higher frequency as compared to trajectories obtained through WiFi. However, even with the increase in accuracy, the problem, of separating traces in periods of stops and movements, remains similar to the one we encountered for WiFi tracking. In this paper, we study three algorithms for determining stops and movements for GPS based datasets and explore their applicability to WiFi-based data. We propose possible improvements to the best-performing algorithm considering the specifics of WiFi tracking data. PMID- 30463270 TI - Towards the Internet of Flying Robots: A Survey. AB - The Internet of Flying Robots (IoFR) has received much attention in recent years thanks to the mobility and flexibility of flying robots. Although a lot of research has been done, there is a lack of a comprehensive survey on this topic. This paper analyzes several typical problems in designing IoFR for real applications, including wireless communication support, monitoring targets of interest, serving a wireless sensor network, and collaborating with ground robots. In particular, an overview of the existing publications on the coverage problem, connectivity of flying robots, energy capacity limitation, target searching, path planning, flying robot navigation with collision avoidance, etc., is presented. Beyond the discussion of these available approaches, some shortcomings of them are indicated and some promising future research directions are pointed out. PMID- 30463271 TI - Actions of Brain-Derived Neurotrophin Factor in the Neurogenesis and Neuronal Function, and Its Involvement in the Pathophysiology of Brain Diseases. AB - It is well known that brain-derived neurotrophic factor, BDNF, has an important role in a variety of neuronal aspects, such as differentiation, maturation, and synaptic function in the central nervous system (CNS). BDNF stimulates mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), phosphoinositide-3kinase (PI3K), and phospholipase C (PLC)-gamma pathways via activation of tropomyosin receptor kinase B (TrkB), a high affinity receptor for BDNF. Evidence has shown significant contributions of these signaling pathways in neurogenesis and synaptic plasticity in in vivo and in vitro experiments. Importantly, it has been demonstrated that dysfunction of the BDNF/TrkB system is involved in the onset of brain diseases, including neurodegenerative and psychiatric disorders. In this review, we discuss actions of BDNF and related signaling molecules on CNS neurons, and their contributions to the pathophysiology of brain diseases. PMID- 30463272 TI - Mycobacterium tuberculosis ClpC1 N-Terminal Domain Is Dispensable for Adaptor Protein-Dependent Allosteric Regulation. AB - ClpC1 hexamers couple the energy of ATP hydrolysis to unfold and, subsequently, translocate specific protein substrates into the associated ClpP protease. Substrate recognition by ATPases associated with various cellular activities (AAA+) proteases is driven by the ATPase component, which selectively determines protein substrates to be degraded. The specificity of these unfoldases for protein substrates is often controlled by an adaptor protein with examples that include MecA regulation of Bacillus subtilis ClpC or ClpS-mediated control of Escherichia coli ClpA. No adaptor protein-mediated control has been reported for mycobacterial ClpC1. Using pulldown and stopped-flow fluorescence methods, we report data demonstrating that Mycobacterium tuberculosis ClpC1 catalyzed unfolding of an SsrA-tagged protein is negatively impacted by association with the ClpS adaptor protein. Our data indicate that ClpS-dependent inhibition of ClpC1 catalyzed SsrA-dependent protein unfolding does not require the ClpC1 N terminal domain but instead requires the presence of an interaction surface located in the ClpC1 Middle Domain. Taken together, our results demonstrate for the first time that mycobacterial ClpC1 is subject to adaptor protein-mediated regulation in vitro. PMID- 30463273 TI - Variation in Cold-Related Mortality in England Since the Introduction of the Cold Weather Plan: Which Areas Have the Greatest Unmet Needs? AB - : The Cold Weather Plan (CWP) in England was introduced to prevent the adverse health effects of cold weather; however, its impact is currently unknown. This study characterizes cold-related mortality and fuel poverty at STP (Sustainability and Transformation Partnership) level, and assesses changes in cold risk since the introduction of the CWP. Time series regression was used to estimate mortality risk for up to 28 days following exposure. Area level fuel poverty was used to indicate mitigation against cold exposure and mapped alongside area level risk. We found STP variations in mortality risk, ranging from 1.74, 1.44-2.09 (relative risk (RR), 95% CI) in Somerset, to 1.19, 1.01-1.40 in Cambridge and Peterborough. Following the introduction of the CWP, national level mortality risk declined significantly in those aged 0-64 (1.34, 1.23-1.45, to 1.09, 1.00-1.19), but increased significantly among those aged 75+ (1.36, 1.28 1.44, to 1.58, 1.47-1.70) and for respiratory conditions (1.78, 1.56-2.02, to 2.4, 2.10-2.79). We show how spatial variation in cold mortality risk has increased since the introduction of the CWP, which may reflect differences in implementation of the plan. Combining risk with fuel poverty information identifies 14 STPs with the greatest need to address the cold effect, and that would gain most from enhanced CWP activity or additional intervention measures. PMID- 30463275 TI - Investigating the Role of MicroRNA and Transcription Factor Co-regulatory Networks in Multiple Sclerosis Pathogenesis. AB - MicroRNAs (miRNAs) and transcription factors (TFs) play key roles in complex multifactorial diseases like multiple sclerosis (MS). Starting from the miRNomic profile previously associated with a cohort of pediatric MS (PedMS) patients, we applied a combined molecular and computational approach in order to verify published data in patients with adult-onset MS (AOMS). Six out of the 13 selected miRNAs (miR-320a, miR-125a-5p, miR-652-3p, miR-185-5p, miR-942-5p, miR-25-3p) were significantly upregulated in PedMS and AOMS patients, suggesting that they may be considered circulating biomarkers distinctive of the disease independently from age. A computational and unbiased miRNA-based screening of target genes not necessarily associated to MS was then performed in order to provide an extensive view of the genetic mechanisms underlying the disease. A comprehensive MS specific miRNA-TF co-regulatory network was hypothesized; among others, SP1, RELA, NF-kappaB, TP53, AR, MYC, HDAC1, and STAT3 regulated the transcription of 61 targets. Interestingly, NF-kappaB and STAT3 cooperatively regulate the expression of immune response genes and control the cross-talk between inflammatory and immune cells. Further functional analysis will be performed on the identified critical hubs. Above all, in our view, this approach supports the need of multidisciplinary strategies for shedding light into the pathogenesis of MS. PMID- 30463274 TI - Molecular Fingerprints of Iron Parameters among a Population-Based Sample. AB - Iron deficiency is the most frequent deficiency disease and parameters of iron metabolism appear to be linked to major metabolic and cardiovascular diseases. We screened a large set of small molecules in plasma for associations with iron status among apparently healthy subjects to elucidate subclinical profiles which may provide a link between iron status and onset of diseases. Based on mass spectrometry and nuclear magnetic resonance spectroscopy we determined 613 plasma metabolites and lipoprotein subfractions among 820 apparently healthy individuals. Associations between ferritin, transferrin, haemoglobin and myoglobin and metabolite levels were tested by sex-specific linear regression analyses controlling for common confounders. Far more significant associations in women (82 out of 102) compared to men became obvious. The majority of the metabolites associated with serum ferritin and haemoglobin in women comprising fatty acid species, branched-chain amino acid catabolites and catabolites of heme. The latter was also obvious among men. Positive associations between serum transferrin and VLDL and IDL particle measures seen in women were observed in men with respect to serum ferritin. We observed a sexual-dimorphic fingerprint of surrogates of iron metabolism which may provide a link for the associations between those parameters and major metabolic and cardiovascular disease. PMID- 30463276 TI - Geographical Prevalence of Polycystic Ovary Syndrome as Determined by Region and Race/Ethnicity. AB - Polycystic ovarian syndrome (PCOS) is thought to be the most common endocrine disorder found in women. Common symptoms include irregular menstrual cycle, polycystic ovaries, and hirsutism, as well as an increased risk for a multitude of conditions, including insulin resistance, dyslipidemia and infertility. The prevalence of polycystic ovarian syndrome is generally thought to be between 3% and 10% but it is widely unknown for specific subpopulations based on geographical location and race/ethnicity. Based on the high degree of variability and inconsistencies between the different diagnostic criteria, there is a unique challenge that exists when determining the prevalence of this syndrome. There are a large percentage of individuals that remain undiagnosed even after visiting multiple health care providers. Most studies conducted across the world are limited by small sample size, selection bias, and lack of comparability across studies. There have been very few studies that have examined the prevalence of polycystic ovary syndrome across the United States. Based on the National Institutes of Health (NIH)'s diagnostic criteria, there is a similar prevalence of PCOS documented across the United States, the United Kingdom, Spain, Greece, Australia, and Mexico. Other studies have shown some differences between geographical location and race. The existing data is not conclusive enough to determine whether or not there is any significant differences in the prevalence of PCOS across geographical location, racial or ethnic groups. This review will seek to determine the prevalence of polycystic ovarian syndrome based on geographical location and race/ethnicity. PMID- 30463277 TI - Vitamin D Status and Seasonal Variation among Danish Children and Adults: A Descriptive Study. AB - The aim of the present study was to describe vitamin D status and seasonal variation in the general Danish population. In this study, 3092 persons aged 2 to 69 years (2565 adults, 527 children) had blood drawn twice (spring and autumn) between 2012 and 2014. A sub-sample of participants had blood samples taken monthly over a year. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were measured by liquid chromatography mass spectrometry, and information on supplement use was assessed from questionnaires. Seasonal variations in 25(OH)D concentrations were evaluated graphically and descriptively, and status according to age, sex, and supplement use was described. It was found that 86% of both adults and children were vitamin D-sufficient in either spring and or/autumn; however, many had a spring concentration below 50 nmol/L. A wide range of 25(OH)D concentrations were found in spring and autumn, with very low and very high values in both seasons. Among adults, women in general had higher median 25(OH)D concentrations than men. Furthermore, vitamin D supplement use was substantial and affected the median concentrations markedly, more so during spring than autumn. Seasonal variation was thus found to be substantial, and bi-seasonal measurements are vital in order to capture the sizable fluctuations in vitamin D status in this Nordic population. PMID- 30463278 TI - Rex Retroelements and Teleost Genomes: An Overview. AB - Repetitive DNA is an intriguing portion of the genome still not completely discovered and shows a high variability in terms of sequence, genomic organization, and evolutionary mode. On the basis of the genomic organization, it includes satellite DNAs, which are organized as long arrays of head-to-tail linked repeats, and transposable elements, which are dispersed throughout the genome. These repeated elements represent a considerable fraction of vertebrate genomes contributing significantly in species evolution. In this review, we focus our attention on Rex1, Rex3 and Rex6, three elements specific of teleost genomes. We report an overview of data available on these retroelements highlighting their significative impact in chromatin and heterochromatin organization, in the differentiation of sex chromosomes, in the formation of supernumerary chromosomes, and in karyotype evolution in teleosts. PMID- 30463280 TI - Six New Phragmalin Limonoids from the Stems of Chukrasia tabularis A. Juss. AB - Six new phragmalin limonoids, named moluccensin Z1 (1), moluccensin Z2 (2), carapanolide Y (3), tabulalin N (4), chukvelutilide A1 (5), and velutinasin J (6), as well as two known compounds, chukvelutilide A (7) and velutinasin D (8) were isolated from the stems of Chukrasia tabularis A. Juss. The structures of the new compounds 1-6 were confirmed by spectroscopic methods, including IR and HRESIMS, as well as 1D and 2D NMR, and by comparisons with the data of known analogues. All compounds were tested for alpha-glucosidase and acetylcholinesterase inhibitory activities. However, none of the compounds was active against alpha-glucosidase and acetylcholinesterase in vitro. PMID- 30463279 TI - Effects of the Extracts from Fruit and Stem of Camellia japonica on Induced Pluripotency and Wound Healing. AB - Small molecules that improve reprogramming, stem cell properties, and regeneration can be widely applied in regenerative medicine. Natural plant extracts represent an abundant and valuable source of bioactive small molecules for drug discovery. Natural products themselves or direct derivatives of them have continued to provide small molecules that have entered clinical trials, such as anticancer and antimicrobial drugs. Here, we tested 3695 extracts from native plants to examine whether they can improve induced pluripotent stem cell (iPSC) generation using genetically homogeneous secondary mouse embryonic fibroblasts (MEFs) harboring doxycycline (dox)-inducible reprograming transgenes. Among the tested extracts, extracts from the fruit and stem of Camellia japonica (CJ) enhanced mouse and human iPSC generation and promoted efficient wound healing in an in vivo mouse wound model. CJ is one of the best-known species of the genus Camellia that belongs to the Theaceae family. Our findings identified the natural plant extracts from the fruit and stem of CJ as novel regulators capable of enhancing cellular reprogramming and wound healing, providing a useful supplement in the development of a more efficient and safer method to produce clinical-grade iPSCs and therapeutics. PMID- 30463281 TI - STE20/PAKA Protein Kinase Gene Releases an Autoinhibitory Domain through Pre-mRNA Alternative Splicing in the Dermatophyte Trichophyton rubrum. AB - Signaling pathways are highly diverse in filamentous fungi, allowing the cells to receive and process ambient information. Interaction of components from different pathways results in signaling networks. The mitogen-activated protein kinase (MAPK) pathway is dependent on phosphorylation that is accomplished by kinase proteins. Thus, the STE/PAK protein kinase family plays essential roles in MAPK signal transduction, regulating several cellular functions. The STE/PAK protein displays an autoinhibitory (Cdc42/Rac interactive binding-CRIB) domain on its N terminal portion, which interacts with the C-terminal catalytic kinase domain. Based on current knowledge, for the STE/PAK kinase to be activated, molecular signals (e.g., interaction with the activated form of Rac1 and Cdc42 proteins) or proteolytic cleavage by caspase 3 is necessary. Both mechanisms release the kinase domain from the CRIB interaction. Here, we hypothesize a novel molecular mechanism for the activation of STE20/PAKA kinase in Trichophyton rubrum based on an alternative pre-mRNA splicing process. Our data suggest that, because of the retention of intron 1 of this gene, it is theoretically possible that the translation of STE20/PAKA kinase will be free of its autoinhibitory CRIB domain. These findings indicate a rapid response system to environmental changes. Furthermore, STE20/PAKA may be a potential T. rubrum virulence factor and an interesting target for new drugs against dermatophytes. PMID- 30463282 TI - Man-In-The-Middle Attacks in Vehicular Ad-Hoc Networks: Evaluating the Impact of Attackers' Strategies. AB - Vehicular Ad-Hoc Network (VANET), a vital component of Intelligent Transportation Systems (ITS) technology, relies on communication between dynamically connected vehicles and static Road Side Units (RSU) to offer various applications (e.g., collision avoidance alerts, steep-curve warnings and infotainment). VANET has a massive potential to improve traffic efficiency, and road safety by exchanging critical information between nodes (vehicles and RSU), thus reducing the likelihood of traffic accidents. However, this communication between nodes is subject to a variety of attacks, such as Man-In-The-Middle (MITM) attacks which represent a major risk in VANET. It happens when a malicious node intercepts or tampers with messages exchanged between legitimate nodes. In this paper, we studied the impact on network performance of different strategies which attackers can adopt to launch MITM attacks in VANET, such as fleet or random strategies. In particular, we focus on three goals of MITM attacks-message delayed, message dropped and message tampered. The simulation results indicate that these attacks have a severe influence on the legitimate nodes in VANET as the network experience high number of compromised messages, high end-to-end delays and preeminent packet losses. PMID- 30463283 TI - Prevention of Occupational Strain: Can Psychological Empowerment and Organizational Commitment Decrease Dissatisfaction and Intention to Quit? AB - In the present study, the demands-control-support model has served as the basis for the assessment of occupational strain. This model has been used as a predictor of health problems. It has also been associated with organizational outcomes and behaviors. The purpose of this study is to relate job demands and resources with job satisfaction and intention to quit the union. We intend to test a multiple mediation model with psychological empowerment and union commitment as mediator variables. The investigation was carried out with 953 delegates of a Spanish trade union (healthcare professionals). We collected 401 questionnaires. Multiple mediation analyses were performed with bootstrapping techniques using the SPSS PROCESS macro. The results underlined the effects of multiple mediation of empowerment and commitment in the relation between resources and job satisfaction. This mediation was also observed in the relation between resources and intention to quit. The lack of relation between demands and satisfaction or intention to quit is of interest. In the presence of adequate resources, delegates are empowered and committed to their union, which leads to lower dissatisfaction and lower rates of quitting. This study advises organizations to give greater importance to motivational and attitudinal factors to attenuate occupational strain. PMID- 30463285 TI - Auxin Controlled by Ethylene Steers Root Development. AB - Roots are important plant ground organs, which absorb water and nutrients to control plant growth and development. Phytohormones have been known to play a crucial role in the regulation of root growth, such as auxin and ethylene, which are central regulators of this process. Recent findings have revealed that root development and elongation regulated by ethylene are auxin dependent through alterations of auxin biosynthesis, transport and signaling. In this review, we focus on the recent advances in the study of auxin and auxin-ethylene crosstalk in plant root development, demonstrating that auxin and ethylene act synergistically to control primary root and root hair growth, but function antagonistically in lateral root formation. Moreover, ethylene modulates auxin biosynthesis, transport and signaling to fine-tune root growth and development. Thus, this review steps up the understanding of the regulation of auxin and ethylene in root growth. PMID- 30463284 TI - A Raman Imaging Approach Using CD47 Antibody-Labeled SERS Nanoparticles for Identifying Breast Cancer and Its Potential to Guide Surgical Resection. AB - Raman spectroscopic imaging has shown great promise for improved cancer detection and localization with the use of tumor targeting surface enhanced Raman scattering (SERS) nanoparticles. With the ultrasensitive detection and multiplexing capabilities that SERS imaging has to offer, scientists have been investigating several clinical applications that could benefit from this unique imaging strategy. Recently, there has been a push to develop new image-guidance tools for surgical resection to help surgeons sensitively and specifically identify tumor margins in real time. We hypothesized that SERS nanoparticles (NPs) topically applied to breast cancer resection margins have the potential to provide real-time feedback on the presence of residual cancer in the resection margins during lumpectomy. Here, we explore the ability of SERS nanoparticles conjugated with a cluster of differentiation-47 (CD47) antibody to target breast cancer. CD47 is a cell surface receptor that has recently been shown to be overexpressed on several solid tumor types. The binding potential of our CD47 labeled SERS nanoparticles was assessed using fluorescence assisted cell sorting (FACS) on seven different human breast cancer cell lines, some of which were triple negative (negative expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2)). Xenograft mouse models were also used to assess the ability of our Raman imaging system to identify tumor from normal tissue. A ratiometric imaging strategy was used to quantify specific vs. nonspecific probe binding, resulting in improved tumor-to background ratios. FACS analysis showed that CD47-labeled SERS nanoparticles bound to seven different breast cancer cell lines at levels 12-fold to 70-fold higher than isotype control-labeled nanoparticles (p < 0.01), suggesting that our CD47-targeted nanoparticles actively bind to CD47 on breast cancer cells. In a mouse xenograft model of human breast cancer, topical application of CD47 targeted nanoparticles to excised normal and cancer tissue revealed increased binding of CD47-targeted nanoparticles on tumor relative to normal adjacent tissue. The findings of this study support further investigation and suggest that SERS nanoparticles topically applied to breast cancer could guide more complete surgical resection during lumpectomy. PMID- 30463286 TI - Description, Distribution, and Relevance of Viruses of the Forest Pathogen Gremmeniella abietina. AB - The European race of the ascomycetous species Gremmeniella abietina (Lagerberg) Morelet includes causal agents of shoot blight and stem canker of several conifers in Europe and North America, which are known to host a diverse virome. GaRV6 is the latest and sixth mycovirus species reported within G. abietina. Before its description, one victorivirus and one gammapartitivirus species were described in biotype A, two mitoviruses in both biotypes A and B and a betaendornavirus in biotype B. Possible phenotypic changes produced by mycoviruses on G. abietina mycelial growth have been reported in Spanish mitovirus-free and GaRV6-hosting G. abietina isolates, which had higher growth rates at the optimal temperature of 15 degrees C, but no other major differences have been observed between partitivirus-like dsRNA and dsRNA-free isolates. In this review, we reappraise the diversity of viruses found in G. abietina so far, and their relevance in clarifying the taxonomy of G. abietina. We also provide evidence for the presence of two new viruses belonging to the families Fusariviridae and Endornaviridae in Spanish isolates. PMID- 30463287 TI - Identification, Characterization, and Expression Patterns of TCP Genes and microRNA319 in Cotton. AB - The TEOSINTE BRANCHED 1, CYCLOIDEA, and PROLIFERATING CELL FACTORS (TCP) gene family is a group of plant-specific transcription factors that have versatile functions in developmental processes and stress responses. In this study, a total of 73 TCP genes in upland cotton were identified and characterizated. Phylogenetic analysis classified them into three subgroups: 50 belonged to PCF, 16 to CIN, and 7 to CYC/TB1. GhTCP genes are randomly distributed in 22 of the 26 chromosomes in cotton. Expression patterns of GhTCPs were analyzed in 10 tissues, including different developmental stages of ovule and fiber, as well as under heat, salt, and drought stresses. Transcriptome analysis showed that 44 GhTCP genes exhibited varied transcript accumulation patterns in the tested tissues and 41 GhTCP genes were differentially expressed in response to heat, salt, and drought stresses. Furthermore, three GhTCP genes of the CIN clade were found to contain miR319-binding sites. An anti-correlation expression of GhTCP21 and GhTCP54 was analyzed with miR319 under salt and drought stress. Our results lay the foundation for understanding the complex mechanisms of GhTCP-mediated developmental processes and abiotic stress-signaling transduction pathways in cotton. PMID- 30463288 TI - Squalene Found in Alpine Grassland Soils under a Harsh Environment in the Tibetan Plateau, China. AB - Squalene is found in a large number of plants, animals, and microorganisms, as well as other sources, playing an important role as an intermediate in sterol biosynthesis. It is used widely in the food, cosmetics, and medicine industries because of its antioxidant, antistatic, and anti-carcinogenic properties. A higher natural squalene component of lipids is usually reported as being isolated to organisms living in harsh environments. In the Tibetan Plateau, which is characterized by high altitude, strong solar radiation, drought, low temperatures, and thin air, the squalene component was identified in five alpine grasslands soils using the pyrolysis gas chromatography-mass spectrometry (Py GC/MS) technique. The relative abundance of squalene ranged from 0.93% to 10.66% in soils from the five alpine grasslands, with the highest value found in alpine desert and the lowest in alpine meadow. Furthermore, the relative abundance of squalene in alpine grassland soils was significantly negatively associated with soil chemical/microbial characteristics. These results indicate that the extreme environmental conditions of the Tibetan Plateau may stimulate the microbial biosynthesis of squalene, and the harsher the environment, the higher the relative abundance of soil squalene. PMID- 30463289 TI - The Regulation of JNK Signaling Pathways in Cell Death through the Interplay with Mitochondrial SAB and Upstream Post-Translational Effects. AB - c-Jun-N-terminal kinase (JNK) activity plays a critical role in modulating cell death, which depends on the level and duration of JNK activation. The kinase cascade from MAPkinase kinase kinase (MAP3K) to MAPkinase kinase (MAP2K) to MAPKinase (MAPK) can be regulated by a number of direct and indirect post transcriptional modifications, including acetylation, ubiquitination, phosphorylation, and their reversals. Recently, a JNK-mitochondrial SH3-domain binding protein 5 (SH3BP5/SAB)-ROS activation loop has been elucidated, which is required to sustain JNK activity. Importantly, the level of SAB expression in the outer membrane of mitochondria is a major determinant of the set-point for sustained JNK activation. SAB is a docking protein and substrate for JNK, leading to an intramitochondrial signal transduction pathway, which impairs electron transport and promotes reactive oxygen species (ROS) release to sustain the MAPK cascade. PMID- 30463290 TI - Diatoms Green Nanotechnology for Biosilica-Based Drug Delivery Systems. AB - Diatom microalgae are the most outstanding natural source of porous silica. The diatom cell is enclosed in a three-dimensional (3-D) ordered nanopatterned silica cell wall, called frustule. The unique properties of the diatom frustule, including high specific surface area, thermal stability, biocompatibility, and tailorable surface chemistry, make diatoms really promising for biomedical applications. Moreover, they are easy to cultivate in an artificial environment and there is a large availability of diatom frustules as fossil material (diatomite) in several areas of the world. For all these reasons, diatoms are an intriguing alternative to synthetic materials for the development of low-cost drug delivery systems. This review article focuses on the possible use of diatom derived silica as drug carrier systems. The functionalization strategies of diatom micro/nanoparticles for improving their biophysical properties, such as cellular internalization and drug loading/release kinetics, are described. In addition, the realization of hybrid diatom-based devices with advanced properties for theranostics and targeted or augmented drug delivery applications is also discussed. PMID- 30463291 TI - Ishige okamurae Extract Suppresses Obesity and Hepatic Steatosis in High Fat Diet Induced Obese Mice. AB - Obesity is caused by the expansion of white adipose tissue (WAT), which stores excess triacylglycerol (TG), this can lead to disorders including type 2 diabetes, atherosclerosis, metabolic diseases. Ishige okamurae extract (IOE) is prepared from a brown alga and has anti-oxidative properties. We investigated the detailed mechanisms of the anti-obesity activity of IOE. Treatment with IOE blocked lipid accumulation by reducing expression of key adipogenic transcription factors, such as CCAAT/enhancer-binding protein alpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma), in 3T3-L1 cells. Administration of IOE to high fat diet (HFD)-fed mice inhibited body and WAT mass gain, attenuated fasting hyperglycemia and dyslipidemia. The obesity suppression was associated with reductions in expression of adipogenic proteins, such as C/EBPalpha and PPARgamma, increases in expression of lipolytic enzymes, such as adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in WAT of HFD-fed mice. In addition, IOE-treated mice had lower hepatic TG content, associated with lower protein expression of lipogenic genes, such as diglyceride acyltransferase 1 (DGAT1), sterol regulatory element-binding protein 1 (SREBP1), fatty acid synthase (FAS). IOE treatment also reduced serum free fatty acid concentration, probably through the upregulation of beta-oxidation genes, suggested by increases in AMPKalpha and CPT1 expression in WAT and liver. In summary, IOE ameliorates HFD-induced obesity and its related metabolic disease, hepatic steatosis, by regulating multiple pathways. PMID- 30463292 TI - Growth and Self-Assembly of Silicon-Silicon Carbide Nanoparticles into Hybrid Worm-Like Nanostructures at the Silicon Wafer Surface. AB - This work describes the growth of silicon-silicon carbide nanoparticles (Si-SiC) and their self-assembly into worm-like 1D hybrid nanostructures at the interface of graphene oxide/silicon wafer (GO/Si) under Ar atmosphere at 1000 degrees C. Depending on GO film thickness, spread silicon nanoparticles apparently develop on GO layers, or GO-embedded Si-SiC nanoparticles self-assembled into some micrometers-long worm-like nanowires. It was found that the nanoarrays show that carbon-silicon-based nanowires (CSNW) are standing on the Si wafer. It was assumed that Si nanoparticles originated from melted Si at the Si wafer surface and GO-induced nucleation. Additionally, a mechanism for the formation of CSNW is proposed. PMID- 30463293 TI - Gelation of Poly(Vinylidene Fluoride) Solutions in Native and Organically Modified Silica Nanopores. AB - The purpose of this study is to highlight the surface and size effects of the nanopores on the thermodynamics and kinetics of gelation. The effects have been probed by applying differential scanning calorimetry to poly(vinylidene fluoride) solutions in tetraethylene glycol dimethyl ether (tetraglyme) and gamma butyrolactone. Nanoconfinement has been accomplished by introducing gels into native and organically modified silica nanopores (4-30 nm). Nanoconfinement has produced two major effects. First, the heat of gelation has decreased three to four times compared to that for the bulk systems. Second, the temperature of gelation has increased by ~40 degrees C (tetraglyme based systems) and ~70 degrees C (gamma-butyrolactone based systems), the increase being stronger in native nanopores. The effects are discussed in terms of acceleration of gelation due to heterogeneous nucleation at the confining surface, and retardation of gelation due to constricted polymer chain mobility in the middle of the pore volume. Calorimetric data have been subjected to isoconversional kinetics analysis. The obtained temperature dependencies of the activation energies of gelation have been interpreted in the frameworks of the nucleation model of Turnbull and Fisher. The results suggest that nanoconfinement leads to a lowering of both the free energy of nucleation and activation energy of diffusion. PMID- 30463294 TI - Ginsenoside Rg1 Prevents Doxorubicin-Induced Cardiotoxicity through the Inhibition of Autophagy and Endoplasmic Reticulum Stress in Mice. AB - Ginsenoside Rg1, a saponin that is a primary component of ginseng, has been demonstrated to protect hearts from diverse cardiovascular diseases with regulating multiple cellular signal pathways. In the present study, we investigated the protective role of ginsenoside Rg1 on doxorubicin-induced cardiotoxicity and its effects on endoplasmic reticulum stress and autophagy. After pre-treatment with ginsenoside Rg1 (50 mg/kg i.g.) for 7 days, male C57BL/6J mice were intraperitoneally injected with a single dose of doxorubicin (6 mg/kg) every 3 days for four injections. Echocardiographic and pathological findings showed that ginsenoside Rg1 could significantly reduce the cardiotoxicity induced by doxorubicin. Ginsenoside Rg1 significantly inhibited doxorubicin-induced formation of autophagosome. At the same time, ginsenoside Rg1 decreased the doxorubicin-induced cardiac microtubule-associated protein-light chain 3 and autophagy related 5 expression. Ginsenoside Rg1 can reduce endoplasmic reticulum dilation caused by doxorubicin. Compared with the doxorubicin group, the expression of cleaved activating transcription factor 6 and inositol-requiring enzyme 1 decreased in group ginsenoside Rg1. Treatment with ginsenoside Rg1 reduces the expression of TIF1 and increases the expression of glucose-regulated protein 78. In the ginsenoside Rg1 group, the expression of p-P70S6K, c-Jun N-terminal kinases 1 and Beclin1 declined. These results indicate that ginsenoside Rg1 may improve doxorubicin-induced cardiac dysfunction by inhibiting endoplasmic reticulum stress and autophagy. PMID- 30463295 TI - Enhanced Electrocatalytic Activity and Stability toward the Oxygen Reduction Reaction with Unprotected Pt Nanoclusters. AB - The Pt particles within diameters of 1-3 nm known as Pt nanoclusters (NCs) are widely considered to be satisfactory oxygen reduction reaction (ORR) catalysts due to higher electrocatalytic performance and cost effectiveness. However, the utilization of such smaller Pt NCs is always limited by the synthesis strategies, stability and methanol tolerance of Pt. Herein, unprotected Pt NCs (~2.2 nm) dispersed on carbon nanotubes (CNTs) were prepared via a modified top-down approach using liquid Li as a solvent to break down the bulk Pt. Compared with the commercial Pt/C, the resultant Pt NCs/CNTs catalyst (Pt loading: 10 wt.%) exhibited more desirable ORR catalytic performance in 0.1 M HClO4. The specific activity (SA) and mass activity (MA) at 0.9 V for ORR over Pt NCs/CNTs were 2.5 and 3.2 times higher than those over the commercial Pt/C (Pt loading: 20 wt.%). Meanwhile, the Pt NCs/CNTs catalyst demonstrated more satisfactory stability and methanol tolerance. Compared with the obvious loss (~69%) of commercial Pt/C, only a slight current decrease (~10%) was observed for Pt NCs/CNTs after the chronoamperometric measurement for 2 * 104 s. Hence, the as-prepared Pt NCs/CNTs material displays great potential as a practical ORR catalyst. PMID- 30463296 TI - Fruit and Vegetable Consumption and Their Polyphenol Content Are Inversely Associated with Sleep Duration: Prospective Associations from the UK Women's Cohort Study. AB - This study aims to investigate the prospective associations between fruit and vegetable (FV) intakes and their polyphenol content with subsequent sleep duration in UK women. In this study, 13,958 women with ~4 years of follow-up in the UK Women's Cohort Study were included in the analyses. FV intakes were assessed at baseline using a food frequency questionnaire (FFQ), and average hours of sleep per day were self-reported in follow-up. Polyphenol intake was calculated by matching FV items from the FFQ with the Phenol-Explorer database. Linear regression models, adjusting for confounders, were used for the analyses. Consuming an additional portion of apples, kiwi, oranges, pineapple, and 100% pure juice were associated with shorter sleep. Similarly, an additional portion of cabbage, celery, aubergine, olives, and peppers were inversely associated with sleep duration. An additional gram of total polyphenols was associated with shorter sleep by 18 min (99% CI -31 to -4, p < 0.001). FV consumption and total polyphenol content were inversely associated with sleep duration; however, effect sizes were small, and polyphenol classes from FV intakes were not associated with sleep duration. Future intervention studies considering the time of FV consumption in relation to sleep are needed to clarify the underlying mechanisms. PMID- 30463297 TI - The Immunomodulatory and Antimicrobial Properties of the Vertebrate Ribonuclease A Superfamily. AB - The Ribonuclease A Superfamily is composed of cationic peptides that are secreted by immune cells and epithelial tissues. Although their physiological roles are unclear, several members of the vertebrate Ribonuclease A Superfamily demonstrate antimicrobial and immune modulation activities. The objective of this review is to provide an overview of the published literature on the Ribonuclease A Superfamily with an emphasis on each peptide's regulation, antimicrobial properties, and immunomodulatory functions. As additional insights emerge regarding the mechanisms in which these ribonucleases eradicate invading pathogens and modulate immune function, these ribonucleases may have the potential to be developed as a novel class of therapeutics for some human diseases. PMID- 30463299 TI - Hsp90 Stabilizes SIRT1 Orthologs in Mammalian Cells and C. elegans. AB - Sirtuin 1 (SIRT1) othologs are ubiquitous NAD+-dependent deacetylases that act as nutrient sensors and modulate metabolism and stress responses in diverse organisms. Both mammalian SIRT1 and Caenorhabditis elegans SIR-2.1 have been implicated in dietary restriction, longevity, and healthspan. Hsp90 is an evolutionarily conserved molecular chaperone that stabilizes a plethora of signaling 'client' proteins and regulates fundamental biological processes. Here we report that Hsp90 is required for conformational stabilization of SIRT1 and SIR-2.1. We find that inhibition of Hsp90 by geldanamycin (GA) induces the depletion of mammalian SIRT1 protein in a concentration and time dependent manner in COS-7 and HepG2 cells. In contrast to SIRT1, SIRT2 level remains unchanged by GA treatment, reflecting a specific Hsp90 SIRT1 interaction. Hsp90 inhibition leads to the destabilization and proteasomal degradation of SIRT1. Moreover, we observe a GA-sensitive physical interaction between SIRT1 and Hsp90 by immunoprecipitation. We also demonstrate that hsp-90 gene silencing also induces SIR-2.1 protein depletion and proteasomal degradation in C. elegans. Our findings identify metazoan SIRT1 orthologs as Hsp90 clients and reveal a novel crosstalk between the proteostasis and nutrient signaling networks, which may have implications in various age related diseases. PMID- 30463298 TI - Sub-Toxic Human Amylin Fragment Concentrations Promote the Survival and Proliferation of SH-SY5Y Cells via the Release of VEGF and HspB5 from Endothelial RBE4 Cells. AB - Human amylin is a 37-residue peptide hormone (hA1-37) secreted by beta-cells of the pancreas and, along with insulin, is directly associated with type 2 diabetes mellitus (T2DM). Amyloid deposits within the islets of the pancreas represent a hallmark of T2DM. Additionally, amylin aggregates have been found in blood vessels and/or brain of patients with Alzheimer's disease, alone or co-deposited with beta-amyloid. The purpose of this study was to investigate the neuroprotective potential of human amylin in the context of endothelial-neuronal "cross-talk". We initially performed dose-response experiments to examine cellular toxicity (quantified by the [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide] MTT assay) of different hA17-29 concentrations in endothelial cells (RBE4). In the culture medium of these cells, we also measured heat shock protein B5 (HspB5) levels by ELISA, finding that even a sub-toxic concentration of hA17-29 (3 uM) produced an increase of HspB5. Using a cell medium of untreated and RBE4 challenged for 48 h with a sub-toxic concentration of hA17-29, we determined the potential beneficial effect of their addition to the medium of neuroblastoma SH-SY5Y cells. These cells were subsequently incubated for 48 h with a toxic concentration of hA17-29 (20 uM). We found a complete inhibition of hA17-29 toxicity, potentially related to the presence in the conditioned medium not only of HspB5, but also of vascular endothelial growth factor (VEGF). Pre-treating SH-SY5Y cells with the anti-Flk1 antibody, blocking the VEGF receptor 2 (VEGFR2), significantly decreased the protective effects of the conditioned RBE4 medium. These data, obtained by indirectly measuring VEGF activity, were strongly corroborated by the direct measurement of VEGF levels in conditioned RBE4 media as detected by ELISA. Altogether, these findings highlighted a novel role of sub-toxic concentrations of human amylin in promoting the secretion of proteic factors by endothelial cells (HspB5 and VEGF) that support the survival and proliferation of neuron-like cells. PMID- 30463300 TI - Inhibition Effect of Graphene on Space Charge Injection and Accumulation in Low Density Polyethylene. AB - Space charge injection and accumulation is attracting much attention in the field of dielectric insulation especially for electronic devices, power equipment and so on. This paper proposes using the inhibition effect of graphene for the injection and accumulation of space charge in low-density polyethylene (LDPE). Scanning electron microscope (SEM) and transmission electron microscopy (TEM) images were employed to observe the dispersion of graphene with a two-dimensional structure in LDPE. The time-dependent space charge dynamic behaviors of graphene/LDPE nanocomposites with the filler content of 0, 0.003, 0.005, 0.007 and 0.01 wt % were characterized by the pulsed electro-acoustic (PEA) test at 40, 60 and 80 degrees C, and the charge mobility was evaluated by its depolarization processes. The experimental results show that for the undoped LDPE film, large amounts of space charges were injected from the electrodes into samples, especially at 60 and 80 degrees C. The graphene/LDPE nanocomposites with a filler content of 0.005 wt % could markedly suppress the space charge injection and accumulation even at 80 degrees C, which is attributed to the large quantities of graphene-polymer in interface regions. These interface regions introduced numbers of deep trap sites within the forbidden band of nanocomposites, which can reduce the de-trapping rate of charges and suppress the space charge accumulation in the polymer bulks. The graphene/LDPE nanocomposites are suggested for dielectric applications, intending the inhibition of space charge injection and accumulation. PMID- 30463301 TI - Reproducibility of Blood Lactate Concentration Rate under Isokinetic Force Loads. AB - (1) Background: Maximum isokinetic force loads show strongly increased post-load lactate concentrations and an increase in the maximum blood lactate concentration rate ( V Lamax), depending on load duration. The reproducibility of V Lamax must be known to be able to better assess training-related adjustments of anaerobic performance using isokinetic force tests. (2) Methods: 32 subjects were assigned to two groups and completed two unilateral isokinetic force tests (210 degrees s-1, Range of Motion 90 degrees ) within seven days. Group 1 (n = 16; age 24.0 +/- 2.8 years, BMI 23.5 +/- 2.6 kg m-2, training duration: 4.5 +/- 2.4 h week-1) completed eight repetitions and group 2 (n = 16; age 23.7 +/- 1.9 years, BMI 24.6 +/- 2.4 kg m-2, training duration: 5.5 +/- 2.1 h week-1) completed 16 repetitions. To determine V Lamax, capillary blood (20 uL) was taken before and immediately after loading, and up to the 9th minute post-load. Reproducibility and variability was determined using Pearson and Spearman correlation analyses, and variability were determined using within-subject standard deviation (Sw) and Limits of Agreement (LoA) using Bland Altman plots. (3) Results: The correlation of V Lamax in group 1 was r = 0.721, and in group 2 r = 0.677. The Sw of V Lamax was 0.04 mmol L-1 s-1 in both groups. In group 1, V Lamax showed a systematic bias due to measurement repetition of 0.02 mmol L-1 s-1 in an interval (LoA) of +/-0.11 mmol L-1 s-1. In group 2, a systematic bias of -0.008 mmol L-1 s 1 at an interval (LoA) of +/-0.11 mmol L-1 s-1 was observed for repeated measurements of V Lamax. (4) Conclusions: Based on the existing variability, a reliable calculation of V Lamax seems to be possible with both short and longer isokinetic force loads. Changes in V Lamax above 0.11 mmol L-1 s-1 due to training can be described as a non-random increase or decrease in V Lamax. PMID- 30463302 TI - In Vitro Anticancer Properties of Table Grape Powder Extract (GPE) in Prostate Cancer. AB - Although the link between diet and cancer is complex, epidemiological data confirm that diet is a risk factor for prostate cancer and indicate a reduced prostate cancer incidence associated with a diet rich in vegetables and fruits. Because of the known protective effect of grape seed extract (GSE) against prostate cancer, we evaluated the effects of grape powder extract (GPE) on cell viability, proliferation, and metastatic capability. Importantly, we explored the possible novel mechanism of GPE through metastasis-associated protein 1 (MTA1) downregulation in prostate cancer, since our previous studies indicated resveratrol (Res)- and pterostilbene (Pter)-induced MTA1-mediated anticancer activities in prostate cancer. We found that GPE inhibited the cell viability and growth of prostate cancer cells only at high 100 MUg/mL concentrations. However, at low 1.5-15 MUg/mL concentrations, GPE significantly reduced the colony formation and wound healing capabilities of both DU145 and PC3M cells. Moreover, we found that GPE inhibited MTA1 in a dose-dependent manner in these cells, albeit with considerably less potency than Res and Pter. These results indicate that stilbenes such as Res and Pter specifically and potently inhibit MTA1 and MTA1-associated proteins compared to GPE, which contains low concentrations of Res and mainly consists of other flavonoids and anthocyanidins. Our findings support continued interest in GPE as a chemopreventive and anti-cancer agent against prostate cancer but also emphasize the unique and specific properties of stilbenes on MTA1-mediated anticancer effects on prostate cancer. PMID- 30463303 TI - Beneficial Effects of Deoxyshikonin on Delayed Wound Healing in Diabetic Mice. AB - Shiunko ointment is composed of five ingredients including Lithospermi Radix (LR), Angelicae Gigantis Radix, sesame seed oil, beeswax, and swine oil. It is externally applied as a treatment for a wide range of skin conditions such as eczema, psoriasis, hair loss, burns, topical wounds, and atopic dermatitis. Deoxyshikonin is the major angiogenic compound extracted from LR. In this study, we investigated the efficacy of LR extract and deoxyshikonin on impaired wound healing in streptozotocin (STZ)-induced diabetic mice. Treatment with LR extract elevated tube formation in human umbilical vein endothelial cells (HUVECs) and exerted antioxidant activity. An open skin wound was produced on the backs of diabetic mice and was then topically treated with deoxyshikonin or vehicle. In addition, deoxyshikonin promoted tube formation in high glucose conditions exposed to HUVECs, and which may be regulated by increased VEGFR2 expression and phosphorylation of Akt and p38. Our results demonstrate that deoxyshikonin application promoted wound repair in STZ-induced diabetic mice. Collectively, these data suggest that deoxyshikonin is an active ingredient of LR, thereby contributing to wound healing in patients with diabetes. PMID- 30463304 TI - Lactobacillus plantarum CQPC11 Isolated from Sichuan Pickled Cabbages Antagonizes d-galactose-Induced Oxidation and Aging in Mice. AB - Chinese pickled cabbage is a traditional fermented food that contains abundant microbes produced during the process of fermentation. In this work, an in vivo animal study was conducted to investigate the effects of a newly isolated lactic acid bacterium (Lactobacillus plantarum CQPC11, LP-CQPC11) on d-galactose-induced oxidation and aging in mice. Analysis of the serum and tissue samples of these mice using molecular biology approaches showed that LP-CQPC11 suppressed the decrease in thymus, brain, heart, liver, spleen, and kidney indices caused by oxidation and aging. Furthermore, LP-CQPC11 increased the levels of SOD (superoxide dismutase), GSH-Px (glutathione peroxidase), and GSH (glutathione), whereas it reduced the levels of NO (nitric oxide) and MDA (malondialdehyde) in the serum, liver, and spleen of oxidation and aging mouse models. Pathological observation indicated that LP-CQPC11 alleviated the damage caused by oxidation and aging on the liver and spleen of mice. qPCR analysis indicated that LP-CQPC11 effectively upregulated the expression of nNOS (neuronal nitric oxide synthase), eNOS (endothelial nitric oxide synthase), Cu/Zn-SOD (cuprozinc-superoxide dismutase), Mn-SOD (manganese superoxide dismutase), CAT (catalase), HO-1 (heme oxygenase-1), Nrf2 (nuclear factor-erythroid 2 related factor 2), gamma-GCS (gamma-glutamylcysteine synthetase), and NQO1 (NAD(P)H dehydrogenase [quinone] 1), but downregulated the expression of iNOS (inducible nitric oxide synthase) in the mouse liver and spleen. Western blot analysis showed that LP-CQPC11 effectively upregulated SOD1 (Cu/Zn-SOD), SOD2 (Mn-SOD), CAT, GSH1 (c glutamylcysteine synthetase), and GSH2 (glutathione synthetase) protein expression in mouse liver and spleen tissues. These findings suggest that LP CQPC11 can effectively prevent d-galactose-induced oxidation and aging in mice, and the effect is even better than that of the commonly used Lactobacillus delbruechii subsp. bulgaricus (LDSB) and vitamin C in the industry. Thus, LP CQPC11 may be potentially employed as a probiotic strain. PMID- 30463305 TI - Climatic Niche Model for Overwintering Monarch Butterflies in a Topographically Complex Region of California. AB - We use climatic conditions that are associated with known monarch butterfly overwintering groves in California to build a Maxent model, and focus on the fine scale probability of overwintering grove occurrence in a topographically complex region of the state (Santa Barbara County). Grove locations are known from recent and historical surveys and a long-term citizen science database. The climatic niche model performs well, predicting that overwintering habitat is most likely to occur along the coast and at low elevations, as shown by empirical data. We then use climatic variables in conjunction with climate change scenarios to model the future location of overwintering habitat, and find a substantial shift in the predicted distribution. Under a plausible scenario, the probability of occurrence of overwintering habitat directly reflects elevation, with coastal regions having a reduced probability relative to today, and higher elevation sites increasing in probability. Under a more extreme scenario, high probability sites are only located along ridgelines and in mountaintop regions of the county. This predicted shift in distribution is likely to have management implications, as sites that currently lack monarchs may become critical to conservation in the future. Our results suggest that estimating the size of the western overwintering population in the future will be problematic, unless annual counts compensate for a shift in the distribution and a potential change in the number and location of occupied sites. PMID- 30463306 TI - Modified Palygorskite Improves Immunity, Antioxidant Ability, Intestinal Morphology, and Barrier Function in Broiler Chickens Fed Naturally Contaminated Diet with Permitted Feed Concentrations of Fusarium Mycotoxins. AB - This study investigated effects of modified palygorskite (MPal) on immunity, antioxidant capacity, and intestinal barrier integrity in broiler chickens challenged with permitted feed Fusarium mycotoxin concentrations. One-day-old chicks were allocated into three treatments with eight replicates. Chickens in three groups were fed a basal diet with normal corn (control), contaminated diet containing moldy corn, with Fusarium mycotoxins contents in the diets lower than permitted feed mycotoxin concentrations, and the contaminated diet supplemented with 1 g/kg MPal for 42 days, respectively. Compared with control, moldy corn decreased bursa of Fabricius weight, jejunal secreted immunoglobulin A concentration, ileal superoxide dismutase (SOD) activity, jejunal and ileal villus height (VH) and VH/crypt depth (CD) ratio, and jejunal zonula occludens-1 and mucin 2 mRNA abundances at 42 days as well as ileal VH/CD ratio at 21 days; while they increased jejunal malondialdehyde accumulation at 21 and 42 days, jejunal SOD activity at 21 days, and serum diamine oxidase activity at 42 days, which were almost recovered by MPal. Moreover, dietary MPal upregulated ileal claudin-2 mRNA abundance compared with other two groups. The results indicated that MPal addition exerted protective effects on immunity, oxidative status, and intestinal barrier integrity in chickens challenged with permitted feed Fusarium mycotoxins levels. PMID- 30463307 TI - Screening, Synthesis, and QSAR Research on Cinnamaldehyde-Amino Acid Schiff Base Compounds as Antibacterial Agents. AB - Development of new drugs is one of the solutions to fight against the existing antimicrobial resistance threat. Cinnamaldehyde-amino acid Schiff base compounds, are newly discovered compounds that exhibit good antibacterial activity against gram-positive and gram-negative bacteria. Quantitative structure-activity relationship (QSAR) methodology was applied to explore the correlation between antibacterial activity and compound structures. The two best QSAR models showed R2 = 0.9354, F = 57.96, and s2 = 0.0020 against Escherichia coli, and R2 = 0.8946, F = 33.94, and s2 = 0.0043 against Staphylococcus aureus. The model analysis showed that the antibacterial activity of cinnamaldehyde compounds was significantly affected by the polarity parameter/square distance and the minimum atomic state energy for an H atom. According to the best QSAR model, the screening, synthesis, and antibacterial activity of three cinnamaldehyde-amino acid Schiff compounds were reported. The experiment value of antibacterial activity demonstrated that the new compounds possessed excellent antibacterial activity that was comparable to that of ciprofloxacin. PMID- 30463308 TI - Calibration of a Constitutive Model from Tension and Nanoindentation for Lead Free Solder. AB - It is challenging to evaluate constitutive behaviour by using conventional uniaxial tests for materials with limited sizes, considering the miniaturization trend of integrated circuits in electronic devices. An instrumented nanoindentation approach is appealing to obtain local properties as the function of penetration depth. In this paper, both conventional tensile and nanoindentation experiments are performed on samples of a lead-free Sn-3.0Ag 0.5Cu (SAC305) solder alloy. In order to align the material behaviour, thermal treatments were performed at different temperatures and durations for all specimens, for both tensile experiments and nanoindentation experiments. Based on the self-similarity of the used Berkovich indenter, a power-law model is adopted to describe the stress-strain relationship by means of analytical dimensionless analysis on the applied load-penetration depth responses from nanoindentation experiments. In light of the significant difference of applied strain rates in the tensile and nanoindentation experiments, two "rate factors" are proposed by multiplying the representative stress and stress exponent in the adopted analytical model, and the corresponding values are determined for the best predictions of nanoindentation responses in the form of an applied load indentation depth relationship. Eventually, good agreement is achieved when comparing the stress-strain responses measured from tensile experiments and estimated from the applied load-indentation depth responses of nanoindentation experiments. The rate factors psi sigma and psi n are calibrated to be about 0.52 and 0.10, respectively, which facilitate the conversion of constitutive behaviour from nanoindentation experiments for material sample with a limited size. PMID- 30463309 TI - The Pub1 and Upf1 Proteins Act in Concert to Protect Yeast from Toxicity of the [PSI+] Prion. AB - The [PSI+] nonsense-suppressor determinant of Saccharomyces cerevisiae is based on the formation of heritable amyloids of the Sup35 (eRF3) translation termination factor. [PSI+] amyloids have variants differing in amyloid structure and in the strength of the suppressor phenotype. The appearance of [PSI+], its propagation and manifestation depend primarily on chaperones. Besides chaperones, the Upf1/2/3, Siw14 and Arg82 proteins restrict [PSI+] formation, while Sla2 can prevent [PSI+] toxicity. Here, we identify two more non-chaperone proteins involved in [PSI+] detoxification. We show that simultaneous lack of the Pub1 and Upf1 proteins is lethal to cells harboring [PSI+] variants with a strong, but not with a weak, suppressor phenotype. This lethality is caused by excessive depletion of the Sup45 (eRF1) termination factor due to its sequestration into Sup35 polymers. We also show that Pub1 acts to restrict excessive Sup35 prion polymerization, while Upf1 interferes with Sup45 binding to Sup35 polymers. These data allow consideration of the Pub1 and Upf1 proteins as a novel [PSI+] detoxification system. PMID- 30463310 TI - Barriers and Facilitators in Implementing Non-Face-to-Face Chronic Care Management in an Elderly Population with Diabetes: A Qualitative Study of Physician and Health System Perspectives. AB - The burden of illness related to diabetes and its complications is exceedingly high and growing globally. Systematic approaches to managing chronic care are needed to address the complex nature of the disease, taking into account health system structures. This study presents data collected from interviews with physicians, health system administrators, and other healthcare staff about chronic care management for elderly people with diabetes co-morbid with other chronic conditions in light of new programs intended to reduce barriers by incentivizing care encounters that take place through telephone and electronic communications (non-face-to-face care). Results indicate that health system personnel view non-face-to-face care as potentially providing value for patients and addressing systemic needs, yet challenging to implement in practice. Barriers and facilitators to this approach for managing diabetes and chronic care management for its complications are presented, with consideration to different types of health systems, and recommendations are provided for implementation. PMID- 30463311 TI - A Cross-Sectional Investigation of Cardiovascular and Metabolic Biomarkers among Conventional and Organic Farmers in Thailand. AB - Pesticide exposure has been implicated as a risk factor for developing a wide range of adverse health issues. Some examples are metabolic syndromes, including diabetes. This study investigated the relationship between current occupational use of pesticides and metabolic and cardiovascular biomarker levels among organic and conventional farmers in Thailand. In total, 436 recruited farmers were divided into two groups: conventional farmers (n = 214) and organic farmers (n = 222). Participants, free of diabetes, were interviewed and submitted to a physical examination. Serum samples were collected for clinical laboratory analyses, i.e., serum glucose and lipid profiles (triglycerides, total cholesterol, high-density lipoproteins, and low-density lipoproteins). Potential risk factors such as smoking, alcohol consumption, and heavy exercise were significantly different between the two groups. There were significant differences in terms of the years of pesticide use, pesticide use at home, sources of drinking water, and distance between the farmers' homes and farms between the groups. After adjusting for confounders, current conventional farmers had significantly higher abnormal body mass index (BMI), waist circumference, body fat percentage (% body fat), triglyceride, total cholesterol, and low density lipoprotein values as compared to organic farmers. Conventional farmers had higher risk of many metabolic and cardiovascular risk factors as compared to organic farmers, putting them at higher risk of metabolic diseases in the future. PMID- 30463312 TI - Interplay of Glycemic Index, Glycemic Load, and Dietary Antioxidant Capacity with Insulin Resistance in Subjects with a Cardiometabolic Risk Profile. AB - BACKGROUND: Dietary total antioxidant capacity (TAC), glycemic index (GI), and glycemic load (GL) are accepted indicators of diet quality, which have an effect on diet-disease relationships. The aim of this study was to evaluate potential associations of dietary TAC, GI, and GL with variables related to nutritive status and insulin resistance (IR) risk in cardiometabolic subjects. METHODS: A total of 112 overweight or obese adults (age: 50.8 +/- 9 years old) were included in the trial. Dietary intake was assessed by a validated 137-item food frequency questionnaire (FFQ), which was also used to calculate the dietary TAC, GI, and GL. Anthropometrics, blood pressure, body composition by dual-energy X-ray absorptiometry (DXA), glycemic and lipid profiles, C-reactive protein (CRP), as well as fatty liver quantification by magnetic resonance imaging (MRI) were assessed. RESULTS: Subjects with higher values of TAC had significantly lower circulating insulin concentration and homeostatic model assessment of insulin resistance (HOMA-IR). Participants with higher values of HOMA-IR showed significantly higher GI and GL. Correlation analyses showed relevant inverse associations of GI and GL with TAC. A regression model evidenced a relationship of HOMA-IR with TAC, GI, and GL. CONCLUSION: This data reinforces the concept that dietary TAC, GI, and GL are potential markers of diet quality, which have an impact on the susceptible population with a cardiometabolic risk profile. PMID- 30463313 TI - Programming of Vascular Dysfunction in the Intrauterine Milieu of Diabetic Pregnancies. AB - With the rising global tide of obesity, gestational diabetes mellitus (GDM) burgeoned into one of the most common antenatal disorders worldwide. Macrosomic babies born to diabetic mothers are more likely to develop risk factors for cardiovascular disease (CVD) before they reach adulthood. Rodent studies in offspring born to hyperglycemic pregnancies show vascular dysfunction characterized by impaired nitric oxide (NO)-mediated vasodilation and increased production of contractile prostanoids by cyclooxygenase 2 (COX-2). Vascular dysfunction is a key pathogenic event in the progression of diabetes-related vascular disease, primarily attributable to glucotoxicity. Therefore, glucose induced vascular injury may stem directly from the hyperglycemic intrauterine environment of GDM pregnancy, as evinced by studies showing endothelial activation and inflammation at birth or in childhood in offspring born to GDM mothers. This review discusses potential mechanisms by which intrauterine hyperglycemia programs dysfunction in the developing vasculature. PMID- 30463315 TI - Evaluation of the Characteristics and Coating Film Structure of Polymer/Ceramic Pressure-Sensitive Paint. AB - Polymer/ceramic pressure-sensitive paint (PC-PSP), which incorporates a high percentage of particles in the binder layer, is proposed in order to improve the characteristics of PSP. The procedure for embedding particles into the binder layer was modified. In the conventional procedure, dye is adsorbed onto a polymer/ceramic coating film (denoted herein as a dye-adsorbed (D-adsorbed) PSP). In the new procedure, the mixture of a dye and particles is adsorbed onto a polymer coating film (denoted herein as the particle/dye-adsorbed (PD-adsorbed) PSP). The effect of particle mass content on PSP characteristics was investigated. In addition, the effect of solvent on PSP characteristics and film structure were evaluated for the PD-adsorbed PSP. As a result, the difference in the PSP characteristics between the two types of PSP was clarified. Although surface roughness and time response increase with increased mass content of particles for both D- and PD-adsorbed PSPs, the critical pigment volume concentration (CPVC) for the PD-adsorbed PSP is smaller than that of the D adsorbed PSP (88 wt% and 93 wt%, respectively). The PD-adsorbed PSP has a higher frequency response comparing with the D-adsorbed PSP while maintaining the same surface roughness. Observation by scanning electron microscope showed that the CPVC of the PC-PSP is governed primarily by surface structure. The coating film structure can be roughly classified into two states depending on the particle mass content. One is a state in which the coating film consisted of two layers: a lower particle-rich layer and an upper polymer-rich layer. This type of structure was observed in the PD-adsorbed PSP as well as in the D-adsorbed PSP. In the other state, polymer and particles are homogeneously distributed in the film, and pores are formed. This difference in the coating structure results in a change in the time response. PMID- 30463317 TI - Chemometric Assessment and Best-Fit Function Modelling of the Toxic Potential of Selected Food Packaging Extracts. AB - Food packaging materials constitute an ever more threatening environmental pollutant. This study examined options to specifically assess the ecotoxicity of packaged wastes, such as cans, subjected to various experimental treatments (in terms of extraction media, time of exposure, and temperature) that imitate several basic conditions of the process of food production. The extracts were studied for their ecotoxicity with bioluminescent Vibrio fischeri bacteria. The first objective of this study was to find patterns of similarity between different experimental conditions; we used multivariate statistical methods, such as hierarchical cluster analysis, to interpret the impact of experimental conditions on the ecotoxicity signals of the package extracts. Our second objective was to apply best-fit function modelling for additional data interpretation, taking into account, that ecotoxicity for various temperature conditions is time- and temperature dependent. We mathematically confirmed that chemometric data treatment allows for better understanding how different experimental conditions imitating the real use of food packaging. We also demonstrate that the level of ecotoxicity depends on different extraction media, time of exposure, and temperature regime. PMID- 30463316 TI - An Enrichment Analysis for Cardiometabolic Traits Suggests Non-Random Assignment of Genes to microRNAs. AB - MicroRNAs (miRNAs) regulate the expression of the majority of genes. However, it is not known whether they regulate genes in random or are organized according to their function. To this end, we chose cardiometabolic disorders as an example and investigated whether genes associated with cardiometabolic disorders are regulated by a random set of miRNAs or a limited number of them. Single nucleotide polymorphisms (SNPs) reaching genome-wide level significance were retrieved from most recent genome-wide association studies on cardiometabolic traits, which were cross-referenced with Ensembl to identify related genes and combined with miRNA target prediction databases (TargetScan, miRTarBase, or miRecords) to identify miRNAs that regulate them. We retrieved 520 SNPs, of which 355 were intragenic, corresponding to 304 genes. While we found a higher proportion of genes reported from all GWAS that were predicted targets for miRNAs in comparison to all protein-coding genes (75.1%), the proportion was even higher for cardiometabolic genes (80.6%). Enrichment analysis was performed within each database. We found that cardiometabolic genes were over-represented in target genes for 29 miRNAs (based on TargetScan) and 3 miRNAs (miR-181a, miR-302d and miR-372) (based on miRecords) after Benjamini-Hochberg correction for multiple testing. Our work provides evidence for non-random assignment of genes to miRNAs and supports the idea that miRNAs regulate sets of genes that are functionally related. PMID- 30463314 TI - The Effect of Small Doses of Fructose and Its Epimers on Glycemic Control: A Systematic Review and Meta-Analysis of Controlled Feeding Trials. AB - Objective: Contrary to the concerns that fructose may have adverse metabolic effects, an emerging literature has shown that small doses (<=10 g/meal) of fructose and its low-caloric epimers (allulose, tagatose, and sorbose) decrease the glycemic response to high glycemic index meals. Whether these acute reductions manifest as sustainable improvements in glycemic control is unclear. Our objective was to synthesize the evidence from controlled feeding trials that assessed the effect of small doses of fructose and its low-caloric epimers on glycemic control. Methods: We searched MEDLINE, EMBASE, and the Cochrane Library through April 18, 2018. We included controlled feeding trials of >=1 week that investigated the effect of small doses (<=50 g/day or <=10% of total energy intake/day) of fructose and its low-caloric epimers on HbA1c, fasting glucose, and fasting insulin. Two independent reviewers extracted data and assessed risk of bias. Data were pooled using the generic inverse variance method and expressed as mean differences (MDs) with 95% confidence intervals (CIs). Heterogeneity was assessed using the Cochran Q statistic and quantified using the I2 statistic. Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessed the certainty of the evidence. Results: We identified 14 trial comparisons (N = 337) of the effect of fructose in individuals with and without diabetes, 3 trial comparisons (N = 138) of the effect of allulose in individuals without diabetes, 3 trial comparisons (N = 376) of the effect of tagatose mainly in individuals with type 2 diabetes, and 0 trial comparisons of the effect of sorbose. Small doses of fructose and tagatose significantly reduced HbA1c (MD = 0.38% (95% CI: -0.64%, -0.13%); MD = -0.20% (95% CI: -0.34%, -0.06%)) and fasting glucose (MD = -0.13 mmol/L (95% CI: -0.24 mmol/L, -0.03 mmol/L)); MD = -0.30 mmol/L (95% CI: -0.57 mmol/L, -0.04 mmol/L)) without affecting fasting insulin (p > 0.05). Small doses of allulose did not have a significant effect on HbA1c and fasting insulin (p > 0.05), while the reduction in fasting glucose was of borderline significance (p = 0.05). The certainty of the evidence of the effect of small doses of fructose and allulose on HbA1c, fasting glucose, and fasting insulin was graded as low. The certainty of the evidence of the effect of tagatose on HbA1c, fasting glucose, and fasting insulin was graded as moderate. Conclusions: Our results indicate that small doses of fructose and tagatose may improve glycemic control over the long term. There is a need for long-term randomized controlled trials for all four sugars to improve our certainty in the estimates. PMID- 30463318 TI - EGFET-Based Sensors for Bioanalytical Applications: A Review. AB - Since the 1970s, a great deal of attention has been paid to the development of semiconductor-based biosensors because of the numerous advantages they offer, including high sensitivity, faster response time, miniaturization, and low-cost manufacturing for quick biospecific analysis with reusable features. Commercial biosensors have become highly desirable in the fields of medicine, food, and environmental monitoring as well as military applications, whereas increasing concerns about food safety and health issues have resulted in the introduction of novel legislative standards for these sensors. Numerous devices have been developed for monitoring biological processes such as nucleic acid hybridization, protein-protein interaction, antigen-antibody bonds, and substrate-enzyme reactions, just to name a few. Since the 1980s, scientific interest moved to the development of semiconductor-based devices, which also include integrated front end electronics, such as the extended-gate field-effect transistor (EGFET) biosensor, one of the first miniaturized chemical sensors. This work is intended to be a review of the state of the art focused on the development of biosensors and chemosensors based on extended-gate field-effect transistor within the field of bioanalytical applications, which will highlight the most recent research reported in the literature. Moreover, a comparison among the diverse EGFET devices will be presented, giving particular attention to the materials and technologies. PMID- 30463319 TI - Discovery of Novel Druggable Sites on Zika Virus NS3 Helicase Using X-ray Crystallography-Based Fragment Screening. AB - The flavivirus family contains several important human pathogens, such as Zika virus (ZIKV), dengue, West Nile, and Yellow Fever viruses, that collectively lead to a large, global disease burden. Currently, there are no approved medicines that can target these viruses. The sudden outbreak of ZIKV infections in 2015 2016 posed a serious threat to global public health. While the epidemic has receded, persistent reservoirs of ZIKV infection can cause reemergence. Here, we have used X-ray crystallography-based screening to discover two novel sites on ZIKV NS3 helicase that can bind drug-like fragments. Both sites are structurally conserved in other flaviviruses, and mechanistically significant. The binding poses of four fragments, two for each of the binding sites, were characterized at atomic precision. Site A is a surface pocket on the NS3 helicase that is vital to its interaction with NS5 polymerase and formation of the flaviviral replication complex. Site B corresponds to a flexible, yet highly conserved, allosteric site at the intersection of the three NS3 helicase domains. Saturation transfer difference nuclear magnetic resonance (NMR) experiments were additionally used to evaluate the binding strength of the fragments, revealing dissociation constants (KD) in the lower mM range. We conclude that the NS3 helicase of flaviviruses is a viable drug target. The data obtained open opportunities towards structure based design of first-in-class anti-ZIKV compounds, as well as pan-flaviviral therapeutics. PMID- 30463320 TI - Multisensor-Based Target-Tracking Algorithm with Out-of-Sequence-Measurements in Cluttered Environments. AB - A localization and tracking algorithm for an early-warning tracking system based on the information fusion of Infrared (IR) sensor and Laser Detection and Ranging (LADAR) is proposed. The proposed Kalman filter scheme incorporates Out-of Sequence Measurements (OOSMs) to address long-range, high-speed incoming targets to be tracked by networked Remote Observation Sites (ROS) in cluttered environments. The Rauch-Tung-Striebel (RTS) fixed lag smoothing algorithm is employed in the proposed technique to further improve tracking accuracy, which, in turn, is used for target profiling and efficient filter initialization at the targeted platform. This efficient initialization increases the probability of target engagement by increasing the distance at which it can be effectively engaged. The increased target engagement range also reduces risk of any damage from debris of the engaged target. Performance of the proposed target localization algorithm with OOSM and RTS smoothing is evaluated in terms of root mean square error (RMSE) for both position and velocity, which accurately depicts the improved performance of the proposed algorithm in comparison with existing retrodiction-based OOSM filtering algorithms. The effects of assisted target state initialization at the targeted platform are also evaluated in terms of Time to Impact (TTI) and true track retention, which also depict the advantage of the proposed strategy. PMID- 30463321 TI - Pharmacokinetics of Toxin-Derived Peptide Drugs. AB - Toxins and venoms produced by different organisms contain peptides that have evolved to have highly selective and potent pharmacological effects on specific targets for protection and predation. Several toxin-derived peptides have become drugs and are used for the management of diabetes, hypertension, chronic pain, and other medical conditions. Despite the similarity in their composition (amino acids as the building blocks), toxin-derived peptide drugs have very profound differences in their structure and conformation, in their physicochemical properties (that affect solubility, stability, etc.), and subsequently in their pharmacokinetics (the processes of absorption, distribution, metabolism, and elimination following their administration to patients). This review summarizes and critically analyzes the pharmacokinetic properties of toxin-derived peptide drugs: (1) the relationship between the chemical structure, physicochemical properties, and the pharmacokinetics of the specific drugs, (2) the major pharmacokinetic properties and parameters of these drugs, and (3) the major pharmacokinetic variability factors of the individual drugs. The structural properties of toxin-derived peptides affect their pharmacokinetics and pose some limitations on their clinical use. These properties should be taken into account during the development of new toxin-derived peptide drugs, and for the efficient and safe use of the clinically approved drugs from this group in the individual patients. PMID- 30463323 TI - Metabolomics of Breast Milk: The Importance of Phenotypes. AB - Breast milk is the gold standard of nutrition for newborns. Its composition is tailored to the nutritional needs of the infant and varies between mothers. In recent years, several bioactive molecules have been discovered in addition to the main nutrients, such as multipotent stem cells, hormones, immunoglobulins, and bacteria. Furthermore, the human milk oligosaccharides (HMOs) seem to exert several important protective biological functions. According to the HMOs' composition, breast milk can be classified as a secretory or non-secretory phenotype. In our study, we investigated the metabolome of milk collected from 58 mothers that delivered neonates at term, that were appropriate, small or large for gestational age, by performing nuclear magnetic resonance spectroscopy (1H NMR). From the data analysis, two groups were distinguished based on their different types of oligosaccharides, and classified according the mother phenotype: secretory and non-secretory. This information is of major importance given the different biological function of the different HMOs, such as immune modulation and protection against disease. This would allow us to predict whether the neonate would be, for instance, more prone to developing certain diseases, and to tailor her or his nutrition to fit their needs perfectly and pave the way to a personalized nutrition. PMID- 30463322 TI - Human Glioma Migration and Infiltration Properties as a Target for Personalized Radiation Medicine. AB - Gliomas are primary brain tumors that present the majority of malignant adult brain tumors. Gliomas are subdivided into low- and high-grade tumors. Despite extensive research in recent years, the prognosis of malignant glioma patients remains poor. This is caused by naturally highly infiltrative capacities as well as high levels of radio- and chemoresistance. Additionally, it was shown that low linear energy transfer (LET) irradiation enhances migration and invasion of several glioma entities which might counteract today's treatment concepts. However, this finding is discussed controversially. In the era of personalized medicine, this controversial data might be attributed to the patient-specific heterogeneity that ultimately could be used for treatment. Thus, current developments in glioma therapy should be seen in the context of intrinsic and radiation-enhanced migration and invasion. Due to the natural heterogeneity of glioma cells and different radiation responses, a personalized radiation treatment concept is suggested and alternative radiation concepts are discussed. PMID- 30463324 TI - Effects of an Aqueous Extract of Withania somnifera on Strength Training Adaptations and Recovery: The STAR Trial. AB - Withania somnifera (Ashwagandha) is an Ayurvedic herb categorized as having "rasayana" (rejuvenator), longevity, and revitalizing properties. Sensoril(r) is a standardized aqueous extract of the roots and leaves of Withania somnifera. Purpose: To examine the impact of Sensoril(r) supplementation on strength training adaptations. Methods: Recreationally active men (26.5 +/- 6.4 years, 181 +/- 6.8 cm, 86.9 +/- 12.5 kg, 24.5 +/- 6.6% fat) were randomized in a double blind fashion to placebo (PLA, n = 19) or 500 mg/d Sensoril(r) (S500, n = 19). Body composition (DEXA), muscular strength, power, and endurance, 7.5 km cycling time trial, and clinical blood chemistries were measured at baseline and after 12 weeks of supplementation and training. Subjects were required to maintain their normal dietary habits and to follow a specific, progressive overload resistance training program (4-day/week, upper body/lower body split). 2 * 2 mixed factorial ANOVA was used for analysis and statistical significance was set a priori at p <= 0.05. Results: Gains in 1-RM squat (S500: +19.1 +/- 13.0 kg vs. PLA +10.0 +/- 6.2 kg, p = 0.009) and bench press (S500: +12.8 +/- 8.2 kg vs. PLA: +8.0 +/- 6.0 kg, p = 0.048) were significantly greater in S500. Changes in DEXA-derived android/gynoid ratio (S500: +0.0 +/- 0.14 vs. PLA: +0.09 +/- 0.1, p = 0.03) also favored S500. No other between-group differences were found for body composition, visual analog scales for recovery and affect, or systemic hemodynamics, however, only the S500 group experienced statistically significant improvements in average squat power, peak bench press power, 7.5 km time trial performance, and perceived recovery scores. Clinical chemistry analysis indicated a slight polycythemia effect in PLA, with no other statistical or clinically relevant changes being noted. Conclusions: A 500 mg dose of an aqueous extract of Ashwagandha improves upper and lower-body strength, supports a favorable distribution of body mass, and was well tolerated clinically in recreationally active men over a 12-week resistance training and supplementation period. PMID- 30463325 TI - P(N-Phenylmaleimide-Alt-Styrene) Introduced with 4-Carboxyl and Its Effect on the Heat Deflection Temperature of Nylon 6. AB - P(N-phenylmaleimide-alt-styrene) (P(NPMI-alt-St)) and P(N-(4 carboxyphenyl)maleimide-alt-styrene) (P(CPMI-alt-St)) were designed and synthesized via free radical copolymerization. Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance spectroscopy (1H NMR and 13C NMR), gel permeation chromatography (GPC), and differential scanning calorimetry (DSC) were used to confirm the structure of P(NPMI-alt-St) and P(CPMI-alt-St). Next, the effect of P(CPMI-alt-St) on the heat deflection temperature (HDT) of nylon 6 was studied. In comparison to the PA6/P(NPMI-alt-St) blend, with the addition of 10 wt %, the HDT value of the PA6/P(CPMI-alt-St) blend increased by 15.7 degrees C, and the glass transition temperature (Tg) by Dynamic mechanical analysis (DMA) increased 2.3 degrees C. According to the analysis of DMA, dynamic viscosity, and the SEM of PA6 and its blends, P(CPMI-alt-St) promoted its compatibility with PA6, and promoted the storage modulus and dynamic viscosity of the blends. Thus, the introduction of 4-carboxyl can significantly improve the effect of P(CPMI-alt-St) on the heat resistance modification of nylon 6. PMID- 30463326 TI - Hydrogen Production from Energy Poplar Preceded by MEA Pre-Treatment and Enzymatic Hydrolysis. AB - The need to pre-treat lignocellulosic biomass prior to dark fermentation results primarily from the composition of lignocellulose because lignin hinders the processing of hard wood towards useful products. Hence, in this work a two-step approach for the pre-treatment of energy poplar, including alkaline pre-treatment and enzymatic saccharification followed by fermentation has been studied. Monoethanolamine (MEA) was used as the alkaline catalyst and diatomite immobilized bed enzymes were used during saccharification. The response surface methodology (RSM) method was used to determine the optimal alkaline pre-treatment conditions resulting in the highest values of both total released sugars (TRS) yield and degree of lignin removal. Three variable parameters (temperature, MEA concentration, time) were selected to optimize the alkaline pre-treatment conditions. The research was carried out using the Box-Behnken design. Additionally, the possibility of the re-use of both alkaline as well as enzymatic reagents was investigated. Obtained hydrolysates were subjected to dark fermentation in batch reactors performed by Enterobacter aerogenes ATCC 13048 with a final result of 22.99 mL H2/g energy poplar (0.6 mol H2/mol TRS). PMID- 30463327 TI - Methyl-beta-Cyclodextrin Impairs the Phosphorylation of the beta2 Subunit of L Type Calcium Channels and Cytosolic Calcium Homeostasis in Mature Cerebellar Granule Neurons. AB - The activation of L-type calcium channels (LTCCs) prevents cerebellar granule neurons (CGNs) from entering low-K+-induced apoptosis. In previous works, we showed that LTCCs are largely associated with caveolin-1-rich lipid rafts in the CGN plasma membrane. In this work, we show that protein kinase A (PKA) and calmodulin-dependent protein kinase II (CaMK-II) are associated with caveolin-1 rich lipid rafts of mature CGNs, and we further show that treatment with the cholesterol-trapping and lipid raft-disrupting agent methyl-beta-cyclodextrin decreases the phosphorylation level of the LTCC beta2 subunit and the steady state calcium concentration in neuronal somas ([Ca2+]i) to values close to those measured in 5 mM KCl proapoptotic conditions. These effects correlate with the effects produced by a short (15 min) treatment of CGNs with H-89 and KN-93 inhibitors of PKA and CaMK-II, respectively-in 25 mM KCl medium. Moreover, only a 15 min incubation of CGNs with H-89 produces about a 90% inhibition of the calcium entry that would normally occur through LTCCs to increase [Ca2+]i upon raising the extracellular K+ from 5 to 25 mM, i.e., from proapoptotic to survival conditions. In conclusion, the results of this work suggest that caveolin-1-rich lipid rafts play a major role in the control of the PKA- and CaMK-II-induced phosphorylation level of the LTCC beta2 subunit, thus preventing CGNs from entering apoptosis. PMID- 30463328 TI - Effect of Samarium on the Microstructure and Corrosion Resistance of AZ91 Magnesium Alloy Treated by Ultrasonic Vibration. AB - The effects of samarium (Sm) on the microstructure and corrosion behavior of AZ91 magnesium alloy treated by ultrasonic vibration were investigated by scanning electron microscopy, X-ray diffraction, transmission electron microscopy, and electrochemical measurements. The results showed that the addition of Sm resulted in the formation of Al2Sm, which reduced the volume fraction of the beta-Mg17Al12 phase and changed its morphology to fine granular. The AZ91-Sm alloys treated by ultrasonic vibration revealed relatively lower weight loss, hydrogen evolution, and corrosion current density values compared to the ultrasonic-treated AZ91 alloy prepared without Sm. Locally, a coarse beta phase in the ultrasonic-treated AZ91 alloy accelerated the possibility of micro-galvanic corrosion growing into the matrix. In the prepared AZ91-Sm alloys treated by ultrasonic vibration, the fine beta and Al2Sm phases reduced the probability of micro-galvanic corrosion growth and, therefore, formed a uniform corrosion layer on the surface of the alloys. PMID- 30463329 TI - Development of Paroxetine Hydrochloride Single Layer Controlled-Release Tablets Based on 32 Factorial Design. AB - Major depressive disorder (MDD) is one of the main contributors to disability and suicide mortality globally. Paroxetine hydrochloride (PHH) is the most potent antidepressant used for MDD treatment. Due to its reduced side effects PAXIL(r) CR is a widely-used controlled-release formulation of PHH. However, the complicated double-layer production of PAXIL(r) CR faces the risk of layer separation. In this study, PHH enteric coating single layer controlled-release tablets (PHH-EC-SLTs) were designed as a simplified substitution of PAXIL(r) CR through a rational formulation screening. The optimized PHH-EC-SLTs showed similar release behaviors in vitro to PAXIL(r) CR and the release profiles corresponded to a zero-order release model (R2 = 0.9958). Polymer matrix erosion was the main release mechanism, according to the fitting exponents n > 1 in the Korsmeyer-Pappas model. Crucial pharmacokinetic parameters including peak reaching time (Tmax), peak concentration (Cmax) and the area under the blood level-time curve (AUC0-48) of PHH-EC-SLTs and PAXIL(r) CR had no significant difference (p > 0.05) and the relative bioavailability (F = 97.97%) of PHH-EC SLTs demonstrated their similar pharmacokinetic profiles in vivo. In view of avoiding layer separation risk and simplifying the preparation processing, the self-made PHH-EC-SLTs could be considered as a safe and economic alternative to PAXIL(r) CR. PMID- 30463330 TI - Feedback-Based Treatments for Eating Disorders and Related Symptoms: A Systematic Review of the Literature. AB - The effectiveness of biofeedback and neurofeedback has been investigated in a range of psychiatric disorders. However, to date, there are few studies on the clinical usefulness of feedback-based techniques for eating disorders (EDs) and EDs-related symptoms (e.g., food craving). A systematic search of PubMed, Scopus and PsychINFO identified 162 articles. Among these, thirteen studies exploring the therapeutic use of biofeedback and neurofeedback in EDs or EDs-related symptoms were included. Biofeedback and neurofeedback were implemented respectively in five and eight of all reviewed articles. No studies incorporated different feedback modalities or both biofeedback and neurofeedback. The considered studies provide preliminary data of the usefulness of feedback-based techniques in the treatment of several dysfunctional eating behaviors (e.g., food craving, rumination). Although no significant effect has been reported for other important EDs-related symptoms (i.e., body image disturbance), feedback-based techniques are also associated with significant modifications of both sympathetic reaction to food-related stimuli and brain activity in several regions of the reward system (e.g., insula). Taken together the results of the present review suggest that feedback-based treatments may be useful in the treatment of several dysfunctional eating behaviors operating both on top-down and bottom-up individual coping strategies. Methodological and clinical issues are also discussed. PMID- 30463331 TI - Adaptation Mechanism of Salt Excluders under Saline Conditions and Its Applications. AB - Global soil salinization is increasingly a serious threat to agriculture worldwide. Therefore, it is imperative to improve crop salt tolerance as a means of adaptation to saline habitats. Some halophytes and most monocotyledonous crops are salt-excluders. Understanding the regulatory mechanisms of salt exclusion at the molecular level in salt-exclusion plants is critical for improving the salt tolerance of monocotyledonous crops such as maize, wheat, rice, and sorghum. In this review, we summarize recent research into salt-exclusion mechanisms and the genes that underlie them. Findings related to salt exclusion may accelerate the process of breeding tolerant cultivars by using genomic and molecular tools. PMID- 30463332 TI - The Plant Circadian Clock and Chromatin Modifications. AB - The circadian clock is an endogenous timekeeping network that integrates environmental signals with internal cues to coordinate diverse physiological processes. The circadian function depends on the precise regulation of rhythmic gene expression at the core of the oscillators. In addition to the well characterized transcriptional feedback regulation of several clock components, additional regulatory mechanisms, such as alternative splicing, regulation of protein stability, and chromatin modifications are beginning to emerge. In this review, we discuss recent findings in the regulation of the circadian clock function in Arabidopsis thaliana. The involvement of chromatin modifications in the regulation of the core circadian clock genes is also discussed. PMID- 30463333 TI - Maritoclax Enhances TRAIL-Induced Apoptosis via CHOP-Mediated Upregulation of DR5 and miR-708-Mediated Downregulation of cFLIP. AB - Maritoclax, an active constituent isolated from marine bacteria, has been known to induce Mcl-1 downregulation through proteasomal degradation. In this study, we investigated the sensitizing effect of maritoclax on tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma cells. We found that combined treatment with maritoclax and TRAIL markedly induced apoptosis in renal carcinoma (Caki, ACHN and A498), lung cancer (A549) and hepatocellular carcinoma (SK-Hep1) cells. The upregulation of death receptor 5 (DR5) and downregulation of cellular FLICE-inhibitory protein (cFLIP) were involved in maritoclax plus TRAIL-induced apoptosis. Maritoclax-induced DR5 upregulation was regulated by induction of C/EBP homologous protein (CHOP) expression. Interestingly, maritoclax induced cFLIP downregulation through the increased expression of miR-708. Ectopic expression of cFLIP prevented combined maritoclax and TRAIL-induced apoptosis. Taken together, maritoclax sensitized TRAIL-induced apoptosis through CHOP-mediated DR5 upregulation and miR-708 mediated cFLIP downregulation. PMID- 30463334 TI - Recombinant Lassa Virus Expressing Green Fluorescent Protein as a Tool for High Throughput Drug Screens and Neutralizing Antibody Assays. AB - Lassa virus (LASV), a mammarenavirus, infects an estimated 100,000-300,000 individuals yearly in western Africa and frequently causes lethal disease. Currently, no LASV-specific antivirals or vaccines are commercially available for prevention or treatment of Lassa fever, the disease caused by LASV. The development of medical countermeasure screening platforms is a crucial step to yield licensable products. Using reverse genetics, we generated a recombinant wild-type LASV (rLASV-WT) and a modified version thereof encoding a cleavable green fluorescent protein (GFP) as a reporter for rapid and quantitative detection of infection (rLASV-GFP). Both rLASV-WT and wild-type LASV exhibited similar growth kinetics in cultured cells, whereas growth of rLASV-GFP was slightly impaired. GFP reporter expression by rLASV-GFP remained stable over several serial passages in Vero cells. Using two well-characterized broad spectrum antivirals known to inhibit LASV infection, favipiravir and ribavirin, we demonstrate that rLASV-GFP is a suitable screening tool for the identification of LASV infection inhibitors. Building on these findings, we established a rLASV GFP-based high-throughput drug discovery screen and an rLASV-GFP-based antibody neutralization assay. Both platforms, now available as a standard tool at the IRF Frederick (an international resource), will accelerate anti-LASV medical countermeasure discovery and reduce costs of antiviral screens in maximum containment laboratories. PMID- 30463335 TI - Cacolides: Sesterterpene Butenolides from a Southern Australian Marine Sponge, Cacospongia sp. AB - Chemical analysis of a marine sponge, Cacospongia sp. (CMB-03404), obtained during deep sea commercial fishing activities off the southern coast of Australia, yielded an unprecedented family of sesterterpene alpha-methyl-gamma hydroxybutenolides, cacolides A-L (1-12), together with biosynthetically related norsesterterpene carboxylic acids, cacolic acids A-C (13-15). Structures were assigned on the basis of detailed spectroscopic analysis with comparisons to known natural products and biosynthetic considerations. In addition to revealing new chemical diversity, this study provided a valuable platform for comparing and contrasting the capabilities of the traditional dereplication technologies of HPLC-DAD, HPLC-MS and NMR, with those of the emerging HPLC-MS/MS approach known as global natural products social molecular networking (GNPS), as applied to marine sponge sesterterpene tetronic acids. PMID- 30463336 TI - Human Activity Recognition Based on Symbolic Representation Algorithms for Inertial Sensors. AB - Mobile sensing has allowed the emergence of a variety of solutions related to the monitoring and recognition of human activities (HAR). Such solutions have been implemented in smartphones for the purpose of better understanding human behavior. However, such solutions still suffer from the limitations of the computing resources found on smartphones. In this sense, the HAR area has focused on the development of solutions of low computational cost. In general, the strategies used in the solutions are based on shallow and deep learning algorithms. The problem is that not all of these strategies are feasible for implementation in smartphones due to the high computational cost required, mainly, by the steps of data preparation and the training of classification models. In this context, this article evaluates a new set of alternative strategies based on Symbolic Aggregate Approximation (SAX) and Symbolic Fourier Approximation (SFA) algorithms with the purpose of developing solutions with low computational cost in terms of memory and processing. In addition, this article also evaluates some classification algorithms adapted to manipulate symbolic data, such as SAX-VSM, BOSS, BOSS-VS and WEASEL. Experiments were performed on the UCI-HAR, SHOAIB and WISDM databases commonly used in the literature to validate HAR solutions based on smartphones. The results show that the symbolic representation algorithms are faster in the feature extraction phase, on average, by 84.81%, and reduce the consumption of memory space, on average, by 94.48%, and they have accuracy rates equivalent to conventional algorithms. PMID- 30463337 TI - A Simple and Efficient Synthesis of Highly Substituted Indeno[1,2-b]pyrrole and Acenaphtho[1,2-b]pyrrole Derivatives by Tandem Three-Component Reactions. AB - A green, convenient and tandem procedure for the efficient synthesis of highly substituted indeno[1,2-b]pyrrole and acenaphtho[1,2-b]pyrrole derivatives by domino three-component reaction of tryptamine/benzylamine, 1,3-dicarbonyl compounds and ninhydrin/ acenaphthenequinone is described. The significant features of this procedure were characterized by mild reaction conditions, high yields, operational simplicity and it being environmentally benign. PMID- 30463338 TI - Nanobody-Alkaline Phosphatase Fusion Protein-Based Enzyme-Linked Immunosorbent Assay for One-Step Detection of Ochratoxin A in Rice. AB - Ochratoxin A (OTA) has become one a focus of public concern because of its multiple toxic effects and widespread contamination. To monitor OTA in rice, a sensitive, selective, and one-step enzyme-linked immunosorbent assay (ELISA) using a nanobody-alkaline phosphatase fusion protein (Nb28-AP) was developed. The Nb28-AP was produced by auto-induction expression and retained an intact antigen binding capacity and enzymatic activity. It exhibited high thermal stability and organic solvent tolerance. Under the optimal conditions, the developed assay for OTA could be finished in 20 min with a half maximal inhibitory concentration of 0.57 ng mL-1 and a limit of detection of 0.059 ng mL-1, which was 1.1 times and 2.7 times lower than that of the unfused Nb28-based ELISA. The Nb28-AP exhibited a low cross-reactivity (CR) with ochratoxin B (0.92%) and ochratoxin C (6.2%), and an ignorable CR (<0.10%) with other mycotoxins. The developed Nb-AP-based one step ELISA was validated and compared with a liquid chromatography-tandem mass spectrometry method. The results show the reliability of Nb-AP-based one-step ELISA for the detection of OTA in rice. PMID- 30463339 TI - Design and Characterisation of a Fast Steering Mirror Compensation System Based on Double Porro Prisms by a Screw-Ray Tracing Method. AB - This study proposes a novel FSM compensation system for four degrees of freedom (DOF) laser errors compensation, which has the advantage of shorter optical path length, fewer elements and an easier set-up process, meaning that it can be used at different locations. A commercial software, Zemax, is used to evaluate the function of the proposed FSM compensation system and the mathematical modelling of the proposed FSM compensation system is established by using a skew-ray tracing method. Finally, the proposed FSM compensation system is then verified experimentally using a laboratory-built prototype and the result shows that the proposed FSM compensation system achieves the ability to compensate the 4 DOF of the laser source. PMID- 30463340 TI - Efficient Removal of Lead, Copper and Cadmium Ions from Water by a Porous Calcium Alginate/Graphene Oxide Composite Aerogel. AB - In this study, we fabricated a porous calcium alginate/graphene oxide composite aerogel by using polystyrene colloidal particles as sacrificial template and graphene oxide as a reinforcing filler. Owing to the excellent metal chelation ability of calcium alginate and controlled nanosized pore structure, the as prepared calcium alginate/graphene oxide composite aerogel (mp-CA/GO) can reach the adsorption equilibrium in 40 min, and the maximum adsorption capacity for Pb2+, Cu2+ and Cd2+ is 368.2, 98.1 and 183.6 mg/g, respectively. This is higher than most of the reported heavy metal ion sorbents. Moreover, the mp-CA/GO can be regenerated through simple acid-washing and be used repeatedly with little loss in performance. The adsorption mechanism analysis indicates that the mp-CA/GO adsorb the heavy metal ions mainly through the ion exchange and chemical coordination effects. PMID- 30463341 TI - Anionic Long-Circulating Quantum Dots for Long-Term Intravital Vascular Imaging. AB - A major impediment to the long-term in vivo vascular imaging is a lack of suitable probes and contrast agents. Our developed mercaptosuccinic acid (MSA) capped cadmium telluride/cadmium sulfide (CdTe/CdS) ultrasmall quantum dots (QDs) have high fluorescent quantum yield, long fluorescence lifetime and long half life in blood, allowing high resolution long-term intravital vascular imaging. In this study, we showed that these QDs can be used to visualize the in vivo the vasculature in normal and cancerous livers in mice using multiphoton microscopy (MPM) coupled with fluorescence lifetime imaging (FLIM), with cellular resolution (~1 um) up to 36 h after intravenous injection. Compared to highly regulated and controlled sinusoids in normal liver tissue, disordered, tortuous, and immature neovessels were observed in tumors. The utilized imaging methods have great potential as emerging tools in diagnosis and monitoring of treatment response in cancer. PMID- 30463342 TI - Web Page Design Recommendations for People with Down Syndrome Based on Users' Experiences. AB - At present, there is a high number of people with Down syndrome interested and trained to be an active part of society. According to the data extracted by our surveys we know that only 6% of the population with Down syndrome feels isolated in daily activities. However, when the activity requires the use of a computer, the percentage of people who feel isolated increases to 18%. This means that there are obvious website accessibility barriers that make it difficult for users with Down syndrome. To solve this problem, it is considered necessary to make an exhaustive study about Down syndrome. We know that the trisomy of chromosome 21 causes a series of symptoms that directly affect ones Internet browsing capabilities. For example, speech disturbances make communication and speed difficult. This guide is based on a neurological study of Down syndrome. Alterations in listening make understanding audio, retention of audio concepts and speed difficult. The alterations in the physiognomy of movement make it difficult for them to act quickly. Many of these alterations are caused by cognitive disability. After assessing the needs, the benefits of Web Content Accessibility Guidelines 2.0 (WCAG 2.0), and the existing usability guidelines are analyzed and those that may be useful for this profile are extracted. User tests are carried out through two websites developed specifically for this study with the aim of demonstrating the level of effectiveness of each of the planned guidelines. Considering the neurological characteristics of this intellectual disability, research is developed that seeks to extract a list of useful accessibility and usability guidelines for web developers. PMID- 30463344 TI - Inverse Identification of Elastic Properties of Constituents of Discontinuously Reinforced Composites. AB - This paper is devoted to determination of elastic properties of composite constituents by using an inverse identification procedure. The aim of the developed identification procedure is to compute the elastic constants of individual material phases on the basis of known properties of composite materials. The inverse problem of identification has been solved by combining an evolutionary algorithm with a micromechanical model. The paper also focuses on selection of a suitable micromechanical model for optimization which should ensure a compromise between accuracy and complexity. Two different cases have been studied: composite reinforced with short cylindrical fibers and composite reinforced with cubic particles. Moreover, Monte Carlo simulations have been carried out to expose a difference in outcome of identification which may occur when uncertain input data is considered. Obtained results show that identification is successful only when properties of composite materials with at least two different volume fractions of the reinforcement are known. PMID- 30463343 TI - Advanced Radiation Techniques in the Treatment of Esthesioneuroblastoma: A 7-Year Single-Institution's Clinical Experience. AB - (1) Background: Esthesioneuroblastoma (ENB) is a rare tumor entity originating from the olfactory neuroepithelium. There is a scarcity of data about different treatment strategies. Intensity modulated radiotherapy (IMRT) and carbon ion radiotherapy (CIRT) are advanced radiation techniques that might improve local tumor control. (2) Methods: This retrospective analysis contained 17 patients with ENB (Kadish stage >= C: 88%; n = 15). Four patients had already undergone previous radiotherapy (RT). The treatment consisted of either IMRT (n = 5), CIRT (n = 4) or a combination of both techniques (n = 8). Median follow-up was 29 months. (3) Results: In patients that had not been irradiated before (n = 13), calculated overall survival (OS) and progression free survival (PFS) rates after 48 months were 100% and 81% respectively (Kaplan-Meier estimates). Two of four patients that underwent reirradiation died after RT, presumably due to tumor progression. Besides common toxicities, five patients (30%) showed mostly asymptomatic radiation-induced brain changes, most likely due to a disturbance of the blood-brain barrier. (4) Conclusions: Our results demonstrate that IMRT, CIRT, a combined approach of IMRT and CIRT as well as reirradiation with CIRT seem to be feasible and effective treatment methods in ENB. PMID- 30463346 TI - Whisper: Programmable and Flexible Control on Industrial IoT Networks. AB - Software Defined Networking (SDN) centralizes network control to improve network programmability and flexibility. Contrary to wired settings, it is unclear how to support SDN in low power and lossy networks like typical Internet of Things (IoT) ones. Challenges encompass providing reliable in-band connectivity between the centralized controller and out-of-range nodes, and coping with physical limitations of the highly resource-constrained IoT devices. In this work, we present Whisper, an enabler for SDN in low power and lossy networks. The centralized Whisper controller of a network remotely controls nodes' forwarding and cell allocation. To do so, the controller sends carefully computed routing and scheduling messages that are fully compatible with the protocols run in the network. This mechanism ensures the best possible in-band connectivity between the controller and all network nodes, capitalizing on an interface which is already supported by network devices. Whisper's internal algorithms further reduce the number of messages sent by the controller, to make the exerted control as lightweight as possible for the devices. Beyond detailing Whisper's design, we discuss compelling use cases that Whisper unlocks, including rerouting around low battery devices and providing runtime defense to jamming attacks. We also describe how to implement Whisper in current IoT open standards (RPL and 6TiSCH) without modifying IoT devices' firmware. This shows that Whisper can implement an SDN-like control for distributed low power networks with no specific support for SDN, from legacy to next generation IoT devices. Our testbed experiments show that Whisper successfully controls the network in both the scheduling and routing plane, with significantly less overhead than other SDN-IoT solutions, no additional latency and no packet loss. PMID- 30463345 TI - Annurca Apple Polyphenols Protect Murine Hair Follicles from Taxane Induced Dystrophy and Hijacks Polyunsaturated Fatty Acid Metabolism toward beta Oxidation. AB - Chemotherapy-induced alopecia (CIA) is a common side effect of conventional chemotherapy and represents a major problem in clinical oncology. Even months after the end of chemotherapy, many cancer patients complain of hair loss, a condition that is psychologically difficult to manage. CIA disturbs social and sexual interactions and causes anxiety and depression. Synthetic drugs protecting from CIA and endowed with hair growth stimulatory properties are prescribed with caution by oncologists. Hormones, growth factors, morphogens could unwontedly protect tumour cells or induce cancer cell proliferation and are thus considered incompatible with many chemotherapy regimens. Nutraceuticals, on the contrary, have been shown to be safe and effective treatment options for hair loss. We here show that polyphenols from Malus Pumila Miller cv Annurca are endowed with hair growth promoting activity and can be considered a safe alternative to avoid CIA. In vitro, Annurca Apple Polyphenolic Extract (AAE) protects murine Hair Follicles (HF) from taxanes induced dystrophy. Moreover, in virtue of its mechanism of action, AAE is herein proven to be compatible with chemotherapy regimens. AAE forces HFs to produce ATP using mitochondrial beta-oxidation, reducing Pentose Phosphate Pathway (PPP) rate and nucleotides production. As consequence, DNA replication and mitosis are not stimulated, while a pool of free amino acids usually involved in catabolic reactions are spared for keratin production. Moreover, measuring the effect exerted on Poly Unsaturated Fatty Acid (PUFA) metabolism, we prove that AAE promotes hair-growth by increasing the intracellular levels of Prostaglandins F2alpha (PGF2alpha) and by hijacking PUFA catabolites toward beta-oxidation. PMID- 30463347 TI - Title IX Mandated Reporting: The Views of University Employees and Students. AB - Per Title IX of the Higher Education Amendments of 1972, many university employees are mandated reporters of sexual assault. University employees (N = 174) and students (N = 783) completed an online survey assessing knowledge and opinions of this reporting requirement. University employees and students generally reported being quite knowledgeable of reporting requirements. Most university employees indicated they would report an incident disclosed by a student, but students were fairly ambivalent about whether they would disclose to faculty members. Nearly one in five students (17.2%) indicated that Title IX reporting requirements decreased their disclosure likelihood. These findings suggest that mandated reporting policies, as well as how they are presented to students and faculty, should be examined in order to increase compliance and facilitate disclosure. PMID- 30463348 TI - Mortality Characteristics of Two Populations in the Northern Mediterranean (Croatia) in the Period 1960-2012: An Ecological Study. AB - In the second half of the 20th century, the town of Bakar (Primorje-Gorski Kotar County, Croatia), where a coking plant was operational 1978-1994, experienced intensive industrialisation. The town of Mali Losinj (Primorje-Gorski Kotar County, Croatia) in this period based its economy on non-industrial sectors. The study goal was comparing mortality characteristics of these populations in the northern Mediterranean for 1960-2012. An ecological study design was used. Data were analysed for 1960-2012 for the deceased with recorded place of residence in the study area. Data on the deceased for 1960-1993 were taken from death reports, for 1994-2012 from digital archives of the Teaching Institute of Public Health, Primorje-Gorski Kotar County. Data on causes of death for 1960-1994 were recoded to the three-digit code of underlying cause of death according to the International Classification of Diseases (ICD-10). Among studied populations significant difference was found among the causes of deaths coded within ICD-10 chapters: neoplasms (particularly stomach carcinoma), mental and behavioural disorders and diseases of the respiratory system (particularly chronic obstructive pulmonary disease, (COPD)). Increase in mortality from neoplasms, increase in respiratory diseases for the area exposed to industrial pollution, also stomach carcinoma and COPD particularly in the town Bakar require further research. PMID- 30463349 TI - Central Nervous System Responses to Simulated Galactic Cosmic Rays. AB - In preparation for lunar and Mars missions it is essential to consider the challenges to human health that are posed by long-duration deep space habitation via multiple stressors, including ionizing radiation, gravitational changes during flight and in orbit, other aspects of the space environment such as high level of carbon dioxide, and psychological stress from confined environment and social isolation. It remains unclear how these stressors individually or in combination impact the central nervous system (CNS), presenting potential obstacles for astronauts engaged in deep space travel. Although human spaceflight research only within the last decade has started to include the effects of radiation transmitted by galactic cosmic rays to the CNS, radiation is currently considered to be one of the main stressors for prolonged spaceflight and deep space exploration. Here we will review the current knowledge of CNS damage caused by simulated space radiation with an emphasis on neuronal and glial responses along with cognitive functions. Furthermore, we will present novel experimental approaches to integrate the knowledge into more comprehensive studies, including multiple stressors at once and potential translation to human functions. Finally, we will discuss the need for developing biomarkers as predictors for cognitive decline and therapeutic countermeasures to prevent CNS damage and the loss of cognitive abilities. PMID- 30463350 TI - Functionalized Keratin as Nanotechnology-Based Drug Delivery System for the Pharmacological Treatment of Osteosarcoma. AB - Osteosarcoma therapy might be moving toward nanotechnology-based drug delivery systems to reduce the cytotoxicity of antineoplastic drugs and improve their pharmacokinetics. In this paper, we present, for the first time, an extensive chemical and in vitro characterization of dual-loaded photo- and chemo-active keratin nanoparticles as a novel drug delivery system to treat osteosarcoma. The nanoparticles are prepared from high molecular weight and hydrosoluble keratin, suitably functionalized with the photosensitizer Chlorin-e6 (Ce6) and then loaded with the chemotherapeutic drug Paclitaxel (PTX). This multi-modal PTX-Ce6@Ker nanoformulation is prepared by both drug-induced aggregation and desolvation methods, and a comprehensive physicochemical characterization is performed. PTX Ce6@Ker efficacy is tested on osteosarcoma tumor cell lines, including chemo resistant cells, using 2D and 3D model systems. The single and combined contributions of PTX and Ce6 is evaluated, and results show that PTX retains its activity while being vehiculated through keratin. Moreover, PTX and Ce6 act in an additive manner, demonstrating that the combination of the cytostatic blockage of PTX and the oxidative damage of ROS upon light irradiation have a far superior effect compared to singularly administered PTX or Ce6. Our findings provide the proof of principle for the development of a novel, nanotechnology-based drug delivery system for the treatment of osteosarcoma. PMID- 30463351 TI - Long Working Hours and Job Quality in Europe: Gender and Welfare State Differences. AB - Chronic extreme long working hours (LWH) have been found consistently associated with poor health status. However, the evidence for moderately LWH (41-60 h a week) is contradictory. Although poor job quality has been proposed as one of the mechanisms of this relationship, there are almost no studies about LWH and job quality. The objectives of this study were to analyze the association between moderately LWH and job quality in the EU27, as well as to examine differences by welfare regimes and gender. This is a cross-sectional study based on data from the 2010 European Working Conditions Survey. A subsample of employees from the EU27 aged 16-64 years who worked 30-60 h a week was selected (12,574 men and 8787 women). Overall, moderately LWH were not consistently associated with poor job quality except among women from Eastern European countries. Therefore, in the EU27 poor job quality does not seem to explain the relationship between moderately LWH and poor health status. The findings among women from Eastern European countries may be related to their weakened position in the labor market and to their work-family conflict resulting from a process of re-familisation that constrains their choices for a good job. PMID- 30463352 TI - It's Hard to Avoid Avoidance: Uncoupling the Evolutionary Connection between Plant Growth, Productivity and Stress "Tolerance". AB - In the last 100 years, agricultural developments have favoured selection for highly productive crops, a fact that has been commonly associated with loss of key traits for environmental stress tolerance. We argue here that this is not exactly the case. We reason that high yield under near optimal environments came along with hypersensitization of plant stress perception and consequently early activation of stress avoidance mechanisms, such as slow growth, which were originally needed for survival over long evolutionary time periods. Therefore, mechanisms employed by plants to cope with a stressful environment during evolution were overwhelmingly geared to avoid detrimental effects so as to ensure survival and that plant stress "tolerance" is fundamentally and evolutionarily based on "avoidance" of injury and death which may be referred to as evolutionary avoidance (EVOL-Avoidance). As a consequence, slow growth results from being exposed to stress because genes and genetic programs to adjust growth rates to external circumstances have evolved as a survival but not productivity strategy that has allowed extant plants to avoid extinction. To improve productivity under moderate stressful conditions, the evolution-oriented plant stress response circuits must be changed from a survival mode to a continued productivity mode or to avoid the evolutionary avoidance response, as it were. This may be referred to as Agricultural (AGRI-Avoidance). Clearly, highly productive crops have kept the slow, reduced growth response to stress that they evolved to ensure survival. Breeding programs and genetic engineering have not succeeded to genetically remove these responses because they are polygenic and redundantly programmed. From the beginning of modern plant breeding, we have not fully appreciated that our crop plants react overly-cautiously to stress conditions. They over-reduce growth to be able to survive stresses for a period of time much longer than a cropping season. If we are able to remove this polygenic redundant survival safety net we may improve yield in moderately stressful environments, yet we will face the requirement to replace it with either an emergency slow or no growth (dormancy) response to extreme stress or use resource management to rescue crops under extreme stress (or both). PMID- 30463353 TI - A DFT Screening of M-HKUST-1 MOFs for Nitrogen-Containing Compounds Adsorption. AB - To develop promising adsorbent candidates for adsorptive denitrogenation, we screened the adsorption of NO, NO2, and NH3 in 19 M-HKUST-1 (M = Be, Fe, Ni, Cr, Co, Cu, V, Zn, Mo, Mn, W, Sn, Ti, Cd, Mg, Sc, Ca, Sr, and Ba) systematically using first-principle calculations. Of these, four variants of M-HKUST-1 (M = Ni, Co, V, and Sc) yield more negative adsorption Gibbs free energy DeltaGads than the original Cu-HKUST-1 for three adsorbates, suggesting stronger adsorbate binding. Ti-HKUST-1, Sc-HKUST-1, and Be-HKUST-1 are predicted to have the largest NO, NO2, and NH3 adsorption energies within the screened M-HKUST-1 series, respectively. With the one exception of NO2 dissociation on V-HKUST-1, dissociative adsorption of NO, NO2, and NH3 molecules on the other considered M HKUST-1 is energetically less favorable than molecular adsorption thermodynamically. The barrier calculations show that the dissociation is difficult to occur on Cu-HKUST-1 kinetically due to the very large dissociation barrier. Electronic analysis is provided to explain the bond nature between the adsorbates and M-HKUST-1. Note that the isostructural substitution of Cu to the other metals is a major simplification of the system, representing the ideal situation; however, the present study provides interesting targets for experimental synthesis and testing. PMID- 30463356 TI - Motion Synchronous Composite Decoupling with Fewer Sensors on Multichannel Hydraulic Force Control for Aircraft Structural Loading Test System. AB - The aircraft full-scale fatigue test is widely used in the modern aircraft industry for the safety of flight. Generally, the aircraft full-scale fatigue test is achieved by structural loading; multiple hydraulic actuators are used to apply load for force control. The fatigue loading test takes approximately several years. A key challenge is how to accelerate the loading frequency to shorten the total test time. Nevertheless, when pluralities of hydraulic actuator simultaneously increase the loading frequency, the mutual coupling force from the low rigidity of the aircraft structure will cause a large loading error, meaning that the test cannot be implemented. Although it is possible to reduce error by adding sensors, the force sensors need to connect several kilometers of cable. This paper proposed a novel motion synchronous composite decoupling control strategy with fewer sensors. The control method compensates the negative coupling effect of the channels by integrating the command signals and feedback signals of all channels. It can suppress coupling force and reduce errors at higher frequencies, thereby shortening the experiment time. Opposed to traditional decoupling control methods, advantages of this strategy are that it only needs force sensors and it does not need additional displacement or velocity and acceleration sensors to collect state variables for building the state space. Furthermore, it has been experimentally verified that the new motion synchronous composite decoupling control method can indeed guarantee sufficient control accuracy when the test frequency is increased. The method has great economic significance for shortening test duration. PMID- 30463355 TI - Design of Controllable Novel Piezoelectric Components for Microfluidic Applications. AB - This paper reviews recent investigations and achievements in the design of controllable functional components for improving microfluidic systems, its effectiveness, and functionality. The main purpose was to design novel microstructures with piezoelectric properties (microresonators), which enable one to control the effectiveness of fluid flow in micro-hydro-mechanical devices for biomedical/biochemical purposes. Controllable properties were obtained by incorporating different types of binders in a piezoelectric ceramic matrix (lead zirconate titanate): polyvinyl butyral (PVB), poly methyl methacrylate (PMMA), and polystyrene (PS). The change in chemical composition of PZT helps to manipulate the piezoelectric characteristics, surface morphology, mechanical properties, etc., of the designed microfluidic element with the microstructure in it. PMID- 30463357 TI - One-Pot Synthesis of Multi-Branch Gold Nanoparticles and Investigation of Their SERS Performance. AB - Gold nanoparticles with multiple branches have attracted intensive studies for their application in sensing of low trace molecules. A large number of the merits found on the gold nanoparticles for the above applications are attributed to the strong localized surface plasmon resonance excited by the incident radiation. However, a facile and flexible way of synthesizing the multi-branch gold nanoparticles with tunable localized surface plasmon resonance frequency is still a challenge for the plasmonic research field. Herein, we report an efficient one pot synthesis of multi-branch gold nanoparticles method that resembles a seed medicated approach while using no further chemicals except chloroauric acid, ascorbic acid and 4-(2-Hydroxyethyl)-1-piperazinyl]-ethanesulfonic acid. By controlling the amounts of ascorbic acid volumes in the reaction mixture, the morphology and the localized surface plasmon resonance frequency of the synthesized multi-branch gold nanoparticles can be manipulated conveniently. Moreover, using the 4-Mercaptobenzoic acid as the Raman reporter, the multi branch gold nanoparticles show superior surface-enhanced Raman spectroscopy characteristics that can be potentially used in chemical and biological sensing. PMID- 30463354 TI - Within-Day Amino Acid Intakes and Nitrogen Balance in Male Collegiate Swimmers during the General Preparation Phase. AB - A higher protein intake is recommended for athletes compared to healthy non exercising individuals. Additionally, the distribution and quality (i.e., leucine content) of the proteins consumed throughout the day should be optimized. This study aimed to determine the nitrogen balance and distribution of protein and amino acid intakes in competitive swimmers during the general preparation phase. Thirteen swimmers (age: 19.7 +/- 1.0 years; VO2max: 63.9 +/- 3.7 mL.kg-1.min-1, mean +/- standard deviation) participated in a five-day experimental training period. Nutrient intakes were assessed using dietary records. Nitrogen balance was calculated from the daily protein intake and urinary nitrogen excretion. The intake amounts of amino acids and protein at seven eating occasions were determined. The average and population-safe intakes for zero nitrogen balance were estimated at 1.43 and 1.92 g.kg-1.day-1, respectively. The intake amounts of protein and leucine at breakfast, lunch, and dinner satisfied current guidelines for the maximization of muscle protein synthesis, but not in the other four occasions. The population-safe protein intake level in competitive swimmers was in the upper range (i.e., 1.2-2.0 g.kg-1.day-1) of the current recommendations for athletes. The protein intake distribution and quality throughout the day may be suboptimal for the maximization of the skeletal muscle adaptive response to training. PMID- 30463358 TI - Epithelial-Mesenchymal Transition and Metastasis under the Control of Transforming Growth Factor beta. AB - Metastasis of tumor cells from primary sites of malignancy to neighboring stromal tissue or distant localities entails in several instances, but not in every case, the epithelial-mesenchymal transition (EMT). EMT weakens the strong adhesion forces between differentiated epithelial cells so that carcinoma cells can achieve solitary or collective motility, which makes the EMT an intuitive mechanism for the initiation of tumor metastasis. EMT initiates after primary oncogenic events lead to secondary secretion of cytokines. The interaction between tumor-secreted cytokines and oncogenic stimuli facilitates EMT progression. A classic case of this mechanism is the cooperation between oncogenic Ras and the transforming growth factor beta (TGFbeta). The power of TGFbeta to mediate EMT during metastasis depends on versatile signaling crosstalk and on the regulation of successive waves of expression of many other cytokines and the progressive remodeling of the extracellular matrix that facilitates motility through basement membranes. Since metastasis involves many organs in the body, whereas EMT affects carcinoma cell differentiation locally, it has frequently been debated whether EMT truly contributes to metastasis. Despite controversies, studies of circulating tumor cells, studies of acquired chemoresistance by metastatic cells, and several (but not all) metastatic animal models, support a link between EMT and metastasis, with TGFbeta, often being a common denominator in this link. This article aims at discussing mechanistic cases where TGFbeta signaling and EMT facilitate tumor cell dissemination. PMID- 30463360 TI - Sedoheptulose-1,7-Bisphosphatase is Involved in Methyl Jasmonate- and Dark Induced Leaf Senescence in Tomato Plants. AB - Leaf senescence represents the final stage of leaf development and is regulated by diverse internal and environmental factors. Jasmonates (JAs) have been demonstrated to induce leaf senescence in several species; however, the mechanisms of JA-induced leaf senescence remain largely unknown in tomato plants (Solanum lycopersicum). In the present study, we tested the hypothesis that sedoheptulose-1,7-bisphosphatase (SBPase), an enzyme functioning in the photosynthetic carbon fixation in the Calvin-Benson cycle, was involved in methyl jasmonate (MeJA)- and dark-induced leaf senescence in tomato plants. We found that MeJA and dark induced senescence in detached tomato leaves and concomitantly downregulated the expression of SlSBPASE and reduced SBPase activity. Furthermore, CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9)-mediated mutagenesis of SlSBPASE led to senescence-associated characteristics in slsbpase mutant plants, including loss of chlorophyll, repressed photosynthesis, increased membrane ion leakage, and enhanced transcript abundance of senescence-associated genes. Collectively, our data suggest that repression of SBPase by MeJA and dark treatment plays a role in JA- and dark-induced leaf senescence. PMID- 30463361 TI - N-(2-Hydroxy)-propyl-3-trimethylammonium, O-Mysristoyl Chitosan Enhances the Solubility and Intestinal Permeability of Anticancer Curcumin. AB - An amphiphilic derivative of chitosan containing quaternary ammonium and myristoyl groups, herein named as ammonium myristoyl chitosan (DMCat), was synthesized by reacting glycidyltrimethylammonium chloride (GTMAC) and myristoyl chitosan (DMCh). The success of the modification was confirmed using Fourier transform infrared spectroscopy (FTIR) and 1H nuclear magnetic resonance (NMR) spectroscopy. The average degrees of alkylation and quaternization ( D Q - ) were determined by using 1H NMR and conductometric titration. The zeta potential of the micelles was higher than 28 mV while its average size and encapsulation efficiency ranged from 280 nm to 375 nm and 68% to 100%, respectively. The in vitro cytotoxicity of the unloaded and curcumin (CUR)-loaded micelles was tested against Caco-2 and HT29-MTX intestinal epithelial cell lines. The results showed no cytotoxic effect from loaded and unloaded micelles as compared to free CUR. In the permeability test, it was observed that both types of micelles, i.e., DMCh and DMCat, improved CUR permeability. Additionally, higher permeability was verified for both systems in Caco-2/HT29-MTX:Raji B because of the mucoadhesive character of chitosan and its ability to open tight junctions. The results indicated that DMCat micelles, due to the physico-chemical, improved characteristics may be a promising carrier to encapsulate CUR aiming cancer therapy. PMID- 30463359 TI - Aberrant RNA Splicing in Cancer and Drug Resistance. AB - More than 95% of the 20,000 to 25,000 transcribed human genes undergo alternative RNA splicing, which increases the diversity of the proteome. Isoforms derived from the same gene can have distinct and, in some cases, opposing functions. Accumulating evidence suggests that aberrant RNA splicing is a common and driving event in cancer development and progression. Moreover, aberrant splicing events conferring drug/therapy resistance in cancer is far more common than previously envisioned. In this review, aberrant splicing events in cancer-associated genes, namely BCL2L1, FAS, HRAS, CD44, Cyclin D1, CASP2, TMPRSS2-ERG, FGFR2, VEGF, AR and KLF6, will be discussed. Also highlighted are the functional consequences of aberrant splice variants (BCR-Abl35INS, BIM-gamma, IK6, p61 BRAF V600E, CD19-?2, AR-V7 and PIK3CD-S) in promoting resistance to cancer targeted therapy or immunotherapy. To overcome drug resistance, we discuss opportunities for developing novel strategies to specifically target the aberrant splice variants or splicing machinery that generates the splice variants. Therapeutic approaches include the development of splice variant-specific siRNAs, splice switching antisense oligonucleotides, and small molecule inhibitors targeting splicing factors, splicing factor kinases or the aberrant oncogenic protein isoforms. PMID- 30463363 TI - IoT-Based Strawberry Disease Prediction System for Smart Farming. AB - Crop diseases cannot be accurately predicted by merely analyzing individual disease causes. Only through construction of a comprehensive analysis system can users be provided with predictions of highly probable diseases. In this study, cloud-based technology capable of handling the collection, analysis, and prediction of agricultural environment information in one common platform was developed. The proposed Farm as a Service (FaaS) integrated system supports high level application services by operating and monitoring farms as well as managing associated devices, data, and models. This system registers, connects, and manages Internet of Things (IoT) devices and analyzes environmental and growth information. In addition, the IoT-Hub network model was constructed in this study. This model supports efficient data transfer for each IoT device as well as communication for non-standard products, and exhibits high communication reliability even in poor communication environments. Thus, IoT-Hub ensures the stability of technology specialized for agricultural environments. The integrated agriculture-specialized FaaS system implements specific systems at different levels. The proposed system was verified through design and analysis of a strawberry infection prediction system, which was compared with other infection models. PMID- 30463364 TI - Antifungal Efficacy of Marine Macroalgae against Fungal Isolates from Bronchial Asthmatic Cases. AB - Fungal sensitization is very common in bronchial asthmatic cases, and the connection with airway colonization by fungi remains uncertain. Antifungal therapy failure is a significant fraction of the cost and morbidity and mortality in the majority of the asthmatic cases. Hence, the present study aimed to investigate the antifungal activity of five marine macroalgae-Acanthaophora specifera, Cladophoropsis sp., Laurencia paniculata, Tydemania sp., and Ulva prolifera-which were tested on selected fungal pathogens isolated from 15 sputum of 45 bronchial asthmatic patients. The highest antifungal activity was observed in ethanol fractions of L. paniculata followed by U. prolifera, Cladophoropsis sp., A. specifera, and Tydemania sp. The minimum fungicidal concentration and minimum inhibitory concentration values of the ethanolic fractions of algal species were found to be 125-1000 ug/mL and 125-500 ug/mL, respectively. The algal extracts contained terpene alcohol, diterpene, steroids, sesquiterpene, and sesquiterpene alcohol, as determined by GC-MS/MS analyses. The present study shows that the marine macroalgae containing bioactive compounds had excellent inhibitory activity against a variety of fungal pathogens, which may be useful for combating fungal infections and recovering from chronic asthmatic states. PMID- 30463366 TI - YAP/TAZ Signaling as a Molecular Link between Fibrosis and Cancer. AB - Tissue fibrosis is a pathological condition that is associated with impaired epithelial repair and excessive deposition of extracellular matrix (ECM). Fibrotic lesions increase the risk of cancer in various tissues, but the mechanism linking fibrosis and cancer is unclear. Yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are core components of the Hippo pathway, which have multiple biological functions in the development, homeostasis, and regeneration of tissues and organs. YAP/TAZ act as sensors of the structural and mechanical features of the cell microenvironment. Recent studies have shown aberrant YAP/TAZ activation in both fibrosis and cancer in animal models and human tissues. In fibroblasts, ECM stiffness mechanoactivates YAP/TAZ, which promote the production of profibrotic mediators and ECM proteins. This results in tissue stiffness, thus establishing a feed forward loop of fibroblast activation and tissue fibrosis. In contrast, in epithelial cells, YAP/TAZ are activated by the disruption of cell polarity and increased ECM stiffness in fibrotic tissues, which promotes the proliferation and survival of epithelial cells. YAP/TAZ are also involved in the epithelial mesenchymal transition (EMT), which contributes to tumor progression and cancer stemness. Importantly, the crosstalk with transforming growth factor (TGF)-beta signaling and Wnt signaling is essential for the profibrotic and tumorigenic roles of YAP/TAZ. In this article, we review the latest advances in the pathobiological roles of YAP/TAZ signaling and their function as a molecular link between fibrosis and cancer. PMID- 30463365 TI - Associations with the In-Hospital Survival Following Extracorporeal Membrane Oxygenation in Adult Acute Fulminant Myocarditis. AB - BACKGROUND: Acute fulminant myocarditis (AFM) is a serious disease that progresses rapidly, and leads to failing respiratory and circulatory systems. When medications fail to reverse the patient's clinical course, extracorporeal membrane oxygenation (ECMO) is considered the most effective, supportive and adjunct strategy. In this paper we analyzed our experience in managing AFM with ECMO support. METHODS: During October 2003 and February 2017, a total of 35 patients (>=18 years) were enrolled in the study. Twenty patients survived, and another 15 patients expired. General demographics, the hemodynamic condition, timing of ECMO intervention, and laboratory data were compared for the survival and non-survival groups. Univariate and multivariate Cox regression analyses were performed to identify the associations with in-hospital mortality following ECMO use in this situation. RESULTS: The survival rate was 57.1% during the in hospital period. The average age, gender, severity of the hemodynamic condition, and cardiac rhythm were similar between the survival and non-survival groups. Higher serum lactic acid (initial and 24 h later), higher peak cardiac biomarkers, higher incidence of acute kidney injury and the need for hemodialysis were noted in the non-survival group. Higher 24-h lactic acid levels and higher peak troponin-I levels were associated with in-hospital mortality. CONCLUSIONS: When ECMO was used for AFM, related cardiogenic shock and decompensated heart failure, higher peak serum troponin-I levels and 24-h serum lactic acid levels following ECMO use were independently associated with in-hospital mortality. PMID- 30463367 TI - Effects of Boswellia Serrata Roxb. and Curcuma longa L. in an In Vitro Intestinal Inflammation Model Using Immune Cells and Caco-2. AB - Inflammatory bowel diseases, which consist of chronic inflammatory conditions of the colon and the small intestine, are considered a global disease of our modern society. Recently, the interest toward the use of herbal therapies for the management of inflammatory bowel diseases has increased because of their effectiveness and favourable safety profile, compared to conventional drugs. Boswellia serrata Roxb. and Curcuma longa L. are amongst the most promising herbal drugs, however, their clinical use in inflammatory bowel diseases is limited and little is known on their mechanism of action. The aim of this work was to investigate the effects of two phytochemically characterized extracts of B. serrata and C. longa in an in vitro model of intestinal inflammation. Their impact on cytokine release and reactive oxygen species production, as well as the maintenance of the intestinal barrier function and on intestinal mucosa immune cells infiltration, has been evaluated. The extracts showed a good protective effect on the intestinal epithelium at 1 ug/mL, with TEER values increasing by approximately 1.5 fold, compared to LPS-stimulated cells. C. longa showed an anti inflammatory mechanism of action, reducing IL-8, TNF-alpha and IL-6 production by approximately 30%, 25% and 40%, respectively, compared to the inflammatory stimuli. B. serrata action was linked to its antioxidant effect, with ROS production being reduced by 25%, compared to H2O2-stimulated Caco-2 cells. C. longa and B. serrata resulted to be promising agents for the management of inflammatory bowel diseases by modulating in vitro parameters which have been identified in the clinical conditions. PMID- 30463368 TI - A Contribution for the Valorisation of Sheep and Goat Cheese Whey through Nanofiltration. AB - The amount of cheese whey generated from the production of speciality sheep and goat cheese is significantly growing due to the acclaimed nutritional and medicinal benefits of the milk from these species. However, most of the cheese whey generated has no applications, thus giving rise to environmental problems. This work focuses on the study of the performance of the nanofiltration process for recovering the permeates of ultrafiltration from sheep and goat cheese whey. Nanofiltration experiments were carried out with membranes of nanofiltration (NF) in total recirculation and concentration modes, at 25 degrees C. Nanofiltration of the ultrafiltration permeates from sheep cheese whey was done at a pressure of 3.0 * 106 Pa and a circulation velocity of 1.42 m.s-1, until a volume concentration factor (VCF) of 2.5. Nanofiltration of the permeates from ultrafiltration of goat cheese whey was performed at a pressure of 2.0 * 106 Pa and a circulation velocity of 0.94 m.s-1, until a VCF of 2.0. From the results, it was concluded that osmotic pressure was the most important factor affecting the performance of the process. In both cases, the final permeates had a much lower organic load and its future use in the process of cheese making should be evaluated. PMID- 30463369 TI - Ionic Liquid-Promoted Three-Component Domino Reaction of Propargyl Alcohols, Carbon Dioxide and 2-Aminoethanols: A Thermodynamically Favorable Synthesis of 2 Oxazolidinones. AB - To circumvent the thermodynamic limitation of the synthesis of oxazolidinones starting from 2-aminoethanols and CO2 and realize incorporation CO2 under atmospheric pressure, a protic ionic liquid-facilitated three-component reaction of propargyl alcohols, CO2 and 2-aminoethanols was developed to produce 2 oxazolidinones along with equal amount of alpha-hydroxyl ketones. The ionic liquid structure, reaction temperature and reaction time were in detail investigated. And 15 mol% 1,5,7-triazabicylo[4.4.0]dec-5-ene ([TBDH][TFE]) trifluoroethanol was found to be able to synergistically activate the substrate and CO2, thus catalyzing this cascade reaction under atmospheric CO2 pressure. By employing this task-specific ionic liquid as sustainable catalyst, 2 aminoethanols with different substituents were successfully transformed to 2 oxazolidinones with moderate to excellent yield after 12 h at 80 degrees C. PMID- 30463362 TI - The Plasma Membrane: A Platform for Intra- and Intercellular Redox Signaling. AB - Membranes are of outmost importance to allow for specific signal transduction due to their ability to localize, amplify, and direct signals. However, due to the double-edged nature of reactive oxygen species (ROS)-toxic at high concentrations but essential signal molecules-subcellular localization of ROS-producing systems to the plasma membrane has been traditionally regarded as a protective strategy to defend cells from unwanted side-effects. Nevertheless, specialized regions, such as lipid rafts and caveolae, house and regulate the activated/inhibited states of important ROS-producing systems and concentrate redox targets, demonstrating that plasma membrane functions may go beyond acting as a securing lipid barrier. This is nicely evinced by nicotinamide adenine dinucleotide phosphate (NADPH)-oxidases (NOX), enzymes whose primary function is to generate ROS and which have been shown to reside in specific lipid compartments. In addition, membrane-inserted bidirectional H2O2-transporters modulate their conductance precisely during the passage of the molecules through the lipid bilayer, ensuring time-scaled delivery of the signal. This review aims to summarize current evidence supporting the role of the plasma membrane as an organizing center that serves as a platform for redox signal transmission, particularly NOX-driven, providing specificity at the same time that limits undesirable oxidative damage in case of malfunction. As an example of malfunction, we explore several pathological situations in which an inflammatory component is present, such as inflammatory bowel disease and neurodegenerative disorders, to illustrate how dysregulation of plasma-membrane-localized redox signaling impacts normal cell physiology. PMID- 30463371 TI - Microduplication of 15q13.3 and Microdeletion of 18q21.32 in a Patient with Moyamoya Syndrome. AB - Moyamoya angiopathy (MA) is a cerebrovascular disease determining a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and their proximal branches and the compensatory development of abnormal "moyamoya" vessels. MA occurs as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes) including several heritable conditions such as Down syndrome, neurofibromatosis type 1 and other genomic defects. Although the mechanism that links MA to these genetic syndromes is still unclear, it is believed that the involved genes may contribute to the disease susceptibility. Herein, we describe the case of a 43 years old woman with bilateral MA and peculiar facial characteristics, having a 484-kb microduplication of the chromosomal region 15q13.3 and a previously unreported 786 kb microdeletion in 18q21.32. This patient may have a newly-recognized genetic syndrome associated with MA. Although the relationship between these genetic variants and MA is unclear, our report would contribute to widening the genetic scenario of MA, in which not only genic mutation, but also genome unbalances are possible candidate susceptibility factors. PMID- 30463372 TI - The Utility of Supertype Clustering in Prediction for Class II MHC-Peptide Binding. AB - MOTIVATION: Extensive efforts have been devoted to understanding the antigenic peptides binding to MHC class I and II molecules since they play a fundamental role in controlling immune responses and due their involvement in vaccination, transplantation, and autoimmunity. The genes coding for the MHC molecules are highly polymorphic, and it is difficult to build computational models for MHC molecules with few know binders. On the other hand, previous studies demonstrated that some MHC molecules share overlapping peptide binding repertoires and attempted to group them into supertypes. Herein, we present a framework of the utility of supertype clustering to gain more information about the data to improve the prediction accuracy of class II MHC-peptide binding. RESULTS: We developed a new method, called superMHC, for class II MHC-peptide binding prediction, including three MHC isotypes of HLA-DR, HLA-DP, and HLA-DQ, by using supertype clustering in conjunction with RLS regression. The supertypes were identified by using a novel repertoire dissimilarity index to quantify the difference in MHC binding specificities. The superMHC method achieves the state of-the-art performance and is demonstrated to predict binding affinities to a series of MHC molecules with few binders accurately. These results have implications for understanding receptor-ligand interactions involved in MHC peptide binding. PMID- 30463370 TI - Emerging Roles of Diacylglycerol-Sensitive TRPC4/5 Channels. AB - Transient receptor potential classical or canonical 4 (TRPC4) and TRPC5 channels are members of the classical or canonical transient receptor potential (TRPC) channel family of non-selective cation channels. TRPC4 and TRPC5 channels are widely accepted as receptor-operated cation channels that are activated in a phospholipase C-dependent manner, following the Gq/11 protein-coupled receptor activation. However, their precise activation mechanism has remained largely elusive for a long time, as the TRPC4 and TRPC5 channels were considered as being insensitive to the second messenger diacylglycerol (DAG) in contrast to the other TRPC channels. Recent findings indicate that the C-terminal interactions with the scaffolding proteins Na+/H+ exchanger regulatory factor 1 and 2 (NHERF1 and NHERF2) dynamically regulate the DAG sensitivity of the TRPC4 and TRPC5 channels. Interestingly, the C-terminal NHERF binding suppresses, while the dissociation of NHERF enables, the DAG sensitivity of the TRPC4 and TRPC5 channels. This leads to the assumption that all of the TRPC channels are DAG sensitive. The identification of the regulatory function of the NHERF proteins in the TRPC4/5 NHERF protein complex offers a new starting point to get deeper insights into the molecular basis of TRPC channel activation. Future studies will have to unravel the physiological and pathophysiological functions of this multi-protein channel complex. PMID- 30463373 TI - A Joint Multi-Path and Multi-Channel Protocol for Traffic Routing in Smart Grid Neighborhood Area Networks. AB - In order to improve the management mechanisms of the electric energy transport infrastructures, the smart grid networks have associated data networks that are responsible for transporting the necessary information between the different elements of the electricity network and the control center. Besides, they make possible a more efficient use of this type of energy. Part of these data networks is comprised of the Neighborhood Area Networks (NANs), which are responsible for interconnecting the different smart meters and other possible devices present at the consumers' premises with the control center. Among the proposed network technologies for NANs, wireless technologies are becoming more relevant due to their flexibility and increasing available bandwidth. In this paper, some general modifications are proposed for the routing protocol of the wireless multi-hop mesh networks standardized by the IEEE. In particular, the possibility of using multiple paths and transmission channels at the same time, depending on the quality of service needs of the different network traffic, is added. The proposed modifications have been implemented in the ns-3 simulator and evaluated in situations of high traffic load. Simulation results show improvements in the network performance in terms of packet delivery ratio, throughput and network transit time. PMID- 30463374 TI - Long Non-Coding RNA Modulation of VEGF-A during Hypoxia. AB - The role and function of long non-coding RNAs (lncRNAs) in modulating gene expression is becoming apparent. Vascular endothelial growth factor A (VEGF-A) is a key regulator of blood vessel formation and maintenance making it a promising therapeutic target for activation in ischemic diseases. In this study, we uncover a functional role for two antisense VEGF-A lncRNAs, RP1-261G23.7 and EST AV731492, in transcriptional regulation of VEGF-A during hypoxia. We find here that both lncRNAs are polyadenylated, concordantly upregulated with VEGF-A, localize to the VEGF-A promoter and upstream elements in a hypoxia dependent manner either as a single-stranded RNA or DNA bound RNA, and are associated with enhancer marks H3K27ac and H3K9ac. Collectively, these data suggest that VEGF-A antisense lncRNAs, RP1-261G23.7 and EST AV731492, function as VEGF-A promoter enhancer-like elements, possibly by acting as a local scaffolding for proteins and also small RNAs to tether. PMID- 30463375 TI - Molecular Factors of Hypochlorite Tolerance in the Hypersaline Archaeon Haloferax volcanii. AB - Halophilic archaea thrive in hypersaline conditions associated with desiccation, ultraviolet (UV) irradiation and redox active compounds, and thus are naturally tolerant to a variety of stresses. Here, we identified mutations that promote enhanced tolerance of halophilic archaea to redox-active compounds using Haloferax volcanii as a model organism. The strains were isolated from a library of random transposon mutants for growth on high doses of sodium hypochlorite (NaOCl), an agent that forms hypochlorous acid (HOCl) and other redox acid compounds common to aqueous environments of high concentrations of chloride. The transposon insertion site in each of twenty isolated clones was mapped using the following: (i) inverse nested two-step PCR (INT-PCR) and (ii) semi-random two step PCR (ST-PCR). Genes that were found to be disrupted in hypertolerant strains were associated with lysine deacetylation, proteasomes, transporters, polyamine biosynthesis, electron transfer, and other cellular processes. Further analysis revealed a DeltapsmA1 (alpha1) markerless deletion strain that produces only the alpha2 and beta proteins of 20S proteasomes was hypertolerant to hypochlorite stress compared with wild type, which produces alpha1, alpha2, and beta proteins. The results of this study provide new insights into archaeal tolerance of redox active compounds such as hypochlorite. PMID- 30463377 TI - Adaptive Data Synchronization Algorithm for IoT-Oriented Low-Power Wide-Area Networks. AB - The Internet of Things (IoT) is by now very close to be realized, leading the world towards a new technological era where people's lives and habits will be definitively revolutionized. Furthermore, the incoming 5G technology promises significant enhancements concerning the Quality of Service (QoS) in mobile communications. Having billions of devices simultaneously connected has opened new challenges about network management and data exchange rules that need to be tailored to the characteristics of the considered scenario. A large part of the IoT market is pointing to Low-Power Wide-Area Networks (LPWANs) representing the infrastructure for several applications having energy saving as a mandatory goal besides other aspects of QoS. In this context, we propose a low-power IoT oriented file synchronization protocol that, by dynamically optimizing the amount of data to be transferred, limits the device level of interaction within the network, therefore extending the battery life. This protocol can be adopted with different Layer 2 technologies and provides energy savings at the IoT device level that can be exploited by different applications. PMID- 30463378 TI - Intersection Intelligence: Supporting Urban Platooning with Virtual Traffic Lights over Virtualized Intersection-Based Routing. AB - The advent of the autonomous car is paving the road to the realization of ideas that will help optimize traffic flows, increase safety and reduce fuel consumption, among other advantages. We present one proposal to bring together Virtual Traffics Lights (VTLs) and platooning in urban scenarios, leaning on vehicle-to-vehicle (V2V) communication protocols that turn intersections into virtual containers of data. Newly-introduced protocols for the combined management of VTLs and platoons are validated by simulation, comparing a range of routing protocols for the vehicular networks with the baseline given by common deployments of traditional traffic lights ruled by state-of-the-art policies. The simulation results show that the combination of VTLs and platoons can achieve significant reductions in travel times and fuel consumption, provided that proper algorithms are used to handle the V2V communications. PMID- 30463376 TI - MicroRNAs as Biomarkers in Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is an incurable and fatal disorder characterized by the progressive loss of motor neurons in the cerebral cortex, brain stem, and spinal cord. Sporadic ALS form accounts for the majority of patients, but in 1-13.5% of cases the disease is inherited. The diagnosis of ALS is mainly based on clinical assessment and electrophysiological examinations with a history of symptom progression and is then made with a significant delay from symptom onset. Thus, the identification of biomarkers specific for ALS could be of a fundamental importance in the clinical practice. An ideal biomarker should display high specificity and sensitivity for discriminating ALS from control subjects and from ALS-mimics and other neurological diseases, and should then monitor disease progression within individual patients. microRNAs (miRNAs) are considered promising biomarkers for neurodegenerative diseases, since they are remarkably stable in human body fluids and can reflect physiological and pathological processes relevant for ALS. Here, we review the state of the art of miRNA biomarker identification for ALS in cerebrospinal fluid (CSF), blood and muscle tissue; we discuss advantages and disadvantages of different approaches, and underline the limits but also the great potential of this research for future practical applications. PMID- 30463379 TI - Correction: Serwotka-Suszczak, A. M. et al. A Conjugate Based on Anti-HER2 Diaffibody and Auristatin E Targets HER2-Positive Cancer Cells. Int. J. Mol. Sci. 2017, 18, 401. AB - It has been brought to our attention that the affiliation of Dr. Jerzy Pieczykolan at the time when he was responsible for the work described in the paper [...]. PMID- 30463381 TI - Adding Active Slot Joint Larger Broadcast Radius for Fast Code Dissemination in WSNs. AB - By using Software Defined Network (SDN) technology, senor nodes can get updated program code which can provide new features, so it has received extensive attention. How to effectively spread code to each node fast is a challenge issue in wireless sensor networks (WSNs). In this paper, an Adding Active Slot joint Larger Broadcast Radius (AAS-LBR) scheme is proposed for fast code dissemination. The AAS-LBR scheme combines the energy of data collection and code dissemination, making full use of the remaining energy in the far-sink area to increase the active slot and the broadcast radius to speed up the code dissemination. The main contributions of the proposed AAS-LBR scheme are the following: (1) Make full use of the remaining energy of the far sink area to expand the broadcast radius, so that the node broadcasts a longer distance. The wide range of broadcasts makes the number of nodes receiving code more, which speeds up the spread of code dissemination. (2) AAS-LBR uses two improved methods to further reduce the number of broadcasts and speed up the code dissemination: (a) When constructing the broadcast backbone whose nodes dominate all nodes in network and are responsible for broadcasting code, the active slot is added to the next hop node in a pipeline style on the diffusion path, which enables the code dissemination process to continue without pause. Thus, the code can quickly spread to the entire broadcast backbone. (b) For the nodes in the non-broadcast backbone whose nodes are dominated by the broadcast backbone and only for receiving code, an active slot is added coincident with its broadcast backbone' active slot, which can reduce the time required for code dissemination and reduce the number of broadcasts. A lot of performance analysis and simulation results show that compared to previous schemed, the AAS-LBR scheme can balance energy consumption, the transmission delay can be reduced 43.09-78.69%, the number of broadcasts can be reduced 44.51-86.18% and the energy efficiency is improved by about 24.5%. PMID- 30463380 TI - Mutational Evolution in Relapsed Diffuse Large B-Cell Lymphoma. AB - Current genomic models in diffuse large B-cell lymphoma (DLBCL) are based on single tumor biopsies, which might underestimate heterogeneity. Data on mutational evolution largely remains unknown. An exploratory study using whole exome sequencing on paired (primary and relapse) formalin fixed paraffin embedded DLBCL biopsies (n = 14) of 6 patients was performed to globally assess the mutational evolution and to identify gene mutations specific for relapse samples from patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. A minority of the mutations detected in the primary sample (median 7.6%, range 4.8-66.2%) could not be detected in the matching relapse sample. Relapsed DLBCL samples showed a mild increase of mutations (median 12.5%, range 9.4-87.6%) as compared to primary tumor biopsies. We identified 264 genes possibly related to therapy resistance, including tyrosine kinases (n = 18), (transmembrane) glycoproteins (n = 73), and genes involved in the JAK-STAT pathway (n = 7). Among the potentially resistance related genes were PIM1, SOCS1, and MYC, which have been reported to convey a risk for treatment failure. In conclusion, we show modest temporal heterogeneity between paired tumor samples with the acquisition of new mutations and identification of genes possibly related to therapy resistance. The mutational evolution could have implications for treatment decisions and development of novel targeted drugs. PMID- 30463382 TI - Message Integration Authentication in the Internet-of-Things via Lattice-Based Batch Signatures. AB - The internet-of-things (also known as IoT) connects a large number of information sensing devices to the Internet to collect all kinds of information needed in real time. The reliability of the source of a large number of accessed information tests the processing speed of signatures. Batch signature allows a signer to sign a group of messages at one time, and signatures' verification can be completed individually and independently. Therefore, batch signature is suitable for data integration authentication in IoT. An outstanding advantage of batch signature is that a signer is able to sign as many messages as possible at one time without worrying about the size of signed messages. To reduce complexity yielded by multiple message signing, a binary tree is usually leveraged in the construction of batch signature. However, this structure requires a batch residue, making the size of a batch signature (for a group of messages) even longer than the sum of single signatures. In this paper, we make use of the intersection method from lattice to propose a novel generic method for batch signature. We further combine our method with hash-and-sign paradigm and Fiat Shamir transformation to propose new batch signature schemes. In our constructions, a batch signature does not need a batch residue, so that the size of the signature is relatively smaller. Our schemes are securely proved to be existential unforgeability against adaptive chosen message attacks under the small integer solution problem, which shows great potential resisting quantum computer attacks. PMID- 30463383 TI - NLOS Identification in WLANs Using Deep LSTM with CNN Features. AB - Identifying channel states as line-of-sight or non-line-of-sight helps to optimize location-based services in wireless communications. The received signal strength identification and channel state information are used to estimate channel conditions for orthogonal frequency division multiplexing systems in indoor wireless local area networks. This paper proposes a joint convolutional neural network and recurrent neural network architecture to classify channel conditions. Convolutional neural networks extract the feature from frequency domain characteristics of channel state information data and recurrent neural networks extract the feature from time-varying characteristics of received signal strength identification and channel state information between packet transmissions. The performance of the proposed methods is verified under indoor propagation environments. Experimental results show that the proposed method has a 2% improvement in classification performance over the conventional recurrent neural network model. PMID- 30463384 TI - Preparation of Enantiomeric beta-(2',5'-Dimethylphenyl)Bromolactones, Their Antiproliferative Activity and Effect on Biological Membranes. AB - Three novel enantiomeric pairs of bromolactones possesing a 2,5-dimethylphenyl substituent at the beta-position of the lactone ring have been synthesized from corresponding enantiomeric (E)-3-(2',5'-dimethylphenyl)hex-4-enoic acids (4) by kinetically controlled bromolactonization with N-bromosuccinimide (NBS). gamma Bromo-delta-lactones (5) were isolated as the major products. Absolute configurations of stereogenic centers of gamma-bromo-delta-lactones (5) were assigned based on X-ray analysis; configurations of cis delta-bromo-gamma lactones (6) and trans delta-bromo-gamma-lactones (7) were determined based on mechanism of bromolactonization. Synthesized compounds exhibited significant antiproliferative activity towards the four canine cancer cell lines (D17, CLBL 1, CLB70, and GL-1) and one human cancer line (Jurkat). Classifying the compounds in terms of activity, the most active were enantiomers of trans delta-bromo-gamma lactones (7) followed by enantiomers of cis isomer (6) and enantiomeric gamma bromo-delta-lactones (5). Higher activity was observed for all stereoisomers with S configuration at C-4 in comparison with their enantiomers with 4R configuration. Synthesized compounds did not induce hemolysis of erythrocytes. The results of the interaction of bromolactones with red blood cell membranes suggest that these compounds incorporate into biological membranes, concentrating mainly in the hydrophilic part of the bilayer but have practically no influence on fluidity in the hydrophobic region. The differences in interactions with the membrane between particular enantiomers were observed only for gamma-lactones: stronger interactions were found for enantiomer 4R,5R,6S of cis gamma-lactone (6) and for enantiomer 4S,5R,6S of trans gamma-lactone (7). PMID- 30463385 TI - Bread Enrichment with Oilseeds. A Review. AB - The use of oilseeds in bakery products has gained popularity in recent years, both for their organoleptic and nutritional characteristics. The aim of this work is to provide an overview of the studies centered on the use of oilseeds (flaxseed, chia, sunflower, pumpkin, sesame and poppyseed) in breads and other bakery products. This review highlights the effect of oilseeds on the mechanical and physical properties of bread according to the enrichment level, origin and way of addition (whole, crushed, oil or mucilage). In general, the incorporation of oilseeds improves the nutritional profile of bakery products with and without gluten, and provides several health benefits. Mucilages of oilseeds can also act as a fat replacer thanks to their properties. The incorporation of oilseeds modifies the rheology of the doughs, the volume of the products and their texture, affecting their organoleptic characteristics and their acceptability. Nevertheless, these changes will depend on the type of seed used, as well as on the method of addition. PMID- 30463387 TI - Associations of Exposure to Air Pollution with Insulin Resistance: A Systematic Review and Meta-Analysis. AB - In this article, we review the available evidence and explore the association between air pollution and insulin resistance (IR) using meta-analytic techniques. Cohort studies published before January 2018 were selected through English language literature searches in nine databases. Six cohort studies were included in our sample, which assessed air pollutants including PM2.5 (particulate matter with an aerodynamic diameter less than or equal to 2.5 MUm), NO2(nitrogen dioxide), and PM10 (particulate matter with an aerodynamic diameter less than 10 MUm). Percentage change in insulin or insulin resistance associated with air pollutants with corresponding 95% confidence interval (CI) was used to evaluate the risk. A pooled effect (percentage change) was observed, with a 1 MUg/m3 increase in NO2 associated with a significant 1.25% change (95% CI: 0.67, 1.84; I2 = 0.00%, p = 0.07) in the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and a 0.60% change (95% CI: 0.17, 1.03; I2 = 30.94%, p = 0.27) in insulin. Similar to the analysis of NO2, a 1 MUg/m3 increase in PM10 was associated with a significant 2.77% change (95% CI: 0.67, 4.87; I2 = 94.98%, p < 0.0001) in HOMA-IR and a 2.75% change in insulin (95% CI: 0.45, 5.04; I2 = 58.66%, p = 0.057). No significant associations were found between PM2.5 and insulin resistance biomarkers. We conclude that increased exposure to air pollution can lead to insulin resistance, further leading to diabetes and cardiometabolic diseases. Clinicians should consider the environmental exposure of patients when making screening and treatment decisions for them. PMID- 30463386 TI - Investigation and Comparison of Nutritional Supplement Use, Knowledge, and Attitudes in Medical and Non-Medical Students in China. AB - The objective of this study is to investigate and compare the prevalence, knowledge, and attitudes of Chinese university students with respect to nutritional supplements. We conducted a cross-sectional study in several universities around China from January to December 2017, and enrolled a total of 8752 students. Of these, 4252 were medical students and 4500 were non-medical students. The use of nutritional supplements was reported by 58.9% in universities students, with a higher rate for medical students as compared to non medical students. It was found 24.2% of participants had taken supplements in the past year. Medical students had a higher level of knowledge on nutritional supplements than non-medical students (p < 0.001). The most commonly used nutritional supplements were vitamin C, calcium, and vitamin B. Gender (p < 0.001), household income (p < 0.001), and health status (p < 0.001) were related to the nutritional supplement use after adjustment for related factors. In conclusion, in China, nutritional supplement use was found to be more common in medical students than those studying other disciplines, and was associated with sex, income, and health status. The attitude towards nutritional supplements by medical students was positive. Students' knowledge levels about nutritional supplements need to be improved. PMID- 30463388 TI - Changes in Metabolic Syndrome Severity Following Individualized Versus Standardized Exercise Prescription: A Feasibility Study. AB - This study sought to investigate the efficacy of standardized versus individualized exercise intensity prescription on metabolic syndrome (MetS) severity following a 12-week exercise intervention. A total of 38 experimental participants (47.8 +/- 12.2 yr, 170.7 +/- 8.0 cm, 82.6 +/- 18.7 kg, 26.9 +/- 6.7 mL.k-1.min-1) were randomized to one of two exercise interventions (exercise intensity prescribed using heart rate reserve or ventilatory threshold). Following the 12-week intervention, MetS z-score was significantly improved for the standardized (-2.0 +/- 3.1 to -2.8 +/- 2.8 [p = 0.01]) and individualized ( 3.3 +/- 2.3 to -3.9 +/- 2.2 [p = 0.04]) groups. When separating participants based on prevalence of MetS at baseline and MetS z-score responsiveness, there were six and three participants in the standardized and individualized groups, respectively, with three or more MetS risk factors. Of the six participants in the standardized group, 83% (5/6) of the participants were considered responders, whereas 100% (3/3) of the individualized participants were responders. Furthermore, only 17% (1/6) of the participants with MetS at baseline in the standardized group no longer had symptoms of MetS following the intervention. In the individualized group, 67% (2/3) of participants with baseline MetS were not considered to have MetS at week 12. These findings suggest that an individualized approach to the exercise intensity prescription may ameliorate the severity of MetS. PMID- 30463390 TI - Scaling Effect of Fused ASTER-MODIS Land Surface Temperature in an Urban Environment. AB - There is limited research in land surface temperatures (LST) simulation using image fusion techniques, especially studies addressing the downscaling effect of LST image fusion. LST simulation and associated downscaling effect can potentially benefit the thermal studies requiring both high spatial and temporal resolutions. This study simulated LSTs based on observed Terra Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) and Terra Moderate Resolution Imaging Spectroradiometer (MODIS) LST imagery with Spatial and Temporal Adaptive Reflectance Fusion Model, and investigated the downscaling effect of LST image fusion at 15, 30, 60, 90, 120, 250, 500, and 1000 m spatial resolutions. The study area partially covered the City of Los Angeles, California, USA, and surrounding areas. The reference images (observed ASTER and MODIS LST imagery) were acquired on 04/03/2007 and 07/01/2007, with simulated LSTs produced for 4/28/2007. Three image resampling methods (Cubic Convolution, Bilinear Interpolation, and Nearest Neighbor) were used during the downscaling and upscaling processes, and the resulting LST simulations were compared. Results indicated that the observed ASTER LST and simulated ASTER LST images (date 04/28/2007, spatial resolution 90 m) had high agreement in terms of spatial variations and basic statistics based on a comparison between the observed and simulated ASTER LST maps. Urban developed lands possessed higher LSTs with lighter tones and mountainous areas showed dark tones with lower LSTs. The Cubic Convolution and Bilinear Interpolation resampling methods yielded better results over Nearest Neighbor resampling method across the scales from 15 to 1000 m. The simulated LSTs with image fusion can be used as valuable inputs in heat related studies that require frequent LST measurements with fine spatial resolutions, e.g., seasonal movements of urban heat islands, monthly energy budget assessment, and temperature-driven epidemiology. The observation of scale-independency of the proposed image fusion method can facilitate with image selections of LST studies at various locations. PMID- 30463389 TI - Broken Energy Homeostasis and Obesity Pathogenesis: The Surrounding Concepts. AB - Obesity represents an abnormal fat accumulation resulting from energy imbalances. It represents a disease with heavy consequences on population health and society economy due to its related morbidities and epidemic proportion. Defining and classifying obesity and its related parameters of evaluation is the first challenge toward understanding this multifactorial health problem. Therefore, within this review we report selected illustrative examples of the underlying mechanisms beyond the obesity pathogenesis which is systemic rather than limited to fat accumulation. We also discuss the gut-brain axis and hormones as the controllers of energy homeostasis and report selected impacts of obesity on the key metabolic tissues. The concepts of "broken energy balance" is detailed as the obesity starting key step. Sleep shortage and psychological factors are also reported with influences on obesity development. Importantly, describing such mechanistic pathways would allow clinicians, biologists and researchers to develop and optimize approaches and methods in terms of diagnosis, classification, clinical evaluation, treatment and prognosis of obesity. PMID- 30463391 TI - Remediating Potentially Toxic Metal and Organic Co-Contamination of Soil by Combining In Situ Solidification/Stabilization and Chemical Oxidation: Efficacy, Mechanism, and Evaluation. AB - Most soil remediation studies investigated single contaminants or multiple contaminants of the same type. However, in field conditions, soils are often contaminated with potentially both toxic metals and organic pollutants, posing a serious technical challenge. Here, batch experiments were conducted to evaluate the performance of combining in situ solidification/stabilization (ISS) and in situ chemical oxidation (ISCO) for the simultaneous removal of aniline (1000 mg/kg) and Cd (10 mg/kg). All four tested ISS amendments, especially quick lime and Portland cement, promoted in situ chemical oxidation with activated persulfate in contaminated soil. Combined ISS/ISCO remediation effectively removed aniline and reduced the bioavailable Cd content at optimal initial persulfate and ISS amendment concentrations of 1.08 mol/kg and 30 wt% with a seven-day curing time, and significantly reduced leaching. Persulfate inhibited the reduction of the bioavailable Cd content, and ISS amendment with persulfate did not synergistically remediate Cd in co-contaminated soil. Strong alkalinity and high temperature were the main mechanisms driving rapid pollutant removal and immobilization. The reaction of CaO with water released heat, and Ca(OH)2 formation increased the pH. The relative contributions of heat vs. alkaline activation, as well as the contaminant removal efficiency, increased with ISS amendment CaO content. Combined treatment altered the soil physicochemical properties, and significantly increased Ca and S contents. Activated persulfate related reactions did not negatively impact unconfined compressive strength and hydraulic conductivity. This work improves the selection of persulfate activation methods for the treatment of soils co-contaminated with both potentially toxic metals and organic pollutants. PMID- 30463392 TI - New Insights into the Runt Domain of RUNX2 in Melanoma Cell Proliferation and Migration. AB - The mortality rate for malignant melanoma (MM) is very high, since it is highly invasive and resistant to chemotherapeutic treatments. The modulation of some transcription factors affects cellular processes in MM. In particular, a higher expression of the osteogenic master gene RUNX2 has been reported in melanoma cells, compared to normal melanocytes. By analyzing public databases for recurrent RUNX2 genetic and epigenetic modifications in melanoma, we found that the most common RUNX2 genetic alteration that exists in transcription upregulation is, followed by genomic amplification, nucleotide substitution and multiple changes. Additionally, altered RUNX2 is involved in unchecked pathways promoting tumor progression, Epithelial Mesenchymal Transition (EMT), and metastasis. In order to investigate further the role of RUNX2 in melanoma development and to identify a therapeutic target, we applied the CRISPR/Cas9 technique to explore the role of the RUNT domain of RUNX2 in a melanoma cell line. RUNT-deleted cells showed reduced proliferation, increased apoptosis, and reduced EMT features, suggesting the involvement of the RUNT domain in different pathways. In addition, del-RUNT cells showed a downregulation of genes involved in migration ability. In an in vivo zebrafish model, we observed that wild-type melanoma cells migrated in 81% of transplanted fishes, while del-RUNT cells migrated in 58%. All these findings strongly suggest the involvement of the RUNT domain in melanoma metastasis and cell migration and indicate RUNX2 as a prospective target in MM therapy. PMID- 30463393 TI - Virtual Screening, Biological Evaluation, and 3D-QSAR Studies of New HIV-1 Entry Inhibitors That Function via the CD4 Primary Receptor. AB - Human immunodeficiency virus type 1 (HIV-1) is responsible for the majority of HIV infections worldwide, and we still lack a cure for this infection. Blocking the interaction of HIV-1 and its primary receptor CD4 is one strategy for identifying new anti-HIV-1 entry inhibitors. Here we report the discovery of a novel ligand that can inhibit HIV-1 entry and infection via CD4. Biological and computational analyses of this inhibitor and its analogs, using bioactivity evaluation, Rule of Five (RO5), comparative molecular field analysis (CoMFA)/comparative molecular similarity index analysis (CoMSIA) models, and three-dimensional quantitative structure-activity relationship (3D-QSAR), singled out compound 3 as a promising lead molecule for the further development of therapeutics targeting HIV-1 entry. Our study demonstrates an effective approach for employing structure-based, rational drug design techniques to identify novel antiviral compounds with interesting biological activities. PMID- 30463394 TI - Dietary Intakes and Dietary Quality during Pregnancy in Women with and without Gestational Diabetes Mellitus-A Norwegian Longitudinal Study. AB - Gestational diabetes mellitus (GDM) is associated with maternal diet, however, findings are inconsistent. The aims of the present study were to assess whether intakes of foods and beverages during pregnancy differed between women who developed GDM and non-GDM women, and to compare dietary intakes with dietary recommendations of pregnancy. This is a nested case-control study within a randomized controlled trial. Women with complete measurements of a 75 g oral glucose tolerance test (OGTT) at 18-22 and 32-36 weeks gestation were included in the cohort (n = 702). Women were diagnosed for GDM according to the simplified International Association of Diabetes and Pregnancy Study Group criteria at 32-36 weeks (GDM women: n = 40; non-GDM women: n = 662). Dietary data (food frequency questionnaire) was collected at both time points and compared between GDM and non GDM women. Variability in OGTT values was assessed in a general linear model. Marginal differences between GDM and non-GDM women in intakes of food groups were found. No associations were found between dietary variables and OGTT values. Not all dietary recommendations were followed in the cohort, with frequently reported alcohol consumption giving largest cause for concern. This study did not find dietary differences that could help explain why 40 women developed GDM. PMID- 30463395 TI - Improvements on the Interfacial Properties of High-k/Ge MIS Structures by Inserting a La2O3 Passivation Layer. AB - In this paper, the impact of La2O3 passivation layers on the interfacial properties of Ge-based metal-insulator-semiconductor (MIS) structures was investigated. It was proven that the formation of a thermodynamically stable LaGeOx component by incorporating a La2O3 interlayer could effectively suppress desorption of the interfacial layer from GeO2 to volatile GeO. The suppression of GeO desorption contributed to the decrease in oxide trapped charges and interfacial traps in the bulk of the gate insulator, or the nearby interfacial regions in the Al2O3/La2O3/Ge structure. Consequently, the hysteretic behavior of the dual-swept capacitance-voltage (C-V) curves and the frequency dispersion of multi-frequency C-V curves were remarkably weakened. Besides, more than one order of magnitude decrease in the gate leakage current density, and higher insulator breakdown electric field were obtained after inserting a La2O3 passivation layer. PMID- 30463396 TI - Targeting Smoothened as a New Frontier in the Functional Recovery of Central Nervous System Demyelinating Pathologies. AB - Myelin sheaths on vertebrate axons provide protection, vital support and increase the speed of neuronal signals. Myelin degeneration can be caused by viral, autoimmune or genetic diseases. Remyelination is a natural process that restores the myelin sheath and, consequently, neuronal function after a demyelination event, preventing neurodegeneration and thereby neuron functional loss. Pharmacological approaches to remyelination represent a promising new frontier in the therapy of human demyelination pathologies and might provide novel tools to improve adaptive myelination in aged individuals. Recent phenotypical screens have identified agonists of the atypical G protein-coupled receptor Smoothened and inhibitors of the glioma-associated oncogene 1 as being amongst the most potent stimulators of oligodendrocyte precursor cell (OPC) differentiation in vitro and remyelination in the central nervous system (CNS) of mice. Here, we discuss the current state-of-the-art of studies on the role of Sonic Hedgehog reactivation during remyelination, referring readers to other reviews for the role of Hedgehog signaling in cancer and stem cell maintenance. PMID- 30463397 TI - Employing Ray-Tracing and Least-Squares Support Vector Machines for Localisation. AB - This article evaluates the use of least-squares support vector machines, with ray traced data, to solve the problem of localisation in multipath environments. The schemes discussed concern 2-D localisation, but could easily be extended to 3-D. It does not require NLOS identification and mitigation, hence, it can be applied in any environment. Some background details and a detailed experimental setup is provided. Comparisons with schemes that require NLOS identification and mitigation, from earlier work, are also presented. The results demonstrate that the direct localisation scheme using least-squares support vector machine (the Direct method) achieves superior outage to TDOA and TOA/AOA for NLOS environments. TDOA has better outage in LOS environments. TOA/AOA performs better for an accepted outage probability of 20 percent or greater but as the outage probability lowers, the Direct method becomes better. PMID- 30463399 TI - Change of Coronary Artery Indices according to Coronary Dominance Pattern in Early Childhood. AB - Purpose: Coronary arterial lesion assessment in children can be difficult depending on the coronary dominance pattern. Although it is easier to determine coronary dominance with echocardiography in children than in adults, difficulty still exists. This study aimed to examine coronary dominance pattern according to objective Coronary artery (CA) indices. Methods: CA diameter, aortic valve annulus, and abdominal aorta were measured with cross-sectional echocardiography in 69 children without any cardiovascular disease at Chungnam National University Hospital. To evaluate the coronary dominance pattern, echocardiography was primarily used and additionally, coronary computed tomographic angiography or Coronary angiography (CAG). Coronary dominance was determined according to the coronary artery that gives rise to the posterior descending artery. Results: The mean age was 4.02+/-2.78 years, and the mean body surface area (BSA) was 0.70+/ 0.22 m2. Right dominance was present in 78% and left in 22% of the subjects. In those with left dominance, the CA to aortic valve annulus diameter ratio was 0.125+/-0.021 in right coronary artery (RCA) and 0.255+/-0.032 in left coronary artery (LCA). In those with right dominance, the corresponding ratio was 0.168+/ 0.028 in RCA and 0.216+/-0.030 in LCA(P<0.05). Significant differences were also found in the diametric ratios of CA to BSA and abdominal aorta (P<0.05). Conclusion: coronary artery indices showed significant difference according to coronary dominance pattern in early childhood. It is possible to indirectly determine the coronary dominance pattern by coronary artery indices in children using echocardiography. The accuracy of CAL diagnosis can be improved by taking coronary dominance into account. PMID- 30463398 TI - A multistep approach for the stratification of the risk of severe hypoglycemia in patients with type 2 diabetes. AB - INTRODUCTION: Hypoglycemia is the major limiting factor in the glycemic management of diabetes. Aim of this study was to produce a risk stratification tool to support the medical decision making, by facilitating the identification of patients at higher risk of hypoglycemia. EVIDENCE ACQUISITION: A multistep approach was adopted, including a systematic review of observational studies investigating risk factors for severe hypoglycemia in type 2 diabetes (T2DM), followed by an expert input forum to identify factors perceived as relevant and at the same time reliably detectable, to be used for the development of a risk score. EVIDENCE SYNTHESIS: The systematic review led to the identification of 41 studies. Many factors have been seldom investigated, and their association with the risk of hypoglycemia is still unclear. Factors more frequently associated with a high risk of hypoglycemia were: low level of education, ethnicity, irregular meals/malnutrition, insulin and sulfonylurea therapy, polypharmacy, previous hypoglycemia, impaired renal function, cognitive impairment, depression and frailty. The expert input forum involved 35 diabetologists. Following the ranking of the relevance of the factors identified, a parsimonious yet comprehensive set of risk factors was identified. CONCLUSIONS: The process led to the identification of relevant factors, to be used for the development of a hypoglycemia risk score. An ad-hoc study will be performed to assess the contribution of these risk factors and their relative weight. If the risk score will confirm its ability to correctly stratify patients according to their risk of hypoglycemia, it will represent a useful support to optimize the care of people with T2DM. PMID- 30463400 TI - Risk factors for the Occurrence and Persistence of Coronary Aneurysm in Kawasaki Disease. AB - Purpose: Prognostic factors of coronary aneurysm in Kawasaki disease have been investigated in many studies. The aim of this study is to identify risk factors associated with early and late coronary artery outcomes in the treated patients with Kawasaki disease. Methods: A total of 392 patients diagnosed with Kawasaki disease from January 2012 to December 2015 in Pusan National University Children's Hospital were retrospectively selected as subjects of the present study to determine risk factors for coronary aneurysm and persistence of coronary aneurysm after one-year follow up. Results: Coronary aneurysm was detected from 30 of 392 patients within one month after occurrence of Kawasaki disease. Coronary aneurysm persisted in 5 of 30 patients after 1-year follow up. Long duration of fever (adjusted OR: 1.47; 95% CI: 1.06- 2.02; P = 0.018) and high platelet count (adjusted OR: 1.00; 95% CI: 1.00- 1.01; P = 0.009) were found to be independent factors to predict the development of coronary aneurysm in early phase. Initial coronary severity (adjusted OR: 46.0; 95% CI: 2.01- 1047.80; P = 0.016) and high white blood cell count (adjusted OR: 1.17; 95% CI: 1.01- 1.36; P = 0.028) were found to be significant factors for the persistence of late coronary aneurysm in univariate analysis. However, no significant factor was found in multivariate analysis. Conclusion: This data showed early and late follow up of coronary aneurysm in our unit. Further studies are needed to determine the mechanisms involved in the disappearance of coronary aneurysm and related factors. PMID- 30463401 TI - The Challenges and Solutions in Developing Ultrasensitive Biosensors. AB - This Perspective focuses on the latest strategies and challenges for the development of bioanalytical sensors with sub-picomolar detection limits. Achieving sub-picomolar detection limits has three major challenges. These are 1) assay sensitivity, 2) response time and 3) selectivity (including limiting background signals). Each of these challenges, and how nanomaterials provide the solutions, is dis-cussed. Strategies to gain greater sensitivity include confining the sensing volume to the nanoscale, as used in nanopore or nanoparticles based sensors, while nanoparticles are ubiquitous in amplification. Methods to improve response time typically focus on obtaining an intimate mixture between the sen-sor and the sample either by extending the length scale of nanoscale sensors using nanostructuring or by dispersing magnetic nanoparticles through the sample to capture the analyte. Nanoparticles loaded with many biorecognition species are one solution to help address the challenge of selectivity. Many of the examples in the perspective explore the detection of prostate specific antigen (PSA) to enable a comparison between strategies. Finally the exciting future opportunities in developing single molecules sensors and the requirement to go even lower in concentration are explored. PMID- 30463402 TI - Measurements of Oxygen Electroadsorption Energies and Oxygen Evolution Reaction on RuO2(110): A Discussion of the Sabatier Principle and its Role in Electrocatalysis. AB - We report the hydroxide (OHad) and oxide (Oad) experimental electroadsorption free energies, their dependences on pH, and their correlations to the oxygen evolution reaction (OER) electrocatalysis on RuO2(110) surface. The Sabatier principle predicts that catalyst is most active when the intermediate stabilization is moderate, not too strong such that the bound intermediate disrupts the subsequent catalytic cycle, nor too weak such that the surface is ineffective. For decades, researchers have used this concept to rationalize the activity trend of many OER electrocatalysts including RuO2, which is among the state-of-the-art OER catalysts. In this article, we report an experimental assessment of the Sabatier principle by comparing the oxygen electroadsorption energy to the OER electrocatalysis for the first time on RuO2. We find that the OHad and Oad electroadsorption energies on RuO2(110) depend on pH and obey the scaling relation. However, we did not observe a direct correlation between the OHad and Oad electroadsorption energies and the OER activity in the comparative analysis that includes both RuO2(110) and IrO2(110). Our result raises a question of whether the Sabatier principle can describe highly active electrocatalysts, where the kinetic aspects may influence the electrocatalysis more strongly than the electroadsorption energy, which captures only the thermodynamics of the intermediates and not yet kinetics. PMID- 30463403 TI - Systematic screening of optimal signal peptides for secretory production of heterologous proteins in Bacillus subtilis. AB - Bacillus subtilis is widely used for large-scale industrial production of heterologous proteins. Due to its high intrinsic secretory capacity, it can efficiently secrete proteins into the culture supernatant via the general Sec type secretion pathway. In this study, the alpha-amylase AmyS was used as a reporter to construct a library encompassing 173 Sec-type signal peptides (SPs) from B. subtilis using a fast, sequence-independent method. The resulting library DNA which harboring different signal peptides in the expression vector was used to transform B. subtilis directly at high efficiency, and 15 SPs which produced a significantly increased yield of AmyS were identified using a starch-iodine based high-throughput assay. Furthermore, the correlation between the sequences of the best-performing signal peptides and their secretion efficiency was analyzed, which revealed several common properties of these SPs. Finally, high-cell-density fermentation of the alpha-amylase-producing strain with the best-performing signal peptide yielded a maximum of 5086 U/mL amylase at 66 h with a high productivity of 77.1 U/mL.h. PMID- 30463404 TI - Branch-Selective Addition of Unactivated Olefins into Imines and Aldehydes. AB - Radical hydrofunctionalization occurs with ease using metal-hydride hydrogen atom transfer (MHAT) catalysis to couple alkenes and competent radicalophilic electrophiles. Traditional two-electron electrophiles have remained unreactive. Herein we report the reductive coupling of electronically unbiased olefins with imines and aldehydes. Iron catalysis allows addition of alkyl-substituted olefins into imines through the intermediacy of free radicals, whereas a combination of catalytic Co(Sal t-Bu, t-Bu) and chromium salts enables a branch-selective coupling of olefins and aldehydes through the formation of a putative alkyl chromium intermediate. PMID- 30463405 TI - Ratiometric Fluorescent Detection of Intracellular Singlet Oxygen by Semiconducting Polymer Dots. AB - Singlet oxygen (1O2) plays important roles in many biological processes. However, it is very difficult to detect 1O2 in the intracellular environment owing to its relatively low concentration and short lifetime. Here, we developed a rati ometric probe based on semiconducting polymer dots (Pdots) that can sensitively detect 1O2 in live cells. An organic dye, singlet oxygen sensor green (SOSG), was doped in polyfluorene Pdots, and excitation energy was efficiently trans-ferred from the polymer to the SOSG dye. Accordingly, the Pdots showed constant blue fluorescence as a reference, and increased green fluorescence upon singlet oxygen generation. The ratiometric response of Pdots was examined in the intracellular environment by in-situ 1O2 generation with a photosensitizer and light irradiation. Both spectroscopic measurements and confocal imaging were performed to monitor intracellular 1O2 generation during photodynamic therapy using the Pdot probe. Our results indicate that the SOSG-doped Pdots are promising for intracellular 1O2 detection. PMID- 30463406 TI - Enantioselective Construction of Vicinal Diaxial Styrenes and Multiaxis System via Organocatalysis. AB - A highly diastereo- and enantioselective methodology for the asymmetric synthesis of vicinal diaxial styrenes and multiaxis system was achieved by organocatalysis. Various vicinal diaxial styrenes and multiaxis systems were obtained in excellent enantioselective manners. The mechanism studies revealed that a new tetra substituted vinylidene ortho-quinone methide (VQM) intermediate was likely involved and accounted for the excellent enantioselectivity. PMID- 30463407 TI - Combination of Three Methods to Reduce Glucose Metabolic Rate for improving N Acetylglucosamine Production in Saccharomyces cerevisiae. AB - Previously, the production of N-acetylglucosamine (GlcNAc) in Saccharomyces cerevisiae was improved by deletion of the genes encoding phosphofructokinase 2 (PFK-2) isoforms, which reduced the glycolytic flux by eliminating the pathway to produce fructose-2,6-bisphosphate, an allosteric activator of phosphofructokinase 1 (PFK-1). We further examined the effects of additional reduction in glucose metabolic rate on N-acetylglucosamine production. Glucose uptake rate was lowered by expressing a truncated glucose-sensing regulator (MTH1-DeltaT). In addition, catalytically dead Cas9 (dCas9) was introduced in order to down-regulate the expression levels of PFK-1 and pyruvate kinase-1 (Pyk1). Finally, the three strategies were introduced into S. cerevisiae strains in a combinatorial way; the strain containing all three modules resulted in the highest N-acetylglucosamine production yield. The results showed that the three modules cooperatively reduced the glucose metabolism and improved N-acetylglucosamine production up to 3.0 g/L in shake flask. PMID- 30463408 TI - Hierarchical structures for superhydrophobic and superoleophobic surfaces. AB - Many surfaces possessing robust super liquid repellency, are hierarchically structured on the nano- and micrometer scale. Several examples are found in nature such as the self-cleaning leaves of lotus plants and anisotropic, water guiding rice leaves. Each surface design has unique properties optimized for specific wetting conditions. In this article, we review both natural and artificial hierarchical surface structures and their function in repelling liquids. We discuss different types of structures needed in various wetting situations and draw some general conclusions as a guideline for designing robust superhydrophobic and superoleophobic surfaces. PMID- 30463409 TI - Combination of PhI(OAc)2 and 2-Nitropropane as the Source of Methyl Radical in Room-Temperature Metal-Free Oxidative Decarboxylation/Cyclization: Construction of 6-Methyl Phenanthridines and 1-Methyl Isoquinolines. AB - A room-temperature metal-free method for generating highly unstable methyl radical was realized from the combination of PhI(OAc)2 and 2-nitropropane, which provides an efficient approach to methylated phenanthridines and isoquinolines. The strategy was also extended to the generation of other alkyl radicals and a concise synthesis of Roxadustat. PMID- 30463410 TI - Electrostatic Stabilization of Carbon Nitride Colloids in Organic Solvents Enables Stable Dispersions and Transparent Homogeneous CN-Films for Optoelectronics. AB - Covalent modification of phenyl modified carbon nitride with vinylthiazole groups via visible light induced grafting is reported. Modified structures express negative charge migration to the thiazole edges while the carbon nitride sheet remains positively charged in organic solutions. Such a phenomenon provides electrostatic stabilization of modified carbon nitride particles in organic media leading to highly organodispersible and colloidally stable carbon nitrides. The resulting structures can be homogeneously dispersed in organic solvents, and can be casted to transparent films. The usefulness of such a processable colloidal carbon nitride building block is here exemplified by its high luminescence and ink jet printing of films. PMID- 30463411 TI - Progress in ligand design for monolayer-protected nanoparticles for nanobio interfaces. AB - Ligand-functionalized inorganic nanoparticles, also known as monolayer-protected nanoparticles, offer great potential as vehicles for in vivo delivery of drugs, genes, and other therapeutics. These nanoparticles offer highly customizable chemistries independent of the size, shape, and functionality imparted by the inorganic core. Their success as drug delivery agents depends on their interaction with three major classes of biomolecules: nucleic acids, proteins, and membranes. Here, the authors discuss recent advances and open questions in the field of nanoparticle ligand design for nanomedicine, with a focus on atomic scale interactions with biomolecules. While the importance of charge and hydrophobicity of ligands for biocompatibility and cell internalization has been demonstrated, ligand length, flexibility, branchedness, and other properties also influence the properties of nanoparticles. However, a comprehensive understanding of ligand design principles lies in the cost associated with synthesizing and characterizing diverse ligand chemistries and the ability to carefully assess the structural integrity of biomolecules upon interactions with nanoparticles. PMID- 30463412 TI - Esophagectomy in a patient with double aortic arch and right descending aorta. AB - We herein report the case of a 57-year-old man with esophageal cancer who was found to have a double aortic arch and right-sided descending aorta. Traditional approaches such as the Ivor Lewis and McKeown were excluded because the descending aorta would obscure the surgical field, and a neck anastomosis with the conduit through the ring could result in compression. We therefore opted for a left thoracoabdominal incision, allowing excellent exposure while reserving the possibility of placing the conduit substernally. PMID- 30463413 TI - Takotsubo syndrome complicated by thrombus formation: is there a need for thrombectomy? PMID- 30463414 TI - Changes in Food Insecurity and Smoking Status over Time: Analysis of the 2003 and 2015 Panel Study of Income Dynamics. AB - PURPOSE:: To examine whether food insecurity longitudinally affects smoking status. DESIGN:: Population-based prospective study. SETTING:: Data from the 2003 and 2015 Panel Study of Income Dynamics (PSID). PARTICIPANTS:: Four thousand five hundred sixty-three adults who were smokers and nonsmokers, participating in the 2003 (current study baseline) and 2015 (current study follow-up) waves of PSID. MEASURES:: Based on self-reported smoking status at baseline and follow-up, respondents were categorized as continued smoking, stopped smoking, started smoking, and continued nonsmoking. Similarly, respondents were categorized as stayed food secure, stayed food insecure, became food insecure, and became food secure based on responses to the Food Security Survey at baseline and follow-up. ANALYSIS:: Two logistic regression analyses to examine (1) among smokers at baseline the odds of stopping versus continuing smoking by follow-up and (2) among nonsmokers at baseline the odds of starting versus continuing nonsmoking by follow-up. In both models, change in food insecurity status was the primary independent variable, controlling for demographics including poverty. RESULTS:: Among smokers at baseline, becoming food insecure (vs staying food secure) was independently associated with lower likelihood of stopping smoking by follow-up (odds ratio [OR] = 0.66). Among nonsmokers at baseline, becoming food insecure (vs staying food secure) was independently associated with higher likelihood of starting smoking by follow-up (OR = 3.77). CONCLUSIONS:: Food insecurity is a risk factor for smoking, which has significant implications for developing interventions to reduce smoking prevalence, especially among low-income groups. PMID- 30463415 TI - Health Professionals Perceived Concerns and Challenges in Providing Palliative and End-of-Life Care: A Qualitative Analysis. AB - BACKGROUND:: The Institute of Medicine identifies that quality palliative/end-of life (EOL) care should be provided to patients with serious, life-limiting illnesses and their families by competently prepared health professionals. PURPOSE:: This study assessed perceived concerns of health professionals pertaining to the delivery of palliative/EOL care in the hospital setting. The specific aim was to determine thematic concerns in the delivery of palliative/EOL care which emerged from respondents' impressions of a memorable palliative/EOL patient experience. METHODS:: Interdisciplinary health professionals at a large academic health system in the Midwest were surveyed to reflect upon a memorable palliative/EOL life care patient situation (positive or negative). A Thematic Analysis approach was used to code qualitative responses to 4 open-ended questions and then extract themes and subthemes from the coded data. RESULTS:: Concerns identified by participants (N = 425) emerged around 7 themes including communication (97%), decision-making/care planning (75%), education needs (60%), EOL care (48%), ethics (24%), satisfaction with care (9%), and spiritual/cultural sensitivity (6%). CONCLUSION:: Challenges exist in the delivery of quality palliative/EOL care in the hospital setting which may be addressed through educational initiatives that focus on recognition of cultural influences on care preferences, improving communication between patients/families and providers, education about the differences between palliative and EOL care, and increased competency of health providers in having EOL/goals-of-care discussions. Health professionals must recognize the benefit of collaborative palliative care in order to meet patient and family needs holistically and comprehensively. PMID- 30463416 TI - Comparison of Management Guidelines for Moderate-to-Severe Plaque Psoriasis: A Review of Phototherapy, Systemic Therapies, and Biologic Agents. AB - INTRODUCTION:: Many international guidelines for management of psoriasis exist and most have variations in grading evidence quality, strength of recommendations, and dosing. The objective of our review is to compare international guidelines published in the United Kingdom, Canada, Europe, and the United States for the management of moderate-to-severe plaque psoriasis. METHODS:: We conducted a literature review on systemic therapies and phototherapy for moderate-to-severe plaque psoriasis in adult patients. The British, Canadian, European, and American guidelines served as the key comparators in our review. To identify relevant supporting clinical trials not referenced in the guidelines, we conducted literature searches in PubMed and EMBASE. Two authors independently extracted data on indications, dosing, efficacy, evidence grade, and strength of clinical recommendation for each therapy. RESULTS:: Monoclonal antibodies directed toward tumour necrosis factor and interleukin (IL)-12/23 received the strongest recommendations for treatment of moderate-to-severe plaque psoriasis, supported by robust, high-quality randomized controlled trials (RCTs). Newer agents such as IL-17 and IL-23 inhibitors are not referenced in most guidelines. There are fewer RCTs for conventional therapies and few head-to-head comparisons with biologics, making it difficult to draw direct comparisons. Among older agents, methotrexate is most strongly recommended for long-term maintenance and cyclosporine is recommended for short-term control of flares. CONCLUSION:: Physicians should individualize psoriasis-management strategies based on medication tolerance, efficacy, safety, patient comorbidities, availability of the medication, and patient preference. PMID- 30463417 TI - Allergic reactions to hydrolysed wheat proteins: clinical aspects and molecular structures of the allergens involved. AB - Wheat gluten can be chemically or enzymatically hydrolysed to produce functional ingredients useful in food and cosmetics. However severe allergies to hydrolysed wheat proteins (HWP) have been described in Europe and Japan since the early 2000's. Triggering proteins and IgE epitopes were described both for French and Japanese cohorts and appeared remarkably similar leading to define a new wheat allergic entity. Deamidation induced by functionalisation generate neo-allergens responsible for this particular allergy. This article aims to review the processes leading to deamidation and the clinical features of the patients suffering from this allergy. Then the molecular determinants involved in HWP allergy were exhaustively described and hypothesis regarding the sensitizing mechanism of HWP-allergy are discussed. Finally, current regulation and tools aiming at managing this risk associated with HWP are presented. PMID- 30463418 TI - Vaccination Guidelines for Patients With Immune-Mediated Disorders on Immunosuppressive Therapies. AB - BACKGROUND:: Patients with immune-mediated diseases on immunosuppressive therapies have more infectious episodes than healthy individuals, yet vaccination practices by physicians for this patient population remain suboptimal. OBJECTIVES:: To evaluate the safety and efficacy of vaccines in individuals exposed to immunosuppressive therapies and provide evidence-based clinical practice recommendations. METHODS:: A literature search for vaccination safety and efficacy in patients on immunosuppressive therapies (2009-2017) was conducted. Results were assessed using the Grading of Recommendation, Assessment, Development, and Evaluation system. RESULTS:: Several immunosuppressive therapies attenuate vaccine response. Thus, vaccines should be administered before treatment whenever feasible. Inactivated vaccines can be administered without treatment discontinuation. Similarly, evidence suggests that the live zoster vaccine is safe and effective while on select immunosuppressive therapy, although use of the subunit vaccine is preferred. Caution regarding other live vaccines is warranted. Drug pharmacokinetics, duration of vaccine-induced viremia, and immune response kinetics should be considered to determine appropriate timing of vaccination and treatment (re)initiation. Infants exposed to immunosuppressive therapies through breastmilk can usually be immunized according to local guidelines. Intrauterine exposure to immunosuppressive agents is not a contraindication for inactivated vaccines. Live attenuated vaccines scheduled for infants and children ?12 months of age, including measles, mumps, rubella, and varicella, can be safely administered as sufficient time has elapsed for drug clearance. CONCLUSIONS:: Immunosuppressive agents may attenuate vaccine responses, but protective benefit is generally maintained. While these recommendations are evidence based, they do not replace clinical judgment, and decisions regarding vaccination must carefully assess the risks, benefits, and circumstances of individual patients. PMID- 30463419 TI - Do Health-Care Professionals Really Understand the Role of Occupational Therapy in Hospice Care? AB - BACKGROUND:: The distinct value of occupational therapy (OT) in end-of-life care is to facilitate quality of life for clients and their caregivers through engagement in occupations during the clients' remaining days. The purpose of this study was to explore health-care professionals' perceptions and knowledge regarding the role of OT in hospice care and to better understand why OT may be underutilized in this setting. PARTICIPANTS:: A total of 104 professionals working in hospice care from 31 different states participated in this study. METHODS:: Electronic surveys were distributed to hospice agencies throughout the United States. DATA ANALYSIS:: Descriptive statistics was used to analyze quantitative data, and content analysis was used to identify patterns with qualitative data. Rigor was enhanced through peer-review, multiple coders, and triangulation. RESULTS:: The results of this study revealed that OT's role in hospice care is misunderstood, and OT services are underutilized. Five themes were identified regarding the underutilization of OT services: (1) lack of reimbursement, (2) timing of referral, (3) knowledge of the role of OT, (4) refusal of services by family members, and (5) lack of OT presence in this setting. CONCLUSION:: This study revealed that health-care professionals do believe that OTs are vital members of the hospice care team. However, many recipients of hospice care are not receiving OT. More consistent referrals to OT may better ensure that the terminally ill are able to attain end-of-life goals and live their lives to the fullest, regardless of life expectancy. PMID- 30463420 TI - Recently isolated antidiabetic hydrolysates and peptides from multiple food sources: a review. AB - Diabetes, a metabolic syndrome of global importance has been on a progressive rise in recent years. Several pharmacological approaches have been made, which have proved effective, but with underlying side effects. Bioactive hydrolysates (BHs) and peptides (BPs) from food sources, however, have shown the relative advantage of imparting less adverse effects. Furthermore, BHs and BPs from food have been discovered to impart their antidiabetic potentials through one or more mechanisms such as inhibition of digestive enzymes, inhibition of the antigenic enzyme - Dipeptyl peptidase IV (DPP-IV), decrease in blood glucose levels and increase in insulin uptake. Several plants and animal sources have been used as protein sources for the isolation of antidiabetic hydrolysates and peptides through different mechanisms and analytical techniques. This review integrates recent research information about several popular and unconventional food sources of BHs and BPs, their isolation techniques, antidiabetic effects and protein profiles. In addition, the fractionation technique(s) employed in each study and inhibition potentials of BHs and BPs are reviewed. This article is intended to supplement accessible scholarly literature and intellectual awareness on the subject of food-oriented approach for the management of diabetes. PMID- 30463421 TI - Evolution of a Novel Tissue Preservation Protocol to Optimize Osteochondral Transplantation Outcomes. AB - OBJECTIVE: Osteochondral allograft transplantation is a procedure to treat focal osteochondral lesions (OCLs), but is limited by tissue availability, the quality of transplanted tissue, and inconsistent storage protocols. The objective of this study was to assess the clinical outcomes of a novel tissue procurement, storage, and quality control protocol in treating OCLs. DESIGN: Prospective case series. Donor cadaveric tissue was processed, stored, and the tissue quality analyzed using the unique tissue preservation protocol developed at our institution. Advanced cross-sectional imaging was used to size match donor tissue with recipient patients. Osteochondral allografts were transplanted using the Arthrex Allograft OATS. Patients were evaluated with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee injury and Osteoarthritis Outcome Score (KOOS), visual analog scale (VAS), and 36-Item Short Form Survey (SF-36) preoperatively and at 1 year and 2 years postoperatively. RESULTS: Twenty patients (17 knees, 3 shoulders) were included in the study. There was a significant improvement in the following scores: overall WOMAC score, WOMAC function and pain subcategories; KOOS pain, knee-related symptoms, activities of daily living, sports and recreation, and quality of life; SF-36 physical functioning, physical role, pain, and social functioning subcategories; and VAS at all time points postoperatively. There was a significant improvement in WOMAC stiffness at 2 years postoperatively. There were 2 failures, defined by graft subsidence and persistent pain requiring reoperation. CONCLUSION: The protocol developed at our institution for OAT resulted in significant clinical improvement in patients with OCLs and is an improvement on existing tissue storage techniques. PMID- 30463422 TI - Socializing for Authentic Caring Engagement in Nursing Practice: Nursing Student Moral Development in Preceptorship. AB - BACKGROUND: The purpose of this study was to explore the basic psychosocial process of undergraduate nursing student moral development in clinical preceptorship. METHOD: A grounded theory approach was used to explore the process within the context of clinical practice and the student-preceptor-faculty member relationship. RESULTS: Socializing for authentic caring engagement in nursing practice emerged from the data as the basic psychosocial process of nursing student moral development in preceptorship. This process included four key categories: (a) distinguishing nursing and moral identity in practice, (b) learning to recognize the patient's experience, (c) identifying moral issues in practice and creating meaning of practice encounters, and (d) becoming an advocate and reconciling moral issues in practice. CONCLUSION: Findings emerging from this study illustrate the processes of how nursing students work through moral issues and the role of faculty and preceptors in engaging students with moral encounters in the context of preceptorship. PMID- 30463423 TI - The Safety and Efficacy of Expiratory Muscle Strength Training for Rehabilitation After Supracricoid Partial Laryngectomy: A Pilot Investigation. AB - OBJECTIVES:: Expiratory muscle strength training (EMST) is a safe, effective intervention that can be performed at home and may be beneficial for individuals with voice and swallowing disorders. To date there have been few studies of EMST in the head and neck cancer population, and there are no previous reports of its use after supracricoid partial laryngectomy (SCPL). The current prospective clinical pilot study was undertaken to determine the safety and efficacy of a 4 week treatment program. METHODS:: Six participants were recruited who had previously undergone SCPL, were medically stable, and had no contraindications for use of the device. At baseline, objective respiratory measurements were collected, dietary status was recorded, and participants were asked to complete a series of validated self-report instruments relating to voice, swallowing, breathing, and cough. Following the completion of treatment, baseline measures were repeated, and participant feedback was solicited. RESULTS:: The majority of individuals found the device easy to use (83%) and beneficial (83%). The side effects of treatment were relatively minor and included dizziness, muscle inflammation, and vocal fatigue. There were improvements in 2 measures from before to after treatment, namely, an average 21% increase in peak cough flow (from 371.67 to 451.33 L/min) and a 38% decrease on the Dyspnea Index (from 6.17 to 3.83). Other measures showed inconsistent changes. CONCLUSIONS:: EMST appeared to improve cough strength and reduce dyspnea symptoms after SCPL. Further study of the relative efficacy of EMST compared to other rehabilitation protocols after SCPL is needed. PMID- 30463424 TI - Defining the Aesthetic Range of Normal Symmetry for Lip and Nose Features in 5 Year-Old Children Using the Computer-Based Program SymNose. AB - OBJECTIVE:: To provide a normal comparison group against which to judge symmetry results after cleft surgery and to introduce the thin lip correction (TLC) feature in SymNose. A lip-aspect ratio algorithm has been added to the latest version of SymNose to compensate for the higher degree of overlap in thicker lips when compared to thin lips. DESIGN:: Retrospective analysis of symmetry in healthy participants, using the computer-based program SymNose on both anteroposterior (AP) and base view images. Photographs of 91 noncleft children were traced twice by 3 independent investigators experienced with SymNose. PARTICIPANTS:: Five-year-old healthy participants from a local state school in Tavistock (West Devon, United Kingdom). MAIN OUTCOME MEASURE:: Asymmetry expressed as the perimeter mismatch percentage for nose and lip features on AP view images and for nose features on base view images. RESULTS:: The perimeter mismatch reference range for the nose (AP view) was 2.65% to 30.91%, for the lip 2.13% to 15.44%, for the nose (base view) 1.69% to 14.84%, for the nostrils 4.68% to 26.6%, and for the width-height ratio 1.15% to 1.80%. The perimeter mismatch percentage for the lip without TLC was significantly higher compared to the perimeter mismatch percentage with TLC ( P < .001). CONCLUSION:: This article provides a noncleft reference range for all perimeters drawn from SymNose against which to compare results after cleft surgery at 5 years of age. Furthermore, it shows the importance of correcting for variance in lip volume per child. PMID- 30463425 TI - A Randomized Controlled Trial on the Effectiveness of Family Group Conferencing in Child Welfare: Effectiveness, Moderators, and Level of FGC Completion. AB - The present study examined the effectiveness of Family Group Conferencing (FGC) in child welfare. Effects were operationalized in terms of child safety (child maltreatment, supervision order, and out-of-home placement), number of professional services used, parental empowerment, and social support in a 1-, 3-, 6-, and 12-month follow-up. Furthermore, the influence of family characteristics and the level of FGC completion were examined. A total of 328 families were included, randomly assigned to an experimental group ( n = 229) and a care as usual (CAU) group ( n = 99). FGC was equally effective as CAU in improving child safety but resulted in more out-of-home placements. Furthermore, FGC resulted in a longer duration of child welfare involvement, a marginally higher number of professional services used, and increased parental empowerment and social support. Family characteristics did not moderate the results. Level of FGC completion was in general low. Higher levels of completion were related to a larger social network, a higher number of professional services used, and, marginally, less parental empowerment. In conclusion, although some beneficial results marginally support the use of FGC, it is the question whether these effects outweigh FGC costs, a longer duration of child welfare involvement and a higher number of professional services used. PMID- 30463426 TI - The Minimal Clinically Important Difference and Substantial Clinical Benefit in the Patient-Reported Outcome Measures of Patients Undergoing Osteochondral Allograft Transplantation in the Knee. AB - OBJECTIVE: Little is known regarding the minimal clinically important difference (MCID) and substantial clinical benefit (SCB) with regard to the Knee injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form, Lysholm score, and Short Form 12 (SF-12) score of patients who undergo osteochondral allograft transplantation (OCA). We aimed to determine the MCID and SCB associated with those patient-reported outcome measures (PROMs) after OCA. DESIGN: We analyzed the data of 86 consecutive patients who underwent OCA and who completed satisfaction surveys at a minimum of 1 year postoperatively and had at least one repeated PROM. MCID was determined using an anchor-based method: the optimal cutoff point for receiver operative characteristic (ROC) curves. If an anchor-based method was inapplicable, distribution-based methods were employed. SCB was determined using ROC curve analysis. RESULTS: Based on the ROC curve analysis, MCID was 16.7 for KOOS pain, 25 for KOOS sports/recreation, and 9.8 for IKDC. SCB was 27.7 for KOOS pain, 10.7 for KOOS symptom, 30 for KOOS sports/recreation, 31.3 for KOOS quality of life, 26.9 for IKDC, 25 for Lysholm, and 12.1 for SF-12 physical component summary. No significant association was noted between SCB achievement and the baseline patient factors and baseline PROMs. CONCLUSION: We demonstrated the MCIDs and SCBs of several PROMs in patients undergoing OCA. These results will aid the interpretation of the effect of treatment and clinical trial settings. Moreover, the SCBs will help surgeons in the counseling of patients, where patients expect optimal results rather than minimal improvement. PMID- 30463427 TI - Development of the Submental Nasal Appearance Scale for the Assessment of Repaired Unilateral Complete Cleft Lip: A Pilot Study. AB - OBJECTIVE:: To develop the "Submental Nasal Appearance Scale" (SNAS), which is an easy-to-use objectified tool to represent a cleft surgeon's standard for assessment of the nasal appearance from the submental perspective. DESIGN:: Eighty-five photographs of patients with unilateral complete cleft lip and palate were selected and cropped, displaying the submental view. Sixty-one photographs were used to develop 5 sets of reference photographs. Three cleft surgeons graded 24 photographs with these sets and subjectively graded the overall nasal appearance as well. Internal agreement for both methods was calculated, as well as correlation between them. The SNAS was created, by only using the combination of sets that showed the highest reliability and correlation. SETTING:: Boston Children's Hospital, Boston, Massachusetts. PATIENTS:: Six- to 9-year-old patients with unilateral complete cleft lip and palate. RESULTS:: The intrarater and interrater reliability was 0.84 and 0.79, respectively, for the SNAS and 0.76 and 0.62, respectively, for the overall appearance assessment. The correlation was 0.74 between the methods. CONCLUSIONS:: The SNAS is a reliable tool that reflects a cleft surgeon's standard and could be used independently or in combination with existing rating scales using the frontal and/or lateral view, for assessment after cleft lip repair. PMID- 30463428 TI - Documentation of breakthrough pain in narrative clinical records of children with life-limiting conditions: Feasibility of a retrospective review. AB - This study explored the feasibility of generating reliable information on the frequency, nature and management of breakthrough pain (BTP) in children with life limiting conditions and life-threatening illnesses (LTIs) from narrative clinical records. In the absence of standardized ways for documenting BTP, we conducted a consensus exercise to develop a glossary of terms that could denote BTP in the records. Thirteen clinicians who contributed to the records reached consensus on 45 terms which could denote BTP, while emphasizing the importance of contextual information. The results of this approach together with guidance for improving the reliability of retrospective reviews informed a data extraction instrument. A pilot test of this instrument showed poor agreement between raters. Given the challenges encountered, we do not recommend a retrospective review of BTP using narrative records. This study highlighted challenges of data extraction for complex symptoms such as BTP from narrative clinical records. For both clinical and research purposes, the recording of complex symptoms such as BTP would benefit from clear criteria for applying definitions, a more structured format and the inclusion of validated assessment tools. This study also showed the value of consensus exercises in improving understanding and interpretation of clinical notes within a service. PMID- 30463429 TI - Metacognitive beliefs and childhood adversities: an overview of the literature. AB - Within the Self-Regulatory Executive Function theory, emerging data suggest that unhelpful metacognitive beliefs might be associated with exposure to early adversities, however the evidence is still sparse and inconclusive. This study aimed to conduct an overview of the literature to evaluate if exposure to childhood adversities might be associated with the presence of unhelpful metacognitive beliefs. A comprehensive research was conducted on PubMed, Science Direct, Google Scholar from inception to May 2017. The search terms used were: 'childhood adversity/childhood abuse/childhood neglect/childhood loss event' AND 'metacognition/metacognitive beliefs'. A manual search of reference lists was run. Five studies were identified: three on psychiatric patients, two on the general population. Findings suggest that: (a) exposure to childhood abuse or childhood neglect might be associated with unhelpful metacognitive beliefs in adulthood; (b) early adversities are more frequently associated with negative beliefs, than other metacognitive beliefs; (c) metacognitive beliefs seem to mediate the association between childhood adversities and, repetitive thinking and negative affect. In conclusion, metacognitive beliefs might be involved in the association between early adversities and negative emotions. Interventions able to identify and reduce metacognitive beliefs associated to childhood adversities could be considered for treating the emotional consequences of childhood adversities. PMID- 30463430 TI - Depression in health college students: relationship factors and sleep quality. AB - This research was conducted to determine depression symptom frequency in health sciences students (n = 445), to investigate sleep quality and some related factors. In this study of the students approximately one fifth of the students showed depressive symptom. Students with poor academic performance, poor economic status, smoking or alcohol use, chronic illness or mental problems are more likely to experience depression. As sleep quality deteriorates, the level of depression also increases. The risk of depressive symptoms in students with poor sleep quality was 3.28 times. PMID- 30463431 TI - Understanding, attitudes and dehumanisation towards autistic people. AB - Research suggests that while individuals may self-report positive attitudes towards autism, dehumanising attitudes (seeing another as less than human) may still prevail. This study investigated knowledge, openness and dehumanising attitudes of non-autistic people towards autistic people. A total of 361 participants completed a survey measuring autism openness, knowledge and experience, along with a measure of dehumanisation. Results showed that knowledge of autism was comparable to past research and females were more open towards autism. Findings also indicated evidence for dehumanisation, with a particular denial of 'human uniqueness' traits. Furthermore, dehumanisation was related to openness towards autism. These findings have implications for targeting attitudes to reduce stigma associated with autism. PMID- 30463432 TI - Impact of botulinum toxin injections on quality of life and self-esteem in patients with blepharospasm. AB - To determine the effects of botulinum toxin type A (BoNT-A) injections on self esteem and quality of life (QOL) in blepharospasm patients, we enrolled 87 patients into the study. Patients completed the WHOQOL-BREF questionnaire, the Self-Esteem Scale (SES), and the Ocular Surface Disease Index (OSDI) before treatment on the date of enrollment and again after 4 weeks of treatment with BoNT-A. The overall QOL, general health status, the physiological and psychological domain scores of the WHOQOL-BREF, and the SES score significantly improved after treatment. The motor symptoms improved, and the OSDI score increased after treatment. Overall QOL and SES scores were correlated with disease duration, while psychological domain scores were correlated with mean duration of therapeutic effect. All variables correlated with OSDI scores. In conclusion, BoNT-A injections improved QOL and self-esteem in blepharospasm patients. PMID- 30463433 TI - Sex and Physiological Cycles Affect the Automatic Perception of Attractive Opposite-Sex Faces: A Visual Mismatch Negativity Study. AB - Facial attractiveness plays important roles in social interaction. Electrophysiological and neuroimaging studies found several brain areas to be differentially responsive to attractive relative to unattractive faces. However, little is known about the time course of the information processing, especially under the unattended condition. Based on a "cross-modal delayed response" paradigm, the present study aimed to explore the automatic mechanism of facial attractiveness processing of females with different physiological cycles and males, respectively, through recording the event-related potentials in response to (un)attractive opposite-sex faces by two experiments. The attractiveness related visual mismatch negativity (attractiveness vMMN) in posterior scalp distribution was recorded in both the experiments, which indicated that attractive faces could be processed automatically. And high-attractive opposite sex faces can elicit larger vMMN in males than females in menstrual period in Study 1, but similar as females in ovulatory period in Study 2. Furthermore, by comparison, the latency of attractiveness vMMN in females with the ovulatory period was the longest. These results indicated as follows: (1) Males were more sensitive to attractive female faces, (2) females in ovulatory period were also attracted by the attractive male faces, (3) the long vMMN latency in females during ovulatory period suggested a special reproductive motivation to avoid being tainted by genes, which takes priority over the breeding motivation. PMID- 30463434 TI - Comparison of a Smartphone Otoscope and Conventional Otoscope in the Diagnosis and Management of Acute Otitis Media. AB - Acute otitis media (AOM) is a leading cause of health encounters and antimicrobial prescriptions in children worldwide. We assessed (1) the rates of antimicrobial prescribing by pediatric emergency department clinicians using a smartphone otoscope device as compared with a conventional otoscope and (2) clinician acceptability of the smartphone device. We conducted a randomized control study in children's hospital emergency departments over 6 months. More than 1500 encounters were analyzed. The odds of prescribing antibiotics after being given a diagnosis of AOM by clinicians assigned to the smartphone group was 11% higher than the conventional group (18.8% vs 18.0%, odds ratio = 1.106, P = .600). Eight (73%) of the 11 physicians in the smartphone group preferred the smartphone device over the conventional otoscope. Use of a smartphone otoscope for detection of AOM in a pediatric emergency department setting did not lead to an increased likelihood of AOM diagnosis. PMID- 30463435 TI - Dispensing Patterns of Blood Pressure Lowering Agents in Older Australians From 2006 to 2016. AB - BACKGROUND: Increasing numbers of blood pressure lowering (BPL) agents are being prescribed for both primary and secondary prevention of cardiovascular disease, especially in the older population. The aim of this study is to describe the temporal trends and patterns of BPL dispensing among older Australians (aged >=65 years). METHODS: We utilized prescription claims data from the Australian Pharmaceutical Benefits Scheme (PBS) for a 10% random sample of people aged >=65 years. The PBS, funded by the Federal government, provides subsidies to make medicines more affordable for Australian residents. We restricted our analysis to "long-term concession" individuals, who would use PBS for the majority of their medication needs. BPL agents were identified using the World Health Organization Anatomical Therapeutic Chemical classification codes. The annual prevalences and proportional distributions of BPL dispensing by categories were summarized from 2006 to 2016. Direct standardization was applied to indicate changes of BPL dispensing over time. RESULTS: Age-standardized dispensing of BPL agents increased by 8% among older Australians from 2006 to 2016 (58%-66%). BPL dispensing in males has exceeded that in females since 2009. Angiotensin converting enzyme inhibitors/angiotensin II receptor blockers were the dominant BPL agents dispensed, with more than 55% of all BPL users over time. Dispensing of diuretics decreased from 27% to 21%, calcium channel blockers decreased from 30% to 25%, while beta-blockers remained stable (29%-31%). The use of fixed-dose combinations increased over time from 23% to 31%. CONCLUSION: The prevalence of BPL dispensing steadily increased among older Australians from 2006 to 2016. The changes in the patterns of BPL dispensing were largely in line with contemporary changes to clinical guidelines for an aging population. PMID- 30463436 TI - Attitudes of general hospital consultants towards psychosocial and psychiatric problems in Netherlands. AB - Psychosocial and psychiatric problems are common in patients admitted to general hospitals, and can negatively influence course of somatic diseases. Hence, early identification and adequate management is important. The aim of this study is to investigate attitudes towards psychosocial and psychiatric problems by non psychiatrist consultants in an academic hospital. Data were collected by anonymous, self- administered questionnaires which were provided to all consultants during morning reports and by email. Of 431 eligible participants, 187(43%) completed the questionnaire: 64% during morning reports, and 36% by email. Almost all consultants report generally positive attitudes towards mental health problems. However, we identified several obstacles towards management. First, there was a discrepancy between positive attitude and the willingness to take on management responsibility. Reported reasons for this discrepancy were time constraints and lack of skills. We also found that consultants feel little responsibility for the management of depression and chronic drinking. Physicians have generally more positive attitudes than surgeons. Finally, all consultants are less likely to refer patients with dementia and treatment non-compliance to psychiatry, for reasons of perceived ineffectiveness and fear of stigmatizing patients. We conclude targeted education on the management of these problems for hospital consultants is still warranted. PMID- 30463437 TI - Determination of endogenous fat loss and true total tract digestibility of fat in mink (Neovison vison). AB - The objective of this study was to determine the endogenous fat loss (EFL) and to calculate true total tract digestibility (TTTD) of fat in mink (Neovison vison) using soybean oil-based diets with different fat levels. In the digestibility assay, four diets with 6.30%, 13.9%, 22.0% and 34.0% fat in dry matter were used. Sixteen adult male mink were distributed in a complete randomised design. The apparent total tract digestibility (ATTD) of dietary fat was 90.8%, 95.9%, 96.9% and 97.8%, respectively. The apparent total digestible fat was linearly related to dietary fat intake (r2 = 0.99). The EFL was estimated from the slope of the regression equation and was determined to be 5.09 g/kg DM intake. The TTTD of soybean oil was determined to be 99.3%. Therefore, TTTD values will have negligible impact in feed formulation as they are close to ATTD values with the dietary fat levels normally used for mink. PMID- 30463438 TI - Mating Effort Predicts Human Menstrual Cycle Frequency. AB - The human menstrual cycle is characterized by substantial variability both within and between women. Here, we sought to account for such variability by examining whether human menstrual cycle frequency varies as a function of the projected fitness payoffs associated with investment in mating effort. We used structural equation modeling to test the prediction that women whose environmental conditions or life histories favor heavier investment in mating effort would have shorter, more regular cycles. Results supported our hypothesis, revealing that women who project more mating success and have faster life history strategies exhibit greater mating effort and shorter, more regular menstrual cycles. An alternative model that specified cycle frequency as a predictor of mating effort was a poor fit for the data, lending support for the hypothesized directionality of the path between these variables. Together, these results provide some of the first empirical evidence that the length and regularity of the human menstrual cycle may be calibrated to investment in mating effort. PMID- 30463439 TI - The microbiome and ophthalmic disease. AB - IMPACT STATEMENT: This review describes a growing body of research on relationships between the microbiome and eye disease. Several groups have investigated the microbiota of the ocular surface; dysregulation of this delicate ecosystem has been associated with a variety of pro-inflammatory states. Other research has explored the effects of the gastrointestinal microbiota on ophthalmic diseases. Characterizing the ways these microbiotas influence ophthalmic homeostasis and pathogenesis may lead to research on new techniques for managing ophthalmic disease. PMID- 30463440 TI - The Interplay Between Tobacco Dependence and Sleep Quality Among Young Adults. AB - OBJECTIVE/BACKGROUND: Sleep disturbances are considered among the negative consequences of smoking. However, the relationship between sleep quality and smoking among young adults, a population in which the prevalence of smoking is highest, has scarcely been examined. The current study aimed at examining differences in sleep indices, assessed by both subjective and objective (actigraphy) measures, between smokers and nonsmokers, and whether such differences are associated with levels of nicotine dependence. PARTICIPANTS: Eighty-six young (19-28 years old) volunteers, of them 46 nonsmokers (69.6% women) and 40 regular smokers (70.0% women) smoking at least 10 cigarettes a day. METHODS: The participants completed the State-Trait Anxiety Inventory, Beck Depression Inventory, Brief Questionnaire on Smoking Urges, the Fagerstrom Test for Nicotine Dependence, and the Pittsburgh Sleep Quality Index. Their sleep was monitored objectively for one week using an actigraph. RESULTS: Smokers' self reported sleep quality was similar to that of nonsmokers. However, actigraphy data pointed to lower sleep continuity in smokers compared to nonsmokers as reflected by increased wake time after sleep onset (Mean +/- SD: 18.56 +/- 15.29 vs. 11.21 +/- 11.19, p < .01) and decreased sleep efficiency (Mean +/- SD: 95.63 +/- 3.53 vs. 97.23 +/- 2.62, p < .012). Total sleep time and sleep onset latency did not differ between the groups. Notably, severity of nicotine dependence was negatively associated with sleep efficiency (beta = -.32; p < .05). CONCLUSION: Young adult smokers have lower sleep continuity without necessarily subjectively experiencing their sleep as poor. Nevertheless, their lower sleep continuity is related to their level of nicotine dependence. PMID- 30463441 TI - Antibiotic Use in Hand Surgery: Surgeon Decision Making and Adherence to Available Evidence. AB - BACKGROUND: There are no clearly defined guidelines from hand surgical societies regarding preoperative antibiotic prophylaxis. Many hand surgeons continue to routinely use preoperative prophylaxis with limited supporting evidence. This study aimed to determine for which scenarios surgeons give antibiotics, the reasons for administration, and whether these decisions are evidence-based. METHODS: An anonymous 25-question survey was e-mailed to the 921-member American Society for Surgery of the Hand listserv. We collected demographic information; participants were asked whether they would administer antibiotics in a number of surgical scenarios and for what reasons. Respondents were broken into 3 groups based on when they said they would administer antibiotics: Group 1 (40 respondents) would give antibiotics in the case of short cases, healthy patients, without hardware; group 2 (9 respondents) would not give antibiotics in any scenario; and group 3 (129 respondents) would give antibiotics situationally. The Fisher exact test compared demographic variables, frequency of use, and indications of antibiotic prophylaxis. RESULTS: Of the 921 recipients, 178 (19%) responded. Demographic variables did not correlate with the antibiotic use group. Operative case time >60 minutes, medical comorbidity, and pinning each increased antibiotic use. Group 1 respondents were more likely to admit that their practice was not evidence-based (74.4%) and that they gave antibiotics for medical-legal concern (75%). Twenty-two percent of respondents reported seeing a complication from routine prophylaxis, including Clostridium difficile infection. CONCLUSIONS: Antibiotics are still given unnecessarily before hand surgery, most often for medical-legal concern. Clear guidelines for preoperative antibiotic use may help reduce excessive and potentially inappropriate treatment and provide medical legal support. PMID- 30463442 TI - Effects of solvents and penetration enhancers on transdermal delivery of thymoquinone: permeability and skin deposition study. AB - Thymoquinone (TQ) is a quinone-based phytochemical that was first identified in 1963 in Nigella sativa (black cumin seed) by El-Dakhakhany. Based on the ideal characteristics of transdermal delivery, TQ is potentially an attractive candidate for transdermal drug delivery. The aim of this study was to investigate the feasibility of transdermal delivery of TQ and to assess the effect of an ethanol and propylene glycol donor solvent system along with various compositions of receptor solvents. The effects of penetration enhancers on the in vitro skin permeation and TQ skin absorption were studied using human cadaver skin in Franz diffusion cells. The permeation of saturated solutions of TQ was investigated with 5% v/v of each of the following enhancers: Azone (laurocapram), Transcutol(r) P (Tc), oleic acid, ethanol, Polysorbate 80 (Tween 80), and N methyl-pyrrolidone (NMP). The results indicated that Azone, oleic acid, and Tc were able to provide adequate TQ flux and may be the agents of choice for use in a novel transdermal formulation of TQ. These penetration enhancers were also able to generate TQ reservoirs in the skin that may be useful to provide sustained release of TQ from the stratum corneum over longer periods of time. PMID- 30463443 TI - More Frequent Nutrition Counseling Limits Weight Loss and Improves Energy Intake During Oncology Management: A Longitudinal Inpatient Study in Taiwan. AB - INTRODUCTION: Malnutrition increases the risk of cancer treatment-related complications. Nutritional intervention is beneficial for the outcomes of outpatients with cancer. This study investigated the impacts of nutrition consultation and care on energy intake and weight change in inpatients receiving cancer treatment. METHODS: We conducted a longitudinal study, enrolling 3221 inpatients with head and neck, lung, hepatobiliary, upper gastrointestinal, colorectal, breast, or gynecological cancer who received at least two nutrition consultations between April 2010 and July 2015. In every consultation, a dietitian calculated the total energy requirement and the actual energy intake was assessed using a 24-h dietary recall. RESULTS: Patients with head and neck cancer lost the most weight (1.16 kg/mo). For every consultation, a 0.03-kg weight gain per month was observed (P = 0.001). The average energy consumption percentage (% estimated energy requirement) at the third consultation was 87.0%. After controlling for potential covariates, the energy consumption percentages at the third, fourth, fifth-seventh, eighth, and subsequent consultations were significantly higher than those at the first consultation (P < 0.05). CONCLUSION: For oncology inpatients, routine screening and at least three active nutrition consultations with dietitians effectively improved energy intake and preserved body weight. PMID- 30463444 TI - Estimating Optimal Weights for Compound Scores: A Multidimensional IRT Approach. AB - A method is proposed for constructing indices as linear functions of variables such that the reliability of the compound score is maximized. Reliability is defined in the framework of latent variable modeling [i.e., item response theory (IRT)] and optimal weights of the components of the index are found by maximizing the posterior variance relative to the total latent variable variance. Three methods for estimating the weights are proposed. The first is a likelihood-based approach, that is, marginal maximum likelihood (MML). The other two are Bayesian approaches based on Markov chain Monte Carlo (MCMC) computational methods. One is based on an augmented Gibbs sampler specifically targeted at IRT, and the other is based on a general purpose Gibbs sampler such as implemented in OpenBugs and Jags. Simulation studies are presented to demonstrate the procedure and to compare the three methods. Results are very similar, so practitioners may be suggested the use of the easily accessible latter method. A real-data set pertaining to the 28-joint Disease Activity Score is used to show how the methods can be applied in a complex measurement situation with multiple time points and mixed data formats. PMID- 30463445 TI - Ivalin Inhibits Proliferation, Migration and Invasion by Suppressing Epithelial Mesenchymal Transition in Breast Cancer Cells. AB - Ivalin, an eudesmane-type sesquiterpene compound, was isolated from the Chinese herb Carpesium divaricatum in our chemistry group. In this study, we investigated the anti-migration and anti-invasion activities and underlying mechanisms of Ivalin in breast cancer cells in vitro. Cell viability was evaluated using the MTT assay, Western blotting was used to determine the expression of E-cadherin, N cadherin, vimentin and ZEB1, and mRNA levels were analyzed by qPCR. The anti migration and anti-invasion effects of Ivalin were measured by wound-healing and Transwell assays. In this connection, Ivalin treatment reduced the mRNA and protein expressions of ZEB1 as well as N-cadherin and vimentin expression in various breast cancer cells. E-cadherin expression was enhanced by Ivalin in the same cells, which implied that Ivalin depressed the process of epithelial-to mesenchymal transition (EMT). Our results revealed that Ivalin significantly inhibited cell proliferation, migration and invasion in breast cancer cells in a dose-dependent manner in vitro. This study suggests that Ivalin may merit further investigation as a potential therapeutic leading compound for the treatment of breast cancer migration and invasion. PMID- 30463446 TI - Yeast-inspired drug delivery: biotechnology meets bioengineering and synthetic biology. AB - INTRODUCTION: Yeast-based drug delivery offers a promising platform for the treatment of various medical conditions. Even the most promising nanoparticulate delivery systems have challenges from gastrointestinal barriers. The novel approach using bio-inspired yeast microcapsule helps in the delivery of charged nanoparticles like quantum dots, iron oxide nanoparticle and various fluorescent nanoparticles. The long-term administration has a good safety profile compared to other delivery systems. Particles can be incorporated into yeast microcapsule by electrostatic interaction, layer-by-layer approach, and surface derivatization. Areas covered: The article highlights the various applications of yeast cells in drug delivery. The authors describe the mechanism of encapsulation into yeast cells. The authors discuss various methods used for cell wall preparation and mechanisms associated with the passage of yeast cell through the gastrointestinal tract. The authors also review the association of biotechnology with bioengineering and synthetic biology approaches in transforming yeast as a delivery vehicle. Expert opinion: Yeast provides an opportunity to use the principles of biotechnology and bioengineering to tune it to an efficient drug delivery carrier. The applications of yeast microcapsule for oral and topical administration are noteworthy. It is proved that yeast microcapsules prepared from yeast cells are promising drug delivery carriers. PMID- 30463447 TI - Molecular Action of Herbal Antioxidants in Regulation of Cancer Growth: Scope for Novel Anticancer Drugs. AB - Continuous accumulation of ROS maintains oxidative stress in tumor microenvironment and is implicated in hyperactivation of signaling pathways that promote cell proliferation, survival, and metabolic adaptations to cancer. Antioxidants are supposed to interfere with tumor microenvironment. Plant-derived flavonoids and curcuminoids are considered as promising therapeutic molecules due to least side effects. Anticarcinogenic activity of various herbal antioxidants is widely reported. However, supports from preclinical studies and clinical trials are insufficient. Critical insight in signaling pathways leading to cancer progression and regulation of specific targets by herbal antioxidants in preclinical studies is a prerequisite to overcome the lacuna in its successful translation into therapeutical medicine. Most of the studies are limited to in vitro tests, revealing the action at cellular level. However, the natural antioxidants need validation at the level of cancer regression and better survival of laboratory animals. This review will focus on various signaling pathways leading to cancer progression and their interception by herbal antioxidants with a greater emphasis on the antioxidants being most widely validated in vitro and in animal models. These drugs are at the preliminary stage of testing as supplementary or alternative drugs in patients. The review will provide insight to overcome the failures in clinical practice and scope for development of novel anticancer drugs. PMID- 30463448 TI - Serum levels of subfatin in patients with type 2 diabetes mellitus and its association with vascular adhesion molecules. AB - Subfatin is a newly discovered adipokine with insulin-sensitizing properties. Studies reported conflicting data with regard to the circulating levels and expression of Subfatin in the context of type 2 diabetes mellitus (T2DM) and obesity. The present study was conducted on 52 patients with T2DM, 36 prediabetes subjects, and 50 controls. The serum levels of Subfatin, adhesion molecules were measured by the ELISA technique. The serum Subfatin was lower in the T2DM and prediabetes groups. The serum levels of adhesion molecules were higher in the T2DM group. In addition, Subfatin demonstrated lower levels in obese patients with T2DM in comparison to lean T2DM patients. Furthermore, Subfatin showed a negative association with vascular adhesion molecules in prediabetes subjects and the T2DM group. A decrease in the serum Subfatin in T2DM patients and prediabetes subjects, and its association with vascular adhesion molecules suggested the possible role of Subfatin in diabetes and endothelial dysfunction. PMID- 30463449 TI - Post-Occupancy Evaluation of a Crisis Shelter Garden and Application of Findings Through the Use of a Participatory Design Process. AB - OBJECTIVE:: This study concerned optimization of an evidence-based crisis shelter garden as a setting for everyday activities and nature-based therapy. The study hereby tested the design guidelines that the garden is based on. BACKGROUND:: Design guidelines for gardens intended to support health are becoming increasingly specialized, targeting different user groups. This study contributes to the knowledge concerning health-supporting garden design at crisis shelters for women and children who are exposed to domestic violence. METHOD:: The study included a post-occupancy evaluation (POE) consisting of landscape analyses, observation of physical traces, and interviews as well as a subsequent participatory design process. RESULTS:: The landscape analyses and the observation of physical traces indicated a minimal level of maintenance and recurrent use being limited to a few areas of the garden. The interviews added nuance and new issues to these results, resulting in the following themes: maintenance, accessibility, safety, therapeutic setting and free space, many ways to play, and social and private spheres. The participatory design process led to an optimization of the garden, including changes to its physical design related to making the garden safer, positively distractive, and more versatile in terms of activities. Improvements were also made regarding policy for use, maintenance, and informing users. CONCLUSION:: The design guidelines were tested, and the evidence was strengthened, adding nuance and new issues to consider during further development of the guidelines. Both the POE and the participatory design process were confirmed as crucial aspects of evidence-based health design. PMID- 30463450 TI - Smoking Increases Postoperative Complications After Distal Radius Fracture Fixation: A Review of 417 Patients From a Level 1 Trauma Center. AB - BACKGROUND: Unstable distal radius fractures that undergo surgical stabilization have varying complication rates in the literature. Smoking is known to affect bone healing and implant fixation rates but has never been definitively shown to affect postoperative outcomes of surgically managed distal radius fractures. METHODS: A retrospective review was performed of patients with surgically treated distal radius fractures at a Level 1 Trauma Center who had at least 6 weeks of follow-up over a 5-year period. Charts were reviewed for basic demographic information, comorbidities, details about the operative procedure, and early complications. Notable physical examination findings were noted, such as wrist stiffness and distal radius tenderness to palpation. Statistical analysis was performed to compare the smoking and nonsmoking groups. To control for confounding differences, a hierarchical multivariable regression analysis was performed. RESULTS: Four hundred seventeen patients were included in the study, and 24.6% were current smokers at the time of surgery. The overall complication rate for smokers was 9.8% compared with 5.6% in nonsmokers. The smoking cohort showed significantly higher rates of hardware removal, nonunion, revision procedures, wrist stiffness, and distal radius tenderness. When controlling for the confounding variables of diabetes and obesity, smokers still had significantly higher rates of the same complications. CONCLUSION: Patients who smoke have a statistically significant higher rate of postoperative distal radius tenderness, wrist stiffness, nonunion, hardware removal, and revision procedures compared with those who do not smoke in a review of 417 total patients undergoing surgical fixation for distal radius fractures. PMID- 30463451 TI - Fluticasone furoate, umeclidinium bromide, and vilanterol as a combination therapy for chronic obstructive pulmonary disease. AB - INTRODUCTION: Triple therapy with two bronchodilators (LABA plus LAMA) and an inhaled corticosteroid (ICS) is recommended for patients suffering from severe chronic obstructive pulmonary disease (COPD). Areas covered: All 12-52 week-long studies comparing triple therapy with umeclidinium (UM) added to either fluticasone furoate/vilanterol (FF/VI) or fluticasone propionate/salmeterol (FP/SAL) vs. other comparators in COPD patients of group B or D (2011 GOLD classification) were considered. When UM was added to ICS/LABA with separate devices or within a single device, triple combination was more effective than comparators (usually, ICS/LABA combinations) regarding improvements to pulmonary function, symptoms, quality of life and, in the longer studies, rate of moderate severe exacerbations. The IMPACT study (a large trial comparing UM/FF/VI with both FF/VI and UM/VI combinations) showed that triple therapy had a greater effect compared to dual therapies in reducing the rate of moderate-severe exacerbations, improving trough FEV1 and improving quality of life. The safety profile was good, without excess cardiovascular effects or pneumonia, however, the presence of comorbidities was frequent. Expert commentary: UM/FF/VI combination represents a good option for severe COPD patients who remain symptomatic and/or with frequent exacerbations despite dual therapies. Once daily administration with a simple and effective device may increase adherence and efficacy of the treatment. PMID- 30463452 TI - Physician compliance with quality and patient safety regulations: The role of perceived enforcement approaches and commitment. AB - The implementation of a quality and patient safety accreditation system is crucial for hospitals. Although control systems-such as accreditation-can contribute to quality improvements, they also run the risk of unintended consequences. As a result, ways should be found to avoid or reduce these undesirable consequences. This study aims to answer this call by exploring the association of different approaches to the enforcement of rules (punishment, based on monitoring and threats of sanctions; and persuasion, based on dialog and suggestion) with compliance. To test the relation between perceived enforcement and compliance, this study used survey data collected from medical specialists (N = 92) of a large academic medical center. The findings indicate that the same system is interpreted differently and that only a perceived persuasion approach is related to higher levels of compliance. This effect is fully mediated by affective commitment. No direct or indirect effects on compliance were found for a perceived coercive approach. These results suggest that control systems can be perceived in different ways and that the implementation of a control system does therefore not automatically lead to negative and unintended outcomes. PMID- 30463453 TI - Identifying logistical parameters in hospitals: Does literature reflect integration in hospitals? A scoping study. AB - In order to improve the quality and efficiency of hospitals, they can be viewed as a logistical system in which integration is a critical factor for performance. This paper describes the results of a scoping study that identifies the logistical parameters mentioned in international research on hospitals and indicates whether literature reflects system integration. When subsystems collaborate in order to accomplish the task of the entire organization, there is integration. A total number of 106 logistical parameters are identified in our study. In addition, the flow type - patients, materials and staff - and hospital subsystems were registered. The results presented in international literature show that logistics is highly fragmented in hospitals. Studies also show integration, although this takes place mainly within the subsystems of hospitals. A multi-agent perspective on hospitals is proposed, following the view that both integration and differentiation are essential for effective organizational performance. Given the widely recognised importance of controlling hospital costs and the potential of logistics to help in this process, it is important to gain more knowledge of hospitals as network organizations, as well as knowledge regarding the degree of integration and the logistical parameters that are required for better hospital performance. PMID- 30463454 TI - The pharmacokinetics and pharmacodynamics of SGLT2 inhibitors for type 2 diabetes mellitus: the latest developments. AB - INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder associated with high cardiovascular (CV) risk. Some of the therapeutic strategies are contraindicated in patients with concomitant heart disease. However, the newest antidiabetic medications, sodium-glucose cotransporter 2 (SGLT2) inhibitors, have shown to significantly reduce CV mortality and heart failure (HF) hospitalizations. The mechanism behind these surprising cardiac benefits remains unclear. Areas covered: This article reviews the pharmacokinetic, pharmacodynamics, efficacy, and safety data for the different SGLT2 inhibitors. Specific attention is devoted to the postulated mechanisms of action for their benefit. The therapeutic efficacy and potential use in different indications outside T2DM such as HF, T1DM, and renal disease are also discussed. Expert opinion: SGLT2 inhibitors have an excellent pharmacokinetic and pharmacodynamic profile. Importantly, SGLT2 inhibitors are a safe and efficacious treatment option for T2DM. Given their cardiac benefits (reduction in HF and death) and the low incidence of adverse events, SGLT2 inhibitors are being currently studied as a treatment for HF also in nondiabetic individuals. These agents seem to represent a shift in the treatment of HF patients regardless their glycemic profile. PMID- 30463455 TI - Assessing the potential of HSPA2 and ADAM2 as two biomarkers for human sperm selection. AB - Selection of the best sperm, with the least defects, is a critical factor in the success of ART especially in male factor infertility. This study assessed the potential Heat shock protein (HSPA2) and metallopeptidase domain2 (ADAM2) biomarkers for sperm selection. Sperm were obtained from 72 asthenoteratozoospermic and 42 normospermic ejaculates. The semen characteristic, DNA fragmentation (DFI), chromatin maturation index (CMI), ADAM2 and HSPA2 levels on sperm, and their correlation with embryo quality were assessed in both groups. Results showed the significant reduction in HSPA2 and ADAM2 in asthenoteratozoospermic compared to normazoospermic ejaculates regarding the cut off value of 14 and 13% for these two biomarkers. The specificity of HSPA2 and ADAM2 separately, and the combination of these two biomarkers, were 95.2, 90.5 and 93.5%, respectively, for sperm from normozoospermic ejaculates. However, they were 48.6, 50.0 and 54.5% for asthenoteratozoospermic ones. A significant correlation was observed with HSPA2, ADAM2 and a combination of these two biomarkers with CMI, DFI and embryo quality. Although a combination of these two biomarkers have the potential to be a good choice for selecting sperm with the lowest level of chromatin damage, it seems that selection according to HSPA2 has priority over ADAM2 or a combination of the two. PMID- 30463456 TI - Investigating the Utility of Fixed-margin Sampling in Network Psychometrics. AB - Steinley, Hoffman, Brusco, and Sher (2017) proposed a new method for evaluating the performance of psychological network models: fixed-margin sampling. The authors investigated LASSO regularized Ising models (eLasso) by generating random datasets with the same margins as the original binary dataset, and concluded that many estimated eLasso parameters are not distinguishable from those that would be expected if the data were generated by chance. We argue that fixed-margin sampling cannot be used for this purpose, as it generates data under a particular null-hypothesis: a unidimensional factor model with interchangeable indicators (i.e., the Rasch model). We show this by discussing relevant psychometric literature and by performing simulation studies. Results indicate that while eLasso correctly estimated network models and estimated almost no edges due to chance, fixed-margin sampling performed poorly in classifying true effects as "interesting" (Steinley et al. 2017, p. 1004). Further simulation studies indicate that fixed-margin sampling offers a powerful method for highlighting local misfit from the Rasch model, but performs only moderately in identifying global departures from the Rasch model. We conclude that fixed-margin sampling is not up to the task of assessing if results from estimated Ising models or other multivariate psychometric models are due to chance. PMID- 30463457 TI - Beclomethasone dipropionate, formoterol fumarate and glycopyrronium bromide as a combination therapy for chronic obstructive pulmonary disease. AB - INTRODUCTION: The triple therapy term covers the combination of inhaled corticosteroid (ICS), long-acting beta-receptor agonist (LABA) and long-acting anticholinergic drug (LAMA) in one or in separate inhalers. The latest GOLD 2018 (Global Initiative for Chronic Obstructive Disease) guidelines recommend the triple therapy in the management of chronic obstructive pulmonary disease (COPD) in patients of group D who despite the combination of two drugs: LAMA/LABA or ICS/LABA continue to have persistent symptoms or suffer from further frequent exacerbations. Areas covered: The first triple fixed-dose combination of extrafine beclomethasone/formoterol/glycopyrronium in one pMDI type inhaler intended for the treatment of COPD has been registered in Europe in 2017. Pharmacokinetic and pharmacodynamic properties, clinical efficacy and safety of this triple combination are presented in the review. Expert commentary: A 20% reduction in the risk of moderate or severe exacerbation was found in patients receiving triple therapy compared to the ICS/LABA combination and LAMA monotherapy. Triple therapy reduces the number of exacerbations in comparison with double bronchodilatation (LABA/LAMA), thus representing an interesting therapeutic option in the management of COPD. The profile of side effects of triple therapy is typical for individual active agents included in the combination. PMID- 30463458 TI - Use of computational fluid dynamics deposition modeling in respiratory drug delivery. AB - INTRODUCTION: Respiratory drug delivery is a surprisingly complex process with a number of physical and biological challenges. Computational fluid dynamics (CFD) is a scientific simulation technique that is capable of providing spatially and temporally resolved predictions of many aspects related to respiratory drug delivery from initial aerosol formation through respiratory cellular drug absorption. Areas Covered: This review article focuses on CFD-based deposition modeling applied to pharmaceutical aerosols. Areas covered include the development of new complete-airway CFD deposition models and the application of these models to develop a next generation of respiratory drug delivery strategies. Expert Opinion: Complete-airway deposition modeling is a valuable research tool that can improve our understanding of pharmaceutical aerosol delivery and is already supporting medical hypotheses, such as the expected under treatment of the small airways in asthma. These complete-airway models are also being used to advance next generation aerosol delivery strategies, like controlled condensational growth. We envision future applications of CFD deposition modeling to reduce the need for human subject testing in developing new devices and formulations, to help establish bioequivalence for the accelerated approval of generic inhalers, and to provide valuable new insights related to drug dissolution and clearance leading to microdosimetry maps of drug absorption. PMID- 30463459 TI - Early Adolescent Patterns of Alcohol and Tobacco Use in Eight Association of South-East Asian Nations (ASEAN) Member States. AB - BACKGROUND: Though alcohol and tobacco are the most commonly used substances among adolescents, little is known about the patterning of early adolescent substance use in Association of South-East Asian Nations (ASEAN) member states. OBJECTIVES: This study examined past month patterns of substances use and its gender difference among adolescents. METHODS: Cross-sectional samples among adolescents aged 13-16 years who completed the Global School-based Student Health Survey (GSHS) from eight ASEAN countries were included in the analysis (n = 40,212). RESULTS: Prevalence of past month any tobacco use was relatively high in Brunei, Indonesia, Malaysia, Thailand, and the Philippines (11-15%), but prevalence of dual cigarette and other forms of tobacco use was about 2-5% in the five countries. Past month alcohol consumption prevalence was also high in Thailand, Viet Nam, and the Philippines (16-24%), compared to the rest countries (1.4-8.2%). Moreover, prevalence of the concurrent alcohol and tobacco use was higher in Thailand and the Philippines (7 and 10%, respectively), particularly in boys (13 and 15%, respectively). Conclusions/importance: Almost 30-40% of the boys and 10-20% of girls in Malaysia, Philippines, Thailand, and Viet Nam are engaged in at least one of the two risk behaviors, and the concurrent alcohol and tobacco use was also relatively high among boys in those countries (5-15%). This study may provide some valuable insights on alcohol and tobacco policy in the region and requires to begin prevention and treatment programs in ASEAN member states. PMID- 30463460 TI - Primary care utilization and clinical quality performance: a comparison between health centres in Medicaid expansion states and non-expansion states. AB - OBJECTIVES: The United States Government's Medicaid expansion policy has important implications for health centres, since a large proportion of health centre patients are Medicaid enrollees. The objective of this study was to compare primary care utilization and clinical quality performance between health centres in Medicaid expansion states and those in Medicaid non-expansion states. METHODS: We conducted a cross-sectional study. Multiple regressions, using a standard linear model, were performed to examine the relationship between Medicaid expansion status and performance measures, accounting for covariates. RESULTS: Our results showed that in unadjusted analyses, health centres in Medicaid expansion states reported larger number of patients served, larger number of medical visits, a higher percentage of Medicaid patients, and better performance in seven of 16 clinical quality measures than those in Medicaid non expansion states. After controlling for relevant health centre-level covariates, the differences in mean patients served, mean medical visits, percentage of Medicaid patients, and five clinical quality measures still existed. CONCLUSIONS: These findings reveal significant associations between Medicaid expansion and primary care utilization and the quality of care. Medicaid expansion has demonstrated its potential role in promoting primary care for vulnerable populations served by health centres. PMID- 30463461 TI - Complications associated with higher order compared to lower order cesarean sections. AB - BACKGROUND: The rate of multiple cesarean sections is persistently on the rise because of cultural demands for large families, and multiple cesarean sections are an important cause of maternal morbidity and mortality. OBJECTIVES: This study was designed to detect the complications associated with higher order compared to lower order cesarean sections. MATERIALS AND METHODS: The hospitals record of women who had a cesarean section performed after three or more previous cesarean sections, and those who had a cesarean section for the second time over 2 years reviewed. Women with >= 3 cesarean sections admitted for elective cesarean section after 38 weeks' gestation, and those with >= 3 cesarean sections admitted in labor for emergency cesarean section were included in group 1. Women with history of previous one lower segment cesarean section (LSCS), who refused trial of labor and women with one LSCS who had an emergency cesarean section after failed trial of labor (TOL) were included in group 2. Antenatal, intraoperative and postoperative data were reviewed. Statistical analysis done using SPSS version 20 (Chicago, Illinois, USA), to detect the complications associated with higher order compared to lower order cesarean sections. Primary outcome measures; complications associated with higher order compared to lower order cesarean sections. Secondary outcome measures; intraoperative, and postoperative complications. RESULTS: Four hundred and fifty (450) women undergoing repeat cesarean section studied; 32.2% (145/450) had >= 3 previous cesarean sections (group 1), and 67.8% (305/450) had previous one cesarean section (group 2). In group 1, 77.2% (112/145) had previous three cesarean sections, 12.4% (18/145) had previous four cesarean sections, 9% (13/145) had previous five cesarean sections, and 1.4% (2/145) had previous six cesarean sections. The proportion of unbooked admission, and emergency cesarean sections were significantly high in group 2 compared to group 1 (11.1% (34/305) and 73.1% (223/305) versus 4.83% (7/145) and 40.7% (59/145); respectively) (p < 0.05, 95% CI; 0.1-0.2) and p < 0.01, 95% CI; 0.4-11.4; respectively. The risk of dense omental adhesions, and bladder injuries were significantly high in group 1 compared to group 2 (4.14% (6/145) and 1.38% (2/145) versus 0.66% (2/305) and 0% (0/305); respectively), (p = 0.01 (95% CI; 0.6-1.6) and p = 0.01 (95% CI; 0.5 5.5); respectively). Logistic regression analysis showed that the bladder injury was 5 times more (odds ratio 5.0 (95% CI; 0.035-711.8)) and the blood transfusion was 4.7 times more (odds ratio 4.7 (95% CI; 0.147-151.5)) in women with > 3 repeat cesarean sections compared to women with previous one cesarean section (insignificant difference p = 0.52 and 0.38; respectively). CONCLUSION: The risk of dense omental adhesions and bladder injury was significantly high in women with previous >= 3 cesarean sections compared to women with previous one cesarean section. Logistic regression analysis showed that the bladder injury was five times more and the blood transfusion was 4.7 times more in women with > 3 repeat cesarean sections compared to women with previous one cesarean section (insignificant difference). PMID- 30463462 TI - Value of rapid on-site evaluation for ultrasound-guided thyroid fine needle aspiration. AB - OBJECTIVE: Application of rapid on-site evaluation (ROSE) for thyroid fine needle aspiration (FNA) is controversial. Therefore, ROSE has not been universally applied. This study aimed to evaluate the value of ROSE for ultrasound-guided thyroid FNA. METHODS: A total of 997 patients with 1103 suspicious thyroid nodules had ultrasound-guided FNA performed from January 2016 to February 2018. There were 513 nodules with ROSE and 590 nodules without ROSE. The cytological nondiagnostic rate, needle passes, and procedural times of thyroid FNA with or without ROSE were compared. The nondiagnostic rates of subsets of suspicious thyroid nodules were further compared. RESULTS: There was no significant effect of ROSE on the nondiagnostic rate of FNA. However, FNA with ROSE significantly reduced the numbers of sub-centimeter, mixed solid-cystic, macrocalcified, and hypervascular nodules. There was a significantly smaller number of needle passes and less procedural times with ROSE than without ROSE. There was no significant difference in the complication rate of FNA with and without ROSE. CONCLUSION: ROSE for thyroid FNA reduces the number of needle passes and procedural times. ROSE has a higher clinical application value in subsets of thyroid nodules, which tend to be difficult to diagnose with FNA. PMID- 30463463 TI - The use of the social skills performance assessment (SSPA) among persons with serious mental illness: psychometric assessment and network analysis. AB - BACKGROUND: Challenges in social functioning are a major obstacle in the recovery process of persons with serious mental illness. Majority of social functioning measures use self-report assessments. AIMS: To validate the use of a performance based measure and examine a network analysis that explores the centrality of items. In addition, to explore the distinctiveness between the social skills performance assessment (SSPA), and a self-report measure of social quality of life (SQoL). METHOD: One hundred fifty eight participants were administrated with the SSPA and SQoL scale. Intra-class correlation, Pearson correlation and Network analysis were performed. RESULTS: A differentiation between the SQoL items and the SSPA items appeared. The strongest nodes in the network were social appropriateness (7.413), focus (7.763) and clarity (7.438) from the SSPA measure. The nodes rated highest on the betweenness measure were affect from the SSPA and satisfaction with getting along with other people from the SQoL scale. CONCLUSIONS: Interventions should target the skills of focus, clarity and social appropriateness as they present the central items in the network. PMID- 30463464 TI - Lipoteichoic acid of Enterococcus faecalis inhibits osteoclastogenesis via transcription factor RBP-J. AB - Lipoteichoic acid (LTA) of Enterococcus faecalis is a potent stimulator of inflammatory responses, but the effects of E. faecalis LTA on osteoclastogenesis remains far from well understood. This study showed that E. faecalis LTA significantly inhibited osteoclastogenesis of wild type murine bone marrow derived macrophages (BMMs) in the presence of a high dose of RANKL, while the inhibition of osteoclastogenesis by E. faecalis LTA was significantly removed in BMMs with deficient expression of the transcription factor RBP-J. In addition, a few small osteoclasts were generated in BMMs with only E. faecalis LTA stimulation, presumably due to the production of TNF-alpha and IL-6. Furthermore, both p38 and ERK1/2 MAPK signaling pathways were activated after 24 h of E. faecalis LTA treatment, but these signaling pathways were not activated after 6 d of treatment with RANKL in mature osteoclasts. In conclusion, E. faecalis LTA, which induces inflammatory response, could inhibit RANKL-induced osteoclastogenesis via RBP-J in BMMs. PMID- 30463465 TI - Perceived Unintended Consequences of Prescription Drug Monitoring Programs. AB - BACKGROUND: Opioid-related injuries and deaths continue to present challenges for public health practitioners. Prescription Drug Monitoring Programs (PDMPs) are a prevalent policy option intended to address problematic opioid pain reliever (OPR) prescribing, but previous research has not thoroughly characterized their unintended consequences. OBJECTIVES: To examine state actors' perceptions of the unintended consequences of PDMPs. METHODS: We conducted 37 interviews with PDMP staff, law enforcement officials, and administrative agency employees in Florida, Kentucky, New Jersey, and Ohio from May 2015 to June 2016. RESULTS: We identified six themes from the interviews. Perceived negative unintended consequences included: access barriers for those with medical needs, heroin use as OPR substitute and related deaths, and need for adequate PDMP security infrastructure and management. Perceived positive unintended consequences were: community formation and problem awareness, proactive population-level OPR monitoring, and increased knowledge about population-level drug diversion. Conclusions/Importance: State actors perceive a range of both negative and positive unintended consequences of PDMPs. Our findings suggest that there may be unintended risks of PDMPs that states should address, but also opportunities to maximize certain benefits. PMID- 30463466 TI - Statins are effective in the treatment of benign prostatic hyperplasia with metabolic syndrome. AB - OBJECTIVE: To compare the efficacy of statins and alpha blockers drug therapies for benign prostatic hyperplasia (BPH) in patients with metabolic syndrome (MetS). MATERIALS AND METHOD: A total of three hundred patients were randomly distributed into three groups of one hundred patients each. Group 1 received only alpha-adrenoceptor antagonist (alpha-blocker, AB) (Tamsulosin), group 2 received only statin (atorvastatin), and group 3 received AB plus statin (Tamsulosin + Atorvastatin). The efficacy measurement was assessed by analyzing the changes from baseline in the total International Prostate Symptom Score (IPSS), disease specific QoL question score and maximum urinary flow rate at the end of 6 months in each group and between the three groups. RESULTS: Pre-treatment and post treatment value of triglycerides (TG), high-density lipoprotein (HDL), and prostate volume (PV) were not significantly different in AB group, while TG and PV were significantly lower in patients taking statin and combined therapy. The significant decrease was demonstrated in maximum urinary flow rate (Qmax) in three groups. However, the most significant decrease was observed in the combination therapy group. IPSS, postvoid residual urine volume (PVR), and Quality of Life score (QoL) significantly changed in three groups. CONCLUSION: We recommend of the use of statins in those men with BPH accompanied by MetS in which AB is ineffective alone. PMID- 30463467 TI - Subclinical Saccadic Eye Movement Dysfunction in Pediatric Multiple Sclerosis. AB - BACKGROUND:: Efferent visual dysfunction in children could lead to impaired quality of life at home and school. Eye-tracking can detect subtle efferent dysfunction missed on bedside examination but has not been validated in the pediatric multiple sclerosis population. OBJECTIVE:: We sought to determine the feasibility of eye-tracking in children and associations with multiple sclerosis. METHODS:: Participants meeting criteria for pediatric multiple sclerosis without acute efferent vision abnormalities and healthy controls were recruited. Multiple sclerosis participants underwent a clinical assessment and saccade and antisaccade testing paradigms. Intraclass correlation coefficients were generated for intertest repeatability. Adjusting for age and intereye correlations, generalized estimating equations compared latencies with case status, Expanded Disability Status Scale and Symbol Digit Modalities Test (SDMT) scores. RESULTS:: We eye-tracked 15 children with multiple sclerosis (n = 30 eyes, mean age 15.6 +/ 2.1, mean disease duration 3.9 years, median Expanded Disability Status Scale 1.5) compared to 6 healthy controls (n = 12 eyes, age 14.3 +/- .95). The intraclass correlation coefficient for repeated trials was 0.85. Adjusting for age, saccadic latency was 60 milliseconds (ms) longer for cases than controls (95% confidence interval = 26.4, 93.8; P = .0005). For antisaccadic latency, we observed a similar trend of 60 ms longer for cases than controls ( P = .06). CONCLUSION:: Eye-tracking is a short noninvasive examination, and high intertest repeatability supports use of eye-tracking technology in pediatric multiple sclerosis. Longer saccadic latencies were seen in children with multiple sclerosis despite short disease duration and low Expanded Disability Status Scale scores. PMID- 30463468 TI - Causality Advocacy: Workers' Compensation Cases as Resources for Identifying and Preventing Diseases of Modernity. AB - An appeal process for an injured worker compensation case is a unique opportunity to debate and integrate evidence concerning a potential causal relationship between observations of occupational disease and exposures to various putative risk factors that may also be of significance in public health protection. Through application of Hill's indicia to the evidence presented in a recent appeal process concerning a breast cancer case for a female border guard, a novel epidemic, tentatively called "occupational BRCAness" has been identified and a causal relationship with exposures to traffic-related air pollution and shift work and possibly secondhand tobacco smoke is inferred. Application of the audit method by worker advocates to other compensation appeals processes for other diseases might similarly yield causal relations with exposures to occupational risk factors with relevance to public health. PMID- 30463469 TI - Novel nano-sized chitosan amphotericin B formulation with considerable improvement against Leishmania major. AB - AIM: Improvement in the treatment of Leishmania major's pathological effects through increasing the dose of amphotericin B loaded into nanochitosan. MATERIALS & METHODS: The phase separation method was used for nanochitosan synthesis and amphotericin loading. Also a novel solvent was designed and the nanodrug efficacy was evaluated in vitro and in vivo (pathology) environments. RESULTS: The drug loading efficiency of 90%, along with slow drug-release with cellular uptake of 98.6% was achieved. The novel solvent was composed of 10% acetic acid, and it was succeeded to dissolve AK10 mg/kg. Also, AK10 mg/kg had no side effects in in vitro and in vivo environments. In addition, the complete wound healing and parasite inhibition were achieved by using AK10 mg/kg in terms of improvement the treatment indicators. CONCLUSION: Increasing the therapeutic dose of AK to 10 mg/kg caused the successful treatment of L. major's pathological effects in in vitro and in vivo environments. PMID- 30463470 TI - Comparing the 1997 update of the 1982 American College of Rheumatology (ACR-97) and the 2012 Systemic Lupus International Collaborating Clinics (SLICC-12) criteria for systemic lupus erythematosus (SLE) classification: which enables earlier classification of SLE in an urban Asian population? AB - OBJECTIVE: We compared the 1997 update of the 1982 American College of Rheumatology (ACR-97) and the 2012 Systemic Lupus International Collaborating Clinics (SLICC-12) criteria, for earlier classification of systemic lupus erythematosus (SLE) in a multiethnic urban Asian SLE population. METHODS: Patients from a retrospective, nested case-control study of the influence of lupus nephritis on mortality in SLE were studied. For each patient, dates of first manifestations of each criteria (both ACR-97 and SLICC-12) were recorded, and the date of disease classification using ACR-97 or SLICC-12 criteria was compared to determine which criteria resulted in earlier classification. RESULTS: Among 182 SLE patients (74.2% Chinese, 18.1% Malay, 4.4% Indian and 3.3% Other ethnicities), 10 (5.5%) did not fulfill the ACR-97 criteria and 2 (1.1%) did not fulfill the SLICC-12 criteria. Using the SLICC-12 criteria, 18% of subjects showed earlier classification, whereas 7% of subjects showed earlier classification using the ACR-97 criteria. The SLICC hematologic criteria of "Leukopenia or lymphopenia" contributed most significantly to earlier diagnosis by SLICC-12. "Leukopenia or lymphopenia'' was present in 59% (19/32) of patients where SLICC-12 criteria allowed for earlier classification than ACR-97, compared with 15.4% (2/13) of patients where ACR-97 allowed earlier classification than SLICC-12 ( p = 0.02). The immunologic criterion that is considered a strength of the SLICC-12 criteria did not appear to contribute significantly to earlier diagnosis in this study. CONCLUSION: SLICC-12 criteria allow for earlier classification of SLE in a multiethnic cohort of Asian patients, supporting the validity of the SLICC-12 criteria and its use in clinical care and research. PMID- 30463471 TI - Brown adipose tissue and glucose homeostasis - the link between climate change and the global rise in obesity and diabetes. AB - There is increasing evidence that the global rise in temperature is contributing to the onset of diabetes, which could be mediated by a concomitant reduction in brown fat activity. Brown (and beige) fat are characterised as possessing a unique mitochondrial protein uncoupling protein (UCP)1 that when activated can rapidly generate large amounts of heat. Primary environmental stimuli of UCP1 include cold-exposure and diet, leading to increased activity of the sympathetic nervous system and large amounts of lipid and glucose being oxidised by brown fat. The exact contribution remains controversial, although recent studies indicate that the amount of brown and beige fat in adult humans has been greatly underestimated. We therefore review the potential mechanisms by which glucose could be utilised within brown and beige fat in adult humans and the extent to which these are sensitive to temperature and diet. This includes the potential contribution from the peridroplet and cytoplasmic mitochondrial sub-fractions recently identified in brown fat, and whether a proportion of glucose oxidation could be UCP1-independent. It is thus predicted that as new methods are developed to assess glucose metabolism by brown fat, a more accurate determination of the thermogenic and non-thermogenic functions could be feasible in humans. PMID- 30463472 TI - Effects of the oxidative stress and genetic changes in varicose vein patients. AB - BACKGROUND: Etiology of the varicose veins is still partly known. It has been proposed that varicose veins formation might be a cause of the oxidative stress and/or cause from genetical reasons. METHOD: The levels of antioxidant defense system enzymes, superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase, and an oxidative stress indicator, malondialdehyde, were measured in saphenous vein samples of varicose veins patients. Additionally, genetical polymorphism of glutathione S-transferase theta-1 has been studied. RESULT: In this study, measurements revealed significant increase in catalase and malondialdehyde levels in the patient group, whereas superoxide dismutase and glutathione peroxidase and glutathione S-transferase enzyme activity and comparison of the null mutation frequency in the glutathione S-transferase theta 1 gene did not show a statistically significant difference. CONCLUSION: We propose that the increase in catalase and malondialdehyde activities in our patient group may be related to each other. Increase in catalase levels, an antioxidant enzyme might be a compensatory response to the increase in malondialdehyde levels, an oxidative molecule. PMID- 30463474 TI - Minimal clinically important difference for the Boston Carpal Tunnel Questionnaire: new insights and review of literature. AB - No consensus exists about the minimal clinically important difference for the Boston Carpal Tunnel Questionnaire, which hampers its clinical application. This study assessed the minimal clinically important difference of this questionnaire. The Boston Carpal Tunnel Questionnaire was completed by 180 patients, with clinically defined carpal tunnel syndrome, preoperatively and at about 8 months follow-up after carpal tunnel release, together with a six-point scale for perceived improvement. Receiver operator characteristics curves showed that relative changes in Symptom Severity Scale and Functional Status Scale scores correspond better to a clinically relevant improvement than absolute changes. The minimal clinically important difference should be individually calculated from baseline Symptom Severity Scale and Functional Status Scale scores, as patients experiencing more symptoms require more improvement to notice a clinically important difference. By taking this into account, the Boston Carpal Tunnel Questionnaire is more meaningful as an outcome measure in research and clinical practice. PMID- 30463473 TI - Month-of-birth-effect in multiple sclerosis in Austria. AB - BACKGROUND:: The month-of-birth-effect (MoBE) describes the finding that multiple sclerosis (MS) patients seem to have been born significantly more frequently in spring, with a rise in May, and significantly less often in autumn and winter with the fewest births in November. OBJECTIVES:: To analyse if the MoBE can also be found in the Austrian MS population, and if so, whether the pattern is similar to the reported pattern in Canada, United Kingdom, and some Scandinavian countries. METHODS:: The data of 7886 MS patients in Austria were compared to all live births in Austria from 1940 to 2010, that is, 7.256545 data entries of the Austrian birth registry and analysed in detail. RESULTS:: Patterns observed in our MS cohort were not different from patterns in the general population, even when stratifying for gender. However, the noticeable and partly significant ups and downs over the examined years did not follow the distinct specific pattern with highest birth rates in spring and lowest birth rates in autumn that has been described previously for countries above the 49th latitude. CONCLUSION:: After correcting for month-of-birth patterns in the general Austrian population, there is no evidence for the previously described MoBE in Austrian MS patients. PMID- 30463475 TI - Oxygen Uptake Kinetics in Youth: Characteristics, Interpretation, and Application. AB - Pulmonary oxygen uptake ([Formula: see text]) kinetics, which describes the aerobic response to near instantaneous changes in metabolic demand, provides a valuable insight into the control and coordination of oxidative phosphorylation during exercise. Despite their applicability to the highly sporadic habitual physical activity and exercise patterns of children, relatively little is known regarding the influence of internal and external stimuli on the dynamic [Formula: see text] response. Although insufficient evidence is available during moderate intensity exercise, an age-related slowing of the phase 2 time constant (tau) and augmentation of the [Formula: see text] slow component appears to manifest during heavy-intensity exercise, which may be related to changes in the muscle phosphate controllers of oxidative phosphorylation, muscle oxygen delivery and utilization, and/or muscle fiber type recruitment patterns. Similar to findings in adults, aerobic training is associated with a faster phase 2 tau and smaller [Formula: see text] slow component in youth, independent of age or maturity, indicative of an enhanced oxidative metabolism. However, a lack of longitudinal or intervention based training studies limits our ability to attribute these changes to training per se. Further, methodologically rigorous studies are required to fully resolve the interaction(s) between age, sex, biological maturity, and external stimuli, such as exercise training and exercise intensity and the dynamic [Formula: see text] response at the onset and offset of exercise. PMID- 30463476 TI - The Vietnamese Community Members Who Were Part of GC-HARMS Are More Aware of Their Health, Environmental Impacts on Their Health, and How They Can Have Better Health: An Interview With Dustin Nguyen. AB - In this interview, Mr. Nguyen, Gulf Coast Health Alliance: Health risks related to the Macondo Spill Vietnamese community project hub manager (D'Iberville, Mississippi), describes his community's cultural and financial difficulties finding adequate avenues for healthcare and wellness information before the Deepwater Horizon oil spill. He comments extensively on how the project's clinical component in tandem with the Affordable Care Act promoted transformational changes in access to healthcare for his community and comments on generational shifts within the community in terms of language marginalization, its relationship to the pace of acculturation, and the allure of commercial fishing as a livelihood and a career. PMID- 30463477 TI - Always on the Edge of the Next Big Storm, the Next Big Spill, Always Vulnerable: An Interview With Bayou Interfaith Shared Community Organizing. AB - In this interview, Sharon and David Gauthe of Bayou Interfaith Shared Community Organizing (Thibodaux, Louisiana) document their personal experiences with adverse health outcomes that seem connected with oil spill exposures and explain their community organizing model based on interfaith collaboration and informed by the methodology and practice values of social work. They also comment on their conceptual framework of the entire Gulf Coast as a regional environmental justice zone, for which they received a Guardian of the Gulf Award by the U.S. Environmental Protection Agency. PMID- 30463478 TI - Social Justice and Environmental Justice Is an Easy Blend For Us: You Can't Have One Without the Other-An Interview With CEEJ. AB - Reverend James Black and his daughter, Joi Black-Tate, are key members of the Center for Environmental and Economic Justice team that served as a community hub for risk dissemination and clinical cohort management during the Gulf Coast Health Alliance: Health risks related to the Macondo Spill effort to characterize risk from the Deepwater Horizon well explosion and crude oil spill. In this interview, Reverend James Black and Ms. Black-Tate discuss how their community in Biloxi, Mississippi, was impacted by the Deepwater Horizon oil spill and connect this catastrophe to their previous experiences with collaborative Environmental Protection Agency projects measuring dioxin in "Back Bay Biloxi" and toxic chemical seepage from the Keesler Air Force Base. They elaborate on why they view their organization's commitment to environmental justice as a natural outgrowth of the struggle for African-American civil rights and social justice in Mississippi and share reflections on the spiritual core of their relationship to community, social change, health, and the natural world. PMID- 30463479 TI - Short-Term Psychological and Physiological Effects of Varying the Volume of High Intensity Interval Training in Healthy Men. AB - We assessed the short-term effects of varying the volume of high-intensity interval training (HIIT) on psychological and physiological responses of 23 healthy adult males ( M = 21 years; M peak oxygen uptake [VO2peak] = 47.2 ml.kg 1.min-1). Participants were randomly assigned to low- and very-low-volume HIIT groups and engaged in nine supervised exercise sessions over three weeks. The low volume HIIT group performed 8-12 60-second work bouts on a cycle ergometer at the peak power output achieved during the incremental test, interspersed by 75 seconds of low-intensity active recovery. The very-low-volume HIIT performed 4-6 work bouts with the same intensity, duration, and rest intervals. During training, participants' ratings of perceived exertion (Borg Category Ratio-10 scale) and their affective responses (Feeling Scale -5/+5) during the last 15 seconds of each work bout were recorded. Physiological data were VO2peak, endurance, and anaerobic performance before and after the intervention. Throughout training, participants in the very-low-volume group (relative to the low-volume group) reported lower ratings of perceived exertion in Week 1 ( M = 4.1 vs. M = 6.3; p < .01) and Week 3 ( M = 4.0 vs. M = 6.2; p < .01), and higher affective response in these same two weeks (Week 1: M = 1.9 vs. M = 0.3; p = .04; Week 3: M = 2.1 vs. M = 0.9; p = .06). Regarding physical fitness, Wingate peak power increased significantly after training in the very-low-volume HIIT group ( M = 1,049 W vs. M = 1,222 W; p < .05), but not in the low-volume HIIT group ( M = 1,050 W vs. M = 1,076 W). No significant change was found after training in physiological variables of peak power output, VO2peak, and endurance performance. In summary, in this short-term training period, the very-low-volume HIIT enhanced anaerobic capacity and was perceived as less strenuous and more pleasurable than low-volume HIIT. PMID- 30463480 TI - Television Watching as Sedentary Behavior and Atrial Fibrillation: The Atherosclerosis Risk in Communities Study. AB - BACKGROUND: There is no research on the association of television (TV) watching with atrial fibrillation (AF). METHODS: From 1987 to 1989, the authors obtained information on the frequency of TV watching in 14,458 participants, aged 45-64 years, without a history of AF. The authors used the Cox proportional hazards model to estimate hazard ratios and their 95% confidence intervals of AF according to the frequency of TV watching ("never or seldom," "sometimes," "often," or "very often"). RESULTS: During the 294,553 person-years of follow-up, the authors identified 2,476 AF events. Adjustment for other potential confounding factors, including physical activity, did not change the associations, in which "very often" watching TV carried 1.28 (95% confidence interval, 1.09-1.50) times AF risk compared with "never or seldom" watching TV (P for trend = .002). Even among individuals who met a recommended level of physical activity, watching TV "very often" carried 1.36 (1.02-1.82) times AF risk, compared with watching TV "never or seldom." CONCLUSION: Greater frequency of TV watching was independently associated with increased risk of AF even after adjusting for physical activity. Moreover, a recommended level of physical activity did not eliminate the increased risk of frequent TV watching for AF. Avoiding frequent TV watching might be beneficial for AF prevention. PMID- 30463481 TI - Area postrema syndrome: A short history of a pearl in demyelinating diseases. AB - In this topical review, we discuss the history of the area postrema syndrome, with special attention given to early studies aimed at identifying the area postrema and its function, possible early cases of the syndrome and its current relevance in neuroimmunology and demyelinating diseases. In 1896, Retzius named a structure in the posterior medulla oblongata as the area postrema. The work of Borison in the middle of the 20th century led to the elucidation of its function as a "vomiting center." The historical medical literature is filled with excellent examples that could be described as "area postrema syndrome." While severe and bilateral optic neuritis and transverse myelitis still constitute the classic components of neuromyelitis optica spectrum disorder (NMOSD), intractable vomiting and hiccups due to area postrema involvement is now recognized as essentially pathognomonic, indeed a shiny pearl in neuroimmunology and demyelinating diseases. PMID- 30463482 TI - Humboldts Preubetaen. Wissenschaft und Technik im Aufbruch. PMID- 30463483 TI - The British Pharmacopoeia, 1864 to 2014: Medicines, International Standards and the State. PMID- 30463484 TI - Pure Intelligence: The Life of William Hyde Wollaston. PMID- 30463485 TI - James Watt: Making the World Anew. PMID- 30463486 TI - Banned: A History of Pesticides and the Science of Toxicology. PMID- 30463487 TI - Bridging Traditions: Alchemy, Chemistry, and Paracelsian Practices in the Early Modern Era. PMID- 30463488 TI - Otto Linne Erdmann an Justus von Liebig - kommentierte Briefe von 1853 bis 1867. PMID- 30463489 TI - Uroscopy in Early Modern Europe. PMID- 30463490 TI - Panaceia's Daughters: Noblewomen as Healers in Early Modern Germany. PMID- 30463491 TI - The Cradle of Chemistry: The Early Years of Chemistry at the University of Edinburgh. PMID- 30463492 TI - Jonas Salk. A Life. PMID- 30463493 TI - Rhodamine B in spices determined by a sensitive UPLC-MS/MS method. AB - Rhodamine B (RhB) is a banned food additive and has been classified as illegal colourant. Therefore, the risk of RhB contamination should be strictly monitored. In this study, a sensitive UPLC-MS/MS method was applied to monitor RhB in 292 various spices such as chilli, pepper and tomato products. The results showed 22.7% of chilli powder samples, 18.5% of pepper powder samples, 11.1% of chilli oil samples and 9.1% of pepper oil samples were contaminated with RhB. Chilli powder contained RhB up to 44,935 MUg/kg with an average of 743 MUg/kg, pepper powder up to 65.9 MUg/kg with an average of 4.1 MUg/kg, chilli oil up to 14.6 MUg/kg with an average of 1.0 MUg/kg and pepper oil up to 1.1 MUg/kg with an average of 0.2 MUg/kg, respectively. Considering the common consumption of chilli products and pepper products by so many consumers, RhB exposure is significant and should be decreased. PMID- 30463494 TI - Induction of the pathological changes and impaired expression of cytokines in developing female rats' spleen after chronic excess fluoride exposure. AB - This study was designed to investigate the effects of excessive fluoride on spleen toxicity. Twenty-four healthy female rats were randomly divided into two groups, each of 12 rats. Each group of female rats was given a control diet and either F- = 0 mg/L or an excessive F- = 150 mg/L in the drinking water for 120 days. The histomorphological and ultrastructural changes in their splenic tissues were observed under light and transmission electron microscopes. DNA damage and splenocyte apoptosis were examined using the micronucleus (MN) assay, single-cell gel electrophoresis (SCGE), and flow cytometry. The expression levels of cytokines, including interleukin (IL)-1beta, IL-2, IL-6, and tumor necrosis factor (TNF)-alpha, were determined through immunohistochemistry and Western-blot analysis. Results demonstrated that the histomorphological characteristics and ultrastructure of the splenic tissues were affected by excessive fluoride. Nuclear dying, nuclear membrane dissolution, mitochondrial vacuolation, and endoplasmic reticulum dilation were observed. SCGE and MN assays showed that the nuclear DNA of splenocytes was damaged by fluoride treatment, and splenocyte apoptosis was exacerbated in the fluoride group. With damage to the splenocyte structure and DNA, the protein expression levels of IL-1beta, IL-2, IL-6, and TNF alpha were significantly downregulated by exposure to fluoride. Excessive fluoride ingestion caused splenic pathological damage and abnormal cytokine expression in female rats. PMID- 30463495 TI - The Absence of TLR4 Prevents Fetal Brain Injury in the Setting of Intrauterine Inflammation. AB - BACKGROUND:: Exposure to intrauterine inflammation during pregnancy is linked to brain injury and neurobehavioral disorders in affected children. Innate immunity, specifically Toll-like receptor (TLR) signaling pathways are present throughout the reproductive tract as well as in the placenta, fetal membranes, and fetus. The TLR pathways are mechanistically involved in host responses to foreign pathogens and may lead to brain injury associated with prenatal inflammation. OBJECTIVE:: We aimed to determine whether the activation of the TLR4 signaling pathway, in the mother and fetus, is critical to fetal brain injury in the setting of intrauterine inflammation. METHODS:: A mini-laparotomy was performed on time pregnant C57B6 mice and 2 knockout mouse strains lacking the function of the Tlr4 and Myd88 genes on embryonic day 15. Intrauterine injections of Escherichia coli lipopolysaccharide or saline were administered as described previously. Dams were killed 6 hours postsurgery, and placental, amniotic fluid, and fetal brain tissue were collected. To assess brain injury, quantitative polymerase chain reaction (qPCR) analysis was performed on multiple components of the NOTCH signaling pathway, including Hes genes. Interleukin (IL) IL6, IL1beta, and CCL5 expression was assessed using qPCR and enzyme-linked immunosorbent assay. RESULTS:: Using an established mouse model of intrauterine inflammation, we demonstrate that the abrogation of TLR4 signaling eliminates the cytokine response in mother and fetus and prevents brain injury associated with increased expression of transcriptional effectors of the NOTCH signaling pathway, Hes1 and Hes5. CONCLUSIONS:: These data show that the activation of the TLR4 signaling pathway is necessary for the development of fetal brain injury in response to intrauterine inflammation. PMID- 30463496 TI - Memory of Love Towards Parents Questionnaire: Development and Psychometric Evaluation. AB - We document the development of the Memory of Love towards Parents Questionnaire for use in multiple areas of psychology. It is designed to measure current feelings of and memory of love towards a specific parent during important time periods in childhood. In all samples (total N = 1527), we consistently found high internal reliability. We report the basic psychometrics of the 28-item subscale version in both undergraduate and US nonclinical adult samples and identified 10 item and 4-item subscale versions. The Memory of Love towards Parents Questionnaire has eight subscales: assessing mother and father separately during first, sixth, and ninth grade, as well as current feelings. We found a pattern of correlations that one would expect between existing attachment scales and the Memory of Love towards Parents Questionnaire. A factor analysis demonstrated that Memory of Love towards Parents Questionnaire items capture something different from the factors in established attachment measures. We found that the order of the subscales can be presented in a fixed order (mother-first and chronologically) without large order effects. The Memory of Love towards Parents Questionnaire demonstrated a single factor within subscales, reliability, and validity. The Memory of Love towards Parents Questionnaire can be used in clinical, social, developmental, and cognitive psychology. PMID- 30463497 TI - Individual dynamic predictions using landmarking and joint modelling: Validation of estimators and robustness assessment. AB - After the diagnosis of a disease, one major objective is to predict cumulative probabilities of events such as clinical relapse or death from the individual information collected up to a prediction time, usually including biomarker repeated measurements. Several competing estimators have been proposed, mainly from two approaches: joint modelling and landmarking. These approaches differ by the information used, the model assumptions and the complexity of the computational procedures. This paper aims to review the two approaches, precisely define the derived estimators of dynamic predictions and compare their performances notably in case of misspecification. The ultimate goal is to provide key elements for the use of individual dynamic predictions in clinical practice. Prediction of two competing causes of prostate cancer progression from the history of prostate-specific antigen is used as a motivated example. We formally define the quantity to estimate and its estimators, propose techniques to assess the uncertainty around predictions and validate them. We then conduct an in-depth simulation study compare the estimators in terms of prediction error, discriminatory power, efficiency and robustness to model assumptions. We show that prediction tools should be handled with care, in particular by properly specifying models and estimators. PMID- 30463498 TI - The role of spatial store and executive strategy in spatial working memory: a comparison between patients with obsessive-compulsive disorder and controls. AB - INTRODUCTION: Patients with obsessive-compulsive disorder (OCD) showed impaired spatial working memory (SWM). We evaluated whether patients and healthy controls (HCs) differed in spatial store capacity, and whether they differed in the relative weight of spatial store capacity and/or executive strategy in SWM. METHODS: Thirty inpatients with OCD and 31 age- and education-matched HCs underwent the CANTAB SWM, SRM (a measure of spatial store). The severity of OC symptoms was assessed using the Y-BOCS. Statistical significance: alpha = 0.05. RESULTS: Patients showed poorer performance than HCs in all neuropsychological outcomes. Both poorer SRM and SWM strategy were significantly associated with poorer SWM in the entire sample. No significant interaction between SRM and Group was found, while a significant interaction between SWM strategy and Group emerged; in patients the magnitude of this association was approximately twofold larger than in HCs. OC symptom severity did not correlate with neuropsychological performance. CONCLUSIONS: Patients with OCD had poorer spatial store capacity than HCs. However, the weight of poorer executive strategy in SWM was greater in patients than HCs, whereas the weight of spatial store was similar. We provided a direct evidence that an impairment in the executive component might be the crucial factor influencing the poorer SWM of these patients. PMID- 30463499 TI - Calcium phosphate product level as a predictor for arteriovenous fistula re operations in patients with chronic renal failure. AB - OBJECTIVES: There is an increased calcium phosphate product level causing the formation of calcification in the arterial wall and thus decreased quality of fistula in patients with chronic renal failure. The purpose of our study is to verify the relationship between arteriovenous fistula re-operation and high calcium phosphate product level. METHODS: Seventy-nine consecutive patients with chronic renal failure between April 2016 and February 2018 were included in the study. Patients having calcium phosphate product level >=50 mg2/dl2 were defined as group 1, whereas those having <50 mg2/dl2 were defined as group 2. Primary outcome of interest was the need for re-operation during the follow-up and to determine the risk factors for re-operation. To determine independent predictors for re-operation, multivariate logistic regression model was used. RESULTS: The rates of redo and tredo operation were significantly higher in group 1 compared to group 2 ( p = 0.01 and 0.04). In multivariate analysis, phosphate (OR: 1.84, 95% CI: 1.00-3.40, p = 0.05) and triglyceride (OR: 1.01, 95% CI: 1.00-1.02, p = 0.04) levels for redo operation and calcium phosphate product level (OR: 1.11, 95% CI: 1.01-1.22, p = 0.03) for tredo operation were found to be independent predictors. CONCLUSIONS: High calcium phosphate product level leads to increased risk of arteriovenous fistula re-operation by causing arterial stiffness in this patient group. Additionally, these re-operations place additional burden on morbidity and cost efficacy. Thus, we recommend keeping the calcium phosphate product level at the optimal level in these patients to avoid both the risk of arteriovenous fistula re-operation and the other cardiovascular problems. PMID- 30463500 TI - Use of a radial artery 'slender' sheath for facilitating transfemoral arterial access for neuroendovascular embolization in a very young infant. AB - Pediatric neuroendovascular procedures are increasingly performed as several studies have shown the safety of these interventions. In the literature, an upper limit of 4 French catheter size is conventionally used for femoral access in neuroangiography of very young infants. However, this constraint in luminal size may not allow for more complex procedures. We present the previously unreported use of a radial 5 French slender catheter with ultrathin walls for femoral access for aneurysm embolization in a 3-month-old boy presenting with left M2 aneurysm rupture. PMID- 30463501 TI - Current state of acute stroke care in Southeast Asian countries. AB - Acute stroke care systems in Southeast Asian countries are at various stages of development, with disparate treatment availability and practice in terms of intravenous thrombolysis and endovascular therapy. With the advent of successful endovascular therapy stroke trials over the past decade, the pressure to revise and advance acute stroke management has greatly intensified. Southeast Asian patients exhibit unique stroke features, such as increased susceptibility to intracranial atherosclerosis and higher prevalence of intracranial haemorrhage, likely secondary to modified vascular risk factors from differing dietary and lifestyle habits. Accordingly, the practice of acute endovascular stroke interventions needs to take into account these considerations. Acute stroke care systems in Southeast Asia also face a unique challenge of huge stroke burden against a background of ageing population, differing political landscape and healthcare systems in these countries. Building on existing published data, further complemented by multi-national interaction and collaboration over the past few years, the current state of acute stroke care systems with existing endovascular therapy services in Southeast Asian countries are consolidated and analysed in this review. The challenges facing acute stroke care strategies in this region are discussed. PMID- 30463502 TI - Accidental guide catheter fracture in mechanical thrombectomy. AB - Endovascular thrombectomy is now the standard of care for large vessel occlusion stroke. The aim is to achieve rapid and complete recanalisation while avoiding complications. Apart from the conventional complications of neurointerventional procedures, mechanical thrombectomy has its unique set of complications, inherent to the disease pathophysiology. We describe an unusual complication of catheter fracture and subsequent distal embolisation into the cerebral vasculature, which was noticed 24 hours after the procedure. Due to a lack of clinical consequences, we decided to manage it conservatively. The patient died within the following few days from respiratory complications unrelated to the stroke or the endovascular thrombectomy procedure. Consequently, we were able to retrieve the fractured segment and carry out histopathological analysis, which helped us to identify exactly its origin from the guide catheter. We believe that systematic reporting and database compilation of such device-related complications will aid in the design and development of neurointerventional devices in the future. PMID- 30463503 TI - 3MAX catheter for thromboaspiration of downstream and new territory emboli after mechanical thrombectomy of large vessel occlusions: initial experience. AB - Distal emboli and emboli to new territories occur in up to 14% and 11% of large vessel occlusion mechanical thrombectomies, respectively. A retrospective review was conducted of 18 consecutive patients with large vessel occlusion acute stroke undergoing mechanical thrombecomy, subsequently developing distal emboli and/or emboli to new territory for which thromboaspiration using the 3MAX catheter was performed. Eighteen distal emboli and two emboli to new territory in 18 patients were treated in the distal M2 and M3 middle cerebral artery, pericallosal and callosomarginal arteries, and P2 posterior cerebral artery (all arteries >=1.5 mm in diameter). 3MAX thromboaspiration was successful in 13/18 distal emboli and 2/2 emboli to new territory (total 15/20, 75%). 3MAX thromboaspiration resulted in improvement in the final modified treatment in cerebral ischaemia (mTICI) score in 14/18 patients (78%) compared with the initial mTICI score after large vessel occlusion thrombectomy. A shift towards higher final mTICI scores was seen with 3MAX catheter aspiration of distal emboli in this series. The initial mTICI score after large vessel occlusion thrombectomy was 2A in 4/18 (22%) patients and 2B in 14/18 (78%) patients. The final mTICI score after distal emboli/emboli to new territory aspiration improved to 2B in 7/18 (39%) patients, 2C in 3/18 (17%) patients and 3 in 8/18 (44%) patients. No procedural complications were noted. In 13 patients with successful distal emboli/emboli to new territory thromboaspiration, a 90-day modified Rankin score of 0-2 was seen in 10 patients (77%). In five patients with unsuccessful distal emboli/emboli to new territory aspiration, a 90-day modified Rankin score of 0-2 was seen in three patients (60%). 3MAX thromboaspiration of select distal emboli and emboli to new territories is feasible. Larger prospective studies are needed to establish the clinical benefit and safety of this approach. PMID- 30463504 TI - The Astana declaration 2018. PMID- 30463505 TI - Drug repositioning using drug-disease vectors based on an integrated network. AB - BACKGROUND: Diverse interactions occur between biomolecules, such as activation, inhibition, expression, or repression. However, previous network-based studies of drug repositioning have employed interaction on the binary protein-protein interaction (PPI) network without considering the characteristics of the interactions. Recently, some studies of drug repositioning using gene expression data found that associations between drug and disease genes are useful information for identifying novel drugs to treat diseases. However, the gene expression profiles for drugs and diseases are not always available. Although gene expression profiles of drugs and diseases are available, existing methods cannot use the drugs or diseases, when differentially expressed genes in the profiles are not included in their network. RESULTS: We developed a novel method for identifying candidate indications of existing drugs considering types of interactions between biomolecules based on known drug-disease associations. To obtain associations between drug and disease genes, we constructed a directed network using protein interaction and gene regulation data obtained from various public databases providing diverse biological pathways. The network includes three types of edges depending on relationships between biomolecules. To quantify the association between a target gene and a disease gene, we explored the shortest paths from the target gene to the disease gene and calculated the types and weights of the shortest paths. For each drug-disease pair, we built a vector consisting of values for each disease gene influenced by the drug. Using the vectors and known drug-disease associations, we constructed classifiers to identify novel drugs for each disease. CONCLUSION: We propose a method for exploring candidate drugs of diseases using associations between drugs and disease genes derived from a directed gene network instead of gene regulation data obtained from gene expression profiles. Compared to existing methods that require information on gene relationships and gene expression data, our method can be applied to a greater number of drugs and diseases. Furthermore, to validate our predictions, we compared the predictions with drug-disease pairs in clinical trials using the hypergeometric test, which showed significant results. Our method also showed better performance compared to existing methods for the area under the receiver operating characteristic curve (AUC). PMID- 30463506 TI - Post-concussion syndrome among patients experiencing head injury attending emergency department of Hawassa University Comprehensive specialized hospital, Hawassa, southern Ethiopia. AB - INTRODUCTION: Post-concussion syndrome (PCS) is defined as the presence of 3 or more of the following signs and symptoms after experiencing head injury such as headache, dizziness, fatigue, irritability, insomnia, difficulty of concentration or memory difficulty. In Ethiopia, even though there was no research conducted on post-concussion syndrome, it is common health problems after experiencing head trauma that affect the productive age group, which directly or indirectly influences the development of the country. OBJECTIVE: To assess the prevalence and determinants of post-concussion syndrome among patients experiencing head injury attending emergency department of Hawassa University Comprehensive Specialized hospital, Hawassa, Southern Ethiopia. METHODS: Institution based cross sectional study was conducted from November 1, 2017 to March 30, 2018, in Hawassa University Comprehensive Specialized Hospital emergency department, Hawassa, Southern Ethiopia. RESULT: A total of 275 cases were interviewed during data collection period with response rate of 95.2%. More than half (55.7%) of patients were within age range of 25-34 and Majorities (55.6%) of patients were married. About two-fifths of study participants (41.5%) had at least three symptoms of post-concussion syndrome components. Headache and restlessness were the most symptoms occurring in varying severity while double vision and fatigue were less severe among others. Occupation, cause of injury and location of injury were significant determinants of post-concussion syndrome. CONCLUSION: About 41.5% of study participants had at least three symptoms of PCS. Occupation, cause of injury and location of injury were significantly associated with the occurrence of PCS. PMID- 30463507 TI - MeioCapture: an efficient method for staging and isolation of meiocytes in the prophase I sub-stages of meiosis in wheat. AB - BACKGROUND: Molecular analysis of meiosis has been hindered by difficulties in isolating high purity subpopulations of sporogenous cells representing the succeeding stages of meiosis. Isolation of purified male meiocytes from defined meiotic stages is crucial in discovering meiosis specific genes and associated regulatory networks. RESULTS: We describe an optimized method termed MeioCapture for simultaneous isolation of uncontaminated male meiocytes from wheat (Triticum spp.), specifically from the pre-meiotic G2 and the five sub-stages of meiotic prophase I. The MeioCapture protocol builds on the traditional anther squash technique and the capillary collection method, and involves extrusion of intact sporogenous archesporial columns (SACs) containing meiocytes. This improved method exploits the natural meiotic synchrony between anthers of the same floret, the correlation between the length of anthers and meiotic stage, and the occurrence of meiocytes in intact SACs largely free of somatic cells. The main advantage of MeioCapture, compared to previous methods, is that it allows simultaneous collection of meiocytes from different sub-stages of prophase I at a very high level of purity, through correlation of stages with anther sizes. A detailed description is provided for all steps, including the collection of tissue, isolation and size sorting of anthers, extrusion of intact SACs, and staging of meiocytes. Precautions for individual steps throughout the procedure are also provided to facilitate efficient isolation of pure meiocytes. The proof of-concept was successfully established in wheat, and a light microscopic atlas of meiosis, encompassing all stages from pre-meiosis to telophase II, was developed. CONCLUSION: The MeioCapture method provides an essential technique to study the molecular basis of chromosome pairing and exchange of genetic information in wheat, leading to strategies for manipulating meiotic recombination frequencies. The method also provides a foundation for similar studies in other crop species. PMID- 30463509 TI - Towards reducing the immunogenic potential of wheat flour: omega gliadins encoded by the D genome of hexaploid wheat may also harbor epitopes for the serious food allergy WDEIA. AB - BACKGROUND: Omega-5 gliadins are a group of highly repetitive gluten proteins in wheat flour encoded on the 1B chromosome of hexaploid wheat. These proteins are the major sensitizing allergens in a severe form of food allergy called wheat dependent exercise-induced anaphylaxis (WDEIA). The elimination of omega-5 gliadins from wheat flour through biotechnology or breeding approaches could reduce the immunogenic potential and adverse health effects of the flour. RESULTS: A mutant line missing low-molecular weight glutenin subunits encoded at the Glu-B3 locus was selected previously from a doubled haploid population generated from two Korean wheat cultivars. Analysis of flour from the mutant line by 2-dimensional gel electrophoresis coupled with tandem mass spectrometry revealed that the omega-5 gliadins and several gamma gliadins encoded by the closely linked Gli-B1 locus were also missing as a result of a deletion of at least 5.8 Mb of chromosome 1B. Two-dimensional immunoblot analysis of flour proteins using sera from WDEIA patients showed reduced IgE reactivity in the mutant relative to the parental lines due to the absence of the major omega-5 gliadins. However, two minor proteins showed strong reactivity to patient sera in both the parental and the mutant lines and also reacted with a monoclonal antibody against omega-5 gliadin. Analysis of the two minor reactive proteins by mass spectrometry revealed that both proteins correspond to omega-5 gliadin genes encoded on chromosome 1D that were thought previously to be pseudogenes. CONCLUSIONS: While breeding approaches can be used to reduce the levels of the highly immunogenic omega-5 gliadins in wheat flour, these approaches are complicated by the genetic linkage of different classes of gluten protein genes and the finding that omega-5 gliadins may be encoded on more than one chromosome. The work illustrates the importance of detailed knowledge about the genomic regions harboring the major gluten protein genes in individual wheat cultivars for future efforts aimed at reducing the immunogenic potential of wheat flour. PMID- 30463508 TI - Coordinate regulation of long non-coding RNAs and protein-coding genes in germ free mice. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) are increasingly recognized as regulators of tissue-specific cellular functions and have been shown to regulate transcriptional and translational processes, acting as signals, decoys, guides, and scaffolds. It has been suggested that some lncRNAs act in cis to regulate the expression of neighboring protein-coding genes (PCGs) in a mechanism that fine tunes gene expression. Gut microbiome is increasingly recognized as a regulator of development, inflammation, host metabolic processes, and xenobiotic metabolism. However, there is little known regarding whether the gut microbiome modulates lncRNA gene expression in various host metabolic organs. The goals of this study were to 1) characterize the tissue-specific expression of lncRNAs and 2) identify and annotate lncRNAs differentially regulated in the absence of gut microbiome. RESULTS: Total RNA was isolated from various tissues (liver, duodenum, jejunum, ileum, colon, brown adipose tissue, white adipose tissue, and skeletal muscle) from adult male conventional and germ-free mice (n = 3 per group). RNA-Seq was conducted and reads were mapped to the mouse reference genome (mm10) using HISAT. Transcript abundance and differential expression was determined with Cufflinks using the reference databases NONCODE 2016 for lncRNAs and UCSC mm10 for PCGs. Although the constitutive expression of lncRNAs was ubiquitous within the enterohepatic (liver and intestine) and the peripheral metabolic tissues (fat and muscle) in conventional mice, differential expression of lncRNAs by lack of gut microbiota was highly tissue specific. Interestingly, the majority of gut microbiota-regulated lncRNAs were in jejunum. Most lncRNAs were co-regulated with neighboring PCGs. STRING analysis showed that differentially expressed PCGs in proximity to lncRNAs form tissue-specific networks, suggesting that lncRNAs may interact with gut microbiota/microbial metabolites to regulate tissue-specific functions. CONCLUSIONS: This study is among the first to demonstrate that gut microbiota critically regulates the expression of lncRNAs not only locally in intestine but also remotely in other metabolic organs, suggesting that common transcriptional machinery may be shared to transcribe lncRNA-PCG pairs, and lncRNAs may interact with PCGs to regulate tissue-specific pathways. PMID- 30463510 TI - Gene ontology analysis of expanded porcine blastocysts from gilts fed organic or inorganic selenium combined with pyridoxine. AB - BACKGROUND: Gene ontology analysis using the microarray database generated in a previous study by this laboratory was used to further evaluate how maternal dietary supplementation with pyridoxine combined with different sources of selenium (Se) affected global gene expression of expanded porcine blastocysts. Data were generated from 18 gilts randomly assigned to one of three experimental diets (n = 6 per treatment): i) basal diet without supplemental Se or pyridoxine (CONT); ii) CONT + 0.3 mg/kg of Na-selenite and 10 mg/kg of HCl-pyridoxine (MSeB610); and iii) CONT + 0.3 mg/kg of Se-enriched yeast and 10 mg/kg of HCl pyridoxine (OSeB610). All gilts were inseminated at their fifth post-pubertal estrus and euthanized 5 days later for embryo harvesting. Differential gene expression between MSeB610 vs CONT, OSeB610 vs CONT and OSeB610 vs MSeB610 was performed using a porcine embryo-specific microarray. RESULTS: There were 559, 2458, and 1547 differentially expressed genes for MSeB610 vs CONT, OSeB610 vs CONT and OSeB610 vs MSeB610, respectively. MSeB610 vs CONT stimulated 13 biological processes with a strict effect on RNA binding and translation initiation. OSeB610 vs CONT and OSeB610 vs MSeB610 impacted 188 and 66 biological processes, respectively, with very similar effects on genome stability, ceramide biosynthesis, protein trafficking and epigenetic events. The stimulation of genes related with these processes was confirmed by quantitative real-time RT-PCR. CONCLUSIONS: Gene expression of embryos from OSeB610 supplemented gilts was more impacted than those from MSeB610 supplemented gilts. Whereas maternal OSeB610 supplementation influenced crucial aspects of embryo development, maternal MSeB610 supplementation was restricted to binding activity. PMID- 30463511 TI - Recombination-independent rapid convergent evolution of the gastric pathogen Helicobacter pylori. AB - BACKGROUND: Helicobacter pylori is a human stomach pathogen, naturally-competent for DNA uptake, and prone to homologous recombination. Extensive homoplasy (i.e., phylogenetically-unlinked identical variations) observed in H. pylori genes is considered a hallmark of such recombination. However, H. pylori also exhibits a high mutation rate. The relative adaptive role of homologous recombination and mutation in species diversity is a highly-debated issue in biology. Recombination results in homoplasy. While convergent mutation can also account for homoplasy, its contribution is thought to be minor. We demonstrate here that, contrary to dogma, convergent mutation is a key contributor to Helicobacter pylori homoplasy, potentially driven by adaptive evolution of proteins. RESULTS: Our present genome wide analysis shows that homoplastic nonsynonymous (amino acid replacement) changes are not typically accompanied by homoplastic synonymous (silent) variations. Moreover, the majority of the codon positions with homoplastic nonsynonymous changes also contain different (i.e. non-homoplastic) nonsynonymous changes arising from mutation only. This indicates that, to a considerable extent, nonsynonymous homoplasy is due to convergent mutations. High mutation rate or limited availability of evolvable sites cannot explain this excessive convergence, as suggested by our simulation studies. Rather, the genes with convergent mutations are overrepresented in distinct functional categories, suggesting possible selective responses to conditions such as distinct micro niches in single hosts, and to differences in host genotype, physiology, habitat and diet. CONCLUSIONS: We propose that mutational convergence is a key player in H. pylori's adaptation and extraordinary persistence in human hosts. High frequency of mutational convergence could be due to saturation of evolvable sites capable of responding to selection pressures, while the number of mutable residues is far from saturation. We anticipate a similar scenario of mutational vs. recombinational genome dynamics or plasticity for other naturally competent microbes where strong positive selection could favor frequent convergent mutations in adaptive protein evolution. PMID- 30463512 TI - Phenotypic and genetic variation in the response of chickens to Eimeria tenella induced coccidiosis. AB - BACKGROUND: Coccidiosis is a major contributor to losses in poultry production. With emerging constraints on the use of in-feed prophylactic anticoccidial drugs and the relatively high costs of effective vaccines, there are commercial incentives to breed chickens with greater resistance to this important production disease. To identify phenotypic biomarkers that are associated with the production impacts of coccidiosis, and to assess their covariance and heritability, 942 Cobb500 commercial broilers were subjected to a defined challenge with Eimeria tenella (Houghton). Three traits were measured: weight gain (WG) during the period of infection, caecal lesion score (CLS) post mortem, and the level of a serum biomarker of intestinal inflammation, i.e. circulating interleukin 10 (IL-10), measured at the height of the infection. RESULTS: Phenotypic analysis of the challenged chicken cohort revealed a significant positive correlation between CLS and IL-10, with significant negative correlations of both these traits with WG. Eigenanalysis of phenotypic covariances between measured traits revealed three distinct eigenvectors. Trait weightings of the first eigenvector, (EV1, eigenvalue = 59%), were biologically interpreted as representing a response of birds that were susceptible to infection, with low WG, high CLS and high IL-10. Similarly, the second eigenvector represented infection resilience/resistance (EV2, 22%; high WG, low CLS and high IL-10), and the third eigenvector tolerance (EV3, 19%; high WG, high CLS and low IL-10), respectively. Genome-wide association studies (GWAS) identified two SNPs that were associated with WG at the suggestive level. CONCLUSIONS: Eigenanalysis separated the phenotypic impact of a defined challenge with E. tenella on WG, caecal inflammation/pathology, and production of IL-10 into three major eigenvectors, indicating that the susceptibility-resistance axis is not a single continuous quantitative trait. The SNPs identified by the GWAS for body weight were located in close proximity to two genes that are involved in innate immunity (FAM96B and RRAD). PMID- 30463513 TI - Integration of transcriptome and proteome profiles in glioblastoma: looking for the missing link. AB - BACKGROUND: Glioblastoma (GB) is the most common and aggressive tumor of the brain. Genotype-based approaches and independent analyses of the transcriptome or the proteome have led to progress in understanding the underlying biology of GB. Joint transcriptome and proteome profiling may reveal new biological insights, and identify pathogenic mechanisms or therapeutic targets for GB therapy. We present a comparison of transcriptome and proteome data from five GB biopsies (TZ) vs their corresponding peritumoral brain zone (PBZ). Omic analyses were performed using RNA microarray chips and the isotope-coded protein label method (ICPL). RESULTS: As described in other cancers, we found a poor correlation between transcriptome and proteome data in GB. We observed only two commonly deregulated mRNAs/proteins (neurofilament light polypeptide and synapsin 1) and 12 altered biological processes; they are related to cell communication, synaptic transmission and nervous system processes. This poor correlation may be a consequence of the techniques used to produce the omic profiles, the intrinsic properties of mRNA and proteins and/or of cancer- or GB-specific phenomena. Of interest, the analysis of the transcription factor binding sites present upstream from the open reading frames of all altered proteins identified by ICPL method shows a common binding site for the topoisomerase I and p53-binding protein TOPORS. Its expression was observed in 7/11 TZ samples and not in PBZ. Some findings suggest that TOPORS may function as a tumor suppressor; its implication in gliomagenesis should be examined in future studies. CONCLUSIONS: In this study, we showed a low correlation between transcriptome and proteome data for GB samples as described in other cancer tissues. We observed that NEFL, SYN1 and 12 biological processes were deregulated in both the transcriptome and proteome data. It will be important to analyze more specifically these processes and these two proteins to allow the identification of new theranostic markers or potential therapeutic targets for GB. PMID- 30463515 TI - Characterising and justifying sample size sufficiency in interview-based studies: systematic analysis of qualitative health research over a 15-year period. AB - BACKGROUND: Choosing a suitable sample size in qualitative research is an area of conceptual debate and practical uncertainty. That sample size principles, guidelines and tools have been developed to enable researchers to set, and justify the acceptability of, their sample size is an indication that the issue constitutes an important marker of the quality of qualitative research. Nevertheless, research shows that sample size sufficiency reporting is often poor, if not absent, across a range of disciplinary fields. METHODS: A systematic analysis of single-interview-per-participant designs within three health-related journals from the disciplines of psychology, sociology and medicine, over a 15 year period, was conducted to examine whether and how sample sizes were justified and how sample size was characterised and discussed by authors. Data pertinent to sample size were extracted and analysed using qualitative and quantitative analytic techniques. RESULTS: Our findings demonstrate that provision of sample size justifications in qualitative health research is limited; is not contingent on the number of interviews; and relates to the journal of publication. Defence of sample size was most frequently supported across all three journals with reference to the principle of saturation and to pragmatic considerations. Qualitative sample sizes were predominantly - and often without justification - characterised as insufficient (i.e., 'small') and discussed in the context of study limitations. Sample size insufficiency was seen to threaten the validity and generalizability of studies' results, with the latter being frequently conceived in nomothetic terms. CONCLUSIONS: We recommend, firstly, that qualitative health researchers be more transparent about evaluations of their sample size sufficiency, situating these within broader and more encompassing assessments of data adequacy. Secondly, we invite researchers critically to consider how saturation parameters found in prior methodological studies and sample size community norms might best inform, and apply to, their own project and encourage that data adequacy is best appraised with reference to features that are intrinsic to the study at hand. Finally, those reviewing papers have a vital role in supporting and encouraging transparent study-specific reporting. PMID- 30463514 TI - MicroRNA 399 as a potential integrator of photo-response, phosphate homeostasis, and sucrose signaling under long day condition. AB - BACKGROUND: Photoperiod-sensitivity is a critical endogenous regulatory mechanism for plant growth and development under specific environmental conditions, while phosphate and sucrose signaling processes play key roles in cell growth and organ initiation. MicroRNA399 is phosphate-responsive, but, whether it has roles in other metabolic processes remains unknown. RESULTS: MicroRNA399 was determined to be sucrose-responsive through a microRNA array assay. High levels of sucrose inhibited the accumulation of microRNA399 family under phosphate starvation conditions in Arabidopsis thaliana. Similarly, exogenous sucrose supplementation also reduced microRNA399 expression in maize at developmental transition stages. RNA sequencing of a near-isogenic line(photoperiod-sensitive) line and its recurrent parent Huangzao4, a photoperiod-insensitive line, was conducted at various developmental stages. Members of microRNA399 family were down-regulated under long-day conditions in the photoperiod-sensitive near-isogenic line that accumulated more sucrose in vivo compared with the control line Huangzao4. CONCLUSION: MicroRNA399s may play central roles in the integration of sucrose sensing and photoperiodic responses under long day conditions in maize. PMID- 30463516 TI - Pneumocystis jiroveci pneumonia in kidney and simultaneous pancreas kidney transplant recipients in the present era of routine post-transplant prophylaxis: risk factors and outcomes. AB - BACKGROUND: The goal of this study was to identify predictors for development of Pneumocystis jirovecii pneumonia (PJP) in kidney and simultaneous kidney and pancreas transplant recipients in the present era of universal primary prophylaxis. METHODS: We reviewed adult recipients of kidney transplant or simultaneous pancreas and kidney transplant at the University of Wisconsin between January 1, 1994 and December 31, 2016. Patients diagnosed with PJP during this time frame were included. Controls were randomly selected from among those whose post-transplant course was not complicated by PJP, matched on time since transplant through incidence density sampling with a 3:1 ratio. RESULTS: 28 (0.45%) of 6270 recipients developed PJP between 1994 and 2016. Median time since transplant was 4.6 years (interquartile range (IQR): 1.4-9.6 years). Affected recipients were older, had more HLA mismatches, and were more likely to have had BK viremia, CMV viremia and invasive fungal infections than matched controls. CMV viremia remained the only significant risk factor in multivariate analysis, and was a strong predictor (OR 6.27; p = 0.002). Ninety percent of the cases with prior CMV viremia had been diagnosed in the year preceding the diagnosis of PJP; among these, median time from diagnosis of CMV to diagnosis of PJP was 3.4 months (IQR: 1.74-11.5 months) and median peak CMV viral load prior to diagnosis of PJP was 3684.5 IU/mL (IQR: 1034-93,300 IU/mL). Additionally, 88.9% of patients with CMV in the preceding year had active infection at time of PJP diagnosis. Patient and graft survival were significantly worse at 2 years in recipients with PJP than our control group (42.4% vs. 88.5, and 37.9% vs. 79.9%; p < 0.001). CONCLUSIONS: Despite the low overall incidence of PJP in the era of universal prophylaxis, outcomes are poor. We suggest extending or re-initiating PJP prophylaxis for at least 6 months in the setting of CMV viremia due to the relatively low risk of therapy and potential significant impact on disease prevention. PMID- 30463517 TI - Neuroprotective effects of vitamin D on high fat diet- and palmitic acid-induced enteric neuronal loss in mice. AB - BACKGROUND: The role of vitamin D in obesity and diabetes is debated. Obese and/or diabetic patients have elevated levels of free fatty acids, increased susceptibility to gastrointestinal symptoms and are suggested to have altered vitamin D balance. The enteric nervous system is pivotal in regulating gastrointestinal activity and high fat diet (HFD) has been shown to cause loss of enteric neurons in ileum and colon. This study investigates the effect of vitamin D on HFD- and palmitic acid-induced enteric neuronal loss in vivo and in vitro. METHODS: Mice were fed either a normal diet (ND) or HFD supplemented with varying levels of vitamin D (from 0x to 20x normal vitamin D level) for 19 weeks. Ileum and colon were analyzed for neuronal numbers and remodeling. Primary cultures of myenteric neurons from mouse small intestine were treated with palmitic acid (4x10-4M) and/or 1alpha,25-hydroxy-vitamin D3 (VD, 10-11- 10-7M) with or without modulators of lipid metabolism and VD pathways. Cultures were analyzed by immunocyto- and histochemical methods. RESULTS: Vitamin D supplementation had no effect on enteric neuronal survival in the ND group. HFD caused substantial loss of myenteric neurons in ileum and colon. Vitamin D supplementation between 0-2x normal had no effect on HFD-induced neuronal loss. Supplementation with 20x normal, prevented the HFD-induced neuronal loss. In vitro supplementation of VD prevented the palmitic acid-induced neuronal loss. The VD receptor (VDR) was not identified in enteric neurons. Enteric glia expressed the alternative VD receptor, protein disulphide isomerase family A member 3 (PDIA3), but PDIA3 was not found to mediate the VD response in vitro. Inhibition of peroxisome proliferator-activated receptor gamma (PPARgamma) and immune neutralization of isocitrate lyase prevented the VD mediated neuroprotection to palmitic acid exposure. CONCLUSIONS: Results show that VD protect enteric neurons against HFD and palmitic acid induced neuronal loss. The mechanism behind is suggested to be through activation of PPARgamma leading to improved neuronal peroxisome function and metabolism of neuronal lipid intermediates. PMID- 30463518 TI - Sonographic guided hydrostatic saline enema reduction of childhood intussusception: a prospective study. AB - BACKGROUND: The management of childhood intussusception in our sub-region is still via surgical intervention. Currently, the gold standard of treatment is non operative reduction. We sought to assess the suitability of hydrostatic (saline) reduction of intussusception in children in our institution. MATERIALS AND METHODS: A prospective study was conducted between January 2016 and June 2017 in all children with ultrasound confirmed intussusception at a tertiary teaching hospital in Nigeria. All children excluding those with signs of peritonitis, bowel gangrene and intestinal prolapse were selected for ultrasound-guided hydrostatic reduction (USGHR). We allowed a maximum of three attempts at reduction. RESULTS: The age range was 3 months to 48 months with a mean of 10.8 +/- 9.1 months. Forty percent (N = 18) presented after 24 h of onset of symptoms. The success rate of hydrostatic reduction with saline enema was 84.4% (N = 38). Two (4.4%) perforations occurred during the procedure. Three (7.5%) patients had recurrent intussusception within six months. The duration of symptoms greater than 24 h, age and sex of patients did not influence successful reduction p > 0.05. The duration of admission between those who had successful non-operative reduction and those who subsequently had operative reduction and or resection attained statistical significant difference, p = 0.001. There was no mortality. We achieved a 68% decrease in the operative reduction of intussusception using USGHR as the primary modality of treatment. CONCLUSION: Our study found out that USGHR is a suitable alternative for the treatment of childhood intussusception. PMID- 30463519 TI - The patient experience with treatment and self-management (PETS) questionnaire: translation and cultural adaption of the Norwegian version. AB - BACKGROUND: Noncommunicable diseases represents long term medical conditions, which often puts the patients under enormous demands when following treatment, exposing them to experiencing treatment burden. The Patient Experience with Treatment and Self-Management (PETS) questionnaire was developed as a patient reported measure to identify treatment burden of chronic illness, using modern measurement theory and tested in a variety of settings. Developed in English, this set of measures had not been previously translated into Norwegian. The objective of this study was to develop a Norwegian version of the PETS and to pretest the translated measures through a cognitive debriefing methodology. METHODS: A rigorous translation approach was applied, guided by Functional Assessment of Chronic Illness Therapy methodology. Bilingual teams from Norway and the United States reviewed the translation to develop a provisional version, which was evaluated for test content validity with cognitive interviews by probing 12 native Norwegian patients with noncommunicable diseases. The interviews applied both concurrent and retrospective verbal probing techniques, guided by a question route. Audio-recorded interviews were transcribed verbatim and analysed using systematic text condensation. RESULTS: Assessment of translatability identified the need for cultural adaptation on several core words, balanced with the need to keep close to the original literal meaning. Seven patients with colorectal cancer and five patients with heart failure participated in cognitive testing of the Norwegian version of the PETS. The analytical process of the cognitive interviews identified two emergent main themes, 'comprehension and readability' and 'relevance of the PETS', with seven corresponding subthemes. Most items, response options and instructions were well understood by the patients. Revisions were made concerning cultural relevance. CONCLUSIONS: PETS items were semantically equivalent to the original. The patients with colorectal cancer and heart failure were able to comprehend the PETS and found it to express their experience with treatment burden in chronic illness. Future work will focus on psychometric construct validation and reliability testing of the PETS. PMID- 30463520 TI - The challenges of recruiting cancer patient/caregiver dyads: informing randomized controlled trials. AB - BACKGROUND: Family members are increasingly involved in the care of cancer patients, however many are not prepared for this challenging role. Intervention based studies are valuable to inform the most appropriate and effective support for caregivers. Barriers in the recruitment of patient/caregiver dyads exist but the reasons for non-participation are less well understood. This analysis determined the factors associated with participation in a randomized controlled trial involving patient/caregiver dyads, reasons for non-participation and factors associated with these reasons. METHODS: Patients with any type of cancer (other than non-melanoma skin cancer), and their caregiver were recruited at four Australian health services. Eligible patients were invited to participate together with their caregiver (N = 737). Non-participation data were collected from non-participants. Bivariate and binary logistic regression analyses were conducted to examine factors associated with participation. RESULTS: Of the 737 eligible dyads, 521 (71%) declined participation. Dyad characteristics associated with participation were caregiver gender, patient treatment modality and hospital type. The odds for participating were almost two times greater for female than male caregivers (p = 0.005); 13 times greater for patients receiving chemoradiotherapy compared to radiotherapy alone (p < 0.001); and three times greater for dyads attending a private versus public hospital (p < 0.001). Reasons for non-participation were lack of interest (33%), lack of time (29%), not requiring support (23%), too burdensome (15%); factors significantly associated with these reasons were treatment modality, patient age, cancer type, and hospital type. Patients diagnosed with prostate cancer and receiving chemotherapy alone were less likely to decline due to a lack of interest. Patients more likely to decline due to lack of time were those aged 40-59 years and receiving chemotherapy alone. Patients who were more likely to decline because they felt participation was too burdensome were those attending a private hospital for treatment. CONCLUSIONS: To optimize recruitment, it is recommended that special attention is given to different cancer types and treatment modalities, gender and age. Approaching dyads at varied time points when their need for support is high is recommended. This analysis provides important information for researchers undertaking randomized controlled trials involving people diagnosed with cancer and their caregivers. PMID- 30463521 TI - Chromosome level high-density integrated genetic maps improve the Pyrus bretschneideri 'DangshanSuli' v1.0 genome. AB - BACKGROUND: Chromosomal level reference genomes provide a crucial foundation for genomics research such as genome-wide association studies (GWAS) and whole genome selection. The chromosomal-level sequences of both the European (Pyrus communis) and Chinese (P. bretschneideri) pear genomes have not been published in public databases so far. RESULTS: To anchor the scaffolds of P. bretschneideri 'DangshanSuli' (DS) v1.0 genome into pseudo-chromosomes, two genetic maps (MH and YM maps) were constructed using half sibling populations of Chinese pear crosses, 'Mantianhong' (MTH) * 'Hongxiangsu' (HXS) and 'Yuluxiang' (YLX) * MTH, from 345 and 162 seedlings, respectively, which were prepared for SNP discovery using genotyping-by-sequencing (GBS) technology. The MH and YM maps, each with 17 linkage groups (LGs), were constructed from 2606 and 2489 SNP markers and spanned 1847 and 1668 cM, respectively, with average marker intervals of 0.7. The two maps were further merged with a previously published genetic map (BD) based on the cross 'Bayuehong' (BYH) * 'Dangshansuli' (DS) to build a new integrated MH-YM BD map. By using 7757 markers located on the integrated MH-YM-BD map, 898 scaffolds (400.57 Mb) of the DS v1.0 assembly were successfully anchored into 17 pseudo-chromosomes, accounting for 78.8% of the assembled genome size. About 88.31% of them (793 scaffolds) were directionally anchored with two or more markers on the pseudo-chromosomes. Furthermore, the errors in each pseudo chromosome (especially 1, 5, 7 and 11) were manually corrected and pseudo chromosomes 1, 5 and 7 were extended by adding 19, 12 and 14 scaffolds respectively in the newly constructed DS v1.1 genome. Synteny analyses revealed that the DS v1.1 genome had high collinearity with the apple genome, and the homologous fragments between pseudo-chromosomes were similar to those found in previous studies. Moreover, the red-skin trait of Asian pear was mapped to an identical locus as identified previously. CONCLUSIONS: The accuracy of DS v1.1 genome was improved by using larger mapping populations and merged genetic map. With more than 400 MB anchored to 17 pseudo-chromosomes, the new DS v1.1 genome provides a critical tool that is essential for studies of pear genetics, genomics and molecular breeding. PMID- 30463522 TI - Menstrual and reproductive outcomes after use of balloon tamponade for severe postpartum hemorrhage. AB - BACKGROUND: The use of intrauterine balloon tamponade to manage postpartum hemorrhage is increasing. However, there is lack of studies on the menstrual and reproductive outcomes after such treatment. The purpose of this study is to explore the menstrual and reproductive outcomes for patients who had been managed by intrauterine balloon tamponade for severe postpartum hemorrhage in her index pregnancy. METHODS: All patients who had delivered in United Christian Hospital from January 2011 to June 2016 with severe postpartum hemorrhage (PPH) (blood loss> = 1 L) were identified by the labour ward delivery registry and a comprehensive obstetric database. Patients who had intrauterine balloon tamponade inserted were compared with those managed solely by uterotonic agents as controls. Patients who had hysterectomy or additional procedures performed, such as compression sutures or uterine artery embolization were excluded from both groups. A questionnaire on menses, fertility and reproductive outcomes was mailed to both groups of patients. Those that had not replied within 4 weeks would receive a telephone survey. RESULTS: A total of 39 patients in the balloon tamponade group and 161 patients in the control group were recruited, which represented 87.0% of all eligible patients within the study period. The median follow up period was 45 months. All patients in the balloon tamponade group had return of menses after delivery. The majority of the patients (87.2%) in the balloon tamponade group had normal menstrual patterns in the 12 months after the index delivery as well as in the most recent 12 months. After excluding the patients with contraception, the subsequent pregnancy rate was 42.9% (9/21) in the balloon tamponade group compared to 45.9% (28/61) in the control group (p = 0.81). Among the 9 subsequent pregnancies in the balloon tamponade group, there were two miscarriages, one scar pregnancy, one induced abortion, while the remaining five were normal pregnancies with full term deliveries without intrauterine growth restriction. The majority of patients replied that they were satisfied with using Bakri balloon for PPH management in their index pregnancy. CONCLUSIONS: Intrauterine balloon tamponade for the management of severe PPH appeared to pose little adverse effects on subsequent menstrual and reproductive function. PMID- 30463523 TI - Proteomic analysis of the response of Funnelifor mismosseae/Medicago sativa to atrazine stress. AB - BACKGROUND: Arbuscular mycorrhizal (AM) fungi form symbiotic associations with host plants can protect host plants against diverse biotic and abiotic stresses, and promote biodegradation of various contaminants. However, the molecular mechanisms of how the arbuscular mycorrhizal fungi and host plant association on atrazine stress were still poorly understood. To better characterize how arbuscular mycorrhizal fungi and host plant interactions increase atrazine stress, we performed physiological and proteomic analysis of Funneliformis mosseae (mycorrhizal fungi) and Medicago sativa (alfalfa) association under atrazine stress. RESULTS: The results showed that in the Arbuscular mycorrhizal, protective enzymes were up regulated and the malondialdehyde content increased relative to those of non-mycorrhizal M.sativa. We also examined the atrazine degradation rates within the nutrient solution, and a 44.43% reduction was observed with the mycorrhizal M.sativa, with 30.83% of the reduction attributed to F. mosseae. The accumulation content in root and stem of mycorrhizal M.sativa were obviously increased 11.89% and 16.33% than those of non- mycorrhizal M.sativa. The activity of PPO, POD, CAT and SOD in mycorrhizal M.sativa were obviously higher than non mycorrhizal M.sativa under atrazine stess. We identified differential root proteins using isobaric tags for relative and absolute quantization coupled with liquid chromatography-mass spectrometry, with 533 proteins identified (276 unregulated and 257 downregulated). The differentially expressed proteins were further examined using GO, BLAST comparisons, and a literature inquiry and were classified into the categories of atrazine degradation (37.1%); atrazine stress response (28.6%); plant immune responses (14.3%); translation, synthesis, and processing (10%); and signal transduction and biological processes (10%). Furthermore, we identified glycosyl transferase, glutathione S-transferase, laccase, cytochrome P450 monooxygenase, peroxidase, and other proteins closely related to the degradation process. CONCLUSIONS: Mycorrhizal Medicago showed improved atrazine degradation within the culturing medium and increased atrazine enrichment in the roots and stems. Additionally, AMF increased the plant root response to atrazine, with relevant enzymes up regulated and toxic effects alleviated. Overall, the findings of this study show that AMF played an important role in easing atrazine stress in plants and contributed to atrazine remediation and further contributed to the understanding of the molecular mechanism associated with atrazine stresses and potential mycorrhizal contributions in M.sativa. PMID- 30463524 TI - A randomized trial to assess retention rates using mobile phone reminders versus physical contact tracing in a potential HIV vaccine efficacy population of fishing communities around Lake Victoria, Uganda. AB - BACKGROUND: High retention (follow-up) rates improve the validity and statistical power of outcomes in longitudinal studies and the effectiveness of programs with prolonged administration of interventions. We assessed participant retention in a potential HIV vaccine trials population of fishing communities along Lake Victoria, Uganda. METHODS: In a community-based individual randomized trial, 662 participants aged 15-49 years were randomized to either mobile phone or physical contact tracing reminders and followed up at months 1, 2, 3, 6, 12 and 18 post enrolment. The visit schedules aimed at mimicking a vaccine efficacy trial representing an early interval (months 1-6) where most vaccinations would be administered and a later period of post-vaccination follow-up. The primary outcome was retention measured as the proportion of post-baseline follow up visits completed by a participant. Retention was estimated in early and later follow-up intervals, and overall for all the six follow-up visits. Adjusted differences in retention between the study arms were determined by multivariable logistic regression using Stata(r) 14. One participant was later dropped from the analysis because of age ineligibility discovered after enrolment. RESULTS: Of the expected total follow up visits of 3966 among 661 participants, 84.1% (3334) were attained; 82.1% (1626/1980) in the phone arm and 86% (1708/1986) in the physical tracing arm (p = 0.001). No statistically significant differences in retention were observed between the study arms in the first 6 months but thereafter, retention was significantly higher for physical contact reminders than mobile phones; 91.5% versus 82.1% (p < 0.0001) at month 12 and 82.8% versus 75.4%, (p = 0.021) at month 18. Controlling for sex, age, education, occupation, community location, length of stay and marital status, the odds of good retention (completing 5 out of 6 follow-up visits) were 1.56 (95% CI;1.08-2.26, p = 0.018) for physical contact tracing compared to mobile phone tracing. Other statistically significant predictors of good retention were residing on islands and having stayed in the fishing communities for 5 or more years. CONCLUSIONS: Among fishing communities of Lake Victoria, Uganda, 84% of follow-up visits can be attained and participant retention is higher using physical contact reminders than mobile phones. TRIAL REGISTRATION NUMBER: PACTR201311000696101 ( http://www.pactr.org/ ). retrospectively registered on 05 November, 2013. PMID- 30463525 TI - Structural diversity across arbuscular mycorrhizal, ectomycorrhizal, and endophytic plant-fungus networks. AB - BACKGROUND: Below-ground linkage between plant and fungal communities is one of the major drivers of terrestrial ecosystem dynamics. However, we still have limited knowledge of how such plant-fungus associations vary in their community scale properties depending on fungal functional groups and geographic locations. METHODS: By compiling a high-throughput sequencing dataset of root-associated fungi in eight forests along the Japanese Archipelago, we performed a comparative analysis of arbuscular mycorrhizal, ectomycorrhizal, and saprotrophic/endophytic associations across a latitudinal gradient from cool-temperate to subtropical regions. RESULTS: In most of the plant-fungus networks analyzed, host-symbiont associations were significantly specialized but lacked "nested" architecture, which has been commonly reported in plant-pollinator and plant-seed disperser networks. In particular, the entire networks involving all functional groups of plants and fungi and partial networks consisting of ectomycorrhizal plant and fungal species/taxa displayed "anti-nested" architecture (i.e., negative nestedness scores) in many of the forests examined. Our data also suggested that geographic factors affected the organization of plant-fungus network structure. For example, the southernmost subtropical site analyzed in this study displayed lower network-level specificity of host-symbiont associations and higher (but still low) nestedness than northern localities. CONCLUSIONS: Our comparative analyses suggest that arbuscular mycorrhizal, ectomycorrhizal, and saprotrophic/endophytic plant-fungus associations often lack nested network architecture, while those associations can vary, to some extent, in their community-scale properties along a latitudinal gradient. Overall, this study provides a basis for future studies that will examine how different types of plant-fungus associations collectively structure terrestrial ecosystems. PMID- 30463527 TI - Effect of exercise and nutritional supplementation on health-related quality of life and mood in older adults: the VIVE2 randomized controlled trial. AB - BACKGROUND: Health-related quality of life (HRQoL) and absence of depressive symptoms are of great importance for older people, which may be achieved through lifestyle interventions, e.g., exercise and nutrition interventions. The aim of this investigation was to analyze the effects of a physical activity program in combination with protein supplementation on HRQoL and depressive symptoms in community-dwelling, mobility-limited older adults. METHODS: In the Vitality, Independence, and Vigor 2 Study (VIVE2), community-dwelling men and women with an average age of 77.5 +/- 5.4 years, some mobility limitations and low serum vitamin D levels (25(OH)Vit D 22.5-60 nmol/l) from two study sites (Stockholm, Sweden and Boston, USA) were randomized to receive a nutritional supplement or a placebo for 6 months. All took part in a physical activity program 2-3 times/ week. The primary outcome examined in VIVE2 was 400 M walk capacity. HRQoL was measured using the Medical Outcomes Study 36-item Short Form Health Survey (SF36), consisting of the Physical Component Summary (PCS) and Mental Component Summary (MCS), and depressive symptoms were measured using The Centre for Epidemiologic Studies Depression Scale (CES-D). In the sensitivity analyses, the sample was divided into sub-groups based on body measures and function (body mass index (BMI), appendicular lean mass index (ALMI), handgrip strength and gait speed). RESULTS: For the whole sample, there was a significant improvement in both MCS, mean (95% CI) 2.68 (0.5, 4.9) (p 0.02), and CES-D -2.7 (- 4.5, - 0.9) (p 0.003) during the intervention, but no difference was detected between those who received the nutritional supplement and those who received the placebo. The results revealed no significant change in PCS or variation in effects across the sub-categories. CONCLUSIONS: This study demonstrates that a six-month intervention using a physical activity program had positive effects on mental status. No additional effects from nutritional supplementation were detected. TRIAL REGISTRATION: Registered at ClinicalTrials.gov, March 2 2012, NCT01542892 . PMID- 30463526 TI - Association of sleep problems with neuroendocrine hormones and coagulation factors in patients with acute myocardial infarction. AB - BACKGROUND: Obstructive sleep apnea (OSA) and insomnia are frequent sleep problems that are associated with poor prognosis in patients with coronary heart disease. The mechanisms linking poor sleep with an increased cardiovascular risk are incompletely understood. We examined whether a high risk of OSA as well as insomnia symptoms are associated with neuroendocrine hormones and coagulation factors in patients admitted with acute myocardial infarction. METHODS: We assessed 190 patients (mean age 60 years, 83% men) in terms of OSA risk (STOP screening tool for the assessment of high vs. low OSA risk) and severity of insomnia symptoms (Jenkins Sleep Scale for the assessment of subjective sleep difficulties) within 48 h of an acute coronary intervention. Circulating concentrations of epinephrine, norepinephrine, cortisol, fibrinogen, D-dimer, and von Willebrand factor were measured the next morning. The association of OSA risk and insomnia symptoms with neuroendocrine hormones and coagulation factors was computed using multivariate models adjusting for demographic factors, health behaviors, somatic and psychiatric comorbidities, cardiac disease-related variables, and OSA risk in the model for insomnia symptoms, respectively, for insomnia symptoms in the model for OSA risk. RESULTS: High OSA risk was identified in 41% of patients and clinically relevant insomnia symptoms were reported by 27% of patients. Compared to those with low OSA risk, patients with high OSA risk had lower levels of epinephrine (p = 0.015), norepinephrine (p = 0.049) and cortisol (p = 0.001). More severe insomnia symptoms were associated with higher levels of fibrinogen (p = 0.037), driven by difficulties initiating sleep, and with lower levels of norepinephrine (p = 0.024), driven by difficulties maintaining sleep. CONCLUSIONS: In patients with acute myocardial infarction, sleep problems are associated with neuroendocrine hormones and coagulation activity. The pattern of these relationships is not uniform for patients with a high risk of OSA and those with insomnia symptoms, and whether they contribute to adverse cardiovascular outcomes needs to be established. TRIAL REGISTRATION: ClinicalTrials.gov NCT01781247 . PMID- 30463528 TI - Effects of PKM2 on global metabolic changes and prognosis in hepatocellular carcinoma: from gene expression to drug discovery. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor that threatens global human health. High PKM2 expression is widely reported in multiple cancers, especially in HCC. This study aimed to explore the effects of PKM2 on global gene expression, metabolic damages, patient prognosis, and multiple transcriptional regulation relationships, as well as to identify several key metabolic genes and screen some small-molecule drugs. METHODS: Transcriptome and clinical HCC data were downloaded from the NIH-GDC repository. Information regarding the metabolic genes and subsystems was collected from the Recon 2 human metabolic model. Drug protein interaction data were obtained from the DrugBank and UniProt databases. We defined patients with PKM2 expression levels >=11.25 as the high-PKM2 group, and those with low PKM2 expression (< 11.25) were defined as the low-PKM2 group. RESULTS: The results showed that the global metabolic gene expression levels were obviously divided into the high- or low-PKM2 groups. In addition, a greater number of affected metabolic subsystems were observed in the high-PKM2 group. Furthermore, we identified 98 PKM2-correlated deregulated metabolic genes that were associated with poor overall patient survival. Together, these findings suggest more comprehensive influences of PKM2 on HCC. In addition, we screened several small-molecule drugs that target these metabolic enzymes, some of which have been used in antitumor clinical studies. CONCLUSIONS: HCC patients with high PKM2 expression showed more severe metabolic damage, transcriptional regulation imbalance and poor prognosis than low-PKM2 individuals. We believe that our study provides valuable information for pathology research and drug development for HCC. PMID- 30463529 TI - Radiomics score: a potential prognostic imaging feature for postoperative survival of solitary HCC patients. AB - BACKGROUND: Radiomics is an emerging field in oncological research. In this study, we aimed at developing a radiomics score (rad-score) to estimate postoperative recurrence and survival in patients with solitary hepatocellular carcinoma (HCC). METHODS: A total of 319 solitary HCC patients (training cohort: n = 212; validation cohort: n = 107) were enrolled. Radiomics features were extracted from the artery phase of preoperatively acquired computed tomography (CT) in all patients. A rad-score was generated by using the least absolute shrinkage and selection operator (lasso) logistic model. Kaplan-Meier and Cox's hazard regression analyses were used to evaluate the prognostic significance of the rad-score. Final nomograms predicting recurrence and survival of solitary HCC patients were established based on the rad-score and clinicopathological factors. C-index and calibration statistics were used to assess the performance of nomograms. RESULTS: Six potential radiomics features were selected out of 110 texture features to formulate the rad-score. Low rad-score positively correlated with aggressive tumor phenotypes, like larger tumor size and vascular invasion. Meanwhile, low rad-score was significantly associated with increased recurrence and reduced survival. In addition, multivariate analysis identified the rad-score as an independent prognostic factor (recurrence: Hazard ratio (HR): 2.472, 95% confident interval (CI): 1.339-4.564, p = 0.004;survival: HR: 1.558, 95%CI: 1.022 2.375, p = 0.039). Notably, the nomogram integrating rad-score had a better prognostic performance as compared with traditional staging systems. These results were further confirmed in the validation cohort. CONCLUSIONS: The preoperative CT image based rad-score was an independent prognostic factor for the postoperative outcome of solitary HCC patients. This score may be complementary to the current staging system and help to stratify individualized treatments for solitary HCC patients. PMID- 30463530 TI - Adjunct clinical interventions that influence vaginal birth after cesarean rates: systematic review. AB - BACKGROUND: Rates of cesarean deliveries have been increasing, and contributes to the rising number of elective cesarean deliveries in subsequent pregnancies with associated maternal and neonatal risks. Multiple guidelines recommend that women be offered a trial of labor after a cesarean (TOLAC). The objective of the study is to systematically review the literature on adjunct clinical interventions that influence vaginal birth after cesarean (VBAC) rates. METHODS: We searched Ovid Medline, Ovid Embase, Wiley Cochrane Library, CINAHL via EBSCOhost; and Ovid PsycINFO. Additional studies were identified by searching for clinical trial records, conference proceedings and dissertations. Limits were applied for language (English and French) and year of publication (1985 to present). Two reviewers independently screened comparative studies (randomized or non randomized controlled trials, and observational designs) according to a priori eligibility criteria: women with prior cesarean sections; any adjunct clinical intervention or exposure intended to increase the VBAC rate; any comparator; and, outcomes reporting changes in TOLAC or VBAC rates. One reviewer extracted data and a second reviewer verified for accuracy. Two reviewers independently conducted methodological quality assessments using the Mixed Methods Appraisal Tool (MMAT). RESULTS: Twenty-three studies of overall moderate to good methodological quality examined adjunct clinical interventions affecting TOLAC and/or VBAC rates: system-level interventions (three studies), provider-level interventions (three studies), guidelines or information for providers (seven studies), provider characteristics (four studies), and patient-level interventions (six studies). Provider-level interventions (opinion leader education, laborist, and obstetrician second opinion for cesarean sections) and provider characteristics (midwifery antenatal care, physicians on night float call schedules, and deliveries by family physicians) were associated with increased rates of VBAC. Few studies employing heterogeneous designs, sample sizes, interventions and comparators limited confidence in the effects. Studies of system-level and patient-level interventions, and guidelines/information for providers reported mixed findings. CONCLUSIONS: Limited evidence indicates some provider-level interventions and provider characteristics may increase rates of attempted and successful TOLACs and/or VBACs, whereas other adjunct clinical interventions such as system-level interventions, patient-level interventions, and guidelines/information for healthcare providers show mixed findings. PMID- 30463531 TI - Renal dysfunction among adult HIV/AIDS patients on antiretroviral therapy at a tertiary facility in Ghana. AB - BACKGROUND: Kidney diseases have emerged as significant cause of morbidity and mortality in HIV subject on antiretroviral therapy (ART). In Ghana, routine follow up of HIV positive clients is by estimation of serum creatinine and urea levels. Glomerular Filtration Rate (GFR) is not routinely calculated and proteinuria is not routinely checked. This study sought to investigate the kidney profiles of adult HIV/AIDS patients being managed on ART at the Cape Coast Teaching Hospital (CCTH), Ghana. METHODS: A hospital-based analytical cross sectional study with a retrospective component was conducted using systematic sampling method to recruit HIV/AIDS who visited the ART clinic. A total of 440 participants of both sexes aged 18 years and above, confirmed as HIV/AIDS positive and on ART were involved in this study. Blood and urine samples were collected from all subjects and the levels of serum creatinine and urea and proteinuria were estimated and eGFR calculated using the Modification of Diet in Renal Disease (MDRD) equations. Data analyses were performed using Stata version 13 software (Stata Corp, Texas USA). RESULTS: The mean age (years) of participants was 45.5 years (+/-11.6) with 288 (65.4%) being on Tenofovir based ART regimen. The mean eGFR was found to decrease from 112.4 ml/min/1.73 m at baseline, to 103.4 ml/min/1.73 m after 6 months on ART and to a mean of 99.4 ml/min/1.73 m at recruitment into this study. Factors which were found to be associated with having eGFR < 60 included age, gender and CD4 count though not statistically significant. Patients > 45 years had the highest odds with OR 2.0 (95% CI: 0.8-5.1), females had higher odds with OR 1.5 (95% CI: 0.5-5.2), and those with CD4 count > 350 had OR of 0.4 (95% CI 0.2-1.3). A total of 30.9% of the participants had proteinuria at recruitment. TDF based ART regimen had no statistically significant effect on serum creatinine and urea levels. CONCLUSION: Estimated GFR decreased after 6 months among patients on ART despite normal serum creatinine and urea levels. This finding suggests that clients in care at HIV/ART clinics in Ghana may benefit from routine estimation of GFR and proteinuria. PMID- 30463533 TI - The impact of clinicopathologic and surgical factors on relapse and pregnancy in young patients (<=40 years old) with borderline ovarian tumors. AB - BACKGROUND: Fertility sparing surgery has been extensively performed among patients with borderline ovarian tumors due to their age and favorable prognosis. Nevertheless, the prognosis and obstetric outcomes in these patients remain uncertain. Thus, the current study was carried out to evaluate the oncological safety and fertility benefits of different fertility sparing surgery subtypes and various clinicopathological parameters. METHODS: Young borderline ovarian tumor patients with an age of <=40 years, who were admitted and treated in Zhejiang Cancer Hospital from January 1996 to December 2016, were enrolled in this study and reviewed retrospectively. The prognostic and obstetric effects of clinicopathological and surgical variables were evaluated using univariate/multivariate analyses and survival curves. RESULTS: A total of 92 eligible patients were enrolled in the analysis. Among these patients, 22 (24%) patients showed recurrence after a median follow-up of 46.5 months. Within the fertility sparing surgery group, patients at advanced stage (>=stage II), of serous type, with micropapillary and bilateral tumors were associated with a higher recurrence rate and a shorter recurrence interval. In terms of different modalities of fertility sparing surgery, adnexectomy was remarkably favored over cystectomy-including (P = 0.012); unilateral salpingo-oophorectomy had better prognosis than cystectomy and bilateral cystectomy was favored over unilateral salpingo-oophorectomy+contralateral cystectomy. Univariate Cox regression analysis indicated that the International Federation of Gynecology and Obstetrics stage (>=Stage II), the presence of bilateral and micropapillary lesions, and the application of cystectomy-including surgery were correlated with poorer disease free survival, while the mucinous type of borderline ovarian tumors was related to improved disease-free survival. In this study, a total of 22 patients attempted to conceive and 15 (68%) of these patients achieved successful pregnancy. CONCLUSIONS: Unilateral salpingo-oophorectomy and bilateral cystectomy should be recommended as the preferred choice of treatment for young patients with unilateral and bilateral borderline ovarian tumor who desire to preserve fertility. In addition, borderline ovarian tumor patients at advanced stage (>=stage II), of serous type, with micropapillary and bilateral tumors should pay more attention to the risk of recurrence. Therefore, these patients should choose fertility sparing surgery carefully and attempt to achieve pregnancy as soon as possible. PMID- 30463532 TI - The genome of the water strider Gerris buenoi reveals expansions of gene repertoires associated with adaptations to life on the water. AB - BACKGROUND: Having conquered water surfaces worldwide, the semi-aquatic bugs occupy ponds, streams, lakes, mangroves, and even open oceans. The diversity of this group has inspired a range of scientific studies from ecology and evolution to developmental genetics and hydrodynamics of fluid locomotion. However, the lack of a representative water strider genome hinders our ability to more thoroughly investigate the molecular mechanisms underlying the processes of adaptation and diversification within this group. RESULTS: Here we report the sequencing and manual annotation of the Gerris buenoi (G. buenoi) genome; the first water strider genome to be sequenced thus far. The size of the G. buenoi genome is approximately 1,000 Mb, and this sequencing effort has recovered 20,949 predicted protein-coding genes. Manual annotation uncovered a number of local (tandem and proximal) gene duplications and expansions of gene families known for their importance in a variety of processes associated with morphological and physiological adaptations to a water surface lifestyle. These expansions may affect key processes associated with growth, vision, desiccation resistance, detoxification, olfaction and epigenetic regulation. Strikingly, the G. buenoi genome contains three insulin receptors, suggesting key changes in the rewiring and function of the insulin pathway. Other genomic changes affecting with opsin genes may be associated with wavelength sensitivity shifts in opsins, which is likely to be key in facilitating specific adaptations in vision for diverse water habitats. CONCLUSIONS: Our findings suggest that local gene duplications might have played an important role during the evolution of water striders. Along with these findings, the sequencing of the G. buenoi genome now provides us the opportunity to pursue exciting research opportunities to further understand the genomic underpinnings of traits associated with the extreme body plan and life history of water striders. PMID- 30463534 TI - Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma. AB - BACKGROUND: Following up on previous work demonstrating the involvement of the transcription factor forkhead box M1 (FOXM1) in the biology and outcome of a high risk subset of newly diagnosed multiple myeloma (nMM), this study evaluated whether FOXM1 gene expression may be further upregulated upon tumor recurrence in patients with relapsed multiple myeloma (rMM). Also assessed was the hypothesis that increased levels of FOXM1 diminish the sensitivity of myeloma cells to commonly used myeloma drugs, such as the proteasome inhibitor bortezomib (Bz) and the DNA intercalator doxorubicin (Dox). METHODS: FOXM1 message was evaluated in 88 paired myeloma samples from patients with nMM and rMM, using gene expression microarrays as measurement tool. Sources of differential gene expression were identified and outlier analyses were performed using statistical methods. Two independent human myeloma cell lines (HMCLs) containing normal levels of FOXM1 (FOXM1N) or elevated levels of lentivirus-encoded FOXM1 (FOXM1Hi) were employed to determine FOXM1-dependent changes in cell proliferation, survival, efflux-pump activity, and drug sensitivity. Levels of retinoblastoma (Rb) protein were determined with the assistance of Western blotting. RESULTS: Upregulation of FOXM1 occurred in 61 of 88 (69%) patients with rMM, including 4 patients that exhibited > 20-fold elevated expression peaks. Increased FOXM1 levels in FOXM1Hi myeloma cells caused partial resistance to Bz (1.9-5.6 fold) and Dox (1.5-2.9 fold) in vitro, using FOXM1N myeloma as control. Reduced sensitivity of FOXM1Hi cells to Bz was confirmed in vivo using myeloma-in-mouse xenografts. FOXM1 dependent regulation of total and phosphorylated Rb agreed with a working model of myeloma suggesting that FOXM1 governs both chromosomal instability (CIN) and E2F-dependent proliferation, using a mechanism that involves interaction with NIMA related kinase 2 (NEK2) and cyclin dependent kinase 6 (CDK6), respectively. CONCLUSIONS: These findings enhanced our understanding of the emerging FOXM1 genetic network in myeloma and provided preclinical support for the therapeutic targeting of the FOXM1-NEK2 and CDK4/6-Rb-E2F pathways using small-drug CDK and NEK2 inhibitors. Clinical research is warranted to assess whether this approach may overcome drug resistance in FOXM1Hi myeloma and, thereby, improve the outcome of patients in which the transcription factor is expressed at high levels. PMID- 30463536 TI - Oxidative stress markers in tears of patients with Graves' orbitopathy and their correlation with clinical activity score. AB - BACKGROUND: To investigate the concentrations of oxidative stress markers, 8 hydroxy-2'-deoxyquanosine (8-OHdG) and malondialdehyde (MDA), in tears and their correlation with the clinical activity score (CAS) in patients with Graves' orbitopathy (GO) according to disease activity. METHODS: We recruited 27 participants with inactive stage GO, 35 participants with active stage GO, and 25 healthy controls without GO. The tear concentrations of 8-OHdG and MDA were determined by enzyme-linked immunosorbent assay. The correlation between CAS and the concentrations of tear 8-OHdG and MDA were analyzed according to the disease activity in the GO patients. RESULTS: The levels of 8-OHdG and MDA were 56.30 +/- 16.81 ng/mL and 5.39 +/- 1.31 pmol/mg, respectively, in the control subjects, and 123.46 +/- 22.67 ng/mL and 13.59 +/- 3.93 pmol/mg, respectively, in patients with inactive stage GO, and 215.14 +/- 35.61 ng/mL and 22.52 +/- 4.63 pmol/mg, in patients with active stage GO. The mean concentrations of 8-OHdG and MDA were higher in patients with inactive and active stage GO compared with the control group (all P < 0.001). Furthermore, in the active stage group, tear concentrations of 8-OHdG and MDA were higher than those in the inactive stage group (all P < 0.001). The level of 8-OHdG (r = 0.676, P < 0.001) and MDA (r = 0.506, P = 0.002) correlated with CAS in the active stage GO group. CONCLUSIONS: The concentrations of 8-OHdG and MDA in tears increased in patients with GO, especially in those in the active stage. In patients with active stage GO, CAS correlated significantly with the tear 8-OHdG and MDA levels. PMID- 30463535 TI - Sleep duration and the risk of cancer: a systematic review and meta-analysis including dose-response relationship. AB - BACKGROUND: The effect of sleep duration on cancer risk remains controversial. We aimed to quantify the available evidence on this relationship using categorical and dose-response meta-analyses. METHODS: Population-based cohort studies and case-control studies with at least three categories of sleep duration were identified by searching PubMed, EMBASE, and the Cochrane Library database up to July 2017. RESULTS: Sixty-five studies from 25 articles were included, involving 1,550,524 participants and 86,201 cancer cases. The categorical meta-analysis revealed that neither short nor long sleep duration was associated with increased cancer risk (short: odds ratio [OR] = 1.01, 95% confidence intervals [CI] = 0.97 1.05; long: OR = 1.02, 95% CI = 0.97-1.07). Subgroup analysis revealed that short sleep duration was associated with cancer risk among Asians (OR = 1.36; 95% CI: 1.02-1.80) and long sleep duration significantly increased the risk of colorectal cancer (OR = 1.21; 95% CI: 1.08-1.34). The dose-response meta-analysis showed no significant relationship between sleep duration and cancer risk. When treated as two linear piecewise functions with a cut point of 7 h, similar nonsignificant associations were found (per 1-h reduction: OR = 1.02, 95% CI = 0.98-1.07; per 1 h increment: OR = 1.003, 95% CI = 0.97-1.03). CONCLUSION: Categorical meta analysis indicated that short sleep duration increased cancer risk in Asians and long sleep duration increased the risk of colorectal cancer, but these findings were not consistent in the dose-response meta-analysis. Long-term randomized controlled trials and well-designed prospective studies are needed to establish causality and to elucidate the mechanism underlying the association between sleep duration and cancer risk. PMID- 30463537 TI - Clustering of diet, physical activity and sedentary behavior among Brazilian adolescents in the national school - based health survey (PeNSE 2015). AB - BACKGROUND: There is a lack of evidence regarding clusters of health-related behaviors among adolescents from low, lower-middle, and upper-middle income countries. This study aimed to identify clustering patterns of health-related behaviors (diet, physical activity [PA] and sedentary behavior [SB]) and association with sociodemographic variables among a population-based sample of Brazilian adolescents. METHODS: Cross-sectional data from the 2015 National School-Based Health Survey (PeNSE). A total of 102,072 (females: 51.7%) students in ninth-grade (age: 14.3 +/- 1.1 years-old) enrolled in public and private schools were investigated in this study. Healthy and unhealthy diet, PA and SB were measured using a validated questionnaire. Two-step cluster analysis was conducted to identify lifestyle patterns. The methodology for complex analysis and weighting was used to inferential statistical procedures. Multinomial logistic regression assessed associations between sociodemographic factors and the clusters. RESULTS: Three reliable and meaningful clusters were identified and labelled as follows: (1) health-promoting SB and diet (32.6%); (2) health promoting PA and diet (44.9%), and (3) health-risk (22.5%). Compared to boys, girls were less likely to be in clusters 1 (OR = 0.85; 95% CI = 0.78-0.93, p < 0.001) and 2 (OR = 0.43; 95% CI = 0.40-0.46, p < 0.001) than the health-risk cluster. Higher socioeconomic status was positively associated with health promoting PA and diet, and negatively related to health-promoting SB and diet. Older adolescents were more likely to be in cluster 1 than in cluster 3, compared to younger adolescents. CONCLUSION: Approximately one-quarter of the population (health-risk cluster) reported engaging in multiple risk behaviors. Interventions may need to be tailored to specific adolescent groups, especially considering sociodemographic differences. PMID- 30463538 TI - Metabolic syndrome among adolescents in Dubai, United Arab Emirates, is attributable to the high prevalence of low HDL levels: a cross-sectional study. AB - BACKGROUND: Metabolic syndrome (MetS) describes a combination of risk factors that increase the risk of developing chronic diseases. The prevalences of MetS and its risk factors are increasing, especially in the Arab region. A cross sectional study was carried out to assess the prevalences of MetS and its associated risk factors among adolescents in the United Arab Emirates (UAE). METHODS: A total of 596 students (308 boys and 288 girls) aged 10 to 15.9 years old were recruited from 14 public secondary schools in Dubai, UAE. Anthropometric and biochemical data were measured. RESULTS: According to the International Diabetes Federation (IDF) criteria, the prevalence of MetS was 3.7%, and it was more common among boys than girls (12 boys versus 10 girls). MetS was also more likely to be found in students who were obese or overweight than those with normal weight. The most prevalent and significant MetS risk factor was low high density lipoprotein (HDL) cholesterol levels. CONCLUSIONS: This study indicates the importance of carrying out further investigations about the constituents of HDL and their atherogenic effects. Additionally, these results strongly recommend setting a consensus for HDL measurement, since small variations in methodologies may lead to substantial deviations in results. PMID- 30463539 TI - Pancreatic cancer: challenges and opportunities. AB - Pancreatic cancer is the fourth leading cause of cancer-related death in the United States, with increasing incidence. The mortality rate of pancreatic cancer is rising rapidly, and is projected to be the second most common of all malignant tumors by 2030. However, the diagnosis and therapy of pancreatic cancer remain a formidable challenge. Recently, enormous efforts have been made to develop several new methods for the early diagnosis and treatment of pancreatic cancer. We briefly introduce the most groundbreaking advances in pancreatic cancer diagnosis and clinical treatment strategies over the past 15 years, including surgery, chemotherapy, endoscopic therapy, immunotherapy and personalized medicine. The signaling pathways that are altered in the progression of pancreatic cancer, which may be used as therapeutic targets, are also discussed. PMID- 30463540 TI - Recognition of bacteria named entity using conditional random fields in Spark. AB - BACKGROUND: Microbe plays a crucial role in the functional mechanism of an ecosystem. Identification of the interactions among microbes is an important step towards understand the structure and function of microbial communities, as well as of the impact of microbes on human health and disease. Despite the importance of it, there is not a gold-standard dataset of microbial interactions currently. Traditional approaches such as growth and co-culture analysis need to be performed in the laboratory, which are time-consuming and costly. By providing predicted candidate interactions to experimental verification, computational methods are able to alleviate this problem. Mining microbial interactions from mass medical texts is one type of computational methods. Identification of the named entity of bacteria and related entities from the text is the basis for microbial relation extraction. In the previous work, a system of bacteria named entities recognition based on the dictionary and conditional random field was proposed. However, it is inefficient when dealing with large-scale text. RESULTS: We implemented bacteria named entity recognition on Spark platform and designed experiments for comparison to verify the correctness and validity of the proposed system. The experimental results show that it can achieve higher F-Measure on the comparison of correctness. Moreover, the predicting speed is much faster than the previous version in large-scale biomedical datasets, and the computational efficiency is improved remarkably by about 3.1 to 6.7 times. CONCLUSIONS: The system for bacteria named entity recognition solves the inefficiency of the previous proposed system on large-scale datasets. The proposed system has good performance in accuracy and scalability. PMID- 30463541 TI - Transcripts of antibacterial peptides in chicken erythrocytes infected with Marek's disease virus. AB - BACKGROUND: Chicken erythrocytes are involved in immunity through binding of toll like receptors (TLRs) with their ligands to activate downstream signaling and lead to cytokine production in erythrocytes. Some avian beta-defensins (AvBDs) are constitutively expressed in tissues and some others can be induced by various bacteria and viruses. However, the expression of AvBDs in erythrocytes has not yet been studied extensively. RESULTS: The transcripts of eight AvBDs (AvBD1 to AvBD7, and AvBD9) and liver-expressed antimicrobial peptide-2 (LEAP-2) were found in normal chicken erythrocytes. The expression levels of AvBD2, 4 and 7 were significantly increased (P < 0.01), whereas the levels of AvBD1, 6 and 9 were significantly decreased (P < 0.01) after Marek's disease virus (MDV) infection. The mRNA expression level of LEAP-2 was not significantly changed after MDV infection. Highest viral nucleic acid (VNA) of MDV in the feather tips among the tested time points was found at 14 days post-infection (d.p.i.). In addition, 35 MD5-related gene segments were detected in the erythrocytes at 14 d.p.i. by transcriptome sequencing. CONCLUSIONS: These results suggest that the AvBDs in chicken erythrocytes may participate in MDV-induced host immune responses. PMID- 30463542 TI - Screening obstructive sleep apnea-hypopnea syndrome in hypertensive patients: a comparative study of the efficiency of the Epworth sleepiness scale. AB - BACKGROUND: Untreated Obstructive Sleep Apnea Hypnopnea Syndrome (OSAHS) is a known factor contributing to resistant hypertension (HT). Continuous Positive Airways Pressure (CPAP) is effective to decrease blood pressure (BP) in severe OSAHS. In our clinical practice, hypertensive patients seem less symptomatic with regard to severe OSAHS than normotensive patients, leading to a risk of underdiagnosis when OSAHS is screened with Epworth Sleepiness Scale (ESS). We aimed to confirm that severe OSAHS is less symptomatic in HT patients than normotensive patients using ESS. METHODS: We retrospectively compared two age, gender-matched groups - 100 hypertensive patients and 100 normotensive patients - with severe OSAHS defined as an AHI (Apnea Hypopnea Index) >=30. OSAHS was considered symptomatic when ESS > 10. RESULTS: The two groups of patients did not differ significantly with respect to main characteristics including Body Mass Index (BMI), AHI and ODI (Oxygen Desaturation Index). Systolic and Diastolic BP were higher in HT patients (p < 0.01). HT patients were less symptomatic with regard to severe OSAHS with a lower ESS (10.0 vs 11.9, p < 0.01), and a lower number of patients with an ESS > 10 (30% vs 58%, p < 0.01). In multivariable analysis adjusted on age, gender, Obesity, Systolic BP, Diastolic BP, AHI and ADO, normotension was significantly associated with symptomatic OSAHS (OR = 2.83, [1.298-6.192], p < 0.01). CONCLUSIONS: In our study on patients with severe OSAHS, ESS score was lower in hypertensive patients than in normotensive patients. This discrepancy may lead to an underestimation of severe OSAHS in hypertensive patients. PMID- 30463543 TI - Prevalence of pain reports in pediatric primary care and association with demographics, body mass index, and exam findings: a cross-sectional study. AB - BACKGROUND: Pediatric pain is associated to patient weight and demographics in specialized settings, but pain prevalence and its associated patient attributes in general pediatric outpatient care are unknown. Our objective was to determine the rate of positive pain screenings in pediatric primary care and evaluate the relationship between reported pain and obesity, demographics, and exam findings during routine pediatric encounters. METHODS: Cross-sectional observational study of 26,180 patients ages 2 to 19 seen in five urban pediatric primary care clinics between 2009 and 2016. Data were collected from systematic screening using a computerized clinical decision support system. Multivariable logistic regressions were used to analyze the association between pain reporting and obesity (body mass index), age, sex, race, season, insurance status, clinic site, prior pain reporting, pain reporting method, and exam findings. RESULTS: Pain was reported by the patient or caregiver in 14.9% of visits. In adjusted models, pain reporting was associated with obesity (Odds Ratio (OR) 1.23, 95% Confidence Intervals (CI) 1.11-1.35) and severe obesity (OR 1.32, CI 1.17-1.49); adolescents (OR 1.47, CI 1.33-1.61); and females (OR 1.21, CI 1.12-1.29). Pain reported at the preceding visit increased odds of pain reporting 2.67 times (CI 2.42-2.95). Abnormal abdominal, extremity, ear, nose, throat, and lymph node exams were associated with pain reporting. Pain reporting increased in minority races within clinics that predominantly saw a concordant race. CONCLUSIONS: Pain is common in general pediatric encounters, and occurs more frequently in obese children and those who previously reported pain. Pain reporting may be influenced by seasonal variation and clinic factors. Future pediatric pain screening may be guided by associated risk factors to improve identification and targeted healthcare interventions. PMID- 30463544 TI - Variant information systems for precision oncology. AB - BACKGROUND: The decreasing cost of obtaining high-quality calls of genomic variants and the increasing availability of clinically relevant data on such variants are important drivers for personalized oncology. To allow rational genome-based decisions in diagnosis and treatment, clinicians need intuitive access to up-to-date and comprehensive variant information, encompassing, for instance, prevalence in populations and diseases, functional impact at the molecular level, associations to druggable targets, or results from clinical trials. In practice, collecting such comprehensive information on genomic variants is difficult since the underlying data is dispersed over a multitude of distributed, heterogeneous, sometimes conflicting, and quickly evolving data sources. To work efficiently, clinicians require powerful Variant Information Systems (VIS) which automatically collect and aggregate available evidences from such data sources without suppressing existing uncertainty. METHODS: We address the most important cornerstones of modeling a VIS: We take from emerging community standards regarding the necessary breadth of variant information and procedures for their clinical assessment, long standing experience in implementing biomedical databases and information systems, our own clinical record of diagnosis and treatment of cancer patients based on molecular profiles, and extensive literature review to derive a set of design principles along which we develop a relational data model for variant level data. In addition, we characterize a number of public variant data sources, and describe a data integration pipeline to integrate their data into a VIS. RESULTS: We provide a number of contributions that are fundamental to the design and implementation of a comprehensive, operational VIS. In particular, we (a) present a relational data model to accurately reflect data extracted from public databases relevant for clinical variant interpretation, (b) introduce a fault tolerant and performant integration pipeline for public variant data sources, and (c) offer recommendations regarding a number of intricate challenges encountered when integrating variant data for clincal interpretation. CONCLUSION: The analysis of requirements for representation of variant level data in an operational data model, together with the implementation-ready relational data model presented here, and the instructional description of methods to acquire comprehensive information to fill it, are an important step towards variant information systems for genomic medicine. PMID- 30463545 TI - An interpretable boosting model to predict side effects of analgesics for osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) is the most common disease of arthritis. Analgesics are widely used in the treat of arthritis, which may increase the risk of cardiovascular diseases by 20% to 50% overall.There are few studies on the side effects of OA medication, especially the risk prediction models on side effects of analgesics. In addition, most prediction models do not provide clinically useful interpretable rules to explain the reasoning process behind their predictions. In order to assist OA patients, we use the eXtreme Gradient Boosting (XGBoost) method to balance the accuracy and interpretability of the prediction model. RESULTS: In this study we used the XGBoost model as a classifier, which is a supervised machine learning method and can predict side effects of analgesics for OA patients and identify high-risk features (RFs) of cardiovascular diseases caused by analgesics. The Electronic Medical Records (EMRs), which were derived from public knee OA studies, were used to train the model. The performance of the XGBoost model is superior to four well-known machine learning algorithms and identifies the risk features from the biomedical literature. In addition the model can provide decision support for using analgesics in OA patients. CONCLUSION: Compared with other machine learning methods, we used XGBoost method to predict side effects of analgesics for OA patients from EMRs, and selected the individual informative RFs. The model has good predictability and interpretability, this is valuable for both medical researchers and patients. PMID- 30463546 TI - A multi-context learning approach for EEG epileptic seizure detection. AB - BACKGROUND: Epilepsy is a neurological disease characterized by unprovoked seizures in the brain. The recent advances in sensor technologies allow researchers to analyze the collected biological records to improve the treatment of epilepsy. Electroencephalogram (EEG) is the most commonly used biological measurement to effectively capture the abnormalities of different brain areas during the EEG seizures. To avoid manual visual inspection from long-term EEG readings, automatic epileptic EEG seizure detection has become an important research issue in bioinformatics. RESULTS: We present a multi-context learning approach to automatically detect EEG seizures by incorporating a feature fusion strategy. We generate EEG scalogram sequences from the EEG records by utilizing waveform transform to describe the frequency content over time. We propose a multi-stage unsupervised model that integrates the features extracted from the global handcrafted engineering, channel-wise deep learning, and EEG embeddings, respectively. The learned multi-context features are subsequently merged to train a seizure detector. CONCLUSIONS: To validate the effectiveness of the proposed approach, extensive experiments against several baseline methods are carried out on two benchmark biological datasets. The experimental results demonstrate that the representative context features from multiple perspectives can be learned by the proposed model, and further improve the performance for the task of EEG seizure detection. PMID- 30463547 TI - Factors related to amblyopia in congenital ptosis after frontalis sling surgery. AB - BACKGROUND: Amblyopia is a main concern in children undergoing frontalis sling surgery for repairing congenital ptosis. This study aimed to evaluate factors related to amblyopia in children undergoing frontalis sling surgery. METHODS: IRB approved retrospective review of children under the age of 12 who received frontalis sling surgery. Preoperative demographic data, strabismus, margin reflex distance 1 (MRD1), lid fissure height, sling type, refraction errors, surgical outcome and amblyopia were evaluated. RESULTS: This study included 48 eyelid procedures performed in 38 patients. Median age was 4.0 years. Etiology was congenital ptosis in 42 eyes (87.5%) and blepharophimosis in 6 eyes (12.5%). Mersilene mesh was the sling material used in 36 eyes (75%), silicone in 6 eyes (12.5%), and polytetrafluoroethylene (PTFE) in 6 eyes (12.5%). Mean duration of follow-up was 27.8 +/- 25.0 months (range, 3 to 128 months). Amblyopia was observed in 17 eyes (35.4%) at the final follow-up. Factors significantly associated with final amblyopia included blepharophimosis (p = 0.017), preoperative MRD1 <= - 1.0 mm (p = 0.038), preoperative lid fissure <=4.5 mm (p = 0.035), preoperative anisometropia (spherical equivalent) (p = 0.011), and postoperative astigmatism (p = 0.026). CONCLUSIONS: Study results suggest that blepharophimosis, preoperative MRD1 <= - 1.0 mm, preoperative lid fissure <=4.5 mm, preoperative anisometropia (spherical equivalent), and postoperative astigmatism are associated with amblyopia after frontalis sling surgery in patients with congenital ptosis. PMID- 30463549 TI - The effectiveness of Dental Health Support Workers at linking families with primary care dental practices: a population-wide data linkage cohort study. AB - BACKGROUND: Link workers (lay health workers, health support workers) based in the community provide additional support to individuals and families to facilitate engagement with primary care and other services and resources. This additional support aims to tackle the wider socio-economic determinants of health that lead to inequalities. To date, there is no clear evidence of the effectiveness of these programmes. This study evaluates the effectiveness of Dental Health Support Workers (DHSW) at linking targeted families with young children to primary care dental practices. The DHSW role is one component of Childsmile, the national oral health improvement programme in Scotland. METHODS: A quasi-experimental approach captured the natural variation in the rollout of the DHSW intervention across Scotland in a cohort of children born between 2010 and 2013. Survival analysis explored "time to attendance" at primary care dental practice. Cox's regression models compared attendance rates and time until first attendance between those families who received support from the DHSW and those who did not. RESULTS: The cohort consisted of 35236 children. Thirty-three percent of the cohort (n = 11495) were considered to require additional support from a DHSW. Of these, 44% (5087) received that support. These families were more likely to attend a dental practice (Hazard Ratio [95% Confidence Interval] =1.87 [1.8 to 1.9]) and, on average, did so 9 months earlier (median time until first attendance: 8.8 months versus 17.8 months), compared to families not receiving additional support. CONCLUSIONS: Link workers (DHSW) within the Childsmile programme are effective at linking targeted children to primary care dental services and, most notably, at a younger age for prevention. This is the first study of its kind to evaluate the effectiveness of link-worker programmes using a robust quasi-experimental design on three, population-wide, linked datasets. These results will inform future health programmes which aim to improve health and reduce inequalities by reaching and supporting families from more disadvantaged backgrounds. PMID- 30463548 TI - HDAC6 regulates dental mesenchymal stem cells and osteoclast differentiation. AB - BACKGROUND: Dental and periodontal tissue development is a complicated process involving a finely regulated network of communication among various cell types. Understanding the mechanisms involved in regulating dental mesenchymal stem cells (MSCs) and osteoclast cell differentiation is critical. However, it is still unclear whether histone deacetylase HDAC6 is involved in dental MSCs fate determination and osteoclast differentiation. METHODS: We used shRNA and siRNA knockdown to explore the role of HDAC6 in dental MSCs odontogenic differentiation and osteoclasts maturation. RESULTS: Based on HDAC6 knockdown dental MSCs, our data suggest that HDAC6 knockdown significantly increases alkaline phosphate activity and mineralized nodules formation. Additionally, mRNA expression of odontogenic marker genes (OSX, OCN, and OPN) was induced by HDAC6 knockdown. By using HDAC6 siRNA, we knocked down HDAC6 in osteoclast precursor RAW 264.7 cells. Our data suggests that HDAC6 knockdown significantly inhibited osteoclasts differentiation. Additionally, mRNA expression of osteoclast marker genes Trap, Mmp9, and Ctsk was decreased by HDAC6 knockdown. CONCLUSIONS: Our study demonstrated that HDAC6 plays an important role in regulating dental MSCs and osteoclasts differentiation. PMID- 30463550 TI - Modeling antibiotic resistance in the microbiota using multi-level Petri Nets. AB - BACKGROUND: The unregulated use of antibiotics not only in clinical practice but also in farm animals breeding is causing a unprecedented growth of antibiotic resistant bacterial strains. This problem can be analyzed at different levels, from the antibiotic resistance spreading dynamics at the host population level down to the molecular mechanisms at the bacteria level. In fact, antibiotic administration policies and practices affect the societal system where individuals developing resistance interact with each other and with the environment. Each individual can be seen as a meta-organism together with its associated microbiota, which proves to have a prominent role in the resistance spreading dynamics. Eventually, in each microbiota, bacterial population dynamics and vertical or horizontal gene transfer events activate cellular and molecular mechanisms for resistance spreading that can also be possible targets for its prevention. RESULTS: In this work we show how to use the Nets-Within-Nets formalism to model the dynamics between different antibiotic administration protocols and antibiotic resistance, both at the individuals population and at the single microbiota level. Three application examples are presented to show the flexibility of this approach in integrating heterogeneous information in the same model, a fundamental property when creating computational models complex biological systems. Simulations allow to explicitly take into account timing and stochastic events. CONCLUSIONS: This work demonstrates how the NWN formalism can be used to efficiently model antibiotic resistance population dynamics at different levels of detail. The proposed modeling approach not only provides a valuable tool for investigating causal, quantitative relations between different events and mechanisms, but can be also used as a valid support for decision making processes and protocol development. PMID- 30463551 TI - Motivations for weight loss in adolescents with overweight and obesity: a systematic review. AB - BACKGROUND: Adolescents with overweight and obesity report various motivations for weight loss other than the desire for better health. However, there is little evidence regarding the main motivations for weight loss in adolescents. The present systematic review aimed to identify the motivations for weight loss in adolescents with overweight and obesity. METHODS: A systematic search for original articles published up to December 2016 was carried out in the PubMed, Scopus, LILACS, and ADOLEC databases. The terms used in the search were: motivation, motive, reason, "weight loss," "lose weight," and adolescent. RESULTS: Six studies (all cross-sectional) met the selection criteria and were included in the review. The instruments used to assess the participants' motivations for weight loss were interviews and questionnaires with open questions. Seventeen motivations for weight loss were identified, the main ones being better health, esthetic/cosmetic reasons, improvements in self-esteem, and avoidance of provocation/bullying. CONCLUSIONS: The results of the present review show the need for validated instruments to assess the motivations for weight loss in adolescents with overweight and obesity. Moreover, the high frequency of motivations for weight loss related to appearance and social acceptance evidences the need for multidisciplinary weight loss interventions that consider not only the biological factors, but also the psychological and social aspects. PMID- 30463552 TI - Performance of a bioglass-based dentine desensitizer under lactid acid exposition: an in-vitro study. AB - BACKGROUND: Dentine hypersensitivity is especially frequent in patients with pronounced periodontal attachment loss. Aim of the treatment is an obstruction of the dentine tubules in order to inhibit liquid or osmotic motion, which is considered as trigger for pain sensations. Novel approaches aim for obstruction by calcium phosphate compounds in order to rely on biocompatible compounds. It was the aim of the study to optically investigate the morphology and to assess the fluid permeability of treated dentine surfaces. METHODS: Dentine discs were pretreated in an ultrasonic bath with 17% EDTA to clean the lumina of the dentine tubules. Samples of group A remained untreated while Seal&Protect(r) as a conventional desensitizer was applied for group B and DentinoCer in group C. Discs were mounted into a pulp fluid simulator (PFS) with a methylene blue solution in order to create a flow pressure of 0.5 bar. Over 12 d, discs were exposed three times per day to 0.1 M nonsaturated lactic acid. At baseline and after 2, 8 and 12 d samples were removed from PFS and prepared for SEM analysis. Tubule obstruction was assessed quantitatively using Olley scores and by qualitative description of the surface. Absorption spectrometry was used to assess the concentration of leaked methylene blue outside the samples in order to estimate dentine permeability. RESULTS: Untreated discs showed clean lumina of all tubules at all time points and magnifications. From day 2 onwards dentine showed exposed collagene fibers due to acid exposition. Seal&Protect(r) initially showed homogenous dentine surface coverage that got a more granulomatous aspect in the course of treatment time. Few samples showed sporadic tubules with open lumen at day 8 and 12. Group C showed samples with a homogeneous, even surface. Narrow slits in the superficial layer are visible from day 4 on, but the dentine surface remained invisible and dentine tubules were closed till the end of the investigation period. CONCLUSION: Over 12 d of lactid acid exposure, samples showed complete coverage of the dentine tubules in the chosen in-vitro-model when treated with Seal&Protect(r) or DentinoCer. PMID- 30463553 TI - Large-scale prediction of protein ubiquitination sites using a multimodal deep architecture. AB - BACKGROUND: Ubiquitination, which is also called "lysine ubiquitination", occurs when an ubiquitin is attached to lysine (K) residues in targeting proteins. As one of the most important post translational modifications (PTMs), it plays the significant role not only in protein degradation, but also in other cellular functions. Thus, systematic anatomy of the ubiquitination proteome is an appealing and challenging research topic. The existing methods for identifying protein ubiquitination sites can be divided into two kinds: mass spectrometry and computational methods. Mass spectrometry-based experimental methods can discover ubiquitination sites from eukaryotes, but are time-consuming and expensive. Therefore, it is priority to develop computational approaches that can effectively and accurately identify protein ubiquitination sites. RESULTS: The existing computational methods usually require feature engineering, which may lead to redundancy and biased representations. While deep learning is able to excavate underlying characteristics from large-scale training data via multiple layer networks and non-linear mapping operations. In this paper, we proposed a deep architecture within multiple modalities to identify the ubiquitination sites. First, according to prior knowledge and biological knowledge, we encoded protein sequence fragments around candidate ubiquitination sites into three modalities, namely raw protein sequence fragments, physico-chemical properties and sequence profiles, and designed different deep network layers to extract the hidden representations from them. Then, the generative deep representations corresponding to three modalities were merged to build the final model. We performed our algorithm on the available largest scale protein ubiquitination sites database PLMD, and achieved 66.4% specificity, 66.7% sensitivity, 66.43% accuracy, and 0.221 MCC value. A number of comparative experiments also indicated that our multimodal deep architecture outperformed several popular protein ubiquitination site prediction tools. CONCLUSION: The results of comparative experiments validated the effectiveness of our deep network and also displayed that our method outperformed several popular protein ubiquitination site prediction tools. The source codes of our proposed method are available at https://github.com/jiagenlee/deepUbiquitylation . PMID- 30463554 TI - Parents' attitudes towards and perceptions of involving minors in medical research from the Japanese perspective. AB - BACKGROUND: Children's intentions should be respected. Parents are the key persons involved in decision-making related to their children. In Japan, the appropriate ages and standards for a child's consent and assent, approval, and decision-making are not clearly defined, which makes the process of obtaining consent and assent for clinical research complex. The purpose of this paper is as follows: to understand the attitudes and motives of parents concerning children's participation in medical research and the factors influencing their decision making. We also sought to clarify who has the right to be involved in decisions regarding children's participation in research. METHODS: A semi-structured Internet survey on parents' opinions and attitudes and preferences concerning medical research involvement was conducted. Children were divided into three age groups (6-10-year-olds, 11-14-year-olds, and 15-18-year-olds), with three illness severity categories. Possible correlations between the number of children, children's ages, parents' educational levels, and parents' attitudes were examined. RESULTS: Among the participants, 42.3% recognized the term "informed consent." The proportion of participants who understood "informed consent" increased with educational level. Four out of five participants did not know, or had not heard of, the term "informed assent." Furthermore, the percentage of those who understood the term "informed assent" increased with academic level. Participants generally believed in prioritizing parents' opinions over children's, and that parents and children would ideally reach a joint decision. Although many parents favored collaborative decision-making, they also wanted their own will reflected in the decision and felt they should receive important information before their children do. Decision-making was affected by the condition's severity and prognosis. This indicates that most Japanese parents believe that their children have the right to know their disease name and treatment; nonetheless, they should be protected. Parents' values and judgments regarding medical intervention involving their children varied. CONCLUSIONS: Children's ability to consent to treatment and research believed to be in their best interests should be assessed appropriately. They should be permitted to provide consent or assent, and their views should be respected. Involving children in decision-making fosters more open communication and transparency between medical professionals, parents, and children. PMID- 30463556 TI - Inferring phenotypes from substance use via collaborative matrix completion. AB - BACKGROUND: Although substance use disorders (SUDs) are heritable, few genetic risk factors for them have been identified, in part due to the small sample sizes of study populations. To address this limitation, researchers have aggregated subjects from multiple existing genetic studies, but these subjects can have missing phenotypic information, including diagnostic criteria for certain substances that were not originally a focus of study. Recent advances in addiction neurobiology have shown that comorbid SUDs (e.g., the abuse of multiple substances) have similar genetic determinants, which makes it possible to infer missing SUD diagnostic criteria using criteria from another SUD and patient genotypes through statistical modeling. RESULTS: We propose a new approach based on matrix completion techniques to integrate features of comorbid health conditions and individual's genotypes to infer unreported diagnostic criteria for a disorder. This approach optimizes a bi-linear model that uses the interactions between known disease correlations and candidate genes to impute missing criteria. An efficient stochastic and parallel algorithm was developed to optimize the model with a speed 20 times greater than the classic sequential algorithm. It was tested on 3441 subjects who had both cocaine and opioid use disorders and successfully inferred missing diagnostic criteria with consistently better accuracy than other recent statistical methods. CONCLUSIONS: The proposed matrix completion imputation method is a promising tool to impute unreported or unobserved symptoms or criteria for disease diagnosis. Integrating data at multiple scales or from heterogeneous sources may help improve the accuracy of phenotype imputation. PMID- 30463555 TI - Ameliorative effects of rutin against cisplatin-induced reproductive toxicity in male rats. AB - BACKGROUND: Cisplatin (CP) or cis-diammine dichloroplatinum (II) is a platinum based standard antineoplastic drug which is used against variety of solid tumors and neoplasms. The present study aimed to evaluate the shielding effects of rutin against CP induced testicular toxicity in rats. METHODS: 28 male rats were divided into four groups. First group was given saline orally while second group received intra-peritoneal (i.p) injection of cisplatin (7 mg/kg) on day first and received saline for next 13 days. Third group received i.p injection of cisplatin at day one and treated with rutin (75 mg/kg) orally for next 13 days. Fourth group was treated with rutin orally for 13 days. Animals were sacrificed on 14th day and reproductive organs were analyzed for various parameters. RESULTS: Cisplatin treatment resulted in a significant decrease in daily sperm production, decrease in head length and % DNA in head, reduction of epithelial cell height, tubular diameter, reduction of the number of spermatogonia, spermatocytes and spermatids, increase in the thiobarbituric acid reactive substances (TBARS) and oxidative stress in testicular tissues, and change of the intra-testicular testosterone concentrations. Rutin co-treatment resulted in reversing cisplatin effect on DNA damage, sperm count, histological and biochemical parameters. CONCLUSION: These results indicated that rutin co-treatment could ameliorate cisplatin-induced reproductive toxicity in male rats. PMID- 30463557 TI - Modalities of using endodontic nickel-titanium rotary instruments and factors influencing their implementation in dental practice. AB - BACKGROUND: To establish the extent of using nickel titanium rotary instruments (NiTi-RIs), to identify reasons for using / not using NiTi-RIs, to explore usage modalities and to identify factors and measures that can increase implementation of NiTi-RIs in general dental practice. METHODS: Two pilot questionnaires were conducted on academic staff members at College of Dentistry, Taibah University, general dentists (GDs) and endodontists to finalise the questionnaire. A sample size was calculated considering the expected and minimum accepted response rates (60 and 48%, respectively) and a 99.9% Confidence Level. The online-questionnaire was sent to 600 GDs and all endodontists (175) working in Saudi Arabia. A reminder was emailed after 10 weeks to encourage non-respondents to complete the questionnaire. Responses, were collected and converted into numerical data which were analysed using the Chi-square test (p = 0.05). RESULTS: Significantly most respondents (71.9%) used NiTi-RIs (p < 0.001); with more endodontists (96.9%) than GDs (60%). Most users (62.5%) had been using NiTi-RIs for More than 3 years (p < 0001). The trend of using NiTi-RIs increased as participants' experience and the number of root-canal treatments performed per week increased (p = 0.021). While most respondents (45.3%) used NiTi-RIs because of faster root-canal preparation, the majority of non-users (85.3%) didn't do so because of high cost. The highest proportion (43.3%) reported better undergraduate education as the most important factor that can significantly increase NiTi-RIs usage. The majority (91.8%) prepared glide-path before using NiTi-RIs; especially with stainless steel hand-files (63.3%). CONCLUSIONS: NiTi-RIs are relatively well adopted in Saudi dental practice. However, better education, especially during undergraduate training and lower cost can increase their usage. Overall, clinicians showed good awareness of NiTi-RIs usage aspects which reflected on usage modalities. PMID- 30463558 TI - Quantifying the relative importance of experimental data points in parameter estimation. AB - BACKGROUND: Ordinary differential equations (ODEs) are often used to understand biological processes. Since ODE-based models usually contain many unknown parameters, parameter estimation is an important step toward deeper understanding of the process. Parameter estimation is often formulated as a least squares optimization problem, where all experimental data points are considered as equally important. However, this equal-weight formulation ignores the possibility of existence of relative importance among different data points, and may lead to misleading parameter estimation results. Therefore, we propose to introduce weights to account for the relative importance of different data points when formulating the least squares optimization problem. Each weight is defined by the uncertainty of one data point given the other data points. If one data point can be accurately inferred given the other data, the uncertainty of this data point is low and the importance of this data point is low. Whereas, if inferring one data point from the other data is almost impossible, it contains a huge uncertainty and carries more information for estimating parameters. RESULTS: G1/S transition model with 6 parameters and 12 parameters, and MAPK module with 14 parameters were used to test the weighted formulation. In each case, evenly spaced experimental data points were used. Weights calculated in these models showed similar patterns: high weights for data points in dynamic regions and low weights for data points in flat regions. We developed a sampling algorithm to evaluate the weighted formulation, and demonstrated that the weighted formulation reduced the redundancy in the data. For G1/S transition model with 12 parameters, we examined unevenly spaced experimental data points, strategically sampled to have more measurement points where the weights were relatively high, and fewer measurement points where the weights were relatively low. This analysis showed that the proposed weights can be used for designing measurement time points. CONCLUSIONS: Giving a different weight to each data point according to its relative importance compared to other data points is an effective method for improving robustness of parameter estimation by reducing the redundancy in the experimental data. PMID- 30463559 TI - A qualitative study on the voluntariness of counselling and testing for HIV amongst antenatal clinic attendees: do women have a choice? AB - BACKGROUND: Mother-to-child transmission (MTCT) of the Human Immunodeficiency Virus (HIV) is a serious public health problem, contributing up to 90% of childhood HIV infections. In Tanzania, the prevention-of-mother-to-child transmission (PMTCT) feature of the HIV programme was rolled out in 2000. The components of PMTCT include counselling and HIV testing directed at antenatal clinic attendees. It is through the process of Provider Initiated Counseling and Testing (PITC) that counselling is offered participant confidentiality and voluntariness are upheld and valid consent obtained. The objective of the study was to explore antenatal clinic attendees' experiences of the concept of voluntariness vis- a- vis the implementation of prior counseling and subsequent testing for HIV under the PITC as part of their antenatal care. METHODS: In-depth interviews were conducted with17 antenatal clinic attendees and 6 nursing officers working at the Muhimbili National Hospital (MNH) antenatal clinic. The study data were analyzed using qualitative content analysis. RESULTS: Antenatal clinic attendees' accounts suggested that counselling and testing for HIV during pregnancy was voluntary, and that knowledge of their HIV status led them to access appropriate treatment for both mother and her newborn baby. They reported feeling no pressure from nursing officers, and gave verbal consent to undergo the HIV test. However, some antenatal clinic attendees reported pressure from their partners to test for HIV. Healthcare providers were thus faced with a dilemma of disclosure/ nondisclosure when dealing with discordant couples. CONCLUSION: Antenatal clinic attendees at MNH undertook the PITC for HIV voluntarily. This was enhanced by their prior knowledge of HIV, the need to prevent mother- to- child transmission of HIV, and the effectiveness of the voluntary policy implemented by nursing officers. PMID- 30463561 TI - Medical termination of pregnancy service delivery in the context of decentralization: social and structural influences. AB - BACKGROUND: Medical termination of pregnancy (MToP) is a safe and acceptable abortion option. Depending on country context, MToP can be administered by general practitioners and mid-level healthcare providers in the first and second trimesters of pregnancy. Like other high-income countries, a range of social and structural barriers to MToP service provision exist in Australia. To counter some of these barriers, geographic decentralization of MToP was undertaken in rural Victoria, Australia, through training service providers about MToP to increase service delivery opportunities. The aim of this study was to investigate the factors that enabled and challenged the decentralization process. METHODS: Face to-face and telephone interviews were undertaken between April and June 2016 with a purposeful sample of six training providers and 13 general practitioners (GP) and nurse training participants. Study participants were asked about their perceptions of motivations, enablers and challenges to MToP provision. A published conceptual framework of synergies between decentralization and service delivery was used to analyse the study findings. RESULTS: Three key themes emerged from the study findings. First, the effort to decentralize MToP was primarily supported by motivations related to making service access more equitable as well as the willingness of training providers to devolve their informal power, in the form of MToP medical expertise, to training participants. Next, the enablers for MToP decentralization included changes in the regulatory environment relating to decriminalization of abortion and availability of required medication, formation of partnerships to deliver training, provision of MToP clinical resources and local collegial support. Finally, challenges to MToP decentralization were few but significant. These included a lack of a state-wide strategy for service provision, provider concerns about coping with service demand, and provider stigma in the form of perceived negative community or collegial attitudes. These were significant enough to create caution for GPs and nurses considering service provision. CONCLUSIONS: Decentralization concepts offer an innovative way for reframing and tackling issues associated with improving MToP service delivery. There is scope for more research about MToP decentralization in other country contexts. These findings are important for informing future rural MToP service expansion efforts that improve equity in service access. PMID- 30463560 TI - Influence of viral infection on the relationships between airway cytokines and lung function in asthmatic children. AB - BACKGROUND: Few longitudinal studies examine inflammation and lung function in asthma. We sought to determine the cytokines that reduce airflow, and the influence of respiratory viral infections on these relationships. METHODS: Children underwent home collections of nasal lavage during scheduled surveillance periods and self-reported respiratory illnesses. We studied 53 children for one year, analyzing 392 surveillance samples and 203 samples from 85 respiratory illnesses. Generalized estimated equations were used to evaluate associations between nasal lavage biomarkers (7 mRNAs, 10 proteins), lung function and viral infection. RESULTS: As anticipated, viral infection was associated with increased cytokines and reduced FVC and FEV1. However, we found frequent and strong interactions between biomarkers and virus on lung function. For example, in the absence of viral infection, CXCL10 mRNA, MDA5 mRNA, CXCL10, IL-4, IL-13, CCL4, CCL5, CCL20 and CCL24 were negatively associated with FVC. In contrast, during infection, the opposite relationship was frequently found, with IL-4, IL-13, CCL5, CCL20 and CCL24 levels associated with less severe reductions in both FVC and FEV1. CONCLUSIONS: In asthmatic children, airflow obstruction is driven by specific pro-inflammatory cytokines. In the absence of viral infection, higher cytokine levels are associated with decreasing lung function. However, with infection, there is a reversal in this relationship, with cytokine abundance associated with reduced lung function decline. While nasal samples may not reflect lower airway responses, these data suggest that some aspects of the inflammatory response may be protective against viral infection. This study may have ramifications for the treatment of viral-induced asthma exacerbations. PMID- 30463562 TI - Early detection of median nerve compression by Electroneurography can improve outcome in children with Mucopolysaccharidoses. AB - BACKGROUND: Carpal tunnel syndrome (CTS) is a common complication of the mucopolysaccharidoses. In severe or attenuated mucopolysaccharidoses patients, clinical symptoms of CTS usually appear at a late stage of median nerve compression. Relying on CTS symptoms is often too late and there is a risk of axonal damage and further irreversible sequelae. Electroneurography is a powerful technique to detect the initial preclinical signs of median nerve compression. In a retrospective series of 13 children with mucopolysaccharidoses (10 Hunter, one Hurler-Scheie and 2 Hurler children), we describe the electroneurography progression of CTS (43 hand evaluations) and the severity of median nerve damage. RESULTS: The average age at mucopolysaccharidoses diagnosis was 33.6 months (11 66 months). Clinical signs of CTS appeared on average 44.6 months (0-73 months) after diagnosis of mucopolysaccharidoses. Electroneurography anomalies suggestive of CTS appeared as early as the age of 3.5 years and probably preceded clinical signs of CTS. Median nerve compression was bilateral and distal, initially on the sensory pathway then becoming motor-sensory. Beyond a threshold of 14 m/sec median distal motor nerve conduction velocity (MNCVd) and index of terminal latency (MNCVd/MNCVp) of 0.27, there was true distal conduction slowdown. CONCLUSIONS: To prevent irreversible sequelae of median nerve compression, we suggest annual electroneurography testing for mucopolysaccharidoses patients starting as early as 3 years of age, including both motor and sensory nerve pathways, on median and, in reference to the ulnar nerves, bilaterally at the wrist and the elbow. Timely surgical intervention can greatly improve the overall function and quality of life of these patients. PMID- 30463563 TI - Occupational health: a world of false promises. AB - The response of the World Health Organization (WHO) to the Ebola outbreak in West Africa in 2015 demonstrated that the global health system is unprepared to address what should be its primary mission, control of disease epidemics while protecting health workers. Critics blamed WHO politics and its rigid culture for the poor response to the epidemic. We find that United Nations agencies, WHO and the International Labor Organization (ILO), are faced with the global problem of inadequate worker protections and a growing crisis in occupational health. The WHO and ILO are given monumental tasks but only trivial budgets, and funding trends show UN agency dependence on private donations which are far larger than funds contributed by member states. The WHO and ILO have limited capacity to make the necessary changes occupational health and safety demand. The UN could strengthen the national and global civil society voice in WHO and ILO structures, and by keeping conflict of interest out of policy decisions, ensure greater freedom to operate without interference. PMID- 30463564 TI - Glial-neuronal signaling mechanisms underlying the neuroinflammatory effects of manganese. AB - BACKGROUND: Exposure to increased manganese (Mn) causes inflammation and neuronal injury in the cortex and basal ganglia, resulting in neurological symptoms resembling Parkinson's disease. The mechanisms underlying neuronal death from exposure to Mn are not well understood but involve inflammatory activation of microglia and astrocytes. Expression of neurotoxic inflammatory genes in glia is highly regulated through the NF-kappaB pathway, but factors modulating neurotoxic glial-glial and glial-neuronal signaling by Mn are not well understood. METHODS: We examined the role of NF-kappaB in Mn-induced neurotoxicity by exposing purified microglia, astrocytes (from wild-type and astrocyte-specific IKK knockout mice), and mixed glial cultures to varying Mn concentrations and then treating neurons with the conditioned media (GCM) of each cell type. We hypothesized that mixed glial cultures exposed to Mn (0-100 MUM) would enhance glial activation and neuronal death compared to microglia, wild-type astrocytes, or IKK-knockout astrocytes alone or in mixed cultures. RESULTS: Mixed glial cultures treated with 0-100 MUM Mn for 24 h showed the most pronounced effect of increased expression of inflammatory genes including inducible nitric oxide synthase (Nos2), Tnf, Ccl5, Il6, Ccr2, Il1b, and the astrocyte-specific genes, C3 and Ccl2. Gene deletion of IKK2 in astrocytes dramatically reduced cytokine release in Mn-treated mixed glial cultures. Measurement of neuronal viability and apoptosis following exposure to Mn-GCM demonstrated that mixed glial cultures induced greater neuronal death than either cell type alone. Loss of IKK in astrocytes also decreased neuronal death compared to microglia alone, wild-type astrocytes, or mixed glia. CONCLUSIONS: This suggests that astrocytes are a critical mediator of Mn neurotoxicity through enhanced expression of inflammatory cytokines and chemokines, including those most associated with a reactive phenotype such as CCL2 but not C3. PMID- 30463565 TI - Asymptomatic myocardial ischemia forecasts adverse events in cardiovascular magnetic resonance dobutamine stress testing of high-risk middle-aged and elderly individuals. AB - BACKGROUND: Current guidelines for assessing the risk of experiencing a hospitalized cardiovascular (CV) event discourage stress testing of asymptomatic individuals; however, these recommendations are based on evidence gathered primarily from those aged < 60 years, and do not address the possibility of unrecognized "silent myocardial ischemia" in middle aged and older adults. METHODS: We performed dobutamine cardiovascular magnetic resonance (CMR) stress testing in 327 consecutively recruited participants aged > 55 years without CV related symptoms nor known coronary artery disease, but otherwise at increased risk for a future CV event due to pre-existing hypertension or diabetes mellitus for at least 5 years. After adjusting for the demographics and CV risk factors, log-rank test and Cox proportional hazards models determined the additional predictive value of the stress test results for forecasting hospitalized CV events/survival. Either stress-induced LV wall motion abnormalities or perfusion defects were used to indicate myocardial ischemia. RESULTS: Participants averaged 68 +/- 8 years in age; 39% men, 75% Caucasian. There were 38 hospitalized CV events or deaths which occurred during a mean follow-up of 58 months. Using Kaplan-Meier analyses, myocardial ischemia identified future CV events/survival (p < 0.001), but this finding was more evident in men (p < 0.001) versus women (p = 0.27). The crude hazard ratio (HR) of myocardial ischemia for CV events/survival was 3.13 (95% CI: 1.64-5.93; p < 0.001). After accounting for baseline demographics, CV risk factors, and left ventricular ejection fraction/mass, myocardial ischemia continued to be associated with CV events/survival [HR: 4.07 (95% CI: 1.95-8.73) p < 0.001]. CONCLUSIONS: Among asymptomatic middle-aged individuals with risk factors for a sentinel CV event, the presence of myocardial ischemia during dobutamine CMR testing forecasted a future hospitalized CV event or death. Further studies are needed in middle aged and older individuals to more accurately characterize the prevalence, significance, and management of asymptomatic myocardial ischemia. TRIAL REGISTRATION: ( ClinicalTrials.gov identifier): NCT00542503 and was retrospectively registered on October 11th, 2007. PMID- 30463566 TI - Alterations in VASP phosphorylation and profilin1 and cofilin1 expression in hyperoxic lung injury and BPD. AB - BACKGROUND: Hyperoxia is a frequently employed therapy for prematurely born infants, induces lung injury and contributes to development of bronchopulmonary dysplasia (BPD). BPD is characterized by decreased cellular proliferation, cellular migration, and failure of injury repair systems. Actin binding proteins (ABPs) such as VASP, cofilin1, and profilin1 regulate cell proliferation and migration via modulation of actin dynamics. Lung mesenchymal stem cells (L-MSCs) initiate repair processes by proliferating, migrating, and localizing to sites of injury. These processes have not been extensively explored in hyperoxia induced lung injury and repair. METHODS: ABPs and CD146+ L-MSCs were analyzed by immunofluorescence in human lung autopsy tissues from infants with and without BPD and by western blot in lung tissue homogenates obtained from our murine model of newborn hyperoxic lung injury. RESULTS: Decreased F-actin content, ratio of VASPpS157/VASPpS239, and profilin 1 expression were observed in human lung tissues but this same pattern was not observed in lungs from hyperoxia-exposed newborn mice. Increases in cofilin1 expression were observed in both human and mouse tissues at 7d indicating a dysregulation in actin dynamics which may be related to altered growth. CD146 levels were elevated in human and newborn mice tissues (7d). CONCLUSION: Altered phosphorylation of VASP and expression of profilin 1 and cofilin 1 in human tissues indicate that the pathophysiology of BPD involves dysregulation of actin binding proteins. Lack of similar changes in a mouse model of hyperoxia exposure imply that disruption in actin binding protein expression may be linked to interventions or morbidities other than hyperoxia alone. PMID- 30463567 TI - Knowledge and attitude of women towards the legalization of abortion in the selected town of Ethiopia: a cross sectional study. AB - BACKGROUND: Unsafe abortion contributes to maternal deaths 13% globally and 25 35% of Ethiopia. By considering the problem of unsafe abortion, Ethiopia amended a law that permits abortion under certain circumstances. However, the country liberalized the service, women are still not using it. Therefore, the possible reason might be a lack of knowledge and attitude is a barrier that hinders women to use safe abortion. METHODS: A community-based cross-sectional study was conducted in Arba Minch town from January 02 to 17, 2017. Women in the reproductive age groups (15-49) who reside in the town for more than six months were included in the study. The sample size was determined using a single population proportion formula. Five kebeles were selected using the lottery method from 11 kebeles. The proportional allocation of the sample was done for each kebeles. Data were collected using a structured questionnaire. Binary and multiple logistic analyses were carried out to identify factors associated with knowledge & attitude toward legalization of abortion. RESULT: A total of 576 women were responded to the question. The finding of our study showed that only 23.4% of women have knowledge about the legalization of abortion. Of all the respondents 323(56%) prefer abortion on demand to be legalized while about 241 (41.9%) do not prefer to be legalized. Again about 57% of women believe that women can use it but the rest 43% believe even if allowed women do not use it. From all participants, 59% don't want to use by themselves and also, 53.3% don't think that women would have the right to use the service or terminate their pregnancy even if the pregnancy fulfill the criteria. Ethnicity, marital status, and family size were the factors significantly associated with knowledge. Again, educational status, marital status and having knowledge about the legalization of abortion were a statistically significant association with the attitude. CONCLUSION: The study indicated that knowledge of women toward the legalization of abortion was low but more than half of respondents prefer abortion on demand to be legalized. PMID- 30463568 TI - Association between chronic obstructive pulmonary disease and serum lipid levels: a meta-analysis. AB - BACKGROUND: Metabolic syndrome is a common extrapulmonary comorbidity in patients with chronic obstructive pulmonary disease (COPD). However, the reported relationship of COPD with dyslipidemia, an important component of metabolic syndrome, is ambiguous. The aim of this meta-analysis is to investigate the association between COPD and the serum levels of high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), total cholesterol (TC), and triglyceride (TG). METHODS: The PubMed and Embase databases were searched to find potential studies using the search terms of ("dyslipidemia" or "HDL" or "LDL" or "cholesterol" or "triglyceride") and COPD. We also performed subgroup analysis enrolling patients who were not receiving treatment for dyslipidemia. Mean differences (MD) with 95% confidence intervals (CI) were estimated with random effects models. RESULTS: A total of 11 studies comprising 615 cases and 471 controls were included in the study. No significant differences were found in the HDL (MD = -2.55, 95% CI [-6.03, 0.93], P = 0.15), LDL (MD = 2.25, 95% CI [-13.36, 8.86], P = 0.69), TC (MD = -2.69, 95% CI [-13.30, 7.92], P = 0.62), and TG (MD = 6.90, 95% CI [-2.81, 16.60], P = 0.16) levels of the 2 groups. However, subgroup analysis enrolling patients who were not receiving treatment for dyslipidemia showed that TG levels were higher in patients with stable COPD than in healthy individuals (MD = 16.35, 95% CI [5.90, 26.80], P = 0.002). CONCLUSIONS: Excluding the impact of hypolipidemic treatment on serum lipid profile, TG levels were higher in patients with COPD than in healthy individuals. This meta-analysis suggested that physicians should screen COPD patients for elevated TG levels to reduce the risk of cardiovascular morbidity and mortality. PMID- 30463569 TI - Ethnotaxonomy of sharks from tropical waters of Brazil. AB - BACKGROUND: Accessing folk knowledge from small-scale fishers is an affordable and reliable approach to understand the dynamic and diversity of shark species worldwide, especially of those eventually caught. In this context, ethnotaxonomy (folk identification and classification) may represent an alternative to support sharks fisheries management, especially in data-poor places. This study aimed to investigate fishing and ethnotaxonomy of the main shark species caught by small scale fisheries from the coastal waters of the Brazilian Northeast. METHODS: Semi structured and structured interviews were conducted with fishers targeting general aspects of fishing activities and specific topics regarding ethnotaxonomy, capture, and commercialization of sharks. For species identification, an ethnobiological systematic perspective was used to analyze the folk nomenclature and classification criteria. Non-parametric statistical tests were used to verify associations between species caught, fishing gear, and harvest period. RESULTS: Fishers mentioned 73 binomial names, 21 main folk species, and eight synonymies. Some species belonging to the same scientific genus are often named and grouped by the same folk name, with no distinction between species by fishers. Sharks are most landed as bycatch and correspond to less than 5% of the total commercial fisheries in the communities, with socioeconomic value for subsistence consumption and local commercialization. Sharks were said to be mainly caught with hand line and surface long line during the rainy season, while gillnet captures were associated to the dry season. At least three of the species most mentioned by fishers are currently classified as vulnerable and endangered worldwide. CONCLUSIONS: Even though landed sharks account for a small proportion of the fishing catches, their biological and life history features place sharks among the most vulnerable organisms globally. Such an ethnobiological approach towards shark identification may contribute to generate basic information on species caught, their frequency in the landings, and how different species belonging to the same genus can be landed and sold together. This type of information can generate subsidies to the development of conservation and management plans for these fishing resources, where knowledge is scarce. PMID- 30463571 TI - Novel EM based ML Kalman estimation framework for superresolution of stochastic three-states microtubule signal. AB - BACKGROUND: Recent research has found that abnormal functioning of Microtubules (MTs) could be linked to fatal diseases such as Alzheimer's. Hence, there is an imminent need to understand the implications of MTs for disease- diagnosis. However, studies of cellular processes like MTs are often constrained by physical limitations of their data acquisition systems such as optical microscopes and are vulnerable to either destruction of the specimen or the probe. In addition, study of MTs is challenged with non-uniform sampling of the MT dynamic instability phenomenon relative to its time-lapse observation of the cellular processes. Thus, the above caveats limit the overall period of time that the MT data can be collected, thereby causing limited data availability scenario. RESULTS: In this work, two novel superresolution frameworks based on Expectation Maximization (EM) based Maximum Likelihood (ML) estimation using Kalman filters (MLK) technique are proposed to address the issues of non-uniform sampling and limited data availability of MT signals. The proposed MLK methods optimizes prediction of missing observations in the MT signal through information extraction using correlation-based patch processing and principal component analysis -based mutual information. Experimental results prove that the proposed MLK-based superresolution methods outperformed nonlinear interpolation and compressed sensing methods. CONCLUSIONS: This work aims to address limited data availability and data/observation loss incurred due to non-uniform sampling of biological signals such as MTs. For this purpose, statistical modelling of stochastic MT signals using EM based ML driven Kalman estimation (MLK) is considered as a fundamental framework for prediction of missing MT observations. It was experimentally validated that the proposed superresolution methods provided superior overall performance, better MT signal estimation using fewer samples, high SNR, low errors, and better MT parameter estimation than other methods. PMID- 30463570 TI - LncRNA XIST/miR-34a axis modulates the cell proliferation and tumor growth of thyroid cancer through MET-PI3K-AKT signaling. AB - BACKGROUND: Thyroid cancer is one of the most prevalent malignancies in endocrine system. Further understanding and revealing the molecular mechanism underlying thyroid cancer are indispensable for the development of effective diagnosis and treatments. In the present study, we attempted to provide novel basis for targeted therapy for thyroid cancer from the aspect of lncRNA-miRNA-mRNA interaction. METHODS: The expression and cellular function of XIST (X-inactive specific transcript) was determined. miRNAs which may be direct targets of XIST were screened for from online GEO database and miR-34a was selected. Next, the predicted binding between XIST and miR-34a, and the dynamic effect of XIST and miR-34a on downstream MET (hepatocyte growth factor receptor)-PI3K (phosphoinositide 3-kinase)-AKT (alpha-serine/threonine-protein kinase) signaling was evaluated. RESULTS: XIST was significantly up-regulated in thyroid cancer tissues and cell lines; XIST knockdown suppressed the cell proliferation in vivo and the tumor growth in vitro. Based on online database and online tool prediction results, miR-34a was underexpressed in thyroid cancer and might be a direct target of XIST. Herein, we confirmed the negative interaction between XIST and miR-34a; moreover, XIST knockdown could reduce the protein levels of MET, a downstream target of miR-34a, and the phosphorylation of PI3K and AKT. In thyroid cancer tissues, MET mRNA and protein levels of MET were up-regulated; MET was positively correlated with XIST while negatively correlated with miR-34a, further confirming that XIST serves as a ceRNA for miR-34a through sponging miR-34a, competing with MET for miR-34a binding, and finally modulating thyroid cancer cell proliferation and tumor growth. CONCLUSION: In the present study, we provided novel experimental basis for targeted therapy for thyroid cancer from the aspect of lncRNA-miRNA-mRNA interaction. PMID- 30463572 TI - Evaluation of four clinical laboratory parameters for the diagnosis of myalgic encephalomyelitis. AB - BACKGROUND: Myalgic encephalomyelitis (ME) is a complex and debilitating disease that often initially presents with flu-like symptoms, accompanied by incapacitating fatigue. Currently, there are no objective biomarkers or laboratory tests that can be used to unequivocally diagnosis ME; therefore, a diagnosis is made when a patient meets series of a costly and subjective inclusion and exclusion criteria. The purpose of the present study was to evaluate the utility of four clinical parameters in diagnosing ME. METHODS: In the present study, we utilized logistic regression and classification and regression tree analysis to conduct a retrospective investigation of four clinical laboratory in 140 ME cases and 140 healthy controls. RESULTS: Correlations between the covariates ranged between [- 0.26, 0.61]. The best model included the serum levels of the soluble form of CD14 (sCD14), serum levels of prostaglandin E2 (PGE2), and serum levels of interleukin 8, with coefficients 0.002, 0.249, and 0.005, respectively, and p-values of 3 * 10-7, 1 * 10-5, and 3 * 10-3, respectively. CONCLUSIONS: Our findings show that these parameters may help physicians in their diagnosis of ME and may additionally shed light on the pathophysiology of this disease. PMID- 30463573 TI - Factors enabling community health workers and volunteers to overcome socio cultural barriers to behaviour change: meta-synthesis using the concept of social capital. AB - BACKGROUND: Community-based health workers and volunteers are not just low-level health workforce; their effectiveness is also due to their unique relationship with the community and is often attributed to social capital, an area not well studied or acknowledged in the literature. METHODS: A qualitative meta-synthesis was conducted using the SPIDER framework and based on critical interpretive synthesis. The protocol was registered with PROSPERO, ID = CRD42018084130. This article reports on the qualitative data extracted from the final 33 articles selected from 147 full-text articles on social capital and community-based health systems. RESULTS: Three constructs were identified that enable community health workers to bring about changes in behaviour in the community: seeing their role as a service or a calling motivated by altruistic values, accompanying community members on their journey and the aim of the journey being empowerment rather than health. Community health workers feel under-resourced to provide for expectations from the community, to fulfil their non-health needs, to meet the expectations of their employers and to be able to deliver health services. CONCLUSION: The dichotomy of needs between the community and health services can be resolved if policy makers and programme designers examine the possibility of two cadres of community-based health workforce: full-time workers and part-time volunteers, with clear scopes of practice and supervision. Community health workers would primarily be concerned with task shifting roles demanded by programmes, and volunteers can focus on the wider empowerment-based needs of communities. PMID- 30463575 TI - Digestion of the glycosaminoglycan extracellular matrix by chondroitinase ABC supports retinal ganglion cell dendritic preservation in a rodent model of experimental glaucoma. AB - Retinal ganglion cell dendritic atrophy is an early feature of glaucoma, and the recovery of retinal ganglion cell dendrites is a viable option for vision improvement in glaucoma. Retinal ganglion cell neurites are surrounded by a specialised glycosaminoglycan extracellular matrix which inhibits dendritic plasticity. Since digestion of the extracellular matrix by chondroitinase ABC has been reported to have neuro-regenerative and neuro-plastic effects within the central nervous system, we explored its potential for dendritic recovery in a rat model of ocular hypertension. Chondroitinase ABC was administrated intravitreally 1 week after ocular hypertension (a time point where dendritic atrophy has already occurred). Retinal ganglion cell dendritic morphology was unaffected by chondroitinase ABC in normal retina. In ocular hypertensive eyes retinal ganglion cells showed significantly decreased dendritic length and area under the Sholl curve with atrophy confined to higher order dendrites. These changes were not observed in chondroitinase ABC injected eyes despite similar total retinal ganglion cell loss (i.e. dendritic protection of surviving retinal ganglion cells). These data suggest that glycosaminoglycan digestion could have a therapeutic role in mitigating the effects of elevated pressure on retinal ganglion cell dendritic structure in glaucoma. PMID- 30463574 TI - Can acute clinical outcomes predict health-related quality of life after stroke: a one-year prospective study of stroke survivors. AB - BACKGROUND: Health-related quality of life (HRQoL) is a key metric to understand the impact of stroke from patients' perspective. Yet HRQoL is not readily measured in clinical practice. This study aims to investigate the extent to which clinical outcomes during admission predict HRQoL at 3 months and 1 year post stroke. METHODS: Stroke patients admitted to five tertiary hospitals in Singapore were assessed with Shah-modified Barthel Index (Shah-mBI), National Institute of Health Stroke Scale (NIHSS), Modified Rankin Scale (mRS), Mini-Mental State Examination (MMSE), and Frontal Assessment Battery (FAB) before discharge, and the EQ-5D questionnaire at 3 months and 12 months post-stroke. Association of clinical measures with the EQ index at both time points was examined using multiple linear regression models. Forward stepwise selection was applied and consistently significant clinical measures were analyzed for their association with individual dimensions of EQ-5D in multiple logistic regressions. RESULTS: All five clinical measures at baseline were significant predictors of the EQ index at 3 months and 12 months, except that MMSE was not significantly associated with the EQ index at 12 months. NIHSS (3-month standardized beta = - 0.111; 12-month standardized beta = - 0.109) and mRS (3-month standardized beta = - 0.122; 12-month standardized beta = - 0.080) were shown to have a larger effect size than other measures. The contribution of NIHSS and mRS as significant predictors of HRQoL was mostly explained by their association with the mobility, self-care, and usual activities dimensions of EQ-5D. CONCLUSIONS: HRQoL at 3 months and 12 months post-stroke can be predicted by clinical outcomes in the acute phase. NIHSS and mRS are better predictors than BI, MMSE, and FAB. PMID- 30463576 TI - Experimental comparisons of passive and powered ankle-foot orthoses in individuals with limb reconstruction. AB - BACKGROUND: Ankle-foot orthoses (AFO) are commonly prescribed to provide functional assistance for patients with lower limb injuries or weakness. Their passive mechanical elements can provide some energy return to improve walking ability, but cannot restore plantar flexor push-off. Powered AFOs provide an assistive torque about the ankle to address the limitations of passive devices, but current designs have yet to be implemented on a large scale clinically. PURPOSE: To compare passive AFOs to a new untethered, powered AFO design in a clinical population with lower limb reconstruction. METHODS: A crossover study design, conducted on three individuals with lower limb reconstruction, compared gait mechanics at a standardized speed (based on leg length) in 4 AFO conditions: 1. None (shoes only), 2. Blue Rocker (BR, Allard, USA), 3. Intrepid Dynamic Exoskeletal Orthosis (IDEO), and 4. PowerFoot Orthosis (PFO BionX Medical Technologies, Inc.). The PFO was a custom, battery-powered device whose damping and power were capable to being tuned to meet patient needs. Subjects performed biomechanical gait analysis and metabolic testing at slow, moderate and fast speeds. Dependent variables included total limb power (calculated using a unified deformable segment model), mechanical work, mechanical efficiency, ankle motion, net metabolic cost across three speeds, and performance measures were calculated. Effect sizes (d) were calculated and d > 0.80 denoted a large effect. RESULTS: Net positive work (d > 1.17) and efficiency (d > 1.43) were greatest in the PFO. There were large effects for between limb differences in positive work for all conditions except the PFO (d = 0.75). The PFO normalized efficiency between the affected and unaffected limbs (d = 0.50), whereas efficiency was less on the affected limb for all other conditions (d > 1.69). Metabolic rate was not consistently lowest in any one AFO condition across speeds. Despite some positive results of the PFO, patient preferred their daily use AFO (2 IDEO, 1 BR). All participants indicated that mass and size were concerns with using the PFO. CONCLUSIONS: A novel PFO resulted in more biomimetic mechanical work and efficiency than commercially-available and custom passive AFO models. Although the powered AFO provided some biomechanical benefits, further improvements are warranted to improve patient satisfaction. PMID- 30463577 TI - Nebulization versus standard application for topical anaesthesia during flexible bronchoscopy under moderate sedation - a randomized controlled trial. AB - BACKGROUND: Endobronchial administration of lidocaine is commonly used for cough suppression during diagnostic bronchoscopy. Recently, nebulization of lidocaine during bronchoscopies under deep sedation with fiberoptic intubation using a distinct spray catheter has been shown to have several advantages over conventional lidocaine administration via syringe. However, there are no data about this approach in bronchoscopies performed under moderate sedation. Therefore, this study compared the tolerability and safety of nebulized lidocaine with conventional lidocaine administration via syringe in patients undergoing bronchoscopy with moderate sedation. METHODS: Patients requiring diagnostic bronchoscopy were randomly assigned to receive topical lidocaine either via syringe or via nebulizer. Endpoints were consumption of lidocaine and sedative drugs, as well as patient tolerance and safety. RESULTS: Sixty patients were included in the study (n = 30 in each group). Patients required lower doses of endobronchial lidocaine when given via nebulizer versus syringe (164.7 +/- 20.8 mg vs. 250.4 +/- 42.38 mg; p < 0.0001) whereas no differences in the dosage of sedative drugs were observed between the two groups (all p > 0.05). Patients in the nebulizer group had higher mean oxygen saturation (96.19 +/- 2.45% vs. 94.21 +/- 3.02%; p = 0.0072) and a lower complication rate (0.3 +/- 0.79 vs. 1.17 +/- 1.62 per procedure; p = 0.0121) compared with those in the syringe group. CONCLUSIONS: Endobronchial lidocaine administration via nebulizer was well tolerated during bronchoscopies under moderate sedation and was associated with reduced lidocaine consumption, a lower complication rate and better oxygenation compared with lidocaine administration via syringe. TRIAL REGISTRATION: The study was registered with clinicaltrials.gov ( NCT02262442 ; 13th October 2014). PMID- 30463578 TI - N-glycosylation patterns of plasma proteins and immunoglobulin G in chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a complex condition, whose diagnosis requires spirometric assessment. However, considering its heterogeneity, subjects with similar spirometric parameters do not necessarily have the same functional status. To overcome this limitation novel biomarkers for COPD have been investigated. Therefore, we aimed to explore the potential value of N-glycans as COPD biomarkers and to examine the individual variation of plasma protein and immunoglobulin G (IgG) glycosylation profiles in subjects with COPD and healthy controls. METHODS: Both the total plasma protein and IgG N-glycome have been profiled in the total of 137 patients with COPD and 95 matching controls from Croatia. Replication cohort consisted of 61 subjects with COPD and 148 controls recruited at another Croatian medical centre. RESULTS: Plasma protein N-glycome in COPD subjects exhibited significant decrease in low branched and conversely, an increase in more complex glycan structures (tetragalactosylated, trisialylated, tetrasialylated and antennary fucosylated glycoforms). We also observed a significant decline in plasma monogalactosylated species, and the same change replicated in IgG glycome. N-glycans also showed value in distinguishing subjects in different COPD GOLD stages, where the relative abundance of more complex glycan structures increased as the disease progressed. Glycans also showed statistically significant associations with the frequency of exacerbations and demonstrated to be affected by smoking, which is the major risk factor for COPD development. CONCLUSIONS: This study showed that complexity of glycans associates with COPD, mirroring also the disease severity. Moreover, changes in N-glycome associate with exacerbation frequency and are affected by smoking. In general, this study provided new insights into plasma protein and IgG N-glycome changes occurring in COPD and pointed out potential novel markers of the disease progression and severity. PMID- 30463579 TI - STING-mediated type-I interferons contribute to the neuroinflammatory process and detrimental effects following traumatic brain injury. AB - BACKGROUND: Traumatic brain injury (TBI) represents a major cause of disability and death worldwide with sustained neuroinflammation and autophagy dysfunction contributing to the cellular damage. Stimulator of interferon genes (STING) induced type-I interferon (IFN) signalling is known to be essential in mounting the innate immune response against infections and cell injury in the periphery, but its role in the CNS remains unclear. We previously identified the type-I IFN pathway as a key mediator of neuroinflammation and neuronal cell death in TBI. However, the modulation of the type-I IFN and neuroinflammatory responses by STING and its contribution to autophagy and neuronal cell death after TBI has not been explored. METHODS: C57BL/6J wild-type (WT) and STING-/- mice (8-10-week-old males) were subjected to controlled cortical impact (CCI) surgery and brains analysed by QPCR, Western blot and immunohistochemical analyses at 2 h or 24 h. STING expression was also analysed by QPCR in post-mortem human brain samples. RESULTS: A significant upregulation in STING expression was identified in late trauma human brain samples that was confirmed in wild-type mice at 2 h and 24 h after CCI. This correlated with an elevated pro-inflammatory cytokine profile with increased TNF-alpha, IL-6, IL-1beta and type-I IFN (IFN-alpha and IFN-beta) levels. This expression was suppressed in the STING-/- mice with a smaller lesion volume in the knockout animals at 24 h post CCI. Wild-type mice also displayed increased levels of autophagy markers, LC3-II, p62 and LAMP2 after TBI; however, STING-/- mice showed reduced LAMP2 expression suggesting a role for STING in driving dysfunctional autophagy after TBI. CONCLUSION: Our data implicates a detrimental role for STING in mediating the TBI-induced neuroinflammatory response and autophagy dysfunction, potentially identifying a new therapeutic target for reducing cellular damage in TBI. PMID- 30463580 TI - International approaches to rural generalist medicine: a scoping review. AB - BACKGROUND: Contemporary approaches to rural generalist medicine training and models of care are developing internationally as part of an integrated response to common challenges faced by rural and remote health services and policymakers (addressing health inequities, workforce shortages, service sustainability concerns). The aim of this study was to review the literature relevant to rural generalist medicine. METHODS: A scoping review was undertaken to answer the broad question 'What is documented on rural generalist medicine?' Literature from January 1988 to April 2017 was searched and, after final eligibility filtering (according to established inclusion and exclusion criteria), 102 articles in English language were included for final analysis. RESULTS: Included papers were analysed and categorised by geographic region, study design and subject themes. The majority of articles (80%) came from Australia/New Zealand and North America, reflecting the relative maturity of programmes supporting rural generalist medicine in those countries. The most common publication type was descriptive opinion pieces (37%), highlighting both a need and an opportunity to undertake and publish more systematic research in this area. Important themes emerging from the review were: Definition Existing pathways and programmes Scope of practice and service models Enablers and barriers to recruitment and retention Reform recommendations There were some variations to, or criticisms of, the definition of rural generalist medicine as applied to this review, although this was only true of a small number of included articles. Across remaining themes, there were many similarities and consistent approaches to rural generalist medicine between countries, with some variations reflecting environmental context and programme maturity. This review identified recent literature from countries with emerging interest in rural generalist medicine in response to problematic rural health service delivery. CONCLUSIONS: Supported, coordinated rural generalist medicine programmes are being established or developed in a number of countries as part of an integrated response to rural health and workforce concerns. Findings of this review highlight an opportunity to better share the development and evaluation of best practice models in rural generalist medicine. PMID- 30463581 TI - Health benefits of electrically-assisted cycling: a systematic review. AB - BACKGROUND: Electrically assisted bicycles (e-bikes) have been highlighted as a method of active travel that could overcome some of the commonly reported barriers to cycle commuting. The objective of this systematic review was to assess the health benefits associated with e-cycling. METHOD: A systematic literature review of studies examining physical activity, cardiorespiratory, metabolic and psychological outcomes associated with e-cycling. Where possible these outcomes were compared to those from conventional cycling and walking. Seven electronic databases, clinical trial registers, grey literature and reference lists were searched up to November 2017. Hand searching occurred until June 2018. Experimental or observational studies examining the impact of e cycling on physical activity and/or health outcomes of interest were included. E bikes used must have pedals and require pedalling for electric assistance to be provided. RESULTS: Seventeen studies (11 acute experiments, 6 longitudinal interventions) were identified involving a total of 300 participants. There was moderate evidence that e-cycling provided physical activity of at least moderate intensity, which was lower than the intensity elicited during conventional cycling, but higher than that during walking. There was also moderate evidence that e-cycling can improve cardiorespiratory fitness in physically inactive individuals. Evidence of the impact of e-cycling on metabolic and psychological health outcomes was inconclusive. Longitudinal evidence was compromised by weak study design and quality. CONCLUSION: E-cycling can contribute to meeting physical activity recommendations and increasing physical fitness. As such, e bikes offer a potential alternative to conventional cycling. Future research should examine the long-term health impacts of e-cycling using rigorous research designs. PMID- 30463582 TI - Novel self-assembling conjugates as vectors for agrochemical delivery. AB - BACKGROUND: Modern agricultural practises rely on surfactant-based spray applications to eliminate weeds in crops. The wide spread and indiscriminate use of surfactants may result in a number of deleterious effects that are not limited to impacts on the crop and surrounding farm eco-system but include effects on human health. To provide a safer alternative to the use of surfactant-based formulations, we have synthesised a novel, self-assembling herbicide conjugate for the delivery of a broad leaf herbicide, picloram. RESULTS: The synthesized self-assembling amphiphile-picloram (SAP) conjugate has three extending arms: a lipophilic lauryl chain, a hydrophilic polyethylene glycol chain and the amphiphobic agrochemical active picloram. We propose that the SAP conjugate maintains its colloidal stability by quickly transitioning between micellar and inverse micellar phases in hydrophilic and lipophilic environments respectively. The SAP conjugate provides the advantage of a phase structure that enables enhanced interaction with the hydrophobic epicuticular wax surface of the leaf. We have investigated the herbicidal efficiency of the SAP conjugate compared against that of commercial picloram formulations using the model plant Arabidopsis thaliana and found that when tested at agriculturally relevant doses between 0.58 and 11.70 mM a dose-dependent herbicidal effect with comparable kill rates was evident. CONCLUSION: Though self-assembling drug carriers are not new to the pharmaceutical industry their use for the delivery of agrochemicals shows great promise but is largely unexplored. We have shown that SAP may be used as an alternative to current surfactant-based agrochemical formulations and has the potential to shift present practises towards a more sustainable approach. PMID- 30463583 TI - Decrease in preovulatory serum estradiol is a valuable marker for predicting premature ovulation in natural/unstimulated in vitro fertilization cycle. AB - BACKGROUND: Premature ovulation occurs at a high rate in natural-cycle in vitro fertilization (IVF), and cycle cancellation further hampers the overall efficiency of the procedure. While lower levels of estradiol (E2) are observed in preovulatory follicles, it is unclear whether declines in E2 can be used as an effective marker of premature ovulation. METHODS: This retrospective analysis includes 801 natural/unstimulated IVF/ICSI cycles undergoing scheduled ovum pick up (OPU) and 153 natural/unstimulated IVF/ICSI cycles undergoing emergency OPU at a university IVF center from May 2014 to February 2017. RESULTS: Among the 801 IVF/ICSI cycles undergoing scheduled OPU, preovulatory E2 levels increased by more than 10% in 403 (50.31%) cycles of the sample (Group A), while 192 (23.97%) cycles experienced a plateau (increased or decreased by 10%; Group B), and 206 (25.72%) cycles decreased by more than 10% (Group C). Group C had more patients who experienced premature LH surges, premature ovulation, as well as the fewest oocytes retrieved, frozen embryos, and top-quality embryos. A multivariate logistic regression analysis indicated that premature ovulation was associated with preovulatory E2/-1E2 ratio and premature LH surge. Moreover, preovulatory E2/-1E2 ratio served as a valuable marker for differentiating premature ovulation, with an AUC (area under the receiver operating curve) of 0.708 and 0.772 in cycles with premature LH surges and cycles without premature LH surges, respectively. Emergency OPU resulted in a significantly decreased rate of premature ovulation and increased number of frozen embryos. CONCLUSION: Decreases in preovulatory serum E2 was a valuable marker for premature ovulation in natural/unstimulated IVF cycle. Emergency OPU based on the preovulatory E2/-1E2 ratio decreased the rate of premature ovulation in cycles that experienced E2 decreases. PMID- 30463584 TI - PD-L1 expression and the prognostic significance in gastric cancer: a retrospective comparison of three PD-L1 antibody clones (SP142, 28-8 and E1L3N). AB - BACKGROUND: Immunohistochemistry (IHC) for programmed cell death ligand 1 (PD-L1) displays staining diversity. We compared IHC staining of PD-L1 in gastric cancer (GC) by using three commercially available antibody clones, and analyzed the correlation with the prognosis. METHODS: IHC using PD-L1 antibodies (clones SP142, 28-8 and E1L3N) in 315 formalin-fixed paraffin-embedded samples was qualitatively compared at the 1, 5 and 10% cut-off by two pathologists on total, tumor and immune/stromal cells. We used computer - assisted scoring to quantitatively analyze and compare the "H-score" of PD-L1 expression in 66 samples on total cells. The antibody clone SP142 was selected to investigate the infiltration of PD-L1+CD8+ T cells using automated quantitative immunofluorescence analyses (n = 50) and the prognostic significance. The prognoses were assessed by log-rank test. RESULTS: PD-L1 clones SP142 and 28-8 displayed great concordance by qualitative (kappa = 0.816, 0.810 for total cells and tumor cells at the 5% cut-off) and quantitative analyses (R2 = 0.7991, 0.8187 for positive percentage and "H-score"). PD-L1 clone SP142 showed the highest positivity in immune/stromal cells staining (18.41%) compared to 28-8 (7.62%), while clone E1L3N showed poor staining in both tumor and immune/stromal cells. Clone SP142, but not 28-8 and E1L3N, predicted a worse prognosis at the 5% cut off (p = 0.0243). Both the clone SP142 and 28-8 had high inter-pathologist correlation for tumor staining (R2 = 0.9805 and R2 = 0.9853), but a moderate correlation for stromal/immune cell staining (R2 = 0.5653 and R2 = 0.5745). Furthermore, a higher density of PD-L1+CD8+ T cells was correlated with a shorter survival time (R2 = 0.0909, p = 0.0352). CONCLUSIONS: PD-L1 antibody clone SP142 was superior in cell staining, particularly in immune/stromal cell and prognosis. These findings are important for selection of PD-L1 antibody clones in the future diagnostic test. PMID- 30463586 TI - Letter on "Pre-hospital transthoracic echocardiography for early identification of non-ST-elevation myocardial infarction in patients with acute coronary syndrome". PMID- 30463585 TI - Physical activity and sedentary time among preschoolers in centre-based childcare: a systematic review. AB - BACKGROUND: Many preschoolers spend a substantial portion of their day enrolled in centre-based childcare; the amounts of physical activity and sedentary time accumulated in this environment are critical to preschoolers' ability to meet movement guidelines. The purpose of this systematic review was to provide a comprehensive overview of the objectively assessed physical activity and sedentary time of preschoolers in centre-based childcare (registration no. CRD42016033502). METHODS: Eight online databases were searched using terms related to physical activity, sedentary time, preschoolers and centre-based childcare. Published, peer-reviewed primary studies written in English that objectively assessed (via accelerometry) the physical activity and sedentary time of preschoolers (2-5 years) in centre-based childcare were included. RESULTS: Fifty-five studies (published 2004-2017) from 11 countries, representing 13,956 participants were included. Studies reported light physical activity (n=38) ranging from 2.94 to 29.96 mins/hr, moderate-to-vigorous physical activity (n=46) which ranged from 1.29 to 22.66 mins/hr, and total physical activity (n=42) ranging from 4.23 to 47.17 mins/hr. Sedentary time (n=47) ranged from 12.38 to 55.77 mins/hr. CONCLUSION: Physical activity and sedentary time were highly varied and inconsistent between studies; therefore, it is difficult to determine preschoolers' true amount of physical activity and sedentary time during childcare hours. Despite this variability, preschoolers were noted to participate in high rates of sedentary time in this setting. The lack of homogeneity is an important finding in and of itself as it highlights the lack of consistency in measuring, processing, and reporting paediatric physical activity data. PMID- 30463587 TI - Human menstrual blood: a renewable and sustainable source of stem cells for regenerative medicine. AB - Stem cells (SCs) play an important role in autologous and even allogenic applications. Menstrual blood discharge has been identified as a valuable source of SCs which are referred to as menstrual blood-derived stem cells (MenSCs). Compared to SCs from bone marrow and adipose tissues, MenSCs come from body discharge and obtaining them is non-invasive to the body, they are easy to collect, and there are no ethical concerns. There is, hence, a growing interest in the functions of MenSCs and their potential applications in regenerative medicine. This review presents recent progress in research into MenSCs and their potential application. Clinical indications of using MenSCs for various regenerative medicine applications are emphasized, and future research is recommended to accelerate clinical applications of MenSCs. PMID- 30463588 TI - Identification of a transcriptome profile associated with improvement of organ function in septic shock patients after early supportive therapy. AB - BACKGROUND: Septic shock is the most severe complication of sepsis and this syndrome is associated with high mortality. Treatment of septic shock remains largely supportive of hemodynamics and tissue perfusion. Early changes in organ function assessed by the Sequential Organ Function Assessment (SOFA) score are highly predictive of the outcome. However, the individual patient's response to supportive therapy is very heterogeneous, and the mechanisms underlying this variable response remain elusive. The aim of the study was to investigate the transcriptome of whole blood in septic shock patients with different responses to early supportive hemodynamic therapy assessed by changes in SOFA scores within the first 48 h from intensive care unit (ICU) admission. METHODS: We performed whole blood RNA sequencing in 31 patients: 17 classified as responders (R) and 14 as non-responders (NR). Gene expression was investigated at ICU admission (time point 1, or T1), comparing R with NR [padj < 0.01; Benjamini-Hochberg (BH)] and over time from T1 to T2 (48 h later) in R and NR independently (paired analysis, padj < 0.01; BH). Then the differences in gene expression trends over time were evaluated (Mann-Whitney, P <0.01). To identify enriched biological processes, we performed an over-representation analysis based on a right-sided hypergeometric test with Bonferroni step-down as multiple testing correction (padj < 0.05). RESULTS: At ICU admission, we did not identify differentially expressed genes (DEGs) between the two groups. In the transition from T1 to T2, the activation of genes involved in T cell-mediated immunity, granulocyte and natural killer (NK) cell functions, and pathogen lipid clearance was noted in the R group. Genes involved in acute inflammation were downregulated in both groups. CONCLUSIONS: Within the limits of a small sample size, our results could suggest that early activation of genes of the adaptive immune response is associated with an improvement in organ function. PMID- 30463589 TI - An intervention to control an ICU outbreak of carbapenem-resistant Acinetobacter baumannii: long-term impact for the ICU and hospital. AB - BACKGROUND: Following a fatal intensive care unit (ICU) outbreak of carbapenem resistant Acinetobacter baumanii (CRAB) in 2015, an aggressive infection control intervention was instituted. We outline the intervention and long-term changes in the incidence and prevalence of CRAB. METHODS: The infection control intervention included unit closure (3 days), environmental cleaning, hand hygiene interventions, and environmental culturing. CRAB acquisition and prevalence and colistin use were compared for the 1 year before and 2 years after the intervention. RESULTS: Following the intervention, ICU CRAB acquisition decreased significantly from 54.6 (preintervention) to 1.9 (year 1) to 5.6 cases (year 2)/1000 admissions (p < 0.01 for comparisons with preintervention period.). Unexpectedly, ICU CRAB admission prevalence also decreased from 56.5 to 5.8 to 13 cases/1000 admissions (p < 0.001) despite the infection control intervention's being directed at the ICU alone. In parallel, hospital CRAB prevalence decreased from 4.4 to 2.4 to 2.5 cases/1000 admissions (p < 0.001), possibly as a result of decreased discharge of CRAB carriers from the ICU to the wards (58.5 to 1.9 to 7.4 cases/1000 admissions; p < 0.001). ICU colistin consumption decreased from 200 to 132 to 75 defined daily dose (DDD)/1000 patient-days (p < 0.05). Hospital colistin consumption decreased from 21.2 to 19.4 to 14.1 DDD/1000 patient-days (p < 0.05). CONCLUSIONS: The ICU infection control intervention was highly effective, long-lasting, and associated with a decrease in last-line antibiotic use. The intervention was associated with the unexpected finding that hospital CRAB prevalence also decreased. PMID- 30463590 TI - The combination of procalcitonin and C-reactive protein or presepsin alone improves the accuracy of diagnosis of neonatal sepsis: a meta-analysis and systematic review. AB - BACKGROUND: Sepsis is an important cause of neonatal morbidity and mortality; therefore, the early diagnosis of neonatal sepsis is essential. METHOD: Our aim was to compare the diagnostic accuracy of procalcitonin (PCT), C-reactive protein (CRP), procalcitonin combined with C-reactive protein (PCT + CRP) and presepsin in the diagnosis of neonatal sepsis. We searched seven databases to identify studies that met the inclusion criteria. Two independent reviewers performed data extraction. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), area under curve (AUC), and corresponding 95% credible interval (95% CI) were calculated by true positive (TP), false positive (FP), false negative (FN), and true negative (TN) classification using a bivariate regression model in STATA 14.0 software. The pooled sensitivity, specificity, PLR, NLR, DOR, AUC, and corresponding 95% CI were the primary outcomes. Secondary outcomes included the sensitivity and specificity in multiple subgroup analyses. RESULTS: A total of 28 studies enrolling 2661 patients were included in our meta-analysis. The pooled sensitivity of CRP (0.71 (0.63, 0.78)) was weaker than that of PCT (0.85 (0.79, 0.89)), PCT + CRP (0.91 (0.84, 0.95)) and presepsin (0.94 (0.80, 0.99)) and the pooled NLR of presepsin (0.06 (0.02, 0.23)) and PCT + CRP (0.10 (0.05, 0.19)) were less than CRP (0.33 (0.26, 0.42)), and the AUC for presepsin (0.99 (0.98, 1.00)) was greater than PCT + CRP (0.96 (0.93, 0.97)), CRP (0.85 (0.82, 0.88)) and PCT (0.91 (0.89, 0.94)). The results of the subgroup analysis showed that 0.5 2 ng/mL may be the appropriate cutoff interval for PCT. A cut-off value > 10 mg/L for CRP had high sensitivity and specificity. CONCLUSIONS: The combination of PCT and CRP or presepsin alone improves the accuracy of diagnosis of neonatal sepsis. However, further studies are required to confirm these findings. PMID- 30463591 TI - Human UCB-MSCs treatment upon intraventricular hemorrhage contributes to attenuate hippocampal neuron loss and circuit damage through BDNF-CREB signaling. AB - BACKGROUND: Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) have been shown to prevent brain damage and improve neurocognition following intraventricular hemorrhage (IVH). However, the molecular mechanisms underlying the effects of hUCB-MSCs are still elusive. Thus, as the hippocampus is essential for learning, memory, and cognitive functions and is intimately involved in the ventricular system, making it a potential site of IVH-induced injury, we determined the molecular basis of the effects of hUCB-derived MSCs on hippocampal neurogenesis and the recovery of hippocampal neural circuits after IVH in a rodent model. METHODS: We inflicted severe IVH injury on postnatal day 4 (P4) in rats. After confirmation of successful induction of IVH using MRI (P5), intracerebroventricular administration of MSCs (ICV-MSC) was performed at 2 days post-injury (P6). For hippocampal synaptic determination, a rat entorhinal hippocampus (EH) organotypic slice co-culture (OSC) was performed using day 3 post-IVH brains (P7) with or without ICV-MSCs. A similar strategy of experiments was applied to those rats receiving hUCB-MSC transfected with BDNF-Si-RNA for knockdown of BDNF or scrambled siRNA controls after IVH. The molecular mechanism of the MSCs effects on neurogenesis and the attenuation of neuron death was determined by evaluation of BDNF-TrkB-Akt-CREB signaling axis. RESULTS: We showed that treatment with hUCB-MSCs attenuated neuronal loss and promoted neurogenesis in the hippocampus, an area highly vulnerable to IVH-induced brain injury. hUCB MSCs activate BDNF-TrkB receptor signaling, eliciting intracellular activation of Akt and/or Erk and subsequent phosphorylation of CREB, which is responsible for promoting rat BDNF transcription. In addition to the beneficial effects of neuroprotection and neurogenesis, hUCB-MSCs also contribute to the restoration of impaired synaptic circuits in the hippocampus and improve neurocognitive functions in IVH-injured neonatal rat through BDNF-TrkB-CREB signaling axis activation. CONCLUSIONS: Our data suggest that hUCB-MSCs possess therapeutic potential for treating neuronal loss and neurocognitive dysfunction in IVH through the activation of intracellular TrkB-CREB signaling that is invoked by hUCB-MSC-secreted BDNF. PMID- 30463592 TI - Exosomes derived from mature chondrocytes facilitate subcutaneous stable ectopic chondrogenesis of cartilage progenitor cells. AB - BACKGROUND: Developing cartilage constructed with the appropriate matrix composition and persistent chondrogenesis remains an enduring challenge in cartilage defects. Cartilage progenitor cell (CPC)-based tissue engineering has attracted recent attention because of its strong chondrogenic differentiation capacity. However, due to the lack of a suitable chondrogenic niche, the clinical application of CPC-regenerated cartilage in the subcutaneous environment remains a challenge. In this study, exosomes derived from chondrocytes (CC-Exos) were used to provide the CPC constructs with a cartilage signal in subcutaneous environments for efficient ectopic cartilage regeneration. METHODS: Rabbit CPC alginate constructs were prepared and implanted subcutaneously in nude mice. CC Exos were injected into the constructs at the same dose (30 MUg exosomes per 100 MUL injection) after surgery and thereafter weekly for a period of 12 weeks. Exosomes derived from bone mesenchymal stem cells (BMSC-Exos) were used as the positive control. The mice in the negative control were administered with the same volume of PBS. At 4 and 12 weeks after implantation, the potential of CC Exos and BMSC-Exos to promote chondrogenesis and stability of cartilage tissue in a subcutaneous environment were analyzed by histology, immunostaining, and protein analysis. The influences of BMSC-Exos and CC-Exos on chondrogenesis and angiogenic characteristics in vitro were assessed via coculturing with CPCs and human umbilical vein endothelial cells. RESULTS: The CC-Exos injection increased collagen deposition and minimized vascular ingrowth in engineered constructs, which efficiently and reproducibly developed into cartilage. The generated cartilage was phenotypically stable with minimal hypertrophy and vessel ingrowth up to 12 weeks, while the cartilage formed with BMSC-Exos was characterized by hypertrophic differentiation accompanied by vascular ingrowth. In vitro experiments indicated that CC-Exos stimulated CPCs proliferation and increased expression of chondrogenesis markers while inhibiting angiogenesis. CONCLUSIONS: These findings suggest that the novel CC-Exos provides the preferable niche in directing stable ectopic chondrogenesis of CPCs. The use of CC-Exos may represent an off-the-shelf and cell-free therapeutic approach for promoting cartilage regeneration in the subcutaneous environment. PMID- 30463593 TI - Mesenchymal stem cell-derived extracellular vesicles affect disease outcomes via transfer of microRNAs. AB - Mesenchymal stem cells (MSCs) are adult stromal cells with the capacity to differentiate into multiple types of cells. MSCs represent an attractive option in regenerative medicine due to their multifaceted abilities for tissue repair, immunosuppression, and anti-inflammation. Recent studies demonstrate that MSCs exert their effects via paracrine activity, which is at least partially mediated by extracellular vesicles (EVs). MSC-derived EVs (MSC-EVs) could mimic the function of parental MSCs by transferring their components such as DNA, proteins/peptides, mRNA, microRNA (miRNA), lipids, and organelles to recipient cells. In this review, we aim to summarize the mechanism and role of miRNA transfer in mediating the effects of MSC-EVs in the models of human diseases. The first three sections of the review discuss the sorting of miRNAs into EVs, uptake of EVs by target cells, and functional transfer of miRNAs via EVs. Then, we describe the composition of miRNAs in MSC-EVs. Next, we provide the existing evidence that MSC-EVs affect the outcomes of renal, liver, heart, and brain diseases by transferring their miRNA contents. In conclusion, EV-mediated miRNA transfer plays an important role in disease-modulating capacity of MSCs. PMID- 30463595 TI - How to improve worldwide early enteral nutrition performance in intensive care units? PMID- 30463594 TI - Characterization, recellularization, and transplantation of rat decellularized testis scaffold with bone marrow-derived mesenchymal stem cells. AB - BACKGROUND: Regenerative medicine potentially offers the opportunity for curing male infertility. Native extracellular matrix (ECM) creates a reconstruction platform to replace the organs. In this study, we aimed to evaluate the efficiency of the testis decellularized scaffold as a proper niche for stem cell differentiation toward testis-specific cell lineages. METHODS: Rats' testes were decellularized by freeze-thaw cycle followed by immersion in deionized distilled water for 2 h, perfused with 1% Triton X-100 through ductus deferens for 4 h, 1% SDS for 48 h and 1% DNase for 2 h. The decellularized samples were prepared for further in vitro and in vivo analyses. RESULT: Histochemical and immunohistochemistry studies revealed that ECM components such as Glycosaminoglycans (GAGs), neutral carbohydrate, elastic fibers, collagen I & IV, laminin, and fibronectin were well preserved, and the cells were completely removed after decellularization. Scanning electron microscopy (SEM) showed that 3D ultrastructure of the testis remained intact. In vivo and in vitro studies point out that decellularized scaffold was non-toxic and performed a good platform for cell division. In vivo implant of the scaffolds with or without mesenchymal stem cells (MSCs) showed that appropriate positions for transplantation were the mesentery and liver and the scaffolds could induce donor loaded MSCs or host migrating cells to differentiate to the cells with phenotype of the sertoli- and leydig-like cells. The scaffolds also provide a good niche for migrating DAZL-positive cells; however, they could not differentiate into post meiotic-cell lineages. CONCLUSION: The decellularized testis can be considered as a promising vehicle to support cell transplantation and may provide an appropriate niche for testicular cell differentiation. PMID- 30463597 TI - Influences of donor and host age on human muscle-derived stem cell-mediated bone regeneration. AB - BACKGROUND: Human muscle-derived stem cells (hMDSCs) have been shown to regenerate bone efficiently when they were transduced with Lenti-viral bone morphogenetic protein 2 (LBMP2). However, whether the age of hMDSCs and the animal host affect the bone regeneration capacity of hMDSCs and mechanism are unknown which prompted the current study. METHODS: We isolated three gender matched young and old populations of skeletal muscle stem cells, and tested the influence of cells' age on in vitro osteogenic differentiation using pellet culture before and after Lenti-BMP2/green fluorescent protein (GFP) transduction. We further investigated effects of the age of hMDSCs and animal host on hMDSC mediated bone regeneration in a critical-size calvarial bone defect model in vivo. Micro-computer tomography (CT), histology, and immunohistochemistry were used to evaluate osteogenic differentiation and mineralization in vitro and bone regeneration in vivo. Western blot, quantitative polymerase chain reaction (PCR), and oxidative stress assay were performed to detect the effects of age of hMDSCs on cell survival and osteogenic-related genes. Serum insulin-like growth factor 1 (IGF1) and receptor activator of nuclear factor-kappa B ligand (RANKL) were measured with an enzyme-linked immunosorbent assay (ELISA). RESULTS: We found LBMP2/GFP transduction significantly enhanced osteogenic differentiation of hMDSCs in vitro, regardless of donor age. We also found old were as efficient as young LBMP2/GFP-transduced hMDSCs for regenerating functional bone in young and old mice. These findings correlated with lower phosphorylated p38MAPK expression and similar expression levels of cell survival genes and osteogenic-related genes in old hMDSCs relative to young hMDSCs. Old cells exhibited equivalent resistance to oxidative stress. However, both young and old donor cells regenerated less bone in old than young hosts. Impaired bone regeneration in older hosts was associated with high bone remodeling due to higher serum levels of RANKL and lower level of IGF-1. CONCLUSION: hMDSC-mediated bone regeneration was not impaired by donor age when hMDSCs were transduced with LBMP2/GFP, but the age of the host adversely affected hMDSC-mediated bone regeneration. Regardless of donor and host age, hMDSCs formed functional bone, suggesting a promising cell resource for bone regeneration. PMID- 30463598 TI - Investigating the effectiveness and feasibility of exercise on microvascular reactivity and quality of life in systemic sclerosis patients: study protocol for a feasibility study. AB - BACKGROUND: Raynaud's phenomenon is one of the first clinical manifestations observed in systemic sclerosis (SSc). This microvasculature disorder affects mostly the digits in over 95% of SSc patients, significantly affecting their health-related quality of life (HRQoL) and incurring higher hospital admissions and other healthcare costs. Exercise is known to improve both micro- and macrovascular function - aerobic exercise and resistance training, separately or combined, have been demonstrated to lead to significant vasculo-physiological improvements in conditions that present vasculopathy. However, the effects of a combined exercise programme on microcirculation in SSc patients has yet to be investigated. Therefore, the purpose of this study is to assess the effects of high-intensity interval training (HIIT) combined with circuit resistance training on the microvascular function in the digital area of SSc patients. METHODS: This will be a randomised controlled, feasibility trial with two arms, wherein 30 patients with SSc in receipt of medical treatment will be randomly assigned to usual care (medical treatment) or to a 12-week supervised exercise programme. Patients in the exercise group will undertake two, 45-min sessions each week consisting of 30 min HIIT (30 s 100% peak power output/30 s passive recovery) on the arm crank ergometer and 15 min of upper body circuit resistance training. Patients will be assessed before as well as at 3 and 6 months following randomisation. Primary outcomes of the study will be recruitment and retention rate, intervention acceptability and adherence to the exercise programme. Secondary outcomes include the digital area cutaneous microvascular function (laser Doppler fluximetry combined with iontophoresis), physical fitness, functional ability, upper back transcutaneous oxygen tension, body composition and quality of life (EQ-5D-5L). Selected interviews with a subsample of patients will be undertaken to explore their experiences of having Raynaud's phenomenon and the acceptability of the exercise intervention and study procedures. DISCUSSION: Data from this study will be used to identify the feasibility of a combined exercise programme to be implemented in SSc patients, the acceptability of the intervention and the study design, and to determine the effects of exercise on the microvasculature. Overall, this study will provide sufficient data to inform and support a full multicentre clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov (NCT number): NCT03058887 , February 23, 2017. PMID- 30463596 TI - Iron deficiency diagnosed using hepcidin on critical care discharge is an independent risk factor for death and poor quality of life at one year: an observational prospective study on 1161 patients. AB - BACKGROUND: Iron deficiency is difficult to diagnose in critically ill patients, but may be frequent and may impair recovery. Measurement of hepcidin could help in the diagnosis of iron deficiency. We aim to assess if iron deficiency diagnosed using hepcidin is associated with poorer outcome one year after an intensive care unit stay. METHODS: We used the prospective FROG-ICU, multicentre (n = 28 ICUs), observational cohort study of critically ill survivors followed up one year after intensive care unit discharge. Iron deficiency was defined as hepcidin < 20 ng/l, ferritin < 100 ng/l or soluble transferrin receptor (sTfR)/log(ferritin) > 0.8, measured in blood drawn at intensive care unit discharge. Main outcomes were one-year all-cause mortality and poor quality of life (defined as a Short Form 36 (SF-36) score below the median). RESULTS: Among the 2087 patients in the FROG-ICU cohort, 1570 were discharged alive and 1161 had a blood sample available at intensive care unit discharge and were included in the analysis. Using hepcidin, 429 (37%) patients had iron deficiency, compared to 72 (6%) using ferritin alone and 151 (13%) using the sTfR/log(ferritin) ratio. Iron deficiency diagnosed according to low hepcidin was an independent predictor of one-year mortality (OR 1.51 (1.10-2.08)) as was high sTfR/log ferritin ratio (OR = 1.95 (1.27-3.00)), but low ferritin was not. Severe ID, defined as hepcidin < 10 ng/l, was also an independent predictor of poor one-year physical recovery (1.58 (1.01-2.49)). CONCLUSIONS: Iron deficiency, diagnosed using hepcidin, is very frequent at intensive care unit discharge and is associated with increased one-year mortality and poorer physical recovery. Whether iron treatment may improve these outcomes remains to be investigated. PMID- 30463599 TI - Stem cell library screen identified ruxolitinib as regulator of osteoblastic differentiation of human skeletal stem cells. AB - BACKGROUND: Better understanding of the signaling pathways that regulate human bone marrow stromal stem cell (hBMSC) differentiation into bone-forming osteoblasts is crucial for their clinical use in regenerative medicine. Chemical biology approaches using small molecules targeting specific signaling pathways are increasingly employed to manipulate stem cell differentiation fate. METHODS: We employed alkaline phosphatase activity and staining assays to assess osteoblast differentiation and Alizarin R staining to assess mineralized matrix formation of cultured hBMSCs. Changes in gene expression were assessed using an Agilent microarray platform, and data normalization and bioinformatics were performed using GeneSpring software. For in vivo ectopic bone formation experiments, hMSCs were mixed with hydroxyapatite-tricalcium phosphate granules and implanted subcutaneously into the dorsal surface of 8-week-old female nude mice. Hematoxylin and eosin staining and Sirius Red staining were used to detect bone formation in vivo. RESULTS: We identified several compounds which inhibited osteoblastic differentiation of hMSCs. In particular, we identified ruxolitinib (INCB018424) (3 MUM), an inhibitor of JAK-STAT signaling that inhibited osteoblastic differentiation and matrix mineralization of hMSCs in vitro and reduced ectopic bone formation in vivo. Global gene expression profiling of ruxolitinib-treated cells identified 847 upregulated and 822 downregulated mRNA transcripts, compared to vehicle-treated control cells. Bioinformatic analysis revealed differential regulation of multiple genetic pathways, including TGFbeta and insulin signaling, endochondral ossification, and focal adhesion. CONCLUSIONS: We identified ruxolitinib as an important regulator of osteoblast differentiation of hMSCs. It is plausible that inhibition of osteoblast differentiation by ruxolitinib may represent a novel therapeutic strategy for the treatment of pathological conditions caused by accelerated osteoblast differentiation and mineralization. PMID- 30463600 TI - Therapeutic efficiency of human amniotic epithelial stem cell-derived functional hepatocyte-like cells in mice with acute hepatic failure. AB - BACKGROUND: Hepatocyte transplantation has been proposed as an effective treatment for patients with acute liver failure (ALF), but its application is limited by a severe shortage of donor livers. Human pluripotent stem cells (hPSCs) have emerged as a potential cell source for regenerative medicine. Human amniotic epithelial stem cells (hAESCs) derived from amniotic membrane have multilineage differentiation potential which makes them suitable for possible application in hepatocyte regeneration and ALF treatment. METHODS: The pluripotent characteristics, immunogenicity, and tumorigenicity of hAESCs were studied by various methods. hAESCs were differentiated to hepatocyte-like cells (HLCs) using a non-transgenic and three-step induction protocol. ALB secretion, urea production, periodic acid-Schiff staining, and ICG uptake were performed to investigate the function of HLCs. The HLCs were transplanted into ALF NOD-SCID (nonobese diabetic severe combined immunodeficient) mouse, and the therapeutic effects were determined via liver function test, histopathology, and survival rate analysis. The ability of HLCs to engraft the damaged liver was evaluated by detecting the presence of GFP-positive cells. RESULTS: hAESCs expressed various markers of embryonic stem cells, epithelial stem cells, and mesenchymal stem cells and have low immunogenicity and no tumorigenicity. hAESC-derived hepatocytes possess the similar functions of human primary hepatocytes (hPH) such as producing urea, secreting ALB, uptaking ICG, storing glycogen, and expressing CYP enzymes. HLC transplantation via the tail vein could engraft in live parenchymal, improve the liver function, and protect hepatic injury from CCl4 induced ALF in mice. More importantly, HLC transplantation was able to significantly prolong the survival of ALF mouse. CONCLUSION: We have established a rapid and efficient differentiation protocol that is able to successfully generate ample functional HLCs from hAESCs, in which the liver injuries and death rate of CCl4-induced ALF mouse can be significantly rescued by HLC transplantation. Therefore, our results may offer a superior approach for treating ALF. PMID- 30463601 TI - Adipose stem cells and their paracrine factors are therapeutic for early retinal complications of diabetes in the Ins2Akita mouse. AB - BACKGROUND: Early-stage diabetic retinopathy (DR) is characterized by neurovascular defects. In this study, we hypothesized that human adipose-derived stem cells (ASCs) positive for the pericyte marker CD140b, or their secreted paracrine factors, therapeutically rescue early-stage DR features in an Ins2Akita mouse model. METHODS: Ins2Akita mice at 24 weeks of age received intravitreal injections of CD140b-positive ASCs (1000 cells/1 MUL) or 20* conditioned media from cytokine-primed ASCs (ASC-CM, 1 MUL). Age-matched wildtype mice that received saline served as controls. Visual function experiments and histological analyses were performed 3 weeks post intravitreal injection. Biochemical and molecular analyses assessed the ASC-CM composition and its biological effects. RESULTS: Three weeks post-injection, Ins2Akita mice that received ASCs had ameliorated decreased b-wave amplitudes and vascular leakage but failed to improve visual acuity, whereas Ins2Akita mice that received ASC-CM demonstrated amelioration of all aforementioned visual deficits. The ASC-CM group demonstrated partial amelioration of retinal GFAP immunoreactivity and DR-related gene expression but the ASC group did not. While Ins2Akita mice that received ASCs exhibited occasional (1 in 8) hemorrhagic retinas, mice that received ASC-CM had no adverse complications. In vitro, ASC-CM protected against TNFalpha-induced retinal endothelial permeability as measured by transendothelial electrical resistance. Biochemical and molecular analyses demonstrated several anti inflammatory proteins including TSG-6 being highly expressed in cytokine-primed ASC-CM. CONCLUSIONS: ASCs or their secreted factors mitigate retinal complications of diabetes in the Ins2Akita model. Further investigation is warranted to determine whether ASCs or their secreted factors are safe and effective therapeutic modalities long-term as current locally delivered therapies fail to effectively mitigate the progression of early-stage DR. Nonetheless, our study sheds new light on the therapeutic mechanisms of adult stem cells, with implications for assessing relative risks/benefits of experimental regenerative therapies for vision loss. PMID- 30463603 TI - Sequence of joint tissue inflammation during rheumatoid arthritis development. AB - OBJECTIVE: Subclinical joint inflammation in patients with arthralgia is predictive for progression to rheumatoid arthritis (RA). However, the time course of progression for bone marrow edema (osteitis), synovitis, and/or tenosynovitis is unsettled. This longitudinal study assessed the course of magnetic resonance imaging (MRI)-detected subclinical joint inflammation during progression to RA. METHODS: Patients that progressed from clinically suspect arthralgia (CSA) to RA underwent 1.5-T MRI of the metacarpophalangeal (MCP), wrist, and metatarsophalangeal (MTP) joints at presentation with arthralgia and at first identification of synovitis assessed through physical examination (n = 31). MRIs were evaluated for osteitis, synovitis, tenosynovitis, and erosions by two readers, blinded for clinical data and order in time. To estimate changes in MRI scores between the asymptomatic state and CSA onset, scores of MRI features at CSA baseline were compared with scores from age-matched symptom-free persons. RESULTS: At presentation with CSA, synovitis and tenosynovitis scores were higher than scores from age-matched symptom-free persons (p = 0.004 and p = 0.001, respectively). Anti-citrullinated protein antibody (ACPA)-positive arthralgia patients also had increased osteitis scores (p = 0.04). Median duration between presentation with arthralgia and RA development was 17 weeks. During progression to RA, synovitis and osteitis increased significantly (p = 0.001 and p = 0.036, respectively) in contrast to tenosynovitis and erosion scores. This pattern was similar in both ACPA subsets, although statistical significance was reached for synovitis and osteitis in ACPA-negative but not ACPA-positive RA. CONCLUSION: Increased tenosynovitis and synovitis scores at CSA onset and the increase in synovitis and osteitis during progression to RA suggest an 'outside-in' temporal relationship of arthritis development, in particular for ACPA-negative RA. For ACPA-positive RA, further studies are needed. PMID- 30463602 TI - Docking simulation between HIV peptidase inhibitors and Trypanosoma cruzi aspartyl peptidase. AB - OBJECTIVE: The low investment in research, diagnosis and treatment are factors that contribute to the continuity of Chagas' disease as a neglected tropical diseases (NTDs). In this context, the repositioning of drugs represents a useful strategy, in the search for new chemotherapeutic approaches for NTDs. HIV aspartic peptidase inhibitors (HIV IPs) are good candidates for drug repurposing. Here, we modeled the three dimensional structure of an aspartyl peptidase of Trypanosoma cruzi, the causative agent of Chagas' disease, aligned it to the HIV aspartyl peptidase and performed docking binding assays with the HIV PIs. RESULTS: The 3D structure confirmed the presence of acid aspartic residues, which are critical to enzyme activity. The docking experiment revealed that HIV IPs bind to the active site of the enzyme, being ritonavir and lopinavir the ones with greater affinity. Benznidazole presented the worst binding affinity, this drug is currently used in Chagas' disease treatment and was included as negative control. These results together with previous data on the trypanocidal effect of the HIV PIs support the hypothesis that a T. cruzi aspartyl peptidase can be the intracellular target of these inhibitors. However, the direct demonstration of the inhibition of T. cruzi aspartyl peptidase activity by HIV PIs is still a goal to be persuaded. PMID- 30463604 TI - Impact of timing of continuous intravenous anesthetic drug treatment on outcome in refractory status epilepticus. AB - BACKGROUND: Patients in refractory status epilepticus (RSE) may require treatment with continuous intravenous anesthetic drugs (cIVADs) for seizure control. The use of cIVADs, however, was recently associated with poor outcome in status epilepticus (SE), raising the question of whether cIVAD therapy should be delayed for attempts to halt seizures with repeated non-anesthetic antiepileptic drugs. In this study, we aimed to determine the impact of differences in therapeutic approaches on RSE outcome using timing of cIVAD therapy as a surrogate for treatment aggressiveness. METHODS: This was a retrospective cohort study over 14 years (n = 77) comparing patients with RSE treated with cIVADs within and after 48 h after RSE onset, and functional status at last follow-up was the primary outcome (good = return to premorbid baseline or modified Rankin Scale score of less than 3). Secondary outcomes included discharge functional status, in hospital mortality, RSE termination, induction of burst suppression, use of thiopental, duration of RSE after initiation of cIVADs, duration of mechanical ventilation, and occurrence of super-refractory SE. Analysis was performed on the total cohort and on subgroups defined by RSE severity according to the Status Epilepticus Severity Score (STESS) and by the variables contained therein. RESULTS: Fifty-three (68.8%) patients received cIVADs within the first 48 h. Early cIVAD treatment was independently associated with good outcome (adjusted risk ratio [aRR] 3.175, 95% confidence interval [CI] 1.273-7.918; P = 0.013) as well as lower chance of both induction of burst suppression (aRR 0.661, 95% CI 0.507-0.861; P = 0.002) and use of thiopental (aRR 0.446, 95% CI 0.205-0.874; P = 0.043). RSE duration after cIVAD initiation was shorter in the early cIVAD cohort (hazard ratio 1.796, 95% CI 1.047-3.081; P = 0.033). Timing of cIVAD use did not impact the remaining secondary outcomes. Subgroup analysis revealed early cIVAD impact on the primary outcome to be driven by patients with STESS of less than 3. CONCLUSIONS: Patients with RSE treated with cIVADs may benefit from early initiation of such therapy. PMID- 30463605 TI - Mismatch between student and tutor evaluation of training needs: a study of traumatology rotations. AB - OBJECTIVE: An e-portfolio was used to determine the optimal number of times students need to repeat a procedure before they are fully capable of performing it without supervision. The results were compared with the actual number of repetitions performed during the internship period. We also asked these students and their teachers about the optimal number of times each skill should be repeated before it could be considered fully acquired. The questionnaire was answered by 98.6% of the students and 70.3% of their teachers. RESULTS: Both students and teachers agreed on a similar optimal value for 16 out of the 21 clinical procedures selected; in the remaining 5, teachers thought that students needed to repeat the procedure more times than the number stated by students. When these optimal values were compared with the actual values recorded in the portfolio during the internships, it was found that about half of all clinical procedures were carried out fewer times than expected, thus providing important feedback about the rotation-based training process. Quantitative information collected in the portfolios revealed a moderate mismatch between students' and teachers' perceptions of training needs. PMID- 30463606 TI - Ethnic-based separation in maternity Departments in Israel - a balanced practical view. AB - Ethnic-based separation in public hospitals in Israel is a sensitive issue that was recently brought forward by the media and was recently discussed in the Israel Journal of Health Policy Research.The above paper maintains that ethnic separation in inpatient rooms does take place some of the time and this runs contrary to the ethos of neutrality in medicine. The authors recommend implementing a national policy that prohibits ethnic-based separation in hospital inpatient rooms.In this commentary I point to the fact that the authors' research indicates that often times ethnic separation is not based on racism, and while the call for unequivocal prohibition of discriminatory ethnic-based separation is of course morally justified, such an across-the-board prohibition is actually an imposition of mixed rooms under all circumstances.I recommend a more balanced and still ethically acceptable approach: any request by patients for a separate room that is overtly based on ethnic discrimination should be immediately rejected and that hospital directors should be called upon by the Ministry of Health not to take a back seat on this issue, to be proactive in explaining to the staff the importance of absolute avoidance of any discriminatory considerations in the placement of patients, and to monitor the extent of ethnic separation expecting to see in every department ethnically mixed rooms. PMID- 30463607 TI - When and how to use predictive biomarkers for corticosteroid treatment of septic shock. PMID- 30463608 TI - Financial IncEntives for Smoking TreAtment: protocol of the FIESTA trial and FIESTA Oral Microbiome Substudy. AB - BACKGROUND: Smoking is the leading preventable cause of death in the United States, but evidence-based smoking cessation therapy is underutilized. Financial incentive strategies represent an innovative approach for increasing the use of counseling and pharmacotherapy. If effective, they could supplement or supplant resource-intensive policy options, particularly in populations for whom smoking has substantial societal costs. FIESTA (Financial IncEntives for Smoking TreAtment) will randomize hospitalized smokers to receive usual smoking cessation care alone or usual smoking care augmented with financial incentives. We aim to compare the impact of these two strategies on 1) smoking abstinence, 2) use of counseling and nicotine replacement therapy, and 3) quality of life of participants. We also will evaluate the short-term and long-term return on the investment of incentives. The FIESTA Oral Microbiome Substudy will compare the oral microbiome of smokers and nonsmokers to longitudinally assess whether smoking cessation changes oral microbiome composition. METHODS: We will enroll 182 inpatient participants from the Manhattan campus of the Veterans Affairs New York Harbor Healthcare System. All participants receive enhanced usual care, including screening for tobacco use, counseling while hospitalized, access to nicotine replacement therapy, and referral to a state Quitline. Patients in the financial incentive arm receive enhanced usual care and up to $550 for participating in the New York Smoker's Quitline, using nicotine replacement therapy (NRT), and achieving biochemically confirmed smoking cessation at 2 months and 6 months. In the microbiome substudy, we enroll nonsmoking control participants matched to each recruited smoker's hospital ward, sex, age, diabetes status, and antibiotic use. After discharge, participants are asked to complete periodic phone interviews at 2 weeks, 2 months, 6 months, and 12 months and provide expired carbon monoxide and saliva samples at 2 months, 6 months, and 12 months for cotinine testing and oral microbiome analysis. DISCUSSION: The incentive interventions of FIESTA may benefit hospitalized smokers, an objective made all the more critical because smoking rates among hospitalized patients are higher than those in the general population. Moreover, the focus of FIESTA on evidence-based therapy and bioconfirmed smoking cessation can help guide policy efforts to reduce smoking-related healthcare costs in populations with high rates of tobacco use and costly illnesses. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02506829 . Registered on 1 July 2014. PMID- 30463609 TI - Aberrant expression of interleukin-23-regulated miRNAs in T cells from patients with ankylosing spondylitis. AB - BACKGROUND: Interleukin (IL)-23 can facilitate the differentiation of IL-17 producing helper T cells (Th17). The IL-23/IL-17 axis is known to play a key role in the immunopathogenesis of ankylosing spondylitis (AS). We hypothesized that the expression of microRNAs (miRNAs, miRs) would be regulated by IL-23 and that these miRNAs could participate in the immunopathogenesis of AS. METHODS: Expression profiles of human miRNAs in K562 cells, cultured in the presence or absence of IL-23 for 3 days, were analyzed by microarray. Potentially aberrantly expressed miRNAs were validated using T-cell samples from 24 patients with AS and 16 control subjects. Next-generation sequencing (NGS) was conducted to search for gene expression and biological functions regulated by specific miRNAs in the IL 23-mediated signaling pathway. RESULTS: Initial analysis revealed that the expression levels of 12 miRNAs were significantly higher, whereas those of 4 miRNAs were significantly lower, in K562 cells after coculture with IL-23 for 3 days. Among these IL-23-regulated miRNAs, the expression levels of miR-29b-1-5p, miR-4449, miR-211-3p, miR-1914-3p, and miR-7114-5p were found to be higher in AS T cells. The transfection of miR-29b-1-5p mimic suppressed IL-23-mediated signal transducer and activator of transcription 3 (STAT3) phosphorylation in K562 cells. After NGS analysis and validation, we found that miR-29b-1-5p upregulated the expression of angiogenin, which was also upregulated in K562 cells after coculture with IL-23. Increased expression of miR-29b-1-5p or miR-211-3p could enhance interferon-gamma expression. CONCLUSIONS: Among the miRNAs regulated by IL-23, expression levels of five miRNAs were increased in T cells from patients with AS. The transfection of miR-29b-1-5p mimic could inhibit the IL-23-mediated STAT3 phosphorylation and might play a role in negative feedback control in the immunopathogenesis of AS. PMID- 30463610 TI - Co-transplantation of mesenchymal stem cells improves spermatogonial stem cell transplantation efficiency in mice. AB - BACKGROUND: Spermatogonial stem cell transplantation (SSCT) could become a fertility restoration tool for childhood cancer survivors. However, since in mice, the colonization efficiency of transplanted spermatogonial stem cells (SSCs) is only 12%, the efficiency of the procedure needs to be improved before clinical implementation is possible. Co-transplantation of mesenchymal stem cells (MSCs) might increase colonization efficiency of SSCs by restoring the SSC niche after gonadotoxic treatment. METHODS: A mouse model for long-term infertility was developed and used to transplant SSCs (SSCT, n = 10), MSCs (MSCT, n = 10), a combination of SSCs and MSCs (MS-SSCT, n = 10), or a combination of SSCs and TGFbeta1-treated MSCs (MSi-SSCT, n = 10). RESULTS: The best model for transplantation was obtained after intraperitoneal injection of busulfan (40 mg/kg body weight) at 4 weeks followed by CdCl2 (2 mg/kg body weight) at 8 weeks of age and transplantation at 11 weeks of age. Three months after transplantation, spermatogenesis resumed with a significantly better tubular fertility index (TFI) in all transplanted groups compared to non-transplanted controls (P < 0.001). TFI after MSi-SSCT (83.3 +/- 19.5%) was significantly higher compared to MS-SSCT (71.5 +/- 21.7%, P = 0.036) but did not differ statistically compared to SSCT (78.2 +/- 12.5%). In contrast, TFI after MSCT (50.2 +/- 22.5%) was significantly lower compared to SSCT (P < 0.001). Interestingly, donor-derived TFI was found to be significantly improved after MSi SSCT (18.8 +/- 8.0%) compared to SSCT (1.9 +/- 1.1%; P < 0.001), MSCT (0.0 +/- 0.0%; P < 0.001), and MS-SSCT (3.4 +/- 1.9%; P < 0.001). While analyses showed that both native and TGFbeta1-treated MSCs maintained characteristics of MSCs, the latter showed less migratory characteristics and was not detected in other organs. CONCLUSION: Co-transplanting SSCs and TGFbeta1-treated MSCs significantly improves the recovery of endogenous SSCs and increases the homing efficiency of transplanted SSCs. This procedure could become an efficient method to treat infertility in a clinical setup, once the safety of the technique has been proven. PMID- 30463612 TI - Listeriosis in fattening pigs caused by poor quality silage - a case report. AB - BACKGROUND: Listeria (L.) monocytogenes as the causative agent of listeriosis in humans and different animal species, has its reservoir in the environment. It can be found in the gut and faeces of healthy pigs, but under certain circumstances it may cause clinical disease. Fatteners are usually not known to get affected by Listeria-associated septicaemia and enteritis. This case report shows, that L. monocytogenes should be part of the list of differential diagnoses, when fattening pigs suffer from haemorrhagic diarrhoea and septicaemia. CASE PRESENTATION: Here, we report of an episode of fatal listeriosis in fattening pigs in a piglet producing farm in Lower Austria, which was combined with a fattening unit with space for 450 fatteners. The mortality rate resulted in 7.8% among fattening pigs after suffering from clinical symptoms such as anorexia, bloody diarrhoea and increased body temperature. Two fattening pigs with clinical symptoms and maize silage samples were used for further diagnostics. L. monocytogenes were isolated from serosa samples of the pigs and in the corresponding fed maize silage. One animal was positively tested for Brachyspira hyodysenteriae, which may have also been involved in the development of colitis. Immunohistochemically, L. monocytogenes could be detected in high amounts in lymphatic tissue of the gut. Molecular biological characterisation of the L. monocytogenes isolates from pigs and maize silage resulted in an identical DNA fingerprint assigned to sequence type (ST) 21. Additionally, a high content of deoxynivalenol (3000 parts per billion) was found in maize silage. Therefore, the maize silage produced under inappropriate ensilaging conditions in a silo, was most likely the source of infection. Antimicrobial therapy with amoxicillin led to a fast cure of the remaining affected fatteners. CONCLUSION: To conclude, we were able to show, that L. monocytogenes can cause clinical disease in finishing pigs, which may have been a result of immunosuppression due to high deoxynivalenol exposure. When feeding silage it is important that all ensilaging procedures occur under appropriate anaerobic conditions to guarantee suppression of listerial growth. PMID- 30463611 TI - Overview of the pathological results and treatment characteristics in the first 1000 patients randomized in the SERC trial: axillary dissection versus no axillary dissection in patients with involved sentinel node. AB - BACKGROUND: Three randomized trials have concluded at non inferiority of omission of complementary axillary lymph node dissection (cALND) for patients with involved sentinel node (SN). However, we can outline strong limitations of these trials to validate this attitude with a high scientific level. We designed the SERC randomized trial ( ClinicalTrials.gov , number NCT01717131) to compare outcomes in patients with SN involvement treated with ALND or no further axillary treatment. The aim of this study was to analyze results of the first 1000 patients included. METHODS: SERC trial is a multicenter non-inferiority phase 3 trial. Multivariate logistic regression analysis was used to identify independent factors associated with adjuvant chemotherapy administration and non-sentinel node (NSN) involvement. RESULTS: Of the 963 patients included in the analysis set, 478 were randomized to receive cALND and 485 SLNB alone. All patient demographics and tumor characteristics were balanced between the two arms. SN ITC was present in 6.3% patients (57/903), micro metastases in 33.0% (298), macro metastases in 60.7% (548) and 289 (34.2%) were non eligible to Z0011 trial criteria. Whole breast or chest wall irradiation was delivered in 95.9% (896/934) of patients, adjuvant chemotherapy in 69.5% (644/926), endocrine therapy in 89.6% (673/751) and the proportions were similar in the two arms. The overall rate of positive NSN was 19% (84/442) for patients with cALND. Crude rates of positive NSN according to SN status were 4.5% for ITC (1/22), 9.5% for micro metastases (13/137), 23.9% for macro metastases (61/255) and were respectively 29.36% (64/218), 9.33% (7/75) and 7.94% (10/126) when chemotherapy was administered after cALND, before cALND and for patients without chemotherapy. CONCLUSION: The main objective of SERC trial is to demonstrate non inferiority of cALND omission. A strong interaction between timing of cALND and chemotherapy with positive NSN rate was observed. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov , number NCT01717131 October 19, 2012. PMID- 30463613 TI - How do patients value and prioritize patient portal functionalities and usage factors? A conjoint analysis study with chronically ill patients. AB - BACKGROUND: Patient portal use can be a stimulant for patient engagement. Yet, the heterogeneous landscape of tethered patient portals, is a major barrier to further portal development and implementation. A variety in portal access means, functionalities, usability and usefulness exists; without having accurate sight on patient perspectives. We aimed to get insights on possible coherence between patients' preferred usage factors of portals and patients' prioritization of functionalities, within the complexity of their disease management across different healthcare organizations. METHODS: A conjoint analysis questionnaire was sent to patient panels of two large patient associations in The Netherlands, centered on heart and vascular diseases and lung diseases. RESULTS: Of 1294 patient respondents, 81% were 55+ years old and 49% were 65+ years old. Overall respondents significantly prioritized user-friendly access to a portal, via a laptop or desktop. Patients aged < 65 were less negative about using tablets to access a portal compared to the total respondents. Patients had no preference for a digital interoperable export functionality; most respondents preferred to create printable overviews. Built-in publication delay of two weeks for medical information was not preferred. Our results show no significant preference of patients between 'instant publication' versus 'publication after new information has been explained by a healthcare provider'. Overall respondents and experienced portal users had a strong preference to be able to communicate with their provider via a portal and to use a portal providing information from multiple providers. Lung patients preferred information from one provider and did not require the possibility to ask online questions. CONCLUSIONS: Heart and vascular patients as well as lung patients prefer similar technical patient portal aspects, independent of their medical condition. Yet, in current portals consistency on this matter is lacking. It is highly assumable that offering a more consistent user-experience across the variety of patient portals could help increase patient portal acceptance, ultimately helping to stimulate patient engagement via patient portal use. We further affirm the need for customization on medical information publication and sharing information of various providers through patient portals, where information provision can be adapted to preferences of patients related to their medical condition(s). PMID- 30463614 TI - Thickness of the buccal bone wall and root angulation in the maxilla and mandible: an approach to cone beam computed tomography. AB - BACKGROUND: The objective of this paper is to anatomically describe the bone morphology in the maxillary and mandibular tooth areas, which might help in planning post-extraction implants. METHODS: CBCT images (Planmeca ProMax 3D) of 403 teeth (208 upper teeth and 195 lower teeth) were obtained from 49 patients referred to the Dental School of Seville from January to December 2014. The thickness of the facial wall was measured at the crest, point A, 4 mm below, point B, and at the apex, point C. The second parameter was the angle formed between the dental axis and the axis of the basal bone. RESULTS: A total of 403 teeth were measured. In the maxilla, 89.4% of incisors, 93.94% of canines, 78% of premolars and 70.5% of molars had a buccal bone wall thickness less than the ideal 2 mm. In the mandible, 73.5% of incisors, 49% of canines, 64% of premolars and 53% of molars had < 1 mm buccal bone thickness as measured at point B. The mean angulation in the maxilla was 11.67 +/- 6.37 degrees for incisors, 16.88 +/ 7.93 degrees for canines, 13.93 +/- 8.6 degrees for premolars, and 9.89 +/- 4.8 degrees for molars. In the mandible, the mean values were 10.63 +/- 8.76 degrees for incisors, 10.98 +/- 7.36 degrees for canines, 10.54 +/- 5.82 degrees for premolars and 16.19 +/- 11.22 degrees for molars. CONCLUSIONS: The high incidence of a buccal wall thickness of less than 2 mm in over 80% of the assessed sites indicates the need for additional regeneration procedures, and several locations may also require custom abutments to solve the angulation problems for screw-retained crowns. PMID- 30463615 TI - The feasibility, acceptability and outcomes of exergaming among individuals with cancer: a systematic review. AB - BACKGROUND: Individuals with cancer have reduced quality of life, functionality, range of motion, strength, and an increase in pain and fatigue. Exergaming appears to be an effective rehabilitation tool for Parkinson's disease, multiple sclerosis and post-stroke patients to improve functionality, balance and quality of life; however, the usefulness of exergaming in individuals with cancer is unknown. The aim of this systematic review is to describe exergaming interventions delivered to adults with a current or previous cancer diagnosis and to report the feasibility, acceptability and outcomes of such interventions. METHODS: Studies reporting on exergaming interventions delivered to individuals with a current or previous cancer diagnosis were included. 12 electronic databases were searched. Eight articles (seven interventions) were identified. Data were extracted and assessed for quality by two reviewers. RESULTS: Three interventions were delivered at hospital, two at home, one at a clinical laboratory, and one did not report. Two interventions were delivered by a physiotherapist, two by an occupational therapist, and one by a nurse, research staff and an exercise physiologist. The Nintendo Wii was used in four of seven studies, whilst the remaining three used the IREX system, BrightArm Duo Rehabilitation System or a custom made exergame. Studies showed that most participants enjoyed the exergaming intervention, and would recommend their use, with some preferring exergaming over standard care interventions. Adherence rates and enjoyment appear greater during exergaming than standard care. Exergaming interventions appear to support improvements balance, function, physical activity levels, strength, fatigue, emotions, cognition and pain. CONCLUSION: Exergaming interventions delivered to individuals with cancer show great heterogeneity; differing in duration, frequency and gaming platform. The disease stage and severity of those included, and the outcome measures assessed also vary widely making it difficult to conclude its effectiveness at this time. However, adherence rates and enjoyment appear greater during exergaming compared to standard care, supporting the feasibility and acceptability of this type of intervention delivery for adults with cancer. PMID- 30463617 TI - Instantaneous mutation rate in cancer initiation and progression. AB - BACKGROUND: Cancer is one of the leading causes for the morbidity and mortality worldwide. Although substantial studies have been conducted theoretically and experimentally in recent years, it is still a challenge to explore the mechanisms of cancer initiation and progression. The investigation for these problems is very important for the diagnosis of cancer diseases and development of treatment schemes. RESULTS: To accurately describe the process of cancer initiation, we propose a new concept of gene initial mutation rate based on our recently designed mathematical model using the non-constant mutation rate. Unlike the widely-used average gene mutation rate that depends on the number of mutations, the gene initial mutation rate can be used to describe the initiation process of a single patient. In addition, we propose the instantaneous tumour doubling time that is a continuous function of time based on the non-constant mutation rate. Our proposed concepts are supported by the clinic data of seven patients with advanced pancreatic cancer. The regression results suggest that, compared with the average mutation rate, the estimated initial mutation rate has a larger value of correlation coefficient with the patient survival time. We also provide the estimated tumour size of these seven patients over time. CONCLUSIONS: The proposed concepts can be used to describe the cancer initiation and progression for different patients more accurately. Since a quantitative understanding of cancer progression is important for clinical treatment, our proposed model and calculated results may provide insights into the development of treatment schemes and also have other clinic implications. PMID- 30463616 TI - The Italian autism network (ITAN): a resource for molecular genetics and biomarker investigations. AB - BACKGROUND: A substantial genetic component accounts for Autism Spectrum Disorders (ASD) aetiology, with some rare and common genetic risk factors recently identified. Large collections of DNAs from thoroughly characterized ASD families are an essential step to confirm genetic risk factors, identify new variants and investigate genotype-phenotype correlations. The Italian Autism Network aimed at constituting a clinical database and a biorepository of samples derived from ASD subjects and first-degree relatives extensively and consistently characterized by child psychiatry centers in Italy. METHODS: The study was approved by the ethical committee of the University of Verona, the coordinating site, and by the local ethical committees of each recruiting site. Certified staff was specifically trained at each site for the overall study conduct, for clinical protocol administration and handling of biological material. A centralized database was developed to collect clinical assessment and medical records from each recruiting site. Children were eligible for recruitment based on the following inclusion criteria: age 4-18 years, at least one parent or legal guardian giving voluntary written consent, meeting DSM-IV criteria for Autistic Disorder or Asperger's Disorder or Pervasive Developmental Disorder NOS. Affected individuals were assessed by full psychiatric, neurological and physical examination, evaluation with ADI-R and ADOS scales, cognitive assessment with Wechsler Intelligence Scale for Children or Preschool and Primary, Leiter International Performance Scale or Griffiths Mental Developmental Scale. Additional evaluations included language assessment, the Krug Asperger's Disorder Index, and instrumental examination such as EEG and structural MRI. DNA, RNA and plasma were collected from eligible individuals and relatives. A central laboratory was established to host the biorepository, perform DNA and RNA extraction and lymphocytes immortalisation. DISCUSSION: The study has led to an extensive collection of biological samples associated with standardised clinical assessments from a network of expert clinicians and psychologists. Eighteen sites have received ADI/ADOS training, thirteen of which have been actively recruiting. The clinical database currently includes information on 812 individuals from 249 families, and the biorepository has samples for 98% of the subjects. This effort has generated a highly valuable resource for conducting clinical and genetic research of ASD, amenable to further expansion. PMID- 30463619 TI - A multiple kernel density clustering algorithm for incomplete datasets in bioinformatics. AB - BACKGROUND: While there are a large number of bioinformatics datasets for clustering, many of them are incomplete, i.e., missing attribute values in some data samples needed by clustering algorithms. A variety of clustering algorithms have been proposed in the past years, but they usually are limited to cluster on the complete dataset. Besides, conventional clustering algorithms cannot obtain a trade-off between accuracy and efficiency of the clustering process since many essential parameters are determined by the human user's experience. RESULTS: The paper proposes a Multiple Kernel Density Clustering algorithm for Incomplete datasets called MKDCI. The MKDCI algorithm consists of recovering missing attribute values of input data samples, learning an optimally combined kernel for clustering the input dataset, reducing dimensionality with the optimal kernel based on multiple basis kernels, detecting cluster centroids with the Isolation Forests method, assigning clusters with arbitrary shape and visualizing the results. CONCLUSIONS: Extensive experiments on several well-known clustering datasets in bioinformatics field demonstrate the effectiveness of the proposed MKDCI algorithm. Compared with existing density clustering algorithms and parameter-free clustering algorithms, the proposed MKDCI algorithm tends to automatically produce clusters of better quality on the incomplete dataset in bioinformatics. PMID- 30463618 TI - Optimizing bone wound healing using BMP2 with absorbable collagen sponge and Talymed nanofiber scaffold. AB - BACKGROUND: Bone is a highly vascularized and resilient organ with innate healing abilities, however some bone injuries overwhelm these attributes and require intervention, such as bone tissue engineering strategies. Combining biomaterials and growth factors, such as bone morphogenetic protein 2 (BMP2), is one of the most commonly used tissue engineering strategies. However, use of BMP2 has been correlated with negative clinical outcomes including aberrant inflammatory response, poor quality bone, and ectopic bone. METHODS: In the present study, a novel poly-n-acetyl glucosamine (pGlcNAc, trade name Talymed) scaffold was utilized in addition to the commonly used acellular collagen sponge (ACS) BMP2 delivery system in a murine calvarial defect model to investigate whether the innate properties of Talymed can reduce the noted negative bone phenotypes associated with BMP2 treatment. RESULTS: Comparison of murine calvarial defect healing between ACS with and without Talymed revealed that there was no measurable healing benefit for the combined treatment. Healing was most effective utilizing the traditional acellular collagen sponge with a reduced dose of BMP2. CONCLUSIONS: The results of this investigation lead to the conclusion that excessive dosing of BMP2 may be responsible for the negative clinical side effects observed with this bone tissue engineering strategy. Rather than augmenting the currently used ACS BMP2 bone wound healing strategy with an additional anti-inflammatory scaffold, reducing the dose of BMP2 used in the traditional delivery system results in optimal healing without the published negative side effects of BMP2 treatment. PMID- 30463620 TI - Regulation of MRTF-A by JMY via a nucleation-independent mechanism. AB - BACKGROUND: MRTF-A (myocardin-related transcription factor A) is a coactivator for SRF-mediated gene expression. The activity of MRTF-A is critically dependent on the dissociation of G-actin from N-terminal RPEL motifs. MRTF-SRF induction often correlates with enhanced polymerization of F-actin. Here we investigate MRTF regulation by the multifunctional JMY protein, which contains three WASP/verprolin homology 2 (WH2/V) domains and facilitates Arp2/3-dependent and independent actin nucleation. METHODS: Co-immunoprecipitation experiments, immunofluorescence and luciferase reporter assays were combined with selective inhibitors to investigate the effect of JMY and its domains on MRTF-A in NIH 3 T3 mouse fibroblasts. RESULTS: JMY induced MRTF-A transcriptional activity and enhanced its nuclear translocation. Unexpectedly, MRTF-A was hyperactivated when the Arp2/3-recruiting CA region of JMY was deleted or mutated, suggesting an autoinhibitory mechanism for full-length JMY. Moreover, isolated WH2/V domains which are unable to nucleate actin were sufficient for nuclear accumulation and SRF activation. Recombinant WH2/V regions of JMY biochemically competed with MRTF A for actin binding. Activation of MRTF-A by JMY was unaffected by Arp3 knockdown, by an Arp2/3 inhibitor, and by latrunculin which disassembles cellular F-actin. Restriction of JMY to the nucleus abrogated its MRTF-A activation. Finally, JMY RNAi reduced basal and stimulated transcriptional activation via MRTF-A. CONCLUSIONS: Our results suggest that JMY activates MRTF-SRF independently of F-actin via WH2/V-mediated competition with the RPEL region for G-actin binding in the cytoplasm. Furthermore, the C-terminal region facilitates an autoinhibitory effect on full-length JMY, possibly by intramolecular folding. PMID- 30463621 TI - Unrecognised cardiovascular disease in type 2 diabetes: is it time to act earlier? AB - Cardiovascular disease (CVD) is the most significant prognostic factor in individuals with type 2 diabetes (T2D). However, a significant number of individuals may develop CVD that does not present with the classic angina-related or heart failure symptoms. In these cases, CVD may seem to be 'silent' or 'asymptomatic', but may be more accurately characterised as unrecognised diabetic cardiac impairment. An initial step to raise awareness of unrecognised CVD in individuals with T2D would be to reach a consensus regarding the terminology used to describe this phenomenon. By standardising the terminologies, and agreeing on the implementation of an efficient screening program, it is anticipated that patients will receive an earlier diagnosis and appropriate and timely treatment. Given the availability of anti-diabetic medications that have been shown to concomitantly reduce CV risk and mortality, it is imperative to improve early identification and initiate treatment as soon as possible in order to enable as many patients with T2D as possible to benefit. PMID- 30463623 TI - Is the aging human ovary still ticking?: Expression of clock-genes in luteinized granulosa cells of young and older women. AB - BACKGROUND: It has been shown - mostly in animal models - that circadian clock genes are expressed in granulosa cells and in corpora luteum and might be essential for the ovulatory process and steroidogenesis. OBJECTIVE: We sought to investigate which circadian clock genes exist in human granulosa cells and whether their expression and activity decrease during aging of the ovary. STUDY DESIGN: Human luteinized granulosa cells were isolated from young (age 18-33) and older (age 39-45) patients who underwent in-vitro fertilization treatment. Levels of clock genes expression were measured in these cells 36 h after human chorionic gonadotropin stimulation. METHODS: Human luteinized granulosa cells were isolated from follicular fluid during oocyte retrieval. The mRNA expression levels of the circadian genes CRY1, CRY2, PER1, PER2, CLOCK, ARNTL, ARNTL2, and NPAS2 were analyzed by quantitative polymerase chain reaction. RESULTS: We found that the circadian genes CRY1, CRY2, PER1, PER2, CLOCK, ARNTL, ARNTL2, and NPAS2, are expressed in cultured human luteinized granulosa cells. Among these genes, there was a general trend of decreased expression in cells from older women but it reached statistical significance only for PER1 and CLOCK genes (fold change of 0.27 +/- 0.14; p = 0.03 and 0.29 +/- 0.16; p = 0.05, respectively). CONCLUSIONS: This preliminary report indicates that molecular circadian clock genes exist in human luteinized granulosa cells. There is a decreased expression of some of these genes in older women. This decline may partially explain the decreased fertility and steroidogenesis of reproductive aging. PMID- 30463624 TI - Longevity of mass-reared, irradiated and packed male Anopheles arabiensis and Aedes aegypti under simulated environmental field conditions. AB - BACKGROUND: To ensure the success of a mosquito control programme that integrates the sterile insect technique (SIT), it is highly desirable to release sterile males with a maximal lifespan to increase release effectiveness. Understanding sterile male survival under field conditions is thus critical for determining the number of males to be released. Our study aimed to investigate the effect of mass rearing, irradiation, chilling, packing and release time on irradiated male mosquito longevity. METHODS: Anopheles arabiensis and Aedes aegypti immature stages were mass-reared using a rack and tray system. Batches of 50 males irradiated at the pupal stage were immobilised, packed into canisters and chilled for 6 hours at 6 degrees C. Mosquitoes were then transferred either in the early morning or early evening into climate chambers set to simulate the weather conditions, typical of the beginning of the rainy season in Khartoum, Sudan and Juazeiro, Brazil for An. arabiensis and Ae. aegypti, respectively. The longevity of experimental males was assessed and compared to mass-reared control males subjected either to simulated field or laboratory conditions. RESULTS: The combined irradiation, chilling and packing treatments significantly reduced the longevity of both An. arabiensis and Ae. aegypti under simulated field conditions (P < 0.001). However, packing alone did not significantly reduce longevity of Ae. aegypti (P = 0.38) but did in An. arabiensis (P < 0.001). Overall, the longevity of mass reared, irradiated and packed males was significantly reduced, with the median survival time (days) lower following an early morning introduction (4.62 +/- 0.20) compared to an evening (7.34 +/- 0.35) in An. arabiensis (P < 0.001). However, there was no significant difference in longevity between morning (9.07 +/- 0.54) and evening (7.76 +/- 0.50) in Ae. aegypti (P = 0.14). CONCLUSIONS: Our study showed that sterile mass-reared males have a reduced lifespan in comparison to laboratory-maintained controls under simulated field conditions, and that An. arabiensis appeared to be more sensitive to the handling process and release time than Ae. aegypti. Longevity and release time are important parameters to be considered for a successful area-wide integrated vector control programme with a SIT component. PMID- 30463622 TI - High-intensity versus low-intensity noninvasive positive pressure ventilation in patients with acute exacerbation of chronic obstructive pulmonary disease (HAPPEN): study protocol for a multicenter randomized controlled trial. AB - BACKGROUND: Despite the positive outcomes of the use of noninvasive positive pressure ventilation (NPPV) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD), NPPV fails in approximately 15% of patients with AECOPD, possibly because the inspiratory pressure delivered by conventional low-intensity NPPV is insufficient to improve ventilatory status for these patients. High-intensity NPPV, a novel form that delivers high inspiratory pressure, is believed to more efficiently augment alveolar ventilation than low intensity NPPV, and it has been shown to improve ventilatory status more than low intensity NPPV in stable AECOPD patients. Whether the application of high intensity NPPV has therapeutic advantages over low-intensity NPPV in patients with AECOPD remains to be determined. The high-intensity versus low-intensity NPPV in patients with AECOPD (HAPPEN) study will examine whether high-intensity NPPV is more effective for correcting hypercapnia than low-intensity NPPV, hence reducing the need for intubation and improving survival. METHODS/DESIGN: The HAPPEN study is a multicenter, two-arm, single-blind, prospective, randomized controlled trial. In total, 600 AECOPD patients with low to moderate hypercapnic respiratory failure will be included and randomized to receive high-intensity or low-intensity NPPV, with randomization stratified by study center. The primary endpoint is NPPV failure rate, defined as the need for endotracheal intubation and invasive ventilation. Secondary endpoints include the decrement of arterial carbon dioxide tension from baseline to 2 h after randomization, in-hospital and 28-day mortality, and 90-day survival. Patients will be followed up for 90 days after randomization. DISCUSSION: The HAPPEN study will be the first randomized controlled study to investigate whether high-intensity NPPV better corrects hypercapnia and reduces the need for intubation and mortality in AECOPD patients than low-intensity NPPV. The results will help critical care physicians decide the intensity of NPPV delivery to patients with AECOPD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02985918 . Registered on 7 December 2016. PMID- 30463625 TI - Traumatic brain injury is associated with increased syndecan-1 shedding in severely injured patients. AB - INTRODUCTION: Head injury and exsanguination are the leading causes of death in trauma patients. Hemorrhagic shock triggers systemic endothelial glycocalyx breakdown, potentially leading to traumatic endotheliopathy (EoT). Levels of syndecan-1, a main glycocalyx component, have been used to assess the integrity of the glycocalyx. In TBI patients, it remains unclear whether syndecan-1 shedding occurs and its correlation with outcomes. We aimed to determine the frequency of EoT+, defined as a syndecan-1 level of 40 ng/ml or higher, after TBI in isolated and polytraumatic injury. We also investigated how the presence of EoT+ affected outcomes in TBI patients. METHODS: Severely injured trauma patients were enrolled. From blood samples collected upon patients' arrival to the hospital, we measured syndecan-1 (main biomarker of EoT+), soluble thrombomodulin (sTM, endothelial activation) adrenaline and noradrenaline (sympathoadrenal activation), and assessed TBI patients' coagulation capacity. RESULTS: Of the enrolled patients (n = 331), those with TBI and polytrauma (n = 68) had the highest rate of EoT+ compared to isolated TBI (n = 58) and Non-TBI patients (n = 205) (Polytrauma-TBI 55.9% vs. Isolated-TBI 20.0% vs. non-TBI polytrauma 40.0%; p = 0.001). TBI patients with EoT+ exhibited marked increases in sTM, adrenaline and noradrenaline levels, and physiological and coagulation derangements. In isolated TBI patients, increasing syndecan-1 levels (beta for every 10 ng/ml increase: 0.14; 95% CI: 0.02, 0.26) and hypocoagulability were negatively associated with survival. CONCLUSIONS: This study provides evidence of syndecan-1 shedding after TBI supporting the notion that breakdown of the glycocalyx contributes to the physiological derangements after TBI. PMID- 30463627 TI - Streptococcus pyogenes bacteremia and toxic shock syndrome related to Strongyloides stercoralis hyperinfection: a case report. AB - BACKGROUND: We describe a patient with Strongyloides stercoralis hyperinfection associated with Streptococcus pyogenes and with streptococcal toxic shock syndrome. To the best of our knowledge this association has not been previously described. CASE PRESENTATION: A 78 year-old Israeli man, who was born in Iraq but lived in Israel for 66 years, presented with multi-organ failure including acute kidney and hepatic injury, coagulopathy, and lactic acidosis. He had a medical history including aortic valve replacement, diabetes mellitus, spinal stenosis, and low back pain treated with repeated local steroid injections. Blood cultures were positive for Streptococcus pyogenes and antibiotic treatment was switched to penicillin G, clindamycin, and intravenous immunoglobulins. Repeated physical examinations failed to identify the source of the bacteremia. On day 12 of hospitalization the serology results for Strongyloides stercoralis sent on admission, because of chronic eosinophilia, came back positive. A microscopic stool examination and stool polymerase chain reaction were positive for Strongyloides stercoralis. Ivermectin therapy was commenced and continued for a total of 4 weeks. He was discharged for rehabilitation after 25 days. He had no exposure to endemic countries or to immigrants. During many years he had multiple gastrointestinal symptoms, respiratory symptoms, cutaneous symptoms, chronic eosinophilia, and high immunoglobulin E levels. He underwent several operative procedures and numerous hospitalizations and medical encounters with different experts but a parasitic infection was not considered. His asymptomatic daughter was also found to be serologically positive. CONCLUSIONS: Strongyloides stercoralis hyperinfection associated with Streptococcus pyogenes bacteremia and toxic shock is described for the first time. The case also highlights the importance of history taking and reviewing past laboratory results, the utility of serological tests for Strongyloides stercoralis, and the importance of screening asymptomatic family members of an infected patient. Strongyloides stercoralis hyperinfection must be considered in the differential diagnosis of any patient with Streptococcus pyogenes bacteremia or toxic shock of no clear source as well as in symptomatic patients with chronic or intermittent eosinophilia, even without any epidemiological risk factors. PMID- 30463626 TI - Risk of sepsis in patients with primary aldosteronism. AB - BACKGROUND: The interaction between hyperaldosteronism and immune dysfunction has been reported and glucocorticoid co-secretion is frequently found in primary aldosteronism (PA). The aforementioned conditions raise the possibility of the infection risk; however, clinical episodes of sepsis have not been reported in PA. METHODS: Using Taiwan's National Health Insurance Research Database between 1997 and 2009, we identified PA and aldosterone-producing adenoma (APA) matched with essential hypertension (EH) at a 1:1 ratio by propensity scores. The incidences of sepsis and mortality after the index date were evaluated, and the risk factors of outcomes were identified using adjusted Cox proportional hazards models and taking mortality as a competing risk. RESULTS: We enrolled 2448 patients with PA (male, 46.08%; mean age, 48.4 years). There were 875 patients who could be ascertained as APA. Taking mortality as the competing risk, APA patients had a lower incidence of sepsis than their matched EH patients (hazard ratio (HR) 0.29; P < 0.001) after target treatments. Patients receiving adrenalectomy showed a benefit of decreasing the risk of sepsis (PA vs EH, HR 0.14, P = 0.001; APA vs EH, HR 0.16, P = 0.003), but mineralocorticoid receptor antagonist treatment may differ. Compared with matched control cohorts, patients with APA had a lower risk of all-cause mortality (PA, adjusted HR 0.84, P = 0.050; APA, adjusted HR 0.31, P < 0.001) after target treatments. CONCLUSIONS: Our study demonstrated that patients with PA/APA who underwent adrenalectomy could attenuate the risk of sepsis compared with their matched EH patients. We further found that APA patients with target treatments could decrease all-cause mortality compared with EH patients. PMID- 30463628 TI - Photoprotection enhanced by red cell wall pigments in three East Antarctic mosses. AB - BACKGROUND: Antarctic bryophytes (mosses and liverworts) are resilient to physiologically extreme environmental conditions including elevated levels of ultraviolet (UV) radiation due to depletion of stratospheric ozone. Many Antarctic bryophytes synthesise UV-B-absorbing compounds (UVAC) that are localised in their cells and cell walls, a location that is rarely investigated for UVAC in plants. This study compares the concentrations and localisation of intracellular and cell wall UVAC in Antarctic Ceratodon purpureus, Bryum pseudotriquetrum and Schistidium antarctici from the Windmill Islands, East Antarctica. RESULTS: Multiple stresses, including desiccation and naturally high UV and visible light, seemed to enhance the incorporation of total UVAC including red pigments in the cell walls of all three Antarctic species analysed. The red growth form of C. purpureus had significantly higher levels of cell wall bound and lower intracellular UVAC concentrations than its nearby green form. Microscopic and spectroscopic analyses showed that the red colouration in this species was associated with the cell wall and that these red cell walls contained less pectin and phenolic esters than the green form. All three moss species showed a natural increase in cell wall UVAC content during the growing season and a decline in these compounds in new tissue grown under less stressful conditions in the laboratory. CONCLUSIONS: UVAC and red pigments are tightly bound to the cell wall and likely have a long-term protective role in Antarctic bryophytes. Although the identity of these red pigments remains unknown, our study demonstrates the importance of investigating cell wall UVAC in plants and contributes to our current understanding of UV-protective strategies employed by particular Antarctic bryophytes. Studies such as these provide clues to how these plants survive in such extreme habitats and are helpful in predicting future survival of the species studied. PMID- 30463631 TI - A Systematic Review of Cognitive Impairments Associated With Kidney Failure in Adults Before Natural Age-Related Changes. AB - OBJECTIVES: Recognition of cognitive impairment in chronic kidney disease (CKD) and its impact on functioning in adults is growing. The vast majority of studies to date have been conducted in older populations where CKD is more pronounced; however, the degree to which age-related cognitive changes could be influencing these findings remains unaddressed. This current study thus aimed to review cognitive impairment findings by stage in non-elderly CKD samples. METHODS: PubMed and Medline via Scopus were searched for cross-sectional or cohort studies and randomized controlled trials that assessed cognitive function in individuals with CKD in any research setting. CKD studies including patients at any illness stage were included providing participants were below 65 years old, were not on peritoneal dialysis and had not undergone a kidney transplant. RESULTS: Fifteen studies, with a total of 9304 participants, were included. Cognitive function broadly deteriorated from stage 1 to stage 5. Early stage CKD was associated with a drop in speed of processing, attention, response speed, and short-term memory abilities. Moderate stage CKD was associated with deficits in executive functioning, verbal fluency, logical memory, orientation and concentration. People with end stage kidney disease manifested significant deficits in all previous cognitive domains, along with cognitive control, delayed and immediate memory, visuospatial impairment, and overall cognitive impairment. CONCLUSIONS: Cognitive impairment is evident across the stages of CKD, independent of age related changes, for both lower-order and higher-order cognitive abilities. These impairments also increase between the stages, suggesting a cumulative effect. Future directions for research are discussed. (JINS, 2018, 22, 1-14). PMID- 30463630 TI - Cell-free therapy with the secretome of adipose tissue-derived stem cells in rats' frozen-thawed ovarian grafts. AB - The use of secretome may be a new strand of cell therapy, which is equal to or even superior to the injection of live cells, called cell-free therapy. In ovarian transplantation, this approach may be a therapeutic possibility for the ovarian graft in hypoxia. We designed the present study to evaluate whether the cell-free therapy with the secretome of adipose tissue-derived stem cells (ASCs) in rat frozen-thawed ovarian grafts could protect a graft against ischemic injury. A single dose of rat ASCs secretome or vehicle was injected into the bilateral frozen-thawed ovaries of 18 adult female rats immediately after an autologous transplant. Nine animals were used to control the cryopreservation protocol and were evaluated before and after the cryopreservation process. Daily vaginal smears were performed for estrous cycle evaluation until euthanasia on postoperative day 30. Follicle viability by trypan blue, graft morphology by HE, and apoptosis by TUNEL and cleaved-caspase-3 were assessed. No differences were found with respect to estrous cycle resumption and follicle viability (p > 0.05). However, compared with the vehicle-treated grafts, the morphology of the secretome-treated grafts was impaired, showing reduced follicular population and increased apoptosis (p < 0.05). ASC secretome impaired the rat frozen-thawed ovarian graft from ischemic injury. However, more studies are needed to evaluate the factors involved and the possibility of applying the secretome in scaffolds to optimize its use. PMID- 30463629 TI - A central role for P2X7 receptors in human microglia. AB - BACKGROUND: The ATP-gated ionotropic P2X7 receptor (P2X7R) has the unusual ability to function as a small cation channel and a trigger for permeabilization of plasmalemmal membranes. In murine microglia, P2X7R-mediated permeabilization is fundamental to microglial activation, proliferation, and IL-1beta release. However, the role of the P2X7R in primary adult human microglia is poorly understood. METHODS: We used patch-clamp electrophysiology to record ATP-gated current in cultured primary human microglia; confocal microscopy to measure membrane blebbing; fluorescence microscopy to demonstrate membrane permeabilization, caspase-1 activation, phosphatidylserine translocation, and phagocytosis; and kit-based assays to measure cytokine levels. RESULTS: We found that ATP-gated inward currents facilitated with repetitive applications of ATP as expected for current through P2X7Rs and that P2X7R antagonists inhibited these currents. P2X7R antagonists also prevented the ATP-induced uptake of large cationic fluorescent dyes whereas drugs that target pannexin-1 channels had no effect. In contrast, ATP did not induce uptake of anionic dyes. The uptake of cationic dyes was blocked by drugs that target Cl- channels. Finally, we found that ATP activates caspase-1 and inhibits phagocytosis, and these effects are blocked by both P2X7R and Cl- channel antagonists. CONCLUSIONS: Our results demonstrate that primary human microglia in culture express functional P2X7Rs that stimulate both ATP-gated cationic currents and uptake of large molecular weight cationic dyes. Importantly, our data demonstrate that hypotheses drawn from work on murine immune cells accurately predict the essential role of P2X7Rs in a number of human innate immune functions such as phagocytosis and caspase-1 activation. Therefore, the P2X7R represents an attractive target for therapeutic intervention in human neuroinflammatory disorders. PMID- 30463632 TI - Factor Structure of the Gratitude Questionnaire in a Spanish Sample. AB - The Gratitude Questionnaire is a short, self-report measure of the disposition to experience gratitude. The Gratitude Questionnaire has been validated in several countries but its factor structure remains controversial. Therefore, the main goal of the study was to examine the factor structure of the Gratitude Questionnaire in a Spanish sample. Two samples were recruited (957 and 920 participants). The confirmatory factor analyses showed that the best fit was the five-item model with errors of item four and five correlated (CFI = .99, NFI = .99, RMSEA = .02). This model demonstrated partial cross-validity based on an analysis of factorial invariance. The Composite Reliability of the five-item Gratitude Questionnaire was .81. In addition, it was found that gratitude was positively related to subjective and psychological well-being. Specifically, the Gratitude Questionnaire was positively correlated to life satisfaction (r = .56, p < .01), affect balance (r = .46, p < .01), self-acceptance (r = .54, p < .01), positive relations (r = .44, p < .01), autonomy (r = .17, p < .01), environmental mastery (r = .49, p < .01), personal growth (r = .36, p < .01), and purpose in life (r = .50, p < .01). According to the results, it can be concluded that the Spanish version of the five-item Gratitude Questionnaire possessed better psychometric properties than the original six-item model. PMID- 30463633 TI - Effect of Heavy Metals Contamination from Cigarette Smoke on Sound and Caries Like Enamel. AB - In this study, we sought to evaluate the influence of cigarette smoke and pH cycling on the chemical composition and surface/cross-sectional enamel microhardness. A total of 40 dental blocks obtained from bovine incisors were divided into four groups (n=10): no treatment (control); exposure to cigarette smoke (CS); exposure to pH cycling (PC); and exposure to cigarette smoke and pH cycling (CS-PC). The samples were analyzed by synchrotron radiation micro X-ray fluorescence, bench mode X-ray fluorescence, as well as surface microhardness (SMH) and cross-sectional microhardness (CSMH) testing. The SMH results were submitted to analysis of variance (ANOVA) and Tukey's test. The CSMH results were evaluated using split-plot ANOVA and Tukey's test. A high amount of Cd and Pb and traces of Ni and As were observed in enamel and dentin after exposure to cigarette smoke (CS and CS-PC). The SMH and CSMH of CS were statistically higher when compared with the control. The PC and CS-PC showed lower SMH and CSMH. We conclude that exposure to cigarette smoke promoted heavy metal deposition in enamel/dentin. In addition, it increased the enamel microhardness but did not promote a protective effect on the in vitro development of caries. The clinical significance of this work is that there is significant bioaccumulation of heavy metals from cigarette smoke on the surface and in the enamel and dentin. PMID- 30463634 TI - Re-estimating annual deaths due to multidrug-resistant organism infections. PMID- 30463635 TI - How Loneliness is Associated with Depressive Symptoms in Spanish College Students: Examining Specific Coping Strategies as Mediators. AB - In this study, we examined coping strategies as a mediator of the association between loneliness and depressive symptoms. A sample of 364 Spanish young adults (75.5% females) completed measures of loneliness, coping, and depressive symptoms. In general, results from computing correlations (controlling for gender) indicated that loneliness was negatively associated with the use of one engaged coping strategy (viz., problem solving) and positively associated with the use of disengaged coping strategies (e.g., problem avoidance). A multiple mediation analysis (controlling for gender) was conducted to test for mediation. Results of this analysis indicated that part of the association between loneliness and depressive symptoms can be explained by the use of one engaged coping strategy (viz., problem solving; indirect effect, p < .05) and a variety of disengaged coping strategies (viz., problem avoidance, wishful thinking, social withdrawal, & self criticism; indirect effects, p < .05). Overall, the prediction model including loneliness and coping strategies was found to account for a large (f2 = .68) 40.5% of the variance in depressive symptoms in Spanish young adults. The present findings are the first to clarify how the association between loneliness and depressive symptoms in Spanish young adults might be due in part to the use of different coping strategies. Some implications for theory and practice are discussed. PMID- 30463636 TI - Caregiver Out-of-Pocket Costs for Octogenarian Intensive Care Unit Patients in Canada. AB - ABSTRACTMedical issues facing the aging population are of growing concern with consequences for patients and their caregivers. This study determined the indirect and out-of-pocket costs incurred by the caregivers of elderly patients in Canadian Intensive Care Units (ICUs). Primary family caregivers were surveyed capturing out-of-pocket costs, hours of work, and hours of leisure forgone in providing patient care while the patient was in the ICU. Total costs of care per month were reported across caregiver sex, age, and geographic region. Average out of-pocket costs were $791 (2016 Canadian dollars) in the first month of ICU care. The mean total cost to family caregivers per patient was $162 per day. Male primary caregivers had higher mean out-of-pocket costs than female caregivers. Subsidization programs covering expenses such as travel, meals, accommodation, and parking are needed to support family caregivers of elderly ICU patients who are incurring considerable out-of-pocket costs. PMID- 30463638 TI - Introduction. PMID- 30463637 TI - The impact of a multilevel childhood obesity prevention intervention on healthful food acquisition, preparation, and fruit and vegetable consumption on African American adult caregivers. AB - OBJECTIVE: To evaluate the secondary impact of a multilevel, child-focused, obesity intervention on food-related behaviours (acquisition, preparation, fruit and vegetable (FV) consumption) on youths' primary caregivers. DESIGN: B'More Healthy Communities for Kids (BHCK) group-randomized controlled trial promoted access to healthy foods and food-related behaviours through wholesaler and small store strategies, peer mentor-led nutrition education aimed at youths, and social media and text messaging targeting their adult caregivers. Measures included caregivers' (n 516) self-reported household food acquisition frequency for FV, snacks and grocery items over 30 d, and usual FV consumption in a sub-sample of 226 caregivers via the NCI FV Screener. Hierarchical models assessed average treatment effects (ATE). Treatment-on-the-treated-effect (TTE) analyses evaluated correlation between behavioural change and exposure to BHCK. Exposure scores at post-assessment were based on self-reported viewing of BHCK materials and participating in activities. SETTING: Thirty Baltimore City low-income neighbourhoods, USA.ParticipantsAdult caregivers of youths aged 9-15 years. RESULTS: Of caregivers, 90.89 % were female; mean age 39.31 (sd 9.31) years. Baseline mean (sd) intake (servings/d) was 1.30 (1.69) fruits and 1.35 (1.05) vegetables. In ATE, no significant intervention effect was found on caregivers' food-related behaviours. In TTE, each point increase in BHCK exposure score (range: 0-6.9) increased caregivers' daily fruit consumption by 0.2 servings (0.24 (se 0.11); 95 % CI 0.04, 0.47). Caregivers reporting greater social media exposure tripled their daily fruit intake (3.16 (se 0.92); 95 % CI 1.33, 4.99) and increased their frequency of unhealthy food purchasing v. baseline. CONCLUSIONS: Child-focused community-based nutrition interventions may also benefit family members' fruit intake. Child-focused interventions should involve adult caregivers and intervention effects on family members should be assessed. Future multilevel studies should consider using social media to improve reach and engage caregiver participants. PMID- 30463639 TI - A Review of Regulations Applied to Spices, Herbs, and Flavorings-What Has Changed? AB - A review of the world-wide regulations pertaining to spices, extracts, and flavorings. The areas covered include (1) guidance documents from trade organizations as well as international and regional regulatory bodies, (2) decontamination of spices and herbs, (3) extraction solvents used to make spice and herb oleoresins, and (4) general flavoring regulations. Specific links and references to guidance documents and regulations have been provided where they have been published on government, organization, and trade association websites. PMID- 30463640 TI - Role of dipeptidyl peptidase-4 as a potentiator of activin/nodal signaling pathway. AB - DPP4 (dipeptidyl peptidase-4), a highly conserved transmembrane glycoprotein with an exo-peptidase activity, has been shown to contribute to glucose metabolism, immune regulation, signal transduction, and cell differentiation. Here, we show that DPP4 is involved in control of activin/nodal signaling in Xenopus early development. In support of this, gain of function of DPP4 augmented Smad2 phosphorylation as well as expression of target genes induced by activin or nodal signal. In addition, Dpp4 and Xnr1 showed synergistic effect on induction of ectopic dorsal body axis, when co-injected at suboptimal doses in early embryos. Conversely, saxagliptin, a DPP4 inhibitor repressed activin induction of Smad2 phosphorylation. Notably, overexpression of Dpp4 disrupted specification of dorsal body axis of embryo, leading to malformed phenotypes such as spina bifida and a shortened and dorsally bent axis. Together, these results suggest that DPP4 functions as a potentiator of activin/nodal signaling pathway. PMID- 30463641 TI - In vivo action of RNA G-quadruplex in phloem development. AB - Phloem network integrates cellular energy status into post-embryonic growth, and development by tight regulation of carbon allocation. Phloem development involves complicated coordination of cell fate determination, cell division, and terminal differentiation into sieve elements (SEs), functional conduit. All of these processes must be tightly coordinated, for optimization of systemic connection between source supplies and sink demands throughout plant life cycle, that has substantial impact on crop productivity. Despite its pivotal role, surprisingly, regulatory mechanisms underlying phloem development have just begun to be explored, and we recently identified a novel translational regulatory network involving RNA G-quadruplex and a zinc-finger protein, JULGI, for phloem development. From this perspective, we further discuss the role of RNA G quadruplex on post-transcriptional control of phloem regulators, as a potential interface integrating spatial information for asymmetric cell division, and phloem development. [BMB Reports 2018; 51(11): 547-548]. PMID- 30463642 TI - Immune inflammatory modulation as a potential therapeutic strategy of stem cell therapy for ALS and neurodegenerative diseases. AB - With emerging evidence on the importance of non-cell autonomous toxicity in neurodegenerative diseases, therapeutic strategies targeting modulation of key immune cells. including microglia and Treg cells, have been designed for treatment of ALS and other neurodegenerative diseases. Strategy switching the patient's environment from a pro-inflammatory toxic to an anti-inflammatory, and neuroprotective condition, could be potential therapy for neurodegenerative diseases. Mesenchymal stem cells (MSCs) regulate innate and adaptive immune cells, through release of soluble factors such as TGF-beta and elevation of regulatory T cells (Tregs) and T helper-2 cells (Th2 cells), would play important roles, in the neuroprotective effect on motor neuronal cell death mechanisms in ALS. Single cycle of repeated intrathecal injections of BM-MSCs demonstrated a clinical benefit lasting at least 6 months, with safety, in ALS patients. Cytokine profiles of CSF provided evidence that BM-MSCs, have a role in switching from pro-inflammatory to anti-inflammatory conditions. Inverse correlation of TGF beta1 and MCP-1 levels, could be a potential biomarker to responsiveness. Thus, additional cycles of BM-MSC treatment are required, to confirm long-term efficacy and safety. [BMB Reports 2018; 51(11): 545-546]. PMID- 30463643 TI - Epigenetic memory in gene regulation and immune response. AB - Cells must fine-tune their gene expression programs for optimal cellular activities in their natural growth conditions. Transcriptional memory, a unique transcriptional response, plays a pivotal role in faster reactivation of genes upon environmental changes, and is facilitated if genes were previously in an active state. Hyper-activation of gene expression by transcriptional memory is critical for cellular differentiation, development, and adaptation. TREM (Transcriptional REpression Memory), a distinct type of transcriptional memory, promoting hyper-repression of unnecessary genes, upon environmental changes has been recently reported. These two transcriptional responses may optimize specific gene expression patterns, in rapidly changing environments. Emerging evidence suggests that they are also critical for immune responses. In addition to memory B and T cells, innate immune cells are transcriptionally hyperactivated by restimulation, with the same or different pathogens known as trained immunity. In this review, we briefly summarize recent progress in chromatin-based regulation of transcriptional memory, and its potential role in immune responses. PMID- 30463644 TI - A Novel Blood Pressure Modulator C1q/TNF-alpha-related Protein 1 (CTRP1). AB - C1q/TNF-alpha-Related Protein 1 (CTRP1) has recently been shown to act as a blood pressure regulator, as it induces vasoconstriction. In the aorta, CTRP1 facilitates recruitment of angiotensin II receptor 1 (AT1R) to plasma membrane, through activation of the AKT/AS160 signaling pathway. This leads to activation of the Ras homolog gene family (Rho)/Rho kinase (ROCK) signaling pathway, resulting in vasoconstriction. Accordingly, mice overexpressing Ctrp1 have hypertensive phenotype. Patients with hypertension also display higher circulating CTRP1 levels, compared to healthy individuals, indicating that excessive CTRP1 may affect development of hypertension. Conversely, CTRP1 is regarded as an 'innate blood pressure modulator' because CTRP1 increases blood pressure under dehydration to prevent hypotension. Mice lacking Ctrp1 fail to maintain normotension under dehydration conditions, resulting in hypotension, suggesting that CTRP1 is an essential protein for maintaining blood pressure homeostasis. In conclusion, CTRP1 is a novel, anti-hypotensive vasoconstrictor that increases blood pressure during dehydration-induced hypotension. PMID- 30463645 TI - Structural insights showing how arginine is able to be glycosylated by pathogenic effector proteins. AB - Glycosylation is one form of protein modification and plays a key role in protein stability, function, signaling regulation and even cancer. NleB and SseK are bacterial effector proteins and possess glycosyltransferase activity, even though they have different substrate preferences. NleB/SseKs transfer the GlcNAc sugar to an arginine residue of host proteins, leading to reduced NF-kappaB-dependent responses. By combining X-ray crystallography, NMR, molecular dynamics, enzyme kinetic assays and in vivo experiments, we demonstrated that a conserved HEN (His Glu-Asn) motif in the active site plays a key role in enzyme catalysis and virulence. The lid-domain regulates the opening and closing of the active site and the HLH domain determines the substrate specificity. Our findings provide evidence for the enzymatic mechanism by which arginine can be glycosylated by SseK/NleB enzymes. PMID- 30463646 TI - [Adiponectin reduces apoptosis of macrophages induced by cobalt chloride and its mechanism]. AB - Objective To investigate the protective effects and mechanism of adiponectin (APN) on RAW264.7 macrophages under cell model of hypoxia established by CoCl2. Methods Cells were treated with CoCl2 (100 MUmol/L) and different concentrations of APN (0.5, 1, 2 MUg/mL APN, pretreated for 2 hours firstly, and treated with CoCl2 in a dose of 100 MUmol/L). The cells' vitality in each group was detected by CCK-8 assay. The distribution of caspase-3, as well as the influences of CoCl2 and APN on the expression of caspase-3 was detected by immunofluorescence technique. Apoptotic rates of cells in all groups were analyzed by flow cytometry. The levels of SOD and MDA in each group were measured by spectrophotometer. The expressions of Bcl2, BAX, cleaved caspase-3 and HIF-1alpha of cells in each group were observed by Western blot analysis. Results Compared with CoCl2 group, pretreatment with APN could increase cell vitality, decrease apoptosis, increase the level of SOD, and decrease the level of MDA. Immunofluorescence results revealed that caspase-3 in each group was mainly distributed in the cell membranes, and compared with CoCl2 group, the expression of Bcl2 was evidently increased, BAX, cleaved caspase-3 and HIF-1alpha were decreased after being pretreated with APN. Conclusion APN could decrease CoCl2 induced apoptosis in RAW264.7 cells, which may occur via enhancing the intracellular antioxidant activity, and by upregulation of Bcl2, downregulation of BAX, cleaved caspase-3 and HIF-1alpha. PMID- 30463647 TI - [Polydatin ameliorates myocardial fibrosis in rats by up-regulating SIRT3 and SDF 1]. AB - Objective To investigate the effects and the possible mechanisms of polydatin on the myocardial fibrosis and cytokines of myocardium induced by adriamycin. Methods Twenty male SD rats was divided into four groups, 5 rats in every group. Control group (only fed with conventional diet), adriamycin group (treated with intraperitoneal injection of 2.5 mg/kg adriamycin for twice a week), polydatin treatment group (treated with intraperitoneal injection of 50 mg/kg polydatin for once a day) and nicotinamide treatment group (treated with intraperitoneal injection of 500 mg/kg SIRT3 inhibitor nicotinamide for twice a week). The effects of polydatin on adriamycin induced myocardial fibrosis and collagen expression in myocardium were evaluated by immunohistochemistry. The content of hydroxyproline (HYP) in myocardium was detected by enzyme labeling method. Spectrofluorometry was used to determine the level of superoxide dismutase (SOD) activity, glutathione (GSH) and malonaldehyde (MDA) level. ELISA was used to detect the content of tumor necrosis factor alpha(TNF-alpha), interleukin 1(IL 1)and IL-10. The levels of SIRT1, SIRT3, transforming growth factor-beta (TGF beta) and stromal cell-derived factor-1(SDF-1) were examined by real-time quantitative PCR and Western blotting.Results Treatment with adriamycin promoted the myocardial fibrosis, reduced the level of IL-10, increased the level of TNF alpha, IL-1 in myocardial tissue. The mRNA and protein levels of SIRT3 and SDF-1 was inhibited by adriamycin, whereas the expression of TGF-beta was promoted. The results showed that polydatin inhibited the fibrosis of myocardium induced by adriamycin, decreased the level of HYP, collagen III and MDA , whereas the level of SOD and GSH was increased. Treatment with nicotinamide attenuated the inhibitory effects of polydatin on the fibrosis of myocardium, inhibited the expression of SIRT3 and SDF-1, promoted the expression of TGF-beta. Conclusion Polydatin upregulates the expression of SIRT3 to increase the ability of anti fibrosis and reduce the level of oxidative stress induced by adriamycin, inhibits the relase of cytokines. PMID- 30463648 TI - [Macrophage and platelets inhibit proliferation of methicillin-resistant Staphylococcus aureus in vitro]. AB - Objective To investigate the effect of platelet and macrophage on the proliferation of methicillin-resistant Staphylococcus aureus (MRSA) in vitro, to explore the mechanisms of the inhibition effect, and to further reveal platelet function. Methods LB culture system with 4*108 CFU/mL MRSA inoculation concentration was established in vitro. Leukocyte-free platelets with a number of 200*109/L (platelet group) and macrophages with a number of 1*109/L (macrophage group) were added, respectively. The system without platelets and macrophages was used as negative control (control group). The absorbance of bacterial solution of the two groups was measured for reflect the proliferation of MRSA at different time points. After 2 hours culture, the bacterial liquid was collected for plating after double dilution, and the concentration of bacterial liquid was obtained through calculation after colony counting. Flow cytometry was also performed to verify the phagocytosis of macrophages and the capture ability of platelets. Results Both macrophages and platelets showed suppressive effect on the proliferation of MRSA compared to control group, while the effect of platelets was more significant. Conclusion Platelets have stronger inhibitory ability on MRSA proliferation in vitro than macrophages. PMID- 30463649 TI - [Rosiglitazone ameliorates TNBS-induced colitis in mice by inhibiting inflammation of the mesenteric adipose tissues]. AB - Objective To evaluate the therapeutic effect and possible mechanism of PPARgamma agonist rosiglitazone on 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in mice. Methods Twenty male BALB/c mice were selected to establish TNBS induced colitis model and were randomly divided into rosiglitazone treated group and model group with 10 rats in each group. Rosiglitazone group was treated with rosiglitazone(0.2 mL, [20 mg/(kg.d)])and model group with normal saline(0.2 mL/d). After 6 weeks of administration, the mice were sacrificed. Inflammatory bowel disease disease activity index (DAI) and HE staining combined with Spencer colitis histological score were used to evaluate the degree of intestinal inflammation and histological changes in the two groups. ELISA was used to detect the levels of interleukin-1beta (IL-1beta), tumor necrosis factor alpha(TNF alpha) and IL-10 in the intestinal mucosa, the levels of IL-6 and monocyte chemoattractant protein 1 (MCP-1) in the mesenteric adipose tissues. The mean diameter of adipocytes in the mesenteric adipose tissues was calculated under light microscope after HE staining.The number of F4/80+ macrophages and the expressions of peripherin, adiponectin and leptin in mesenteric adipose tissues were detected by immunohistochemical staining. The phosphorylation of NF kappaBp65, IKK, IkappaB proteins in the mesenteric adipose tissues was detected by Western blot analysis. Results The DAI score of rosiglitazone group was significantly lower than that of model group at 5 and 6 weeks after rosiglitazone treatment. At the same time, the levels of IL-1beta and TNF-alpha in the intestinal mucosa of the treated group were significantly lower than those in the model group, while the IL-10 levels were significantly higher in the treated group than in the model group. Compared with the model group, the mesenteric adipocyte diameter and the perilipin level of adipocyte maturation markers in rosiglitazone treated mice were significantly higher than those in model group. Meanwhile, the number of infiltration of macrophages in mesenteric adipose tissues of mice treated with rosiglitazone and the levels of inflammatory mediators IL-6 and MCP-1 were significantly lower than that of the model group. Rosiglitazone significantly promoted the expression of adiponectin and inhibited the expression of leptin in mesenteric adipocytes. The phosphorylation of NF kappaBp65, IKK and IkappaB proteins in mesenteric adipose tissues of rosiglitazone treated mice was significantly lower than those of model group. Conclusion Rosiglitazone significantly inhibites intestinal inflammation in TNBS induced colitis in mice, which may be related to the inhibition of NF-kappaBp65 pathway in mesenteric adipose tissues. PMID- 30463650 TI - [HMGB1 promotes myocardial ischemic injury and regulates the proportion of CD4+, CD8+T cells and Th17 cells in spleen through TLR4]. AB - Objective To elucidate how high-mobility group box 1 (HMGB1) exacerbates myocardial damage and infuences CD4+, CD8+ and Th17 T lymphocytes of spleen through Toll like receptor 4 (TLR4) in ischemia myocardial injury. Methods 30 wild-type (WT) and 30 TLR4 knockout (TLR4-/-) C57BL/6 mice were randomly divided into the control group, isoproterenol induced ischemia myocardial damage group (ISO) and ISO-rHMGB1 group. The cardiac function of mice was evaluated by echocardiography, and the pathological changes of myocardial tissue were observed by HE staining and Sirius red staining. The apoptosis index of myocardial cells was detected by TUNEL, and the proportion of CD4+, CD8+T cells and Th17 cells in spleen tissues was detected by flow cytometry. Results Compared with the control group, ISO treated mice showed cardiac function impairment, myocardial tissue necrosis and fibrosis, myocardial cell apoptosis, and increased the proportion of CD4+T lymphocytes, CD4+/CD8+ T ratio and Th17 cells in the spleen. Compared to the ISO group, cardiac function damage, myocardial tissue necrosis and fibrosis, and myocardial cell apoptosis were aggravated in the ISO combined rHMGB1 group, and the proportion of CD4+T lymphocytes, CD4+/CD8+T ratio and Th17 cells in the spleen was higher. Compared with wild-type mice in the ISO combined rHMGB1 group, TLR4-/- mice in the ISO combined rHMGB1 group showed decreased cardiac function, myocardial tissue necrosis, fibrosis and myocardial cell apoptosis, and significantly reduced the proportion of CD4+ T lymphocytes, CD4+/CD8+ T ratio and Th17 cells. Conclusion HMGB1 induces myocardial injury in myocardial ischemia through TLR4, and up-regulates the proportion of CD4+ T cells, CD4+/CD8+ T ratio and Th17 cells in the spleen, which may promote myocardial inflammatory damage. PMID- 30463651 TI - [PD-1 overexpression in HEK293T cells transfected with pMH3-PD1]. AB - Objective To optimize the transfection conditions of HEK293T cells and compare the expression levels of human programmed death 1 (hPD-1) in different eukaryotic vectors to obtain the target protein efficiently. Methods L9(33) orthogonal test was designed to optimize the conditions of cell transfection.The DNA sequence of hPD-1 extracellular domain gene was amplified by PCR and then cloned into different vectors:pcDNA3.1, pCMV3 and pMH3, PD-1 recombinant protein was expressed in HEK293T cells transiently and the expression levels was evaluated by ELISA and Western blot analysis. Results The gene of hPD-1 extracellular domain was successfully cloned into pcDNA3.1 and pMH3 eukaryotic expression vectors, and the target protein was successfully expressed. Under the optimal transfection conditions, the expression level of hPD-1 recombinant protein in pMH3 vector was the highest, followed by that of pCMV3 and pcDNA3.1 vectors. Conclusion The extracellular domain of hPD-1 is successfully expressed and the expression level of pMH3-PD1 was the highest among the three vectors tested. PMID- 30463652 TI - [Knockdown of lncRNA SNHG6 inhibites the proliferation and epithelial mesenchymal transition in tongue cancer cells]. AB - Objective To investigate the expression of lncRNA SNHG6 in tongue cancer and Tca1183 cells, and its effect on the biological characteristics of tongue cancer cells. Methods SNHG6 expression levels in tongue cancer tissue, normal tissue, normal tongue cells and cancer cells were detected by real time quantitative PCR to analyze the correlation between SNHG6 expression and clinicopathological characteristics of tongue cancer. SNHG6 interference plasmid was constructed and transfected into Tca1183 cells. MTT assay was used to detect the viability of Tca1183 cells. Colony formation assay was used to measure the proliferation of Tca1183 cells. The apoptosis of Tca1183 cells was detected by flow cytometry. Western blot analysis was used to evaluate the epithelial mesenchymal transition (EMT) related protein levels of beta-catenin, E-cadherin, N-cadherin and vimentin. Results Compared to normal tissue or normal tongue epithelial cells, SNHG6 expression levels increased significantly in tongue cancer tissue or Tca1183 cells. SNHG6 expression in tongue cancer tissue was not correlated with age and gender, but with tissue differentiation degree, clinical stage and lymph node metastasis. Knockdown of SNHG6 in Tca1183 cells significantly inhibited the cell viability and proliferation and induced apoptosis. Furthermore, knockdown of SNHG6 significantly inhibited the EMT of Tca1183 cells by inducing the beta catenin and E-cadherin protein expression and inhibiting N-cadherin and vimentin protein expression. Conclusion SNHG6 expression is significantly increased in tongue cancer, and the interference of SNHG6 expression can inhibit the proliferation and EMT of tongue cancer cells. PMID- 30463653 TI - [Alpha-lipoic acid inhibits the expression of alpha-synuclein in PC12 cells induced by 6-hydroxydopamine and its mechanism]. AB - Objective To investigate the effects of alpha-lipoic acid (alpha-LA) on the expression of alpha-synuclein(alpha-syn)in cellular models of Parkinson's disease (PD) induced by 6-hydroxydopamine (6-OHDA) and its mechanism. Methods PC12 cells were induced by 6-OHDA to establish the cellular models of PD, which was treated with alpha-LA. Cell viability was detected using MTT assay. The contents of intracellular iron and malondialdehyde (MDA) were detected by colorimetry.The level of intracellular reactive oxygen species (ROS) was detected by 2, 7 dichlorodihydrofluorescein diacetate (DCFH-DA) staining. Western blot analysis was performed to detect the level of alpha-syn protein. Results Compared with the normal control group, the cell viability of the model group was significantly decreased, the contents of intracellular iron and MDA and the level of ROS were significantly increased, and the expression level of alpha-syn was significantly increased; compared with the model group, the cell viability of the alpha-LA treat group was significantly increased, the contents of intracellular iron and MDA and the level of ROS were significantly decreased, and the expression level of alpha-syn was significantly decreased. Conclusion alpha-LA can inhibit the overexpression of alpha-syn and attenuate the damage of PC12 cells induced by 6 OHDA, which may be related to the decrease of contents of intracellular iron and oxidative stress level by alpha-LA. PMID- 30463654 TI - [Establishment of BV2 cell line with steady knockdown of Mg2+/Mn2+-dependent protein phosphatase 1A(PPM1A)]. AB - Objective To construct a short hairpin RNA (shRNA) lentiviral of Mg2+/Mn2+ dependent protein phosphatase 1A (PPM1A) gene and establish mouse brain microglia cell line(BV2) which PPM1A was knocked down stably. Methods According to the Coding sequence (CDS) region of PPM1A gene, two pairs of short hairpin RNA (shRNA) sequences (shRNA1, shRNA2) were designed and cloned into GV493 vector, then it was transformed into competent Escherichia coli DH5alpha strain and cultured. The positive clones were picked for sequencing. Finally, lentiviral packaging and titer determination were performed. Two groups of lentiviruses were transfected into BV2 cells and screened with puromycin. Fluorescence microscopy and flow cytometry were used to observe the expression of green fluorescent protein (GFP), and the expression of PPM1A were evaluated by RT-qPCR and Western blot analysis. Results The PPM1A shRNA lentiviral expression vector was successfully constructed. The expression of GFP was more than 80%. Compared with the control group, the mRNA and protein levels of PPM1A were significantly decreased in shRNA1 and shRNA2 knockdown groups. Conclusion The PPM1A knockdown BV2 cell line was successfully constructed using the lentiviral shRNA. PMID- 30463655 TI - [Primary culture and identification of adult dermal fibroblasts]. AB - Objective To establish a method for primary culture of adult dermal fibroblasts. Methods Fresh skin tissues were digested with dispase II to separate the epidermis from dermis. Then fibroblasts were isolated from the dermis by tissue adhesive and type I collagenase digestion method respectively. The growth of cells was observed under an inverted phase contrast microscope. the expression of vimentin in cultured cells was detected by immunofluorescence cytochemical staining to identify cell type and assess the purity of fibroblasts. The proliferation activity of fibroblasts was analyzed by MTT assay and drew growth curve. Cell cycle distribution was detected by flow cytometry. Results The fibroblasts were cultured for 48 hours, and more than 95% adherent cells were obtained by collagen protease separation. At the same time, the cells began to grow from the adherent wall at the edge of the tissue block. A large number of fibroblasts adherently grew on day 5. The cells grew rapidly, and on day 7, the layers of proliferating cells were covered in petri dishes. A small number of epithelial cells were mixed in fibroblasts obtained from the tissue-adhesive method, while the vimentin positive rate of cells isolated by collagenase digestion method was nearly 100%, almost all of which were fibroblasts. Conclusion Both collagenase digestion and tissue-adhesive method are rapid, economical and effective methods for obtaining dermal fibroblasts. Collagenase digestion method can prevent epithelial cell contamination more effectively, and the isolated dermal fibroblasts have good proliferative capacity. PMID- 30463656 TI - [STAT4 rs7574865 polymorphism is associated with the susceptibility of rheumatoid arthritis in Wuling mountain area]. AB - Objective To investigate the association of single nucleotide polymorphisms (SNPs) of signal transducer and activator of transcription 4 (STAT4) rs7574865 and miRNA146a rs2910164 with rheumatoid arthritis (RA) in Wuling mountain area. Methods 287 RA patients and 305 age-matched healthy controls were included. The rs7574865 and rs2910164 SNPs of RA patients and control subjects were measured by multiplex PCR combined with high throughput sequencing(HI-SNP). The distributions of genotype and allele frequencies in the two groups were analyzed by the Chi squared test, and also the relationship between these two SNPs and the risk of RA, rheumatoid factor (RF) and anti-cyclic citrullinated peptide (ACCP) antibody were investigated. Results Data showed that the genotype distribution of rs7574865 were significantly different between the cases and controls. The TT genotype and the T allele from rs7574865 were all associated with the risk of RA (OR=2.42, 95%CI: 1.37-4.28; OR=1.43, 95%CI: 1.12-1.82), and dominant and recessive models showed similar results. While, we found miRNA146a rs2910164 has no role in susceptibility to RA, and there was no statistically significant association between the SNPs of rs7574865 and rs2910164 and the level of RF or ACCP antibody. Conclusion STAT4 rs7574865 polymorphism is associated with RA, but not with RF or ACCP antibody levels in Wuling mountain area. In contrast, miRNA146a rs2910164 polymorphism is not correlated with RA. PMID- 30463657 TI - [The decreased number of regulatory T cells in peripheral blood is accompanied by decreased autophagy in pediatric immune thrombocytopenia]. AB - Objective To detect the number of CD4+CD25+FOXP3+ regulatory T cells (Tregs) and the expression of autophagy related proteins in autoantibody positive children with immune thrombocytopenia (ITP). Methods Flow cytometry was used to sort Tregs in peripheral blood of newly-diagnosed ITP children or healthy donor controls, the expression of autophagy related gene ATG5 or ATG7 was calculated by their mean fluorescence intensity, and the phosphorylation of protein kinase B (AKT) or extracellular signal regulatory kinase (ERK) of CD4+CD25+ Tregs was determined by Western blot analysis. Results Compared with healthy donor control, the number of Tregs in ITP children decreased significantly, the expression of ATG5 and ATG7 decreased, and the phosphorylation of AKT and ERK decreased significantly. Conclusion In newly-diagnosed auto-antibody positive ITP children, the number of Tregs is reduced, and the levels of protein phosphorylation related to the proliferation and autophagy of Tregs is decreased. PMID- 30463658 TI - [Development and application of monoclonal antibodies against human free prostate specific antigen(f-PSA)]. AB - Objective Construction of monoclonal antibody cell lines against human free prostate specific antigen (f-PSA), and establish double antibody sandwich CLIA for human f-PSA. Methods Two hybridoma cell lines secreting anti-f-PSA mAb were obtained by hybridoma technique. The cell lines were expanded by spinner bottles and purified by affinity purification, from which the antibodies were tested for antibody titers, specificity, epitopes by ELISA and affinity by surface plasmon resonance. Establishment, analysis and performance evaluation of a double mAbs sandwich CLIA system using standard curve quantitative method. In total 426 (130 gray area) clinical specimens were used for system comparison between our assay and Roche f-PSA assay. Results anti- f-PSA(f-10-1, f-14-1) mAbs were obtained. The CLIA system with detection range of 0.1-30 ng/mL, sensitivity of 0.05 ng/mL, relative detection deviation of +/-5% and not cross-react with the tumor marker AFP, CEA and c-PSA. The correlation coefficient of our reagent with Roche's was 0.99. The positive coincidence rate, negative coincidence rate and total coincidence rate of gray area specimens were all higher than 90%. Conclusion mAbs against human f-PSA were successfully prepared, and the double mAbs sandwich CLIA for specific quantitative detection of human f-PSA was established. PMID- 30463659 TI - [Preparation and identification of anti-HaCHT4 mouse polyclonal antibody]. AB - Objective The group IV chitinase from Helicoverpa armigera (HaCHT4)was expressed in prokaryotic and its polyclonal antibody against HaCHT4 was prepared. Methods The fusion protein His-HaCHT4 was expressed in E.coli and purified the target protein by Ni-column, and immunized the mice by footpad and subcutaneous injection. The titer of polyclonal antibody against His-HaCHT4 was determined by ELISA after four immunizations. The immunological specificity of the anti His HaCHT4 was assayed by Western blot analysis. Results Fusion protein His-HaCHT4 was purified successfully and the titer of mouse anti His-HaCHT4 polyclonal antibody was higher than 1:204 800. The results of Western blot showed that the anti His-HaCHT4 polyclonal antibody was able to bind the fusion protein His HaCHT4, and also specifically recognize the natural HaCHT4 in Helicoverpa armigera, but not the protein in Tenebrio molitor. Conclusion His-HaCHT4 was successfully expressed in prokaryotic and purified, and its mouse anti His-HaCHT4 polyclonal antibody was prepared. PMID- 30463660 TI - Improving the utility of multisource feedback for medical consultants in a tertiary hospital: a study of the psychometric properties of a survey tool. AB - Objective The aim of this study was to investigate the psychometric properties of a multisource review survey tool for medical consultants in an Australian health care setting.Methods Two sets of survey data from a convenience sample of medical consultants were analysed using SPSS, comprising self-assessment data from 73 consultants and data from 734 peer reviewers. The 20-question survey consisted of three subscales, plus an additional global question for reviewers. Analysis included the reliability coefficient (alpha) of the scale and the three subscales, inter-rater reliability or agreement and validity of the model, correlation between the single global question, the total performance score and the three survey subfactors (Pearson's), interrater agreement (rWG(J)), the optimal number of peer reviewers required and model-based reliability (rho).Results The global question, total performance score and the three subfactors were strongly correlated (general scale r = 0.81, clinical subscale r = 0.78, humanistic subscale r =0.74, management subscale r = 0.75; two-tailed P < 0.01 for all). The scale showed very good internal consistency, except for the five-question management subscale. Model-based reliability was excellent (rho = 0.93). Confirmatory factor analysis showed the model fit using the 20-item scale was not satisfactory (minimum discrepancy/d.f. = 7.70; root mean square error of approximation = 0.10; comparative fit index = 0.79; Tucker-Lewis index = 0.76). A modified 13-item model provided a good fit. Using the 20-item scale, a 99% level of agreement could be achieved with eight to 10 peer reviewers; for the same level of agreement, the number of reviewers increased to >10 using a revised 13 item scale.Conclusions Overall, the 20-item multisource review survey tool showed good internal consistency reliability for both self and peer ratings; however, further investigation using a larger dataset is needed to analyse the robustness of the model and to clarify the role that a single global question may play in future multisource review processes.What is known about the topic? Defining and measuring skills and behaviours that reflect competence in the health setting have proven to be complex, and this has resulted in the development of specific multisource feedback surveys for individual medical specialities. Because little literature exists on multisource reviews in an Australian context, a pilot study of a revised survey tool was undertaken at an Australian tertiary hospital.What does this paper add? The aim of this study was to investigate the psychometric properties of a generic tool (used across specialities) by assessing the validity, reliability and interrater reliability of the scale and to consider the contribution of a single global question to the overall multisource feedback process. This study provides evidence of the validity and reliability of the survey tool under investigation. The strong correlation between the global item, the total performance score and the three subfactors suggests that this is an area requiring further investigation to determine the role that a robust single global question like this may play in future multisource review surveys. Our five question management skills subscale provides answers to questions relevant to the specific organisation surveyed, and we anticipate that it may serve to stimulate further exploration in this area.What are the implications for practitioners? The survey tool may provide a valid and reliable basis for performance review of medical consultants in an Australian healthcare setting. PMID- 30463661 TI - Allied health pre-entry student clinical placement capacity: can it be sustained? AB - Objective Meeting the demand for clinical placements in an environment of increasing university cohort growth and changes in health service delivery models is challenging. This paper describes the outcomes of a quality review activity designed to gain key stakeholder perspectives on the enablers and barriers to sustaining effort to placement provision and reports on: (1) measures used to determine the effect of a jurisdiction-wide initiative in clinical education for five allied health professions; (2) outcomes of data related to key factors affecting placement supply and demand; and (3) qualitative perspectives from management, workforce and university stakeholders on placement sustainability.Methods This study reviewed clinical placement, staff full-time equivalent numbers, university program and student cohort data for five allied health professions from 2013 to 2016. In addition, qualitative response data from key stakeholder surveys was analysed thematically.Results In the study period, the rate of growth in placement offers did not match that of university program student numbers and full-time equivalent staff numbers. All stakeholders agreed that sustaining placement provision is enabled by collaboration, continuation of management support for dedicated clinical education staff, a focus on clinical education capacity building activities, outcome data reporting and statewide profession-specific governance, including leadership positions. Collaborations and networks across health and education sectors were reported to enhance efficiency, minimise duplication, streamline communication and support information and resource sharing within and across professions and stakeholders, ultimately sustaining placement provision. Identified barriers to sustainability centred on resourcing and the continued increasing demand for placements.Conclusion Sustaining pre-entry student placements requires stakeholder flexibility and responsiveness and is underpinned by collaboration, information and resource sharing. Dedicated clinical education positions were highly valued and seen as a key contributor to placement sustainability.What is known about the topic? The increasing demand for student placements and strategies used to enhance placement capacity are well known. To date, there have been limited studies investigating cross-sectoral trends and health service enablers and barriers to sustaining responses to placement demand.What does this paper add? This paper describes outcomes of a clinical placement capacity building initiative within public health services, developed from a unique opportunity to provide funding through an industrial agreement. It presents key allied health staff and university partner perspectives on enablers to sustaining placement supply in an environment of increasing placement demand.What are the implications for practitioners? This paper demonstrates that key enablers for the sustainability of placement provision are collaboration between university and health sectors, continuation of management support for dedicated clinical education staff, outcome data reporting and statewide profession-specific governance and leadership. It supports current practices of profession-specific and interprofessional clinical education resource and strategy development and the sharing of expertise for sustained placement provision. PMID- 30463662 TI - Patient out-of-pocket medical expenses over 2 years among Queenslanders with and without a major cancer. AB - Medical out-of-pocket costs paid by patients can be problematic when it adversely affects access to care. Survey research involving patients with out-of-pocket expenses may have selection biases, so accurate estimates are unknown. During 2010-11, 419 participants from the QSkin Sun and Health Study (n=43794) had a confirmed diagnosis of either melanoma, prostate, breast, colorectal or lung cancer. These were matched to a general population group (n=421) and a group of high users of GP services (n=419). Medical fees charged and out-of-pocket medical expenses for Medicare services were analysed. Over 2 years, three-quarters of individuals with cancer paid up-front provider fees of up to A$20551 compared with A$10995 for the high GP user group and A$6394 for the general population group. Out-of-pocket expenses were significantly higher for those with cancer (mean A$3514) compared with the high GP-user group (mean A$1837) and general population group (A$1245). Highest expenses were for therapeutic procedures (mean A$2062). Older individuals, those with poor perceived health or private health insurance had the highest costs. Regardless of private insurance status, patients with one of the main five cancers pay significantly higher out-of-pocket costs for health care compared with those without cancer. PMID- 30463663 TI - Re: Liselotte M.S. Boeve, Maarten C.C.M. Hulshof, Andre N. Vis, et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2018.09.008: Future Steps for Definitive Therapy in Metastatic Prostate Cancer: Lessons from the HORRAD Trial. PMID- 30463664 TI - What Is the Current Role of beta3-Adrenergic Receptor Agonists and How Do They Work? PMID- 30463665 TI - Peer effects on low-income children's learning and development. AB - Using data from a large study of 78 high-quality Head Start classrooms in 12 sites across the U.S., this study examined whether peers' receptive vocabulary skills and teacher-reported social-emotional (S-E) functioning (i.e., behavior problems and self-regulation) measured at the beginning of the preschool year were related to children's gains in these three domains over a school year. Analyses included over 75% of the children in each classroom and produced three noteworthy findings. First, children in classrooms where average peers had higher behavior problems demonstrated increased teacher-reported behavior problems themselves at the end of the year. Second, children in classrooms where average peers had higher self-regulation skills demonstrated larger gains in teacher reported self-regulation skills at the end of the school year. Third, peers' higher baseline self-regulation skills were found to be associated with children's higher self-regulation in spring, especially when children began the school year with higher levels of self-regulation. This finding indicates that children who have higher baseline self-regulation may be better positioned to benefit from their peers' high self-regulation in developing their own self regulation skills. In contrast, no evidence was found that peers' baseline receptive vocabulary skills were related to children's receptive vocabulary gains over a school year. Additionally, no significant cross-domain peer effects were found between peers' baseline S-E functioning and children's receptive vocabulary gains nor peers' baseline receptive vocabulary skills and children's S-E development over a school year. Implications of these findings for classroom practice and further research are discussed. PMID- 30463666 TI - Cognitive profile analysis in school psychology: History, issues, and continued concerns. AB - Intelligence testing remains a fixture in school psychology training and practice. Despite their popularity, the use of IQ tests is not without controversy and researchers have long debated how these measures should be interpreted with children and adolescents. A controversial aspect of this debate relates to the utility of cognitive profile analysis, a class of interpretive methods that encourage practitioners to make diagnostic decisions and/or treatment recommendations based on the strengths and weaknesses observed in ability score profiles. Whereas numerous empirical studies and reviews have challenged long-standing assumptions about the utility of these methods, much of this literature is nearly two decades old and new profile analysis methods (e.g., XBA, PSW) have been proffered. To help update the field's understanding of these issues, the present review traces the historical development of cognitive profile analysis and (re)introduces readers to a body of research evidence suggesting new and continued concerns with the use of these methods in school psychology practice. It is believed that this review will serve as a useful resource to practitioners and trainers for understanding and promoting a countering view on these matters. PMID- 30463667 TI - Sources of individual differences in young Chinese children's reading and mathematics skill: A longitudinal study. AB - This study investigated the longitudinal associations between four key elements of school readiness-receptive vocabulary, socioemotional behavior, behavioral self-regulation, and approaches to learning-and individual differences in young children's reading and mathematics trajectories. Chinese children (N = 588) were tested three times between the ages of five and six on their Chinese reading and mathematics skills, and their receptive vocabulary, problem behavior, behavioral self-regulation, and approaches to learning (competence motivation, learning strategy, and attention/persistence) were assessed at five years of age. Latent growth modeling revealed that receptive vocabulary and behavioral self-regulation played unique roles in predicting the levels of Chinese reading (vocabulary: beta = 0.15, p = .023; self-regulation: beta = 0.16, p = .001) and mathematics skills (vocabulary: beta = 0.25, p < .001; self-regulation: beta = 0.36, p < .001). Problem behavior and competence motivation were associated with the levels of mathematics skills (problem behavior: beta = -0.06, p = .046; competence motivation: beta = 0.16, p < .001) but not those of reading skills. Moreover, competence motivation predicted the growth rate of Chinese reading skills (beta = 0.18, p = .015). The findings extend the current literature by explicating the independent contributions made by early school readiness skills to individual differences in young Chinese children's acquisition of reading and mathematics skills. PMID- 30463668 TI - A systematic review of the Second Step program. AB - This article presents findings from a meta-analysis of 24 primary research studies on the Second Step social emotional learning program. Program content knowledge, outcomes related to prosociality, and outcomes related to antisociality are examined as outcome categories in randomized controlled trials, quasi-experimental studies and, separately, single-group repeated measures design studies. Students participating in Second Step demonstrated increased knowledge of program content and increased prosocial outcomes. Participation in the program was not associated with significant changes in antisocial outcomes. Evidence suggests the possibility of publication bias in studies reporting knowledge outcomes but no evidence of publication bias in studies reporting prosocial and antisocial outcomes. This study complements broader meta-analyses on SEL programs and aims to inform local decision making by providing an estimate of the overall effects of the Second Step program on a variety of student outcomes. PMID- 30463669 TI - Meta-analysis of the relationship between academic achievement and broad abilities of the Cattell-horn-Carroll theory. AB - Interpretation of intelligence tests has changed over time, from a focus on the elevation of general ability in the early 1900s, to the shape and/or scatter of subtest and index scores in the mid-1900s to the early 2000s, and back to elevation today. The primary emphasis of interpretation now, however, is widely recommended to be on normative strengths and weaknesses of scores reflecting broad and narrow abilities in the Cattell-Horn-Carroll (CHC) theory (Schneider & McGrew, 2012). Decisions about which abilities are important to assess for the diagnosis of learning difficulties are based largely on literature reviews by Flanagan, Ortiz, Alfonso, and Mascolo (2006) and McGrew and Wendling (2010). These were narrative research syntheses, however, and did not attempt to estimate the magnitude of the relations between CHC abilities and academic achievement. The purpose of this study, therefore, was to conduct a meta-analysis to determine the effect size for these relations across age groups. Results of our analyses found that psychometric g and one or more broad cognitive abilities are substantially related to each area of academic achievement. Across all achievement domains and ages, g had by far the largest effect, with a mean effect size of r2 = 0.540. In fact, psychometric g explained more variance in academic outcomes than all broad abilities combined. Most broad abilities explained less than 10% of the variance in achievement and none explained more than 20%. Some age-related changes in cognitive ability-achievement relations were also observed. In sum, results of our meta-analysis support the interpretation of the overall score on intelligence tests as a measure of psychometric g for diagnosing difficulties in reading and mathematics, but only the interpretation of index scores measuring Comprehension-Knowledge (Gc) when diagnosing difficulties in reading. Implications of these results for research and practice are discussed. PMID- 30463670 TI - Assessing malleable social-psychological academic attitudes in early adolescence. AB - Although it is important to accurately assess and promote student achievement, it is also critical to accurately assess and promote student social and emotional well-being and positive attitudes about school. Recent research has shown the promise of school-based interventions to improve certain student academic attitudes but has also raised concerns about a lack of reliable measures of these attitudes for early adolescents. We compiled the Malleable Social-Psychological Academic Attitudes (MSPAA) survey to measure school trust, social belonging, evaluation anxiety, self-complexity, locus of control, and identification with school. We adapted MSPAA measures to make them more appropriate for early adolescents in the school context, assessed the measurement properties of the MSPAA survey, and examined how student responses differed based on various demographic factors. We found that this brief survey reliably measured these constructs among early adolescents (N = 2158). Additionally, differences by grade level, school context, gender, and racial group revealed insightful patterns of variation that have implications for social and psychological theory, as well as for practices in schools. We close by suggesting further study of this survey for use among education researchers and within schools. PMID- 30463671 TI - Inclusive classroom norms, children's sympathy, and intended inclusion toward students with hyperactive behavior. AB - As the classroom represents an important social context for the development of out-group attitudes, the current study investigated the role of inclusive classroom norms for students' attitudes toward hyperactive peers. The study included 1209 Swiss children from 61 school classes who were surveyed in the fifth grade (T1) and in the sixth grade (T2) (MageT1 = 11.55 years, MageT2 = 12.58 years). Students' attitudes toward hyperactive children was assessed by self-reports on students' sympathy and intended inclusion toward hypothetical children who show hyperactive behavior. Moreover, students rated their classmates' inclusive attitudes. Analyses with an autoregressive multilevel path model revealed that inclusive classrooms norms in the fifth grade predicted students' sympathy and intended inclusion toward hyperactive children in the sixth grade. The results implicate that group-level analyses are important in order to explain hyperactive children's peer group problems. PMID- 30463672 TI - Racial/ethnic measurement invariance of the School Success Profile (SSP)'s future orientation scale. AB - Future orientation (FO) has received increasing attention for its positive effects on adolescent well-being and successful transition to adulthood. Although numerous measures of FO exist, most are not developmentally appropriate for diverse populations of adolescents, do not assess all theoretical components of FO, and/or were not developed for administration in schools. Additionally, the invariance of existing measures across racial/ethnic groups has not been examined using appropriately rigorous procedures. Using data from 2575 students in grades 6-9, this study examined the psychometric quality and measurement invariance of the FO scale on the School Success Profile (SSP) across African American (34.8%), Latino (27.0%), and European American (38.1%) subsamples. A one-factor model fit the data well in all three groups. Analyses identified only a small number of noninvariant parameters, supporting the conclusion that the scale has partial measurement invariance across the three groups. On average, African Americans had significantly higher levels of FO than the other two groups; mean scores for Latinos and European Americans were lower and statistically equivalent to each other. Construct validity of the SSP FO scale was also supported by findings of medium-sized relationships of FO scores to scores on five other constructs: low grades, school engagement, parent educational support, psychological distress, and school behavior. Multiple group tests of the magnitude and direction of the validity relationships indicated statistical equivalence across the three groups. Results support the use of the SSP FO scale by school psychologists to assess FO and to evaluate the effects of interventions targeting FO as a promoter of well being and school success. PMID- 30463673 TI - Critical evaluation of electron transfer kinetics in P700-FA/FB, P700-FX, and P700-A1 Photosystem I core complexes in liquid and in trehalose glass. AB - This work aims to fully elucidate the effects of a trehalose glassy matrix on electron transfer reactions in cyanobacterial Photosystem I (PS I). Forward and backward electron transfer rates from A1A- and A1B- to FX, and charge recombination rates from A0-, A1B-, A1A-, FX-, and [FA/FB]- to P700+ were measured in P700-FA/FB complexes, P700-FX cores, and P700-A1 cores, both in liquid and in a trehalose glassy matrix at 11% humidity. By comparing CONTIN resolved kinetic events over 6 orders of time in increasingly simplified versions of PS I at 480 nm, a wavelength that reports primarily A1A-/A1B- oxidation, and over 9 orders of time at 830 nm, a wavelength that reports P700+ reduction and A0 oxidation, assignments could be made for nearly all of the resolved kinetic phases. Trehalose-embedded PS I samples demonstrated partially arrested forward electron transfer. The fractions of complexes in which electron transfer did not proceed beyond A0, A1 and FX were 53%, 16% and 22%, respectively, with only 10% of electrons reaching the terminal FA/FB clusters. The ~10 MUs and ~150 MUs components in both liquid and trehalose-embedded PS I were assigned to recombination between A1B- and P700+ and between A1A- and P700+, respectively. The kinetics and amplitudes of these resolved kinetic phases in liquid and trehalose-embedded PS I samples could be well-fitted by a kinetic model that allowed us to calculate the asymmetrical contribution of the A1A- and A1B- quinones to the electrochromic signal at 480 nm. Possible reasons for these effects are discussed. PMID- 30463674 TI - A new mechanistic model for an O2-protected electron-bifurcating hydrogenase, Hnd from Desulfovibrio fructosovorans. AB - The genome of the sulfate-reducing and anaerobic bacterium Desulfovibrio fructosovorans encodes different hydrogenases. Among them is Hnd, a tetrameric cytoplasmic [FeFe] hydrogenase that has previously been described as an NADP specific enzyme (Malki et al., 1995). In this study, we purified and characterized a recombinant Strep-tagged form of Hnd and demonstrated that it is an electron-bifurcating enzyme. Flavin-based electron-bifurcation is a mechanism that couples an exergonic redox reaction to an endergonic one allowing energy conservation in anaerobic microorganisms. One of the three ferredoxins of the bacterium, that was named FdxB, was also purified and characterized. It contains a low-potential (Em = -450 mV) [4Fe4S] cluster. We found that Hnd was not able to reduce NADP+, and that it catalyzes the simultaneous reduction of FdxB and NAD+. Moreover, Hnd is the first electron-bifurcating hydrogenase that retains activity when purified aerobically due to formation of an inactive state of its catalytic site protecting against O2 damage (Hinact). Hnd is highly active with the artificial redox partner (methyl viologen) and can perform the electron bifurcation reaction to oxidize H2 with a specific activity of 10 MUmol of NADH/min/mg of enzyme. Surprisingly, the ratio between NADH and reduced FdxB varies over the reaction with a decreasing amount of FdxB reduced per NADH produced, indicating a more complex mechanism than previously described. We proposed a new mechanistic model in which the ferredoxin is recycled at the hydrogenase catalytic subunit. PMID- 30463675 TI - Differential evolution of cerebral and cerebellar fossae in recent Homo: A new methodological approach. AB - The endocranium shows the influence of the shape and development of brain tissues and overall brain modifications. During the late Upper Pleistocene and Holocene smaller brains appeared and the higher position of endinion relative to inion might indicate changes in cerebellar and occipital lobes. In previous studies, the depths of the cerebral and cerebellar fossae were not specifically considered; new tools for quantitatively measuring these irregular, problematic curved areas need to be developed. This paper's main objective is to investigate to what degree changes in the fossae's depths of extant humans have occurred with respect to fossil anatomically modern humans (AMH) and older Homo species. The proportions of the occipital and nuchal planes are compared measuring the inner and outer surfaces of the bone. Additionally, this paper proposes a quantitative geometric methodology based on endocranial landmarks that create a plane with which to measure the position of the deepest part of the fossa: it represents a curvature maxima - concavity - associated with local structures. The four points thus obtained could be framed in Bookstein's Type II landmarks but without biomechanical implication. Through univariate, bivariate and multivariate analyses (principal components analysis) of raw and size-corrected data we study the differential evolution in recent Homo species, which presents a more vertical occipital area than ancient fossils. Our results corroborate this derived trait; additionally, we have observed a tendency towards a relative decrease in the depth of the cerebral fossae and maintenance of the cerebellar fossae. PMID- 30463676 TI - Erratum to Gut flora-dependent metabolite trimethylamine-N-oxide accelerates endothelial cell senescence and vascular aging through oxidative stress [Free Radic. Biol. Med. 116C (2018) 88-100]. PMID- 30463677 TI - ApoB in clinical care: Pro and Con. AB - Whether apoB adds significantly to the assessment of the risk and therapy of the atherogenic dyslipoproteinemias has been vigorously contested over many years. That trapping of apoB lipoprotein particles within the arterial wall is fundamental to the initiation and maturation of atherosclerotic lesions within the arterial wall is now widely accepted. At the same time, the concept that primary prevention should be based on the risk of a cardiovascular event, a measure that integrates the effects of age, sex, blood pressure, lipids and other factors, has also become widely accepted. Within the risk framework, the issue becomes whether apoB adds significantly to the assessment of risk. On the other hand, it can be argued that the risk model undervalues how important a role that LDL and blood pressure play as causes of atherosclerosis and that when considered as causes, the importance of apoB emerges. These are the two sides of the debate that will be presented in the article that follows: one will highlight the pros of measuring apoB, the second the cons. The reader can make up his or her mind which side of the issue they favour. PMID- 30463678 TI - Mechanisms involved in proton pump inhibitors-induced increases in ischemic events. PMID- 30463679 TI - Novel Roles for SUMOylation in Cellular Plasticity. AB - Cell fate transitions involve rapid changes in gene expression patterns, yet the role of post-translational modifications in these processes remains underexplored. A recent study identifies SUMOylation as a guardian of cell identity that acts during differentiation and reprogramming by reinforcing active enhancers and maintaining silenced heterochromatin in a context-specific manner. PMID- 30463680 TI - Cetuximab Alone or With Irinotecan for Resistant KRAS-, NRAS-, BRAF- and PIK3CA wild-type Metastatic Colorectal Cancer: The AGITG Randomized Phase II ICECREAM Study. AB - BACKGROUND: The Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation (ICECREAM) study assessed the efficacy of cetuximab monotherapy compared with cetuximab combined with chemotherapy for quadruple wild-type (KRAS, NRAS, BRAF, or P13KCA exon 20) metastatic colorectal cancer. PATIENTS AND METHODS: Patients were enrolled in an open-label, multicenter, phase II trial and randomly assigned to cetuximab 400 mg/m2, then 250 mg/m2 cetuximab weekly, with or without irinotecan 180 mg/m2 every 2 weeks. The primary endpoint was 6-month progression free survival; secondary endpoints were response rate, overall survival, toxicity, and quality of life. RESULTS: From 2012 to 2016, 48 patients were recruited. Two were ineligible, and 2 were not evaluable for response. Characteristics were balanced, except gender (male, 62% vs. 72%) and primary sidedness (left, 95% vs. 68%). For cetuximab compared with cetuximab-irinotecan, progression-free survival was 14% versus 41% (hazard ratio, 0.39; 95% confidence interval, 0.20-0.78; P = .008); response rate was 10% (2 partial responses) versus 38% (1 complete, 8 partial); P = .04. Grade 3 to 4 toxicities were less with cetuximab monotherapy (23% vs. 50%); global and specific quality of life scores did not differ. CONCLUSION: In comparison with cetuximab alone, cetuximab plus irinotecan increases the response rate and delays progression in irinotecan resistant RAS wild-type colorectal cancer. This echoes data from molecularly unselected patients. PMID- 30463681 TI - The spectrum of the dyslipidemia in Colombia: The PURE study. AB - BACKGROUND: Dyslipidemia is a major risk factor for cardiovascular diseases (CVD). Worldwide, a third of ischemic heart disease is due to abnormal cholesterol levels and it is the most common cause of cardiovascular deaths in Colombia. In Colombia, no representative, large-scale study has assessed the prevalence of dyslipidemia. The aim of the present analysis was to identify the magnitude of the problem in Colombia, a middle-income-country with large regional, geographic, and socio-economical differences. MATERIAL AND METHODS: The sample comprised 6628 individuals aged 35 to 70 years (mean age 50.7 years, 64.1% women) residing in the four Colombian regions. RESULTS: The overall prevalence of dyslipidemia was 87.7% and was substantially higher among participants older than 50 years, male, rural residents, and those with a lower level of education (66.8%), and with a lower income (66.4%). High non HDL-c was the most common abnormality (75.3%). The values of total cholesterol and non-HDL-cholesterol were higher in areas with the lowest health needs index than in the areas with intermediate and highest health need index, the isolated HDL-c value was much lower. CONCLUSION: Colombia has a high prevalence of abnormalities of the lipid profile. The causes of the high rates of dyslipidemia were not well define in this study, but were more common in rural and poorer regions and among those with lower socio-economical status. Strategies to tackle the adverse lipid profile to reduce CVD are needed in Colombia, particularly in rural areas and among the areas with the higher health need index. PMID- 30463683 TI - Pattern and impact of metastatic cardiophrenic lymph nodes in advanced epithelial ovarian cancer. AB - BACKGROUND: Cardiophrenic lymph nodes (CPLN) define FIGO stage IVB disease. We evaluate the pattern of CPLN metastases, their prognostic impact and the potential role of CPLN resection in patients with epithelial ovarian cancer (EOC). METHODS: Analysis of 595 consecutive patients with EOC treated in the period 01/2011-05/2016. CT scans were re-reviewed by two radiologists. Positive CPLN were defined as >=5 mm in the short-axis diameter. The role of CPLN resection was evaluated in a case-control matched-pair analysis. RESULTS: Of 595 patients 458 had FIGO stage IIIB-IV disease. We excluded patients undergoing interval surgery (n = 54), without debulking surgery (n = 32) and without sufficient pre-operative imaging (n = 22), resulting in a study cohort of 350 patients. Of these, 133 (37.9%) had negative CPLN and 217 (62.0%) had radiologically positive CPLN. In patients with postoperative residual tumor, enlarged CPLN had no impact on survival. In patients with complete resection (n = 223), 98 (44.0%) had negative CPLN and a 5-year OS of 69% and a 5-year PFS of 41%; in contrast, in the 125 patients (56.0%) with positive CPLN, 5-year OS was 30% and 5-year PFS was 13%. In 52 patients we resected CPLN. The matched-pair case-control analysis did not demonstrate any significant impact on survival of CPLN resection. CONCLUSION: CPLN metastases are associated with impaired PFS and OS in patients with macroscopically completely resected tumor. Intraabdominal residual tumor has a greater prognostic impact than positive CPLN. The impact of the resection of CPLN remains unclear. PMID- 30463682 TI - Catheter ablation for fascicular ventricular tachycardia: A systematic review. AB - INTRODUCTION: Catheter ablation has been evaluated as treatment for fascicular ventricular tachycardia (FVT) in several single-centre cohort studies, with variable results regarding efficacy and outcomes. METHODS: A systematic search was performed on PubMed, EMBASE and Cochrane database (from inception to November 2017) that included studies on FVT catheter ablation. RESULTS: Thirty-eight observational non-controlled case series comprising 953 patients with FVT undergoing catheter ablation were identified. Three studies were prospective and only 5 were multi-centre. Eight-hundred and eighty-four patients (94.2%) had left posterior FVT, 25 (3.4%) left anterior FVT and 30 (2.4%) other forms. In 331 patients (41%), ablation was performed in sinus rhythm (SR). The mean follow-up period was 41.4 +/- 10.7 months. Relapse of FVT occurred in 100 patients (10.7%). Among the 79 patients (8.3%) requiring a further procedure after the index ablation, 19 (2%) had further FVT relapses. Studies in which ablation was performed in FVT had similar success rate after multiple procedures compared to ablation in SR only (95.1%, CI95% 92.2-97%, I2 = 0% versus 94.8%, CI95% 87.6 97.9%, I2 = 0%, respectively). Success rate was numerically lower in paediatric only series compared to non-paediatric cases (90.0%, CI95% 82.1-94.6%, I2 = 0% versus 94.3%, CI95% 92.2-95.9%, I2 = 0%, respectively). CONCLUSION: Data derived from observational non-controlled case series, with low-methodological quality, suggest that catheter ablation is a safe and effective treatment for FVT, with a 93.5% success rate after multiple procedures. Ablation during FVT represents the first-line and most commonly used approach; however, a strategy of mapping and ablation during SR displayed comparable procedural results to actively mapping patients in FVT and should therefore be considered in selected cases where FVT is not inducible. PMID- 30463684 TI - [Elderly patients with coronary artery disease are at high bleeding risk]. AB - Bleeding complications are frequent in coronary artery disease patients and are associated with increased mortality. Among clinical factors increasing the risk of bleeding, age appears to be a major determinant, whatever the clinical presentation (stable disease, acute coronary syndrome, PCI). Evidence of the role of age comes from the weight given to age in most existing bleedingrisk scores. PMID- 30463685 TI - [Radial approach in the elderly]. AB - Due to the steady increase in life expectancy, the number of patients over 80 years of age proposed for coronary angioplasty is increasing significantly. The elderly patient is a patient at high cardiovascular risk and high risk of bleeding; whose severity of prognosis depends of comorbidities. The radial approach presents particularities and technical difficulties that have to be known in this part of the population, but reduce vascular and hemorrhagic complications, as well as mortality. Because of greater safety, the radial approach is therefore the first choice for the elderly. PMID- 30463686 TI - [Treatment of chronic thromboembolic pulmonary hypertension in elderly patients]. AB - AIM OF THE STUDY: To establish efficacy and security of invasive treatments for chronic thromboembolic pulmonary hypertension (CTEPH) in elderly patients (>=80 years old): pulmonary endarterectomy (PEA) and balloon pulmonary angioplasty (BPA). PATIENTS AND METHODS: Between 2014 and 2017, 549 CTEPH patients were addressed to our hospital for PEA (364 patients) or BPA (225). From this total, patients 80 years old and over were: 17 treated by PEA and 21 by BPA. Demographic characteristics as well as hemodynamic parameters, results and complications were compared for both groups (Young - Y - versus Old - O). RESULTS: Elderly BPA patients presented a higher functional class (mean O: 3,16 versus Y: 2,73; P=0,001), with similar hemodynamics parameters compared with the younger patients. Indication for BPA in the elderly was the presence of comorbidities contraindicating surgery in 33% of cases vs. 9,3% in the younger group (P=0,005). Response to treatment was comparable in both groups with significant reductions of mPAP, PVR and improvement of functional class. Complications rate was alike between groups for hemoptysis, reperfusion lesions or mortality, with the exception of a higher incidence of contrast-induced nephropathy, without need for dialysis, in the elderly group (O: 8,4% versus 2,6%; P=0,010). Elderly PEA patients were more often male (O: 76,5% versus Y: 50,1%; P=0,034) and with a lower creatinine clearance (O: 57,6+/-13,4 versus Y: 72,2+/-21,2mL/min/m2; P=0,004). Functional class, hemodynamics, surgical times and in-hospital stay was similar between groups. There is a non-significant trend towards higher in hospital mortality in the elderly group, CONCLUSIONS: In our experience, treatment of CPC PE in elderly patients, either by PEA or BPA is effective with acceptable complication rates. PMID- 30463687 TI - MicroRNA-98 promotes drug resistance and regulates mitochondrial dynamics by targeting LASS2 in bladder cancer cells. AB - MicroRNA-98(miR-98) has been shown to be critical for tumorigenesis, however its involvement in bladder cancer are unclear. The present study aims to investigate the expression, biological roles and potential mechanisms of miR-98 in human bladder cancer. We found that miR-98 was upregulated in bladder urothelial carcinoma tissues compared with adjacent normal tissues. In addition, miR-98 expression was higher in bladder cancer cell lines than in uroepithelial cell line SV-HUC-1. Functional studies revealed that miR-98 mimic promoted proliferation of T24 cells while miR-98 inhibitor inhibited proliferation of BIU 87 cells. Moreover, miR-98 mimic increased cisplatin/doxorubicin resistance and inhibited apoptosis in T24 cells, while miR-98 inhibitor decreased chemoresistance and facilitated apoptosis in BIU-87 cells. Further experiments using MitoTracker and JC-1 staining showed that miR-98 could regulate mitochondrial fission/fusion balance and mitochondrial membrane potential. Western blot showed that miR-98 upregulated cyclin D1, p-Drp1 and Drp1. Using luciferase reporter assay, we demonstrated that LASS2 acted as a direct target of miR-98. LASS2 overexpression induced mitochondrial fusion and downregulated mitochondrial potential, with decreased p-Drp1 status. Additionally, LASS2 siRNA abrogated the effects of miR-98 mimic on Drp1phosphorylation and chemoresistance. We also found a negative correlation between LASS2 and miR-98 in bladder cancer tissues. In conclusion, our study demonstrates that miR-98 targets LASS2 and regulates bladder cancer chemoresistance through modulation of mitochondrial function. PMID- 30463688 TI - Toluidine blue staining for cell and tissue biology applications. AB - Toluidine blue (TB) staining either alone or in association with other methodologies has the potential to answer a variety of biological questions regarding the human, animal and plant tissues or cells. In this brief review, we not only report the primary use of TB to detect the anionic substrates and availability of their binding sites, but also unveil the resulting applications of TB staining in biological research. Among these applications, the uses of TB staining to identify the changes in chromatin DNA-protein complexes, nucleolus location, and extracellular matrix proteoglycan complexes associated with different physiological and pathological events are described. The usefulness of TB staining to monitor the effects elicited by environmental insults on chromatin and intercalation of drugs into the DNA is also included. PMID- 30463689 TI - Inhibition of CYP2E1 attenuates myocardial dysfunction in a murine model of insulin resistance through NLRP3-mediated regulation of mitophagy. AB - Insulin resistance leads to myocardial contractile dysfunction and deranged autophagy although the underlying mechanism or targeted therapeutic strategy is still lacking. This study was designed to examine the impact of inhibition of the cytochrome P450 2E1 (CYP2E1) enzyme on myocardial function and mitochondrial autophagy (mitophagy) in an Akt2 knockout model of insulin resistance. Adult wild type (WT) and Akt2-/- mice were treated with the CYP2E1 inhibitor diallyl sulfide (100 mg/kg/d, i.p.) for 4 weeks. Cardiac geometry and function were assessed using echocardiographic and IonOptix systems. Western blot analysis was used to evaluate autophagy, mitophagy, inducible NOS (iNOS), and the NLRP3 inflammasome, a multi-protein intracellular pattern recognition receptor complex. Akt2 deletion triggered insulin resistance, compromised cardiac contractile and intracellular Ca2+ property, mitochondrial ultrastructural damage, elevated O2- production, as well as suppressed autophagy and mitophagy, accompanied with elevated levels of NLRP3 and iNOS, the effects of which were significantly attenuated or ablated by diallyl sulfide. In vitro studies revealed that the NLRP3 activator nigericin nullified diallyl sulfide-offered benefit against Akt2 knockout on cardiomyocyte mechanical function and mitophagy (using Western blot and colocalization of GFP LC3 and MitoTracker Red). Moreover, inhibition of iNOS but not mitochondrial ROS production attenuated Akt2 deletion-induced activation of NLRP3, substantiating a role for iNOS-mediated NLRP3 in insulin resistance-induced changes in mitophagy and cardiac dysfunction. In conclusion, these data depict that insulin resistance through CYP2E1 may contribute to the pathogenesis of myopathic changes including myocardial contractile dysfunction, oxidative stress and mitochondrial injury, possibly through activation of iNOS and NLRP3 signaling. PMID- 30463690 TI - Galectin-1 attenuates cardiomyocyte hypertrophy through splice-variant specific modulation of CaV1.2 calcium channel. AB - Pressure overload-induced cardiac hypertrophy occurs in response to chronic blood pressure increase, and dysfunction of CaV1.2 calcium channel involves in cardiac hypertrophic processes by perturbing intracellular calcium concentration ([Ca2+]i) and calcium-dependent signaling. As a carbohydrate-binding protein, galectin-1 (Gal-1) is found to bind with CaV1.2 channel, which regulates vascular CaV1.2 channel functions and blood pressure. However, the potential roles of Gal 1 in cardiac CaV1.2 channel (CaV1.2CM) and cardiomyocyte hypertrophy remain elusive. By whole-cell patch clamp, we find Gal-1 decreases the ICa,L with or without isoproterenol (ISO) application by reducing the channel membrane expression in neonatal rat ventricular myocytes (NRVMs). Moreover, Gal-1 could inhibit the current densities of CaV1.2CM by an alternative exon 9*-dependent manner in heterologously expressed HEK293 cells. Of significance, overexpression of Gal-1 diminishes ISO or KCl-induced [Ca2+]i elevation and attenuates ISO induced hypertrophy in NRVMs. Mechanistically, Gal-1 decreases the ISO or Bay K8644-induced phosphorylation of intracellular calcium-dependent signaling proteins deltaCaMKII and HDAC4, and inhibits ISO-triggered translocation of HDAC4 in NRVMs. Pathologically, we observe that the expressions of Gal-1 and CaV1.2E9* channels are synchronously increased in rat hypertrophic cardiomyocytes and hearts. Taken together, our study indicates that Gal-1 reduces the channel membrane expression to inhibit the currents of CaV1.2CM in a splice-variant specific manner, which diminishes [Ca2+]i elevation, and attenuates cardiomyocyte hypertrophy by inhibiting the phosphorylation of deltaCaMKII and HDAC4. Furthermore, our work suggests that dysregulated Gal-1 and CaV1.2 alternative exon 9* might be attributed to the pathological processes of cardiac hypertrophy, and provides a potential anti-hypertrophic target in the heart. PMID- 30463691 TI - Early calcium handling imbalance in pressure overload-induced heart failure with nearly normal left ventricular ejection fraction. AB - Heart failure with preserved ejection fraction (HFpEF) is a common clinical syndrome associated with high morbidity and mortality. Therapeutic options are limited due to a lack of knowledge of the pathology and its evolution. We investigated the cellular phenotype and Ca2+ handling in hearts recapitulating HFpEF criteria. HFpEF was induced in a portion of male Wistar rats four weeks after abdominal aortic banding. These animals had nearly normal ejection fraction and presented elevated blood pressure, lung congestion, concentric hypertrophy, increased LV mass, wall stiffness, impaired active relaxation and passive filling of the left ventricle, enlarged left atrium, and cardiomyocyte hypertrophy. Left ventricular cell contraction was stronger and the Ca2+ transient larger. Ca2+ cycling was modified with a RyR2 mediated Ca2+ leak from the sarcoplasmic reticulum and impaired Ca2+ extrusion through the Sodium/Calcium exchanger (NCX), which promoted an increase in diastolic Ca2+. The Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA2a) and NCX protein levels were unchanged. The phospholamban (PLN) to SERCA2a ratio was augmented in favor of an inhibitory effect on the SERCA2a activity. Conversely, PLN phosphorylation at the calmodulin dependent kinase II (CaMKII)-specific site (PLN-Thr17), which promotes SERCA2A activity, was increased as well, suggesting an adaptive compensation of Ca2+ cycling. Altogether our findings show that cardiac remodeling in hearts with a HFpEF status differs from that known for heart failure with reduced ejection fraction. These data also underscore the interdependence between systolic and diastolic "adaptations" of Ca2+ cycling with complex compensative interactions between Ca2+ handling partner and regulatory proteins. PMID- 30463692 TI - Bile acids and glucocorticoid metabolism in health and disease. AB - Glucocorticoids are regulators of stress response essential for survival. Liver disease can alter this homeostatic mechanism in patients with liver cirrhosis - a finding that might mirror the controversially discussed condition of critical illness related corticosteroid insufficiency. Underlying mechanisms might be shared molecular pathways in both bile acid as well as glucocorticoid metabolism at the level of synthesis, catabolism or the hypothalamus and the pituitary gland. Molecular links include the farnesoid X receptor FXR or the G protein coupled bile acid receptor TGR5 expressed in the liver and the adrenals. In this review we sum up knowledge on the regulation of adrenal gland function and steroidogenesis, focussing on bile acids and potential alterations under cholestatic conditions, depict molecular links between glucocorticoid and bile acid metabolism and discuss the difficulties of assessment of adrenal function in humans in general and more specifically in liver diseases. PMID- 30463693 TI - Modeling squid axon Na+ channel by a nucleation and growth kinetic mechanism. AB - A kinetic model accounting for all salient features of the Na+ channel of the squid giant axon is provided. The model furnishes explanations for the Cole-Moore like effect, the rising phase of the ON gating current and the slow 'intermediate component' of its decaying phase, as well as the gating charge immobilization. Experimental ON ionic currents are semi-quantitatively simulated by the use of only three free parameters, upon assuming that the Na+ channel opening proceeds along with the stepwise aggregation of its four domains, while they are moving their gating charge outward under depolarizing conditions. The inactivation phase of the ON ionic current is interpreted by a progressive electrostatic attraction between the positively charged 'hinged lid' containing the hydrophobic IFM triad and its receptor inside the channel pore, as the stepwise outward movement of the S4 segments of the Na+ channel progressively increases the negative charge attracting the triad to its receptor. The Na+ channel closing is assumed to proceed by repolarization-induced disaggregation of its domains, accompanied by inward movement of their gating charge. The phenomenon of 'gating charge immobilization' can be explained by assuming that gradual structural changes of the receptor over the time course of depolarization strengthen the interaction between the IFM triad and its receptor, causing a slow release of the gating charge during the subsequent repolarization. PMID- 30463694 TI - Fine-tuning of the stability of beta-strands by Y181 in perfringolysin O directs the prepore to pore transition. AB - Perfringolysin O (PFO) is a toxic protein that forms beta-barrel transmembrane pores upon binding to cholesterol-containing membranes. The formation of lytic pores requires conformational changes in PFO that lead to the conversion of water soluble monomers into membrane-bound oligomers. Although the general outline of stepwise pore formation has been established, the underlying mechanistic details await clarification. To extend our understanding of the molecular mechanisms that control the pore formation, we compared the hydrogen-deuterium exchange patterns of PFO with its derivatives bearing mutations in the D3 domain. In the case of two of these mutations F318A, Y181A, known from previous work to lead to a decreased lytic activity, global destabilization of all protein domains was observed in their water-soluble forms. This was accompanied by local changes in D3 beta-sheet, including unexpected stabilization of functionally important beta1 strand in Y181A. In case of the double mutation (F318A/Y181A) that completely abolished the lytic activity, several local changes were retained, but the global destabilization effects of single mutations were reverted and hydrogen-deuterium exchange (HDX) pattern returned to PFO level. Strong structural perturbations were not observed in case of remaining variants in which other residues of the hydrophobic core of D3 domain were substituted by alanine. Our results indicate the existence in PFO of a well-tuned H-bonding network that maintains the stability of the D3 beta-strands at appropriate level at each transformation step. F318 and Y181 moieties participate in this network and their role extends beyond their direct intermolecular interaction during oligomerization that was identified previously. PMID- 30463695 TI - Thermodynamics and kinetics of joint action of antiviral agent tilorone and DMSO on model lipid membranes. AB - Individual and joint action of two water-soluble drugs, DMSO and tilorone, on model l-alpha-dipalmitoylphosphatidylcholine (DPPC) membranes were studied in equilibrium and kinetic regimes by differential scanning calorimetry (DSC). For equilibrium experiments, the drugs were introduced during preparation of the model membrane. In kinetic studies, one of the drugs was added to the DPPC membrane already containing the other drug, and the effects of drug-membrane interactions were monitored in real-time regime. It was found that tilorone and DMSO had opposite effects on the membrane melting temperature, which were non additive under joint introduction of these drugs. Analysis of kinetics of DSC profiles under drugs introduction allowed us to discriminate two processes in drug-membrane interactions with different characteristic times, i.e., drug sorption onto the membrane (minutes) and drug diffusion through stacks of lipid bilayers (hours). It was established that 0.1 mol% DMSO effectively enhanced membrane penetration for tilorone with the rate of tilorone diffusion being dependent upon the scheme of drugs administration. A model was proposed describing how sorption of a dopant onto lipid membrane could affect the membrane permeability for other dopants. Conditions were determined for enhancement of membrane permeability, as it was observed for DPPC/DMSO/tilorone system. PMID- 30463696 TI - The use of styrene-maleic acid copolymer (SMA) for studies on T cell membrane rafts. AB - An emerging alternative to the use of detergents in biochemical studies on membrane proteins is apparently the use styrene-maleic acid (SMA) amphipathic copolymers. These cut the membrane into nanodiscs (SMA-lipid particles, SMALPs), which contain membrane proteins possibly surrounded by their native lipid environment. We examined this approach for studies on several types of T cell membrane proteins, previously defined as raft or non-raft associated, to see whether the properties of the raft derived SMALPs differ from non-raft SMALPs. Our results indicate that two types of raft proteins, GPI-anchored proteins and two Src family kinases, are markedly present in membrane fragments much larger (>250 nm) than those containing non-raft proteins (<20 nm). Lipid probes sensitive to membrane fluidity (membrane order) indicate that the lipid environment in the large SMALPs is less fluid (more ordered) than in the small ones which may indicate the presence of a more ordered lipid Lo phase which is characteristic of membrane rafts. Also the lipid composition of the small vs. large SMALPs is markedly different - the large ones are enriched in cholesterol and lipids containing saturated fatty acids. In addition, we confirm that T cell membrane proteins present in SMALPs can be readily immunoisolated. Our results support the use of SMA as a potentially better (less artifact prone) alternative to detergents for studies on membrane proteins and their complexes, including membrane rafts. PMID- 30463697 TI - Electrophysiological characterization of Tityus obscurus beta toxin 1 (To1) on Na+-channel isoforms. AB - To1, previously named Tc49b, is a peptide neurotoxin isolated from venom of the scorpion Tityus obscurus that is responsible for lethal human poisoning cases in the Brazilian Amazonian region. Previously, To1 was shown to be lethal to mice and to change Na+ permeation in cerebellum granular neurons from rat brain. In addition, To1 did not affect Shaker B K+ channels. Based on sequence similarities, To1 was described as a beta-toxin. In the present work, To1 was purified from T. obscurus venom and submitted to an electrophysiological characterization in human and invertebrate NaV channels. The analysis of the electrophysiological experiments reveal that To1 enhances the open probability at more negative potentials of human NaV 1.3 and 1.6, of the insect channel BgNaV1 and of arachnid VdNaV1 channel. In addition, To1 reduces the peak of Na+ currents in some of the NaVs tested. These results support the classification of the To1 as a beta-toxin. A structure and functional comparison to other beta-toxins that share sequence similarity to To1 is also presented. PMID- 30463698 TI - Investigating the interaction of Grammostola rosea venom peptides and model lipid bilayers with solid-state NMR and electron microscopy techniques. AB - Spider venom contains a number of small peptides that can control the gating properties of a wide range of ion channels with high affinity and specificity. These ion channels are responsible for coordination and control of many bodily functions such as transducing signals into sensory functions, smooth muscle contractions as well as serving as sensors in volume regulation. Hence, these peptides have been the topic of many research efforts in hopes that they can be used as biomedical therapeutics. Several peptides are known to control the gating properties of ion channels by involving the lipid membrane. GsMTx4, originally isolated from the Chilean Rose tarantula (Grammostola rosea), is known to selectively inhibit mechanosensitive ion channels by partitioning into the lipid bilayer. To further understand this indirect gating mechanism, we investigated the interactions between native GsAF2, VsTx1 and a synthetic form of GsMTx4 with model DMPC lipid bilayers using 31P solid-state NMR, 13C CP-MAS NMR, NS-TEM and cryo-TEM. The results reveal that these inhibitor cystine knot peptides perforate the DMPC lipid vesicles similarly with some subtle differences and ultimately create small spherical vesicles and anisotropic cylindrical and discoidal vesicles at concentrations near 1.0-1.5 mol% peptide. The anisotropic components align with their long axes along the NMR static B0 magnetic field, a property that should be useful in future NMR structural investigations of these systems. These findings move us forward in our understanding of how these peptides bind and interact with the lipid bilayer. PMID- 30463699 TI - Calcium enhances binding of Clostridium perfringens epsilon toxin to sulfatide. AB - Epsilon toxin (Etx) from Clostridium perfringens is synthesized as a very low active prototoxin form (proEtx) that becomes active upon proteolytic activation and has the capacity to cross the blood-brain barrier (BBB), thereby producing severe neurological effects. The identity and requirements of host receptors of Etx remain a matter of controversy. In the present study, we analysed the binding of proEtx or Etx to liposomes containing distearoylphosphatidylcholine (DSPC), cholesterol and sulfatide, or alternatively to detergent-solubilized lipids, using surface plasmon resonance (SPR). We also tested the influence of calcium on Etx or proEtx binding. Our findings show that the presence of sulfatide in liposomes increases both Etx and proEtx binding, and Etx binding is enhanced by calcium. These results were corroborated when SPR was conducted with immobilized toxin, since detergent-solubilized sulfatide increases its binding to Etx in the presence of calcium, but not to proEtx. Moreover, binding affinity is also affected, since the treatment of liposomes with sulfatase causes the dissociation rate constants (KD) in both proEtx and Etx to increase, especially in the case of proEtx in the presence of calcium. In addition, protein-lipid overlay assays corroborated the calcium-induced enhancement of Etx binding to sulfatide, and to lipids extracted from sulfatide-enriched rat brain lipid rafts. In conclusion, the present work highlights the role of sulfatide as an important element in the pathophysiology of Etx and reveals the influence of calcium in the interaction of Etx, but not of proEtx, with the target membrane. PMID- 30463700 TI - Membrane order and ionic strength modulation of the inhibition of the membrane bound acetylcholinesterase by epigallocatechin-3-gallate. AB - In the present work, we analyzed how external factors can modulate the efficiency of epigallocatechin-3-O-gallate (EGCG) inhibition of a membrane-bound isoform of the acetylcholinesterase. Increasing the ionic strength but not the osmolarity of the bulk medium proved to be an important factor. In addition, we verified a clear correlation between the inhibitory activity with the order degree of the membranes by using cholesterol-partially depleted red blood cell ghosts. These two factors i.e. high salt concentration in the bulk medium and less viscous membranes, allow a deeper insertion of the EGCG into the lipid bilayer, thus leading to a greater inhibition of AChE. As a corollary, we propose that any treatment or process that leads to a slight decrease in cholesterol content in the membranes can efficiently enhance the inhibitory activity of EGCG, which can have important consequences in all the pathologies where the inhibition of AChE is recommended. PMID- 30463701 TI - Fast and potent bactericidal membrane lytic activity of PaDBS1R1, a novel cationic antimicrobial peptide. AB - Antimicrobial peptides (AMPs) are promising candidates for the development of future antibiotics. In an attempt to increase the efficacy of therapeutic AMPs, computer-based design methods appear as a reliable strategy. In this study, we evaluated the antimicrobial efficiency and mechanism of action of a novel designed AMP named PaDBS1R1, previously designed by means of the Joker algorithm, using a fragment of the ribosomal protein L39E from the archaeon Pyrobaculum aerophilum as a template. PaDBS1R1 displayed low micromolar broad-spectrum antimicrobial activity against Gram-negative (MIC of 1.5 MUM) and Gram-positive (MIC of 3 MUM) bacteria, including carbapenem-resistant Klebsiella pneumoniae (MIC of 6.25 MUM) and methicillin-resistant Staphylococcus aureus (MIC of 12.5 MUM), without cytotoxicity towards HEK-293 cells. In addition, membrane permeabilization and depolarization assays, combined with time-kill studies and FEG-SEM imaging, indicated a fast membrane permeation and further leakage of intracellular content. Biophysical studies with lipid vesicles show a preference of PaDBS1R1 for Gram-negative bacteria-like membranes. We investigated the three dimensional structure of PaDBS1R1 by CD and NMR analyses. Our results suggest that PaDBS1R1 adopts an amphipathic alpha-helix upon interacting with hydrophobic environments, after an initial electrostatic interaction with negative charges, suggesting a membrane lytic effect. This study reveals that PaDBS1R1 has potential application in antibiotic therapy. PMID- 30463702 TI - Corrigendum to "The YhhN protein of Legionella pneumophila is a Lysoplasmalogenase" [Biochim. Biophys. Acta, Biomembr. 1848 (2) (2015) 742-751]. PMID- 30463703 TI - Are the short cationic lipopeptides bacterial membrane disruptors? Structure Activity Relationship and molecular dynamic evaluation. AB - Short cationic lipopeptides are amphiphilic molecules that exhibit antimicrobial activity mainly against Gram-positives. These compounds bind to bacterial membranes and disrupt their integrity. Here we examine the structure-activity relation (SAR) of lysine-based lipopeptides, with a prospect to rationally design more active compounds. The presented study aims to explain how antimicrobial activity of lipopeptides is affected by the charge of lipopeptide headgroup and the length of lipopeptide acyl chain. The obtained SAR models suggest that the lipophilicity of short synthetic cationic lipopeptides is the major factor that determines their antimicrobial activities. In order to link the differences in antimicrobial activity to the mechanism of action of lipopeptides containing one and two hydrophobic chains, we additionally performed molecular dynamic (MD) simulations. By using combined coarse-grained and all-atom simulations we also show that these compounds neither affect the organization of the membrane lipids nor aggregate to form separate phases. These results, along with the onset of antimicrobial activity of lipopeptides well below the critical micelle concentration (CMC), indicate that lipopeptides do not act in a simple detergent like manner. PMID- 30463704 TI - Evaluation of Probe Angles for Synchronous Waveform 915-MHz Microwave Ablation. AB - BACKGROUND: The purpose of this study is to compare the ablation performance between a synchronous microwave ablation (MWA) system and a commercially available asynchronous system in ex vivo bovine liver and evaluate the efficacy of ablation at varying entrance angles. MATERIALS AND METHODS: Two 915-MHz MWA systems were used in bench top ex vivo bovine livers with various conditions (synchronous versus asynchronous). Using synchronous technology ablations to liver, kidney, or lung at angles of 0, 15, 30, and 90 degrees were evaluated. RESULTS: Synchronous and asynchronous MWA systems created mean ablation zone volumes of 26.4 and 15.8 cm3, 62.9 and 45.4 cm3, 90.8 and 56.4, and 75.7 and 54.8 cm3 with single, double (2 microwave probes in use simultaneous) (2 cm spacing), and triple (three probes in use simultaneously) (2 cm and 3 cm spacing) antennae configurations, respectively; adjusted P-values <= 0.006. Ablation defects were similar across all groups when evaluated for entrance angle. Specifically, when comparing 0-degree angle to all other angles, achieved zones of ablation (ZA) were similar (mean +/- standard deviation for 0-degree versus all other angles: 8.72 +/- 4.84 versus 9.38 +/- 4.11 cm2, P = 0.75). The use of the long-tip probe resulted in a statistically significant increase in the achieved ZA when compared to the short tip probe (10.9 +/- 4.3 versus 6.5 +/- 2.4, respectively; P = 0.01). CONCLUSIONS: Newly developed synchronous microwave technology creates significantly larger ablation zones when compared to an existing asynchronous commercially available system. The angle of approach does not affect the resulting ZA. This is clinically relevant as true 0-degree angle is often difficult to obtain. PMID- 30463705 TI - Implementing the Trauma Evaluation and Management (TEAM) Course in Kenya. AB - BACKGROUND: Trauma training provides crucial knowledge and skills for health-care providers in low- and middle-income countries (LMICs). Although such training has been adapted for physicians and emergency personnel in LMICs, few courses have been offered for medical students. The Trauma Evaluation and Management (TEAM) course, developed by the American College of Surgeons, provides a valuable framework for providing this content to medical students in an LMIC-context. MATERIALS AND METHODS: We implemented the TEAM course at a single medical school in rural Kenya, for final-year medical students, utilizing the multimodal instruction and reference materials provided by the American College of Surgeons. We administered precourse and postcourse assessments, adapted the content for particular low-resource considerations, expanded the course to 2 d, and utilized a multidisciplinary and multinational group of surgical expert instructors. RESULTS: The entire final-year medical school class participated, and all completed pretesting and posttesting (100%, n = 61). Posttesting revealed significant improvement (P < 0.001), demonstrating successful knowledge acquisition, with the greatest improvements among the poorest performing decile on the pretest (P < 0.05). On narrative course feedback (100% completion, n = 61), participants appreciated instructors' interactive teaching style and the course's practical demonstrations, while requesting more time allotment for trauma training. CONCLUSIONS: We describe the feasibility of implementing TEAM training for final-year medical students in Kenya and demonstrate the course's effectiveness in this context as shown by knowledge acquisition. We plan for additional study to assess interval knowledge and skill retention. With refinement based on these results, we plan to repeat and expand trauma-education initiatives for medical students in LMICs. PMID- 30463706 TI - Trends and Attributable Costs of Anorectal Involvement in Pediatric Crohn's Disease. AB - BACKGROUND: Pediatric Crohn's disease (CD) with anorectal involvement has not been well characterized. We sought to describe trends in the prevalence of pediatric CD with anorectal involvement and its influence on health-care utilization. MATERIALS AND METHODS: Patients (<21 y of age) with an International Classification of Diseases, Ninth Revision diagnosis of CD (555.X) were identified in the Kid's Inpatient Database (2003, 2006, 2009, 2012) and stratified by anorectal involvement based on the International Classification of Diseases, Ninth Revision diagnosis and procedural codes. Patient characteristics and resource utilization (length of stay [LOS] and costs) were compared between CD patients with and without anorectal involvement using univariate and multivariable analyses. Propensity score matching was used to estimate attributable LOS and costs. RESULTS: There were 26,029 patients with CD identified in the study interval. Of these, 1706 (6.6%) had anorectal involvement. Those with anorectal disease were younger (age 16 versus 17 y old), more likely to be male (59.4% versus 49.9%) and black or Hispanic (24.7% versus 18.2%), and were more commonly treated in urban teaching hospitals compared with rural or nonteaching hospitals (83.2% versus 70.9%) (P < 0.001 for all). The proportion of patients with anorectal involvement increased over time (odds ratio 1.03, 95% confidence interval 1.02-1.05). After propensity score matching, attributable LOS and costs were 0.5 d and approximately $1600, respectively. CONCLUSIONS: There has been an increase in the proportion of pediatric CD hospitalizations with anorectal manifestations. This pattern of disease is associated with longer hospitalization and higher costs compared with CD alone. Further research is required to understand the underlying etiology of these observed trends. PMID- 30463707 TI - Bubble Counter for Measurement of Air Bubbles During Thoracic Stent-Graft Deployment in a Flow Model. AB - BACKGROUND: The aim of our study was to describe and validate the use of a bubble counter in an aortic flow model assessing the distribution of air bubbles in the supra-aortic vessel during thoracic stent-graft deployment. MATERIALS AND METHODS: In an aortic flow model made by glass, identical tubular thoracic stent grafts (Zenith TX2 ProForm; Cook Medical, Bjaeverskov, Denmark) were deployed distal to the left subclavian artery. Four steps were defined during deployment: (1) introduction of the stent graft in the arch; (2) deployment of the stent graft; (3) proximal release of the stent graft; and (4) retrieval of the introduction system. On both sides, the common carotid and the vertebral artery were connected together, and the air bubbles were measured with one bubble counter probe per side. The number of air bubbles, as well as their size and distribution, is analyzed during these four steps for the left and right sides with a bubble counter. RESULTS: Ten thoracic stent grafts were included in the study. The total number of air bubbles measured during all steps was significantly higher on the left side (1091 +/- 255 versus 545 +/- 288, P < 0.00001). During the third step, significantly higher numbers of bubbles were observed on the left side (P = 0.0000001) compared with the right side. The analysis of all bubbles by size revealed that a higher number of bubbles ranged 100-200 MUm (P < 0.02) and 200-300 MUm (P < 0.03) on the left side. Small bubbles were observed during all steps of deployment, whereas large bubbles appeared more commonly during the second and third steps. CONCLUSIONS: A significant number of air bubbles are released during deployment of tubular thoracic stent grafts distally of the left subclavian artery in an aortic flow model. The distribution of air bubbles is bilateral with a higher number of air bubbles released on the left side. PMID- 30463708 TI - Expression Analysis of ACSL5 and Wnt2B in Human Congenital Pulmonary Airway Malformations. AB - BACKGROUND: The objective of this study was to determine acyl-CoA synthetase 5 (ACSL5) and Wnt2B expression patterns in human congenital pulmonary airway malformations (CPAMs) and to identify the possible roles of ACSL5 and Wnt2B in the pathogenesis of CPAM. METHODS: Expression of ACSL5 and Wnt2B was evaluated by immunohistochemical staining, Western blotting, and quantitative real-time polymerase chain reaction, which were performed on surgical specimens of CPAM and adjacent normal lung tissues as controls. RESULTS: Immunohistochemistry revealed that ACSL5 and Wnt2B immunopositive cells were predominantly detected in the mesenchymal cell nucleus, and there were lower expressions of ACSL5 and Wnt2B immunopositive cells in CPAM tissues than those in adjacent normal lung tissues. Western blotting and quantitative real-time polymerase chain reaction showed that ACSL5 and Wnt2B protein and mRNA expressions were significantly decreased in CPAM tissues as compared to the adjacent normal lung tissues (P < 0.05). In addition, there was a reduced level of ACSL5 relative to that of Wnt2B. CONCLUSIONS: The decreased ACSL5 and Wnt2B expressions correlated with aberrations in pulmonary development and in the pathogenesis of CPAM, so downregulation of ACSL5 and Wnt2B could play an important role in the development of bronchial-alveolar structures in CPAM. PMID- 30463709 TI - Reduced Hypoxia-Related Genes in Porcine Limbs in Ex Vivo Hypothermic Perfusion Versus Cold Storage. AB - BACKGROUND: Ischemia-reperfusion injury remains the major limiting factor for limb replantation and transplantation. Static cold storage (SCS) on ice currently represents the standard mode of preservation but is limited to 6 h of duration. Ex vivo machine perfusion has evolved as a potential alternative to safely extend the duration of ex vivo preservation by providing continuous supply of oxygen and nutrients. This study aims to evaluate underlying molecular mechanisms of both preservation modalities. METHODS: We assessed molecular changes in amputated porcine forelimbs stored on ice at 4 degrees C for 2 h (n = 2) and limbs perfused with Perfadex solution at 10 degrees C for 2 h (n = 3) or 12 h (n = 3) before replantation. Muscle biopsies were examined for histological changes and gene expression levels using H&E staining and a hypoxia-related PCR gene array, respectively. RESULTS: Histology revealed only minor differences between the ice (SCS) and perfusion groups after 2 h of preservation, with decreased muscle fiber disruption in the perfusion groups compared with the ice (SCS) group. Perfused limbs demonstrated downregulation of genes coding for glycolytic pathways and glucose transporters after 2 h and 12 h when compared with SCS after 2 h. Similarly, genes that induce angiogenesis and those that are activated on DNA damage were downregulated in both perfusion groups as compared with SCS. CONCLUSIONS: Perfusion of porcine limbs resulted in less activation of hypoxia related gene families when compared with SCS. This may indicate a state more closely resembling physiological conditions during perfusion and potentially limiting ischemic injury. Our study confirms ex vivo perfusion for up to 12 h as a viable alternative for preservation of vascularized composite tissues. PMID- 30463710 TI - Cerebral Blood Flow in Polytrauma: Transcranial Doppler Analysis in a Nonhuman Primate Shock Model. AB - BACKGROUND: In combat-related trauma, resuscitation goals are to attenuate tissue hypoxia and maintain circulation. During hemorrhagic shock, compensatory and autoregulatory mechanisms are activated to preserve cerebral blood flow. Transcranial Doppler (TCD) ultrasonography may be an ideal noninvasive modality to monitor cerebral hemodynamics. Using a nonhuman primate (NHP) model, we attempted to characterize cerebral hemodynamics during polytraumatic hemorrhagic shock using TCD ultrasonography. MATERIALS AND METHODS: The ophthalmic artery was insonated at multiple time points during varying stages of shock. Hemorrhage was controlled and pressure targeted to 20 mmHg to initiate and maintain the shock period. Mean flow velocity (MFV), peak systolic velocity (PSV), end diastolic velocity (EDV), pulsatility index (PI), and resistance index (RI) were recorded. Results represent mean +/- standard deviation; statistical significance is P < 0.05; n = 12. RESULTS: Compared to baseline, MFV, PSV, EDV, and RI show significant changes after 60 min of hemorrhagic shock, (9.81 +/- 3.60 cm/s; P < 0.01), (21.15 +/- 8.59 cm/s; P < 0.01), (5.15 +/- 0.21 cm/s; P < 0.01), (0.70 +/- 0.11; P < 0.05), respectively. PI did not change during hemorrhagic shock. At end of prehospital care (T30), cerebral flow recovers for MFV, PSV, and RI while EDV remained decreased at T30 (6.15 +/- 1.13 cm/s; P < 0.01) and 1 h of simulated transport (T90) (5.87 +/- 0.62 cm/s; P < 0.01). Changes in PI at T30 and T90 were not significant. MFV diminished (16.45 +/- 3.85 cm/s; P < 0.05) at T90. CONCLUSIONS: This study establishes baseline and hemorrhagic shock values for NHP cerebral blood flow velocities and cerebrovascular indices. TCD ultrasonography may represent an important area of research for targeted resuscitation investigations using a hemorrhagic shock model in NHPs. PMID- 30463711 TI - Objective Preoperative Parameters Predict Difficult Pelvic Dissections and Clinical Outcomes. AB - BACKGROUND: Objective criteria to predict difficult pelvic dissection with prognostic significance are lacking. Previous studies have focused on predicting intraoperative conversion and not evaluated factors specific to pelvic surgery. We aimed to develop an objective, prognostic, preoperative assessment to predict difficult pelvic dissections and clinical outcomes. Such a model is much needed, may facilitate objective comparisons between rectal cancer centers, or may serve as a stratification variable in clinical trials. MATERIALS AND METHODS: Patients who underwent low anterior resection or abdominoperineal resection for rectal cancer within 10 cm of the anal verge (2009-2014) were retrospectively analyzed. Procedures were categorized into "routine" or "difficult" based on predefined criteria. All patients underwent 14 measurements on preoperative imaging. Outcomes were compared between the two groups. Stepwise multivariate logistic regression was used to develop the prediction model, which was validated in an independent data set. RESULTS: Of the 280 patients analyzed, 80 fulfilled the inclusion criteria. Baseline characteristics were similar except for more males having a "difficult" pelvis. "Difficult" patients were significantly more likely to have a narrower pelvis, smaller pelvic volumes, a longer pelvis, more curved sacrum, and more acute anorectal angle. Difficult cases correlated significantly with higher blood loss, hospital costs, longer operative time, and length of stay. A practical model to predict difficult pelvic dissections was created and included male gender, previous radiation, and length from promontory to pelvic floor > 130 mm. Model validation was performed in 40 patients from an independent data set. CONCLUSIONS: An objective, validated model that predicts a difficult pelvic dissection and associated worse clinical outcome is possible. PMID- 30463712 TI - Buprenorphine-Sustained Release Alters Hemodynamic Parameters in a Rat Burn Model. AB - BACKGROUND: It has been previously shown that anesthesia and analgesia can affect outcomes in the rat burn model and that buprenorphine alleviated pain without drastically altering the outcomes of interest. Recently, the use of a sustained release (SR) formulation of buprenorphine has been promoted over conventional buprenorphine. In this study, we assessed whether buprenorphine-SR altered hemodynamic parameters in our rat model of severe burn injury. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were randomized to receive either conventional buprenorphine (0.05 mg/kg) or buprenorphine-SR (1 mg/kg). Buprenorphine-SR was administered 24 h before the experiment. Buprenorphine was administered on the day of experiment. These groups were further randomized to control or scald burn (60% of total body surface area). Systolic and diastolic blood pressure (SBP, DBP) and heart rate (HR) were measured using a noninvasive blood pressure system before receiving analgesia and after 72 h. RESULTS: As expected, HR was significantly higher after burn injury regardless of analgesic (P <0.0001). Both SBP and DBP were significantly decreased in burned animals receiving conventional buprenorphine (P < 0.0001), but neither was altered in the buprenorphine-SR-treated burned animals. However, SBP, DBP, and HR were significantly increased after 72 h in control animals receiving buprenorphine-SR (P < 0.0001). CONCLUSIONS: These data indicate that buprenorphine-SR alters the hemodynamic response to injury and may not be an appropriate choice for a model of severe burn injury. If this analgesic is used, investigators must cautiously form conclusions, especially in experimental conditions that would be expected to alter cardiac hemodynamics. PMID- 30463713 TI - Evaluation of Accredited Trauma, Surgical Critical Care, and Acute Care Surgery Fellowship Websites. AB - OBJECTIVES: Surgical residents are increasingly pursuing fellowships and rely heavily on fellowship programs' web sites as a primary source of information. Accessibility, quality, and content of a program web site can encourage or deter an applicant from applying to a particular program. The goal of this study was to perform an analysis of trauma, surgical critical care, and acute care surgery fellowship program web sites. MATERIALS AND METHODS: A list of trauma, surgical critical care, and acute care surgery fellowship programs was obtained from the Eastern Association for the Surgery of Trauma (EAST) web site. The existence of a functional hyperlink in the EAST program directory and a systematic Google search was assessed to determine web site accessibility. Twenty-one content criteria were used to evaluate accessible web sites. RESULTS: The EAST directory contained 102 fellowship programs. Ninety-one programs had web sites accessible through a Google search. No web site contained all 21 criteria. Only 29 web sites contained at least half of the evaluated content criteria. The most common data point included was program description (97%), while role of seeing patients in clinic (4%) was the least common criteria present. CONCLUSIONS: Many programs in the EAST directory lack functional links and accessible web sites. Content that has been deemed important to applicants is lacking in varying degrees. Incorporation of this missing content may benefit both applicants and programs, allowing for more informed decision-making when choosing a program, thus promoting better fit of fellows with programs during the application process. PMID- 30463714 TI - To Scan or Not to Scan: Overutilization of Computed Tomography for Minor Head Injury at a Pediatric Trauma Center. AB - BACKGROUND: Degree of compliance with Pediatric Emergency Care Applied Research Network (PECARN) recommendations for radiographic evaluation following minor head injury in children is not well understood. The aim of this study was to assess PECARN compliance at a pediatric trauma center. The secondary aim was to determine whether children with indeterminate history of loss of consciousness (LOC) are at greater risk for clinically important traumatic brain injury (ciTBI) than those with no LOC. MATERIALS AND METHODS: We identified children aged 0-17 y who presented <24 h after minor head injury with Glasgow Coma Scale >=14 in our institutional trauma registry. Predictor variables for ciTBI (TBI resulting in admission >=2 nights, intubation >=24 h, neurosurgery, or death) were reviewed. Simple and multivariate logistic regressions were performed to estimate the independent effects of demographic and clinical characteristics on the outcome of ciTBI. RESULTS: We included 739 children. Incidence of ciTBI was 5.4%. Only 5.6% did not undergo computed tomography (CT). PECARN compliance was 92.6% overall, but only 23.0% in those for whom CT was not indicated. Among those for whom either CT or observation was acceptable, 93.7% underwent CT. LOC history was indeterminate in 8.5%. On multivariate analysis, indeterminate LOC was not a risk factor for ciTBI. Vomiting and presence of occipital/parietal/temporal scalp hematoma were independent risk factors for ciTBI. CONCLUSIONS: CT is overutilized in pediatric trauma patients presenting to our institution after minor head injury when compared to PECARN criteria. Indeterminate LOC history was not a risk factor for ciTBI. Education of parents and clinicians regarding the risk to benefit ratio of CT in trauma patients with minor head injury is needed. PMID- 30463715 TI - Inhibition of Postinfarction Ventricular Remodeling by High Molecular Weight Polyethylene Glycol. AB - BACKGROUND: Myocardial infarction (MI) is a major etiology for the development of heart failure. We have previously shown that high molecular weight polyethylene glycol (PEG) can protect cardiac myocytes from hypoxia-reoxygenation injury in vitro. In this study, we investigated the potential protective effects of 15-20 kD PEG postinfarction without reperfusion. METHODS: One milliliter of PEG 15-20 was delivered intravenously following permanent left anterior descending ligation in adult male rats with phosphate buffer saline (PBS) as control (n = 9 in each group). Echocardiography was performed at baseline and at 8 wk post-MI. Left ventricles (LVs) were harvested to quantify fibrosis, apoptosis, cell survival signaling, regulation of beta-adrenergic signaling, and caveolin (Cav) expression. RESULTS: The PEG group had significant recovery of LV function at 8 wk compared with the PBS group. There was less LV fibrosis in both the infarct and remote territory. Cell survival signaling was upregulated in the PEG group with increased Akt and ERK phosphorylation. PEG inhibited apoptosis as measured by terminal deoxynucleotidyl transferase [TdT]-mediated dUTP nick-end labeling positive nuclei and caspase-3 activity. There was maintenance of Cav-1, Cav-2, and Cav-3 expression following PEG treatment versus a decline in the PBS group. Negative regulators of beta-adrenergic signaling, G protein-coupled receptor kinase-2, and beta-arrestin 1 and 2 were all upregulated in PBS-treated samples compared to normal control; however, PEG treatment led to decreased expression. CONCLUSIONS: These data suggest that PEG 15-20 may have significant protective effects post-MI even in the setting of no acute reperfusion. Upregulation of Cav expression appears to be a key mechanism for the beneficial effects of PEG on ventricular remodeling and function. PMID- 30463716 TI - Assessment of Bowel End Perfusion After Mesenteric Division: Eye Versus SPY. AB - BACKGROUND: Anastomotic complications related to tissue ischemia cause morbidity in gastrointestinal (GI) surgery. Surgeons' standard practice to predict bowel perfusion is inspection of mesenteric perfusion before anastomosing bowel ends. Augmenting this assessment with fluorescent imaging is under study. A standardized system to evaluate this imaging has not yet been developed. This study compared the surgeon's intraoperative assessment to a novel GI-specific imaging analysis method. MATERIALS AND METHODS: Forty-nine consecutive patients undergoing open or laparoscopic-assisted bowel resections were enrolled. After mesenteric division, the surgeon marked the site for bowel transection. Near infrared fluorescence imaging was performed on the marked bowel ends. Imaging analysis identified theoretical transection sites based on the quantification of arterial and microvascular inflow (Perfusion) and venous outflow (Timing). The primary outcome was the measured disparity between the site marked by the surgeon using current standard of care parameters and the imaging-determined site. No clinical outcomes were assessed. RESULTS: Seventy-two bowel end segments from 46 patients were analyzed. Disparity was found in 11 of 72 (15%) bowel end segments. In five (7%), the disparity was due to either Perfusion or Timing (single), and in six (8%), due to both Perfusion and Timing (combined). In the single disparity group, the median disparity distance was 2.0 cm by Perfusion and 4.0 cm by Timing, and in the combined group, 3.8 cm by Perfusion and 3.5 cm by Timing. Disparity (either single or combined) was in 25% of colon and 11.5% of small bowel (P = NS). Combined and single disparity had equivalent lengths of disparity distance (P = NS). CONCLUSIONS: Imaging coupled with this GI-specific analysis provides objective, real-time, and interpretable data of intramural blood supply. A 15% disparity rate from current clinical practice was observed. PMID- 30463717 TI - Different Roles of Sphingosine Kinase 1 and 2 in Pancreatic Cancer Progression. AB - BACKGROUND: Pancreatic cancer is a disease with poor prognosis, and development of new treatments is necessary. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator produced by sphingosine kinases (SphK1 and SphK2), plays a critical role in progression of many types of cancer. However, little is known about the role of sphingosine kinases in pancreatic cancer. This study investigated the roles of sphingosine kinases in pancreatic cancer progression. MATERIALS AND METHODS: S1P levels in pancreatic cancer and noncancerous pancreatic tissue were measured in 10 patients. We generated PAN02 murine pancreatic cancer cell lines with a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated system genes 9 (Cas9)-mediated deletion of SphK1 or SphK2 and assessed cell growth and migration. In an animal model, we assessed the survival of mice injected with PAN02 cells intraperitoneally. RESULTS: S1P levels in the pancreatic cancer tissue were significantly higher than those in noncancerous tissue. SphK1 knockout (KO) cells showed greater proliferation and migration than wild type (WT) cells, and SphK2 KO cells showed less proliferation and migration than WT cells. Animal experiments showed that the survival of mice injected with SphK1 KO cells was significantly shorter than those injected with WT cells, and the survival of mice injected with SphK2 KO cells was longer than those injected with WT cells. Surprisingly, cytotoxic assay using gemcitabine showed that SphK1 KO cells survived less than WT cells, and SphK2 KO cells survived more than WT cells. CONCLUSIONS: S1P produced by SphK1 and SphK2 may have different functions in pancreatic cancer cells. Targeting both SphK1 and SphK2 may be a potential strategy for pancreatic cancer treatment. PMID- 30463718 TI - Rapid Detection of Clostridium difficile Toxins in Serum by Raman Spectroscopy. AB - BACKGROUND: Clostridium difficile infection (CDI) is due to the effects of toxins, toxin A and toxin B on the host. Severe CDI is associated with systemic signs of infection. Animal models of CDI demonstrate a strong correlation between systemic toxemia and the occurrence of severe disease. However, current technologies have low sensitivity to detect C difficile toxemia in human subjects. Raman spectroscopy (RS) is an upcoming technology that is used to detect bacteria and their toxins. We speculate that RS may be a sensitive method to detect clinically relevant concentrations of C difficile toxins in serum. MATERIALS AND METHODS: Serum samples were spiked with varying concentrations of toxin A, toxin B, and both. RS was performed on an air-dried serum drop that was placed on a mirror-polished stainless steel slide. Raman spectra were obtained, background corrected, vector normalized, and analyzed by Partial Least Square Linear Discriminant Analysis and Support Vector Machine for Classification. Model accuracy was measured by cross-validation and bootstrap methods. RESULTS: Toxin spiked sera of various concentrations (1 ng/mL, 1 pg/mL, and 0.1 pg/mL) were distinguished from control serum 100% with cross-validation error rate ranging from 0% to 18% and bootstrap error rate ranging from 0% to 12% for various concentrations. The sensitivity ranged from 87% to 100% and specificity ranged from 77% to 100% for various concentrations of toxin-spiked serum. CONCLUSIONS: We conclude that RS may be a sensitive method to detect clinically relevant concentrations of C difficile toxins in serum and thus to help diagnose severe CDI in patients in real-time at the point of care. PMID- 30463719 TI - Utilizing Technology for Global Surgery: A Survey of the West African College of Surgeons. AB - BACKGROUND: Information and communication technology (ICT) has been heralded as a possible mechanism for expanding global surgery collaborations. However, little is known regarding feasibility of ICT use in low- and middle-income countries (LMIC). We sought to determine the appropriate ICT platforms for surgical education initiatives and international collaborations. MATERIALS AND METHODS: We conducted a survey of members of the West African College of Surgeons. Topics included computer and internet access/utilization, familiarity with ICT, such as social media (SM), virtual document sharing platforms (VDS), virtual meeting applications (VM), and learning management systems (LM), and interest in ICT adoption. Statistical analyses were done using chi-squared tests, with Bonferroni corrections. RESULTS: Survey respondents included 83 individuals from 10 countries, 50% of whom had been in practice >10 y. All had computer access, with most (95%) using SM compared to all other modalities (P < 0.001); 77% used SM for professional reasons and 57% for education. Sixty percent of participants used VDS, 73% of whom used it for education. The utilization of other ICTs was lower (VM 43%, LM 32%). Unreliable Wi-Fi hindered every ICT, less often SM (41%) and VDS (23%), and more commonly VM (64%) and LM (52%). Despite this, VM was most often used in international collaboration (79%, P < 0.01). Most respondents (98%) supported ICT use for international collaboration. CONCLUSIONS: ICT platforms can support education initiatives and international collaborations in resource limited areas. Deployment of similar surveys and ICT workshops across other LMIC regions could maximize ICT utilization, further expanding global surgical collaborations. PMID- 30463720 TI - The Challenges of Providing Feedback to Referring Physicians After Discovering Their Medical Errors. AB - BACKGROUND: Physicians are encouraged through formalized systems to discuss their own errors with peers for the purposes of quality improvement. However, no clear professional norms exist regarding peer review when physicians discover errors that occurred at other institutions before referral. Our objective was to determine specialist physicians' attitudes and practices regarding providing feedback to referring physicians when prereferral errors are discovered. METHODS: We conducted semistructured interviews of specialists from two National Cancer Institute-designated Cancer Centers. Thematic analysis of transcripts was performed to determine physicians' attitudes toward the delivery of negative feedback regarding prereferral errors, whether and how they communicate these errors to referring physicians, and perceived barriers to doing so. RESULTS: We purposively sampled specialists by discipline, gender, and experience level, who described greater than 50% reliance on external referrals (n = 30). Specialists believed regular, explicit feedback was ideal, but the majority of participants reported practices that did not meet this standard. While there were some structural barriers to providing feedback (lack of time or contact information), the majority of barriers were internal psychological concerns (general discomfort with providing negative feedback, fear of conflict, or defensive reactions) or fears about implications for future referrals or medicolegal risk. CONCLUSIONS: Policies and interventions that structure the approach to this sometimes difficult, yet critically important, opportunity for reducing medical errors warrant investigation as potential mechanisms by which to improve consistency and quality of care while maintaining positive professional relationships. PMID- 30463721 TI - The Early Impact of Medicaid Expansion on Uninsured Patients Undergoing Emergency General Surgery. AB - BACKGROUND: Under the Affordable Care Act, eligibility for Medicaid coverage was expanded to all adults with incomes up to 138% of the federal poverty level in states that participated. We sought to examine the national impact Medicaid expansion has had on insurance coverage for patients undergoing emergency general surgery (EGS) and the cost burden to patients. MATERIALS AND METHODS: The National Inpatient Sample (NIS) was used to identify adults >=18 y old who underwent the 10 most burdensome EGS operations (defined as a combination of frequency, cost, and morbidity). Distribution of insurance type before and after Medicaid expansion and charges to uninsured patients was evaluated. Weighted averages were used to produce nationally representative estimates. RESULTS: A total of 6,847,169 patients were included. The percentage of uninsured EGS patients changed from 9.4% the year before Medicaid expansion to 7.0% after (P < 0.01), whereas the percentage of patients on Medicaid increased from 16.4% to 19.4% (P < 0.01). The cumulative charges to uninsured patients for EGS decreased from $1590 million before expansion to $1211 million after. CONCLUSIONS: In the first year of Medicaid expansion, the number of uninsured EGS patients dropped by 2.4%. The cost burden to uninsured EGS patients decreased by over $300 million. PMID- 30463722 TI - Feasibility of Selective Lateral Node Dissection Based on Magnetic Resonance Imaging in Rectal Cancer After Preoperative Chemoradiotherapy. AB - BACKGROUND: Lateral pelvic node metastasis is one of the major causes of local recurrence in advanced rectal cancer after preoperative chemoradiotherapy (CRT). However, lateral pelvic node dissection (LPND) is still a challenging surgical procedure in terms of surgical morbidity. This study aimed to investigate the feasibility and safety of LPND in patients with advanced rectal cancer after preoperative CRT. MATERIALS AND METHODS: Records of 80 consecutive patients who underwent total mesorectal excision (TME) with LPND for initially enlarged lateral pelvic nodes (LPNs) (short-axis diameter >=5 mm on magnetic resonance imaging before preoperative CRT) between 2011 and 2016 were retrospectively reviewed. Surgical outcomes of these patients were compared with those of 281 patients who underwent TME alone. RESULTS: Ninety-nine LPND procedures were performed, including 19 bilateral LPNDs. Pathologically proven LPN metastasis was identified in 32 (32.3%) LPND cases after preoperative CRT. Multiple (odds ratio = 12.908, 95% confidence interval: 3.355-49.660, P < 0.001) and persistently enlarged LPNs (odds ratio = 27.093, 95% confidence interval: 6.072-120.896, P < 0.001) were independently associated with LPN metastasis. The rates of overall postoperative 30-d morbidity (42.5% versus 32.4%, P = 0.093) and urinary retention (11.3% versus 7.1%, P = 0.230) were similar between the TME with LPND and TME-only groups. CONCLUSIONS: The postoperative morbidity of TME with LPND was comparable with TME-only group. The rate of LPN metastasis remained high after preoperative CRT, especially in patients with multiple or persistently enlarged LPNs. PMID- 30463723 TI - Innominate Versus Axillary Artery Cannulation for the Hemiarch Repair. AB - BACKGROUND: Innominate artery cannulation has gained some popularity over the last decade as an alternative to axillary artery cannulation for providing selective antegrade cerebral perfusion during repair of the ascending aorta and arch. Innominate artery cannulation provides several advantages including avoidance of an additional incision and use of a larger caliber artery to provide less resistance to high flow during bypass and selective antegrade cerebral perfusion. We hypothesize that these advantages make innominate artery cannulation superior to axillary artery cannulation as it can decrease operative times and potentially decrease blood loss. METHODS: This was a single-center retrospective analysis of 206 patients who underwent hemiarch replacement between 2009 and 2017. All patients qualified including emergent cases. Groups were separated by mode of cannulation: axillary and innominate. Outcomes evaluated included cardiopulmonary bypass (CPB) time, cross-clamp time, circulatory arrest (CA) time, postoperative transfusions, intensive care unit length of stay, development of any neurological complications, end-organ failure, and mortality. Subgroup analysis was performed for elective and emergent cases. RESULTS: Axillary and innominate artery cannulation accounted for 37% (n = 77) and 67% (n = 129) of cases, respectively. There was no difference in patient characteristics except for a higher incidence of renal disease in the axillary group (16% versus 6%, P = 0.05). More emergent cases were performed in the axillary group (61% versus 17%, P < 0.001). Innominate cases had shorter CPB times (189 versus 150 min, P < 0.001) and CA (22.5 versus 11 min, P < 0.001) times overall. In the elective subgroup, CA times were shorter for the innominate cases. However, the emergent subgroup displayed no difference in operative times. Less transfusions were given in the innominate group including units of red blood cells (2 [0-6] versus 0 [0-2], P < 0.001), units of platelets (2 [1-3] versus 1 [0-2], P = 0.001), and units of plasma (6 [2-9] versus 2 [0-4], P < 0.001). A similar trend was observed in the elective subgroup. No difference in transfusions was observed in the emergent subgroup. There was no statistical difference in remaining outcomes between cases of axillary and innominate cannulation in the combined, elective, and emergent groups. CONCLUSIONS: Alternate cannulation strategies for open arch anastomoses are evolving with a trend toward using the innominate artery. These data suggest that innominate cannulation is at least equivalent to, and may be superior to, axillary cannulation. The innominate artery provides a larger conduit vessel for perfusion and this decrease in resistance to flow, allowing for faster cooling and rewarming, maybe why CPB times were lower in this group. Innominate cannulation is a safe and potentially advantageous technique for hemiarch repair. PMID- 30463724 TI - Missing Data in Surgical Data Sets: A Review of Pertinent Issues and Solutions. AB - Incomplete data is a common problem in research studies. Methods to address missing observations in a data set have been extensively researched and described. Disseminating these methods to the greater research community is an ongoing effort. In this article, we describe some of the basic principles of missing data and identify practical, commonly used methods of adjustment relevant to surgical data sets. Through an example data set, we compare models generated through complete case analysis, single imputation (SI), and multiple imputation (MI). We also provide information on the steps to conduct MI using Stata IC. In our comparisons, we found that differences in odds ratios were greatest between the results from complete case analysis compared to the SI and MI models indicating that in this case the reduction in statistical power has a non negligible effect on the parameter estimates. Odds ratio estimates from the SI and MI methods were largely similar. In some instances, when compared to the MI method, the SI method tended to overestimate effect sizes. While in this example the differences in odds ratios do not vary greatly between the SI and MI methods, there are clear indications supporting the use of MI over SI. By describing the issues surrounding missing data and the available options for adjustment, we hope to encourage the use of robust imputation methods for missing observations. PMID- 30463725 TI - Internal Versus External Drainage With a Pancreatic Duct Stent For Pancreaticojejunostomy During Pancreaticoduodenectomy for Patients at High Risk for Pancreatic Fistula: A Comparative Study. AB - BACKGROUND: The aim of this study was to determine whether internal or external drainage with a pancreatic duct stent is the optimal pancreaticojejunostomy method to prevent pancreatic fistula (PF) after pancreaticoduodenectomy (PD) for subgroups of patients at high risk for PF. MATERIALS AND METHODS: A total of 495 patients who underwent PD were reviewed. Univariate and multivariate analyses were used to identify risk factors for PF after PD. We further compared the incidence of PF and outcomes between the internal and external drainage groups for subgroups of patients at high risk for PF. RESULTS: There was no difference in the incidence of complications according to the Clavien-Dindo classification or the rate of PF after PD in both groups (P = 0.961 and P = 0.505, respectively). The incidence of mortality was 3.8% in the internal drainage group and 3.9% in the external drainage group (P = 0.980). Univariate and multivariate analyses identified male gender (odds ratio [OR] = 2.93; 95% confidence interval [CI], 1.78-4.83; P = 0.000), pancreatic duct diameter (<3 mm) (OR = 2.58; 95% CI, 1.57-4.23; P = 0.000), and soft pancreatic texture (OR = 2.92; 95% CI, 1.71-4.98; P = 0.000) as independent risk factors for PF after PD. No differences in the incidence of PF for the subgroups of patients with one, two, or three risk factors were observed between the internal and external drainage groups (P = 0.334, P = 1.000, and P = 0.936, respectively). No differences in total complications, delayed gastric emptying, postpancreatectomy hemorrhage, biliary fistula, infection complications, reoperation, perioperative mortality, or postoperative hospital stay were noted. In addition, liquid loss and tube-related complications occurred in the external drainage group. CONCLUSIONS: Internal drainage is the optimal method to prevent PF after PD for subgroups of patients at high risk for PF because the surgical procedure is simple and prevents liquid loss and tube-related complications associated with external drainage. However, no differences in the incidence of PF and other complications after PD were observed between the two approaches. PMID- 30463726 TI - Incidence, Outcomes, and Recidivism of Elderly Patients Admitted For Isolated Hip Fracture. AB - INTRODUCTION: Isolated hip fracture (IHF) is a common injury in the elderly after a fall. However, there is limited study on elderly IHF patients' subsequent hospitalization for a new injury, that is, trauma-related recidivism. METHODS: A retrospective review of the trauma registry at an ACS level I trauma center was performed for all elderly (age >= 65 y) blunt trauma patients admitted between 2007 and 2017, with a focus on IHF patients. IHF was defined as a fracture of the femoral head, neck, and/or trochanteric region without any other injuries except minor soft tissue trauma after a fall. RESULTS: Of the 4986 elderly blunt trauma admissions, 974 (19.5%) had an IHF. The rate of trauma-related recidivism was 8.9% (n = 87) for a second injury requiring hospitalization. The majority of recidivist (74.7%) and nonrecidivist (66.5%) patients were females. Hospital length of stay was similar at index admission (7 d for recidivists versus 8 d for nonrecidivists). The median interval between index hospitalization and admission for a second injury was 373 d (IQR 156-1002). The most common mechanism of injury at index admission (95.4%) and at second injury-related hospitalization (95.4%) was a low-level fall. Among recidivist patients at second admission, a second hip fracture was present in 34.5% and intracranial hemorrhage in 17.2%. CONCLUSIONS: After initial admission for an IHF, 8.9% of patients were readmitted for a second injury, at a median time of approximately 1 y, overwhelmingly from a low-level fall. Emphasis on fall prevention programs and at index admission is recommended. PMID- 30463727 TI - Outcomes After Laparoscopic Gastrostomy Suture Techniques in Children. AB - BACKGROUND: There are various suture techniques used during laparoscopic gastrostomy to secure the stomach to the anterior abdominal wall. However, it remains unclear whether temporary fixation or subcutaneous absorbable sutures predispose pediatric patients to fewer postoperative complications. Our goal was to determine if a particular suture technique resulted in an increased risk for the development of postoperative complications. MATERIALS AND METHODS: A retrospective cohort analysis was performed for patients less than 18 y of age who underwent laparoscopic gastrostomy at a tertiary Children's Hospital between 2012 and 2016. Children were grouped according to suture techniques for laparoscopic gastrostomy placement: temporary sutures or subcutaneous absorbable sutures. Postoperative outcomes at 30 d were defined as major complications (tube dislodgement, unplanned reoperation, readmission) and minor complications (stitch abscess, surgical site infection, emergency department visit). The chi squared test was used to determine if an association existed between the suture techniques and 30 d postoperative complications. RESULTS: We identified 682 pediatric patients who underwent laparoscopic gastrostomy. There were 301 (44%) patients with subcutaneous sutures placed and 381 (56%) with temporary sutures placed. The overall rate of major and minor complications was 8.3% and 22%, respectively. We observed a significant difference in the occurrence of major postoperative complications between the subcutaneous and temporary suture techniques (11% versus 6.3%, P = 0.029). There was no significant difference in the development of minor complications between subcutaneous and temporary suture techniques. CONCLUSIONS: Children who receive subcutaneous sutures during laparoscopic gastrostomy are at an increased risk for developing a major postoperative complication. PMID- 30463728 TI - Litigation Patterns in Inguinal Hernia Surgery: A 25 Year Review. AB - BACKGROUND: Inguinal herniorraphyis among the most common procedures performed by general surgeons, but risk factors for litigation related to this surgery are poorly defined. METHODS: Cases were retrieved by searching the Westlaw database from 1991 through 2016 using the search terms "inguinal hernia" OR "inguinal herniorrhaphy" OR "inguinal hernioplasty" and "medical malpractice." Data were compiled on the demographics of the patient, operative case details, nature of injury, legal allegations, verdicts, and indemnities. RESULTS: Forty-six cases met inclusion criteria and were selected for review. Verdicts for the defendant predominated (67%). The average plaintiff's monetary award for a plaintiff verdict or settlement was $1.21 million (median $500,000). The most frequent legal argument was improper performance (n = 35, 76%), followed by failure of informed consent (n = 14, 30%). The most common complications were nerve/chronic pain (n = 20, 45%) and testicular damage (n = 10, 23%). No association was discovered between case outcome and patient gender (P = 0.231) or age (P = 0.899). Case outcome was not different between open and laparoscopic repairs (P = 0.722). Patient mortality was not associated with case outcome (P = 0.311). There was no chronological trend in case outcome or award amount. Settlement award amounts were not significantly different than plaintiff awards (P = 0.390). CONCLUSIONS: Successful litigation after inguinal hernia surgery was relatively infrequent-only 21.7%-with an additional 10.9% resulting in settlement awards. Case outcome in litigation for hernia surgery was not predicted by patient demographics, type of procedure, or type of complication in this data set. PMID- 30463729 TI - Accessibility and Content of Abdominal Transplant Fellowship Program Websites in the United States. AB - OBJECTIVES: Organ transplant volume is at an all-time high. Prospective applicants often utilize individual programs' websites for information when deciding if and where to apply for fellowship training. Accessibility and content from one program's website to the next is highly variable and may contribute to the selection of programs. The aim of this study was to evaluate the accessibility and content of abdominal transplant surgery fellowship websites. MATERIALS AND METHODS: The American Society of Transplant Surgeons (ASTS) website provides a complete list of abdominal transplant fellowship programs in the United States. A Google search was performed to determine the presence and accessibility of a program's website. Available websites were evaluated on the presence of 20 content criteria. RESULTS: Sixty-five programs in the United States were identified using the ASTS directory. Websites for fifty-one (78%) fellowship programs were identified. Three-fourths of websites contained 50% or less of the 20 evaluated data points, whereas 24% of websites contained 5 or less criteria. The most and least included data points were program description (100%) and on-call expectations (10%), respectively. CONCLUSIONS: The accessibility and content of a program's website is one major factor that can influence a potential applicant's decision on where to pursue transplant surgery fellowship training. This study revealed that a significant percentage of programs fail to provide a functional website. Of the fifty-one programs that did have websites, information deemed important to prospective applicants may be considered inadequate. PMID- 30463730 TI - Predictive Value of Leukocyte- and Platelet-Derived Ratios in Rectal Adenocarcinoma. AB - BACKGROUND: Advances in treatment of rectal cancer have improved survival, but there is variability in response to therapy. Recent data suggest the utility of the lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) in predicting survival. Our aim was to examine these ratios in rectal cancer patients and determine whether any association exists with overall survival (OS). METHODS: Using prospectively maintained institutional data, a query was completed for clinical stage II-III rectal adenocarcinoma patients treated from 2002 to 2016. We included patients who had a complete blood count collected before neoadjuvant chemoradiation (pre-CRT) and again before surgery (post-CRT). The LMR, NLR, and PLR were calculated for the pre-CRT and post-CRT time points. Potential cutpoints associated with OS differences were determined using maximally selected rank statistics. Survival curves were compared using log-rank tests and were adjusted for age and stage using Cox regression. RESULTS: A total of 146 patients were included. Cutpoints were significantly associated with OS for pre-CRT ratios but not for post-CRT ratios. Within the pretreatment group, a "low" (<2.86) LMR was associated with decreased OS (log-rank P = 0.004). In the same group, a "high" (>4.47) NLR and "high" PLR (>203.6) were associated with decreased OS (log-rank P < 0.001). With covariate adjustment for age, and separately for final pathologic stage, the associations between OS and LMR, NLR, and PLR each retained statistical significance. CONCLUSIONS: If obtained before the start of neoadjuvant chemoradiation, LMR, NLR, and PLR values are accurate predictors of 5-y OS in patients with locally advanced rectal adenocarcinoma. PMID- 30463732 TI - Splenic Embolization After Trauma: An Opportunity to Improve Best Immunization Practices. AB - BACKGROUND: The spleen is the second most commonly injured solid organ during blunt abdominal trauma. Although total splenectomy is frequently performed for injury, splenic rupture can also be managed by splenic embolization. For these patients, current Advisory Committee on Immunization Practices (ACIP) recommendations indicate that if 50% or more of the splenic mass is lost, patients should be treated as though they are asplenic. We have previously demonstrated that compliance with ACIP guidelines regarding immunization after splenectomy is poor. Compliance with vaccination in the setting of splenic embolization for trauma is unknown and we hypothesized patients would not receive the recommended immunizations. MATERIALS AND METHODS: All admissions at our level 1 trauma center requiring splenic embolization secondary to traumatic injury between January 1, 2010, and November 1, 2015, were reviewed. Demographic and injury data, dates and imaging of splenic embolizations, immunization documentation, subsequent vaccination boosters received, and outcomes were collected from the medical record. The proportion of spleen embolized was estimated by review of angiographic imaging using an established method. RESULTS: Nine thousand nine hundred sixty-five trauma patients were admitted during the period studied. Nineteen patients met inclusion and exclusion criteria. Median age of the patient population was 35 y, 85% were male, and median injury severity score was 28. Of these, 15 patients underwent a splenic embolization, in which 50% or more of their splenic mass was lost through embolization. Eight patients received at least one immunization before discharge. Six received initial immunizations against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae, while three received only the initial immunization against S pneumoniae. None of the 15 patients received any ACIP-recommended booster. Of the four patients having less than 50% of their spleen embolized, three wrongly received immunization against encapsulated organisms before hospital discharge. CONCLUSIONS: Trauma patients undergoing splenic embolization at our institution receive postsplenectomy immunizations incorrectly and had no recorded booster vaccines. We speculate that this is common among the U.S. trauma centers. Review of immunization practices in our trauma and nontrauma patient populations is underway in our health system to improve the care of these patients, and our experience may serve as a guide for other centers to reduce complications associated with asplenia. PMID- 30463731 TI - Antifibrosis Effect of Novel Oridonin Analog CYD0618 Via Suppression of the NF kappaB Pathway. AB - BACKGROUND: Liver fibrosis is characterized as excessive deposition of the extracellular matrix proteins, primarily by activated hepatic stellate cells (HSCs). NF-kappaB has been reported as one of the major mediators of HSC activation. Previously, our team reported that oridonin exhibited antihepatic fibrogenetic activity in vitro. In this study, we examined the effects of its novel derivative CYD0618 on HSC viability, apoptosis, and NF-kappaB signaling. METHODS: Cell proliferation of activated human and rat HSC lines LX-2 and HSC-T6 was measured using Alamar Blue Assay. Apoptosis was measured by a Cell Death Detection ELISA kit. Cellular proteins were determined by Western blots and immunofluorescence. RESULTS: CYD0618 significantly inhibited LX-2 and HSC-T6 cell proliferation in a dose-dependent manner. CYD0618 induced cell apoptosis in both cell lines. CYD0618 treatment increased cell cycle inhibitory protein p21, p27, and induced apoptosis marker cleaved poly (ADP-ribose) polymerase, while suppressing the expression of Collagen type 1. CYD0618 blocked lipopolysaccharide (LPS)-induced NF-kappaB p65 nuclear translocation and DNA binding activity and prevented LPS-induced NF-kappaB inhibitory protein IkappaBalpha phosphorylation and degradation. LPS-stimulated NF-kappaB downstream target cytokines IL-6 and MCP-1 were attenuated by CYD0618. Endogenous and LPS-stimulated NF-kappaB p65 S536 phosphorylation was inhibited by CYD0618 treatment. CONCLUSIONS: The potent antihepatic fibrogenetic effect of CYD0618 may be mediated via suppression of the NF-kappaB pathway. PMID- 30463733 TI - Estimating Surgical Risk in Younger and Older Children With Congenital Heart Disease. AB - BACKGROUND: As management of congenital heart disease (CHD) improves, children with CHD increasingly present for noncardiac surgery. Prior studies report conflicting results on the association between CHD and adverse outcomes in noncardiac surgery. Studies reporting no such association predominantly analyze older children and adolescents. We evaluated whether the association between CHD and adverse surgical outcomes was attenuated by increased age. METHODS: Patients aged 0-17 y, undergoing elective noncardiac surgery, were identified in the National Surgical Quality Improvement Program-Pediatric registry. CHD status was classified as none, minor, major, or severe. Multivariable logistic regression evaluated the association of CHD status with the occurrence of any postoperative complication for groups defined by quintiles of patient age (<1, 1-3, 4-8, 9-13, and 14-17 y). Specific complications included cardiac arrest, reintubation, infection, renal failure, neurological complication, thromboembolic complication, reoperation, 30-d unplanned revisit, 30-d prolonged hospital stay, and mortality. RESULTS: The analysis included 131,164 children, of whom 6420 had minor CHD, 3825 had major CHD, and 963 had severe CHD. The overall rate of complications was 9%. In multivariable analysis, children <1 y old had greater risk of postoperative complications if they had minor (odds ratio [OR] = 1.97; 95% confidence interval [CI]: 1.70, 2.20; P < 0.001), major (OR = 2.58; 95% CI: 2.28, 2.91; P < 0.001), or severe CHD (OR = 4.37; 95% CI: 3.45, 5.54; P < 0.001). In older age groups, however, the presence of CHD was not independently associated with postoperative complications. CONCLUSIONS: In pediatric noncardiac surgery, an independent association of CHD with postoperative complications was only evident among children <1 y old. PMID- 30463735 TI - Rapid Ground Transport of Trauma Patients: A Moderate Distance From Trauma Center Improves Survival. AB - BACKGROUND: There is debate within the emergency medical services (EMS) community over the value of calling a helicopter for trauma patients within a moderate distance/<45 min, of a trauma center. Helicopter EMS (HEMS) generally have a wider scope and more advanced training than the ground EMS (GEMS). GEMS, on the other hand, have the benefit of being able to immediately initiate rapid transport to the trauma center without the delay involved with HEMS flying to the scene, landing, and assuming patient care. METHODS: We retrospectively analyzed patients brought to a level I trauma center who were admitted with blunt traumatic injuries between 2010 and 2015 in the Trauma Quality Improvement Program database. Two analyses were performed, one in which the patient's reported initial scene vitals met criteria for step one of the Centers for Disease Control's 2011 National Field Triage Guidelines (NFTG) and the other in which the patient's initial scene vitals met those same guidelines and/or had a pulse greater than 110 beats per minute. Patients were categorized on scene to emergency department (ED) transport mode, either HEMS or GEMS. Inclusion criteria were a HEMS response time to the scene that was between 15 and 45 min with a transport time from the scene to the ED that was between 10 and 35 min or a GEMS transport time from the scene to the ED that was between 15 and 45 min. Statistical significance (P < 0.05) was established through logit regression. Mortality rates were then calculated within each transport mode-based population. RESULTS: Four hundred subjects were included in the analysis of patients meeting the first step of the NFTG, with 212 HEMS patients and 188 in the GEMS group. HEMS had a higher mortality rate at 0.184 and GEMS at 0.101, which was statistically significant (P = 0.019). When 606 subjects meeting the first step of the NFTG or with a pulse greater than 110 beats per minute were analyzed, the results were statistically significant (P < 0.001), with the HEMS category having a higher mortality rate at 0.154 and the GEMS category having a lower mortality at 0.056. CONCLUSIONS: Our data demonstrate that scene-to-ED time is paramount, and rapid ground transport should be used in blunt trauma patients when the scene is up to a moderate ground distance away from the trauma center and there would be a moderate-to-prolonged HEMS response time. In both analyses, hemodynamically unstable trauma patients had lower rates of mortality following ground transport. We recognize that there may be a subset of patients at these distances who could benefit from HEMS response, particularly if the flight crew can offer more advanced and specialized techniques; however, every effort should be made to minimize the scene-to-ED time, and HEMS response, scene, and transport time must be considered. This study only analyzed the patients within a moderate distance of the trauma center and at longer distances or in different environments; HEMS transport may indeed minimize the scene to ED time. PMID- 30463734 TI - Put Me in the Game Coach! Resident Participation in High-risk Surgery in the Era of Big Data. AB - BACKGROUND: With the emphasis on quality metrics guiding reimbursement, concerns have emerged regarding resident participation in patient care. This study aimed to evaluate whether resident participation in high-risk elective general surgery procedures is safe. MATERIALS AND METHODS: The American College of Surgeons National Surgical Quality Improvement Program database (2005-2012) was used to identify patients undergoing one of five high-risk general surgery procedures. Resident and nonresident groups were created using a 2:1 propensity score match. Postoperative outcomes were calculated using univariate statistics and multivariable logistic regression for the two groups. Predictors of mortality and morbidity were identified using machine learning in the form of decision trees. RESULTS: Twenty-five thousand three hundred sixty three patients met our inclusion criteria. Following matching, each group contained 500 patients and was comparable for matched characteristics. Thirty-day mortality was similar between the groups (2.4% versus 2.6%; P = 0.839). Deep surgical site infection (0% versus 1.6%; P = 0.005), urinary tract infection (5% versus 2.5%; P = 0.029), and operative time (275.6 min versus 250 min; P = 0.0064) were significantly higher with resident participation. Resident participation was not predictive of mortality or complications, while age, American society of anesthesiologists class, and functional status were leading predictors of both. CONCLUSIONS: Despite growing time constraints and pressure to perform, surgical resident participation remains safe. Residents should be given active roles in the operating room, even in the most challenging cases. PMID- 30463736 TI - Loss of Intestinal Alkaline Phosphatase Leads to Distinct Chronic Changes in Bone Phenotype. AB - BACKGROUND: The gut is becoming increasingly recognized as the source of various systemic diseases, and recently, it has been linked to bone metabolism via the so called gut-bone axis. The microbiome and gut-derived mediators are thought to impact upon bone metabolism, and administration of probiotics has been shown to have beneficial effects in bone. The gut brush border enzyme intestinal alkaline phosphatase (IAP) plays an important role in controlling calcium absorption, inhibiting lipopolysaccharides, and other inflammatory mediators responsible for endotoxemia and appears to preserve the normal gut microbiota. Interestingly, IAP deficient mice (AKP3-/-) also display a significant decrease in fecal Lactobacillus, the genus shown to be beneficial to bone. MATERIALS AND METHODS: IAP mRNA levels in mouse bone were measured using quantitative real-time polymerase chain reaction. Femurs of IAP-knockout (KO) and wild-type (WT) mice were analyzed by microcomputed tomography and histopathology. Serum levels of alkaline phosphatase, calcium, and phosphorus were measured. Target cell response upon exposure to serum from IAP-KO and WT mice was quantified using primary bone marrow macrophages. RESULTS: IAP was not significantly expressed in bones of WT or KO animals. IAP (alkaline phosphatase 3) expression in bone was vanishingly low compared to the duodenum (bone versus duodenum, 56.9 +/- 17.7 versus 25,430.3 +/- 10,884.5 relative expression, P = 0.01). Bone histology of younger IAP-KO and WT animals was indistinguishable, whereas older IAP-deficient mice showed a distinctly altered phenotype on histology and computed tomography scan. Younger KO mice did not display any abnormal levels in blood chemistry. Older IAP-KO animals showed an isolated increase in serum alkaline phosphatase levels reflecting an environment of active bone formation (IAP-WT versus IAP-KO, 80 +/- 27.4 U/I versus 453 +/- 107.5 U/I, P = 0.004). There was no significant difference in serum calcium or phosphorus levels between KO and WT mice. Serum from IAP-KO mice induced a significantly higher inflammatory target cell response. CONCLUSIONS: Through its multiple functions, IAP seems to play a crucial role in connecting the gut to the bone. IAP deficiency leads to chronic changes in bone formation, most likely through dysbiosis and systemic dissemination of proinflammatory mediators. PMID- 30463737 TI - Occurrence and Treatment of Pediatric Appendicitis in Finland 2004-2014. AB - BACKGROUND: We aimed to investigate the trends in occurrence and the treatment approaches of appendicitis in Finnish children. MATERIAL AND METHODS: All patients aged <16 y hospitalized for appendicitis in Finland in 2004-2014 were included. Data were retrospectively collected from the Finnish Care Register for Health Care and Statistics Finland. RESULTS: Altogether 8494 children were hospitalized for appendicitis, with standardized incidence rate of 80.7 (95% confidence interval 79.0-82.0)/100,000 person years. The incidence rate of appendicitis decreased by 3.3% per year during the study period. Appendicitis was more common with increasing age, in boys compared to girls at 8 to 15 y of age, and during the summer compared to the other seasons. Most children (83.2%) were treated with conventional open appendectomy, but laparoscopic appendectomies were slowly increasing during the study period. The length of hospital stay (LOS) was shorter in boys than girls, in those treated laparoscopically, and in those with uncomplicated appendicitis. There was no significant seasonal variation in the LOS. However, the LOS decreased during the study period. CONCLUSIONS: The incidence of pediatric appendicitis is decreasing, and there is a decreasing trend in LOS. While still relatively rare in the Finnish pediatric surgical centers, the use of laparoscopic appendectomy is increasing. PMID- 30463738 TI - The Transition to Data-Driven Quality Metrics: Determining the Optimal Surveillance Period for Complications After Surgery. AB - BACKGROUND: Thirty-day complications frequently serve in the surgical literature as a quality indicator. This metric is not meant to capture the full array of complication resulting from surgical intervention. However, this period is largely based on convention, with little evidence to support it. This study sought to determine the optimal surveillance period for postsurgical complications, defined as the shortest period that also encompassed the highest proportion of postsurgical adverse events. METHODS: TRICARE data (2006-2014) were queried for adult (18-64 y) patients who underwent one of 11 surgical procedures. Patients were assessed for complications up to 90 d after surgery. Kaplan-Meier curves, linear spline regression models at each incremental postsurgical day, and adjusted R-squared values were used to identify critical time point cutoffs for the surveillance of complications. Optimal length of surveillance was defined as the postsurgical day on which the model demonstrated the highest R-squared value. A supplemental analysis considered these measures for orthopedic and general surgical procedures. RESULTS: One lakh ninety-eight patients met the inclusion criteria. A total of 21.8% patients experienced at least one complication during the follow-up period, with 59% occurring within the first 15 d. Kaplan-Meier curves for complications showed a demonstrable inflection before 20 d and 14-15 d possessed the highest R-squared values. CONCLUSIONS: In this analysis, the optimal surveillance period for postsurgical complications was 15 d. While the conventional 30-d period may still be appropriate for a variety of reasons, the shorter interval identified here may represent a superior quality measure specific to surgical practice. PMID- 30463739 TI - Impact of Packed Red Blood Cell and Platelet Transfusions in Patients Undergoing Dissection Repair. AB - BACKGROUND: Transfusion of blood products commonly occur in patients undergoing repair of acute type A aortic dissection (AADA). MATERIALS AND METHODS: The medical records of 102 AADA patients were retrospectively reviewed and stratified into cohorts by packed red blood cell (PRBC) and platelet units received: PRBC <=2 units (n = 68) versus PRBC >2 units (n = 34); platelets <=1 unit (n = 74) versus platelets >1 unit (n = 28). Continuous and categorical variables were assessed by analysis of variance testing and chi-square or Fisher's testing as appropriate. Multivariate logistic regression was applied to derive P values for post-transfusion complications. Kaplan-Meier survival analyses were used to compare the hospital length of stay (LOS) and survival rate at 1 mo and 1 y. RESULTS: Patients receiving >2 units of PRBC had a median LOS of 14 d versus 9 d for those receiving <=2 units (P < 0.002). Transfusion of >2 units of PRBC was a risk factor for postoperative infection (odds ratio [OR] = 5.4, 95% confidence interval [CI]: 1.5-19.0, P = 0.009). Survival at 1 mo was 91% versus 94% (P = 0.783) and 1 y survival was 82% versus 93% (P = 0.269) between the two groups. Patients receiving >1 unit of platelets had a median LOS of 15 d versus 10 d for those receiving <=1 unit (P = 0.005). Transfusion of >1 unit of platelets was a risk factor for postoperative atrial fibrillation and acute kidney injury (OR = 2.9, 95% CI: 1.1-7.6, P = 0.031; OR = 3.3, 95% CI: 1.2-9.4, P = 0.025, respectively). Survival at 1 mo was 93% versus 93% (P = 0.872) and 1 y survival was 81% versus 92% (P = 0.582) between the two groups. CONCLUSIONS: Transfusion of PRBC and platelets above a threshold increases the incidence of postoperative complications and hospital LOS among patients undergoing repair of AADA. PMID- 30463740 TI - Same-Day Discharge for Nonperforated Appendicitis in Children: An Updated Institutional Protocol. AB - BACKGROUND: The evolving demands of our current health care system for enhanced efficiency and safety while decreasing hospital length of stay has led to our institutional protocol for same-day discharge (SDD) after laparoscopic appendectomy. We have previously demonstrated a 28% rate of SDD in children with nonperforated appendicitis. The purpose of our study is to assess the effectiveness of a mature protocol for SDD by evaluating discharge success, duration of hospital stay, and readmission rates. MATERIALS AND METHODS: A retrospective review of prospectively collected data was conducted. All children undergoing a laparoscopic appendectomy for nonperforated appendicitis at Children's Mercy Hospital between December 2015 and July 2017 were included. Patients were classified according to whether they were discharged home the same day as their operation or had an overnight stay. Demographic data, time of day the procedure was completed, postoperative length of stay, and readmission rates were abstracted from patient medical records. Comparative analysis was performed in STATA using chi-squared or Fisher exact tests for categorical variables and t test or Wilcoxon rank sum test for continuous variables. RESULTS: A total of 569 children were included, with 87% (n = 495) discharged home the same day as their appendectomy. Of the patients discharged home the same day of surgery, their median length of postoperative stay was 4 h (IQR: 3, 5) compared with 19 h for the patients who stayed overnight (IQR: 15, 25, P < 0.0001). Approximately two thirds of patients who had their appendectomies after 6 PM stayed overnight. In addition, patients discharged home the same day had similar hospital readmission rates compared with patients who stayed overnight (2% vs. 4%, P = 0.155). CONCLUSIONS: After laparoscopic appendectomy in children with nonperforated appendicitis, SDD not only reduces postoperative length of stay but also is not associated with higher hospital readmission rates. PMID- 30463741 TI - Systematic Review: Online Crowdsourcing to Assess Perceptual Speech Outcomes. AB - BACKGROUND: Speech is integral for human interaction and development. Speech assessments are critical in the growing child, especially in the surgical evaluation of patients undergoing cleft palate and speech surgeries. Online crowdsourcing enables layperson raters, allowing rapid and large-scale data collection. This systematic review analyzes the utility of online crowdsourcing to evaluate perceptual speech outcomes. METHODS: Terms related to "crowdsourcing" and "speech" were searched on PubMed, Scopus, CINAHL, Cochrane CENTRAL, and PsycINFO on August 16, 2017, returning 2812 unique articles. Inclusion and exclusion criteria concentrated on online crowdsourcing of perceptual speech outcomes: titles led to 140 abstracts that yielded 35 full-text articles, of which eight articles met criteria for analysis. RESULTS: All studies used Amazon Mechanical Turk for online crowd raters, and one used an additional crowdsourcing site (CrowdFlower). Disordered speech was provided by 376 speakers, for which 2203 crowd workers produced over 700,000 unique ratings. Five studies compared crowdsourced assessments to gold standards and found high concordances. Data collection time ranged from 59 min to 23 h, with worker payments ranging from $0.05 to $2.00 per task. Studies examined child pronunciation of the /r/ sound, dysarthria in Parkinson's speech, and articulation of English words produced by non-English speakers learning English. CONCLUSIONS: Online crowdsourcing for perceptual speech outcomes provides high-quality data consistent with previous speech-assessment standards in a rapid, cost-effective manner. This novel methodology incorporates lay perspective of speech intelligibility and has the potential to revolutionize surgical speech outcome assessments, including cleft palate and speech surgery. PMID- 30463742 TI - Utilization of Indocyanine Green to Aid in Identifying Sentinel Lymph Nodes in Merkel Cell Cancer. AB - BACKGROUND: Merkel cell carcinoma (MCC) is a relatively rare skin cancer with high rates of regional lymph node involvement and metastatic spread. National Comprehensive Cancer Network guidelines recommend sentinel lymph node biopsy (SLNB) for staging purposes. The goal of this study is to report our experience utilizing indocyanine green (ICG) fluorescence-based technology to aid in SLNB detection in MCC. METHODS: Consecutive MCC patients who underwent SLNB with radioisotope lymphoscintigraphy, with intraoperative handheld gamma probe, and ICG-based fluorescence imaging from 2012 to 2017 were prospectively studied (Cohort A). A group of historical controls that underwent SLNB for MCC with radioisotope lymphoscintigraphy and vital blue dye (VBD) (lymphazurin or methylene blue dye) was also analyzed (Cohort B). RESULTS: Twenty-four consecutive patients underwent SLNB with lymphoscintigraphy and ICG-based fluorescence and 11 controls underwent SLNB with lymphoscintigraphy and VBD. The localization rate by node with VBD was 63.6% and ICG-based fluorescence was 94.8%. For two patients, a positive sentinel lymph node (SLN) was detected only by ICG-based fluorescence and the nodes were not detected by gamma probe and one patient's only positive node was identified via ICG fluorescence only. VBD or gamma probe did not identify any unique positive SLNs in either cohort B or either cohort, respectively. CONCLUSIONS: In this study, we indicate that ICG based fluorescence is not only feasible to augment SLN identification, but it has a higher node localization rate as compared to blue dye and it was able to identify positive SLNs otherwise missed by gamma probe. This study suggests the importance of utilizing two modalities to augment SLN identification and that ICG based fluorescence may be able to identify nodes that would have been otherwise missed by gamma probe. We will continue to follow these patients and enroll more patients in this prospective study to further determine the role that ICG-based fluorescence has in identifying sentinel lymph nodes in MCC. PMID- 30463743 TI - Neutrophil Lymphocyte Ratio and Transarterial Chemoembolization in Neuroendocrine Tumor Metastases. AB - BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) has been shown to be predictive of outcomes in various cancers, including neuroendocrine tumors (NETs), and cancer-related treatments, including transarterial chemoembolization (TACE). We hypothesized that NLR could be predictive of response to TACE in patients with metastatic NET. METHODS: We reviewed 262 patients who underwent TACE for metastatic NET at a single tertiary medical center from 2000 to 2016. NLR was calculated from blood work drawn 1 d before TACE, as well as 1 d, 1 wk, and 6 mo after treatment. RESULTS: The median post-TACE overall survival (OS) of the entire cohort was 30.1 mo. Median OS of patients with a pre-TACE NLR <= 4 was 33.3 mo versus 21.1 mo for patients with a pre-TACE NLR >4 (P = 0.005). At 6 mo, the median OS for patients with post-TACE NLR > pre-TACE NLR was 21.4 mo versus 25.8 mo for patients with post-TACE NLR <= pre-TACE NLR (P = 0.007). On multivariate analysis, both pre-TACE NLR and 6-mo post-TACE NLR were independent predictors of survival. NLR values from 1-d and 1-wk post-TACE did not correlate with outcome. CONCLUSIONS: An elevated NLR pre-TACE and an NLR that has not returned to its pre-TACE value several months after TACE correlate with outcomes in patients with NET and liver metastases. This value can easily be calculated from laboratory results routinely obtained as part of preprocedural and postprocedural care, potential treatment strategies. PMID- 30463744 TI - Acute Kidney Injury on Presentation to a Major Trauma Service is Associated with Poor Outcomes. AB - BACKGROUND: This study sought to describe the burden of disease of acute kidney injury (AKI) among adult South African trauma patients who presented to a tertiary level trauma service. METHODS: The trauma database was interrogated for the period from December 2012 to July 2017. All patients over the age of 18 y, who were admitted following trauma, were included. Outcome data were reviewed. This included in-hospital mortality, need for intensive care unit admission, and length of stay. AKI was defined according to the latest Kidney Disease Improving Global Outcomes guidelines using the presentation serum creatinine. RESULTS: A total of 7613 patients were admitted for trauma over the period under review. Four thousand two hundred sixty-six patients were suitable for analysis. A total of 238 (5.6%) patients presented with AKI, 149 (62.6%) had stage 1 AKI, 40 (16.8%) had stage 2 AKI, and 49 (20.6%) had stage 3 AKI. There was a higher incidence of AKI in patients with blunt trauma. The length of stay, need for intensive care unit admission, and mortality were significantly higher in patients presenting with AKI than in those who did not present with AKI. There were 172 deaths (4.0%). The patients who died were older and had significantly higher Injury Severity Score than survivors. They were more acidotic on presentation, had lower Glasgow Coma Scale, and were more likely to be hypotensive on presentation. They also were significantly more likely to have AKI on presentation. (30.2% versus 5.6% P < 0.001). AKI on presentation was an independent risk factor for mortality (odds ratio 3.038 95% confidence interval 1.260-7.325). CONCLUSIONS: AKI is common in patients presenting to our center with acute trauma. The presence of AKI is associated with increased morbidity and mortality. Efforts must be directed to improving recognition of at-risk patients. Prompt referral and adequate resuscitation of trauma patients before transfer must be prioritized. PMID- 30463745 TI - A Phase II Trial of Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Recurrent Adrenocortical Carcinoma. AB - BACKGROUND: Recurrent adrenocortical carcinoma (ACC) is an aggressive disease with few options offering durable survival benefit. Despite metastasectomy, recurrence is common. Cytoreduction and intraperitoneal chemotherapy have offered improved survival in other advanced cancers. We sought to evaluate the use of cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of recurrent intraperitoneal ACC. METHODS: A phase II, single institution clinical trial was approved for patients with radiographic evidence of resectable ACC limited to the peritoneum. Patients underwent treatment if optimal cytoreduction was deemed possible at exploratory laparotomy. Primary outcome was intraperitoneal progression-free survival. Secondary outcomes were treatment-related morbidities and overall survival. RESULTS: Sixty-three patients were evaluated, of whom 11 met eligibility criteria. Nine patients underwent cytoreduction and HIPEC, including one patient who recurred and was re-treated (n = 10 treatments). One patient could not be optimally cytoreduced for HIPEC and therefore did not receive intraperitoneal chemotherapy. There was no perioperative mortality; perioperative comorbidities were limited to Clavien Dindo grade 2 or 3 and included hematologic, infectious, and neurologic complications. Seven patients experienced disease recurrence and two patients died of disease during follow-up (median 24 mo). Intraperitoneal progression-free survival was 19 mo, and median overall survival has not yet been reached. CONCLUSIONS: Cytoreduction and HIPEC can be performed safely in selected patients. Patients with recurrent ACC confined to the peritoneal cavity can be considered for regional therapy in experienced hands. However, disease recurrence is common, and other treatment options should be explored. PMID- 30463746 TI - Impact of Trauma Hospital Ransomware Attack on Surgical Residency Training. AB - BACKGROUND: A recent ransomware attack led to the shutdown of the electronic health information system (HIS) at our trauma center for 2 mo. We investigated its impact on residency training during the downtime. MATERIAL AND METHODS: General and orthopedic surgical residents who rotated at the hospital were invited to participate in a survey regarding their patient care and residency training experiences during the downtime. Attending surgeons from both the specialties were invited to participate in a semistructured interview regarding their attitude toward residency training during the downtime. RESULTS: Twenty nine residents responded to the survey with a response rate of 78.4%. Residents acknowledged significant increases in face-to-face communication and decreases in use of online educational resources during the downtime (P < 0.01). Residents were significantly stressed by the dearth of online resources (P < 0.0001) and by paper-based orders and outpatient clinic (P < 0.05). A multivariate analysis demonstrated an inverse relationship between postgraduate year and stress from paper orders (P = 0.003). Attending surgeon's interviews revealed that they recognized residents' unpreparedness and strove harder to teach more effectively. CONCLUSIONS: Our study demonstrated that an unexpected shutdown of the hospital HIS imposed significant stress upon surgical residents providing trauma patient care and made attending surgeons take greater efforts to be more effective teachers. Residents who are digital natives lack adaptability to handle a paper based workflow. With cyber security threats increasing in health care, preparedness should be included in the graduate medical education curriculum. PMID- 30463747 TI - Single-Visit Surgery Offers Added Convenience and Excellent Family Satisfaction. AB - BACKGROUND: The traditional model for elective ambulatory surgical care includes three separate visits to the surgeon: an initial consultation, a second for outpatient surgery, and a third for postoperative follow-up. Single-Visit Surgery (SVS) is an alternative model of ambulatory surgical care that consolidates care into a single appointment where patients with straightforward surgical problems are evaluated in the morning and undergo a surgical procedure later that same afternoon. In April 2016, SVS was introduced at a tertiary-care freestanding children's hospital. Our objective for this study was to evaluate our early experience and conduct a survey of our patient's caregivers to evaluate their satisfaction with SVS. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients that were seen as part of SVS from April 2016 through December 2016. Data collected included demographics, diagnoses, procedures performed, clinical outcomes, and distance traveled to the hospital. In addition, adult caregivers of SVS patients were asked to participate in a telephone survey. RESULTS: There were 43 patients seen through SVS during the study period. The median age was 7 y. Of the 43 patients evaluated through SVS, 40 (93%) of them underwent surgery. Of the 40 patients that had surgery, 27 (68%) of the families participated in the telephone survey. Of those responding, 93% were strongly satisfied, and 7% were satisfied with the care through SVS. All families said they would recommend the SVS program to a friend. CONCLUSIONS: SVS is an alternative model of ambulatory surgical care that adds convenience to the patient experience and results in excellent family satisfaction. PMID- 30463748 TI - Exosomes of Endothelial Progenitor Cells Inhibit Neointima Formation After Carotid Artery Injury. AB - BACKGROUND: Exosomes released from endothelial progenitor cells (EPCs) play a protective role in various disease models. Both endothelial cell (EC) damage and smooth muscle cell (SMC) proliferation are involved in the pathological process of restenosis after angioplasty and stenting. Few studies have focused on the therapeutic role of exosomes in EC damage and SMC proliferation. In this study, we sought to investigate the effect of exosomes released by human fetal aorta derived EPCs on the rat carotid artery balloon injury model in vivo. We also sought to determine the effect of exosomes on both ECs and SMCs in vitro. METHODS: Exosomes (Exo group) or saline (Con group) were injected in rat carotid balloon injury model animals. The rats were sacrificed after 2, 4, 14, and 28 d, and injured carotid specimens were collected for Evans blue staining, hematoxylin eosin staining, and immunohistochemistry. RESULTS: When the Con group and the Exo group were compared, the reendothelialized areas were not significantly different after 2 or 4 d, as shown by Evans blue staining. The hematoxylin-eosin results showed that the intimal to medial area ratio was slightly but not significantly higher in the Exo group after 2 and 4 d. The immunohistochemistry results showed that the proliferation of SMCs was slightly higher in the Exo group after 2 and 4 d, but the difference was not significant. The reendothelialization area of the Con group was significantly smaller than that of the Exo group at day 14. Both the intimal to medial area ratio and SMC proliferation in the Exo group were significantly smaller than those of the Con group at 14 or 28 d. In the in vitro study, exosome treatment significantly enhanced the proliferation and migration of both ECs and SMCs. CONCLUSIONS: Exosomes derived from EPCs could inhibit neointimal hyperplasia after carotid artery injury in rats. The protective effect of exosomes may manifest through the promotion of EC repair rather than direct suppression of proliferation and migration of smooth muscles cells. PMID- 30463749 TI - Does Imaging Before Percutaneous Drain Removal Affect Rates of Intra-abdominal Abscess Recurrence? AB - BACKGROUND: Intra-abdominal abscesses account for a large proportion of surgical complications and carry high mortality if not promptly controlled. Image-guided percutaneous drainage is standard of care. The objective of the study was to identify factors that predict abscess recurrence after percutaneous drain (PD) removal and determine if imaging before drain removal effects recurrence. METHODS: A consecutive multicenter retrospective cohort analysis of all patients who underwent PD insertion for abscesses between January 1, 2015, and December 31, 2015, was performed. Patient characteristics, PD details, and abscess recurrence were assessed. RESULTS: One hundred eighty-eight patients underwent PD insertion for spontaneous or postoperative abscesses, and overall abscess recurrence was 21%. Drains remained in situ for a median of 21.5 d (interquartile range: 9-42 d) with antibiotics used in 91% of cases. Forty-seven patients (25%) had a sinogram before PD removal, while 22% had computed tomography (CT) scans and 11% had ultrasounds. Hierarchical multivariable regression analysis showed that imaging before PD removal was associated with a 66% reduction in the odds of abscess recurrence (OR 0.34; 95% confidence interval [CI] 0.13-0.70; P = 0.006). Sinogram use was associated with an 86% reduction in the odds of recurrence (OR 0.14; 95% CI 0.02-0.39; P = 0.002) and ultrasound use was associated with a 78% reduction in the odds of recurrence (OR 0.22; 95% CI 0.02-0.76; P = 0.044) while CT use was not associated with a significant reduction in recurrence. CONCLUSIONS: Imaging before PD removal is associated with a reduction in the rates of abscess recurrence and requirement for additional drainage procedures or surgery. In addition, CT is not superior to ultrasound or sinograms as an imaging modality. PMID- 30463750 TI - Teenage Trauma Patients Are at Increased Risk for Readmission for Mental Diseases and Disorders. AB - BACKGROUND: Most studies of readmission after trauma are limited to single institutions or single states. The purpose of this study was to determine the risk factors for readmission after trauma for mental illness including readmissions to different hospitals across the United States. MATERIALS AND METHODS: The Nationwide Readmission Database for 2013 and 2014 was queried for all patients aged 13 to 64 y with a nonelective admission for trauma and a nonelective readmission within 30 d. Multivariable logistic regression was performed for readmission for mental diseases and disorders. RESULTS: During the study period, 53,402 patients were readmitted within 30 d after trauma. The most common major diagnostic category on readmission was mental diseases and disorders (12.1%). The age group with the highest percentage of readmissions for mental diseases and disorders was 13 to 17 y (38%). On multivariable regression, the teenage group was also the most likely to be readmitted for mental diseases and disorders compared to 18-44 y (odds ratio [OR] 0.45, P < 0.01) and 45-64 y (OR 0.24, P < 0.01). Other high-risk comorbidities included HIV infection (OR 2.4, P < 0.01), psychosis (OR 2.2, P < 0.01), drug (OR 2.0, P < 0.01), and alcohol (OR 1.4, P < 0.01) abuse. CONCLUSIONS: Teenage trauma patients are at increased risk for hospital readmission for mental illness. Efforts to reduce these admissions should be targeted toward individuals with high-risk comorbidities such as HIV infection, psychosis, and substance abuse. PMID- 30463751 TI - The Role of Surgical Resection for Stage IV Gastric Cancer With Synchronous Hepatic Metastasis. AB - BACKGROUND: With improved responses to chemotherapy and targeted treatments, the role of surgery in metastatic gastric cancer (MGC) to the liver needs to be revisited. We sought to examine whether surgical resection is associated with improvement of long-term survival. METHODS: The National Cancer Database was queried for MGC to the liver (2010-2014). Survival analysis was performed to compare the effect of gastrectomy and perioperative chemotherapy (G-CT) to palliative chemotherapy (PCT) alone. RESULTS: We identified 3175 patients with MGC to the liver. Most patients (94%, n = 2979) were treated with PCT, whereas 6% (n = 196 patients) underwent G-CT. Overall survival improved in patients treated with G-CT compared to PCT alone (16 versus 9.7 mo, P < 0.001). In patients undergoing G-CT, neoadjuvant chemotherapy was associated with increased overall survival compared to adjuvant chemotherapy (18.9 versus 14.8 mo, P = 0.011). Hazards of death significantly decreased with gastrectomy (hazard ratio [HR]: 0.53, 95% confidence interval [CI]: 0.44-0.63, P < 0.001). Negative prognostic factors included advanced age (HR: 1.10, 95% CI: 1.06-1.14, P < 0.001), treatment at nonacademic institution (HR: 1.23, 95% CI: 1.13-1.33, P < 0.001), and poorly differentiated grade (HR: 1.54, 95% CI: 1.17-2.03, P < 0.001). CONCLUSIONS: G-CT is associated with improved survival in patients with gastric cancer and synchronous liver metastasis. Further experience with well-designed prospective trials may be warranted to confirm these findings. PMID- 30463752 TI - MELD-Na Score as a Predictor of Anastomotic Leak in Elective Colorectal Surgery. AB - BACKGROUND: For cirrhotic patients awaiting liver transplantation, the Model for End-Stage Liver Disease Sodium (MELD-Na) model is extensively studied. Because of the simplicity of the scoring system, there has been interest in applying MELD-Na to predict patient outcomes in the noncirrhotic surgical patient, and MELD-Na has been shown to predict postoperative morbidity and mortality after elective colectomy. Our aim was to identify the utility of MELD-Na to predict anastomotic leak in elective colorectal cases. METHODS: The American College of Surgeons National Surgical Quality Improvement Program targeted colectomy database was queried (2012-2014) for all elective colorectal procedures in patients without ascites. Leak rates were compared by MELD-Na score using chi-square tests and multivariate logistic regression analysis. RESULTS: We identified 44,540 elective colorectal cases (mean age, 60.5 y +/- 14.4, mean body mass index 28.8 +/- 6.6 kg/m2, 52% female), of which 70% were colon resections and 30% involved partial rectal resections (low anterior resections). Laparoscopic approach accounted for 64.72% while 35.3% were open. The overall complication and mortality rates were 21% and 0.7%, respectively, with a total anastomotic leak rate of 3.4%. Overall, 98% had a preoperative MELD-Na score between 10 and 20. Incremental increases in MELD-Na score (10-14, 15-19, and >=20) were associated with an increased leak rate, specifically in partial rectal resections (3.9% versus 5.1% versus 10.7% P <0.028). MELD-Na score >=20 had an increased leak rate when compared with those with MELD-Na 10-14 (odds ratio [OR] 1.627; 95% confidence interval [CI] [1.015, 2.607]). An MELD-Na score increase from 10-14 to 15-19 increases overall mortality (OR 5.22; 95% CI [3.55, 7.671]). In all elective colorectal procedures, for every one-point increase in MELD-Na score, anastomotic leak (OR 1.04 95% CI [1.006, 1.07]), mortality (OR 1.24; 95% CI, [1.20, 1.27]), and overall complications (OR 1.10; 95% CI [1.09, 1.12]) increased. MELD-Na was an independent predictor of anastomotic leak in partial rectal resections, when controlling for gender, steroid use, smoking, approach, operative time, preoperative chemotherapy, and Crohn's disease (OR 1.06, 95% CI [1.002, 1.122]). CONCLUSIONS: MELD-Na is an independent predictor of anastomotic leak in partial rectal resections. Anastomotic leak risk increases with increasing MELD-Na in elective colorectal resections, as does 30-d mortality and overall complication rate. As MELD-Na score increases to more than 20, restorative partial rectal resection has a 10% rate of anastomotic leak. PMID- 30463753 TI - Recurrence of Pilonidal Disease: Our Best is Not Good Enough. AB - BACKGROUND: Recurrence rates of pilonidal disease have been reported to be high as 30%. Patients with recurrent pilonidal disease often develop chronic wounds and draining sinuses that incur long-term morbidity, disability, and decreased quality of life. The aim of this study was to characterize rates of recurrence in patients with pilonidal disease treated by pediatric surgeons. METHODS: A single center retrospective review of patients with pilonidal disease evaluated by pediatric surgeons from 2010 to 2015 was performed. Recurrence of pilonidal disease was defined as an episode of active pilonidal disease that required medical or surgical intervention >30 days from the preceding treatment. Repeated events proportional hazards regression modeling was performed to identify factors associated with time to recurrence. RESULTS: Among 307 patients treated for pilonidal disease, nearly 50% were male, and the median age at initial evaluation was 16 years (IQR 15-17). Approximately 45% were obese (BMI >= 95th percentile). The initial treatment during the study period was surgical excision in two-thirds and incision and drainage and/or antibiotics in one-third. The overall recurrence rate was 33%, with the majority of recurrences (80%) occurring within the first year. On multivariable analysis, obese BMI was the only factor independently associated with time to disease recurrence. CONCLUSIONS: Pilonidal disease has a substantial recurrence rate even after surgical excision. Future studies investigating treatments that can prevent disease recurrence are needed. PMID- 30463754 TI - Preoperative Hypoglycemia and Hyperglycemia Are Related to Postoperative Infection Rates in Implant-Based Breast Reconstruction. AB - OBJECTIVES: Diabetic patients undergoing surgery are known to have a higher risk for infection. However, current literature does not adequately investigate the effects of preoperative hypoglycemia or hyperglycemia on postoperative infection risk. METHODS: A retrospective review of a national private payer database within the PearlDiver Supercomputer application (Warsaw, IN) for patients undergoing breast reconstruction with implant/expander (BR) was conducted. These patients were identified by Current Procedural Terminology (CPT) and International Classification of Disease (ICD-9) ninth revision codes. Glucose ranges were identified by filtering for Logical Observation Identifiers Names and Codes ranging from 25 to 219 mg/dL, in 15 mg/mL increments. Patients with preexisting diabetes diagnoses were excluded. These patients were longitudinally tracked for infection at the 90 d and 1-y postoperative period using ICD-9 codes. RESULTS: The search query yielded 13,237 BR procedures with preoperative glycemic levels ranging from 25 to 219 mg/mL. Most procedures (34.6%) were performed on patients with preoperative glycemic levels ranging from 70 to 99 mg/dL. Of the total procedures performed (n = 13,237), 19.4% (n = 2564) resulted in infections documented at the 90-d interval, and 24.8% (n = 3285) resulted in infections documented at the 1-y interval. BR patients within the 40-54 mg/dL range had the highest rate of infection (90 d: 30.1%; 1 y: 53.4%). There was a statistically higher incidence of infection among patients with preoperative hypoglycemia (<70 mg/dL). CONCLUSIONS: The incidence of infection remains high in preoperatively hyperglycemic patients undergoing breast reconstruction procedures. However, our results show that preoperatively hypoglycemic patients also have an increased incidence of infection. PMID- 30463756 TI - Leaving Contaminated Trauma Laparotomy Wounds Open Reduces Wound Infections But Does Not Add Value. AB - BACKGROUND: The incidence of surgical site infection (SSI) has become a key quality indicator following clean and clean/contaminated surgical procedures. In contrast, contaminated and dirty wounds have garnered little attention with this quality metric because of the expected higher complication incidence. We hypothesized that wound management strategies in this high-risk population vary significantly and might not add value to the overall care. MATERIALS AND METHODS: This is a retrospective, observational study of trauma patients who underwent an exploratory laparotomy at an urban, academic, level 1 trauma center from 2014 to 2016. Deaths before hospital discharge were excluded. Wounds were classified using the Centers for Disease Control and Prevention definition on review of the operative reports. SSI was determined by review of the medical record, also per Centers for Disease Control and Prevention definition. Wound management strategies were categorized as either primary skin closure or closure by secondary intention. Outcomes were compared using Chi square or Kruskal-Wallis test. RESULTS: There were 128 patients who met study criteria. Fifty-five (42.9%) wounds were left open to close by secondary intention. In the wounds that were closed primarily (n = 73), eight (10.9%) developed an SSI. There were significant differences in the average length of stay (25.0 versus 11.6 d, P = 0.032), number of office visits (3.0 versus 1.8, P = 0.008), and time from last laparotomy to the last wound care office visit (112.8 versus 57.4, P = 0.012) between patients who were treated with secondary intention closure compared to those closed primarily who did not suffer from SSI. CONCLUSIONS: There is significant incidence of SSI in contaminated and dirty traumatic abdominal wounds; however, wound management strategies vary widely within this cohort. Closure by secondary intention requires significantly more resource utilization. Isolating risk factors for SSI may allow additional patients to undergo primary skin closure and avoid the morbidity of closure by secondary intention. PMID- 30463755 TI - Infarct-Sparing Effect of Adenosine A2B Receptor Agonist Is Primarily Due to Its Action on Splenic Leukocytes Via a PI3K/Akt/IL-10 Pathway. AB - BACKGROUND: Adenosine A2B receptor (A2BAR) agonist reduces myocardial reperfusion injury by acting on inflammatory cells. Recently, a cardiosplenic axis was shown to mediate the myocardial postischemic reperfusion injury. This study aimed to explore whether the infarct-squaring effect of A2BAR agonist was primarily due to its action on splenic leukocytes. METHODS: C57BL6 (wild type [WT]) mice underwent 40 min of left coronary artery occlusion followed by 60 min of reperfusion. A2BAR knockout (KO) and interleukin (IL)-10KO mice served as donors for splenic leukocytes. Acute splenectomy was performed 30 min before ischemia. The acute splenic leukocyte adoptive transfer was performed by injecting 5 * 106 live splenic leukocytes into splenectomized mice. BAY 60-6583, an A2BAR agonist, was injected by i.v. 15 min before ischemia. The infarct size (IS) was determined using 2,3,5-triphenyltetrazolium chloride and Phthalo blue staining. The expression of p-Akt and IL-10 was estimated by Western blotting. Immunofluorescence staining assessed the localization of IL-10 expression. RESULTS: BAY 60-6583 reduced the myocardial IS in intact mice but failed to reduce the same in splenectomized mice, which had a smaller IS than intact mice. BAY 60-6583 reduced the IS in splenectomized mice with the acute transfer of WT splenic leukocytes; however, it did not protect the heart of splenectomized mice with the acute transfer of A2BRKO splenic leukocytes. Furthermore, BAY 60-6583 increased the levels of p-Akt and IL-10 in the WT spleen. Moreover, it did not exert any protective effect in IL-10KO mice. CONCLUSIONS: A2BAR activation before ischemia stimulated the IL-10 production in splenic leukocytes via a PI3K/Akt pathway, thereby exerting anti-inflammatory effects that limited the myocardial reperfusion injury. PMID- 30463757 TI - The Malnourished Patient With Obesity: A Unique Paradox in Bariatric Surgery. AB - BACKGROUND: Hypoalbuminemia is a known risk factor for poor outcomes following surgery. Obesity can be associated with modest to severe malnutrition. We evaluated the impact of hypoalbuminemia on surgical outcomes in patients with obesity undergoing elective bariatric surgical procedures. MATERIALS AND METHODS: The 2015 metabolic and bariatric surgery accreditation and quality improvement program database was queried. Patients >= 18 y with body mass index >=35 undergoing bariatric surgery were included. Revision procedures were excluded. Patients were classified by albumin level (albumin >=3.5 g/dL [normal], 3.49-3.0 g/dL [mild], 2.99-2.5 g/dL [moderate], and <2.5 g/dL [severe]). Independent logistic regression models were developed to estimate the adjusted odds of (1) death or serious morbidity (DSM); (2) mild to moderate complications; (3) severe complications; and (4) 30-d readmissions by albumin level. In addition, effect modification by >10% weight loss was examined. RESULTS: A total of 106,577 patients were included in the study. Over 6% of patients had hypoalbuminemia. Fifty-five percent of complications were severe as categorized by the Clavien Dindo classification. Patients with mild hypoalbuminemia had 20% increased odds of DSM (95% confidence interval: 1.1-1.4). There was increasing likelihood of DSM with severe hypoalbuminemia. Patients with mild hypoalbuminemia had 20% increased odds of 30-d readmission (confidence interval: 1.1-1.3). A >10% weight loss modified the effect of moderate to severe hypoalbuminemia on DSM. CONCLUSIONS: More than 6% of patients with obesity undergoing bariatric surgery are malnourished. Hypoalbuminemia is an important and modifiable risk factor for postoperative adverse outcomes following bariatric surgery. Preoperative weight loss >10% combined with moderate to severe hypoalbuminemia is synergistic for high rates of DSM and should be addressed before proceeding with bariatric surgery. PMID- 30463758 TI - Assessment of Differential Pressures in Chest Drainage Systems: Is What You See What You Get? AB - BACKGROUND: Dry-suction chest drainage systems are used to achieve proper drainage of the pleural space after cardiothoracic operations. Data on the actual intrapleural pressure during the use of these systems is lacking. The present study was performed to evaluate pressure differences across the circuit using an ex vivo model. METHODS: An ex vivo apparatus coupled to a hospital-grade pleural drainage system was devised to provide calibrated levels of suction and air leak. Simultaneous pressure measurements were obtained at the system outlet and the simulated patient entry site. Trials were conducted with increasing levels of water between the patient and drainage modules at various levels of suction and leak pressures. Signals were recorded at 100 Hz and analyzed using two-way ANOVA. RESULTS: With no obstruction, the drainage system provided precise levels of negative pressure at the patient level (10-40 cm H2O). Addition of fluid in the drainage tubing caused significant differences in transmitted suction (P < 0.001). With increasing air leakage and fluid volume, the pressure differential between the system and patient increased significantly (1.14 to 36.69 cm H2O, P < 0.001). In the off-suction setting, increasing levels of obstruction to 22 cm of water led to development of positive intrapleural pressures (2.6 to 11.1 cm H2O, P < 0.001). CONCLUSIONS: While commercially available chest drainage systems are able to provide predictable levels of suction at the device, intrapleural pressures can be highly variable and depend on complete patency of connecting tubes. Systems capable of modulating the level of suction based on actual intrapleural pressures may enhance recovery after procedures requiring tube thoracotomy. PMID- 30463759 TI - Double Percutaneous Transesophageal Gastrotubing for Gastric Cancer: A Pilot Study. AB - BACKGROUND: The management of gastric cancer causing gastric outlet obstruction and dilatation must include decompression of the stomach and intravenous nutrition. Percutaneous transesophageal gastrotubing (PTEG) is an effective technique for either gastric decompression or enteral nutrition. Here, we investigated the efficacy and safety of double PTEG (dPTEG), that is, using PTEG for both purposes simultaneously, in patients with gastric cancer. MATERIALS AND METHODS: Eleven patients with gastric outlet obstruction due to gastric cancer were admitted to our hospital between January 2015 and March 2017 and enrolled in this study. Each patient underwent dPTEG as soon as possible. After dPTEG tubes were placed, gastric decompression was started immediately and enteral nutrition was started within 1 d. Feeding and decompression through the double tubes were continued until the day before operation. Using data from these patients, we investigated the efficacy and safety of dPTEG. RESULTS: dPTEG was performed successfully in all patients and no critical adverse effects were observed. Eight of the 11 patients underwent radical or palliative resection. Decompression of the stomach was achieved and nutritional status was significantly improved after dPTEG in all patients. CONCLUSIONS: We conclude that dPTEG is a safe and effective management technique for patients with gastric outlet obstruction and gastric dilatation due to gastric cancer. PMID- 30463760 TI - Disparities in Radiation Burden from Trauma Evaluation at Pediatric Versus Nonpediatric Institutions. AB - BACKGROUND: Computed tomography (CT) imaging protocols and prescribing practices vary across institutions. Pediatric trauma patients imaged at a pediatric trauma center (PTC) may receive less radiation than patients imaged at non-PTCs before transfer. Our objective was to determine differences in radiation exposure from imaging performed at a PTC versus non-PTCs. METHODS: This retrospective analysis included patients <18 y old who underwent CT imaging from January 2013 to August 2015 during a trauma-related encounter. Radiation doses from CT scans were estimated and compared between scans performed at our PTC and non-PTCs before patient transfer using propensity score-weighted median regression. RESULTS: Of 3530 CT scans, 3021 were performed at our PTC and 509 at non-PTCs. Patients imaged at non-PTCs were older and had higher injury severity (all P < 0.05). Patients imaged at non-PTCs more frequently had neck CT (29.0% versus 7.3%) and chest CT (8.3% versus 2.7%), less frequently had abdomen/pelvis CT (19.5% versus 27.9%, all P < 0.01), and had similar rates of head CT (83.9% versus 80.9%, P = 0.18). After propensity weighting, CT scanning was more frequent at non-PTCs and patients received higher cumulative radiation exposure overall (median effective dose 2.36 versus 1.57 mSv, P < 0.001) and for each body region imaged (17% more for head, 191% for neck, 81% for chest, and 33% for abdomen/pelvis). CONCLUSIONS: Pediatric trauma patients imaged at a PTC receive lower radiation burden from CT imaging than patients initially imaged at adult institutions. Broader adoption of pediatric dosing protocols or deferring noncritical CT scans until transfer may mitigate these disparities. PMID- 30463761 TI - From Procedure to Poverty: Out-of-Pocket and Catastrophic Expenditure for Pediatric Surgery in Uganda. AB - BACKGROUND: Financial protection from catastrophic health care expenditure (CHE) and patient out-of-pocket (OOP) spending are key indicators for sustainable surgical delivery. We aimed to calculate these metrics for a hospital stay requiring surgery in Uganda's pediatric population. METHODS: A survey was administered to family members of postoperative patients in the pediatric surgical ward at Mulago Hospital. Cost categories included direct medical costs, direct nonmedical costs, indirect costs, plus money borrowed and items sold to pay for the hospital stay. CHE was defined as spending greater than 10% of annual household expenditure. Costs were reported in Ugandan shillings and US dollars. RESULTS: One hundred and thirty-two patient families were surveyed between November 2016 and April 2017. Median direct costs were $27.55 (IQR 18.73-183.69) for diagnostics, $18.36 (IQR 9.52-41.33) for medications, $26.63 (IQR 9.19-45.92) for transportation, and $32.60 (IQR 12.85-64.29) for food and lodging. Forty-four percent of respondents were employed, and median indirect cost from productivity loss was $95.52 (IQR 55.10-243.38). Eighteen percent (16/87) borrowed money, and 9% (8/87) sold possessions to pay for the hospital stay. Total median OOP cost for patient families per hospital stay was $150.62 (IQR 65.21-339.82). Sixteen percent (21/132) of families incurred CHE from direct costs, and the proportion rose to 27% (32/132) when indirect cost was included. CONCLUSIONS: Although pediatric surgical services in Uganda are formally provided for free by the public sector, families accrue substantial OOP expenditure and almost a third of households incur CHE for a pediatric surgical procedure. This study suggests that broader financial protection must be established to meet Sustainable Development Goal targets. PMID- 30463762 TI - Inpatient Pain Medication Administration: Understanding the Process and Its Delays. AB - BACKGROUND: A patient's impression of quality of care is strongly influenced by pain management. MATERIALS AND METHODS: We sought to understand the process of pro re nata (PRN) pain medication administration through direct observation and use of timestamped data from the electronic medical record (EMR). The total time from nurse notification to administration was compared between PRN narcotics, non narcotic pain, and nonpain medications. RESULTS: We noted two pathways: patient initiated requests and nurses preemptively asking about pain. We observed 44 instances of PRN medication administration (33 narcotics, 5 non-narcotics, 6 nonpain). Patients waited a median of 14.5 min for all PRN medications, interquartile range 6.5, 36. There was no significant difference in times for the patient-initiated pathway (n = 39, median 15 min, [7, 40]) compared to preemptive rounding (n = 5, 10 min [5, 30]), P = 0.88. Narcotics (median 14 min, [5, 30]) did not take longer than non-narcotic (11, [10, 88]) or nonpain medications (19.5, [11, 40]), P = 0.75. Electronic medical record data included only the time from medication retrieval to administration, which took approximately 5 min for all medications. CONCLUSIONS: Medication administration is complex, comprising multiple vital steps. The findings of this study suggest opportunities for process improvement that may enhance the experience and overall satisfaction of the surgical patient. PMID- 30463763 TI - The Application of a Shorter Loop in Kasai Portoenterostomy Reconstruction for Ohi Type III Biliary Atresia: A Prospective Randomized Controlled Trial. AB - BACKGROUND: A 30-40 cm Roux loop is widely accepted in Kasai portoenterostomy in infants with Ohi Type III biliary atresia (BA), regardless of patient's size, to avoid reflux cholangitis. However, the redundant length of the jejunal limb may lead to complications; hence, we compared the outcome of a shorter Roux loop with the standard loop length in Kasai portoenterostomy in infants with Ohi Type III BA. METHODS: There were 166 patients with Ohi Type III BA who underwent the Kasai procedure and were prospectively randomized into two groups: (1) the long Roux loop group (LRLG) contained 91 patients, where a standard 30-40 cm Roux loop was used regardless of the child's size and (2) the short Roux loop group (SRLG) included 75 patients in which the Roux loop length was based on the distance between hepatic hilum and umbilicus. The follow-up periods were 3 to 50 mo. Contrast-enhanced ultrasonography of the upper gastrointestinal tract was studied, and laboratory tests were included during the follow-up period. RESULT: The mean Roux loop length of SRLG was 17.42 +/- 3.91 cm (13-20 cm); it was significantly shorter than that of the LRLG (32.87 +/- 3.91 cm [30-40 cm], P = 0.00). There were no significant differences between the LRLG and SRLG in terms of age, body weight at time of the operation, length of operation, blood loss during the operation, and length of postoperative hospital stay (64.50 +/- 20.41 d versus 68.34 +/- 17.59 d, 4.3 +/- 0.8 kg versus 4.1 +/- 1.2 kg, 187.6 +/- 35.7 min versus 172.3 +/- 20.4 min, 21.71 +/- 9.41 mL versus 25.32 +/- 10.82 mL, 9.01 +/- 3.97 d versus 8.16 +/- 2.40 d; P = 0.63, 0.47, 0.09, 0.89, and 0.61, respectively). Six months after the operation, the clearance of jaundice rate in the LRLG was 45.1% (41/91), while the rate was 50.7% (38/75) in the SRLG; there was no statistically significant difference (P = 0.47). The incidence of cholangitis in the LRLG was 42.9% (39/91), which was similar to that of the SRLG (46.7%, 35/75) (P = 0.62). The incidence of overall complications (such as intestinal obstruction, gastrointestinal bleeding, bile leak, and anastomotic stenosis) in the SRLG was lower than that of the LRLG, but the difference did not reach statistical significance (4/91, 4.4% versus 5/75, 6.7%; P = 0.76). According to the Kaplan-Meier survival analysis and log rank test, the native liver survival rate in the LRLG and the SRLG also showed no significant difference (P = 0.964, log rank test). Grade I reflux was detected in three patients in the LRLG and two patients in the SRLG (P = 0.54). However, the reflux subsided 6 months later in all five patients. CONCLUSIONS: A shorter Roux-loop length in Kasai portoenterostomy reconstruction had a similar efficacy as the conventional Roux-loop length. PMID- 30463764 TI - Emergent Laparoscopic Ventral Hernia Repairs. AB - BACKGROUND: Emergent repairs of incarcerated and strangulated ventral hernia repairs (VHR) are associated with higher perioperative morbidity and mortality than those repaired electively. Despite increasing utilization of minimally invasive techniques in elective repairs, the role for laparoscopy in emergent VHR is not well defined, and its feasibility has been demonstrated only in single center studies. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database (2009-2016) was queried for emergent VHR. Laparoscopic and open techniques were compared using univariate and multivariate analyses. RESULTS: A total of 11,075 patients who underwent emergent ventral and incisional hernia repairs were identified: 85.5% open ventral hernia repair (OVHR), 14.5% laparoscopic ventral hernia repair (LVHR). Patients who underwent emergent OVHRs were older, more comorbid, and more likely to be septic at the time of surgery than those undergoing emergent LVHRs. Emergent OVHR patients were more likely to have minor complications (22.1% versus 11.0%; OR 1.7; 95% CI 1.069 2.834). After controlling for confounding variables, LVHR and OVHR had similar outcomes, with the exception of higher rates of superficial surgical site infection in OVHR (5.0% versus 1.8%; odd's ratio (OR) 2.7; 95% confidence interval (CI) 1.176-6.138). Following multivariate analysis, laparoscopic approach demonstrated similar outcomes in major complications, reoperation, and 30-d mortality compared to open repairs. However, when controlling for other confounding factors, LVHR had reduced length of stay compared to OVHR (6.7 versus 4.0 d; 1.6 d longer, standard error 0.77, P < 0.03). CONCLUSIONS: Emergent LVHR is associated with fewer superficial surgical site infection and shorter length of stay than OVHR but no difference in major complications, reoperation or 30-d mortality is associated with LVHR in the emergency setting. PMID- 30463765 TI - Effects of Limb Revascularization Procedures on Oxidative Stress. AB - Revascularization procedures to treat patients with peripheral artery disease are among the most common operations performed by vascular surgeons. However, there are major limitations to revascularizations, readmission rates due to procedural complications are high, and greater risks of cardiovascular and limb adverse outcomes have been reported for patients with peripheral artery disease undergoing limb revascularization. Specifically, surgical revascularization may be associated with increased generation of reactive oxygen species based on the ischemia reperfusion injury theory, as restored blood flow and reoxygenation of ischemic areas may be accompanied by increased oxidative stress. In this review, we present the current evidence regarding the effects of revascularization procedures on oxidative stress. We also discuss potential therapeutic interventions to prevent ischemia reperfusion injury-mediated tissue damage. PMID- 30463766 TI - Performing Trauma Surgery in the Emergency Room Impacts the Timeliness of Surgery. AB - BACKGROUND: Our institution has emergency rooms (ERs) with an operating room (OR) setup, which enables surgeons to perform thoracotomy and/or laparotomy for trauma patients without transferring patients to the OR. We hypothesized that the ERs with an OR setup improve the timeliness of surgery for trauma patients. MATERIALS AND METHODS: Data were reviewed from trauma patients who underwent emergency surgeries performed by our acute care surgery group from April 2013 to June 2017. Patients' demographics, diagnoses, location of the operation (ER versus regular OR), type of operation, time from admission to operation, and perioperative outcomes including in-hospital mortality were analyzed. These data were compared between patients who underwent surgery in the ER versus the OR. RESULTS: There were 105 trauma patients who met the inclusion criteria. Of these 105 patients, 50 underwent surgery in the ER (47.6%, ER group), whereas 55 underwent surgery in the OR (52.4%, OR group). Compared with the OR group, the ER group had a shorter time from admission to operation (median 43 min [range 3-105 min] versus 109 min [range 15-1340 min], P < 0.04), and higher in-hospital mortality rate (38.2% versus 0%, P < 0.01). CONCLUSIONS: An ER with an OR setup can enable surgery to be started sooner. Compared with the OR group, patients who underwent surgery performed in the ER tended to be in a more serious condition, and were thus likely to have a higher mortality rate. Further study is warranted to determine which patients would benefit best from this approach. PMID- 30463767 TI - Echocardiographic Guidance During Neonatal and Pediatric Jugular Cannulation for ECMO. AB - BACKGROUND: Internal jugular vein extracorporeal membrane oxygenation (ECMO) cannula position is traditionally confirmed via plain film. Misplaced cannulae can result in need for repositioning and increased morbidity. Echocardiography (ECHO) may be used during cannulation as a more accurate means of guiding cannula position. This study reviews the effect of a protocol encouraging the use of ECHO at cannulation. METHODS AND MATERIALS: Single institution retrospective review of patients who received ECMO support using jugular venous cannulation. We compared those who underwent ECHO (ECHO+) at the time of cannulation with those who did not (ECHO-). RESULTS: Eighty-nine patients were included: 26 ECHO+, 63 ECHO-. Most ECHO+ patients underwent dual-lumen veno-venous (VV) cannulation (65%); 32% of ECHO- patients had VV support (P = 0.003). There was no difference in the rate of cannula repositioning between the two groups: 8% ECHO+ and 10% ECHO-, P = 0.78. In the VV ECMO subgroup, ECHO+ patients required no repositioning (0/17), while 20% (4/20) of ECHO- VV patients did (P = 0.10). After cannulation, there were 0.58 ECHO studies per patient to verify cannula position in the ECHO+ group compared with 0.22 in the ECHO- group (P = 0.02). Each group had a major mechanical complication: atrial perforation from a guidewire during cannulation in ECHO+ and late atrial perforation from a loose cannula in ECHO-, and there was no difference in minor complications. CONCLUSIONS: ECHO guidance during neonatal and pediatric jugular cannulation for ECMO did not decrease morbidity or reduce the need for cannula repositioning. ECHO may still be a useful adjunct for precise placement of a dual-lumen VV cannula and during difficult cannulations. PMID- 30463768 TI - Very Early Versus Early Readmissions in General Surgery Patients. AB - BACKGROUND: Hospital readmission rates are an important quality metric. A readmission very soon after discharge may be related to a different cause than readmissions that occur later in the first 30 d. MATERIALS AND METHODS: The National Surgical Quality Improvement Program data sets from 2014 to 2015 were used to identify patients undergoing general surgery procedures. Demographics, comorbidities, and morbidity were analyzed. Stepwise regression was used to determine statistical predictors for any readmission. The final model variables were a combination of selected clinical variables and statistically significant variables. Multinomial logistic regression was then used with these variables to develop models for "very early" (days 0-3 after discharge) and "early" (days 4 30) readmissions. RESULTS: A total of 744,492 patients were included with 5.9% readmitted within 30 d and 1.5% readmitted within 3 d of discharge (26.1% of all readmissions). Significant risk factors for any readmission included >=3 comorbidities, major surgery (operative time >1 h, length of stay greater >2 d), and American Society of Anesthesiologists class >=3. When examining "very early" readmissions, the greatest risk factor was experiencing a severe complication (>=Grade III) before discharge. CONCLUSIONS: Readmissions within 3 d of discharge constitute a large portion of all 30 d readmissions. The greatest risk factor for "very early" readmission was a severe complication before discharge. Better understanding of the reason for this association is needed to develop effective prevention strategies. PMID- 30463769 TI - Effect of Simvastatin on the Intestinal Rho/ROCK Signaling Pathway in Rats With Sepsis. AB - BACKGROUND: Simvastatin may alleviate the intestinal barrier dysfunction induced by sepsis. This study aimed to investigate the role of the Ras homolog (Rho)/Rho associated coiled-coil forming protein kinase (ROCK) signaling pathway in the intestinal barrier of simvastatin-treated rats with sepsis. MATERIALS AND METHODS: Male Wistar rats were pretreated with simvastatin (0.2 MUg/g of body weight) for 1 week before cecal ligation and puncture. Twenty-four hours after cecal ligation and puncture, the condition of bacterial translocation was evaluated. Plasma levels of intestinal fatty acid binding protein, D-lactic acid and inflammatory factors, and oxidative stress in the intestine were determined. The intestinal injury scores, as well as the protein levels of Rho, ROCK1, and tight junction proteins ZO-1 and occludin were analyzed. RESULTS: Treatment with simvastatin alleviated the sepsis-induced increases in the plasma concentration of intestinal fatty acid binding protein and D-lactic acid, as well as the number of colony-forming units in the bacterial culture of the blood, liver, spleen, and kidney. In addition, simvastatin effectively reduced the intestinal levels of tumor necrosis factor alpha, interleukin-6, high-mobility group box 1, and malondialdehyde and increased the activity of superoxide dismutase in rats with sepsis. Staining with hematoxylin and eosin showed that severe intestinal injury occurred in the sepsis group, which was reduced by the treatment of simvastatin. Furthermore, the expression of Rho and ROCK1 was significantly downregulated and the protein expression levels of ZO-1 and occludin were significantly increased in simvastatin-treated rats (P < 0.05). CONCLUSIONS: Simvastatin can ameliorate the intestinal barrier dysfunction caused by sepsis by inhibiting the Rho/ROCK signaling pathway and reducing the levels of inflammatory factors and oxidative stress in the intestine, which also increase the expression of tight junction proteins. PMID- 30463770 TI - Percutaneous Cholecystostomy in Acute Cholecystitis-Predictors of Recurrence and Interval Cholecystectomy. AB - BACKGROUND: Percutaneous cholecystostomy (PC) tube is a preferred option in acute cholecystitis for patients who are high risk for cholecystectomy (CCY). There are no evidence-based guidelines for patient care after PC. We identified the predictors of disease recurrence and successful interval CCY. METHODS: A retrospective review of 145 PC patients between 2008 and 2016 at a tertiary hospital was performed. Primary outcomes included mortality, readmissions, hospital and intensive care unit length of stay (LOS), disease recurrence, and interval CCY. RESULTS: There were 96 (67%) calculous and 47 (33%) acalculous cholecystitis cases. Seventy-two (49%) had chronic and 73 (51%) had acute prohibitive risks as an indication for PC. There were 54 (37%) periprocedural complications, which most commonly were dislodgements. Twenty-six (18%) patients had a recurrence at a median time of 65 days. Calculous cholecystitis (odds ratio [OR] 3.44, P = 0.038) and purulence in the gallbladder (OR 3.77, P = 0.009) were predictors for recurrence. Forty-one (28%) patients underwent interval CCY. Patients with acute illness were likely to undergo interval CCY (OR 6.67, P = 0.0002). Patients with acalculous cholecystitis had longer hospital LOS (16 versus 8 days) and intensive care unit LOS (2 versus 0 days), and higher readmission rates (OR 2.42, P = 0.02). Thirty-day mortality after PC placement was 9%. Patients receiving interval CCY were noted to have increased survival compared to PC alone. However, this should not be attributed to interval CCY alone in absence of randomization in this study. CONCLUSIONS: Calculous cholecystitis and purulence in the gallbladder are independent predictors of acute cholecystitis recurrence. Acute illness is a strong predictor of successful interval CCY. The association of interval CCY and prolonged survival in patients with PC as noted in this study should be further assessed in future prospective randomized trials. PMID- 30463771 TI - Evaluation of Anemia and Nutritional Status on Children Undergoing Resection of Primary Liver Tumors. AB - INTRODUCTION: Complete tumor resection of primary malignant liver tumors offers the best chance of survival. However, many of these children may experience anemia and failure to thrive. This study analyzes the association of preoperative anemia and nutritional support with outcomes in children undergoing major resection of primary malignant liver tumors. METHODS: Using the National Surgical Quality Improvement Program Pediatric database from 2012 to 2015, children undergoing major liver resections for primary malignant hepatic tumors were selected. Patient demographics, comorbidities, and 30-d outcomes were compared with respect to the presence of preoperative anemia and the need for nutritional support. Outcomes included 30-d postoperative complications, perioperative blood transfusions, and hospital readmissions. Propensity score matching was performed to control for significant confounders. RESULTS: One hundred ten children were included, 76 (69.1%) with preoperative anemia, and 36 (32.7%) receiving nutritional support. Anemia was associated with preoperative chemotherapy (P = 0.02) and steroids (P = 0.03). Nutritional support was associated with cardiac (P = 0.01), respiratory (P < 0.01), neurologic (P < 0.01), and hematologic comorbidities (P = 0.02). There were 20 (18.2%) postoperative complications and 6 (5.5%) hospital readmissions. After propensity score matching, there was no difference in complications between anemic and nonanemic patients (P = 0.13). Preoperative nutritional support was associated with an increased rate of complications (P < 0.01). Neither anemia (P = 1.00) nor nutritional support (P = 0.49) were associated with readmissions. CONCLUSIONS: The need for nutritional support is common in children undergoing resection of primary malignant hepatic tumors. Anemia was not significantly associated with postoperative complications. In this study, nutritional support was associated with an increased risk of postoperative complications. The need for nutritional support may warrant special attention to the patient's overall conditioning during operative planning. PMID- 30463772 TI - Rapid Release Protocol Optimizes Product Utilization Compared With Massive Transfusion Protocol in Selected Patients. AB - BACKGROUND: While massive transfusion protocols (MTPs) are effective means of expeditiously delivering blood products to patients with exsanguinating hemorrhage, activation often occurs in cases with small blood volume deficits, leading to product wastage and overtransfusion. We sought to determine whether the additional implementation of a new protocol (called Rapid Release [RR]), which uses less resources, would result in decrease in blood product wastage. We hypothesized that RR would result in the reservation of MTPs for sicker patients and that blood product wastage would decrease. METHODS: All MTP activations 1.5 y pre-RR and 1.5 y post-RR were analyzed. Compared with MTP (six units packed red blood cells [pRBCs], six units fresh frozen plasma [FFP], six units platelets), RR only releases four units pRBCs and one unit FFP per activation. MTP resource utilization and wastage was compared before and after RR in trauma and nontrauma populations. P <= 0.05 was considered significant. RESULTS: One hundred nine MTPs were activated pre- (n = 48) to post-RR (n = 61), with 69 RRs activated in the post-RR period. Of these 69 RRs, 10 (14.5%) were eventually upgraded to MTP. Compared with the pre-RR group, significantly higher transfusion rates were observed for FFP and platelets. FFP wastage increased (pre: 0.65 +/- 1.78 versus post: 3.46 +/- 4.29; P < 0.001) over the study duration with no differences between the trauma and nontrauma populations. CONCLUSIONS: Contrary to our hypothesis, institution of the RR protocol resulted in higher mean wastage of FFP per activation despite the appropriateness of the RR protocol. Further efforts are warranted to refine the MTP to increase efficiency. PMID- 30463773 TI - Prevalence and Perceptions of Team Training Programs for Pediatric Surgeons and Anesthesiologists. AB - BACKGROUND: Team training programs adapt crew resource management principles from aviation to foster communication and prevent medical errors. Although multiple studies have demonstrated that team training programs such as TeamSTEPPS improve patient outcomes and safety across medical disciplines, limited data exist about their application to pediatric surgical teams. The purpose of this study was to investigate usage and perceptions of team training programs by pediatric surgeons and anesthesiologists. We hypothesized that team training programs are not widely available to pediatric surgical teams. MATERIALS AND METHODS: We performed an online survey of Pediatric Surgery (General, Plastic, Urologic, Orthopedic, Otolaryngologic, and Ophthalmologic) and Anesthesiology members of the American Academy of Pediatrics. The survey inquired about completion and perceptions regarding efficacy of team training programs. Simple descriptive statistics and a Student t-test were used to evaluate the data. RESULTS: One hundred fifty-two pediatric surgeons and 12 anesthesiologists completed the survey with a 10% response rate. Over half of the respondents were general pediatric surgeons. Home institutions offered TeamSTEPPS or another crew resource management style team training program for 39% of respondents. Of those with a program, 77% of respondents had completed training. Although most (76%) who participated in team training programs did so by requirement, 90% found it helpful. Of the 61% of surgeons who said their institution did not offer team training programs, 60% said they would participate if one were offered and an additional 32% said they might participate. The biggest barriers to participation were not enough free time or that the team training program was not offered to their department. CONCLUSIONS: Team training programs are considered beneficial among pediatric surgeons and anesthesiologists who have completed them. Unfortunately, despite substantial evidence showing training for team work improves team functioning and patient outcomes, many pediatric surgical teams do not have team training programs at their institutions. Further expansion of team training programs may be valuable to improving a culture of safety in children's hospitals. PMID- 30463774 TI - Comparing Outcomes Between "Pull" Versus "Push" Percutaneous Endoscopic Gastrostomy in Acute Care Surgery: Under-Reported Pull Percutaneous Endoscopic Gastrostomy Incidence of Tube Dislodgement. AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) complications are often under-reported in the literature, especially regarding the incidence of tube dislodgement (TD). TD can cause significant morbidity depending on its timing. We compared outcomes between "push" and "pull" PEGs. We hypothesized that push PEGs, because of its T-fasteners and balloon tip, would have a lower incidence of TD and complications compared with pull PEGs. METHODS: We performed a chart review of our prospectively maintained acute care surgery database for patients who underwent PEG tube placement from July 1, 2009 through June 30, 2013. Data regarding age, gender, body mass index, indications (trauma versus nontrauma), and complications (including TD) were extracted. Procedure-related complications were classified as either major if patients required an operative intervention or minor if they did not. We compared outcomes between pull PEG and push PEG. Multiple regression analysis was performed to identify risk factors associated with major complications. RESULTS: During the 4-y study period, 264 patients underwent pull PEGs and 59 underwent push PEGs. Age, gender, body mass index, and indications were similar between the two groups. The overall complications (major and minor) were similar (20% pull versus 22% push, P = 0.61). The incidence of TD was also similar (12% pull versus 9% push, P = 0.49). However, TD associated with major complications was higher in pull PEGs but was not statistically significant (6% pull versus 2% push, P = 0.21). Multiple regression analysis showed that dislodged pull PEG was associated with major complications (odds ratio 29.5; 95% confidence interval, 11.3-76.9; P < 0.001). CONCLUSIONS: The incidence of pull PEG TD associated with major complications is under-recognized. Specific measures should be undertaken to help prevent pull PEG TD. LEVEL OF EVIDENCE: IV, therapeutic. PMID- 30463775 TI - Timely Evaluation and Management of Primary Hyperparathyroidism in Patients With Kidney Stones. AB - BACKGROUND: Nephrolithiasis is a classic, treatable manifestation of primary hyperparathyroidism (PHPT). We examined predictors of kidney stone formation in PHPT patients and determined how efficiently the diagnosis of PHPT is made in patients whose initial presentation is with stones. MATERIALS AND METHODS: We performed a retrospective analysis of surgically treated PHPT patients, comparing 247 patients who were kidney stone formers and 1047 patients with no kidney stones. We also analyzed 51 stone-forming patients whose stone evaluation and treatment were completed within our health system before PHPT diagnosis. RESULTS: Stone-forming patients had higher 24-h urinary calcium (342 versus 304 mg/d, P = 0.005), higher alkaline phosphatase (92 versus 85 IU/L, P = 0.012), and were more likely to be normocalcemic (26.6% versus 16.9%, P = 0.001). Surprisingly, 47.3% of stone formers had normal urinary calcium levels (<300 mg/d). Of the 51 stone forming patients treated at our institution, serum calcium was measured within 6 mo of stone diagnosis in 37 (72.5%) patients. Only 16 (31.4%) of these patients had elevated calcium levels, and only 10 (62.5%) of these 16 had a serum parathyroid hormone ordered within the following 3 mo. These patients had a significantly shorter time from their first stone to surgical treatment compared to other patients (median 8.5 versus 49.1 mo, P = 0.001). CONCLUSIONS: Elevated serum and urinary calcium levels are not evaluated in the majority of PHPT patients presenting with kidney stones. In nephrolithiasis patients, provider consideration of PHPT with prompt serum calcium and parathyroid hormone evaluation significantly reduces time to treatment. PMID- 30463777 TI - Developing Trauma Audit Filters for Regional Referral Hospitals in Cameroon: Mixed-Methods Approach. AB - BACKGROUND: Injuries are a leading cause of death and disability worldwide. Developing countries account for 90% of injury-related deaths globally. Trauma audit filters can facilitate trauma quality improvement initiatives and reduce the injury burden. Little is known about context-appropriate trauma audit filters for developing countries such as Cameroon. This study aimed to (1) develop context-appropriate trauma audit filters for the setting of a regional referral hospital in Cameroon and (2) to assess the barriers and facilitators to their implementation. METHODS: Feasible audit filters were identified by a panel of Cameroonian surgeons using the Delphi technique. A Likert scale (1 to 5, with 5 as "Most Useful") was used to rank the filters for utility in a regional referral hospital setting, analyzed using the median and interquartile range. Semistructured interviews were conducted with 16 health care providers from three hospital facilities to explore their perceptions of supervision and support they receive from hospital administration, availability of resources, their work environment, and potential concerns and impacts of trauma audit filters. Interviews were coded and thematically analyzed. RESULTS: Within a panel of seven surgeons, 23 of 40 trauma audit filter variables met majority consensus criteria. Twenty-one of these, comprising mostly of primary survey and basic resuscitation techniques, had a median score of >=4. Filters meeting consensus include, but are not limited to, vitals obtained, breathing assessment made, and two large bore intravenous established within 15 min of arrival; patient with open fracture receives intravenous antimicrobials within 1 h of arrival; patients with suspected spine injury are immobilized and given X-ray. The provider interviews revealed that the barriers to providing quality care were limited human and material resources and patients' inability to pay. Regular staff training in trauma care and the belief that trauma audit filters would potentially streamline work practices and improve the quality of care were cited as promoters of successful implementation. CONCLUSIONS: Primary survey and basic resuscitative techniques are key elements of context-appropriate audit filters in Cameroon. Such audit filters may not be costly, require complex infrastructure, or equipment that exceed the site's capabilities. Proper staff orientation and participation in the use of trauma audit filters, as quality improvement tools, are key to local buy-in and implementation success. PMID- 30463776 TI - Tracking Macrophage Infiltration in a Mouse Model of Pancreatic Cancer with the Positron Emission Tomography Tracer [11C]PBR28. AB - BACKGROUND: The tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) contains abundant immunosuppressive tumor-associated macrophages. High level of infiltration is associated with poor outcome and is thought to represent a major roadblock to lymphocyte-based immunotherapy. Efforts to block macrophage infiltration have been met with some success, but noninvasive means to track tumor-associated macrophagess in PDAC are lacking. Translocator protein (TSPO) is a mitochondrial membrane receptor which is upregulated in activated macrophages. We sought to identify if a radiotracer-labeled cognate ligand could track macrophages in PDAC. MATERIALS AND METHODS: A murine PDAC cell line was established from a transgenic mouse with pancreas-specific mutations in KRAS and p53. After confirming lack of endogenous TSPO expression, tumors were established in syngeneic mice. A radiolabeled TSPO-specific ligand ([11C] peripheral benzodiazepine receptor [PBR]28) was delivered intravenously, and tumor uptake was assessed by autoradiography, ex vivo, or micro-positron emission tomography imaging. RESULTS: Resected tumors contained abundant macrophages as determined by immunohistochemistry and flow cytometry. Immunoblotting revealed murine macrophages expressed TSPO with increasing concentration on activation and polarization. Autoradiography of resected tumors confirmed [11C]PBR28 uptake, and whole mount sections demonstrated the ability to localize tumors. To confirm the findings were macrophage specific, experiments were repeated in CD11b-deficient mice, and the radiotracer uptake was diminished. Micro-positron emission tomography imaging validated radiotracer uptake and tumor localization in a clinically applicable manner. CONCLUSIONS: As new immunotherapeutics reshape the PDAC microenvironment, tools are needed to better measure and track immune cell subsets. We have demonstrated the potential to measure changes in macrophage infiltration in PDAC using [11C]PBR28. PMID- 30463779 TI - Is There a Drawback of Converting a Laparoscopic Colectomy in Colon Cancer? AB - BACKGROUND: Laparoscopic resection is well established in the treatment of colon cancer. However, conversion rates remain high and the impact of conversion is disputed. MATERIAL AND METHODS: We retrospectively identified 1347 patients who underwent surgery for colon cancer between 2004 and 2014 at our tertiary center. Morbidity and oncological outcomes were compared between patients who underwent successfully completed laparoscopic surgery (LS), planned open surgery (OS), and conversion to open surgery (CS). Long-term analysis included patients with stage I-III disease. In addition, we performed propensity score matching to adjust for the heterogeneity and selection bias between the treatment groups. RESULTS: Of all patients, 505 underwent LS, 789 underwent OS, and 53 underwent CS, which corresponded to a conversion rate of 9.5%. Conversion was associated with male gender, left-sided tumors, and stage III disease. Length of stay, morbidity, and readmission rates were lower for LS patients. Kaplan-Meier curves demonstrated worse overall, disease-specific, and disease-free survival in CS than LS, with similar outcomes to OS. However, after propensity score matching, CS was only associated with admission duration and the requirement of blood transfusion, whereas survival outcomes were comparable between all groups. CONCLUSIONS: CS is associated with adverse short- and long-term outcomes compared to LS. However, when accounting for differences in baseline and pathologic features, CS remained only associated with a longer length of stay and more blood transfusions. Because outcomes were comparable between CS and OS, regardless of stage and other risk factors, our data support a surgeon's attempt to perform LS in patients with colon cancer. PMID- 30463778 TI - Preoperative Gastroesophageal Reflux Disorder Is Associated With Increased Morbidity in Patients Undergoing Abdominal Surgery. AB - BACKGROUND: In North America, the prevalence of gastroesophageal reflux disorder ranges from 18.1% to 27.8%. We measured the risk posed by preoperative esophageal disease for patients undergoing abdominal operations. METHOD: American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP; 2005-2015) data were merged with institutional clinical data repository records to identify esophageal disease in surgical patients undergoing intra-abdominal procedures. Patients with esophageal disease were classified as gastroesophageal reflux disorder (GERD) or other, which included patients with esophageal stricture, spasm, ulcer, or diverticuli, achalasia, esophagitis, reflux esophagitis, Barrett's esophagus, and multiple esophageal diagnoses, excluding GERD. ACS NSQIP targeted procedure groups included were colectomy, proctectomy, ventral hernia repair, bariatric surgery, hepatectomy, appendectomy, abdominal aortic aneurysm repair, open aortoiliac repair, hysterectomy, myomectomy, and oophorectomy. Multivariable logistic regression was used to model postoperative complication rates, adjusting for ACS NSQIP risk of morbidity, demographic factors, ACS NSQIP targeted procedure groups, and open versus laparoscopic surgery. RESULTS: Of 9172 intra-abdominal cases, 21.3% had preoperative esophageal disease (19.6% GERD and 1.7% other). After adjustment, patients with GERD were at higher risk for experiencing a number of complications, including all-cause 30-d complication (odds ratio [OR] = 1.21, 95% confidence interval [CI] 1.05-1.41, P = 0.044), renal complication (OR = 1.43, 95% CI 1.09-1.87, P = 0.036), wound complication (OR = 1.40, 95% CI 1.10-1.79, P = 0.028), and readmission within 30 d (OR = 1.66, 95% CI 1.35-2.04, P < 0.001). CONCLUSIONS: Preoperative GERD is associated with increased postoperative complication rate. Surgeons should consider assessing GERD in patients undergoing abdominal operations. PMID- 30463780 TI - The Liver and Small Intestine Can Partly Compensate Severe Normovolemic Hemodilution in a Rat Model. AB - BACKGROUND: Knowing the individual critical hematocrit for every organ is essential in operative scenarios in which extensive blood losses are expected. In the past, experimental settings were very heterogeneous resulting in the publication of widely differing values even for one organ in the same species. This study aimed to investigate the compensatory capacity of the liver and the small intestine in a rat model of severe normovolemic hemodilution. MATERIALS AND METHODS: Male rats were subjected to a stepwise hemodilution with a succinylated gelatin-containing solution to a final hematocrit of 10%, being observed for additional 150 min. During the course of the experiment, blood glucose and L lactate, as well as D-lactate and intestinal fatty acid-binding protein-2 measurements, were performed eight times in total. The amino acids alanine and glutamine were measured during dilution and at the end of the experiment (four times in total). Hemodilutional effects on the blood and oxygen supply of the liver and the small intestine were measured in a minimally invasive manner. RESULTS: In the liver and the small intestine, there were no substantial changes in the blood flow of the microcirculation. Plasma glucose and lactate levels rose transiently, whereas lactate values did not exceed the upper threshold of aerobic metabolism. Plasma levels of the amino acids alanine and glutamine rose significantly and stayed elevated, whereas D-lactate and intestinal fatty acid binding protein-2 were not significantly increased at any point during the whole experimental time compared to the initial value. CONCLUSIONS: Severe hemodilution with a succinylated gelatin-containing solution is tolerated at a profoundly low hematocrit value of 10% during the experimental phase of 150 min. PMID- 30463781 TI - Technical Considerations for Nephron-Sparing Surgery in Children: What Is Needed to Preserve Renal Units? AB - BACKGROUND: Chemotherapy is used preoperatively for children with bilateral Wilms tumor (BWT) or unilateral high-risk Wilms tumor (UHRWT) to promote tumor regression to facilitate renal preservation with nephron-sparing surgery (NSS). In adults, various surgical techniques have been described to preserve renal tissue. Few studies have examined the use of surgical adjuncts in NSS in children with renal tumors. METHODS: We performed a multi-institutional retrospective review of patients with BWT or UHRWT. Patient demographics, tumor size at diagnosis, following neoadjuvant chemotherapy, utilization of surgical adjuncts including intraoperative ultrasound (IOUS), margin status, complications, renal function, and follow-up were recorded. RESULTS: The cohort comprised 23 patients: 18 BWT, 3 UHRWT, and 2 patients with solitary kidney. Twenty-two of the 23 patients had successful NSS. IOUS was used 19 times, and seven had positive margins after surgery. Cooling/vascular isolation was used six times. At a median follow-up of 18 mo, median estimated glomerular filtration rate Schwartz was 126 mL/min/1.73 m2 and median serum creatinine 0.39 mg/dL in the 22 patients who had successful NSS. There have been no tumor recurrences. CONCLUSIONS: In patients with BWT and UHRWT, surgical adjuncts such as cooling/vascular isolation are uncommonly performed. IOUS may be helpful but does not guarantee negative microscopic margins. LEVEL OF EVIDENCE: Level 4, Case series with no comparison group. PMID- 30463782 TI - Positron Emission Tomography 18F-Fluorodeoxyglucose Uptake Correlates with KRAS and EMT Gene Signatures in Operable Esophageal Adenocarcinoma. AB - BACKGROUND: 18F-fluorodeoxyglucose positron emission tomography is an imaging modality critical to the diagnosis and staging of esophageal cancer. Despite this, the genetic abnormalities associated with increased 18F-fluorodeoxyglucose (FDG)-maximum standardized uptake value (SUVmax) have not been previously explored in esophageal adenocarcinoma. MATERIALS AND METHODS: Treatment-naive patients, for whom frozen tissue and 18F-fluorodeoxyglucose positron emission tomography data were available, undergoing esophagectomy from 2003 to 2012, were identified. Primary tumor FDG-uptake (SUVmax) was quantified as low (<5), moderate, or high (>10). Genome-wide expression analyses (e.g., microarray) were used to examine gene expression differences associated with FDG-uptake. RESULTS: Eighteen patients with stored positron emission tomography data and tissue were reviewed. Overall survival was similar between patients with high (n = 9) and low (n = 6) FDG-uptake tumors (P = 0.71). Differences in gene expression between tumors with high and low FDG-uptake included enriched expression of various matrix metalloproteinases, extracellular-matrix components, oncogenic signaling members, and PD-L1 (fold-change>2.0, P < 0.05) among the high-FDG tumors. Glycolytic gene expression and pathway involvement were similar between the high- and low-FDG tumor subsets (P = 0.126). Gene ontology analysis of the most differentially expressed genes demonstrated significant upregulation of gene sets associated with extracellular matrix organization and vascular development (P < 0.005). Gene set enrichment analysis further demonstrated associations between FDG-uptake intensity and canonical oncogenic processes, including hypoxia, angiogenesis, KRAS signaling, and epithelial-to-mesenchymal transition (P < 0.001). Interestingly, KRAS expression did not predict worse survival in a larger cohort (n = 104) of esophageal adenocarcinomas (P = 0.64). CONCLUSIONS: These results suggest that elevated FDG-uptake is associated with a variety of oncogenic alterations in operable esophageal adenocarcinoma. These pathways present potential therapeutic targets among tumors exhibiting high FDG-uptake. PMID- 30463783 TI - Race Is Associated With Burden of Anal Condyloma and Need for Operative Intervention. AB - BACKGROUND: Human papillomavirus is a common sexually transmitted infection that may affect the oropharynx, genitalia, or anus. Some strains of this virus may cause bulky growths around the anus known as giant anal condylomas. These can become large, disfiguring, and may cause bleeding, as well as difficulty with defecation and hygiene. Surgical management is usually necessary for large condylomas, whereas office-based procedures are common for smaller lesions. It is unclear why some develop large anal margin tumors, whereas others develop limited disease. The aim of the present study was to evaluate for risk factors that may play a role in the development of extensive disease warranting operative management. MATERIALS AND METHODS: A retrospective chart review of patients seen within the Anal Dysplasia Clinic at the Medical College of Wisconsin was undertaken. Clinic encounters for patients with anogenital condyloma were abstracted for demographic information, operative interventions, Human Immunodeficiency Virus status, and smoking history to determine risk factors that predicted operative intervention for giant anal condylomas. RESULTS: A total of 239 patients met inclusion criteria; 211 (88.3%) were male and 28 (11.7%) were female. Racial makeup of the cohort included 49% Caucasian, 38.9% African American, 9.2% Hispanic, and 2.9% were identified as another ethnicity. One hundred forty-three patients (60.1%) were current or past smokers. One hundred ninety-eight (82.8%) patients tested positive for human immunodeficiency virus (HIV), whereas 41 (17.2%) were negative. Multiple linear regression identified only African-American race as predictive of greater disease burden. CONCLUSIONS: African-American race was associated with increased size of anal condyloma. As the size of anal condylomas increase, management shifts from topical treatments to operative intervention. This is the first study to correlate race with burden of disease in the general population. PMID- 30463784 TI - Outcomes and Costs of Common Surgical Procedures at Children's and Nonchildren's Hospitals. AB - BACKGROUND: Variations in the management of pediatric patients at children's hospitals (CHs) and non-CHs (NCHs) have been well described, especially within the trauma literature. However, little is known about the outcomes and costs of common general surgical procedures at NCHs. The purpose of this study was to evaluate the effect of CH designation on the outcomes and costs of appendectomy and cholecystectomy. METHODS: The Kids' Inpatient Database (2003-2012) was queried for patients aged under 18 y who underwent appendectomy or cholecystectomy at CHs and NCHs. Outcomes analyzed included disease severity, complications, laparoscopy, length of stay (LOS), and cost. RESULTS: Most of appendectomies and cholecystectomies were performed at NCHs. Overall, CHs cared for younger children were more likely to be teaching hospitals, had higher costs, and longer LOS. On multivariate analysis for appendectomies, CHs were associated with higher rates of perforated appendicitis (OR = 1.53, 95% CI = 1.42-1.66, P < 0.001), less complications (OR = 0.68, 95% CI = 0.61-0.75, P < 0.001), increased laparoscopy (OR = 2.93, 95% CI = 2.36-3.64, P < 0.001), longer LOS (RR = 1.13, 95% CI = 1.09-1.17, P < 0.001), and higher costs (exponentiated log $ = 1.19, 95% CI = 1.13-1.24, P < 0.001). Multivariate analysis for cholecystectomies revealed that CHs were associated with less laparoscopy (OR = 0.58, 95% CI = 0.50-0.67, P < 0.001), longer LOS (RR = 1.26, 95% CI = 1.19-1.34, P < 0.001), and higher costs (exponentiated log $ = 1.29, 95% CI = 1.22-1.37, P < 0.001) with similar complications. Independent predictors of LOS and cost included CH designation, negative appendectomy, perforated appendicitis, complications, younger age, black patients, and public insurance. CONCLUSIONS: Variations in surgical management, outcomes, and costs after appendectomy and cholecystectomy exist between CHs and NCHs. CHs excelled in treating complicated appendicitis. NCHs effectively performed cholecystectomies. These differences in outcomes require further investigation to identify modifiable factors to optimize care across all hospitals for these common surgical diseases. PMID- 30463785 TI - Contamination After Disinfectant Rectal Washout in Left Colectomy as a Model for Transrectal NOTES: A Randomized Controlled Trial. AB - BACKGROUND: In natural orifice transluminal endoscopic surgery (NOTES) with transrectal (TR) access the intraoperative opening of the rectal wall poses a risk of intraperitoneal contamination and subsequent infectious complications. A rectal washout with a disinfectant may reduce this risk. The aim of the study was to assess the intraoperative contamination on the circular stapler pin when a rectal washout with povidone-iodine (RW-PI) or Ringer solution was performed in patients undergoing left-sided colectomy. Furthermore, the additional effect of an irrigation instrument on the contamination was evaluated. METHODS: In a patient and assessor blinded randomized controlled trial, patients undergoing left-sided colectomy were assigned to rectal washout with PI with an irrigation instrument (RW-PI; n = 23), rectal washout with Ringer solution with an irrigation instrument (RW-R; n = 21) or rectal washout with Ringer solution without an irrigation instrument (RW; n = 25). An end-to-end anastomosis with a circular stapler was performed. The contamination on the pin of the circular stapler was chosen as primary endpoint in order to simulate the intraabdominal contamination risk during TR NOTES. Secondary endpoints were contamination of the rectal mucosa, peritoneal contamination and postoperative morbidity. RESULTS: The contamination rate of the pin of the circular stapler did not differ (RW-PI 39.1%, RW-R 33.3%, RW 52.0%; P = 0.421), but contamination of the rectal mucosa was reduced (47.8% versus 95.2% versus 100%; P < 0.001) and peritoneal contamination tended to be reduced (39.1% versus 71.4% versus 60.0%; P = 0.09) when a rectal washout with PI was performed. The rates of infectious complications (17.4% versus 9.5% versus 12.0%; P = 0.821) and of overall complications (30.4% versus 28.6% versus 44.0%; P = 0.476) did not differ. CONCLUSIONS: Despite an intense rectal washout with PI, contamination of the stapler pin did not differ. Intraabdominal bacterial translocation was frequently encountered even after disinfectant rectal washout with PI. Further studies might focus on the clinical impact of intraabdominal contamination in TR NOTES. PMID- 30463786 TI - Outcomes After the Implementation of Practice Management Guidelines for the Treatment of Cardiovascular Implantable Device Pocket Infections. AB - BACKGROUND: Treatment of cardiovascular implantable device pocket infections (CIDPIs) requires a multimodal approach that includes antimicrobials, device explantation, and local wound care. Our institution implemented a practice management guideline (PMG) to standardize the care of CIDPIs and engage our acute care surgeons in 2013. Our PMG includes wound culture, complete capsulectomy, pulse lavage, and the placement of a negative pressure wound therapy appliance at the time of device extraction. Forty-eight hours later, wounds are irrigated and closed in a delayed primary fashion over drains. Our objective was to compare the outcomes of patients who underwent device extraction before and after the implementation of the PMG for the treatment of CIDPIs. METHODS: An IRB-approved retrospective review of 155 patients at our institution from 2012 to 2015 who underwent device explantation. Evaluated outcomes measured included days from device explant to wound closure, and postoperative complications. Outcomes data were analyzed before (pre-PMG) and after (post-PMG) enactment of the PMG. RESULTS: Fifty-eight patients (42 males; mean age 68 years) were managed prior to PMG implementation; 97 (72 males; mean age 67) were managed after. Mean days from device explantation to wound closure were compared (pre-PMG 6 +/- 3.5 and post PMG 2.8 +/- 1.8), and time to closure was reduced by 3-d post-PMG implementation (P < 0.05). No increase in surgical site infection, hematoma, or unplanned return to operating room was demonstrated between groups (P < 0.05). CONCLUSIONS: The implementation of a PMG for the management of CIDPIs is effective in reducing the number of days to pocket wound closure; acute care surgeons are well equipped to participate in this practice and improve patient outcomes. PMID- 30463787 TI - Impact of Medical School Experience on Attrition From General Surgery Residency. AB - BACKGROUND: Medical school experience informs the decision to pursue graduate surgical education. However, it is possible that inadequate preparation in medical school is responsible for the high rate of attrition seen in general surgery residency. MATERIALS AND METHODS: We performed a national prospective cohort study of all categorical general surgery interns who entered training in the 2007-2008 academic year. Interns answered questions about their medical school experience and reasons for pursuing general surgery residency. Responses were linked with American Board of Surgery residency completion data. Multivariable logistic regression was used to evaluate the association between medical school experiences and residency attrition. RESULTS: Seven hundred and ninety-two surgery interns participated, and the overall attrition rate was 19.3%. Most interns had performed <=8 wk of third year surgery clerkships (53.2% of those who completed versus 49.7% of those who dropped out, P = 0.08). After multivariable adjustment, shorter duration of third year rotations was protective from attrition (OR: 0.53, 95% CI: 0.29-0.99; P = 0.05). There was no difference in attrition based on whether a surgical subinternship was performed (OR: 0.67, 95% CI: 0.38-1.19; P = 0.18). Residents who perceived that their medical school surgical faculty were happy with their careers were less likely to experience attrition (OR: 0.57, 95% CI: 0.34-0.96; P = 0.03), but those who had gotten along well with attending surgeons had higher odds of attrition (OR: 2.93, 95% CI: 1.34 6.39, P < 0.01). CONCLUSIONS: Increased quality, rather than quantity, of clerkships is associated with improved rates of residency completion. Learner relationships with positive yet demanding role models were associated with a reduced risk of attrition. PMID- 30463788 TI - Clinical Significance of BRAF Non-V600E Mutations in Colorectal Cancer: A Retrospective Study of Two Institutions. AB - BACKGROUND: Recent advances in next-generation sequencing have enabled the detection of BRAF V600E mutations as well as BRAF non-V600E mutations in a single assay. The present work aimed to describe the clinicopathological characteristics and clinical outcome of the BRAF non-V600E mutant-type in colorectal cancer (CRC). PATIENTS AND METHODS: CRC samples from 111 Stage IV patients were analyzed for somatic mutations using a 415-gene comprehensive genomic sequencing panel. Patients were classified according to BRAF status as wild-type, V600E mutant type, or non-V600E mutant-type. Differences between clinicopathological characteristics and genetic alterations were analyzed among the three groups. Overall survival (OS) and the response to anti-EGFR therapy were also analyzed. RESULTS: Comprehensive genomic sequencing revealed that 98 patients (88%), 7 patients (6%), and 6 patients (6%) were wild-type, V600E mutant-type, and non V600E mutant-type, respectively. Non-V600E mutant-type tumors were frequently left-sided (83%), while V600E mutant-type tumors were frequently right-sided (86%; P = 0.025). Non-V600E mutant-type showed better OS than V600E mutant-type (P = 0.038), with no significant difference compared with wild-type tumors. The two patients with non-V600E mutations who underwent repeated metastasectomies showed no evidence of disease at final follow-up. Regarding the efficacy of anti EGFR therapy, the patient with an I326V mutation had progressive disease (+115%) despite no genetic alterations detected in the EGFR pathway that could drive resistance, suggesting an alternate resistance mechanism. CONCLUSIONS: Non-V600E mutant-type is more likely to be left-sided and demonstrates better OS than V600E mutant-type. Further preclinical and clinical investigations are needed to clarify the role of non-V600E mutations in CRC. PMID- 30463789 TI - Oral Xa Inhibitors Versus Low Molecular Weight Heparin for Thromboprophylaxis After Nonoperative Spine Trauma. AB - BACKGROUND: Thromboprophylaxis with oral Xa inhibitors (Xa-Inh) are recommended after major orthopedic operation; however, its role in spine trauma is not well defined. The aim of our study was to assess the impact of Xa-Inh in spinal trauma patients managed nonoperatively. METHODS: A 4-y (2013-2016) review of the Trauma Quality Improvement Program database. We included all patients with an isolated spine trauma (Spine-abbreviated injury scale >=3 and other-abbreviated injury scale <3) who were managed nonoperatively and received thromboprophylaxis with either low molecular weight heparin (LMWH) or Xa-Inh. Patients were divided into two groups based on the thromboprophylactic agent received: Xa-Inh and LMWH and were matched in a 1:2 ratio using propensity score matching for demographics, vitals and injury parameters, and level of spine injury. Outcomes were rates of deep venous thrombosis, pulmonary embolism, and mortality. RESULTS: We analyzed a total of 58,936 patients, of which 1056 patients (LMWH: 704, Xa-Inh: 352) were matched. Matched groups were similar in demographics, vital and injury parameters, length of hospital stay (P = 0.31), or time to thromboprophylaxis (P = 0.79). Patients who received Xa-Inh were less likely to develop a deep venous thrombosis (2.3% versus 5.7%, P < 0.01). There were no differences in the rate of pulmonary embolism (P = 0.73), postprophylaxis packed red blood cells transfusions (P = 0.79), postprophylaxis surgical decompression of spinal column (P = 0.75), and mortality rate (P = 0.77). CONCLUSIONS: Oral Xa-Inh seems to be more effective as prophylactic pharmacologic agent for the prevention of deep venous thrombosis in patients with nonoperative spinal trauma compared to LMWH. The two drugs had similar safety profile. Further prospective trials should be performed to change current guidelines. PMID- 30463790 TI - Racial and Ethnic Postoperative Outcomes After Surgery: The Hispanic Paradox. AB - BACKGROUND: The Hispanic population in the United States have previously been shown to have, in some cases, better health outcomes than non-Hispanic whites (NHWs) despite having lower socioeconomic status and higher frequency of comorbidities. This epidemiologic finding is coined as the Hispanic Paradox (HP). Few studies have evaluated if the HP exists in surgical patients. Our study aimed to examine postoperative complications between Hispanic and NHW patients undergoing low- to high-risk procedures. MATERIALS AND METHODS: We conducted a retrospective cohort study analyzing adult patients who underwent high-, intermediate-, and low-risk procedures. The Healthcare Cost and Utilization Project California State Inpatient Database between 2006 and 2011 was used to identify the patient cohort. Candidate variables for the adjusted model were determined a priori and included patient demographics with the ethnic group as the exposure of interest. RESULTS: The median age for Hispanics was 52 (SD 19.3) y, and 38.8% were male (n = 87,837). A higher proportion of Hispanics had Medicaid insurance (23.9% versus 3.8%) or were self-pay (14.2% versus 4.5%) compared with NHWs. In adjusted analysis, Hispanics had a higher odds risk for postoperative complications across all risk categories combined (OR 1.06, 95% CI 1.04-1.09). They also had an increased in-hospital (OR 1.38, 95% CI 1.14-1.30) and 30-d mortality in high-risk procedures (OR 1.34, 95% CI 1.19-1.51). CONCLUSIONS: Hispanics undergoing low- to high-risk surgery have worse outcomes compared with NHWs. These results do not support the hypothesis of an HP in surgical outcomes. PMID- 30463791 TI - Use of Mock Oral Examinations in Vascular Surgery Training Programs: A Nationwide Survey. AB - BACKGROUND: Mock oral examinations (MOEs) are valuable tools for knowledge assessment and preparation for the surgical certifying examinations. Use of MOE is not standardized. We sought to determine the current use in vascular residencies/fellowships. METHODS: Program directors (PD) of all U.S. vascular training programs were sent anonymous online surveys in July of 2015 evaluating importance of MOEs, current use, barriers to implementation, and preparedness of trainees to sit for the certifying board examination (CE). Comparisons were performed between programs that use MOEs and those that do not. RESULTS: Fifty four percent (59/108) of program directors completed the survey. The majority believed MOEs are important for vascular residents and fellows (86% versus 81%); however, only 51% (30/59) use them. The most common reason for using MOE was to provide feedback about readiness for the CE (90%). Of programs not giving MOE, 69% expected their trainees to get oral examinations at national conferences. The most common barriers to implementation/continuation of MOEs were availability of faculty (48%) or time (31%). Irrespective of whether they used MOE or not, 29% believed vascular fellows were better prepared for the CE than vascular residents. CONCLUSIONS: MOEs are regarded as a valuable tool to prepare trainees for the CE. However, it is not a commonly adopted practice, due to variables such as institutional/faculty availability. A third of program directors believed that vascular fellows were more prepared to pass the CE than vascular residents which may warrant further investigation into how programs can more rigorously prepare vascular residents for the vascular CEs. PMID- 30463792 TI - Rate of Secondary Intervention After Open Versus Endovascular Abdominal Aortic Aneurysm Repair. AB - BACKGROUND: Although long-term durability and improved perioperative outcome of endovascular abdominal aortic aneurysm (AAA) repair has been demonstrated, some studies have suggested an increased rate of secondary interventions compared with open AAA repair. More recent data suggest that rates between the two modalities may be similar. We investigated the rate of secondary intervention in patients undergoing endovascular aortic aneurysm repair (EVAR) or open AAA repair for intact AAA and the effect of secondary intervention on long-term mortality in these two groups of patients. METHODS: A retrospective, single-institution review was conducted between January 2003 and December 2012. Secondary intervention was defined as any intervention within 30 d of the procedure or an AAA repair-related procedure after 30 d, which included repair of endoleaks and incisional hernia repair. Group differences in demographic and baseline characteristics were examined using Cochran-Mantel-Haenszel and Wilcoxon rank sum tests for categorical and continuous variables, respectively. RESULTS: A total of 342 patients underwent operative repair of intact AAA. Two hundred seventy four patients underwent EVAR and 68 patients underwent open AAA repair. The mean age overall was 68.6 y and was not significantly different between the two repair groups. The overall rate of secondary intervention was significantly lower in the EVAR group compared with the open AAA repair group (11% versus 27%, P = 0.001). In the EVAR group, 30 patients underwent 37 secondary interventions. In the open repair group, 18 patients underwent 20 reinterventions. The most common secondary intervention was repair of type 2 endoleak (n = 13, 4.7% of patients) after EVAR and incisional hernia repair (n = 4, 5.9% of patients) after open AAA repair. Most secondary interventions (15/20) after open AAA repair occurred within 30 d, whereas most secondary intervention (33/37) after EVAR occurred after 30 d. Comparison of late (>30 d) reintervention between the two groups revealed a significantly lower rate of secondary intervention after open AAA repair (27.8% of all reinterventions after open versus 86.7% of all reinterventions after EVAR, P < 0.001). The overall 10-y mortality rate was 39.1%, and not statistically different between the two repair groups. Estimated survival analysis demonstrated no significant effect of secondary intervention on mortality after EVAR (logrank P = 0.45). Secondary intervention after open repair did not significantly affect long-term survival (logrank P = 0.05). CONCLUSIONS: This study highlights the dramatic change in practice pattern in AAA repair over time. In this study, patients treated with EVAR had a significantly lower overall rate of secondary intervention compared with patients treated with open AAA repair. This was likely secondary to increased perioperative morbidity and mortality and a bias toward more complex patients in the open repair group. In the long term, however, there were significantly fewer reinterventions after open AAA repair. Secondary interventions did not affect long-term survival after EVAR. PMID- 30463793 TI - Predicting local drug availability of locally acting lozenges: From method design to a linear level A IVIVC. AB - Lozenges are commonly applied in the treatment of sore throat. They often contain drugs intended to exert their effect locally in the oral cavity and throat. In the recent past, an increasing interest in development of generic products for locally acting lozenges could be noted. However, it was not clear, if therapeutic equivalence of locally applied, locally acting lozenges can be predicted based on results from in vitro studies. The aim of the present study was to determine an in vitro model that enables the assessment of local availability and bioequivalence of locally acting lozenges. Two novel in vitro dissolution setups (prototypes I and II) developed for simulating parameters relevant to drug release in the oral cavity, were screened for their biopredictivity. In the first step of the respective study in vitro mass loss and drug release of two marketed flurbiprofen lozenge formulations was determined. Then, an in vivo sucking study was performed to determine in vivo mass loss of the lozenges in 12 healthy volunteers. In the final step in vivo mass loss was correlated with in vitro mass loss resulting in a point to point (level A) correlation both lozenge formulations when using in vitro data obtained in the prototype II-based in vitro setup indicating biopredictivity of this in vitro model. PMID- 30463794 TI - Solid lipid nanoparticles and nanostructured lipid carriers: A review emphasizing on particle structure and drug release. AB - Colloidal systems based on lipids have attracted attention during the last two decades as a delivery method of drugs that are poorly soluble in water. The investigations carried out have focused on the development of different formulations using a wide variety of excipients and active molecules. However, there is no consensus on the structure of the particles in these colloidal systems. This is partly due since there are few studies oriented to understand both the preferential location of the drug in the particle and the arrangement of the lipids and the stabilizing agents during the particle formation. As a contribution in this sense, in this review the most common materials and preparation methods to obtain lipid particles are presented. Also, the particle characteristics, including the shape, size and size distribution, zeta potential, drug load capacity and drug entrapment efficiency are synthesized and analyzed with the help of scientometrics tools. Emphasis has been placed on the latest advances regarding the particle structure especially as it relates to the drug release behavior. In addition to the available evidence, a model of particle structure based on the formation of the different polymorphic forms of the solid lipid because of the starting materials and the processing conditions is proposed. In general, the importance of obtaining a detailed knowledge of the structure of the lipid nanoparticles is highlighted, which is useful for the rational design of this type of nanocarriers and propose solutions to the challenges involved in their formulation. PMID- 30463796 TI - Fostering quality experiences: Qualitative perspectives from program members and providers in a community-based exercise program for adults with physical disabilities. AB - BACKGROUND: Opportunities to be physically active within one's community need to be available and accessible to individuals with physical disabilities in order to increase participation; however, what constitutes quality participation within these opportunities and how exercise programs can foster quality experiences for this population have yet to be explored. OBJECTIVES: (1) To explore the participation experiences of adults with physical disabilities in a community based exercise program from two perspectives; (2) To establish whether the participants' experiences could be understood through an existing quality participation framework. METHODS: Participants were thirteen members and ten providers (i.e., coordinators, trainers, and supervisors) recruited from a community-based exercise program for adults with physical disabilities. Six focus groups (three with program members and three with each distinct group of program providers) were carried out, audio recorded and transcribed. Following an initial inductive thematic analysis, themes were deductively mapped to Martin Ginis and colleagues' (2017) conceptualization of the experiential aspects of participation. RESULTS: Six themes (autonomy, belongingness, challenge, engagement, mastery and meaning) important for experiencing quality participation were identified and were in line with Martin Ginis and colleagues' (2017) framework. CONCLUSION: Findings support the use of Martin Ginis and colleagues' (2017) conceptualization of quality participation within the context of community based exercise programs for adults with physical disabilities. Practitioners and researchers can use the findings as a starting point for designing, implementing and evaluating programs with the goal of optimizing quality participation. PMID- 30463797 TI - In reply to: Letter by Derimay et al. regarding the article, "A randomized trial comparing two stent sizing strategies in coronary bifurcation treatment with bioresorbable vascular scaffolds - The Absorb Bifurcation Coronary (ABC) trial" by Rampat et al. PMID- 30463795 TI - [Assessment of comorbidity and social anxiety in adolescents with attention deficit hyperactivity disorder: the SELFIE study]. AB - INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) and its comorbidities have an impact on the social anxiety of children and adolescents, but there are practically no studies addressing this topic in adolescence. Our objective was to assess the degree of social anxiety and to analyse the presence of psychiatric comorbidities (PSCs) in adolescents with ADHD. METHODOLOGY: We conducted a cross-sectional observational study in patients aged 12 to 18 years with a confirmed diagnosis of ADHD (DSM-5). We collected data on the presence and type of PSCs and assessed social anxiety by means of the Social Anxiety Scale for Adolescents (SAS-A). RESULTS: Forty-six child and adolescent psychiatrists and paediatric neurologists participated in the study and recruited 234 patients. Of the total patients, 68.8% (159) were male and 31.2% (72) female, with a mean age in the sample of 14.9 years (95% CI, 14.6-15.1). The type of ADHD was combined type (C) in 51.7% (121), predominantly inattentive (PI) in 37.2% (87), and predominantly hyperactive-impulsive (PH) in 9% (21). Of all patients, 97.9% (229) received pharmacological therapy: 78.6% (184) methylphenidate, 15% (35) lisdexamfetamine and 4.3% (10) atomoxetine.We found PSCs in 50.4% of the patients (118), of which the most frequent were learning and communication disorders (20.1%, n=47) and anxiety disorders (19.2%, n=45). The patients scored significantly higher in the SAS-A compared to reference values in the healthy population. The scores in the SAS-A were less favourable in adolescents with the PI type compared to those with the PH type (P=.015). The presence of a comorbid anxiety disorder was associated with worst scores in SAS-A (P<.001) showing an increased social anxiety. CONCLUSION: Adolescents with ADHD classified as PI and those with comorbid anxiety had a higher degree of social anxiety as measured by the SAS-A. This psychological aspect must be identified and controlled in adolescents with ADHD to promote their social adaptation. PMID- 30463798 TI - Vision stolen by a hidden thief: 5-Year retention of a bandage contact lens. AB - An 80 year-old male patient was prescribed a bandage contact lens on the left eye 5 years ago because of an injury on the eye by a wooden stick. He was never followed up to remove the contact lens. Two years ago, he suffered from gradually decreased visual acuity in the left eye. After removing the contact lens, his visual acuity gradually increased to 12/20 and the symptom revealed. Intraocular pressure, corneal endothelium density, corneal curvature, and the anterior chamber depth were within the normal range in the left eye, and were comparable with the right eye. Although no permanent damage was found in the patient, a strict follow-up procedure is strongly recommended for patients who receive a bandage contact lens. PMID- 30463799 TI - Predicting the need for critical care intervention in community acquired pneumonia. PMID- 30463800 TI - Physiological and anatomical studies of two wheat cultivars irrigated with magnetic water under drought stress conditions. AB - The aim of this study was to assess some physiological parameters and anatomical changes in two wheat plant cultivars (Triticum aestivum L. cvs. Sakha 93 and Sids 9) in response to irrigation with magnetized water under two levels of drought stress (field capacity (FC) of 75% and 50%) and the control (FC 100%) in two consecutive winter growing seasons (November 20 to May 5 2014/2015 and 2015/2016). Pot experiments were carried out in a greenhouse in the experimental farm of the Faculty of Agriculture, Menoufia University, Shibin El-Kom, Egypt. A water deficit, particularly at 50% FC, significantly decreased growth and parameter values, above all in Sakha 93, and disrupted most physiological aspects, biochemical constituents and internal structural features of both wheat cultivars. Irrigation with magnetized water alleviated the negative consequences of drought stress on most physiological and biochemical parameters to a variable extent: the whole plant dry weight, total water content, total soluble sugar concentration in leaves, total free amino acids and proline increased by about 32, 12, 17, 27 and 73%, respectively, under 50% FC drought stress in Sids 9 compared to the control. As the levels of drought increased, the grain yield (g/plant) decreased considerably, from about 81% in Sakha 93 at 50% FC to 26% in Sids 9 at 75% FC. The use of magnetic water increased grain yield from 61% in Sakha 93 at 75% FC to about 268% in Sids 9 at 50% FC. Magnetic water also increased the thickness of the flag leaf midvein and lamina, as well as the metaxylem vessel diameter of Sakha 93 by 28.8, 11.7 and 20.0%, respectively, compared to the control. The application of magnetic water increased the growth and the other parameter values studied in both cultivars but above all in Sakha 93, whereas Sids 9 produced more grain yield under all levels of drought stress. As the growth and grain production increased in both cultivars when using magnetic water, this study recommends this type of irrigation for these wheat plants, which are widespread in Egypt. PMID- 30463801 TI - Comparative "phenol-omics" and gene expression analyses in peach (Prunus persica) skin in response to different postharvest UV-B treatments. AB - Ultraviolet-B (UVB) radiation impacts the plant behaviour in many ways, including modifying their secondary metabolism. Although several studies have quantified the UV-B effects on phenolic composition, most of them focused on leaves or investigated a limited amount of phenolics. The present work aimed to investigate the phenolic changes after two postharvest UV-B treatments, 10 and 60 min (1.39 kJ m-2 and 8.33 kJ m-2, respectively), on peach (Prunus persica cv Fairtime) fruit with a non-targeted, whole profiling approach, and targeted gene expression analysis on skin. After both UV-B exposures, peach fruit were harvested at 24 and 36 h for "phenol-omics" analysis, while additional 6 h and 12 h recovery times were used for gene expression analysis. Our results revealed that both UV-B exposures resulted in a decrease of several phenolic compounds, such as anthocyanins, after 24 h from the exposure. In contrast, the expression of the UV B signalling components, the phenylpropanoid biosynthesis genes and their transcriptional regulators increased 6 h after the treatment, mostly with a UV-B dose dependent behaviour, preceding an accumulation of most phenolics in both the UV-B treatments at 36 h compared to 24 h. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) revealed that flavonoids, particularly anthocyanins, were the main phenolic subclasses accumulated after UV-B exposure. PMID- 30463802 TI - Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor. AB - We have identified a potent, cell permeable and CNS penetrant class IIa histone deacetylase (HDAC) inhibitor 22, with >500-fold selectivity over class I HDACs (1,2,3) and ~150-fold selectivity over HDAC8 and the class IIb HDAC6 isoform. Dose escalation pharmacokinetic analysis demonstrated that upon oral administration, compound 22 can reach exposure levels in mouse plasma, muscle and brain in excess of cellular class IIa HDAC IC50 levels for ~8 h. Given the interest in aberrant class IIa HDAC function for a number of neurodegenerative, neuromuscular, cardiac and oncology indications, compound 22 (also known as CHDI 390576) provides a selective and potent compound to query the role of class IIa HDAC biology, and the impact of class IIa catalytic site occupancy in vitro and in vivo. PMID- 30463803 TI - The diagnostic and prognostic significance of long non-coding RNA CRNDE in pan cancer based on TCGA, GEO and comprehensive meta-analysis. AB - BACKGROUND: Accumulating evidence has confirmed that CRNDE is significantly expressed in various cancers, suggesting that it may be a potential biomarker for cancer. However, its diagnostic and prognostic values of CRNDE in cancer are not completely clear. Therefore, we conduct a comprehensive study on CRNDE in cancer. MATERIALS AND METHODS: CRNDE expression data were downloaded from The Cancer Genome Atlas (TCGA). Microarray data were derived from the Gene Expression Omnibus (GEO) database to validate its differential expression. Furthermore, the receiver operator characteristic curve (ROC) and Kaplan-Meier survival analysis were used to evaluate the diagnostic and prognostic values of CRNDE in cancer, respectively. Finally, we carried out a meta-analysis to comprehensively evaluate the diagnostic and prognostic values of CRNDE in cancer. RESULTS: In TCGA database, CRNDE was overexpressed in nine types of cancer, among which polymorphic glioblastoma and colonic adenocarcinoma are the most highly expressed. The area under curves (AUC) of nine cancer types ranged from 0.855 to 0.984. Additionally, the high expression level of CRNDE was significantly associated with poor overall survival only in hepatocellular carcinoma (p = 0.032) among the nine cancers in the Kaplan-Meier survival analysis. Finally, the results of the meta-analysis on the literatures showed that the pooled sensitivity, specificity, summary receiver operator characteristic curve (SROC), and the overall hazard ratio of CRNDE in cancers were 0.77 (95% CI: 0.71-0.82), 0.90 (95% CI: 0.82-0.95), 0.87 (95% CI: 0.84-0.90), and 1.66 (95% CI: 1.37-2.01), respectively. CONCLUSION: CRNDE could be a potential biomarker for cancer diagnosis and prognosis. PMID- 30463804 TI - Regulation between two alternative splicing isoforms ZNF148FL and ZNF148DeltaN, and their roles in the apoptosis and invasion of colorectal cancer. AB - OBJECTIVE: To investigate the effect of two alternative splicing isoforms of zinc finger protein (ZNF) 148 gene on the invasion and metastasis of human colorectal cancer (CRC) cells and their related mechanisms. METHODS: Quantitative RT-PCR assays were used to detect the expression of twoZNF148 alternative splicing isoforms in SW480 cells. ZNF148FL-siRNA, ZNF148FL-over express vector, ZNF148DeltaN-siRNA, and ZNF148DeltaN-over express vector were introduced into SW480 cells. The transfection efficiency was confirmed by RT-PCR. The proliferation, invasion, and migration in vitro as well as the apoptosis of SW480 cells were detected by MTT, transwell, scratch assay and flow cytometry, respectively. RESULTS: Both ZNF148FL and ZNF148DeltaN were expressed in SW480 cells, and the level of ZNF148FL protein was higher than ZNF148DeltaN. After ZNF148FL-siRNA and ZNF148DeltaN-over express transfection, the expression level of ZNF148FL and ZNF148DeltaN were significantly decreased and increased, respectively. In contrast, the expression of ZNF148FL and ZNF148DeltaN were significantly increased and decreased, respectively, after ZNF148FL-over express and ZNF148DeltaN-siRNA transfection (all P < 0.05). The proliferation of SW480 cells was increased in ZNF148FL-over express group and the ZNF148DeltaN-siRNA group, while decreased in ZNF148FL-siRNA group and ZNF148DeltaN-over express group. The invaded cell number and migrated distance in ZNF148FL-siRNA group and ZNF148DeltaN-over express group were significantly decreased, but the apoptotic rate was significantly increased. In contrast, ZNF148FL-over express and ZNF148DeltaN-siRNA group showed the significantly increased ability of invasion and migration but decreased apoptosis rate (all P < 0.05). CONCLUSION: ZNF148FL could increase proliferation, invasion, and migration of CRC cells, while ZNF148DeltaN showed opposite effect; the two splicing isoforms of ZNF148 may exert a mutual antagonistic effect to each other on the malignant biological activities. PMID- 30463805 TI - CAV1 polymorphisms rs1049334, rs1049337, rs7804372 might be the potential risk in tumorigenicity of urinary cancer: A systematic review and meta-analysis. AB - Background As an integral membrane, Caveolin-1 (CAV1), is a pivotal component to make up the caveolae protein. It has been demonstrated to influence tumorigenicity, including bladder, colon, liver, stomach, breast and lung cancer. Several publications had illustrated the relationship of between CAV1 polymorphism and urinary cancer, but the results were not consistent. We performed a comprehensive meta-analysis to explore the associations and remove the fog. Material and methods Extensive retrieve was performed in PubMed, Embase, Medline, Web of Science, CNKI, and Wanfang database up to September, 2018. Odds ratios (ORs) and 95% confidence intervals (CIs) were conducted to evaluate the overall strength of the associations in five genetic models, as well as in subgroup analyses, stratified by ethnicity, cancer type or source of control. Q test, Egger's test and Begg's funnel plot were applied to evaluate the heterogeneity and publication bias. In-silico analysis was managed to demonstrate the relationship of polymorphism and CAV1 mRNA expression level. Results 34 case control studies with a total of 13,778 cancer cases and 20,581 healthy controls were enrolled into the meta-analysis. The polled result shown that an increased risk of rs1049334 polymorphism on urinary cancer were reveled in homozygote comparison model (MM vs. WW: OR = 1.240, 95% CI = 1.052-1.462, P = 0.011) and recessive comparison model (MM vs. MW + WW: OR = 1.198, 95% CI = 1.018-1.410, P = 0.030). What's more, rs17878467 polymorphism may play a protect role in the tumorigenesis of urinary cancer, shown in heterozygote comparison model (MW vs. WW: OR = 0.882, 95% CI = 0.78-0.999, P = 0.048). For rs7804372, the overall pooled results revealed a reducing risk in allelic contrast model (M vs. W: OR = 0.734, 95%CI = 0.544-0.99, P = 0.043), homozygote comparison model (MM vs. WW: OR = 0.532, 95% CI = 0.313-0.905, P = 0.020) and recessive comparison model (MM vs. MW + WW: OR = 0.580, 95% CI = 0.437-0.77, P < 0.001). In the stratified analyses by cancer types, the risk of PCa is downgrade by rs7804372 in all five genetic models. The GTEx in-silico analysis index that the polymorphism of CAV1 influence its mRNA expression by a dose-dependent effective of its mutant allele. Conclusion rs1049334 polymorphismof CAV1 upgrade the risk of urinary cancer, while rs1049337 and rs7804372 polymorphisms may act as a protector of urinary cancer. Further large and well-designed studies in various populations are needed to confirm the results. PMID- 30463806 TI - Method of deflection corrected tonometry with phantom vessel experiments. AB - BACKGROUND: The Continuous Non-Invasive measurement of arterial Blood Pressure [CNIBP] is possible via the method of arterial tonometry and the arterial volume clamp methods. Arterial tonometry successfully measures continuous arterial pressure but requires large vessel deformation and a highly miniaturized pressure sensor to obtain a direct calibration of pressure. A properly designed tonometer is capable of achieving pressure accuracy of less than 5% error at the radial artery. The volume clamp method achieves comparable errors but is generally restricted to the very peripheral arteries. Since the brachial or radial arteries are preferable sites to record blood pressure, tonometry is generally preferred. However, due to its strict operating requirements, tonometry requires a highly skilled operator. The greatest source of measurement error results from slight deviation from the artery wall applanation position. In this study, a method for correcting tonometry deflection error is introduced and evaluated using preliminary experiments. METHODS-MODELING: In prior analysis it has been shown that arterial wall flattening causes contact stress to become uniform and equal to the arterial pressure. In this article, we derive the contact stress for deflections other than the ideal applanation position and to allow variable vessel deflection. This analysis permits the contact stress to be corrected for tonometer positions that are not exact so that pressure accuracy is maintained in spite of less than ideal positioning. This will alleviate the necessity for highly skilled users and allow rapid determination of the pulse pressure. METHODS EXPERIMENTAL: Experiments were performed to evaluate applied model corrections for tonometer accuracy versus vessel deflection. Two experiments were performed to evaluate tonometer accuracy when deflection is varied. The first experiment used no deflection correction and the second experiment applied model derived deflection correction. A force sensor was used to deflect a phantom latex vessel of known internal pressure. The corrected contact pressure was then compared with known pressures to evaluate the pressure accuracy. RESULTS-MODELING: a geometric model was derived for vessel contact area versus deflection. This resulted in a formula that provides contact area continuously for any amount of deflection. Once the contact area is known the average tonometer contact pressure was obtained that corresponds with the vessel internal pressure. RESULTS - EXPERIMENTAL: A latex tubing phantom vessel was pressurized to a known amount and was deflected in increments over its full diameter while measuring contact force at each position. The model-derived formula was then used to calculate pressure at each position. The calculated pressure was then compared with known internal pressure to evaluate pressure accuracy for all the phantom pressure and deflection points. CONCLUSIONS: A modeling method for tonometer deflection correction was derived and evaluated using a phantom vessel. Average error was significantly reduced over the non-corrected data. The variability of error was also reduced for all data points collected. The experiments reveal that blood pressure measurement error can be reduced to levels obtained in near ideal tonometry conditions without the need for precise position control. The relaxed user precision is anticipated to simplify the use and design requirements for arterial tonometry in practice. PMID- 30463807 TI - Bow Hunter Syndrome with Associated Pseudoaneurysm. AB - BACKGROUND: Bow hunter syndrome describes a mechanical compression of the vertebral artery on head rotation leading to reversible symptomatic vertebrobasilar insufficiency. Patients are commonly presenting with syncope, vertigo, dizziness, and visual disturbances. These symptoms usually resolve when the head is turned back into neutral position. Treatment options involve surgical decompression with or without fusion, bypass surgery, or endovascular intervention. CASE DESCRIPTION: We report about a 49-year-old female who presented with vague neck pain and severe vertigo, nausea, and near syncope when her head turned up and right. Computed tomography angiography revealed a pseudoaneurysm at the dominant left V3 and near total occlusion of the left vertebral artery as it exited the C2 foramen when the head was turned to the previously mentioned position. The patient could be successfully treated by computed tomography-navigated posterior instrumentation using bilateral C1 lateral mass screws and C2 translaminar screws. To promote segmental fusion, bilateral intrafacet cages were implanted. Postoperatively, the patient remained without neurologic deficits and experienced no further episodes of the preoperatively reported transient vertebrobasilar insufficiency symptoms. CONCLUSIONS: The reported case is unique as the bow hunter syndrome was further complicated by a pseudoaneurysm of the V3 segment. Surgical intervention proved to be an efficient treatment by stabilizing the affected segment in this patient. PMID- 30463808 TI - I-kappaB kinase-epsilon knockout protects against angiotensin II induced aortic valve thickening in apolipoprotein E deficient mice. AB - Aortic stenosis (AS) is considered to be an actively regulated progress that involves similar pathophysiological processes as atherosclerosis. I-kappaB kinase epsilon (IKKepsilon) is a proinflammatory molecule involved in atherosclerosis. The objective of the present study was to define the role of IKKepsilon in pathological valvular remodeling. Aortic valves (AVs) from 52 patients undergoing AV replacement (AS) and 13 patients undergoing heart transplant (Control) were analyzed. ApoE-/- mice (AK, n = 20) and ApoE-/-IKKepsilon-/- mice (DK, n = 20) were generated and infused with saline or Ang II for 4 weeks. We found an upregulation of IKKepsilon in human stenotic aortic valves compared to that in control AVs. Our results demonstrated that AK mice receiving AngII exhibited more advanced valvular remodeling and markedly increased IKKepsilon expression. Conversely, loss of IKKepsilon reduced adverse aortic valve thickening in response to Ang II, as measured by histological analyses. Furthermore, according to immunofluorescence analysis, Ang II resulted in obvious increases in the expression of alpha-SMA, TGF-beta and NF-kappaB pathway components in the AK group, especially in the thickened area, while these increases were blocked in the DK group. Moreover, IKKepsilon was co-expressed with alpha-SMA in valvular interstitial cells in ApoE-/- mice after an AngII infusion. These data provide evidence that IKKepsilon plays a key role in the development of valvular remodeling and that it may be a novel target for the treatment of AS. PMID- 30463809 TI - Modulation of sustained fear by transcranial direct current stimulation (tDCS) of the right inferior frontal cortex (rIFC). AB - Downregulation of emotional responses to threat is strongly associated with frontal cortex functions. Additionally pathological anxiety has been proposed to be associated with the altered frontal control. Understanding the frontal regulation of both initial and sustained fear responses seems to be crucial for further research on the treatment of anxiety disorders. Therefore, this study aims to examine the effects of transcranial direct current stimulation (tDCS) over the right inferior frontal cortex (rIFC) on the subjects' psychophysiological responses as measured by skin conductance reaction (SCR) during a sustained threat paradigm. 80 participants were randomly assigned to an anodal and sham stimulation group in a double-blinded manner. Indicated by visual cues, participants anticipated the temporally unpredictable occurrence of aversive or neutral auditory stimuli. We found a significant interaction effect of condition x tDCS for SCR during the sustained threat. Post-hoc tests revealed a significant reduction in SCR during sustained fear in verum stimulated group. The results confirm that tDCS of the rIFC attenuates sustained fear. This supports the suggested role of the rIFC in psychophysiological emotional regulation and the potential use of tDCS to enhance these effects. PMID- 30463810 TI - Rational application of antiseptic drugs in arthroplasty and nursing intervention. AB - The problem of bacterial resistance caused by the irrational use of antibiotics has become a global public health problem. How to improve the rational application of antimicrobial agents is the focus of attention in the global medical industry. In this paper, we analyze the rational application of antibacterial drugs in arthroplasty and nursing intervention. The results showed that the utilization rate of the first generation cephalosporins was the highest, accounting for 43.91%, followed by lincomycin, accounting for 26.59%. At the same time, we analyzed the wound infection and its distribution and drug resistance after artificial joint replacement. In the selection of drug varieties, cleaning surgery should be the first generation of cephalosporins for the prevention of Staphylococcus aureus infection. At the same time, in the process of clinical nursing, the high quality nursing service mode is implemented. The nursing staff should do a good job for the patient's medication guidance after the operation, and charge the attention in the process of drug use. PMID- 30463811 TI - Comparison of the analgesic effects of dezocine, tramadol and butorphanol after cesarean section. AB - At present, the drugs used in the field of postoperative analgesia are mainly opioids. The three analgesics selected in this study are opioid receptor agonists, but opioids are easy to produce adverse reactions. In this study, the visual analogue score of resting pain and dynamic pain at two time points of 4 hours and 12 hours was observed in group B and group C were higher than that in group A (P<0.05), indicating that the analgesic effect of dezocine was better. Follow up observation of adverse reactions, dezocine group patients had fewer adverse reactions (P<0.05). It can be seen that although there are certain differences in the mechanism of these three drugs, there are some relevant evidence that all three drugs can be used safely and effectively for postoperative obstetric analgesia. PMID- 30463812 TI - Clinical comparison of mifepristone and gestrinone for laparoscopic endometriosis. AB - Endometriosis is a common disease among women of childbearing age, and it is the main cause of dysmenorrhea and infertility. This article analyzes the efficacy of mifepristone and gestrinone in the treatment of endometriosis. The results showed that the recurrence rate of mifepristone group and gestrinone group were 8.33% and 5%, respectively, which was significantly lower than 23.33% of the control group. Before and after treatment, LH, endocrine test results FSH PRL had no obvious change in mifepristone group and gestrinone group, while E2 decreased, as mifepristone group (141.7+/-31.2) pmol/L, gestrinone group (64.2+/-11.7) pmol/L. The incidence of adverse reactions and liver dysfunction in the mifepristone group were significantly lower than those the gestrinone group (P<0.05). Mifepristone and gestrinone can be used for endometriosis postoperative adjuvant treatment, is safe and effective, but using mifepristone has the lower rate of adverse reaction. In conclusion, mifepristone is a current research focus, its mechanism of action in the process of exploration, has broad prospects in the treatment of endometriosis, its long-term application security is paid more and more attention. PMID- 30463813 TI - Efficacy comparison of rosuvastatin and atorvastatin in the treatment of atherosclerosis and drug safety analysis. AB - Previous studies have shown that the commonly used statin lipid lowering drugs can delay the progression of atherosclerotic plaque. Atorvastatin can stabilize atherosclerotic plaque, but it can not reverse atheromatous plaque. This study will compare the efficacy of rosuvastatin and atorvastatin in the treatment of atherosclerosis and try to prove that the use of statins can improve peripheral atherosclerosis and reverse atherosclerotic plaque. The results showed that 10 mg rosuvastatin was more effective than 20 mg atorvastatin in lowering serum lipid level and elevating ABI index, ABI as rosuvastatin group (0.782+/-0.236) and atorvastatin group(0.541+/-0.196). After 6 months of treatment, the carotid artery IMT in rosuvastatin group and atorvastatin group decreased compared with before treatment, and the difference was statistically significant (P<0.05). The TC/mmol?L-1 is 2.83+/-0.56 in rosuvastatin group and 3.24+/-0.71 in atorvastatin group. In addition, rosuvastatin did not increase the risk of adverse reactions compared with atorvastatin. The results confirm that statin therapy can improve peripheral atherosclerosis and reverse atherosclerotic plaques. PMID- 30463814 TI - Pharmacological analysis of dexmedetomidine hydrochloride in pediatric anesthesia during magnetic resonance imaging. AB - Dexmendetomidine hydrochloride (DEX) is a new common adrenergic receptor agonist, which not only keeps children calm but also has analgesic effect. Dexmedetomidine hydrochloride will enable children to maintain the natural non-REM sleep, which can be stimulated sedation or language arousal. The aim of this study is to observe the sedative effect and adverse drug reactions of dexmedetomidine hydrochloride injection and propofol injection in MRI examination. In this study, no children in the experimental group were required to add sedative drugs, and 2 cases in the control group were treated with sedative drugs. In experimental group, it used dexmedetomidine hydrochloride as (1.64+/-0.91) g/kg; in control group, dosage of narcotic drugs as (5.26+/-1.82) g/kg, and the total complication rate of the children in the experimental group was lower than that of the control group (P<0.05). After returning to the ward, the doses of phenobarbital sedation were dexmedetomidine group (4.28+/-1.53) mg/kg and propofol group (6.40+/-1.71) mg/kg. There was significant difference between the two groups. The total complication rate in the experimental group was lower than that in the control group (P<0.05). The quality of MRI in the test group was significantly higher than that in the control group, which showed that dexmedetomidine hydrochloride could provide a satisfactory sedative effect in the MRI examination of children. To sum up, dexmedetomidine hydrochloride is a wide range of clinical applications. It is an effective drug for the maintenance of sedation in clinical disease treatment. It is flexible in the way of administration and with less adverse reactions. It is suitable for popularization and application in clinical practice. PMID- 30463815 TI - Rational use of antibacterials and drug sensitivity analysis in the repair of large lip defect with skin flap. AB - In this study the wound status of skin flap repair patients were closely observed, there were sign of infection. The secretion were taken for bacterial culture and sensitivity analysis and given sensitive antibiotics to active treatment. Patients received intravenous antibiotics 30 minutes before surgery to prevent infection. If postoperative infection occurred, according to susceptibility test results, patients were given sensitive antibiotics. Drug sensitivity analysis showed that 85.71% of gram-negative bacteria were sensitive to cefoperazone/shubatan and imipenem and 72.72% of gram-negative bacteria were sensitive to cefoperazone/tazobactam, so these 3 antibiotics were the first choice for treatment. And gram-positive bacteria were sensitive to teicoplanin and vancomycin. Therefore, scientific and rational use of antibiotics has great significance to effectively prevent postoperative infection and reduce the production of drugresistant bacteria. At the same time, L-extension deltopectoral flap was used to reconstruct a full-thickness labiomental defect concurrent infection. All the surgeries were successful without any necrosis. There are many kinds of pathogens for skin flap infection, and their sensitivity to antibiotics is not the same. Therefore, it is suggested that combination therapy should be carried out at the early stage, so as to ensure a good antibacterial effect. PMID- 30463816 TI - Clinical effect of Caulis decoction on iron deficiency anemia and the hepcidin iron metabolism. AB - Studies have shown that Chinese herb caulis extract can effectively inhibit the expression of the core regulatory hormone hepcidin in iron metabolism and significantly increase the iron level in the body. On this basis, this paper analyzed clinical efficacy and safety of oral niferex (polysaccharide iron complex) combined with caulis Decoction in the treatment of iron deficiency anemia. The results showed that the recovery rate of the Caulis group, Niferex group and the combined treatment group were 41.6%, 46.6% and 58.3% respectively. The difference of recovery rate was statistically significant. The RBC, Hb, Hct, SI, SF, Tf, TIBC and serum Hepcidin in the combined treatment group were significantly higher than those in the other groups (P<0.05). Caulis group has 3 cases of gastrointestinal symptoms, and the incidence of adverse reactions was 5%. Chinese medicine caulis can significantly improve erythrocyte count, hemoglobin, hematocrit and related iron metabolism, but the improvement of the combined treatment group is more obvious. In conclusion, Chinese medicine caulis can significantly improves the clinical symptoms and iron metabolism in patients with iron deficiency anemia, combined oral niferex therapy has better effect. PMID- 30463817 TI - Postoperative analgesic effect of different doses of naloxone combined with butorphanol and psychological nursing intervention. AB - Cesarean section, as a stressor, inevitably produces negative emotions such as anxiety and may cause intraoperative discomfort and postoperative pain. Butorphanol is a commonly used analgesic in cesarean section. Butorphanol's postoperative analgesia can reduce the incidence of postoperative respiratory depression and play a good sedative effect. In this study, we observed the effect of the combination of naloxone and butorphanol on postoperatively analgesia. The result proved that the effect of naloxone and butorphanol on postoperative intravenous analgesia was significant, and the adverse effects of narcolepsy, dizziness, nausea and vomiting after operation were less. Medium concentration of naloxone and high concentration of naloxone had better effect on labor pain, but the adverse reaction rate of high concentration naloxone was higher. Therefore, we suggest that the concentration of naloxone should be 0.20~0.30 MUg?kg-1?h-1. At the same time, research shows that good psychological nursing can obviously relieve patients' anxiety, and also has a certain effect on reducing pain during and after operation. PMID- 30463818 TI - Antibiotics use and drug resistance analysis of neurology patients' Infection. AB - Recent studies have shown that nosocomial infection is an important factor affecting the quality and service level of neurology. Based on the characteristics of neurology patients, the application of antibacterial drugs has certain particular characteristic. In this paper, we analyzed the distribution of pathogenic bacteria in neurology patients in 2016-2017 year, and made statistics on the utilization of antibiotics. The results showed that 84 strains of pathogenic bacteria were isolated from the neurology department, including Gram negative bacteria (44 strains, 52.38%), Gram-positive bacteria (31, 36.9%), and fungi (9, 10.71%). At the same time, as for the use of antibiotics, the drug category is most cephalosporins and the top 5 antiseptic drugs are cephalosporins, beta lactamase inhibitors, quinolones, aminosides and penicillins. The highest DUI (drug utilization index) value was for cefoperazone tazobactam (1.33), followed by ceftriaxone Mino (1.20) and ciprofloxacin (1.18). Clinicians should guide the selection of antimicrobial agents based on the results of etiological examination, and formulate a reasonable treatment plan based on the characteristics of patients, common pathogens and drug resistance. PMID- 30463819 TI - Comparison of the use of different analgesics in the course of anesthesia care based on pharmacoeconomics. AB - Narcotic analgesics play an important role in the treatment of pain. If the drug is not standardized, it is easy to cause tolerance and addiction, so scientific management and rational application is very important. In this article, we analyzed the use of narcotic analgesics in a tertiary hospital in 2015-2017. The results showed that the top 3 drugs in DDDs (defined daily doses) were fentanyl transdermal patch (4.2 mg), fentanyl transdermal patch (8.4 mg) and morphine sulfate sustained-release tablets (30 mg). Because of its strong analgesic activity and dosage form, fentanyl has become one of the first choices for severe and moderate pain in clinical practice. Morphine sulfate sustained-release tablets (30 mg) DDDs ranked third in 2015-2017, and the B/A value was 1.75. At the same time, morphine sulfate sustained-release tablets' DDDs declined in 2017 because of the analgesic advantage of bucinnazine hydrochloride injection in emergency treatment. The dosage of pethidine hydrochloride injection is declining year by year, because its analgesic action time is very short and easy to be addicted to, and the long-term application of its metabolite, normethidine, will accumulate in the body, causing neurotoxic symptoms. The price of oxycodone hydrochloride prolonged-release tablets is relatively high, which limits its use to a certain extent. Therefore, recommend rational use of narcotic analgesics in hospitals. PMID- 30463820 TI - Effect of terbutaline combined with budesonide in treatment of bronchial asthma and rehabilitation nursing. AB - Terbutaline aerosol and budesonide suspension are commonly used in the treatment of bronchial asthma, and budesonide suspension has local high efficiency and anti inflammatory effects. In this paper, we selected 240 patients with bronchial asthma and randomly divided them into two groups. The experimental group was treated with atomization inhalation of terbutaline, after 5 minutes interval, nebulized inhalation of budesonide was performed. The control group was treated with atomized inhalation of mixed liquid as terbutaline and budesonide. After treatment, the cough scores of the two groups decreased, and the dyspnea score improved significantly compared with that before treatment (P<0.05).After treatment, the levels of IL-6, BNP and CRP were decreased in the two groups. There was a significant difference between the two groups after treatment (P<0.05). The incidence of adverse drug reactions was low. There were 2 cases of panic disorder and 8 cases of pharyngeal discomfort in the experimental group. The results show that the interval medication of terbutaline and budesonide in the treatment of bronchial asthma can achieve better clinical efficacy and can provide reference for clinical treatment. In addition, this method can effectively reduce the level of inflammatory factors in acute asthma patients, thereby reducing the damage of inflammatory factors to the body. PMID- 30463821 TI - Effect of carboprost tromethamine in prevention of postpartum hemorrhage in cesarean section. AB - Carboprost tromethamine is a synthetic prostaglandin derivative, which can effectively promote law contraction of the uterus and significantly reduce the amount of bleeding during and after delivery. In this study, we explored the effect of carboprost tromethamine on the prevention of postpartum hemorrhage after cesarean section and the effect on coagulation function and hemodynamics. At the same time, the effects of oxytocin and carboprost tromethamine were studied in different groups. The results showed that the amount of 2h bleeding (256.7+/-65.21) mL and the amount of 24h hemorrhage (308.3+/-78.3) after the operation were significantly decreased, and the difference was statistically significant (P<0.05). After the operation, the levels of APTT, TT and Fib in the two groups were significantly lower than those before the operation. The levels of SBP (119.4+/-8.24) mmHg and DBP (79.6+/-6.21) mmHg in the experimental group were significantly higher than those of the control group. In summary, carboprost tromethamine has a significant effect on the prevention of postpartum hemorrhage in cesarean section, and has a significant effect on improving the state of hypercoagulable blood and maintaining the stable hemodynamic state, which has clinical a value. PMID- 30463822 TI - Rational drug use analysis of antibiotics in surgical operation with nursing intervention. AB - Rational use of antibiotics is an important part of clinical pharmacy in hospitals. In this paper, we compared and analyzed the use of antibiotics in 2016 and 2017, and put forward corresponding interventions. The results showed that the irrational use of drugs after the intervention was significantly reduced (p<0.05). The antibacterials used before the intervention was mainly cephalosporins (45.4%) and quinolones (26.2%). The antibiotics used after intervention was mainly cephalosporins (77.9%) and clindamycin (11.6%). There is no significant difference in the incidence of SSI in combination with a selection of appropriate antimicrobial agents and a variety of antibiotics and an irrational combination of drugs will increase the incidence of adverse drug reactions. Through the implementation of various intervention measures, the clinicians' awareness of the rational application of antimicrobial drugs has been improved significantly, and the rationality of drug use indications, medication course, drug selection, sample delivery rate and so on have been improved to varying degrees. PMID- 30463823 TI - Apoptosis and antitumor effects between beta-elemene and astragaloside and drug mechanism analysis. AB - beta-elemene is an effective anticancer drug extracted from Rhizoma curcumae. It is a non cytotoxic antineoplastic agent, which can obviously inhibit the proliferation of tumor cells. In this paper, we observed the proliferation inhibition and apoptosis of beta-elemene and Astragaloside on human hepatoma cell HepG2 and mouse hepatoma H22 cells, and provide a reference for further proof that beta-elemene and astragaloside can induce tumor cell apoptosis. The results showed that after 24 h, group astragaloside, beta-elemene group and combined treatment group had inhibitory effect on the proliferation of HePG2 cells, in which the combined treatment group had the best effect and the inhibition rate reached 66.71%. The apoptosis rates of Hep G2 cells in the drug treatment group were 0.9%, 22.4% and 45.8%, respectively, and there was statistical significance in each drug group compared with the control group (P<0.05). It can be seen that Astragalus membranaceus and beta-elemene have obvious inhibitory effects on the growth of liver cancer cells and their combination has synergistic effect. PMID- 30463824 TI - Effect of dexmedetomidine on postoperative delirium in elderly patients undergoing hip fracture surgery. AB - Dexmedetomidine is a highly selective central alpha2 adrenergic receptor agonist, which has anti sympathetic, sedative and analgesic effects. The aim of this study was to investigate the effect of dexmedetomidine on postoperative delirium in elderly patients undergoing hip fracture surgery. The results showed that the dosage of sufentanil and propofol decreased significantly in the experimental group (P<0.05). The price-henry pain scores of 10min, 1H and 6h in the experimental group were significantly reduced after the operation. At the same time, there were 3 cases (4.28%) of postoperative delirium in the experimental group, which were significantly less than 12 cases (17.14%) in the control group. The dosage of propofol in the operation is a risk factor for postoperative delirium. Dexmedetomidin can significantly reduce the amount of propofol in the operation and it has a neuroprotective effect, which can reduce the incidence of postoperative delirium in the elderly. In the elderly patients with hip surgery, its adjuvant to general anesthesia can effectively reduce narcotic drug dosage and reduce the incidence of postoperative delirium. PMID- 30463825 TI - Application of conjugated estrogen cream in the treatment of postmenopausal atrophic vaginitis. AB - To observe and analyze the effect of conjugated estrogen cream in the treatment of postmenopausal atrophic vaginitis. The 160 patients clearly diagnosed with postmenopausal atrophic vaginitis and treated in our hospital were selected as subjects and divided into study group and reference group with equal number of cases. The reference group was treated with compound metronidazole suppository, while the study group was treated with conjugated estrogen cream. The treatment efficacy of the two groups was compared and observed. Comparison of estradiol and folliclestimulating hormone levels after treatment in the two groups show that the study group has obvious advantage over the reference group, p<0.05; comparison of vagina cleanliness in the two groups after treatment shows the study group is significantly superior to the reference group, p<0.05; comparison of incidence of adverse reactions in the two groups shows that the study group has lower incidence, with statistical significance in comparison between the groups, p<0.05. Treatment of postmenopausal atrophic vaginitis with combination of conjugated estrogen cream and compound metronidazole suppository can achieve good results with high safety and reliability. PMID- 30463826 TI - Treatment of caesarean section scar pregnancy with systemic administration of methotrexate. AB - To observe and analyze the therapeutic effect of systemic administration of methotrexate on caesarean section scar pregnancy. The 160 patients who had been confirmed with caesarean section scar pregnancy in our hospital were selected research objects. They were randomly divided into two groups (research group and control group), each containing 80 patients. The research group was subjected to systemic administration of methotrexate, while control group was applied with local administration of methotrexate. The total treatment effective rates of two groups were observed and compared. The total treatment effective rate of research group was higher than that of control group, p<0.05; in terms of time required for a-HCG restoring to normal state, the research group was significantly shorter than control group, p<0.05; the time required for disappearing of scar lump for research group was shorter than that of control group, p<0.05. No complications were observed for both groups. Systemic administration of methotrexate can significantly improve the curative effect for patients with caesarean section scar pregnancy. PMID- 30463827 TI - Clinical efficacy and pharmaco-economic analysis of xiaozhong zhitong decoction on preventing deep venous thrombosis in major orthopaedic operation. AB - The clinical efficacy and pharmacoeconomics of Xiaozhong Zhitong Decoction on preventing deep venous thrombosis in major orthopaedic operation are observed and analyzed. The 160 patients who are implemented major orthopaedic operation in our hospital are selected as the subjects, which are randomly divided into research group applying Xiaozhong Zhitong decoction and reference group using low molecular heparin with same cases in each group for observing their treatment efficacy and analyzing pharmacoeconomics. Through observing and comparing the rate of deep venous thrombosis in two groups, the results show that study group is significantly lower than reference group with p<0.05. The incidence of adverse reactions in study group is significantly lower than that of reference group with P<0.05; after observing the postoperative quality of life and analyzing cost effectiveness in two groups, it shows that study group has more significant advantage than reference group with p<0.05. The Xiaozhong Zhitong decoction has a better clinical effect on preventing deep venous thrombosis in major orthopaedic operation with higher safety and reliability and has a better cost effect ratio at the same time. PMID- 30463828 TI - Clinical research on therapeutic effect of combined application of lobaplatin and irinotecan in treating recurrant small cell lung cancer. AB - To observe and analyze the therapeutic effect of combinated application of lobaplatin and irinotecan in treating recurrant small cell lung cancer. The 140 patients who were treated in our hospital for recurrant small cell lung cancer were selected as research objects. All selected patients were subjected to combined application of obaplatin and irinotecan, the total therapeutic effect was observed, and the adverse reactions occurring during treatment were recorded. Through observing the total treatment effective ratio of 140 patients recurrant small cell lung cancer, the number of complete remission cases, number of partial remission cases, number of stable disease cases, and number of disease progression cases were 40(28.57%), 28(20.00%), 30(21.43%), 42(30.00%), respectively, with total effective ratio of 48.57%. The average time to progression (TTP) was (4.5+/-0.8) months, average overall survival (OS) was (7.6+/-1.2) months. The toxic and adverse effects mainly included hematological toxicity and gastrointestinal adverse reaction, such as leukocyte reduction, neutrophil reduction, thrombocytopenia, decreased hemoglobin, nausea and vomiting, diarrhea. No toxicity-related death occurred. In treatment of patients with recurrant small cell lung cancer, the combined application of lobaplatin and irinotecan can achieve great results, which is a safe and reliable way of treatment. PMID- 30463829 TI - Clinical efficacy and safety of S-1 monotherapy in the treatment of advanced breast cancer in elderly patients. AB - To observe and analyze the therapeutic efficacy of S-1 monotherapy in the treatment of advanced breast cancer in elderly patients. A total of 180 elderly patients diagnosed as advanced breast cancer and treated at our hospital were enrolled. All patients were randomized into study group and control group, with 90 patients in each group. Of those, capecitabine monotherapy was administered in control group, while S-1 monotherapy was applied in study group. Clinical efficacy and safety of both groups were compared. By comparing recent therapeutic effects, results showed that the overall treatment efficacy was 51.11% in study group, while the value was 35.56% in control group, suggesting a higher therapeutic efficacy in study group (P<0.05). Also, the incidence of side effects was significantly lower in study group compared with control group (P<0.05). Moreover, quality of life was better preserved in study group (P<0.05). S-1 monotherapy was relatively effective and safe in the treatment of advanced breast cancer in elderly patients. PMID- 30463830 TI - Comparison of clinical efficacy and safety between articaine and lidocaine in the anaesthesia management of tooth pulp disease. AB - To evaluate and compare the clinical efficacy and safety between articaine and lidocaine in the anaesthesia management of tooth pulp disease. The 160 patients with tooth pulp disease treated at our hospital were enrolled. After informed consent was obtained, patients were randomly assigned to study group and control group, with 80 patients in each group. Of those, lidocaine was administered to the control group while articaine was given to the study group. The onset time, analgesic effect and adverse events were recorded. Compared with control group, the onset time was significantly reduced in study group (p<0.05). Patients treated with articaine had better analgesic effect than patients in control group (p<0.05). And the incidence of adverse events was notably lower in study group (p<0.05). Compared with lidocaine, articaine presents higher analgesic efficacy and safety for patients with tooth pulp disease. PMID- 30463831 TI - Observation on efficacy for rectal medication of methyl carprost suppository combined with oxytocin in preventing hemorrhage after cesarean section. AB - The efficacy for rectal medication of methyl carprost suppository combined with oxytocin in preventing and controlling hemorrhage after cesarean section is observed and analyzed. The 180 parturients who are conducted cesarean section in our hospital are selected as research subjects. All parturients are entitled to the right to know and randomly divided into research group and control group with 90 cases in each group. Among them, the parturients in control group are given oxytocin to prevent and control hemorrhage during the operation, while the research group combines with rectal medication of methyl carprost suppository to prevent and control postoperative hemorrhage base on the ways of control group. The condition of hemorrhage in two groups is observed and compared. By comparing with the time of the third stage of labor in two groups, the results don't demonstrate significant difference (p>0.05). Compared with the amount of hemorrhage during the operation, 2h and 24h after delivery, the amount of hemorrhage in research group is less than control group with obvious difference (p<0.05); through recording the change of blood pressure before and after medication in two groups, the result shows that there is no significant difference (p<0.05), which indicates higher safety. In preventing and controlling hemorrhage after cesarean section, rectal medication of methyl carprost suppository combining with oxytocin can achieve good efficacy, significantly reduce the amount of postpartum hemorrhage and will not affect the blood pressure index. PMID- 30463832 TI - Effect of different doses of ulinastatin on cellular immunity and hepatorenal functions in patients undergoing laparoscopic colorectalcarcinoma surgery. AB - The effect of different doses of ulinastatin on cellular immunity and hepatorenal functions in patients undergoing laparoscopic colorectal-carcinoma surgery was observed and analyzed. The 200 patients with laparoscopic colorectal-carcinoma surgery in our hospital were selected as research subjects and divided into 4 groups containing equal patients, namely, saline group, 0.5 x 104U/kg ulinastatin group, 1 x 104U/kg ulinastatin group, and 1.5 x 104U/kg ulinastatin group, which were denoted as group A, group B, group C and group D, respectively. The treatment effect of patients in 4groups was observed and compared. By observing the Narcotrend cerebral state index (NT index), the results showed that NT index at tracheal intubation, pneumoperitoneum beginning, pneumoperitoneum 30min, resection of tumor, end of operation in 4 groups was significantly lower than that at preoperative anesthesia (T0) (p<0.05); differences in hepatorenal values (AST, ALT, BUN and Cr) among 4 groups at T0 were of no statistical significance (P>0.05); each index in T cell subsets in the postoperative third days (T1) was significantly lower than that at T0; indexes of T cell subgroup of group B, C and D at T1 were higher than that of group A at T1 (p<0.05). For 4 groups, the difference in liver and kidney function indicators at T1 and T0 was of no statistical significance, p>0.05. Different doses of ulinastatin have a certain effect on cellular immunity in patients undergoing laparoscopic colorectal carcinoma surgery and do not significantly affect hepatorenal function. PMID- 30463833 TI - Assessment of Feng-Liao-Chang-Wei-Kang as a potential inducer of cytochrome P450 3A4 and pregnane X receptors. AB - Feng-Liao-Chang-Wei-Kang (FLCWK), a traditional Chinese patent medicine, consists primarily of Polygonum hydropiper and Daphniphyllum calycinum roots. As a complex containing several kinds of flavonoids, FLCWK has the potential to impact the drug metabolism enzyme P450 3A4 (CYP3A4) and nuclear receptors. The purpose of this research was to probe the effects of FLCWK on CYP3A1, the homolog of CYP3A4 in rats, and to confirm whether FLCWK interferes with PXR and CAR-mediated transactivation of CYP3A4. The effects of FLCWK on Cyp3a1 mRNA, catalytic activity levels, and protein expression in Sprague-Dawley (SD) rat liver tissues were examined using real-time PCR, western blotting, and high-performance liquid chromatography (HPLC) assays, respectively. The efficacy of PXR and CAR on CYP3A4 transcriptional activity were detected using luciferase reporter assays and further research of the impact of FLCWK on CYP3A4 gene expression mediated by the PXR pathway was examined by transient transfection of PXR siRNA. FLCWK significantly increased Cyp3a1 mRNA, CYP3A1 activity, and protein expression levels in SD rats. FLCWK highly induced CYP3A4 luciferase activity mediated by PXR in PXRCYP3A4 co-transfected cells. A siRNA-mediated drop-off in PXR expression greatly cut the effect of FLCWK on CYP3A4 mRNA expression in HepG2 cells. These findings show that FLCWK up-regulates CYP3A4 levels via the PXR pathway. This effect should be considered being applied in clinical use as FLCWK has the potential to interact with other drugs. PMID- 30463834 TI - Smartphone Apps About Crystal Methamphetamine ("Ice"): Systematic Search in App Stores and Assessment of Composition and Quality. AB - BACKGROUND: Amid considerable community concern about the prevalence and harms associated with the use of crystal methamphetamine ("ice"), the increased use of smartphones to access health information and a growing number of available smartphone apps related to crystal methamphetamine, no previous reviews have examined the content and quality of these apps. OBJECTIVE: This study aims to systematically review existing apps in the iTunes and Google Play Stores to determine the existence, composition, and quality of educational smartphone apps about methamphetamines, including ice. METHODS: The iTunes and Google Play Stores were systematically searched in April 2017 for iOS Apple and Android apps, respectively. English-language apps that provided educational content or information about methamphetamine were eligible for inclusion. Eligible apps were downloaded and independently evaluated for quality by 2 reviewers using the Mobile Application Rating Scale (MARS). RESULTS: A total of 2205 apps were initially identified, of which 18 were eligible and rated using the MARS. The mean MARS quality total score for all rated apps was 3.0 (SD 0.6), indicating poor to acceptable quality. Overall, mean scores were the highest for functionality (mean 4.0, SD 0.5) and lowest for engagement (mean 2.3, SD 0.7). CONCLUSIONS: This study demonstrates a shortage of high-quality educational and engaging smartphone apps specifically related to methamphetamine. The findings from this review highlight a need for further development of engaging and evidence-based apps that provide educational information about crystal methamphetamine. PMID- 30463835 TI - Developing Digital Games to Address Airway Clearance Therapy in Children With Cystic Fibrosis: Participatory Design Process. AB - BACKGROUND: Children affected with cystic fibrosis do respiratory exercises to release the mucus stuck in their lungs. OBJECTIVE: The objective of our study was to develop prototypes of digital games that use breath pressure to make this daily physiotherapy more fun. METHODS: We used a participatory design approach and organized short events to invite contributors from different disciplines to develop game prototypes. From the 6 prototypes, 3 were tested by 10 children during a prestudy. The source code of the games, of which 2 continue to be developed, has been released on the internet under fair use licenses. RESULTS: We discuss 7 themes of importance in designing games for health, combining our experience with a review a posteriori of literature. CONCLUSIONS: This study provides examples of games and their pitfalls as well as recommendations to create games for health in a participatory approach that enables everyone to improve and adapt the work done. PMID- 30463836 TI - Application and Effectiveness of Telehealth to Support Severe Mental Illness Management: Systematic Review. AB - BACKGROUND: People with severe mental illness (SMI) must receive early interventions to prevent mental health deterioration or relapse. Telecommunications and other technologies are increasingly being used to assist in health care delivery using "telehealth," which includes telephones and mobile phones, computers, remote sensors, the internet, and other devices, to provide immediate real-time information to service users to improve the management of chronic health conditions. Some initial findings have suggested that technology could improve the quality of life of people with SMI. OBJECTIVE: In this systematic review, we aimed to identify the various uses and efficacy of telehealth technology for SMI. METHODS: We systematically searched electronic databases from inception to March 2016 (MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, Allied and Complementary Medicine Database, Health Technology Assessment, CINAHL Plus, and NHS Economic Evaluations Database) to identify randomized controlled trials evaluating telehealth for adults with SMI published in English. Additional literature was identified through searching reference lists of key articles. The articles meeting the inclusion criteria were systematically reviewed and assessed for quality and risk of bias. RESULTS: Our search identified 31 articles describing 29 trials as eligible for the review. The included studies evaluated the use of computers to deliver cognitive rehabilitation (15 trials), patient education (3 trials), and Web-based self-management interventions (2 trials) and to support consultations (1 trial). Virtual reality was used to simulate work and social situations (2 trials) and to deliver cognitive training (1 trial). Telephones were used to prompt service users to take medications (3 trials) and to report symptoms to their health care team (1 trial). Remote sensors were used to monitor medication use (1 trial). Telephone support was found effective in improving medication adherence and reducing the severity of symptoms and inpatient days. Computer assisted cognitive rehabilitation was effective in improving cognitive function. The impact of telehealth on other outcomes was inconsistent. The results of this review should be taken in the context of varied quality in study design, with only 5 studies demonstrating a low risk of bias. CONCLUSIONS: A growing variety of telehealth technologies are being used to support the management of SMI. Specific technology types have been found to be effective for some outcomes (eg, telephone and remote medication monitoring for adherence to treatment), while other types of telehealth technologies (eg, delivery of patient education using computers) had no benefit over traditional nurse-based methods and were less acceptable to patients. Further research is warranted to establish the full potential benefits of telehealth for improving the quality of life in people with SMI, acceptability from the service user perspective, and cost-effectiveness. The findings of this review are limited by the poor quality of many of the studies reviewed. PMID- 30463837 TI - Clients' Experiences With Internet-Based Psychological Treatments for Mental Disorders: Protocol for a Metasynthesis of Qualitative Studies. AB - BACKGROUND: Given the rise of internet-based treatments as an effective therapeutic tool for psychological disorders, it is necessary to carry out research that examines clients' experiences with this type of intervention. The qualitative methodology has been found to be useful for analyzing clients' perceptions in terms of facilitators and barriers, acceptability, and negative effects of internet-based treatments. However, a lack of integration of these primary studies has prevented their findings from being applied to new research and in clinical practice. OBJECTIVE: The objective of this paper is to describe the protocol for a metasynthesis of qualitative studies exploring the experiences of clients who underwent an internet-based treatment. METHODS: Elliot and Timulak's metasynthesis approach will be used to review and synthesize qualitative studies related to client experiences in terms of the barriers and facilitators they perceived when undergoing internet-based treatment. For each search string, the features in the Sample, Phenomenon of Interest, Design, Evaluation, Research type (SPIDER) tool will be considered. Electronic databases (PubMed, PsycINFO, and Web of Science) will be searched. Two independent reviewers will analyze the material in order to determine whether the eligibility criteria are fulfilled. Findings will make it possible to create a hierarchy of domains in terms of their relevance across all the primary studies. The data obtained from primary studies will be cross-analyzed using descriptive and interpretative procedures. RESULTS: The search strategy is currently being conducted. First results are expected to be submitted for publication in 2019. CONCLUSIONS: We will develop conceptual framework of the barriers and facilitators perceived by clients and propose their implications and recommendations for clinical practice, research, and training. TRIAL REGISTRATION: PROSPERO CRD42018079894; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=79894 (Archived by WebCite at http://www.webcitation.org/73C6OtlS7). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/9722. PMID- 30463838 TI - Impact of a Wearable Device-Based Walking Programs in Rural Older Adults on Physical Activity and Health Outcomes: Cohort Study. AB - BACKGROUND: Community-dwelling older adults living in rural areas are in a less favorable environment for health care compared with urban older adults. We believe that intermittent coaching through wearable devices can help optimize health care for older adults in medically limited environments. OBJECTIVE: We aimed to evaluate whether a wearable device and mobile-based intermittent coaching or self-management could increase physical activity and health outcomes of small groups of older adults in rural areas. METHODS: To address the above evaluation goal, we carried out the "Smart Walk" program, a health care model wherein a wearable device is used to promote self-exercise particularly among community-dwelling older adults managed by a community health center. We randomly selected older adults who had enrolled in a population-based, prospective cohort study of aging, the Aging Study of Pyeongchang Rural Area. The "Smart Walk" program was a 13-month program conducted from March 2017 to March 2018 and included 6 months of coaching, 1 month of rest, and 6 months of self-management. We evaluated differences in physical activity and health outcomes according to frailty status and conducted pre- and postanalyses of the Smart Walk program. We also performed intergroup analysis according to adherence of wearable devices. RESULTS: We recruited 22 participants (11 robust and 11 prefrail older adults). The two groups were similar in most of the variables, except for age, frailty index, and Short Physical Performance Battery score associated with frailty criteria. After a 6-month coaching program, the prefrail group showed significant improvement in usual gait speed (mean 0.73 [SD 0.11] vs mean 0.96 [SD 0.27], P=.02), International Physical Activity Questionnaire scores in kcal (mean 2790.36 [SD 2224.62] vs mean 7589.72 [SD 4452.52], P=.01), and European Quality of Life-5 Dimensions score (mean 0.84 [SD 0.07] vs mean 0.90 [SD 0.07], P=.02), although no significant improvement was found in the robust group. The average total step count was significantly different and was approximately four times higher in the coaching period than in the self-management period (5,584,295.83 vs 1,289,084.66, P<.001). We found that participants in the "long-self" group who used the wearable device for the longest time showed increased body weight and body mass index by mean 0.65 (SD 1.317) and mean 0.097 (SD 0.513), respectively, compared with the other groups. CONCLUSIONS: Our "Smart Walk" program improved physical fitness, anthropometric measurements, and geriatric assessment categories in a small group of older adults in rural areas with limited resources for monitoring. Further validation through various rural public health centers and in a large number of rural older adults is required. PMID- 30463839 TI - App Features for Type 1 Diabetes Support and Patient Empowerment: Systematic Literature Review and Benchmark Comparison. AB - BACKGROUND: Research in type 1 diabetes management has increased exponentially since the irruption of mobile health apps for its remote and self-management. Despite this fact, the features affect in the disease management and patient empowerment are adopted by app makers and provided to the general population remain unexplored. OBJECTIVE: To study the gap between literature and available apps for type 1 diabetes self-management and patient empowerment and to discover the features that an ideal app should provide to people with diabetes. METHODS: The methodology comprises systematic reviews in the scientific literature and app marketplaces. We included articles describing interventions that demonstrated an effect on diabetes management with particular clinical endpoints through the use of mobile technologies. The features of these apps were gathered in a taxonomy of what an ideal app should look like to then assess which of these features are available in the market. RESULTS: The literature search resulted in 231 matches. Of these, 55 met the inclusion criteria. A taxonomy featuring 3 levels of characteristics was designed based on 5 papers which were selected for the synthesis. Level 1 includes 10 general features (Personalization, Family support, Agenda, Data record, Insulin bolus calculator, Data management, Interaction, Tips and support, Reminders, and Rewards) Level 2 and Level 3 included features providing a descriptive detail of Level 1 features. Eighty apps matching the inclusion criteria were analyzed. None of the assessed apps fulfilled the features of the taxonomy of an ideal app. Personalization (70/80, 87.5%) and Data record (64/80, 80.0%) were the 2 top prevalent features, whereas Agenda (5/80, 6.3%) and Rewards (3/80, 3.8%) where the less predominant. The operating system was not associated with the number of features (P=.42, F=.81) nor the type of feature (P=.20, chi2=11.7). Apps were classified according to the number of level 1 features and sorted into quartiles. First quartile apps had a regular distribution of the ten features in the taxonomy whereas the other 3 quartiles had an irregular distribution. CONCLUSIONS: There are significant gaps between research and the market in mobile health for type 1 diabetes management. While the literature focuses on aspects related to gamification, rewarding, and social communities, the available apps are focused on disease management aspects such as data record and appointments. Personalized and tailored empowerment features should be included in commercial apps for large-scale assessment of potential in the self-management of the disease. PMID- 30463840 TI - Assessing Preference Shift and Effects on Patient Knowledge and Decisional Conflict: Cross-Sectional Study of an Interactive Prostate-Specific Antigen Test Patient Decision Aid. AB - BACKGROUND: Randomized trials of Web-based decision aids for prostate-specific antigen (PSA) testing indicate that these interventions improve knowledge and reduce decisional conflict. However, we do not know about these tools' impact on people who spontaneously use a PSA testing patient decision aid on the internet. OBJECTIVE: The objectives of this study were to (1) determine the impact of the Web-based PSA Option Grid patient decision aid on preference shift, knowledge, and decisional conflict; (2) identify which frequently asked questions (FAQs) are associated with preference shift; and (3) explore the possible relationships between these outcomes. METHODS: Data were collected between January 1, 2016, and December 30, 2017. Users who accessed the Web-based, interactive PSA Option Grid were provided with 3 options: have a PSA test, no PSA test, or unsure. Users first declared their initial preference and then completed 5 knowledge questions and a 4-item (yes or no) validated decisional conflict scale (Sure of myself, Understand information, Risk-benefit ratio, Encouragement; SURE). Next, users were presented with 10 FAQs and asked to identify their preference for each question based on the information provided. At the end, users declared their final preference and completed the same knowledge and decisional conflict questions. Paired sample t tests were employed to compare before and after knowledge and decisional conflict scores. A multinomial regression analysis was performed to determine which FAQs were associated with a shift in screening preference. RESULTS: Of all the people who accessed the PSA Option Grid, 39.8% (186/467) completed the interactive journey and associated surveys. After excluding 22 female users, we analyzed 164 responses. At completion, users shifted their preference to "not having the PSA test" (43/164, 26.2%, vs 117/164, 71.3%; P<.001), had higher levels of knowledge (112/164, 68.3%, vs 146/164, 89.0%; P<.001), and lower decisional conflict (94/164, 57.3%, vs 18/164, 11.0%; P<.001). There were 3 FAQs associated with preference shift: "What does the test involve?" "If my PSA level is high, what are the chances that I have prostate cancer?" and "What are the risks?" We did not find any relationship between knowledge, decisional conflict, and preference shift. CONCLUSIONS: Unprompted use of the interactive PSA Option Grid leads to preference shift, increased knowledge, and reduced decisional conflict, which confirms the ability of these tools to influence decision making, even when used outside clinical encounters. PMID- 30463841 TI - Development and Validation of Apolipoprotein AI-Associated Lipoprotein Proteome Panel for the Prediction of Cholesterol Efflux Capacity and Coronary Artery Disease. AB - BACKGROUND: Cholesterol efflux capacity (CEC) is a measure of HDL function that, in cell-based studies, has demonstrated an inverse association with cardiovascular disease. The cell-based measure of CEC is complex and low throughput. We hypothesized that assessment of the lipoprotein proteome would allow for precise, high-throughput CEC prediction. METHODS: After isolating lipoprotein particles from serum, we used LC-MS/MS to quantify 21 lipoprotein associated proteins. A bioinformatic pipeline was used to identify proteins with univariate correlation to cell-based CEC measurements and generate a multivariate algorithm for CEC prediction (pCE). Using logistic regression, protein coefficients in the pCE model were reweighted to yield a new algorithm predicting coronary artery disease (pCAD). RESULTS: Discovery using targeted LC-MS/MS analysis of 105 training and test samples yielded a pCE model comprising 5 proteins (Spearman r = 0.86). Evaluation of pCE in a case-control study of 231 specimens from healthy individuals and patients with coronary artery disease revealed lower pCE in cases (P = 0.03). Derived within this same study, the pCAD model significantly improved classification (P < 0.0001). Following analytical validation of the multiplexed proteomic method, we conducted a case-control study of myocardial infarction in 137 postmenopausal women that confirmed significant separation of specimen cohorts in both the pCE (P = 0.015) and pCAD (P = 0.001) models. CONCLUSIONS: Development of a proteomic pCE provides a reproducible high throughput alternative to traditional cell-based CEC assays. The pCAD model improves stratification of case and control cohorts and, with further studies to establish clinical validity, presents a new opportunity for the assessment of cardiovascular health. PMID- 30463842 TI - How should doctors communicate the risks of Brexit to the public? PMID- 30463843 TI - Hepatitis C: NHS seeks to identify 55 000 patients for treatment. PMID- 30463845 TI - Immediate postnatal contraception: what women know and think. AB - INTRODUCTION: Postpartum women are at risk of rapid repeat, unplanned pregnancy with associated adverse outcomes for mother and child. We aimed to better understand their contraceptive needs to improve delivery of services and prevent unplanned pregnancies. METHODS: A cross-sectional survey of women on the postnatal ward of an inner-city hospital was administered over a 6-week period in June and July 2017 to determine their level of knowledge, intentions and preferences regarding postnatal contraception. RESULTS: 272 women were surveyed: 86% of all women on the postnatal ward during the study period. 10% (26/272) had never used any method of contraception previously and 22% (59/272) had ever used a long-acting reversible contraception (LARC) method. 18% (48/272) recalled a health professional speaking to them about contraception at any point during their pregnancy and 32% (87/272) said they needed more information to decide on their postnatal contraceptive method. 54% (147/272) of women did not think any LARC methods were safe immediately postnatally, rising to 71% (194/272) if breastfeeding. However, 47% (129/272) of women said that they would prefer to get their contraception from the ward before discharge and 46% (126/272) were likely to accept LARC, if safe, in this setting. CONCLUSIONS: Almost half the women in our survey would welcome provision of postnatal contraception, including LARC, on the postnatal ward but the women surveyed currently lack the knowledge to make informed choices in this setting. There is therefore a need for effective, tailored contraceptive choices discussions with every woman during pregnancy, as well as integrated planning for postnatal provision of the woman's chosen method. PMID- 30463846 TI - Hepatitis B screening in an integrated sexual health service: an analysis of the cost-effectiveness of using a set hepatitis B serology panel for screening. PMID- 30463847 TI - Association between type of contraceptive use and haemoglobin status among women of reproductive age in 24 sub-Saharan Africa countries. AB - BACKGROUND: Little is known whether contraceptive methods differentially modify women's risk of anaemia or not. We compared the haemoglobin status of women currently using different fertility regulation methods in sub-Saharan Africa (SSA) where anaemia is a major concern. METHODS: We conducted the study based on the secondary data of 24 nationally representative demographic and health surveys carried out recently in SSA. The data of 105 532 women were included in the analysis. In the original surveys, respondents were selected using multistage sampling techniques and haemoglobin was determined using the HemoCue analyser. The association between method of contraception and anaemia status was determined via a mixed-effects logistic regression model adjusted for potential confounders. The outputs are presented using adjusted odds ratio (AOR) with 95% CI. RESULTS: The mean (+/-SD deviation) haemoglobin was 12.3 (+/-1.7) g/dl and 36.7% of the women had anaemia. Current use of modern contraceptives, as compared with non use, was associated with a 25% reduction (AOR=0.75 (95% CI: 0.73 to 0.78)) in the odds of anaemia. Comparison among individual modern methods showed, as compared with current barrier methods users, use of injectables (AOR=0.62 (95% CI: 0.57 to 0.67)), oral contraceptive pills (OCP) (AOR=0.62 (95% CI: 0.57 to 0.66)) and implants (AOR=0.63 (95% CI: 0.58 to 0.70)) were significantly associated with reduced odds of anaemia. With reference to women with less than 12 months of use, the odds were significantly reduced by about a quarter among women with more than 12 months of OCP or injectables use. CONCLUSION: The use of hormonal contraceptives is associated with lower odds of anaemia. PMID- 30463849 TI - First CAR to Pass the Road Test: Tisagenlecleucel's Drive to FDA Approval. AB - In August 2017, the U.S. Food and Drug Administration (FDA) took historic action in granting the first approval of gene therapy to tisagenlecleucel. This landmark step brought CAR T-cell therapy to the commercial space and heralded a new era in managing refractory B-cell malignancies and FDA oversight of gene-modified therapies. PMID- 30463848 TI - Cancer associated fibroblasts-promoted LncRNA DNM3OS confers radioresistance by regulating DNA damage response in esophageal squamous cell carcinoma. AB - PURPOSE: Our study aimed to investigate whether CAFs (cancer associated fibroblasts) were involved in lncRNAs regulated radioresponse in ESCC Experimental Design: By use of lncRNAs PCR array, 38 lncRNAs were screened in esophageal cancer cells and in normal esophageal epithelial cells Het-1A. LncRNA DNM3OS was detected in tumor tissues of ESCC patients and in matched normal esophageal epithelial tissues by qRT-PCR analysis and in situ hybridization assay. The association of DNM3OS and tumor radioresistance was investigated in vitro and in vivo. The influences of DNM3OS on DNA damage response was investigated by western blotting, immunofluorescence imaging and comet assay. The mechanisms by which CAFs promoted DNM3OS expression was investigated by kinase inhibitors screening, luciferase assay and chromatin immunoprecipitation. RESULTS: Among the 38 lncRNAs tested, DNM3OS was found to have a much higher expression level in esophageal cancer cells than in Het-1A. In tumor tissues of 16 ESCC patients, the expression level of DNM3OS showed an average increase of 6.3429-fold compared with that in matched normal tissues. DNM3OS conferred significant radioresistance in vitro and in vivo by regulating DNA damage response. CAFs promoted the expression of DNM3OS with a 39.2554-fold and 38.3163 fold increase in KYSE-30 and KYSE-140, respectively. CAFs promoted the expression of DNM3OS in a PDGFb/PDGFRb/FOXO1 signaling pathway-dependent manner. FOXO1, a transcription factor downstream of PDGFb/PDGFRb signaling pathway initiated the transcription of DNM3OS by binding to DNM3OS promoter. CONCLUSIONS: Our study highlighted CAFs-promoted DNM3OS as an attractive target to reverse tumor radioresistance in ESCC. PMID- 30463850 TI - Biological Consequences of Major Histocompatibility Class-II Expression by Tumor Cells in Cancer. AB - Immunotherapy has emerged as a key pillar of cancer treatment. To build upon the recent successes of immunotherapy, intense research efforts are aimed at a molecular understanding of anti-tumor immune responses, identification of biomarkers of immunotherapy response and resistance, and novel strategies to circumvent resistance. These studies are revealing new insight into the intricacies of tumor cell recognition by the immune system, in large part through Major Histocompatibility Complexes (MHCs). Though tumor cells widely express MHC I, a subset of tumors originating from a variety of tissues also express MHC-II, an antigen presenting complex traditionally associated with professional antigen presenting cells (APCs). MHC-II is critical for antigen presentation to CD4+ T lymphocytes, whose role in anti-tumor immunity is becoming increasingly appreciated. Accumulating evidence demonstrates that tumor-specific MHC-II associates with favorable outcomes in patients with cancer, including those treated with immunotherapies, and with tumor rejection in murine models. Herein, we will review current research regarding tumor-enriched MHC-II expression and regulation in a range of human tumors and murine models, and the possible therapeutic applications of tumor-specific MHC-II. PMID- 30463844 TI - Food sources of fructose-containing sugars and glycaemic control: systematic review and meta-analysis of controlled intervention studies. AB - OBJECTIVE: To assess the effect of different food sources of fructose-containing sugars on glycaemic control at different levels of energy control. DESIGN: Systematic review and meta-analysis of controlled intervention studies. DATA SOURCES: Medine, Embase, and the Cochrane Library up to 25 April 2018. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Controlled intervention studies of at least seven days' duration and assessing the effect of different food sources of fructose-containing sugars on glycaemic control in people with and without diabetes were included. Four study designs were prespecified on the basis of energy control: substitution studies (sugars in energy matched comparisons with other macronutrients), addition studies (excess energy from sugars added to diets), subtraction studies (energy from sugars subtracted from diets), and ad libitum studies (sugars freely replaced by other macronutrients without control for energy). Outcomes were glycated haemoglobin (HbA1c), fasting blood glucose, and fasting blood glucose insulin. DATA EXTRACTION AND SYNTHESIS: Four independent reviewers extracted relevant data and assessed risk of bias. Data were pooled by random effects models and overall certainty of the evidence assessed by the GRADE approach (grading of recommendations assessment, development, and evaluation). RESULTS: 155 study comparisons (n=5086) were included. Total fructose-containing sugars had no harmful effect on any outcome in substitution or subtraction studies, with a decrease seen in HbA1c in substitution studies (mean difference -0.22% (95% confidence interval to -0.35% to -0.08%), -25.9 mmol/mol (-27.3 to -24.4)), but a harmful effect was seen on fasting insulin in addition studies (4.68 pmol/L (1.40 to 7.96)) and ad libitum studies (7.24 pmol/L (0.47 to 14.00)). There was interaction by food source, with specific food sources showing beneficial effects (fruit and fruit juice) or harmful effects (sweetened milk and mixed sources) in substitution studies and harmful effects (sugars-sweetened beverages and fruit juice) in addition studies on at least one outcome. Most of the evidence was low quality. CONCLUSIONS: Energy control and food source appear to mediate the effect of fructose containing sugars on glycaemic control. Although most food sources of these sugars (especially fruit) do not have a harmful effect in energy matched substitutions with other macronutrients, several food sources of fructose containing sugars (especially sugars-sweetened beverages) adding excess energy to diets have harmful effects. However, certainty in these estimates is low, and more high quality randomised controlled trials are needed. STUDY REGISTRATION: Clinicaltrials.gov (NCT02716870). PMID- 30463851 TI - Neonatal Outcomes of Very Preterm or Very Low Birth Weight Triplets. AB - OBJECTIVES: To compare the neonatal outcomes of very preterm triplets with those of matched singletons using a large international cohort. METHODS: A retrospective matched-cohort study of preterm triplets and singletons born between 2007 and 2013 in the International Network for Evaluation of Outcomes in neonates database countries and matched by gestational age, sex, and country of birth was conducted. The primary outcome was a composite of mortality or severe neonatal morbidity (severe neurologic injury, treated retinopathy of prematurity, and bronchopulmonary dysplasia). Unadjusted and adjusted odds ratios with 95% confidence intervals (CIs) were calculated for model 1 (maternal hypertension and birth weight z score) and model 2 (variables in model 1, antenatal steroids, and mode of birth). Models were fitted with generalizing estimating equations and random effects modeling to account for clustering. RESULTS: A total of 6079 triplets of 24 to 32 weeks' gestation or 500 to 1499 g birth weight and 18 232 matched singletons were included. There was no difference in the primary outcome between triplets and singletons (23.4% vs 24.0%, adjusted odds ratio: 0.91, 95% CI: 0.83-1.01 for model 1 and 1.00, 95% CI: 0.90-1.11 for model 2). Rates of severe neonatal morbidities did not differ significantly between triplets and singletons. The results were also similar for a subsample of the cohort (1648 triplets and 4944 matched singletons) born at 24 to 28 weeks' gestation. CONCLUSIONS: No significant differences were identified in mortality or major neonatal morbidities between triplets who were very low birth weight or very preterm and matched singletons. PMID- 30463852 TI - Gli2 modulates cell cycle re-entry through autophagy-mediated regulation on the length of primary cilia. AB - The primary cilium is a tiny cell protrusion known to transduce key extracellular signals, including the sonic hedgehog pathway, which activates Gli transcription factors for various cellular functions. To understand the significance of Gli2 transcription factor in fibroblasts, we establish a Gli2 knockout NIH3T3 cell line by CRISPR/Cas9 technology. Surprisingly, NIH3T3 fibroblasts lacking Gli2 expression through gene knockout or RNA interference possess longer primary cilia after stimulation of ciliogenesis by serum starvation. This lengthening of primary cilia is associated with enhanced autophagy-mediated Ofd1 degradation and can be reversed by pharmacological and genetic inhibition of autophagy. Meanwhile, flow cytometry reveals that Gli2-/- NIH3T3 fibroblasts exhibit a delay in cell cycle re-entry after serum re-stimulation. Ablation of their primary cilia by Kif3a knockdown rescues the delay in cell cycle re-entry. These results suggest that Gli2 plays an unexpected role for cell cycle re-entry through autophagy-mediated regulation on ciliary length in fibroblasts. PMID- 30463854 TI - FDA approves single-dose oral influenza treatment. PMID- 30463853 TI - Lack of G1/S control destabilizes the yeast genome via replication stress-induced DSBs and illegitimate recombination. AB - The protein Swi6 in Saccharomyces cerevisiae is a cofactor in two complexes that regulate the transcription of the G1/S transition genes. It also ensures proper oxidative and cell wall stress responses. Previously, we found Swi6 to be crucial for the survival of genotoxic stress. Here, we show that a lack of Swi6 causes replication stress leading to double-strand break (DSB) formation, inefficient DNA repair, and DNA content alterations, resulting in high cell mortality. Comparative genome hybridization showed random genome rearrangement in swi6Delta, whereas in diploid swi6Delta/swi6Delta, chromosome V is duplicated. SWI4 and PAB1, known multicopy suppressors of swi6Delta phenotypes located on chromosome V, partially reverse swi6Delta genome instability when overexpressed. Another gene on chromosome V, RAD51, also supports swi6Delta survival, but at a high cost. Rad51-dependent illegitimate recombination in swi6Delta appears to connect DSBs, leading to genome rearrangement and preventing cell death. PMID- 30463856 TI - Zellmer Lecture sets tone for Policy Week. PMID- 30463855 TI - ISMP's Cohen delivers Zellmer Lecture, offers insights on influencing public policy. PMID- 30463857 TI - Oddis, ASHP members honored as fellows of FIP. PMID- 30463858 TI - ASHP supports global antimicrobial resistance challenge. PMID- 30463859 TI - Promotion. PMID- 30463860 TI - Summaries of safety labeling changes approved by FDA-Boxed warnings highlights, July-September 2018. PMID- 30463861 TI - Implementation of a pharmacist-driven formulary management service within a community health-system insurance plan. PMID- 30463862 TI - Further steps for parenteral nutrition in the electronic health record. PMID- 30463863 TI - Longitudinal emergency medical services experience within a postgraduate year 2 pharmacy residency in emergency medicine. PMID- 30463864 TI - Using the Practice Advancement Initiative to expand pharmacy student involvement. PMID- 30463865 TI - Effect of plasma exchange on antifactor Xa activity of enoxaparin and serum levetiracetam levels. AB - PURPOSE: The effect of therapeutic plasma exchange (TPE) on antifactor Xa activity in a patient treated with enoxaparin and levetiracetam is reported. SUMMARY: A 52-year-old woman was treated with levetiracetam and prophylactic enoxaparin while receiving TPE to manage respiratory failure due to anti-MDA5 antibody-associated interstitial lung disease (ILD) with dermatomyositis. Due to a scant amount of evidence regarding the management of these medications in TPE, therapeutic monitoring principles were used to assess the effect TPE had on these medications. A pre-TPE antifactor Xa activity level and levetiracetam serum assay, a post-TPE antifactor Xa activity level and levetiracetam serum assay, levetiracetam serum assays at 1 and 6 hours after the patient received her next dose, and a levetiracetam assay of the waste plasma from the TPE were collected for therapeutic drug monitoring and pharmacokinetic calculations. Utilizing standard population pharmacokinetic data, the expected antifactor Xa activity without TPE was 0.14 IU/mL. This concentration was significantly higher than the undetectable concentration (<0.1 IU/mL) that was drawn immediately after TPE, suggesting significant removal of antifactor Xa activity. The measured levetiracetam level did not significantly differ from the expected post-TPE levetiracetam level that was calculated using patient-specific pharmacokinetic data. CONCLUSION: In a patient receiving TPE to manage anti-MDA5 antibody ILD associated with dermatomyositis and a prior seizure, TPE significantly altered enoxaparin antifactor Xa activity as evidenced by the undetectable antifactor Xa activity level drawn after TPE. Alternatively, TPE had a minimal effect on the clearance of levetiracetam as evidenced by the post-TPE level and fraction elimination of only 5% of total body stores. PMID- 30463866 TI - Longitudinal trends in U.S. shortages of sterile solutions, 2001-17. AB - PURPOSE: Trends in the shortages of sterile solutions in the United States were evaluated. METHODS: A retrospective review of shortage data from the University of Utah Drug Information Service (UUDIS) was performed. Shortages of sterile solutions, including saline, dextrose, lactated Ringer's, and sterile water for injection, were identified. We extracted the product name, reason for the shortage, shortage duration, and primary use of the solution, examining trends in shortages over time. RESULTS: There were 37 sterile solution shortages in the UUDIS data set, 22 of which had been resolved. The mean +/- S.D. duration of a resolved shortage was 13.9 +/- 9.6 months. The most common category of solution shortage was for saline products (n = 11). Manufacturing delay was the most common reason given for shortages (n = 19). In 2017, 12 new shortages were reported, and 15 solutions remained in shortage by year's end. This was the highest number of shortages at any time during the study period. The longest active shortage was for 5% dextrose/0.45% sodium chloride, which began in October 2007 and has yet to be resolved. CONCLUSION: There were 37 shortages of sterile solutions from 2001 through 2017. Shortages became more severe after Hurricane Maria damaged manufacturing facilities in Puerto Rico, with 12 new shortages reported in 2017. PMID- 30463867 TI - Systematic review of computerized prescriber order entry and clinical decision support. AB - PURPOSE: Results of a systematic review of published data on the effect of computerized prescriber order entry (CPOE) with clinical decision support on medication error (ME) and adverse drug event (ADE) rates are presented. METHODS: Literature searches of MEDLINE, Embase, and other databases were conducted to identify English- and Spanish-language articles on selected CPOE outcomes published from 1995 through 2016; in addition, 5 specific journals were searched for pertinent articles published during the period 2010-16. Publications on controlled prospective studies and before-and-after studies that assessed MEs and/or ADEs as main outcomes were selected for inclusion in the review. RESULTS: Nineteen studies met the inclusion criteria. Data on MEs and ADEs could not be pooled, mainly due to heterogeneity in outcome definitions and study methodologies. The reviewed evidence indicated that CPOE implementation led to an overall reduction in errors at the prescription stage of the medication-use process (relative risk reduction, 0.29 [95% confidence interval, 0.10-0.85]; I 2 = 99%) and reductions in most types of prescription errors, but CPOE also resulted in the emergence of other types of errors. CONCLUSION: CPOE reduces the overall ME rate in the prescription process, as well as specific types of errors, such as wrong dose or strength, wrong drug, frequency, administration route, and drug-drug interaction errors. The implementation of CPOE can lead to new errors, such as wrong drug selection from drop-down menus. PMID- 30463868 TI - Using technology to enhance medication regimen education after solid organ transplantation. AB - PURPOSE: The design and implementation of a tool that combines clinical teaching with cutting-edge, simplified technology for providing medication education to solid organ transplant (SOT) recipients are described. METHODS: In a retrospective study of adults who received kidney transplants from February 2015 through May 2017, patients were educated about their medications using a tablet computer application, Medication Regimen Education (MRxEd), that presented concise videos describing the name, indication, dose, adverse effects, and associated interactions of all medications received, as well as special considerations applicable to each agent. Assessment questions were used to reinforce key concepts and identify knowledge gaps. RESULTS: The digital educational intervention was provided to 282 kidney transplant recipients. Patients were predominantly white (48%) and/or male (63%), with a median age of 51 years (interquartile range, 37-61 years). Patients came from a variety of education backgrounds. Most patients (81%) were educated on dual maintenance immunosuppression (with tacrolimus and mycophenolate) and 3 infection prophylaxis agents (nystatin, sulfamethoxazole-trimethoprim, and valganciclovir). Most patients (90%) correctly answered questions related to medication indications, dosing, and special rules, but many (61%) had difficulty correctly answering questions about adverse effects. CONCLUSION: An innovative approach for interactive and engaging medication teaching with the MRxEd application enhanced the education process for SOT recipients. PMID- 30463869 TI - Summaries of safety labeling changes approved by FDA-Boxed warnings highlights, July-September 2018. PMID- 30463870 TI - Diverse Lineages of Candida albicans Live on Old Oaks. AB - The human pathogen, Candida albicans, is considered an obligate commensal of animals, yet it is occasionally isolated from trees, shrubs and grass. We generated genome sequence data for three strains of C. albicans that we isolated from oak trees in an ancient wood-pasture, and compared these to the genomes of over 200 clinical strains. C. albicans strains from oak are similar to clinical C. albicans in that they are predominantly diploid and can become homozygous at the mating locus through whole-chromosome loss of heterozygosity. Oak strains differed from clinical strains in showing slightly higher levels of heterozygosity genome-wide. Using phylogenomic analyses and in silico chromosome painting, we show that each oak strain is more closely related to strains from humans and other animals than to strains from other oaks. The high genetic diversity of C. albicans from old oaks shows that they can live in this environment for extended periods of time. PMID- 30463871 TI - Structural enzymology reveals the molecular basis of substrate regiospecificity and processivity of an exemplar bacterial Glycoside Hydrolase Family 74 endo xyloglucanase. AB - Paenibacillus odorifer produces a single multimodular enzyme containing a glycoside hydrolase (GH) family 74 module (AIQ73809). Recombinant production and characterization of the GH74 module ( Po GH74cat) revealed a highly specific, processive endo -xyloglucanase that is able to hydrolyze the polysaccharide backbone at both branched and unbranched positions. X-ray crystal structures obtained for the free enzyme and oligosaccharide complexes evidenced an extensive hydrophobic binding platform - the first in GH74 extending from subsites -4 to +6 - and unique mobile active-site loops. Site-directed mutagenesis revealed that glycine-476 was uniquely responsible for the promiscuous backbone-cleaving activity of Po GH74cat; replacement with tyrosine, which is conserved in many GH74 members, resulted in exclusive hydrolysis at unbranched glucose units. Likewise, systematic replacement of the hydrophobic platform residues constituting the positive subsites indicated their relative contributions to the processive mode of action. Specifically, W347 (+3 subsite) and W348 (+5 subsite) are essential for processivity, while W406 (+2 subsite) and Y372 (+6 subsite) are not strictly essential but nonetheless aid processivity. PMID- 30463872 TI - Current opinions for the management of asthma associated with ear, nose and throat comorbidities. AB - Ear, nose and throat (ENT) comorbidities are common in patients with asthma and are frequently associated with poorer asthma outcomes. All these comorbidities are "treatable traits" in asthma. Identification and management of these disorders may spare medication usage and contribute to improved asthma control and quality of life, and a decrease in exacerbation rates.This review summarises recent data about the prevalence, clinical impact and treatment effects of ENT comorbidities in asthma including allergic rhinitis, chronic rhinosinusitis with and without nasal polyposis, aspirin-exacerbated respiratory disease, obstructive sleep apnoea and vocal cord dysfunction.Many of these comorbidities are possible to be managed by the pulmonologist, but the collaboration with the ENT specialist is essential for patients with chronic rhinosinusitis or vocal cord dysfunction. Further rigorous research is needed to study the efficacy of comorbidity treatment to improve asthma outcomes, in particular with the development of biotherapies in severe asthma that can also be beneficial in some ENT diseases. PMID- 30463874 TI - "Cardiovascular disease and COPD: dangerous liaisons." Klaus F. Rabe, John R. Hurst and Samy Suissa. Eur Respir Rev 2018; 27: 180057. PMID- 30463873 TI - Risk factors for mortality and mortality rates in interstitial lung disease patients in the intensive care unit. AB - Data on interstitial lung disease (ILD) outcomes in the intensive care unit (ICU) is of limited value due to population heterogeneity. The aim of this study was to examine risk factors for mortality and ILD mortality rates in the ICU.We performed a systematic review using five databases. 50 studies were identified and 34 were included: 17 studies on various aetiologies of ILD (mixed-ILD) and 17 on idiopathic pulmonary fibrosis (IPF). In mixed-ILD, elevated APACHE score, hypoxaemia and mechanical ventilation are risk factors for mortality. No increased mortality was found with steroid use. Evidence is inconclusive on advanced age. In IPF, evidence is inconclusive for all factors except mechanical ventilation and hypoxaemia. The overall in-hospital mortality was available in 15 studies on mixed-ILD (62% in 2001-2009 and 48% in 2010-2017) and 15 studies on IPF (79% in 1993-2004 and 65% in 2005-2017). Follow-up mortality rate at 1 year ranged between 53% and 100%.Irrespective of ILD aetiology, mechanical ventilation is associated with increased mortality. For mixed-ILD, hypoxaemia and APACHE scores are also associated with increased mortality. IPF has the highest mortality rate among ILDs, but since 1993 the rate appears to be declining. Despite improving in-hospital survival, overall mortality remains high. PMID- 30463875 TI - Reversal and prevention of the respiratory-depressant effects of heroin by the novel u opioid receptor antagonist methocinnamox in rhesus monkeys. AB - One consequence of the ongoing opioid epidemic is a large number of overdose deaths. Naloxone reverses opioid-induced respiratory depression; however, its short duration of action limits the protection it can provide. Methocinnamox (MCAM) is a novel opioid receptor antagonist with a long duration of action. This study examined the ability of MCAM to prevent and reverse the respiratory depressant effects (minute volume [VE]) of heroin in 5 monkeys. MCAM (0.32 mg/kg) was given before heroin to determine whether it prevents respiratory depression; heroin dose-effect curves were generated 1, 2, 4, and 8 days later, and these effects were compared to those of naltrexone (0.032 mg/kg). Heroin dose dependently decreased VE. MCAM and naltrexone prevented respiratory depression, shifting the heroin dose-effect curve at least 10-fold rightward. MCAM, but not naltrexone, attenuated these effects of heroin for 4 days. MCAM (0.1-0.32 mg/kg) was given 30 min after heroin to determine whether it reverses respiratory depression; heroin dose-effect curves were generated 1, 2, 4, 8, and 16 days later, and these effects were compared to those of naloxone (0.0032-0.1 mg/kg). MCAM and naloxone reversed respiratory depression within 30 min, although only MCAM antagonized heroin on subsequent days. Thus, MCAM prevents and reverses respiratory depression, the potentially lethal effect of heroin, longer than currently used opioid receptor antagonists. Because of its sustained effects, MCAM might provide more effective rescue from and protection against the fatal respiratory-depressant effects of opioids, thereby improving treatment of opioid overdose. PMID- 30463876 TI - The E3 ligase VHL controls alveolar macrophage function via metabolic-epigenetic regulation. AB - Metabolic pathways such as glycolysis or oxidative phosphorylation play a key role in regulating macrophage function during inflammation and tissue repair. However, how exactly the VHL-HIF-glycolysis axis is involved in the function of tissue-resident macrophages remains unclear. Here we demonstrate that loss of VHL in myeloid cells resulted in attenuated pulmonary type 2 and fibrotic responses, accompanied by reduced eosinophil infiltration, decreased IL-5 and IL-13 concentrations, and ameliorated fiber deposition upon challenge. VHL deficiency uplifted glycolytic metabolism, decreased respiratory capacity, and reduced osteopontin expression in alveolar macrophages, which impaired the function of type 2 innate lymphoid cells but was significantly reversed by HIF1alpha inhibition or ablation. The up-regulated glycolysis altered the epigenetic modification of osteopontin gene, with the metabolic intermediate 3 phosphoglyceric acid as a key checkpoint controller. Thus, our results indicate that VHL acts as a crucial regulatory factor in lung inflammation and fibrosis by regulating alveolar macrophages. PMID- 30463878 TI - gammadelta T cells: A disappearing act with a big reveal. AB - In this issue of JEM, Sandrock et al. (https://doi.org/10.1084/jem.20181439) compare the origin of IL-17-producing gammadelta T cells (Tgammadelta17) with other gammadelta T cell populations and demonstrate the role Tgammadelta17 cells play in skin pathology. Using two genetically modified mouse models, one with inducible gammadelta T cell-specific labeling and the other with conditional gammadelta T cell depletion, the authors find that Tgammadelta17 are mostly long lived lymphocytes and that depleting gammadelta T cells protects mice from psoriasis. PMID- 30463879 TI - David Oliver: Will robotic automation solve social care? PMID- 30463880 TI - N-cadherin signaling via Trio assembles adherens junctions to restrict endothelial permeability. AB - Vascular endothelial (VE)-cadherin forms homotypic adherens junctions (AJs) in the endothelium, whereas N-cadherin forms heterotypic adhesion between endothelial cells and surrounding vascular smooth muscle cells and pericytes. Here we addressed the question whether both cadherin adhesion complexes communicate through intracellular signaling and contribute to the integrity of the endothelial barrier. We demonstrated that deletion of N-cadherin (Cdh2) in either endothelial cells or pericytes increases junctional endothelial permeability in lung and brain secondary to reduced accumulation of VE-cadherin at AJs. N-cadherin functions by increasing the rate of VE-cadherin recruitment to AJs and induces the assembly of VE-cadherin junctions. We identified the dual Rac1/RhoA Rho guanine nucleotide exchange factor (GEF) Trio as a critical component of the N-cadherin adhesion complex, which activates both Rac1 and RhoA signaling pathways at AJs. Trio GEF1-mediated Rac1 activation induces the recruitment of VE-cadherin to AJs, whereas Trio GEF2-mediated RhoA activation increases intracellular tension and reinforces Rac1 activation to promote assembly of VE-cadherin junctions and thereby establish the characteristic restrictive endothelial barrier. PMID- 30463881 TI - Bruised apples: violence against women in the education sector. PMID- 30463877 TI - HDAC stimulates gene expression through BRD4 availability in response to IFN and in interferonopathies. AB - In contrast to the common role of histone deacetylases (HDACs) for gene repression, HDAC activity provides a required positive function for IFN stimulated gene (ISG) expression. Here, we show that HDAC1/2 as components of the Sin3A complex are required for ISG transcriptional elongation but not for recruitment of RNA polymerase or transcriptional initiation. Transcriptional arrest by HDAC inhibition coincides with failure to recruit the epigenetic reader Brd4 and elongation factor P-TEFb due to sequestration of Brd4 on hyperacetylated chromatin. Brd4 availability is regulated by an equilibrium cycle between opposed acetyltransferase and deacetylase activities that maintains a steady-state pool of free Brd4 available for recruitment to inducible promoters. An ISG expression signature is a hallmark of interferonopathies and other autoimmune diseases. Combined inhibition of HDAC1/2 and Brd4 resolved the aberrant ISG expression detected in cells derived from patients with two inherited interferonopathies, ISG15 and USP18 deficiencies, defining a novel therapeutic approach to ISG associated autoimmune diseases. PMID- 30463882 TI - Perturbations of Transcription and Gene Expression-Associated Processes Alter Distribution of Cell Size Values in Saccharomyces cerevisiae. AB - The question of what determines whether cells are big or small has been the focus of many studies because it is thought that such determinants underpin the coupling of cell growth with cell division. In contrast, what determines the overall pattern of how cell size is distributed within a population of wild type or mutant cells has received little attention. Knowing how cell size varies around a characteristic pattern could shed light on the processes that generate such a pattern and provide a criterion to identify its genetic basis. Here, we show that cell size values of wild type Saccharomyces cerevisiae cells fit a gamma distribution, in haploid and diploid cells, and under different growth conditions. To identify genes that influence this pattern, we analyzed the cell size distributions of all single-gene deletion strains in Saccharomyces cerevisiae We found that yeast strains which deviate the most from the gamma distribution are enriched for those lacking gene products functioning in gene expression, especially those in transcription or transcription-linked processes. We also show that cell size is increased in mutants carrying altered activity substitutions in Rpo21p/Rpb1, the largest subunit of RNA polymerase II (Pol II). Lastly, the size distribution of cells carrying extreme altered activity Pol II substitutions deviated from the expected gamma distribution. Our results are consistent with the idea that genetic defects in widely acting transcription factors or Pol II itself compromise both cell size homeostasis and how the size of individual cells is distributed in a population. PMID- 30463883 TI - Suppressor Analysis Uncovers That MAPs and Microtubule Dynamics Balance with the Cut7/Kinesin-5 Motor for Mitotic Spindle Assembly in Schizosaccharomyces pombe. AB - The Kinesin-5 motor Cut7 in Schizosaccharomyces pombe plays essential roles in spindle pole separation, leading to the assembly of bipolar spindle. In many organisms, simultaneous inactivation of Kinesin-14s neutralizes Kinesin-5 deficiency. To uncover the molecular network that counteracts Kinesin-5, we have conducted a genetic screening for suppressors that rescue the cut7-22 temperature sensitive mutation, and identified 10 loci. Next generation sequencing analysis reveals that causative mutations are mapped in genes encoding alpha-, beta tubulins and the microtubule plus-end tracking protein Mal3/EB1, in addition to the components of the Pkl1/Kinesin-14 complex. Moreover, the deletion of various genes required for microtubule nucleation/polymerization also suppresses the cut7 mutant. Intriguingly, Klp2/Kinesin-14 levels on the spindles are significantly increased in cut7 mutants, whereas these increases are negated by suppressors, which may explain the suppression by these mutations/deletions. Consistent with this notion, mild overproduction of Klp2 in these double mutant cells confers temperature sensitivity. Surprisingly, treatment with a microtubule-destabilizing drug not only suppresses cut7 temperature sensitivity but also rescues the lethality resulting from the deletion of cut7, though a single klp2 deletion per se cannot compensate for the loss of Cut7. We propose that microtubule assembly and/or dynamics antagonize Cut7 functions, and that the orchestration between these two factors is crucial for bipolar spindle assembly. PMID- 30463884 TI - New Drosophila Long-Term Memory Genes Revealed by Assessing Computational Function Prediction Methods. AB - A major bottleneck to our understanding of the genetic and molecular foundation of life lies in the ability to assign function to a gene and, subsequently, a protein. Traditional molecular and genetic experiments can provide the most reliable forms of identification, but are generally low-throughput, making such discovery and assignment a daunting task. The bottleneck has led to an increasing role for computational approaches. The Critical Assessment of Functional Annotation (CAFA) effort seeks to measure the performance of computational methods. In CAFA3, we performed selected screens, including an effort focused on long-term memory. We used homology and previous CAFA predictions to identify 29 key Drosophila genes, which we tested via a long-term memory screen. We identify 11 novel genes that are involved in long-term memory formation and show a high level of connectivity with previously identified learning and memory genes. Our study provides first higher-order behavioral assay and organism screen used for CAFA assessments and revealed previously uncharacterized roles of multiple genes as possible regulators of neuronal plasticity at the boundary of information acquisition and memory formation. PMID- 30463885 TI - Using a 10-step framework to support the implementation of an evidence-based clinical pathways programme. AB - BACKGROUND: Integration of evidence into practice is suboptimal. Clinical pathways, defined as multidisciplinary care plans, are a method for translating evidence into local settings and have been shown to improve the value of patient care. OBJECTIVE: To describe the development of a clinical pathways programme across a large academic healthcare system. METHODS: We use a 10-step framework (grounded in the Knowledge-to-Action framework and ADAPTE Collaboration methodology for guideline adaptation) to support pathway development and dissemination, including facilitating clinical owner and stakeholder engagement, developing pathway prototypes based on rapid reviews of the existing literature, developing tools for dissemination and impact assessment. We use a cloud-based technology platform (Dorsata, Washington, DC) to assist with development and dissemination across our geographically distributed care settings and providers. Content is viewable through desktop and mobile applications. We measured programme adoption and penetration by examining number of pathways developed as well as mobile application use and pathway views. RESULTS: From 1 February 2016 to 30 April 2018, a total of 202 pathways were disseminated. The three most common clinical domains represented were oncology (46.5%, n=94), pulmonary/critical care (8.9%, n=18) and cardiovascular medicine (7.4%, n=15). Users opting to register for a personal account totalled 1279; the three largest groups were physicians (45.1%, n=504), advanced practice providers (19.5%, n=245) and nurses (19.1%, n=240). Pathway views reached an average of 2150 monthly views during the last 3 months of the period. The majority of pathways reference at least one evidence-based source (93.6%, n=180). CONCLUSIONS: A healthcare system can successfully use a framework and technology platform to support the development and dissemination of pathways across a multisite institution. PMID- 30463886 TI - BET 1: Lenient or strict rate control for atrial fibrillation. AB - A short cut review was carried out to establish whether the degree of rate control influences mortality in patients with atrial fibrillation. 22 papers presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are shown in the two tables. It is concluded that there is insufficient evidence to recommend any specific rate control target to decrease mortality in rate-controlled rapid atrial fibrillation. PMID- 30463888 TI - BET 2: Missed diagnosis of ischaemic stroke in the emergency department. AB - A short cut review was carried out to establish the rate and clinical characteristics of missed diagnosis of acute ischaemic stroke in the emergency department (ED). Two papers presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are shown in table 1 It is concluded that acute ischaemic stroke is missed in approximately 9%-14% of patients with this diagnosis who present to the ED. This is especially true in patients presenting with non-specific complaints such as dizziness, nausea/vomiting or altered level of consciousness. PMID- 30463889 TI - Toxin B PCR amplification cycle threshold adds little to clinical variables to predict outcomes in Clostridium difficile infection: a retrospective cohort study. AB - Objectives: To evaluate the predictive value of PCR cycle threshold (Ct) for recurrence/severity, compared to toxin detection plus clinical variables.Methods: First episodes of CDI diagnosed during 2015 at our institution were included. Samples were tested for GDH and toxin A/B with a single EIA. Xpert(r) C. difficile PCR assay was performed to GDH positive samples. Medical data were reviewed by investigators blinded to diagnostic results to compare patients with/without recurrence or poor outcome (severe/severe-complicated CDI episode and all-cause death). We generated two sets of predictive models by incorporating to clinical variables the presence of a positive toxin EIA ("EIA-including model") and the optimal PCR Ct cut-off value ("PCR-including model"), respectively.Results: Among 227 episodes of CDI included, the rates of recurrence and poor outcome were 15.8% and 30.8%. Mean PCR Ct was lower in episodes with recurrence (24.00+/-3.28 vs. 26.02+/-4.54; P-value=0.002) and poor outcome (24.9 +/- 4.24 vs. 26.05 +/- 4.47; P-value = 0.07). The optimal cut-off value for recurrence was 25.65 [sensitivity 77.8% (95% CI: 60.9-89.9), specificity 46.6% (95% CI: 39.4-53.9)]. The auROC for the "PCR-including model" was similar to that of the "EIA-including model" (0.785 vs. 0.775, respectively). The optimal PCR Ct value was 27.55 [sensitivity 78.6% (95% CI: 67.1-87.5), specificity of 35.7% (95% CI: 28.2-43.7)]. The auROC of the "PCR-including model" was again similar to that of the "EIA-including model" (0.804 vs. 0.801).Conclusions: Despite the inverse correlation between PCR Ct and the risk of CDI recurrence/severity, this determination does not meaningfully increase the predictive value of clinical variables plus toxin EIA. PMID- 30463890 TI - The Search for a Practical Method for Colistin Susceptibility Testing: Have We Found it by Going Back to the Future? AB - Polymyxins are relied upon for the treatment of carbapenem-resistant Gram negative infections, but polymyxin resistance is increasing. Only broth microdilution is recommended for polymyxin susceptibility testing, a method that is impractical for most clinical microbiology laboratories. An article in this issue of the Journal of Clinical Microbiology (P. J. Simner, Y. Bergman, M. Trejo, A. A. Roberts, R. Marayan, T. Tekle, S. Campeau, A. Kazmi, D. Bell, S. Lewis, P. D. Tamma, R. Humphries, J. A. Hindler, J Clin Microbiol, 57:e01163-18, 2018, https://doi.org/10.1128/JCM.01163-18) found that colistin broth disk elution, a method that requires only colistin disks and broth, had excellent performance compared to broth microdilution for all strains except mcr-positive Escherichia coli. PMID- 30463891 TI - Discrimination of Mycobacterium leprae and Mycobacterium haemophilum in clinical isolates/specimens by multiple PCR assay and prediction of drug susceptibility. AB - Next generation sequencing technology revealed the existence of more viable but non-culturable bacteria (VBNC) relative to culturable bacteria (1)..... PMID- 30463892 TI - Invasive Infections due to Trichosporon: Species Distribution, Genotyping, and Antifungal Susceptibilities from a Multi-center Study in China. AB - One hundred and thirty-three clinical Trichosporon isolates were collected in the National China Hospital Invasive Fungal Surveillance Net (CHIF-NET) program (2009 to 2016). Accurate identification was performed by sequencing of the intergenic spacer (IGS) 1 region. Among these isolates T. asahii (108, 81.2%) was the leading species, followed by T. dermatis (7, 5.3%), T. asteroides (5, 3.8%), T. inkin (5, 3.8%), T. dohaense (3, 2.3%), and one (0.7%) each of T. faecale, T. jirovecii, T. mucoides, T. coremiiforme and T. montevideense Both the VITEK MS (bioMerieux, Marcy l'Etoile, France) and Bruker Biotyper MS (Bruker Daltonics GmbH, Germany) platforms gave a high level (>97.5%) of correct identification when the species were present in the database. Geometric mean (GM) of amphotericin B MICs for T. asahii was 2-fold higher than for non-asahii Trichosporon High fluconazole MICs (>=8 MUg/ml) were observed in 25% (27/108) of T. asahii and 16% (4/25) of non-asahii Trichosporon isolates. Itraconazole MICs were <=0.5 MUg/ml for 89.5% of the isolates. Voriconazole was the most potent antifungal agent in vitro, with GM of 0.09 MUg/ml. Genotyping of the isolates using the IGS1 sequences alignment revealed that genotype1 was most common (41.7%), followed by genotype 4 (31.5%), 3 (23.1%), 5 (0.9%), 6 (0.9%) and 7 (1.8%). Our data of species distribution, genotypes and antifungal susceptibilities may contribute to a better understanding of the epidemiology of invasive Trichosporon infections throughout China. PMID- 30463893 TI - Multicenter clinical evaluation of the automated ARIES(r) Group A Strep PCR Assay from throat swabs. AB - Group A Streptococcus (GAS) is one of the leading causes of bacterial pharyngitis. Early GAS diagnosis is critical for appropriate antibiotic administration that reduces the risk of GAS sequela and limits spread of the infection. The ARIES(r) Group A Strep (GAS) Assay (Luminex, Austin, TX) is a fully automated PCR assay for direct detection of GAS in throat swab specimens in less than two hours with minimum hands-on time. This multicenter prospective study evaluated the clinical performance of the ARIES(r) GAS Assay as compared to Streptococcus pyogenes culture. Subjects with symptoms consistent with pharyngitis were enrolled across four sites in the United States and a throat swab in liquid Amies medium was obtained. ARIES(r) and reference testing was performed within 72 and 48 hours after sample collection, respectively. Of 623 throat-swab specimens from patients with pharyngitis (93.6% <18-years-old, 54.3% female), the reference method yielded valid results for 618 specimens. Reference and ARIES(r) assay testing showed GAS positive results for 160 (25.9%) and 166 specimens (26.9%), respectively. As compared to the reference method, ARIES(r) assay sensitivity was 97.5% (95% CI:93.7-99.0%), specificity was 97.8% (95% CI:96.0-98.8%), positive predictive value was 94.0% (95% CI:89.3-96.7%), and negative predictive value was 99.1% (95% CI:97.7-99.7%). There were ten false positive and four false negative detections with the ARIES(r) assay. Discrepant analysis with bidirectional sequencing yielded concordant results with the ARIES(r) assay for nine of 14 discordant samples. The ARIES(r) assay had high sensitivity and specificity for qualitative detection of Group A Streptococcus from patients with pharyngitis. PMID- 30463894 TI - Predicting Antimicrobial Resistance and Associated Genomic Features from Whole Genome Sequencing. AB - Thanks to the genomics revolution, thousands of strain-specific whole-genome sequences are now accessible for a wide range of pathogenic bacteria. This availability enables big-data informatics approaches to be used to study the spread and acquisition of antimicrobial resistance (AMR). In this issue of the Journal of Clinical Microbiology, M. Nguyen et al. (J Clin Microbiol 57:e01260 18, 2018, https://doi.org/10.1128/JCM.01260-18) report the results of their machine learning models based on whole-genome sequencing data to predict minimum inhibitory concentrations (MIC) of antibiotics for 5,728 nontyphoidal Salmonella genomes collected over 15 years in the USA. Their major finding demonstrates that MIC can be predicted with an average accuracy of 95% within +/-1 two-fold dilution step (confidence interval of 95-95%), an average very major error rate of 2.7% and an average major error rate of 0.1%. Importantly, these models predict MICs with no a priori information about the underlying gene content or resistance phenotypes of the strains enabling the possibility to identify AMR determinants and rapidly diagnose and prioritize antibiotic use directly from sequence. Employing such tools to diagnose and limit the spread of resistance conferring mechanism could help ameliorate the looming antibiotic resistance crisis. PMID- 30463895 TI - Multicenter Evaluation of NeuMoDxTM Group B Streptococcus (GBS) Assay on the NeuMoDxTM 288 Molecular System. AB - Group B Streptococcus (GBS) is the leading cause of neonatal sepsis and meningitis in developed countries. Recommendations for antepartum GBS detection include enriched culture with several options for identifying GBS, some of which are time consuming. To reduce time-to-identification and determination of maternal GBS colonization status, rapid nucleic acid amplification technologies have been developed and commercialized. For rapid detection of GBS, a 3-site clinical study was conducted to evaluate the NeuMoDxTM GBS Assay, a real-time polymerase chain reaction (PCR) test performed for vaginal/rectal swab specimens in Lim broth enrichment culture on the NeuMoDxTM 288 Molecular System (NeuMoDxTM System); this data was used to a support 510(k) submission. A total of 1,250 eligible remnant samples were prospectively enrolled and tested during the study. Results of the PCR assay were compared to results of the CDC-recommended enriched culture method, which served as the gold standard reference method for the study. The NeuMoDxTM GBS Assay results yielded a sensitivity of 96.9% (95% CI; 94.1 98.4), specificity of 96.0% (95% CI; 94.6-97.1), and a total agreement with the reference method of 96.2% (95% CI; 93.8-98.3). NeuMoDx GBS Assay results were also compared to results obtained using the BD MAXTM GBS Assay on the BD MAXTM System. The two systems demonstrated a total percent agreement of 98.0% (95% CI; 95.5-100.0). The performance of the NeuMoDx GBS Assay implemented on the NeuMoDx System compared favorably to the CDC enriched culture method and to the BD MAXTM GBS Assay. PMID- 30463896 TI - Clinical validation of the cobas HPV test on the cobas 6800 system for the purpose of cervical screening. AB - This study demonstrates that the clinical sensitivity, specificity and reproducibility of the novel cobas HPV test on the cobas 6800 system for high risk HPV types fulfils the criteria for use in population based cervical screening. The criteria were formulated by an international consortium, using the cobas 4800 HPV test as a validated reference assay. The cobas HPV test detected over 98% of histologically confirmed CIN2+ lesions in woman aged 30 years or older with a specificity of 98.9% when compared with the reference cobas 4800 test. Both the intra- and inter-laboratory agreement for the cobas HPV test were 98%. The clinical performance of the cobas HPV test is comparable to longitudinally validated HPV assays and fulfils the criteria for use in primary cervical screening. PMID- 30463897 TI - Direct identification of 80% of bacteria from blood culture bottles by MALDI-TOF MS using a 10-minute extraction protocol. AB - MALDI-TOF Mass Spectrometry is not widely used to identify bacteria directly from positive blood culture bottles (BCBs) because of overlong protocols. The objective of this work was to develop and evaluate a simple extraction protocol for reliable identification from BCBs. The 10-minute protocol was applied over a five-month period. Direct identifications on Day0 were compared with those obtained from colonies on Day1 (log(score) >= 2). We evaluated a range of seven log(score) thresholds on Day0 from 1.4 to 2.0 to find the lower confidence score that provides the higher percentage of direct identifications without loss of accuracy. With a log(score) threshold >= 1.5 at Day0, our protocol allowed us to identify 80% of bacteria in 632 BCBs (96% of Enterobacteriaceae, 95% of Staphylococcus aureus, 92% of enterococci and 62% of streptococci). At least one bacterial species of the mixture was identified in 77% of the polymicrobial samples.The rapidity and reliability of the protocol were factors in its adoption for routine use, allowing us to save up to 24 hours in identifying 80% of the bacteria in the BCBs and thus to supply useful information to adapt antibiotic therapy when necessary. We currently provide reliable daily direct identifications of staphylococci, enterococci, Enterobacteriaceae, Pseudomonas aeruginosa and beta-hemolytic streptococci. PMID- 30463898 TI - The field performance and diagnostic accuracy of a low-cost instrument-free point of-care CD4 test (VISITECT(r) CD4) performed by different health worker cadres among pregnant women. AB - BACKGROUND: Measuring CD4 counts remains an important component of HIV care. The VISITECT(r) CD4 is the first-ever instrument-free low-cost point-of-care CD4 test with results interpreted visually after 40 minutes, providing a result of above or below 350 CD4 cells/mm3. METHODS: Field performance and diagnostic accuracy of the test was assessed among HIV-infected pregnant women in South Africa. A nurse performed testing at the point-of-care using both venous and finger-prick blood, and a counsellor and laboratory staff tested venous blood in the clinic laboratory (four VISITECT(r) CD4 tests/participant). Performance was compared to the mean CD4 count from duplicate flow cytometry tests on venous blood (FACSCalibur Trucount). FINDINGS: In 2017, 156 patients were enrolled, providing a total of 624 VISITECT(r) CD4 tests (468 venous and 156 finger-prick samples). Of 624 tests, 28 (4.5%) were inconclusive. Generalised Linear Mixed Modelling showed better performance of the test on venous blood (sensitivity=81.7%, 95%CI=72.3-91.1; and specificity=82.6%, 95%CI=77.1-88.1) than on finger-prick specimens (sensitivity=60.7%, 95%CI=45.0-76.3; and specificity=89.5%, 95%CI=83.2 95.8; p=0.001). No difference in performance was detected by cadre of health worker (p=0.113) or between point-of-care versus laboratory-based testing (p=0.108). CONCLUSIONS: Adequate performance of VISITECT(r) CD4 with different operators and at the point-of-care, and no need of electricity or instrument, shows the potential utility of this device, especially for facilitating decentralization of CD4 testing services in rural areas. FUNDING: Funding was provided by the Saving Lives at Birth partners and the Australian NHMRC Project Grant GNT1063725. PMID- 30463899 TI - Role of Toxoplasma IgA as part of a Reference Panel for the Diagnosis of Acute Toxoplasmosis During Pregnancy. AB - This study evaluated the usefulness of adding the Toxoplasma gondii IgA antibody ELISA test to the serologic panel of tests done for the diagnosis of acute toxoplasmosis in pregnant women in a reference laboratory in the United States. We conducted a retrospective study of 690 consecutive pregnant women with positive T. gondii IgG antibody test results who also had T. gondii IgA and IgM antibody tests performed. Patients were defined as acutely or chronically infected with T. gondii based on a panel of serologic tests performed at the Palo Alto Medical Foundation - Toxoplasma Serology Laboratory (PAMF-TSL). Among the 81 women who were positive by T. gondii IgA antibody ELISA testing, 61 (75.3%) were acutely infected with T. gondii, while of the 547 who were negative by IgA testing, only 24 (4.4%) were acutely infected (p<0.001). Among the 71 women who were positive by both IgA and IgM antibody tests, 61 (85.9%) were acutely infected, compared to 24 (19.2%) of the 125 women who were positive by only the IgM ELISA (p<0.001). These results demonstrate that pregnant women with T. gondii IgA antibodies are more likely to have had a recent infection with T. gondii compared to pregnant women without T. gondii IgA antibodies. Toxoplasma IgA antibody testing can therefore improve the accuracy of a serologic panel for the diagnosis of acute toxoplasmosis during pregnancy. Physicians who ordered testing only for T. gondii IgG and IgM should also request additional testing for IgA and IgG avidity, if both IgG and IgM are positive. This further testing should be ideally performed in a reference laboratory. PMID- 30463900 TI - Maternal Eed knockout causes loss of H3K27me3 imprinting and random X inactivation in the extraembryonic cells. AB - Genomic imprinting is essential for mammalian development. Recent studies have revealed that maternal histone H3 Lys27 trimethylation (H3K27me3) can mediate DNA methylation-independent genomic imprinting. However, the regulatory mechanisms and functions of this new imprinting mechanism are largely unknown. Here we demonstrate that maternal Eed, an essential component of the Polycomb group complex 2 (PRC2), is required for establishing H3K27me3 imprinting. We found that all H3K27me3-imprinted genes, including Xist, lose their imprinted expression in Eed maternal knockout (matKO) embryos, resulting in male-biased lethality. Surprisingly, although maternal X-chromosome inactivation (XmCI) occurs in Eed matKO embryos at preimplantation due to loss of Xist imprinting, it is resolved at peri-implantation. Ultimately, both X chromosomes are reactivated in the embryonic cell lineage prior to random XCI, and only a single X chromosome undergoes random XCI in the extraembryonic cell lineage. Thus, our study not only demonstrates an essential role of Eed in H3K27me3 imprinting establishment but also reveals a unique XCI dynamic in the absence of Xist imprinting. PMID- 30463902 TI - Multilayered gene control drives timely exit from the stem cell state in uncommitted progenitors during Drosophila asymmetric neural stem cell division. AB - Self-renewal genes maintain stem cells in an undifferentiated state by preventing the commitment to differentiate. Robust inactivation of self-renewal gene activity following asymmetric stem cell division allows uncommitted stem cell progeny to exit from an undifferentiated state and initiate the commitment to differentiate. Nonetheless, how self-renewal gene activity at mRNA and protein levels becomes synchronously terminated in uncommitted stem cell progeny is unclear. We demonstrate that a multilayered gene regulation system terminates self-renewal gene activity at all levels in uncommitted stem cell progeny in the fly neural stem cell lineage. We found that the RNA-binding protein Brain tumor (Brat) targets the transcripts of a self-renewal gene, deadpan (dpn), for decay by recruiting the deadenylation machinery to the 3' untranslated region (UTR). Furthermore, we identified a nuclear protein, Insensible, that complements Cullin mediated proteolysis to robustly inactivate Dpn activity by limiting the level of active Dpn through protein sequestration. The synergy between post transcriptional and transcriptional control of self-renewal genes drives timely exit from the stem cell state in uncommitted progenitors. Our proposed multilayered gene regulation system could be broadly applicable to the control of exit from stemness in all stem cell lineages. PMID- 30463901 TI - BAP1 regulation of the key adaptor protein NCoR1 is critical for gamma-globin gene repression. AB - Human globin gene production transcriptionally "switches" from fetal to adult synthesis shortly after birth and is controlled by macromolecular complexes that enhance or suppress transcription by cis elements scattered throughout the locus. The DRED (direct repeat erythroid-definitive) repressor is recruited to the epsilon-globin and gamma-globin promoters by the orphan nuclear receptors TR2 (NR2C1) and TR4 (NR2C2) to engender their silencing in adult erythroid cells. Here we found that nuclear receptor corepressor-1 (NCoR1) is a critical component of DRED that acts as a scaffold to unite the DNA-binding and epigenetic enzyme components (e.g., DNA methyltransferase 1 [DNMT1] and lysine-specific demethylase 1 [LSD1]) that elicit DRED function. We also describe a potent new regulator of gamma-globin repression: The deubiquitinase BRCA1-associated protein-1 (BAP1) is a component of the repressor complex whose activity maintains NCoR1 at sites in the beta-globin locus, and BAP1 inhibition in erythroid cells massively induces gamma-globin synthesis. These data provide new mechanistic insights through the discovery of novel epigenetic enzymes that mediate gamma-globin gene repression. PMID- 30463903 TI - Adaptation to DNA damage checkpoint in senescent telomerase-negative cells promotes genome instability. AB - In cells lacking telomerase, telomeres gradually shorten during each cell division to reach a critically short length, permanently activate the DNA damage checkpoint, and trigger replicative senescence. The increase in genome instability that occurs as a consequence may contribute to the early steps of tumorigenesis. However, because of the low frequency of mutations and the heterogeneity of telomere-induced senescence, the timing and mechanisms of genome instability increase remain elusive. Here, to capture early mutation events during replicative senescence, we used a combined microfluidic-based approach and live-cell imaging in yeast. We analyzed DNA damage checkpoint activation in consecutive cell divisions of individual cell lineages in telomerase-negative yeast cells and observed that prolonged checkpoint arrests occurred frequently in telomerase-negative lineages. Cells relied on the adaptation to the DNA damage pathway to bypass the prolonged checkpoint arrests, allowing further cell divisions despite the presence of unrepaired DNA damage. We demonstrate that the adaptation pathway is a major contributor to the genome instability induced during replicative senescence. Therefore, adaptation plays a critical role in shaping the dynamics of genome instability during replicative senescence. PMID- 30463904 TI - Genetic interactions between specific chromosome copy number alterations dictate complex aneuploidy patterns. AB - Cells that contain an abnormal number of chromosomes are called aneuploid. High rates of aneuploidy in cancer are correlated with an increased frequency of chromosome missegregation, termed chromosomal instability (CIN). Both high levels of aneuploidy and CIN are associated with cancers that are resistant to treatment. Although aneuploidy and CIN are typically detrimental to cell growth, they can aid in adaptation to selective pressures. Here, we induced extremely high rates of chromosome missegregation in yeast to determine how cells adapt to CIN over time. We found that adaptation to CIN occurs initially through many different individual chromosomal aneuploidies. Interestingly, the adapted yeast strains acquire complex karyotypes with specific subsets of the beneficial aneuploid chromosomes. These complex aneuploidy patterns are governed by synthetic genetic interactions between individual chromosomal abnormalities, which we refer to as chromosome copy number interactions (CCNIs). Given enough time, distinct karyotypic patterns in separate yeast populations converge on a refined complex aneuploid state. Surprisingly, some chromosomal aneuploidies that provided an advantage early on in adaptation are eventually lost due to negative CCNIs with even more beneficial aneuploid chromosome combinations. Together, our results show how cells adapt by obtaining specific complex aneuploid karyotypes in the presence of CIN. PMID- 30463905 TI - RNA m6 A modification enzymes shape innate responses to DNA by regulating interferon beta. AB - Modification of mRNA by N 6-adenosine methylation (m6A) on internal bases influences gene expression in eukaryotes. How the dynamic genome-wide landscape of m6A-modified mRNAs impacts virus infection and host immune responses remains poorly understood. Here, we show that type I interferon (IFN) production triggered by dsDNA or human cytomegalovirus (HCMV) is controlled by the cellular m6A methyltrasferase subunit METTL14 and ALKBH5 demethylase. While METTL14 depletion reduced virus reproduction and stimulated dsDNA- or HCMV-induced IFNB1 mRNA accumulation, ALKBH5 depletion had the opposite effect. Depleting METTL14 increased both nascent IFNB1 mRNA production and stability in response to dsDNA. In contrast, ALKBH5 depletion reduced nascent IFNB1 mRNA production without detectably influencing IFN1B mRNA decay. Genome-wide transcriptome profiling following ALKBH5 depletion identified differentially expressed genes regulating antiviral immune responses, while METTL14 depletion altered pathways impacting metabolic reprogramming, stress responses, and aging. Finally, we determined that IFNB1 mRNA was m6A-modified within both the coding sequence and the 3' untranslated region (UTR). This establishes that the host m6A modification machinery controls IFNbeta production triggered by HCMV or dsDNA. Moreover, it demonstrates that responses to nonmicrobial dsDNA in uninfected cells, which shape host immunity and contribute to autoimmune disease, are regulated by enzymes controlling m6A epitranscriptomic changes. PMID- 30463906 TI - Toxicity of overexpressed MeCP2 is independent of HDAC3 activity. AB - Duplication of the X-linked MECP2 gene causes a severe neurological syndrome whose molecular basis is poorly understood. To determine the contribution of known functional domains to overexpression toxicity, we engineered a mouse model that expresses wild-type or mutated MeCP2 from the Mapt (Tau) locus in addition to the endogenous protein. Animals that expressed approximately four times the wild-type level of MeCP2 failed to survive to weaning. Strikingly, a single amino acid substitution that prevents MeCP2 from binding to the TBL1X(R1) subunit of nuclear receptor corepressor 1/2 (NCoR1/2) complexes, when expressed at equivalent high levels, was phenotypically indistinguishable from wild type, suggesting that excessive corepressor recruitment underlies toxicity. In contrast, mutations affecting the DNA-binding domain were toxic when overexpressed. As the NCoR1/2 corepressors are thought to act through histone deacetylation by histone deacetylase 3 (HDAC3), we asked whether mutations in NCoR1 and NCoR2 that drastically reduced their ability to activate this enzyme would relieve the MeCP2 overexpression phenotype. Surprisingly, severity was unaffected, indicating that the catalytic activity of HDAC3 is not the mediator of toxicity. Our findings shed light on the molecular mechanisms underlying MECP2 duplication syndrome and call for a re-evaluation of the precise biological role played by corepressor recruitment. PMID- 30463907 TI - Total flavonoids extracted from Nervilia Fordii function in the treatment of polycystic ovary syndrome through IL-6 mediated JAK2/STAT3 signaling pathway. AB - Large doses of flavonoids could cure many diseases with no serious side effects. However, the role of flavonoids in the treatment of polycystic ovary syndrome (PCOS) has not been reported. Therefore, total flavonoids extracted from Nervilia Fordii were selected to explore its therapeutic efficiency in PCOS. PCOS rat model was constructed to explore the role of total flavonoids in the treatment of PCOS. ELISA was used to assess the changes of ovulation function under the treatment of total flavonoids with or without exogenous interleukin 6 (IL-6). Western blot, real time PCR and immunohistochemistry were carried out to assess the related molecular mechanisms. We explored that total flavonoids obviously increased the serum levels of follicle-stimulating hormone (FSH), and sharply decreased the serum levels of luteinizing hormone (LH), testosterone (T) and insulin (INS) in the PCOS-IR rats via partly inhibiting the activation of JAK2/STAT3 pathway, partially up-regulating the IL-6 expression and partially down-regulating the suppressor of cytokine signaling 3 (SOCS3) expression in ovaries of PCOS rats. The effect of total flavonoids on estrous cycles, serum levels of FSH, LH, T and INS were partially attenuated by IL-6 in PCOS rat model. Moreover, IL-6 significantly reversed the effect of total flavonoids on the phosphorylation of JAK2/STAT3, the expression of IL-6 and SOCS3 in ovaries of PCOS rats. Total flavonoids extracted from Nervilia Fordii might induce expression of IL-6 inovary and act as a potential therapeutic drug for the treatment of PCOS. PMID- 30463908 TI - Hypoxia potentiates monocyte-derived dendritic cells for release of tumor necrosis factor alpha via MAP3K8. AB - Dendritic cells (DCs) constantly sample peripheral tissues for antigens, which are subsequently ingested to derive peptides for presentation to T-cells in lymph nodes. To do so, DCs have to traverse many different tissues with varying oxygen tensions. Additionally, DCs are often exposed to low oxygen tensions in tumors, where vascularization is lacking, as well as in inflammatory foci, where oxygen is rapidly consumed by inflammatory cells during the respiratory burst. DCs respond to oxygen levels to tailor immune responses to such low-oxygen environments. In this study, we identified a mechanism of hypoxia-mediated potentiation of release of tumor necrosis factor alpha (TNF-alpha), a pro inflammatory cytokine with important roles in both anti-cancer immunity and autoimmune disease. We show in human monocyte-derived DCs that this potentiation is controlled exclusively via the p38/MAPK pathway. We identified MAP3K8 as a target gene of Hypoxia Induced Factor (HIF), a transcription factor controlled by oxygen tension, upstream of the p38/MAPK pathway. Hypoxia increased expression of MAP3K8 concomitant with the potentiation of TNF-alpha secretion. This potentiation was no longer observed upon siRNA silencing of MAP3K8 or with a small molecule inhibitor of this kinase, and this also decreased p38/MAPK phosphorylation. However, expression of DC maturation markers CD83, CD86 and HLA DR were not changed by hypoxia. Since DCs play an important role in controlling T cell activation and differentiation, our results provide novel insight in understanding T-cell responses in inflammation, cancer, autoimmune disease and other diseases where hypoxia is involved. PMID- 30463909 TI - The role of Chamaejasmine in cellular apoptosis and autophagy in MG-63 cells. AB - Background:Osteosarcoma (OS) is the most common malignant neoplasm in children and adolescents with a very high propensity for local invasion and poor response to current therapy. Anticancer effect of chamaejasmine is newly discovered from Stellera chamaejasmine L. Our study focuses on investigating the effect of chamaejasmine on the cellular apoptosis, proliferation, autophagy, and the underlying mechanisms in MG-63. Methods:Our study investigated the concentration of chamaejasmine in MG-63 cells by MTT and verified that chamaejasmine inhibited cell invasion by transwell. We also used Hoechst staining as well as apoptotic associated-proteins in MG-63 cells .Meanwhile, we also detected the lysophagesome and autophagsome by Lysotracker. AMPK knockdown was performed with siRNA.Results: Our results show that chamaejasmine exerts cellular growth inhibition, pro apoptotic and pro-autophagic effect via activating AMPK in MG-63 cells. Furthermore, chamaejasmine significantly increases autophagic cell via the inhibition of mammalian target of rapamycin (mTOR) and activation of AMPK signaling pathways. Administrated with chamaejasmine also induces Reactive Oxygen Species (ROS) generation, indicating cross-talking between these two primary modes of programmed cell death.Conclusion:Our results show that chamaejasmine promotes apoptosis and autophagy by activating AMPK /mTOR signaling pathways with involvement of ROS in MG-63 cells. Chamaejasmine is a promising anti-cancer agent in OS treatment and further studies are needed to confirm its efficacy and safety in vivo or other cancer cells. PMID- 30463910 TI - Dependency relationships between IFT-dependent flagellum elongation and cell morphogenesis in Leishmania. AB - Flagella have multiple functions that are associated with different axonemal structures. Motile flagella typically have a 9 + 2 arrangement of microtubules, whereas sensory flagella normally have a 9 + 0 arrangement. Leishmania exhibits both of these flagellum forms and differentiation between these two flagellum forms is associated with cytoskeletal and cell shape changes. We disrupted flagellum elongation in Leishmania by deleting the intraflagellar transport (IFT) protein IFT140 and examined the effects on cell morphogenesis. Deltaift140 cells have no external flagellum, having only a very short flagellum within the flagellar pocket. This short flagellum had a collapsed 9 + 0 (9v) axoneme configuration reminiscent of that in the amastigote and was not attached to the pocket membrane. Although amastigote-like changes occurred in the flagellar cytoskeleton, the cytoskeletal structures of Deltaift140 cells retained their promastigote configurations, as examined by fluorescence microscopy of tagged proteins and serial electron tomography. Thus, Leishmania promastigote cell morphogenesis does not depend on the formation of a long flagellum attached at the neck. Furthermore, our data show that disruption of the IFT system is sufficient to produce a switch from the 9 + 2 to the collapsed 9 + 0 (9v) axonemal structure, echoing the process that occurs during the promastigote to amastigote differentiation. PMID- 30463911 TI - Cardiac and skeletal actin substrates uniquely tune cardiac myosin strain dependent mechanics. AB - Cardiac ventricular myosin (betamys) translates actin by transducing ATP free energy into mechanical work during muscle contraction. Unitary betamys translation of actin is the step-size. In vitro and in vivo betamys regulates contractile force and velocity autonomously by remixing three different step sizes with adaptive stepping frequencies. Cardiac and skeletal actin isoforms have a specific 1 : 4 stoichiometry in normal adult human ventriculum. Human adults with inheritable hypertrophic cardiomyopathy (HCM) upregulate skeletal actin in ventriculum probably compensating the diseased muscle's inability to meet demand by adjusting betamys force-velocity characteristics. betamys force velocity characteristics were compared for skeletal versus cardiac actin substrates using ensemble in vitro motility and single myosin assays. Two competing myosin strain-sensitive mechanisms regulate step-size choices dividing single betamys mechanics into low- and high-force regimes. The actin isoforms alter myosin strain-sensitive regulation such that onset of the high-force regime, where a short step-size is a large or major contributor, is offset to higher loads probably by the unique cardiac essential light chain (ELC) N terminus/cardiac actin contact at Glu6/Ser358. It modifies betamys force-velocity by stabilizing the ELC N-terminus/cardiac actin association. Uneven onset of the high-force regime for skeletal versus cardiac actin modulates force-velocity characteristics as skeletal/cardiac actin fractional content increases in diseased muscle. PMID- 30463912 TI - The multi-faceted role of Gata3 in developmental haematopoiesis. AB - The transcription factor Gata3 is crucial for the development of several tissues and cell lineages both during development as well as postnatally. This importance is apparent from the early embryonic lethality following germline Gata3 deletion, with embryos displaying a number of phenotypes, and from the fact that Gata3 has been implicated in several cancer types. It often acts at the level of stem and progenitor cells in which it controls the expression of key lineage-determining factors as well as cell cycle genes, thus being one of the main drivers of cell fate choice and tissue morphogenesis. Gata3 is involved at various stages of haematopoiesis both in the adult as well as during development. This review summarizes the various contributions of Gata3 to haematopoiesis with a particular focus on the emergence of the first haematopoietic stem cells in the embryo-a process that appears to be influenced by Gata3 at various levels, thus highlighting the complex nature of Gata3 action. PMID- 30463913 TI - HoxA9 transforms murine myeloid cells by a feedback loop driving expression of key oncogenes and cell cycle control genes. AB - Ectopic expression of the oncogenic transcription factor HoxA9 is a major cause of acute myeloid leukemia (AML). Here, we demonstrate that HoxA9 is a specific substrate of granule proteases. Protease knockout allowed the comprehensive determination of genome-wide HoxA9 binding sites by chromatin immunoprecipitation sequencing in primary murine cells and a human AML cell line. The kinetics of enhancer activity and transcription rates in response to alterations of an inducible HoxA9 were determined. This permitted identification of HoxA9 controlled enhancers and promoters, allocation to their respective transcription units, and discrimination against HoxA9-bound, but unresponsive, elements. HoxA9 triggered an elaborate positive-feedback loop that drove expression of the complete Hox-A locus. In addition, it controlled key oncogenic transcription factors Myc and Myb and directly induced the cell cycle regulators Cdk6 and CyclinD1, as well as telomerase, drawing the essential blueprint for perturbation of proliferation by leukemogenic HoxA9 expression. PMID- 30463914 TI - Plasma cell proliferative index is an independent predictor of progression in smoldering multiple myeloma. AB - The plasma cell proliferative index (PCPI), determined by a slide technique or by flow cytometry, detects cells in the S phase of the cell cycle and is a useful prognostic tool in patients with plasma cell disorders such as multiple myeloma and amyloidosis. We conducted a retrospective review analyzing the prognostic effect of PCPI in 306 patients with smoldering multiple myeloma (SMM). Seventy nine (26%) patients had an elevated PCPI (>0.5). An elevated PCPI predicted an inferior time to progression (median, 3.0 vs 7.1 years for those with a low PCPI; P = .0004). Within 24 months, the progression rate was significantly higher for patients with an elevated PCPI (49% vs. 20%; P < .0001). PCPI is a valuable tool in risk stratifying patients with SMM and identifies patients with earlier progression who may benefit from closer follow-up and consideration of early intervention trials. PMID- 30463915 TI - Prospective comparison of the HEP score and 4Ts score for the diagnosis of heparin-induced thrombocytopenia. AB - The HIT Expert Probability (HEP) score compared favorably with the 4Ts score in a retrospective study. We assessed the diagnostic accuracy of the HEP score compared with the 4Ts score in a prospective cohort of 310 patients with suspected heparin-induced thrombocytopenia (HIT). A member of the clinical team calculated the HEP score and 4Ts score. An independent panel adjudicated HIT status based on a clinical summary as well as the results of HIT laboratory testing. The prevalence of HIT in the study population was 14.7%. At a cutoff of >=3, the HEP score was 95.3% sensitive (95% confidence interval [CI], 84.2-99.4) and 35.7% specific (95% CI, 29.8-42.0) for HIT. A 4Ts score of >=4 had a sensitivity of 97.7% (95% CI, 86.2-99.8) and specificity of 32.9% (95% CI, 27.2 39.1). The areas under the receiver operating characteristic (ROC) curves (AUCs) for the HEP score and 4Ts score were similar (0.81 [95% CI, 0.74-0.87] vs 0.76 [95% CI, 0.69-0.83]; P = .12). The HEP score exhibited a significantly higher AUC than the 4Ts score in patients in the intensive care unit (ICU) (0.86 vs 0.79; P = .03). Among trainee scorers, the HEP score performed significantly better than the 4Ts score (AUC, 0.80 vs 0.73; P = .03). Our data suggest that either the 4Ts score or the HEP score may be used in clinical practice. The HEP score may be preferable in ICU patients and among less experienced clinicians. PMID- 30463916 TI - Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis. AB - Fibrosis is the major determinant of morbidity and mortality in patients with nonalcoholic steatohepatitis (NASH) but has no approved pharmacotherapy in part because of incomplete understanding of its pathogenic mechanisms. Here, we report that hepatocyte Notch activity tracks with disease severity and treatment response in patients with NASH and is similarly increased in a mouse model of diet-induced NASH and liver fibrosis. Hepatocyte-specific Notch loss-of-function mouse models showed attenuated NASH-associated liver fibrosis, demonstrating causality to obesity-induced liver pathology. Conversely, forced activation of hepatocyte Notch induced fibrosis in both chow- and NASH diet-fed mice by increasing Sox9-dependent Osteopontin (Opn) expression and secretion from hepatocytes, which activate resident hepatic stellate cells. In a cross-sectional study, we found that OPN explains the positive correlation between liver Notch activity and fibrosis stage in patients. Further, we developed a Notch inhibitor [Nicastrin antisense oligonucleotide (Ncst ASO)] that reduced fibrosis in NASH diet-fed mice. In summary, these studies demonstrate the pathological role and therapeutic accessibility of the maladaptive hepatocyte Notch response in NASH associated liver fibrosis. PMID- 30463917 TI - Long-term mechanical function and integration of an implanted tissue-engineered intervertebral disc. AB - Tissue engineering holds great promise for the treatment of advanced intervertebral disc degeneration. However, assessment of in vivo integration and mechanical function of tissue-engineered disc replacements over the long term, in large animal models, will be necessary to advance clinical translation. To that end, we developed tissue-engineered, endplate-modified disc-like angle ply structures (eDAPS) sized for the rat caudal and goat cervical spines that recapitulate the hierarchical structure of the native disc. Here, we demonstrate functional maturation and integration of these eDAPS in a rat caudal disc replacement model, with compressive mechanical properties reaching native values after 20 weeks in vivo and evidence of functional integration under physiological loads. To further this therapy toward clinical translation, we implanted eDAPS sized for the human cervical disc space in a goat cervical disc replacement model. Our results demonstrate maintenance of eDAPS composition and structure up to 8 weeks in vivo in the goat cervical disc space and maturation of compressive mechanical properties to match native levels. These results demonstrate the translational feasibility of disc replacement with a tissue-engineered construct for the treatment of advanced disc degeneration. PMID- 30463918 TI - Lung-restricted inhibition of Janus kinase 1 is effective in rodent models of asthma. AB - Preclinical and clinical evidence indicates that a subset of asthma is driven by type 2 cytokines such as interleukin-4 (IL-4), IL-5, IL-9, and IL-13. Additional evidence predicts pathogenic roles for IL-6 and type I and type II interferons. Because each of these cytokines depends on Janus kinase 1 (JAK1) for signal transduction, and because many of the asthma-related effects of these cytokines manifest in the lung, we hypothesized that lung-restricted JAK1 inhibition may confer therapeutic benefit. To test this idea, we synthesized iJak-381, an inhalable small molecule specifically designed for local JAK1 inhibition in the lung. In pharmacodynamic models, iJak-381 suppressed signal transducer and activator of transcription 6 activation by IL-13. Furthermore, iJak-381 suppressed ovalbumin-induced lung inflammation in both murine and guinea pig asthma models and improved allergen-induced airway hyperresponsiveness in mice. In a model driven by human allergens, iJak-381 had a more potent suppressive effect on neutrophil-driven inflammation compared to systemic corticosteroid administration. The inhibitor iJak-381 reduced lung pathology, without affecting systemic Jak1 activity in rodents. Our data show that local inhibition of Jak1 in the lung can suppress lung inflammation without systemic Jak inhibition in rodents, suggesting that this strategy might be effective for treating asthma. PMID- 30463920 TI - Erratum for the Research Article: "The ERBB network facilitates KRAS-driven lung tumorigenesis" by B. Kruspig, T. Monteverde, S. Neidler, A. Hock, E. Kerr, C. Nixon, W. Clark, A. Hedley, S. Laing, S. B. Coffelt, J. Le Quesne, C. Dick, K. Vousden, C. P. Martins, D. J. Murphy. PMID- 30463919 TI - Two recombinant human monoclonal antibodies that protect against lethal Andes hantavirus infection in vivo. AB - Andes hantavirus (ANDV) is an etiologic agent of hantavirus cardiopulmonary syndrome (HCPS), a severe disease characterized by fever, headache, and gastrointestinal symptoms that may progress to hypotension, pulmonary failure, and cardiac shock that results in a 25 to 40% case-fatality rate. Currently, there is no specific treatment or vaccine; however, several studies have shown that the generation of neutralizing antibody (Ab) responses strongly correlates with survival from HCPS in humans. In this study, we screened 27 ANDV convalescent HCPS patient sera for their capacity to bind and neutralize ANDV in vitro. One patient who showed high neutralizing titer was selected to isolate ANDV-glycoprotein (GP) Abs. ANDV-GP-specific memory B cells were single cell sorted, and recombinant immunoglobulin G antibodies were cloned and produced. Two monoclonal Abs (mAbs), JL16 and MIB22, potently recognized ANDV-GPs and neutralized ANDV. We examined the post-exposure efficacy of these two mAbs as a monotherapy or in combination therapy in a Syrian hamster model of ANDV-induced HCPS, and both mAbs protected 100% of animals from a lethal challenge dose. These data suggest that monotherapy with mAb JL16 or MIB22, or a cocktail of both, could be an effective post-exposure treatment for patients infected with ANDV induced HCPS. PMID- 30463921 TI - Independent origins of female penis and its coevolution with male vagina in cave insects (Psocodea: Prionoglarididae). AB - The cave-dwelling psocid tribe Sensitibillini (Afrotrogla, Neotrogla and Sensitibilla) is of special morphological and evolutionary interest because of its possession of reversed copulatory organs: i.e. females of Afrotrogla and Neotrogla have a penis-like organ. The female penis structure is highly variable among taxa, as is the case of the male penis in animals with normal copulatory organs. Here, we present the first molecular phylogeny of Sensitibillini and analyse the evolutionary pattern of their genitalia. Afrotrogla and Neotrogla did not form a monophyletic clade, and their female penis structures are significantly different, suggesting two independent origins of the female penis within Sensitibillini. In Neotrogla, the species that has a simple female penis is embedded among species that have an elaborate penis, and detailed structures of the female penis elaborations are in exact agreement among species, suggesting a secondary simplification of the female penis. A correlated evolutionary pattern between male and female genitalia was also detected. This coevolution of genitalia may suggest that sexual conflict or cryptic 'male' choice drove the diversity of the female penis, as is the case of male penile diversity in animals with conventional genitalia. PMID- 30463922 TI - The adaptive shaping of social behavioural phenotypes during adolescence. AB - Developmental behavioural plasticity is a process by which organisms can alter development of their behavioural phenotype to be better adapted to the environment encountered later in life. This 'shaping' process depends on the presence of reliable cues by which predictions can be made. It is now established that cues detected by the mother can be used (primarily via hormones prenatally and maternal behaviour in the early postnatal stage) to shape the behavioural phenotype of her offspring. However, it is becoming increasingly clear that adolescence is another period in which conditions are well-suited for such shaping to occur. We review here how mammalian social behaviour may be shaped in adolescence. We identify limited extant examples, briefly discuss underlying mechanisms, and provide evidence that observed changes are indeed adaptive. We contend that while plasticity diminishes with age, the shaping of the behavioural phenotype in adolescence offers several advantages, including that adolescence is closer to the onset of mating than are earlier phases of life; that unlike earlier phases, information is obtained directly from the environment rather than mediated by the mother; and unlike later in adulthood, there is substantial underlying neural plasticity associated with development to support behavioural change. We also consider conditions that favour the occurrence of social behaviour plasticity during adolescence, including a high degree of sociality and a prolonged developmental period and the implication of these conditions for the occurrence of sex differences in the shaping process. PMID- 30463923 TI - An exceptionally preserved association of complete dinosaur skeletons reveals the oldest long-necked sauropodomorphs. AB - The rise of sauropodomorphs is still poorly understood due to the scarcity of well-preserved fossils in early Norian rocks. Here, we present an association of complete and exceptionally well-preserved dinosaur skeletons that helps fill that gap. They represent a new species, which is recovered as a member of a clade solely composed of Gondwanan Triassic taxa. The new species allows the definition of a set of anatomical changes that shaped sauropodomorph evolution along a period from 233 to 225 Ma, as recorded in the well dated Late Triassic beds of Brazil. In that time span, apart from achieving a more herbivorous diet, sauropodomorph dinosaurs increased their size in a ratio of 230% and their typical long neck was also established, becoming proportionally twice longer than those of basal taxa. Indeed, the new dinosaur is the oldest-known sauropodomorph with such an elongated neck, suggesting that the ability to feed on high vegetation was a key trait achieved along the early Norian. Finally, the clustered preservation mode of the skeletons represents the oldest evidence of gregarious behaviour among sauropodomorphs. PMID- 30463924 TI - Genetic Analysis of NDT80 Family Transcription Factors in Candida albicans Using New CRISPR-Cas9 Approaches. AB - Ndt80 family transcription factors are highly conserved in fungi, where they regulate diverse processes. The human fungal pathogen Candida albicans contains three genes (NDT80, REP1, and RON1) that encode proteins with similarity to Saccharomyces cerevisiae Ndt80, although the homology is restricted to the DNA binding domain. To better understand their role in virulence functions, we used clustered regularly interspaced short palindromic repeat/CRISPR-associated gene 9 (CRISPR/Cas9) to delete the three NDT80-family genes. An ndt80Delta mutant showed strong defects in forming hyphae in response to serum or N-acetylglucosamine (GlcNAc), which was linked to the ability of Ndt80 to regulate the expression of RAS1, an upstream regulator of hyphal signaling. Conversely, the ndt80Delta mutant formed hyphal cells on glycerol medium, indicating that Ndt80 is not required for hyphal growth under all conditions. In contrast to our previously published data, a ron1Delta single mutant could grow and form hyphae in response to GlcNAc. However, deleting RON1 partially restored the ability of an ndt80Delta mutant to form hyphae in response to GlcNAc, indicating a link to GlcNAc signaling. REP1 was required for growth on GlcNAc, as expected, but not for GlcNAc or serum to induce hyphae. The ndt80Delta mutant was defective in growing under stressful conditions, such as elevated temperature, but not the ron1Delta mutant or rep1Delta mutant. Quantitative assays did not reveal any significant differences in the fluconazole susceptibility of the NDT80-family mutants. Interestingly, double and triple mutant analysis did not identify significant genetic interactions for these NDT80 family genes, indicating that they mainly function independently, in spite of their conserved DNA binding domain.IMPORTANCE Transcription factors play key roles in regulating virulence of the human fungal pathogen C. albicans In addition to regulating the expression of virulence factors, they also control the ability of C. albicans to switch to filamentous hyphal growth, which facilitates biofilm formation on medical devices and invasion into tissues. We therefore used new CRISPR/Cas9 methods to examine the effects of deleting three C. albicans genes (NDT80, REP1, and RON1) that encode transcription factors with similar DNA binding domains. Interestingly, double and triple mutant strains mostly showed the combined properties of the single mutants; there was only very limited evidence of synergistic interactions in regulating morphogenesis, stress resistance, and ability to metabolize different sugars. These results demonstrate that NDT80, REP1, and RON1 have distinct functions in regulating C. albicans virulence functions. PMID- 30463925 TI - Impact of Amoxicillin-Clavulanate followed by Autologous Fecal Microbiota Transplantation on Fecal Microbiome Structure and Metabolic Potential. AB - Strategies to prevent multidrug-resistant organism (MDRO) infections are scarce, but autologous fecal microbiota transplantation (autoFMT) may limit gastrointestinal MDRO expansion. AutoFMT involves banking one's feces during a healthy state for later use in restoring gut microbiota following perturbation. This pilot study evaluated the effect of autoFMT on gastrointestinal microbiome taxonomic composition, resistance gene content, and metabolic capacity after exposure to amoxicillin-clavulanic acid (Amox-Clav). Ten healthy participants were enrolled. All received 5 days of Amox-Clav. Half were randomized to autoFMT, derived from stool collected pre-antimicrobial exposure, by enema, and half to saline enema. Participants submitted stool samples pre- and post-Amox-Clav and enema and during a 90-day follow-up period. Shotgun metagenomic sequencing revealed taxonomic composition, resistance gene content, and metabolic capacity. Amox-Clav significantly altered gut taxonomic composition in all participants (n = 10, P < 0.01); however, only three participants exhibited major changes at the phylum level following exposure. In the cohort as a whole, beta-lactamase genes were enriched following Amox-Clav (P < 0.05), and predicted metabolic capacity was significantly altered (P < 0.01). Species composition, metabolic capacity, and beta-lactamase abundance returned to pre-antimicrobial exposure state 7 days after either autoFMT or saline enema (P > 0.05, compared to enrollment). Alterations to microbial metabolic capacity occurred following antimicrobial exposure even in participants without substantial taxonomic disruption, potentially creating open niches for pathogen colonization. Our findings suggest that metabolic potential is an important consideration for complete assessment of antimicrobial impact on the microbiome. AutoFMT was well tolerated and may have contributed to phylogenetic recovery. (This study has been registered at ClinicalTrials.gov under identifier NCT02046525.)IMPORTANCE The spread of multidrug resistance among pathogenic organisms threatens the efficacy of antimicrobial treatment options. The human gut serves as a reservoir for many drug-resistant organisms and their resistance genes, and perturbation of the gut microbiome by antimicrobial exposure can open metabolic niches to resistant pathogens. Once established in the gut, antimicrobial-resistant bacteria can persist even after antimicrobial exposure ceases. Strategies to prevent multidrug resistant organism (MDRO) infections are scarce, but autologous fecal microbiota transplantation (autoFMT) may limit gastrointestinal MDRO expansion. AutoFMT involves banking one's feces during a healthy state for later use in restoring gut microbiota following perturbation. This pilot study evaluated the effect of amoxicillin-clavulanic acid (Amox-Clav) exposure and autoFMT on gastrointestinal microbiome taxonomic composition, resistance gene content, and metabolic capacity. Importantly, we found that metabolic capacity was perturbed even in cases where gross phylogeny remained unchanged and that autoFMT was safe and well tolerated. PMID- 30463926 TI - Glycerol Monolaurate (GML) and a Nonaqueous Five-Percent GML Gel Kill Bacillus and Clostridium Spores. AB - Glycerol monolaurate is a broadly antimicrobial fatty acid monoester, killing bacteria, fungi, and enveloped viruses. The compound kills stationary-phase cultures of Bacillus anthracis, suggesting that the molecule may kill spores. In this study, we examined the ability of glycerol monolaurate alone or solubilized in a nonaqueous gel to kill vegetative cells and spores of aerobic B. anthracis, B. subtilis, and B. cereus and anaerobic Clostridium perfringens and Clostridium (Clostridioides) difficile. Glycerol monolaurate alone was bactericidal for all five organisms tested. Glycerol monolaurate alone was effective in killing spores. When solubilized in a nonaqueous gel, the glycerol monolaurate gel was bactericidal for all spores tested. The data suggest that glycerol monolaurate nonaqueous gel could be effective in decontaminating environmental and body surfaces, such as skin.IMPORTANCE Bacillus and Clostridium spores are known to be highly resistant to killing, persisting on environmental and human body surfaces for long periods of time. In favorable environments, these spores may germinate and cause human diseases. It is thus important to identify agents that can be used on both environmental and human skin and mucosal surfaces and that are effective in killing spores. We previously showed that the fatty acid monoester glycerol monolaurate (GML) kills stationary-phase cultures of Bacillus anthracis Since such cultures are likely to contain spores, it is possible that GML and a human-use-approved GML nonaqueous gel would kill Bacillus and Clostridium spores. The significance of our studies is that we have identified GML, and, to a greater extent, GML solubilized in a nonaqueous gel, as effective in killing spores from both bacterial genera. PMID- 30463928 TI - Health promotion. AB - EBN Perspectives brings together key issues from the commentaries in one of our nursing topic themes. PMID- 30463929 TI - Critical illness and recovery should be viewed as a social process in which the patient and family members' experiences are different but complimentary. PMID- 30463930 TI - In the aftermath of a perioperative death: who cares for the clinician? PMID- 30463927 TI - Label-Free Digital Holo-tomographic Microscopy Reveals Virus-Induced Cytopathic Effects in Live Cells. AB - Cytopathic effects (CPEs) are a hallmark of infections. CPEs are difficult to observe due to phototoxicity from classical light microscopy. We report distinct patterns of virus infections in live cells using digital holo-tomographic microscopy (DHTM). DHTM is label-free and records the phase shift of low-energy light passing through the specimen on a transparent surface with minimal perturbation. DHTM measures the refractive index (RI) and computes the refractive index gradient (RIG), unveiling optical heterogeneity in cells. We find that vaccinia virus (VACV), herpes simplex virus (HSV), and rhinovirus (RV) infections progressively and distinctly increased RIG. VACV infection, but not HSV and RV infections, induced oscillations of cell volume, while all three viruses altered cytoplasmic membrane dynamics and induced apoptotic features akin to those caused by the chemical compound staurosporine. In sum, we introduce DHTM for quantitative label-free microscopy in infection research and uncover virus type specific changes and CPE in living cells with minimal interference.IMPORTANCE This study introduces label-free digital holo-tomographic microscopy (DHTM) and refractive index gradient (RIG) measurements of live, virus-infected cells. We use DHTM to describe virus type-specific cytopathic effects, including cyclic volume changes of vaccinia virus infections, and cytoplasmic condensations in herpesvirus and rhinovirus infections, distinct from apoptotic cells. This work shows for the first time that DHTM is suitable to observe virus-infected cells and distinguishes virus type-specific signatures under noninvasive conditions. It provides a basis for future studies, where correlative fluorescence microscopy of cell and virus structures annotate distinct RIG values derived from DHTM. PMID- 30463931 TI - Excising the "surgeon ego" to accelerate progress in the culture of surgery. PMID- 30463932 TI - 'Yes' to mitochondrial replacement techniques and lesbian motherhood: a reply to Francoise Baylis. AB - In a recent paper - Lesbian motherhood and mitochondrial replacement techniques: reproductive freedom and genetic kinship - we argued that lesbian couples who wish to have children who are genetically related to both of them should be allowed access to mitochondrial replacement techniques (MRTs). Francoise Baylis wrote a reply to our paper -'No' to lesbian motherhood using human nuclear genome transfer- where she challenges our arguments on the use of MRTs by lesbian couples, and on MRTs more generally. In this reply we respond to her claims and further clarify our position. PMID- 30463933 TI - Drawing the line on physician-assisted death. AB - Drawing the line on physician assistance in physician-assisted death (PAD) continues to be a contentious issue in many legal jurisdictions across the USA, Canada and Europe. PAD is a medical practice that occurs when physicians either prescribe or administer lethal medication to their patients. As more legal jurisdictions establish PAD for at least some class of patients, the question of the proper scope of this practice has become pressing. This paper presents an argument for restricting PAD to the terminally ill that can be accepted by defenders as well as critics of PAD for the terminally ill. The argument appeals to fairness-based paternalism and the social meaning of medical practice. These two considerations interact in various ways, as the paper explains. The right way to think about the social meaning of medical practice bears on fair paternalism as it relates to PAD and vice versa. The paper contends that these considerations have substantial force when directed against proposals to extend PAD to non terminally ill patients, but considerably less force when directed against PAD for the terminally ill. The paper pays special attention to the case of non terminally ill patients who suffer from treatment-resistant depression, as these patients present a potentially strong case for extending PAD beyond the terminally ill. PMID- 30463934 TI - Should clinicians boycott Australian immigration detention? AB - Australian immigration detention has been called state sanctioned abuse, cruel and degrading and likened to torture. Clinicians have long worked both within the system providing healthcare and outside of it advocating for broader social and political change. It has now been over 25 years and little, if anything, has changed. The government has continued to consolidate power to enforce these policies and has continued to attempt to silence dissent. It was in this context that a boycott was raised as a possible course of action. Despite discussions among the healthcare community about the merits of such action, a number of questions have been overlooked. In this article, I will examine whether a boycott is both ethical and feasible. Taking into account the costs and benefits of current engagement and the potential impact of a boycott, more specifically the potential it has to further harm those detained, I conclude that under current circumstance a boycott cannot be justified. This however does not mean that a boycott should be dismissed completely or that the status quo should be accepted. I discuss potential ways forward for those seeking change. PMID- 30463935 TI - Managing chest drains on medical wards. PMID- 30463936 TI - Modified approach to fibrinogen replacement in the setting of dysfibrinogenaemia. AB - Most fibrinogen replacement strategies focus on quantitative deficiencies. A thrombin time (TT) mixing study helped to assess qualitative defects caused by dysfibrinogens. Plasma samples were collected from non-anticoagulated subjects (n=6) meeting laboratory criteria for suspected dysfibrinogenaemia (TT > 22 s; fibrinogen activity <180) and from a control group. TT mixing studies were performed on subject plasma with increasing volumes of pooled normal plasma at 1:2, 1:4 and 1:5 dilutions. No subjects with dysfibrinogenaemia demonstrated a complete TT correction at 1:2, but 50% corrected at 1:4 and 100% at 1:5 dilution. Based on these data, a correction factor (CF), defined as the reciprocal dilution yielding complete correction, was incorporated into our clinical practice formula for fibrinogen dosing in patients with dysfibrinogenaemias. Our study incorporates TT mixing studies for assessment of dysfibrinogens. The addition of a mix-derived CF to classical formulae may better approximate dosing in patients with dysfibrinogenaemia. PMID- 30463937 TI - An Investigational RNAi Therapeutic Targeting Factor XII (ALN-F12) for the Treatment of Hereditary Angioedema. AB - BACKGROUND: Hereditary angioedema (HAE) is a genetic disorder mostly caused by mutations in the C1 esterase inhibitor gene (C1INH) that results in poor control of contact pathway activation and excess bradykinin generation. Bradykinin increases vascular permeability and is ultimately responsible for the episodes of swelling characteristic of HAE. OBJECTIVE: We hypothesized that the use of RNA interference (RNAi) to reduce plasma Factor XII (FXII), which initiates the contact pathway signaling cascade, would reduce contact pathway activation and prevent excessive bradykinin generation. METHOD: A subcutaneously administered GalNAc-conjugated small interfering RNA (siRNA) targeting F12 mRNA (ALN-F12) was developed and potency was evaluated in mice, rats and cynomolgus monkeys. The effect of FXII reduction by ALN-F12 administration was evaluated in two different vascular leakage mouse models. An ex vivo assay was developed to evaluate the correlation between human plasma FXII levels and high-molecular weight kininogen (HK) cleavage. RESULTS: A single subcutaneous dose of ALN-F12 led to potent, dose dependent reduction of plasma FXII in mice, rats and NHP. In Cynomolgus monkeys, a single subcutaneous dose of ALN-F12 at 3 mg/kg resulted in >85% reduction of plasma FXII. Administration of ALN-F12 resulted in dose-dependent reduction of vascular permeability in two different mouse models of bradykinin-driven vascular leakage, demonstrating that RNAi-mediated reduction of FXII can potentially mitigate excess bradykinin stimulation. Lastly, ex vivo human plasma HK cleavage assay indicated FXII-dependent bradykinin generation. CONCLUSIONS: Together, these data suggest that RNAi-mediated knockdown of FXII by ALN-F12 is a potentially promising approach for the prophylactic treatment of HAE. PMID- 30463938 TI - CRISPR/Cas9 and glycomics tools for Toxoplasma glycobiology. AB - Infection with the protozoan parasite Toxoplasma gondii is a major health risk owing to birth defects, its chronic nature, ability to reactivate to cause blindness and encephalitis, and high prevalence in human populations. Unlike most eukaryotes, Toxoplasma propagates in intracellular parasitophorous vacuoles, but as for nearly all other eukaryotes, Toxoplasma glycosylates many cellular proteins and lipids and assembles polysaccharides. Toxoplasma glycans resemble those of other eukaryotes but species-specific variations have prohibited deeper investigations into their roles in parasite biology and virulence. The Toxoplasma genome encodes a suite of likely glycogenes expected to assemble N-glycans, O glycans, a C-glycan, GPI-anchors, and polysaccharides, along with their precursors and membrane transporters. To investigate the roles of specific glycans in Toxoplasma, here we coupled genetic and glycomics approaches to map the connections between 67 glycogenes, their enzyme products, the glycans to which they contribute, and cellular functions. We applied a double-CRISPR/Cas9 strategy, in which two guide RNAs promote replacement of a candidate gene with a resistance gene; adapted MS-based glycomics workflows to test for effects on glycan formation; and infected fibroblast monolayers to assess cellular effects. By editing 17 glycogenes, we discovered novel Glc0-2-Man6-GlcNAc2-type N-glycans, a novel HexNAc-GalNAc-mucin-type O-glycan, and Tn-antigen, identified the glycosyltransferases for assembling a novel nuclear O-Fuc-type and cell surface Glc-Fuc-type O-glycans, and showed that they are important for in vitro growth. The guide sequences, editing constructs, and mutant strains are freely available to researchers to investigate the roles of glycans in their favorite biological processes. PMID- 30463939 TI - Inhibition of ezrin causes PKCalpha-mediated internalization of erbb2/HER2 tyrosine kinase in breast cancer cells. AB - Unlike other ErbB family members, HER2 levels are maintained on the cell surface when the receptor is activated, allowing prolonged signaling and contributing to its transforming ability. Interactions between HER2, HSP90, PMCA2 and NHERF1 within specialized plasma membrane domains contribute to the membrane retention of HER2. We hypothesized that the scaffolding protein, ezrin, which has been shown to interact with NHERF1, might also help stabilize the HER2/PMCA2/NHERF1 complex at the plasma membrane. Therefore, we examined ezrin expression and its relationship to HER2, NHERF1 and PMCA2 levels in murine and human breast cancers. We also used genetic knockdown and/or pharmacologic inhibition of ezrin, HSP90, NHERF1, PMCA2 and HER2 to examine the functional relationships between these factors and membrane retention of HER2. We found ezrin to be expressed at low levels at the apical surface of normal mammary epithelial cells, but its expression is upregulated and correlates with HER2 expression in hyperplasia and tumors in MMTV-Neu mice, in human HER2-positive breast cancer cell lines and in DCIS and invasive breast cancers from human patients. In breast cancer cells, ezrin co-localizes and interacts with HER2, NHERF1, PMCA2 and HSP90 in specialized membrane domains, and inhibiting ezrin disrupts interactions between HER2, PMCA2, NHERF1 and HSP90, thereby inhibiting HER2 signaling, and causing PKCa-mediated internalization and degradation of HER2. Inhibition of ezrin synergizes with lapatinib in a PKCa-dependent fashion to inhibit proliferation and promote apoptosis in HER2-positive breast cancer cells. We conclude that ezrin stabilizes a multiprotein complex that maintains active HER2 at the cell surface. PMID- 30463940 TI - Elevated histone H3 acetylation and loss of the Sp1-HDAC1 complex de-repress the GM2-synthase gene in renal cell carcinoma. AB - GM2-synthase produces sialic acid-containing glycosphingolipids called gangliosides, and its mRNA overexpression and the gangliosides it generates are linked to tumor progression, migration, and suppression of tumor-specific host immune responses. However, the mechanism underlying GM2-synthase de-repression in renal cell carcinoma (RCC) is poorly understood. Here, we demonstrate that higher GM2-synthase mRNA expression levels in various cancer cells and in human RCC tumors correlate with higher histone acetylation levels (H3K9, H3K14, or both) at region +38/+187 relative to the transcription start site (TSS) of the GM2 synthase gene than in normal kidney epithelial (NKE) cells or healthy adjacent tissues. An increase in GM2-synthase mRNA expression in cells treated with a histone deacetylase (HDAC) inhibitor was accompanied by increased histone acetylation levels at this promoter region. DNA methylation around the TSS was absent in both RCC cell lines and NKE cells. Of note, both the transcription factor Sp1 and corepressor HDAC1 associated with the +38/+187 region when the GM2 synthase gene was repressed in NKE and tumor-adjacent tissues, indicating plausible site-specific repressive roles of HDAC1 and Sp1 in GM2-synthase mRNA expression. Site-directed mutagenesis of the Sp1-binding site within the +38/+187 region relieved repressed luciferase activity of this region by limiting HDAC1 recruitment. Moreover, Sp1 or HDAC1 knockdown increased GM2-synthase transcription, and butyrate-mediated activation of GM2-synthase mRNA expression in SK-RC-45 cells was accompanied by Sp1 and HDAC1 loss from the +37/+187 region. Taken together, we have identified an epigenetic mechanism for the de-repression of the GM2-synthase gene in RCC. PMID- 30463942 TI - Jump rope vortex in liquid metal convection. AB - Understanding large-scale circulations (LSCs) in turbulent convective systems is important for the study of stars, planets, and in many industrial applications. The canonical model of the LSC is quasi-planar with additional horizontal sloshing and torsional modes [Brown E, Ahlers G (2009) J Fluid Mech 638:383-400; Funfschilling D, Ahlers G (2004) Phys Rev Lett 92:194502; Xi HD et al. (2009) Phys Rev Lett 102:044503; Zhou Q et al. (2009) J Fluid Mech 630:367-390]. Using liquid gallium as the working fluid, we show, via coupled laboratory-numerical experiments in tanks with aspect ratios greater than unity ([Formula: see text]), that the LSC takes instead the form of a "jump rope vortex," a strongly 3D mode that periodically orbits around the tank following a motion much like a jump rope on a playground. Further experiments show that this jump rope flow also exists in more viscous fluids such as water, albeit with a far smaller signal. Thus, this jump rope mode is an essential component of the turbulent convection that underlies our observations of natural systems. PMID- 30463941 TI - Establishment of a continuous in vitro culture of Babesia duncani in human erythrocytes reveals unusually high tolerance to recommended therapies. AB - Human babesiosis is an emerging tick-borne disease caused by apicomplexan parasites of the genus Babesia Clinical cases caused by Babesia duncani have been associated with high parasite burden, severe pathology and death. In both mice and hamsters, the parasite causes uncontrolled fulminant infections, which ultimately lead to death. Resolving these infections requires knowledge of B. duncani biology, virulence, and susceptibility to anti-infectives, but little is known and further research is hindered by a lack of relevant model systems. Here, we report the first continuous in vitro culture of B. duncani in human red blood cells. We show that during its asexual cycle within human erythrocytes, B. duncani develops and divides to form four daughter parasites with parasitemia doubling every ~22 h. Using this in vitro culture assay, we found that B. duncani has low susceptibility to the four drugs recommended for treatment of human babesiosis, atovaquone, azithromycin, clindamycin and quinine, with IC50 values ranging between 500 nM and 20 MUM. These data suggest that current practices are of limited effect in treating the disease. We anticipate this new disease model will set the stage for a better understanding of the biology of this parasite and will help guide better therapeutic strategies to treat B. duncani-associated babesiosis. PMID- 30463943 TI - Visualizing atomic sizes and molecular shapes with the classical turning surface of the Kohn-Sham potential. AB - The Kohn-Sham potential [Formula: see text] is the effective multiplicative operator in a noninteracting Schrodinger equation that reproduces the ground state density of a real (interacting) system. The sizes and shapes of atoms, molecules, and solids can be defined in terms of Kohn-Sham potentials in a nonarbitrary way that accords with chemical intuition and can be implemented efficiently, permitting a natural pictorial representation for chemistry and condensed-matter physics. Let [Formula: see text] be the maximum occupied orbital energy of the noninteracting electrons. Then the equation [Formula: see text] defines the surface at which classical electrons with energy [Formula: see text] would be turned back and thus determines the surface of any electronic object. Atomic and ionic radii defined in this manner agree well with empirical estimates, show regular chemical trends, and allow one to identify the type of chemical bonding between two given atoms by comparing the actual internuclear distance to the sum of atomic radii. The molecular surfaces can be fused (for a covalent bond), seamed (ionic bond), necked (hydrogen bond), or divided (van der Waals bond). This contribution extends the pioneering work of Z.-Z. Yang et al. [Yang ZZ, Davidson ER (1997) Int J Quantum Chem 62:47-53; Zhao DX, et al. (2018) Mol Phys 116:969-977] by our consideration of the Kohn-Sham potential, protomolecules, doubly negative atomic ions, a bond-type parameter, seamed and necked molecular surfaces, and a more extensive table of atomic and ionic radii that are fully consistent with expected periodic trends. PMID- 30463944 TI - Navigating the fitness landscape using multiallele genome editing. PMID- 30463945 TI - Measurability of the epidemic reproduction number in data-driven contact networks. AB - The basic reproduction number is one of the conceptual cornerstones of mathematical epidemiology. Its classical definition as the number of secondary cases generated by a typical infected individual in a fully susceptible population finds a clear analytical expression in homogeneous and stratified mixing models. Along with the generation time (the interval between primary and secondary cases), the reproduction number allows for the characterization of the dynamics of an epidemic. A clear-cut theoretical picture, however, is hardly found in real data. Here, we infer from highly detailed sociodemographic data two multiplex contact networks representative of a subset of the Italian and Dutch populations. We then simulate an infection transmission process on these networks accounting for the natural history of influenza and calibrated on empirical epidemiological data. We explicitly measure the reproduction number and generation time, recording all individual-level transmission events. We find that the classical concept of the basic reproduction number is untenable in realistic populations, and it does not provide any conceptual understanding of the epidemic evolution. This departure from the classical theoretical picture is not due to behavioral changes and other exogenous epidemiological determinants. Rather, it can be simply explained by the (clustered) contact structure of the population. Finally, we provide evidence that methodologies aimed at estimating the instantaneous reproduction number can operationally be used to characterize the correct epidemic dynamics from incidence data. PMID- 30463946 TI - Molecular mechanisms of biogenesis of apoptotic exosome-like vesicles and their roles as damage-associated molecular patterns. AB - Recent research has led to contradictory notions regarding the conventional theory that apoptotic cell death can evoke inflammatory or immunogenic responses orchestrated by released damage-associated patterns (DAMPs). By inducing IL-1beta from bone marrow-derived macrophages in an effort to determine the inflammatory mediators released from apoptotic cells, we found that exosomal fractions called "apoptotic exosome-like vesicles" (AEVs) prepared from apoptotic-conditioned medium were the main inflammatory factors. These AEVs showed characteristics of exosomes in their size, density, morphology, and protein expression but had unique marker proteins, sphingosine-1-phosphate receptors 1 and 3 (S1PR1 and 3). Their biogenesis was completely dependent on cellular sphingosine-1-phosphate (S1P)/S1PRs signaling from multiple fine spindles of plasma membrane accompanied by F-actin, S1PR1, S1PR3, and CD63 at the early apoptotic phase and progressing to the maturation of F-actin-guided multivesicular endosomes mediated by Gbetagamma subunits of S1PRs downstream. S1P-loaded S1PRs on AEVs were critical factors for inducing IL-1beta via NF-kappaB transcriptional factor and p38 MAPK, possibly through the RHOA/NOD2 axis, in differentiating macrophages. The AEVs induced genes of proinflammatory cytokines, chemokines, and mediators in both in vitro and in vivo models. In conclusion, AEVs could be key inflammatory mediators, acting as DAMPs that could explain the pathogeneses of various chronic inflammations, autoimmune diseases, or cancers in the future. PMID- 30463947 TI - Janzen's mountain passes hypothesis is comprehensively tested in its fifth decade. PMID- 30463948 TI - TRPV1 pore turret dictates distinct DkTx and capsaicin gating. AB - Many neurotoxins inflict pain by targeting receptors expressed on nociceptors, such as the polymodal cationic channel TRPV1. The tarantula double-knot toxin (DkTx) is a peptide with an atypical bivalent structure, providing it with the unique capability to lock TRPV1 in its open state and evoke an irreversible channel activation. Here, we describe a distinct gating mechanism of DkTx-evoked TRPV1 activation. Interestingly, DkTx evokes significantly smaller TRPV1 macroscopic currents than capsaicin, with a significantly lower unitary conductance. Accordingly, while capsaicin evokes aversive behaviors in TRPV1 transgenic Caenorhabditis elegans, DkTx fails to evoke such response at physiological concentrations. To determine the structural feature(s) responsible for this phenomenon, we engineered and evaluated a series of mutated toxins and TRPV1 channels. We found that elongating the DkTx linker, which connects its two knots, increases channel conductance compared with currents elicited by the native toxin. Importantly, deletion of the TRPV1 pore turret, a stretch of amino acids protruding out of the channel's outer pore region, is sufficient to produce both full conductance and aversive behaviors in response to DkTx. Interestingly, this deletion decreases the capsaicin-evoked channel activation. Taken together with structure modeling analysis, our results demonstrate that the TRPV1 pore turret restricts DkTx-mediated pore opening, probably through steric hindrance, limiting the current size and mitigating the evoked downstream physiological response. Overall, our findings reveal that DkTx and capsaicin elicit distinct TRPV1 gating mechanisms and subsequent pain responses. Our results also indicate that the TRPV1 pore turret regulates the mechanisms of channel gating and permeation. PMID- 30463949 TI - Evolution of host support for two ancient bacterial symbionts with differentially degraded genomes in a leafhopper host. AB - Plant sap-feeding insects (Hemiptera) rely on bacterial symbionts for nutrition absent in their diets. These bacteria experience extreme genome reduction and require genetic resources from their hosts, particularly for basic cellular processes other than nutrition synthesis. The host-derived mechanisms that complete these processes have remained poorly understood. It is also unclear how hosts meet the distinct needs of multiple bacterial partners with differentially degraded genomes. To address these questions, we investigated the cell-specific gene-expression patterns in the symbiotic organs of the aster leafhopper (ALF), Macrosteles quadrilineatus (Cicadellidae). ALF harbors two intracellular symbionts that have two of the smallest known bacterial genomes: Nasuia (112 kb) and Sulcia (190 kb). Symbionts are segregated into distinct host cell types (bacteriocytes) and vary widely in their basic cellular capabilities. ALF differentially expresses thousands of genes between the bacteriocyte types to meet the functional needs of each symbiont, including the provisioning of metabolites and support of cellular processes. For example, the host highly expresses genes in the bacteriocytes that likely complement gene losses in nucleic acid synthesis, DNA repair mechanisms, transcription, and translation. Such genes are required to function in the bacterial cytosol. Many host genes comprising these support mechanisms are derived from the evolution of novel functional traits via horizontally transferred genes, reassigned mitochondrial support genes, and gene duplications with bacteriocyte-specific expression. Comparison across other hemipteran lineages reveals that hosts generally support the incomplete symbiont cellular processes, but the origins of these support mechanisms are generally specific to the host-symbiont system. PMID- 30463950 TI - Staphylococcus aureus coagulases are exploitable yet stable public goods in clinically relevant conditions. AB - Coagulation is an innate defense mechanism intended to limit blood loss and trap invading pathogens during infection. However, Staphylococcus aureus has the ability to hijack the coagulation cascade and generate clots via secretion of coagulases. Although many S. aureus have this characteristic, some do not. The population dynamics regarding this defining trait have yet to be explored. We report here that coagulases are public goods that confer protection against antimicrobials and immune factors within a local population or community, thus promoting growth and virulence. By utilizing variants of a methicillin-resistant S. aureus we infer that the secretion of coagulases is a cooperative trait, which is subject to exploitation by invading mutants that do not produce the public goods themselves. However, overexploitation, "tragedy of the commons," does not occur at clinically relevant conditions. Our micrographs indicate this is due to spatial segregation and population viscosity. These findings emphasize the critical role of coagulases in a social evolution context and provide a possible explanation as to why the secretion of these public goods is maintained in mixed S. aureus communities. PMID- 30463951 TI - The unusual rainbow trout sex determination gene hijacked the canonical vertebrate gonadal differentiation pathway. AB - Evolutionary novelties require rewiring of transcriptional networks and/or the evolution of new gene functions. Sex determination (SD), one of the most plastic evolutionary processes, requires such novelties. Studies on the evolution of vertebrate SD revealed that new master SD genes are generally recruited from genes involved in the downstream SD regulatory genetic network. Only a single exception to this rule is currently known in vertebrates: the intriguing case of the salmonid master SD gene (sdY), which arose from duplication of an immune related gene. This exception immediately posed the question of how a gene outside from the classical sex differentiation cascade could acquire its function as a male SD gene. Here we show that SdY became integrated in the classical vertebrate sex differentiation cascade by interacting with the Forkhead box domain of the female-determining transcription factor, Foxl2. In the presence of Foxl2, SdY is translocated to the nucleus where the SdY:Foxl2 complex prevents activation of the aromatase (cyp19a1a) promoter in cooperation with Nr5a1 (Sf1). Hence, by blocking a positive loop of regulation needed for the synthesis of estrogens in the early differentiating gonad, SdY disrupts a preset female differentiation pathway, consequently allowing testicular differentiation to proceed. These results also suggest that the evolution of unusual vertebrate master sex determination genes recruited from outside the classical pathway like sdY is strongly constrained by their ability to interact with the canonical gonadal differentiation pathway. PMID- 30463952 TI - Directing the reactivity of metal hydrides for selective CO2 reduction. AB - A critical challenge in electrocatalytic CO2 reduction to renewable fuels is product selectivity. Desirable products of CO2 reduction require proton equivalents, but key catalytic intermediates can also be competent for direct proton reduction to H2 Understanding how to manage divergent reaction pathways at these shared intermediates is essential to achieving high selectivity. Both proton reduction to hydrogen and CO2 reduction to formate generally proceed through a metal hydride intermediate. We apply thermodynamic relationships that describe the reactivity of metal hydrides with H+ and CO2 to generate a thermodynamic product diagram, which outlines the free energy of product formation as a function of proton activity and hydricity (?GH-), or hydride donor strength. The diagram outlines a region of metal hydricity and proton activity in which CO2 reduction is favorable and H+ reduction is suppressed. We apply our diagram to inform our selection of [Pt(dmpe)2](PF6)2 as a potential catalyst, because the corresponding hydride [HPt(dmpe)2]+ has the correct hydricity to access the region where selective CO2 reduction is possible. We validate our choice experimentally; [Pt(dmpe)2](PF6)2 is a highly selective electrocatalyst for CO2 reduction to formate (>90% Faradaic efficiency) at an overpotential of less than 100 mV in acetonitrile with no evidence of catalyst degradation after electrolysis. Our report of a selective catalyst for CO2 reduction illustrates how our thermodynamic diagrams can guide selective and efficient catalyst discovery. PMID- 30463953 TI - The calculation of transcript flux ratios reveals single regulatory mechanisms capable of activation and repression. AB - The regulation of transcription allows cells to adjust the rate of RNA polymerases (RNAPs) initiated in a promoter-specific manner. Classically, transcription factors are directed to a subset of promoters via the recognition of DNA sequence motifs. However, a unique class of regulators is recruited directly through interactions with RNAP. Surprisingly, these factors may still possess promoter specificity, and it has been postulated that the same kinetic mechanism leads to different regulatory outcomes depending on a promoter's basal rate constants. However, mechanistic studies of regulation typically report factor activity in terms of changes in the thermodynamics or kinetics of individual steps or states while qualitatively linking these observations to measured changes in transcript production. Here, I present online calculators that allow for the direct testing of mechanistic hypotheses by calculating the steady-state transcript flux in the presence and absence of a factor as a function of initiation rate constants. By evaluating how the flux ratio of a single kinetic mechanism varies across promoter space, quantitative insights into the potential of a mechanism to generate promoter-specific regulatory outcomes are obtained. Using these calculations, I predict that the mycobacterial transcription factor CarD is capable of repression in addition to its known role as an activator of ribosomal genes. In addition, a modification of the mechanism of the stringent response factors DksA/guanosine 5'-diphosphate 3'-diphosphate (ppGpp) is proposed based on their ability to differentially regulate transcription across promoter space. Overall, I conclude that a multifaceted kinetic mechanism is a requirement for differential regulation by this class of factors. PMID- 30463954 TI - Coiled-coil 1-mediated fastening of the neck and motor domains for kinesin-3 autoinhibition. AB - In kinesin-3, the coiled-coil 1 (CC1) can sequester the preceding neck coil (NC) for autoinhibition, but the underlying mechanism is poorly understood. Here, we determined the structures of the uninhibited motor domain (MD)-NC dimer and inhibited MD-NC-CC1 monomer of kinesin-3 KIF13B. In the MD-NC-CC1 monomer, CC1 is broken into two short helices that unexpectedly interact with both the NC and the MD. Compared with the MD-NC dimer, the CC1-mediated integration of NC and MD not only blocks the NC dimer formation, but also prevents the neck linker (NL) undocking and the ADP release from the MD. Mutations of the essential residues in the interdomain interaction interface in the MD-NC-CC1 monomer restored the MD activity. Thus, CC1 fastens the neck domain and MD and inhibits both NC and NL. This CC1-mediated lockdown of the entire neck domain may represent a paradigm for kinesin autoinhibition that could be applicable to other kinesin-3 motors. PMID- 30463955 TI - Tissue-specific contributions of Tmem79 to atopic dermatitis and mast cell mediated histaminergic itch. AB - Atopic dermatitis (AD) is the most common skin disease in children. It is characterized by relapsing inflammation, skin-barrier defects, and intractable itch. However, the pathophysiology of itch in AD remains enigmatic. Here, we examine the contribution of Tmem79, an orphan transmembrane protein linked to AD in both mice and humans. We show that Tmem79 is expressed by both keratinocytes and sensory neurons, but that loss of keratinocytic Tmem79 is sufficient to elicit robust scratching. Tmem79 -/- mice demonstrate an accumulation of dermal mast cells, which are diminished following chronic treatment with cyclooxygenase inhibitors and an EP3 receptor antagonist. In Tmem79 -/- mice, mast cell degranulation produces histaminergic itch in a histamine receptor 1/histamine receptor 4 (H4R/H1R)-dependent manner that may involve activation of TRPV1- afferents. TMEM79 has limited sequence homology to a family of microsomal glutathione transferases and confers protection from cellular accumulation of damaging reactive species, and may thus play a role in regulating oxidative stress. In any case, mechanistic insights from this model suggest that therapeutics targeting PGE2 and/or H1R/H4R histaminergic signaling pathways may represent useful avenues to treat Tmem79-associated AD itch. Our findings suggest that individuals with mutations in Tmem79 develop AD due to the loss of protection from oxidative stress. PMID- 30463956 TI - Germline genetic polymorphisms influence tumor gene expression and immune cell infiltration. AB - Cancer immunotherapy has emerged as an effective therapy in a variety of cancers. However, a key challenge in the field is that only a subset of patients who receive immunotherapy exhibit durable response. It has been hypothesized that host genetics influences the inherent immune profiles of patients and may underlie their differential response to immunotherapy. Herein, we systematically determined the association of common germline genetic variants with gene expression and immune cell infiltration of the tumor. We identified 64,094 expression quantitative trait loci (eQTLs) that associated with 18,210 genes (eGenes) across 24 human cancers. Overall, eGenes were enriched for their being involved in immune processes, suggesting that expression of immune genes can be shaped by hereditary genetic variants. We identified the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene as a pan-cancer type eGene whose expression levels stratified overall survival in a subset of patients with bladder cancer receiving anti-PD-L1 (atezolizumab) therapy. Finally, we identified 103 gene signature QTLs (gsQTLs) that were associated with predicted immune cell abundance within the tumor microenvironment. Our findings highlight the impact of germline SNPs on cancer-immune phenotypes and response to therapy; and these analyses provide a resource for integration of germline genetics as a component of personalized cancer immunotherapy. PMID- 30463957 TI - Individual synaptic vesicles mediate stimulated exocytosis from cochlear inner hair cells. AB - Spontaneous excitatory postsynaptic currents (sEPSCs) measured from the first synapse in the mammalian auditory pathway reach a large mean amplitude with a high level of variance (CV between 0.3 and 1). This has led some to propose that each inner hair cell (IHC) ribbon-type active zone (AZ), on average, releases ~6 synaptic vesicles (SVs) per sEPSC in a coordinated manner. If true, then the predicted change in membrane capacitance (Cm) for such multivesicular fusion events would equate to ~300 attofarads (aF). Here, we performed cell-attached Cm measurements to directly examine the size of fusion events at the basolateral membrane of IHCs where the AZs are located. The frequency of events depended on the membrane potential and the expression of Cav1.3, the principal Ca2+-channel type of IHCs. Fusion events averaged 40 aF, which equates to a normal-sized SV with an estimated diameter of 37 nm. The calculated SV volumes showed a high degree of variance (CV > 0.6). These results indicate that SVs fused individually with the plasma membrane during spontaneous and evoked release and SV volume may contribute more variability in EPSC amplitude than previously assumed. PMID- 30463958 TI - A2A adenosine receptor functional states characterized by 19F-NMR. AB - The human proteome contains 826 G protein-coupled receptors (GPCR), which control a wide array of key physiological functions, making them important drug targets. GPCR functions are based on allosteric coupling from the extracellular orthosteric drug binding site across the cell membrane to intracellular binding sites for partners such as G proteins and arrestins. This signaling process is related to dynamic equilibria in conformational ensembles that can be observed by NMR in solution. A previous high-resolution NMR study of the A2A adenosine receptor (A2AAR) resulted in a qualitative characterization of a network of such local polymorphisms. Here, we used 19F-NMR experiments with probes at the A2AAR intracellular surface, which provides the high sensitivity needed for a refined description of different receptor activation states by ensembles of simultaneously populated conformers and the rates of exchange among them. We observed two agonist-stabilized substates that are not measurably populated in apo-A2AAR and one inactive substate that is not seen in complexes with agonists, suggesting that A2AAR activation includes both induced fit and conformational selection mechanisms. Comparison of A2AAR and a constitutively active mutant established relations between the 19F-NMR spectra and signaling activity, which enabled direct assessment of the difference in basal activity between the native protein and its variant. PMID- 30463959 TI - Structural snapshots of OxyR reveal the peroxidatic mechanism of H2O2 sensing. AB - Hydrogen peroxide (H2O2) is a strong oxidant capable of oxidizing cysteinyl thiolates, yet only a few cysteine-containing proteins have exceptional reactivity toward H2O2 One such example is the prokaryotic transcription factor OxyR, which controls the antioxidant response in bacteria, and which specifically and rapidly reduces H2O2 In this study, we present crystallographic evidence for the H2O2-sensing mechanism and H2O2-dependent structural transition of Corynebacterium glutamicum OxyR by capturing the reduced and H2O2-bound structures of a serine mutant of the peroxidatic cysteine, and the full-length crystal structure of disulfide-bonded oxidized OxyR. In the H2O2-bound structure, we pinpoint the key residues for the peroxidatic reduction of H2O2, and relate this to mutational assays showing that the conserved active-site residues T107 and R278 are critical for effective H2O2 reduction. Furthermore, we propose an allosteric mode of structural change, whereby a localized conformational change arising from H2O2-induced intramolecular disulfide formation drives a structural shift at the dimerization interface of OxyR, leading to overall changes in quaternary structure and an altered DNA-binding topology and affinity at the catalase promoter region. This study provides molecular insights into the overall OxyR transcription mechanism regulated by H2O2. PMID- 30463960 TI - Vectorial Release of Hepatitis E Virus in Polarized Human Hepatocytes. AB - Hepatitis E virus (HEV) is a common cause of acute viral hepatitis worldwide. Most HEV infections are asymptomatic but immunocompromised patients infected with HEV3, HEV4 or HEV7 may develop chronic infections. The HEV particles in stools are naked (nHEV) while those in the serum and culture supernatants (eHEV) are associated with lipids. Hepatocytes are polarized epithelial cells that have basolateral (to blood) and apical (to bile) exosomal pathways. We isolated a subclone, F2, from the human hepatocarcinoma cell line HepG2/C3A that grew as a polarized monolayer culture and had better HEV production than HepG2/C3A. F2 cells cultured on semi-permeable collagen inserts and infected basolaterally with nHEV3 released 94.6% of virus particles apically, those infected with eHEV3 released 96.8% apically, and eHEV1-infected cells released 99.3% apically. Transcytosis was not involved. Density gradient centrifugation and NP40 treatment showed that HEV particles released both apically and basolaterally were lipid associated. The apically-released HEV3 and HEV1 particles were six- and nine times more infectious than those released basolaterally, respectively. Confocal microscopy indicated that the ORF2 capsid protein colocalized apically with ORF3 virus protein, the apical marker DPP4, and the recycling endosome GTPase Rab27a. The amounts of soluble glycosylated ORF2 secreted apically and basolaterally were similar. These polarized hepatocyte data suggest that infectious HEV particles are mainly released to bile, while the small fraction released to blood could spread HEV throughout the host.ImportanceThe hepatitis E virus (HEV) in stools is naked while those in culture supernatants and patients' blood are lipid associated. Its life cycle in hepatocytes, polarized cells with basolateral side communicating with blood and apical side connected with bile, is incompletely understood. We have developed a polarized hepatocyte model, and used these cells to analyze the supernatants bathing the apical and basolateral sides and HEV subcellular distribution. HEV viral particles from both sides were lipid associated and most infectious HEV particles left the cell via its apical side. Similar amounts of the soluble capsid protein ORF2 were secreted from both sides of the hepatocytes. This model mimicking physiological conditions should help clarify the HEV cell cycle in polarized hepatocytes. PMID- 30463961 TI - Genetic compatibility of reassortants between avian H5N1 and H9N2 influenza viruses with higher pathogenicity in mammals. AB - The co-circulation of H5N1 and H9N2 avian influenza viruses in birds in Egypt provides reassortment opportunities between these two viruses. However, little is known about the emergence potential of reassortants derived from Egyptian H5N1 and H9N2 viruses and about the biological properties of such reassortants. To evaluate the potential public health risk of reassortants of these viruses, we used reverse genetics to generate the 63 possible reassortants derived from contemporary Egyptian H5N1 and H9N2 viruses, containing the H5N1 surface gene segments and combinations of the H5N1 and H9N2 internal gene segments, and analyzed their genetic compatibility, replication ability and virulence in mice. Genes in the reassortants showed remarkably high compatibility. Replication of most reassortants was higher than the parental H5N1 virus in human cells. Six reassortants were thought to emerge in birds under neutral or positive selective pressure, and four of them had higher pathogenicity in vivo than the parental H5N1 and H9N2 viruses. Our results indicated that H5N1-H9N2 reassortants could be transmitted efficiently to mammals with significant public health risk if they emerge in Egypt, although the viruses might not emerge frequently in birds.IMPORTANCEClose interaction between avian influenza (AI) viruses and humans in Egypt appears to have resulted in many of the worldwide cases of human infections by both H5N1 and H9N2 AI viruses. Egypt is regarded as a hot spot of AI virus evolution. Although no natural reassortant of H5N1 and H9N2 AI viruses has been reported so far, their co-circulation in Egypt may allow emergence of reassortants that may present a significant public health risk. Using reverse genetics, we report here the first comprehensive data showing that H5N1-N9N2 reassortants have fairly high genetic compatibility and possibly higher pathogenicity in mammals, including humans, than the parental viruses. Our results provide insight into the emergence potential of avian H5N1-H9N2 reassortants that may pose a high public health risk. PMID- 30463962 TI - Existing host range mutations constrain further emergence of RNA viruses. AB - RNA viruses are capable of rapid host shifting, typically due to a point mutation that confers expanded host range. As additional point mutations are necessary for further expansions, epistasis among host range mutations can potentially affect the mutational neighborhood and frequency of niche expansion. We mapped the mutational neighborhood of host range expansion using three genotypes of the dsRNA bacteriophage phi6 (wildtype and two isogenic host range mutants) on the novel host Pseudomonas syringae pv. atrofaciens (PA). Sanger sequencing of fifty PA mutant clones for each genotype and population Illumina sequencing both revealed the same high frequency mutations allowing infection of PA. Wildtype phi6 had at least nine different ways of mutating to enter the novel host, eight of which are in p3 (host attachment protein gene), and 13/50 clones had unchanged p3 genes. However, the two isogenic mutants had dramatically restricted neighborhoods: only one or two mutations, all in p3. Deep sequencing revealed that wildtype clones without mutations in p3 likely had changes in p12 (morphogenic protein), a region that was not polymorphic for the two isogenic host range mutants. Sanger sequencing confirmed that 10/13 of the wildtype phi6 clones had nonsynonymous mutations in p12 and two others had point mutations in p9 and p5 - none of these genes had previously been associated with host range expansion in phi6. We demonstrate, for the first time, epistatic constraint in an RNA virus due to host range mutations themselves, which has implications for models of serial host range expansion.ImportanceRNA viruses mutate rapidly and frequently expand their host ranges to infect novel hosts, leading to serial host shifts. Using an RNA bacteriophage model system (Pseudomonas phage phi6), we studied the impact of pre-existing host range mutations on another host range expansion. Results from both clonal Sanger and Illumina sequencing show extant host range mutations dramatically narrow the neighborhood of potential host range mutations compared to wildtype phi6. This research suggests that serial host shifting viruses may follow a small number of molecular paths to enter additional novel hosts. We also identified new genes involved in phi6 host range expansion, expanding our knowledge of this important model system in experimental evolution. PMID- 30463963 TI - Early Infection of Porcine Sapovirus Disrupts Tight Junction and Uses Occludin as a Co-receptor. AB - Sapovirus is a genus in the Caliciviridae family, and its members are common causative agents of severe, acute gastroenteritis in both humans and animals. Some caliciviruses are known to use either terminal sialic acids or histo-blood group antigens as attachment factors and/or cell surface proteins such as CD300lf, CD300ld, and junctional adhesion molecule 1 of tight junctions (TJs) as receptors. However, the role of TJs and their proteins in sapovirus entry has not been examined. In this study, we found that porcine sapovirus (PSaV) significantly decreased transepithelial electrical resistance and increased paracellular permeability early in infection of LLC-PK cells, suggesting that PSaV dissociates TJs of cells. This led to the interaction between PSaV particles and occludin, which travelled in a complex into late endosomes via Rab5- and Rab7 dependent trafficking. Inhibition of occludin using siRNA, specific antibody, or a dominant-negative mutant significantly blocked the entry of PSaV. Transient expression of occludin in non-permissible Chinese hamster ovary (CHO) cells conferred susceptibility to PSaV, but only for a limited time. Although claudin 1, another TJ protein, neither directly interacted, nor was internalized with PSaV particles, it facilitated PSaV entry and replication in the LLC-PK cells. We conclude that PSaV particles enter LLC-PK cells by binding to occludin as a co receptor in PSaV-dissociated TJs. PSaV and occludin then form a complex that moves to late endosomes via Rab5- and Rab7-dependent trafficking. In addition, claudin-1 in the opened TJs by PSaV infection facilitates PSaV entry and infection as an entry factor.IMPORTANCE Sapoviruses (SaVs) cause severe acute gastroenteritis in humans and animals. Although they replicate in intestinal epithelial cells, which are tightly sealed by apical junctional complexes such as tight junctions (TJs), the mechanisms by which SaVs hijack TJs and their proteins for successful entry and infection remain largely unknown. Here, we demonstrate that porcine SaVs (PSaVs) induce early dissociation of TJs, allowing them to bind to the TJ protein, occludin, as a functional co-receptor. PSaVs then travel in a complex with occludin into late endosomes through Rab5- and Rab7-dependent trafficking. Claudin-1, another TJ protein, does not directly interact with PSaV, but facilitates the entry of PSaV into cells as an entry factor. This work contributes to our understanding of the entry of SaV and other caliciviruses into cells and may aid in the development of efficient and affordable drugs to treat SaV infections. PMID- 30463964 TI - Functional analysis and anti-virulent properties of a new depolymerase from a myovirus that infects Acinetobacter baumannii capsule K45. AB - Acinetobacter baumannii is an important pathogen causative of healthcare associated infections and is able to rapidly develop resistance to all known antibiotics including colistin. As an alternative therapeutic agent, we have isolated a novel myovirus (vB_AbM_B9) which specifically infects and makes lysis from without in strains of the K45 and K30 capsule type, respectively. Phage B9 has a genome of 93,641 bp and encodes 167 predicted proteins, of which 29 were identified by mass spectrometry. This phage holds a capsule depolymerase (B9gp69) able to digest extracted exopolysaccharides of both K30 and K45 strains and that remains active in a wide range of pH values (5 to 9), ionic strengths (0 to 500 mM), and temperatures (20 to 80 degrees C). B9gp69 demonstrated to be non-toxic in a cell line model of the human lung, and to make the K45 strain fully susceptible to serum killing in vitro Contrary to the phage, no resistance development was observed by bacteria targeted with the B9gp69. Therefore, capsular depolymerases may represent attractive antimicrobial agents against A. baumannii infections.IMPORTANCECurrently, phage therapy has revived interest for controlling hard-to-treat bacterial infections. Acinetobacter baumannii is an emerging Gram-negative pathogen able to cause a variety of nosocomial infections. Additionally, this species is becoming more resistant to several classes of antibiotics. Herein, we describe the isolation of a novel lytic myophage B9 and its recombinant depolymerase. While the phage can be a promising alternative antibacterial agent, its success in the market will ultimately depend on new regulatory frameworks and general public acceptance. We therefore characterised the phage-encoded depolymerase which is a natural enzyme that can be more easily managed and used. To our knowledge, the therapeutic potential of phage depolymerase against A. baumannii is still unknown. We show for the first time that K45 capsule type is an important virulence factor of A. baumannii and that capsule removal via the recombinant depolymerase activity helps the host immune system to combat the bacterial infection. PMID- 30463965 TI - Defective viral genomes alter how Sendai virus interacts with cellular trafficking machinery leading to heterogeneity in the production of viral particles among infected cells. AB - Defective viral genomes (DVGs) generated during RNA virus replication determine infection outcome by triggering innate immunity, diminishing virulence, and, in many cases, facilitating the establishment of persistent infections. Despite the critical role of DVGs during virus-host interactions, the mechanisms regulating production and propagation of DVGs are poorly understood. Visualization of viral genomes using RNA fluorescent in situ hybridization revealed a striking difference in the intracellular localization of DVGs and full-length viral genomes during infections with the paramyxovirus Sendai. In cells enriched in full-length virus, viral genomes clustered in a perinuclear region and associated with cellular trafficking machinery, including microtubules and the GTPase Rab11a. However, in cells enriched in DVGs, defective genomes distributed diffusely throughout the cytoplasm and failed to interact with this cellular machinery. Consequently, cells enriched in full-length genomes produced both DVG and full-length genome-containing viral particles, while DVG-high cells poorly produced viral particles, yet strongly stimulated antiviral immunity. These findings reveal the selective production of both standard and DVG-containing particles by a subpopulation of cells during infection that can be differentiated by the intracellular localization of DVGs. This study highlights the importance of considering this functional heterogeneity in analyses of virus-host interactions during infection.SignificanceDefective viral genomes (DVGs) generated during Sendai virus infections accumulate in the cytoplasm of some infected cells and stimulate antiviral immunity and cell survival. DVGs are packaged and released as defective particles and have a significant impact on infection outcome. We show that the subpopulation of DVG-high cells poorly engage the virus packaging and budding machinery and do not effectively produce viral particles. In contrast, cells enriched in full-length genomes are the primary producers of both standard and defective viral particles during infection. This study demonstrates heterogeneity in the molecular intracellular interactions occurring within infected cells and highlights distinct functional roles for cells as either initiators of immunity or as producers and perpetuators of viral particles depending on their content and intracellular localization of viral genomes. PMID- 30463966 TI - The Ectodomain of the Vaccinia Virus Glycoprotein A34 is Required for Cell Binding by Extracellular Virions and Contains a Large Region Capable of Interaction with the Glycoprotein B5. AB - An interaction between the orthopoxvirus glycoproteins A34 and B5 has been reported. The transmembrane and ectodomain of A34 is sufficient for interaction with B5, localization of B5 to the site of intracellular wrapping, and subsequent incorporation into the envelope of released extracellular virions. Several mutagenic approaches were undertaken to better define the B5 interaction domain on A34. A set of C-terminal truncations in A34 identified residues 1-80 as sufficient for interaction with B5. Additional truncations identified residues 80 130 of A34 as sufficient for interaction with B5. To better understand the function of this region, a set of recombinant viruses expressing an A34 with the full, partial, or no B5 interaction site (residues 1-130, 1-100, and 1-70, respectively) were constructed. All the recombinants expressing truncations of A34 incorporated B5 into extracellular virions but had a small plaque phenotype similar in size to a virus with the A34R gene deleted (vDeltaA34R). Further characterization indicated that the small plaque phenotype exhibited by these viruses is due to a combination of abrogated actin tail formation, reduced cell binding, and a defect in polyanion-induced non-fusogenic dissolution. Taken together, these results suggest that residues 80-130 of A34 are not necessary for the proper localization and incorporation of B5 into extracellular virions and furthermore, that the C-terminal residues of A34 are involved in cell binding and dissolution.IMPORTANCEPrevious studies have shown that the vaccinia virus glycoproteins A34 and B5 interact, and in the absence of A34, B5 is mis-localized and not incorporated into extracellular virions. Here, using a transient transfection assay, residues 80-130 of the ectodomain of A34 were determined to be sufficient for interaction with B5. Recombinant viruses expressing an A34 with a full, partial, or no B5 interaction site were constructed and characterized. All of the A34 truncations interacted with B5 as predicted by the transient transfection studies but had a small plaque phenotype. Further analysis revealed that all of the recombinants incorporated detectable levels of B5 into released virions, but, were defective in cell binding and EV dissolution. This study is the first to directly demonstrate that A34 is involved in cell binding and implicate the ectodomain in this role. PMID- 30463967 TI - Epidemiological Evidence for Lineage-specific Differences in the Risk of Inapparent Chikungunya Virus Infection. AB - In late 2013, chikungunya virus (CHIKV) was introduced into the Americas, leading to widespread epidemics. A large epidemic caused by the Asian chikungunya virus (CHIKV) lineage occurred in Managua, Nicaragua, in 2015. Literature reviews commonly state that the proportion of inapparent CHIKV infections ranges from 3 to 28%. This study estimates the symptomatic-to-asymptomatic ratio of CHIKV infections and identifies risk factors of infection. In October-November 2015, 60 symptomatic CHIKV-infected children were enrolled as index cases and prospectively followed, alongside 236 household contacts, in an index cluster study. Samples were collected upon enrollment and on days 14 or 35 and tested by rRT-PCR, IgM-ELISA, and Inhibition ELISA to detect pre- and post-enrollment CHIKV infections. Of 236 household contacts, 55 (23%) had experienced previous or very recent infections, 41 (17%) had active infections at enrollment, and 21 (9%) experienced incident infections. Vehicle ownership (multivariate-adjusted risk ratio (aRR): 1.58) increased the risk of CHIKV infection whereas >=4 municipal trash collections/week (aRR: 0.38) and having an external water faucet (aRR: 0.52) protected against CHIKV infection. Among 63 active and incident infections, 31 (49%, 95% CI: 36%, 62%) were asymptomatic, yielding a symptomatic-to asymptomatic ratio of 1:0.97 (95% CI: 1:0.56, 1:1.60). Although our estimate is outside the 3-28% range reported previously, Bayesian and simulation analyses, informed by a systematic literature search, suggested that the proportion of inapparent CHIKV infections is lineage-dependent and that more inapparent infections are associated with the Asian lineage than the ECSA lineage. Overall, these data substantially improve knowledge regarding chikungunya epidemics.ImportanceChikungunya virus (CHIKV) is an understudied threat to human health. During the 2015 chikungunya epidemic in Managua, Nicaragua, we estimated the ratio of symptomatic-to-asymptomatic CHIKV infections, which is important for understanding transmission dynamics and public health impact. This index cluster study identified persons at risk of infection and followed them, enabling capture of asymptomatic infections. We estimated that 31 (49%) of 63 at-risk participants had asymptomatic CHIKV infections, which is significantly outside the 3-28% range reported in literature reviews. However, recent seroprevalence studies, including two large pediatric cohort studies in the same setting, had also found percentages of inapparent infections outside the 3-28% range. Bayesian and simulation analyses, informed by a systematic literature search, revealed that the percentage of inapparent infections in epidemic settings varies by the phylogenetic lineage of CHIKV. Our study quantifies and provides the first epidemiological evidence that chikungunya epidemic characteristics are strongly influenced by CHIKV lineage. PMID- 30463968 TI - Packaging of the influenza A virus genome is governed by a plastic network of RNA/protein interactions. AB - The genome of influenza A virus is organized into eight ribonucleoproteins, each composed of a distinct RNA segment bound by the viral polymerase and oligomeric viral nucleoprotein. Packaging sequences unique to each RNA segment together with specific nucleoprotein amino acids are thought to ensure the precise incorporation of these eight ribonucleoproteins into single virus particles, yet the underlying interaction network remains largely unexplored. Here we show that the genome packaging mechanism of an H7N7 subtype influenza A virus widely tolerates the mutation of individual packaging sequences in three different RNA segments. However, combinations of these modified RNA segments cause distinct genome packaging defects, marked by the absence of specific RNA segment subsets from the viral particles. Furthermore, we find that combining a single mutated packaging sequence with sets of specific nucleoprotein amino acid substitutions greatly impairs the viral genome packaging process. Along with previous reports, our data propose that influenza A virus uses a redundant and plastic network of RNA-RNA and potentially RNA-nucleoprotein interactions to coordinately incorporate its segmented genome into virions.IMPORTANCE The genome of influenza A virus is organized into eight viral ribonucleoproteins (vRNPs), which provides evolutionary advantages but complicates genome packaging. Although it has been shown that RNA packaging sequences and specific amino acids in the viral nucleoprotein (NP), both components of each vRNP, ensure selective packaging of one copy of each vRNP per virus particle, the required RNA-RNA and RNA-NP interactions remain largely elusive. We identified that the genome packaging mechanism tolerates the mutation of certain individual RNA packaging sequences, while their combined mutation provokes distinct genome packaging defects. Moreover, we found that seven specific amino acid substitutions in NP impair the function of RNA packaging sequences, and that this defect is partially restored by another NP amino acid change. Collectively, our data indicate that packaging of the influenza A virus genome is controlled by a redundant and plastic network of RNA/protein interactions, which may facilitate natural reassortment processes. PMID- 30463969 TI - The Alphavirus E2 Membrane-Proximal Domain Impacts Capsid Interaction and Glycoprotein Lattice Formation. AB - Alphaviruses are small enveloped RNA viruses that bud from the host cell plasma membrane. Alphavirus particles have a highly organized structure, with a nucleocapsid core containing the RNA genome surrounded by the capsid protein, and a viral envelope containing 80 spikes, each a trimer of heterodimers of the E1 and E2 glycoproteins. The capsid protein and envelope proteins are both arranged in organized lattices that are linked via the interaction of the E2 cytoplasmic tail/endodomain with the capsid protein. We previously characterized the role of 2 highly conserved histidine residues, H348 and H352, located in an external, juxtamembrane region of the E2 protein termed the D-loop. Alanine substitutions of H348 and H352 inhibit virus growth by impairing late steps in the assembly/budding of virus particles at the plasma membrane. To investigate this budding defect, we selected for revertants of the E2-H348/352A double mutant. We identified eleven second-site revertants with improved virus growth and mutations in the capsid, E2 and E1 proteins. Multiple isolates contained the mutation E2 T402K in the E2 endodomain or E1-T317I in the E1 ectodomain. Both of these mutations were shown to partially restore H348/352A growth and virus assembly/budding, while neither rescued the decreased thermostability of H348/352A. Within the alphavirus particle, these mutations affect the E2-capsid interaction or the E1-mediated inter-trimer interactions at the 5-fold axis of symmetry. Together our results support a model in which the E2 D-loop promotes the formation of the glycoprotein lattice and its interactions with the internal capsid protein lattice.IMPORTANCE Alphaviruses include important human pathogens such as Chikungunya and the encephalitic alphaviruses. There are currently no licensed alphavirus vaccines or effective antiviral therapies, and more molecular information on virus particle structure and function are needed. Here we highlight the important role of the E2 juxtamembrane D-loop in mediating virus budding and particle production. Our results demonstrated that this E2 region affects both the formation of the external glycoprotein lattice and its interactions with the internal capsid protein shell. PMID- 30463970 TI - Efficient inhibition of avian and seasonal influenza A viruses by a virus specific Dicer-substrate siRNA swarm in human monocyte-derived macrophages and dendritic cells. AB - Influenza A viruses (IAVs) are viral pathogens that cause epidemics and occasional pandemics of significant mortality. The generation of efficacious vaccines and antiviral drugs remains a challenge due to the rapid appearance of new influenza types and antigenic variants. Consequently, novel strategies for the prevention and treatment of IAV infections are needed given the limitations of the presently available antivirals. Here, we used enzymatically produced IAV specific double-stranded RNA (dsRNA) molecules and Giardia intestinalis Dicer for the generation of a swarm of small interfering RNA (siRNA) molecules. The siRNAs target multiple conserved genomic regions of the IAVs. In mammalian cells, the produced 25-27 nucleotide long siRNA molecules are processed by endogenous Dicer into 21-nucleotide siRNAs and are thus designated as Dicer-substrate siRNAs (DsiRNAs). We evaluated the efficacy of the above DsiRNA swarm at preventing IAV infections in human primary monocyte-derived macrophages and dendritic cells. The replication of different IAV strains, including avian influenza H5N1 and H7N9 viruses, was significantly inhibited by pre-transfection of the cells with the IAV-specific DsiRNA swarm. Up to 7 orders of magnitude inhibition of viral RNA expression was observed, which led to a dramatic inhibition of IAV protein synthesis and virus production. The IAV-specific DsiRNA swarm inhibited virus replication directly through the RNA interference pathway although a weak induction of innate interferon responses was detected. Our results provide direct evidence for the feasibility of the siRNA strategy and the potency of DsiRNA swarms in the prevention and treatment of influenza, including the highly pathogenic avian influenza viruses.IMPORTANCE In spite of the enormous amount of research, influenza virus is still one of the major challenges for medical virology due to its capacity to generate new variants, which potentially lead to severe epidemics and pandemics. We demonstrated here that a swarm of small interfering RNA (siRNA) molecules, including more than one hundred different antiviral RNA molecules targeting the most conserved regions of influenza A virus genome, could efficiently inhibit the replication of all tested avian and seasonal influenza A variants in human primary monocyte-derived macrophages and dendritic cells. The wide antiviral spectrum makes the virus-specific siRNA swarm a potentially efficient treatment modality against both avian and seasonal influenza viruses. PMID- 30463971 TI - RNA helicase A is an important host factor involved in dengue virus replication. AB - Dengue virus (DENV) utilizes host factors throughout its life cycle. In this study, we identified RNA helicase A (RHA), a member of the DEAD/H helicase family, as an important host factor of DENV. In response to DENV2 infection, nuclear RHA protein was partially redistributed into the cytoplasm. The siRNA mediated knockdown of RHA significantly the amounts of infectious viral particles in various cells. The RHA knockdown reduced the multi-step viral growth of DENV2 and Japanese encephalitis virus, but not Zika virus. Further study showed that the absence of RHA resulted in a reduction of both viral RNA and protein levels, and the data obtained from the reporter replicon assay indicated that RHA does not directly promote viral protein synthesis. RHA binds to the DENV RNA, and associates with three nonstructural proteins including NS1, NS2B3, and NS4B. Further study showed that different domains of RHA mediate its interaction with these viral proteins. The expression of RHA or RHA-K417R mutant protein lacking ATPase/helicase activity in RHA-knockdown cells successfully restored DENV2 replication levels, suggesting that the helicase activity of RHA is dispensable for its proviral effect. Overall, our work reveals that RHA is an important factor of DENV and might serve as a target for antiviral agents.IMPORTANCE Dengue, caused by dengue virus, is the most rapidly spreading disease, and currently there are no treatments available. Host factors involved in the viral replication of dengue virus are potential antiviral therapeutic targets. Although RHA has been shown to promote the multiplication of several viruses such as HIV and adenovirus, its role in the flavivirus family, including dengue virus, Japanese encephalitis virus, and emerging Zika virus remains elusive. The current study revealed that RHA relocalized into the cytoplasm upon DENV infection, and associated with viral RNA and nonstructural proteins, implying that RHA was actively engaged in the viral life cycle. We further provide evidence that RHA promoted the viral yields of DENV2 independent of its helicase activity. These findings demonstrated that RHA is a new host factor required for DENV replication and might serve as a target for antiviral drugs. PMID- 30463972 TI - A novel type of influenza A virus-derived defective interfering particle with nucleotide substitutions in its genome. AB - Defective interfering particles (DIPs) replicate at the expense of co-infecting, fully infectious homologous virus. Typically, they contain a highly deleted form of the viral genome. Utilizing single-cell analysis, we here report the discovery of a yet unknown DIP type, derived from influenza A viruses (IAV), termed OP7 virus. Instead of deletions, the genomic viral RNA (vRNA) of segment 7 (S7) carried 37 point mutations compared to the reference sequence, affecting promotor regions, encoded proteins and genome packaging signals. Co-infection experiments demonstrated strong interference of OP7 virus with IAV replication, manifested by a dramatic decrease in infectivity of released virions. Moreover, an over proportional quantity of S7 in relation to other genome segments was observed, both intracellularly and in the released virus population. Concurrently, OP7 virions lacked a large fraction of other vRNA segments, which appears to constitute its defect in virus replication. OP7 virus might serve as a promising candidate for antiviral therapy. Furthermore, this novel form of DIP may also be present in other IAV preparations.IMPORTANCE Defective-interfering particles (DIPs) typically contain a highly deleted form of the viral genome, rendering them defective in virus replication. Yet, upon complementation through co infection with fully infectious standard virus (STV), interference with the viral life cycle can be observed, leading to a suppressed STV replication and the release of mainly non-infectious DIPs. Interestingly, recent research indicates that DIPs may serve as an antiviral agent. We here report the discovery of a yet unknown type of influenza A virus-derived DIP (termed "OP7" virus) that contains numerous point mutations instead of large deletions in its genome. Furthermore, the underlying principles that render OP7 virions interfering and apparently defective seem to differ from conventional DIPs. In conclusion, we believe that OP7 virus might be a promising candidate for antiviral therapy. Moreover, it exerts strong effects, both on virus replication and on host cell response, and may have been overlooked in other IAV preparations. PMID- 30463973 TI - The dengue virus non-structural protein 1 (NS1) is secreted from mosquito cells in association with the intracellular cholesterol transporter chaperone caveolin complex. AB - Dengue virus (DENV) is a mosquito-borne virus of the family Flaviviridae The RNA viral genome encodes three structural and seven non-structural proteins. The non structural protein 1 (NS1) is a multifunctional protein actively secreted in vertebrate and mosquito cells during infection. In mosquito cells, NS1 is secreted in a caveolin-1 dependent manner by an unconventional route. The caveolin chaperone complex (CCC) is a cytoplasmic complex formed by caveolin-1 and the chaperones FKBP52, Cy40 and CyA responsible for the cholesterol traffic inside the cell. In this work, we demonstrate that in mosquito cells, but not in vertebrate cells, NS1 associates and relies on the CCC for secretion. Treatment of mosquito cells with classic secretion inhibitors such as brefeldin A, golgicide A and Fli-06 showed no effect on NS1 secretion, but significant reductions in recombinant luciferase secretion and virion release. Silencing the expression of CAV1, FKBP52 with siRNAs or the inhibition of CyA by cyclosporine A resulted in significant decrease in NS1 secretion, again without affecting virion release. Co-localization, co-inmunoprecipitation and proximity ligation assays, indicated that NS1 co-localizes and interacts with all the proteins of the CCC. In addition, CAV-1 and FKBP52 expression was found augmented in DENV infected cells. Results obtained with zika virus infected cells suggest that in mosquito cells, ZIKV NS1 also follows the same secretory pathway observed for DENV NS1. These results uncover important differences in the dengue virus-cell interactions between the vertebrate host and the mosquito vector, as well as novel functions for the chaperone caveolin complex.IMPORTANCE The dengue virus protein NS1 is secreted efficiently from both infected vertebrate and mosquito cells. Previously, our group reported that NS1 secretion in mosquito cells follows an unconventional secretion pathway dependent on Caveolin-1. In this work, we demonstrate that in mosquito cells, but not in vertebrate cells, NS1 secretion takes place in association with the chaperone caveolin complex, a complex formed by caveolin-1 and the chaperones FKBP52, CyA and Cy40, in charge of cholesterol transport inside the cell. Results obtained with ZIKV infected mosquito cells suggest that also ZIKV NS1 is released following an unconventional secretory route in association with the chaperone caveolin complex. These results uncover important differences in the virus-cell interactions between the vertebrate host and the mosquito vector, as well as novel functions for the chaperone caveolin complex. Moreover, manipulation of the NS1 secretory route may prove a valuable strategy to combat these two mosquito borne diseases. PMID- 30463974 TI - 2.8 A resolution cryo-EM structure of human parechovirus 3 in complex with Fab from a neutralizing antibody. AB - Human parechovirus 3 (HPeV3) infection is associated with sepsis in neonates characterized by significant immune activation and subsequent tissue damage. Strategies to limit infection have been unsuccessful due to inadequate molecular diagnostic tools for early detection and lack of a vaccine or specific antiviral therapy. Towards the latter, we present a 2.8 A-resolution structure of HPeV3 in complex with fragments from a neutralizing human monoclonal antibody AT12-015 using cryo-EM and image reconstruction. Modeling revealed that the epitope extends across neighboring asymmetric units with contributions from capsid proteins VP0, VP1, and VP3. Antibody decoration was found to block binding of HPeV3 to cultured cells. Additionally at high-resolution, it was possible to model a stretch of RNA inside the virion and from this identify the key features that drive and stabilize protein-RNA association during assembly.IMPORTANCE HPeV3 is receiving increasing attention as a prevalent cause of sepsis-like symptoms in neonates, which despite the severity of disease, there are no effective treatments available. Structural and molecular insights into virus neutralization are urgently needed, especially as clinical cases are on the rise. Towards this goal, we present the first structure of HPeV3 in complex with fragments from a neutralizing monoclonal antibody. At high-resolution it was possible to precisely define the epitope that when targeted, prevents virions from binding to cells. Such an atomic-level description is useful for understanding host-pathogen interaction, viral pathogenesis mechanisms, and for finding potential cures for infection and disease. PMID- 30463975 TI - A Nanobody Targeting Viral Non-Structural Protein 9 Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication. AB - Porcine Reproductive and Respiratory Syndrome (PRRS) is a great concern to the swine industry due to the pandemic outbreak of the disease, current ineffective vaccinations, and lack of efficient antiviral strategies. In our previous study, a PRRSV Nsp9-specific nanobody Nb6 was successfully isolated and the intracellularly expressed Nb6 could dramatically inhibit PRRSV replication in MARC-145 cells. However, despite its small size, the application of Nb6 protein in infected cells is greatly limited as the protein itself cannot enter the cells physically. In this study, a trans-activating transduction (TAT) peptide was fused with Nb6 to promote the protein entry into cells. TAT-Nb6 was expressed as an inclusion body in E.coli, and indirect ELISA and pulldown assays showed that E.coli-expressed TAT-Nb6 maintained the binding ability to E.coli-expressed or PRRSV-encoded Nsp9. We demonstrated that TAT delivered Nb6 into MARC-145 cells and PAMs in a dose-and time-dependent manner and TAT-Nb6 efficiently inhibited the replication of several PRRSV genotype 2 strains as well as a genotype 1 strain. Using a yeast two-hybrid assay, Nb6 recognition sites were identified in the C-terminal part of Nsp9 which spanned two discontinuous regions (Nsp9aa454 551 and Nsp9aa599-646). Taken together, these results suggest that TAT-Nb6 could be developed as a potential antiviral drug for the inhibition of PRRSV replication and controlling the PRRS disease.IMPORTANCE The pandemic outbreak of PRRS, which is caused by PRRSV, has greatly affected the swine industry. We still lack efficient vaccination and immense challenge to control its infection. An intracellularly expressed Nsp9-specific nanobody Nb6 has been shown to be able to inhibit PRRSV replication in MARC-145 cells. However, its application is limited because Nb6 cannot physically enter cells. Herein, we demonstrated that cell penetrating peptide TAT could deliver Nb6 into cultured cells. In addition, TAT Nb6 fusion protein could suppress the replication of various PRRSV strains in MARC-145 cells and PAMs. These findings may provide a new approach for the drug development to control PRRS. PMID- 30463976 TI - A human gain-of-function STING mutation causes immunodeficiency and gammaherpesvirus-induced pulmonary fibrosis in mice. AB - We previously generated STING N153S knockin mice that have a human disease associated gain-of-function mutation in STING. Patients with this mutation (STING N154S in human) develop STING-associated vasculopathy with onset in infancy (SAVI), a severe pediatric autoinflammatory disease characterized by pulmonary fibrosis. Since this mutation promotes up-regulation of antiviral type I interferon-stimulated genes (ISGs), we hypothesized that STING N153S knockin mice may develop more severe autoinflammatory disease in response to a virus challenge. To test this hypothesis, we infected heterozygous STING N153S mice with murine gammaherpesvirus 68 (gammaHV68). STING N153S mice were highly vulnerable to infection and developed pulmonary fibrosis after infection. In addition to impairing CD8+ T cell responses and humoral immunity, STING N153S also promoted replication of gammaHV68 in cultured macrophages. In further support of a combined innate and adaptive immunodeficiency, gammaHV68 infection was more severe in Rag1-/- STING N153S mice than in Rag1-/- littermate mice, which completely lack adaptive immunity. Thus, a gain-of-function STING mutation creates a combined innate and adaptive immunodeficiency that leads to virus induced pulmonary fibrosis.IMPORTANCE A variety of human rheumatologic disease causing mutations have recently been identified. Some of these mutations are found in viral nucleic acid-sensing proteins, but whether viruses can influence the onset or progression of these human diseases is less well understood. One such autoinflammatory disease called STING-associated vasculopathy with onset in infancy (SAVI) affects children and leads to severe lung disease. We generated mice with a SAVI-associated STING mutation and infected them with gammaHV68, a common DNA virus that is related to human Epstein-Barr virus. Mice with the human disease-causing STING mutation were more vulnerable to infection than wild-type littermate control animals. Furthermore, the STING mutant mice developed lung fibrosis similar to patients with SAVI. These findings reveal that a human STING mutation creates severe immunodeficiency, leading to virus-induced lung disease in mice. PMID- 30463977 TI - Oncogenic KSHV Upregulates Argininosuccinate Synthase 1, a Rate-Limiting Enzyme of the Citrulline-Nitric Oxide Cycle, to Activate the STAT3 Pathway and Promote Growth Transformation. AB - Cancer cells are required to rewire existing metabolic pathways to support their abnormal proliferation. We have previously shown that, unlike glucose-addicted cancers, Kaposi's sarcoma-associated herpesvirus (KSHV)-transformed cells depend on glutamine rather than glucose for energy production, and amino acid and nucleotide syntheses. High-level consumption of glutamine is tightly regulated and often coupled with the citrulline-nitric oxide (NO) cycle. We have found that KSHV infection accelerates the nitrogen efflux by upregulating the expression of argininosuccinate synthase 1 (ASS1), a key enzyme in the citrulline-NO cycle. KSHV utilizes multiple microRNAs to upregulate ASS1 expression. Depletion of either ASS1 or inducible nitric oxide synthase (iNOS) in KSHV-transformed cells suppresses growth proliferation, abolishes colony formation in soft agar, and decreases NO generation. Furthermore, by maintaining intracellular NO level, ASS1 expression facilitates KSHV-mediated activation of the STAT3 pathway, which is critical for virus-induced transformation. These results illustrate a novel mechanism by which an oncogenic virus hijacks a key metabolic pathway to promote growth transformation and reveal a potential novel therapeutic target for KSHV induced malignancies.IMPORTANCE We have previously shown that Kaposi's sarcoma associated herpesvirus (KSHV)-transformed cells depend on glutamine rather than glucose for energy production, and amino acid and nucleotide syntheses. In this study, we have further examined how the KSHV-reprogramed metabolic pathways are regulated and discovered that KSHV hijacks the citrulline-nitric oxide (NO) cycle to promote growth proliferation and transformation. Multiple KSHV-encoded microRNAs upregulate argininosuccinate synthase 1 (ASS1), a key enzyme in the citrulline-NO cycle. ASS1 is required for KSHV-induced proliferation, colony formation in soft agar, and NO generation of KSHV-transformed cells, which also depends on inducible nitric oxide synthase. By maintaining intracellular NO level, ASS1 mediates KSHV activation of the STAT3 pathway, which is essential for KSHV-induced abnormal cell proliferation and transformation. These results illustrate a novel mechanism by which an oncogenic virus hijacks a key metabolic pathway to promote growth transformation and reveal a potential novel therapeutic target for KSHV-induced malignancies. PMID- 30463978 TI - Early T follicular helper cell responses and germinal center reactions are associated with viremia control in immunized Rhesus macaques. AB - T follicular helper (TFH) cells are fundamental in germinal center (GC) maturation and selection of antigen-specific B cells within secondary lymphoid organs. GC-resident TFH cells have been fully characterized in human HIV infection. However, the role of GC TFH cells in GC B cell responses following various SIV vaccine regimens in Rhesus macaques (RMs) has not been fully investigated. We characterized GC TFH cells of RMs over the course of a mucosal/systemic vaccination regimen to elucidate GC formation and SIV humoral response generation. Animals were mucosally primed twice with replicating Ad5hr SIV recombinants and systemically boosted with ALVAC/Env or DNA&Env including SIV gp120 proteins. Lymph nodes were biopsied in macaque subgroups pre-vaccination and at days 3, 7, or 14 after the 2nd Ad5hr-SIV prime and the 2nd vector/Env boost. Evaluations of GC TFH and GC B cell dynamics including correlation analyses supported a significant role of early GC TFH cells in providing B cell help during initial phases of GC formation. GC TFH responses at day 3 post mucosal priming were consistent with generation of Env-specific memory B cells in GCs and elicitation of prolonged Env-specific humoral immunity in the rectal mucosa. GC Env-specific memory B cell responses elicited early post-systemic boosting correlated significantly with decreased viremia post-infection. Our results highlight the importance of early GC TFH cell responses for robust GC maturation and generation of long-lasting SIV specific humoral responses at mucosal and systemic sites. Further investigation of GC TFH cell dynamics should facilitate development of an efficacious HIV vaccine.IMPORTANCE The modest HIV protection observed in the human RV144 vaccine trial associated antibody responses with vaccine efficacy. T follicular helper (TFH) cells are CD4+ T cells that select antibody secreting cells with high antigenic affinity in germinal centers (GCs) within secondary lymphoid organs. To evaluate the role of TFH cells in eliciting prolonged viral-specific humoral responses, we vaccinated Rhesus macaques with a combined mucosal prime/systemic boost regimen followed by repeated low-dose intrarectal challenges with SIV mimicking human exposure to HIV 1. Although the vaccine regimen did not prevent SIV infection, decreased viremia was observed in the immunized macaques. Importantly, vaccine-induced TFH responses elicited at day 3 post-immunization and robust GC maturation were strongly associated. Further, early TFH-dependent SIV-specific B cell responses were also correlated with decreased viremia. Our findings highlight the contribution of early vaccine-induced GC TFH responses to elicitation of SIV specific humoral immunity and implicate their participation in SIV control. PMID- 30463979 TI - Capture of a hyena-specific retroviral envelope gene with placental expression associated in evolution with the unique emergence among carnivorans of hemochorial placentation in Hyaenidae. AB - Capture of retroviral envelope genes from endogenous retroviruses has played a role in the evolution of mammals, with evidence for the involvement of these genes in the formation of the materno-fetal interface of the placenta. It has been shown that the diversity of captured genes is likely to be responsible for the diversity of placental structures, ranging from poorly invasive (epitheliochorial) to highly invasive (hemochorial) with an intermediate state (endotheliochorial) as found in carnivorans. The latter recapitulate part of this evolution, with the hyena being the sole carnivoran with a hemochorial placenta. Here we performed RNAsequencing on hyena placental transcripts and searched for endogenous retroviral envelope genes that have been captured specifically in the Hyaenidae clade and are not found in any other carnivoran. We identified an envelope gene that is expressed in the placenta at the level of the materno-fetal interface, as evidenced by in situ hybridization/immunohistochemistry. The gene entry is coincidental with the emergence of the Hyaenidae clade 30 Mya, being found at the same genomic locus in all 4 extant hyena species. Its coding sequence has further been maintained during all of Hyaenidae evolution. It is not found in any of the 30 other carnivorans -both Felidae and Canidae- that we screened. This envelope protein does not disclose any fusogenic activity in ex vivo assays, at variance with the Syncytin-Car1 gene that is found in all carnivorans -including hyena where it is still present, transcriptionally active in the placenta, and fusogenic. Altogether, the present results illustrate the permanent renewal of placenta-specific genes by retroviral captures, and de facto provide a candidate gene for the endotheliochorial to hemochorial transition of Hyaenidae among carnivorans.IMPORTANCE The placenta is the most diverse organ among mammals, due in part to stochastic capture of retroviral envelope genes. In carnivorans, capture of Syncytin-Car1 took place 80 Mya. It is fusogenic, expressed at the syncytialized placental materno-fetal interface and conserved among all carnivorans, consistent with their shared "endotheliochorial" placenta. Hyenas are a remarkable exception, with a highly invasive "hemochorial" placenta, as found in humans, where disruption of maternal blood vessels results in maternal blood bathing the syncytial materno-fetal interface. Here we identified a retroviral envelope gene capture and exaptation that took place about 30 Mya and is coincident with the emergence of the Hyaenidae, being conserved in all extant hyena species. It is expressed at the materno-fetal interface in addition to the shared syncytin-Car1 gene. This new env gene, not present in any other carnivoran, is a likely candidate to be responsible for the specific structure of the hyena placenta. PMID- 30463980 TI - The host DHX9 DExH Box helicase is recruited to Chikungunya virus replication complexes for optimal genomic RNA translation. AB - Beyond their role in cellular RNA metabolism, DExD/H-box RNA helicases are hijacked by various RNA viruses in order to assist replication of the viral genome. Here, we identify the DExH-box RNA helicase 9 (DHX9) as a binding partner of Chikungunya virus (CHIKV) nsP3 mainly interacting with the C-terminal hypervariable domain. We show that during early CHIKV infection, DHX9 is recruited to the plasma membrane where it associates to replication complexes. At later stage of infection, DHX9 is however degraded through a proteasome-dependent mechanism. Using silencing experiments we demonstrate that while DHX9 negatively controls viral RNA synthesis, it is also required for optimal nsPs translation. Altogether this study identifies DHX9 as a novel cofactor for CHIKV replication in human cells that differently regulates the various steps of CHIKV life cycle and may therefore mediate a switch in RNA usage from translation to replication during the earliest steps of CHIKV replication.IMPORTANCE The re-emergence of chikungunya virus (CHIKV), an alphavirus that is transmitted to humans by Aedes mosquitoes, is a serious global health threat. In absence of effective antiviral drugs CHIKV infection has a significant impact on human health with chronic arthritis being one of the most serious complications. The molecular understanding of host-virus interactions is a prerequisite to the development of targeted therapeutics capable to interrupt viral replication and transmission. Here, we identify the host cell DHX9 DExH-Box helicase as an essential cofactor for early CHIKV genome translation. We demonstrate that CHIKV nsP3 protein acts as a key factor for DHX9 recruitment to replication complexes. We finally establish that DHX9 behaves as a switch that regulates the progression of the viral cycle from translation to genome replication. This study might therefore have a significant impact for the development of antiviral strategies. PMID- 30463981 TI - Increased frequency of virus shedding by herpes simplex virus type 2-infected guinea pigs in the absence of CD4+ T lymphocytes. AB - Reactivation of HSV-2 results in infection of epithelial cells at the neuro epithelial junction and shedding of virus at the epithelial surface. Virus shedding can occur in either the presence or absence of clinical disease and is usually of short duration although the shedding frequency varies among individuals. The basis for host control of virus shedding is not well understood although adaptive immune mechanisms are thought to play a central role. To determine the importance of CD4+ T cells in control of HSV-2 shedding, this subset of immune cells was depleted from HSV-2-infected guinea pigs by injection of an anti-CD4 monoclonal antibody (mAb). Guinea pigs were treated with the depleting mAb after establishment of a latent infection and vaginal swabs were taken daily to monitor shedding by qPCR. The cumulative number of HSV-2 shedding days and the mean number of days virus was shed was significantly increased in CD4-depleted compared to control-treated animals. However, there was no difference in the incidence of recurrent disease between the two treatment groups. Serum antibody levels and the number of HSV-specific antibody secreting cells in secondary lymphoid tissues were unaffected by depletion of CD4+ T cells, however, the frequency of functional HSV-specific, CD8+ IFNgamma secreting cells was significantly decreased. Together, these results demonstrate an important role for CD4+ T lymphocytes in control of virus shedding that may be mediated in part by maintenance of HSV-specific CD8+ T cell populations. These results have important implications for development of therapeutic vaccines designed to control HSV-2 shedding.IMPORTANCE Sexual transmission of HSV-2 results from viral shedding following reactivation from latency. The immune cell populations and mechanisms that control HSV-2 shedding are not well understood. This study examined the role of CD4+ T cells in control of virus shedding using a guinea pig model of genital HSV-2 infection that recapitulates the shedding of virus experienced by humans. We found that the frequency of virus shedding episodes, but not the incidence of clinical disease was increased by depletion of CD4+ T cells. The HSV-specific antibody response was not diminished, but frequency of functional HSV-reactive CD8+ Tells was significantly diminished by CD4-depletion. These results confirm the role of cell-mediated immunity and highlight the importance of CD4+ T cells in controlling HSV shedding suggesting that therapeutic vaccines designed to reduce transmission by controlling HSV shedding should most likely include specific enhancement of HSV-specific CD4+ T cell responses. PMID- 30463982 TI - Taking the 'Disease' out of 'Parkinson's': has the disease had its day? PMID- 30463983 TI - A pain to the patient and to the doctor. PMID- 30463984 TI - Exposure to acid-suppressing medications in the first 6 months of life is associated with an increased risk of allergic disease diagnosis. PMID- 30463985 TI - Protein and lipid fingerprinting of native-like membrane complexes by combining thin layer chromatography and protein electrophoresis: the example of lung surfactant. AB - Traditionally, thin layer chromatography (TLC) has been used for the analysis of lipids isolated from membrane complexes. Here, we describe a method based on the combination of TLC and SDS-polyacrylamide gel electrophoresis (SDS-PAGE) for the qualitative analysis of the protein/lipid profile of membrane complexes such as those of lung surfactant. For this purpose, native lung surfactant was applied onto a silica TLC plate in the form of an aqueous suspension, preserving not only hydrophilic proteins associated to lipids, but also native protein-lipid interactions. Using native membrane complexes in a TLC allows the differential migration of lipids and their separation from the protein components. As a result, (partly) delipidated protein-enriched bands can be visualized and analysed by SDS-PAGE to identify proteins originally associated with lipids. Interestingly, the hydrophobic surfactant protein SP-C, which interact tightly with lipids in native membrane complexes, migrate through the TLC plate configuring specific bands that differ from those corresponding to lipids or proteins. This method therefore allows the detection and analysis of strong native-like protein-lipid interactions. PMID- 30463986 TI - Brain oxylipin concentrations following hypercapnia / ischemia: effects of brain dissection and dissection time. AB - PUFAs are precursors to bioactive oxylipin metabolites that increase in the brain following CO2-induced hypercapnia-ischemia. It is not known whether the brain dissection process and its duration also alters these metabolites. We applied 2 minutes of CO2 with or without head-focused microwave fixation to evaluate the effects of CO2 asphyxiation, dissection and dissection time on brain oxylipin concentrations. Compared to microwave irradiation, CO2 followed by microwave fixation prior to dissection increased oxylipins derived from lipoxygenase (LOX), 15-hydroxyprostaglandin-dehydrogenase (15-PGDH), cytochrome (CYP) P450 and soluble epoxide hydrolase (sEH) pathways. This effect was enhanced when the duration of post-mortem ischemia was prolonged by 6.4 minutes prior to microwave fixation. Brains dissected from rats subjected to CO2 without microwave fixation showed greater increases in LOX, 15-PGDH, CYP and sEH metabolites compared to all other groups, as well as increased cyclooxygenase (COX) metabolites. In non microwave irradiated brains, sEH metabolites and one CYP metabolite correlated positively and negatively with dissection time, respectively. This study presents new evidence that the dissection process and duration enhance brain oxylipin concentrations, and this is preventable by microwave fixation. When microwave fixation is not available, lipidomic studies should account for dissection time to reduce these artifacts. PMID- 30463987 TI - Cell-associated, Heparin-like Molecules Modulate the Ability of LDL to Regulate PCSK9 Uptake. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) targets the LDL receptor (LDLR) for degradation, increasing plasma LDL and, consequently, cardiovascular risk. Uptake of secreted PCSK9 is required for its effect on the LDLR, and LDL itself inhibits this uptake, though how it does so remains unclear. In this study, we investigated the relationship between LDL, the PCSK9:LDLR interaction, and PCSK9 uptake. We show that LDL inhibits binding of PCSK9 to the LDLR in vitro more impressively than it inhibits PCSK9 uptake in cells. Furthermore, cell surface, heparin-like molecules (HLMs) can partly explain this difference, consistent with heparan sulfate proteoglycans (HSPGs) acting as co-receptors for PCSK9. We also show that HLMs can interact with either PCSK9 or LDL to modulate the inhibitory activity of LDL on PCSK9 uptake, with such inhibition rescued by competition with the entire PCSK9 prodomain, but not its truncated variants. Additionally, we show that the gain-of-function (GOF) PCSK9 variant S127R, located in the prodomain near the HSPG binding site, exhibits increased affinity for HLMs, potentially explaining its phenotype. Overall, our findings suggest a model where LDL acts as a negative regulator of PCSK9 function by decreasing its uptake via direct interactions with either the LDLR or HLMs. PMID- 30463988 TI - Lysophospholipid G protein-coupled receptor binding parameters as determined by backscattering interferometry (BSI). AB - Lysophosphatidic acid (LPA) activates cognate G protein-coupled receptors (GPCRs) to initiate biological signaling cascades. Lysophospholipid (LP) receptors binding properties remain incompletely assessed because of difficulties with ligand lipophilicity and lipid stickiness. These inherent attributes produce high levels of non-specific binding within cell membrane preparations used to assess GPCRs, as was shown in classical binding assays using radioactivity. Backscattering interferometry (BSI) is an optical technology that measures molecular binding interactions by reporting changes in the refractive index of a solution after binding events. Here we report the use of BSI to assess LPA1 for its ability to bind to naturally occurring lipids and a synthetic LPA1 antagonist (ONO-9780307), under both primary- and competition-binding conditions. Assessment of 12 different lipids identified the known LP ligand, 1-oleoyl-LPA, as well as an endocannabinoid metabolite, anandamide phosphate, as specific ligands for LPA1, without specific binding by other LPs. Newly determined dissociation constants (Kds) for orthosteric lipid ligands approximated 10-9 M, which has a substantially lower value (i.e., with higher affinity) than classical binding or cell-based assays. BSI may have particular utility in assessing binding interactions between lipid receptors and their lipid ligands and could provide new screening approaches for lipid receptor identification and drug discovery. PMID- 30463989 TI - Evaluation of the associations between cervical microbiota and HPV infection, clearance, and persistence in cytologically normal women. AB - The aim of this study was to investigate the associations between cervical microbiota and different HPV (Human Papillomavirus) infection statuses in cytologically normal women. The cervical microbiota of HPV-positive or -negative women with a normal cytologic diagnosis was characterized and compared using 16S rDNA-based high-throughput sequencing, and the differences in cervical microbiota associated with new acquisition, persistence, and clearances of HPV genotypes were analyzed via one-year follow-up. The results showed that the cervical microbial richness of HPV-positive women was lower than for HPV-negative women, and the difference was more significant in the post-menopausal group relative to the pre-menopausal group. Ureaplasma parvum and related taxa were associated with baseline HPV positivity, while Brochothrix, Diplorickettsia, Ezakiella, Faecalibacterium, and Fusobacterium genera and their related taxa and Pseudomonas aeruginosa were associated with baseline HPV negativity. For HPV-positive women, the baseline abundance of Actinomyces was negatively associated with new HPV infection, Alloprevotella tannerae, Prevotella nigrescens, and Prevotella oulorum; and Dialister invisus was positively associated with new HPV type infection within the year of follow-up. Lactobacillus delbrueckii was found to be negatively associated with persistent HPV infection and nine taxa belonging to Prevotella, Dialister, and Lachnospiraceae were found to be positively associated with persistence, and/or negatively associated with clearance of HPV types. We also observed 10 novel taxa associated with the clearance/persistence of HPV that had not been reported elsewhere. Those taxa associated with different infection statuses of HPV could be used as a biomarker to help predict the risk of developing persistent HPV infection. PMID- 30463990 TI - Interaction between susceptibility loci in MAVS and TRAF3 genes, and high-risk HPV infection on the risk of cervical precancerous lesions in Chinese population. AB - Persistent high-risk HPV infection is considered as a major cause of cervical cancer. Nevertheless, only some infected individuals actually develop cervical cancer. The RIG-I pathway in innate immunity plays an important role in antivirus response. Here, we hypothesized that altered function of mitochondrial antiviral signaling protein (MAVS) and mitochondrial TNF receptor-associated factor 3(TRAF3), key molecules downstream of the viral sensors RIG-I, may impair their ability of clearing HPV and thereby influence the risk for cervical precancerous lesions. To investigate the effects of MAVS and TRAF3 polymorphisms on susceptibility to cervical precancerous lesions, 8 SNPs were analyzed in 164 cervical precancerous lesion cases and 428 controls. Gene-environment interactions were also calculated. We found that CA genotype of rs6052130 in MAVS gene were at 1.48 times higher risk of developing cervical precancerous lesion than individuals with CC genotype (CA vs CC: ORadjusted=1.48, 95%CI=1.02-2.16). Additionally, a significant synergetic interaction between high-risk HPV infection and rs6052130 was found on an additive scale. A significantly decreased risk of cervical precancerous lesions for the TC genotype of rs12435483 in the TRAF3 gene (ORadjusted=0.67, 95%CI=0.45-0.98) was also found. Moreover, MDR analysis identified a significant three-locus interaction model, involving high risk HPV infection, TRAF3 rs12435483 and number of full-term pregnancies. Our results indicate that the MAVS rs6052130 and TRAF3 rs12435483 confer genetic susceptibility to cervical precancerous lesions. Moreover, MAVS rs6052130-mutant individuals have an increased vulnerability to high-risk HPV-induced cervical precancerous lesions. PMID- 30463991 TI - Activation of AXL as a preclinical acquired resistance mechanism against osimertinib treatment in EGFR-mutant non-small cell lung cancer cells. AB - Osimertinib (AZD9291) has an efficacy superior to that of standard EGFR-tyrosine kinase inhibitors for the first-line treatment of EGFR-mutant advanced non-small cell lung cancer (NSCLC) patients. However, patients treated with osimertinib eventually acquire drug resistance, and novel therapeutic strategies to overcome acquired resistance are needed. In clinical or preclinical models, several mechanisms of acquired resistance to osimertinib have been elucidated. However, the acquired resistance mechanisms when osimertinib is initially used for EGFR mutant NSCLC remain unclear. In this study, we experimentally established acquired osimertinib-resistance cell lines from EGFR-mutant NSCLC cell lines and investigated the molecular profiles of resistant cells to uncover the mechanisms of acquired resistance. Various resistance mechanisms were identified, including the acquisition of MET amplification, EMT induction, and the upregulation of AXL. Using targeted next-generation sequencing with a multi-gene panel, no secondary mutations were detected in our resistant cell lines. Among three MET-amplified cell lines, one cell line was sensitive to a combination of osimertinib and crizotinib. Acquired resistance cell lines derived from H1975 harboring the T790M mutation showed AXL upregulation, and the cell growth of these cell lines was suppressed by a combination of osimertinib and cabozantinib, an inhibitor of multiple tyrosine kinases including AXL, both in vitro and in vivo. Our results suggest that AXL might be a therapeutic target for overcoming acquired resistance to osimertinib. Implications: Upregulation of AXL is one of the mechanisms of acquired resistance to osimertinib, and combination of osimertinib and cabozantinib might be a key treatment for overcoming osimertinib resistance. PMID- 30463992 TI - Hepatozoon canis in three imported dogs: a new tickborne disease reaching the United Kingdom. AB - An increasing number of non-endemic vectorborne pathogens have been described in dogs imported to the UK in the past two decades. Recently, an outbreak of canine babesiosis in south-east England has raised veterinary awareness with regard to the impact of such diseases on the UK canine population. Canine hepatozoonosis, caused by Hepatozoon canis and transmitted by the ingestion of Rhipicephalus sanguineus ticks, is widespread in the Mediterranean basin. Herein we describe the first three molecularly confirmed clinical cases of canine hepatozoonosis in dogs imported into the UK. Veterinarians in the UK should be aware of H canis as a potential infection in imported dogs, especially in the face of the expanding distribution of R sanguineus ticks in Europe. PMID- 30463993 TI - Drug-drug interactions in an era of multiple anticoagulants: a focus on clinically relevant drug interactions. AB - Oral anticoagulants are commonly prescribed but high risk to cause adverse events. Skilled drug interaction management is essential to ensure safe and effective use of these therapies. Clinically relevant interactions with warfarin include drugs that modify cytochrome 2C9, 3A4, or both. Drugs that modify p glycoprotein may interact with all direct oral anticoagulants, and modifiers of cytochrome 3A4 may interact with rivaroxaban and apixaban. Antiplatelet agents, nonsteroidal anti-inflammatory drugs, and serotonergic agents, such as selective serotonin reuptake inhibitors, can increase risk of bleeding when combined with any oral anticoagulant, and concomitant use should be routinely assessed. New data on anticoagulant drug interactions are available almost daily, and therefore, it is vital that clinicians regularly search interaction databases and the literature for updated management strategies. Skilled drug interaction management will improve outcomes and prevent adverse events in patients taking oral anticoagulants. PMID- 30463994 TI - Anticoagulating patients with high-risk acquired thrombophilias. AB - Antiphospholipid syndrome (APS), heparin-induced thrombocytopenia, and paroxysmal nocturnal hemoglobinuria are 3 acquired thrombophilias that carry a high risk of venous and arterial thromboembolism. Management of these conditions has largely included anticoagulation with a vitamin K antagonist after an initial period of a parenteral anticoagulant, for as long as the thrombotic risk is still present. The available evidence for the use of direct oral anticoagulants (DOACs) is limited and primarily consists of case series and cohort studies, which are summarized in this chapter. Randomized trials evaluating DOACs in patients with APS are reviewed. Further research is needed prior to widely adopting DOACs for use in these high-risk acquired thrombophilias; however, there may be selected low-risk subgroups where DOAC use is possible after careful consideration and patient discussion. PMID- 30463995 TI - GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. AB - Chimeric antigen receptor T (CAR-T) cell therapy is a new pillar in cancer therapeutics; however, its application is limited by the associated toxicities. These include cytokine release syndrome (CRS) and neurotoxicity. While the IL-6R antagonist tocilizumab is approved for treatment of CRS, there is no approved treatment of neurotoxicity associated with CD19 targeted CAR-T (CART19) cell therapy. Recent data suggest that monocytes and macrophages contribute to the development of CRS and neurotoxicity after CAR-T cell therapy. Therefore, we investigated neutralizing granulocyte macrophage colony-stimulating factor (GM CSF) as a potential strategy to manage CART19 cell associated toxicities. In this study, we show that GM-CSF neutralization with lenzilumab does not inhibit CART19 function in vitro or in vivo. Moreover, CART19 cell proliferation was enhanced and durable control of leukemic disease was maintained better in patient derived xenografts after GM-CSF neutralization with lenzilumab. In a primary acute lymphoblastic leukemia (ALL) xenograft model of CRS and neuro-inflammation (NI), GM-CSF neutralization resulted in a reduction of myeloid and T cell infiltration in the central nervous system and a significant reduction in NI and prevention of CRS. Finally, we generated GM-CSF deficient CART19 cells through CRISPR/Cas9 disruption of GM-CSF during CAR-T cell manufacturing. These GM-CSFk/o CAR-T cells maintained normal functions, had enhanced anti-tumor activity in vivo, and improved overall survival compared to CART19. Together, these studies illuminate a novel approach to abrogate NI and CRS through GM-CSF neutralization, which may potentially enhance CAR-T cell function. Phase II studies with lenzilumab in combination with CART19 therapy are planned. PMID- 30463997 TI - Radiotherapy May Sensitize to CTLA4 Blockade in Patients with NSCLC. AB - When combined with ipilimumab, radiotherapy may induce an abscopal response in metastatic NSCLC. PMID- 30463996 TI - EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2 Amplified Esophagogastric Cancer. AB - The anti-HER2 antibody trastuzumab is standard care for advanced esophagogastric (EG) cancer with ERBB2 (HER2) amplification or overexpression, but intrinsic and acquired resistance are common. We conducted a phase 2 study of afatinib, an irreversible pan-HER kinase inhibitor, in trastuzumab-resistant EG cancer. We analyzed pretreatment tumor biopsies and, in select cases, performed comprehensive characterization of postmortem metastatic specimens following acquisition of drug resistance. Afatinib response was associated with co amplification of EGFR and ERBB2. Heterogeneous 89Zr-trastuzumab PET uptake was associated with genomic heterogeneity and mixed clinical response to afatinib. Resistance to afatinib was associated with selection for tumor cells lacking EGFR amplification or with acquisition of MET amplification, which could be detected in plasma cell free DNA. The combination of afatinib and a MET inhibitor induced complete tumor regression in ERBB2 and MET co-amplified patient-derived xenograft models established from a metastatic lesion progressing on afatinib. Collectively, differential intra- and interpatient expression of HER2, EGFR, and MET may determine clinical response to HER kinase inhibitors in ERBB2-amplified EG cancer. PMID- 30463999 TI - Osteogenic Cells Supply Calcium to Tumor Cells to Enhance Bone Metastasis. AB - Calcium signaling and mTOR signaling drive bone metastasis progression. PMID- 30463998 TI - Targeting BCMA Achieves Deep and Durable Responses in Multiple Myeloma. AB - Targeting BCMA with the antibody-drug conjugate GSK2857916 is well tolerated in a phase I trial. PMID- 30464000 TI - The Metabolite BH4 Drives T-cell Growth in Autoimmunity and Cancer. AB - BH4, which is involved in the production of neurotransmitters and NO, promotes mature T-cell growth. PMID- 30464001 TI - Anti-CD47 Agent Boosts Macrophage Activity in NHL. AB - The anti-CD47 drug Hu5F9-G4, also known as 5F9, in combination with the anti-CD20 therapy rituximab, may be a promising treatment for some forms of non-Hodgkin lymphoma because it allows macrophages to recognize and attack cancer cells. In a phase Ib trial testing the combination, patients with relapsed/refractory diffuse large B-cell lymphoma or follicular lymphoma had an objective response rate of 50% and few side effects. PMID- 30464002 TI - PD-L1 Inhibitor Improves Survival in TNBC. AB - Combining the PD-L1 inhibitor atezolizumab with standard chemotherapy improves overall survival among patients with metastatic triple-negative breast cancer relative to chemotherapy alone. These findings could lead to a new treatment option for patients with this disease. PMID- 30464003 TI - Parents Support Teach-back, Demonstration, and a Postdischarge Phone Call to Augment Discharge Education. AB - OBJECTIVES: To identify caregiver preferences for discharge education components, content, and techniques. METHODS: Before discharge education, a 9-question structured interview was performed with caregivers of children from 2 populations admitted to the hospital medicine service: patients with asthma (age 2-17 years) or children who were not dependent on technology (age <2 years). McNemar's tests were used to evaluate for significant differences between response options. Open coding was used for theme development to interpret qualitative responses about information caregivers wished to receive before leaving the hospital. RESULTS: The interview was administered to 100 caregivers. More than 90% of caregivers believed that instruction regarding follow-up appointments, medications, and reasons to call the pediatrician or return to the emergency department were important aspects of discharge education. Caregivers also identified a desire for education on their child's condition, care at home, and illness prevention. Most caregivers reported that teach-back, early discharge education, and a postdischarge phone call would be beneficial. Caregivers varied in their preferences for written, verbal, and video instruction, whereas live demonstration was rated almost universally as an effective method by 97% of caregivers (P < .0001). CONCLUSIONS: In our study, we provide insight into caregivers' perspectives on the content, timing, and style of education needed to promote a safe transition of care from the hospital to the home. These findings add caregiver support to the expert consensus in Project Improving Pediatric Patient-Centered Care Transitions and elucidate additional themes to aid in further study and optimization of discharge education. PMID- 30464004 TI - Current use of probiotics to prevent necrotising enterocolitis. PMID- 30464005 TI - Randomised cross-over study of automated oxygen control for preterm infants receiving nasal high flow. AB - OBJECTIVE: To evaluate a prototype automated controller (IntellO2) of the inspired fraction of oxygen (FiO2) in maintaining a target range of oxygen saturation (SpO2) in preterm babies receiving nasal high flow (HF) via the Vapotherm Precision Flow. DESIGN: Prospective two-centre order-randomised cross over study. SETTING: Neonatal intensive care units. PATIENTS: Preterm infants receiving HF with FiO2 >=25%. INTERVENTION: Automated versus manual control of FiO2 to maintain a target SpO2 range of 90%-95% (or 90%-100% if FiO2=21%). MAIN OUTCOME MEASURES: The primary outcome measure was per cent of time spent within target SpO2 range. Secondary outcomes included the overall proportion and durations of SpO2 within specified hyperoxic and hypoxic ranges and the number of in-range episodes per hour. RESULTS: Data were analysed from 30 preterm infants with median (IQR) gestation at birth of 26 (24-27) weeks, study age of 29 (18-53) days and study weight 1080 (959-1443) g. The target SpO2 range was achieved 80% of the time on automated (IntellO2) control (IQR 70%-87%) compared with 49% under manual control (IQR 40%-57%; p<0.0001). There were fewer episodes of SpO2 below 80% lasting at least 60 s under automated control (0 (IQR 0-1.25)) compared with manual control (5 (IQR 2.75-14)). There were no differences in the number of episodes per hour of SpO2 above 98% (4.5 (IQR 1.8-8.5) vs 5.5 (IQR 1.9-14); p=0.572) between the study arms. CONCLUSIONS: The IntellO2 automated oxygen controller maintained patients in the target SpO2 range significantly better than manual adjustments in preterm babies receiving HF. TRIAL REGISTRATION NUMBER: NCT02074774. PMID- 30464006 TI - Social gradient of birthweight in England assessed using the INTERGROWTH-21st gestational age-specific standard. AB - OBJECTIVE: To determine the socioeconomic gradient of birthweights in England with reference to the prescriptive INTERGROWTH-21st Birthweight Standard. DESIGN: National cross-sectional study using data from Hospital Episode Statistics. SETTING: National Health Service in England. PARTICIPANTS: All singleton babies, live born between 34 weeks' gestation and 42 weeks' gestation, between 1 April 2011 and 31 March 2012. MAIN OUTCOME MEASURES: Birthweight distribution of babies with a birthweight of <10th centile or >90th centile, that is, small for gestational age (SGA) or large for gestational age (LGA) using Index of Multiple Deprivation quintiles as a proxy for socioeconomic status. RESULTS: Of 508 230 babies born alive between 1 April 2011 and 31 March 2012, 38 838 (7.6%) were SGA and 81 026 (15.9%) were LGA. Median birthweight was 3405 g, median z-score was 0.25 (SD 1.06). Birthweight z-score demonstrated a social gradient, from 0.26 (SD 1.1) in the most deprived areas to 0.53 (1.0) in the least deprived. Women in the most deprived areas were twice as likely to have SGA babies using the INTERGROWTH 21st chart (OR 1.94; 95% CI 1.87 to 2.01) compared with those in the least deprived areas. If all women had the same rate of SGA equivalent to those living in the least deprived areas, approximately 12 410 (30%) fewer babies would be born SGA in England each year. CONCLUSIONS: This study gives a measure of the social gradient in singleton SGA and LGA babies across England using an international standard of newborn size at birth. PMID- 30464007 TI - Coordination of eukaryotic cilia and flagella. AB - Propulsion by slender cellular appendages called cilia and flagella is an ancient means of locomotion. Unicellular organisms evolved myriad strategies to propel themselves in fluid environments, often involving significant differences in flagella number, localisation and modes of actuation. Remarkably, these appendages are highly conserved, occurring in many complex organisms such as humans, where they may be found generating physiological flows when attached to surfaces (e.g. airway epithelial cilia), or else conferring motility to male gametes (e.g. undulations of sperm flagella). Where multiple cilia arise, their movements are often observed to be highly coordinated. Here I review the two main mechanisms for motile cilia coordination, namely, intracellular and hydrodynamic, and discuss their relative importance in different ciliary systems. PMID- 30464008 TI - Composition, structure and function of the eukaryotic flagellum distal tip. AB - Cilia and flagella are long extensions commonly found on the surface of eukaryotic cells. In fact, most human cells have a flagellum, and failure to correctly form cilia leads to a spectrum of diseases gathered under the name 'ciliopathies'. The cilium distal tip is where it grows and signals. Yet, out of the flagellar regions, the distal tip is probably the least intensively studied. In this review, we will summarise the current knowledge on the diverse flagellar tip structures, the dynamicity and signalling that occurs here and the proteins localising to this important cellular region. PMID- 30464009 TI - Human asparagine synthetase associates with the mitotic spindle. AB - Cancer cells are characterized by extensive reprogramming of metabolic pathways in order to promote cell division and survival. However, the growth promotion effects of metabolic reprogramming can be due to moonlighting functions of metabolic enzymes as well as the redirection of flux through particular pathways. To identify metabolic enzymes that might have potential moonlighting functions in oncogenesis, we have examined recent screens of the yeast GFP strain collection for metabolic enzymes that have been implicated in cancer metabolism with an unusual subcellular localization. Asparagine synthetase forms filaments in yeast in response to nutrient limitation and is part of a pathway that is a chemotherapy target in acute lymphoblastic leukemia. Interestingly, while yeast asparagine synthetase forms cytoplasmic filaments in response to nutrient stress, human asparagine synthetase is associated with the centrosomes and mitotic spindles. This localization is disrupted by both nocodazole and asparaginase treatments. This failure to localize occurs even though asparagine synthetase is highly up-regulated in response to asparaginase treatment. Together, these results argue that human asparagine synthetase undergoes regulated recruitment to the mitotic spindles and that it may have acquired a second role in mitosis similar to other metabolic enzymes that contribute to metabolic reprogramming in cancer cells. PMID- 30464010 TI - Intra-breath measures of respiratory mechanics in healthy African infants detect risk of respiratory illness in early life. AB - RATIONALE: Lower respiratory tract illness (LRTI) is a leading cause of mortality and morbidity in children. Sensitive and non-invasive infant lung function techniques are needed to measure risk for and impact of LRTI on lung health. OBJECTIVE: To investigate whether lung function derived from the intra-breath forced oscillation technique (FOT), was able to identify healthy infants at risk of LRTI in the first year. METHODS AND MEASUREMENTS: Lung function was measured with the novel intra-breath FOT, in six-week infants in a South African birth cohort (Drakenstein Child Health Study). LRTI during the first year was confirmed by study staff. The association between baseline lung function and LRTI was assessed with logistic regression and odds ratios (ORs) determined using optimal cut-off values. RESULTS: Of the 627 healthy infants with successful lung function testing, 161(24%) had 238 LRTI episodes subsequently during the first year. Volume dependence of respiratory resistance (DeltaR) and reactance (DeltaX) were associated with LRTI. The predictive value was stronger if LRTI was recurrent (n=50, 31%): OR=2.5, DeltaX; required hospitalisation (n=38, 16%): OR=5.4, DeltaR; or was associated with wheeze (n=87, 37%): OR=3.9, DeltaX. CONCLUSION: Intra-breath FOT can identify healthy infants at risk of developing LRTI, wheezing or severe illness in the first year of life. PMID- 30464011 TI - Inflammation and Endothelial Activation in Early Adulthood are Associated with Future Emphysema: The CARDIA Lung Study. PMID- 30464012 TI - Exacerbations of severe asthma in patients treated with Mepolizumab. PMID- 30464013 TI - High COPD prevalence at high altitude: does household air pollution play a role? AB - Studies comparing COPD prevalence across altitudes report conflicting results. Yet, household air pollution, a major COPD risk factor, was mostly not accounted for in previous analyses and never objectively measured. We aimed to compare the prevalence of COPD and its risk factors between low-resource highlands and lowlands, with a particular focus on objectively-measured household air pollution.We conducted a population-based, observational study in a highland (~2050 m) and lowland (~750 m) setting in rural Kyrgyzstan. We performed spirometry in randomly selected households, measured indoor particulate matter <2.5 um (PM2.5), and administered a questionnaire on other COPD risk factors. Descriptive statistics and multivariable logistic regressions were used for analyses.We included 392 participants: 199 highlanders and 193 lowlanders. COPD was more prevalent among highlanders (36.7% versus 10.4%, p<0.001). Also, their average PM2.5-exposure was higher (290.0 versus 72.0 ug.m-3, p<0.001). Besides high PM2.5-exposure (OR 3.174; 95% CI 1.061-9.493), the altitude setting (3.406; 1.483-7.825), pack years (1.037; 1.005-1.070), and age (1.058; 1.037-1.079) also contributed to a higher COPD prevalence among highlanders.COPD prevalence and household air pollution were highest in the highlands and were independently associated. Preventive interventions seem warranted in these low-resource, highland settings. With this study being one of the first spirometry-based prevalence studies in Central-Asia, generalisability needs to be assessed. PMID- 30464014 TI - Restricted visiting reduces nosocomial viral respiratory tract infections in high risk neonates. PMID- 30464015 TI - Hypersensitivity pneumonitis and its correlation with ambient air pollution in urban India. PMID- 30464016 TI - Airway Microbiome in Adult Survivors of Extremely Preterm Birth (The EPICure Study). AB - Bronchopulmonary Dysplasia(BPD) is a major complication of preterm birth that leads to lifelong respiratory morbidity. The EPICure study has investigated the longitudinal health outcomes of infants born extremely preterm (<26 weeks gestation). Our aim was to characterise the airway microbiome in young adults born extremely preterm (EP), with and without neonatal BPD, in comparison to matched term-born controls.Induced sputum was collected from 92 young adults age 19 years (51 EP and 41 controls). Typical respiratory pathogens were detected using quantitative-PCR. 16S-rRNA gene sequencing was completed on 74 samples (29 EP with BPD, 9 EP without BPD and 36 controls).The preterm group with BPD had the least diverse bacterial communities. The relative-abundance of Bacteriodetes, particularly Prevotella melaninogenica was significantly lower in the preterm group compared to controls. This decline was balanced by a nonsignificant increase in Firmicutes. Total Prevotella relative-abundance correlated with FEV1 z-score (rho=0.272; p<0.05). Typical respiratory pathogens loads and prevalence were similar between groups.In conclusion, extremely preterm birth is associated with a significant dysbiosis in airway microbiome in young adulthood regardless of neonatal BPD status. This is characterised by a shift in the community composition away from Bacteriodetes as manifested in a significant drop in Prevotella relative-abundance. PMID- 30464017 TI - Immediate bronchodilator response in FEV1 as a diagnostic criterion for adult asthma. AB - BACKGROUND: Asthma is characterised by variable and reversible expiratory airflow limitations. Thus, it is logical to use the change in FEV1 in response to a bronchodilator (DeltaFEV1BDR) as a diagnostic tool; increases of >=12% and >=200 mL from the baseline FEV1 are commonly used values. AIM: To evaluate the historical development of diagnostic cut-off levels for the DeltaFEV1BDR for adults and the evidence behind these recommendations. METHODS: We searched for studies from the reference lists of all the main statements, reports and guidelines concerning the interpretation of spirometry and diagnostics for asthma and conducted a literature search. RESULTS: A limited amount of evidence regarding the DeltaFEV1BDR in healthy populations was found, and even fewer patient studies were found. In healthy persons, the upper 95th percentile for the absolute DeltaFEV1BDR ranges between 240 and 320 mL, for the relative DeltaFEV1BDR calculated from the initial FEV1 ranges from 5.9-13.3%, and for the DeltaFEV1BDR calculated from the predicted FEV1 ranges from 8.7-11.6%. However, the absolute and percentage DeltaFEV1BDR values calculated from the initial FEV1 are dependent on age, sex, height and the degree of airway obstruction. Thus, the use of the DeltaFEV1BDR calculated from the predicted FEV1 might be more appropriate. CONCLUSIONS: Not enough data exist to assess the sensitivity of any of the cut-off levels for the DeltaFEV1BDR to differentiate asthma patients from healthy subjects. Further studies in newly diagnosed asthma patients are needed. PMID- 30464018 TI - Electronic Cigarettes - Task Force report from the European Respiratory Society. AB - There is a marked increase in the development and use of electronic nicotine delivery systems (ENDS) or electronic cigarettes (ECIGs). This statement covers electronic cigarettes (ECIGs), defined as "electrical devices that generate an aerosol from a liquid" and thus excludes devices that contain tobacco. Database searches identified published articles that were used to summarise the current knowledge on: the epidemiology of ECIG use; their ingredients and accompanied health effects; secondhand exposure; use of ECIGs for smoking cessation; behavioural aspects of ECIGs and social impact, in vitro and animal studies; and user perspectives.ECIG aerosol contains potentially toxic chemicals. As compared to conventional cigarettes, these are fewer and generally in lower concentrations. Second-hand exposures to ECIG chemicals may represent a potential risk, especially to vulnerable populations. There is not enough scientific evidence to support that ECIGs are an aid to smoking cessation due to a lack of controlled trials, including those that compare ECIGs with licensed stop-smoking treatments. So far, there is conflicting data that use of ECIGs results in a renormalisation of smoking behaviour or for the gateway hypothesis. Experiments in cell cultures and animal studies show that ECIGs can have multiple negative effects. The long-term effects of ECIGs use are unknown, and there is therefore no evidence that ECIGs are safer than tobacco in the long term. Negative health effects cannot, based on the current knowledge, be ruled out. PMID- 30464019 TI - Fertility treatment among women with asthma - A case-control study of 3689 women with live births. AB - Asthma has been linked with prolonged time to pregnancy. Our aim was to explore a possible association between asthma and need for fertility treatment among women with live births.All women enrolled in the Management of Asthma during Pregnancy (MAP) program at Hvidovre Hospital (HH), Denmark, (cases) were each matched with the three consecutive women giving birth at HH (controls). Information from the Danish National Assisted Reproductive Technology registry was cross-linked with the Danish Medical Birth registry to identify live births. The primary outcome of interest was births following fertility treatment.Our sample comprised pregnancies from asthmatic (n=932, cases) and non-asthmatic (n=2757, controls) mothers (n=932), with 12% (n=114) and 8% (n=212), respectively, having had fertility treatment (OR 1.67, 95% CI 1.32-2.13, p<0.001). This association remained statistically significant after adjusting for confounders, incl. BMI (OR 1.31, 95% CI 1.00-1.70, p=0.047). In women >=35 years, it was 25% (n=63) and 13% (n=82) of cases and controls, respectively, (OR 2.12, 95% CI 1.47-3.07, p<0.001), which also remained statistically significant after adjusting for confounders (OR 1.65, 95% CI (1.11-2.46), p=0.013).A higher proportion of the births from asthmatic mothers, compared to non-asthmatic mothers, involved fertility treatment, not least among women aged 35 years and older. PMID- 30464020 TI - Vigorous physical activity is associated with metastatic-lethal progression in prostate cancer and differential tumor DNA methylation in the CRACR2A gene. AB - BACKGROUND: There is preliminary evidence linking physical activity to better prostate cancer (PCa) outcomes, though the molecular mechanisms underlying this association are not clear. METHODS: In a Seattle-based cohort of patients diagnosed with clinically localized PCa and prospective follow-up for outcomes (n=1354), we studied the association between self-reported vigorous physical activity and PCa progression to a metastatic-lethal phenotype. A subset of patients have prostate cancer tissue samples available for investigating DNA methylation (Infinium(r) HumanMethylation450 BeadChip array) and exercise (n=524). RESULTS: Patients who had vigorous physical activity at least once per week during the year before diagnosis (~79% of the cohort) were significantly less likely to progress to metastatic-lethal PCa compared to those who had vigorous physical activity less frequently (adjusted hazard ratio =0.63, p value=0.029). Among the subset of men who had radical prostatectomy as primary treatment and tumor tissue available, a differentially methylated region (DMR) was identified (family-wise error rate=0.03, hypo-methylated in the weekly exercise group), with 9 methylation probes located in the promoter region of CRACR2A. This gene encodes a calcium binding protein involved in innate immune response. The methylation level of the nine CpGs was inversely correlated with CRACR2A gene expression (average correlation coefficient= - 0.35). CONCLUSIONS: Vigorous physical activity before diagnosis is associated with epigenetic alterations of CRACR2A and PCa metastatic lethal progression. IMPACT: This analysis provides strong evidence for the association between vigorous physical activity and a less likelihood to develop metastatic lethal progression, and a suggestive link between exercise and DNA methylation in CRACRA2A gene. PMID- 30464021 TI - Combined Mineral Intakes and Risk of Colorectal Cancer in Postmenopausal Women. AB - BACKGROUND: Despite considerable biological plausibility, other than for calcium, there are few reported epidemiologic studies on mineral intake-colorectal cancer (CRC) associations, none of which investigated multiple minerals in aggregate. METHODS: Accordingly, we incorporated 11 minerals into a mineral score and investigated its association with incident CRC in the Iowa Women's Health Study, a prospective cohort study of 55 - 69-year-old women who completed a food frequency questionnaire in 1986. In the analytic cohort (n = 35, 221), 1,731 incident CRC cases were identified via the State Health Registry of Iowa. Participants' calcium, magnesium, manganese, zinc, selenium, potassium, and iodine intakes were ranked 1 - 5, with higher ranks indicating higher, potentially anti-carcinogenic, intakes, whereas for iron, copper, phosphorus, and sodium intakes, the rankings were reversed to account for their possible pro carcinogenic properties. The rankings were summed to create each woman's mineral score. The mineral score-incident CRC association was estimated using multivariable Cox proportional hazards regression. RESULTS: There was decreasing risk with an increasing score (P-trend = 0.001). The hazard ratios and 95% confidence intervals (CI) for those in mineral score quintiles 2 - 5 relative to those in the lowest were 0.91 (CI, 0.88-1.08), 0.85 (CI, 0.75-0.95), 0.86 (CI, 0.75-0.97), and 0.75 (CI, 0.71-0.95), respectively. CONCLUSIONS: Our findings suggest that a predominance of putative anti- relative to pro-colorectal carcinogenic mineral intakes may be inversely associated with CRC risk. IMPACT: These results support further investigation of CRC etiology using composite mineral intake scores. PMID- 30464022 TI - Trends in pediatric central nervous system tumor incidence in the United States, 1998-2013. AB - BACKGROUND: Brain and other central nervous system (CNS) cancers are the leading cause of US pediatric cancer mortality. Incidence trends can provide etiological insight. We report trends in incidence rates of pediatric malignant CNS cancers and pilocytic astrocytoma (non-malignant but historically registered) in the US. METHODS: Age-standardized incidence rates and annual percent changes (APCs) in rates during 1998-2013 were calculated for children aged 0-19, stratified by subtype, age, sex, and for gliomas, histology and location. We estimated the absolute change in number of cases diagnosed US-wide during 2013 compared to the expected number of cases had 1998 rates remained stable. RESULTS: Rates of all pediatric malignant CNS cancer combined (n=18,612) did not change (APC:0.16, 95% confidence interval [CI]: -0.21,0.53). There were statistically-significant changes in several sub-types, however: glioma incidence (n=10,664) increased by 0.77%/year (95% CI:0.29,1.26), embryonal cancer rates (n=5,423) decreased by 0.88%/year (95% CI: -1.33, -0.43) and pilocytic astrocytoma rates (n=6,858) increased by 0.89%/year (95% CI:0.21,1.58). Of the 1,171 malignant tumors and 450 pilocytic astrocytomas diagnosed in US children in 2013, we estimated 120 excess gliomas, 94 excess pilocytic astrocytomas, and 72 fewer embryonal CNS tumors than would be expected had 1998 rates remained stable. CONCLUSIONS: The gradual changes in incidence we observed for specific types of pediatric CNS cancers are likely due to a combination of changes in classification and diagnosis and true changes in CNS cancer. IMPACT: Continued surveillance of pediatric CNS tumors should remain a priority given their significant contribution to pediatric cancer deaths. PMID- 30464024 TI - PGR5-Dependent Cyclic Electron Flow Protects Photosystem I under Fluctuating Light at Donor and Acceptor Sides. AB - In response to a sudden increase in light intensity, plants must cope with absorbed excess photon energy to protect photosystems from photodamage. Under fluctuating light, photosystem I (PSI) is severely photodamaged in the Arabidopsis (Arabidopsis thaliana) proton gradient regulation5 (pgr5) mutant defective in the main pathway of PSI cyclic electron transport (CET). Here, we aimed to determine how photosystem I is protected by two proposed regulatory roles of CET via trans-thylakoid DeltapH formation: (1) reservation of electron sink capacity by adjusting the ATP/NADPH production ratio (acceptor-side regulation), and (2) downregulation of the cytochrome b6f (Cyt b6f) complex activity called photosynthetic control for slowing down the electron flow toward PSI (donor-side regulation). We artificially enhanced donor- and acceptor-side regulation in the wild-type and pgr5 backgrounds by introducing the pgr1 mutation conferring the hypersensitivity of the Cyt b6f complex to luminal acidification and moss Physcomitrella patens flavodiiron protein (Flv) genes, respectively. Enhanced photosynthetic control partially alleviated PSI photodamage in the pgr5 mutant background but restricted linear electron transport under constant high light, suggesting that the strength of photosynthetic control should be optimized. Flv-dependent O2 photoreduction formed a large electron sink and alleviated PSI photoinhibition, accompanied by the induction of photosynthetic control. Thus, donor-side regulation is essential for PSI photoprotection but acceptor-side regulation is also important to rapidly induce donor-side regulation. In angiosperms, PGR5-dependent CET is required for both functions. PMID- 30464023 TI - GALAD Score for Hepatocellular Carcinoma Detection in Comparison to Liver Ultrasound and Proposal of GALADUS Score. AB - BACKGROUND/AIM: The GALAD score is a serum biomarker-based model that predicts the probability of having hepatocellular carcinoma (HCC) in patients with chronic liver disease. We aimed to assess the performance of the GALAD score in comparison to liver ultrasound for detection of HCC. METHODS: A single center cohort of 111 HCC and 180 controls with cirrhosis or chronic hepatitis B and a multicenter cohort of 233 early HCC and 412 cirrhosis patients from the Early Detection Research Network (EDRN) Phase 2 HCC Study were analyzed. RESULTS: The area under the ROC curve (AUC) of the GALAD score for HCC detection was 0.95 [95% confidence interval (CI): 0.93-97], which was higher than the AUC of ultrasound (0.82, P<0.01). At a cut off of -0.76, the GALAD score had a sensitivity of 91% and a specificity of 85% for HCC detection. The AUC of the GALAD score for early stage HCC detection remained high at 0.92 [95%CI: 0.88-0.96] (cut off -1.18, sensitivity 92%, specificity 79%). The AUC of the GALAD score for HCC detection was 0.88 (95% CI, 0.85-0.91) in the EDRN cohort. The combination of GALAD and ultrasound (GALADUS score) further improved the performance of the GALAD score in the single center cohort, achieving an AUC of 0.98 [95%CI: 0.96-0.99] (cut off 0.18, sensitivity 95%, specificity 91%). CONCLUSIONS: The performance of the GALAD score was superior to ultrasound for HCC detection. The GALADUS score further enhanced the performance of the GALAD score. IMPACT: The GALAD score was validated in the US. PMID- 30464025 TI - Rotating night shift work and adherence to unhealthy lifestyle in predicting risk of type 2 diabetes: results from two large US cohorts of female nurses. AB - OBJECTIVES: To prospectively evaluate the joint association of duration of rotating night shift work and lifestyle factors with risk of type 2 diabetes risk, and to quantitatively decompose this joint association to rotating night shift work only, to lifestyle only, and to their interaction. DESIGN: Prospective cohort study. SETTING: Nurses' Health Study (1988-2012) and Nurses' Health Study II (1991-2013). PARTICIPANTS: 143 410 women without type 2 diabetes, cardiovascular disease, or cancer at baseline. EXPOSURES: Rotating night shift work was defined as at least three night shifts per month in addition to day and evening shifts in that month. Unhealthy lifestyles included current smoking, physical activity levels below 30 minutes per day at moderate to vigorous intensity, diet in the bottom three fifths of the Alternate Healthy Eating Index score, and body mass index of 25 or above. MAIN OUTCOME MEASURES: Incident cases of type 2 diabetes were identified through self report and validated by a supplementary questionnaire. RESULTS: During 22-24 years of follow-up, 10 915 cases of incident type 2 diabetes occurred. The multivariable adjusted hazard ratios for type 2 diabetes were 1.31 (95% confidence interval 1.19 to 1.44) per five year increment of duration of rotating night shift work and 2.30 (1.88 to 2.83) per unhealthy lifestyle factor (ever smoking, low diet quality, low physical activity, and overweight or obesity). For the joint association of per five year increment rotating night shift work and per unhealthy lifestyle factor with type 2 diabetes, the hazard ratio was 2.83 (2.15 to 3.73) with a significant additive interaction (P for interaction <0.001). The proportions of the joint association were 17.1% (14.0% to 20.8%) for rotating night shift work alone, 71.2% (66.9% to 75.8%) for unhealthy lifestyle alone, and 11.3% (7.3% to 17.3%) for their additive interaction. CONCLUSIONS: Among female nurses, both rotating night shift work and unhealthy lifestyle were associated with a higher risk of type 2 diabetes. The excess risk of rotating night shift work combined with unhealthy lifestyle was higher than the addition of risk associated with each individual factor. These findings suggest that most cases of type 2 diabetes could be prevented by adhering to a healthy lifestyle, and the benefits could be greater in rotating night shift workers. PMID- 30464026 TI - Barriers to specialist palliative care in interstitial lung disease: a systematic review. AB - BACKGROUND: Current guidelines recommend palliative care based on individual needs for patients with idiopathic pulmonary fibrosis. However, patients with interstitial lung disease (ILD) are less likely to receive specialist palliative care services compared with patients with malignant disease. The aim of this review is to summarise recent studies addressing barriers to referring patients to specialist palliative care services. METHODS: PubMed, Embase, Medline and Web of Science were reviewed to identify relevant publications. Studies were selected if they examined the frequency of specialist palliative care referral and/or addressed issues surrounding access to palliative care services for patients with ILD. RESULTS: Ten studies with a total of 4073 people with ILD, 27 caregivers and 18 healthcare professionals were selected and analysed. Frequency of palliative care referrals ranged from 0% to 38%. Delay in palliative care referrals and end of-life decisions, patients' fear of talking about the future, prognostic uncertainty and confusion about the roles of palliative care were identified as barriers to accessing palliative care services. CONCLUSION: Further research should concentrate on the early identification of patients who need specialist palliative care possibly with establishment of criteria to trigger referral ensuring that referrals are also based on patient's needs. PMID- 30464027 TI - Ban on legal highs fails to curb use among children. PMID- 30464028 TI - Transcranial magnetic stimulation predicts cognitive decline in patients with Alzheimer's disease. AB - OBJECTIVE: To determine the ability of transcranial magnetic stimulation (TMS) in detecting synaptic impairment in patients with Alzheimer's disease (AD) and predicting cognitive decline since the early phases of the disease. METHODS: We used TMS-based parameters to evaluate long-term potentiation (LTP)-like cortical plasticity and cholinergic activity as measured by short afferent inhibition (SAI) in 60 newly diagnosed patients with AD and 30 healthy age-matched subjects (HS). Receiver operating characteristic (ROC) curves were used to assess TMS ability in discriminating patients with AD from HS. Regression analyses examined the association between TMS-based parameters and cognitive decline. Multivariable regression model revealed the best parameters able to predict disease progression. RESULTS: Area under the ROC curve was 0.90 for LTP-like cortical plasticity, indicating an excellent accuracy of this parameter in detecting AD pathology. In contrast, area under the curve was only 0.64 for SAI, indicating a poor diagnostic accuracy. Notably, LTP-like cortical plasticity was a significant predictor of disease progression (p=0.02), while no other neurophysiological, neuropsychological and demographic parameters were associated with cognitive decline. Multivariable analysis then promoted LTP-like cortical plasticity as the best significant predictor of cognitive decline (p=0.01). Finally, LTP-like cortical plasticity was found to be strongly associated with the probability of rapid cognitive decline (delta Mini-Mental State Examination score <=-4 points at 18 months) (p=0.04); patients with AD with lower LTP-like cortical plasticity values showed faster disease progression. CONCLUSIONS: TMS-based assessment of LTP-like cortical plasticity could be a viable biomarker to assess synaptic impairment and predict subsequent cognitive decline progression in patients with ADs. PMID- 30464030 TI - Long-term intake of vegetables and fruits and subjective cognitive function in US men. AB - OBJECTIVE: To evaluate the prospective association of long-term intake of vegetables and fruits with late-life subjective cognitive function (SCF). METHODS: Among 27,842 men with a mean age of 51 years in 1986, we used multinomial logistic regression to examine the relation of vegetable and fruit consumption to future SCF. Average dietary intake was calculated from 5 repeated food frequency questionnaires collected every 4 years until 2002. SCF score was assessed twice (2008 and 2012) using a 6-item questionnaire; validity was supported by strong associations with APO epsilon4 genotype. We categorized the average of the 2 scores as good, moderate, and poor SCF. RESULTS: Higher intakes of total vegetables, total fruits, and fruit juice were each significantly associated with lower odds of moderate or poor SCF after controlling for major nondietary factors and total energy intake. The association with total fruit intake was weaker after further adjusting for major dietary factors. In this model, the multivariate odds ratios (95% confidence intervals) for vegetable intake (top vs bottom quintile) were 0.83 (0.76-0.92), p trend <0.001 for moderate SCF and 0.66 (0.55-0.80), p trend <0.001 for poor SCF. For orange juice, compared to <1 serving/mo of intake, daily consumption was associated with a substantially lower odds of poor SCF (0.53 [0.43-0.67], p trend <0.001). Higher consumption of vegetables and fruits 18 to 22 years before SCF assessment was associated with lower odds of poor SCF independent of more proximal intake. CONCLUSION: Our findings support a long-term beneficial role of vegetable, fruit, and orange juice consumption on SCF. PMID- 30464029 TI - Developing and validating Parkinson's disease subtypes and their motor and cognitive progression. AB - OBJECTIVES: To use a data-driven approach to determine the existence and natural history of subtypes of Parkinson's disease (PD) using two large independent cohorts of patients newly diagnosed with this condition. METHODS: 1601 and 944 patients with idiopathic PD, from Tracking Parkinson's and Discovery cohorts, respectively, were evaluated in motor, cognitive and non-motor domains at the baseline assessment. Patients were recently diagnosed at entry (within 3.5 years of diagnosis) and were followed up every 18 months. We used a factor analysis followed by a k-means cluster analysis, while prognosis was measured using random slope and intercept models. RESULTS: We identified four clusters: (1) fast motor progression with symmetrical motor disease, poor olfaction, cognition and postural hypotension; (2) mild motor and non-motor disease with intermediate motor progression; (3) severe motor disease, poor psychological well-being and poor sleep with an intermediate motor progression; (4) slow motor progression with tremor-dominant, unilateral disease. Clusters were moderately to substantially stable across the two cohorts (kappa 0.58). Cluster 1 had the fastest motor progression in Tracking Parkinson's at 3.2 (95% CI 2.8 to 3.6) UPDRS III points per year while cluster 4 had the slowest at 0.6 (0.1-1.1). In Tracking Parkinson's, cluster 2 had the largest response to levodopa 36.3% and cluster 4 the lowest 28.8%. CONCLUSIONS: We have found four novel clusters that replicated well across two independent early PD cohorts and were associated with levodopa response and motor progression rates. This has potential implications for better understanding disease pathophysiology and the relevance of patient stratification in future clinical trials. PMID- 30464032 TI - Kevin Stewart: More safety, less blame. PMID- 30464031 TI - High prevalence of neutralizing antibodies after long-term botulinum neurotoxin therapy. AB - OBJECTIVE: To investigate the prevalence of neutralizing antibodies (NABs) against botulinum neurotoxin type A (BoNT/A) during long-term BoNT/A treatment in different neurologic indications. METHODS: In this monocentric, observational cross-sectional study, 596 outpatients treated with BoNT/A for different indications were tested for BoNT/A binding antibodies by ELISA. Positive samples were investigated for NABs with the mouse hemidiaphragm test. The prevalence of NABs was analyzed for different indications: facial hemispasm, blepharospasm, cervical dystonia, other dystonia, and spasticity. Besides the rate of NAB positive patients overall and per patient subgroup, a Kaplan-Meier analysis of the probability of remaining NAB negative with duration of treatment is provided, and a stepwise binary logistic regression analysis is performed to identify factors significantly contributing to the induction of NABs. RESULTS: Overall, 83 of 596 patients (13.9%) had measurable NABs. The probability of developing NABs increased with the single and cumulative dose of treatment and was influenced by the BoNT/A formulation, while all other factors analyzed, including disease entity and treatment duration, had no additional influence. CONCLUSIONS: We present the largest study to date of the prevalence of BoNT/A NABs in a large unbiased cohort of patients including the relevant neurologic indications. Repeated injections of BoNT/A inevitably bear the risk of developing NABs. However, in addition to avoiding booster injections and providing short intervals between injections, reducing the individual injected doses may diminish the risk of NAB induction independently of the indication for which BoNT/A is used. PMID- 30464033 TI - The EU referendum and mental health in the short term: a natural experiment using antidepressant prescriptions in England. AB - BACKGROUND: Previous research has highlighted the impact of economic conditions and uncertainty on physical and mental health. The unexpected result of the Brexit referendum in 2016 triggered high levels of economic uncertainty. OBJECTIVE: To examine whether prescriptions for antidepressants increased after the referendum result, benchmarking them against other drug classes. METHODS: We used GP practice prescribing data to compile the number of defined daily doses per capita every month in each of the 326 voting areas in England over the period 2011-2016. We used a difference-in-differences (DID) approach to identify the effects of Brexit on antidepressant prescriptions, compared with trends in a control group (antigout and iron preparations) that were unlikely to be associated with uncertainty and depression. RESULTS: Antidepressant prescribing continued to increase after the referendum but at a slower pace. Therapeutic classes used as controls showed a decrease. The DID approach shows that there was a relative increase of 13.4% in antidepressants compared with other therapeutic classes (DID coeff: 0.134; 95% CI 0.093 to 0.174). CONCLUSION: Our results are open to different interpretations and should be treated with caution. This relative increase in antidepressant prescribing after the referendum may be attributed to increased uncertainty for certain parts of the population, but does not rule out an improvement in mood for others. Alternatively, some other factor for example, distraction, might have contributed to a decrease in the control therapeutic classes. A possible policy implication is that programmes for the promotion of mental health may need to be intensified during periods of uncertainty. PMID- 30464034 TI - Corn ChIPs and RNA-seq: Researchers Dip into Advanced Tools and Resources to Examine bZIP Transcription Factor Function in the Maize Endosperm. PMID- 30464035 TI - Phosphatidic Acid Directly Regulates PINOID-Dependent Phosphorylation and Activation of the PIN-FORMED 2 Auxin Efflux Transporter in Response to Salt Stress. AB - Remodeling of auxin distribution in the integration of plant growth responses with the environment requires the precise control of auxin influx and efflux transporters. The plasma membrane-localized PIN-FORMED (PIN) proteins facilitate auxin efflux from cells, and their activity is regulated by reversible phosphorylation. How PIN modulates plant cellular responses to external stresses, and whether its activity is coordinated by phospholipids, remains unclear. Here, we reveal that in Arabidopsis, the phosphatidic acid (PA)-regulated PINOID (PID) kinase is a crucial modulator of PIN2 activity and auxin redistribution in response to salt stress. Under salt stress, loss of phospholipase D (PLD) function impaired auxin redistribution and resulted in markedly reduced primary root growth; these effects were reversed by exogenous PA. The PLD-derived PA interacted with PID and increased PID-dependent phosphorylation of PIN2, which activated auxin efflux and altered auxin accumulation, promoting root growth when exposed to salt stress. Ablation of the PA-binding motif not only diminished PID accumulation at the plasma membrane, but also abolished PA-promoted PID phosphorylation of PIN2 and its function in coping with salt stress, however, did not affect inflorescence and cotyledon development or PIN2-dependent gravitropic and halotropic responses. Our data indicate a role for PA in coupling extracellular salt signaling to PID-directed PIN2 phosphorylation and polar auxin transport, highlighting the importance of lipid-protein interactions in the spatiotemporal regulation of auxin signaling. PMID- 30464036 TI - Small Talk: Protons Help Calcium Get the Message Across. PMID- 30464037 TI - PAPST2 plays a critical role for PAP removal from the cytosol and subsequent degradation in plastids and mitochondria. AB - The different compartmentation of 3'-phosphoadenosine 5'-phosphosulfate (PAPS) synthesis (mainly in plastids), PAPS consumption (in the cytosol), and 3' phosphoadenosine 5'-phosphate (PAP) degradation (in plastids and mitochondria) necessitates organellar transport systems for PAPS and PAP. The plastidial transporter PAPST1 was shown to deliver newly synthesized PAPS from the stroma to the cytosol. Here, we studied the closest PAPST1 homolog, termed PAPST2, which in contrast to PAPST1 is targeted to both, plastids and mitochondria. Biochemical characterization revealed that PAPST2 mediates the antiport of PAP, PAPS, ATP and ADP. A strong increase in cellular PAP concentration has negative effects on plant growth as observed in the fry1papst2 mutant that lacks the PAP catabolizing enzyme SAL1 and the PAPST2 transporter. The concentration of PAP is specifically increased in the cytosol of papst2 and fry1papst2, but not in papst1 and fry1papst1 mutants. PAPST1 was unable to complement the papst2 mutant phenotype in mitochondria as it probably removes PAPS from the cell as demonstrated by increased expression of PSKs. Overexpression of SAL1 in mitochondria is able to rescue the phenotype of fry1 but not that of fry1papst2. Altogether our data show that PAPST2 represents an important organellar importer of PAP, providing piece of puzzle in understanding organelle-to-nucleus PAP retrograde signaling pathway. PMID- 30464038 TI - Tumor lysis syndrome: a rare, but serious complication of radioligand therapies. AB - Radioligand therapy (RLT) is considered a safe treatment for patients with metastasized neuroendocrine tumors (NET) and prostate cancer (PC), and the occurrence of tumor lysis syndrome (TLS) with 177Lutetium (177Lu)-labeled peptides has not been reported so far. We retrospectively screened our patients' database for TLS after RLT in NET and PC. Methods: The database was searched for patients receiving RLT with 177Lu-DOTATATE, -DOTATOC or -PSMA and showing laboratory or clinical abnormalities typical for TLS within 7 days after start of treatment. Results: 205 patients (539 cycles) were screened; 4 patients developed TLS with clinical symptoms and characteristic changes of laboratory parameters, which normalized after appropriate treatment. Follow-up revealed partial remission (n = 2), mixed response (n = 1) and progressive disease (n = 1). Conclusion: Clinical TLS is a rare, but definite complication of RLT suggesting patient monitoring for TLS as mandatory. PMID- 30464039 TI - Measuring Estrogen Receptor Functionality using Progesterone Receptor PET Imaging: Rising to the (Estradiol) Challenge! PMID- 30464040 TI - First-in-Human Phase I study of CTT1057, a Novel 18F Labeled Imaging Agent with Phosphoramidate Core Targeting Prostate Specific Membrane Antigen in Prostate Cancer. AB - Prostate-specific membrane antigen (PSMA) targeting agents comprise a rapidly emerging class of radiopharmaceuticals for prostate cancer diagnostic imaging. Unlike most other PSMA agents with a urea-backbone, CTT1057 is based on a phosphoramidate scaffold that irreversibly binds to PSMA. We conducted a first-in human Phase I study of CTT1057 in patients with localized and metastatic prostate cancer. Methods: Two patient cohorts were recruited. Cohort A were patients with biopsy-proven localized prostate cancer preceding radical prostatectomy, and cohort B were patients with metastatic castrate resistant prostate cancer. Cohort A patients were imaged on multiple time points after intravenous (IV) injection with 362 +/- 8 MBq CTT1057 to evaluate the kinetics of CTT1057 and estimate radiation dose profiles. Mean organ-absorbed doses and effective doses were calculated using OLINDA. CTT1057 uptake in the prostate gland and regional lymph nodes was correlated with pathology, PSMA staining, and results of conventional imaging. In cohort B, patients were imaged 60 to 120 minutes after injection of CTT1057. PET images were assessed for overall image quality, and areas of abnormal uptake were contrasted with conventional imaging. Results: No radiotracer-related adverse events were reported in either cohort. Five patients were enrolled in cohort A and 15 in cohort B. In cohort A, the average total effective dose was 0.023 mSv/MBq. The kidneys exhibited the highest absorbed dose, 0.067 mGy/MBq. Absorbed doses of the liver, red marrow, and salivary glands were 0.016, 0.007, and 0.015 mGy/MBq, respectively. For cohort B, CTT1057 PET detected 97 metastatic lesions (median SUVmax: 12.17; IQR: 5.9 - 19.02). Of 56 bone metastases detected on CTT1057 PET, 44 (78.5%) were also detectable on whole body bone scan. Of 32 positive lymph nodes visualized on CTT1057 PET, 8 (25%) were enlarged by size criteria on CT. Conclusion: CTT1057 is a promising novel phosphoramidate PSMA-targeting 18F-labeled PET radiopharmaceutical that demonstrates similar biodistribution to urea-based PSMA-targeted agents with lower exposure to the kidneys and salivary glands. CTT1057 detects metastatic lesions with higher sensitivity than conventional imaging. Further prospective studies with CTT1057 are warranted to eludicate its role in cancer imaging. PMID- 30464041 TI - MEK inhibition induces therapeutic iodine uptake in a murine model of anaplastic thyroid cancer. AB - RATIONALE: Anaplastic thyroid carcinoma (ATC) is refractory to radioiodine therapy in part due to impaired iodine metabolism. We targeted the MAPK and PI3'K pathways with the intent to induce radioiodine uptake for radioiodine treatment of ATC. Methods: Human ATC cells were used to evaluate the ability of pharmacological inhibition of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways to induce radioiodine uptake. Thyrocyte specific double mutant BRAFV600E PIK3CAH1047R mice were treated with a MEK inhibitor followed by radioiodine treatment and tumor burden was monitored by ultrasound imaging. Results: ATC cell lines showed an increase in sodium-iodine symporter transcription when treated with a MEK or BRAFV600E inhibitor alone and in combination with PI3'K inhibitor. This translated into a dose-dependent elevation of iodine uptake following treatment with a MEK inhibitor alone and in combination with a PI3'K inhibitor. In vivo, MEK inhibition but not BRAF nor PI3'K inhibition upregulated sodium-iodine symporter transcription. This translated into a stable reduction of tumor burden when mice were treated with a MEK inhibitor prior to radioiodine administration. Conclusion: This study confirms the ability of MEK inhibition to induce iodine uptake in in vitro and in vivo models of ATC. The approach of using a MEK inhibitor before radioiodine treatment could readily be translated into clinical practice and provide a much needed therapeutic option for patients with ATC. PMID- 30464042 TI - The function of the ophiuroid nerve ring: how a decentralized nervous system controls coordinated locomotion. AB - Echinoderms lack a centralized nervous control system yet each extant echinoderm class has evolved unique and effective strategies for locomotion. Brittle stars (Ophiuroidea) stride swiftly over the seafloor by coordinating motions of their five muscular arms. Their arms consist of many repeating segments, requiring them to use a complex control system to coordinate motions among segments and between arms. We conducted in vivo experiments with brittle stars to analyze the functional role of the nerve ring, which connects the nerves in each arm. These experiments were designed to determine how the ophiuroid nervous system performs complex decision-making and locomotory actions under decentralized control. Our results show that brittle star arms must be connected by the nerve ring for coordinated locomotion, but information can travel bidirectionally around the nerve ring so that it circumvents the severance. Evidence presented indicates that ophiuroids rely on adjacent nerve ring connections for sustained periodic movements. The number of arms connected via the nerve ring is correlated positively with the likelihood that the animal will show coordinated locomotion, indicating that integrated nerve ring tissue is critical for control. The results of the experiments should provide a basis for the advancement of complex artificial decentralized systems. PMID- 30464043 TI - AMGSEFLamide, a member of a broadly conserved peptide family, modulates multiple neural networks in Homarus americanus. AB - Recent genomic/transcriptomic studies have identified a novel peptide family whose members share the carboxyl terminal sequence -GSEFLamide. However, the presence/identity of the predicted isoforms of this peptide group have yet to be confirmed biochemically, and no physiological function has yet been ascribed to any member of this peptide family. To determine the extent to which GSEFLamides are conserved within the Arthropoda, we searched publicly accessible databases for genomic/transcriptomic evidence of their presence. GSEFLamides appear to be highly conserved within the Arthropoda, with the possible exception of the Insecta, in which sequence evidence was limited to the more basal orders. One crustacean in which GSEFLamides have been predicted using transcriptomics is the lobster, Homarus americanus Expression of the previously published transcriptome derived sequences was confirmed by RT-PCR of brain and eyestalk ganglia cDNAs; mass spectral analyses confirmed the presence of all six of the predicted GSEFLamide isoforms, IGSEFLamide, MGSEFLamide, AMGSEFLamide, VMGSEFLamide, ALGSEFLamide, and AVGSEFLamide, in Homarus brain extracts. AMGSEFLamide, of which there are multiple copies in the cloned transcripts, was the most abundant isoform detected in the brain. Because the GSEFLamides are present in the lobster nervous system, we hypothesized that they might function as neuromodulators, as is common for neuropeptides. We thus asked whether AMGSEFLamide modulates the rhythmic outputs of the cardiac ganglion and the stomatogastric ganglion. Physiological recordings showed that AMGSEFLamide potently modulates the motor patterns produced by both ganglia, suggesting that the GSEFLamides may serve as important and conserved modulators of rhythmic motor activity in arthropods. PMID- 30464044 TI - Gut microbiota dynamics and uraemic toxins: one size does not fit all. PMID- 30464045 TI - Unusual endoscopic treatment of recurrent cough and pneumonia. AB - CLINICAL PRESENTATION: A 51-year-old male patient presented to our emergency department with fever, aggravating coughing and orthopnoea. Clinical evaluation revealed pneumonia in the right lower lobe of the lung and due to typical radiological hallmarks, aspiration pneumonia was suspected. During the last months, he had suffered from several pneumonias. The patient's history showed that he suffered from alveolar soft tissue sarcoma which was first diagnosed in 1985. He was treated with right-sided hemihepatectomy for resection of liver metastases, further liver resections, 12 sessions of radiation therapy and seven transarterial chemoembolisation sessions. Moreover, the patient developed a stenosis of the left hepatic bile duct and required repeated biliary stenting (10F stent) by endoscopic retrograde cholangiopancreaticography (ERCP; 24 ERCPS within 3.5 years).The patient still suffered from persisting coughing with yellow sputum, although inflammation parameters were decreasing under antibiotic treatment. Further, due to elevated bilirubin levels, a bile duct stent dysfunction was suspected and an ERCP was performed showing the following picture (figure 1).gutjnl;gutjnl-2018-317682v1/F1F1F1Figure 1Due to suspected bile duct stent dysfunction, an endoscopic retrograde cholangiopancreaticography was performed. Multiple surgical clips were detectable following extensive hepatic and thoracic surgery for alveolar soft tissue sarcoma. QUESTION: What is your diagnosis? What would be an appropriate treatment approach? PMID- 30464046 TI - Animal protein intake and hepatic steatosis in the elderly: authors' response. PMID- 30464047 TI - Photoreceptor actin dysregulation in syndromic and non-syndromic retinitis pigmentosa. AB - Retinitis pigmentosa (RP) is the leading cause of inherited blindness. RP is a genetically heterogeneous disorder, with more than 100 different causal genes identified in patients. Central to disease pathogenesis is the progressive loss of retinal photoreceptors. Photoreceptors are specialised sensory neurons that exhibit a complex and highly dynamic morphology. The highly polarised and elaborated architecture of photoreceptors requires precise regulation of numerous cytoskeletal elements. In recent years, significant work has been placed on investigating the role of microtubules (specifically, the acetylated microtubular axoneme of the photoreceptor connecting cilium) and their role in normal photoreceptor function. This has been driven by the emerging field of ciliopathies, human diseases arising from mutations in genes required for cilia formation or function, of which RP is a frequently reported phenotype. Recent studies have highlighted an intimate relationship between cilia and the actin cystoskeleton. This review will focus on the role of actin in photoreceptors, examining the connection between actin dysregulation in RP. PMID- 30464048 TI - Membrane protein nanoparticles: the shape of things to come. AB - The use of styrene-maleic acid (SMA) for the purification of a wide range of membrane proteins (MPs) from both prokaryotic and eukaryotic sources has begun to make an impact in the field of MP biology. This method is growing in popularity as a means to purify and thoroughly investigate the structure and function of MPs and biological membranes. The amphiphilic SMA copolymer can effectively extract MPs directly from a native lipid bilayer to form discs ~10 nm in diameter. The resulting lipid particles, or styrene-maleic acid lipid particles (SMALPs), contain SMA, protein and membrane lipid. MPs purified in SMALPs are able to retain their native structure and, in many cases, functional activity, and growing evidence suggests that MPs purified using SMA have enhanced thermal stability compared with detergent-purified proteins. The SMALP method is versatile and is compatible with a wide range of cell types across taxonomic domains. It can readily be adapted to replace detergent in many protein purification methods, often with only minor changes made to the existing protocol. Moreover, biophysical analysis and structural determination may now be a possibility for many large, unstable MPs. Here, we review recent advances in the area of SMALP purification and how it is affecting the field of MP biology, critically assess recent progress made with this method, address some of the associated technical challenges which may remain unresolved and discuss opportunities for exploiting SMALPs to expand our understanding of structural and functional properties of MPs. PMID- 30464049 TI - ABCG2: does resolving its structure elucidate the mechanism? AB - ABCG2 is one of a few human membrane transporters which display the amazing ability to transport multiple different chemicals out of cells. These multidrug pumps, which have orthologues in all organisms, are important in humans in the context of drug pharmacokinetics, especially with respect to resistance to chemotherapy. In 2016, we presented a mini-review on ABCG2 which identified many areas of exciting research progress as well as many areas of frustrating ignorance. Just 2 years on the field has advanced, particularly with respect to structural biology as the cryo-electron microscopy revolution has brought us new insights into the structure and mechanism of ABCG2. In this update, we evaluate the degree to which new data have enhanced our understanding of the structure and mechanism of ABCG2 and whether we are now in a position to translate some of these findings into inhibitor design and development. PMID- 30464050 TI - Myeloid-Specific Deletion of Mcl-1 Yields Severely Neutropenic Mice That Survive and Breed in Homozygous Form. AB - Mouse strains with specific deficiency of given hematopoietic lineages provide invaluable tools for understanding blood cell function in health and disease. Whereas neutrophils are dominant leukocytes in humans and mice, there are no widely useful genetic models of neutrophil deficiency in mice. In this study, we show that myeloid-specific deletion of the Mcl-1 antiapoptotic protein in Lyz2 Cre/Cre Mcl1 flox/flox (Mcl1 DeltaMyelo) mice leads to dramatic reduction of circulating and tissue neutrophil counts without affecting circulating lymphocyte, monocyte, or eosinophil numbers. Surprisingly, Mcl1 DeltaMyelo mice appeared normally, and their survival was mostly normal both under specific pathogen-free and conventional housing conditions. Mcl1 DeltaMyelo mice were also able to breed in homozygous form, making them highly useful for in vivo experimental studies. The functional relevance of neutropenia was confirmed by the complete protection of Mcl1 DeltaMyelo mice from arthritis development in the K/B*N serum-transfer model and from skin inflammation in an autoantibody-induced mouse model of epidermolysis bullosa acquisita. Mcl1 DeltaMyelo mice were also highly susceptible to systemic Staphylococcus aureus or Candida albicans infection, due to defective clearance of the invading pathogens. Although neutrophil-specific deletion of Mcl-1 in MRP8-CreMcl1 flox/flox (Mcl1 DeltaPMN) mice also led to severe neutropenia, those mice showed an overt wasting phenotype and strongly reduced survival and breeding, limiting their use as an experimental model of neutrophil deficiency. Taken together, our results with the Mcl1 DeltaMyelo mice indicate that severe neutropenia does not abrogate the viability and fertility of mice, and they provide a useful genetic mouse model for the analysis of the role of neutrophils in health and disease. PMID- 30464051 TI - Meteorin-like/Meteorin-beta Is a Novel Immunoregulatory Cytokine Associated with Inflammation. AB - We have described a novel cytokine encoded by a gene called Meteorin-like (Metrnl). Metrnl is a small (~28 kDa) secreted protein expressed by activated macrophages and barrier tissues (mucosa and skin). Metrnl production by bone marrow macrophages is induced by several cytokines including TNF-alpha, IL 17alpha, IL-12, and IL-4 and inhibited by IFN-gamma and TGF-beta. Metrnl expression in macrophages is also induced by LPS, and its levels in circulation are associated with inflammatory responses in vivo. Furthermore, Metrnl regulates the production of several cytokines and chemokines in macrophages. We have produced a Metrnl-/- mouse, which is viable and shows normal development. However, it exhibits dysregulated cytokine production, alterations in IgG production, and is highly susceptible to LPS in a sepsis model. Furthermore, older Metrnl-/- mice develop inflammatory lesions, suggesting that Metrnl participates in the control of inflammatory responses. Taken together, these observations indicate that Metrnl encodes a novel immunoregulatory cytokine associated with inflammatory responses that we have designated Meteorin-beta. PMID- 30464052 TI - Practice evaluation of biobank ethics and governance: current needs and future perspectives. AB - BACKGROUND: Biobank research faces many ethical challenges. Ethics research aims to develop standards for governance to meet these challenges by elaborating overarching normative principles of medical ethics in the context of biobanking. Most ethical standards are widely agreed on among biobank stakeholders and entail specific governance solutions, for example, adoption of consent procedures. In order to fully meet its goal, every governance solution needs to be implemented, evaluated and, if necessary, adapted and improved in practice. This study reviews the scientific literature on biobank ethics and governance in order to identify studies that specifically focus on practice evaluation of biobank governance. METHODS: A PubMed search was carried out. Retrieved literature was categorised and thematically clustered. All studies that focus on practice evaluation were reviewed and their objectives, results, and recommendations for practice summarised. RESULTS: The findings show that the majority of studies on biobank ethics and governance are theoretical; only 25 out of 922 studies empirically evaluate biobank governance in practice. The majority of these (14; 59%) focused on informed consent. Six studies (24%) addressed practice evaluation of sample and data access; the rest focused on public involvement, ethics reporting and incidental findings. Other relevant governance areas such as ethics review, priority setting and sample ownership were not addressed. CONCLUSION: In order to fulfil the ethical goals, more empirical research is needed that provides information on how governance mechanisms perform in practice and what improvements are needed. PMID- 30464054 TI - Cancer immunotherapy: challenges and clinical applications. PMID- 30464053 TI - From gestalt to gene: early predictive dysmorphic features of PMM2-CDG. AB - INTRODUCTION: Phosphomannomutase-2 deficiency (PMM2-CDG) is associated with a recognisable facial pattern. There are no early severity predictors for this disorder and no phenotype-genotype correlation. We performed a detailed dysmorphology evaluation to describe facial gestalt and its changes over time, to train digital recognition facial analysis tools and to identify early severity predictors. METHODS: Paediatric PMM2-CDG patients were evaluated and compared with controls. A computer-assisted recognition tool was trained. Through the evaluation of dysmorphic features (DFs), a simple categorisation was created and correlated with clinical and neurological scores, and neuroimaging. RESULTS: Dysmorphology analysis of 31 patients (4-19 years of age) identified eight major DFs (strabismus, upslanted eyes, long fingers, lipodystrophy, wide mouth, inverted nipples, long philtrum and joint laxity) with predictive value using receiver operating characteristic (ROC) curveanalysis (p<0.001). Dysmorphology categorisation using lipodystrophy and inverted nipples was employed to divide patients into three groups that are correlated with global clinical and neurological scores, and neuroimaging (p=0.005, 0.003 and 0.002, respectively). After Face2Gene training, PMM2-CDG patients were correctly identified at different ages. CONCLUSIONS: PMM2-CDG patients' DFs are consistent and inform about clinical severity when no clear phenotype-genotype correlation is known. We propose a classification of DFs into major and minor with diagnostic risk implications. At present, Face2Gene is useful to suggest PMM2-CDG. Regarding the prognostic value of DFs, we elaborated a simple severity dysmorphology categorisation with predictive value, and we identified five major DFs associated with clinical severity. Both dysmorphology and digital analysis may help physicians to diagnose PMM2-CDG sooner. PMID- 30464055 TI - SEC31A mutation affects ER homeostasis, causing neurological syndrome. AB - BACKGROUND: Consanguineous kindred presented with an autosomal recessive syndrome of intrauterine growth retardation, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness and optic nerve atrophy with no eye fixation. Affected individuals died by the age of 4. Brain MRI demonstrated microcephaly, semilobar holoprosencephaly and agenesis of corpus callosum. We aimed at elucidating the molecular basis of this disease. METHODS: Genome-wide linkage analysis combined with whole exome sequencing were performed to identify disease-causing variants. Functional consequences were investigated in fruit flies null mutant for the Drosophila SEC31A orthologue. SEC31A knockout SH-SY5Y and HEK293T cell-lines were generated using CRISPR/Cas9 and studied through qRT-PCR, immunoblotting and viability assays. RESULTS: Through genetic studies, we identified a disease-associated homozygous nonsense mutation in SEC31A. We demonstrate that SEC31A is ubiquitously expressed, and that the mutation triggers nonsense-mediated decay of its transcript, comprising a practical null mutation. Similar to the human disease phenotype, knockdown SEC31A flies had defective brains and early lethality. Moreover, in line with SEC31A encoding one of the two coating layers comprising the Coat protein complex II (COP-II) complex, trafficking newly synthesised proteins from the endoplasmic reticulum (ER) to the Golgi, CRISPR/Cas9-mediated SEC31A null mutant cells demonstrated reduced viability through upregulation of ER-stress pathways. CONCLUSION: We demonstrate through human and Drosophila genetic and in vitro molecular studies, that a severe neurological syndrome is caused by a null mutation in SEC31A, reducing cell viability through enhanced ER-stress response, in line with SEC31A's role in the COP-II complex. PMID- 30464056 TI - EuMoBot: replicating euglenoid movement in a soft robot. AB - Swimming is employed as a form of locomotion by many organisms in nature across a wide range of scales. Varied strategies of shape change are employed to achieve fluidic propulsion at different scales due to changes in hydrodynamics. In the case of microorganisms, the small mass, low Reynolds number and dominance of viscous forces in the medium, requires a change in shape that is non-invariant under time reversal to achieve movement. The Euglena family of unicellular flagellates evolved a characteristic type of locomotion called euglenoid movement to overcome this challenge, wherein the body undergoes a giant change in shape. It is believed that these large deformations enable the organism to move through viscous fluids and tiny spaces. The ability to drastically change the shape of the body is particularly attractive in robots designed to move through constrained spaces and cluttered environments such as through the human body for invasive medical procedures or through collapsed rubble in search of survivors. Inspired by the euglenoids, we present the design of EuMoBot, a multi-segment soft robot that replicates large body deformations to achieve locomotion. Two robots have been fabricated at different sizes operating with a constant internal volume, which exploit hyperelasticity of fluid-filled elastomeric chambers to replicate the motion of euglenoids. The smaller robot moves at a speed of [Formula: see text] body lengths per cycle (20 mm min-1 or 2.2 cycles min-1) while the larger one attains a speed of [Formula: see text] body lengths per cycle (4.5 mm min-1 or 0.4 cycles min-1). We show the potential for biomimetic soft robots employing shape change to both replicate biological motion and act as a tool for studying it. In addition, we present a quantitative method based on elliptic Fourier descriptors to characterize and compare the shape of the robot with that of its biological counterpart. Our results show a similarity in shape of 85% and indicate that this method can be applied to understand the evolution of shape in other nonlinear, dynamic soft robots where a model for the shape does not exist. PMID- 30464057 TI - Metabolic cost underlies task-dependent variations in motor unit recruitment. AB - Mammalian skeletal muscles are comprised of many motor units, each containing a group of muscle fibres that have common contractile properties: these can be broadly categorized as slow and fast twitch muscle fibres. Motor units are typically recruited in an orderly fashion following the 'size principle', in which slower motor units would be recruited for low intensity contraction; a metabolically cheap and fatigue-resistant strategy. However, this recruitment strategy poses a mechanical paradox for fast, low intensity contractions, in which the recruitment of slower fibres, as predicted by the size principle, would be metabolically more costly than the recruitment of faster fibres that are more efficient at higher contraction speeds. Hence, it would be mechanically and metabolically more effective for recruitment strategies to vary in response to contraction speed so that the intrinsic efficiencies and contraction speeds of the recruited muscle fibres are matched to the mechanical demands of the task. In this study, we evaluated the effectiveness of a novel, mixed cost function within a musculoskeletal simulation, which includes the metabolic cost of contraction, to predict the recruitment of different muscle fibre types across a range of loads and speeds. Our results show that a metabolically informed cost function predicts favoured recruitment of slower muscle fibres for slower and isometric tasks versus recruitment that favours faster muscles fibres for higher velocity contractions. This cost function predicts a change in recruitment patterns consistent with experimental observations, and also predicts a less expensive metabolic cost for these muscle contractions regardless of speed of the movement. Hence, our findings support the premise that varying motor recruitment strategies to match the mechanical demands of a movement task results in a mechanically and metabolically sensible way to deploy the different types of motor unit. PMID- 30464058 TI - Estimating the relative importance of demic and cultural diffusion in the spread of the Neolithic in Scandinavia. AB - Using a database of early farming sites in Scandinavia, we estimate that the spread rate of the Neolithic was in the range 0.44-0.66 km yr-1 This is substantially slower (by about 50%) than the rate in continental Europe. We interpret this result in the framework of a new mathematical model that includes horizontal cultural transmission (acculturation), vertical cultural transmission (interbreeding) and demic diffusion (reproduction and dispersal of farmers). To parametrize the model, we estimate reproduction rates of early farmers using archaeological data (sum-calibrated probabilities for the dates of early Neolithic Scandinavian sites) and use them in a wave-of-advance model for the first time. Comparing the model with the archaeological data, we find that the percentage of the spread rate due to cultural diffusion is below 50% (except for very extreme parameter values, and even for them it is below 54%). This strongly suggests that the spread of the Neolithic in Scandinavia was driven mainly by demic diffusion. This conclusion, obtained from archaeological data, agrees qualitatively with the implications of ancient genetic data, but the latter are yet too few in Scandinavia to produce any quantitative percentage for the spread rate due to cultural diffusion. We also find that, on average, fewer than eight hunter-gatherers were incorporated in the Neolithic communities by each group of 10 pioneering farmers, via horizontal and/or vertical cultural transmission. PMID- 30464059 TI - Measuring bilayer surface energy and curvature in asymmetric droplet interface bilayers. AB - For the past decade, droplet interface bilayers (DIBs) have had an increased prevalence in biomolecular and biophysical literature. However, much of the underlying physics of these platforms is poorly characterized. To further our understanding of these structures, lipid membrane tension on DIB membranes is measured by analysing the equilibrium shape of asymmetric DIBs. To this end, the morphology of DIBs is explored for the first time using confocal laser scanning fluorescence microscopy. The experimental results confirm that, in accordance with theory, the bilayer interface of a volume-asymmetric DIB is curved towards the smaller droplet and a lipid-asymmetric DIB is curved towards the droplet with the higher monolayer surface tension. Moreover, the DIB shape can be exploited to measure complex bilayer surface energies. In this study, the bilayer surface energy of DIBs composed of lipid mixtures of phosphatidylgylcerol (PG) and phosphatidylcholine are shown to increase linearly with PG concentrations up to 25%. The assumption that DIB bilayer area can be geometrically approximated as a spherical cap base is also tested, and it is discovered that the bilayer curvature is negligible for most practical symmetric or asymmetric DIB systems with respect to bilayer area. PMID- 30464060 TI - Correction to 'Uncovering the underlying mechanism of cancer tumorigenesis and development under immune microenvironment from global quantification of the landscape'. PMID- 30464061 TI - Is biasing offspring sex ratio adaptive? A test of Fisher's principle across multiple generations of a wild mammal in a fluctuating environment. AB - Fisher's principle explains that population sex ratio in sexually reproducing organisms is maintained at 1 : 1 owing to negative frequency-dependent selection, such that individuals of the rare sex realize greater reproductive opportunity than individuals of the more common sex until equilibrium is reached. If biasing offspring sex ratio towards the rare sex is adaptive, individuals that do so should have more grandoffspring. In a wild population of North American red squirrels (Tamiasciurus hudsonicus) that experiences fluctuations in resource abundance and population density, we show that overall across 26 years, the secondary sex ratio was 1 : 1; however, stretches of years during which adult sex ratio was biased did not yield offspring sex ratios biased towards the rare sex. Females that had litters biased towards the rare sex did not have more grandoffspring. Critically, the adult sex ratio was not temporally autocorrelated across years, thus the population sex ratio experienced by parents was independent of the population sex ratio experienced by their offspring at their primiparity. Expected fitness benefits of biasing offspring sex ratio may be masked or negated by fluctuating environments across years, which limit the predictive value of the current sex ratio. PMID- 30464062 TI - Reproductive control via the threat of eviction in the clown anemonefish. AB - In social groups, high reproductive skew is predicted to arise when the reproductive output of a group is limited, and dominant individuals can suppress subordinate reproductive efforts. Reproductive suppression is often assumed to occur via overt aggression or the threat of eviction. It is unclear, however, whether the threat of eviction alone is sufficient to induce reproductive restraint by subordinates. Here, we test two assumptions of the restraint model of reproductive skew by investigating whether resource limitation generates reproductive competition and whether the threat of eviction leads to reproductive restraint in the clown anemonefish Amphiprion percula First, we use a feeding experiment to test whether reproduction is resource limited, which would create an incentive for the dominant pair to suppress subordinate reproduction. We show that the number of eggs laid increased in the population over the study period, but the per cent increase in fed groups was more than twice that in unfed groups (205% and 78%, respectively). Second, we use an eviction experiment to test whether the dominant pair evicts mature subordinates, which would create an incentive for the subordinates to forgo reproduction. We show that mature subordinates are seven times more likely to be evicted than immature subordinates of the same size. In summary, we provide experimental support for the assumptions of the restraint model by showing that resource limitation creates reproductive competition and a credible threat of eviction helps explain why subordinates forego reproduction. Transactional models of reproductive skew may apply well to this and other simple systems. PMID- 30464063 TI - Rethinking dopamine as generalized prediction error. AB - Midbrain dopamine neurons are commonly thought to report a reward prediction error (RPE), as hypothesized by reinforcement learning (RL) theory. While this theory has been highly successful, several lines of evidence suggest that dopamine activity also encodes sensory prediction errors unrelated to reward. Here, we develop a new theory of dopamine function that embraces a broader conceptualization of prediction errors. By signalling errors in both sensory and reward predictions, dopamine supports a form of RL that lies between model-based and model-free algorithms. This account remains consistent with current canon regarding the correspondence between dopamine transients and RPEs, while also accounting for new data suggesting a role for these signals in phenomena such as sensory preconditioning and identity unblocking, which ostensibly draw upon knowledge beyond reward predictions. PMID- 30464065 TI - Discovery and exploitation of a natural ecological trap for a mosquito disease vector. AB - Ecological traps occur due to a mismatch between a habitat's attractiveness and quality, wherein organisms show preference for low-quality habitats over other available high-quality habitats. Our previous research identified leaf litter from common blackberry (Rubus allegheniensis) as a natural ecological trap for an important vector for West Nile virus (Culex pipiens), attracting mosquitoes to oviposit in habitats deleterious to the survival of their larvae. Here we demonstrate that manipulation of leaf litter in stormwater catch basins, an important source of disease vector mosquitoes in urban environments, can increase Cx. pipiens oviposition but reduce survival. In a series of experiments designed to elucidate the mechanisms that explain the attractive and lethal properties of this native plant, behavioural bioassays suggest that oviposition site selection by Cx. pipiens is mediated primarily by chemical cues as leaves decompose. However, we also show that juvenile mosquito survival is mainly related to the suitability of the bacterial community in the aquatic habitat for mosquito nutritional needs, which does not appear to create a cue that influences oviposition choice. This mismatch between oviposition cues and drivers of larval habitat quality may account for the ecological trap phenomenon detected in this study. Our findings provide new insights into potential mechanistic pathways by which ecological traps may occur in nature and proof-of-concept for a new 'attract-and-kill' tool for mosquito control. PMID- 30464066 TI - Cultural revolutions reduce complexity in the songs of humpback whales. AB - Much evidence for non-human culture comes from vocally learned displays, such as the vocal dialects and song displays of birds and cetaceans. While many oscine birds use song complexity to assess male fitness, the role of complexity in humpback whale (Megaptera novaeangliae) song is uncertain owing to population wide conformity to one song pattern. Although songs change gradually each year, the eastern Australian population also completely replaces their song every few years in cultural 'revolutions'. Revolutions involve learning large amounts of novel material introduced from the Western Australian population. We examined two measures of song structure, complexity and entropy, in the eastern Australian population over 13 consecutive years. These measures aimed to identify the role of complexity and information content in the vocal learning processes of humpback whales. Complexity was quantified at two hierarchical levels: the entire sequence of individual sound 'units' and the stereotyped arrangements of units which comprise a 'theme'. Complexity increased as songs evolved over time but decreased when revolutions occurred. No correlation between complexity and entropy estimates suggests that changes to complexity may represent embellishment to the song which could allow males to stand out amidst population-wide conformity. The consistent reduction in complexity during song revolutions suggests a potential limit to the social learning capacity of novel material in humpback whales. PMID- 30464064 TI - The role of citizen science in addressing grand challenges in food and agriculture research. AB - The power of citizen science to contribute to both science and society is gaining increased recognition, particularly in physics and biology. Although there is a long history of public engagement in agriculture and food science, the term 'citizen science' has rarely been applied to these efforts. Similarly, in the emerging field of citizen science, most new citizen science projects do not focus on food or agriculture. Here, we convened thought leaders from a broad range of fields related to citizen science, agriculture, and food science to highlight key opportunities for bridging these overlapping yet disconnected communities/fields and identify ways to leverage their respective strengths. Specifically, we show that (i) citizen science projects are addressing many grand challenges facing our food systems, as outlined by the United States National Institute of Food and Agriculture, as well as broader Sustainable Development Goals set by the United Nations Development Programme, (ii) there exist emerging opportunities and unique challenges for citizen science in agriculture/food research, and (iii) the greatest opportunities for the development of citizen science projects in agriculture and food science will be gained by using the existing infrastructure and tools of Extension programmes and through the engagement of urban communities. Further, we argue there is no better time to foster greater collaboration between these fields given the trend of shrinking Extension programmes, the increasing need to apply innovative solutions to address rising demands on agricultural systems, and the exponential growth of the field of citizen science. PMID- 30464067 TI - Frogs adapt to physiologically costly anthropogenic noise. AB - Human activities impose novel pressures on amphibians, which are experiencing unprecedented global declines, yet population-level responses are poorly understood. A growing body of literature has revealed that noise is an anthropogenic stressor that impacts ecological processes spanning subcellular to ecosystem levels. These consequences can impose novel selective pressures on populations, yet whether populations can adapt to noise is unknown. We tested for adaptation to traffic noise, a widespread sensory 'pollutant'. We collected eggs of wood frogs (Rana sylvatica) from populations from different traffic noise regimes, reared hatchlings under the same conditions, and tested frogs for differences in sublethal fitness-relevant effects of noise. We show that prolonged noise impaired production of antimicrobial peptides associated with defence against disease. Additionally, noise and origin site interacted to impact immune and stress responses. Noise exposure altered leucocyte production and increased baseline levels of the stress-relevant glucocorticoid, corticosterone, in frogs from quiet sites, but noise-legacy populations were unaffected. These results suggest noise-legacy populations have adapted to avoid fitness-relevant physiological costs of traffic noise. These findings advance our understanding of the consequences of novel soundscapes and reveal a pathway by which anthropogenic disturbance can enable adaptation to novel environments. PMID- 30464068 TI - The influence of cactus spine surface structure on puncture performance and anchoring ability is tuned for ecology. AB - Spines are common morphological features found in almost all major biological groups offering an opportunity to explore large-scale evolutionary convergence across disparate clades. As an example, opuntioid cacti have spines with barbed ornamentation that is remarkably similar in form and scale to that found on porcupine quills, suggesting specific biomechanical convergence across the animal and plant kingdoms. While the mechanics of porcupine quills as defensive mechanisms has been previously tested, the mechanics of cactus spines (which have evolved to fill a number of functions including defence, climbing and dispersal) has not been characterized. Here we study the puncturing and anchoring ability of six species of cactus, including both barbed and non-barbed spines. We found that barbed spines require less work to puncture a variety of targets than non-barbed spines. Barbed spines also require more work than non-barbed spines to withdraw from biological materials, owing to their barbs engaging with tissue fibres. These results closely match those found previously for barbed versus non-barbed porcupine quills, implying biomechanical convergence. The variation in performance of barbed versus non-barbed spines, as well as between barbed spines from different species, is probably tied to the diversity of ecological functions of cactus spines. PMID- 30464069 TI - Sex bias in ability to cope with cancer: Tasmanian devils and facial tumour disease. AB - Knowledge of the ecological dynamics between hosts and pathogens during the initial stages of disease emergence is crucial to understanding the potential for evolution of new interspecific interactions. Tasmanian devil (Sarcophilus harrisii) populations have declined precipitously owing to infection by a transmissible cancer (devil facial tumour disease, DFTD) that emerged approximately 20 years ago. Since the emergence of DFTD, and as the disease spreads across Tasmania, the number of devils has dropped up to 90% across 80% of the species's distributional range. As a result, the disease is expected to act as a strong selective force on hosts to develop mechanisms of tolerance and/or resistance to the infection. We assessed the ability of infected devils to cope with infection, which translates into host tolerance to the cancer, by using the reaction norm of the individual body condition by tumour burden. We found that body condition of infected hosts is negatively affected by cancer progression. Males and females presented significant differences in their tolerance levels to infection, with males suffering declines of up to 25% of their body condition, in contrast to less than 5% in females. Sex-related differences in tolerance to cancer progression may select for changes in life-history strategies of the host and could also alter the selective environment for the tumours. PMID- 30464070 TI - Correction to 'Variation in individual temperature preferences, not behavioural fever, affects susceptibility to chytridiomycosis in amphibians'. PMID- 30464074 TI - Rosai Dorfman disease and peripheral T-cell lymphoma: A rare co-occurrence. PMID- 30464072 TI - Pathophysiological Role of S-Nitrosylation and Transnitrosylation Depending on S Nitrosoglutathione Levels Regulated by S-Nitrosoglutathione Reductase. AB - Nitric oxide (NO) mediates various physiological and pathological processes, including cell proliferation, differentiation, and inflammation. Protein S nitrosylation (SNO), a NO-mediated reversible protein modification, leads to changes in the activity and function of target proteins. Recent findings on protein-protein transnitrosylation reactions (transfer of an NO group from one protein to another) have unveiled the mechanism of NO modulation of specific signaling pathways. The intracellular level of S-nitrosoglutathione (GSNO), a major reactive NO species, is controlled by GSNO reductase (GSNOR), a major regulator of NO/SNO signaling. Increasing number of GSNOR-related studies have shown the important role that denitrosylation plays in cellular NO/SNO homeostasis and human pathophysiology. This review introduces recent evidence of GSNO-mediated NO/SNO signaling depending on GSNOR expression or activity. In addition, the applicability of GSNOR as a target for drug therapy will be discussed in this review. PMID- 30464073 TI - Inhibition of the Expression of Matrix Metalloproteinases in Articular Chondrocytes by Resveratrol through Affecting Nuclear Factor-Kappa B Signaling Pathway. AB - In the present study, we tried to examine whether resveratrol regulates the expression of matrix metalloproteinases (MMPs) through affecting nuclear factor kappa B (NF-kappaB) in articular chondrocytes. Rabbit articular chondrocytes were cultured in a monolayer, and reverse transcription-polymerase chain reaction (RT PCR) was used to measure interleukin-1beta (IL-1beta)-induced gene expression of MMP-3, MMP-1, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4), ADAMTS-5 and type II collagen. Effect of resveratrol on IL 1beta-induced secretion of MMP-3 was investigated in rabbit articular chondrocytes using western blot analysis. To elucidate the action mechanism of resveratrol, effect of resveratrol on IL-1beta-induced NF-kappaB signaling pathway was investigated in SW1353, a human chondrosarcoma cell line, by western blot analysis. The results were as follows: (1) resveratrol inhibited the gene expression of MMP-3, MMP-1, MMP-13, ADAMTS-4, and ADAMTS-5, but increased the gene expression of type II collagen; (2) resveratrol reduced the secretion of MMP 3; (3) resveratrol inhibited IL-1beta-induced activation (phosphorylation) of inhibitory kappa B kinase (IKK), and thus phosphorylation and degradation of inhibitory kappa Balpha (IkappaBalpha); (4) resveratrol inhibited IL-1beta induced phosphorylation and nuclear translocation of NF-kappaB p65. This, in turn, led to the down-regulation of gene expression of MMPs in SW1353 cells. These results suggest that resveratrol can regulate the expression of MMPs through affecting NF-kappaB by directly acting on articular chondrocytes. PMID- 30464075 TI - Detection of avian encephalomyelitis virus in chickens in Japan using RT-PCR. AB - A reverse transcription-polymerase chain reaction (RT-PCR) method was developed for broadly detecting the avian encephalomyelitis virus (AEV). The new primers were based on conserved sequences of the 5'-untranslated region of AEV, because the virus was not detected using previous reported RT-PCR. By applying this method to the chicken samples with suspected AEV infection in Japan, we successfully obtained PCR products of the predicted size from all samples, and we confirmed the presence of AEV via sequence analysis. PMID- 30464071 TI - Sex Differences in Cardiovascular Risk Factors for Dementia. AB - Dementia, characterized by a progressive cognitive decline and a cumulative inability to behave independently, is highly associated with other diseases. Various cardiovascular disorders, such as coronary artery disease and atrial fibrillation, are well-known risk factors for dementia. Currently, increasing evidence suggests that sex factors may play an important role in the pathogenesis of diseases, including cardiovascular disease and dementia. Recent studies show that nearly two-thirds of patients diagnosed with Alzheimer's disease are women; however, the incidence difference between men and women remains vague. Therefore, studies are needed to investigate sex-specific differences, which can help understand the pathophysiology of dementia and identify potential therapeutic targets for both sexes. In the present review, we summarize sex differences in the prevalence and incidence of dementia by subtypes. This review also describes sex differences in the risk factors of dementia and examines the impact of risk factors on the incidence of dementia in both sexes. PMID- 30464076 TI - Severe whipworm (Trichuris spp.) infection in the hamadryas baboon (Papio hamadryas). AB - A 3-year-old male hamadryas baboon (Papio hamadryas) at the Seoul Zoo, Korea, died without any previous symptoms. Necropsy revealed severe whipworm infection in the large intestine. The animal weighed 2.6 kg and had a blood clot at the anus. Numerous whipworms were found attached to the intestinal wall, with their anterior ends embedded in the mucosa. Fecal microscopy revealed typical barrel shaped, brown eggs of Trichuris spp., with hyaline polar plugs at each end. Histopathological examination revealed the thin anterior part of Trichuris spp. embedded in the mucosal layer and the thick posterior part at the mucosal surface or hanging freely in the intestinal lumen. This case emphasizes the importance of parasitic infection management in zoo animals. PMID- 30464077 TI - Immunohistochemical characterization of myofibroblasts appearing in isoproterenol induced rat myocardial fibrosis. AB - Fibrotic lesion is formed by myofibroblasts capable of producing collagens. The myofibroblasts are characterized by immunoexpressions of vimentin, desmin and alpha-smooth muscle actin (alpha-SMA) in varying degrees. The cellular characteristics remain investigated in myocardial fibrosis. We analyzed immunophenotypes of myofibroblasts appearing in isoproterenol-induced myocardial fibrosis in rats until 28 days after injection (10 mg/kg body weight); the lesions developed as interstitial edema and inflammatory cell reaction on 8 hr and days 1 and 3, and fibrosis occurred on days 1, 3, 7, 14, and 21 by gradual deposition of collagens, showing the greatest grade on day 14; the lesions gradually reduced with sporadic scar until day 28. Myofibroblasts expressing vimentin and alpha-SMA increased with a peak on day 3, and then, gradually decreased onwards. Interestingly, Thy-1 expressing cells appeared in the affected areas, apparently being corresponding to the grade similar to vimentin- and alpha SMA-positive cells. Thy-1 is expressed in immature mesenchymal cells such as pericytes with pluripotent nature. The immunoreactivity for A3-antigen, a marker for immature mesenchymal cells, was seen in some surrounding cells. There were no cells reacting with antibodies to nestin or glial fibrillary acidic protein, although hepatic myofibroblats have been reported to react with these antibodies. Collectively, myofibroblasts appearing in rat myocardial fibrosis may have been derived from immature mesenchymal cells positive for Thy-1 or A3-antigen, with thereafter showing expressions of vimentin and alpha-SMA in differentiation. PMID- 30464078 TI - [ALLERGIC SKIN DISORDERS]. PMID- 30464079 TI - [TOPICS 2017 IN BRONCHIAL ASTHMA]. PMID- 30464080 TI - [JAPANESE PEDIATRIC GUIDELINE FOR THE TREATMENT AND MANAGEMENT OF ASTHMA 2017 KEY ESSENCE OF THE LONG-TERM MANAGEMENT IN THE REVISED VERSION]. PMID- 30464081 TI - [ASTHMA PREVENTION AND MANAGEMENT GUIDELINE 2018]. PMID- 30464082 TI - [ASTHMA AND MENTAL STRESS]. PMID- 30464083 TI - [ROLE OF GLUTATHIONE REDOX IN ALLERGIC DISEASES]. PMID- 30464084 TI - ? PMID- 30464085 TI - ? PMID- 30464086 TI - ? PMID- 30464087 TI - [Erratum : EVALUATION OF DRUG ERUPTION RELATED HELICOBACTER PYLORI ERADICATION THERAPY[Japanese Journal of Allergology Vol.67 (2018) No.8 p.1020-1026]]. PMID- 30464088 TI - Magmaris Bioresorbable Scaffold - Possible Dismantling 2 Months After Implantation on Intravascular Ultrasound. PMID- 30464090 TI - Variation in the MC1R, ASIP, and MATP genes responsible for coat color in Kiso horse as determined by SNaPshotTM genotyping. AB - Kiso horse is a breed of Japanese native horses. In this study, to clarify coat color gene variation in Kiso horses, we used SNaPshotTM genotyping to evaluate variation in MC1R, ASIP, and MATP genes at the Extension (E), Agouti (A), and Cream dilution (C) loci. The coat color of 149 horses was documented. The coat color of 140, 3, and 6 horses was bay, chestnut, and buckskin, respectively. Furthermore, the frequency of alleles E, e, A, a, C, and Cr was 0.80, 0.20, 0.86, 0.14, 0.98, and 0.02, respectively. Current status of coat color genes in Kiso horses was clarified, and this information will help plan further conservation of these horses. PMID- 30464089 TI - Hatano rats are a suitable metabolic syndrome model for studying feeding behavior, blood pressure levels, and percent body fat. AB - Currently, metabolic syndrome is a worldwide concern. Thus, it is imperative to understand the mechanism of metabolic syndrome by establishing various metabolic syndrome models. In this study, we used Hatano high-avoidance animals (HAA) and low-avoidance animals (LAA), both derived from Sprague-Dawley rats by selective breeding to determine high- or low-avoidance rates in shuttle-box active avoidance tests. HAA and LAA rats have some strain differences related to eating and appetite. Therefore, we determined whether Hatano rats could be used as a metabolic syndrome model. We compared food intake, body weights, blood pressure levels, plasma component levels, and fat contents between HAA and LAA rats. The HAA rats showed more active eating, higher blood pressure, higher percentage fat, and higher triglyceride levels than the LAA rats-these features correspond to some of the risk factors associated with metabolic syndrome. Our study suggests that HAA rats can be considered as a metabolic syndrome model by focusing on their feeding behavior, blood pressure levels, and percent body fat. PMID- 30464091 TI - Heat challenge influences serum metabolites concentrations and liver lipid metabolism in Japanese quail (Coturnix japonica). AB - High temperature induces various metabolic disturbances in animals. However, no comprehensive information is currently available on the metabolic pathway affected by high environmental temperature. The present study examined metabolite content in the serum of heat challenged quails using metabolomic analysis. In the present study, female quails with normal laying rate at 20 weeks kept in standard condition (control group) or exposed to 34 degrees C 4 hr per day (12:00 hr to 16:00 hr) (heat group) for 10 consecutive days. The metabolomic analysis identified 165 metabolites in the serum, and significant differences were observed in the serum for 7 metabolites between two groups. An analysis by MetaboAnalyst, a web-based metabolome data tool, indicate that high temperature affect ketone body metabolism, butyrate metabolism, arginine and proline metabolism. Furthermore, histological examination of liver indicates a heat challenge induced abnormal lipid metabolism. Triglyceride and cholesterol level in the liver increased, however cholesterol level decreased in the serum. Genes related to lipid metabolism significantly increased in the liver after heat challenge. The present study demonstrated that high temperature cause liver damage, thus lipid metabolic was affected. Protect liver under high temperature could be one solution for coping with high temperatures in summer. PMID- 30464092 TI - Triterpenoid saponins from Ardisia gigantifolia stapf. and mechanism on inhibiting proliferation of MDA-MB-231 cells. AB - Seventeen 13, 28-epoxy triterpenoid saponins obtained from Ardisia gigantifolia stapf. were evaluated their anti-proliferative activities on MCF-7 cells. The structure-activity relationship analysis indicated that CH3 group at C-30, four saccharide units with L-rhamnose at R6 in the sugar units are crucial for the cytotoxic activity on MCF-7. Compounds 1, 2, 6, 7, 12, 14 were selected to identify the anti-proliferative activity on the other three breast cancer cell lines (T47D, MDA-MB-231 and SK-BR-3). Compounds (2, 6, 7) with good activity on MCF-7 also showed activity on T47D, MDA-MB-231 and SK-BR-3. Compounds (12 and 14) without cytotoxic activity on MCF-7 almost showed no activities on the other three cell lines. For the triple-negative breast cancer MDA-MB-231,Saponins 7 and 14 showed selective cytotoxic activity, 7 showed much more activity than 14, suggesting the six saccharide units in sugar units and CH3 on C-30 were the key moieties for the anti-proliferative activities. Further molecular mechanism of saponin 7 was studied on inhibiting cell proliferation of MDA-MB-231 cells. Saponin 7 could enhance apoptosis, arrest cell cycles, decrease MMPs, and considered the involvement of ROS may explain this conundrum. PMID- 30464093 TI - [Kinetic Analysis and Motion Management]. PMID- 30464094 TI - [Impact of Respiratory Motion on Dose Variation in Radiation Therapy for Glottic Cancer]. AB - In radiation therapy for glottic cancer, respiratory motion of larynx may change the dose variation in the target. The purpose of this study is to measure the respiratory motion of the larynx, and quantify the impact of the motion on the dose variation. This study included 10 patients treated by opposing portal irradiation for glottic cancer. We acquired fluoroscopy and respiratory waveform of the patients simultaneously and formulated the relationship between the displacement of larynx and the respiratory phase. We divided one field into 39 sub-fields on the basis of control points. Dose distributions accounting for the displacement were calculated by shifting isocenter calculated using the formula in every sub-fields. Dose variations of clinical target volume (CTV) were evaluated by subtracting dose distributions with displacement consideration and dose distributions without it. Average amplitude and the maximum amplitude of respiratory motion were 2.5 and 8.7 mm, respectively. Average of mean dose variation in CTV was 0.1% of the prescribed dose, and maximum of local dose variation was 2.0% of the prescribed dose. Hence, it is realized that dose variation in CTV by respiratory motion was slight. PMID- 30464095 TI - [Standardization of Analysis Conditions and Prediction of Increase Prediction Using Blood Flow Analysis Software for Cerebral Aneurysms: Phantom Study and Clinical Study]. AB - In recent years, reports have been made that predict the state of aneurysm by performing computational fluid dynamics (CFD) analysis using cerebral aneurysm blood flow analysis software. However, analysis results are not constant and there are various opinions, and it is conceivable that the image quality and analysis conditions of medical images used for CFD analysis are not standardized. In this study, CFD analysis of cerebral aneurysm phantom was performed, and image quality and analysis conditions were standardized. Then, we investigated whether increase of cerebral aneurysm and prediction of rupture are possible. From this study, stable results of wall shear stress analysis were obtained under slice thickness 1.0 mm or less, CT value 400 HU or more, reconstruction function as soft part function, image SD under 10 HU. In addition, as the size of the cerebral aneurysm became larger, wall shear stress tended to be lower, and the same tendency was shown also in clinical cases. Although CFD analysis using software dedicated to blood flow analysis did not reach the prediction of rupture, it can be evaluated based on the quantitative values for the aneurysm increase at the preceding stage and plays an important role in prediction there is a possibility. PMID- 30464096 TI - [Development of Monitoring Method of Respiratory Waveform in Thoracicoabdominal Part Using Web Camera]. AB - Countermeasures against respiratory movement are important for tumors of thorax and abdomen in stereotactic body radiation therapy. In the present paper, a web camera-based-respiratory monitoring method without contact with patient's body was proposed for respiratory study. Thoracic and abdominal motion images were taken by a web camera, and were analyzed using simple image-processing techniques for obtaining respiratory waveforms. Four motion images with different respiration rate were obtained from resusci anne simulator. Respiration waveforms were estimated from the moving images by the proposed method, and were compared with respiration waveforms obtained by the conventional respiratory monitoring device. That was found to have a strong correlation. In addition, the two waveforms were similar in Bland-Altman method comparison. The proposed method can provide non-contact, non-invasive, simple, and realistic respiratory monitoring system for radiotherapy. PMID- 30464097 TI - [Imaging Parameter Optimization of 3D Phase Contrast-MRA to Reduce Susceptibility artifact and Radiofrequency-shielding around the Intracranial Stent]. AB - The purpose of this study was to evaluate the degree of signal attenuation generated around the stent by the susceptibility artifacts and radiofrequency (RF) shielding in phase contrast-magnetic resonance angiography (PCA) images and construct optimal PCA imaging parameters for intracranial stent lumen images. The two types of PCA images of stents (Neuroform, Enterpraise II) placed in the vascular flow phantom were imaged with different the flip angle (FA) and echo time (TE). Each original image of the vascular flow phantom was reconstructed into a coronal multiplanar reconstruction (MPR) image and a profile curve along the long axis of the stent was calculated. The reduction of in-stent signal was assessed by relative in-stent signal (RIS) calculated by comparing intra-stent signal intensity to the reference tube in the original images. When the TE was 2.3 ms, the profile curve was the highest signal intensity. However, RIS had not changed by the extension of TE. When the FA was high, the RIS showed a high value, but when it exceeded 25 degrees, the signal attenuated in the distal part of the slab.The susceptibility artifacts and RF shielding generated around the stent can be reduced by the shortest TbE (2.3 ms) and 20 degrees of FA in the PCA imaging. PMID- 30464098 TI - [Basic Investigation of a Cerebral Blood Flow Quantification Method without Blood Sampling Method (Improved Brain Uptake Ratio (IBUR)) Using a Fan-beam Collimator]. AB - We performed a basic evaluation for measuring the input function using a fan-beam collimator. Furthermore, we examined the validity of the brain blood flow quantitative measurement from the input function. Using the fanbeam collimator, we imaged syringes of various diameters containing 99 mTc as well as a virtual aorta inside a thoracic phantom. We changed the collimator distance and angle in relation to the sources, and the syringe was placed in vertical and horizontal positions as well. For evaluation, we used region of interest (ROI) of various sizes and positions. Furthermore, we conducted clinical evaluation for 19 subjects and calculated whole-brain mean cerebral blood flow using improved brain uptake ratio method by examination of 99 mTc-ECD cerebral blood flow. For ROIs smaller in size than diameter of the syringes and virtual ascending aorta, amount of change in the ROI counts by fan-beam collimator became smaller as distance to the source became closer, with less than 5% at 175 mm. Also, change with respect to angle of the collimator was less than 5% at 20 degrees . In a clinical study, aortas could be imaged without truncation and input-functions could be measured in all 19 patients. By using ROIs smaller than the aorta diameter and placing the collimator close to the source, it was suggested that fan-beam collimator can be used to determine the input function. PMID- 30464099 TI - [Comparison of Kinetic Curve between Gadodiamide Hydrate and Gadobutrol on Breast Dynamic Contrast-enhanced Magnetic Resonance Imaging in Invasive Ductal Carcinoma]. AB - The shape of the kinetic curve for gadobutrol is reportedly different compared with that for other conventional contrast agents. We speculate that the shape of gadobutrol kinetic curve may be influenced by different magnetic resonance imaging (MRI) protocols and evaluation methods. The purpose of our study was to assess the influence between gadobutrol and other conventional contrast agent (gadodiamide hydrate) on the kinetic curve in invasive ductal carcinoma (IDC). We assessed 139 women of IDC in this study. Gadodiamide hydrate (2 ml/s) was administered to 69 women, and gadobutrol (1 ml/s) was administrated to 70 women, both contrast agents at 0.1 mmol/kg BW. When the kinetic curves of contrast agents were evaluated between by Breast Imaging Reporting and Data System (BI RADS) 4th edition and BI-RADS 5th edition, suggested that the analysis method of BI-RADS may affect. Patient group who were administered gadobutrol demonstrated a lower washout rate when compared with patient group who were administered gadodiamide hydrate administration (P<0.01). These results suggest that the kinetic curve characteristics of gadobutrol are an important consideration in diagnosis. Therefore, it is necessary to perform image diagnosis by considering the influence of the contrast agent and the analysis method, when image diagnostic doctor perform image diagnosis. PMID- 30464100 TI - [Usefulness of the Principle of Selective Excitation Technique Non electrocardiogramgated 3D-TOF Method in Lower-extremity MRA Using a Whole-body Coil]. AB - PURPOSE: Generally, non-contrast, lower-extremity, magnetic resonance angiography (MRA) uses electrocardiography; thus, examination is difficult in patients who exhibit arrhythmia. However, the use of electrocardiography can be avoided by using the selective excitation technique in non-electrocardiogram-gated three dimensional time-of-flight (TOF) (pNon-Gate) MRA. Therefore, patients who exhibit arrhythmia can be examined with pNon-Gate MRA. The purpose of this study was to assess the usefulness of pNon-Gate MRA by using a whole-body coil. METHODS: Images acquired using pNon-Gate MRA were compared with images acquired using electrocardiogram-gated two-dimensional TOF (Gate) MRA. Comparisons comprised visual evaluation, as well as comparisons of contrast-to-noise ratio and imaging time. RESULTS: In visual evaluation of the pelvic region, Gate MRA showed better results than pNon-Gate MRA. In terms of contrast-to-noise ratio, there were no significant differences in either region. Imaging time showed no significant differences between the two methods. However, it exceeded 30 minutes frequently for Gate MRA, but rarely for pNon-Gate MRA. CONCLUSIONS: pNon-Gate MRA is useful in patients with frequent arrhythmia and in those with difficulty in maintaining long-term postures. By using a whole-body coil, pNon-Gate MRA enables easier patient positioning and setting. Therefore, pNon-Gate MRA can be used in routine examinations. PMID- 30464102 TI - [Visualization of Organ Motion Using Four Dimensional Cone-beam CT and Its Applications]. PMID- 30464101 TI - [Analysis of Myocardial T1 Value for Japanese Healthy Subjects with Non-contrast Myocardium T1 Mapping]. AB - The purpose of this study was to analyze the native T1 value of myocardium and the relationship between myocardial native T1 value and gender, age and myocardial areas in Japanese. The subject of this study was 145 Japanese healthy subjects who underwent cardiac magnetic resonance imaging (MRI) at medical examination. MRI scanner was Ingenia 1.5T (Philips Healthcare, Best, The Netherlands). T1 mapping was acquired with modified look-locker inversion recovery method using IR pulse. The native T1 value of all subjects was 983.5+/ 34.8 ms, and we were able to acquire the reference value of the native T1 value at our hospital. The native T1 value was significantly higher in females than in males. There was variation in native T1 value among the myocardial areas, and the native T1 value was significantly higher in the septum than in the lateral region. In the future, collaborative research in multicenter is necessary to obtain the reference value of Japanese. PMID- 30464103 TI - [Medicine in New Era with Artificial Intelligence and Systems Biology]. PMID- 30464104 TI - [4. Commissioning and Clinical Application of the Respiratory Motion Management in Radiation Therapy]. PMID- 30464105 TI - [Reconsideration of Hepatic Multiphasic Contrast-enhanced CT Theory? What Should We Give Priority to? ?]. PMID- 30464106 TI - [Radiomics in Nuclear Medicine]. PMID- 30464107 TI - [Participation/Dispatch Reports on International Conferences in 2018]. PMID- 30464108 TI - [Revision of Fair Competition Code Operation Standard]. PMID- 30464109 TI - [Aiming to Next-generation for Japanese Society of Radiological Technology]. PMID- 30464110 TI - Prognostic Impact of beta-Blocker Dose After Acute Myocardial Infarction. AB - BACKGROUND: The differential prognostic impact of beta-blocker dose after acute myocardial infarction (AMI) has been under debate. The current study sought to compare clinical outcome after AMI according to beta-blocker dose using the Korea Acute Myocardial Infarction Registry-National Institutes of Health (KAMIR-NIH). Methods and Results: Of the total population of 13,104 consecutive AMI patients enrolled in the KAMIR-NIH, the current study analyzed 11,909 patients. These patients were classified into 3 groups (no beta-blocker; low-dose [<25% of target dose]; and high-dose [>=25% of target dose]). The primary outcome was cardiac death at 1 year. Compared with the no beta-blocker group, both the low-dose and high-dose groups had significantly lower risk of cardiac death (HR, 0.435; 95% CI: 0.363-0.521, P<0.001; HR, 0.519; 95% CI: 0.350-0.772, P=0.001, respectively). The risk of cardiac death, however, was similar between the high- and low-dose groups (HR, 1.194; 95% CI: 0.789-1.808, P=0.402). On multivariable adjustment and inverse probability weighted analysis, the result was the same. CONCLUSIONS: The use of beta-blockers in post-AMI patients had significant survival benefit compared with no use of beta-blockers. There was no significant additional benefit of high-dose beta-blockers compared with low-dose beta-blockers, however, in terms of 1-year risk of cardiac death. PMID- 30464111 TI - Greater Nocturnal Blood Pressure Is Associated With Natriuretic Peptide Level in Aortic Stenosis With Preserved Ejection Fraction. AB - BACKGROUND: Although careful monitoring of asymptomatic severe aortic stenosis (AS) is recommended to prevent missing the optimal timing of surgical or transcatheter aortic valve replacement, prophylactic treatment that could extend the asymptomatic period remains unknown. In a hypertensive population, high blood pressure (BP) measured at the doctor's office is known to be associated with B type natriuretic peptide (BNP) level, a surrogate marker for symptomatic deterioration in AS. Little is known regarding the association between nocturnal BP variables and BNP in severe AS with preserved ejection fraction (EF). Methods and Results: The subjects consisted of 78 severe AS patients (mean age, 79+/-6 years) with preserved EF. Nocturnal BP was measured hourly using a home BP monitoring device. On multiple regression analysis, nocturnal mean systolic BP (SBP) remained independently associated with BNP after adjustment for age, sex, body mass index, estimated glomerular filtration rate, antihypertensive medication class, early diastolic mitral annular velocity, and left ventricular mass index (P=0.03), whereas diastolic BP (DBP) and variables of BP variability were not. CONCLUSIONS: Higher nocturnal SBP rather than DBP or indices of BP variability was independently associated with BNP in AS patients with preserved EF. Intervention for nocturnal SBP may therefore extend the asymptomatic period and improve prognosis. PMID- 30464112 TI - Low Cholesterol Levels Increase Symptomatic Intracranial Hemorrhage Rates After Intravenous Thrombolysis: A Multicenter Cohort Validation Study. AB - AIM: Although a lower level of non-high-density lipoprotein cholesterol (HDL-C) was reported to be inversely associated with spontaneous intracranial hemorrhage (ICH), no enough evidence has verified whether lipid profiles modify hemorrhagic transformation and functional outcomes in patients with acute ischemic treated with thrombolysis. METHODS: This multicenter cohort study included 2373 patients with acute ischemic stroke treated with intravenous thrombolysis between December 2004 and December 2016. Of these, 1845 patients were categorized into either the hyperlipidemia or non-hyperlipidemia group. Symptomatic ICH (SICH) rates within 24-36 h of thrombolytic onset and functional outcomes at 30 and 90 days were longitudinally surveyed. Models of predicting hemorrhagic transformation were used to validate our findings. RESULTS: For enrolled 1845 patients, SICH rates were >=2-fold reduced for the hyperlipidemia group by the NINDS (adjusted RR: 0.488 [0.281-0.846], p=0.0106), the ECASS II (adjusted RR: 0.318 [0.130-0.776], p=0.0119), and SITS-MOST standards (adjusted RR: 0.214 [0.048-0.957], p=0.0437). The favorable functional rates between the two groups were not significantly different. Lower levels of LDL-C were showed in robust association with SICH. With a cut-off LDL-C value of <130 mg/dL, new models are more robust and significant in predicting hemorrhagic transformation within 24-36 h. CONCLUSIONS: This study supports the strong association between reduced LDL-C and increased SICH, but not for functional outcomes in patients with acute ischemic stroke treated with intravenous thrombolysis. LDL-C level of <130 mg/dL is supposed to a candidate marker for predicting SICH within 24-36 h. PMID- 30464113 TI - Screening for Lipomyces strains with high ability to accumulate lipids from renewable resources. AB - The yeast Lipomyces accumulates triacylglycerols (TAGs) as intracellular fat globules, and these TAGs can be used as source materials for biodiesel production. In this study, we aimed to use this yeast to produce lipids from renewable resources. Using plate culture and micrograph methods, strains with a high lipid-accumulation ability were screened from 15,408 types of systems combining renewable resources, strains, and culture temperatures. The lipid accumulation ability of the strains was estimated from the fat globule volume, which was calculated using a micrograph. The reliability of this method was examined, and strains with a high lipid-accumulation ability were identified for each renewable resource. Seventy-seven Lipomyces strains (7 deposit, 68 wild type, 2 mutants) with a high lipid-accumulation ability were selected. A few strains possessed the ability to accumulate large amounts of TAGs from more than four different renewable resources. We found that strains with a high lipid accumulation ability could efficiently convert consumed carbon sources into TAGs, which could be easily recovered from the fat globules of these strains through physical disruption. PMID- 30464114 TI - Stent Recoil in Overlapping Stent 18 Years After Wiktor Stent Implantation. AB - In this paper, we look at the case of a 79 years old male who received a Wiktor stent (WS) implantation for myocardial infarction in proximal left anterior descending artery 18 years ago. Eleven years later, an Everolimus eluting stent (EES; Xience VTM) was implanted for the proximal edge restenosis of WS from mid left main trunk to the middle part of WS. Seven years after EES implantation, the angiography and optical coherence tomography revealed in-stent restenosis with severe stent recoil just distal to the overlapping zone of WS. In the present case, stent recoil seems to have occurred due to different radial stiffness and flexibility between the two stents. PMID- 30464115 TI - Medical Therapy Induced Regression of Plaque in a Female Patient with ASCVD. AB - The initiation and progression of atherosclerotic cardiovascular disease (ASCVD) has always been associated with a series of risk factors. Evidences of statin therapy from randomized clinical trials are abundant, whereas discussions regarding patients with ASCVD without evidence-based risk factors are rare. Here, we describe a case of a 58-year-old woman who was diagnosed with ASCVD with none of these evidence-based risk factors. After four years of medical interventions, including atorvastatin, the patient recovered completely from severe chest pain with significant regression of atherosclerotic plaques in coronary arteries. PMID- 30464116 TI - MicroRNA-138 Suppresses Osteoblastic Differentiation of Valvular Interstitial Cells in Degenerative Calcific Aortic Valve Disease. AB - The aim of this study was to explore the function of miR-138 in the pathogenesis of degenerative calcific aortic valve disease (DCAVD).Aortic valve calcification tissue and normal tissue from DCAVD patients were collected to detect the expression of miR-138 by qRT-PCR, and immunohistochemical staining was performed to identify the phenotype of valve interstitial cells. QRT-PCR was performed to analyze the expression of miR-138, Runx2, MSX2, and ALP at day 7 after osteogenic differentiation. Alkaline phosphatase activity assay was performed at day 14 after osteogenic differentiation. Alizarin red staining was used to analyze the calcium nodule formation. TargetScan was used to predict potential targets of miR 138. QRT-PCR and Western blotting were performed to analyze the expression of FOXC1 in valve interstitial cells (VICs). The aortic valve calcification was evaluated by quantitative analysis of the velocity in the aortic annulus and transvalvular pressure gradients.In this study, we demonstrated the role of miR 138 in VIC osteogenesis. QRT-PCR results revealed miR-138 was significantly down regulated in calcified aortic valves compared with non-calcified valves. MiR-138 overexpression inhibited VIC osteogenic differentiation in vitro, while down regulation of miR-138 enhanced the process. Target prediction analysis and dual luciferase reporter assay confirmed FOXC1 was a direct target of miR-138. Further research found FOXC1 overexpression promoted VIC osteogenic differentiation. In addition, animal experiments validated indirectly miR-138 could suppress aortic valve calcification.Our findings suggest miR-138 could function as a new inhibitor of VIC osteogenic differentiation, which may act by targeting FOXC1. PMID- 30464117 TI - Watch out for the Thrombus Adhering to the Puncture Site of the Atrial Septum during Left Atrial Appendage Closure. AB - We present a rare case of thrombus adhering to the puncture site of the atrial septum during left atrial appendage closure. By discussing the case, we suggest that some preventive measurements be taken during left atrial appendage closure and that conventional transesophageal echocardiography for the atrial septal puncture site be performed after the delivery sheath is removed. PMID- 30464118 TI - Valve Hemodynamics and Clinical Outcomes After Transcatheter Aortic Valve Replacement for a Small Aortic Annulus. AB - The hemodynamics and outcomes in patients with a small aortic annulus (SAA) after transcatheter aortic valve replacement (TAVR) with a second-generation transcatheter heart valve remain unclear. We investigated whether TAVR with a Sapien XT (Edwards Lifesciences, Irvine, California) influences postprocedural valve hemodynamics and long-term outcome in high-risk SAA patients compared with surgical aortic valve replacement (SAVR).We retrospectively identified 94 SAA patients who underwent aortic valve replacement (TAVR = 35 and SAVR = 59). SAA was defined as an aortic annulus diameter <= 20 mm, measured by preprocedural transesophageal echocardiography.The mean age was 80.2 years. The mean Society of Thoracic Surgeons-Predicted Risk of Mortality was 6.8%. The post-procedural peak transvalvular velocity and mean pressure gradient were significantly lower in the TAVR cohort than in the SAVR cohort, whereas the postprocedural aortic valve area was significantly higher in the TAVR cohort. Severe prosthesis-patient mismatch (PPM) occurred less frequently after TAVR than SAVR (TAVR 2.9% versus SAVR 22.0%, P = 0.01). The two-year mortality in SAA patients was similar between the two groups.TAVR with a Sapien XT in SAA patients improved the valve hemodynamics and reduced the incidence of PPM compared with SAVR. TAVR patients had a similar 2 year mortality despite higher risk baseline characteristics. To avoid PPM and the consequent poor outcomes, TAVR can be considered an alternative option to SAVR in high surgical risk patients with SAA. PMID- 30464119 TI - Long-Term Effects of Enzyme Replacement Therapy for Anderson-Fabry Disease. AB - Anderson-Fabry disease is a rare X-linked lysosomal storage disease caused by alpha-galactosidase A (alpha-GalA) gene variants and characterized by a large genotypic and phenotypic spectrum. Enzyme replacement therapy (ERT) using recombinant alpha-GalA has been approved for > 10 years as a specific therapy for the disease. However, the long-term clinical efficacy for cardiac manifestations has been equivocal because it depends on several factors such as genotype, sex, age, and disease severity at the initiation of ERT. We report the differences in the clinical effects of ERT continued for > 10 years in three patients with the same genotype. Left ventricular hypertrophy and myocardial dysfunction progressed in the heterozygote proband even under ERT, although disease progression was prevented in two sons of Case 1. PMID- 30464120 TI - Case of Invasive Streptococcus Dysgalactiae Infection Presenting as Infective Endocarditis with Multiple Brain Embolisms. AB - A 65-year-old Japanese man complaining of general malaise and presenting with high fever was admitted to our hospital. He had untreated diabetes and hepatocellular carcinoma with liver cirrhosis. Overall findings of the patient indicated sepsis. Two blood cultures were positive for Streptococcus dysgalactiae, a group C or G Streptococcus. Transthoracic and transesophageal echocardiography revealed vegetations on the aortic and mitral valves. Although antimicrobial therapy with aminobenzyl penicillin was effective for controlling infection, multiple cerebral embolisms occurred in the clinical course of the disease. Primary care doctors should consider invasive Streptococcus dysgalactiae infections when treating elderly patients with underlying diseases, and Streptococcus dysgalactiae should be included in the list of microorganisms considered to cause endocarditis in such patients. PMID- 30464121 TI - Successful Inflammation Imaging of Non-Human Primate Hearts Using an Antibody Specific for Tenascin-C. AB - Inflammation after myocardial infarction (MI) may be a major factor influencing ventricular remodeling, leading to congestive heart failure and arrhythmia. Therefore, inflammation in the heart needs to be monitored. Tenascin-C (TNC) is an extracellular matrix molecule not normally expressed, but it is strongly upregulated when associated with active inflammation. Based on this characteristic, we successfully imaged in vivo inflammatory lesions in rat models using 111Indium (111In)-labeled anti-TNC antibodies. The aim of the present study was to further assess the applicability of this molecular imaging probe to detect inflammatory activity in primate hearts.We generated an MI model of cynomolgus monkeys (Macaca fascicularis) by coronary artery ligation and performed dual isotope single-photon emission computed tomography (SPECT) imaging with an 111In labeled anti-TNC antibody Fab' fragment (111In-TNC Fab') and 99mtechnetium methoxy-isobutyl isonitrile (99mTc-MIBI). Dual autoradiography was used to compare the uptake of 111In-TNC Fab' with histology and immunostaining for TNC. Dual-isotope SPECT showed the regional myocardial uptake of 111In-TNC Fab' complementary to a defect in the perfusion image by 99mTc-MIBI. The high radioactivity of 111In-TNC Fab' by autoradiography corresponded to immunostaining for TNC, which was observed in inflammatory lesions at the border zone between the infarcted and non-infarcted areas of the left ventricle and at the epi/pericarditis lesions of the right ventricle. These results demonstrate the potential of 111In-TNC-Fab' imaging to monitor myocardial injury and inflammation and suggest the feasibility of the non-invasive detection of cardiac inflammation following acute MI in a preclinical stage before testing in humans. PMID- 30464122 TI - A Patient-Specific Hollow Three-Dimensional Model for Simulating Percutaneous Occlusion of Patent Ductus Arteriosus. AB - Percutaneous catheter closure of patent ductus arteriosus (PDA) is difficult when the ductus is large and long or shows calcification. We created a patient specific 3-dimensional (3D) model for PDA, with which we simulated device deployment, thereby selecting the device/size in a patient-by-patient manner. We assessed whether this 3D model is effective for catheter PDA closure.The 3D model was created in this institute, requiring 3 days and 90 US dollars. After its introduction, 7 consecutive patients (the study group) with severe PDA underwent closure with the aid of the 3D model. The control group consisted of 4 patients before 3D-model introduction, with all having severe PDA: the requirement of computed tomography was considered a criterion of severe or difficult-procedure requiring PDA.In all study group patients, the devices/sizes could be pre selected based on the simulation, whereas devices were changed during the procedure in 2 of 4 in the control group. In the study group, compared with the control group, the fluoroscopic (median 31 [interquartile range of 16-42] versus 39 [19-71] minutes, respectively) and total procedural times (median 107 [interquartile range 67-114] versus 124 [78-184] minutes, respectively) were shorter. A questionnaire confirmed the doctors' understanding of the procedure.This 3D model may be effective for percutaneous catheter closure of PDA. This may be especially true in cases of severe or difficult-procedure requiring PDA. PMID- 30464123 TI - Magnetocardiography Using a Magnetoresistive Sensor Array. AB - In previous magnetocardiography studies, magnetocardiograms (MCGs) have been obtained using superconducting quantum interference device (SQUID) systems. SQUID is the most sensitive instrument for measuring low-frequency magnetic fields, but it requires liquid helium for cooling, so operating costs are high. In contrast, magnetoresistive (MR) magnetometers function by detecting the change in resistance, caused by an external magnetic field, and have much lower costs. This study was aimed to evaluate feasibility of the MR sensor array for acquiring MCGs.We used an MR sensor array, which was developed for measuring magnetic fields in the picotesla range, with a reduced noise level (TDK Corporation, Tokyo, Japan). A 30-channel MR sensor array was placed in a magnetically shielded room, and the cardiac magnetic field over the anterior chest walls of five healthy subjects was recorded.For all five subjects, MCGs were successfully recorded using the MR sensor array. The cardiac magnetic field corresponding to P, QRS, and T waves on an electrocardiogram (ECG) was detectable by signals averaging 272 +/- 27.5 beats.An MR sensor array can be used to measure cardiac magnetic fields. Our results will contribute to the development of low-cost devices for recording MCGs, which will help develop non-invasive diagnostics in cardiovascular medicine. PMID- 30464124 TI - Soluble ST2 for Prediction of Clinical Outcomes in Patients with ST-Segment Elevation Myocardial Infarction Receiving Primary PCI. AB - Soluble suppression of tumorigenicity 2 (sST2), a biomarker representing myocardial fibrosis and inflammation, has been applied in risk stratification of patients with myocardial infarction (MI). However, whether primary PCI (PPCI) will eliminate the predictive value of sST2 in STEMI patients has not been well studied. Here, we conducted a prospective clinical trial to evaluate the correlation between sST2 and prognosis in STEMI patients undergoing PPCI. sST2 levels were measured in 295 STEMI patients (60.2 +/- 10.8 years) at admission using a high sensitivity assay. Baseline sST2 levels were significantly associated with heart function, biomarkers of inflammation, and myocardial injury. During a 12-month follow-up, 19 patients had major adverse cardiovascular events (MACEs). Greater sST2 was continuously associated with a higher risk of incident MACEs. Such association remained even after adjusting for other risk factors in a multivariate Cox analysis. A baseline sST2 level in the highest quartile (>= 58.7 ng/mL) was independently associated with mortality (HR: 5.01, 95%CI: 1.02-16.30, P = 0.048). More incident heart failure was seen in the group with greater sST2, however, the association was not significant after adjustment. Therefore, baseline sST2 may be useful to predict MACEs, especially mortality, in STEMI patients receiving PPCI. PMID- 30464125 TI - A Slower Heart Rate and Therapeutic Hypothermia Unmasked Early Repolarization Syndrome in a Ventricular Fibrillation Survivor. AB - Patients presenting with aborted cardiac arrest who display early repolarization generally are diagnosed with early repolarization syndrome. Therapeutic hypothermia is a standard strategy to improve neurological outcome in comatose patients after cardiac arrest. We present here a patient in whom therapeutic hypothermia exacerbated the J-wave amplitude and morphology, which resulted in episodes of refractory ventricular fibrillation. PMID- 30464126 TI - Variation of Electrocardiogram Features Across Sleep Stages in Healthy Controls and in Patients with Sleep Apnea Hypopnea Syndrome. AB - Sleep apnea hypopnea syndrome (SAHS) is an independent risk factor for various cardiovascular diseases. Electrocardiogram (ECG) features such as the RR, PR, QT, QTc, Tpe intervals and the Tpe/QT, Tpe/QTc ratios are used to predict and study cardiovascular diseases. It is not clear whether regular patterns of PR and Tpe related features across sleep stages exist in SAHSs or healthy controls nor whether sleep stages affect the short- and long-range influences of respiratory events on ECG indices. We enrolled 36 healthy controls and 35 patients with SAHS in our study and analyzed the abovementioned ECG features. In the healthy controls, a significant regularity existed in these indices across sleep stages, which were weakened or disturbed in the patient group, especially the Tpe-related features. The differences between the patients and healthy controls were generally consistent across all sleep stages: patients had smaller RR, PR, QT and Tpe/QTc values, but larger QTc, Tpe and Tpe/QT values. After filtering the short range influence of respiratory events, the differences in most features remained highly significant, except the QT interval. In the patient group, respiratory events decreased RR and PR intervals in most sleep stages and increased the Tpe related features' values in deep sleep stages. These results may aid in the study of the relationships among SAHS, sleep disorders and cardiovascular diseases. PMID- 30464127 TI - Blunted Nighttime Sympathetic Nervous System Response to Stress Among Thai Men with Positive Family History of Sudden Unexplained Nocturnal Death Syndrome. AB - Sudden unexplained nocturnal death syndrome (SUNDS) is prominent among northeast Thai men. This study tests the hypothesis that Thai men with positive family history of SUNDS display abnormal diurnal, autonomic nervous system responses to stress. Healthy northeast Thai men (20-49 years old) lived in the same rural area were divided into two groups based on their positive (PF) or negative family (NF1) history of SUNDS. A second control included Thai men with an NF history of SUNDS from a non-endemic area (NF2). All data were collected at 4:00-6:00 AM (nighttime) and 4:00-6:00 PM (daytime). All three groups displayed nighttime decreases in mean arterial pressure, heart rate, and blood glucose. Furthermore, all subjects displayed similar glucose tolerance and electrolyte balance. The tachycardic responses to a four-minute step test were similar among groups in the daytime, but the nighttime responses were significantly blunted in the PF group compared to either control group (about 20 bpm less). Tachycardic responses to a cold pressor test tended to decrease more during the nighttime in the PF compared to NF1 and NF2 groups, but the difference was not significant. Arterial pressure responses to the exercise were similar among the three groups during the nighttime, whereas in the NF2, daytime mean arterial pressures increased more than those in the other groups. The present data suggest that Thai men with a PF history of SUNDS display blunted sympathetic nervous system responses to stress during the nighttime, a potential factor that may trigger cardiac arrhythmias and contribute to SUNDS. PMID- 30464128 TI - Combined Primary PCI with Multiple Thrombus Burden Reduction Therapy Improved Cardiac Function in Patients with Acute Anterior Myocardial Infarction. AB - High thrombus burden induced slow-flow and no-reflow during primary percutaneous coronary intervention (PCI) and is associated with a poor prognosis. We aimed to investigate whether a combined thrombus burden reduction therapy during primary PCI, could improve microcirculation and enhance cardiac function in the long term.Anterior wall STEMI patients with high thrombus burden were randomly assigned to receive a combined thrombus burden reduction therapy or thrombus aspiration alone. The primary end points included the percentage of patients with TMPG (TIMI myocardial perfusion grade) 3, STR (ST-segment resolution) above 70%, the index of microcirculatory resistance (IMR) and left ventricular ejection fraction (LVEF) difference.Twenty-two patients in the combined interventional group and 24 in the control group completed 1-year follow-up. The percentages of patients with TMPG 3 (68.2% versus 33.3%, P = 0.006) and STR above 70% (63.6% versus 25%, P = 0.016) were significantly higher in the combined group. IMR was significantly lower in the combined interventional group (31.50 +/- 13.39 U versus 62.72 +/- 22.80 U, P = 0.002). At 3 months and 1 year, the overall LVEF value was better in the combined interventional group (42.1% versus 40.0%, P = 0.049; 41.9% versus 39.8%, P = 0.042), respectively. The IMR value was negatively correlated with the EF value at 3 months (r = -0.145, P = 0.013) and 1 year (r = 0.333, P = 0.031).A combined thrombus burden reduction therapy during primary PCI can safely reduce thrombus burden, improve myocardial tissue perfusion, and improve cardiac function among STEMI patients with high thrombus burden. IMR might be a good predictor for post-myocardial infarction cardiac function. PMID- 30464129 TI - Medically Treated Ventricular Septal Perforation Caused by Takotsubo Cardiomyopathy. AB - Takotsubo cardiomyopathy is a common disease, but Takotsubo cardiomyopathy complicated by ventricular septal perforation is very rare. We describe the case of a 92-year-old male who had Takotsubo cardiomyopathy complicated by ventricular septal perforation. We treated the patient medically without surgical or catheter interventions. In three weeks, his abnormal wall motion recovered completely, whereas the ventricular septal perforation remained open. He was ambulatory, subsequently discharged, and had been uneventful for one year. In this manuscript, we discuss the importance of non-invasive management for Takotsubo cardiomyopathy complicated by ventricular septal perforation. PMID- 30464130 TI - Comparison of Clinical Outcomes between the Ostial Versus Non-Ostial Culprit in Proximal Left Anterior Descending Artery Acute Myocardial Infarction. AB - Percutaneous coronary interventions to the proximal left anterior descending artery (pLAD)-acute myocardial infarction (AMI) are still challenging, especially in the ostial pLAD. Clinical outcomes of the ostial pLAD-AMI were not well investigated. The aim of the present study was to compare clinical outcomes of the ostial pLAD-AMI with those of the non-ostial pLAD-AMI. The primary endpoint was the major cardiovascular events (MACE), defined as the composite of cardiac death, AMI, stent thrombosis (ST), target lesion revascularization (TLR), and target vessel revascularization (TVR). Between January 2009 and March 2016, a total of 401 pLAD-AMI were included as the study population and were divided into 78 ostial pLAD-AMI (the ostial pLAD group), and 323 non-ostial pLAD-AMI (the non ostial pLAD group). The median follow-up duration was 414 days. The MACE tended to be higher in the ostial pLAD group (8.0% at 30 days, 19.9% at 400 days) than in the non-ostial pLAD group (4.4% at 30 days, 12.9% at 400 days) without reaching statistical significance (P = 0.087). The prevalence of cardiac death was significantly higher in the ostial pLAD group (6.6% at 30 days, 9.5% at 400 days) as compared with the non-ostial pLAD group (3.1% at 30 days, 4.5% at 400 days) (P = 0.034). There were no significant differences in ST, AMI, TLR, or TVR. We concluded that, as compared with the non-ostial pLAD-AMI, the clinical outcomes of the ostial pLAD-AMI, especially cardiac death, tended to be worse, requiring special attention to the ostial pLAD-AMI. PMID- 30464131 TI - Feasibility and Safety of Left Atrial Appendage Closure Using the LAmbre Device in Patients with Nonvalvular Atrial Fibrillation with or Without Prior Catheter Ablation. AB - Left atrial appendage (LAA) closure (LAAC) has emerged as an alternative therapeutic approach to medical therapy for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). However, complex LAA anatomy may preclude its use. LAmbre is a new, self-expanding LAA occluder, and is highly adaptable to different LAA morphologies. We explored the feasibility, safety, and efficacy of LAAC using LAmbre device in NVAF patients with or without prior catheter ablation (CA). LAAC using LAmbre device was applied in NVAF patients with (group C) or without (group N) prior CA. Transesophageal echocardiography (TEE) was performed at 3, and 12 months post-LAAC. Among 17 LAAC patients (group C, 6 & group N, 11), 4 cases were implanted with special type devices, 5 were implanted with large devices. Besides one case of cardiac tamponade (N group), there were two minor peri-procedural complications only. Successful sealing of the LAA was documented in all the patients (100%) by TEE both post LAAC and at 3 months. At 3 months, no residual flow was achieved in 11 patients (64.7%); six patients (35.3%) had residual flow < 5 mm. There was no device dislocation or leakage during the mean of 30 months follow up. At 545 days after LAAC, one patient in group C experienced sudden death. Baseline, peri-procedural, and follow-up characteristics were similar between two groups (P > 0.05). LAAC with LAmbre device, subsequent to prior CA for AF, can be performed successfully and safely. The design and distinguishing features of this device could be of help in patients with complex anatomy of LAA. PMID- 30464132 TI - Recruitment of Complete Right Bundle Branch Block by Permanent Para-Hisian Pacing. AB - His-bundle pacing has recently emerged as a means to maintain a physiological ventricular activation and eliminate the risk of pacing-induced myopathy associated with traditional right ventricular pacing. With His-bundle pacing, the exact stimulated structure and resulting excitation wavefront may be highly dependent on the pacing output, dimensions of the stimulatory electrodes, and orientation of the cathode and anode relative to the approximated conduction tissue and surrounding myocardium, owing to the juxtaposition of tissues with very different conduction properties. We herein present an 89-year-old woman with an infra-Hisian conduction disease in whom lower output pacing resulted in pure His-bundle pacing, and higher output pacing resulted in para-Hisian pacing that recruited diseased portions of the conduction system, narrowing the QRS complex. PMID- 30464133 TI - A Steam Pop Detected by Intracardiac Echocardiography During Catheter Ablation of the Left Ventricular Papillary Muscle. AB - A 60-year-old female with premature ventricular contractions (PVCs) originating from the bottom of the posteromedial papillary muscle of the left ventricle underwent radiofrequency catheter ablation (RFCA) using an irrigated-tip catheter. During ablation of the PVCs, a loud steam pop was observed. Intracardiac echocardiography (ICE) revealed a growing, hyperechogenic intramyocardial microbubble formation around the catheter tip. The formation disappeared slowly and completely, leaving an endocardial laceration without pericardial effusion. ICE imaging is valuable during a difficult RFCA procedure, because ICE reveals the exact anatomical position of the catheter and thus allows rapid evaluation of the occurrence of steam popping and any possible subsequent complication. PMID- 30464134 TI - Prognostic Significance of Serum Indoxyl Sulfate and Albumin for Patients with Cardiovascular Disease. AB - The progression of renal dysfunction reduces serum albumin and deteriorates the binding capacity of protein-bound uremic toxins. We evaluated the prognostic implications of serum indoxyl sulfate (IS) and albumin levels in patients with cardiovascular disease.We prospectively enrolled 351 consecutive patients undergoing percutaneous revascularization for coronary artery disease or peripheral artery disease. The primary endpoint was all-cause mortality. Patients were assigned to four groups according to the median levels of serum IS (0.1 mg/dL) and albumin (3.9 g/dL).During the median follow-up time of 575 days, 16 patients died. The IS level was significantly higher in nonsurvivors (0.33 versus 0.85 mg/dL, P < 0.05). On the Kaplan-Meier curve, the high IS/low albumin group presented the highest mortality rate (log-rank test, P < 0.01). Cox proportional hazard analysis revealed that high IS/low albumin (hazard ratio (HR): 5.33; 95% confidence interval (CI): 1.71-16.5; P < 0.01), diastolic pressure (HR: 0.94; 95% CI: 0.91-0.98; P < 0.01), prior stroke (HR: 4.54; 95% CI: 1.33-15.4; P = 0.01), and left ventricular ejection fraction (LVEF) (HR: 0.92; 95% CI: 0.88-0.96; P < 0.001) were associated with increased mortality. Furthermore, the combination of IS and albumin levels significantly conferred an additive value to LVEF for predicting mortality (C-statistic: 0.69 versus 0.80; P < 0.001; net reclassification improvement: 0.83; P < 0.001; integrated discrimination improvement: 0.02; P = 0.02).A lower albumin level adds potentiating effects on IS as a prognostic factor for cardiovascular disease. PMID- 30464135 TI - Idiopathic Ventricular Arrhythmia Ablation Using Non-Fluoroscopic Catheter Visualization System. AB - A novel, sensor-based, electromagnetic, non-fluoroscopic catheter visualization (NFCV) system shows tracked catheters directly on pre-acquired fluoroscopy or cine loops. We aimed to evaluate the effectiveness of this system in the setting of catheter ablation for idiopathic premature ventricular contractions/ventricular tachycardia (i-PVC/VT).A total of 30 i-PVC/VT ablation procedures were performed using the NFCV system in conjunction with three dimensional electroanatomic mapping system (3D-EMS) between January 2013 and April 2017. At the beginning of the procedure, cine loops of right and left anterior oblique views were obtained and replayed for subsequent mapping and ablation. Right ventriculography, aortography, or coronary angiography was performed, depending on the chamber of interest. We reviewed procedural parameters, comparing with the i-PVC/VT ablation procedure using conventional fluoroscopy (CvF) system (pre-, and post-NFCV implementation; 20 and 11 cases, respectively).I-PVC/VTs were successfully eliminated in 26 patients (87%) in the NFCV group and in 26 (84%) in the CvF group (P = 1.000). The procedure time in the NFCV group was comparable to that in the CvF group (119.8 versus 125.0 minutes, respectively, P = 0.868); the total fluoroscopy time was significantly shorter in the NFCV group (3.3 versus 16.6 minutes, P < 0.001). One patient in the CvF group experienced cardiac tamponade, requiring pericardial drainage. No major complications were encountered in the NFCV group.NFCV system, in conjunction with 3D-EMS, was safe and feasible for i-PVC/VT mapping and ablation. The system contributed to dramatically reduced fluoroscopy time, compared with CvF. PMID- 30464136 TI - Endovascular Therapy Using Diluted Contrast Medium for Critical Limb Ischemia in a Patient with Chronic Kidney Disease. AB - A high percentage of patients with critical limb ischemia have concurrent chronic kidney disease (CKD). However, endovascular therapy (EVT) can be problematic in CKD patients. Thus, we developed a method of EVT using digital subtraction angiography (DSA) with diluted contrast medium (low-concentration DSA), wherein DSA parameters were adjusted for diluted contrast angiography (1:10 dilution). Herein, we report the case of an 88-year-old woman with a foot wound and severe CKD. Her estimated glomerular filtration rate was 7.9 mL/minute/1.73 m2. Therefore, EVT was performed with low-concentration DSA. Control angiography revealed total occlusion of the anterotibial and posterotibial arteries as well as severe stenosis of the peroneal artery. EVT with ballooning of the below-the knee (BTK) lesions resulted in sufficient flow to the wound. Angiographic images of sufficient quality and visible wound blush were obtained with 1:10 diluted contrast medium. Because only 20 mL of contrast medium was required, renal function was preserved. EVT using DSA with diluted contrast medium was shown to be an effective BTK intervention in this CKD patient. PMID- 30464137 TI - Analysis of Biphasic Right Ventricular Outflow Doppler Waveform in Patients with Pulmonary Hypertension. AB - Pulmonary hypertension (PH) with pulmonary vascular disease (PVD) is a progressive and debilitating disease associated with increased pulmonary vascular resistance (PVR). Biphasic right ventricular outflow tract (RVOT) Doppler flow is frequently seen in severe PH patients with PVD. In association with hemodynamics, the precise analysis of biphasic RVOT Doppler flow (RVDF) has not been fully elucidated. Therefore, the purpose of the present study is to analyze the relation between the hemodynamics and indices of biphasic RVDF in PH patients with PVD.Seventy PH patients with biphasic RVDF were analyzed. All patients underwent transthoracic echocardiography and right heart catheterization. For the analysis of biphasic RVDF, the early waveform was determined as P1 while the late waveform was determined as P2. For each P1 and P2, the duration (D, seconds) and peak flow velocity (PFV, in m/second) were measured.P1D and P2PFV were significantly correlated with PVR (P1D: r = -0.542, P < 0.0001, P2PFV: r = 0.513, P < 0.0001). Therefore, we propose a novel RVDF formula for estimation of PVR, as follows. PVR = 26 - 77 * P1D - 14 * P2PFV. The PVR could be estimated by this proposed formula (r = 0.649, P < 0.0001), which is derived from one Doppler image only unlike previously used PVR prediction formula.P1D and P2PFV were associated with PVR. Moreover, this simple RVDF formula proposed herein can estimate PVR in PH patients with PVD. PMID- 30464138 TI - Old-Age Onset Progressive Cardiac Contractile Dysfunction in a Patient with Polycystic Kidney Disease Harboring a PKD1 Frameshift Mutation. AB - A 70-year-old man with dyspnea was admitted to our department and received standard therapy for recurrent heart failure. He was diagnosed with polycystic kidney disease (PKD) in his thirties and received hemodialysis for 4 years before undergoing renal transplantation at age 45. Although his left ventricular ejection fraction (LVEF) was preserved in his 50s, LVEF decreased progressively from 61% to 24%, while left ventricular diastolic dimension (LVDd) increased from 54 mm to 65 mm between 63 and 69 years of age. Right ventricular endomyocardial biopsy demonstrated myocardial disarray and interstitial fibrosis. Genetic analysis identified a heterozygous frameshift mutation in PKD1, which encodes polycystin-1, a major causative gene of PKD. We detected PKD1 protein expression in myocardial tissue by immunostaining. Recent epidemiological studies and animal models have clarified the pathological correlation between ventricular contractile dysfunction and PKD1 function. Here, we present a case of old-age onset progressive cardiac contractile dysfunction with a PKD1 gene mutation. PMID- 30464139 TI - APSS 2017 special issue. PMID- 30464140 TI - Nonsyndromic Congenital Absence of the Pectoralis Muscles. AB - The congenital absence of the pectoralis muscle is usually a manifestation of Poland syndrome. However, a nonsyndromic congenital absence of this muscle is rare, and such absences are usually partial and unilateral. A complete or bilateral absence is even rarer. Two young men presented to our outpatient clinic with incidentally noted unilateral flat chest walls. By chest computed tomography, they were diagnosed with a congenital unilateral absence of the pectoralis muscles. They did not show any functional disability of the arms. As the congenital absence of the pectoralis muscles is often associated with leukemia and genitourinary anomalies, it is advised that hematological testing and renal ultrasonography be performed, even in nonsyndromic cases. PMID- 30464141 TI - Serum Cytokine Interactions Are Implicated in the Mechanism of Action of Sublingual Immunotherapy for Japanese Cedar Pollinosis. AB - OBJECTIVE: This study aimed to investigate whether interactions between multiple serum cytokines may be implicated in the mechanism of action (MOA) of sublingual immunotherapy (SLIT) for Japanese cedar pollinosis. METHODS: A Tokyo Metropolitan Bureau of Social Welfare and Public Health-initiated clinical study of active SLIT involving 202 patients with Japanese cedar pollinosis was jointly conducted by Tokyo Metropolitan Institute of Medical Science and Nippon Medical School between 2006 and 2008. Fifty target cytokines were quantified in serum samples collected at 6 times from baseline to the end of the study, for 300 cytokine measurements in total, using Bio-Plex Pro Human Cytokine Group I/II Panels. Therapeutic outcome was assessed based on nasal symptom scores and quality-of life questionnaire results. RESULTS: Fifty-five percent of patients were free of symptoms or reported symptomatic improvements by 2 grades or greater after 2 years of SLIT treatment, while 27% showed no improvement or worsening of symptoms. Thirty-eight patients who benefited the most from treatment (responders) as well as 37 patients who benefited the least from treatment (non responders) were identified and their serum cytokine profiles were compared. Cluster analysis of the 300 cytokine measurements identified 6 cytokine clusters that were strongly correlated with a positive response to treatment, and this correlation was consistent throughout the treatment. CONCLUSION: Certain cytokine clusters are strongly correlated with a positive therapeutic outcome, suggesting they have a role in the MOA of immunotherapy. PMID- 30464142 TI - Correlation between Pathological Findings and the Usefulness of Clinical Guidelines for the Treatment of ANCA-Positive RPGN: A Retrospective Analysis. AB - BACKGROUND: The physical condition of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated rapidly progressive glomerulonephritis (RPGN) is at times too critical for physicians to undertake a renal biopsy. In such cases, physicians need to start treatments without determining the pathological features of the disease. However, the prevalent clinical practice guidelines for ANCA associated RPGN in Japan do not necessitate the pathological findings in a renal biopsy for determining first-line treatments. The aim of this study was to assess the correlation between the pathological findings and the clinical guideline based treatments of ANCA-associated RPGN. METHODS: We investigated clinical and pathological features of patients who were admitted to our hospital to undergo a percutaneous renal biopsy for the diagnosis of ANCA-associated RPGN and were treated per clinical practice guidelines formulated by the Japanese Society of Nephrology. We divided patients into the following three groups according to their treatments: (a) group A, oral intake of prednisolone (PSL) only; (b) group B, methylprednisolone (mPSL) pulse therapy followed by oral intake of PSL; and (c) group C, mPSL pulse therapy followed by oral intake of PSL and the administration of immunosuppressive agents. We compared the crescent formation ratio (CFR) in glomeruli in each treatment group. RESULTS: The median CFR (%; +/ standard deviation [SD]) in group A (8.7%+/-7.7%) was significantly lower than that in groups B (30.2%+/-15.7%) and C (71.3%+/-25.5%); group A vs. group B, P<0.05; group A vs. group C, P<0.0001. In addition, the median CFR in group B was significantly lower than that in group C (P<0.01). The median serum creatinine levels (mg/dL; +/-SD) in both groups A (2.03+/-0.96 mg/dL) and B (1.90+/-0.86 mg/dL) were significantly lower than that in group C (4.30+/-1.63 mg/dL); group A vs. group C, P<0.01; group B vs. group C, P<0.01. No significant difference was observed in the serum levels of C-reactive protein and ANCA in each treatment group. Although the pathological features of renal biopsy are not included in the factors in the clinical scores described in the guidelines, guideline-based treatments reflected the severity of the crescent formation in each treatment group. CONCLUSIONS: This study suggests that the clinical practice guidelines for ANCA-associated RPGN used in Japan facilitate physicians to determine disease management in patients presenting difficulties in undergoing a renal biopsy. PMID- 30464143 TI - Anti-Inflammatory Effects of EM900 on Cultured Human Nasal Epithelial Cells. AB - OBJECTIVES: Macrolide therapy is an important conservative therapy for chronic rhinosinusitis, especially in Japan. The mechanism underlying this therapy involves anti-inflammatory and not antimicrobial activity. However, the administration of long-term low-dose macrolides (LTLMs) causes an increase in the number of antibiotic-resistant bacteria. EM900 is a derivative of erythromycin (EM), with anti-inflammatory but not antibacterial effects. It does not induce macrolide-resistant bacteria as shown by LTLM. In the present study, we analyzed the inhibitory effects of EM900 in comparison with those of clarithromycin (CAM) on inflammatory cytokine production in human nasal epithelial cells (HNEpCs). METHODS: After HNEpCs were cultured for 4 days, CAM or EM900 was added into the culture, followed by stimulation with tumor necrosis factor (TNF)-alpha. Interleukin (IL)-8 and vascular endothelial growth factor (VEGF) levels were measured using real-time polymerase chain reaction (RT-PCR) and an enzyme-linked immunosorbent assay (ELISA). RESULTS: Both the ELISA and RT-PCR showed that EM900 and CAM significantly inhibited IL-8 production in HNEpCs. In contrast, EM900 and CAM did not suppress the increased VEGF production when HNEpCs were stimulated with TNF-alpha. CONCLUSION: EM900 showed an anti-inflammatory effect, such as that of CAM, due to the inhibitory effect on IL-8 production in HNEpCs. PMID- 30464144 TI - Challenges in the Diagnosis of bone Metastasis in Patients without a History of Malignancy at Their First Clinic Visit. AB - BACKGROUND: Many patients with bone metastases whose diagnoses came only after they had suffered aggravated conditions are still frequently encountered. However, there have been few studies regarding the early diagnosis of such metastases. We retrospectively reviewed the clinical courses of cases we experienced between 2004 and 2014 to clarify the practical situation of diagnosis of such bone metastases. METHODS: We undertook a retrospective review of 56 of our patients with bone metastasis who had no history of malignancy at their first visit, who visited our departments between 2004 and 2014. The initial diagnoses at the first visit to any clinic, the period from the first visit to any clinic to diagnosis of bone metastasis, the process to make the diagnosis, the frequency of severe skeletal-related events at diagnosis, and the examination serving as the basis for diagnosis were evaluated. RESULTS: The diagnosis of bone metastasis was made at the first visit in only 6 of the 56 patients. Pathological fractures, paralysis and/or calcemia were seen in 62.5% of the patients at diagnosis of bone metastasis. The median period from the first visit to any clinic to diagnosis was 7.0 weeks. Typically, the diagnosis of bone metastasis was made only after aggravation. The most frequent examination to serve as the basis of diagnosis was magnetic resonance imaging. CONCLUSIONS: Diagnosis of bone metastasis is challenging in patients without a history of malignancy at their first visit. For early diagnosis, it is important to recognize this challenge and to keep it in mind together with ongoing observation. PMID- 30464145 TI - Two Cases of Granular Cell Tumors that Clinically Mimicked Hypertrophic Scars and Keloids. AB - We report two cases of granular cell tumors (GCTs) arising on rare sites, namely, the nape and umbilicus. While GCTs have a very characteristic histology, their clinical signs and symptoms are non-specific. Therefore, it is extremely difficult to make a diagnosis of GCT on the basis of clinical findings only. The two cases reported here were clinically similar to hypertrophic scars and keloids, respectively. Skin surgeons should remember that GCTs are an important differential diagnosis from hypertrophic scars and keloids. PMID- 30464146 TI - Two Cases of Sclerotic Fibroma of the Skin that Mimicked Keloids Clinically. AB - Sclerotic fibromas of the skin (SFSs) have a very characteristic histology but the clinical signs are non-specific. Consequently, it is extremely difficult to make a diagnosis of SFS on the basis of the clinical findings only. We report here two cases of SFS arising on the right scapular region and the right lower leg, respectively. Both cases were clinically similar to keloids. Skin surgeons should remember that SFSs are an important differential diagnosis from keloids. PMID- 30464147 TI - Valproate-Induced Polycystic Ovary Syndrome in a Girl with Epilepsy: A Case Study. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a common ovulatory disorder that can be induced by sodium valproate (VPA). PATIENT: We report a case of PCOS that developed in a 15-year-old girl with idiopathic epilepsy after she took VPA. VPA administration stopped her seizures, but it also led to weight gain and amenorrhea, and the patient was diagnosed with PCOS on the basis of diagnostic imaging and serological examination results. Cessation of VPA administration led to reduced weight gain and restored menstruation. CONCLUSIONS: The risk of PCOS developing in patients with epilepsy is known to be high, and the association of VPA with PCOS is well established, so if physicians feel this is the best drug to prescribe for female patients with epilepsy, they should carefully monitor the patients' weight and menstruation, and immediately perform ovarian imaging and hormonal examinations if any abnormalities are observed. PMID- 30464148 TI - Small Cell Lung Cancer with Sarcoidosis in Spontaneous Remission: A Case Report. AB - A 69-year-old woman was diagnosed with sarcoidosis, which was not treated with corticosteroid therapy. Her levels of angiotensin converting enzyme decreased significantly over 4 years and a mass lesion was detected near the lower part of her left main bronchus, and diagnosed as small cell lung cancer (SCLC). Treatment of the SCLC with a series of chemotherapeutic agents produced excellent results. The pulmonary sarcoidosis did not show any deterioration despite the frequent use of amrubicin, which is known to be a cause of interstitial pneumonia. This is a case report of SCLC complicated with sarcoidosis in a stage of spontaneous remission, possibly suggesting an association between sarcoidosis and tumor immunity, since recent reports have suggested that immune checkpoint inhibitors might be involved in the development of sarcoidosis. PMID- 30464149 TI - Congenital Mesoblastic Nephroma Presenting with Hematuria in a Neonate. AB - Congenital mesoblastic nephroma (CMN) is a rare tumor of infancy. CMNs can be histologically divided into classic, cellular, and mixed subtypes. Cellular CMNs are difficult to differentiate from Wilms tumors. Herein, a neonate with cellular CMN accompanied by macroscopic hematuria, is described. The clinical, pathological, and imaging features of the disease are discussed. PMID- 30464150 TI - Boron Neutron Capture Therapy Combined with Early Successive Bevacizumab Treatments for Recurrent Malignant Gliomas - A Pilot Study. AB - Recurrent malignant gliomas (RMGs) are difficult to control, and no standard protocol has been established for their treatment. At our institute, we have often treated RMGs by tumor-selective particle radiation called boron neutron capture therapy (BNCT). However, despite the cell-selectivity of BNCT, brain radiation necrosis (BRN) may develop and cause severe neurological complications and sometimes death. This is partly due to the full-dose X-ray treatments usually given earlier in the treatment course. To overcome BRN following BNCT, recent studies have used bevacizumab (BV). We herein used extended BV treatment beginning just after BNCT to confer protection against or ameliorate BRN, and evaluated; the feasibility, efficacy, and BRN control of this combination treatment. Seven patients with RMGs (grade 3 and 4 cases) were treated with BNCT between June 2013 and May 2014, followed by successive BV treatments. They were followed-up to December 2017. Median overall survival (OS) and progression-free survival (PFS) after combination treatment were 15.1 and 5.4 months, respectively. In one case, uncontrollable brain edema occurred and ultimately led to death after BV was interrupted due to meningitis. In two other cases, symptomatic aggravation of BRN occurred after interruption of BV treatment. No BRN was observed during the observation period in the other cases. Common terminology criteria for adverse events grade 2 and 3 proteinuria occurred in two cases and necessitated the interruption of BV treatments. Boron neutron capture therapy followed by BV treatments well-prevented or well-controlled BRN with prolonged OS and acceptable incidence of adverse events in our patients with RMG. PMID- 30464151 TI - Endovascular Treatment for Vasospasm after Aneurysmal Subarachnoid Hemorrhage Based on Data of JR-NET3. AB - Endovascular treatments for vasospasm after subarachnoid hemorrhage are typically performed for patients who are refractory to recommended medical therapies. We analyzed the current status of endovascular treatments based on the data of Japanese Registry of Neuroendovascular Therapy (JR-NET)3, and evaluated factors related to improvement of imaging findings and neurological condition, and to mechanical hemorrhage complications. We collected data of 1211 treatments performed from 2010 to 2014. Target vessels for treatments were anterior circulation (n = 1079), posterior circulation (n = 91), and both (n = 32); the distribution of vasospasm was the proximal vessel (n = 754) to the Circle of Willis, distal vessel (n = 329), and both (n = 119). Of the treatments, 948 cases (78.3%) were intra-arterial administration of vasodilators and 259 (21.4%) were percutaneous transluminal angioplasty (PTA); 879 cases were the first intervention. The treatment time from onset was within 3 h in 378 (31.2%) cases, between 3 and 6 h in 349 (28.8%) cases, and over 6 h in 245 (20.2%) cases. The statistically significant factors associated with improvement on imaging findings was the first treatment, and treatment within 3 h from onset compared with that after 6 h. Additionally, the first and early treatments after the symptoms were associated with significantly improved neurological condition. All complications of mechanical hemorrhage occurred along with PTA. The findings show that endovascular treatment for vasospasm was effective, especially for cases who suffered from symptomatic vasospasm with a short interval after onset. PMID- 30464152 TI - Optimal needle size for thyroid fine needle aspiration cytology. AB - Concerning the needle size for thyroid fine needle aspiration cytology (FNAC), 25 27-gauge needles are generally used in Western countries. However, in Japan, the use of larger needles (21-22-gauge needles) is common. The aim of our study was to determine the optimal needle size for thyroid FNAC. We performed ultrasound guided FNAC for 200 thyroid nodules in 200 patients using two different-sized needles (22 and 25 gauge). For each nodule, two passes with the different-sized needles were performed. The order of needle sizes was reversed for the second group of 100 nodules. The second aspiration was more painful than the first, regardless of the needle size. An association with more severe blood contamination was more frequently observed with the use of 22-gauge needles (32.0%) than with the use of 25-gauge needles (17.5%) and in the second aspiration (37.5%) than in the initial aspiration (12.0%). The initial aspiration samples were more cellular than the second aspiration samples. Regarding the unsatisfactory and malignancy detection rates, there was no statistical difference between the needles. In three of seven markedly calcified nodules, it was difficult to insert 25-gauge needles into the nodules. In terms of the diagnostic accuracy and pain, either needle size can be used. We recommend using 22-gauge needles for markedly calcified nodules because 25-gauge needles bend more easily in such cases. We demonstrated that the initial aspiration tended to obtain more cellular samples and to be less contaminated. Thus, the initial aspiration is more important and should be closely attended. PMID- 30464154 TI - ? PMID- 30464153 TI - Statin Intolerance and Suboptimal Statin Therapy. PMID- 30464155 TI - Destabilization of spindle assembly checkpoint causes aneuploidy during meiosis II in murine post-ovulatory aged oocytes. AB - Mammalian oocyte quality degrades over time after ovulation in vitro, which can cause fatal defects such as chromosomal aneuploidy. As various oocyte manipulations employed in assisted reproductive technology are time consuming, post-ovulatory aging is a serious problem to overcome in reproductive medicine or ova research. In this study, we investigated the effects of postovulatory aging on the incidence of chromosome aneuploidy during meiosis II, with a focus on the expression of functional proteins from the spindle assembly checkpoint (SAC). Chromosome analysis was used to assess the rate of aneuploidy in in vitro aged oocytes, or in early embryos derived from aged oocytes. Immunofluorescent staining was used to detect the localization of MAD2, which is a SAC signal that monitors the correct segregation of sister chromatids. Immunoblotting was used to quantify cohesin subunits, which are adhesion factors connecting sister chromatids at the metaphase II (MII) centromere. It was shown that post-ovulatory oocyte aging inhibits MAD2 localization to the sister kinetochore. Furthermore, oocyte aging prevented cohesin subunits from being maintained or degraded at the appropriate time. These data suggest that the destabilization of SAC signaling causes sister chromatid segregation errors in MII oocytes, and consequently increases the incidence of aneuploidy in early embryos. Our findings have provided distinct evidence that the post-ovulatory aging of oocytes might also be a risk factor for aneuploidy, irrespective of maternal age. PMID- 30464156 TI - Antioxidant activity and potential of Caesalpinia sappan aqueous extract on synthesis of silver nanoparticles. AB - The aim of this study was to investigate the antioxidant activity of Caesalpinia sappan aqueous extract (CE) and its potential on synthesis of silver nanoparticles (AgNPs). The antioxidant activity of CE was investigated using ferric reducing antioxidant power (FRAP) assay and two radical scavenging methods using 2,20-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) as free radicals. Silver nitrate (AgNO3) was used as precursor for the synthesis of AgNPs. Effects of AgNO3 concentration, reaction temperature, and duration of reaction were investigated. The obtained AgNPs was characterized using UV-Vis and photon correlation spectrophotometers. The antimicrobial activity of AgNPs was studied by means of diffusion method. The results from FRAP demonstrated that CE had high reducing property of 78.7 +/- 2.4 mM Fe2+/mg. The trolox equivalent antioxidant capacity of CE determined by ABTS was 64.8 +/- 4.2 uM/mg. The concentration of CE that can inhibit 50% of DPPH radicals (IC50) was 51.2 +/- 3.2 uM. These results indicated that CE possesses strong antioxidant and reducing activities. The present study also showed that CE can act as reducing agent to produce AgNPs. The concentration of AgNO3, reaction temperature, and reaction time play an important role on the particles size and zeta potential of the obtained AgNPs. The antimicrobial activity of the AgNPs against Escherichia coli, Candida albicans, and Streptococcus mutants was stronger than against Staphylococcus aureus. PMID- 30464157 TI - Effect of rice variety and reaction parameters on synthesis and antibacterial activity of silver nanoparticles. AB - In the present study, three different rice varieties; Jasmine (JM), Niaw Koko-6 (NKK), and Saohai (SH) were determined for reducing power using ferric reducing antioxidant power (FRAP) assay. SH showed the highest reducing property followed by JM and NKK, respectively. All modified rice samples were used to fabricate silver nanoparticles (AgNPs) by reducing silver nitrate (AgNO3) to metallic Ag. The obtained AgNPs from JM, NKK, and SH namely JM-AgNPs, NKK-AgNPs, and SH-AgNPs, respectively, showed maximum absorption at 410, 408, and 409 nm, respectively, which confirmed the spectra of AgNPs. Reaction parameters such as AgNO3 and modified rice concentration as well as the reaction period were investigated. It was found that increasing of these parameters gave better AgNPs until the concentration of modified rice and AgNO3 reached to 0.3% and 10 mM, respectively and the reaction period reached to 60 min, the most suitable AgNPs were obtained. Among the three rice varieties, SH showed the most potential for synthesis of AgNPs. SH-AgNPs showed the smallest size of 80.4 +/- 2.8 nm and the highest zeta potential of - 45.9 +/- 1.4 mV. The AgNPs obtained from all three rice varieties showed effective against Escherichia coli than Staphylococcus aureus and SH-AgNPs showed significantly higher antibacterial activity than JM- AgNPs and NKK-AgNPs. PMID- 30464158 TI - Preparation and characterization of rice gels containing tooth bleaching agent. AB - In the present study, the modified white rice of Jasmine (JM) and Saohai (SH) were used to prepare the rice gels. Carbamide peroxide (CP) containing rice gels (CP rice gels) of JM (CP-JM) and SH (CP-SH) were prepared. The rice gels and CP rice gels show homogenous texture. Rice variety influences the characteristics and properties of the rice gels. Amylose content of JM was lower than SH. Rheological behavior of JM and CP-JM was pseudoplastic without thixotropy whereas that of SH and CP-SH was pseudoplastic with thixotropy. CP-SH showed higher adhesive property and viscosity than CP-JM whereas CP-JM showed faster in vitro drug release than CP-SH. For ex vivo efficacy evaluation, 55 normal human teeth were subjected to the CP rice gels. Samples were applied on tooth surface according to the dental bleaching techniques. For at-home bleaching technique, the CP rice gels with 10% and 20% CP were used with bleaching time of 8h and 4h, respectively. For in-office bleaching technique, the CP rice gels with 35% CP was used with bleaching time of 1 h. The developed CP rice gels showed significantly higher efficacy than the positive and negative controls. For at-home bleaching technique, CP-SH was the most effective gels whereas for in-office bleaching technique, CP-JM was the most effective gels. PMID- 30464159 TI - The process of surplus medicine accumulation by elderly Japanese patients with chronic disease: A qualitative study. AB - The Japanese government actively urges pharmacists to support efforts to reduce surplus medicines. However, these activities currently serve only to dispose of surplus medicines; no measures are being taken to fundamentally prevent the accumulation of surplus medicines from the outset. A deep understanding of patients' views about storing medicines at home and how they might be accumulating surplus medicines would contribute to the prevention of surplus accumulation. This study aimed to characterize the process by which elderly chronic disease patients in Japan accumulate surplus medicines. Semi-structured interviews were conducted with 18 elderly patients, and the interview data were analyzed using a modified grounded theory approach (M-GTA) to present the process by which surplus medicines were accumulated at patients' homes. The results suggest that elderly patients with chronic diseases often wish to avoid unnecessary medications because of anxiety about medicines, and that these patients seek to maximize medicine suppression. In this context, patients use their own judgment to decide whether to use medicines as needed. Additionally, when patients accumulate surplus medicines, they hesitate to throw them away because they feel that to do so is mottainai (wasteful), or because they accumulate surplus medicines as emergency household medicines. These findings reveal when and how surplus medicine accumulation occurs and the points at which pharmacists can easily intervene to promote a close relationship with patients. PMID- 30464160 TI - Establishment of a gnotobiotic silkworm model. AB - Gnotobiotic animals are useful for investigation of the effects of specific lactic acid bacteria on individual animals. Here we report that lactic acid bacteria colonize and proliferate in the intestinal tract of germ-free silkworms. When silkworms hatching from formalin-treated eggs were reared to fifth-instar larvae with an artificial diet containing antibiotics, bacteria and fungi were not observed in their intestines. An antibiotic-free diet supplemented with viable lactic acid bacteria, such as Enterococcus faecalis 0831-07, Lactococcus lactis 11/19-B1, or Leuconostoc carnosum #7-2, was fed to the germ-free silkworms for 1 day. After feeding the larvae on a diet without lactic acid bacteria for 5 days, each type of lactic acid bacterium was found in the intestine. Moreover, an increase in the number of Enterococcus faecalis 0831-07 was observed in the intestine 2-5 days after ingestion. These findings suggest that we successfully established a method to construct a gnotobiotic silkworm model. PMID- 30464161 TI - Is there a need for shifting patients on long term nevirapine based regimens to efavirenz based regimens: a cross-sectional study? AB - Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the backbone of effective anti-retroviral therapy in the developing world. Efavirenz is the current NNRTI of choice due to reports of higher incidence of serious adverse events with nevirapine. Majority of patients with Human immunodeficiency virus (HIV) infection in India are still on nevirapine based therapy. The aim of the study was to evaluate the need of shifting these patients to efavirenz based therapy. A cross-sectional study was conducted on adult patients, who were on NNRTI based regimen for more than one year with good adherence. The patients were divided into efavirenz or nevirapine groups based on the treatments they were receiving at the time of study. The different arms were compared based on their clinical and laboratory profile, adverse events and immunological response. A total of 244 patients were recruited. A total of 125 patients were receiving nevirapine based regimen while 119 patients were receiving efavirenz based regimen. There was no significant difference in the frequency of hematological and biochemical derangements between the two groups. There was no difference in the median highest CD4 count achieved during therapy between the two groups. Clinically observed side effects were more common in the efavirenz group. These results suggest that there isn't enough evidence to shift patients tolerating long term nevirapine based therapy to efavirenz based therapy. PMID- 30464162 TI - Bio-guided fractionation and iron chelating activity of agricultural residues. AB - Iron overload is implicated in many disorders in the body such as heart failure, liver cirrhosis and fibrosis, gallbladder disorders, diabetes, arthritis, depression, infertility, and cancer. Even though synthetic chelating agents are available, they have several limitations such as poor oral bioavailability, short plasma half-life, high cost and numerous side effects. Therefore, the aim of this study is using agricultural residues as sources for alternative efficient, benign, and economic iron chelators of natural origin. Eighteen agricultural residues were screened for iron chelating activity using 2, 2'-bipyridyl assay. The results showed that the extract of Mangifera indica leaves had the highest iron chelation activity (69.7%), in comparison to ethylenediaminetetraacetic acid (EDTA) (70.3%) (standard iron chelator). The M. indica leaves extract was further investigated for its flavonoidcontent, phenolic content and antioxidant activity. The high concentration of phenolic (405.5ug/g expressed as gallic acid equivalent) and flavonoid (336.9 ug/g expressed as quercetin equivalent) phytochemicals in the extract, as well as its significant antioxidant capacity (96.95%) compared to ascorbic acid (91.90%) (standard antioxidant agent), suggested that the M. indica leaves could represent a good source for new iron chelating agents in iron overload disorders. PMID- 30464163 TI - Ultrasonographic evaluation of changes over time in one defecation cycle in adults with functional constipation: A report of two cases. AB - We described fecal retention during the defecation cycles of adults with functional constipation via ultrasonography (US) of the large intestine. US was performed continuously after the last defecation until the next defecation. We defined the fecal finding level on US as follows: weak fecal retention, a marginally high echo in the colonic lumen; or strong fecal retention, a strongly echoic colon lumen with showing a crescent-shaped acoustic shadow on transverse images and haustrations on longitudinal images. The findings confirmed weak fecal retention in the colon throughout the defecation cycle and a pattern of strong fecal retention in the descending and sigmoid colon and over the colon, including the transverse colon and ascending colon, in patients with functional constipation. PMID- 30464164 TI - Successful treatment of repeated hematemesis secondary to postsclerotherapy esophageal ulcer in a cirrhotic patient: A case report. AB - Esophageal variceal bleeding is a common lethal complication of cirrhosis. Endoscopic injection sclerotherapy (EIS) is one of the major endoscopic approaches for treating esophageal variceal bleeding. However, complications may occur after EIS, which mainly include retrosternal discomfort/pain, dysphagia, re bleeding, esophageal ulcer, esophageal strictures, and esophageal perforation, etc. In this article, we reported a 36-year-old male who developed esophageal ulcer related bleeding after EIS. Currently, there is no consensus on the treatment strategy for esophageal ulcer-related bleeding after EIS. In the present case, the following treatment strategy may be effective for ulcer related bleeding. The first step is to inhibit gastric acid secretion and reduce portal pressure by intravenous infusion of esomeprazole and somatostatin, respectively. The second is local hemostasis by oral norepinephrine and lyophilizing thrombin powder. The third is to protect digestive tract mucosa by oral Kangfuxin Ye and aluminum phosphate. PMID- 30464165 TI - Necrotizing Autoimmune myopathy: A case report on statin induced rhabdomyolysis requiring immunosuppressive therapy. AB - Statins can cause a wide spectrum of muscular adverse effects ranging from asymptomatic elevation of Creatine Kinase (CK), myalgia and exercise intolerance to rhabdomyolysis. Most of these effects generally resolve on stopping the medication. However, statins can be associated with a unique autoimmune myopathy wherein symptoms persist or even progress after statin discontinuation and require immunosuppressive therapy. The case presented is a 60-year-old woman who was on statin treatment for a period of 2 years. She developed muscle weakness with a limb girdle distribution. She had persistent elevation of CK even after discontinuation of statin therapy. EMG done revealed irritable myopathy and muscle biopsy showed necrosis without inflammation. She subsequently tested positive for anti-3-hydroxy-3-methylglutaryl-coenzyme A (anti-HMG CoA) antibody which is found to be present in patients with statin-associated necrotizing autoimmune myopathy. Patient was started on steroid without much improvement in her symptoms. After a month of follow up, her upper extremity strength was back but lower extremity continued to be weak which prompted us to start her on Methotrexate and Azathioprine. Like our patient, there are rare subgroup of patients with an immune-mediated necrotizing myopathy that does not improve after discontinuation of the drug and requires aggressive treatment with immunosuppressive agents. Awareness and early recognition of this disease is very important in patients who continue to have CK elevation and weakness after discontinuation of statin therapy. PMID- 30464166 TI - Three-Dimensional (3D) Computed Tomographic (CT) Assessment of the Sustentaculum Tail to Find Distinctive Characteristics: Implications for Surgery. AB - BACKGROUND With the complexity of calcaneal fracture (CF) increasing, its treatment has changed to include inserting the screw used to secure the facies articular posterior into the sustentaculum tail (ST). Some research progress has been made in this area, but there has been little in-depth research on the anatomical morphology of the sustentaculum tail, which is necessary for clinical surgery, and more information about Chinese anatomic characteristics and improved surgical techniques for CF are needed. MATERIAL AND METHODS This anatomical study, based on a three-dimensional (3D) computed tomographic (CT) reconstruction technique, included 287 dry calcaneus, consisting of 144 left and 143 right calcaneus. The images were reconstructed in 3D after CT scanning. Seven subjects were enrolled (L and R): (1) The vertical distance from inside the sustentaculum tail (IST) to inside the facies articularis talaris posterior; (2) The vertical distance from IST to the outside facies articularis talaris posterior; (3) The thickness of sulcus calcaneal nadir; (4) The distance from IST to processus medislis tuberis calcaneus; (5) The distance from IST to calcaneal posterosuperior tuber; (6) The angle of the prolate axial intersection between ST and calcaneus on the normal superior as ?alpha; and (7) The angle of the prolate axial intersection between ST and calcaneus on the normal posterior as ?beta. All measurement results were analyzed by SPSS 22.0. RESULTS Based on morphological classification, the average length of AB, AC, AE, and AF on left ST were 16.956+/ 1.391 mm, 37.803+/-2.525 mm, 43.244+/-3.617 mm, and 51.113+/-4.455 mm, respectively. Among the others, ?beta was 81.227+/-6.317 mm on the left and 74.581+/-9.008 mm on the right (P<0.05). CONCLUSIONS These results suggest better ways to treat the special characteristics and to reduce the risk of CF surgery. PMID- 30464167 TI - Sigmoido-Cecal Fistula: A Rare Case of Complicated Recurrent Diverticulitis and a Review of the Literature. AB - BACKGROUND Although diverticular disease is well described and treated in daily clinical practice, there are cases that attract great interest because of their complexity and difficulty in management. Herein, we describe a rare case of colo colonic fistula-complicated diverticulitis that necessitated urgent surgical intervention. CASE REPORT A 76-year-old female patient with a known history of diverticular disease of the sigmoid colon presented in the Emergency Department for evaluation of left lower quadrant abdominal pain. The clinical and radiological examinations revealed a recurrent episode of acute diverticulitis of the sigmoid colon. However, it was of great interest that we detected a sigmoido cecal fistula in the abdominal computed tomography (CT). The patient was admitted to the hospital for conservative treatment. After 48 hours, the patient's clinical status deteriorated, with pain aggravation, abdominal distension, bloating, and metallic bowel sounds. The simple abdominal x-ray revealed large bowel obstruction and the CT demonstrated worsening inflammation of the sigmoid colon. An exploratory laparotomy revealed an inflamed dolichol-sigmoid colon forming a fistulous tract with the cecum and thus, mimicking a closed loop obstruction. The sigmoid colon was transected en bloc with the sigmoido-cecal fistula and a Hartmann's procedure was performed. CONCLUSIONS This case is extremely unusual as the patient presented at the same time two complications of diverticular disease, both obstruction and this rare formation of sigmoido-cecal fistula. It is presented in order to acquaint surgeons with the possibility of an unexpected course of this disease which indeed necessitates an individualized management. PMID- 30464168 TI - miR-330-5p targets SPRY2 to promote hepatocellular carcinoma progression via MAPK/ERK signaling. AB - MicroRNAs (miRNAs) have been identified as critical modulators of cell proliferation and growth, which are the major causes of cancer progression including hepatocellular carcinoma (HCC). Our previous miRNA microarray data have shown that miR-330-5p was always upregulated in HCC. However, the accurate role of miR-330-5p in HCC is still uncertain. Here, we report that miR-330-5p expression is upregulated in HCC tissues and cell lines, and is associated with tumor size, tumor nodule number, capsule formation and Tumor Node Metastasis (TNM) stage in HCC patients. Overexpression of miR-330-5p promotes proliferation and growth of HCC cells in vitro and in vivo, while miR-330-5p knockdown has the inverse effect. Moreover, using miRNA databases and dual luciferase report assay, we find miR-330-5p directly binds to the 3'-untranslated region (3'-UTR) of Sprouty2 (SPRY2). Then we find the novel biofunctional role of SPRY2 inactivation in promoting HCC progression. Finally, we confirm that miR-330-5p suppresses SPRY2 to promote proliferation via mitogen-activated protein kinases (MAPK)/extracellular regulated kinase (ERK) signaling in HCC. Taken together, our findings demonstrate the critical role of miR-330-5p in promoting HCC progression via targeting SPRY2 to activate MAPK/ERK signaling, which may provide a novel and promising prognostic marker and therapeutic target for HCC. PMID- 30464169 TI - Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma. AB - Therapeutic options for the treatment of glioblastoma remain inadequate despite concerted research efforts in drug development. Therapeutic failure can result from poor permeability of the blood-brain barrier, heterogeneous drug distribution, and development of resistance. Elucidation of relationships among such parameters could enable the development of predictive models of drug response in patients and inform drug development. Complementary analyses were applied to a glioblastoma patient-derived xenograft model in order to quantitatively map distribution and resulting cellular response to the EGFR inhibitor erlotinib. Mass spectrometry images of erlotinib were registered to histology and magnetic resonance images in order to correlate drug distribution with tumor characteristics. Phosphoproteomics and immunohistochemistry were used to assess protein signaling in response to drug, and integrated with transcriptional response using mRNA sequencing. This comprehensive dataset provides simultaneous insight into pharmacokinetics and pharmacodynamics and indicates that erlotinib delivery to intracranial tumors is insufficient to inhibit EGFR tyrosine kinase signaling. PMID- 30464170 TI - LncRNA UCA1 promotes tumor metastasis by inducing miR-203/ZEB2 axis in gastric cancer. AB - Increasing studies showed that long-noncoding RNAs (lncRNAs) play important roles in the biological processes, including cancer initiation and progression. However, little is known about the exact role and regulation mechanism of lncRNA UCA1 during the progression of gastric cancer (GC). In this study, we found that UCA1 was aberrantly elevated in gastric cancer tissues, and was significantly associated with lymph node metastasis and TNM stage. In vivo and in vitro, enforced UCA1 level promoted cell migration and invasion of GC cell. Depleted UCA1 expression level attenuated the ability of cell migration and invasion in GC. And then, we detected that expression level of ZEB2, a transcription factor related to tumor metastasis, was regulated by UCA1 in GC cells. miR-203 targets and suppresses to ZEB2 expression. Furthermore, we found that UCA1 could directly interact with miR-203 and lead to the release of miR-203-targeted transcripts ZEB2. Herein, we revealed the novel mechanism of UCA1 on regulating metastasis related gene by sponge regulatory axis during GC metastasis. Our findings indicated that UCA1 plays a critical role in metastatic GC by mediating sponge regulatory axis miR-203/ZEB2. To explore function of UCA1-miR-203-ZEB2 axis may provide an informative biomarker of malignancy and a highly selective anti-GC therapeutic target. PMID- 30464172 TI - Graphene controlled Brewster angle device for ultra broadband terahertz modulation. AB - Terahertz modulators with high tunability of both intensity and phase are essential for effective control of electromagnetic properties. Due to the underlying physics behind existing approaches there is still a lack of broadband devices able to achieve deep modulation. Here, we demonstrate the effect of tunable Brewster angle controlled by graphene, and develop a highly-tunable solid state graphene/quartz modulator based on this mechanism. The Brewster angle of the device can be tuned by varying the conductivity of the graphene through an electrical gate. In this way, we achieve near perfect intensity modulation with spectrally flat modulation depth of 99.3 to 99.9 percent and phase tunability of up to 140 degree in the frequency range from 0.5 to 1.6 THz. Different from using electromagnetic resonance effects (for example, metamaterials), this principle ensures that our device can operate in ultra-broadband. Thus it is an effective principle for terahertz modulation. PMID- 30464171 TI - Hedgehog stimulates hair follicle neogenesis by creating inductive dermis during murine skin wound healing. AB - Mammalian wounds typically heal by fibrotic repair without hair follicle (HF) regeneration. Fibrosis and regeneration are currently considered the opposite end of wound healing. This study sought to determine if scar could be remodeled to promote healing with HF regeneration. Here, we identify that activation of the Sonic hedgehog (Shh) pathway reinstalls a regenerative dermal niche, called dermal papilla, which is required and sufficient for HF neogenesis (HFN). Epidermal Shh overexpression or constitutive Smoothened dermal activation results in extensive HFN in wounds that otherwise end in scarring. While long-term Wnt activation is associated with fibrosis, Shh signal activation in Wnt active cells promotes the dermal papilla fate in scarring wounds. These studies demonstrate that mechanisms of scarring and regeneration are not distant from one another and that wound repair can be redirected to promote regeneration following injury by modifying a key dermal signal. PMID- 30464173 TI - Defining human cardiac transcription factor hierarchies using integrated single cell heterogeneity analysis. AB - Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become a powerful tool for human disease modeling and therapeutic testing. However, their use remains limited by their immaturity and heterogeneity. To characterize the source of this heterogeneity, we applied complementary single cell RNA-seq and bulk RNA-seq technologies over time during hiPSC cardiac differentiation and in the adult heart. Using integrated transcriptomic and splicing analysis, more than half a dozen distinct single-cell populations were observed, several of which were coincident at a single time-point, day 30 of differentiation. To dissect the role of distinct cardiac transcriptional regulators associated with each cell population, we systematically tested the effect of a gain or loss of three transcription factors (NR2F2, TBX5, and HEY2), using CRISPR genome editing and ChIP-seq, in conjunction with patch clamp, calcium imaging, and CyTOF analysis. These targets, data, and integrative genomics analysis methods provide a powerful platform for understanding in vitro cellular heterogeneity. PMID- 30464174 TI - The essential genome of the crenarchaeal model Sulfolobus islandicus. AB - Sulfolobus islandicus is a model microorganism in the TACK superphylum of the Archaea, a key lineage in the evolutionary history of cells. Here we report a genome-wide identification of the repertoire of genes essential to S. islandicus growth in culture. We confirm previous targeted gene knockouts, uncover the non essentiality of functions assumed to be essential to the Sulfolobus cell, including the proteinaceous S-layer, and highlight essential genes whose functions are yet to be determined. Phyletic distributions illustrate the potential transitions that may have occurred during the evolution of this archaeal microorganism, and highlight sets of genes that may have been associated with each transition. We use this comparative context as a lens to focus future research on archaea-specific uncharacterized essential genes that may provide valuable insights into the evolutionary history of cells. PMID- 30464175 TI - A time-resolved multi-omic atlas of the developing mouse stomach. AB - The mammalian stomach is structurally highly diverse and its organ functionality critically depends on a normal embryonic development. Although there have been several studies on the morphological changes during stomach development, a system wide analysis of the underlying molecular changes is lacking. Here, we present a comprehensive, temporal proteome and transcriptome atlas of the mouse stomach at multiple developmental stages. Quantitative analysis of 12,108 gene products allows identifying three distinct phases based on changes in proteins and RNAs and the gain of stomach functions on a longitudinal time scale. The transcriptome indicates functionally important isoforms relevant to development and identifies several functionally unannotated novel splicing junction transcripts that we validate at the peptide level. Importantly, many proteins differentially expressed in stomach development are also significantly overexpressed in diffuse type gastric cancer. Overall, our study provides a resource to understand stomach development and its connection to gastric cancer tumorigenesis. PMID- 30464176 TI - Electrochemical surface passivation of LiCoO2 particles at ultrahigh voltage and its applications in lithium-based batteries. AB - Lithium cobalt oxide, as a popular cathode in portable devices, delivers only half of its theoretical capacity in commercial lithium-ion batteries. When increasing the cut-off voltage to release more capacity, solubilization of cobalt in the electrolyte and structural disorders of lithium cobalt oxide particles are severe, leading to rapid capacity fading and limited cycle life. Here, we show a class of ternary lithium, aluminum, fluorine-modified lithium cobalt oxide with a stable and conductive layer using a facile and scalable hydrothermal-assisted, hybrid surface treatment. Such surface treatment hinders direct contact between liquid electrolytes and lithium cobalt oxide particles, which reduces the loss of active cobalt. It also forms a thin doping layer that consists of a lithium aluminum-cobalt-oxide-fluorine solid solution, which suppresses the phase transition of lithium cobalt oxide when operated at voltages >4.55 V. PMID- 30464177 TI - Deep Feature Learning for Sudden Cardiac Arrest Detection in Automated External Defibrillators. AB - Ventricular fibrillation and ventricular tachycardia (VF/VT), known as shockable (SH) rhythms, are the mainly cause of sudden cardiac arrests (SCA), which is cured efficiently by the automated external defibrillator (AED). The performance of the shock advice algorithm (SAA) applied in the AED has been improved by using machine learning technique and variously conventional features, recently. In this paper, we propose a novel algorithm with relatively high performance for the SCA detection on electrocardiogram (ECG) signal. The algorithm consists of a convolutional neural network as a feature extractor (CNNE) and a Boosting (BS) classifier. A grid search with nested 5-folds cross validation (CV) is used to select the CNNE trained with preprocessed ECG, SH, and NSH signals using the modified variational mode decomposition technique. The deep feature vector learned by this CNNE is extracted at the first fully connected layer and then fed into BS classifier to validate its performance using 5-folds CV procedure. The secondary learning of the BS classifier and the use of three input channels for the CNNE improve certainly the detection performance of the proposed SAA with the validated accuracy of 99.26%, sensitivity of 97.07%, and specificity of 99.44%. PMID- 30464178 TI - Isolation and characterization of 21 polymorphic microsatellite loci for the rockpool shrimp Palaemon elegans using Illumina MiSeq sequencing. AB - The rockpool shrimp Palaemon elegans is considered an important crustacean species within the European coastline fauna. This species is experiencing an ongoing geographical expansion beyond its native distribution range due to unintentional human introductions. A better knowledge of the genetic diversity, geographic structure and connectivity of its populations is necessary. In the present study, microsatellite loci were isolated using the Illumina MiSeq platform. The microsatellite-enriched library sequencing produced 3.9 million raw reads. Reads were processed and primer pairs were designed for microsatellite sequences amplification. Ninety-six microsatellite loci were preliminary screened in individuals from Atlantic and Mediterranean localities. From them, 21 loci exhibited reliable polymorphism and were thoroughly characterized in 30 individuals from a Cantabrian locality (Spain). No linkage disequilibrium between pairs of loci was detected. Number of alleles per locus ranged from 2 to 12. Observed and expected heterozygosities ranged from 0.033 to 0.833 and from 0.033 to 0.869 respectively. No significant departure from the Hardy-Weinberg equilibrium was detected in most of loci. This is the first time that microsatellite markers have been developed for P. elegans. This characterized microsatellite suite provides new suitable tools for further analyses, facilitating the understanding of population genetics both in natural and introduced populations. PMID- 30464179 TI - Pre-B acute lymphoblastic leukemia expresses cell surface nucleolin as a 9-O acetylated sialoglycoprotein. AB - Precursor B acute lymphoblastic leukemias (pre-B ALLs) abnormally express a specific glycan structure, 9-O-acetylated sialic acid (9-O-Ac-Sia), on their cell surface, but glycoproteins that carry this modification have not been identified. Using three different lectins that specifically recognize this structure, we establish that nucleolin (NCL), a protein implicated in cancer, contains 9-O-Ac Sia. Surprisingly, antibodies against the glycolipid 9-O-Ac-Sia GD3 also detected 9-O-Ac-Sia NCL. NCL is present on the surface of pre-B ALL cells as a sialoglycoprotein that is partly 9-O-acetylated and conversely, 9-O-Ac-Sia containing structures other than NCL are present on these cells as well. Interestingly, NCL and the 9-O-Ac-Sia signal had less co-localization on normal pre-B cells. We also investigated regulation of NCL on the cell surface and found that sialidase treatment increased the percentage of cells positive for cell surface NCL, suggesting that sialylation of NCL promotes internalization. Treatment of pre-B ALL cells with the chemotherapy drug vincristine also increased the percentage of cells with surface NCL and correlated with increased 9-O-Ac-Sia expression. All tested leukemia cells including primary samples expressed NCL, suggesting it as a possible therapeutic target. We confirmed this by showing inhibition of cell proliferation in some pre-B ALLs by exposure to a NCL-specific aptamer AS1411. PMID- 30464180 TI - Superdislocations and point defects in pyrochlore Yb2Ti2O7 single crystals and implication on magnetic ground states. AB - This study reports atomic-scale characterization of structural defects in Yb2Ti2O7, a pyrochlore oxide whose subtle magnetic interactions is prone to small perturbations. Due to discrepancies in the reported magnetic ground states, it has become a pressing issue to determine the nature of defects in this system. In the present study, we use atomic resolution scanning transmission electron microscopy techniques to identify the type of defects in the ytterbium titanate single crystals grown by the conventional optical floating zone (FZ) method. In addition to the known point defects of substitution Yb on Ti B-sites, extended defects such as dissociated superdislocations and anti-phase boundaries were discovered for the first time in this material. Such defects were prevalently observed in the FZ grown single crystals (of a darker color), in contrast to the stoichiometric white polycrystalline powders or high quality colorless single crystals grown by the traveling solvent floating zone technique. The lattice strains from these extended defects result in distortions of Yb-tetrahedron. A change of Ti valance was not detected at the defects. Our findings provide new insights into understanding the nature of defects that are of great importance for the physical property studies of geometrically frustrated compounds. Furthermore, this work sheds light on the complicated core structure of superdislocations that have large Burgers vectors in oxides with complex unit cells. PMID- 30464182 TI - Investigating social-contextual determinants of cooperation in incarcerated violent offenders. AB - Antisocial and psychopathic personality traits constitute a severe and treatment resistant form of externalizing psychopathology. While deficits in social information processing have been extensively investigated in these individuals, less is known about their capacity for altruism and cooperation. In particular, no studies to date have investigated whether established social-contextual determinants of cooperation, e.g., group affiliation and number of expected interactions, can motivate cooperative behaviour in antisocial individuals. The present study compared cooperative behaviour of incarcerated violent offenders (N = 52) and controls (N = 46) by using an established social interaction paradigm (Give Some Dilemma) where two players divide monetary units between themselves and the counterpart. Group affiliation (in- vs. out-group) and number of expected interactions (single-trial vs. repeated-trial interactions) were manipulated. Violent offenders as compared to controls shared less monetary units with their counterparts, indicating an overall reduced cooperation. Both groups showed increased cooperation rates towards in-group members and in repeated interactions. Higher psychopathic traits were associated with lower cooperation in single-trial interactions in the violent offender group. Although cooperation was comparably reduced in violent offenders, behaviour in both groups was determined by the number of expected interactions as well as group affiliation, thus providing evidence for equivalent social-contextual determinants. PMID- 30464181 TI - Benefits of pallidal stimulation in dystonia are linked to cerebellar volume and cortical inhibition. AB - Clinical benefits of pallidal deep brain stimulation (GPi DBS) in dystonia increase relatively slowly suggesting slow plastic processes in the motor network. Twenty-two patients with dystonia of various distribution and etiology treated by chronic GPi DBS and 22 healthy subjects were examined for short latency intracortical inhibition of the motor cortex elicited by paired transcranial magnetic stimulation. The relationships between grey matter volume and intracortical inhibition considering the long-term clinical outcome and states of the GPi DBS were analysed. The acute effects of GPi DBS were associated with a shortening of the motor response whereas the grey matter of chronically treated patients with a better clinical outcome showed hypertrophy of the supplementary motor area and cerebellar vermis. In addition, the volume of the cerebellar hemispheres of patients correlated with the improvement of intracortical inhibition which was generally less effective in patients than in controls regardless of the DBS states. Importantly, good responders to GPi DBS showed a similar level of short-latency intracortical inhibition in the motor cortex as healthy controls whereas non-responders were unable to increase it. All these results support the multilevel impact of effective DBS on the motor networks in dystonia and suggest potential biomarkers of responsiveness to this treatment. PMID- 30464183 TI - Impact of preanalytical conditions on plasma concentration and size distribution of extracellular vesicles using Nanoparticle Tracking Analysis. AB - Optimal pre-analytical handling is essential for valid measurements of plasma concentration and size distribution of extracellular vesicles (EVs). We investigated the impact of plasma preparation, various anticoagulants (Citrate, EDTA, CTAD, Heparin), and fasting status on concentration and size distribution of EVs measured by Nanoparticle Tracking Analysis (NTA). Blood was drawn from 10 healthy volunteers to investigate the impact of plasma preparation and anticoagulants, and from 40 individuals from a population-based study to investigate the impact of postprandial lipidemia. Plasma concentration of EVs was measured by NTA after isolation by high-speed centrifugation, and size distribution of EVs was determined using NTA and scanning electron microscopy (SEM). Plasma concentrations and size distributions of EVs were essentially similar for the various anticoagulants. Transmission electron microscopy (TEM) confirmed the presence of EVs. TEM and SEM-analyses showed that the EVs retained spherical morphology after high-speed centrifugation. Plasma EVs were not changed in postprandial lipidemia, but the mean sizes of VLDL particles were increased and interfered with EV measurements (explained 66% of the variation in EVs concentration in the postprandial phase). Optimization of procedures for separating VLDL particles and EVs is therefore needed before NTA-assessment of EVs can be used as biomarkers of disease. PMID- 30464184 TI - Experimental Comparison of the Performance of Cutting Bone and Soft Tissue between Piezosurgery and Conventional Rotary Instruments. AB - Piezosurgery is an innovative technique widely used for osteotomies in the field of oral and maxillofacial surgery. The surgical technique has been clinically supposed to cut mineralized bone selectively with reducing the risk of damage to adjacent soft tissues. However, none of the previous literature has reported any evidence of scientific experiments to examine performance of the piezoelectric device, i.e. the time required for cutting bone and the effect on soft tissues under the standardized conditions. This study was designed to test the hypothesis that cutting time of the piezoelectric device is longer than that of rotary instruments while the cut surface of bone is smoother and soft tissues are less damaged with piezosurgery under the standardized experimental system. We measured the time for cutting bone and soft tissues of rats with the piezoelectric device and rotary instruments. Damage to soft tissues was examined histologically, and the cut surface of bone was investigated using scanning electron microscopy. Our study demonstrated experimentally that piezosurgery provides a smooth cut bony surface with no damage to soft tissues and takes longer time to cut bone than conventional drillings. We propose that piezosurgery is beneficial for medical safety and usability. PMID- 30464185 TI - The Trans Golgi Region is a Labile Intracellular Ca2+ Store Sensitive to Emetine. AB - The Golgi apparatus (GA) is a bona fide Ca2+ store; however, there is a lack of GA-specific Ca2+ mobilizing agents. Here, we report that emetine specifically releases Ca2+ from GA in HeLa and HL-1 atrial myocytes. Additionally, it has become evident that the trans-Golgi is a labile Ca2+ store that requires a continuous source of Ca2+ from either the external milieu or from the ER, to enable it to produce a detectable transient increase in cytosolic Ca2+. Our data indicates that the emetine-sensitive Ca2+ mobilizing mechanism is different from the two classical Ca2+ release mechanisms, i.e. IP3 and ryanodine receptors. This newly discovered ability of emetine to release Ca2+ from the GA may explain why chronic consumption of ipecac syrup has muscle side effects. PMID- 30464186 TI - Epidemiology of Breakthrough Varicella after the Implementation of a Universal Varicella Vaccination Program in Taiwan, 2004-2014. AB - National one-dose varicella vaccination at 12 months of age was implemented in Taiwan since 2004.Our study aimed to evaluate breakthrough varicella (BV) in post vaccine era and its associated risk factors. We retrospectively identified children vaccinated against varicella between 12-23 months of age during 2004 2008. Their vaccination information was extracted from the national vaccination registry system and linked to the 2004-2014 National Health Insurance database. BV was defined as a diagnosis of varicella (ICD-9-CM codes 052 and 052.0-052.9) beyond 42 days post-vaccination. Multiple Cox regression model was used to identify risk factors for BV. Among 932,874 enrolled vaccinees, 26,446 (2.8%) had BV and 219 (0.024%) required hospitalization over the study period. Varicella incidence declined from 4.71 per 1000 person-year (PY) in 2004 to 0.81/1000 PY in 2014. BV incidence decreased from 3.90/1000 PY at first year to 1.94/1000 PY at 11th year after vaccination. Females had a lower risk for BV than males (hazard ratio [HR] 0.85, 95% CI, 0.83-0.87); Varivax(r) recipients had a lower risk for BV than Varilrix(r) recipients (HR 0.75, 95% CI, 0.72-0.78). Our study showed the incidence of varicella, BV and varicella-related hospitalizations in Taiwan were kept low in post-vaccine era. PMID- 30464187 TI - The human olfactory cleft mucus proteome and its age-related changes. AB - Age-related decreases in olfactory sensitivity are often accompanied by a decrease in the quality of life. However, the molecular mechanisms underlying these changes are not well described. Inhaled substances including odorants are detected by sensory neurons in the olfactory cleft covered with a layer of mucus. This olfactory mucus is the first molecular machinery responsible for tissue protection and for detection of environmental odorants. Yet, little is known about the molecular identities of the actors because of the lack of information on the mucus proteome and its age-related changes. Here, we sampled human mucus from different nasal locations and from young and elderly subjects. The composition of the mucus was extensively analyzed by shotgun proteomic analysis for a vast array of proteins. We also explored correlations between the levels of each mucus proteins with the olfactory sensitivity of subjects. This analysis revealed previously unrecognized proteins with potentially important functions in olfaction. Taken together, this report describes the most comprehensive catalogue of the nasal mucus proteins to date, their positional and age-related differences, and candidate proteins associated with olfaction. This catalogue will provide fundamental information useful for future studies, such as identification of olfactory auxiliary proteins, causes of age-related declines in olfaction, and biomarkers for neurodegenerative disorders. PMID- 30464188 TI - DENV-1 Genotype V in Brazil: Spatiotemporal dispersion pattern reveals continuous co-circulation of distinct lineages until 2016. AB - In Brazil, DENV-1 introduced in the 80's, remained the prevalent serotype from 2012 to 2016. After its re-emergence in the country in 2009, the co-circulation of different viral lineages was identified, however, its transmission dynamics afterwards, was not fully characterized. In this study, we performed the continuous molecular surveillance after the reemergence period (2012 to 2016), covering the 30 years of circulation of DENV-1 in Brazil. Phylogenetic analysis allowed confirmation of the continued presence of genotype V, as well as three distinct co-circulating lineages. The molecular characterization of the E gene presented two new amino acid substitutions previously unidentified in the country. Phylogeographic analysis has shown that a large flow of migrations has occurred between Brazil and Argentina in the last 10 years. PMID- 30464189 TI - Changes in retinal flow density measured by optical coherence tomography angiography in patients with carotid artery stenosis after carotid endarterectomy. AB - The aim of the study presented here was to evaluate retinal and optic nerve head (ONH) perfusion in patients with severe asymptomatic carotid artery stenosis (CAS) compared with healthy controls and to analyze the impact of carotid endarterectomy using optical coherence tomography angiography (OCT-A). 25 eyes of 25 patients with CAS (study group) and 25 eyes of 25 healthy controls (control group) were prospectively included in this study. OCT-A was performed using RTVue XR Avanti (Optovue, Inc, Fremont, California, USA). The flow density data in the superficial and deep retinal OCT-angiogram of the macula and in the radial peripapillary capillary network (RPC) of the ONH were extracted and analyzed. The flow density in the superficial retinal OCT angiogram of the macula and in the ONH were significantly lower in the study group compared with the control group (macula: p = 0.003) (ONH: p = 0.013). The flow density in the ONH improved significantly after carotid endarterectomy (p = 0.004). A reduced flow density was observed in patients with CAS when compared with healthy controls. The flow density also improved after carotid endarterectomy. Quantitative changes in the microvascular density, as measured using OCT-A, could well be useful in the diagnosis of CAS and the evaluation of therapy success. PMID- 30464190 TI - Exposure history, post-exposure prophylaxis use, and clinical characteristics of human rabies cases in China, 2006-2012. AB - Rabies is still a public health threat in China. Evaluating the exposure history, clinical characteristics, and post-exposure prophylaxis (PEP) of the cases could help in identifying approaches to reducing the number of these preventable deaths. We analysed data collected from 10,971 case-investigations conducted in China from 2006 to 2012. Most cases (n = 7,947; 92.0%) were caused by animal bites; 5,800 (55.8%) and 2,974 (28.6%) exposures were from domestic and free roaming dogs, respectively. Only 278 (4.8%) of these domestic dogs had previously received rabies vaccination. Among all cases, 5,927 (59.7%) cases had category III wounds, 1,187 (11.7%) cases initiated the rabies PEP vaccination and 234 (3.9%) cases with category III wounds received rabies immunoglobulin. In our adjusted logistic regression model, male cases (adjusted odds ratio [aOR] = 1.25, 95% confidence interval [CI]: 1.09-1.44) and farmers (aOR = 1.39, 95% CI: 1.10 1.77) and person older than 55 years (aOR = 1.48, 95% CI: 1.01-2.17) were less likely than females and persons in other occupations or younger than 15 years to initiate PEP vaccination. The median incubation period was 66 days (interquartile range (IQR): 33-167 days). To reduce the number of human deaths due to rabies, rabies prevention campaigns targeting males and farmers and older people should be conducted. Increasing routine rabies vaccination among domestic dogs will be essential in the long term. PMID- 30464191 TI - Root Mean Square Minimum Distance as a Quality Metric for Stochastic Optical Localization Nanoscopy Images. AB - A localization algorithm in stochastic optical localization nanoscopy plays an important role in obtaining a high-quality image. A universal and objective metric is crucial and necessary to evaluate qualities of nanoscopy images and performances of localization algorithms. In this paper, we propose root mean square minimum distance (RMSMD) as a quality metric for localization nanoscopy images. RMSMD measures an average, local, and mutual fitness between two sets of points. Its properties common to a distance metric as well as unique to itself are presented. The ambiguity, discontinuity, and inappropriateness of the metrics of accuracy, precision, recall, and Jaccard index, which are currently used in the literature, are analyzed. A numerical example demonstrates the advantages of RMSMD over the four existing metrics that fail to distinguish qualities of different nanoscopy images in certain conditions. The unbiased Gaussian estimator that achieves the Fisher information and Cramer-Rao lower bound (CRLB) of a single data frame is proposed to benchmark the quality of localization nanoscopy images and the performance of localization algorithms. The information-achieving estimator is simulated in an example and the result demonstrates the superior sensitivity of RMSMD over the other four metrics. As a universal and objective metric, RMSMD can be broadly employed in various applications to measure the mutual fitness of two sets of points. PMID- 30464192 TI - Core genes in diverse dinoflagellate lineages include a wealth of conserved dark genes with unknown functions. AB - Dinoflagellates are a diverse group of unicellular primary producers and grazers that exhibit some of the most remarkable features known among eukaryotes. These include gigabase-sized nuclear genomes, permanently condensed chromosomes and highly reduced organelle DNA. However, the genetic inventory that allows dinoflagellates to thrive in diverse ecological niches is poorly characterised. Here we systematically assess the functional capacity of 3,368,684 predicted proteins from 47 transcriptome datasets spanning eight dinoflagellate orders. We find that 1,232,023 proteins do not share significant sequence similarity to known sequences, i.e. are "dark". Of these, we consider 441,006 (13.1% of overall proteins) that are found in multiple taxa, or occur as alternative splice variants, to comprise the high-confidence dark proteins. Even with unknown function, 43.3% of these dark proteins can be annotated with conserved structural features using an exhaustive search against available data, validating their existence and importance. Furthermore, these dark proteins and their putative homologs are largely lineage-specific and recovered in multiple taxa. We also identified conserved functions in all dinoflagellates, and those specific to toxin-producing, symbiotic, and cold-adapted lineages. Our results demonstrate the remarkable divergence of gene functions in dinoflagellates, and provide a platform for investigations into the diversification of these ecologically important organisms. PMID- 30464193 TI - FAST-1 antisense RNA epigenetically alters FXN expression. AB - Friedreich ataxia (FRDA) is a multisystem genetic disorder caused by GAA repeat expansion mutations within the FXN gene, resulting in heterochromatin formation and deficiency of frataxin protein. Elevated levels of the FXN antisense transcript (FAST-1) have previously been detected in FRDA. To investigate the effects of FAST-1 on the FXN gene expression, we first stably overexpressed FAST 1 in non-FRDA cell lines and then we knocked down FAST-1 in FRDA fibroblast cells. We observed decreased FXN expression in each FAST-1 overexpressing cell type compared to control cells. We also found that FAST-1 overexpression is associated with both CCCTC-Binding Factor (CTCF) depletion and heterochromatin formation at the 5'UTR of the FXN gene. We further showed that knocking down FAST 1 in FRDA fibroblast cells significantly increased FXN expression. Our results indicate that FAST-1 can act in trans in a similar manner to the cis-acting FAST 1 overexpression that has previously been identified in FRDA fibroblasts. The effects of stably transfected FAST-1 expression on CTCF occupancy and heterochromatin formation at the FXN locus suggest a direct role for FAST-1 in the FRDA molecular disease mechanism. Our findings also support the hypothesis that inhibition of FAST-1 may be a potential approach for FRDA therapy. PMID- 30464194 TI - A refined two-step oligoribonucleotide interference-PCR method for precise discrimination of nucleotide differences. AB - We previously developed oligoribonucleotide (ORN) interference-PCR (ORNi-PCR), in which an ORN hybridises with a complementary DNA sequence and inhibits PCR amplification across the sequence in a sequence-specific manner. Suppression of target amplification by ORNi-PCR can be used to detect nucleotide differences such as mutations in a target sequence. In the present study, we refined the ORNi PCR method and established a detailed technical protocol to precisely discriminate single-nucleotide differences. We first revealed that a two-step (denaturing and annealing plus elongation) rather than a standard three-step (denaturing, annealing and elongation) method is more suitable for stably hybridising an ORN to its target DNA sequence for sequence-specific suppression of target amplification. We then optimised the ORNi-PCR method using two-step cycles and established a step-by-step technical protocol. The optimised Two-Step ORNi-PCR method could discriminate single-nucleotide differences in genomic DNA or cDNA introduced by genome editing or mutations in cancer cells. In addition, we showed that Two-Step ORNi-PCR can detect the cancer cells possessing a single nucleotide mutation in a target locus mixed with a large number of cells harboring wild-type sequences in the locus so that the number of the cancer cells is only 0.2% of the total cell number. Two-Step ORNi-PCR is useful for simple, precise, cost-effective and positive detection of nucleotide differences in a wide range of molecular biology and medical applications. PMID- 30464195 TI - Wide-field choroidal thickness profile in healthy eyes. AB - The introduction of wide field optical coherence tomography (WF-OCT) has provided newer insights in the imaging of peripheral choroid. We evaluated choroidal thickness (CT) and large choroidal vessel thickness (LCVT) of 20 eyes in horizontal and vertical meridians using WF-OCT. A high-definition line scan through the fovea in both horizontal and vertical meridian was captured in primary and extremes of gaze to obtain scans up to mid-equator. CT and LCVT measurements were done across predefined points in macular area and all quadrants. LCVT was calculated after identifying a large choroidal vessel near choroidoscleral interface. The main outcome measures were differences in CT and LCVT in macular and four quadrants. Mean CT (331.23 +/- 76.34 u) and LCVT (201.46 +/- 54.31 u) in vertical macular segment were significantly more than CT (245.79 +/- 55.38 u; p = 0.0002) and LCVT (150.48 +/- 52.58 u; p = 0.004) in horizontal macular segment. CT at peripheral points in all quadrants was significantly reduced as compared to subfoveal CT (all p values < 0.05) with maximum reduction in inferior quadrant (64.5%). Using linear regression, only quadrant had a significant effect on CT and LCVT (both p < 0.001). CT and LCVT are highest at the macular area with reduction towards the periphery. The contribution of LCVT to CT is less at the fovea compared to other peripheral points. PMID- 30464196 TI - Optical coherence tomography angiography analysis of changes in the retina and the choroid after haemodialysis. AB - The purpose of this study is to evaluate the effect of haemodialysis on perfused vessel density, choroidal thickness (CT), and retinal thickness in end-stage renal disease (ESRD) using swept-source optical coherence tomography angiography (SS-OCTA). We studied twenty-nine eyes of 29 ESRD patients by ophthalmologic examination and SS-OCTA before and after haemodialysis. The colour-coded perfusion density maps were generated and perfused vessel density was calculated. Changes in systemic and other ocular parameters such as retinal and choroidal thickness were measured and analysed. Total perfused vessel density decreased significantly after haemodialysis in the choriocapillaris; it was not significantly different in the superficial capillary plexus (SCP) and the deep capillary plexus (DCP). Total CT decreased significantly, but total retinal thickness was not significantly different. There was no significant correlation between choriocapillaris perfused vessel density and CT. The reduction in choriocapillaris perfused vessel density correlated with the decrease in systolic and mean arterial blood pressures. The decrease in CT correlated with the ultrafiltration volume. There were no significant systemic and ocular factors affecting change in retinal thickness and perfused vessel density of SCP and DCP. This is the first study to assess the effect of haemodialysis on blood flow changes using SS-OCTA; changes may be more prominent in the choroidal compared to the retinal layer. PMID- 30464197 TI - Origin of the largest South American transcontinental water divide. AB - Interbasin arches between hydrographic systems have a heterogeneous geological origin, forming under the influence of several different geomorphological processes. Independent of the underlying processes, these arches compartmentalize present-day river basins, encompassing different water chemistries, habitat types, soil domains, potential energy and, on a geological/evolutionary time scale, aquatic life varieties in the ecosystem. Through most of its length, the water divide between the Amazonian, Parana-Paraguay, and Sao Francisco river basins in central South America coincides with an Upper Cretaceous intracontinental igneous alkaline province. This magmatism, independent of its nature, caused intense crustal uplift and influenced hydrological networks at different scales: from continental-scale crustal doming to continental break-up, and finally to local-scale phenomena. The available ages for alkaline rocks indicate a well-defined time-interval between 72.4 to 91 Ma (concentrated between 76 and 88 Ma) period of uplift that contributed to large-scale drainage compartmentalization in the region. Here we show that uplift associated with intrusive magmatism explains the origin and maintenance of the divide between the Amazonian, Parana-Paraguay, and Sao Francisco river basins. PMID- 30464198 TI - Characterization of fume particles generated during arc welding with various covered electrodes. AB - Arc welding operations are considered to be risky procedures by generating hazardous welding fume for human health. This study focuses on the key characteristics, as well as dispersion models, of welding fumes within a work zone. Commercial and widely used types of electrodes with various types of covering (rutile, basic, acidic and rutile-cellulose) were used in a series of experiments on arc welding operations, under 100 and 150 amps of electric current. According to the results of this study, maximum levels of pollution with particles of PM10 fraction occur in the workspace during arc welding operations. Disregarding the types of electrodes used, the 3D models of dispersion of the RM10 particles at the floor plane exhibit corrugated morphologies while also demonstrate high concentrations of the RM10 particles at distances 0-3 m and 4-5 m from the emission source. The morphology of these particles is represented by solid and hollow spheres, 'nucleus-shell' structures, perforated spheres, sharp edged plates, agglomerates of the tree-like (coral) shape. At last the bifractional mechanism of fume particle formation for this type of electrodes is also shown and described. In this article results are reported, which demonstrate the hazards of the arc welding process for human health. The results of the characterization of WFs reported improve our understanding of risks that these operations pose to human health and may strengthen the need for their control and mitigation. PMID- 30464199 TI - Less invasive is not always better. PMID- 30464200 TI - Suppression of Hepatic Bile Acid Synthesis by a non-tumorigenic FGF19 analogue Protects Mice from Fibrosis and Hepatocarcinogenesis. AB - Critical regulation of bile acid (BA) pool size and composition occurs via an intensive molecular crosstalk between the liver and gut, orchestrated by the combined actions of the nuclear Farnesoid X receptor (FXR) and the enterokine fibroblast growth factor 19 (FGF19) with the final aim of reducing hepatic BA synthesis in a negative feedback fashion. Disruption of BA homeostasis with increased hepatic BA toxic levels leads to higher incidence of hepatocellular carcinoma (HCC). While native FGF19 has anti-cholestatic and anti-fibrotic activity in the liver, it retains peculiar pro-tumorigenic actions. Thus, novel analogues have been generated to avoid tumorigenic capacity and maintain BA metabolic action. Here, using BA related Abcb4-/- and Fxr-/- mouse models of spontaneous hepatic fibrosis and HCC, we explored the role of a novel engineered variant of FGF19 protein, called FGF19-M52, which fully retains BA regulatory activity but is devoid of the pro-tumoral activity. Expression of the BA synthesis rate-limiting enzyme Cyp7a1 is reduced in FGF19-M52-treated mice compared to the GFP-treated control group with consequent reduction of BA pool and hepatic concentration. Treatment with the non-tumorigenic FGF19-M52 strongly protects Abcb4-/- and Fxr-/- mice from spontaneous hepatic fibrosis, cellular proliferation and HCC formation in terms of tumor number and size, with significant reduction of biochemical parameters of liver damage and reduced expression of several genes driving the proliferative and inflammatory hepatic scenario. Our data bona fide suggest the therapeutic potential of targeting the FXR-FGF19 axis to reduce hepatic BA synthesis in the control of BA-associated risk of fibrosis and hepatocarcinoma development. PMID- 30464201 TI - IL-21 and anti-CD40 restore Bcl-2 family protein imbalance in vitro in low survival CD27+ B cells from CVID patients. AB - Common variable immunodeficiency (CVID) is characterized by an abnormal B cell differentiation to memory and antibody-secreting B cells. The defective functionality of CVID patients' B cells could be the consequence of alterations in apoptosis regulation. We studied the balance of Bcl-2 family anti-/pro apoptotic proteins to identify molecular mechanisms that could underlie B cell survival defects in CVID. We used flow cytometry to investigate Bcl-2, Bcl-XL, Bax, and Bim expression in B cells ex vivo and after anti-CD40 or anti-BCR activation with or without IL-21, besides to spontaneous and stimulation-induced Caspase-3 activation and viable/apoptotic B cell subpopulations. We found increased basal levels of Bax and Bim in CVID B cells that correlated with low viability and high Caspase-3 activation only in CD27+ B cells, particularly in a subgroup of apoptosis-prone CVID (AP-CVID) patients with low peripheral B cell counts and high autoimmunity prevalence (mostly cytopenias). We detected a broad B cell defect in CVID regarding Bcl-2 and Bcl-XL induction, irrespective of the stimulus used. Therefore, peripheral CVID memory B cells are prompted to die from apoptosis due to a constitutive Bcl-2 family protein imbalance and defective protection from activation-induced apoptosis. Interestingly, anti-CD40 and IL-21 induced normal and even higher levels of Bcl-XL, respectively, in CD27+ B cells from AP-CVID, which was accompanied by cell viability increase. Thus low-survival memory B cells from AP-CVID can overcome their cell death regulation defects through pro-survival signals provided by T cells. In conclusion, we identify apoptosis regulation defects as disease-contributing factors in CVID. B cell counts and case history of cytopenias might be useful to predict positive responses to therapeutic approaches targeting T-dependent signaling pathways. PMID- 30464202 TI - Resolving orbital pathways for intermolecular electron transfer. AB - Over 60 years have passed since Taube deduced an orbital-mediated electron transfer mechanism between distinct metal complexes. This concept of an orbital pathway has been thoroughly explored for donor-acceptor pairs bridged by covalently bonded chemical residues, but an analogous pathway has not yet been conclusively demonstrated for formally outer-sphere systems that lack an intervening bridge. In our present study, we experimentally resolve at an atomic level the orbital interactions necessary for electron transfer through an explicit intermolecular bond. This finding was achieved using a homologous series of surface-immobilized ruthenium catalysts that bear different terminal substituents poised for reaction with redox active species in solution. This arrangement enabled the discovery that intermolecular chalcogen?iodide interactions can mediate electron transfer only when these interactions bring the donor and acceptor orbitals into direct contact. This result offers the most direct observation to date of an intermolecular orbital pathway for electron transfer. PMID- 30464204 TI - High-sensitivity cardiac troponin assays: finally ready for prime time? PMID- 30464203 TI - Structural snapshot of a bacterial phytochrome in its functional intermediate state. AB - Phytochromes are modular photoreceptors of plants, bacteria and fungi that use light as a source of information to regulate fundamental physiological processes. Interconversion between the active and inactive states is accomplished by a photoinduced reaction sequence which couples the sensor with the output module. However, the underlying molecular mechanism is yet not fully understood due to the lack of structural data of functionally relevant intermediate states. Here we report the crystal structure of a Meta-F intermediate state of an Agp2 variant from Agrobacterium fabrum. This intermediate, the identity of which was verified by resonance Raman spectroscopy, was formed by irradiation of the parent Pfr state and displays significant reorientations of almost all amino acids surrounding the chromophore. Structural comparisons allow identifying structural motifs that might serve as conformational switch for initiating the functional secondary structure change that is linked to the (de-)activation of these photoreceptors. PMID- 30464205 TI - DolFin: an innovative digital platform for studying Risso's dolphins in the Northern Ionian Sea (North-eastern Central Mediterranean). AB - The Risso's dolphin is a widely distributed species, found in deep temperate and tropical waters. Estimates of its abundance are available in a few regions, details of its distribution are lacking, and its status in the Mediterranean Sea is ranked as Data Deficient by the IUCN Red List. In this paper, a synergy between bio-ecological analysis and innovative strategies has been applied to construct a digital platform, DolFin. It contains a collection of sighting data and geo-referred photos of Grampus griseus, acquired from 2013 to 2016 in the Gulf of Taranto (Northern Ionian Sea, North-eastern Central Mediterranean Sea), and the first automated tool for Smart Photo Identification of the Risso's dolphin (SPIR). This approach provides the capability to collect and analyse significant amounts of data acquired over wide areas and extended periods of time. This effort establishes the baseline for future large-scale studies, essential to providing further information on the distribution of G. griseus. Our data and analysis results corroborate the hypothesis of a resident Risso's dolphin population in the Gulf of Taranto, showing site fidelity in a relatively restricted area characterized by a steep slope to around 800 m in depth, north of the Taranto Valley canyon system. PMID- 30464206 TI - Correction: Let-7b attenuates cisplatin resistance and tumor growth in gastric cancer by targeting AURKB. AB - The original version of this Article neglected to indicate that the study was supported by Anhui Natural Science Foundation Project (1608085MH201). This has now been corrected in both the PDF and HTML versions of the Article. PMID- 30464207 TI - Targeting GD2-positive glioblastoma by chimeric antigen receptor empowered mesenchymal progenitors. AB - Tumor targeting by genetically modified mesenchymal stromal/stem cells (MSCs) carrying anti-cancer molecules represents a promising cell-based strategy. We previously showed that the pro-apoptotic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can be successfully delivered by MSCs to cancer sites. While the interaction between TRAIL and its receptors is clear, more obscure is the way in which MSCs can selectively target tumors and their antigens. Several neuroectoderm-derived neoplasms, including glioblastoma (GBM), sarcomas, and neuroblastoma, express high levels of the tumor-associated antigen GD2. We have already challenged this cell surface disialoganglioside by a chimeric antigen receptor (CAR)-T cell approach against neuroblastoma. With the intent to maximize the therapeutic profile of MSCs delivering TRAIL, we here originally developed a bi-functional strategy where TRAIL is delivered by MSCs that are also gene modified with the truncated form of the anti-GD2 CAR (GD2 tCAR) to mediate an immunoselective recognition of GD2-positive tumors. These bi functional MSCs expressed high levels of TRAIL and GD2 tCAR associated with a robust anti-tumor activity against GD2-positive GBM cells. Most importantly, the anti-cancer action was reinforced by the enhanced targeting potential of such bi functional cells. Collectively, our results suggest that a truncated anti-GD2 CAR might be a powerful new tool to redirect MSCs carrying TRAIL against GD2 expressing tumors. This affinity-based dual targeting holds the promise to combine site-specific and prolonged retention of MSCs in GD2-expressing tumors, thereby providing a more effective delivery of TRAIL for still incurable cancers. PMID- 30464208 TI - Mitochondria as central regulators of neural stem cell fate and cognitive function. AB - Emerging evidence now indicates that mitochondria are central regulators of neural stem cell (NSC) fate decisions and are crucial for both neurodevelopment and adult neurogenesis, which in turn contribute to cognitive processes in the mature brain. Inherited mutations and accumulated damage to mitochondria over the course of ageing serve as key factors underlying cognitive defects in neurodevelopmental disorders and neurodegenerative diseases, respectively. In this Review, we explore the recent findings that implicate mitochondria as crucial regulators of NSC function and cognition. In this respect, mitochondria may serve as targets for stem-cell-based therapies and interventions for cognitive defects. PMID- 30464209 TI - Biological activity of PtIV prodrugs triggered by riboflavin-mediated bioorthogonal photocatalysis. AB - We have recently demonstrated that riboflavin (Rf) functions as unconventional bioorthogonal photocatalyst for the activation of PtIV prodrugs. In this study, we show how the combination of light and Rf with two PtIV prodrugs is a feasible strategy for light-mediated pancreatic cancer cell death induction. In Capan-1 cells, which have high tolerance against photodynamic therapy, Rf-mediated activation of the cisplatin and carboplatin prodrugs cis,cis,trans [Pt(NH3)2(Cl)2(O2CCH2CH2CO2H)2] (1) and cis,cis,trans [Pt(NH3)2(CBDCA)(O2CCH2CH2CO2H)2] (2, where CBDCA = cyclobutane dicarboxylate) resulted in pronounced reduction of the cell viability, including under hypoxia conditions. Such photoactivation mode occurs to a considerable extent intracellularly, as demonstrated for 1 by uptake and cell viability experiments. 195Pt NMR, DNA binding studies using circular dichroism, mass spectrometry and immunofluorescence microscopy were performed using the Rf-1 catalyst-substrate pair and indicated that cell death is associated with the efficient light-induced formation of cisplatin. Accordingly, Western blot analysis revealed signs of DNA damage and activation of cell death pathways through Rf-mediated photochemical activation. Phosphorylation of H2AX as indicator for DNA damage, was detected for Rf-1 in a strictly light-dependent fashion while in case of free cisplatin also in the dark. Photochemical induction of nuclear pH2AX foci by Rf-1 was confirmed in fluorescence microscopy again proving efficient light-induced cisplatin release from the prodrug system. PMID- 30464210 TI - Bone histology provides insights into the life history mechanisms underlying dwarfing in hipparionins. AB - Size shifts may be a by-product of alterations in life history traits driven by natural selection. Although this approach has been proposed for islands, it has not yet been explored in continental faunas. The trends towards size decrease experienced by some hipparionins constitute a good case study for the application of a life history framework to understand the size shifts on the continent. Here, we analysed bone microstructure to reconstruct the growth of some different-sized hipparionins from Greece and Spain. The two dwarfed lineages studied show different growth strategies. The Greek hipparions ceased growth early at a small size thus advancing maturity, whilst the slower-growing Spanish hipparion matured later at a small size. Based on predictive life history models, we suggest that high adult mortality was the likely selective force behind early maturity and associated size decrease in the Greek lineage. Conversely, we infer that resource limitation accompanied by high juvenile mortality triggered decrease in growth rate and a relative late maturity in the Spanish lineage. Our results provide evidence that different selective pressures can precipitate different changes in life history that lead to similar size shifts. PMID- 30464211 TI - Integrative epigenetic taxonomy of primary prostate cancer. AB - The Androgen Receptor (AR) is the key-driving transcription factor in prostate cancer, tightly controlled by epigenetic regulation. To date, most epigenetic profiling has been performed in cell lines or limited tissue samples. Here, to comprehensively study the epigenetic landscape, we perform RNA-seq with ChIP-seq for AR and histone modification marks (H3K27ac, H3K4me3, H3K27me3) in 100 primary prostate carcinomas. Integrative molecular subtyping of the five data streams revealed three major subtypes of which two were clearly TMPRSS2-ERG dictated. Importantly, we identify a third subtype with low chromatin binding and activity of AR, but with high activity of FGF and WNT signaling. While positive for neuroendocrine-hallmark genes, these tumors were copy number-neutral with low mutational burden, significantly depleted for genes characteristic of poor outcome associated luminal B-subtype. We present a unique resource on transcriptional and epigenetic control in prostate cancer, revealing tight control of gene regulation differentially dictated by AR over three subtypes. PMID- 30464213 TI - Author Correction: Balance training improves memory and spatial cognition in healthy adults. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30464212 TI - A single Gal4-like transcription factor activates the Crabtree effect in Komagataella phaffii. AB - The Crabtree phenotype defines whether a yeast can perform simultaneous respiration and fermentation under aerobic conditions at high growth rates. It provides Crabtree positive yeasts an evolutionary advantage of consuming glucose faster and producing ethanol to outcompete other microorganisms in sugar rich environments. While a number of genetic events are associated with the emergence of the Crabtree effect, its evolution remains unresolved. Here we show that overexpression of a single Gal4-like transcription factor is sufficient to convert Crabtree-negative Komagataella phaffii (Pichia pastoris) into a Crabtree positive yeast. Upregulation of the glycolytic genes and a significant increase in glucose uptake rate due to the overexpression of the Gal4-like transcription factor leads to an overflow metabolism, triggering both short-term and long-term Crabtree phenotypes. This indicates that a single genetic perturbation leading to overexpression of one gene may have been sufficient as the first molecular event towards respiro-fermentative metabolism in the course of yeast evolution. PMID- 30464214 TI - Single-pot, solid-phase-enhanced sample preparation for proteomics experiments. AB - A critical step in proteomics analysis is the optimal extraction and processing of protein material to ensure the highest sensitivity in downstream detection. Achieving this requires a sample-handling technology that exhibits unbiased protein manipulation, flexibility in reagent use, and virtually lossless processing. Addressing these needs, the single-pot, solid-phase-enhanced sample preparation (SP3) technology is a paramagnetic bead-based approach for rapid, robust, and efficient processing of protein samples for proteomic analysis. SP3 uses a hydrophilic interaction mechanism for exchange or removal of components that are commonly used to facilitate cell or tissue lysis, protein solubilization, and enzymatic digestion (e.g., detergents, chaotropes, salts, buffers, acids, and solvents) before downstream proteomic analysis. The SP3 protocol consists of nonselective protein binding and rinsing steps that are enabled through the use of ethanol-driven solvation capture on the surface of hydrophilic beads, and elution of purified material in aqueous conditions. In contrast to alternative approaches, SP3 combines compatibility with a substantial collection of solution additives with virtually lossless and unbiased recovery of proteins independent of input quantity, all in a simplified single-tube protocol. The SP3 protocol is simple and efficient, and can be easily completed by a standard user in ~30 min, including reagent preparation. As a result of these properties, SP3 has successfully been used to facilitate examination of a broad range of sample types spanning simple and complex protein mixtures in large and very small amounts, across numerous organisms. This work describes the steps and extensive considerations involved in performing SP3 in bottom-up proteomics, using a simplified protein cleanup scenario for illustration. PMID- 30464215 TI - Nanotube-structured Na2V3O7 as a Cathode Material for Sodium-Ion Batteries with High-rate and Stable Cycle Performances. AB - Sodium ion batteries meet the demand for large-scale energy storage, such as in electric vehicles, due to the material abundance of sodium. In this report, nanotube-type Na2V3O7 is proposed as a cathode material because of its fast sodium diffusivity, an important requirement for sodium ion batteries, through the investigation of ~4300 candidates via a high-throughput computation. High rate performance was confirmed, showing ~65% capacity retention at a current density of 10C at room temperature, despite the large particle size of >5 MUm. A good cycle performance of ca. 94% in capacity retention after 50 cycles was obtained owing to a small volumetric change of <0.4%. PMID- 30464217 TI - Mechanisms of action of Panax notoginseng ethanolic extract for its vasodilatory effects and partial characterization of vasoactive compounds. AB - Panax notoginseng is the most valuable medicinal plant and has been used clinically for more than two thousand years to treat various diseases, including hypertension. Previous studies claimed that different isolated compounds from P. notoginseng are involved in different pathways for vasodilation. It is strongly believed that these vasodilating compounds might act synergistically in contributing vasodilatory effects via holistic signaling pathways. The present study aims to evaluate the vasodilatory effect and mechanism of action employed by the crude extract of P. notoginseng. The fingerprint of P. notoginseng was developed using tri-step FTIR and HPTLC. The contents of Rg1 and Rb1 in the active extract (PN95) were further quantified via HPTLC. The vasodilatory effect of PN95 was evaluated using an in vitro aortic ring model. The results showed that PN95 contains a high amount of Rg1 and Rb1, 25.9 and 13.6%, respectively. The vasodilatory effect of PN95 was elicited via the NO/sGC/cGMP and beta2 adrenergic receptors pathways. Furthermore, PN95 could manage vascular tone by regulating action potentials via potassium and both VOCC and IP3R pathways. The results obtained fulfilled the expected outcome where the PN95 employed more signaling pathways than any of the single active compounds; hence, the holistic therapeutic effect could be achieved and would more easily translate to applications for the treatment of human diseases. PMID- 30464216 TI - Detecting heritable phenotypes without a model using fast permutation testing for heritability and set-tests. AB - Testing for association between a set of genetic markers and a phenotype is a fundamental task in genetic studies. Standard approaches for heritability and set testing strongly rely on parametric models that make specific assumptions regarding phenotypic variability. Here, we show that resulting p-values may be inflated by up to 15 orders of magnitude, in a heritability study of methylation measurements, and in a heritability and expression quantitative trait loci analysis of gene expression profiles. We propose FEATHER, a method for fast permutation-based testing of marker sets and of heritability, which properly controls for false-positive results. FEATHER eliminated 47% of methylation sites found to be heritable by the parametric test, suggesting a substantial inflation of false-positive findings by alternative methods. Our approach can rapidly identify heritable phenotypes out of millions of phenotypes acquired via high throughput technologies, does not suffer from model misspecification and is highly efficient. PMID- 30464218 TI - The adrenal gland circadian clock exhibits a distinct phase advance in spontaneously hypertensive rats. AB - The circadian clock influences a multitude of cellular and biological processes, including blood pressure control. Spontaneously hypertensive rats (SHR) exhibit aberrant circadian rhythms affecting cardiovascular parameters, and they also have abnormal clock gene expression profiles in several organs. Given the important role of the adrenal gland in orchestrating circadian oscillations, we investigated the adrenal gland circadian clock in SHR and control Wistar-Kyoto rats maintained under a 12-hour light-dark cycle. Adrenal glands, livers, and serum samples were collected every 4 h and mRNA was extracted for analysis of clock gene expression. Serum levels of corticosterone and aldosterone were also analyzed. Overall, the circadian profiles of Bmal1, Per2, Per3, Cry1, RevErba, Revervb, and Dbp gene expression in SHR adrenal glands were phase-advanced relative to controls. The expression profile of StAR (a representative gene under circadian control in the adrenal gland), as well as the circadian rhythms of serum concentrations of corticosteroid and aldosterone were also phase advanced. E4bp4 gene expression was significantly higher during the dark period, yet the expression of its transcriptional activator, Rora, was significantly lower throughout the 24 h period in SHR adrenal glands than in controls. This paradoxical high E4bp4 gene expression was, however, not observed in the liver. In addition, Per1, Per2, Per3, Reverba, and Reverbb mRNA tended to be lower in SHR adrenal glands than in controls. Thus, we conclude that SHR possess an abnormal adrenal circadian clock, which may affect the transcriptional regulation of clock-controlled genes, and steroid hormone secretion by the adrenal gland. PMID- 30464219 TI - Cancellation of Bessel beam side lobes for high-contrast light sheet microscopy. AB - An ideal illumination for light sheet fluorescence microscopy entails both a localized and a propagation invariant optical field. Bessel beams and Airy beams satisfy these conditions, but their non-diffracting feature comes at the cost of the presence of high-energy side lobes that notably degrade the imaging contrast and induce photobleaching. Here, we demonstrate the use of a light droplet illumination whose side lobes are suppressed by interfering Bessel beams of specific k-vectors. Our droplet illumination readily achieves more than 50% extinction of the light distributed across the Bessel side lobes, providing a more efficient energy localization without loss in transverse resolution. In a standard light sheet fluorescence microscope, we demonstrate a two-fold contrast enhancement imaging micron-scale fluorescent beads. Results pave the way to new opportunities for rapid and deep in vivo observations of large-scale biological systems. PMID- 30464220 TI - Freshwater lake ecosystem shift caused by social-economic transitions in Yangtze River Basin over the past century. AB - Global lake systems have undergone rapid degradation over the past century. Scientists and managers are struggling to manage the highly degraded lake systems to cope with escalating anthropogenic pressures. Improved knowledge of how lakes and social systems co-evolved up to the present is vital for understanding, modeling, and anticipating the current and future ecological status of lakes. Here, by integrating paleoenvironmental, instrumental and historical documentary resources at multi-decadal scales, we demonstrate how a typical shallow lake system evolved over the last century in the Yangtze River Basin, an urbanized region containing thousands of shallow lakes. We find abrupt ecological shift happened in the lake ecosystem around the 1970s, with the significant reorganization of macrophyte, diatom and cladocera communities. The lake social ecological system went through three stages as the local society transformed from a traditional agricultural before 1950s to an urbanized and industrialized society during the recent thirty years. The timing and interaction between social, economic and ecological feedbacks govern the transient and long-term dynamics of the freshwater ecosystem. Our results highlight the importance of accounting for the long-term dynamics and feedbacks between ecological, social and economic changes when defining safe operating spaces for sustainable freshwater ecosystem management. PMID- 30464221 TI - Agreement of an echocardiogram-based diagnosis of pulmonary hypertension in infants at risk for bronchopulmonary dysplasia among masked reviewers. AB - OBJECTIVE: To evaluate the agreement of an echocardiogram-based pulmonary hypertension diagnosis in premature infants at risk for bronchopulmonary dysplasia (BPD). STUDY DESIGN: Echocardiograms from infants born <=28 weeks post menstrual age were retrospectively reviewed with a standardized reading protocol by three pediatric cardiologists masked to patient's clinical history to determine the presence of pulmonary hypertension. RESULTS: A total of 483 echocardiograms from 49 unique patients were each reviewed by three pediatric cardiologists. Overall there was an 82.9% agreement on the presence of pulmonary hypertension among the three readers (95% CI: 78.4%, 85.4%) with a modified Fleiss' kappa of 0.759 (95% CI: 0.711, 0.801). Percent agreement between rereads was 92.4%, and modified Fleiss' kappa was 0.847 (95% CI: 0.750, 0.931). CONCLUSIONS: Using a standardized reading protocol and echocardiogram-based definition of pulmonary hypertension, there is high inter- and intra-rater agreement for the diagnosis of pulmonary hypertension in at-risk premature infants, suggesting echocardiography can be successfully used for clinical and research monitoring of pulmonary hypertension in infants. PMID- 30464222 TI - Neurocognitive function of 10-year-old multiples born less than 28 weeks of gestational age. AB - INTRODUCTION: Few studies have examined the relationship between birth plurality and neurocognitive function among children born extremely preterm. STUDY DESIGN: We compared rates of Z-scores <=-2 on 18 tests of neurocognitive function and academic achievement at age 10 years in 245 children arising from twin pregnancies, 55 from triplet pregnancies, and 6 from a septuplet pregnancy to that of 568 singletons, all of whom were born before the 28th week of gestation. RESULTS: In total, 874 children were evaluated at the age of 10 years. After adjusting for confounders, children of multifetal pregnancies performed significantly better on one of six subtests of executive function than their singleton peers. Performance was similar on all other assessments of intelligence, language, academic achievement, processing speed, visual perception, and fine motor skills. CONCLUSION: We found no evidence that children born of multifetal pregnancies had worse scores than their singleton peers on assessments of neurocognitive and academic function. PMID- 30464224 TI - Function, clinical application, and strategies of Pre-mRNA splicing in cancer. AB - Pre-mRNA splicing is a fundamental process that plays a considerable role in generating protein diversity. Pre-mRNA splicing is also the key to the pathology of numerous diseases, especially cancers. In this review, we discuss how aberrant splicing isoforms precisely regulate three basic functional aspects in cancer: proliferation, metastasis and apoptosis. Importantly, clinical function of aberrant splicing isoforms is also discussed, in particular concerning drug resistance and radiosensitivity. Furthermore, this review discusses emerging strategies how to modulate pathologic aberrant splicing isoforms, which are attractive, novel therapeutic agents in cancer. Last we outline current and future directions of isoforms diagnostic methodologies reported so far in cancer. Thus, it is highlighting significance of aberrant splicing isoforms as markers for cancer and as targets for cancer therapy. PMID- 30464223 TI - Genome-wide prediction of bacterial effector candidates across six secretion system types using a feature-based statistical framework. AB - Gram-negative bacteria are responsible for hundreds of millions infections worldwide, including the emerging hospital-acquired infections and neglected tropical diseases in the third-world countries. Finding a fast and cheap way to understand the molecular mechanisms behind the bacterial infections is critical for efficient diagnostics and treatment. An important step towards understanding these mechanisms is the discovery of bacterial effectors, the proteins secreted into the host through one of the six common secretion system types. Unfortunately, current prediction methods are designed to specifically target one of three secretion systems, and no accurate "secretion system-agnostic" method is available. Here, we present PREFFECTOR, a computational feature-based approach to discover effector candidates in Gram-negative bacteria, without prior knowledge on bacterial secretion system(s) or cryptic secretion signals. Our approach was first evaluated using several assessment protocols on a manually curated, balanced dataset of experimentally determined effectors across all six secretion systems, as well as non-effector proteins. The evaluation revealed high accuracy of the top performing classifiers in PREFFECTOR, with the small false positive discovery rate across all six secretion systems. Our method was also applied to six bacteria that had limited knowledge on virulence factors or secreted effectors. PREFFECTOR web-server is freely available at: http://korkinlab.org/preffector . PMID- 30464225 TI - BICD1 mediates HIF1alpha nuclear translocation in mesenchymal stem cells during hypoxia adaptation. AB - Hypoxia inducible factor 1alpha (HIF1alpha) is a master regulator leading to metabolic adaptation, an essential physiological process to maintain the survival of stem cells under hypoxia. However, it is poorly understood how HIF1alpha translocates into the nucleus in stem cells under hypoxia. Here, we investigated the role of a motor adaptor protein Bicaudal D homolog 1 (BICD1) in dynein mediated HIF1alpha nuclear translocation and the effect of BICD1 regulation on hypoxia adaptation and its therapeutic potential on human umbilical cord blood derived mesenchymal stem cells (UCB-MSCs). In our results, silencing of BICD1 but not BICD2 abolished HIF1alpha nuclear translocation and its activity. BICD1 overexpression further enhanced hypoxia-induced HIF1alpha nuclear translocation. Hypoxia stimulated direct bindings of HIF1alpha to BICD1 and the intermediate chain of dynein (Dynein IC), which was abolished by BICD1 silencing. Akt inhibition reduced the binding of BICD1 to HIF1alpha and nuclear translocation of HIF1alpha. Conversely, Akt activation or GSK3beta silencing further enhanced the hypoxia-induced HIF1alpha nuclear translocation. Furthermore, BICD1 silencing abolished hypoxia-induced glycolytic reprogramming and increased mitochondrial ROS accumulation and apoptosis in UCB-MSCs under hypoxia. In the mouse skin wound healing model, the transplanted cell survival and skin wound healing capacities of hypoxia-pretreated UCB-MSCs were reduced by BICD1 silencing and further increased by GSK3beta silencing. In conclusion, we demonstrated that BICD1 induced HIF1alpha nuclear translocation is critical for hypoxia adaptation, which determines the regenerative potential of UCB-MSCs. PMID- 30464226 TI - Long noncoding RNA lncAIS downregulation in mesenchymal stem cells is implicated in the pathogenesis of adolescent idiopathic scoliosis. AB - Adolescent idiopathic scoliosis (AIS) is a complex, three dimensional deformity of the spine that commonly occurs in pubescent girls. Abnormal osteogenic differentiation of mesenchymal stem cells (MSCs) is implicated in the pathogenesis of AIS. However, the biological roles of long noncoding RNAs (lncRNAs) in the regulation of osteogenic differentiation of MSCs are unknown. Through microarray analyses of bone marrow (BM) MSCs from healthy donors and AIS patients, we identified 1483 differentially expressed lncRNAs in AIS BM-MSCs. We defined a novel lncAIS (gene symbol: ENST00000453347) is dramatically downregulated in AIS BM-MSCs. In normal BM-MSCs, lncAIS interacts with NF90 to promote HOXD8 mRNA stability that enhances RUNX2 transcription in BM-MSCs, leading to osteogenic differentiation of normal BM-MSCs. By contrast, lncAIS downregualtion in AIS BM-MSCs cannot recruit NF90 and abrogates HOXD8 mRNA stability, which impedes RUNX2 transcription for osteogenic differentiation. Thereby lncAIS downregualtion in BM-MSCs suppresses osteogenic differentiation that is implicated in the pathogenesis of AIS. PMID- 30464227 TI - Novel crosstalk between Vps26a and Nox4 signaling during neurogenesis. AB - Despite numerous studies on the molecular switches governing the conversion of stemness to differentiation in embryonic stem cells (ESCs), little is known about the involvement of the retromer complex. Under neural differentiation conditions, Vps26a deficiency (Vps26a-/-) or knockdown suppressed the loss of stemness and subsequent neurogenesis from ESCs or embryonic carcinoma cells, respectively, as evidenced by the long-lasting expression of stemness markers and the slow appearance of neuronal differentiation markers. Interestingly, relatively low reactive oxygen species (ROS) levels were generated during differentiation of Vps26a-/- ESCs, and treatment with an antioxidant or inhibitor of NADPH oxidase (Nox), a family of ROS-generating enzymes, led to restoration of stemness in wild type cells to the level of Vps26a-/- cells during neurogenesis. Importantly, a novel interaction between Vps26a and Nox4 linked to the activation of ERK1/2 depended highly on ROS levels during neurogenesis, which were strongly suppressed in differentiating Vps26a-/- ESCs. Moreover, inhibition of phosphorylated ERK1/2 (pERK1/2) resulted in decreased ROS and Nox4 levels, indicating the mutual dependency between pERK1/2 and Nox4-derived ROS during neurogenesis. These results suggest that Vps26a regulates stemness by actively cooperating with the Nox4/ROS/ERK1/2 cascade during neurogenesis. Our findings have important implications for understanding the regulation of stemness via crosstalk between the retromer molecule and redox signaling, and may contribute to the development of ESC-based therapeutic strategies for the mass production of target cells. PMID- 30464228 TI - Self-Transforming Configuration Based on Atmospheric-Adaptive Materials for Solid Oxide Cells. AB - Solid oxide cells (SOC) with a symmetrical configuration have been focused due to the practical benefits of such configurations, such as minimized compatibility issues, a simple fabrication process and reduced cost compared to SOCs with the asymmetrical configuration. However, the performance of SOCs using a single type of electrode material (symmetrical configuration) is lower than the performance of those using the dissimilar electrode materials (asymmetrical configuration). Therefore, to achieve a high-performance cell, we design a 'self-transforming cell' with the asymmetric configuration using only materials of the single type, one based on atmospheric adaptive materials. Atmospheric-adaptive perovskite Pr0.5Ba0.5Mn0.85Co0.15O3-delta (PBMCo) was used for the so-called self transforming cell electrodes, which changed to layered perovskite and metal in the fuel atmosphere and retained its original structure in the air atmosphere. In fuel cell mods, the self-transforming cell shows excellent electrochemical performance of 1.10 W cm-2 at 800 degrees C and good stability for 100 h without any catalyst. In electrolysis mode, the moderate current densities of -0.42 A cm 2 for 3 vol.% H2O and -0.62 A cm-2 for 10 vol.% H2O, respectively, were observed at a cell voltage of 1.3 V at 800 degrees C. In the reversible cycling test, the transforming cell maintains the constant voltages for 30 h at +/- 0.2 A cm-2 under 10 vol. % H2O. PMID- 30464229 TI - Top-down guidance of attention to food cues is enhanced in individuals with overweight/obesity and predicts change in weight at one-year follow up. AB - BACKGROUND: Changing eating behaviour may be challenging for individuals with obesity and this may be related to attentional bias towards food. Previous paradigms used to assess attentional bias to food stimuli have not distinguished between bottom-up processes related to assessment of rewarding stimuli versus top down processes related to effects of mind-set on attention. We investigated whether attentional bias for food cues varies between individuals with overweight/obesity and healthy weight individuals, due to differential top-down control of attention. We also determined whether top-down biases predict food consumption in the lab and weight change in our sample over one-year. METHODS: Forty-three participants with overweight/obesity and 49 healthy weight participants between the ages of 18 and 58 participated. Participants completed two attention tasks in a counterbalanced order: (i) a priming task assessing bottom-up control of attention and (ii) a working memory task assessing top-down control of attention. Eating behaviour was assessed by a taste test. At one-year follow-up participants returned to the laboratory to assess changes in their body mass index (BMI). RESULTS: The healthy weight and overweight/obese groups did not differ in demographics and baseline measures (appetite, food liking, taste test food intake). Participants with overweight/obesity showed greater top-down attentional bias towards food cues than did healthy weight participants but had no difference in bottom-up attentional bias. Top down attentional bias towards food cues predicted weight change over one-year but did not predict food intake in the taste test. CONCLUSIONS: The present findings illustrate that the relationship between attentional bias for food, food intake, and body weight is complex. Top-down effects of mind-set on attention, rather than bottom-up control of attention to food may contribute to patterns of eating that result in development and/or maintenance of overweight/obesity. Interventions targeted at top down biases could be effective in facilitating prevention of weight gain. PMID- 30464230 TI - In response to: 'Information bias in measures of self-reported physical activity'. PMID- 30464231 TI - Maternal corticotropin-releasing hormone is associated with LEP DNA methylation at birth and in childhood: an epigenome-wide study in Project Viva. AB - BACKGROUND: Corticotropin-releasing hormone (CRH) plays a central role in regulating the secretion of cortisol which controls a wide range of biological processes. Fetuses overexposed to cortisol have increased risks of disease in later life. DNA methylation may be the underlying association between prenatal cortisol exposure and health effects. We investigated associations between maternal CRH levels and epigenome-wide DNA methylation of cord blood in offsprings and evaluated whether these associations persisted into mid-childhood. METHODS: We investigated mother-child pairs enrolled in the prospective Project Viva pre-birth cohort. We measured DNA methylation in 257 umbilical cord blood samples using the HumanMethylation450 Bead Chip. We tested associations of maternal CRH concentration with cord blood cells DNA methylation, adjusting the model for maternal age at enrollment, education, maternal race/ethnicity, maternal smoking status, pre-pregnancy body mass index, parity, gestational age at delivery, child sex, and cell-type composition in cord blood. We further examined the persistence of associations between maternal CRH levels and DNA methylation in children's blood cells collected at mid-childhood (n = 239, age: 6.7-10.3 years) additionally adjusting for the children's age at blood drawn. RESULTS: Maternal CRH levels are associated with DNA methylation variability in cord blood cells at 96 individual CpG sites (False Discovery Rate <0.05). Among the 96 CpG sites, we identified 3 CpGs located near the LEP gene. Regional analyses confirmed the association between maternal CRH and DNA methylation near LEP. Moreover, higher maternal CRH levels were associated with higher blood-cell DNA methylation of the promoter region of LEP in mid-childhood (P < 0.05, beta = 0.64, SE = 0.30). CONCLUSION: In our cohort, maternal CRH was associated with DNA methylation levels in newborns at multiple loci, notably in the LEP gene promoter. The association between maternal CRH and LEP DNA methylation levels persisted into mid-childhood. PMID- 30464232 TI - Maternal mental health at 5 years and childhood overweight or obesity at 11 years: evidence from the UK Millennium Cohort Study. AB - BACKGROUND/OBJECTIVES: Maternal psychological distress is associated with a range of adverse child outcomes. We sought to determine whether children's exposure to medium or severe distress at 5 years was associated with increased risks of overweight and obesity when they were aged 11 years. We also investigated whether any association was attenuated after accounting for potential confounding and mediating factors. SUBJECTS/METHODS: We analysed data from the UK Millennium Cohort Study, a nationally representative sample with data collected throughout childhood, imputing missing covariates (analytic sample: n = 9206). Multinomial regression was used to examine whether maternal psychological distress (Kessler-6 scale, using medium and severe score thresholds) at 5 years of age predicted children's objectively measured overweight and obesity at 11 years, adjusting for sex and ethnicity. We then carried out a series of models incorporating potential confounders (early life and socio-demographic, recorded at 9 months) and mediators (physical activity and dietary factors, at 7 years) in turn, and then simultaneously. RESULTS: A third of mothers reported distress when their child was aged 5 years (29% medium; 4% severe distress), and over a quarter of children were overweight at 11 years (22% overweight; 6% obese). Risks of obesity at 11 years increased with severity of maternal distress at 5 years (medium distress: relative risk ratio (RRR) = 1.43, 95% confidence interval [CI] 1.17-1.75; severe RRR = 2.27, CI 1.42-3.63). Adjusting for each set of explanatory factors in turn (particularly early years and socio-demographic confounding factors) reduced but did not eliminate these elevated risks. However, risks were attenuated in the fully adjusted model (medium: RRR = 1.14, CI 0.92-1.41; severe: RRR = 1.26, CI 0.75-2.11). CONCLUSIONS: We demonstrated that maternal psychological distress, particularly if severe, at 5 years was associated with risk of obesity (but not overweight) at 11 years. Accounting for potential explanatory factors attenuated this association to non-significance, suggesting a range of mechanisms may be implicated. Future research should seek to disentangle the potentially complex pathways linking explanatory factors, maternal distress and child obesity. PMID- 30464233 TI - Maternal adipokines longitudinally measured across pregnancy and their associations with neonatal size, length, and adiposity. AB - BACKGROUND/OBJECTIVES: Maternal obesity impacts fetal growth as early as second trimester of pregnancy, yet little is known about the molecular mechanisms involved. We aimed to examine associations between maternal adipokines throughout pregnancy and neonatal size by prepregnancy obesity status. METHODS: In a prospective cohort of 2802 U.S. pregnant women from the NICHD Fetal Growth Studies-Singleton Cohort (2009-2013), biospecimens were analyzed in a matched case-control subset of 321 women. Blood was collected at 10-14, 15-26 (fasting), 23-31, and 33-39 gestational weeks. Plasma leptin and soluble leptin receptor (sOB-R) and total and high-molecular-weight (HMW)-adiponectin were measured. Free leptin was calculated as leptin/sOB-R. Birthweight was abstracted from medical records. Neonatal length and skinfolds were measured. RESULTS: Leptin and sOB-R in late pregnancy tended to be positively and negatively associated with neonatal length, respectively, while free leptin throughout pregnancy tended to be positively associated with length. Free leptin associations with neonatal length were differential by obesity (i.e., inversely among women without obesity and positively among women with obesity). A per unit increase in free leptin at 33-39 weeks was associated with a shorter neonatal length by -0.55 cm (95%CI, -0.83, 0.28) in women without obesity and longer length by 0.49 cm (95%CI, 0.34, 0.65) in women with obesity. HMW-adiponectin at 33-39 weeks was inversely associated with neonatal length (beta = -1.29 cm; 95%CI, -1.74, -0.85) and skinfold thickness (beta = -1.46 mm; 95%CI, -1.58, -0.56) among women with obesity. Free leptin across pregnancy tended to be negatively associated with neonatal skinfold thickness among women without obesity, while free leptin in early pregnancy was positively associated with skinfold thickness. CONCLUSIONS: Maternal adipokines were associated with multiple pathways that influence neonatal size including length and adiposity, which differed in timing across pregnancy and by prepregnancy obesity. These findings provide new potential insights into mechanisms and timing by which maternal obesity may impact fetal growth. PMID- 30464234 TI - Influence of aerobic exercise on maternal lipid levels and offspring morphometrics. AB - BACKGROUND: Maternal BMI, lipid levels (cholesterol, triglyceride, LDL, HDL), and exercise amount are interrelated and each influence offspring body size. This study proposed to determine the influence of exercise on maternal lipid levels and infant body size. METHODS: We had 36 participants complete these measures. Participants in the aerobic exercise intervention (n = 14) completed three 50-min sessions weekly from 16 weeks gestation to delivery and were compared with a non exercise control group (n = 22). Maternal lipid profiles were assessed at 16 and at 36 weeks gestation. Fetal body size was measured at 36 weeks gestational age using ultrasound assessment. Neonatal body size measures were acquired from birth records. Statistical analysis included two-sample t-tests, correlations, and regression models. RESULTS: Participants were similar in age, pre-pregnancy BMI, gravida, parity, education, and gestational weight gain (GWG). There were no differences in gestational age, Apgar scores at 1 and 5 min for infants of exercisers relative to controls. Exercisers had higher pre-training triglycerides (p = 0.004) and pregnancy change in triglycerides (p = 0.049) compared to controls. Head circumference was significantly larger in exercise exposed infants relative to infants of controls. Pregnancy METs had a positive relationship with birth length (r = .445, p = .006) and birth weight (r = .391, p = .02). GWG had a moderate, positive relationship with fetal abdominal circumference (r = .570, p = .004). Regression analysis indicated 5 predictors explained 61.7% of the variance in birth weight (Adj.R2 = 0.469, F(5,13) = 5,13, p = 0.02); it was found that pregnancy METs (beta = .724, p = .007), 36 week cholesterol (beta = 1.066, p = .02), and 36 week LDL (beta = -1.267, p = .006) significantly predict birth weight. Regression analysis indicated 4 predictors explained 43.8% of the variance in birth length (Adj.R2 = 0.306, F(4,17) = 3.32, p = 0.04); it was found that pregnancy METs (beta = .530, p = .03), and 36 week LDL (beta = -.891, p = .049) significantly predict birth length. CONCLUSION: The primary association and predictors of infant body size was related to pregnancy exercise and late pregnancy cholesterol and LDL levels. Considering these relationships, it is essential that women maintain aerobic exercise during pregnancy, but should also be cognizant of lipid levels during their pregnancy. Therefore intervention during pregnancy focused on infant body size should involve exercise and and quality nutritional intake foods during pregnancy. PMID- 30464235 TI - Very low calorie diets are associated with transient ventricular impairment before reversal of diastolic dysfunction in obesity. AB - OBJECTIVES: Very low calorie diets (VLCDs) are effective at clearing hepatic steatosis and improving insulin sensitivity. Whilst long-term weight loss is beneficial to the cardiovascular system, the acute elevation in fatty acids during caloric restriction is potentially detrimental to cardiac metabolism and function. We sought to investigate any cardiovascular changes occurring over the course of a modern VLCD regime, alongside the expected peripheral metabolic improvements. METHODS: 25 obese volunteers (BMI 36.8 +/- 5.8 kg/m2) underwent magnetic resonance imaging, echocardiography, metabolic profiling, and bio impedance analysis before 1 and 8 weeks following a VLCD (800 kcal/day). Results were compared to 15 age- and sex-matched controls. RESULTS: After 1 week of VLCD, despite only modest weight loss, significant drops occurred in liver fat and insulin resistance (HOMA-IR; by 14-50%, all p < 0.01). In contrast, myocardial triglyceride content (MTGC) increased (by 48%, p = 0.030), and was associated with deterioration in both systolic (LVEF by 4%, p = 0.041) and diastolic function (e/e' 8.6 +/- 1.4 to 9.4 +/- 1.7, p = 0.019). Aortic stiffness also increased by 35% (p = 0.015). At 8 weeks, liver steatosis and visceral fat were lower than baseline (by 20-55%, p < 0.001), and peripheral metabolic improvements continued. MTGC also fell to below baseline (1.5 +/- 0.6 vs 2.1 +/- 1%, p = 0.05) with improved myocardial function (e/e' 8.6 +/- 1.4 to 7.5 +/- 1.5, p = 0.003). CONCLUSIONS: Whilst VLCDs result in dramatic improvements in insulin resistance, they are associated with transient but significant cardiovascular functional decline, which may have an impact on those with the coexisting cardiac disease. However, after 8 weeks, the diet was associated with normalisation of cardiac function, suggesting they may form a potential therapeutic intervention for diastolic dysfunction in obesity and diabetes. PMID- 30464236 TI - The relationship between obesity and tertiary education outcomes: a systematic review. AB - Previous reviews have documented an overall weak or uncertain association between obesity and school-based educational attainment in children and young people. However, up to half of young adults will go on to further college or university education by age 30. The study aim was to systematically review evidence on the association between obesity and tertiary education outcomes in young men and women. A search of multiple databases, including Embase, Global Health, ERIC, Medline, PsycInfo, and Science Citation Index was conducted in March 2018. Cross sectional and longitudinal studies were included that reported on young people aged 16+, an association between obesity and academic achievement, and a comparison to healthy weight students. Risk of bias was assessed using criteria from the STROBE checklist. From 1297 records, 16 studies met all inclusion criteria. All six cross-sectional studies and 8/10 longitudinal studies reported lower educational achievement by students with obesity. All longitudinal studies were at low risk of bias but four cross-sectional studies were at medium risk and two at high risk of bias. Three of four studies showed reduced enrolment, in 6/8 graduation was less likely, and all 6 studies reporting on performance showed this was lower in those with obesity. Five of nine studies reported that obesity had a greater impact on educational achievement for women. Overall, there is compelling evidence of weight bias in that students with obesity do less well in tertiary education than their healthy weight peers. It is likely that university/college attainment is less impacted by socio-economic factors than school-based achievement. A better understanding of the processes that underpin this weight bias is needed, including stakeholder (student, staff) experiences of weight stigma, perceived or enacted. Responsive actions could mirror those to address disability or gender bias, or in health promotion in tertiary education settings. PMID- 30464237 TI - Determination of the two-dimensional distributions of gold nanorods by multiwavelength analytical ultracentrifugation. AB - Properties of nanoparticles are influenced by various parameters like size, shape or composition. Comprehensive high throughput characterization techniques are urgently needed to improve synthesis, scale up to production and make way for new applications of multidimensional particulate systems. In this study, we present a method for measuring two-dimensional size distributions of plasmonic nanorods in a single experiment. Analytical ultracentrifuge equipped with a multiwavelength extinction detector is used to record the optical and sedimentation properties of gold nanorods simultaneously. A combination of sedimentation and extinction properties, both depending on diameter and length of the dispersed nanorods, is used to measure two-dimensional distributions of gold nanorod samples. The length, diameter, aspect ratio, volume, surface and cross-sectional distributions can be readily obtained from these results. As the technique can be extended to other non-spherical plasmonic particles and can be used for determining relative amounts of particles of different shapes it provides complete and quantitative insights into particulate systems. PMID- 30464238 TI - Identifying chondroprotective diet-derived bioactives and investigating their synergism. AB - Osteoarthritis (OA) is a multifactorial disease and nutrition is a modifiable factor that may contribute to disease onset or progression. A detailed understanding of mechanisms through which diet-derived bioactive molecules function and interact in OA is needed. We profiled 96 diet-derived, mainly plant based bioactives using an in vitro model in chondrocytes, selecting four candidates for further study. We aimed to determine synergistic interactions between bioactives that affected the expression of key genes in OA. Selected bioactives, sulforaphane, apigenin, isoliquiritigenin and luteolin, inhibited one or more interleukin-1-induced metalloproteinases implicated in OA (MMP1, MMP13, ADAMTS4, ADAMTS5). Isoliquiritigenin and luteolin showed reactive oxygen species scavenging activity in chondrocytes whereas sulforaphane had no effect and apigenin showed only a weak trend. Sulforaphane inhibited the IL-1/NFkappaB and Wnt3a/TCF/Lef pathways and increased TGFbeta/Smad2/3 and BMP6/Smad1/5/8 signalling. Apigenin showed potent inhibition of the IL-1/NFkappaB and TGFbeta/Smad2/3 pathways, whereas luteolin showed only weak inhibition of the IL 1/NFkappaB pathway. All four bioactives inhibited cytokine-induced aggrecan loss from cartilage tissue explants. The combination of sulforaphane and isoliquiritigenin was synergistic for inhibiting MMP13 gene expression in chondrocytes. We conclude that dietary-derived bioactives may be important modulators of cartilage homeostasis and synergistic relationships between bioactives may have an anti-inflammatory and chondroprotective role. PMID- 30464239 TI - Anti-obesity activity of OBEX is regulated by activation of thermogenesis and decreasing adiposity gain. AB - The incidence of obesity has been increasing dramatically worldwide over the past decades, thus requiring novel and effective therapeutic approaches. OBEX is an oral nutritional supplement composed of antioxidants with antiobesity activity. The effects of OBEX have been tested in vivo and in vitro. In vivo, OBEX reduces weight gain by decreasing adiposity gain and increasing energy expenditure in high fat diet-fed mice through the activation of thermogenesis in brown adipose tissue (BAT) independent of eating behaviors. In vitro analysis with 3T3-F442A cells revealed anti-proliferative and anti-differentiation effects of OBEX. In addition, OBEX induced a clear reduction of the lipid load in mature adipocytes obtained from 3T3-F442A cells. Overall, our findings suggest that OBEX has a protective effect against an obesogenic environment. PMID- 30464240 TI - Plant pathogen responses to Late Pleistocene and Holocene climate change in the central Atacama Desert, Chile. AB - Future climate change has the potential to alter the distribution and prevalence of plant pathogens, which may have significant implications for both agricultural crops and natural plant communities. However, there are few long-term datasets against which modelled predictions of pathogen responses to climate change can be tested. Here, we use 18S metabarcoding of 28 rodent middens (solidified deposits of rodent coprolites and nesting material) from the Central Atacama, spanning the last ca. 49 ka, to provide the first long-term late Quaternary record of change in plant pathogen communities in response to changing climate. Plant pathogen richness was significantly greater in middens deposited during the Central Andean Pluvial Event (CAPE); a period of increased precipitation between 17.5-8.5 ka. Moreover, the occurrence frequency of Pucciniaceae (rust fungi) was significantly greater during the CAPE, and the highest relative abundances for five additional potentially pathogenic taxa also occurred during this period. The results demonstrate the promising potential for ancient DNA analysis of late Quaternary samples to reveal insights into how plant pathogens responded to past climatic and environmental change, which could help predict how pathogens may responded to future change. PMID- 30464241 TI - Metabolic engineering of Escherichia coli for de novo biosynthesis of vitamin B12. AB - The only known source of vitamin B12 (adenosylcobalamin) is from bacteria and archaea. Here, using genetic and metabolic engineering, we generate an Escherichia coli strain that produces vitamin B12 via an engineered de novo aerobic biosynthetic pathway. In vitro and/or in vivo analysis of genes involved in adenosylcobinamide phosphate biosynthesis from Rhodobacter capsulatus suggest that the biosynthetic steps from co(II)byrinic acid a,c-diamide to adocobalamin are the same in both the aerobic and anaerobic pathways. Finally, we increase the vitamin B12 yield of a recombinant E. coli strain by more than ~250-fold to 307.00 ug g-1 DCW via metabolic engineering and optimization of fermentation conditions. Beyond our demonstration of E. coli as a microbial biosynthetic platform for vitamin B12 production, our study offers an encouraging example of how the several dozen proteins of a complex biosynthetic pathway can be transferred between organisms to facilitate industrial production. PMID- 30464242 TI - Analysis of Zika virus neutralizing antibodies in normal healthy Thais. AB - Zika virus (ZIKV) infections have been reported from all over Thailand, but the number of reported cases remains low, suggesting a degree of immune protection against ZIKV infection. To address this possibility, the presence of ZIKV neutralizing antibodies was determined in serum from 135 healthy Thai adults with a plaque reduction neutralization test (PRNT), and a number of samples were subsequently analyzed for the presence of neutralizing antibodies to dengue virus (DENV) and Japanese encephalitis virus (JEV). Results showed that 70.4% (PRNT50 >= 10), 55.6 (PRNT50 >= 20) or 22.2% (PRNT90 >= 20) of the samples showed neutralizing antibodies to ZIKV. Detailed analysis showed no association between the presence of neutralizing antibodies to other flaviviruses (DENV, JEV) and the presence of ZIKV neutralizing antibodies. These results suggest that the level of ZIKV neutralizing antibodies in the Thai population is enough to dampen the transmission of the virus in Thailand. PMID- 30464244 TI - Terahertz rectification in ring-shaped quantum barriers. AB - Tunneling is the most fundamental quantum mechanical phenomenon with wide-ranging applications. Matter waves such as electrons in solids can tunnel through a one dimensional potential barrier, e.g. an insulating layer sandwiched between conductors. A general approach to control tunneling currents is to apply voltage across the barrier. Here, we form closed loops of tunneling barriers exposed to external optical control to manipulate ultrafast tunneling electrons. Eddy currents induced by incoming electromagnetic pulses project upon the ring, spatiotemporally changing the local potential. The total tunneling current which is determined by the sum of contributions from all the parts along the perimeter is critically dependent upon the symmetry of the loop and the polarization of the incident fields, enabling full-wave rectification of terahertz pulses. By introducing global geometry and local operation to current-driven circuitry, our work provides a novel platform for ultrafast optoelectronics, macroscopic quantum phenomena, energy harvesting, and multi-functional quantum devices. PMID- 30464243 TI - HIV-1 Envelope Glycoproteins Induce the Production of TNF-alpha and IL-10 in Human Monocytes by Activating Calcium Pathway. AB - Human HIV-1 infection leads inevitably to a chronic hyper-immune-activation. However, the nature of the targeted receptors and the pathways involved remain to be fully elucidated. We demonstrate that X4-tropic gp120 induced the production of TNF-alpha and IL-10 by monocytes through activation of a cell membrane receptor, distinct from the CD4, CXCR4, and MR receptors. Gp120 failed to stimulate IL-10 and TNF-alpha production by monocytes in Ca2+ free medium. This failure was total for IL-10 and partial for TNF-alpha. However, IL-10 and TNF alpha production was fully restored following the addition of exogenous calcium. Accordingly, addition of BAPTA-AM and cyclosporine-A, fully and partially inhibited IL-10 and TNF-alpha respectively. The PKA pathway was crucial for IL-10 production but only partially involved in gp120-induced TNF-alpha. The PLC pathway was partially and equivalently involved in gp120-induced TNF-alpha and IL 10. Moreover, the inhibition of PI3K, ERK1/2, p38 MAP-kinases and NF-kappaB pathways totally abolished the production of both cytokines. In conclusion, this study revealed the crucial calcium signaling pathway triggered by HIV-1 gp120 to control the production of these two cytokines: TNF-alpha and IL-10. The finding could help in the development of a new therapeutic strategy to alleviate the chronic hyper-immune-activation observed in HIV-1 infected patients. PMID- 30464245 TI - Exposure to Chemical Cues from Predator-Exposed Conspecifics Increases Reproduction in a Wild Rodent. AB - Predation involves more than just predators consuming prey. Indirect effects, such as fear responses caused by predator presence, can have consequences for prey life history. Laboratory experiments have shown that some rodents can recognize fear in conspecifics via alarm pheromones. Individuals exposed to alarm pheromones can exhibit behavioural alterations that are similar to those displayed by predator-exposed individuals. Yet the ecological and evolutionary significance of alarm pheromones in wild mammals remains unclear. We investigated how alarm pheromones affect the behaviour and fitness of wild bank voles (Myodes glareolus) in outdoor enclosures. Specifically, we compared the effects of exposure of voles living in a natural environment to a second-hand fear cue, bedding material used by predator-exposed voles. Control animals were exposed to bedding used by voles with no predator experience. We found a ca. 50% increase in litter size in the group exposed to the predator cue. Furthermore, female voles were attracted to and males were repelled by trap-associated bedding that had been used by predator-exposed voles. Movement and foraging were not significantly affected by the treatment. Our results suggest that predation risk can exert population-level effects through alarm pheromones on prey individuals that did not encounter a direct predator cue. PMID- 30464246 TI - Single-cell imaging of phosphorus uptake shows that key harmful algae rely on different phosphorus sources for growth. AB - Single-cell measurements of biochemical processes have advanced our understanding of cellular physiology in individual microbes and microbial populations. Due to methodological limitations, little is known about single-cell phosphorus (P) uptake and its importance for microbial growth within mixed field populations. Here, we developed a nanometer-scale secondary ion mass spectrometry (nanoSIMS) based approach to quantify single-cell P uptake in combination with cellular CO2 and N2 fixation. Applying this approach during a harmful algal bloom (HAB), we found that the toxin-producer Nodularia almost exclusively used phosphate for growth at very low phosphate concentrations in the Baltic Sea. In contrast, the non-toxic Aphanizomenon acquired only 15% of its cellular P-demand from phosphate and ~85% from organic P. When phosphate concentrations were raised, Nodularia thrived indicating that this toxin-producer directly benefits from phosphate inputs. The phosphate availability in the Baltic Sea is projected to rise and therefore might foster more frequent and intense Nodularia blooms with a concomitant rise in the overall toxicity of HABs in the Baltic Sea. With a projected increase in HABs worldwide, the capability to use organic P may be a critical factor that not only determines the microbial community structure, but the overall harmfulness and associated costs of algal blooms. PMID- 30464247 TI - Hyperlipidemia, statin use and dengue severity. AB - Multiple in vitro and mice model studies suggest statins may attenuate dengue severity. However, little is known about statin use and dengue severity in adult dengue patients with hyperlipidemia. We conducted a retrospective cohort study from 2004-2008 and 2012-2013 in Tan Tock Seng Hospital, Singapore on adult dengue patients with hyperlipidemia, comparing those with and without statin usage at hospitalization in terms of primary outcome of dengue hemorrhagic fever (DHF) or shock syndrome (DSS), and severe dengue (SD). Of 13,975 subjects screened, 257 dengue patients were included; 191 (74.3%) were statin users and 66 (25.7%) were non-users. Compared with non-users, statin use was not associated with decreased risk of DHF/DSS (adjusted risk ratio [aRR] = 0.66, 95%confidence interval [CI]: 0.41-1.08, P = 0.10) and SD (aRR = 1.43, 95%CI: 0.84-2.43, P = 0.19). Therefore, statin usage had minimal effect on dengue severity in our study population in Singapore. PMID- 30464248 TI - Generation of uniform-sized multicellular tumor spheroids using hydrogel microwells for advanced drug screening. AB - Even though in vitro co-culture tumor spheroid model plays an important role in screening drug candidates, its wide applications are currently limited due to the lack of reliable and high throughput methods for generating well-defined and 3D complex co-culture structures. Herein, we report the development of a hydrogel microwell array to generate uniform-sized multicellular tumor spheroids. Our developed multicellular tumor spheroids are structurally well-defined, robust and can be easily transferred into the widely used 2D culture substrates while maintaining our designed multicellular 3D-sphere structures. Moreover, to develop effective anti-cancer therapeutics we integrated our recently developed gold graphene hybrid nanomaterial (Au@GO)-based photothermal cancer therapy into a series of multicellular tumor spheroid co-culture system. The multicellular tumor spheroids were harvested onto a two-dimensional (2D) substrate, under preservation of their three-dimensional (3D) structure, to evaluate the photothermal therapy effectiveness of graphene oxide (GO)-wrapped gold nanoparticles (Au@GO). From the model of co-culture spheroids of HeLa/Ovarian cancer and HeLa/human umbilical vein endothelial cell (HUVEC), we observed that Au@GO nanoparticles displayed selectivity towards the fast-dividing HeLa cells, which could not be observed to this extent in 2D cultures. Overall, our developed uniform-sized 3D multicellular tumor spheroid could be a powerful tool for anticancer drug screening applications. PMID- 30464249 TI - Tuning the balance between dispersion and entropy to design temperature responsive flexible metal-organic frameworks. AB - Temperature-responsive flexibility in metal-organic frameworks (MOFs) appeals to the imagination. The ability to transform upon thermal stimuli while retaining a given crystalline topology is desired for specialized sensors and actuators. However, rational design of such shape-memory nanopores is hampered by a lack of knowledge on the nanoscopic interactions governing the observed behavior. Using the prototypical MIL-53(Al) as a starting point, we show that the phase transformation between a narrow-pore and large-pore phase is determined by a delicate balance between dispersion stabilization at low temperatures and entropic effects at higher ones. We present an accurate theoretical framework that allows designing breathing thermo-responsive MOFs, based on many-electron data for the dispersion interactions and density-functional theory entropy contributions. Within an isoreticular series of materials, MIL-53(Al), MIL-53(Al) FA, DUT-4, DUT-5 and MIL-53(Ga), only MIL-53(Al) and MIL-53(Ga) are proven to switch phases within a realistic temperature range. PMID- 30464250 TI - Rapid Pulsed Light Sintering of Silver Nanowires on Woven Polyester for personal thermal management with enhanced performance, durability and cost-effectiveness. AB - Fabric-based personal heating patches have small geometric profiles and can be attached to selected areas of garments for personal thermal management to enable significant energy savings in built environments. Scalable fabrication of such patches with high thermal performance at low applied voltage, high durability and low materials cost is critical to the widespread implementation of these energy savings. This work investigates a scalable Intense Pulsed Light (IPL) sintering process for fabricating silver nanowire on woven polyester heating patches. Just 300 microseconds of IPL sintering results in 30% lesser electrical resistance, 70% higher thermal performance, greater durability (under bending up to 2 mm radius of curvature, washing, humidity and high temperature), with only 50% the added nanowire mass compared to state-of-the-art. Computational modeling combining electromagnetic and thermal simulations is performed to uncover the nanoscale temperature gradients during IPL sintering, and the underlying reason for greater durability of the nanowire-fabric after sintering. This large-area, high speed, and ambient-condition IPL sintering process represents an attractive strategy for scalably fabricating personal heating fabric-patches with greater thermal performance, higher durability and reduced costs. PMID- 30464251 TI - US gynecologists' estimates and beliefs regarding ovarian cancer screening's effectiveness 5 years after release of the PLCO evidence. AB - Efficient patient care requires the conscientious use of current best evidence. Such evidence on ovarian cancer screening showed that the screening has no survival benefit but considerable harms; currently no medical organization recommends it. In a cross-sectional online survey study with 401 US outpatient gynecologists we investigated whether they follow the recommendation of their medical organizations in daily practice and report estimates of ovarian cancer screening's effectiveness that approximate current best evidence (within a +/- 10 percent margin of error), and if not, whether a fact box intervention summarizing current best evidence improves judgments. Depending on question, 44.6% to 96.8% reported estimates and beliefs regarding screening's effectiveness that diverged from evidence, and 57.6% reported regularly recommending the screening. Gynecologists who recommend screening overestimated the benefit and underestimated the harms more frequently. After seeing the fact box, 51.6% revised initial estimates and beliefs, and the proportion of responses approximating best evidence increased on all measures (e.g., mortality reduction: 32.9% [95% CI, 26.5 to 39.7] before intervention, 77.3% [71.0 to 82.8] after intervention). Overall, results highlight the need for intensified training programs on the interpretation of medical evidence. The provision of fact box summaries in medical journals may additionally improve the practice of evidence based medicine. PMID- 30464254 TI - Unilateral ex vivo gene therapy by GDNF in epileptic rats. AB - Temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults. This neurological disorder is characterized by focal seizures originating in the temporal lobe, often with secondary generalization. A variety of pharmacological treatments exist for patients suffering from focal seizures, but systemically administered drugs offer only symptomatic relief and frequently cause unwanted side effects. Moreover, available drugs are ineffective in one third of the epilepsy patients. Thus, developing more targeted and effective treatment strategies for focal seizures, originating from, e.g., the temporal lobe, is highly warranted. In order to deliver potential anti-epileptic agents directly into the seizure focus we used encapsulated cell biodelivery (ECB), a specific type of ex vivo gene therapy. Specifically, we asked whether unilateral delivery of glial cell line-derived neurotrophic factor (GDNF), exclusively into the epileptic focus, would suppress already established spontaneous recurrent seizures (SRS) in rats. Our results show that GDNF delivered by ECB devices unilaterally into the seizure focus in the hippocampus effectively decreases the number of SRS in epileptic rats. Thus, our study demonstrates that focal unilateral delivery of neurotrophic factors, such as GDNF, using ex vivo gene therapy based on ECB devices could be an effective anti-epileptic strategy providing a bases for the development of a novel, alternative, treatment for focal epilepsies. PMID- 30464253 TI - Need for high-resolution Genetic Analysis in iPSC: Results and Lessons from the ForIPS Consortium. AB - Genetic integrity of induced pluripotent stem cells (iPSCs) is essential for their validity as disease models and for potential therapeutic use. We describe the comprehensive analysis in the ForIPS consortium: an iPSC collection from donors with neurological diseases and healthy controls. Characterization included pluripotency confirmation, fingerprinting, conventional and molecular karyotyping in all lines. In the majority, somatic copy number variants (CNVs) were identified. A subset with available matched donor DNA was selected for comparative exome sequencing. We identified single nucleotide variants (SNVs) at different allelic frequencies in each clone with high variability in mutational load. Low frequencies of variants in parental fibroblasts highlight the importance of germline samples. Somatic variant number was independent from reprogramming, cell type and passage. Comparison with disease genes and prediction scores suggest biological relevance for some variants. We show that high-throughput sequencing has value beyond SNV detection and the requirement to individually evaluate each clone. PMID- 30464255 TI - Correction: The Use of International Classification of Diseases Codes to Identify Patients with Pancreatitis: A Systematic Review and Meta-analysis of Diagnostic Accuracy Studies. AB - The original version of this Article presented incorrect information for citation 50. This has now been corrected in both the PDF and HTML versions of the Article. Petrov, M. S. Predicting the severity of acute pancreatitis: choose the right horse before hitching the cart. Dig. Dis. Sci. 56, 3402-3404 (2011).Parikh, R. et al. Understanding and using sensitivity, specificity and predictive values Indian J. Ophthalmol. 56, 45-50 (2008). PMID- 30464252 TI - Reduced Uteroplacental Perfusion Pressure (RUPP) causes altered trophoblast differentiation and pericyte reduction in the mouse placenta labyrinth. AB - This study characterized the effect of the reduced utero-placental perfusion pressure (RUPP) model of placental insufficiency on placental morphology and trophoblast differentiation at mid-late gestation (E14.5). Altered trophoblast proliferation, reduced syncytiotrophoblast gene expression, increased numbers of sinusoidal trophoblast giant cells, decreased Vegfa and decreased pericyte presence in the labyrinth were observed in addition to changes in maternal blood spaces, the fetal capillary network and reduced fetal weight. Further, the junctional zone was characterized by reduced spongiotrophoblast and glycogen trophoblast with increased trophoblast giant cells. Increased Hif-1alpha and TGF beta-3 in vivo with supporting hypoxia studies in trophoblast stem (TS) cells in vitro, support hypoxia as a contributing factor to the RUPP placenta phenotype. Together, this study identifies altered cell populations within the placenta that may contribute to the phenotype, and thus support the use of RUPP in the mouse as a model of placenta insufficiency. As such, this model in the mouse provides a valuable tool for understanding the phenotypes resulting from genetic manipulation of isolated cell populations to further understand the etiology of placenta insufficiency and fetal growth restriction. Further this study identifies a novel relationship between placental insufficiency and pericyte depletion in the labyrinth layer. PMID- 30464256 TI - Apparent self-heating of individual upconverting nanoparticle thermometers. AB - Individual luminescent nanoparticles enable thermometry with sub-diffraction limited spatial resolution, but potential self-heating effects from high single particle excitation intensities remain largely uninvestigated because thermal models predict negligible self-heating. Here, we report that the common "ratiometric" thermometry signal of individual NaYF4:Yb3+,Er3+ nanoparticles unexpectedly increases with excitation intensity, implying a temperature rise over 50 K if interpreted as thermal. Luminescence lifetime thermometry, which we demonstrate for the first time using individual NaYF4:Yb3+,Er3+ nanoparticles, indicates a similar temperature rise. To resolve this apparent contradiction between model and experiment, we systematically vary the nanoparticle's thermal environment: the substrate thermal conductivity, nanoparticle-substrate contact resistance, and nanoparticle size. The apparent self-heating remains unchanged, demonstrating that this effect is an artifact, not a real temperature rise. Using rate equation modeling, we show that this artifact results from increased radiative and non-radiative relaxation from higher-lying Er3+ energy levels. This study has important implications for single-particle thermometry. PMID- 30464257 TI - Nausea in the peri-traumatic period is associated with prospective risk for PTSD symptom development. AB - While nausea often develops following exposure to trauma, little is known regarding the relationship between peri-traumatic nausea and prospective risk for developing posttraumatic stress disorder (PTSD). We examined the association between peri-traumatic nausea and PTSD symptom development in three independent cohorts. Participants were recruited from (1) the Emergency Departments (ED) at Grady Memorial Hospital (GMH) in Atlanta, GA, (2) from multiple other ED sites in the TRYUMPH Research Network, and (3) from the ED during evaluation for suspected acute coronary syndrome in the REACH cohort. Administration of IV ondansetron, the most predominant antiemetic used at GMH, was used as a surrogate marker for nausea in the initial GMH cohort; nausea was then directly assessed in the internal validation at GMH, and within the replication TRYUMPH Research Network and REACH cohorts. In the GMH cohort (N = 363), ondansetron administration was associated with increased 1- and 3-month posttrauma PTSD symptoms in adjusted models (all p's < 0.05). In the GMH internal validation, nausea significantly predicted 1 month (p = 0.009; n = 68) and 3 month (p = 0.029; n = 54) PTSD symptoms. In the TRYUMPH cohort (N = 1846), patient reported nausea in the ED was significantly associated with increased PTSD symptoms (p = 0.009) in adjusted models. In the REACH cohort (N = 758), peri-traumatic nausea was associated with PTSD symptom severity at the 1-month follow-up in adjusted models (p's <= 0.008). The current prospective data from three independent cohorts suggest that peri traumatic nausea is a prospective predictor of PTSD symptom development. Further studies are needed to determine the mechanistic role of nausea as an intermediate phenotype of PTSD risk. PMID- 30464258 TI - miR-21 promotes EGF-induced pancreatic cancer cell proliferation by targeting Spry2. AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant cancer that lacks effective targets for therapy. Alteration of epidermal growth factor (EGF) expression has been recognized as an essential molecular event in pancreatic carcinogenesis. Accumulating studies have demonstrated that miRNAs play critical roles in EGF signaling regulation, tumor initiation, cell proliferation and apoptosis. Here, we demonstrated that miR-21 expression was induced by EGF in pancreatic cancer cells. miR-21 promoted EGF-induced proliferation, inhibited cell apoptosis and accelerated cell cycle progression. In vivo experiments confirmed the influence of miR-21 on tumor growth. Mechanistic studies revealed that miR-21 targeted MAPK/ERK and PI3K/AKT signaling pathways to modulate cell proliferation. In addition, Spry2 was proven to be a target of miR-21. Furthermore, miR-21 and Spry2 were significantly related to clinical features and may be valuable predictors of PDAC patient prognosis. PMID- 30464260 TI - Grazers extend blue carbon transfer by slowing sinking speeds of kelp detritus. AB - Marine plant communities such as kelp forests produce significant amounts of detritus, most of which is exported to areas where it can constitute an important trophic subsidy or potentially be sequestered in marine sediments. Knowing the vertical transport speed of detrital particles is critical to understanding the potential magnitude and spatial extent of these linkages. We measured sinking speeds for Laminaria hyperborea detritus ranging from whole plants to small fragments and sea urchin faecal pellets, capturing the entire range of particulate organic matter produced by kelp forests. Under typical current conditions, we determined that this organic material can be transported 10 s of m to 10 s of km. We show how the conversion of kelp fragments to sea urchin faeces, one of the most pervasive processes in kelp forests globally, increases the dispersal potential of detritus by 1 to 2 orders of magnitude. Kelp detritus sinking speeds were also faster than equivalent phytoplankton, highlighting its potential for rapid delivery of carbon to deep areas. Our findings support arguments for a significant contribution from kelp forests to subsidizing deep sea communities and the global carbon sink. PMID- 30464259 TI - Correction: Putting genome-wide sequencing in neonates into perspective. AB - The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 30464262 TI - DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells. AB - Limited DNA end resection is the key to impaired homologous recombination in BRCA1-mutant cancer cells. Here, using a loss-of-function CRISPR screen, we identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, we infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy. PMID- 30464261 TI - COMP and TSP-4 interact specifically with the novel GXKGHR motif only found in fibrillar collagens. AB - COMP (cartilage oligomeric matrix protein) is a member of the thrombospondin family and forms homopentamers as well as mixed heterooligomers with its closely related family member TSP-4. COMP is long known to bind to collagens and to influence collagen fibril formation. Recent work indicates that already intracellular interaction with collagen is important for collagen secretion. However, the exact binding site of COMP on the collagen triple helix has not been described up to now. In this study we have identified a GXKGHR motif on the collagen II helix to bind to COMP, using a recombinantly expressed collagen II peptide library. This binding sequence is conserved throughout evolution and we demonstrate that TSP-4 binds to the same sequence. The identified binding motif overlaps with the recognition sites of many other collagen-binding partners (e.g. PEDF, Heparin) and also spans the lysine residues, which form collagen cross links. COMP might thereby protect collagen helices from premature modification and cross-linking. Interestingly, this motif is only found in classical fibrillar collagens, although COMP is known to also bind other types. This might indicate that COMP has a unique interface for fibrillar collagens, thus making it an interesting target for the development of antifibrotic drugs. PMID- 30464263 TI - TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle. AB - A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP the gene that encodes TDP-43-that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here we show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which we call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease. PMID- 30464264 TI - Dinosaur egg colour had a single evolutionary origin. AB - Birds are the only living amniotes with coloured eggs1-4, which have long been considered to be an avian innovation1,3. A recent study has demonstrated the presence of both red-brown protoporphyrin IX and blue-green biliverdin5-the pigments responsible for all the variation in avian egg colour-in fossilized eggshell of a nonavian dinosaur6. This raises the fundamental question of whether modern birds inherited egg colour from their nonavian dinosaur ancestors, or whether egg colour evolved independently multiple times. Here we present a phylogenetic assessment of egg colour in nonavian dinosaurs. We applied high resolution Raman microspectroscopy to eggshells that represent all of the major clades of dinosaurs, and found that egg colour pigments were preserved in all eumaniraptorans: egg colour had a single evolutionary origin in nonavian theropod dinosaurs. The absence of colour in ornithischian and sauropod eggs represents a true signal rather than a taphonomic artefact. Pigment surface maps revealed that nonavian eumaniraptoran eggs were spotted and speckled, and colour pattern diversity in these eggs approaches that in extant birds, which indicates that reproductive behaviours in nonavian dinosaurs were far more complex than previously known3. Depth profiles demonstrated identical mechanisms of pigment deposition in nonavian and avian dinosaur eggs. Birds were not the first amniotes to produce coloured eggs: as with many other characteristics7,8 this is an attribute that evolved deep within the dinosaur tree and long before the spectacular radiation of modern birds. PMID- 30464265 TI - Twentieth-century contribution to sea-level rise from uncharted glaciers. AB - Global-mean sea-level rise (GMSLR) during the twentieth century was primarily caused by glacier and ice-sheet mass loss, thermal expansion of ocean water and changes in terrestrial water storage1. Whether based on observations2 or results of climate models3,4, however, the sum of estimates of each of these contributions tends to fall short of the observed GMSLR. Current estimates of the glacier contribution to GMSLR rely on the analysis of glacier inventory data, which are known to undersample the smallest glacier size classes5,6. Here we show that from 1901 to 2015, missing and disappeared glaciers produced a sea-level equivalent (SLE) of approximately 16.7 to 48.0 millimetres. Missing glaciers are those small glaciers that we expect to exist today, owing to regional analyses and theoretical scaling relationships, but that are not represented in the inventories. These glaciers contributed approximately 12.3 to 42.7 millimetres to the historical SLE. Additionally, disappeared glaciers (those that existed in 1901 but had melted away by 2015, and that therefore cannot be included in modern global glacier inventories) made an estimated contribution of between 4.4 and 5.3 millimetres. Failure to consider these uncharted glaciers may be an important cause of difficulties in closing the GMSLR budget during the twentieth century: their contribution is on average between 0.17 and 0.53 millimetres of SLE per year, compared to a budget discrepancy of about 0.5 millimetres of GMSLR per year between 1901 and 1990. Although the uncharted glaciers will have a minimal role in sea-level rise in the future, and are less important after 1990, these findings imply that undiscovered physical processes are not required to close the historical sea-level budget. PMID- 30464267 TI - Efficient radical-based light-emitting diodes with doublet emission. AB - Organic light-emitting diodes (OLEDs)1-5, quantum-dot-based LEDs6-10, perovskite based LEDs11-13 and micro-LEDs14,15 have been championed to fabricate lightweight and flexible units for next-generation displays and active lighting. Although there are already some high-end commercial products based on OLEDs, costs must decrease whilst maintaining high operational efficiencies for the technology to realise wider impact. Here we demonstrate efficient action of radical-based OLEDs16, whose emission originates from a spin doublet, rather than a singlet or triplet exciton. While the emission process is still spin-allowed in these OLEDs, the efficiency limitations imposed by triplet excitons are circumvented for doublets. Using a luminescent radical emitter, we demonstrate an OLED with maximum external quantum efficiency of 27 per cent at a wavelength of 710 nanometres-the highest reported value for deep-red and infrared LEDs. For a standard closed-shell organic semiconductor, holes and electrons occupy the highest occupied and lowest unoccupied molecular orbitals (HOMOs and LUMOs), respectively, and recombine to form singlet or triplet excitons. Radical emitters have a singly occupied molecular orbital (SOMO) in the ground state, giving an overall spin-1/2 doublet. If-as expected on energetic grounds-both electrons and holes occupy this SOMO level, recombination returns the system to the ground state, giving no light emission. However, in our very efficient OLEDs, we achieve selective hole injection into the HOMO and electron injection to the SOMO to form the fluorescent doublet excited state with near-unity internal quantum efficiency. PMID- 30464266 TI - Protocadherin-1 is essential for cell entry by New World hantaviruses. AB - The zoonotic transmission of hantaviruses from their rodent hosts to humans in North and South America is associated with a severe and frequently fatal respiratory disease, hantavirus pulmonary syndrome (HPS)1,2. No specific antiviral treatments for HPS are available, and no molecular determinants of in vivo susceptibility to hantavirus infection and HPS are known. Here we identify the human asthma-associated gene protocadherin-1 (PCDH1)3-6 as an essential determinant of entry and infection in pulmonary endothelial cells by two hantaviruses that cause HPS, Andes virus (ANDV) and Sin Nombre virus (SNV). In vitro, we show that the surface glycoproteins of ANDV and SNV directly recognize the outermost extracellular repeat domain of PCDH1-a member of the cadherin superfamily7,8-to exploit PCDH1 for entry. In vivo, genetic ablation of PCDH1 renders Syrian golden hamsters highly resistant to a usually lethal ANDV challenge. Targeting PCDH1 could provide strategies to reduce infection and disease caused by New World hantaviruses. PMID- 30464268 TI - Structural superlubricity and ultralow friction across the length scales. AB - Structural superlubricity, a state of ultralow friction and wear between crystalline surfaces, is a fundamental phenomenon in modern tribology that defines a new approach to lubrication. Early measurements involved nanometre scale contacts between layered materials, but recent experimental advances have extended its applicability to the micrometre scale. This is an important step towards practical utilization of structural superlubricity in future technological applications, such as durable nano- and micro-electromechanical devices, hard drives, mobile frictionless connectors, and mechanical bearings operating under extreme conditions. Here we provide an overview of the field, including its birth and main achievements, the current state of the art and the challenges to fulfilling its potential. PMID- 30464269 TI - LEDs for photons, physiology and food. AB - Lighting based on light-emitting diodes (LEDs) not only is more energy efficient than traditional lighting, but also enables improved performance and control. The colour, intensity and distribution of light can now be controlled with unprecedented precision, enabling light to be used both as a signal for specific physiological responses in humans and plants, and as an efficient fuel for fresh food production. Here we show how a broad and improved understanding of the physiological responses to light will facilitate greater energy savings and provide health and productivity benefits that have not previously been associated with lighting. PMID- 30464270 TI - Flight of an aeroplane with solid-state propulsion. AB - Since the first aeroplane flight more than 100 years ago, aeroplanes have been propelled using moving surfaces such as propellers and turbines. Most have been powered by fossil-fuel combustion. Electroaerodynamics, in which electrical forces accelerate ions in a fluid1,2, has been proposed as an alternative method of propelling aeroplanes-without moving parts, nearly silently and without combustion emissions3-6. However, no aeroplane with such a solid-state propulsion system has yet flown. Here we demonstrate that a solid-state propulsion system can sustain powered flight, by designing and flying an electroaerodynamically propelled heavier-than-air aeroplane. We flew a fixed-wing aeroplane with a five metre wingspan ten times and showed that it achieved steady-level flight. All batteries and power systems, including a specifically developed ultralight high voltage (40-kilovolt) power converter, were carried on-board. We show that conventionally accepted limitations in thrust-to-power ratio and thrust density4,6,7, which were previously thought to make electroaerodynamics unfeasible as a method of aeroplane propulsion, are surmountable. We provide a proof of concept for electroaerodynamic aeroplane propulsion, opening up possibilities for aircraft and aerodynamic devices that are quieter, mechanically simpler and do not emit combustion emissions. PMID- 30464271 TI - Largest overhaul of scientific units since 1875 wins approval. PMID- 30464273 TI - Lab life - when privileged are a minority, equity stands a chance. PMID- 30464272 TI - African clinician scientists - mentors and networks help. PMID- 30464274 TI - Lessons from recordings lost in Brazil fire: deposit and back up. PMID- 30464275 TI - Patchwork regulation won't stop antimicrobial resistance. PMID- 30464276 TI - How it f eels t o b e s wallowed b y a b lack hole. PMID- 30464277 TI - Flying with ionic wind. PMID- 30464278 TI - Efficiency breakthrough for radical LEDs. PMID- 30464279 TI - Stop exploitation of foreign postdocs in the United States. PMID- 30464281 TI - When skin's defence against pollution fails. PMID- 30464280 TI - Mars rover, French research integrity and NIPS renamed. PMID- 30464282 TI - Skin. PMID- 30464283 TI - Skin microbiota's community effort. PMID- 30464284 TI - Vitiligo's impact is in the eye of the beholder. PMID- 30464286 TI - Moving skin beyond the biological. PMID- 30464285 TI - The edible skincare diet. PMID- 30464287 TI - Superpowered skin. PMID- 30464288 TI - Unlocking the secrets of scar-free skin healing. PMID- 30464289 TI - The microscope revolution that's sweeping through materials science. PMID- 30464290 TI - Deterioration of willow seeds during storage. AB - Willow (Salix spp.) seeds are able to tolerate desiccation, but differ from typical orthodox seeds in that they lose viability in a few days at room temperature, and in that the chloroplasts in embryo tissues do not dedifferentiate during maturation drying, thus retaining chlorophyll and maintaining intact their thylakoid membranes. In the present study, we investigated the damage generated in willow seeds during storage under appropriate conditions to exclude the eventual generation of reactive oxygen species by photooxidation. To this end, we measured different indicators of molecular damage, such as changes in the fatty acid profile, protein degradation, nuclease activities, and DNA damage, and evaluated normal germination and total germination in seeds stored for one, ten and sixteen years. We found: (i) a decrease in the fraction of unsaturated fatty acids; (ii) changes in the protein profile due to a decrease in protein solubility; (iii) activation of nucleases; and (iv) DNA fragmentation. Taken together, our findings identified programmed cell death as a key mechanism in seed deterioration during storage. We also found that, although the seeds maintained high percentages of total germination, the death program had already started in the seeds stored for ten years and was more advanced in those stored for sixteen years. PMID- 30464291 TI - Preparation of Lauroyl Grafted Alginate-Psyllium Husk Gel Composite Film with Enhanced Physicochemical, Mechanical and Antimicrobial Properties. AB - In this study, a lauroyl grafted hydrophobic glycolipid derivative of alginate has been successfully synthesized and characterized. This glycolipid has been incorporated into Psyllium husk gel-alginate composite films and compared with the films containing only Psyllim husk gel and Psyllim husk gel-alginate for its mechanical and physicochemical properties. Additionally, the composite film has also been evaluated for protein adsorption and antimicrobial property to verify its utility in biomedical applications. The results showed that the composite films have enhanced physicochemical and mechanical properties. The film produced better swelling characteristic and lower protein adsorption property indicating the usefulness of the film in wound care dressing, particularly for low suppurating wounds. Incorporation of the synthesised glycolipid derivative also imparts antimicrobial activity to the composite film. Therefore, the developed film is capable of sustaining the microbial contamination during the storage and also valuable in the biomedical utility including wound dressings. PMID- 30464292 TI - Evaluation of Structure-Function Relationships in Longitudinal Changes of Glaucoma using the Spectralis OCT Follow-Up Mode. AB - The detection of glaucoma progression is an essential part of glaucoma management. Subjectivity of standard automated perimetry (SAP) prevents the accurate evaluation of progression, thus the detection of structural changes by optical coherence tomography (OCT) is attracting attention. Despite its objectivity, there is controversy about the appropriateness of the use of OCT, because many previous studies have indicated OCT results may not reflect the deterioration of visual field. A reason for this dissociation may be the test retest variability of OCT, a major cause of which is misplacement of the measurement location. Recent advantages of spectral-domain OCT (SD-OCT), especially Spectralis OCT with an eye-tracking system (follow-up mode) enable measurement at approximately the same location as previous examinations. In addition to utilizing Spectralis follow-up mode, we introduced structure-function relationship map and nonlinear relationship between SAP and OCT results in considering structure-function relationship in longitudinal changes. The introduction of these two ideas in our study population improved the correlation between the SAP and OCT (R = 0.589 at most). The results of this study support the practical use of OCT in glaucoma progression but also stress the importance of focus on the corresponding focal changes and the consideration of disease severity. PMID- 30464294 TI - Dendritic cell subsets in T cell programming: location dictates function. AB - Dendritic cells (DCs) can be viewed as translators between innate and adaptive immunity. They integrate signals derived from tissue infection or damage and present processed antigen from these sites to naive T cells in secondary lymphoid organs while also providing multiple soluble and surface-bound signals that help to guide T cell differentiation. DC-mediated tailoring of the appropriate T cell programme ensures a proper cascade of immune responses that adequately targets the insult. Recent advances in our understanding of the different types of DC subsets along with the cellular organization and orchestration of DC and lymphocyte positioning in secondary lymphoid organs over time has led to a clearer understanding of how the nature of the T cell response is shaped. This Review discusses how geographical organization and ordered sequences of cellular interactions in lymph nodes and the spleen regulate immunity. PMID- 30464295 TI - Kinetic Equilibrium of Dipolarization Fronts. AB - The unprecedented high-resolution data from the Magnetospheric Multi-Scale (MMS) satellites is revealing the physics of dipolarization fronts created in the aftermath of magnetic reconnection in extraordinary detail. The data shows that the fronts contain structures on small spatial scales beyond the scope of fluid framework. A new kinetic analysis, applied to MMS data here, predicts that global plasma compression produces a unique particle distribution in a narrow boundary layer with separation of electron and ion scale physics. Layer widths on the order of an ion gyro-diameter lead to an ambipolar potential across the magnetic field resulting in strongly sheared flows. Gradients along the magnetic field lines create a potential difference, which can accelerate ions and electrons into beams. These small-scale kinetic effects determine the plasma dynamics in dipolarization fronts, including the origin of the distinctive broadband emissions. PMID- 30464293 TI - Limited prefrontal cortical regulation over the basolateral amygdala in adolescent rats. AB - Cognitive regulation of emotion develops from childhood into adulthood. This occurs in parallel with maturation of prefrontal cortical (PFC) regulation over the amygdala. The cellular substrates for this regulation may include PFC activation of inhibitory GABAergic elements in the amygdala. The purpose of this study was to determine whether PFC regulation over basolateral amygdala area (BLA) in vivo is immature in adolescence, and if this is due to immaturity of GABAergic elements or PFC excitatory inputs. Using in vivo extracellular electrophysiological recordings from anesthetized male rats we found that in vivo summation of PFC inputs to the BLA was less regulated by GABAergic inhibition in adolescents (postnatal day 39) than adults (postnatal day 72-75). In addition, stimulation of either prelimbic or infralimbic PFC evokes weaker inhibition over basal (BA) and lateral (LAT) nuclei of the BLA in adolescents. This was dictated by both weak recruitment of inhibition in LAT and weak excitatory effects of PFC in BA. The current results may contribute to differences in adolescent cognitive regulation of emotion. These findings identify specific elements that undergo adolescent maturation and may therefore be sensitive to environmental disruptions that increase risk for psychiatric disorders. PMID- 30464297 TI - Seasonal succession of ciliate Mesodinium spp. with red, green, or mixed plastids and their association with cryptophyte prey. AB - Mesodinium spp. are commonly found in marine and brackish waters, and several species are known to contain red, green, or both plastids that originate from cryptophyte prey. We observed the seasonal succession of Mesodinium spp. in a Japanese brackish lake, and we analysed the origin and diversity of the various coloured plastids within the cells of Mesodinium spp. using a newly developed primer set that specifically targets the cryptophyte nuclear 18S rRNA gene. Mesodinium rubrum isolated from the lake contained only red plastids originating from cryptophyte Teleaulax amphioxeia. We identified novel Mesodinium sp. that contained only green plastids or both red and green plastids originating from cryptophytes Hemiselmis sp. and Teleaulax acuta. Although the morphology of the newly identified Mesodinium sp. was indistinguishable from that of M. rubrum under normal light microscopy, phylogenetic analysis placed this species between the M. rubrum/major species complex and a well-supported lineage of M. chamaeleon and M. coatsi. Close associations were observed in cryptophyte species composition within cells of Mesodinium spp. and in ambient water samples. The appearance of suitable cryptophyte prey is probably a trigger for succession of Mesodinium spp., and the subsequent abundance of Mesodinium spp. appears to be influenced by water temperature and dissolved inorganic nutrients. PMID- 30464296 TI - Quantum fluctuation theorem for error diagnostics in quantum annealers. AB - Near term quantum hardware promises unprecedented computational advantage. Crucial in its development is the characterization and minimization of computational errors. We propose the use of the quantum fluctuation theorem to benchmark the accuracy of quantum annealers. This versatile tool provides simple means to determine whether the quantum dynamics are unital, unitary, and adiabatic, or whether the system is prone to thermal noise. Our proposal is experimentally tested on two generations of the D-Wave machine, which illustrates the sensitivity of the fluctuation theorem to the smallest aberrations from ideal annealing. In addition, for the optimally operating D-Wave machine, our experiment provides the first experimental verification of the integral fluctuation in an interacting, many-body quantum system. PMID- 30464298 TI - Hydrodynamic assembly of two-dimensional layered double hydroxide nanostructures. AB - Formation mechanisms of two-dimensional nanostructures in wet syntheses are poorly understood. Even more enigmatic is the influence of hydrodynamic forces. Here we use liquid flow cell transmission electron microscopy to show that layered double hydroxide, as a model material, may form via the oriented attachment of hexagonal nanoparticles; under hydrodynamic shear, oriented attachment is accelerated. To hydrodynamically manipulate the kinetics of particle growth and oriented attachment, we develop a microreactor with high and tunable shear rates, enabling control over particle size, crystallinity and aspect ratio. This work offers new insights in the formation of two-dimensional materials, provides a scalable yet precise synthesis method, and proposes new avenues for the rational engineering and scalable production of highly anisotropic nanostructures. PMID- 30464299 TI - A split luciferase-based probe for quantitative proximal determination of Galphaq signalling in live cells. AB - The earlier an activation of a G protein-dependent signalling cascade at a G protein-coupled receptor (GPCR) is probed, the less amplificatory effects contribute to the measured signal. This is especially useful in case of a precise quantification of agonist efficacies, and is of paramount importance, when determining agonist bias in relation to the beta-arrestin pathway. As most canonical assays with medium to high throughput rely on the quantification of second messengers, and assays affording more proximal readouts are often limited in throughput, we developed a technique with a proximal readout and sufficiently high throughput that can be used in live cells. Split luciferase complementation (SLC) was applied to assess the interaction of Galphaq with its effector phospholipase C-beta3. The resulting probe yielded an excellent Z' value of 0.7 and offers a broad and easy applicability to various Galphaq-coupling GPCRs (hH1R, hM1,3,5R, hNTS1R), expressed in HEK293T cells, allowing the functional characterisation of agonists and antagonists. Furthermore, the developed sensor enabled imaging of live cells by luminescence microscopy, as demonstrated for the hM3R. The versatile SLC-based probe is broadly applicable e.g. to the screening and the pharmacological characterisation of GPCR ligands as well as to molecular imaging. PMID- 30464302 TI - New approaches along the IBD course: diet, tight control and stem cells. PMID- 30464300 TI - Tendon Fascicle-Inspired Nanofibrous Scaffold of Polylactic acid/Collagen with Enhanced 3D-Structure and Biomechanical Properties. AB - Surgical treatment of tendon lesions still yields unsatisfactory clinical outcomes. The use of bioresorbable scaffolds represents a way forward to improve tissue repair. Scaffolds for tendon reconstruction should have a structure mimicking that of the natural tendon, while providing adequate mechanical strength and stiffness. In this paper, electrospun nanofibers of two crosslinked PLLA/Collagen blends (PLLA/Coll-75/25, PLLA/Coll-50/50) were developed and then wrapped in bundles, where the nanofibers are predominantly aligned along the bundles. Bundle morphology was assessed via SEM and high-resolution x-ray computed tomography (XCT). The 0.4-micron resolution in XCT demonstrated a biomimetic morphology of the bundles for all compositions, with a predominant nanofiber alignment and some scatter (50-60% were within 12 degrees from the axis of the bundle), similar to the tendon microstructure. Human fibroblasts seeded on the bundles had increased metabolic activity from day 7 to day 21 of culture. The stiffness, strength and toughness of the bundles are comparable to tendon fascicles, both in the as-spun condition and after crosslinking, with moderate loss of mechanical properties after ageing in PBS (7 and 14 days). PLLA/Coll-75/25 has more desirable mechanical properties such as stiffness and ductility, compared to the PLLA/Coll-50/50. This study confirms the potential to bioengineer tendon fascicles with enhanced 3D structure and biomechanical properties. PMID- 30464301 TI - Impact of uranium uptake on isotopic fractionation and endogenous element homeostasis in human neuron-like cells. AB - The impact of natural uranium (U) on differentiated human neuron-like cells exposed to 1, 10, 125, and 250 uM of U for seven days was assessed. In particular, the effect of the U uptake on the homeostatic modulation of several endogenous elements (Mg, P, Mn, Fe, Zn, and Cu), the U isotopic fractionation upon its incorporation by the cells and the evolution of the intracellular Cu and Zn isotopic signatures were studied. The intracellular accumulation of U was accompanied by a preferential uptake of 235U for cells exposed to 1 and 10 uM of U, whereas no significant isotopic fractionation was observed between the extra- and the intracellular media for higher exposure U concentrations. The U uptake was also found to modulate the homeostasis of Cu, Fe, and Mn for cells exposed to 125 and 250 uM of U, but the intracellular Cu isotopic signature was not modified. The intracellular Zn isotopic signature was not modified either. The activation of the non-specific U uptake pathway might be related to this homeostatic modulation. All together, these results show that isotopic and quantitative analyses of toxic and endogenous elements are powerful tools to help deciphering the toxicity mechanisms of heavy metals. PMID- 30464303 TI - Differential impacts of different keyboard inputting methods on reading and writing skills. AB - Nowadays, typewriting has become an important mode of written communication. A report that typewriting may hinder Chinese children's reading development has sparked substantial concern about whether typing on electronic devices would increase the rate of reading disorders, wherein children used a pronunciation based input system that associates alphabet letters with phonemes in standard Chinese (Putonghua) and may conflict with the traditional visuomotor-based learning processes for written Chinese. If orthographic-based input methods that require good awareness of the orthographic structure of characters are used, different outcomes might be observed. This study examined the impact of participants' experience in different typewriting methods on the literacy abilities of fluent Chinese-English bilingual readers. We found that orthographic based typewriting measures correlated positively with Chinese reading measures, whereas pronunciation-based typewriting measures did not correlate with Chinese reading measures but correlated positively with English reading and spelling performance. Orthographic-based typewriters also performed better than pronunciation-based typewriters in Chinese reading and dictation when their age, typewriting skills and pre-University language ability were statistically controlled. Our findings based on two contrastive writing systems suggest that typewriting methods that tally with the learning principles of a writing system should be used to promote and preserve literacy skills in the digital era. PMID- 30464305 TI - EUS-IR-Guided Revision of Whipple Anatomy for Concomitant Afferent and Efferent Limb Obstruction. PMID- 30464304 TI - Design and modeling of pulsed-laser three-dimensional imaging system inspired by compound and human hybrid eye. AB - A pulsed-laser three-dimensional imaging system inspired by compound and human hybrid eye is proposed. A diffractive optical element is used to enlarge field of view (FOV) of transmitting system and a receiving system consisting of a non uniform microlens array, an aperture array, and an avalanche photodiode array is designed. The non-uniform microlens array is arranged on a curved surface to mimic large FOV feature of the compound eye. Meanwhile, the non-uniform microlens array is modeled to mimic space-variant resolution property of the human eye. On the basis of the proposed system, some simulation experiments are carried out. Results show that the entire FOV is up to 52 degrees , and the resolution is 30 * 18. The proposed system has a high resolution in the center FOV and a low resolution in the peripheral FOV. The rotation and scaling invariances of the human eye are verified on the proposed system. The signal-to-noise ratio (SNR) increases with the increase in the number of rings and the maximum SNR locates at the outmost periphery area. This work is beneficial to the design of the pulsed laser three-dimensional imaging system with large FOV, high speed, and high resolution. PMID- 30464306 TI - Bridging Medical and Surgical Treatment of Inflammatory Bowel Disease: The Role of Interventional IBD. PMID- 30464307 TI - Digital mapping and spatial characteristics analyses of heavy metal content in reclaimed soil of industrial and mining abandoned land. AB - The reclaimed soil properties of industrial and mining wasteland have strong spatial specificity. The paper aimed to screen out a hybrid multifractal and kriging (Named as Mkriging) method for digital mapping and scientifically reveal the spatial distribution characteristics in view of heavy metal in reclaimed soil of industrial and mining abandoned land. The results of the study showed that for reasons of history and reclamation, the original samples of heavy metals in reclaimed soil of industrial and mining abandoned land showed a very large range and variation degree, the C0/(C0 + C1) values of different heavy metals basically were all greater than 50%, random factors played a dominant role. The five kinds of heavy metals in reclaimed soil were in the following descending order in terms of homogeneity: Cd, As, Hg, Ni and Cr. Compared with ordinary Kriging method, the relative improvement of root mean squared errors of elements Cd, Hg, As, Cr and Ni based on Mkriging were 95.28%, 61.74%, 78.54%, 82.51% and 83.58% respectively. The higher the fractal degree of heavy metals in reclaimed soil was, the higher the prediction accuracy will be. Mkriging method is more suitable for spatial prediction of heavy metals in reclaimed soil of industrial and mining abandoned land. PMID- 30464308 TI - Comparative survival analysis of preoperative and postoperative radiotherapy in stage II-III rectal cancer on the basis of long-term population data. AB - This study compared long-term population-based survival outcomes of preoperative and postoperative radiotherapy (RT) approaches in rectal cancer. Patients with stage II-III rectal cancer between 1998 and 2013 were identified using the Surveillance, Epidemiology, and End Results database. Overall survival (OS) and disease-specific survival (DSS) rates were estimated in propensity-matched study population according to the use of RT. Among the 28,320 eligible patients, a total of 18,400 patients were identified from propensity score matching process balancing the distribution of prognostic covariates. The 10-year OS and DSS rates were higher in patients with preoperative RT than the postoperative group (51.6% vs. 49.8% with P < 0.001, and 65.4% vs. 64.8% with P = 0.037, respectively). However, in multivariate analysis, selection of combined RT sequence did not affect the survival (hazard ratio [HR] 1.04 and 95% confidence interval [CI] 0.98 1.10 for OS; HR 0.97 and 95% CI 0.90-1.05 for DSS). Regarding hazard rate functions of cancer-specific mortality, the overall time-course risks after preoperative and postoperative RT were comparable. This study provides additional insight into the long-term prognostic implications of the two RT strategies, suggesting that the sequence of RT does not lead to differential survival in stage II-III rectal cancer. PMID- 30464310 TI - Nitrogen acquisition and resource allocation strategies in temperate seagrass Zostera nigricaulis: Uptake, assimilation and translocation processes. AB - The dominant seagrass in Port Phillip Bay (PPB), Australia, Zostera nigricaulis, declined between 2000 and 2011, coinciding with the 'Millennium drought' that ended in 2009. These seagrasses are nitrogen-limited, underpinning the need to develop nitrogen budgets for better ecosystem management. Environmentally realistic measurements of specific uptake rates and resource allocation were undertaken to develop nitrogen budgets and test the hypothesis that the above ground and below-ground compartments are able to re-mobilise ammonium and nitrate through uptake, translocation and assimilation to adapt to varying levels of nitrogen in the ecosystem. Uptake of 15N labelled ammonium and nitrate by above- and below-ground seagrass biomass, epiphytes and phytoplankton was quantified in chambers in situ. Preferential uptake of ammonium over nitrate was observed, where the uptake rate for nitrate was about one sixth of that for ammonium. Epiphytes and phytoplankton also registered an increased affinity for ammonium over nitrate. Translocation experiments demonstrated the uptake by both the above ground and below-ground biomass, respectively from the water column and pore water, and subsequent translocation to the opposite compartment. Acropetal translocation (below- to above-ground biomass) was more prevalent than basipetal translocation. This is a unique outcome given basipetal translocation has been widely reported for Zostera by other researchers. PMID- 30464309 TI - Eight-month-old infants' behavioral responses to peers' emotions as related to the asymmetric frontal cortex activity. AB - Infants are sensitive to and converge emotionally with peers' distress. It is unclear whether these responses extend to positive affect and whether observing peer emotions motivates infants' behaviors. This study investigates 8-month-olds' asymmetric frontal EEG during peers' cry and laughter, and its relation to approach and withdrawal behaviors. Participants observed videos of infant crying or laughing during two separate sessions. Frontal EEG alpha power was recorded during the first, while infants' behaviors and emotional expressions were recorded during the second session. Facial and vocal expressions of affect suggest that infants converge emotionally with their peers' distress, and, to a certain extent, with their happiness. At group level, the crying peer elicited right lateralized frontal activity. However, those infants with reduced right and increased left frontal activity in this situation, were more likely to approach their peer. Overall, 8-month-olds did not show asymmetric frontal activity in response to peer laughter. But, those infants who tended to look longer at their happy peer were more likely to respond with left lateralized frontal activity. The link between variations in left frontal activity and simple approach behaviors indicates the presence of a motivational dimension to infants' responses to distressed peers. PMID- 30464311 TI - Reconstructing charge-carrier dynamics in porous silicon membranes from time resolved interferometric measurements. AB - We performed interferometric time-resolved simultaneous reflectance and transmittance measurements to investigate the carrier dynamics in pump-probe experiments on thin porous silicon membranes. The experimental data was analysed by using a method built on the Wentzel-Kramers-Brillouin approximation and the Drude model, allowing us to reconstruct the excited carriers' non-uniform distribution in space and its evolution in time. The analysis revealed that the carrier dynamics in porous silicon, with ~50% porosity and native oxide chemistry, is governed by the Shockley-Read-Hall recombination process with a characteristic time constant of 375 picoseconds, whereas diffusion makes an insignificant contribution as it is suppressed by the high rate of scattering. PMID- 30464312 TI - Inter-tissue communication in cancer cachexia. AB - Cachexia is a systemic condition that occurs during many neoplastic diseases, such as cancer. Cachexia in cancer is characterized by loss of body weight and muscle and by adipose tissue wasting and systemic inflammation. Cancer cachexia is often associated with anorexia and increased energy expenditure. Even though the cachectic condition severely affects skeletal muscle, a tissue that accounts for ~40% of total body weight, it represents a multi-organ syndrome that involves tissues and organs such as white adipose tissue, brown adipose tissue, bone, brain, liver, gut and heart. Indeed, evidence suggests that non-muscle tissues and organs, as well as tumour tissues, secrete soluble factors that act on skeletal muscle to promote wasting. In addition, muscle tissue also releases various factors that can interact with the metabolism of other tissues during cancer. In this Review, we examine the effect of non-muscle tissues and inter tissue communication in cancer cachexia and discuss studies aimed at developing novel therapeutic strategies for the condition. PMID- 30464313 TI - A computational model of internal representations of chemical gradients in environments for chemotaxis of Caenorhabditis elegans. AB - The small roundworm Caenorhabditis elegans employs two strategies, termed pirouette and weathervane, which are closely related to the internal representation of chemical gradients parallel and perpendicular to the travelling direction, respectively, to perform chemotaxis. These gradients must be calculated from the chemical information obtained at a single point, because the sensory neurons are located close to each other at the nose tip. To formulate the relationship between this sensory input and internal representations of the chemical gradient, this study proposes a simple computational model derived from the directional decomposition of the chemical concentration at the nose tip that can generate internal representations of the chemical gradient. The ability of the computational model was verified by using a chemotaxis simulator that can simulate the body motions of pirouette and weathervane, which confirmed that the computational model enables the conversion of the sensory input and head-bending angles into both types of gradients with high correlations of approximately r > 0.90 (p < 0.01) with the true gradients. In addition, the chemotaxis index of the model was 0.64, which is slightly higher than that in the actual animal (0.57). In addition, simulation using a connectome-based neural network model confirmed that the proposed computational model is implementable in the actual network structure. PMID- 30464314 TI - Machine learning based classification of cells into chronological stages using single-cell transcriptomics. AB - Age-associated deterioration of cellular physiology leads to pathological conditions. The ability to detect premature aging could provide a window for preventive therapies against age-related diseases. However, the techniques for determining cellular age are limited, as they rely on a limited set of histological markers and lack predictive power. Here, we implement GERAS (GEnetic Reference for Age of Single-cell), a machine learning based framework capable of assigning individual cells to chronological stages based on their transcriptomes. GERAS displays greater than 90% accuracy in classifying the chronological stage of zebrafish and human pancreatic cells. The framework demonstrates robustness against biological and technical noise, as evaluated by its performance on independent samplings of single-cells. Additionally, GERAS determines the impact of differences in calorie intake and BMI on the aging of zebrafish and human pancreatic cells, respectively. We further harness the classification ability of GERAS to identify molecular factors that are potentially associated with the aging of beta-cells. We show that one of these factors, junba, is necessary to maintain the proliferative state of juvenile beta-cells. Our results showcase the applicability of a machine learning framework to classify the chronological stage of heterogeneous cell populations, while enabling detection of candidate genes associated with aging. PMID- 30464316 TI - Clonality and non-linearity drive facultative-cooperation allele diversity. AB - Kin discrimination describes the differential interaction of organisms with kin versus non-kin. In microorganisms, many genetic loci act as effective kin discrimination systems, such as kin-directed help and non-kin-directed harm. Another important example is facultative cooperation, where cooperators increase their investment in group-directed cooperation with the abundance of their kin in the group. Many of these kin-discrimination loci are highly diversified, yet it remains unclear what evolutionary mechanisms maintain this diversity, and how it is affected by population structure. Here, we demonstrate the unique dependence of kin-discriminative interactions on population structure, and how this could explain facultative-cooperation allele-diversity. We show mathematically that low relatedness between microbes in non-clonal social groups is needed to maintain the diversity of facultative-cooperation alleles, while high clonality is needed to stabilize this diversity against cheating. Interestingly, we demonstrate with simulations that such population structure occurs naturally in expanding microbial colonies. Finally, analysis of experimental data of quorum-sensing mediated facultative cooperation, in Bacillus subtilis, demonstrates the relevance of our results to realistic microbial interactions, due to their intrinsic non-linear frequency dependence. Our analysis therefore stresses the impact of clonality on the interplay between exploitation and kin discrimination and portrays a way for the evolution of facultative cooperation. PMID- 30464315 TI - Effect-based assessment of recipient waters impacted by on-site, small scale, and large scale waste water treatment facilities - combining passive sampling with in vitro bioassays and chemical analysis. AB - Waste water treatment facilities are a major sources of organic micropollutants (MPs) in surface water. In this study, surface water samples were collected from seven sites along a river system in Uppsala, Sweden, during four seasons and evaluated based on the occurrence of MPs in the samples and bioactivity using in vitro bioassays. The sampling sites were differentially impacted by on-site sewage treatment facilities (OSSFs), small scale, and large scale waste water treatment plants (WWTPs). The bioassays used included activation of aryl hydrocarbon receptor (AhR), estrogen receptor (ER), nuclear factor kappa-light chain-enhancer of activated B cells (NFkB), nuclear factor erythroid 2-related factor 2 (Nrf2), and androgen receptor (AR). Occurrence of 80 MPs, were analyzed using liquid chromatography coupled to tandem mass spectrometry. Most water samples induced AhR activity, and all sampling sites showed a similar profile regarding this activity. With the exception of one water sample, we did not detect any NFkB, Nrf2 or AR activity of the water samples. The exception was a sample impacted by OSSFs, which showed an activity in multiple bioassays, but the activity could not be explained by the occurrence of target MPs. The occurrence of MPs showed a spatial trend, with the highest number and amount of MPs detected in the samples collected downstream of the WWTPs, where up to 47 MPs were detected in one single sample. A seasonal variation was observed with highest levels of MPs and highest AhR activities in samples collected in June and September 2015. However, neither the seasonal activity nor the on-site activity could be explained by the measured MPs, suggesting unknown contributory agents in the water. PMID- 30464318 TI - Another view on Gilbert damping in two-dimensional ferromagnets. AB - A keen interest towards technological implications of spin-orbit driven magnetization dynamics requests a proper theoretical description, especially in the context of a microscopic framework, to be developed. Indeed, magnetization dynamics is so far approached within Landau-Lifshitz-Gilbert equation which characterizes torques on magnetization on purely phenomenological grounds. Particularly, spin-orbit coupling does not respect spin conservation, leading thus to angular momentum transfer to lattice and damping as a result. This mechanism is accounted by the Gilbert damping torque which describes relaxation of the magnetization to equilibrium. In this study we work out a microscopic Kubo Streda formula for the components of the Gilbert damping tensor and apply the elaborated formalism to a two-dimensional Rashba ferromagnet in the weak disorder limit. We show that an exact analytical expression corresponding to the Gilbert damping parameter manifests linear dependence on the scattering rate and retains the constant value up to room temperature when no vibrational degrees of freedom are present in the system. We argue that the methodology developed in this paper can be safely applied to bilayers made of non- and ferromagnetic metals, e.g., CoPt. PMID- 30464317 TI - The absence of SigX results in impaired carbon metabolism and membrane fluidity in Pseudomonas aeruginosa. AB - In Pseudomonas aeruginosa, SigX is an extra-cytoplasmic function sigma factor that belongs to the cell wall stress response network. In previous studies, we made the puzzling observation that sigX mutant growth was severely affected in rich lysogeny broth (LB) but not in minimal medium. Here, through comparative transcriptomic and proteomic analysis, we show that the absence of SigX results in dysregulation of genes, whose products are mainly involved in transport, carbon and energy metabolisms. Production of most of these genes is controlled by carbon catabolite repression (CCR), a key regulatory system than ensures preferential carbon source uptake and utilization, substrate prioritization and metabolism. The strong CCR response elicited in LB was lowered in a sigX mutant, suggesting altered nutrient uptake. Since the absence of SigX affects membrane composition and fluidity, we suspected membrane changes to cause such phenotype. The detergent polysorbate 80 (PS80) can moderately destabilize the envelope resulting in non-specific increased nutrient intake. Remarkably, growth, membrane fluidity and expression of dysregulated genes in the sigX mutant strain were restored in LB supplemented with PS80. Altogether, these data suggest that SigX is indirectly involved in CCR regulation, possibly via its effects on membrane integrity and fluidity. PMID- 30464321 TI - The wetter the better. PMID- 30464320 TI - Physical origin of higher-order soliton fission in nanophotonic semiconductor waveguides. AB - Supercontinuum generation in Kerr media has become a staple of nonlinear optics. It has been celebrated for advancing the understanding of soliton propagation as well as its many applications in a broad range of fields. Coherent spectral broadening of laser light is now commonly performed in laboratories and used in commercial "white light" sources. The prospect of miniaturizing the technology is currently driving experiments in different integrated platforms such as semiconductor on insulator waveguides. Central to the spectral broadening is the concept of higher-order soliton fission. While widely accepted in silica fibers, the dynamics of soliton decay in semiconductor waveguides is yet poorly understood. In particular, the role of nonlinear loss and free carriers, absent in silica, remains an open question. Here, through experiments and simulations, we show that nonlinear loss is the dominant perturbation in wire waveguides, while free-carrier dispersion is dominant in photonic crystal waveguides. PMID- 30464319 TI - Interplay among steroids, body condition and immunity in response to long-term captivity in toads. AB - Stressful experiences can promote harmful effects on physiology and fitness. However, stress-mediated hormonal and immune changes are complex and may be highly dependent on body condition. Here, we investigated captivity-associated stress effects, over 7, 30, 60, and 90 days on plasma corticosterone (CORT) and testosterone (T) levels, body index, and innate immunity (bacterial killing ability and phagocytosis of peritoneal cells) in toads (Rhinella icterica). Toads in captivity exhibited elevated CORT and decreased T and immunity, without changes in body index. The inter-relationships between these variables were additionally contrasted with those obtained previously for R. schneideri, a related species that exhibited extreme loss of body mass under the same captive conditions. While T and phagocytosis were positively associated in both species, the relationship between CORT and bacterial killing ability was dependent on body index alterations. While CORT and bacterial killing ability were positively associated for toads that maintained body index, CORT was negatively associated with body index in toads that lost body mass over time in captivity. In these same toads, body index was positively associated with bacterial killing ability. These results demonstrate that steroids-immunity inter-relationships arising from prolonged exposure to a stressor in toads are highly dependent on body condition. PMID- 30464322 TI - Magnetic control of a reaction path. PMID- 30464324 TI - Redox activity goes organic. PMID- 30464323 TI - Promethium puzzles. PMID- 30464325 TI - Exploiting evolution. PMID- 30464326 TI - Neurofilament heavy polypeptide protects against reduction in synaptopodin expression and prevents podocyte detachment. AB - Podocytes are highly specialized cells that line the glomerulus of the kidney and play a role in filtration. Podocyte injury plays a critical role in the development of many kidney diseases, but the underlying mechanisms remain unclear. In this study, we identified that neurofilament heavy polypeptide (NEFH), an intermediate filament component, protects podocyte from injury. We observed that NEFH was upregulated after ADRIAMYCIN(ADR)-induced podocyte injury in both mice and cultured murine podocytes. Immunofluorescence and co immunoprecipitation analyses revealed that NEFH was colocalized with synaptopodin, a podocyte-specific marker. High NEFH expression in podocytes prevented the Adriamycin-induced reduction in synaptopodin expression. The siRNA mediated knockdown of NEFH in podocytes reduced the number of vinculin-containing focal contacts, thereby reducing adhesion to the extracellular matrix and increasing podocyte detachment. In addition, NEFH expression was significantly increased in renal biopsy specimens from patients with focal segmental glomerulosclerosis and membranous nephropathy, but in those with minimal change disease. These findings indicate that NEFH is expressed in podocytes during the disease course and that it prevents the reduction in synaptopodin expression and detachment of podocytes. PMID- 30464327 TI - Live E. coli bacteria label-free sensing using a microcavity in-line Mach-Zehnder interferometer. AB - The paper presents the first study to date on selective label-free biosensing with a microcavity in-line Mach-Zehnder interferometer induced in an optical fiber. The sensing structures were fabricated in a single-mode fiber by femtosecond laser micromachining. In contrast to other studies of this sensing scheme, where only the sensitivity to refractive index changes in the cavity was investigated, this research used chemical surface treatment of the sensor to ensure detection specificity. Immobilized MS2 bacteriophages were applied as recognition elements specifically targeting live E. coli C3000 bacteria. It is shown that the sensor allows for real-time monitoring of biological phenomena taking place on the surface of the microcavity. The developed biosensor exhibits ultrahigh refractive index sensitivity of 15,000 nm/RIU and is capable of detecting live E. coli bacteria concentrations as low as 100 colony forming units (CFU)/mL in liquid volume as low as picoliters. PMID- 30464328 TI - Correction: 18F-FIBT may expand PET for beta-amyloid imaging in neurodegenerative diseases. AB - The author listing has been updated to indicate that Timo Grimmer and Kuangyu Shi are equally contributing authors. PMID- 30464329 TI - Correction: Healthy dietary indices and risk of depressive outcomes: a systematic review and meta-analysis of observational studies. AB - This article was originally published under standard licence, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the paper have been modified accordingly. PMID- 30464330 TI - Correction: Integrative approach to sporadic Alzheimer's disease: deficiency of TYROBP in cerebral Abeta amyloidosis mouse normalizes clinical phenotype and complement subnetwork molecular pathology without reducing Abeta burden. AB - This article was originally published under standard licence, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the paper have been modified accordingly. PMID- 30464332 TI - B-cell-specific accumulation of inclusion bodies loaded with HLA class II molecules in patients with mucolipidosis II (I-cell disease). AB - BACKGROUND: I-cell disease is characterized by the presence of vacuole-like inclusions in lymphocytes. However, the nature and clinical significance of these inclusions have seldom been characterized. In this study, the authors tried to elucidate the distribution in different lymphocyte subpopulations, and the histological nature of the inclusions. METHODS: Blood samples from three unrelated patients were analyzed. Lymphocyte subpopulations were separated using monoclonal antibodies conjugated to immunomagnetic beads. Cytochemical studies were performed using FITC-conjugated lectins. The expressions of surface and cytoplasmic class II molecules were analyzed by flow cytometry. RESULTS: Virtually all B cells from the patients contained the inclusions. In contrast, CD4+ T cells, CD8+ T cells, natural killer cells, monocytes, or neutrophils did not contain the inclusions. Both fibroblasts and B cells from I-cell patients were stained intensely by multiple FITC-conjugated lectins with distinct binding profiles. The inclusions of B cells were stained intensely by fluorescence conjugated antibodies against class II antigens. CONCLUSIONS: Inclusions in I cell disease reflect the accumulation of HLA class II molecules within B cells. These results suggest a potential role for N-acetylglucosamine-1 phosphotransferase in immune functions. Furthermore, the fact that only B cells contain the inclusions provides a novel diagnostic aid for the diagnosis of I cell disease. PMID- 30464331 TI - Preventing bronchopulmonary dysplasia: new tools for an old challenge. AB - Bronchopulmonary dysplasia (BPD) is the most prevalent chronic lung disease in infants and presents as a consequence of preterm birth. Due to the lack of effective preventive and treatment strategies, BPD currently represents a major therapeutic challenge that requires continued research efforts at the basic, translational, and clinical levels. However, not all very low birth weight premature babies develop BPD, which suggests that in addition to known gestational age and intrauterine and extrauterine risk factors, other unknown factors must be involved in this disease's development. One of the main goals in BPD research is the early prediction of very low birth weight infants who are at risk of developing BPD in order to initiate the adequate preventive strategies. Other benefits of determining the risk of BPD include providing prognostic information and stratifying infants for clinical trial enrollment. In this article, we describe new opportunities to address BPD's complex pathophysiology by identifying prognostic biomarkers and develop novel, complex in vitro human lung models in order to develop effective therapies. These therapies for protecting the immature lung from injury can be developed by taking advantage of recent scientific progress in -omics, 3D organoids, and regenerative medicine. PMID- 30464333 TI - Anti-thymic stromal lymphopoietin antibody suppresses airway remodeling in asthma through reduction of MMP and CTGF. AB - BACKGROUND: Thymic stromal lymphopoietin (TSLP) mediates immune reaction in patients with asthma. Matrix metalloproteinase (MMP), connective tissue growth factor (CTGF), and transforming growth factor-beta (TGF-beta) are inflammatory mediators whose responses to the anti-TSLP antibody are unknown. This study examined the effect of an anti-TSLP antibody on MMP, CTGF, TGF-beta, and airway structural changes in airway remodeling in asthma. METHODS: Mice were randomly divided into phosphate-buffered-saline-challenged (PBS), ovalbumin-challenged (OVA), and ovalbumin-challenged with anti-TSLP antibody (OVA + anti-TSLP) groups. Airway responsiveness and serum ovalbumin-specific immunoglobulin E were measured. Differential cell counts and MMP-2 and MMP-9 were evaluated in bronchoalveolar lavage fluid (BALF). Airway structural changes were quantified using morphometric analysis and presentation by immunohistochemistry staining. Lung CTGF, TGF-beta, and TSLP were analyzed using western blot. RESULTS: Airway responsiveness was significantly lower in OVA + anti-TSLP and PBS groups than in OVA group. Airway structural changes exhibited less smooth muscle thickness in OVA + anti-TSLP and PBS groups than in OVA group. MMP-2 and MMP-9 in BALF and CTGF, TGF-beta, and TSLP in lungs significantly decreased in OVA + anti-TSLP and PBS groups compared with OVA group. CONCLUSION: Anti-TSLP antibody exerts the preventive effect of decreasing airway structural changes through reduction of MMP, TGF-beta, and CTGF in airway remodeling of asthma. PMID- 30464334 TI - Calendar of Courses, Symposiums and Conferences. AB - American Journal of Gastroenterology is pleased to publish notices of educational events relating to topics covered in the Journal. Announcements in this column are limited to the dates, title, location, and main sponsor of the course; and the name, address, and telephone and fax numbers for further information. PMID- 30464336 TI - Continuing Medical Education Questions: November 2018. PMID- 30464335 TI - Continuing Medical Education Questions: November 2018. PMID- 30464337 TI - TIC236 links the outer and inner membrane translocons of the chloroplast. AB - The two-membrane envelope is a defining feature of chloroplasts. Chloroplasts evolved from a Gram-negative cyanobacterial endosymbiont. During evolution, genes of the endosymbiont have been transferred to the host nuclear genome. Most chloroplast proteins are synthesized in the cytosol as higher-molecular-mass preproteins with an N-terminal transit peptide. Preproteins are transported into chloroplasts by the TOC and TIC (translocons at the outer- and inner-envelope membranes of chloroplasts, respectively) machineries1,2, but how TOC and TIC are assembled together is unknown. Here we report the identification of the TIC component TIC236; TIC236 is an integral inner-membrane protein that projects a 230-kDa domain into the intermembrane space, which binds directly to the outer membrane channel TOC75. The knockout mutation of TIC236 is embryonically lethal. In TIC236-knockdown mutants, a smaller amount of the inner-membrane channel TIC20 was associated with TOC75; the amount of TOC-TIC supercomplexes was also reduced. This resulted in a reduced import rate into the stroma, though outer-membrane protein insertion was unaffected. The size and the essential nature of TIC236 indicate that-unlike in mitochondria, in which the outer- and inner-membrane translocons exist as separate complexes and a supercomplex is only transiently assembled during preprotein translocation3,4-a long and stable protein bridge in the intermembrane space is required for protein translocation into chloroplasts. Furthermore, TIC236 and TOC75 are homologues of bacterial inner-membrane TamB5 and outer-membrane BamA, respectively. Our evolutionary analyses show that, similar to TOC75, TIC236 is preserved only in plants and has co-evolved with TOC75 throughout the plant lineage. This suggests that the backbone of the chloroplast protein-import machinery evolved from the bacterial TamB-BamA protein secretion system. PMID- 30464338 TI - Somatic APP gene recombination in Alzheimer's disease and normal neurons. AB - The diversity and complexity of the human brain are widely assumed to be encoded within a constant genome. Somatic gene recombination, which changes germline DNA sequences to increase molecular diversity, could theoretically alter this code but has not been documented in the brain, to our knowledge. Here we describe recombination of the Alzheimer's disease-related gene APP, which encodes amyloid precursor protein, in human neurons, occurring mosaically as thousands of variant 'genomic cDNAs' (gencDNAs). gencDNAs lacked introns and ranged from full-length cDNA copies of expressed, brain-specific RNA splice variants to myriad smaller forms that contained intra-exonic junctions, insertions, deletions, and/or single nucleotide variations. DNA in situ hybridization identified gencDNAs within single neurons that were distinct from wild-type loci and absent from non neuronal cells. Mechanistic studies supported neuronal 'retro-insertion' of RNA to produce gencDNAs; this process involved transcription, DNA breaks, reverse transcriptase activity, and age. Neurons from individuals with sporadic Alzheimer's disease showed increased gencDNA diversity, including eleven mutations known to be associated with familial Alzheimer's disease that were absent from healthy neurons. Neuronal gene recombination may allow 'recording' of neural activity for selective 'playback' of preferred gene variants whose expression bypasses splicing; this has implications for cellular diversity, learning and memory, plasticity, and diseases of the human brain. PMID- 30464339 TI - Quantum control of surface acoustic-wave phonons. AB - One of the hallmarks of quantum physics is the generation of non-classical quantum states and superpositions, which has been demonstrated in several quantum systems, including ions, solid-state qubits and photons. However, only indirect demonstrations of non-classical states have been achieved in mechanical systems, despite the scientific appeal and technical utility of such a capability1,2, including in quantum sensing, computation and communication applications. This is due in part to the highly linear response of most mechanical systems, which makes quantum operations difficult, as well as their characteristically low frequencies, which hinder access to the quantum ground state3-7. Here we demonstrate full quantum control of the mechanical state of a macroscale mechanical resonator. We strongly couple a surface acoustic-wave8 resonator to a superconducting qubit, using the qubit to control and measure quantum states in the mechanical resonator. We generate a non-classical superposition of the zero- and one-phonon Fock states and map this and other states using Wigner tomography9 14. Such precise, programmable quantum control is essential to a range of applications of surface acoustic waves in the quantum limit, including the coupling of disparate quantum systems15,16. PMID- 30464340 TI - Creation and control of multi-phonon Fock states in a bulk acoustic-wave resonator. AB - Quantum states of mechanical motion can be important resources for quantum information, metrology and studies of fundamental physics. Recent demonstrations of superconducting qubits coupled to acoustic resonators have opened up the possibility of performing quantum operations on macroscale motional modes1-3, which can act as long-lived quantum memories or transducers. In addition, they can potentially be used to test decoherence mechanisms in macroscale objects and other modifications to standard quantum theory4,5. Many of these applications call for the ability to create and characterize complex quantum states, such as states with a well defined phonon number, also known as phonon Fock states. Such capabilities require fast quantum operations and long coherence times of the mechanical mode. Here we demonstrate the controlled generation of multi-phonon Fock states in a macroscale bulk acoustic-wave resonator. We also perform Wigner tomography and state reconstruction to highlight the quantum nature of the prepared states6. These demonstrations are made possible by the long coherence times of our acoustic resonator and our ability to selectively couple a superconducting qubit to individual phonon modes. Our work shows that circuit quantum acoustodynamics7 enables sophisticated quantum control of macroscale mechanical objects and opens up the possibility of using acoustic modes as quantum resources. PMID- 30464341 TI - Mannose impairs tumour growth and enhances chemotherapy. AB - It is now well established that tumours undergo changes in cellular metabolism1. As this can reveal tumour cell vulnerabilities and because many tumours exhibit enhanced glucose uptake2, we have been interested in how tumour cells respond to different forms of sugar. Here we report that the monosaccharide mannose causes growth retardation in several tumour types in vitro, and enhances cell death in response to major forms of chemotherapy. We then show that these effects also occur in vivo in mice following the oral administration of mannose, without significantly affecting the weight and health of the animals. Mechanistically, mannose is taken up by the same transporter(s) as glucose3 but accumulates as mannose-6-phosphate in cells, and this impairs the further metabolism of glucose in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and glycan synthesis. As a result, the administration of mannose in combination with conventional chemotherapy affects levels of anti-apoptotic proteins of the Bcl-2 family, leading to sensitization to cell death. Finally we show that susceptibility to mannose is dependent on the levels of phosphomannose isomerase (PMI). Cells with low levels of PMI are sensitive to mannose, whereas cells with high levels are resistant, but can be made sensitive by RNA-interference-mediated depletion of the enzyme. In addition, we use tissue microarrays to show that PMI levels also vary greatly between different patients and different tumour types, indicating that PMI levels could be used as a biomarker to direct the successful administration of mannose. We consider that the administration of mannose could be a simple, safe and selective therapy in the treatment of cancer, and could be applicable to multiple tumour types. PMID- 30464342 TI - Methicillin-resistant Staphylococcus aureus alters cell wall glycosylation to evade immunity. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of difficult-to-treat, often fatal infections in humans1,2. Most humans have antibodies against S. aureus, but these are highly variable and often not protective in immunocompromised patients3. Previous vaccine development programs have not been successful4. A large percentage of human antibodies against S. aureus target wall teichoic acid (WTA), a ribitol-phosphate (RboP) surface polymer modified with N-acetylglucosamine (GlcNAc)5,6. It is currently unknown whether the immune evasion capacities of MRSA are due to variation of dominant surface epitopes such as those associated with WTA. Here we show that a considerable proportion of the prominent healthcare-associated and livestock associated MRSA clones CC5 and CC398, respectively, contain prophages that encode an alternative WTA glycosyltransferase. This enzyme, TarP, transfers GlcNAc to a different hydroxyl group of the WTA RboP than the standard enzyme TarS7, with important consequences for immune recognition. TarP-glycosylated WTA elicits 7.5 40-fold lower levels of immunoglobulin G in mice than TarS-modified WTA. Consistent with this, human sera contained only low levels of antibodies against TarP-modified WTA. Notably, mice immunized with TarS-modified WTA were not protected against infection with tarP-expressing MRSA, indicating that TarP is crucial for the capacity of S. aureus to evade host defences. High-resolution structural analyses of TarP bound to WTA components and uridine diphosphate GlcNAc (UDP-GlcNAc) explain the mechanism of altered RboP glycosylation and form a template for targeted inhibition of TarP. Our study reveals an immune evasion strategy of S. aureus based on averting the immunogenicity of its dominant glycoantigen WTA. These results will help with the identification of invariant S. aureus vaccine antigens and may enable the development of TarP inhibitors as a new strategy for rendering MRSA susceptible to human host defences. PMID- 30464343 TI - Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release. AB - Development and routine tissue homeostasis require a high turnover of apoptotic cells. These cells are removed by professional and non-professional phagocytes via efferocytosis1. How a phagocyte maintains its homeostasis while coordinating corpse uptake, processing ingested materials and secreting anti-inflammatory mediators is incompletely understood1,2. Here, using RNA sequencing to characterize the transcriptional program of phagocytes actively engulfing apoptotic cells, we identify a genetic signature involving 33 members of the solute carrier (SLC) family of membrane transport proteins, in which expression is specifically modulated during efferocytosis, but not during antibody-mediated phagocytosis. We assessed the functional relevance of these SLCs in efferocytic phagocytes and observed a robust induction of an aerobic glycolysis program, initiated by SLC2A1-mediated glucose uptake, with concurrent suppression of the oxidative phosphorylation program. The different steps of phagocytosis2-that is, 'smell' ('find-me' signals or sensing factors released by apoptotic cells), 'taste' (phagocyte-apoptotic cell contact) and 'ingestion' (corpse internalization)-activated distinct and overlapping sets of genes, including several SLC genes, to promote glycolysis. SLC16A1 was upregulated after corpse uptake, increasing the release of lactate, a natural by-product of aerobic glycolysis3. Whereas glycolysis within phagocytes contributed to actin polymerization and the continued uptake of corpses, lactate released via SLC16A1 promoted the establishment of an anti-inflammatory tissue environment. Collectively, these data reveal a SLC program that is activated during efferocytosis, identify a previously unknown reliance on aerobic glycolysis during apoptotic cell uptake and show that glycolytic by-products of efferocytosis can influence surrounding cells. PMID- 30464345 TI - Helios is a key transcriptional regulator of outer hair cell maturation. AB - The sensory cells that are responsible for hearing include the cochlear inner hair cells (IHCs) and outer hair cells (OHCs), with the OHCs being necessary for sound sensitivity and tuning1. Both cell types are thought to arise from common progenitors; however, our understanding of the factors that control the fate of IHCs and OHCs remains limited. Here we identify Ikzf2 (which encodes Helios) as an essential transcription factor in mice that is required for OHC functional maturation and hearing. Helios is expressed in postnatal mouse OHCs, and in the cello mouse model a point mutation in Ikzf2 causes early-onset sensorineural hearing loss. Ikzf2cello/cello OHCs have greatly reduced prestin-dependent electromotile activity, a hallmark of OHC functional maturation, and show reduced levels of crucial OHC-expressed genes such as Slc26a5 (which encodes prestin) and Ocm. Moreover, we show that ectopic expression of Ikzf2 in IHCs: induces the expression of OHC-specific genes; reduces the expression of canonical IHC genes; and confers electromotility to IHCs, demonstrating that Ikzf2 can partially shift the IHC transcriptome towards an OHC-like identity. PMID- 30464344 TI - Structural plasticity of D3-D14 ubiquitin ligase in strigolactone signalling. AB - The strigolactones, a class of plant hormones, regulate many aspects of plant physiology. In the inhibition of shoot branching, the alpha/beta hydrolase D14 which metabolizes strigolactone-interacts with the F-box protein D3 to ubiquitinate and degrade the transcription repressor D53. Despite the fact that multiple modes of interaction between D14 and strigolactone have recently been determined, how the hydrolase functions with D3 to mediate hormone-dependent D53 ubiquitination remains unknown. Here we show that D3 has a C-terminal alpha-helix that can switch between two conformational states. The engaged form of this alpha helix facilitates the binding of D3 and D14 with a hydrolysed strigolactone intermediate, whereas the dislodged form can recognize unmodified D14 in an open conformation and inhibits its enzymatic activity. The D3 C-terminal alpha-helix enables D14 to recruit D53 in a strigolactone-dependent manner, which in turn activates the hydrolase. By revealing the structural plasticity of the SCFD3-D14 ubiquitin ligase, our results suggest a mechanism by which the E3 coordinates strigolactone signalling and metabolism. PMID- 30464346 TI - Distinct activity-gated pathways mediate attraction and aversion to CO2 in Drosophila. AB - Carbon dioxide is produced by many organic processes and is a convenient volatile cue for insects1 that are searching for blood hosts2, flowers3, communal nests4, fruit5 and wildfires6. Although Drosophila melanogaster feed on yeast that produce CO2 and ethanol during fermentation, laboratory experiments7-12 suggest that walking flies avoid CO2. Here we resolve this paradox by showing that both flying and walking Drosophila find CO2 attractive, but only when they are in an active state associated with foraging. Their aversion to CO2 at low-activity levels may be an adaptation to avoid parasites that seek CO2, or to avoid succumbing to respiratory acidosis in the presence of high concentrations of CO2 that exist in nature13,14. In contrast to CO2, flies are attracted to ethanol in all behavioural states, and invest twice the time searching near ethanol compared to CO2. These behavioural differences reflect the fact that ethanol is a unique signature of yeast fermentation, whereas CO2 is generated by many natural processes. Using genetic tools, we determined that the evolutionarily conserved ionotropic co-receptor IR25a is required for CO2 attraction, and that the receptors necessary for CO2 avoidance are not involved in this attraction. Our study lays the foundation for future research to determine the neural circuits that underlie both state- and odorant-dependent decision-making in Drosophila. PMID- 30464348 TI - U-Pb-dated flowstones restrict South African early hominin record to dry climate phases. AB - The Cradle of Humankind (Cradle) in South Africa preserves a rich collection of fossil hominins representing Australopithecus, Paranthropus and Homo1. The ages of these fossils are contentious2-4 and have compromised the degree to which the South African hominin record can be used to test hypotheses of human evolution. However, uranium-lead (U-Pb) analyses of horizontally bedded layers of calcium carbonate (flowstone) provide a potential opportunity to obtain a robust chronology5. Flowstones are ubiquitous cave features and provide a palaeoclimatic context, because they grow only during phases of increased effective precipitation6,7, ideally in closed caves. Here we show that flowstones from eight Cradle caves date to six narrow time intervals between 3.2 and 1.3 million years ago. We use a kernel density estimate to combine 29 U-Pb ages into a single record of flowstone growth intervals. We interpret these as major wet phases, when an increased water supply, more extensive vegetation cover and at least partially closed caves allowed for undisturbed, semi-continuous growth of the flowstones. The intervening times represent substantially drier phases, during which fossils of hominins and other fossils accumulated in open caves. Fossil preservation, restricted to drier intervals, thus biases the view of hominin evolutionary history and behaviour, and places the hominins in a community of comparatively dry-adapted fauna. Although the periods of cave closure leave temporal gaps in the South African fossil record, the flowstones themselves provide valuable insights into both local and pan-African climate variability. PMID- 30464349 TI - [Programa de deteccion del alelo APOE-E4 en adultos mayores mexicanos con deterioro cognitivo]. AB - Introduction: In Mexico, the prevalence of neurocognitive disorders (NCDs) has increased in parallel with the increase in life expectancy. The E4 allele of the gene that encodes apolipoprotein E (APOE) is the main genetic risk factor for cognitive impairment. Objective: To replicate the association of APOE-E4 allele with neurocognitive impairment in a Mexican population, as well as to implement a genetic risk-detection program with the APOE-E4 allele. Method: A program was structured for the detection of APOE-E4 allele risk in different recruiting centers from the central zone of the Mexican Republic, with three stages: recruitment and selection of candidates for the detection of the risk-allele, genetic risk analysis and delivery of results. Results: In the genetic association study to replicate the association with neurocognitive disorders by means of multivariate logistic models, the APOE-E4 allele increased the risk for cognitive impairment in the Mexican populations by approximately 6 % (OR: 5.83, p = 0.0025). In addition, 367 genetic risk results were delivered. Conclusions: The present program is the first one to be implemented in Mexico with the purpose to inform on a genetic risk factor for neurocognitive disorders in several centers of the country. PMID- 30464347 TI - Amphioxus functional genomics and the origins of vertebrate gene regulation. AB - Vertebrates have greatly elaborated the basic chordate body plan and evolved highly distinctive genomes that have been sculpted by two whole-genome duplications. Here we sequence the genome of the Mediterranean amphioxus (Branchiostoma lanceolatum) and characterize DNA methylation, chromatin accessibility, histone modifications and transcriptomes across multiple developmental stages and adult tissues to investigate the evolution of the regulation of the chordate genome. Comparisons with vertebrates identify an intermediate stage in the evolution of differentially methylated enhancers, and a high conservation of gene expression and its cis-regulatory logic between amphioxus and vertebrates that occurs maximally at an earlier mid-embryonic phylotypic period. We analyse regulatory evolution after whole-genome duplications, and find that-in vertebrates-over 80% of broadly expressed gene families with multiple paralogues derived from whole-genome duplications have members that restricted their ancestral expression, and underwent specialization rather than subfunctionalization. Counter-intuitively, paralogues that restricted their expression increased the complexity of their regulatory landscapes. These data pave the way for a better understanding of the regulatory principles that underlie key vertebrate innovations. PMID- 30464351 TI - Recent History of Aedes aegypti: Vector Genomics and Epidemiology Records. AB - Aedes aegypti bears the common name "the yellow fever mosquito," although, today, it is of more concern as the major vector of dengue, chikungunya, and, most recently, Zika viruses. In the present article, we review recent work on the population genetics of this mosquito in efforts to reconstruct its recent (approximately 600 years) history and relate these findings to epidemiological records of occurrences of diseases transmitted by this species. The two sources of information are remarkably congruent. Ae. aegypti was introduced to the New World 400-550 years ago from its ancestral home in West Africa via European slave trade. Ships from the New World returning to their European ports of origin introduced the species to the Mediterranean region around 1800, where it became established until about 1950. The Suez Canal opened in 1869 and Ae. aegypti was introduced into Asia by the 1870s, then on to Australia (1887) and the South Pacific (1904). PMID- 30464352 TI - Temperature-Driven Biodiversity Change: Disentangling Space and Time. AB - Temperature regimes have multiple spatial and temporal dimensions that have different impacts on biodiversity. Signatures of warming across these dimensions may contribute uniquely to the large-scale species redistributions and abundance changes that underpin community dynamics. A comprehensive review of the literature reveals that 86% of studies were focused on community responses to temperature aggregated over spatial or temporal dimensions (e.g., mean, median, or extremes). Therefore, the effects of temperature variation in space and time on biodiversity remain generally unquantified. In the present article, we argue that this focus on aggregated temperature measures may limit advancing our understanding of how communities are being altered by climate change. In light of this, we map the cause-and-effect pathways between the different dimensions of temperature change and communities in space and time. A broadened focus, shifted toward a multidimensional perspective of temperature, will allow better interpretation and prediction of biodiversity change and more robust management and conservation strategies. PMID- 30464353 TI - Poetry as a Creative Practice to Enhance Engagement and Learning in Conservation Science. AB - Creativity is crucial to the capacity to do science well, to communicate it in compelling ways, and to enhance learning. Creativity can be both practiced and enhanced to strengthen conservation science professionals' efforts to address global environmental challenges. We explore how poetry is one creative approach that can further conservation scientists' engagement and learning. We draw on evidence from peer-reviewed literature to illustrate benefits of integrating science and poetry, and to ground our argument for the growth of a science-poetry community to help conservation scientists develop skills in creative practices as a component of professional development. We present examples from literature as well as two short poetry exercises for scientists to draw on when considering writing poetry, or deciding on forms of poetry to include, in their practice. Opportunity exists to grow science-poetry projects to further our understanding of what such initiatives can offer. PMID- 30464354 TI - Corrigendum: Rethinking Living Fossils. AB - [This corrects the article DOI: 10.1093/biosci/biy084.]. PMID- 30464355 TI - Fruit Morphology and Anatomy of the Spondioid Anacardiaceae. AB - The Spondioideae subfamily of the Anacardiaceae is widely distributed today in tropical regions. Recent molecular phylogenetic investigations indicate that the Spondioideae are not monophyletic, but rather comprise at least two separate clades that are difficult to distinguish using vegetative and floral characters. Nevertheless, the syndrome of fruit characters traditionally used in identifying the subfamily is useful in discriminating genera of these clades and for identification of both modern and fossil anacardiaceous fruits. Here we document the morphology and anatomy of endocarps for representatives of all extant genera traditionally treated as Spondioideae, plus two genera that have been placed close to them in molecular investigations, Buchanania and Campnosperma. All genera are characterized by drupe-like fruits with sclerified stones that vary from uni- to multilocular depending on the genus. Germination modes vary throughout the Spondioideae. Some have characteristic plug-like opercula; others have recessed bilabiate germination valves, and still others open by apical flaps or simple slits. Although most currently recognized genera appear to be monophyletic, fruit morphology indicates that current circumscriptions of Cyrtocarpa, Poupartia and Tapirira are in need of revision. PMID- 30464356 TI - DOES UNDOCUMENTED IMMIGRATION INCREASE VIOLENT CRIME? AB - Despite substantial public, political, and scholarly attention to the issue of immigration and crime, we know little about the criminological consequences of undocumented immigration. As a result, fundamental questions about whether undocumented immigration increases violent crime remain unanswered. In an attempt to address this gap, we combine newly developed estimates of the unauthorized population with multiple data sources to capture the criminal, socioeconomic, and demographic context of all 50 states and Washington, DC, from 1990 to 2014 to provide the first longitudinal analysis of the macro-level relationship between undocumented immigration and violence. The results from fixed-effects regression models reveal that undocumented immigration does not increase violence. Rather, the relationship between undocumented immigration and violent crime is generally negative, although not significant in all specifications. Using supplemental models of victimization data and instrumental variable methods, we find little evidence that these results are due to decreased reporting or selective migration to avoid crime. We consider the theoretical and policy implications of these findings against the backdrop of the dramatic increase in immigration enforcement in recent decades. PMID- 30464357 TI - Mortality and life expectancy forecast for (comparatively) high mortality countries. AB - Background: The Lee-Carter method and its later variants are widely accepted extrapolative methods for forecasting mortality and life expectancy in industrial countries due to their simplicity and availability of high quality long time series data. Objective: We compared and contrasted mortality forecasting models for higher mortality regimes that lack long time series data of good quality, which is common in several Central and Eastern European (CEE) countries. Data and methods: We utilized seven different variants of the Lee-Carter method and coherent mortality forecasts of various CEE countries, and the Bayesian Hierarchical Model used by the United Nations to produce probabilistic forecasts. The data of nine CEE countries with comparatively higher mortality have been considered. Results: The performance of the forecasting models for the nine CEE countries was found to be lower than that observed for low-mortality countries. No model gives uniquely best performance for all the nine CEE countries. Most of the LC variants produced lower forecasts of life expectancies than current life expectancy values for Belarus, Russia, and Ukraine. A coherent mortality forecast could not overcome the limitations of single population forecasting techniques due to increasing mortality differences between these countries over the fitting period (mortality divergence). In the same context, the use of the probabilistic forecasting technique from the Bayesian framework resulted in a better forecast than some of the extrapolative methods but also produced a wider prediction interval for several countries. The more detailed analysis for Hungary indicates that a better fit of certain forecasting methods may occur in the later part of the life span rather than the whole life span. Conclusion: These findings imply the necessity of inventing a new forecasting technique for high-mortality countries. PMID- 30464358 TI - An analysis of the complementary stereoselective alkylations of imidazolidinone derivatives toward alpha-quaternary proline-based amino amides. AB - Alkylations of proline-based imidazolidinones are described based on the principle of self-regeneration of stereocenters (SRS), affording high levels of either the cis or trans configured products. Stereoselectivity is dictated solely on the nature of the "temporary" group, where isobutyraldehyde-derived imidazolidinones provide the cis configured products and 1-naphthaldehyde-derived imidazolidinones afford the complementary trans configured products. These stereodivergent products can be readily cleaved to afford both alpha-alkylated proline enantiomers from readily available L-proline. A series of imidazolidinones were alkylated to investigate the origin of the anti selectivity. Potential contributions toward the observed anti-selectivity are discussed on the basis of these experiments, suggesting a refined hypothesis for selectivity may be in order. PMID- 30464359 TI - A macrolactonization-based strategy to obtain microtuble-stabilizing agent (-) laulimalide. AB - An alternative synthesis of anti-tumor macrolide (-)-laulimalide is described. The synthesis was achieved utilizing Yamaguchi macrolactonization as the key step. The sensitive C2-C3 cis-olefin functionality has been installed by a macrolactonization of hydroxy alkynic acid and subsequent hydrogenation over Lindlar's catalyst. PMID- 30464360 TI - Convergence or Divergence? Life Expectancy Patterns in Post-communist Countries, 1959-2010. AB - In the 1960s and 1970s, the countries of Central and Eastern Europe and the Soviet Union experienced an unanticipated stagnation in the process of mortality reduction that was accelerating in the west. This was followed by even starker fluctuations and overall declines in life expectancy during the 1980s and 1990s. We identify statistically the extent to which, since the 1990s, the countries of the post-communist region have converged as a group towards other regional or cross-regional geopolitical blocks, or whether there are now multiple steady states ('convergence clubs') emerging among these countries. We apply a complex convergence club methodology, including a recursive analysis, to data on 30 OECD countries (including 11 post-communist countries) drawn from the Human Mortality Database and spanning the period 1959-2010. We find that, rather than converging uniformly on western life expectancy levels, the post-communist countries have diverged into multiple clubs, with the lowest seemingly stuck in low-level equilibria, while the best performers (e.g. Czech Republic) show signs of catching-up with the leading OECD countries. As the post-communist period has progressed, the group of transition countries themselves has become more heterogeneous and it is noticeable that distinctive gender and age patterns have emerged. We are the first to employ an empirical convergence club methodology to help understand the complex long-run patterns of life expectancy within the post communist region, one of very few papers to situate such an analysis in the context of the OECD countries, and one of relatively few to interpret the dynamics over the long-term. PMID- 30464361 TI - Effects of isometric contraction of the affected-side upper limb in the supine position on the opposite side muscle activity of the body trunk muscles of normal adults. AB - [Purpose] This study examines the effect of isometric contraction of the upper limb on the affected side in the supine position on the activity of body trunk muscles on the opposite side of normal adults. [Participants and Methods] The research participants included 10 normal adults. A handheld dynamometer device was used to measure the isometric contraction of the upper limb. The muscle activity of the body trunk was analyzed by electromyography. [Results] The muscle activities of rectus abdominis, internal oblique abdominis, erector spinae muscle, and multifidus muscle of the body trunk on the opposite side were significantly larger in the case of the adduction and flexion of the shoulder joint on the affected side than in the case of abduction and extension. [Conclusion] The isometric contraction induced by the adduction and flexion of the shoulder joint on the affected side altered the muscle activity of the body trunk on the opposite side. PMID- 30464362 TI - Effect of manual chest wall compression in participants with chronic obstructive pulmonary disease. AB - [Purpose] Pulmonary rehabilitation is appropriate for most individuals with chronic obstructive pulmonary disease (COPD). Pulmonary rehabilitation consists of conditioning and exercise therapy. Conditioning includes relaxation, breathing exercises, and manual chest wall compression during expiration (CWC). CWC improves the symptoms in individuals with respiratory disease who have undergone mechanical ventilation. However, evidence supporting the effectiveness of CWC for COPD has been insufficient. This study aimed to determine physiological responses to CWC in participants with COPD. [Participants and Methods] Twenty-nine participants with COPD were included in the study. Manual CWC techniques were performed in a comfortable position chosen by the participants (sitting, forward leaning (sitting), or semi-Fowler's). Ventilatory parameters, occlusion airway pressure (P0.1), and dyspnea were assessed using a visual analog scale and were compared before and during CWC. [Results] During manual CWC, oxygen consumption, carbon dioxide production, end-tidal carbon dioxide concentration, and dyspnea were significantly decreased; however, P0.1 was not affected. [Conclusion] Manual CWC for COPD had an immediate physiological effect, including a decrease in dyspnea that may have been facilitated by a reduced workload of the respiratory muscles. Thus, manual CWC may be effective for dyspnea by reducing oxygen consumption in the respiratory muscles. PMID- 30464363 TI - Effect of orbicularis oris muscle training on muscle strength and lip closure function in patients with stroke and swallowing disorder. AB - [Purpose] We aimed to investigate the effect of resistance training of the orbicularis oris muscles on lip muscle strength and closure function in patients with swallowing disorder with facial palsy after stroke. [Participants and Methods] This study recruited 10 patients with swallowing disorder and facial palsy after stroke. All the participants received orbicularis oris muscle training at an intensity of 70% of 1 repetition maximum by using an Iowa oral performance instrument. Muscle strength and lip closure function were evaluated after orbicularis oris muscle training. [Results] After the intervention, the orbicularis oris muscle strength showed a statistically significant increase from 20.5 +/- 5.15 to 25.3 +/- 4.2 kilopascal. Lip closure function showed a statistically significant improvement from 2.6 +/- 1.5 to 1.2 +/- 1.0. [Conclusion] This study recommends to train at an intensity of 70% of 1 repetition maximum for 4 weeks to increase theorbicularis oris muscle strength and improve lip closure function. PMID- 30464364 TI - Oropharyngeal swallowing function in patients with presbyphagia. AB - [Purpose] This study investigated the characteristics of oropharyngeal swallowing function in patients with presbyphagia. [Participants and Methods] Data for 25 patients with presbyphagia were retrospectively analyzed. The oropharyngeal swallowing function was evaluated using VDS based on videofluoroscopic swallowing study. [Results] Lip closure, mastication, laryngeal elevation, and aspiration showed a relative decrease in function. [Conclusion] This study showed a reduction in oropharyngeal swallowing in patients with presbyphagia. Our results may help in the diagnosis and treatment of presbyphagia. PMID- 30464365 TI - An exploration of the relationship between foot skin temperature and blood flow in type 2 diabetes mellitus patients: a cross-sectional study. AB - [Purpose] The current study aimed to investigate the reliability of infrared thermography as a method of determining foot skin temperature, and to determine the relationship between foot skin temperature and blood flow in type 2 diabetes mellitus (DM) patients. [Participants and Methods] Eighty-five patients were recruited and their foot skin temperature and the ankle brachial index (ABI) were measured using infrared thermography and an automated oscillometry, respectively. A correlation between foot skin temperature and blood flow was performed. The patients were screened and classified according to two groups; diabetic peripheral neuropathy (DPN) and non-DPN. Discriminant validity was determined by comparing the foot skin temperature between the two groups. [Results] The test retest reliability of foot skin temperature was high. A positive correlation was found between foot skin temperature and ABI in both feet. The foot skin temperatures in the DPN group were found to be significant lower when compared with those in the non-DPN group. [Conclusion] Foot skin temperature is an indirect method of evaluating blood flow in the feet of diabetic patients and can be used as a clinical outcome measurement of treatments used to improve blood flow in type 2 DM patients. PMID- 30464367 TI - Efficacy of scrambler therapy on breast cancer-related lymphedema. AB - [Purpose] This study aimed to determine the effect of scrambler therapy on upper extremity pain in patient who had undergone breast cancer related lymphedema. [Participant and Methods] The patient was a 39-year-old woman who developed pain and lymphedema in the right upper extremity after mastectomy. Scrambler therapy was administered once a day every 45 minutes for 10 days to patient. [Results] After 10 sessions of scrambler therapy, pain was reduced 6 points. Bioimpedence and circumference was not increased after 10 treatment sessions. [Conclusion] Thus, scrambler therapy reduced pain without increased lymphedema. PMID- 30464366 TI - Increasing the cervical and lumbar lordosis is possible despite overt osteoarthritis and spinal stenosis using extension traction to relieve low back and leg pain in a 66-year-old surgical candidate: a CBP(r) case report. AB - [Purpose] To present the case of the dramatic relief of low back pain, leg pain and disability in an older female with osteoarthritis, lumbar spinal stenosis and hypolordosis of the cervical and lumbar spine. [Participant and Methods] A 66 year-old female presented with chronic low back pain, right leg pain, numbness and weakness. Despite being recommended for surgery, the patient sought alternative treatment. The patient was treated with Chiropractic BioPhysics(r) rehabilitation of the spine with the objective to increase the lumbar and cervical lordoses. Cervical and lumbar extension exercises and traction were performed as well as spinal manipulation. Treatment was performed approximately three times per week for 6.5 months. [Results] Re-assessment after treatment demonstrated significant reduction of low back pain, leg pain and other health improvements. X-rays showed structural improvements in the cervical and lumbar spine despite advanced osteoarthritis. [Conclusion] Lumbar and cervical hypolordosis subluxation may be increased in those with spinal deformity caused symptoms, despite the presence of osteoarthritis and degenerative stenosis of the spine. Spinal x-rays as used in the assessment and monitoring of patients being treated with contemporary spinal rehabilitation methods are not harmful and should be used for routine screening purposes. PMID- 30464368 TI - Evaluation of primary headache associated with temporomandibular dysfunction in adolescents from Santos, SP, Brazil: an observational study. AB - [Purpose] Evaluate the association of primary headache and Temporomandibular Dysfunction in healthy adolescents from the Santos, SP, Brazil. [Participants and Methods] A total of 208 adolescents, aged 11 to 16 years old were randomly selected at the dentistry clinic at Universidade Metropolitana de Santos. For that, the Fonseca Anamnestic Index was applied, including information such as: limitation when opening the mouth and moving the jaw, headaches, pain in the temporomandibular joint, noises in the temporomandibular joint, and the habit of tightening or grinding the teeth. The data were submitted to descriptive statistical analysis and the chi2 test and Fisher's exact test were used to evaluate the association of categorical variables. [Results] The results were 63% of male participants, and 61% of female participants had Temporomandibular Dysfunction. In both genders headache was associated with the presence of Temporomandibular Dysfunction, with 93 participants with light headache and 39 with moderate headache. [Conclusion] There was an association between headache and the presence of Temporomandibular Dysfunction, and the percentage of affected males was slightly higher among this association. In the sample of adolescents who presented Temporomandibular Dysfunction, moderate headache was the main reported symptom of both genders. PMID- 30464369 TI - Baseline muscle tendon unit stiffness does not affect static stretching of the ankle plantar flexor muscles. AB - [Purpose] The aim of this study was to investigate the influence of baseline muscle tendon unit stiffness on static stretching. [Participants and Methods] Eighteen healthy males were divided into two groups according to their muscle tendon unit stiffness as follows: High (n=9) and Low (n=9). Flexibility assessment was performed before and after 10 minutes of static stretching. Alterations in range of motion, passive torque at the terminal range of motion, muscle tendon unit stiffness, muscle tendon junction displacement, and tendon length were examined. [Results] No significant interactions were found in all the measurements. After static stretching, the range of motion, passive torque, muscle tendon junction displacement, and tendon length increased, while muscle tendon unit stiffness decreased. There were significant differences in range of motion, muscle tendon unit stiffness, and muscle tendon junction displacement between the groups. [Conclusion] Ten minutes of static stretching increased the range of motion through a decrease in muscle tendon unit stiffness and an increase in tolerance in both groups. Differences in muscle tendon unit stiffness and muscle tendon junction displacement caused the differences in range of motion. Baseline muscle tendon unit stiffness had no effects on static stretching. PMID- 30464370 TI - Contribution of muscle activity at different gait phases for improving walking performance in chronic stroke patients with hemiparesis. AB - [Purpose] The aim of this study was to clarify the optimal timing for increasing muscle activity in the paralyzed lower limb of stroke survivors by evaluating the relationship between gait muscle activity patterns and gait parameters. [Participants and Methods] Electromyography of the tibialis anterior, soleus, rectus femoris, and biceps femoris on the paralyzed side and spatiotemporal gait parameters were evaluated in 40 chronic post-stroke patients as they walked at a comfortable speed. The normalized average amplitude and asymmetry indexes of each gait phase were calculated. The correlations between gait velocity or asymmetry indexes and the activity amplitudes of various muscles during each gait phase were analyzed. Multiple regression analysis was performed with gait velocity or asymmetry indexes as the response variable and the muscle activity amplitudes in the various gait phases as explanatory variables. [Results] The major determinants of gait velocity were the tibialis anterior activity (beta=-0.35) and biceps femoris activity (beta=0.45) during the swing phase. In addition, the biceps femoris activity during the swing phase was the major determinant of the asymmetry index for the swing phase duration (beta=-0.41). [Conclusion] For patients with hemiparesis, increasing the biceps femoris activity during the swing phase is considered optimal, which may lead to improvement in walking performance. PMID- 30464371 TI - Differences in body awareness and its effects on balance function and independence in activities of daily living for stroke. AB - [Purpose] The present study aimed to investigate the association between body awareness with postural control and independence in performing activities of daily living in patients with hemispheric stroke. Eighty-one patients who were diagnosed with stroke participated in this study. [Participants and Methods] The participants were divided into three groups according to their risk for falls. Furthermore, these participants were classified into four groups according to their degree of independence in performing activities of daily living. This study used three measuring tools, namely the body awareness questionnaire, Berg balance scale, and modified Barthel index. [Results] Body awareness was significantly correlated with balance function in the group with low risk for falls compared with that in the group with high risk for falls. Body awareness was significantly correlated with the degree of independence in performing activities of daily living in the group that needed minimal assistance compared with the groups that needed moderate and severe assistance. Results showed that body awareness was associated with postural control and the degree of independence in performing activities of daily living in individuals with hemiparetic stroke. [Conclusion] Body awareness is among the primary factors that affect the motor function of patients with stroke in rehabilitation settings. PMID- 30464372 TI - The effect of core stabilization exercise on lumbar joint position sense in patients with subacute non-specific low back pain: a randomized controlled trial. AB - [Purpose] This study aimed to examine the effect of core stabilization exercise (CSE) on joint position sense, pain intensity, and functional disability in patients with subacute non-specific low back pain (NSLBP). [Participants and Methods] Thirty-eight participants with subacute nonspecific low back pain of 6 12 weeks duration, aged 18-60 years, were included in this study. Participants were randomly divided into two groups: a core stabilization exercise group (n=19) or a control group (n=19). Outcomes measures included lumbar joint repositioning error (LJRE), numeric pain rating scale (11-NRS), and the Roland-Morris disability questionnaires (RMDQ). Measures were taken at baseline, 4 weeks, 7 weeks of intervention, and at 4 weeks after the last intervention. [Results] All outcomes measures were significantly improved in the core stabilization exercise group, compared with the control group. [Conclusion] Core stabilization exercise can improve acuity of joint position sense, reduce pain, and functional disability compared with thermal therapy. The finding demonstrated that core stabilization exercises are more suitable for patients with subacute NSLBP than thermal therapy and this should be useful to clinicians. PMID- 30464374 TI - Periodic Solutions of Asymptotically Linear Autonomous Hamiltonian Systems with Resonance. AB - In this paper we define the index at infinity of an asymptotically linear autonomous Hamiltonian system. We use this index to prove the existence and bifurcation from infinity of periodic solutions of the system. We apply the degree for G-invariant strongly indefinite functionals defined by Golebiewska and Rybicki in (Nonlinear Anal 74:1823-1834, 2011). PMID- 30464373 TI - Real-world evidence research based on big data: Motivation-challenges-success factors. AB - Background: In recent years there has been an increasing, partially also critical interest in understanding the potential benefits of generating real-world evidence (RWE) in medicine. Objectives: The benefits and limitations of RWE in the context of randomized controlled trials (RCTs) are described along with a view on how they may complement each other as partners in the generation of evidence for clinical oncology. Moreover, challenges and success factors in building an effective RWE network of cooperating cancer centers are analyzed and discussed. Material and methods: This article is based on a selective literature search (predominantly 2015-2017) combined with our practical experience to date in establishing European oncology RWE networks. Results: RWE studies can be highly valuable and complementary to RCTs due to their high external validity. If cancer centers successfully address the various challenges in the establishment of an effective RWE study network and in the consequent execution of studies, they may efficiently generate high-quality research findings on treatment effectiveness and safety. Concerns pertaining to data privacy are of utmost importance and discussed accordingly. Securing data completeness, accuracy, and a common data structure on routinely collected disease and treatment-related data of patients with cancer is a challenging task that requires high engagement of all participants in the process. Conclusion: Based on the discussed prerequisites, the analysis of comprehensive and complex real-world data in the context of a RWE study network represents an important and promising complementary partner to RCTs. This enables research into the general quality of cancer care and can permit comparative effectiveness studies across partner centers. Moreover, it will provide insights into a broader optimization of cancer care, refined therapeutic strategies for patient subgroups as well as avenues for further research in oncology. PMID- 30464375 TI - Yum-Me: A Personalized Nutrient-Based Meal Recommender System. AB - Nutrient-based meal recommendations have the potential to help individuals prevent or manage conditions such as diabetes and obesity. However, learning people's food preferences and making recommendations that simultaneously appeal to their palate and satisfy nutritional expectations are challenging. Existing approaches either only learn high-level preferences or require a prolonged learning period. We propose Yum-me, a personalized nutrient-based meal recommender system designed to meet individuals' nutritional expectations, dietary restrictions, and fine-grained food preferences. Yum-me enables a simple and accurate food preference profiling procedure via a visual quiz-based user interface and projects the learned profile into the domain of nutritionally appropriate food options to find ones that will appeal to the user. We present the design and implementation of Yum-me and further describe and evaluate two innovative contributions. The first contriution is an open source state-of-the art food image analysis model, named FoodDist. We demonstrate FoodDist's superior performance through careful benchmarking and discuss its applicability across a wide array of dietary applications. The second contribution is a novel online learning framework that learns food preference from itemwise and pairwise image comparisons. We evaluate the framework in a field study of 227 anonymous users and demonstrate that it outperforms other baselines by a significant margin. We further conducted an end-to-end validation of the feasibility and effectiveness of Yum-me through a 60-person user study, in which Yum-me improves the recommendation acceptance rate by 42.63%. PMID- 30464376 TI - Caring as a Facilitator of Sensitive Research Studies with Immigrant Latino Families. AB - Although caring is a fundamental concept in nursing, it is underutilized in our research with underserved populations and communities. Disch's definition of patient-centered care was adapted to define the elements of caring in research work with underserved communities. The study's purpose was to demonstrate how to conceptualize and operationalize caring in the research process. Demonstrating caring in our attitudes and actions is essential to the success of our research work. The proposed research process aids in applying caring into our engagement with community stakeholders and recruitment of minority participants, whether we conduct community-based participatory research or clinical trials. PMID- 30464377 TI - Polypoidal choroidal vasculopathy (PCV): the 4-year review of the real-life treatment experiences. AB - Purpose: The purpose of this article was to study the real-life treatment results of polypoidal choroidal vasculopathy (PCV). Design: This was a retrospective study. Methods: Patients with presumed age-related macular degeneration were reviewed, and PCV diagnosis was made using the EVEREST study criteria. Outcomes were changes in visual acuity (VA) and central retinal thickness, time between treatments, follow-up time, and number of treatments. Results: The prevalence of PCV was 30.8%. At the beginning, 195 eyes received monotherapy of anti-vascular endothelial growth factor (anti-VEGF) injections, either bevacizumab or ranibizumab, and only six eyes received the combination of anti-VEGF injection and photodynamic therapy (PDT) at the time of the first treatment. During the follow-up, some patients received "rescue or add-on" PDT when they had a poor response after anti-VEGF injections. After 4 years, the average number of injections was 8.25 and 9.15 for the anti-VEGF monotherapy and the combination groups, respectively. The average time between the first anti-VEGF injections and the first PDT was 21.4 months. The average VA in the anti-VEGF monotherapy group increased by 1.5 letters, whereas it decreased by 0.95 letters in the combination group (P=0.48). Conclusion: The review demonstrated the same visual outcomes between the combination therapy of anti-VEGF injections and rescue or add-on PDT vs monotherapy anti-VEGF injections in PCV treatment. When compared with EVEREST II and Planet studies, the "initial" or "rescue or add-on PDT" might have different effects on the final visual outcomes. PMID- 30464378 TI - A comparison of NCT, Goldman application tonometry values with and without fluorescein. AB - Purpose: The aim of the study was to statistically compare intraocular pressure (IOP) values measured using noncontact tonometer (NCT), Goldmann applanation tonometry (GAT) with fluorescein (fGAT), and GAT without fluorescein (nGAT). The study was also performed to test whether the values obtained using each technique change in accordance with the central corneal thickness (CCT) and refractive and keratometric values. Study design: This study was a prospective study of 188 eyes of 94 healthy volunteers. Methods: IOP was measured using fGAT, nGAT and NCT. CCT, refractive values, and keratometric values were measured, and the correlations and differences in the IOP for each tonometer were investigated. Results: The mean IOP values obtained with the NCT, nGAT, and fGAT were 17.5+/ 3.7, 12.3+/-2.7, and 12.5+/-2 mmHg. The mean CCT was 538.2+/-34.4 um, the mean refractive value was 0.9+/-1.2 D, and the mean keratometric value was 43.5+/-1.5 D. NCT was positively correlated with fGAT and GAT values and was significantly higher than both the values. There were no differences between fGAT and GAT values. No correlation was observed between the CCT and keratometric and refractive values and the difference between NCT and nGAT or fGAT. Conclusion: Differences in the measurements obtained using nGAT and fGAT were insignificant (P>0.05). Both values were positively correlated with NCT measurements (r =0.354, P<0.05) and were independent of CCT, keratometry, and refraction values. nGAT appears to be suitable for use in routine clinic practice. PMID- 30464379 TI - Treatment patterns in diabetic macular edema in Taiwan: a retrospective chart review. AB - Objectives: To characterize diabetic macular edema (DME) treatment patterns in Taiwan and examine their impact on health care resource utilization and visual and anatomic outcomes. Methods: Retrospective, observational cohort study of longitudinal data from medical records of five hospital ophthalmology clinics. Patients with type 2 diabetes and DME who received >=1 laser treatment or pharmacotherapy (intravitreal/subtenon corticosteroids and/or intravitreal anti vascular endothelial growth factor [VEGF] agents) between January 2012 and December 2013 (index period) and attended >=1 follow-up visit after the first treatment during that period were identified (prevalent population, N=431). In addition, a subset that received no anti-VEGFs before 2012 (anti-VEGF-naive population, N=77) was analyzed. Outcome measures were change in DME treatment distribution between January 2009 and December 2014 and health care resource utilization over up to 3 years from the first DME treatment received in the index period (prevalent population), mean number of anti-VEGF injections and change from baseline in visual acuity and central macular thickness over 12 months (anti VEGF-naive population). Results: Between 2009 and 2014, laser treatment use declined, overall use of anti-VEGFs increased, and bevacizumab use decreased proportionately as ranibizumab use increased. Patients receiving corticosteroids and anti-VEGFs in the first 6 months post-index had greater health care resource utilization than those treated with laser, corticosteroids, or anti-VEGF alone (P<0.0001, cross-cohort comparison). Among anti-VEGF-naive patients, 69% received one to four anti-VEGF injections in the first year post-index. Overall, visual acuity improvement from baseline was minimal at 1 year (0.4 letters, observed data; 0.1 letters, last observation carried forward), and modest central macular thickness reduction (28 um [last observation carried forward]) was detected. Conclusion: In Taiwanese clinics, DME treatment patterns have shifted from use of laser to anti-VEGFs (with higher health care resource utilization); however, few patients receive anti-VEGF injections at the frequency reported in landmark trials, consistent with poorer visual outcomes. Effective alternative treatments with lower treatment burden should be considered. PMID- 30464380 TI - Universal eye health in Odisha, India, Sunetra. Report # 1. Program planning. AB - Purpose: To describe the program planning of Sunetra (Healthy Eyes), the universal eye health coverage in the Indian state Odisha. Methods: The Indian state of Odisha launched the universal eye health coverage in October 2017. This is the first Indian state to officially respond to the World Health Organization's Global Action Plan. Results: The Government of Odisha pledged INR 6,820 million (US$ 100 million approximately) spread over 5 years. Each third of the pledged money is allocated for immediate direct benefit, building the infrastructure and human resources, and creating a digital eye health platform for uniform documentation and policy planning. Conclusion: It is hoped that at the end of 5 years, by 2022, the state will attain the goals prescribed in the Global Action Plan in eye care. PMID- 30464381 TI - Posterior uveal melanoma in adolescents and children: current perspectives. AB - Recognizing that <1% of all uveal melanomas occur in young persons, and that very few clinicians encounter more than a few such cases over an extended career, we felt that a retrospective review of literature and sharing of our clinical experience would be appropriate to remind readers about this age subgroup of patients with posterior uveal melanoma. This interest stems from the increase in reported cases of uveal melanoma in younger individuals and recent advances in the field. PMID- 30464382 TI - Relationships between retinal break locations and the shapes of the detachments. AB - Purpose: Detecting primary breaks and confirming detachment preoperatively are important. Lincoff stated that retinal detachments progress according to gravity; his law has become popular. We evaluated Lincoff's law with a slight modification to determine whether it remains suitable for present cases independent of refractive error and previous cataract surgery. Patients and methods: Group 1 included superior region detachments not exceeding the 12 o'clock midline; the original break was within 1 1/2 clock hours of the highest detachment border. Group 2 included shallow inferior detachment; the original break corresponded to the more spread side of the 6 o'clock midline. Group 3 detachments were beyond 12 o'clock; the original break was within a triangle with a 12 o'clock apex (A) or within 1 1/2 hours of 12 o'clock (B); (A) and (B) were stated in the original report. Another five classifications were applied for small numbers of detachments. Consecutive initial rhegmatogenous retinal detachment surgery patients were included; medical records and detachment charts were examined. Eyes were classified into categories and rates were calculated. Eyes that had never undergone previous cataract surgery besides those in which the macula remained attached were divided into groups at a -6 D cutoff (Groups 1, 2, and 3[B]); we compared groups in each category. We compared phakic eyes, pseudophakic eyes, and eyes ruptured at the posterior capsule (Groups 1, 2, and 3[B]). Results: Finally, 747 eyes were categorized. In Groups 1, 2, 3(A), and 3(B), corresponding rates were 92, 86, 70, and 89%, respectively. Between the above and below -6 D groups, there was no significant difference in rate in any category. There were no significant differences between phakic, pseudophakic, and ruptured eyes. Conclusion: Lincoff's law was suitable for the present cases and independent of refractive error and previous cataract surgery. PMID- 30464384 TI - Comparison of visual performance of toric vs non-toric intraocular lenses with same material. AB - Aim: We compared the visual performance of toric intraocular lenses (IOLs) and non-toric IOLs made of the same material. Patients and materials: The subjects included patients implanted with either Acrysof IQ(r) toric IOLs (SN6AT3-9) or Acrysof IQ(r) IOLs (SN60WF) bilaterally. The toric group included 103 patients who were implanted with Acrysof IQ toric IOLs bilaterally. The non-toric group was a corneal astigmatism-matched control group and included 103 patients who were implanted with Acrysof IQ IOLs bilaterally. Results: The uncorrected distance visual acuity was significantly better in the toric group, whereas the uncorrected 50 cm visual acuity was better in the non-toric group. There was no significant difference in contrast sensitivity (with and without glare) between both the groups. The rate of spectacle dependency for distance vision was significantly lower in the toric group. There were no significant differences between the two groups in all items of the postoperative quality-of-vision questionnaire (25-item Visual Function Questionnaire). Conclusion: The toric IOLs used in this study reduced spectacle dependency more than the non-toric IOLs and did not compromise the subjective visual function, but the uncorrected 50 cm vision was worse in toric IOL implanted eyes. PMID- 30464383 TI - Intracameral dexamethasone injection in the treatment of cataract surgery induced inflammation: design, development, and place in therapy. AB - Cataract surgery is one of the most commonly performed surgeries worldwide, with nearly 20 million cases annually. Appropriate prophylaxis after cataract surgery can contribute to a safe and quick visual recovery with high patient satisfaction. Despite being the current standard of care, the use of multiple postoperative eye drops can create a significant burden on these patients, contributing to documented and significant non-adherence to the postoperative regimen. Over the past 25 years, there have been a few studies analyzing the use of intracameral dexamethasone (DXM) in controlling inflammation following cataract surgery. This review explores various drug delivery approaches for managing intraocular inflammation after cataract surgery, documenting the strengths and weaknesses of these options and examining the role of intracameral DXM (among these other strategies) in controlling postoperative intraocular inflammation. Intracameral DXM has a particular advantage over topical steroids in possibly decreasing postoperative inflammatory symptoms and objective anterior cell and flare scores. Compared to topical steroids, there may be a slightly less theoretical risk of significant intraocular pressure spikes and systemic absorption. In addition, surveys indicate patients prefer an intraoperative intracameral injection over a self-administered postoperative eye drop regimen. However, there are several adverse effects associated with intracameral DXM delivery that are not seen with the noninvasive topical approach. Although it is unlikely that intracameral DXM will replace topical medications as the standard management for postoperative inflammation, it is seemingly another safe and effective strategy for controlling postoperative inflammation after routine cataract surgery. PMID- 30464385 TI - Comparison of agreement and efficiency of a swept source-optical coherence tomography device and an optical low-coherence reflectometry device for biometry measurements during cataract evaluation. AB - Purpose: To compare the agreement and efficiency of a swept source-optical coherence tomography biometer, IOLMaster 700 (IOLM700), and a low-coherence optical reflectometry biometer, LENSTAR LS 900 (LS900), when acquiring biometry measurements during cataract evaluation. Methods: A retrospective chart review of biometry measurements that were performed in 64 eyes of 32 patients on the same day using the LS900 and the IOLM700. The total image acquisition time per subject was compared between the two machines using a Wilcoxon rank-sum test. Bland Altman plots showing the mean difference and 95% limits of agreement were graphed. Intraclass correlation coefficients (ICCs) were calculated for the mean axial length (AL), anterior chamber depth (ACD), lens thickness (LT), and two keratometry mean values (K1 and K2) that were output from each device. Results: The average time to complete biometry measurements in both eyes was significantly shorter for the IOLM700 compared with the LS900 (44.5+/-12.4 vs 168.8+/-67.2 seconds, P<0.001). The Bland-Altman analysis and ICCs showed high degrees of agreement for the mean biometry values (ICC: AL 0.9999, ACD 0.9993, LT 0.9571, K1 0.9922, K2 0.9926) generated by the two devices. Conclusion: There was a high level of agreement between the mean biometry output measures for IOLM700 and LS900. However, it took ~73% less time on average to acquire the images when using the IOLM700 compared with the LS900. In a busy clinic setting, use of the IOLM700 for biometry measures may save time and prove more efficient. PMID- 30464386 TI - Macular ganglion cell asymmetry for detecting paracentral scotoma in early glaucoma. AB - Purpose: We evaluated macular ganglion cell asymmetry as a tool for diagnosing paracentral scotoma (PCS) in early glaucoma. Patients and methods: This prospective study compared 58 patients with early glaucoma and PCS to 58 age matched control individuals. All glaucomatous eyes had scotoma within the central 12 degrees of fixation and confined to one hemifield. We measured circumpapillary retinal nerve fiber layer (cpRNFL) thickness, macular ganglion cell-inner plexiform layer (GCIPL) thickness, and optic nerve head (ONH) parameters with Cirrus spectral domain optical coherence tomography. Macular ganglion cell asymmetry was expressed as the absolute differences and the ratios between the inferior and superior hemispheres, inferotemporal (IT) and superotemporal (ST) areas, IT and superonasal (SN) areas, IT and inferonasal (IN) areas, and ST and IN areas. The asymmetry index was the absolute log10 of the ratio. The area under the receiver operating characteristics curve (AUROC) and partial AUROC (pAUROC, specificities >=90%) were analyzed for each parameter. Results: All GCIPL parameters and most cpRNFL parameters were significantly lower in early glaucoma than in controls. The best discriminating parameters were inferior RNFL thickness, average RNFL thickness, and minimum GCIPL thickness. The macular ganglion cell asymmetry parameters with the largest AUROCs were the log IT/ST index, the absolute difference in IT-ST GCIPL thicknesses, and the log IT/SN index. Performance was comparable between the log IT/ST index and the cpRNFL (inferior RNFL thickness, P=0.129), GCIPL (minimum GCIPL thickness, P=0.358), and ONH parameters (vertical cup-to-disc ratio, P=0.475). Conclusion: The IT/ST asymmetry index may be useful as a new parameter for detecting structural changes in glaucoma patients with PCS. PMID- 30464387 TI - Coding patterns used by ophthalmologists for hydroxychloroquine retinal toxicity. AB - Purpose: The aim of this study was to characterize International Classification of Diseases (ICD-9) coding patterns used by ophthalmologists in clinical practice for hydroxychloroquine (HCQ) retinal toxicity. Design: This is a retrospective cohort study. Subjects: Patients enrolled in the Kaiser Permanente Southern California health plan who were dispensed HCQ between 2001 and 2014 were included in this study. Methods: Patients' medical records were electronically searched for the following ICD-9 codes that can be used to characterize retinopathy or maculopathy: toxic maculopathy, non-exudative age-related macular degeneration (AMD), drusen (degenerative), and/or (other) background retinopathy. The charts of patients with these codes were then manually reviewed to determine which of these patients had been diagnosed by their ophthalmologists with HCQ retinopathy. Main outcome measures: ICD-9 codes used to indicate HCQ toxicity. Results: A total of 23,362 patients were dispensed HCQ between 2001 and 2014. Of whom, 678 (2.9%) patients received at least one of the aforementioned ICD-9 codes with 53 having confirmed HCQ toxicity on chart review. Forty-three patients who were taking HCQ received a diagnosis code for toxic maculopathy, and of whom, 35 (81.4%) had HCQ toxicity. Of the patients with confirmed HCQ toxicity, 32.1% received a code other than toxic maculopathy to connote the presence of disease. Conclusion: Although toxic maculopathy is the most commonly used ICD-9 code to identify patients with HCQ toxicity, a significant number of patients with toxicity received other codes in their medical records. Additionally, almost one fifth of the patients who were coded as having toxic maculopathy were ultimately not diagnosed with HCQ toxicity. This study underscores the often imprecise nature of ICD coding, especially in conditions without a specific associated code. The limitations of using coding information should also be considered when conducting research that utilizes electronic databases. Future investigations should determine how to improve database searches and methods to create more uniform coding standards among ophthalmologists, especially for rare conditions such as HCQ toxicity. PMID- 30464388 TI - Morphometrical evaluation of the choriocapillaris imaged by swept-source optical coherence tomography angiography. AB - Purpose: To assess the reproducibility of quantitative morphometrical evaluation of the choriocapillaris imaged with swept-source optical coherence tomography angiography (SS-OCTA). Subjects and methods: This observational, cross-sectional case series included 35 eyes of healthy individuals and 32 eyes of 32 patients. Two images of the fovea were taken using SS-OCTA with 3*3 mm squares. Images of the choriocapillaris within 800*800 pixel squares centered at the fovea were analyzed morphometrically using open-source software "AngioTool" that applies a Gaussian recursive filter and multiscale Hessian enhancement. This program's vessel thickness and intensity parameters can be changed to aid vessel detection. We measured the pairs of images per eye with different parameter sets and calculated the intraclass correlation (ICC) for the morphometrical results. After determining the parameters that produced high reproducibility, we evaluated regional variations in 800*800 pixel mm squares within the fovea. Results: The ICCs for vessel area, total vessel length, vessel diameter index, and mean lacunarity were over 0.9 using the parameters of "vessel thickness" 3-4 and intensity 15 in the group including all subjects. When measurements were performed using these same parameter values, the vessel density and mean vessel diameter index were 60.5% and 19.1+/-0.389, respectively. Vessel density, vessel length, vessel diameter index, and mean lacunarity did not change significantly within an 800*800 pixel square centered at the fovea except for the 200*200 pixel square at the foveal center. Conclusion: SS-OCTA images of the choriocapillaris can be measured with high reproducibility by morphometrical evaluation using open source software with multiscale Hessian enhancement. Such automated morphometric analysis can provide an objective evaluation of the choriocapillaris. PMID- 30464389 TI - Two decades with omalizumab: what we still have to learn. AB - From its availability for clinical use nearly two decades ago for severe asthma, omalizumab has gained strong evidence of efficacy and safety in the treatment of severe asthma not controlled by standard-of-care therapy. It has been acknowledged by Global Initiative on Asthma guidelines as add-on therapy against severe uncontrolled asthma. Thanks to controlled trials supporting its efficacy, omalizumab has also been licensed for the treatment of chronic spontaneous urticaria. The optimal duration of treatment in either disease has not been established. Despite its high price, omalizumab appears to be cost-effective in severe uncontrolled asthma as well as in chronic urticaria. The literature suggests a wide range of applications for omalizumab in various disorders regardless of allergic or non-allergic pathophysiology. PMID- 30464390 TI - Lobaplatin inhibits breast cancer progression, cell proliferation while it induces cell apoptosis by downregulating MTDH expression. AB - Objective: Lobaplatin shows antitumor activity against a wide range of tumors, including metastatic breast cancer (BCa). The overexpression of metadherin (MTDH) is associated with poor prognosis of BCa patients. This study was designed to investigate the effect of lobaplatin on MCF-7 cell proliferation and its association with MTDH expression. Patients and methods: Clinical treatment for BCa using lobaplatin, in combination with other general chemotherapy drugs, was administered to 32 BCa patients. The safety, effectiveness, and prognosis in lobaplatin-treated BCa patients were compared with those in controls (n=32). In vitro experiments were performed in MCF-7 cells to investigate the effect of lobaplatin on cell proliferation, apoptosis, and MTDH expression. Results: We found the intraoperative local chemotherapy using lobaplatin was safe and effective for BCa treatment, in comparison with the patients administered general chemotherapy drugs. Treatment of MCF-7 cell cultures with lobaplatin significantly reduced cell proliferation and increased cell apoptotic percentage. The expression of MTDH and Bcl-2 was inhibited by lobaplatin and that of Bax was increased by lobaplatin. Moreover, we observed the inhibition of MTDH by shRNA reduced cell proliferation and enhanced cell apoptosis. Conclusion: Lobaplatin was a safe and effective adjuvant chemotherapy for BCa. The effect of lobaplatin on inhibiting MCF-7 cell proliferation and inducing cell apoptosis might be, as least in part, mediated by suppressing the expression of oncogene MTDH. PMID- 30464391 TI - Asiatic acid ameliorates CCl4-induced liver fibrosis in rats: involvement of Nrf2/ARE, NF-kappaB/IkappaBalpha, and JAK1/STAT3 signaling pathways. AB - Purpose: Currently, there are no effective therapies for liver fibrosis; hence, the development of anti-liver fibrosis agents is urgently needed. Here, we attempted to investigate the therapeutic effect and mechanism of asiatic acid (AA) on liver fibrosis, mainly focusing on the impact of AA on nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE), nuclear factor-kappa B (NF-kappaB)/IkappaBalpha, and JAK1/signal transducer and activator of transcription 3 (STAT3) signaling pathways. Methods: Rats were induced liver fibrosis by carbon tetrachloride (CCl4) for 6 weeks and concomitantly treated with AA (5 and 15 mg/kg) or vehicle by daily gavage. After AA treatment, the morphology of liver tissue was analyzed by H&E and Masson's trichrome staining, and serum biochemical indicators were also assayed. Thereafter, the protein levels of Nrf2, HO-1, NQO-1, GCLC, NF-kappaB, IkappaBalpha, JAK1, p-JAK1, STAT3, and p-STAT3 were determined by Western blotting. Results: Our results showed that AA treatment dramatically ameliorated CCl4-induced oxidative stress, inflammation, and fibrosis in rats. The expression of nuclear Nrf2 was increased after AA treatment, whereas cytoplasm Nrf2 levels were decreased. The protein expression of Nrf2 target proteins including HO-1, NQO-1, and GCLC was significantly increased by AA treatment. Furthermore, AA treatment decreased the levels of nuclear NF-kappaB to inhibit NF-kappaB/IkappaBalpha signaling pathway. In addition, we also found that AA treatment regulated JAK1/STAT3 signaling by decreasing the phosphorylation levels of JAK1 and STAT3. Conclusion: These results demonstrate that AA ameliorates CCl4-induced liver fibrosis in rats by regulating Nrf2/ARE, NF-kappaB/IkappaBalpha, and JAK1/STAT3 signaling pathways, which suggests that AA might be a new antifibrosis agent that improves liver fibrosis. PMID- 30464392 TI - Pharmacokinetic and bioequivalence study comparing a fimasartan/rosuvastatin fixed-dose combination with the concomitant administration of fimasartan and rosuvastatin in healthy subjects. AB - Purpose: A new fixed-dose combination (FDC) formulation of 120 mg fimasartan and 20 mg rosuvastatin was developed to increase therapeutic convenience and improve treatment compliance. Methods: A randomized, open-label, single-dose, two treatment, two-way crossover study with a 7-day washout period was conducted to compare the pharmacokinetic (PK) characteristics and bioequivalence between an FDC of fimasartan/rosuvastatin and the separate co-administration of fimasartan and rosuvastatin in healthy Korean volunteers. The plasma concentrations of fimasartan and rosuvastatin were analyzed by a validated liquid chromatography tandem mass spectrometry method, for which serial blood samples were collected for up to 48 hours post-administration of fimasartan and 72 hours post administration of rosuvastatin, in each period. The PK parameters were calculated using a non-compartmental method. Results: A total of 78 subjects completed the study. All the 90% CIs of the geometric mean ratios (GMRs) fell within the predetermined acceptance range. The GMR and 90% CI for the area under the plasma concentration-time curve from time 0 to the last measurement (AUC0-t) and the maximum plasma concentration (Cmax) for fimasartan were 0.9999 (0.9391-1.0646) and 1.0399 (0.8665-1.2479), respectively. The GMR and 90% CI for the AUC0-t and Cmax for rosuvastatin were 1.0075 (0.9468-1.0722) and 1.0856 (0.9944-1.1852), respectively. Treatment with fimasartan and rosuvastatin was generally well tolerated without serious adverse events. Conclusion: The new FDC formulation of 120 mg fimasartan and 20 mg rosuvastatin can be substituted for the separate co administration of fimasartan and rosuvastatin, for the advantage of better compliance with convenient therapeutic administration. PMID- 30464393 TI - Dexmedetomidine protects the developing rat brain against the neurotoxicity wrought by sevoflurane: role of autophagy and Drp1-Bax signaling. AB - Background: The effect of sevoflurane on the nervous system is controversial. As an adjuvant anesthetic, dexmedetomidine has a protective role in various nerve injury diseases. We investigated the effect of dexmedetomidine on injury to the developing brain induced by sevoflurane anesthesia, and if autophagy and mitochondrial damage are involved in the neuroprotective effects of dexmedetomidine. Methods: Pregnant rats on gestational day 20 were exposed to 3% sevoflurane for 4 hours. Saline and dexmedetomidine were injected intraperitoneally 15 minutes before exposure to sevoflurane or control gas. Bilateral hippocampi were harvested on postnatal day 1. Hippocampal morphology was observed by Nissl staining and expression of the microtubule-related protein LC3I/II, p62, Drp1, Bax, and Bcl2 were evaluated by Western blotting and immunohistochemistry. Results: Nissl staining showed that sevoflurane anesthesia during the third trimester caused neuronal damage to the hippocampi of rat pups. Western blotting and immunohistochemistry showed that pregnant rats exposed to sevoflurane during the third trimester led to pups having increased expression of LC3 and p62, suggesting that sevoflurane blocked autophagic flow in the hippocampus. Expression of Drp1 and Bax was increased after sevoflurane exposure, whereas Bcl2 expression was downregulated. All these effects were alleviated by pretreatment with dexmedetomidine. Conclusion: Sevoflurane exposure during the third trimester caused neurological injury to rat pups. Autophagy and abnormalities in mitochondrial dynamics were involved in this neurotoxic process and were antagonized by dexmedetomidine. PMID- 30464394 TI - Clinical effectiveness of ranibizumab and conbercept for neovascular age-related macular degeneration: a meta-analysis. AB - Introduction: To assess the ocular efficacy of intravitreal ranibizumab and conbercept injection in patients with neovascular age-related macular degeneration. Materials and methods: We searched PubMed, Wed of Science, Cochrane Library, EMBASE, Google Scholar, Medline, China National Knowledge Infrastructure, and WANFANG DATA databases, up to June 20, 2018. We also searched abstracts and clinical study presentations at meetings as well as trial registries; we contacted authors of included studies if questions arose. Eligibility criteria for selection of studies were randomized controlled trials and retrospective trials that compared ranibizumab with conbercept for treatment of neovascular age-related macular degeneration. Results: Eight randomized controlled trials and four retrospective studies were included with a total of 853 patients. Best-corrected visual acuity after loading dosage was improved in the conbercept group, compared with the ranibizumab group (weighted mean difference: -0.04; 95% CI: -0.07 to 0.00; P=0.04). There was a significant difference between conbercept and ranibizumab therapy with respect to unchanged or recurrent leakage of choroidal neovascularization (OR: 0.46; 95% CI: 0.24 0.88; P=0.02). No significant differences were observed in central macular thickness (weighted mean difference: -2.92; 95% CI: -9.00 to 3.17; P=0.35), complete and partial closure of leakage of choroidal neovascularization (complete closure, P=0.70; partial closure, P=0.35), or number of injections (weighted mean difference: 0.42; 95% CI: -0.46 to 1.29; P=0.35) between the conbercept and ranibizumab groups at the end of the follow-up periods. Conclusion: Pooled evidence confirmed that conbercept was superior to ranibizumab with respect to visual gain after treatment. Additional studies with long-term follow-up are needed to support our conclusion. PMID- 30464395 TI - Darunavir-cobicistat-emtricitabine-tenofovir alafenamide: safety and efficacy of a protease inhibitor in the modern era. AB - A fixed-dose combination consisting of darunavir (Drv), cobicistat (Cobi), emtricitabine (2',3'-dideoxy-5-fluoro-3'-thiacytidine [FTC]), and tenofovir alafenamide (Taf) has been recently approved by the European Medicines Agency for the treatment of HIV infection, and is the first ever protease-inhibitor-based single-tablet regimen. This article provides a detailed description of its pharmacokinetic, efficacy, and safety profile. The pharmacokinetics of single compounds were analyzed, with a special focus on contrasts between Drv/Cobi and Drv/ritonavir (Rtv). When comparing Cobi and Rtv, multiple interactions must be taken into account: in comparison to Rtv, Cobi is a more selective CYP3A4 inhibitor and has no clinical effect on other isoenzymes inhibited by Rtv (eg, 2C8 and 2C9). Moreover, unlike Cobi, Rtv shows in vivo induction activity on some CYP isoenzymes (eg, 1A2, 2C19, 2C8, 2C9, and 2B6), glucuronyltransferases (eg, UGT1A4), and Pgp. Drv-Cobi-FTC-Taf has recently been demonstrated to be of equal efficacy to Drv-Rtv and other protease inhibitors in both experienced (EMERALD study) and naive (AMBER study) patients. Moreover, kidney and bone safety profiles have been shown to be good, as has central nervous system tolerance. Total cholesterol:low-density-lipoprotein cholesterol and total cholesterol:high density-lipoprotein cholesterol ratios are generally high in Drv-Cobi-FTC-Taf vs Rtv-Drv-FTC + tenofovir disoproxil fumarate. An unlikely role of Drv in influencing cardiovascular risk in HIV infection has also been reported. Kidney safety profile is influenced by Cobi, with an increase in creatinine plasma concentration of 0.05-0.1 mg/dL and a parallel glomerular filtration-rate reduction of 10 mL/min within the first 4 weeks after Cobi introduction, which remains stable during treatment. Bone and central nervous system safety profiles were found to be good in randomized clinical trials of both experienced and naive patients. The efficacy and safety of Drv/Cobi/FTC/Taf are comparable to other drug regimens recommended for HIV treatment. PMID- 30464396 TI - Transfer of rosuvastatin into breast milk: liquid chromatography-mass spectrometry methodology and clinical recommendations. AB - Introduction: Rosuvastatin reduces concentrations of total cholesterol (TC) and is used for the management of hypercholesterolemia and prevention of acute coronary syndromes. There are no published reports estimating infant exposure to rosuvastatin through breast milk. Purpose: The aims of this study were to quantify concentrations of rosuvastatin in human milk and plasma from a lactating woman taking rosuvastatin and to investigate potential infant exposure. Materials and methods: A 38-year-old breastfeeding mother was commenced on rosuvastatin 20 mg daily for secondary prevention of an acute coronary syndrome. Eight maternal breast milk samples and a single plasma sample were collected over a 24-hour period. The samples were quantified using a sensitive liquid chromatography-mass spectrometry (LC-MS/MS) method. Results: The average concentration of rosuvastatin in breast milk was 30.84 ng/mL, and a peak concentration of 58.59 ng/mL occurred at 17 hours after oral administration. Although the milk-to-plasma (M/P) ratio was 16.49 at 14 hours, the theoretical infant dosage (TID) and relative infant dose (RID) were 0.005 mg/kg/day and 1.50%, respectively. Conclusion: The findings suggest that only small amounts of rosuvastatin pass into breast milk. Should the maternal condition necessitate treatment, consideration could be given to the use of rosuvastatin during breastfeeding provided the infant is monitored. PMID- 30464397 TI - Pharmacokinetic evaluation of a transdermal anastrozole-in-adhesive formulation. AB - Background and objective: Anastrozole is a well-established active pharmaceutical ingredient (API) used for the treatment of hormone-sensitive breast cancer (BC) in postmenopausal women. However, treatment with the only available oral formulation is often associated with concentration-dependent serious side effects such as hot flashes, fatigue, muscle and joint pain, nausea, diarrhea, headache, and others. In contrast, a sustained-release system for the local application of anastrozole should minimize these serious adverse drug reactions. Methods: Anastrozole-in-adhesive transdermal drug delivery systems (TDDS) were developed offering efficient loading, avoidance of inhomogeneity or crystallization of the drug, the desired controlled release kinetics, storage stability, easy handling, mechanical stability, and sufficient stickiness on the skin. In vitro continuous anastrozole release profiles were studied in Franz diffusion cells. In vivo, consecutive drug plasma kinetics from the final anastrozole transdermal system was tested in beagle dogs. For drug analysis, a specific validated liquid chromatography- mass spectrometry method using fragment ion detection was developed and validated. Results: After efficient drug loading, a linear and sustained 65% drug release from the TDDS over 48 h was obtained. In vivo data showed a favorable anastrozole plasma concentration-time course, avoiding side effect-associated peak concentrations as obtained after oral administration but matching therapeutic plasma levels up to 72 h. Conclusion: These results provide the basis for establishing the transdermal application of anastrozole with improved pharmacokinetics and drug safety as novel therapeutic approach and promising option to treat human BC by decreasing the high burden of unwanted side effects. PMID- 30464398 TI - Efficacy and safety of Tongfu powder in acute pancreatitis patients with gastrointestinal dysfunction: a clinical trial. AB - Objective: To evaluate the efficacy and safety of Tongfu powder for external application on Shenque (the umbilicus, hereafter, Tongfu powder) versus mosapride in acute pancreatitis (AP) patients with gastrointestinal dysfunction. Methods: A total of 102 AP patients were diagnosed using the latest Atlanta Criterion and recruited at the Department of Infectious Disease, Beijing Friendship Hospital (Beijing, People's Republic of China) from August 2014 to December 2016. Patients were randomized into the Tongfu powder group and mosapride group using the random table. Information on scores (eg, the gastrointestinal function score) on days 1 and 7 of hospitalization, biochemical indicators (eg, interleukin [IL]-2 and IL 6), indicators for curative effects (eg, first defecation time, bowel sound recovery time, hospitalization costs, and duration) were collected and compared between the 2 groups. Results: The gastrointestinal function score decreased significantly after treatment, and the changes were significantly different between the Tongfu powder group and the mosapride group (P<0.05). Significantly shorter time to first defecation and bowel sound recovery was observed in the Tongfu powder group versus the mosapride group (P<0.05). The improvements of IL 2, IL-4, intestinal fatty acid binding protein, motilin, and vasoactive intestinal peptide in the Tongfu powder group were higher than those in the mosapride group (P<0.05). There were no significant differences in hospital cost and length of hospital stay between the 2 groups. Conclusion: This study suggested that Tongfu powder for external application may improve gastrointestinal function for AP patients compared with mosapride. PMID- 30464399 TI - Formononetin induces vasorelaxation in rat thoracic aorta via regulation of the PI3K/PTEN/Akt signaling pathway. AB - Background: Formononetin (FMN) is an isoflavone that produces arterial vasodilation. However, the underlying molecular mechanisms are unclear. Purpose: The purpose of this study was to explore the vasorelaxant effect and the potential mechanism of FMN in vascular endothelium in isolated rat aorta. Methods: The thoracic aortas of Sprague Dawley rats were isolated to test the arterial reactivity in the presence of FMN with or without inhibitors. Bioinformatics analyses, including a Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine and molecular docking methods, were performed to predict therapeutic targets responsible for the vascular protection produced by FMN. We used rat aortic endothelial cells (RAOECs) as an in vitro model to verify the potential mechanism through molecular biological analyses. The production of nitric oxide (NO) metabolites were evaluated via an NO assay kit according to the manufacturer's instruction. The mRNA expression of eNOS was analyzed by polymerase chain reaction, and the protein levels of PTEN, phosphorylated Akt, and eNOS were measured by Western blot. Results: We found that FMN dilated rat aortic rings in a concentration-dependent manner, which was reduced by endothelium denudation and eNOS inhibition. The bioinformatics analyses indicated that FMN activity was associated with the PI3K/PTEN/Akt signaling pathway. Molecular biological studies demonstrated that FMN significantly elevated the levels of NO and eNOS mRNA and markedly increased the protein expression of phosphorylated Akt and eNOS in RAOECs, and decreased PTEN compared with a dimethyl sulfoxide group. Conclusion: FMN performs vasorelaxation of the thoracic aorta through activating the PI3K/PTEN/Akt signaling pathway. PMID- 30464400 TI - Meta-analysis of rosuvastatin efficacy in prevention of contrast-induced acute kidney injury. AB - Background: Contrast-induced nephropathy (CIN) is a complication after the intravascular administration of a contrast medium injection. Previous studies have investigated statins as therapy for CIN due to its positive results in the prevention of contrast-induced acute kidney injury (CI-AKI). Nevertheless, the beneficial effects of rosuvastatin pretreatment in preventing CIN in patients with acute coronary syndromes still remain controversial. In this study, we performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the beneficial impact of rosuvastatin in the prevention of CI-AKI in acute coronary syndrome patients. Methods: PubMed, Embase, and Cochrane library were searched, for RCTs, updated on January 2018. The method was to evaluate rosuvastatin prior to angiography for the prevention of CI-AKI in patients undergoing coronary angiography, of which the main outcome was the incidence of CIN. Results: A total of five RCTs were included in this analysis. Patients treated with rosuvastatin prior to invasive angiography had a significantly lower incidence of CI-AKI than controls (odds ratio [OR]: 0.53, 95% CI: 0.40-0.71, P<0.0001). Moreover, the subgroup analysis also showed that the benefit of rosuvastatin for patients with chronic kidney disease (OR: 0.49, 95% CI: 0.26-0.92, P=0.03) and diabetes mellitus (OR: 0.56, 95% CI: 0.38-0.83, P=0.004) which was consistent in compared with the respective control groups. Conclusion: The findings of this meta analysis suggest that the preoperative rosuvastatin treatment significantly reduces the risk of renal insufficiency of CIN in at-risk patients with chronic kidney disease or diabetes mellitus. Additional studies are needed to identify at risk patients, provide optimum dose peri-procedural treatment, and reduce the incidence of CIN. PMID- 30464401 TI - Arminin 1a-C, a novel antimicrobial peptide from ancient metazoan Hydra, shows potent antileukemia activity against drug-sensitive and drug-resistant leukemia cells. AB - Purpose: Due to the emergence of multidrug resistance (MDR), traditional antileukemia drugs no longer meet the treatment needs. Therefore, new antileukemia drugs with different action mechanisms are urgently needed to cope with this situation. Materials and methods: Arminin 1a-C is an antimicrobial peptide (AMP) developed from the ancient metazoan marine Hydra. In this study, we first explored its antileukemia activity. Results: Our results showed that Arminin 1a-C formed an alpha-helical structure and efficaciously suppressed the viability of leukemia cell lines whether or not they were multidrug resistant or sensitive, and there were no obvious differences between these cell lines. Arminin 1a-C exhibited distinct selectivity between noncancerous and cancerous cell lines. Arminin 1a-C interfered with K562/adriamycin (ADM) cell (a kind of multidrug-resistant leukemia cell line) proliferation in a very rapid manner and formed pores in its cell membrane, making it difficult to develop resistance against Arminin 1a-C. Conclusion: Our data show that Arminin 1a-C possesses great potential as a therapeutic candidate for the treatment of multidrug-resistant leukemia. PMID- 30464402 TI - Saponins enhance exon skipping of 2'-O-methyl phosphorothioate oligonucleotide in vitro and in vivo. AB - Background: Antisense oligonucleotide (ASO)-mediated exon skipping has been feasible and promising approach for treating Duchenne muscular dystrophy (DMD) in preclinical and clinical trials, but its therapeutic applications remain challenges due to inefficient delivery. Methods: We investigated a few Saponins for their potential to improve delivery performance of an antisense 2'-Omethyl phosphorothioate RNA (2'-OMePS) in muscle cells and in dystrophic mdx mice. This study was carried out by evaluating these Saponins' toxicity, cellular uptake, transduction efficiency in vitro, and local delivery in vivo for 2'-OMePS, as well as affinity study between Saponin and 2'-OMePS. Results: The results showed that these Saponins, especially Digitonin and Tomatine, enhance the delivery of 2'-OMePS with comparable efficiency to Lipofectamine 2k (LF-2k) -mediated delivery in vitro. Significant performance was further observed in mdx mice, up to 10-fold with the Digitonin as compared to 2'-OMePS alone. Cytotoxicity of the Digitonin and Glycyrrhizin was much lower than LF-2k in vitro and not clearly detected in vivo under the tested concentrations. Conclusion: This study potentiates Saponins as delivery vehicle for 2'-OMePS in vivo for treating DMD or other diseases. PMID- 30464403 TI - Efficacy evaluation of reteplase in a novel canine acute pulmonary thromboembolism model developed by minimally invasive surgery and digital subtraction angiography. AB - Purpose: In order to evaluate the thrombolytic effects of reteplase in pulmonary thromboembolism (PTE), we developed a novel canine PTE model. The efficacy of reteplase against PTE in comparison to alteplase was clarified for the first time, and this PTE model could be further applied to studies of novel thrombolytic therapies. Patients and methods: Twenty-four dogs were divided into four groups: sham operation, vehicle, alteplase, and reteplase. Autologous thrombi/saline were injected into the pulmonary artery, and thrombolytic agents were administrated. Thrombus formation and dissolution were monitored by real time digital subtraction angiography (DSA), and pulmonary pressures were measured simultaneously. Blood coagulation, blood gas, hematology, and histopathologic examinations were used as subsidiary methods. Results: The canine PTE model was established with a significant decrease of blood flow and ~75% blocking area. Administration of reteplase (0.6 mg/kg) resulted in effective thrombus dissolution with a recovery of over 80% blood flow, as effective as alteplase (1.6 mg/kg). Correspondingly, the elevated pulmonary systolic, diastolic, and mean arterial pressures declined to the normal level. Blood coagulation was changed by reteplase, with a dramatic elongation of prothrombin time, activated partial thromboplastin time, and thrombin time, even longer than alteplase. In contrast to the vehicle group, no obvious pathological changes were found in the two thrombolytic groups. Hematological, blood biochemical, and blood gas results also indicated that reteplase had no adverse reactions in this PTE model. Conclusion: Reteplase proved to be an effective and safe therapy for PTE for the first time, and a small dosage of reteplase exerted an efficacy comparable to the routine dosage of alteplase. Our findings indicated the potential of reteplase as clinical treatment against PTE. This technically innovative, stability- and validity-proved canine PTE model developed by minimally invasive surgery and DSA resembled major clinical features. This may further facilitate our understanding of thrombotic disorders and development of prophylactic and therapeutic approaches. PMID- 30464404 TI - Two-drug regimens for treatment of naive HIV-1 infection and as maintenance therapy. AB - As people live longer with HIV infection, there has been a resurgence of interest in challenging the use of three-drug therapy, including two nucleoside reverse transcriptase inhibitors plus a third drug, as initial treatment of HIV infection or for maintenance therapy in virologically suppressed individuals. Although initial studies showed poor efficacy and/or substantial toxicity, more recent regimens have held greater promise. The SWORD-1 and -2 studies were pivotal trials of dolutegravir plus rilpivirine as maintenance therapy in virologically suppressed patients with no history of drug resistance, leading to the US Food and Drug Administration's approval of the regimen as a small, single tablet. More recently, the GEMINI-1 and -2 studies demonstrated that dolutegravir plus lamivudine is as safe and effective as the same regimen when combined with tenofovir disoproxil fumarate in treatment-naive individuals. Together, these and other studies of novel two-drug regimens offer the potential for improved tolerability and simplicity, as well as a reduction in cost. We will review historical and recent trials of two-drug therapy for the treatment of HIV-1 infection. PMID- 30464405 TI - Identification of new inhibitors of Mdm2-p53 interaction via pharmacophore and structure-based virtual screening. AB - Background: The tumor suppressor protein p53 plays an important role in preventing tumor formation and progression through its involvement in cell division control and initiation of apoptosis. Mdm2 protein controls the activity of p53 protein through working as ubiquitin E3 ligase promoting p53 degradation through the proteasome degradation pathway. Inhibitors for Mdm2-p53 interaction have restored the activity of p53 protein and induced cancer fighting properties in the cell. Purpose: The objective of this study is to use computer-aided drug discovery techniques to search for new Mdm2-p53 interaction inhibitors. Methods: A set of pharmacophoric features were created based on a standard Mdm2 inhibitor and this was used to screen a commercial drug-like ligand library; then potential inhibitors were docked and ranked in a multi-step protocol using GLIDE. Top ranked ligands from docking were evaluated for their inhibition activity of Mdm2 p53 interaction using ELISA testing. Results: Several compounds showed inhibition activity at the submicromolar level, which is comparable to the standard inhibitor Nutlin-3a. Furthermore, the discovered inhibitors were evaluated for their anticancer activities against different breast cancer cell lines, and they showed an interesting inhibition pattern. Conclusion: The reported inhibitors can represent a starting point for further SAR studies in the future and can help in the discovery of new anticancer agents. PMID- 30464406 TI - Hydralazine HCl rapidly disintegrating sublingual tablets: simple dosage form of higher bioavailability and enhanced clinical efficacy for potential rapid control on hypertensive preeclampsia. AB - Background: Hypertensive disorders are the most common complication in pregnancy which can even lead to maternal mortality. Hydralazine hydrochloride (HHC), a direct-acting vasodilator, is intravenously used as the first-line therapy in controlling hypertension in pregnancy (preeclampsia). It suffers poor oral bioavailability (26%-50%) due to first-pass metabolism. Objective: This work aims for the preparation of HHC rapidly disintegrating sublingual tablets of higher absorption rate, short onset of action, and higher bioavailability for rapid control on blood pressure (BP) in hypertensive emergencies especially preeclampsia. Methods: HHC sublingual tablet mixtures were prepared using starch sodium glycolate and Pharmaburst as super disintegrants at three different levels by direct compression and were subjected to full in vitro evaluation; the drug bioavailability from the optimized sublingual tablet formula was assessed in comparison to conventional oral tablets in rabbits, and the clinical efficacy on controlling BP in induced preeclampsia like mouse model was also studied. Results: The results indicated compatibility of the prepared tablet mixtures, good flow, and acceptable mechanical strength. Sublingual tablet formula containing Pharmaburst (7%) that showed fastest disintegration (21 seconds) and 100% drug release within 5 minutes was selected for further bioavailability and pharmacodynamic studies. The drug bioavailability was significantly increased with C max = 28.2767+/-4.61 ug/mL, AUC(0-alpha) = 52.85+/-3.18 ug.h/mL, and T max = 0.33+/-0.011 hour in comparison to 18.0633+/-23.2 ug/mL, 33.18+/-5.18 ug?h/mL, and 0.75+/-0.025 hour for conventional oral tablets. Results of pharmacodynamic studies proved significant rapid control on both systolic and diastolic BP to normal values within only 30 minutes without any significant difference from intravenous data. Conclusion: These results confirm the suitability of the prepared HHC sublingual tablets for use in rapid control on hypertensive crisis especially in pregnant women as an alternate to parenteral administration. PMID- 30464407 TI - Concomitant food intake does not affect the efficacy of entecavir in chronic hepatitis B patients with virological response: a randomized, multicenter, noninferiority trial. AB - Background: Little clinical data are available about the effect of food on the antiviral efficacy of entecavir for chronic hepatitis B virus (HBV) infection. The present study evaluated whether entecavir administration in the fed state had comparable efficacy to the fasted condition for maintenance of viral suppression in HBV-infected patients with virological response on entecavir therapy. Methods: In this multicenter, randomized, open-label, noninferiority study, patients who were currently receiving entecavir and showed a serum HBV DNA level of <20 IU/mL were randomized to take entecavir either under the fasted or fed condition for 48 weeks. Results: We randomly assigned 50 patients to the fasted group and 46 patients to the fed group. The full analysis set consisted of 49 patients in the fasted group and 44 patients in the fed group. At week 48, the proportion of patients with HBV DNA <20 IU/mL was not significantly different between the fasted and fed groups (98% vs 100%, P=1.00). The mean log10 HBV DNA changes from baseline were similar between the two groups (-0.004 vs -0.012 log10 IU/mL, P=0.43). There were no significant differences in the proportions of patients with normal alanine aminotransferase (87.8% vs 95.5%, P=0.27) and hepatitis B e antigen seroconversion (0% vs 6.7%, P=0.47) between the two groups. None of the patients showed viral breakthrough. In pharmacokinetic analysis, the maximum concentration and the area under the concentration- time curve to the last quantifiable concentration decreased by 26.4% and 9.3%, respectively, in the fed group compared with the fasted group. However, the differences between two groups were not statistically significant (P=0.28 and 0.83, respectively). Conclusion: In patients with virological response under entecavir therapy, concomitant food intake did not affect the antiviral efficacy. For patients with adherence problem, taking entecavir with food may be considered to improve compliance. PMID- 30464408 TI - Effect of intrathecal dexmedetomidine on preventing shivering in cesarean section after spinal anesthesia: a meta-analysis and trial sequential analysis. AB - Objective: Intrathecal dexmedetomidine (DEX) has been used to prevent shivering in patients undergoing cesarean section. The aim of this meta-analysis was to evaluate whether intrathecal DEX could prevent shivering in cesarean section after spinal anesthesia. Methods: We searched PubMed, Embase, Web of Science, and the Cochrane Library for randomized controlled trials (RCTs) comparing intrathecal DEX in cesarean section after spinal anesthesia with placebo and reporting on shivering, postoperative nausea and vomiting (PONV), hypotension, and bradycardia. Trial sequential analysis (TSA) was also carried out for RCTs comparing DEX with placebo. This meta-analysis has been registered on PROSPERO, and the registration number is CRD42017071640. Results: Six randomized clinical trials comparing 360 patients were included in this study. Compared with placebo, intrathecal DEX significantly reduced the incidence of shivering (risk ratio [RR]=0.40; 95% CI [0.26, 0.62]; P<0.0001). No significant difference was found in the incidence of PONV (RR=1.34; 95% CI [0.82, 2.18]; P=0.24), hypotension (RR=1.09; 95% CI [0.84, 1.42]; P=0.50), or bradycardia (RR=1.55; 95% CI [0.54, 4.42]; P=0.42). However, no firm conclusions can be made based on the results of all outcomes according to the TSA. Conclusion: This meta-analysis found that intrathecal DEX could prevent shivering in cesarean section after spinal anesthesia and did not induce PONV, hypotension, or bradycardia. However, firm conclusions cannot be made until more studies are conducted. PMID- 30464410 TI - Erratum: The effect of food and liquid pH on the integrity of enteric-coated beads from cysteamine bitartrate delayed-release capsules [Corrigendum]. AB - [This corrects the article on p. 2795 in vol. 12.]. PMID- 30464409 TI - Histopathological study of liver tissue due to methadone consumption and its effect on liver enzymes and inflammatory indices in rat. AB - Background: Methadone (MET)-based treatment is currently one of the best known approaches in the treatment of opioid dependence. It is claimed that MET use exerts adverse effects on the performance of some organs, especially liver. Thus, the present study aims to investigate MET effects on the hepatic tissue as well as its effect on the hepatic enzyme levels and inflammatory markers in rats. Materials and methods: Twenty-eight mature male Wistar rats underwent an 8-week treatment in four equal groups including the control group (an ordinary daily dietary regime) as well as the experimental groups 1, 2, and 3 (an ordinary daily dietary regime and gavage-fed on MET syrup for 5, 20, and 40 mg/kg body weight per day). Blood samples were collected from all rats in the beginning and end of the study to measure their hepatic enzyme levels and inflammatory markers. In the end, their livers were subjected to histological examinations. Results: The mean serum levels of hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase) increased considerably across all the three groups that had received various dosages of MET (5, 20, and 40 mg/kg) in the end of the study as compared to the beginning of the study (P<0.001). It was also found that the inflammatory indicators (interleukin-6, tumor necrosis factor alpha, and C-reactive protein) rose significantly in the groups that had received various dosages of MET in contrast to the control group (P<0.01, P<0.001, and P<0.001, respectively). The histopathological images of the liver cross-sections revealed dosage-dependent tissue changes in the groups that had received various dosages of MET. Conclusion: The present study tried to prove the adverse effects of MET in the development of liver damage. Since MET-based treatment is frequently prescribed by physicians for curing the addiction to narcotics, better strategies are required for its correct usage. PMID- 30464411 TI - Comparative pharmacokinetics of an adalimumab biosimilar SB5 administered via autoinjector or prefilled syringe in healthy subjects. AB - Purpose: The objective of this study was to demonstrate comparable pharmacokinetic (PK), safety, and tolerability parameters of the adalimumab biosimilar SB5 administered via autoinjector (AI) pen or prefilled syringe (PFS). Patients and methods: In this phase 1, randomized, open-label, single-dose, parallel-group study, healthy subjects aged 18-55 years were randomized 1:1 to a single dose of 40 mg SB5 delivered subcutaneously via AI or PFS. PK parameters, safety, and tolerability were assessed for 57 days post-dose. The primary endpoint was area under the curve (AUC) of the concentration-time curve from zero to infinity (AUCinf) and from zero to last quantifiable concentration (AUClast) and maximum serum concentration (Cmax). Equivalence was determined using predefined margins of 0.80-1.25 for the 90% CI for the ratio of SB5 AI to SB5 PFS. Results: Ninety-five subjects were randomized to each group. Mean serum concentration-time profiles were superimposable between groups. Mean values for AUCinf, AUClast, and Cmax were similar between the SB5 AI and SB5 PFS groups. For the primary endpoints, the 90% CIs for the ratio of geometric least squares means for SB5 AI to SB5 PFS ranged between 0.9503 and 1.2240, which were all within the equivalence margin of 0.80-1.25. Incidence of treatment-emergent adverse events and injection site reactions was similar between groups. Conclusion: In healthy subjects receiving a single dose of SB5 via AI or PFS, PK parameters and corresponding 90% CIs were within the predefined margins, showing bioequivalence between the two delivery methods. Safety and tolerability assessments were also similar between groups. ClinicalTrialsgov identifier: NCT02326233. EudraCT number: 2014-005178-12. PMID- 30464413 TI - The effects of vasoactive intestinal peptide in the rat model of experimental autoimmune neuritis and the implications for treatment of acute inflammatory demyelinating polyradiculoneuropathy or Guillain-Barre syndrome. AB - Background: Guillain-Barre syndrome is an acute inflammatory demyelinating polyneuropathy that is characterized histologically by demyelination of peripheral nerves and nerve roots, infiltrates of T lymphocytes, and an inflammatory response that includes macrophage infiltrates. The aim of this study was to evaluate the effects of vasoactive intestinal peptide (VIP) in a rat model of experimental autoimmune neuritis (EAN). Methods: Forty male Lewis rats were divided into a control group (N=10), an EAN group (N=10), an EAN group treated with 15 nmol of VIP (N=10), and an EAN group treated with 30 nmol of VIP (N=10). The rat model was created by subcutaneous injection of P2 polypeptide (200 ug P257-81) into the base of the tail. Intraperitoneal injection of VIP was given on day 7. Rats were weighed and functionally evaluated using an EAN score (0-10). On day 16, the rats were euthanized. The sciatic nerve was examined histologically and using immunohistochemistry with antibodies against CD8, CD68, and forkhead box p3 (Foxp3). Serum concentrations of IL-17 and interferon-alpha (IFN-alpha) were measured by ELISA on day 16 after creating the EAN model. Results: The VIP treated EAN groups had increased body weight and improved EAN scores compared with the untreated EAN group. CD8-positive and CD68-positive cells were significantly reduced in the EAN group treated with 30 nmol of VIP compared with 15 nmol of VIP. Foxp3-positive cells were significantly decreased in both EAN groups treated with VIP, and serum concentrations of IL-17 and IFN-alpha were significantly lower compared with the untreated EAN group (P<0.05). Conclusion: In a rat model of EAN, treatment with VIP resulted in functional improvement, reduced nerve inflammation, and decreased serum levels of inflammatory cytokines. PMID- 30464414 TI - A decision-making process to undergo orthodontic treatment: a qualitative study. AB - Background: Orthodontics is a medical treatment and a rehabilitation service provided for individuals in need. Due to the high cost involved in performing this type of treatment along with the current attitude in communities toward it as a cosmetic service, it is essential to investigate the decision-making process to undergo orthodontic interventions among Iranian individuals and families. Methods: To conduct this qualitative study using grounded theory, 18 participants were selected through purposive sampling method and received semi-structured interviews each lasting 50-70 minutes. Eventually, the data were saturated after the fulfillment of 19 interviews. During the interviews, simultaneous analysis was also performed according to the method proposed by Strauss and Corbin (1998) and then the data were analyzed within three stages of open, axial, and selective coding. Results: Analysis of the clients' statements produced 207 codes, 22 sub categories, and 9 main categories, including distorted mental self-image, hope to look more attractive, inappropriate interactions with family and those around, family's views toward the problem, social conditions, financial constraints, challenges in the family, as well as decision making to undergo orthodontic treatment, and finally, the main factor of hope for a better future were highlighted. Conclusion: The results showed that the main facilitating factor was "hope for a better future" for which families could accept numerous difficulties, such as high cost and repeated follow-ups due to the importance of beauty and meeting their children's sense of satisfaction. PMID- 30464412 TI - An insight into new strategies to combat antifungal drug resistance. AB - Invasive fungal infections especially in immunocompromised patients represent a dominating cause of mortality. The most commonly used antifungal agents can be divided into three broad categories, including triazoles, echinocandins and polyenes. Antifungal resistance is on the increase, posing a growing threat to the stewardship of immunocompromised patients with fungal infections. The paucity of currently available antifungals leads to the rapid emergence of drug resistance and thus aggravates the refractoriness of invasive fungal infections. Therefore, deep exploration into mechanisms of drug resistance and search for new antifungal targets are required. This review highlights the therapeutic strategies targeting Hsp90, calcineurin, trehalose biosynthesis and sphingolipids biosynthesis, in an attempt to provide clinical evidence for overcoming drug resistance and to form the rationale for combination therapy of conventional antifungals and agents with novel mechanisms of action. What's more, this review also gives a concise introduction of three new-fashioned antifungals, including carboxymethyl chitosan, silver nanoparticles and chromogranin A-N46. PMID- 30464415 TI - Demand and willingness to pay for different treatment and care services among patients with heart diseases in Hanoi, Vietnam. AB - Introduction: In Vietnam, cardiovascular diseases (CVDs) are serious health issues, especially in the context of overload central heart hospitals, insufficient primary healthcare, and lack of customer-oriented care and treatment. Attempts to measure demand and willingness-to-pay (WTP) for different CVD treatments and care services have been limited. This study explored the preferences and WTP of patients with heart diseases for different home- and hospital-based services in Hanoi, Vietnam. Methods: A cross-sectional survey was performed at the Hanoi Heart Hospital from July to December 2017. A contingent valuation was adopted to determine the preferences of patients and measure their WTP. Interval regressions were employed to determine the potential predictors of patients' WTP. Results: Hospital-based services were most preferred by patients, with demand ranging from 45.6% to 82.3% of total participants, followed by home based (45.4%-45.8%) and administrative services (28.9%-34%). WTP for hospital based services were in the range of US$ 9.8 (US$ 8.4-11.2)-US$ 21.9 (US$ 20.3 23.4), while figures for home-based and administrative services were US$ 9.8 (US$ 8.4-11.2)-US$ 22 (US$ 18.7-25.3) and 1.9 (US$ 1.6-2.2)-US$ 7.5 (US$ 6.3-8.6), respectively. Patients who lived in urban areas, were employed, were having higher level of education, and were not covered by health insurance were willing to pay more for services, especially home-based ones. Conclusion: Demand and WTP for home-based services among heart disease patients were moderately low compared with hospital-based ones. There is a need for more policies supporting home-based services, better communication of services' benefits to general public and patients, and introduction of services packages based on patients' preferences. PMID- 30464416 TI - Patient adherence, compliance, and perspectives on evolocumab for the management of resistant hypercholesterolemia. AB - Evolocumab is a PCSK9 inhibitor which is administered subcutaneously, and when added to statin therapy it has been shown to cause a significant incremental LDL C reduction, leading to a reduction of cardiovascular risk. Evolocumab has a favorable side effect profile, and its self-administration at home appears to be safe and effective with the appropriate training and instructions from a health care provider. Current studies are showing encouraging results regarding adherence to evolocumab in real-life settings, and adherence rates to evolocumab appear to be better than those to statins. However, further larger studies are needed for a more definitive assessment of the short- and long-term patient adherence rates to evolocumab. In addition, reductions in the price of evolocumab may also be necessary to improve cost-effectiveness of the drug. PMID- 30464418 TI - A qualitative study on the attitudes of patients with gastrointestinal cancer toward being informed of the truth. AB - Objective: The aim of this study is to investigate the attitudes of hospitalized patients with gastrointestinal cancer toward being informed of the truth and to provide references for informing patients of their gastrointestinal cancer diagnosis. Methods: Nine patients with gastrointestinal cancer were selected for this study by using a purposive sampling technique from a general surgery ward in a tertiary-level general hospital in Zhejiang Province from June 2016 to October 2016. Semi-structured, in-depth interviews were conducted, and the descriptive phenomenological method (developed by Amedeo Giorgi) was used to analyze the interview data. Results: Five themes were developed through reading, analysis, reflection, and classification of the data: Theme 1, guessing the diagnosis of gastrointestinal cancer before being informed of the truth; Theme 2, eagerness to know the diagnosis results; Theme 3, expectations related to beginning treatment for cancer; Theme 4, stress and anxiety during treatment; and Theme 5, providing patients with hope and optimism at the early diagnosis stage. Conclusion: Patients have a strong desire to survive and can confidently confront their gastrointestinal cancer diagnosis. Medical staff should carefully select the appropriate time to inform patients of their diagnosis by evaluating their attitudes toward being informed, thereby actively meeting patients' needs for information and treatment. PMID- 30464417 TI - Eliciting vulnerable patients' preferences regarding colorectal cancer screening: a systematic review. AB - Background: Patient preferences are important to consider in the decision-making process for colorectal cancer (CRC) screening. Vulnerable populations, such as racial/ethnic minorities and low-income, veteran, and rural populations, exhibit lower screening uptake. This systematic review summarizes the existing literature on vulnerable patient populations' preferences regarding CRC screening. Methods: We searched the CINAHL, PsycINFO, PubMed, Scopus, and Web of Science databases for articles published between January 1, 1996 and December 31, 2017. We screened studies for eligibility and systematically abstracted and compared study designs and outcomes. Results: A total of 43 articles met the inclusion criteria, out of 2,106 articles found in our search. These 43 articles were organized by the primary sub-population(s) whose preferences were reported: 27 report on preferences among racial/ethnic minorities, eight among low-income groups, six among veterans, and two among rural populations. The majority of studies (n=34) focused on preferences related to test modality. No single test modality was overwhelmingly supported by all sub-populations, although veterans seemed to prefer colonoscopy. Test attributes such as accuracy, sensitivity, cost, and convenience were also noted as important features. Furthermore, a preference for shared decision-making between vulnerable patients and providers was found. Conclusion: The heterogeneity in study design, populations, and outcomes of the selected studies revealed a wide spectrum of CRC screening preferences within vulnerable populations. More decision aids and discrete choice experiments that focus on vulnerable populations are needed to gain a more nuanced understanding of how vulnerable populations weigh particular features of screening methods. Improved CRC screening rates may be achieved through the alignment of vulnerable populations' preferences with screening program design and provider practices. Collaborative decision-making between providers and vulnerable patients in preventive care decisions may also be important. PMID- 30464419 TI - A systematic review of questionnaires about patient's values and preferences in clinical practice guidelines. AB - Objective: We conducted a systematic review to evaluate questionnaires about patient's values and preferences to provide information on the most appropriate questionnaires to be used when developing clinical practice guidelines. Methods: A systematic literature search of the Cochrane Library, MEDLINE, Embase, Web of Science, Chinese Biomedical Database, China National Knowledge Infrastructure, and the Wanfang Database was performed to identify studies on questionnaires evaluating patient's values and preferences. The articles that used fully structured questionnaires or scales with standardized questions and answer options were included. We assessed the questionnaires' construction and content with a psychometric methodology and summarized the domains and items about patient's preferences and values. Results: A total of 7,008 records were retrieved by the search strategy and scanned, and 20 articles were finally included. Of these, 10 (50%) articles described the process of item generation and only four questionnaires (20%, 4/20) mentioned the pilot testing. Regarding "validity", seven questionnaires (35%, 7/20) assessed validity and only one (5%, 1/20) questionnaire assessed internal consistency, with Cornbrash's alpha values of 0.74-0.87. For "acceptability", the time to complete the questionnaires ranged from 10 to 30 minutes and only nine studies (45%, 9/20) reported the response rates. In addition, the results of domains and items about patient's preferences and values showed that the "effectiveness" domain was the most considered item in the patient's value questionnaire followed by "safety", "prognosis", and others, whereas the least considered domain was "physician's experience". Conclusion: Only a few studies have developed questionnaires with rigorous psychometric methods to measure patient's preferences and values. Currently, still there is no valid or reliable questionnaire for patient's preferences and values for use when developing clinical practice guidelines. Further study should be conducted to develop standardized instruments to measure patient's preferences and values. This study provides the domains and items that may be used in formulating questionnaires about patient's preferences and values. PMID- 30464421 TI - How to meet patients' individual needs for drug information - a scoping review. AB - Purpose: The aim of this study was to 1) describe drug information desired by patients and 2) analyze how such information could be customized to be presented to patients according to their individual information needs. Materials and methods: We performed a scoping literature search and identified relevant drug information topics by assessing and clustering 1) studies analyzing patients' enquiries to drug information hotlines and services, and 2) qualitative studies evaluating patient drug information needs. For the two most frequently mentioned topics, we further analyzed which components (ie, information domains) the topics contained and examined patients' and health care professionals' (HCPs) views on these components. Results: Of 27 identified drug information topics in the literature search, patients most frequently requested information on adverse drug reactions (ADRs) and drug-drug interactions (DDIs). Hypothetically, those topics are composed of seven distinct information domains each (eg, ADR and DDI classification by frequency, severity, or onset; information on management strategies, monitoring, and prevention strategies). Patients' and HCPs' appraisal concerning the information content of these domains varies greatly and is even lacking sometimes. Conclusion: Patients particularly request information on ADRs and DDIs. Approaches to customize such information are sparse. The identified information domains of each topic could be used to structure corresponding drug information and to thus facilitate customization to individual information needs. PMID- 30464420 TI - Health literacy in solid-organ transplantation: a model to improve understanding. AB - Optimizing wellness and health are the most critical goals for patients post solid-organ transplantation. Low health literacy has important implications for wellness and health, increasing patient risk for negative health outcomes. More than 30% of the general US patient population has low health literacy, and solid organ transplant recipients (SOTRs) may be especially vulnerable to low health literacy and its adverse impact on health outcomes. A comprehensive literature review was conducted and a model was adapted to better depict factors associated with low health literacy. Based on the Paasche-Orlow and Wolf model of health literacy, the Health Literacy Model in Transplantation (HeaL-T) provides a foundation to visually demonstrate the relationships among variables associated with low health literacy and to develop evidence-based strategies to improve care. The model depicts a number of patient and healthcare level factors associated with health literacy, several of which have bi-directional or reciprocal relationships, including access and utilization of healthcare, provider-patient interaction, and self-management/adherence. The impact of these factors and their relationships to SOTR outcomes are reviewed. The HeaL-T represents an important step in developing holistic understanding of the complexity of health literacy in SOTRs and offers clinicians a base from which to design strategies to mitigate adverse health effects including increased hospitalizations, graft failure, and mortality. PMID- 30464422 TI - Analysis of riluzole's profile of use in a Central Hospital in Lisbon. AB - Purpose: Riluzole is indicated to prolong life or delay the institution of mechanical ventilation in patients with amyotrophic lateral sclerosis (ALS). Clinical studies have shown that this drug prolongs survival, defined as living patients who are not intubated for mechanical ventilation and without tracheotomy. The purpose of this study is to characterize riluzole's use as well as the user population in order to contribute to a rational and safe use. Patients and methods: Descriptive, observational, retrospective study describing and characterizing the use of riluzole in ALS patients between July 2006 and December 2016 conducted in a Lisbon's Central Hospital. Results: Over the course of the study period, 77 patients with different phenotypes of ALS received riluzole. The majority of patients (63%, n=49) were male. The median survival was 10.1 months, but 12 patients (16%) remained on therapy for more than 3 years; 65% of patients were lost to follow-up. The mean adherence rate was 91.2%, and the median adherence rate was 99.3%. One patient discontinued therapy due to gastrointestinal intolerance. Dyspnea and cough were the most common side effects, with roughly one third of patients experiencing each, followed by asthenia and hepatic effects. Conclusion: Despite the extended enrollment period, only 77 patients met the criteria for study inclusion. Nonetheless, statistical data regarding our population is in accordance with reported international data. High adherence rates were observed, but 14% of patients discontinued riluzole. In such cases, assessment by a multidisciplinary team is warranted. PMID- 30464423 TI - Factors influencing the quality of life perceptions of cognitively impaired older adults in a nursing home and their informal and professional caregivers: a mixed methods study. AB - Background: Identifying the objective and subjective aspects of the quality of life (QoL) of institutionalized cognitively impaired older adults (CIOAs) is a challenge. However, it can reveal which aspects of their care require improvement. Aim: The aim of this study was to identify the core aspects of the QoL of CIOAs living in a nursing home (NH) by involving informal and professional caregivers (PCs). Methods: Our sequential, mixed methods study exploring the QoL of CIOAs was based on Lodgson et al's (2002) quantitative quality of life Alzheimer's disease (QoL-AD) questionnaire. Subsequently, a qualitative phase study analyzed perceptions and impressions of QoL using interviews of CIOAs and their most significant informal caregivers (SICs) and PCs. Results: Fifteen CIOAs, 12 SICs, and 2 PCs were recruited. Two-thirds of the older adults were females, overall average age was 86 years (SD=6.1), and all had a severe clinical dementia rating (CDR=3). A high level of comorbidity (measured using the Cumulative Illness Rating Scale for Geriatrics) was significantly associated with a lower QoL-AD score (P=0.046). Higher numbers of visits by SICs or family members had a positive effect on QoL-AD scores (P=0.036). No significant differences were found in overall QoL-AD scores as rated by CIOAs, SICs, and PCs (P=0.080). Combining quantitative and qualitative data analyses revealed four significant themes influencing the QoL of CIOAs: 1) human dignity and acceptance; 2) development and existence; 3) functionality and health; and 4) recognizability and safety. Conclusion: Sequentially using mixed methods proved an appropriate way to examine the QoL of severe CIOAs living in an NH, and these results were compared with the perceptions of informal and PCs. The factors optimizing overall health were visits by SICs and family members, and the major aspect that increases the QoL was freedom of movement inside and outside the NH. PMID- 30464424 TI - Falls among physically active elderly in senior housings, Bangkok, Thailand: situations and perceptions. AB - Purpose: A mixed-method study aimed to assess situations in which falls occur including prevalence and associated risk factors of falls among physically active elderly who are at risk of experiencing a fall in senior housings, Bangkok, Thailand, and their perceptions regarding falls. Patients and methods: In the first phase, a cross-sectional study was conducted on 64 physically active elderly senior housing residents. Data on sociodemographics, health status, Barthel Index (BI) of activities of daily living, and fall experiences were collected through face-to-face interviews. Data on balance scores were obtained from Time Up and Go (TUG) test and Berg Balance Scale (BBS). In the second phase, a qualitative study was conducted on 41 physically active elderly who had experienced falls. Data regarding perception on falls, fall preventions, and fall management, were gathered through in-depth interviews from November 2017 to December 2017. Results: The prevalence of falls among participants in senior housings was 64.1%. Univariate analysis found that a higher BI was associated with fall (P<0.004). Multivariate analysis using binary logistic regression showed that a higher BI (OR=6.00, 95% CI=1.24-29.10) together with >=2 environmental hazards (OR=6.33, 95% CI=1.24-32.29) were associated with fall. The result from content analysis indicated that the elderly were aware that they were at risk of fall. In addition, the elderly also perceived that fall could be avoided even though they did not know how to prevent it. Conclusion: The prevalence of fall among physically active elderly in senior housings was relatively high. A higher BI scale and having >=2 environmental hazards were associated risk factors of falls. Although the elderly perceived that fall could be avoided, they did not know how to prevent it. The intervention that focuses on environmental modification, balancing enchantment, and education on fall prevention is highly required. PMID- 30464425 TI - Aortic stiffness and brain integrity in elderly patients with cognitive and functional complaints. AB - Purpose: Cerebral white matter lesions (WML) and brain atrophy are frequent in older persons and are associated with adverse outcomes. It has been suggested that aortic stiffness plays a role in the pathogenesis of WML and gray matter (GM) loss. There is, however, little evidence on the association between aortic stiffness and brain integrity in older patients. In this study, we investigated whether aortic stiffness is associated with WML and GM volume in older patients with cognitive and functional complaints. Patients and methods: Fazekas score was used to analyze WML on brain imaging data of 84 persons; in a subanalysis on 42 MRI scans, the exact volume of white matter hyperintensities (WMH) and GM was determined using a brain-tissue and WMH tool. Aortic stiffness, measured as aortic pulse wave velocity (aPWV) and central pulse pressure (cPP), and blood pressure levels were non-invasively measured by the Mobil-O-Graph. Results: Mean age was 76.6 (+/-6.8) years. Age was correlated with cPP (Spearman's rho =0.296, P=0.008), aPWV (r 2=0.785, P<0.001) and WMH volume (r 2=0.297, P<0.001). cPP did not differ between categories of Fazekas, whereas aPWV increased with increasing Fazekas score (P for trend <0.001). After additional adjustment for age, levels of aPWV did not differ between categories. Both cPP and aPWV were associated with WMH volumes (lnB 0.025, P=0.055 and lnB 0.405, P<0.001, respectively); after additional adjustment for age, estimates were less consistent. Both cPP and aPWV were negatively associated with GM volumes in multivariate analysis (B=2.805, P=0.094 and B=111.052, P=0.032). Conclusion: Higher aortic stiffness was partly associated with increased volume of WMH and decreased volume of GM and slightly influenced by blood pressure. Age also plays a role in this association in older patients. PMID- 30464426 TI - Effect of passive finger exercises on grip strength and the ability to perform activities of daily living for older people with dementia: a 12-week randomized controlled trial. AB - Background: Dementia adds burden to society. As it is not curable, physical exercise activities are optimal to improve the physical strength and quality-of life of people with dementia. Aim: Design, implementation, and examination of a set of passive finger exercises and their effects on improving grip strength and activities of daily living (ADL) for older people with dementia. Methods: Forty older people with dementia were recruited and randomly allocated into an experimental group and a control group, each with 20 people. The control group received routine nursing care. In addition to this, the experimental group received 25-minutes of passive finger exercises every day for 12 weeks. The health outcomes measured were grip strength and ADL, before and after the intervention. Grip strength was assessed by electrical hand muscle dynamometer. ADL were assessed with Barthel index. Results: Although there was no effect on grip strength, passive finger exercises led to significant improvements in urinary control, defecation function, and overall ADL in comparison with the control group. Implications for practice: Passive finger exercises can be integrated into physical exercise programs for older people with dementia to improve their urinary control, defecation function, and ADL. PMID- 30464427 TI - Treatment satisfaction with pharmaceutical interventions in Japanese adults with osteoarthritis and chronic knee pain: an analysis of a web-based survey. AB - Purpose: Patient satisfaction is an important outcome in successful osteoarthritis (OA) treatment. The aim of this study was to evaluate treatment satisfaction for medication (TSM) in people with knee OA (KOA), identify the factors predictive of treatment satisfaction, and describe the burden of illness. Patients and methods: This cross-sectional, patient-reported study used an Internet-based survey and analyzed responses of respondents with KOA (N=400) on characteristics including pain sites and levels (including pain ratings using the Numerical Rating Scale and Short-Form McGill Pain Questionnaire), treatment satisfaction (Global, Effectiveness, and Convenience scores) based on the Treatment Satisfaction Questionnaire for Medication (TSQM-9), and quality of life (QoL; based on the Arthritis Impact Measurement Scale 2-Short Form). Respondents with only KOA (n=237) were compared with those having KOA and additional painful sites (KOA+; n=163). Factors predicting TSM were identified using multivariable linear regression analyses. Results: Respondents with KOA were more likely to report intermittent pain for 3 months or more compared with those with KOA+ (58.6% vs 48.5%, respectively; P=0.044), while those with KOA+ were more likely to report consistent pain for 3 months or more (P=0.022). Respondents with KOA+ also had more difficulty due to their knee pain while sleeping (P=0.022) and resting (P=0.015). Reported TSM did not differ significantly across KOA vs KOA+ groups, with both groups reporting low satisfaction; all domains of QoL were worse for those with KOA+. Knee pain reduction by medication predicted higher satisfaction across domains, while lower pre-medication pain and post-medication pain matching expectations predicted higher TSQM-9 Global and Effectiveness scores. Conclusion: Medication treatment satisfaction rates were low among Japanese respondents with KOA. Given that lower pain, greater pain reduction post medication, and meeting pain management expectations were predictive of higher satisfaction, treatment strategies that can better address pain may prove beneficial for overall patient satisfaction. PMID- 30464428 TI - Ultrasound measurements of gastrocnemius muscle thickness in older people with sarcopenia. AB - Background: Sarcopenia, defined as low muscle mass and low muscle strength and/or low physical performance, is affecting more and more people. The European Working Group on Sarcopenia in Older People has suggested the routine community screening. However, selecting the most suitable method to evaluate muscle mass to detect sarcopenia in community screening is a challenge. This study sought to analyze the correlation between ultrasound (US) measurements of the gastrocnemius muscle and low muscle mass, as defined by sarcopenia. Methods: One hundred thirty five elderly participants were enrolled. US measurements included muscle thickness (MT), fat thickness (FT), MT/body mass index (BMI), and MT/FT. The definition of low muscle mass was based on the proposal from the Asian Working Group for Sarcopenia, in which the cutoff values for low muscle mass were 7.0 kg/m2 for men and 5.4 kg/m2 for women using dual energy X-ray absorptiometry (DXA). The participants were divided into low and normal muscle mass groups. Participants with low muscle mass were divided into presarcopenia, sarcopenia, and severe sarcopenia groups. Results: Those in the low muscle mass group were older and had lower weights and BMIs (P<0.05). In addition, MT and MT/BMI were lower in the low muscle mass group (P<0.05). Binary logistic regression analysis revealed that MT was the factor associated with low skeletal muscle mass (OR =0.001, P<0.001). ANOVA revealed that MT was not significantly different between subjects with presarcopenia, sarcopenia, and severe sarcopenia (F=1.69, P=0.192). Receiver operating characteristic curve analyses indicated that the cutoff value of the gastrocnemius MT for low muscle mass was 1.50 cm. Conclusion: MT measured by US was identified as the factor associated with low skeletal muscle mass. Those with gastrocnemius MT less than 1.5 cm can be considered as low muscle mass. PMID- 30464429 TI - Antibacterial treatment of aspiration pneumonia in older people: a systematic review. AB - Background: Aspiration pneumonia is a common problem in older people with high mortality and increasing prevalence. Objective: The aims of this paper were to systematically review the literature on the antibacterial treatment of aspiration pneumonia in elderly patients and identify the microbiology of aspiration pneumonia. Materials and methods: EMBASE, MEDLINE, and Cochrane databases were systematically searched for studies that examined the clinical efficacy of antibiotic treatment in elderly patients with aspiration pneumonia. Information on study design, antibiotic treatment, study population, participants, microbiology, clinical outcomes, adverse events, and mortality was recorded. Results: There were no definitive clinical trials, placebo-controlled trials, or meta-analyses. Of the eight studies selected for inclusion in the review, the majority utilized and/or compared broad-spectrum antibiotics. No specific antibacterial agent had evidence of superior efficacy. Broad-spectrum antibiotics resulted in the emergence of multiresistant organisms. Anaerobic bacteria were infrequently isolated, suggesting a less important role in the pathogenesis of aspiration pneumonia. Conclusion: There is limited evidence with regard to the use of antibiotics in older patients with aspiration pneumonia. Research providing an evidence base for the treatment of aspiration pneumonia in older people is required. PMID- 30464430 TI - The effects of an empowering self-management model on self-efficacy and sense of coherence among retired elderly with chronic diseases: a randomized controlled trial. AB - Background: Being elderly and retired are related phenomena that overlap in a time symmetry. The present study aimed to assess the effect of an empowering self management model on the self-efficacy and sense of coherence (SOC) in retired elderly with chronic diseases. Methods: A randomized controlled trial that included 60 elderly people was carried out in Bushehr (Iran) in 2016. The participants were randomly assigned to either a control group or an intervention group. Based on an empowering self-management model, the intervention group participated in a five-stage plan: 1) self-awareness of changes and understanding their personal level of performance and expectations; 2) optimal goal setting; 3) planning; 4) adjusting physical, psychological, and social structures; and 5) evaluation. Self-efficacy and SOC were measured using the questionnaires developed by Sherer and Antonovsky, respectively, before and after the intervention. The results of the observed differences between the groups were subsequently compared. Data were presented as mean+/-SD. Results: The mean change of the self-efficacy score in the intervention and control groups was 9.48+/-5.32 and 1.68+/- 6.04, respectively, (t[56]=5.20, P<0.001). The mean change of the SOC score in the intervention and control groups was 24.17+/-12.05 and 0.10+/-13.42, respectively, (t[56]=7.18, P<0.001). Conclusion: The applied empowering self management model led to an improved self-efficacy and SOC among the retired elderly with chronic diseases. This model can be used to empower the elderly to achieve comprehensibility, manageability, and meaningfulness in their lives. PMID- 30464431 TI - Categorization of sentence recognition for older adults under noisy and time altered conditions. AB - Purpose: While evaluating the speech recognition ability of older adults, the present study aimed to analyze their error types in parts of speech and find error patterns under various conditions of background noise level and speed of speech. Methods: Twenty older adults with normal hearing for their age (NHiA) and 20 older adults with sensorineural hearing loss (SNHL) participated. Their cognitive function was screened as within the normal range (mini-mental state examination scores >25). The SNHL listeners were divided into high performers (SNHL-H; n=12) and low performers (SNHL-L; n=8), based on their achieving word recognition scores above or below 70%, respectively. A sentence recognition test was conducted at four levels of signal-to-noise ratio (SNR; eg, no noise, +6, +3, 0 dB) and four conditions of time alteration (eg, 30% and 15% of compression and expansion) at the most comfortable level for each participant. Results: As expected, the three groups showed that the error percentage increased in sentence recognition as either the SNR decreased or the speech rate became faster. Interestingly, a larger performance difference was found between the SNHL-H and SNHL-L groups in the condition of time alteration than in that of background noise. Among the parts of speech, nouns presented the highest error scores for all participants regardless of degree of listening difficulty. The noun errors of the three groups mainly consisted of no response and fail patterns, but substitution and omission were identified as the third pattern of noun error for background noise and fast speech, respectively. Conclusion: Deterioration of speech recognition from the hearing threshold and supra-threshold auditory processing was seen in the elderly in difficult listening environments such as background noise and time alteration. Although different group performance ran across the eight experimental conditions, the robustness of noun errors and the error patterns were very similar, which might be extended to a possible clinical application of aural rehabilitation for the elderly population. PMID- 30464432 TI - Impact of frailty on do-not-resuscitate orders and healthcare transitions among elderly Koreans with pneumonia. AB - Purpose: Pneumonia poses a significant health risk in aging societies. We aimed to elucidate the determinative value of frailty for do-not-resuscitate (DNR) orders in pneumonia patients. Patients and methods: This was a retrospective cohort study conducted at the Seoul National University Bundang Hospital (SNUBH) in Korea. Medical records of 431 pneumonia patients, aged 65 years and older, who were admitted between June 2014 and May 2015 were analyzed. Patients were categorized into DNR and no-DNR groups. Results: Among the 65 patients (15.1% of pneumonia patients) who completed DNR documents, 24 patients were survived, and 21 patients decided imminent to death (<24 hours before death), with all decisions determined by surrogates. The DNR group tended to be older and frail, with higher rates of renal impairment and malnutrition, and had a lower microbiology detection effort than the no-DNR group. The DNR group used a high number of broad-spectrum antibiotics, experienced high levels of in-hospital (63.1% vs 5.7%, P<0.001) and 30-day (64.6% vs 9.6%, P<0.001) mortality rates, and had prolonged hospital stays (median length of hospital stay, 12 vs 9 days, P=0.020). Frailty was independently associated with DNR status even after adjustment for sepsis, septic shock, and the pneumonia severity index (PSI) score. Frailty also significantly influenced healthcare setting transitions after adjustment for sepsis, septic shock, and the PSI. Conclusion: We identified the factors associated with DNR orders and their prognoses among elderly Koreans with pneumonia. Frailty was significantly associated with DNR decision and healthcare setting transitions in pneumonia patients. PMID- 30464433 TI - Prevalence of thiamine deficiency in older hospitalized patients. AB - Purpose: Despite some reports of high prevalence of thiamine deficiency in elderly people, the reported prevalence is controversial mainly due to the methods used in assessing thiamin concentrations. In this study, we sought to investigate the prevalence of vitamin B1 deficiency, using the high-performance liquid chromatography (HPLC) method, among older hospitalized patients. Patients and methods: This cross-sectional study retrospectively analyzed the results of routine measurements of vitamin B1 of 238 older patients who were consecutively hospitalized to a geriatric acute care ward. Whole blood vitamin B1 concentrations were measured using the HPLC method at hospital admission, and the whole blood vitamin B1 level of <20 ng/mL was considered as deficiency. Results: Of 238 patients, with a mean age of 82.1+/-7.1 years, 63% of patients were women. In total, the mean whole blood vitamin B1 level was 66.1+/-24.8 ng/mL (range 29.5 215 ng/mL), indicating no vitamin B1 deficiency in the entire population. In addition, no significant differences in the mean whole blood vitamin B1 concentrations between sexes were observed (P=0.356). Conclusion: This study indicates that the mean whole blood vitamin B1 concentrations using the HPLC method were within the normal range in older hospitalized patients suggesting that thiamine deficiency appears to be rather uncommon among these patients. PMID- 30464435 TI - Understanding low COPD exacerbation rates in Japan: a review and comparison with other countries. AB - COPD is associated with significant morbidity and is one of the leading causes of death worldwide. Periods of exacerbation, the acute worsening of symptoms, are interspersed throughout the disease's natural history and can result in increased treatment burden and hospitalization for patients with COPD. The frequency of exacerbations varies between countries, with both epidemiological studies and randomized controlled trials (RCTs) showing significant differences in observed prevalence rates. Differences in study design and the healthcare setting are likely to contribute to differences in exacerbation frequency, however the perceived rate of exacerbations in Japan is currently lower then the rest of the world. This review identified nine cohort studies and five RCTs that reported COPD annual exacerbation rates in Japan in the ranges of 0.1-2.1 and 0.33-1.79, respectively. The difference in exacerbation rate between studies appeared greater than the difference between Japan and Western countries, likely because of disparities between settings, design, and inclusion criteria. Of these, only one (Understanding the Long-Term Impacts of Tiotropium) had uniform inclusion criteria across different regions. This study found that the annual rate of exacerbation events per patient in Japan was 0.61, compared with 0.85 worldwide in the placebo groups. This review summarizes the published rates of COPD exacerbations in Japan and the rest of the world and explores the hypotheses as to why rates in Japan might be lower than other countries. These include access to medical care, variance in the associated morbidity profile, environmental factors, diagnostic crossover with related diseases, and differences in study design (including the underreporting of COPD exacerbations in Japan). Understanding the reasons why COPD exacerbation rates appear lower in Japan could help clinicians to recognize and modify treatment behaviors, which may lead to improved patient outcomes in all populations. PMID- 30464434 TI - Benign paroxysmal positional vertigo in the elderly: current insights. AB - Balance disorders, unsteadiness, dizziness and vertigo in the elderly are a significant health problem, needing appropriate treatment. One third of elderly patients with vertigo were diagnosed with benign paroxysmal positional vertigo (BPPV), the most common cause of dizziness in both primary care specialist Neurology and Ear Nose Throat settings. BPPV presents a specific paroxysmal positional nystagmus which can be obtained using the appropriate diagnostic positional test and can be treated effectively using specific therapeutic maneuvers. This review presents current insights into the diagnostic, pathogenetic and therapeutic aspects of BPPV in the elderly. BPPV in older patients does not differ significantly from BPPV in younger patients, with regard to pathogenesis, diagnosis and treatment. However, in older patients, its prevalence is higher and it responds less effectively to treatment, having a tendency for recurrence. Specific issues which should be considered in the elderly are: 1) difficulty in obtaining an accurate history; 2) difficulty in performing the diagnostic and therapeutic maneuvers, which should be executed with slow and gentle movements and extremely cautiously to avoid any vascular or orthopedic complications; and 3) the relation between BPPV and falls. PMID- 30464436 TI - Exercise performance and symptoms in lowlanders with COPD ascending to moderate altitude: randomized trial. AB - Objective: To evaluate the effects of altitude travel on exercise performance and symptoms in lowlanders with COPD. Design: Randomized crossover trial. Setting: University Hospital Zurich (490 m), research facility in mountain villages, Davos Clavadel (1,650 m) and Davos Jakobshorn (2,590 m). Participants: Forty COPD patients, Global Initiative for Obstructive Lung Disease (GOLD) grade 2-3, living below 800 m, median (quartiles) age 67 y (60; 69), forced expiratory volume in 1 second 57% predicted (49; 70). Intervention: Two-day sojourns at 490 m, 1,650 m, and 2,590 m in randomized order. Outcome measures: Six-minute walk distance (6MWD), cardiopulmonary exercise tests, symptoms, and other health effects. Results: At 490 m, days 1 and 2, median (quartiles) 6MWD were 558 m (477; 587) and 577 m (531; 629). At 2,590 m, days 1 and 2, mean changes in 6MWD from corresponding day at 490 m were -41 m (95% CI -51 to -31) and -40 m (-53 to -27), n=40, P<0.05, both changes. At 1,650 m, day 1, 6MWD had changed by -22 m (-32 to 13), maximal oxygen uptake during bicycle exercise by -7% (-13 to 0) vs 490 m, P<0.05, both changes. At 490 m, 1,650 m, and 2,590 m, day 1, resting PaO2 were 9.0 (8.4; 9.4), 8.1 (7.5; 8.6), and 6.8 (6.3; 7.4) kPa, respectively, P<0.05 higher altitudes vs 490 m. While staying at higher altitudes, nine patients (24%) experienced symptoms or adverse health effects requiring oxygen therapy or relocation to lower altitude. Conclusion: During sojourns at 1,650 m and 2,590 m, lowlanders with moderate to severe COPD experienced a mild reduction in exercise performance and nearly one quarter required oxygen therapy or descent to lower altitude because of adverse health effects. The findings may help to counsel COPD patients planning altitude travel. Registration: ClinicalTrials.gov: NCT01875133. PMID- 30464437 TI - Outcomes for symptomatic non-obstructed individuals and individuals with mild (GOLD stage 1) COPD in a population based cohort. AB - Background: We aimed to study the adverse outcomes of symptomatic and asymptomatic non-obstructed individuals and those with mild COPD longitudinally in participants from three Latin-American cities. Methods: Two population-based surveys of adults with spirometry were conducted for these same individuals with a 5- to 9-year interval. We evaluated the impact of respiratory symptoms (cough, phlegm, wheezing or dyspnea) in non-obstructed individuals, and among those classified as Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1, COPD on exacerbation frequency, mortality and FEV1 decline, compared with asymptomatic individuals without airflow obstruction or restriction. Results: Non obstructed symptomatic individuals had a marginal increased risk of mortality (HR 1.3; 95% CI 0.9-1.94), increased FEV1 decline (-4.5 mL/year; 95% CI -8.6, -0.4) and increased risk of 2+ exacerbations in the previous year (OR 2.6; 95% CI 1.2 6.5). Individuals with GOLD stage 1 had a marginal increase in mortality (HR 1.5; 95% CI 0.93-2.3) but a non-significant impact on FEV1 decline or exacerbations compared with non-obstructed individuals. Conclusions: The presence of respiratory symptoms in non-obstructed individuals was a predictor of mortality, lung-function decline and exacerbations, whereas the impact of GOLD stage 1 was mild and inconsistent. Respiratory symptoms were associated with asthma, current smoking, and the report of heart disease. Spirometric case-finding and treatment should target individuals with moderate-to-severe airflow obstruction and those with restriction, the groups with consistent increased mortality. PMID- 30464440 TI - Erratum: Tiotropium/olodaterol versus tiotropium in Japanese patients with COPD: results from the DYNAGITO study [Corrigendum]. AB - [This corrects the article on p. 2147 in vol. 13, PMID: 30034230.]. PMID- 30464438 TI - Influence of the type of emphysema in the relationship between COPD and lung cancer. AB - Introduction: There are no studies analyzing the relationship between emphysema and lung cancer (LC). With this aim and in order to make some comparisons between different clinical variables, we carried out the present study. Methods: This is a case-control study, patients with COPD and LC being the cases and subjects with stable COPD being the controls. Clinical and functional parameters, as well as the existence of radiological emphysema, were evaluated in a qualitative and quantitative way, using a radiological density of -950 Hounsfield units as a cutoff point in the images. The existence of several different types of emphysema (centrilobular, paraseptal, panacinar, or bullae) was analyzed, allowing patients to have more than one simultaneously. The extent to which lobes were involved was evaluated and the extension of emphysema was graduated for each type and location, following a quantitative scale. Differences between cases and controls were compared by using bivariate and multivariate analyzes with results expressed as OR and 95% CI. Results: We included 169 cases and 74 controls, 84% men with a FEV1 (%) of 61.7+/-18.5, with 90.1% non-exacerbators. Most of them (50%) were active smokers and 47.2% were ex-smokers. Emphysema was found in 80.2% of the subjects, the most frequent type being centrilobular (34.4%). The only significantly different factor was the presence of paraseptal emphysema (alone or combined; OR =2.2 [95% CI =1.1-4.3, P = 0.03]), with adenocarcinoma being significantly more frequent in paraseptal emphysema with respect to other types (67.2% vs 32.8%, P =0.03). Conclusion: Patients with COPD and paraseptal emphysema could be a risk group for the development of LC, especially adenocarcinoma subtype. PMID- 30464439 TI - Interventions to increase referral and uptake to pulmonary rehabilitation in people with COPD: a systematic review. AB - Pulmonary rehabilitation (PR) reduces the number and duration of hospital admissions and readmissions, and improves health-related quality of life in patients with COPD. Despite clinical guideline recommendations, under-referral and limited uptake to PR contribute to poor treatment access. We reviewed published literature on the effectiveness of interventions to improve referral to and uptake of PR in patients with COPD when compared to standard care, alternative interventions, or no intervention. The review followed recognized methods. Search terms included "pulmonary rehabilitation" AND "referral" OR "uptake" applied to MEDLINE, EMBASE, CINAHL, PsycINFO, ASSIA, BNI, Web of Science, and Cochrane Library up to January 2018. Titles, abstracts, and full papers were reviewed independently and quality appraised. The protocol was registered (PROSPERO # 2016:CRD42016043762). We screened 5,328 references. Fourteen papers met the inclusion criteria. Ten assessed referral and five assessed uptake (46,146 patients, 409 clinicians, 82 hospital departments, 122 general practices). One was a systematic review which assessed uptake. Designs, interventions, and scope of studies were diverse, often part of multifaceted evidence-based management of COPD. Examples included computer-based prompts at practice nurse review, patient information, clinician education, and financial incentives. Four studies reported statistically significant improvements in referral (range 3.5%-36%). Two studies reported statistically significant increases in uptake (range 18%-21.5%). Most studies had methodological and reporting limitations. Meta-analysis was not conducted due to heterogeneity of study designs. This review demonstrates the range of approaches aimed at increasing referral and uptake to PR but identifies limited evidence of effectiveness due to the heterogeneity and limitations of study designs. Research using robust methods with clear descriptions of intervention, setting, and target population is required to optimize access to PR across a range of settings. PMID- 30464442 TI - Erratum: The impact of dual bronchodilation on cardiovascular serious adverse events and mortality in COPD: a quantitative synthesis [Corrigendum]. AB - [This corrects the article on p. 3469 in vol. 12, PMID: 29255354.]. PMID- 30464441 TI - Blood eosinophil count as a prognostic biomarker in COPD. AB - Background: High blood eosinophil count is a predictive biomarker for response to inhaled corticosteroids in prevention of acute exacerbation of COPD, and low blood eosinophil count is associated with pneumonia risk in COPD patients taking inhaled corticosteroids. However, the prognostic role of blood eosinophil count remains underexplored. Therefore, we investigated the associated factors and mortality based on blood eosinophil count in COPD. Methods: Patients with COPD were recruited from 16 hospitals of the Korean Obstructive Lung Disease cohort (n=395) and COPD in Dusty Area cohort (n=234) of Kangwon University Hospital. The two merged cohorts were divided based on blood eosinophil count into three groups: high (>=5%), middle (2%-5%), and low (<2%). Results: The high group had longer six-minute walk distance (high =445.8+/-81.4, middle =428.5+/-88.0, and low =414.7+/-86.3 m), higher body mass index (23.3+/-3.1, 23.1+/-3.1, and 22.5+/ 3.2 kg/m2), lower emphysema index (18.5+/-14.1, 22.2+/-15.3, and 23.7+/-16.3), and higher inspiratory capacity/total lung capacity ratio (32.6+/-7.4, 32.4+/ 9.2, and 29.9% +/- 8.9%) (P<0.05). The survival period increased with increasing blood eosinophil count (high =9.52+/-0.23, middle =8.47+/-1.94, and low =7.42+/ 0.27 years, P<0.05). Multivariate linear regression analysis revealed that the emphysema index was independently and negatively correlated with blood eosinophil count (P<0.05). Conclusion: In COPD, the severity of emphysema was independently linked with low blood eosinophil count and the longer survival period was associated with increased blood eosinophil count, though it was not proven in the multivariate analysis. PMID- 30464443 TI - Exercise capacity in COPD patients with exercise-induced pulmonary hypertension. AB - Background: Pulmonary hypertension (PH) in patients with COPD is associated with reduced exercise capacity. A subgroup of COPD patients has normal mean pulmonary artery pressure (mPAP) at rest, but develops high mPAP relative to cardiac output (CO) during exercise, a condition we refer to as exercise-induced pulmonary hypertension (EIPH). We hypothesized that COPD patients with EIPH could be identified by cardiopulmonary exercise test (CPET) and that these patients have lower exercise capacity and more abnormal CPET parameters compared to COPD patients with normal hemodynamic exercise response. Methods: Ninety-three stable outpatients with COPD underwent right heart catheterization with the measurement of mPAP, CO, and capillary wedge pressure at rest and during supine exercise. Resting mPAP <25 mmHg with DeltamPAP/DeltaCO slope above or below 3 mmHg/L/min were defined as COPD-EIPH and COPD-normal, respectively. Pulmonary function tests and CPET with arterial blood gases were performed. Linear mixed models were fitted to estimate differences between the groups with adjustment for gender, age, and airflow obstruction. Results: EIPH was observed in 45% of the study population. Maximal workload was lower in COPD-EIPH compared to COPD-normal, whereas other CPET measurements at peak exercise in % predicted values were similar between the two groups. After adjustment for gender, age, and airflow obstruction, patients with COPD-EIPH showed significantly greater increase in oxygen uptake, ventilation, respiratory frequency, heart rate, and lactate with increasing work load, as well as more reduction in pH compared to those with normal hemodynamic responses. Conclusion: COPD-EIPH could not be discriminated from COPD-normal by CPET. However, COPD-EIPH experienced a higher cost of exercise in terms of higher oxygen uptake, ventilation, respiratory frequency, heart rate, and lactate for a given increase in workload compared to COPD-normal. PMID- 30464444 TI - Cholinergic mechanisms in an organic dust model simulating an acute exacerbation in patients with COPD. AB - Background: Exposure in a pig barn induces airway inflammation that has similarities with the response observed in acute exacerbations in COPD. Methods: A total of 15 smokers with COPD and 15 healthy non-smokers were exposed for 2 hours in a pig barn (in vivo exposure). Symptoms were assessed, lung function measured, and blood and sputum samples taken before and after exposure. Blood neutrophils were isolated and stimulated ex vivo with dust from a pig barn and acetylcholine, and inflammatory markers were analyzed. Results: In vivo exposure caused more symptoms and greater lung function fall in COPD patients than in controls. Baseline concentrations of MMP9, TIMP1, IL6, CXCL8, in sputum and neutrophil blood count were higher in COPD patients than in controls. In vivo exposure increased MMP9, TIMP1, IL6, CXCL8, TNFalpha, and LTB4 in sputum and MMP9 and IL6 in blood, with no difference between the groups, and serum CRP increased more in COPD subjects. Expression of choline acetyltransferase and acetylcholinesterase on sputum and blood cells was similar in the groups and uninfluenced by in vivo exposure. Dust exposure ex vivo increased choline acetyltransferase expression in neutrophils, but the dust and acetylcholine response did not differ between the groups before and after in vivo exposure. Conclusion: COPD patients exposed in a pig barn experience symptoms similar to those in acute exacerbations and lung function deterioration that is unrelated to bronchial responsiveness. Cholinergic mechanisms are involved in the inflammatory response to dust, with no difference between COPD and non-smokers. PMID- 30464445 TI - Improvement in hypercapnia does not predict survival in COPD patients on chronic noninvasive ventilation. AB - Purpose: It has recently been shown that chronic noninvasive ventilation (NIV) improves a number of outcomes including survival, in patients with stable hypercapnic COPD. However, the mechanisms responsible for these improved outcomes are still unknown. The aim of the present study was to identify parameters associated with: 1) an improved arterial partial pressure of carbon dioxide (PaCO2) and 2) survival, in a cohort of hypercapnic COPD patients treated with chronic NIV. Patients and methods: Data from 240 COPD patients treated with chronic NIV were analyzed. Predictors for the change in PaCO2 and survival were investigated using multivariate linear and Cox regression models, respectively. Results: A higher level of bicarbonate before NIV initiation, the use of higher inspiratory ventilator pressures, the presence of anxiety symptoms, and NIV initiated following an exacerbation compared to NIV initiated in stable disease were associated with a larger reduction in PaCO2. A higher body mass index, a higher FEV1, a lower bicarbonate before NIV initiation, and younger age and NIV initiation in stable condition were independently associated with better survival. The change in PaCO2 was not associated with survival, neither in a subgroup of patients with a PaCO2 >7.0 kPa before the initiation of NIV. Conclusion: Patients with anxiety symptoms and a high bicarbonate level at NIV initiation are potentially good responders in terms of an improvement in hypercapnia. Also, higher inspiratory ventilator pressures are associated with a larger reduction in PaCO2. However, the improvement in hypercapnia does not seem to be associated with an improved survival and emphasizes the need to look beyond PaCO2 when considering NIV initiation. PMID- 30464446 TI - Nasal high flow, but not supplemental O2, reduces peripheral vascular sympathetic activity during sleep in COPD patients. AB - Introduction: Patients with COPD have increased respiratory loads and altered blood gases, both of which affect vascular function and sympathetic activity. Sleep, particularly rapid eye movement (REM) sleep, is known to exacerbate hypoxia and respiratory loads. Therefore, we hypothesize that nasal high flow (NHF), which lowers ventilatory loads, reduces sympathetic activity during sleep and that this effect depends on COPD severity. Methods: We performed full polysomnography in COPD patients (n=17; FEV1, 1.6+/-0.6 L) and in matched controls (n=8). Participants received room air (RA) at baseline and single night treatment with O2 (2 L/min) and NHF (20 L/min) in a random order. Finger pulse wave amplitude (PWA), a measure of vascular sympathetic tone, was assessed by photoplethysmography. Autonomic activation (AA) events were defined as PWA attenuation >=30% and indexed per hour for sleep stages (AA index [AAI]) at RA, NHF, and O2). Results: In COPD, sleep apnea improved following O2 (REM-apnea hypopnea index [AHI] with RA, O2, and NHF: 18.6+/-20.9, 12.7+/-18.1, and 14.4+/ 19.8, respectively; P=0.04 for O2 and P=0.06 for NHF). REM-AAI was reduced only following NHF in COPD patients (AAI-RA, 21.5+/-18.4 n/h and AAI-NHF, 9.9+/-6.8 n/h, P=0.02) without changes following O2 (NHF-O2 difference, P=0.01). REM-AAI reduction was associated with lung function expressed as FEV1 and FVC (FEV1: r= 0.59, P=0.001; FEV1/FVC: r=-0.52 and P=0.007). Conclusion: NHF but not elevated oxygenation reduces peripheral vascular sympathetic activity in COPD patients during REM sleep. Sympathetic off-loading by NHF, possibly related to improved breathing mechanics, showed a strong association with COPD severity. PMID- 30464447 TI - Endobronchial coil treatment in severe emphysema patients with alpha-1 antitrypsin deficiency. AB - Endobronchial coil treatment (ECT) is a minimally invasive procedure developed for palliative care of patients with severe emphysema. ECT has demonstrated a decrease in hyperinflation, an improvement in quality of life, and an acceptable safety profile in randomized controlled trials (RCTs). Because alpha-1 antitrypsin deficiency (AATD) is a classical exclusion criterion in RCTs, there is no available data for ECT in AATD. In this post hoc analysis of the REVOLENS study (Reduction volumique endobronchique par spirales; ClinicalTrials.gov Identifier: NCT01822795), a multicenter 1:1 RCT which compared bilateral ECT with usual care in severe emphysema, we analyzed the efficacy and safety results at 1 year in six patients with AATD (five males, one female; mean age: 52+/-9 years) who underwent ECT. A significant decrease in hyperinflation (0.35 L decrease in residual volume [RV]) was observed in four out of six patients at 6 months and three out of six patients at 12 months, and an improvement in quality of life (improvement of 4 points in the St George's Respiratory Questionnaire [SGRQ]) was observed in four out of six patients at both 6 and 12 months. Efficacy results at 6 and 12 months from the six AATD patients were compared with 84 non-AATD patients who underwent ECT, and no statistically significant differences were found for FEV1, RV, 6MWT score and SGRQ score. Respiratory-related serious adverse event was limited to pneumonia in one AATD patient at 1 year post-ECT. This post hoc study suggests that AATD patients may have similar efficacy and safety outcomes at 1 year as non-AATD patients. Because of the paucity of available data, appropriately powered studies are needed to determine the effects of ECT in AATD. PMID- 30464448 TI - Defining the role of neutrophil-to-lymphocyte ratio in COPD: a systematic literature review. AB - COPD is characterized by a pulmonary and systemic inflammatory process. Several authors have reported the elevation of multiple inflammatory markers in patients with COPD; however, their use in routine clinical practice has limitations. The neutrophil-to-lymphocyte ratio (NLR) is a useful and cost-effective inflammatory marker derived from routine complete blood count. We performed a systematic literature review using the PRISMA statement. Twenty-two articles were included, recruiting 7,601 COPD patients and 784 healthy controls. Compared with controls, COPD patients had significantly higher NLR values. We found a significant correlation between the NLR and clinical/functional parameters (FEV1, mMRC, and BODE index) in COPD patients. Elevation of the NLR is associated with the diagnosis of acute exacerbation of COPD (pooled data propose a cut-off value of 3.34 with a median sensitivity, specificity, and area under the curve of 80%, 86%, and 0.86, respectively). Additionally, increased NLR is also associated with the diagnosis of a bacterial infection in exacerbated patients, with a cut-off value of 7.30, although with a low sensitivity and specificity. The NLR is an independent predictor of in-hospital and late mortality after exacerbation. In conclusion, the NLR could be a useful marker in COPD patients; however, further studies are needed to better identify the clinical value of the NLR. PMID- 30464449 TI - Blood eosinophils: a biomarker of COPD exacerbation reduction with inhaled corticosteroids. AB - Background: Growing evidence suggests that blood eosinophil count is associated with patient responsiveness to inhaled corticosteroids (ICS). We performed post hoc predictive modeling on data from the FORWARD study and two replicate studies by Dransfield, to evaluate the relationships between baseline eosinophil count and the effect of ICS on exacerbations and lung function in patients with COPD. Methods: The studies assessed ICS/long-acting beta2 agonist (LABA) combinations vs LABA alone. Using data from each study, we modeled COPD exacerbation rates, predose FEV1, and St George's Respiratory Questionnaire score ([FORWARD only]) over a continuous range of eosinophils (0-1,000 eosinophils/uL in FORWARD, 0-993 eosinophils/uL in Dransfield). Results: In all studies, ICS/LABA reduced exacerbations versus LABA alone across all eosinophil levels, with progressively greater reductions at increasing baseline blood eosinophil counts. In FORWARD, annual exacerbation rates ranged from 0.78 to 0.83 per year between 0 and 1,000 eosinophils/uL in the ICS/LABA arm, and from 0.81 to 1.54 per year in the LABA only arm. In the Dransfield studies, exacerbation rates ranged from 0.54 to 1.02 per year in the ICS/LABA arm between 0 and 993 eosinophils/uL, and from 0.56 to 1.75 per year in the LABA-only arm. Change in FEV1 was not associated with eosinophil count in ICS-treated patients in FORWARD, whereas an increased treatment benefit in terms of FEV1 was observed at higher eosinophil levels in the Dransfield studies. ICS/LABA led to greater improvements in St George's Respiratory Questionnaire total scores compared to LABA alone in patients in FORWARD with >=67 eosinophils/uL. Conclusion: Higher blood eosinophil count in patients with COPD is associated with an increased beneficial effect from ICS in terms of exacerbation reduction. Further prospective data are required to assess the role of blood eosinophils as a biomarker for therapeutic recommendations. PMID- 30464450 TI - Peptide T7-modified polypeptide with disulfide bonds for targeted delivery of plasmid DNA for gene therapy of prostate cancer. AB - Background: Vectors are essential for successful gene delivery. In the present study, a tumor-targeting cationic gene vector, known as the disulfide cross linked arginine-aspartic acid peptide modified by HAIYPRH (T7) peptide (CRD-PEG T7), was designed for targeted delivery of plasmid DNA (pDNA) for gene therapy of prostate cancer (PCa). Methods: The structure of CRD-PEG-T7 was determined and the cellular uptake efficacy, gene transfection efficacy, cytotoxicity, and the targeting effect of the CRD-PEG-T7-plasmid DNA complex were examined. Results: The results demonstrated that the CRD-PEG-T7-plasmid DNA complex was nanosized and had a positively charged surface, good cellular uptake efficacy, minimal cytotoxicity, and a dual-targeting effect as compared with the CRD-PEG-plasmid DNA complex. The peptide T7-modifed new delivery system was able to target the highly expressed transferrin receptor (TfR) on tumor cells with an efficiency four-fold higher than that of the non-modified system. Conclusion: The results above indicatd that the CRD-PEG-T7-plasmid DNA complex may prove to be a promising gene delivery system targeting bone-metastatic tumor. PMID- 30464451 TI - Functionalized selenium nanoparticles for targeted delivery of doxorubicin to improve non-small-cell lung cancer therapy. AB - Background: Selenium nanoparticles (SeNPs) loaded with chemotherapeutic drugs provided a novel perspective for cancer therapy. Materials and methods: Here, SeNPs were modified with cyclic peptide (Arg-Gly-Asp-d-Phe-Cys [RGDfC]) to fabricate tumor-targeting delivery carrier RGDfC-SeNPs and, then, doxorubicin (DOX) was loaded to the surface of RGDfC-SeNPs for improving the antitumor efficacy of DOX in non-small-cell lung carcinoma therapy. Results: The chemical structure characterization of RGDfC-Se@DOX showed that DOX was successfully loaded to the surface of RGDfC-SeNPs to prepare functionalized antitumor drug delivery system RGDfC-Se@DOX. RGDfC-Se@DOX exhibited effective cellular uptake in A549 cells and entered A549 cells mainly by clathrin-mediated endocytosis pathway. Compared to free DOX or Se@DOX at the equivalent dose of DOX, RGDfC Se@DOX showed greater activity to inhibit A549 cells' proliferation and migration/invasion and induce A549 cells' apoptosis. More importantly, compared with passive targeting delivery system Se@DOX, active targeting delivery system RGDfC-Se@DOX exhibited more significant antitumor efficacy in vivo. Conclusion: Taken together, RGDfC-Se@DOX may be a novel promising drug candidate for the lung carcinoma therapy. PMID- 30464452 TI - Functionalization-dependent effects of cellulose nanofibrils on tolerogenic mechanisms of human dendritic cells. AB - Background: Cellulose nanofibrils (CNF) are attractive nanomaterials for various biomedical applications due to their excellent biocompatibility and biomimetic properties. However, their immunoregulatory properties are insufficiently investigated, especially in relation to their functionalization, which could cause problems during their clinical application. Methods: Using a model of human dendritic cells (DC), which have a central role in the regulation of immune response, we investigated how differentially functionalized CNF, ie, native (n) CNF, 2,2,6,6-tetramethylpiperidine 1-oxyl radical-oxidized (c) CNF, and 3 aminopropylphosphoric acid-functionalized (APAc) CNF, affect DC properties, their viability, morphology, differentiation and maturation potential, and the capacity to regulate T cell-mediated immune response. Results: Nontoxic doses of APAcCNF displayed the strongest inhibitory effects on DC differentiation, maturation, and T helper (Th) 1 and Th17 polarization capacity, followed by cCNF and nCNF, respectively. These results correlated with a specific pattern of regulatory cytokines production by APAcCNF-DC and their increased capacity to induce suppressive CD8+CD25+IL-10+ regulatory T cells in immunoglobulin-like transcript (ILT)-3- and ILT-4- dependent manner. In contrast, nCNF-DC induced predominantly suppressive CD4+CD25hiFoxP3hi regulatory T cells in indolamine 2,3-dioxygenase-1 dependent manner. Different tolerogenic properties of CNF correlated with their size and APA functionalization, as well as with different expression of CD209 and actin bundles at the place of contact with CNF. Conclusion: The capacity to induce different types of DC-mediated tolerogenic immune responses by functionalized CNF opens new perspectives for their application as well-tolerated nanomaterials in tissue engineering and novel platforms for the therapy of inflammatory T cell-mediated pathologies. PMID- 30464453 TI - Doxorubicin-loaded protease-activated near-infrared fluorescent polymeric nanoparticles for imaging and therapy of cancer. AB - Introduction: Despite significant progress in the field of oncology, cancer remains one of the leading causes of death. Chemotherapy is one of the most common treatment options for cancer patients but is well known to result in off target toxicity. Theranostic nanomedicines that integrate diagnostic and therapeutic functions within an all-in-one platform can increase tumor selectivity for more effective chemotherapy and aid in diagnosis and monitoring of therapeutic responses. Material and methods: In this work, theranostic nanoparticles were synthesized with commonly used biocompatible and biodegradable polymers and used as cancer contrast and therapeutic agents for optical imaging and treatment of breast cancer. These core-shell nanoparticles were prepared by nanoprecipitation of blends of the biodegradable and biocompatible amphiphilic copolymers poly(lactic-co-glycolic acid)-b-poly-l-lysine and poly(lactic acid)-b poly(ethylene glycol). Poly-l-lysine in the first copolymer was covalently decorated with near-infrared fluorescent Alexa Fluor 750 molecules. Results: The spherical nanoparticles had an average size of 60-80 nm. The chemotherapeutic drug doxorubicin was encapsulated in the core of nanoparticles at a loading of 3% (w:w) and controllably released over a period of 30 days. A 33-fold increase in near-infrared fluorescence, mediated by protease-mediated cleavage of the Alexa Fluor 750-labeled poly-l-lysine on the surface of the nanoparticles, was observed upon interaction with the model protease trypsin. The cytocompatibility of drug free nanoparticles and growth inhibition of drug-loaded nanoparticles on MDA-MB 231 breast cancer cells were investigated with a luminescence cell-viability assay. Drug-free nanoparticles were found to cause minimal toxicity, even at high concentrations (0.2-2,000 ug/mL), while doxorubicin-loaded nanoparticles significantly reduced cell viability at drug concentrations >10 uM. Finally, the interaction of the nanoparticles with breast cancer cells was studied utilizing fluorescence microscopy, demonstrating the potential of the nanoparticles to act as near-infrared fluorescence optical imaging agents and drug-delivery carriers. Conclusion: Doxorubicin-loaded, enzymatically activatable nanoparticles of less than 100 nm were prepared successfully by nanoprecipitation of copolymer blends. These nanoparticles were found to be suitable as controlled drug delivery systems and contrast agents for imaging of cancer cells. PMID- 30464454 TI - Biosafety evaluation of Janus Fe3O4-TiO2 nanoparticles in Sprague Dawley rats after intravenous injection. AB - Introduction: Newly synthesized Janus-structured Fe3O4-TiO2 nanoparticles (NPs) appear to be a promising candidate for the diagnosis and therapy of cancer. Although the toxicity of individual Fe3O4 or TiO2 NPs has been studied extensively, the toxicity of Janus Fe3O4-TiO2 NPs is not clear. Methods: In this study, the biosafety of both Janus Fe3O4-TiO2 NPs (20-25 nm) and the maternal material TiO2 NPs (7-10 nm) were evaluated in Sprague Dawley rats after one intravenous injection into the tail vein. Healthy rats were randomly divided into one control group and six experimental groups. Thirty days after treatment, rats were killed, then blood and tissue samples were collected for hematological, biochemical, element-content, histopathological, and Western blot analysis. Results: The results show that only a slight Ti element accumulation in the heart, spleen, and liver could be found in the Janus Fe3O4-TiO2 NP groups (P>0.05 compared with control). However, significant Ti element accumulation in the spleen, lungs, and liver was found in the TiO2 NP-treated rats. Both Fe3O4-TiO2 NPs and TiO2 NPs could induce certain histopathological abnormalities. Western blot analysis showed that both NPs could induce certain apoptotic or inflammatory related molecular protein upregulation in rat livers. A certain degree of alterations in liver function and electrolyte and lipid parameters was also observed in rats treated with both materials. However, compared to Janus structure Fe3O4-TiO2 NP-treated groups, TiO2 NPs at 30 mg/kg showed more severe adverse effects. Conclusion: Our results showed that under a low dose (5 mg/kg), both NP types had no significant toxicity in rats. Janus NPs certainly seem less toxic than TiO2 NPs in rats at 30 mg/kg. To ensure safe use of these newly developed Janus NPs in cancer diagnosis and therapy, further animal studies are needed to evaluate long-term bioeffects. PMID- 30464455 TI - Macroporous nanofibrous vascular scaffold with improved biodegradability and smooth muscle cells infiltration prepared by dual phase separation technique. AB - Introduction: The fast degradation of vascular graft and the infiltration of smooth muscle cells (SMCs) into the vascular graft are considered to be critical for the regeneration of functional neo-vessels. In our previous study, a novel dual phase separation technique was developed to one-pot prepare macroporous nanofibrous poly(L-lactic acid) (PLLA)/poly(epsilon-caprolactone) (PCL) vascular scaffold by phase separating the immiscible polymer blend. However, the slow degradation of PLLA/PCL limited cell infiltration. Herein, we hypothesized that poly(lactic-co-glycolic acid) (PLGA) would be miscible with PLLA but immiscible with PCL. Then, PLGA can be introduced into the PLLA/PCL blend to fabricate macroporous nanofibrous scaffold with improved biodegradability by using dual phase separation technique. Materials and methods: The miscibility of PLGA with PLLA and PCL was evaluated. Then, the PLLA/PLGA/PCL scaffold was prepared by dual phase separation technique. The prepared scaffolds were characterized in terms of the morphology, in vitro degradation, mechanical properties, and cells' infiltration and viability for human vascular SMCs (HVSMCs). Finally, platelet derived growth factor-BB (PDGF-BB) was immobilized on the scaffold and its effect on the bioactivity of HVSMCs was studied. Results: PLGA is miscible with PLLA but immiscible with PCL as hypothesized. The addition of PLGA enlarged the pore size and improved the biodegradability of composite scaffold. Notably, PLLA/PLGA/PCL scaffold with the blend ratio of 30:40:30 possessed improved pore interconnectivity for cells' infiltration and enough mechanical properties. Moreover, HVSMCs could grow and infiltrate into this scaffold, and surface modification with PDGF-BB on the nanofibrous scaffold enhanced HVSMCs migration and proliferation. Conclusion: This study provides a strategy to expand dual phase separation technique into utilizing ternary even multinary polymer blend to fabricate macroporous nanofibrous scaffold with improved physicochemical properties. The prepared PLLA/PLGA/PCL scaffold would be promising for the regeneration of functional tunica media in vascular tissue engineering. PMID- 30464456 TI - Injectable hydrogel composite containing modified gold nanoparticles: implication in bone tissue regeneration. AB - Background: For effective bone regeneration, it is necessary to implant a biocompatible scaffold that is capable of inducing cell growth and continuous osteogenic stimulation at the defected site. Here, we suggest an injectable hydrogel system using enzymatic cross-linkable gelatin (Gel) and functionalized gold nanoparticles (GNPs). Methods: In this work, tyramine (Ty) was synthesized on the gelatin backbone (Gel-Ty) to enable a phenol crosslinking reaction with horseradish peroxidase (HRP). N-acetyl cysteine (NAC) was attached to the GNPs surface (G-NAC) for promoting osteodifferentiation. Results: The Gel-Ty hydrogels containing G-NAC (Gel-Ty/G-NAC) had suitable mechanical strength and biocompatibility to embed and support the growth of human adipose derived stem cells (hASCs) during a proliferation test for three days. In addition, G-NAC promoted osteodifferentiation both when it was included in Gel-Ty and when it was used directly in hASCs. The osteogenic effects were demonstrated by the alkaline phosphatase (ALP) activity test. Conclusion: These findings indicate that the phenol crosslinking reaction is suitable for injectable hydrogels for tissue regeneration and G-NAC stimulate bone regeneration. Based on our results, we suggest that Gel-Ty/G-NAC hydrogels can serve both as a biodegradable graft material for bone defect treatment and as a good template for tissue engineering applications such as drug delivery, cell delivery, and various tissue regeneration uses. PMID- 30464457 TI - Inverse opal substrate-loaded mesenchymal stem cells contribute to decreased myocardial remodeling after transplantation into acute myocardial infarction mice. AB - Background: The two-dimensional incubation method is now the most commonly method for mesenchymal stem cell (MSC) production. however, gene expression and secretion of growth factors are relatively low; thus, the transplanted cells cannot be effectively utilized for potential clinical applications after acute myocardial infarction (AMI). Objectives: We aimed to investigate whether our newly made substrates of inverse opal with specific surface microstructures for MSC culturing can increase the viability of the cells and can contributes to decreased myocardial remodeling after transplanted to AMI mice. Methods: The inverse opal structure is fabricated by the convenient bottom-up approach of the self-assembly of colloidal nanoparticles. Mouse-derived MSCs were then cultured on the substrates when expanded at different times to investigate the cell growth status including morphology. Then the inverse opal substrates loaded MSCs were transplanted to AMI mice, cardiomyocyte apoptosis and LV remodeling were further compared. To explore the possible mechanisms of curation, the secretions and viability of MSCs on substrates were determined using mice ELISA kits and JC-1 mitochondrial membrane potential assay kits respectively at normal and hypoxic conditions. Results: 6 times expanded inverse opals allowed greatly the orderly growth of MSCs as compared to four (34% +/- 10.6%) and two (20%+/-7.2%) times expanded as well as unexpanded (13%+/-4.1%) (P<0.001). Nearly 90% of MSCs showed orientation angle intervals of less than 30 degrees when at the 6X expanded (89.6%+/-25%) compared to the percent of cells with 30 degrees -60 degrees (8.7%+/-2.6%) or >=60 degrees (1.7%+/-1.0%) orientation angle (P<0.001). After inverse opal loaded MSCs transplanted to AMI mice, greatly decreased apoptosis of cardiomyocytes (20.45%+/-8.64% vs.39.63%+/-11.71%, P<0.001) and infarction area (5.87+/-2.18 mm2 vs 9.31+/-3.11 mm2, P<0.001) were identified. In the end, the viability of inverse opal loaded MSCs determined by membrane potential (P<0.001) and the secretion of growth factors including VEGF-alpha, SDF-1 and Ang-1 (P<0.001) were both confirmed significantly higher than that of the conventional culture in petri dish. Conclusion: The structure of inverse opal can not only adjust the arrangement of MSCs but also contribute to its orientated growth. Inverse opal loaded MSCs transplantation extremely curbed myocardial remodeling, the underlying mechanisms might be the high viability and extremely higher secretions of growth factors of MSCs as devoted by this method. PMID- 30464458 TI - Synthesis of gold nanoparticles with Solanum xanthocarpum extract and their in vitro anticancer potential on nasopharyngeal carcinoma cells. AB - Background: Nasopharyngeal cancer (NPC) is one of the subtypes of head and neck cancers. It occurs rarely, and its prevalence depends mainly on geographical location. Modern-day research is focused on coupling nanotechnology and traditional medicine for combating cancers. Gold nanoparticles (AuNPs) were synthesized from Solanum xanthocarpum (Sx) leaf extract using reduction method. Methods: Characterization of the synthesized AuNPs was done by different techniques such as ultraviolet-visible spectrum absorption, X-ray diffraction, dynamic light scattering, Fourier transform infrared spectroscopy, transmission electron microscopy, and energy-dispersive X-ray analysis. Results: All the results showed the successful green synthesis of AuNPs from Sx, which induced apoptosis of C666-1 cell line (NPC cell line). There was a decline in both cell viability and colony formation in C666-1 cells upon treatment with Sx-AuNPs. The cell death was proved to be caused by autophagy and mitochondrial-dependent apoptotic pathway. Conclusion: Thus, due to their anticancer potential, these nanoparticles coupled with Sx can be used for in vivo applications and clinical research in future. PMID- 30464459 TI - Pulmonary impact of titanium dioxide nanorods: examination of nanorod-exposed rat lungs and human alveolar cells. AB - Background: Titanium dioxide nanoparticles have numerous applications, resulting in human exposure. Nonetheless, available toxicological and safety data are insufficient regarding aspherical particles, such as rod-shaped nanoparticles. Methods: In a combined in vitro-in vivo approach, cultured A549 lung alveolar adenocarcinoma cells were treated with approximately 15*65 nm TiO2 nanorod containing medium, while young adult rats received the same substance by intratracheal instillation for 28 days in 5 and 18 mg/kg body-weight doses. Nanoparticle accumulation in the lungs and consequent oxidative stress, cell damage, and inflammation were assessed by biochemical and histopathological methods. Results: Titanium was detected in tissue samples by single-particle inductively coupled plasma mass spectrometry. Nanoparticles were visualized inside cultured A549 cells, within pulmonary macrophages, and in hilar lymph nodes of the rats. A549 cells showed dose-dependent oxidative stress and lethality, and the observed nanoparticle-laden endosomes suggested deranged lysosomal function and possible autophagy. Strongly elevated Ti levels were measured in the lungs of nanorod-treated rats and moderately elevated levels in the blood of the animals. Numerous cytokines, indicating acute and also chronic inflammation, were identified in the lung samples of TiO2-exposed rodents. Conclusion: Several signs of cell and tissue damage were detected in both the cultured alveolar cells and in treated rats' lungs. Rod-shaped nanoparticulate TiO2 may consequently be more harmful than has generally been supposed. The occupational health risk suggested by the results calls for improved safety measures. PMID- 30464460 TI - Stearyl polyethylenimine complexed with plasmids as the core of human serum albumin nanoparticles noncovalently bound to CRISPR/Cas9 plasmids or siRNA for disrupting or silencing PD-L1 expression for immunotherapy. AB - Purpose: In this study, a double emulsion method for complexing plasmids with stearyl poly-ethylenimine (stPEI) as the core to form human serum albumin (HSA) (plasmid/stPEI/HSA) nanoparticles (NPs) was developed for gene delivery by non covalently binding onto plasmid/stPEI/HSA nanoparticles with CRISPR/Cas9 or siRNA, which disrupts or silences the expression of programmed cell death ligand 1 (PD-L1) for immunotherapy. Materials and methods: Chemically synthesized stearyl-polyethyenimine (stPEI)/plasmids/HSA nanoparticles were maded by double emulsion method. They were characterized by dynamic light scattering (DLS), transmission electron microscope and also evaluated by in vitro study on CT 26 cells. Results: stPEI was synthesized by an N-(3-dimethylaminopropyl)-N ethylcarbodiimide hydrochloride (EDC)-N-hydroxysuccinimide (NHS) reaction, and we found that the degree of substitution was ~1.0 when the ratio of PEI to stearic acid was 1:7 in the reaction. Then, two sgRNA sequences were selected and evaluated for their ability to knock out PD-L1 by decreasing its expression by about 20%. Based on the trend of particle size/zeta potential values as a function of ratio, F25P1 containing 25 MUg of plasmid/stPEI/HSA NPs noncovalently bound to 1 MUg plasmids via charge-charge interactions was found to be optimal. Its particle size was about 202.7+/-4.5 nm, and zeta potential was 12.60+/-0.15 mV. In an in vitro study, these NPs showed little cytotoxicity but high cellular uptake. Moreover, they revealed the potential for transfection and PD-L1 knockout in an in vitro cell model. Furthermore, F25P1S0.5 containing 25 MUg of plasmid/stPEI/HSA NPs noncovalently bound to 1 MUg of plasmids and 0.5 MUg siRNA was prepared to simultaneously deliver plasmids and siRNA. An in vitro study demonstrated that the siRNA did not interfere with the transfection of plasmids and showed a high-transfection efficiency with a synergistic effect on inhibition of PD-L1 expression by 21.95%. Conclusion: The plasmids/stPEI/HSA NPs could be a promising tool for gene delivery and improved immunotherapy. PMID- 30464461 TI - Orlistat-loaded solid SNEDDS for the enhanced solubility, dissolution, and in vivo performance. AB - Background: The present study aimed to develop orlistat-loaded solid self nanoemulsifying drug delivery system preconcentrate (SSP) with the minimum use of lipid excipients for the enhanced solubility, in vitro dissolution, lipase inhibition, and in vivo performance. Materials and methods: In the screening of solubilizing vehicles, Solutol HS15 and Lauroglycol 90 were selected as the surfactant and oil phase, respectively. A pseudo-ternary phase diagram composed of Solutol HS15, Lauroglycol 90, and orlistat as an anti-obesity agent and lipid component was constructed, and the SSP regions were confirmed in terms of the particle size distribution in water, melting point by differential scanning calorimetry, and crystallinity by X-ray diffraction. Results: Physicochemical interaction between Solutol HS15 and orlistat resulted in SSP with various melting points in the range of 26 degrees ~33 degrees C. The representative maximum orlistat-loaded SSP (orlistat/Solutol HS15/Lauroglycol 90=55/40/5, weight ratio) showed the melting point of 32.23 degrees C and constructed uniform nanoemulsion with the particle size of 141.7+/-1.1 nm dispersed in water. In the dissolution test at pH 1.2 without any detergent, the SSP reached 98.12%+/-0.83% until 45 minutes, whereas raw orlistat showed no significant dissolution rate. The dissolution samples containing SSP showed a lipase inhibition of 90.42%+/ 1.58% within 45 minutes. In terms of the reduction level of fat absorption in rats, the intake group of SSP gave a significantly higher fat excretion into stool than the one observed in the raw orlistat group (P<0.05). Conclusion: In conclusion, the suggested novel SSP formulation would be an effective and promising candidate for the treatment of obesity. PMID- 30464462 TI - Cationic vesicles for efficient shRNA transfection in the MCF-7 breast cancer cell line. AB - Introduction: Novel and safe delivery solutions for RNAi therapeutics are essential to obtain the full potential of cancer gene therapy. Methods: In this study, cationic vesicular nanocarrier was applied for delivering lnc urothelial carcinoma-associated 1 (lnc UCA1) shRNA expression vector to MCF-7 cells. The physicochemical characteristics, cytotoxicity, and transfection efficiency of cationic vesicles prepared from various molar ratios of amphiphilic surfactant Tween 80 (T), squalene (S), cationic charge lipid didodecyldimethylammonium bromide, and polyethylenimine were investigated. The particle sizes of the vesicles in the nanosize range were determined by dynamic light scattering and transmission electron microscopy. Results: Gel protection assay with agarose gel electrophoresis showed cationic vesicles can protect the shRNA plasmid from DNase 1 enzyme. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4 sulfophenyl)-2H tetrazolium, inner salt result showed no significant cytotoxicity was caused in MCF-7 cancer cell line by (T:S):polyethylenimine cationic vesicles. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium, inner salt assay, fluorescence microscope images, and flow cytometry analyses confirmed that (T:S)1,040 MUM with 4.3 MUg/mL of PEI vesicles provided effective transfection without significant cytotoxicity. Furthermore, we found efficient UCA1 shRNA transfection and significant (P<0.05) cell cycle arrest and apoptosis in MCF-7 cancer cells. Conclusion: The novel nonviral vesicular nanocarrier, (T:S)1,040 MUM with 4.3 MUg/mL of PEI, might be safe and efficient for cancer gene therapy and can be used in further in vitro and in vivo studies. PMID- 30464463 TI - Nitroxide-radicals-modified gold nanorods for in vivo CT/MRI-guided photothermal cancer therapy. AB - Purpose: This article presents a report of the synthesis, characterization, and biomedical application of nitroxide-radicals-modified gold nanorods (Au-TEMPO NRs) for imaging-guided photothermal cancer therapy. Patients and methods: Au nanorods were synthesized through seed-mediated growth method, 4-Amino-TEMPO was added and the reaction proceeded under magnetic stirring. Results: With a mean length of 39.2 nm and an average aspect ratio of approximately 3.85, Au-TEMPO NRs showed good photothermal ability when they were irradiated by 808-nm laser. Au TEMPO NRs could be stored in PBS for more than 1 month, showed no cytotoxicity against both tumor and normal cells at a concentration of up to 3 mg/mL, and functioned as a dual-mode contrast agent for CT/magnetic resonance (MR) imaging in vitro and in vivo, due to their high X-ray attenuation of Au and good r1 relaxivity of nitroxide radicals. Further, they had a long retention time (~4 hours) in the main organs, which enabled a long CT/MR imaging time window for diagnosis. Bio-distribution results revealed that these Au-TEMPO NRs passively aggregated in the liver and spleen. After irradiation by 808-nm laser, Au-TEMPO NRs could ablate the solid tumor in 4T1 tumor-bearing mice, which implied they were a potential theranostic agent for dual-mode imaging and photothermal cancer therapy. Conclusion: This type of Au-TEMPO NRs with the abilities of CT/MR imaging and photothermal therapy, can play an active role in imaging-guided photothermal cancer therapy. PMID- 30464464 TI - A novel disulfide bond-mediated cleavable RGD-modified PAMAM nanocomplex containing nuclear localization signal HMGB1 for enhancing gene transfection efficiency. AB - Background: Polyamidoamine (PAMAM) dendrimers modified by polyethylene glycol (PEG) have frequently been investigated as a delivery carrier for gene therapy. However, modification of PAMAM with PEG using covalent linkage significantly reduces the cellular uptake rate and the transfection efficiency. How to conquer these barriers becomes a burning question in gene delivery. Materials and methods: The present study constructed an effective disulfide bond-mediated cleavable RGD modified gene delivery system to overcome the aforementioned limitations. The disulfide bond was introduced between PAMAM dendrimers and PEG chains to realize the cleavage of PEG from the carrier system, whereas the arginine-glycine-aspartate (RGD) peptide was expected to promote the cellular uptake rate. A high mobility group Box 1 (HMGB1) protein containing nuclear localization signal (NLS) was simultaneously introduced to further promote gene expression efficiency. A pDNA/HMGB1/PAMAM-SS-PEG-RGD (DHP) nanocomplex was prepared via electrostatic interaction and characterized. Results: The results showed that DHP generated small particles and was able to condense and protect pDNA against degradation. In addition, the RGD peptide could significantly promote the cellular uptake of a nanocomplex. Intracellular trafficking and in vitro expression study indicated that the DHP nanocomplex escaped from lysosomes and the disulfide bonds between PAMAM and PEG cleaved due to the high concentration of GSH in the cytoplasm, pDNA consequently became exclusively located in the nucleus under the guidance of HMGB1, thereby promoting the red fluorescence protein (RFP) expression. Importantly, an in vivo antitumor activity study demonstrated that the DHP nanocomplex had higher antitumor activity than any other reference preparation. Conclusion: All these results confirm that DHP could be a new strategy for improving the transfection and expression efficiency in gene delivery. PMID- 30464465 TI - Synthesis and characterization of a polyurethane carrier used for a prolonged transmembrane transfer of a chili pepper extract. AB - Purpose: Red chili peppers have been highly valued in gastronomy and traditional medicine since ancient times; it seems that it is not just an ingredient for food but also a good remedy for various medical conditions such as increased blood pressure and high levels of serum triglycerides and cholesterol, myocardial infarction, arthritis, and migraines. The objective of this study is the characterization of a new carrier used for encapsulated extract. Methods: Chili pepper extract was obtained and was physically entrapped inside polyurethane microparticles in order to diminish the irritative potential of this extract. The particles were evaluated by Zetasizer measurements, small-angle neutron scattering and thermal analysis, scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy; the encapsulation efficacy and the drug release profile were assessed by UV-Vis spectroscopy. Bioevaluations on mice skin were performed to predict the irritative potential of the samples. Results: Two different types of samples were compared: hollow polyurethane microparticles vs polyurethane particles containing the natural extract. The sizes of the particles were very similar, but the sample containing the extract presents three particle populations (the polydispersity index increases from 0.3 to 0.6 from one sample to another). The zeta-potential measurements and SEM images indicate a medium tendency to form clusters, while the UV-Vis study revealed an almost 70% encapsulation efficacy. Conclusion: The results suggest that encapsulation of a chili pepper extract inside polyurethane microparticles leads to a non-irritative product with a prolonged release: ~30% of encapsulated extract is released within the first 8 days and a maximum 45% is reached in 2 weeks. PMID- 30464466 TI - Small molecules modified biomimetic gelatin/hydroxyapatite nanofibers constructing an ideal osteogenic microenvironment with significantly enhanced cranial bone formation. AB - Background: Repair of nonunion critical-sized bone defects is a significant clinical challenge all over the world. Construction of osteogenic microenvironment that provides osteoconductive and osteoinductive signals is a leading strategy. Materials and methods: In the present study, ascorbic acid (AA) and beta-glycerophosphate disodium salt hydrate (beta-GP) modified biomimetic gelatin/hydroxyapatite (GH) nanofibrous scaffolds were developed by electrospinning. Then the scaffolds were crosslinked by N-hydroxysulfo succinimide sodium salt (NHS) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). The morphology of the non-crosslinked and crosslinked scaffolds was evaluated by scanning electron microscope (SEM). Fourier transform infrared spectroscopy (FT-IR) was used to assess the interacting model between the small molecules and GH scaffold. Then MTT, Alamar Blue, and CCK8 assays were used to investigate the biocompatibility of the various crosslinked scaffolds. Subsequently, the osteogenic genes expression of bone marrow stromal cells (BMSCs) cultured on the scaffolds were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Finally, the crosslinked scaffolds were implanted in a rat calvarial defect model to assess the osteogenic effects in vivo. Results: SEM results showed that the various scaffolds presented extracellular matrix (ECM)-like fibrous porous structure. (FT-IR) spectrum indicated that AA and beta-GP were covalently bonded with GH scaffolds. The MTT, Alamar Blue, and CCK8 assays demonstrated that all the scaffolds can support BMSCs' growth well. The qRT-PCR results showed that the expression level of Alp and Runx2 in BMSCs on GH/A/B scaffold was about 3.5- and 1.5-fold, respectively, compared with that of GH group on day 7. The results also showed that AA- and beta-GP-modified GH scaffolds can significantly induce the higher levels of osteogenic gene expression in a temporal specific manner. Importantly, AA and beta-GP synergistically promoted osteoblast differentiation in vitro and dramatically induced bone regeneration in vivo. Impressively, AA and beta-GP dual modified GH nanofibrous scaffold could serve as a template for guiding bone regeneration and the bone defects were almost repaired completely (94.28%+/ 5.00%) at 6 weeks. Besides, single AA or beta-GP-modified GH nanofibrous scaffolds could repair 62.95%+/-9.39% and 66.56%+/-18.45% bone defects, respectively, at 12 weeks in vivo. In addition, AA and beta-GP exhibit an anti inflammatory effect in vivo. Conclusion: Our data highlighted that, AA, beta-GP, and GH nanofibers created a fine osteoconductive and osteoinductive microenvironments for bone regeneration. We demonstrated that AA and beta-GP dual modified GH nanofiber is a versatile bone tissue engineering scaffold. PMID- 30464468 TI - Neuroprogression: the hidden mechanism of depression. AB - For many years, depressive disorder (DD) was considered a transient and natural disease of people's mood. Its etiology had been attributed mainly to biochemical alterations of the monoamines and their receptors. Nevertheless, its prevalence and considerable impact on the family and social environment of those afflicted by it have placed the disease as a global public health problem. Neuroprogression is the term used to describe the changes in several psychiatric conditions evidenced and observed in the clinical manifestations, biochemical markers, and cerebral structures of the patients with major depressive disorder (MDD), which frequently overlap with neurodegenerative disorders. DD is considered a potentially aggressive state of neuronal deterioration involving apoptosis, reduced neurogenesis, decreased neuronal plasticity, and increased immune response. Clinically, it encompasses a poor response to treatment and an increase in depressive episodes, both of which bring about vulnerability and decline of functions associated with structural changes in the brain. The interest of this work is to review the metabolic processes involved in the morphologic alterations in the limbic system reported in patients with MDD, as well as the neurologic bases of this complex pathology that include environmental stress, genetic vulnerability, alterations in the neurotransmission, and changes in the neuroplasticity, all of which today bring into limelight a mechanism of progressive neuronal damage. PMID- 30464467 TI - Neuromodulation in eating disorders and obesity: a promising way of treatment? AB - Neuromodulation can affect the functioning of the central nervous system (CNS), and emotional/eating behavior is an exciting facet of that functioning. Therefore, it would be possible to offer an alternative (or complement) treatment to psychotropic medications and different psychological and nutritional approaches to both eating disorders (EDs) and obesity. Although there are a number of publications in these areas, a systematic review has not been conducted to date. Abstracts, letters, conference reports, dissertations, and reviews were excluded. Clinical trials and controlled human clinical trials were filtered and included in this study. Articles included were based on the population suffering from anorexia nervosa, bulimia nervosa, binge ED, overweight, and obesity. No restrictions were placed on the sample size. Only trials investigating the effect of neuromodulation by means of deep brain stimulation (DBS), transcranial direct current stimulation (tDCS), and transcranial magnetic stimulation (TMS) were included. The following databases were used to conduct the search: MEDLINE/ PubMed, PsycINFO, PsycArticles, and Cochrane (Search Trials, CENTRAL). Study selection was performed following the PRISMA process (PRISMA 2009 Checklist). The total number of participants in all the trials was 562 (DBS, 25; tDCS, 138; TMS, 399; range, 3-90; median, 23.5). As a result, 50% of the studies had samples of between 14 and 38 participants. Neuro-modulation in ED seems to have certain clinical potential, and therefore, this is a promising area for further research. Developments in ED neuromodulation will be linked to neuroimaging to identify potential stimulation targets and possible biomarkers of treatment response. To date, TMS and/or direct current stimulation (DCS) is not the first-line treatment yet, but it could become a preferred option of treatment in the future. Further studies should avoid small sample sizes and the use of different methodologies. Currently, neuromodulation techniques are in the experimental phase, and they are not an evidence-based treatment for ED. PMID- 30464469 TI - Sexual dysfunction in cervical dystonia and blepharospasm. AB - Background: Sexual dysfunction is a frequent, yet underrated, symptom of neurological disease. While knowledge of non-motor comorbidity in focal dystonia is growing rapidly, there is no information on the prevalence of sexual dysfunction in cervical dystonia (CD) or blepharospasm (BL). Methods: In this controlled study, we examined sexual dysfunction in 65 patients with CD and 54 patients with BL by the Arizona Sexual Experience Scale, a validated self-rating scale. Results: Sexual dysfunction was significantly higher in CD patients (45%) than in controls (24%), and frequent in BL (39%). Interestingly, variables of dystonia such as disease duration or severity did not influence sexuality; yet, 23% of CD patients ascribed worsening of their sexual life to dystonia. Symptoms of depression were identified as the most important predictors for sexual dysfunction, followed by age, and personal status (single). Conclusion: Our observations establish sexual dysfunction as a frequent non-motor symptom in CD and BL that is perceived as a burden. It should be considered when investigating patients with adult-onset focal dystonia. PMID- 30464470 TI - Predictors of sleep disturbance in heroin users receiving methadone maintenance therapy: a naturalistic study in Taiwan. AB - Introduction: Sleep disturbance is a major health concern for heroin users receiving methadone maintenance treatment (MMT). The present study was aimed to investigate the predictors for new-onset clinically predominant sleep disturbance (CPSD) among heroin users receiving MMT. Methods: This 2-year retrospective study included 152 individuals (127 males and 25 females) with heroin use disorder who visited our MMT clinics for the first time. A univariate Cox proportional hazards regression model (Cox model) was used to estimate the potential factors of subsequent CPSD, followed by a multivariate Cox model to identify significant predictors of CPSD after adjusting for other covariates. Results: Twenty-nine (19.1%) participants developed CPSD during the 2-year period. After forward selection in the Cox model, earlier age at onset of heroin exposure (OR=0.95; P=0.044), lower attendance rate (OR =0.04; P=0.03), greater maximum dose of methadone (OR =1.01; P=0.022), and shorter time to maximum methadone dose (OR =0.98; P=0.007) were significantly associated with new-onset CPSD. Conclusion: We identified predictors that were significantly associated with new-onset CPSD, and clinicians should be aware of sleep disturbance in heroin users receiving MMT with these risk factors. Future studies are necessary to verify our findings and extend the applicability. PMID- 30464471 TI - Psychometric validation of the Perceived Deficits Questionnaire-Depression (PDQ D) instrument in US and UK respondents with major depressive disorder. AB - Background: Although depression and cognitive dysfunction are connected, limited tools exist to capture the patient's perspective on cognitive dysfunction and its impact on major depressive disorder (MDD). We report results of a psychometric validation of the Perceived Deficits Questionnaire-Depression (PDQ-D), a self report measure of cognitive dysfunction for use in MDD. Methods: A non interventional, prospective, panel-recruited, online survey was conducted using the PDQ-D in adults with and without MDD in the US and UK. Respondents were assessed at baseline and after 6 weeks (MDD only) (baseline: US n=418, UK n=437, 49% MDD; follow-up: US n=169, UK n=153, all MDD). The criterion measures included: Medical Outcomes Study Cognitive Functioning Scale-Revised-acute form (MOS COG-R), Patient Health Questionnaire-9 (PHQ-9), Patient Global Impression of Severity scale (PGI-Severity), Sheehan Disability Scale (SDS), Work Productivity and Activity Impairment Questionnaire: Specific-Health Problem (WPAI:SHP), and modified Lam Employment Absence and Productivity Scale (LEAPS). US and UK data were analyzed separately. Results: Internal consistency was high for PDQ-D total scale and four subscales (Cronbach's alpha 0.81-0.96). Convergent validity was good, with strong concordance with MOS COG-R and moderate/small correlations with PHQ-9, SDS, WPAI:SHP, LEAPS, and PGI-Severity. Significant differences (all P<0.001) existed for all PDQ-D subscale and total scores between MDD/non-MDD samples. The PDQ-D was responsive to changes in depression symptom severity. Confirmatory factor analysis supported scoring of a global overall scale for perceived cognitive dysfunction. Conclusion: The PDQ-D provides a reliable and valid measure of subjective cognitive dysfunction in patients with MDD. PMID- 30464472 TI - Short duration of focal onset awareness and impaired awareness seizure are characteristic features of epilepsy in elderly patients. AB - Purpose: Diagnosing epilepsy in the elderly population can be difficult due to mimicking symptoms. Furthermore, epileptic symptoms can also be masked by various symptoms. We hypothesized that elderly patients with epilepsy exhibit specific clinical features among the various symptoms. Patients and methods: From 2009 to 2017, 177 patients who were older than 65 years were referred to our epilepsy center. Out of this group, the onset of symptoms occurred after reaching the age of 50 years in 152 of the patients, who were additionally being treated at our clinic. We divided their symptoms in accordance with their consciousness levels, which were defined as follows: full wakefulness level I, impaired awareness level II, and loss of consciousness level III. We also classified the duration of the symptoms as <10 seconds, >=10 seconds but <1 minute, >=1 minute but <5 minutes, >=5 minutes but <10 minutes, >=10 minutes but <1 hour, and >=1 hour. Results: Among the 152 patients analyzed (mean age 72.9 years, standard deviation 6.71, range 65-92), 84 patients had epilepsy (epilepsy group) while 68 did not exhibit epilepsy (nonepilepsy group). For the consciousness levels, there were more level I patients in the nonepilepsy vs epilepsy group (P<0.028), with symptom duration lasting <1 minute (sensitivity 0.857, specificity 1) in the epilepsy group. In contrast, there were more level II patients in the epilepsy vs the nonepilepsy group (P=0.015), with the duration of symptoms lasting <1 minute (sensitivity 0.8125, specificity 0.930) in the epilepsy group. For the level III consciousness, convulsions were more commonly seen in the epilepsy group (P=0.044). Conclusion: Symptoms that last <1 minute with awareness and impaired awareness might be epileptic in the elderly population. PMID- 30464474 TI - Neurofeedback versus psychostimulants in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a systematic review. AB - This systematic review aimed to evaluate the efficacy of neurofeedback (NF) compared to stimulant medication in treating children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Included in this review are eight randomized controlled trials that compared an NF condition, either alone or combined with medication, to a medication condition, which was mainly methylphenidate. Outcome measures included behavioral assessments by parents and teachers, self-reports, neurocognitive measures, electroencephalogram power spectra and event-related potentials. When only trials are considered that include probably blinded ratings or those that are sham-NF or semi-active controlled or those that employed optimally titration procedures, the findings do not support theta/beta NF as a standalone treatment for children or adolescents with ADHD. Nevertheless, an additive treatment effect of NF was observed on top of stimulants and theta/beta NF was able to decrease medication dosages, and both results were maintained at 6-month follow-up. This review concludes that the present role of NF in treating children diagnosed with ADHD should be considered as complementary in a multimodal treatment approach, individualized to the needs of the child, and may be considered a viable alternative to stimulants for a specific group of patients. Particularly patients with the following characteristics may benefit from NF treatment: low responders to medication, intolerable side effects due to medication, higher baseline theta power spectra and possibly having no comorbid psychiatric disorders. Future research should prioritize the identification of markers that differentiate responders from nonresponders to NF treatment, the potential of NF to decrease stimulant dosage, the standardization of NF treatment protocols and the identification of the most favorable neurophysiological treatment targets. PMID- 30464473 TI - Structural and functional brain abnormalities in drug-naive, first-episode, and chronic patients with schizophrenia: a multimodal MRI study. AB - Background: Structural and functional brain abnormalities in schizophrenia (SZ) have been widely reported. However, a few studies have investigated both structural and functional characteristics in SZ patients at different stages to understand the neuropathology of SZ. Methods: In this study, we recruited 44 first-episode drug-naive SZ (FESZ) patients, 44 medicated chronic SZ (CSZ) patients, and 56 normal controls (NCs) and acquired their structural and resting state functional magnetic resonance imaging (MRI). We then made group comparisons on structural and functional characteristics, including regional gray matter volume (GMV), regional homogeneity, amplitude of low-frequency fluctuation, and degree centrality. A linear support vector machine (SVM) combined with a recursive feature elimination (RFE) algorithm was implemented to discriminate three groups. Results: Our results indicated that the regional GMV was significantly decreased in patients compared with that in NCs; CSZ patients have more diffused GMV decreases primarily involved in the frontal and temporal lobes when compared with FESZ patients. Both FESZ and CSZ patients showed significant functional alterations compared with NCs; when compared with FESZ patients, CSZ patients showed significant reductions in functional characteristics in several brain regions associated with auditory, visual processing, and sensorimotor functions. Moreover, a linear SVM combined with a RFE algorithm was implemented to discriminate three groups. The accuracies of the three classifiers were 79.80%, 83.16%, and 81.71%, respectively. The performance of classifiers in this study with multimodal MRI was better than that of previous discriminative analyses of SZ patients with single-modal MRI. Conclusion: Our findings bring new insights into the understanding of the neuropathology of SZ and contribute to stage-specific biomarkers in diagnosis and interventions of SZ. PMID- 30464475 TI - Memantine treatment for Japanese patients with moderate to severe Alzheimer's disease: a meta-analysis of double-blind, randomized, placebo-controlled trials. AB - Purpose: Although previous meta-analyses of randomized trials in the world literature have provided strong evidence that supports the efficacy and safety of memantine for the treatment of patients with Alzheimer's disease (AD), it is unclear whether the drug is beneficial in the treatment of Japanese patients with moderate to severe AD because of differences in the formulation and regimen of memantine and the cholinesterase inhibitor (ChEI) used in combination with memantine between the drugs made in Japan and those made in other countries. To address this issue, we conducted a meta-analysis on the efficacy and safety of memantine using data from only double-blind, randomized, placebo-controlled trials (DBRPCTs) in Japan on Japanese patients with moderate to severe AD. Patients and methods: Our primary analysis was conducted using data from both memantine monotherapy (memantine vs placebo) and memantine combination therapy (memantine+ChEI vs ChEI+placebo) studies. The primary outcomes measured were cognitive function and behavioral disturbances. The secondary outcomes measured were the subscale scores of Behavioral Pathology in Alzheimer's Disease (Behave AD), discontinuation rate, and individual adverse events. Results: Four DBRPCTs (n=1,328) were detected. Memantine was superior to the control in cognitive functions (standardized mean difference [SMD]=-0.31, 95% CI=-0.53, -0.10) and behavioral disturbances (SMD=-0.16, 95% CI=-0.28, -0.05). Only memantine monotherapy was superior in both outcomes. It was also superior to the control in delusions, aggression, and diurnal rhythm disturbances based on the Behave-AD subscale scores. Although memantine was associated with a lower incidence of AD progression than that of the control, the incidence of somnolence was higher with memantine. There were no significant differences in other safety outcomes, including all-cause discontinuation, between the groups. Conclusion: Our results suggest that memantine is useful for the treatment of patients in Japan with moderate to severe AD even though our meta-analysis comprised only four DBRPCTs. PMID- 30464476 TI - Structural equation modeling analysis of social support, coping strategies, depression and suicidal ideation among people living with HIV/AIDS in Changsha, China. AB - Introduction: People living with HIV/AIDS (PLWHA) have a higher rate of suicide compared to the general population. Psychosocial factors closely correlate with suicidal ideation and it is essential to explain the relationships between related factors among PLWHA. Objectives: To establish a structural equation model and examine direct and indirect effects of social support, coping strategy, depression symptoms and suicidal ideation among PLWHA. Patients and methods: A total of 504 PLWHA completed a set of questionnaires in the HIV clinic of Changsha Infectious Disease Hospital between December 2015 and January 2016. Results: Among the 504 respondents, a total of 27.2% (n=137) had experienced suicidal ideation in their lifetime. The goodness of fit for the two structural equations model was highly satisfactory. Depression symptoms had a significant direct impact on suicidal ideation (beta 1=0.401, beta 2=0.422), while problem focused coping (beta=-0.067), emotion-focused coping (beta=-0.081) and social support (beta=-0.137) had a significant indirect effect with suicidal ideation via depression symptoms. Factors of total effects were ranked from large to small as follows: depression, social support, emotion-focused coping and problem focused coping. Conclusion: Findings provide more understanding of direct and indirect associations between variables, suggesting that depression screening services, and the strengthening of social support and psychological care services among PLWHA can potentially prevent suicide. PMID- 30464477 TI - Removal of blood amyloid-beta with hemodialysis reduced brain amyloid-beta, confirmed by brain imaging: a case report. AB - The accumulation of amyloid-beta protein (Abeta) in the brain signifies a major pathological change of Alzheimer's disease (AD). Extracorporeal blood Abeta removal system (E-BARS) has been under development as a tool for enhancing the clearance of Abeta from the brain. Previously, we revealed that dialyzers remove blood Abetas effectively, evoking substantial Abeta influx into the blood during hemodialysis sessions as one form of blood Abeta removal by E-BARS, and that postmortem brains of hemodialysis patients exhibited lower Abeta accumulation. Here, we present a case report of a 77-year-old male patient with end-stage renal failure whose Abeta accumulation in the brain declined by initiating and continuing hemodialysis for 6 months. This report suggests that blood Abeta removal by E-BARS could be an effective therapeutic method for AD. PMID- 30464478 TI - Detection of cognitive impairment using a machine-learning algorithm. AB - Purpose: The Mini-Mental State Examination (MMSE) is one of the most frequently used bedside screening measures of cognition. However, the Korean Dementia Screening Questionnaire (KDSQ) is an easier and more reliable screening method. Instead, other clinical variables and raw data were used for this study without the consideration of a cutoff value. The objective of this study was to develop a machine-learning algorithm for the detection of cognitive impairment (CI) based on the KDSQ and the MMSE. Patients and methods: The original dataset from the Clinical Research Center for Dementia of South Korea study was obtained. In total, 9,885 and 300 patients were randomly allocated to the training and test datasets, respectively. We selected up to 24 variables including sex, age, education duration, diabetes mellitus, and hypertension. We trained a machine learning algorithm using TensorFlow based on the training dataset and then calculated its accuracy using the test dataset. The cost was calculated by conducting a logistic regression. Results: The accuracy of the model in predicting CI based on the KDSQ only, the MMSE only, and the combination of the KDSQ and MMSE was 84.3%, 88.3%, and 86.3%, respectively. For the KDSQ, the sensitivity for detecting CI was 91.50% and the specificity for detecting normal cognition (NL) was 59.60%. The sensitivity of the MMSE was 94.35%, and the specificity was 59.62%. When combining the KDSQ and the MMSE, the sensitivity for detecting CI was 91.5% and the specificity for detecting NL was 61.5%. Conclusion: The algorithm predicting CI based on the MMSE is superior. However, the KDSQ can be administered more easily in clinical practice and the algorithm using KDSQ is a comparable screening tool. PMID- 30464479 TI - Low levels of serum magnesium are associated with poststroke cognitive impairment in ischemic stroke patients. AB - Purpose: Population-based studies have revealed a high prevalence of cognitive impairment after stroke. We aimed to determine the impact of serum magnesium (Mg2+) levels on the occurrence of poststroke cognitive impairment (PSCI). Patients and methods: Acute ischemic stroke patients (n = 327) were enrolled in our study and serum Mg2+ levels were assessed on admission. The cognitive performance of each patient was evaluated using the Mini-Mental State Examination (MMSE) at a 1-month follow-up visit. Results: One hundred five (32.1%) patients were diagnosed with PSCI at 1-month poststroke. The serum Mg2+ levels in both the PSCI group and the non-PSCI group were significantly lower than those in normal control group (P<0.001). In addition, the PSCI group had lower levels of serum Mg2+ compared to the non-PSCI group (P=0.003). In the binary logistic regression analysis, a serum Mg2+ level of <=0.82 mmol/L was significantly associated with an increased risk of developing PSCI by the 1-month follow-up (OR 2.236, 95% CI 1.232-4.058, P=0.008), as was age (OR 1.043, 95% CI 1.014-1.073, P=0.003). Conclusion: Our results demonstrate the existence of a significant association between low levels of serum Mg2+ and the occurrence of PSCI 1-month poststroke, and these results suggest that low levels of serum Mg2+ on admission may serve as a risk factor for developing PSCI by 1-month poststroke. PMID- 30464480 TI - Profile of inhaled levodopa and its potential in the treatment of Parkinson's disease: evidence to date. AB - Inhaled levodopa is a newly emerging therapeutic option in the treatment of "off " symptoms associated with Parkinson's disease (PD). Its mode of delivery offers more rapid absorption of levodopa and shorter onset of clinical benefit compared to oral formulations, and has been shown to be feasible for use in patients with PD experiencing worse motor function due to declining plasma levodopa levels. Clinical development of this compound is supported by preclinical, Phase I-III, long-term-safety studies and studies in special populations, including otherwise healthy asthmatics and smokers. These investigations demonstrated that the drug is well tolerated without risk of long-term (up to 1 year) changes in pulmonary function or spirometry measures. The most common side effects among PD patients were a mild cough, upper respiratory tract infection, nausea, sputum discoloration, and dyskinesia. Inhaled levodopa offers a different administration method and side-effect profile from the currently available options for rescue therapy for Off periods in PD, though comparative studies have not been performed. The drug is presently under review by the US Food and Drug Administration. PMID- 30464481 TI - Efficacy of betahistine plus cognitive behavioral therapy on residual dizziness after successful canalith repositioning procedure for benign paroxysmal positional vertigo. AB - Background: Some patients still complain of residual dizziness after successful canalith repositioning procedure (CRP) for benign paroxysmal positional vertigo (BPPV). Previous study found that compared to the low-dose betahistine, the high dose betahistine could yield better efficacy in treating residual dizziness. Therefore, this study was conducted to assess whether the addition of cognitive behavioral therapy (CBT) could make low-dose betahistine produce similar results to high-dose betahistine in treating residual dizziness. Methods: The recruited patients were randomly assigned to receive either low-dose betahistine (6 mg/time, three times/day) or high-dose betahistine (12 mg/time, three times/day). Patients in the low-dose group also received CBT (twice a week, 1 hour per time). The treatment was continued for 4 weeks. The duration of residual dizziness, 25 item Dizziness Handicap Inventory (DHI), Hamilton Anxiety Rating Scale (HARS), and Hamilton Depression Rating Scale (HDRS) were recorded and analyzed. The duration of residual dizziness and DHI score were the primary outcomes, and the HARS and HDRS scores were the secondary outcomes. Results: Each group had 50 patients. After treatment, the average DHI scores, HDRS scores, and HARS scores were significantly decreased in both groups. The duration of residual dizziness and average DHI score were nonsignificantly different (P=0.08; P=0.06) between the two groups, although they were lower in the low-dose group. Compared to the high-dose group, the low-dose group had the significantly lower average HDRS score (P=0.007) and HARS score (P=0.02). Meanwhile, four patients in the high dose group experienced intolerable stomach upset. Conclusion: These results demonstrated that the addition of CBT could make low-dose beta-histine produce similar results to high-dose betahistine in treating residual dizziness. Moreover, the low-dose betahistine plus CBT showed some advantages over high-dose betahistine in relieving depressive and anxiety symptoms and should be further explored. PMID- 30464482 TI - Parents' impaired emotion recognition abilities are related to children's autistic symptoms in autism spectrum disorder. AB - Objective: We aimed to explore whether parents of children with autism spectrum disorder (ASD) had impaired emotion recognition abilities and whether this deficit was related to their children's autistic symptoms. Methods: The autistic symptoms of 31 ASD children were assessed using the Autism Diagnostic Interview Revised (ADI-R). Fifty parents of ASD children and 34 parents of typically developing (TD) children completed an emotion recognition task (ERT). Results: The numbers of correct ERT responses were lower for parents of ASD children than for parents of TD children with respect to recognizing sadness, disgust, fear, and all emotions (P=0.01, 0.04, 0.02, and 0.00, respectively). Controlled for parental age, gender, and the intelligence quotients of both the parents and children, a negative correlation was found between the total number of correct ERT responses for parents of ASD children and these children's "restricted, repetitive, and stereotyped patterns of behavior" scores on the ADI-R (r=-0.32; P=0.03). Conclusion: Parents of ASD children showed impaired emotion recognition abilities compared with parents of TD children. This parental deficit in emotion recognition ability was related to the autistic symptoms of ASD children. PMID- 30464483 TI - Association study between COMT, DRD2, and DRD3 gene variants and antipsychotic treatment response in Mexican patients with schizophrenia. AB - Purpose: The efficacy of schizophrenia treatments using antipsychotics (APs) has long been established, but the benefit obtained by several patients using conventional APs (typical or atypical) has not been enough. Currently, the genetic study of the primary mechanisms of action of the APs has been focused on the dopaminergic pathways. The objective of this study was to determine if the response phenotypes (responder, resistance to treatment, and ultra-resistance to treatment groups) are associated with six single-nucleotide polymorphisms: COMT (Val158Met), DRD2 (A-241G, C376G, C939T, Taq1A), and DRD3 (Ser9Gly). Patients and methods: We classified the patients through a retrospective/prospective methodology to define response phenotypes. Results: COMT/Val158Met and DRD3/Ser9Gly were associated with the responder group (P<0.05). The single nucleotide polymorphism A-241G of DRD2 gene was related with the resistant-to treatment group (P<0.001). Finally, Met/Met of COMT and Ser/Gly of DRD3 genes showed a predictive effect associated with the resistant-to-treatment phenotype. Conclusion: Further analyses should be performed to validate these genetic markers as mediators for the response to APs. PMID- 30464486 TI - Erratum: Experience with alendronate treatment for four years among Japanese men with osteoporosis or osteopenia and clinical risk factors for fractures [Expression of concern]. AB - [This corrects the article on p. 593 in vol. 6, PMID: 21206758.]. PMID- 30464485 TI - Increased IL-17-producing CD8+ T cell frequency predicts short-term mortality in patients with hepatitis B virus-related acute-on-chronic liver failure. AB - Background: IL-17-producing CD8+ T (Tc17) cells promote inflammation and have been identified in chronic hepatitis. However, the role of Tc17 cells in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (HBV-ACLF) remains unclear. Methods: The frequency of Tc17 cells in blood samples from 66 patients with HBV-ACLF was determined by flow cytometry. The levels of Tc17 cell related cytokines were measured by FlowCytomix assays. The prognostic prediction accuracy was evaluated by the receiver operating characteristic (ROC) curve analysis. Survival was analyzed using Kaplan-Meier curves. Mortality predictors were determined by the Cox regression analysis. Results: The frequency of Tc17 cells was markedly higher in patients with HBV-ACLF than in those with chronic hepatitis B and normal control subjects. Increased frequencies of Tc17 cells may indicate liver injury and were positively correlated with disease severity. The Tc17 cell frequency was significantly higher in non-surviving patients with HBV ACLF than in surviving patients. The ROC curve analysis showed that Tc17 cell frequency accurately predicted 90-day survival in patients with HBV-ACLF, with an accuracy equivalent to those of the Model for End-Stage Liver Disease (MELD), MELD-Na, and Chronic Liver Failure Consortium ACLF scores. Kaplan-Meier analysis showed an association between the increase in circulating Tc17 cells and poor overall survival in patients with HBV-ACLF. Moreover, the multivariate Cox regression analysis showed that Tc17 cell frequency was an independent predictor of overall survival in patients with HBV-ACLF. Conclusion: Tc17 cells may play a proinflammatory role in HBV-ACLF pathogenesis. Furthermore, the increased frequency of circulating Tc17 cells could be an independent prognostic biomarker in patients with HBV-ACLF. PMID- 30464487 TI - Analysis of a pharmacist-led adverse drug event management model for pharmacovigilance in an academic medical center hospital in China. AB - Background: Spontaneous reporting of adverse drug events (ADEs) has long been the cornerstone of pharmacovigilance. Medical institutions in China have been a major source of ADE case reports, but the proportion of reports from tertiary hospitals is low due to the serious underreporting of case reports. The same problem existed in the Second Affiliated Hospital of Zhejiang University School of Medicine (SAHZU). Objective: In order to increase the number of ADE reports and promote hospital pharmacovigilance, SAHZU's clinical pharmacists established a pharmacist-led ADE management model. The aim of this paper is to introduce this management model and explore the advantages and disadvantages of the model. Methods: Pharmacist-led ADE management model was gradually formed from 2015 to 2017 in the SAHZU. This "pharmacist-led" model is reflected not only in the fact that clinical pharmacists are the main reporters of SAHZU's ADEs but also in that they are the main groups to analyze and manage ADE and drug errors. The sources of ADEs reported by clinical pharmacists mainly include pharmacy rounds, ADE related pharmacist consultations, centralized monitoring, ADE warning signal analysis, newly introduced drug evaluations, and drug safety research. Results: A total of 533 ADEs were reported by SAHZU to China's spontaneous reporting system (SRS) in 2017, while the data in 2012 was 177, with an increase by 201%. In 2012, the proportion of "new" and "serious" reports was 16.4%. The proportions during the period from 2015 to 2017 were 41.4%, 60.8%, and 52.2%, respectively, which were statistically significant compared with the proportion in 2012. The proportion of ADEs reported by clinical pharmacists during the period from 2014 to 2017 were 51.5%, 57.3%, 68.8%, and 90.8%, respectively, which were statistically significant compared with the proportion in 2013 (P<0.05). There was a correlation between the proportions of severe ADEs and the proportion of ADEs reported by clinical pharmacists (r=0.873, P=0.023). Four hundred eighty four ADE cases reported by clinical pharmacists to China's SRS in 2017 were mainly found in rounds of clinical pharmacists (74.17% [359/484]). Conclusion: The pharmacist-led pharmacovigilance working model significantly increased the quantity and quality of ADE reporting in SAHZU and promoted pharmacovigilance. This model is worth developing in Chinese tertiary hospitals and the following hospitals, where the physicians working there spend little time and energy on ADE reporting or the cost of physicians is high, while the clinical pharmacist team has strong professional skills. PMID- 30464488 TI - Effect of intrawound vancomycin application in spinal surgery on the incidence of surgical site infection: a meta-analysis. AB - Background: Despite great advances in aseptic surgical techniques, surgical site infection (SSI) is still one of the main complications after spine surgery. SSI can bring tremendous physical, psychological, and economic challenges to patients. Intrawound vancomycin application is a much disputed method for the prevention of SSI after spine surgery. Objective: The aim of this study is to review the current literature for studies on the intra-wound application of vancomycin powder and to analyze its effectiveness in the prevention of postoperative SSI. Methods: PubMed, Medline, Elsevier, and CNKI were searched for the key words "vancomycin", "local/intraoperative/topical/intra-wound", "spine/spinal/lumbar/cervical/thoracolumbar surgery", "infection", and "SSI" in published studies on the effectiveness of intrawound vancomycin application to prevent postoperative SSI. RevMan 5.3 was used to compare the data extracted from the studies included. Results: A total of 27 studies involving 17,321 patients were included in the final analysis. Among those patients, 7,423 patients were treated with vancomycin to prevent SSI, with 9,898 in control groups. SSI incidence after surgery in experimental groups was 0.39 times as high as control groups, and this difference was statistically significant (P<0.01). Among patients who underwent internal fixation, vancomycin application significantly reduced the incidence of postoperative SSI (OR 0.31 95% CI 0.19-0.50; P<0.01). Meanwhile, vancomycin did not affect SSI incidence in patients who did not receive internal fixation (P=0.17) or received deformity correction (P=0.25). Conclusion: SSI incidence after spinal surgery can be significantly reduced by intrawound application of vancomycin in most circumstances. This method can be applied in various spinal procedures involving instrumentation to prevent postoperative SSI. PMID- 30464489 TI - Risk factors for surgical site infection following lumbar spinal surgery: a meta analysis. AB - Objective: To identify risk factors for surgical site infection (SSI) in patients who had undergone lumbar spinal surgery. Methods: Studies published in PubMed, Web of Science, and Embase were systematically reviewed to determine risk factors for SSI following lumbar spinal surgery. Results are expressed as risk ratios (RRs) with 95% CIs and weighted mean difference (WMD) with 95% CI. A fixed-effect or random-effect model was used to pool the estimates according to heterogeneity among the studies included. Results: Sixteen studies involving 13,393 patients were included in this meta-analysis. Pooled estimates suggested that diabetes (RR 2.19, 95% CI 1.43-3.36; P<0.001), obesity (RR 2.87, 95% CI 1.62-5.09; P<0.001), BMI (WMD 1.32 kg/m2, 95% CI 0.39-2.25; P=0.006), prolonged operating time (WMD 24.96 minutes, 95% CI 14.77-35.15; P<0.001), prolonged hospital stay (WMD 2.07 days, 95% CI 0.28-3.87; P=0.024), hypertension (RR 1.28, 95% CI 1.08-1.52; P=0.005), and previous surgery (RR 2.06, 95% CI 1.39-3.06; P<0.001) were independent risk factors for SSI in patients who had undergone lumbar spine surgery. Current smoking (RR 0.89, 95% CI 0.75-1.06; P=0.178), American Society of Anesthesiologists grade >2 (RR 2.63, 95% CI 0.84-8.27; P=0.098), increased age (WMD 1.43 years, 95% CI -1.15 to 4.02; P=0.278), COPD (RR 1.21, 95% CI 0.68-2.17; P=0.521), cardiovascular disease (RR 1.63, 95% CI 0.40-6.70; P=0.495), rheumatoid arthritis (RR 1.76, 95% CI 0.53-5.90; P=0.359), and osteoporosis (RR 1.91, 95% CI 0.79-4.63; P=0.152) were not risk factors for postoperative SSI. Conclusion: Our results identified several important factors that increased the risk of postoperative SSI. Knowing these risk factors, surgeons could adequately analyze and evaluate risk factors in patients and then develop prevention measurements to reduce the rate of SSI. PMID- 30464491 TI - The association between metabolic syndrome and asymptomatic carotid artery stenosis in menopausal women: a cross-sectional study in a Chinese population. AB - Background: To examine the association of metabolic syndrome (MetS) with carotid artery stenosis (CAS), especially in menopausal women in China. Materials and methods: A cross-sectional study of menopause women aged >=40 years were enrolled from the Jidong community of Tangshan City between 2013 and 2014 to examine the association between MetS and CAS. Logistic regression analyses were performed to analyze the association between MetS and the presence of CAS. Results: A total of 762 menopause women with mean age 59.3+/-5.6 years were enrolled in our analysis. Of all the people, 111 participants in CAS group (n=159) and 297 participants in no CAS group (n=603) were diagnosed with MetS meantime. Menopausal women with MetS had increased risk of CAS (OR, 2.383; 95% CI, 1.639-3.464), and the association was further verified by adjusting for confounding factors (OR, 1.949; 95% CI, 1.269-2.994). In addition, age, physical activity (never or moderate), body mass index (>24 kg/m2), and family income (<3,000 RMB) were independent important factors to CAS development in those with MetS. Conclusion: MetS is associated with CAS especially in women after menopause. PMID- 30464490 TI - Mycophenolate therapy in interstitial pneumonia with autoimmune features: a cohort study. AB - Objectives: International experts recently characterized interstitial pneumonia with autoimmune features (IPAF) as a provisional diagnosis for patients with interstitial lung disease who have characteristics of autoimmune disease but do not meet criteria for a specific autoimmune disease. We describe clinical characteristics of IPAF patients and examine responses to mycophenolate as a therapy for IPAF. Methods: This retrospective cohort included adult patients meeting European Respiratory Society/American Thoracic Society classification criteria for IPAF. Sociodemographic, clinical, and pulmonary function test data were abstracted for patients with and without mycophenolate treatment and followed longitudinally from interstitial lung disease diagnosis for change in pulmonary function test results. Results: We identified 52 patients who met criteria for IPAF. Of 52 IPAF patients, 24 did not receive mycophenolate and 28 did, with median time to mycophenolate treatment 22 months. Changes in FVC% and percentage predicted lung diffusion capacity for carbon monoxide (DLCO%) between the mycophenolate-treated and untreated groups were not significantly different (FVC% change P=0.08, DLCO% change P=0.17). However, there was a trend toward more rapid baseline decline of both FVC% and DLCO% in the mycophenolate-treated cohort before vs after mycophenolate therapy. The slope of both FVC% and DLCO% values improved after onset of mycophenolate exposure for the treated group, although this finding was not statistically significant. Conclusion: Patients with IPAF might benefit from mycophenolate therapy. Larger prospective clinical trials are needed to evaluate the efficacy of mycophenolate for patients who meet criteria for IPAF. PMID- 30464492 TI - Targeted treatment of advanced ovarian cancer: spotlight on rucaparib. AB - The last 2 years have ushered in a new era in ovarian cancer therapy with the US Food and Drug Administration's (FDA) approval of poly-ADP ribose polymerase (PARP) inhibitors (PARPi). One of the deadliest cancers that women experience, ovarian cancer, is most often diagnosed in advanced stages. Although cytoreductive surgery and (platinum/taxane-based) chemotherapy can place the majority of patients into remission, most will experience a relapse of their disease in their lifetime. This has led to studies exploring the benefits and efficacy of maintenance treatment. This review will briefly discuss the history of maintenance therapy as well as focus on the FDA's approval of rucaparib and its companion tumor profiling test, in the US. It will describe how women with deleterious mutations in the BRCA gene, through their inherent deficiency in homologous recombination, presented scientists with a target to exploit through a concept known as synthetic lethality. Not only did this lead to a targeted treatment for BRCA mutation carriers but for other patients with deficiencies in homologous recombination and, more broadly, also in platinum-sensitive patients. The focus of this review will be on rucaparib in the US, approved for both maintenance of platinum-sensitive recurrent ovarian cancer and treatment in the third-line setting and beyond. It has the broadest indication amongst the three PARPi in ovarian cancer. Furthermore, the ongoing trials using rucaparib in ovarian cancer and other disease types will be discussed. PMID- 30464484 TI - A comprehensive overview on osteoporosis and its risk factors. AB - Osteoporosis is a bone disorder with remarkable changes in bone biologic material and consequent bone structural distraction, affecting millions of people around the world from different ethnic groups. Bone fragility is the worse outcome of the disease, which needs long term therapy and medical management, especially in the elderly. Many involved genes including environmental factors have been introduced as the disease risk factors so far, of which genes should be considered as effective early diagnosis biomarkers, especially for the individuals from high-risk families. In this review, a number of important criteria involved in osteoporosis are addressed and discussed. PMID- 30464493 TI - Balancing intubation time with postoperative risk in cardiac surgery patients - a retrospective cohort analysis. AB - Introduction: Intubation time in patients undergoing cardiac surgery may be associated with increased mortality and morbidity. Premature extubation can have serious adverse physiological consequences. The aim of this study was to determine the influence of intubation time on morbidity and mortality in patients undergoing cardiac surgery. Methods: We performed a retrospective analysis of data on 1,904 patients undergoing isolated coronary artery bypass grafting (CABG) and stratified them by duration of intubation time after surgery - 0-6, 6-9, 9 12, 12-24 and over 24 hours. Postoperative complications risk analysis was performed using multivariate logistic regression analysis for patients extubated <=12 and >12 hours. Results: Intubation percentages in each time cohort were as follows: 0-6 hours - 7.8%, 6-9 hours - 17.3%, 9-12 hours - 26.8%, 12-24 hours - 44.4% and >24 hours - 3.7%. Patients extubated <=12 hours after CABG were younger, mostly males, more often smokers, with lower preoperative risk. They had lower 30-day mortality (2.02% vs 4.59%, P=0.002), shorter hospital stay (7.68+/ 4.49 vs 9.65+/-12.63 days, P<0.001) and shorter intensive care unit stay (2.39 vs 3.30 days, P<0.001). Multivariate analysis showed that intubation exceeding 12 hours after CABG increases the risk of postoperative delirium (OR 1.548, 95% CI 1.161-2.064, P=0.003) and risk of postoperative hemofiltration (OR 1.302, 95% CI 1.023-1.657, P=0.032). Conclusion: Results indicate that risk of postoperative complications does not increase until intubation time exceeds 12 hours. Shorter intubation time is seen in younger, men and smokers. Intubation time >12 hours is a risk factor for postoperative delirium and hemofiltration after cardiac surgery. PMID- 30464494 TI - Use of photoplethysmography to predict mortality in intensive care units. AB - Purpose: The aim of this study was to evaluate and compare the capacity to predict hemodynamic variables obtained with photoplethysmography (PPG) and Acute Physiology and Chronic Health Evaluation (APACHE II) in patients hospitalized in the intensive care unit (ICU). Materials and methods: A prospective cohort study was conducted in the adult ICU of Hospital Nossa Senhora da Conceicao, located in Tubarao, Santa Catarina, Brazil. The data collected included the diagnosis for hospitalization, age, gender, clinical or surgical profile, PPG pulse curve signal, and APACHE II score in the first 24 hours. A bivariate and a multivariate logistic regressions were performed, with death as an outcome. A mortality model using artificial neural networks (ANNs) was proposed. Results: A total of 190 individuals were evaluated. Most of them were males (6:5), with a median age of 67 (54-75) years, and the main reasons for hospitalization were cardiovascular and neurological causes; half of them were surgical cases. APACHE II median score was 14 (8-19), with a median length of stay of 6 (3-15) days, and 28.4% of the patients died. The following factors were associated with mortality: age (OR=1.023; 95% CI 1.001-1.044; P=0.039), clinical profile (OR=5.481; 95% CI 2.646 11.354; P<0.001), APACHE II (OR=1.168; 95% CI 1.106-1.234; P<0.001), heart rate in the first 24 hours (OR=1.020; 95% CI 1.001-1.039; P=0.036), and time between the systolic and diastolic peak (?T) intervals obtained with PPG (OR=0.989; 95% CI 0.979-0.998; P=0.015). Compared with the accuracy (area under the receiver operating characteristic curve) 0.780 of APACHE II (95% CI 0.711-0.849; P<0.001), the multivariate logistic model showed a larger area of 0.858 (95% CI 0.803 0.914; P<0.001). In the model using ANNs, the accuracy was 0.895 (95% CI 0.851 0.940; P<0.001). Conclusion: The mortality models using variables obtained with PPG, with the inclusion of epidemiological parameters, are very accurate and, if associated to APACHE II, improve prognostic accuracy. The use of ANN was even more accurate, indicating that this tool is important to help in the clinical judgment of the intensivist. PMID- 30464495 TI - Successful recruitment and retention strategies for women health volunteers: viewpoints of the volunteers' supervisors and relevant researchers. AB - Background: Women health volunteers (WHVs) are a link between people and healthcare workers. Despite their key role in promoting community health, strategies are rarely designed to keep them volunteering. The aim of this research was to find successful strategies to overcome barriers to recruitment and retention of the volunteers in assigned activities. Subjects and methods: A three-round online national Delphi technique was used to ask the opinions of Iranian health volunteers' supervisors and the relevant researchers. At the first round, the participants were asked ten open-ended questions across four barriers: inadequate capability of the volunteers and trainers, inadequate acceptance of the volunteers, restrictive social norms, and organizational problems. At the second round, with the questionnaire consisting of closed-ended questions, the experts were asked to rank the feasibility of each strategy using a seven-point Likert scale. Items along with the feedback received from the second round were included in the third-round questionnaire. Strategies with a median of 6 or higher and with an interquartile range <=1 were regarded to be feasible. Results: Consensus was obtained on 100 of the 133 strategies. A mixture of improving group work, implementing motivation tactics, assessing the needs of people/WHVs, reforming policy, monitoring and evaluation of WHVs/trainers, mobilizing the community, empowering WHVs/trainers, rationalizing WHVs/trainers/people, improving intersectional collaboration, implementing problem-based approaches, allocating proper resources, appropriate recruitment of WHVs, using social networks, and information dissemination were found to be the effective strategies to overcome the barriers to active participation. Conclusion: The highest consensuses among experts were on implementing motivation tactics and mobilizing the community. It seems that community mobilization, incentives, and logistical supplies such as providing prizes and transportation facilities for volunteers are mechanisms that can help retain WHVs and also overcome barriers to their active participation. PMID- 30464496 TI - Teaching the principles of safe prescribing to a mixed profession postgraduate cohort: program development. AB - Background: Prescribing medicines is a complex task. A robust prerequisite curriculum that enables the efficient and consistent training of safe and effective prescribers is important. Despite differing prescribing contexts and professional attributes, the core elements of safe and effective prescribing relevant to all prescribers can be identified. This article describes the development process and content of a training program for safe prescribing, which was designed for a mixed cohort of allied health professionals in Queensland, Australia. Methods: The allied health prescribing training program was designed to align with national standards for prescribing and competencies for safe prescribing. International training programs, for nonmedical prescribing, were examined to inform the program development. Content was delivered by experienced prescribers from a range of professions. The inaugural cohort was surveyed before and after training to ascertain their confidence to prescribe. Results: A training program for allied health prescribers was developed and delivered to enable the implementation of a state-sponsored research trial in Queensland public facilities. The program consisted of two modules (the second of which is described in this article) complemented by a mandatory period of supervised workplace learning. Remote blended learning, comprising online prerecorded lectures, self-directed learning, teleconference seminars, and a 2-day on-campus intensive residential, was used to deliver content. A total of 19 allied health professionals (12 physiotherapists and 7 pharmacists) completed the program that equipped them to begin a prescribing trial within their specific practice settings. Post module completion, 90% of the cohort felt confident to prescribe for patients in their practice area. Conclusion: Program development and delivery were challenging, requiring attention to both the needs of each profession and those of the individual practitioner who was required to apply generic prescribing principles to their specific practice setting. Further refinement of content, delivery, assessment, and resource allocation is required for future cohorts. PMID- 30464497 TI - Options of medical treatment and laryngeal function preservation in elderly patients with medial wall pyriform sinus cancer. AB - Objective: To retrospectively investigate the clinical efficacy and larynx preservation of two different treatments: radiotherapy followed by surgery (R+S) and surgery followed by radiotherapy (S+R), in elderly patients with medial wall pyriform sinus cancer. Materials and methods: Medical records from 48 patients over 70 years old with medial wall pyriform sinus cancer who underwent different treatments between 2001 and 2010 were analyzed. Twenty-one patients underwent radiotherapy first followed by surgery (R+S), and the other 27 patients underwent surgery first followed by radiotherapy (S+R). A Kaplan-Meier method was used to calculate the survival rate. Results: Overall 3-year and 5-year survival rates were 60.4% and 35.4%, respectively. The 5-year survival rates in R+S group and S+R group were 38.1% and 33.3%, respectively, without a statistically significant difference between the two groups (P>0.05). Also, comparisons of the decannulation rates (64.3% for R+S group vs 50.0% for S+R group) and postoperative complication rates (42.9% for R+S group vs 37.0% for S+R group) between the two groups of patients did not show obvious differences. However, the laryngeal preservation rates in R+S group and S+R group were 66.7% and 37.0%, respectively, with significantly statistical difference between the two groups (P<0.05). Conclusion: Based on the data analysis of 48 patients, the survival rates of elderly patients who underwent R+S or S+R were comparable, but R+S treatment could improve the laryngeal preservation rate of patients. Further study on large-scale sample pool should be performed to confirm this conclusion. PMID- 30464498 TI - Knockdown of CCNO decreases the tumorigenicity of gastric cancer by inducing apoptosis. AB - Purpose: Recently, Cyclin O (CCNO) has been reported to be a novel protein of the cyclin family. However, the clinical significance and functional roles of CCNO in human cancer, including gastric cancer (GC), remain largely unexplored. In this study, we investigated the clinical and functional roles of CCNO in GC. Methods: We analyzed CCNO expression patterns in GC patients. To investigate the role of CCNO in malignancy of GC, we used lentivirus-delivered short hairpin RNA to knockdown CCNO expression in GC cell lines. Then multiparametric high-content screening and MTT incorporation assay were used to assess the cell proliferation capability. Cell apoptosis was detected by flow cytometry and Caspase 3/7 assays. Furthermore, the effect of CCNO on tumorigenicity of GC was also determined in vivo. Finally, microarray analysis was performed to elucidate the molecular mechanisms by which shCCNO inhibited the malignancy of GC cells. Results: The analysis from The Cancer Genome Atlas database revealed elevated CCNO mRNA expression in GC tissue than in the adjacent normal tissue. Immunohistochemical studies also showed that stronger cytoplasmic staining of CCNO was detected in GC tissues. Downregulation of CCNO in GC cells efficiently, through infection with the lentivirus-mediated specific short hairpin RNA, could significantly induce cell apoptosis and inhibit the proliferative properties both in vitro and in vivo. Microarray analysis further revealed 652 upregulated genes and 527 downregulated genes in the shCCNO group compared with control, and indicated that CCNO knockdown could inhibit the malignancy of GC cells through inducing genome wide gene expression changes. Conclusion: Our work is the first to reveal that elevated CCNO expression is closely associated with human GC development and that CCNO knockdown could efficiently inhibit the malignant properties of GC cells by inducing cell apoptosis. Therefore, CCNO could be used as a potential biomarker for prognosis or even as a therapeutic target in human GC. PMID- 30464499 TI - Re-biopsy status among Chinese non-small-cell lung cancer patients who progressed after icotinib therapy. AB - Objective: Acquired T790M mutations account for 50%-60% of tyrosine kinase inhibitor (TKI)-resistant mechanisms in EGFR mutation-positive (m+) non-small cell lung cancer (NSCLC) patients, and re-biopsy is recommended to detect these mutations. We investigated the re-biopsy status and the T790M incidence rate in patients after treatment with icotinib, which is the first-generation EGFR-TKI widely used in China. Patients and methods: Target patients had EGFRm+NSCLC, who were progressed after icotinib therapy. The primary end point was the re-biopsy rate (number of cases in which re-biopsies were performed successfully/total number of patients progressed after icotinib therapy). Secondary end points included the T790M mutation incidence rate, differences between the first biopsy and re-biopsy, and details of why re-biopsy was not performed in relevant patients. Results: A total of 77 adenocarcinoma patients were evaluated (median age, 58 years). Tissue re-biopsy was successful in 41 patients (53.2%). Compared with the first biopsy, percutaneous tissue biopsies increased from 51.2% to 70.7% (P=0.008), while bronchoscopy biopsies and the surgical rate decreased from 19.5% to 14.6% (P<0.001) and 17.1% to 7.3% (P<0.001), respectively. Primary lung lesions were more common in the first biopsy than in re-biopsy (80.5% vs 65.9%, P=0.008), but metastatic lesions were more often selected for re-biopsy (14/41 [34.1%], including metastases in the bone, lymph nodes, and liver). The incidence rate of T790M was 56.1% (23/41). The reasons for not performing re-biopsies included lesion sizes and/or locations unsuitable for biopsy (n=17), a positive circulating tumor DNA (ctDNA) result (n=3), patient unwillingness (n=7), older age or severe comorbidity (n=4), and poor health (n=5). No severe complications were found. Conclusion: In this real-world study, the re-biopsy rate was 53.2% and the incidence rate of T790M mutations was 56.1%. Further efforts are needed to increase the re-biopsy rate in patients who progress after icotinib therapy. PMID- 30464500 TI - The impact of immunosenescence on the efficacy of immune checkpoint inhibitors in melanoma patients: a meta-analysis. AB - Background: Immunosenescence, the age-related decline of immunity, affects the immune responses of melanoma patients. Through immune responses, immune checkpoint inhibitors (ICIs) exert their antitumor robustness. In different ages of melanoma patients, especially the older patients, the effectiveness of ICIs remains unclear. It is still controversial whether ICIs should be used in treating older patients. Materials and methods: The authors included clinical trials of ICIs in older and younger patients. The authors used hazard ratio (HR) and 95% CI of overall survival (OS). Results: From four phase III randomized clinical trials 2,251 melanoma patients were included. We found that ICIs significantly prolonged the OS for melanoma patients in both younger (HR, 0.71; 95% CI, 0.60-0.82; P<0.001) and older groups (HR, 0.62; 95% CI, 0.41-0.83; P<0.001) compared with controls. Anti-programmed death-1 (PD-1) agents appeared to be more efficient in older melanoma patients (HR, 0.34; 95% CI, 0.14-0.53) versus younger patients (HR, 0.52; 95% CI, 0.26-0.78). Conclusion: ICIs significantly prolonged the OS for melanoma patients in both younger and older groups than controls. Anti-PD-1 agents were more efficient in older melanoma patients versus younger patients. ICIs could be used for older melanoma patients. PMID- 30464501 TI - Clinical and molecular characteristics associated with the efficacy of PD-1/PD-L1 inhibitors for solid tumors: a meta-analysis. AB - We conducted a meta-analysis to estimate the impact of different clinical and molecular characteristics on the efficacy of programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors. PubMed and Web of Science were searched for related trials. Eleven eligible studies, comprising 5,663 patients, were included in this meta-analysis. We found that the PD-1/PD-L1 inhibitor was associated with a 31% reduction in the risk of death (hazard ratio [HR]=0.69; 95% CI 0.64-0.74; P<0.00001) for patients with melanoma, non-small-cell lung cancer (NSCLC), urothelial carcinoma, head and neck carcinoma, and renal cell carcinoma. In subgroup analyses, all the patients with PD-L1-positive tumors had overall survival (OS) benefits from PD-1/PD-L1 inhibitors regardless of PD-L1 expression level, and a dose-effect relationship between the expression of PD-L1 and OS benefit from PD-1/PD-L1 inhibitors was observed. There was an OS improvement for patients with a smoking history (P<0.00001), but no OS benefit was observed for nonsmokers (P=0.28). In addition, first-line therapy had better OS than second line or later treatment (P=0.02). No significant improvement of OS was observed (P=0.70) in patients aged >=75 years. The relative treatment efficacy was similar according to sex (male vs female, P=0.60), performance status (0 vs >=1, P=0.68), tumor histology (squamous NSCLC vs non-squamous NSCLC vs melanoma vs urothelial carcinoma vs head and neck carcinoma vs renal cell carcinoma, P=0.64), and treatment type (PD-1 inhibitor vs PD-L1 inhibitor, P=0.36). In conclusion, PD-L1 positive tumors, smoking history, and first-line treatment were potential factors for the efficacy of PD-1/PD-L1 inhibitors. Patients with higher PD-L1 expression might achieve greater OS benefits. In addition, sex, performance status, tumor histology, and treatment type could not predict the efficacy of this therapy. In contrast, patients aged >75 years and nonsmokers might not get OS benefits from this treatment. These results may improve treatment strategies and patient selection for PD-1/PD-L1 inhibitors. PMID- 30464503 TI - Successful alternative treatment for relapsed adult acute lymphoblastic leukemia with dendritic cells-cytokine-induced killer cells combined with a rituximab based regimen. AB - Objective: Acute lymphoblastic leukemia (ALL) is a malignant disease characterized by the accumulation of lymphoblasts, and a poor prognosis for adults with ALL is closely associated with disease recurrence. Thus far, treatment approaches have been limited, particularly in patients who are unable to tolerate chemotherapy. In this study, we report an effective treatment for such patients. Materials and methods: A 52-year-old man diagnosed with Ph negative B-precursor ALL went into remission after inductive treatment. Unfortunately, when he subsequently relapsed, severe complications drove him to refuse intensive chemotherapy. Instead, he received a cycle of dendritic cells cytokine-induced killer cells (DC-CIK) before chemotherapy. Result: The patient tolerated rituximab in combination with a vincristine, daunorubicin, l asparaginase, and prednisone regimen without complications, and was in remission after DC-CIK infusion. After consolidation chemotherapy, including rituximab followed by eight cycles of DC-CIK, the patient has been free of leukemia for 2 years since the relapse. Conclusion: This case of relapsed ALL was successfully treated with DC-CIK combined with a rituximab regimen. PMID- 30464502 TI - BMP-2 inhibits lung metastasis of osteosarcoma: an early investigation using an orthotopic model. AB - Background: Bone morphogenetic proteins (BMPs), members of the TGF-beta superfamily, are known to regulate cell proliferation, differentiation, apoptosis, chemotaxis, and angiogenesis. BMPs also participate in the development of most tissues and organs in vertebrates. Recombinant human (rh) BMPs, such as rhBMP-2, rhBMP-4, and rhBMP-7, have been recently approved to augment spinal fusion and recalcitrant long-bone non-unions because of their equivalent or superior efficacy to autogenous bone graft in enhancing bony fusion. Nonetheless, the use of BMPs is contraindicated in surgery for bone tumors because of concerns that this anabolic growth factor may cause tumor proliferation. However, we have repeatedly reported that BMP-2 is effective in inducing osteogenic differentiation of a subpopulation of osteosarcoma (OSA) cells that acquire stem cell attributes and are capable of reconstituting tumor masses, which in turn suppress the malignancy of the bone tumor. Methods: 3*105/20 uL human OSA 143B cells were inoculated into 5-6 weeks old BABL/c nude mice to establish orthotopic OSA. X-ray device was used to monitor the developed tumors in animals. Necropsy was performed and the pathology of lung metastasis were tested by Haemotoxylin and Eosin. Moreover, bone formation induced by rhBMP-2 was investigated through micro-computed tomography. In addition, immunohistochemistry staining was used to evaluate the tumorigenicity and growth of OSA cells after rhBMP-2 treatment. Results: In the present study, we established an orthotopic model of OSA by inoculating 143B cells into BABL/c mice, which resulted in a tumor occurrence rate of 100%. Following the treatment with rhBMP-2, lung metastasis, which contributes to poor prognosis, was significantly restricted, indicating an additional aspect of rhBMP-2 to suppress expansion of OSA. Concurrently, our micro-computed tomography and radiographic analyses showed that rhBMP-2 reduced the invasion of tumor cells into adjacent bone tissue, which in turn helped to preserve the integrity of the affected bone tissue. Finally, the growth of Ki-67 positive cells and those cells that express high levels of aldehyde dehydrogenase (ALDHbr) was found to be inhibited in the developed tumors. Conclusion: On the basis of these results, we conclude that rhBMP-2 can impede the malignancy of OSA by reducing lung metastasis of the tumor. Induction of the tumor cells by rhBMP-2 also helps to preserve the impaired skeleton. These results imply that BMP-2 or BMP-2-mimetic drugs, if properly combined with traditional therapies, may provide a new therapeutic option for the treatment of OSA. PMID- 30464504 TI - Sirt3 enhances glioma cell viability by stabilizing Ku70-BAX interaction. AB - Background: As one of the most prevalent malignancies, glioma is characterized by poor prognosis and high mortality rate. Glioma patients may show completely distinct clinical outcomes due to their different molecular patterns. Sirtuin 3 (Sirt3) participates in aging, stress resistance, and metabolic regulation. Here we aimed to test the expression and function of Sirt3 in glioma. Methods: We enrolled 114 patients and tested the protein level of Sirt3 in their glioma tissues. The correlation between prognosis and Sirt3 was evaluated by univariate and multivariate analyses. We also conducted cellular experiments in U87 and U251 glioma cells, including overexpression and knockdown assays. Results: Sirt3 expression was lower in glioma tissues than normal brain tissues. Higher Sirt3 is significantly correlated to advanced tumor grade (P=0.004), showing its potential role in cancer progression. Consistently, univariate and multivariate analyses identified Sirt3 as an independent prognostic factor (P=0.017). Patients with higher Sirt3 expression showed significantly shorter overall survival time. Moreover, overexpression of Sirt3 in either cell line enhanced cell viability, while silencing Sirt3 attenuated cell growth. Molecular assays showed Sirt3 can deacetylate Ku70 protein, therefore stabilizing the Ku70-BAX interaction. Since Ku70 can help prevent BAX transporting into mitochondria and decrease cell apoptosis, Sirt3 protein may play roles in maintaining cell viability. In addition, silencing Ku70 inhibited the pro-proliferative effect by Sirt3. Conclusion: Taken together, our results not only identified the prognostic role of Sirt3 in glioma patients but also provided signaling pathway evidence for its functioning mechanisms. PMID- 30464505 TI - ADAMTS8 targets ERK to suppress cell proliferation, invasion, and metastasis of hepatocellular carcinoma. AB - Introduction: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system. A disintegrin and metallopeptidase with thrombospondin motif (ADAMTS) has been identified as a secreted metalloproteinase that participates in the inhibition of tumor cell growth and invasion. The aims of the present study were to investigate the clinical significance of ADAMTS8 in patients with HCC and to determine the effect of ADAMTS8 on HCC cell biological activity in vitro and in vivo. Methods: The tumor tissues and matched adjacent non-tumor tissues were collected from 61 patients with HCC, and ADAMTS8 expression was detected with immunohistochemistry. Flow cytometry and MTT assays were used to assess cell apoptosis and cell viability, respectively, and ERK, p ERK, Stat3, p-Stat3, Akt, and p-Akt protein expressions were measured by Western blot. Results: The results showed that ADAMTS8 expression was significantly lower in HCC tissues than that in adjacent non-tumor tissues. Moreover, ADAMTS8 expression was inversely associated with clinical stages and metastasis in patients with HCC. Furthermore, we found that transfection with exogenous ADAMTS8 inhibited proliferation and migration and induced apoptosis in HepG2 cells. In the in vivo study, tumor growth of upregulated HepG2 cells in nude mice was significantly slower. Moreover, decreased ERK activity was detected after transfection with ADAMTS8. Conclusion: These results indicate that low ADAMTS8 expression is a predictor of a poor prognosis in patients with HCC and that ADAMTS8 plays an important role in regulating HCC growth, invasion, and apoptosis by modulating the ERK signaling pathway. ADAMTS8 maybe a new target in HCC treatment. PMID- 30464506 TI - GATA3 is downregulated in osteosarcoma and facilitates EMT as well as migration through regulation of slug. AB - Background: GATA3 functions as a tumor suppressor and has been observed in multiple types of cancer, but the effects and mechanisms of GATA3 in osteosarcoma (OS) are not yet known. Methods: The GATA3 expression in OS cells and tissues were detected using quantitative reverse-transcription PCR and Western blotting assay. CCK-8 assay, colony formation assay, wound healing assay as well as transwell assay, were performed to determine the effects of GATA3 on cell proliferation, migration and invasion. ChIP and qChIP as well as luciferase assay were performed whether GATA3 transcriptionally regulated slug expression. Results: GATA3 was downregulated in OS cells and tissues. The GATA3 expression was closely associated with tumor size as well as metastasis. GATA3 significantly suppressed OS cells proliferation, migration and invasion. EMT-associated transcript factor, slug, was transcriptionally inhibited by GATA3, thereby regulation of EMT in OS. Conclusion: GATA3 serves as a tumor suppressor in OS and suppresses the progression and metastasis of OS through regulation of slug. PMID- 30464508 TI - Erratum: Knockdown of immature colon carcinoma transcript-I inhibits proliferation of glioblastoma multiforme cells through Gap 2/mitotic phase arrest [Expression of concern]. AB - [This corrects the article on p. 1119 in vol. 8, PMID: 26056476.]. PMID- 30464507 TI - RGS17 inhibits tumorigenesis and improves 5-fluorouracil sensitivity in nasopharyngeal carcinoma. AB - Background: Nasopharyngeal carcinoma (NPC) is a poorly differentiated malignant tumor, and 5-fluorouracil (5-FU) is one of the most effective chemotherapeutic drugs used for the treatment of NPC. Abnormal expression of RGS17 had been shown to improve the sensitivity of many cancers to chemotherapy; however, the effects of RGS17 on NPC remain unclear. Methods: We cultured NPC cell lines and altered the RGS17 expression with vector. Subsequently colony formation assays and CCK8 cell viability assay was used to test the proliferation of NPC cells, flow cytometry was used to determine the percentage of apoptotic cells, MMP kit and flow cytometry was used to measure the mitochondrial membrane potential, and a xenograft tumour model was attached to investigate the effects of RGS17 on the growth of NPC cells in vivo. Additionally, RT-PCR and western blot was induced to examine the expression of RGS17 and the mechanism. Results: Here, we report for the first time that RGS17 is downregulated in NPC cell lines and that RGS17 overexpression significantly reduces cell proliferation, decreases the mitochondrial membrane potential, and induces cell apoptosis in NPC cells. In vivo, RGS17 also inhibits the tumorigenicity of NPC. In addition, RGS17 could significantly improve the sensitivity of NPC cells to 5-FU. Furthermore, investigation into the underlying mechanisms showed that RGS17 upregulated the levels of IRE1alpha, p53, and active caspase-3 and cleaved PARP. Conclusion: These results indicate that RGS17 could play important roles in the proliferation, apoptosis, and chemotherapeutic sensitivity of NPC cells. PMID- 30464509 TI - Protein tyrosine phosphatase L1 inhibits high-grade serous ovarian carcinoma progression by targeting IkappaBalpha. AB - Background: High-grade serous ovarian cancer (HGSOC) represents most of the ovarian cancers and accounts for 70%-80 % of related deaths. The overall survival of HGSOC has not been remarkably improved in the past decades, due to the tumor dissemination in peritoneal cavity and invasion of adjacent organs. Therefore, identifying molecular biomarkers is invaluable in helping predicting clinical outcomes and developing targeted chemotherapies. Although there have been studies revealing the prognostic significance of protein tyrosine phosphatase L1 (PTPL1) in breast cancer and lung cancer, its involvement and functions in HGSOC remains to be elucidated. Methods: We retrospectively enrolled a cohort of HGSOC patients after surgical resection. And analyzed the mRNA and protein levels of PTPL1 in tissue samples. Results: We found that PTPL1 presented a lower expression in HGSOC tissues than in adjacent normal ovarian tissues. Besides, the PTPL1 level was negatively correlated with tumor stage, implying its potential role as a tumor suppressor. Univariate and multivariate analyses identified that patients with higher PTPL1 showed a better overall survival compared to those with lower PTPL1 expression. In addition, cellular experiments confirmed the role of PTPL1 in suppressing tumor proliferation and invasion. Furthermore, we demonstrated that PTPL1 negatively regulated phosphorylation of tyrosine 42 on IkappaBalpha (IkappaBalpha-pY42). To our knowledge, this is the initial finding on PTPL1 targeting IkappaBalpha-pY42 site. Finally, our data indicated that PTPL1 suppressed tumor progression by dephosphorylating IkappaBalpha-pY42, which stabilized IkappaBalpha and attenuated nucleus translocation of NF-kappaB. Conclusion: Our study revealed a tumor-suppressing role of PTPL1 in HGSOC by targeting IkappaBalpha. PMID- 30464510 TI - SIRT6 overexpression induces apoptosis of nasopharyngeal carcinoma by inhibiting NF-kappaB signaling. AB - Background: Previous reports show that SIRT6 serves as a critical modulator of the development of multiple malignancies as well as other disorders. However, its role in nasopharyngeal carcinoma (NPC) is unknown. Thus, we elucidated the effects of SIRT6 on the survival of NPC cells, and modulation of cell death. Methods: We found that expression of SIRT6 is downregulated in ten human NPC specimens as well as in the human NPC cell lines, 5-8 F and CNE1, as compared with that in healthy tissues and normal nasopharyngeal NP69 cells. The MTT assay and colony formation assay revealed that upregulation of SIRT6 impaired the proliferation, as well as the survival of 5-8 F and CNE1 cells. The TUNEL assay, annexin V-FITC/propidium iodide, and flow cytometry were performed to detect apoptosis. The results revealed that the expression of SIRT6 resulted in increased apoptosis. Results: Western blotting results showed that SIRT6 overexpression decreased anti-apoptotic Bcl-2 levels, whereas it promoted an increase in pro-apoptotic Bax and cleaved caspase-3 levels. Moreover, NF-kappaB levels were markedly reduced in cells expressing SIRT6, whereas they were increased in cells transfected with shRNA-SIRT6. Recovery of NF-kappaB expression was found to counter the suppressive influence of SIRT6 on NPC cell survival, whereas, NF-kappaB knockdown increased apoptosis of NPC cells. Conclusion: Thus, the findings of our study offer insight into the biological and molecular mechanisms underlying the development of NPC and may lead to the development of new and innovative strategies for the treatment of NPC. PMID- 30464511 TI - Significance of PYK2 level as a prognosis predictor in patients with colon adenocarcinoma after surgical resection. AB - Background: Proline-rich/Ca2+-activated tyrosine kinase 2 (PYK2) belongs to the non-receptor tyrosine kinase family, regulates downstream signaling via catalyzing protein phosphorylation. We aimed to investigate clinical significance and mechanisms of PYK2 in colon adenocarcinoma (CAC). Methods: Real time quantitative PCR and immunohistochemistry staining was used to evaluate the expression of PYK2 in clinical CAC tissues. Its association with clinicopathologic characteristics was analyzed by Chi-square test. Kaplan-Meier univariate survival analysis and multivariate Cox regression analysis were used to identify clinical significance of PYK2 in the overall survival of CAC patients. Transfection of PYK2 were conducted to reveal the underlying mechanism in regulating CAC progression. Results: We found that PYK2 was upregulated in CAC tissues compared with normal colon tissues on both RNA and protein levels. Higher tissue PYK2 expression level was closely associated with lymph node metastasis. Statistical analyses indicated PYK2 as an independent prognostic biomarker for CAC. Cellular studies demonstrated that PYK2 enhanced the capacities of tumor proliferation and invasion. Moreover, the phosphorylation level of AKT was positively correlated with PYK2 expression, subsequently modulate expression of c Myc and Cyclin D1, suggesting that PYK2 may promote tumor progression through activating AKT signaling. Conclusion: High PYK2 in CAC tissues indicate poor prognosis. PMID- 30464512 TI - Clinicopathological analysis of PD-L2 expression in colorectal cancer. AB - Background: (PD-L2), a ligand of programmed cell death protein 1 (PD-1), is an inhibitory receptor of T cells and activated B cells. Many studies have focused on PD-L1, another ligand of PD-1, and the prognostic significance of PD-L1 has been reported in many tumors. However, the expression of PD-L2 in relation to clinical outcomes has not been fully investigated in cancer patients. Patients and methods: In this study, we investigated the expression of PD-L2 via immunohistochemistry (IHC) in the pathological specimens of 348 patients treated for colorectal cancer (CRC). Results: Strong PD-L2 expression was found in the cancer tissues from 41% of the CRC patients who also had a high TNM stage and carcinoembryonic antigen (CEA) concentration. We also carried out functional studies in vitro, which showed that PD-L2 did not influence the growth of the CRC cell line HCT116, but increased cell invasion. Conclusion: Collectively, these findings suggest that PD-L2 may be a potential therapeutic target for CRC. PMID- 30464513 TI - Acyl-CoA dehydrogenase long chain expression is associated with esophageal squamous cell carcinoma progression and poor prognosis. AB - Background: Acyl-CoA dehydrogenase long chain (ACADL) was revealed to have a correlation with malignant progression of cancer. However, whether ACADL plays a role in clinical therapy remains unclear. The clinicopathological role of ACADL in esophageal squamous cell carcinoma (ESCC) will be discussed in this study. Materials and methods: The expression of ACADL was analyzed via real-time PCR and Western blotting to assess mRNA and protein levels in ESCC cell lines and normal esophageal epithelial cells (NEECs), in six paired ESCC tumors and relative normal tissues. Furthermore, immunohistochemical staining was performed on 135 paraffin-embedded ESCC specimens to assess ACADL expression. The clinicopathological significance of ACADL expression was further investigated via survival analysis and Cox regression analysis. Results: ACADL was found to be markedly upregulated in ESCC cell lines when compared with NEECs. Moreover, various experiments such as quantitative real-time PCR, Western blot, and immunohistochemical analyses all revealed that ACADL expression was increased in all six paired ESCC tumors and matched normal tissues. Furthermore, immunohistochemical analysis revealed an increased level of ACADL protein expression in all 135 paraffin-embedded samples from ESCC patients, which increased with disease progression. Conclusion: We demonstrated that ACADL is overexpressed in ESCC, both in cell lines and clinical specimens. ACADL is found to be a vital regulator in ESCC progression and can predict a worse outcome for ESCC patients, suggesting that ACADL might be a valuable molecule to be targeted for clinical therapy of ESCC treatment. PMID- 30464514 TI - A systematic review and meta-analysis of gastrointestinal events associated with nonoperative therapies for neuroendocrine tumors. AB - The risk of gastrointestinal (GI) events induced by nonoperative therapies in patients with neuroendocrine tumors (NETs) is unclear. Nonoperative therapies include somatostatin analogs, molecular targeted agents, cytotoxic chemotherapy, interferon-alpha, and peptide receptor radionuclide therapy. We undertook an up to-date meta-analysis to determine the incidence and relative risks (RRs) of GI events in NET patients treated with these therapies. MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched to identify relevant trials. Eligible trials were selected according to the PRISMA statement. Summary incidence, RR, and 95% CIs were calculated using random- and fixed-effects models. We included 2,890 patients from 17 randomized controlled trials in this meta-analysis. The experimental treatments led to increased incidence and risks of GI events compared to the control treatments (P<0.05). Diarrhea was the most common GI event. The experimental treatments were associated with increased risks of high-grade nausea (RR 2.36; 95% CI 1.05-5.25; P<0.01) and vomiting (RR 1.89; 95% CI 1.04-3.44; P<0.05). In regard to specific therapy regimens, everolimus led to increased risks of diarrhea (RR 2.97; 95% CI 1.83-4.83; P<0.05), vomiting (RR 2.19; 95% CI 1.38-3.48; P<0.05), and anorexia (RR 3.20; 95% CI 1.69-6.06; P<0.05), whereas VEGFR inhibitors led to increased risk of diarrhea (RR 2.12; 95% CI 1.39-3.25; P<0.05). Additionally, GI NETs led to higher risk of GI events than pancreatic NETs. Thus, nonoperative therapies are associated with increased risks of GI events in NET patients, and rigorous management is warranted to minimize the adverse impact on treatment outcomes and to improve quality of life. PMID- 30464515 TI - Cytotoxic effect of Drimia maritima bulb extract and induction of mitochondrial apoptotic signaling in human breast cancer cells, MCF-7 and MDA-MB-468. AB - Background: Drimia maritima (D. maritima) is a plant belonging to the family Asparagaceae, which has been used for the treatment of several ailments including cancer around the world. To our knowledge, there is no comprehensive study about the molecular mechanisms of anticancer activity of this plant, yet. Materials and methods: In the current study, cell viability, apoptosis induction, ROS production, mitochondrial apoptotic pathway, and ER stress mediators have been evaluated in breast cancer cells, MCF7, and MDA-MB-468 treated with D. maritima. Results: Significant cytotoxic effects were observed in MCF-7 and MDA-MB-468 cells after exposure to D. maritima. Apoptosis induction was determined using Annexin-V-FITC and propidium iodide staining. Furthermore, an increase of ROS, loss of mitochondrial membrane potential, the release of cytochrome c, activation of caspases, and elevation in the Bax/Bcl-2 ratio was determined. D. maritima dose-dependently increased the mRNA expression of ER stress markers such as CHOP, ATF-4, GADD34, and TRIB3 in MCF-7, and MDA-MB-468 cells. Conclusion: These data suggest that D. maritima induces apoptosis in human breast cancer cells via the mitochondrial-mediated pathway. In addition, endoplasmic reticulum stress seems to be involved in D. maritima-induced cell death. PMID- 30464516 TI - 16-Hydroxycleroda-3,13-dien-15,16-olide induces anoikis in human renal cell carcinoma cells: involvement of focal adhesion disassembly and signaling. AB - Background: Clerodane diterpene, 16-hydroxycleroda-3,13-dien-15,16-olide (CD) isolated from Polyalthia longifolia Benth. & Hook. f. var. pendula was found to be a potential apoptotic inducer in human leukemia, lung cancer, and colon cancer cells. However, the molecular mechanism remains elusive in renal system. Thus, in the present study, the regulatory mechanisms of CD-induced apoptosis in clear cell renal cell carcinoma (ccRCC) cells were investigated. Materials and methods: Cell proliferation was evaluated by colony formation assay and cell cycle analyses. Protein expressions of focal adhesion (FA) related complexes were examined by immunofluorescence staining and Western blot analyses. Cell migration and invasion capabilities of renal cell carcinoma (RCC) cells were determined by wound healing and Transwell assays. Results: CD inhibited cell colony formations, induced cell arrest at G2/M phase, and increased subG1 cell population both in 786-O and A-498. During CD treatment, the "rounded-up" cells were observed. The immune-staining of phosphorylated focal adhesion kinase (pFAK), vinculin, and paxillin displayed disassembly of the FA. Moreover, disruption of actin stress fibers was noted after CD treatment. Consistent with the findings, the expressions of pSrc, pFAK, FAK, vinculin, vimentin, and paxillin were all downregulated by CD. In addition, CD attenuated cell migration and invasion activities accompanied by the reductions of pNF-kappaB, matrix metallo-proteinase (MMP)-2, MMP-9 as well as vascular endothelial growth factor expressions. Conclusion: CD induced cell cycle arrest, FA complex disassembly, and the inactivation of migratory-related signaling pathways to induce apoptosis in ccRCC cells. PMID- 30464517 TI - A meta-analysis of nivolumab for the treatment of advanced non-small-cell lung cancer. AB - Background: Non-small-cell lung cancer (NSCLC) is often associated with rapid progression following standard chemotherapy. Nivolumab, an inhibitor of PD-1/PD L1, is reported to have potential efficacy for the treatment NSCLC. Objective: The purpose of this meta-analysis was to systematically evaluate the efficacy and safety of nivolumab in patients with advanced NSCLC. Methods: Online electronic databases were searched in June 2017, including: PubMed, Embase, and the Cochrane Library. Randomized controlled trials were included that compared nivolumab to chemotherapy in NSCLC patients with regard to oncological outcome profiles. Review Manager Version 5.3 software was used. Results: Three studies were included in this analysis, comprising 1,395 patients with NSCLC, of whom 698 received nivolumab and 697 received chemotherapy without nivolumab. The pooled hazard ratios for overall survival (OS) and prolonged progression-free survival (PFS) were 0.77 (95% CI: 0.57-1.03; P=0.08) and 0.88 (95% CI: 0.64-1.20; P=0.41), respectively. The pooled odds ratio for overall response rate was 1.40 (95% CI: 0.66-2.96; P=0.39), indicating that no benefit with nivolumab was found for OS, PFS, or overall response rate. However, the odds ratio for treatment-related adverse events, grades 3 or 4, between the patients who received nivolumab and chemotherapy was 0.13 (95% CI: 0.09-0.17; P<0.00001). For patients with a PD-L1 expression level of 5% or more, no difference was observed in PFS (95% CI: 0.70 1.00; P=0.05) and OS benefit (95% CI: 0.34-1.15; P=0.13) between the groups. Conclusion: These data demonstrate no clinical survival benefit with nivolumab for NSCLC patients, even in a subpopulation of patients with levels of PD-L1>5%. However, nivolumab had a more favorable safety profile than chemotherapy. Future investigations are needed to determine whether the efficacy of nivolumab can be improved. PMID- 30464518 TI - Low expression level of ASK1-interacting protein-1 correlated with tumor angiogenesis and poor survival in patients with esophageal squamous cell cancer. AB - Objective: To investigate the expression of tumor suppressor protein ASK1 interacting protein-1 (AIP1) in human esophageal squamous cell carcinoma (ESCC) and its role in tumor progression, angiogenesis, and prognosis. Methods: A total of 117 biopsy samples were obtained from ESCC patients. None of the patients had distant metastasis before surgery, and did not receive preoperative chemotherapy or radiotherapy. Immunohistochemistry was used to detect the expression of AIP1 protein and vascular endothelial growth factor receptor 2 (VEGFR2) in ESCC specimens collected from 117 patients who underwent esophageal cancer radical surgery. Microvessel density (MVD) was evaluated by immunohistochemical staining of vascular endothelial CD34. The correlation between AIP1 protein and clinicopathological characteristics, tumor angiogenesis, and prognosis was analyzed. Results: The downregulation of AIP1 protein in esophageal carcinoma tissues was detected in 63 cases. This downregulation significantly correlated with lymph node metastasis, clinicopathological staging, and tumor MVD (P<0.05). Survival analysis showed that ESCC patients with a low expression of AIP1, a high expression of VEGFR2, and a high level of MVD had a lower 5-year survival rate (P<0.05). Multivariate analysis confirmed that the downregulation of AIP1 significantly affected patient survival. Conclusion: The downregulation of AIP1 correlated with ESCC progression, tumor angiogenesis, and poor prognosis. AIP1 could be a promising biomarker for predicting ESCC prognosis and a potential target for anti-angiogenic therapy. PMID- 30464519 TI - The clinical feasibility of flexible bronchoscopy interventional therapy in patients with central airway stenosis and respiratory failure caused by malignancy. AB - Objective: The aim of this study was to investigate the clinical effects and feasibility of using flexible bronchoscopy intervention in cases of malignancy that causes central airway stenosis and respiratory failure. Methods: The clinical data of patients who were admitted to the Department of Respiratory Medicine at the First Affiliated Hospital of Nanjing Medical University and underwent treatment of a malignant tumor with central airway stenosis and respiratory failure by flexible bronchos-copy from February 2010 to May 2013 were analyzed using a retrospective method. The age, gender, location, extent of airway stenosis, interventional therapy, efficacy, and complications for 12 patients were collected and analyzed using the SPSS 13.0 software. Results: After interventional therapy, the dyspnea index for all the patients improved signifi cantly, and compared with before treatment, the difference was statistically significant (t=13.40, P<0.01). Eleven patients with respiratory failure were corrected, and only one patient was treated via tracheal intubation with mechanical ventilation. There were no severe complications, such as massive hemorrhaging or cardiac arrest in any case. Conclusion: Flexible bronchoscopy interventional treatment for central airway stenosis and respiratory failure caused by malignant tumors is an effective and safe method. It should be applied in clinical work. PMID- 30464520 TI - lncRNA PCAT6 promotes non-small cell lung cancer cell proliferation, migration and invasion through regulating miR-330-5p. AB - Background: Investigating the roles of lncRNA prostate cancer-associated transcript 6 (PCAT6) in modulating the growth and aggressiveness of non-small cell lung carcinoma (NSCLC) cell. Method: The levels of PCAT6 in NSCLC tissues and cell lines were determined by quantitative real-time PCR assay. MTT as well as colony formation assays were applied to explore the effect of PCAT6 on the growth of NSCLC cell in vitro. Wound healing and Transwell assays were utilized to analyze the impact of PCAT6 on the migration and invasion of NSCLC cell. Bioinformatics analysis and luciferase reporter assay were used to prove that miR 330-5p was the target of PCAT6. Colony formation, wound healing, and Transwell invasion assays were applied to demonstrate that PCAT6 promoted NSCLC cell growth, migration, and invasion through binding miR-330-5p. Finally, xenograft model was used to explore the role of PCAT6 in the tumor growth of NSCLC cell in vivo. Results: PCAT6 was highly overexpressed in NSCLC tissues and cells compared with normal tissues and non-tumorigenic bronchial epithelial cell line, BEAS-2B. Downregulation of PCAT6 markedly reduced the proliferation, migration, and invasion of NSCLC cell. Moreover, down-expression of PCAT6 significantly increased the level of miR-330-5p in NSCLC cell. Further functional experiments indicated that down-expression of miR-330-5p reversed the inhibitory effect of PCAT6 on NSCLC cell growth, migration, and invasion. Conclusion: Our results reveal that lncRNA PCAT6 facilitates the proliferation, migration, and invasion of NSCLC cell via competitively binding to miR-330-5p. PMID- 30464521 TI - Underexpression of INPPL1 is associated with aggressive clinicopathologic characteristics in papillary thyroid carcinoma. AB - Purpose: To study the relationship between INPPL1 gene and clinicopathologic characteristics of papillary thyroid carcinoma (PTC). Patients and methods: INPPL1 expression in PTCs was tested by quantitative real-time reverse transcription PCR. The Cancer Genome Atlas (TCGA) RNA-seq data and our mRNA data were used to analyze and reveal the relationship between INPPL1 and aggressive clinicopathologic characteristics of PTC. Results: When compared to normal thyroid tissues, INPPL1 was significantly downregulated in PTC tissues, as revealed by our data and TCGA data. INPPL1 underexpression was remarkably related to aggressive clinicopathologic characteristics such as lymph node metastasis (LNM), histological type, tumor size, mulitifocality, and disease stage in TCGA data. Meanwhile, LNM was confirmed to be associated with underexpression of INPPL1 in our data. In addition, logistic analysis clearly showed that underexpression of INPPL1 was an independent factor for LNM in PTC. Conclusion: INPPL1 may be a novel tumor suppressor gene in PTC, which was significantly correlated with aggressive clinicopathologic characteristics, especially LNM. PMID- 30464523 TI - Decreased expression of peroxiredoxin1 inhibits proliferation, invasion, and metastasis of ovarian cancer cell. AB - Aim: The aim of this study was to explore the expression of peroxiredoxin1 (PRDX1) in epithelial ovarian cancer, analyze the relationship between PRDX1 and clinicopathologic parameters of patients with ovarian cancer, including their prognosis, and describe changes and the mechanisms involved in malignant biologic behavior of ovarian cancer cells when PRDX1 expression is inhibited. Methods: The expression of PRDX1 was detected immunohistochemically in 15 samples of normal ovarian tissue, 21 benign, 11 borderline, and 101 malignant epithelial ovarian tumors. Changes in ovarian cancer cell proliferation, invasion, and metastasis before and after inhibiting PRDX1 expression were assessed by cell function assay. Additionally, gene set enrichment analysis (GSEA) of PRDX1 was performed by the Cancer Genome Atlas database. A protein- protein interaction network was then constructed and a pathway function analysis of the genes in the network was conducted. Results: PRDX1 expression was mainly localized to the cytoplasm, as well as the nucleus of cells. The expression rate of PRDX1 in epithelial ovarian malignant tissues (96.04%) was significantly higher than that in borderline (72.72%) and benign (57.14%) epithelial ovarian tumors, and normal ovarian tissue (20%; all P<0.05). Cox multivariate regression analysis indicated that advanced clinical stage, low tissue differentiation, and high expression of PRDX1 were independent risk factors affecting the prognosis of epithelial ovarian cancer (all P<0.05). Cell function assay verified that the decreased expression of PRDX1 inhibited ovarian cancer cell proliferation, invasion, and metastasis. GSEA analysis indicated that PRDX1 was significantly related to the Wnt signaling pathway. Western blot analysis confirmed that PRDX1 could regulate the expression of beta-catenin in the Wnt pathway. Conclusion: Decreased expression of PRDX1 can attenuate cell proliferation, invasion, and metastasis of ovarian cancer cells. The expression of PRDX1 is related to the prognosis of patients with ovarian cancer and can therefore be used as a biomarker. PMID- 30464522 TI - MicroRNA-645 targets urokinase plasminogen activator and decreases the invasive growth of MDA-MB-231 triple-negative breast cancer cells. AB - Background: Urokinase plasminogen activator (uPA) promotes the in vivo invasive growth of HCC cells by cleaving and activating matrix metalloproteinases (MMPs) to induce the destruction of the extracellular matrix of triple-negative breast cancer (TNBC) cells. The identification of microRNAs that target uPA and decrease uPA expression would be useful for attenuating the in vivo invasive growth of TNBC cells. Materials and methods: MicroRNA-645 (miR-645) was identified using an online tool (miRDB) as potentially targeting uPA; miR-645 inhibition of uPA was confirmed by western blot experiments. The effects of miR-645 on the in vivo invasive growth of TNBC cells were examined using an intrahepatic tumor model in nude mice, and the miR-645 mechanism of action was explored with MMP cleaving experiments. Results: Through virtual screening, we discovered that miR-645 potentially targeted the uPA 3' untranslated region. This targeting was confirmed by western blot experiments and miR-645 lentiviral particle (LV-645) transduction that inhibited uPA expression in MDA-MB-231 TNBC cells. The LV-645 inhibition of uPA led to the decreased invasive growth of TNBC cells in nude mice. The mechanism data indicated that the uPA inhibition resulted in a decreased cleaving of the pro-MMP-9 protein. Conclusion: Targeting uPA with miR-645 decreased the in vivo invasive growth of TNBC cells. These results suggest that miR-645 may represent a promising treatment strategy for TNBC. PMID- 30464524 TI - Potential targets of TMEM176A in the growth of glioblastoma cells. AB - Background: Human transmembrane protein 176A (TMEM176A) is upregulated in several tumors. Growing evidence has suggested the high clinical value of TMEM176A as a biomarker for early tumor diagnosis. However, less is known about the function of TMEM176A in glioblastomas (GBMs). Methods: In this study, we systematically analyzed the effect of TMEM176A knockdown and overexpression in GBM cells (U87, T98G and A172) on cell proliferation, cell cycle and cell apoptosis. Results: Our results indicated that TMEM176A acted as a tumor-promoting factor in GBM cells. Moreover, a specific ERK1/2 inhibitor, U0126, suppressed the function of TMEM176A in GBM cells. Therefore, we proposed that TMEM176A may be involved in a pathway including ERK1/2 in the regulation of the cell cycle. Moreover, we also found that TMEM176A affected the expression of Bcl2 and played a central role in apoptosis of GBM cells. Conclusion: Taken together, our results not only elucidated the multiple functions of TMEM176A in GBM cells but also provided a deep insight into the potential targets of TMEM176A in the growth of GBM cells. PMID- 30464525 TI - Resveratrol, an activator of SIRT1, induces protective autophagy in non-small cell lung cancer via inhibiting Akt/mTOR and activating p38-MAPK. AB - Background: Resveratrol, a natural polyphenolic phytoalexin, has potent anti tumor activity. Recently, it was found to induce autophagy in cancer cells. However, the effects of resveratrol on autophagy in non-small-cell lung cancer (NSCLC) cells have not yet been clearly elucidated. Materials and methods: A549 and H1299 cells were treated with different concentrations of resveratrol. Cell growth and apoptosis were measured by CCK-8 assay and flow cytometry, respectively. A549 cells were then treated with 200 MUM resveratrol or SRT1720. Cell autophagy was detected by western blot and immunofluorescence. Results: In this study, we found that resveratrol exerted the anti-tumor effect through inhibiting cell proliferation and promoting cell apoptosis in NSCLC cells dose dependently. Resveratrol has also increased the relative expression of Beclin1 and LC3 II/I while decreased p62 expression, suggesting that resveratrol induced autophagy in NSCLC cells. In addition, resveratrol increased SIRT1 expression and SIRT1 activator SRT1720-induced autophagy of NSCLC cells. SIRT1 knockdown reduced resveratrol-induced autophagy significantly. These results indicated that resveratrol might induce autophagy through upregulating SIRT1 expression. Moreover, inhibiting autophagy by autophagy inhibitor 3-methyladenine or SIRT1 inhibitor nicotinamide significantly suppressed proliferation while promoted apoptosis compared with the resveratrol 200 MUM group, suggesting that resveratrol-induced autophagy might act as a protective mechanism to promote NSCLC cell survival and inhibiting autophagy can enhance the anti-tumor effect of resveratrol. Besides that, resveratrol treatment inhibited Akt/mTOR while p38 MAPK was activated in NSCLC cells in a dose-dependent manner. Activating Akt/ mTOR pathway by IGF-1 or inhibiting p-38-MAPK pathway by doramapimod significantly inhibited cell proliferation while increased cell apoptosis of NSCLC cells compared with the resveratrol 200 MUM group. Conclusion: Taken together, our findings suggest that resveratrol inhibited proliferation but induced apoptosis and autophagy via inhibiting Akt/mTOR and activating p38-MAPK pathway. Resveratrol-induced autophagy might act as a protective mechanism to promote NSCLC cell survival. Therefore, inhibition of autophagy may enhance the anti-tumor activity of resveratrol in NSCLC. PMID- 30464526 TI - Huge borderline phyllodes breast tumor with repeated recurrences and progression toward more malignant phenotype: a case report and literature review. AB - Background: Phyllodes tumor (PT) is a rare breast fibroepithelial biphasic tumor composed of stromal and epithelial components. The patients suffering from this disease present with a large, round, mobile, fast-growing lump, and the giant PT of more than 10 cm in diameter is so uncommon. Surgery is regarded as the primary treatment, but curative efficiency of adjuvant chemotherapy and radiotherapy is so indefinite. Case presentation: We reported one case of a middle-aged woman with a huge borderline PT in the right breast, over 20 cm in size. The pathology of needle core biopsy of the lump was suggestive of PT of the borderline subgroup, and then she underwent mastectomy of the right breast. The patient had recovered well without any postoperative treatment until a local recurrence occurred 1 year after operation. The tumor was removed with lumpectomy, which was pathologically diagnosed as malignant PT. We followed up her by telephone and heard about her postoperative adjuvant radiotherapy and chemotherapy, as well as her well recovery. Conclusion: The pathology of PT with low incidence is mostly benign, but local recurrence is common, and the histopathology progresses toward worsen trend. Besides, due to the difficulty in precise diagnosis of the borderline PTs, it is recommended that this subtype of patients should undergo total mastectomy. Although the curative effect of postoperative treatment has not been recognized internationally, patients, especially those with huge tumors, may benefit from these treatments. PMID- 30464527 TI - PTPRF as a novel tumor suppressor through deactivation of ERK1/2 signaling in gastric adenocarcinoma. AB - Background: Protein tyrosine phosphatase, receptor type F (PTPRF) is an important phosphatase playing roles in regulating cell growth, differentiation and oncogenic transformation. Overexpression of PTPRF has been observed in non-small cell lung cancer, but its clinical significance in other malignancies is still unknown. Methods: We explored the expression pattern of PTPRF in gastric adenocarcinoma by using RT-qPCR and immunohistochemistry staining. The clinical significance of PTPRF was evaluated by univariate and multivariate analyses. Furthermore, the signaling pathways downstream of PTPRF was investigated by knockdown and overexpression assays combined with cellular studies. Results: We found a remarkable down-regulation of PTPRF in gastric adenocarcinomas, which was significantly associated with advanced tumor TNM stages. Survival analysis showed that lower PTPRF level indicated a poorer overall survival of gastric adenocarcinoma patients. By conducting knockdown and overexpression studies in gastric adenocarcinoma cells, we revealed the role of PTPRF on inhibiting extracellular signal-regulated kinase-1/2 (ERK1/2) phosphorylation and its downstream signaling. Consistent with clinical findings, cellular results demonstrated that overexpressing PTPRF can significantly inhibit tumor migration and invasion, while silencing PTPRF showed opposite effects. Conclusion: In conclusion, patients with lower PTPRF expression in gastric adenocarcinoma tissues were more predisposed to advanced tumor stage and unfavorable prognosis. PMID- 30464528 TI - Rab18 overexpression promotes proliferation and chemoresistance through regulation of mitochondrial function in human gastric cancer. AB - Background: Dysregulation of Rab18 has been implicated in human cancers. However, its clinical significance and biological function in gastric cancer have not been investigated. Methods: We examined Rab18 expression in gastric cancer tissues using immunohistochemistry. We used SNU-1 and AGS cell lines for plasmid and siRNA transfection respectively. MTT, colony formation assay, cell cycle analysis, matrigel invasion, wound healing assay, AnnexinV/PI analysis and western blotting were used to examine the biological effect and mechanism of Rab18 in gastric cancer cell lines. Results: Rab18 protein expression was upregulated in gastric cancer tissues and this correlated with advanced stage and poor prognosis. Rab18 overexpression promoted proliferation in vitro and in vivo. Cell cycle analysis showed that Rab18 overexpression upregulated, while its depletion downregulated S phase percentage. Matrigel invasion and wound healing assays indicated that Rab18 positively regulated SNU-1 cell invasion and migration while its knockdown inhibited AGS cell invasion and migration. Rab18 maintained cell viability and downregulated apoptosis after cisplatin treatment, with upregulated mitochondrial membrane potential and downregulated mitochondrial reactive oxygen species (ROS) production. Rab18 overexpression upregulated p-Rb, survivin while downregulated cytochrome c, cleaved caspase-3 and cleaved PARP. Conclusion: In conclusion, our results indicate that Rab18 promoted gastric cancer growth and chemoresistance, possibly through regulation of mitochondrial function and survivin. PMID- 30464529 TI - Intestinal metastasis from primary ROS1-positive lung adenocarcinoma cancer patients responding to crizotinib. AB - Small intestinal metastases from primary lung cancer are rare. Such patients have a poor prognosis. Early diagnosis of small intestinal metastases is difficult because of the low incidence of clinically apparent symptoms. The standard treatment for small intestinal metastases has not been established. A 69-year-old Chinese man presented for evaluation of a tumor in the right lower lung and mediastinal lymph node enlargement on clinical examination. The clinical stage was cT2N2M0 (stage IIIA). Histologic examination of the tumor revealed lung adenocarcinoma. He could not tolerate surgery; hence, he received two chemotherapy regimens. However, the disease progressed. He had bloating after chemotherapy and decreased flatus. An abdominal CT scan showed an intestinal effusion with local intestinal obstruction. Medical treatment was ineffective; hence, he underwent a diagnostic laparoscopy. The pathologic evaluation suggested an intestinal metastatic adenocarcinoma from the primary lung cancer. Based on an real-time PCR assay, the tumor had a ROS1 fusion and responded well to crizotinib. The progression-free survival was 7 months. Physicians must be aware of the possibility of intestinal metastases from primary lung cancer. With an accurate diagnosis and thorough evaluation, patients may benefit from targeted therapy. PMID- 30464530 TI - Long noncoding RNA HOXD-AS1 in various cancers: a meta-analysis and TCGA data review. AB - : Background and aims: HOXD antisense growth-associated long noncoding RNA (HOXD AS1) was reported to be upregulated in various cancers, such as gastric cancer, hepatocellular carcinoma, colorectal cancer, and glioma. Here, we conducted a meta-analysis and The Cancer Genome Atlas data review to investigate the clinicopathologic and prognostic value of HOXD-AS1 in patients with malignant tumors. Materials and methods: Systematic literatures were searched from PubMed, Medline, Cochrane Library, Web of Science, EMBASE database, Ovid, Chinese CNKI, and the Chinese WanFang database. The role of HOXD-AS1 in cancers was evaluated by pooled ORs and HRs with 95% CIs. The Cancer Genome Atlas dataset was used to explore the prognostic value of HOXD-AS1 in various cancers. Results: Fifteen studies with 1,678 patients were included in this meta-analysis. The results indicated that HOXD-AS1 was associated with tumor size, differentiation, lymph node metastasis, and TNM stage. Moreover, the high HOXD-AS1 expression indicated a poor overall survival (OS) rate and can be an independent predictive factor for OS. The TCGA dataset, which included 9,502 cancer patients, showed that the expression of HOXD-AS1 was related to poor OS and disease-free survival. We also analyzed the prognostic role in different kinds of cancers such as digestive cancers, female reproductive system cancers, respiratory system cancers, and urinary system cancers. Conclusion: This study demonstrated that HOXD-AS1 was closely correlated with tumor size, lymph node metastasis, distant metastasis, and TNM stage, and an increased HOXD-AS1 expression could be a reliable prognostic biomarker in human cancers. However, more studies are needed to confirm this conclusion. PMID- 30464531 TI - TRIM32 overexpression improves chemoresistance through regulation of mitochondrial function in non-small-cell lung cancers. AB - Background: TRIM32 is overexpressed in several human cancers. However, its expression pattern, biological characteristics and mechanisms in human non-small cell lung cancer (NSCLC) have not been reported. Methods: We examined TRIM32 protein in 115 cases of NSCLC specimens. TRIM32 plasmid transfection and siRNA knockdown was carried out in NSCLC cell lines. AnnexinV/PI and JC-1 staining were performed to examine the change of apoptosis and mitochondrial membrane potential. Western blot was used to detect change of downstream proteins. Results: We found that TRIM32 protein was upregulated in 69 cases and positively correlated with advanced TNM stage. TRIM32 overexpression also correlated with poor survival of NSCLC patients. Biological assays demonstrated that TRIM32 overexpression promoted while it depletion inhibited cell growth, colony formation and invasion. In addition, TRIM32 maintained NSCLC cell viability and reduced apoptosis when treated with cisplatin. JC-1 and CellRox staining demonstrated that TRIM32 could maintain mitochondrial membrane potential and reduce Reactive Oxygen Species (ROS) production after cisplatin treatment. Western blot analysis showed that TRIM32 overexpression downregulated caspase 3 cleavage and cytochrome c release. TRIM32 also positively regulated Bcl-2 protein expression and NF-kappaB signaling. Inhibition of NF-kappaB abolished the effects of TRIM32 on Bcl-2. Conclusion: Taken together, our results indicated that TRIM32 is overexpressed in NSCLC and regulates cisplatin resistance, possibly through NF kappaB and Bcl-2. PMID- 30464532 TI - EZH2 contributes to 5-FU resistance in gastric cancer by epigenetically suppressing FBXO32 expression. AB - Background: Increasing evidence suggests the involvement of enhancer of zeste homologue 2 (EZH2) in chemoresistance of cancer treatment. Nevertheless, its function and molecular mechanisms in gastric cancer (GC) chemoresistance are still not well elucidated. Materials and methods: In the present study, we investigated the functional role of EZH2 in 5-fluorouracil (5-FU) resistance of GC cells and discovered the underlying molecular mechanism. Results: Results revealed that EZH2 was upregulated in 5-FU-resistant GC tissues and cell lines. High ZEH2 expression was correlated with poor prognosis of GC patients. EZH2 knockdown enhanced 5-FU sensitivity of AGS/5-FU and SGC-7901/5-FU cells. Moreover, EZH2 could epigenetically suppress FBXO32 expression. FBXO32 overexpression could mimic the functional role of downregulated EZH2 in 5-FU resistance. FBXO32 knockdown counteracted the inductive effect of EZH2 inhibition on 5-FU sensitivity of AGS/5-FU and SGC-7901/5-FU cells. Furthermore, EZH2 knockdown facilitated 5-FU sensitivity of 5-FU-resistant GC cells in vivo. Conclusion: In summary, EZH2 depletion overcame 5-FU resistance in GC by epigenetically silencing FBXO32, providing a novel therapeutic target for GC chemoresistance. PMID- 30464533 TI - Inhibition of GLUT-1 expression and the PI3K/Akt pathway to enhance the chemosensitivity of laryngeal carcinoma cells in vitro. AB - Background: The mechanism of chemoresistance remains unknown. Here, we investigated if glucose transporter-1 (GLUT-1) and PI3K/Akt pathways are associated with the sensitivity to cisplatin in Hep-2 laryngeal carcinoma cells and whether the inhibition of GLUT-1 and the PI3K/Akt pathways enhances the chemosensitivity of Hep-2 cells. Method: The effects of inhibiting GLUT-1 by a GLUT-1 siRNA, and PI3K/Akt by Ly294002, on cisplatin-induced effects were assessed in vitro. Results: GLUT-1 siRNA and cisplatin showed a synergistic effect in inhibiting the proliferation of Hep-2. LY294002 and cisplatin also showed a synergistic effect in inhibiting the proliferation of Hep-2. GLUT-1 siRNA, LY294002 and cisplatin effectively inhibited the mRNA expressions and protein expressions of GLUT-1, Akt, PI3k and HIF-1alpha in Hep-2 cells. Furthermore, GLUT-1 siRNA and cisplatin demonstrated a synergism to inhibit the mRNA expression of HIF-1alpha. Moreover, it was found in this study that GLUT-1 siRNA, LY294002 and cisplatin induced the suppression of the cell cycle at G1/G2 and the increasing of apoptosis in Hep-2 cells. Conclusion: This study showed that inhibiting GLUT-1, by a GLUT-1 siRNA and inhibiting PI3K/Akt by Ly294002, could suppress the proliferation of Hep-2 alone and together with cisplatin synergistically, which demonstrated the potentials to treat laryngeal carcinoma in the future therapy. Additionally, the synergistic effect between LY294002 and cisplatin to suppress the proliferation of Hep-2 might not be from GLUT-1, Akt, PI3k and HIF-1alpha; the synergistic effect between GLUT-1 siRNA and cisplatin to suppress the proliferation of Hep-2 might not be from GLUT-1, Akt and PI3k and might be more or less related to HIF-1alpha. PMID- 30464534 TI - OCT4, SOX2, and NANOG positive expression correlates with poor differentiation, advanced disease stages, and worse overall survival in HER2+ breast cancer patients. AB - Objective: This study aimed to evaluate the correlations of expression of OCT4, SOX2, and NANOG with clinicopathological features and overall survival (OS) in human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients. Methods: One hundred and thirty-four surgical HER2+ BC patients who received doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab adjuvant therapy were enrolled in this study. Immunofluorescence assay was used to detect OCT4, SOX2, and NANOG expressions. The median follow-up duration was 104 months, and the last follow-up date was December 31, 2017. Results: The expressions of OCT4 (P=0.001), SOX2 (P=0.003), and NANOG (P=0.005) were higher in tumor tissues compared with paired adjacent tissues. OCT4 positive expression was associated with poor pathological differentiation (P=0.028), larger tumor size (P=0.022), advanced N stage (P<0.001), and higher TNM stage (P<0.001). SOX2 positive expression was correlated with poor pathological differentiation (P=0.005), larger tumor size (P=0.013), and increased T stage (P=0.024). NANOG positive expression was associated with poor pathological differentiation (P=0.028), higher N stage (P=0.001), and elevated TNM stage (P=0.001). Kaplan Meier curves disclosed that OCT4 (P=0.001) and NANOG (P=0.001) positive expressions were associated with worse OS, while SOX2 (P=0.058) positive expression was only numerically correlated with poor OS, but without statistical significance. Further analyses revealed that co-expression of these three biomarkers disclosed even better predictive value for shorter OS. Conclusion: OCT4, SOX2, and NANOG positive expressions correlate with poor differentiation and advanced disease stage, and OCT4 and NANOG present with predictive values for poor OS in HER2+ BC patients. PMID- 30464535 TI - Transcatheter hepatic arterial infusion chemotherapy vs sorafenib in the treatment of patients with hepatocellular carcinoma of Barcelona Clinic Liver Cancer stage C: a meta-analysis of Asian population. AB - Objective: To compare the clinical efficacy and safety of transcatheter hepatic arterial infusion chemotherapy (HAIC) with those of sorafenib in the treatment of patients with hepatocellular carcinoma (HCC) of Barcelona Clinic Liver Cancer (BCLC) stage C. Methods: Potentially relevant studies comparing the clinical efficacy and safety of HAIC with those of sorafenib were searched using Medline, PubMed, Embase, Cochrane Library, and Chinese databases (Wanfang Data and China National Knowledge Infrastructure). Overall survival rate (OSR), tumor response rate, disease control rate (DCR), and serious adverse events (SAEs) were compared and analyzed. Pooled ORs with 95% CIs were calculated using either the fixed effects model or the random-effects model. All statistical analyses were conducted using Review Manager (version 5.3) from the Cochrane Collaboration. Results: A total of 1,264 patients were included in this meta-analysis. The results of this study showed that HAIC was associated with significantly higher 1 , 2-, and 3-year OSRs than sorafenib (OR 1.88, 95% CI1-year: [1.27-2.78], P1 year=0.002; OR 2.15, 95% CI2-year: [1.06-4.37], P2-year=0.03; OR 7.90, 95% CI3 year: [2.12-29.42], P3-year=0.002). Compared to sorafenib, HAIC was associated with superior complete response (CR), partial response (PR), and objective response rate (ORR) (OR 3.90, 95% CICR: [1.89-8.03], P CR =0.0002; OR 3.47, 95% CIPR: [2.31-5.24], P PR <0.00001; OR 3.02, 95% CIOR: [2.05-4.45], P OR <0.0001). There was no statistically significant difference between HAIC and sorafenib in stable disease (SD), progressive disease (PD), DCR, and SAEs (OR 0.86, 95% CISD: [0.51-1.45], P SD =0.56; OR 0.62, 95% CIPD: [0.35-1.11], P PD =0.11; OR 0.53, 95% CISAE: [0.14-1.92], P SAE =0.33). Conclusion: This study showed that HAIC was associated with better efficacy than sorafenib in terms of OSR and tumor response. Therefore, HAIC can be considered as an alternative treatment option for patients with HCCs of BCLC stage C. PMID- 30464536 TI - Use of paracrine factors from stem cells to treat local radiation burns in rats. AB - Background: Mesenchymal stem cells based paracrine bioactive factors that deploy their task as an essential mechanism, but their efficiency for skin regeneration still requires clarification. Methods: The mesenchymal stem cell-based paracrine factors were administered by subcutaneous injection of 0.5 mL peptides (general protein 8 mg/mL). These were performed after radiation on different days like the first, third, sixth, eighth, and 10th. To determine the consequences, we performed photography, planimetry, and preclinical test each week after 15 days of radiation. MSC-based peptides were injected into a rat that had radiation burns, and its observation encouraged cell-free therapeutic remedies to regenerate skin. Both control and experimental groups were exposed to 110 Gy of X rays, which resulted in the formation of localized radiation burns on the skin (S=6 cm2) 15 days later. Thirty days after radiation, the wound stabilized (surface of the wound was S=2.2+/-0.2 cm2) and fluctuated throughout the course of the pathological process. Results: The wounded area on the skin from the 15th to the 29th day after radiation was practically the same in both groups. The wounded area gradually reduced by 6.1+/-0.4 cm2 (experimental group) and 5.9+/ 0.6 cm2 (control group) 15 days after radiation up to 2.2+/-0.3 cm2 (in both control and experimental groups) on the 29th day after radiation. However, starting from the 36th day, there was a constant reduction in the burn area in the experimental group up to 0.2+/-0.1 cm2 till the 71st day after radiation. Conclusion: In the control group, the area of the lesion ranged from 1.4+/-0.6 cm2 on the 50th day to 1.9+/-0.8 cm2 on the 71st day. During the 57th to the 71st day, the difference between the affected area in the experimental and control groups was 1:8. The experimental group has a significantly higher level of skin regeneration and significant decrease in the level of leukocyte infiltration, thereby reducing necrosis. PMID- 30464537 TI - Non-eosinophilic asthma: current perspectives. AB - Although non-eosinophilic asthma (NEA) is not the best known and most prevalent asthma phenotype, its importance cannot be underestimated. NEA is characterized by airway inflammation with the absence of eosinophils, subsequent to activation of non-predominant type 2 immunologic pathways. This phenotype, which possibly includes several not well-defined subphenotypes, is defined by an eosinophil count <2% in sputum. NEA has been associated with environmental and/or host factors, such as smoking cigarettes, pollution, work-related agents, infections, and obesity. These risk factors, alone or in conjunction, can activate specific cellular and molecular pathways leading to non-type 2 inflammation. The most relevant clinical trait of NEA is its poor response to standard asthma treatments, especially to inhaled corticosteroids, leading to a higher severity of disease and to difficult-to-control asthma. Indeed, NEA constitutes about 50% of severe asthma cases. Since most current and forthcoming biologic therapies specifically target type 2 asthma phenotypes, such as uncontrolled severe eosinophilic or allergic asthma, there is a dramatic lack of effective treatments for uncontrolled non-type 2 asthma. Research efforts are now focusing on elucidating the phenotypes underlying the non-type 2 asthma, and several studies are being conducted with new drugs and biologics aiming to develop effective strategies for this type of asthma, and various immunologic pathways are being scrutinized to optimize efficacy and to abolish possible adverse effects. PMID- 30464539 TI - Effectiveness of empiric aztreonam compared to other beta-lactams for treatment of Pseudomonas aeruginosa infections. AB - Purpose: To evaluate the use of aztreonam as an active empiric therapy against subsequent culture of Pseudomonas aeruginosa (P. aeruginosa). Methods: This was a retrospective cohort study conducted among patients who received either aztreonam or an antipseudomonal beta-lactam (BL) as an empiric therapy with subsequent culture with P. aeruginosa. All patients with at least one positive culture for P. aeruginosa between January 2014 and August 2016 were included in this analysis. The primary composite outcome was empiric therapy failure, defined as inappropriate empiric therapy, alteration of empiric antibiotic following culture results, or 30-day in-hospital mortality. Secondary outcomes included appropriate empiric therapy, alteration of empiric therapy, 30-day-in-hospital mortality, and post-culture hospital length of stay. Results: The primary outcome of empiric therapy failure was significantly higher in the aztreonam group than in the BL group (77.8% vs 41.9%; P=0.004). The aztreonam group had a lower rate of appropriate empiric therapy compared with the BL group (44.4% vs 66.1%; P=0.074) and higher alteration of empiric therapy once susceptibilities were known than when compared with the BL group (61.1%vs 28.2%; P=0.005). Although numerically higher, 30-day-in-hospital mortality and median hospital length of stay were not significantly different between the two groups. Conclusion: Empiric therapy failure occurred more often when initially using aztreonam vs a BL in a patient who subsequently had a P. aeruginosa infection. Only a third of patients within the aztreonam group had a documented BL allergy, demonstrating an inclination for clinicians to utilize this drug as an empiric therapy when there were more appropriate therapies available. PMID- 30464538 TI - Management of complicated skin and soft tissue infections with a special focus on the role of newer antibiotics. AB - Complicated skin and soft tissue infections (cSSTIs) represent the severe form of infectious disease that involves deeper soft tissues. Involvement of methicillin resistant Staphylococcus aureus (MRSA) further complicates cSSTI with increased hospitalization, health care costs, and overall mortality. Various international guidelines provide recommendations on the management of cSSTIs, with the inclusion of newer antibiotics. This literature-based review discusses the overall management of cSSTI, including appropriate use of antibiotics in clinical practice. Successful treatment of cSSTIs starts with early and precise diagnosis, including identification of causative pathogen and its load, determination of infection severity, associated complications, and risk factors. The current standard-of-care for cSSTIs involves incision, drainage, surgical debridement, broad-spectrum antibiotic therapy, and supportive care. In recent years, the emergence of newer antibiotics (eg, ceftaroline, tigecycline, daptomycin, linezolid, etc) has provided clinicians wider options of antimicrobial therapy. Selection of antibiotics should be based on the drug characteristics, effectiveness, safety, and treatment costs, alongside other aspects such as host factors and local multidrug resistance rates. However, larger studies on newer antibiotics are warranted to refine the decision making on the appropriate antimicrobial therapy. Local Antimicrobial Stewardship Program strategies in health care settings could guide clinicians for early initiation of specific treatments to combat region-specific antimicrobial resistance, minimize adverse effects, and to improve outcomes such as reduction in Clostridium difficile infections. These strategies involving iv-to-oral switch, de-escalation to narrow spectrum antibiotics, and dose optimization have an impact on the overall improvement of cSSTI therapy outcomes, especially in countries like Singapore that has a high disease burden. PMID- 30464540 TI - In vitro activity of ceftazidime-avibactam, ceftolozane-tazobactam, and other comparable agents against clinically important Gram-negative bacilli: results from the 2017 Surveillance of Multicenter Antimicrobial Resistance in Taiwan (SMART). AB - Objectives: We investigated the in vitro antimicrobial susceptibilities of clinically important Gram-negative bacteria (GNB) from 16 major teaching hospitals in Taiwan in 2017. Materials and methods: Escherichia coli (n=686) and Klebsiella pneumoniae bloodstream isolates (n=673), non-typhoid Salmonella (NTS; n=221) from various sources, Shigella species (n=21) from fecal samples, and Neisseria gonorrhoeae (n=129) from the genitourinary tract were collected. Antibiotic minimum inhibitory concentrations (MICs) were determined using the broth microdilution method. Alleles encoding K. pneumoniae carbapenemases (KPCs), New Delhi metallo-beta-lactamases (NDMs), Verona integron-encoded metallo-beta lactamase, imipenemase, OXA-48-like, and mcr-1-5 genes were detected by molecular methods in Enterobacteriaceae isolates. Results: Five (0.7%) E. coli isolates harbored mcr-1 alleles. Twenty-four (3.6%), seven (1.0%), four (0.6%), and one (0.15%) K. pneumoniae isolates contained bla KPC, bla OXA-48-like, mcr-1, and bla NDM, respectively. Three (1.4%) NTS and no Shigella isolates harbored mcr-1 genes. Seventy-one (10.5%) K. pneumoniae isolates displayed non-susceptibility (NS) to carbapenem agent(s). Phenotypically extended-spectrum beta-lactamase (ESBL)-producing K. pneumoniae isolates showed significantly higher rates of ertapenem, tigecycline, and ceftolozane-tazobactam (CLZ- TAZ) NS (40.2%, 16.3%, and 71%-80%, respectively) than E. coli isolates exhibiting ESBL phenotypes (5.4%, 0.7%, and 18%-28%, respectively). All phenotypically ESBL-producing E. coli isolates were ceftazidime-avibactam (CAZ-AVB) susceptible. Two (8.3%) KPC producing K. pneumoniae isolates showed CAZ-AVB NS. Hospital-acquired K. pneumoniae isolates were significantly less susceptible to ertapenem and CLZ-TAZ than hospital-acquired E. coli isolates. Conclusion: Third-generation cephalosporins remain the optimal choice for treating NTS, Shigella, and gonococcal infections in Taiwan. Hospital-acquired and phenotypically ESBL producing K. pneumoniae are a heavy resistance burden in Taiwan. PMID- 30464541 TI - Prevalence of resistance-associated substitutions to direct-acting antiviral agents in hemodialysis and renal transplant patients infected with hepatitis C virus. AB - Background: Direct-acting antiviral agents (DAAs) permit the use of interferon (IFN)-free regimens to treat hepatitis C (HCV) in patients with chronic kidney disease (CKD) on hemo-dialysis (HD) or renal transplant (RTx) recipients, with excellent response rates and safety. However, the occurrence of basal or therapy induced resistance-associated substitutions (RASs) to DAAs can result in treatment failure. The aim of this study was to estimate the prevalence of RASs to NS3A, NS5A and NS5B inhibitors, and particularly the Q80K polymorphism, in CKD patients on HD and RTx recipients infected with HCV. Patients and methods: HD and RTx patients infected with HCV-genotype 1 (GT1) were subjected to sequencing of the NS3, NS5A and NS5B regions. Results: Direct sequencing of NS3 protease, NS5A and NS5B was performed in 76 patients (HD, n=37; RTx, n=39). The overall prevalence of RASs was 38.2%, but only 5.3% of the patients had mutations in more than one region. Substitutions were detected in NS3A (17.8%), NS5A (21.9%) and NS5B (8.4%). Q80K was detected in 1.5 % of the patients. Highly inhibitory RASs were uncommon (L31M, 2.6%; L159F+C316N, 2.6%). RASs were more prevalent in HCV GT1a (42.9%) than in HCV-GT1b (32.4%), P=0.35. RASs were detected in 52.4% of treatment-naive patients and 27.8% of peg-IFN/ribavirin-experienced patients (P=0.12). The presence of RASs was associated with time of RTx (P=0.01). Conclusion: The Q80K polymorphism was uncommon in our sample of HD and RTx patients. Despite the high prevalence of naturally occurring RASs, most of the substitutions detected were associated with a low level of resistance to DAAs. PMID- 30464542 TI - Entecavir add-on or switch-to pegylated interferon improves HBsAg clearance in HBe antigen negative chronic hepatitis B patients. AB - Background and aims: Chronic hepatitis B (CHB) patients rarely achieve hepatitis B surface antigen (HBsAg) loss with nucleoside/nucleotide analog therapy. Methods: In this retrospective study, it was evaluated that the rate of HBsAg loss in the HBe antigen negative (HBeAg-) patients (n=101) treated with entecavir (ETV) for >=24 weeks followed by switching to (n=22) or adding on (n=26) pegylated interferon (PEG-IFN), and continuing ETV (n=53). Results: HBsAg clearance rate at week 48 was 9% (2/22), 15% (4/26), and 0% (0/53) (P<0.05), in switch-to or add-on, or ETV monotherapy CHB patients, respectively. HBsAg reduction at week 48 was 1.182, 0.6614, or 0.056 log IU/mL, in switch-to, add-on, and ETV patients, respectively (P<0.001). The response rate (HBsAg reduction >1 log IU/mL at week 48) in the switch-to, add-on, and ETV monotherapy CHB patients was 60%, 40%, and 2%, respectively (P<0.001). In the switch-to and add-on patients, HBsAg reduction and clearance were associated with HBsAg titers at week 0 and HBsAg reduction at week 24. Furthermore, HBsAg reduction at week 24 was associated with the response rate at week 48 in the switch-to and add-on patients, showing that the area under the receiver operating characteristic curve was 0.904. Positive predictive value and negative predictive value for response rate was 70% and 100% with cut-off value 0.2 log IU/mL, respectively. Conclusion: In summary, we demonstrated that PEG-IFN enhanced HBsAg loss in HBeAg- CHB patients. High HBsAg clearance was achieved in the patients with HBsAg titers at baseline <1,000 IU/mL and HBsAg reduction >0.2 log IU/mL. PMID- 30464543 TI - Daptomycin versus teicoplanin for bloodstream infection due to methicillin resistant Staphylococcus aureus with a high teicoplanin minimal inhibitory concentration >=1.5 mg/L: a propensity score-based analysis. AB - Background: Recent reports have described decreased effectiveness of teicoplanin in the treatment of bacteremia due to methicillin-resistant Staphylococcus aureus (MRSA) with teicoplanin minimal inhibitory concentration (MIC) >=1.5 mg/L. Consensus guidelines recommend considering use of alternative agents for MRSA infections involving a higher teicoplanin MIC, despite of limited data to support this recommendation. Patients and methods: To compare the clinical outcome among patients with bacteremia due to MRSA with teicoplanin MIC >=1.5 mg/L, we included patients who received high-dose daptomycin (>=8 mg/kg/day) and those who received standard-dose (6 mg/kg/day) or high-dose (6 mg/kg/12 hours) maintenance teicoplanin. The primary endpoint was a favorable outcome, defined as the resolution of clinical signs and symptoms and a negative culture report at the end of therapy. Adjusted analyses were performed by multivariate analysis and propensity score-based matching. Results: Of 142 patients eligible for inclusion, 28 (19.7%) were treated with high-dose daptomycin, 27 (19.0%) with high-dose teicoplanin, and 87 (61.3%) with standard-dose teicoplanin. In multivariate regression analysis, Pittsburgh bacteremia score >=4 (OR, 5.3; 95%CI, 1.9-14.5) was independently associated with an unfavorable outcome. After propensity-score matching with age and Pittsburgh bacteremia score >=4, patients on high-dose daptomycin were more likely to have favorable outcomes than those on standard dose teicoplanin (74.1% vs 42.6%; P=0.02). However, there was no significant difference in terms of favorable outcomes (P=0.12) between patients receiving high-dose daptomycin and those receiving high-dose teicoplanin after the same propensity-score matching. Conclusion: Treatment with high-dose daptomycin resulted in significantly better outcomes than with standard-dose teicoplanin in the treatment of MRSA bacteremia with teicoplanin MIC >=1.5 mg/L. However, the clinical outcome of the patients receiving high-dose teicoplanin was similar to that of the patients receiving high-dose daptomycin. PMID- 30464544 TI - Retrospective comparative analysis of risk factors and outcomes in patients with carbapenem-resistant Acinetobacter baumannii bloodstream infections: cefoperazone sulbactam associated with resistance and tigecycline increased the mortality. AB - Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) is a rapidly emerging, life-threatening nosocomial infection. This study aimed to explore the risk factors, clinical features, antimicrobial therapy, and outcomes of CRAB bloodstream infections (BSIs). Methods: This is a retrospective, comparative analysis of data from patients with A. baumannii BSI, treated from 2012 to 2015 at a tertiary teaching hospital. Risk factors associated with CRAB BSI and factors associated with the 28-day mortality were evaluated using logistic analyses. Results: Data from 293 patients with confirmed A. baumannii BSI were included; 242 (82.6%) patients had CRAB BSI and 51 (17.4%) patients had non-CRAB BSI. Risk factors significantly associated with CRAB BSI were a previous intensive care unit (ICU) stay (P=0.029), cefoperazone-sulbactam use (P=0.030), and carbapenem use (P=0.004). Among 236 patients with A. baumannii BSI who were evaluable at 28 days after receiving antibacterial therapy, there were 86 deaths. Factors associated with the 28-day mortality were ICU stay after BSI (P=0.040), readmission within 90 days (P=0.029), Acute Physiology and Chronic Health Evaluation II (APACHE II) score at diagnosis >19 (P=0.012), tigecycline therapy (P=0.021), presence of septic shock (P=0.029), and multiple organ failure (P=0.016). Death rates in patients treated with tigecycline were 53.5% vs 24.1% in patients treated with other agents. Among 186 patients with CRAB BSI evaluable at 28 days, 84 patients died. The associated risk factors were an ICU stay after BSI (P=0.036), APACHE II score >19 at diagnosis (P = 0.002), presence of septic shock (P=0.030), and multiple organ failure (P=0.007). Conclusion: This study demonstrated that an ICU stay and cefoperazone-sulbactam or carbapenem use were seen to be the risk factors associated with the development of CRAB BSI. Critical illness and tigecycline therapy were significantly associated with higher mortality of patients with A. baumannii BSI. PMID- 30464545 TI - Malaria parasite clearance from patients following artemisinin-based combination therapy in Cote d'Ivoire. AB - Introduction: Parasite clearance is useful to detect artemisinin resistance. The aim of this study was to investigate parasite clearance in patients treated with artesunate + amodiaquine (AS + AQ) and artemether + lumefantrine (AL): the two artemisinin-based combination therapies (ACTs) recommended in the first-line treatment of uncomplicated malaria in Cote d'Ivoire. Methods: This study was conducted in Bouake, Cote d'Ivoire, from April to June 2016. Patients aged at least 6 months with uncomplicated malaria and treated with AS + AQ or AL were hospitalized for 3 days, and follow-up assessments were performed on days 3, 7, 14, 21, 28, 35, and 42. Blood smears were collected at the time of screening, pre dose, and 6-hour intervals following the first dose of administration until two consecutive negative smears were recorded, thereafter at day 3 and follow-up visits. Parasite clearance was determined using the Worldwide Antimalarial Resistance Network's parasite clearance estimator. The primary end points were parasite clearance rate and time. Results: A total of 120 patients (57 in the AS + AQ group and 63 in the AL group) were randomized among 298 patients screened. The median parasite clearance time was 30 hours (IQR, 24-36 hours), for each ACT. The median parasite clearance rate had a slope half-life of 2.36 hours (IQR, 1.85 2.88 hours) and 2.23 hours (IQR, 1.74-2.63 hours) for AS + AQ and AL, respectively. The polymerase chain reaction-corrected adequate clinical and parasitological response was 100% and 98.07% at day 42 for AS + AQ and AL, respectively. Conclusion: Patients treated with AS + AQ and AL had cleared parasites rapidly. ACTs are still efficacious in Bouake, Cote d'Ivoire, but continued efficacy monitoring of ACTs is needed. PMID- 30464546 TI - Molecular epidemiology of Pseudomonas aeruginosa in University Clinical Center of Kosovo. AB - Background: Pseudomonas aeruginosa is an important opportunistic pathogen. It is frequently resistant to many commonly used antibiotics and develops easily resistant forms. Colonization with this organism often precedes infection, and its prevention is, therefore, critical. There is no information on molecular epidemiological investigation of outbreaks caused by P. aeruginosa in Kosovo. Materials and methods: The present investigation was carried out to enlighten molecular epidemiology of P. aeruginosa in University Clinical Center of Kosovo (UCCK) using pulsed-field gel electrophoresis (PFGE). During our study period, 80 isolates of P. aeruginosa were included. The overall antimicrobial susceptibility pattern showed a high level of resistance against amino-glycosides and the lowest against carbapenems. Forty isolates of P. aeruginosa were subjected to genotyping, of whom 31 (77.5%) were male patients and nine (22.5%) were female patients. Results: The most common diagnosis upon admission was polytrauma, sepsis, and coma cerebri. Majority of the patients were in mechanical ventilation (76.2%). Bacterial isolates were most frequently recovered from respiratory tract specimens (60%) and wounds (22.5%). Majority of the samples were recovered from intensive care unit (ICU) (47.5%). The length of ICU stay was higher compared to patients from other units. Genotype analysis of P. aeruginosa isolates identified seven distinct PFGE patterns, with the predominance of PFGE clone A (40%) and PFGE clone N (12.5%). All of these isolates were indistinguishable. The appearance of the indistinguishable genotypes supports the possibility of a cross and horizontal transmission of P. aeruginosa due to insufficient preventive measures. Conclusion: The results emphasize the need for strict infection control measures to prevent the nosocomial transmission of P. aeruginosa in our hospital. PMID- 30464548 TI - Acute epiglottitis caused by community-acquired methicillin-resistant Staphylococcus aureus in a healthy infant. AB - Haemophilus influenzae was the main causative organism for acute epiglottitis in the pre-Haemophilus influenzae type b (Hib) vaccine era. However, with current widespread Hib vaccination, the causative organisms may have changed. Here, we report the case of a healthy infant with acute epiglottitis caused by community acquired methicillin-resistant Staphylococcus aureus (MRSA). The patient was a healthy 17-day-old male infant without a family history of immunodeficiency syndrome. He had not been started on any vaccines. On the third day of illness, he was diagnosed with acute pharyngitis with exudation on the back of the larynx. Although treatment using cefotaxime was initiated, he showed stridor, difficulty in pronunciation, and cyanosis upon crying on the fourth day. On the fifth day, he was diagnosed with acute epiglottitis by laryngoscopy, which showed a downward spread of the exudation and laryngeal edema. He was intubated and started on artificial respiration. Due to the detection of MRSA from a pharyngeal swab culture, he was treated with vancomycin. His fever disappeared on the first day after admission, and he was extubated on the eighth day after admission. MRSA genome analysis of the patient sample revealed negative Panton-Valentine leukocidin, positive toxic shock syndrome toxin 1, and type IV clone of staphylococcal cassette chromosome mec. This is a first case of acute epiglottitis caused by MRSA with a Panton-Valentine leukocidin-negative and toxic shock syndrome toxin 1-positive staphylococcal cassette chromosome mec type IV clone, which is known as a community-acquired MRSA in Japan. Community-acquired MRSA may be considered a causative organism for acute epiglottitis in the post Hib vaccine era. PMID- 30464547 TI - Noninvasive screening identifies patients at risk for spontaneous bacterial peritonitis caused by multidrug-resistant organisms. AB - Background and aims: Spontaneous bacterial peritonitis (SBP) is a severe complication of decompensated cirrhosis. The prevalence of multidrug-resistant organisms (MDROs) in patients with cirrhosis is increasing. Identification of patients at risk for SBP due to MDROs (ie, SBP with the evidence of MDROs or Stenotrophomonas maltophilia in ascitic culture, MDRO-SBP) is crucial to the early adaptation of antibiotic treatment in such patients. We therefore investigated whether MDROs found in ascitic cultures can also be found in specimens determined by noninvasive screening procedures. Patients and methods: This retrospective study was conducted at the liver center of the University Hospital Frankfurt, Germany. Between 2011 and 2016, patients with cirrhosis were included upon diagnosis of SBP and sample collection of aerobic/anaerobic ascitic cultures. Furthermore, the performance of at least one complete MDRO screening was mandatory for study inclusion. Results: Of 133 patients diagnosed with SBP, 75 (56.4%) had culture-positive SBP and 22 (16.5%) had MDRO-SBP. Multidrug resistant Escherichia coli (10/22; 45.5%) and vancomycin-resistant enterococci (7/22; 36.4%) resembled the major causatives of MDRO-SBP. Rectal swabs identified MDROs in 17 of 22 patients (77.3%) who developed MDRO-SBP with a time-dependent sensitivity of 77% and 87% after 30 and 90 days upon testing, while negative predictive value was 83% and 76%, respectively. The majority of patients were included from intensive care unit or intermediate care unit. Conclusion: MDRO screening may serve as a noninvasive diagnostic tool to identify patients at risk for MDRO-SBP. Patients with decompensated cirrhosis should be screened for MDROs from the first day of inpatient treatment onward. PMID- 30464549 TI - Amputation of a finger in a patient with multidrug-resistant Mycobacterium marinum skin infection. AB - Mycobacterium marinum is the etiologic agent of fish tank granuloma. The clinical course is usually benign: spontaneous healing is possible within weeks or months. However, fish tank granuloma is sometimes resistant to several antibiotics. We report a case of M. marinum infection of a finger in a 73-year-old cook. The disease was resistant to a number of antibiotics and required the amputation. The history of this patient testifies that M. marinum can be resistant to several antibiotics and that skin infections can be sometimes so severe as to require the amputation of a finger. PMID- 30464550 TI - Efficacy of a 14-day quadruple-therapy regimen for third-line Helicobacter pylori eradication. AB - Purpose: To assess the efficacy of amoxicillin, tetracycline, high-dose metronidazole, and a proton-pump inhibitor for third-line Helicobacter pylori eradication. Methods: We enrolled 70 consecutive patients who had registered, failed to respond to two rounds of H. pylori eradication, and undergone endoscopy for H. pylori culture. Seven patients were lost to follow-up. Patients were treated according to the results of antibiotic-susceptibility testing reports (cultured group, n=39). Those who failed the H. pylori culture were prescribed 14 day quadruple therapy containing esomeprazole 40 mg twice daily, amoxicillin 1 g twice daily, tetracycline 500 mg four times daily, and metronidazole 500 mg three times daily (empirical group, n=24). A follow-up urea breath test was performed 8 weeks later. Results: Antibiotic-resistance rates were 79.5% (clarithromycin), 94.9% (levofloxacin), 66.7% (metronidazole), 2.6% (amoxicillin), and 0 (tetracycline). Eradication rates attained by the cultured and empirical group were 89.7% (95% CI 72.7%-97.1%) and 58.3% (95% CI 36.6%-77.9%) in per-protocol analysis (P=0.004) and 81.4% (95% CI 66.6%-91.6%) and 51.8% (95% CI 31.9%-71.3%) in intention-to-treat analysis (P=0.014), respectively. Culture-guided therapy was the only clinical factor influencing the efficacy of H. pylori eradication (OR 0.16, 95% CI 0.04-0.60; P=0.006). Despite the high metronidazole-resistance rate (66.7%) after two treatment failures, the eradication rate in patients with this condition was 84%. Conclusion: Empirical 14-day modified quadruple therapy is not acceptable as an alternative third-line rescue H. pylori treatment. The success rate of third-line susceptibility-guided treatment was near 90%. This report is valuable as a reminder to medical practitioners that rather than a try and-see approach, susceptibility-guided therapy should always be considered whenever possible for patients who have undergone several treatment failures. PMID- 30464551 TI - Interventions targeting the prescribing and monitoring of vancomycin for hospitalized patients: a systematic review with meta-analysis. AB - Purpose: Vancomycin prescribing requires individualized dosing and monitoring to ensure efficacy, limit toxicity, and minimize resistance. Although there are nationally endorsed guidelines from several countries addressing the complexities of vancomycin dosing and monitoring, there is limited consideration of how to implement these recommendations effectively. Methods: We conducted a systematic search of multiple databases to identify relevant comparative studies describing the impact of interventions of educational meetings, implementation of guidelines, and dissemination of educational material on vancomycin dosing, monitoring, and nephrotoxicity. Effect size was assessed using ORs and pooled data analyzed using forest plots to provide overall effect measures. Results: Six studies were included. All studies included educational meetings. Two studies used implementation of guidance, educational meetings, and dissemination of educational materials, one used guidance and educational meetings, one educational meetings and dissemination of educational materials, and two used educational meetings solely. Effect sizes for individual studies were more likely to be significant for multifaceted interventions. In meta-analysis, the overall effect of interventions on outcome measures of vancomycin dosing was OR 2.50 (95% CI 1.29-4.84); P< 0.01. A higher proportion of sampling at steady-state concentration was seen following intervention (OR 1.95, 95% CI 1.26-3.02; P<0.01). Interventions had no effect on appropriate timing of trough sample (OR 2.02, 95% CI 0.72-5.72; P=0.18), attaining target concentration in patients (OR 1.50, 95% CI 0.49-4.63; P=0.48, or nephrotoxicity (OR 0.75, 95% CI 0.42-1.34; P=0.33). Conclusion: Multifaceted interventions are effective overall in improving the complex task of dosing vancomycin, as well as some vancomycin monitoring outcome measures. However, the resulting impact of these interventions on efficacy and toxicity requires further investigation. These findings may be helpful to those charged with designing implementation strategies for vancomycin guidelines or complex prescribing processes in hospitals. PMID- 30464552 TI - Clinical features, risk factors, and impact of antibiotic treatment of diarrhea caused by Shigella in children less than 5 years in Manhica District, rural Mozambique. AB - Objectives: During the period from December 2007 to November 2012, the epidemiology of diarrhea caused by Shigella was studied among children <5 years of age residing in Manhica District, Southern Mozambique. Materials and methods: Children from 0 to 5 years with moderate-to-severe diarrhea (MSD) and less severe diarrhea (LSD) were enrolled along with matched controls (by age, gender, and neighborhood). Age-stratified logistic regression analyses were conducted to identify clinical features and risk factors associated with Shigella positivity in cases of diarrhea. The impact of antibiotic treatment was assessed for patients with known outcome. Results: A total of 916 cases of MSD and 1979 matched controls, and 431 cases of LSD with equal number of controls were enrolled. Shigella was identified as significant pathogen in both cases of MSD and LSD compared to their respective controls. Shigella was detected in 3.9% (17/431) of LSD compared to 0.5% (2/431) in controls (P=0.001) and in 6.1% (56/916) of MSD cases compared to 0.2% (4/1979) in controls (P<0.0001), with an attributable fraction of 8.55% (95% CI: 7.86-9.24) among children aged 12-23 months. Clinical symptoms associated to Shigella among MSD cases included dysentery, fever, and rectal prolapse. Water availability, giving stored water to child, washing hands before preparing baby's food, and mother as caretaker were the protective factors against acquiring diarrhea caused by Shigella. Antibiotic treatment on admission was associated with a positive children outcome. Conclusion: Shigella remains a common pathogen associated with childhood diarrhea in Mozambique, with dysentery being a significant clinical feature of shigellosis. Adherence to the basic hygiene rules and the use of antibiotic treatment could contribute to the prevention of most of diarrhea due to Shigella. PMID- 30464553 TI - In vitro activity and post-antibiotic effects of linezolid in combination with fosfomycin against clinical isolates of Staphylococcus aureus. AB - Objectives: Linezolid combination therapy is recommended for the treatment of Staphylococcus aureus (S. aureus) infections. However, the optimal regimen of the combination therapy for S. aureus is unknown. The objective of this study was to investigate the antibacterial activity, post-antibiotic effect (PAE), and post antibiotic subminimum inhibitory concentration (MIC) effect (PA-SME) of linezolid alone and in combination with fosfomycin against eleven clinical isolates of S. aureus. Methods: The synergistic effects and antibacterial activity of linezolid and fosfomycin were assessed by checkerboard and time-kill assays. To determine the PAE and PA-SME, S. aureus strains in the logarithmic phase of growth were exposed for 1, 2, and 3 hours to the antibiotics, alone and in combination. Recovery periods of test strains were evaluated using viable counting after dilution. Results: Synergistic effects were observed for eight strains and no antagonism was found with any combination. Moreover, linezolid combined with fosfomycin at 4x MIC showed the best synergistic antibacterial effect, and this effect was retained after 24 hours. In addition, both the antibiotics alone and in combination showed increased PAE and PA-SME values in a concentration- and time-dependent manner. Conclusion: Linezolid combined with fosfomycin exerted a good antibacterial effect against S. aureus, and the combinations have significant PAE and PA-SME. PMID- 30464554 TI - Clinical and virological properties of hepatitis C virus genotype 4 infection in patients treated with different direct-acting antiviral agents. AB - Background: The efficacy of direct-acting antivirals (DAAs) depends on the hepatitis C virus (HCV) genotype 4 (GT4) subtype which are used in the treatment of HCV. We aimed to retrospectively investigate the baseline prevalence of HCV NS5A and NS5B polymorphisms and their impact on virological outcome in GT4 infected patients treated with various DAA regimens. Patients and methods: Available plasma samples from HCV GT4-infected patients treated with different DAA regimens were analyzed at baseline and after treatment failure, where applicable. Sanger sequencing of patient-derived NS5A and NS5B regions was performed on all available samples, while ultradeep pyrosequencing (UDPS) of NS5A and NS5B regions was performed only on samples from treatment failures at different time points. Results: Sustained virological response (SVR) was achieved by 96% (48/50) of patients. Of 16 patients with baseline NS5A sequence, polymorphisms at amino acid positions associated with drug resistance were detected only at position 58: P58 (69.2%) and T58 (30.8%). Of 21 patients with baseline NS5B sequence, N142S was detected only in the two treatment failures, both with GT4d were treated with sofosbuvir (SOF)-based regimens, suggesting a potential involvement in SOF efficacy. Two patients (patient 1 [Pt1] and patient 2 [Pt2]) relapsed. In Pt1, NS5A-T56I and NS5A-Y93H/S emerged. In Pt2, NS5A-L28F emerged and a novel NS5B resistance-associated substitution (RAS), L204F, representing 1.5% of the viral population at baseline, enriched to 71% and 91.6% during and after treatment failure, respectively. UDPS of NS5B from Pt2 indicated a mixed infection of approximately 1:5, GT1a:GT4d, at baseline and GT4d during failure. Phylogenetic analysis of NS5A sequences indicated no clustering of HCV strains from patients achieving SVR vs patients who relapsed. The mean genetic distance in NS5A sequences was 5.8%, while a lower genetic distance (3.1%) was observed in NS5B sequences. Conclusion: Results from these analyses confirm the importance of UDPS in the analysis of viral quasispecies variability and the identification of novel RASs potentially associated with DAA treatment failure in HCV GT4-infected patients. PMID- 30464556 TI - Novel mechanism responsible for high-level macrolide resistance in Moraxella catarrhalis. AB - Background: High-level macrolide-resistant Moraxella catarrhalis strains have been isolated; however, the underlying mechanism has not been well elucidated. We investigated the role of mutations in the 23S rRNA gene and the L4 and L22 ribosomal proteins using spontaneous erythromycin-resistant mutants and transformants. Materials and methods: The erythromycin-susceptible M. catarrhalis ATCC25238 and clinical isolate Mc19 were used as parental strains. To obtain spontaneous erythromycin-resistant mutants, in vitro stepwise selection was performed using brain-heart infusion agar plates containing various concentrations of erythromycin. The role of the mutations identified in the spontaneous mutants was validated using transformation experiments. Results: We obtained two spontaneous mutants with high-level resistance to erythromycin, S25 32-af10 and S19-256-af10, from ATCC25238 and Mc19, respectively. S25-32-af10 exhibited mutations of Q61R in L4 and Insertion98SRADRIS in L22. S19-256-af10 exhibited three C2611T-mutated alleles in the 23S rRNA gene and G65A in L4. Transformants with single mutations identified in S25-32-af10 or S19-256-af10 showed higher erythromycin and azithromycin minimum inhibitory concentrations (MICs) than those of each parental strain. However, transformants with multiple mutations identified in S25-32-af10 or S19-256-af10 showed macrolide MICs similar to those of each parental strain. Conclusion: Our results provide the first evidence suggesting that Q61R in L4 and Insertion98SRADRIS in L22 are involved in the synergistic acquisition of high-level resistance to both 14- and 15-member macrolides, and that C2611T in the 23S rRNA gene and G65A in L4 also synergistically contribute toward conferring high-level 14-member macrolide resistance to M. catarrhalis. PMID- 30464555 TI - The effects of cytochrome P450 2C19 polymorphism on the metabolism of voriconazole in vitro. AB - Background: CYP/CYP450 2C19 (CYP2C19) is a highly polymorphic enzyme and exhibits individual differences in metabolic activity. The purpose of this research was mainly to explore the catalytic activities of 30 CYP2C19 variants on the substrate voriconazole in vitro, including 24 novel CYP2C19 variants (2C19.2E .2H, .2J, .3C, .29-.33, L16F, 35FS, R124Q, R125G, T130M, N231T, M255T, R261W, N277K, S303N, I327T, N403I, and A430V) found in Chinese Han population for the first time. Methods: These CYP2C19 variants were expressed in Spodoptera frugiperda (Sf) 21 insect cells using the baculovirus-mediated expression system. The substrate voriconazole was incubated with the abovementioned proteins at 37 degrees C for 30 minutes in an appropriate designed system. Then through detecting its major metabolite voriconazole N-oxide by ultra-performance liquid chromatography tandem mass spectrometry, available data were obtained to explain the influence of CYP2C19 polymorphisms on voriconazole. Results: From the results, when compared to CYP2C19.1, most variants exhibited either reduced Vmax and/or increased Km value, indicating that the intrinsic clearance (Vmax/Km ) values of most variants were significantly altered. The catalytic activities of 20 novel variants exhibited decreases in different degrees compared to CYP2C19.1, with relative clearance values ranging from 1.11% to 83.78%. However, L16F exhibited the increased catalytic activity for 135.68%. In addition, the kinetic parameters of four variants (2C19.2H, .3, 35FS, and R124Q) could not be detected, due to the defective gene. Conclusion: This is the first study to report the effects of CYP2C19 polymorphisms on vori-conazole metabolism in vitro, and we hope these data could lay the foundation for the early clinical research and individualized treatment. PMID- 30464557 TI - Community acquired pneumonia among adult patients at an Egyptian university hospital: bacterial etiology, susceptibility profile and evaluation of the response to initial empiric antibiotic therapy. AB - Background: Effective empirical antibiotic therapy for community acquired pneumonia (CAP), based on frequently updated data about the pattern of bacterial distribution and their antimicrobial susceptibilities, is mandatory. Aim: To identify the bacterial etiology of CAP in adults and their antibiotic susceptibility patterns and to evaluate the response to initial empirical antibiotic therapy in an Egyptian university hospital. Settings and design: A cross-sectional hospital-based study. Patients and methods: CAP cases were selected by systemic random sampling from those admitted to the chest department. All were evaluated at admission and 4 days after starting empiric therapy. Typical bacteria were isolated, identified and tested for their antibiotic susceptibility. An indirect IF assay was used to diagnose atypical bacteria. Clinical response to initial empiric antibiotic therapy was clinically, laboratory and radiologically evaluated. Results: Two hundred and seventy CAP patients were included. Bacteria represented 50.4% of them. Klebsiella pneumoniae was the most prevalent bacterium (10.37%) followed by Streptococcus pneumoniae and P. aeruginosa (7.78% each). Overall, 76.2% of isolates showed a multidrug resistant phenotype: 82.61% (19/23) S. pneumoniae, 89.66 % (26/29) K. pneumoniae, 65.22% (15/23) Pseudomonas aeruginosa, 87.50% (7/8) Escherichia coli and 81.25 % (13/16) Staphylococcus aureus. Broad spectrum beta-lactams, especially carbapenems, and moxifloxacin showed in vitro efficacy on most of the tested isolates. Forty-three cases (15.9%) were nonresponders, 37 (86%) of them showed bacterial etiology. The highest rate of nonresponsiveness (30.43%) was observed in cases receiving antipseudomonal/antipneumococcal beta-lactam plus a fluoroquinolone for suspected P. aeruginosa infection. Conclusion: Multidrug resistance in bacteria causing CAP and high frequency of isolation of hospital pathogens are prominent features of this study. Azithromycin containing regimens were associated with the lowest rates of nonresponsiveness. Development and implementation of an antibiotic stewardship program are highly recommended for CAP management. PMID- 30464558 TI - Phenotypic and genotypic characterizations of extended-spectrum beta-lactamase producing Escherichia coli in Thailand. AB - Purpose: Extended-spectrum beta-lactamases (ESBLs) have become an issue in community worldwide due to an increase in antibiotic resistance over the past decade. This study was aimed to investigate the phenotypic and genotypic characteristics of ESBL-producing Escherichia coli in Thailand. Materials and methods: In this study, all clinical isolates collected from tertiary hospitals in Thailand were identified as E. coli by biochemical tests and MALDI-TOF mass spectrometry. ESBL-producing E. coli was preliminary screened with disk diffusion method by cephalosporin disks and confirmed by the method of combination disk diffusion. Antimicrobial susceptibility test was used to determine MIC values of all ESBL-producing E. coli. For genotypic detection, a variety of ESBL genes were determined by PCR. Moreover, multilocus sequence typing (MLST) analysis was performed on internal portions of seven housekeeping genes for the diversity and phylogenetic relatedness of E. coli clonal group. Results: Of the 285 ESBL producing E. coli, most were susceptible to carbapenems. These strains showed a high resistance rate to ciprofloxacin (85.26%). The most frequently detected gene was bla CTX-M1 group at about 71.23% followed by bla CTX-M9 group (38.95%). The bla TEM, bla PER, bla GES, bla VEB, and bla SHV genes were identified in 31.93%, 5.96%, 4.56%, 3.51%, and 0.70% of ESBL-producing isolates, respectively. The bla OXA-10 gene was detected in only one strain. ESBL-producing E. coli isolates with high antimicrobial resistance were further investigated. Among those, E. coli sequence type ST38 was mostly found, followed by ST405, ST410, and ST131. It is noteworthy that the bla CTX-M gene was mainly detected in all four ST-type E. coli clones (ST38, ST405, ST410, and ST131). Conclusion: This study provided a recent evidence of the genetic diversity of ESBL-producing E. coli in Thailand. In addition, the profile related to antimicrobial resistance pattern in this region was also demonstrated. PMID- 30464559 TI - Molecular characteristics and comparative genomics analysis of a clinical Enterococcus casseliflavus with a resistance plasmid. AB - Purpose: The aim of this work was to investigate the molecular characterization of a clinical Enterococcus casseliflavus strain with a resistance plasmid. Materials and methods: En. casseliflavus EC369 was isolated from a patient in a hospital in southern China. The minimum inhibitory concentration was found by means of the agar dilution method to determine the antimicrobial susceptibilities of the strains. Whole-genome sequencing and comparative genomics analysis were performed to analyze the mechanism of antibiotic resistance and the horizontal gene transfer of the resistance gene-related mobile genetic elements. Results: En. casseliflavus EC369 showed resistance to erythromycin, kanamycin, and streptomycin, but was susceptible to vancomycin, ampicillin, and streptothricin and other antimicrobials. There were six resistance genes (aph3', ant6, bla, sat4, and two ermBs) carried by a transposon identified on the plasmid pEC369 and a complete resistance gene cluster of vancomycin and a tet (M) gene encoded on the chromosome. This is the first complete plasmid sequence reported in clinically isolated En. casseliflavus. The plasmid with the greatest sequence identity with pEC369 was the plasmid of Enterococcus sp. FDAARGOS_375, followed by the plasmids of Enterococcus faecium strains F12085 and pRE25, whereas the sequence with the greatest identity to the resistance genes carrying a transposon of pEC369 was on the chromosome of Staphylococcus aureus strain GD1677. Conclusion: The resistance profiles of En. casseliflavus EC369 might contribute to the resistance genes encoded on the plasmid. The fact that the most similar sequence to the transposon carrying resistance genes of pEC369 was encoded in the chromosome of a S. aureus strain provides insights into the mechanism of dissemination of multidrug resistance between bacteria of different species or genera through horizontal gene transfer. PMID- 30464560 TI - Economic benefits of implementing patient-centered medical home among patients with hypertension. AB - Introduction: Despite the strong evidence of an association between adoption of the patient-centered medical home (PCMH) and improved clinical outcomes among patients with hypertension, evidence for associations between the PCMH and health care utilization and cost reduction within the general adult population with hypertension is less developed. Objective: This study was designed to examine the effect of PCMH on health service expenditures and utilization in a national sample of the US adult population who were diagnosed with hypertension. Methods: The 2010-2015 Medical Expenditure Panel Survey data were used. The study sample was limited to adults (>=18 years) diagnosed with essential hypertension. We investigated the impact of PCMH on the direct hypertension-related total and on the costs of inpatient stays, prescription medications, outpatient visits, emergency room visits, office-based services, and other medical expenditures by using log-transformed multiple linear regression models and the propensity score method. Results: Of the 18,630 adults identified with hypertension, 19.2% (n=3,583) of them had received PCMH care from 2010 to 2015. After matching, the no PCMH group showed greater mean in all hypertension-related health service costs and utilization. After adjusting for the remaining con-founders, the PCMH group showed a significant association with lower total costs, office-based services, number of office-based visits, and outpatient visits compared with the control group. Conclusion: A significant relationship between experiencing PCMH care and a lower total health care expenditure was found in patients with hypertension. PMID- 30464562 TI - Incremental health care resource utilization and expenditures associated with autosomal-dominant polycystic kidney disease. AB - Purpose: Incremental health care resource utilization and expenditures associated with autosomal dominant polycystic kidney disease (ADPKD) were estimated. Methods: Study data were from a large administrative claims database. Individuals aged 18 years or older enrolled in tracked health plans for 12 months from April 1, 2011 through March 31, 2012, and with an International Classification of Disease, Ninth Revision, Clinical Modification diagnosis code for "polycystic kidney, autosomal dominant" (753.13) or for "polycystic kidney, unspecified type" (753.12) were identified as having ADPKD, and linked one-to-one with individuals without ADPKD based on age and gender. Zero-inflated negative binomial models estimated incremental health care resource utilization and expenditures, adjusting for risk factors. Results: A total of 3,844 individuals with ADPKD who satisfied selection criteria were linked one-to-one with 3,844 individuals without ADPKD. Multivariate, regression models adjusting for risk factors revealed incremental mean (standard error) resource use associated with ADPKD of 0.68 (0.090) hospital days, equal to 68 additional hospital days per 100 ADPKD patients, and 6.9 (0.28) outpatient visits, equal to 690 additional visits per 100 ADPKD patients. Mean (standard error) incremental total expenditures associated with ADPKD were US$8,639 ($470). Mean incremental expenditures were largest for outpatient expenditures at US$4,918 ($198), followed by mean incremental hospital expenditures of US$2,603 ($263), and mean incremental medication expenditures of US$1,589 ($77). Based on sub-group analysis, mean incremental total expenditures were US$2,944 ($417) among ADPKD patients without end-stage renal disease and US$38,962 ($6,181) for those with end-stage renal disease. Conclusion: ADPKD was associated with considerable incremental health care resource utilization and expenditures. Significant illness burden was found even before patients reached end-stage renal disease. PMID- 30464563 TI - Cost-consequence model comparing eltrombopag versus romiplostim for adult patients with chronic immune thrombocytopenia. AB - Background: Thrombopoietin-receptor agonists eltrombopag (EPAG) and romiplostim (ROMI) are treatment options for adults with chronic immune thrombocytopenia (cITP) who have had an insufficient response to corticosteroids or immunoglobulins. Methods: A cost-consequence model was developed to evaluate the costs relative to treatment success of EPAG, ROMI, and watch and rescue (W&R) in previously treated patients. The primary endpoint assessed was severe bleeding, derived from all identified phase III registered clinical trials. Health outcomes were compared via indirect treatment comparison. Costs incorporated in the model included drug and administration, routine care, rescue medications, bleeding related adverse events, other adverse events, and mortality costs. A trial (26 week) time horizon was used, as certain endpoints used in the model were bound to within-trial results. Results: In the intent-to-treat (ITT) population, the overall estimated cost per patient for EPAG was US$66,560 compared to US$91,039 for ROMI and US$30,099 for W&R. Compared to the ITT population, the difference in cost between EPAG and ROMI was slightly greater in splenectomized patients (US$65,998 for EPAG compared to US$91,485 for ROMI) and slightly less in non splenectomized patients (US$67,151 for EPAG compared to US$91,455 for ROMI), though the overall trend remained the same. When assessing cost per severe bleeding event avoided in the ITT population, EPAG dominated (less expensive, more effective) ROMI. Sensitivity analyses confirmed these results. Conclusion: EPAG was preferred over ROMI in the treatment of cITP, largely driven by the reduction in severe bleeding events associated with its use. PMID- 30464561 TI - Burden of cancer pain in developing countries: a narrative literature review. AB - Cancer pain is one of the most common, feared, debilitating, and often undertreated symptoms among cancer patients. It needs attention since it has a significant impact on the quality of life (QoL) of the patients. Also, since cancer has emerged as a major health problem in developing countries, there is a need to strengthen preventive strategies for effective cancer pain management and provide comfort to cancer patients. Nonetheless, various barriers limit developing countries toward optimal cancer pain management. To bridge the gap between adequate pain management and burden of cancer pain in developing countries, a comprehensive understanding of the limitations faced and the prevalence of cancer pain should be addressed. The aim of this literature review is to provide a deeper understanding on the factors associated with cancer pain as well as barriers toward optimal cancer pain management in developing countries. Some of the barriers addressed were administrative, judicial, economic, and professional barriers. Also, estimates on the prevalence of cancer pain and detrimental effects of pain on the QoL of cancer patients have been addressed. In summary, pain, which is one of the most debilitating symptoms of cancer, remains uncontrolled and undertreated in developing countries. It has a profound impact on the patient's QoL and can have physical, psychological, and social consequences; therefore, it needs to be managed urgently and appropriately. Most importantly, optimal treatment of cancer pain should be highlighted as a priority in developing countries and concerted efforts should be made to eliminate different barriers discussed in this review for effective and humane care. PMID- 30464564 TI - Cost-consequence model comparing eltrombopag and romiplostim in pediatric patients with chronic immune thrombocytopenia. AB - Background: Immune thrombocytopenia (ITP) is an auto-immune disorder characterized by enhanced platelet destruction and, subsequently, the potential for increased bleeding. Thrombopoietin receptor (TPO-R) agonists have recently emerged as promising therapies for ITP patients who are refractory to other treatments. While eltrombopag (EPAG) is the only TPO-R agonist US Food and Drug Administration approved for use in pediatric patients, romiplostin (ROMI) has been used in Phase III clinical studies. Methods: A cost-consequence model (CCM) was developed to evaluate the costs of EPAG, ROMI, and watch-and-rescue (W&R) in relation to their respective treatment outcomes in previously-treated pediatric chronic ITP (cITP) over a 26-week time horizon. The costs of drugs, administration, routine care, rescue medications, adverse events, and mortality were included. Data on platelet count response rate, bleeding events, and adverse events were derived from all relevant identified Phase III-registered clinical trials, health outcomes were compared via indirect treatment comparison. Results: The overall estimated cost of EPAG per patient was US$66,550, compared to US$101,056 for ROMI and US$32,720 for W&R. EPAG's lower cost compared to ROMI was largely due to lower drug costs (US$62,202 vs US$84,396), administration costs (US$0 vs US$1,955), and significantly lower costs due to severe bleeding (US$354 vs US$10,191). When assessing cost per severe bleeding event avoided, EPAG was dominant over ROMI (less expensive and more effective). EPAG was again dominant over ROMI when assessing the cost per responder and per bleeding event (any grade). Sensitivity analysis was consistent with the base case findings. Conclusion: EPAG was the preferred TPO-R agonist to treat cITP when indirectly compared to ROMI, largely driven by its favorable severe bleeding outcomes and lower drug and administration costs. PMID- 30464565 TI - Multiple sclerosis patients who are stable on interferon therapy show better outcomes when staying on same therapy than patients who switch to another interferon. AB - Background: Real-world outcomes from staying on an interferon beta (IFNbeta) vs switching to another IFNbeta could help guide treatment decisions. This study's objective was to compare outcomes of stable multiple sclerosis (MS) patients on an IFNbeta who stayed on therapy vs those who switched to another IFNbeta. Methods: MS patients were identified from the Optum Insights Clinformatics Data Mart Multi-Plan who were 18-64 years old and relapse-free (stable) over 1 year while continuously being treated with an IFNbeta. Patients were propensity score matched 3:1 using age, gender, initial IFNbeta, adherence, and month and year for patients who stayed on the initial IFNbeta (No Switch) to patients who switched to another IFNbeta (Switch). Patients had to be continuously enrolled for 1 year prior to and 1 year after the index date (date of the first claim of the switched to IFNbeta or the match date when continuing on initial IFNbeta treatment). Patients were enrolled with index dates between January 1, 2005 and September 30, 2014. Relapses were recorded during the 1-year follow-up period after index date. Results: After matching, there were 381 patients in the Switch group and 1,143 in the No Switch group. Baseline characteristics were well matched between groups (average age 46 years, 72% female). The percentage of patients experiencing a relapse during the follow-up was significantly higher in the Switch group than in the No Switch group (21% vs 12%, P<0.0001). Annual relapse rate during the follow up was significantly higher in the Switch group than in the No Switch group (0.35 vs 0.20, P<0.0001). Conclusion: MS patients stable on IFNbeta therapy who remain on initial therapy had significantly better outcomes (lower annual relapse rate and percentage of patients with relapses) than patients who switched to another IFNbeta. This supports the benefits of allowing patients to remain on current IFNbeta therapy when stable. PMID- 30464568 TI - Papular elastorrhexis: clinical perspectives. AB - First described by Bordas in 1987, papular elastorrhexis (PE) is a rare elastic fiber disorder of the skin characterized by multiple, discrete, asymptomatic, firm, nonfollicular, monomorphous, 1-5 mm, circumscribed, hypopigmented, oval to round papules, symmetrically distributed on the chest, abdomen, back, shoulders, arms, and thighs. The onset of the condition is usually in the first or second decade of life. PE appears to be an exceedingly rare entity, with 33 cases reported in the literature until now. However, the disorder might be underestimated probably because of its subtlety, asymptomatic course, and benign nature of clinical alterations, which can easily be confused with other dermatoses such as acne scars. Clinical and histopathological differential diagnosis of PE is broad and includes papular acne scars, eruptive collagenoma, disseminated lenticular dermatofibrosis (as a component of Buschke-Ollendorff syndrome), white fibrous papulosis of the neck, pseudoxanthoma elasticum, pseudoxanthoma elasticum-like papillary dermal elastolysis, middermal elastolysis, and perifollicular elastolysis. Treatment of PE is a matter of debate and no reliable curative option exists. PMID- 30464567 TI - Autologous non-cultured melanocyte-keratinocyte transplantation in the treatment of vitiligo: patient selection and perspectives. AB - Autologous non-cultured melanocyte-keratinocyte transplantation procedure (MKTP) is one of the simplest cellular grafting techniques. Various modifications were done over the years to make the technique easier and more economical which led to its great popularity among dermatologists. Proper patient selection and good technical skills are essential for achieving success with this technique. In this review, different patient-related and procedure-related factors that affect the outcome are discussed. This review may guide dermatologists to select suitable candidates, and explains what to expect in each case and indicates different techniques which can be used. The expected complications and stability of acquired pigmentation, which are an essential part of the pretreatment patient counseling, are also discussed. PMID- 30464569 TI - A diagnostic checklist for generalized dermatitis. AB - Purpose: Generalized dermatitis (defined as histological spongiotic dermatitis affecting more than three anatomical areas of the skin surface) has many potential causes that mimic atopic dermatitis and contact dermatitis. If a treatable cause is missed, the patient may be treated with chronic immunosuppressive therapy that carries more risk than specific treatment for a disease mimicking dermatitis. Checklists have been shown to improve patient safety, primarily in procedural contexts. This work assessed the utility of a diagnostic checklist for subacute and chronic generalized dermatitis in patients who had not improved after at least 1 month of avoidance of contact allergens identified by comprehensive patch testing, if indicated. Patients and methods: Designed as a quality improvement project using Standards for Quality Improvement Reporting Excellence (SQUIRE) guidelines, a diagnostic checklist was used by the principal investigator for 1 year in a tertiary referral dermatitis clinic for patients without a confirmed cause for the dermatitis after two to three visits with the investigator. All patients had had diagnostic patch testing if indicated. Almost all had undergone skin biopsy by their referring provider. Fifteen patients met the criteria for inclusion in this study. Outcome measures included provider and patient perception of efficiency and/or confusion caused by the checklist. Length of time from the initiation of use of the checklist to final diagnosis was recorded. Additional diagnoses considered that were not included in the initial checklist were added to the checklist during the course of the study. Results: The checklist was useful in improving diagnostic efficiency (prompting consideration of diagnoses not otherwise considered upon initiation of the visit that resulted in a final plan of care) in these complex cases of recalcitrant dermatitis. Open utilization of the checklist by the investigator during the clinical encounter was well accepted by patients and families. Conclusion: Checklists can be useful for complex cognitive diagnostic work. IRB approval status: University Hospitals Cleveland Medical Center Institutional Review Board # 11-15-34. PMID- 30464566 TI - COSMIC project: consensus on the objectives of the metabolic syndrome in clinic. AB - Metabolic syndrome (MetS), a disorder with a high and growing prevalence, is a recognized risk factor for cardiovascular disease (CVD) and type 2 diabetes. It is a constellation of clinical and metabolic risk factors that include abdominal obesity, dyslipidemia, glucose intolerance, and hypertension. Unfortunately, MetS is typically underrecognized, and there is great heterogeneity in its management, which can hamper clinical decision-making and be a barrier to achieving the therapeutic goals of CVD and diabetes prevention. Although no single treatment for MetS as a whole currently exists, management should be targeted at treating the conditions contributing to it and possibly reversing the risk factors. All this justifies the need to develop recommendations that adapt existing knowledge to clinical practice in our healthcare system. In this regard, professionals from different scientific societies who are involved in the management of the different MetS components reviewed the available scientific evidence focused basically on therapeutic aspects of MetS and developed a consensus document to establish recommendations on therapeutic goals that facilitate their homogenization in clinical decision-making. PMID- 30464570 TI - Inflammatory bowel disease epidemiology in Sao Paulo State, Brazil. AB - Purpose: This study aimed to estimate the incidence and prevalence of inflammatory bowel disease (IBD) in Sao Paulo, Brazil, for 2012-2015. Patients and methods: This observational, descriptive, and cross-sectional study included 22,638 IBD patients out of 43,046,555 inhabitants, who had initiated their treatment through the Governmental Program of the Brazilian Unified National Health System between the years of 2012 and 2015. The onset of the disease (used to determine incidence) was established as the date of the patient's initial registration in the Governmental Program with a diagnosis for Crohn's disease (CD) or ulcerative colitis (UC). Every patient registered in the system as of December 2015 was included in determining the prevalence. The demographic and clinical data, such as age and sex, were collected for each patient. Statistical analysis included mean and SD, absolute and percentage frequencies, and Pearson's chi-squared test (c2). The incidence and prevalence rates were calculated based on the estimated annual population of the State of Sao Paulo. Results: The study population consisted of 10,451 (46.16%) CD patients and 12,187 (53.84%) UC patients. The mean age was 42.66 (SD+/-16.2) years for the CD group and 47.87 (SD+/-16.6) years for the UC group. There was a predominance of females corresponding to 59.70% of the study population (female:male =1.48:1.00; P<0.0001). The incidence of IBD was 13.30 new cases/100,000 inhabitants per year, while the overall prevalence was 52.6 cases/100,000 inhabitants. Conclusion: This population-based study demonstrated a stability in IBD incidence rates and an increase in IBD prevalence rates in Sao Paulo state between 2012 and 2015. The IBD incidence and prevalence rates were comparable to European countries, with a higher occurrence in the female participants. PMID- 30464571 TI - Evaluation of chemokine CXCL10 in human gingival crevicular fluid, saliva, and serum as periodontitis biomarker. AB - Purpose: The aim of this study was to evaluate CXCL10 as a biomarker for periodontitis by determining the CXCL10 levels in saliva, serum, and gingival crevicular fluid (GCF) samples from periodontally healthy control subjects and adult subjects with chronic periodontitis. Patients and methods: Adult patients seeking dental treatment at Umm Al-Qura University dental clinic underwent a complete periodontal examination, and saliva, serum, and GCF samples were collected. Subjects were classified as chronic periodontitis patients (n=31) if they have a periodontal probing depth (PD) of >=4 mm and/or clinical attachment level (CAL) of >=3 mm in >30% of the teeth. The control group (n=25) had PD <=3 mm and/or CAL <=2 mm. ELISA was performed to determine the concentration of CXCL10 in saliva, serum, and GCF samples. Student's t-test was carried out to evaluate the significant difference between different groups. Spearman's correlation test was used to analyze the relationship between the levels of CXCL10 and the clinical periodontal parameters. P-value of <=0.05 was considered significant. Results: Significantly higher concentrations of CXCL10 were found in saliva and serum in chronic periodontitis patients as compared with the controls (272+/-60.4 pg/mL and 72+/-13.4 pg/mL vs 130+/-22.2 pg/mL and 44.08+/-4.5 pg/mL, P<=0.05). The CXCL10 levels in GCF were higher in the periodontitis group as compared with the control group (66.36+/-32.0 pg/mL and 44.56+/-17.5 pg/mL, respectively); the difference did not reach statistical significance (P>=0.05). Moreover, serum CXCL10 level was significantly higher in periodontitis patients with moderate to severe bone loss as compared with those with mild bone loss (71.05+/-4.7 pg/mL vs 54.8+/-7.7 pg/mL, P<=0.05). The serum CXCL10 levels were found to be related to CAL measurements (r=0.3, P=0.026), while the saliva CXCL10 levels were related to PD measurements (r=0.8, P=0.0007). Conclusion: CXCL10 is significantly increased in periodontitis subjects as compared with controls and could be used as a marker for periodontal disease. PMID- 30464572 TI - 2LARTH(r), a micro-immunotherapy medicine, exerts anti-inflammatory effects in vitro and reduces TNF-alpha and IL-1beta secretion. AB - Background: Tumor necrosis factor-alpha (TNF-alpha) and IL-1beta are 2 pro inflammatory cytokines known to be involved in rheumatic diseases. The therapeutic strategy used in micro-immunotherapy (MI) to reduce chronic inflammation and attenuate pain consists in mainly targeting these 2 cytokines. 2LARTH(r) is a sublingually administered medicine consisting of lactose saccharose globules impregnated with ethanolic preparations of immune mediators and nucleic acids at ultra-low doses. Purpose: The aim of the study is to explore the effect of the MI medicine on TNF-alpha and IL-1beta secretion in human primary enriched monocytes exposed to lipopolysaccharide (LPS). Materials and methods: Placebo and active globules were diluted in culture medium to test 5 lactose-saccharose globules concentrations (from 1.75 to 22 mM). Freshly isolated enriched monocytes from 6 healthy donors were treated with or without LPS (10 ng/mL), LPS+ placebo, or LPS+ 2LARTH(r) for 24 hours. IL-1beta, TNF-alpha, and IL 6 release were evaluated by ELISA. Results: The medicine has significantly decreased the level of IL-1beta secretion compared with placebo at these concentrations: 22 mM (P<0.0001), 11 mM (P=0.0086), 5.5 mM (P= 0.0254), and compared with untreated LPS control at these concentrations: 22 mM, 11 mM (P=0.0008), and 5.5 mM (P=0.002). The effect of active globules on the reduction of TNF-alpha release is significant compared with placebo at these concentrations: 22 mM (P=0.0018), 11 mM (P=0.0005), 5.5 mM (P=0.0136), and compared with untreated LPS control at these concentrations: 22 mM (P=0.0021), 11 mM (P=0.0017), 5.5 mM (P=0.0052) and 2.25 mM (P=0.0196). Besides, IL-6 secretion decreased compared with placebo at 22 mM (P=0.0177) and 11 mM (P=0.0031). Conclusion: The results indicate that the tested product exerts significant anti inflammatory effects on human LPS-stimulated monocytes. PMID- 30464574 TI - Influence of MSI and 18q LOH markers on capecitabine adjuvant monotherapy in colon cancer patients. AB - Purpose: The aim of this study was to evaluate whether pretreatment analysis of selected molecular markers can be used for the prediction of disease-free survival (DFS)/overall survival (OS) of capecitabine adjuvant monotherapy in colon cancer patients. Patients and methods: A total of 126 patients enrolled in a capecitabine Phase IV clinical trial were analyzed for microsatellite instability (MSI), 18q loss of heterozygosity (LOH), thymidylate synthase (TYMS) 5' variable number of tandem repeat (VNTR), and methylene tetrahydrofolate reductase (MTHFR) C677T variants. The significance in predicting 5-year DFS/OS was assessed by Kaplan-Meier and Cox regression analyses. Results: The MSI-high (MSI-H) genotype was significantly associated with DFS (HR 0.205, 95% CI 0.05 0.88, P=0.033) and OS (HR 0.208, 95% CI 0.05-0.89, P=0.035) compared to the microsatellite stable genotype. In models stratified according to clinicopathologic characteristics, the MSI-H genotype remained a positive predictive factor for DFS/OS only in patients with stage III (P=0.023) and patients with tumors localized proximally to the splenic flexure (P=0.004). Distal colon cancers with 18q LOH have a greater survival rate when treated with capecitabine than patients with stable tumors (81.3% vs 50.0%, HR for relapse 0.348, 95% CI 0.13-0.97, P=0.043). TYMS 5'VNTR and MTHFR C677T variants were not associated with DFS or OS. Conclusion: MSI and 18q LOH markers have the potential to be utilized in the selection of colon cancer patients eligible for capecitabine adjuvant monotherapy. PMID- 30464573 TI - Mechanisms of NF-kappaB p65 and strategies for therapeutic manipulation. AB - The transcription factor NF-kappaB is a critical regulator of immune and inflammatory responses. In mammals, the NF-kappaB/Rel family comprises five members: p50, p52, p65 (Rel-A), c-Rel, and Rel-B proteins, which form homo- or heterodimers and remain as an inactive complex with the inhibitory molecules called IkappaB proteins in resting cells. Two distinct NF-kappaB signaling pathways have been described: 1) the canonical pathway primarily activated by pathogens and inflammatory mediators, and 2) the noncanonical pathway mostly activated by developmental cues. The most abundant form of NF-kappaB activated by pathologic stimuli via the canonical pathway is the p65:p50 heterodimer. Disproportionate increase in activated p65 and subsequent transactivation of effector molecules is integral to the pathogenesis of many chronic diseases such as the rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and even neurodegenerative pathologies. Hence, the NF-kappaB p65 signaling pathway has been a pivotal point for intense drug discovery and development. This review begins with an overview of p65-mediated signaling followed by discussion of strategies that directly target NF-kappaB p65 in the context of chronic inflammation. PMID- 30464575 TI - Novel agonist of alpha4beta2* neuronal nicotinic receptor with antinociceptive efficacy in rodent models of acute and chronic pain. AB - Objective: To demonstrate the antinociceptive and antihypersensitivity mechanisms of Cris-104 (1-{2-[5-(4-fluorophenyl)-1H-pyrazol-4-yl]ethyl}piperidine), a novel selective alpha4beta2* nicotinic acetylcholine receptor (nAChR) agonist, in rodent acute/inflammatory and chronic pain models. Materials and methods: Hot plate and formalin tests in mice were used to examine Cris-104-induced antinociceptive effects on thermal/inflammatory pain. Cris-104 effects on hypersensitivity, norepinephrine (NE) release in the spinal dorsal horn, and neuronal activity in the locus coeruleus (LC) were examined in rats with lumbar spinal nerve ligation using behavioral, microdialysis, and extracellular recording methods. Cris-104 effects on spontaneous locomotion were examined in an open-field test. Results: Cris-104 induced dose-dependent antinociception effects in hot-plate and formalin tests, and these effects were blocked by the general nAChR antagonist mecamylamine, the selective alpha4beta2* nAChR antagonist dihydro-beta-erythroidine, and the alpha2-adrenoceptor antagonist yohimbine, but not by the alpha1-adrenoceptor antagonist prazosin. Systemic and spinally perfused Cris-104 increased NE concentrations in microdialysates from the spinal cord in both normal and SNL rats. Systemic Cris-104 increased neuronal activity in the LC of normal rats. Mecamylamine blocked the effects of Cris-104 on spinal NE release and LC neuronal activity. Systemic Cris-104 did not affect locomotor activity significantly. Conclusion: The alpha4beta2 neuronal nAChR agonist, Cris 104, was effective for treatment of pain via descending noradrenergic inhibition of pain signaling. PMID- 30464576 TI - Resilience, depression, and quality of life in elderly individuals with chronic pain followed up in an outpatient clinic in the city of Sao Paulo, Brazil. AB - Purpose: In this study, we assessed resilience, depression, and quality of life in a group of elderly individuals with or without chronic pain. Patients and methods: A cross-sectional study assessing elderly individuals followed up at a geriatrics outpatient clinic and divided into two groups: 54 elderly patients with chronic pain and 54 elderly with no chronic pain. Results: The sample comprised mainly women (67.6%), with mean age 79.9 years. The mean resilience index in the group with pain was 69.4 and, in the group with no pain, 80.1 (P<0.001). Depression was observed in 35.2% of patients with chronic pain; there was no case of depression in those without chronic pain. Quality of life of the elderly with chronic pain was worse in all the domains assessed: physical, mental, emotional, social, vitality, and pain. Conclusion: In the study sample, resilience was lower, depression was more frequent, and quality of life was worse in the group of elderly with chronic pain. PMID- 30464577 TI - Riluzole induces LTD of spinal nociceptive signaling via postsynaptic GluR2 receptors. AB - Purpose: Riluzole - a major therapeutic medicine for patients with amyotrophic lateral sclerosis - reportedly has anti-nociceptive and anti-allodynic efficacies in neuropathic pain models. However, little is known about its effect on neurotransmission in the spinal superficial dorsal horn (SDH). The present study aims to investigate the effects of riluzole on the synaptic transmission of SDH nociceptive pathways in both physiological and pathological conditions. Materials and methods: Spinal nerve ligation was used to produce a neuropathic pain model. Mechanical allodynia behavior was assessed with Von Frey filaments. Riluzole's effects on nociceptive synaptic transmission under both physiological and pathological conditions were examined by patch-clamp recordings in rat SDH neurons. Results: The principal findings of the present study are three-fold. First, we affirm that riluzole has a remarkable long-lasting analgesic effect on both in vitro and in vivo pathological pain models. Second, the prolonged inhibitory effects of riluzole on spinal nociceptive signaling are mediated by both presynaptic and postsynaptic mechanisms. Finally, endocytosis of post synaptic GluR2 contributes to the riluzole-induced long-term depression (LTD) of the spinal nociceptive pathway. Conclusion: The present study finds that riluzole induces LTD of nociceptive signaling in the SDH and produces long-lasting anti allodynia effects in nerve injury-induced neuropathic pain conditions via postsynaptic AMPA receptors associated with the endocytosis of GluR2. PMID- 30464578 TI - Practical management of opioid rotation and equianalgesia. AB - Purpose: To review the recent literature on opioid rotation (ie, switching from one opioid drug to another or changing an opioid's administration route) in cancer patients experiencing severe pain and to develop a novel equianalgesia table for use in routine clinical practice. Methods: The MEDLINE database was searched with terms "cancer pain," "opioid rotation," "opioid switching," "opioid ratio," "opioid conversion ratio," and "opioid equianalgesia" for the major opioids (morphine, oxycodone, fentanyl, and hydromorphone) and the intravenous, subcutaneous, oral, and transdermal administration routes. Selected articles were assessed for the calculated or cited opioid dose ratio, bidirectionality, and use of the oral morphine equivalent daily dose or a direct drug-to-drug ratio. Results: Twenty publications met our selection criteria and were analyzed in detail. We did not find any large-scale, prospective, double-blind randomized controlled trial with robust design, and most of the studies assessed relatively small numbers of patients. Bidirectionality was investigated in seven studies only. Conclusion: The updated equianalgesic table presented here incorporates the latest data and provides information on bidirectionality. Despite the daily use of equianalgesic tables, they are not based on high-level scientific evidence. More clinical research is needed on this topic. PMID- 30464579 TI - Response to duloxetine in patients with knee pain due to osteoarthritis: an exploratory post hoc analysis of a Japanese Phase III randomized study. AB - Purpose: To assess whether patients with knee osteoarthritis pain who have early pain reduction or treatment-related adverse events of special interest (TR-AESIs; constipation, decreased appetite, malaise, nausea, somnolence, thirst) with duloxetine treatment are more likely to have later improvements in pain and quality of life (QOL) relative to placebo than patients without these early indicators. Patients and methods: This was a post hoc analysis of 14-week randomized trial of Japanese patients with knee osteoarthritis pain (Brief Pain Inventory [BPI]-Severity average pain score >=4) receiving duloxetine 60 mg/day (n=177 analyzed) or placebo (n=176). Primary trial outcome was change from baseline in BPI-Severity average pain at Week 14. Subgroups included early pain reduction (>=30%, 10%-30%, or <10% decrease in BPI-Severity average pain at Week 4) and early TR-AESIs (with/without TR-AESIs by Week 2). Measures included changes from baseline in BPI-Severity average pain, QOL (BPI-Interference, Western Ontario and McMaster Universities Osteoarthritis Index), Patient Global Impression of Improvement (PGI-I), and response rate (proportion achieving >=30% or >=50% pain reduction at Week 14). Results: The >=30% early pain reduction subgroup (n=93) had significantly greater improvements in pain, QOL, and PGI-I and higher >=30% and >=50% response rates than placebo; the 10%-30% (n=45) and the <10% (n=33) pain reduction subgroups did not show the same (except 10%-30% group: PGI-I at Week 10 and some QOL at Weeks 10 and/or 14). Both TR-AESI subgroups (with, n=52; without, n=125) had significantly greater improvements in pain, PGI-I, and most QOL measures and higher response rates than placebo. Conclusion: Early efficacy responses to duloxetine treatment, but not early TR AESIs, may predict later pain reduction and QOL improvements in Japanese patients with knee osteoarthritis pain. ClinicalTrialsgov: NCT02248480. PMID- 30464580 TI - Preoperative Modic changes are related to axial symptoms after anterior cervical discectomy and fusion. AB - Background: The objective of this study was to compare the clinical and radiological outcomes between patients with or without axial symptoms (AS) and investigate the risk factors associated with AS by multivariate regression analysis in anterior cervical discectomy and fusion (ACDF). Materials and methods: The records of 117 patients who underwent ACDF were reviewed for clinical and radiological outcomes. These outcomes were evaluated before and after surgery and at the last follow-up. Preoperative Modic changes (MCs) adjacent to the treated disc were identified. Risk factors for AS were detected through logistic regression analysis. Results: The patients were divided into two groups: one with AS (AS group, n=35) and the other without (NAS group, n=82). Visual Analog Scale values after the operation (P=0.013) and at final follow-up (P<0.001) and preoperative segmental angle (P=0.031) were significantly different between the two groups. There were no significant differences with respect to other clinical and radiographic outcomes between the two groups (P>0.05). Logistic regression analysis revealed that preoperative segmental kyphosis (OR =2.912, P=0.035) and MCs (odds ratio =3.268, P=0.015) were the risk factors for the occurrence of AS. Conclusion: AS do not correlate with recovery of neural function in patients treated by ACDF. In addition, preoperative segmental kyphosis and MCs at the fusion segment were found to affect the incidence of AS after ACDF. PMID- 30464581 TI - Which one is more effective for the treatment of very severe osteoporotic vertebral compression fractures: PVP or PKP? AB - Purpose: The purpose of this study was to compare the clinical efficacy and safety of percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP) in the treatment of the elderly with very severe osteoporotic vertebral compression fractures (vsOVCFs). Methods: From September 2012 to September 2015, 57 patients with vsOVCFs who had undergone PVP and PKP surgeries at our medical center were reviewed retrospectively, at least 2 years follow-up. All patients were divided into PVP group (n=31) and PKP group (n=26). Clinical data including clinical and radiological evaluation results were performed pre- and postoperatively. Results: The operation time of PVP group (29.6+/-3.3 minutes) was less than that of PKP group (37.4+/-4.2 minutes), with significant differences (P<0.05). Compared with preoperative data, the VAS scores, Oswestry disability index (ODI) scores, and local kyphotic angle were improved with significant differences at 1 day after surgery and the last follow-up in two groups (P<0.05). However, there were no differences in VAS and ODI scores between the two groups (P>0.05). The local kyphotic angle of PVP group was more than that of PKP group after surgery, with significant differences (P<0.05). At 1 day after surgery and the last follow-up, the anterior height of vertebrae fractured was significantly improved compared with preoperative in PKP group (P<0.05), and there was no statistical difference compared with preoperative in PVP group (P>0.05). However, there were no significant differences between the two groups in the leakage rate of bone cement (P>0.05) and incidence of adjacent-level vertebra fracture (P>0.05). Conclusion: Both PVP and PKP can significantly relieve the pain of the patients with vsOVCFs. Restoring the vertebral height and local kyphotic angle corrections of PKP are comparatively better than those of PVP. However, the operation time of PKP is significantly longer than that of PVP and PKP is not superior in the leakage rate of bone cement and incidence of adjacent-level vertebra fracture compared to PVP. PMID- 30464582 TI - Prolonged-duration pulsed radiofrequency is associated with increased neuronal damage without further antiallodynic effects in neuropathic pain model rats. AB - Aim of investigation: Pulsed radiofrequency (PRF) is a safe and effective approach for treating neuropathic pain. However, the optimal treatment conditions and analgesic mechanisms of PRF remain unclear. The aim of our study was to assess the beneficial and adverse effects of prolonged-duration PRF and the analgesic mechanisms of PRF treatment with neuropathic pain rats. Methods: Male Sprague Dawley rats received L5 spinal nerve ligation (SNL) for developing neuropathic pain. Fourteen days after L5 SNL surgery, they were divided into three groups according to duration of PRF current for 6 minutes, 12 minutes, and none. PRF current was delivered via direct visualization adjacent to the L5 dorsal root ganglion (DRG). Pain behavior was evaluated every week after L5 SNL surgery, until day 28. Seven days after PRF treatment, L5 DRG tissue was harvested to detect levels of activating translation factor 3 (ATF3; a marker of neuronal damage) and hyperpolarization-activated cyclic nucleotide (HCN)-gated cation channels (key factors in neuropathic pain) using quantitative PCR. Results: Before PRF application, withdrawal thresholds were significantly lower than at baseline and did not differ significantly between the three groups. After PRF application, withdrawal thresholds in the PRF6 and PRF12 groups were significantly increased compared to those in the sham group. However, those in the PRF6 and PRF12 groups did not differ significantly. The expression level of ATF3 mRNA in the PRF12 group was significantly higher than that in the sham group (P<0.01), but the expression of HCN1 and HCN2 channels did not differ significantly between the three groups. Conclusion: Prolonged PRF exposure, from 6 to 12 minutes, was not only ineffective but also associated with increased neuronal damage. These findings do not support prolonged PRF exposure as a helpful treatment for neuropathic pain. In this study, the involvement of HCN channels in the antiallodynic effects of PRF was uncertain. PMID- 30464583 TI - Impact of attachment behavior on the treatment process of chronic pain patients. AB - Background: Insecure attachment patterns are related to the onset and development of chronic pain. However, it is less documented on how short- and long-term effects of pain therapy might differ with the attachment style in interaction with specific pain conditions. We therefore examined how two different groups of chronic pain patients differ in their treatment trajectories and in regard to attachment. Method: N=85/76/67 (T1/T2/T3) patients with medically unexplained musculoskeletal pain (UMP group) were compared to n=89/76/56 patients with joint pain from osteoarthritis (OA group), using multilevel modeling. UMP patients received a multimodal pain program, and OA patients received surgery. Pain intensity before (T1) and after (T2) treatment and at a 6 months follow-up (T3) was assessed by using a visual analog scale of pain. Results: Pain patients report a significant reduction in pain intensity upon the completion of the treatment compared to T1. Over the next 6 months, the pain intensity has further declined for patients with low attachment anxiety. In contrast, patients with highly anxious attachment report an increase in pain intensity. This main effect of anxious attachment on pain is significant when predicting changes both in acute treatment and during follow-up while controlling for group effect. In addition, there is also an interactive effect of group by avoidant attachment. In the UMP group, high scores in avoidant attachment were associated with the lower reduction in pain severity, while in the OA group, high scores in attachment avoidance were associated with a steeper reduction in pain severity. Conclusion: The results indicate that insecurely attached patients with pain symptoms only benefit from a multimodal pain therapy in limited ways in regard to posttreatment trajectories. Maintaining positive results over a period of 6 months is a challenge, compared with securely attached patients. Significance: The results of this study suggest the importance of direct and indirect mechanisms of attachment and its relevance for the management of pain experiences. Therefore, to include the individual attachment patterns in the treatment may be a promising way to enhance the treatment prospects. PMID- 30464584 TI - Oxycodone regulates incision-induced activation of neurotrophic factors and receptors in an acute post-surgery pain rat model. AB - Background: Oxycodone, which is one of the most commonly used opiates in postoperative pain management, has a different affinity for MU-opioid receptors (MOR), kappa-opioid receptors (KOR), and delta-opioid receptors (DOR). Accumulating research has suggested that neurotrophins (NTs) are involved in opioid analgesia. In the current exploratory study, we aimed to investigate the underlying mechanisms of the analgesic effects of oxycodone on post-surgery pain in rats and to determine whether neurotrophic factors and receptors were involved in these effects. Methods: Mechanical and thermal sensitivity tests were used to evaluate the validity of the postoperative pain rat model and to determine the analgesic effect of oxycodone. Quantitative PCR and Western blot analysis were used to detect the changes in the expression of three types of opioid receptors and NTs and their high-affinity receptors in the spinal cord after surgery and oxycodone administration. Results: Oxycodone showed an analgesic effect on plantar incision (PI)-induced hyperalgesia, especially thermal hyperalgesia. We detected an obvious increase in MOR expression levels but insignificant changes in KOR and DOR levels in the spinal cord after PI. Moreover, we found that oxycodone was able to reverse the increased expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor (TrK) A, and TrkB and the decreased expression of NT-3 and TrkC, after PI. Pretreatment with oxycodone also altered the expression of these mediators. Conclusion: Based on the results, possible underlying mechanisms for the antinociceptive properties of oxycodone in acute postoperative pain include the activation of MOR downstream signaling and the regulation of NTs and receptor expression through attenuation of glial activation and fortification of antinociceptive mediators in the spinal cord. This study may provide new insights into the molecular mechanisms underlying the analgesic action of oxycodone. PMID- 30464585 TI - Epidural dexmedetomidine infusion for perioperative analgesia in patients undergoing abdominal cancer surgery: randomized trial. AB - Objective: To assess the postoperative analgesic efficacy of epidural dexmedetomidine added to bupivacaine infusion for patients undergoing major abdominal cancer surgery. Methods: Patients scheduled for major upper abdominal cancer surgery were allocated to group bupivacaine (n =32), in which patients received epidural bupivacaine infusion (6 mL/h bupivacaine 0.1%) for 48 hours postoperatively, or group bupivacaine + dexmedetomidine (n=32), in which patients received epidural dexmedetomidine added to bupivacaine infusion (6 mL/h of bupivacaine 0.1% + dexmedetomidine, 0.5 ug/mL) for 48 hours postoperatively. The cumulative morphine consumption, the time to first analgesic request, and the VAS pain score were evaluated. Results: The cumulative morphine consumption was significantly reduced in group bupivacaine + dexmedetomidine compared with group bupivacaine: mean +/- SD of 10.40+/-5.16 mg vs 23.23+/-8.37 mg with an estimated difference (95% CI) of -12.83 (-16.43, -9.24), (P<0.001). The time to the first analgesic demand was significantly delayed in group bupivacaine + dexmedetomidine compared with group bupivacaine: median (IQR) of 6 (1.75, 8.25) h vs 1 (0, 4)h, (P<0.001). The mean collapsed over time of overall VAS pain scores at rest and movement was significantly reduced in group bupivacaine + dexmedetomidine compared with group bupivacaine : mean +/- SE of 1.6+/-0.08 vs 2.38+/-0.08 with an estimated difference (95% CI) of -0.8 (-1, -0.86), (P<0.001), and mean +/- SE of 2.17+/-0.07 vs 3.25+/-0.07 with an estimated difference (95% CI) of -1.1 ( 1.27, - 0.89), (P<0.001), respectively. Conclusion: Epidural infusion of dexmedetomidine added to bupivacaine for patients undergoing major abdominal cancer surgery significantly reduced morphine consumption, delayed time to first analgesic supplementation, and decreased pain intensity during the first 48 hours postoperatively without harmful derangement on hemodynamics. PMID- 30464586 TI - Magnetic resonance imaging analysis of work-related chronic low back pain: comparisons of different lumbar disc patterns. AB - Background: Currently, there is a lack of comparative research about different lumbar disc patterns in patients with work-related chronic low back pain (CLBP) based on magnetic resonance imaging (MRI) analysis. Therefore, this study, on different patterns of lumbar disc degeneration or herniation in patients with CLBP, is valuable. In this study, we retrospectively investigated lumbar degenerative changes in patients with CLBP by using MRI analysis. Materials and methods: Two hundred and eighty-three patients (110 women and 173 men) with work related CLBP were enrolled and divided into four groups based on intervertebral disc morphology from MRI analysis, including normal discs (ND) group, degenerative discs (DD) group, bulging discs (BD) group, and herniated discs (HD) group. Demographic characteristics, occupational information, Visual Analog Scale (VAS) scores, and Oswestry Disability Index (ODI) scores were analyzed. Moreover, multiple parameters were investigated in the MRI analysis. Results: The mean age of all 283 patients was 41.8+/-12.0 years (range, 18-80) and the mean duration of CLBP for all patients was 24.5+/-24.9 months. There were no significant differences in the patients' BMI, history of smoking, and education level (P>0.05). The three most common occupational types were manual worker, desk worker, and technician. The VAS and ODI scores of patients with CLBP in the DD, BD, and HD groups were significantly higher than those of patients in the ND group (P<0.05). The degrees of degeneration of L4/5 and L5/S1 were significantly higher than those of other intervertebral discs (P<0.05). The disc heights of L4/5 in the BD and HD groups were significantly lower than those of the ND group (P<0.05) and the disc height of L5/S1 in the HD group was significantly lower than that of the ND group (P<0.05). At the neutral position, the distances of L3/4, L4/5, and L5/S1 discs' bulge/herniation in the BD and HD groups were significantly higher than those in the ND and DD groups (P<0.05). Conclusion: In summary, more severe degenerative changes of lower lumbar discs (L4/5 and L5/S1) such as higher degree of degeneration of disc, lower disc height, and significant displacement of disc were found in patients with work-related CLBP based on MRI analysis. PMID- 30464587 TI - Activation of spinal nociceptin receptors induces cardiovascular depression and antinociception in an independent manner in mice. AB - Purpose: The nociceptin receptor (NOP) was discovered in 1994 and was designated opioid-like receptor; activation of NOP leads to reduced neuronal excitability. Although suggested by the anatomical localization of NOP in brain or spinal cord, the cardiovascular or nociceptive effects of its endogenous ligand, nociceptin, are equivocal. Taking advantage from intrathecal application of nociceptin to simultaneously activate NOP on sympathetic preganglionic neurons in the intermediolateral column (IML) and superficial laminae of dorsal horn, we investigated whether the nociceptin-induced cardiovascular effects engage the participation of baroreflex, and whether the concurrently elicited changes in blood pressure and pain responses are interrelated. Methods: NOPs in the thoracic spinal cord of ICR or C57BL/6 mice were identified with immunofluorescence staining and were activated through intrathecal administration of nocicetpin. The elicited changes in cardiovascular parameters and tail-flick nociceptive responses were measured. Results: Positive immunoreactivity against NOP colocalized with neurons in the IML and superficial dorsal horn layers of thoracic spinal cord. Intrathecal administration of nociceptin (1, 2, or 5 nmol) elicited a significant and dose-dependent decrease in blood pressure or heart rate that was paralleled by reduced baroreflex-mediated sympathetic vasomotor tone and mirrored by augmented cardiac vagal baroreflex, alongside prolonged tail flick latency with an efficacy of hypotension <<< antinociception. Coadministration of the specific NOP antagonist, UFP101 (10 nmol), blunted all nociceptin-elicited responses. However, restoring blood pressure to baseline level failed to affect the antinociceptive actions of nociceptin. Conclusion: Activation of thoracic spinal NOP in ICR and C57BL/6 mice induces blood pressure and heart rate by decreasing the sympathetic outflow of both arms of the baroreflex arc to the blood vessels and the heart, and the antinociceptive responses to nociceptin are independent of and disproportional to its cardiovascular actions. PMID- 30464588 TI - Caffeic acid phenethyl ester attenuates neuropathic pain by suppressing the p38/NF-kappaB signal pathway in microglia. AB - Background: Management of neuropathic pain is still a clinical challenge. Evidence has accumulated indicating that propolis is effective in attenuating neuropathic pain; however, the mechanism is not fully understood. Our present study investigated the effects and the possible mechanism of caffeic acid phenethyl ester (CAPE), the main ingredient of propolis, in improving neuropathic pain via its inhibition on p38/NF-kappaB signal pathway in microglia. Materials and methods: Chronic constriction injury (CCI) mice model and the microglial cell line BV-2 were used to investigate the effects and the mechanism of CAPE. Cell signaling was measured by real-time PCR, Western blotting and immunofluorescence assay. Results: CAPE relieved neuropathic pain behaviors induced by CCI in mice. CAPE also inhibited CCI-induced activation of microglia. Furthermore, CAPE suppressed the phosphorylation of p38 mitogen-activated protein kinase, inhibited the translocation of NF-kappaB and decreased the expression of proinflammatory cytokines tumor necrosis factor-alpha, IL-1beta and IL-6. Conclusion: CAPE was found to be an effective and safe drug candidate for alleviating neuropathic pain by its powerful inhibition on the P38/NF-kappaB signal pathway. PMID- 30464590 TI - Palliative gastrectomy plus chemotherapy versus chemotherapy alone for incurable advanced gastric cancer: a meta-analysis. AB - Background: Whether palliative gastrectomy combined with chemotherapy can improve the survival of patients with advanced gastric cancer remains controversial. We performed a meta-analysis to clarify whether palliative gastrectomy plus chemotherapy can benefit patients with incurable advanced gastric cancer and to explore the best candidates in this patient population. Methods: We searched the literature systematically using electronic databases including PubMed, EMBASE, and the Cochrane Library. And HRs and their 95% CIs were used to express the results for overall survival (OS) and progression-free survival (PFS). Results: One randomized controlled trial with 175 patients and 12 cohort studies with 2,193 patients were analyzed. The pooled HR for OS (HR=0.43, 95% CI=0.29-0.65, P<0.001), subgroup analysis of stage M1 (HR=0.53, 95% CI=0.40-0.72, P<0.001), peritoneal dissemination (HR=0.46, 95% CI=0.28-0.73, P=0.001), and liver metastasis (HR=0.46, 95% CI=0.33-0.65, P<0.001) all indicated the superiority of palliative gastrectomy plus chemotherapy. However, the pooled HR for PFS (HR=0.61, 95% CI=0.33-1.13, P=0.110) got separate outcome. Conclusion: The results of this meta-analysis indicated that palliative gastrectomy plus chemotherapy can improve OS for incurable advanced gastric cancer. In addition, analyses based on liver metastasis and peritoneal dissemination demonstrated the advantages of palliative gastrectomy plus chemotherapy. However, the PFS of incurable advanced gastric cancer with palliative gastrectomy plus chemotherapy was no better than that under chemotherapy alone. PMID- 30464591 TI - Comparison of the effects of stellate ganglion block and paroxetine on hot flashes and sleep disturbance in breast cancer survivors. AB - Background: The incidence of menopausal symptoms, including hot flashes and sleep disturbance, caused by drug treatment is a common problem in breast cancer survivors. Considering the limitations of hormone therapy in such patients, several studies have been conducted to find alternative methods. The aim of this study was to investigate and compare the effectiveness of stellate ganglion block (SGB) with that of paroxetine, which was approved by the US Food and Drug Administration (FDA) as a medicine for the treatment of hot flashes and ensuing sleep disturbance. Patients and methods: A total of 40 patients survived from breast cancer and complaining of these symptoms were equally assigned to two groups of 20 each. In the study group, SGB was performed successfully under sonography guidance using 10 mL of 0.5% bupivacaine, and in the control group (paroxetine), the daily administration of 7.5 mg of paroxetine was conducted for 6 weeks. The frequency and severity of hot flash attacks and sleep quality of patients were evaluated prior to the intervention and after 2, 4 and 6 weeks. The incidence of adverse events during treatment or follow-up was recorded. Results: A significant decrease in hot flash score and sleep disturbance index (SDI) was observed in both groups. Comparison of the results showed no noticeable difference between the two groups. Two participants in the control group had discontinued medication due to gastrointestinal symptoms, and only one case of mild headache was reported in the study group. Conclusion: SGB is as much effective as paroxetine in controlling hot flashes and sleep disturbances in breast cancer survivors and is associated with few complications. PMID- 30464589 TI - Celecoxib in breast cancer prevention and therapy. AB - Breast cancer has a high incidence worldwide. The results of substantial studis reveal that inflammation plays an important role in the initiation, development, and aggressiveness of many malignancies. The use of celecoxib, a novel NSAID, is repetitively associated with the reduced risk of the occurrence and progression of a number of types of cancer, particularly breast cancer. This observation is also substantiated by various meta-analyses. Clinical trials have been implemented on integration treatment of celecoxib and shown encouraging results. Celecoxib could be treated as a potential candidate for antitumor agent. There are, nonetheless, some unaddressed questions concerning the precise mechanism underlying the anticancer effect of celecoxib as well as its activity against different types of cancer. In this review, we discuss different mechanisms of anticancer effect of celecoxib as well as preclinical/clinical results signifying this beneficial effect. PMID- 30464592 TI - The fluctuating incidence, improved survival of patients with breast cancer, and disparities by age, race, and socioeconomic status by decade, 1981-2010. AB - Purpose: Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer-related deaths among women worldwide. However, the data on breast cancer incidence and survival over a long period, especially the dynamic changes in the role of race and socioeconomic status (SES), are scant. Materials and methods: To evaluate treatment outcomes of patients with breast cancer over the past 3 decades, the data from the Surveillance, Epidemiology, and End Results (SEER) registries were used to assess the survival of patients with breast cancer. Period analysis was used to analyze the incidence and survival trend; survival was evaluated by the relative survival rates (RSRs) and Kaplan-Meier analyses. The HRs for age, race, stage, and SES were assessed by Cox regression. Results: A total of 433,366 patients diagnosed with breast cancer between 1981 and 2010 were identified from the original nine SEER registries. The incidences of breast cancer in each decade were 107.1 per 100,000, 117.5 per 100,000, and 109.8 per 100,000. The 10-year RSRs improved each decade, from 70.8% to 81.5% to 85.6% (P<0.0001). The lower survival in black race and high-poverty group is confirmed by Kaplan-Meier analyses and RSRs. Furthermore, Cox regression analyses demonstrated that age, race, SES, and stage are independent risk factors for patients with breast cancer in each decade. Conclusion: The current data demonstrated a fluctuating incidence trend with improving survival rates of patients with breast cancer over the past 3 decades. In addition, the survival disparity exists among different races, ages, SESs, and stages. PMID- 30464593 TI - Clinicopathological and survival analysis of uterine papillary serous carcinoma: a single institutional review of 106 cases. AB - Objectives: The objectives of this study were to analyze clinicopathological features and to investigate the prognostic determinants in patients with uterine papillary serous carcinoma (UPSC). Materials and methods: A cohort of 106 UPSC patients diagnosed and treated at Peking Union Medical College Hospital between 2000 and 2016 were retrospectively reviewed. The Kaplan-Meier method and Cox regression analysis were used for survival analysis. Differences between categorical data were calculated by using the chi-squared test. Results: The median follow-up was 29.0 months (range =2-170 months), with an overall recurrence rate of 35.8%. The coincidence rate between preoperative endometrial sampling and postoperative definitive pathology of hysteroscopy group was significantly higher than that of the dilation and curettage group (88.5% vs 65.0%, P=0.019). Adjuvant therapy-treated patients with stage I UPSC experienced significantly fewer recurrences than those receiving observation (P=0.003). Patients with advanced-stage UPSC who received combination therapy demonstrated a lower risk of local recurrence compared with those who received chemotherapy alone with a borderline significance (P=0.051). Elevated serum cancer antigen 125 level was associated with advanced-stage disease and recurrence (P<0.001). In multivariate analysis, tumor stage and optimal cytoreduction were independent predictors of survival. In substage analysis, complete surgical staging was associated with better overall survival (OS; yes vs no, HR: 0.05 [95% CI: 0.01 0.51], P=0.037) in patients with stage I UPSC. As for advanced stage, paclitaxel platinum chemotherapy regimen and optimal cytoreduction were independent favorable prognostic factors for progression-free survival (paclitaxel carboplatin [TC] vs other; HR =0.38, P=0.010; yes vs no, HR =0.45, P=0.032) and OS (TC vs other, HR =0.38, P=0.022; yes vs no, HR =0.54, P=0.013). Conclusion: In patients with stage I UPSC, complete staging was associated with better OS, and therefore, it should be performed in all patients. Tumor stage and optimal cytoreduction are the most significant prognostic factors. Recurrence can be improved in stage I patients treated with adjuvant therapy and in patients with advanced-stage disease treated with combined therapy. TC regimen may be the preferred regimen for chemotherapy. PMID- 30464594 TI - Sarcopenia is associated with the neutrophil/lymphocyte and platelet/lymphocyte ratios in operable gastric cancer patients: a prospective study. AB - Purpose: Sarcopenia is distinguished by decreased skeletal muscle plus low muscle strength and/or physical performance. This study was designed to demonstrate the relationship between sarcopenia and systemic inflammatory response (neutrophil/lymphocyte ratio [NLR], platelet/lymphocyte ratio [PLR], and large platelet/lymphocyte ratio [LPLR]) prior to radical gastrectomy for gastric cancer. Patients and methods: We conducted a prospective study of gastric cancer patients who underwent radical gastrectomy. The clinical utility of the NLR, PLR, and LPLR was evaluated by receiver operating characteristic curves. Sarcopenia components including skeletal muscle index, handgrip strength, and 6 m usual gait speed were measured. Logistic analysis was used to identify the independent indices associated with sarcopenia. Results: A total of 670 patients were included, representing 504 men and 166 women. Of these, 104 patients (15.5%) were diagnosed with sarcopenia and 567 (84.5%) were non-sarcopenia. PLR has a diagnostic sensitivity of 91.3% for sarcopenia. In addition to the indicators of preoperative age, nutritional risk screening, body mass index, preoperative albumin, and diabetes, the NLR and PLR were independent predictors for sarcopenia (P<0.05). Conclusion: The present study showed that at-diagnosis sarcopenia was associated with inflammation in patients with operable gastric cancer. Due to the complex assessment of muscle condition, PLR may be used as a primary screening test for sarcopenia. How systemic inflammatory response influences changes in sarcopenia may provide new therapeutic perception toward improving outcomes. PMID- 30464596 TI - The association of XRCC1 polymorphism with osteosarcoma risk, clinicopathologic features, and prognosis in a Chinese Han population. AB - Introduction: The association of single-nucleotide polymorphisms at X-ray repair cross-complementing group-1 (XRCC1) with osteosarcoma (OS) development has not been fully clear to date. The aim of the present study is to evaluate the association of XRCC1 polymorphisms with risk, clinicopathologic features, and prognosis in Chinese OS patients. Methods: A total of 146 patients with primary OS and 248 age- and gender-matched controls were included in the present study. The frequencies of four XRCC1 polymorphisms (rs25487, rs1799782, rs25489, and rs3213245) were determined between OS patients and controls. The association of XRCC1 polymorphism with clinicopathologic characteristics, prognosis, and XRCC1 expression was further evaluated. Results: Compared with TT genotype, individuals carrying the minor C allele (TC+ CC) of rs3213245 had significantly increased risk of OS development (OR =1.83, 95% CI 1.14-3.00). OS patients carrying TC genotype and C allele at rs3213245 were more likely to be with larger tumor size and metastasis. Survival analysis demonstrated that OS patients carrying C allele (TC + CC) at rs3213245 had shorter survival time than those with TT genotype. The T to C substitution at rs3213245 could decrease XRCC1 gene transcriptional activity in vitro. XRCC1 mRNA and protein expression levels were lower in OS patients carrying TC or CC genotype at rs3213245. Besides, no significant association of rs25487, rs1799782, and rs25489 with OS was observed. Conclusion: In conclusion, these findings revealed that XRCC1 rs3213245 polymorphism was associated with increased risk of OS, which could affect XRCC1 expression in vitro and in vivo. PMID- 30464595 TI - Exosomes derived from rAAV/AFP-transfected dendritic cells elicit specific T cell mediated immune responses against hepatocellular carcinoma. AB - Background: Dendritic cell (DC)-derived exosomes (Dexs) have been proved to induce and enhance antigen-specific T cell responses in vivo, and previous clinical trials have shown the feasibility and safety of Dexs in multiple human cancers. However, there is little knowledge on the efficacy of Dexs against hepatocellular carcinoma (HCC) until now. Methods: In this study, human peripheral blood-derived DCs were loaded with recombinant adeno-associated viral vector (rAAV)-carrying alpha-fetoprotein (AFP) gene (rAAV/AFP), and high-purity Dexs were generated. Then naive T cells were stimulated with Dexs to investigate the specific T cell-mediated immune responses against HCC. Results: Our findings showed that Dexs were effective to stimulate naive T cell proliferation and induce T cell activation to become antigen-specific cytotoxic T lymphocytes (CTLs), thereby exhibiting antitumor immune responses against HCC. In addition, Dex-sensitized DC precursors seemed more effective to trigger major histocompatibility complex class I (MHC I)-restricted CTL response and allow DCs to make full use of the minor antigen peptides, thereby maximally activating specific immune responses against HCC. Conclusion: It is concluded that Dexs, which combine the advantages of DCs and cell-free vectors, are promising to completely, or at least in part, replace mature DCs (mDCs) to function as cancer vaccines or natural antitumor adjuvant. PMID- 30464597 TI - Higher autocrine motility factor/glucose-6-phosphate isomerase expression is associated with tumorigenesis and poorer prognosis in gastric cancer. AB - Background: Glucose-6-phosphate isomerase (GPI) is a glycolytic-related enzyme that inter-converts glucose-6-phosphate and fructose-6-phosphate in the cytoplasm. This protein is also secreted into the extracellular matrix by cancer cells and is, therefore, also called autocrine motility factor (AMF). Methods: To clarify the roles of AMF/GPI in gastric cancer (GC), we collected 335 GC tissues and the corresponding adjacent noncancerous tissues, performed immunohistochemical studies, and analyzed the relationship between AMF/GPI expression and the patients' clinicopathologic features. Results: AMF/GPI expression was found to be significantly higher in the GC group than in the corresponding noncancerous tissue group (P<0.001). Additionally, AMF/GPI expression positively associated with a higher TNM stage and poorer prognosis in patients. Through Kaplan-Meier analysis and according to the Oncomine database, we found that AMF/GPI was overexpressed in GC tissues compared to normal mucosa, and the patients with higher AMF/GPI expression had poorer outcomes. We used AMF/GPI-silenced GC cell lines to observe how changes in AMP/GPI affect cellular phenotypes. AMF/GPI knockdown suppressed proliferation, migration, invasion, and glycolysis, and induced apoptosis in GC cells. Conclusion: These findings suggest that AMF/GPI overexpression is involved in carcinogenesis and promotes the aggressive phenotypes of GC cells. PMID- 30464598 TI - Improving risk prediction for pancreatic cancer in symptomatic patients: a Saudi Arabian study. AB - Background: Imaging tests used in our center are usually inadequate to confirm the high risk for pancreatic cancer. We aimed to use a combination of potential predictors including imaging tests to quantify the risk of pancreatic cancer and evaluate its utility. Methods: This was a retrospective cohort study of patients who were suspected as having pancreatic cancer and underwent biopsy examination of pancreatic mass at King Abdulaziz Medical City, Riyadh, Saudi Arabia, between January 1, 2013, and December 31, 2016. We retrieved data on demographics, clinical history, imaging tests, and final pancreatic diagnosis from medical records. Results: Of the 206 who underwent pancreatic biopsies, the mean age was 63.6 years; 54.4% were male. Of all the biopsies, 57.8% were malignant and 42.2% were benign masses. Nine factors contributed significantly to the risk of pancreatic cancer and were noted: older age (adjusted odds ratio [aOR] =1.048; P=0.010), male gender (aOR =4.670; P=0.008), weight loss (aOR =14.810; P=0.001), abdominal pain (aOR =7.053; P=0.0.001), blood clots (aOR =20.787; P=0.014), pancreatitis (aOR =4.473; P=0.021), jaundice (aOR =7.446; P=0.003), persistent fatigue (aOR =22.015; P=0.015), and abnormal imaging tests (aOR =67.124; P=0.001). The model yielded powerful calibration (P=0.953), excellent predictive utility (area under the receiver operating characteristic curve 96.3%; 95% CI =94.1, 98.6), with optimism-corrected area under the curve bootstrap resampling of 94.9%. An optimal cut-off risk probability of 0.513 yielded a sensitivity of 94% and specificity of 84.7% for risk classification. Conclusion: The study developed and validated a risk model for quantifying the risk of pancreatic cancer. Nine characteristics were associated with increased risk of pancreatic cancer. This risk assessment model is feasible and highly sensitive and could be useful to improve screening performance and the decision-making process in clinical settings in Saudi Arabia. PMID- 30464599 TI - Contrast-enhanced ultrasound for the differential diagnosis between benign and metastatic superficial lymph nodes: a meta-analysis. AB - Purpose: Contrast-enhanced ultrasound (CEUS) is a new technique used to distinguish benign from metastatic superficial lymph nodes (LNs) with variable accuracy. The objective of this meta-analysis was to evaluate the accuracy of CEUS for the diagnosis of superficial metastatic LNs. Methods: A comprehensive literature search of PubMed, Web of Science, Medline, Embase, and the Cochrane Library was performed until April 2018. Nine articles reporting the diagnosis of 436 LNs by CEUS were investigated. The Mantel-Haenszel and DerSimonian-Laird methods were used to analyze pooled sensitivity, specificity, diagnostic OR, positive likelihood ratio (LR), and negative LR, and a summary receiver operating characteristic (SROC) curve was also evaluated. Results: The pooled sensitivity and specificity of CEUS for the differential diagnosis of benign and metastatic superficial LNs were 0.88 (95% CI, 0.83-0.92) and 0.80 (95% CI, 0.74-0.85), respectively. The pooled positive LR, negative LR, and diagnostic OR were 4.36 (95% CI, 2.38-7.99), 0.17 (95% CI, 0.10-0.31), and 32.75 (95% CI, 11.08-96.84), respectively. SROC area under the curve (AUC) was 0.9288. The subgroup analysis excluding outliers implied that the heterogeneity was almost eliminated, and the pooled sensitivity and specificity were 0.87 (95% CI, 0.81-0.92) and 0.79 (95% CI, 0.71-0.85), respectively. The SROC AUC was 0.8950. Conclusion: CEUS, a novel imaging modality for the characterization of superficial LNs, shows a high sensitivity and specificity in the diagnosis of superficial metastatic LNs. The different diagnostic standards, contrast agents, and contrast modes contribute to a considerable level of heterogeneity among studies. A uniform standard for distinguishing between benign and metastatic LNs is needed for further clinical application. PMID- 30464600 TI - Overexpression of lncRNA PANDAR predicts adverse prognosis in acute myeloid leukemia. AB - Background and purpose: Abundant studies have shown that lncRNA PANDAR plays an oncogenic role in human solid tumors. Although abnormal expression of PANDAR has been well investigated in solid tumors, it was rarely studied in hematologic diseases. Hence, the aim of this study was to determine the PANDAR expression level and its clinical significance in patients with acute myeloid leukemia (AML). Materials and methods: For detecting the expression level of PANDAR in 119 AML patients and 26 controls, real-time quantitative PCR was used in this study. The prognostic values were evaluated by using Kaplan-Meier analysis, Cox regression analyses, and logistic regression analysis. Results: PANDAR was significantly overexpressed in AML and might be a promising biomarker which could distinguish AML from normal samples (P<0.001). Patients with high expression of PANDAR (PANDAR high) were older and showed higher bone marrow blasts than patients in PANDAR low group (P=0.029 and 0.032, respectively). Significant differences between these groups were also detected regarding risk group and karyotype finding (P=0.009 and 0.041, respectively). Importantly, PANDAR high patients presented a significant lower complete remission rate compared to PANDAR low patients (P<0.001). Furthermore, Kaplan-Meier analysis showed that PANDAR high patients had shorter overall survival compared to PANDAR low patients observing the whole AML cohort, and also in the non-M3 group of patients (P<0.001 and P=0.005, respectively). Multivariate analysis of Cox and logistic regression analysis confirmed that high PANDAR expression was an independent unfavorable risk factor for overall survival and complete remission in both observed patient groups. Conclusion: These results revealed that PANDAR was overexpressed in AML, and that higher PANDAR expression was associated with poor clinical outcome. Our study therefore suggests that PANDAR expression is a promising biomarker for prognostic prediction for AML. PMID- 30464602 TI - Peroxiredoxin 1 silencing inhibited the growth and promoted apoptosis of pancreatic cancer cells via targeting FOXO3 gene. AB - Objective: Our study aimed to investigate the interaction between peroxiredoxin 1 (Prx1) and forkhead box O3 (FOXO3) and to explore the role of PI3K/AKT pathway in the development of pancreatic cancer. Material and methods: Human pancreatic normal cells HPDE6-C7 and pancreatic cancer cells PANC-1 were randomly divided into control group, Prx1-silencing (si-Prx1) group, Prx1/FOXO3 dual-silencing (si Prx1/FOXO3) group, and negative control group. Cell proliferation assay, clone formation assay, and cell apoptosis assay were performed to investigate the effects of Prx1 silencing and FOXO3 silencing on the proliferation and apoptosis ability of pancreatic cancer cells. qRT-PCR and Western blot were performed to study the Prx1 and FOXO3 mRNA in the two cells and FOXO3 protein expression in PANC-1 cells. Result: We found Prx1 silencing could inhibit growth and promote apoptosis of PANC-1 cells. And Prx1 silencing could decrease the Prx1 mRNA level and increase FOXO3 mRNA level. To further explore the role of Prx1 in PI3K/AKT, we study the cell proliferation and apoptosis ability after adding the PI3K inhibitor and PI3K activator. We observed that PI3K inhibitor could inhibit tumor cell growth and promote cell apoptosis. And PI3K inhibitor also downregulated Prx1 protein expression. Conclusion: We concluded that the Prx1 silencing inhibited the growth and promoted apoptosis of pancreatic cancer cells via modulation of PI3K/AKT pathway by targeting FOXO3 gene. PMID- 30464601 TI - Calcium channel alpha2delta1 subunit (CACNA2D1) enhances radioresistance in cancer stem-like cells in non-small cell lung cancer cell lines. AB - Purpose: Radiotherapy is a major treatment method for patients with non-small cell lung cancer (NSCLC). However, the presence of radioresistant cancer stem cells (CSCs) may be associated with disease relapse or a poor outcome after radiotherapy. Voltage-gated calcium channel alpha2delta1 subunit (encoded by the gene CACNA2D1) isoform 5 is a marker of CSCs in hepatocellular carcinoma. This study aimed to investigate the radiosensitivity of alpha2delta1-high cells in NSCLC cell lines. Materials and methods: NSCLC cell lines A549, H1975, H1299, and PC9 were used. CACNA2D1-knockdown and CACNA2D1-overexpressing cell lines were established by lentiviral infection. Colony formation assay was performed to determine radiosensitivity. Sphere formation assay in serum-free medium was performed to evaluate self-renewal capacity. Proteins associated with DNA damage repair were analyzed by immunofluorescence or Western blot. The monoclonal antibody of alpha2delta1 was applied alone or in combination with radiation either in vitro or in vivo to determine the anti-tumor effect of the antibody. Results: alpha2delta1-high cells showed greater sphere-forming efficiency than alpha2delta1-low cells and were relatively resistant to radiation. CACNA2D1 knockdown in A549 cells enhanced radiosensitivity, whereas CACNA2D1 overexpression in PC9 and H1975 cells reduced radiosensitivity, suggesting that alpha2delta1 imparted radioresistance to NSCLC cells. Analysis of proteins involved in DNA damage repair suggested that alpha2delta1 enhanced the efficiency of DNA damage repair. The monoclonal antibody of alpha2delta1 had a synergistic effect with that of radiation to block the self-renewal of alpha2delta1-high cells and enhanced the radiosensitivity of alpha2delta1-positive cells in colony formation assays. The combination of the alpha2delta1 antibody with radiation repressed A549 xenograft growth in vivo. Conclusion: alpha2delta1 enhances radioresistance in cancer stem-like cells in NSCLC. The alpha2delta1 monoclonal antibody sensitizes alpha2delta1-high cells to radiation, suggesting that the antibody may be used to improve the treatment outcome when combined with radiation in NSCLC. PMID- 30464603 TI - Prognostic value of plasma fibrinogen in hepatocellular carcinoma: a meta analysis. AB - Background: Elevated plasma fibrinogen levels have been associated with tumor progression in several malignancies. Our study aims to characterize the clinical significance of elevated plasma fibrinogen levels in patients with hepatocellular carcinoma (HCC). Materials and methods: Relevant published articles were systematically searched in electronic databases including PubMed, Embase, and Web of Science. The pooled differences in plasma fibrinogen levels among HCC, cirrhotic, and control groups were expressed as weighted mean differences (WMDs) and their corresponding 95% CIs. The associations between elevated fibrinogen and overall survival (OS) and disease-free survival (DFS)/recurrence-free survival (RFS) were expressed as HRs and their 95% CIs, whereas the associations between elevated fibrinogen and various types of clinical characteristic of patients with HCC were expressed as ORs and their corresponding 95% CIs. Results: Results showed that the plasma fibrinogen levels in patients with HCC were not significantly different than that in healthy controls (WMD = 0.50, 95% CI = [ 0.82, 1.82], P = 0.457) or patients with cirrhosis (WMD = -0.62, 95% CI = [-1.56, 0.33], P = 0.200). However, our results showed that compared to those with normal levels, patients with HCC and elevated plasma fibrinogen levels showed poorer OS (HR = 2.08, 95% CI = [1.67, 2.59], P < 0.0001) and DFS/RFS (HR = 1.90, 95% CI = [1.52, 2.37], P < 0.0001). Results of trial sequential analysis of the OS indicated that currently available studies were sufficient to validate the negative prognostic value of elevated plasma fibrinogen in patients with HCC. Clinicopathological analyses showed that high plasma fibrinogen levels were associated with tumor progression as indicated by advanced tumor stage, larger tumor size, increased tumor number, and the presence of vascular invasion. Conclusion: Elevated plasma fibrinogen levels are associated with poor prognosis and advanced tumor progression. Plasma fibrinogen may serve as a negative prognostic biomarker in patients with HCC. PMID- 30464604 TI - NSAID consumption and risk of acute myeloid leukemia: a national population-based case-control study. AB - Background: Most cases of acute leukemia arise without identifiable risk factors. Studies investigating the impact of autoimmune diseases and infections on leukemogenesis have revealed conflicting results. If inflammation increases the risk of acute myeloid leukemia (AML), nonsteroidal anti-inflammatory drug (NSAID) use may decrease the risk of leukemia. Methods: We conducted a case-control study of 3,053 patients with AML diagnosed between 2000 and 2013, who were registered in the Danish National Acute Leukemia Registry, and 30,530 population controls matched on sex and age. We identified prescriptions through the Danish National Health Service Prescription Database. We used conditional logistic regression analysis to compute ORs associating AML with NSAID use overall, in patients with inflammatory diseases, and for specific AML subtypes (de novo AML, AML related to previous hematological disease, ie, secondary AML [sAML], or therapy-related AML [tAML; exposed to previous cytotoxic therapy]). Results: Overall, NSAID use was not associated with a lower risk of AML (OR 1.1, 95% CI=1.0-1.2), de novo AML (OR 1.0, 95% CI=0.9-1.1), and sAML/tAML (OR 1.3, 95% CI=1.1-1.5). In addition, in patients with known inflammatory diseases, NSAIDs did not affect AML risk (OR 0.9, 95% CI=0.5-1.6). Number of prescriptions, type of NSAID, age, or sex did not influence the results. Conclusion: In line with our recent findings that showed no association between autoimmune diseases and infections and de novo AML, NSAID use was not found to reduce the risk of AML. PMID- 30464605 TI - Hypofractionated postoperative helical tomotherapy in prostate cancer: a mono institutional report of toxicity and clinical outcomes. AB - Purpose: This is a mono-institutional study of acute and late toxicities and early biochemical control of a retrospective series of 75 prostate cancer patients treated with moderate postoperative hypofractionation delivered by helical tomotherapy (HT). Patients and methods: From April 2013 to June 2017, 75 patients received adjuvant (n=37) or salvage (n=38) treatment, delivering to prostate bed a total dose of 63.8 Gy (equivalent dose in 2-Gy fractions=67.4 Gy) using 2.2 Gy fractions. Whole-pelvis irradiation was performed in 63% of cases (median dose, 49.3 Gy; range, 48-55.1 Gy). Concurrent hormonal therapy was administered in 46% of cases. Common Terminology Criteria for Adverse Events (version 4.0) was adopted for acute and late genitourinary (GU) and gastrointestinal (GI) toxicity evaluations. Biochemical progression was defined as PSA level increase of >=0.2 or more above the postoperative radiotherapy (RT) nadir. Results: Acute GU toxicities were as follows: G1 in 46% and G2 in 4%, detecting no G>=3 events. For GI toxicity, we recorded G1 in 36% and G2 in 18%. With a median follow-up of 30 months (range, 12-58 months), we found late toxicity G2 GI in 6.6% and G>=2 GU in 5.3%, including two patients who underwent surgical incontinence correction. Acute GI>=2 toxicity and diabetes were found to be predictive of late GI>=2 toxicity (P=0.04 and P=0.0019). Actuarial 2- and 3 year biochemical recurrence-free survivals were 88% and 73%, respectively, for the entire population. Conclusion: In our experience, moderate hypofractionated postoperative RT with HT was feasible and safe, with reports of low incidence of toxicity and promising biochemical control rates. PMID- 30464606 TI - Pegaspargase, gemcitabine, dexamethasone, and cisplatin (P-GDP) combined chemotherapy is effective for newly diagnosed extranodal NK/T-cell lymphoma: a retrospective study. AB - Purpose: l-asparaginase or pegaspargase-based chemotherapies have shown promising results in the treatment of extranodal NK/T-cell lymphoma. A retrospective study was conducted to determine the efficacy and safety of pegaspargase, gemcitabine, dexamethasone, and cisplatin (P-GDP) combined chemotherapy in patients with newly diagnosed extranodal NK/T-cell lymphoma. Patients and methods: From September 2013 to November 2016, 57 patients with newly diagnosed, stages I to IV, extranodal NK/T-cell lymphoma received P-GDP chemotherapy. Clinical data from these patients were collected and analyzed to evaluate the efficacy and safety of P-GDP. Results: All patients were subjected to 1-6 cycles of P-GDP chemotherapy, and the median number of cycles of P-GDP regimen administered was 3. The overall response rate was 89.5% (51/57), including a complete response rate of 70.2% (40/59) and a partial response rate of 19.3% (11/57). The median follow-up time was 28 months (range 2-54 months). The 2-year overall survival and progression free survival (PFS) rates were 82.9% and 75.9%, respectively. For stage I/II patients and stage III/IV patients, 2-year PFS were 80.8% and 66.7%, respectively. The most common grade 3/4 adverse events were neutropenia (42.1%), thrombocytopenia (38.6%), and hypofibrinogenemia (26.3%). No treatment-related deaths were observed. Conclusion: P-GDP combination chemotherapy is highly effective and safe for newly diagnosed patients with extranodal NK/T-cell lymphoma, nasal type. Additional large sample prospective trials are required to confirm these results. PMID- 30464607 TI - Knockdown of PRL-3 increases mitochondrial superoxide anion production through transcriptional regulation of RAP1. AB - Background: Phosphatase of regenerating liver-3 (PRL-3) has been shown to be highly expressed in various types of cancers and is related to poor prognosis. Our previous study showed that silencing of PRL-3 leads to increased reactive oxygen species (ROS). However, the mechanism of PRL-3 regulating ROS is not clear. Materials and methods: PRL-3 or Repressor activator protein 1 (RAP1) was knockdown in human colorectal cancer cell lines HCT116 and SW480. The mRNA level was measured by quantitative real-time (qRT)-PCR and the protein level was measured by western blot. ROS was detected by specific oxidationsensitive fluorescent probes. Cell cycle was analyzed through flow cytometry. Luciferase assay and chromatin immunoprecipitation (ChIP) were performed to investigate the regulation of RAP1 by PRL-3. Gene expression correlation was analyzed through an interactive web server. Statistical analysis was performed with SPSS software. Results: Knockdown of PRL-3 significantly increases mitochondrial superoxide anion, mitochondria membrane potential, and induces cell cycle arrest. Decreased PRL-3-induced mitochondrial superoxide anion accumulation is related to the downregulation of RAP1, which could also affect the level of mitochondria superoxide anion. PRL-3 regulates the expression of RAP1 through binding to the promoter of rap1 gene. PRL-3 could regulate the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha) through the mediation of RAP1. Both PRL-3 and RAP1 could regulate the expression of manganese superoxide dismutase 2 (SOD2) and the uncoupling protein 2 (UCP2), which may be related to PRL-3 suppression induced mitochondria superoxide anion. Conclusion: Our study presents the first evidence that PRL-3 is involved in the regulation of mitochondria superoxide anion as a transcriptional factor. PMID- 30464608 TI - Elevated DKK1 expression is an independent unfavorable prognostic indicator of survival in head and neck squamous cell carcinoma. AB - Purpose: DKK1 is an antagonist of the Wnt signaling pathway that has various roles in human physiology. Notably, aberrant DKK1 expression is observed in several cancers. In this retrospective study, we assessed the association between DKK1 expression levels and head and neck squamous cell carcinoma (HNSCC) and its prognostic value. Materials and methods: Using RNA-seq data from HNSCC tumors (N=520) and adjacent normal tissue (N=44) in The Cancer Genome Atlas, we evaluated DKK1 expression levels. Additionally, we evaluated the association of DKK1 expression levels and pathophysiological features of patients with HNSCC and the value of DKK1 expression for prediction of overall survival (OS). We also explored the correlation between DKK1 expression and methylation of its promoter in HNSCC. Results: DKK1 expression was significantly upregulated in HNSCC compared with normal tissues. Moreover, DKK1 expression was significantly associated with smoking, alcohol abuse, sex, human papillomavirus status, tumor site, tumor invasion, and pathologic stage in HNSCC patients. Kaplan-Meier curves showed that high DKK1 expression was correlated with inferior OS. In addition, univariate and multivariate analyses showed that elevated DKK1 expression was an independent prognostic factor for poor OS (HR: 1.85, 95% CI: 1.31-2.62, P<0.001). Regression analysis identified a strong negative correlation between DKK1 expression and methylation of its promoter. Conclusion: These findings support the hypothesis that elevated DKK1 expression is modulated via methylation of its promoter and indicate that DKK1 expression is a highly informative prognostic biomarker for patients with HNSCC. PMID- 30464609 TI - NKAP functions as an oncogene and its expression is induced by CoCl2 treatment in breast cancer via AKT/mTOR signaling pathway. AB - Purpose: NKAP plays an important role in transcriptional repression, T-cell development, maturation and function acquisition, maintenance and survival of hematopoietic stem cells, and RNA splicing. In this study, we tried to explore the physiological role of NKAP in breast cancer. Methods: We investigated NKAP expression in breast cancer patients and normal controls and its correlation with survival in breast cancer patients by searching on GEPIA. We knocked down the expression of NKAP in MCF-7 cells by RNAi technique and studied its effect on cell proliferation, migration, invasion, and apoptosis. And we revealed the effect of NKAP on MCF-7 cells under hypoxic conditions in vitro. Results: NKAP was differentially expressed in breast cancer and normal tissues and is a potential prognostic indicator of breast cancer. Subsequently, NKAP knockdown significantly inhibited the proliferation and clonality of MCF-7 cells and induced its apoptosis through caspase 3-dependent pathway. In addition, knockdown of NKAP could strongly inhibit the migration and invasion of MCF-7 cells. In MCF 7 cells, NKAP affected the AKT/mTOR signaling pathway and markedly reduced the phosphorylation of AKT and mTOR, as well as the downstream protein. What's interesting is CoCl2 was found to induce NKAP expression in MCF-7 cells. Downregulation of NKAP hindered the impact of CoCl2 on the MCF-7 cells, including cell proliferation and invasion, by adjusting AKT/mTOR signaling. Conclusion: NKAP functioned as an oncogene, and its expression was induced by hypoxia in breast cancer via AKT/mTOR signaling pathway. PMID- 30464610 TI - Downregulation of PIM1 regulates glycolysis and suppresses tumor progression in gallbladder cancer. AB - Background: PIM1, a serine/threonine kinase, plays an essential role in tumorigenesis of multiple types of tumors. However, the expression pattern and functions of PIM1 in gallbladder cancer (GBC) remain largely unknown. Materials and methods: Immunohistochemistry, quantitative real-time PCR, and western blot analysis were performed to measure the expression of PIM1. Tissue microarray analysis was used to confirm the relationship between PIM1 expression and clinical outcomes of GBC patients. Finally, in vivo and in vitro functional studies were performed to detect the inhibition of PIM1 by RNAi or specific inhibitor in GBC cells. Results: We observed that PIM1 was dramatically overexpressed in GBC tissues, and its expression levels were positively related with clinical malignancies and a poor prognosis. Inhibition of PIM1 via RNAi or enzyme-specific inhibitor could suppress GBC cell proliferation, migration, and invasion both in vitro and vivo. Additionally, flow cytometry assays and cell cycle assays indicated that PIM1 inhibition promoted cell apoptosis and induced cell cycle arrest. Remarkably, inhibition of PIM1 could drive a metabolic shift from aerobic glycolysis to oxidative phosphorylation. We found that inhibition of PIM1 mechanistically reduced glucose consumption by regulating key molecules in aerobic glycolysis. Conclusion: PIM1 may serve as an oncogene in GBC and be involved in the regulation of glycolysis. PIM1 is a promising therapeutic target for the treatment of human GBC. PMID- 30464611 TI - CCNA2 acts as a novel biomarker in regulating the growth and apoptosis of colorectal cancer. AB - Objective: Colorectal cancer (CRC) is considered to be the most prevalent malignant tumors that contribute to high cancer-related mortality. However, the signaling pathways involved in CRC and CRC-driven genes are largely unknown. We seek to discover a novel biomarker in CRC. Materials and methods: All clinical CRC samples (n=33) were from Xiangya Hospital. We first selected CCNA2 by integrated bioinformatics analysis of four GSE databases. Next, the expression of CCNA2 in tissues and cell lines was verified by quantitative real-time PCR. The effects of CCNA2 on cell growth, proliferation, cell cycle, and apoptosis were examined by in vitro assays. Results: We identified 498 shared DEGs (294 upregulated and 204 downregulated), and the top ten hub genes were selected by integrated analysis. These hub genes were significantly overexpressed in CRC samples and were positively correlated. Our data revealed that the expression of CCNA2 in CRC tissues is higher than that in normal tissues. The CCNA2 knockdown could significantly suppress CRC cell growth by impairing cell cycle progression and inducing cell apoptosis. Conclusion: CCNA2, as a novel oncogenic gene, plays a role in regulating cancer cell growth and apoptosis. It could be used as a new biomarker for diagnosis and therapy in CRC. PMID- 30464613 TI - Downregulation of FOXO6 in breast cancer promotes epithelial-mesenchymal transition and facilitates migration and proliferation of cancer cells. AB - Purpose: Increasing evidence indicates that members of forkhead transcription factor family (FOXO) play key roles in cell proliferation and apoptosis in multiple cancers, including prostate cancer. However, the underlying mechanism of FOXO6 was not yet known. The aim of our work is to investigate the function of FOXO6 in breast cancer. Methods: In the present study, quantitative real-time polymerase chain reaction and Western blotting analyses were used to detect the expression of FOXO6 in breast cancer tissues and cell lines. Results: The results revealed that FOXO6 was downregulated in breast cancer tissues and cell lines, compared with adjacent normal tissues and MCF-10A cells, respectively. Moreover, the expression of FOXO6 was associated with the expression of epithelial mesenchymal transition (EMT) indicator proteins, such as E-cadherin and N cadherin. Additionally, our findings suggested that FOXO6 expression was negatively associated with tumor size (p=0.002), pathological grade (p=0.018) and lymph node metastasis (p=0.003). Sirt6 has been found to promote cell proliferation and metastasis in several cancers, and quantitative chromatin immunoprecipitation and luciferase reporter assays indicated FOXO6 transcriptionally regulated Sirt6 expression. Furthermore, various functional experiments, including wound healing assay, transwell invasion assay, colony formation assay and Cell Counting Kit-8 assay, revealed that FOXO6 suppressed cell migration, invasion, and proliferation of breast cancer cells. Conclusion: In conclusion, FOXO6 serves as a tumor suppressor in breast cancer, and suppresses EMT through regulation of Sirt6. PMID- 30464612 TI - Behavior change techniques for increasing physical activity in cancer survivors: a systematic review and meta-analysis of randomized controlled trials. AB - Purpose: The purpose of this systematic review and meta-analysis is to investigate how physical activity (PA) can be effectively promoted in cancer survivors. The effect of PA-promoting interventions in general, behavior change techniques (BCTs), and further variables as moderators in particular are evaluated. Methods: This study included randomized controlled trials of lifestyle interventions aiming at an increase in PA that can be carried out independently at home, published by December 2016, for adults diagnosed with cancer after completion of the main treatment. Primary outcomes were subjective and objective measures of PA prior to and immediately after the intervention. Meta-analysis and meta-regression were used to estimate effect sizes (ES) in terms of standardized mean differences, variation between ES in terms of heterogeneity indices (I2), and moderator effects in terms of regression coefficients. Results: This study included 30 studies containing 45 ES with an overall significant small positive effect size of 0.28 (95% confidence interval=0.18-0.37) on PA, and I2=54.29%. The BCTs Prompts, Reduce prompts, Graded tasks, Non-specific reward, and Social reward were significantly related to larger effects, while Information about health consequences and Information about emotional consequences, as well as Social comparison were related to smaller ES. The number of BCTs per intervention did not predict PA effects. Interventions based on the Theory of Planned Behavior were associated with smaller ES, and interventions with a home-based setting component were associated with larger ES. Neither the duration of the intervention nor the methodological quality explained differences in ES. Conclusion: Certain BCTs were associated with an increase of PA in cancer survivors. Interventions relying on BCTs congruent with (social) learning theory such as using prompts and rewards could be especially successful in this target group. However, large parts of between-study heterogeneity in ES remained unexplained. Further primary studies should directly compare specific BCTs and their combinations. PMID- 30464614 TI - Laparoscopic right hemicolectomy oriented by superior mesenteric artery for right colon cancer: efficacy evaluation with a match-controlled analysis. AB - Background: Laparoscopic right hemicolectomy (LRC) with a principle of D3 lymphadenectomy seems to be appropriate in treatment of right-sided colon cancer (RCC). This study aimed to evaluate clinical efficacy of superior mesenteric artery (SMA)-guided LRC (SLRC) for RCC patients. Patients and methods: Data for RCC patients with radical resection were retrieved from our database and electronic medical records (January 2010 to December 2014). Patients undergoing SLRC procedure were compared with those undergoing conventional laparoscopic right hemi-colectomy (CLRC), with a match ratio of 1:2 for group balance. Perioperative and long-term outcomes were compared between two groups. Results: In sum, 102 matched patients were selected, with a median follow-up of 32 (range, 3-68) months. The mean operative time was significantly reduced in the SLRC group compared to the CLRC group (206.9 vs 240.0 minutes, P=0.007), with increased incidence of postoperative complications observed (14.7% vs 8.8%, P=0.499). Average length of stay after surgery (7.4 vs 8.0 days), estimated blood loss (85.3 vs 105.4 mL), number of harvested (28.4 vs 28.2) and positive (0.6 vs 0.9) lymph nodes, and overall costs ($4826.9 vs $4874.6) were comparable between two groups (P>0.05). The 3-year disease-free survival rate (89.4% vs 92.1%, P=0.840) and overall survival rate (93.0% vs 83.1%, P=0.273) were similar in both groups. Older age (>=65 years, P=0.049) and advanced tumor stage (>=II, P=0.009) were independent risk factors of recurrence. Conclusion: The perioperative and oncologic outcomes of SLRC were not superior, but comparable to CLRC. SMA-guided dissection was a feasible surgical approach in treatment of RCC. PMID- 30464615 TI - MicroRNA-365 targets multiple oncogenes to inhibit proliferation, invasion, and self-renewal of aggressive endometrial cancer cells. AB - Background: MicroRNA-365 (miR-365) has been reported to be a tumor suppressor miRNA. However, the role of miR-365 in progression of endometrial cancer (EC) has not been explored, in this study, we have found that re-expression of miRNA-365 inhibits cell proliferation, causes apoptosis and senescence. Materials and methods: Overexpression of miR-365 attenuated cell migration and invasion, inhibited sphere-forming capacity, and enhanced the chemosensitivity to paclitaxel. In silico prediction tools identified the potential targets of miR 365. Results: We identified EZH2 and FOS as targets of miR-365 and found that downregulating these genes imitated the tumor suppressive effect of miR-365. The outcomes of the study suggested that a reverse correlation existed between low miR-365 and overexpression of FOS and EZH2 in EC tissue specimens. Conclusion: The study concludes that miR-365 acts as an important tumor suppressor and contributes by suppressing cell invasiveness, proliferation, and self-renewal in cancer cell lines by regulating multiple oncogenes. We establish that miR-365 EZH2/FOS pathway is an important target for treating EC. PMID- 30464616 TI - MicroRNA-588 regulates invasion, migration and epithelial-mesenchymal transition via targeting EIF5A2 pathway in gastric cancer. AB - Background: miRNAs are potential regulators of genes in many cancers. Here, we confirmed that the expression of miR-588 decreased in gastric cancer (GC) tissues and cells. Materials and methods: Sixty-seven GC tissues along with noncancerous tissues adjacent to them were included in the study. Quantitative real-time reverse transcription-PCR study was done to quantify the expression levels of mature miRNA. The expression of proteins was determined by Western blot and transwell chamber assay for invasion and migration studies. Immunohistochemical analysis and luciferase assay were done for evaluating the expression of epithelial-mesenchymal transition (EMT) markers and activity of EIF5A2, respectively. In vivo metastatic assay was done by injecting MGC-803 cells into nude mice. Results: In the 5-year predicted survival study of GC patients included in the study, we found that miR-588 acted as a specific prognostic marker. Overexpression of miR-588 resulted in suppression of cell invasion, migration and progression of EMT, whereas suppression of miR-588 inverted the effects in both in vivo and in vitro experiments. miR-588 retained EIF5A2 by directly binding to the 3'-UTR. EIF5A2 was overexpressed in GC tissue samples, and the expression of miR-588 was inversely correlated to the levels of EIF5A2. The impact of miR-588 on invasion, migration and progression of EMT may be partially due to miR-588-mediated alterations of EiF5A2. Conclusion: Overall, the findings of the study suggest that miR-588 acts as a tumor suppressor by regulating the invasion, migration and EMT via EIF5A2 pathway, hence presenting miR-588 as a prognostic marker as well as a therapeutic target for GC. PMID- 30464617 TI - Interleukin-18 promoter genotype is associated with the risk of nasopharyngeal carcinoma in Taiwan. AB - Background: The incidence rate of nasopharyngeal carcinoma (NPC) has been documented to be high in Southeast Asia. Interleukin-18 (IL-18) is a multifunctional cytokine that augments interferon-gamma production and acts as an important immunomediator in the development of several types of cancer. Patients and methods: This case-control study evaluated the role of IL-18 in NPC at the DNA level by genotyping its promoter polymorphisms at positions -656, -607, and 137 in a Taiwanese population. A total of 176 patients with NPC and age- and gender-matched 352 noncancer controls were included in this study. Results: The CC genotype of the IL-18-607 polymorphism was found to be associated with significantly decreased risks of NPC compared to the AA genotype (crude OR =0.50, 95% CI =0.29-0.84, P=0.0093). This significant difference persisted even in the dominant and recessive models. A significantly lower C allele frequency at position -607 was detected in the NPC group(41.8% vs 50.3%; OR =0.77; 95% CI =0.63-1.04, P=0.0089). Regarding IL-18-656 and -137 polymorphisms, there were no differential distributions of their genotypes between the NPC and control groups. After substratification of the subjects according to their smoking, alcohol consumption, and areca chewing status, the genotype distribution of the IL-18-607 polymorphism was found to be different only among nonsmokers between the NPC and control subgroups. Conclusion: This study suggests that IL-18 plays an important role in the carcinogenesis of NPC in Taiwan and that the genotype-phenotype correlation of IL-18-607 polymorphism and its contribution to NPC need to be investigated further. PMID- 30464618 TI - Genetic variants in lncRNA HOTAIR are associated with lung cancer susceptibility in a Chinese Han population in China: a case-control study. AB - Purpose: HOX transcript antisense RNA (HOTAIR) plays important roles in carcinogenesis of various kinds of malignant tumors, including lung cancer. Single nucleotide polymorphisms (SNPs) in HOTAIR were reported to be associated with susceptibility of several kinds of cancers. The present study assessed the associations between three SNPs (rs4759314, rs12826786, and rs920778) and lung cancer susceptibility, as well as gene-environment interaction between smoking exposure and the polymorphisms. Patients and methods: A case-control study including 551 patients and 543 healthy controls was performed. The associations between SNPs and lung cancer susceptibility were assessed by logistic regression model. Results: rs4759314 was observed to increase the susceptibility of lung cancer, lung adenocarcinoma, squamous lung cancer, and small cell lung cancer statistically significantly (OR of 4.048 for lung cancer; 3.584 for lung adenocarcinoma; 4.671 for squamous lung cancer; 4.502 for small cell lung cancer). In stratified analysis for sex and smoking exposure, rs4759314 GG and AG genotype was also observed to increase the risk of lung cancer statistically significantly (OR of 5.221 for male; 3.491 for female; 3.653 for nonsmoking individuals; 4.458 for smoking individuals). Results of gene-environment interaction analysis showed that there was no interaction between smoking exposure and rs4759314 on additive scale. Results of logistic regression model suggested that the interaction between smoking and rs4759314 was statistically significant on multiplicative scale. rs12826786 CT genotype carriers and T allele could decrease the risk of developing lung cancer (OR of 0.751 for CT carriers; 0.785 for T allele), and in dominant model, TC and TT genotype carriers also have a 0.249-fold decrease risk compared with CC genotype carriers. In stratified analysis for smoking exposure, TC and TT have a 0.432-fold decreased risk compared with CC genotype carriers. Conclusion: HOTAIR rs4759314 and rs12826786 were associated with lung cancer susceptibility in Chinese Han population. PMID- 30464619 TI - ypTNM category combined with AJCC tumor regression grade for screening patients with the worst prognosis after neoadjuvant chemoradiation therapy for locally advanced rectal cancer. AB - Background: The purpose of this study was to investigate the value of the postsurgical pathological T and N (ypTN) category combined with the American Joint Committee on Cancer-tumor regression grade (AJCC-TRG) in evaluating the prognosis of neoadjuvant chemoradiation therapy (NeoCRT) for locally advanced rectal cancer (LARC) to screen for a subgroup of patients with the worst prognosis. Patients and methods: In total, 265 patients with LARC were enrolled in the trial. All patients received NeoCRT. Total mesorectal excision was performed 6-8 weeks after the completion of radiotherapy. The surgical specimens were re-evaluated based on the AJCC-TRG (seventh edition) and the AJCC-tumor-node metastasis (TNM; seventh edition) systems. We followed up these patients and calculated their overall survival (OS), disease-free survival (DFS), local recurrence-free survival (RFS), and distant metastasis (DM)-free survival (MFS) rates through the Kaplan-Meier analysis. The logrank test was further applied to evaluate the predictive value of the ypTN stage combined with AJCC-TRG for several survival indexes. Results: The median follow-up period was 65.1 months. The 5-year OS, DFS, RFS, and MFS rates were 79.4%, 68.8%, 94.4%, and 76.5%, respectively. There were significant differences in OS, DFS, and MFS rates among different ypT+AJCC-TRG and ypN+AJCC-TRG subgroups. The 5-year OS, DFS, and MFS rates for ypT3-4+TRG 1 and ypT3-4+TRG2-3 subgroups were 73.9% vs 65.3%, 61.2% vs 52.9%, and 65.0% vs 61.5%, respectively. The 5-year OS, DFS, and MFS rates for ypN1-2+TRG 0-1 and ypN1-2+TRG2-3 subgroups were 64.8% vs 54.1%, 44.9% vs 41.7%, and 61.4% vs 46.3%, respectively. Conclusion: The ypTNM category combined with the AJCC-TRG can more accurately evaluate the prognosis of patients with LARC and identify the subgroup of patients with the worst prognosis and high risk of developing DM, thereby demonstrating clinical significance in guiding individualized postoperative adjuvant therapy and follow-up for LARC. PMID- 30464620 TI - Radiofrequency ablation with systemic chemotherapy in the treatment of colorectal cancer liver metastasis: a 10-year single-center study. AB - Objective: To retrospectively evaluate the long-term efficacy and safety of radiofrequency ablation (RFA) with systemic chemotherapy (CT) in treatment of solitary liver metastasis after surgery for colorectal cancer (CRC). Methods: This single-center study was conducted at the Hunan Provincial Cancer Hospital from June 2006 to December 2015 with median follow-up time of 26 months. Percutaneous ultrasound-guided RFA was carried out on eligible patients with solitary liver metastasis after surgery for CRC. After a week, ablation status was confirmed by MRI. Post MRI, all patients received systemic CT with or without molecular-targeted therapy. Survival rate was evaluated and survival curve was constructed with Kaplan-Meier analysis. Log-rank test and Cox regression model were used for univariate and multivariate analysis, respectively, to determine the independent prognostic factors for survival rate. Results: A total of 109 eligible patients (mean age, 53.84+/-11.71; mean tumor mass diameter, 3.4+2.01 cm) were enrolled in this 10-year study. After RFA, 95 patients achieved complete ablation, and 14 patients achieved partial ablation, with median ablation time of 26 minutes (range: 12-120 minutes). The median survival time required for achieving complete and partial ablation was 56.0 and 19.0 months, respectively (P<.01). After RFA and adjuvant systemic CT, the 1-, 3-, and 5-year survival rates were 92.3%, 50.7%, and 41.6%, respectively, with the median (mean) survival time of 39.0 (56.5) months. Age was the only significant independent prognostic factor with better survival rate observed in patients aged >=50 years than those aged <50 years (P<0.05). The incidence of complications was minimal (1.8%) with only two cases: one biliary fistula and one liver hemorrhage. Conclusion: RFA combination with systemic CT was safe; it showed long-term efficacy in patients with solitary liver metastasis after surgery for CRC and can be a preferred treatment. PMID- 30464622 TI - Association between matrix-metalloproteinase polymorphisms and prostate cancer risk: a meta-analysis and systematic review. AB - Background: Data from published articles on the relationship between MMP polymorphisms and prostate cancer risk are conflicted and inconclusive, so a meta analysis and systematic review were performed to assess the relationship. Methods: Relevant research articles were identified from databases using a search strategy. Studies with the same MMP polymorphisms that could be quantitatively synthesized were included in the meta-analysis. Five comparison models (homozygote, heterozygote, dominant, recessive, and additive) were applied, and a subgroup analysis by case-group sample type was performed. Studies with different polymorphisms that could not be quantitatively synthesized were included in the systematic review. Results: Eleven articles encompassing 22 studies involving 12 MMP polymorphisms were included in this paper. Among the studies included, 13 studies involving MMP1 rs1799750, MMP2 rs243865, and MMP7 rs11568818 were quantitatively synthesized for meta-analysis, and the other nine studies involving nine polymorphisms (MMP2 rs2285053, MMP2 rs1477017, MMP2 rs17301608, MMP2 rs11639960, MMP3 11715A/6A, MMP3 1161A/G, MMP3 5356A/G, MMP9 rs17576, and MMP13 rs2252070) were included in the systematic review. Meta-analysis showed no associations between MMP1 rs1799750, MMP2 rs243865, or MMP7 rs11568818 and prostate cancer risk overall. Subgroup analysis by case-group sample type confirmed that no associations existed. The systematic review suggested that MMP3 11715A/6A and MMP9 rs17576 were associated with prostate cancer risk. Conclusion: MMP polymorphisms are not associated with prostate cancer risk, except for MMP3 11715A/6A and MMP9 rs17576. However, it is necessary to conduct larger-scale, high-quality studies in future. PMID- 30464621 TI - Transanal total mesorectal excision for low rectal cancer: a case-matched study comparing TaTME versus standard laparoscopic TME. AB - Background: Transanal total mesorectal excision (TaTME) is emerging as a novel alternative to laparoscopic total mesorectal excision (LaTME). The aim of this study was to compare clinical and pathological results from these two techniques in patients undergoing rectal resections because of low rectal cancer. Materials and methods: Thirty-five patients undergoing TaTME were matched with 35 patients operated on using LaTME. Composite primary endpoint (complete TME, negative circumferential resection margin [pCRM], and distal resection margin [pDRM]) was used to assess pathological quality specimens. Secondary outcomes included operative and postoperative parameters (operative time, total blood loss, postoperative morbidity, length of stay, 30-day mortality). Results: Composite primary endpoint was achieved by 85% of subjects in the TaTME group and 82% of subjects in the LaTME group (P=0.66). Mean pCRM was 1.1+/-1.29 vs 0.99+/-0.78 mm (P=0.25). Distal pDRM was 1.57+/-0.92 and 1.98+/-1.22 cm (P=0.15). In the TaTME and LaTME groups, respectively, complete mesorectal excision was achieved in 89% and 83% of subjects, while excision was nearly complete for the remaining 11% and 17% (P=0.23). Conclusion: TaTME appears to be a noninferior alternative to laparoscopic surgery. TaTME allows for quality retrieval of surgical specimens with comparable clinical outcomes with LaTME. PMID- 30464623 TI - Inhibition of long non-coding RNA HOTAIR enhances radiosensitivity via regulating autophagy in pancreatic cancer. AB - Background: Resistance to radiation therapy is still a challenge for treatment of pancreatic cancer(PC). Long non-coding RNAs (lncRNA) HOTAIR has been found to play a oncogenic role in several cancers. However, the correlation between HOTAIR and radiotherapy in PC is still unclear. Methods: TCGA data was collected to analyze the expression of HOTAIR and its relationship with PC progression. A series of functional experiments were conducted to explore the role of HOTAIR in PC radiosensitivity and its underlying molecular mechanisms. Results: By the analysis of the TCGA data, we found HOTAIR expression in PC tissues was significantly higher than normal tissues and associated with tumor progression. The function analysis showed HOTAIR was enriched in biological regulation and response to stimulus. And in vitro study, the expression of HOTAIR was increased in PANC-1 and AsPC-1 cells after radiation. We identified that HOTAIR knockdown could enhance radiosensitivity and influence autophagy by up-regulating ATG7 expression in PC cells. By futher rescue experiments using rapamycin, activation of autophagy could reversed the the inhibition of cell proliferation and colony formation, as well as promotion of apoptosis mediated by HOTAIR knockdown, indicating that HOTAIR knockdown promoted radiosensitivity of PC cells by regulating autophagy. Conclusion: Our finding revealed the the regulatory role of HOTAIR in radiosensitivity and provided a a new sight to improve radiotherapy effciency in PC. PMID- 30464624 TI - Transcatheter arterial chemoembolization monotherapy vs combined transcatheter arterial chemoembolization-percutaneous microwave coagulation therapy for massive hepatocellular carcinoma (>=10 cm). AB - Background: The prognosis of massive hepatocellular carcinomas (MHCCs; >=10 cm) remains worse. Purpose: The aim of this study was to evaluate the clinical benefits of transcatheter arterial chemoembolization (TACE) or TACE combined with percutaneous microwave coagulation therapy (PMCT) and the long-term survival rate of MHCC patients treated with these techniques. Patients and methods: A retrospective study was performed using data involving 102 MHCC patients admitted to the Second Hospital of Nanjing from September 2010 to August 2015. The median interval between treatments and overall survival (OS) was hierarchically analyzed using log-rank tests. Multivariate analysis was done using Cox regression model analysis. Results: The median survival time of MHCC patients was 3 months (range, 1-10 months) in the palliative group, 3 months (range, 1-39 months) in the TACE group, and 7.5 months (range, 3-30 months) in the TACE-PMCT group (P=0.038). The 6-, 12-, and 18-month OS rates for MHCC patients were 15%, 0%, and 0% in the palliative group, 30%, 25.63%, and 17.97% in the TACE group, and 50%, 41.67%, and 16.67% in the TACE-PMCT group, respectively (P=0.0467). In addition, TACE sessions had positive correlation with the survival time of MHCC patients (rho = 0.462, P<0.001). TACE treatment more than three times (HR =0.145, P<0.001) was an independent predictor of the survival of MHCC patients, which was identified by the Cox regression model analysis. Conclusions: These results indicated that TACE PMCT treatment in MHCC patients had advantages in prolonging OS and improving liver function. Multiple TACE treatments might be a suitable treatment for the MHCC patients. PMID- 30464625 TI - Treatment features of systemic chemotherapy in young adults with unresectable advanced or recurrent gastric cancer. AB - Purpose: Gastric cancer in young adults (GCYA) is known to have distinct clinicopathological features, including a female predominance and diffuse-type histology. Previous reports have focused on patients who had undergone gastrectomy with curative intent. Information concerning the treatment of unresectable advanced- or recurrent-stage GCYA is lacking. Therefore, we aimed to investigate whether the distinct clinicopathological features of GCYA affect the outcome of systemic chemotherapy. Patients and methods: We conducted a retrospective cohort study at a single institution in Japan. GCYA was classified as a disease in individuals who were <40 years of age at diagnosis. Initial systemic chemotherapy regimens for GCYA were investigated with a focus on patients who received S-1 plus cisplatin (SP) as a representative standard regimen. The efficacy, safety, and feasibility of systemic chemotherapy were evaluated. Results: Eighty-nine (7.5%) of 1,184 consecutive patients who received systemic chemotherapy at our institute between December 2005 and June 2016 were enrolled. As reported previously, the female sex (57.3%) and diffuse-type histology (91.0%) were the dominant features of GCYA. Thirty-two patients (36.0%) received SP as first-line treatment. The median overall survival and progression free survival times were 13.2 (95.0% CI: 9.5-18.7) and 5.6 (95.0% CI: 4.7-7.9) months, respectively. The median number of treatment cycles, relative dose intensity, and cumulative dose of cisplatin were 4.5 (range: 1-10), 92.0% (IQR: 83.5-98.3), and 286.5 mg/m2 (IQR: 172.5-367.5), respectively. The most common adverse event of Grade 3 or higher was neutropenia (n=5 patients; 15.6%). No patient had febrile neutropenia. Non-hematological adverse events of Grade 3 or higher were only observed in 2 (6.3%) of 32 patients. Conclusion: Standard chemotherapy used for general-aged GC patients has similar efficacy, reduced toxicity, and higher intensity in GCYA patients. PMID- 30464626 TI - Evaluation and prediction of hepatocellular carcinoma prognosis based on molecular classification. AB - Purpose: Prediction of hepatocellular carcinoma (HCC) prognosis faced great difficulty due to tumor heterogeneity. We aimed to identify the prognosis associated molecular subtypes existing in HCC patients and construct an evaluation model based on identified molecular classification. Materials and methods: Non-negative matrix factorization consensus clustering was performed using 371 HCC patients from The Cancer Genome Atlas (TCGA) to identify molecular subtypes, based on the expression profile of the survival-associated genes. Signature genes for different subtypes were identified by Significance Analysis of Microarray and Prediction Analysis for Microarrays. Model for subtype discrimination and prognosis evaluation was established using binary logistic regression. The model and its clinical implications were further validated in GSE5436 cohort and Fujian cohort. Results: Based on TCGA data, we observed two molecular subtypes with distinct clinical outcomes including significantly different overall survival, tumor differentiation, TNM stage, and vascular invasion (all P<0.05). The existence of these two molecular subtypes was further validated in five other Gene Expression Omnibus datasets. Furthermore, we constructed an evaluation model based on six subtype signature genes, which can discriminate different subtypes with the cutoff of 0.385. Meanwhile, both Cox regression analysis and stratification analysis showed that the calculated continuous prognostic value could also effectively indicate HCC prognosis, regardless of patients' clinical conditions. The prognostic evaluation model was successfully validated in GSE54236 cohort and Fujian cohort. Conclusion: Two prognostic molecular subtypes existed among HCC patients, which provided promising strategies for overcoming HCC heterogeneity and could be utilized in future clinical application for predicting HCC prognosis. PMID- 30464627 TI - A novel 12-marker panel of cancer-associated fibroblasts involved in progression of hepatocellular carcinoma. AB - Background/Aim: Cancer-associated fibroblasts (CAFs) are important factors in the progression of hepatocellular carcinoma (HCC). But the characterization of these cells remains incomplete. This study aims to identify a panel of markers for CAFs that are associated with HCC progression. Materials and methods: The sequencing data and clinicopathological characteristics of 366 patients were obtained from the Cancer Genome Atlas (TCGA) database (366 HCC tissues and there were 50/366 cases with corresponding normal liver tissues). In vitro validation of the markers was performed by quantitative real-time PCR using the hepatic stellate cell line LX2 induced by the HCC cell line Huh7. The activation of LX2 was confirmed by alpha-smooth muscle actin and fibroblast activation protein, using quantitative real-time PCR and immunofluorescence staining. In vivo detections of the 12 markers were done in 40 tissue samples (30 HCC and 10 normal). Results: We successfully identified 12 CAF markers from TCGA data: FGF5, CXCL5, IGFL2, MMP1, ADAM32, ADAM18, IGFL1, FGF8, FGF17, FGF19, FGF4, and FGF23. The 12-marker panel was associated with the pathological and clinical progressions of HCC. All 12 markers were upregulated in vitro. In vivo expressions of these markers were paralleled with those in TCGA data. Conclusion: A 12-marker panel of CAFs in HCC is identified, which is associated with both pathological and clinical progressions of cancer. PMID- 30464629 TI - Breast cancer subtypes and the risk of distant metastasis at initial diagnosis: a population-based study. AB - Background: It was unclear whether breast cancer subtypes are associated with the risk of site-specific metastases. This study aimed to evaluate the relationship between molecular subtypes and distant metastatic sites and their prognostic significance. Methods: We identified 295,213 patients with invasive breast cancer from 2010 to 2014 using the Surveillance, Epidemiology and End Results database. Subtypes were classified into four categories: hormone receptor (HR+)/human epidermal growth factor receptor 2 (HER2-), HR+/HER2+, HR-/HER2+, and triple negative (HR-/HER2-). Logistic regression was used to assess the association between metastasis location and subtypes. Multivariate Cox models were used to estimate the overall survival (OS) of related factors. Results: According to our study, 3.28%, 1.52%, 1.20%, and 0.35% of newly diagnosed breast cancers presented bone, lung, liver, and brain metastases at diagnosis, respectively. Both metastatic sites and subtypes significantly affected the OS after metastasis. In multivariate analysis, HR+/HER2+ subtype (OR as compared with HR+/HER2- subtype, 1.30 [95% CI, 1.22-1.39]) significantly correlated with elevated bone metastasis risk, whereas HR-/HER2+ did not. Both HER2+ subtypes (HR+/HER2+ and HR-/HER2+) were significantly associated with higher rates of liver, brain, and lung metastases, while the highest OR was observed in liver metastases. Triple negative tumors had a higher rate of brain (OR, 1.95 [95% CI, 1.61-2.35]), liver (OR, 1.35 [95% CI, 1.20-1.51]), and lung metastases (OR, 1.34 [95% CI, 1.21 1.47]), but a significantly lower rate of bone metastases (OR, 0.64 [95% CI, 0.59 0.69]) than HR+/HER2-tumors. Conclusions: Breast cancer subtypes are associated with different metastatic patterns and confer different prognostic impacts. Molecular subtypes can identify patients at increased risk of site-specific metastases. PMID- 30464628 TI - Diagnostic and prognostic values of the mRNA expression of excision repair cross complementation enzymes in hepatitis B virus-related hepatocellular carcinoma. AB - Background: The current study aims at using the whole genome expression profile chips for systematically investigating the diagnostic and prognostic values of excision repair cross-complementation (ERCC) genes in hepatitis B virus (HBV) related hepatocellular carcinoma (HCC). Materials and methods: Whole genome expression profile chips were obtained from the GSE14520. The receiver-operating characteristic (ROC) curve, survival analysis, and nomogram were used to investigate the diagnostic and prognostic values of ERCC genes. Investigation of the potential function of ERCC8 was carried out by gene set enrichment analysis (GSEA) and genome-wide coexpression analysis. Results: ROC analysis suggests that six ERCC genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, and ERCC8) were dysregulated and may have potential to distinguish between HBV-related HCC tumor and paracancerous tissues (area under the curve of ROC ranged from 0.623 to 0.744). Survival analysis demonstrated that high ERCC8 expression was associated with a significantly decreased risk of recurrence (adjusted P=0.021; HR=0.643; 95% CI=0.442-0.937) and death (adjusted P=0.049; HR=0.631; 95% CI=0.399-0.998) in HBV related HCC. Then, we also developed two nomograms for the HBV-related HCC individualized prognosis predictions. GSEA suggests that the high expression of ERCC8 may have involvement in the energy metabolism biological processes. As the genome-wide coexpression analysis and functional assessment of ERCC8 suggest, those coexpressed genes were significantly enriched in multiple biological processes of DNA damage and repair. Conclusion: The present study indicates that six ERCC genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, and ERCC8) were dysregulated between HBV-related HCC tumor and paracancerous tissues and that the mRNA expression of ERCC8 may serve as a potential biomarker for the HBV-related HCC prognosis. PMID- 30464630 TI - Ki-67 index and percentage of sarcomatoid differentiation were two independent prognostic predictors in sarcomatoid renal cell carcinoma. AB - Purpose: To identify whether and which of pathological features of sarcomatoid differentiation (SD) in renal cell carcinoma (RCC) can be used as independent predictors associated with overall survival (OS). Materials and methods: After institutional review board approval, patients with a diagnosis of sarcomatoid RCC (sRCC), spindled RCC, or RCC with the presence of spindle cells between 2003 and 2017 were further selected and re-examined. The primary pathological features including histological subtypes, tumor necrosis, Ki-67 index of SD, and the percent of SD (%SD) were included into analysis. Histological subtypes were categorized into clear-cell RCC and nonclear-cell RCC. Ki-67 index of SD was confirmed by immunohistochemical staining. %SD was estimated through reviewing all of the tumor sections microscopically and then giving an approximate %SD within the entire tumor. The clinical relevant prognostic predictor's association with OS was analyzed within Cox proportional hazards regression models. Survival curves were generated using the Kaplan-Meier method, and OS differences were compared using the log-rank test. Results: A total of 2,089 consecutive patients of RCC were referred to our department, of whom 62 (3.0%) patients were identified with histological element of SD after re-examining the available slides of suspicious cases. Finally, 53 patients were included into survival analysis after excluding 9 patients without adequate information. Thirty-eight (71.7%) patients died at last follow-up. The median OS for all patients was 11.0 months from the date of surgery. In patients with clinical distant metastasis (cM1), the median OS was only 3 compared with 21 months for patients with no clinical distant metastasis (cM0). Tumor stage, status of clinical distant metastasis, Ki-67 index, and %SD were independent predictors of multivariate analysis in overall 53 patients. However, in the cohort of cM0 patients, we found that only %SD and Ki-67 index were two independent predictors of OS in multivariate analysis. Conclusion: Patients with sRCC are associated with very poor prognosis. Ki-67 index of SD and %SD were identified as the two most important independent predictors particularly for nonmetastatic patients. The limitations of our study were also observed, and further studies are needed. PMID- 30464631 TI - Epigenetic regulation of HOTAIR in advanced chronic myeloid leukemia. AB - Purpose: Chronic myeloid leukemia (CML) accounts for ~10% of leukemia cases, and its progression involves epigenetic gene regulation. This study investigated epigenetic regulation of HOTAIR and its target microRNA, miR-143, in advanced CML. Patients and methods: We first isolated bone marrow mononuclear cells from 70 patients with different phases of CML and from healthy donors as normal control; we also cultured K562 and KCL22 cells, treated with demethylation drug; MTT assay, flow cytometry, quantitative real-time polymerase chain reaction (qPCR), methylation-specific polymerase chain reaction (MSP), Western blot, luciferase assay, RNA pull-down assay and RNA-binding protein immunoprecipitation (RIP) assay were performed. Result: As measured by qPCR, HOTAIR expression in K562 cells, KCL22 cells, and samples from cases of advanced-stage CML increased with levels of several DNA methyltransferases and histone deacetylates, including DNMT1, DNMT3A, HDAC1, EZH2, and LSD1, and miR-143 levels were decreased and HOTAIR levels were increased. Treatment with 5-azacytidine, a DNA methylation inhibitor, decreased DNMT1, DNMT3A, HDAC1, EZH2, LSD1 mRNA, protein levels, and HOTAIR mRNA levels but increased miR-143 levels. HOTAIR knockdown and miR-143 overexpression both inhibited proliferation and promoted apoptosis in KCL22 and K562 cells through the PI3K/AKT pathway. RNA pull-down, mass spectrometry, and RIP assays showed that HOTAIR interacted with EZH2 and LSD1. A dual-luciferase assay demonstrated that HOTAIR interacted with miR-143. Conclusion: Our findings demonstrate the key epigenetic interactions of HOTAIR related to CML progression and suggest HOTAIR as a potential therapeutic target for advanced CML. Furthermore, our results support the use of demethylation drugs as a CML treatment strategy. PMID- 30464632 TI - Chemotherapy combined with dendritic cell vaccine and cytokine-induced killer cells in the treatment of colorectal carcinoma: a meta-analysis. AB - Aim: To investigate the efficacy and safety of dendritic cell (DC) vaccine combined with cytokine-induced killer (CIK) cell therapy in colorectal carcinoma (CRC). Patients and methods: PubMed, Embase, and Cochrane Library databases were searched systematically for clinical trials of DC vaccine and CIK cell therapy combined with chemotherapy for CRC. The primary and secondary endpoints were overall survival (OS) and disease-free survival (DFS), respectively. Pooled risk ratios were used to assess the treatment efficacy. Both random and fixed effects models were used for statistical analysis. The study population consisted of 871 CRC patients enrolled in four trials. Results: OS and DFS were significantly improved in patients who received chemotherapy combined with DC vaccine and CIK cells, and no severe adverse events were shown. Conclusions: The study demonstrated that the addition of DC vaccine and CIK cell therapy to chemotherapy is feasible and effective in patients with CRC. PMID- 30464633 TI - Urine exosome gene expression of cancer-testis antigens for prediction of bladder carcinoma. AB - Background: Exosomes have been regarded as emerging tools for cancer diagnosis. Tumor-derived exosomes contain molecules that enhance cancer progression and affect immune responses. Material and methods: In the present study, we evaluated expression of seven cancer-testis antigens (CTAs) that are regarded as putative biomarkers and immunotherapeutic targets along with NMP22 in urinary exosomes of bladder cancer patients, healthy subjects and patients affected with nonmalignant urinary disorders. Results: Exosomal expression of MAGE-B4 was significantly higher in bladder cancer patients compared with normal samples (expression ratio=2.68, P=0.01). However, its expression was lower in bladder cancer patients compared with benign prostate hyperplasia (BPH) patients (expression ratio=0.17, P=0.01). Exosomal expression of NMP22 was significantly higher in bladder cancer patients compared with BPH patients (expression ratio=9.22, P=0.02). Expressions of other genes were not significantly different between bladder cancer patients and normal/nonmalignant samples. We found significant correlation between MAGE-A3 and MAGE-B4 expressions in exosomes obtained from controls. In addition, TSGA10 expression was correlated with expression of NMP22 in both cancer patients and controls. Conclusion: The present study provides evidences for differential expression of CTAs in urinary exosomes of bladder cancer patients and urogenital disorders and warrants further studies for assessment of their significance in cancer diagnosis and immunotherapeutic approaches. PMID- 30464634 TI - Prognostic impact of lactic dehydrogenase to albumin ratio in hepatocellular carcinoma patients with Child-Pugh I who underwent curative resection: a prognostic nomogram study. AB - Background: Radical resection is the treatment of choice for hepatocellular carcinoma (HCC). However, even with this treatment, HCC prognosis and the efficacy of current predictive models for such patients remain unsatisfactory. Here, we describe an accurate and easy-to-use prognostic index for patients with HCC who have undergone curative resection. Methods: The study population comprised of 1,041 patients with HCC who underwent curative resection at Zhongshan Hospital. This population was reduced to 768 patients who were treated in 2012 analyzed as the training cohort and 273 patients treated in 2007 who were used as a validation cohort. Results: The lactic dehydrogenase to albumin ratio (LAR) was identified as a significant prognostic index for both overall survival and recurrence-free survival in two independent cohorts. The optimal cutoff value for LAR was determined to be 5.5. The C-index of LAR was superior to other inflammatory scores and serum parameters. This biomarker was also shown to be a stable predictive index in the validation cohort. The new nomogram combining LAR with the Barcelona Clinic Liver Cancer staging system had an improved ability to discriminate overall survival and recurrence-free survival. Nomogram predictions were consistent with observations based on calibration and decisive curve analysis in both independent cohorts. Conclusion: LAR is a novel, convenient, reliable, and accurate prognostic predictor in patients with HCC undergoing curative resection. Our results suggest the recommendation of LAR to be used in routine clinical practice. PMID- 30464635 TI - Dietary vitamin B intake and the risk of esophageal cancer: a meta-analysis. AB - Background: Several epidemiology studies have explored the association between dietary B vitamins' intake and the risk of esophageal cancer (EC). However, the results remain inconclusive. Thus, we conducted a systematic review with meta analysis to evaluate such association. Methods: Literature retrieval was performed using PubMed (Medline), ScienceDirect, and Cochrane Library electronic databases for all studies published from database inception to December 2017. Results: The meta-analysis included 19 studies and showed an overall decreased risk of EC (OR=0.77, 95% CI: 0.68-0.87) in association with multivitamin B (ie, B1, B2, B3, B5, B6, B9, and B12) dietary intake. In a subgroup analysis based on vitamin B subclass, B1, B3, B6, and B9 vitamins were associated with decreased EC risk (vitamin B1: OR=0.68, 95% CI: 0.56-0.82; vitamin B3: OR=0.70, 95% CI: 0.53 0.94; vitamin B6: OR=0.64, 95% CI: 0.49-0.83; and vitamin B9: OR=0.69, 95% CI: 0.55-0.86). By contrast, no association was detected between dietary vitamin B2 and vitamin B5 intake and EC risk (vitamin B2: OR=0.86, 95% CI: 0.64-1.16; vitamin B5: OR=0.49, 95% CI: 0.20-1.20), whereas a potential non-linear dose response association was found between dietary vitamin B12 intake and EC risk. A statistically significant, inverse association was observed for an increase of 100 ug/day in supplemental vitamin B6 and B9 and EC risk (vitamin B6: OR=0.98, 95% CI: 0.98-0.99; vitamin B9: OR= 0.89; 95% CI: 0.86-0.94). Conclusion: These findings support that vitamin B may have an influence on carcinogenesis of the esophagus. Vitamin B1, B3, B6, B9 showed a decreased risk of EC, and vitamin B12 showed an increased risk of EC. PMID- 30464636 TI - Association between educational level and cardiovascular disease and all-cause mortality in patients with type 2 diabetes: a prospective study in the Joint Asia Diabetes Evaluation Program. AB - Purpose: The aim of this study was to describe the association between educational level and incident cardiovascular disease (CVD) and all-cause mortality in Hong Kong Chinese patients with type 2 diabetes. Patients and methods: We included 12,634 patients with type 2 diabetes who were enrolled into the Joint Asia Diabetes Evaluation Program between June 1, 2007, and June 30, 2017. We classified patients' educational level into the following three groups: <=6 years, 6-13 years, and >13 years. Incident CVD events were identified using hospital discharge diagnoses. Death was identified from Hong Kong Death Register. We estimated HRs for incident CVD and all-cause mortality using Cox regression models. Results: Patients with the highest educational level were younger and had shorter diabetes duration and better glycemic control at enrollment than those with the lowest educational level. During the median follow-up of 6.2 years for CVD and 6.4 years for all-cause mortality, 954 CVD events and 833 deaths were recorded. HRs for CVD and all-cause mortality were 0.73 (95% CI: 0.57, 0.94) and 0.71 (95% CI: 0.54, 0.94) for the highest educational level compared to the lowest educational level, after adjustment for age, sex, diabetes duration, and family history of diabetes. Conclusion: Educational level is inversely associated with the risk of CVD and all-cause mortality among Hong Kong Chinese patients with type 2 diabetes. Hong Kong Chinese patients with type 2 diabetes and low educational level should be given special attention for the prevention of key complications of diabetes. PMID- 30464637 TI - Oral metronidazole use and risk of acute pancreatitis: a population-based case control study. AB - Objective: Oral metronidazole used in combined regimens for Helicobacter pylori eradication has been associated with an increased risk of acute pancreatitis; however, it is less clear whether a similar association exists for single-regimen metronidazole. We, therefore, examined the association of single and combined regimens of oral metronidazole with risk of acute pancreatitis. Methods: In this population-based case-control study, all individuals in Sweden (aged 40-84 years) hospitalized with acute pancreatitis between January 2006 and December 2008 were identified from a national hospital register (n=5,996). Controls, matched for calendar year, age, and sex, were randomly sampled from a national population register (n=60,681). Data on oral metronidazole and covariates were extracted from national health and prescription registers. Odds ratios (ORs) of acute pancreatitis, according to timing of the latest metronidazole prescription before hospitalization, were estimated using logistic regression models. Confounding by indication was examined by contrasting the main results with the association when amoxicillin was used as exposure. The robustness of results was examined by calculating incidence rate ratios using a self-controlled case series approach. Results: After adjustment for potential confounders, there was a substantially increased risk of acute pancreatitis within 30 days of oral metronidazole exposure, both for single (OR: 4.06; 95% confidence interval [CI]: 1.90-8.64) and combined (OR: 11.80; 95% CI: 6.86-20.28) regimens, compared to nonexposure. In contrast, the adjusted OR was 1.79 (95% CI: 1.25-2.54) for current use of amoxicillin compared to nonexposure. These results were supported by the self controlled cases series analysis (incidence rate ratio: 3.30; 95% CI: 2.69-4.06, for single and combined regimens of oral metronidazole pooled). There was no strong association between oral metronidazole and acute pancreatitis more than 30 days after exposure. Conclusion: There was an increased risk of acute pancreatitis within 30 days of exposure to single and combined regimens of oral metronidazole. While reverse causality and confounding by indication cannot be entirely excluded, they are unlikely to fully explain the association. These results warrant an increased awareness among physicians. PMID- 30464638 TI - Short- and long-term outcomes after postsurgical acute kidney injury requiring dialysis. AB - Objective: Prompt assessment of perioperative complications is critical for the comprehensive care of surgical patients. Acute kidney injury requiring dialysis (AKI-D) is associated with high mortality, yet little is known about how long term outcomes of patients have evolved. The association of AKI-D with postsurgical outcomes has not been well studied. Methods: We investigated patients from the National Health Insurance Research Database and validated by the multicenter Clinical Trial Consortium for Renal Diseases cohort. All patients with AKI-D 18 years or older undergoing four major surgeries (cardiothoracic, esophagus, intestine, and liver) were retrospectively investigated (N=106,573). Patient demographics, surgery type, comorbidities before admission, and postsurgical outcomes, including the in-hospital, 30-day, and long-term mortality together with dialysis dependence were collected. Results: AKI-D is the top risk factor for 30-day and long-term mortality after major surgery. Of 1,664 individuals with AKI-D and 6,656 matched controls, AKI-D during the hospital stay was associated with in-hospital (adjusted hazard ratio [aHR]=3.04, 95% CI 2.79 3.31), 30-day (aHR=3.65, 95% CI 3.37-3.94), and long-term (aHR=3.22, 95% CI 3.01 3.44) mortality. Patients undergoing cardiothoracic surgery (CTS) showed less in hospital (aHR=0.85, 95% CI 0.75-0.97), 30-day (aHR=0.79, 95% CI 0.70-0.89), and long-term (aHR=0.80, 95% CI 0.72-0.90) mortality compared with non-CTS patients with AKI-D. CTS patients had a high risk of 30-day dialysis dependence (subhazard ratio [sHR]=1.67, 95% CI 1.18-2.38), but the risk of long-term dialysis dependence was similar (sHR=1.38, 95% CI 0.96-2.00) after AKI-D by taking mortality as a competing risk. Non-CTS patients had more comorbidities of sepsis, azotemia, hypoalbuminemia, and metabolic acidosis compared with CTS patients. Conclusion: AKI exhibits paramount effects on postsurgical outcomes that extend well beyond discharge from the hospital. The goal of the perioperative assessment should include the reassurance of enhancing renal function recovery among different surgeries, and optimized follow-up is warranted in attenuating the complications after postsurgical AKI has occurred. PMID- 30464639 TI - Maternal depression and antidepressant use during pregnancy and the risk of autism spectrum disorder in offspring. AB - Background: Results of some studies suggest that prenatal antidepressant exposure increases the risk of autism spectrum disorder (ASD) in offspring, while other studies suggest that depression independently increases the risk of having a child with ASD. Thus, confounding by indication is a concern. Objective: The aim of this study was to estimate the risk of ASD in offspring of women who were exposed to antidepressants and/or had depression during pregnancy compared to unexposed women. Materials and methods: We conducted a cohort study with nested sibling case-control analysis. Using the UK Clinical Practice Research Datalink (CPRD), we identified mother- baby pairs where the mother had >=12 months of history before the delivery date and the child had >=3 years of follow-up. Exposures during pregnancy were classified as 1) depression treated with antidepressants, 2) untreated depression, 3) other indications for antidepressant use, and 4) 4:1 match of unexposed women with no history of depression or antidepressant use. We calculated the prevalence of ASD and relative risk (RR) with 95% CI. In the sibling analysis, we compared exposure among ASD cases to that of non-ASD siblings born to the same mother. We calculated ORs and 95% CIs for women with treated and untreated depression, compared to unexposed. Results: We identified 2,154 offspring with ASD among 194,494 mother-baby pairs. Compared to unexposed, the RR of ASD was 1.72 (95% CI 1.54-1.93) for treated depression and 1.50 (95% CI 1.28-1.75) for untreated depression, while the RR was not elevated in women who received antidepressants for other indications (RR =0.73, 95% CI 0.41-1.29). Additional analyses to assess the effects of severity of depression suggest that the risk of ASD in offspring increases with increasing severity, not with the antidepressant treatment. The results of the sibling analysis were similar to the main analysis. Conclusion: Women with depression during pregnancy have an increased risk of having a child with ASD, regardless of antidepressant use. PMID- 30464640 TI - Preparedness and willingness of dental care providers to treat patients with special needs. AB - This study aimed to review the available literature about special needs dentistry, factors affecting treatment of patients with special needs, dental education, and the preparedness and willingness of dental care providers to treat patients with special needs. The study also aimed to assess the validity and reliability of available scales that measure the preparedness of dental care providers to treat patients with special needs. Forty studies from esteemed refereed journals were reviewed in this article. The topics in the study were relevant to special needs dentistry, Saudi Arabia, and dental care providers' perceptions of treating patients with special needs. Reviewed studies were extracted from several electronic databases, such as PubMed and Medline. Studies in Saudi Arabia about special needs dentistry and the preparedness of dental care providers to treat patients with special needs are scarce. Further research in this area needs to be conducted in Saudi Arabia. PMID- 30464641 TI - Profile of bictegravir/emtricitabine/tenofovir alafenamide fixed dose combination and its potential in the treatment of HIV-1 infection: evidence to date. AB - Modern pharmacologic management of people living with HIV involves the use of fixed dose combinations of antiretrovirals that are simple to take, well tolerated, and highly effective. Specific recent pharmacologic advancements include 1) the second-generation integrase strand transfer inhibitors (dolutegravir and bictegravir) that consistently show less side effects, high tolerability, minimal drug interactions, and rapid rates of HIV viral load decline and 2) tenofovir alafenamide, a prodrug of tenofovir that concentrates in lymphoid tissue and minimizes off target effects. Bictegravir/emtricitabine/tenofovir alafenamide or B/F/TAF is a recently approved fixed dose combination that incorporates these new advancements in the management of HIV. This review focuses on the data supporting the use of B/F/TAF, reviews clinically relevant findings, and highlights the unanswered questions that may limit its clinical utility. PMID- 30464642 TI - Dolutegravir/rilpivirine for the treatment of HIV-1 infection. AB - Much progress has been made in the development of antiretroviral therapies (ARTs) for HIV-1 infection. Beginning a little over a decade ago, single tablet combination regimens (STRs) became available, and subsequently, newer STR formulations with improved safety profiles have emerged. Recently, there is a growing interest in regimen simplification with the primary goal of further reducing long-term toxicities of ART and improving medication adherence. Dolutegravir/rilpivirine (DTG/RPV) was approved by the US Food and Drug Administration (FDA) as the first dual antiretroviral STR for the maintenance therapy of HIV-1 infection. Following an extensive review of all published papers on RPV and DTG, administered alone and in combination, extracted from databases including PubMed, Google scholar, and EMBASE, as well as drug package inserts and conference abstracts and proceedings, this review discusses the chemical properties and composition, pharmacodynamics and pharmacokinetic properties, clinical trial efficacy and safety data, as well as important drug-drug interactions associated with DTG/RPV. An expert opinion section discusses ideal candidates for DTG/RPV in the context of available but limited data and in comparison to currently available and emerging ART alternatives. PMID- 30464643 TI - Prevalence of extrapulmonary tuberculosis among people living with HIV/AIDS in sub-Saharan Africa: a systemic review and meta-analysis. AB - Background: The double burden of infectious diseases such as tuberculosis (TB) and HIV disproportionately affects Africa. Our objective was to summarize the prevalence of extrapulmonary TB (EPTB) among people living with HIV/AIDS (PLWHA) in sub-Saharan Africa (SSA). Methods: We searched PubMed and Google Scholar for studies done on the prevalence of EPTB among PLWHA which published in English from 1990 to 2017. We also searched bibliographic indices and browsed through reference lists of articles and journals. We critically appraised the quality of articles and abstracted the data with Joanna Briggs Institute (JBI) checklists. We used Review Manager Software (version 5.3) and Compressive Meta-analysis Software (version 2.2) for analysis. Finally, we summarized the effect estimate by using random-effects model and explored potential sources of heterogeneity by subgroup and sensitivity analyses. We assessed publication bias by funnel plot and statistical test. Finally, we used PRISMA format for reporting. Results: We included, in this review, 31 studies that fulfilled our inclusion criteria, with a total population of 28,659. The prevalence estimate of EPTB among PLWHA ranged from 6.4% (95% CI: 3.8, 9.0) to 36.8% (95% CI: 28.6, 45); random-effects pooled prevalence of EPTB among PLWHA was found to be 20% (95% CI: 17, 22; heterogeneity: tau2=0; chi2=509.09, degrees of freedom [df]=30, P<0.00001; I 2=94%). No evidence of publication bias was observed (P=0.44 for Egger's regression analysis and P=0.11 for Begg's rank correlation analysis). Conclusion: We can conclude from our analyses that the prevalence of EPTB among PLWHA was high. It is necessary to give emphasis for EPTB, especially when screening TB among PLWHA, widening the spectrum of screening to include all EPTB sites in the countries with high EPTB and/or HIV prevalence in the general population. PMID- 30464644 TI - Risk of female athlete triad development in Japanese collegiate athletes is related to sport type and competitive level. AB - Introduction: Menstrual dysfunction, musculoskeletal injury, and poor nutrition combine to form the female athlete triad (FAT), which results in serious health consequences for affected athletes. To this point, the risk factors of this phenomenon have not been fully explored in Japanese female college athletes. Additionally, the effect of competitive level on FAT risk factors has also not been reported. Therefore, we aimed to examine FAT risk factors in Japanese female athletes of various sports as well as examine the impact of competitive level on FAT. Methods: A Japanese-language survey was completed by 531 athletes and 20 nonathletes at two Japanese universities and answers with regard to menstrual status, musculoskeletal injury, nutrition, and other variables were analyzed based on classification of the sports into nine distinct groups based on activity type. Sport intensity, training volume, and competitive levels were used to further classify each sport. One-way ANOVA and the Bonferroni post hoc test using SPSS were carried out to analyze significance for relationships between sport intensity and FAT risk factors. Additionally, the relationship between competitive level and FAT risk factors was analyzed by ANOVA and Bonferroni post hoc tests. Results: Sport intensity was positively correlated with a delay in menarche as well as dysmenorrhea and poor nutrition while musculoskeletal injury was correlated with repetitive, high-training volume sports. Lower competitive levels increased dysmenorrhea but did not impact injury status or nutrition. Conclusion: Sport intensity and training volume, but not competitive level, are the critical factors affecting FAT risk in Japanese female college athletes. PMID- 30464645 TI - Reconstruction of feminine identity: the strategies of women with breast cancer to cope with body image altered. AB - Background: Body image altered is the most important psychosocial concern associated with breast cancer. Yet, there is a paucity of information regarding strategies for coping with this problem. This study aimed to explore Iranian breast cancer women's strategies for coping with body image altered. Methods: This qualitative study was conducted in 2016-2017. A purposive sample of 36 women with breast cancer was selected with maximum variation from three health care centers in Alborz Province, Iran. Data were collected by semi-structured interviews and analyzed by performing conventional qualitative content analysis. Results: The main theme of the study was "reconstruction of feminine identity" with the six main categories of physical appearance improvement, active information seeking, self-care for managing limits, psychological self empowerment, maintaining maternal role, and maintaining wife role. Conclusion: Iranian breast cancer women's strategies for coping with body image altered are multidimensional and are mainly based on personal resources. Breast cancer women use these strategies to reconstruction of their feminine identity. Health policy makers can use the findings of the present study to develop interventions and programs for improving breast cancer women's body image care. PMID- 30464646 TI - A road to obstetric fistula in Malawi: capturing women's perspectives through a framework of three delays. AB - Introduction: Obstetric fistula (OF) is a devastating birth injury, which leaves a woman with leaking urine and/or feces accompanied by bad smell, a situation that has been likened to death itself. The condition is caused by neglected obstructed labor. Many factors underlie fistula formation, most of which are preventable. The main purpose of this study was to explore labor and childbirth experiences of women who developed OF with a focus on accessibility of care in the central region of Malawi. Methods: We conducted semi-structured interviews with 25 women with OF at Bwaila Fistula Care Center in Lilongwe and in its surrounding districts. We interviewed 20 women at Bwaila Fistula Care Center; additional five women were identified through snowball sampling and were interviewed in their homes. Data were categorized using Nvivo 11 and were analyzed using thematic analysis. The three delays model by Thaddeus and Maine was used for data analysis. Findings: The majority of women in our study suffered from OF with their subsequent pregnancies. All women experienced delays in one form or another consistent with the three-phase delays described by Thaddeus and Maine. Most of the participants (16) experienced two delays and 15 experienced second-phase delay, which was always coupled with the other; nine participants experienced delay while at the hospital. None of the participants experienced all three delays. Most decisions to seek health care when labor was complicated were made by mothers-in-law and traditional birth attendants. All but two delivered stillborn babies. Conclusion: Testimonies by women in our study suggest the complexity of the journey to developing fistula. Poverty, illiteracy, inaccessible health facilities, negligence, lack of male involvement in childbirth issues, and shortage of staff together conspire to fistula formation. To prevent new cases of OF in Malawi, the above mentioned issues need to be addressed, more importantly, increasing access to skilled attendance at birth and emergency obstetric care and promoting girls' education to increase their financial autonomy and decision-making power about their reproductive lives. Also men need to be educated and be involved in maternal and women's reproductive health issues to help them make informed decisions when their spouses end up with a complicated labor or delivery. PMID- 30464647 TI - Risk factors for maternal mortality associated with eclampsia presenting at a Nigerian tertiary hospital. AB - Background: Eclampsia remains a leading contributor to maternal mortality, particularly in developing countries, and remains a challenge even to the most experienced obstetrician. We aimed to determine the factors associated with maternal mortality in eclamptics at the Lagos State University Teaching Hospital (LASUTH), Nigeria, in order to suggest ways to prevent this avoidable tragedy. Materials and methods: Data were prospectively collected with the aid of a specially designed proforma from January 1, 2011 to December 31, 2012. Comparison was made between the patients who died (cases) and the survivors (control). Univariate and multivariate analyses were carried out using logistic regression. Results: The case fatality rate was 19.4%. Factors independently associated with mortality were as follows: period between onset of seizures to arrival in LASUTH >12 hours (adjusted OR=22.04; 95% CI=4.62-104.95; P=0.001), vaginal delivery (adjusted OR=10.96; 95% CI=2.54-47.27; P=0.0013), presence of aspiration pneumonitis (adjusted OR=7.77; 95% CI=2.37-25.46; P=0.0007), and presence of renal failure (adjusted OR=7.09; 95% CI=2.14-23.48; P=0.0014). The use of magnesium sulfate reduced the risk of mortality (adjusted OR=0.25; 95% CI=0.09 0.72; P=0.0104). Conclusion: Maternal mortality in patients with eclampsia was associated largely with preventable factors. The use of standard obstetric services, prompt referral of patients for definitive care, and the use of simplified dosing regimen of magnesium sulfate may improve its utilization and also improve maternal outcome. PMID- 30464648 TI - Postsplenectomy Kawasaki disease in a 17-year-old male. AB - Kawasaki disease (KD) is characterized with an acute systemic vasculitis of the medium- and small-sized vessels. This disease mainly involves children within the age of 6 months to 5 years and it is often self-limited and patients seem to recover well; however, it may lead to devastating and fatal cardiovascular complications such as coronary artery aneurysm. Thus, early diagnosis and appropriate management of this disease have a significant effect on improving the prognosis and preventing its serious complications. Adult-onset KD (AKD) is rare and often misdiagnosed. Here we report a rare case of KD that occurred in a 17 year-old young adult who presented 4 weeks post splenectomy, with clinical signs and symptoms consistent with AKD. This may potentially highlight the association of AKD with infectious etiologies. PMID- 30464649 TI - Sympathetic ophthalmia in fellow eye after vitrectomy for massive subretinal hemorrhage secondary to polypoidal choroidal vasculopathy. AB - We experienced a case of sympathetic ophthalmia in a fellow eye after vitrectomy for subretinal hemorrhage related to polypoidal choroidal vasculopathy. A 60-year old male consulted us for polypoidal choroidal vasculopathy with subretinal hemorrhage in his left eye. The recurrence of massive subretinal hemorrhage refractory to repeated pars plana vitrectomies leads to phthisis bulbi. Two months later, multiple serous retinal detachments were observed in his right eye. Positive human leukocyte antigen-DR4 and the uveitis were helpful in distinguishing between sympathetic ophthalmia and age-related macular degeneration. High-dose pulse intravenous steroid contributed to recovery of visual acuity after resolution of serous retinal detachment. PMID- 30464650 TI - Isolated absence of right pulmonary artery in a 4-year old child: a case report. AB - Isolated unilateral absence of the pulmonary artery is a rare anomaly with congenital absence of the left or right pulmonary artery in the absence of other cardiac malformation, and diagnosis is usually made during adolescence. We report a 4-year old male child with isolated absence of the right pulmonary artery, who presented with recurrent chest infection and wheezing since infancy. PMID- 30464651 TI - Congenital saccular cyst of the larynx: a case series. AB - Background: Congenital saccular cyst of the larynx is a very rare cause of respiratory obstruction in the neonatal period and in older children. It can be a potentially life-threatening condition. It can also present less dramatically later in childhood as a voice disorder. Early diagnosis and treatment are very important to avoid the high mortality associated with undiagnosed cases. Subjects and method: I report here two cases of laryngeal saccular cyst with different clinical scenarios. The first patient presented immediately after birth with respiratory problems and the second presented later at an older age. Both patients were managed with endoscopic excision. Conclusion: Congenital saccular laryngeal cyst remains an important cause of respiratory obstruction in the neonate albeit being rare. It is amenable to treatment with minimally invasive procedures. PMID- 30464652 TI - Mixed connective tissue disease complicated by heart failure in Ile-Ife, Nigeria: management challenges in a resource-limited economy. AB - Background: Mixed connective tissue disease (MCTD; also known as Sharp's syndrome) is a rare autoimmune inflammatory disorder characterized by high titer of U1 ribonucleoprotein (U1RNP) antibody and clinical and serological overlap of systemic lupus erythematosus, systemic sclerosis, and polymyositis. The diagnosis is based on clinical and serological factors in criteria such as Alarcon-Segovia, Khan, Kusakawa, and Sharps. Cardiac disease can be a complication of connective tissue disease (CTD). There are few reports in Africa. Aims: To present MCTD as underlying cause of heart failure with reduced ejection fraction and highlight challenges of investigations and treatment. Objectives: To highlight the first case in our center and discuss the cardiac, respiratory, and rheumatologic management. Patient and methods: We present a 52-year-old woman with 3 weeks history of productive cough with whitish sputum, severe dyspnea, orthopnea, paroxysmal nocturnal dyspnea, right sided abdominal pain, leg swellings, a one year history of recurrent fever, Raynaud's phenomenon, small joint swellings and deformities with pain in both hands. Results: On examination there was microstomia, tethered forehead and lower eyelid skin, tender swelling of the interphalangeal joints and arthritis mutilans. Laboratory findings showed estimated glomerular filtration rate <60 mL/kg/min/1.73 m2, U1RNP antibody levels were eight times upper limit of normal, elevated rheumatoid factor, speckled antinuclear antibody pattern, negative anticentromere antibody, anti Scl-70 and anticyclic citrullinated peptide. Chest X-ray/CT revealed pulmonary fibrosis. Echocardiography findings showed reduced ejection fraction of 40%, elevated pulmonary arterial pressure at rest of 60.16 mmHg. The patient showed improvement on antifailure drugs, but prednisolone was stopped for sudden reversal of previously controlled stage 2 hypertension (HTN), and the patient was discharged in a stable condition. Difficulties ensued in obtaining prompt definite results due to the unavailability of serologic tests in the hospital, and the tests were done outside the state and country. Conclusion: Identifying MCTD is critical, especially in patients requiring steroids that may worsen systemic HTN and heart failure. There is a need to have definitive investigative facilities for such patients in hospitals. PMID- 30464653 TI - Porous titanium-coated polyetheretherketone implants exhibit an improved bone implant interface: an in vitro and in vivo biochemical, biomechanical, and histological study. AB - Purpose: Spinal interbody fusion cages are designed to provide immediate stabilization for adjoining vertebrae and ideally enable bony ingrowth to achieve successful integration. For such an implant, cells must be able to attach, move, grow, and differentiate on its surface. These cellular interactions are dependent on how the implant surface enables the coating and binding of blood and tissue fluid proteins that support cell adhesion. The purpose of this study was to evaluate the in vitro and in vivo osteoblast cell-implant surface interactions that result in osseointegration onto a surface composed of plasma-sprayed titanium on a polyetheretherketone (PEEK) substrate or titanium-coated PEEK (Ti PEEK) (PlasmaporeXP(r)) as compared to uncoated PEEK implants. Materials and methods: The influence of the Ti-PEEK surface modification on the biochemical, biomechanical, and histological properties at the bone-implant interface is demonstrated both in vitro using simulated bone-forming cell culture experiments and in vivo using a 12- and 24-week ovine implant model. Results: Osteoblast-like cells attached to the Ti-PEEK surface upregulated early bone-forming activity as measured by an increase in transcription and translation of ALP and BMP-2 when compared to cells on PEEK. Similarly, a significant increase in new bone formation, bony apposition, and pullout strength was demonstrated on Ti-PEEK implants when compared to PEEK implants at 12 and 24 weeks in an ovine implant in vivo model. Conclusion: The study shows that the Ti-PEEK surface demonstrated enhanced osseointegrative properties compared to PEEK both in vitro and in vivo. PMID- 30464654 TI - Potential mortality and cost reduction in adult severe sepsis and septic shock through the use of an innovative fluid delivery device. AB - Background: While early fluid resuscitation has been shown to significantly improve health and economic metrics in septic shock, providers are often unable to achieve fluid delivery guidelines using current techniques. Purpose: To examine expected clinical and economic consequences of more consistent achievement of fluid resuscitation guidelines through use of a novel fluid delivery technology. Patients and methods: A decision analytic model was developed to compare expected costs and outcomes associated with the standard technique vs a novel, faster technique for rapid fluid resuscitation in adult patients with severe sepsis or septic shock. Results: Use of an innovative fluid delivery device (LifeFlow) resulted in lower expected mortality compared to standard intravenous fluid delivery methods (reduction of 10 fewer deaths per 500 cases). Compared to standard methods, use of the innovative rapid fluid delivery device also resulted in lower expected hospital costs (US$1,569,131 cost reduction per 500 cases), a lower required use of mechanical ventilation (24% vs 31%), decreased average length of stay (11 vs 13 days), decreased average intensive care unit length of stay (2 vs 3 days), and decreased use of vasopressors (17% vs 21%). A sensitivity analysis showed that utilization of the rapid fluid delivery device is more cost-effective than standard methods, even under the most conservative assumptions. Conclusion: Based on existing data supporting the importance of early, controlled fluid resuscitation in septic shock patients, the analytical model developed in this study demonstrated the benefit of a novel device that facilitates earlier fluid bolus completion and better adherence to sepsis bundles. PMID- 30464655 TI - Temporomandibular joint dislocation: a retrospective study from a Swiss urban emergency department. AB - Purpose: Temporomandibular joint (TMJ) dislocation is an uncommon and debilitating condition of the facial skeleton. The condition may be traumatic or nontraumatic, in an acute or chronic form, and with bilateral or monolateral expression. Patients and methods: In this study, conducted from May 2012 to July 2016, we retrospectively analyzed TMJ dislocations treated in the Department of Emergency Medicine, Inselspital, University Hospital Bern, University of Bern, by focusing on the following parameters: age, gender, reason, localization, frequency, and therapy. Results: Thirty-two patients were included. The mean age was 42.06 years and there was no predominant gender. Most cases of TMJ dislocation were nontraumatic (93.7%). Dislocations were mostly bilateral (59.4%) and appeared in a chronic situation and with repetitive events (62.5%). Thirty one patients received conservative treatment, which consists of reposition of the TMJ with (38.7%) or without (61.3%) analgosedation. Only one patient needed surgical reposition due to previous surgical treatment. Conclusion: This is the first attempt to evaluate TMJ dislocations in Switzerland in an acute hospital setting. To our knowledge, there are no other studies that systematically analyze these injuries by focusing on the patients' characteristics. Surgical reposition is only indicated in complicated and very rare situations. Conservative approaches are commonly used and should be exhausted before any surgery. PMID- 30464656 TI - Chronic lateral epicondylitis: challenges and solutions. AB - Lateral epicondylitis (LE) is a significant source of pain and dysfunction resulting from repetitive gripping or wrist extension, radial deviation, and/or forearm supination. Although most cases are self-limiting over several years, controversy exists regarding the best treatment strategy for chronic LE. Nonsteroidal anti-inflammatory drugs (NSAIDs), physical therapy (PT), shockwave therapy, and injections with corticosteroids or biologics are all conservative treatment options for LE. For refractory cases, surgical options include open, arthroscopic, and percutaneous techniques. In this review, the current evidence behind these treatment strategies is presented. The data demonstrate that NSAIDs, PT, bracing, and shockwave therapy provide limited benefit for treating LE. Biologics such as platelet-rich plasma and autologous whole-blood injections may be superior to steroid injections in the long-term management of LE. Although the initial results are promising, larger comparative studies on stem cell injections are needed. For refractory LE, open, arthroscopic, and percutaneous techniques are all highly effective, with no method seemingly superior over another. Arthroscopic and percutaneous approaches may result in faster recovery and earlier return to work. PMID- 30464657 TI - Factors associated with life satisfaction among married women in rural China: a cross-sectional study based on large-scale samples. AB - Purpose: The living environment in rural China may predispose individuals there to low life satisfaction (LS). This study aims to evaluate factors that affect LS among married women in rural China. Materials and methods: This cross-sectional study was conducted in rural Liaoning Province in China, in 2015. Out of 3,900 married women, 3,385 (86.8%) completed a questionnaire survey. LS was assessed using the Satisfaction with Life Scale (SWLS), with 35 as the maximal possible score. Stress (quantified by the Perceived Stress Scale [PSS]), resilience (assessed by the Ego-Resiliency Scale [ERS]), and demographic and living/health conditions factors were collected through self-reported questionnaires. Hierarchical multiple regression and structural equation modeling were used to explore the contributing and mediating factors related to LS. Results: The overall LS score was 18.94+/-4.96. A younger age, lower monthly income, presence of chronic diseases, left-behind status, and sense of marriage insecurity were negatively associated with LS. Perceived stress was a strong predictor of LS, as it explained 19.7% of the variance. Higher levels of resilience were related to higher levels of LS, explaining 15.4% of the variance. Resilience partially mediated the relationship between stress and LS for rural residents in China. Conclusion: Overall, married women living in rural China experienced a relatively low level of LS. The construction of additional recreational facilities, provision of convenient access to medical information, facilitation of communication between couples, reduction of stress, and development of resilience could all be beneficial intervention strategies to improve LS for these rural residents. PMID- 30464658 TI - Stigma toward people with mental health problems in Indonesia. AB - Introduction: Mental health problems are serious issues in Indonesia. The prevalence of severe mental disorder in Indonesian population is 1.70/00. In community, people with mental disorder are often stigmatized, while in fact this stigmatization could negatively impact them. One of the most common form of discrimination toward people with mental disorder is the practice of pasung. Method: This research conducted a survey study on 1,269 respondents in East Java (in which the prevalence of severe mental disorder is 2.20/00). The instruments used were Community Attitudes towards Mental Illness (CAMI), Mental Health Knowledge Schedule (MAKS), and a sociodemographic questionnaire. Result: The result shows that better knowledge about mental health was associated with lower public stigma toward people with mental disorder. Significance differences in stigma toward people with mental illness were also found across groups of age, sex, experience of contact, history of mental disorder, attitude toward pasung, marital status, and income level. Conclusion: The finding implies that anti stigma interventions in Indonesia should consider associated sociodemographic factors and use psychosocial approach to improve literacy and contact with mental health patients. PMID- 30464659 TI - Perceived threat and benefit toward community compliance of filariasis' mass drug administration in Pekalongan district, Indonesia. AB - Purpose: Lymphatic filariasis (LF) is a chronic infection of Brugia malayi, Brugia timori, and Wuchereria bancrofti and is a mosquito-transmitted disease. Mass drug administration (MDA) needs to be done annually to control LF and requires adherence of endemic populations to take medication properly. Maintaining high coverage of MDA is a challenge because the activity needs to be done in several years. This study would like to know the compliance of the community in taking medication during MDA periods in Pekalongan district using the health belief model (HBM) approach. Patients and methods: Study population was people living in endemic areas in Pekalongan district, Central Java Province. This was a cross-sectional study. HBM approach was used to analyze community perceived in regard to MDA. There were six of the 19 subdistrict selected as study location, and 100 subjects were selected from each sub-district. Therefore, a total of 600 subjects participated in this study. Data were collected using the structured questionnaire. Data were analyzed quantitatively using the Chi-squared test. Multivariate analysis was used for logistic regression. Results: Results of this study showed that the mean age of subjects was 38.6 years and had been staying in their villages for more than 30 years. Gender, marital status, history of LF, history of LF in the family, and external cues to action did not relate to MDA compliance. Perceived susceptibility, perceived severity, perceived benefits, and perceived barriers were factors related to the compliance of MDA. After multivariate analysis, the perceived susceptibility did not have relationship with compliance. Conclusion: This study showed HBM variables, ie, perceived susceptibility, perceived severity, perceived benefit, and perceived barrier associated with the medication adherence of LF. The role of elimination officers was important to increase community knowledge about MDA program and the benefit to control LF disease. PMID- 30464660 TI - Associations between structures and resources of primary care at the district level and health outcomes: a case study of diabetes mellitus care in Thailand. AB - Background: The structural factors of primary care potentially influence its performance and quality. This study investigated the association between structural factors, including available primary care resources and health outcomes, by using diabetes-related ambulatory care sensitive conditions hospitalizations under the Universal Coverage Scheme in Thailand. Methods: A 2 year panel study used secondary data compiled at the district level. Administrative claim data from 838 districts during the 2014-2015 fiscal years from the National Health Security Office were used to analyze overall diabetes mellitus (DM) hospitalizations and its three subgroups: hospitalizations for uncontrolled diabetes, short-term complications, and long-term complications. Primary care structural data were obtained from the Ministry of Public Health. Generalized estimating equations were used to estimate the influence of structural factors on the age-standardized DM hospitalization ratio. Results: A higher overall DM and uncontrolled diabetes hospitalization ratio was related to an increasing concentration of outpatient utilization (using the Herfindahl Hirschman Index) (overall DM; beta [standard error, SE]=0.003 [0.001], 95% CI 0.000, 0.006) and decreasing physician density and bed supply (overall DM; beta [SE]=-1.350 [0.674], 95% CI -2.671, -0.028), beta [SE]=-0.023 [0.011], 95% CI 0.045, -0.001, respectively). Hospitalizations for short-term complications increased with a decrease in health care facility density, whereas hospitalizations for long-term complications increased as that density increased. Rurality was strongly associated with higher hospitalization ratios for all DM hospitalizations except short-term complications. Conclusions: This study identified structural factors associated with health outcomes, many of which can be changed through reorganization at the district level. PMID- 30464661 TI - The evolving Semashko model of primary health care: the case of the Russian Federation. AB - This paper addresses the major developments in primary care in the Russian Federation under the evolving Semashko model. The overview of the original model and its current version indicates some positive characteristics, including the financial accessibility of care, focus on prevention, patient lists, and gatekeeping by primary-care providers. However, in practice these characteristics do not work according to expectations. The current primary-care system is inefficient and has low quality of care by international standards. The major reasons for the gap between the positive characteristics of the model and the actual developments are discussed, including the excessive specialization of primary care, weak health-workforce policy, the delay in the shift to a general practitioner model, and the dominance of the multispecialty polyclinic, which does not prove advantageous over alternative models. Government attempts to strengthen primary care cover a wide range of activities, but they are not enough to improve the system and cannot do this without more a systematic and consistent approach. The major lesson learnt is that the lack of generalists and coordination cannot be compensated for by the growing number of specialists in the staff of primary-care facilities. Big multispecialty settings (polyclinics in the Russian context) have the potential for more integrated service delivery, but to make it happen, action is needed. Simple decisions, like merging polyclinics, do not help much. PMID- 30464662 TI - Impact of seasons on an individual's chronotype: current perspectives. AB - Diurnal preference, or chronotype, determined partly by genetics and modified by age, activity, and the environment, defines the time of day at which one feels at his/her best, when one feels sleepy, and when one would prefer to start his/her day. Chronotype affects the phase relationship of an individual's circadian clock with the environment such that morning types have earlier-phased circadian rhythms than evening types. The phases of circadian rhythms are synchronized to the environment on a daily basis, undergoing minor adjustments of phase each day. Light is the most potent time cue for phase-shifting circadian rhythms, but the timing and amount of solar irradiation vary dynamically with season, especially with increasing distance from the equator. There is evidence that chronotype is modified by seasonal change, most likely due to the changes in the light environment, but interindividual differences in photoperiod responsiveness mean that some people are more affected than others. Differences in circadian light sensitivity due to endogenous biological reasons and/or previous light history are responsible for the natural variation in photoperiod responsiveness. Modern lifestyles that include access to artificial light at night, temperature controlled environments, and spending much less time outdoors offer a buffer to the environmental changes of the seasons and may contribute to humans becoming less responsive to seasons. PMID- 30464663 TI - Relationships between sleep paralysis and sleep quality: current insights. AB - Sleep paralysis is the unusual experience of waking up in the night without the ability to move. Currently little is known about the experience, despite the fact that the vast majority of episodes are associated with extreme fear and in a minority of cases can lead to clinically significant levels of distress. The aim of this work was to review the existing literature pertaining to the relationship sleep paralysis has to sleep more generally, measured both with subjective questionnaires and objective laboratory recordings. In terms of subjective sleep variables, worse sleep quality has been found in multiple studies to be associated with increased odds of sleep paralysis occurrence. In addition, insomnia symptoms (but not a diagnosed insomnia disorder) have also been found to predict sleep paralysis. Associations between sleep paralysis and other unusual and/or threatening sleep experiences such as nightmares, exploding head syndrome, and lucid dreaming have been reported. In terms of objective measurements, the limited literature to date shows sleep paralysis to be a "mixed" state of consciousness, combining elements of rapid eye movement sleep with elements of wakefulness. Future research needs to focus on longitudinal designs to disentangle the direction of effects and more typically employ a broader assessment of sleep paralysis that better captures associated features such as hallucinations, fear, and distress. PMID- 30464664 TI - Sleep disturbances in patients with liver cirrhosis: prevalence, impact, and management challenges. AB - Sleep-wake disturbances are common in liver cirrhosis and associated with impaired quality of life. The most common abnormalities are insomnia (difficulties falling asleep and maintaining sleep, or unrefreshing sleep), excessive daytime sleepiness, and sleep-wake inversion (disturbances of circadian rhythmicity). The underlying pathophysiological mechanisms for sleep disturbances in cirrhosis are complex and may include disturbed metabolism of melatonin and glucose, alterations in thermoregulation, and altered ghrelin secretion profiles. Sleep-wake abnormalities are related to the presence of hepatic encephalopathy (HE) and improvement in sleep parameters can be observed when HE is properly managed. A few non-specific treatments for sleep-wake abnormalities have been tried with encouraging results for hydroxyzine and modafinil. However, due to the potential for medication toxicity in these disabled patients, further studies are needed to address the potential role of non-drug therapies in this population (eg, cognitive behavioral therapy, mindfulness, yoga) that have demonstrated usefulness in insomnia disorders. PMID- 30464665 TI - The DSM-5 Self-Rated Level 1 Cross-Cutting Symptom Measure identifies high levels of coexistent psychiatric symptomatology in patients referred for insomnia treatment. AB - Purpose: Referrals to sleep psychology services, even for a perceived single problem such as insomnia, can present with complex, coexistent psychiatric symptoms and comorbid disorders. This study aimed to assess the feasibility of implementing the DSM-5 Self-Rated Level 1 Cross-Cutting Symptom Measure (CCSM) into a sleep psychology clinic to identify coexistent psychiatric symptomatology in insomnia referrals. Patients and methods: Patients were 50 consecutive referrals to a private sleep psychology service within a sleep disorders center in Melbourne, Australia. Patients who attended sleep psychology services between June 2015 and January 2017 had their clinical records reviewed. Basic demographic information, comorbidities, and responses to the Insomnia Severity Index were gathered. The Diagnostic and Statistical Manual of Mental Disorders Ed. 5 Task Force and Work Groups created the CCSM in 2013 to deal with the issue of coexistent psychiatric symptomatology across mental health conditions, and this measure was included into the sleep psychology intake procedure and patient responses were reviewed. Results: The CCSM was simple and quick to administer and score and revealed high levels of psychiatric symptomatology in sleep psychology referrals. Sleep problems were the most common domain of psychiatric symptomatology reported (86%). Anxiety (66%), depression (64%), anger (64%), and somatic symptoms (50%) were also very common. Suicidal ideation was acknowledged by 26% of patients. In addition, 82% of patients had at least one diagnosed comorbidity upon referral (eg, psychiatric, physical health, or other sleep disorder). Conclusion: The findings support the CCSM as a feasible measure for identifying the high levels of coexistent psychiatric symptomatology in patients presenting for insomnia treatment at sleep psychology services. PMID- 30464666 TI - The importance of patient-reported outcomes in clinical trials and strategies for future optimization. AB - Patient-reported outcomes (PROs) can be included in clinical trials as primary or secondary endpoints and are increasingly recognized by regulators, clinicians, and patients as valuable tools to collect patient-centered data. PROs provide unique information on the impact of a medical condition and its treatment from the patient's perspective; therefore, PROs can be included in clinical trials to ensure the impact of a trial intervention is comprehensively assessed. This review first discusses examples of how PRO endpoints have added value to clinical trial interpretation. Second, it describes the problems with current practices in designing, implementing, and reporting PRO studies, and how these problems may be addressed by complying with guidance for protocol development, selecting appropriate PRO measures to match clinically motivated PRO hypotheses, minimizing the rates of avoidable missing PRO data, analyzing and interpreting PRO data, and transparently reporting PRO findings. PMID- 30464667 TI - Clinical outcomes following advanced respiratory motion management (respiratory gating or dynamic tumor tracking) with stereotactic body radiation therapy for stage I non-small-cell lung cancer. AB - Purpose: To report the outcomes of stereotactic body radiation therapy (SBRT) for stage I non-small-cell lung cancer (NSCLC) according to respiratory motion management method. Methods: Patients with stage I NSCLC who received SBRT from 2007 to 2015 were reviewed. Computed tomography (CT) simulation with four dimensional CT was performed for respiratory motion assessment. Tumor motion >1 cm in the craniocaudal direction was selectively treated with advanced respiratory management: either respiratory gating to a pre-specified portion of the respiratory cycle or dynamic tracking of an implanted fiducial marker. Comparisons were made with internal target volume approach, which treated all phases of respiratory motion. Results: Of 297 patients treated with SBRT at our institution, 51 underwent advanced respiratory management (48 with respiratory gating and three with tumor tracking) and 246 underwent all-phase treatment. Groups were similarly balanced with regard to mean age (P=0.242), tumor size (P=0.315), and histology (P=0.715). Tumor location in the lower lung lobes, as compared to middle or upper lobes, was more common in those treated with advanced respiratory management (78.4%) compared to all-phase treatment (25.6%, P<.0001). There were 17 local recurrences in the treated lesions. Kaplan-Meier analyses showed that there were no differences with regard to mean time to local failure (91.5 vs 98.8 months, P=0.56), mean time to any failure (73.2 vs 78.7 months, P=0.73), or median overall survival (43.3 vs 45.5 months, P=0.56) between patients who underwent advanced respiratory motion management and all-phase treatment. Conclusion: SBRT with advanced respiratory management (the majority with respiratory gating) showed similar efficacy to all-phase treatment approach for stage I NSCLC. PMID- 30464669 TI - Erratum: Ethical and legal considerations regarding the ownership and commercial use of human biological materials and their derivatives [Corrigendum]. AB - [This corrects the article on p. 87 in vol. 3, PMID: 22977316.]. PMID- 30464668 TI - Evaluation of bleeding disorders in patients with Noonan syndrome: a systematic review. AB - Background: Noonan syndrome (NS) is an autosomal dominant genetic condition that has a number of clinical features, including bleeding diathesis and a number of hematological abnormalities including clotting factor deficiencies, von Willebrand disease and abnormal platelet count/function. Methods: We evaluated the frequency/types of bleeding disorders, and associated hematological laboratory findings, in patients with NS, using published data from 1965 to 2014. Results: Of 45 studies identified, 31 included data for 428 patients with NS. Of these patients, 43% had reported bleeding, 26% had no reported bleeding and no bleed data was reported for 31%. Most patients (90%) had bleeding-related laboratory test abnormalities, but only 194 (45%) had a confirmed diagnosis of a specific bleeding disorder. Abnormal laboratory tests included: prolonged prothrombin time, activated partial thromboplastin time, and other platelet related disorders. Of the 194 patients with a confirmed diagnosis of a specific bleeding disorder, 153 (79%) had single clotting factor deficiencies, von Willebrand disease or platelet-related disorders, and 41 (21%) had multiple deficiencies including platelet-related disorders. Conclusion: As patients with NS can experience multiple bleeding disorders, including abnormal platelet function, clinical evaluations should be performed at diagnosis, after diagnosis, before any surgery is undertaken, and if patients become symptomatic. PMID- 30464670 TI - Prevalence, morphological characterization, and associated factors of anemia among children below 5 years of age attending St. Mary's Hospital Lacor, Gulu District, Northern Uganda. AB - Aim/objective: The aim of this study was to determine the prevalence, severity, morphological characterization, and the associated factors of anemia among children under the age of 5 years at St. Mary's Hospital Lacor, Gulu District, Northern Uganda. Materials and methods: A structured questionnaire was administered to each participant's parent/caregiver to collect data on sociodemographic factors, feeding pattern, and history of chronic illness. Hemoglobin (Hb) estimation was performed using a HemoCue 201+ analyzer. Peripheral thin and thick blood films were made from venous blood and stained with Giemsa to morphologically characterize red blood cells (RBCs) and investigate hemoparasites, respectively. We collected and examined stool specimens from each participant using wet preparations and formol-ether concentration technique for intestinal parasites. Descriptive statistics was used to describe study participants and to determine the prevalence of anemia. Logistic regression analysis was done to determine the factors associated with acquiring anemia at a P-value<= 0.05. Results: The study enrolled 343 children below the age of 5 years. Of these, 62.7% (N=215) were females. The IQR, median, and mean Hb levels were 5.1+/-3.2 g/dL, 8.2 g/dL, and 7.9 g/dL, respectively. Overall, 160 (46.6%, 95% CI: 42.1-51.46) children had anemia. The magnitude of severe, moderate, and mild anemia was 11.9%, 58.8%, and 29.4%, respectively. Morphologic characterization of anemia revealed hypochromic-microcytic (65.4%, N=106), hypochromic-macrocytic (15.4%, N=25), and normochromic-microcytic (19.1%, N=31) anemia. Factors associated with anemia were parasitic infestation, history of chronic disease, lack of complementary foods, complementary feeding for not more than twice a month, and households' with annual income less than 200,000 Ugandan Shillings. Conclusion: We report the high prevalence of anemia among children below 5 years of age in Gulu District, Northern Uganda. Thus, strategies geared at addressing the etiologic causes (such as, nutrient deficiency and parasitic infections) are key to reduce it in the region. PMID- 30464671 TI - Hematological parameters in Ghanaian sickle cell disease patients. AB - Background: Effective treatment and management of sickle cell disease (SCD) has been a challenge in Africa over the years. Hematological parameters are very useful profiles in the effective management of the disease. However, there is scarcity of studies on the hematological parameters of SCD in Ghana. This study aimed at determining hematological parameters among SCD patients with vaso occlusion, those in the steady state as well as healthy controls at a teaching hospital in Ghana. Methodology: This was a cross-sectional study involving a total of 628 subjects, including 148 HbAA controls, 208 HbSS patients in steady state, 82 HbSC patients in steady state, 156 HbSS patients in vaso-occlusive crises (VOC), and 34 HbSC patients in VOC. Venous blood sample was collected from all study participants. A full blood count was done within 2 hours of collection, and hemoglobin (Hb) concentration, packed cell volume, red blood cell (RBC) concentration, mean corpuscular Hb, mean cell volume, mean corpuscular Hb concentration, and white blood cells (WBC) and platelet (PLT) counts were recorded. Results: WBC and PLT counts were significantly higher in both female and male patients with SCD, compared with their healthy counterparts (P<0.05). The level of WBC was, however, significantly higher in patients with HbSS VOC among the SCD patients (P<0.001). Levels of Hb, RBC, and hematocrit were significantly higher in the controls (P<0.001). There was no significant difference in mean cell Hb among male patients with SCD (P=0.274) and female patients with SCD (P=0.5410). Conclusion: The SCD patients had lower Hb and RBC than the controls; however, higher PLT and WBC are noted in various status of SCD, possibly reflecting spleen effect in these patients. Further studies are needed to confirm these findings. PMID- 30464672 TI - Prevalence and factors associated with dysglycemia among girls in selected boarding secondary schools in Wakiso District, Uganda. AB - Background: There is limited information on dysglycemia in adolescents in low income countries. The objective of this study was to determine the prevalence and factors associated with dysglycemia among boarding secondary school adolescent girls in a peri-urban district. Methods: The design was a cross-sectional survey. A total of 688 adolescents from four randomly selected girls-only boarding secondary schools in Wakiso District, Uganda, participated in this study. Fasting plasma glucose, body mass index (BMI), and blood pressure (BP) were measured. A questionnaire was used to assess demographic and lifestyle factors. Suspected dysglycemia was defined using the American Diabetes Association cutoff of fasting glucose >=5.6 mmol/L. Overweight and hypertension were defined being above two SDs or the 95th percentile of the WHO BMI for age and BP for age reference charts, respectively. Logistic regression was used to determine the factors independently associated with dysglycemia. Results: The mean age of the participants was 15.4 years (SD=1.7 years). Probable dysglycemia was found in 44 of 688 (6.4%) participants, ranging from 3.5% in the least affluent school to 9.8% in the most affluent school. No case of type 2 diabetes was found. 11.6% of the participants were found to have probable hypertension. Dysglycemia was higher in adolescents who were overweight (adjusted OR [AOR] 2.3; 95% CI 1.22-4.48), those with hypertension (AOR 4.0; 95% CI 1.86-8.45), and those who frequently stocked biscuits (AOR 3.0; 95% CI 1.21-7.28). Dysglycemia was lower in older adolescents (AOR 0.3; 95% CI 0.10-0.86) and those who took water with meals (AOR 3.0; 95% CI 1.21-7.28). Conclusion: In these predominantly peri-urban boarding secondary schools, 6.4% of the adolescent girls have probable dysglycemia. As Africa undergoes the epidemiological transition, there is a need for closer surveillance for diabetes and hypertension in peri-urban schools and school health measures against lifestyle diseases. PMID- 30464673 TI - Integrated pathology and radiology learning for a musculoskeletal system module: an example of interdisciplinary integrated form. PMID- 30464674 TI - Medical students' perspective on the place of team-based learning in the curriculum. PMID- 30464675 TI - Evolving role of pharmaceutical physicians in medical evidence and education. AB - The role of pharmaceutical physicians who are the experts working in pharmaceutical companies has progressed over the last few decades, from supervising research and development (R&D) studies and/or providing support to marketing teams to serving an independent critical function. In this review, we focus on pharmaceutical physicians serving medical affairs functions in the pharmaceutical industry. Historically, members of the medical affairs team mainly provided a bridge between commercial teams and the R&D sector and between the organization and external stakeholders. Such teams may even have been managed by other departments, with an emphasis on acquiring and generating data for regulatory purposes. In recent years, the role of medical affairs has broadened due to a change in focus and the increasingly stringent regulatory landscape. Strict regulations require the detachment of commercial from medical activities within pharmaceutical organizations. This change provides an opportunity for a different type of partnership, allowing scientifically minded and medically driven initiatives. This article summarizes the key role of pharmaceutical industry-based physicians in medical affairs and discusses the emerging and evolving role of medical affairs for value creation in evidence generation and medical education. PMID- 30464676 TI - Butane hash oil and dabbing: insights into use, amateur production techniques, and potential harm mitigation. AB - The use of marijuana concentrates has escalated in recent years with butane extracts appearing particularly popular. The administration of butane hash oil, colloquially referred to as "dabbing," is distinct from traditional flower cannabis usage due to the THC content of samples and the presence of impurities such as unpurged butane. While this may confer heightened risk to the user, additional significant concerns are tied to fires and explosions. Using butane as a solvent in amateur "blasting" methods may result in a flammable vapor pooling in enclosed spaces and igniting when exposed to a spark. As research on butane extract users, amateur production techniques, health risks, and legality is in its infancy, we explored existing studies on the topic to create a review of substantiated knowledge related to THC extracted using butane. The resulting assessment centers on three areas: 1) dab users including both recreational users and medical marijuana patients; 2) butane extraction techniques including illicit amateur open methods and the safer closed-loop system employed in medicinal/recreational states; and 3) risks, both related to fires and legality. We follow the presentation of this material with a summary of the (mis)information reaching the public in print and online sources so that public educational campaigns can focus on dispelling the inaccuracies and false notions of safety that may be tied to amateur production. PMID- 30464678 TI - Only if you view it through a different lens. PMID- 30464679 TI - Evaluation of subcutaneous rituximab administration on Canadian systemic therapy suites. AB - Background: Non-Hodgkin lymphoma (nhl) is the most common hematologic malignancy. Diffuse large B-cell lymphoma (dlbcl) and follicular lymphoma (fl) constitute 55% of new nhl cases and are initially treated with rituximab-based chemoimmunotherapy. Relative to intravenous (IV) rituximab, a subcutaneous (sc) formulation approved in 2016 has comparable pharmacokinetics, efficacy, and safety, and a greatly reduced administration time; it is also preferred by patients. The objective of the present study was to estimate the effect (on systemic therapy suite time and on the costs of drug acquisition and administration) of implementing sc rituximab in the initial chemoimmunotherapy for fl and dlbcl over 3 years in the Canadian market. Methods: An Excel (Microsoft Corporation, Redmond, WA, U.S.A.)-based model was created with a population size based on epidemiologic data and current rituximab use, duration of use considering initial therapy, time savings for sc rituximab administration from published studies, costs from standard Canadian sources, and assumed uptake in implementing provinces of 65%, 75%, and 80% over 3 years. Key parameters and sensitivity analysis values were validated by clinical experts located in various Canadian jurisdictions. Costs are reported in 2017 Canadian dollars from the perspective of the health care system. Results: More than 3 years after implementation of sc rituximab, we estimated that 5762 Canadians would be receiving sc rituximab, resulting in savings of 128,715 hours in systemic therapy suite time and approximately $40 million in drug and administration costs. Sensitivity analyses suggest that the model is most sensitive to sc market uptake, number of induction therapy cycles, and eligible patients. Conclusions: Subcutaneous administration of rituximab can significantly reduce systemic therapy suite time and achieve substantial savings in drug and administration costs. PMID- 30464677 TI - Perforation risk in pediatric appendicitis: assessment and management. AB - Perforated appendicitis, as defined by a visible hole in the appendix or an appendicolith free within the abdomen, carries significant morbidity in the pediatric population. Accurate diagnosis is challenging as there is no single symptom or sign that accurately predicts perforated appendicitis. Younger patients and those with increased duration of symptoms are at higher risk of perforated appendicitis. Elevated leukocytosis, bandemia, high C-reactive protein, hyponatremia, ultrasound, and CT are all useful tools in diagnosis. Distinguishing patients with perforation from those without is important given the influence of a perforation diagnosis on the management of the patient. Treatment for perforated appendicitis remains controversial as several options exist, each with its indications and merits, illustrating the complexity of this disease process. Patients may be managed non-operatively with antibiotics, with or without interval appendectomy. Patients may also undergo appendectomy early in the course of their index hospitalization. Factors known to predict failure of non-operative management include appendicolith, leukocytosis greater than 15,000 white blood cells per microliter, increased bands, and CT evidence of disease beyond the right lower quadrant. In this review, the indications and benefits of each treatment strategy will be discussed and an algorithm to guide treatment decisions will be proposed. PMID- 30464680 TI - Survival outcome differences based on treatments used and knowledge of the primary tumour site for patients with cancer of unknown and known primary in Ontario. AB - Introduction: Patients with cancer of unknown primary (cup) have pathologically confirmed metastatic tumours with unidentifiable primary tumours. Currently, very little is known about the relationship between the treatment of patients with cup and their survival outcomes. Thus, we compared oncologic treatment and survival outcomes for patients in Ontario with cup against those for a cohort of patients with metastatic cancer of known primary site. Methods: Using the Ontario Cancer Registry and the Same-Day Surgery and Discharge Abstract databases maintained by the Canadian Institute for Health Information, we identified all Ontario patients diagnosed with metastatic cancer between 1 January 2000 and 31 December 2005. Ontario Health Insurance Plan treatment records were linked to identify codes for surgery, chemotherapy, or therapeutic radiation related to oncology. Multivariable Cox regression models were constructed, adjusting for histology, age, sex, and comorbidities. Results: In 45,347 patients (96.3%), the primary tumour site was identifiable, and in 1743 patients (3.7%), cup was diagnosed. Among the main tumour sites, cup ranked as the 6th largest. The mean Charlson score was significantly higher (p < 0.0001) in patients with cup (1.88) than in those with a known primary (1.42). Overall median survival was 1.9 months for patients with cup compared with 11.9 months for all patients with a known-primary cancer. Receipt of treatment was more likely for patients with a known primary site (n= 35,012, 77.2%) than for those with cup (n = 891, 51.1%). Among patients with a known primary site, median survival was significantly higher for treated than for untreated patients (19.0 months vs. 2.2 months, p < 0.0001). Among patients with cup, median survival was also higher for treated than for untreated patients (3.6 months vs. 1.1 months, p < 0.0001). Conclusions: In Ontario, patients with cup experience significantly lower survival than do patients with metastatic cancer of a known primary site. Treatment is associated with significantly increased survival both for patients with cup and for those with metastatic cancer of a known primary site. PMID- 30464681 TI - Canadian perspectives: update on inhibition of ALK-positive tumours in advanced non-small-cell lung cancer. AB - Background: Inhibition of the anaplastic lymphoma kinase (alk) oncogenic driver in advanced non-small-cell lung carcinoma (nsclc) improves survival. In 2015, Canadian thoracic oncology specialists published a consensus guideline about the identification and treatment of ALK-positive patients, recommending use of the alk inhibitor crizotinib in the first line. New scientific literature warrants a consensus update. Methods: Clinical trials of alk inhibitor were reviewed to assess benefits, risks, and implications relative to current Canadian guidance in patients with ALK-positive nsclc. Results: Randomized phase iii trials have demonstrated clinical benefit for single-agent alectinib and ceritinib used in treatment-naive patients and as second-line therapy after crizotinib. Phase ii trials have demonstrated activity for single-agent brigatinib and lorlatinib in further lines of therapy. Improved responses in brain metastases were observed for all second- and next/third-generation alk tyrosine kinase inhibitors in patients progressing on crizotinib. Canadian recommendations are therefore revised as follows:? Patients with advanced nonsquamous nsclc have to be tested for the presence of an ALK rearrangement.? Treatment-naive patients with ALK positive disease should initially be offered single-agent alectinib or ceritinib, or both sequentially.? Crizotinib-refractory patients should be treated with single-agent alectinib or ceritinib, or both sequentially.? Further treatments could include single-agent brigatinib or lorlatinib, or both sequentially.? Patients progressing on alk tyrosine kinase inhibitors should be considered for pemetrexed-based chemotherapy.? Other systemic therapies should be exhausted before immunotherapy is considered. Summary: Multiple lines of alk inhibition are now recommended for patients with advanced nsclc with an ALK rearrangement. PMID- 30464682 TI - Treatment algorithm in cancer-associated thrombosis: Canadian expert consensus. AB - Management of anticoagulant therapy for the treatment of venous thromboembolism (vte) in cancer patients is complex because of an increased risk of recurrent vte and major bleeding complications in those patients relative to the general population. Subgroups of patients with cancer also show variation in their risk for recurrent vte and adverse bleeding events. Accordingly, a committee of 10 Canadian clinical experts developed the consensus risk- stratification treatment algorithm presented here to provide guidance on tailoring anticoagulant treatment choices for the acute and extended treatment of symptomatic and incidental vte, to prevent recurrent vte, and to minimize the bleeding risk in patients with cancer. During a 1-day live meeting, a systematic review of the literature was performed, and a draft treatment algorithm was developed. The treatment algorithm was refined through the use of a Web-based platform and a series of online teleconferences. Clinicians using this treatment algorithm should consider the bleeding risk, the type of cancer, and the potential for drug-drug interactions in addition to informed patient preference in determining the most appropriate treatment for patients with cancer-associated thrombosis. Anticoagulant therapy should be regularly reassessed as the patient's cancer status and management change over time. PMID- 30464683 TI - Discrepancies between Canadian cancer research funding and site-specific cancer burden: a spotlight on ten disease sites. AB - Background: Cancer research is essential in evaluating the safety and effectiveness of emerging cancer treatments, which in turn can lead to ground breaking advancements in cancer care. Given limited research funding, allocating resources in alignment with societal burden is essential. However, evidence shows that such alignment does not typically occur. The objective of the present study was to provide an updated overview of site-specific cancer research investment in Canada and to explore potential discrepancies between the site-specific burden and the level of research investment. Methods: The 10 cancer sites with the highest mortality in 2015-which included brain, female breast, colorectal, leukemia, lung, non-Hodgkin lymphoma, ovary, pancreas, prostate, and uterus-were selected for the analysis. Information about site-specific research investment and cancer burden (raw incidence and mortality) was obtained from the Canadian Cancer Research Survey and Statistics Canada's cansim (the Canadian Socio Economic Information Management System) respectively. The ratio of site-specific research investment to site-specific burden was used as an indicator of overfunding (ratio > 1) or underfunding (ratio < 1). Results: The 3 cancer sites with the highest research investments were leukemia, prostate, and breast, which together represented 51.3% of 2015 cancer research funding. Conversely, the 3 cancer sites with the lowest investments were uterus, pancreas, and ovary, which together represented 7.8% of 2015 research funding. Relative to site-specific cancer burden, the lung, uterus, and colorectal sites were consistently the most underfunded. Conclusions: Observed discrepancies between cancer burden and research investment indicate that some cancer sites (such as lung, colorectal, and uterus) seem to be underfunded when site-specific incidence and mortality are taken into consideration. PMID- 30464684 TI - Immune-related adverse events of immune checkpoint inhibitors: a brief review. AB - Immune checkpoint inhibitors (icis) such as inhibitors of ctla-4, PD-1, and PD L1, given as monotherapy or combination therapy have emerged as effective treatment options for immune-sensitive solid tumours and hematologic malignancies. The benefits of icis can be offset by immune-related adverse events (iraes) that leave all organ systems vulnerable and subsequently increase the risk for morbidity and mortality. Because of fluctuating onset and prolonged duration, the toxicities associated with iraes represent a shift from the understanding of conventional anticancer toxicities. The ctla-4 and PD-1/PD-L1 inhibitors modulate T-cell response differently, resulting in distinct toxicity patterns, toxicity kinetics, and dose-toxicity relationships. Using individualized patient education, screening, and assessment for the early identification of iraes is key to proactive management and is therefore key to improving outcomes and prolonging therapy. Management of iraes is guided by appropriate grading, which sets the stage for the treatment setting (outpatient vs. inpatient), ici treatment course (delay vs. discontinuation), supportive care, corticosteroid use, organ specialist consultation, and additional immunosuppression. Health care professionals in oncology must work collaboratively with emergency and community colleagues to facilitate an understanding of iraes in an effort to optimize seamless care. PMID- 30464685 TI - Access to care and outcomes for neuroendocrine tumours: does socioeconomic status matter? AB - Introduction: Neuroendocrine tumours (nets) are a poorly understood malignancy lacking standardized care. Differences in socioeconomic status (ses) might worsen the effect of non-standardized care. We examined the effect of ses on net peri diagnostic care patterns and outcomes. Methods: In this population-based cohort study, net cases identified from a provincial cancer registry (1994-2009) were divided into low (1st and 2nd income quintiles) and high (3rd, 4th, and 5th quintiles) ses groups. We compared peri-diagnostic health care utilization (-2 years to +6 months), metastatic recurrence, and overall survival (os) between the groups. Results: Of 4966 net patients, 38.3% had a low ses. Neither the primary net sites (p = 0.15), nor the metastatic presentation (p = 0.31) differed. Patients with low ses had a higher mean number of physician visits (20.1 +/- 19.9 vs. 18.1 +/- 16.5, p = 0.001) and imaging studies (56 +/- 50 vs. 52 +/- 44, p = 0.009) leading to the net diagnosis. Rates of primary tumour resection (p = 0.14), hepatectomy (p = 0.45), systemic therapy (p = 0.38), and liver embolization (p = 0.13) did not differ with ses. In the low-ses group, metastatic recurrence was more likely (41.1% vs. 37.6%, p = 0.01) during a median follow-up of 61.7 months, and the 10-year os was inferior (47.1% vs. 52.2%, p < 0.01). Low ses was associated with worse os (hazard ratio: 1.16; 95% confidence interval: 1.06 to 1.26) after adjustment for age, sex, comorbidity burden, primary net site, and rural living. Conclusions: Low ses was associated with more physician visits and imaging before a net diagnosis, but not with more advanced stage at presentation nor with an effect on the pattern of therapy. Long-term outcomes were inferior in the low-ses group. These data can help to inform the design of health care delivery for nets. PMID- 30464686 TI - Exploring cancer centres for physical activity and sedentary behaviour support for breast cancer survivors. AB - Background: Up to 90% of breast cancer survivors report low levels of physical activity (pa) and spend approximately 70% of the day in sedentary behaviour. Survivors might not be receiving information about the health benefits of pa and the consequences of sedentary behaviour in the context of their cancer. The primary purpose of the present study was to evaluate cancer centres for pa and sedentary behaviour information and infrastructure. A secondary aim was to evaluate the quality of the information that is accessible to breast cancer survivors in cancer centres. Methods: A built-environment scan of the 14 regional cancer centres in Ontario and an evaluation of the text materials about pa available at the cancer centres were completed. Data analyses included descriptive statistics, proportions, and inter-rater reliability. Results: The infrastructure of the cancer centres provided few opportunities for dissemination of information related to pa through signs and printed notices. Televisions were present in all waiting rooms, which could provide a unique opportunity for dissemination of information about pa and sedentary behaviour. Text materials were rated as trustworthy, used some behaviour change techniques (for example, information about the consequences of lack of pa, barrier identification, and setting graded tasks), and were aesthetically pleasing. Conclusions: These findings represent areas for knowledge dissemination both for the centre and for resources that could be further improved. PMID- 30464687 TI - Current landscape of immunotherapy in the treatment of solid tumours, with future opportunities and challenges. AB - Immunotherapy has emerged as a new standard of care, showing survival benefit for solid tumours in multiple disease sites and indications. The survival improvements seen in diseases that were highly resistant to traditional therapies, with a poor prognosis, are unprecedented. Although the benefits observed in clinical trials are undeniable, not all patients derive those benefits, leading to emerging combination strategies and an ongoing quest for biomarker selection. Here, we summarize the current evidence for immunotherapy in the treatment of solid tumours, and we discuss emerging strategies at the forefront of research. We discuss future challenges that will be encountered as experience and knowledge continue to expand in this rapidly emerging field. PMID- 30464688 TI - Afatinib in advanced pretreated non-small-cell lung cancer- a Canadian experience. AB - Background: Afatinib, an irreversible epidermal growth factor receptor tyrosine kinase inhibitor (egfr tki), is approved for first-line therapy in advanced EGFR mutation-positive non-small-cell lung cancer (nsclc) and has previously demonstrated activity after failure of chemotherapy and reversible egfr tkis, with improved response and progression-free survival, compared with placebo. Outcomes in pretreated patients with advanced nsclc receiving afatinib through a Canadian special access program (sap) are reported here. Methods: Patients with nsclc progressing after at least 1 line of chemotherapy and an egfr tki were eligible to enrol in the sap. Characteristics of patients from the two largest accruing Canadian centres were retrospectively reviewed, including demographics, disease and treatment data, and patient outcomes. Results: The 53 patients who received afatinib (57% women, 51% never-smokers, 26% of East Asian ethnicity, and 66% with adenocarcinoma) had a median age of 59 years. EGFR mutations were documented in 25%, and EGFR wild-type in 8%. All patients had received prior egfr tki treatment, with 42% achieving a response. Patients took afatinib for a median of 2 months (range: 0-26 months); 17% required 1 or more dose reductions. Of 47 evaluable patients receiving afatinib, 10 experienced tumour shrinkage, and 11, stable disease. Median survival from afatinib initiation was 5 months (95% confidence interval: 2 months to 8 months). Grade 3 or greater diarrhea, rash, paronychia, and stomatitis were seen in 9%, 11%, 6%, and 4% of patients respectively. Conclusions: In an unselected population of pretreated patients with advanced nsclc after tki failure, median survival with afatinib therapy was 5 months. Through a sap, afatinib demonstrated activity in clinical practice, with manageable toxicity. PMID- 30464689 TI - Paroxysmal nocturnal hemoglobinuria testing in patients with myelodysplastic syndrome in clinical practice-frequency and indications. AB - Background: Myelodysplastic syndrome (mds) is characterized by peripheral blood cytopenias, with most patients developing significant anemia and dependence on red blood cell (rbc) transfusion. In paroxysmal nocturnal hemoglobinuria (pnh), mutations in the PIGA gene lead to lack of cell-surface glycosylphosphatidylinositol, allowing complement-mediated lysis to occur. Paroxysmal nocturnal hemoglobinuria results in direct antiglobulin test-negative hemolysis and cytopenias, and up to 50% of patients with mds test positive for pnh cells. We wanted to determine whether pnh is considered to be a contributor to anemia in mds. Methods: Patients with a diagnosis of mds confirmed by bone marrow biopsy since 2009 were reviewed. High-resolution pnh testing by flow cytometry examined flaer (fluorescein-labeled proaerolysin) binding and expression of CD14, CD15, CD24, CD45, CD59, CD64, and CD235 on neutrophils, monocytes, and rbcs. Results: In 152 patients with mds diagnosed in 2009 or later, the mds diagnosis included subtypes associated with pnh positivity (refractory anemia, n = 7, and hypoplastic mds, n = 4). Of 11 patients who underwent pnh testing, 1 was positive (9.0%). Reasons for pnh testing were anemia (n = 3), new mds diagnosis (n = 2), hypoplastic mds (n = 2), decreased haptoglobin (n= 1), increased rbc transfusion requirement (n= 1), and unexplained iron deficiency (n= 1). Conclusions: Testing for pnh was infrequent in mds patients, and the criteria for testing were heterogeneous. Clinical indicators prompted pnh testing in 6 of 11 patients. Given that effective treatment is now available for pnh and that patients with pnh-positive mds can respond to immunosuppressive therapy, pnh testing in mds should be considered. Prospective analyses to clarify the clinical significance of pnh positivity in mds are warranted. PMID- 30464690 TI - Patients with non-small-cell lung cancer harbouring a BRAF mutation: a multicentre study exploring clinical characteristics, management, and outcomes in a real-life setting: EXPLORE GFPC 02-14. AB - Background: Mutations in BRAF are rare oncogene mutations, found in 2% of non small-cell lung cancers (nsclcs). Little information is available about the management of patients with BRAF-mutated nsclc, except for those included in clinical trials. We undertook the present study to assess the clinical characteristics, management, and outcomes of those patients in a real-life setting. Methods: This retrospective multicentre observational study included all patients with BRAF-mutated nsclc diagnosed between January 2012 and December 2014. Results: Patients (n = 59) from 24 centres were included: 57.6% men; mean age: 64.5 +/- 14.5 years; 82% with a performance status of 0-1 at diagnosis; smoking status: 40.3% current, 32.6% former; 93% with adenocarcinoma histology; 75% stage iv; 78% with V600E mutations; 2 with EGFR and 2 with ALK co-mutations. Of the stage iv patients, 79% received first-line therapy (14.2% anti-BRAF), and 48% received second-line treatment (23.8% anti-BRAF). Response rate and progression-free survival were, respectively, 51.7% and 8.7 months [95% confidence interval (ci): 6.4 months to 15.2 months] for first-line therapy and 35.3% and 4.1 months (95% ci: 2 months to 10.9 months) for second-line treatments. The 2-year overall survival was 58.5% (95% ci: 45.8% to 74.8%). Outcomes in patients with stage iv nsclc harbouring BRAF V600E mutations (n = 32) did not differ significantly from those of patients with other BRAF mutations. Conclusions: In this real-world analysis, most nsclc patients with a BRAF mutation were men and current or former smokers. Survival appears to be better in these BRAF-mutated patients than in nsclc patients without an oncogenic driver. PMID- 30464691 TI - Predictors of immunotherapy-induced immune-related adverse events. AB - Purpose: We aimed to elucidate predictive factors for the development of immune related adverse events (iraes) in patients receiving immunotherapies for the management of advanced solid cancers. Methods: This retrospective study involved all patients with histologically confirmed metastatic or inoperable melanoma, non small-cell lung cancer, or renal cell carcinoma receiving immunotherapy at the Cancer Centre of Southeastern Ontario. The type and severity of iraes, as well as potential protective and exacerbating factors, were collected from patient charts. Results: The study included 78 patients receiving ipilimumab (32%), nivolumab (33%), or pembrolizumab (35%). Melanoma, non-small-cell lung cancer, and renal cell carcinoma accounted for 70%, 22%, and 8% of the cancers in the study population. In 41 patients (53%) iraes developed, with multiple iraes developing in 12 patients (15%). In most patients (70%), the iraes were of severity grade 1 or 2. Female sex [adjusted odds ratio (oradj): 0.094; 95% confidence interval (ci): 0.021 to 0.415; p = 0.002] and corticosteroid use before immunotherapy (oradj: 0.143; 95% ci: 0.036 to 0.562; p = 0.005) were found to be associated with a protective effect against iraes. In contrast, a history of autoimmune disease (oradj: 9.55; 95% ci: 1.34 to 68.22; p = 0.025), use of ctla-4 inhibitors (oradj: 6.25; 95% ci: 1.61 to 24.25; p = 0.008), and poor kidney function of grade 3 or greater (oradj: 10.66; 95% ci: 2.41 to 47.12; p = 0.025) were associated with a higher risk of developing iraes. A Hosmer-Lemeshow goodness-of-fit test demonstrated that the logistic regression model was effective at predicting the development of iraes (chi-square: 1.596; df = 7; p = 0.979). Conclusions: Our study highlights several factors that affect the development of iraes in patients receiving immunotherapy. Although future studies are needed to validate the resulting model, findings from the study can help to guide risk stratification, monitoring, and management of iraes in patients given immunotherapy for advanced cancer. PMID- 30464692 TI - Computed tomography-quantified body composition predicts short-term outcomes after gastrectomy in gastric cancer. AB - Background: Malnutrition is a common and critical problem that influences outcome in cancer patients. Body composition reflects a patient's metabolic profile and physiologic reserves, which might be the true determinant of prognosis. In the present study, which aimed to identify valuable new prognostic indicators, we investigated the association between computed tomography-quantified body composition and short-term outcomes after gastrectomy for gastric cancer. Methods: Skeletal muscle index, mean muscle attenuation, and ratio of visceral-to subcutaneous adipose tissue area (vsr) were calculated from preoperative computed tomography images. Low skeletal muscle index, low mean muscle attenuation, and high vsr were respectively termed "sarcopenia," "myosteatosis," and "visceral obesity." The association of body composition with postoperative complications and serum markers of nutrition and inflammation after radical gastrectomy were analyzed. Results: The overall complication rate was significantly higher in the sarcopenia (62.5% vs. 27.3%, p = 0.001) and myosteatosis groups (38.2% vs. 4%, p = 0.002). Patients with visceral obesity had a higher incidence of inflammatory complications (20.3% vs. 6.5%, p = 0.01). Multivariate logistic regression analysis demonstrated that sarcopenia (p = 0.013), myosteatosis (p = 0.017), and low serum retinol-binding protein (p = 0.019) were independent risk factors for overall complications. Compared with control subjects, patients with sarcopenia had lower postoperative levels of serum retinol-binding protein (p = 0.007), and patients with visceral obesity had higher levels of C-reactive protein (p = 0.026). Conclusions: Sarcopenia, myosteatosis, and visceral obesity were significantly associated with increased rates of postoperative complications and affected the postoperative nutrition and inflammation status of patients with gastric cancer. PMID- 30464693 TI - Elective nodal irradiation or involved-field irradiation in definitive chemoradiotherapy for esophageal squamous cell cancer: a retrospective analysis in clinical N0 patients. AB - Objective: We compared failure patterns and survival after elective nodal irradiation (eni) or involved-field irradiation (ifi) in patients with thoracic esophageal squamous cell carcinoma (escc), clinical stage T2-4N0M0, to determine whether ifi is feasible for such patients. Methods: Between 2005 and 2015, 126 patients with clinical stage T2-4N0M0 thoracic escc who received definitive concurrent chemoradiotherapy in Shandong Cancer Hospital and Institute and who had complete data, were analyzed retrospectively. Of those patients, 49 received ifi, and 77 received eni. In the ifi group, the radiation field included the primary tumour, with a 3-cm to 4-cm margin in the craniocaudal direction, and the elective irradiation was delivered to the adjacent regional lymphatics according to the location of the primary tumour. Patterns of failure were classified using the first site of failure, which included primary tumour failure, regional lymph node failure, and distant metastasis. Results: Median progression-free survival was 20 months [95% confidence interval (ci): 7.87 months to 39.2 months] in the ifi group and 30 months (95% ci: 17.4 months to 44.6 months) in the eni group (p = 0.580). Median overall survival (os) was 36 months (95% ci: 21.9 months to 50.1 months) in the ifi group and 38 months (95% ci: 26.1 months to 49.9 months) in the eni group (p = 0.761). The estimated 1-year, 3-year, and 5-year os rates were, respectively, 87.8%, 49.4%, and 32.3% for the ifi patients and 92.2%, 52.0%, and 28.9% for the eni patients. Disease persistence and primary lesion recurrence after complete remission (cr) were the most frequent causes of treatment failure in the patients overall (83 of 124, 66.9%). Of the 66 patients achieving a clinical cr, 25 experienced recurrence of the primary lesion, 12 experienced distant relapse, 10 experienced regional nodal failure, and 2 experienced an isolated recurrence. No significant differences in the pattern of failure or in the incidences of grade 3 or greater treatment-related myelosuppression or esophagitis were found between the ifi and eni groups. Conclusions: In patients with thoracic escc clinical stage T2-4N0M0 receiving definitive chemoradiotherapy, failure patterns and os were similar with either eni or ifi. Large prospective randomized studies are needed to further investigate and verify those results in this subgroup of patients. PMID- 30464694 TI - Changes in preoperative endoscopic and percutaneous bile drainage in patients with periampullary cancer undergoing pancreaticoduodenectomy in Ontario: effect on clinical practice of a randomized trial. AB - Background: In 2010, a multicentre randomized controlled trial reported increased postoperative complications in pancreaticoduodenectomy (pde) patients undergoing preoperative biliary decompression (pbd). We evaluated the effect of that publication on rates of pbd at the population level. Methods: This retrospective observational cohort study identified patients undergoing pde for malignancy, 2005-2013, linking them with administrative health care databases covering medical services for a population of 13.5 million. Patients undergoing pbd within 6 weeks before their surgery were identified using physician billing codes and were divided into those undergoing pde before and after article publication, with a 6-month washout period. Chi-square tests were used to compare rates of pbd. Results: Of 1997 pde patients identified, 963 underwent surgery before article publication, and 911, after (123 during the washout period). The rate of pbd was 47.5% before publication, and 41.6% after (p = 0.01). The lowest pbd rates occurred immediately after publication, in 2010 and 2011. Similar results were observed when the cohort was restricted to patients seen preoperatively by a gastroenterologist (n = 1412). Conclusions: Rates of pbd have declined a small, but significant, amount after randomized trial publication. Persistence of pbd might relate to suboptimal knowledge translation, the role of pbd in diagnosis of periampullary malignancy, and treatment of complications (cholangitis, severe hyperbilirubinemia) or anticipation of delay from diagnosis to surgery. The nadir in pbd rates after article publication and the subsequent rise suggest an element of transience in the effect of article publication on clinical practice. Further investigation into the reasons for persistent pbd is needed. PMID- 30464695 TI - Geographic variation in surgical practice patterns and outcomes for resected nonmetastatic gastric cancer in Ontario. AB - Background: Gastrectomy with negative resection margins and adequate lymph node dissection is the cornerstone of curative treatment for gastric cancer (gc). However, gastrectomy is a complex and invasive operation with significant morbidity and mortality. Little is known about surgical practice patterns or short- and long-term outcomes in early-stage gc in Canada. Methods: We undertook a population-based retrospective cohort study of patients with gc diagnosed between 1 April 2005 and 31 March 2008. Chart review provided clinical and operative details such as disease stage, primary tumour location, surgical approach, operation, lymph nodes, and resection margins. Administrative data provided patient demographics, geography, and vital status. Variations in treatment and outcomes were compared for 14 local health integration networks. Descriptive statistics and log-rank tests were used to examine geographic variation. Results: We identified 722 patients with nonmetastatic resected gc. We documented significant provincial variation in case mix, including primary tumour location, stage at diagnosis, and tumour grade. Short-term surgical outcomes varied across the province. The percentage of patients with 15 or fewer lymph nodes removed and examined varied from 41.8% to 73.8% (p = 0.02), and the rate of positive surgical margins ranged from 15.2% to 50.0% (p = 0.002). The 30-day surgical mortality rates did not vary statistically significantly across the province (p = 0.13); however, rates ranged from 0% to 16.7%. Overall 5-year survival was 44% and ranged from 31% to 55% across the province. Conclusions: This cohort of patients with resected stages i-iii gc is the largest analyzed in Canada, providing important historical information about treatment outcomes. Understanding the causes of regional variation will support interventions aiming to improve gc operative outcomes in the cancer system. PMID- 30464696 TI - Is there a role for adjuvant therapy after surgery in "high risk for recurrence" kidney cancer? An update on current concepts. AB - Background: Although surgical resection remains the standard of care for localized kidney cancers, a significant proportion of patients experience systemic recurrence after surgery and hence might benefit from effective adjuvant therapy. So far, several treatment options have been evaluated in adjuvant clinical trials, but only a few have provided promising results. Nevertheless, with the recent development of targeted therapy and immunomodulatory therapy, a series of clinical trials are in progress to evaluate the potential of those novel agents in the adjuvant setting. In this paper, we provide a narrative review of the progress in this field, and we summarize the results from recent adjuvant trials that have been completed. Methods: A literature search was conducted. The primary search strategy at the medline, Cochrane reviews, and http://ClinicalTrials.gov/databases included the keywords "adjuvant therapy," "renal cell carcinoma," and "targeted therapy or/and immunotherapy." Conclusions: Data from the s-trac study indicated that, in the "highest risk for recurrence" patient population, disease-free survival was increased with the use of adjuvant sunitinib compared with placebo. The assure trial showed no benefit for adjuvant sunitinib or sorafenib in the "intermediate- to high-risk" patient population. The ariser (adjuvant girentuximab) and protect (adjuvant pazopanib) trials indicated no survival benefit, but subgroup analyses in both trials recommended further investigation. The inconsistency in some of the current results can be attributed to a variety of factors pertaining to the lack of standardization across the trials. Nevertheless, patients in the "high risk of recurrence" category after surgery for their disease would benefit from a discussion about the potential benefits of adjuvant treatment and enrolment in ongoing adjuvant trials. PMID- 30464697 TI - Radiation therapy and immunotherapy-a potential combination in cancer treatment. AB - Background: Radiation therapy (rt) is a longstanding treatment modality for cancer. In addition, immune checkpoint blockade has been a significant development in the field of immunotherapy, modifying key immunosuppressive pathways of cancer cells. Methods: The aim of the present work was to review current concepts of rt and immunotherapy synergism, the abscopal effect, and the molecular effects of rt in the tumour microenvironment, its influence on immune stimulation, and potential clinical outcomes that might evolve from ongoing studies. We also discuss potential predictors of clinical response. Results: Up to-date literature concerning the mechanisms, interactions, and latest knowledge about rt and immunotherapy was reviewed and summarized, and is presented here. Conclusions: The possibility of using hyperfractionated rt to combine an abscopal effect with the enhanced effect of immune treatment using checkpoint blockade is a very promising method for future tumour treatments. PMID- 30464699 TI - Are patient-reported outcomes of physical function a valid substitute for objective measurements? AB - Background: Physical function is important for defining treatment strategies in patients with cancer and can be estimated using patient-reported outcomes (pros). Although pros are subjective, physical activity and fitness can be tested objectively with adequate, but more labour-intensive methods that are rarely used in daily clinical practice. To determine whether pros for physical function (pro pf) accurately predict physical function, we studied their interrelationships with objective measures of physical activity and fitness in patients with cancer who had completed cancer treatment, including adjuvant or neoadjuvant chemotherapy or autologous stem-cell transplantation. Methods: Baseline data from the react (Resistance and Endurance Exercise After Chemotherapy) and exist (Exercise Intervention After Stem-Cell Transplantation) studies were evaluated. In those studies, the effects of an exercise intervention on physical fitness, fatigue, and health-related quality of life in patients with cancer shortly after completion of chemotherapy or stem-cell transplantation were studied. Interrelationships between pro-pf (physical function subscale of the European Organisation for Research and Treatment of Cancer 30-question core Quality of Life Questionnaire), physical activity (accelerometer), and cardiorespiratory fitness (peak oxygen uptake) were assessed using univariable and multivariable multilevel linear mixed-model analyses. Results: After adjustment for age, sex, and body mass index, the pro-pf was significantly associated with physical activity (beta = 1.75; 95% confidence interval: 1.08 to 2.42) and cardiorespiratory fitness (beta = 0.10; 95% confidence interval: 0.06 to 0.13). Standardized coefficients were 0.28 and 0.26 respectively, indicating a weak association. Conclusions: The pro-pf is only weakly associated with objective physical activity and fitness evaluation in patients after curative treatment for cancer. The pro-pf cannot, therefore, be used in clinical practice as a substitute for objective measures of physical function. PMID- 30464698 TI - Canadian evidence-based guideline for the first-line treatment of chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (cll) is the most common adult leukemia in North America. In Canada, no unified national guideline exists for the front-line treatment of cll; provincial guidelines vary and are largely based on funding. A group of clinical experts from across Canada developed a national evidence-based treatment guideline to provide health care professionals with clear guidance on the first-line management of cll. Consensus recommendations based on available evidence are presented for the first-line treatment of cll. PMID- 30464700 TI - Opportunity is the greatest barrier to providing palliative care to advanced colorectal cancer patients: a survey of oncology clinicians. AB - Palliative care (pc) is part of the recommended standard of care for patients with advanced cancer. Nevertheless, delivery of pc is inconsistent. Patients who could benefit from pc services are often referred late-or not at all. In planning for improvements to oncology pc practice in our health care system, we sought to identify barriers to the provision of earlier pc, as perceived by health care providers managing patients with metastatic colorectal cancer (mcrc). We used the Michie Theoretical Domains Framework (tdf) and Behaviour Change Wheel (bcw), together with knowledge of previously identified barriers, to develop a 31 question survey. The survey was distributed by e-mail to mcrc health care providers, including physicians, nurses, and allied staff. Responses were obtained from 57 providers (40% response rate). The most frequently cited barriers were opportunity-related-specifically, lack of time, of clinic space for consultations, and of access to specialist pc staff or services. Qualitative responses revealed that resource limitations varied by cancer centre location. In urban centres, time and space were key barriers. In rural areas, access to specialist pc was the main limiter. Self-perceived capability to manage pc needs was a barrier for 40% of physicians and 30% of nurses. Motivation was the greatest facilitator, with 89% of clinicians perceiving that patients benefit from pc. Based on the Michie tdf and bcw model, interventions that best address the identified barriers are enablement and environmental restructuring. Those findings are informing the development of an intervention plan to improve oncology pc practices in a publicly funded health care system. PMID- 30464701 TI - Medical assistance in dying for cancer patients one year after legalization: a collaborative approach at a comprehensive cancer centre. AB - Medical assistance in dying (maid) is a new medical service in Canada. Access to maid for patients with advanced cancer can be daunting during periods of declining health near the end of life. In this report, we describe a collaborative approach between the centralized coordination service and a regional cancer centre as an effective strategy for enabling interdisciplinary care delivery and enhancing patient-centred care at the end of the patient's cancer journey. PMID- 30464702 TI - Hemispheric Organization in Disorders of Development. AB - A recent theoretical account posits that, during the acquisition of word recognition in childhood, the pressure to couple visual and language representations in the left hemisphere (LH) results in competition with the LH representation of faces, which consequently become largely, albeit not exclusively, lateralized to the right hemisphere (RH). We explore predictions from this hypothesis using a hemifield behavioral paradigm with words and faces as stimuli, with concurrent ERP measurement, in a group of adults with developmental dyslexia (DD) or with congenital prosopagnosia (CP), and matched control participants. Behaviorally, the DD group exhibited clear deficits in both word and face processing relative to controls, while the CP group showed a specific deficit in face processing only. This pattern was mirrored in the ERP data too. The DD group evinced neither the normal ERP pattern of RH dominance for faces nor the LH dominance for words. In contrast, the CP group showed the typical ERP superiority for words in the LH but did not show the typical RH superiority for faces. These findings are consistent with the hypothesis that the typical hemispheric organization for words can develop in the absence of typical hemispheric organization for faces but not vice versa, supporting the account of interactive perceptual development. PMID- 30464703 TI - Multidisciplinary team functioning and decision making within forensic mental health. AB - Purpose: The purpose of this paper is to investigate the operation of multidisciplinary team (MDT) meetings within a forensic hospital in England, UK. Design/methodology/approach: Mixed methods, including qualitative face to face interviews with professionals and service users, video observations of MDT meetings and documentary analysis. Data were collected from 142 staff and 30 service users who consented to take part in the research and analysed using the constant comparison technique of grounded theory and ethnography. Findings: Decisions taken within MDT meetings are unequally shaped by the professional and personal values and assumptions of those involved, as well as by the power dynamics linked to the knowledge and responsibility of each member of the team. Service users' involvement is marginalised. This is linked to a longstanding tradition of psychiatric paternalism in mental health care. Research limitations/implications: Future research should explore the nuances of interactions between MDT professionals and service users during the meetings, the language used and the approach taken by professionals to enable/empower service user to be actively involved. Practical implications: Clear aims, responsibilities and implementation actions are a pre-requisite to effective MDT working. There is a need to give service users greater responsibility and power regarding their care. Originality/value: While direct (video) observations were very difficult to achieve in secure settings, they enabled unmediated access to how people conducted themselves rather than having to rely only on their subjective accounts (from the interviews). PMID- 30464704 TI - QTL identification and KASP marker development for productive tiller and fertile spikelet numbers in two high-yielding hard white spring wheat cultivars. AB - Selecting high-yielding wheat cultivars with more productive tillers per unit area (PTN) combined with more fertile spikelets per spike (fSNS) is difficult. QTL mapping of these traits may aid understanding of this bottleneck and accelerate precision breeding for high yield via marker-assisted selection. PTN and fSNS were assessed in four to five trials from 2015 to 2017 in a doubled haploid population derived from two high-yielding cultivars "UI Platinum" and "SY Capstone." Two QTL for PTN (QPTN.uia-4A and QPTN.uia-6A) and four QTL for fSNS (QfSNS.uia-4A, QfSNS.uia-5A, QfSNS.uia-6A, and QfSNS.uia-7A) were identified. The effects of the QTL were primarily additive and, therefore, pyramiding of multiple QTL may increase PTN and fSNS. However, the two QTL for PTN were positioned in the flanking regions for the two QTL for fSNS on chromosomes 4A and 6A, respectively, suggesting either possible pleiotropic effect of the same QTL or tightly linked QTL and explaining the difficulty of selecting both high PTN and fSNS in phenotypic selection. Kompetitive allele-specific PCR (KASP) markers for all identified QTL were developed and validated in a recombinant inbred line (RIL) population derived from the same two cultivars. In addition, KASP markers for three of the QTL (QPTN.uia-6A, QfSNS.uia-6A, and QfSNS.uia-7A) were further validated in a diverse spring wheat panel, indicating their usefulness under different genetic backgrounds. These KASP markers could be used by wheat breeders to select high PTN and fSNS. PMID- 30464705 TI - Impact assessment of climate policy on Poland's power sector. AB - This article addresses the impact of the European Union Emissions Trading System (EU ETS) on Poland's conventional energy sector in 2008-2020 and further till 2050. Poland is a country with over 80% dependence on coal in the power sector being under political pressure of the European Union's (EU) ambitious climate policy. The impact of the increase of the European Emission Allowance (EUA) price on fossil fuel power sector has been modelled for different scenarios. The innovation of this article consists in proposing a methodology of estimation actual costs and benefits of power stations in a country with a heavily coal dependent power sector in the process of transition to a low-carbon economy. Strong political and economic interdependence of coal and power sector has been demonstrated as well as the impact caused by the EU ETS participation in different technology groups of power plants. It has been shown that gas-fuelled combined heat and power units are less vulnerable to the EU ETS-related costs, whereas the hard coal-fired plants may lose their profitability soon after 2020. Lignite power plants, despite their high emissivity, may longer remain in operation owing to low operational costs. Additionally, the results of long-term, up to 2050, modelling of Poland's energy sector supported an unavoidable need of deep decarbonisation of the power sector to meet the post-Paris climate objectives. It has been concluded that investing in coal-based power capacity may lead to a carbon lock-in of the power sector. Finally, the overall costs of such a transformation have been discussed and confronted with the financial support offered by the EU. The whole consideration has been made in a wide context of changes ongoing globally in energy markets and compared with some other countries seeking transformation paths from coal. Poland's case can serve as a lesson for all countries trying to reduce coal dependence in power generation. Reforms in the energy sector shall from the very beginning be an essential part of a sustainable transition of the whole nation's economy. They must scale the power capacity to the future demand avoiding stranded costs. The reforms must be wide ranging, based on a wide political consensus and not biased against the coal sector. Future energy mix and corresponding technologies shall be carefully designed, matched and should remain stable in the long-term perspective. Coal based power capacity being near the end of its lifetime provides an economically viable option to commence a fuel switch and the following technology replacement. Real benefits and costs of the energy transition shall be fairly allocated to all stakeholders and communicated to the society. The social costs and implications in coal-dependent regions may be high, especially in the short-term perspective, but then the transformation will bring profits to the whole society. PMID- 30464706 TI - ARTHROSCOPIC ASSESSMENT OF THE WRIST WITH KIENBOCK'S DISEASE. AB - Objective: Treatment of Kienbock's disease is challenging and the variability of results, despite the surgical technique, shows that there must be other aspects that can influence outcomes. The objective of this study is determine, through arthroscopic approach, the pattern of impairment of the carpal bones in Lichtman stage III patients. Method: Wrist arthroscopy was performed in patients with symptoms and evidence of lunate necrosis on x-rays, with signs of 3A and 3B stages. The Outerbridge classification was used to grade the articular status of the carpal bones. Results: Fifteen patients with stage 3 disease were assessed, five of whom were staged as type 3A and ten as 3B using the Lichtman stages. According to the Outerbridge classification, the lunate sulcus was the most affected with means of 2.8 at 3A and 2.9 at 3B. Other areas were significantly less affected with means of 1.1 and 1.3, respectively. Conclusion: Arthroscopic assessment of the wrist could aid in surgical decision making, offering more details on cartilage status in stage 3 Kienbock's disease. Level of Evidence III, Study of nonconsecutive patients, without consistently applied reference "gold" standard. PMID- 30464707 TI - HOW SCAPHOID FRACTURES ARE TREATED IN BRAZIL. AB - Objective: To verify how hand surgeons manage scaphoid fractures and their complications. Methods: Two hundred questionnaires were distributed during the 36th Brazilian Hand Surgery Congress (2016). Results: On suspicion of fracture without radiographic confirmation, 57% of surgeons request a CT or MRI scan, while 43% opt for immobilization and consecutive radiographs. In stable fractures the preference was for treatment with plaster cast. In fractures with no scaphoid waist displacement, 33% opt for percutaneous fixation. In displaced waist or proximal pole fractures, 66% and 99.4%, respectively, opted for surgical treatment. Most surgeons treat waist nonunion with a nonvascularized bone graft. When absorption at the site of nonunion is greater than 4 mm, 50% prefer to use iliac graft and screw fixation. In proximal pole nonunion, the Zaidemberg technique is preferred by 64%. More experienced surgeons are more likely to request tests in occult fractures (63.9% versus 47.6%; p=0.04), and tend to recommend surgery for distal third fractures more frequently (16.4% versus 4.7%; p=0.02). Conclusions: We have provided an overview of treatment preferences for scaphoid fractures. It should be noted that more experienced surgeons are more likely to request additional tests for occult fractures and to recommend surgical treatment of distal third fractures. Level of Evidence IV, Cross-sectional survey. PMID- 30464708 TI - TREATMENT OF FINGERTIP INJURIES BY SPECIALISTS IN HAND SURGERY IN BRAZIL. AB - Objective: To verify if there is consensus about the treatment of each type of injury or amputation of the fingertips, and if there is a statistical difference among the treatment options according to the surgeon's length of time in the hand surgery specialty. Methods: A cross-sectional survey was conducted during the 37th Brazilian Congress of Hand Surgery, when one hundred and twenty questionnaires were randomly distributed. Observing the inclusion and exclusion criteria, ninety completed questionnaires were included. The answers were submitted to descriptive and inferential analysis with a significance level of p <0.05. Results: This study showed agreement of 63.3% for the treatment with statistical difference for dorsal oblique injury less than 1 cm with bone exposure for the VY advancement flap alternative; 46.7% for volar tip oblique injury with bone exposure less than 1 cm for the Cross Finger alternative; 47.8% for oblique thumb volar injury greater than 1 cm with no bone exposure to the Moberg alternative; 54.4% for thumb pulp injury up to 2.5 cm with bone exposure to the Moberg alternative with proximal release, and 92.2% for antibiotic use, for the "cephalexin" alternative. Conclusion: There is no consensus regarding the treatment of most types of fingertip lesions, with agreement of 45.4%. When we subdivided by time group of specialty in hand surgery, there was an increase in agreement to 54.5% of the questions per subgroup. Further comparative studies are needed to assess the consensus among surgeons regarding the treatment of fingertip injury. Level of Evidence III; Cross-sectional survey. PMID- 30464709 TI - INCISIONAL NEGATIVE-PRESSURE WOUND THERAPY IN REVISION TOTAL HIP ARTHROPLASTY DUE TO INFECTION. AB - Objective: To present our institution's experience with negative-pressure wound therapy (NPWT) as an adjuvant in wound healing of patients who have undergone revision total hip arthroplasty (THA) due to septic loosening in the presence of active fistula. Methods: We prospectively assessed patients presenting with THA infection, associated with the presence of fistula, treated with a PICO(r) device for NPWT, in combination with the standard treatment for prosthesis infection in our institution. Resolution of the infectious process and healing of the surgical wound without complications were considered an initial favorable outcome. Results: We assessed 10 patients who used PICO(r) in our department. No complications were identified in association with the use of the NPWT device. The mean follow-up of the patients after use of the device was 12.7 months. Only one patient progressed with fistula reactivation and recurrence of infection. Conclusion: NPWT can be used in wound complications and infection following THA procedures safely and with promising results. Randomized prospective studies should be conducted to confirm its effectiveness. Level of Evidence IV, Case Series. PMID- 30464710 TI - BONE TUNNEL ENLARGEMENT WITH NON-METALLIC INTERFERENCE SCREWS IN ACL RECONSTRUCTION. AB - Objective: To compare the widening of bone tunnels between poly-etheretherketone (PEEK), absorbable polylactic acid DL (PLDL) and tricalcium phosphate (TCP) interference screws in anterior cruciate ligament (ACL) reconstruction. Methods: Three groups of patients undergoing ACL reconstruction with at least 1 year of follow-up using the out-in drilling technique and hamstring as a graft were assessed. The patients were divided according to the type of interference screw used (PEEK, PLDL and TCP). Computed tomography (CT) was performed to measure the greatest femoral and tibial tunnel widening regarding to the initial tunnel, and then it was compared between groups. Results: Mean widening in group 1 (PEEK) was 39.56% (SD 16%) in the femoral tunnel and 33.65% (SD 20%) in the tibia. In group 2 (PLDL) mean widening was 48.43% in the femoral tunnel (SD 18%) and 35.24% (SD 13%) in the tibial tunnel. In group 3 (TCP) mean widening was 44.51% in the femur (SD 14%) and 36.83% in the tibia (SD 14%). The comparison between groups (PLDL PEEK, PLDL-TCP, PEEK-TCP) shows no statistically significant difference. Conclusion: Bone tunnel enlargement values after ACL reconstruction with the use of different types of materials (bioinert and biomaterials) of interference screws (PEEK, PLDL and TCP) were similar. Level of Evidence III, Comparative retrospective study. PMID- 30464711 TI - RISK FACTORS FOR EARLY HOSPITAL READMISSION FOLLOWING TOTAL KNEE ARTHROPLASTY. AB - Objective: To identify independent risk factors, complications and early hospital readmission following total knee arthroplasty. Methods: Using the ACS-NSQIP database, we identified patients who underwent primary TKA from 2012-2015. The primary outcome was early hospital readmission. Patient demographics, preoperative comorbidities, laboratory data, operative characteristics, and postoperative complications were compared between readmitted and non-readmitted patients. Logistic regression identified independent risk factors for 30-day readmission. Results: 137,209 patients underwent TKA; 3.4% were readmitted within 30 days. Advanced age, male sex, black ethnicity, morbid obesity, presence of preoperative comorbidities, high ASA classification, and increased operative time were independently related risk factors. Asian and no reported race were negative risk factors. Postoperative complications: acute myocardial infarction, acute renal failure, stroke, pneumonia, pulmonary embolism, and deep vein thrombosis show positive associations. Conclusions: Advanced age, male sex, black ethnicity, morbid obesity, presence of comorbidities, high ASA classification and long operative time are independent risk factors for postoperative complications and early hospital readmission following total knee arthroplasty. Level of Evidence III, Case control study. PMID- 30464712 TI - PERCUTANEOUS TREATMENT OF ANEURYSMAL BONE CYST WITH CALCITONIN AND METHYLPREDNISOLONE. AB - Objective: To introduce the intralesional calcitonin and methylprednisolone percutaneous injection method, which results in the promotion of primary aneurysmal bone cyst (ABC) healing. Methods: A retrospective cohort study involving 76 patients diagnosed with ABC was performed between 2005 and 2014. Patients treated with calcitonin and methylprednisolone injection and who underwent more than 2 years of follow-up were considered eligible for the study (n=47). The Enneking staging and Capanna classification systems were used during the initial evaluation. Treatment response was assessed by Rastogi radiographic grading based on the degree of healing. X2 and Wilcoxon signed-rank tests and odds ratio calculations were used in the statistical analysis with a 5% significance level. Results: The proximal tibia extremity was the most commonly affected site (17.0%). Thirty-three (70.3%) ABC cases were staged as B3 and 28 (59.7%) were classified as type II. The average number of injections performed was 2.8 per patient, with an average reduction of the initial lytic area of 83.7% (p-value=0.00001). Satisfactory results for 91.4% (n=43; p-value=0.00001) were obtained and 5 recurrences occurred. No side effects were observed. Conclusion: Intralesional calcitonin and methylprednisolone percutaneous injection is a minimally invasive, effective, and safe method for promoting primary ABC healing. Level of evidence IV, Type of study: case series. PMID- 30464713 TI - PROGNOSTIC FACTORS IN PATIENTS WITH APPENDICULAR MYXOFIBROSARCOMA. AB - Objective: Myxofibrosarcoma (MFS) is a common soft tissue sarcoma (STS) that affects the extremities in elderly patients. The objective was to analyze the prognostic factors and outcomes of patients with MFS treated at a single institution. Methods: We retrospectively reviewed the records of 75 patients with MFS. We compared age, sex, tumor size and location, grade and stage of the disease. Median age was 49.7 years (range, 1 to 88 y). Location: upper extremity (25.4%), lower extremity (66.6%) and pelvis (8%). Patients had high-grade tumors in 46.7% of the reports. Margins were negative in 76% of the cases. Bivariate Cox regression analysis was used to determine associations between clinical and treatment factors with local recurrence (LR). Results: Median follow-up time was 30.7 months (range, 1.8 to 383.8 m). We found 26.7% of LR. Distant metastasis (DM) was reported in 27 (36%) patients. Lung was the most common site of DM, reported in 92.6% of patients. Overall survival (OS) with metastasis was 21.2 months (range, 4.8 to 114.8 m). Predictors of OS were grade, LR (hazard ratio [HR] 5.13, 95% confidence interval, 2.15-12.24, P <0.001), and DM (HR 540.97, 95% confidence interval, 5.04-58112.03, P< 0.001). Conclusions: Tumor grade, LR, positive margins and DM were significant predictors of poor OS prognosis. Level of Evidence IV, Case Series. PMID- 30464714 TI - CASE STUDY OF CONGENITAL ANOMALIES OF THE UPPER LIMB IN REFERENCE AMBULATORY CARE FACILITY. AB - Objective: The epidemiological profile of congenital anomalies of the upper limbs (CAULs) is of major relevance to monitoring and planning. A study of this profile may reveal if there is prevalence of some specific type of malformation in comparison to a more comprehensive epidemiological sample. The Latin American Collaborative Study of Congenital Malformations (ECLAMC) has an extensive database, providing an excellent source of comparison. This study aims to evaluate the epidemiological profile of CAULs at the hand surgery department of the Hospital Federal da Lagoa (HFL) in Brazil, and compare it to the ECLAMC data. Methods: We conducted a retrospective analysis of patients who underwent treatment at the pediatric outpatient hand surgery clinic. The sample universe consisted of 126 patients (4 of these patients presented with 2 simultaneous anomalies), totaling 130 malformations. Results: The results demonstrated that the comparable pathologies have significantly similar incidence rates. It is worth noting the polydactylies (pre- and post-axial), where the percentile of incidence in the ECLAMC was higher. Conclusion: This study showed that the epidemiological profile of patients who underwent treatment at this hospital was equivalent to that found in the ECLAMC database. Level of evidence III, Retrospective epidemiological study. PMID- 30464715 TI - ARTHROSCOPIC LATARJET TECHNIQUE COMBINED WITH ENDOBUTTONS: FUNCTIONAL OUTCOMES IN 26 CASES. AB - Objective: The cause of anterior shoulder instability is not fully understood and surgical management remains controversial. The objective of this study was to evaluate the results of patients undergoing arthroscopic Latarjet procedure with endobuttons. Methods: A retrospective study of 26 patients undergoing arthroscopic Latarjet procedure with endobuttons to treat anterior shoulder instability. Patients with previous glenohumeral instability, failure of Bankart procedure or Instability Severity Index Score (ISIS) greater than or equal to 6, were included. Patients were assessed by: DASH, UCLA, Rowe, Visual Analog Scale (VAS) of pain and Short-Form 36 (SF36) scores. Correct position and consolidation of the graft were evaluated. Results: Mean age was 31.5 years (16 to 46). Preoperative duration of symptoms was 1.7 years (1 month to 10 years). Mean follow-up was 14.3 (6 to 24) months. Mean postoperative scores were: 10 points in DASH; 1.6 in VAS, where 23 (88%) patients experienced mild pain and 3 (12%) moderate pain; 89 in Rowe; 32 in UCLA and 78 in SF-36. Positioning of the graft was correct in 25 (96%) cases, and was consolidated in 23 (88%). We had two cases of graft fracture (7%) and postoperative migration (7%). Conclusion: Surgical treatment using arthroscopic Latarjet with endobuttons is safe and effective, producing good functional outcomes in patients. Level of Evidence IV, Case Series. PMID- 30464716 TI - ASSESSMENT OF THE RESULTS OF ACCESSORY TO SUPRASCAPULAR NERVE TRANSFER. AB - Objective: Nerve transfers are an alternative in the reconstruction of traumatic brachial plexus injuries. In this study, we report the results of branchial plexus reconstruction using accessory to suprascapular nerve transfer. Methods: Thirty-three patients with traumatic brachial plexus injuries underwent surgical reconstruction with accessory to suprascapular nerve transfers. The patients were divided into groups in which surgery was performed either within 6 months after the injury or more than 6 months after the injury. Results were assessed using the Constant score. Results: There was no significant difference between the groups with respect to the Constant score. Conclusion: Accessory to suprascapular nerve transfer was not an efficient method for recovering active ROM or strength in the shoulder. However, it effectively improved pain control and shoulder stability. Level of evidence II, Retrospective Study. PMID- 30464717 TI - RELIABILITY OF A BRAZILIAN PORTUGUESE TRANSLATED AND CROSS-CULTURALLY ADAPTED VERSION OF THE MJOA SCALE. AB - Objective: To assess the intra- and inter-observer reliability of a Brazilian Portuguese translated and cross-culturally adapted version of the mJOA questionnaire. Methods: The reliability of the Brazilian Portuguese version of the mJOA scale was assessed through the evaluation of a sample of patients with cervical myelopathy by two independent experienced spine surgeon examiners. Inter observer reliability was defined by the Intraclass Correlation Coefficient (ICC) between the evaluations of the two examiners, and intra-observer reliability was assessed by the ICC between the two evaluations of one examiner. Results: Fifty five patients were included in the study (mean age 58.7 years). The ICC for inter observer reliability of the Brazilian Portuguese version of the mJOA was 0.967, and the ICC for intra-observer reliability was 0.869, both classified as "almost perfect" (> 0.81). Conclusion: The Brazilian Portuguese translated and cross culturally adapted version of the mJOA questionnaire appears to be valid and reliable. Level of evidence I, Diagnostic Studies, Investigating a Diagnostic Test. PMID- 30464718 TI - ORTHOPEDIC INJURIES IN MEN'S PROFESSIONAL SOCCER IN BRAZIL: PROSPECTIVE COMPARISON OF TWO CONSECUTIVE SEASONS 2017/2016. AB - Purpose: The purpose is to compare the incidence and characteristics of injuries sustained in two consecutive seasons of the Sao Paulo State Football Championship. Methods: Prospective study performed using an electronic form previously developed by the Medical Committee of the Sao Paulo State Football Federation, sent to the physicians responsible for the tournament's series A1 and A2 teams, after each round. Results: 17.63 injuries sustained per 1000 hours of matches in the A1 series and 14.91 injuries sustained per 1000 hours of matches in the A2 series. Incidence of injuries per 1000 hours of matches decreased from 24.16 to 17.63 in the A1 series (p<0.037) and from 19.10 to 14.01 in the A2 series (p<0.064). External defenders suffered most injuries, while muscular injuries were most common and lower limbs, the most affected areas. Most injuries occurred between 30 and 45 minutes of the match and only 11.9% of the injuries required surgery. Conclusions: Prevalence and frequency of injuries decreased between seasons. Most injuries were sustained in the lower limbs; strains were the most common injuries, followed by strains and contusions; MRIs were the most frequently requested exams and most injuries were classified as moderate (8-28 days). Level of evidence III, Cross-Sectional Study. PMID- 30464719 TI - FACTORS RELATED TO AMPUTATION LEVEL AND WOUND HEALING IN DIABETIC PATIENTS. AB - Objective: There are no specific criteria that define the level of amputation in diabetic patients. The objective of this study was to assess the influence of clinical and laboratory parameters in determining the level of amputation and the wound healing time. Methods: One hundred and thirty-nine diabetic patients were retrospectively assessed. They underwent surgical procedures due to infection and/or ischemic necrosis. Type of surgery, antibiotic use, laboratory parameters and length of hospital stay were evaluated in this study. Results: The most common amputation level was transmetatarsal, occurring in 26 patients (28.9%). The wound healing time increased with statistical significance in individuals undergoing debridement, who did not receive preoperative antibiotics and did not undergo vascular intervention. Higher levels of amputation were statistically related to limb ischemia, previous amputation and non-use of preoperative antibiotics. Conclusion: Patients with minor amputations undergo stump revision surgery more often, but the act of always targeting the most distal stump possible decreases energy expenditure while walking, allowing patients to achieve better quality of life. Risk factors for major amputations were ischemia and previous amputations. A protective factor was preoperative antibiotic therapy. Level of Evidence III, Retrospective Study. PMID- 30464720 TI - NEUROMUSCULAR ELECTRICAL STIMULATION OF MEDIUM AND LOW FREQUENCY ON THE QUADRICEPS FEMORIS. AB - Objective: The purpose of this study was to investigate the effects of neuromuscular electrical stimulation (NMES) in different frequencies on the quadriceps femoris. A randomized, controlled, blind cross-sectional study. Methods: Thirty subjects (12 men and 18 women), with an average age of 24.67 years, weight of 65.62 kg and height of 1.69 m were evaluated. Three random test conditions were applied: maximum voluntary isometric contraction (MVIC), maximum voluntary isometric contraction with medium frequency current (MVIC-MF) and maximum voluntary isometric contraction with low frequency current (MVIC-LF). Four MVICs were applied in each situation. The time between different isometric contraction types was 90 seconds while the time between the same conditions of contraction was 10 seconds. Results: Two-way ANOVA test showed that MVIC-MF had higher values for peak torque than MVIC-LF (p=0.02). Significant statistical results were found when comparing MVIC-MF and MVIC (p=0.03), but not for MVIC and MVIC-LF (p=0.52). Conclusion: Maximum voluntary isometric contraction associated with medium-frequency electrical stimulation was more effective than other NMES conditions. Level of Evidence II, Therapeutic Studies - Investigation of treatment results. PMID- 30464721 TI - SPORTS ACTIVITY AND HIP, KNEE, SHOULDER AND INTERVERTEBRAL DISC ARTHROPLASTIES. AB - The success of joint replacement surgery has been responsible for raising patients' expectations regarding the procedure. Many of these procedures are currently designed not only to relive the pain caused by arthrosis, but also to enable patients to achieve functional recovery and to engage in some degree of physical activity and sports. However, as physical exercise causes an increase in forces exercised through the articular prosthesis, it can be an important risk factor for its early failure. Scientific literature on sports after arthroplasty is limited to small-scale retrospective studies with short-term follow-up, which are mostly insufficient to evaluate articular prosthesis durability. This article presents a review of the literature on sports in the context of hip, knee, shoulder and intervertebral disc arthroplasty, and puts forward general recommendations based on the current scientific evidence. Systematic Review, Level of Evidence III. PMID- 30464722 TI - Local and global interpolations along the adiabatic connection of DFT: a study at different correlation regimes. AB - Interpolating the exchange-correlation energy along the density-fixed adiabatic connection of density functional theory is a promising way to build approximations that are not biased toward the weakly correlated regime. These interpolations can be performed at the global (integrated over all spaces) or at the local level, using energy densities. Many features of the relevant energy densities as well as several different ways to construct these interpolations, including comparisons between global and local variants, are investigated here for the analytically solvable Hooke's atom series, which allows for an exploration of different correlation regimes. We also analyze different ways to define the correlation kinetic energy density, focusing on the peak in the kinetic correlation potential. PMID- 30464723 TI - Mapping the "housing with care" concept with stakeholders: insights from a UK case study. AB - Purpose: The purpose of this paper is to present the findings of an early stage, exploratory case study of a proposed housing with care initiative (the Crichton Care Campus (CCC)). This sought the perspectives of a range of key stakeholders on the proposed model and how it might be best realised. The analyses of these findings show their relevance to debates on integrated housing with care, and reflect on the methodology used and its potential relevance to similar projects. Design/methodology/approach: The study used a transactive planning approach, where grounded views are sought from a variety of stakeholders. A purposive sample identified informants from relevant health, social care and housing organisations and nine semi-structured interviews were conducted. These were transcribed and data analysis was undertaken on an "interactive" basis, relating care theory to empirical expressions. Findings: The authors identify two contrasting orientations - inclusive "community-oriented" and professional "service-oriented". This distinction provides the basis for a rudimentary conceptual map which can continue to be used in the planning process. Two significant variables within the conceptual map were the extent to which CCC should be intergenerational and as such, the degree to which care should come from formalised and self-care/informal sources. The potential to achieve an integrated approach was high with stakeholders across all sectors fully supporting the CCC concept and agreeing on the need for it to have a mixed tenure basis and include a range of non-care amenities. Originality/value: This paper offers originality in two respects. Methodologically, it describes an attempt to undertake early stage care planning using a needs led transactive methodology. In more practical terms, it also offers an innovative environment for considering any approach to care planning that actively seeks integration - based on an acknowledgement of complexity, a variety of perspectives and possible conflicts. The authors propose that the concepts of "community-orientation" and "service orientation" are used as a helpful basis for planning negotiations, making implicit divergences explicit and thus better delineated. PMID- 30464724 TI - An integrated care programme in London: qualitative evaluation. AB - Purpose: A well-funded, four-year integrated care programme was implemented in south London. The programme attempted to integrate care across primary, acute, community, mental health and social care. The purpose of this paper is to reduce hospital admissions and nursing home placements. Programme evaluation aimed to identify what worked well and what did not; lessons learnt; the value of integrated care investment. Design/methodology/approach: Qualitative data were obtained from documentary analysis, stakeholder interviews, focus groups and observational data from programme meetings. Framework analysis was applied to stakeholder interview and focus group data in order to generate themes. Findings: The integrated care project had not delivered expected radical reductions in hospital or nursing home utilisation. In response, the scheme was reformulated to focus on feasible service integration. Other benefits emerged, particularly system transformation. Nine themes emerged: shared vision/case for change; interventions; leadership; relationships; organisational structures and governance; citizens and patients; evaluation and monitoring; macro level. Each theme was interpreted in terms of "successes", "challenges" and "lessons learnt". Research limitations/implications: Evaluation was hampered by lack of a clear evaluation strategy from programme inception to conclusion, and of the evidence required to corroborate claims of benefit. Practical implications: Key lessons learnt included: importance of strong clinical leadership, shared ownership and inbuilt evaluation. Originality/value: Primary care was a key player in the integrated care programme. Initial resistance delayed implementation and related to concerns about vertical integration and scepticism about unrealistic goals. A focus on clinical care and shared ownership contributed to eventual system transformation. PMID- 30464725 TI - Let's Talk About Sex: Integrating Sex as a Biological Variable Into Epilepsy Research. AB - There is a long history of underrepresentation of women and female animals being studied in scientific research, which has resulted in gaps in knowledge and at times, inaccurate clinical recommendations. There is a gradual shift in the mindset of the scientific community on this issue, in part related to policy changes enacted by the National Institute of Health (NIH). Sex must now be accounted for as a biological variable in both basic and clinical research. This review discusses the history of evolving policies on inclusion of sex-informed data in scientific research, and the ways in which epilepsy researchers can approach future studies in a manner that takes sex as a biological variable into account. PMID- 30464726 TI - Epilepsy and Alzheimer's Disease: Ubiquitous Entities Subject to the Same Cosmic Forces but on Different Astral Planes. PMID- 30464727 TI - Hippocampal Sclerosis and Memory: Continuing the Search for a Link in Temporal Lobe Epilepsy. PMID- 30464728 TI - NORSE Versus FIRES: What's in a Name? PMID- 30464729 TI - Drug Resistant Epilepsy and New AEDs: Two Perspectives. PMID- 30464730 TI - More Than Meets the Eye: Antiepileptic Drug Use During Pregnancy and its Effects Beyond Teratogenesis. PMID- 30464731 TI - Women With Epilepsy and Control Women: Two Peas in a WEPOD. PMID- 30464732 TI - Defining a Place for Lacosamide in the Intensive Care Unit. PMID- 30464733 TI - The Highs and Lows of the Endocannabinoid System-Another Piece to the Epilepsy Puzzle? PMID- 30464734 TI - A Metabolic Paradigm for Epilepsy. AB - There is a resurgence of interest in the role of metabolism in epilepsy. Long considered ancillary and acknowledged only in the context of clinical application of ketogenic diets, metabolic control of epilepsy is gaining momentum and mainstream interest among researchers. A metabolic paradigm for epilepsy rests upon known perturbations in three major interconnected metabolic nodes and therapeutic targets therefrom (i.e., glycolysis, mitochondria, and redox balance). PMID- 30464735 TI - Cognition in Epilepsy: DeltaFosB Takes Center Stage (and May Star in the Prologue). PMID- 30464736 TI - Round Up the Unusual Suspects: Can Noninflammatory Microglia Drive Epileptogenesis? PMID- 30464737 TI - Adult Neurogenesis in the Human Brain: Paradise Lost? PMID- 30464738 TI - A BAD Insight into a Molecular Mechanism of the Ketogenic Diet? PMID- 30464739 TI - cPLA2 in Epilepsy: Shutting Down the Leaker at Its Source. PMID- 30464740 TI - Volatile metabolic diversity of Klebsiella pneumoniae in nutrient-replete conditions. AB - Introduction: Microorganisms catabolize carbon-containing compounds in their environment during growth, releasing a subset of metabolic byproducts as volatile compounds. However, the relationship between growth media and the production of volatile compounds has been largely unexplored to-date. Objectives: To assess the core and media-specific components of the Klebsiella pneumoniae volatile metabolome via growth in four in vitro culture media. Methods: Headspace volatiles produced by cultures of K. pneumoniae after growth to stationary phase in four rich media (brain heart infusion broth, lysogeny broth, Mueller-Hinton broth, and tryptic soy broth) were analyzed using comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC*GC-TOFMS). Differences in the composition of headspace volatiles as a function of growth media was assessed using hierarchical clustering analysis (HCA) and principal component analysis (PCA). Results: A total of 365 volatile compounds were associated with the growth of K. pneumoniae across all media, of which 36 (10 %) were common to all growth media, and 148 (41 %) were specific to a single medium. In addition, utilizing all K. pneumoniae-associated volatile compounds, strains clustered as a function of growth media, demonstrating the importance of media in determining the metabolic profile of this organism. Conclusion: K. pneumoniae produces a core suite of volatile compounds across all growth media studied, although the volatile metabolic signature of this organism is fundamentally media-dependent. PMID- 30464741 TI - G2019S LRRK2 Increases Stress Susceptibility Through Inhibition of DAF-16 Nuclear Translocation in a 14-3-3 Associated-Manner in Caenorhabditis elegans. AB - Mutations in leucine-rich repeat kinase 2 (LRRK2) are common causes of familial Parkinson's disease (PD). Oxidative stress plays a key role in the pathogenesis of PD. Mutations in LRRK2 have been shown to increase susceptibility to oxidative stress. To explore mechanisms underlying susceptibility to oxidative stress in LRRK2 mutants, we generated stable Caenorhabditis elegans (C. elegans) strains in which human LRRK2 proteins including wild type LRRK2 (WT), G2019S LRRK2 (G2019S), and G2019S-D1994A kinase-dead LRRK2 (KD) were expressed in all neurons. Human 14 3-3 beta was injected into LRRK2 transgenic worms to allow co-expression of 14-3 3 beta and LRRK2 proteins. We found that G2019S transgenic worms had increased sensitivity to stress (heat and juglone treatment) and impaired stress-induced nuclear translocation of DAF-16. In addition, G2019S inhibited ftt2 (a 14-3-3 gene homolog in C. elegans) knockdown-associated nuclear translocation of DAF-16. Comparably, overexpression of human 14-3-3 beta could attenuate G2019S-associated toxicity in response to stress and rescued G2019S-mediated inhibition of sod-3 and dod-3 expression. Taken together, our study provides evidence suggesting that 14-3-3-associated inhibition of DAF-16 nuclear translocation could be a mechanism for G2019S LRRK2-induced oxidative stress and cellular toxicity. Our findings may give a hint that the potential of 14-3-3 proteins as neuroprotective targets in PD patients carrying LRRK2 mutations. PMID- 30464742 TI - Addendum: Effects of a 5-HT1B Receptor Agonist on Locomotion and Reinstatement of Cocaine-Conditioned Place Preference after Abstinence from Repeated Injections in Mice. PMID- 30464743 TI - The Role of the Intestinal Microbiome in Chronic Psychosocial Stress-Induced Pathologies in Male Mice. AB - Chronic psychosocial stress is a risk factor for the development of physical and mental disorders accompanied or driven by an activated immune system. Given that chronic stress-induced systemic immune activation is lacking in germ-free and antibiotics-treated mice, a causal role of the gut microbiome in the development of stress-related disorders is likely. To address this hypothesis in the current study we employed the chronic subordinate colony housing (CSC, 19 days) paradigm, a pre-clinically validated mouse model for chronic psychosocial stress, known to alter the gut microbial signature and to induce systemic low-grade inflammation, as well as physical and mental abnormalities. In detail, we investigated if (i) CSC-induced alterations can be prevented by repeated transplantation of feces (FT) from non-stressed single-housed control (SHC) mice during CSC exposure, and (ii) if the transplantation of a "stressed" CSC microbiome is able to induce CSC effects in SHC mice. Therefore, we repeatedly infused SHC and CSC recipient mice rectally with SHC donor feces at days 4 and 11 of the CSC paradigm and assessed anxiety-related behavior on day 19 as well as physiological, immunological, and bone parameters on day 20. Furthermore, SHC and CSC recipient mice were infused with CSC donor feces at respective days. To exclude effects of rectal infusions per se, another set of SHC and CSC mice was infused with saline, respectively. Our results showed that transplantation of SHC feces had mild stress-protective effects, indicated by an amelioration of CSC-induced thymus atrophy, anxiety, systemic low-grade inflammation, and alterations in bone homeostasis. Moreover, transplantation of CSC feces slightly aggravated CSC-induced systemic low-grade inflammation and alterations in bone homeostasis in SHC and/or CSC animals. In conclusion, our data provide evidence for a role of the host's microbiome in many, but not all, adverse consequences of chronic psychosocial stress. Moreover, our data are consistent with the hypothesis that transplantation of healthy feces might be a useful tool to prevent/treat different adverse outcomes of chronic stress. Finally, our data suggests that stress effects can be transferred to a certain extend via FT, proposing therapeutic approaches using FT to carefully screen fecal donors for their stress/trauma history. PMID- 30464744 TI - Training on an Appetitive (Delay)-Conditioning Task Enhances Oscillatory Waves During Sleep in the Cortical and Amygdalar Network. AB - Oscillating waves during sleep play an essential role in memory consolidation. The cortical slow wave activity (SWA) and sigma waves during NREM sleep and theta waves during REM sleep increase after a variety of memory tasks including declarative, procedural and associative learning tasks. These oscillatory waves during sleep help to promote neural dialog between circuitries, which possibly plays a causal role in memory consolidation. However, the role of sleep associated oscillating waves in a complex appetitive-conditioning paradigm is not clear. The parietal cortex and amygdala are involved in the cognitive evaluation of the environmental stimuli, and appetitive conditioning. Here, we have studied the changes in sleep architecture and oscillatory waves during NREM and REM sleep in the parietal cortices and amygdalar-local field potential (A-LFP) after appetitive-conditioning in the rat. We observed that REM sleep increased significantly after appetitive conditioning, which significantly positively correlated with performance on the appetitive-conditioning task. Further, the cortical SWA (0.1-4.5 Hz), and sigma (12-14.25 Hz) waves during NREM sleep, theta (6-9 Hz) waves during REM sleep, the amygdalar SWA (0.1-3.75 Hz) during NREM sleep and theta (6-8.25 Hz) waves during REM sleep significantly increased after appetitive conditioning. Interestingly, the augmented oscillatory waves significantly positively correlated with the performances on the appetitive conditioning task. Our results suggest that the augmented REM sleep after conditioning may be required for the consolidation of appetitive-conditioned memory. Further, a significant correlation between augmented power in oscillatory waves during sleep and performance suggesting that these waves may be playing a crucial role in the consolidation of appetitive-conditioned memory. PMID- 30464745 TI - Elucidating the Interaction of CF Airway Epithelial Cells and Rhinovirus: Using the Host-Pathogen Relationship to Identify Future Therapeutic Strategies. AB - Chronic lung disease remains the primary cause of mortality in cystic fibrosis (CF). Growing evidence suggests respiratory viral infections are often more severe in CF compared to healthy peers and contributes to pulmonary exacerbations (PEx) and deterioration of lung function. Rhinovirus is the most prevalent respiratory virus detected, particularly during exacerbations in children with CF <5 years old. However, even though rhinoviral infections are likely to be one of the factors initiating the onset of CF lung disease, there is no effective targeted treatment. A better understanding of the innate immune responses by CF airway epithelial cells, the primary site of infection for viruses, is needed to identify why viral infections are more severe in CF. The aim of this review is to present the clinical impact of virus infection in both young children and adults with CF, focusing on rhinovirus infection. Previous in vitro and in vivo investigations looking at the mechanisms behind virus infection will also be summarized. The review will finish on the potential of transcriptomics to elucidate the host-pathogen responses by CF airway cells to viral infection and identify novel therapeutic targets. PMID- 30464746 TI - Hypokalemia-Induced Arrhythmias and Heart Failure: New Insights and Implications for Therapy. AB - Routine use of diuretics and neurohumoral activation make hypokalemia (serum K+ < 3. 5 mM) a prevalent electrolyte disorder among heart failure patients, contributing to the increased risk of ventricular arrhythmias and sudden cardiac death in heart failure. Recent experimental studies have suggested that hypokalemia-induced arrhythmias are initiated by the reduced activity of the Na+/K+-ATPase (NKA), subsequently leading to Ca2+ overload, Ca2+/Calmodulin dependent kinase II (CaMKII) activation, and development of afterdepolarizations. In this article, we review the current mechanistic evidence of hypokalemia induced triggered arrhythmias and discuss how molecular changes in heart failure might lower the threshold for these arrhythmias. Finally, we discuss how recent insights into hypokalemia-induced arrhythmias could have potential implications for future antiarrhythmic treatment strategies. PMID- 30464747 TI - Hypomania Symptoms Across Psychiatric Disorders: Screening Use of the Hypomania Check-List 32 at Admission to an Outpatient Psychiatry Clinic. AB - Introduction: Hypomania symptoms are best described as a continuum, ranging beyond Bipolar Spectrum Disorders (BSD). Other nosological entities, such as major depressive disorder, schizoaffective disorder, or borderline personality disorder, may also share symptoms with BSD, raising challenges for differential diagnosis. While the Hypomania Checklist-32 is one of the most widely used tools for screening hypomania, there is limited evidence describing its use in a real world outpatient psychiatric clinical setting. Methods: Here we tested the psychometric properties of a European Portuguese adaptation of the HCL-32, establishing its factor structure, reliability and construct validity. Furthermore, we analyzed differences in hypomanic symptoms among several clinical groups and in a non-clinical sample. Data was obtained retrospectively in an ecological setting from a clinical sample of an outpatient psychiatry and psychology clinic, comprising 463 Portuguese individuals, 326 of whom had a psychiatric diagnosis, namely BSD (n = 66), major depressive disorder (n = 116), or other psychiatric disorders (n = 144). A separate non-clinical sample was also collected among healthy volunteers (n = 62). A battery of self-report measures of affective symptoms was applied, and in a subset of patients, diagnosis was established using a structured diagnostic interview. Results: Psychometric properties of the HCL-32 were adequate, with good internal consistency (Cronbach's alpha = 0.86) and test-retest stability (ICC = 0.86), and two subscores ("active/elated" and "risk-taking/irritable") defined by Principal Component Analysis. Receiver Operating Characteristic curve analysis demonstrated that the test score discriminated moderately between patients with BSD and other clinical samples as well as healthy volunteers, with a cut-off score of 17 for the total score of the HCL-32 rendering the best combination of sensitivity and specificity. When compared to the HCL-32 total score, the risk-taking/irritable subscore seems to provide additional benefit in discriminating between different clinical groups, namely regarding specificity in the discrimination from patients with a diagnosis of major depressive disorder that was low for the full scale and the alternate subscale. Conclusions: HCL-32 can be used as a screening tool for BSD among adult patients presenting in an outpatient psychiatric clinical setting. PMID- 30464749 TI - Lower Choline Rate in the Left Prefrontal Cortex Is Associated With Higher Amount of Alcohol Use in Alcohol Use Disorder. AB - Excessive and long-term alcohol consumption produce metabolic changes, such as of choline, in many brain regions in alcohol use disorder (AUD) and in non-AUD subjects as well. This study examined the association of choline proportion in the prefrontal cortex with pattern of alcohol use in AUD patients. The choline metabolite was acquired through a single voxel Proton Magnetic Resonance Spectroscopy (1H MRS). Between-groups comparison corrected by age showed that the ratio of Choline/Creatine (Cho/Cr) was significantly smaller (p = 0.005) in the Left Prefrontal (LPF) of AUD patients when compared to paired non-AUD subjects. A multiple regression analysis corrected by age showed that decreasing ratios of Cho/Cr in the LPF was associated with increasing amount of alcohol consumption in drinks per day (p < 0.01) in AUD patients. Rates of Cho/Cr in the LPF was inversely related to amounts of alcohol consumption possibly indicating the severity of the AUD. Thus, low proportion of Cho/Cr in the LPF could indicate more severe AUD (higher alcohol intake). PMID- 30464750 TI - A Conceptual Restructuring of Spatial Motion Expressions in Chinese L2. AB - This paper focuses on the patterns in the encoding of spatial motion events that play a major role in the acquisition of these type of expressions. The goal is to single out the semantic contribution of the linguistic items which surface in Chinese locative constructions. In this way, we intend to provide learners with an account of the spatial representation encoded in the Chinese language. In fact, Chinese grammar is often perceived as idiosyncratic, thus generating a frustration that turns into learned helplessness (Maier and Seligman, 1976). We will analyze Talmy (2000a,b) framework under the light of investigations such as Landau and Jackendoff (1993), Svenonius (2004, 2006, 2007), and Terzi (2010). It will be shown that in Chinese locative structures, the Axial Part information is signaled by localizers and can be specified only when the Ground is considered as an object with "axially determined parts" (Landau and Jackendoff, 1993). Thus, we will elaborate on present account on the localizer's function (Peyraube, 2003; Lamarre, 2007; Lin, 2013) by showing that the localizer highlights an axially determined part within a reference object, consistently with Terzi (2010) definition of Place, and with Wu (2015) decomposition of Place into Ground and Axial Part. Moreover, it will be shown that the preposition zai 'at' encodes a Locative type of Motion event (Talmy, 2000b), thus, it is not semantically vacuous. Other categories will be presented, such as the semantic class of locational verbs (Huang, 1987). We will indicate the contexts wherein such notions can trigger the conceptual restructuring which enables adult learners to switch from L1 "thinking for speaking" to L2 "thinking for speaking" (Slobin, 1987). The paper is structured as follows: Section "Introduction" provides introduction to the theme; Section "Theoretical Framework" includes a surveys on the semantic and syntactic decompositions of spatial motion expressions; Section "Discussion" offers an account of the instantiation; the findings and the relevant pedagogical implications are presented in Section "Findings." PMID- 30464751 TI - "When You Make a Movie, and You See Your Story There, You Can Hold It": Qualitative Exploration of Collaborative Filmmaking as a Therapeutic Tool for Veterans. AB - Despite the availability of effective treatments for coping with traumatic experiences, a large percentage of military veterans in need do not seek help. The "I Was There" model is a new filmmaking program which is a creative expressive tool, developed to enable veterans to reflect on their experiences and jointly create short artistic films. These artistic films articulate, often metaphorically, aspects of the veterans' service experiences, traumatic events, and reintegration challenges. The current study employed a qualitative methodology to explore participants' subjective experience of the program. We interviewed 50 participants following the intervention, focusing specifically on their perceptions of the filmmaking process, the aspects they viewed as meaningful, and whether and how the process affected them. Most participants reported their experience as positive and empowering. Three overarching themes emerged as significant in describing the benefits of participation: Gaining a new sense of agency, regaining a sense of affiliation, and processing the trauma. The findings are illustrated and discussed within the context of narrative therapy, as is the potential of video-based therapy, especially regarding non-articulated, sensory traumatic memories, and for the process of (re)construction of the trauma narrative. PMID- 30464748 TI - Sugar Addiction: From Evolution to Revolution. AB - The obesity epidemic has been widely publicized in the media worldwide. Investigators at all levels have been looking for factors that have contributed to the development of this epidemic. Two major theories have been proposed: (1) sedentary lifestyle and (2) variety and ease of inexpensive palatable foods. In the present review, we analyze how nutrients like sugar that are often used to make foods more appealing could also lead to habituation and even in some cases addiction thereby uniquely contributing to the obesity epidemic. We review the evolutionary aspects of feeding and how they have shaped the human brain to function in "survival mode" signaling to "eat as much as you can while you can." This leads to our present understanding of how the dopaminergic system is involved in reward and its functions in hedonistic rewards, like eating of highly palatable foods, and drug addiction. We also review how other neurotransmitters, like acetylcholine, interact in the satiation processes to counteract the dopamine system. Lastly, we analyze the important question of whether there is sufficient empirical evidence of sugar addiction, discussed within the broader context of food addiction. PMID- 30464752 TI - A Narrative Review of School-Based Physical Activity for Enhancing Cognition and Learning: The Importance of Relevancy and Integration. AB - Engaging in regular physical activity can have substantial cognitive and academic benefits for children, and is generally promoted for its beneficial effects on children's physical and mental health. Although embodied cognition research has convincingly shown the integral relationship of the human body and mind, in schools physical activity and cognitive activity are typically treated as unrelated processes. Consequently, most physical activities used are neither sufficiently relevant for nor fully integrated into the learning tasks. In reviewing the literature regarding the integration of physical activity into education to promote cognition and learning, two main lines of research emerged: exercise and cognition research vs. embodied cognition research. In this narrative review, we describe these two separately evolved schools of thought, highlighting their differences and commonalities. In categorising the existing studies on a 2 * 2 matrix, concerning the two main categories of relevance for and integration into the learning task, it becomes clear where the different foci lie, and how both lines of research could profit from learning from each other. Finally, a new instructional model that integrates task-relevant physical activities into the cognitive/learning task is proposed to inform both further research and educational practice. PMID- 30464753 TI - Video Games for Well-Being: A Systematic Review on the Application of Computer Games for Cognitive and Emotional Training in the Adult Population. AB - Background: Although several excellent reviews and meta-analyses have investigated the effect of video game trainings as tools to enhance well-being, most of them specifically focused on the effects of digital games on brain plasticity or cognitive decline in children and seniors. On the contrary, only one meta-analysis results to be focused on the adult population, and it is restricted to examining the effects of training with a particular genre of games (action video games) on cognitive skills of healthy adults. Objectives: This systematic review was aimed to identify research evidences about the impact on cognitive [i.e., processing and reaction times (RTs), memory, task switching/multitasking, and mental spatial rotation] and emotional skills of video games training in the healthy adult population. Methods: A multi-component analysis of variables related to the study, the video games, and the outcomes of the training was made on the basis of important previous works. Databases used in the search were PsycINFO, Web of Science (Web of Knowledge), PubMed, and Scopus. The search string was: [("Video Games" OR "Computer Games" OR "Interactive Gaming")] AND [("Cognition") OR ("Cognitive") OR ("Emotion") OR ("Emotion Regulation")] AND ["Training"]. Results: Thirty-five studies met the inclusion criteria and were further classified into the different analysis' variables. The majority of the retrieved studies used commercial video games, and action games in particular, which resulted to be the most commonly used, closely followed by puzzle games. Effect sizes for training with video games on cognitive skills in general ranged from 0.06 to 3.43: from 0.141 to 3.43 for processing and RTs, 0.06 to 1.82 for memory, 0.54 to 1.91 for task switching/multitasking, and 0.3 to 3.2 for mental spatial rotation; regarding video games for the training of emotional skills, effect sizes ranged from 0.201 to 3.01. Conclusion: Overall, findings give evidences of benefits of video games training on cognitive and emotional skills in relation to the healthy adult population, especially on young adults. Efficacy has been demonstrated not only for non-commercial video games or commercial brain-training programs, but for commercial video games as well. PMID- 30464754 TI - Improving Hand Function of Severely Impaired Chronic Hemiparetic Stroke Individuals Using Task-Specific Training With the ReIn-Hand System: A Case Series. AB - Purpose: In this study, we explored whether improved hand function is possible in poststroke chronic hemiparetic individuals with severe upper limb motor impairments when they participate in device-aided task-specific practice. Subjects: Eight participants suffering from chronic stroke (>1-year poststroke, mean: 11.2 years) with severely impaired upper extremity movement (Upper Extremity Subscale of the Fugl-Meyer Motor Assessment (UEFMA) score between 10 and 24) participated in this study. Methods: Subjects were recruited to participate in a 20-session intervention (3 sessions/7 weeks). During each session, participants performed 20-30 trials of reaching, grasping, retrieving, and releasing a jar with the assistance of a novel electromyography-driven functional electrical stimulation (EMG-FES) system. This EMG-FES system allows for Reliable and Intuitive use of the Hand (called ReIn-Hand device) during multi joint arm movements. Pre-, post-, and 3-month follow-up outcome assessments included the UEFMA, Cherokee McMaster Stroke Assessment, grip dynamometry, Box and Blocks Test (BBT), goniometric assessment of active and passive ranges of motion (ROMs) of the wrist and the metacarpophalangeal flexion and extension (II, V fingers), Nottingham Sensory Assessment-Stereognosis portion (NSA), and Cutaneous Sensory Touch Threshold Assessment. Results: A nonparametric Friedman test of differences found significant changes in the BBT scores (chi2 = 10.38, p < 0.05), the passive and active ROMs (chi2 = 11.31, p < 0.05 and chi2 = 12.45, p < 0.01, respectively), and the NSA scores (chi2 = 6.42, p < 0.05) following a multi-session intervention using the ReIn-Hand device. Conclusions: These results suggest that using the ReIn-Hand device during reaching and grasping activities may contribute to improvements in gross motor function and sensation (stereognosis) in individuals with chronic severe UE motor impairment following stroke. PMID- 30464755 TI - O-GlcNAc as an Integrator of Signaling Pathways. AB - O-GlcNAcylation is an important posttranslational modification governed by a single pair of enzymes-O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). These two enzymes mediate the dynamic cycling of O-GlcNAcylation on a wide variety of cytosolic, nuclear and mitochondrial proteins in a nutrient- and stress responsive fashion. While cellular functions of O-GlcNAcylation have been emerging, little is known regarding the precise mechanisms how the enzyme pair senses the environmental cues to elicit molecular and physiological changes. In this review, we discuss how the OGT/OGA pair acts as a metabolic sensor that integrates signaling pathways, given their capability of receiving signaling inputs from various partners, targeting multiple substrates with spatiotemporal specificity and translocating to different parts of the cell. We also discuss how the pair maintains homeostatic signaling within the cell and its physiological relevance. A better understanding of the mechanisms of OGT/OGA action would enable us to derive therapeutic benefits of resetting cellular O-GlcNAc levels within an optimal range. PMID- 30464756 TI - Foodborne Pathogen Survival in Commercial Alorena de Malaga Table Olive Packaging. AB - This study presents an approach to determine the survival of diverse foodborne pathogens (Escherichia coli, Staphylococcus aureus, Listeria monocytogenes, and Salmonella enterica) in three Alorena de Malaga table olive commercial presentations (fresh green, traditional, and cured olives). The microbial survival in this green natural table olive speciality was fit using a log-linear regression model implemented in GInaFIT. The contents of sugars, phenolic compounds, additives, salt, pH, and levels of autochthonous microorganisms differed among presentations and affected the survival of microorganisms. The inoculated initial populations of pathogens (7-8 log10 CFU/mL brine) decreased rapidly and, 48 h after inoculation, their counts were always below the detection limit (<1.3 log10 CFU/mL), except for S. aureus in the fresh green presentation which was ~ 5.0 log10 CFU/mL. The highest maximum death rates (kmax ) and lowest periods for 4 log10 reductions (4Dr) were observed in cured olives but decreased and increased, respectively, from the traditional to the fresh green presentations. L. monocytogenes and S. aureus were the most resistant species. The multivariate analysis showed that high concentrations of compounds released from the olives (sugars and phenols) were positively associated to 4Dr and negatively to kmax . Conversely, the presence of preservatives reduced 4Dr. This study, executed in commercial products, pointed out that packaged table olives are adverse habitats for foodborne pathogens with their effects being presentation dependent. The survival of S. aureus was particularly long in green fresh Alorena de Malaga table olives packaged without preservatives; therefore, its changes in this presentation still requires further in-deep research. PMID- 30464757 TI - Low Temperature Synthesis of Superparamagnetic Iron Oxide (Fe3O4) Nanoparticles and Their ROS Mediated Inhibition of Biofilm Formed by Food-Associated Bacteria. AB - In the present study, a facile environmentally friendly approach was described to prepare monodisperse iron oxide (Fe3O4) nanoparticles (IONPs) by low temperature solution route. The synthesized nanoparticles were characterized using x-ray diffraction spectroscopy (XRD), Raman spectroscopy, field emission scanning electron microscopy (FESEM) measurements, Fourier-Transform Infrared Spectroscopy (FTIR), and Thermogravimetric analysis (TGA) analyses. XRD patterns revealed high crystalline quality of the nanoparticles. SEM micrographs showed the monodispersed IONPs with size ranging from 6 to 9 nm. Synthesized nanoparticles demonstrated MICs of 32, 64, and 128 MUg/ml against Gram negative bacteria i.e., Serratia marcescens, Escherichia coli, and Pseudomonas aeruginosa, respectively, and 32 MUg/ml against Gram positive bacteria Listeria monocytogenes. IOPNs at its respective sub-MICs demonstrated significant reduction of alginate and exopolysaccharide production and subsequently demonstrated broad-spectrum inhibition of biofilm ranging from 16 to 88% in the test bacteria. Biofilm reduction was also examined using SEM and Confocal Laser Scanning Microscopy (CLSM). Interaction of IONPs with bacterial cells generated ROS contributing to reduced biofilm formation. The present study for the first time report that these IONPs were effective in obliterating pre-formed biofilms. Thus, it is envisaged that these nanoparticles with broad-spectrum biofilm inhibitory property could be exploited in the food industry as well as in medical settings to curtail biofilm based infections and losses. PMID- 30464758 TI - Enhanced Biofilm Formation and Membrane Vesicle Release by Escherichia coli Expressing a Commonly Occurring Plasmid Gene, kil. AB - Escherichia coli is one of the most prevalent microorganisms forming biofilms on indwelling medical devices, as well as a representative model to study the biology and ecology of biofilms. Here, we report that a small plasmid gene, kil, enhances biofilm formation of E. coli. The kil gene is widely conserved among naturally occurring colicinogenic plasmids such as ColE1 plasmid, and is also present in some plasmid derivatives used as cloning vectors. First, we found that overexpression of the kil gene product dramatically increased biofilm mass enriched with extracellular DNA in the outer membrane-compromised strain RN102, a deep rough LPS mutant E. coli K-12 derivative. We also found that the kil enhanced biofilm formation was further promoted by addition of physiologically relevant concentrations of Mg2+, not only in the case of RN102, but also with the parental strain BW25113, which retains intact core-oligosaccharide LPS. Biofilm formation by kil-expressing BW25113 strain (BW25113 kil+ ) was significantly inhibited by protease but not DNase I. In addition, a large amount of proteinous materials were released from the BW25113 kil+ cells. These materials contained soluble cytoplasmic and periplasmic proteins, and insoluble membrane vesicles (MVs). The kil-induced MVs were composed of not only outer membrane/periplasmic proteins, but also inner membrane/cytoplasmic proteins, indicating that MVs from both of the outer and inner membranes could be released into the extracellular milieu. Subcellular fractionation analysis revealed that the Kil proteins translocated to both the outer and inner membranes in whole cells of BW25113 kil+ . Furthermore, the BW25113 kil+ showed not only reduced viability in the stationary growth phase, but also increased susceptibility to killing by predator bacteria, Vibrio cholerae expressing the type VI secretion system, despite no obvious change in morphology and physiology of the bacterial membrane under regular culture conditions. Taken together, our findings suggest that there is risk of increasing biofilm formation and spreading of numerous MVs releasing various cellular components due to kil gene expression. From another point of view, our findings could also offer efficient MV production strategies using a conditional kil vector in biotechnological applications. PMID- 30464759 TI - Editorial: Microorganisms for a Sustainable Viticulture and Winemaking. PMID- 30464760 TI - First Insights Into Within Host Translocation of the Bacillus cereus Toxin Cereulide Using a Porcine Model. AB - Bacillus cereus is a gram-positive pathogen mainly known to evoke two types of foodborne poisonings. The diarrheal syndrome is caused by enterotoxins produced during growth in the intestine. In contrast, the emetic type is caused by the dodecadepsipeptide cereulide pre-formed in food. Usually, both diseases are self limiting but occasionally more severe forms, including fatal ones, are reported. Since the mechanisms of cereulide toxin uptake and translocation within the body as well as the mechanism of its toxic action are still unknown, we used a porcine model to investigate the uptake, routes of excretion and distribution of cereulide within the host. Pigs were orally challenged with cereulide using single doses of 10-150 MUg cereulide kg-1 body weight to study acute effects or using daily doses of 10 MUg cereulide kg-1 body weight administered for 7 days to investigate effects of longtime, chronic exposure. Our study showed that part of cereulide ingested with food is rapidly excreted with feces while part of the cereulide toxin is absorbed, passes through membranes and is distributed within the body. Results from the chronic trial indicate bioaccumulation of cereulide in certain tissues and organs, such as kidney, liver, muscles and fat tissues. Beside its detection in various tissues and organs, our study also demonstrated that cereulide is able to cross the blood-brain-barrier, which may partially explain the cerebral effects reported from human intoxication cases. The neurobehavioral symptoms, such as seizures and lethargy, observed in our porcine model resemble those reported from human food borne intoxications. The rapid onset of these symptoms indicates direct effects of cereulide on the central nervous system (CNS), which warrant further research. The porcine model presented here might be useful to study the specific neurobiological effect in detail. Furthermore, our study revealed that typical diagnostic specimens used in human medicine, such as blood samples and urine, are not suitable for diagnostics of food borne cereulide intoxications. Instead, screening of fecal samples by SIDA LC-MS may represent a simple and non-invasive method for detection of cereulide intoxications in clinical settings as well as in foodborne outbreak situations. PMID- 30464761 TI - Prevalence and Clinical Associations of Antiphospholipid Antibodies in Systemic Sclerosis: New Data From a French Cross-Sectional Study, Systematic Review, and Meta-Analysis. AB - Objectives: Antiphospholipid antibodies (aPL) can be present in the sera of systemic sclerosis (SSc) patients. This study aimed to determine the prevalence of aPL in a cross-sectional study of SSc patients, to assess their clinical associations, to perform a systematic review of published reports and a meta analysis to estimate the worldwide prevalence of aPL in SSc. Methods: Two-hundred and forty-nine SSc patients were consecutively tested once for lupus anticoagulant (LA), anticardiolipin (aCL), and anti-beta2glycoprotein I (anti beta2GpI) antibodies. Clinical associations with aPL positivity were studied using a logistic regression model. A systematic review of the literature was carried out in PubMed and Embase. Meta-analysis was performed using number of aPL positive (at least one of the three antibodies positive) and negative patients. Meta-regression was used to study potential factors explaining the heterogeneity between studies. Results: In our cross-sectional study, aPL positivity was found in 16 patients (prevalence 6.4%; 95%CI [3.8-10.4]). In multivariate analysis, there was a significant association between aPL positivity and venous thrombosis (VT) (OR 6.25 [1.18-33.00]; p = 0.028) and miscarriage (OR 5.43; 95%CI [1.31 22.13]; p = 0.017). Twenty-four studies were included in the meta-analysis, representing a total population of 3036 SSc patients. The overall pooled prevalence of aPL in SSc was 14% (9-20) with a high degree of heterogeneity among studies. Conclusion: This study found a prevalence of aPL positivity in our SSc population of 6.4% (3.8-10.4) and an overall worldwide pooled prevalence of 14% (9-20). In our SSc population, aPL positivity was associated with VT and miscarriage. These data provide additional insights into the role of aPL in the vasculopathy observed in SSc. PMID- 30464762 TI - Efficient and Non-genotoxic RNA-Based Engineering of Human T Cells Using Tumor Specific T Cell Receptors With Minimal TCR Mispairing. AB - Genetic engineering of T cells with tumor specific T-cell receptors (TCR) is a promising strategy to redirect their specificity against cancer cells in adoptive T cell therapy protocols. Most studies are exploiting integrating retro- or lentiviral vectors to permanently introduce the therapeutic TCR, which can pose serious safety issues when treatment-related toxicities would occur. Therefore, we developed a versatile, non-genotoxic transfection method for human unstimulated CD8+ T cells. We describe an optimized double sequential electroporation platform whereby Dicer-substrate small interfering RNAs (DsiRNA) are first introduced to suppress endogenous TCR alpha and beta expression, followed by electroporation with DsiRNA-resistant tumor-specific TCR mRNA. We demonstrate that double sequential electroporation of human primary unstimulated T cells with DsiRNA and TCR mRNA leads to unprecedented levels of transgene TCR expression due to a strongly reduced degree of TCR mispairing. Importantly, superior transgenic TCR expression boosts epitope-specific CD8+ T cell activation and killing activity. Altogether, DsiRNA and TCR mRNA double sequential electroporation is a rapid, non-integrating and highly efficient approach with an enhanced biosafety profile to engineer T cells with antigen-specific TCRs for use in early phase clinical trials. PMID- 30464763 TI - Microglia: Immune Regulators of Neurodevelopment. AB - Microglia, the tissue-resident macrophages of the central nervous system (CNS), have characterized roles in combating infection, clearing cellular debris, and maintaining tissue homeostasis. In addition to these typical immunological roles, microglia have been revealed to be active players in complex neurodevelopmental programs such as neurogenesis and synaptic pruning, during which they interact with neurons and macroglia to provide trophic support, respond to cytokine, and metabolic signals derived from the local neural environment, and drive the refinement of functional neuronal circuits. Microglia appear to be developmentally regulated by the host microbiome, and have been shown to dynamically respond to metabolic products from gut microbiota in a sex-dependent manner. Due to their constant surveillance of the brain parenchyma, involvement in development, and salient reactivity to both peripheral immune and microbiome derived signals, microglia may additionally serve as a key cellular intermediate linking neurodevelopmental disorders such as autism and schizophrenia with microbiota influences in models of maternal immune activation (MIA). This review examines both well-established and emerging literature and perspectives on microglia in the context of neurodevelopment, with a particular emphasis on the role of the host microbiome in influencing microglial function during health and disease states. PMID- 30464764 TI - Connexin 30 Deficiency Attenuates Chronic but Not Acute Phases of Experimental Autoimmune Encephalomyelitis Through Induction of Neuroprotective Microglia. AB - Glial connexins (Cxs) form gap junction channels through which a pan-glial network plays key roles in maintaining homeostasis of the central nervous system (CNS). In multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), expression of astrocytic Cx43 is lost in acute lesions but upregulated in chronic plaques, while astrocytic Cx30 is very low in normal white matter and changes in its expression have not been convincingly shown. In Cx30 or Cx43 single knockout (KO) mice and even in Cx30/Cx43 double KO mice, acute EAE is unaltered. However, the effects of Cx30/Cx43 deficiency on chronic EAE remains to be elucidated. We aimed to clarify the roles of Cx30 in chronic neuroinflammation by studying EAE induced by myelin oligodendrocyte glycoprotein peptide 35-55 in Cx30 KO mice. We found that Cx30 deficiency improved the clinical symptoms and demyelination of chronic but not acute EAE without influencing CD3+ T cell infiltration. Furthermore, increased ramified microglia in the naive state and induced earlier and stronger microglial activation in the acute and chronic phases of EAE was observed. These activated microglia had an anti-inflammatory phenotype, as shown by the upregulation of arginase-1 and brain derived neurotrophic factor and the downregulation of nitric oxide synthase 2. In the naive state, Cx30 deficiency induced modest enlargement of astrocytic processes in the spinal cord gray matter and a partial reduction of Cx43 expression in the spinal cord white matter. These astrocytes in Cx30 KO mice showed earlier and stronger activation during the acute phase of EAE, with upregulated A2 astrocyte markers and a significant decrease in Cx43 in the chronic phases. Spinal cord neurons and axons were more preserved in Cx30 KO mice than in littermates in the chronic phase of EAE. These findings suggest that Cx30 deficiency increased ramified microglia in the CNS in the naive state and improved chronic EAE through redirecting microglia toward an anti-inflammatory phenotype, suggesting a hitherto unknown critical role of astrocytic Cx30 in regulating microglial number and functional state. PMID- 30464765 TI - Automated Alignment of Multi-Modal Plant Images Using Integrative Phase Correlation Approach. AB - Modern facilities for high-throughput phenotyping provide plant scientists with a large amount of multi-modal image data. Combination of different image modalities is advantageous for image segmentation, quantitative trait derivation, and assessment of a more accurate and extended plant phenotype. However, visible light (VIS), fluorescence (FLU), and near-infrared (NIR) images taken with different cameras from different view points in different spatial resolutions exhibit not only relative geometrical transformations but also considerable structural differences that hamper a straightforward alignment and combined analysis of multi-modal image data. Conventional techniques of image registration are predominantly tailored to detection of relative geometrical transformations between two otherwise identical images, and become less accurate when applied to partially similar optical scenes. Here, we focus on a relatively new technical problem of FLU/VIS plant image registration. We present a framework for automated alignment of FLU/VIS plant images which is based on extension of the phase correlation (PC) approach - a frequency domain technique for image alignment, which relies on detection of a phase shift between two Fourier-space transforms. Primarily tailored to detection of affine image transformations between two structurally identical images, PC is known to be sensitive to structural image distortions. We investigate effects of image preprocessing and scaling on accuracy of image registration and suggest an integrative algorithmic scheme which allows to overcome shortcomings of conventional single-step PC by application to non-identical multi-modal images. Our experimental tests with FLU/VIS images of different plant species taken on different phenotyping facilities at different developmental stages, including difficult cases such as small plant shoots of non-specific shape and non-uniformly moving leaves, demonstrate improved performance of our extended PC approach within the scope of high-throughput plant phenotyping. PMID- 30464766 TI - Plant Microbiome and Its Link to Plant Health: Host Species, Organs and Pseudomonas syringae pv. actinidiae Infection Shaping Bacterial Phyllosphere Communities of Kiwifruit Plants. AB - Pseudomonas syringae pv. actinidiae (Psa) is the causal agent of the bacterial canker, the most devastating disease of kiwifruit vines. Before entering the host tissues, this pathogen has an epiphytic growth phase on kiwifruit flowers and leaves, thus the ecological interactions within epiphytic bacterial community may greatly influence the onset of the infection process. The bacterial community associated to the two most important cultivated kiwifruit species, Actinidia chinensis and Actinidia deliciosa, was described both on flowers and leaves using Illumina massive parallel sequencing of the V3 and V4 variable regions of the 16S rRNA gene. In addition, the effect of plant infection by Psa on the epiphytic bacterial community structure and biodiversity was investigated. Psa infection affected the phyllosphere microbiome structures in both species, however, its impact was more pronounced on A. deliciosa leaves, where a drastic drop in microbial biodiversity was observed. Furthermore, we also showed that Psa was always present in syndemic association with Pseudomonas syringae pv. syringae and Pseudomonas viridiflava, two other kiwifruit pathogens, suggesting the establishment of a pathogenic consortium leading to a higher pathogenesis capacity. Finally, the analyses of the dynamics of bacterial populations provided useful information for the screening and selection of potential biocontrol agents against Psa. PMID- 30464767 TI - Drought-Induced Accumulation of Root Exudates Supports Post-drought Recovery of Microbes in Mountain Grassland. AB - Droughts strongly affect carbon and nitrogen cycling in grasslands, with consequences for ecosystem productivity. Therefore, we investigated how experimental grassland communities interact with groups of soil microorganisms. In particular, we explored the mechanisms of the drought-induced decoupling of plant photosynthesis and microbial carbon cycling and its recovery after rewetting. Our aim was to better understand how root exudation during drought is linked to pulses of soil microbial activity and changes in plant nitrogen uptake after rewetting. We set up a mesocosm experiment on a meadow site and used shelters to simulate drought. We performed two 13C-CO2 pulse labelings, the first at peak drought and the second in the recovery phase, and traced the flow of assimilates into the carbohydrates of plants and the water extractable organic carbon and microorganisms from the soil. Total microbial tracer uptake in the main metabolism was estimated by chloroform fumigation extraction, whereas the lipid biomarkers were used to assess differences between the microbial groups. Drought led to a reduction of aboveground versus belowground plant growth and to an increase of 13C tracer contents in the carbohydrates, particularly in the roots. Newly assimilated 13C tracer unexpectedly accumulated in the water extractable soil organic carbon, indicating that root exudation continued during the drought. In contrast, drought strongly reduced the amount of 13C tracer assimilated into the soil microorganisms. This reduction was more severe in the growth-related lipid biomarkers than in the metabolic compounds, suggesting a slowdown of microbial processes at peak drought. Shortly after rewetting, the tracer accumulation in the belowground plant carbohydrates and in the water extractable soil organic carbon disappeared. Interestingly, this disappearance was paralleled by a quick recovery of the carbon uptake into metabolic and growth related compounds from the rhizospheric microorganisms, which was probably related to the higher nitrogen supply to the plant shoots. We conclude that the decoupling of plant photosynthesis and soil microbial carbon cycling during drought is due to reduced carbon uptake and metabolic turnover of rhizospheric soil microorganisms. Moreover, our study suggests that the maintenance of root exudation during drought is connected to a fast reinitiation of soil microbial activity after rewetting, supporting plant recovery through increased nitrogen availability. PMID- 30464768 TI - Comparison of Osteoporosis Pharmacotherapy Fracture Rates: Analysis of a MarketScan(r) Claims Database Cohort. AB - Background: Several different classes of medications have been shown to be efficacious at preventing fractures in patients with osteoporosis. No study has compared real world efficacy at preventing fractures between all currently approved medications. Objectives: To directly compare the efficacy of all currently available osteoporosis medications by using a large population claims database. Methods: The Truven Health Analytics MarketScan(r) database from 2008 - 2012 was used to identify all patients who started a new osteoporosis medication. Patients who experienced a fracture after at least 12 months of treatment were identified and risk factors for fracture for all patients were recorded. Logistic regression was used to account for and quantify the contribution of risk factors, and to make direct comparisons between different osteoporosis medications. Results: A total of 51649 patients were included in the cohort, with an average age of 56 years. The overall incidence rate of fracture was 1.55 per 100 person - years of treatment. Orally administered medications had the lowest fracture rates, led by raloxifene and alendronate (1.24 and 1.54 respectively), while parenterally administered medications including teriparatide and zolerdonic acid had the highest rates (3.90 and 1.98 respectively). No statistically significant differences found between oral or parenterally administered bisphosphonate medications. Conclusions: While patients taking orally administered drugs including bisphosphonates had less frequent incident fracture no statistically significant differences were found between most drugs in head - to - head comparisons, even considering the route of administration of bisphosphonates. These findings support previous evidence that minimal differences in efficacy exist between different osteoporosis medications. This is the first study using a large database to compare all currently available osteoporosis treatments and will hopefully be augmented by further study to provide more evidence to make clinical decisions on osteoporosis medication use. PMID- 30464769 TI - World Bank Income Group, Health Expenditure or Cardiometabolic Risk Factors? A Further Explanation of the Wide Gap in Cardiometabolic Mortality Between Worldwide Countries: An Ecological Study. AB - Background: For addressing the burden of non-communicable diseases and policymaking, the world health organization uses World Bank income group to classify countries. This calcification method might not be optimal. This study aimed to investigate the role of World Bank income group, health expenditure, and cardiometabolic risk factors of countries in explaining the gap between their cardiometabolic mortality. Methods: In total, 190 countries were categorized into four income groups according to the World Bank definition. The energy consumption, health expenditure, and data of sex-specified age-standardized prevalence of obesity, hypercholesterolemia, hypertension, diabetes, smoking, and physical inactivity in 2008 and cardiometabolic mortality in 2012 were used. Multivariable-adjusted mixed-effect linear regression models were applied to relate country-level predictors to their mortality outcomes. Results: While the lowest cardiometabolic mortality was recorded in high-income countries in both genders, the highest rates were recorded in the low-income category for women and in low and middle-income for men. Countries had lower cardiometabolic mortality for women compared to men; however, such a difference was not shown in low-income countries. World Bank income group of countries, per se, explained one-third of the variation in their mortality outcomes while adding health expenditure, energy consumption, and cardiometabolic risk factors increased the explanatory power of the model considerably. Moreover, the more the health expenditure, the weaker the association of prevalence of hypertension with cardiometabolic mortality. Conclusions: Adding countries' health expenditure and/or the prevalence of risk factors to their World Bank income group may contribute to the better explanation of the gap between them in cardiometabolic mortality. PMID- 30464770 TI - Waist Circumference to Height Ratio: Better Correlation with Fat Mass Than Other Anthropometric Indices During Dietary Weight Loss in Different Rates. AB - Background: The first-line strategy for the treatment of obesity is weight loss (WL) through decreasing calorie intake. However, a diet that is capable of attenuating fat free mass decline following WL is preferred. Furthermore, it is required to choose proper measurements and appropriate obesity-assessment indices to monitor weight and body composition during WL program. Methods: A total of 68 adults with overweight and/or obesity underwent a WL program (rapid and slow WL). Dependent variables include: weight, resting metabolic rate (RMR), body composition, and related measurements such as waist circumference (WC), waist to height ratio (WHtR), body adiposity index (BAI), a body shape index (ABSI), fat mass to lean body mass (FM/LBM), and percentage body fat (PBF). Results: Obesity measurements decreased in both groups (all P < 0.05) while LBM and RMR decreased more in the rapid WL group (P < 0.05). After age and sex adjustment, a robust correlation was observed between FM/LBM and PBF (r = 0.918), LBM% and PBF (r = 0.949), LBM% and FM/LBM (r = -0.904), WHtR and WC (r = 0.986), and BAI% and HC (r = 0.986) (P < 0.001 for all correlations). FM has the highest correlation with WHtR among other indices (r = 0.706). Conclusions: Compared to fast WL, our data support that slow and gradual WL is more effective to improve body composition and obesity-assessment indices. The robust relationship was observed between FM and WHtR, among other indices such as BMI or ABSI. Therefore, in order to evaluate FM, where the FM is not measurable, the WHtR might be the reasonable index. PMID- 30464771 TI - The Effect of Aerobic Training and Green Tea Supplementation on Cardio Metabolic Risk Factors in Overweight and Obese Females: A Randomized Trial. AB - Background: The use of exercise along with green tea supplements has been shown to have beneficial effects on obesity and its complications. Objectives: This study aimed at exploring the effect of aerobic training (AT) and green tea (GT) supplementation on body composition, blood lipids, blood glucose, and cardiovascular risk factors in overweight and obese females. Methods: Thirty-nine healthy non-athlete overweight and obese females with an average age of 28.11 +/- 6.50 years were sampled and randomly assigned to control (n = 13), AT (n = 13), and AT + GT (n = 13). Participants of the latter group received 33 mg of green tea after each main meal every day, and in addition, they were subjected to AT for eight weeks, including three 90-minute training sessions that were progressive, reaching 80% of the target heart rate (THR). Blood samples were taken from participants one week before the initiation of the study and 48 hours after the last training session. Results: Compared to the control group, body weight, body fat percentage, body mass index (BMI), triglyceride, low-density lipoprotein, blood pressure, and heart rate (HR) significantly decreased in the groups treated with AT and AT + GT (P < 0.05). However, no significant changes occurred in FBS, HDL, TC, and WHR (P > 0.05). Conclusions: AT was effective in modifying cardiovascular risk factors, e.g. hypertension, heart rate (HR), triglyceride, and low-density lipoprotein (LDL). However, GT addition was not effective. Considering Iranians' high tendency towards the consumption of plant materials, this finding needs further investigation. PMID- 30464772 TI - Factors Affecting Self-Care Performance in Adolescents with Type I Diabetes According to the PEN-3 Cultural Model. AB - Background: Adolescence is the most difficult period to control and manage type 1 diabetes (T1D), and various perceptions, enablers, and nurturers influence self care behaviors in these patients. Objectives: The purpose of this study was to identify factors affecting self-care performance in adolescents with T1D, according to the PEN-3 cultural model. Methods: In this study, in-depth interviews were conducted initially with 26 participants, and one group discussion was held with 13 participants. Assessment domains of the PEN-3 model (key influence on health behaviors and impact of behavior on health) guided the analysis of qualitative study and focus group data. Finally, the data were classified to a 3 * 3 table, based on the PEN-3 model. Results: The most common positive PEN included awareness of self-care behaviors, attitude towards the disease, impact of spirituality on self-care, easy access to needed medical services, and maternal support. The negative PEN included attitude of patients and parents towards reasons of becoming sick (why me), awareness about the disease and its causes, low self-efficacy, limited training, high cost of blood glucose test strips, lack of educational therapeutic curricula based on spirituality, ignoring the role of spirituality in treatment and self-care, and conflict between parents and patients. Conclusions: The results of this study can be used to guide the development of cultural group therapy interventions aimed at increasing adherence to self-care behaviors among Iranian adolescents with T1D. PMID- 30464773 TI - The Relationship Between Human Development Index and Its Components with Thyroid Cancer Incidence and Mortality: Using the Decomposition Approach. AB - Background: The link between age specific-rates of thyroid cancer (TC) and human development index (HDI) and also its components can be a new direction for planning by policy makers. Objectives: This study aimed at identifying the relationship between TC rates by gender, and HDI and its components in different regions of the world. Methods: An ecological study was conducted; the data was obtained from the GLOBOCAN project in 2012. Inequality in TC estimates (age specific incidence and mortality rates), according to the HDI and its components was calculated. Concentration index (CI) was used to estimate inequality and CI was decomposed to determine contribution of HDI and its components in inequality. Results: The inequality index (CI) was 0.29 (95% CI: 0.21 - 0.38) and -0.15 (95% CI: -0.23 - 0.06) for incidence and mortality of TC by HDI, respectively. The important contributors in inequality for incidence rates of TC were life expectancy at birth (0.30), mean years of schooling (0.26), and expected years of schooling (0.18). The important contributors in inequality of mortality rates were mean years of schooling (0.19), expected years of schooling (0.17), and urbanization (0.17). Conclusions: According to the findings of this study, global inequalities exist in the TC incidence and mortality rates; incidence rates of TC are more concentrated in countries with high HDI, yet inequality index showed that deaths occurred more in disadvantaged countries. PMID- 30464774 TI - Effect of Restraint Stress on Plasma PTH Concentration and Its Molecular Targets Expressions in Wistar Rats. AB - Background: There are limited numbers of experimental studies related to the potential role of parathormone/parathyroid hormone (PTH) in response to psychological stress. In the current study, we aimed to cross-examine, for the first time, changes in PTH plasma concentration and the expression of its molecular targets mediated by restraint stress in rats. Methods: Male Wistar rats (n = 42) were separated into control and stressed groups. They were further divided into two groups that received chronic restraint stress (CRS) for 7 and 28 consecutive days (n = 7 for each group). Elevated plus maze and tail suspension test were used to determine the anxiety- and depressive-like behaviors of a different set of rats including stress and control groups (n = 7 for each group). The plasma levels of adrenocorticotropic hormone (ACTH), corticosterone, and intact parathormone (iPTH) were measured by enzyme-linked immunosorbent assay (ELISA). In addition, alterations in the expressions of glucocorticoid receptor (GR), calcium sensing receptor (CaSR), and parathormone receptor (PTHR1) of kidney and total thyroid gland tissues were estimated by Western Blotting. Results: There was no significant difference in the plasma level of iPTH while significant increases in the levels of ACTH and corticosterone were noted in the stressed-animals at day 7 and 21 (P = 0.010 and P = 0.016, respectively) of restraint stress. However, we found a negative correlation between iPTH and corticosterone levels in acute restraint stress (r = 0.771, P = 0.002). In addition, the expression of PTHR1 significantly decreased in the kidney at day 7 (P = 0.001) and in the thyroid gland at day 28 (P = 0.05) in response to CRS. Conclusions: To sum up, CRS has a significant effect on the expression of parathormone receptor rather than the iPTH concentration. The present results add a new dimension to stress research through the negative effect of chronic stress on the PTH signaling pathway. PMID- 30464775 TI - Human Prolactinoma: A View of Protein-Protein Interaction Pattern. AB - The aim of this study was to identify the highly expressed genes in terms of interaction concept in Prolactinoma. The study was conducted by additional analysis of the available data from the GEO database. The online tool, GEO2R, was used to analyze the gene expression profile of GSE36314 dataset using the GPL8300 platform. Consequently, a PPI network of up-regulated and down-regulated genes was constructed and examined to introduce the possible targets with possible therapeutic values. A number of 46 genes were dysregulated in Prolactinoma and their network indicated 15 essential genes via topological analysis. Moreover, the present study found that the highlighted genes of prolactinoma are involved in two major biological processes including growth regulation and metabolic function. Thus, the determined genes may be valuable for diagnosis, treatment, and patient follow-up. However, further studies are essential to validate this conclusion. PMID- 30464776 TI - The Principles of Biomedical Scientific Writing: Introduction. AB - A well-written introduction of a scientific paper provides relevant background knowledge to convince the readers about the rationale, importance, and novelty of the research. The introduction should inform the readers about the "problem", "existing solutions", and "main limitations or gaps of knowledge". The authors' hypothesis and methodological approach used to examine the research hypothesis should also be stated. After reading a good introduction, readers should be guided through "a general context" to "a specific area" and "a research question". Incomplete, inaccurate, or outdated reviews of the literature are the more common pitfalls of an introduction that may lead to rejection. This review focuses on the principles of writing the introduction of an article and provides a quick look at the essential points that should be considered for writing an optimal introduction. PMID- 30464777 TI - Barriers to Promoting Advance Care Planning for Residents Living in a Sanatorium for Hansen's Disease: A Qualitative Study of Residents and Staff in Japan. AB - In Japan, most residents with Hansen's disease (leprosy) live in dedicated sanatoria because of an established quarantine policy, even after being cured of the primary disease. They suffer from secondary diseases and are advancing in age, and advance care planning (ACP) is increasingly crucial for them to live their lives with dignity in a sanatorium. In this study, we have three aims: (1) to understand how to promote communication about their wishes for medical treatment, care, and recuperation; (2) to identify required assistance; and (3) to explore how to promote ACP in a sanatorium. This study is a qualitative research conducted through semi-structured interviews. The study included 57 ex Hansen's disease patients and 66 staff (10 doctors, 27 nurses, 23 care workers, and 6 social workers) from 10 facilities. Ex-Hansen's disease patients were expected to consider ACP, but this was in the context of uncertainty about whether a sanatorium would close and whether there would be doctors to manage their needs. They reported being confused when staff rushed to confirm their advance directives, feeling that they were not provided with enough information before being approached. Barriers to promoting ACP were found to be insufficient of team-based care and information sharing, ex-Hansen's disease patients' weak interest in their end of life, and their conservative thoughts. We believe that ACP can be achieved by listening to the wishes of recovered patients through regular home care visits by nurses and everyday support by care workers. Furthermore, multidisciplinary coordination is urgently needed for promoting ACP. PMID- 30464778 TI - Whose Responsibility is Adolescent's Mental Health in the UK? Perspectives of Key Stakeholders. AB - The mental health of adolescents is a salient contemporary issue attracting the attention of policy makers in the UK and other countries. It is important that the roles and responsibilities of agencies are clearly established, particularly those positioned at the forefront of implementing change. Arguably, this will be more effective if those agencies are actively engaged in the development of relevant policy. An exploratory study was conducted with 10 focus groups including 54 adolescents, 8 mental health practitioners and 16 educational professionals. Thematic analysis revealed four themes: (1) mental health promotion and prevention is not perceived to be a primary role of a teacher; (2) teachers have limited skills to manage complex mental health difficulties; (3) adolescents rely on teachers for mental health support and education about mental health; and (4) the responsibility of parents for their children's mental health. The research endorses the perspective that teachers can support and begin to tackle mental well-being in adolescents. However, it also recognises that mental health difficulties can be complex, requiring adequate funding and support beyond school. Without this support in place, teachers are vulnerable and can feel unsupported, lacking in skills and resources which in turn may present a threat to their own mental well-being. PMID- 30464779 TI - What is in It for Them? Understanding the Impact of a 'Support, Appreciate, Listen Team' (SALT)-Based Suicide Prevention Peer Education Program on Peer Educators. AB - Youth suicide is a public health problem in India, and young people in school, particularly adolescents, experience heavy psychological burden. Prevention programs, involving peer educators (PEs), have proved useful strategies to address this problem, but their impact on the PEs is less understood, particularly in India. This qualitative study aims to explore the changes observed in PE students who were involved in a 'mindfulness' and 'Support Appreciate-Listen-Team' (SALT)-based peer education program to address suicidal behavior in Indian school students. One hundred and fourteen students were trained as PEs in six high schools in Pune to identify and respond to the needs of students in distress. By listening to the narratives of the PEs, their parents, school authorities, and the associated NGO team, we reflect on perceived social, emotional, behavioral, and cognitive changes in PEs. The PEs demonstrated enhanced caring for those in distress both inside and outside school by improved listening skills, self-awareness, care, and empathy. Furthermore, the program had a positive impact on their broad emotional intelligence and PEs expressed increased ownership of life, taking action, and seeking support where needed. The study concludes that mindfulness and SALT-based peer education (PE) programs are valuable for the PEs. This could be used to motivate PEs to volunteer in such programs. Other results are discussed and further research areas are suggested. PMID- 30464780 TI - Family Caregiver Satisfaction With End-of-Life Care Following Advanced Cancer. PMID- 30464781 TI - Domestic Exposures to Polycyclic Aromatic Hydrocarbons in a Houston, Texas, Environmental Justice Neighborhood. AB - Polycyclic aromatic hydrocarbons (PAHs) are a class of >100 chemicals that naturally occur in coal tar, crude oil, and gasoline and can be manufactured as part of dyes, plastics, and pesticides. PAHs are complex environmental toxicants and exposure to them have been linked to adverse health outcomes including cancer, as well as diseases of the skin, liver, and immune system. Residents of the environmental justice neighborhood of Manchester, located on Houston's East End, are disproportionally exposed to toxic pollutants from both industry and transportation infrastructure. Based on a longstanding community engagement partnership with the research team, neighborhood residents sought to better understand their domestic exposure to PAHs. Particulate wipes were used to collect dust from a marked area within the entryway of randomly selected homes to assess for the presence of PAHs. Nineteen of the 61 PAH analytes, including the Environmental Protection Administration's 16 priority PAHs and the subgroup of 7 probable human carcinogens, were found in the sampled homes. Residents of the Houston neighborhood of Manchester potentially have significant domestic exposure to PAHs from combustion sources. More research is needed to assess the source of the PAHs and to better understand the potential health impacts of these exposures. PMID- 30464782 TI - Differences in chronic spontaneous urticaria between Europe and Central/South America: results of the multi-center real world AWARE study. AB - Background: Global chronic urticaria (CU) disease experience and management is not well documented. This study descriptively compares these aspects among CU patients residing in Europe (EU) and Central and South America (C/SA). Methods: AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) is a global prospective, non-interventional study of CU in the real world setting. Patients were >= 18 years with a diagnosis of H1-antihistamine refractory CU for > 2 months. Differences between the EU and C/SA regions in demographic and clinical characteristics, quality of life (QoL), work and activity impairment, pharmacological treatment, and healthcare resource use were examined. Results: In total, 4224 patients were included in the analysis (C/SA 492; EU 3732). Rates of untreated patients were greater in the C/SA region (45.1% vs. 31.9%; P < 0.005) and escalation to third-line therapy was rare in both regions. Differences in disease experience emerged, with C/SA patients more commonly experiencing angioedema (C/SA 50.8% vs. EU 46.1%; P = 0.03) or comorbid chronic inducible urticaria (C/SA 30% vs. EU 22%; P < 0.001). Correspondingly, rates of uncontrolled urticaria were higher among C/SA patients (82.8% vs. 77.5%; P = 0.017) and patients in the C/SA region showed significantly greater work and activity impairment (absenteeism: 10.4 +/- 19.7 vs. 6.7 +/- 19.0, P = 0.004; presenteeism: 30.3 +/- 31.9 vs. 24.4 +/- 25.8, P = 0.001; work productivity loss: 33.9 +/- 33.9 vs. 26.5 +/- 27.5, P < 0.001; activity impairment: 37.7 +/- 34.7 vs. 32.7 +/- 30.1, P = 0.001). However, QoL impairment was greater in the EU region (Dermatology Life Quality Index: C/SA 6.5 +/- 5.9 vs. EU 8.3 +/- 7.0; P < 0.001). There was a significant difference in use of healthcare resources, including emergency services (39.6% vs. 29.3%; P < 0.001), hospitalization (7.7% vs 21.9%; P < 0.001) general practitioners (31.7% vs 57.3%; P < 0.001), and additional allergists or dermatologists (50.6% vs. 47.3%, P < 0.001), among patients in the C/SA and EU region, respectively. In both regions, patients with a primary diagnosis of CU with angioedema had significantly greater impairment in work and non-work activities and healthcare resource utilization compared to those without angioedema. Conclusions: This study revealed that CU is a heterogeneous condition with differences in healthcare utilization and outcomes between EU and C/SA. However, overall there is a high unmet need of H1 antihistamine-refractory CU patients, which is associated with high use of healthcare resources, and has a large negative effect on QoL and work productivity. PMID- 30464784 TI - Can We Make Medicines Affordable? PMID- 30464783 TI - Coronary CTA for Surveillance of Cardiac Allograft Vasculopathy. AB - Purpose of Review: The purpose of this review is to highlight recent hardware and software advances in coronary computed tomography angiography (CTA) that make it a potentially viable alternative to invasive coronary angiography for surveillance of cardiac allograft vasculopathy (CAV) in heart transplant recipients. Recent Findings: Dual-source CT, multisegment reconstruction, and intracycle motion correction algorithms are all technologies applied during or after image acquisition that can improve image quality and diagnostic accuracy in patients with elevated heart rates, such as heart transplant recipients. CT fractional flow reserve may also add value in this clinical scenario. Summary: Coronary CTA now has equivalent diagnostic accuracy, offers more nuanced anatomic information, is inherently safer, and could be less costly than invasive coronary angiography. For these reasons, coronary CTA may now be a viable alternative to ICA for CAV surveillance in heart transplant recipients. PMID- 30464785 TI - Prior Authorization for Elective Diagnostic Catheterization: The Value of Reviewers in Cases with Clinical Ambiguity. AB - Background: In many situations, evidence-based guidelines cannot provide definitive guidance on the appropriateness of diagnostic catheterization. One specialty benefit management company has taken a 2-step approach to address this ambiguity by evaluating the appropriateness of diagnostic catheterization orders using a rule-based decision support system, and then having reviewers provide input through the consult system of a nondenial prior authorization program that involves peer discussion. Objective: To describe the outcomes of a 2-step approach to evaluating the appropriateness of elective diagnostic catheterization orders. Method: This program evaluation used data from elective diagnostic catheterization orders from 2015 that pertained to 1 health insurer's Medicare Advantage plans. The classifications of orders by the rule-based system and the approval rates after review by the consult system are presented for these plans. Chi-square tests were conducted to examine whether classifications of the orders by the rule-based and consult systems were independent of plan type, specialty of the ordering physician, or state of residence of the patient. Results: A total of 3808 orders for elective diagnostic catheterization in 2015 met the inclusion criteria. Inadequate initial justification was provided for 699 (18.4%) of the orders; after inquiry through the consult system, 509 (72.8%) of the remaining orders were approved. Among the 344 (9%) orders that were deemed potentially nonindicated according to the rule-based system, the consult system approved 298 (86.6%). Of the 2765 (72.6%) orders that were deemed potentially appropriate by the rule-based system, the consult system approved 2740 (99.1%). Chi-square tests did not show a significant association between plan type or physician specialty and the classification produced by the rule-based system or the consult system. The patients' state of residence was significantly associated with the classification of orders for the rule-based system (P <.001), but not for the consult system. Conclusion: Rule-based decision support can be combined with consult-based peer discussion to determine whether care is appropriate when guidelines are ambiguous. Poorly justified orders are often supportable after gathering information on the patient's presentation. PMID- 30464786 TI - Long-Term Outcomes of a Cardiovascular and Diabetes Risk-Reduction Program Initiated by a Self-Insured Employer. AB - Background: Cardiovascular disease remains the leading cause of death in America and poses a significant challenge for self-insured employers attempting to improve employee health and well-being while controlling healthcare costs. Disease state management programs can be an effective means of achieving these outcomes, but the durability and long-term effects of such programs have limited evaluation. Objective: To assess the 5-year health, economic, and quality-of-life patient outcomes of an employer-sponsored disease state management program. Methods: This was a longitudinal, 5-year, quasi-experimental, pre-/postenrollment study. Self-insured health plan members with hypertension, hyperlipidemia, diabetes, or a combination of these conditions met with a pharmacist regularly (monthly for the first year, then varied by participant) to implement lifestyle medicine programs, optimize medication therapy, and facilitate the coordination of care. Biometric markers, lifestyle behaviors, quality of life, and work productivity were assessed on an annual basis. Results: The significant biometric improvements (mean) seen after 5 years of program participation compared with pre enrollment included decreased low-density lipoprotein cholesterol levels (96.71 mg/dL vs 84.83 mg/dL, respectively), increased high-density lipoprotein cholesterol levels (39.32 mg/dL vs 46.12 mg/dL), and decreased systolic blood pressure (132.04 mm Hg vs 123.63 mm Hg) and diastolic blood pressure (85.75 mm Hg vs 75.83 mm Hg). The average exercise time increased (50 minutes weekly vs 156.04 minutes weekly), as did fruit and vegetable consumption (3.98 servings daily vs 5.27 servings daily). The program participants reported improved general health and a reduced number of unhealthy days. The combined healthcare and productivity return on investment for the program at 5 years was $9.64 for every $1 invested. Conclusions: Significant changes in employees' health, well-being, and health related costs are possible through sustained participation in an employer sponsored disease state management program. PMID- 30464787 TI - Treatment Persistence and Healthcare Costs Among Patients with Rheumatoid Arthritis After a Change in Targeted Therapy. AB - Background: Targeted disease-modifying antirheumatic drug (DMARD) options for rheumatoid arthritis (RA) include tumor necrosis factor (TNF) inhibitors (adalimumab, certolizumab, etanercept, golimumab, infliximab) or alternative mechanisms of action (MOAs), such as a T-cell co-stimulation modulator (abatacept), Janus kinase inhibitor (tofacitinib), or interleukin-6 inhibitor (tocilizumab). Objective: To examine treatment persistence and healthcare costs in patients with RA who changed therapy by cycling therapy (ie, switching within the same drug class), or switching between, the TNF inhibitors and alternative MOA medication classes. Methods: We analyzed medical and pharmacy claims for commercially insured patients who cycled or switched between targeted DMARD agents between January 1, 2010, and September 30, 2014 (ie, the index date), to determine treatment patterns (ie, treatment switching, discontinuation, restarting after a gap >=60 days, or persistence) and costs (plan- and patient paid) for 1 year postindex. The cost per persistent patient was the total healthcare cost divided by the number of treatment-persistent patients. Results: The analysis included 6203 patients who cycled between TNF inhibitors, 2640 patients who switched from TNF inhibitors to alternative MOA agents, 699 patients who cycled between alternative MOA agents, and 687 patients who switched from alternative MOA agents to TNF inhibitors. The 1-year treatment persistence rates (with P values vs TNF inhibitor cyclers) were 45.2% for TNF inhibitor cyclers, 50.3% for TNF inhibitor-alternative MOA switchers (P <.001), 51.4% for alternative MOA agent cyclers (P = .002), and 46.1% for alternative MOA-TNF inhibitor switchers (P = .63). Compared with TNF inhibitor cyclers, the cost per persistent patient was lower for TNF inhibitor-alternative MOA switchers ( $16,853 RA-related; -$19,280 targeted DMARDs), alternative MOA agent cyclers ( $21,662 RA-related; -$25,153 targeted DMARDs), and alternative MOA-TNF inhibitor cyclers (-$7206 RA-related; -$7919 targeted DMARDs). Conclusion: Among patients with RA, patients who switched from a TNF inhibitor to an alternative MOA agent and those who cycled between alternative MOA agents had significantly higher treatment persistence rates and a substantially lower cost per persistent patient than those who cycled between TNF inhibitors. These findings support the evaluation of switching medication classes for patients with RA when a targeted therapy fails. PMID- 30464789 TI - Oncology Drugs Approved by the FDA in Early 2018. PMID- 30464788 TI - Can Technologic Innovations and Formulary Considerations Improve Healthcare Outcomes? AB - The following summaries represent a small sample of the many real-world, evidence based studies presented at the 30th Annual Meeting of the Academy of Managed Care Pharmacy (AMCP), April 23-26, 2018, in Boston, MA. PMID- 30464790 TI - Namaste. PMID- 30464791 TI - Assessing the Level of Patient-Specific Treatment Recommendations in Clinical Practice Guidelines for Hemodialysis Vascular Access in the United States. AB - Background: Hemodialysis is a procedure that requires efficient removal and return of blood to a patient's body. Despite being a life-sustaining process, hemodialysis is associated with morbidity, mortality, and high societal costs. A significant part of the financial costs to patients and society at large can be attributed to vascular access dysfunction. The cornerstone to efficient hemodialysis is a well-functioning vascular access that simultaneously allows efficient blood flow for dialysis and easy cannulation. It is hypothesized that the poor health outcomes associated with vascular access dysfunction can be improved by paying closer attention to patient-specific factors in clinical guidelines for hemodialysis vascular access. This may require a shift to a more patient-centered approach to vascular access management. Objective: To assess the presence of patient-specific treatment recommendations in the current clinical practice guidelines for hemodialysis vascular access. Methods: We conducted a systematic search of PubMed and professional nephrology organization websites for full-text clinical practice guidelines with treatment recommendations regarding hemodialysis vascular access. We developed a coding sheet to document the number of patient-specific treatment recommendations and other quality attributes found in the extracted clinical practice guidelines. Results: Our search resulted in the extraction of 5 clinical practice guidelines for final review. Only 1 of the 5 extracted guidelines was found to contain patient-specific treatment recommendations, but the treatment recommendations were limited to juvenile patients. Of the 5 clinical practice guidelines, 4 were published within the past decade (ie, after 2006). Conclusion: Our findings show that current clinical practice guidelines for hemodialysis vascular access lack patient-specific recommendations. Future clinical guidelines must consider patient-specific treatment recommendations with the goal of improving hemodialysis vascular access outcomes for patients, a goal that is supported in the recommendations of the National Kidney Foundation. PMID- 30464792 TI - The Prevalence and Payer Costs of Potentially Avoidable Emergent Care Visits for Suspected Amniotic Membrane Rupture in Pregnant Women. AB - Background: Concern over amniotic fluid leakage is common among pregnant women. Uncertainty about prelabor rupture of amniotic membranes (PROM) can lead women to present to emergency departments or to labor and delivery units for medical evaluation. Many of such visits do not result in delivery, yet they carry significant, and potentially unnecessary, healthcare expenditures. Objective: To estimate the prevalence and payer cost of potentially avoidable visits by pregnant women to an emergent care facility (including emergency departments, labor and delivery units, or observation units) for suspected PROM. Methods: This study included 2 processes-an electronic medical records chart review and a commercial health insurance claims data analysis. The medical chart review included 843 scheduled and 1250 unscheduled pregnancy-related visits at Robert Wood Johnson University Hospital between January 4 and June 30, 2017, which was conducted to determine the rates of visits by pregnant women with suspected PROM and their results (ie, hospital admission or discharge). In addition, we performed a retrospective analysis of medical claims data from the Truven Health MarketScan Commercial Database to measure population-level incidence rates and the costs of pregnancy-related emergent care visits for suspected PROM. Results: Of the 1250 unscheduled visits reviewed, 663 did not result in delivery; of these, 68 had a primary complaint of suspected PROM, and 55 (81%) of them were discharged with PROM ruled out. Of all scheduled and unscheduled nondelivery visits (N = 1069), 5.1% (N = 55) were associated with suspected PROM but were discharged home with PROM ruled out. In the commercial claims analysis, the average rate of emergent care visits by pregnant women was 436.69 per 1000 deliveries, with an estimated average cost of $1428 per visit (in 2018 dollars), or $0.58 per member per month. Applying the rates from our chart review to the claims data, we estimated that commercial insurers pay, on average, for approximately 22.47 facility visits per 1000 deliveries for suspected and ruled out PROM. Conclusions: Our findings suggest that for most PROM cases that do not result in delivery, PROM is ruled out and patients are sent home. Reducing the number of PROM-related visits to emergent care facilities that result in ruled out PROM could reduce healthcare costs and help patients and providers avoid these inconvenient visits. PMID- 30464793 TI - Budget Impact of Adding Vedolizumab to a Health Plan Formulary as Another First Line Biologic Option for Ulcerative Colitis and Crohn's Disease. AB - Background: Vedolizumab is a biologic drug approved by the US Food and Drug Administration (FDA) for the treatment of adults with moderately to severely active Crohn's disease (CD) or ulcerative colitis (UC) who have had inadequate response to, lost response to, or were intolerant of immunomodulators or tumor necrosis factor (TNF) blocker therapy, or who had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroid therapy. The biologics approved by the FDA for CD and/or UC include adalimumab, infliximab, golimumab, certolizumab, and ustekinumab. Objective: To assess the budget impact of including vedolizumab in a health plan formulary among current options as a preferred first-line biologic therapy for UC and CD rather than only for patients who failed anti-TNF therapy. Methods: We developed a 3-year budget impact model for a 1-million-member health plan. Comparators included all currently approved brand-name biologic and biosimilar agents for the treatment of UC (ie, adalimumab, infliximab, and golimumab) and CD (ie, adalimumab, certolizumab, infliximab, and ustekinumab). Clinical inputs included therapy response probabilities, disease remission, and surgery risk. Given the lack of head-to head clinical trials, we estimated indirect comparisons of treatment efficacy based on clinical trial data using the Bucher method. The drug and medical costs were obtained from published literature. The model compared hypothetical health plan costs for 2 scenarios-(1) a market mix with vedolizumab included on the formulary with currently existing first- and second-line preferred treatments, and (2) vedolizumab included only with existing preferred second-line treatments on the hypothetical formulary. These scenarios were compared in the context of 3 hypothetical health plan formulary cases. Results: Including vedolizumab in a hypothetical formulary with currently preferred first-line biologic treatment options (Scenario 1) resulted in cost-savings compared with vedolizumab as a preferred second-line biologic option (Scenario 2). The total cost-savings were from $0.13 million to $1.63 million in year 1, and from $0.38 million to $4.68 million in year 3. The per-member per-month cost-savings were from $0.01 to $0.14 in year 1 and from $0.03 to $0.39 in year 3. Conclusion: Based on our model's results, including vedolizumab among the current health plan formulary biologic options as a preferred first-line treatment for UC and CD can result in substantial cost-savings compared with including vedolizumab as a preferred second-line treatment only. PMID- 30464794 TI - "The Dirty Dozen". PMID- 30464795 TI - Trends in Utilization, Spending, and Prices of Smoking-Cessation Medications in Medicaid Programs: 25 Years Empirical Data Analysis, 1991-2015. AB - Background: Smoking remains the single largest preventable cause of death and disease. Smoking-cessation medications provide patients a multitude of benefits and can prevent certain diseases, including some cancers. Because of the limited amount of studies on smoking-cessation medications, we wanted to find general trends about the use of these medications. Objective: To examine trends in the utilization, pharmacy reimbursement, and prices of smoking-cessation medications and nicotine replacement therapy in the US Medicaid-covered population. Methods: Using national summary files for outpatient drug utilization and expenditure, we extracted data on smoking-cessation medications from the Centers for Medicare & Medicaid Services in the 25 years from January 1991 through June 2015. We conducted a retrospective drug utilization study to examine the annual (or quarterly) trends of the number of prescriptions, reimbursement expenditures, and the prices of smoking-cessation medications. The study drugs included varenicline (Chantix), bupropion (Zyban), and nicotine. We calculated per-prescription pharmacy reimbursement, which was used as a proxy for drug price, as the total quarterly expenditure for the drug, divided by the total number of prescriptions. All expenditures were inflated to 2015 US dollars using the medical services component of the Consumer Price Index. Results: The total number of prescriptions for smoking-cessation medications increased rapidly from 46,396 in 1991 to 942,562 in 2014, an increase of more than 1931%. During the same period, the total pharmacy reimbursement for smoking-cessation medications in Medicaid increased by 3562%, from approximately $2.8 million in 1991 to approximately $101 million in 2014. The use of the nonnicotine prescription drugs varenicline and bupropion also increased rapidly, with a high cost expenditure. The price per nonnicotine prescription drug increased over time, ranging from approximately $169 for bupropion to approximately $251 for varenicline in 2015. Conclusions: The substantial increase in nonnicotine prescription drugs and nicotine replacement therapy between 2007 and 2015 may be attributed to smoking-cessation participants nationwide. Cost-containment policies might have inadvertently prevented Medicaid-covered smokers from obtaining appropriate pharmacotherapy. PMID- 30464796 TI - Analysis of Real-World Dosing Patterns for the 3 FDA-Approved Medications in the Treatment of Fibromyalgia. AB - Background: Fibromyalgia is a chronic condition characterized by widespread pain, fatigue, and sleep disturbances that affects approximately 2% to 4% of the adult population in the United States, with minimal real-world data related to the use of medications and associated dosages for this condition. Objective: To analyze the real-world dosing patterns of the 3 medications approved by the US Food and Drug Administration for fibromyalgia-pregabalin, duloxetine, and milnacipran. Methods: Using QuintilesIMS' (now IQVIA) electronic medical record data linked to administrative claims, we identified adults with fibromyalgia who were newly prescribed pregabalin, duloxetine, or milnacipran between January 1, 2006, and December 31, 2014. We summarized and compared the starting and maximum doses with United States prescribing information (USPI) dosing recommendations. Results: In all, 1043 patients who were receiving pregabalin, 1281 receiving duloxetine, and 326 patients receiving milnacipran with similar age and comorbidity profiles were included in the study. The mean starting dose was 176 mg daily, 56 mg daily, and 95 mg daily for pregabalin, duloxetine, and milnacipran, respectively. More patients receiving pregabalin (35%) had a starting dose lower than recommended compared with patients receiving duloxetine (7%) or milnacipran (17%; P <.0001). Of the patients who received pregabalin, 27% had USPI-recommended maintenance dosing versus 91% of patients who received duloxetine and 80% who received milnacipran (P <.0001). The mean duration of treatment was longer for duloxetine (205 days; P <.0001) than for pregabalin (167 days) and milnacipran (167 days). The duration of using the maximum dose of each medication as a percentage of the total time of medication use was 77% for pregabalin, 84% for duloxetine, and 90% for milnacipran (P <.0001). Conclusions: Patients using pregabalin were the most likely of the 3 cohorts to receive lower than label-recommended starting doses and the least likely to receive the recommended maintenance doses during follow up compared with those receiving duloxetine or milnacipran. Real-world prescribing patterns indicate that factors other than label recommendations may be influencing prescribed dosing. PMID- 30464797 TI - Estimating the Real-World Cost of Diabetes Mellitus in the United States During an 8-Year Period Using 2 Cost Methodologies. AB - Background: Diabetes is associated with substantial clinical and economic burdens on patients and on the US healthcare system. Treatment options for patients with type 1 or type 2 diabetes have increased significantly, from only 3 drug classes in 1995 to more than 12 distinct classes today. Although several of the newer treatments are reported to have improved efficacy and safety profiles, they are often substantially more costly than older medications. Consequently, as drug options increase, the cost of diabetes management continues to grow. Objectives: To estimate the annual real-world costs of type 1 and 2 diabetes, as well as diabetes prevalence, treatment patterns, care quality, and resource utilization during 8 years. Methods: In this cross-sectional study, we examined 8 annual cohorts of patients with type 1 or type 2 diabetes, on a biennial basis, using claims data from the HealthCore Integrated Research Database between 2006 and 2014. Patients were matched with controls by age, sex, residency, and health plan type. We assessed the prevalence of diabetes, treatment patterns, care quality measures, and all-cause and diabetes-related healthcare costs using 2 methods. Method 1 calculated the annual costs as the difference in all-cause costs between patients with diabetes and matched controls. Method 2 calculated the costs for healthcare encounters based on specific codes for a diabetes diagnosis or for antidiabetes medications. Results: Between 346,486 and 410,234 patients with type 2 diabetes and between 21,176 and 26,228 patients with type 1 diabetes were included in each study year cohort. Between 2007 and 2014, the prevalence of type 2 diabetes increased from 4.9% to 6.3%. The costs associated with using Method 1 were almost double the cost estimates in Method 2 during most of the study period. For patients with type 1 diabetes, the associated costs were twice greater with Method 1 than with Method 2. Projections to the entire US population in 2014 indicated a total of 19.3 million individuals with diabetes and associated direct costs of $314.8 billion that year. Conclusion: Cost estimates can guide the prioritization of healthcare expenditures. The results of this study showed that costs attributable to diabetes differed by approximately 2 fold, depending on the estimation method. The management of the escalating expenses for diabetes management in the United States requires judicious selection of the methods for estimating costs. PMID- 30464798 TI - INFANT BRAIN DEVELOPMENT PREDICTION WITH LATENT PARTIAL MULTI-VIEW REPRESENTATION LEARNING. AB - The early postnatal period witnesses rapid and dynamic brain development. Understanding the cognitive development patterns can help identify various disorders at early ages of life and is essential for the health and well-being of children. This inspires us to investigate the relation between cognitive ability and the cerebral cortex by exploiting brain images in a longitudinal study. Specifically, we aim to predict the infant brain development status based on the morphological features of the cerebral cortex. For this goal, we introduce a multi-view multi-task learning approach to dexterously explore complementary information from different time points and handle the missing data simultaneously. Specifically, we establish a novel model termed as Latent Partial Multi-view Representation Learning. The approach regards data of different time points as different views, and constructs a latent representation to capture the complementary underlying information from different and even incomplete time points. It uncovers the latent representation that can be jointly used to learn the prediction model. This formulation elegantly explores the complementarity, effectively reduces the redundancy of different views, and improves the accuracy of prediction. The minimization problem is solved by the Alternating Direction Method of Multipliers (ADMM). Experimental results on real data validate the proposed method. PMID- 30464799 TI - BET inhibitors: Betting on improved outcomes in uterine serous carcinoma. PMID- 30464800 TI - Making cytology specimens solid materials for testing predictive marker of immunotherapy in NSCLC. PMID- 30464801 TI - Pathologic stage dictates survival after neoadjuvant radiation for rectal cancer. PMID- 30464802 TI - IMiDs for myeloma induced renal impairment. PMID- 30464803 TI - The genomic features associated with high-risk multiple myeloma. PMID- 30464804 TI - Transcriptional co-expression regulatory network analysis for Snail and Slug identifies IL1R1, an inflammatory cytokine receptor, to be preferentially expressed in ST-EPN-RELA and PF-EPN-A molecular subgroups of intracranial ependymomas. AB - Recent molecular subgrouping of ependymomas (EPN) by DNA methylation profiling has identified ST-EPN-RELA and PF-EPN-A subgroups to be associated with poor outcome. Snail/Slug are cardinal epithelial-to-mesenchymal transcription factors (EMT-TFs) and are overexpressed in several CNS tumors, including EPNs. A systematic analysis of gene-sets/modules co-expressed with Snail and Slug genes using published expression microarray dataset (GSE27279)identified 634 genes for Snail with enriched TGF-beta, PPAR and PI3K signaling pathways, and 757 genes for Slug with enriched focal adhesion, ECM-receptor interaction and regulation of actin cytoskeleton related pathways. Of 37 genes commonly expressed with both Snail and Slug, IL1R1, a cytokine receptor of interleukin-1 receptor family, was positively correlated with Snail (r=0.43) and Slug (r=0.51), preferentially expressed in ST-EPN-RELA and PF-EPN-A molecular groups, and enriched for pathways related to inflammation, angiogenesis and glycolysis. IL1R1 expression was fairly specific to EPNs among various CNS tumors analyzed. It also showed significant positive correlation with EMT, stemness and MDSC (myeloid derived suppressor cell) markers. Our study reports IL1R1 as a poor prognostic marker associated with EMT-like phenotype and stemness in EPNs. Our findings emphasize the need to further examine and validate IL1R1 as a novel therapeutic target in aggressive subsets of intracranial EPNs. PMID- 30464805 TI - Difference in the prevalence of non-fatal suicidal behaviours in patients with unipolar and bipolar depression in China: a meta-analysis. AB - Difference in the prevalence of non-fatal suicidal behaviours in patients with unipolar and bipolar depression in China is rarely reported. We conducted a meta analysis to examine this difference. Major Chinese and English literature databases were searched online to collect studies comparing the prevalence of non fatal suicidal behaviours of patients with unipolar and bipolar depression. The quality of the included studies was assessed according to the matching principle. Risk difference (RD) of prevalence rates of non-fatal suicidal behaviours between patients with unipolar and bipolar depression was calculated. A total of 16 studies, containing 1678 cases with unipolar depression and 1069 cases with bipolar depression, were included. Differences in rates of suicidal ideation and attempt were not statistically significant between patients with unipolar and bipolar depression, but rates of overall non-fatal suicidal behaviours in patients with unipolar depression was significantly higher than those with bipolar depression (RD: 0.28, 95% CI: 0.20, 0.36). In summary, the rate of overall non-fatal suicidal behaviours of patients with unipolar depression is higher than that of patients with bipolar depression in China. PMID- 30464807 TI - Correction: NLRP6 targeting suppresses gastric tumorigenesis via P14ARF-Mdm2-P53 dependent cellular senescence. AB - [This corrects the article DOI: 10.18632/oncotarget.22876.]. PMID- 30464806 TI - Renin-angiotensin inhibitors reprogram tumor immune microenvironment: A comprehensive view of the influences on anti-tumor immunity. AB - Renin-angiotensin system inhibitors (RASi) have shown potential anti-tumor effects that may have a significant impact in cancer therapy. The components of the renin-angiotensin system (RAS) including both, conventional and alternative axis, appear to have contradictory effects on tumor biology. The mechanisms by which RASi impair tumor growth extend beyond their function of modulating tumor vasculature. The major focus of this review is to analyze other mechanisms by which RASi reprogram the tumor immune microenvironment. These involve impairing hypoxia and acidosis within the tumor stroma, regulating inflammatory signaling pathways and oxidative stress, modulating the function of the non-cellular components and immune cells, and regulating the cross-talk between kalli krein kinin system and RAS. PMID- 30464808 TI - The quality of guidelines in non-pharmacological prevention and management of chemotherapy-induced neuropathy: A review. AB - Chemotherapy-induced peripheral neuropathy is a common adverse effect occurring in patients undergoing neurotoxic chemotherapy. However, there is no FDA-approved treatment option for it. Given the importance of clinical practice guidelines in this area, this study aimed to determine the methodological quality of extant CIPN guidelines. The study was done as part of the adaptation process of CIPN related CPGs at Isfahan University of Medical Sciences, Iran. A systematic search of published CPGs about chemotherapy-induced CIPN in which the AGREE II instrument was applied for appraising CPGs of CIPN was performed. In general, amongst all of the AGREE II Instrument's domains in the evaluated CPGs, the clarity of presentation and stakeholder involvement domains took favorable scores; and other domains obtained unfavorable and relatively favorable scores. The quality of cancer therapy-induced neuropathy CPGs needs to be improved and designing high-quality CPGs must be considered. PMID- 30464809 TI - Cephalexin-induced acute generalized exanthematous pustulosis. AB - Cephalexin is a cephalosporin antibiotic that is commonly used in the treatment of infectious diseases. We report a patient exhibiting a rare adverse effect of cephalexin: drug-induced Acute Generalized Exanthematous Pustulosis (AGEP). We present this case because of the scarcity of reports associating cephalexin with AGEP in hopes that clinicians will consider AGEP in their differential diagnosis in the appropriate clinical setting. PMID- 30464810 TI - Spatial scale-dependent phylogenetic signal in species distributions along geographic and elevation gradients in a mountainous rangeland. AB - The mechanisms determining community phylogenetic structure range from local ecological mechanisms to broad biogeographical processes. How these community assembly processes determine phylogenetic structure and patterns in rangeland communities across multiple spatial scales is still poorly understood. We sought to determine whether the structure of herbaceous and shrub assemblages along local environmental gradients (elevation) and broad geography (latitude) exhibited phylogenetic signal at different spatial scales, across 2,500 ha of a mountainous rangeland. We analyzed species distribution and phylogenetic data at two spatial scales: the community level (1 m2 sample units obtained by stratified random sampling) and the habitat level (plant assemblages identified categorically based on environmental and geographical variables). We found significant phylogenetic signal in structure and pattern at both spatial scales, along local elevational, and latitudinal gradients. Moreover, beta diversity was affected by different environmental variables in herbaceous and shrub species distributions across different spatial scales. Our results highlight the relative importance of local ecological mechanisms, including niche-based deterministic processes (environmental filtering and species interactions) as well as those of biogeographical processes, such as stochastic dispersal limitation and habitat specialization in plant assemblages of mountainous rangeland. PMID- 30464811 TI - Genetic variation for tolerance to high temperatures in a population of Drosophila melanogaster. AB - The range of thermal tolerance is one of the main factors influencing the geographic distribution of species. Climate change projections predict increases in average and extreme temperatures over the coming decades; hence, the ability of living beings to resist these changes will depend on physiological and adaptive responses. On an evolutionary scale, changes will occur as the result of selective pressures on individual heritable differences. In this work, we studied the genetic basis of tolerance to high temperatures in the fly Drosophila melanogaster and whether this species presents sufficient genetic variability to allow expansion of its upper thermo-tolerance limit. To do so, we used adult flies derived from a natural population belonging to the Drosophila Genetic Reference Panel, for which genomic sequencing data are available. We characterized the phenotypic variation of the upper thermal limit in 34 lines by measuring knockdown temperature (i.e., critical thermal maximum [CTmax]) by exposing flies to a ramp of increasing temperature (0.25 degrees C/min). Fourteen percent of the variation in CTmax is explained by the genetic variation across lines, without a significant sexual dimorphism. Through a genomewide association study, 12 single nucleotide polymorphisms associated with the CTmax were identified. In most of these SNPs, the less frequent allele increased the upper thermal limit suggesting that this population harbors raw genetic variation capable of expanding its heat tolerance. This potential upper thermal tolerance increase has implications under the global warming scenario. Past climatic records show a very low incidence of days above CTmax (10 days over 25 years); however, future climate scenarios predict 243 days with extreme high temperature above CTmax from 2045 to 2070. Thus, in the context of the future climate warming, rising temperatures might drive the evolution of heat tolerance in this population by increasing the frequency of the alleles associated with higher CTmax. PMID- 30464812 TI - Prey exploitation and dispersal strategies vary among natural populations of a predatory mite. AB - When predators commonly overexploit local prey populations, dispersal drives the dynamics in local patches, which together form a metapopulation. Two extremes in a continuum of dispersal strategies are distinguished: the "Killer" strategy, where predators only start dispersing when all prey are eliminated, and the "Milker" strategy, in which predator dispersal occurs irrespective of prey availability. Theory shows that the Milker strategy is not evolutionarily stable if local populations are well connected by dispersal. Using strains of the predatory mite Phytoseiulus persimilis, collected from 11 native populations from coastal areas in Turkey and Sicily, we investigated whether these two strategies occur in nature. In small wind tunnels, we measured dispersal rates and population dynamics of all populations in a system consisting of detached rose leaves, spider mites (Tetranychus urticae) as prey, and P. persimilis. We found significant variation in the exploitation and dispersal strategies among predator populations, but none of the collected strains showed the extreme Killer or Milker strategy. The results suggest that there is genetic variation for prey exploitation and dispersal strategies. Thus, different dispersal strategies in the Milker-Killer continuum may be selected for under natural conditions. This may affect the predator-prey dynamics in local populations and is likely to determine persistence of predator-prey systems at the metapopulation level. PMID- 30464813 TI - Functional Redundancy in bird community decreases with riparian forest width reduction. AB - Riparian ecosystems are suffering anthropogenic threats that reduce biodiversity and undermine ecosystem services. However, there is a great deal of uncertainty about the way species composition of assemblages is related to ecosystem function, especially in a landscape fragmentation context.Here, we assess the impact of habitat loss and disturbance on Functional Diversity (FD) components Functional Redundancy (FRed), Functional Evenness (FEve), and Functional Richness (FRic) of riparian forest bird assemblages to evaluate (a) how FD components respond to riparian forest width reduction and vegetation disturbance; (b) the existence of thresholds within these relationships; (c) which of the main birds diet guild (frugivores, insectivores, and omnivores) respond to such thresholds. We predict that FD components will be affected negatively and nonlinearly by riparian changes. However, guilds could have different responses due to differences of species sensitivity to fragmentation and disturbance. We expect to find thresholds in FD responses, because fragmentation and disturbance drive loss of specific FD components.Our results show that FRed and FEve were linearly affected by width and disturbance of riparian habitats, respectively. FRed was significantly lower in riparian forests assemblages below 400 m wide, and FEve was significantly higher above 60% disturbance. These responses of FD were also followed to the decline in insectivores and frugivores richness in riparian forests most affected by these changes.Consequently, our study suggests communities do not tolerate reduction in riparian forest width or disturbance intensification without negative impact on FD, and this becomes more critical for riparian area <400-m wide or with more than 60% disturbance. This minimum riparian width required to maintain FRed is greater than the minimum width required for riparian forests by Brazilian law. Thus, it is important to consider mechanisms to expand riparian habitats and reduce the disturbance intensity in riparian forests so that riparian bird community FD may be effectively conserved. PMID- 30464814 TI - Phenotypic correlation between queen and worker brood care supports the role of maternal care in the evolution of eusociality. AB - Cooperative brood care by siblings, a defining feature of eusociality, is hypothesized to be evolutionarily derived from maternal care via shifts in the timing of the expression of genes underlying maternal care. If sibling and maternal care share a genetic basis, the two behaviors are expected to be genetically and phenotypically correlated. We tested this prediction in the black garden ant Lasius niger by quantifying the brood retrieval rate of queens and their first and later generation worker offspring. Brood retrieval rate of queens was positively phenotypically correlated with the brood retrieval rate of first generation but not with later generation workers. The difference between first and later generation workers could be due to the stronger similarity in care behavior provided by queens and first generation workers compared to later generations. Furthermore, we found that queen retrieval rate was positively correlated with colony productivity, suggesting that natural selection is acting on maternal care. Overall, our results support the idea of a shared genetic basis between maternal and sibling care as well as queen and worker traits more generally, which has implications for the role of intercaste correlations in the evolution of queen and worker traits and eusociality. PMID- 30464815 TI - The extent of mangrove change and potential for recovery following severe Tropical Cyclone Yasi, Hinchinbrook Island, Queensland, Australia. AB - Cyclones are significant drivers of change within mangrove ecosystems with the extent of initial damage determined by storm severity, location and distribution (exposure), and influenced by species composition and structure (e.g., height). The long-term recovery of mangroves is often dependent upon hydrological regimes, as well as the frequency of storm events. On February 3, 2011, Tropical Cyclone Yasi (Category 5) made landfall on the coast of north Queensland Australia with its path crossing the extensive mangroves within and surrounding Hinchinbrook Island National Park. Based on a combination of Landsat-derived foliage projective cover (FPC), Queensland Globe aerial imagery, and RapidEye imagery, 16% of the 13,795 ha of mangroves experienced severe windthrow during the storm. The greatest damage from the cyclone was inflicted on mangrove forests dominated primarily by Rhizophora stylosa, whose large prop roots were unable to support them as wind speeds exceeded 280 km/hr. Classification of 2016 RapidEye data indicated that many areas of damage had experienced no or very limited recovery in the period following the cyclone, with this confirmed by a rapid decline in Landsat-derived FPC (from levels > 90% from 1986 to just prior to the cyclone to < 20% postcyclone) and no noticeable increase in subsequent years. Advanced Land Observing Satellite (ALOS-1) Phased Arrayed L-band Synthetic Aperture Radar (SAR) L-band HH backscatter also increased initially and rapidly to 5 +/- 2 dB (2007 2011) due to the increase in woody debris but then decreased subsequently to -20 +/- 2 dB (postcyclone), as this decomposed or was removed. The lack of recovery in affected areas was attributed to the inability of mangrove species, particularly R. stylosa, to resprout from remaining plant material and persistent inundation due to a decrease in sediment elevation thereby preventing propagule establishment. This study indicates that increases in storm intensity predicted with changes in global climate may lead to a reduction in the area, diversity, and abundance of mangroves surrounding Hinchinbrook Island. PMID- 30464816 TI - A metabarcoding approach for the feeding habits of European hake in the Adriatic Sea. AB - European hake (Merluccius merluccius) is one of the most economically important fish for the Mediterranean Sea. It is an important predator of deep upper shelf slope communities currently characterized by growth overexploitation: the understanding of hake's diet might support next generation management tools. However, all current European hake diet studies depend on the morphological identification of prey remains in stomach content, with consequent limitations. In this study, we set up a metabarcoding approach based on cytochrome oxidase I PCR amplification and Miseq Illumina paired-end sequencing of M. merluccius stomach content remains and compared the results to classic morphological analyses. A total of 95 stomach contents of M. merluccius sampled in the North Central Adriatic Sea were analyzed with both the metabarcoding and morphological approaches. Metabarcoding clearly outperformed the morphological method in the taxonomic identification of prey describing more complex trophic relationships even when considering the morphological identification of 200 stomach contents. Statistical analysis of diet composition revealed a weak differentiation among the hake's size classes, confirming an opportunistic feeding behavior. All the analyses performed showed the presence of a core of shared prey among the size classes and a cloud of size-specific prey. Our study highlights the exceptional potential of metabarcoding as an approach to provide unprecedented taxonomic resolution in the diet of M. merluccius and potentially of other marine predators, due to the broad-spectrum of detection of the primers used. A thorough description of these complex trophic relationships is fundamental for the implementation of an ecosystem approach to fisheries. PMID- 30464817 TI - Sex-specific effects of outbreeding on offspring quality in pike (Esox lucius). AB - Intraspecific genetic admixture occurs when previously separated populations within a species start interbreeding, and it can have either positive, negative, or neutral effects on reproductive performance. As there currently is no reliable predictor for the outcome of admixture, an increased knowledge about admixture effects in different species and populations is important to increase the understanding about what determines the response to admixture. We tested for effects of admixture on F1 offspring quality in three subpopulations of pike (Esox lucius). Gametes were collected in the field, and eggs from each female were experimentally fertilized with milt from a male from each population (one "pure" and two "admixed" treatments). Three offspring quality measures (hatching success, fry survival, and fry length) were determined and compared between (a) pure and admixed population combinations and (b) the sex-specific treatments within each admixed population combination (based on the origin of the male and female, respectively). The results suggested that although there were no overall effects of admixture on offspring quality, the consequences for a given population combination could be sex-specific and thus differ depending on which of the parents originated from one or the other population. All offspring quality traits were influenced by both maternal ID and paternal ID. Sex- and individual specific effects can have implications for dispersal behavior and gene flow between natural populations, and are important to consider in conservation efforts. PMID- 30464818 TI - A study of the transit amplification divisions during spermatogenesis in Oncopetus fasciatus to assess plasticity in sperm numbers or sperm viability under different diets. AB - Oncopeltus fasciatus males fed the ancestral diet of milkweed seeds prioritize reproduction over lifespan as evidenced by higher rates of fertility and shorter lifespans than males from the same population fed the adapted diet of sunflower seeds. We examined the proximate mechanisms by which milkweed-fed males maintained late-life fertility. We tested the hypothesis that older milkweed-fed males maintained fertility by producing more, higher quality sperm. Our results, that older males have more sperm, but their sperm do not have higher viability, are in general agreement with other recent studies on how nutrition affects male fertility in insects. We further examined the mechanisms by which sperm are produced by examining the progression of spermatogonial cells through the cell cycle during the transit amplification divisions. We demonstrated that diet affects the likelihood of a spermatocyst being in the S-phase or M-phase of the cell cycle. Given work in model systems, these results have implications for subtle effects on sperm quality either through replication stress or epigenetic markers. Thus, viability may not be the best marker for sperm quality and more work is called for on the mechanisms by which the germline and the production of sperm mediate the cost of reproduction. PMID- 30464819 TI - Implications of survey effort on estimating demographic parameters of a long lived marine top predator. AB - Effective management of wildlife populations rely on knowledge of their abundance, survival, and reproductive rates. Maintaining long-term studies capable of estimating demographic parameters for long-lived, slow-reproducing species is challenging. Insights into the effects of research intensity on the statistical power to estimate demographic parameters are limited. Here, we investigate implications of survey effort on estimating abundance, home range sizes, and reproductive output of Indo-Pacific bottlenose dolphins (Tursiops aduncus), using a 3-year subsample of a long-term, capture-recapture study off Bunbury, Western Australia. Photo-identification on individual dolphins was collected following Pollock's Robust Design, where seasons were defined as "primary periods", each consisting of multiple "secondary periods." The full dataset consisted of 12 primary periods and 72 secondary periods, resulting in the study area being surveyed 24 times/year. We simulated reduced survey effort by randomly removing one, two, or three secondary periods per primary period. Capture-recapture models were used to assess the effect of survey intensity on the power to detect trends in population abundance, while individual dolphin sighting histories were used to assess the ability to conduct home range analyses. We used sighting records of adult females and their calving histories to assess survey effort on quantifying reproductive output. A 50% reduction in survey effort resulted in (a) up to a 36% decline in population abundance at the time of detection; (b) a reduced ability to estimate home range sizes, by increasing the time for individuals to be sighted on >=30 occasions (an often used metric for home range analyses) from 7.74 to 14.32 years; and (c) 33%, 24%, and 33% of annual calving events across three years going undocumented, respectively. Results clearly illustrate the importance of survey effort on the ability to assess demographic parameters with clear implications for population viability analyses, population forecasting, and conservation efforts to manage human-wildlife interactions. PMID- 30464820 TI - Morphological adaptations for relatively larger brains in hummingbird skulls. AB - A common allometric pattern called Haller's Rule states that small species have relatively larger brains and eyes than larger species of the same taxonomic group. This pattern imposes drastic structural changes and energetic costs on small species to produce and maintain a disproportionate amount of nervous tissue. Indeed, several studies have shown the significant metabolic costs of having relatively larger brains; however, little is known about the structural constraints and adaptations required for housing these relatively larger brains and eyes. Because hummingbirds include the smallest birds, they are ideal for exploring how small species evolve morphological adaptations for housing relatively larger brain and eyes. We here present results from a comparative study of hummingbirds and show that the smallest species have the lowest levels of ossification, the most compact braincases, and relatively larger eye sockets, but lower eye/head proportion, than larger species. In contrast to Passerines, skull ossification in hummingbirds correlates with body and brain size but not with age. Correlation of these skull traits with body size might represent adaptations to facilitate housing relatively larger brain and eyes, rather than just heterochronic effects related to change in body size. These structural changes in skull traits allow small animals to accommodate disproportionately larger brains and eyes without further increasing overall head size. PMID- 30464821 TI - Multiple components of environmental change drive populations of breeding waders in seminatural grasslands. AB - Environments are rapidly changing due to climate change, land use, intensive agriculture, and the impact of hunting on predator populations. Here, we analyzed long-term data recorded during 1928-2014 on the size of breeding populations of waders at two large nature reserves in Denmark, Vejlerne and Tipperne, to determine the effects of components of environmental change on breeding populations of waders. Environmental variables and counts of waders were temporally autocorrelated, and we used generalized least square (GLS) by incorporating the first-order autoregressive correlation structure in the analyses. We attempted to predict the abundance of waders for short-term trends for two nature reserves (35 years) and for long-term trends for one nature reserve (86 years), using precipitation, temperature, nutrients, abundance of foxes Vulpes vulpes, area grazed, and number of cattle. There was evidence of impacts of nutrients, climate (long-term changes in temperature and precipitation), grazing, mowing, and predation on bird populations. We used standard random effects meta-analyses weighted by (N-3) to quantify these mean effects. There was no significant difference in effect size among species, while mean effect size differed consistently among environmental factors, and the interaction between effect size for species and environmental factors was also significant. Thus, environmental factors affected the different species differently. Mean effect size was the largest at +0.20 for rain, +0.11 for temperature, -0.09 for fox abundance, and -0.03 for number of cattle, while there was no significant mean effect for fertilizer, area grazed, and year. Effect sizes for two short-term time series from Tipperne and Vejlerne were positively correlated as were effect sizes for short-term and long-term time series at Tipperne. This implies that environmental factors had consistent effects across large temporal and spatial scales. PMID- 30464822 TI - Species distribution models and empirical test: Comparing predictions with well understood geographical distribution of Bothrops alternatus in Argentina. AB - Species distribution models (SDMs) estimate the geographical distribution of species although with several limitations due to sources of inaccuracy and biases. Empirical tests arose as the most important steps in scientific knowledge to assess the efficiency of model predictions, which are poorly rigorous in SDMs. A good approach to the empirical distribution (ED) of a species can be obtained from comprehensive empirical knowledge, that is, well-understood distributions gathered from large amount of data generated with appropriate spatial and temporal samples coverage. The aims of this study were to (a) compare different SDMs predictions with an ED; and (b) evaluate if fuzzy global matching (FGM) could be used as an index to compare SDMs predictions and ED. Six algorithms with 5 and 20 variables were used to assess their accuracy in predicting the ED of the venomous snake Bothrops alternatus (Viperidae). Its entire distribution is known, thanks to thorough field surveys across Argentina, with 1,767 records. ED was compared with SDMs predictions using Map Comparison Kit. SDMs predictions showed important biases in all methods used, from 70% sub-estimation to 40% over estimation of ED. BIOCLIM predicted ~31% of B. alternatus ED. DOMAIN predicted 99% of ED, but over-estimated 40% of the area. GLM with five variables calculated 75% of ED, while Genetic Algorithm for Rule-set Prediction showed ~60% of ED; the last two presenting overpredictions in areas with favorable climatic conditions but not inhabited by the species. MaxEnt and RF were the only methods to detect isolated populations in the southern distribution of B. alternatus. Although SDMs proved useful in making predictions about species distribution, predictions need validation with expert maps knowledge and ED. Moreover, FGM showed a good performance as an index with values similar to True Skill Statistic, so that it could be used to relate ED and SDMs predictions. PMID- 30464823 TI - Ecological patterns in the skin microbiota of frogs from tropical Australia. AB - The microbiota of frog skin can play an important role in protecting against diseases and parasites. The frog skin microbial community represents a complex mix of microbes that are promoted by the chemical environment of the frog skin and influenced by the animal's immediate past environment. The microbial communities of six species of frogs sampled from the campus of Charles Darwin University (CDU) were more similar within species than between species. The microbiota of the introduced cane toad (Rhinella marina) was most dissimilar among the species. Pairwise comparisons showed that the microbial communities of each species were different, except for the terrestrial Litoria nasuta and the arboreal L. rothii. The microbial communities of the six species were not related to ecological habit (arboreal or terrestrial), and neither was the alpha diversity of the microbes. The core microbes (defined as being on >=90% of individuals of a species or group) were significantly different among all species, although 89 microbial operational taxonomic units (OTUs) were core microbes for all six species at CDU. Two species, Rhinella marina and Litoria rothii, were sampled at additional sites approximately 10 and 30 km from CDU. The microbial communities and the core OTU composition were different among the sites, but there were nevertheless 194 (R. marina) and 181 (L. rothii) core OTUs present at all three sites. Thus, the core microbiota varied with respect to geographic range and sample size. PMID- 30464824 TI - Identification of marine Important Bird and Biodiversity Areas for penguins around the South Shetland Islands and South Orkney Islands. AB - Aim: To provide a method of analyzing penguin tracking data to identify priority at-sea areas for seabird conservation (marine IBAs), based on pre-existing approaches for flying seabirds but revised according to the specific ecology of Pygoscelis penguin species. Location: Waters around the Antarctic Peninsula, South Shetland, and South Orkney archipelagos (FAO Subareas 48.1 and 48.2). Methods: We made key improvements to the pre-existing protocol for identifying marine IBAs that include refining the track interpolation method and revision of parameters for the kernel analysis (smoothing factor and utilization distribution) using sensitivity tests. We applied the revised method to 24 datasets of tracking data on penguins (three species, seven colonies, and three different breeding stages-incubation, brood, and creche). Results: We identified five new marine IBAs for seabirds in the study area, estimated to hold ca. 600,000 adult penguins. Main conclusions: The results demonstrate the efficacy of a new method for the designation of a network of marine IBAs in Antarctic waters for penguins based on tracking data, which can contribute to an evidence-based, precautionary, management framework for krill fisheries. PMID- 30464825 TI - Taxonomy-based hierarchical analysis of natural mortality: polar and subpolar phocid seals. AB - Knowledge of life-history parameters is frequently lacking in many species and populations, often because they are cryptic or logistically challenging to study, but also because life-history parameters can be difficult to estimate with adequate precision. We suggest using hierarchical Bayesian analysis (HBA) to analyze variation in life-history parameters among related species, with prior variance components representing shared taxonomy, phenotypic plasticity, and observation error. We develop such a framework to analyze U-shaped natural mortality patterns typical of mammalian life history from a variety of sparse datasets. Using 39 datasets from seals in the family Phocidae, we analyzed 16 models with different formulations for natural morality, specifically the amount of taxonomic and data-level variance components (subfamily, species, study, and dataset levels) included in mortality hazard parameters. The highest-ranked model according to DIC included subfamily-, species-, and dataset-level parameter variance components and resulted in typical U-shaped hazard functions for the 11 seal species in the study. Species with little data had survival schedules shrunken to the mean. We suggest that evolutionary and population ecologists consider employing HBA to quantify variation in life-history parameters. This approach can be useful for increasing the precision of estimates resulting from a collection of (often sparse) datasets, and for producing prior distributions for populations missing life-history data. PMID- 30464826 TI - Predicting the potential distribution of the endangered red panda across its entire range using MaxEnt modeling. AB - An upsurge in anthropogenic impacts has hastened the decline of the red panda (Ailurus fulgens). The red panda is a global conservation icon, but holistic conservation management has been hampered by research being restricted to certain locations and population clusters. Building a comprehensive potential habitat map for the red panda is imperative to advance the conservation effort and ensure coordinated management across international boundaries. Here, we use occurrence records of both subspecies of red pandas from across their entire range to build a habitat model using the maximum entropy algorithm (MaxEnt 3.3.3k) and the least correlated bioclimatic variables. We found that the subspecies have separate climatic spaces dominated by temperature-associated variables in the eastern geographic distribution limit and precipitation-associated variables in the western distribution limit. Annual precipitation (BIO12) and maximum temperature in the warmest months (BIO5) were major predictors of habitat suitability for A. f. fulgens and A. f. styani, respectively. Our model predicted 134,975 km2 of red panda habitat based on 10 percentile thresholds in China (62% of total predicted habitat), Nepal (15%), Myanmar (9%), Bhutan (9%), and India (5%). Existing protected areas (PAs) encompass 28% of red panda habitat, meaning the PA network is currently insufficient and alternative conservation mechanisms are needed to protect the habitat. Bhutan's PAs provide good coverage for the red panda habitat. Furthermore, large areas of habitat were predicted in cross-broader areas, and transboundary conservation will be necessary. PMID- 30464827 TI - Evaluating the effectiveness of conservation measures for European grassland breeding waders. AB - Farmland birds are among the most threatened bird species in Europe, largely as a result of agricultural intensification which has driven widespread biodiversity losses. Breeding waders associated with grassland and arable habitats are particularly vulnerable and a frequent focus of agri-environment schemes (AES) designed to halt and reverse population declines. We review existing literature, providing a quantitative assessment of the effectiveness of policy and management interventions used throughout Europe to improve population and demographic metrics of grassland-breeding waders. Targeted AES and site protection measures were more likely to be effective than less targeted AES and were ten times more likely to be effective than would be expected by chance, particularly for population trend and productivity metrics. Positive effects of AES and site protection did not appear synergistic. Management interventions which had the greatest chance of increasing population growth or productivity included modification of mowing regimes, increasing wet conditions, and the use of nest protection. Success rates varied according to the species and metric being evaluated. None of the policy or management interventions we evaluated were associated with a significant risk of negative impacts on breeding waders. Our findings support the use of agri-environment schemes, site protection, and management measures for grassland-breeding wader conservation in Europe. Due to publication bias, our findings are most applicable to intensively managed agricultural landscapes. More studies are needed to identify measures that increase chick survival. Despite broadly effective conservation measures already in use, grassland-breeding waders in Europe continue to decline. More research is needed to improve the likelihood and magnitude of positive outcomes, coupled with wider implementation of effective measures to substantially increase favorable land management for these species. PMID- 30464828 TI - Sensory deficiencies affect resource selection and associational effects at two spatial scales. AB - Many insect species have limited sensory abilities and may not be able to perceive the quality of different resource types while approaching patchily distributed resources. These restrictions may lead to differences in selection rates between separate patches and between different resource types within a patch, which may have consequences for associational effects between resources. In this study, we used an oviposition assay containing different frequencies of apple and banana substrates divided over two patches to compare resource selection rates of wild-type Drosophila melanogaster at the between- and within patch scales. Next, we compared the wild-type behavior with that of the olfactory deficient strain Orco 2 and the gustatory-deficient strain Poxn DeltaM22-B5 and found comparable responses to patch heterogeneity and similarly strong selection rates for apple at both scales for the wild-type and olfactory-deficient flies. Their oviposition behavior translated into associational susceptibility for apple and associational resistance for banana. The gustatory-deficient flies, on the other hand, no longer had a strong selection rate for apple, strongly differed in between- and within-patch selection rates from the wild-type flies, and caused no associational effects between the resources. Our study suggests that differences in sensory capabilities can affect resource selection at different search behavior scales in different ways and in turn underlie associational effects between resources at different spatial scales. PMID- 30464829 TI - Extensive diversity of malaria parasites circulating in Central African bats and monkeys. AB - The order Haemosporidia gathers many protozoan parasites which are known to infect many host species and groups. Until recently, the studies on haemosporidian parasites primarily focused on the genus Plasmodium among a wide range of hosts. Genera, like the genus Hepatocystis, have received far less attention. In the present study, we present results of a survey of the diversity of Hepatocystis infecting bats and monkeys living in a same area in Gabon (Central Africa). Phylogenetic analyses revealed a large diversity of Hepatocystis lineages circulating among bats and monkeys, among which certain were previously observed in other African areas. Both groups of hosts harbor parasites belonging to distinct genetic clades and no transfers of parasites were observed between bats and monkeys. Finally, within each host group, no host specificity or geographical clustering was observed for the bat or the primate Hepatocystis lineages. PMID- 30464830 TI - DNA barcoding the flowering plants from the tropical coral islands of Xisha (China). AB - Aim: DNA barcoding has been widely applied to species diversity assessment in various ecosystems, including temperate forests, subtropical forests, and tropical rain forests. However, tropical coral islands have never been barcoded before due to the difficulties in field exploring. This study aims at barcoding the flowering plants from a unique ecosystem of the tropical coral islands in the Pacific Ocean and supplying valuable evolutionary information for better understanding plant community assembly of those particular islands in the future. Location: Xisha Islands, China. Methods: This study built a DNA barcode database for 155 plant species from the Xisha Islands using three DNA markers (ITS, rbcL, and matK). We applied the sequence similarity method and a phylogenetic-based method to assess the barcoding resolution. Results: All the three DNA barcodes showed high levels of PCR success (96%-99%) and sequencing success (98%-100%). ITS performed the highest rate of species resolution (>95%) among the three markers, while plastid markers delivered a relatively poor species resolution (85%-90%). Our analyses obtained a marginal increase in species resolution when combining the three DNA barcodes. Main conclusions: This study provides the first plant DNA barcode data for the unique ecosystem of tropical coral islands and considerably supplements the DNA barcode library for the flowering plants on the oceanic islands. Based on the PCR and sequencing success rates, and the discriminatory power of the three DNA regions, we recommend ITS as the most successful DNA barcode to identify the flowering plants from Xisha Islands. Due to its high sequence variation and low fungal contamination, ITS could be a preferable candidate of DNA barcode for plants from other tropical coral islands as well. Our results also shed lights on the importance of biodiversity conservation of tropical coral islands. PMID- 30464831 TI - The evolution of bequeathal in stable habitats. AB - Adults sometimes disperse, while philopatric offspring inherit the natal site, a pattern known as bequeathal. Despite a decades-old empirical literature, little theoretical work has explored when natural selection may favor bequeathal. We present a simple mathematical model of the evolution of bequeathal in a stable environment, under both global and local dispersal. We find that natural selection favors bequeathal when adults are competitively advantaged over juveniles, baseline mortality is high, the environment is unsaturated, and when juveniles experience high dispersal mortality. However, frequently bequeathal may not evolve, because the fitness cost for the adult is too large relative to inclusive fitness benefits. Additionally, there are many situations for which bequeathal is an ESS, yet cannot invade the population. As bequeathal in real populations appears to be facultative, yet-to-be-modeled factors like timing of birth in the breeding season may strongly influence the patterns seen in natural populations. PMID- 30464832 TI - Size does matter: Parallel evolution of adaptive thermal tolerance and body size facilitates adaptation to climate change in domestic cattle. AB - The adaptive potential of livestock under a warming climate is increasingly relevant in relation to the growing pressure of global food security. Studies on heat tolerance demonstrate the interplay of adaptation and acclimatization in functional traits, for example, a reduction in body size and enhanced tolerance in response to a warming climate. However, current lack of understanding of functional traits and phylogenetic history among phenotypically distinct populations constrains predictions of climate change impact. Here, we demonstrate evidence of parallel evolution in adaptive tolerance to heat stress in dwarf cattle breeds (DCB, Bos taurus indicus) and compare their thermoregulatory responses with those in standard size cattle breeds (SCB, crossbred, Bos taurus indicus * Bos taurus taurus). We measured vital physiological, hematological, biochemical, and gene expression changes in DCB and SCB and compared the molecular phylogeny using mitochondrial genome (mitogenome) analysis. Our results show that SCB can acclimatize in the short term to higher temperatures but reach their tolerance limit under prevailing tropical conditions, while DCB is adapted to the warmer climate. Increased hemoglobin concentration, reduced cellular size, and smaller body size enhance thermal tolerance. Mitogenome analysis revealed that different lineages of DCB have evolved reduced size independently, as a parallel adaptation to heat stress. The results illustrate mechanistic ways of dwarfing, body size-dependent tolerance, and differential fitness in a large mammal species under harsh field conditions, providing a background for comparing similar populations during global climate change. These demonstrate the value of studies combining functional, physiological, and evolutionary approaches to delineate adaptive potential and plasticity in domestic species. We thus highlight the value of locally adapted breeds as a reservoir of genetic variation contributing to the global domestic genetic resource pool that will become increasingly important for livestock production systems under a warming climate. PMID- 30464833 TI - The Antarctic Circumpolar Current isolates and connects: Structured circumpolarity in the sea star Glabraster antarctica. AB - Aim: The Antarctic Circumpolar Current (ACC) connects benthic populations by transporting larvae around the continent, but also isolates faunas north and south of the Antarctic Convergence. We test circumpolar panmixia and dispersal across the Antarctic Convergence barrier in the benthic sea star Glabraster antarctica. Location: The Southern Ocean and south Atlantic Ocean, with comprehensive sampling including the Magellanic region, Scotia Arc, Antarctic Peninsula, Ross Sea, and East Antarctica. Methods: The cytochrome c oxidase subunit I (COI) gene (n = 285) and the internal transcribed spacer region 2 (ITS2; n = 33) were sequenced. We calculated haplotype networks for each genetic marker and estimated population connectivity and the geographic distribution of genetic structure using PhiST for COI data. Results: Glabraster antarctica is a single circum-Antarctic species with instances of gene flow between distant locations. Despite the homogenizing potential of the ACC, population structure is high (PhiST = 0.5236), and some subpopulations are genetically isolated. Genetic breaks in the Magellanic region do not align with the Antarctic Convergence, in contrast with prior studies. Connectivity patterns in East Antarctic sites are not uniform, with some regional isolation and some surprising affinities to the distant Magellanic and Scotia Arc regions. Main conclusions: Despite gene flow over extraordinary distances, there is strong phylogeographic structuring and genetic barriers evident between geographically proximate regions (e.g., Shag Rocks and South Georgia). Circumpolar panmixia is rejected, although some subpopulations show a circumpolar distribution. Stepping-stone dispersal occurs within the Scotia Arc but does not appear to facilitate connectivity across the Antarctic Convergence. The patterns of genetic connectivity in Antarctica are complex and should be considered in protected area planning for Antarctica. PMID- 30026931 TI - Study protocol for the Anesthesiology Control Tower-Feedback Alerts to Supplement Treatments (ACTFAST-3) trial: a pilot randomized controlled trial in intraoperative telemedicine. AB - Background: Each year, over 300 million people undergo surgical procedures worldwide. Despite efforts to improve outcomes, postoperative morbidity and mortality are common. Many patients experience complications as a result of either medical error or failure to adhere to established clinical practice guidelines. This protocol describes a clinical trial comparing a telemedicine based decision support system, the Anesthesiology Control Tower (ACT), with enhanced standard intraoperative care. Methods: This study is a pragmatic, comparative effectiveness trial that will randomize approximately 12,000 adult surgical patients on an operating room (OR) level to a control or to an intervention group. All OR clinicians will have access to decision support software within the OR as a part of enhanced standard intraoperative care. The ACT will monitor patients in both groups and will provide additional support to the clinicians assigned to intervention ORs. Primary outcomes include blood glucose management and temperature management. Secondary outcomes will include surrogate, clinical, and economic outcomes, such as incidence of intraoperative hypotension, postoperative respiratory compromise, acute kidney injury, delirium, and volatile anesthetic utilization. Ethics and dissemination: The ACTFAST-3 study has been approved by the Human Resource Protection Office (HRPO) at Washington University in St. Louis and is registered at clinicaltrials.gov ( NCT02830126). Recruitment for this protocol began in April 2017 and will end in December 2018. Dissemination of the findings of this study will occur via presentations at academic conferences, journal publications, and educational materials. PMID- 30464835 TI - Anabolic and antiresorptive actions of locally delivered bisphosphonates for bone repair: A review. AB - During the last decades, several research groups have used bisphosphonates for local application to counteract secondary bone resorption after bone grafting, to improve implant fixation or to control bone resorption caused by bone morphogenetic proteins (BMPs). We focused on zoledronate (a bisphosphonate) due to its greater antiresorptive potential over other bisphosphonates. Recently, it has become obvious that the carrier is of importance to modulate the concentration and elution profile of the zoledronic acid locally. Incorporating one fifth of the recommended systemic dose of zoledronate with different apatite matrices and types of bone defects has been shown to enhance bone regeneration significantly in vivo. We expect the local delivery of zoledronate to overcome the limitations and side effects associated with systemic usage; however, we need to know more about the bioavailability and the biological effects. The local use of BMP-2 and zoledronate as a combination has a proven additional effect on bone regeneration. This review focuses primarily on the local use of zoledronate alone, or in combination with bone anabolic factors, in various preclinical models mimicking different orthopaedic conditions. Cite this article: I. Qayoom, D. B. Raina, A. Sirka, S. Tarasevicius, M. Tagil, A. Kumar, L. Lidgren. Anabolic and antiresorptive actions of locally delivered bisphosphonates for bone repair: A review. Bone Joint Res 2018;7:548-560. DOI: 10.1302/2046-3758.710.BJR-2018 0015.R2. PMID- 30464836 TI - Management of acute Achilles tendon ruptures: A review. AB - Objectives: The incidence of acute Achilles tendon rupture appears to be increasing. The aim of this study was to summarize various therapies for acute Achilles tendon rupture and discuss their relative merits. Methods: A PubMed search about the management of acute Achilles tendon rupture was performed. The search was open for original manuscripts and review papers limited to publication from January 2006 to July 2017. A total of 489 papers were identified initially and finally 323 articles were suitable for this review. Results: The treatments of acute Achilles tendon rupture include operative and nonoperative treatments. Operative treatments mainly consist of open repair, percutaneous repair, mini open repair, and augmentative repair. Traditional open repair has lower re rupture rates with higher risks of complications. Percutaneous repair and mini open repair show similar re-rupture rates but lower overall complication rates when compared with open repair. Percutaneous repair requires vigilance against nerve damage. Functional rehabilitation combining protected weight-bearing and early controlled motion can effectively reduce re-rupture rates with satisfactory outcomes. Biological adjuncts help accelerating tendon healing by adhering rupture ends or releasing highly complex pools of signalling factors. Conclusion: The optimum treatment for complete rupture remains controversial. Both mini-open repair and functional protocols are attractive alternatives, while biotherapy is a potential future development.Cite this article: X. Yang, H. Meng, Q. Quan, J. Peng, S. Lu, A. Wang. Management of acute Achilles tendon ruptures: A review. Bone Joint Res 2018;7:561-569. DOI: 10.1302/2046-3758.710.BJR-2018-0004.R2. PMID- 30464837 TI - Use of Stimulan absorbable calcium sulphate beads in revision lower limb arthroplasty: Safety profile and complication rates. AB - Aims: Calcium sulphate has traditionally been used as a filler of dead space arising during surgery. Various complications have been described following the use of Stimulan bio-absorbable calcium sulphate beads. This study is a prospective observational study to assess the safety profile of these beads when used in revision arthroplasty, comparing the complication rates with those reported in the literature. Methods: A total of 755 patients who underwent 456 revision total knee arthroplasties (TKA) and 299 revision total hip arthroplasties (THA), with a mean follow-up of 35 months (0 to 78) were included in the study. Results: A total of 32 patients (4.2%) had wound drainage, and this was higher with higher bead volumes and in McPherson grade C patients. There was also a significantly higher bead volume in the 41 patients who developed hypercalcaemia, two of which were symptomatic (p < 0.0001). A total of 13 patients (1.7%) had heterotopic ossification (HO). There was no statistically significant relationship between the development of HO and bead volume (p > 0.05). Conclusion: The strength of this study lies in the large number of patients and the detailed data collection, making it the most comprehensive report available in the literature on the use of calcium sulphate-based bone substitutes.Cite this article: R. Kallala, W. Edwin Harris, M. Ibrahim, M. Dipane, E. McPherson. Use of Stimulan absorbable calcium sulphate beads in revision lower limb arthroplasty: Safety profile and complication rates. Bone Joint Res 2018;7:570-579. DOI: 10.1302/2046-3758.710.BJR-2017-0319.R1. PMID- 30464838 TI - Time-dependent behaviour of bone accentuates loosening in the fixation of fractures using bone-screw systems. AB - Aims: Loosening is a well-known complication in the fixation of fractures using devices such as locking plates or unilateral fixators. It is believed that high strains in the bone at the bone-screw interface can initiate loosening, which can result in infection, and further loosening. Here, we present a new theory of loosening of implants. The time-dependent response of bone subjected to loads results in interfacial deformations in the bone which accumulate with cyclical loading and thus accentuates loosening. Methods: We used an 'ideal' bone-screw system, in which the screw is subjected to cyclical lateral loads and trabecular bone is modelled as non-linear viscoelastic and non-linear viscoelastic viscoplastic material, based on recent experiments, which we conducted. Results: We found that the interfacial deformation in the bone increases with the number of cycles, and the use of a non-linear viscoelastic-viscoplastic model results in larger deformations, some of which are irrecoverable. There is an apparent trend in which interfacial deformations increase with increasing porosity of bone. Conclusion: The developed time-dependent model of the mechanical behaviour of bone permits prediction of loosening due to cyclical loads, which has not been possible previously. Application of this model shows that implant loosening will be accentuated by cyclical loading due to physiological activities, and the risks of loosening are greater in osteoporotic patients.Cite this article: S. Xie, K. Manda, P. Pankaj. Time-dependent behaviour of bone accentuates loosening in the fixation of fractures using bone-screw systems. Bone Joint Res 2018;7:580-586. DOI: 10.1302/2046-3758.710.BJR-2018-0085.R1. PMID- 30464839 TI - Enhancing surface immobilization of bioactive molecules via a silica nanoparticle based coating. AB - Surface modification is of significant interest in biomaterials, biosensors, and device biocompatibility. Immobilization of bioactive or biomimetic molecules is a common method of disguising a foreign body as host tissue to decrease the foreign body response (FBR) and/or increase device-tissue integration. For example, in neural interfacing devices, immobilization of L1, a neuron-specific adhesion molecule, has been shown to increase neuron adhesion and reduce inflammatory gliosis on and around the implants. However, the activity of modified surfaces is limited by the relatively low concentration of the immobilized component, in part due to the low surface area of flat surfaces available for modification. In this work, we demonstrate a novel method for increasing the device surface area by attaching a layer of thiolated silica nanoparticles (TNPs). This coating method results in an almost two-fold increase in the immobilized L1 protein. L1 immobilized nanotextured surfaces showed a 100% increase in neurite outgrowth than smooth L1 immobilized surfaces without increasing the adhesion of astrocytes in vitro. The increased bioactivity observed in the cell assay was determined to be mainly due to the higher protein surface density, not the increase in surface roughness. In addition, we tested immobilization of a superoxide dismutase mimic (SODm) on smooth and roughened substrates. The SODm immobilized rough surfaces demonstrated an increase of 145% in superoxide scavenging activity compared to chemically matched smooth surfaces. These results not only show promise in improving biomimetic coating for neural implants, but may also improve surface immobilization efficacy in other fields such as catalysts, protein purification, sensors, and tissue engineering devices. PMID- 30464840 TI - Thyroid hormone levels and temperature during development alter thermal tolerance and energetics of Xenopus laevis larvae. AB - Environmental variation induced by natural and anthropogenic processes including climate change may threaten species by causing environmental stress. Anuran larvae experiencing environmental stress may display altered thyroid hormone (TH) status with potential implications for physiological traits. Therefore, any capacity to adapt to environmental changes through plastic responses provides a key to determining species vulnerability to environmental variation. We investigated whether developmental temperature (T dev), altered TH levels and whether the interactive effect of both affect standard metabolic rate (SMR), body condition (BC), survival and thermal tolerance in larvae of the African clawed frog (Xenopus laevis) reared at five temperatures with experimentally altered TH levels. At metamorphosis, SMR, BC and survival were significantly affected by T dev, TH status and their interaction with the latter often intensified impacts. Larvae developing at warmer temperatures exhibited significantly higher SMRs and BC was reduced at warm T dev and high TH levels suggesting decreased ability to acclimate to variation in temperature. Accordingly, tadpoles that developed at warm temperatures had higher maximum thermal limits but more narrow thermal tolerance windows. High and low TH levels decreased and increased upper thermal limits, respectively. Thus, when experiencing both warmer temperatures and environmental stress, larvae may be less able to compensate for changes in T dev. Our results demonstrate that physiological traits in larvae of X. laevis are strongly affected by increased TH levels and warmer temperatures. Altered TH levels and increasing T dev due to global change may result in a reduced capacity for physiological plasticity. This has far reaching consequences since the energetic requirement at the onset of metamorphosis is known to determine metamorphic success and thus, is indirectly linked to individual fitness in later life stages. PMID- 30464841 TI - Ecotourism effects on health and immunity of Magellanic penguins at two reproductive colonies with disparate touristic regimes and population trends. AB - Negative effects of ecotourism on wildlife are rising worldwide. Conservation physiology can play a major role in protecting wildlife by providing early alerts on changes in the status of individuals exposed to tourist activities. We measured an integrated set of immune and health-state indices to evaluate the effects of ecotourism on Magellanic penguins (Spheniscus magellanicus). We studied two reproductive colonies that differed in the intensity of tourism and population trends: Punta Tombo (higher tourism intensity, declining population) and San Lorenzo (lower tourism intensity, growing population). Within each colony, we compared individuals from an area that was exposed to tourists and a control area where tourism was excluded. Adult penguins exposed to tourism at Punta Tombo, but not at San Lorenzo, showed physiological alterations indicative of chronic stress (higher heterophil to lymphocyte ratios) and parasitic infection (elevated heterophil and eosinophil counts). Penguin chicks exposed to tourism at Punta Tombo, but not at San Lorenzo, also showed physiological alterations indicative of poor immune and general-health condition: lower humoral innate immunity, haematocrit, and glucose levels and higher inflammatory responses likely due to increased prevalence of fleas. Our results indicate that individuals of a declining population exposed to high levels of tourism express physiological indicators of chronic stress and poor health that could make adults and juveniles vulnerable to disease. These effects are expressed despite a long history of exposure and behavioural habituation to human visitation. In contrast, individuals of a growing population exposed to more recent and lower levels of tourism showed no effect. Our study demonstrates how a diverse physiological toolkit within a conservation physiology approach can provide important information for a better comprehension of anthropogenic effects on wild animals in our changing world. PMID- 30464842 TI - Nonclinical safety assessment of a human interleukin-22FC IG fusion protein demonstrates in vitro to in vivo and cross-species translatability. AB - Although Interleukin-22 (IL-22) is produced by various leukocytes, it preferentially targets cells with epithelial origins. IL-22 exerts essential roles in modulating various tissue epithelial functions, such as innate host defense against extracellular pathogens, barrier integrity, regeneration, and wound healing. Therefore, IL-22 is thought to have therapeutic potential in treating diseases associated with infection, tissue injury or chronic tissue damage. A number of in vitro and in vivo nonclinical studies were conducted to characterize the pharmacological activity and safety parameters of UTTR1147A, an IL-22 recombinant fusion protein that links the human cytokine IL-22 with the Fc portion of a human immunoglobulin. To assess the pharmacological activity of UTTR1147A, STAT3 activation was evaluated in primary hepatocytes isolated from human, cynomolgus monkey, minipig, rat, and mouse after incubation with UTTR1147A. UTTR1147A activated STAT3 in all species evaluated, demonstrating that all were appropriate nonclinical species for toxicology studies. The nonclinical safety profile of UTTR1147A was evaluated in rats, minipigs, and cynomolgus monkeys to establish a safe clinical starting dose for humans in Phase I trials and to support clinical intravenous, subcutaneous and/or topical administration treatment regimen. Results demonstrate the cross-species translatability of the biological response in activating the IL-22 pathway as well as the translatability of findings from in vitro to in vivo systems. UTTR1147A was well tolerated in all species tested and induced the expected pharmacologic effects of epidermal hyperplasia and a transient increase in on-target acute phase proteins. These effects were all considered to be clinically predictable, manageable, monitorable, and reversible. PMID- 30464843 TI - Guest Editorial: Papers from the 12th Workshop on Augmented Environments for Computer-Assisted Interventions. PMID- 30464844 TI - Augmented reality-based feedback for technician-in-the-loop C-arm repositioning. AB - Interventional C-arm imaging is crucial to percutaneous orthopedic procedures as it enables the surgeon to monitor the progress of surgery on the anatomy level. Minimally invasive interventions require repeated acquisition of X-ray images from different anatomical views to verify tool placement. Achieving and reproducing these views often comes at the cost of increased surgical time and radiation. We propose a marker-free 'technician-in-the-loop' Augmented Reality (AR) solution for C-arm repositioning. The X-ray technician operating the C-arm interventionally is equipped with a head-mounted display system capable of recording desired C-arm poses in 3D via an integrated infrared sensor. For C-arm repositioning to a target view, the recorded pose is restored as a virtual object and visualized in an AR environment, serving as a perceptual reference for the technician. Our proof-of-principle findings from a simulated trauma surgery indicate that the proposed system can decrease the 2.76 X-ray images required for re-aligning the scanner with an intra-operatively recorded C-arm view down to zero, suggesting substantial reductions of radiation dose. The proposed AR solution is a first step towards facilitating communication between the surgeon and the surgical staff, improving the quality of surgical image acquisition, and enabling context-aware guidance for surgery rooms of the future. PMID- 30464845 TI - Endoscopic image enhancement with noise suppression. AB - Stereoscopic endoscopes have been used increasingly in minimally invasive surgery to visualise the organ surface and manipulate various surgical tools. However, insufficient and irregular light sources become major challenges for endoscopic surgery. Not only do these conditions hinder image processing algorithms, sometimes surgical tools are barely visible when operating within low-light regions. In addition, low-light regions have low signal-to-noise ratio and metrication artefacts due to quantisation errors. As a result, present image enhancement methods usually suffer from heavy noise amplification in low-light regions. In this Letter, the authors propose an effective method for endoscopic image enhancement by identifying different illumination regions and designing the enhancement design criteria for desired image quality. Compared with existing image enhancement methods, the proposed method is able to enhance the low-light region while preventing noise amplification during image enhancement process. The proposed method is tested with 200 images acquired by endoscopic surgeries. Computed results show that the proposed algorithm can outperform state-of-the-art algorithms for image enhancement, in terms of naturalness image quality evaluator and illumination index. PMID- 30464846 TI - Augmented reality guidance in cerebrovascular surgery using microscopic video enhancement. AB - Cerebrovascular surgery treats vessel abnormalities in the brain and spinal cord, including arteriovenous malformations (AVMs) and aneurysms. These procedures often involve clipping the vessels feeding blood to these abnormalities, making accurate classification of blood vessel types (feeding versus draining) important during surgery. Previous work to guide the intraoperative identification of the vessels included augmented reality (AR) using pre-operative images, injected dyes, and Doppler ultrasound, but each with their drawbacks. The authors propose and demonstrate a novel technique to help differentiate vessels by enhancing short videos of a few seconds from the surgical microscope using motion magnification and spectral analysis, and constructing AR views that fuse the analysis results as intuitive colourmaps and the surgical microscopic view. They demonstrated the proposed technique retrospectively with two real cerebrovascular surgical cases: one AVM and one aneurysm. The results showed that the proposed technique can help characterise different vessel types (feeding and draining the abnormality), which agree with those identified by the operating surgeon. PMID- 30464847 TI - Augmented reality in computer-assisted interventions based on patient-specific 3D printed reference. AB - Augmented reality (AR) can be an interesting technology for clinical scenarios as an alternative to conventional surgical navigation. However, the registration between augmented data and real-world spaces is a limiting factor. In this study, the authors propose a method based on desktop three-dimensional (3D) printing to create patient-specific tools containing a visual pattern that enables automatic registration. This specific tool fits on the patient only in the location it was designed for, avoiding placement errors. This solution has been developed as a software application running on Microsoft HoloLens. The workflow was validated on a 3D printed phantom replicating the anatomy of a patient presenting an extraosseous Ewing's sarcoma, and then tested during the actual surgical intervention. The application allowed physicians to visualise the skin, bone and tumour location overlaid on the phantom and patient. This workflow could be extended to many clinical applications in the surgical field and also for training and simulation, in cases where hard body structures are involved. Although the authors have tested their workflow on AR head mounted display, they believe that a similar approach can be applied to other devices such as tablets or smartphones. PMID- 30464848 TI - Experience-based SEEG planning: from retrospective data to automated electrode trajectories suggestions. AB - StereoElectroEncephaloGraphy (SEEG) is a minimally invasive technique that consists of the insertion of multiple intracranial electrodes to precisely identify the epileptogenic focus. The planning of electrode trajectories is a cumbersome and time-consuming task. Current approaches to support the planning focus on electrode trajectory optimisation based on geometrical constraints but are not helpful to produce an initial electrode set to begin with the planning procedure. In this work, the authors propose a methodology that analyses retrospective planning data and builds a set of average trajectories, representing the practice of a clinical centre, which can be mapped to a new patient to initialise planning procedure. They collected and analysed the data from 75 anonymised patients, obtaining 30 exploratory patterns and 61 mean trajectories in an average brain space. A preliminary validation on a test set showed that they were able to correctly map 90% of those trajectories and, after optimisation, they have comparable or better values than manual trajectories in terms of distance from vessels and insertion angle. Finally, by detecting and analysing similar plans, they were able to identify eight planning strategies, which represent the main tailored sets of trajectories that neurosurgeons used to deal with the different patient cases. PMID- 30464849 TI - Concepts for augmented reality visualisation to support needle guidance inside the MRI. AB - During MRI-guided interventions, navigation support is often separated from the operating field on displays, which impedes the interpretation of positions and orientations of instruments inside the patient's body as well as hand-eye coordination. To overcome these issues projector-based augmented reality can be used to support needle guidance inside the MRI bore directly in the operating field. The authors present two visualisation concepts for needle navigation aids which were compared in an accuracy and usability study with eight participants, four of whom were experienced radiologists. The results show that both concepts are equally accurate ( 2.0+/-0.6 and 1.7+/-0.5mm ), useful and easy to use, with clear visual feedback about the state and success of the needle puncture. For easier clinical applicability, a dynamic projection on moving surfaces and organ movement tracking are needed. For now, tests with patients with respiratory arrest are feasible. PMID- 30464850 TI - BronchoX: bronchoscopy exploration software for biopsy intervention planning. AB - Virtual bronchoscopy (VB) is a non-invasive exploration tool for intervention planning and navigation of possible pulmonary lesions (PLs). A VB software involves the location of a PL and the calculation of a route, starting from the trachea, to reach it. The selection of a VB software might be a complex process, and there is no consensus in the community of medical software developers in which is the best-suited system to use or framework to choose. The authors present Bronchoscopy Exploration (BronchoX), a VB software to plan biopsy interventions that generate physician-readable instructions to reach the PLs. The authors' solution is open source, multiplatform, and extensible for future functionalities, designed by their multidisciplinary research and development group. BronchoX is a compound of different algorithms for segmentation, visualisation, and navigation of the respiratory tract. Performed results are a focus on the test the effectiveness of their proposal as an exploration software, also to measure its accuracy as a guiding system to reach PLs. Then, 40 different virtual planning paths were created to guide physicians until distal bronchioles. These results provide a functional software for BronchoX and demonstrate how following simple instructions is possible to reach distal lesions from the trachea. PMID- 30464851 TI - Multiuser virtual reality environment for visualising neuroimaging data. AB - The recent advent of high-performance consumer virtual reality (VR) systems has opened new possibilities for immersive visualisation of numerous types of data. Medical imaging has long made use of advanced visualisation techniques, and VR offers exciting new opportunities for data exploration. The author presents a new framework for interacting with neuroimaging data, including MRI volumes, neuroanatomical surface models, diffusion tensors, and streamline tractography, as well as text-based annotations. The system was developed for the HTC Vive using C++, OpenGL, and the OpenVR software development kit. The author developed custom GLSL shaders for each type of data to provide high-performance real-time rendering suitable for use in a VR environment. These are integrated with an interface that enables the user to manipulate the scene through the Vive controllers and perform operations such as volume slicing, fibre track selection, and structural queries. The software can read data generated by existing automated brain MRI analysis packages, enabling the rapid development of subject specific visualisations of multimodal data or annotated atlases. The system can also support multiple simultaneous users, placing them in the same virtual space to interact with each other while visualising the same datasets, opening new possibilities for teaching and for collaborative exploration of neuroimaging data. PMID- 30464852 TI - Fast and accurate vision-based stereo reconstruction and motion estimation for image-guided liver surgery. AB - Image-guided liver surgery aims to enhance the precision of resection and ablation by providing fast localisation of tumours and adjacent complex vasculature to improve oncologic outcome. This Letter presents a novel end-to-end solution for fast stereo reconstruction and motion estimation that demonstrates high accuracy with phantom and clinical data. The authors' computationally efficient coarse-to-fine (CTF) stereo approach facilitates liver imaging by accounting for low texture regions, enabling precise three-dimensional (3D) boundary recovery through the use of adaptive windows and utilising a robust 3D motion estimator to reject spurious data. To the best of their knowledge, theirs is the only adaptive CTF matching approach to reconstruction and motion estimation that registers time series of reconstructions to a single key frame for registration to a volumetric computed tomography scan. The system is evaluated empirically in controlled laboratory experiments with a liver phantom and motorised stages for precise quantitative evaluation. Additional evaluation is provided through testing with patient data during liver resection. PMID- 30464853 TI - Comparison of interactive and automatic segmentation of stereoelectroencephalography electrodes on computed tomography post-operative images: preliminary results. AB - Stereoelectroencephalography is a surgical procedure used in the treatment of pharmacoresistant epilepsy. Multiple electrodes are inserted in the patient's brain in order to record the electrical activity and detect the epileptogenic zone at the source of the seizures. An accurate localisation of their contacts on post-operative images is a crucial step to interpret the recorded signals and achieve a successful resection afterwards. In this Letter, the authors propose interactive and automatic methods to help the surgeon with the segmentation of the electrodes and their contacts. Then, they present a preliminary comparison of the methods in terms of accuracy and processing time through experimental measurements performed by two users, and discuss these first results. The final purpose of this work is to assist the neurosurgeons and neurologists in the contacts localisation procedure, make it faster, more precise and less tedious. PMID- 30464854 TI - Augmenting Microsoft's HoloLens with vuforia tracking for neuronavigation. AB - Major hurdles for Microsoft's HoloLens as a tool in medicine have been accessing tracking data, as well as a relatively high-localisation error of the displayed information; cumulatively resulting in its limited use and minimal quantification. The following work investigates the augmentation of HoloLens with the proprietary image processing SDK Vuforia, allowing integration of data from its front-facing RGB camera to provide more spatially stable holograms for neuronavigational use. Continuous camera tracking was able to maintain hologram registration with a mean perceived drift of 1.41 mm, as well as a mean sub 2-mm surface point localisation accuracy of 53%, all while allowing the researcher to walk about a test area. This represents a 68% improvement for the later and a 34% improvement for the former compared with a typical HoloLens deployment used as a control. Both represent a significant improvement on hologram stability given the current state-of-the-art, and to the best of the authors knowledge are the first example of quantified measurements when augmenting hologram stability using data from the RGB sensor. PMID- 30464855 TI - Exploring community capacity: Karen refugee women's mental health. AB - Purpose: The purpose of this paper is to describe Karen refugee women's experience of resettlement and the factors which structured community capacity to support their mental health and well-being. Design/methodology/approach: A postcolonial and feminist standpoint was used to bring Karen women's voice to the knowledge production process. Data were collected through ethnographic field observation, in-depth semi-structured individual and focus group interviews with Karen women as well as healthcare and social service providers. Findings: Three interrelated themes emerged from the data: Karen women's construction of mental health as "stress and worry"; gender, language and health literacy intersected, shaping Karen women's access to health care and social resources; flexible partnerships between settlement agencies, primary care and public health promoted community capacity but were challenged by neoliberalism. Research limitations/implications: Karen women and families are a diverse group with a unique historical context. Not all the findings are applicable across refugee women. Practical implications: This paper highlights the social determinants of mental health for Karen women and community responses for mitigating psychological distress during resettlement. Social implications: Public health policy requires a contextualized understanding of refugee women's mental health. Health promotion in resettlement must include culturally safe provision of health care to mitigate sources of psychological distress during resettlement. Originality/value: This research brings a postcolonial and feminist analysis to community capacity as a public health strategy. PMID- 30464856 TI - Erratum: Whole genome analysis of local Kenyan and global sequences unravels the epidemiological and molecular evolutionary dynamics of RSV genotype ON1 strains. AB - [This corrects the article DOI: 10.1093/ve/vey027.][This corrects the article DOI: 10.1093/ve/vey027.]. PMID- 30464858 TI - Use of Mannose-Binding Lectin Gene Polymorphisms and the Serum MBL Level for the Early Detection of Neonatal Sepsis. AB - Background Mannose-binding lectin (MBL) is a component of innate immunity and is particularly important in neonates, in whom adaptive immunity has not yet completely developed. MBL deficiency and MBL2 gene polymorphisms are associated with an opsonization defect and have been associated with neonatal sepsis. Aim The aim of our study was to assess serum MBL levels and genotype MBL2 genes to determine whether they can serve as markers for predicting neonatal sepsis in neonatal intensive care units. Patients and Methods A case-control study was conducted with 114 neonates classified into two groups: the septic group included 64 neonates (41 preterm and 23 full-term infants), and the non-septic control group included 50 neonates (29 preterm and 21 full-term infants). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was used to genotype MBL2 gene exon 1 (rs1800450) and (rs1800451) SNPs. Enzyme-linked immunosorbent assay (ELISA) was used to measure MBL serum concentrations. Results The polymorphic genotypes BB and AC at codons 54 and 57, respectively, showed higher frequencies than the wild-type genotype (AA) (14.1% versus 12.9% and 28.1% versus 19.4% respectively) in both groups, and this difference was greater in the septic group than in the non-septic group; however, the differences did not reach statistical significance. The B and C allele frequencies were also higher in the septic group than in the non-septic group, but the differences did not reach statistical significance ( p = 0.282 and 0.394, respectively). The serum levels of MBL were significantly lower in the septic group than in the non-septic group ( p = 0.028). Conclusion This study found no association between MBL levels or MBL2 exon 1 genotypes or alleles and neonatal sepsis risk. Further studies with larger sample sizes are needed to determine the role of the MBL2 gene as a risk factor and early predictor of neonatal sepsis. PMID- 30464859 TI - A Missing Link between Neuron Specific Enolase Release and Poor Prognosis in Aging Patients with B-cell Lymphoma. PMID- 30464857 TI - In Silico Studies of Small Molecule Interactions with Enzymes Reveal Aspects of Catalytic Function. AB - Small molecules, such as solvent, substrate, and cofactor molecules, are key players in enzyme catalysis. Computational methods are powerful tools for exploring the dynamics and thermodynamics of these small molecules as they participate in or contribute to enzymatic processes. In-depth knowledge of how small molecule interactions and dynamics influence protein conformational dynamics and function is critical for progress in the field of enzyme catalysis. Although numerous computational studies have focused on enzyme-substrate complexes to gain insight into catalytic mechanisms, transition states and reaction rates, the dynamics of solvents, substrates, and cofactors are generally less well studied. Also, solvent dynamics within the biomolecular solvation layer play an important part in enzyme catalysis, but a full understanding of its role is hampered by its complexity. Moreover, passive substrate transport has been identified in certain enzymes, and the underlying principles of molecular recognition are an area of active investigation. Enzymes are highly dynamic entities that undergo different conformational changes, which range from side chain rearrangement of a residue to larger-scale conformational dynamics involving domains. These events may happen nearby or far away from the catalytic site, and may occur on different time scales, yet many are related to biological and catalytic function. Computational studies, primarily molecular dynamics (MD) simulations, provide atomistic-level insight and site-specific information on small molecule interactions, and their role in conformational pre-reorganization and dynamics in enzyme catalysis. The review is focused on MD simulation studies of small molecule interactions and dynamics to characterize and comprehend protein dynamics and function in catalyzed reactions. Experimental and theoretical methods available to complement and expand insight from MD simulations are discussed briefly. PMID- 30464860 TI - Heterogeneous Presentation of Neonatal Hemochromatosis in Dichorionic Twins. AB - Acute liver failure (ALF) in neonates is rare. Although the incidence is reported to be rare, neonatal hemochromatosis (NH) has to be considered as one of the causes of neonatal ALF. We present a pair of dichorionic twin who had a diverse clinical presentation of NH. One twin passed away despite medical treatment with exchange transfusion and intravenous immunoglobulin (IVIg), whereas the other twin suffered from only mildly deranged liver function, which normalized spontaneously. Early identification of liver failure and clinical awareness of this disease entity are essential to its timely diagnosis and treatment. Antenatal management using IVIg prevents the recurrence of NH in subsequent pregnancies. PMID- 30464861 TI - Sleep Apnea Syndrome Sensing at C-Band. AB - A non-intrusive sleep apnea detection system using a C-Band channel sensing technique is proposed to monitor sleep apnea syndrome in real time. The system utilizes perturbations of RF signals to differentiate between patient's breathing under normal and sleep apnea conditions. The peak distance calculation is used to obtain the respiratory rates. A comparison of the datasets generated by the proposed method and a wearable sensor is made using a concordance correlation coefficient to establish its accuracy. The results show that the proposed sensing technique exhibits high accuracy and robustness, with more than 80% concordance with the wearable breathing sensor. This method is, therefore, a good candidate for the real-time wireless detection of sleep apnea. PMID- 30464862 TI - An Initial Investigation of Unmanned Aircraft Systems (UAS) and Real-Time Organ Status Measurement for Transporting Human Organs. AB - Organ transportation has yet to be substantially innovated. If organs could be moved by drone, instead of ill-timed commercial aircraft or expensive charter flights, lifesaving organs could be transplanted more quickly. A modified, six rotor UAS was used to model situations relevant to organ transportation. To monitor the organ, we developed novel technologies that provided the real-time organ status using a wireless biosensor combined with an organ global positioning system. Fourteen drone organ missions were performed. Temperatures remained stable and low (2.5 degrees C). Pressure changes (0.37-0.86 kPa) correlated with increased altitude. Drone travel was associated with less vibration (<0.5 G) than was observed with fixed-wing flight (>2.0 G). Peak velocity was 67.6 km/h (42 m/h). Biopsies of the kidney taken prior to and after organ shipment revealed no damage resulting from drone travel. The longest flight was 3.0 miles, modeling an organ flight between two inner city hospitals. Organ transportation may be an ideal use-case for drones. With the development of faster, larger drones, long distance drone organ shipment may result in substantially reduced cold ischemia times, subsequently improved organ quality, and thousands of lives saved. PMID- 30464863 TI - Virtual Neonatal Echocardiographic Training System (VNETS): An Echocardiographic Simulator for Training Basic Transthoracic Echocardiography Skills in Neonates and Infants. AB - There is a great need for training in pediatric echocardiography. In addition to physicians being trained in pediatric cardiology and echocardiography technologists, neonatologist, pediatric intensivists, and other health care professionals may be interested in such training. Since, there is limited opportunity of training on live patients, echocardiographic simulators may be of help. No simulator with complete range of echocardiographic modalities is available for neonates and infants. The aim of this project was to develop a mannequin-based echocardiographic simulator capable of simulating full range of pediatric 2D, color flow Doppler, spectral Doppler, and M-mode echocardiograms. A mannequin, a laptop computer, a magnetic tracking device, and a six-degree freedom (6DOF) sensor incorporated in a dummy transducer serve as the hardware platform of the simulator. We obtained six to seven 4D echocardiographic datasets in DICOM format through five acoustic windows from each infant along with a complete set of 2D video clips of color flow, Doppler, and M-mode. The 4D datasets are sliced into 3D slices using the visualization toolkit and are displayed as 2D echocardiograms through the information obtained by the 6DOF sensor. The coordinates from specific 3D slices triggers display of video clips of color flow, M-mode, and Doppler echocardiogram. Software written in C++ programming language controls the basic function of the program. The main simulator screen displays the full range of 2D echocardiograms including color flow Doppler, spectral Doppler, and M-mode from each acoustic window, whereas the side screen display the position and motion of the cutting planes through a 3D heart model. The system includes a software module to perform hemodynamic measurements from specific video clips images. Our hybrid, mannequin-based pediatric echocardiography simulator provides full range of pediatric echocardiography training experience. This simulator may help training in pediatric echocardiography for which there is a growing demand in clinical medicine. PMID- 30464864 TI - Addressing the gap in clinical research education: Implementation of the Introduction to Clinical Research Training-Japan program. PMID- 30464865 TI - Clinical features and seasonal variations in the prevalence of macrolide resistant Mycoplasma pneumoniae. AB - Background: Mycoplasma pneumoniae is a common pathogen causing pneumonia; macrolide-resistant strains are rapidly spreading across Japan. However, the clinical features of macrolide-resistant M. pneumoniae pneumonia have not been well established. Here, we evaluated the clinical characteristics and seasonal variations in the prevalence of M. pneumoniae with macrolide-resistant mutations (MRM). Methods: The monthly prevalence of MRM in M. pneumoniae strains isolated from May 2016 to April 2017 was retrospectively analyzed, and the clinical characteristics of pneumonia cases with MRM were compared to those of cases without MRM. The M. pneumoniae isolates and point mutations at site 2063 or 2064 in domain V of 23S rRNA were evaluated by the GENECUBE system and GENECUBE Mycoplasma detection kit. Results: Mycoplasma pneumoniae infection was identified in 383 cases, including 221 cases of MRM (57.7%). The MRM prevalence was 86.3% (44/51) between May and July 2016, demonstrating an apparent decrease in September 2016, subsequently reaching 43.0% (34/79) in November 2016. Mycoplasma pneumoniae pneumonia was diagnosed in 275 cases, including 222 pediatric and 53 adult cases. Macrolide use preceding evaluation was found to be the only feature of MRM pneumonia cases both in children (odds ratio [OR] 3.86, 95% confidence interval [CI]:1.72-8.66) and in adults (OR 7.43, 95% CI: 1.67-33.1). Conclusions: The determination rate of MRM varied widely throughout the year, and our study demonstrated the challenges in predicting M. pneumoniae with MRM based on clinical features at diagnosis. Therefore, continuous monitoring of the prevalence of MRM is warranted, which may help in selecting an effective treatment. PMID- 30464866 TI - Qualitative exploration of Japanese rural citizens' consideration of terminal home care through an educational forum. AB - Background: The need for home care services for older adults is gradually increasing in many countries. In the past, Japanese older adults typically died at home, but the current trend is toward hospital death. Few studies in Japan have explored peoples' viewpoint on home care, however, especially in rural areas. Therefore, we clarified Japanese rural residents' views of terminal home care. Methods: We conducted a qualitative study of 152 participants who are current or potential caregivers of older adults and who live in the city of Unnan, Shimane Prefecture, which has a large elderly population. An educational forum consisting of presentations and a workshop were used to provide information on terminal home care to rural citizens. A thematic analysis of the workshop's content regarding participants' perceived difficulties related to terminal home care was conducted. Results: Participants described four themes regarding problems of terminal home care: medical aspects, care burden, health care system, and patient problems. Besides the need for more knowledge of the medical and health system, participants were anxious about the burden of care on their lives and the perceptions of others in their community. Conclusion: This study is the first report on Japanese rural citizens' views of terminal home care. The findings suggest that the limited use of home care in Japanese rural areas might relate to a lack of understanding of terminal home care and health care systems, a substantial care burden for caregivers, and conflicts between patients and families. PMID- 30464867 TI - Are the kind of medications and patient's background associated with improving polypharmacy in elderly? AB - Background: Polypharmacy is associated with negative outcomes in older population. Managing polypharmacy is important but there is no definite method for regulating it. Our aim was to evaluate what medications and patient's background are associated with reducing polypharmacy. Methods: A prospective, single-center, cohort study was conducted from June to October in 2016. Participants were 65 and older hospitalized patients. We evaluated the difference between the numbers of medications used at the time of admission and discharge for individual drug class. Univariate analyses using paired t tests were applied to evaluate reduction in prescription medications, and logistic regression was used to evaluate factors for any reduction of prescription medications used at discharge. Results: There were 494 subjects, and the mean of age was 79.6 +/- 7.8 years. The mean number of medications used at admission was 6.9 +/- 4.7 and that at discharge was 6.8 +/- 4.3. The types of medications that reduced between admission and discharge were drugs for functional gastrointestinal disorders and agents acting on the renin-angiotensin system, etc. Individual components that were strongly associated with a reduction of the number of medications used were only length of hospital stay (OR 0.99, 95% CI, 0.99-1.0), while the number of medications on admission was related to increasing medication during hospitalization (OR 1.05, 95% CI, 1.01-1.06). Conclusions: Most of the kinds and the number of medications prescribed might not be changed during hospitalization despite those were probably the causes of admission. The factor associated with improvements in polypharmacy was length of hospital stay. PMID- 30464868 TI - A case of syphilis presenting with prolonged etiology-unrevealed fever, accompanying activated partial thromboplastin time prolongation. AB - A 58-year-old woman presenting with 3-week-prolonged fever was referred to our department. Her present history and physical examination results were unremarkable. Her activated partial thromboplastin time (APTT) was prolonged. Upon further investigation, anticardiolipin/beta2-glycoprotein I complex antibodies (CL-beta2GPI) were detected, occasionally associated with syphilis. On day 14 of her fourth visit as an outpatient, serological tests confirmed the diagnosis, with newly appeared roseola on her palms and soles. She was in the transitional phase to secondary syphilis. Four months later, after successful treatment, her APTT was normalized with CL-beta2GPI negative. Syphilis should be considered in patients with APTT prolongation. PMID- 30464869 TI - Intestinal spirochetosis: An unusual cause of postantibiotic diarrhea. AB - (A) A blue fringe along the surface epithelium of the colonic mucosa on hematoxylin-eosin staining, a characteristic histology of intestinal spirochetosis. (B) Numerous spirochetes highlighted on Warthin-Starry silver staining. PMID- 30464870 TI - Diagnostic clue for pleural metastasis of malignant melanoma. AB - This case demonstrated the importance of recognition of melanin pigments in pleural effusion as a diagnostic tool for metastasis of malignant melanoma. PMID- 30464871 TI - Giant adenomatous thyroid nodule compressing the trachea. AB - This paper details the clinical history and management of a 20-year-old male patient who presented with a 2-year history of a neck swelling which was gradually enlarging during the last 3 months. The tumor was histologically diagnosed as an adenomatous nodule of the thyroid gland. PMID- 30464872 TI - Oral diverticulum. AB - Oral diverticulum . PMID- 30464873 TI - Bibliographic title search for medical cardiological "signs" (eponyms). AB - Background: The word "sign" refers to important physical findings or observations that are useful in diagnosis; however, there are no scientific reviews of "signs." The aim of this paper was to list and review these terms using a bibliographic approach. Methods: We performed a title search of "sign" using a bibliographic search and review approach in MEDLINE and EMBASE. Results: We detected 398 papers including 217 medical signs in cardiology. Conclusions: This is the first literature review of eponyms specifically for signs using a bibliographic method, which is useful for the discussion of the appropriateness of eponyms. PMID- 30464874 TI - The electroencephalogram in syncope. PMID- 30464875 TI - Reply to "The electroencephalogram in syncope". PMID- 30464876 TI - The Tokyo GIM Conference: Clinical reasoning conference from real cases. AB - The view of Tokyo GIM Conference. PMID- 30464878 TI - Erratum: A Review of Skull Base Tumor Clinical Trials: Past Trends and Future Opportunities. AB - [This corrects the article DOI: 10.1055/s-0036-1586759.]. PMID- 30464877 TI - Reviewing the relevance of dioxin and PCB sources for food from animal origin and the need for their inventory, control and management. AB - Background: In the past, cases of PCDD/F and PCB contamination exceeding limits in food from animal origin (eggs, meat or milk) were mainly caused by industrially produced feed. But in the last decade, exceedances of EU limit values were discovered more frequently for PCDD/Fs or dioxin-like(dl)-PCBs from free range chicken, sheep, and beef, often in the absence of any known contamination source. Results: The German Environment Agency initiated a project to elucidate the entry of PCBs and PCDD/Fs in food related to environmental contamination. This paper summarizes the most important findings. Food products from farm animals sensitive to dioxin/PCB exposure-suckling calves and laying hens housed outdoor-can exceed EU maximum levels at soil concentrations that have previously been considered as safe. Maximum permitted levels can already be exceeded in beef/veal when soil is contaminated around 5 ng PCB-TEQ/kg dry matter (dm). For eggs/broiler, this can occur at a concentration of PCDD/Fs in soil below 5 ng PCDD/F-PCB-TEQ/kg dm. Egg consumers-especially young children-can easily exceed health-based guidance values (TDI). The soil-chicken egg exposure pathway is probably the most sensitive route for human exposure to both dl-PCBs and PCDD/Fs from soil and needs to be considered for soil guidelines. The study also found that calves from suckler cow herds are most prone to the impacts of dl PCB contamination due to the excretion/accumulation via milk. PCB (and PCDD/F) intake for free-range cattle stems from feed and soil. Daily dl-PCB intake for suckler cow herds must in average be less than 2 ng PCB-TEQ/day. This translates to a maximum concentration in grass of 0.2 ng PCB-TEQ/kg dm which is less than 1/6 of the current EU maximum permitted level. This review compiles sources for PCDD/Fs and PCBs relevant to environmental contamination in respect to food safety. It also includes considerations on assessment of emerging POPs. Conclusions: The major sources of PCDD/F and dl-PCB contamination of food of animal origin in Germany are (1) soils contaminated from past PCB and PCDD/F releases; (2) PCBs emitted from buildings and constructions; (3) PCBs present at farms. Impacted areas need to be assessed with respect to potential contamination of food-producing animals. Livestock management techniques can reduce exposure to PCDD/Fs and PCBs. Further research and regulatory action are needed to overcome gaps. Control and reduction measures are recommended for emission sources and new listed and emerging POPs to ensure food safety. PMID- 30464879 TI - Erratum: Skull Base Invasion Patterns and Survival Outcomes of Nonmelanoma Skin Cancers. AB - [This corrects the article DOI: 10.1055/s-0036-1594239.]. PMID- 30464880 TI - Erratum: The Laparoscopically Harvested Omental Free Flap: A Compelling Option for Craniofacial and Cranial Base Reconstruction. AB - [This corrects the article DOI: 10.1055/s-0036-1597138.]. PMID- 30464881 TI - Peritoneal Tuberculosis in Infants: Diagnostic Challenges. AB - Abdominal tuberculosis is rare in immunocompetent infants. We report on two infants with peritoneal tuberculosis (6 and 8 months) who underwent laparotomy for suspected intussusception. In the first patient, characteristic lesions of peritoneal tuberculosis were observed intraoperatively with presence of multiple granulations. Tuberculin intradermal reaction (IDRt) was positive and tuberculous contagium could be cultured. In the second patient, the IDRt and GeneXpert tests were negative. In both patients, the histopathological examination of the biopsy specimens confirmed the diagnosis of peritoneal tuberculosis. The clinical courses under tuberculostatic therapy were favorable in both cases. PMID- 30464882 TI - Central Airway Obstruction Due to Tracheal Glomus Tumor. AB - Background Tracheal glomus tumors are rare mesenchymal neoplasms that have the potential to cause malignant, central airway obstruction. They require a thoughtful approach to safely secure the airway and definitively resect the tumor. Case Description We report the clinical course of a 25-year-old man in severe respiratory distress secondary to tracheal glomus tumor and the subsequent surgical management. Conclusion Due to their hypervascular nature, greater familiarity with tracheal glomus tumors is needed to ensure appropriate preoperative planning and intervention. PMID- 30464883 TI - German Virtues in an International Journal. PMID- 30464884 TI - PID, BFO-optimized PID, and PD-FLC control of a two-wheeled machine with two direction handling mechanism: a comparative study. AB - In this paper; three control approaches are utilized in order to control the stability of a novel five-degrees-of-freedom two-wheeled robotic machine designed for industrial applications that demand a limited-space working environment. Proportional-integral-derivative (PID) control scheme, bacterial foraging optimization of PID control method, and fuzzy logic control method are applied to the wheeled machine to obtain the optimum control strategy that provides the best system stabilization performance. According to simulation results, considering multiple motion scenarios, the PID controller optimized by bacterial foraging optimization method outperformed the other two control methods in terms of minimum overshoot, rise time, and applied input forces. PMID- 30464885 TI - Sleep Before and After Retirement. AB - Purpose of Review: In this review, we focus on the association of sleep and retirement from two perspectives. Firstly, we examine the role of sleep during the working years on retirement timing. Secondly, we examine how sleep changes during the transition to retirement. Recent Findings: Persons with sleep difficulties are more likely to retire due to health problems, such as depression and musculoskeletal disorders. Retirement, on the other hand, is associated with both increased sleep duration and decreased sleep difficulties, mainly premature awakenings and nonrestorative sleep. Summary: Promotion of sleep quantity and quality could be a potential way to support employees' work ability and possibly even to postpone retirement, at least in relation to early retirement. Possible proposed mechanisms for the improved sleep after retirement include removal of work stress and increased flexibility in time use, which could be targeted in attempt to promote adequate and good quality of sleep already during the working years. PMID- 30464887 TI - Intervertebral Disc Biology: Genetic Basis of Disc Degeneration. AB - Purpose of Review: This review aims to highlight recent advances in understanding the genetic basis of intervertebral disc degeneration (IDD). Recent Findings: It has been known for some time that IDD is highly heritable. Recent studies, and in particular the availability of agnostic techniques such as genome-wide association studies, have identified new variants in a variety of genes which contribute to the risk of IDD and to back pain. Summary: A variety of genetic variants are involved in IDD. Some are shared with variants predisposing to back pain, but few have been identified reliably in either phenotype. Further research is required to explain fully the high heritability and how the genetic variants influence cell biology to lead to IDD. PMID- 30464886 TI - Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury. AB - Purpose of this Review: In order to combat the development of drug resistance, the clinical treatment of tuberculosis requires the combined use of several anti tuberculosis (anti-TB) drugs, including isoniazid and rifampicin. Combinational treatment approaches are suggested by the World Health Organization (WHO) and are widely accepted throughout the world. Unfortunately, a major side effect of the treatment is the development of anti-tuberculosis drug-induced liver injury (AT DILI). Many factors contribute to isoniazid- and rifampicin-mediated AT-DILI and genetic variations are among the most common factors. The purpose of this review is to provide information on genetic variations associated with isoniazid- and rifampicin-mediated AT-DILI. Recent Findings: The genetic variations associated with AT-DILI have been identified in the genomic regions within or near genes encoding proteins in the following pathways: drug metabolizing enzymes (NAT2, CYP2E1, and GSTs), accumulation of bile acids, lipids, and heme metabolites (CYP7A1, BSEP, UGTs, and PXR), immune adaptation (HLAs and TNF-alpha), and oxidant challenge (TXNRD1, SOD1, BACH1, and MAFK). Summary: The information summarized in this review considers the genetic bases of risk factors contributing to AT-DILI and provides information that may help for future studies. Some of the implicated genetic variations can be used in the design of genetic tests and serve as biomarkers for the prediction of isoniazid- and rifampicin-mediated AT-DILI risk in personalized medicine. PMID- 30464888 TI - Cannabinoids for Treating Cardiovascular Disorders: Putting Together a Complex Puzzle. AB - Cannabinoids have been increasingly gaining attention for their therapeutic potential in treating various cardiovascular disorders. These disorders include myocardial infarction, hypertension, atherosclerosis, arrhythmias, and metabolic disorders. The aim of this review is to cover the main actions of cannabinoids on the cardiovascular system by examining the most recent advances in this field and major literature reviews. It is well recognized that the actions of cannabinoids are mediated by either cannabinoid 1 or cannabinoid 2 receptors (CB2Rs). Endocannabinoids produce a triphasic response on blood pressure, while synthetic cannabinoids show a tissue-specific and species-specific response. Blocking cannabinoid 1 receptors have been shown to be effective against cardiometabolic disorders, although this should be done peripherally. Blocking CB2Rs may be a useful way to treat atherosclerosis by affecting immune cells. The activation of CB2Rs was reported to be useful in animal studies of myocardial infarction and cardiac arrhythmia. Although cannabinoids show promising effects in animal models, this does not always translate into human studies, and therefore, extensive clinical studies are needed to truly establish their utility in treating cardiovascular disease. PMID- 30464889 TI - First Insights into the Ultrastructure of Myosin and Actin Bands Using Transmission Electron Microscopy in Gyrodactylus (Monogenea). AB - This study aims to describe the ultrastructure of coiled musculature fibers component of Gyrodactylus gasterostei and its role in this parasite transmission. The present work employs transmission electron microscopy to analyze G. gasterostei musculature, revealing the presence of myosin and actin bands in the underlying epithelium, typical arrangement of the skeletal muscle. This study unravels for the first time the existence of a coil muscle component in which it seems to be responsible for the remarkable flexibility of the musculature of Gyrodactylus and the efficiency of its transmission method to reach a nearby fish host. The elasticity of the musculature described in this study may be comparable with the other specialized elastic musculature within the animal kingdom (i.e., lizards tongue). The clarification of the basic biology of these monogenean parasites and its musculature biochemical systems hold the promise of possible novel muscle targets for a new generation of antiparasitic drugs. PMID- 30464890 TI - Preparation of Sliver and Selenium Nanoparticles and Its Characterization by Dynamic Light Scattering and Scanning Electron Microscopy. AB - Aim: In our study, two different methods were used to determine the size and size distribution of the sliver and selenium nanoparticles via dynamic light scattering (DLS) and scanning electron microscopy (SEM). Background: Nanotechnology dealing with metal and metalloid nanoparticles has been usually applied in nearly each field of science, engineering, and technology including biology and medicine etc due to presence of size and shape dependent unusual physical and chemical properties. In the most recent decade, numerous groups including appreciably developed metal and metalloid nanoparticles based theranostic approaches for the treatment of almost human diseases. Amongst many nanoparticles, recently silver and selenium nanoparticles have been broadly used in the antimicrobial coatings, textiles, paints, keyboards, engineering, food industry, electronics, cosmetics, bio-sensing, wound dressings, and even in biomedical devices. Methods: In our study, silver nanoparticles were prepared by using the chemical reduction method. Selenium nanoparticles (SeNPs) were synthesized by the chemical reduction of sodium selenite by glutathione (reduced form) and stabilized by bovine serum albumin (BSA). Characterization of silver and selenium nanoparticles samples were analyzed by dynamic light scattering (DLS) and Scanning Electron Microscopy (SEM). Conclusions: Due to characterization by DLS technique, nanoparticles size was found the range of 79.22 nm and 178 nm for Sliver and Selenium Nanoparticles respectively. Sliver nanoparticles shown morphological average size and shape with SEM reveals spherical shape particles with the size of 80.32 nm whereas Selenium nanoparticles shown rod shape particles with the size of 74.29 nm. PMID- 30464891 TI - Prevalence of Methicillin-Resistant Staphylococcus aureus in Hospitals in Chittagong, Bangladesh: A Threat of Nosocomial Infection. AB - Background: As a life threatening infectious disease, methicillin resistant Staphylococcus aureus (MRSA) infection has been turned into a global health concern recently. In a developing country like Bangladesh, the situation is vulnerable because of inadequate and inappropriate practices of control measures to prevent the spread of nosocomial infection. Materials and Methods: In this study, 100 clinical, nonclinical, and environmental samples were collected from different hospitals in Bangladesh and examined for the detection of methicillin resistant and multidrug resistant S. aureus by cultural methods. Antibiotic sensitivity pattern of isolates was also evaluated by Kirby-Bauer disc diffusion method. Results: Out of the total 100 samples, 66 isolates of S. aureus were determined. Among them, 53 isolates (80.30%) revealed a positive result for oxacillin test, but avoiding any false result, 53 oxacillin positive isolates were again examined by cefoxitin, whereas 43 isolates (65.15%) were resistant to cefoxitin and consequently confirmed as MRSA and rest of the 23 isolates (34.85%) were fixed as methicillin sensitive S. aureus. In antibiotic sensitivity test, S. aureus showed the highest (83%) resistance to gentamycin, oxacillin and cefotaxime than other antibiotics. Finally, the risk practices were assessed which are potential factors for spreading infections. Conclusion: Since, MRSA as well as other antibiotic resistant S. aureus are potent threat to human, therefore, we should consider it as a great concern to minimize or prevent the prevalence and adverse effects of MRSA. PMID- 30464892 TI - Ultrastructural Alterations of Liver Tissue Cells in Methotrexate-Treated Balb/c Mice. AB - Aim: The current study investigated the efficacy of methotrexate (MTX) on liver tissue cells of Balb/c mice at the ultrastructural level using transmission electron microscopy. Background: This agent is well known and used as a chemotherapeutic agent for a long time and not selective for cancer cells so, healthy cells beside cancer cells are also affected by MTX. Materials and Methods: Experimental animals were divided into two groups; the first group was kept without treatment and served as the control, the second group was treated with 115 mg/kg MTX i.p. once weekly for 4 weeks and sacrificed under anesthesia after the 4th week. The liver tissues were osmium fixed and embedded in araldite, sectioned and observed under transmission electron microscope. Results: Normal cell ultrastructure was determined in the control group whereas the liver cells of the MTX-treated group revealed ultrastructural alterations, such as the increase in lipid droplets, discontinuity of rough endoplasmic reticulum cisternae and vacuole formation. In addition, the loss of cytoplasmic material in hepatocytes was also evident. Condensation of nuclear chromatin and fusion of nucleic membranes were observed in the liver cells of the treated group. Conclusions: Results of the study indicated that MTX, used for different types of medical treatment, disturbed liver cell ultrastructure. PMID- 30464893 TI - Histological Study on the Protective Effect of Endogenous Stem Cell Mobilization in Busulfan-Induced Testicular Injury in Albino Rats. AB - Background: Testicular damage is one of the most hazardous effects of chemotherapy as it is frequently associated with oligozoospermia and azoospermia. Aim of the Work: This study aimed at evaluating the protective effect of hematopoietic stem cell mobilization by granulocyte colony-stimulating factor (G CSF) in a rat model of busulfan-induced testicular injury. Materials and Methods: Twenty-four adult albino rats were divided into four groups: group I, the control, Group II: rats received two doses of busulfan (each 15 mg/kg) intraperitoneally (IP) with 14 days interval, Group III: rats received busulfan and left untreated, and Group IV received busulfan IP then G-CSF (70 MUg/kg/day) subcutaneously for 5 consecutive days. Testicular sections were stained with H and E and immunohistochemically for CD34, proliferating cell nuclear antigen (PCNA) and caspase-3, and semithin sections were stained with toluidine blue. Results: Groups II and III showed loss of the normal histological architecture of the testis and spermatogenic cells, with increased apoptosis confirmed by significantly increased caspase-3 and significantly decreased PCNA immunoexpression. While Group IV revealed improved testicular histology, decreased apoptosis, and increased proliferative capacity of spermatogenic cells. This was confirmed by significantly decreased caspase-3 immunoexpression and increased PCNA immunoreaction. Conclusion: Mobilization of stem cells with G-CSF was found to improve the testicular histology following busulfan chemotherapy in albino rats. PMID- 30464894 TI - Ultrastructural Study of Rat Testis Following Conventional Phototherapy during Neonatal Period. AB - Introduction: Phototherapy is the most common treatment for neonatal jaundice. This study sought to determine ultrastructural changes in testis, at different time-points, after 48 hours of conventional phototherapy was given to newborn rats. Methods: Newborn male Wistar rats (n = 36) were divided into two groups as follows - group 1 (G1), control (without phototherapy) and group 2 (G2), exposure to conventional phototherapy for 48 h. Six animals from each group were sacrificed on postnatal days (PND) 70, 100 and 130. The testes were dissected out and processed for Transmission Electron Microscopy (TEM). Results: TEM showed that G2 on PND 70 and 100 showed damaged organelles, including nuclei, mitochondria, endoplasmic reticulum, vacuoles and electron dense bodies in the testes. Seminiferous Tubule on PND130 showed lesser damage. On PND70 ST wall thickness (STWT) of G2 was significantly higher (P < 0.001) than G1 STWT of G2 was significantly lower than G1 on PND100 (P = 0.047) and on PND130 (P < 0.001). Mitochondrial diameter in spermatogonia was significantly higher in G2 on PND70 (P = 0.001), PND100 (P = 0.031) and PND130 (P = 0.028). Primary spermatocytes in G2 also had larger mitochondria on PND70 (P < 0.001), PND100 (P = 0.007) and PND130 (P = 0.008). Further, spermatids had larger mitochondria in G2 on PND70 (P < 0.001), PND100 (P = 0.044) and PND130 (P < 0.001). Conclusion: Phototherapy causes degenerative changes in rat testis on PND70 and 100 that partially recover by PND 130. PMID- 30464895 TI - Primary Myeloid Sarcoma of the Breast: A Case Report and Review of Literature. AB - Myeloid sarcoma (MS) of the breast is uncommon. We report this case of a 29-year old female presented with a breast lump that was diagnosed as hamartoma by radiology. The lump was removed surgically. Pathological examination revealed a malignant tumor composed of immature cells with eosinophilic cytoplasm and single or multiple nucleoli, diffusely infiltrating the mammary parenchyma and sparing a few ducts and lobules. Immunostaining revealed positivity for leukocytic common antigen, myeloperoxidase, and CD68, and focally positive for CD34 and CD117. The final diagnosis was released as primary MS of the breast. The patient was treated with radiotherapy and chemotherapy. Three consecutive bone marrow biopsies were negative for neoplastic infiltration. PMID- 30464896 TI - Re: Presence of Multidrug Resistant Bacteria on Mobile Phones of Healthcare Workers Accelerates the Spread of Nosocomial Infections and Regarded as a Threat to Public Health in Bangladesh. PMID- 30464897 TI - Local governance of immigrant incorporation: how city-based organizational fields shape the cases of undocumented youth in New York City and Paris. AB - City-based organizations and governments play an important role in incorporating undocumented immigrant youth. This article investigates how localities socio politically incorporate these immigrants by examining the governance constellations and institutional logics of the organizational field that manages undocumented youth. Comparing sets of municipal and civil society organizations in different national settings, I use the two cases of New York City and Paris to ask how the 'city-based organizational field of immigrant incorporation' shapes citizenship experiences of undocumented youth. Data come from multi-level longitudinal ethnography over 8 years with two dozen undocumented youth and with organizations in each city as well as interviews with immigrant organization staff and other governance actors in New York and Paris. Organizational field dynamics in Paris provide a stronger possibility of citizenship and rights acquisition, evidence of socio-political incorporation. In contrast, New York's robust and flexible labor market and ethnic and immigrant legitimacy offer its undocumented youth a marginalized socio-political incorporation. These findings support practice-based understandings of local governance of incorporation of undocumented youth. PMID- 30464898 TI - Anticholinergic discontinuation and cognitive functions in patients with schizophrenia: a pharmacist-physician collaboration in the outpatient department. AB - Introduction: Cognitive impairment is a core feature and shows the highest impact on functional outcome in patients with schizophrenia. There have been no previous studies investigating the role of the pharmacist in a multidisciplinary team on cognitive outcomes in patients with schizophrenia. Purpose: We evaluated the impact of pharmacist intervention on cognitive outcomes in patients with schizophrenia by focusing on anticholinergic discontinuation. Patients and methods: A prospective, open-label, randomized, controlled study was conducted. Patients with schizophrenia were randomly assigned to either the pharmacist intervention or usual care groups. In the pharmacist intervention group, the pharmacist identified drug-related problems (DRPs) and provided a pharmacotherapy suggestion, while there was no intervention in the usual care group. The primary outcome was mean change from baseline of executive function by using Wisconsin Card Sorting Test (WCST) perseverative errors within the pharmacist intervention group at week 12. Results: A total of 30 patients completed the study (13 in the pharmacist intervention group and 17 in the usual care group). WCST perseverative errors at the end of the study within the pharmacist intervention group improved significantly from baseline (P=0.003). DRPs at week 12 were reduced by 85.19% and 9.76% in the pharmacist intervention and usual care groups, respectively. The most common intervention was the discontinuation of anticholinergics in patients without extrapyramidal side effects. Conclusion: Added-on pharmacist intervention in a multidisciplinary team could help to improve cognitive functions in patients with schizophrenia by reducing DRPs and optimizing the drug therapy regimen, especially for anticholinergic discontinuation. PMID- 30464899 TI - Long Term Oncological Results of Transoral Laser Microsurgery for Early and Moderately Advanced Glottic Carcinoma in Primary and Salvage Settings. AB - The aim of the study is to document the long term oncological results of trans oral laser microsurgery (TLM) for early and moderately advanced glottic cancer in primary and salvage settings. In this prospective cohort study 43 consecutive patients of glottic cancer (T1-30, T2-7, and selected T3 with mobile cords-6) were recruited. TLM was performed in these 35 primary and 8 previously treated cases. In our series, the local disease control rate with TLM was 90% (27/30) for T1 disease, 71.4% (5/7) for T2 cancer and 66.6% (4/6) for T3 lesions. The overall disease control rates after subsequent treatment for locoregional recurrences were 100% (30/30), 85.7% (6/7) and 83.3% (5/6) for T1, T2, and T3 glottic cancers respectively. The 5-years disease free survival rate for primary cases was 100% and 50% for salvage cases. The 5-years local disease control rate was 96.4% and 41.67% in primary and salvage TLM settings respectively. The 5-years laryngectomy free rates were 96.3% and 18.75% for primary and salvage cases respectively. TLM offers a minimally invasive and oncologically robust treatment option for early glottic cancer with an overall disease free survival of 100% at 5 years noted for primary untreated cases in this experience. TLM for post radiation salvage cases has however been disappointing and alternate larynx preserving option of open partial laryngectomy needs to be considered in this setting. PMID- 30464900 TI - A Retrospective Study to Assess the Role of Using Fine Needle Aspiration Cytology and Frozen Section in the Diagnosis of Thyroid Swelling. AB - The most cost-effective test is fine needle aspiration cytology (FNAC). Many surgeons use intraoperative frozen section to confirm the FNAC findings and to guide the extent of thyroid surgery. Though it is a valuable tool in the diagnosis of the thyroid lesion and determining the extent of thyroid surgery, still in certain cases diagnosis can be incorrect or inconclusive, so histopathology of the excised specimen remains the most reliable test. The purpose of this study will be to compare the result attained by FNAC and frozen section of the thyroid to the final histopathological diagnosis, in order to establish their role in thyroid surgery today. A retrospective study with a total of 140 patients who underwent thyroid surgery at the ENT department, of a tertiary hospital in coastal Karnataka. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated for FNAC and frozen section. The sensitivity, specificity, positive predictive rate, and negative predictive rate of frozen section was found to be 66.7%, 88.4%,76.6%, 82.4% respectively for detecting malignancy. This was found to be higher than the results of FNAC for the same which were 64.4%, 77.8%, 64.4%, 77.8% respectively. As the sensitivity of FNAC is similar to frozen section in detecting malignant cases, FNAC is a good tool for screening the patient for determining malignancy in thyroid, but frozen section is more specific in confirming the malignancy. PMID- 30464901 TI - Improving the Results of Endonasal Dacryocystorhinostomy with Mitomycin C Application: A Prospective Case-Control Study. AB - Many surgical advancement paved to surgical success in endonasal endoscopic dacryocystorhinostomy. Mitomycin C is a systemic chemotherapeutic agent derived from Streptomyces caespitosus that inhibits the synthesis of DNA, cellular RNA, and protein by inhibiting the synthesis of collagen by fibroblasts. The objective of the study was to evaluate the advantage of mitomycin C in primary endoscopic endonasal dacryocystorhinostomy without stenting. Randomised case control design. Tertiary academic centre in central India. 112 patients who presented with epiphora and diagnosed as chronic dacryocystitis after syringing by ophthalmologist, were selected and randomised into two groups with or without mitomycin C intraoperative application. 112 eyes underwent endoscopic dacryocystorhinostomy. Additional surgeries were done according to necessity. Mitomycin C was applied in concentration of 0.4 mg/dl for 5 min. Patients were followed up on OPD-basis at the end of 1st week, 1st month, 3rd month and over phone call at end of 1 year. Symptomatic improvement assessed by verbal enquiry and clinically by syringing by ophthalmologist. 8 patients underwent septal surgery in case group and 4 in control group along with 1 concha bullosa correction in the case group (p < 0.05). Nil intraoperative complications (p < 0.05) and nil postoperative complication noted (p < 0.05). Functional and anatomical patency found to be 100% at the end of 1st week in both groups, 96.5% at 3rd month in case group and 96.4% and 92.9% at 1 month and 3 month respectively in control group. Nasal endoscopy of all surgical failures showed restenosis in both case group and control group except 1 patient with granulation in control group. Eventhough intraoperative mitomycin C application is effective in increasing the success rate of endonasal DCR surgery in standard nasolacrimal duct obstruction, and with no significant complications from its use, the study did not show added benefit in the primary endoscopic endoscopic dacryocystorhinostomy without stenting. PMID- 30464902 TI - Understanding Malignancies of the Thyroid Gland: Institutional Experience. AB - To study the epidemiological, pathological characters and determine survival in patients diagnosed of having thyroid gland malignancies. Retrospective chart review of patients having thyroid gland malignancies, which were managed by the two senior authors at our tertiary care institute from January 2000 to December 2006, were performed and evaluated in terms of various clinical, operative and histological parameters. Patients in which follow up of at least 10 years are available were included in the study. Survival was enquired telephonically in those patients who got cured and did not consent to come for follow up. Slides were reviewed. Statistical analysis was done using SPSS statistical software. Kaplan-Meier method was used for calculating survival. A total of 182 patients were included in the study. Papillary carcinoma was the commonest malignant lesion with a frequency of 87.91% followed by follicular carcinoma (7.69%), medullary carcinoma (3.29%) and anaplastic carcinoma (1.09%). Female predominance was seen (F:M-5.06:1). The 5 year and 10 year survival rates were 89% and 73% respectively. The most common postoperative squeal was transient hypocalcaemia, seen in (27/182) 15% patients which was followed by permanent hypocalcaemia 16/182 (8.79%), transient recurrent laryngeal nerve paresis 12/182 (6.59%) and permanent recurrent laryngeal nerve palsy 8/182 (4.39%). Thyroid malignancies affect all age groups and have good long term prognosis. Management yields promising results and hence early and adequate treatment is emphasized. PMID- 30464903 TI - Pediatric Otolaryngological Emergency: An Experience from a Tertiary Care Teaching Institution at Kolkata, India. AB - Otolaryngological conditions constitute a major share of emergency medical problem among children. The present study was conducted to assess the patient profiles, incidences morbidities, mode of presentation and managements of different otolaryngological emergencies among pediatric patients presented in a tertiary care hospital. Descriptive cross-sectional study by analysing retrospectively collected information pertaining to the patients attended ENT emergency service department of a tertiary care hospital, Kolkata. Data were collected using predesigned proforma and were analysed with the help of SPSS version 20. About 39.0% of total ENT emergency attendance was contributed by pediatric age group. The male female ratio was 1:1.33 with average age of 58.95 +/- 34.42 (mean +/- SD) months. Half of the attendees had ear problem and almost one-third reported complaints related to nose. The major complaints at the time of presentation were earache (32.3%), nasal foreign body (24.0%) and aural foreign body (13.3%) closely followed by aero-digestive tract foreign body (12.0%). Inflammatory conditions affected the ears more, foreign bodies found most commonly in nose and miscellaneous condition such as impacted wax was found to be related to ear in significantly higher proportion. Conservative management was provided to 96.25% of patients. Foreign body insertion was found to be associated with lower age group. Most of the emergencies were managed conservatively which might be done at subdivision or district level to reduce the undesirable burden on the tertiary care medical colleges. PMID- 30464904 TI - Ahila's Diathermy Round Knife for Endoscopic Ear Surgery. AB - As endoscopic ear surgery is evolving day by day there is a constant need for improvisation in terms of instrumentation, visualization and clear bloodless surgical field. The applications of Ahila's Diathermy Round Knife for Endoscopic Ear Surgery are presented. The development of Ahila's diathermy round knife will prevent shifting to two handed ear surgery or the need for Endo holders. This new instrument is a game changer in endoscopic ear surgery creating a clean incision and bloodless field to operate. Surgical Instruments represent a major financial asset to the healthcare facility. Careful attention to care, handling and sterilization is essential to avoid costly replacements, enhance patient and surgeon satisfaction, reduce costs and delays in the Operating room and enhance patient safety. Ahila's round diathermy knife may facilitate the performance of surgery and advance the art of Endoscopic surgery to a higher level. PMID- 30464905 TI - The Video Head Impulse Test: Our Experience in 45 Cases. AB - To evaluate the role of video head impulse test in the diagnosis of peripheral vestibular disorders, we performed an observational study in the outpatient department in a tertiary setup in which the clinical head impulse test and the video head impulse test were performed on 45 patients with clinically suspected peripheral vestibular disorders, and their results were correlated. To analyse our results, each ear was counted individually and hence, among 45 patients, 12 out of 90 ears showed abnormal clinical head impulse test for lateral semicircular canals and 27 out of 90 ears showed abnormal video head impulse test for lateral semicircular canals. This gave us an additional diagnostic accuracy of 21.1% on using video head impulse test for the lateral semicircular canals as compared to the clinical head impulse test. Video head impulse test is a physiological, quick and well tolerated test for assessing the vestibular function, and the only practical test for assessing the vertical semicircular canal function. Video head impulse test provides valuable information in localising the site of lesion as it assesses the semicircular canals individually. Video head impulse is merely not an objectification and registration system for the clinical head impulse test as it provides additional information such as vestibulo-ocular reflex gain, and occurrence of covert refixation saccades which cannot be picked up by naked eyes. PMID- 30464906 TI - Aural Polyp is not Always Due to Chronic Otitis Media (COM): Preoperative Computed Tomographic Scan is Good Pointer for Sinister Lesions. AB - Twenty five patients of aural polyp who underwent canal wall down mastoidectomy were analysed retrospectively. Histopathological examination revealed cholesteatoma in 22 (88%) patients. However, histopathological diagnosis in 3 of these patients was unusual and rare benign tumors of the middle ear cleft meningioma, neurilemmoma and capillary hemangioma. Review of the preoperative High Resolution Computed Tomography (HRCT) temporal bone revealed an unusual picture in all of the three cases. Features noted were: widening of the jugular foramen (meningioma), destruction of the anterior wall of mesotympanum (neurilemmoma), enhancing soft tissue density lesion (capillary hemangioma). Further, there was only partial loss of pneumatisation of the mastoid air cells in all of the 3 cases. It was observed that though HRCT temporal bone is a commonly advised investigation in patients of chronic otitis media (COM) with aural polyp, meticulous interpretation may reveal unusual features pointing towards sinister diagnosis. Conclusion: Aural polyp with preservation of pneumatisation of mastoid air cells points towards diagnosis other than COM. PMID- 30464907 TI - Access to Round Window Niche via Posterior Tympanotomy and Impact of Drilling Its Overhangs: A Cadaveric Descriptive Study. AB - We intended to study the morphological parameters of round window region and assess the gain in exposure achieved by drilling the round window niche overhang. The Exposure of the round window membrane (RWM) is of prime importance to carry out atraumatic electrode insertion for cochlear implantation. The anatomy of round window has been a subject of considerable debate in literature. Fifty-one Formalin preserved adult cadaveric temporal bones were micro-dissected to carry out an 'optimal' posterior tympanotomy to expose the round window region. The bony overhangs of round window niche (RWN) were next drilled to achieve maximal possible exposure the RWM without violating the annulus of the same. The exposure was classified as per St Thomas' Hospital classification. The round window could not be visualized in 3 bones (5.9%). The commonest morphology of RWN was dome shaped, found in 18 (37.5%) and that of the RWM was oval shaped, found in 14 (29.2%) bones. Pre drilling 41 bones had a > 50% exposure of RWM while post drilling > 50% exposure could be achieved in all the bones except the 3 bones in which RWN could not be visualized to begin with. The drilling of the RWN overhangs exposed RWM in entirety in 91.7% of bones with a visible morphology of RWN pre drilling. RWN and RWM exhibit varied morphology. Drilling of the round window niche overhangs can considerably enhance the exposure of RWM. PMID- 30464908 TI - New Cartilage Slicer for Slicing Techniques in Tympanoplasty: Design and Applications. AB - Abstract: Cartilage-perichondrium composite graft is used in middle ear surgery for tympanic membrane, ossicular and for soft wall reconstruction. The thickness of the cartilage is thought to interfere with the sound conduction. In our otology practice for tympanic membrane reconstruction, we prefer the sliced cartilage graft to achieve acoustic benefit. At times in the process of slicing, the cartilage gets wasted if not sliced with a precision slicing instrument. We have designed and developed a multi-purpose cartilage slicer for precise reduction of the thickness of the cartilage. To describe the design of our cartilage slicer and to report our preliminary experience with the cartilage slicer. Descriptive study. The technique of slicing with our new cartilage slicer and its usage has been described in detail. A total number of 689 cartilages in tympanoplasty and mastoidectomy have been sliced with it from 2013 to 2017. Our study reports the technique of slicing the tragal cartilage for tympanoplasty, highlighting its advantages and precision of the cartilages slices obtained. Our cartilage slicer is a good option for cartilage slicing in tympanoplasty. Level of Evidence: Level 4. PMID- 30464909 TI - A Comprehensive Study of Oxidative Stress in Tinnitus Patients. AB - Oxidative stress is considered to be one of the molecular changes that are the underlying causes of tinnitus. The aim of this study was to investigate the dynamic thiol/disulphide homeostasis as a new oxidative stress parameter in tinnitus patients as well as to investigate the lipid hydroperoxide (LOOH), total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) parameters and compare the results with the results of the healthy control group. A prospective controlled trial was performed on tinnitus patients in Harran University hospital. A total of 70 subjects, including 35 tinnitus patients and 35 healthy individuals participated in this study. Their total thiol, native thiol levels and LOOH, TAS, TOS levels were measured in plasma of all tinnitus patients and healthy volunteers participants. TOS and OSI levels were significantly increased, and TAS levels were significantly lower in the patient groups compared with the control group (p < 0.01). Native thiol levels and Native thiol/total thiol ratios were significantly lower in the tinnitus group compared to the control group (p < 0.01). Disulphide level and disulphide/native thiol and disulphide/total thiol ratios were significantly higher in the patients (p < 0.01). Also, LOOH ratios were significantly higher in the tinnitus group (p < 0.01). The results of this study reveal that in tinnitus cases, the oxidative stress and antioxidant enzyme imbalance were more significant than in healthy control group. The nature of the relationship between oxidative stress and tinnitus should be clarified with larger studies. PMID- 30464910 TI - A Revisit to High Jugular Bulb: A Newer Clinical Grading. AB - A revisit to high riding jugular bulb with a newer classification. Observational study. Patients in the age group between 15 to 60 years, who underwent various Tympanomastoid and otosclerotic surgeries from April 2015 to 2018, have been included in the study. An analysis was made on high riding jugular bulb which encountered and different anatomical variations were noticed. A total of 531 patients underwent various tympanomastoid surgeries and 48 patients underwent otosclerotic surgeries. Out of which 8% of the cases (n = 49) were noticed to have high riding jugular bulb. In those 49 cases, 81% (n = 37) have Grade I, 11% (n = 5) have Grade II, 6% (n = 3) have grade III, 6% of the case (n = 3) have Grade IV and 2% (n = 1) has Grade V high riding Jugular bulb. Among these the prevalence of Grade I jugular bulb is high followed by Grade II. With the observation of our clinical study the authors have made a revisit to high riding jugular bulb and proposed a new clinical grading for high jugular bulb called BPH, that is Basava Prasad's grading clinical on High jugular bulb (Channa Basava Hubli and K. C. Prasad) as: Grade I high riding jugular bulb up to the level of inferior tympanic annulus. Grade II extending from the level of tympanic annulus up to the inferior margin of the round window niche. Grade III Completely obliterating the round window niche. Grade IV Lies between superior margin of round window niche and stapes. Grade V Abuting the Stapes Arch. PMID- 30464911 TI - Surgical Management of Parapharyngeal Space Tumours in a Single Tertiary Care Center. AB - Because of the inaccessibility and overcrowding of the vital neurovascular structures, management of the parapharyngeal space (PPS) tumour is always a challenge to the surgeons. Here we have discussed the clinical findings and management of the PPS tumours with special concern to the surgical approaches. It is a retrospective study containing 14 patients of PPS tumour from June 2015 to January 2018 in the department of Otorhinolaryngology and Head Neck Surgery in a tertiary care referral hospital. 14 consecutive patients with PPS tumours were included in the study. The retrospective clinical data, diagnostic procedures, surgical approaches and the complications were analyzed after 12 months of surgery. Of 14 patients included in the study, 10 patients were males and 4 were females. Prestyloid and poststyloid spaces were involved in 28.57% and 71.42% cases respectively. Transcervical excision of the tumours were performed in 10 patients, 2 patients had undergone transcervical-transoral approach. Transcervical transmandibular and transcervical transparotid excision of tumours were performed in one patient each. Facial nerve injury was detected in 3(21.42%) patients. Injury to the internal carotid artery and wound infection were detected in one patient each. Radiological imaging, especially the MRI helps by narrowing the spectrum of the differential diagnosis distinguishing the benign from malignant lesions, especially in cases where FNAC is contraindicated. Although the transcervical approach is commonly practiced, the combined surgical approach can be effectively applied specially for extensive PPS tumours associated with satisfactory clinical outcomes. PMID- 30464912 TI - Anthropometric Overview of Lower Alar Cartilage: An Indian Perspective. AB - The anatomy of the lower lateral cartilage varies according to the ethnicity of the patient. Considering that the manipulation of the lower lateral cartilage has become more prevalent in Indian rhinoplasties, understanding the comprehensive anatomy is of utmost importance. The aim of this descriptive study was to evaluate the anthropometric and morphological variations of the lower lateral cartilage in Indian noses and to compare this data from studies of various ethnic groups. Seventy lower lateral cartilages of thirty-five patients of Indian origin who underwent primary open rhinoplasty were dissected and assessed intraoperatively. There was no previous history of nasal trauma. The medial, middle and lateral distances from the caudal border of the alar cartilage to the alar rim were measured. Morphology of the cartilage was assessed. The results were analysed and comparison were made between the genders and various ethnic groups. A statistically significant difference (p < 0.05) was observed in terms of length, width, distance from the alar rim, compared to the other study. Convex type (56%) of lateral crura was most commonly seen, with no significant gender difference. This study highlights the anatomical differences among various ethnic groups and stresses the need to be aware of the complexities of the anatomical aspect of the cartilage, to avoid complications and provide acceptable aesthetic result to the patient. PMID- 30464913 TI - Cochlear Implant in Prelingually Deaf Children: Our Experience. AB - Retrospective study of the prelingual cochlear implantation programme under government scheme done at medical college hospital in central India. Forty-two prelingually deaf children screened and sent for cochlear implantation at our centre From March 2015 to Feb 2018 were reviewed with respect to their age, sex, preimplantation hearing aid use, surgical technique for cochlear implantation, type of FDA (USA) approved cochlear implant, post operative speech therapy and its outcome with respect to categories of auditory perception and speech intelligibility scoring were compared for children younger than 4 years and older than 4 years. For outcome measurement non parametric statistical method was used for any significance between the two groups. There was a wide range of children implanted ranging from 2 to 7 years. Both varia and mastoidectomy and posterior tympanotomy method of cochlear implantations were done with good rate complete insertion and electrode activation. There was no significant difference between the two group with regard to CAP and SIR outcomes after 1 year. In order to get better outcomes with respect to the speech language development, there is need to strengthen the early identification and cochlear implantation before 4 years of age in government approved schemes. PMID- 30464914 TI - The Role of Surgical Debridement in Cases of Refractory Malignant Otitis Externa. AB - Malignant Otitis externa is a necrotizing condition of external ear involving causing the osteomyelitis of the bone and surrounding soft tissue leading to multiple cranial nerve palsies. Though most patients respond to oral ciprofloxacin but due to emerging resistance cases of refractory malignant otitis externa which are unresponsive to antibiotic therapy for at least 6 weeks are being encountered lately. A study of 20 patients of refractory malignant otitis Externa was conducted at a tertiary care centre in north India; 10 patients were randomly allotted in group A and group B each. Group A was subjected to i/v ceftazidine 1 gm bd with oral ciprofloxacin 750 mg bd and Group B was subjected to surgical debridement with oral ciprofloxacin 750 mg bd. The improvement in symptoms was tabulated and statistical analysis was done using Mann-Whitney U test. There was better resolution of nocturnal pain in patients of group B who underwent surgical debridement although existing facial palsy didn't improve in both the groups. The improvement of symptoms in group B was statistically significant with P <= 0.05. We strongly recommend the role of surgical debridement in cases of refractory malignant otitis externa to relieve the patient of nocturnal pain. As the sample size of the study is small we are looking forward to the compilation of a multi institutional data so that a consensus on definitive protocol in cases unresponsive to oral multidrug therapy can be established. PMID- 30464915 TI - Human Immunodeficiency Virus Infection: Does Highly Active Antiretroviral Therapy Influence Ear Nose Throat Manifestations? AB - To study the change in trend of ear, nose and throat (ENT) manifestations in patients who were on treatment, before and after availability of highly active antiretroviral therapy (HAART). To find out the prevalence of ENT manifestations in human immunodeficiency virus (HIV) infected people who were on treatment, in the year of 2004 (before the availability of HAART) and in 2014 (after the availability of HAART). Design A combination of a retrospective and prospective study. Setting Anti Retroviral Therapy (ART) Center at Our Hospital. Subjects Patients with HIV infection on ART. Methods Retrospective review of case records of the patients visiting the center in the year 2004 and prospective study of the patients visiting in the year 2014 was conducted. Sample size was calculated as 200 in each group based on 95% confidence and 96% power. Convenience sampling was used in our study. The prevalence of ENT manifestations in HIV patients were found to be 86% in 2004 and 93% in 2014. Among ENT manifestations oropharyngeal manifestations were most common. Lesser the CD4 count more was the prevalence of disorders in oropharynx. Our study showed a high prevalence of ENT manifestations in HIV patients who were on treatment, irrespective of the gap of 10 years and introduction of HAART therapy. Most common ENT manifestation both in 2004 and 2014 was oropharyngeal candidiasis. Lesser the CD4 count more was the prevalence of disorders in oropharynx. PMID- 30464916 TI - Functional Nasal Surgery and Use of CPAP in OSAS Patients: Our Experience. AB - The surgical correction of nasal obstruction is definitely effective and recommended in patients with poor CPAP compliance, often secondary to the high pressures that need to be given in patients with nasal sub stenosis. For this reason, the objective of this study is the evaluation of the effectiveness and effects of the functional nose surgery on adherence to CPAP- therapy in patients (with moderate to severe OSAS with indication of ventilation therapy) poorly compliant with CPAP. The study was performed on a sample of 52 patients, 40 male and 12 female, aged between 29 and 72 years followed by the Otolaryngology Unit of the University Palermo in the period between January 2015 and January 2017. All patients were subjected to the following s iter: anamnesis with Epworth Sleepiness Scale, NOSE scale, evaluation of "CPAP usage data." Upper airway optical fiber endoscopy with Muller's maneuver. We performed various type of nasal surgery (septoplasty, decongestion of the lower turbinates and FESS) 6 months after the surgery, CPAP usage was evaluated and the NOSE scale has been reapplied. All patients had a subjective degree of obstruction classified in severe or extreme by the NOSE scale before surgery. Almost all patients reported a mild degree of obstruction after the surgery. About CPAP usage, the average usage has passed by 2, 3 h at night to 6, 8 h after the surgery. The result is significant because it shows how the nasal functional surgery can make selected patients suitable to ventilation therapy. As our work shows, a better nasal function allows to reduce the CPAP pressure, Therefore, we believe that all patients with medium to severe obstructive apnea syndrome and for whom night-time ventilation therapy (CPAP) is advised should be evaluated with endoscopy and anamnesis oriented to evaluate nasal obstructive pathologies that may reduce effectiveness of CPAP. PMID- 30464917 TI - Post Temporal Bone Fracture Facial Paralysis: Strategies in Decision Making and Analysis of Efficacy of Surgical Treatment. AB - Management of traumatic facial nerve injuries after temporal bone fractures is both challenging and controversial. The dilemma is whether to operate or not and if operating, when to operate and how much of the nerve to decompress. The aim of this study is to review our criteria for decision making in management of patients with temporal bone fracture induced facial nerve palsy, and analyze outcome of patients selected for surgical management. Review of 28 cases of temporal bone fracture between 2012 and 2016 was carried out. Patient assessment included clinical, audiological, computer tomography scans and electromyography (EMG) examinations. All 28 cases were initially started on conservative medical treatment. Based on criteria of complete clinical paralysis at onset, no improvement with conservative treatment and fibrillation potential in EMG, 10 cases underwent surgical decompression through the transmastoid approach. Among the 10 surgically-treated patients, lesions were predominantly found in geniculate ganglion area. Analysis of results after 12 months revealed 70% of cases who underwent surgery had House Brackmann (HB) Grade I-II recovery. Good recovery was achieved in all 18 medically treated patients (HB Grade I-II). Candidate selection based on accurate clinical judgment and judicious use of electrodiagnostic tests plays a vital role in outcomes in the treatment of post traumatic facial injury. Early surgical intervention gave better results in our study. PMID- 30464918 TI - CBNAAT: A Boon for Early Diagnosis of Tuberculosis-Head and Neck. AB - Tuberculosis of head and neck has been an under diagnosed entity due to large number of smear negative cases, which results in missing out the positive cases, further increasing the burden of TB. The role of cartridge- based nucleic acid amplification test (CBNAAT) with a potential to diagnose TB and rifampicin resistance within 2 h is promising. The study highlights the extended implications of CBNAAT in infectious lesions of head and neck, where the pus or aspirate was subjected to this test, along with other investigations which have been routinely used for detection of extra pulmonary tuberculosis. Twelve patients with infective lesions of head and neck were included in this prospective study, conducted in Department of Otorhinolaryngology, Netaji Subhash Chandra Bose Medical College and hospital, Jabalpur from September 2016 to March 2017. They were investigated for pulmonary and extra pulmonary TB. CBNAAT, microscopy, FNAC and HPR from the site of lesion were done. Nine out of twelve patients were diagnosed positive for Tuberculosis. Microscopy (ZN staining) could detect only two such cases, whereas FNAC showed granulomatous lesion in 3 cases (33.3%). CBNAAT was positive in 77.7% of the total positive cases. Histopathological examination showed 100% results but was feasible only in selected number of cases (4 in this study). CBNAAT provides a promising role in early diagnosis of TB in head and neck. Its high sensitivity and less time taking procedure makes it an excellent tool for timely diagnosis of such cases. PMID- 30464919 TI - Congenital Cholesteatoma in Adults-Interesting Presentations and Management. AB - To report a series of adult patients diagnosed with congenital cholesteatoma (CC) with respect to symptoms, different varieties of presentation, surgical findings and approach used, complications and the postoperative results. A retrospective chart review of adult cases of CC who were treated in the period from January 2014-2017 was carried out in a tertiary care center. Levenson's criteria were used for diagnosis. Diagnosis was confirmed by imaging and intraoperatively. Postoperative results and complications were also analyzed. Six adult cases of CC were studied with a mean follow up of 10 months. Interesting presentations included otitis media with effusion, non-resolving facial nerve palsy, post aural discharge and meningitis. It included 3 cases of petrous apex cholesteatoma, 2 patients with cholesteatoma involving both the middle ear and mastoid and 1 patient with mastoid cholesteatoma. The operative procedures included canal wall up mastoidectomy (1 patient), atticotomy (1 patient), canal wall down mastoidectomy (1 patient), translabyrinthine and transotic excision of mass with blind sac closure (2 patients) and partial labyrinthectomy (1 patient). Complications encountered during surgery were cerebrospinal fluid leak and worsening of hearing in 2 patients and 1 patient respectively. CC can have variety of interesting presentations in adult population and they may or may not have the classical white mass behind the tympanic membrane. Appropriate individualized surgical planning and intervention gives good results. PMID- 30464920 TI - Effect of Duration of Exposure to Personal Listening Devices on Hearing Thresholds in Young Adults. AB - To analyze the effect of duration of use of personal listening devices on hearing impairment in young adults. Hospital-based cross-sectional study. Department of ENT, NEIGRIHMS, India. 50 consenting undergraduate medical students. This study was conducted over a period of 2 months. After eliminating all previous and current otological pathologies, Pure Tone Audiometry was conducted on each subject for both air and bone conducted sound stimuli. The subjects were divided into different groups based on duration of exposure. The audiograms were then closely evaluated for the existence of an association between the duration of personal listening devices (PLD) use and hearing impairment. The data was then evaluated by Chi Square test and Mann-Whitney U test using GraphPad InStat 3 software for the existence of an association between the duration of PLD usage and hearing impairment. The hearing thresholds varied only in isolated frequencies irrespective of the categorisation of duration of exposure to PLDs. There was no significant association between duration of use of personal listening devices and hearing impairment in young adults. PMID- 30464921 TI - Aural Atresia with Cholesteotoma and Its Management Strategies. AB - The term congenital aural atresia is used to describe failure of external auditory canal to open. Thus it results in conductive hearing loss. There are ways to improve the transmission of sound to the healthy inner ear, we have performed surgery to open the ear canal and restore the natural sound-conducting mechanism to the inner ear. Thus avoiding multiple surgeries. The study was conducted among patients aged between 12 and 24 years, our study included 8 patients with aural atresia with cholesteotoma. After a detailed examination of patients were subjected to surgery. In our study with the sample size of eight patients Where, all our patients underwent canal wall down mastoidectomy with simultaneous single stage reconstruction of ossicular chain. All our patients were discharge free and Had subjective improvement in hearing with the post operative period was well accomplished to < 35 dB. In our study all eight patients who underwent canal wall down mastoidectomy had good hearing outcome. As to avoid unnecessary recurrence and complications which are usually seen in intact canal wall down mastoidectomies, we suggest canal wall down and single stage reconstruction. PMID- 30464922 TI - "Hanger" in Intubation and Laryngoscopy. AB - Achieving an adequate exposure in laryngoscopy is an extremely tedious task for the operating surgeon, especially for the anterior commissure lesions. Various maneuvers have been described to overcome this difficulty, but failed in providing an adequate exposure leading to a poor outcome. To create a device that can deliver uniform pressure over the laryngeal cartilage and succeed in providing an adequate exposure of the glottic lesion. A total of 44 patients were included in the study, divided into two groups containing 22 patients each. The distance at the level of anterior commissure from the superior border of the distal end of the laryngoscope was noted and compared. Group A subjected to digital cricoid pressure showed a mean distance of 9.09 of exposure with variance of 1.22 and Group B subjected to cricoid pressure with the cricoid catapult showed a mean distance of 11.76 with variance of 1.59. The groups were statistically analyzed using Anova Test and the test was found to be very significant (p < 0.0001). The catapult is made of a hanger defining its economics, which has a vital role in difficult intubations especially in anterior placed larynx, short neck and obese patients, also succeeds in providing an adequate exposure of the glottic lesion, (especially the anterior commissure) by delivering uniform pressure over the laryngeal cartilage, leading to a superior operative outcome. PMID- 30464923 TI - Is Acoustic Radiation Force Impulse (ARFI) Ultrasound Elastography Valuable in the Assessment of Cervical Lymphadenopathy? AB - Cervical lymphadenopathy frequently poses a diagnostic challenge as neither clinical nor imaging assessment can reliably differentiate between benign and malignant lymphadenopathy. Non-invasive differentiation between the two may help to reduce the number of FNAC or biopsy. The purpose of this study was to evaluate whether the new ARFI technique (Virtual Touch Quantification), in conjunction with gray scale sonography and Doppler, can help in the characterization and differentiation of benign from malignant cervical lymphadenopathy. Fifty adult patients with cervical lymphadenopathy were included in the study and sonoelastography was done. Sonoelastographic findings were compared to the gold standard histopathology or cytopathology. ARFI measurements in benign and malignant enlarged lymph nodes were compared using the Student t test and ROC curve was used to arrive at the Youden index, sensitivity, specificity, PPV, NPV and diagnostic accuracy. Sonographic patterns indicative of malignancy includes heterogenous echopattern, short axis/long axis ratio > 0.5, absent echogenic fatty hilum and mixed vascular pattern. Sensitivity, specificity, PPV, NPV and accuracy in differentiation between the benign and malignant lymph nodes using ARFI elastography was 79.17, 100, 100, 83.9 and 89.9% respectively. ROC curve analysis of SWVs for differentiation between the malignant and benign lymph nodes gave a cut-off value of 2.8 m/s with an area under curve of 0.892. ARFI imaging technique quantifies the tissue stiffness of the cervical lymph nodes non invasively and aids in characterisation and differentiation of benign from malignant cervical lymphadenopathy in conjunction with conventional sonography. PMID- 30464924 TI - Mini Inferior Turbinoplasty-Tunneling Technique. AB - Techniques for inferior turbinate reduction vary with various surgical methods, which differ in the approach of preservation of tissue from total turbinectomy to limited submucosal cauterization. Our preferred method to address hypertrophic inferior turbinate by mini turbinoplasty-tunneling technique are presented. Critical steps include creation of window in the inferior turbinate with a 4 mm microdebrider blade and removal of both inferior turbinate mucosal hypertrophy and bony component to convert a convex looking inferior turbinate to concave shape. This allows proper debulking of the entire medial aspect of the inferior turbinate and widening of the nasal valve area. Mini turbinoplasty-tunneling technique for hypertrophic inferior turbinates, is a safe method in achieving turbinate size reduction with minimal morbidity and long-term relief of nasal obstructive symptoms without added risk of complications. PMID- 30464925 TI - Robot Assisted Trans Axillary Thyroidectomy: A Subcontinent Experience. PMID- 30464926 TI - Completely Endoscopic Approach Using a Skeeter Drill to Treat Bilateral Congenital Choanal Atresia in a 33 Week Born Pre-term Baby. AB - Choanal atresia (CA) is a relatively rare condition manifesting with respiratory distress. Endoscopic approaches have superseded transnasal and transpalatal approaches. We present a case of a premature baby of 1.10 kg, who developed respiratory distress and was diagnosed with bilateral CA. A nasal airway was created endoscopically using a skeeter drill. PMID- 30464927 TI - Synergistic Effects of NOTCH/gamma-Secretase Inhibition and Standard of Care Treatment Modalities in Non-small Cell Lung Cancer Cells. AB - Background: Lung cancer is the leading cause of cancer death worldwide. More effective treatments are needed to increase durable responses and prolong patient survival. Standard of care treatment for patients with non-operable stage III-IV NSCLC is concurrent chemotherapy and radiation. An activated NOTCH signaling pathway is associated with poor outcome and treatment resistance in non-small cell lung cancer (NSCLC). NOTCH/gamma-secretase inhibitors have been effective in controlling tumor growth in preclinical models but the therapeutic benefit of these inhibitors as monotherapy in patients has been limited so far. Because NOTCH signaling has been implicated in treatment resistance, we hypothesized that by combining NOTCH inhibitors with chemotherapy and radiotherapy this could result in an increased therapeutic effect. A direct comparison of the effects of NOTCH inhibition when combined with current treatment combinations for NSCLC is lacking. Methods: Using monolayer growth assays, we screened 101 FDA-approved drugs from the Cancer Therapy Evaluation Program alone, or combined with radiation, in the H1299 and H460 NSCLC cell lines to identify potent treatment interactions. Subsequently, using multicellular three-dimensional tumor spheroid assays, we tested a selection of drugs used in clinical practice for NSCLC patients, and combined these with a small molecule inhibitor, currently being tested in clinical trials, of the NOTCH pathway (BMS-906024) alone, or in combination with radiation, and measured specific spheroid growth delay (SSGD). Statistical significance was determined by one-way ANOVA with post-hoc Bonferroni correction, and synergism was assessed using two-way ANOVA. Results: Monolayer assays in H1299 and H460 suggest that 21 vs. 5% were synergistic, and 17 vs. 11% were additive chemoradiation interactions, respectively. In H1299 tumor spheroids, significant SSGD was obtained for cisplatin, etoposide, and crizotinib, which increased significantly after the addition of the NOTCH inhibitor BMS-906024 (but not for paclitaxel and pemetrexed), and especially in triple combination with radiation. Synergistic interactions were observed when BMS-906024 was combined with chemoradiation (cisplatin, paclitaxel, docetaxel, and crizotinib). Similar results were observed for H460 spheroids using paclitaxel or crizotinib in dual combination treatment with NOTCH inhibition and triple with radiation. Conclusions: Our findings point to novel synergistic combinations of NOTCH inhibition and chemoradiation that should be tested in NSCLC in vivo models for their ability to achieve an improved therapeutic ratio. PMID- 30464928 TI - Oral poliovirus vaccine-induced programmed cell death involves both intrinsic and extrinsic pathways in human colorectal cancer cells. AB - Purpose: Colorectal cancer (CRC) is one of the most common causes of cancer death throughout the world. Replication-competent viruses, which are naturally able to infect and lyse tumor cells, seem to be promising in this field. The aim of this study was to evaluate the potential of oral poliovirus vaccine (OPV) on human CRC cells and elucidate the mechanism of apoptosis induction. Materials and methods: Protein and gene expression of poliovirus (PV) receptor (CD155) on four human CRC cell lines including HCT116, SW480, HT-29, and Caco-2 and normal fetal human colon (FHC) cell line as a control were examined by flow cytometry and SYBR Green Real-Time PCR, respectively. Cytotoxicity of OPV on indicated cell lines was tested using MTT assay. The ability of OPV on apoptosis induction for both intrinsic and extrinsic pathways was examined using caspase-8 and caspase-9 colorimetric assay kits. The PV propagation in mentioned cell lines was investigated, and the quantity of viral yields (cells associated and extracellular) was determined using TaqMan PCR. Results: CD155 mRNA and protein were expressed significantly higher in studied CRC cell lines rather than the normal cell line (P=0). OPV induced cell death in a time- and dose-dependent manner in human CRC cells. Apoptosis through both extrinsic and intrinsic pathways was detected in CRC cells with the minimum level found in FHC. PV viral load was significantly correlated with apoptosis via extrinsic (R=0.945, P=0.0001) and intrinsic (R=0.756, P=0.001) pathways. Conclusion: This study suggests that OPV has potential for clinical treatment of CRC. However further studies in animal models (tumor xenografts) are needed to be certain that it is qualified enough for treatment of CRC. PMID- 30464929 TI - Use of venous-thrombotic-embolic prophylaxis in patients undergoing surgery for renal tumors: a questionnaire survey in the Nordic countries (The NORENCA-2 study). AB - Purpose: To examine the variation in venous thromboembolism prophylactic treatment (VTEP) among renal cancer patients undergoing surgery. Materials and methods: An Internet-based questionnaire on renal tumor management before and after surgery was mailed to all Nordic departments of urology. The questions focused on the use of VTEP and were subdivided into different surgical modalities. Results: Questionnaires were mailed to 91 institutions (response rate 53%). None of the centers used VTEP before surgery, unless the patient had a vena caval tumor thrombus. Overall, the VTEP utilized during hospitalization for patients undergoing renal surgery included early mobilization (45%), compression stockings (52%) and low-molecular-weight heparin (89%). In patients undergoing open radical Nx, 80% of institutions used VTEP during their hospitalization (23% compression stockings and 94% low-molecular-weight heparin). After leaving the hospital, the proportion and type of VTEP received varied considerably across institutions. The most common interval, used in 60% of the institutions, was for a period of 4 weeks. The restriction to the Nordic countries was a limitation and, therefore, may not reflect the practice patterns elsewhere. It is a survey study and, therefore, cannot measure the behaviors of those institutions that did not participate. Conclusion: We found variation in the type and duration of VTEP use for each type of local intervention for renal cancer. These widely disparate variations in care strongly argue for the establishment of national and international guidelines regarding VTEP in renal surgery. PMID- 30464930 TI - Patient positioning during percutaneous nephrolithotomy: what is the current best practice? AB - Percutaneous nephrolithotomy (PCNL) is the gold standard procedure for treatment of large stones and complex kidney disorders, but its morbidity remains the highest among stone treatment procedures. In pursuit of minimizing complication rates, surgeons have developed different variations of the classic prone position in which PCNL is usually performed; one among them is supine position. In this study, we review the literature and present all available evidence on different variations in positioning during PCNL, in an effort to identify if there is a position that can minimize the morbidity of this procedure. PMID- 30464931 TI - Potential of ramucirumab in treating hepatocellular carcinoma patients with elevated baseline alpha-fetoprotein. AB - Hepatocellular carcinoma (HCC) represents ~90% of primary liver cancers and constitutes a major global health problem. Since a decade ago, the management of advanced disease that cannot be locally treated has mainly been based on multi targeted antiangiogenic therapies. Some have demonstrated improvement in overall survival over best supportive care in first- and second-line treatment. This study focused on the efficacy of antiangiogenics in patients with advanced HCC and particularly the rising role of ramucirumab in patients with elevated alpha fetoprotein at diagnosis. PMID- 30464932 TI - Evaluation of Cytotoxic Effect of Different Extracts of Seidlitzia rosmarinus on HeLa and HepG2 Cell Lines. AB - Background: Seidlitzia rosmarinus which is commonly called "Oshnan" or "Eshnan" in Persian belongs to Chenopodiaceae family. Conventionally, it is believed that this plant is toxic. This study was aimed to evaluate the cytotoxic effect of S. rosmarinus against HeLa and HepG2 cell lines. Materials and Methods: S. rosmarinus was collected from the desert near Yazd, Iran. Hexane, chloroform, chloroform/methanol (9:1), and butanol extracts of aerial parts of S. rosmarinus were prepared. Doxorubicin and dimethyl sulfoxide 10% were used as positive and negative control, respectively. The cytotoxic activity was measured using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results: All extracts significantly and concentration dependently reduced viability of HeLa and HepG2 cells. Hexane, chloroform, and butanol extracts at doses of 200, 500, 750, and 1000 MUg/ml significantly reduced HeLa cell viability (P < 0.05). Chloroform/methanol extract at doses of 100-500 MUg/ml significantly reduced HeLa cell viability (P < 0.05). Hexane, chloroform, and butanol extracts at doses of 500, 750, and 1000 MUg/ml significantly reduced HepG2 cell viability (P < 0.05). Chloroform/methanol extract at doses of 200, 300, 400, and 500 MUg/ml significantly reduced HepG cell viability (P < 0.05). The most cytotoxic extract was chloroform/methanol extract in both cell lines. Furthermore, in the both cell lines, the second potent extract was chloroform extract. Conclusions: It can be concluded from the findings of this study that S. rosmarinus is a good candidate for further study to find new cytotoxic agents. Phytochemical investigation on chloroform/methanol extract and their structures is recommended. PMID- 30464933 TI - Comparison of CAT-21A/T Gene Polymorphism in Women with Preeclampsia and Control Group. AB - Background: Preeclampsia (PE) is one of the main causes of maternal and perinatal mortality and morbidity. Evidence shows that oxidative stress plays an important role in the pathophysiology of the PE. As catalase is a key enzyme in antioxidant enzymatic defense which protects cell from oxidative damage, in this study, we aimed to investigate the relationship between CAT-21A/T (rs7943316) polymorphism and PE susceptibility. Materials and Methods: This case-control study was conducted on 155 PE women and 159 normotensive pregnant women. Polymerase chain reaction-restriction fragment length polymorphism method was used for genotyping. Results: There was no association between CAT-21AT and TT genotypes and PE susceptibility. However, the CAT-21A/T polymorphism was associated with 1.6-fold higher risk of PE in dominant model (AA vs. AT + TT) (odds ratio [OR] 1.6 [95% confidence interval [CI]: 0.9-2.9]; P = 0.04). However, the CAT-21A/T polymorphism was not associated with PE in recessive model (TT vs. AA + AT) (OR 1.3 [95% CI: 0.8-2.1]; P = 0.4). Conclusions: The CAT-21A/T polymorphism could be a risk factor for PE susceptibility in dominant model. PMID- 30464934 TI - Comparison of Propofol and Ketamine Combination (Ketofol) and Propofol and Fentanyl Combination (Fenofol) on Quality of Sedation and Analgesia in the Lumpectomy: A Randomized Clinical Trial. AB - Background: Breast lumpectomy is an integral part of the treatment of mammary masses in women. This study was conducted to evaluate and compare two-drug combinations of propofol-ketamine (PK) (ketofol) and propofol-fentanyl (PF) (fenofol) on quality of sedation and analgesia in lumpectomy. Materials and Methods: This was a randomized, double-blind, clinical trial performed on 64 patients aged 15-70 years with breast cancer lumpectomy referred to Isfahan's Seyed Al-Shohada Hospital. Consequently, patients were divided into two groups of 32 patients, each group receiving PF combination or PK combination during anesthesia. Results: The patients in two groups, PF and PK, were compared in their sedation levels, severity of pain, and other variables. The mean arterial blood pressure, systolic blood pressure, and heart rate (HR) did not show any significant difference at the beginning of the study in the two groups, but the fenofol (PF) group had a significantly lower oxygen saturation than the ketofol (PK) group. The sedation level was significantly lower in the fenofol group than the ketofol group (P < 0.001). The mean pain intensity was significantly lower in the PF group than the PK group (P < 0.001). Conclusion: The two combinations of ketofol and fenofol cause rapid, favorable, safe anesthetic with minimal side effects and hemodynamic effects but it may be a superior alternative to fenofol combination, in terms of respiratory depression. PMID- 30464935 TI - Feasibility Study of Using Radio-frequency Identification Technology in Estimating the Time Pattern of Exposure to Causative Agents of Occupational Diseases. AB - Background: At workplaces, the workers exposed to several harmful agents such as physical, chemical, and biological pollutant that cause occupational diseases. There are a lot of jobs that not allow a certain pattern of exposure to this agent. In this article, we introduce a technology named radio-frequency identification (RFID) to estimate the exposure time of workers to harmful agent. Materials and Methods: This applied study was carried out experimentally in an industry in Isfahan province, Iran. Twenty-nine participants selected from the workers without a fixed pattern of exposure. Two methods used to measure the exposure time of them. The first method was based on a self-made RFID device and conducted by the workers. The second method performed by stopwatch, which was carried out by the occupational hygienist. The results were analyzed using SPSS 20 and descriptive statistics, Spearman correlation coefficient, and paired samples t-test. Results: The mean age of the participants was 36.48 +/- 5.889 and job experience was 9.06 +/- 6.316 years. Spearman correlation coefficient shows that there is a significant correlation between the exposure times measured by the workers and occupational hygienist (R in all zones was higher than 0.9, P < 0.05). Paired samples t-test shows that there are no significant differences between the mean exposure times measured by the workers and occupational hygienist in each zone and in all the zones (P > 0.05). Conclusion: RFID technology is an appropriate method to evaluate the exposure time of workers without fixed pattern of exposure to causative factors of occupational diseases. It can also be used in other fields of occupational health engineering. PMID- 30464936 TI - What are the Predictive Factors for the Treatment Outcomes in Multi Drug Poisoning Including Antidepressants/Antipsychotic Drugs? AB - Background: There have been studies on the outcome of acute intoxication with antidepressants or antipsychotics. We performed outcome prediction analysis in acute poisoning patients with antidepressants/antipsychotics with or without combination with other drugs. Materials and Methods: A cross-sectional study was performed in Khorshid (PBUH) University Hospital affiliated with Isfahan University of Medical Sciences from March 2016 to May 2017. Patients with acute poisoning ingested antidepressants and antipsychotics with or without other drugs were included in the study. The outcome was categorized as survived without complications and complications/death. Binary regression analysis was performed for outcome prediction. Results: The data from 239 patients were analyzed. Most of the patients were female (68.2%), 5.9% of patients admitted to the Intensive Care Unit. About 94.99% of patients survived without complications. There was a significant difference between patients with and without complications with respect to the level of consciousness, hypotension, seizure, electrocardiography findings, pulse rate after 24 hours (h) of admission, and need to endotracheal intubation (P < 0.0001). Binary logistic regression analysis showed admission level of consciousness (stupor/coma) (odds ratio [OR] =8.07; P = 0,005), hypotension (OR = 12.16; P = 0.001), seizure (OR = 11.15; P = 0.009), tachycardia after 24 h of admission (OR = 22.50; P = 0.003), and need for endotracheal intubation (OR = 10.47; P = 0.002) were determinant factors in outcome prediction. Conclusions: Stupor/coma and hypotension were the predictive factors for outcome. Patients with seizure and tachycardia after 24 h of admission; and those intubated and received mechanical ventilation had a higher chance of complications. PMID- 30464937 TI - Effect of Crocin, Exercise, and Crocin-accompanied Exercise on Learning and Memory in Rats under Chronic Unpredictable Stress. AB - Background: Stress affects brain functions and induces psychological disorders. Previous studies have indicated different effects of crocin and exercise on the improvement of memory in some types of stress. The present study investigated the effect of crocin, exercise, and crocin-accompanied exercise on learning, memory, and memory consolidation in rats under chronic unpredictable stress (CUS). Materials and Methods: Male rats were randomly allocated to different groups: control, sham, stress, stress-exercise, stress-crocin, and stress-crocin accompanied exercise groups. The CUS and treadmill running were applied 2 h/day and 1 h/day, respectively, for 21 days. Crocin (30 mg/kg) was daily intraperitoneally injected to the rats and their behavioral variables were evaluated as a brain function using the passive avoidance test. Results: Results showed that the CUS significantly decreased learning and memory compared to the control group, while crocin alone and crocin-accompanied exercise significantly improved learning and memory compared to the stressed group. It was found that exercise alone caused learning but did not improve memory in unpredictable stress rats. Conclusion: The data indicated that unpredictable stress had very destructive effects on the brain functions. Furthermore, unlike exercise, crocin improved memory under unpredictable stress conditions. Overall, it seems that the beneficial effects of crocin-accompanied exercise on learning and memory were probably because of crocin, but not exercise. PMID- 30464938 TI - Corrigendum: Augmenting Pentose Utilization and Ethanol Production of Native Saccharomyces Cerevisiae LN Using Medium Engineering and Response Surface Methodology. AB - [This corrects the article DOI: 10.3389/fbioe.2018.00132.]. PMID- 30464939 TI - Assessing a Method of Mechanical Cervical Dislocation as a Humane Option for On Farm Killing Using Anesthetized Poults and Young Turkeys. AB - Our objective was to determine the efficacy of manual cervical dislocation vs. a mechanical cervical dislocation device for on-farm killing of poults and young turkeys. Forty-two 1- and 3-week old turkeys were randomly assigned to one of three experimental groups: awake manual cervical dislocation (CD), anesthetized manual cervical dislocation (aCD), or anesthetized mechanical cervical dislocation (MCD). Anesthetized birds received an intramuscular dose of 0.3 mg/kg medetomidine and 30 mg/kg of ketamine to achieve a light plane of anesthesia. A comparison of CD vs. aCD responses indicated that the anesthetic plane did not affect jaw tone or pupillary light reflex, indicators of loss of sensibility and brain death, respectively. MCD was unsuccessful for killing 1-week old poults as indicated by the ongoing presence of the pupillary eye reflex as well as failure to achieve cardiac arrest within 5 min in 5 of 5 birds. Radiographs also indicated no vertebral dislocation or fracture. Pupillary light reflex was present in 98% and jaw tone was present in 73% of turkeys, respectively, for all groups combined, but retention of the pupillary light reflex (P < 0.001) and jaw tone (P = 0.001) was longer for birds killed by MCD. Time to last movement (P = 0.797) and cardiac arrest (P = 0.057) did not differ between method. Survey radiographs demonstrated an effect of method for the average displacement distance at the site of vertebral dislocation, with a greater distance observed in birds killed by CD compared to MCD (P = 0.003). A method by age interaction was observed between CD and MCD for the number of birds with fractures; more vertebral fractures were observed in 3-week old turkeys killed with MCD compared to CD (P = 0.047). Upon gross examination, the majority of birds killed by either method had minimal to no hemorrhage within the brain and spinal cord. However, turkeys killed using CD had more microscopic subdural brain hemorrhage (P = 0.020). Ante-mortem and post-mortem measures suggest that neither manual CD nor the MCD tool used in this study caused immediate insensibility, but CD resulted in a shorter latency to brain death and fewer fractures compared to MCD. PMID- 30464940 TI - Heterostructured Electrocatalysts for Hydrogen Evolution Reaction Under Alkaline Conditions. AB - The hydrogen evolution reaction (HER) is a half-cell reaction in water electrolysis for producing hydrogen gas. In industrial water electrolysis, the HER is often conducted in alkaline media to achieve higher stability of the electrode materials. However, the kinetics of the HER in alkaline medium is slow relative to that in acid because of the low concentration of protons in the former. Under the latter conditions, the entire HER process will require additional effort to obtain protons by water dissociation near or on the catalyst surface. Heterostructured catalysts, with fascinating synergistic effects derived from their heterogeneous interfaces, can provide multiple functional sites for the overall reaction process. At present, the activity of the most active known heterostructured catalysts surpasses (platinum-based heterostructures) or approaches (noble-metal-free heterostructures) that of the commercial Pt/C catalyst under alkaline conditions, demonstrating an infusive potential to break through the bottlenecks. This review summarizes the most representative and recent heterostructured HER catalysts for alkaline medium. The basics and principles of the HER under alkaline conditions are first introduced, followed by a discussion of the latest advances in heterostructured catalysts with/without noble-metal-based heterostructures. Special focus is placed on approaches for enhancing the reaction rate by accelerating the Volmer step. This review aims to provide an overview of the current developments in alkaline HER catalysts, as well as the design principles for the future development of heterostructured nano or micro-sized electrocatalysts. PMID- 30464941 TI - CoFe2O4-Graphene Nanocomposites Synthesized through An Ultrasonic Method with Enhanced Performances as Anode Materials for Li-ion Batteries. AB - CoFe2O4-graphene nanocomposites (CoFe2O4-GNSs) have been synthesized through an ultrasonic method combined with calcination process. The nanocomposite calcinated at 350 degrees C shows better rate capabilities, e.g., 696, 495, 308, and 254 mAh g-1 at 1, 2, 5, and 10 A g-1, respectively. PMID- 30464942 TI - Composites of Graphene and LiFePO4 as Cathode Materials for Lithium-Ion Battery: A Mini-review. AB - This mini-review highlights selectively the recent research progress in the composites of LiFePO4 and graphene. In particularly, the different fabrication protocols, and the electrochemical performance of the composites are summarized in detail. The structural and morphology characters of graphene sheets that may affect the property of the composites are discussed briefly. The possible ongoing researches in area are speculated upon. PMID- 30464943 TI - Amplified Detection of Iron Ion Based on Plasmon Enhanced Fluorescence and Subsequently Fluorescence Quenching. AB - A facile and rapid approach for detecting low concentration of iron ion (Fe3+) with improved sensitivity was developed on the basis of plasmon enhanced fluorescence and subsequently amplified fluorescence quenching. Au1Ag4@SiO2 nanoparticles were synthesized and dispersed into fluorescein isothiocyanate (FITC) solution. The fluorescence of the FITC solution was improved due to plasmon enhanced fluorescence. However, efficient fluorescence quenching of the FITC/Au1Ag4@SiO2 solution was subsequently achieved when Fe3+, with a concentration ranging from 17 nM to 3.4 MUM, was added into the FITC/Au1Ag4@SiO2 solution, whereas almost no fluorescence quenching was observed for pure FITC solution under the same condition. FITC/Au1Ag4@SiO2 solution shows a better sensitivity for detecting low concentration of Fe3+ compared to pure FITC solution. The quantized limit of detection toward Fe3+ was improved from 4.6 MUM for pure FITC solution to 20 nM for FITC/Au1Ag4@SiO2 solution. PMID- 30464944 TI - Very-High Color Rendering Index Hybrid White Organic Light-Emitting Diodes with Double Emitting Nanolayers. AB - A very-high color rendering index white organic light-emitting diode (WOLED) based on a simple structure was successfully fabricated. The optimized device exhibits a maximum total efficiency of 13.1 and 5.4 lm/W at 1,000 cd/m2. A peak color rendering index of 90 and a relatively stable color during a wide range of luminance were obtained. In addition, it was demonstrated that the 4,4',4"-tri(9 carbazoyl) triphenylamine host influenced strongly the performance of this WOLED. These results may be beneficial to the design of both material and device architecture for high-performance WOLED. PMID- 30464945 TI - Cuprous Chloride Nanocubes Grown on Copper Foil for Pseudocapacitor Electrodes. AB - In this paper, for the first time, we report the synthesis of nanoscale cuprous chloride (CuCl) cubic structure by a facile hydrothermal route. A possible mechanism for the growth of those nanostructures is proposed based on the experimental results. It is discovered that the existence of HCl could affect the surface of CuCl nanocubes. This unique cube-like nanostructure with rough surface significantly enhances the electroactive surface areas of CuCl, leading to a high special capacitance of 376 mF cm-2 at the current density of 1.0 mA cm-2. There is still a good reversibility with cycling efficiency of 88.8 % after 2,000 cycles, demonstrating its excellent long-term cycling stability and might be the promising candidates as the excellent electrode material. PMID- 30464946 TI - Si-Based Anode Materials for Li-Ion Batteries: A Mini Review. AB - Si has been considered as one of the most attractive anode materials for Li-ion batteries (LIBs) because of its high gravimetric and volumetric capacity. Importantly, it is also abundant, cheap, and environmentally benign. In this review, we summarized the recent progress in developments of Si anode materials. First, the electrochemical reaction and failure are outlined, and then, we summarized various methods for improving the battery performance, including those of nanostructuring, alloying, forming hierarchic structures, and using suitable binders. We hope that this review can be of benefit to more intensive investigation of Si-based anode materials. PMID- 30464947 TI - Role of TbFe on Perpendicular Magnetic Anisotropy and Giant Magnetoresistance Effect in [Co/Ni]N-Based Spin Valves. AB - The exchange-coupled [Co/Ni]N/TbFe nano-magnetic films can display strong perpendicular magnetic anisotropy (PMA) which depends on the Tb:Fe component ratio, TbFe layer thickness and the repetition number N of [Co/Ni]N multilayer. Perpendicular spin valves in the nano thickness scale, consisting of a [Co/Ni]3 free and a [Co/Ni]5/TbFe reference multilayer, show high giant magnetoresistance (GMR) signal of 6.5 % and a large switching field difference over 3 kOe. However, unexpected slanting of the free layer magnetization, accompanied by a reduced GMR ratio, was found to be caused by the presence of a thick Fe-rich or even a thin but Tb-rich TbFe layer. We attribute this phenomenon to the large magnetostriction effect of TbFe which probably induces strong stress acting on the free layer and hence reduces its interfacial PMA. PMID- 30464948 TI - Spin-dependent Transport Properties of CrO2 Micro Rod. AB - The CrO2 micro rod powder was synthesized by decomposing the CrO3 flakes at a specific temperature to yield precursor and annealing such a precursor in a sealed glass tube. The magneto-transport properties have been measured by a direct current four-probe method using a Cu/CrO2 rods/colloidal silver liquid electrode sandwich device. The largest magnetoresistance (MR) around ~72 % was observed at 77 K with applied current of 0.05 MUA. The non-linear I-V curve indicates a tunneling type transport properties and the tunneling barrier height is around 2.2 +/- 0.04 eV at 77 K, which is obtained with fitting the non-linear I-V curves using Simmons' equation. A mixing of Cr oxides on the surface of CrO2 rod observed by X-ray photoemission spectroscopy provides a tunneling barrier rather than a single phase of Cr2O3 insulating barrier. The MR shows strong bias voltage dependence and is ascribed to the two-step tunneling process. PMID- 30464949 TI - Angle-Resolved Plasmonic Properties of Single Gold Nanorod Dimers. AB - Through wet-chemical assembly methods, gold nanorods were placed close to each other and formed a dimer with a gap distance ~1 nm, and hence degenerated plasmonic dipole modes of individual nanorods coupled together to produce hybridized bonding and antibonding resonance modes. Previous studies using a condenser for illumination result in averaged signals over all excitation angles. By exciting an individual dimer obliquely at different angles, we demonstrate that these two new resonance modes are highly tunable and sensitive to the angle between the excitation polarization and the dimer orientation, which follows cos2 phi dependence. Moreover, for dimer structures with various structure angles, the resonance wavelengths as well as the refractive index sensitivities were found independent of the structure angle. Calculated angle-resolved plasmonic properties are in good agreement with the measurements. The assembled nanostructures investigated here are important for fundamental researches as well as potential applications when they are used as building blocks in plasmon-based optical and optoelectronic devices. PMID- 30464950 TI - Dipping Process Characteristics Based on Image Processing of Pictures Captured by High-speed Cameras. AB - The dipping process was recorded firstly by high-speed camera system; acceleration time, speed, and dipping time were set by the control system of dipping bed, respectively. By image processing of dipping process based on Otsu's method, it was found that low-viscosity flux glue eliminates the micelle effectively, very low speed also leads to small micelle hidden between the bumps, and this small micelle and hidden phenomenon disappeared when the speed is >=0.2 cm s-1. Dipping flux quantity of the bump decreases by about 100 square pixels when flux viscosity is reduced from 4,500 to 3,500 mpa s. For the 3,500 mpa s viscosity glue, dipping flux quantity increases with the increase of the speed and decreases with the increase of the speed after the speed is up to 0.8 cm s-1. The stable time of dipping glue can be obtained by real-time curve of dipping flux quantity and is only 80-90 ms when dipping speed is from 1.6 to 4.0 cm s-1. Dipping flux quantity has an increasing trend for acceleration time and has a decreasing trend for acceleration. Dipping flux quantity increases with the increase of dipping time, and is becoming saturated when the time is >=55 ms. PMID- 30464951 TI - Rational Design of WO3 Nanostructures as the Anode Materials for Lithium-Ion Batteries with Enhanced Electrochemical Performance. AB - A facile, one-step hydrothermal method was employed to synthesize two kinds of WO3 nanostructures. By using different kinds of sylvine, tungsten trioxide (WO3) with different morphologies of microflowers and nanowires was obtained, respectively. The discharge capacities for microflowers and nanowires are 107 and 146 mAh g-1 after 180 cycles, and their corresponding capacity retentions after the first cycle are 72 and 85 %, respectively. Even at a high current density of 1,600 mAh g-1, the discharge capacities of WO3 microflowers and nanowires are as high as 433 and 557 mAh g-1 after 40 cycles, in which the current densities were increased stepwise. It is worth mentioned that the rate capability of the nanowires is superior to that of the microflowers. However, the cycle performance of the microflowers is better than nanowires, revealing that the morphology and structure of the as-synthesized WO3 products can exert great influence on the electrochemical performances. PMID- 30464952 TI - The Effect of Thermal Exfoliation Temperature on the Structure and Supercapacitive Performance of Graphene Nanosheets. AB - Graphene nanosheets (GSs) were prepared from graphite oxide by thermal exfoliation method. The effect of thermal exfoliation temperature on the structure and supercapacitive performance of GSs has been investigated. The results show that the GSs with pore sizes center around 4.0 nm. With an increase of thermal reduction temperature, the number of stacking layers and the structure disorder degree increase, while the oxygen-containing groups content, BET surface area, and electrical resistivity of GSs decrease. The results indicate that 673 K is the preferable thermal exfoliation temperature to acquire good supercapacitive performance. In this case, the GSs have the best supercapacitive performance (233.1 F g-1) in a 6 mol L-1 KOH electrolyte. The prepared GSs at the preferable thermal exfoliation temperature have good rate performance and cycle stability. PMID- 30464953 TI - Fabrication and Characterization of Au Nanoparticle-aggregated Nanowires by Using Nanomeniscus-induced Colloidal Stacking Method. AB - We fabricate and characterize Au nanoparticle-aggregated nanowires by using the nano meniscus-induced colloidal stacking method. The Au nanoparticle solution ejects with guidance of nanopipette/quartz tuning fork-based atomic force microscope in ambient conditions, and the stacking particles form Au nanoparticle aggregated nanowire while the nozzle retracts from the surface. Their mechanical properties with relatively low elastic modulus are in situ investigated by using the same apparatus. PMID- 30464954 TI - Low-Programmable-Voltage Nonvolatile Memory Devices Based on Omega-shaped Gate Organic Ferroelectric P(VDF-TrFE) Field Effect Transistors Using p-type Silicon Nanowire Channels. AB - A facile approach was demonstrated for fabricating high-performance nonvolatile memory devices based on ferroelectric-gate field effect transistors using a p type Si nanowire coated with omega-shaped gate organic ferroelectric poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)). We overcame the interfacial layer problem by incorporating P(VDF-TrFE) as a ferroelectric gate using a low-temperature fabrication process. Our memory devices exhibited excellent memory characteristics with a low programming voltage of +/-5 V, a large modulation in channel conductance between ON and OFF states exceeding 105, a long retention time greater than 3 * 104 s, and a high endurance of over 105 programming cycles while maintaining an I ON/I OFF ratio higher than 102. PMID- 30464955 TI - Voltage-Dependent Electronic Transport Properties of Reduced Graphene Oxide with Various Coverage Ratios. AB - Graphene is mainly implemented by these methods: exfoliating, unzipping of carbon nanotubes, chemical vapour deposition, epitaxial growth and the reduction of graphene oxide. The latter option has the advantage of low cost and precision. However, reduced graphene oxide (rGO) contains hydrogen and/or oxygen atoms hence the structure and properties of the rGO and intrinsic graphene are different. Considering the advantages of the implementation and utilization of rGO, voltage dependent electronic transport properties of several rGO samples with various coverage ratios are investigated in this work. Ab initio simulations based on density functional theory combined with non-equilibrium Green's function formalism are used to obtain the current-voltage characteristics and the voltage dependent transmission spectra of rGO samples. It is shown that the transport properties of rGO are strongly dependent on the coverage ratio. Obtained results indicate that some of the rGO samples have negative differential resistance characteristics while normally insulating rGO can behave as conducting beyond a certain threshold voltage. The reasons of the peculiar electronic transport behaviour of rGO samples are further investigated, taking the transmission eigenstates and their localization degree into consideration. The findings of this study are expected to be helpful for engineering the characteristics of rGO structures. PMID- 30464956 TI - Silver Nanowire Electrodes: Conductivity Improvement Without Post-treatment and Application in Capacitive Pressure Sensors. AB - Transparent electrode based on silver nanowires (AgNWs) emerges as an outstanding alternative of indium tin oxide film especially for flexible electronics. However, the conductivity of AgNWs transparent electrode is still dramatically limited by the contact resistance between nanowires at high transmittance. Polyvinylpyrrolidone (PVP) layer adsorbed on the nanowire surface acts as an electrically insulating barrier at wire-wire junctions, and some devastating post treatment methods are proposed to reduce or eliminate PVP layer, which usually limit the application of the substrates susceptible to heat or pressure and burden the fabrication with high-cost, time-consuming, or inefficient processes. In this work, a simple and rapid pre-treatment washing method was proposed to reduce the thickness of PVP layer from 13.19 to 0.96 nm and improve the contact between wires. AgNW electrodes with sheet resistances of 15.6 and 204 Omega sq-1 have been achieved at transmittances of 90 and 97.5 %, respectively. This method avoided any post-treatments and popularized the application of high-performance AgNW transparent electrode on more substrates. The improved AgNWs were successfully employed in a capacitive pressure sensor with high transparency, sensitivity, and reproducibility. PMID- 30464957 TI - Hollow Carbon Microspheres/MnO2 Nanosheets Composites: Hydrothermal Synthesis and Electrochemical Behaviors. AB - This article reported the electrochemical behaviors of a novel hollow carbon microspheres/manganese dioxide nanosheets (micro-HC/nano-MnO2) composite prepared by an in situ self-limiting deposition method under hydrothermal condition. The results of scanning electron microscopy reveal that MnO2 nanosheets homogeneously grow onto the surface of micro-HC to form a loose-packed microstructure. The quantity of MnO2 required in the electrode layer has thereby been reduced significantly, and higher specific capacitances have been achieved. The micro HC/nano-MnO2 electrode presents a high capacitance of 239.0 F g-1 at a current density of 5 mA cm-2, which is a strong promise for high-rate electrochemical capacitive energy storage applications. PMID- 30464958 TI - High-Throughput Screening of Nanoparticle-Stabilizing Ligands: Application to Preparing Antimicrobial Curcumin Nanoparticles by Antisolvent Precipitation. AB - Water-dispersible curcumin nanoparticles were prepared by bottom-up antisolvent precipitation approach. A new high-throughput screening technique was developed for selecting appropriate ligands stabilizing the nanoparticles in aqueous medium and improving their performance. The initial set of twenty-eight potential stabilizing ligands was evaluated based on their capacity to improve curcumin dispersibility in aqueous medium. The performance of four promising ligands (amino acid proline, polyphenol tannic acid, polycation Polyquaternium 10, and neutral polymer polyvinylpyrrolidone) was tested in ultrasound-aided antisolvent precipitation trials. Using the selected stabilizing ligands diminished the average particle size from ca. 1,200 to 170-230 nm, reduced their dispersity, improved stability, and allowed reaching curcumin concentration of up to 1.4 mM in aqueous medium. Storage stability of the aqueous nanodispersions varied from 2 days to 2 weeks, depending on stabilizing ligand. Studying the effects of ionic strength and pH on size and zeta-potential of the particles suggested that electrostatic forces and hydrophobic interactions could be the major factors affecting their stability. The ligand-protected nanoparticles showed minimal inhibitory concentration of 400 or 500 uM toward Escherichia coli. We suggest that the presented screening approach may be useful for preparing nanoparticles of various poorly water-soluble bioactive materials. PMID- 30464959 TI - Hydrothermal Preparation and White-Light-Controlled Resistive Switching Behavior of BaWO4 Nanospheres. AB - In this work, BaWO4 nanospheres were successfully prepared by hydrothermal process. The bipolar resistive switching behavior of Ag/BaWO4/FTO device is observed. Moreover, this resistive switching behavior can be modulated by white light. The device can maintain superior stability in the dark and under white light illumination. This study is useful for developing the light-controlled nonvolatile memory devices. PMID- 30464960 TI - Three-dimensional Porous Networks of Ultra-long Electrospun SnO2 Nanotubes with High Photocatalytic Performance. AB - Recent progress in nanoscience and nanotechnology creates new opportunities in the design of novel SnO2 nanomaterials for photocatalysis and photoelectrochemical. Herein, we firstly highlight a facile method to prepare three-dimensional porous networks of ultra-long SnO2 nanotubes through the single capillary electrospinning technique. Compared with the traditional SnO2 nanofibers, the as-obtained three-dimensional porous networks show enhancement of photocurrent and photocatalytic activity, which could be ascribed to its improved light-harvesting efficiency and high separation efficiency of photogenerated electron-hole pairs. Besides, the synthesis route delivered three-dimensional sheets on the basis of interwoven nanofibrous networks, which can be readily recycled for the desirable circular application of a potent photocatalyst system. PMID- 30464961 TI - Zinc Oxide Nanostructures for NO2 Gas-Sensor Applications: A Review. AB - Because of the interesting and multifunctional properties, recently, ZnO nanostructures are considered as excellent material for fabrication of highly sensitive and selective gas sensors. Thus, ZnO nanomaterials are widely used to fabricate efficient gas sensors for the detection of various hazardous and toxic gases. The presented review article is focusing on the recent developments of NO2 gas sensors based on ZnO nanomaterials. The review presents the general introduction of some metal oxide nanomaterials for gas sensing application and finally focusing on the structure of ZnO and its gas sensing mechanisms. Basic gas sensing characteristics such as gas response, response time, recovery time, selectivity, detection limit, stability and recyclability, etc are also discussed in this article. Further, the utilization of various ZnO nanomaterials such as nanorods, nanowires, nano-micro flowers, quantum dots, thin films and nanosheets, etc for the fabrication of NO2 gas sensors are also presented. Moreover, various factors such as NO2 concentrations, annealing temperature, ZnO morphologies and particle sizes, relative humidity, operating temperatures which are affecting the NO2 gas sensing properties are discussed in this review. Finally, the review article is concluded and future directions are presented. PMID- 30464962 TI - Controlling Ion Conductance and Channels to Achieve Synaptic-like Frequency Selectivity. AB - Enhancing ion conductance and controlling transport pathway in organic electrolyte could be used to modulate ionic kinetics to handle signals. In a Pt/Poly(3-hexylthiophene-2,5-diyl)/Polyethylene+LiCF3SO3/Pt hetero-junction, the electrolyte layer handled at high temperature showed nano-fiber microstructures accompanied with greatly improved salt solubility. Ions with high mobility were confined in the nano-fibrous channels leading to the semiconducting polymer layer, which is favorable for modulating dynamic doping at the semiconducting polymer/electrolyte interface by pulse frequency. Such a device realized synaptic like frequency selectivity, i.e., depression at low frequency stimulation but potentiation at high-frequency stimulation. PMID- 30464963 TI - Elucidating the Uptake and Distribution of Nanoparticles in Solid Tumors via a Multilayered Cell Culture Model. AB - Multicellular layers (MCLs) have previously been used to determine the pharmacokinetics of a variety of different cancer drugs including paclitaxel, doxorubicin, methotrexate, and 5-fluorouracil across a number of cell lines. It is not known how nanoparticles (NPs) navigate through the tumor microenvironment once they leave the tumor blood vessel. In this study, we used the MCL model to study the uptake and penetration dynamics of NPs. Gold nanoparticles (GNPs) were used as a model system to map the NP distribution within tissue-like structures. Our results show that NP uptake and transport are dependent on the tumor cell type. MDA-MB-231 tissue showed deeper penetration of GNPs as compared to MCF-7 one. Intracellular and extracellular distributions of NPs were mapped using CytoViva imaging. The ability of MCLs to mimic tumor tissue characteristics makes them a useful tool in assessing the efficacy of particle distribution in solid tumors. PMID- 30464964 TI - Specific Recognition of Breast Cancer Cells In Vitro Using Near Infrared-Emitting Long-Persistence Luminescent Zn3Ga2Ge2O10:Cr3+ Nanoprobes. AB - In this paper, near-infrared emitting long-persistence luminescent Zn3Ga2Ge2O10:Cr3+ (ZGG) nanoparticles with diameters of 30-100 nm and bright luminescence were prepared by a sol-gel synthesis method. After the surface amination, the nanoparticles were further bioconjugated with breast cancer specific monoclonal antibody (anti-EpCAM) to form ZGG-EpCAM nanoprobes which can specifically target breast cancer cell lines (MCF7) in vitro. The results of in vitro images show that the luminescence signals from the cells treated with ZGG EpCAM nanoprobes are stronger than those from cells treated with ZGG-unconjugated antibody, indicating that the prepared ZGG-EpCAM nanoprobes possessed excellent specific recognition capability. Furthermore, due to their long afterglow properties, the imaging could persist more than 1 h. Therefore, these nanoprobes could not only provide a high specificity detection method for cancer cells but also realize the long-time monitoring. Developed near-infrared emitting long persistence luminescent nanoprobes will be expected to find new perspectives for cell therapy research and diagnosis applications. PMID- 30464965 TI - Controlling DNA Bundle Size and Spatial Arrangement in Self-assembled Arrays on Superhydrophobic Surface. AB - The use of superhydrophobic surfaces (SHSs) is now emerging as an attractive platform for the realization of one-dimensional (1D) nanostructures with potential applications in many nanotechnological and biotechnological fields. To this purpose, a strict control of the nanostructures size and their spatial arrangement is highly required. However, these parameters may be strongly dependent on the complex evaporation dynamics of the sessile droplet on the SHS. In this work, we investigated the effect of the evaporation dynamics on the size and the spatial arrangement of self-assembled 1D DNA bundles. Our results reveal that different arrangements and bundle size distributions may occur depending on droplet evaporation stage. These results contribute to elucidate the formation mechanism of 1D nanostructures on SHSs. PMID- 30464966 TI - Advances in MoS2-Based Field Effect Transistors (FETs). AB - This paper reviews the original achievements and advances regarding the field effect transistor (FET) fabricated from one of the most studied transition metal dichalcogenides: two-dimensional MoS2. Not like graphene, which is highlighted by a gapless Dirac cone band structure, Monolayer MoS2 is featured with a 1.9 eV gapped direct energy band thus facilitates convenient electronic and/or optoelectronic modulation of its physical properties in FET structure. Indeed, many MoS2 devices based on FET architecture such as phototransistors, memory devices, and sensors have been studied and extraordinary properties such as excellent mobility, ON/OFF ratio, and sensitivity of these devices have been exhibited. However, further developments in FET device applications depend a lot on if novel physics would be involved in them. In this review, an overview on advances and developments in the MoS2-based FETs are presented. Engineering of MoS2-based FETs will be discussed in details for understanding contact physics, formation of gate dielectric, and doping strategies. Also reported are demonstrations of device behaviors such as low-frequency noise and photoresponse in MoS2-based FETs, which is crucial for developing electronic and optoelectronic devices. PMID- 30464967 TI - Review on Zinc Oxide Nanoparticles: Antibacterial Activity and Toxicity Mechanism. AB - Antibacterial activity of zinc oxide nanoparticles (ZnO-NPs) has received significant interest worldwide particularly by the implementation of nanotechnology to synthesize particles in the nanometer region. Many microorganisms exist in the range from hundreds of nanometers to tens of micrometers. ZnO-NPs exhibit attractive antibacterial properties due to increased specific surface area as the reduced particle size leading to enhanced particle surface reactivity. ZnO is a bio-safe material that possesses photo-oxidizing and photocatalysis impacts on chemical and biological species. This review covered ZnO-NPs antibacterial activity including testing methods, impact of UV illumination, ZnO particle properties (size, concentration, morphology, and defects), particle surface modification, and minimum inhibitory concentration. Particular emphasize was given to bactericidal and bacteriostatic mechanisms with focus on generation of reactive oxygen species (ROS) including hydrogen peroxide (H2O2), OH- (hydroxyl radicals), and O2 -2 (peroxide). ROS has been a major factor for several mechanisms including cell wall damage due to ZnO-localized interaction, enhanced membrane permeability, internalization of NPs due to loss of proton motive force and uptake of toxic dissolved zinc ions. These have led to mitochondria weakness, intracellular outflow, and release in gene expression of oxidative stress which caused eventual cell growth inhibition and cell death. In some cases, enhanced antibacterial activity can be attributed to surface defects on ZnO abrasive surface texture. One functional application of the ZnO antibacterial bioactivity was discussed in food packaging industry where ZnO-NPs are used as an antibacterial agent toward foodborne diseases. Proper incorporation of ZnO-NPs into packaging materials can cause interaction with foodborne pathogens, thereby releasing NPs onto food surface where they come in contact with bad bacteria and cause the bacterial death and/or inhibition. PMID- 30464968 TI - Mesoporous TiO2/Carbon Beads: One-Pot Preparation and Their Application in Visible-Light-Induced Photodegradation. AB - Mesoporous TiO2/Carbon beads have been prepared via a facile impregnation carbonization approach, in which a porous anion-exchange resin and K2TiO(C2O4)2 were used as hard carbon and titanium source, respectively. Characterization results reveal that the self-assembled composites have disordered mesostructure, uniform mesopores, large pore volumes, and high surface areas. The mesopore walls are composed of amorphous carbon, well-dispersed and confined anatase or rutile nanoparticles. Some anatase phase of TiO2 was transformed to rutile phase via an increase of carbonization temperature or repeated impregnation of the resin with TiO(C2O4)2 2- species. X-ray photoelectron spectroscopy, carbon, hydrogen, and nitrogen element analysis, and thermal gravity analysis results indicate the doping of carbon into the TiO2 lattice and strong interaction between carbon and TiO2 nanoparticles. A synergy effect by carbon and TiO2 in the composites has been discussed herein on the degradation of methyl orange under visible light. The dye removal process involves adsorption of the dye from water by the mesopores in the composites, followed by photodegradation on the separated dye loaded catalysts. Mesopores allow full access of the dye molecules to the surface of TiO2 nanoparticles. Importantly, the bead format of such composite enables their straightforward separation from the reaction mixture in their application as a liquid-phase heterogeneous photodegradation catalyst. PMID- 30464969 TI - Improvement of a Real Gas-Sensor for the Origin of Methane Selectivity Degradation by u-XAFS Investigation. AB - We have directly investigated the chemical state of the Pd species in a real MU gas sensor device by examining the MU-fluorescence X-ray absorption fine structure. The MU-gas sensor device was heavily damaged by a heating process in which the temperature was ill-controlled, resulting in decrease of methane selectivity. We found that the PdO in the fresh MU-gas sensor was reduced to Pd metal particles as the methane selectivity decreased. Based on the investigation results, we modified the device structure so as to heat up homogeneously. The lifetime of the sensor was then successfully increased by more than 5 years. PMID- 30464970 TI - Ultra-thin Glass Film Coated with Graphene: A New Material for Spontaneous Emission Enhancement of Quantum Emitter. AB - We propose an ultra-thin glass film coated with graphene as a new kind of surrounding material which can greatly enhance spontaneous emission rate (SER) of dipole emitter embedded in it. With properly designed parameters, numerical results show that SER-enhanced factors as high as 1.286 * 106 can be achieved. The influences of glass film thickness and chemical potential/doping level of graphene on spontaneous emission enhancement are also studied in this paper. A comparison is made between graphene and other coating materials such as gold and silver to see their performances in SER enhancement. PMID- 30464971 TI - Novel Nano-composites SDC-LiNaSO4 as Functional Layer for ITSOFC. AB - As an ionic conductive functional layer of intermediate temperature solid oxide fuel cells (ITSOFC), samarium-doped ceria (SDC)-LiNaSO4 nano-composites were synthesized by a sol-gel method and their properties were investigated. It was found that the content of LiNaSO4 strongly affected the crystal phase, defect concentration, and conductivity of the composites. When the content of LiNaSO4 was 20 wt%, the highest conductivity of the composite was found to be, respectively, 0.22, 0.26, and 0.35 S cm-1 at temperatures of 550, 600, and 700 degrees C, which are much higher than those of SDC. The peak power density of the single cell using this composite as an interlayer was improved to, respectively, 0.23, 0.39, and 0.88 W cm-2 at 500, 600, and 700 degrees C comparing with that of the SDC-based cell. Further, the SDC-LiNaSO4(20 wt%)-based cell also displayed better thermal stability according to the performance measurements at 560 degrees C for 50 h. These results reveal that SDC-LiNaSO4 composite may be a potential good candidate as interlayer for ITSOFC due to its high ionic conductivity and thermal stability. PMID- 30464972 TI - High-Performance Solid-State Supercapacitors Fabricated by Pencil Drawing and Polypyrrole Depositing on Paper Substrate. AB - A solid-state powerful supercapacitor (SC) is fabricated with a substrate of Xerox paper. Its current collector based on a foldable electronic circuit is developed by simply pencil drawing. Thin graphite sheets on paper provide effective channels for electron transmission with a low resistance of 95 Omega sq 1. The conductive organic material of polypyrrole coated on thin graphite sheets acts as the electrode material of the device. The as-fabricated SC exhibits a high specific capacitance of 52.9 F cm-3 at a scan rate of 1 mV s-1. An energy storage unit fabricated by three full-charged series SCs can drive a commercial light-emitting diode robustly. This work demonstrated a simple, versatile and cost-effective method for paper-based devices. PMID- 30464973 TI - Micro-accelerometer Based on Vertically Movable Gate Field Effect Transistor. AB - A vertically movable gate field effect transistor (VMGFET) is proposed and demonstrated for a micro-accelerometer application. The VMGFET using air gap as an insulator layer allows the gate to move on the substrate vertically by external forces. Finite element analysis is used to simulate mechanical behaviors of the designed structure. For the simulation, the ground acceleration spectrum of the 1952 Kern County Earthquake is employed to investigate the structural integrity of the sensor in vibration. Based on the simulation, a prototype VMGFET accelerometer is fabricated from silicon on insulator wafer. According to current voltage characteristics of the prototype VMGFET, the threshold voltage is measured to be 2.32 V, which determines the effective charge density and the mutual transconductance of 1.545*10-8 C cm-2 and 6.59 mA V-1, respectively. The device sensitivity is 9.36-9.42 mV g-1 in the low frequency, and the first natural frequency is found to be 1230 Hz. The profile smoothness of the sensed signal is in 3 dB range up to 1 kHz. PMID- 30464974 TI - A Simple Method of Electrospun Tungsten Trioxide Nanofibers with Enhanced Visible Light Photocatalytic Activity. AB - The present study involves the fabrication of tungsten trioxide (WO3) nanofibers by an electrospinning technique using polyvinyl pyrrolidone (PVP)/citric acid/tungstic acid as precursor solution. It was found that the PVP concentration was one of the most crucial processing parameters determining the final properties of WO3 nanofibers. The optimum concentration of PVP was from 75 to 94 g L-1. The average diameter of the nanofibers increases with increasing the PVP concentration, whereas it is decreased after sintering and orthorhombic structure were formed at 500 degrees C. The photocatalytic properties of the as synthesized nanofibers were also investigated by degrading methylene blue and twofold efficiency was obtained compared with that of commercial WO3 microparticles. PMID- 30464975 TI - Enhanced Electrocatalytic Activity by RGO/MWCNTs/NiO Counter Electrode for Dye sensitized Solar Cells. AB - We applied the reduced graphene oxide/multi-walled carbon nanotubes/nickel oxide (RGO/MWCNTs/NiO) nanocomposite as the counter electrode (CE) in dye-sensitized solar cells (DSSCs) on fluorine-doped tin oxide substrates by blade doctor method. Power conversion efficiency (PCE) of 8.13 % was achieved for this DSSCs device, which is higher than that of DSSCs devices using NiO, RGO, and RGO/NiO-CE (PCE = 2.71 %, PCE = 6.77 % and PCE = 7.63 %). Also, the fill factor of the DSSCs devices using the RGO/MWCNTs/NiO-CE was better than that of other CEs. The electron transfer measurement of cyclic voltammetry and electrochemical impedance spectroscopy showed that RGO/MWCNTs/NiO film could provide fast electron transfer between the CE and the electrolyte, and high electrocatalytic activity for the reduction of triiodide in a CE based on RGO/MWCNTs/NiO in a DSSC. PMID- 30464976 TI - Green-chemistry Compatible Approach to TiO2-supported PdAu Bimetallic Nanoparticles for Solvent-free 1-Phenylethanol Oxidation under Mild Conditions. AB - TiO2-supported PdAu bimetallic nanoparticles (NPs) with small size and good dispersity were prepared by the room-temperature ionic liquid-assisted bimetal sputtering, which is simple, environmentally friendly, and free of additives and byproducts. Pd/Au atomic ratio can be tuned by controlling the sputtering conditions simply. High catalytic activity was found in PdAu-NPs-TiO2 hybrids for solvent-free selective oxidation of 1-phenylethanol using O2 as the oxidant at the low temperature of 50 degrees C and low pressure of 1 atm. It was found that Pd/Au ratio strongly affected the catalytical activity, and the highest conversion of about 35 % and turnover frequency of about 421 h-1 were achieved at 1:1 of Pd/Au atomic ratio. The synergistic effect in PdAu NPs was also discussed based on the comprehensive characterization results. The present approach may offer an alternative platform for future development of green-chemistry compatible bimetallic nanocatalysts. PMID- 30464977 TI - Synthesis of Zinc Oxide Nanostructures on Graphene/Glass Substrate via Electrochemical Deposition: Effects of Potassium Chloride and Hexamethylenetetramine as Supporting Reagents. AB - The effects of the supporting reagents hexamethylenetetramine (HMTA) and potassium chloride (KCl) mixed in zinc nitrate hexahydrate (Zn(NO3)2.6H2O) on the morphological, structural, and optical properties of the resulting ZnO nanostructures electrodeposited on graphene/glass substrates were investigated. The supporting reagent HMTA does not increase the density of nanorods, but it does remarkably improve the smoothness of the top edge surfaces and the hexagonal shape of the nanorods even at a low temperature of 75 degrees C. Hydroxyl (OH-) ions from the HMTA suppress the sidewall growth of non-polar planes and promote the growth of ZnO on the polar plane to produce vertically aligned nanorods along the c axis. By contrast, the highly electronegative chlorine (Cl-) ions from the supporting reagent KCl suppress the growth of ZnO on the polar plane and promote the growth on non-polar planes to produce vertical stacking nanowall structures. HMTA was found to be able to significantly improve the crystallinity of the grown ZnO structures, as indicated by the observation of much lower FWHM values and a higher intensity ratio of the emission in the UV region to the emission in the visible region. Equimolar mixtures of Zn(NO3)2.6H2O and the supporting reagents HMTA and KCl seem to provide the optimum ratio of concentrations for the growth of high-density, uniform ZnO nanostructures. The corresponding transmittances for such molar ranges are approximately 55-58 % (HMTA) and 63-70 % (KCl), which are acceptable for solar cell and optoelectronic devices. PMID- 30464978 TI - Novel Hybrid Ligands for Passivating PbS Colloidal Quantum Dots to Enhance the Performance of Solar Cells. AB - We developed novel hybrid ligands to passivate PbS colloidal quantum dots (CQDs), and two kinds of solar cells based on as-synthesized CQDs were fabricated to verify the passivation effects of the ligands. It was found that the ligands strongly affected the optical and electrical properties of CQDs, and the performances of solar cells were enhanced strongly. The optimized hybrid ligands, oleic amine/octyl-phosphine acid/CdCl2 improved power conversion efficiency (PCE) to much higher of 3.72 % for Schottky diode cell and 5.04 % for p-n junction cell. These results may be beneficial to design passivation strategy for low-cost and high-performance CQDs solar cells. PMID- 30464979 TI - One-Pot Microwave-Assisted Synthesis of Graphene/Layered Double Hydroxide (LDH) Nanohybrids. AB - A facile and rapid method to synthesize graphene/layered double hydroxide (LDH) nanohybrids by a microwave technique is demonstrated. The synthesis procedure involves hydrothermal crystallization of Zn-Al LDH at the same time in situ reduction of graphene oxide (GO) to graphene. The microstructure, composition, and morphology of the resulting graphene/LDH nanohybrids were characterized. The results confirmed the formation of nanohybrids and the reduction of graphene oxide. The growth mechanism of LDH and in situ reduction of GO were discussed. The LDH sheet growth was found to prevent the scrolling of graphene layers in resulting hybrids. The electrochemical properties exhibit superior performance for graphene/Zn-Al LDH hybrids over pristine graphene. The present approach may open a strategy in hybridizing graphene with multimetallic nano-oxides and hydroxides using microwave method. PMID- 30464980 TI - Capacitive Control of Spontaneously Induced Electrical Charge of Droplet by Electric Field-Assisted Pipetting. AB - The spontaneously generated electrical charge of a droplet dispensed from conventional pipetting is undesirable and unpredictable for most experiments that use pipetting. Hence, a method for controlling and removing the electrical charge needs to be developed. In this study, by using the electrode-deposited pipet tip (E-pipet tip), the charge-controlling system is newly developed and the electrical charge of a droplet is precisely controlled. The effect of electrolyte concentration and volume of the transferred solution to the electrical charge of a dispensed droplet is theoretically and experimentally investigated by using the equivalent capacitor model. Furthermore, a proof-of-concept example of the self alignment and self-assembly of sequentially dispensed multiple droplets is demonstrated as one of the potential applications. Given that the electrical charge of the various aqueous droplets can be precisely and simply controlled, the fabricated E-pipet tip can be broadly utilized not only as a general charge controlling platform of aqueous droplets but also as a powerful tool to explore fundamental scientific research regarding electrical charge of a droplet, such as the surface oscillation and evaporation of charged droplets. PMID- 30464981 TI - Three-Dimensional Hierarchical Nanostructured Cu/Ni-Co Coating Electrode for Hydrogen Evolution Reaction in Alkaline Media. AB - In this work, three-dimensional hierarchical nickel-cobalt alloy coating for hydrogen evolution cathode was fabricated by electrodeposition processes. The coatings' morphology evolves from sea cucumber-like nanostructure to caterpillar like one with the increase of cobalt content. A large amount of nanometric "steps," served as the active sites for hydrogen evolution reaction, were observed. According to Tafel polarization measurements, the exchange current density of the as-synthesized coating with hierarchical nanostructure was 21.9 times compared with that of flat nickel coating. In addition, the hierarchical coating also displayed good electrochemical stability from the galvanostatic test. PMID- 30464982 TI - Controlling the Diameter of Single-Walled Carbon Nanotubes by Improving the Dispersion of the Uniform Catalyst Nanoparticles on Substrate. AB - To have uniform nanoparticles individually dispersed on substrate before single walled carbon nanotubes (SWNTs) growth at high temperature is the key for controlling the diameter of the SWNTs. In this letter, a facile approach to control the diameter and distribution of the SWNTs by improving the dispersion of the uniform Fe/Mo nanoparticles on silicon wafers with silica layer chemically modified by 1,1,1,3,3,3-hexamethyldisilazane under different conditions is reported. It is found that the dispersion of the catalyst nanoparticles on Si wafer surface can be improved greatly from hydrophilic to hydrophobic, and the diameter and distribution of the SWNTs depend strongly on the dispersion of the catalyst on the substrate surface. Well dispersion of the catalyst results in relatively smaller diameter and narrower distribution of the SWNTs due to the decrease of aggregation and enhancement of dispersion of the catalyst nanoparticles before growth. It is also found that the diameter of the superlong aligned SWNTs is smaller with more narrow distribution than that of random nanotubes. PMID- 30464983 TI - Impact of Morphology of Conductive Agent and Anode Material on Lithium Storage Properties. AB - In this study, the impact of morphology of conductive agent and anode material (Fe3O4) on lithium storage properties was throughly investigated. Granular and belt-like Fe3O4 active materials were separately blended with two kinds of conductive agents (i.e., granular acetylene black and multi-walled carbon nanotube) as anodes in lithium-ion batteries (LIBs), respectively. It was found that the morphology of conductive agent is of utmost importance in determining LIBs storage properties. In contrast, not as the way we anticipated, the morphology of anode material merely plays a subordinate role in their electrochemical performances. Further, the morphology-matching principle of electrode materials was discussed so as to render their utilization more rational and effective in LIBs. PMID- 30464984 TI - Direct Synthesis of Co-doped Graphene on Dielectric Substrates Using Solid Carbon Sources. AB - Direct synthesis of high-quality doped graphene on dielectric substrates without transfer is highly desired for simplified device processing in electronic applications. However, graphene synthesis directly on substrates suitable for device applications, though highly demanded, remains unattainable and challenging. Here, a simple and transfer-free synthesis of high-quality doped graphene on the dielectric substrate has been developed using a thin Cu layer as the top catalyst and polycyclic aromatic hydrocarbons as both carbon precursors and doping sources. N-doped and N, F-co-doped graphene have been achieved using TPB and F16CuPc as solid carbon sources, respectively. The growth conditions were systematically optimized and the as-grown doped graphene were well characterized. The growth strategy provides a controllable transfer-free route for high-quality doped graphene synthesis, which will facilitate the practical applications of graphene. PMID- 30464986 TI - Effects Associated with Nanostructure Fabrication Using In Situ Liquid Cell TEM Technology. AB - We studied silicon, carbon, and SiC x nanostructures fabricated using liquid phase electron-beam-induced deposition technology in transmission electron microscopy systems. Nanodots obtained from fixed electron beam irradiation followed a universal size versus beam dose trend, with precursor concentrations from pure SiCl4 to 0 % SiCl4 in CH2Cl2, and electron beam intensity ranges of two orders of magnitude, showing good controllability of the deposition. Secondary electrons contributed to the determination of the lateral sizes of the nanostructures, while the primary beam appeared to have an effect in reducing the vertical growth rate. These results can be used to generate donut-shaped nanostructures. Using a scanning electron beam, line structures with both branched and unbranched morphologies were also obtained. The liquid-phase electron-beam-induced deposition technology is shown to be an effective tool for advanced nanostructured material generation. PMID- 30464985 TI - Highly Efficient Labeling of Human Lung Cancer Cells Using Cationic Poly-l-lysine Assisted Magnetic Iron Oxide Nanoparticles. AB - Cell labeling with magnetic iron oxide nanoparticles (IONPs) is increasingly a routine approach in the cell-based cancer treatment. However, cell labeling with magnetic IONPs and their leading effects on the biological properties of human lung carcinoma cells remain scarcely reported. Therefore, in the present study the magnetic gamma-Fe2O3 nanoparticles (MNPs) were firstly synthesized and surface-modified with cationic poly-l-lysine (PLL) to construct the PLL-MNPs, which were then used to magnetically label human A549 lung cancer cells. Cell viability and proliferation were evaluated with propidium iodide/fluorescein diacetate double staining and standard 3-(4,5-dimethylthiazol-2-diphenyl tetrazolium) bromide assay, and the cytoskeleton was immunocytochemically stained. The cell cycle of the PLL-MNP-labeled A549 lung cancer cells was analyzed using flow cytometry. Apoptotic cells were fluorescently analyzed with nuclear-specific staining after the PLL-MNP labeling. The results showed that the constructed PLL-MNPs efficiently magnetically labeled A549 lung cancer cells and that, at low concentrations, labeling did not affect cellular viability, proliferation capability, cell cycle, and apoptosis. Furthermore, the cytoskeleton in the treated cells was detected intact in comparison with the untreated counterparts. However, the results also showed that at high concentration (400 ug mL-1), the PLL-MNPs would slightly impair cell viability, proliferation, cell cycle, and apoptosis and disrupt the cytoskeleton in the treated A549 lung cancer cells. Therefore, the present results indicated that the PLL-MNPs at adequate concentrations can be efficiently used for labeling A549 lung cancer cells and could be considered as a feasible approach for magnetic targeted anti-cancer drug/gene delivery, targeted diagnosis, and therapy in lung cancer treatment. PMID- 30464987 TI - Observation of Resistive Switching Memory by Reducing Device Size in a New Cr/CrO x /TiO x /TiN Structure. AB - The resistive switching memory characteristics of 100 randomly measured devices were observed by reducing device size in a Cr/CrO x /TiO x /TiN structure for the first time. Transmission electron microscope image confirmed a via-hole size of 0.4 um. A 3-nm-thick amorphous TiO x with 4-nm-thick polycrystalline CrO x layer was observed. A small 0.4-um device shows reversible resistive switching at a current compliance of 300 uA as compared to other larger size devices (1-8 um) owing to reduction of leakage current through the TiO x layer. Good device-to device uniformity with a yield of >85 % has been clarified by weibull distribution owing to higher slope/shape factor. The switching mechanism is based on oxygen vacancy migration from the CrO x layer and filament formation/rupture in the TiO x layer. Long read pulse endurance of >105 cycles, good data retention of 6 h, and a program/erase speed of 1 us pulse width have been obtained. PMID- 30464988 TI - Recent Advances in Visible-Light-Driven Photoelectrochemical Water Splitting: Catalyst Nanostructures and Reaction Systems. AB - Photoelectrochemical (PEC) water splitting using solar energy has attracted great attention for generation of renewable hydrogen with less carbon footprint, while there are enormous challenges that still remain for improving solar energy water splitting efficiency, due to limited light harvesting, energy loss associated to fast recombination of photogenerated charge carriers, as well as electrode degradation. This overview focuses on the recent development about catalyst nanomaterials and nanostructures in different PEC water splitting systems. As photoanode, Au nanoparticle-decorated TiO2 nanowire electrodes exhibited enhanced photoactivity in both the UV and the visible regions due to surface plasmon resonance of Au and showed the largest photocurrent generation of up to 710 nm. Pt/CdS/CGSe electrodes were developed as photocathode. With the role of p-n heterojunction, the photoelectrode showed high stability and evolved hydrogen continuously for more than 10 days. Further, in the Z-scheme system (Bi2S3/TNA as photoanode and Pt/SiPVC as photocathode at the same time), a self-bias (open circuit voltage V oc = 0.766 V) was formed between two photoelectrodes, which could facilitate photogenerated charge transfers and enhance the photoelectrochemical performance, and which might provide new hints for PEC water splitting. Meanwhile, the existing problems and prospective solutions have also been reviewed. PMID- 30464989 TI - Room-Temperature Magnetism of Ceria Nanocubes by Inductively Transferring Electrons to Ce Atoms from Nearby Oxygen Vacancy. AB - Ceria (CeO2) nanocubes were synthesized by a hydrothermal method and weak ferromagnetism was observed in room temperature. After ultraviolet irradiation, the saturation magnetization was significantly enhanced from ~3.18 * 10-3 to ~1.89 * 10-2 emu g-1. This is due to the increase of oxygen vacancies in CeO2 structure which was confirmed by X-ray photoelectron spectra. The first-principle calculation with Vienna ab-initio simulation package was used to illustrate the enhanced ferromagnetism mechanism after calculating the density of states (DOSs) and partial density of states (PDOSs) of CeO2 without and with different oxygen vacancies. It was found that the increase of oxygen vacancies will enlarge the PDOSs of Ce 4f orbital and DOSs. Two electrons in one oxygen vacancy are respectively excited to 4f orbital of two Ce atoms neighboring the vacancy, making these electron spin directions on 4f orbitals of these two Ce atoms parallel. This superexchange interaction leads to the formation of ferromagnetism in CeO2 at room temperature. Our work indicates that ultraviolet irradiation is an effective method to enhance the magnetism of CeO2 nanocube, and the first principle calculation can understand well the enhanced magnetism. PMID- 30464990 TI - Hydrogen Gas Sensor Based on Nanocrystalline SnO2 Thin Film Grown on Bare Si Substrates. AB - In this paper, high-quality nanocrystalline SnO2 thin film was grown on bare Si (100) substrates by a sol-gel method. A metal-semiconductor-metal gas sensor was fabricated using nanocrystalline SnO2 thin film and palladium (Pd) metal. The contact between Pd and nanocrystalline SnO2 film is tunable. Ohmic barrier contact was formed without addition of glycerin, while Schottky contact formed by adding glycerin. Two kinds of sensor devices with Schottky contact were fabricated (Device 1: 8 h, 500 degrees C; Device 2: 10 h, 400 degrees C). The room temperature sensitivity for hydrogen (H2) was 120 and 95 % in 1000 ppm H2, and the low power consumption was 65 and 86 uW for two devices, respectively. At higher temperature of 125 degrees C, the sensitivity was increased to 195 and 160 %, respectively. The sensing measurements were repeatable at various temperatures (room temperature, 75, 125 degrees C) for over 50 min. It was found that Device 1 has better sensitivity than Device 2 due to its better crystallinity. These findings indicate that the sensors fabricated on bare Si by adding glycerin to the sol solution have strong ability to detect H2 gas under different concentrations and temperatures. PMID- 30464991 TI - Single-Crystalline InGaAs Nanowires for Room-Temperature High-Performance Near Infrared Photodetectors. AB - InGaAs is an important bandgap-variable ternary semiconductor which has wide applications in electronics and optoelectronics. In this work, single-crystal InGaAs nanowires were synthesized by a chemical vapor deposition method. Photoluminescence measurements indicate the InGaAs nanowires have strong light emission in near-infrared region. For the first time, photodetector based on as grown InGaAs nanowires was also constructed. It shows good light response over a broad spectral range in infrared region with responsivity of 6.5 * 103 A W-1 and external quantum efficiency of 5.04 * 105 %. This photodetector may have potential applications in integrated optoelectronic devices and systems. PMID- 30464992 TI - Peptide Functionalized Nanoplasmonic Sensor for Explosive Detection. AB - In this study, a nanobiosensor for detecting explosives was developed, in which the peptide was synthesized with trinitrotoluene (TNT)-specific sequence and immobilized on nanodevice by Au-S covalent linkage, and the nanocup arrays were fabricated by nanoimprint and deposited with Au nanoparticles to generate localized surface plasmon resonance (LSPR). The device was used to monitor slight change from specific binding of 2,4,6-TNT to the peptide. With high refractive index sensing of ~104 nm/RIU, the nanocup device can detect the binding of TNT at concentration as low as 3.12 * 10-7 mg mL-1 by optical transmission spectrum modulated by LSPR. The nanosensor is also able to distinguish TNT from analogs of 2,4-dinitrotoluene and 3-nitrotoluene in the mixture with great selectivity. The peptide-based nanosensor provides novel approaches to design versatile biosensor assays by LSPR for chemical molecules. PMID- 30464993 TI - Size-Dependent Gold Nanoparticle Interaction at Nano-Micro Interface Using Both Monolayer and Multilayer (Tissue-Like) Cell Models. AB - Gold nanoparticles (GNPs) are emerging as a novel tool to improve existing cancer therapeutics. GNPs are being used as radiation dose enhancers in radiation therapy as well as anticancer drugs carriers in chemotherapy. However, the success of GNP-based therapeutics depends on their ability to penetrate tumor tissue. GNPs of 20 and 50 nm diameters were used to elucidate the effects of size on the GNP interaction with tumor cells at monolayer and multilayer level. At monolayer cell level, smaller NPs had a lower uptake compared to larger NPs at monolayer cell level. However, the order was reversed at tissue-like multilayer level. The smaller NPs penetrated better compared to larger NPs in tissue-like materials. Based on our study using tissue-like materials, we can predict that the smaller NPs are better for future therapeutics due to their greater penetration in tumor tissue once leaving the leaky blood vessels. In this study, tissue-like multilayer cellular structures (MLCs) were grown to model the post vascular tumor environment. The MLCs exhibited a much more extensive extracellular matrix than monolayer cell cultures. The MLC model can be used to optimize the nano-micro interface at tissue level before moving into animal models. This would accelerate the use of NPs in future cancer therapeutics. PMID- 30464994 TI - A Versatile Method for Uniform Dispersion of Nanocarbons in Metal Matrix Based on Electrostatic Interactions. AB - Realizing the uniform dispersion of nanocarbons such as carbon nanotube and graphene in metals, is an essential prerequisite to fully exhibit their enhancement effect in mechanical, thermal, and electrical properties of metal matrix composites (MMCs). In this work, we propose an effective method to achieve uniform distribution of nanocarbons in various metal flakes through a slurry based method. It relies on the electrostatic interactions between the negatively charged nanocarbons and the positively charged metal flakes when mixed in slurry. For case study, flake metal powders (Al, Mg, Ti, Fe, and Cu) were positively charged in aqueous suspension by spontaneous ionization or cationic surface modification. While nanocarbons, given examples as carboxylic multi-walled carbon nanotubes, pristine single-walled carbon nanotube, and carbon nanotube-graphene oxide hybrid were negatively charged by the ionization of oxygen-containing functional groups or anionic surfactant. It was found that through the electrostatic interaction mechanism, all kinds of nanocarbons can be spontaneously and efficiently adsorbed onto the surface of various metal flakes. The development of such a versatile method would provide us great opportunities to fabricate advanced MMCs with appealing properties. PMID- 30464995 TI - Study of Cell Behaviors on Anodized TiO2 Nanotube Arrays with Coexisting Multi Size Diameters. AB - It has been revealed that the different morphologies of anodized TiO2 nanotubes, especially nanotube diameters, triggered different cell behaviors. However, the influence of TiO2 nanotubes with coexisting multi-size diameters on cell behaviors is seldom reported. In this work, coexisting four-diameter TiO2 nanotube samples, namely, one single substrate with the integration of four different nanotube diameters (60, 150, 250, and 350 nm), were prepared by repeated anodization. The boundaries between two different diameter regions show well-organized structure without obvious difference in height. The adhesion behaviors of MC3T3-E1 cells on the coexisting four-diameter TiO2 nanotube arrays were investigated. The results exhibit a significant difference of cell density between smaller diameters (60 and 150 nm) and larger diameters (250 and 350 nm) within 24 h incubation with the coexistence of different diameters, which is totally different from that on the single-diameter TiO2 nanotube arrays. The coexistence of four different diameters does not change greatly the cell morphologies compared with the single-diameter nanotubes. The findings in this work are expected to offer further understanding of the interaction between cells and materials. PMID- 30464996 TI - Investigation of Single-Wall MoS2 Monolayer Flakes Grown by Chemical Vapor Deposition. AB - Recently, two-dimensional monolayer molybdenum disulfide (MoS2), a transition metal dichalcogenide, has received considerable attention due to its direct bandgap, which does not exist in its bulk form, enabling applications in optoelectronics and also thanks to its enhanced catalytic activity which allows it to be used for energy harvesting. However, growth of controllable and high quality monolayers is still a matter of research and the parameters determining growth mechanism are not completely clear. In this work, chemical vapor deposition is utilized to grow monolayer MoS2 flakes while deposition duration and temperature effect have been systematically varied to develop a better understanding of the MoS2 film formation and the influence of these parameters on the quality of the monolayer flakes. Different from previous studies, SEM results show that single-layer MoS2 flakes do not necessarily grow flat on the surface, but rather they can stay erect and inclined at different angles on the surface, indicating possible gas-phase reactions allowing for monolayer film formation. We have also revealed that process duration influences the amount of MoO3/MoO2 within the film network. The homogeneity and the number of layers depend on the change in the desorption-adsorption of radicals together with sulfurization rates, and, inasmuch, a careful optimization of parameters is crucial. Therefore, distinct from the general trend of MoS2 monolayer formation, our films are rough and heterogeneous with monolayer MoS2 nanowalls. Despite this roughness and the heterogeneity, we observe a strong photoluminescence located around 675 nm. PMID- 30464997 TI - Bovine Serum Albumin-Conjugated Ferrimagnetic Iron Oxide Nanoparticles to Enhance the Biocompatibility and Magnetic Hyperthermia Performance. AB - Abstract: Magnetic hyperthermia is a fast emerging, non-invasive cancer treatment method which is used synergistically with the existing cancer therapeutics. We have attempted to address the current challenges in clinical magnetic hyperthermia-improved biocompatibility and enhanced heating characteristics, through a single combinatorial approach. Both superparamagnetic iron oxide nanoparticles (SPIONs) of size 10 nm and ferrimagnetic iron oxide nanoparticles (FIONs) of size 30 nm were synthesized by thermal decomposition method for comparison studies. Two different surface modifying agents, viz, Cetyl Trimethyl Ammonium Bromide and 3-Aminopropyltrimethoxysilane, were used to conjugate Bovine Serum Albumin (BSA) over the iron oxide nanoparticles via two different methods surface charge adsorption and covalent amide bonding, respectively. The preliminary haemolysis and cell viability experiments show that BSA conjugation mitigates the haemolytic effect of the iron oxide nanoparticles on erythrocytes and is non-cytotoxic to the healthy Baby Hamster Kidney cells. It was observed from the results that due to better colloidal stability, the SAR value of the BSA iron oxide nanoparticles is higher than the iron oxide nanoparticles without BSA, irrespective of the size of the iron oxide nanoparticles and method of conjugation. The BSA-FIONs seem to show improved biocompatibility, as the haemolytic index is less than 2 % and cell viability is up to 120 %, when normalized with the control. The SAR value of BSA-FIONs is 2300 W g-1 when compared to 1700 W g-1 of FIONs without BSA conjugation. Thus, we report here that BSA conjugation over FIONs (with a high saturation magnetization of 87 emu g 1) provide a single combinatorial approach to improve the biocompatibility and enhance the SAR value for magnetic hyperthermia, thus addressing both the current challenges of the same. Graphical Abstract: PMID- 30464998 TI - Plant Surfaces: Structures and Functions for Biomimetic Innovations. AB - An overview of plant surface structures and their evolution is presented. It combines surface chemistry and architecture with their functions and refers to possible biomimetic applications. Within some 3.5 billion years biological species evolved highly complex multifunctional surfaces for interacting with their environments: some 10 million living prototypes (i.e., estimated number of existing plants and animals) for engineers. The complexity of the hierarchical structures and their functionality in biological organisms surpasses all abiotic natural surfaces: even superhydrophobicity is restricted in nature to living organisms and was probably a key evolutionary step with the invasion of terrestrial habitats some 350-450 million years ago in plants and insects. Special attention should be paid to the fact that global environmental change implies a dramatic loss of species and with it the biological role models. Plants, the dominating group of organisms on our planet, are sessile organisms with large multifunctional surfaces and thus exhibit particular intriguing features. Superhydrophilicity and superhydrophobicity are focal points in this work. We estimate that superhydrophobic plant leaves (e.g., grasses) comprise in total an area of around 250 million km2, which is about 50% of the total surface of our planet. A survey of structures and functions based on own examinations of almost 20,000 species is provided, for further references we refer to Barthlott et al. (Philos. Trans. R. Soc. A 374: 20160191, 1). A basic difference exists between aquatic non-vascular and land-living vascular plants; the latter exhibit a particular intriguing surface chemistry and architecture. The diversity of features is described in detail according to their hierarchical structural order. The first underlying and essential feature is the polymer cuticle superimposed by epicuticular wax and the curvature of single cells up to complex multicellular structures. A descriptive terminology for this diversity is provided. Simplified, the functions of plant surface characteristics may be grouped into six categories: (1) mechanical properties, (2) influence on reflection and absorption of spectral radiation, (3) reduction of water loss or increase of water uptake, moisture harvesting, (4) adhesion and non-adhesion (lotus effect, insect trapping), (5) drag and turbulence increase, or (6) air retention under water for drag reduction or gas exchange (Salvinia effect). This list is far from complete. A short overview of the history of bionics and the impressive spectrum of existing and anticipated biomimetic applications are provided. The major challenge for engineers and materials scientists, the durability of the fragile nanocoatings, is also discussed. PMID- 30464999 TI - Structural changes of Zn(II)bleomycin complexes when bound to DNA hairpins containing the 5'-GT-3' and 5'-GC-3' binding sites studied through NMR spectroscopy. AB - Bleomycins are antitumor antibiotics that can chelate a metal center and cause site-specific DNA cleavage at 5'-Gpyrimidine-3' regions of DNA. These antibiotics are successful in the treatment of various cancers, but are known to cause pulmonary fibrosis to patients under bleomycin regimes. Substantial research has resulted in the development of over 300 bleomycin analogs, aiming to improve the therapeutic index of the drug. Previous studies have proposed that the lung toxicity caused by bleomycin is related to the C-terminal regions of these drugs, which have been shown to closely interact with DNA in metal-bleomycin-DNA complexes. Some of the research studying metallo-bleomycin-DNA interactions have suggested three different binding modes of the metal form of the drug to DNA, including total and/or partial intercalation, and minor groove binding. However, there is still lack of consensus regarding this matter, and solid conclusions on the subject have not yet been established. Previously we investigated the diverse levels of disruption caused to DNA hairpins containing 5'-GC-3' and 5'-GT-3' binding sites, which are consequence of the binding of bleomycins with different C-termini. The results of these investigation indicate that both the DNA-binding site and the bleomycin C-termini have an impact on the final conformations of drug and target. The present study focuses on the structural alterations exhibited by Zn(II)bleomycin-A2, -B2, -A5 and Zn(II)peplomycin upon binding to DNA hairpins containing 5'-GC-3' and 5'-GT-3' binding sites. Evidence that each Zn(II)bleomycin is structurally affected depending on both its C-terminus and the DNA-binding site present in the hairpin is provided. PMID- 30465000 TI - Prevalence and Reasons of Self-Medication in Pregnant Women: A Systematic Review and Meta-Analysis. AB - Background: Given the importance of having valid information about the prevalence and reasons of self-medication among pregnant women for preventing self medication during this period, this study aimed to systematically review and perform a meta-analysis on the prevalence and reasons of self-medication during pregnancy. Methods: This systematic review and meta-analysis was conducted in 2018 to estimate the overall self-medication prevalence based on the database sources PubMed, Scopus, Google Scholar, MagIran, IranMedex and SID. Required data were collected using keywords: medication, self-medication, over-the-counter, non prescription, prevalence, etiology, and occurrence and pregnant. Descriptive and cross-sectional studies in English and Persian languages were included. There was no time limitation for search. R software was applied for meta-analysis. Random effects model was applied to estimate the self-medication prevalence with 95% confidence interval. Q statistics and I2 were used to measure the heterogeneity. Results: Out of 490 retrieved articles, finally 13 studies were included in meta analysis, 6 studies of which reported the cause of self-medication. The overall estimated prevalence of self-medication based on the random effect model was 32% (95% CI, 22% - 44%). The most important reasons of self-medication were previous experience of the disease. The most important group of disease in which patients self-medicated was anemia. Also, the most important group of medication was herbal. Conclusion: The results of this study showed that the prevalence of self medication among pregnant women was relatively high and required effective interventions to reduce and prevent self-medication among this group. Providing required information and raising awareness about complications resulting from self-medication, in particular herbal medicines and dietary supplements, should be taken into account. PMID- 30465001 TI - Effect of Group Counseling on Parents' Self-Efficacy, Knowledge, Attitude, and Communication Practice in Preventing Sexual Abuse of Children Aged 2-6 Years: A Randomized Controlled Clinical Trial. AB - Background: The present study aimed to examine the effectiveness of group counseling on parents' self-efficacy, knowledge, attitude, and communication practice in preventing sexual abuse of children aged 2-6 years. Methods: A randomized controlled clinical trial was carried out on 62 parents in Karaj (Iran) during the period of March-November 2016. Three kindergartens were randomly selected using the cluster sampling technique. Block randomization was used to assign the participants into two groups (N=31 in each group), namely the intervention group and the control group. Data collection included demographic characteristics, a "Parental Knowledge, Attitude, and Practice" questionnaire on the prevention of child sexual abuse, and the Farrell and Walsh self-efficacy pretest-posttest. The participants in the intervention group attended a counseling program of a 90-minute session per week, for 3 consecutive weeks. The participants were evaluated before, immediately after, and one month after the intervention. All statistical analyses were performed using the SPSS software (version 19.0). Data were analyzed using the Chi-square, independent t-test, Mann Whitney, and Friedman tests. P<0.05 was considered statistically significant. Results: There was no significant difference between the intervention and control groups in terms of the mean knowledge (P=0.50), attitude (P=0.48), practice (P=0.93), and self-efficacy (P=0.43) before the intervention. However, a significant difference was observed between the groups immediately after (P<0.001) and one month after (P<0.001) the intervention. Conclusion: Counseling is an effective tool in increasing the self-efficacy of parents on child sexual abuse. The awareness of child sexual abuse and its prevention should be raised in the society through effective training programs. Trial Registration Number: IRCT2017051227557N4. PMID- 30465002 TI - Effect of Post-Hospital Discharge Follow-up on Health Status in Patients with Burn Injuries: A Randomized Clinical Trial. AB - Background: Patients with burn injuries still face various burn-related challenges after being discharged from the hospital. Hence, a follow-up program for such patients is essential. The present study aimed to evaluate the health status of burn victims after 1.5 months follow-up. Methods: The present randomized clinical trial was of a pretest-posttest design, carried out in Kermanshah (Iran) from July 2016 to September 2017. A total of 117 participants were recruited out of which 86 were included in the analysis. The participants were randomly assigned into two groups, namely the intervention group (N=42) and the control group (N=44). All participants were evaluated both at the time of hospital discharge and at 1.5 months post-discharge. The follow-up plan for the intervention group included home visits, telenursing, and referral to specialists or health education centers. To evaluate the physical and psychological status of the participants, five different instruments were used; namely the Burn Specific Health Scale-Brief (BSHS-B), the General Health Questionnaire-28 (GHQ-28), the Brief Pain Inventory (BPI), the Vancouver Scar Scale (VSS), and the Visual Analogue Scale (VAS). All statistical analyses were performed using the SPSS software (version 17.0). Data were analyzed using the Chi-square test, independent t-test, and paired t-test. P<0.05 was considered statistically significant. Results: The mean score of the BSHS-B questionnaire at both the time of discharge and 1.5 months post-discharge follow-up for the control and intervention groups was 61.22+/-19.07, 57.14+/-18.92; 83.70+/-24.73 and 105.16+/ 29.17, respectively. There was a significant difference between the groups at 1.5 months post-discharge follow-up (P<0.001). At 1.5 months, the VSS score was 5.16+/-1.68 and 6.77+/-3.46 for the intervention and control groups, respectively. The GHQ-28 score was 28.69+/-12.39 and 40.79+/-16.20 for the intervention and control groups, respectively. The VAS and BPI scores of the control group were 5.56+/-3.11 and 21.93+/-29.25, respectively. For the intervention group, these scores were 4.85+/-3.49 and 15.61+/-27.47, respectively. There was a significant difference between the groups as to the GHQ and VSS scores (P<0.05). However, no significant difference was noted in the BPI and VAS scores (P<0.05). Conclusion: Health status, psychological status, and scar management were improved due to post-discharge follow-up. However, burn patients required continued care for pain, psychological health, and itching problems. Trial Registration Number: IRCT2016110630712N. PMID- 30465003 TI - The Relationship between Fear-Avoidance Beliefs and Pain in Pregnant Women with Pelvic Girdle Pain: A Cross-Sectional Study. AB - Background: Pelvic Girdle Pain (PGP) is one of the most common problems during pregnancy. Psychological variables including attitude, belief, cognition, and fear have more effects on risk factors for back pain, compared to biomechanical factors. Moreover, fear and anxiety may be provoked by the prospect of pain, which is associated with higher levels of disability, compared to pain itself. Therefore, this study aimed to investigate the relationship between fear avoidance beliefs and pain in pregnant women with pelvic girdle pain. Methods: This descriptive cross-sectional study was conducted on 148 pregnant women with PGP, who referred to the healthcare centers affiliated to Shahid Beheshti University of Me-dical Sciences in Tehran, Iran from September to December 2017. The samples were selected by the multi-stage method. Data collection tools included a demographic questionnaire, Pelvic Girdle Questionnaire (PGQ) and Fear Avoidance Beliefs Questionnaire (FABQ). Data analysis was performed in SPSS version 22, using descriptive statistics, ANOVA, t-test and multiple regression. A P-value less than 0.05 was considered significant. Results: The subjects' mean age and gestational age were 29.35+/-5.89 years and 32.78+/-5.13 weeks, respectively. Mean and SD of Fear-Avoidance Beliefs (FAB) toward PGQ was 41.27+/ 13.67 (from 66). In addition, PGQ was moderate in the majority of participants [84 (56.75%)]. Results of one-way ANOVA demonstrated a significant relationship between the mean total score and the score of dimensions of physical and occupational activities of FAB in different severities of PGQ (P<0.001). Conclusion: The results of this study indicated that fear-avoidance and catastrophic beliefs, in women with PGP can be predicted. According to the results of the study, FAB varied with the severity of pain. In addition, increased pain intensity was associated with elevated score of FAB. PMID- 30465004 TI - Understanding Non-Adherence to Treatment in Hypertension: A Qualitative Study. AB - Background: Hypertension is a major public health issue. With regard to the current trend, it has been estimated that one out of three people will be suffering from hypertension by 2025. This study was designed to provide a better insight into the adherence to treatment and its underlying reasons. Methods: A directed qualitative content analysis approach was conducted in collaboration with 35 hypertensive patients and 3 cardiologists in the form of in-depth interviews and focused group discussions from October 2015 to February 2016. Sampling was carried out from patients with hypertension using purposeful and heterogeneous method. Some of the PRECEDE model structures were applied as the conceptual framework. Results: The reasons affecting adherence to hypertension treatment were analyzed in three general categories of predisposing, enabling and reinforcing factors based on the model structures. Factors such as "knowledge", "belief and attitude", "mental-personality traits", "culture and lifestyle" were classified as the predisposing factors category. "Access to health service" and "access to facilities in the workplace, home and society" were fit in the enabling factor category. The reinforcing factors category addresses "individuals' internal incentives" and "family and health service providers' support". Conclusion: Several reasons account for non-adherence to treatment in hypertensive patients. Diversity of these reasons is an indication that design and implementation of different kinds of interventions are required in order to increase the patients' awareness, empower them and encourage self-efficacy. PMID- 30465005 TI - The Effect of Coping Skills Training on Depression, Anxiety, Stress, and Self Efficacy in Adolescents with Diabetes: A Randomized Controlled Trial. AB - Background: Diabetes patients are at risk of psychosocial problems. Some interventions might decrease these problems. This study aimed to evaluate the effect of coping skills training on depression, anxiety, stress, and self efficacy of adolescents with type I diabetes. Methods: This randomized controlled trial with pre- and post-test design was performed in the diabetes clinic in Shiraz from June to November 2015. This study was conducted on 100 adolescents with type 1 diabetes who were randomly divided into an intervention (receiving coping skills training in groups for eight sessions) and a control group (usual care). Depression, Anxiety, and Stress Scales (42-items, scores=0-42) and General Self-Efficacy questionnaire (17-items, scores=17-85) were used. The variables were measured at baseline and two months after starting the intervention. Data were analyzed using SPSS, version 16 through Chi-square test, independent t-test, and paired t-test. P<0.05 was significant. Results: After the intervention, the mean scores of depression, anxiety and stress in the intervention group were 5.41+/-4.58, 6.44+/-7.01, and 7.46+/-7.01, and in the control groups they were 19.73+/-11.80, 18.28+/-10.51, 21.10+/-10.94, respectively. Moreover, after the intervention, the mean scores of self-efficacy were 70.82+/-10.84, and 50.13+/ 15.42 in the intervention and control groups, respectively. The results showed differences between the two groups regarding depression, anxiety, stress, and self-efficacy after starting the intervention (P<0.001). Conclusion: As coping skills training reduced depression, anxiety, and stress and improved the patients' self-efficacy, the use of this intervention could be a part of community-based nursing practice for adolescents with diabetes and more research for improving evidence-based practice in this regard are warranted. - Trial Registration Number: IRCT201505011369N4. PMID- 30465006 TI - Development and Assessment of Respectful Maternity Care Questionnaire in Iran. AB - Background: Disrespectful and undignified care during childbirth has been documented in health facilities all over the world. The purpose of this study was to develop and pretest a new instrument, the Quality of Respectful Maternity Care Questionnaire in Iran (QRMCQI), with an ensured validity and reliability to evaluate and measure Respectful Maternity Care (RMC) in three sections of labor, delivery and post-partum. Methods: This is a study with mixed sequential exploratory design. Here, the questionnaire design is a part of descriptive survey study and consists of five phases implemented in one year. The phases include item or questions generation, face validation, content validity assessment, confirmatory factor analysis and reliability assurance of the questionnaire. The participants were selected from the mothers referring to health care centers affiliated to Iran University of Medical Sciences in five cities after recruitment from hospital for after-care services of delivery. Results: The primary questionnaire was developed, face validity was performed by experts and their comments were implemented. The content validity index (CVI), Kappa index and Content Validity Ratio (CVR) were calculated for each item and they were satisfactory in an acceptable range. Confirmatory factor analysis (CFA) showed good fit of the hypothesized model for 453 participants in the interview. Testing showed an acceptable internal consistency and reliability by calculating Cronbach's alpha coefficient for questions in labor (0.86), in delivery (0.85), and in postpartum care (0.78). Conclusion: We have developed a new instrument as the 59-item QRMCQI for evaluating respectful maternity care in Iran through a rigorous process of item generation and validity-reliability assessment besides confirmatory factor analysis that were in an acceptable range and can be used as a reliable instrument for RMC in Iran. PMID- 30465007 TI - A Rare Cause of Dysphagia and Cough: Bronchoesophageal Fistula from Silicosis. AB - Dysphagia and cough in an older male smoker raise concern for malignancy. However, a history of environmental exposures led to a much more interesting diagnosis in this case of pneumoconiosis due to silicosis. Silicosis is an uncommon pulmonary disease with rare associated gastrointestinal symptoms. We report a bronchoesophageal fistula resulting from silicosis causing dysphagia and cough. This is the first report of using endoscopic stenting to manage an esophageal fistula from silicosis. This case highlights how common symptoms of cough and dysphagia can masquerade as a pulmonary or oropharyngeal problem, when they are actually gastrointestinal manifestations of a rare disease. PMID- 30465008 TI - Autoimmune Enteropathy in an Ulcerative Colitis Patient. AB - Autoimmune enteropathy is a rare but severe disorder with significant immune mediated changes. We present a 54-year-old woman with history of refractory ulcerative colitis status post total colectomy with end ileostomy who presented 1 month after her surgery with high ostomy output of 4 L/d. After a negative workup, ileoscopy with biopsies showed severe chronic active ileitis. Enteroscopy revealed diffuse chronic enteritis concerning for autoimmune enteropathy. She was started on budesonide and intravenous solumedrol, but her ostomy output remained high. She was then started on cyclosporine and later tacrolimus with significant clinical improvement and normalization of ostomy output on tacrolimus. PMID- 30465009 TI - Gastric Metastasis of an Ovarian Granulosa Cell Tumor Diagnosed in a Patient with Worsening Reflux. PMID- 30465010 TI - Changes in Waist Circumference in HIV-Infected Individuals Initiating a Raltegravir or Protease Inhibitor Regimen: Effects of Sex and Race. AB - Background: This study investigates the association of clinical and demographic predictors with abdominal fat gain, measured using waist circumference (WC) and self-reported abdominal size. Methods: We analyzed data from ACTG A5257, a clinical trial that randomized treatment-naive HIV-infected participants to 1 of 3 antiretroviral regimens: raltegravir (RAL) or the protease inhibitors (PIs) atazanavir/ritonavir (ATV/r) or darunavir/ritonavir (DRV/r), each in combination with tenofovir disoproxil fumarate/emtricitabine. Associations of treatment and baseline/demographic characteristics with 96-week WC change were assessed using repeated-measures models. Ordinal logistic regression was used to examine the associations of predictors with week 96 self-reported abdominal changes. Results: The study population (n = 1809) was 76.0% male and predominantly black non Hispanic (41.9%) and white non-Hispanic (34.1%). Mean baseline WC was 90.6 cm, with an average 96-week increase of 3.4 cm. WC increases were higher in the RAL arm compared with DRV/r (P = .0130). Females experienced greater increases in WC on RAL vs ATV/r than males (P = .0065). Similarly, a larger difference in WC change was found for RAL vs DRV/r for black vs nonblack individuals (P = .0043). A separate multivariable model found that in addition to the treatment regimen, higher baseline viral load and lower CD4+ were also associated with WC increases. Conclusions: With antiretroviral therapy initiation, higher WC increases in the RAL arm compared with PIs were more pronounced in female and black participants, and a more advanced baseline HIV disease state was a strong predictor of larger abdominal increases. Understanding factors predisposing individuals to abdominal fat gain could inform health management after therapy initiation. PMID- 30465011 TI - Unusually High Incidences of Pseudomonas Bacteremias Within Topical Polymyxin Based Decolonization Studies of Mechanically Ventilated Patients: Benchmarking the Literature. AB - Background: Topical polymyxin (PM)-based regimens to decolonize patients receiving prolonged mechanical ventilation (MV) have been widely studied. However, paradoxical bacteremia incidences remain unexplained. Methods: The literature was searched for studies of topical PM-based regimens used to decontaminate MV patients reporting incidences of overall and Pseudomonas bacteremia data. In addition, observational groups without any intervention and trials of various interventions other than topical PM (non-PM studies) served to provide external benchmarks and additional points of reference, respectively. The bacteremia incidences were extracted from the control and intervention (component) groups of these studies and compared with metaregression using generalized estimating equation methods. Results: The summary odds ratio derived from studies of topical PM-based interventions against overall bacteremia was 0.60 (95% confidence interval [CI], 0.53-0.69). Benchmark incidences per 100 MV patients for overall (mean, 8.9%; 95% CI, 6.9% to 10.9%) and Pseudomonas (mean, 0.7%; 95% CI, 0.5% to 1.1%) bacteremia were derived from 16 observational studies. By contrast, among 17 studies of topical PM, the mean incidences among control groups for overall (mean, 15.3%; 95% CI, 11.5% to 20.3%) and Pseudomonas (mean, 1.6%; 95% CI, 0.9% to 3.1%) bacteremia were both higher, whereas these incidences in the intervention groups for both topical PM and non-PM studies were in each case more similar to the respective benchmarks. These paradoxical incidences cannot readily be explained in metaregression models. Conclusions: Paradoxically, despite an apparent prevention effect of topical PM-based methods against bacteremia overall, the incidences of Pseudomonas bacteremia within the component groups of these studies are unusually high vs literature-derived benchmarks. PMID- 30465012 TI - Clinical Validation of a Commercial LAMP Test for Ruling out Malaria in Returning Travelers: A Prospective Diagnostic Trial. AB - The mainstay of malaria diagnosis relies on rapid diagnostic tests (RDTs) and microscopy, both of which lack analytical sensitivity. This leads to repeat testing to rule out malaria. A prospective diagnostic trial of the Meridian illumigene Malaria assay (loop-mediated isothermal amplification [LAMP]) was conducted comparing it with reference microscopy and RDTs (BinaxNOW Malaria) in returning travelers between June 2017 and January 2018. Returning travelers with signs and symptoms of malaria were enrolled in the study. RDTs, microscopy, and LAMP assays were performed simultaneously. A total of 298 patients (50.7% male; mean age, 32.5 years) were enrolled, most visiting friends and relatives (43.3%), presenting with fever (88.9%), not taking prophylaxis (82.9%), and treated as outpatients (84.1%). In the prospective arm (n = 348), LAMP had a sensitivity of 98.1% (95% confidence interval [CI], 90.0%-100%) and a specificity of 97.6% (95% CI, 95.2%-99.1%) vs microscopy. After discrepant resolution with real-time polymerase chain reaction, LAMP had a sensitivity of 100% (95% CI, 93.7%-100%) and a specificity of 100% (95% CI, 98.7%-100%) vs microscopy. After discrepant resolution, RDTs had a sensitivity of 83.3% (95% CI, 58.6%-96.4%) and a specificity of 96.2% (95% CI, 93.2%-98.1%) vs microscopy. When including retrospective specimens (n = 377), LAMP had a sensitivity of 98.8% (95% CI, 93.2% 100%) and a specificity of 97.6% (95% CI, 95.2%-99.1%) vs microscopy, and after discrepant resolution of this set, LAMP had a sensitivity of 100% (95% CI, 95.8% 100%) and a specificity of 100% (95% CI, 98.7%-100%). A cost-benefit analysis of reagents and labor suggests savings of up to USD$13 per specimen using a novel algorithm with LAMP screening. PMID- 30465013 TI - Potentially Serious Drug Interactions Resulting From the Pretravel Health Encounter. AB - Travelers seen for pretravel health encounters are frequently prescribed new travel-related medications, which may interact with their previously prescribed medications. In a cohort of 76 324 travelers seen at 23 US clinics, we found that 2650 (3.5%) travelers were prescribed travel-related medications with potential for serious drug interactions. PMID- 30465015 TI - When the Perpetual Patient becomes the Doctor: Dr. Paul Sax Interviews Dr. Eric Winer. PMID- 30465016 TI - Natalizumab may control immune checkpoint inhibitor-induced limbic encephalitis. PMID- 30465014 TI - Patterns of Co-occurring Comorbidities in People Living With HIV. AB - Background: The aims of this study were to identify common patterns of comorbidities observed in people living with HIV (PLWH), using a data-driven approach, and evaluate associations between patterns identified. Methods: A wide range of comorbidities were assessed in PLWH participating in 2 independent cohorts (POPPY: UK/Ireland; AGEhIV: Netherlands). The presence/absence of each comorbidity was determined using a mix of self-reported medical history, concomitant medications, health care resource use, and laboratory parameters. Principal component analysis (PCA) based on Somers' D statistic was applied to identify patterns of comorbidities. Results: PCA identified 6 patterns among the 1073 POPPY PLWH (85.2% male; median age [interquartile range {IQR}], 52 [47-59] years): cardiovascular diseases (CVDs), sexually transmitted diseases (STDs), mental health problems, cancers, metabolic disorders, chest/other infections. The CVDs pattern was positively associated with cancer (r = .32), metabolic disorder (r = .38), mental health (r = .16), and chest/other infection (r = .17) patterns (all P < .001). The mental health pattern was correlated with all the other patterns (in particular cancers: r = .20; chest/other infections: r = .27; both P < .001). In the 598 AGEhIV PLWH (87.6% male; median age [IQR], 53 [48-59] years), 6 patterns were identified: CVDs, chest/liver, HIV/AIDS events, mental health/neurological problems, STDs, and general health. The general health pattern was correlated with all the other patterns (in particular CVDs: r = .14; chest/liver: r = .15; HIV/AIDS events: r = .31; all P < .001), except STDs (r = .02; P = .64). Conclusions: Comorbidities in PLWH tend to occur in nonrandom patterns, reflecting known pathological mechanisms and shared risk factors, but also suggesting potential previously unknown mechanisms. Their identification may assist in adequately addressing the pathophysiology of increasingly prevalent multimorbidity in PLWH. PMID- 30465017 TI - A young man with numbness in arms and legs: From the National Multiple Sclerosis Society Case Conference Proceedings. PMID- 30465018 TI - Diagnostic and treatment challenges, a new section in N2. PMID- 30465019 TI - Bio-inspired imager improves sensitivity in near-infrared fluorescence image guided surgery. AB - Image-guided surgery can enhance cancer treatment by decreasing, and ideally eliminating, positive tumor margins and iatrogenic damage to healthy tissue. Current state-of-the-art near-infrared fluorescence imaging systems are bulky and costly, lack sensitivity under surgical illumination, and lack co-registration accuracy between multimodal images. As a result, an overwhelming majority of physicians still rely on their unaided eyes and palpation as the primary sensing modalities for distinguishing cancerous from healthy tissue. Here we introduce an innovative design, comprising an artificial multispectral sensor inspired by the Morpho butterfly's compound eye, which can significantly improve image-guided surgery. By monolithically integrating spectral tapetal filters with photodetectors, we have realized a single-chip multispectral imager with 1000 * higher sensitivity and 7 * better spatial co-registration accuracy compared to clinical imaging systems in current use. Preclinical and clinical data demonstrate that this technology seamlessly integrates into the surgical workflow while providing surgeons with real-time information on the location of cancerous tissue and sentinel lymph nodes. Due to its low manufacturing cost, our bio inspired sensor will provide resource-limited hospitals with much-needed technology to enable more accurate value-based health care. PMID- 30465020 TI - NHE8 Deficiency Promotes Colitis-Associated Cancer in Mice via Expansion of Lgr5 Expressing Cells. AB - Background & Aims: Lgr5 overexpression has been detected in colorectal cancers (CRCs), including some cases of colitis-associated CRCs. In colitis-associated CRCs, chronic inflammation is a contributing factor in carcinogenesis. We recently reported that intestinal Na+/H+ exchanger isoform 8 (NHE8) plays an important role in intestinal mucosal protection and that loss of NHE8 expression results in an ulcerative colitis-like condition. Therefore, we hypothesized that NHE8 may be involved in the development of intestinal tumors. Methods: We assessed NHE8 expression in human CRCs by immunohistochemistry and studied tumor burden in NHE8 knockout (KO) mice using an azoxymethane/dextran sodium sulfate colon cancer model. We also evaluated cell proliferation in HT29NHE8KO cells and assessed tumor growth in NOD scid gamma (NSG) mice xenografted with HT29NHE8KO cells. To verify if a relationship exists between Lgr5 and NHE8 expression, we analyzed Lgr5 expression in NHE8KO mice by polymerase chain reaction and in situ hybridization. Lgr5 expression and cell proliferation in the absence of NHE8 were confirmed in colonic organoid cultures. The expression of beta-catenin and c-Myc also were analyzed to evaluate Wnt/beta-catenin activation. Results: NHE8 was undetectable in human CRC tissues. Although only 9% of NHE8 wild-type mice showed tumorigenesis in the azoxymethane/dextran sodium sulfate colon cancer model, almost 10 times more NHE8KO mice (89%) developed tumors. In the absence of NHE8, a higher colony formation unit was discovered in HT29NHE8KO cells. In NSG mice, larger tumors developed at the site where HT29NHE8KO cells were injected compared with HT29NHE8 wild type cells. Furthermore, NHE8 deficiency resulted in increased Lgr5 expression in the colon, in HT29-derived tumors, and in colonoids. The absence of NHE8 also increased Wnt/beta-catenin activation. Conclusions: NHE8 might be an intrinsic factor that regulates Wnt/beta-catenin in the intestine. PMID- 30465021 TI - Network analysis of the NetHealth data: exploring co-evolution of individuals' social network positions and physical activities. AB - Understanding the relationship between individuals' social networks and health could help devise public health interventions for reducing incidence of unhealthy behaviors or increasing prevalence of healthy ones. In this context, we explore the co-evolution of individuals' social network positions and physical activities. We are able to do so because the NetHealth study at the University of Notre Dame has generated both high-resolution longitudinal social network (e.g., SMS) data and high-resolution longitudinal health-related behavioral (e.g., Fitbit physical activity) data. We examine trait differences between (i) users whose social network positions (i.e., centralities) change over time versus those whose centralities remain stable, (ii) users whose Fitbit physical activities change over time versus those whose physical activities remain stable, and (iii) users whose centralities and their physical activities co-evolve, i.e., correlate with each other over time. We find that centralities of a majority of all nodes change with time. These users do not show any trait difference compared to time stable users. However, if out of all users whose centralities change with time we focus on those whose physical activities also change with time, then the resulting users are more likely to be introverted than time-stable users. Moreover, users whose centralities and physical activities both change with time and whose evolving centralities are significantly correlated (i.e., co-evolve) with evolving physical activities are more likely to be introverted as well as anxious compared to those users who are time-stable and do not have a co evolution relationship. Our network analysis framework reveals several links between individuals' social network structure, health-related behaviors, and the other (e.g., personality) traits. In the future, our study could lead to development of a predictive model of social network structure from behavioral/trait information and vice versa. PMID- 30465022 TI - Statistical methods for constructing disease comorbidity networks from longitudinal inpatient data. AB - Tools from network science can be utilized to study relations between diseases. Different studies focus on different types of inter-disease linkages. One of them is the comorbidity patterns derived from large-scale longitudinal data of hospital discharge records. Researchers seek to describe comorbidity relations as a network to characterize pathways of disease progressions and to predict future risks. The first step in such studies is the construction of the network itself, which subsequent analyses rest upon. There are different ways to build such a network. In this paper, we provide an overview of several existing statistical approaches in network science applicable to weighted directed networks. We discuss the differences between the null models that these models assume and their applications. We apply these methods to the inpatient data of approximately one million people, spanning approximately 17 years, pertaining to the Montreal Census Metropolitan Area. We discuss the differences in the structure of the networks built by different methods, and different features of the comorbidity relations that they extract. We also present several example applications of these methods. PMID- 30465023 TI - The construction of Chinese microblog gender-specific thesauruses and user gender classification. AB - Based on the statistical features, short text messages published by different gender users are different in terms of the words and semantics used. In this paper, two new features are constructed after constructing a gender-specific thesaurus. A new classification model is constructed by combining the traditional statistical features and the improved text implicitness feature. The experimental evaluation performed on the Sina Weibo dataset demonstrated the effectiveness of gender-specific thesaurus-based features, and the improved text implicitness feature improved the accuracy of gender classification to 84.7%. PMID- 30465024 TI - The Role of Social Support vs. Modeling on Adolescents' Diet and Physical Activity: Findings from a School-based Weight Management Trial. AB - Objective: Social influences play an important role in shaping adolescents' dietary and physical activity behaviors. We examined the role of perceived modeling and perceived social support from family and friends on diet and physical activity behaviors among overweight and obese adolescents participating in a weight management trial. Methods: Six high schools were randomized to a school-nurse delivered behavioral weight management intervention or an information attention-control. Data on perceived support and modeling of healthy eating and physical activity from family and friends and dietary and physical activity behaviors were obtained from participants (N=82) at baseline and 2- and 6-months follow-up. Results: Linear mixed models were used to examine associations between social factors at baseline and diet and physical behaviors at 6 months. Friend support was correlated with increased fruit and vegetable consumption (0.4 servings/day) and decreased added sugar intake (-14.2 grams/day) (p's<0.05). Family support for physical activity, friend support for physical activity, and family modeling of physical activity were associated with increased number of days/week active for >= 60 minutes/day (0.7 days/week; 0.6 days/week; and 0.4 days/week, respectively, p's<0.05). Conclusions: Among overweight and obese high school adolescents, support from family and friends was associated with a greater number of improvements in diet and physical activity at follow-up than modeling. Strategies to solicit support may maximize efficacy of adolescent obesity intervention efforts. PMID- 30465025 TI - Graphene Quantum Dots Potently Block Copper-Mediated Oxidative DNA Damage: Implications for Cancer Intervention. AB - Our early work suggested that graphene quantum dots (GQDs) block Cu(II)/Cu(I) redox cycle in biological systems. Here we report that GQDs could also potently protect against copper redox-mediated oxidative DNA damage. Using Cu(II)/hydrogen peroxide, Cu(II)/hydroquinone, and Cu(II)/ascorbic acid as three biologically relevant systems for inducing oxidative DNA damage, we demonstrated that GQDs protected against the above system-induced DNA strand breaks in phix-174 plasmid DNA in a concentration-dependent manner. Notably, a significant protection was observed with GQDs at 1 MUg/ml, and a nearly complete protection was shown with 10 and 100 MUg/ml of GQDs. Using electron paramagnetic resonance (EPR) spectrometry in conjunction with alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN)-spin trapping, we showed that the above three systems generated hydroxyl radicals, as evidenced by the formation of a POBN-CH3 radical adduct in the presence of 0.5 M dimethyl sulfoxide (DMSO). Consistent with the protective effects of GQDs on DNA damage, the hydroxyl radical formation was markedly reduced in the presence of GQDs in a concentration dependent manner. A nearly complete blockage of the hydroxyl radical generation was seen with GQDs at 10 and 100 MUg/ml. Taken together, our results showed that GQDs potently protected against oxidative DNA damage. Considering the critical role of copper in cancer development, our findings might have important implications for cancer intervention with GQD-based nanotech modality. PMID- 30465026 TI - Mediators of the Effect of Childhood Socioeconomic Status on Late Midlife Cognitive Abilities: A Four Decade Longitudinal Study. AB - Background and Objectives: Childhood socioeconomic status (cSES) is found to predict later-life cognitive abilities, yet the mechanisms underlying these associations remain unclear. The objective of this longitudinal study was to examine the direct and indirect paths through which cSES influences late midlife cognitive outcomes. Research Design and Methods: Participants were 1,009 male twins in the Vietnam Era Twin Study of Aging (VETSA). At mean ages 20 and 62, participants completed a standardized test for general cognitive ability (GCA). The age 62 cognitive assessment also included in-person tests of processing speed, episodic memory, abstract reasoning, working memory, verbal fluency, visual-spatial ability, and executive functions. At mean age 56, participants were interviewed regarding their own and their parents' education and occupation, and completed questionnaires about cognitive leisure activities and sociodemographic information. Multiple mediation analyses were conducted to examine the direct path effects and indirect path effects of cSES through age 20 GCA, adult SES, and cognitive leisure activities on seven cognitive outcomes at age 62, adjusting for age, ethnicity, and non-independence of observations. Results: Total (direct plus indirect) effects were significant for all measures with the exception of executive functions. Men from lower cSES backgrounds had poorer cognitive functioning in late midlife. The direct effect of cSES was partially mediated for abstract reasoning, and was fully mediated for the remaining six cognitive outcomes. Total indirect effects accounted for at least half of the total effects in each model, with paths through age 20 GCA explaining most of the total indirect effects. Discussion and Implications: cSES predicted cognitive functioning in late middle age Using multiple mediation models, we show that lower cSES predicts poorer cognition in late midlife primarily through young adult cognitive ability and to a lesser extent through SES in adulthood and engagement in cognitively stimulating activities. PMID- 30465027 TI - HF etched glass substrates for improved thin-film solar cells. AB - A hemisphere-array textured glass substrate was fabricated for the development of an improved thin-film (TF) silicon solar cell. The HF-H2SO4-etchant system influenced the light path owing to the formation of the strong fluorine containing HSO3F acid. In particular, the etching system of the various HF concentration with a constant H2SO4 solution is related to make an improvement of optical transmittance and light trapping structure without a uniform pattern. According to the specular transmittance measurements, the haze ratio was maintained for the glass sample etched with 35% HF in the longer-wavelength region. The proposed substrate was implemented in a TF-Si solar cell, and an improved conversion efficiency was observed according to the short-circuit current density owing to the increase in the haze ratio. This morphology, therefore, induces more scattering at the front side of the cell and leads to an improvement of the open circuit voltage gain for the HF 25% cell. It will be helpful to understand the application of thin film solar cell based on the HF H2SO4 etching system for the readers. PMID- 30465028 TI - Color, flavonoids, phenolics and antioxidants of Omani honey. AB - Our objectives were to analyze and correlate the color, flavonoids, phenolics and antioxidants of 26 honey samples from 6 honey producing regions in the Sultanate of Oman. The Pfund method was used to measure color, aluminum chloride method for flavonoids determination, Folin-Ciocalteu method for phenolic measurement and DPPH assay to determine antioxidants. Sumer honey was the highest among other samples in terms of color, which ranged 129.8-336.2 mm pfund, flavonoids (1613 2890 mg/kg), phenolics (1624-2898 mg/kg) and antioxidants (7.8-48.6 mg/ml). There was a strong correlation between color, flavonoids and phenolics, where it's moderate between these parameters and antioxidants. The Omani honey was rich in color and phenolics compare to other honey and regarded as a good source of antioxidants to the human diet. PMID- 30465029 TI - Energy efficient production of clay bricks using industrial waste. AB - Clay brick manufacturing is a sector which involves a lot of firing processes requiring higher temperature. To maintain this temperature, large amount of fuel in the form of wood, coal, biomass etc. need to be burnt in the kiln causing serious issues of air pollution. Also, with the increase in the number of industries coming up, large amount of un-disposable waste gets accumulated. If suitable remedies are not adopted for its safe disposal, it may pollute the water bodies through runoff. This project is an effort to reduce the brick firing temperature in the kiln to about 600 degrees C thereby reducing the cost of production and making the whole process environmental friendly. This work will put forward a suitable alternative for the safe disposal of industrial debris like quarry dust and glass powder by incorporating them as a partial substitute for river sand which is one of the costly constituent of clay brick and thereby further reducing the cost of production. Experimental results showed higher compressive strength of 21.31 N/mm2when the brick was casted with mix proportion of Cement: Sand: Red earth: Glass Powder: Quarry Dust = 4:1:1:1.5:2.5. The strength measured at temperature 600 degrees C met the requirements of the National Standards. PMID- 30465030 TI - Evaluation of breastfeeding self-efficacy of puerperal women in shared rooming units. AB - Purpose: To evaluate the perception of breastfeeding self-efficacy in puerperal women and to verify the association between Breastfeeding Self-Efficacy Scale Brazilian Version (BSES-VB) scores and sociodemographic and obstetric variables. The practice of breastfeeding is of extreme importance, not only because of its affective value but also because the nutritional composition of human milk is essential nutrients for the adequate growth and development of the newborn. Design and methods: This is a quantitative and cross-sectional study. The sample consisted of 100 puerperal women. The research instruments used were form with demographic, economic, obstetric and breastfeeding data and the BSES-VB. Results: 40% of the mothers obtained scores compatible with average breastfeeding self efficacy, 35% of them presented high efficacy and 25% low efficacy. There was no significant relationship between sociodemographic and obstetric variables with the BSES-VB mean scores in the puerperal period. In the association between some variables and items of the breastfeeding self-efficacy scale, it was observed that breastfeeding guidance in the prenatal period and marital status were statistically significant with the mean scores of each item on the scale. Conclusion: Only 35% of the puerperal women presented high breastfeeding efficacy. Breastfeeding guidance variables in prenatal care and marital status were statistically significant. Practice implications: the work of the professionals who work in the care of puerperal women becomes of great importance to provide information on the breastfeeding theme and determining the adherence to the practice of breastfeeding. PMID- 30465032 TI - Fungal Diseases in the 21st Century: The Near and Far Horizons. AB - Fungal diseases became a major medical problem in the second half of the 20th century when advances in modern medicine together with the HIV epidemic resulted in large numbers of individuals with impaired immunity. Fungal diseases are difficult to manage because they tend to be chronic, hard to diagnose, and difficult to eradicate with antifungal drugs. This essay considers the future of medical mycology in the 21st century, extrapolating from current trends. In the near horizon, the prevalence of fungal diseases is likely to increase, as there will be more hosts with impaired immunity and drug resistance will inevitably increase after selection by antifungal drug use. We can expect progress in the development of new drugs, diagnostics, vaccines, and immunotherapies. In the far horizon, humanity may face new fungal diseases in association with climate change. Some current associations between chronic diseases and fungal infections could lead to the establishment of fungi as causative agents, which will greatly enhance their medical importance. All trends suggest that the importance of fungal diseases will increase in the 21st century, and enhanced human preparedness for this scourge will require more research investment in this group of infectious diseases. PMID- 30465034 TI - Management of an Unusual Periprosthetic Giant Cell Tumor of Bone of the Proximal Tibia. AB - Giant cell tumor of bone is a relatively rare type of bone tumor, accounting for approximately 4.9% to 9% of all primary osseous neoplasms.1 Management options include intralesional curettage, or more uncommonly, wide resection. This process is then followed by reconstruction with bone graft or bone cementation. We present a case of giant cell tumor of bone adjacent to the tibial component of a preexisting total knee arthroplasty, treated with extensive curettage, argon beam coagulation, polymethyl methacrylate cementation with strut reinforcement, and mesh reconstruction of the extensor mechanism. Twenty months after treatment, the patient was recurrence free with a stable prosthesis and had return to functional activity. We report this treatment modality as a potentially effective method of approaching this rare orthopaedic entity. PMID- 30465031 TI - [The universal influenza vaccination in children with Vaxigrip Tetra(r) in Italy: an evaluation of Health Technology Assessment]. PMID- 30465033 TI - Spontaneous cognitive processes and the behavioral validation of time-varying brain connectivity. AB - In cognitive neuroscience, focus is commonly placed on associating brain function with changes in objectively measured external stimuli or with actively generated cognitive processes. In everyday life, however, many forms of cognitive processes are initiated spontaneously, without an individual's active effort and without explicit manipulation of behavioral state. Recently, there has been increased emphasis, especially in functional neuroimaging research, on spontaneous correlated activity among spatially segregated brain regions (intrinsic functional connectivity) and, more specifically, on intraindividual fluctuations of such correlated activity on various time scales (time-varying functional connectivity). In this Perspective, we propose that certain subtypes of spontaneous cognitive processes are detectable in time-varying functional connectivity measurements. We define these subtypes of spontaneous cognitive processes and review evidence of their representations in time-varying functional connectivity from studies of attentional fluctuations, memory reactivation, and effects of baseline states on subsequent perception. Moreover, we describe how these studies are critical to validating the use of neuroimaging tools (e.g., fMRI) for assessing ongoing brain network dynamics. We conclude that continued investigation of the behavioral relevance of time-varying functional connectivity will be beneficial both in the development of comprehensive neural models of cognition, and in informing on best practices for studying brain network dynamics. PMID- 30465035 TI - Postoperative Pain After Surgical Treatment of Ankle Fractures: A Prospective Study. AB - Background: Postoperative pain after fixation of ankle fractures has a substantial effect on surgical outcome and patient satisfaction. Patients requiring large amounts of narcotics are at higher risk of long-term use of pain medications. Few prospective studies investigate patient pain experience in the management of ankle fractures. Methods: We prospectively evaluated the pain experience in 63 patients undergoing open reduction and internal fixation of ankle. The Short-Form McGill Pain Questionnaire was administered preoperatively and postoperatively (PP) at 3 days (3dPP) and 6 weeks (6wPP). Anticipated postoperative pain (APP) was recorded. Results: No significant differences were found between PP, APP, and 3dPP; however, 6wPP was markedly lower. Significant correlations were found between PP and APP and between preoperative and postoperative Short-Form McGill Pain Questionnaire scores. PP and APP were independent predictors of 3dPP; however, only APP was predictive of 6wPP. Sex, age, and inpatient versus outpatient status were not notable factors. No statistically significant differences were found in pain scores between fracture types. Conclusions: Both preoperative pain severity and anticipated postoperative pain are predictive of postoperative pain levels. Orthopaedic surgeons should place a greater focus on the postoperative management of patient pain and expectations after surgical procedures. PMID- 30465036 TI - Clinical and CT Analysis of Lumbar Spine Arthrodesis: beta-Tricalcium Phosphate Versus Demineralized Bone Matrix. AB - Background: Bone graft substitutes have been developed to circumvent donor site morbidity associated with iliac crest bone graft, but sparse literature compares the efficacy of various substitutes. Two commonly used bone graft substitutes used in lumbar fusion are beta-tricalcium phosphate (BTP) and demineralized bone matrix (DBM). Methods: A retrospective review of patients who underwent instrumented posterolateral lumbar fusion was conducted by a single surgeon from January 2013 to December 2016. Patients were divided into two groups based on whether DBM or BTP as graft in conjunction with local autograft. Clinical outcomes scores were collected at a minimum of 1-year follow-up. Postoperative CT scans were evaluated to assess fusion. Results: Forty-one patients (DBM, 21 and BTP, 20) were reviewed. No significant differences were found in terms of age, sex, body mass index, smoking, diabetes, steroids, osteoporosis, American Society of Anesthesiologists classification, number of levels fused, estimated blood loss, length of stay, or surgical time between the DBM and BTP groups. A trend was found toward lower revision surgery (zero versus 15%), improved visual analog scale scores (postoperative change of 1.81 versus 3.25; P = 0.09), and higher rates of fusion (90% versus 70%; P = 0.09) in the DBM group compared with the BTP group. Conclusions: No significant difference was found in clinical outcomes at 1 year, with a trend toward a higher fusion rate and lower revision surgery with DBM. PMID- 30465037 TI - Allergic Contact Dermatitis to Mastisol Adhesive Used for Skin Closure in Orthopedic Surgery: A Case Report. AB - We report on a rare case of allergic contact dermatitis (ACD) from Mastisol liquid adhesive. We are aware of a few reports in the medical literature, but none describes an allergic reaction during the third exposure to the offending agent. Our patient was a 20-year-old Caucasian man with a history of cerebral palsy spastic hemiplegia who underwent single-event multilevel soft-tissue surgery to optimize function of his left upper extremity. He developed a severe cutaneous allergic reaction after his third exposure to Mastisol. He was subsequently admitted to the inpatient service and managed without further complications by a multidisciplinary team comprising orthopedics, pediatrics, and dermatology. We discuss the etiology, clinical features, diagnosis, and treatment of this entity, and we also review relevant available literature on the subject. We aim at creating further awareness of allergic reactions because of exposure to available skin-prepping and wound-dressing agents. PMID- 30465038 TI - Dual Motor Drill Continuously Measures Drilling Energy to Calculate Bone Density and Screw Pull-out Force in Real Time. AB - Introduction: Low bone density complicates the surgical management of fractures. Screw stripping in osteoporotic bone leads to decreased fixation strength and weakening of the fixation construct. If low density could be detected during drilling, augmentation may be performed to prevent screw stripping. Furthermore, continuous monitoring of the drill bit depth and bone density can allow detection of the far cortex where density suddenly increases, providing immediate and accurate screw length measurement and reducing the risk of overpenetration or plunge in osteoporotic bone. Therefore, a dual motor drill was created to calculate bone density and pull-out force in real time. The purpose of this study was to determine whether real-time monitoring of drill bit torque and depth could be used to estimate bone density and pull-out force. We hypothesized that the calculated drilling energy could be used to determine density and would correlate with pull-out force. Methods: Drilling and screw insertion were performed using a validated composite unicortical bone model. Screws of 5-, 10-, and 20-mm length were placed into blocks of known densities (10, 20, 30, and 40 pounds per cubic foot). During creation of holes by the dual motor drill, drilling energy was recorded and used to calculate density. Calculated bone density was then compared with the known density of the block. The drill bit was exchanged for a screwdriver, and screw insertion energy was recorded in a similar fashion during screw placement. Screws were then subjected to maximal axial pull-out force testing with a material testing device. Recorded drilling energy and screw insertion energy were then correlated with the measured pull-out force. Results: Calculated bone density correlated very strongly with the known control density, confirming the accuracy of density calculations in real time. Drilling energy and screw insertion energy correlated very strongly with the measured pull-out force by destructive testing confirming ultimate pull-out force could be quantified during drilling or placement of a screw. Discussion: Our results confirmed that a dual motor drill can accurately and immediately allow determination of bone density and screw pull-out force before placing a screw. This knowledge could allow a surgeon to perform augmentation or alter surgical technique to prevent screw stripping and loss of fixation as well as detect the far cortex and prevent overpenetration in osteoporotic bone. PMID- 30465039 TI - G-CSF in stem cell mobilization: new insights, new questions. PMID- 30465040 TI - Platelets Protect Cardiomyocytes from Ischaemic Damage. AB - Platelets are classically known for their roles in bleeding control and occlusive thrombus formation causing ischaemic tissue damage. Recently non-classical roles for platelets have been described, many of which may be mediated by the heterogeneous cargo that platelets secrete from granular stores upon activation. Using an in vitro model of ischaemic injury to ventricular cardiomyocytes, we observed that platelets, through secreted factors, delayed the rate of cardiomyocyte death during ischaemia. This protective effect appeared independent of platelet dense granule cargo, but required alpha-granule components stromal cell-derived factor (SDF)-1alpha and transforming growth factor (TGF) beta1. Protein kinase C (PKC) activity within cardiomyocytes was responsible for mediating the protective signals initiated by the released platelet cargo. Importantly, pretreating platelets with a P2Y12 antagonist, but not the cyclooxygenase inhibitor aspirin, substantially attenuated this protective effect. These findings therefore reveal a paradoxically protective role for platelet activation during cardiac ischaemia and could have important implications for the use of anti-platelet therapeutics in the management of myocardial infarction. PMID- 30465041 TI - Extent of Risk-Aligned Surveillance for Cancer Recurrence Among Patients With Early-Stage Bladder Cancer. AB - IMPORTANCE: Cancer care guidelines recommend aligning surveillance frequency with underlying cancer risk, ie, more frequent surveillance for patients at high vs low risk of cancer recurrence. OBJECTIVE: To assess the extent to which such risk aligned surveillance is practiced within US Department of Veterans Affairs facilities by classifying surveillance patterns for low- vs high-risk patients with early-stage bladder cancer. DESIGN SETTING AND PARTICIPANTS: US national retrospective cohort study of a population-based sample of patients diagnosed with low-risk or high-risk early-stage bladder between January 1, 2005, and December 31, 2011, with follow-up through December 31, 2014. Analyses were performed March 2017 to April 2018. The study included all Veterans Affairs facilities (n = 85) where both low-and high-risk patients were treated. EXPOSURES: Low-risk vs high-risk cancer status, based on definitions from the European Association of Urology risk stratification guidelines and on data extracted from diagnostic pathology reports via validated natural language processing algorithms. MAIN OUTCOMES AND MEASURES: Adjusted cystoscopy frequency for low-risk and high-risk patients for each facility, estimated using multilevel modeling. RESULTS: The study included 1278 low-risk and 2115 high-risk patients (median [interquartile range] age, 77 [71-82] years; 99% [3368 of 3393] male). Across facilities, the adjusted frequency of surveillance cystoscopy ranged from 3.7 to 6.2 (mean, 4.8) procedures over 2 years per patient for low-risk patients and from 4.6 to 6.0 (mean, 5.4) procedures over 2 years per patient for high-risk patients. In 70 of 85 facilities, surveillance was performed at a comparable frequency for low- and high-risk patients, differing by less than 1 cystoscopy over 2 years. Surveillance frequency among high-risk patients statistically significantly exceeded surveillance among low-risk patients at only 4 facilities. Across all facilities, surveillance frequencies for low- vs high-risk patients were moderately strongly correlated (r = 0.52; P < .001). CONCLUSIONS AND RELEVANCE: Patients with early-stage bladder cancer undergo cystoscopic surveillance at comparable frequencies regardless of risk. This finding highlights the need to understand barriers to risk-aligned surveillance with the goal of making it easier for clinicians to deliver it in routine practice. PMID- 30465043 TI - Learning Time Series Detection Models from Temporally Imprecise Labels. AB - In this paper, we consider the problem of learning time series detection models from temporally imprecise labels. In this problem, the data consist of a set of input time series, and supervision is provided by a sequence of noisy time stamps corresponding to the occurrence of positive class events. Such temporally imprecise labels occur in areas like mobile health research when human annotators are tasked with labeling the occurrence of very short duration events. We propose a general learning framework for this problem that can accommodate different base classifiers and noise models. We present results on real mobile health data showing that the proposed framework significantly outperforms a number of alternatives including assuming that the label time stamps are noise-free, transforming the problem into the multiple instance learning framework, and learning on labels that were manually aligned. PMID- 30465042 TI - Neuroprotective potential of exercise preconditioning in stroke. AB - Stroke is one of leading causes of mortality and morbidity in the world with limited availability of therapeutic intervention. Exercise has been shown to improve stroke functional outcome in different preclinical and clinical setup. Exercise preconditioning induced neuroprotection in preclinical stroke models is believed to be mediated through its ability to restore brain vasculature and blood brain barrier integrity, promote neurogenesis, and help fight against neuroinflammation and excitotoxicity. In this short review, we will summarize the molecular mechanisms of exercise preconditioning described in preclinical stroke studies. We will also discuss the neuroprotective effects of pre-ischemic exercise. PMID- 30465044 TI - GANimation: Anatomically-aware Facial Animation from a Single Image. AB - Recent advances in Generative Adversarial Networks (GANs) have shown impressive results for task of facial expression synthesis. The most successful architecture is StarGAN [4], that conditions GANs' generation process with images of a specific domain, namely a set of images of persons sharing the same expression. While effective, this approach can only generate a discrete number of expressions, determined by the content of the dataset. To address this limitation, in this paper, we introduce a novel GAN conditioning scheme based on Action Units (AU) annotations, which describes in a continuous manifold the anatomical facial movements defining a human expression. Our approach allows controlling the magnitude of activation of each AU and combine several of them. Additionally, we propose a fully unsupervised strategy to train the model, that only requires images annotated with their activated AUs, and exploit attention mechanisms that make our network robust to changing backgrounds and lighting conditions. Extensive evaluation show that our approach goes beyond competing conditional generators both in the capability to synthesize a much wider range of expressions ruled by anatomically feasible muscle movements, as in the capacity of dealing with images in the wild. PMID- 30465045 TI - Repurposing Citizen Science Games as Software Tools for Professional Scientists. AB - Scientific software is often developed with professional scientists in mind, resulting in complex tools with a steep learning curve. Citizen science games, however, are designed for citizen scientists- members of the general public. These games maintain scientific accuracy while placing design goals such as usability and enjoyment at the forefront. In this paper, we identify an emerging use of game-based technology, in the repurposing of citizen science games to be software tools for professional scientists in their work. We discuss our experience in two such repurposings: Foldit, a protein folding and design game, and Eyewire, a web-based 3D neuron reconstruction game. Based on this experience, we provide evidence that the software artifacts produced for citizen science can be useful for professional scientists, and provide an overview of key design principles we found to be useful in the process of repurposing. PMID- 30465046 TI - A Novel Oncolytic Herpes Simplex Virus Design based on the Common Overexpression of microRNA-21 in Tumors. AB - Background: Recognition sequences for microRNAs (miRs) that are down-regulated in tumor cells have recently been used to render lytic viruses tumor-specific. Since different tumor types down-regulate different miRs, this strategy requires virus customization to the target tumor. We have explored a feature that is shared by many tumor types, the up-regulation of miR-21, as a means to generate an oncolytic herpes simplex virus (HSV) that is applicable to a broad range of cancers. Methods: We assembled an expression construct for a dominant-negative (dn) form of the essential HSV replication factor UL9 and inserted tandem copies of the miR-21 recognition sequence (T21) in the 3' untranslated region. Bacterial Artificial Chromosome (BAC) recombineering was used to introduce the dnUL9 construct with or without T21 into the HSV genome. Virus was produced by transfection and replication was assessed in different tumor and control cell lines. Results: Virus production was conditional on the presence of the T21 sequence. The dnUL9-T21 virus replicated efficiently in tumor cell lines, less efficiently in cells that contained reduced miR-21 activity, and not at all in the absence of miR-21. Conclusion: miR-21-sensitive expression of a dominant negative inhibitor of HSV replication allows preferential destruction of tumor cells in vitro. This observation provides a basis for further development of a widely applicable oncolytic HSV. PMID- 30465047 TI - Adversarial Domain Adaptation for Classification of Prostate Histopathology Whole Slide Images. AB - Automatic and accurate Gleason grading of histopathology tissue slides is crucial for prostate cancer diagnosis, treatment, and prognosis. Usually, histopathology tissue slides from different institutions show heterogeneous appearances because of different tissue preparation and staining procedures, thus the predictable model learned from one domain may not be applicable to a new domain directly. Here we propose to adopt unsupervised domain adaptation to transfer the discriminative knowledge obtained from the source domain to the target domain with-out requiring labeling of images at the target domain. The adaptation is achieved through adversarial training to find an invariant feature space along with the proposed Siamese architecture on the target domain to add a regularization that is appropriate for the whole-slide images. We validate the method on two prostate cancer datasets and obtain significant classification improvement of Gleason scores as compared with the baseline models. PMID- 30465048 TI - Increased Fluoroquinolone-Susceptibility and Preserved Nitrofurantoin Susceptibility among Escherichia coli Urine Isolates from Women Long-Term Care Residents: A Brief Report. AB - Suspected urinary tract infection is a common indication for antimicrobial therapy in long-term care residents. We sought to characterize antimicrobial susceptibilities among urine isolates collected from women long-term care residents enrolled in a clinical trial across 21 long-term care facilities in Connecticut, United States of America between August 2012 and October 2015. Among 967 urine cultures collected from 175 women long-term care residents with and without suspected urinary tract infection, we identified 456 bacterial isolates. Escherichia coli (55.3%), Klebsiella (13.8%) and Enterococcus (8.3%) species were the predominant organisms identified. Among all 456 urine isolates, 68.1% were ciprofloxacin-susceptible, 77.2% were trimethoprim/sulfamethoxazole-susceptible, 86.3% were cefazolin-susceptible, and 72.6% were nitrofurantoin-susceptible. Among 252 Escherichia coli urine isolates, 60.2% were ciprofloxacin-susceptible, 73.7% were trimethoprim/ sulfamethoxazole-susceptible, 84.5% were cefazolin susceptible, and 86.5% were nitrofurantoin-susceptible. These findings suggest that trimethoprim/sulfamethoxazole may be favorable empiric therapy while the urinary isolate is unknown, and nitrofurantoin may be optimal therapy for uncomplicated urinary tract infection due to Escherichia coli in women long-term care residents. PMID- 30465049 TI - Fluxional motion in a dinuclear copper(i) complex with a propeller-type ligand: metal hopping on both sides. AB - The first study of fluxional motion in [Cu2(2-HPB)(MeCN)2Cl2] (1,2-HPB = hexa(2 pyridyl)benzene) is presented. For detailed examination of the fluxional motion mechanism, a monofluorinated derivative of the ligand (MFHPB) and its copper(i) complexes were synthesized and characterized. The solution NMR studies of monofluoro copper(i) complex 1a suggest the existence of five species in equilibrium. NMR spectra and DFT calculations suggest the fluxional motion of 1 resulting in the "metal hopping process" of two copper(i) ions. PMID- 30465050 TI - On-chip oocyte denudation from cumulus-oocyte complexes for assisted reproductive therapy. AB - Human infertility can be treated using assisted reproductive technology (ART) such as intracytoplasmic sperm injection (ICSI). But current ART techniques suffer from multiple cumbersome processes requiring technically skilled personnel. Microfluidics technologies offer unique opportunities to streamline ART procedures, reduce stress imposed upon gametes and embryos, and minimize the operator-to-operator variability. However, there have been no automated and continuous processing systems that can reduce the dependence on well-trained embryologists to obtain ICSI-ready oocytes from patients. In this study, using mouse models, we developed a microfluidic device to denude oocytes from the surrounding cumulus-corona cell mass, facilitating the evaluation of oocyte quality and the injection of sperm. Enzyme-treated cumulus-oocyte complexes pass through a series of jagged-surface constriction microchannels of optimized geometries. The jagged inner wall of constriction channels facilitates stripping off of the cumulus-corona cell mass. Oocytes that were denuded by the device showed comparable fertilization and developmental competence compared with mechanical pipetting. The device developed in this study achieves the automation of a manual process for oocyte denudation in a continuous flow, as well as improving standardization and ease-of-use. Our denudation-on-a-chip approach requires inexpensive and simple equipment, which represents one step forward towards improving the accessibility and affordability of assisted reproductive therapy. PMID- 30465051 TI - Simulation of the gastric digestion of proteins of meat bolus using a reaction diffusion model. AB - A reaction-diffusion mathematical model has been developed to predict the gastric digestion of meat proteins. The model takes into account pepsin diffusion and proton diffusion in bolus particles and the pH buffering capacity of meat. The computations show that the size of bolus particles and the change in gastric pH have a substantial effect on the percentage of protein digested in the stomach and that the pH buffering capacity of meat has to be accounted for to properly calculate the gastric digestibility of meat. The intensity of surface transfers between stomach fluid and bolus particles has a significant impact on protein digestibility, whereas the variation in pepsin content in the stomach between individuals appears to have little effect on protein digestibility. From a nutritional standpoint, the simulations show that meat protein digestibility is high under normal physiological stomach conditions. However, in a situation where masticatory capacity, hydrochloric acid secretion and gastric motor function performances are reduced, such as with advancing age, protein digestibility rapidly decreases, ultimately leading to near-zero digestibility value in the stomach in extreme cases. PMID- 30465052 TI - Deep blue emitting Cu(i) tripod complexes. Design of high quantum yield materials showing TADF-assisted phosphorescence. AB - In a previous investigation, it was shown that [Cu(tpym)(PPh3)]PF61 with tpym = tris(2-pyridyl)methane represents a deep blue emitter (lambdamax = 466 nm) though with a low emission quantum yield PhiPL if doped in a polymer (7%) or dissolved in a fluid solvent (?1%). In this study, we present new tripod compounds with sterically demanding ligands: [Cu(tpym)(P(o-tol)3)]PF62 and [Cu(tpym)(P(o-butyl ph)3)]PF63 with P(o-tol)3 = tris(ortho-tolyl)phosphine and P(o-butyl-ph)3 = tris(ortho-n-butylphenyl)phosphine. These compounds show high emission quantum yields even in a fluid solution (dichloromethane) reaching a benchmark value for 3 of PhiPL = 76%. This becomes possible due to the specific design of rigidifying the complexes. Importantly, the deep blue emission color is maintained or even further blue shifted to lambdamax = 452 nm (compound 3 powder). Compound 2 is characterized photophysically in detail. In particular, it is shown that the lowest excited triplet state T1 experiences very efficient spin-orbit coupling (SOC). Accordingly, the phosphorescence decay rate is as large as 5 * 104 s-1 (20 MUs) belonging to the fastest T1-> S0 transition values (shortest decay times) reported so far. Investigations down to T = 1.5 K reveal a large total zero-field splitting (ZFS) of 7 cm-1 (0.9 meV). Although thermally activated delayed fluorescence (TADF) grows in at T>= 160 K, the phosphorescence of 2 still dominates (60%) over TADF (40%) at ambient temperature. Thus, the compound represents a singlet harvesting-plus-triplet harvesting material, if applied in an OLED. PMID- 30465053 TI - Folate receptor-targeted theranostic IrSx nanoparticles for multimodal imaging guided combined chemo-photothermal therapy. AB - Nano-drug delivery systems with multi-modality imaging capacities are worth pursuing because they integrate diagnostic and therapeutic functions. Herein, we report the design, synthesis and evaluation of modified iridium sulfide (IrSx) nanoparticles (NPs) for cancer therapy in vitro and in vivo. This nanosystem was prepared by modifying IrSx with polyethylene glycol (PEG) conjugated to the targeting ligand folate (FA) for multimodal imaging-guided combined chemo photothermal therapy. Upon PEG modification, the small IrSx NPs (about 4 nm) self assembled into much larger (about 120 nm) IrSx-PEG-FA NPs, which exhibited high photostability, ideal photothermal effect, high drug loading and pH-/photothermal responsive drug release properties. By using the model anticancer drug camptothecin (CPT), we demonstrated that CPT@IrSx-PEG-FA can effectively target FA-receptor-positive cancer cells in vitro and show efficient tumor accumulation in vivo. The combination of CPT@IrSx-PEG-FA treatment and irradiation with an 808 nm laser resulted in complete tumor elimination. Moreover, photothermal/photoacoustic (PA)/computed tomography (CT) imaging provided an effective means to monitor the therapeutic effects. Interestingly, the nanoparticles can be cleared, resulting in low systematic toxicity of CPT@IrSx PEG-FA. Our work demonstrates that the as-prepared IrSx-PEG-FA NPs present a promising platform for the construction of multifunctional theranostic agents for cancer therapy. PMID- 30465054 TI - Anti-leukemia activity of 4-amino-2-aryl-6,9-dichlorobenzo[g]pteridines. AB - Pteridines are bicyclic heterocyclic compounds with a pyrazino[2,3-d]pyrimidine nucleus that have shown a wide range of therapeutic utilities. Concretely, 4 aminopteridine derivatives have demonstrated both anti-inflammatory and anti cancer properties, and some of them, such as methotrexate, are profusely used in medical practice. We have recently synthesized and tested the biological activity of a novel series of 4-amino-2-aryl-6,9-dichlorobenzo[g]pteridines, finding that they present anti-inflammatory properties, as they were able to inhibit in vitro the production of pro-inflammatory cytokines TNF-alpha and IL-6. Now, we have evaluated the anti-tumor potential of these compounds on HL-60 and K562 leukemia cell lines. Cells growing at exponential rate were exposed to decreasing doses of each compound, from 50 to 0.39 MUM, for 24, 48, and 72 h. Cell viability was tested by MTT assay and cell death fashion determined by annexin V/propidium iodide assay. The cytotoxicity of the compounds was determined in differentiated macrophage-like HL-60 cells and in human peripheral blood mononuclear cells to evaluate the potential side effects on quiescent tumor cells and normal cells, respectively. Among the series, compounds 1a, 1b, 1g, 1j, and 1k showed anti proliferative activity. Compounds 1j and 1k were active against both HL-60 and K562 cells, with a lower IC50 against HL-60 cells. Compounds 1a, 1b, and 1g had a great cytotoxic activity against HL-60, but they were far less potent against K562 cells. None had side effects in differentiated tumor cells or in human peripheral blood mononuclear cells. In conclusion, our results demonstrate that some compounds of this series of 4-amino-2-aryl-6,9-dichlorobenzo[g]pteridines have anti-cancer properties in vitro. PMID- 30465055 TI - Rutin and orlistat produce antitumor effects via antioxidant and apoptotic actions. AB - Cancer is a broad term used to describe a large number of diseases characterized by uncontrolled cell proliferation that leads to tumor production. Cancer is associated with mutations in genes controlling proliferation and apoptosis, oxidative stress, fatty acid synthase (FAS) expression, and other mechanisms. Currently, most antineoplastic drugs have severe adverse effects and new effective and safe drugs are needed. This study aims to investigate the possible anticancer activity of rutin and orlistat which are both safely used clinically in humans against two breast cancer models (in vivo EAC and in vitro MCF7) and the pancreatic cancer cell line (PANC-1). Our results have shown that both rutin and orlistat exerted an in vivo anticancer activity as evidenced by the decrease in tumor volume, CEA level, cholesterol content, FAS, and the exerted antioxidant action (reduced MDA level and increased GSH content) and through histopathological examination. In addition, both were cytotoxic to MCF-7 and Panc 1 cell lines by promoting apoptosis. In conclusion, the anticancer activity of rutin and orlistat makes them promising candidates for cancer treatment alone or in combination with other anticancer drugs specially that they are used clinically with an acceptable safety profile. PMID- 30465056 TI - Highlight Report: humanized mice reveal interspecies differences in triclosan hepatotoxicity. PMID- 30465057 TI - Filtered back projection revisited in low-kilovolt computed tomography angiography: sharp filter kernel enhances visualization of the artery of Adamkiewicz. AB - PURPOSE: The reliability of assessment of the artery of Adamkiewicz before the aortic repair is highly dependent on the display of the continuity of this artery with the aorta, mainly around the vertebral pedicle, by computed tomography angiography (CTA). We hypothesized that the sharp filter kernel can improve visualization of this continuity of the vessel structure because of its edge enhancement and high-spatial resolution. This study was performed to compare the subjective and objective image quality of spinal CTA reconstructed with sharp and smooth filter kernels. METHODS: We retrospectively reviewed 40 consecutive patients who had undergone 80-kV CTA to detect the artery of Adamkiewicz before aortic repair. We measured the CT number and the contrast-to-noise ratio of the anterior spinal artery to the spinal cord. Furthermore, the continuity of the artery of Adamkiewicz was evaluated using a 3-point scale (2 points, absolute; 0 points, undetectable). RESULTS: CTA with the sharp filter kernel showed a significantly higher CT number and contrast-to-noise ratio of the spinal artery than did CTA with the smooth filter kernel (P < .001 for both). Moreover, the sharp filter kernel showed a significantly higher continuity of the artery of Adamkiewicz with the aorta than did the smooth filter kernel (P < .001). CONCLUSIONS: The sharp filter kernel significantly improved the image quality in low-tube-voltage CTA for the assessment of the artery of Adamkiewicz. Thus, CTA with the sharp filter kernel can generate a high-confidence level in the evaluation of the artery of Adamkiewicz. PMID- 30465058 TI - Inhibition of YAP with siRNA prevents cartilage degradation and ameliorates osteoarthritis development. AB - The Hippo/YAP signaling pathway is important for mediating organ size and tissue homeostasis, but its role in osteoarthritis (OA) remains unclear. We aimed to investigate the role of Hippo/YAP signaling pathway in OA development. YAP expression in OA cartilage was assessed by immunohistochemistry, RT-qPCR, and Western blotting. The effects of YAP overexpression or knockdown on gene expression related to chondrocyte hypertrophy induced by IL-1beta were examined. The in vivo effects of YAP inhibition were studied. Subchondral bone was analyzed by micro-CT. YAP was increased in mice and human OA articular cartilage and chondrocytes. YAP mRNA expression level was also increased in IL-1beta-induced chondrocytes. YAP overexpression resulted in increased expression of catabolic genes in response to IL-1beta. Suppression of YAP by siRNA inhibited IL-1beta stimulated catabolic genes expression and chondrocytes apoptosis. Intra-articular injection of YAP siRNA ameliorated OA development in mice. Micro-CT results showed the aberrant subchondral bone formation was also reduced. We provided evidence that YAP was upregulated in OA cartilage. Inhibition of YAP using YAP siRNA is a promising way to prevent cartilage degradation in OA. KEY MESSAGES: YAP was upregulated in human and mice osteoarthritis cartilage and chondrocytes. YAP siRNA decreased IL-1beta-induced catabolic gene expression. Intra-articular injection of YAP siRNA ameliorated OA development. Intra-articular injection of YAP siRNA reduced aberrant subchondral bone formation. PMID- 30465059 TI - Long non-coding RNA H19 inhibition promotes hyperglycemia in mice by upregulating hepatic FoxO1 levels and promoting gluconeogenesis. AB - In a previous report from our laboratory, it was reported that hepatic levels of the long non-coding RNA (lncRNA), H19 are decreased in diabetic mice which elevates hepatic gluconeogenesis and glucose output. But, the mechanisms of H19 inhibition in elevating gluconeogenic genes' transcription and promoting hepatic glucose output were not known. In this study, we aimed to decipher this regulatory role of H19 on glucose metabolism and on FoxO1, an important transcriptional regulator of gluconeogenesis. While H19 inhibition in HepG2 cells increased the levels of FoxO1, its overexpression led to significant inhibition in FoxO1 levels, thereby identifying H19 as an important regulator of FoxO1. Our data also demonstrates that in the absence of H19, there is increased occupancy of p53 on the FoxO1 promoter that possibly is responsible for increased FoxO1 transcription. In vivo silencing of H19 in normal mice caused hyperglycemia, hyperinsulinemia and impaired glucose, insulin, and pyruvate tolerance. Serum triglyceride and cholesterol levels, however, did not show any change. H19 inhibition significantly elevated the hepatic levels of FoxO1 and all the gluconeogenic genes. While fasting increased gluconeogenic genes' transcription, the levels of H19 were decreased and these patterns reversed upon refeeding the mice. Thus, gluconeogenic genes and H19 levels show inverse patterns of expression, and these results indicate towards an important regulatory role of the lncRNA, H19. It acts as an upstream regulator of gluconeogenesis by regulating the transcription of FoxO1, an important transcription factor of gluconeogenic genes, and hence, regulates hepatic glucose metabolism. KEY MESSAGES: H19 regulates FoxO1 transcript and protein levels. H19 inhibition increases p53 occupancy on the FoxO1 promoter that promotes FoxO1 transcription. H19 inhibition in vivo induces hyperglycemia and impairs glucose, insulin, and pyruvate tolerance. In vivo H19 inhibition increases the hepatic transcript levels of gluconeogenic genes and FoxO1. Transcript levels of H19 and gluconeogenic genes are inversely regulated during fed and fasted states. PMID- 30465060 TI - An alphavirus-based therapeutic cancer vaccine: from design to clinical trial. AB - Cancer immunotherapy has greatly advanced in recent years. Most immunotherapeutic strategies are based on the use of immune checkpoint blockade to unleash antitumor immune responses or on the induction or adoptive transfer of immune effector cells. We aim to develop therapeutic vaccines based on recombinant Semliki Forest virus vectors to induce tumor-specific effector immune cells. In this review, we describe our ongoing work on SFV-based vaccines targeted against human papillomavirus- and hepatitis C virus-related infections and malignancies, focusing on design, delivery, combination strategies, preclinical efficacy and product development for a first-in-man clinical trial with an HPV-specific vaccine. PMID- 30465061 TI - Validation of the Amharic version of the Pelvic Organ Prolapse Symptom Score (POP SS). AB - INTRODUCTION AND HYPOTHESIS: We aimed to translate and culturally adapt the Pelvic Organ Prolapse Symptom Score (POP-SS) into Amharic and evaluate its psychometric properties. METHODS: We followed an intercultural adaptation procedure to translate and adapt the POP-SS. One hundred and eighty-six women with POP symptoms completed the Amharic POP-SS and Prolapse Quality of Life (P QoL) questionnaires. All women were examined using a simplified Pelvic Organ Prolapse Quantification (SPOP-Q) system and were divided into four groups based on the POP-Q scores as stage 1, 2, 3, and 4. Internal consistency and test-retest reliability were determined using Cronbach's alpha and the intraclass correlation coefficient (ICC), respectively. Criterion validity was assessed against the SPOP Q stage and the P-QoL scale. Furthermore, we tested construct validity using exploratory factor analysis. RESULTS: The POP-SS score was successfully translated and achieved good content validity. It had high internal consistency (Cronbach's alpha = 0.86) and test-retest reliability (ICC = 0.81; p < 0.001). There was a statistically significant difference among four groups of stages in POP-SS score. and women with stage 3 had the highest median score (Kruskal-Wallis test; p < 0.05). The POP-SS score was also significantly correlated with the P QoL score (Spearman's correlation coefficient = 0.28, p < 0.001). The exploratory factor analysis identified two factors, namely, physical symptoms and evacuation symptoms. CONCLUSIONS: The POP-SS scale was successfully translated to Amharic and appears reliable and valid for women with symptoms of POP. However, further studies are needed to evaluate its responsiveness. PMID- 30465062 TI - Efficacy of vitamin C for the prevention and treatment of upper respiratory tract infection. A meta-analysis in children. AB - PURPOSE: Upper respiratory tract infection (URTI) is a common infection in children, generally caused by viral respiratory infection. Vitamin C is currently proposed as prophylaxis for URTI. The purpose of this study was to assess the effectiveness of vitamin C administration in children for the prevention and reduced duration of URTI through a systematic literature review. METHODS: Review of the literature conducted between October 2017 and January 2018 in the main medical databases (CENTRAL, Medline and Embase) and by a gray literature approach. The selection criteria were: double-blind randomized controlled trials (RCTs) comparing vitamin C use to placebo in children aged 3 months to 18 years without chronic infection. Efficacy was assessed in terms of incidence, duration and severity of symptoms of URTI. A meta-analysis was conducted where possible. RESULTS: Eight RCTs, including 3135 children aged 3 months to 18 years, were selected. Quantitative analysis showed no difference between vitamin C administration and placebo (odds ratio = 0.75, 95% CI [0.54-1.03], p = 0.07, I2 = 74%). Vitamin C administration was found to decrease the duration of URTI by 1.6 days (standardized mean differences = -0.30 [-0.53; -0.08], p = 0.009, I2 = 70%). Children under 6 years of age benefit from more effective vitamin C supplementation associated with echinacea. No serious adverse events were reported. CONCLUSIONS: Although no preventive effects were found, vitamin C intake reduced the duration of URTI. Considering the frequency of URTI, the inappropriate prescription of antibiotics, and the safe nature of vitamin C, its supplementation is justified, especially in children under 6 years of age and those who present a high frequency of URTI. There is a sound rationale for further trials with greater statistical power among children of this age. PMID- 30465063 TI - Fine mapping of qGL5H, a major grain length locus in barley (Hordeum vulgare L.). AB - KEY MESSAGE: A major grain length QTL on chromosome 5H was fine mapped from 180.5 to 1.7 Mb. Quantitative trait loci (QTLs) mapping has been used extensively in barley to detect QTLs that underlie complex traits such as grain size. In the present study, we utilised 312 double haploid lines derived from a cross between two Australian malting varieties, Vlamingh and Buloke, to dissect the genetic control of a number of grain size characteristics. Digital image analysis was used to measure grain size characteristics including length, width, thickness and plumpness which are important traits influencing barley yield and grain physical quality. Using data from four independent environments and molecular marker genotype data, we identified 23 significant QTLs for these four traits, ten of which were consensus QTLs and identified in two or more environments. A QTL region on chromosome 5H designated qGL5H that was associated with grain size was fine mapped to a 1.7 Mb interval. qGL5H was able to explain 21.6% of phenotypic variation for grain length within the population. This major QTL is an appropriate candidate for further genetic dissection. PMID- 30465064 TI - Construction of introgression lines of Oryza rufipogon and evaluation of important agronomic traits. AB - Cultivated rice (Oryza sativa) originated from common wild rice (Oryza rufipogon) and inherited its advantages. However, during the rice domestication process, some valuable features of wild rice, such as tolerance to biotic and abiotic stress, were lost. To fully utilize wild rice germplasm resources, we constructed a set of introgression lines (ILs) using a common wild rice material from Lingshui, China. A set of high-resolution InDel molecular markers with an average interval of 2.39 Mb were designed to carry out marker-assisted selection and identification of segment characteristics. The ILs contained 77 lines including 1.286 introgressed fragments with an average length of 6.511 Mb, covering 93.59% of the donor parent's chromosomes. The agricultural traits of 77 lines were investigated. Many old quantitative trait loci (QTLs) involved in plant height, awn length, seed traits and other characteristics reappeared in our ILs, proving that our system was reliable. Further, many new QTLs were identified. A QTL related to drought tolerance located on chromosome 4 was thoroughly elaborated. This set of ILs provides a new resource for utilizing the excellent features of wild rice. PMID- 30465065 TI - Up Front. PMID- 30465066 TI - The many secret lives of adipocytes: implications for diabetes. AB - Adipose tissue remains a cryptic organ. The ubiquitous presence of adipocytes, the different fat pads in distinct anatomical locations, the many different types of fat, in each case with their distinct precursor populations, and the ability to interchange into other types of fat cells or even de-differentiate altogether, offers a staggering amount of complexity to the adipose tissue organ as a whole. Adipose tissue holds the key to improving our understanding of systemic metabolic homeostasis. As such, understanding adipose tissue physiology offers the basis for a mechanistic understanding of the pathophysiology of diabetes. This review presents some of the lesser known aspects of this fascinating tissue, which consistently still offers much opportunity for the discovery of novel targets for pharmacological intervention. PMID- 30465067 TI - Lip Morphology and Aesthetics: Study Review and Prospects in Plastic Surgery. AB - The lip profile plays an important role in the perception of facial aesthetics; lip morphology and aesthetics research is receiving increasing attention. The advancement of research tools such as three-dimensional imaging technology has led to the clarification of lip morphologic and aesthetic characteristics. After studies of lip characteristics according to gender, ethnicity and age provided basic data, studies on lip aesthetics have been conducted by scholars worldwide. These studies could provide a basic theory to support diagnosis and treatment options, as well as the basis for evaluative criteria for precise treatment and technical improvements. According to the conclusions of the above studies, new ideas for cosmetic surgery design, including lip, perioral and labial-facial relationships, have been discovered.Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 30465068 TI - Population and Culture Age Influence the Microbiome Profiles of House Dust Mites. AB - Interactions with microorganisms might enable house dust mites (HDMs) to derive nutrients from difficult-to-digest structural proteins and to flourish in human houses. We tested this hypothesis by investigating the effects of changes in the mite culture growth and population of two HDM species on HDM microbiome composition and fitness. Growing cultures of laboratory and industrial allergen producing populations of Dermatophagoides farinae (DFL and DFT, respectively) and Dermatophagoides pteronyssinus (DPL and DPT, respectively) were sampled at four time points. The symbiotic microorganisms of the mites were characterized by DNA barcode sequencing and quantified by qPCR using universal/specific primers. The population growth of mites and nutrient contents of mite bodies were measured and correlated with the changes in bacteria in the HDM microbiome. The results showed that both the population and culture age significantly influenced the microbiome profiles. Cardinium formed 93% and 32% of the total sequences of the DFL and DFT bacterial microbiomes, respectively, but this bacterial species was less abundant in the DPL and DPT microbiomes. Staphylococcus abundance was positively correlated with increased glycogen contents in the bodies of mites, and increased abundances of Aspergillus, Candida, and Kocuria were correlated with increased lipid contents in the bodies of mites. The xerophilic fungus Wallemia accounted for 39% of the fungal sequences in the DPL microbiome, but its abundance was low in the DPT, DFL, and DFT microbiomes. With respect to the mite culture age, we made three important observations: the mite population growth from young cultures was 5-8-fold higher than that from old cultures; specimens from old cultures had greater abundances of fungi and bacteria in their bodies; and yeasts predominated in the gut contents of specimens from young cultures, whereas filamentous mycelium prevailed in specimens from old cultures. Our results are consistent with the hypothesis that mites derive nutrients through associations with microorganisms. PMID- 30465069 TI - Focus on extracorporeal life support. PMID- 30465070 TI - Erythromycin versus metoclopramide for post-pyloric spiral nasoenteric tube placement: a randomized non-inferiority trial. AB - PURPOSE: To determine whether erythromycin is non-inferior to metoclopramide in facilitating post-pyloric placement of self-propelled spiral nasoenteric tubes (NETs) in critically ill patients. METHODS: A prospective, multicenter, open label, parallel, and non-inferiority randomized controlled trial was conducted comparing erythromycin with metoclopramide in facilitating post-pyloric placement of spiral NETs in critically ill patients admitted to intensive care units (ICUs) of eight tertiary hospitals in China. The primary outcome was procedure success defined as post-pyloric placement (spiral NETs reached the first portion of the duodenum or beyond confirmed by abdominal radiography 24 h after tube insertion). RESULTS: A total of 5688 patients were admitted to the ICUs. Of these, in 355 patients there was a plan to insert a nasoenteric feeding tube, of whom 332 were randomized, with 167 patients assigned to the erythromycin group and 165 patients assigned to the metoclopramide group. The success rate of post-pyloric placement was 57.5% (96/167) in the erythromycin group, as compared with 50.3% (83/165) in the metoclopramide group (a difference of 7.2%, 95% CI - 3.5% to 17.9%), in the intention-to-treat analysis, not including the prespecified margin of - 10% for non-inferiority. The success rates of post-D1 (reaching the second portion of the duodenum or beyond), post-D2 (reaching the third portion of the duodenum or beyond), post-D3 (reaching the fourth portion of the duodenum or beyond), and proximal jejunum placement and the incidence of any adverse events were not significantly different between the groups. CONCLUSIONS: Erythromycin is non inferior to metoclopramide in facilitating post-pyloric placement of spiral NETs in critically ill patients. The success rates of post-D1, post-D2, post-D3, and proximal jejunum placement were not significantly different. PMID- 30465071 TI - Comparative mtDNA phylogeographic patterns reveal marked differences in population genetic structure between generalist and specialist ectoparasites of the African penguin (Spheniscus demersus). AB - To address factors affecting genetic diversity and dispersal of ectoparasites, we compared mitochondrial DNA (mtDNA) population genetic structures of the generalist soft tick Ornithodoros capensis to the more host-specific nest flea Parapsyllus humboldti. A total of 103 ticks and 92 fleas were sampled at five distinct South African island/mainland African penguin (Spheniscus demersus) colonies. With its wide host range, O. capensis showed no evidence of significant cytochrome c oxidase subunit I (COI) mtDNA population differentiation among the five sampling sites (phist = 0.00 +/- 0.004; p = 0.80), as well as a higher level of genetic diversity (pi = 0.8% +/- 0.06%) when compared to P. humboldti. In contrast, the flea showed significant population structure among most of the same sampling sites (phist = 0.22 +/- 0.11; p <= 0.05) and a lower level of genetic diversity (pi = 0.2% +/- 0.01%). Our findings suggest that despite both parasites being mostly nest bound, O. capensis have few barriers to dispersal among island and mainland colonies. However, P. humboldti are more dependent on the African penguin for dispersal and thus have more impediments to gene flow among the same colonies. These findings broadly support the SGVH (specialist generalist variation hypothesis) and provide the first evidence for this hypothesis in parasites restricted to seabird colonies. PMID- 30465072 TI - How does the bopyrid isopod Gyge branchialis interfere with trace metal bioaccumulation in the mud shrimp Upogebia cf. pusilla? AB - Parasites are widespread in natural environments, and their impacts on the fitness of their host and, at a broader scale, on ecosystem functioning are well recognized. Over the last two decades, there has been an increasing interest in the effects of parasites in conjunction with other stressors, especially pollutants, on the health of organisms. For instance, parasites can interfere with the bioaccumulation process of contaminants in their host leading to parasitized organisms exhibiting lower pollutants burdens than unparasitized individuals for example. However, the mechanisms underlying these patterns are not well understood. This study examined how the bopyrid parasite Gyge branchialis could lower the cadmium (Cd) uptake of its mud shrimp host Upogebia cf. pusilla. When exposed to water-borne Cd, parasites were able to bioaccumulate this trace metal. However, the uptake of Cd by the parasite was low and cannot entirely explain the deficit of Cd contamination of the host. The weight of gills of parasitized organisms was significantly reduced compared with unparasitized organisms. We suggest that by reducing the surface for metal uptake, parasites could lower the contaminant burden of their host. PMID- 30465073 TI - Laryngopharyngeal reflux and benign lesions of the vocal folds. PMID- 30465074 TI - Multiple muscular abnormalities in a fetal cadaver with CHARGE syndrome. AB - The CHARGE syndrome characterized by coloboma, heart defects, atresia of the choanae, retarded growth, genitourinary hypoplasia, and ear anomalies is one of the rare syndromes. Although certain clinical issues (scapular winging, sloping shoulder, Sprengel's deformity, kyphosis and scoliosis) which could be related to abnormalities in musculoskeletal structures of the neck and shoulder have been identified in CHARGE syndrome, data on details of muscle anomalies seem to be quite limited in the literature. In this case report, bilateral multiple muscular abnormalities (agenesis of the trapezius, presence of the rhombo-atloid muscle, and presence of the bipartite rhomboid minor with superficial and deep parts) was presented in a fetus cadaver with atypical CHARGE syndrome to attract the attention of clinicians for definitive diagnoses and surgical reconstruction of the shoulders deformity such as scapular winging and Sprengel's deformity. By considering the previous studies, we propose that the absence of the trapezius, as well as the other muscle abnormalities around the neck and shoulder, should be revised as being a component of CHARGE syndrome. PMID- 30465075 TI - Induced expression of GINS complex is an essential step for reactivation of quiescent stem-like tumor cells within the peri-necrotic niche in human glioblastoma. AB - PURPOSE: Glioblastoma is still intractable despite the progress in therapies, and the intractability is attributable to a minor population of stem-like tumor cells. As a niche harboring quiescent stem-like tumor cells with potentially high tumorigenicity, we have specified an area around large ischemic necrosis, termed 'peri-necrotic niche', in glioblastoma. In this study, the behavior of tumor cells inside and outside the peri-necrotic niche was analyzed to find out molecules responsible for reactivation of quiescent stem-like tumor cells to proliferate outside the niche. METHODS: Expression of Ki-67 and GINS complex composed of SLD5, PSF1, PSF2 and PSF3 was analyzed by immunohistochemistry in human glioblastoma tissue samples. Proliferation assays, immunoblotting and siRNA experiments were performed using a glioblastoma cell line. RESULTS: Immunohistochemical analysis revealed quiescent and proliferative phenotypes of tumor cells inside and outside the niche, respectively, and the proliferation was spatially correlated with the expression of GINS components in tumor cells. To mimic the tissue microenvironment inside versus outside the niche, glioblastoma cells were cultured under hypoxic versus normoxic conditions, or without versus with serum. Quiescence and proliferation of tumor cells were reversibly determined by the microenvironment inside and outside the niche, respectively, and proliferative activities paralleled the expression levels of GINS components. Furthermore, the reactivation of proliferation after reoxygenation or serum replenishment was suppressed in quiescent tumor cells with PSF1 knockdown. CONCLUSIONS: These findings indicate the essential role of GINS complex in the switch between quiescence and proliferation of tumor cells inside and outside the peri-necrotic niche. PMID- 30465076 TI - Novel positioning from obesity to cancer: FTO, an m6A RNA demethylase, regulates tumour progression. AB - PURPOSE: The fat mass- and obesity-associated (FTO) gene on chromosome 16q12.2 shows an intimate association with obesity and body mass index. Recently, research into the FTO gene and its expression product has attracted widespread interest due to the identification of FTO as an N6-methyladenosine (m6A) demethylase. FTO primarily regulates the m6A levels of downstream targets via their 3' untranslated regions. FTO not only plays a critical role in obesity related diseases but also is involved in the occurrence, development and prognosis of many types of cancer, such as acute myeloid leukaemia, glioblastoma and breast cancer. Currently, studies indicate that FTO is a crucial component of m6A modification, it regulates cancer stem cell function, and promotes the growth, self-renewal and metastasis of cancer cells. In this review, we summarized and analysed the data regarding the structural features and biological functions of FTO as well as its association with different cancers and possible molecular mechanisms. METHODS: We systematically reviewed the related literatures regarding FTO and its demethylation activity in many pathologic and physiological processes, especially in cancer-related diseases based on PubMed databases in this article. RESULTS: Mounting evidence indicated that FTO plays a critical role in occurrence, progression and treatment of various cancers, even acting as a cancer oncogene in acute myeloid leukaemia, research on which is no longer restricted to metabolic diseases such as obesity and diabetes. CONCLUSION: Considering FTO's critical role in many diseases, FTO may become a new promising target for the diagnosis and treatment of various diseases in the near future, especially for specific types of cancers, such as acute myeloid leukaemia, glioblastoma and breast cancer. PMID- 30465077 TI - Pure laparoscopic donor right hepatectomy: perspectives in manipulating a flexible scope. AB - BACKGROUND: Interest in pure laparoscopic donor hepatectomy (PLDH) is increasing worldwide with the donor's cosmetic demands and improvements in surgical techniques. Efficient manipulation of flexible scope is mandatory for successful PLDH, especially in right hepatectomy which requires more mobilization. This study provides guidelines on how to manipulate optimally a flexible scope. METHODS: Data from 158 donors who underwent pure laparoscopic donor right hepatectomy (PLDRH) between November 2015 and December 2017 were retrospectively reviewed. RESULTS: None of the donors required transfusion, conversion to open hepatectomy, or experienced any irreversible disabilities or mortalities. Three types of laparoscopic view provided by the flexible scope, which are bird's eye view, low angle view, and lateral view, were applied to each step of the procedure. CONCLUSIONS: PLDRH can be successfully performed with maximizing visibility given by the tips and pitfalls in manipulating the flexible scope. PMID- 30465078 TI - The Relationship Between Leukoaraiosis Involving Contralateral Corticobulbar Tract and Dysphagia in Patients with Acute Unilateral Corona Radiata Infarction with Corticobulbar Tract Involvement. AB - This study investigated the impact of leukoaraiosis (LA) involving the contralateral corticobulbar tract (CBT) on dysphagia in patients with unilateral corona radiata (CR) infarction with CBT involvement. Patients admitted to the Department of Neurology (September 2011-August 2014) were evaluated; those with a first episode of acute unilateral CR infarction involving the CBT and with LA were included. The 'Case' group comprised patients with LA involving the contralateral CBT; the 'Control' group comprised patients with LA not involving the contralateral CBT. The primary outcome was the feeding method at discharge; secondary outcomes were the feeding method at admission and results of the bedside swallowing test, videofluoroscopic swallowing study (VFSS), videofluoroscopic dysphagia scale, penetration-aspiration scale, American Speech Language-Hearing Association National Outcome Measurement System Swallowing Scale (ASHA NOMS), oral transit time, and pharyngeal transit time. Infarct size was measured using brain magnetic resonance imaging; LA severity was rated using the Fazekas scale. Eighty-one patients were included (mean age 64.6 +/- 11.5 years; 64% male; Case group: 20, 5 underwent VFSS; Control group: 67, 11 underwent VFSS). The Case group was older and had higher total Fazekas scale score than the Control group. The feeding method at discharge and ASHA NOMS score were significantly worse in the Case group than in the Control group. Multivariate analysis revealed that LA involving the contralateral CBT independently predicted the feeding method at discharge and ASHA NOMS score. In conclusion, LA involving the contralateral CBT is associated with dysphagia in patients with unilateral CR infarction involving the CBT. PMID- 30465079 TI - Edged weapons awareness. AB - Edged weapons (sometimes referred to as sharp weapons or blades) are an increasing threat to military personnel, the blue light community (police, ambulance, firefighters, other first responders) and the general public worldwide. The use of edged weapons in criminal and terrorist incidents internationally means the forensic community needs an awareness of the technology of edged weapons, how they are used, the damage (clothing and wounding) that might be caused and any other forensic implications. In this paper, the magnitude of the problem is presented, prior research summarised and implications for forensic investigations discussed. PMID- 30465080 TI - Simplified Bayesian method: application in cytogenetic biological dosimetry of mixed n + gamma radiation fields. AB - This article describes the application of a simplified Bayesian method for estimation of doses from a mixed field using cytogenetic biological dosimetry, taking as an example neutron and gamma radiation emitted from the MARIA nuclear research reactor in Poland. The Bayesian approach is a good alternative to the commonly used iterative method, which allows separate dose estimation. In the present paper, a computer program, which uses the iterative and simplified Bayesian methods to calculate mixed radiation doses, is introduced. PMID- 30465081 TI - Genome Analysis of Cytochrome in Dinotefuran-Treated Apolygus lucorum (Meyer Dur). AB - In this study, two CYP genes, CYP395G1 and CYP4EY1, were analyzed in Apolygus lucorum (Hemiptera: Miridae). The expression pattern in different developmental stages of both CYP395G1 and CYP4EY1 revealed that first instar nymphs possessed the highest gene-transcript levels. After 12 h of dinotefuran treatments, the expression levels of CYP395G1 increased by 1.92-fold, while the CYP4EY1 expression decreased. It was observed that the sensitivities of dinotefuran to laboratory strains from F0 to F9 and the mRNA expression levels of CYP395G1 in the F9 dinotefuran selected strain were higher when compared to the control strain. The results suggest that CYP395G1 was possibly a candidate P450 that was involved in dinotefuran detoxification. The dinotefuran resistant strain of A. lucorum was difficult to increase, due to its special molecular structure of dinotefuran compared with other neonicotinoids. PMID- 30465082 TI - End-stage kidney disease in infancy: an educational review. AB - An increasing number of infants with end-stage kidney disease (ESKD) are surviving and receiving renal replacement therapy (RRT). Unique clinical issues specific to this age group of patients influence their short- and long-term outcomes. This review summarizes current epidemiology, clinical characteristics, ethical dilemmas, management concerns, and outcomes of infants requiring chronic dialysis therapy. Optimal care during infancy requires a multidisciplinary team working closely with the patient's family. Nutritional management, infection prevention, and attention to cardiovascular status are important treatment targets. Although mortality rates remain higher among infants on dialysis compared to older pediatric dialysis patients, outcomes have improved over time. Most importantly, infants who subsequently receive a kidney transplant are now experiencing graft survival rates that are comparable to older pediatric patients. PMID- 30465083 TI - Heparan sulfate proteoglycan (HSPG) can take part in cell division: inside and outside. AB - Prior to the cytokinesis, the cell-matrix interactions should be disrupted, and the mitotic cells round up. Prerequisite of mitosis, the centrosomes duplicate, spindle fibers are generated and move away from each other to opposite sides of the cells marking the cell poles. Later, an invagination in the plasma membrane is formed a few minutes after anaphase. This furrow ingression is driven by a contractile actomyosin ring, whose assembly is regulated by RhoA GTPase. At the completion of cytokinesis, the two daughter cells are still connected by a thin intercellular bridge, which is subjected to abscission, as the terminal step of cytokinesis. Here, it is overviewed, how syndecan-4, a transmembrane, heparan sulfate proteoglycan, can contribute to these processes in a phosphorylation dependent manner. PMID- 30465084 TI - Evaluation of the sub-optimal induction strategies for heterologous proteins production by Pichia pastoris Mut+/MutS strains and related transcriptional and metabolic analysis. AB - Heterologous proteins induction by methylotrophic recombinant Pichia pastoris is generally implemented at high cells density condition. Methanol concentration (MeOH) and dissolved oxygen concentration (DO) are two crucial operating parameters controlling proteins production. It is difficult to control MeOH/DO at their desired levels simultaneously due to the extremely high oxygen consumption features. Methanol utilization plus (Mut+) and slow (MutS) strains are the two typical phenotypes of recombinant P. pastoris with quite different dynamic characteristics. Therefore, different MeOH/DO combinational control strategies or sub-optimal induction strategies could be adopted. Environments of "high MeOH/low DO" and "high DO/low MeOH" are the realistic induction strategies. In this study, we summarized our own experimental results (using Mut+/MutS strains to produce human serum albumin-human granulocyte colony stimulating factor-HSA-GCSFm/porcine interferon-alpha-pIFN-alpha), and compared to data from the literature using the above mentioned two induction strategies. The results suggested that, heterologous proteins production by Mut+ strains favors "high DO/low MeOH (DO ~ 10%, MeOH ~ 0 g/L)" induction condition, while proteins production by MutS strains prefers "high MeOH/low DO (MeOH 5-10 g/L, DO ~ 0%)" induction environment. Thus, based on the P. pastoris types, the corresponding sub-optimal induction strategies should be applied accordingly. The related metabolic analysis indicating methanol utilizing efficiency and the transcriptional analysis reflecting gene up- or down-regulations involved in several key routes in methanol and sorbitol metabolism were implemented. The analysis results strongly supported the conclusions of using the proposed sub-optimal induction strategies for different heterologous proteins production by Mut+ and MutS strains. PMID- 30465085 TI - Bone Mineral Density as a Risk Factor for Patients Undergoing Surgery for Hepatocellular Carcinoma. AB - BACKGROUND: We have reported the impact of sarcopenia and body composition on patients undergoing hepatectomy for hepatocellular carcinoma (HCC). However, the impact of bone mineral density (BMD) on outcomes after hepatectomy for HCC and correlation with other parameters including sarcopenia are unclear. METHODS: We retrospectively analyzed 465 patients who underwent primary hepatectomy for HCC between April 2005 and March 2015. We analyzed the plain CT images at the level of the eleventh thoracic vertebra with the region of interest and defined as preoperative BMD. RESULTS: In this cohort, male (n = 367) and female (n = 98) patients showed significant heterogeneity in age, body composition markers, tumor factors, peri-operative parameters and so on. The median preoperative BMD in male and female patients was 155 and 139 HU, respectively (P = 0.005). BMD was negatively correlated with age in female (r = -0.590, P < 0.001) and intramuscular adipose tissue content in both male and female (r = -0.332 and 0.359, respectively, P < 0.001). For males, BMD < 160 HU was associated with worse cancer-specific survival post-hepatectomy (P = 0.015). In contrast, females were not (P = 0.135). For male patients, multivariate analysis identified low BMD as an independent risk factor for death (hazard ratio 1.720, 95% confidence interval 1.038-2.922, P = 0.035) after hepatectomy for HCC. CONCLUSION: Preoperative low BMD was an independent risk factor for cancer-specific mortality after hepatectomy for HCC. PMID- 30465086 TI - Occult Contralateral Lateral Lymph Node Metastases in Unilateral N1b Papillary Thyroid Carcinoma. AB - OBJECTIVE: Therapeutic lateral neck dissection (ND) is recommended for N1b papillary thyroid carcinoma (PTC), while prophylactic contralateral lateral ND is not. Given the paucity of data, we investigated the frequency of and risk factors for occult lymph node metastases (LNM) in the contralateral lateral neck for N1b patients. PATIENTS AND METHODS: This is a retrospective study conducted at a cancer center. Inclusion criteria were: unilateral PTC and ipsilateral lateral LNM confirmed by fine-needle aspiration biopsy. Patients with contralateral lateral LNM or bilateral tumor on ultrasound were excluded. All patients were treated with total thyroidectomy, bilateral central ND, ipsilateral therapeutic lateral ND and prophylactic contralateral ND of levels III-IV, followed by radioactive iodine. RESULTS: Sixty-three patients met the inclusion criteria. Occult contralateral lateral LNM were found in 23/63 patients (36.5%) who had more LNM in ispilateral (p = .01) and contralateral level VI (p < .0001), more frequent microscopic tumor in the contralateral lobe (p = .017) and a trend toward being at high risk (p = .06). Using receiver operating characteristic analysis, a cutoff of >4 LNM in ipsilateral level VI optimized sensitivity and specificity for predicting contralateral lateral LNM, with a sensitivity of 74%, specificity of 65%, positive predictive value of 55% and negative predictive value of 81%. Neck recurrence occurred in 14%, with only 1 patient recurring only in the contralateral lateral neck (1.5%). CONCLUSION: Occult LNM in the contralateral lateral neck was found in 36.5% of patients. Five or more ipsilateral central LNM may aid in predicting contralateral lateral LNM, and high risk patients may be more at risk. The clinical benefit of prophylactic contralateral lateral ND remains doubtful, however. PMID- 30465087 TI - Procedure-Specific Volume and Nurse-to-Patient Ratio: Implications for Failure to Rescue Patients Following Liver Surgery. AB - BACKGROUND: The effect of various hospital characteristics on failure to rescue (FTR) after liver surgery has not been well examined. We sought to examine the relationship between hospital characteristics and FTR after liver surgery. METHODS: The 2013-2015 Medicare-Provider Analysis and Review (MEDPAR) database was used to identify Medicare beneficiaries who underwent liver surgery. The effect of various hospital characteristics on FTR was compared among the highest mortality hospitals (HMH) and the lowest mortality hospitals (LMH). RESULTS: Among 4902 patients undergoing hepatectomy, patients treated at HMH had a higher risk of FTR (OR 3.08, 95% CI 2.03-4.66). Hospital factors such as total number of beds (OR 0.80, 95% 0.56-1.15), operating rooms (OR 0.81, 95% 0.57-1.14), and overall hospital surgical volume (OR 0.88, 95% 0.61-1.25) were not associated with FTR (all p > 0.05). In contrast, hospitals with a greater nurse-to-patient ratio had a markedly lower risk of FTR following a complication (OR 0.70, 95% CI 0.54-0.91; p = 0.007) (Table 3). As volume of liver operations and nurse-to patient ratio decreased the risk of FTR increased (p > 0.001). After risk adjusting for patient characteristics, both the effect of surgical volume (adjusted OR 0.66, 95% CI 0.46-0.94; p = 0.022) and nurse-to-patient ratio (adjusted OR 0.68, 95% CI 0.51-0.90; p = 0.008) remained strongly associated with FTR. CONCLUSION: FTR rates varied considerably among hospital performing hepatectomy. Higher procedure-specific hepatectomy volume, as well as a higher nurse-to-patient ratio, accounted for a reduction in the FTR rates. These data highlight the importance of not only procedure volume, but also adequate nurse staffing in reducing FTR and improving mortality following complex procedures such as hepatectomy. PMID- 30465088 TI - Laparoscopic right posterior sectionectomy: single-center experience and technical aspects. AB - PURPOSE: Laparoscopic right posterior sectionectomy (LRPS) is a technically demanding procedure. The aim of this article is to share our experience with LRPS and to highlight technical aspects of this procedure. METHODS: This is a single center retrospective analysis of all patients who underwent LRPS between September 2011 and October 2017. Data were retrieved from a prospectively maintained database. Video-in-picture (VIP) technology is used to facilitate and to highlight the technical aspects of this procedure. RESULTS: In total, 18 patients underwent LRPS. Indication for surgery was mainly liver metastases (n = 11) and hepatocellular carcinoma (n = 6). The Glissonean approach for inflow control was used in 13 patients. Median operative time was 162 (140-190) minutes. Median blood loss was 325 mL (IQR: 150-450). One conversion (5.5%) was required. There were two minor complications and one major complication. Median hospital stay was 6 days (range 5-8 days). All patients had an R0 resection. There was no 90-day mortality. CONCLUSION: The results of our experience in LRPS add weight to the feasibility and safety of this approach. PMID- 30465089 TI - miR-195 contributes to human osteoarthritis via targeting PTHrP. AB - The dysregulated expression of the osteoarthritis (OA)-related genes in cartilage, such as matrix metalloproteinase 13 (MMP-13) and type X collagen (Col X), facilitates the onset and progression of OA. Reduced parathyroid hormone related protein (PTHrP) may also accelerate this progression. Furthermore, miRNAs, endogenous regulators of mRNAs, are thought to play key roles in the pathogenesis of OA. In this study, we found that miR-195 levels were significantly upregulated in OA tissue, while PTHrP mRNA/protein expression was substantially downregulated, and there was a negative correlation between miR-195 and PTHrP. Upregulated miR-195 strongly inhibited Aggrecan, type II collagen (Col II) mRNA/protein expression, while it enhanced the expression of MMP-13 and Col X at mRNA/protein level; conversely, downregulated miR-195 significantly increased Col II mRNA/protein expression, while it decreased the expression of MMP-13 and Col X mRNA/protein. Moreover, our study demonstrated that PTHrP is a novel target of miR-195 using dual luciferase reporter assay. Finally, miR-195-mediated changes of Col II and OA-related genes were substantially attenuated by siRNAPTHrP treatment. These results suggested that miR-195 is involved in the pathogenesis of OA via PTHrP. PMID- 30465090 TI - Bone microstructure is significantly altered in CRPS-affected distal tibiae as detected by HR-pQCT: a retrospective cross-sectional study. AB - In the course of complex regional pain syndrome (CRPS), local osteopenia in the subchondral/subcortical areas of the affected limb represents a central manifestation. Mechanistic aspects of CRPS-associated pathologies remain unclear, and knowledge about bone morphology in CRPS-affected areas is rare. The aim of this study was to assess trabecular and cortical bone microstructure in patients with CRPS of the distal tibiae. We retrospectively analysed 14 women diagnosed with unilateral CRPS type I of the lower limb whose affected and unaffected distal tibiae were examined by high-resolution peripheral quantitative computed tomography (HR-pQCT). Laboratory tests included serum levels of calcium, phosphate, 25-hydroxyvitamin D, bone alkaline phosphatase, parathyroid hormone, osteocalcin and urinary levels of deoxypyridinoline (DPD). Bone mineral density was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and both proximal femurs. Average urinary DPD levels, a biochemical marker of bone resorption, were elevated in the examined patient cohort (7.1 +/- 1.9 nmol/mmol, reference 3.0-7.0 nmol/mmol). According to HR-pQCT, CRPS-affected distal tibiae showed significantly lower values of cortical BMD and cortical thickness compared to the unaffected contralateral side. Also, bone volume relative to total volume was significantly lower. Trabecular number and trabecular thickness tended to be lower in the affected tibiae. CRPS is associated with significant alterations in bone microstructure of the affected tibiae. Increased bone resorption seems to play a crucial role within a multifactorial process of CRPS-mediated bone atrophy. HR-pQCT could possibly serve as a diagnostic tool in specific CRPS therapy. PMID- 30465091 TI - Re-fracture and correlated risk factors in patients with osteoporotic vertebral fractures. AB - Re-fracture risk is higher following osteoporotic fracture. However, there is no accurately reported rate of re-fracture incidence in southwest China. The purpose of this study was to describe the osteoporotic vertebral fracture (OVF) survival for re-fracture state and analyze the risk of re-fracture. This historical cohort study was conducted in four hospitals in southwest China. Patients aged >= 50 years (n = 586) with OVF who were supposed to receive anti-osteoporosis drugs after the fracture were included (2012-2017). Telephone follow-up and referring case files were used to estimate the survival for re-fracture and identify the determinants of re-fracture. A total of 555 patients completed the follow-up investigation. Overall, 285 patients experienced a re-fracture, and the longest follow-up investigation time was 72 months. The survival rates for re-fracture at 12 months, 24 months, 36 months, and 48 months were 82.0%, 71.5%, 61.7%, and 34.0%, respectively. The factors correlated with re-fracture hazard were advanced age [hazard ratio (HR) = 1.996], being female (HR = 1.342), smoking (HR = 1.435), history of hypertension (HR = 1.219) and diabetes (HR = 3.271), and persistence of taking anti-osteoporosis drugs after fracture [0-3 months, 4-6 months, 7-12 months, and more than 12 months (HR = 0.703)]. OVF patients with advanced age, who were female, smoked, had fracture with hypertension or diabetes, and who complied poorly with anti-osteoporosis drug treatment presented higher prevalence of re-fracture and low anti-osteoporosis adherence in southwest China. The management of anti-osteoporosis after fracture is necessary in this area. PMID- 30465092 TI - Quantitation and distribution of metallic elements in sequestra of medication related osteonecrosis of jaw (MRONJ) using inductively coupled plasma atomic emission spectroscopy and synchrotron radiation X-ray fluorescence analysis. AB - Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse effect of antiresorptive agents like bisphosphonates. Abnormal concentrations of various trace metallic elements contained in bone minerals have been associated with MRONJ. In this study, we focused on trace metallic elements contained in the MRONJ sequestrum; their content and distribution were compared to those in osteomyelitis and non-inflammatory bones using inductively coupled plasma atomic emission spectroscopy (ICP-AES) and synchrotron radiation X-ray fluorescence analysis (SR-XRF). On ICP-AES analyses, various trace elements (Co, Cr, Cu, Fe, K, Mg, Ni, Sb, Ti, V, Pb) were significantly more in MRONJ sequestra than non inflammatory bones. The Cu content was significantly higher in MRONJ sequestra than osteomyelitis and non-inflammatory bones. The Cu content in MRONJ sequestra was high even after decalcification. Additionally, Cu was distributed along the trabecular structures in decalcified MRONJ specimens, as observed using SR-XRF analysis. Therefore, this study was indicative of the characteristic behavior of Cu in MRONJ. PMID- 30465093 TI - Innovations in Professional Inpatient Diabetes Education. AB - PURPOSE OF REVIEW: In the rapidly evolving and complex field of inpatient diabetes, complex care teams of physicians, nurse practitioners, physician assistants, nurses, and pharmacists are challenged to remain well informed of the latest clinical treatments and health care trends. Traditional continuing medical education (CME) and continuing education unit (CEU) strategies that require travel and/or time away from work pose a major barrier. With advancements in technology, there are media and other electronic strategies for delivering CME/ CEU that may overcome these current challenges. RECENT FINDINGS: Electronic and internet-based formats are growing due to their convenience, ease of use, lower cost, and ready access to large audiences. Some formats are already being used such as computer-based programs, simulations, and mobile CMEs and CEUs. Other strategies could be further explored including hospital credentialing, stewardship programs, and interdisciplinary health care professional education. However, there is little data on the utilization and efficacy of these newer formats. While traditional CME/CEU meetings prevail, there is a need and an emerging trend using electronic and internet based strategies that are particularly suited for inpatient diabetes education. These methods show great potential and deserve further exploration and development. PMID- 30465094 TI - Targeted deletion of rice retrotransposon Tos17 via CRISPR/Cas9. AB - KEY MESSAGE: A successful example of transposon deletion via CRISPR/Cas9-mediated genome editing suggests a novel alternative approach to plant breeding. Transposition of transposable elements (TEs) can affect adjacent genes, leading to changes in genetic traits. Expression levels and patterns, splicing and epigenetic status, and function of genes located in, or near, the inserted/excised locus can be affected. Artificial modification of loci adjacent to TEs, or TEs themselves, by genome editing could mimic the translocation of TEs that occurs in nature, suggesting that it might be possible to produce novel plants by modification of TEs via genome editing. To our knowledge, there are no reports thus far of modification of TEs by genome editing in plants. In this study, we performed targeted deletion of the Tos17 retrotransposon, which is flanked at both ends by long terminal repeat (LTR) sequences, via genome editing in rice. We succeeded in targeted mutagenesis of the LTR, and targeted deletion between LTRs, in calli transformed with CRISPR/Cas9 vectors for the Tos17 LTR. Moreover, we also successfully obtained regenerated plants derived from transformed calli and plants homozygous for lacking Tos17 in the next generation. Taken together, our results demonstrate successful deletion of the Tos17 retrotransposon from the rice genome by targeted mutagenesis using CRISPR/Cas9. We believe that this strategy could be applied to other TEs in many plant species, providing a rapid breeding technology as an alternative means to re activate expression of agronomically important genes that have been inactivated by TE insertion, especially in plants such as fruit trees, in which it is difficult to maintain parental agronomical traits by cross-breeding due to high heterozygosity. PMID- 30465095 TI - Validation of the French version of the KOOS-child questionnaire. AB - PURPOSE: The Knee Injury Osteoarthritis Outcome Score (KOOS) questionnaire is one of the frequently used outcome scores in pediatric studies. However, a recent study demonstrated that the pediatric population had a limited understanding of some of its questions. Therefore, the KOOS-Child questionnaire was developed specifically for this population. Our team produced a French adaptation based on the English version. The objective of the current study was to validate the French adaptation of the KOOS-Child questionnaire. METHODS: After ethic board approval, the questionnaire was translated from English to French by two French speaking orthopedic surgeons. Following consensus, the translated version was retranslated to English by a professional translator. A group of experts compared the original and back translated version and decided on a final adapted questionnaire version. Ninety-nine 8-16 year-old patients were prospectively recruited from our pediatric orthopedic surgery clinic. Twenty-one control participants and 78 patients suffering from knee pain were recruited. The participants were asked to answer the translated French version of the KOOS-Child questionnaire and two validated French pediatric quality of life surveys. RESULTS: Statistical analysis demonstrated no statistically significant demographic difference between the control population and the patients suffering from a knee pathology. The mean for the five different domains of the KOOS-Child questionnaire showed statistical differences (p < 0.001) between the two groups. Construct validity was demonstrated through testing of previously validated hypothesis of correlation. Internal consistency was also confirmed in injured patients. CONCLUSIONS: In conclusion, the current study results demonstrate good to excellent internal consistency, good construct validity and inconclusive discriminant capacity of the French adaptation of the KOOS-Child questionnaire. LEVEL OF EVIDENCE: II. PMID- 30465096 TI - Mountain ultramarathon results in temporary meniscus extrusion in healthy athletes. AB - PURPOSE: In recent literature medial meniscus extrusion (MME) was demonstrated as an age, BMI and load dependent physiological phenomenon in healthy knees. The aim of the present study was to evaluate the influence of mountain ultramarathon running on the medial meniscus extrusion (MME) in healthy athletes. METHODS: Healthy athletes of the 2017 Gore-Tex(r) Transalpine run (seven stages with in total 270.5 km and 16453 m altitude) with asymptomatic knee, and no history of knee injuries or surgeries were included. All athletes underwent standard knee examination, MRI to exclude further knee pathologies and ultrasound imaging (USI) for measurement of MME before the competition. Extrusion in USI was determined in supine position (unloaded) and in standing position with full weight bearing and 20 degrees of flexion (loaded). After the 1st, 3rd, and 7th stage ultrasound measurements were repeated directly after the competition. For evaluation of recovery, ultrasound measurement of MME was repeated 2 weeks after the race. Difference between ultrasound measurements of MME was assessed by unpaired t-test with significance set at p < 0.05. RESULTS: Eighteen athletes (mean age 37.4 +/- 8.3 years, 5 females, 13 males) were included in the study. The mean USI MME before the race was 1.9 mm +/- 0.3 mm in supine position and 2.4 mm +/- 0.4 mm under full weight bearing. During the race the mean MME increased significantly compared to baseline measurements. After 7th stage the mean MME in supine position was 2.7 mm +/- 0.7 mm and 3.1 mm +/- 0.6 mm under full weight bearing. After 2 weeks of recovery medial meniscus demonstrated a complete reversibility of the extrusion to normal (N.S). CONCLUSION: Medial meniscus extrusion observed under extreme loads generated by a mountain ultramarathon is a temporary and reversible phenomenon in healthy athletes. This suggests, that the meniscus has viscoelastic capacities showing short-term adaptions to high loads, which are completely reversible over time. For clinical practice assessment of the MME by ultrasound might be favorable compared to MRI due to the ability of dynamic evaluation and the easy access. Furthermore, load should be taken in account when assessing the MME and the current cut-off value of 3 mm for meniscus pathologies should be reconsidered. LEVEL OF EVIDENCE: IV. PMID- 30465097 TI - Relationship between bone plug position and morphological changes of tunnel aperture in anatomic rectangular tunnel ACL reconstruction. AB - PURPOSE: In animal studies after ACL reconstruction (ACL-R) using the bone patellar tendon-bone (BTB), the graft-healing pattern was found to depend on the relationship between bone plug and the tunnel wall. This difference of graft healing pattern could influence the postoperative morphological changes of the tunnel. However, no study has assessed the relationship between bone plug position and the change of tunnel morphology. Therefore, the main purpose of this study was to investigate the relationship between the bone plug position within femoral or tibial tunnel and morphological changes of each tunnel aperture in ACL R using computed tomography. METHODS: Subjects were 30 consecutive patients (six females and 24 males; mean age, 20.4 +/- 5.4 years) who underwent primary ACL-R using BTB. The distance from the tunnel aperture to the tendon-bone junction (TBJ) at 2 weeks postoperatively, and tunnel aperture enlargement and tunnel wall migration from 2 weeks to 6 months postoperatively, were evaluated. RESULTS: The distance from the femoral tunnel aperture to the TBJ in most cases was less than 2 mm, whereas the TBJ was located within the tibial tunnel. Femoral tunnel aperture was significantly enlarged (17.0 +/- 11.7%) distally, and the tibial tunnel aperture was significantly enlarged (19.6 +/- 12.5%) posterolaterally. Only the position at distal portion of femoral bone plug was correlated with femoral tunnel aperture enlargement (r = 0.454, p = 0.0015). CONCLUSION: Both femoral and tibial tunnel aperture were significantly enlarged distally and posterolaterally 6 months postoperatively. Only correlation between the position at distal portion of femoral bone plug and femoral tunnel enlargement were found, suggesting the deep plug position in the tunnel is a risk factor for femoral tunnel enlargement, highlighting the importance of accurately locating the TBJ just at the femoral tunnel aperture. Another option is to deviate the harvest site in the patellar tendon to match the shape of the TBJ and the tunnel aperture. LEVEL OF EVIDENCE: 4 (case series). PMID- 30465098 TI - Surgical treatment of posterior cruciate ligament lesions does not cause growth disturbances in pediatric patients. AB - PURPOSE: The aim of the present study was to describe epidemiology, management and outcome of pediatric and adolescent patients with posterior cruciate ligament (PCL) injuries. METHODS: Sixteen patients of less than 18 years of age with 7 PCL avulsion fractures and 9 PCL tears were included over a 10-year period. Trauma mechanism, additional injuries and treatment methods were analyzed. Follow-up examination included range of motion and ability to perform squats. Pedi-IKDC and Lysholm score were obtained and posterior shift was measured in kneeling view radiographs and compared to the contralateral side. Patients were grouped into pediatric patients with open physes at the time surgery and adolescent patients with closing or closed physes. In case of open physes, growth disturbances were assessed. RESULTS: Six of the treated patients (median age 12.5 years, range 10 13) had open physes at time of surgery. Five of those sustained avulsion fractures and treatment consisted of open reduction and screw fixation in four cases and graft reconstruction in one case. One patient sustained a PCL tear and underwent graft reconstruction. Follow-up at a median of 71.5 months (range 62 100) did not reveal any growth disturbances. Median Pedi-IKDC was 71.9 (range 51.7-92.1), median Lysholm score was 81.5 (range 66-88) and median posterior shift difference was 2.5 mm (range 0-11). The remaining 10 patients (median age 16 years, range 14-17) had closing/closed physis at the time of operation. Two patients presented with avulsion fractures treated with open reduction and screw fixation and 8 patients sustained PCL tears treated with graft reconstruction. At a median follow-up of 69.5 months (range 11-112), median Pedi-IKDC was 86.8 (range 36.8-97.7), median Lysholm score was 84.0 (range 45-95) and median posterior shift difference was 4 mm (range 0-15). CONCLUSIONS: In our small number of pediatric patients with PCL injuries, open reduction and epiphyseal screw fixation of displaced avulsed fractures and steep tunnel drilling in case of PCL reconstruction did not cause growth disturbances. Nevertheless, long-term functional impairment should be expected and close follow-up has to be recommended. LEVEL OF EVIDENCE: Therapeutic, Level IV. PMID- 30465099 TI - Minimally invasive Oxford unicompartmental knee arthroplasty ensures excellent functional outcome and high survivorship in the long term. AB - PURPOSE: Whether unicompartimental or total knee arthroplasty is superior for treatment of anteromedial knee osteoarthritis, is still uncertain. Therefore, the purpose of this study was to evaluate clinical and radiological outcome as well as long-term survivorship of medial Oxford unicompartmental knee arthroplasty (OUKA) at an independent center with a minimum follow-up of 10 years. METHODS: This single-center retrospective cohort study reports the 10-15 years follow-up results of 113 consecutive patients (126 knees) after medial OUKA. Survivorship analysis was performed with several different endpoints and clinical outcome was measured using the Oxford Knee Score (OKS), American Knee Society Score (AKSS-O), range of motion (ROM), Tegner activity score and UCLA score. Radiological analysis was performed with focus on progression of arthritis in the lateral compartment. RESULTS: A total of 16 patients (16 knees) underwent revision surgery resulting in a survival rate of 92.4% at 10 years and 88.6% at 15 years with the endpoint device-related revisions. The main reason for revision surgery was progression of arthritis in five patients (31.3%) followed by persistency of pain in three patients (18.7%). Clinical outcome was good to excellent with an OKS of 39.9 at 11 years, an AKSS-O of 89.3 and a mean range of motion of 122 degrees . The radiological analysis revealed a significant progression of degenerative changes in the lateral compartment, however without any impact on the functional outcome. CONCLUSION: Oxford UKA of the medial compartment ensures good long-term survivorship with an excellent functional outcome. Therefore, the results of this study support the continued use of OUKA in patients with anteromedial osteoarthritis. LEVEL OF EVIDENCE: Retrospective cohort study, Level III. PMID- 30465100 TI - An unusual presentation of superficial siderosis with focal dystonia and 'Giant panda morphology' on MRI: atypical clinicoradiological amalgam. PMID- 30465101 TI - MR evaluation of encephalic leukoaraiosis in sudden sensorineural hearing loss (SSNHL) patients. AB - Epidemiological evidence suggests a strict correlation between sudden sensorineural hearing loss (SSNHL) and cerebrovascular disorders. Leukoaraiosis represents a diffuse alteration of the periventricular and subcortical white matter. The aim of our study was to verify if the presence of white matter hyperintensity (WMH) was higher in patients affected by SSNHL compared to controls and evaluate the correlation between WMH and the cardiovascular risk factors, hearing level, and the response to therapy in SSNHL patients. The study group included 36 subjects affected by unilateral SSNHL. Thirty-six age- and sex matched normal subjects with a negative history of SSNHL were used as controls. All patients underwent magnetic resonance imaging (MRI) (1.5 Tesla GE Signa) and the extent of leukoaraiosis was assessed with the Fazekas scale. The results of the present study demonstrate a high prevalence of WMH in SSNHL patients compared to controls confirming the hypothesis of a vascular impairment in SSNHL patients. The higher recovery rate in patients with greater periventricular white matter hyperintensity (PWMH) may suggest a vascular etiology that is still responsive to medical treatment. We aim to expand both the number of patients and the controls to avoid the limitation of the still small number to warrant solid scientific conclusions. PMID- 30465102 TI - Classics in abdominal imaging: the atoll sign. PMID- 30465103 TI - People's explanatory preferences for scientific phenomena. AB - Previous work has found that people are drawn to explanations of psychological phenomena when these explanations contain neuroscience information, even when that information is irrelevant. This preference may be due to a general preference for reductive explanations; however, prior work has not investigated whether people indeed prefer such explanations or whether this preference varies by scientific discipline. The current study asked 82 participants to choose which methods would be most appropriate for investigating topics in six scientific fields. Participants generally preferred methods that either matched the field of investigation (e.g., biology for biology) or that came from the immediately more reductive field (e.g., chemistry for biology). Both of these patterns were especially evident for the pairing of psychology and neuroscience. Additionally, participants selected significantly more methods as being useful for explaining neuroscience phenomena. These results suggest that people's sense of the relations among scientific fields are fairly well calibrated but display some general attraction to neuroscience. PMID- 30465104 TI - Novel use of argon plasma coagulation (APC) in the treatment of high output small bowel mucous fistula. PMID- 30465105 TI - Discovery, properties, and biosynthesis of pseudouridimycin, an antibacterial nucleoside-analog inhibitor of bacterial RNA polymerase. AB - Pseudouridimycin (PUM) is a novel pseudouridine-containing peptidyl-nucleoside antibiotic that inhibits bacterial RNA polymerase (RNAP) through a binding site and mechanism different from those of clinically approved RNAP inhibitors of the rifamycin and lipiarmycin (fidaxomicin) classes. PUM was discovered by screening microbial fermentation extracts for RNAP inhibitors. In this review, we describe the discovery and characterization of PUM. We also describe the RNAP-inhibitory and antibacterial properties of PUM. Finally, we review available information on the gene cluster and pathway for PUM biosynthesis and on the potential for discovering additional novel pseudouridine-containing nucleoside antibiotics by searching bacterial genome and metagenome sequences for sequences similar to pumJ, the pseudouridine-synthase gene of the PUM biosynthesis gene cluster. PMID- 30465106 TI - Adherence to Antiretroviral Therapy Among Incarcerated Persons with HIV: Associations with Methadone and Perceived Safety. AB - With adequate support, people with HIV (PWH) may achieve high levels of adherence to antiretroviral therapy (ART) during incarceration. We examined factors associated with ART utilization and adherence among incarcerated PWH (N = 150) in Indonesia. ART utilization was positively associated with HIV status disclosure (adjusted odds ratio [aOR] = 5.5, 95% CI 1.2-24.1, p = 0.023), drug dependency (aOR = 3.9, 95% CI 1.2-12.6, p = 0.022), health service satisfaction (aOR = 3.2, 95% CI 1.7-6.2, p < 0.001), and perceived need for medical treatment (aOR = 1.6, 95% CI 1.1-2.5, p = 0.011), and negatively associated with chance locus of control (aOR = 0.3, 95% CI 0.1-0.7, p = 0.013). Most participants utilizing ART (74.5%) reported less than "perfect" ART adherence. ART adherence was independently associated with perceived personal safety (beta = 0.21, 95% CI 0.01 0.40, p = 0.032) and methadone utilization (beta = 0.84, 95% CI 0.10-1.67, p = 0.047). PWH receiving methadone had a sixfold higher adjusted odds of being highly-adherent to ART (aOR = 6.3, 95% CI 1.1-35.7, p = 0.036). Interventions that increase methadone utilization and personal safety may improve ART adherence among incarcerated PWH. PMID- 30465107 TI - Gender Differences and Psychosocial Factors Associated with Problem Drinking Among Adults Enrolling in HIV Care in Tanzania. AB - Problem drinking is commonly reported among people living with HIV (PLWH), associated with suboptimal HIV care outcomes and differs by gender. Psychosocial factors associated with problem drinking among PLWH remain poorly understood, including whether they differ by gender. This analysis examines the relationship between psychosocial factors and problem drinking separately by gender among PLWH in Tanzania. Cross-sectional data were collected from 812 men and non-pregnant women living with HIV aged 18 or older enrolling in HIV care at four health facilities in Tanzania. Problem drinking was assessed with the CAGE Questionnaire and defined as responding yes to two or more items. Sex-stratified multivariable logistic regression modeled the association of social support, HIV-related stigma, and physical or sexual violence on problem drinking, controlling for age, relationship status, employment, having been away from home for more than one month, and timing of first HIV-positive diagnosis. Thirteen percent of the sample reported problem drinking, with problem drinking significantly more commonly reported among men than non-pregnant women (17.6% vs. 9.5%). Among men and non pregnant women, in multivariable analyses, enacted and internalized HIV-related stigma were significantly positively associated with problem drinking. Screening and treatment of problem drinking should be integrated into HIV care. Evidence based substance abuse interventions should be adapted to address HIV-related stigma. Future research should longitudinally investigate the interrelationships between stigma, violence, and problem drinking among PLWH. PMID- 30465108 TI - Dispersive micro-solid phase extraction of 16 priority polycyclic aromatic hydrocarbons from water by using thermally treated clinoptilolite, and their quantification by GC-MS. AB - The authors report on a novel sorbent (thermally treated natural zeolite; clinoptilolite) for use in dispersive micro-solid phase extraction (D-MU-SPE) of polycyclic aromatic hydrocarbons (PAHs) from water samples. The method was applied to the D-MU-SPE of 16 priority PAHs which then were quantified by gas chromatography with mass spectrometric detection (GC-MS). The method was validated in terms of specificity and selectivity, linearity and linear range, accuracy, precision, uncertainty, limits of detection and quantification. Figures of merit include (a) linear analytical ranges between 2.08 and 208 ppb, and (b) detection limits in the range from 0.01 to 0.92 ppb. The method was successfully applied to the determination of PAHs in river waters. Graphical abstract Schematic representation of dispersive micro-solid phase extraction (D-MU-SPE) of trace levels of PAHs in water samples by using thermally treated clinoptilolite as sorbent prior to gas chromatography-mass spectrometry analysis (GC-MS). PMID- 30465109 TI - Can ultrasonographic measurement of carotid intima-media thickness predict hypotension after induction of general anesthesia? AB - Hypotension in patients under general anesthesia is prevalent and causes unfavorable outcomes. Carotid intima-media thickness (CIMT) is a surrogate marker for atherosclerosis and useful for evaluating the risk of cardiovascular diseases. We investigated the usefulness of preoperative CIMT measurement as a predictor of post-induction hypotension (PIH). The ultrasonographic measurement of CIMT was performed preoperatively on 82 patients scheduled for elective surgery under general anesthesia in a prospective, observational study. Mean blood pressure (MBP) was recorded before induction. Hypotension was defined as a 20% decrease in MBP from baseline. The ultrasonographic measurement of CIMT was unsuccessful in 2 (2.43%) patients, leaving 80 patients for analyses. Hypotension developed in 41 patients. CIMT was higher in the patient group with PIH than in the group without PIH (p < 0.001). There was statistically significant correlation between MBP decrease after induction and CIMT (r = 0.529, p < 0.0001). CIMT correlated positively with age (r = 0.739, p < 0.0001). The area under curve for CIMT was 0.753 [95% confidence interval (CI) 0.642-0.863]. The optimal cutoff value of CIMT was 0.65 mm with a sensitivity of 75.6% and a specificity of 74.4%. CIMT was an independent predictor of PIH after adjusting other factors with an odds ratio of 1.833 (95% CI 1.23-2.72; p = 0.003). The ultrasonographic imaging and measurement of CIMT can reliably predict hypotension with a 0.65-mm threshold level. We believe that the ultrasonographic measurements of CIMT may be included in point-of-care application in anesthesiology. PMID- 30465110 TI - Digital quantification of KI-67 in breast cancer. AB - Ki-67 proliferative index (Ki-67) is a predictive and prognostic factor in breast cancer (BC). However, some international committees do not recommend its use in routine practice due to insufficient clinical evidence and lack of standardisation and assessment method reproducibility. Scoring of Ki-67 by digital pathology may contribute to overcome these drawbacks. We evaluated 136 core biopsies of BC patients and calculated the correlation of Ki-67 scored by two breast pathologists with two methods, eyeballing visual assessment (EB) on the microscope and digital image analysis (DI), both assessed from hot spot areas (HS) and the average between hot and cold spot areas (AVE). Good and higher correlation between pathologists was observed for HS using DI in comparison to EB (0.861 vs. 0.828). Correlation in HS with both methods was very similar in homogeneous tumours (0.869 vs. 0.866). Lower correlation was found in heterogeneous tumours if EB was used instead of DI (0.691 vs. 0.838). Good agreement with DI in AVE areas was observed in both homogenous and heterogeneous tumours (0.898 and 0.887). Concordance of tumour molecular profiles based on Ki 67 was better using DI in comparison to EB (Kappa index, 0.589 vs. 0675). Whereas EB and DI were alike in homogeneous tumour, DI improved agreement in heterogeneous tumours, particularly in AVE areas. Subgroup analysis for tumour grades also showed improvement of correlation by DI in AVE areas in all G1/G2/G3 groups. Digital pathology using AVE method can be useful for Ki-67 scoring in daily practice, especially in heterogeneous and G2 tumours, by a substantial improvement of agreement between observers and results accuracy. PMID- 30465111 TI - Correction to: Abstracts : 30th European Congress of Pathology. AB - The authors of PS-03-018 wish to clarify the Funding details related to their abstract. The abstract is included in full below - no changes have been made to the abstract beyond listing the Funding information. PMID- 30465112 TI - A novel recombinant genome of minute virus of canines in China. AB - In this study, we determined almost all of the genome sequence of minute virus of canines (MVC) strain CDK47/2017 and performed phylogenetic analysis with this isolate and other MVC isolates. The genome of CDK47/2017 has the following characteristics: 1) The amino acid sequence of the NS1 protein is similar to that of the novel strain 15D009/KT241026.1, which has 17 identical amino acid changes and two identical amino acid insertions compared with other known MVC strains. These two strains clustered in a unique branch in an NSI-based phylogenetic tree. 2) Phylogenetic analysis based on the NP1 protein showed that strain CDK47/2017clustered in an independent branch with strains 15D009/KT241026.1 and HM-6/AB158475.1, both of which has 10 identical amino acid changes compared with other known MVC strains. 3) Eight unique amino acid substitutions of the CDK47/2017 capsid protein resulted in it forming a unique branch in the phylogenetic tree. 4) Recombination events were identified between the 3' end of the NS1 gene and 5' end of NP1 gene. Together, these characteristics suggest that strain CDK47/2017 represents a novel MVC strain that is distinct from all known MVC strains with sequences in the GenBank database. This contributes to a greater understanding of the genetic evolution of MVC. PMID- 30465113 TI - BEST and SOFAST experiments for resonance assignment of histidine and tyrosine side chains in 13C/15N labeled proteins. AB - Aromatic amino-acid side chains are essential components for the structure and function of proteins. We present herein a set of NMR experiments for time efficient resonance assignment of histidine and tyrosine side chains in uniformly 13C/15N-labeled proteins. The use of band-selective 13C pulses allows to deal with linear chains of coupled spins, thus avoiding signal loss that occurs in branched spin systems during coherence transfer. Furthermore, our pulse schemes make use of longitudinal 1H relaxation enhancement, Ernst-angle excitation, and simultaneous detection of 1H and 13C steady-state polarization to achieve significant signal enhancements. PMID- 30465114 TI - Abiotic stress regulates expression of galactinol synthase genes post transcriptionally through intron retention in rice. AB - MAIN CONCLUSION: Expression of the Galactinol synthase genes in rice is regulated through post-transcriptional intron retention in response to abiotic stress and may be linked to Raffinose Family Oligosaccharide synthesis in osmotic perturbation. Galactinol synthase (GolS) is the first committed enzyme in raffinose family oligosaccharide (RFO) synthesis pathway and synthesizes galactinol from UDP-galactose and inositol. Expression of GolS genes has long been implicated in abiotic stress, especially drought and salinity. A non canonical regulation mechanism controlling the splicing and maturation of rice GolS genes was identified in rice photosynthetic tissue. We found that the two isoforms of Oryza sativa GolS (OsGolS) gene, located in chromosomes 3(OsGolS1) and 7(OsGolS2) are interspersed by conserved introns harboring characteristic premature termination codons (PTC). During abiotic stress, the premature and mature transcripts of both isoforms were found to accumulate in a rhythmic manner for very small time-windows interrupted by phases of complete absence. Reporter gene assay using GolS promoters under abiotic stress does not reflect this accumulation profile, suggesting that this regulation occurs post transcriptionally. We suggest that this may be due to a surveillance mechanism triggering the degradation of the premature transcript preventing its accumulation in the cell. The suggested mechanism fits the paradigm of PTC induced Nonsense-Mediated Decay (NMD). In support of our hypothesis, when we pharmacologically blocked NMD, the full-length pre-mRNAs were increasingly accumulated in cell. To this end, our work suggests that a combined transcriptional and post transcriptional control exists in rice to regulate GolS expression under stress. Concurrent detection and processing of prematurely terminating transcripts coupled to repressed splicing can be described as a form of Regulated Unproductive Splicing and Translation (RUST) and may be linked to the stress adaptation of the plant, which is an interesting future research possibility. PMID- 30465115 TI - Engineering cyanobacteria for production of terpenoids. AB - MAIN CONCLUSION: This review summarizes recent advances in cyanobacterial terpenoid production. The challenges and opportunities of improving terpenoid production by cyanobacteria are discussed. Terpenoids are a diverse group of natural products with a variety of commercial applications. With recent advances in synthetic biology and metabolic engineering, microbial terpenoid synthesis is being viewed as a feasible approach for industrial production. Among different microbial hosts, cyanobacteria have the potential of sustainable production of terpenoids using light and CO2. Terpene synthases and the precursor pathways have been expressed in cyanobacteria for enhanced production of various terpene hydrocarbons, including isoprene, limonene, beta-phellandrene, and farnesene. However, the productivities need to be further improved for commercial production. Many barriers remain to be overcome in order to efficiently convert CO2 to terpenoids. In this review, we will summarize recent efforts on photosynthetic production of terpenoids and discuss the challenges and opportunities of engineering cyanobacteria for terpenoid bioproduction. PMID- 30465117 TI - The Family Practice. PMID- 30465116 TI - Immigration Legal Services as a Structural HIV Intervention for Latinx Sexual and Gender Minorities. AB - Lack of legal immigration status is associated with poor HIV-related outcomes for immigrant Latinx sexual and gender minorities (LSGM). LSGM often meet eligibility criteria for legal immigration relief. A Medical-Legal Partnership (MLP) may thus be strategic to improve their health. We know little about the challenges LSGM face during the immigration legal process. We conducted in-depth interviews with six key informants and sixteen LSGM who recently applied for immigration legal relief. We coded and analyzed the data for emergent themes. Challenges to instituting an MLP for LSGM included lack of specialized training on working with SGM for immigration attorneys, and for clients: knowledge about legal deadlines, lack of housing and family support, and re-traumatizing experiences. Clients' outcomes were positive when attorneys and mental health providers collaborated. For LSGM, the benefits of immigration relief included reduced HIV risk. An MLP that addresses the surmountable challenges could improve HIV-related outcomes among LSGM. PMID- 30465118 TI - International Conference on "Photosynthesis and Hydrogen Energy Research for Sustainability-2017". PMID- 30465119 TI - The regulatory network of miR-141 in the inhibition of angiogenesis. AB - The miR-200 family, consisting of miR-200a/b/c, miR-141, and miR-429, is well known to inhibit epithelial-to-mesenchymal transition (EMT) in cancer invasion and metastasis. Among the miR-200 family members, miR-200a/b/c and miR-429 have been reported to inhibit angiogenesis. However, the role of miR-141 in angiogenesis remains elusive, as contradicting results have been found in different cancer types and tumor models. Particularly, the effect of miR-141 in vascular endothelial cells has not been defined. In this study, we used several in vitro and in vivo models to demonstrate that miR-141 in endothelial cells inhibits angiogenesis. Additional mechanistic studies showed that miR-141 suppresses angiogenesis through multiple targets, including NRP1, GAB1, CXCL12beta, TGFbeta2, and GATA6, and bioinformatics analysis indicated that miR 141 and its targets comprise a powerful and precise regulatory network to modulate angiogenesis. Taken together, these data not only demonstrate an anti angiogenic effect of miR-141, further strengthening the critical role of miR-200 family in the process of angiogenesis, but also provides a valuable cancer therapeutic target to control both angiogenesis and EMT, two essential steps in tumor growth and metastasis. PMID- 30465120 TI - Osteoblasts Regulate Angiogenesis in Response to Mechanical Unloading. AB - During mechanical unloading, endothelial cells reduce osteogenesis and increase bone resorption. Here we describe the feedback response of endothelial cells to unloaded osteoblasts. Primary endothelial cells, ex vivo mouse aortic rings and chicken egg yolk membranes were incubated with conditioned medium from mouse primary osteoblasts (OB-CM) subjected to unit gravity or simulated microgravity, to assess its effect on angiogenesis. In vivo injection of botulin toxin A (Botox) in the quadriceps and calf muscles of C57BL/6J mice was performed to mimic disuse osteoporosis. Unloaded osteoblasts showed strong upregulation of the pro-angiogenic factor, VEGF, and their conditioned medium increased in vitro endothelial cell viability, Cyclin D1 expression, migration and tube formation, ex vivo endothelial cell sprouting from aortic rings, and in ovo angiogenesis. Treatment with the VEGF blocker, avastin, prevented unloaded OB-CM-mediated in vitro and ex vivo enhancement of angiogenesis. Bone mechanical unloading by Botox treatment, known to reduce bone mass, prompted the overexpression of VEGF in osteoblasts. The cross talk between osteoblasts and endothelial cells plays a pathophysiologic role in the response of the endothelium to unloading during disuse osteoporosis. In this context, VEGF represents a prominent osteoblast factor stimulating angiogenesis. PMID- 30465121 TI - Molecular signatures for CCN1, p21 and p27 in progressive mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is a comparatively rare non-Hodgkin's lymphoma characterised by overexpression of cyclin D1. Many patients present with or progress to advanced stage disease within 3 years. MCL is considered an incurable disease with median survival between 3 and 4 years. We have investigated the role(s) of CCN1 (CYR61) and cell cycle regulators in progressive MCL. We have used the human MCL cell lines REC1 < G519 < JVM2 as a model for disease aggression. The magnitude of CCN1 expression in human MCL cells is REC1 > G519 > JVM2 cells by RQ-PCR, depicting a decrease in CCN1 expression with disease progression. Investigation of CCN1 isoform expression by western blotting showed that whilst expression of full-length CCN1 was barely altered in the cell lines, expression of truncated forms (18-20 and 28-30 kDa) decreased with disease progression. We have then demonstrated that cyclin D1 and cyclin dependent kinase inhibitors (p21CIP1and p27KIP1) are also involved in disease progression. Cyclin D1 was highly expressed in REC1 cells (OD: 1.0), reduced to one fifth in G519 cells (OD: 0.2) and not detected by western blotting in JVM2 cells. p27KIP1 followed a similar profile of expression as cyclin D1. Conversely, p21CIP1 was absent in the REC1 cells and showed increasing expression in G519 and JVM2 cells. Subcellular localization detected p21CIP1/ p27KIP1 primarily within the cytoplasm and absent from the nucleus, consistent with altered roles in treatment resistance. Dysregulation of the CCN1 truncated forms are associated with MCL progression. In conjunction with reduced expression of cyclin D1 and increased expression of p21, this molecular signature may depict aggressive disease and treatment resistance. PMID- 30465122 TI - Reflections on a Health Psychology Service for Patients with Uveal Melanoma: The Challenge of Psychological Screening and Intervention When Distress is 'Normal'. AB - We appraise the role of screening for distress as part of health psychology assessment of patients newly diagnosed with cancer. We reviewed records of consecutive patients who accepted a health psychologist's assessment over 4 years, examining convergence and divergence of the result of screening (whether patients reached threshold as 'cases') with the psychologist's clinical judgment of need for intervention. Of 261 patients, 88 (33.7%) were 'cases'. Of these, need for psychological intervention was identified in 70 (79.5%). Of the 173 (66.3%) 'non-cases', need was identified in 59 (34.1%). Examination of cases where the psychologist's judgment diverged from screening showed that 'caseness' can arise from distress that patients can manage themselves and, conversely, that psychological needs arise in the absence of overt distress. Formal screening may not identify need for psychological intervention. The psychologist's role is to make expert judgments of patients' current and future needs. Dialogue with patients should be the vehicle for assessment. PMID- 30465123 TI - Body Weight Considerations in the Management of Type 2 Diabetes. AB - Obesity is one of the main risk factors for type 2 diabetes (T2D), representing a major worldwide health crisis. Modest weight-loss (>= 5% but < 10%) can minimize and reduce diabetes-associated complications, and significant weight-loss can potentially resolve disease. Treatment guidelines recommend that intensive lifestyle interventions, pharmacologic therapy, and/or metabolic surgery be considered as options for patients with T2D and obesity. The benefits and risks of such interventions should be evaluated in the context of their weight-loss potential, ability to sustain weight change, side effect profile, and costs. Antihyperglycemia therapies have considerable effects on patient weight, prompting careful consideration of weight-loss or weight-neutral therapies for patients with T2D who also have obesity. Metformin, sodium glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), alpha glucosidase inhibitors, and amylin mimetics promote weight-loss. Dipeptidyl peptidase-4 inhibitors and fixed-ratio insulin/GLP-1 RA combination therapies (IDegLira, iGlarLixi) appear to be weight-neutral. Thiazolidinediones, insulin secretagogues (sulfonylureas, meglitinides), and insulins are associated with weight gain. Sulfonylureas are additionally associated with a higher risk of serious hypoglycemia from hyperinsulinemia, making them less suitable for the treatment of patients who are overweight or have obesity. Patients are often overtitrated on basal insulin, resulting in an increased risk of hypoglycemia and weight gain without achieving glycemic goals. Given these observations, the effects of antihyperglycemia agents on weight should be considered when individualizing T2D therapy.Funding: Sanofi US, Inc. PMID- 30465124 TI - Transcutaneous bilirubin nomogram for evaluating the risk of hyperbilirubinemia in Iranian healthy newborns. AB - BACKGROUND: Hyperbilirubinemia, which is mostly benign, is one of the most common problems in neonates. This study was conducted to draw a skin bilirubin nomogram for evaluating the risk of hyperbilirubinemia requiring treatment. METHODS: This cross-sectional study recruited 1066 healthy infants. The first transcutaneous bilirubin (TcB) measurement was performed before hospital discharge and within 12 48 h of birth. The neonates were followed up for 6 days after discharge based on their age at the time of discharge. The neonates were divided into four groups based on the TcB values before discharge and age in hours, including the low risk, medium-low-risk, medium-high-risk and high-risk groups. The percentage of neonates who progressed toward severe hyperbilirubinemia was then calculated in each percentile based on the follow-up TcB measurement. Stata software was used to draw the nomogram. Based on the TcB values at discharge and the neonate's age in hours, the skin bilirubin nomogram was drawn in 40, 75 and 95 percentiles. RESULTS: A total of 4.9% of the neonates were in the high-risk group, 18.9% in the medium-high-risk group, 34.8% in the medium-low-risk group and 41.2% in the low-risk group. The risk of severe jaundice in the follow-up of the neonates in the highest-risk to the lowest-risk groups was 48.9, 14.5, 9.7 and 3.3%, respectively. CONCLUSION: The skin bilirubin nomogram can be used to predict severe hyperbilirubinemia in Iranian infants. PMID- 30465125 TI - Liver fibrosis in biliary atresia. AB - BACKGROUND: Biliary atresia (BA) is the most common cause of obstructive jaundice in infants. Although the Kasai procedure has greatly improved the prognosis, most patients still need liver transplantation (LT) for long-term survival. The pathogenesis of BA has not been fully clarified, and liver fibrosis in BA is far beyond biliary obstructive cirrhosis. DATA SOURCES: Literature reviews were underwent through PubMed. Persistent inflammation, immune response, biliary epithelial-mesenchymal transition, matrix deposition, decompensated angiogenesis, and unique biliary structure development all contribute to the fibrosis process. Observed evidences in such fields have been collected and form the backbone of this review. RESULTS: Interactions of the multiple pathways accelerate this process. CONCLUSIONS: Understanding the mechanisms of the liver fibrosis in BA may pave the way to improved survival after the Kasai procedure. PMID- 30465126 TI - Perceptions of parents of children with hearing loss of genetic origin in South Africa. AB - More than 80% of people with hearing loss (HL) live in low- and middle-income countries. Up to 90% of deaf children are born to hearing parents, leading to novel parenting, communication, educational, and psychosocial experiences. Half of congenital pre-lingual HL is genetic, with a relatively high recurrence risk that may lead to specific challenges for parents of affected children. Currently, little is known of genes implicated and causative mutations for most populations who have HL in Sub-Saharan Africa, as well as genetic counseling services needs for this population. Therefore, this study aimed to explore parents' perceptions and understanding of the genetic etiology of their child's HL, in order to inform policies and services. In-depth qualitative interviews were conducted with 11 parents of children who have non-syndromic HL of putative genetic origin. Data were analyzed through the framework approach. Three salient themes emerged, namely comprehension and understanding of the cause, in which most parents were unable to identify the potential hereditary cause of their child's HL; responsibility and blame; and their perception of genetic counseling and testing. Most of the participants had positive attitudes towards genetic testing, describing that it may provide answers and that the information gained would be helpful for the future. The data could assist in understanding the challenges faced by parents, in the absence of genetic testing, emphasizing the need for accurate genetic testing to support counseling services to parents of children with HL in an African Setting. PMID- 30465127 TI - Universal tumor screening for Lynch syndrome: perspectives of Canadian pathologists and genetic counselors. AB - Universal screening of all newly diagnosed colorectal cancer tumors can identify individuals at high risk for Lynch syndrome (LS), a hereditary cancer syndrome predisposing carriers to increased risk of colorectal, endometrial, and other cancers. To inform planning of a universal tumor screening program for LS in our jurisdiction, we undertook online surveys of Canadian pathologists and genetic counselors to describe existing tumor screening programs. Online surveys were hosted on SurveyMonkey between October 2016 and March 2017. Fifty-three pathologists and 66 genetic counselors completed surveys (total n = 119). While attitudes towards tumor screening were positive, considerable variability was observed in the existence of tumor screening, test ordering criteria, and practices. Most respondents indicated consent was not obtained for tumor screening nor were educational materials provided to patients; however, opting out of additional mutation testing in the event of a positive tumor screen was endorsed. Results add to the growing literature on providers' perspectives on population-based tumor screening programs and inform ways to offer these. Findings highlight the need to develop methods of patient education that allow meaningful opt-out decisions. The variability we observed also suggests the need for national standards and guidance on tumor screening for LS. PMID- 30465128 TI - Cardiac T2 star mapping: standardized inline analysis of long and short axis at three identical 1.5 T MRI scanners. AB - T2 star mapping can be applied for in vivo cardiac iron quantification. Current recommendations of imaging acquisition, post-processing and interpretation of normal values are based on old scanner types and in house software packages. A standardized comparison of short (SAX) and long axis (LAX) segments using commercially available software packages and modern scanners is lacking. To provide a standardized comparison of T2 star time values in SAX and LAX and to investigate intersegmental, interregional and inter-level comparison and the interscanner reproducibility. 84 cardiac MRIs in 28 healthy volunteers were performed with three structurally identical 1.5 T MRI scanners. A commercially available software package for T2 star mapping with automatic in-line motion correction was used for analysis. Regions of interest were manually placed in each of the 16 myocardial segments according to the AHA model in three SAX and three LAX. A total of 2856 ROIs were drawn and 102 segments per volunteer were analysed. Interscanner reproducibility was high (91%) and the mean myocardial T2 star time value for all evaluated segments was 34 +/- 5.7 ms. No significant difference was found between all measurements in SAX (35 +/- 5.5 ms) and LAX (34 +/- 5.8 ms). T2 star time values varied significantly between heart segments in the same axis and in 44% between corresponding SAX and LAX segments. T2 star time values in SAX and LAX have a high interscanner reproducibility but can vary significantly between heart segments in the same axis. Comparability between corresponding SAX and LAX segments is limited. To get representative results T2 star time values should be obtained in more than one heart segment and for follow up studies identical segments should be used to avoid a systematic bias. PMID- 30465129 TI - Evaluation of Chlorella sorokiniana isolated from local municipal wastewater for dual application in nutrient removal and biodiesel production. AB - The isolated microalga Chlorella sorokiniana BENHA721_ABO4 was grown in Bold's basal medium (BBM) as a control, municipal wastewater (WW), and wastewater enriched with BBM elements (WW+). Cultivation in WW+ showed the highest cell number which represented 25.3 and 47.3% over that grown in WW and BBM, respectively. However, rapid growth in WW+ was accompanied by significant reduction in lipid content. Due to lipid accumulation in WW, it showed the maximum significant lipid productivity of 16.2 mg L-1 day-1. Microalgae cultivation in WW for 10 days showed 74.2, 83.3, and 78.0% removal efficiency for NO3-N, NH3-N and TP, respectively. In addition, growth in WW significantly reduced polyunsaturated fatty acids by 36.0% with respect to BBM in favor of monounsaturated fatty acids. The present results confirmed that C. sorokiniana isolate BENHA721_ABO4 grown in secondary effluent municipal wastewater offers real potential for future application in wastewater treatment and biodiesel production. PMID- 30465130 TI - Assessment of the impact of public hospital associations (PHAs) on the efficiency of hospitals under the ministry of health in Turkey with data envelopment analysis. AB - This study aimed to reflect the efficiency of hospitals under the Ministry of Health (MoH) before and after the implementation of Public Hospital Associations (PHAs). This study covered 3 years before (2010-2012) and 3 years after (2013 2015) the implementation. The population of the study included 865 hospitals under the MoH providing health care services in 81 provinces. No sample was selected; all hospitals were included under the scope of study. The provinces were chosen as the decision-making unit. Changes in the efficiency values of hospitals were analyzed with the Malmquist Total Factor Efficiency Index. The results showed that, for the pre-PHAs period, 24 provinces in 2010, 27 provinces from 2010 to 2011, and 32 provinces from 2011 to 2012 were assessed as efficient. From 2012, the year of implementation, to 2013, the number of efficient provinces dropped to 16. However, 20 provinces were subsequently found to be efficient from 2013 to 2014, and 26 from 2014 to 2015. The efficiency scores average of all provinces were found to be 0.89, 0.92, 0.92, 0.82, 0.88, and 0.90, respectively. Further, the efficiency score average of the 3 years before PHAs (0.91 +/- 0.09) was significantly higher than the score obtained 3 years after PHAs (0.86 +/- 0.11; p < 0.05). In consideration of such finding, the PHAs established at the provinces were identified as hampering increased efficiency. PMID- 30465132 TI - Regulation mechanism of microRNA in plant response to abiotic stress and breeding. AB - microRNAs (miRNAs) in plants are a class of small RNAs consisting of approximately 21-24 nucleotides. The mature miRNA binds to the target mRNA through the formation of a miRNA-induced silencing complex (MIRISC), and cleaves or inhibits translation, thereby achieving negative regulation of the target gene. Based on miRNA plays an important role in regulating plant gene expression, studies on the prediction, identification, function and evolution of plant miRNAs have been carried out. In addition, many researches prove that miRNAs are also involved in many kinds of abiotic and biotic stress, under abiotic stress, plants can express some miRNA, and act on stress-related target genes, which can make plants adapt to stress in physiological response. In this review, the synthetic pathway and mechanism of plant miRNA are briefly described, and we discuss the biological functions and regulatory mechanisms of miRNAs responding to abiotic stresses including low temperature, salt, drought stress and breeding to lay the foundation for further exploring the mechanism of action of miRNAs in stress resistance of plant. And analyze its utilization prospects in plant stress resistance research. PMID- 30465131 TI - Pharmacological Treatment of Pain in Osteoarthritis: A Descriptive Review. AB - PURPOSE OF REVIEW: Osteoarthritis (OA) is the most common form of arthritis that is characterized by loss of articular cartilage and new formation of bone. Pain and functional disability are common features that lead to disability and poor quality of life. This review discusses the current state of knowledge concerning the treatment of pain in OA, with a focus on pharmacological treatments. This includes the use of non-steroidal anti-inflammatory drugs, acetaminophen, and other disease-modifying agents. RECENT FINDINGS: An updated review of the role of anti-nerve growth factor monoclonal antibodies and other novel agents in the treatment of OA is also presented. In addition, a discussion of current research on biological agents such as small molecules targeting ion channels and G protein coupled receptors is included. These new pharmacological interventions expand the frontier for treatment of patients with OA. The purpose of the review is to provide clinicians with information about the effectiveness of different pharmacological modalities in order to enable them to make the best choices for the treatment of their patients. PMID- 30465133 TI - Designing of an epitope-based peptide vaccine against walking pneumonia: an immunoinformatics approach. AB - Mycoplasma pneumoniae is a substantial respiratory pathogen that develops not only pneumonia but also other respiratory diseases, which mimic viral respiratory syndromes. Nevertheless, vaccine development for this pathogen delays behind as immunity correlated with protection is now predominantly unknown. In the present study, an immunoinformatics pipeline is utilized for epitope-based peptide vaccine design, which can trigger a critical immune response against M. pneumoniae. A total of 105 T-cell epitopes from 12 membrane associated proteins and 7 T-cell epitopes from 5 cytadherence proteins of M. pneumoniae were obtained and validated. Thus, 18 peptides with 9-mer core sequence were identified as best T-cell epitopes by considering the number of residues with > 75% in favored region. Further, the crucial screening studies predicted three peptides with good binding affinity towards HLA molecules as best T-cell and B-cell epitopes. Based on this result, visualization, and dynamic simulation for the three epitopes (WIHGLILLF, VILLFLLLF, and LLAWMLVLF) were assessed. The predicted epitopes needs to be further validated for their adept use as vaccine. Collectively, the study opens up a new horizon with extensive therapeutic application against M. pneumoniae and its associated diseases. PMID- 30465134 TI - Omidenepag Isopropyl Ophthalmic Solution 0.002%: First Global Approval. AB - Omidenepag isopropyl ophthalmic solution 0.002% (EYBELIS(r)) is a selective prostaglandin E2 receptor 2 agonist with a non-prostaglandin structure that is being developed by Ube Industries and Santen Pharmaceutical in Japan, Singapore and the USA for the treatment of glaucoma and ocular hypertension. Based on results from phase III trials, omidenepag isopropyl ophthalmic solution 0.002% received approval in Japan in September 2018 for this indication. This article summarizes the milestones in the development of omidenepag isopropyl ophthalmic solution 0.002% leading to this first global approval for the treatment of glaucoma and ocular hypertension. PMID- 30465135 TI - Enzyme-catalyzed regio-selective demethylation of papaverine by CYP105D1. AB - OBJECTIVES: To investigate the regio-selective demethylation of papaverine by CYP105D1 and develop a whole-cell biocatalytic system for the preparative synthesis of 6-O-demethyl-papaverine. RESULTS: CYP105D1 from Streptomyces griseus ATCC 13273 was used for the regioselective demethylation of papaverine at C-6 using putidaredoxin reductase (PDR) and putidaredoxin (Pdx) as the electron transport system. The Km value of CYP105D1 towards papaverine was estimated to be 92.24 MUM. Furthermore, a CYP105D1-based whole-cell system was established in E. coli BL21(DE3). The whole cell biotransformation condition was optimized as 25 degrees C, pH 7.5, 8 g (cell dry weight) L-1 whole cell biomass and 3% (v/v) PEG 200 as cosolvent. Under the optimal condition, the conversion yield of papaverine reached to 61.15% within 24 h. CONCLUSIONS: The selective demethylation of papaverine by CYP105D1 was accomplished. The CYP105D1-based whole-cell biocatalyst has a potential used for the efficient synthesis of 6-O-demethyl papaverine. PMID- 30465136 TI - Fibroblast growth factor-23 correlates with advanced disease conditions and predicts high risk of major adverse cardiac and cerebral events in end-stage renal disease patients undergoing continuous ambulatory peritoneal dialysis. AB - BACKGROUND: This study aimed to investigate the correlation of serum fibroblast growth factor-23 (FGF-23) level with clinical indexes, in particular to explore the value of FGF-23 in predicting major adverse cardiac and cerebral event (MACCE) risk in end-stage renal disease (ESRD) patients undergoing continuous ambulatory peritoneal dialysis (CAPD). METHODS: In 270 ESRD patients undergoing CAPD consecutively enrolled in this prospective cohort study, we collected serum samples and performed enzyme-linked immunosorbent assay to detect FGF-23 expression. MACCE-free survival was defined as the date from enrollment to the date of MACCE occurrence. RESULTS: High levels of FGF-23 correlated with longer duration of dialysis (p = 0.002), elevated levels of calcium (p < 0.001), phosphorus (p = 0.037) and low density lipoprotein cholesterol (p = 0.027). MACCE occurrence rate was higher in the FGF-23 high-expression than low-expression group at 2 years (p = 0.028), 3 years (p = 0.001) and 4 years (p = 0.004). Kaplan Meier curves revealed that MACCE-free survival was shorter in the FGF-23 high expression than low-expression group (p = 0.004). Multivariate Cox's analysis showed that high FGF-23 expression (p = 0.011) as well as the duration of dialysis (p = 0.017), C-reactive protein (p = 0.011) and fasting blood glucose (p = 0.038) were independent predictive factors for reduced MACCE-free survival in ESRD patients undergoing CAPD. CONCLUSION: High FGF-23 expression correlates with advanced disease conditions as well as increased MACCE risk, and is an independent factor predicting worse MACCE-free survival in ESRD patients undergoing CAPD. PMID- 30465137 TI - Control of metabolic predisposition to cardiovascular complications of chronic kidney disease by effervescent calcium magnesium citrate: a feasibility study. AB - AIMS: Cardiovascular (CV) complications are common in chronic kidney disease (CKD). Numerous metabolic disturbances including hyperphosphatemia, high circulating calciprotein particles (CPP), hyperparathyroidism, metabolic acidosis, and magnesium deficiency are associated with, and likely pathogenic for CV complications in CKD. The goal of this feasibility study was to determine whether effervescent calcium magnesium citrate (EffCaMgCit) ameliorates the aforementioned pathogenic intermediates. METHODS: Nine patients with Stage 3 and nine patients with Stage 5D CKD underwent a randomized crossover study, where they took EffCaMgCit three times daily for 7 days in one phase, and a conventional phosphorus binder calcium acetate (CaAc) three times daily for 7 days in the other phase. Two-hour postprandial blood samples were obtained on the day before and on the 7th day of treatment. RESULTS: In Stage 5D CKD, EffCaMgCit significantly increased T50 (half time for conversion of primary to secondary CPP) from baseline by 63% (P = 0.013), coincident with statistically non significant declines in serum phosphorus by 25% and in saturation of octacalcium phosphate by 35%; CaAc did not change T50. In Stage 3 CKD, neither EffCaMgCit nor CaAc altered T50. With EffCaMgCit, a significant increase in plasma citrate was accompanied by statistically non-significant increase in serum Mg and phosphate. CaAc was without effect in any of these parameters in Stage 3 CKD. In both Stages 3 and 5D, both drugs significantly reduced serum parathyroid hormone. Only EffCaMgCit significantly increased serum bicarbonate by 3 mM (P = 0.015) in Stage 5D. CONCLUSIONS: In Stage 5D, EffCaMgCit inhibited formation of CPP, suppressed PTH, and conferred magnesium and alkali loads. These effects were unique, since they were not observed with CaAc. In Stage 3 CKD, neither of the regimens have any effect. These metabolic changes suggest that EffCaMgCit might be useful in protecting against cardiovascular complications of CKD by ameliorating pathobiologic intermediates. PMID- 30465138 TI - Body composition as a predictor of toxicity after treatment with eribulin for advanced soft tissue sarcoma. AB - BACKGROUND: Despite the clinical benefits of eribulin on overall survival of advanced soft tissue sarcoma (STS) patients, treatment-related toxicity reduces their QOL. Body composition metrics (BCMs) are associated with poor outcome and drug toxicities in several cancers. This study investigated whether BCMs could predict drug toxicity occurrence in advanced STS patients treated with eribulin. METHODS: This study included 23 advanced STS patients treated with eribulin between March 2016 and April 2018. BCMs were evaluated using a CT scan obtained within 1 month before or after treatment initiation. The relationship of BCMs and other clinical factors was evaluated and CART analysis used to develop classification models for risk groups of drug toxicity. RESULTS: Sixteen patients (69.6%) experienced any grade 3/4 toxicity. Eleven patients (47.8%) developed G4 hematologic toxicity, which was significantly higher in those with low skeletal muscle gauge (SMG) (P = 0.02) and low pretreatment neutrophil count (P = 0.0002). Six patients (26.1%) had grade 3/4 non-hematologic toxicity, and was higher in those with low SMG (P = 0.004), and low serum albumin level (P = 0.02). Five patients with high BMI (P = 0.03) experienced febrile neutropenia (FN) and low pretreatment neutrophil count (P = 0.02). CART analysis classified three risk groups, and area under the receiver operating characteristic curve (AUROCC) was 0.92, 0.88, 0.92 in G4 hematologic AE, G3/4 non-hematologic AE, FN, respectively. CONCLUSIONS: SMG is a significant predictive factor of eribulin drug toxicity in advanced STS patients. Risk classification of drug toxicity through combining predictive factors, could improve the therapeutic strategy used in chemotherapy. PMID- 30465139 TI - Quantitative proteomic analysis reveals novel stress-associated active proteins (SAAPs) and pathways involved in modulating tolerance of wheat under terminal heat. AB - Terminal heat stress has detrimental effect on the growth and yield of wheat. Very limited information is available on heat stress-associated active proteins (SAAPs) in wheat. Here, we have identified 159 protein groups with 4271 SAAPs in control (22 +/- 3 degrees C) and HS-treated (38 degrees C, 2 h) wheat cvs. HD2985 and HD2329 using iTRAQ. We identified 3600 proteins to be upregulated and 5825 proteins to be downregulated in both the wheat cvs. under HS. We observed 60.3% of the common SAAPs showing upregulation in HD2985 (thermotolerant) and downregulation in HD2329 (thermosusceptible) under HS. GO analysis showed proton transport (molecular), photosynthesis (biological), and ATP binding (cellular) to be most altered under HS. Most of the SAAPs identified were observed to be chloroplast localized and involved in photosynthesis. Carboxylase enzyme was observed most abundant active enzymes in wheat under HS. An increase in the degradative isoenzymes (alpha/beta-amylases) was observed, as compared to biosynthesis enzymes (ADP-glucophosphorylase, soluble starch synthase, etc.) under HS. Transcript profiling showed very high relative fold expression of HSP17, CDPK, Cu/Zn SOD, whereas downregulation of AGPase, SSS under HS. The identified SAAPs can be used for targeted protein-based precision wheat-breeding program for the development of 'climate-smart' wheat. PMID- 30465140 TI - Hybrid Airway Segmentation Using Multi-Scale Tubular Structure Filters and Texture Analysis on 3D Chest CT Scans. AB - Airway diseases are frequently related to morphological changes that may influence lung physiology. Accurate airway region segmentation may be useful for quantitative evaluation of disease prognosis and therapy efficacy. The information can also be applied to understand the fundamental mechanisms of various lung diseases. We present a hybrid method to automatically segment the airway regions on 3D volume chest computed tomography (CT) scans. This method uses multi-scale filtering and support vector machine (SVM) classification. The proposed scheme is comprised of two hybrid steps. First, a tubular structure based multi-scale filter is applied to find the initial candidate airway regions. Second, for identifying candidate airway regions using the fuzzy connectedness technique, the small and disconnected branches of airway regions are detected using SVM classification trained to differentiate between airway and non-airway regions through texture analysis of user-defined landmark points. For development and evaluation of the method, two datasets were incorporated: (1) 55 lung-CT volumes from the Korean Obstructive Lung Disease (KOLD) Cohort Study and (2) 20 cases from the publicly open database (EXACT'09). The average tree-length detection rates of EXACT'09 and KOLD were 56.9 +/- 11.0 and 70.5 +/- 8.98, respectively. Comparison of the results for the EXACT'09 data set between the presented method and other methods revealed that our approach was a high performer. The method limitations were higher false-positive rates than those of the other methods and risk of leakage. In future studies, application of a convolutional neural network will help overcome these shortcomings. PMID- 30465141 TI - Glomerular Filtration Rate Calculator App Review. PMID- 30465142 TI - Automatic Labeling of Special Diagnostic Mammography Views from Images and DICOM Headers. AB - Applying state-of-the-art machine learning techniques to medical images requires a thorough selection and normalization of input data. One of such steps in digital mammography screening for breast cancer is the labeling and removal of special diagnostic views, in which diagnostic tools or magnification are applied to assist in assessment of suspicious initial findings. As a common task in medical informatics is prediction of disease and its stage, these special diagnostic views, which are only enriched among the cohort of diseased cases, will bias machine learning disease predictions. In order to automate this process, here, we develop a machine learning pipeline that utilizes both DICOM headers and images to predict such views in an automatic manner, allowing for their removal and the generation of unbiased datasets. We achieve AUC of 99.72% in predicting special mammogram views when combining both types of models. Finally, we apply these models to clean up a dataset of about 772,000 images with expected sensitivity of 99.0%. The pipeline presented in this paper can be applied to other datasets to obtain high-quality image sets suitable to train algorithms for disease detection. PMID- 30465143 TI - Total parenteral nutrition versus early enteral nutrition after cystectomy: a meta-analysis of postoperative outcomes. AB - BACKGROUND: This study aimed to systematically summarize and analyze the current evidence regarding the effect of total parenteral nutrition (TPN) versus early enteral nutrition (EEN) on postoperative outcomes of cystectomy. METHODS: A comprehensive search of online databases was conducted to identify comparative studies on the postoperative outcomes of patients receiving TPN and EEN after cystectomy. Our subsequent meta-analysis followed the PRISMA Protocol and the Cochrane Handbook. RESULTS: Five studies with 556 participants were included for meta-analysis. EEN was shown to have a significant effect on reducing the overall complications (odds ratio (OR) 0.52, 95% confidence interval (CI) 0.37-0.75, P < 0.01) and infectious complications (OR 0.32, 95% CI 0.21-0.49, P < 0.01) compared with TPN. Additionally, EEN saved ?614-?3120 in costs compared to TPN. There were no significant differences between TPN and EEN groups regarding mortality rate (OR 0.47, 95% CI 0.06-3.51, P = 0.46), the incidence of postoperative ileus (OR 0.90, 95% CI 0.55-1.47, P = 0.68), length of hospital stay (mean difference (MD) 2.12, 95% CI - 0.15 to 4.40, P = 0.07), or time to resume a full diet (MD 1.31, 95% CI - 1.15 to 3.77, P = 0.30). CONCLUSION: EEN was found to have a significant effect on reducing infectious complications and costs compared with TPN treatment after cystectomy. Remarkably, EEN had no significant impact on mortality incidence, postoperative ileus, length of hospital stay, or the time to resumption of full diet. PMID- 30465144 TI - The success of the representation maintenance affects the memory-guided search processing: an ERP study. AB - Previous evidence showed that working memory (WM) contents can bias visual selection. However, less is known about how the WM effects change when the WM representation is not held successfully. Here, we investigated this problem using event-related potentials. Subjects maintained a color in WM while performing a search task. The color cue contained the target (valid) or the distractor (invalid). Subjects could either remember the color accurately (correct WM) or not (incorrect WM). An N2-posterior contralateral component and a sustained posterior contralateral negativity (SPCN) were recorded in the valid and incorrect WM condition, while only an attenuated SPCN was elicited in the valid and correct WM condition. No reliable lateralized components were found for the invalid trials. These findings suggest that the WM effects on visual search are affected by the resource interchange between WM and search processes. PMID- 30465146 TI - Redescription of three species of nematodes (Nematoda) parasitising fishes in the USA, with a key to the species of Dichelyne Jagerskiold, 1902 parasitic in freshwater and brackish-water fishes of North America. AB - Three species of parasitic nematodes are redescribed based on light and scanning electron microscopical (SEM) examinations of newly collected specimens in fishes of South Carolina, USA: Dichelyne (Cucullanellus) bullocki Stromberg & Crites, 1972 from Fundulus heteroclitus (Linnaeus) (Fundulidae); Dichelyne (Dichelyne) diplocaecum Chandler, 1935 from Ictalurus furcatus (Valenciennes) (Ictaluridae); and Hysterothylacium pelagicum Deardorff & Overstreet, 1982 from Coryphaena hippurus Linnaeus (Coryphaenidae). For the first time, intraspecific variations in the number of intestinal caeca were observed in D. bullocki, as well as previously unknown males and gravid females of D. diplocaecum are described; this enabled to synonymise D. mexicanus Caspeta-Mandujano, Moravec & Salgado Maldonado, 1999 with D. diplocaecum. Unlike most congeneric species, H. pelagicum has no double postanal papillae, as confirmed by SEM. A key to the species of Dichelyne Jagerskiold, 1902 parasitic in freshwater and brackish-water fishes in North America is provided. PMID- 30465145 TI - Chilean Registry for Neuroendocrine Tumors: A Latin American Perspective. AB - Neuroendocrine tumors (NETs) are relatively rare and highly heterogeneous neoplasms. Despite this, recent studies from North America and Central Europe have suggested an increase in incidence. In Latin America, NET data are scarce and scattered with only a few studies reporting registries. Our goal was to establish a NET registry in Chile. Here, we report the establishment and our first 166 NET patients. We observed a slight preponderance of males, a median age at diagnosis of 53 years and a median overall survival of 110 months. As anticipated, most tumors were gastroenteropancreatic (GEP). Survival analyses demonstrated that non-GEP or stage IV tumors presented significantly lower overall survival (OS). Similarly, patients with surgery classified as R0 had better OS compared to R1, R2, or no surgery. Furthermore, patients with elevated chromogranin A (CgA) or high Ki67 showed a trend to poorer OS; however, these differences did not reach statistical significance (log-rank test p = 0.07). To the best of our knowledge, this is the first report of a NET registry in Chile. Median OS in our registry (110 months) is in line with other registries from Argentina and Spain. Other variables including age at diagnosis and gender were similar to previous studies; however, our data indicate a high proportion of small-bowel NETs compared to other cohorts, reflecting the need for NET regional registries. Indeed, these registries may explain regional discrepancies in incidence and distribution, adding to our knowledge on this seemingly rare, highly heterogeneous disease. PMID- 30465147 TI - Bucephalus damriyasai n. sp. (Digenea: Bucephalidae) from the blacktip trevally Caranx heberi (Bennett) (Perciformes: Carangidae) off Bali, Indonesia. AB - The new species Bucephalus damriyasai n. sp. is described from Caranx heberi (Bennett) from off Bali, Indonesia. It can be distinguished from other Bucephalus spp. recorded from carangid hosts by its narrow elongate body shape and the relatively long distance between the rhynchus and the vitellarium, as well as other features distinguishing it from individual species. The most similar species are differentiated from B. damriyasai n. sp. as follows: B. carangis Yamaguti, 1970 has a much greater length, the rhynchus is smaller and the cirrus sac is small, not always reaching to the posterior testis; B. fragilis Velasquez, 1959 is a tiny species, the pre-vitelline distance is short and the caecum is saccular; B. gorgon (Linton, 1905) is much longer and relatively broader, the uterus reaches distinctly anterior to the vitellarium and the rhyncheal tentacles appear more complex; B. labracis Paggi & Orecchia, 1965 is distinctly longer, slightly broader, with a slightly larger rhynchus, and has shorter pre-uterine and pre-mouth distances; B. paraheterotentaculatus Velasquez, 1959 is much longer, relatively rather broad, the rhynchus is said to bear 21 tentacles, the post-testicular region and cirrus-sac reach are longer and the caecum is described as saccular; B. sphyraenae Yamaguti, 1952 is longer, slightly broader, the uterus reaches anteriorly to the vitellarium and the caecum is claviform and oriented anteriorly; B. margaritae Ozaki & Ishibashi, 1934 (syn. B. varicus Manter, 1940) is relatively squat, has shorter pre-vitelline and pre-mouth distances and a longer post-testicular distance and cirrus-sac reach; B. yamagutii Gupta & Singh, 1985 is broader, with a relatively short pre-vitelline distance, the caecum extends anteriorly to the pharynx, but not posteriorly and the rhynchus is said to carry five tentacles. The distinctive features of B. damriyasai n. sp. are compared with those of all other marine Bucephalus spp. in a table. The number of bucephalid trematodes known from Indonesian waters is now 13, two of them await further identification. They have been described from the fish families Carangidae, Platycephalidae, Sciaenidae, Serranidae and Sphyraenidae. PMID- 30465148 TI - Mediation of Impacts of Elevated CO2 and Light Environment on Arabidopsis thaliana (L.) Chemical Defense against Insect Herbivory Via Photosynthesis. AB - Elevated CO2 alters C3 plant tolerance to insect herbivory, as well as the induction kinetics of defense hormones salicylic acid (SA) and jasmonic acid (JA), but the underlying physiological mechanism causing this response is not well understood. In principle, SA could be induced under elevated CO2 by reactive oxygen signals generated in photosynthesis, ultimately influencing chemical defense. To test whether the effects of elevated CO2 on C3 plant chemical defense against herbivorous insects are modulated by photosynthesis, Arabidopsis thaliana var. Col-0 plants were grown in two 2 * 2 * 2 nested factorial combinations of ambient (400 ppm) and elevated (800 ppm) CO2, and two dimensions of light regimes comprising intensity ('mild' 150 MUmol E m-2 s-1 vs. 'low' light, 75 MUmol E m-2 s-1) and periodicity ('continuous', 150 MUmol E m-2 s-1 vs. 'dynamic', in which lights were turned off, then on, for 15 min every 2 h). Plants were challenged with herbivore damage from third instar Trichoplusia ni (cabbage looper). Consistent with experimental predictions, elevated CO2 interacted with light as well as herbivory to induce foliar concentration of SA, while JA was suppressed. Under dynamic light, foliar content of total glucosinolates was reduced. Under combination of elevated CO2 and dynamic light, T. ni removed significantly more leaf tissue relative to control plants. The observations that CO2 and light interactively modulate defense against T. ni in A. thaliana provide an empirical argument for a role of photosynthesis in C3 plant chemical defense. PMID- 30465149 TI - Some Neuropsychological Profiles and Personality Traits of Undergraduate Regular Online Football Gamblers (a New Online Gambling Game) in Nigeria. AB - Online football (soccer) gambling is among the relatively new sports betting games in Nigeria that use internet connections. Like other gambling games, some psychological profiles either propel or sustain the behavior. We tested some neuropsychological profiles and personality traits that distinguish the regular online football gamblers from non-gamblers. Using a between group design, we tested 140 (60: online football gamblers; 80: non-gamblers) university undergraduate students between the ages of 18-26 years on specific neuropsychological domains (i.e., attention, inhibition and executive function) and personality traits. The neuropsychological tasks used were the Series Addition Task (a modified version of Paced Auditory Serial Addition Task), Stroop Word Color Test and Trail Making Test (TMT), Parts A and B. The personality traits were assessed using the Big Five Personality Inventory. The findings showed significant differences between the online football gamblers and non gamblers, reflecting greater agreeableness, conscientiousness, neuroticism and openness to experience for the football gamblers. However, on the attention tasks, the non-gamblers made significantly fewer errors on forward addition and backward subtraction tasks, but did take more time to complete the backward counting task as compared to gamblers. On the other hand, online football gamblers took significantly less time to complete the Stroop congruence task and made significantly fewer errors on Stroop incongruence task. Similarly, the online football gamblers took less time to complete the TMT B and made fewer errors on TMT A. University undergraduate regular online football gamblers, as compared to non-gamblers, demonstrate stronger personality traits of ambition and gregariousness, and perform better on tasks of executive function, though they had more difficulty on tasks of divided and sustained attention. PMID- 30465150 TI - Peer Group Identification as Determinant of Youth Behavior and the Role of Perceived Social Support in Problem Gambling. AB - Gambling opportunities have increased rapidly during recent years. Previous research shows that gambling is a popular activity among youth, which may contribute to problem gambling. This study examined how social identification with online and offline peer groups associates with youth problem gambling behavior and if perceived social support buffers this relationship. Data were gathered with an online survey with 1212 American and 1200 Finnish participants between 15 and 25 years of age. Measures included the South Oaks Gambling Screen for problem gambling, and items for peer group identification and perceived social support. It was found that youth who identify strongly with offline peer groups were less likely to engage in problem gambling, while strong identification with online peer groups had the opposite effect. We also found that the associations between social identification and problem gambling behavior were moderated by perceived social support. Online peer groups may be a determinant in youth problem gambling. Focusing on offline peer groups and increasing social support can hold significant potential in youth gambling prevention. PMID- 30465151 TI - Towards Identification of Correspondence Rules to Relate Traumatic Brain Injury in Different Species. AB - Traumatic brain injury analysis in humans is exceedingly difficult due to the intrusive methods by which data can be collected; thus, many researchers commonly implement animal surrogates. However, ethical concerns and cost limit the scope of these tests on animal subjects too. Computational models, which provide an alternative method to data collection, are not constrained by these concerns and are able to generate significant amounts of data in relatively short time. This paper shows how the data generated from models of a human and pig head can be used towards developing interspecies correspondence rules for blast overpressure effects. The blast overpressure is simulated using an explosive of known weight and standoff distance and injury is evaluated using criteria in published literature. Results indicate that equivalent blasts in the human and pig produce significantly different injuries, and when equating total injured brain volume, the locations of injury in the brain vary between the species. Charge weight and total injured brain volume are related using a linear regression of the data such that a known injury in the pig or known blast can be used to predict injury or the blast experienced by a human, thus creating a correspondence between the species. PMID- 30465152 TI - Localization of Ventricular Activation Origin from the 12-Lead ECG: A Comparison of Linear Regression with Non-Linear Methods of Machine Learning. AB - We have previously developed an automated localization method based on multiple linear regression (MLR) model to estimate the activation origin on a generic left ventricular (LV) endocardial surface in real time from the 12-lead ECG. The present study sought to investigate whether machine learning-namely, random forest regression (RFR) and support-vector regression (SVR)-can improve the localization accuracy compared to MLR. For 38 patients the 12-lead ECG was acquired during LV endocardial pacing at 1012 sites with known coordinates exported from an electroanatomic mapping system; each pacing site was then registered to a generic LV endocardial surface subdivided into 16 segments tessellated into 238 triangles. ECGs were reduced to one variable per lead, consisting of 120-ms time integral of the QRS. To compare three regression models, the entire dataset ([Formula: see text]) was partitioned at random into a design set with 80% and a test set with the remaining 20% of the entire set, and the localization error-measured as geodesic distance on the generic LV surface was assessed. Bootstrap method with replacement, using 1000 resampling trials, estimated each model's error distribution for the left-out sample ([Formula: see text]). In the design set ([Formula: see text]), the mean accuracy was 8.8, 12.1, and 12.9 mm, respectively for SVR, RVR and MLR. In the test set ([Formula: see text]), the mean value of the localization error in the SVR model was consistently lower than the other two models, both in comparison with the MLR (11.4 vs. 12.5 mm), and with the RFR (11.4 vs. 12.0 mm); the RFR model was also better than the MLR model for estimating localization accuracy (12.0 vs. 12.5 mm). The bootstrap method with 1,000 trials confirmed that the SVR and RFR models had significantly higher predictive accurate than the MLR in the bootstrap assessment with the left-out sample (SVR vs. MLR ([Formula: see text]), RFR vs. MLR ([Formula: see text])). The performance comparison of regression models showed that a modest improvement in localization accuracy can be achieved by SVR and RFR models, in comparison with MLR. The "population" coefficients generated by the optimized SVR model from our dataset are superior to the previously derived "population" coefficients generated by the MLR model and can supersede them to improve the localization of ventricular activation on the generic LV endocardial surface. PMID- 30465153 TI - Urocortins and their unfolding role in mammalian social behavior. AB - The corticotropin-releasing factor (CRF) system is well known for its major role in coordinating the endocrine, autonomic and behavioral responses to stress. These functions have been shown to be mediated mainly by the binding of the CRF neuropeptide to its specific receptor CRFR1. Yet, the CRF system comprises several more neuropeptides, including the three urocortins, UCN1, UCN2 and UCN3, of which the latter two bind specifically to a distinct receptor-CRFR2. Unlike the brain-wide abundant expression of CRF and CRFR1, the brain expression of the urocortins and CRFR2 is rather restricted and seems to be focused in limbic areas associated with social behavior. Here, we will review accumulating evidence from recent studies that unfold the role of UCN2 and UCN3 in regulating mammalian social behavior, via activation of CRFR2. PMID- 30465154 TI - The impact of ethnicity on efficacy and toxicity of cyclin D kinase 4/6 inhibitors in advanced breast cancer: a meta-analysis. AB - PURPOSE: Adding cyclin-dependent kinase (CDK) 4/6 inhibitor to endocrine therapy improves progression-free survival (PFS) in advanced breast cancer but the impact of ethnicity on efficacy and toxicity is unclear. We aimed to estimate the relative treatment efficacy and toxicity of endocrine therapy with and without CDK4/6 inhibitors, and compare between Asian/non-Asian subgroups. METHOD: This meta-analysis included published first-line randomized trials comparing CDK4/6 inhibitor-endocrine therapy versus endocrine monotherapy. Hazard ratios (HR) and 95% confidence intervals (CI) for the overall population and Asian/non-Asian subgroups were extracted. The inverse-variance-weighted method was used to pool treatment estimates of PFS. RESULTS: Four trials (N = 2499) were included. Patients received combination CDK4/6 inhibitor-endocrine therapy (N = 1441; ribociclib, [46.4%]; palbociclib, [30.8%]; or abemaciclib, [22.8%]) versus endocrine monotherapy (N = 1058). CDK4/6 inhibitor-endocrine therapy was associated with prolonged PFS compared with endocrine monotherapy (HR 0.56; 95% CI 0.50-0.62). In Asians (N = 492), PFS HR was 0.39 (95% CI 0.29-0.51, P < 0.0001). In non-Asians (N = 2007), PFS HR was 0.62 (95% CI 0.54-0.71, P < 0.0001). There was a significant treatment-by-ethnicity interaction (P = 0.002). Toxicity data by ethnic subgroup were only available from two trials (n = 1334) with no convincing evidence that the risk of toxicity between CDK4/6 inhibitor endocrine therapy and endocrine monotherapy varied by ethnicity. CONCLUSION: Adding CDK4/6 inhibitor to endocrine therapy prolongs PFS compared to endocrine therapy alone as first-line treatment in advanced breast cancer. The magnitude of PFS benefit is ethnicity-dependent but there is no interethnic differences in relative treatment-related toxicities. These findings may assist in the design and interpretation of trials, inform economic analyses, and stimulate pharmacogenomic research. PMID- 30465155 TI - A nationwide study of breast cancer, depression, and multimorbidity among hospitalized women and men in the United States. AB - PURPOSE: Breast cancer is the most common and second most deadly cancer for women in the US. Comorbidities like depression exacerbate the burden. This national study provides data on depression and comorbidity for both women and men with breast cancer. METHODS: We conducted a serial cross-sectional analysis of the 2002-2014 National Inpatient Sample, the largest all-payer inpatient discharge database in the United States. We identified patients with primary site breast cancer, and captured information on their concomitant depression and other major chronic comorbidities. Logistic regression was used to generate adjusted odds ratios representing associations between patient and hospital characteristics and depression. Joinpoint regression was used to estimate temporal trends in depression rates. RESULTS: Depression prevalence was higher for women than men, with little difference between cancer subtypes. Comorbidity burden was nearly twice as high for men. From 2002 to 2014, the average number of comorbidities doubled. Depression rates were highest for patients with four or more chronic comorbidities and those with unplanned hospitalizations. Significant yearly increases of 6-10% in depression were also observed. CONCLUSIONS: Breast cancer patient depression rates were higher than the general inpatient population with a strong gradient effect between increasing numbers of comorbidities and the odds of depression. Comorbidities, including mental health-related, negatively impact breast cancer prognosis, increasing cancer-specific mortality as well as mortality for other conditions. Unplanned hospitalization episodes in a patient with breast cancer can be noted as an opportunity for mental health screening and intervention. PMID- 30465156 TI - Anthracycline and taxane-based chemotherapy versus docetaxel and cyclophosphamide in the adjuvant treatment of HER2-negative breast cancer patients: a systematic review and meta-analysis of randomized controlled trials. AB - PURPOSE: Standard adjuvant chemotherapy for HER2-negative breast cancer consists generally in an anthracycline and taxane-based regimen (A+T). The TC (docetaxel and cyclophosphamide) regimen arises as a potential alternative, although individual randomized controlled trials (RCTs) could not demonstrate the non inferiority of TC over A+T. This is a systematic review and meta-analysis of RCTs comparing 6 cycles of TC versus sequential A+T in the adjuvant treatment of HER2 negative breast cancer. METHODS: A systematic literature search was performed to identify RCTs comparing TC versus A+T. Disease-free survival (DFS) and overall survival (OS) were assessed. Subgroup analyses of DFS according to hormone receptor status, lymph node involvement, and menopausal status were performed. Hazard ratios (HRs) and 95% confidence intervals (CI) for DFS and OS were extracted from each trial, and a pooled analysis was conducted using the random effect model. The Higgins' I-Squared Test was used to quantify heterogeneity. RESULTS: Seven RCTs were included (12,741 patients). Overall, no difference was observed between TC and A+T in DFS (HR 1.08, 95% CI 0.96-1.20) and OS (HR 1.05; 95% CI 0.90-1.22). A trend favoring A+T was observed in hormone receptor-negative (HR 1.12, 95% CI 0.93-1.34) and N2 patients (HR 1.25; 95% CI 0.82-1.90). Emesis/vomiting, mucositis, thrombocytopenia and sensory neuropathy were significantly more frequent with A+T. CONCLUSION: As adjuvant treatment of HER2 negative breast cancer, sequential A+T regimen was associated with increased risk of toxicities and no clear survival benefit as compared to 6 cycles of TC. Higher risk patients may benefit the most from A+T, whilst TC may be an efficacious and less toxic alternative for lower-risk patients. PMID- 30465157 TI - Impact of preexisting mental illness on breast cancer endocrine therapy adherence. AB - PURPOSE: Patients with estrogen receptor positive (ER+) breast cancer are often non-adherent to endocrine therapies, despite clear survival benefits. We utilized a nationally representative cancer cohort to examine the role of specific mental illnesses on endocrine therapy adherence. METHODS: Using the SEER-Medicare database, we included 21,894 women aged 68+ at their first surgically treated stage I-IV ER+ breast cancer during 2007-2013. All had continuous fee-for-service Medicare Parts A and B for 36+ months before, 18+ months after diagnosis, and continuous Part D for 4+ months before, 18+ after diagnosis. Mental illness was defined as occurring in the 36 months prior to cancer onset. We analyzed endocrine therapy adherence, initiation, and discontinuation using longitudinal linear and Cox regression models. RESULTS: Unipolar depression (11.0%), anxiety (9.5%), non-schizophrenia psychosis (4.6%), and dementias (4.6%) were the most prevalent diagnoses. Endocrine therapies were initiated by 80.0% of women. Among those with at least one year of use, 28.0% were non-adherent (< 0.80 adherence, mean = 0.84) and 25.7% discontinued. Patients with dementia or bipolar depression/psychotic/schizophrenia disorders had lower adjusted initiation probabilities by year one of follow-up, versus those without these diagnoses [0.74 95% CI (0.73-0.74) and 0.73 (0.72-0.73), respectively, reference 0.76 (0.76 0.77)]. Patients with substance use or anxiety disorders less frequently continued endocrine therapy for at least one year, after adjustment, [0.85 95% CI (0.85-0.86) and 0.88 (0.87-0.88), respectively, reference 0.90 (0.89-0.90)]. Patients with substance use disorders had 2.3% lower adherence rates (p < 0.001). CONCLUSIONS: Nearly one-quarter of female Medicare beneficiaries have diagnosed mental illness preceding invasive breast cancer. Those with certain mental illnesses have modestly reduced rates of initiation, adherence, and discontinuation and this may help define patients at higher risk of treatment abandonment. Overall, endocrine therapy adherence remains suboptimal, unnecessarily worsening recurrence and mortality risk. PMID- 30465158 TI - Metabolic syndrome and risk of breast cancer mortality by menopause, obesity, and subtype. AB - PURPOSE: To investigate the association between metabolic syndrome (MetS) and risk of breast cancer mortality by menopausal status, obesity, and subtype. METHODS: Data from 94,555 women free of cancer at baseline in the National Institute of Health-American Association of Retired Persons Diet and Health Study cohort (NIH-AARP) were used to investigate the prospective associations of baseline MetS and components with risk of breast cancer mortality using Cox proportional hazard regression models adjusted for baseline behavioral and demographic covariates. RESULTS: During a mean follow-up duration of 14 years, 607 women in the cohort died of breast cancer. Overall, MetS was associated with a 73% increased risk of breast cancer mortality (HR 1.73; 95% CI 1.09-2.75); the association remained significant among post-menopausal women overall (HR 2.07, 95% CI 1.32, 3.25), and among those with overweight/obesity (HR 1.15, 95% CI 0.81, 1.64). MetS was associated with increased risk of breast cancer mortality for ER+/PR+ (HR 1.28, 95% CI 0.52, 3.16) and lower risk for ER-/PR- (HR 0.44, 95% CI 0.11, 1.75) subtypes; however, the associations were not statistically significant. Of the individual MetS components, high waist circumference (HR 1.32, 95% CI 1.03, 1.70), high cholesterol (HR 1.24, 95% CI 1.05, 1.46), and hypertension (HR 1.24, 95% CI 1.05, 1.46) were independently associated with increased risk of breast cancer mortality. CONCLUSIONS: MetS was associated with increased risk of breast cancer mortality, especially among post-menopausal women. Further studies with larger sample sizes are needed to definitively determine the extent to which these associations vary by breast cancer subtype. PMID- 30465159 TI - Autoantibodies to heat shock proteins 60, 70, and 90 in patients with rheumatoid arthritis. AB - Heat shock proteins (HSP) have been reported to impact immune responses and to be associated with rheumatoid arthritis (RA). Recently, we provided evidence for a role of autoantibodies to Hsp40 in patients with RA. In this study, we aimed at investigating the humoral autoimmune response to Hsp60, Hsp70, and Hsp90 in RA patients (n = 39). In comparison with healthy controls (n = 40), circulating IgG, IgM, and IgA autoantibodies against Hsp60, Hsp70, and Hsp90 were significantly increased in RA patients. Non-parametric statistical analysis, however, revealed no significant association between anti-HSP and disease activity or disease progression. On the other hand, positive correlations between serum levels of anti-Hsp60 IgG and IL-4 (Th2-like cytokine) or between serum levels of anti-Hsp90 IgG and IFN-gamma (Th1-like cytokine) were found to be statistically significant in RA. In addition, a significant inverse correlation was found for serum levels of anti-Hsp70 IgM and TNF-alpha (Th1-like cytokine) in RA. Our results suggest a pronounced anti-Hsp60, anti-Hsp70, and anti-Hsp90 humoral autoimmune response in RA patients that seems not to be directly linked to RA pathophysiology, however, may have a potential modulatory impact on inflammatory status in this disease. Further investigations are needed to clarify the role of anti-HSP autoantibodies in RA. PMID- 30465160 TI - Reasonable Glycemic Control Would Help Wound Healing During the Treatment of Diabetic Foot Ulcers. AB - INTRODUCTION: The effect of glycemic control on wound healing in patients with diabetic foot ulcers (DFUs) is inconsistent among different studies. This study was performed to investigate the association between level of hemoglobin A1c (HbA1c) at baseline as well as during treatment and wound healing and mortality in patients with DFU. METHODS: Hospitalized DFU patients were recruited consecutively with their basic clinical data collected and treated according to clinical practice guidelines. These patients were followed-up for 1 year to observe the outcomes, including ulcer healing and death. The associations between baseline HbA1c level or mean HbA1c level during treatment and wound healing as well as mortality were evaluated in univariate and multivariate logistic regression models. RESULTS: By the end of the follow-up, 40 (13.4%) patients had died. A total of 168 (65.1%) patients achieved ulcer healing in the remaining 258 living participants. Baseline HbA1c was not associated with ulcer healing in unadjusted or adjusted models (P > 0.05). The wound healing rate was higher (OR 2.01, 95% CI 1.02-3.96, P < 0.05) after adjustment when HbA1c was controlled between 7.0% and 8.0% during treatment compared to HbA1c controlled at less than 7.0%. This probability of ulcer healing increased to 3 (OR = 3.01, 95% CI 1.32 6.86, P = 0.01) after adjustment in the subgroup with baseline HbA1c no more than 8.0%. Neither baseline HbA1c nor mean HbA1c during treatment presented any correlation with 1-year death rate. CONCLUSION: A reasonable HbA1c target, a range between 7.0% and 8.0% during treatment, could facilitate ulcer healing without increase of mortality in patients with DFU, especially for those with better glycemic control at admission. PMID- 30465161 TI - Measurement of the total angiotensinogen and its reduced and oxidised forms in human plasma using targeted LC-MS/MS. AB - Angiotensinogen (AGT) is a critical protein in the renin-angiotensin-aldosterone system and may have an important role in the pathogenesis of pre-eclampsia. The disulphide linkage between cysteines 18 and 138 has a key role in the redox switch of AGT which modulates the release of angiotensin I with consequential effects on blood pressure. In this paper, we report a quantitative targeted LC MS/MS method for the reliable measurement of the total AGT and its reduced and oxidised forms in human plasma. AGT was selectively enriched from human plasma using two-dimensional chromatography employing concanavalin A lectin affinity and reversed phase steps and then deglycosylated using PNGase F. A differential alkylation approach was coupled with targeted LC-MS/MS method to identify the two AGT forms in the plasma chymotryptic digest. An additional AGT proteolytic marker peptide was identified and used to measure total AGT levels. The developed MS workflow enabled the reproducible detection of total AGT and its two distinct forms in human plasma with analytical precision of <= 15%. The LC-MS/MS assay for total AGT in plasma showed a linear response (R2 = 0.992) with a limit of quantification in the low nanomolar range. The method gave suitable validation characteristics for biomedical application to the quantification of the oxidation level and the total level of AGT in plasma samples collected from normal and pre eclamptic patients. PMID- 30465162 TI - Cancer-associated fibroblasts as key regulators of the breast cancer tumor microenvironment. AB - Tumor cells exist in close proximity with non-malignant cells. Extensive and multilayered crosstalk between tumor cells and stromal cells tailors the tumor microenvironment (TME) to support survival, growth, and metastasis. Fibroblasts are one of the largest populations of non-malignant host cells that can be found within the TME of breast, pancreatic, and prostate tumors. Substantial scientific evidence has shown that these cancer-associated fibroblasts (CAFs) are not only associated with tumors by proximity but are also actively recruited to developing tumors where they can influence other cells of the TME as well as influencing tumor cell survival and metastasis. This review discusses the impact of CAFs on breast cancer biology and highlights their heterogeneity, origin and their role in tumor progression, ECM remodeling, therapy resistance, metastasis, and the challenges ahead of targeting CAFs to improve therapy response. PMID- 30465163 TI - Modified Genomic Self-DNA Influences In Vitro Survival of HT29 Tumor Cells via TLR9- and Autophagy Signaling. AB - In relation of immunobiology, the consequence of the crosstalk between TLR9 signaling and autophagy is poorly documented in HT29 cancer cells. To assess the TLR9-mediated biologic effects of modified self-DNA sequences on cell kinetics and autophagy response HT29 cells were incubated separately with intact genomic (g), hypermethylated (m), fragmented (f), and hypermethylated/fragmented (m/f) self-DNAs. Cell viability, apoptosis, cell proliferation, colonosphere-formation were determined. Moreover, the relation of TLR9-signaling to autophagy response was assayed by real-time RT-PCR, immunocytochemistry and transmission electron microscopy (TEM). After incubation with g-, m-, and m/f-DNAs cell viability and proliferation decreased, while apoptosis increased. F-DNA treatment resulted in an increase of cell survival. Methylation of self-DNA resulted in decrease of TLR9 expression, while it did not influence the positive effect of DNA fragmentation on MyD88 and TRAF6 overexpression, and TNFalpha downregulation. Fragmentation of DNA abrogated the positive effect of methylation on IRAK2, NFkappaB and IL-8 mRNA upregulations. In case of the autophagy genes and proteins, g- and f-DNAs caused significant upregulation of Beclin1, Atg16L1, and LC3B. According to TEM analyses, autophagy was present in each group of tumor cells, but to a varying degree. Incubation with m-DNA suppressed tumor cell survival by inducing features of apoptotic cell death, and activated mitophagy. F DNA treatment enhanced cell survival, and activated macroautophagy and lipophagy. Colonospheres were only present after m-DNA incubation. Our data provided evidence for a close existing interplay between TLR9-signaling and the autophagy response with remarkable influences on cell survival in HT29 cells subjected to modified self-DNA treatments. PMID- 30465164 TI - Combination index of the concentration and in vivo antagonism activity of racemic warfarin and its metabolites to assess individual drug responses. AB - The present study was undertaken to examine whether in vivo vitamin K epoxide reductase complex 1 (VKOR) "actual" antagonism activity, calculated by the concentrations and the reported anticoagulant activities of the R- and S-warfarin enantiomers and their metabolites, correlates with the weekly dose of warfarin. Five patients under palliative care were enrolled in our study and 20 serum samples were analyzed by an enantioselective high-performance liquid chromatography-ultraviolet detection method. In vivo VKOR inhibition activities of S-warfarin, R-warfarin, 7- and 10-hydroxywarfarin were calculated as the ratio of drug or metabolite concentration to the IC50. The mean drug concentrations (+/ SD) of S- and R-warfarin, 7-hydroxywarfarin and 10-hydroxywarfarin were 334 +/- 154 ng/ml, 370 +/- 115 ng/ml, 42 +/- 15 ng/ml and 80 +/- 44 ng/ml, respectively. Then, in vivo VKOR actual antagonism activities of S- and R-warfarin, 7 hydroxywarfarin and 10-hydroxywarfarin were calculated. Good correlation (R2 = 0.69-0.72) was obtained between the weekly warfarin dose and the ratios of INR/actual antagonism activity, while poor correlation was observed between the weekly warfarin dose and INR (R2 = 0.32) or the activities (R2 = 0.17-0.21). Actual antagonism activities along with the INR correlated well with the warfarin dose. This parameter may be useful for predicting or altering warfarin doses, although further verification in a larger study is required. PMID- 30465165 TI - [The right thing to do with airmiles]. PMID- 30465166 TI - Complement component 4 variations may influence psychopathology risk in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. AB - CYP21A2 defects result in congenital adrenal hyperplasia (CAH), an autosomal recessive disorder characterized by impaired adrenal steroidogenesis. CYP21A2 lies within the major histocompatibility complex in an area of the genome highly susceptible to genetic variation. Alterations in the neighboring complement component 4 isotypes C4A and C4B have been associated with psychiatric and autoimmune disease. The purpose of this study was to evaluate C4A and C4B in patients with CAH in relation to CYP21A2 genotype and psychiatric and autoimmune comorbidity. We determined the copy numbers of C4A and C4B in 145 patients with CAH (median age: 15.5 years, IQR: 16.8) and 108 carrier relatives (median age: 41.5 years, IQR: 12.0) and evaluated serum C4 concentrations. Comorbidity was determined by medical record review. Only 30% of subjects had the expected two copies each of the two C4 genes. C4B copy number determined total C4 copy number and serum C4 concentration, negatively correlated with carriership of a 30-kb deletion (P < 10- 5), and positively correlated with carriership of p.V281L (P < 10- 5). High C4A copy number (>= 3) was associated with increased risk of having an externalizing psychiatric condition (relative risk: 2.67, 95% CI: 1.03-6.89, P = 0.04). No association was found between C4 copy number and autoimmune disease. Mutation-specific C4 structural variations commonly occur in patients with CAH and may have important clinical consequences, including increased risk of psychiatric morbidity. Trial registration NCT00250159 (November 7, 2005). PMID- 30465167 TI - Hair Trace Element Levels in Han and Indigenous Hualien Inhabitants in Taiwan. AB - The objective of the present study was to assess the impact of ethnicity on hair trace element content in Han and aboriginal inhabitants of Hualien in Taiwan. Fifty Han (female/male = 35/15) and 50 aboriginal (female/male = 40/10) Hualien inhabitants aged 40-60 years were involved in the present study. Anthropometric data and dietary patterns were recorded. Hair mineral, essential, and toxic trace element levels were assessed using inductively coupled plasma mass spectrometry at NexION 300D (PerkinElmer Inc., USA) equipped with ESI SC-2 DX4 autosampler (Elemental Scientific Inc., USA). No group difference in gender, age, body weight, height, or physical activity was observed. Fish intake was more frequent in Han inhabitants, whereas aborigines consumed significantly more nuts. Indigenous people were characterized by higher hair Al (45%), Ca (threefold), Co (71%), Fe (twofold), I (74%), K (60%), Mg (2.5-fold), Na (62%), P (6%), Sn (78%), and V (46%) content. In turn, Han Hualien inhabitants had higher hair Be (twofold), Li, Se, Si levels as compared to indigenous counterparts. Multiple regression analysis demonstrated that ethnicity was significantly associated with hair Ca (beta = 0.302), Mn (beta = 0.284), P (beta = 0.387), and Se (beta = - 0.310) levels after adjustment for other confounders. At the same time, the overall models were significant for Ca, Mn, Se, and As. The obtained data may provide a background for monitoring and correction of trace element status in patients of different ethnic groups. However, further detailed studies are required to highlight the mechanisms underlying the observed associations. PMID- 30465168 TI - Associations of Internal-Migration Status with Maternal Exposure to Stress, Lead, and Selenium Deficiency Among Pregnant Women in Shanghai, China. AB - Internal migration and urbanization are occurring on a global scale. Although the risk of exposure to stress/lead/low selenium is assumed to be high among migrant pregnant women, population-based evidence is limited. This study aims to explore the association of internal-migration status with maternal exposure to lead, low selenium, and stress among pregnant women. A total of 1931 pregnant women were investigated in 2010. The internal-migration status was grouped based on their hukou (registered residence) and length-of-residency in Shanghai. Maternal blood lead and serum selenium concentrations were assessed. Life event stress and emotional stress were evaluated using "Event-Stress-Scale-for-Pregnant-Women" and "Symptom-Checklist-90-R-Scale" (SCL-90-R), respectively. Logistic regression and general linear models were used to evaluate associations between migration status and lead/stress/low selenium exposure. Compared with the local (with Shanghai hukou and length-of-residency >= 5 years), new migrants (without Shanghai hukou and length-of-residency < 2 years) had lower social-economic-status (SES), higher lead, life event and emotional stress, and lower selenium levels. After adjusting for SES, new migrants had higher risks of emotional stress (for interpersonal sensitivity of SCL-90-R, OR = 2.10, 95% CI 1.22-3.64) and low selenium [lg(selenium): beta = - 0.08, 95% CI - 0.11, - 0.05], but no significant risks for life event stress and high lead. Compared with the local, migrant pregnant women in big cities may have emotional stress and low selenium independent of SES, and high lead and life event stress dependent on SES. PMID- 30465169 TI - The Protective Effect of alpha-Tocopherol on the Content of Selected Elements in the Calvaria for Exposed Hens to TCDD in the Early Embryonic Period. AB - This paper focuses on negative effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on element content in male chicken calvaria and alpha-tocopherol (vitamin E) ability to reduce its toxic potential on bone mineralization in offspring. In the experiment carried out once, a solution containing only DMSO, TCDD, TCDD + alpha-tocopherol, and exclusively alpha-tocopherol was administrated. Subsequently, on the 5th day after hatching, the mineral composition of the chicken calvaria was evaluated. The results obtained suggest that the use of alpha-tocopherol contributes to the maintenance of the concentration of calcium, magnesium, and manganese in the chicken calvaria treated with TCDD in the embryonic period. In turn, vitamin E increases the level of zinc. It has been found that alpha-tocopherol in chicken embryos has a protective effect against disturbance of level of chosen trace elements in the bones of offspring caused by the TCDD. PMID- 30465170 TI - Investigating the Essentiality and Requirements of Iron from the Ancient to the Present. AB - This review discusses the development of studies that evaluated the essentiality and requirements of iron from the ancient to the present. The therapeutic effects of iron compounds were recognized by the ancient Greeks and Romans. The earliest recognition of the essentiality of iron was stated by Paracelsus, a distinguished physician alchemist, in the sixteenth century. Iron was included in the earliest nutritional standard prepared for the Royal Army by E. A. Parkes, the first professor of hygiene. The League of Nations Health Organisation determined average iron requirements based on literature review. In the first US Recommended Dietary Allowances (RDA), the RDA of iron was determined from the results of iron balance studies. In the current Dietary Reference Intakes, iron requirements were determined based on the factorial method with the aid of Monte Carlo simulation for combining basal and menstrual iron losses. Population data analysis is a recently developed alternative that does not use the pre-estimated iron absorption rate and requires the prevalence of inadequacy instead. Population data analysis uses the convolution integral for combining basal and menstrual iron losses to ensure the required accuracy. This review also provides new estimates of hair and nail iron losses. PMID- 30465171 TI - Neural Differentiation of Mouse Neural Stem Cells as a Tool to Assess Developmental Neurotoxicity of Drinking Water in Taihu Lake. AB - In this study, we used neural stem cells (NSCs) as a toxicology tool to assess the potential developmental neurotoxicity of drinking water from Taihu Lake. We found that the condensed drinking water could inhibit the proliferation and differentiation of NSCs, especially the tap water. Inductively coupled plasma mass spectrometry and high-performance liquid chromatography analysis showed that nickel was detected in the tap water with a high concentration. Our study revealed that nickel could inhibit NSCs proliferation and differentiation, which is induced not only by the intracellular reactive oxygen species generation, but also by the protein levels upregulation of p-c-Raf, p-MEK1/2 and p-Erk1/2 through the axon guidance signal pathways. These findings will provide a new way of research insight for investigation of nickel-induced neurotoxicity. Meanwhile, our test method confirmed the feasibility and reliability of stem cell assays for developmental neurotoxicity testing. PMID- 30465172 TI - Pharmacokinetics of Sodium Selenite Administered Orally in Blood and Tissues of Selenium-Deficient Ducklings. AB - Selenium (Se) is an essential trace element for humans and animals. Appropriate amount of Se in the body can prevent a variety of diseases. However, Se deficiency leads to pathological changes such as skeletal muscle necrosis and pancreatic atrophy in livestock and poultry. Se preparations are widely used in the prevention and treatment of Se-deficient disease, but there is no unified standard of medication, and the safe dose range of Se is narrow. Therefore, it is of great significance to study the pharmacokinetics of low-Se ducklings and to formulate drug administration schemes. In the present study, eighty 1-day-old healthy ducklings were randomly selected, and fed with low-Se diet to 30 days of age (blood Se content ? 0.03 MUg/mL). After the low Se duckling models were duplicated, blood samples and tissues of livers, pancreases, and thigh muscles were collected at different time points to detect Se content following oral administration of 0.1% sodium selenite (Na2SeO3) at 0.8 mg/kg BW, and the pharmacokinetics parameters were automatically calculated by MCPKP program. The results showed that pharmacokinetics characteristics of Na2SeO3 in blood, livers, and pancreases of ducklings were consistent with the first-order absorption and two-compartment open models; in thigh muscles was consistent with the first-order absorption and one compartment with a lag time open model. The primary kinetic parameters of Na2SeO3 in blood: the half-life of absorption was 5.9026 h, the time of reaching maximum concentration was 23.03 h, and the half-life of elimination was 131.13 h. The absorption of Na2SeO3 in livers was the quickest, pancreases and thigh muscles were in order of becoming slower, and the elimination of Na2SeO3 in thigh muscles was the quickest, livers and pancreases were in order of becoming slower. The administration parameters of multi-dose were calculated according to the kinetic of single-dose: loading dose (D*) was 1.7046 mg/kg BW, maintenance dose (D0) was 0.8 mg/kg BW, and dosing interval (tau) was 120 h. The results of this study can supplement and improve the theoretical system of Se metabolic kinetics, and provide experimental basis for the prevention and treatment of Se deficiency disease by rational drug use. PMID- 30465173 TI - Metal concentrations in waters, sediments and biota of the far south-east coast of New South Wales, Australia, with an emphasis on Sn, Cu and Zn used as marine antifoulant agents. AB - Tin, Cu, Zn, Cd, Pb, Ag and Hg concentrations were measured in waters, sediments and three ubiquitous sedentary molluscs: the oyster, Saccostrea glomerata, a rocky intertidal gastropod, Austrocochlea porcata, and a sediment-dwelling gastropod, Batillaria australis, at 12 locations along the far south coast of NSW, Australia, from Batemans Bay to Twofold Bay during 2009. Metal concentrations in water for Sn, Cd, Ag and Hg were below detection limits (< 0.005 MUg/L). Measurable water metal concentrations were Cu: 0.01-0.08 MUg/L, Zn: 0.005-0.11 MUg/L and Pb: 0.005-0.06 MUg/L. Mean metal concentration in sediments were Sn < 0.01-2 MUg/g, Cu < 0.01-605 MUg/g, Zn 23-765 MUg/g, Cd < 0.01-0.5 MUg/g, Pb < 0.01-0.3 MUg/g, Ag < 0.01-0.9 MUg/g and Hg < 0.01-2.3 MUg/g. Several locations exceeded the Australian and New Zealand Environment and Conservation Council and Agriculture and Resource Management Council of Australia and New Zealand (Australian and New Zealand guidelines for fresh and marine water quality 2000) low and high interim sediment quality guidelines' levels for Cu, Zn, Cd and Hg. Some sites had measurable Sn concentrations, but these were all well below the levels of tributyltin known to cause harm to marine animals. Elevated metal concentrations are likely to be from the use of antifoulants on boats, historical mining activities and agriculture in the catchments of estuaries. All molluscs had no measurable concentrations of Sn (< 0.01 MUg/g) and low mean Ag (< 0.01-1.5 MUg/g) and Hg (< 0.01-0.5 MUg/g) concentrations. Mean Cu (24-1516 MUg/g), Zn (45 4644 MUg/g), Cd (0.05-5MUg/g) and Pb (0.05-1.1 MUg/g) in oysters were close to background concentrations. Oysters have Cd and Pb concentrations well below the Australian Food Standards Code (2002).] There were no significant correlations between metal concentrations in sediments and in organisms within locations, and no relationship with levels of boating activity and suspected antifouling contamination. Although not pristine, the low levels of metal contamination in sediments and molluscs in comparison with known metal-contaminated areas indicate that this region is not grossly contaminated with metals and suitable for the development of mariculture.]. PMID- 30465174 TI - The impact of disc hemorrhage studies on our understanding of glaucoma: a systematic review 50 years after the rediscovery of disc hemorrhage. AB - PURPOSE OF REVIEW: To trace the influence of disc hemorrhage studies on our understanding of glaucoma. SOURCES: Major articles published during the last 50 years since the rediscovery of disc hemorrhage were identified. A total of 196 articles were selected from 435 articles retrieved using the keywords glaucoma and disc hemorrhage as of August 9 2018 from PubMed. RECENT FINDINGS: The main characteristics of disc hemorrhage, including its morphology, recurrence rate, duration, increased incidence in glaucoma, and role in the progression of normal tension glaucoma was well understood by the year 2000. Since then, studies have focused on more sophisticated and accurate methods of elucidating both structural and functional progression, with special attention to the role of the lamina cribrosa. Nevertheless, both the mechanism of disc hemorrhage development and its fuller relationship with glaucoma remain unclear. Disc hemorrhage research requires careful study of glaucomatous optic neuropathy. This has been facilitated by recent advances in optical coherence tomography (OCT) angiography and other OCT technologies. Furthermore, animal studies of disc hemorrhage promise new insights into glaucomatous optic neuropathy. PMID- 30465175 TI - Adding Acotiamide to Gastric Acid Inhibitors Is Effective for Treating Refractory Symptoms in Patients with Non-erosive Reflux Disease. AB - BACKGROUND: Approximately 30% of patients who are treated with proton pump inhibitors (PPIs) for gastroesophageal reflux disease (GERD) experience persistent symptoms. No prokinetic agent regiments are useful for symptom relief. AIMS: This study was conducted to examine the effect of adding acotiamide to PPI or vonoprazan refractory GERD. METHODS: This was a randomized, prospective, double-blind, placebo-controlled trial. Seventy-one patients were enrolled. Patients underwent upper endoscopy before initial therapy [15 reflux esophagitis and 55 non-erosive reflux disease (NERD)]. Patients with persistent reflux symptoms were administered 300 mg/day acotiamide or placebo for 2 weeks. The primary endpoint was overall treatment effect (OTE), and gastrointestinal symptoms were evaluated. High-resolution manometry (HRM) and 24-h multiple intraluminal impedance-pH (MII-pH) monitoring were conducted before and after treatment when possible. RESULTS: Seventy patients were randomized (35 acotiamide and 35 placebo). Sixteen and 10 patients in the acotiamide and placebo groups, respectively, completed MII-pH and HRM. The OTE improvement rates were 28.6% and 14.3% in patients administered acotiamide and placebo, respectively (p = 0.145). In patients with NERD, however, the OTE improvement rate and responder rate for regurgitation in the acotiamide group was significantly higher than those in the placebo group (29.6 vs. 7.1%; p = 0.030, 37.0 vs. 10.7%; p = 0.021, respectively). Acotiamide significantly reduced the total reflux episodes (p = 0.001), acid (p = 0.020), proximal reflux (p = 0.007), and liquid reflux (p = 0.013) episodes. CONCLUSION: Adding acotiamide to gastric acid inhibitors can improve symptoms in patients with refractory NERD. PMID- 30465176 TI - Macrophage Migration Inhibitor Promoted the Intrahepatic Bile Duct Injury in Rats with Severe Acute Pancreatitis. AB - BACKGROUND: Macrophage migration inhibitory factor (MIF) is involved in many acute and chronic inflammatory diseases. However, its role in intrahepatic bile duct (IBD) cell damage associated with severe acute pancreatitis (SAP) remains unclear. AIMS: This study was aimed to identify the role of MIF and its underlying mechanisms in SAP complicated by IBD cell damage. METHODS: Forty-eight specific-pathogen-free male Wistar rats were randomly divided into four groups (N = 12): a sham operation group (SO group) and three SAP model groups (SAP-3h, SAP 6h, and SAP-12h). Immunohistochemistry was used to detect the expression of MIF and P38 in IBD cells. MIF mRNA expression in IBD cells was observed using real time fluorescent quantitative polymerase chain reaction (real-time PCR). In addition, Western blotting was performed to detect the protein expression of P38, phosphorylated P38 (P-P38), nuclear factor-kappaB (NF-kappaB p65), and tumor necrosis factor alpha (TNF-alpha). Enzyme-linked immunosorbent assays were used to analyze the levels of TNF-alpha, IL-1beta, and IL-6 in the IBD of rats. RESULTS: Compared with the SO group, the expression of MIF in the IBD was significantly upregulated both at mRNA and at protein levels in the SAP group. Besides, the protein expression levels of P38, P-P38, NF-kappaB, p65, TNF-alpha, IL-1beta, and IL-6 in the IBD in rats were also significantly increased in the SAP group and the levels increased gradually as acute pancreatitis progressed (all P < 0.05). CONCLUSIONS: MIF may promote the IBD injury and inflammatory reaction in SAP via activating the P38-MAPK and NF-kappaB signaling pathways. PMID- 30465177 TI - Exosomal miR-155 Derived from Hepatocellular Carcinoma Cells Under Hypoxia Promotes Angiogenesis in Endothelial Cells. AB - PURPOSE: In this study, we aim to clarify whether exosomes secreted from hepatocellular carcinoma (HCC) cells under hypoxia affect angiogenesis in endothelial cells. METHODS: Exosomes derived from human liver cancer cell lines were cultured under hypoxic or normoxic conditions for 24 h, isolated using ExoQuick-TC(r), and co-cultured with HUVECs to evaluate angiogenic activity. We also evaluated the expression of miR-155 in the exosomes from 40 patients with HCC. RESULTS: Exosomes under hypoxia remarkably enhanced tube formation of HUVECs. Both cellular and exosomal miR-155 were significantly up-regulated under hypoxic conditions. Knockdown of miR-155 in HCC cells attenuated the promotion of tube formation by exosomes under hypoxia in HUVECs, and high expression of exosomal miR-155 in preoperative plasma was significantly correlated with early recurrence. CONCLUSION: These results suggest that exosomes derived from HCC cells under hypoxia induce tube formation of HUVECs and that exosomal miR-155 may affect angiogenic activity in HCC. PMID- 30465178 TI - New Risk Factors for Infected Pancreatic Necrosis Secondary to Severe Acute Pancreatitis: The Role of Initial Contrast-Enhanced Computed Tomography. AB - BACKGROUND AND AIMS: Pancreatic necrosis is a risk factor for poor prognosis of acute pancreatitis (AP). However, the associations between the findings on initial contrast-enhanced computed tomography (CT) of the pancreas and infected pancreatic necrosis (IPN) are unclear. METHODS: This was a retrospective cohort study. Patients with severe AP (SAP) from January 2014 to December 2016 at the First Affiliated Hospital of Nanchang University were enrolled and assigned to an IPN group and a non-IPN group. Univariate and multivariate logistic regression analyses were sequentially performed to assess the associations between the variables and IPN development. A receiver operating characteristic (ROC) curve was generated for the qualified independent risk factor. RESULTS: Forty-two patients with IPN were compared with 100 patients without IPN. Contrast-enhanced CT was performed 7 (range 3-10) days after AP onset. Multivariate stepwise logistic regression analyses showed that the number of acute peripancreatic fluid collections (APFCs) (OR 1.328, P = 0.006), presence of peripancreatic and pancreatic parenchymal necrosis (OR 4.001, P = 0.001), and gastrointestinal wall thickening (OR 3.353, P = 0.006) were independent risk factors for IPN secondary to SAP. The area under an ROC curve for the number of APFCs was 0.714, the sensitivity was 78.60%, and the specificity was 57.30% at a cutoff value of 4.5. CONCLUSIONS: The number of APFCs, presence of peripancreatic and pancreatic parenchymal necrosis, and gastrointestinal wall thickening were independent risk factors associated with IPN. As initial contrast-enhanced CT (about 7 days from AP onset) plays an important role in predicting IPN, it is important for clinicians to consider initial imaging of the pancreas. PMID- 30465179 TI - Treatment Satisfaction with Subcutaneous Immunoglobulin Replacement Therapy in Patients with Primary Immunodeficiency: a Pooled Analysis of Six Hizentra(r) Studies. AB - PURPOSE: Primary immunodeficiency diseases (PIDDs) are a heterogenous group of disorders characterized by intrinsic impairment in the immune system. Most patients with PIDD require life-long immunoglobulin G replacement therapy, which has been shown to reduce the rate of infections and, related hospitalizations and reduce health-related quality of life (HRQOL). Here, treatment satisfaction and HRQOL in patients with PIDD was evaluated upon switching from intravenous (IVIG) or subcutaneous immunoglobulins (SCIGs) to 20% SCIG (Hizentra(r)), and during long-term steady-state Hizentra(r) treatment. METHODS: Analyses were based on two pivotal (switch) and four extension/follow-up (maintenance) Phase III studies of Hizentra(r) conducted in Europe (EU), Japan (JP), and the United States (US). Two validated questionnaires were used: Life Quality Index (LQI) for assessment of IgG-specific perceptions of HRQOL and Short Form 36 version 2 (SF-36v2). RESULTS: In the EU and JP switch studies, there was significant and meaningful improvement from Screening in LQI domain scores at all time points, largely driven by patients switching from IVIG to SCIG. In the EU switch study, there were also significant increases in mean SF-36v2 domain scores for Physical Function and General Health from Screening to Week 12. These improvements were observed also at Week 24. Overall, LQI and SF-36v2 domain scores were generally sustained in the maintenance studies. CONCLUSIONS: These results showed that switching patients from IVIG to SCIG improves patient self-reported health status and IgG specific HRQOL perception. The maintenance studies generally showed no deterioration of this improved health status over a long follow-up period. PMID- 30465180 TI - Autoimmunity and Inflammation in CVID: a Possible Crosstalk between Immune Activation, Gut Microbiota, and Epigenetic Modifications. AB - Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency among adults and is characterized by a B cell dysfunction and increased risk of respiratory tract infections with encapsulated bacteria. However, a large proportion of patients also has inflammatory and autoimmune complications. It may seem like a paradox that immunodeficiency and inflammation/autoimmunity coexist within the same individuals. In this commentary, we propose that CVID immunopathogenesis involves an interplay of genes, environmental factors, and dysregulation of immune cells, where gut microbiota and gastrointestinal inflammation can both be important contributors or endpoints to the systemic immune activation seen in CVID, and where epigenetic mechanism may be the undiscovered link between these contributors. In our opinion, these pathways could represent novel targets for therapy in CVID directed against autoimmune and inflammatory manifestations that represent the most severe complications in these patients. Considering the heterogeneous nature of CVID, these mechanisms may not be present in all patients, and different complications may be triggered by different risk factors. CVID is really a variable disease and in the future there is clearly a need for a more personalized medicine based on both genotypic and phenotypic findings. PMID- 30465181 TI - Novel metformin-containing resin promotes odontogenic differentiation and mineral synthesis of dental pulp stem cells. AB - This represents the first report on the development of metformin-containing dental resins. The objectives were to use the resin as a carrier to deliver metformin locally to stimulate dental cells for dental tissue regeneration and to investigate the effects on odontogenic differentiation of dental pulp stem cells (DPSCs) and mineral synthesis. Metformin was incorporated into a resin at 20% by mass as a model system. DPSC proliferation attaching on resins was evaluated. Dentin sialophosphoprotein (DSPP), dentin matrix phosphoprotein 1 (DMP-1), alkaline phosphatase (ALP), and runt-related transcription factor 2 (Runx2) genes expressions were measured. ALP activity and alizarin red staining (ARS) of mineral synthesis by the DPSCs on resins were determined. DPSCs on metformin containing resin proliferated well (mean +/- SD; n = 6), and the number of cells increased by 4-fold from 1 to 14 days (p > 0.1). DSPP, ALP, and DMP-1 gene expressions of DPSCs on metformin resin were much higher than DPSCs on control resin without metformin (p < 0.05). ALP activity of metformin group was 70% higher than that without metformin at 14 days (p < 0.05). Mineral synthesis by DPSCs on metformin-containing resin at 21 days was 9-fold that without metformin (p < 0.05). A novel metformin-containing resin was developed, achieving substantial enhancement of odontoblastic differentiation of DPSCs and greater mineral synthesis. The metformin resin is promising for deep cavities and perforated cavities to stimulate DPSCs for tertiary dentin formation, for tooth root coatings with metformin release for periodontal regeneration, and for root canal fillings with apical lesions to stimulate bone regeneration. PMID- 30465182 TI - Health-related quality of life analysis in stage III melanoma patients treated with adjuvant dendritic cell therapy. AB - BACKGROUND: Health-related quality of life (HRQoL) is an important issue in the rapidly evolving field of adjuvant treatment for stage III melanoma. Dendritic cell vaccination is one of the adjuvant forms of therapy currently investigated. METHODS: We enrolled adults with stage III melanoma to receive adjuvant dendritic cell vaccination after a complete radical lymph node dissection. HRQoL assessment was one of the secondary endpoints of this trial and investigated with the EORTC QLQ-C30 questionnaire at baseline and week 26. RESULTS: Fifteen patients with a median age of 50 years were included in the study, with twelve evaluable patients on study at time of the second questionnaire. Global health status and role functioning improved clinically relevant with a mean difference of 15 (p = 0.010) and 26 points (p = 0.005), respectively. DISCUSSION: Despite the small number of patients, we found a clinically relevant improved global health status. Besides, compared to the other investigated therapies, toxicity of dendritic cell vaccination is low, which supports our finding. CONCLUSION: This is the first description of HRQoL in melanoma patients receiving dendritic cell vaccination. We show the expected improvement in global health status after surgical treatment of stage III melanoma. Thus, adjuvant dendritic cell vaccination does not seem to hamper this improvement, as shown in our small explorative study. PMID- 30465183 TI - Laparoscopy adjuvant total colorectal resection for the treatment of familial adenomatous polyposis (FAP). AB - OBJECTIVE: To discuss and evaluate the safety and value of laparoscopy adjuvant total colorectal resection for the treatment of familial adenomatous polyposis (FAP). METHODS: From March 2010 to June 2015, 38 cases were retrospectively analyzed and divided into 2 groups, of which 17 cases used laparoscopy adjuvant total colorectal resection, and 21 cases used conventional laparotomy. Clinical data were obtained, and the safety and prognosis were observed. RESULTS: Seventeen cases using laparoscopy adjuvant total colorectal resection achieved success with no conversion to laparotomy and intraoperative complications. There was no significant difference in operation time between the two groups. There were significant differences in blood loss, the length of incision, postoperative recovery time of intestinal function and postoperative hospital stay between the two groups (P < 0.05). The trauma in laparoscopy group was less, and could recover faster, and there was no significant difference in complications between the two groups. In addition, there were no recurrence, distant metastasis and death in the follow-up period from 6 to 56 months. CONCLUSION: Laparoscopy adjuvant total colorectal resection is more safe and feasible, which has minimal invasion and can recover fast. PMID- 30465184 TI - Statin treatment and outcomes of metastatic pancreatic cancer: a pooled analysis of two phase III studies. AB - BACKGROUND: The current analysis aims to evaluate the impact of statin co treatment on the survival of patients with metastatic pancreatic cancer. METHODS: This is a pooled analysis of de-identified patient data from two clinical trials (NCT01124786; NCT00844649). Overall and progression-free survival according to patient subsets (patients who received or who did not receive statins) were assessed through Kaplan-Meier analysis and log-rank test. Univariate and multivariate Cox regression analysis was performed to evaluate different factors potentially affecting overall and progression-free survival. Propensity score matching was performed to address heterogeneity in baseline characteristics of different subgroups of patients. RESULTS: A total of 797 patients were assessed in the current study; of which 156 patients received statins and 641 did not receive statins. Using Kaplan-Meier survival estimates, patients who received statins seem to have better overall and progression-free survival compared to patients who did not (P = 0.008; P < 0.001, respectively). In multivariate analysis for factors affecting overall survival, the following factors were associated with worse overall survival: worse performance status (P < 0.001), no statin use (P = 0.044) and multiple sites of metastatic disease (P = 0.023); likewise in multivariate analysis for factors affecting progression-free survival, the following factors were associated with worse progression-free survival: worse performance status (P < 0.001), gemcitabine elaidate chemotherapy (P = 0.015) and no statin use (P = 0.048). Following propensity score matching and using Kaplan-Meier estimates, statin use was also associated with better overall and progression-free survival (P = 0.005; P = 0.040, respectively). CONCLUSION: Statin use seems to be associated with better overall survival among patients with metastatic pancreatic cancer treated with first-line chemotherapy. Prospective studies designed specifically to assess this potential effect of statins are needed. PMID- 30465185 TI - Comments on Contemporary Management of Sigmoid Volvulus. PMID- 30465186 TI - Extrahepatic Neuroendocrine Tumor Causing Biliary Obstruction. PMID- 30465187 TI - Future Liver Remnant (FLR) Increase in Patients with Colorectal Liver Metastases Is Highest the First Week After Portal Vein Occlusion : FLR Increase in Patients with CRLM Is Highest the First Week After PVO. AB - BACKGROUND: Portal vein occlusion (PVO) is an established method to increase the volume of the future liver remnant (FLR). The main reasons for not proceeding to radical hepatectomy are lack of volume increase and tumor progression due to a wait-time interval of up to 8 weeks. The hypothesis was that the increase in FLR volume is not linear and is largest during the first weeks. METHODS: Patients with colorectal liver metastases (CRLM) and standardized future liver remnant (sFLR) < 30% treated with PVO were prospectively included. All patients had at least one CT evaluation before radical hepatectomy. RESULTS: Forty-eight patients were included. During the first week after PVO, the kinetic growth rate (KGR) was 5.4 (+/- 4), compared to 1.5 (+/- 2) between the first and second CT (p < 0.05). For patients reaching adequate FLR and therefore treated with radical hepatectomy, the KGR was 7 (+/- 4) the first week, compared to 4.3 (+/- 2) for patients who failed to reach a sufficient volume (p = 0.4). During the interval between the first and second CT, the KGR was 2.2 (+/- 2), respectively (+/- 0.1) (p = 0.017). DISCUSSION: The increase in liver volume after PVO is largest during the first week. As KGR decreases over time, it is important to shorten the interval between PVO and the first volume evaluation; this may aid in decision making and reduce unnecessary waiting time. PMID- 30465188 TI - Managing Refractory Postoperative Fistulas as Chronic Wounds Using Video-Assisted Hydrodebridement (VAHD). AB - Postoperative fistula formation remains a serious complication following abdominal surgical procedures. Refractory fistulas requiring further surgical intervention delay adjuvant chemotherapy and functional recovery. Here, we present six cases of refractory fistulas and describe a new management technique, which we call video-assisted hydrodebridement. We postulate that refractory fistulas are a type of chronic wound, for which hydrodebridement may be used to hasten wound healing. In all cases, patients had undergone a prolonged period of conservative management and surgical intervention was not considered appropriate. Here, we describe the steps of the procedure in detail. We achieved timely closure of the refractory fistula in five of six cases. The median duration of attempted conservative management was 122 days (63-346 days) and median time to fistula closure after the procedure was 35 days (22-64 days) in the five successful cases. The findings during each procedure are discussed. We suspect that this procedure applies the same benefits to refractory fistulas that hydrodebridement provides to chronic wounds. The combination of endoscopic exploration and hydrodebridement can elucidate barriers to fistula resolution while creating a clean base for wound healing. This technique may be a useful tool to reduce the morbidity of refractory fistula management. PMID- 30465189 TI - Rates of Serious Complications Estimated by the ACS-NSQIP Surgical Risk Calculator in Predicting Oncologic Outcomes of Patients Treated with Pancreaticoduodenectomy for Pancreatic Head Cancer. AB - BACKGROUND: The purpose of this study was to validate the predictive value of the oncologic outcome in addition to the validation of the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) surgical risk calculator in patients treated with pancreaticoduodenectomy (PD) or pylorus preserving pancreaticoduodenectomy (PPPD) for pancreatic head cancer. METHODS: From June 2005 to December 2014, 199 patients underwent PD or PPPD for pancreatic head cancer. Medical records were retrospectively reviewed for investigating general patient characteristics and any comorbid diseases. The calculated perioperative complication risks from the ACS NSQIP calculator were compared with observed complication rates. In a propensity score matching analysis, disease free survival (DFS) and overall survival (OS) were estimated according to calculated severe complication rate (CSCR). RESULTS: The CSCR > 17.9% (n = 69) and CSCR < 17.9% (n = 130) groups were significantly different considering number of the retrieved lymph nodes (22.95 +/- 14.0 vs 18.80 +/- 10.1, p = 0.029), histologic grade (p = 0.0235), and incidence of lymphovascular invasion (p = 0.026). The CSCR < 17.9% group had longer DFS (17.0 vs. 11.0 months, p = 0.015), but the OS was similar between the groups (39.0 vs. 23.0 months, p = 0.48). In the 1:2 propensity score analysis, the CSCR < 17.9% group had longer DFS and OS (DFS 26.0 vs. 11.0 months, p = 0.009; OS 44.0 vs. 26.0 months, p = 0.023). CONCLUSION: The ACS NSQIP surgical risk calculator predicts surgical risk in patients with pancreatic head cancer who undergo PD or PPPD. Furthermore, this tool can help predict the prognosis of surgically treated pancreatic head cancer. PMID- 30465190 TI - Laparoscopic Repair for Perforated Peptic Ulcer Disease Has Better Outcomes Than Open Repair. AB - PURPOSE: Over the last 3 decades, laparoscopic procedures have emerged as the standard treatment for many elective and emergency surgical conditions. Despite the increased use of laparoscopic surgery, the role of laparoscopic repair for perforated peptic ulcer remains controversial among general surgeons. The aim of this study was to compare the outcomes of laparoscopic versus open repair for perforated peptic ulcer. METHODS: A systemic literature review was conducted using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. A search was conducted using MEDLINE, EMBASE, PubMed and Cochrane Database of all randomised controlled trials (RCT) that compared laparoscopic (LR) with open repair (OR) for perforated peptic ulcer (PPU). Data was extracted using a standardised form and subsequently analysed. RESULTS: The meta-analysis using data from 7 RCT showed that LR for PPU has decreased overall post-operative morbidity (LR = 8.9% vs. OR = 17.0%) (OR = 0.54, 95% CI 0.37 to 0.79, p < 0.01), wound infections, (LR = 2.2% vs. OR = 6.3%) (OR = 0.3, 95% CI 0.16 to 0.5, p < 0.01) and shorter duration of hospital stay (6.6 days vs. 8.2 days, p = 0.01). There were no significant differences in length of operation, leakage rate, incidence of intra-abdominal abscess, post-operative sepsis, respiratory complications, re-operation rate or mortality. There was no publication bias and the quality of the studies ranged from poor to good. CONCLUSION: These results demonstrate that laparoscopic repair for perforated peptic ulcer has a reduced morbidity and total hospital stay compared with open approach. There are no significant differences in mortality, post-operative sepsis, abscess and re operation rates. LR should be the preferred treatment option for patients with perforated peptic ulcer disease. PMID- 30465191 TI - Non-Hepatic Abdominal Surgery in Patients with Cirrhotic Liver Disease. AB - Cirrhotic liver disease is an important cause of peri-operative morbidity and mortality in general surgical patients. Early recognition and optimization of liver dysfunction is imperative before any elective surgery. Patients with MELD <12 or classified as Child A have a higher morbidity and mortality than matched controls without liver dysfunction, but are generally safe for elective procedures with appropriate patient education. Patients with MELD >20 or classified as Child C should undergo transplantation before any elective procedure given mortality exceeds 40%. Laparoscopic procedures are feasible and safe in cirrhotic patients. PMID- 30465192 TI - Usage of Droplet Digital PCR (ddPCR) Assays for T Cell Quantification in Cancer. AB - T cells fulfill a central role in cell-mediated immunity and can be found in the circulation and lymphoid organs upon maturation. For clinical applications, it can be important to quantify (infiltrated) T cells accurately in a variety of body fluids and tissues of benign, inflammatory, or malignant origin. For decades, flow cytometry and immunohistochemistry have been the accustomed methods to quantify T cells. Although these methods are widely used, they depend on the accessibility of T-cell epitopes and therefore require fresh, frozen, or fixated material of a certain quality. Whenever samples are low in quantity or quality, an accurate quantification can be impeded. By shifting the focus from epitopes to DNA, quantification of T cells remains achievable.Mature T cells differ genetically from other cell types as a result of T-cell receptor (TCR) gene rearrangements. This genetic dissimilarity can be exploited to quantify the T cell fraction in DNA specimens. Conventionally, multiplex PCR and droplet digital PCR (ddPCR), combined with deep-sequencing techniques, can be applied to determine T-cell content. However, these approaches typically target the whole TCR repertoire, thereby supplying additional information about TCR use. Considering this, a simple T-cell quantification, unwantedly, turns into a complex, expensive, and time-consuming procedure. We have developed two generic single duplex ddPCR assays as alternative methods to quantify T cells in a relatively simple, cheap, and fast manner by targeting sequences located between the Ddelta2 and Ddelta3 genes (TRD locus) and Dbeta1 and Jbeta1.1 genes (TRB locus). These specific TCR loci become deleted systematically early during lymphoid differentiation and therefore will serve as biomarkers for the quantification of mature T cells. Here, we describe a simple and sensitive ddPCR based method to quantify T cells relatively fast, accurately and independently of the cellular context. PMID- 30465193 TI - An Economical, Quantitative, and Robust Protocol for High-Throughput T Cell Receptor Sequencing from Tumor or Blood. AB - The T cell receptor repertoire provides a window to the cellular adaptive immune response within a tumor, and has the potential to identify specific and personalized biomarkers for tracking host responses during cancer therapy, including immunotherapy. We describe a protocol for amplifying, sequencing, and analyzing T cell receptors which is economical, robust, sensitive, and versatile. The key experimental step is the ligation of a single-stranded oligonucleotide to the 3' end of the T cell receptor cDNA, which allows easy amplification of all possible rearrangements using only a single set of primers per locus, while simultaneously introducing a unique molecular identifier to label each starting cDNA molecule. After sequencing, this molecular identifier can be used to correct both sequence errors and the effects of differential PCR amplification efficiency, thus producing a more accurate measure of the true T cell receptor frequency within the sample. This method has been applied to the analysis of unfractionated human tumor lysates, subpopulations of tumor-infiltrating lymphocytes, and peripheral blood samples from patients with a variety of solid tumors. PMID- 30465194 TI - Generation of Tumor Antigen-Specific Cytotoxic T Lymphocytes from Pluripotent Stem Cells. AB - Immunotherapy is a developing but very promising arsenal to treat cancer. Acquiring a more potent and effective approach in cancer immunotherapy is always the ultimate pursuance. CTL-based therapies are highly acclaimed recently due to its direct killing property. However, difficulty in obtaining adequate number of CTLs is still a major obstacle. In previous studies, it is shown that pluripotent stem cell-derived cytotoxic T lymphocytes (CTL)-especially the genetically engineered tumor antigen-specific CTLs-may serve as a good candidate for this goal. Here we introduce a novel approach in generating tumor antigen-specific CTLs from induced pluripotent stem cells (iPSCs) by using both in vitro and in vivo priming mechanisms for the tumor management in a murine melanoma model. PMID- 30465195 TI - Expansion and Adoptive Transfer of Human Vdelta2+ T Cells to Assess Antitumor Effects In Vivo. AB - Recent clinical trials have yielded promising results suggesting that gammadelta T cell62-based immunotherapies can be effective against hematological malignancies. Human T cells expressing Vgamma9Vdelta2+ receptors are particularly attractive candidates for this application, since they can be readily expanded in vitro in large quantities for adoptive transfer and do not require HLA-matching of donors and recipients. While it is well established that Vgamma9Vdelta2+ T cells are potently cytolytic against many human cancers and it has been shown that they can control transplanted human tumors in xenogeneic model systems, little is known about the parameters that determine the antitumor efficacy of adoptively transferred Vgamma9Vdelta2+ T cells in physiologically relevant scenarios. In particular, it may be important to separate their immunosurveillance functions from those employed in the context of an established tumor. Moreover, it is critical to understand how the presence of an immunosuppressive environment, such as one where tumor-infiltrating T cells are held in check by inhibitory ligands, affects the functions of Vgamma9Vdelta2+ T cells. This chapter describes how to establish Epstein-Barr virus (EBV) infection of human umbilical cord blood mononuclear cells (CBMCs) within immunodeficient mice, so as to drive the in vivo formation of human B cell lymphomas that contain an immunosuppressive environment. Details are provided on how to expand human Vgamma9Vdelta2+ T cells from peripheral blood mononuclear cells (PBMCs), administer them to the mice, and evaluate tumors and other tissues. PMID- 30465196 TI - Usage of Single-Cell RNA Sequencing to Unveil Immune Lymphoid Cell Precursors. AB - Single-cell RNA sequencing (scRNA-seq) is a powerful tool to study immune cells, which enables an unbiased way to discover novel cell populations, biological meaningful cellular heterogeneity, and cell lineage development trajectories. Advances in scRNA-seq technologies and computational data analysis have driven a revolution in our understanding of the immune system in health and disease. Technically, the key step for scRNA-seq analysis is making a high-quality cDNA library for sequencing. Here, we describe a plate-based protocol to prepare single-cell cDNA library of bone marrow innate lymphoid precursors for next generation sequencing-based transcriptome analysis. PMID- 30465197 TI - Isolation, Expansion, and Characterization of Natural Killer Cells and Their Precursors as a Tool to Study Cancer Immunosurveillance. AB - This chapter will describe the current methodologies to isolate and expand NK cells from Peripheral Blood (PB) or tissues for "in vitro" studies, including NK cell antitumor immune function. In addition, methods to induce NK cell maturation, differentiation, and expansion from CD34+ precursors will also be described. Finally, it will also be treated the topical issue of the characterization of new functionally and phenotypically defined NK cell subsets. PMID- 30465198 TI - CD107a Degranulation Assay to Evaluate Immune Cell Antitumor Activity. AB - Cancer development is under surveillance by the immune system of the host. Tumor cells can be recognized and killed by cytotoxic lymphocytes- such as CD8+ T lymphocytes and natural killer (NK) cells-mainly through the immune secretion of lytic granules that kill target cells. This process involves the fusion of the granule membrane with the cytoplasmic membrane of the immune effector cell, resulting in surface exposure of lysosomal-associated proteins that are typically present on the lipid bilayer surrounding lytic granules, such as CD107a. Therefore, membrane expression of CD107a constitutes a marker of immune cell activation and cytotoxic degranulation. In this chapter, we detail the steps required to isolate peripheral blood mononuclear cells (PBMCs), coculture them with target tumor cell lines, and evaluate the cytotoxic immune function by means of flow cytometry evaluation of CD107a expression on the surface of NK cells. PMID- 30465199 TI - A Flow Cytometric NK Cell-Mediated Cytotoxicity Assay to Evaluate Anticancer Immune Responses In Vitro. AB - The immune system is able to detect and eliminate nascent and developing tumors. Thus, T lymphocytes of the adaptive immunity recognize cancer cells by detecting tumor-associated antigens, whereas certain innate immune cells scan for molecules that are mainly overexpressed on malignant and infected cells. The best example of the latter is natural killer (NK) cells. The activity of these immune cells is strictly governed by a balance between positive and negative signals provided by stress-regulated molecules that bind NK cell membrane receptors, such as the activatory receptor NKG2D. Given the key role of NK cells in eradicating cancer cells, the development of assays to study the cellular and molecular determinants of NK cell antitumor activity are of great relevance. In this chapter, we describe a flow cytometric in vitro assay to evaluate the cytotoxic activity of NK cells against a given target cell, including tumor cells. Moreover, this method is highly versatile, as it can be complemented with the use of antibodies blocking cell surface proteins (receptors or ligands) or a variety of chemical modulators, which allows the elucidation of molecules and signaling pathways that regulate NK cell anticancer function. PMID- 30465200 TI - Mouse Models to Study Natural Killer Cell-Mediated Immunosurveillance and Metastatic Latency. AB - Metastatic latency is a major concern in the clinic, yet how these disseminated cancer cells survive and initiate metastases is unknown (Massague and Obenauf, Nature 529:298-306, 2016). Here, we describe an approach to isolate latency competent cancer (LCC) cells from early stage human lung and breast carcinoma cell lines using mouse xenograft models (Malladi, Cell 165:45-60, 2016). Cancer cell lines labeled with GFP-luciferase and antibiotic selection markers were injected intracardially into athymic mice. Three months, post-injection, LCC cells were identified in situ and isolated. Upon reinjection, LCC cells retain their tumorigenic potential, enter a slow-cycling or quiescent state, and evade NK cell-mediated innate immune surveillance. PMID- 30465201 TI - Tumor-Associated Macrophage Isolation and In Vivo Analysis of Their Tumor Promoting Activity. AB - Characterization of individual cell populations from the tumor microenvironment is critical to understand their functional contribution to tumor progression. Magnetic bead enrichment and fluorescence-activated cell sorting (FACS) allow for the isolation of specific cell types that can be used in downstream applications, including in vitro and in vivo functional studies and molecular profiling. In this chapter, we describe the process of isolation of tumor-associated macrophages (TAMs) from primary murine breast tumors subsequent to therapeutic or experimental intervention. Additionally, we further detail how to analyze their ability to support tumor cell growth by co-injecting isolated TAMs with tumor cells orthotopically into the mammary gland of immune-deficient hosts, and monitoring tumor progression by live imaging and caliper measurement. PMID- 30465202 TI - Conditional Genetic Ablation Mouse Models as a Tool to Study Cancer Immunosurveillance In Vivo. AB - Over the last decades, it has been established that the immune system is crucial for the impediment of cancer development by recognizing and destroying transformed cells. This process has been termed cancer immunosurveillance. Small animal models have significantly facilitated our understanding of it. Dissecting the contribution of any specific immune cell type participating in this process requires the ability to specifically target it while leaving the other immune components as well as the cancer model system unperturbed in vivo. Here, we provide a simple and rapid protocol for the generation of transgenic mice expressing Cre recombinase in a cell type-specific manner-in our example we chose cells expressing Ncr1, which encodes for the surface protein NKp46-and the use of those mice to ablate NKp46+ cells in order to study their role in a model of cancer immunosurveillance against experimental pulmonary metastases. This protocol can easily be adapted to target other cell types and other cancer models. PMID- 30465203 TI - Determination and Isolation of Immune Populations from Brain Tumor Microenvironments. AB - Flow cytometry analysis and fluorescence-activated cell sorting (FACS) allow the determination and isolation of different cell types from a given tumor sample. Here we describe and comment a method consisting of the preparation of a single cell suspension from a freshly dissected mouse brain tumor mass, staining with a combination of fluorescently labeled antibodies and analysis by flow cytometry to determine, characterize, and isolate different immune populations. PMID- 30465204 TI - Mouse Model of Colitis-Associated Colorectal Cancer (CAC): Isolation and Characterization of Mucosal-Associated Lymphoid Cells. AB - Colorectal cancer (CRC) is the third most common malignancy worldwide presenting high mortality due to low treatment efficacy. Existing evidence indicates that inflammatory bowel disease (IBD) is associated with a higher risk of developing CRC. Many murine models of inflammation-related colon carcinogenesis (CAC) have been developed to study colon carcinogenesis and novel treatments. A commonly used model involves the combination of a single dose of azoxymethane (AOM), together with three cycles of the inflammatory agent dextran sodium sulfate (DSS) (5 days in drinking water followed by a two-week rest). Following this protocol, around 50% of the animals develop CRCs after 45 days and almost 100% of animals after 60 days. During CAC development, immune cells, cytokines, and other immune mediators are involved in both tumorigenesis and the elimination of cancer cells during immunotherapy. Thus, the study of mucosal immune responses (including lamina propria mononuclear cells and intraepithelial lymphocytes) is important to understand the role of the immune system during development and therapy in CRC. Single immune cell suspensions from lamina propria and epithelium can be purified combining selective tissue digestion and Percoll gradient centrifugation. Isolated cells can be characterized using flow cytometry by analyzing surface antigens or intracellular cytokines and cytotoxic mediators or employed for further investigations like comparative studies of mRNA expression, cell proliferation assay, protein analysis, or even functional cytotoxicity assays. The CAC model is useful to study the involvement of immune cells not only during the carcinogenesis process but, in addition, during the treatment with novel immunotherapy protocols. PMID- 30465205 TI - Cancer Exome-Based Identification of Tumor Neo-Antigens Using Mass Spectrometry. AB - Neo-antigens expressed on tumors are targets for development of cancer immunotherapy strategies. Use of prediction algorithms to identify neo-antigens yields a significant number of peptides that must be validated in laborious and time-consuming methods; many prove to be false-positive identifications. The use of HLA peptidomics allows the isolation of the HLA-peptide complexes directly from cells and can be done on fresh tumor, patient-derived xerographs, or cell lines when the tissue sample is limited. This method can be used to identify both HLA class I and HLA class II or any different MHC from different species. Here we describe the steps to create the immune-affinity columns used from the process, the immunoprecipitation procedure, and also the isolation of the peptides that will be analyzed by mass spectrometry. PMID- 30465206 TI - Single-Cell Mass Cytometry of Archived Human Epithelial Tissue for Decoding Cancer Signaling Pathways. AB - The emerging phenomenon of cellular heterogeneity in tissue requires single-cell resolution studies. A specific challenge for suspension-based single-cell analysis is the preservation of intact cell states when single cells are isolated from tissue contexts, in order to enable downstream analyses to extract accurate, native information. We have developed DISSECT (Disaggregation for Intracellular Signaling in Single Epithelial Cells from Tissue) coupled to mass cytometry (CyTOF: Cytometry by Time-of-Flight), an experimental approach for profiling intact signaling states of single cells from epithelial tissue specimens. We have previously applied DISSECT-CyTOF to fresh mouse intestinal samples and to Formalin-Fixed, Paraffin-Embedded (FFPE) human colorectal cancer specimens. Here, we present detailed protocols for each of these procedures, as well as a new method for applying DISSECT to cryopreserved tissue slices. We present example data for using DISSECT on a cryopreserved specimen of the human colon to profile its immune and epithelial composition. These techniques can be used for high resolution studies for monitoring disease-related alternations in different cellular compartments using specimens stored in cryopreserved or FFPE tissue banks. PMID- 30465207 TI - Purification of Leukemia-Derived Exosomes to Study Microenvironment Modulation. AB - Exosomes are membrane-enclosed vesicles released by different cell types into the extracellular space. As mediators of intercellular communication, they are involved in multiple physiological processes, but they are also associated with the pathogenesis of human malignancies including leukemia. Isolation of exosomes enables the characterization of their role in microenvironment modulation as well as their participation in disease pathology. A variety of strategies and techniques exists to purify exosomes from many biological fluids (e.g., blood, urine, and saliva). Here, we describe the efficient production of large quantities of exosomes from leukemic cell lines by using CELLine bioreactors based on two-compartment technology, as well as their isolation and purification by combining differential centrifugation and ultracentrifugation through a density gradient (17% OptiPrepTM cushion). Thus, exosomes are appropriately prepared for characterization by western blotting to detect exosome markers or imaging flow cytometry (ImageStream), and for downstream analyses such as the internalization in microenvironmental cells by confocal imaging or flow cytometry, methods which are also described in this chapter. PMID- 30465208 TI - Molecular Characterization of Circulating Tumor Cells to Study Cancer Immunoevasion. AB - Cancer cells leaving the primary tumor immunosuppressive microenvironment become vulnerable to active immune surveillance and require mechanisms of immunoevasion to survive in the circulation. Studies have identified several pathways by which circulating tumor cells (CTCs) might escape the immune system/immunotherapy attack. The PD-1/PD-L1 axis is an immune checkpoint regulator, playing a major role in maintaining self-tolerance. It is now well recognized that tumor cells co opt the PD-1/PD-L1 axis of immune regulation to interfere with cytotoxic T lymphocyte function. Transcriptional changes in CTCs, leading to the upregulation of PD-L1, might enable them to survive in circulation. Very recent data revealed a previously unappreciated role of epithelial-mesenchymal transition (EMT) in reprogramming the immune response in the local tumor microenvironment and a mutual regulation between EMT and immunoevasion is becoming apparent. In this chapter, we will describe in detail both EpCAM-dependent and -independent approaches that allow the identification of PD-L1 expression and EMT-like features in circulating tumor cells. PMID- 30465209 TI - Quantitative Identification of Senescent Cells in Cancer. AB - Cellular senescence, a state of permanent growth arrest, is an important mechanism preventing the propagation of damaged cells. It suppresses cancer development in premalignant lesions in response to activated oncogenes and in tumors following therapy. The presence of senescent cells in premalignant lesions and tumors is controlled by the immune system. The ability to identify and quantify senescent cells more efficiently in vivo is necessary in order to evaluate the effect of these cells on tumorigenesis and cancer therapy. Through combining senescent-associated beta-galactosidase staining with ImageStream X analysis, we have developed an effective method to identify and quantify senescent cancer cells in vivo. PMID- 30465210 TI - Generation and Harnessing of Heterotypic Tumor-Stroma Spheroids to Study Cancer Immunosurveillance. AB - Clinically apparent tumors have often established an immunosuppressive tumor microenvironment which renders them "cold," meaning that there are low numbers of immune cells within the tumor. Consequently, novel immunotherapy approaches such as checkpoint inhibitors fail to reactivate the tumor-targeted immune cells. Here we describe the generation of heterotypic tumor-stroma spheroids to study various approaches aiming at the reactivation of cancer immunosurveillance. These spheroids allow to investigate whether a certain immunotherapy or a combination treatment is able to stimulate antitumor immunity in poorly immunological ("cold") tumors, by increasing the number of tumor-infiltrating immune cells ("hot" tumors). PMID- 30465211 TI - Establishment of Slice Cultures as a Tool to Study the Cancer Immune Microenvironment. AB - Although immunotherapy is currently being widely applied to treat a variety of cancers, there is great heterogeneity in the response to these treatments. Many in the field hypothesize that this may be attributable to the characteristics of each individual tumor immune microenvironment, in addition to systemic immune factors. Therefore, understanding the immune cell microenvironment in a variety of tumors is critically important. Specifically, the interactions among immune, stromal, and cancer cells, along with other factors in tumors, may hold the key to developing rational personalized combinations of immunotherapeutic drugs. We recently developed an organotypic slice culture technique, which enables precise study of the pancreatic ductal adenocarcinoma (PDA) tumor microenvironment. We used a Vibratome to cut fresh human tumor tissue into 250 MUm thick slices, and cultured slices on cell culture inserts with 0.4 MUm pore to produce our tumor slice culture (TSC) system. We showed that TSC maintained many elements of the original tumor microenvironment and architecture for approximately one week. Using this slice culture technique for PDA, we demonstrated that immune cells, including T cells and macrophages, cancer cells, and stromal myofibroblasts were present throughout the culture period. TSCs were functionally responsive to drug treatment. Live PDA slices could be stained for multicolor immunofluorescence imaging of each of the primary cellular constituents of the tumor. Finally, autologous CFSE-labeled splenocytes were observed to readily migrate into cocultured tumor slices. PMID- 30465212 TI - Gold Standard Assessment of Immunogenic Cell Death in Oncological Mouse Models. AB - The efficacy of cancer therapies strongly relies on their ability to reinstate cancer immunosurveillance. Numerous biomedical approaches with immunotherapeutic activity have been developed to reeducate the host immune system to detect and clear tumor cells. Cytotoxicants have been primarily designed to slow down malignant cell proliferation and to induce programmed cell death. Some cytotoxic stimuli are able to activate a particular type of apoptosis, which is referred to as immunogenic cell death (ICD), that de facto convert cancer cells into their own vaccine. This effect ultimately facilitates the establishment of an antitumor immune response that potentially annihilates spared malignant cells, as well as an immune memory that prevents cancer recurrence. Based on the characteristic hallmarks of ICD, protocols have been developed to validate ICD induction in vitro, ex vivo, and in vivo. These methods may contribute to identify novel ICD inducers and to design multimodal regimens with superior therapeutic efficacy. Moreover, their translation into clinical research could have prognostic or predictive value. This chapter will introduce the "gold standard" protocol for the in vivo assessment of ICD in mice. The procedure relies on vaccination with treated cancer cells, followed by rechallenge with living entities of the same type, in syngeneic immunocompetent animals. PMID- 30465213 TI - A Novel Dendritic Cell-Based Vaccination Protocol to Stimulate Immunosurveillance of Aggressive Cancers. AB - A major challenge in the development of a successful tumor vaccination is to break immune tolerance and to sensitize efficiently the immune system toward relevant tumor antigens, thus enabling T-cell-mediated antitumor responses in vivo. Dendritic cell (DC)-based immunotherapy shows the advantage to induce an adaptive immune response against the tumor, with the potential to generate a long lasting immunological memory able to prevent further relapses and hopefully metastasis. Recently different preclinical studies highlighted the golden opportunity to exploit the features of immunogenic cell death (ICD) to generate ex vivo a highly immunogenic tumor cell lysate as potent antigen formulation for improved DC-based vaccine against aggressive cancers. This chapter focuses on the methods to obtain tumor lysates from cells undergoing ICD to be used for DC pulsing and to test the functionality of the generated DCs for antitumor vaccine development. PMID- 30465214 TI - Development of Bispecific Antibody Derivatives for Cancer Immunotherapy. AB - Development of antibody-based immunotherapeutics has progressed from direct tumor targeting, with antibodies such as rituximab, to blocking of immune checkpoints to reactivate antitumor immunity. In addition, bispecific antibodies/antibody fragments are also of great interest in cancer therapy, as these constructs have the ability to redirect immune effector cells to cancer targets and, thereby, enhance therapeutic efficacy. A number of bispecific antibody formats have been reported, with the first FDA-approved bispecific antibody being blinatumomab, a so-called bispecific T cell engager (BiTE), which redirects and potently activates T cell immune responses. Recently, we described an additional novel bispecific antibody derivative, termed RTX-CD47, which was designed to inhibit the innate immune checkpoint CD47-SIRPalpha only on -positive cancer cells. RTX CD47 contains two antibody fragments in tandem and has monovalent binding specificity for CD47 and . Only upon dual binding to and CD47 RTX-CD47 blocks CD47 "Don't eat me" signaling. Here, we provide a detailed protocol for the construction and functional evaluation of such a bispecific antibody derivative. PMID- 30465215 TI - Generation of CAR-T Cells for Cancer Immunotherapy. AB - T cells engineered with chimeric antigen receptors (CARs) are emerging as powerful cancer immunotherapies. Remarkable efficacies have been demonstrated in treating B-cell malignancies with CAR-T cells, leading to the FDA's first approval of gene therapy. Currently, numerous clinical trials for hematological malignancies and solid tumors are underway worldwide. Production of CAR-T cells with proper qualities is essential for CAR-T success in vivo. Here we detail optimized protocols for the generation of CAR-T cells for preclinical studies using lentiviral gene transfer, expansion of CAR-T cells in culture, detection of CAR expression, and evaluation of CAR-T cellular cytotoxicity in vitro. PMID- 30465216 TI - Socioeconomic status and risk of osteoporotic fractures and the use of DXA scans: data from the Danish population-based ROSE study. AB - : There is a need of studies exploring the link between socioeconomic status and DXA scans and osteoporotic fracture, which was the aim of the present study. No differences in socioeconomic status and risk of osteoporotic fractures were found. However, women with further/higher education and higher income are more often DXA-scanned. INTRODUCTION: Lower socioeconomic status is known to be associated with a range of chronic conditions and with access to health care services. The link between socioeconomic status and the use of DXA scans and osteoporotic fracture, however, needs to be explored more closely. Therefore, the aim of this study was to examine the relationship between socioeconomic status and both DXA scan utilization and major osteoporotic fractures (MOF) using a population-based cohort of Danish women and national registers. METHODS: The study included 17,155 women (65-81 years) sampled from the Risk-stratified Osteoporosis Strategy Evaluation study (ROSE). Information on socioeconomic background, DXA scans, and MOFs was retrieved from national registers. Competing risk regression analyses were performed. Mean follow-up was 4.8 years. RESULTS: A total of 4245 women had a DXA scan (24.7%) and 1719 (10.0%) had an incident MOF during follow-up. Analyses showed that women with basic education had a lower probability of undergoing DXA scans than women with further or higher education (greater than upper secondary education and vocational training education) (subhazard ratio (SHR) = 0.82; 95% CI 0.75-0.89, adjusted for age and comorbidity). Moreover, women with disposable income in the low and medium tertiles had a lower probability of undergoing DXA scans than women in the high income tertile (SHR = 0.90; 95% CI 0.84-0.97 and SHR = 0.88, 95% CI 0.82-0.95, respectively, adjusted for age and comorbidity). No association between socioeconomic background and probability of DXA was found in adjusted analyses. CONCLUSION: The study found no differences in risk of osteoporotic fractures depending on socioeconomic status. However, women with further or higher education as well as higher income are more often DXA-scanned. PMID- 30465217 TI - ASO Author Reflections: Outcomes of Appendiceal Goblet Cell Carcinoid Tumors. PMID- 30465218 TI - Isolated Limb Infusion and Isolated Limb Perfusion for Melanoma: Can the Outcomes of these Procedures be Compared? PMID- 30465219 TI - ASO Author Reflections: Nipple-Sparing Mastectomy and Treatment Delay. PMID- 30465220 TI - Prognostic Factors and Appropriate Lymph Node Dissection in Salvage Esophagectomy for Locally Advanced T4 Esophageal Cancer. AB - BACKGROUND: A suitable treatment strategy for esophageal cancer after definitive chemoradiotherapy for T4 cases has not been established and remains unclear. This study aimed to clarify the independent prognostic factors, surgical indications, and optimal extent of lymphadenectomy for T4 esophageal cancer. METHODS: Of 803 patients who underwent esophagectomy for esophageal cancer at the authors' institution from 2006 to March 2018, the study included 33 patients who underwent salvage esophagectomy with locally advanced T4 cancer. The study examined the baseline attributes and treatment results of these cases and evaluated the prognostic factors and treatment strategies. RESULTS: The independent favorable prognostic factors in T4 cancer (T4a/T4b = 11/22) included non-T4b status [hazard ratio (HR), 15.311; 95% confidence-interval (CI), 1.277-183.5] and R0 resection (HR, 14.706; 95% CI, 1.193-166.67). For the cases in which R0 resection was possible (n = 14), both the 1- and 5-year survival rates were 90.9%, whereas for the cases without R0 dissection (n = 19), the 1- and 5-year survival rates were respectively 44.9% and 0%. In the univariate analysis, the patients who underwent two- or three-field lymph node dissection tended to have a better prognosis (p = 0.062), and those with 60 or more lymph nodes dissected had a significantly better prognosis (p = 0.038). For the patients who underwent salvage esophagectomy with typical lymph node dissection, the rate of complications classified as Clavien-Dindo grade 3 or higher (33.3%) was not increased, indicating that the procedure was relatively safe. CONCLUSIONS: The results showed that in salvage esophagectomy for T4 esophageal cancer, R0 resection led to improved prognosis. Because typical two- or three-field lymph node dissection including prophylactic dissection could be performed safely and led to a better prognosis in salvage esophagectomy, typical esophagectomy including prophylactic lymph node dissection should be performed if possible. PMID- 30465221 TI - ASO Author Reflections: Changes in Use of Neoadjuvant Chemotherapy Over Time Highest Rates of Use Now in Triple-Negative and HER2+ Disease. PMID- 30465222 TI - Internal Mammary Chain Sentinel Nodes in Early-Stage Breast Cancer Patients: Toward Selective Removal. AB - BACKGROUND: Removal of internal mammary chain sentinel nodes (IMCSNs) affects prognosis and treatment of breast cancer, and internal mammary chain radiotherapy (IMCRT) can improve survival for selected patients. This study aimed to determine the effect of IMCSN biopsy on recurrence-free survival (RFS) and overall survival (OS) and to identify predictive factors for IMCSN and distant metastasis. METHODS: Patients with IMCSNs were selected from a prospective database for the period 1999-2007. Lymphoscintigraphy was performed after intratumoral technetium 99 m injection, and all sentinel nodes were removed. Both RFS and OS were calculated for subgroups with tumor-positive, tumor-negative, or non-removed IMCSNs. Predictive factors were identified for tumor-positive IMCSNs and distant metastasis by regression analysis. RESULTS: For 287 (85%) of 336 patients, IMCSN biopsy was performed, and metastasis was detected in 38 patients (13%). The patients with tumor-positive IMCSNs had poorer OS than the patients with no IMCSN metastasis or non-removed IMCSNs (p = 0.002). These patients also had worse RFS due to distant metastasis (p = 0.002). Axillary metastasis was predictive for tumor-positive IMCSNs (positive predictive value, 38.5%). The predictive factors for distant metastasis were tumor-positive IMCSNs (hazard ratio [HR], 2.5), non removed IMCSNs (HR, 2.3), tumor diameter greater than 1.5 cm (HR, 3.5), and age older than 65 years (HR, 3.1; reference, < 50 years). CONCLUSIONS: Patients with IMCSNs have worse survival due to distant metastasis. The clinically relevant predictive factor for distant metastasis is tumor larger than 1.5 cm. According to the authors' current protocol, IMCSN biopsy is performed for patients younger than 70 years who have a tumor larger than 1.5 cm, with the cardiotoxicity of the adjuvant IMCRT weighed against the survival benefit. PMID- 30465223 TI - ASO Author Reflections: Eighty is the New Sixty-Breast Cancer Treatment Strategies in the Octogenarian Patient Population. PMID- 30465224 TI - Middle Hepatic Vein Roadmap for a Safe Laparoscopic Right Hepatectomy. AB - BACKGROUND: When performing a right hepatectomy, the middle hepatic vein (MHV) should guide the parenchymal transection. MHV hotspots for bleeding can be anticipated when applying the previously developed MHV Roadmap to a minimally invasive approach.1 This video demonstrates application of the MHV Roadmap to perform a safe laparoscopic right hepatectomy. PATIENT: A 44-year-old woman with a solitary and large breast cancer liver metastasis in the right liver was considered for a laparoscopic right hepatectomy following an excellent response to neoadjuvant chemotherapy. The MHV anatomy was reconstructed using automated vascular reconstruction software (Synapse, Fuji) ahead of surgery. TECHNIQUE: With the patient in the French position, the hilar vessels are exposed and the inflow is controlled. Parenchymal transection begins along the demarcation line.2,3 The constant relationship between the portal bifurcation and the V5 ventral and dorsal allows for easy intraparenchymal identification of the MHV. The parenchymal transection is performed in a convex fashion to optimize exposure of the MHV. Using MHV guidance, the parenchymal transection is continued and V8 is safely identified. The operation is completed with division of the anterior fissure and right hepatic vein. CONCLUSION: Outlining the MHV anatomy according to the MHV Roadmap preoperatively helps to anticipate hotspots of bleeding. Guidance along the MHV through the parenchymal transection allows for early identification of tributaries, thereby preventing injury and remnant liver ischemia. PMID- 30465225 TI - ASO Author Reflections: Is It Important to Do Exercise Before Surgery for HPB Malignancy? PMID- 30465226 TI - ASO Author Reflections: Locoregional Recurrence Rates are Low with the Selective Use of PMRT in Patients with T1-2 Tumors and One to Three Positive Lymph Nodes. PMID- 30465227 TI - Correction to: Ceritinib for Untreated Anaplastic Lymphoma Kinase-Positive Advanced Non-Small-Cell Lung: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal. AB - The title of the article should read. PMID- 30465228 TI - Dinutuximab Beta for Treating Neuroblastoma: An Evidence Review Group and Decision Support Unit Perspective of a NICE Single Technology Appraisal. AB - As part of its Single Technology Appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer (EUSA Pharma) of dinutuximab beta (Qarziba(r)) to submit evidence of its clinical and cost effectiveness for treating neuroblastoma. The BMJ Technology Assessment Group (BMJ-TAG) was commissioned to act as the Evidence Review Group (ERG), reviewing the submission from the company. The Decision Support Unit (DSU) was commissioned to review additional evidence submitted by the company and to undertake further analyses. This article presents the critical review of the company's submissions by the ERG and DSU, further analyses undertaken by the DSU, and the outcome of the NICE guidance. The clinical effectiveness for dinutuximab beta was derived from a phase III randomised controlled trial (RCT) that assessed the safety and efficacy of the addition of interleukin (IL)-2 to dinutuximab beta plus isotretinoin. This trial did not inform the relative effectiveness of dinutuximab beta versus isotretinoin alone, which was established practice in the UK for maintenance treatment. In the absence of direct evidence, the company initially conducted a naive indirect treatment comparison against a historical control, and later performed a matching-adjusted indirect comparison (MAIC) against the isotretinoin arm of an RCT comparing dinutuximab alpha and isotretinoin. The company submitted a partitioned survival analysis model that calculated the incremental cost effectiveness of dinutuximab beta versus isotretinoin. The company's original incremental cost-effectiveness ratio (ICER) was L22,338 per quality-adjusted life-year (QALY) gained. However, the ERG were concerned that the company's ICER was not suitable for decision making, and thus carried out initial exploratory analysis as a first step to overcome the naive estimation of treatment effectiveness in the model. The ERG's analysis estimated an ICER of L111,858 per QALY gained. In their revised analysis incorporating the MAIC and other changes as requested by the appraisal committee, the company's ICER was L24,661 per QALY gained. When the DSU incorporated longer-term isotretinoin data and made corrections to the model, the ICER increased to between L62,886 and L87,164 per QALY gained depending on the choice of survival model. A confidential Patient Access Scheme (PAS) decreased the ICERs. The ICERs with the PAS were over L40,000 per QALY gained, but the NICE committee additionally considered the patient population and its size, the disease severity, the potential for significant survival benefit and uncaptured health benefits, and recommended dinutuximab beta as a treatment option, subject to the company providing the agreed discount in the PAS. PMID- 30465229 TI - The Inclusion of Spillover Effects in Economic Evaluation: A Public Health Economics Perspective. PMID- 30465230 TI - The Heart of the Meaning: Honoring the Work of Byron J. Good. PMID- 30465231 TI - Whole genome engineering by synthesis. AB - Whole genome engineering is now feasible with the aid of genome editing and synthesis tools. Synthesizing a genome from scratch allows modifications of the genomic structure and function to an extent that was hitherto not possible, which will finally lead to new insights into the basic principles of life and enable valuable applications. With several recent genome synthesis projects as examples, the technical details to synthesize a genome and applications of synthetic genome are addressed in this perspective. A series of ongoing or future synthetic genomics projects, including the different genomes to be synthesized in GPwrite, synthetic minimal genome, massively recoded genome, chimeric genome and synthetic genome with expanded genetic alphabet, are also discussed here with a special focus on theoretical and technical impediments in the design and synthesis process. Synthetic genomics will become a commonplace to engineer pathways and genomes according to arbitrary sets of design principles with the development of high-efficient, low-cost genome synthesis and assembly technologies. PMID- 30465232 TI - Targeting histones for degradation in cancer cells as a novel strategy in cancer treatment. AB - The anticancer therapies with the joint treatment of a histone deacetylase (HDAC) inhibitor and a DNA-damaging approach are actively under clinical investigations, but the underlying mechanism is unclear. Histone homeostasis is critical to genome stability, transcriptional accuracy, DNA repair process, senescence, and survival. We have previously demonstrated that the HDAC inhibitor, trichostatin A (TSA), could promote the degradation of the core histones induced by gamma radiation or the DNAalkylating agent methyl methanesulfonate (MMS) in non-cancer cells, including mouse spermatocyte and embryonic fibroblast cell lines. In this study, we found that the joint treatment by TSA and MMS induced the death of the cultured cancer cells with an additive effect, but induced degradation of the core histones synergistically in these cells. We then analyzed various combinations of other HDAC inhibitors, including suberoylanilide hydroxamic acid and valproate sodium, with MMS or other DNAdamaging agents, including etoposide and camptothecin. Most of these combined treatments induced cell death additively, but all the tested combinations induced degradation of the core histones synergistically. Meanwhile, we showed that cell cycle arrest might not be a primary consequence for the joint treatment of TSA and MMS. Given that clinic treatments of cancers jointly with an HDAC inhibitor and a DNA-damaging approach often show synergistic effects, histone degradation might more accurately underlie the synergistic effects of these joint treatments in clinic applications than other parameters, such as cell death and cell cycle arrest. Thus, our studies might suggest that the degradation of the core histones can serve as a new target for the development of cancer therapies. PMID- 30465233 TI - Attenuation correction in multipinhole-CZT gamma camera : Differences in attenuation pattern in myocardial SPECT between CZT and conventional gamma cameras. Oddstig J, Martinsson E, Jogi J, Engblom H, Hindorf C. J Nucl Cardiol. 2018. PMID- 30465234 TI - Dasatinib: A Review in Pediatric Chronic Myeloid Leukemia. AB - Chronic myeloid leukemia (CML) is a rare hematopoietic stem cell disease that is typically characterized by the abnormal BCR-ABL1 fusion gene on the Philadelphia (Ph) chromosome in neoplastic cells. Dasatinib (Sprycel(r)) is an orally administered, small molecule tyrosine kinase inhibitor indicated for the treatment of certain hematological malignancies, including Ph-positive CML in the chronic phase (Ph+ CML-CP) in adult and pediatric patients. In open-label phase 1 and phase 2 clinical trials, dasatinib produced early and durable target responses (i.e. molecular, cytogenetic and/or hematologic) in pediatric patients with Ph+ CML-CP that was newly diagnosed or resistant/intolerant to imatinib, with some recipients of the drug also experiencing deep molecular responses. Dasatinib therapy in pediatric patients with Ph+ CML-CP was reported to have a similar safety profile to that observed in adults, except there were no occurrences of pleural effusion, pericardial effusion, pulmonary edema, or pulmonary hypertension adverse events. Although long-term outcomes remain to be determined, dasatinib expands the first- and second-line options available for the treatment of Ph+ CML-CP in pediatric patients. PMID- 30465235 TI - Cerebrospinal Fluid Galectin-1 Levels Discriminate Patients with Parkinsonism from Controls. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder in elderly people. Currently, the diagnosis of PD is based on neurological examination, neuroimaging, and the response to dopaminergic medication. The diagnosis can be challenging, especially at early disease stages, when the symptoms of patients with atypical parkinsonism (APD) may strongly overlap. Therefore, reliable biomarkers that are able to identify patients with PD are much needed. Here, we aimed to identify and validate new biomarkers for PD in cerebrospinal fluid (CSF). We performed a profiling experiment using mass spectrometry (MS) of CSF from ten PD patients and ten matched non-neurological controls. We selected one protein, galectin-1 (Gal-1), which was differentially expressed in PD vs. controls, and quantified its concentrations in CSF by enzyme linked immunosorbent assay (ELISA) in three new cohorts of 37 PD patients, 21 APD patients, and 44 controls. CSF levels of Gal-1 were lower in PD in both the discovery and validation experiments and discriminated PD from controls with moderate-high accuracy levels (ELISA: area under the curve = 0.7). Similar levels of Gal-1 were found in PD and APD. Gal-1 levels were correlated to age in all groups and correlated in the PD patients to CSF levels of total tau, phosphorylated tau, neurofilament light chain (NFL), and the mini-mental state examination (MMSE) score. We conclude that MS profiling of proteins may be a useful tool to identify novel biomarkers of neurological diseases and that CSF Gal-1 levels may discriminate PD from non-neurological controls. PMID- 30465236 TI - Near Vision Improvement with the Use of a New Topical Compound for Presbyopia Correction: A Prospective, Consecutive Interventional Non-Comparative Clinical Study. AB - INTRODUCTION: To report the outcomes in near vision, optical quality and pupil diameter of a new pharmacological therapy (FOV tears) for presbyopia. METHODS: This was a prospective, consecutive, interventional, non-comparative clinical study in which 117 presbyopic patients were given one drop of the novel therapy (FOV tears) in each eye, followed 2 h after the instillation of the eye drop by an evaluation of the binocular uncorrected near visual acuity (UNVA) and uncorrected distance visual acuity. The objective scatter index and pupil diameter under photopic and scotopic conditions before and after instillation were also assessed. The patients were divided into two groups according to their age, with group 1 patients being 41 and 50 years old and group 2 patients, between 51 and 65 years old. RESULTS: The mean age of the patients was 50.2 years. The mean UNVA before the use of the eye drop was 0.35 LogMAR, which improved to 0.16 LogMAR at 2 h after the use of the eye drop (p = 0.000). Nine patients did not show an improvement in UNVA, but no patient showed a loss of lines. Fourteen patients (11.9%) reported headaches as a side effect of the therapy. CONCLUSION: This pharmacological therapy improved near vision by one or more lines (mean improvement 0.18 lines) in 92.3% of the patients at 2 h following the instillation of the eye drops. The group with the youngest patients gained more lines than the group with the oldest patients. PMID- 30465237 TI - Competition during sugarcane crop raiding by blond capuchin monkeys (Sapajus flavius). AB - Shifting to fallback food (FBF) consumption and crop raiding are behavioral adjustments that support primates' ability to endure in human-altered habitats. Nutritional models predict that the consumption of preferred foods leads to increased competition, while consumption of staple fallback foods results in decreased competition. We analyzed the competitive regime faced by individuals in a group of 133 blond capuchin monkeys (Sapajus flavius), an endangered species that inhabits a 270-ha fragment of Atlantic forest in northeast Brazil. During the study year, quantitative analyses show that fruits were a preferred food, while sugarcane was used as a staple FBF. As predicted by primate fallback foraging models, the consumption of sugarcane helped the group to survive in this fragment by providing these animals with half of the food they consumed throughout the year. Contrary to predictions, group dispersion increased with greater fruit abundance, while direct competition peaked during the consumption of sugarcane. We suggest that, although it is abundant and scattered in the area, the long handling time required to process sugarcane before consumption facilitates the direct competition. Overall, the pattern found indicates that consumption of a staple FBF does not directly translate into decreased competition and increased stability of social groups in forest fragments. PMID- 30465238 TI - Current status of immunotherapy in metastatic colorectal cancer. AB - BACKGROUND: Immunotherapy focuses on selectively enhancing the host's immune response against malignant disease. It has been investigated as an important treatment modality against malignant disease for many years, but until recently its use was mostly limited to a few cancers. The advent of new immunemodulating agents in the recent past has changed the landscape for management of many solid tumors. Currently, immunotherapy offers a valuable, and in many cases, a more effective alternate to the conventional cytotoxic therapy. Colorectal cancer is a leading cause of cancer-related death. Despite progress in systemic therapy, most patients with metastatic colorectal cancer die of their disease. There is an unmet need for more effective treatments for patients with metastatic colorectal cancer. The current data support that colorectal tumors are immunoresponsive and a subset of patients with advanced disease achieve long term benefit with immunotherapy. OBJECTIVES: This review aims to provide the current status of immunotherapy in patients with metastatic colorectal cancer. METHODS: We researched sources published in the English language between January 2000 and August 2018 and listed within the PubMed database using combinations of the key words and reviewed the proceedings of international cancer conferences and current guidelines made by major cancer societies. RESULTS: In this review, we summarize the current status of research on immunotherapy in metastatic colorectal cancer and discuss various treatment modalities including checkpoint inhibitors, cancer vaccines, adoptive cell transfer, oncolytic virus therapy, and various other agents that are under investigation with a special emphasis on immune checkpoint inhibitors. Since the toxicity profile of immunotherapy is very different from conventional cytotoxic agents and could involve any organ system, we briefly review common adverse effects and their management. PMID- 30465239 TI - Better understanding and applications of ammonium 12-molybdophosphate-based diffusive gradient in thin film techniques for measuring Cs in waters. AB - This study deals with further and systematic laboratory evaluation of the already known ammonium 12-molybdophosphate (AMP)-diffusive gradient in thin film (DGT) method, which is used for measuring total Cs concentration in environmental waters. This study confirms that the AMP-binding gel is not stable for pH > 6. In order to reveal a potential impact of AMP degradation on DGT application, time series experiments were performed by deploying AMP-DGT samplers in Cs-doped moderately basic soft and hard water up to total AMP-binding gel degradation (60 and 175 h of deployment time, respectively). Linear accumulation of Cs by AMP-DGT samplers was observed up to 48 and 58 h in hard and soft waters, respectively. For this deployment time range, AMP-DGT measured over 77 +/- 10 and 94 +/- 16% of total Cs concentration in hard and soft water, respectively. The difference in DGT response was attributed to Ca2+ and Mg2+ competition reducing the uptake of AMP-DGT samplers in hard water. Shrinkage of agarose-polyacrylamide diffusive gel was experimentally observed only in hard water due to more intensive AMP-binding gel degradation in hard water. Even if the AMP-DGT response was not impacted in this study, it is recommended to use agarose hydrogel as standard diffusive gel. Based on the experience obtained from this detailed validation process, the authors propose a number of key requirements that need to be considered when developing DGT devices, with testing the performance over longer deployment times being critical. Graphical abstract ?. PMID- 30465240 TI - Bifenthrin exerts proatherogenic effects via arterial accumulation of native and oxidized LDL in rats: the beneficial role of vitamin E and selenium. AB - The purpose of this study was to investigate, for the first time, the effects of Bifenthrin (Bif) chronic exposure on plasmatic and aortic lipid parameters disturbance and their pro-atherogenic possibility in Wistar rats. The ameliorative role of vitamin E (Vit E) and selenium (Se) were also targeted. Thus, rats were treated by gastric gavage with combination of Vit E (100 mg/kg/bw) and Se (0.25 mg/kg/bw) in alone and co-treated groups for 90 days. Apart from control and Vit E-Se groups, all the groups were subjected to Bif (3 mg/kg, via gavage) toxicity. Results showed that Bif increased markedly plasmatic and aortic total cholesterol, LDL-cholesterol, native LDL-apoB-100, and oxidized LDL, compared to the control. Moreover, Bif treatment significantly increased the plasmatic levels of the pro-inflammatory cytokines TNF-alpha, IL-2, and IL-6. In addition, the densitometric quantification of protein bands showed that the amount of hepatic native LDL-receptor protein decreased significantly in the intoxicated rats compared to the control group. The expression of arterial LDL receptors (LDLRs) and scavenger receptors (CD36) was amplified owing to Bif toxicity. This harmful effect was confirmed by histological study using Oil-Red-O staining. Owing to their antioxidant capacities, Vit E and Se have maintained all the changes in plasma and aorta lipids and prevented the pro-atherogenic effect observed in Bif-treated animals. PMID- 30465241 TI - Horizontal distribution of pelagic crustacean zooplankton biomass and body size in contrasting habitat types in Lake Poyang, China. AB - To evaluate the possible effects of habitat type on crustacean plankton (hereafter zooplankton) biomass and body size, a 5-year study (2011 to 2015) was conducted during wet seasons in three habitats in Lake Poyang, China. The lacustrine habitat with the most stable hydrologic regime had the highest zooplankton biomass coinciding with the highest phytoplankton biomass. The riverine habitat with the lowest Secchi depth overall had the largest zooplankton body size, but high zooplankton biomass only in high water level years. The seasonally inundated floodplain habitats had the lowest zooplankton biomass and the smallest individual body size, coinciding with the lowest phytoplankton biomass and the highest predation pressure, the latter indicated by a low zooplankton: phytoplankton biomass ratio (ZB:PB). Multiple linear regression analyses indicated that pelagic zooplankton assemblages were primarily influenced by phytoplankton biomass in lacustrine habitat, by advection and turbidity in riverine regions, and by predation pressure in seasonally inundated floodplain region. We conclude that the importance of bottom-up and top-down effects on zooplankton biomass and body size varied with habitat type in Lake Poyang. PMID- 30465242 TI - An experimental investigation of performance and emission of thumba biodiesel using butanol as an additive in an IDI CI engine and analysis of results using multi-objective fuzzy-based genetic algorithm. AB - The present work studies the effect of butanol in thumba (Citrullus colocynthis) biodiesel in an IDI CI engine at varying percentages of 5 and 10% in 15 and 10% thumba biodiesel respectively with 80% diesel in each blend. Another blend was introduced with 80% diesel and 20% biodiesel without any additive. The experiment was conducted in a single cylinder four-stroke IDI CI engine at 1500 rpm varying from 25% to full-load (100%) conditions. The results showed diesel with less bio diesel and higher butanol in percentage gives good performance and emission compared to diesel at higher loads. Blend containing 10% bio diesel, 10% butanol, and 80% diesel (D80B10Bu10) showed higher cylinder pressure, heat release rate, BThE, and less NOx. Biodiesels gave less UHC, CO emissions. In this work, multi objective fuzzy-based genetic algorithm was introduced for the best fit result. Four parameters were used for optimization (BSFC, BThE, CO, NOx). The result from genetic algorithm was taken for validation and the optimized result was found adequate after validation. PMID- 30465243 TI - Removal of ciprofloxacin from simulated wastewater by pomegranate peels. AB - The adsorption of Ciprofloxacin (CPX) from aqueous solution by Pomegranate peels (POP) was investigated in a batch process. The influence of time (5-60 min) and CPX concentration (100-10,000 mg/L) on the adsorption ability of POP was studied. The POP was characterized by FTIR, scanning electron microscopy (SEM), and Zeta sizer. The kinetic of adsorption was analyzed by the pseudo-first-order and the pseudo-second-order kinetic equations using non-linear regression analysis. As well as non-linear regression analysis of Langmuir and Freundlich models were applied to specify the best non-linear curves, fitted to experimental data and estimate isotherm parameters. In order to assess the best-fit kinetic model or adsorption isotherm, three error analysis methods were used to evaluate the result of adsorption process, namely the sum of the squares of the errors (SSE), residual root mean square error (RMSE), and chi-square (chi2). On the basis of low three error analysis and high correlation (R2) of determination, it can be concluded that both the non-linear form of pseudo-second-order kinetic model and non-linear form of Langmuir are best suited to explain the adsorption of CPX onto POP. The maximum adsorption capacity for pomegranate peel as calculated by non linear Langmuir curve was much higher than in previous work (999 mg/g) at natural pH (4-5) and 25 degrees C. The high adsorption capacity of POP makes them very low-cost and effective adsorbent materials for CPX from aqueous solution. PMID- 30465244 TI - Trace elements in Plantago lanceolata L., a plant used for herbal and food preparations: new data and literature review. AB - Plantago lanceolata L. is a common grassland and roadside plant, widely used in many countries in food and herbal preparations. In this study, samples of this wild plant were collected from rural, suburban/urban, and industrial environments; the concentrations of As, Cd, Co, Cu, Fe, Mn, Ni, P, Pb, V, and Zn were measured in the edible parts of the plant (leaves), in the roots, and in the soils in order to calculate the bioaccumulation and translocation factors. The data obtained were compared with literature data available. Except for samples collected near mines and smelting plants, where Cd, Pb, and Zn concentrations were up to 15 times higher, in all other cases, no differences were observed with respect to samples from rural areas, except for Pb concentration, which was 3 times higher in urban areas. In the samples collected in our study area, the metal content does not pose particular health risks; however, even within a quite restricted region like the investigated area, high metal concentrations, possibly due to the presence of particular substrates, were observed in some samples collected from areas considered "clean" and suitable for wild food plant gathering. PMID- 30465245 TI - Field assessment of the effects of land-cover type and pattern on PM10 and PM2.5 concentrations in a microscale environment. AB - The microscale environment is a very important human-scale outdoor spatial unit. Aimed at investigating the effects of microscale land-cover type and pattern on levels of PM10 and PM2.5, we monitored PM10 and PM2.5 concentrations among different land-cover type and pattern sites through field measurements, during four seasons (December 2015 to November 2016) in Beijing, China. Differences of daily PM10 and PM2.5 concentrations among seven typical land-cover types, and correlations between daily two-sized PM levels and various microscale land-cover patterns as explained by landscape metrics were analyzed. Results show that concentrations of the two-sized particles had stable daytime and seasonal trends. During the four seasons, there were various differences in daily PM10 and PM2.5 levels among the seven land-cover types. Overall, bare soil always had the highest daily PM10 level, whereas high canopy density vegetation and water bodies had low levels. Maximum PM2.5 levels were always found in high canopy density vegetation. Moderate canopy density vegetation and water bodies had lower concentrations. Correlations between different landscape metrics and daily levels of two-sized PM varied by season. Metrics reflecting the dominance and distribution of land-cover classifications had closer relationships with particle concentrations in the microscale environment. The patterns of pavement along with low and moderate canopy density vegetation had a greater impact on PM10 level. The responses of PM2.5 level to patterns of building and low and moderate canopy density vegetation were sensitive. Reasonable design of land-cover structure would be conducive to ameliorate air particle concentrations in the microscale environment. Graphical abstract ?. PMID- 30465246 TI - Sources and distribution of 241Am in the vicinity of a deep geologic repository. AB - The detection, distribution, and long-term behavior of 241Am in the terrestrial environment at the Waste Isolation Pilot Plant (WIPP) site were assessed using historical data from an independent monitoring program conducted by the Carlsbad Environmental Monitoring & Research Center (CEMRC), and its predecessor organization the Environmental Evaluation Group (EEG). An analysis of historical data indicates frequent detections of trace levels of 241Am in the WIPP environment. Positive detections and peaks in 241Am concentrations in ambient air samples generally occur during the March to June timeframe, which is when strong and gusty winds in the area frequently give rise to blowing dust. A study of long term measurements of 241Am in the WIPP environment suggest that the resuspension of previously contaminated soils is likely the primary source of americium in the ambient air samples from WIPP and its vicinity. Furthermore, the 241Am/239 + 240Pu ratio in aerosols and soils was reasonably consistent from year to year and was in agreement with the global fallout ratios. Higher than normal activity concentrations of 241Am and 241Am/239 + 240Pu ratios were measured in aerosol samples during 2014 as a result of February 14, 2014 radiation release event from the WIPP underground. However, after a brief spike, the activity concentrations of 241Am have returned to the normal background levels. The long-term monitoring data suggest there is no persistent contamination and no lasting increase in radiological contaminants in the region that can be considered significant by any health-based standard. PMID- 30465247 TI - Evaluation of body composition using dual-energy X-ray absorptiometry in patients with non-functioning adrenal incidentalomas and an intermediate phenotype: Is there an association with metabolic syndrome? AB - PURPOSE: Metabolic syndrome (MS) and sarcopenia are associated with increased cardiovascular risk. No studies using dual-energy x-ray absorptiometry (DXA) have evaluated association between body composition (BC) changes and MS in adrenal incidentaloma (AI). Our aim was to analyse BC in non-functioning AI (NFAI) and intermediate phenotype (IP) relative to controls and to correlate with cortisol levels. METHODS: Cross-sectional study with 44 NFAI (serum cortisol <= 50 nmol/L after the overnight 1 mg dexamethasone suppression test), 27 IP (cortisol 51-138 nmol/L), and 41 controls (normal adrenal on imaging examination) using DXA. Autonomic cortisol secretion (cortisol > 138 nmol/L) was excluded from the study. BC data were compared using criteria for MS (World Health Organization, National Cholesterol Education Program-Adult Treatment Panel-III, American Association of Clinical Endocrinologists (AACE), and International Diabetes Federation). RESULTS: There was no significant difference in clinical data and body mass index (BMI) among the three groups. Waist circumference (WC) was larger in AI vs. controls (p < 0.01). Waist-to-hip ratio was higher in NFAI vs. controls and waist to-height ratio was higher in IP vs. controls (p = 0.03 and p = 0.02, respectively). The frequency of MS was higher in AI vs. controls. BC was not different among the groups. Patients with AI there was a significant association of MS with both an increase in total fat and body fat index (all criteria), and a significant difference between MS and smaller BMI-adjusted lean mass (AACE, p = 0.036). No correlation of cortisol after 1 mg dexamethasone test with BC or MS. AI and WC were independently associated with MS. CONCLUSIONS: AI presented high frequency of MS and was independently associated with MS. Possible deleterious effects of cortisol secretion seem to initially affect the muscular system. PMID- 30465248 TI - Type 2 diabetes treatment and progression of chronic kidney disease in Italian family practice. AB - AIMS: Progressive chronic kidney disease represents a dreadful complication of type 2 diabetes mellitus (T2DM). We tested the pattern of use and the renal effects of old glucose-lowering drugs in T2DM patients cared for by Italian general practitioners (GPs). METHODS: Data of 2606 T2DM patients were extracted from the databases of GPs, who do not have access to the most recent glucose lowering drugs in Italy. The rate of kidney function decline was calculated by CKD-EPIcr, based on two consecutive creatinine values. RESULTS: Metformin was used in 55% of cases, either alone or with sulfonylureas/repaglinide, across the whole spectrum of CKD (from 66% in stage G1 to only 8% in G4). Sulfonylurea use peaked at 21-22% in stage G2-G3a, whereas repaglinide use significantly increased from 8% in G1 to 22% in G4. The median rate of CKD decline was - 1.64 mL/min/1.73 m2 per year; it was higher in G1 (- 3.22 per year) and progressively lower with CKD severity. 826 cases (31.7%) were classified as fast progressors (eGFR decline more negative than - 5 mL/min/1.73 m2 per year). The risk of fast progressing CKD was associated with increasing BMI, albuminuria, and sulfonylurea use, alone (OR, 1.47; 95% confidence interval, 1.16-1.85), or in association with metformin (OR, 1.40; 95% CI 1.04-1.88). No associations were demonstrated for metformin, cardiovascular and lipid lowering drug use. CONCLUSION: In the setting of Italian family practice, sulfonylurea use is associated with progressive CKD in patients with T2DM. Metformin, at doses progressively reduced according to CKD stages, as recommended by guidelines, is not associated with fast progression. PMID- 30465249 TI - Association of serum ghrelin with weight gain during pregnancy in overweight and normal women. AB - PURPOSE: Despite the fact that the ghrelin hormone plays pivotal role in the process of weight gain, its correlation with weighing during pregnancy has not been elucidated. Hence, the present study was conducted to evaluate the correlation between plasma ghrelin levels and gestational weight gain in overweight and normal women. METHODS: This prospective cohort study was conducted in 27 overweight and 18 normal body mass index (BMI) pregnant women referring to Tehran health care centers. Weight gain during all trimesters of pregnancy was measured and the blood samples were collected at 8-12 (first trimester) and 16-20 weeks (second trimester) of pregnancy. The plasma total ghrelin concentration was measured by ELISA method. RESULTS: The overweight pregnant women exhibited significantly lower weight gain at the second (p = 0.002), third trimesters (p = 0.005) as well as total weighing during pregnancy (p = 0.001) compared to the normal BMI pregnant women. There was no significant difference in plasma ghrelin levels between the groups from the first to the second trimesters of pregnancy (p > 0.05). Moreover, no correlation was found between ghrelin levels and gestational weight gain in the overweight and normal groups. CONCLUSIONS: Our results indicate that the increased level of serum ghrelin could not be considered as a key mediator for weight gain difference during pregnancy of overweight women. PMID- 30465250 TI - Correction to: Low-Grade Inflammation Aggravates Rotenone Neurotoxicity and Disrupts Circadian Clock Gene Expression in Rats. AB - The original version of this article contained mistakes, and the authors would like to correct them. Some parts of the image in Figure 5 were missing. The correct Figure 5 is shown at the next page. PMID- 30465251 TI - Design and synthesis of novel 2-(6-thioxo-1,3,5-thiadiazinan-3-yl)-N' phenylacethydrazide derivatives as potential fungicides. AB - A series of novel 2-(6-thioxo-1,3,5-thiadiazinan-3-yl)-N'-phenylacethydrazide derivatives were designed, synthesized and evaluated for their antifungal activities against Fusarium graminearum (Fg), Rhizoctonia solani (Rs), Botrytis cinerea (Bc) and Colletotrichum capsici (Cc). The bioassay results in vitro showed that most of the title compounds exhibited impressive antifungal activities against the above plant fungi. Particularly, the compounds 5c, 5f, 5g, 5i, 5m and 5p displayed desirable anti-Rs activities, with the corresponding EC50 values of 0.37, 0.32, 0.49, 0.50, 0.46 and 0.45 ug/mL, respectively, which are superior to the positive control carbendazim (0.55 ug/mL). Further in vivo bioassay results showed that the anti-Rs activity of title compound 5f at 200 ug/mL reached 95.84% on detached rice leaves and 93.96% on rice plants. Featuring convenient synthesis, novel structures and desirable antifungal activity, these 2 (6-thioxo-1,3,5-thiadiazinan-3-yl)-N'-phenylacethydrazide derivatives could be further studied as the potential candidates of novel agricultural fungicides. PMID- 30465252 TI - Ammonium chloride-catalyzed green multicomponent synthesis of dihydropyrazine and tetrahydrodiazepine derivatives "on water". AB - This research describes a simple and efficient one-pot synthetic approach for the preparation of tetrahydrodiazepine and dihydropyrazine (or dihydroquinoxaline) derivatives in high yields in the presence of a substoichiometric amount of ammonium chloride as a green accelerator on water at 50 degrees C within 1-3 h. PMID- 30465253 TI - Interlaboratory Validation of a Method for Hepatitis E Virus RNA Detection in Meat and Meat Products. AB - Increasing numbers of hepatitis E cases are currently recognized in many European countries. The zoonotic hepatitis E virus (HEV) genotype 3 mainly circulates in domestic pigs and wild boars, and can be transmitted to humans via consumption of insufficiently heated meat or meat products produced from those animals. Here, a detailed protocol for detection of HEV RNA in meat products is provided, which is based on the method originally described by Szabo et al. (Intl J Food Microbiol 215:149-156, 2015). It consists of a TRI Reagent(r)/chloroform-based food matrix homogenization, a silica bead-based RNA extraction and a real-time RT-PCR-based RNA detection. The method was further validated in a ring trial with nine independent laboratories using pork liver sausage samples artificially contaminated with different amounts of HEV. The results indicate sufficient sensitivity, specificity, and accuracy of the method for its broad future use in survey studies, routine food control or outbreak investigations. PMID- 30465254 TI - Neurological and electroneurography findings in patients with systemic sclerosis and symptoms of neuropathic pain in extremities. AB - OBJECTIVE: To analyze neurological and electroneurography (ENG) findings in patients with systemic sclerosis (SSc) and symptoms of neuropathic pain in upper and lower extremities. PATIENTS AND METHODS: Using the PainDetect questionnaire, 42 consecutive patients with SSc (38 women and 4 men) were screened for the presence of neuropathic pain in upper and/or lower extremities. Patients with previously diagnosed diabetes or other metabolic diseases, malignancy, other autoimmune disorders, or any neurological or psychiatric disease, were not included. Neurological examination, ENG, and laboratory analyses (glycated hemoglobin-HbA1C, and vitamin B12) were performed in SSc patients with neuropathic pain in extremities. Methods of descriptive statistics were used to summarize the data. RESULTS: Eleven patients (26.2%) had significant symptoms of neuropathic pain in extremities. Neurological examination indicated polyneuropathy in 10/11 (90.9%) of patients. Symmetrical hyperesthesia in the lower and/or upper extremities was found in ten patients. Symmetrical hyporeflexia was found in 7/11 (63.6%) of patients in the arms, and 6/11 (54.4%) of patients in the legs. Proprioception was diminished in 3/11 (27.3%), whilst pallhypesthesia was present in all patients. However, polyneuropathy could be confirmed by ENG only in four out of ten SSc patients, who had typical neurological findings for polyneuropathy. Hypoesthesia in a specific lumbar root dermatome, suggesting radiculopathy, was found in 6/11 (54.5%) of patients. Asymmetrical hyporeflexia was noticed in 2/11 (18.1%) of patients in the lower limbs. Seven patients (63.6%) had signs of radiculopathy in at least one root dermatome on ENG. CONCLUSION: A significant number of SSc patients with neuropathic pain in the upper and/or lower extremities have symptoms and signs of polyneuropathy undetectable by ENG, which indirectly suggests the presence of small-fiber polyneuropathy in these patients. In some patients, radiculopathy cannot be excluded as possible co-morbid non-scleroderma condition associated with neuropathic pain. PMID- 30465255 TI - Percutaneous Irreversible Electroporation (IRE) of Hepatic Malignancy: A Bi institutional Analysis of Safety and Outcomes. AB - AIM: Irreversible electroporation (IRE) is a non-thermal ablative option in patients unsuitable for standard thermal ablation, due to its potential to preserve collagenous structures (vessels and ducts) and a reduced susceptibility to heat sink effects. In this series from two large tertiary referral hepatobiliary centres, we aim to assess the safety/outcomes of hepatic IRE. MATERIALS AND METHODS: Bi-institutional retrospective, longitudinal follow-up series of IRE for primary hepatic malignancy; [hepatocellular carcinoma (n = 20), cholangiocarcinoma (n = 3)] and secondary metastatic disease; colorectal (n = 28), neuroendocrine (n = 1), pancreatic (n = 1), breast (n = 1), gastrointestinal stromal tumour (GIST, n = 1) and malignant thymoma (n = 1). Outcome measures included procedural safety/effectiveness, time to progression and time to death. RESULTS: Between 2013 and 2017, 52 patients underwent percutaneous IRE of 59 liver tumours in 53 sessions. All tumours were deemed unsuitable for thermal ablation. Cases were performed using ultrasound (US) or computed tomography (CT) guidance. A complete ablation was achieved in n = 44, (75%) of cases with an overall complication rate of 17% (n = 9). Of the complete ablation group, median time to progression was 8 months. At 12 months, 44% were progression-free (95% CI 30-66%). The data suggest that larger lesion size (> 2 cm) is associated with shorter time to progression and there is highly significant difference with faster time to progression in mCRC compared with HCC. Median survival time was 38 months. CONCLUSION: This bi-institutional review is the largest UK series of IRE and suggests this ablative technology can be a useful tool, but appears to mainly induce local tumour control rather than cure with HCC having better outcomes than mCRC. PMID- 30465256 TI - Multiple Bifurcated Covered Self-Expanding Metallic Stents for Complex Tracheobronchial Fistulas or Stenosis. AB - OBJECTIVE: We aimed to determine the safety and feasibility of bifurcated covered self-expanding stents for the treatment of complex tracheobronchial fistulas or stenosis. METHODS: Twenty-eight patients were treated by multiple bifurcated covered airway stents (Micro-Tech Co. Ltd., Nanjing, China), including 18 cases of gastrobronchial or gastrotracheal fistula, 6 cases of bronchopleural fistula and 4 cases of severe tracheobronchial stenosis. The large bifurcated covered stent was placed at the main carina, and the small stents were inserted into primary right carina or secondary left carina. Clinical and imaging data were retrospectively analyzed. RESULTS: Stents were successfully inserted in 27 patients at the first attempt. In total, 29 large bifurcated covered stents, 27 small bifurcated covered stents and 5 small bifurcated covered single-plugged stents were inserted. All patients with fistula could resume eating without coughing after the procedure. No perioperative death or severe complications occurred. Two patients underwent stent removal due to intolerance of stenting; the clinical success rate was 93% (26/28). Nineteen complications were found in 12 patients; 8 patients needed stent removal or replacement, for a major complication rate of 29% (8/28). Eight patients underwent successful stent removal due to complications. Fifteen patients died of tumors and one patient died of pulmonary infection. The median survival was 33 months. Fistula recurrence was found in one patient 5 months after stenting, and second small bifurcated covered stent was inserted. CONCLUSIONS: Multiple bifurcated covered metallic stenting is effective and safe for complex tracheobronchial fistulas or stenosis, with good symptom palliation. PMID- 30465257 TI - Inflammation in ALS/FTD pathogenesis. AB - Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that overlap in their clinical presentation, pathology and genetics, and likely represent a spectrum of one underlying disease. In ALS/FTD patients, neuroinflammation characterized by innate immune responses of tissue-resident glial cells is uniformly present on end-stage pathology, and human imaging studies and rodent models support that neuroinflammation begins early in disease pathogenesis. Additionally, changes in circulating immune cell populations and cytokines are found in ALS/FTD patients, and there is evidence for an autoinflammatory state. However, despite the prominent role of neuro- and systemic inflammation in ALS/FTD, and experimental evidence in rodents that altering microglial function can mitigate pathology, therapeutic approaches to decrease inflammation have thus far failed to alter disease course in humans. Here, we review the characteristics of inflammation in ALS/FTD in both the nervous and peripheral immune systems. We further discuss evidence for direct influence on immune cell function by mutations in ALS/FTD genes including C9orf72, TBK1 and OPTN, and how this could lead to the altered innate immune system "tone" observed in these patients. PMID- 30465258 TI - Chromosome arm 1q gain is an adverse prognostic factor in localized and diffuse leptomeningeal glioneuronal tumors with BRAF gene fusion and 1p deletion. PMID- 30465259 TI - TIA1 regulates the generation and response to toxic tau oligomers. AB - RNA binding proteins (RBPs) are strongly linked to the pathophysiology of motor neuron diseases. Recent studies show that RBPs, such as TIA1, also contribute to the pathophysiology of tauopathy. RBPs co-localize with tau pathology, and reduction of TIA1 protects against tau-mediated neurodegeneration. The mechanism through which TIA1 reduction protects against tauopathy, and whether TIA1 modulates the propagation of tau, are unknown. Previous studies indicate that the protective effect of TIA1 depletion correlates with both the reduction of oligomeric tau and the reduction of pathological TIA1 positive tau inclusions. In the current report, we used a novel tau propagation approach to test whether TIA1 is required for producing toxic tau oligomers and whether TIA1 reduction would provide protection against the spread of these oligomers. The approach used young PS19 P301S tau mice at an age at which neurodegeneration would normally not yet occur and seeding oligomeric or fibrillar tau by injection into hippocampal CA1 region. We find that propagation of exogenous tau oligomers (but not fibrils) across the brain drives neurodegeneration in this model. We demonstrate that TIA1 reduction essentially brackets the pathophysiology of tau, being required for the production of tau oligomers, as well as regulating the response of neurons to propagated toxic tau oligomers. These results indicate that RNA binding proteins modulate the pathophysiology of tau at multiple levels and provide insights into possible therapeutic approaches to reduce the spread of neurodegeneration in tauopathy. PMID- 30465260 TI - Using Network and Spatial Data to Better Target Overdose Prevention Strategies in Rural Appalachia. AB - This analysis uses network and spatial data to identify optimal individuals to target with overdose prevention interventions in rural Appalachia. Five hundred and three rural persons who use drugs were recruited to participate in the Social Networks among Appalachian People Study (2008-2010). Interviewer-administered surveys collected information on demographic characteristics, risk behaviors (including overdose history), network members, and residential addresses. We restricted the sample to individuals with at least one confirmed relationship to another study participant (N = 463). Using dyadic analyses (N = 1428 relationships), we identified relationship-level correlates of relationships with network members who have previously overdosed. We then examined individual- and network-level factors associated with (1) having at least one first-degree alter (i.e., network member) with a prior overdose and (2) each additional network member with a prior overdose (N = 463 study participants). Overall, 28% of the sample had previously overdosed and 57% were one-degree away from someone who previously overdosed. Relationships with those who had overdosed were characterized by closer residential proximity. Those with at least one network member who previously overdosed were more geographically central and occupied more central network positions. Further, the number of network members with an overdose history increased with decreasing distance to the town center, increasing network centrality, and prior enrollment in an alcohol detox program. Because fatal overdoses can be prevented through bystander intervention, these findings suggest that strategies that target more central individuals (both geographically and based on their network positions) and those who have previously enrolled in alcohol detox programs with overdose prevention training and naloxone may optimize intervention reach and have the potential to curb overdose fatalities in this region. PMID- 30465261 TI - Building a Data Platform for Cross-Country Urban Health Studies: the SALURBAL Study. AB - Studies examining urban health and the environment must ensure comparability of measures across cities and countries. We describe a data platform and process that integrates health outcomes together with physical and social environment data to examine multilevel aspects of health across cities in 11 Latin American countries. We used two complementary sources to identify cities with >= 100,000 inhabitants as of 2010 in Argentina, Brazil, Chile, Colombia, Costa Rica, El Salvador, Guatemala, Mexico, Nicaragua, Panama, and Peru. We defined cities in three ways: administratively, quantitatively from satellite imagery, and based on country-defined metropolitan areas. In addition to "cities," we identified sub city units and smaller neighborhoods within them using census hierarchies. Selected physical environment (e.g., urban form, air pollution and transport) and social environment (e.g., income, education, safety) data were compiled for cities, sub-city units, and neighborhoods whenever possible using a range of sources. Harmonized mortality and health survey data were linked to city and sub city units. Finer georeferencing is underway. We identified 371 cities and 1436 sub-city units in the 11 countries. The median city population was 234,553 inhabitants (IQR 141,942; 500,398). The systematic organization of cities, the initial task of this platform, was accomplished and further ongoing developments include the harmonization of mortality and survey measures using available sources for between country comparisons. A range of physical and social environment indicators can be created using available data. The flexible multilevel data structure accommodates heterogeneity in the data available and allows for varied multilevel research questions related to the associations of physical and social environment variables with variability in health outcomes within and across cities. The creation of such data platforms holds great promise to support researching with greater granularity the field of urban health in Latin America as well as serving as a resource for the evaluation of policies oriented to improve the health and environmental sustainability of cities. PMID- 30465262 TI - The Pornography Debate: Religiosity and Support for Censorship. AB - Pornography has become an increasingly salient topic in public discourse. We sought to better understand the role of religiosity in shaping people's support of policy stances against pornography, in the form of censorship, using nationally representative data from the 2014 General Social Survey (n = 1676). Results from logistic regression indicate that high religiosity significantly increases odds of supporting censorship. Holding control variables at their sample means, the least religious persons had a predicted probability of 0.09 of supporting censorship, compared to 0.57 for the most religious respondents. We discuss these findings within the context of the current public health debate. PMID- 30465263 TI - Spirituality and Religiosity are Associated with Quality of Life in Patients with Lung Disease. AB - Patients were separated into two groups: (1) non-waiting list (NWL) and (2) waiting list (WL) for the lung transplantation. We found greater levels of the faith and spirituality, in those awaiting transplantation. In the NWL group, higher 'meaning' was associated with higher 'vitality,' 'emotional well-being,' and 'mental health'; higher 'peace' was associated with higher 'mental health.' In the WL group, higher 'peace' was associated with and better 'mental health' and 'emotional well-being.' Regardless of whether patients are lung transplantation candidates or not, spirituality/religiosity may help those with lung diseases cope better with their disease and have better quality of life. PMID- 30465264 TI - The Development and Validation of a Modesty Measure for Diverse Muslim Populations. AB - This paper reports on the multi-phase development of an English-language modesty measure for use among Muslim populations. The process yielded a 10-item measure that has high levels of internal consistency reliability (Cronbach's alpha of 0.83), and has acceptable discriminant and predictive validity. Specifically although our modesty measure for Muslim women was found to be significantly correlated with measures of positive and negative religious (Islamic) coping, it was not significantly correlated with religious practice-based religiosity (discriminant validity). Further logistic modeling revealed higher modesty levels positively associated with forgoing mammography because of concerns about lack of same-sex providers (predictive validity). PMID- 30465265 TI - Incidence of second primary cancers after radiotherapy combined with platinum and/or cetuximab in head and neck cancer patients. AB - PURPOSE: The second primary cancer (SPC) incidence after treatment with platinum based chemotherapy and cetuximab in combination with radiotherapy has not been previously reported. Our aim was to compare SPC risk following radiotherapy in combination with these agents for the treatment of head and neck squamous cell carcinoma (HNSCC). METHODS: The charts of 296 cases treated for loco-regionally advanced HNSCC between 2009 and 2015 were retrospectively reviewed for patient, tumor, and procedural characteristics. All patients were planned to undergo radiotherapy either with platinum compounds (group: Platinum) or monoclonal antibody cetuximab (group: Cetuximab). A third group of patients switched from platinum compounds to cetuximab due to toxicity (group: Switch). Treatment groups were evaluated for the incidence of SPC with log-rank test. Possible confounders were investigated with multivariate Cox's proportional hazards model. All tests were two-sided, and a p < 0.05 was set to indicate statistical significance. RESULTS: Median follow-up was 36 months. Platinum, Cetuximab, and Switch groups consisted of 158, 101, and 37 patients, respectively. Three-year overall survival in the whole cohort was 70%. The rate of SPC was comparable between Platinum (9.2%) and Cetuximab (11.5%) groups (p = 0.98), whereas the patients in the Switch group were exposed to a significantly higher incidence of SPC (23.3%) in 3 years (p = 0.01). The multivariate model indicated Switch to be the only variable correlating with an increased risk for SPC. CONCLUSIONS: The Switch strategy may expose the patients to an increased risk of developing SPC. The use of switch should be advocated with caution until robust pre-clinical and clinical data are available. PMID- 30465266 TI - Decision tree for mapping of halophyte cover around Ghannouch, Tunisia. AB - Environment of Ghannouch in the south-east of Tunisia is characterized by the wide-spread hypersaline soils, typically colonized by halophytes. The study of their distribution is required in order to reveal the extent of salinization and its dynamic. Mapping and monitoring with a remote sensing approach are foreseen as the ways to trace the spatial and temporal dimensions of the phenomenon. The identification of halophyte vegetation can take advantage by analyzing optical remote sensing data. Here, we propose using a decision tree approach applied to European Space Agency Sentinel-2 imagery, for an accurate land cover mapping of Ghannouch district in Gabes governorate. Data pre-processing was carried out using the European Space Agency's Sentinel Application Platform and the SEN2COR toolboxes. The mapping approach combines the spectral information in several channels of the visible-near-infrared spectrum. The land cover identification was performed following a spectral classification approach, exploiting several optical indices, normalized difference water index, normalized difference vegetation index, and several soil salinity index, in order to elaborate a decision tree algorithm. As a result, for an area of interest of 50 * 50 km2, at least 68% was classified as halophyte land cover. This mapping exercise represents an important step toward improved halophytes mapping in Tunisia and could be used to monitor the status of other salinity prone regions in the world. PMID- 30465267 TI - [Communication with relatives]. AB - BACKGROUND: Communication with relatives is a central part of the decision-making process. In the absence of the patient's direct consent to a potential organ donation, the next of kin must provide information about a potential wish to donate and give permission in the context of an extended consent solution. At the same time, family members must also cope with the death of a loved one. OBJECTIVE: To determine how relatives can be optimally supported during the decision-making process. MATERIALS AND METHODS: Narrative review. RESULTS: In the context of potential or confirmed irreversible brain death, communication with family members or legal representatives serves to deliver bad news as well as to determine whether the patient had a wish to donate his/her organs and to clarify the resultant steps. Communication strategies such as the SPIKES or VALUE models provide emotional and cognitive support for relatives and strengthen clinicians' communication skills. Clinicians' behavior towards patients, deceased, and next of kin may influence relatives' decision-making; respectful and competent behavior seems to contribute towards relatives granting permission for organ donation. CONCLUSION: Clinicians must be trained and skilled in communication strategies which are used in critical situations to provide emotional support to relatives during the organ donation decision-making process. Relatives are more likely to achieve a satisfying and sustainable decision if a strong relationship exists between clinicians and relatives based on information giving, openness, trust, and empathy. PMID- 30465268 TI - Contiguity in episodic memory. AB - Contiguity is one of the major predictors of recall dynamics in human episodic memory. But there are many competing theories of how the memory system gives rise to contiguity. Here we provide a set of benchmark findings for which any such theory should account. These benchmarks are drawn from a review of the existing literature as well as analyses of both new and archival data. They include 34 distinct findings on how various factors including individual and group differences, task parameters, and type of stimuli influence the magnitude of the contiguity effect. We will see that contiguity is observed in a range of tasks including recognition, paired associates, and autobiographical recall and across a range of time scales including minutes, days, weeks, and years. The broad pattern of data point toward a theory in which contiguity arises from fundamental memory mechanisms that encode and search an approximately time scale invariant representation of temporal distance. PMID- 30465269 TI - Affective influences without approach-avoidance actions: on the congruence between valence and stimulus-response mappings. AB - The valence of stimuli can influence performance in the spatial stimulus-response compatibility task, but this observation could arise from the process of selecting responses or selecting stimulus-response mappings. The response selection account proposes that spatial compatible and incompatible keypress responses serve as approaching and avoiding actions to a valenced target. The mapping-selection account suggests that there is congruence between stimulus valence and stimulus-response mappings; positive-compatible/negative-incompatible is more congruent than negative-compatible/positive-incompatible. Whereas affective valence was part of the target stimuli to which participants responded in previous studies, the present study isolated affective valence from the target by presenting an additional mapping cue separately from the target, so that spatially compatible and incompatible keypress responses could no longer serve as approaching and avoiding actions to valenced target stimuli. The present results revealed that responses were still faster when positive and negative mapping cues were assigned to the spatially compatible and incompatible mappings than when the assignment was reversed. The finding supports the mapping-selection account, indicating that positive and negative cues influence performance without approach avoidance actions to valenced stimuli. The experiment provides important implications as to how tasks are represented and are dependent on affective processing. PMID- 30465270 TI - Tocilizumab treatment in refractory polyarteritis nodosa: a case report and review of the literature. AB - Polyarteritis nodosa (PAN) is a rare systemic vasculitis affecting multiple organs. Current standard treatment includes the use of glucocorticoids and cyclophosphamide. Unfortunately, some patients do not respond to this treatment and other therapeutic options are needed. We present a case of a young male with refractory PAN and ongoing biopsy evidence of active vasculitis despite optimal standard therapies, who was successfully treated with interleukin-6 antagonist, tocilizumab. A 24-year-old male presented with severe immobilizing polyneuropathy and myalgias. Clinical features included fasciitis, tenosynovitis, early signs of polyneuropathy, and panniculitis, which were largely refractory to the standard therapies. The previous unsuccessful treatments included high-dose glucocorticoids, methotrexate, cyclophosphamide, rituximab, anakinra, and intravenous immunoglobulins. Magnetic resonance imaging showed signs of myositis, with muscle biopsy confirming the diagnosis of PAN. Rapid clinical improvement and sustained remission occurred after interleukin-6 inhibition with tocilizumab at increased dose of 800 mg every 4 weeks. The used search strategy identified 20 publications of which four articles were included for the further analysis. In total, we report the clinical outcome of five PAN cases from the literature and the present one. The present case and the systematic review of literature suggest that tocilizumab is a possible treatment option for, otherwise, refractory hepatitis B virus negative PAN. Randomized-controlled trials are required to evaluate the safety and efficacy of tocilizumab in PAN. PMID- 30465271 TI - The transition from transesophageal to transthoracic echocardiography during transcatheter aortic valve replacement: an evolving field. AB - The advent of transcatheter aortic valve replacement (TAVR) has dramatically transformed the clinical approach to severe aortic stenosis. Over the last decade, several trials have shown the equivalence or even superiority of transcatheter valve replacement over the conventional surgical approach. As a result, TAVR as a treatment for severe, symptomatic aortic stenosis has rapidly extended from inoperable or prohibited-risk patients to intermediate-risk patients. The success of TAVR has led to the wide adaptation of this technique and, subsequently, a significant increase in the number of these procedures performed annually. As the number of these procedures is expected to further increase, especially if its indication will include those with low surgical risk, there is a great demand to improve patient recovery and early discharge without compromising outcomes. In this review, we will discuss the role of echocardiography in the perioperative planning and assessment of transcatheter aortic valve replacement. In addition, we will review the current evidence behind the use of intraprocedureal transthoracic echocardiography and the recommended steps for successful transition from transesophageal to transthoracic echocardiography. PMID- 30465272 TI - Maternal smoking during pregnancy and risk of cryptorchidism: a systematic review and meta-analysis. AB - The risk factors for undescended testes in male infants and the underlying pathogenesis still remain unclear. The aim of this study is to identify the relationship between maternal smoking during pregnancy and risk of cryptorchidism. A systematic review was conducted using appropriate search terms to identify articles pertaining to maternal smoking during pregnancy and risk of cryptorchidism. Entries up to December 23, 2017 were taken into consideration, without any language or regional restriction. The crude ORs and their 95% CIs were computed by using the fixed-effect model. Twenty studies involving 111,712 infants were included in our meta-analysis. The risk of having a male infant with cryptorchidism was significantly different between mothers who smoked during pregnancy and those who did not (pooled crude OR 1.18, 95% confidence interval [CI] 1.12-1.24, p < 0.00001).Conclusion: Our findings suggest that smoking during pregnancy increased the risk of cryptorchidism by 1.18 times. Further investigations that are well-designed, multicentric studies measuring variables, such as the number of cigarettes smoked in a day and the stage of pregnancy during which the mothers smoked, are necessary to precisely determine the relationship between maternal smoking and risk of cryptorchidism. What is Known: * Preterm and low birth weight have been definitively shown to be risk factors for cryptorchidism. * The relationship between with maternal smoking during pregnancy and risk of cryptorchidism remains controversial all the time. What is New: * Mothers who smoked during pregnancy had a 1.18 times higher risk of having a child with cryptorchidism as compared to those who did not smoke. * Evidence has been found that maternal smoking during pregnancy is a definitive risk factor for cryptorchidism. PMID- 30465273 TI - The association between psychological and social factors and spinal pain in adolescents. AB - Spinal pain, back pain, and/or neck pain begins early in life and is strongly associated with spinal pain in adulthood. Understanding the relationship between psychological and social factors and adolescent spinal pain may be important in both the prevention and treatment of spinal pain in this age group. We aimed to determine if psychological and social factors were associated with spinal pain in a cross-sectional study of a school-based cohort of 1279 Danish adolescents aged 11-13, who were categorized into "any" and "substantial" spinal pain. "Substantial spinal pain" was defined as a lifetime frequency of "sometimes" or "often" and a pain intensity of at least two on the revised Faces Pain Scale. Logistic regression analyses, stratified by sex, were conducted for single and all variables together. Eighty-six percent of participants reported "any spinal pain" and 28% reported "substantial spinal pain". Frequency of psychological and social factors was significantly higher in those with spinal pain compared to those without. As the frequency of psychological and social factors increased, the odds of both "any spinal pain" and "substantial spinal pain" also increased.Conclusion: Psychological and social factors may be important determinants in adolescent spinal pain. What is Known: * Spinal pain begins early in life to reach adult levels by age 18. Spinal pain in adolescence is strongly associated with spinal pain in adulthood. * In adults, psychological and social factors and spinal pain are strongly related; however, this relationship in adolescence is poorly understood. What is New: * Adolescents with spinal pain reported a significantly higher frequency of psychological factors and loneliness and lower levels of pupil acceptance. * Adolescents reporting higher levels of loneliness, lower levels of pupil acceptance, and increased frequency of psychological factors had increased odds of reporting "substantial spinal pain". PMID- 30465274 TI - Forecasting the spatiotemporal variability of soil CO2 emissions in sugarcane areas in southeastern Brazil using artificial neural networks. AB - Carbon dioxide (CO2) is considered one of the main greenhouse effect gases and contributes significantly to global climate change. In Brazil, the agricultural areas offer an opportunity to mitigate this effect, especially with the sugarcane crop, since, depending on the management system, sugarcane stores large amounts of carbon, thereby removing it from the atmosphere. The CO2 production in soil and its transport to the atmosphere are the results of biochemical processes such as the decomposition of organic matter and roots and the respiration of soil organisms, a phenomenon called soil CO2 emissions (FCO2). The objective of the study was to investigate the use of neural networks with backpropagation algorithm to predict the spatial patterns of soil CO2 emission during short periods in sugarcane areas. FCO2 values were collected in three commercial crop areas in the Sao Paulo state, southeastern Brazil, registered through the LI-8100 system during the years 2008 (Motuca), 2010 (Guariba city), and 2012 (Pradopolis), in the period after the mechanical harvesting (green cane). A neural network multilayer perceptron with a backpropagation algorithm was applied to estimate the FCO2 in 2012, using data from 2008 and 2010 as training for the neural network. The neural network initially presented a mean absolute percentage error (MAPE) of 18.3852 and a coefficient of determination (R2) of 0.9188. Data obtained from the observed and estimated values of FCO2 present moderate spatial dependence, and it is observed from the maps of the spatial pattern of the CO2 flow that the results from the neural network show considerable similarity to the observed data. The model results identify the higher and lower characteristics in sample points of CO2 emissions and produce an overestimation of the range of spatial dependence (0.45 m) and an underestimation of the interpolated values in the field (R2 = 0.80; MAPE = 12.0591), when compared to the actual soil CO2 emission values. Therefore, the results indicate that the artificial neural network provides reliable estimates for the evaluation of FCO2 from data of the soil's physical and chemical attributes and describes the spatial variability of FCO2 in sugarcane fields, thereby contributing to the reduction of uncertainties associated with FCO2 accountings in these areas. PMID- 30465275 TI - Bolt-connected external ventricular drainage: The key to a better accuracy and less complications? PMID- 30465276 TI - Impact of intraoperative stimulation mapping on high-grade glioma surgery outcome: a meta-analysis. AB - BACKGROUND: Intraoperative stimulation mapping (ISM) using electrocortical mapping (awake craniotomy, AC) or evoked potentials has become a solid option for the resection of supratentorial low-grade gliomas in eloquent areas, but not as much for high-grade gliomas. This meta-analysis aims to determine whether the surgeon, when using ISM and AC, is able to achieve improved overall survival and decreased neurological morbidity in patients with high-grade glioma as compared to resection under general anesthesia (GA). METHODS: A systematic search was performed to identify relevant studies. Adult patients were included who had undergone craniotomy for high-grade glioma (WHO grade III or IV) using ISM (among which AC) or GA. Primary outcomes were rate of postoperative complications, overall postoperative survival, and percentage of gross total resections (GTR). Secondary outcomes were extent of resection and percentage of eloquent areas. RESULTS: Review of 2049 articles led to the inclusion of 53 studies in the analysis, including 9102 patients. The overall postoperative median survival in the AC group was significantly longer (16.87 versus 12.04 months; p < 0.001) and the postoperative complication rate was significantly lower (0.13 versus 0.21; p < 0.001). Mean percentage of GTR was significantly higher in the ISM group (79.1% versus 47.7%, p < 0.0001). Extent of resection and preoperative patient KPS were indicated as prognostic factors, whereas patient KPS and involvement of eloquent areas were identified as predictive factors. CONCLUSIONS: These findings suggest that surgeons using ISM and AC during their resections of high-grade glioma in eloquent areas experienced better surgical outcomes: a significantly longer overall postoperative survival, a lower rate of postoperative complications, and a higher percentage of GTR. PMID- 30465277 TI - Long-term outcome of trans-sphenoidal surgery for Cushing's disease in Indian patients. AB - BACKGROUND: The results of trans-sphenoidal surgery (TSS) in Cushing's disease (CD) vary widely depending upon patient characteristics as well as surgical experience. Patients in India are often referred late to referral centers. We studied the rates of remission and endocrine deficiencies after TSS in patients with CD presenting to a referral hospital in India. METHODS: Sixty consecutive patients (45 females, median age 24.5 years) who underwent TSS between 2000 and 2015 were studied. The median (range) duration of follow-up was 40 (3-138) months. Initial and long-term remission and relapse rates and pituitary hypofunction post-TSS were evaluated. RESULTS: Eighteen (30%) patients harbored macroadenomas. Twenty-eight (47%) patients achieved remission in the immediate post-operative period (8 AM serum cortisol < 140 nmol/l), while a higher remission rate was noted at 6 months (39/54 patients, 72%). At 1 year 70% patients and at final follow-up [median duration 40 (range 3-138) months], 58% of patients were in remission. No pre- or post-surgical variables were consistently associated with remission, except for the 8-AM serum cortisol level on the fifth day after surgery. Seven (18%) patients relapsed on follow-up, including five patients who had fifth post-operative day 8 AM serum cortisol < 140 nmol/l. Twelve (25%) patients newly developed hypothyroidism and one (1.6%) patient developed amenorrhoea after TSS. CONCLUSION: Remission rate at 6 months was higher than immediately after TSS. A significant proportion of patients relapsed, thus necessitating life-long follow-up. New-onset hypothyroidism was frequent after TSS. PMID- 30465278 TI - Prevalence of subcutaneous implantable cardioverter-defibrillator based on template ECG screening and ineligible surface ECG predicting factors in patients with hypertrophic cardiomyopathy in China. AB - The subcutaneous implantable cardioverter-defibrillator (S-ICD) may provide comparable protection while avoiding the disadvantage of transvenous lead, but the abnormal features of the hypertrophic cardiomyopathy (HCM) electrocardiogram (ECG) make it a challenge for S-ICD template screening. We aimed to investigate S ICD eligibility according to the S-ICD manufacturer's surface ECG screening template in China, and further analyze its corresponding ineligible predicting factors in 12-lead suface ECG. A total of 179 HCM patients (114 males; mean age: 45 +/- 14 years) underwent S-ICD screening at rest and on exercise, among which 91 patients (50.8%) were eligible for S-ICD. Among the patients who passed screening, 43 (47.3%) had 3 vectors eligibility; 64 (70.3%) screening qualified on both sides; 10 patients (11.0%) passed the screening while the electrodes located only on the left parasternal line versus 17 patients (18.7%) moved to the right line. The secondary sensing vector (Lead III) was mostly appropriate (53.6%), followed by the primary sensing vector (lead II, 53.1%) and the alternate sensing vector (Lead I, 46.9%). Higher R wave was the major cause, accounted for 70.5%, for screening failure. There existed significant difference in T wave in lead II, aVF, V5 and V6, adds R/T ratio in lead V5 and V6, between the screening success group (group A) and screening failure group (group B) at rest and on exercise. A multivariable logistic regression analysis was performed to identify that R/T <= 3.5 in lead V5 was the independent factor to predict the screening ineligibility, with odds ratio 3.648. S-ICD screening success is 50.8% in HCM patients, which is much lower than that in other studies. R/T <= 3.5 in lead V5 in 12-lead surface ECG was an independent predicting factor for screening failure. PMID- 30465279 TI - Study of Molecular Mechanism of the Interaction Between MEK1/2 and Trametinib with Docking and Molecular Dynamic Simulation. AB - Trametinib was endorsed by the FDA in 2013 as a single agent for adult melanoma patients. Trametinib inhibits cell growth and proliferation in multiple tumor xenografts by preventing RAF phosphorylation of MEK and thus restricting accumulation of activated MEK. In this study, the focus of investigation was the mechanism of the interaction between trametinib and MEK1/2 via computational simulation. To specify the best interaction site of inhibitor with MEK1/2 based on the interaction energy ranking, first we performed a docking and then we studied the interactions of the ATP-bound MEK with trametinib, with RAF and the complex of the ATP-bound MEK-trametinib with RAF via molecular dynamic simulations. The results showed that trametinib inactivates the enzyme by bonding to a group of amino acids including Lys97/101, SER218/216, Asp208/212, and Met143/147 in MEK1/2. By bonding to the essential amino acids, trametinib inhibits the activity of the enzyme. All in all, the acquired results can be of great use in designing new inhibitors. PMID- 30465280 TI - Tiny Rare-Earth Fluoride Nanoparticles Activate Tumour Cell Growth via Electrical Polar Interactions. AB - Localised extracellular interactions between nanoparticles and transmembrane signal receptors may well activate cancer cell growth. Herein, tiny LaF3 and PrF3 nanoparticles in DMEM+FBS suspensions stimulated tumour cell growth in three different human cell lines (A549, SW837 and MCF7). Size distribution of nanoparticles, activation of AKT and ERK signalling pathways and viability tests pointed to mechanical stimulation of ligand adhesion binding sites of integrins and EGFR via a synergistic action of an ensemble of tiny size nanoparticles (< 10 nm). While tiny size nanoparticles may be well associated with the activation of EGFR, integrin interplay with nanoparticles remains a multifaceted issue. A theoretical motif shows that, within the requisite pN force scale, each ligand adhesion binding site can be activated by a tiny size dielectric nanoparticle via electrical dipole interaction. The size of the active nanoparticle stayed specified by the amount of the surface charges on the ligand adhesion binding site and the nanoparticle, and also by the separating distance between them. The polar component of the electrical dipole force remained inversely proportional to the second power of nanoparticle's size, evincing that only tiny size dielectric nanoparticles might stimulate cancer cell growth via electrical dipole interactions. The work contributes towards recognising different cytoskeletal stressing modes of cancer cells. PMID- 30465281 TI - Honey bee workers generate low-frequency vibrations that are reliable indicators of their activity level. AB - In social insects, the tuning of activity levels among different worker task groups, which constitutes a fundamental basis of colony organization, relies on the exchange of reliable information on the activity level of individuals. The underlying stimuli, however, have remained largely unexplored so far. In the present study, we describe low-frequency thoracic vibrations generated by honey bee workers (Apis mellifera) within the colony, whose velocity amplitudes and main frequency components significantly increased with the level of an individual's activity. The characteristics of these vibrations segregated three main activity level-groups: foragers, active hive bees, and inactive hive bees. Nectar foragers, moreover, modulated their low-frequency vibrations during trophallactic food unloading to nestmates according to the quality of the collected food. Owing to their clear association with the activity level of an individual and their potential perceptibility during direct contacts, these low frequency thoracic vibrations are candidate stimuli for providing unambiguous local information on the motivational status of honey bee workers. PMID- 30465282 TI - Molecularly imprinted photonic hydrogel sensor for optical detection of L histidine. AB - A molecularly imprinted photonic hydrogel (MIPH) is described for the optical determination of L-histidine (L-His). The inverse opal structure of MIPH was obtained by placing silica particles (230 nm) in molecularly imprinted polymer on a glass slide. After being fully etched by hydrofluoric acid, this inverse opal structure brings about a high specific surface and plentiful binding sites for L His. If L-His is absorbed by the modified MIPH, its average effective refraction coefficient is increased. This causes the Bragg diffraction peak to be red shifted by about 34 nm as the concentration of L-His increases from 0 to 100 nM. Much smaller diffraction peak shifts are obtained for other amino acids. The detection limit of this method is 10 pM. The response time towards L-His is as short as 60 s. In addition, the sensor can be recovered by treatment with 0.1 M acetic acid/methanol. It was applied to the determination of L-His in drinks sample. Graphical abstract After absorbing L-histidine, the average effective refractive index of this molecularly imprinted photonic hydrogel (MIPH) is increased, and the Bragg diffraction peak is shifted. The shift of the diffraction peak can be used for the detection of L-His. PMID- 30465283 TI - Canadian Journal of Public Health commits to qualitative research : La Revue canadienne de sante publique s'engage envers la recherche qualitative. PMID- 30465284 TI - Knowledge brokering: (mis)aligning population knowledge with care of fat bodies. AB - OBJECTIVE: Two prominent Canadian knowledge brokers aim to influence how primary care clinicians address obesity, through the dissemination of texts: the Canadian Task Force on Preventive Health Care (guideline) and the Canadian Obesity Network (5As). While written for the same clinician and adult patient population, the recommendations differ. This analysis highlights active decisions that produced the difference. METHODS: Frame analysis of the guideline and 5As texts. RESULTS: The brokers both frame obesity as a chronic and pathological threat to health, at least to a point. The guideline texts frame obesity primarily as a sign of a behavioural problem, discrediting or ignoring many complicating sources of knowledge. In contrast, the 5As frames obesity as complex through diversifying the knowledge foundation embedded in the texts (e.g., including fat-related stigmatisation; health status differences among those classified as obese). Both de-emphasize social and environmental determinants of weight and health. CONCLUSION: Frames of problems used by brokers are not neutral, nor are decisions about how knowledge is excluded and included. Knowledge brokering, no matter how scientific and systematic, is limited by its frame. Recognizing the limits of each frame supports reflexivity in knowledge brokering and interventions taken to enhance health. PMID- 30465285 TI - Is 'health equity' bad for our health? A qualitative empirical ethics study of public health policy-makers' perspectives. AB - OBJECTIVES: 'Social justice' and 'health equity' are core values in public health. Yet, despite their normative character, the numerous normative accounts of social justice and equity are rarely acknowledged, meaning that these values are often unaccompanied by an explanation of what they require in practice. The objective of this study was to bridge this normative scholarship with information about how these 'core values' are integrated and interpreted by Canadian public health policy-makers. METHODS: Twenty qualitative interviews with public health policy-makers recruited from public health organizations in Canada, analyzed using an 'empirical ethics' methodology that combined empirical data with normative ethical analysis involving theories of justice. FINDINGS: Participants viewed health equity and social justice as distinct, where the former was perceived as 'clearer'. Health equity was conceptualized as focusing attention to 'proximal' disparities in access to services and 'materialistic' determinants of health, whereas social justice was conceptualized as focusing on structural issues that lead to disadvantage. Health equity was characterized as 'neutral' and 'comfortable', whereas social justice was characterized as 'political' and 'uncomfortable'. CONCLUSION: These findings indicate that health equity dominates the discursive space wherein justice-based considerations are brought to bear on public health activities. As a result, 'uncomfortable' justice-based considerations of power imbalances and systematic disadvantage can be eschewed in practice in favour of attending to 'proximal' inequities. These findings reveal the problematic ways in which considerations of justice and equity are, and are not, being taken up in public health policy, which in turn may have negative implications for the public's health. PMID- 30465286 TI - Beyond bare bones: critical, theoretically engaged qualitative research in public health. AB - While qualitative inquiry has been a part of the Canadian Journal of Public Health (CJPH) for many years, CJPH does not yet have the reputation as a home for qualitative research that has a critical focus and that is cqqqonversant with contemporary developments in social theory and qualitative methodology. This paper describes efforts to establish CJPH as a welcoming home for critical, theoretically engaged qualitative research in public health. The paper introduces the Special Section that heralds the forward vision for qualitative research at CJPH. We specify what we mean by critical, theoretically engaged qualitative research and make the case for its significance for public health research and practice. We describe changes made in how qualitative manuscript submissions are handled at CJPH and highlight the contribution to public health scholarship made by the articles that comprise the Special Section. We issue an invitation to the public health community to support and participate in our vision to enhance critical, theoretically informed qualitative research in public health. PMID- 30465287 TI - "This drug turned me into a robot": an actor-network analysis of a web-based ethnographic study of psychostimulant use. AB - OBJECTIVES: This study aims to understand contemporary psychostimulant use within the socio-cultural context of Western societies. Two objectives are addressed: to describe accounts of practices related to psychostimulant use among members of selected online fora and to examine how these are related to representations of the self. METHODS: This research is a qualitative study of psychostimulant use among members of selected online fora. Drawing on actor-network theory (ANT), this study focuses on three publicly accessible online discussion fora belonging to the Reddit website. Non-participant observation was performed over a period of 18 months to observe exchanges between members, interactions with moderators, and esthetic elements. In total, 331 postings were collected from the selected fora for qualitative analysis. We present our analysis of one discussion forum, corresponding to 149 posts (515 pages, double spaced). RESULTS: Our study reveals the emergence of an online socio-cultural space formed around psychostimulant use. Members share their experiences openly and some offer guidance, sometimes contrary to prescribers' directives. An ANT analysis points to translations fostering positive or negative subjectivities, related to psychostimulant effects, and to translations fostering healthy or harmful practices, related to r/Adderall as an agentic space. CONCLUSION: These findings may contribute to shaping public health policies and interventions that acknowledge the values of the individuals they seek to help, and that attempt to reduce the potential harms associated with these pharmaceuticals as an alternative to more prohibitive approaches. PMID- 30465288 TI - Genome-wide association study and candidate gene analysis of rice cadmium accumulation in grain in a diverse rice collection. AB - BACKGROUND: Cadmium (Cd) accumulation in rice followed by transfer to the food chain causes severe health problems in humans. Breeding of low Cd accumulation varieties is one of the most economical ways to solve the problem. However, information on the identity of rice germplasm with low Cd accumulation is limited, particularly in indica, and the genetic basis of Cd accumulation in rice is not well understood. RESULTS: Screening of 312 diverse rice accessions revealed that the grain Cd concentrations of these rice accessions ranged from 0.12 to 1.23 mg/kg, with 24 accessions less than 0.20 mg/kg. Three of the 24 accessions belong to indica. Japonica accumulated significantly less Cd than indica (p < 0.001), while tropical japonica accumulated significantly less Cd than temperate japonica (p < 0.01). GWAS in all accessions identified 14 QTLs for Cd accumulation, with 7 identified in indica and 7 identified in japonica subpopulations. No common QTL was identified between indica and japonica. The previously identified genes (OsHMA3, OsNRAMP1, and OsNRAMP5) from japonica were colocalized with QTLs identified in japonica instead of indica. Expression analysis of OsNRAMP2, the candidate gene of the novel QTL (qCd3-2) identified in the present study, demonstrated that OsNRAMP2 was mainly induced in the shoots of high Cd accumulation accessions after Cd treatment. Four amino acid differences were found in the open reading frame of OsNRAMP2 between high and low Cd accumulation accessions. The allele from low Cd accumulation accessions significantly increased the Cd sensitivity and accumulation in yeast. Subcellular localization analysis demonstrated OsNRAMP2 expressed in the tonoplast of rice protoplast. CONCLUSION: The results suggest that grain Cd concentrations are significantly different among subgroups, with Cd concentrations decreasing from indica to temperate japonica to tropical japonica. However, considerable variations exist within subgroups. The fact that no common QTL was identified between indica and japonica implies that there is a different genetic basis for determining Cd accumulation between indica and japonica, or that some QTLs for Cd accumulation in rice are subspecies-specific. Through further integrated analysis, it is speculated that OsNRAMP2 could be a novel functional gene associated with Cd accumulation in rice. PMID- 30465289 TI - Size-dependent characteristics of diurnal particle concentration variation in an underground subway tunnel. AB - Understanding characteristics of diurnal particle concentration variation in an underground subway tunnel is important to reduce subway passengers' exposure to high levels of toxic particle pollution. In this study, real-time particle monitoring for eight consecutive days was done at a shelter located in the middle of a one-way underground subway tunnel in Seoul, Republic of Korea, during the summer of 2015. Particle mass concentration was measured using a dust monitor and particle number concentration using an optical particle counter. From the diurnal variations in PM10, PM2.5, and PM1, concentrations of particles larger than 0.54 MUm optical particle diameter were affected by train frequency whereas those of particles smaller than 0.54 MUm optical particle diameter were not changed by train frequency. Number concentration of particles smaller than 1.15 MUm optical particle diameter was dependent on outdoor ambient air particle concentration level, whereas that of particles larger than 1.15 MUm optical particle diameter was independent of outdoor ambient air due to low ventilation system transmission efficiency of micrometer-sized particles. In addition, an equation was suggested to predict the diurnal particle concentration in an underground tunnel by considering emission, ventilation, and deposition effects. PMID- 30465290 TI - Ultrasensitive impedimetric mercury(II) sensor based on thymine-Hg(II)-thymine interaction and subsequent disintegration of multiple sandwich-structured DNA chains. AB - An impedimetric method is described for ultrasensitive analysis of mercury(II). It is based on thymine-Hg(II)-thymine interaction which causes the disintegration of multiple-sandwich structured DNA chains. DNA strands were selected that are partially complementary to the T-rich Hg(II)-specific oligonucleotides (MSO). They were immobilized on a gold electrode via Au-S interaction. Next, the MSO and the bridging strands (BS) that can connect adjacent MSOs were alternately attached through layer-by-layer hybridization. Thus, a multiple-sandwich structured interface in created that carries numerous MSOs. This leads to a change-transfer resistance (Rct) values of the electrode-electrolyte interface at faradic electrochemical impedance spectroscopy measurements in the presence of the hexacyanoferrate(II)/(III) redox probe at 0.2 V (vs. Ag/AgCl). If Hg(II) is added to the solution, the MSOs selectively interact with Hg(II) to produce T Hg(II)-T structures. Hence, the multiple-sandwich hybridization chains become disintegrated, and this causes a decrease in resistivity. The effect can be used to quantify Hg(II) over an analytical range that extends over four orders of magnitude (1 fM to 10 pM), and it has a 0.16 fM limit of detection under optimal conditions. Graphical abstract An electrochemical sensor for femtomolar level detection of Hg2+ is realized on the basis of thymine-Hg2+-thymine interaction which causes disintegration of multiple sandwich DNA hybridization strands. PMID- 30465292 TI - Comparison of two popular nuclear disassembly techniques for cataract surgeons in training: divide and conquer versus stop and chop. AB - PURPOSE: To compare two common phacoemulsification techniques in the learning curve phase, and their effect on ultrasound energy dissipation. METHODS: One hundred and ten consecutive patients scheduled for cataract surgery with the same surgeon in training were prospectively enrolled. Study was divided in two parts. In the first one, 60 patients were stratified for cataract grade [nuclear opalescence (NO) grade 2-4] and divided in two groups receiving surgery with the divide-and-conquer technique (Group-1) and with the stop-and-chop technique (Group-2). In the second part, 50 patients were stratified according to cataract grade (NO2-6), and the surgeon had to choose one of the two techniques according to personal preference. The primary outcome was the cumulative dissipated energy (CDE). RESULTS: Significant differences of CDE were observed between the NO3 and NO4 cataracts in Group-1. In Group-2, this difference was not significant, suggesting that with more advanced cataracts, the stop-and-chop technique allows less ultrasound use. In the second part of the study, the stop and chop was most frequently used for more advanced cataracts. When considering harder cataracts (NO5-NO6), patients receiving surgery with the divide-and-conquer technique had higher CDE values compared to stop and chop. CONCLUSIONS: Both divide-and-conquer and stop-and-chop techniques are efficient in the learning curve. Stop and chop dissipates less energy in harder nuclei. Once surgeons reach sufficient experience with both techniques, they should switch to a stop-and-chop technique, allowing lower levels of ultrasound energy. PMID- 30465293 TI - Spotting Signs of Autism in 3-Year-Olds: Comparing Information from Parents and Preschool Staff. AB - Preschool informants may provide valuable information about symptoms of autism spectrum disorder (ASD) in young children. We compared the diagnostic accuracy of ratings by preschool staff with those by parents of 3-year-old children using the Achenbach System of Empirically Based Assessment Preschool Forms. The sample consisted of 32 children at familial risk for ASD without diagnosis, 10 children at risk for ASD with diagnosis, and 14 low-risk typically developing controls. Preschool staff ratings were more accurate than parent ratings at differentiating children with and without ASD, and more closely associated with clinician-rated symptoms. These results point to the value of information from preschool informants in early detection and diagnostic assessments. PMID- 30465294 TI - Brief Report: Autism Knowledge and Stigma in University and Community Samples. AB - Increased public understanding of autism may lead to better access to services and participation in the community for individuals with autism. The goal of this study was to explore autism understanding and stigma among university students, and general community members recruited at a state fair. Participants between 18 and 79 years of age (n = 478) completed the Autism Stigma and Knowledge Questionnaire (ASK-Q; Harrison et al., Journal of Autism and Developmental Disorders 47(10):3281-3295, 2017). All ASK-Q means fell within the adequate knowledge range, indicating relatively high levels of autism knowledge and low levels of stigma. ASK-Q scores were correlated with gender, education, and self ratings of understanding but not age. The results of this study suggest the need for continued inquiry into metrics that indicate autism understanding and stigma. PMID- 30465295 TI - Inpatient Psychiatric Treatment of Serious Behavioral Problems in Children with Autism Spectrum Disorder (ASD): Specialized Versus General Inpatient Units. AB - Psychiatric hospitalization of children with autism spectrum disorder (ASD) is common, but there is little comparative information available on different psychiatric hospital treatment models. Children with ASD ages 4-20 were enrolled upon admission to either a specialized (N = 53) or a general child psychiatric unit (N = 27). Caregivers completed the Aberrant Behavioral Checklist Irritability Sub-scale (ABC-I) at admission, discharge, and 2 months post discharge and reported information on crisis service utilization 2 months post discharge. Children treated in the specialized unit had lower ABC-I scores at discharge and 2 months post-discharge (F = 8.98, p = 0.003) and were significantly less likely to experience an ER visit within 2 months post discharge (X2 = 5.51, p = 0.019). Specialized inpatient units may be more effective for children with ASD in need of psychiatric hospitalization. PMID- 30465296 TI - Potential causal associations of serum 25-hydroxyvitamin D with lipids: a Mendelian randomization approach of the HUNT study. AB - Observational studies have shown consistent associations between higher circulating 25-hydroxyvitamin D [25(OH)D] levels and favorable serum lipids. We sought to investigate if such associations were causal. A Mendelian randomization (MR) study was conducted on a population-based cohort comprising 56,435 adults in Norway. A weighted 25(OH)D allele score was generated based on vitamin D increasing alleles of rs2282679, rs12785878 and rs10741657. Linear regression analyses of serum lipid levels on the allele score were performed to assess the presence of causal associations of serum 25(OH)D with the lipids. To quantify the causal effects, the inverse-variance weighted method was used for calculating MR estimates based on summarized data of individual single-nucleotide polymorphisms. The MR estimate with 95% confidence interval (CI) represents percentage difference in the lipid level per genetically determined 25 nmol/L increase in 25(OH)D. The 25(OH)D allele score demonstrated a clear association with high density lipoprotein (HDL) cholesterol (p = 0.007) but no association with total or non-HDL cholesterol or triglycerides (p >= 0.27). The MR estimate showed 2.52% (95% CI 0.79-4.25%) increase in HDL cholesterol per genetically determined 25 nmol/L increase in 25(OH)D, which was stronger than the corresponding estimate of 1.83% (95% CI 0.85-2.81%) from the observational analysis. The MR estimates for total cholesterol (0.60%, 95% CI - 0.73 to 1.94%), non-HDL cholesterol (0.04%, 95% CI - 1.79 to 1.88%) and triglycerides (- 2.74%, 95% CI - 6.16 to 0.67%) showed no associations. MR analysis of data from a population-based cohort suggested a causal and positive association between serum 25(OH)D and HDL cholesterol. PMID- 30465297 TI - The Extremely Enhanced Photocurrent Response in Topological Insulator Nanosheets with High Conductance. AB - The photocurrent was performed in topological insulator nanosheets with different conductances. The higher photocurrent is observed in the nanosheet with higher conductance. The responsivity is proportional to the nanosheet conductance over two orders. The responsivity is independent of the light power intensity in vacuum, but responsivity drastically decreases at low power intensity in air. The ratio of the responsivity in air to that in vacuum is negatively proportional to the the inverse of the light power intensity. These behaviors are understood as the statistical photocurrent in a system with blocked molecules. The time constant decreases as the thickness increases. A longer time constant is observed in lower atmosphere pressure. PMID- 30465298 TI - Genetically Engineered Oil Seed Crops and Novel Terrestrial Nutrients: Ethical Considerations. AB - Genetically engineered (GE) organisms have been at the center of ethical debates among the public and regulators over their potential risks and benefits to the environment and society. Unlike the currently commercial GE crops that express resistance or tolerance to pesticides or herbicides, a new GE crop produces two bioactive nutrients (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) that heretofore have largely been produced only in aquatic environments. This represents a novel category of risk to ecosystem functioning. The present paper describes why growing oilseed crops engineered to produce EPA and DHA means introducing into a terrestrial ecosystem a pair of highly bioactive nutrients that are novel to terrestrial ecosystems and why that may have ecological and physiological consequences. More importantly perhaps, this paper argues that discussion of this novel risk represents an opportunity to examine the way the debate over genetically modified crops is being conducted. PMID- 30465299 TI - O Organism, Where Art Thou? Old and New Challenges for Organism-Centered Biology. AB - This paper addresses theoretical challenges, still relevant today, that arose in the first decades of the twentieth century related to the concept of the organism. During this period, new insights into the plasticity and robustness of organisms as well as their complex interactions fueled calls, especially in the UK and in the German-speaking world, for grounding biological theory on the concept of the organism. This new organism-centered biology (OCB) understood organisms as the most important explanatory and methodological unit in biological investigations. At least three theoretical strands can be distinguished in this movement: Organicism, dialectical materialism, and (German) holistic biology. This paper shows that a major challenge of OCB was to describe the individual organism as a causally autonomous and discrete unit with consistent boundaries and, at the same time, as inextricably interwoven with its environment. In other words, OCB had to conciliate individualistic with anti-individualistic perspectives. This challenge was addressed by developing a concept of life that included functionalist and metabolic elements, as well as biochemical and physical ones. It allowed for specifying organisms as life forms that actively delimit themselves from the environment. Finally, this paper shows that the recent return to the concept of the organism, especially in the so-called "Extended Evolutionary Synthesis," is challenged by similar anti-individualistic tendencies. However, in contrast to its early-twentieth-century forerunner, today's organism-centered approaches have not yet offered a solution to this problem. PMID- 30465300 TI - Relative and Absolute Risk of Tendon Rupture with Fluoroquinolone and Concomitant Fluoroquinolone/Corticosteroid Therapy: Population-Based Nested Case-Control Study. AB - BACKGROUND AND OBJECTIVE: Tendon rupture can result from fluoroquinolone exposure. The objective of this study was to quantify relative and absolute risk and determine how risk is affected by timing of exposure. METHODS: The UK Health Improvement Network primary care database was used to perform a nested case control study measuring the association between fluoroquinolone exposure and tendon rupture. Adults with tendon rupture were matched on age, sex, general practice and calendar time to four controls selected from a cohort prescribed systemic fluoroquinolone or co-amoxiclav antibiotics. The relative and absolute risk of tendon rupture with fluoroquinolone exposure was calculated. RESULTS: Current fluoroquinolone exposure was associated with an increased risk of any tendon rupture (adjusted incidence rate ratio [aIRR] 1.61, 95% CI 1.25-2.09) and Achilles tendon rupture (aIRR 3.14, 95% CI 2.11-4.65) that persisted for 60 days. Risk increased with cumulative exposure and was greatest when co-prescribed with oral corticosteroids (aIRR 19.36, 95% CI 7.78-48.19 for Achilles tendon rupture). The adjusted rate difference (aRD) with fluoroquinolone exposure was 2.9 and 2.1 per 10,000 patients for any and Achilles tendon rupture, respectively, and was greatest in people aged >= 60 years prescribed concomitant oral corticosteroid therapy (aDR 19.6 for any tendon and 6.6 Achilles tendon rupture per 10,000). No association was seen with co-amoxiclav or statin exposure, or with biceps or other tendon ruptures. CONCLUSIONS: Risk of tendon rupture with fluoroquinolones depends on timing, cumulative dose and concomitant exposure to oral corticosteroids. Absolute risk significantly varied by age and concomitant corticosteroid exposure, affecting elderly patients the greatest. PMID- 30465301 TI - Neutrophil Cytosolic Factor 1 Contributes to the Development of Sepsis. AB - To identify differentially expressed genes in sepsis and potential key role of reactive oxygen species (ROS) genes associated with sepsis. Gene expression dataset was available from GSE46599. Firstly, we screened the differentially expressed genes between sepsis and healthy samples. Then, the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tools were utilized to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses at the functional level. Differentially expressed genes mediating ROS levels were validated in the next investigation and analysis. We identified 1094 genes expressed differentially between normal and sepsis samples, including 655 upregulated genes and 439 downregulated genes. At the functional level, GO and KEGG pathway enrichment analysis showed that those differentially expressed genes were majorly associated with the immune response and metabolic process in sepsis. Further analysis revealed that neutrophil cytosolic factor 1(NCF1), a critical gene in the ROS system, upregulated in THP-1 cell and monocytes under lipopolysaccharides stimulation. Moreover, we identified the upregulation of NCF1 in a sepsis model. We screened the differentially expressed genes from the global level and identified NCF1 might be a critical target gene in sepsis. PMID- 30465302 TI - Bone Microdamage in Acute Knee Injury. AB - PURPOSE OF REVIEW: This review summarizes what is known about how bone tissue responds to microdamage, and how this applies to the subchondral region. This has significant relevance to acute joint injury, and is related to the occurrence of bone marrow lesions (BMLs) which are seen by MRI in 80% of acute knee joint injuries. Here, we review what is known about these phenomena (microcracks and BMLs) in the literature and discuss potential mechanisms by which they may be linked. RECENT FINDINGS: The recent findings in this field have shown that microcracks in bone initiate targeted remodeling via RANKL expression in osteocytes. Other work has shown that subchondral microcracks co-localize with BMLs as viewed by MRI. Finally, BMLs are associated with pain and structural joint degeneration. This paper demonstrates that subchondral microcracks likely occur during acute joint injury, and are closely linked to BML that are seem by clinical MRI and thus are potentially involved in the subsequent joint degeneration that occurs after injury. PMID- 30465303 TI - A novel long non-coding RNA, lncKBTBD10, involved in bovine skeletal muscle myogenesis. AB - Accumulating evidence suggests that long non-coding RNAs (lncRNAs) play a crucial role in regulating skeletal muscle myogenesis, a highly coordinated multistep biological process. However, most studies of lncRNAs have focused on humans, mouse, and other model animals. In this study, we identified a novel lncRNA, named lncKBTBD10, located in the nucleus and involved in the proliferation and differentiation of bovine skeletal muscle satellite cells. Prediction of coding potential and in vitro translation system illustrated that lncKBTBD10 has no encoding capability. With the process of myogenic differentiation, the expression of lncKBTBD10 gradually increased. To elucidate the functions of lncKBTBD10 during myogenesis, the gain/loss-of-function experiments were performed. Results showed that the proliferation and differentiation of bovine skeletal muscle satellite cells were all suppressed whether lncKBTBD10 was knocked down or over expressed. Furthermore, we found that lncKBTBD10 may affect its proximity gene KBTBD10 to involve in myogenesis. Results indicated that the protein level of KBTBD10 was all diminished after induced differentiation for 2 d in differentiation medium (DM2) whether lncKBTBD10 was knocked down or over expressed. It may support why the altering of lncKBTBD10 can suppress the proliferation and differentiation of bovine skeletal muscle satellite cells. In short, our study elucidated that lncKBTBD10 could induce a decrease of KBTBD10 protein and further to affect bovine skeletal muscle myogenesis. The novel identified lncKBTBD10 may provide a reference for lncRNAs involved in myogenesis of bovine skeletal muscle. PMID- 30465304 TI - A robotic microsurgical forceps for transoral laser microsurgery. AB - PURPOSE: In transoral laser microsurgery (TLM), the close curved cylindrical structure of the laryngeal region offers functional challenges to surgeons who operate on its malignancies with rigid, single degree-of-freedom (DOF) forceps. These challenges include surgeon hand tremors, poor reachability, poor tissue surface perception, and reduced ergonomy in design. The integrated robotic microsurgical forceps presented here is capable of addressing the above challenges through tele-operated tissue manipulation in TLM. METHODS: The proposed device is designed in compliance with the spatial constraints in TLM. It incorporates a novel 2-DOF motorized microsurgical forceps end-effector, which is integrated with a commercial 6-DOF serial robotic manipulator. The integrated device is tele-operated through the haptic master interface, Omega.7. The device is augmented with a force sensor to measure tissue gripping force. The device is called RMF-2F, i.e. robotic microsurgical forceps with 2-DOF end-effector and force sensing. RMF-2F is evaluated through validation trials and pick-n-place experiments with subjects. Furthermore, the device is trialled with expert surgeons through preliminary tasks in a simulated surgical scenario. RESULTS: RMF 2F shows a motion tracking error of less than 400 MUm. User trials demonstrate the device's accuracy in task completion and ease of manoeuvrability using the Omega.7 through improved trajectory following and execution times. The tissue gripping force shows better regulation with haptic feedback (1.624 N) than without haptic feedback (2.116 N). Surgeons positively evaluated the device with appreciation for improved access in the larynx and gripping force feedback. CONCLUSIONS: RMF-2F offers an ergonomic and intuitive interface for intraoperative tissue manipulation in TLM. The device performance, usability, and haptic feedback capability were positively evaluated by users as well as expert surgeons. RMF-2F introduces the benefits of robotic teleoperation including, (i) overcoming hand tremors and wrist excursions, (ii) improved reachability and accuracy, and (iii) tissue gripping feedback for safe tissue manipulation. PMID- 30465305 TI - Concept of microbial gatekeepers: Positive guys? AB - Microorganisms contribute diverse and fundamental roles in biogeochemical processes. In a given microbial community, individuals interact with one another to form complex regulatory networks in which gatekeepers contribute disproportional roles in sustaining stability, dynamics, and function. Owing to the ecological and functional importance of microbial gatekeeper, this review provides an overview on its history, identification, roles, application in biological sciences, and clinical diagnostics. The roles of microbial gatekeepers can be beneficial or detrimental, which depends on our purpose. As the field is rather new, some limitations are raised, and further efforts devoted to solving these concerns are proposed. Collectively, gatekeepers provide promising targets for sustaining and re-establishing a desired microbial community. However, substantial obstacles, such as factors governing gatekeepers, must be overcome to manipulate gatekeepers as positive guys. PMID- 30465306 TI - Bioprospecting cold-adapted plant growth promoting microorganisms from mountain environments. AB - Mountain soils are challenging environments for all kinds of living things, including plants and microorganisms. Many cold-adapted microorganisms colonizing these extreme soils play important roles as promoters of plant growth and development; for that reason, they are called collectively plant growth-promoting microorganisms (PGPM). Even though there is seldom doubt concerning the usefulness of PGPM to develop eco-friendly bioinoculants, including biofertilizers and biocontrollers, a series of aspects need to be addressed in order to make this technology field-applicable. Among these aspects, the ecological and rhizosphere competences of PGPM are of paramount importance, particularly when considering the development of bioinoculants, well suited for the intensification of mountainous agricultural production. Studies on native, cold-adapted PGPM conducted in the Indian Himalayan region (IHR) and the Tropical Andes (TA) lead nowadays the research in this field. Noticeably, some common themes are emerging. For instance, soils in these mountain environments are colonized by many cold-adapted PGPM able to mobilize soil nutrients and to inhibit growth of plant pathogens. Studies aimed at deeply characterizing the abilities of such PGPM is likely to substantially contribute towards a better crop productivity in mountainous environments. The present review focuses on the importance of this microbial resource to improve crop productivity in IHR and TA. We also present a number of successful examples, which emphasize the effectiveness of some bioinoculants-developed from naturally occurring PGPM-when applied in the field. PMID- 30465307 TI - Biopolymer gels as a basis of cryoprotective medium for testicular tissue of rats. AB - Cryopreservation of testis tissue is a promising approach to save fertility in prepubertal boys under going gonadotoxic cancer therapies. The using biopolymers as a basis of cryoprotective medium can be effective for the optimization of cryopreservation protocols of immature testicular tissue. The research purpose was to determine morphological parameters and metabolic activity of seminiferous tubules of immature rat testes under exposure to cryoprotective solution (DMSO) based on collagen or fibrin gels (CG or FG) as one of the first stages of developing the cryopreservation protocol. It was found that 30-min exposure of tissue samples to CG and FG with 0.6 M DMSO did not impair the spermatogenic epithelium and metabolic activity of the cells (MTT test and total lactate dehydrogenase activity). The use of FG at the time of exposure of 45 min did not lead to significant changes in the metabolic activity in contrast to other groups. The findings could be used to substantiate and develop the effective techniques for cryopreservation of immature seminiferous tubules. PMID- 30465308 TI - Memories. PMID- 30465309 TI - Lung metastases regression with increased CD8+ T lymphocyte infiltration following preoperative spinal embolization and total en bloc spondylectomy using tumor-bearing frozen autograft in a patient with spinal metastatic leiomyosarcoma. AB - PURPOSE: To report systemic immunological enhancement following preoperative spinal embolization and total en bloc spondylectomy (TES) using tumor-bearing frozen autograft in a patient with spinal metastatic leiomyosarcoma. METHODS: A 44-year-old woman with metastatic uterine leiomyosarcoma of the lung and L1 vertebra underwent TES following bilateral three-level preoperative segmental artery embolization. Resected tumor-bearing lamina was frozen using liquid nitrogen and used as tumor-bearing bone graft for spinal reconstruction. RESULTS: Tumor necrosis and obstructing material used in preoperative embolization were detected in the resected specimen of L1. Five days after TES, chest computed tomography scan demonstrated decreased solitary lung mass size without adjuvant treatment. Lobectomy was performed for the lung metastasis 42 days after TES. Infiltration of CD8+ T lymphocyte into tumor tissue significantly increased in shrunk lung metastasis. On the other hand, slight infiltration in both the resected L1 and primary uterine lesion was observed. Six months after TES, activities of daily living were normal with no evidence of local recurrence or distant metastasis. One year after TES, however, lung CT revealed occurrence of another lung metastasis, and molecular-targeting therapy (pazopanib) was initiated. CONCLUSIONS: There were no reports demonstrating metastasis regression with CD8+ T lymphocyte infiltration after TES. This case demonstrated that preoperative tumor embolization combined with TES using tumor-bearing autograft provided both a local radical cure and systemic antitumor immunological enhancement, although the long-term effect can be limited. PMID- 30465310 TI - Do the Predictors of Atypical Sexual Orientations in Women Generalize Across Different Evolutionary Tests? PMID- 30465311 TI - Attachment, Sexual Desire, and Object of Desire Self-Consciousness Trade-Up Effects. PMID- 30465312 TI - The Prevalence and Correlates of Sexual Arrangements in a National Cohort of HIV Negative Gay and Bisexual Men in the United States. AB - Sexual agreements have received considerable attention as an aspect of dyadic functioning associated with HIV risk. To date, this research has primarily utilized convenience samples which overrepresented men from large urban areas and with higher HIV risk. The current study utilized a national cohort of 1061 HIV negative gay and bisexual men recruited to be geographically diverse within the U.S. The sample included 531 (50.0%) men who identified as single. Of the 530 partnered men, 240 (45.3%) were monogamous; 238 (44.9%) were in open relationships (where sex with outside partners was permitted); and 52 (9.8%) were in monogamish relationships (where sex with outside partners was limited to instances where both primary partners were present). Regardless of urban (vs. non urban) residence, men in monogamous relationships engaged in less anal sex generally and condomless anal sex (CAS) specifically with casual partners. Single men reported significantly more frequent anal sex with casual partners compared to open and monogamish men; however, there were no significant differences among these three groups with respect to CAS with casual partners. In multivariable models, monogamish men reported significantly more frequent marijuana use and alcohol consumption compared to all other groups. Urban (vs. non-urban) residence moderated associations between sexual arrangements and depression as well as the use of illicit drugs other than marijuana. These findings point to the need to better examine the potentially unique mechanisms which confer risk and resilience for gay male couples in urban versus non-urban settings. The observed association between sexual arrangements and substance use suggests interventions which facilitate the negotiation of sexual agreements may present an opportunity to engage in dyadic substance use intervention. PMID- 30465313 TI - Are Healthy Parental Attachments and Resilience to Societal Objectification Basic to Women's Sexual Health? PMID- 30465314 TI - Implementing Patient-Reported Outcomes to Improve the Quality of Care for Weight of Patients with Schizophrenia. AB - "Enhancing QUality of Care In Psychosis" (EQUIP) was an eight-site clustered controlled trial of the implementation and effectiveness of patient-reported outcomes to support evidence-based practice and improve care for schizophrenia. Implementation sites chose to improve care for weight. Implementation included monitoring patient-reported outcomes using kiosks, patient and staff education, quality improvement teams, and phone care management. Qualitative and quantitative methods compared implementation and effectiveness between sites for 13 months. Eighty percent of 801 randomly selected patients were overweight. Two hundred one clinicians varied in competency. Baseline use of behavioral weight services was low. At implementation sites, patients became 2.3 times more likely to use weight services compared with control sites (95% CI, 1.5-3.6; chi2 = 14.4; p < 0.01). There was no effect on the weight gain liability of medications prescribed. Controlling for baseline, patients' final weight at control sites was 5.9 +/- 2.7 kg heavier than at implementation sites (F = 4.8, p = 0.03). Patient reported outcomes can inform implementation of evidence-based practice and improvement in outcomes. PMID- 30465315 TI - Correction to: The Emerging Roles of Steroid Hormone Receptors in Ductal Carcinoma in Situ (DCIS) of the Breast. AB - The original version of this article unfortunately contained mistakes. PMID- 30465316 TI - Caffeic acid phenethyl ester exerts apoptotic and oxidative stress on human multiple myeloma cells. AB - Caffeic acid phenethyl ester (CAPE) is a phenolic compound initially identified in bee glue. CAPE is reported to exhibit antitumor activity in many cancer models. However, the effect of CAPE on multiple myeloma (MM) is not well studied. We investigated the anti-myeloma effect of CAPE, and the data showed that CAPE inhibited the growth of human MM cells in a dose (1 ~ 30 MUM) and time (24 ~72 h) dependent manner without altering the viability of normal human peripheral blood B cells. Stress and toxicity pathway analysis demonstrated that CAPE, in a dose- and time-related fashion, induced the expression of apoptotic and oxidative stress-response genes including growth arrest and DNA-damage inducible, alpha and gamma (GADD45A and GADD45G) and heme oxygenase-1. Apoptosis of MM cells by CAPE was further confirmed through flow cytometric analysis with up to 50% apoptotic cells induced by 50 MUM CAPE within 24 h. Western blot analysis revealed the CAPE induced activation of apoptosis executioner enzyme caspase-3, and corresponding cleavage of its downstream target poly(ADP-ribose)polymerase (PARP). The oxidative stress caused by CAPE cytotoxicity in MM cells was evaluated through measurement of reactive oxygen species (ROS) level, antioxidant intervention and glutathione depletion. The intracellular ROS level was not elevated by CAPE, but the pretreatment of antioxidant (N-acetyl cysteine) and glutathione synthesis inhibitor (buthionine sulfoximine) suggested that CAPE may cause oxidative stress by decrease of intracellular antioxidant level rather than over production of ROS. These data suggest that CAPE promotes apoptosis through oxidative stress in human multiple myeloma cells. PMID- 30465317 TI - Pain, skin sensations symptoms, and cognitive functioning predictors of health related quality of life in pediatric patients with Neurofibromatosis Type 1. AB - OBJECTIVES: The aim was to investigate pain, skin sensations symptoms and patient self-reported, and parent proxy-reported cognitive functioning as predictors of generic health-related quality of life (HRQOL) in pediatric patients with Neurofibromatosis Type 1 (NF1) from the perspectives of patients and parents. METHODS: The Pain, Skin Itch Bother, Skin Sensations, and Cognitive Functioning Scales from the PedsQLTM Neurofibromatosis Type 1 Module and the PedsQLTM Generic Core Scales were completed in a multi-site national study by 323 patients and 335 parents. Patients were 5-25 years of age. Pain and skin symptoms and cognitive functioning were tested for bivariate and multivariate linear associations with generic HRQOL. RESULTS: Pain, skin itch bother, skin sensations, and cognitive functioning were associated with decreased HRQOL in bivariate analyses (Ps < 0.001). In predictive analytics models, utilizing hierarchical multiple regression analyses controlling for demographic covariates, pain, skin itch bother, skin sensations, and cognitive functioning as a group accounted for 61 percent of the variance in patient-reported generic HRQOL (P < 0.001), reflecting a large effect size. For parent proxy-report, the predictor variables as a group accounted for 53% of the variance in generic HRQOL. CONCLUSIONS: Pain, skin symptoms, and patient self-reported and parent proxy-reported cognitive functioning are key predictors of generic HRQOL in pediatric patients with NF1. Delineating NF1-specific symptoms and cognitive functioning as high-priority predictors from the patient and parents perspective enhances a family-centered approach in clinical research, clinical trials, and clinical practice intended to improve the global generic HRQOL of pediatric patients with NF1. PMID- 30465318 TI - Patient-reported outcomes in stroke clinical trials 2002-2016: a systematic review. AB - OBJECTIVE: Given the global and economic burden of stroke as a major cause of long-term disability, patient-reported outcomes (PRO) data from clinical trials can elucidate differential benefits/harms of interventions from patients' perspectives and influence clinical decision making in stroke care management. METHODS: This systematic review examines stroke-related randomized controlled trials (RCT) published in 12 high-impact journals between 2002 and 2016 for (1) associations between trial characteristics and the reporting of PRO measures; and (2) psychometric properties of PRO instruments used in these studies. The study combines clinical trials identified in a prior review with trials identified with an updated literature search. RESULTS: Only 34 of 159 stroke-related RCTs reported PRO measures. Among the 34 trials, most were published in rehabilitation and general medical journals, were conducted in the United States or Europe, were funded by government/non-industry sponsors, and focused on post-stroke care. Thirty-one PRO instruments were employed in these studies. Only 5 instruments were stroke-specific measures, whereas the remaining 26 instruments were generic measures. Eight instruments assessed functional status, 9 measured quality of life, and 14 assessed symptoms. The most common health domains measured were emotional status and physical function. CONCLUSIONS: This study highlights the paucity of information from patients' perspective in stroke-related RCTs. This trend may change over time as researchers increase adherence to reporting guidelines for clinical trial protocols. PMID- 30465319 TI - Cost Effectiveness of New Diagnostic Tools for Cutaneous Leishmaniasis in Afghanistan. AB - BACKGROUND AND OBJECTIVES: Cutaneous leishmaniasis is responsible for chronic and disfiguring skin lesions resulting in morbidity and social stigma. The gold standard to diagnose cutaneous leishmaniasis is microscopy but has a variable sensitivity and requires trained personnel. Using four scenarios, the objective of this study is to compare the cost effectiveness of microscopy with two new tools: LoopampTM Leishmania Detection Kit (LAMP) and CL DetectTM Rapid Test (RDT). METHODS: Data related to the cost and accuracy of these tools were collected at the clinic of the National Malaria and Leishmaniasis Control Program in Kabul, Afghanistan. The effectiveness estimates were measured based on the tools' performance but also indirectly, using the disability-adjusted life years. A decision tree was designed in TreeAge Healthcare Pro 2016, combined with a Markov model representing the natural history of cutaneous leishmaniasis. In addition to a deterministic analysis, univariate sensitivity and probabilistic analyses were performed to test the robustness of the results. RESULTS: If the tools are compared at the National Malaria and Leishmaniasis Control Program level in a period of low incidence, microscopy remains the preferred option. LAMP becomes more appropriate during cutaneous leishmaniasis seasons or outbreaks when its capacity to process several tests (e.g. up to 48) at a time can be maximised. RDT has a cost similar to microscopy when used at the reference clinic but as it is relatively easy to use, it could be implemented at the peripheral level, which would become cheaper than employing microscopy at the reference clinic. Moreover, combining RDT with microscopy or LAMP at the reference clinic for the negative suspects is economically more interesting than directly performing LAMP or microscopy respectively on all cutaneous leishmaniasis suspects at the reference clinic. CONCLUSIONS: When taking advantage of their respective strengths, LAMP and RDT can prove to be cost-effective alternatives to using microscopy alone at the reference clinic. PMID- 30465320 TI - Dynamics of hepatitis B virus serum markers in an acute hepatitis B patient in the incubation phase. AB - Patients with acute hepatitis B (AHB) usually present after developing symptoms; therefore, the temporal kinetics of viral markers during the incubation period have not been documented clearly. We describe an AHB infection before the onset of hepatitis, throughout the course of the disease and without anti-viral therapy. The patient initially visited our hospital for immunization against HBV and was found to be positive for viral markers: 0.0 IU/mL of anti-HBs, 0.06 S/CO of anti-HBc and 2.93 IU/mL of HBsAg. During the 14 days after his first visit, HBsAg, HBV DNA, HBe antigen and HBV core-related antigen, but not anti-HBc or anti-HBs, levels increased. On day 22, he developed acute hepatitis. The period of logarithmic viral replication was estimated to be 7.0 days. HBV genomic sequencing and phylogenetic analysis indicated transmission from the patient's wife. Although sexual intercourse could not be ruled, another possible route of transmission was the unusual occurrence of kissing his wife when she had macroscopic bleeding after tooth brushing, 2 months before his positive HBsAg result; the day of the episode being consistent with the calculated HBV replication velocity. This study reveals the temporal kinetics of viral markers during the incubation period of AHB. PMID- 30465321 TI - Impact of Ixekizumab Treatment on Itch and Psoriasis Area and Severity Index in Patients with Moderate-to-Severe Plaque Psoriasis: An Integrated Analysis of Two Phase III Randomized Studies. AB - INTRODUCTION: We evaluated baseline itch and its impact on the efficacy of ixekizumab (IXE) in clearing psoriasis and improving quality-of-life measures, and we explored the relationship between itch and psoriatic skin improvement. METHODS: Data were analyzed from two double-blind, randomized, controlled phase III studies (UNCOVER-2/3) comparing etanercept (ETN), IXE, and placebo (PBO) in patients with moderate-to-severe plaque psoriasis. Long-term analysis included UNCOVER-3 data from week 0 to week 156. RESULTS: At week 12, a clinically meaningful improvement in itch [Itch Numeric Rating Scale (NRS) reduction >= 4] was seen in 70.0%, 88.6%, and 90.8% of the IXE-treated patients in the baseline Itch NRS 4-6, 7-8, and 9-10 groups, respectively (all itch severity groups p < 0.001 versus ETN and PBO). Also, 68.9%, 67.1%, and 73.6% of the IXE-treated patients in the baseline Itch NRS 4-6, 7-8, and 9-10 groups, respectively, showed an improvement of >= 90.0% in the Psoriatic Area and Severity Index (PASI) at week 12 as compared to the baseline (PASI 90) (all itch severity groups p < 0.001 versus ETN and PBO). For most patients, itch reduction preceded psoriatic plaque improvement. Sustained effects of IXE on itch and PASI were observed during 3 years of treatment. CONCLUSIONS: Regardless of baseline itch severity, IXE treatment provided a rapid improvement in itch followed by clinically meaningful improvements in psoriasis. FUNDING: Eli Lilly and Company. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT01597245 and NCT01646177. PMID- 30465322 TI - Models for temporal-spatial parameters in walking with cadence ratio as the independent variable. AB - Accurate models that describe temporal-spatial parameters are desirable in gait estimation and rehabilitation. This study aimed to explore simple but relatively accurate models to describe stride length (SL), speed (SP) and walk ratio (WR) at various cadences. Twenty-four able-bodied participants (16 in a test group and 8 in a validation group) walked at seven cadence ratios (CRs). The individual and group mean SL, SP and WR were studied. Suitable temporal-spatial model structures were proposed and used to approximate the individual SL, SP and WR at various CRs. After the temporal-spatial model structures were found to be feasible, the general temporal-spatial models were analysed using the test group mean SL, SP and WR. Accuracy was assessed using the validation group mean values. Individual approximation accuracies showed that the proposed model structure deduced from the linear SL model was suitable for WR approximation. The linear, deduced quadratic and power functions approximated the individual SL, SP and WR, respectively, with high accuracy. Based on the test group mean SL, SP and WR, the general temporal-spatial models were obtained and produced comparable approximation accuracies in the validation group. The general temporal-spatial models predicted well the individual gait parameters with similar individual errors for both groups. These temporal-spatial models clearly describe SL, SP and especially WR at various cadences. They provide accurate reference data for gait estimation and have potential to guide speed modulation in robot-assisted gait rehabilitation. Graphical abstract Twenty-four able-bodied participants (16 in test group and 8 in validation group) walked at seven cadence ratios (CRs), with the individual and group mean stride length (SL), speed (SP) and walk ratio (WR) studied. This work selected the cadence ratio as the independent variable and yielded general temporal-spatial models based on the test group data, which were a linear model for SL, a quadratic function for SP and a power function for WR. The general temporal-spatial model produced comparable approximation accuracies in the validation group. Clearly describing SL, SP and especially WR at various cadences, these temporal-spatial models provide accurate references for gait estimation and have the potential to guide speed modulation in robot-assisted gait rehabilitation. Approximation of the group mean temporal-spatial parameters at seven cadences. Solid lines in parts (a, b): the general linear SL model. Solid lines in (c, d): the general quadratic SP model. Solid lines in (e, f): the general WR model. Dots and stars in (a, c, e): the individual and group mean values for the test group. Dots and stars in (b, d, f): the individual and group mean values for the validation group. PMID- 30465323 TI - Glycomyces luteolus sp. nov., a novel actinomycete isolated from rhizosphere soil of wheat (Triticum aestivum L.). AB - Three Gram-stain positive, aerobic actinomycete strains, designated NEAU-A15T, NEAU-A13 and NEAU-C4, were isolated from rhizosphere soil of wheat (Triticum aestivum L.) collected from Langfang, Hebei Province, China. Based on their morphological characteristics, biochemical features and molecular phylogenetic studies, these strains were concluded to belong to a new member of the genus Glycomyces. 16S rRNA gene sequence analysis showed that strain NEAU-A15T shares 99.91% and 99.80% 16S rRNA gene sequence similarity with NEAU-A13 and NEAU-C4, respectively, and these three strains showed high sequence similarities to Glycomyces algeriensis DSM 44727T (99.24, 99.45, 99.38%), Glycomyces lechevalierae DSM 44724T (98.97, 99.17, 99.11%) and Glycomyces rutgersensis DSM 43812T (98.83, 99.04, 98.97%). Phylogenetic analysis indicated that these three strains clustered together and formed a cluster with Glycomyces tritici NEAU-C2T (97.30, 97.73, 99.48%), G. algeriensis DSM 44727T, G. lechevalierae DSM 44724T and G. rutgersensis DSM 43812T. These three strains were observed to contain MK 10(H2), MK-10(H6) and MK-11 as menaquinones. The whole cell sugar profiles were found to contain galactose, ribose and xylose. The polar lipids were found to consist of diphosphatidylglycerol, phosphatidylinositol, phosphatidylglycerol, phosphoglycolipid, phosphatidylinositol mannoside and an unidentified glycolipid. The major fatty acids were identified as anteiso-C15:0, iso-C16:0, anteiso-C17:0 and iso-C15:0. The DNA-DNA hybridization values between strain NEAU-A15T and NEAU A13/NEAU-C4 were 86.2 +/- 2.3% and 83.4 +/- 3.5%, respectively. The values between these three strains and their close phylogenetic relatives were 48-52%, supporting the conclusion that they belong to a distinct genomic species. An array of phenotypic characteristics also differentiated these isolates from their closely related species. On the basis of the genetic and phenotypic properties, strains NEAU-A15T, NEAU-A13 and NEAU-C4 can be classified as representatives of a novel species of the genus Glycomyces, for which the name Glycomyces luteolus sp. nov., is proposed. The type strain is NEAU-A15T (= DSM 104643T = CGMCC 4.7394T). PMID- 30465324 TI - Calcite formation induced by Ensifer adhaerens, Microbacterium testaceum, Paeniglutamicibacter kerguelensis, Pseudomonas protegens and Rheinheimera texasensis. AB - A wide range of bacterial species are able to induce calcium carbonate precipitation. Using our own laboratory-preserved strains, we have newly discovered that Ensifer sp. MY11e, Microbacterium sp. TMd9a1, Paeniglutamicibacter sp. MSa1a, Pseudomonas sp. GTc3, and Rheinheimera sp. ATWe6 can induce the formation of calcite crystals on an agar medium. Type strains of their closely related species (Ensifer adhaerens, Microbacterium testaceum, Paeniglutamicibacter kerguelensis, Pseudomonas protegens, and Rheinheimera texasensis) could also induce calcite formation. Although the initial pH value of the agar medium was 6.1, the pH of the agar media containing calcite, induced by cultivation of the 10 bacterial strains, increased to 8.0-8.4. The ammonification (oxidative deamination) of amino acids may been responsible for this increase in pH. The crystals formed both on and around the bacterial colonies. Furthermore, when these strains (excepting two Microbacterium strains) were cultivated on a cellulose acetate membrane filter (0.20 MUm pore size) resting on the surface of the agar medium (i.e., in the membrane filter culture method), the crystals formed on the agar medium separate from the bacterial cells. These results indicate that the bacterial cells did not necessarily become nucleation sites for these crystals. We also investigated whether the studied strains could be applied to the biocementation of sand, and found that only two Ensifer strains were able to form large sand lumps. PMID- 30465325 TI - Correction to: Survivorship Care Plan Implementation in US Cancer Programs: a National Survey of Cancer Care Providers. AB - The original version of this article contained an error. Citation 17 in the original publication referenced the wrong article. PMID- 30465326 TI - Traumatic Brain Injury and Psychiatric Co-Morbidity in the United States. AB - The objective of the present study was to provide a nationally representative psychiatric epidemiologic investigation of traumatic brain injury (TBI) and its co-morbid conditions. Data from the National Epidemiologic Survey of Alcohol and Related Conditions (NESARC-III) collected between 2012 and 2013 was used. Results indicated that TBI was significantly associated with any lifetime mental health (AOR = 2.32, 95% CI = 1.65-3.70), substance use disorder (AOR = 1.57-1.01-2.42), and violent (AOR = 1.65, 95% CI = 1.03-2.65) and nonviolent (AOR = 1.84, 95% CI = 1.25-2.70) criminal behaviors. In our study, TBI was highly comorbid with psychiatric disorders and especially antisocial behaviors, both violent and non violent. PMID- 30465327 TI - Dialysis drains as a possible source for carbapenem-resistant pathogens causing an ICU outbreak. AB - OBJECTIVE DESIGN: We describe a case series of patients colonized with KPC producing Enterobacteriaceae related to dialysis drains at patient's bedside. SETTING: The study was set at the intensive care unit (ICU) of a tertiary referral hospital. PATIENTS: In March 2016, we discovered four ICU patients to be colonized with KPC-producing Enterobacteriaceae in routine screening. All of these patients had already received contact isolation, and all of them were treated with continuous veno-venous dialysis. Environmental examinations showed KPC-producing Enterobacteriaceae in dialysis drains in different ICU rooms and even in rooms not hosting KPC-colonized patients. INTERVENTIONS: Based on our findings, we suspected the dialysis drains as a reservoir of KPC-producing Enterobacteriaceae with a potential risk for the patients. Therefore, we decided to change the dialysis waste management. RESULTS: As a result, no KCP-producing Enterobacteriaceae were detected during the following weekly screening of the patients. CONCLUSIONS: Installation of dialysis connection units including a drain system at the patient's bedside is a comfortable way to provide water supply. In many ICUs, such dialysis drains are installed near the patients' head and directly besides the infusion systems. When the drains are not used properly, in our opinion, they pose a risk of transmission of pathogens from the drain to the patient. Our findings support the need of specific precautions. PMID- 30465328 TI - From Analysis of Ischemic Mouse Brain Proteome to Identification of Human Serum Clusterin as a Potential Biomarker for Severity of Acute Ischemic Stroke. AB - Ischemic stroke is a devastating neurological disease that can cause permanent brain damage, but to date, few biomarkers are available to reliably assess the severity of injury during acute onset. In this study, quantitative proteomic analysis of ischemic mouse brain detected the increase in expression levels of clusterin (CLU) and cystatin C (CST3). Since CLU is a secretary protein, serum samples (n = 70) were obtained from acute ischemic stroke (AIS) patients within 24 h of stroke onset and together with 70 matched health controls. Analysis of CLU levels indicated significantly higher levels in AIS patients than healthy controls (14.91 +/- 4.03 vs. 12.79 +/- 2.22 ng/L; P = 0.0004). Analysis of serum CST3 also showed significant increase in AIS patients as compared with healthy controls (0.90 +/- 0.19 vs. 0.84 +/- 0.12 ng/L; P = 0.0064). The serum values of CLU were also positively correlated with the NIH Stroke Scale (NIHSS) scores, the time interval after stroke onset, as well as major stroke risk factors associated with lipid profile. These data demonstrate that elevated levels of serum CLU and CST3 are independently associated with AIS and may serve as peripheral biomarkers to aid clinical assessment of AIS and its severity. This pilot study thus contributes to progress toward preclinical proteomic screening by using animal models and allows translation of results from bench to bedside. PMID- 30465329 TI - Probiotic Supplementation for Prevention of Atopic Dermatitis in Infants and Children: A Systematic Review and Meta-analysis. AB - BACKGROUND: Probiotic supplementation in early life may be effective in preventing atopic dermatitis (AD); however, results regarding efficacy have been controversial. OBJECTIVE: The aim of our study was to investigate the effect of probiotic supplementation on the risk of AD. METHODS: We systematically searched PubMed, EBSCO, Embase and Web of Science databases up to 8 March 2018 for potentially relevant studies regarding probiotic supplementation and AD. Included infants and children were those with probiotic exposure in utero and/or after birth who were not previously diagnosed with AD. We calculated the odds ratios (ORs) and 95% confidence intervals (CIs) and used the Jadad and Newcastle-Ottawa scales to assess methodologic quality. RESULTS: A total of 28 studies met the inclusion criteria. Compared with controls, probiotic treatment was associated with a reduced risk of AD (OR 0.69; 95% CI 0.58-0.82, P < 0.0001). The use of probiotics during both the prenatal and the postnatal period significantly reduced the incidence of AD (OR 0.67; 95% CI 0.54-0.82); however, analysis of studies of probiotics given prenatally only or postnatally only did not reach statistical significance. CONCLUSIONS: Our meta-analysis showed that probiotic supplementation during both the prenatal and the postnatal period reduced the incidence of AD in infants and children. Our findings suggest that starting probiotic treatment during gestation and continuing through the first 6 months of the infant's life may be of benefit in the prevention of AD. PMID- 30465330 TI - Trigeminal herpes zoster and Ramsay Hunt syndrome in an elderly adult: Presentation with prodromal toothache. AB - OBJECTIVE: This article describes an atypical herpes zoster (HZ) infection heralded by prodromic dental pain. BACKGROUND: Trigeminal HZ is associated with any of the three divisions of the trigeminal nerve, and Ramsay Hunt syndrome is a rare variant of HZ infection of the ear, often accompanied with unilateral facial nerve palsy. MATERIALS AND METHODS: An 87-year-old man sought remedy for tooth like pain. Within a week, he developed cutaneous, intraoral and otic eruptions, hearing loss, and mild facial palsy. RESULTS: After ruling out odontogenic pain, he was diagnosed with trigeminal HZ and Ramsay Hunt syndrome. CONCLUSION: Herpes zoster infection should be included as a possible aetiologic factor with atypical presentations of odontogenic pain. Diagnosis of trigeminal HZ infection and the Ramsay Hunt syndrome may lead to timely intervention with antivirals and improved patient outcomes. PMID- 30465331 TI - Metrics of progress in the understanding and management of threats to Australian birds. AB - Although evidence-based approaches have become commonplace for determining the success of conservation measures for the management of threatened taxa, there are no standard metrics for assessing progress in research or management. We developed 5 metrics to meet this need for threatened taxa and to quantify the need for further action and effective alleviation of threats. These metrics (research need, research achievement, management need, management achievement, and percent threat reduction) can be aggregated to examine trends for an individual taxon or for threats across multiple taxa. We tested the utility of these metrics by applying them to Australian threatened birds, which appears to be the first time that progress in research and management of threats has been assessed for all threatened taxa in a faunal group at a continental scale. Some research has been conducted on nearly three-quarters of known threats to taxa, and there is a clear understanding of how to alleviate nearly half of the threats with the highest impact. Some management has been attempted on nearly half the threats. Management outcomes ranged from successful trials to complete mitigation of the threat, including for one-third of high-impact threats. Progress in both research and management tended to be greater for taxa that were monitored or occurred on oceanic islands. Predation by cats had the highest potential threat score. However, there has been some success reducing the impact of cat predation, so climate change (particularly drought), now poses the greatest threat to Australian threatened birds. Our results demonstrate the potential for the proposed metrics to encapsulate the major trends in research and management of both threats and threatened taxa and provide a basis for international comparisons of evidence-based conservation science. PMID- 30465332 TI - Care of Women with Obesity in Pregnancy: Green-top Guideline No. 72. PMID- 30465333 TI - Time to Full Enteral Feeding for Very Low-Birth-Weight Infants Varies Markedly Among Hospitals Worldwide But May Not Be Associated With Incidence of Necrotizing Enterocolitis: The NEOMUNE-NeoNutriNet Cohort Study. AB - BACKGROUND: Transition to enteral feeding is difficult for very low-birth-weight (VLBW; <=1500 g) infants, and optimal nutrition is important for clinical outcomes. METHOD: Data on feeding practices and short-term clinical outcomes (growth, necrotizing enterocolitis [NEC], mortality) in VLBW infants were collected from 13 neonatal intensive care units (NICUs) in 5 continents (n = 2947). Specifically, 5 NICUs in Guangdong province in China (GD), mainly using formula feeding and slow feeding advancement (n = 1366), were compared with the remaining NICUs (non-GD, n = 1581, Oceania, Europe, United States, Taiwan, Africa) using mainly human milk with faster advancement rates. RESULTS: Across NICUs, large differences were observed for time to reach full enteral feeding (TFF; 8-33 days), weight gain (5.0-14.6 g/kg/day), ?z-scores (-0.54 to -1.64), incidence of NEC (1%-13%), and mortality (1%-18%). Adjusted for gestational age, GD units had longer TFF (26 vs 11 days), lower weight gain (8.7 vs 10.9 g/kg/day), and more days on antibiotics (17 vs 11 days; all P < .001) than non-GD units, but NEC incidence and mortality were similar. CONCLUSION: Feeding practices for VLBW infants vary markedly around the world. Use of formula and long TFF in South China was associated with more use of antibiotics and slower weight gain, but apparently not with more NEC or higher mortality. Both infant- and hospital-related factors influence feeding practices for preterm infants. Multicenter, randomized controlled trials are required to identify the optimal feeding strategy during the first weeks of life. PMID- 30465334 TI - Postnatal condition of the second twin in respect to mode of delivery, chorionicity and type of fetal growth. AB - BACKGROUND: The increased use of assisted reproductive techniques (ART) contributes to the increased rate of twin pregnancies, which are burdened with a higher risk of complications. Factors that affect the condition of the second twin are understudied. OBJECTIVES: The objective of this study was to assess the impact of the delivery mode, chorionicity, amnionicity, and the type of fetal growth on the postnatal condition of the second twin. MATERIAL AND METHODS: The study included data from 475 pregnant women with twin pregnancies. Maternal age, parity, chorionicity, amnionicity, type of fetal growth, mode of delivery, gestational weeks at delivery, Apgar score, and umbilical arterial blood pH were retrospectively analyzed. Data normality was checked with the Kolmogorov-Smirnov test. The paired Wilcoxon signed-rank test and chi2 test were used for comparisons between groups. To check predictive value of the analyzed variables multiple linear regression was used. RESULTS: The mean maternal age was 29.22 (standard deviation (SD) +/-5.19) years. The maternal age and gestational age at delivery did not differ significantly between women who delivered by cesarean section (CS) and vaginal delivery (VD). In the second twin, the Apgar score and values of arterial umbilical blood pH were lower in infants delivered by VD than in those delivered by CS (6.30 +/-2.83 and 7.30 +/-0.12; p = 0.0209 and 7.26 +/ 0.12 and 7.30 +/-0.11; p = 0.0236, respectively). In monochorionic diamniotic twins with asymmetric growth, the second twin achieved significantly lower outcome than the first twin. Vaginal delivery was a predictive factor for a lower Apgar score and lower values of umbilical arterial blood pH in second twins, while not in first twins. Symmetrical fetal growth of twins was a predictive factor for better postnatal condition for both twins. CONCLUSIONS: In twin pregnancies, VD, but not CS, is associated with increased risk of worse postnatal condition of the second twin. In monochorionic diamniotic pregnancies complicated by growth discordance, CS seems to be a reasonable mode of delivery. PMID- 30465335 TI - Calophyllum inophyllum in vaginitis treatment: Stimulated by electroporation with an in vitro approach. AB - BACKGROUND: Vaginitis is one of the most common problems in clinical medicine and is cited most often during visits to obstetricians and gynecologists. Most of the inflammation cases are caused by candidiasis trichomoniasis and bacterial vaginosis. Therefore, treatment of vaginal infections must use antibiotic or antifungal drugs, which often provide quick relief to the patient. The real cause of the problem - disrupting the ecosystem of the vagina - remains unchanged. Thus, new therapeutic compounds are being explored. OBJECTIVES: The aim of our study was to evaluate the effect of a natural substance: tamanu oil, an extract from the plant Calophyllum inophyllum, applied to the human fibroblast cell line (normal human dermal fibroblasts - NHDFs) and to the isolated human fibroblasts from the vagina (human vaginal fibroblasts - HVFs) in vitro. MATERIAL AND METHODS: We evaluated the viability of cells by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assay after incubation only with tamanu oil and with electroporation (EP). We also examined the immunocytochemical reaction of collagen type III and mitochondrial superoxide dismutase (MnSOD) under established conditions. RESULTS: Tamanu oil increased the proliferation of cells and the amount of collagen III. It has been shown that the C. inophyllum extract stimulates the proliferation of commercial fibroblasts. For direct application in patients, one should use C. inophyllum extract in the range of 1:10-1:100 (saline dilution). CONCLUSIONS: The use of this extract (at concentrations indicated by the studies presented here) stimulates the healing processes (increased expression of collagen type III), and has anti-inflammatory, analgesic and antiseptic qualities. PMID- 30465336 TI - [Oral health management for children]. AB - Pediatric dentistry should focus not only on the treatment of various oral diseases during the entire growth and development of children but also on the early prevention, diagnosis, and intervention of various oral diseases in this process. Early identification and removal of risk factors or early intervention for common oral diseases is necessary to the implementation of oral health management for pregnant women, infants, preschool and school-age children, and adolescents with different general and oral physiological characteristics and common oral diseases. The treatment enables the growth and development of the teeth, as well as occlusion and facials along the normal trajectory, ultimately achieving the functional perfection and aesthetic coordination of the cranio maxillary and occlusion. PMID- 30465337 TI - [Current situation and strategy on perforation repair]. AB - Perforations are common complications of root canal therapy. In clinic, perforations that were improperly and untimely repaired can seriously affect the prognosis of teeth after root canal treatment. At present, the status of perforation repair in our country is worrisome. This paper focused on the progress of perforation repair in the country by discussing the current situation of repair methods and materials. This review aims to improve knowledge and aid clinical doctors in the sophistication of perforation repair in order to improve the retention rate of root-canal-treated teeth. PMID- 30465338 TI - [Expression of triggering receptors expressed by myeloid cells-1 in macrophages stimulated by Porphyromonas gingivalis-lipopolysaccharide]. AB - OBJECTIVE: Soluble triggering receptors expressed by myeloid cells-1 (sTREM-1) and inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in macrophage cells were stimulated by Porphyromonas gingivalis-lipopolysaccharide (Pg-LPS) to investigate the expression of triggering receptors expressed by myeloid cells-1 (TREM-1) and further explore the correlation between TREM-1 and the pathogenesis of periodontitis. METHODS: THP-1 cells (a human monocytic cell line derived from an acute monocytic leukemia patient) were induced to differentiate THP-1 macrophages by phorbol-12-myristate-13-acetate and were injected with 0 (blank control), 0.5, or 1.0 MUg.mL-1 Pg-LPS. The THP-1 cells were then grouped in accordance with incubation time, and each group was incubated for 4, 6, 12, or 24 h. The expression of the TREM-1 mRNA in macrophages was detected by real-time quantitative polymerase chain reaction, while the expression of TREM-1 protein was detected by Western blot; the site where TREM-1 protein expression was observed in macrophages was detected by immunofluorescence staining, and the expression of soluble sTREM-1 and TNF-alpha in cell culture medium was detected by enzyme-linked immunosorbent assay. RESULTS: Compared with the blank control group, the expression of TREM-1 mRNA, TREM-1 protein, and sTREM-1 in Pg-LPS stimulated macrophages was significantly upregulated (P<0.05). The expression of TREM-1 mRNA, TREM-1 protein, and sTREM-1 in the supernatant of cell culture was higher in the 1.0 MUg.mL-1 Pg-LPS group than in the 0.5 MUg.mL-1 group; this expression was statistically significant since the 6, 4, and 4 h time point (P<0.05). Cell immunofluorescence staining showed that TREM-1 protein was positive when the THP-1 macrophages was stimulated by Pg-LPS (1.0 MUg.mL-1) for 24 h, and the staining sites of TREM-1 were mainly located in the cell membrane of the macrophages (P<0.05). The expression level of TNF-alpha increased in groups stimulated by Pg-LPS, and the expression level of TNF-alpha was significantly higher in 1.0 MUg.mL-1 Pg-LPS stimulated groups than in 0.5 MUg.mL 1 Pg-LPS-stimulated groups since the 6 h time point (P<0.05). The expressions of TREM-1 mRNA, TREM-1 protein, and sTREM-1 in 0.5 MUg.mL-1 Pg-LPS-stimulated macrophages were positively correlated with one another (r=1, P<0.05), but no statistically significant correlation was found in the expression of TNF-alpha. The positive correlation between sTREM-1 and TNF-alpha expressions was detected when macrophages were stimulated by 1.0 MUg.mL-1 Pg-LPS (r=1, P<0.05). CONCLUSIONS: The expression of TREM-1 mRNA, TREM-1 protein, and sTREM-1 in the culture supernatant in Pg-LPS-stimulated macrophages was significantly upregulated on the basis of the concentration of Pg-LPS; moreover, their upregulation was positively correlated with one another. The expression of TNF alpha in the supernatant of cell culture was also upregulated and was positively correlated with the expression of sTREM-1 at the group of high Pg-LPS concentration (1.0 MUg.mL-1). Results reveal that TREM-1, which has been realized as a proinflammatory receptor protein, can promote the development of periodontitis by regulating the expression of TNF-alpha in macrophages. PMID- 30465339 TI - [Effects of bond strength evaluation on different durations of adult permanent teeth and youth permanent teeth by using universal adhesives to dentin]. AB - OBJECTIVE: To compare the dentin bonding strength evaluation between adult permanent teeth and youth permanent teeth after treatment for different durations by universal adhesives. METHODS: Ten adult permanent teeth and ten youth permanent teeth were selected for this study. The occlusal enamel layer was removed, and each tooth was cut into three pieces along the long axis. In total, 30 pieces of adult and youth teeth were prepared. The adult and youth teeth pieces were randomly divided into three groups and treated by universal adhesives for 10, 20, and 30 s. In this study, Scotchbond Universal (SBU) was selected as the universal adhesive. Slabs were treated by dual-cure resin cements. The specimens were tested by microshear strength test through a universal testing machine. Fracture modes were observed by a stereomicroscope. Other adult teeth and youth teeth were selected, two for each type, and treated and grouped in the same manner. Fluorescein (0.1% Rhodamine B) was dissolved in SBU adhesive, and the specimens were treated by the adhesives for 10, 20, and 30 s. Micromorphology of the resin protrusions on the adhesive surface was observed by laser confocal microscopy (CLSM). RESULTS: For the adult teeth, the highest micro-shear bonding strength was observed in the 20 and 30 s groups, and the values were higher than that of the 10 s group (P<0.05). For the youth teeth, the highest micro-shear bonding strength was observed in the 10 and 20 s groups, and the values were higher than that of the 30 s group (P<0.05). The micro-shear bonding strength in the 10 s youth teeth group was higher than that of the 10 s adult teeth (P<0.05) and was same as the adult teeth treated for 20 s (recommendation time of material instructions) (P>0.05). The main break patterns in different groups comprised adhesive failure fractures and several mixed failure fractures. No resin fracture mode was observed. CLSM revealed very few short resin protrusions in 10 s adult teeth group, whereas the number and length of resin protrusions significantly increased in the 20 s adult teeth group. The resin protrusions of the 30 s group were shorter than those of the 20 s adult teeth group. In different durations, the bonding interface in different youth teeth groups presented the same trend of change as the adult teeth. However, the number and length of resin protrusions in the 10 s group of youth teeth were all higher than those of the 10 s adult teeth group. CONCLUSIONS: In clinical practice, the bonding agent treatment duration shall be shortened appropriately for youth permanent teeth, and that for adult permanent teeth shall not be shortened to less than 20 s. On the whole, the bond strength of youth permanent teeth can achieve no significant difference with the adult permanent teeth. PMID- 30465340 TI - [Comparison of stripping of steep sheep maxillary sinus mucosal with new-type memory elastic silk sleeve stripper and umbrella stripper]. AB - OBJECTIVE: This work aims to investigate the effect of stripping of steep sheep maxillary sinus by using 0.012 or 0.014 model new-type memory elastic silk sleeve stripper and umbrella stripper. METHODS: Goats with sinus floor gradients of 60 degrees to 90 degrees were selected by computed tomography of sheep head. A total of 72 animal models were established and randomized into three groups (n=24): group A (0.012 model), B (0.014 model) and C (umbrella stripper). Alveolar and maxillary sinus mucosa were stripped after crowning, and stripping length was measured when the stripping limit was reached or mucosal perforation occurred. RESULTS: The average stripping length of mucosa in group A was 11.3 mm+/-4.6 mm, and three cases experienced perforation of sinus floor mucosa. The average stripping length of mucosa in group B was 17.5 mm+/-5.0 mm, and one case experienced perforation of sinus floor mucosa. The average stripping length of mucosa in group C was 4.2 mm+/-1.3 mm, and four cases experienced perforation of sinus floor mucosa. The difference among the three groups was statistically significant (P<0.01) according to variance analysis. Moreover, the comparison between any two means was also statistically significant according to Dunnett's T3 test (P<0.05). CONCLUSIONS: The new-type memory elastic silk sleeve stripper effectively stripped steep maxillary sinus mucosa. The 0.014 model exhibited superior peeling effect and was relatively safe. PMID- 30465341 TI - [Three-year retrospective clinical evaluation of pulp-less molars with defects of varying degree repaired by cast ceramic onlays of three marginal types]. AB - OBJECTIVE: This study aimed to evaluate the clinical effect of pulp-less molars with defects of different degrees repaired by cast ceramic onlays of three marginal types. METHODS: A total of 165 endodontically treated molars of 105 patients were included in this study and were divided into three kinds of defect (mild, moderate, severe) according to the number of remaining axial walls. Each defect was divided into three groups according to the shape of edge to edge, bevel edge, and concave shoulder. After tooth preparation, the casting of ceramic onlays was performed. Treatment follow-up was done for the evaluation of the success and survival rates of three groups under the same defect. RESULTS: The average follow-up was 925.44 days. Under the mild defect, the success and survival rates of the edge to edge onlays were respectively 100% and 100%; bevel edge onlays, 100% and 100%; and concave shoulder onlays, 94.4% and 100%. Under the moderate defect, the success and survival rates of the edge to edge onlays were respectively 96.0% and 100%; bevel edge onlays, 80.0% and 93.3%; and concave shoulder onlays, 95.2% and 95.2%. Under the severe defect, the success and survival rates of the edge to edge onlays were respectively 95.2% and 100%; bevel edge onlays, 73.7% and 89.5%; and concave shoulder onlays, 73.3% and 80.0%. Under different defects, the success or survival rates of the three kinds of onlays had no significant difference (P>0.05). CONCLUSIONS: The edge to edge type is the most preferable way of onlay tooth preparation and can achieve good clinical results in the mild, middle, and severe tooth defection with root canal treatment. PMID- 30465342 TI - [Radiological characteristics of the cyst-like lesion of condyle in temporomandibular joint by cone beam computed tomography]. AB - OBJECTIVE: To analyze the radiological characteristics and classifications of the cyst-like lesion of condyle in temporomandibular joint (TMJ) by cone beam computed tomography (CBCT). METHODS: The study was conducted retrospectively on TMJ images from 194 patients who underwent CBCT examinations. Location, size, amount, surrounding bone trabecula, cortical bone white line of cyst-like lesion, and the overall condition of the condylar bone were evaluated. According to the overall condition of the condylar bone, the cyst-like lesion of condyle were divided into typesIand II. The location, size, amount, surrounding bone trabecula, and cortical bone white line of the two types of cyst-like lesions were compared. RESULTS: In 198 condylars of 194 patients, cyst-like lesions were detected in the left side of 94 patients, in the right of 96 patients, and in both sides of 4 patients. The size of lesions ranged from 1.2 mm to 13.5 mm, with an average size of (3.4+/-1.5) mm. Half of the cyst-like lesions were located underneath the anterior lateral cortical bony layer (99 condylars, 50.0%). Most cyst-like lesions were solitary (149 condylars, 75.3%), while 62.6% (124 condylars) were surrounded by continuous bony white lines. Bone sclerosis could be observed in 160 condylars (80.8%). A total of 132 condyles (66.7%) were accompanied by changes in late-stage osteoarthrosis, while the others were only accompanied by early-stage osteoarthrosis (10 osteoarthrosis, 5.1%) or showed no evidence of osteoarthrosis (56 osteoarthrosis, 28.3%). Statistical difference were observed in the location, amount, and surrounding bone trabecula of the two types of cyst-like lesions. TypeIcyst-like lesions had more frequent and bone sclerosis than type II, whereas type II cyst-like lesions occurred more on condylar internal or condyle neck than typeI. CONCLUSIONS: The pathogenesis and mechanism of the two types of cyst-like lesions may be different from each other. PMID- 30465343 TI - [Associations among PRDM16 polymorphisms, environmental exposure factors during mother's pregnancy, and nonsyndromic cleft lip with or without cleft palate]. AB - OBJECTIVE: We aimed to study the association between rs7525173, rs2236518, rs2493264 single nucleotide polymorphism (SNP) in the PRDM16 gene, smoking, alcohol exposures, and nonsyndromic cleft lip with or without cleft palate (NSCL/P). METHODS: A total of 157 case-parent trios were selected, and SNPs were genotyped by using ligase detection reaction (LDR) and direct sequencing methods. Transmission disequilibrium test (TDT) and linkage disequilibrium (LD) tests were con-ducted to analyze the data. A total of 1 710 patients with orofacial clefts and 956 healthy newborns were enrolled in the epidemiological survey. The smoking and drinking exposures of parents during early pregnancy were analyzed. RESULTS: The C allele at rs2236518 was over-transmitted for NSCPO (P<0.05). Statistical differences were observed among three factors, namely, maternal smoking, maternal passive smoking, and maternal drinking (P<0.05). CONCLUSIONS: The rs2236518 at PRDM16 gene, maternal smoking, maternal passive smoking, and maternal drinking were closely related to the occurrence of NSCL/P. PMID- 30465344 TI - [Saliva of periodontitis patients promotes macrophage differentiation and activation]. AB - OBJECTIVE: The aim of this study was to investigate the effect of saliva of patients with chronic periodontitis (CPD) on the differentiation, activation, and secretion of osteoclast-maturing mediators of macrophages. METHODS: A total of 40 saliva samples were collected from healthy donors (n=20) and severe periodontitis patients (n=20). Peripheral blood mononuclear cells (PBMCs) and THP-1 monocyte line cells were challenged with 15% saliva for 5 days. The phenotype, surface marker, and phagocytosis of macrophages were analyzed by flow cytometry and microscopy. Osteoclast-maturing mediators were assayed by using enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: When PBMCs were treated with CPD saliva for 5 days, 61.25%+/-11.33% of cells were transformed into large granular cells; 86.78%+/-13.69% of large granular cells were identified as CD14++CD16+ macrophages. When THP-1 cells were treated with CPD saliva, most cells attached to the bottom of cell culture plates, thereby exhibiting macrophage morphology and releasing additional osteoclast-maturing mediators. Furthermore, the phagocytosis of THP-1 cells considerably increased in the presence of CPD saliva (66.35%+/-9.67%) compared with medium control (33.33%+/-7.52%), or healthy saliva (40.71%+/-3.52%). CONCLUSIONS: Saliva from patients with CPD can induce macrophage differentiation, activate phagocytose microorganisms, and secrete osteoclast-maturing mediators. PMID- 30465345 TI - [Impacts of periodontitis on visceral organ weight and weight percentage in obese mice]. AB - OBJECTIVE: This study aimed to explore the impacts of periodontitis on the visceral weight and weight percentage of obese animal models. METHODS: A total of 64 C57BL/6J mice were divided into the following diet groups: high-fat diet (HFD) group (n=36), which was fed with high-fat diet to induce obesity, and low-fat diet (LFD) group (n=28), which was fed with low-fat diet as the control. After 16 weeks on diet, each diet group was divided into periodontitis (P) and control (C) groups. The P groups were induced for periodontitis by ligation with Porphyromonas gingivalis-adhered silk for 5 or 10 days, and the C groups were sham-ligated as the control. Visceral organs were resected and weighed. The organ weight percentage was calculated. RESULTS: Compared with the LFD group, the HFD group significantly upregulated the weight and weight percentage of visceral adipose tissue and spleen (P<0.05), upregulated the weight of liver and kidney (P<0.05), and downregulated the weight percentage of liver and kidney (P<0.01). In the HFD group, the weight and weight percentage of spleen were downregulated in the P group (P<0.05), but were upregulated in the 10-day group compared with the 5-day group (P<0.05). CONCLUSIONS: Periodontitis can affect the general morphology of the viscera (especially spleen) in obese animal models. Pathological indications in terms of immunometabolism might be present in the correlation between obesity and periodontitis. PMID- 30465346 TI - [Effect of water immersion on a dental self-healing and antibacterial resin composite]. AB - OBJECTIVE: This investigation aimed to develop a novel self-healing and antibacterial dental resin composite. The effects of water immersion on its properties were also evaluated. METHODS: Microcapsules filled with healing agent of triethylene glycol dimethacrylate were synthesized on the basis of previous studies. Antibacterial resin composite contained nano-antibacterial inorganic fillers that were modified by quaternary ammonium salt with long-chain alkyl. Microcapsules were incorporated into antibacterial resin composite at mass fraction of 7.5%. A commercial resin composite named Tetric N-Ceram was used as control. The resin samples were immersed in 37 degrees C distilled water for different periods. A flexural test was used to measure the mechanical properties of the novel resin composite. A single-edge V-notched beam method was used to measure fracture toughness and self-healing efficiency. A dental plaque microcosm biofilm model with human saliva as inoculum was formed. Colony-forming units (CFU) and lactic acid production of biofilm on the novel resin composite were calculated to test the antibacterial property. RESULTS: Mechanical properties and fracture toughness decreased significantly after the composite was immersed in water for 30 days (P<0.05), and no significant reduction was found from then on (P>0.05). Water immersion did not weaken the self-healing capability of the composite (P>0.05), and self-healing efficiency of 64% could still be obtained even after 270 days. The antibacterial resin composite showed a strong inhibition effect on the biofilm metabolic activity versus water immersion time from 1 day to 270 days. Therefore, the composite could still have a promising antibacterial property even after being immersed in water (P<0.05). CONCLUSIONS: Water immersion could weaken the mechanical properties of the novel self-healing and antibacterial resin composite, but it insignificantly affected the self-healing and antibacterial properties of the composite. PMID- 30465347 TI - [Effects of body-shade resin layer thickness on the color of polyetheretherketone Crea.lign restorations]. AB - OBJECTIVE: This study aims to assess the effects of the different thicknesses of body-shade resin layers on the color of polyetheretherketone (PEEK)-Crea.lign restorations. METHODS: Five PEEK specimens with the thickness of 0.6 mm were prepared. The color values of PEEK specimens were measured. Afterward, opaque shade resin layers (0.1 mm) and body-shade resin layers (1.5 mm) were stacked with mold. The five specimens were evenly ground to a thickness of 1.4, 1.2, 1.0, 0.8, 0.6, 0.4, 0.2, and 0.0 mm in sequence. After grinding and ultrasonic cleaning, the color value was measured. RESULTS: With the constant thickness of PEEK and 0.1 mm thickness of opaque-shade resin layer, the L*, a*, and b* values all showed downward trend with the increased thickness of the body-shade resin layer (1.0-1.4 mm). With the constant thickness of PEEK and 0.1 mm thickness of opaque-shade resin layer, the color difference between the adjacent groups was less than 1.5 NBS. This difference between nonadjacent groups was more than 1.5 NBS when the thickness of the body-shade resin layer reached 0.6 mm. Color difference between PEEK-Crea.lign restoration and PEEK was more than 1.5 NBS. CONCLUSIONS: The thickness change in the body-shade resin layers influence the color of the PEEK-Crea.lign restorations. Using A2 shade Crea.lign, opaque-shade resin layer thickness is 0.1 and 0.6 mm thickness of body-shade resin layer can produce color which clinically acceptable. PMID- 30465348 TI - [Selective laser sintering and performances of porous titanium implants]. AB - OBJECTIVE: This work aims to analyze the mechanical properties and biocompatibility of porous titanium (Ti) implants fabricated by selective laser sintering (SLS) and investigate the promotion of osseointegration by porous titanium implant combined with chitosan (CS)/hydroxyapatite(HA) composite coating. METHODS: Ti6Al4V specimens were prepared, and CS/HA composite coating was fabricated on the surface of a portion of the specimens. The mechanical properties of the samples were observed by scanning electron microscope. MC3T3-E1 cells were cultured in vitro, and their biological properties in vitro were analyzed using live and dead viability cell staining method, methyl thiazolyl tetrazolium (MTT) staining, and alkaline phosphatase (ALP) level detection. The thread implant specimens were implanted in the femoral condyle of rabbits, and biological performance was evaluated in vivo. RESULTS: Quasi-elastic gradient of porous specimens decreased with increasing porosity, and the quasi-elastic gradient were close to cortical and cancellous bone when the porosities were 30% and 70%. The specimens showed good biocompatibility. Combined with CS/HA coating, the implants promoted the proliferation and differentiation of MC3T3-E1 cells and facilitated the entry of bone tissue into pores and good osteogenesis. CONCLUSIONS: The porous titanium implant exhibited favorable mechanical properties and biocompatibility. Combined with CS/HA coating, the implant exhibited bone inducibility, which leads to stable osteogenesis. PMID- 30465349 TI - [Effect of different sandblasting conditions on the metal-ceramic bonding strength of Co-Cr alloy fabricated by selective laser melting technology]. AB - OBJECTIVE: To investigate the effect of different sandblasting conditions on the metal-ceramic bonding strength of Co-Cr alloy fabricated by selective laser melting (SLM) technology. METHODS: A total of 63 specimens of Co-Cr alloy fabricated by SLM were prepared and randomly divided into nine groups (n=7). Each group was treated with different powder particles (A1=50 um, A2=100 um, and A3=150 um) and pressures (B1=0.2 MPa, B2=0.4 MPa, and B3=0.6 MPa) in sandblasting. One sample was randomly selected from each group for microstructure observation by scanning electron microscope (SEM). Ceramic was fired at the center of the specimens. Metal-ceramic bonding strength was measured with universal testing machine. Results were statistically analyzed with SPSS 17.0 software. RESULTS: The mean bond strengths were as follows: Group A1B1: 27.22 MPa+/-0.95 MPa, Group A1B2: 27.58 MPa+/-0.47 MPa, Group A1B3: 26.80 MPa+/-0.71 MPa, Group A2B1: 27.54 MPa+/-0.78 MPa, Group A2B2: 30.75 MPa+/-0.43 MPa, Group A2B3: 26.93 MPa+/-0.88 MPa, Group A3B1: 28.18 MPa+/-0.93 MPa, Group A3B2: 29.55 MPa+/-0.57 MPa, and Group A3B3: 28.11 MPa+/-0.91 MPa. The particle factor of Al2O3 and the pressure factor of blasting showed statistical significance (P<0.05). An interaction was observed between the factors of particle and pressure (P<0.05). Mixed fracture mode of all specimens was observed after the shear strength test. CONCLUSIONS: In conclusion, metal-ceramic bonding strength reaches the maximum when specimens are sandblasted with 100 um alumina oxide at 0.4 MPa pressure. PMID- 30465350 TI - [Invasion and metastasis mechanism of human papillomavirus in head and neck squamous cell carcinomas]. AB - Human papillomavirus (HPV) is a major causative agent of head and neck squamous cell carcinomas (HNSCC). Over the past several decades, an increasing number of studies established the strong association of HPV with the invasion and metastasis of HNSCC. In the present study, we reviewed the gene mutations in HPV associated HNSCC and the unique mechanism of E6- and E7-mediated carcinogenesis via interactions with an array of cellular elements. We further discussed the progress in the mechanisms of invasion and metastasis; these mechanisms include non-coding RNAs, deregulating cellular energetics, tumor microenvironment, cancer stem cells, angiogenesis, and lymphangiogenesis. PMID- 30465351 TI - [Development and homeostasis of taste buds in mammals]. AB - Taste is mediated by multicellular taste buds distributed throughout the oral and pharyngeal cavities. The taste buds can detect five basic tastes: sour, sweet, bitter, salty and umami, allowing mammals to select nutritious foods and avoid the ingestion of toxic and rotten foods. Once developed, the taste buds undergo continuous renewal throughout the adult life. In the past decade, significant progress has been achived in delineating the cellular and molecular mechanisms governing taste buds development and homeostasis. With this knowledges and in depth investigations in the future, we can achieve the precise management of taste dysfunctions such as dysgeusia and ageusia. PMID- 30465352 TI - [The role of bone morphogenetic protein signaling pathway in tooth root development]. AB - The bone morphogenetic protein (BMP) family is an important factor in the regulation of cell ular life activities and in the development of almost all tissues. BMP-mediated signaling plays an important role in tooth root development, which is a part of tooth development. Epithelial and mesenchymal interactions are involved in tooth root development, but the BMP signaling pathway has a different effect on tooth root development in epithelial and mesenchymal. This review summarizes the advances of BMP signaling in tooth root development. PMID- 30465353 TI - [Prevention of infectious diseases through microecology modulation techniques]. AB - The microbe is small in volume, but large in quantity and species. The symbiotic microbe, which is far more than human cells, code millions times of genes than human being. Somatic cells and these symbiotic microbe distributing in human body skin, respiratory tract, oral cavity and gastrointestinal tract, urinary tract and other parts form a complex ecosystem whose dynamic balance is highly related to body health. With the successful implementation of Human Microbiome Project, more attentions have been paid to the next generation microbiome technologies. New tools and methods for ecological regulation of human microbiome are emerging. The way we improve the world of human microbiology will be more convenient. This paper will make a review on the modulation techniques of human microbiome. PMID- 30465354 TI - [Progress on medication-related osteonecrosis of the jaw]. AB - Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of bisphosphonates (BPs) or other targeted agent therapies. MRONJ appears as exposed bone, pus, and swelling in the oral and maxillofacial regions. However, neither surgery nor conservative therapy can eliminate symptoms thoroughly. In addition to BPs, several antiresorptive and antiangiogenic agents, such as denosumab and bevacizumab, as well as targeted agents, such as sunitinib and temsirolimus, can cause osteonecrosis of the jaw according to the literature. This review aims to summarize the research progress on these new drugs. PMID- 30465355 TI - [Primary acinic cell carcinoma in mandible: a case report]. AB - Acinic cell carcinoma is a relatively rare salivary gland tumor predominantly occurring in the major glands. Therefore, acinic cell carcinoma rarely occurs in the mandible. In this study, a case of primary acinic cell carcinoma of the mandible was reported, and relevant literature was reviewed. The etiology, clinical symptom, image and histological features, diagnosis, treatment, and prognosis of acinic cell carcinoma in the mandible were discussed. PMID- 30465356 TI - [Mandibular first molar with C-shaped root canal system: a two-case report]. AB - The root and canal anatomy of the mandibular first molar is highly complicated. A mandibular first molar with a C-shaped root canal system is rare. This article describes two different cases of this system. Case 1 has a complete C-shaped fused root. The root canal is characterized by a mesial lingual root canal and a C-shaped fused root canal. Case 2 has a C-shaped fused root in the buccal region and a distal lingual root. The root canal is characterized by a type II-Iroot canal in the buccal region and a distal lingual root canal. PMID- 30465357 TI - A good diet means less medicine - but is that enough? PMID- 30465358 TI - Comparison Of Two Intracanal Medicaments In Resolution Of Apical Radiolucency. AB - Background: As a gold standard, calcium hydroxide has always been used as a root canal medicament against root canal pathogens but its combination with chlorhexidine is not being employed in routine despite its documented efficacy and results. The objective of the study is to compare calcium hydroxide and combination of calcium hydroxide with 2% CHX on the basis of radiographic evidence of resolution of periapical radiolucency when they are used as an interappointment dressing /intracanal medicament for 14 days.. Methods: A total of 60 patients of either gender was included in the study. The age range was 15 60 years with the radiographic evidence of radiolucency of 2-4 mm in size. Both maxillary and mandibular teeth till first molar were selected. Teeth with previous endodontic treatment mentally handicapped and terminally ill patients were excluded. Selected patients were placed randomly into Group 1 (calcium hydroxide alone) and in Group 2 (calcium hydroxide in combination with 2% chlorhexidine gel). Obturation and permanent filling was done at 14th day. The patient was recalled after 90 days of obturation and a radiograph was taken. Final outcome was measured at the end of 90thday of obturation. Results: The mean of percentage reduction in size of apical radiolucency at 3 months was 91.03% for group 1 and 97.26% for group 2 with p-value 0.13 (not significant). The results suggested equivalent results after medication with 2%chlorhexidine with calcium hydroxide but 2% chlorhexidine still showed better results than the group without CHX in terms of healing. Conclusions: This study concluded that calcium hydroxide in combination with 2% chlorhexidene as intracanal medicament results in better resolution of periapical radiolucency in terms of percentage resolution of periapical radiolucency. PMID- 30465359 TI - Role Of Immunohistochemistry In Subtyping Renal Cell Carcinomas With Overlapping Morphological Features. AB - BACKGROUND: Renal cell carcinoma (RCC), accounts for 2-3% of all new cancers diagnosed. Most renal tumours have characteristic histological features, which help in their sub classification. However, some cases do show overlapping morphology which pose a diagnostic challenge for the pathologists. Tumour ancillary studies such as immunohistochemistry (IHC) may play a significant role in segregation of these tumours. This study was undertaken to determine the role of IHC in diagnosing these tumours. METHODS: December 2015. It was carried out in histopathology laboratory of Shifa International Hospital, Islamabad. A total of fifty-five (n=55) nephrectomy specimens having RCC subtypes were included. A specific morphological diagnosis was rendered in each case on H&E.. A panel of six immunohistochemical markers CK7, CD10, CD117, CA IX, AMACR and Vimentin was then applied in each case and a final diagnosis considering both morphology and IHC was given. Statistical analysis was done using SPSS version 20.0. Mean and SD were calculated for quantitative variables where as frequencies and percentages were calculated for qualitative variables. RESULTS: Out of a total of 55 cases, 36 (65.55%) were males whereas 19 (34.5%) were females. The mean age of patients was 54.04+/-14.40 years. Clear cell RCC comprised 70.9% (n=39), Papillary RCC 14.5% (n=8), Chromophobe RCC 10.9% (n=6) and clear cell papillary RCC 3.6% (n=2) of cases on morphology. After application of IHC stains in all cases, 83.6% (n=46) of cases were found to have correct diagnosis on H& E. However, 16.4% (n=9) of cases could not be correctly diagnosed on morphology alone and it was in these cases that IHC played a major role in reaching a final diagnosis. CONCLUSIONS: Although most RCC subtypes display a characteristic morphology on H&E, in a significant proportion of the cases there are considerable overlapping morphological features. Our study shows that a correct diagnosis cannot be made on H & E alone in a notable number of cases. Therefore, IHC should be applied in all cases to reach a final diagnosis, which has both prognostic and therapeutic implications. PMID- 30465360 TI - Comparison Of The Efficacy Of Sildenafil Alone Versus Sildenafil Plus Bosentan In Newborns With Persistent Pulmonary Hypertension. AB - BACKGROUND: Persistent pulmonary hypertension is a serious disease among new borns. Inhaled nitric oxide is first line of therapy along with extracorporeal membrane oxygenation. Pulmonary vasodilators such as sildenafil, bosentan and milrinone are also used to treat persistent pulmonary hypertension especially in resource limited centres where inhaled nitric oxide is not available. The objective of this study was to compare the effect of sildenafil alone and sildenafil with bosentan on severity of tricuspid regurgitation and duration of hospitalization in new-borns with persistent pulmonary hypertension. METHODS: This was single blinded clinical trial conducted at The Children's Hospital & the Institute of Child Health, Multan, Pakistan, from July 2016 to December 2016. New borns with pulmonary hypertension were admitted and divided into two groups. Group A was treated with sildenafil (2mg per kg per dose three times a day) and group B with both sildenafil (2 mg per kg per dose three times a day) and bosentan (1 mg per kg per dose twice a day). RESULTS: There were 50 new-borns in each group. The mean age, sex distribution and baseline TR measurement (mmHg) at the time of admission was similar in both the groups. Measurement of TR (mmHg) after 72 hours admission was significantly less in Group B as compared to group A (11+/-4.62 versus 23+/-4.78), p-value<0.0001. The mean duration of hospital stays (days) was 10.12+/-5.20 in group A and 7.56+/-3.77 in group B (p-value <0.0001). There was no mortality in any group and no case of hypotension in both groups. CONCLUSIONS: The combined use of sildenafil and bosentan is more effective than sildenafil alone for control of pulmonary hypertension in resource limited centres. PMID- 30465361 TI - Do Serum Acute Phase Reactants Predict Clinical Outcome In Emergency General Surgical Admissions? AB - BACKGROUND: Identifying general surgical patients at risk of poor outcome can be a diagnostic challenge. This study aimed to determine the significance of admission serum acute phase reactants in predicting emergency general surgical outcome. METHODS: An electronic database containing all acute general surgical admissions over two years was analysed to correlate admission acute phase reactants (including C-reactive protein (CRP), absolute neutrophil count (ANC) and serum albumin) with outcome. Study endpoints included: cross-sectional imaging, surgery, intensive care admission, in-hospital mortality and length-of stay (LOS). RESULTS: A total of 9738 patients were enrolled in the study. Elevated CRP (n= 4635; 47%) was associated with: advanced imaging 17% vs 30% (p=0.0001), surgery 15% vs 28% (p=0.0001), ITU admission 3% vs 7% (p=0.0001) and mortality 0.5% vs 2% (p=0.0001). A cut-off level of >150 mg/L was most significant. Abnormal ANC (n= 4104; 42%) was significant in predicting advanced imaging 15% vs 55% (p=0.0001), surgery 17% vs 27% (p=0.0001), and ITU admission 3% vs 8% (p=0.0001). Hypoalbuminaemia (n= 1392; 14%) was associated with a 12 fold rise in mortality 0.5% vs 6%. Normal CRP, ANC with hypoalbuminaemia was a strong negative predictor of mortality (0.015% vs 1.24%), while an abnormal combination was associated with mortality of 8%. CONCLUSIONS: Admission acute phase reactants are useful to enhance acute surgical patient stratification during clinical decision making. An admission CRP above 150 should alert the clinician of a potentially high-risk patient who may require prompt intervention. A combination of abnormal results has the highest in-hospital mortality. PMID- 30465362 TI - Morphology Of Bone Marrow In Visceral Leishmaniasis. AB - BACKGROUND: Visceral Leishmaniasis (Kala Azar), a vector borne parasitic disease is endemic in many parts of the world including South East Asia. It is a chronic febrile ailment caused by Leishmania Donovani (LD). More than three hundred million people living in the endemic areas are at high risk and fourteen million are living with the disease. METHODS: This prospective study was conducted on seventy-five patients over a period of twelve years at the department of Pathology Ayub Medical College Abbottabad, focusing on the morphology of bone marrow aspirate obtained from patients. The aspirate was smeared on glass slides, fixed with alcohol and stained with Giemsa stain. The microscopic examination of stained slides was carried out by the single microscopist to avoid the difference of opinion. The initial diagnosis was further confirmed by tow experienced microscopists. RESULTS: A minor difference was observed in the number of male and female participants, 38 versus 37, with male to female ratio of 1.02:1. The majority of the patients were 1- 15 years old. As much as 45.2% patients were 1-5 years old. In this age group, males were affected more than the females with male to female ratio of 1.4:1. Most of the patients belonged to district Battagram and Tor Ghar. Bone marrow aspiration was easy and the marrow aspirate was found having marrow fragments on naked eye examination in majority of the patients. Extrahistiocytic LD bodies alone were seen in 100%, extra and intrahistiocytic in 80% and intrahistiocytic alone in 33.3% patients. The parasite index was 1-5 to 1 10 in 53.4% and 26.6% patients respectively. CONCLUSIONS: Visceral Leishmaniasis is endemic in the study area. Bone marrow examination, although an invasive procedure, gives direct microscopic diagnosis of visceral Leishmaniasis and may be considered where indicated. PMID- 30465363 TI - Medical Complications Of Renal Transplant - 2 Years' Experience At Armed Forces Institute Of Urology. AB - BACKGROUND: Renal transplant is the renal replacement therapy of choice for all patients of chronic kidney disease. The aim of this study was to analyse the trends of medical complications in renal transplant recipients at our centre. METHODS: it is a prospective cross sectional descriptive study. All the patients undergoing renal transplant at Armed Forces Institute of Urology from September 2013 to September 2015 were included in the study. The patients were followed prospectively till March 2016 and a complete data about their complications and lab investigations was maintained.. RESULTS: This study included a total of 63 patients with a mean duration of follow-up of 14.05 months (SD+/-4.45). Infective complications as a group are the commonest complication occurring in over 50% of cases followed by haematological complications (17.5%), new onset diabetes after transplant (15.9%) and transplant dysfunction (14.3%) Cardiovascular complications were seen in only 4.8% cases but with high mortality. Gingival hypertrophy was seen in 4.8% cases. CONCLUSIONS: Medical complications are common after renal transplant especially in the early post-operative period. The only way forward is early recognition and aggressive treatment, as delays can cost losses in the form of kidney function, life and higher health care cost. PMID- 30465364 TI - Reactive Blood Donor Notification; Their Responses And Perceptions: Experience From Southern Pakistan. AB - BACKGROUND: Donor notification of reactive status is important to prevent the spread of disease. Response of reactive donors to seek confirmation and treatment is a direct reflection of their knowledge and attitudes towards transfusion transmittable infections. METHODS: A cross sectional observational study was conducted from August 2014 to July 2015 at the blood bank of a tertiary care hospital, Karachi, Pakistan. Reactive donors' notification and responses were noted with reasons of failure. A cross-sectional analytical survey with non probability purposive sampling was done on 350 potential consenting blood donors using a pre-tested questionnaire to assess their knowledge and attitude about disease awareness, transmission routes, financial implications and disease sensitization. RESULTS: Out of 16660 donations, 5.57% were rejected on positive screening tests. Repeat donors (69.5%) with primary to secondary qualifications constituted the bulk of reactive donors. Donor notification rate were 54.25% whereas 28.68% donors responded to blood bank in person. The survey showed limited awareness about transfusion transmitted infections. Respondents who were ignorant of disease spread through blood transfusion comprised of 48%. 96.6% donors did not know the financial impact of treatment and 69.7% were unable to afford it. Moreover, 94.9% donors were not protected against hepatitis B. Participants with secondary education had significantly less odds of being adequately knowledgeable (OR=0.372, 95% CI: 0.203-0.681, p-value <0.01) but more likely to have a positive attitude. CONCLUSIONS: There is need for structured pre donation counselling to sensitize donors about transfusion related diseases in resource limited countries where treatment costs are high and out of reach for most donors.. PMID- 30465365 TI - Reliability and validity of maxillary and sphenoid Sinus morphological variations in the assessment of Skeletal maturity. AB - BACKGROUND: The present study aimed at assessing the relationship between growth changes in maxillary (MS) and sphenoid sinus (SS) and cervical vertebral maturation (CVM) and to evaluate their reliability and validity in assessing the skeletal maturity of an individual. METHODS: A crosssectional study was conducted on the pretreatment lateral cephalograms of 224 patients (males=116, females=108) aged 8-17 years. MS and SS heights, widths and indices were evaluated. The subjects were classified according to six stages based on CVM using Baccetti's method. Kruskal-Wallis test was applied to compare MS and SS measurements at different cervical stages for each gender. Kappa statistics, positive predictive value, negative predictive value, sensitivity and specificity were calculated to test the diagnostic accuracy of MS and SS indices. RESULTS: The MS and SS indices varied significantly (p<0.001) at different cervical stages for both gender. Kappa statistics showed significant agreement using MS (p<0.001) and SS indices (p<0.05). The diagnostic performance of MS index (Sensitivity >=71%) was found to be better than SS index (Sensitivity >=65%).. CONCLUSIONS: The MS height, width and index in genders and SS height, width and index in males and only SS width and index in females were significantly associated with the CVM stages. The validity of MS and SS indices were comparable for females; whereas, the MS index offers significant advantage over SS index for the assessment of growth status of males. PMID- 30465366 TI - Bladder Cancer In Patients With Type 2 Diabetes Treated With Pioglitazone, A Comparative Study. AB - BACKGROUND: This study was conducted to determine the frequency of bladder cancer in diabetic mellitus type II patients treated with Pioglitazone as compared with diabetic mellitus type II patients treated with other oral therapy or insulin therapy. METHODS: It was a comparative; cross sectional survey in it 1,168 patients were selected from Medical and Endocrinology out-patient departments of Jinnah hospital, Lahore and a Periphery Diabetic using non-probability purposive sampling. Patients with Duration of Type 2 Diabetics more than or equals to 2 years, both male and female aged above or equal to 40 years were selected in the study. In Group A, type 2 diabetic patients taking Pioglitazones for >=2 years were selected and in group B type 2 Diabetic patients taking oral hypo-glycaemic or insulin were selected. The ethical committee of Allama-Iqbal Medical College, Lahore, approved this study. RESULTS: Five hundred & eighty-four patients of Group A and 584 Patients of group B were selected in the study. In group A, 321 (54.97%) were male and 263 (45.03%) were female, whereas in group B 317 (54.28%) were male and 267 (45.72%) were female. Mean age of the group A patients was 47.01+/-8.27 years and mean age of group B patients was 58.97+/-8.14years. In group A mean duration of diabetes was 8.65+/-3.72 years and in group B the mean duration of diabetes was 10.86+/-4.48 years. Mean duration of Pioglitazone use was 6.92+/-2.28 years. Overall none of the patient was reported with the bladder cancer in the study. CONCLUSIONS: It is concluded from the study that none of the patient from either group was reported with bladder cancer haematuria and UTI. It is suggested that a randomized control trials should be conducted to single out the association of bladder cancer in patients with type II diabetes.. PMID- 30465367 TI - Association Of Antenatal Depression And Household Food Insecurity Among Pregnant Women: A Crosssectional Study From Slums Of Lahore. AB - Background: Pregnant women are more likely to develop antenatal depression due to multiple factors including sickness and death of close family member, unwanted pregnancy, unplanned pregnancy, economic and relationship difficulties. Food insecurity is a major issue in low resource settings, especially in developing countries. Malnourishment in pregnant women along with antenatal depression can lead to adverse effect on growth of foetus and can lead to adverse pregnancy outcomes. The aim of this study was to determine an association between food insecurity and antenatal depression among pregnant women living in slum settlements of Lahore. Methods: A community based, crosssectional study was conducted in slum settlements of district Lahore, with a sample of 367 pregnant women. Antenatal depression and household food insecurity was measured using Edinburgh Postnatal Depression Scale (EPDS) and Household food insecurity access scale (HFIAS). Data was entered and analysed in SPSS-20.0. Chi-square and multivariate logistic regression analysis was used to estimate effect of food insecurity on antenatal depression among pregnant women. Results: Prevalence ofantenatal depression was 39.5% among pregnant women. Majority of the sample, i.e., 46% were food insecure. In an adjusted model, multivariate logistic regression showed existence of strong association between food insecurity and antenatal depression (AOR=2.58, 95%, CI: 1.64-4.075) in women surveyed. Conclusions: Study results show strong association between food insecurity and antenatal depression. Findings also suggest the need of an effective intervention at community level to combat food insecurity and antenatal depression in marginalized populations. PMID- 30465368 TI - Iron Deficiency Anaemia In Pakistan: Celiac Disease An Underlying Cause. AB - BACKGROUND: Iron deficiency anaemia (IDA) is common in Pakistani population and an important cause of morbidity. Celiac disease (CD) is an important contributor and its diagnosis is frequently missed especially if present in atypical/non diarrhoeal form. Non-responders to iron replacement therapy typically raises suspicion of celiac disease as underlying cause. Aim of this study is to determine the frequency of CD in patients with IDA.. METHODS: A cross sectional study was conducted at tertiary health care centre Islamabad from 12th March to 12th September 2016. Two hundred & ninety patients of newly diagnosed IDA age more than 12 years, including both genders were selected trough non-probability purposive method. Patients with overt Blood loss (gastrointestinal, genitourinary, Pulmonary, recent Trauma or Surgery) were excluded. Active worm infestation and inadequate iron intake were also excluded. After informed consent, all the enrolled patients were investigated for presence of Anti-Tissue tansglutaminase antibody (Human Anti TTG IgA type) by ELISA in their serum at pathology laboratory of PIMS. RESULTS: Out of 290 patients of IDA 32 (11%) had celiac disease (p=0.0002), more common in younger age <40 years 24 (75%), predominantly in female 22 (68.75%), more prevailing in Kashmiri population 9(28.12%). CONCLUSIONS: Celiac disease is common in patients who present with IDA. Diagnosis of CD is frequently missed in the absence of classic features and IDA may be the only manifestation of CD.. PMID- 30465369 TI - Efficacy Of Phenylephrine Infusion Verses Colloid Preloading In Resolving Hypotension Due To Spinal Anaesthesia During Caesarean Section. AB - BACKGROUND: Spinal anaesthesia causes hypotension that is countered through various methods. Phenylephrine is a vasoconstrictor and haemocoel increases the intravascular vascular volume; both have an effect in preventing this hypotension; but their comparison has not been done in local setting. METHODS: Randomized control trial was conducted in month of June, 2017 at Ayub Teaching Hospital, Abbottabad. Block randomization with sealed envelopes was employed. Sample size was set at 90. Two equal groups were formed; Group A received 500 ml of haemocoel before spinal anaesthesia administration and Group B received 300MUg of phenylephrine in 100ml infusion over 3 minutes.. RESULTS: An average drop of 8.2 mmHg, 9.7 mmHg and 3.1 mmHg in MAP was observed in Group A participants at 5 minutes, 10 minutes and 15 minutes respectively after spinal anaesthesia. In Group B, an average drop of 1.2mmHg was observed in first 5 minutes. MAP did not change significantly from this value throughout the monitoring period. There was a drop of 1.2 mmHg at 5 minutes in group B. After this, no further drop in blood pressure was observed. CONCLUSIONS: Phenylephrine infusion is better than haemocoel preload in preventing hypotension due to spinal anaesthesia. PMID- 30465370 TI - Perceptions Of Medical Teachers About Integrated Curriculum: A Qualitative Study. AB - BACKGROUND: Curriculum is a plan of educational experiences and activities offered to a learner. Curricular reform is a dynamic process. To make a curricular change impactful the curriculum needs to be accepted and followed by all stakeholders otherwise it will be unsuccessful. Change is not readily accepted as evidence suggests that there have been frequent curricular reforms but with little change in medical education. Evidence suggests that teachers agree for upgrading themselves towards recent trends in the field of medical education. In light of these facts perceptions of medical teachers of AJK Medical College were evaluated for the purpose of identification of issues and continuation of this process. METHODS: Qualitative study design was used. Study setting was AJK Medical College; duration of study was six months from February 1 to July 31 2014. The interviews conducted with the help of a semi structured guide were recorded, and all the recordings were then fully transcribed. Transcripts were read several times by investigators separately to select units of significance and identifying themes.. RESULTS: Four themes namely curricular design, integrated curricular implementation, teacher's issues and student's issues were identified. Regarding integrated curriculum teachers think that it should be continued in the institution. Teachers believe that proper training is mandatory for the integrated curriculum to be successfully implemented. CONCLUSIONS: It is concluded that teachers should be aware of universal practices in medical education, and the curriculum of their university. Teacher's training is mandatory for implementation and continuation of this curricular reform. PMID- 30465371 TI - Diagnostic Accuracy Of Plain X-Ray Lateral Neck In The Diagnosis Of Cervical Esophageal Foreign Bodies Keeping Oesophagoscopy As Gold Standard. AB - BACKGROUND: Detection of foreign body oesophagus has always been a challenge for the otolaryngologists. Among different investigations available X -ray is valuable for detection of foreign bodies as it is readily available, inexpensive and easy to operate. However, this still remains to be decided that how accurate it is? The objective of the study is to determine the diagnostic accuracy of plain X ray lateral neck in the diagnosis of foreign bodies in cervical oesophagus keeping esophagoscopy as the gold standard. METHODS: This descriptive study was conducted at department of ENT, Ayub Medical Institute (AMI) Abbottabad, from Mar to Sep 2016. A total of 290 patients were included in this study and all the patients had X-ray lateral view of neck, followed by oesophagoscopy (gold standard). Diagnostic accuracy of plain X-ray lateral view of neck was detected by determining sensitivity, specificity and accuracy. RESULTS: The sensitivity, specificity and accuracy of plain X-ray lateral view of neck was 91.7%, 80%, and 89.7%, respectively. CONCLUSIONS: X-Ray lateral view of neck is a reliable investigation and should be advised among all the patients with history of foreign body ingestion. PMID- 30465372 TI - Political Architecture And Legal Framework Related To Social Health Protection Schemes In Pakistan: Qualitative Inquiry Of Policy Makers' Viewpoint. AB - BACKGROUND: Pakistan is a federal state with three tiers of government. Following contentious general elections in 2013, ever first democratic transition took place in Pakistan. Subsequently, two social health protection schemes were launched. Current paper's objective is to understand the political context in which these schemes were launched and to explore the constitutional position of access to healthcare in Pakistan. This paper also explores the legal protection/ sustainability with regards to these schemes. METHODS: We used qualitative research techniques with interpretivist paradigm and case-study approach. In depth interviews were conducted, followed by content analysis. Triangulation and data saturation were observed to guide our sample size. Officials involved with these schemes at policy and implementation level were interviewed. Ethical approval was taken from ethics board of Khyber Medical University. Based on purposive sampling, in-depth interviews were conducted and thematic analysis was performed. RESULTS: We identified two themes in response to question-1 of our interview, asking about the cause of action behind starting these schemes and their legal protection. These themes were: (i) [initiation of] Social Health Protection as democratization of healthcare, and (ii) [initiation of] Social health protection in legal void. Implicitly, these schemes are a product of grass root political activism and health found berth in election manifestos recently. Also, we deduce that health is not a constitutional right in Pakistan. These schemes lack constitutional guarantee and ensued in absence of overarching legal framework. CONCLUSIONS: These social health protection schemes are high on political agenda but lack constitutional and legal protection. PMID- 30465373 TI - HCV-RNA Pcr Positivity In Hcv Antibody Negative Patients Undergoing Haemodialysis. AB - BACKGROUND: It's estimated that almost 2.2% of the world's inhabitants suffer from hepatitis C virus (HCV). The most common cause of chronic liver disease in haemodialysis centres is due to HCV. In 1993, it was first described by Bukh and colleagues that HCV viremia can occur without any detectable antibodies to the HCV. Keeping this in mind the purpose of this cross-sectional study was to assess the frequency of HCV in haemodialysis patients by PCR who are serologically negative for HCV. METHODS: This cross-sectional study was conducted from 1st June to 31st December 2016 on all haemodialysis patients at MH Rawalpindi. Epidemiological data for gender, age, duration on haemodialysis, cause of chronic renal failure and any associated risk factor for acquiring hepatitis C infection was asked. Patients undergoing haemodialysis were investigated by fourth generation ELISA for Anti HCV antibodies, HCV DNA polymerase chain reaction, HCV genotype (where required) and liver function test were also done. RESULTS: A total of 201 patients were undergoing haemodialysis. Among these patients 73 were hepatitis "C" negative and 128 were hepatitis "C" positive. Among the 73 patients who were hepatitis C negative by ELISA method 17 (23%) were PCR positive. Of the 17 patients 13 (76.5%) were men and 4 (23.5%) were women. The mean age of the patients was 49.7+/-18.0 years and mean duration of haemodialysis was 4.4+/-4.1 months. The most common cause of CKD requiring haemodialysis was hypertension (64.7%). The most common genotype was type 1 (58.8%) followed by genotype 3 (41.2%). The mean viral load was 23583615.70 IU. CONCLUSIONS: HCV-RNA detection by PCR should be used as standard of care to detect HCV infection in patients undergoing haemodialysis. PMID- 30465374 TI - Comparing The Functional Outcome Of Different Dose Regimes Of Succinylcholine When Used For Rapid Induction And Intubation. AB - BACKGROUND: This study was conducted to compare outcomes of different doses of succinylcholine, in terms of intubation condition, onset of action, duration of action and abdominal fasciculation. METHODS: Thus, randomized control trial was conducted in the department of anaesthesia and ICU, Nishter Hospital Multan from April 2016 to November 2016. A total number of 60 patients with ASA status I and II were enrolled. All patients were divided into three groups by lottery method. Data was entered and analysed by computer software SPSS version 23.2. Descriptive variables like age and onset of action were presented as mean and SD and continues statistics like gender, abdominal fasciculation and incubation condition were presented as frequency and percentages. Chi square test and one way ANOVA was applied to see effect modification and significance of results. The p-value 0.05 was considered as significant. RESULTS: A Total number of 60 patients included in this study and all were female. The mean age of the patients was 28.15+/-4.5 years. The main outcome variables of this study were the fasciculation, satisfactory intubation, onset time (seconds) and duration of action (in minutes). In group (A) 1mg, abdominal fasciculation was found 80%, 85% and 75% in group A, B, C respectively. It was also observed that satisfactory intubation was found 90%, 80% and 30% in three groups respectively. The mean onset time was 50.95+/-4.6, 70.7+/-5.66 and 94.15+/-8.73 seconds in three groups respectively. Similarly, the mean duration of action was 16.1+/-3.76, 13.55+/ 3.01 and 8+/-2.05 minutes respectively. CONCLUSIONS: Results of our clinical trial suggest that succinylcholine in low doses shorter duration of action and low rate of abdominal fasciculation which is desirable for rapid induction but onset of action is prolonged and intubation conditions were not satisfactory predominantly. So, we concluded that low doses of succnylcholine are not so much beneficial that I can replace full doses of succinylcholine when used for rapid induction and intubation. PMID- 30465375 TI - Association Of Different Risk Factors In Prevalence Of Cerebral Infaraction. AB - BACKGROUND: Cerebral infraction is one of the important causes of cerebrovascular accident. This study was conducted to see which risk factors are more prevalent in cerebral infraction. METHODS: It is a hospital based descriptive study of 130 patients of different types of strokes. Results: Out of 130 patients 70 were male and 60 females. Majority (58%) of the patients were between 41-60 years of age. Patient presented with variable risk factors. The majority (60% male and 73% female) were hypertensive. The percentage of other factors including diabetes mellitus, atrial fibrillation, smoking, high serum cholesterol, obesity and carotid artery stenosis was observed. RESULTS: Five program directors (83.3%) and 195 interns (82.9%) responded to the questionnaires. Implant dentistry was taught to the undergraduate students in multidisciplinary departments with teaching hours ranging from 22-30 hours. Only three schools exposed students to laboratory (workshop) or clinical training. There was agreement among the program directors in respect of the didactic contents. Majority of the interns reportedly acquired knowledge regarding implant dentistry based on theoretical (96.1%), laboratory (33.5%) and/or clinical (30%) training. While 50% of the interns agreed to acquire knowledge by assisting and observing dental implant procedures, only 52.8% of the interns expressed satisfaction regarding implant dentistry training obtained during their undergraduate period. CONCLUSIONS: Cerebral infraction is the most common cause of stroke in our community and all the other factors that are included in our study showed their association in occurrence of cerebral infraction. PMID- 30465376 TI - Association Of Different Risk Factors In Prevalence Of Cerebral Infaraction. AB - BACKGROUND: WHO MCS in 2011 evaluated the incidence and management strategies linked with maternal and neonatal mortality in facilities across 26 countries including Pakistan. This study, a sub-analysis assessed the availability of essential obstetric and newborn care at referral level facilities of Pakistan that were selected for WHO MCS to correlate it with maternal and neonatal outcomes. METHODS: This cross-sectional study assessed the infrastructure, equipment and services in 16 referral level government hospitals participating in WHO MCS from 1st March to 30th May, 2011. The association was found between this data and maternal & neonatal outcomes of each facility using chi square test. RESULTS: The studied facilities had basic infrastructure, most components of Essential Maternal and Neonatal Obstetric Care services with part time/full time availability of obstetricians, anaesthetists and paediatricians. Adult intensive care unit was available in 68%, and neonatal intensive care unit was available in half of the facilities. The incidence of severe maternal outcomes had a positive correlation with presence of adult intensive care unit, mechanical ventilator and twenty-four hours (24/7) availability of anaesthesiologist, nurses & paramedics. The neonatal mortality was also higher in facilities with neonatal intensive care unit facility. CONCLUSIONS: Most components of Essential Maternal and Neonatal Obstetric Care were present in the studied facilities. Tertiary level facilities even with availability of Adult and neonatal intensive care units had more adverse maternal and new-born outcomes perhaps due to more disease burden. PMID- 30465377 TI - Mean Tip-Apex Distance In Lag Screw Cut-Out After Dynamic Hip Screw Fixation Of Hip Fracture. AB - BACKGROUND: To determine mean tip-apex distance after Dynamic Hip Screw fixation of intertrochanteric fracture. METHODS: This descriptive cross-sectional study was conducted in the Department of Orthopaedics, Hayatabad Medical Complex, Peshawar from October 2015 to September 2016 on a total 285 patients. RESULTS: A total of 285 patients were observed. Status of TAD among 285 patients was analysed as 171 (60%) patients had TAD ranged 15 mm to 20 mm, 91(32%) patients had TAD ranged 21 mm to 25 mm, 23 (8%) patients had TAD ranged >25mm. Mean TAD was 18 mm with SD+/-7.45. Eight percent patients had screw cut out while 92% patients didn't had screw cut out. CONCLUSIONS: To avoid lag screw cut out in dynamic hip screw for intertrochanteric fracture of hip the Tip apex distance must be accurate otherwise there will be cut out of lag screw. PMID- 30465378 TI - Changes In Learning Style Preferences Of Postgraduates After Entering A New Learning Environment. AB - BACKGROUND: The aim of this study was to investigate whether the learning style preferences of post-graduate medical students change with time when they enter a new learning environment. The learning styles of post-graduate medical students from Pakistan were assessed on Kolb's Learning style inventory and prospectively monitored for any change when the students entered a degree program at the University of Glasgow. METHODS: Medical doctors from Pakistan who joined post graduate program in Evidence Based Medicine and Health Professions Education participated in the study. Kolb's learning style inventory was used to evaluate the learning preferences. Learning styles were evaluated twice in the study, in the first term of the course and then at the end, with a time span of 7 months. RESULTS: The predominant learning style preferences of students were 'Assimilating' type, both at the beginning and at follow up. Some change in the learning style preferences of students was noted as 2/10 students moved to a different learning grid at follow-up. These results were assessed against gender, clinical and teaching experience using linear regression however no significant correlation was found. CONCLUSIONS: There was not enough evidence to suggest that learning style preferences of students change in a meaningful way after coming to a new learning environment. This study however, leads to a suggestion that further large sized longitudinal study should be done with enough statistical power to accept or reject the null hypothesis. PMID- 30465379 TI - Pregnancy Outcomes Of Consanguinity Among Antenatal Patients Attending Combined Military Hospital Quetta, Pakistan. AB - BACKGROUND: All definitions of consanguinity encompass the basic concept of close blood relation. Highest rates of consanguineous unions are observed for North and Sub Saharan Africa, Middle East, and west, central and south Asia, where 20-50% marriages are consanguineous. In Pakistan, we can hardly find any rigorous research on the pregnancy outcomes of consanguinity except those conducted by Allan Bittles. This study was conducted with the objective to measure statistically if there existed any association of consanguinity with pregnancy outcomes in the form of stillbirths, abortion and Rh-incompatibility. METHODS: This cross sectional analytical study was conducted at the Obstetrics department of Combined Military Hospital Quetta, Pakistan from 1st November 2017 to 28th February 2018. All pregnant women visiting Out Patient Department were included. Women unwilling to participate or needing emergency intervention were excluded. Sample size, i.e., 384 was calculated using online OpenEpi calculator and simple random sampling technique was applied. A structured interviewer administered questionnaire was used to extract retrospective information. Descriptive statistics, 95% Confidence Intervals, Chi-Square test and Contingency Coefficient were calculated using SPSS Version 20. Results were regarded significant at p<0.05. RESULTS: Out of 384 study participants, 188 (48.9% with 95% CI:43.9- 53.9%) were married to first cousins. Mean+/-SD age of the study participants was 27.5+/-4.8 years. Difference between stillbirth, and abortion among consanguineous unions and nonconsanguineous unions was significant while that of Rh-incompatibility was non-significant.. CONCLUSIONS: Large population based studies are needed before declaring consanguinity as a health problem in our setting. PMID- 30465380 TI - Analysis Of Palatal Rugae Pattern In Population Of Abbottabad: A Forensic Study. AB - BACKGROUND: Identification of unknown dead bodies' especially bony remains is done by different methods like DNA typing, Finger printing, Dental and other skeletal data, facial reconstruction and rugae pattern study. Palatal rugae pattern study or Ruguscopy gives a unique method of identification in cases of skeletal remains due to its uniqueness, resistance to heat, and stability throughout life. METHODS: This simple random sampling was carried out on 102 study models (casts of palate) of patients having 880 rugae patterns above 20 years of age in Khan Dental Clinic near Ayub Medical College, Abbottabad. The study is based on classification given by Thomas et al. Casts were taken from palate and then individual casts studied for rugae pattern. They were classified and variations studied for uniqueness. RESULTS: Each individual had different set of palatal rugae which are not same, in all its dimensions like size shape number etc. CONCLUSIONS: With the help of this study we can conclude that Palatal rugae pattern give unique method for individual identification. PMID- 30465381 TI - Spectrum Of Bacterial Culture And Drug Sensitivity Vs Resistance In Uncomplicated Urinary Tract Infection. AB - BACKGROUND: The growing antibiotic resistance against uropathogens has made its treatment a challenge for the physicians. This study was conducted to know the spectrum of bacteria responsible for urinary tract infection and their susceptibility and resistance to available antibiotics. METHODS: This hospital based cross-sectional study was carried out from May to October 2017. All patients presenting with urinary tract infection signs and symptoms and were included in the study. A sample of 168 patients of both gender and age were recruited for the study using convenient sampling technique. Antimicrobial isolation and differentiation was determined by using Cystine-lactose Electrolyte Deficient (CLED) Agar. Susceptibility and resistance to 30 available antibiotics were determined. Data was collected on the predesigned proforma. SPSS version 16 was used for data entry and analysis. RESULTS: There were 62 (36.9%) males and 106 (63.1%) females. Mean age of the male patients was 55.34+/-21.33 years whereas the mean age of the female patients was 45.8+/-22.07 years and the difference was statistically significant (p=0.007). Gram negative bacteria were isolated from 141 (83.9%) of the cases. Gender wise distribution of Gram negative and positive strains was found statistically significant (p=0.032). E. coli was the commonest bacterium found in 70.8% of cases. It was sensitive to only seven (23%) antibiotics in over 80% of the cases. E. faecalis, K. pneumoniae, P. aeruginosa and S. faecalis were susceptible to 13%, 26.7%, 40% and 23% of antibiotics respectively in over 60% of the cases. 90% of the cultured pathogens were susceptible to Nitrofurantoin in over 80% of the cases. Among cultured pathogens, 70% showed susceptibility to Imipenem, Meropenem, Amikacin, Doxycycline, Fosfomycin and Cefoperazone/Sulbactam in over 60% of the cases. CONCLUSIONS: UTI is more common in women as compared men. E. coli, E. faecalis, K. pneumoniae and P. aeruginosa are the major pathogens responsible for UTI in this part of the country and in over 80% of the cases are still sensitive to Nitrofurantoin. PMID- 30465382 TI - Proximal Arterio Venous Fistula Creation - A Gold Standard In Chronic Renal Failure Patients With Multiple Comorbidities. AB - BACKGROUND: Patients with end stage renal disease need an accurate and effective vascular access for haemodialysis. This study was conducted to postulate a hypothesis that proximal arterio venous fistula (AVF) creation should be a gold standard in Chronic Renal Failure (CRF) patients with multiple co morbidities.. METHODS: A total of 230 patients reporting to Vascular Surgery Clinic in Combined Military Hospital Lahore and Peshawar from January 2014 to January 2016 for AVF creation, were included and equally divided into two groups by random draw method. Distal AVF created in Group A and proximal AVFs at elbow in Group B. The data regarding age, gender, atherosclerotic risk factors, body mass index (BMI) was recorded. The groups were compared for functional maturation of AVF and their patency at 6 and 12 months. RESULTS: Mean age was 30+/-SD 6.5 years (31+/-SD 5.1 in Group A, 30+/-SD 6.9 in Group B) with a male to female ratio of 5.4:1. In terms of age (p-value 0.529), gender (p-value 0.716), diabetes (p-value 0.682), hypertension (p-value 0.659) and BMI; there was no difference between two groups. 85.2% (n=98) AVFs matured in Group B as compared to 44.3% (n=51) AVFs in Group A (pvalue= 0.0045). Furthermore, statistically significant differences between the two groups were found in terms of patency rates at 6 and 12 months (73.9% and 66% in Group B: 26.9% and 16.5% in Group A; p-value 0.0039 and 0.0007 respectively). CONCLUSIONS: Proximal AVF creation in CRF patients with multiple co morbidities should be the gold standard as a primary procedure in terms of better long term primary patency.. PMID- 30465383 TI - Knowledge And Attitude Of Undergraduate Dental Students Towards Research. AB - BACKGROUND: Scientific research is an important part of healthcare curricula and a vital exercise to help develop clinician's research skills. The aim of this study was to evaluate quantitatively the knowledge and attitude of undergraduate dental students towards scientific research. In addition, the study explored the reasons for lack of interest in research by the dental students. METHODS: This cross-sectional study was conducted among students of three dental schools in Riyadh. The required information was collected through a self-designed, pretested and validated questionnaire used for investigating the students' knowledge, attitudes and reasons for lack of interest if any in research. Descriptive, chi square and t-tests were used for statistical analysis of the responses considering a p-value of <0.05 as the cut-off level for significance. RESULTS: Out of 701 completed questionnaires (Response Rate=77.88%), 360 (51.4%) and 341 (48.6%) were for males and female students respectively. Subjects, stratified according to year of study, included students of first year=144 (20.5%); second year=151 (21.5%); third year=132 (18.8%); fourth year=145 (20.7%) and fifth year=129 (18.4%). The mean and standard of the knowledge score was 3.36+/-1.76 and attitude score was 3.87+/-2. Students' knowledge and attitude scores tended to increase as the study year went higher. CONCLUSIONS: A moderate level of knowledge about research was found among dental students. However, attitude of the dental students towards research was positive. Improvements were seen in the knowledge and attitude of students over the study years. Curriculum overload, exposure, literature search, knowledge and finding a topic or mentor in the school seemed to be the barriers in pursuing research. PMID- 30465384 TI - Role Of Radiosurgery In Arteriovenous Malformations. AB - BACKGROUND: Intracranial arteriovenous malformations (AVMs) consist of an abnormal nidus of blood vessels that shunt blood directly from an artery to a vein and thereby bypass an intervening capillary bed. AVMs may be found as an incidental finding. They may be associated with intracranial haemorrhage, seizures, headaches or neurological deficits. There are different treatment options for AVM. These include observation, microsurgery, Stereotactic radio surgery (SRS), endovascular embolization and intensity modulated radiotherapy (IMRT). METHODS: Data was collected using searching engines like Pubmed, Google scholar, Embase, Cinahl and Medline. MeSH and Non-MeSH terms were used like Arterio-venous malformations, microsurgery, endovascular embolization. RESULTS: Multiple interventional radiosurgical techniques have been introduced in recent years. The most effective and least risk-associated methods are Stereotactic radiosurgery, Microsurgery, Embolization and Intensity modulated radiotherapy (IMRT). However, the outcome of such treatment modalities depends upon Site of malformation, grade of AVM, patient's age/gender, dose and volume of radiosurgery. Digital substraction angiography (DSA) and MR angiography (MRA) are most suitable methods for the follow-up of AVMs. CONCLUSIONS: Stereotactic radiosurgery is the most suitable technique for AVMs considering the good prognosis and the risks associated with this procedure. However, large AVMs require multidisciplinary approach for better results. PMID- 30465385 TI - Female Pseudo Hermaphroditism: Late Onset Congenital Adrenal Hyperplasia. AB - Non-classic congenital adrenal hyperplasia is a genetic condition caused by deficiency of 21- hydroxylase deficiency (NCAH). It is a milder and later onset form of a genetic condition known as congenital adrenal hyperplasia. We present four cases of non-classical congenital adrenal hyperplasia presented in gynae OPD foundation university medical college Fauji foundation hospital from Jan 2016 to March 2017. The presenting complaints were hirsuitim, menstrual problem and virilization of genitalia. Two girls were having primary amenorrhea while rests of two were having secondary amenorrhea. Two patients were already diagnosed as non-classical congenital adrenal hyperplasia due to ambiguous genitalia at the time of birth while the rest of two with marked clitoromegaly were diagnosed during workup in gynae OPD. Menarche was achieved successfully among those with primary amenorrhea after treatment. All four girls were referred to plastic surgery for clitoral reduction surgery. The post-surgery patient satisfaction level was high. Correct diagnosis of the disease can cure the patient instead of letting her live a life of being labeled with social stigmata of an intersex individual. PMID- 30465386 TI - Pathogenesis And Radiological Findings In Rare Case Of Salter Harris Type I Distal Tibial Fracture With Associated Osteonecrosis In The Paediatric Population. AB - Salter-Harris type I fractures of the distal tibia are commonly seen in paediatrics and management of such fractures follows an algorithm established in the literature. Despite this, osteonecrosis of the distal tibia can subsequently develop. Osteonecrosis or avascular necrosis is cell death that occurs secondary to trauma, metabolic disturbances, sickle cell disease, or medication side effect. It most frequently affects the femur, talus, or humerus, and rarely the tibia. Radiographs and MRI are pivotal in making a timely diagnosis in order to minimize patient discomfort. To the best of our knowledge, there has only been one previous documented case of osteonecrosis following a Salter Harris Type I distal tibial fracture. Here, we present the second such case. PMID- 30465387 TI - Isolated Tear Of Posterolateral Bundle Of Anterior Cruciate Ligament. AB - Anterior cruciate ligament injuries are very commonly encountered during routine MRI reporting and various signs have been described for their identification. However, the diagnosis of isolated bundle tears is difficult using MRI, thus can be easily overlooked, especially isolated tear of posterolateral bundle. We present a case of a young male with "Gap" and "Footprint" signs on MRI knee joint, which are considered highly specific of posterolateral ACL bundle tear. PMID- 30465388 TI - Bilateral Psoas Abscess After Extracorporeal Shock Wave Lithotripsy: Reminder Of A Rare Complication. AB - Extracorporeal shock wave lithotripsy (ESWL) is among the most widely used modalities for treatment of urolithiasis since its introduction in the 1980s. The non-invasive technique reduces the risk of post-procedure complications and produces excellent stone free rates. However, complications may still follow and albeit rare, there are reports in literature of abscess formation post ESWL. Herein, we report the case of a young, immunocompetent gentleman who developed bilateral psoas abscess after undergoing this procedure. He was successfully managed at our institute with intravenous antibiotics, percutaneous abscess drainage and was discharged on day 5 post-intervention in a stable condition. There have been two similar cases reported in literature. PMID- 30465389 TI - Chondroectodermal Syndrome. AB - Chondroectodermal syndrome or Ellis Van Creveld (EVC) is a rare autosomal recessive congenital disorder. It was first described by Richard W.B.Ellis and Simon Van Creveld in 1940. Parental consanguinity is present in about 30% of the cases. A large number of cases were reported in Amish population of Lancaster County, Pennsylvania USA and also in Aboriginal community of Australia in 1964. The incidence in Amish population is 1/5000 live births and in general population 7/1,000,000. There are only 150 cases reported worldwide. The principal feature of this syndrome is a tetrad of disproportionate dwarfism, ectodermal dysplasia, bilateral postaxial polydactyly and congenital heart defects. PMID- 30465390 TI - Nystagmus And Beyond: A Rare Ocular Motility Disorder. AB - Joubert syndrome is a rare autosomal recessive disorder predominantly involving the cerebellar vermis and brain stem. It is characterized clinically by global developmental delay, abnormal ocular movements, hypotonia, ataxia, intellectual disability and neonatal breathing abnormalities. Due to its uncommon and unconventional presentation, its diagnosis is usually delayed. Diagnosis of this atypical disease essentially relies upon the atypical finding of the "molar tooth" sign on Magnetic Resonance Imaging (MRI). We report a case of a 5-year-old boy who presented with abnormal eye movements, regression of milestones and developmental delay. MRI investigation revealed the distinctive molar tooth sign and bat wing shaped 4th ventricle. It requires high levels of clinical suspicion and holistic approach to such children who present with delayed milestones and abnormal eye movements, to reach at early detection and diagnosis of such rare pathologies. PMID- 30465391 TI - Improvement In Symptoms Of Gaucher's Disease By Enzyme Replacement Therapy. AB - Gaucher's disease is the most common lysosomal storage disease which occurs due to a deficiency of the enzyme glucocerebrosidase. This enzyme deficiency leads to accumulation of glucocerebrosidase in the cells of macrophage-monocyte system. It is inherited as an autosomal recessive mutation and has three clinical subtypes. The disease presents with anaemia, hepatosplenomegaly, skeletal disorders and organ dysfunction. We present the case of an 18- month old male child who had presented to Civil Hospital, Karachi with fever, progressive pallor, abdominal distention for 6 months and was diagnosed as a case of type 1 Gaucher's disease on the basis of low leukocyte glucocerebrosidase activity, raised plasma chitotriosidase and the presence of Gaucher cells on bone marrow biopsy. The disease was treated with Intravenous replacement of the enzyme Imiglucerase (cerezyme) and the patient was followed. An informed Consent of the parents was taken prior to the writing of the manuscript. PMID- 30465392 TI - Progress Of Khyber Pakhtunkhwa (Pakistan) Towards Universal Health Coverage. AB - Background: Khyber Pakhtunkhwa (KP) launched its flagship Social health protection initiative (SHPI), named Sehat Sahulat Program (SSP). SSP envisions to improve access to healthcare for poorest of the poor and contribute towards achieving Universal Health Coverage (UHC). Current study was undertaken to analyze SSP in context of UHC framework i.e. to see as to (i) who is covered, (ii) what services are covered, and (iii) what extent of financial protection is conferred. METHODS: We conducted thorough archival research. Official documents studied were concept paper(s), approved planning commission documents (PC-1 forms) and signed agreement(s) between government of KP and the insurance firm. RESULTS: SSP enrolled poorest 51% of province' population i.e. 14.4 million people. It covers for all secondary and limited tertiary services. Maximum expenditure limit per family per year is Rs.540, 000/-. Government pays a premium of Rs.1549/- per year per household to 3rd party (insurance firm) which ensures services through a mix of public-private providers. CONCLUSIONS: The breadth, depth and height of SSP are significant. It is a phenomenal progress towards achieving UHC. PMID- 30465393 TI - Outbreak Of Chikungunya Virus In Karachi, Pakistan. AB - In this report, aim is to highlight the recent outbreak of Chikungunya virus in Karachi, the largest city of Pakistan. Chikungunya virus is transmitted by infected Aedes mosquitoes. Firstly, described as an outbreak in southern Tanzania in 1952 and later spread in Africa, Asia, Europe, and Pacific and Indian Oceans. In late 2016, the virus has been reported to cause severe morbidity and fatality among patients reporting to the local government hospital in Malir region of Karachi. Patients came to emergency ward with complaints of fever, skin rashes, fatigue and joint pain. To improve the existing knowledge and current epidemic in this area we reported the causes, sign & symptoms, precautions and treatment measures for the control from this virus spreading in mass gatherings. In addition, self-awareness, preventive measures implementation by public health officials in response to reports of Chikungunya virus will help to evaluate the outbreak settings. PMID- 30465395 TI - Warthin's Tumour Of Floor Of The Mouth - Correlation Of Fnac And Histopathoogical Findings. PMID- 30465394 TI - Updated Recommendations Of Rcog On Prevention Of Early Onset Neonatal Group B Streptococcus Infection. PMID- 30465396 TI - Role of HMGB1 in Post-traumatic Endoplasmic Reticulum Stress in Rat Lung Tissues. AB - OBJECTIVES: To explore the role of high mobility group B1 (HMGB1) protein in the post-traumatic endoplasmic reticulum stress (ERS) in rat lung tissues. METHODS: The rat model of acute lung injury was established by crushing the hind limbs of rats with standard weight. The first experiment was to divide rats into postural control group and crush groups (6 h, 18 h and 30 h after crushing). The second experiment was to divide rats into postural control group, 18 h crush group, HMGB1 inhibitor sodium butyrate (SB) group and 18 h crush+SB group. The protein expression changes of HMGB1 and ERS- related proteins (GRP78, caspase-12, CHOP and IRE1alpha) in rat lung tissues were detected with Western blotting. Meanwhile, the pathological changes of rat lungs were observed by HE stain. RESULTS: Compared with the postural control group, the expression levels of ERS related proteins (GRP78, caspase-12, CHOP and IRE1alpha) and HMGB1 protein in rat lung tissues by crushing the hind limbs of rats were obviously increased. The protein levels reduced at 30 h after crushing but were still higher than those of postural control group and obvious pathological changes of acute lung injury were observed simultaneously in rats. Compared with the 18 h crush group, the expression levels of the ERS-related proteins and HMGB1 protein in rat lung tissues were attenuated in 18 h crush+SB group, and the pathological changes of rat lung injury began to alleviate. CONCLUSIONS: HMGB1-ERS pathway activated by traumatic stress can lead to acute lung injury in rats. PMID- 30465397 TI - Estimation on Formation Time of Thrombus. AB - OBJECTIVES: To observe the changes of the formation time of venous thrombus in rats, and to provide new ideas and methods for the estimation on thrombus formation time of the forensic cases died from thrombosis. METHODS: Totally 80 rats were randomly divided into 10 groups (0 h, 3 h, 6 h, 12 h, 1 d, 3 d, 1 week, 2 weeks, 3 weeks and 4 weeks after operation). A vein thrombosis model was established by the "narrow" method. The processes of thrombosis, organization, recanalization and the features of change on hemosiderin and calcium salt were observed by HE stain, Perls stain and Von Kossa stain. The expression changes of CD61, alpha-SMA and CD34 were observed by immunohistochemical staining technique. RESULTS: Platelets adhered to the exposed blood vessel intima 3 h after operation, and platelet trabeculae were formed by the repeated accumulation of platelets 1 d after operation. The thrombus organization formed through the fibroblasts from vessel wall that grew into the interior of the thrombus 3 d after operation. Endothelial cells covered the surface of thrombus and then the new blood vessels were reformed, and the vessels were reconstructed. The expression of CD61 upregulated at the stages of the thrombus formation (3 h) and thrombus reformation (4 weeks), and reached the peak 1 d after thrombus formation. The release of hemosiderin and the initial expression of alpha-SMA were detected 3 d later. Calcium deposit and expression of CD34 were observed 1 week later. CONCLUSIONS: The hemosiderin, calcium salt, CD61, alpha-SMA and CD34 show time-dependent changing characteristics, which is expected to provide a reference for the estimation on thrombus formation time of the forensic cases died from thrombosis. PMID- 30465398 TI - Assessment of the Original Height of L1~2 after Vertebral Compression Fracture. AB - OBJECTIVES: To explore the assessment method of original height of L1-2 after vertebral compression fracture and its application value in forensic clinical practice. METHODS: A total of 154 normal thoracic and lumbar X-ray films were collected, and 140 cases were used as experimental group while 14 cases as validation group. The heights of anterior (Ha) and posterior (Hp) vertebral body of T12-L3 vertebrae in each X-ray image were measured. In the experimental group, the correlation analysis between HaL1 and HaT12, HpT12, HpL1, HaL2 and HpL2 was carried out, and regression equation was established via fitting. The correlation analysis between HaL2 and HaL1, HpL1, HpL2, HaL3, HpL3 was performed, and the regression equation was also established via fitting. The difference between the predicted and measured values of HaL1 and HaL2 in validation group was compared. RESULTS: In the 140 normal subjects, HaL1 (y1) was well correlated with HaT12 (x1) and HaL2(x2), and the multiple linear regression equation was y1=2.545+0.423 x1+0.486 x2 (determining coefficient R2=0.712, P<0.05; F=169.206, P<0.05). There was no significant difference between the predicted and actual measured values of HaL1 in the validation group ( P>0.05). HaL2 (y2) was well correlated with HaL1 (x3) and HaL3 (x4), and the multiple linear regression equation was y2=4.354+0.530 x3+0.349 x4 (determining coefficient R2=0.689, P<0.05; F=151.575, P<0.05). There was no significant difference between the predicted and actual measured values of HaL2 in the validation group ( P>0.05). CONCLUSIONS: It is more appropriate to evaluate the original height of L1 or L2 single vertebrae by comparing with the height of the anterior edge of the upper and lower adjacent vertebral bodies. PMID- 30465399 TI - Age Estimation and Age-related Facial Reconstruction of Xinjiang Uygur Males by Three-dimensional Human Facial Images. AB - OBJECTIVES: To search age-correlated facial features and construct an age estimation model based on the three-dimensional (3D) facial images of Xinjiang Uygur males, and to structure individual face images of old age and young age. METHODS: Pretreatment was performed to collect 105 3D facial images of Xingjiang Uygur males aged between 17-57 years by Artec Studio software. The facial images were transferred to high-density 3D dot matrix data by FaceAnalysis software, and each image could be represented with 32 251 vertexes. Central correction of the facial images was done and all the data were aligned to a standard coordinate frame by generalized Procrustes analysis (GPA). The age estimation model was established by partial least square regression (PLSR). Furthermore, the changes of age-correlated facial features were presented on the heat map of average face, and the reconstruction of facial images at different ages was performed based on this model. RESULTS: With age, the average faces showed a series of changes including the nasolabial sulcus deepening, cheek sinking, cheekbone protruding and eye corner drooping. The Pearson correlation coefficient (r) between estimated age and chronological age was 0.71. The mean absolute deviation (MAD) of age estimation was 6.37 years. The results of age estimation in >30-40 years group showed a best accuracy (MAD=4.27 years), and the deviations increased with age after 40 years. The composite facial images represented a significant result with age on facial morphological features and aging. CONCLUSIONS: The results of this study reveal the age-correlated facial features and aging markers in Uygur population, which help to construct a reliable age estimation model. PMID- 30465400 TI - Formula Derivation for the Probability Distribution of IBS Score in Unrelated Individual Pairs. AB - OBJECTIVES: To derive the probability equation given by STR allele frequencies of identity by state (IBS) score shared by unrelated individual pairs. METHODS: By comparing the STR genotypes of two unrelated individuals, three mutually exclusive combinations could be obtained: (1) sharing 2 identical alleles, a2=1, otherwise a2=0; (2) sharing 1 identical allele, a1=1, otherwise a1=0; (3) sharing 0 identical allele, a0=1, otherwise a0=0. And the IBS score of the one STR locus in this unrelated individual pair could be given by the formula: ibs=2a2+a1. The probability of a2=1 (p2), a1=1 (p1) and a0=1 (p0) were derived and expressed in powers of the allele frequencies. Subsequently, for a genotyping system including n independent STR loci, the characteristics of binomial distribution of IBS score shared by a pair of unrelated individuals could be given by p2l and p1l (l=1, 2, ..., n). RESULTS: All the general equations of p2, p1 and p0 were derived from the basic conceptions of a2, a1 and a0, respectively. Given fi (i=1, 2, ..., m) as the ith allele frequency of a STR locus, the general equations of p2, p1 and p0 could be respectively expressed in powers of fi: [Formula: see text],[Formula: see text] and [Formula: see text]. The sum of p2, p1 and p0 must be equal to 1. Then, the binomial distribution of IBS score shared by unrelated individual pairs genotyped with n independently STR loci could be written by: IBS~B(2n, pi), and the general probability, pi, could be given by the formula: [Formula: see text]. CONCLUSIONS: In the biological full sibling identification, the probability of null hypothesis corresponding to any specific IBS score can be directly calculated by the general equations presented in this study, which is the basement of the evidence explanation. PMID- 30465401 TI - Rapid Determination of Cocaine and Its Metabolite Benzoylecgonine in Hair by LC MS/MS. AB - OBJECTIVES: To establish a rapid determination method with LC-MS/MS for cocaine and its metabolite benzoylecgonine in hair. METHODS: Deuterated internal standards (cocaine-D3 and benzoylecgonine-D8) were added to the decontaminated hair. After the extraction by ultrasonication with methanol, the compounds were separated by the Restek Allure PFP propyl column, and cocaine and benzoylecgonine were simultaneously analysed in multiple reaction monitoring mode. RESULTS: The cocaine and benzoylecgonine in hair showed a good linearity in the range of mass fraction between 0.02 and 10.00 ng/mg with the limits of detection of 0.01 ng/mg. CONCLUSIONS: The developed method is simple and rapid with a good selectivity, which is suitable for the determination of cocaine and its metabolite benzoylecgonine in hair. PMID- 30465402 TI - Determination of Endosulfan Concentrations in Biological Samples by GC-MS/MS. AB - OBJECTIVES: To establish an analytical method of the endosulfan concentrations (alpha-endosulfan and beta-endosulfan) in biological samples by GC-MS/MS. To observe the distribution of endosulfan in aquatic animals and provide experimental evidence for forensic identification of relevant cases. METHODS: Acetonitrile was added to the blood and muscle samples for precipitating the protein. The endosulfan concentrations were determined by GC-MS/MS in multiple reaction monitoring mode. Qualitative analysis was performed according to the retention time and ion rate, and quantitative analysis was performed by external standard working curve method. RESULTS: In blood samples, the calibration curves of alpha-endosulfan and beta-endosulfan ranging from 0.062 5 to 10 MUg/mL had good linear relationship, the correlation coefficients (r) of which were >0.99. The limits of detection (LOD) were 1 ng/mL and 2 ng/mL and the limits of quantification (LOQ) were 4 ng/mL and 8 ng/mL, respectively. In muscle samples, the calibration curves of alpha-endosulfan and beta-endosulfan ranging from 0.062 5 to 10 MUg/g, the r of which were >0.98. The LOD were 1 ng/g and 4 ng/g and the LOQ were 4 ng/g and 16 ng/g, respectively. The accuracy of alpha-endosulfan and beta-endosulfan was 90.76%-108.91% both in blood and muscle samples, the interday and intraday precision were 2.35%-8.71% and 5.44%-10.29%, respectively. In poisoning cases, endosulfan were detected in all parts of fish and crab and the content difference was statistically significant. CONCLUSIONS: The endosulfan detection method based on GC-MS/MS established in the present study is rapid, sensitive and accurate, which can be applied to the endosulfan detection in traces biological samples. The distribution of endosulfan in fish and crab was different, which can provide evidence to the sample collection and analysis for toxicological analysis in relevant forensic identification. PMID- 30465403 TI - Forensic Pathology Analysis of 363 Sudden Death Cases in Yunnan Province. AB - OBJECTIVES: To study the epidemiological and pathological features of sudden death (SD) in Yunnan Province and to provide scientific evidence for prevention and forensic identification of sudden death. METHODS: Totally 363 SD cases were collected from the autopsies between 2009 and 2017 in the Forensic Centre of Kunming Medical University. The related factors such as etiology, age, inducing factor, time interval between the onset of disease and death, morbidity season and pathological change were retrospectively analysed. RESULTS: The incidence of SD in males was significantly higher than that of females. The peak age was >=35 55 years. The mortality rate was relatively high within 6 h after the onset of disease. The season order with descending number of deaths was spring, summer, winter and autumn. The top ten causes of SD were coronary heart disease, sudden unexplained death (SUD), cerebral hemorrhage, acute hemorrhagic necrotic pancreatitis, aortic dissection rupture, cardiomyopathy, pneumonia, pulmonary thromboembolism, amniotic fluid embolism and allergy. Exercise, infusion, surgery, medication and minor injury were the most common predisposing factors of sudden coronary death. Consciousness disorder or coma, chest pain or chest tightness, and abdominal pain were the most common premortem symptoms of sudden coronary death. CONCLUSIONS: The SD is more common in middle-aged males, which is the key population for the prevention of SD. For the forensic identification and prevention of SD, the attention on SUD should be paid. PMID- 30465404 TI - Forensic Analysis on 52 Medical Malpractice Cases of Cardiac Death. AB - OBJECTIVES: To synthetically analyse the medical malpractice cases of cardiac death in forensic identification, and to explore the generality and characteristic of cause of death, medical malpractice and assessment of participation degree. METHODS: Totally 52 medical malpractice cases of cardiac death examined in the Xiaoshan Branch Office, Hangzhou Minghao Forensic Judical Appraisal Institute, from January 2015 to April 2018 were collected. The general information of cases, medical institutions and situations of hospital stay, cause of death, medical malpractice and assessment of participation degree were retrospectively analysed. RESULTS: In 52 cases, the male to female ratio was 2.25:1, and most subjects aged >50-60. Cardiac death caused by hypertensive heart disease or coronary heart disease was most common (67.3%), followed by viral myocarditis and cardiomyopathy (13.5%). There were 24 cases involved surgery, and the survival time after surgery was from 1 h to 118 d with a 7 d medium value. There were 63 medical institutes involved in these medical malpractices. Medical malpractice presented in most hospitals more or less, and the participation degree was >20%-30%. CONCLUSIONS: Forensic appraisal contributes to determine causes of death, which not only provides scientific evidence for medical malpractice identification, but also improves diagnosis and treatment levels of medical institutions. PMID- 30465405 TI - Retrospective Analysis of 24 Cases of Forensic Medical Identification on Traumatic Tympanic Membrane Perforations. AB - OBJECTIVES: To study the case characteristics of forensic medical identification of traumatic tympanic membrane perforations, and to discuss the key points of forensic medical identification and evaluations methods for tympanic membrane perforations. METHODS: Twenty-four cases of traumatic tympanic membrane perforations accepted by the Academy of Forensic Science during 2017 were retrospectively analysed. The data of perforation size, form, predilection site, healing time and healing mode were evaluated. RESULTS: For the traumatic tympanic membrane perforations, the study showed that the small size of perforation (<1/2 quadrant) with irregular shape was common. The location of perforations was almost on the anterior and inferior quadrant, and centripetal migration healing was common. The healing rate within 6 weeks was up to 90%. CONCLUSIONS: In the identification cases of traumatic tympanic membrane perforations, the key is to determine whether it is traumatic and whether it will heal spontaneously within 6 weeks. It is suggested to check the tympanic membrane weekly by an otic endoscope combined with acoustic impedance measurement at the sixth week, which can improve the accuracy, objectivity and scientificity of the identification. PMID- 30465406 TI - Detection and Analysis of 12 Suspected Amelogenin Allelic Loss Cases. AB - OBJECTIVES: To observe and analyse the Amelogenin allelic loss in parent-child identification cases, and to explore the type and mechanism of Amelogenin allelic loss as well as its influence on gender identification and solutions. METHODS: After the detection by SiFaSTRTM 23plex DNA identification system, samples had the characteristics of the peak area of Amelogenin X was the same as the one of adjacent heterozygote or lower than one half of adjacent homozygote in females while Amelogenin X loss was observed in males were selected. X chromosome STR (X STR) typing and Amelogenin X sequencing were performed. The samples with Amelogenin Y loss in males were confirmed by the detection of Y chromosome STR typing and sex-determining region of Y (SRY). The type and rate of Amelogenin allelic loss were confirmed and calculated, and the mechanism and influence of this variation were also analysed. RESULTS: Amelogenin X allelic loss was observed in one male sample, the mutation in primer-binding region was confirmed by sequencing. The suspected Amelogenin X allelic loss was observed in four female samples, but the mutation in primer-binding region was confirmed by sequencing in only one sample. Amelogenin Y allelic loss was observed in seven male samples, SRY positive cases was detected in five of them, and two were SRY negative. Y-STR type was detected in four cases of the five SRY positive cases, which was not detected in the two SRY negative cases. The rate of Amelogenin allelic loss was about 0.029%. CONCLUSIONS: Amelogenin X allelic loss does not affect the gender identification, but Amelogenin Y allelic loss may cause wrong gender identification. Thus, Y-STR or SRY should be detected for gender confirmation. When Y-STR genotypes are not detected in a "male" whose SRY detection is also negative, then the chromosome karyotype analysis and sex differentiation related genes test should be taken to further confirm the gender. PMID- 30465407 TI - Comparison of Single Piece of Dandruff DNA Extraction under Microscope and EZ tape Method. AB - OBJECTIVES: To collect single piece of dandruff with microscopes to improve the regular EZ-tape method for DNA extraction and genotyping, increase the utilization of samples, reduce the miss rate as well as the proportion of genotyping results of mixed stains. METHODS: The insides of the hats worn by two volunteers were stuck by EZ-tape and scotch tape respectively. DNA on EZ-tape was directly extracted using traditional method. Single piece of dandruff was collected from the scotch tapes under microscope. The two kinds of methods were both performed under continuous oscillation and standing digestion, respectively. DNA was extracted through Chelex-100 method, and STR genotypes were obtained after amplification and electrophoresis. The results of STR genotypes obtained by EZ-tape method and single piece of dandruff analytical method were compared. RESULTS: Miss detections happened in 11 samples (45.8%) by EZ-tape method and only single-source typing results were obtained. Ten samples (41.7%) showed the genotype results of mixed stain and six of which showed allele insertions and deletions. The genotype results were obtained successfully using the single piece of dandruff analytical method, and two samples showed mixed stain genotype. The number of exact typing processed by oscillation was higher than that by standing digestion ( P<0.05). CONCLUSIONS: The oscillation during the DNA extraction process is in favour of the DNA releasing. Single piece of dandruff analytical method can be used to obtain single-source STR genotype with high successful ratio and low miss rate. This method can be a collection method of special samples such as dandruff in forensic practice. PMID- 30465408 TI - Application of Multiple Kits in Special Parentage Testing Cases. AB - OBJECTIVES: To analyse the genetic polymorphism of 21 autosome STR loci in Han population of Shandong Province and the cases with loci mutation or allelic loss typed by Goldeneye(r) DNA identification system 25A. METHODS: Totally 40 autosome STR loci types of 273 unrelated individuals in Han population of Shandong Province were typed by Goldeneye(r) DNA identification system 25A and 22NC, and the genetic polymorphism of 21 STR loci in those was analysed. Meanwhile, six cases with loci mutation were analysed by adding the tests with Goldeneye(r) DNA identification system 22NC, 20Y and 17X. Another three cases with allelic loss were tested by AmpFlSTR(r) Identifiler(r) Plus PCR and analysed by gene sequencing. RESULTS: The genetic parameters of 21 autosome STR loci in Han population of Shandong Province were obtained. When STR loci were added up to 40, five of those with loci mutation met the identification requirements, and the results of X-STR or Y-STR types were consistent with that of STR loci. There was another duo case with one suspected loci mutation, biological source of six STR loci genotypes could not be found in the genotypes of supposed father. The Y-STR genotype of two individuals was identical that indicated both of them came from same paternal line. However, the fatherhood was excluded according to the autosome STR loci system. For two cases with allelic loss on D18S51, base mutation or loss were found in the primer binding domain of mother and child by gene sequencing. Another mother-child case with allelic loss on D13S317 was certified by AmpFlSTR(r) Identifiler(r) Plus PCR kit. CONCLUSIONS: The 21 autosome STR loci in Han population of Shandong Province have high polymorphism, which can be used in routine cases of paternity identification. For some duo cases with loci mutation, Goldeneye(r) DNA identification system 25A cannot satisfy the identification requirements, thus more autosome STR loci should be added properly. For the cases with allelic loss, the problem can be resolved by gene sequencing or using different merchant kits. PMID- 30465409 TI - Genetic Polymorphisms and Mutations of 30 Y-STR Loci in Chinese Han Population. AB - OBJECTIVES: To investigate the genetic polymorphisms and mutations of 30 Y-STR loci in Chinese Han males and to evaluate its forensic application. METHODS: The DNA extracted from blood samples of 1 005 unrelated males and 1 008 father-son pairs (1 949 individuals in all) in Chinese Han population were typed using developed 30 Y-STR loci identification system. The parameters of population genetics and the mutation rates of each locus were analysed statistically. RESULTS: A total of 983 haplotypes were found in 1 005 unrelated males from Chinese Han population, of which 963 were unique. The overall haplotype diversity (HD) and discrimination capacity (DC) were 0.999 955 and 0.978 109, respectively. Totally 340 alleles were detected on 30 Y-STR loci, the value of gene diversity (GD) ranged from 0.410 3 to 0.952 3. The GD values of 24 out of the 30 loci were over 0.6. There were 30 269 allele transfers in 1 008 father-son pairs, one mutation in 68 father-son pairs, and the mutation of three father-son pairs occurred at two loci. On 26 Y-STR loci, 74 mutations were detected in 71 father son pairs. The average mutation rates were 2.4*10-3 (95% CI: 1.9*10-3-3.1*10-3). Seventy-three mutation events were one-step mutation (98.6%), 1 mutation event was two-step mutation (1.4%). CONCLUSIONS: The multiplex PCR system with 30 Y-STR loci has high genetic polymorphism and low mutation rates in Chinese Han males. Therefore, the system shows important values in Y-STR database construction and population genetic research. PMID- 30465410 TI - Extraction of DNA from Sperm Cells in Mixed Stain by Nylon Membrane Bushing Separation Technique. AB - OBJECTIVES: To establish a novel method for the separation of sperm cells in mixed stain, and to evaluate its application value. METHODS: Totally 40 mixed stain samples were collected from sexual assault cases. Sperm cells were separated by the conventional differential lysis method and the nylon membrane bushing separation technique, respectively. The DNA of sperm cells was extracted with the silicon membrane kit (Forensic DNA Extraction Kit for Soft Tissues). The PCR amplification was performed using AmpFlSTR(r) Identifiler(r) Plus kit, and the products were electrophoresed by 3500xL genetic analyser. The results of two separation methods were then compared. RESULTS: Complete and single-source male STR genotypes could be obtained from all the 40 mixed stain samples except three samples with minimal residual of female DNA by the nylon membrane bushing separation technique. The STR genotypes of sperm cells could not be detected in 25 samples, which were obtained in 15 samples (seven were of incomplete male STR genotypes, six with residual of female DNA, two were complete and single-source STR genotypes of sperm cells). CONCLUSIONS: The nylon membrane bushing separation technique developed in present study can be used in the separation of sperm cells in mixed stain, especially for the extraction of a small amount of sperm from a large quantity of female cells, which is inexpensive, rapid and simple. PMID- 30465411 TI - Research Progress on InDel Genetic Marker in Forensic Science. AB - Genetic markers in forensic DNA typing experienced the variable number of tandem repeats (VNTR) sequences and the short tandem repeats (STR) sequences. With the emerge of sequencing technology, the third generation of genetic markers were found out, which usually have two alleles including single nucleotide polymorphism (SNP) and insertion/deletion (InDel), also known as biallelic genetic markers. Because of the insertions or deletions of DNA fragments, InDel genetic marker reveals DNA fragment length polymorphism and widely distributes across the whole genome. InDel genetic marker is numerous and has the characteristics of STR and SNP genetic markers, which has been applied in the fields of genetics and anthropology. This review focuses on the research progress of InDel genetic marker in forensic science, aiming to review and summarize the main research findings in recent years and provide clues for future researches. PMID- 30465412 TI - Evaluation of safety and skin tolerability of organic cotton pads in case of irritative vulvitis. AB - BACKGROUND: The woman vaginal environment is a fragile and delicate ecosystem that is often impaired by physical and chemical agents. This condition tends to damage skin barrier causing allergic reactions that lead to chronic irritating conditions. METHODS: Clinical and in-vitro studies were performed on organic cotton pads in order to assess if their use can prevent the onset of irritant conditions. During clinical studies, the panelists' skin and mucosae state were checked through a gynecological clinical examination in order to assess tissue dryness and alterations. Moreover, each panelist answered a sensorial questionnaire at the end of the test. Data were gathered and the product acceptability of use was registered in terms of itching, irritations and burning feelings. The panelist score was calculated based on VNS Scale (0-10, where 0 is the minimum value and 10 is the maximum). RESULTS: From a careful analysis of the first part of the study, it is possible to state that the tested product (organic cotton pads) has proved to reduce the onset of irritative phenomena and slight undesired effects caused by the conventional use of synthetic pads. In-vitro tests were conducted to study possible biological processes involved during allergic and sensitizing events produced by vulvitis. In particular, a pro sensitizing test, a skin irritation on RHE (adapted from OECD 439) and tests to assess the soothing activity were performed on cell substrates. CONCLUSIONS: Results demonstrated that organic cotton pads, in each part, are safe and do not impair any physiological activities of the tissue substrates. PMID- 30465413 TI - Is fertility sparing surgery a treatment option for young patients with yolk sac tumor? AB - Yolk sac tumor (YST) is the third most frequent ovarian germ cell type ovarian tumor. YST occurs primarily in young girls and in women at reproductive age and thus, the preservation of fertility is considered to be a crucial option if possible for these patients. Compared to previous years, the use of innovative chemotherapeutic regimens in the treatment of YSTs improved significantly the prognosis and outcomes of this rare type of neoplasia. As YSTs are chemosensitive, this fact favors fertility sparing surgical approach and less aggressive type of operations. We present a narrative review of the multispecialty fertility sparing surgical and medical approach of women with YST. PMID- 30465414 TI - Post-EVAR aneurysm sac shrinkage is prognostically favorable, but does not justify withholding follow-up. AB - BACKGROUND: One of the main drawbacks of endovascular aortic aneurysm repair (EVAR) compared to open aortic surgery is the possibility of developing endoleaks and secondary aneurysm rupture, requiring frequent imaging follow-up. This study aims to identify prognostic factors that could be incorporated in follow-up protocols, which might lead to better personalized, lower cost and safe EVAR follow-up. METHODS: A retrospective study was performed including all patients who underwent elective EVAR from January 2000 to December 2015. Follow-up data were gathered by reviewing medical files for radiographic imaging. Linear and logistic regressions were used to assess predictive factors for aneurysm shrinkage. RESULTS: In 361 patients, aneurysm sac shrinkage of 10 millimeter or more was measured in 152 (42.1%) patients. Patients with >=10mm aneurysm shrinkage had fewer endoleaks (4.3% vs 24.6%, p<0.0001) and fewer re interventions for endoleak (3.0% vs 10.1%, p=0.007). Aneurysm sac shrinkage was correlated with the absence of endoleak development (OR 0.36, 95%CI 0.19-0.66, p=0.001). In patients who had achieved >=10mm shrinkage of the aneurysm sac, no further significant growth was seen, compared to 38 (15.3%) patients who did not attain size reduction (p<0.001). CONCLUSIONS: Once patients achieve >=10mm aneurysm sac shrinkage, they are less prone to developing subsequent aneurysm growth and have significantly lower risk of requiring surgery for endoleaks. However, a small number of patients remain at risk of requiring endoleak surgery after aneurysm shrinkage. Therefore, we would not recommend ceasing life-long imaging follow-up after significant aneurysm sac shrinkage, though it might be safe to increase the interval of follow-up. PMID- 30465415 TI - Association between false lumen segmental arteries and spinal cord ischemia in type A acute aortic dissection. AB - BACKGROUND: Spinal cord ischemia (SCI) and paraplegia are complications of surgery for type A acute aortic dissection (TAAAD). Since the segmental arteries play a key role in SCI, this study evaluated the association between SCI and false lumen segmental arteries (FLSAs: segmental arteries originating from the false lumen). METHODS: The study included 101 consecutive TAAAD patients (mean age, 66+/-13; range, 34-89 years) who underwent surgery from January 2011 to April 2017. The diagnosis of TAAAD and the number of FSLAs were determined by preoperative computed tomography (CT). Patients were divided into two groups according to the number of FLSAs at the Th9-L2 level: Group A (n=13), >=8 FLSAs; and group B (n=88), <=7 FLSAs. Preoperative, perioperative, and postoperative findings were compared between the groups, and risk factors for SCI were evaluated. RESULTS: The frequency of preoperative paralysis was significantly higher in Group A than Group B (P=.0070). The overall incidence of postoperative SCI was 8% (8/101) and significantly higher in Group A than Group B (5/13 (45%) vs 3/88 (4%), P<.0001). Hospital mortality was 8% (8/101) and significantly higher in Group A than Group B (3/13 (23%) vs 5/88 (6%), P=.0302). Multivariate analysis showed that the independent risk factors for SCI were >=8 FLSAs at Th9 L2 (odds ratio [OR], 20.4; 95% confidence interval [95% CI], 3.34-124.9, P=.0011) and diabetes mellitus (OR, 22.3; 95% CI, 1.69-294.5; P=.0184). CONCLUSIONS: In patients who underwent surgery for TAAAD, >=8 FLSAs at the Th9-L2 levels on preoperative CT was a risk factor for SCI. PMID- 30465416 TI - Left ventricular reconstruction surgery in ischemic heart disease: a systematic review of the past two decades. AB - INTRODUCTION: We sought to systematically review the existing literature reporting on patients recruited during the past twenty years regarding the role of left ventricular (LV) reconstruction in ischemic cardiomyopathy in terms of efficacy and mortality and provide an updated overview of the current evidence. EVIDENCE ACQUISITION: The PubMed and Cochrane bibliographical databases were thoroughly searched for the following MeSH terms: "ventricular reconstruction" OR ventriculoplasty OR "ventricular aneurysm" OR "ventricular restoration". Original studies -recruiting patients during the past twenty years- on LV reconstruction surgery in more than five cases and reporting on the associated peri- or post operative mortality were deemed eligible. EVIDENCE SYNTHESIS: Twenty-seven studies were included and provided data for 3,220 patients with a mean age of 61 years. Angina was present in 66.6% (510/766) of the patients, while nine out of ten (635/699) had a history of myocardial infarction. Average pre-operative ejection fraction was 29.9% and end-systolic volume index was 93.6 mL/m2. With respect to complications, low cardiac output syndrome and the need for intra aortic balloon pump were prevalent in 9.3% (79/850) and 18.8% (334/1,773), respectively. 30-day mortality was 7.1% (230/3,220) and late-mortality (mean follow-up of 36.9 months) was 19.6% (548/2,791), while the rate of MACCE was 40.1% (367/915). 5-year mortality was 29% (340/1,171). CONCLUSIONS: Our findings provide a current perspective of the role of LV reconstruction in the treatment of ischemic cardiomyopathy suggesting its benefit in survival. Taking into consideration the existing debate, further studies are required so that a solid conclusion to be made. PMID- 30465417 TI - Modified sizing technique with newly designed tools to facilitate the valve sparing aortic root replacement "David" procedure with mid-term results. AB - BACKGROUND: Valve sparing root replacement differs in specific points. The main target remains to achieve a perfect intraoperative result and long-term stability. We aimed in this study to present our modified sizing technique for valve-sparing "David" procedure and its mid-term results. METHODS: We present a retrospective single-centre study. A newly designed sizing ring in addition to triple-armed forceps (Trifeet(r)) was used to measure the proper size of the Valsalva(r) prosthesis for patients undergoing David-procedure. Primary endpoints are intraoperative aortic regurgitation (AR) and early postoperative outcomes. Secondary endpoints included freedom from aortic regurgitation or reoperation and overall mortality. RESULTS: A total of 63 consecutive patients who underwent David procedure between 09/2012 and 12/2016 were evaluated. Mean age was 52+/-15 years and 76.2% were male. Moderate to severe aortic regurgitation was reported in 60 (95.2%) patients. Four (6.3%) patients presented with type-A aortic dissection, 20 (31.7%) patients had bicuspid and 3 (4.8%) had a unicuspid aortic valve, 2 (3.2%) patients had a prior aortic valve repair. Intraoperative echocardiography revealed no 34 (54%), trace 26 (41.2%) or moderate 3 (4.8%) AR. Stroke, myocardial infarction, and 30-day mortality occurred in 1 patient (1.6%). During follow-up 5 (7.9%) patients needed reoperation due to recurrent AR within a mean of 35+/-18 months. One could be re-repaired, and the other four underwent aortic valve replacement. A second patient died in the late follow-up. CONCLUSIONS: Our modified sizing technique simplifies the "David-procedure" and allows to achieve a good intraoperative and mid-term results. However, these results have to be confirmed in a larger cohort with a long-term follow-up. PMID- 30465418 TI - Mid- and long-term prognosis of off- vs. on-pump coronary artery bypass graft in patients with multisite artery disease. AB - BACKGROUND: Among patients with coronary artery disease (CAD), around 25% have multisite artery disease (MSAD). Patients with CAD and MSAD are at higher risk of peri-operative and long-term cardiovascular events. Whether off-pump coronary bypass grafting (CABG) can improve their prognosis is unknown.We aimed to assess the benefits of off- vs. on-pump cardiac surgery in patients undergoing CABG, according to coexistence of extra-cardiac artery disease. METHODS: Between April 1998 and September 2008, 1221 patients undergoing CABG without any other intervention were enrolled. Overall death and major cardiovascular events were recorded at 1-month and during long-term follow-up. A propensity score (PS), derived from all relevant variables (p<0.25) associated with on-pump as compared to off-pump CABG, and representing the likelihood for each individual patient to receive off-pump CABG, was calculated. RESULTS: MSAD was observed in 279 patients (23%). Off-pump CABG was performed in 208 (17%) patients. The median follow-up was 7.6 years. The 10-year mortality was significantly lower in offvs. on-pump CABG group (74+/-4% vs. 68+/-2%, p=0.024). In patients with MSAD, there was a trend for better survival for off- vs. on-pump CABG (63+/-8% vs. 50+/-4%, p=0.078). After adjustment for PS, we found no further difference between on- and off-pump CABG both in the whole cohort (HR=1.30, p=0.10), as well as in MSAD patients (HR=1.51, p=0.14). CONCLUSIONS: Patients with MSAD receiving CABG are at worst prognostic than those with isolated CAD. In these patients, we found no significant difference in the long-term mortality and cardiovascular events between on- and off-pump CABG. PMID- 30465419 TI - Treatment of DVT with rivaroxaban and its potential to prevent the post thrombotic syndrome. AB - BACKGROUND: The study was initiated following the observation of complete recanalization of thrombus in subjects with DVT treated with rivaroxaban after 1 2 weeks. The aim of this observational retrospective study was to evaluate clinically and by means of Echo color Duplex, the fibrinolytic effect of rivaroxaban in patients with recent and previous DVT. To accomplish this two populations of patients were evaluated. METHODS: Group 1 was comprised of 31 patients (ranging in age 52-73 years) with popliteal- femoral DVT (12 months ago) treated with standard anticoagulant therapy. In these patients we found a complete superficial femoral recanalization and partial recanalization of the popliteal vein (30% of residual thrombus). The patients had normal creatinine clearance and liver function. The patients were switched from warfarin to rivaroxaban due to a lack of compliance with warfarin therapy. Group 2 was comprised of 22 patients (ranging in age 65-82 years) with previous popliteal femoral DVT and documented complete common femoral veins recanalization who presented with a recent superficial femoral vein re-thrombosis (1 week before). The patients had normal creatinine clearance and liver function. The patients switched from warfarin to rivaroxaban due to a lack of compliance with warfarin therapy. RESULTS: In Group 1 all patients exhibited the complete recanalization of the popliteal veins after 4 weeks of rivaroxaban therapy. In groups 2 all patients exhibited the complete recanalization of the popliteal veins after 4 weeks, and the complete recanalization of the acute re-thrombosis of the superficial femoral veins after 2 weeks of rivaroxaban therapy. No adverse events for both groups were observed. CONCLUSIONS: Our results suggest that rivaroxaban could have a pro-fibrinolytic effect not only on recent thrombus but also on organized thrombus that results in a complete recanalization of affected veins. It is proposed that this lytic effect will preserve venous valve structure and lead to a reduction of incidence of post-thrombotic syndrome in rivaroxaban treated patients. PMID- 30465420 TI - Endovenous ablation. AB - Varicose vein surgery is among the most commonly performed surgical interventions. The standard treatment 'high ligation and stripping' has in many countries been replaced by endovenous techniques. However there are many different techniques available. All have a different way of action and sometimes need different skills. The purpose of this review article is to give an update in those different endovenous ablation techniques. We describe the indications, technique, mechanisms of action and results. We conclude that all different techniques can be used safely and are effective. Even on long term there seems to be no difference in outcome, even compared to high ligation and stripping. PMID- 30465421 TI - Efficient xylitol production from cornstalk hydrolysate using engineered Escherichia coli whole cells. AB - Economic transformation of lignocellulose hydrolysate into valued-added products is of particular importance for energy and environmental issues. In this study, xylose reductase and glucose dehydrogenase were cloned into plasmid pETDuet-1 and then simultaneously expressed in Escherichia coli BL21(DE3), which was used as whole-cell catalyst for the first time to convert xylose into xylitol coupled with gluconate production. When tested with reconstituted xylose and glucose solution, 0.1 g/mL cells could convert 1 M xylose and 1 M glucose completely and produced 145.81 g/L xylitol with a yield of 0.97 (g/g) and 184.85 g/L gluconic acid with a yield of 1.03 (g/g) in 24 hours. Subsequently, the engineered cells were applied in real cornstalk hydrolysate, which generated 30.88 g/L xylitol and 50.89 g/L gluconic acid. The cells were used without penetration treatment and CaCO3 was used to effectively regulate the pH during the production, which further saved costs. PMID- 30465422 TI - Multifunctional Mechanical Sensors for Versatile Physiological Signals Detection. AB - Nowadays, the flexible and wearable mechanical sensors have attracted great attentions due to the potential applications in monitoring various physiological signals. However, conventional mechanical sensors rarely have both pressure and strain sensing abilities, which cannot simultaneously meet the demands of human subtle and large motions detection. Besides, the mechanical sensors with tunable sensitivity or measuring range are also essential for their practical applications. Herein, the graphene ink dip coating method with merits of time saving, low cost and large scale was used to fabricate the foam structured graphene sensors with both pressure and strain sensing performance. Due to the high elasticity of styrene butadiene rubber (SBR) substrate and stacked graphene flakes, the tunable mechanical sensors exhibit high gauge factor (GF) and large measuring range for specific human motions detection. The pressure sensor shows a GF of 2.02 kPa-1 with a pressure range up to 172 kPa, and the strain sensor displays a GF of 250 with a strain range up to 86%. On one hand, various detection of subtle vital signals with small strain change were demonstrated by the pressure sensor due to its flexibility and high sensitivity. On another hand, the strain sensor with large strain change shows excellent ability to detect various large human motions including the bending of neck, finger, wrist and knee. Interestingly, both pressure sensor and strain sensor exhibit great recognition capability for the hand-writing 26 letters. The working mechanism based on the contact area variation was also investigated by the morphology evolution and resistance model. We suppose that the foam structured graphene mechanical sensors would be promising wearable electronics for the human healthcare and activity monitoring in the future. PMID- 30465423 TI - Metallacycle-Cored Supramolecular Polymers: Fluorescence Tuning by Variation of Substituents. AB - Herein, we present a method for the preparation of supramolecular polymers with tunable fluorescence via the combination of metal-ligand coordination and phenanthrene-21-crown-7 (P21C7)-based host-guest interactions. A suite of rhomboidal metallacycles with different substituents were prepared via the coordination-driven self-assembly of a P21C7-based 60 degrees diplatinum(II) acceptor and 120 degrees dipyridyl donors. Upon variation of the substituents on the dipyridyl donors, the metallacycles exhibit emission wavelengths spanning the visible region (lambdamax = 427-593 nm). Metallacycle-cored supramolecular polymers were obtained via host-guest interactions between bis-ammonium salts and P21C7. The supramolecular polymers exhibit emission wavelengths similar to those of the individual metallacycles and higher fluorescent efficiency in solution and thin films. Utilizing a yellow-emitting supramolecular polymer thin film with high quantum yield (0.22), a white-light-emitting LED was fabricated by painting the thin film onto an ultraviolet LED. This study presents an efficient approach for tuning the properties of fluorescent supramolecular polymers and the potential of the metallacycle-cored supramolecular polymers as a platform for the fabrication of light-emitting materials with good processability and tunability. PMID- 30465424 TI - Reactive Oxygen Species (ROS)-Responsive Charge-Switchable Nanocarriers for Gene Therapy of Metastatic Cancer. AB - The application of non-viral gene vectors has been limited by their insufficient transfection efficiency because of poor serum stability, high endosomal entrapment, limited intracellular release and low accumulation in the targeted organelle. It has been still challenging to design gene carriers with properties that can overcome all the barriers. We previously developed a ROS-responsive cationic polymer, poly[(2-acryloyl)ethyl(p-boronic acid benzyl) diethylammonium bromide] (B-PDEAEA), which switches the charge at high concentrations of intracellular ROS to promote intracellular DNA release. However, its gene delivery efficiency has been limited by serum instability and lysosomal trapping, and coating with an anionic PEGylated lipid only showed mild enhancement. Herein, we coated the ROS-responsive B-PDEAEA polymer with two cationic lipids to form ROS-responsive lipopolyplexes with integrated properties to overcome multiple delivery barriers. The surface cationic lipids endowed the nanocarrier with improved serum stability, effective cellular uptake and lysosomal evasion. The interior B-PDEAEA/DNA polyplexes, which were highly stable in the extracellular environment, but quickly dissociated, released DNA, promoted nuclei localization and achieved efficient transcription. The mechanisms of ROS-responsive and charge switchable properties of B-PDEAEA were quantitatively studied. The transfection efficiency and antitumor activity of lipopolyplexes were studied in vitro and in vivo. We found that the ROS-responsive lipopolyplexes effectively delivered therapeutic genes into cell nuclei and caused high tumor inhibition in mice bearing peritoneal or lung metastases. PMID- 30465425 TI - The Influence of Moisture on the Energy Level Alignment at the MoO3/Organic Interfaces. AB - MoO3 is widely used in polymer-based organic solar cells as an anode buffer layer due to its high workfunction and formation of a strong dipole at the MoO3/polymer interface facilitating the charge transfer across the MoO3/polymer interface. In the present work we show that exposure of the MoO3/polymer interface to moisture attracts water molecules to the interface via diffusion. Due to their own strong dipole water molecules counter the dipole at the MoO3/polymer interface. As a consequence, the charge transfer across the MoO3/polymer will reduce and affect the charge transport across the interface. The outcome of this work thus suggest that it is critical to keep the MoO3/polymer interface moisture free which requires special precautions in device fabrications. The composition of the MoO3/P3HT:PC61BM interface is analyzed with X-ray photoelectron spectroscopy and the depth profiling technique neutral impact collision ion scattering spectroscopy. The results show that the concentration of oxygen increases upon exposure but leave the oxidation state of the Mo unchanged. Valence electron spectroscopy technique shows that the dipole across the MoO3/P3HT:PC61BM interface decreases even for short time exposure to atmosphere due to the diffusion of water molecules to the interface. The far-ranging consequences for organic electronic devices are discussed. PMID- 30465426 TI - Unipept 4.0: functional analysis of metaproteome data. AB - Unipept (https://unipept.ugent.be) is a web application for metaproteome data analysis, with an initial focus on tryptic peptide based biodiversity analysis of MS/MS samples. As the true potential of metaproteomics lies in gaining insights in the expressed functions of complex environmental samples, the 4.0 release of Unipept introduces complementary functional analysis based on GO terms and EC numbers. Integration of this new functional analysis with the existing biodiversity analysis is an important asset of the extended pipeline. As a proof of concept, a human faecal metaproteome dataset from 15 healthy subjects was reanalysed with Unipept 4.0, yielding fast, detailed and straightforward characterization of taxon-specific catalytic functions that is shown to be consistent with earlier results from a BLAST-based functional analysis of the same data. PMID- 30465427 TI - Tat-independent secretion of polyethylene terephthalate hydrolase PETase in Bacillus subtilis 168 mediated by its native signal peptide. AB - Widespread utilization of polyethylene terephthalate (PET) has caused critical environmental pollution. The enzymatic degradation of PET is a promising solution to this problem. In this study, PETase, which exhibits much higher PET-hydrolytic activity than other enzymes, was successfully secreted into extracellular milieu from Bacillus subtilis 168 under the direction of its native signal peptide (named SPPETase). SPPETase is predicted to be a twin-arginine signal peptide. Intriguingly, inactivation of twin-arginine translocation (Tat) complexes improved the secretion amount by 3.8-fold, indicating that PETase was exported via Tat-independent pathway. To the best of our knowledge, this is the first report on the improvement of Tat-independent secretion by inactivating Tat components of B. subtilis 168 in LB medium. Furthermore, PET film degradation assay showed that the secreted PETase was fully active. This study paves the first step to construct an efficient engineered strain for PET degradation. PMID- 30465428 TI - Synthesis of Diversely Functionalized 2H-Chromenes through Pd-Catalyzed Cascade Reactions of 1,1-Dibromoolefin Derivatives with Arylboronic Acids. AB - In this paper, an unprecedented synthesis of (2H-chromen-2-ylidene)acetates and (2H-chromen-2-ylidene)ethanones with controlled stereoselectivity via Pd catalyzed cascade reactions of 3-(2-(2,2-dibromovinyl)phenoxy)acrylates or 3-(2 (2,2-dibromovinyl)phenoxy)enones with aryl boronic acids has been established. This protocol combines two C-C bond forming reactions (an intermolecular Suzuki coupling followed by an intramolecular Heck coupling) in one pot under the catalysis of the same catalyst. Compared with literature methods for the preparation of 2H-chromene derivatives, it has advantages such as easily obtainable or commercially available substrates, diverse substitution pattern of products, simple procedure, and excellent stereoselectivity. Interestingly, this cascade reaction could distinguish the subtle difference of the electron withdrawing capacity and the size of various functional groups, and thus resulted in different chemoselectivity. In addition, the utility of the (2H-chromen-2 ylidene)acetate thus obtained was showcased by its facile transformation into the synthetically and photophysically significant 3H-xanthen-3-one derivative. PMID- 30465429 TI - Insights into high conductivity of the two-dimensional iodine-oxidized sp2-c-COF. AB - The conductivity of newly synthesized two-dimensional (2D) sp2-carbon-hybridized ?-conjugated covalent organic framework (sp2-c-COF) can be enhanced by as much as 12 orders of magnitude after iodine oxidation processing (Science, 2017, 357, 673 676). To understand the chemical mechanism underlying such a huge increase in conductivity due to iodine oxidation, we performed multi-scale computation for the iodine oxidized 2D COF. We find that the high conductivity can be attributed to both hole transfer and ion transfer owing to the presence of both anionic iodine trimer (I3-) with nearly-linear structure and COF cations in the 2D COF. The computed low ionization energies of the organic node TFPPy and the linker PDAN suggest that the delocalized ? electrons can be easily transferred. This result is also supported by the dominant charge distribution due to the ? electrons on the TFPPy. Meanwhile, the cations of 2D COF can induce a shift of the Fermi level to cross the valence band maximum, thereby enhancing the hole mobility to 86.75 cm2 v-1s-1. Complementary classical molecular dynamics simulation demonstrates a relatively high value of anion conductivity of 13.63 ? 10-2 S m-1, consistent with the experimental results. Lastly, for the potential application of the iodine-oxidized 2D sp2-c-COF, we design a prototypical model of the 2D spirally wound lithium-ion battery, and show that the model system exhibits an excellent conductivity for ion transfer. PMID- 30465430 TI - Proline-Based Boronic Acid Receptors for Chiral Recognition of Glucose. AB - Chiral recognition remains a major challenge in the area of molecular receptor design. With this research we set out to explore the use of proline based receptors for chiral recognition. Importantly, the proline structure allows for the in-troduction of at least two different binding groups due to the availability of both an amine and carboxylic acid group. Here we report a proof of-concept exploration into the chiral recognition of D-/L-glucose, as model chiral species which prefers to bind to at least two boronic acid groups. We evaluated several proline-based receptors incorporating two phenylboronic acid groups, respectively at the N- and C-termini of the amino acid residue, via amide bonds. We confirmed that the receptors exhibited chiral recognition using CD, 1H NMR and 19F NMR spectroscopy. Given the der-ivation diversity available, our strategy to use proline-based receptors for chiral recognition holds significant promise for extension to other chiral systems. PMID- 30465431 TI - Copper-catalyzed Domino Addition, Hydroamination and Cyclization: A Multicomponent Approach to Spiro Oxazolidinone Derivatives. AB - Copper-catalysed one-pot multicomponent protocol has been developed for construction of spiro heterocycles. The domino approach, leads to synthesis of spiro oxazolidinones starting from ketones, arylacetylenes, and isocyanates via catalytic addition, hydroamination and cyclization involving consecutive C-C, C O, and C-N bond formations. PMID- 30465432 TI - Admittance and Conductance Detection in the Capillary Scale. AB - Admittance detection, more commonly called Capacitively Coupled Contactless Conductivity Detection, is widely used. While the true conductance of a solution is linear with concentration up to ~1 meq/L, the admittance signal is nonlinear. In small bore capillaries and highly resistive solutions, such as in suppressed open tubular ion chromatography (SOTIC), the admittance sig-nal is exponentially related to concentration. Galvanic contact conductivity detection is common in microfluidics, but no true conductivity measurement efforts have been made with conventional capillaries in the last two decades. We examine five gal-vanic contact cell geometries: (a) wire/disk electrodes perpendicular to the flow direction (like Anal. Chem. 1987, 59, 2747), (b) annular tubular electrodes facing the flow (that exits through the center tube), (c) ring-disk electrodes facing the flow that exits through the annulus, (d) coplanar parallel wire/disk electrodes facing the flow that exit around the electrodes, and (e) planar electrodes separated by a thin insulating layer with a through-hole in which the liquid flows. Present limitations in the available components as well as the designs themselves do not allow type A and B cells to reach low enough dispersion levels. Types C-E all produce the same efficiency for chloride in a SOTIC set up (12,000+/-200 plates/m), limited by dispersion in the suppressor. Further choice and refinement will be dictated by the availability of a lower dispersion suppressor. All galvanic contact con-ductance results were linear with concentration and initial results suggest that attainable LODs will be competitive with those from benchtop ICs. PMID- 30465433 TI - Electrochemical Determination of Adrenaline using MXene/Graphite composite paste electrodes. AB - MXene/Graphite composite paste electrode (MXene/GCPE) based electrochemical sensor has been fabricated for the detection of adrenaline. The electrode exhibits a sensitive response to adrenaline in phosphate buffer solution of pH 7.4, and its catalytic activity is much higher than that of the bare graphite paste electrode. The electron transfer reaction of MXene/GCPE is a diffusion controlled process. The graph of concentration of adrenaline with the peak current exhibits two linearities, one in the lower and other in the higher concentration range with a detection limit of 9.5 nM. The simultaneous analyses of adrenaline, ascorbic acid and serotonin reveal that the fabricated electrode could separate the overlapped cyclic voltammetric peaks of these ternary mixtures. This electrode has been further employed in the detection of adrenaline in pharmaceutical samples with 99.2%-100.8% recoveries. PMID- 30465434 TI - A Lysosome-Targetable Fluorescent Probe for Simultaneously Sensing Cys/Hcy, GSH, and H2S from Different Signal Patterns. AB - Biothiols, a vital branch of reactive sulfur species (RSS) family, are indispensable in human physiology. However, the exact functional roles of each biothiol involved in complicated physiological activities are still not fully clarified. A critical barrier is a lack of robust molecular tools which can simultaneously visualize different biothiols with distinct emission signals. Herein, the first lysosome-targetable fluorescent probe, Lyso-RC, which could respond to Cys/Hcy, GSH, and H2S with different sets of signal patterns was developed. Lyso-RC responds to Cys/Hcy, GSH, and H2S with the fluorescence signal patterns of blue-red, green-red, and red, respectively. Significantly, Lyso-RC is capable of discriminating lysosomal Cys/Hcy, GSH, and H2S in HeLa cells. PMID- 30465435 TI - Posterior "Open Book" approach for type 1 internal hemipelvectomy. AB - INTRODUCTION:: Internal limb-sparing hemipelvectomy is currently the preferred surgical option for resection of pelvic tumours. Obtaining an acceptable functional outcome through the standard ilioinguinal or iliofemoral incisions, only compounds the already challenging dissection, resection and reconstruction of these extensive en-bloc extirpative oncologic operations. SURGICAL TECHNIQUE:: We describe a novel surgical approach to the lateral pelvis that minimises injury to the gluteal muscles, spares the gluteal vessels and provides a broad yet shallow operative field conducive to microsurgery with sizeable vasculature in close proximity to facilitate any microsurgical reconstruction. Access to the ilium and sacrum for Enneking Type 1 and Type 4 resections respectively is obtained by reflecting a skin and soft tissue flap anteriorly while the gluteal muscles are reflected posteriorly and inferiorly. This technique minimises the amount of tissue reflected in any particular direction, therefore, providing a broad and shallow operative field which benefits the orthopaedic oncologic surgeon and the plastic reconstructive surgeon. CONCLUSION:: The "posterior open book" approach offers a promising alternative to the standard ilioinguinal or iliofemoral incisions for internal limb-sparing Type 1 hemipelvectomies while also optimising the exposure for subsequent reconstructive procedures. PMID- 30465436 TI - Diabetic hip arthropathy is associated with a higher prevalence of femoral head chondromalacia: a case-controlled study. AB - INTRODUCTION:: No previous studies have characterised hip joint disease in diabetic patients undergoing hip arthroscopy. The purpose of our study was to evaluate intra-articular hip pathology and surgical variables in patients with diabetes compared to matched, non-diabetic controls. We hypothesised that diabetic patients would demonstrate a higher prevalence and severity of hip chondral pathology. METHODS:: We retrospectively reviewed 795 consecutive hip arthroscopies performed by a single surgeon between 2010 and 2015. Patients ?18 years of age without a history of diabetes served as controls and were matched based on age, sex, body mass index, duration of symptoms, and operative side. Clinical symptoms, preoperative physical examination, and radiologic and intraoperative findings were assessed. The primary outcomes were the acetabular and femoral head chondromalacia index (CMI), calculated as the product of the Outerbridge chondromalacia grade and surface area (mm2*severity). RESULTS:: 15 diabetic patients were matched to 137 non-diabetic controls. Diabetic patients demonstrated a higher prevalence of femoral head chondromalacia compared to controls both on magnetic resonance imaging (45.5% vs. 7.5%, p = 0.002) and during arthroscopy (100% vs. 75.9%, p = 0.042). Femoral head chondromalacia in diabetic patients had higher Outerbridge grade (2.4 vs. 2.0, p = 0.030) but similar CMI (513.0 vs. 416.4, p = 0.298) compared to controls. DISCUSSION:: Femoral head chondral pathology was more prevalent and of higher severity grade in diabetic patients. The prevalence, size, and severity of acetabular chondral disease were similar between diabetic and non-diabetic patients. Multivariate analysis demonstrated that diabetic status was independently associated with the presence of femoral head chondromalacia. PMID- 30465438 TI - How to manage a spontaneous coronary artery dissection: reconsidering diagnosis and therapy. PMID- 30465437 TI - Designing multifunctional cancer-targeted nanosystem for magnetic resonance molecular imaging-guided theranostics of lung cancer. AB - The integration of diagnosis and therapy is an effective way to improve therapeutic effects for cancer patients, which has acquired widely attentions from researchers. Herein, a multifunctional drug-loaded nanosystem (F/A PLGA@DOX/SPIO) has been designed and synthesized to reduce the side effects of traditional chemotherapy drugs and realize simultaneous tumor diagnosis and treatment. The surface modification of folic acid (FA) and activatable cell penetrating peptide (ACPP) endows the nanosystem with excellent cancer targeting capabilities, thus reducing toxicity to normal organs. Besides, the F/A PLGA@DOX/SPIO nanosystem can serve as an excellent magnetic resonance imaging (MRI) T2-negative contrast agent. More importantly, according to in vitro experiments, the F/A-PLGA@DOX/SPIO nanosystem can promote the overproduction of reactive oxygen species (ROS) within A549 lung cancer cells, inducing cell apoptosis, greatly enhancing the antineoplastic effect. Furthermore, with the help of MRI technology, the targeting imaging of the F/A-PLGA@DOX/SPIO nanosystem within tumors and the dynamic monitoring of medicine efficacy can be realized. Therefore, this study provided a multifunctional drug-loaded F/A-PLGA@DOX/SPIO targeted nanosystem for magnetic resonance molecular imaging-guided theranostics, which has excellent potential for the application in tumor diagnosis and therapy. PMID- 30465439 TI - Efficacy of gelatin tannate for acute diarrhea in children: a systematic review and meta-analysis. AB - AIM: To investigate by meta-analysis the efficacy of gelatin tannate (GT), a mucosal barrier protector, in children with acute gastroenteritis. METHODS: A comprehensive literature search was conducted. Studies were selected according to PICO: Participants: children aged 0-12 years with acute diarrhea; Intervention: GT; Comparison: oral rehydration solution and/or placebo; Outcomes: diarrhea related outcomes. RESULTS: Three published randomized controlled trials were identified of pediatric diarrhea treated with GT (n = 203) or control (n = 204). GT significantly (p < 0.01) reduced stool frequency at 12 h in two randomized controlled trials. A significant treatment effect (risk ratio = 0.74; p < 0.01) in favor of GT was found for the exploratory composite outcome of 'diarrhea or liquid stools at 24 h' in three studies. Risk ratios in a single study which reported the percentage of patients with liquid stools at 12, 24 and 48 h favored GT at all time points. No significant differences were found between GT and control for patients with diarrhea at 12 or 24 h or for duration of diarrhea. CONCLUSION: GT improved stool frequency and stool consistency in children with acute diarrhea, although further well-controlled studies would be useful to confirm a beneficial treatment effect. PMID- 30465440 TI - Discourse recovery after severe traumatic brain injury: exploring the first year. AB - OBJECTIVES: Although much is known about discourse impairment, little is known about discourse recovery after severe traumatic brain injury (TBI). This paper explores discourse recovery across the critical first year, controlling for pre injury, injury and post-injury variables. DESIGN AND METHODS: An inception cohort comprising 57 participants with severe TBI was examined at 3, 6, 9 and 12 months post-injury and compared to a cross-section of matched healthy control participants. A narrative discourse task was analyzed with main concept analysis (MCA). A mixed linear model approach was used to track recovery controlling for pre-injury, injury and post-injury variables. RESULTS: An upward trajectory of recovery was observed, with peak periods of improvement between 3-6 and 9-12 months and all time points were significantly below controls. Years of education and PTA duration were significant covariates in the recovery model. Presence of aphasia also influenced the recovery model. CONCLUSIONS: Individuals with TBI typically improve over the first year, however many will continue to have discourse deficits at 12 months. Years of education, PTA duration and aphasia should be considered when planning services. The 3-6- and 9-12-month periods may offer optimal periods for discourse recovery and increased supports may be beneficial between 6-9 months. PMID- 30465441 TI - Bifidobacterium longum IM55 and Lactobacillus plantarum IM76 alleviate allergic rhinitis in mice by restoring Th2/Treg imbalance and gut microbiota disturbance. AB - This study aimed to examine whether probiotics, which suppressed the differentiation of splenic T cells into type 2 helper T (Th2) cells and induced into regulatory T cells in vitro, alleviate allergic rhinitis (AR) and gut microbiota disturbance. We isolated Bifidobacterium longum IM55 and Lactobacillus plantarum IM76 from human faecal microbiota and kimchi, respectively, and examined their effects on ovalbumin (OVA)-induced AR and gut microbiota disturbance in mice. Treatment with IM55, IM76, or their probiotic mixture (PM) significantly reduced OVA-induced allergic nasal symptoms and blood immunoglobulin E (IgE) levels in mice. These also reduced OVA-induced interleukin (IL)-4 and IL-5 levels in nasal tissues and bronchoalveolar lavage fluid (BALF) but increased OVA-suppressed IL-10 levels. Treatment with IM55, IM76, or PM reduced OVA-induced increase in the populations of mast cells, eosinophils, and Th2 cells and increased OVA-suppressed population of regulatory T cells in the BALF. Treatment with IM55, IM76, or PM also inhibited OVA-induced expression of IL-5 in lung and colon tissues and restored OVA-disturbed composition of gut microbiota Proteobacteria, Bacteroidetes, and Actinobacteria. These results suggest that IM55 and IM67 can alleviate AR by restoring Th2/Treg imbalance and gut microbiota disturbance. PMID- 30465442 TI - Local carotid arterial stiffness is an independent determinant of left ventricular remodeling in never-treated hypertensive patients. AB - PURPOSE: The aim was to investigate the association between blood pressure (BP), carotid stiffness, carotid-femoral pulse wave velocity (cfPWV) and left ventricular (LV) remodeling in never-treated hypertensive patients. MATERIAL AND METHODS: 178 never-treated hypertensive underwent transthoracic echocardiography, 24-hour ambulatory BP monitoring (ABPM), local carotid stiffness and regional cfPWV assessed using a high-definition echo-tracking ultrasound system and a tonometric transducer, respectively. LV parameters and arterial stiffness were also considered in dippers and non-dippers. RESULTS: Mean night-time BP best correlated with carotid and LV parameters. Carotid stiffness parameters (beta index, pressure-strain elastic modulus, one-point PWV) correlated with LV mass, relative wall thickness, and E/A ratio while cfPWV correlated only with E/A ratio. In multiple regression analysis, age and mean night-time ABPM had a stroger relation with carotid stiffness than cfPWV. In a second multiple regression analysis, day and night ABPM and carotid stiffness were independently related with LV remodeling and left atrial volume. In non-dippers, local carotid stiffness parameters were significantly higher than in dippers, whereas cfPWV was not significantly different. CONCLUSIONS: Carotid stiffness parameters are independently associated with LV remodeling and have an additive effect to BP and over cfPWV moreover local arterial stiffness is higher in non-dippers. PMID- 30465443 TI - Exercise augments the modulatory effects of vitamin E on pre-diabetes-induced aortopathy: a potential role of adiponectin. AB - BACKGROUND: We tested the hypothesis that vitamin E may protect against pre diabetes-induced aortic injury (aortopathy), and exercise can augment the action of vitamin E. MATERIAL AND METHODS: Rats were either fed with a high fat and fructose diet (HFD) (model group) or a standard laboratory chow (control group) for 15 weeks before being sacrificed. The three protective groups were treated with vitamin E (HFD + Vit E), swimming exercises (HFD + Ex), and vitamin E plus swimming exercises (HFD + VitE + Ex), respectively. RESULTS: Aortopathy was developed in the model group as demonstrated by substantial tissue ultrastructural alterations, which were partially protected by vitamin E and effectively protected with vitamin E plus swim exercise. Also, swimming exercises significantly (p < .05) increased the modulatory effects of vitamin E on dyslipidemia, insulin resistance, blood pressure, oxidative stress, inflammation, leptin, and adiponectin, except coagulation and thrombosis. CONCLUSIONS: Swim exercise augments the protective effects of vitamin E in a pre-diabetic animal model. PMID- 30465444 TI - Primary M1 macrophages as multifunctional carrier combined with PLGA nanoparticle delivering anticancer drug for efficient glioma therapy. AB - Glioma remains difficult to treat because of the infiltrative growth of tumor cells and their resistance to standard therapy. Despite rapid development of targeted drug delivery system, the current therapeutic efficacy is still challenging. Based on our previous studies, macrophages have been proved to be promising drug carrier for active glioma delivery. To make full use of macrophage carrier, primary M1 macrophages were proposed to replace regular macrophage to deliver nanodrugs into glioma, because M1 macrophages not only have the natural ability to home into tumor tissues, but they also have stronger phagocytic capability than other types of macrophage, which can enable them to uptake enough drug-loaded nanoparticles for therapy. In addition, M1 macrophages are not easily affected by harsh tumor microenvironment and inhibit tumor growth themselves. In this study, M1 macrophage-loaded nanoparticles (M1-NPs) were prepared by incubating poly(lactide-co-glycolide) (PLGA) nanoparticles with primary M1 macrophages. In vitro cell assays demonstrated M1 macrophage still maintained good tumor tropism capability after particle loading, and could efficiently carry particles across endothelial barrier into tumor tissues. In vivo imaging verified that M1-NPs exhibited higher brain tumor distribution than free nanoparticles. DOX@M1-NPs (doxorubicin-loaded M1-NPs) presented significantly enhanced anti glioma effect with prolonged survival median and increased cell apoptosis. In conclusion, the results provided a new strategy exploiting M1 macrophage as carrier for drug delivery, which improved targeting efficiency and therapeutic efficacy of chemodrugs for glioma therapy. PMID- 30465445 TI - Sources of stress and worry in the development of stress-related mental health problems: A longitudinal investigation from early- to mid-adolescence. AB - BACKGROUND AND OBJECTIVES: Stress and stress-related mental health complaints are common and increasing among adolescents, especially girls. Identifying typical sources of stress as well as central intervention targets is an important effort in the development of effective prevention and treatment protocols. This study investigated worry as potential mediator in the development of mental health problems in response to common stressors in adolescence. We also examined to what sources adolescents ascribe their stress over the years from the 7th through the 9th grade. DESIGN: Prospective cohort study. METHODS: Self-reported subjective stressor load, worry, anxiety and depressive symptoms were assessed in a sample of Swedish 7th graders (N = 1137; 46% girls, mean age 13.2) with follow-up assessments one and two years later. RESULTS: School was the most common source of stress across all time-points, with girls reporting considerable more stress than boys. Worry mediated the relationship between overall stressor load and depressive symptoms and anxiety over time and was not moderated by gender. CONCLUSIONS: Worry may be an important target in stress prevention and efforts to prevent stress-related problems would benefit from focusing on early adolescence as especially school stress is already relatively common in grade 7. PMID- 30465446 TI - "Just a Heads Up, My Father Has Alzheimer's": Changes in Communication and Identity of Adult Children of Parents with Alzheimer's Disease. AB - Alzheimer's disease is the most common type of dementia, accounting for 60-80 percent of cases. The disease causes devastating impairment and often loss of cognitive and relational functioning for the individual and creates disorder and chaos for the family system. Even when not stepping into the formal role of caretaker, children of parents with Alzheimer's disease experience increased vulnerability to physical and psychological illness, changes in family roles, and uncertainty about navigating a relationship with a parent they no longer know. In the present study, I sought to understand, through the lens of identity and identity-work, how adult children of parents with the disease perceived that their communication with and about the parent changed. Data from interviews with 12 adult children, none of whom were formal caregivers to their parents with the illness but all reported experiencing shifts in their identity and roles as a child of a parent with the disease, revealed four significant communication changes: communicating with a parent who was the same but different, communicating in multiple roles, correcting or reprimanding the parent, and managing parent's private information. I discuss these findings, their implications, practical suggestions from the data, and suggested areas of future research. PMID- 30465447 TI - Tempol modulates the leukocyte response to inflammatory stimuli and attenuates endotoxin-induced sickness behaviour in mice. AB - BACKGROUND AND AIMS: Lipopolysaccharide (LPS), an endotoxin, is a component of the outer membrane of Gram-negative bacteria that is able to activate the peripheral immune system, leading to changes in signalling pathways that act locally and systemically to achieve adaptive responses. Sickness behaviour is a motivational state in response to endotoxin exposure and includes depressed activity and a reduction of exploratory behaviour, potentially reorganising organism priorities to cope with infectious diseases. We hypothesised that 4 hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol) modulates the leukocyte response to endotoxins and decreases LPS-induced sickness behaviour in mice. METHODS: The effects of Tempol on LPS-induced peritonitis and the respiratory burst of neutrophils primed with LPS and triggered by phorbol 12-myristate-13 acetate (PMA) were evaluated. To evaluate the effects of Tempol on sickness behaviour, the mice were submitted to an open field and forced swim tests. RESULTS: Tempol (50-100 MUM/106 cells) decreased the respiratory burst of LPS primed and PMA-stimulated neutrophils in vitro. In vivo, this nitroxide (30 and 100 mg/kg body weight) inhibited leukocyte migration to the peritoneal cavity after LPS administration in mice. Moreover, Tempol pretreatment (30 and 100 mg/kg body weight) before LPS administration also attenuated sickness behavioural changes. CONCLUSIONS: Together, these findings shed light on the mechanisms underlying the anti-inflammatory potential and confirm the therapeutic potential of nitroxides. PMID- 30465448 TI - Plasmid copy number and qnr gene expression in selection of fluoroquinolone resistant Escherichia coli. AB - Fluoroquinolone resistance in Enterobacteriales is developed by chromosomal and plasmid-mediated mechanisms. Plasmids play an important role in dissemination of resistant genes and they carry genes that protect bacteria in different stress induced situations. In this study, we studied Escherichia coli strains, each carried one plasmid-mediated quinolone resistance determinant namely, qnrA1, qnrB1, qnrC1, and qnrD1. We exposed 0.5 McFarland density of each strain to 0.5 mg/L ciprofloxacin from the period of 30, 60, 90, and 120 min over 24 h. All treated strains were further exposed to a constantly increasing 1, 2, 4, and 8 mg/L ciprofloxacin solution through 24, 48, and 120 h. In given timepoints, RNA was extracted from all treated strains. Expression of qnrA1, qnrB1, qnrC1, and qnrD1 was investigated by quantitative PCR. Mutations in gyrA and parC genes were analyzed by PCR and nucleic acid sequencing. In this study, during 0.5 mg/L ciprofloxacin exposition, the following expression levels were detected: 1.2 for qnrA1, 1.47 for qnrD1, 12.44 for qnrC1, and 80.63 for qnrB1. In case of long-term study, we selected a resistant strain in qnrB1-positive E. coli, and its expression increased from 105.91 to 212.31. On the contrary, plasmid copy number increased in time from 1 to 4.13. No mutations in gyrA or in parC chromosomal genes of treated strains were detected. Our results show that qnrB1-positive E. coli strain was able to develop fluoroquinolone resistance by upregulated qnrB1 expression that was linked to a minor increase in plasmid copy number but no mutations occurred in gyrA or parC. PMID- 30465449 TI - High prevalence of vancomycin and high-level gentamicin resistance in Enterococcus faecalis isolates. AB - Multiple drug-resistant enterococci are major cause of healthcare-associated infections due to their antibiotic resistance traits. Among them, Enterococcus faecalis is an important opportunistic pathogen causing various hospital-acquired infections. A total of 53 E. faecalis isolates were obtained from various infections. They were identified by phenotypic and genotypic methods. Determination of antimicrobial resistance patterns was done according to CLSI guidelines. The isolates that were non-susceptible to at least one agent in >=3 antimicrobial categories were defined as multidrug-resistant (MDR). Detection of antimicrobial resistance genes was performed using standard procedures. According to MDR definition, all of the isolates were MDR (100%). High-level gentamicin resistance was observed among 50.9% of them (MIC >= 500 MUg/ml). The distributions of aac(6')-Ie-aph(2'')-Ia and aph(3')-IIIa genes were 47.2% and 69.8%, respectively. The aph(2'')-Ib, aph(2'')-Ic, aph(2'')-Id, and ant(4')-Ia genes were not detected. Vancomycin resistance was found in 45.3% of strains. The vanA gene was detected in 37.7% of isolates, whereas vanB and vanC1 genes were not observed in any strain. Erythromycin resistance rate was 79.2% and the frequencies of ermB and ermC genes were 88.6% and 69.8%, respectively. The ermA and msrA genes were not present in any of the isolates. Our data indicate a high rate of MDR E. faecalis strains. All of high-level gentamicin-resistant isolates carried at least one of aac(6')-Ie-aph(2'')-Ia or aph(3')-IIIa genes. Distribution of vanA was notable among the isolates. In addition, ermB and ermC were accountable for resistance to erythromycin. PMID- 30465450 TI - Changes in mRNA expression of members of TGFB1-associated pathways in human leukocytes during EBV infection. AB - Transforming growth factor beta 1 (TGFB1) likely contributes to the pathogenesis of Epstein-Barr virus (EBV)-mediated cancer. A microarray containing 59 probes for detecting mRNA of members of TGFB1-associated pathways was developed. mRNA expression of TGFB1 receptors and members of connected pathways were examined in peripheral blood leukocytes of patients during acute EBV infection and after recovery. TGFB1 and TGFBR2 mRNA expression was increased in patients with EBV infection. Similarly, mRNA expression of protein kinase C (PRKCB), MAP3K7, PDLIM7, and other members of TGFB1 and NF-kappaB signaling pathways increased. A shift of mRNA transcript variant expression of some key members (TGFBR2, PRKCB, and NFKBIB) of involved signaling pathways was detected. After the patients' recovery, most of the altered mRNA expression has been normalized. We speculate that in patients with EBV infection, members of TGFB1-associated pathways contribute to the suppression of proapoptotic and induction of pro-survival factors in leukocytes. The modulation of TGFB1-associated pathways may be considered as a potential risk factor in the development of EBV-associated tumors in patients with acute EBV infection. PMID- 30465451 TI - Periportal hepatic involvement of non-Hodgkin lymphoma: a rare case report with magnetic resonance imaging findings. AB - Lymphoma with hepatic involvement can present with three morphological patterns: diffuse infiltrative, nodular, and mixed infiltrative-nodular. However, lymphoma with periportal infiltrative hepatic involvement is rare. There have been a few reports of cases with this type of hepatic involvement including ultrasound or computed tomography (CT) findings. In this case report, we present CT, magnetic resonance imaging (MRI), and diffusion-weighted MRI findings together with the histopathological results for a patient with periportal hepatic lymphoma presenting with obstructive jaundice. PMID- 30465452 TI - Effect of gastric fluid aspiration on the lung microbiota of laboratory rats. AB - AIM OF THE STUDY: The pulmonary microbiota is important for both normal homeostasis and the progression of disease, and may be affected by aspiration of gastric fluid. The aim of this study was to investigate changes in the lung microbiota induced by aspiration of gastric fluid in a laboratory rat model. MATERIAL AND METHODS: Using the intratracheal application method, male rats received aspiration with 0.9% normal saline (n = 11); gastric fluid (n = 24) or sterilized (gamma-irradiated) gastric fluid (n = 12) once-weekly for four weeks. On the fifth week, the animals were sacrificed, and the microbiota of the lung was assessed by 16S ribosomal RNA gene sequencing. RESULTS: Lungs without aspiration and lungs after aspiration with normal saline had similar microbial compositions, dominated by bacteria of the genera Serratia, Ralstonia and Brucella. Evaluation of the microbiota following aspiration of gastric fluid revealed a much different profile that was dominated by bacteria from the genera Romboutsia and Turicibacter and largely independent of sterilization of the gastric fluid. CONCLUSION: In a laboratory rat model, aspiration with gastric fluid caused a substantial shift of the lung microbiota that could be characterized as a shift from Proteobacteria towards Firmicutes, possibly of enteric origin. Bacteria contained in the gastric fluid are not apparently responsible for this change. PMID- 30465453 TI - Dose adjustment in orphan disease populations: the quest to fulfill the requirements of physiologically based pharmacokinetics. AB - INTRODUCTION: While the media is engaged and fascinated by the idea of 'Precision Medicine', the nuances related to 'Precision Dosing' seem to be largely ignored. Assuming the 'right drug' is selected, clinicians still need to decide on the 'right dose' for individuals. Ideally, optimal dosing should be studied in clinical trials; however, many drugs on the market lack evidence-based dosing recommendations, and small groups of patients (orphan disease populations) are dependent on local guidance and clinician experience to determine drug dosage adjustments. Areas Covered: This report explores the current understanding of dosing adjustment in special populations and examines the requirements for developing 'in silico' models for pediatric, elderly and pregnant patients. The report also highlights current use of modeling to provide evidence-based recommendations for drug labeling in the absence of complete clinical trials in orphan disease populations. Expert Opinion: Physiologically based pharmacokinetics (PBPK) is an attractive prospect for determining the best drug dosage adjustments in special populations. However, it is not sufficient for individualized, or even stratified dosing, unless the systems (drug-independent) data required to build robust PBPK models are obtained. Such models are not a substitute for clinical trials, but they are an alternative to undocumented and inconsistent guesswork. PMID- 30465454 TI - The relationships among verbal ability, executive function, and theory of mind in young children with cochlear implants. AB - This study aims to examine the complex relationships among verbal ability (VA), executive function (EF), and theory of mind (ToM) in young Chinese children with cochlear implants (CCI). All participants were tested using a set of nine measures: one VA, one non-VA, three EF, and four ToM. Our study cohort comprised 82 children aged from 3.8 to 6.9 years, including 36 CCI and 46 children with normal hearing (CNH). CNH outperformed CCI on measures of VA, EF, and ToM. One of the EF tasks, inhibitory control, was significantly associated with ToM after controlling for VA. VA was the primary predictor of EF, while inhibitory control significantly predicted ToM. Our findings suggest that inhibitory control explains the association between EF and ToM, thereby supporting the hypothesis that EF may be a prerequisite for ToM. PMID- 30465455 TI - Isolating and culturing of sputum macrophages: A potential ex vivo/in vitro model. AB - PURPOSE: This paper aimed to test whether induced sputum samples acquired from human volunteers could be used to isolate and culture airway macrophages for in vitro exposures. This was assessed in terms of the culturing success rate, culture purity, viability and responsiveness of cultured cells. MATERIALS AND METHODS: The isolation and culturing procedure was performed over three days. On Day 1, induced sputum samples were obtained, processed and seeded in culture wells. Differential cell counts and viability tests were performed to allow for calculation of viable macrophage numbers and appropriate sample dilution. After a 1 h rest, seeded wells were washed to remove non-adherent cells, resulting in macrophage isolation. Then, cells rested overnight (Day 1-Day 2), before in vitro exposure for 2-24 h (Day 2-Day 3). The criteria for progressing into the culturing procedure was cell viability >40% and total cell number >106. Successful culturing was evaluated based on cell attachment (N = 40). Culture purity by differential cell analysis and viability was monitored during culturing (N = 4-8). Macrophage responsivity was assessed by measurement of inflammatory cytokine gene expression (N = 4) and cytokine levels (N = 6) following in vitro exposure to lipopolysaccharide (LPS) (2-24 h) and live bacteria (S. aureus) (4h). RESULTS: Overall, 88% (35/40) of the samples acquired were suitable for isolation, and 80% (32/40) were successfully progressed through the 2-3 day culturing protocol. Macrophage purity (88%) and viability (85%) were adequate. Moreover, cultured macrophages were responsive to in vitro stimulation with LPS and viable S. aureus showing positive mRNA responses for TNFalpha, IL-1beta and IL-8 and release of IL-1beta, respectively. CONCLUSION: Sputum macrophage isolation by plate adherence and subsequent culturing of sputum macrophages was successfully performed and represents a promising in vitro model for examination of airway macrophage behavior. PMID- 30465456 TI - Biochemical changes associated with temporomandibular disorders. AB - OBJECTIVE: To assess vitamin D, parathyroid hormone, calcitonin, calcium, phosphorus and magnesium levels in patients with versus without temporomandibular disorders (TMDs). METHODS: This prospective observational study included patients with TMDs and age-matched healthy controls. TMDs were diagnosed via physical and radiologic examination, and serum levels of 25 (OH) vitamin D, parathyroid hormone, calcitonin, calcium, magnesium, and phosphorus were determined. The impact of age, sex and seasonal variations in serum 25 (OH) vitamin D levels was controlled by the inclusion of age, sex and date-matched control patients. RESULTS: The study included 100 patients, comprising 50 patients with TMDs and 50 control patients. No statistically significant between-group differences were found regarding age or sex. No statistically significant between-group differences were found in terms of serum 25 (OH) vitamin D, calcitonin, calcium, magnesium or phosphorus levels. Parathyroid hormone levels were statistically significantly higher in patients with TMDs versus healthy control patients. CONCLUSION: In patients with temporomandibular disorders, increased parathyroid hormone levels in response to vitamin D deficiency was significantly more prominent. These data suggest that, in patients with temporomandibular disorders, vitamin D deficiency should be assessed and corrected. PMID- 30465457 TI - Psychometric properties of the symptom check list 90 (SCL-90) for Chinese undergraduate students. AB - BACKGROUND: Despite the widespread application of the Chinese version of Symptom Check List 90 (SCL-90) amongst undergraduate students, researchers have not thoroughly evaluated its psychometric features with representative samples of Chinese undergraduate students. AIM: To evaluate its psychometric properties based on a large, representative sample of Chinese undergraduate students. METHODS: A total of 4456 Chinese undergraduate students (age range = 17-25 years) completed the SCL-90. Correlation analysis, confirmatory factor analysis and structural equation modeling were used to evaluate its reliability and validity. RESULTS: The evidence for item-total correlations, internal consistency reliability, intraclass correlation coefficients and composite reliability, and the hypothesized factor structure was satisfactory. The evidence for convergent validity was acceptable; however, the evidence for discriminant validity was not satisfactory. CONCLUSION: Based on a large, representative sample of Chinese undergraduate students, the Chinese version of the SCL-90 revealed both strengths and limitations, suggesting the need for further research. PMID- 30465459 TI - Correction. PMID- 30465458 TI - Expression of beta-catenin in human trophoblast and its role in placenta accreta and placenta previa. AB - OBJECTIVES: To investigate the expression of beta-catenin in chorionic villi, and to explore its roles in placenta accreta and placenta previa. METHODS: We compared beta-catenin expression in the control group, placenta accreta group (lesion area and normal zones), and placenta previa group (placental central and placental edge zones) by immunohistochemistry, Western blotting, and RT-PCR techniques. RESULTS: Compared with the normal group, the placenta accreta group had a longer length of stay, greater bleeding volume, and lower newborn birth weight. Further, the expression of beta-catenin was lower in both placenta previa and placenta accreta groups than in the control group, as measured by immunohistochemistry. Compared with the control group, expression of beta-catenin was significantly lower in the placenta previa and placenta accreta groups by Western blotting and RT-PCR. Importantly, the level of placental beta-catenin was significantly different when compared between the lesion and normal zones of placenta. CONCLUSION: The expression of beta-catenin in placenta accreta might play an important role in the regulation of placental cell invasion; low expression of beta-catenin in placenta accreta might be responsible for excessive trophoblastic invasion. PMID- 30465460 TI - Military Service Member Perspectives About Occupational Therapy Treatment in a Military Concussion Clinic. AB - The purpose of this study is to describe important features of occupational therapy practice for treatment of military service members with chronic symptoms and a history of mild traumatic brain injury (mTBI) in a military concussion care clinic from service members' perspectives with support from occupational therapy practitioners. Two series of focus groups were conducted with service members with chronic mTBI-related symptoms ( n = 6) and practitioners ( n = 5). Data were analyzed concurrently with collection. We identified five main themes: therapeutic relationship, consistent inclusion of family members, combat versus noncombat injuries, loss of military identity, and assessment against population norms. The findings of this study suggest that service members' evaluations of occupational therapy are based on the overall experience of the encounter, centered by the therapeutic relationship, rather than specific intervention strategies or technology. PMID- 30465461 TI - Resting-state MEG measurement of functional activation as a biomarker for cognitive decline in MS. AB - BACKGROUND:: Neurophysiological measures of brain function, such as magnetoencephalography (MEG), are widely used in clinical neurology and have strong relations with cognitive impairment and dementia but are still underdeveloped in multiple sclerosis (MS). OBJECTIVES:: To demonstrate the value of clinically applicable MEG-measures in evaluating cognitive impairment in MS. METHODS:: In eyes-closed resting-state, MEG data of 83 MS patients and 34 healthy controls (HCs) peak frequencies and relative power of six canonical frequency bands for 78 cortical and 10 deep gray matter (DGM) areas were calculated. Linear regression models, correcting for age, gender, and education, assessed the relation between cognitive performance and MEG biomarkers. RESULTS:: Increased alpha1 and theta power was strongly associated with impaired cognition in patients, which differed between cognitively impaired (CI) patients and HCs in bilateral parietotemporal cortices. CI patients had a lower peak frequency than HCs. Oscillatory slowing was also widespread in the DGM, most pronounced in the thalamus. CONCLUSION:: There is a clinically relevant slowing of neuronal activity in MS patients in parietotemporal cortical areas and the thalamus, strongly related to cognitive impairment. These measures hold promise for the application of resting-state MEG as a biomarker for cognitive disturbances in MS in a clinical setting. PMID- 30465462 TI - Occurrence and characterization of lipofuscin and ceroid in human atherosclerotic plaque. AB - Atherosclerotic plaque formation starts early in life, develops silently over decades, and often displays clear evidence of accelerated biological aging. Lipofuscin has been classically defined as "the most consistent and phylogenetically conserved cellular morphologic change of aging," however, despite this traditional view different lines of evidence have recently demonstrated that, besides aging, various noxious influences can engeder its accumulation in cells and also that specific experimental conditions can revert this effect. Lipofuscin has been also proven to interact with disease-related factors to enhance cell loss. Along with lipofuscin, ceroid, another autofluorescent lipopigment usually produced under various pathological conditions unrelated to aging, has been suggested to jeopardize cell performance and viability by inducing membrane fragility, mitochondrial dysfunction, DNA damage, and oxidative stress-induced apoptosis. With regard to atherosclerosis, very few investigations have been conducted to assess whether a link could exist between lipofuscin/ceroid accumulation and the progression of the disease and no information still exist regarding the anatomy and the ultrastructural diversification of lipofuscin and ceroid in the lesional vascular tissue. At the same time, data concerning their potential toxicity at the cellular level are fragmentary, dated, and scarce. The present study investigates the occurrence and distribution of lipofuscin and ceroid in human atherosclerotic plaque and adjacent healthy tissues and analyzes the ultrastructural changes associated with their accumulation within the cell. PMID- 30465463 TI - Necessity of technicians for computerized neuropsychological assessment devices in multiple sclerosis. AB - OBJECTIVE:: Determine the influence of technician supervision on computer administered cognitive tests in multiple sclerosis (MS). METHODS:: Eighty MS patients underwent assessment using the CogState Brief Battery (CSBB) and the Cleveland Clinic Cognitive Battery (C3B). Each was administered twice, once with a technician guiding assessment, and once with technician-absent. Twenty-eight healthy controls were also evaluated. RESULTS:: The influence of technician guidance was not statistically significant for group means on either test. For CSBB, administration problems were more common in the technician-absent condition. CONCLUSION:: In this MS sample, reliable and valid test results were obtained from computer-assisted cognitive testing without technician guidance. PMID- 30465464 TI - 25-Hydroxy cholecalciferol, anti-Mullerian hormone, and thyroid profiles among infertile men. AB - BACKGROUND AND AIM: We examined the relationship among vit.D3, AMH, FT3, FT4, and TSH, in addition to the serum levels of reproductive hormones (FSH, LH, prolactin, and free testosterone), in oligoasthenoteratozoospermia and azoospermia patients in a cohort of infertile men from Egypt to establish a clinical marker/cause-effect relationship. METHODS: This cross-sectional cohort study was carried out on 301 men (105 males with oligoasthenoteratozoospermia and 96 males with azoospermia), in addition to 100 controls. Measurements of serum vit.D3, AMH, FT3, FT4, and TSH levels, in addition to reproductive hormone assays, were performed on all included subjects, using ELISA kits. RESULTS: Overall, results showed significantly lower serum levels of vit.D3 in infertile men than in the controls, with a greater decrease observed in men with azoospermia than in oligoasthenoteratozoospermia patients, (p < .05 for all). Significantly higher serum TSH and FSH levels and significantly lower serum free testosterone levels were observed in males with azoospermia than in males with oligoasthenoteratozoospermia and the controls (p < .05 for both). There were no significant differences between the studied groups in terms of AMH, FT3 or FT4 levels. LH levels were negatively correlated with TSH levels and positively correlated with AMH levels among men with oligoasthenoteratozoospermia, while among men with azoospermia, LH levels were positively correlated with vit.D3 levels (p < .05 for all). CONCLUSION: Decreased Vit.D3 could play a role in male infertility, in addition to abnormal thyroid function, which needs further investigation. PMID- 30465465 TI - Gating defects of disease-causing de novo mutations in Cav1.3 Ca2+ channels. AB - Recently, we and others identified somatic and germline de novo gain-of-function mutations in CACNA1D, the gene encoding the alpha1-subunit of voltage-gated Cav1.3 Ca2+-channels. While somatic mutations identified in aldosterone producing adenomas (APAs) underlie treatment-resistant hypertension, germline CACNA1D mutations are associated with a neurodevelopmental disorder characterized by a wide symptomatic spectrum, including autism spectrum disorder. The number of newly identified CACNA1D missense mutations is constantly growing, but their pathogenic potential is difficult to predict in silico, making functional studies indispensable to assess their contribution to disease risk. Here we report the functional characterization of previously identified CACNA1D APA mutations F747L and M1354I using whole-cell patch-clamp electrophysiology upon recombinant expression in tsA-201 cells. We also investigated if alternative splicing of Cav1.3 affects the aberrant gating of the previously characterized APA mutation R990H and two mutations associated with autism spectrum disorder (A479G and G407R). Splice-variant dependent gating changes are of particular interest for germline mutations, since the relative expression of Cav1.3 splice variants differs across different tissues and within brain regions and might therefore result in tissue-specific phenotypes. Our data revealed a complex gain-of function phenotype for APA mutation F747L confirming its pathogenic role. Furthermore, we found splice-variant dependent gating changes in R990H, A749G and G407R. M1354I did not change channel function of Cav1.3 splice variants and should therefore be considered a rare non-pathogenic variant until further proof for its pathogenicity is obtained. Our new findings together with previously published data allow classification of pathogenic CACNA1D mutations into four categories based on prototypical functional changes. PMID- 30465466 TI - The Measure of Quality of the Environments' Turkish Validity and Reliability. AB - The aim of this study was to translate the Measure of Quality of the Environment Short Form (MQE-SF) into Turkish language and to evaluate the validity and reliability. The MQE-SF was culturally adapted via an internationally suggested method. A total of 185 volunteers with disabilities (age range = 18-55 y/o, 107 males; 78 females) from the Disabled People Association of Turkey completed the MQE-SF. To evaluate the MQE-SF's criterion/concurrent validity, the Craig Hospital Inventory of Environmental Factors (CHIEF) was also administered. Test retest reliability was evaluated by administering MQE-SF to 85 participants a second time within 14 days of initial administration. The alpha coefficient measuring the internal consistency of the questionnaire were .84 and .83. The criterion-related validity was moderate between the MQE-SF Barriers and the CHIEF ( r = -.46, p < .05). The questionnaire was moderately reliable in terms of the test-retest reliability ( r = .69, .70 p < .05). The Turkish adaptation of the MQE-SF had good internal consistency and moderate criterion-related validity as well as test-retest reliability for people with disabilities. PMID- 30465467 TI - Human Factors-Based Mobile Application Design for Global Health. AB - BACKGROUND: The rapid adoption of smartphones and software applications (apps) has become prevalent worldwide, making these technologies nearly universally available. Low-cost mobile health (M-health) platforms are being rapidly adopted in both developed and emerging markets and have transformed the health care delivery landscape. Human factors optimization is critical to the safe and sustainable adoption of M-health solutions. The overall goal of engaging human factors requirements in the software app design process is to decrease patient safety risks while increasing usability and productivity for the end user. METHODS: An extensive review of the literature was conducted using PubMed and Google search engines to identify best approaches to M-health software design based on human factors and user-centered design to optimize the usability, safety, and efficacy of M-health apps. Extracted data were used to create a health care app development algorithm. RESULTS: A best practice algorithm for the design of mobile apps for global health care, based on the extracted data, was developed. The approach is based on an iterative 4-stage process that incorporates human factors and user-centered design processes. This process helps optimize the development of safe and effective mobile apps for use in global health care delivery and disease prevention. CONCLUSION: Mobile technologies designed for developing regions offer a potential solution to provide effective, low-cost health care. Applying human factors design principles to global health care app development helps ensure the delivery of safe and effective technologies tailored to the end-users requirements. PMID- 30465468 TI - Impact of a Massage Therapy Intervention for Pediatric Palliative Care Patients and Their Family Caregivers. AB - CONTEXT:: All inpatient children receiving pediatric palliative care consults at a free-standing children's hospital. OBJECTIVES:: To explore the impact of massage therapy on pediatric palliative care patients' symptom burden and medication use pattern, to describe the impact of massage therapy on family caregiver distress, and to report on bedside nursing staff perception of massage therapy for children and their families. METHODS:: A 1-time point, single-center exploratory study offering 10-minute bedside massage to children receiving palliative care and 10-minute massage to their family caregivers. RESULTS:: A total of 135 massages were provided to children and their caregivers. Difference in child Face, Legs, Activity, Cry, Consolability scale (FLACC) score was detectable ( P < .0001) with the median (interquartile range [IQR]) before FLACC score being 2 (1-3) and after FLACC score being 0 (0-1). Difference in "as needed" pain medication usage in the 24 hours before and after the massage was detectable ( P = .0477). Median difference in family caregiver distress with massage was -3.0 (IQR = 2.0, P < .0001). Bedside nurses (100%) reported massage to be a meaningful way to care for their families and patients. CONCLUSION:: Massage therapy is a potentially meaningful intervention for pediatric palliative care patients with noted impact on symptom burden, benefit to family caregivers, and acceptance by nursing staff. PMID- 30465469 TI - Brief Exposure to Pictures Depicting Poor Environments Leads to Increased Consumption of Beer in Adult Social Drinkers. AB - Previous studies have suggested a trait-like association between neighborhood deprivation and alcohol consumption. However, it is not known whether temporarily manipulating poverty and affluence states by exposure to stimuli signifying resource-scarcity or resource-wealth would influence alcohol-seeking behavior. Here, we aimed to investigate whether implicit exposure to affluence and poverty related pictures would influence beer consumption. Participants in a "poverty" group viewed pictures depicting impoverished environments, and participants in an "affluence" group viewed images of wealthy environments. After priming, participants were provided with nonalcoholic beer (which they were told was alcohol-containing beer) and orange juice under the guise of a bogus taste test, to measure their alcohol-seeking behavior. Results showed that priming participants with a resource-scarce environment led to an increase in beer consumption (as a percentage of total fluid consumed), compared to priming with a resource-rich environment. The same pattern of results was obtained in both a Western European sample (Experiment 1) and a West Indian sample (Experiment 2). In Experiment 2, we also tested whether risk-taking behavior, measured by the Balloon Analogue Risk Task, was influenced by the environmental priming; no differences between groups were observed. These results provide the first experimental evidence that manipulation of poverty-affluence state, by brief exposure to pictures of impoverished or wealthy neighborhoods, can influence alcohol-seeking behavior in adult social drinkers. PMID- 30465470 TI - Quality of Life of Family Caregivers of Patients With Cancer in Korce, Albania. AB - PURPOSE:: The primary objective of this study was to quantify cancer family caregiver (FCG) quality of life (QOL) in a Southern Albanian population and to determine whether differences exist between 4 domains of QOL (physical, psychological, social, and spiritual). This study also sought to compare QOL in our cohort to QOL in historical studies that used the same survey instrument, and to examine correlations between demographic characteristics and QOL to identify any high-risk groups. METHODS:: A sample of 40 FCGs was recruited at the Mary Potter Palliative Care Clinic in Korce, Albania. Each participant completed the City of Hope Quality of Life (Family Version), a validated 37-question instrument that measures caregiver well-being in 4 domains: physical, psychological, social, and spiritual well-being. RESULTS:: There were no significant differences between the composite scores of the 4 QOL domains in our study. However, there were differences when comparing self-reported QOL between domains ("Rate your overall physical/psychological/social/spiritual well-being"). The QOL measured in our study was significantly lower than in 3 studies from the United States that used the same questionnaire. There were no significant correlations between demographic groups and QOL. CONCLUSIONS:: This study examines the impact that the paucity of palliative services has on the QOL of Albanian cancer FCGs. Although there were no domains of QOL or demographic groups identified in our study that were faring significantly worse than others, the poor overall QOL provides further evidence to support the continued development of palliative services for both patients and family members in Albania. PMID- 30465471 TI - Advanced Care Planning for Persons With Dementia in Primary Care: Attitudes and Barriers Among Health-Care Professionals. AB - BACKGROUND:: Advance care planning (ACP) provides clarity on goals and preferences for future health-care decisions, the timeliness of which is critical for persons with dementia. AIM:: This study assessed Primary Care Collaborative Memory Clinic (PCCMC) health-care practitioners' desire for more education on ACP, capacity for and attitudes toward ACP, and current ACP practices in their regular family practice and in their PCCMC. METHODS:: Primary Care Collaborative Memory Clinic health-care professionals completed a questionnaire in which they rated their interest in learning various ACP-related topics (5-point scale: not at all to very much so), attitudes toward ACP, and the importance of and perceived degree of responsibility for ACP (5-point scale: not at all to extremely). Respondents estimated ACP completion in regular family practice and PCCMC. RESULTS:: Two hundred and sixty one surveys were completed. Mean knowledge ratings were moderate (M = 3.0) and mean ratings of interest in ACP topics were all high (median >= 4). Despite the perception that ACP is very important (M = 4.9) and the responsibility of PCCMCs (M = 3.7), the majority of respondents estimated that 40% or fewer patients have had ACP. Ratings of willingness to conduct ACP (M = 3.7) and comfort level (M = 3.4) were moderate but significantly exceeded ratings of ability (M = 2.9), comfort (M = 3.5), and confidence (M = 2.8). CONCLUSION:: There was a striking disconnect between perceptions of the importance of completing ACP for persons with dementia and actual ACP completion rates. Primary Care Collaborative Memory Clinics may be in an ideal position to support ACP discussions; however, there is a need to improve health-care professionals' knowledge and attitudes toward ACP. PMID- 30465472 TI - Survivin c.-31G>C (rs9904341) gene transversion and urinary system cancers risk: a systematic review and a meta-analysis. AB - AIM: To investigate the possible association between survivin c.-31G>C (rs9904341) gene polymorphism and urinary system cancers by a meta-analysis approach. METHODS: Standard electronic literature databases were searched to find eligible studies. The odds ratios (ORs) with 95% CIs were estimated to find the associations possibility. RESULTS: Overall meta-analysis revealed significant associations between c.-31G>C transversion and risk of urinary tract cancers in dominant (OR: 1.34; 95% CI: 1.02-1.75; p = 0.035), recessive (OR: 1.52; 95% CI: 1.33-1.74; p < 0.001) and homozygote codominant (OR: 1.90; 95% Cl: 1.37-2.62; p < 0.001) genetic models. CONCLUSION: The c.-31G>C transversion might be a risk factor for urinary system cancers. However, more articles with different ethnicities will help to obtain a more accurate conclusion. PMID- 30465473 TI - Men's motivation for contraceptive use in Inanda township, KwaZulu-Natal, South Africa. AB - Men's involvement in sexual and reproductive health is under-researched in South Africa despite evidence to suggest that men are key decision-makers in various household matters. Against this background, this study aimed to explore men's perspectives on contraceptive use in a South African township with a focus on motivations for contraception use and the challenges men face in using contraceptives. In-depth interviews were conducted with a sample of 20 men. Findings suggest that awareness of contraception among men is high and attitudes towards contraceptives are generally favourable. Contraceptive use is strongly influenced by the perceived risk of unplanned pregnancy and HIV infection. Condoms are the most commonly known and used method of contraception by men. Men complained that there are limited contraceptive options for them and consistent condom use remains difficult. To increase the uptake and use of contraceptives, sexual and reproductive programmes should fully include men in design and delivery. In the longer term, investment in the development of a wider range of contraceptive methods will increase options for men. PMID- 30465474 TI - Knowledge Gaps About End-of-Life Decision Making Among Mexican American Older Adults and Their Family Caregivers: An Integrative Review. AB - INTRODUCTION: Mexican Americans (MAs) are the largest, fastest growing Latino subgroup in the United States, yet their use of hospice is limited. To better understand this disparity, the authors conducted an integrative review focused on MA caregiving families' end-of-life (EOL) care decisions. METHOD: In this literature review, the authors content analyzed results and discussions of 22 research studies focused on EOL decisions, which sampled MA adults at least 50 years old and/or families. The authors used Whittemore and Knafl's integrative review process, employing constructs from the Ethno-Cultural Gerontological Nursing Model. RESULTS: Topics included attitudes toward hospice, life-sustaining treatment, advance care planning, EOL decision making, perceptions of a good death, and life-limiting illnesses. EOL research for MA caregiving families is meager, largely atheoretical, and rarely validated by subsequent studies. DISCUSSION: Nursing research is needed to extend theory and policy in order to skillfully match EOL care with MA caregiving families' needs. PMID- 30465475 TI - The 'full stack' of healthcare innovation skills: combining clinical informatics with care delivery innovation. PMID- 30465476 TI - Collaboration between key populations in a global partnership for health and human rights: Lessons learned from 'Bridging the Gaps'. AB - Because HIV and AIDS key populations share common social-cultural factors challenging their sexual health and rights (e.g. stigma, criminalisation), there is an assumed benefit of collaborative programmes where various key populations work in solidarity. In this paper, we reflect on how partners collaborated in a complex alliance of over 100 different NGOs, representing and supporting three key populations - lesbian, gay, bisexual and transgender (LGBT) people, sex workers and people who use drugs - working across 16 countries. We used a multiple-method approach of participant observation, qualitative interviews, and a survey to explore the benefits, facilitators and challenges of collaboration. Results show that motivators for collaboration included being part of the larger funding structure with applied impacts, a repressive human rights context, and intersectionality. Barriers for collaboration included identity politics, stigma, and constraints regarding the appropriate timing of new collaborations. Finally, facilitators include practical support for engagement, the framing of human rights in a medical agenda, and recognition of implicit differences. We conclude that for building the capacity for collaboration among socially marginalised groups it is important to develop trust and the ability to recognise strength in difference beyond the initial identification of shared norms and common goals. PMID- 30465477 TI - Telementoring of Surgeons: A Systematic Review. AB - BACKGROUND: Telementoring is a technique that has shown potential as a surgical training aid. Previous studies have suggested that telementoring is a safe training modality. This review aimed to review both the technological capabilities of reported telementoring systems as well as its potential benefits as a mentoring modality. METHODS: A systematic review of the literature, up to July 2017, was carried out in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Study quality was assessed using the Oxford Levels of Evidence proforma. Data were extracted regarding technical capabilities, bandwidth, latency, and costs. Additionally, the primary aim and key results were extracted from each study and analyzed. RESULTS: A total of 66 studies were identified for inclusion. In all, 48% of studies were conducted in general surgery; 22 (33%), 24 (36%), and 20 (30%) of studies reported telementoring that occurred within the same hospital, outside the hospital, and outside the country, respectively. Sixty-four (98%) of studies employed video and audio and 38 (58%) used telestration. Twelve separate studies directly compared telementoring against on-site mentoring. Seven (58%) showed no difference in outcomes between telementoring and on-site mentoring. No study found telementoring to result in poorer postoperative outcomes. CONCLUSIONS: The results of this review suggest that telementoring has a similar safety and efficacy profile as on-site mentoring. Future analysis to determine the potential benefits and pitfalls to surgical education through telementoring are required to determine the exact role it shall play in the future. Technological advances to improve remote connectivity would also aid the uptake of telementoring on a larger scale. PMID- 30465478 TI - Low Self-Esteem Predicts Indirect Support Seeking and Its Relationship Consequences in Intimate Relationships. AB - Indirect support seeking involves sulking, whining, and/or displaying sadness to elicit social support. Ironically, this strategy tends to backfire by prompting rejection from close others. The current research examines how low self-esteem contributes to the use and relational consequences of indirect support seeking during couples' interactions. Results across two dyadic, observational studies (Study 1 = 76 couples, Study 2 = 100 couples) demonstrated that support seekers with lower self-esteem engaged in greater indirect support seeking, and seekers' greater indirect support seeking was associated with greater negative support from partners. Furthermore, partners' negative support was associated with lower seeker perceptions of partner responsiveness, but only when support seekers were low in self-esteem. These results demonstrate how low self-esteem individuals' attempts to protect themselves from social rejection by utilizing indirect support seeking may ironically elicit negative partner support, and undermine the feelings of acceptance that low self-esteem individuals crave. PMID- 30465479 TI - The Effect of modality specific interference on working memory in recalling aversive auditory and visual memories. AB - Both auditory and visual emotional memories can be made less emotional by loading working memory (WM) during memory recall. Taxing WM during recall can be modality specific (giving an auditory [visuospatial] load during recall of an auditory [visual] memory) or cross modal (an auditory load during visual recall or vice versa). We tested whether modality specific loading taxes WM to a larger extent than cross modal loading. Ninety-six participants undertook a visual and auditory baseline Random Interval Repetition task (i.e. responding as fast as possible to a visual or auditory stimulus by pressing a button). Then, participants recalled a distressing visual and auditory memory, while performing the same visual and auditory Random Interval Repetition task. Increased reaction times (compared to baseline) were indicative of WM loading. Using Bayesian statistics, we compared five models in terms of general and modality specific taxation. There was support for the model describing the effect on WM of dual tasking in general, irrespective of modality specificity, and for the model describing the effect of modality specific loading. Both models combined gained the most support. The results suggest a general effect of dual tasking on taxing WM and a superimposed effect of taxing in matched modality. PMID- 30465480 TI - Sleep in Caregivers of Children With Type 1 Diabetes. AB - PURPOSE: The purpose of this study was to explore caregivers' descriptions of their experience of nighttime sleep. DESIGN AND METHODS: Caregivers (N = 22) of children 10 to 18 years of age with type 1 diabetes (T1D) were recruited for this descriptive study. Anonymous questionnaires contained demographic information and both open- and closed-ended questions that focused on caregiving as it related to sleep. Open-ended questions were reviewed to help understand the effect of nocturnal caregiving activities on parental sleep. RESULTS: The sample of caregivers were all female and had a mean age of 43 years; 96% graduated high school, 68% were married or partnered, and 100% were white. Children had been diagnosed with T1D for a mean of 5 years, with a mean age of 12.2 years. Caregivers reported short sleep duration (mean, 5.8 hours). Over half of the participants reported they required >=7 hours of sleep to feel their best, 64% indicated trouble sleeping at night, and 86% reported that caregiving interfered with their nighttime sleep, while 54% responded that sleep was "very important." Content analysis of the open-ended questions revealed 2 themes: (1) anxiety about the child's blood glucose levels and (2) nighttime disruptions. CONCLUSIONS: Caregivers are frequently sleep deprived and worry about their child's nighttime glucose. Caregiving duties, anxiety, and sleep fragmentation may contribute to their poor sleep. PMID- 30465481 TI - A Novel Wireless In-Ear Device for Surgical Care: An Innovative Idea to Improve Operating Room Miscommunication. PMID- 30465482 TI - Effects of using a document holder when typing on head excursion and neck muscle activity among computer users with and without neck pain. AB - PURPOSE: The aim of this study was to examine the effects of document holder while typing on head excursion and neck muscle activity among computer users with and without neck pain. METHOD: An experimental study with a total of 52 individuals with (n = 26) and without (n = 26) neck pain were conducted. Head excursion and neck muscle activity were measured using accelerometer and surface electromyography (EMG) respectively. Two-way analysis of variance (ANOVA) was conducted to examine the effects of using a document holder between computer users with and without neck pain. RESULTS: The results demonstrated decrease in head excursion (p < 0.001) and muscle activity of both right and left upper trapezius; left lower trapezius and right anterior deltoid (p < 0.05) with the use of document holder. Computer users with neck pain had significantly (p < 0.001) higher right lower trapezius muscle activity compared to the group without neck pain. CONCLUSION: The results of the study supported the use of a document holder to assist in decreasing head excursion and neck muscle activity. The use of document holder while typing may be beneficial in preventing repetitive strain injuries among computer users. PMID- 30465483 TI - Acquisition and expression of sucrose conditioned flavor preferences following dopamine D1, opioid and NMDA receptor antagonism in C57BL/6 mice. AB - The study of inbred mouse strains is a useful animal model to assess differences in ingestive behavior responses, including conditioned flavor preferences (CFP). C57BL/6, BALB/c and SWR inbred mice display differential sensitivity to dopamine (DA) D1, opioid and muscarinic cholinergic receptor antagonism of sucrose or saccharin intake as well as to muscarinic cholinergic antagonism of acquisition (learning) of sucrose-CFP. Given that DA D1, opioid and N-methyl-D-aspartate (NMDA) receptor antagonists differentially alter sucrose-CFP in BALB/c and SWR inbred mice, the present study examined whether systemic administration of naltrexone, SCH23390 or MK-801 altered acquisition and expression of sucrose-CFP in C57BL/6 mice. In acquisition experiments, male food-restricted C57BL/6 mice were treated with vehicle, naltrexone (1, 5 mg/kg), SCH23390 (50, 200 nmol/kg) or MK-801 (100, 200 ug/kg) 30 min prior to each of ten daily sessions in which they alternately consumed a flavored (CS+, e.g. cherry) 16% sucrose solution and a differently-flavored (CS-, e.g. grape) 0.05% saccharin solution followed by six two-bottle CS choice tests mixed in 0.2% saccharin without injections. SCH23390 and MK-801, but not naltrexone eliminated sucrose-CFP acquisition in food restricted C57BL/6 mice. In expression experiments, food-restricted C57BL/6 mice underwent the ten training sessions without injections followed by two-bottle CS choice tests 30 min following vehicle, naltrexone (1, 5 mg/kg), SCH23390 (200, 800 nmol/kg) or MK-801 (100, 200 ug/kg). SCH23390 more effectively reduced the magnitude of sucrose-CFP expression than naltrexone or MK-801 in food-restricted C57BL/6 mice. Thus, dopamine D1 and NMDA receptor signaling is essential for learning of sucrose-CFP in C57BL/6 mice. PMID- 30465484 TI - Bereavement experiences following a death under Oregon's Death with Dignity Act. AB - This qualitative study explores bereavement experiences with an assisted death. Thematic analysis of data from interviews with 22 people who had a family member die under Oregon's Death with Dignity Act revealed the following five themes: (a) general grief reactions, (b) anticipating the death, (c) sense of control, (d) level of agreement with assisted death, and (e) grief expression and stigma. Grief from an assisted death is a varied experience, including aspects that are unique to this mode of death, and aspects that can both ease and bring challenges to the grieving process. PMID- 30465485 TI - Governing integrated care networks through collaborative inquiry. AB - PURPOSE: The purpose of this paper is to develop a theory of governing in integrated care networks. Asking how and why the governance of these networks emerges and evolves over time, it responds to calls for more innovative thinking in this field. DESIGN/METHODOLOGY/APPROACH: Data result from a rare longitudinal qualitative case study conducted with the Healthcare Centre Lower Engadin, the lead organisation of pioneering health and social care network in a rural Swiss region. FINDINGS: Actors governed the network through repetitive sequences of collaborative inquiry, a practice through which they defined and addressed recurrent problems of network governance and joint network action in creative and experimental ways. RESEARCH LIMITATIONS/IMPLICATIONS: Explaining how and why the governance of integrated care networks emerges and evolves, this study adds a dynamic theory to previous research, which has studied the determinants of effective network governance without considering their temporal evolution. It also contributes to the wider network literature, drawing attention to the pivotal role of meaning making, creativity and experimentation for understanding network governance dynamics. PRACTICAL IMPLICATIONS: The study invites practitioners to reflect on how they want to design collaborative inquiry in their own contexts. Important design levers include the creation of communication forums, trust and information transparency. ORIGINALITY/VALUE: The study adds a rare longitudinal perspective on the governance of integrated care networks. PMID- 30465486 TI - Exploring a transition in Dutch healthcare. AB - PURPOSE: Healthcare systems are facing persistent challenges, such as dealing with an ageing population, related increases in chronic diseases and healthcare costs facilitated by technological progress. The authors argue that the boundaries of optimisation are being reached and a more fundamental change or transition is necessary. The purpose of this paper is to explore the contours of this transition in the Netherlands. The authors do this from the perspective of healthcare organisations that have participated in the "Expedition to Sustainable Healthcare": a learning programme organised by the Dutch Network for Sustainable Healthcare aimed at creating frontrunners in this transition. DESIGN/METHODOLOGY/APPROACH: The paper combines conceptual with experimental empirical work. The authors use the transition research frameworks to conceptualise persistent problems and transitional dynamics in the healthcare system. In a longitudinal study, the authors analysed how the participating organisations developed after the expedition. FINDINGS: The process validated the initial understanding of persistent sustainability challenges. An integral approach to sustainable healthcare is translated as a transformation of culture, structures and practices and the development of capacity for crossing borders and domains, inside and outside of the organisation. To facilitate and stimulate such a process the authors found that problem structuring and collective identification of persistent problems and the unsustainability in the healthcare system is a crucial step towards a shared view and discourse that supports change. ORIGINALITY/VALUE: A transition in the Dutch healthcare system is just starting to emerge and has barely been subject of research. This paper provides an empirical description of a transition management process in this context. The authors hope to lay a foundation for future work that seeks to explore transitions in healthcare in theory and practice. PMID- 30465487 TI - Doctor-patient communication: a review and a rationale for using an assessment framework. AB - PURPOSE: The purpose of this paper is to explore the extent to which improving doctor-patient communication (DPC) can address and alleviate many healthcare delivery inefficiencies. DESIGN/METHODOLOGY/APPROACH: The authors survey causes and costs of miscommunication including perceptual gaps between how physicians believe they perform their communicative duties vs how patients feel and highlight thresholds such as the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) used by hospitals to identify health outcomes and improve DPC. FINDINGS: The authors find that DPC correlates with better and more accurate care as well as with more satisfied patients. The authors utilize an assessment framework, doctor-patient communication assessment (DPCA), empirically measuring the effectiveness of DPC. While patient care is sometimes viewed as purely technical, there is evidence that DPC strongly predicts clinical outcomes as well as patients' overall ratings of hospitals. RESEARCH LIMITATIONS/IMPLICATIONS: More research is needed to extend our understanding of the impact of the DPC on the overall HCAHPS ratings of hospitals. The authors think that researchers should adopt a qualitative method (e.g. content analysis) for analyzing DPC discourse. PRACTICAL IMPLICATIONS: When a sufficient amount of DPCA training is initiated, a norming procedure could be developed and a database may be employed to demonstrate training program's efficacy, a critical factor in establishing the credibility of the measurement program and nurturing support for its use. ORIGINALITY/VALUE: The authors highlight clinical and operational issues as well as costs associated with miscommunication and the need to use metrics such as HCAHPS that allow consumers to see how hospitals differ on specific characteristics. PMID- 30465488 TI - Developing allied health leaders to enhance person-centred healthcare. AB - PURPOSE: The purpose of this paper is to present findings from a mixed methods study investigating leadership development of allied health practitioners within a large public healthcare organization in Australia. DESIGN/METHODOLOGY/APPROACH: The South Eastern Sydney Local Health District Allied Health Leadership Development Program was undertaken with an allied health cohort ( n=16) between May 2014 and March 2015 and comprised all-day workshops, action learning sets and individual coaching. Using experiential learning, the program tested whether practice development methods and action learning approaches developed the leadership skills of participants compared with a control group ( n=17). Descriptive statistics were collected to evaluate participant and program outcomes. Leadership, workplace culture and engagement measures were analyzed as part of the study. FINDINGS: The Allied Health Leadership Development Program received high ratings by participants. They reported enhanced skills in leading self and others through mechanisms such as critical reflection and facilitation, and greater confidence managing change and with engaging staff, colleagues and patients in decision making, affecting the quality and safety of healthcare. Statistically significant differences were found with transformational leadership elements, leadership outcomes, and measures of workplace culture and engagement after program completion for intervention group participants, compared with the control group. RESEARCH LIMITATIONS/IMPLICATIONS: Results provide new empirical evidence about the effectiveness of using practice development for allied health leadership development. PRACTICAL IMPLICATIONS: This low-cost leadership program can be replicated by other organizations. ORIGINALITY/VALUE: Outcomes from an Allied Health Leadership Development Program have not been previously reported in the literature. PMID- 30465489 TI - On measuring the quality of hospitals. AB - PURPOSE: Researchers, policymakers and hospital managers often encounter numerous quality measures when assessing hospital quality. The purpose of this paper is to address the challenge of summarising, interpreting and comparing multiple quality measures across different quality dimensions by proposing a simple method of constructing a composite quality index. The method is applied to hospital administrative data to demonstrate its use in analysing hospital performance. DESIGN/METHODOLOGY/APPROACH: Logistic and fixed effects regression analyses are applied to secondary admitted patient data from all hospitals in the state of Victoria, Australia for the period 2000/2001-2011/2012. FINDINGS: The derived composite quality index was used to rank hospital performance and to assess changes in state-wide average hospital quality over time. Further regression analyses found private hospitals, day hospitals and non-acute hospitals were associated with higher composite quality, while small hospitals were associated with lower quality. PRACTICAL IMPLICATIONS: The method will enable policymakers and hospital managers to better monitor the performance of hospitals. It allows quality to be related to other attributes of hospitals such as size and volume, and enables policymakers and managers to focus on hospitals with relevant characteristics such that quantity and quality changes can be better understood, monitored and acted upon. ORIGINALITY/VALUE: A simple method of constructing a composite quality is an indispensable practical tool in tracking the quality of hospitals when numerous measures are used to capture different aspects of quality. The derived composite quality can be used to summarise hospital performance and to identify factors associated with quality via regression analyses. PMID- 30465490 TI - Smelling multiple sclerosis: Different qualities of olfactory function reflect either inflammatory activity or neurodegeneration. AB - BACKGROUND:: Peripapillary retinal nerve fiber layer (pRNFL) thickness and olfactory function are both emerging biomarkers in multiple sclerosis (MS). Impairment of odor identification and discrimination is an irreversible feature of more advanced MS suggested to be associated with neurodegeneration, while olfactory threshold is a transient feature of early, active MS possibly associated with short-term inflammatory disease activity. OBJECTIVE:: The aim of this study was to validate the association of olfactory (dys)function and parameters of MS disease course in a large cohort of MS patients and to correlate olfactory function with pRNFL thickness as a surrogate biomarker of neurodegeneration. METHODS:: In a cross-sectional design, olfactory function was assessed using the Sniffin' Sticks test, which quantifies three different qualities of olfactory function (threshold, discrimination, and identification). pRNFL thickness was measured by spectral-domain optical coherence tomography (OCT). Results were correlated with age, sex, disease duration, relapses, Expanded Disability Status Scale (EDSS), cognitive function, depression, smoking, and pRNFL thickness by multivariable linear regression models. RESULTS:: We included 260 MS patients (mean age of 35.9 years, 68.7% female). Olfactory threshold correlated significantly with number of relapses in the year prior to assessment and shorter disease duration. Odor discrimination, identification, and their sum score were significantly correlated with longer disease duration, higher EDSS, and reduced cognitive function. pRNFL thickness was associated with identification and discrimination, but not with threshold. CONCLUSION:: Olfactory threshold is a marker of short-term inflammatory relapse activity unrelated to parameters of neurodegeneration, while odor identification and discrimination are markers of neurodegeneration mostly independent of relapse activity. Assessment of olfactory function provides an opportunity to stratify MS patients with regard to inflammation and neurodegeneration. PMID- 30465491 TI - Apolipoprotein E genotype moderates the association between dietary polyunsaturated fat and brain function: an exploration of cerebral glutamate and cognitive performance. AB - OBJECTIVE: To investigate the effect of Apolipoprotein E (APOE) genotype on the association between dietary polyunsaturated fat (PUFA), cognitive function, and cerebral glutamate. METHODS: A participant sample of 122 middle-aged adults were grouped according to APOE genotype (epsilon4 carrier or epsilon4 non-carrier) and asked to record dietary intake for three consecutive days. All participants also underwent neuropsychological testing and a proton magnetic resonance spectroscopy (1H MRS) scan to assess glutamate in the posterior cingulate cortex. RESULTS: Multiple regression analyses revealed a significant interaction between APOE genotype and PUFA intake on memory performance, F(1,113) = 6.749, p = .016. Greater PUFA intake was associated with better memory performance in healthy middle-aged adults who were APOE epsilon4 non-carriers, but not for epsilon4 carriers. Furthermore, there was a significant interaction between APOE genotype and PUFA intake on cerebral glutamate, in that dietary PUFA was associated with greater cerebral glutamate in APOE epsilon4 carriers, but not for epsilon4 non carriers, F(1,114) = 5.173, p = .025. CONCLUSIONS: The findings suggest that PUFA action on the brain differs according to APOE polymorphism and points towards cerebral glutamate as a potential marker of genetic risk for Alzheimer's disease (AD). Early treatment consisting of PUFA supplementation that is tailored to APOE genotype may be an important intervention for the prevention of cognitive decline. PMID- 30465492 TI - The Organochalcogen Compound (MeOPhSe)2 Inhibits Both Formation and the Viability of the Biofilm Produced by Candida albicans, at Different Stages of Development. AB - BACKGROUND: Candida albicans is a commensal and opportunistic fungus which is able to produce both local and systemic infections in immunocompromised patients. A correlation has been demonstrated between the resistance to conventional antifungal drugs and C. albicans ability to produce biofilms. Therefore, the potential of the organochalcogen compounds as antifungal therapy has been demonstrated. METHOD: In this work, we studied the effect of the organochalcogen compound (MeOPhSe)2 on both formation and the viability of the biofilm produced by C. albicans, at different stages of development. Biofilm formation and viability were determined by a metabolic assay based on the reduction of XTT assay. In addition, the morphology of the biofilm was observed using light microscopy. RESULTS: A significant reduction was observed in both growth and biofilm formation by C. albicans, in a dependent manner of cell density. In the presence of 2 uM (MeOPhSe)2 it was observed an inhibition of 87, 72, 69 and 56 % in C. albicans growth, using cell densities of 104, 105, 106 and 107 cells/mL, respectively. C. albicans growth was inhibited >90 % in the presence of 10 uM (MeOPhSe)2 in all cell densities used. Also, (MeOPhSe)2 was found to be able to decrease the viability of the biofilm produced by C. albicans at different stages of development. This effect was more pronounced in early biofilms as compared to mature biofilms. Biofilms forming at 6 and 12 hours was inhibited ~80% in the presence of 10 uM (MeOPhSe)2. However, mature biofilms presented an inhibition of ~40 % in the presence of 10 uM (MeOPhSe)2. The analyses of the structure of the biofilm shown a significant reduction in the number of both yeast and filamentous form after treatment with (MeOPhSe)2. In addition, the organochalcogen compound (MeOPhSe)2 did not modify the viability of Fibroblastic cells. CONCLUSION: Taken together, these results demonstrated the potential of the organochalcogen compound (MeOPhSe)2 as a promising antifungal therapy. PMID- 30465493 TI - The role of calcium handling mechanisms in reperfusion injury. AB - Cardiovascular diseases, such as stroke and myocardial infarction (MI) remain the major cause of death and disability worldwide. However, the mortality of MI has declined dramatically over the past several decades because of advances in medicines (thrombolytic agents, antiplatelet drugs, beta blockers, and angiotensin converting enzyme inhibitors) and approaches to restore tissue perfusion(percutaneous coronary intervention and cardiopulmonary bypass). Animals studies have been shown that these treatments have been effective in reducing acute myocardial ischemic injury and limiting MI size. The paradox is that the process of reperfusion can itself amplify cell injury and death, known as myocardial ischemia-reperfusion injury (I/R). Intensive research has uncovered several complex mechanisms of cardiomyocyte damage after reperfusion,and potential therapeutic targets for preventing I/R. Importantly, it is now recognized that excessive elevation of intracellular and mitochondrial Ca2+during reperfusion predisposes the cells to hypercontracture, proteolysis and mitochondrial failure and eventually to necrotic or apoptotic death. These enormous alterations in cytosolic Ca2+ levels are induced by the Ca2+ channels of the sarcolemma(L-Type Ca2+channels, sodium/calcium exchanger), the endoplasmic/sarcoplasmic reticulum (SERCA ATPase) and ryanodine receptors, SOCE(store-operated calcium entry), lysosomals and others, which are modified by I/R injury. The overall goal of this review is to describe the different pathways that lead to I/R injury via Ca2+ overload, focus on recent discoveries and highlight prospects for therapeutic strategies for clinical benefit. PMID- 30465494 TI - Progresses in microRNA Delivery Using Synthetic Nanovectors for Cancer Therapy. AB - MicroRNAs are small noncoding RNAs that have key roles in gene expression. In recent decades, it has been revealed that aberrant expression of microRNAs is related to abnormality in gene expression and it is believed that they have potential to be used as anti-cancer drugs. However, the delivery of these small molecules is limited due to some obstacles including low uptake and insufficient endosomal release, intracellular nucleases degradation, phagocytic elimination and renal filtration. To overcome these issues, there are many novel delivery systems developed to improve efficiency of microRNAs therapy ranged from viral to synthetic; some are further developed with targeted ligands for active targeting purposes. Such delivery systems provide efficient cellular uptake and endosomal release as well as low cytotoxicity and minimum unwanted host immune response. Nevertheless, more complementary studies are needed before they can be applied in human. This review deals with the challenges and achievements of each pharmaceutical classification of gene delivery vehicles. It has also been tried to introduce the miRNA delivery systems, related achievements and challenges against cancer promotion. Besides, some representative examples of designed delivery systems and their effects on cancer treatment have been highlighted. PMID- 30465495 TI - Advanced carbon-based nanoplatforms combining drug delivery and thermal therapy for cancer treatment. AB - Anticancer treatment has become a research highlight in recent years. Despite several techniques have been developed and applied in the clinic, this area still meets great challenges in the construction of smart anticancer devices with accurate targeting, controlled release and microenvironment response properties. Most of carbon-based materials are biocompatible, possessing abundant and tunable pore structures and particularly large surface areas. These properties make them suitable materials as drug carriers. In addition, some carbon-based materials are capable of absorbing near-infrared radiation (NIR) and have highly efficient photothermal effects. The generated heat in situ can be tuned to kill cancer cells in short time on the position to be the purpose. This review describes the recent and significant application of four kinds of carbon materials including carbon nanotubes, graphene, carbon dots, mesoporous carbon for drug delivery and photothermal therapy. After a short introduction of the structures and properties of these materials, the construction and application of these nanoplatforms in drug delivery, photothermal therapy or the combination of them will be summarized and discussed in depth. Finally, the perspectives and challenges of these materials used in anticancer treatments will be given. PMID- 30465496 TI - Antimicrobial, anticancer drug carrying properties of biopolymers-based nanocomposites-A mini review. AB - Biopolymers are ubiquitous in biomedical and healthcare application. Its nanocomposites have gained the more attention as antimicrobials, drug carrier, sensors, disease diagnosis, tissue engineering, wound healing and cancer therapy. These biopolymer composites are efficient in holding, protect and releasing the bioactive drugs such as pharmaceutics, nutraceuticals, enzymes and probiotics. Several studies are revealed that polymer based drug delivery system in cancer therapy and microbial treatments so on. However, this mini review emphasized the source, extraction, and characterizations of the biopolymers and their use in the fabrication of various drug or metals based nanocomposites followed by its utilization as drug carrier or drug to treat the various diseases such as antimicrobial infections and cancer. Keywords: polymers: drug delivery system, antimicrobials, anticancer agents, drug carrier. PMID- 30465497 TI - Iron oxide nanoparticles for breast cancer theranostics. AB - BACKGROUND: Breast cancer is the second leading cause of death in women worldwide. The extremely fast rate of metastasis and ability to develop resistance mechanism to all the conventional drugs make them very difficult to treat which are the causes of high morbidity and mortality of breast cancer patients. Scientists throughout the world have been focusing on the early detection of breast tumor so that treatment can be started at the very early stage. Moreover, conventional treatment processes such as chemotherapy, radiotherapy, and local surgery suffer from various limitations including toxicity, genetic mutation of normal cells, and spreading of cancer cells to healthy tissues. Therefore, new treatment regimens with minimum toxicity to normal cells need to be urgently developed. METHODS: Iron oxide nanoparticles have been widely used for targeting hyperthermia and imaging of breast cancer cells. They can be conjugated with drugs, proteins, enzymes, antibodies or nucleotides to deliver them to target organs, tissues or tumors using external magnetic field. RESULTS: Iron oxide nanoparticles have been successfully used as theranostic agents for breast cancer both in vitro and in vivo. Furthermore, their functionalization with drugs or functional biomolecules enhance their drug delivery efficiency and reduces the systemic toxicity of drugs. CONCLUSION: This review mainly focuses on the versatile applications of superparamagnetic iron oxide nanoparticles on the diagnosis, treatment, and detecting progress of breast cancer treatment. Their wide application is because of their excellent superparamagnetic, biocompatible and biodegradable properties. PMID- 30465498 TI - Magnetic Nanoparticles: Current Trends and Future Aspects in Diagnostics and Nanomedicine. AB - BACKGROUND: Biomedical applications of Magnetic Nanoparticles (MNPs) are creating major impact in disease diagnosis and nanomedicine or a combined platform called theranostics. A significant progress has been made to engineer novel and hybrid MNPs for their multifunctional modalities such as imaging, biosensors, chemotherapeutic or photothermal and antimicrobial agents. MNPs are successfully applied in biomedical applications due to their unique and tunable properties such as superparamagnetism, stability, and biocompatibility. Approval of ferumoxytol (feraheme) for MRI imaging and the fact that several Superparamagnetic Iron Oxide Nanoparticles (SPIONs) are currently undergoing clinical trials have paved a path for future MNPs formulations. Intensive research is being carried out in designing and developing novel nanohybrids for multiple applications in nanomedicine. OBJECTIVES: The objective of the present review is to summarize recent developments of MNPs in imaging modalities like MRI, CT, PET and PA, biosensors and nanomedicine including their role in targeting and drug delivery. Relevant theory and examples of the use of MNPs in these applications have been cited and discussed to create a thorough understanding of the developments in this field. CONCLUSION: MNPs have found widespread use as contrast agents in imaging modalities, as tools for bio sensing, and as therapeutic and theranostics agents. Multiple formulations of MNPs are in clinical testing and may be accepted in clinical settings in near future. PMID- 30465499 TI - In Silico design and synthesis of targeted curcumin derivatives as Xanthine Oxidase inhibitors. AB - BACKGROUND: Curcumin is a well-known pharmacophore and some of its derivatives are shown to target xanthine oxidase (XO) to alleviate disorders caused by the excess production of uric acid. OBJECTIVE: Curcumin based derivatives were designed, synthesized and evaluated for their antioxidant and xanthine oxidase inhibitory potential. METHOD: In this report, we designed and synthesized two series of curcumin derivatives modified by inserting pyrazole and pyrimidine ring to central keto group. The synthesized compounds were evaluated for their antioxidant and xanthine oxidase inhibitory potential. RESULTS: Results showed that pyrazole analogues of curcumin produced excellent XO inhibitory potency with the IC50 values varying from 06.255 uM to 10.503 MUM. Among pyrimidine derivatives compound CU3a1 having ortho nitro substitution exhibited more potent xanthine oxidase inhibitory activity than any other curcumin derivative of this series. CONCLUSION: Curcumin derivatives CU5b1, CU5b2, CU5b3, and CU3a1 showed a potent inhibitory activity against xanthine oxidase along with good antioxidant potential. PMID- 30465500 TI - Three-Dimensional Manufactured Supports for Breast Cancer Stem Cell Population Characterization. AB - Breast Cancer (BC) is the most common cancer among women as well as it is the second cause of female deaths. When the tumor is not correctly eradicated there is a high relapse risk and incidence of metastasis. Breast Cancer Stem Cells (BCSCs) are responsible for initiating tumors and are resistant to current anti cancer therapies being in part responsible of relapse tumor and metastasis. The study of BCSCs is limited due to low percentage of this subpopulation and differentiation in primary tumors. Hence, three-dimensional (3D) supports are presented as an interesting tool to keep the stem-like features in 3D cell cultures. In this review, several 3D culture systems are discussed. Moreover, scaffolds are presented as a tool to enrich in BCSCs in order to find new specific therapeutic strategies against this malignant subpopulation. Anticancer treatments focused on BCSC population could be useful for BC patients, with particular interest in Triple Negative Breast Cancer (TNBC), a BC subtype with a high relapse rate and a lack of validated targeted therapies. PMID- 30465501 TI - Commentary: Lectins and Nanostructured Drug Delivery Systems. AB - The advances and the impact of nanostructured systems on therapeutics constitute a constantly evolving reality. New strategies have been developed for drug delivery control and for directing these systems to the targeted site improving the therapy. In this commentary, the lectins are briefly reviewed; their fundamentals and the proposed applications as ligands in nanostructured drug delivery systems are discussed. PMID- 30465502 TI - Formulation and characterization of Genistein-loaded nanostructured lipid carriers: Pharmacokinetic, Biodistribution and In vitro cytotoxicity studies. AB - BACKGROUND: Genistein (Gen) is a naturally occurring soy isoflavonoid, possessing anticancer, antiproliferation & antioxidant-like properties. The disadvantage of poor solubility and less oral bioavailability restrict its use as a potential anticancer agent. OBJECTIVES: The current work was focused on the formulation and characterization of the genistein loaded nanostructured lipid carriers that can entrap enough quantity of the drug which will provide sustained release of the drug for the treatment of ovarian cancer. METHODS: The nanostructure lipid carriers of genistein were developed with the aid of solvent emulsification and evaporation technique by employing TPGS as a surfactant. The resultant formulation was characterized by various physicochemical properties. Pharmacokinetics and biodistribution studies were carried out to estimate the mean plasma concentrations of the drug. Percentage cytotoxicity was evaluated by using PA-1 ovarian cancer cell lines. RESULTS: The resultant formulation exhibited a particle size of 130.23 nm, and entrapment efficiency of 94.27 %, & zeta potential of -20.21 mV with unimodal size distribution. Pharmacokinetics and biodistribution studies revealed that the formulation was able to provide sufficient plasma drug concentration for the longer period of time and the drug was more distributed in ovarian cancer tissues. Results of MTT assay concluded that GenNLC were more effective in comparison to pristine Gen. CONCLUSION: In a nutshell, GenNLC seems to be a superior alternative carrier system for the formulation industry to obtain the higher entrapment with excellent stability of the formulation. PMID- 30465503 TI - Intelligently applying Artificial Intelligence in Chemoinformatics. AB - The intertwining of chemoinformatics with artificial intelligence (AI) has given a tremendous fillip to the field of drug discovery. With the rapid growth of chemical data from high throughput screening and combinatorial synthesis, AI has become an indispensable tool for drug designers to mine chemical information from large compound databases for developing drugs at a much faster rate as never before. The applications of AI have gone beyond bioactivity predictions and have shown promise in addressing diverse problems in drug discovery like de novo molecular design, synthesis prediction and biological image analysis. In this article, we provide an overview of all the algorithms under the umbrella of AI, enlist the tools/frameworks required for implementing these algorithms as well as present a compendium of web servers, databases and open-source platforms implicated in drug discovery, Quantitative Structure-Activity Relationship (QSAR), data mining, solvation free energy and molecular graph mining. PMID- 30465504 TI - In silico protein interaction network analysis of virulence proteins associated with invasive aspergillosis for drug discovery. AB - Protein-Protein interaction (PPI) network analysis of virulence proteins of Aspergillus fumigatus is prevailing strategy to understand the mechanism behind the virulence of A. fumigatus. The identification of major hub proteins and targeting the hub protein as a new antifungal drug target will help in treating the invasive aspergillosis. In the present study, the PPI network of 96 virulence (drug target) proteins of A. fumigatus were investigated which resulted in 103 nodes and 430 edges. Topological enrichment analysis of the PPI network was also carried out by using STRING database and Network analyzer a cytoscape plug inn app. The key enriched KEGG pathway and protein domains were analyzed by STRING. Manual curation of PPI data identified three proteins (PyrABCN-43, AroM-34, and Glt1-34) of A. fumigatus possess the highest interacting partners. Top 10% hub proteins were also identified from the network using cytohubba on the basis of seven algorithms, i.e. betweenness, radiality, closeness, degree, bottleneck, MCC and EPC. Homology model and the active pocket of top three hub proteins were also predicted. PMID- 30465505 TI - DNA Methyltransferase Inhibitors and Their Therapeutic Potential. AB - Aberrant DNA methylation at the 5-position of cytosine, catalyzed by DNA methyltransferases (DNMTs), is associated with not only various cancers by silencing of tumor suppressor genes but also other diseases. The DNMTs, especially the DNMT1, DNMT3A and DNMT3B, are often overexpressed in various cancer tissues and cell lines. DNMTs are important epigenetic targets for drug development since the DNA methylation is reversible. This review summarizes an array of nucleoside and non-nucleoside inhibitors of DNMTs, as well as their biological activities. Among these inhibitors, the nucleoside analogue azacytidine and its deoxy derivative decitabine are both irreversible DNMT inhibitors and approved for the treatment of myelodysplastic syndrome. PMID- 30465506 TI - Personalized Medicine and Medicinal Chemistry:Toward a legal framework in the European Union ]. AB - In the last years the fields of Medicinal Chemistry and especially the ones related to the so-called Personalized Medicine, has received a great attention. Significant investment and remarkable researches surround the matter; however, not all those promising advances are reaching patients as quickly as they should. The absence of an adequate regulatory framework could be not helping. The complete and/or massive sequencing of individual genomes faces many ethical-legal challenges. Some of them are the access to Personalized Medicine; the treatment of a large volume of sensitive information and the use of tools produced by "big data" systems in clinical care or in predictive models. In addition, the legal protection of personal data related to health, the exercise of autonomy by patients, closely related to the regulation regarding clinical trials, are seriously involved. Our purpose with this work is to review the regulations of the European Union, in an attempt to contribute to a better understanding of the legal framework for the implementation and development of health systems based on Personalized Medicine. PMID- 30465507 TI - Flavanoids and Anthranquinones as Xanthine oxidase and Monoamine oxidase inhibitors: A new approach towards Inflammation and oxidative stress. AB - The development of xanthine oxidase and monoamine oxidase inhibitors led to important breakthroughs in the therapy of oxidative damage, hyperuricemia, gout, neurological, neuropsychiatric disorders and management of reperfusion injury. Drugs obtained from natural sources play an important role in treatment of various pathological disorders and act as lead compound for the discovery of new synthetic drug substances. In this review various pharmacological effects produced by inhibition of xanthine oxidase and monoamine oxidase through natural and synthetic flavanoids as well as anthraquinones are discussed in detail. Several methods have been designed for monitoring enzymatic activity and its inhibitor screening of bioactive natural and synthetic flavanoids and anthraquinones. In this review, all the in-vitro and other computational approaches are critically discussed which provided the clue about structure activity requirements for further precise modifications on the basic scaffold. PMID- 30465508 TI - Application of Computational Techniques to Unravel Structure-Function Relationship and Their Role in Therapeutic Development. AB - Application of computational tools and techniques has emerged as an invincible instrument to unravel the structure-function relationship and offered better mechanistic insights in the designing and development of new drugs along with treatment regime. The use of in silico tools equipped modern chemist with armamentarium of extensive methods to meticulously comprehend the structural tenacity of receptor-ligand interactions and their dynamics. In silico methods offers a striking property of being less resource intensive and viable economically as compared to experimental evaluation. These techniques have proved their mettle in the designing of potential lead compounds to combat life threatening diseases such as AIDS, cancer, tuberculosis and malaria etc. In the present scenario,computer-aided drug designing ascertained as an essential and indispensable gizmo in therapeutic development. This review will present a brief outline of computational methods used at different facets of drug designing and its latest advancements. The aim of this review article is to briefly highlight the methodologies and techniques used in structure-based/ ligand-based drug designing viz., molecular docking, pharmacophore modelling, density functional theory, protein-hydration and molecular dynamics simulation which helps in better understanding of macromolecular events and complexities. PMID- 30465509 TI - NMR based metabolomics: An exquisite and facile method for evaluating therapeutic efficacy and screening drug toxicity. AB - Metabolomics is an analytical approach to metabolism and involves quantitative and comparative analysis of low-molecular-weight metabolites in body fluids or cellular/tissues extracts. Owing to its ability to reveal disease-specific metabolic patterns or metabolic changes produced in response to a therapeutic intervention; it is gaining widespread applications virtually in all aspects of biomedical and pharmaceutical research pertaining to human healthcare management. It has also started playing a strategic role in pharmacological and toxicological research for evaluating therapeutic efficacy/safety of promising drug candidates either alone or in conjunction with other omics tools such as genomics, transcriptomics and proteomics. The metabolic profiling capabilities of nuclear magnetic resonance (NMR) spectroscopy along with pattern recognition methods have successfully been applied for identifying diagnostic panel of biomarkers, evaluating drug efficacy/safety, screening toxicity and disease mechanism. Particularly, the interest in applying NMR-based metabolomics for the assessment of therapeutic efficacy and safety is increasing among drug researchers and drug regulators owing to its non-destructive, non-selective and minimal sample preparation requirement. On top of this, it offers the potential for high throughput (i.e. >100 samples a day is attainable) and provides highly reproducible results. In this review, we will discuss some of the recent developments related to NMR based metabolomics followed by some recent literature examples to highlight its potential in (a) the evaluation of therapeutic efficacy and safety of lead discovery compounds, (b) monitoring disease status and recovery after treatment and (c) identification and evaluation of biomarkers of systemic/organ-specific toxicity. Additionally, the review will also highlight its role to facilitate clinical trial testing and improve post-approval drug monitoring. PMID- 30465510 TI - Current Breakthroughs in Structure-Based Design of Synthetic and Natural Sourced Inhibitors against Zika Viral Targets. AB - BACKGROUND: Zika is a worldwide pandemic dreadful viral transmission through Aedes mosquito vector. It significantly causes fever, joint pain or rash, and conjunctivitis. Pregnant mothers suffering from Zika viral infection may have fetal abnormalities due to severe neurological problems, characterized by microcephaly along with Guillain-Barre syndrome, issuing ZIKV a major public health concern as declared by the World Health Organization. There is hardly any FDA approved anti-Zika viral drugs available. OBJECTIVE: Therefore, it is a big panic for the scientists to destroy the virus completely by generating potent inhibitors. METHOD: For the purpose, various Zika viral targets were explored by structure-based design in the present review in connection with the discovery of various synthetic and natural sourced inhibitors against Zika virus. RESULTS: The structure-based drug design tools such as x-ray crystallography and molecular docking reported various co-crystallized ligands and Zika virus inhibitors. CONCLUSION: Such inhibitors could further be modified for the design of highly active leads to combat Zika virus utilizing chemoinformatics modules. PMID- 30465511 TI - Childhood solitary cutaneous mastocytoma: clinical manifestations, diagnosis, evaluation, and management. AB - BACKGROUND: The diagnosis of solitary cutaneous mastocytoma is mainly clinical, based on lesion morphology, the presence of a positive Darier sign, and absence of systemic involvement. Knowledge of this condition is important so that an accurate diagnosis can be made. OBJECTIVE: To familiarize physicians with the clinical manifestations, diagnosis, evaluation, and management of a solitary cutaneous mastocytoma. METHODS: A PubMed search was completed in Clinical Queries using the key term "solitary cutaneous mastocytoma". The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews. Only papers published in the English language were included. The information retrieved from the above search was used in the compilation of the present article. RESULTS: Typically, a solitary cutaneous mastocytoma presents as an indurated, erythematous, yellow-brown or reddish-brown macule, papule, plaque or nodule, usually measuring up to 5 cm in diameter. The lesion often has a peau d'orange appearance and a leathery or rubbery consistency. A solitary cutaneous mastocytoma may urticate spontaneously or when stroked or rubbed (Darier sign). Organomegaly and lymphadenopathy are characteristically absent. The majority of patients with skin lesions that erupt within the first two years of life have spontaneous resolution of the lesions before puberty. Treatment is mainly symptomatic. Reassurance and avoidance of triggering factors suffice in most cases. CONCLUSION: The diagnosis is mainly clinical, based on the morphology of the lesion, the presence of a positive Darier sign, and absence of systemic involvement. A skin biopsy is usually not necessary unless the diagnosis is in doubt. PMID- 30465512 TI - Pycnogenol Protects against Pentylenetetrazole-Induced Oxidative Stress and Seizures in Mice. AB - BACKGROUND: Epilepsy is one of the most common and severe brain disorders in the world, characterized by recurrent spontaneous seizures due to an imbalance between cerebral excitability and inhibition. Oxidative stress is a biochemical state in which reactive oxygen species are generated and associated with various diseases including epilepsy. Pycnogenol, a polyphenol obtained from the pine tree and has antioxidant& anti-inflammatory activity. So, The aim of the study was carried out to evaluate the effect of pycnogenol on pentylenetetrazole (PTZ) induced seizures in mice. METHOD: The mice of swiss strain each weighing 18-30g were used. Pycnogenol (50&100mg/kg) were suspended in carboxy methyl cellulose in saline and administered orally. Diazepam (1mg/kg, i.p) was used as a standard drug. The anticonvulsant effects of the drugs were measured using PTZ and cognitive behaviour was also assessed. The biochemical estimation was done by measuring Thio barbituric acid , Superoxide dismutase (, Catalase, and reduced glutathione followed by histopathological study. RESULT: Pycnogenol 50 & 100mg/kg, showed significant increase in latency to PTZ-induced seizures, decrease in duration and frequency of convulsions compared to control animals; however, the effects were dose-dependent and were more significant at higher dose. No impairment in cognitive functions like memory and muscle relaxant was observed following pycnogenol 50 & 100 mg/kg. The effect of pycnogenol on biochemical parameter was found to be significant. It decrease significantly (p<0.01) the level of TBARS and increase the levels of SOD, catalase, and GSH in brain tissue. The histopathological evaluation showed less neuronal degeneration in brain due to PTZ induced seizures in comparison to control group. CONCLUSION: Thus pycnogenol has a protective approach towards the convulsion and can be included as an adjuvant therapy with antiepileptic drugs. PMID- 30465513 TI - Cytotoxic Action of N-aryl, Furan-derived Aminophosphonates against HT29 and HCT116 Cancer Cell Lines. AB - Background The anticancer activity of aminophosphonic derivatives has been described extensively, some recent papers included furan-derived aminophosphonates and their cytostatic action against various cancer cells Objective A series of twelve furan-derived dibenzyl and diphenyl aminophosphonates 2a-f and 3a-f was synthesized and tested in aspect of their cytotoxic action on two cell lines of colorectal cancer: HT29 and HCT116. Seven of them are new compounds, while the rest five have already been published by us, together with their cytotoxic action against squamous esophageal cancer cells. Method To estimate the cytotoxicity effect of tested compounds MTT test was used. Pro-apoptotic activity of five selected compounds was evaluated using APC Annexin V Apoptosis Detection Kit on a flow cytometer. Quantification of caspases-3/7 activity was performed using Caspase-Glo(r) 3/7 Assay kit Results Five of these aminophosphonates showed significant cytotoxicity higher than those of cisplatin. Simultaneous evaluation of their cytotoxicity against PBLs revealed that these compounds are rather not harmful for regular human lymphocytes. Tests on apoptosis vs. their necrotic actions on cells were performed with selected compounds showing the most significant cytotoxicity against cancer cells and all tested compounds did not induce significant increase of necrosis in cells, whereas they showed moderate-to-strong proapoptotic actions even at the lowest applied concentration. Caspase 3/7 activity results confirmed proapoptotic properties of tested aminophosphonates. Conclusion From among studied compounds, dibenzyl N-phenyl substituted amino(2-furyl)methylphsophonates were found to be more potent compounds in aspect of their antiproliferative action than the corresponding diphenyl derivatives. PMID- 30465514 TI - Novel benzo[b]furans with anti-microtubule activity upregulate expression of apoptotic genes and arrest leukemia cells in G2/M phase. AB - BACKGROUND: Novel derivatives of benzo[b]furan were found to be highly toxic towards human chronic myelogenous (K562), acute myelogenous (HL-60) and acute lymphoblastic (MOLT-4) leukemia cells. OBJECTIVE: Characterization of the biological activity of novel benzofurans (influence on apoptosis, mitogen activated protein kinases and on the cell cycle). Identification of cellular protein(s) targeted by test benzofurans and defining the mechanism of action. METHOD: chemical synthesis, fluorescence assays, flow cytometry, gene expression by DNA microarray and real time RT-PCR, western blotting, cytotoxicity assays, pull-down assay, mass spectroscopy, in vitro polymerization of tubulin, molecular docking. RESULTS: 1,1'-[3-(bromomethyl)-5,6- dimethoxy-1-benzofuran-2,7 diyl]diethanone (1) and methyl 4-bromo-6-(dibromoacetyl)-5-hydroxy-2-methyl-1 benzofuran-3-carboxylate (2) induced apoptosis in K562 and MOLT-4 cells. The profiling of gene expression revealed that 1 and 2 increased the expression of proapoptotic genes involved in both receptor (TNFRSF 10A, TNFRSF 10B, CASP8) and mitochondrial (BAX, BID, NOXA, APAF1) pathways of apoptosis. Test benzo[b]furans activated c-Jun N-terminal kinase (JNK) and p38 kinase in K562 cells. Tubulin was identified as a protein target for benzo[b]furans in pull-down experiments with biotinylated 2. Test benzo[b]furans inhibited polymerization of tubulin monomers in vitro, decreased the level of cellular microtubules and arrested cells in a G2/M phase. Molecular docking suggests that benzo[b]furans 1 and 2 bind to tubulin via colchicine binding pocket and the complex is stabilized mainly by hydrophobic interactions. CONCLUSION: Novel benzo[b]furans with anti-microtubule activity were identified. They induce apoptosis in cancer cells and cause G2/M cell cycle arrest. Biological activity of 1 and 2 makes them potential lead compounds for development as anticancer drugs. PMID- 30465515 TI - Single-chain antibody against Reg4 suppresses gastric cancer cell growth and enhances 5-FU-induced cell death in vitro. AB - Regenerating islet-derived gene family member 4 (Reg4), a well-investigated growth factor in the regenerative pancreas, has recently been reported to be highly associated with a majority of gastrointestinal cancers. Pathological hyper expression or artificial over-expression of Reg4 causes acceleration of tumor growth, migration, and resistance to chemotherapeutic 5-Fluorouracil (5-FU). Until now, no method has been successfully established for eliminating the effects of Reg4 protein. This study reports the production of an engineered immunoglobin, a single-chain variable fragment (scFv-Reg4), to specifically bind Reg4 and block the bioactivity. The complementary-determining regions (CDRs) against Reg4 were assigned using MOE and ZDOCK servers. The binding affinity (KD) of scFv-Reg4 to Reg4 was determined to be 1.91*10-8 by bio-layer interferometry (BLI). In MKN45 and AGS cell lines, scFv-Reg4 depressed Reg4-stimulated cell proliferation and the inhibitory rates were 27.7+/-1.5% and 17.3+/-2.6%, respectively. Furthermore, scFv significantly enhanced 5-FU-induced cell death, from 23.0+/-1.0% to 28.4+/-1.2% in MKN45 and 28.2+/-0.7% to 36.6+/-0.6% in AGS cells. Treatment with scFv alone could lyse cancer cells to a certain extent, but no significance has been observed. Conclusion: The single-chain antibody (scFv Reg4) significantly inhibited gastric cancer cell proliferation and synergistically enhanced the lethal effect of 5-FU. Thus, traditional chemo /radio- therapeutics supplemented with scFv-Reg4 may provide advances in the strategy for gastrointestinal cancer treatment. PMID- 30465516 TI - Design, synthesis, anticonvulsant activity, preclinical study and pharmacokinetic performance of N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin-2-yl] methyl}, 2-[(2-isopropyl-5-methyl) 1-cyclo hexylidene] hydrazinecarboxamide. AB - N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin-2-yl] methyl}, 2-[(2 isopropyl-5-methyl) 1-cyclohexylidene] hydrazinecarboxamide QS11 was designed by computational study. It possessed essential pharmacophoric features for anticonvulsant activity and showed good docking with iGluRs (Kainate) glutamate receptor. QSAR and ADMET screening results suggested that QS11 would possess good potency for anticonvulsant activity. QS11 was synthesised and evaluated for its anticonvulsant activity and neurotoxicity. QS11 showed protection in strychnine, thiosemicarbazide, 4-aminopyridine and scPTZ induced seizure models and MES seizure model. QS11 showed higher ED50, TD50 and PI values as compared to the standard drugs in both MES and scPTZ screen. A high safety profile (HD50/ED50 values) was noted and hypnosis, analgesia, and anaesthesia were only observed at higher doses. No considerable increase or decrease in the concentration of liver enzymes was observed. Optimized QS11 was subjected to preclinical (in-vivo) studies and the pharmacokinetic performance of the sample was investigated. The result revealed that the pharmacokinetic performance of QS11 achieved maximum plasma concentrations (Cmax) of 0.315 +/- 0.011 ug/mL at Tmax of 2.0 +/- 0.13 h, area under the curve (AUC0-infinity) value 4.591 +/- 0.163 ug/ml x h, elimination half-life (T1/2) 6.28 +/- 0.71 h and elimination rate constant was found 0.110 +/ 0.013 h-1 . Above evidences indicat that QS11 could serve as a lead compound for development of antiepileptic drugs. PMID- 30465517 TI - Pentraxin level is the key to determine primary Percutaneous Coronary Intervention (PCI) or fibrinolysis. AB - AIM: To examine if pentraxin can help identifying patients benefitting most from primary Percutaneous Coronary Intervention (PCI) vs. fibrinolysis. METHODS: Patients with acute ST-Elevation Myocardial Infarction (STEMI) were consecutively recruited from a community center without PCI and a tertiary center with PCI facilities.Left ventricular ejection fraction (LVEF) was determined echocardiographically at baseline and 5 day after the index admission; the difference between two measurements was considered as the magnitude of improvement. We used regression models to test the hypothesis that the magnitude of the advantage of PCI over fibrinolysis in preserving LVEF 5 days after STEMI is modified by pentraxin 3 (PTX3). RESULTS: The functional advantage (LVEF) of the PCI over fibrinolysis has been determined by PTX3. LVEF attenuated and even reversed as PTX3 level increased. The primary PCI of the participants with less than 7 ng.ml-1 PTX3 level, achieved a clinically significantly increase in the LVEF in compare to fibrinolysis. At lower levels of PTX3, PCI shows a conspicuous advantage over fibrinolysis in terms of the probability of developing a LVEF <40%. CONCLUSION: We demonstrated not only the functional advantage of PCI over fibrinolysis performed within the recommended time frames but also the relative advantage of its relevant to the baseline PTX3 levels. PTX3 can play a role in determining the choice of best therapy. More than 75% of patients with STEMI who have PTX3 levels <=7 ng.ml-1 implies the need of the PCI. PMID- 30465518 TI - Histone acetylation regulates natriuretic peptides and neprilysin gene expressions in diabetic cardiomyopathy and nephropathy. AB - BACKGROUND: Natriuretic peptide system (NPS) alterations are involved in pathogenesis of diabetic cardiomyopathy (DCM) and nephropathy (DN), however its epigenetic regulation is still unclear. Interestingly, histone acetylation epigenetically regulates neprilysin expression in Alzheimer's disease. OBJECTIVES: The present study was aimed at delineating role of histone acetylation in regulation of NPS in DCM and DN. METHODS: Streptozotocin (55 mg/kg, i.p.)-induced diabetic male Wistar rats were used to mimic pathogenesis of DCM and DN. After haemodynamic measurements, all the rat's plasma, heart and kidney were collected for biochemistry, ELISA, protein isolation and western blotting, RT-PCR and chromatin immunoprecipitation (ChIP) assay. RESULTS: Diabetic rats heart and kidney exhibited activation of NF-kappaB and TGF-beta signalling with increased histone acetyl transferases (PCAF/CBP) expressions and augmented H2AK5Ac, H2BK5Ac, H3K18Ac, and H4K8Ac levels. ChIP assay results showed increased enrichment of H3K18Ac and H2BK5Ac at Nppa, Nppb (Heart) and Mme promoter (Heart/Kidney) in diabetic rats. Enrichment of H2AK5Ac was augmented on Nppa and Mme promoters in diabetic heart, while it remained unchanged on Nppb promoter in heart and Mme promoter in kidney. CONCLUSION: Augmented histone acetylation at promoter regions of NPS gene(s), at least in a part, responsible for increased expressions of ANP, BNP and NEP in diabetic heart and kidney. Hence, histone acetylation inhibitors can be considered as novel therapeutic targets against DCM and DN. PMID- 30465519 TI - Biochemical and histopathological evaluation of the radioprotective effects of melatonin against Gamma ray-induced skin damage in rats. AB - BACKGROUND: Radiotherapy is one of the treatment methods for cancers using ionizing radiations. About 70% of cancer patients undergo radiotherapy. Radiation effect on the skin is one of the main complications of radiotherapy and dose limiting factor. To ameliorate this complication, we used melatonin as a radioprotective agent due to its antioxidant and anti-inflammatory effects, free radical scavenging, improving overall survival after irradiation as well as minimizing the degree of DNA damage and frequency of chromosomal abrasions. METHODS: Sixty male Wistar rats were randomly assigned to 4 groups: control (C), melatonin (M), radiation (R) and melatonin + radiation (MR). A single dose of 30 Gy gamma radiation was exposed to the right hind legs of the rats while 40 mg/ml of melatonin was administered 30 minutes before irradiation and 2 mg/ml once daily in the afternoon for one month till the date of rat's sacrifice. Five rats from each group were sacrificed 4, 12 and 20 weeks after irradiation. Afterwards, their exposed skin tissues were examined histologically and biochemically. RESULTS: In biochemical analysis, we found that malondialdehyde (MDA) levels significantly increased in R group and decreased significantly in M and MR groups after 4, 12, and 20 weeks, whereas catalase (CAT) and superoxide dismutase (SOD) activities decreased in the R group and increased in M and MR groups during the same time periods compared with the C group (p<0.05). Histopathological examination found there were statistically significant differences between R group compared with the C and M groups for the three different time periods (p<0.005, p<0.004 and p<0.004) respectively, while R group differed significantly with MR group (p<0.013). No significant differences were observed between C and M compared with MR group (p>0.05) at 4 and 20 weeks except for inflammation and hair follicle atrophy, while there were significant effects at 12 weeks (p<0.05) Conclusion: Melatonin can be successfully used for the prevention and treatment of radiation-induced skin injury. We recommend the use of melatonin in optimal and safe doses. These doses should be administered over a long period of time for effective radioprotection and amelioration of skin damages as well as improving the therapeutic ratio of radiotherapy. PMID- 30465520 TI - Utility Of Molecular Imaging With 2-Deoxy-2-[Fluorine-18] Fluoro-D-Glucose Positron Emission Tomography (18f-Fdg Pet) For Small Cell Lung Cancer (Sclc): A Radiation Oncology Perspective. AB - BACKGROUND AND OBJECTIVE: Although accounting for a relatively small proportion of all lung cancers, small cell lung cancer (SCLC) remains to be a global health concern with grim prognosis. Radiotherapy (RT) plays a central role in SCLC management either as a curative or palliative therapeutic strategy. There has been considerable progress in RT of SCLC thanks to improved imaging techniques leading to accurate target localization for precise delivery of RT. Positron emission tomography (PET) is increasingly used in oncology practice as a non invasive molecular imaging modality. METHODS: Herein, we review the utility of molecular imaging with 2-deoxy-2-[fluorine-18] fluoro-D-glucose PET (18F-FDG PET) for SCLC from a radiation oncology perspective. RESULTS: There has been extensive research on the utility of PET for SCLC in terms of improved staging, restaging, treatment designation, patient selection for curative/palliative intent, target localization, response assessment, detection of residual/recurrent disease, and prediction of treatment outcomes. CONCLUSION: PET provides useful functional information as a non-invasive molecular imaging modality and may be exploited to improve management of patients with SCLC. Incorporation of PET/CT in staging of patients with SCLC may aid in optimal treatment allocation for an improved therapeutic ratio. From a radiation oncology perspective, combination of functional and anatomical data provided by integrated PET/CT improves discrimination between atelectasis and tumor, and assists in designation of RT portals with its high accuracy to detect intrathoracic tumor and nodal disease. Utility of molecular imaging for SCLC should be further investigated in prospective randomized trials to acquire higher level of evidence for future potential applications of PET. PMID- 30465521 TI - Vascular calcification and not arrhythmia in idiopathic atrial fibrillation associates with sex differences in diabetic microvascular injury miRNA profiles. AB - Background Atrial fibrillation (AF) in patients without concomitant cardiovascular pathophysiological disease, is called idiopathic atrial fibrillation (iAF). Nonetheless, iAF patients have oftentimes subclinical coronary (micro)vascular dysfunction and, particularly in women, a higher prevalence of subsequent cardiovascular comorbidities. Previously, we identified a plasma miRNA association with diabetes and microvascular injury in diabetic nephropathy (DN) patients. Therefore, in this study we assessed whether plasma levels of these diabetic, microvascular injury associated miRNAs reflect microvascular integrity in iAF patients, associate with the presence of paroxysmal arrhythmia or instead are determined by concealed coronary artery disease. Methods Circulating levels of a pre-selected set of diabetic, (micro) vascular injury associated miRNAs, were measured in 59 iAF patients compared to 176 sinus rhythm (SR) controls. Furthermore, the presence of coronary artery and aortic calcification in each patient was assessed using cardiac computed tomography angiography (CCTA). Results Paroxysmal arrhythmia in iAF patients did not result in significant miRNA expression profile differences in iAF patients compared to SR controls. Nonetheless, coronary artery calcification (CAC) was associated with higher levels of miRNAs-103, -125a-5p, -221 and -223 in men. In women, CAC associated with higher plasma levels of miRNA-27a and miRNA-126 and correlated with Agatston scores. Within the total population, ascending aortic calcification (AsAC) patients displayed increased plasma levels of miRNA-221, while women in particular demonstrated a descending aorta calcification (DAC) associated increase in miRNA-212 levels. Conclusions Diabetic microvascular injury associated miRNAs in iAF associate with subclinical coronary artery disease in a sex-specific way and confirm the notion that biological sex identifies iAF subgroups that may require dedicated clinical care. PMID- 30465522 TI - Metazoan evolution of glutamate receptors reveals unreported phylogenetic groups and divergent lineage-specific events. AB - Glutamate receptors are divided in two unrelated families: ionotropic (iGluR), driving synaptic transmission, and metabotropic (mGluR), which modulate synaptic strength. The present classification of GluRs is based on vertebrate proteins and has remained unchanged for over two decades. Here we report an exhaustive phylogenetic study of GluRs in metazoans. Importantly, we demonstrate that GluRs have followed different evolutionary histories in separated animal lineages. Our analysis reveals that the present organization of iGluRs into six classes does not capture the full complexity of their evolution. Instead, we propose an organization into four subfamilies and ten classes, four of which have never been previously described. Furthermore, we report a sister class to mGluR classes I III, class IV. We show that many unreported proteins are expressed in the nervous system, and that new Epsilon receptors form functional ligand-gated ion channels. We propose an updated classification of glutamate receptors that includes our findings. PMID- 30465524 TI - Evaluation of the blood ammonia level as a non-invasive predictor for the presence of esophageal varices and the risk of bleeding. AB - BACKGROUND/AIMS: The development of esophageal varices (EV) and resultant bleeding are the most critical complications of portal hypertension. Upper gastrointestinal endoscopy is the gold standard for diagnosis of EV. To find a non-invasive method for diagnosis of EV and to predict the bleeding risk is appealing and would decrease the cost and discomfort of upper endoscopy. The aim of our study was to evaluate the blood ammonia level as a predictor of the presence of EV and of a high risk of bleeding. MATERIALS AND METHODS: In this cross-sectional study, a total of 359 patients with cirrhosis were examined for the presence of EV by upper endoscopy. Abdominal ultrasonography, calculation of the Child-Pugh score, and measurement of blood ammonia were performed for each patient. RESULTS: The blood ammonia level was significantly higher in patients with EV than in those without it (p<0.001), and in patients with a high risk of variceal bleeding than in those with a low risk (p=0.026). CONCLUSION: An increased blood ammonia level and splenic vein diameter are predictors for the presence of EV and bleeding risk factors. The blood ammonia level may be clinically useful as it correlates with and is an independent predictor for both the endoscopic risk signs and risk factors of bleeding, and therefore, it could be used in patients with cirrhosis to decrease the number of screening endoscopies they are subjected to. PMID- 30465523 TI - A time-stamp mechanism may provide temporal information necessary for egocentric to allocentric spatial transformations. AB - Learning the spatial organization of the environment is essential for most animals' survival. This requires the animal to derive allocentric spatial information from egocentric sensory and motor experience. The neural mechanisms underlying this transformation are mostly unknown. We addressed this problem in electric fish, which can precisely navigate in complete darkness and whose brain circuitry is relatively simple. We conducted the first neural recordings in the preglomerular complex, the thalamic region exclusively connecting the optic tectum with the spatial learning circuits in the dorsolateral pallium. While tectal topographic information was mostly eliminated in preglomerular neurons, the time-intervals between object encounters were precisely encoded. We show that this reliable temporal information, combined with a speed signal, can permit accurate estimation of the distance between encounters, a necessary component of path-integration that enables computing allocentric spatial relations. Our results suggest that similar mechanisms are involved in sequential spatial learning in all vertebrates. PMID- 30465525 TI - Differential diagnosis of Crohn's disease using antibodies to glycoprotein 2 and Saccharomyces cerevisiae. AB - BACKGROUND/AIMS: Glycoprotein 2 (GP2), the major autoantigen of Crohn's disease (CD)-specific pancreatic autoantibodies, is reportedly correlated with several characteristics of CD. We investigated this serological marker in Turkish patients with CD and assessed its utility in combination with anti-Saccharomyces cerevisiae antibodies (ASCAs) for differential diagnosis of CD. MATERIALS AND METHODS: A total of 60 patients with CD, 62 patients with ulcerative colitis (UC), and 46 healthy controls with a definite diagnosis who were similar in age and sex were enrolled in the study conducted from November 2011 to October 2012. ASCA and anti-GP2 levels were measured using commercially available kits. RESULTS: Anti-GP2 IgA and IgG levels were higher in patients with CD (25%) than in those with UC (5%) and controls (2%). The seroprevalence of anti-GP2 IgA was markedly higher than that of IgG in patients with CD in contrast to previous studies. The specificity and positive predictive value of seropositivity for both ASCA and anti-GP2 were 100%. ASCA IgA seropositivity was correlated with a complicated disease course and a history of surgery. There was no correlation between anti-GP2 seropositivity and disease location, disease behavior, or a history of surgery. CONCLUSION: The combination of ASCA and anti-GP2 may enable differentiation of CD from UC. As ASCA seropositivity is associated with a more complicated disease course, patients seropositive for ASCA at the initial diagnosis should undergo more intense therapy. PMID- 30465526 TI - [Possible technical elements for the ultimate nucleotide sequencers]. AB - The DNA sequencing technology invented in 1970's has been a leading tool for genomics and its sequel ? precision medicine. The needs for advancement of the DNA sequencing technology comes from increasing resolutions in cellular and molecular studies, not only DNA or cDNA sequences but also their covalent modifications, such as various kinds of DNA or RNA methylations. Sequencing single RNA molecules directly without conversion into cDNAs appears to be the last generation of nucleotide sequencers. Some cutting-edge technological elements are clearly expected for the ultimate design of nucleotide sequencers, which must include, but not limited to, nanopores, nanofabrication, surface- or tip-enhanced Raman spectrometry, single-molecule photonics and plasmonics, artificial-intelligence based data analysis tools. The complexity of biological systems is also calling for new syntheses, frameworks, paradigms and more concerted efforts and projects internationally. Here we discuss possible roles and capacities of such technical elements for the fourth-generation nucleotide sequencers in details. PMID- 30465527 TI - [Prospects for national biological big data centers]. AB - In the era of big data, scientific big data have become the new driving force for both science and technology innovation and social and economic development. China is a powerhouse in generating vast quantities of biological data, which are an essential strategic resource for population health and national security. The current situation of data loss due to the isolated data storage and the lack of systematic data monitoring and management, and the heavy dependency on international biological data centers urgently calls for China's own life big data storage and management system at the national level. Taking NCBI as an example, this article introduces the development history and present situation of the international biological big data centers. In addition, the importance, urgency, current historical opportunity and prospect of establishing a national biological big data center in China are also expounded in detail. In order to promote the development of the national center and improve China's international competitiveness and influence in life science research, the BIG Data Center at Beijing Institute of Genomics (BIG), Chinese Academy of Sciences, has taken many efforts on big data deposition, integration and translation and achieved initial progress. PMID- 30465528 TI - [Advances of sequencing and assembling technologies for complex genomes]. AB - Complex genomes are noted to be extremely difficult to sequence or assemble by using ordinary methods. Complex genomes are typically characterized as being highly repetitive, highly heterozygous, extremely GC biased, or naturally contaminated, i.e., contaminations which cannot be removed before sequencing. To solve these problems with sequencing and assembling complex genomes, three major techniques include: (1) DNA extraction experiments, (2) Sequencing technologies and platforms, and (3) Algorithms and strategies for assembling. In this review, we summarize these state-of-the-art technologies and strategies used in these directions. We also review the representative projects of complex genome sequencing and address the development of these technologies and strategies for solving the challenges when sequencing or assembling complex genomes. PMID- 30465529 TI - [RNA methylation: regulations and mechanisms]. AB - Epigenetic modifications include the chemical modifications on DNA, RNA and proteins characterized by altered gene expression and function without any changes in the gene sequence. In addition to well-established DNA and protein epigenetic modifications, the reversible RNA methylation has led the third wave of studies in the epigenetic field. RNA has more than 100 chemical modifications, among which methylation is the major type. The identification of catalyzing enzymes for RNA methylation and the development of high-throughput detection technologies for RNA modification at the transcriptomic level are the prerequisites for revealing the regulatory role of RNA methylation in gene expression and biological functions. In this review, we summarize the recent frontier in RNA methylation-mediated epitranscriptomics from our and other laboratories, with emphasis on the discoveries of RNA modification demethylase , methyltransferase and binding protein as well as the illustration of regulatory roles of RNA methylation modification in hematopoietic stem cell differentiation, spermatogenesis, brain development and other pivotal life processes. These findings have shown that RNA methylation is just as reversible as DNA methylation, and opened up a novel field in RNA methylation-mediated epitranscriptomics, which appends a new layer of epigenetic regulation to the central genetic dogma. PMID- 30465530 TI - [The inheritance and reprogramming of chromatin structure in early animal embryos]. AB - The chromatin accessibility and 3D high-order structure play an important role in gene expression and regulation, and are involved in numerous cellular processes such as differentiation, development and tumorigenesis. It is currently one of the hottest research fields in epigenetics. The animal embryonic development initiates from the terminally differentiated mature eggs, which are fertilized by sperms to establish totipotent zygotes. During this complex process, the epigenome encompassing chromatin accessibility and high-order structures changes dramatically, undergoes inheritance, reprogramming and re-establishment, so that the zygote could eventually develop into a new multicellular and multi-tissue organism. In this review, we summarize the research methods and technology for chromatin accessibility and 3D high-order structures, the dynamics of chromatin structures during the animal embryonic development and how to regulate early embryogenesis, the relationship between chromatin structure and other epigenetic information such as methylation and histone modification. We hope that this review may shed light on the research of epigenome regulating embryo development. PMID- 30465531 TI - [Precision genomic and translational medicine for acute myeloid leukemia]. AB - Leukemia is a group of hematologic malignancy that has unfavorable prognosis and unclear mechanisms. In recent years, advances in leukemia research encompass the discovery of novel targets in acute myeloid leukemia drug resistance, epigenetic crosstalk in mixed lineage leukemia (MLL) leukemogenesis, genetic mechanisms of aggressive NK-cell leukemia, as well as the critical role of key epigenetic regulator in acute myeloid malignancy. Remarkably, researchers revealed that the histone modifying gene SETD2 as a new tumor suppressor and therapeutic target in patients with acute myeloid leukemia. Furthermore, low-dose chemotherapy as a frontline regiment in treating pediatric acute myeloid leukemia can substantially reduce the toxic side effects and treatment costs without impairing efficacy. Although advances in cancer genomics have greatly increased our understanding of the molecular characteristics in tumor biology, recent studies suggest that Darwinian evolution of intratumor heterogeneity represents a major challenge to develop therapeutic strategies to improve disease control. Researchers also dissected the distinct evolutionary dynamics under different chemotherapy regimens and the corresponding applications in the evaluation of treatment outcomes. Altogether, these efforts offered new opportunities for the development of acute myeloid leukemia diagnostics and therapeutics. PMID- 30465532 TI - [Synergistic regulation of the erythroid differentiation of K562 cells by KLF1 and KLF9]. AB - Kruppel-like factors (KLFs) regulate diverse physiological processes such as the differentiation and development of red blood cells. However, it remains unclear whether KLFs exhibit synergistic regulatory effects. Transcriptomic data from our previous study showed that KLF1 and KLF9 expression was significantly higher in differentiated red blood cells than in hematopoietic stem cells. In the present study, we manipulated KLF1 and KLP9 gene expression by overexpressing or knocking down KLF1 and KLF9 in K562 cells and revealed a positive correlation between the expression of KLF1 and KLF9; their co-expression can significantly promote erythroid differentiation and specifically enhance beta-globin gene expression. Further, we analyzed the transcriptome data of K562 cells with altered KLF1/KLF9 levels and found that KLF1 and KLF9 synergistically regulated erythroid differentiation through the PI3K-Akt and FoxO signaling pathways. KLF1 and KLF9 may exert this synergistic effect through FOS, TF, and IL8 in K562 cells. We have provided evidence that KLF1 and KLF9 play a synergistic role in regulating erythroid differentiation. PMID- 30465533 TI - [RAD51 regulates REV1 recruitment to DNA double-strand
break sites]. AB - REV1 is one of the major Y-family DNA polymerases. It not only functions as a scaffold protein to mediate other specialized DNA polymerases to sites of lesions, but also inserts deoxycytidine across the lesion strand during translesion DNA synthesis (TLS). Meanwhile, REV1 has been reported to be involved in homologous recombination (HR) repair. Here we further explore the roles of REV1-interacting proteins RAD51 and RAD51C in REV1-mediated DNA double-strand break (DSB) repair. We found that RAD51 but not RAD51C regulates REV1 recruitment to DSB sites via pulsed laser microirradiation. Interestingly, immunofluorescence staining exhibits that REV1 also regulates RAD51 focus formation in response to CPT treatment. These results suggest that REV1 and RAD51 might be mutually dependent on each other in the REV1-related HR pathway. PMID- 30465534 TI - [Application of BIG-Annotator in the genome sequencing data functional annotation and genetic diagnosis]. AB - The next generation sequencing (NGS) technology has been playing important roles in genetic diagnosis of diseases in recent years, and serving as a technological basis of precision medicine. In analyzing NGS data, the variant annotation is an important step. In this study, we developed a computationally efficient software (BIG-Annotator) to perform functional annotation for whole-genome single nucleotide polymorphisms. BIG-Annotator integrates the widely used databases and pipelines for variant annotation of genetic diseases and tumors, and follows the 2015 ACMG-AMP Standard Guide for Interpretation and Reporting of Clinical Variants. BIG-Annotator is ten times faster than the existing software, and suitable for annotating genomic sequencing data from large samples. Here we present two analysis cases of genetic diagnosis using BIG-Annotator to show its applications. PMID- 30465535 TI - [The effect of EDARV370A on facial and ear morphologies in Uyghur population]. AB - The ectodysplasinA receptor gene (EDAR) plays an important role in the development of ectoderm. The derived G allele of its key missense variant EDARV370A is prevalent in East Asians and Americans, but rare in Africans and Europeans. This leads to distinct ectodermal-derived phenotypes between different continental groups, such as the straighter and thicker hair, more eccrine sweat glands, feminine smaller breasts, shovel incisors characteristic of East Asians. At present, we know little about the association between EDARV370A and facial and ear morphology characteristics. To better understand the effect of EDARV370A on craniofacial phenotypes, we systematically examined the association between EDARV370A and 136 facial quantitative phenotypes, one chin ordinal phenotype and six ear ordinal phenotypes in 715 Uyghurs. The quantitative phenotypes were derived by applying our automated landmark annotation method to facial 3D photos and the ordinal phenotypes were manually graded from facial 2D photos. The analysis identified significant association (P<0.05 after multiple testing correction) between EDARV370A and eight facial phenotypes, one chin phenotype and three ear morphology phenotypes. Our study thus elucidated the pleotropic effect of EDARV370A on craniofacial phenotypes in a European-Asian admixed Uyghur population. PMID- 30465536 TI - [Correlation studies of distinct mutational signatures with common cancer pathological subtyping]. AB - It holds great promises to precisely stratify cancer subtypes to improve cancer diagnosis, therapy and prognosis. In the past, the diagnosis of pathological subtypes mainly relied on hematoxylin-eosin staining and immunohistochemistry. With the development of sequencing technologies, genotype and phenotype analysis of individuals has become possible and precision medicine is on the rise in healthcare. As different tumor subtypes have different cell-of-origin, risk factors and clinical phenotypes, they generate unique combinations of mutation types, termed "Mutational Signatures". Herein, using the exome sequencing data from The Cancer Genome Atlas (TCGA), we evaluated the utility of mutational landscape for differentiating cell-of-origin within three common cancers (kidney, lung and esophageal cancers). We found that mutational signatures predicted histological subtypes of kidney cancers, clear cell renal cell carcinoma (KIRC) vs. chromophobe renal cell carcinoma (KICH), which had different cell-of-origin, with 100% accuracy (95% CI: 0.93-1.00). The mutational signatures also predicted histological subtypes of lung cancers (lung adenocarcinoma vs. lung squamous cell carcinoma) and esophageal cancers (esophageal adenocarcinoma vs. esophageal squamous cell carcinoma) with 78% (95% CI: 0.66-0.86) and 84% accuracy (95% CI: 0.60-0.97), respectively. Collectively, mutational signatures-based subtyping is good at pathological classification, personalized diagnosis, especially early detection for common cancers. PMID- 30465537 TI - [The BIG Data Center's database resources]. AB - Omics data in life and health sciences are of fundamental significance for scientific research and biomedical technology development. However, there is yet to be a platform for biological data management and sharing in China, making it difficult to meet the development needs of biomedical and related fields and consequently leading to severe issues in big data management, sharing and translation. To address these issues, Beijing Institute of Genomics (BIG) of Chinese Academy of Sciences founded the BIG Data Center (BIGD) in 2016, which is dedicated to establish a biological big data management platform and multi-omics databases, with a particular focus on national population healthcare and important strategic biological resources. In this paper, we describe core database resources in BIGD, including GSA (Genome Sequence Archive), GWH (Genome Warehouse), GVM (Genome Variation Map), GEN (Gene Expression Nebulas), MethBank (Methylation Bank), BioCode and Science Wikis. Taken together, all these resources provide a series of services for data deposition, integration and sharing, laying solid foundations for enhancing national biological science data management and further promoting the construction of national bioinformatics center. PMID- 30465538 TI - [GSA: Genome Sequence Archive]. AB - The Genome Sequence Archive (GSA), a new data repository for raw sequence reads in China, has been developed in compliance with the International Nucleotide Sequence Database Collaboration (INSDC) standards. It supports data generated from a variety of sequencing platforms ranging from Sanger sequencing to single cell sequencing and provides data storing and sharing services freely for worldwide scientific communities. Since it went online in late 2015, GSA has archived more than 500 TB data and been acknowledged by many high-profile journals, including Cell, Nature, PNAS, GPB, etc. Focusing on omics data submission, storing and sharing typically for Chinese users, GSA promotes the initiative of the National Bioinformatics Center of China. This paper introduces the specifies of GSA as data collection, curation, management and exchange to facilitate users to understand and use GSA database. PMID- 30465539 TI - [Database resources of the reference genome and genetic variation maps for the Chinese population]. AB - With the implementation of the international human genome project and 1000 genome project, hundreds of Chinese individual genome sequences have been published. Establishing a high-precision Chinese population reference genome and identifying the unique genome variations are fundamental for future precision medicine research in China. To further meet the needs of scientific management and deep mining on the rapidly growing Chinese genomic data, Beijing Institute of Genomics, Chinese Academy of Sciences, has developed a Virtual Chinese Genome Database (VCGDB, http://bigd.big.ac.cn/vcg/) and Genome Variation Map (GVM, http://bigd.big.ac.cn/gvm/) based on the public whole genome sequencing data, which provides the worldwide services of data retrieval, sharing, downloading and online analysis. This paper presents the brief introduction of characteristics and functions of the two databases, as well as their future development and application prospects, aiming to provide useful information for the promotion and development of the reference genome and genome variation map database in China. PMID- 30465540 TI - Phase transition and electrical properties of aggregations of ethoxylated phytosterol surfactants by dielectric spectroscopy. AB - The aggregation behaviors of the bio-friendly nonionic phytosterol ethoxylated (BPS-n) surfactants, in water were investigated by dielectric spectroscopy over a frequency range from 40 Hz to 110 MHz. Only the BPS-5 solution system observes dielectric relaxation and we judge this is because due to the difference in the chain length of BPS-n surfactants. Then we further analyze the BPS-5 solution system. Interestingly, we found that BPS-5 lamellar aggregations exist two phases before and after 6%-8% BPS-5 concentration by using the dielectric parameters and the phase parameters obtained by fitting dielectric spectrum and the theoretical model respectively. In addition, we concluded that the change of the electrical parameters such as surface conductivity and zeta potential are related to the lamellar phase structure. Besides, lamellar phases formed at a lower concentration are more stable than those at higher concentration by the thermodynamic analysis. PMID- 30465541 TI - Comparison of five one-step reconstruction algorithms for spectral CT. AB - Over the last decade, dual-energy CT scanners have gone from prototypes to clinically available machines, and spectral photon counting CT scanners are following. They require a specific reconstruction process, consisting of two steps: material decomposition and tomographic reconstruction. Image-based methods perform reconstruction, then decomposition, while projection-based methods perform decomposition first, and then reconstruction. As an alternative, 'one step inversion' methods have been proposed, which perform decomposition and reconstruction simultaneously. Unfortunately, one-step methods are typically slower than their two-step counterparts, and in most CT applications, reconstruction time is critical. This paper therefore proposes to compare the convergence speeds of five one-step algorithms. We adapted all these algorithms to solve the same problem: spectral photon-counting CT reconstruction from five energy bins, using a three materials decomposition basis and spatial regularization. The paper compares a Bayesian method which uses non-linear conjugate gradient for minimization (Cai et al 2013 Med. Phys. 40 111916-31), three methods based on quadratic surrogates (Long and Fessler 2014 IEEE Trans. Med. Imaging 33 1614-26, Weidinger et al 2016 Int. J. Biomed. Imaging 2016 1-15, Mechlem et al 2018 IEEE Trans. Med. Imaging 37 68-80), and a primal-dual method based on MOCCA, a modified Chambolle-Pock algorithm (Barber et al 2016 Phys. Med. Biol. 61 3784). Some of these methods have been accelerated by using MU preconditioning, i.e. by performing all internal computations not with the actual materials the object is made of, but with carefully chosen linear combinations of those. In this paper, we also evaluated the impact of three different MU preconditioners on convergence speed. Our experiments on simulated data revealed vast differences in the number of iterations required to reach a common image quality objective: Mechlem et al (2018 IEEE Trans. Med. Imaging 37 68-80) needed ten iterations, Cai et al (2013 Med. Phys. 40 111916-31), Long and Fessler (2014 IEEE Trans. Med. Imaging 33 1614-26) and Weidinger et al (2016 Int. J. Biomed. Imaging 2016 1-15) several hundreds, and Barber et al (2016 Phys. Med. Biol. 61 3784) several thousands. We also sum up other practical aspects, like memory footprint and the need to tune extra parameters. PMID- 30465542 TI - The impact of 2D cine MR imaging parameters on automated tumor and organ localization for MR-guided real-time adaptive radiotherapy. AB - 2D cine MR imaging may be utilized to monitor rapidly moving tumors and organs-at risk for real-time adaptive radiotherapy. This study systematically investigates the impact of geometric imaging parameters on the ability of 2D cine MR imaging to guide template-matching-driven autocontouring of lung tumors and abdominal organs. Abdominal 4D MR images were acquired of six healthy volunteers and thoracic 4D MR images were obtained of eight lung cancer patients. At each breathing phase of the images, the left kidney and gallbladder or lung tumor, respectively, were outlined as volumes of interest. These images and contours were used to create artificial 2D cine MR images, while simultaneously serving as 3D ground truth. We explored the impact of five different imaging parameters (pixel size, slice thickness, imaging plane orientation, number and relative alignment of images as well as strategies to create training images). For each possible combination of imaging parameters, we generated artificial 2D cine MR images as training and test images. A template-matching algorithm used the training images to determine the tumor or organ position in the test images. Subsequently, a 3D base contour was shifted to the determined position and compared to the ground truth via centroid distance and Dice similarity coefficient. The median centroid distance between adapted and ground truth contours was 1.56 mm for the kidney, 3.81 mm for the gallbladder and 1.03 mm for the lung tumor (median Dice similarity coefficient: 0.95, 0.72 and 0.93). We observed that a decrease in image resolution led to a modest decrease in localization accuracy, especially for the small gallbladder. However, for all volumes of interest localization accuracy varied substantially more between subjects than due to the different imaging parameters. Automated tumor and organ localization using 2D cine MR imaging and template-matching-based autocontouring is robust against variation of geometric imaging parameters. Future work and optimization efforts of 2D cine MR imaging for real-time adaptive radiotherapy is needed to characterize the influence of sequence- and anatomical site-specific imaging contrast. PMID- 30465543 TI - Autosegmentation of prostate anatomy for radiation treatment planning using deep decision forests of radiomic features. AB - Machine learning for image segmentation could provide expedited clinic workflow and better standardization of contour delineation. We evaluated a new model using deep decision forests of image features in order to contour pelvic anatomy on treatment planning CTs. 193 CT scans from one UK and two US institutions for patients undergoing radiotherapy treatment for prostate cancer from 2012-2016 were anonymized. A decision forest autosegmentation model was trained on a random selection of 94 images from Institution 1 and tested on 99 scans from Institution 1, 2, and 3. The accuracy of model contours was measured with the Dice similarity coefficient (DSC) and the median slice-wise Hausdorff distance (MSHD) using clinical contours as the ground truth reference. Two comparison studies were performed. The accuracy of the model was compared to four commercial software packages on twenty randomly-selected images. Additionally, inter-observer variability (IOV) of contours between three radiation oncology experts and the original contours was evaluated on ten randomly-selected images. The highest median values of DSC across all institutions were 0.94-0.97 for bladder (with interquartile range, or IQR, of 0.92-0.98) and 0.96-0.97 (IQR 0.94-0.97) for femurs. Good agreement was seen for prostate, with median DSC 0.75-0.76 (IQR 0.67 0.82), and rectum, with median DSC 0.71-0.82 (IQR 0.63-0.87). The lowest median scores were 0.49-0.70 for seminal vesicles (IQR 0.31-0.79). For the commercial software comparison, model-based segmentation produced higher DSC than atlas based segmentation, with decision forests producing highest DSC for all organs of interest. For the interobserver study, variability in DSC between observers was similar to the agreement between the model and ground truth. Deep decision forests of radiomic features can generate contours of pelvic anatomy with reasonable agreement with physician contours. This method could be useful for automated treatment planning, and autosegmentation may improve efficiency and increase standardization in the clinic. PMID- 30465544 TI - Grinding of nano-graphite inkjet inks for application in organic solar cells. AB - The production of printable graphene flakes is not easy to scale up when produced by ultrasonication and purified by centrifugation. In this work, natural graphite flakes were exfoliated by wet ball milling in water supported by the addition of sodium deoxycholate as a surfactant and the dispersion was formulated for inkjet printing. By subsequent dilution and filtration of the milling paste, more than 45 l of a stable dispersion of nano-graphite particles in one batch process was obtained. The dispersion was characterized by thermogravimetric analysis and UV vis spectroscopy to determine concentration, and experiments to measure long-term stability were conducted. The nano-graphite particles were analyzed by optical microscopy, scanning electron microscopy and Raman spectroscopy, revealing 300 400 nm sized particles. The dispersion was formulated into an inkjet ink and tested as interfacial hole transport layer between the anode and the photo-active bulk-heterojunction layer of an organic solar cell with inverted structure. The nano-graphite flakes are inkjet printable and conductive and therefore show potential as a low-cost alternative to polymer poly(3,4-ethylenedioxythiophene) polystyrene sulfonate. PMID- 30465545 TI - Pseudocapacitive Li-ion storage boosts high-capacity and long-life performance in multi-layer CoFe2O4/rGO/C composite. AB - Due to the intrinsic low electrical conductivity and large volume expansion of the CoFe2O4 based active materials, designing more novel structures is still one of the most important challenges for its lithium ion battery application. In this work, the CoFe2O4/reduced graphene oxide/carbon (CFO/rGO/C) composite with integrated multi-layer structure has been synthesized through a facial two-step hydrothermal method. Benefiting from the introduction of the graphene network and amorphous carbon coating layer, as well as the accompanying synergistic effect, this composite can exhibit fast and reversible lithium intercalation/deintercalation reactions. With the aid of a surface-induced capacitive process, the CFO/rGO/C composite delivers a superior specific capacity (945 mA h g-1 at 0.1 A g-1) and excellent long-term cyclic stability (421 mA h g 1 at 4 A g-1 with closely 100% Coulombic efficiency after 2000 cycles). Significantly, at a high current density of 1 A g-1, the reversible capacity exhibits a rapid increasing after 100 cycles and finally shows an ultra-high capacity of 1430 mA h g-1 over 500 cycles. This method could be generalized to the preparation of other similar transition metal oxide-based materials for the development of high-performance energy storage systems. PMID- 30465546 TI - Shearlet-based compressed sensing for fast 3D cardiac MR imaging using iterative reweighting. AB - High-resolution three-dimensional (3D) cardiovascular magnetic resonance (CMR) is a valuable medical imaging technique, but its widespread application in clinical practice is hampered by long acquisition times. Here we present a novel compressed sensing (CS) reconstruction approach using shearlets as a sparsifying transform allowing for fast 3D CMR (3DShearCS) using 3D radial phase encoding (RPE). An iterative reweighting scheme was applied during image reconstruction to ensure fast convergence and high image quality. Shearlets are mathematically optimal for a simplified model of natural images and have been proven to be more efficient than classical systems such as wavelets. 3DShearCS was compared to three other commonly used reconstruction approaches. Image quality was assessed quantitatively using general image quality metrics and using clinical diagnostic scores from expert reviewers. The proposed technique had lower relative errors, higher structural similarity and higher diagnostic scores compared to the other reconstruction techniques especially for high undersampling factors, i.e. short scan times. 3DShearCS provided ensured accurate depiction of cardiac anatomy for fast imaging and could help to promote 3D high-resolution CMR in clinical practice. PMID- 30465547 TI - Measurement of breast-tissue x-ray attenuation by spectral imaging: fresh and fixed normal and malignant tissue. AB - Knowledge of x-ray attenuation is essential for developing and evaluating x-ray imaging technologies. In mammography, measurement of breast density, dose estimation, and differentiation between cysts and solid tumours are example applications requiring accurate data on tissue attenuation. Published attenuation data are, however, sparse and cover a relatively wide range. To supplement available data we have previously measured the attenuation of cyst fluid and solid lesions using photon-counting spectral mammography. The present study aims to measure the attenuation of normal adipose and glandular tissue, and to measure the effect of formalin fixation, a major uncertainty in published data. A total of 27 tumour specimens, seven fibro-glandular tissue specimens, and 15 adipose tissue specimens were included. Spectral (energy-resolved) images of the samples were acquired and the image signal was mapped to equivalent thicknesses of two known reference materials, from which x-ray attenuation as a function of energy can be derived. The spread in attenuation between samples was relatively large, partly because of natural variation. The variation of malignant and glandular tissue was similar, whereas that of adipose tissue was lower. Formalin fixation slightly altered the attenuation of malignant and glandular tissue, whereas the attenuation of adipose tissue was not significantly affected. The difference in attenuation between fresh tumour tissue and cyst fluid was smaller than has previously been measured for fixed tissue, but the difference was still significant and discrimination of these two tissue types is still possible. The difference between glandular and malignant tissue was close-to significant; it is reasonable to expect a significant difference with a larger set of samples. We believe that our studies have contributed to lower the overall uncertainty of breast tissue attenuation in the literature due to the relatively large sample sets, the novel measurement method, and by clarifying the difference between fresh and fixed tissue. PMID- 30465548 TI - Feasibility of achieving high detectivity at short- and mid-wavelength infrared using nanowire-plasmonic photodetectors with p-n heterojunctions. AB - Photodetection at short- and mid-wavelength infrared (SWIR and MWIR) enables various sensing systems used in heat seeking, night vision, and spectroscopy. As a result, uncooled photodetection at these wavelengths is in high demand. However, these SWIR and MWIR photodetectors often suffer from high dark current, causing them to require bulky cooling accessories for operation. In this study, we argue for the feasibility of improving the room-temperature detectivity by significantly suppressing dark current. To realize this, we propose using (1) a nanowire-based platform to reduce the photoabsorber volume, which in turn reduces trap state population and hence generation-recombination current, and (2) p-n heterojunctions to prevent minority carrier diffusion from the large bandgap substrate into the nanowire absorber. We prove these concepts by demonstrating a comprehensive three-dimensional photoresponse model to explore the level of detectivity offered by vertical InAs(Sb) nanowire photodetector arrays with self assembled plasmonic gratings. The resultant electrical simulations show that the dark current can be reduced by three to four orders at room temperature, leading to a peak detectivity greater than 3.5 * 1010 cm Hz1/2 W-1 within the wavelength regime of 2.0-3.4 MUm, making it comparable to the best commercial and research InAs p-i-n homojunction photodiodes. In addition, we show that the plasmonic resonance peaks can be easily tuned by simply varying the exposed nanowire height. Finally, we investigate the impact of nanowire material properties, such as carrier mobility and carrier lifetime, on the nanowire photodetector detectivity. This work provides a roadmap for the electrical design of nanowire optoelectronic devices and stimulates further experimental validation for uncooled photodetectors at SWIR and MWIR. PMID- 30465549 TI - Integrating a low-field open MR scanner with a static proton research beam line: proof of concept. AB - On-line image guidance using magnetic resonance (MR) imaging is expected to improve the targeting accuracy of proton therapy. However, to date no combined system exists. In this study, for the first time a low-field open MR scanner was integrated with a static proton research beam line to test the feasibility of simultaneous irradiation and imaging. The field-of-view of the MR scanner was aligned with the beam by taking into account the Lorentz force induced beam deflection. Various imaging sequences for extremities were performed on a healthy volunteer and on a patient with a soft-tissue sarcoma of the upper arm, both with the proton beam line switched off. T 1-weighted spin echo images of a tissue mimicking phantom were acquired without beam, with energised beam line magnets and during proton irradiation. Beam profiles were acquired for the MR scanner's static magnetic field alone and in combination with the dynamic gradient fields during the acquisition of different imaging sequences. It was shown that MR imaging is feasible in the electromagnetically contaminated environment of a proton therapy facility. The observed quality of the anatomical MR images was rated to be sufficient for target volume definition and positioning. The tissue mimicking phantom showed no visible beam-induced image degradation. The beam profiles depicted no influence due to the dynamic gradient fields of the imaging sequences. This study proves that simultaneous irradiation and in-beam MR imaging is technically feasible with a low-field MR scanner integrated with a static proton research beam line. PMID- 30465550 TI - Nanoscale surface reactions by laser irradiation of Al nanoparticles on MoO3 flakes. AB - Surface reactions between heated aluminum nanoparticles (Al NPs) and thin alpha MoO3 sheets are investigated. Localized photothermal heating on Al NP clusters is provided by a Raman spectrometer laser, while enhanced heating rates and imaging resolution are enabled by the use of a plasmonic grating substrate. Prominent linear reaction zones extending from Al NPs in the <001> crystal direction are observed on the surface of the host MoO3 sheets after heating. Raman spectroscopy and x-ray diffraction indicate that alpha-Al2O3 is generated within these extended reacted regions, while AFM and SEM indicate that the topology of the reaction regions are indistinguishable from the MoO3 host. We hypothesize that these Al2O3 zones are formed by surface diffusion and subsequent sub-surface adsorption of heated Al adatoms along the low-energy <001> MoO3 direction. Understanding and controlling these reaction mechanisms could lead to enhanced combustion of Al/MoO3 nanothermite systems. PMID- 30465551 TI - The interaction of ethylene with free gold cluster cations: infrared photodissociation spectroscopy combined with electronic and vibrational structure calculations. AB - The interaction of ethylene with free gold clusters of different sizes and charge states has been previously shown theoretically to involve two different adsorption modes of the C2H4 molecule, namely: the di-sigma- and pi-bonded ethylene adsorption configurations. Here, we present the first experimental investigation of the structure of a series of gas-phase gold-ethylene complexes, [Formula: see text]. By employing infrared multiple-photon dissociation spectroscopy in conjunction with first-principles calculations it is revealed that up to three C2H4 molecules preferably bind to gold cations in a pi-bonded configuration. The binding of all ethylene molecules is found to be dominated by partial electron donation from the ethylene molecules to the gold clusters leading to an activation of the C-C bond. The cooperative action of multiple coadsorbed C2H4 on [Formula: see text] is shown to enable additional charge back donation and an enhanced C-C bond activation. In contrast, the strong C-H bond is not weakened and the experimental spectra do not give any indication for C-H bond dissociation. The possible correlations of the C-C bond stretch vibration with the C-C bond length and the net charge transfer are discussed. PMID- 30465552 TI - Uterus Allo-Transplantation in a Swine Model: Long-Term Graft Survival and Reproductive Function. AB - BACKGROUND The present study examined the feasibility and safety of allogeneic uterus transplantation (UTx) from a living donor and assessed long-term graft survival and the resumption of reproductive function in a swine model. MATERIAL AND METHODS Ten female miniature swine with regular menstrual cycles were used; the animals were either donors or recipients (n=5) depending on the sibling. Retrieval surgery included uterus and uterine arteries together with the anterior branches of the internal iliacs from the living donor; the vaginal canal was cut. After the back-table had been prepared, bilateral internal iliac arteries were anastomosed end-to-side with the external iliac arteries. The transplanted uterus was evaluated based on the arterial blood flow by transabdominal ultrasonography and observed by secondary laparotomy after surgery; estrus recovery was stimulated by mating with a male, and artificial embryo transfer was performed in healing swine. RESULTS All 5 pigs revealed successful surgery without any surgical complications, injuries to other organs, or unanticipated vascular injury. All recipients survived for >3 months after the surgery, except pig 5, which died due to uterus necrosis 3 days post-surgery. A 100% surgical success rate and 80% long-term survival rate of the receptor were observed. Pig 2 had temporary estrus resumed, and the artificial embryo was transplanted 3 months after surgery; however, apparent gestation was not found by ultrasonography. CONCLUSIONS This study evaluated the safety and feasibility of the technology of allogeneic UTx, which was performed only by transplant uterine artery system from living-donor surgery in a swine model. Laboratory animals can show long-term survival and resumed estrous after UTx, which can be monitored by ultrasonography to assess the arterial blood flow of the grafted uterus. PMID- 30465553 TI - Structural analysis of the Abeta(15-40) amyloid fibril based on hydrophobicity distribution. AB - The Abeta42 amyloid is the causative factor behind various neurodegenerative processes. It forms elongated fibrils which cause structural devastation in brain tissue. The structure of an amyloid seems to be a contradiction of protein folding principles. Our work focuses on the Abeta(15-40) amyloid containing the D23N mutation (also known as the "Iowa mutation"), upon which an in silico experiment is based. Models generated using I-Tasser software as well as the fuzzy oil drop model - regarded as alternatives to the amyloid conformation - are compared in terms of their respective distributions of hydrophobicity (i.e. the existence of a hydrophobic core). In this process, fuzzy oil drop model parameters are applied in assessing the propensity of selected fragments for undergoing amyloid transformation. PMID- 30465554 TI - Versatile functionalization of surface-tailorable polymer nanohydrogels for drug delivery systems. AB - Surface decoration of nanohydrogels with functional molecules as well as nanomaterials offers a facile approach for developing multifunctional drug nanocarriers. Herein, the surface-tailorable polymer nanohydrogels, with the catechol groups as a universal anchor, were prepared by simple reflux precipitation polymerization for versatile functionalization as drug delivery systems. The resultant polymer nanohydrogels were not only capable of delivering doxorubicin (DOX) through electrostatic interactions, but also exhibited facile conjugation with magnetic Fe3O4 nanoparticles and anticancer drug bortezomib (BTZ) via the versatile catechol-based coupling chemistry. The DOX and Fe3O4 loaded nanohydrogels (DOX-Fe3O4@NG) exhibited high DOX loading capability and triggered drug release behaviors in the acidic and redox environment. Furthermore, the DOX-Fe3O4@NG achieved improved cellular uptake in the presence of external magnetic field due to the active magnetic targeting properties. As for the dual drug delivery system (DOX-BTZ@NG), the DOX-BTZ@NG also released the drugs in response to the external stimuli including low pH and GSH presence, indicating their intelligent drug delivery properties. In particular, the DOX BTZ@NG showed higher antiproliferation efficacy to cancer cells in comparison with the single drug loaded nanohydrogels, suggesting a synergistic effect of the dual drug combination therapy. The degradable poly(AA-co-DMA) nanohydrogels with surface-tailorable functionalities are thus a promising versatile platform for conjugation with both nanomaterials and drug molecules. PMID- 30465555 TI - Naphthalene and perylene diimides - better alternatives to fullerenes for organic electronics? AB - The LUMO levels of rylene diimides are highly comparable to those of fullerenes but this class of molecules offers tunability of both HOMO and LUMO levels and the related band gap by either simple substitution at the aromatic core or annulation to give expanded pi-scaffolds. In this article we highlight the most outstanding achievements during the last decade in terms of charge carrier mobility for organic thin-film and single crystal field-effect transistors as well as photovoltaic performance for both small molecule and polymeric compounds. PMID- 30465565 TI - van der Waals interaction-induced photoluminescence weakening and multilayer growth in epitaxially aligned WS2. AB - Recently, transition metal dichalcogenides (TMDCs) have attracted great interest due to their unique electronic and optical properties. Chemical vapor deposition (CVD) has been regarded as the most promising method for the synthesis of large area TMDCs with high reproducibility. Having similar hexagonal crystal structures with many TMDCs, c-plane sapphire is commonly used as a growth substrate in CVD. However, few studies have been reported on the influence of the sapphire substrate on the growth behavior and physical properties of TMDCs. In this work, we demonstrate that higher strain is induced in epitaxially grown WS2 grains via van der Waals interactions with sapphire as compared with misaligned WS2 grains. In addition, this strain was found to enhance overlayer deposition on monolayer WS2, while multilayer growth was not observed in non-epitaxial WS2. Photoluminescence (PL) of the epitaxially grown WS2 grains was reduced, reflecting the effective van der Waals interaction with sapphire. Moreover, low temperature PL measurements revealed strong influence of the c-plane sapphire surface on the optical properties of WS2. Density functional theory (DFT) calculation supports that the aligned WS2 grains are more strongly bound to the sapphire surface, as compared with misaligned WS2. Our work offers a new insight into the understanding of the influence of the substrate on the CVD-grown TMDC materials. PMID- 30465566 TI - Room temperature d0 ferromagnetism in PbS films: nonuniform distribution of Pb vacancies. AB - Because of the importance of ferromagnetism at room temperature, we search for new materials that can exhibit a non-vanishing magnetic moment at room temperature and at the same time can be used in spintronics. The experimental results indicate that d0 ferromagnetism without any magnetic impurities takes place in PbS films made of close-packed lead sulfide nanoparticles of 30 nm. To explain the existence of the d0 ferromagnetism, we propose a model where various PbS bulk and surface configurations of Pb-vacancies are analyzed. The bulk configurations have a zero magnetic moment while the two surface configurations with Pb vacancies with the same non-vanishing magnetic moments and lowest ground state energies contribute to the total magnetization. Based on the experimental value of the saturation magnetization, 0.2 emu g-1, we have found that the calculated Pb vacancy concentration should be about 3.5%, which is close to typical experimental values. Besides being very important for applications, there is one feature of PbS d0 ferromagnetism that makes this material special for fundamental research: PbS ferromagnetism can exhibit topologically driven spatial magnetic moment distributions (e.g., magnetic skyrmions) due to large spin-orbit coupling. PMID- 30465567 TI - Operando investigations of lithiation and delithiation processes in a BiVO4 anode material. AB - BiVO4 undergoes a series of conversion and alloying reactions as an anode material in lithium ion batteries. The current work demonstrates a charge capacity of 485 mA h g-1 after 50 cycles in a voltage range of 0-2.00 V (graphite has a capacity of 372 mA h g-1 theoretically). An exceptionally high volumetric capacity makes BiVO4 suitable for compact applications (volumetric capacity of 3984 mA h cm-3 for BiVO4 in comparison to 756 mA h cm-3 for graphite theoretically). Reaction steps and electronic transformations have been identified by operando quasi simultaneous synchrotron X-ray diffraction and absorption spectroscopy studies. An irreversible reaction step occurs for the Bi3+/Bi0 redox pair, whereas reversible mechanisms are found for the V5+/V3+ and Bi0/Bi3- redox pairs. The proposed mechanisms are supported by density functional theory (DFT) calculations. PMID- 30465569 TI - The role of hydrophobic, aromatic and electrostatic interactions between amino acid residues and a titanium dioxide surface. AB - Understanding the nature of interactions between inorganic surfaces and biomolecules, such as amino acids and peptides, can enhance the development of new materials. Here, we present single molecule force spectroscopy (SMFS) measurements of the interactions between an atomic force microscopy (AFM) probe, modified with various amino acids, and a titanium dioxide surface. Specifically, we study the affinity of amino acids toward a titanium dioxide surface bearing hydrophobic (Leu), aromatic (Phe) and hydrophilic (Orn) residues. We find that aromatic interactions dominate over aliphatic in their affinity to the titanium dioxide surface. In addition, we show that by combining aromatic and hydrophilic moieties in a single amino acid (NH2-Phe), the adhesion of the latter to the surface increases. Furthermore, the affinity of positively charged amino acids to the titanium dioxide surface is higher than that of uncharged, and can be increased more, with elevating the pH of the buffer above the pKa of the basic residues. The kinetic and thermodynamic parameters imply that the dynamics of the surface-amino acid interface are mostly governed by hydrophobic interactions. PMID- 30465570 TI - Energy transfer and spatial scrambling of an exciton in a conjugated dendrimer. AB - Photoexcitation of multichromophoric light harvesting molecules induces a number of intramolecular electronic energy relaxation and redistribution pathways that can ultimately lead to ultrafast exciton self-trapping on a single chromophore unit. We investigate the photoinduced processes that take place on a phenylene ethynylene dendrimer, consisting of nine equivalent linear chromophore units or branches. meta-Substituted links between branches break the conjugation giving rise to weak couplings between them and to localized excitations. Our nonadiabatic excited-state molecular dynamics simulations reveal that the ultrafast internal conversion process to the lowest excited state is accompanied by an inner -> outer inter-branch migration of the exciton due to the entropic bias associated with energetically equivalent conjugated segments. The electronic energy redistribution among chromophore units occurs through several possible pathways in which through-bond transport and through-space exciton hopping mechanisms can be distinguished. Besides, triple bond excitations coincide with the localization of the electronic transition densities, suggesting that the intramolecular energy redistribution is a concerted electronic and vibrational energy transfer process. PMID- 30465571 TI - Factors governing when a metal-bound water is deprotonated in proteins. AB - Understanding when a metal-bound water molecule in a protein is deprotonated is important as this affects the charge distribution in the metal-binding/enzyme active site and thus their interactions, the enzyme mechanism, and inhibitor design. The protonation state of the metal-bound water molecule at a given pH depends on its pKa value, which in turn depends on the properties of the cation, its ligands, and the protein environment. Here, we reveal how and the extent to which (i) the first-shell composition (type, charge, and number of ligands), (ii) the metal site's immediate surroundings (first-shellsecond-shell hydrogen-bonding interactions, metal-ligand distance constraints, and ligand-binding mode) and (iii) the protein architecture and coupled solvent interactions (long-range electrostatic interactions and solvent exposure of the site) affect the Zn2+ bound water pKa. The results, which are consistent with available experimental pKa values of Zn2+-bound water, provide guidelines to predict when Zn2+-bound water would likely be deprotonated at physiological pH. PMID- 30465572 TI - A versatile quinoxaline derivative serves as a colorimetric sensor for strongly acidic pH. AB - A facile and reliable method to monitor strongly acidic pH was developed. The sensing mechanism was found to involve the protonation-deprotonation equilibrium of the synthesized probe HQphy (1) (N-phenyl-N'-quinoxalin-2-ylmethylene hydrazine) within a working range of pH 0.7-2.7. The eventual sensing of Fe3+ was the outcome of acidity imparted by [Fe(H2O)6]3+ ions in solution during the formation of [Fe(H2O)5(OH)]2+. The protonation-deprotonation phenomenon of HQphy was investigated using 1H NMR and single crystal X-ray diffraction experiments. The protonated probe, H2Qphy+, was crystallized with FeCl4-/ClO4- counter anions as [H2Qphy][FeCl4].H2O (2)/[H2Qphy][ClO4].H2O (3). A further complex containing the [H2Qphy] cation (4) was also formed. The complexes were characterized by SC XRD experiments. Moreover, single crystal to single crystal transformation is observed between 1 and 3. In order to understand the sensing mechanism, various analytical studies, such as UV-Vis titration, ESI-MS spectrometry analysis and 1H NMR, were carried out in detail. A theoretical study correlates well with the experimental data, where the pi(L) -> pi*(L) transition of the ligand is red shifted by 100 nm due to protonation of the quinoxaline moiety. The probe enables discrimination of trihalo acetic acid from its mono- and di-analogues. PMID- 30465574 TI - Licochalcone A inhibits the invasive potential of human glioma cells by targeting the MEK/ERK and ADAM9 signaling pathways. AB - Licochalcone A (LicA) has been reported to possess antitumor properties. However, its effect on human glioma cells remains unknown. In this study, we observed that LicA significantly suppressed the ADAM9 expression and the migration and invasion activities of human glioma cells (M059K, U-251 MG, and GBM8901) and exhibited no cell cytotoxicity. The human proteinase antibody array and immunoblot analysis indicated that the LicA treatment inhibited the expression of ADAM9 protein in human glioma cells. Recombinant human ADAM-9 (Rh-ADAM9) treatment significantly reversed the LicA-induced reduction in the ADAM9 level and the migration and invasion activities of human glioma cells. Additionally, the phosphorylation/activation of the mitogen-activated protein kinase kinase (MEK) extracellularly responsive kinases (ERK) signaling pathway was significantly suppressed in LicA-treated human glioma cells. Cotreatment with LicA and PD98059 synergistically inhibited the ADAM9 expression, cell migration, and cell invasion, which suggested that the MEK-ERK signaling pathway was involved in the LicA-induced inhibition of the ADAM9 expression and the invasion activity of human glioma cells. These findings are the first evidence of LicA's anti-invasive properties against human glioma cells. PMID- 30465575 TI - Cross-talk between emulsion drops: how are hydrophilic reagents transported across oil phases? AB - Emulsion drops are frequently used as vessels, for example, to conduct biochemical reactions in small volumes or to perform screening assays at high throughputs while consuming minimal sample volumes. These applications typically require drops that do not allow exchange of reagents such that no cross contamination occurs. Unfortunately, in many cases, reagents are exchanged between emulsion drops even if they have a low solubility in the surrounding phase, resulting in cross-contaminations. Here, we investigate the mechanism by which hydrophilic reagents are transported across an oil phase using water-oil water double emulsion drops as a model system. Remarkably, even large objects, including 11 000 base pair double-stranded circular DNA are transported across oil shells. Importantly, this reagent transport, that is to a large extent caused by aqueous drops that spontaneously form at the water-oil interface, is not limited to double emulsions but also occurs between single emulsion drops. We demonstrate that the uncontrolled reagent transport can be decreased by at least an order of magnitude if appropriate surfactants that lower the interfacial tension only moderately are employed or if the shell thickness of double emulsions is decreased to a few hundreds of nanometers. PMID- 30465580 TI - Charge-governed phase manipulation of few-layer tellurium. AB - Few-layer tellurium is an emerging quasi-one-dimensional layered material. The striking feature of Te is its presence as various few-layer allotropes (alpha delta). Although these allotropes offer substantially different physical properties, only the alpha phase has been synthesized in neutral few-layers as it is so far the most stable few-layer form. Herein, we show that hole or electron doping could maintain a certain Te phase. The beta, alpha, gamma and delta phases appear as the most stable forms of Te bilayer, in sequence, with bandgap variations over 1 eV. In Te trilayer, a novel metallic chiral alpha + delta phase emerges, leading to the appearance of chirality. Transitions among these phases, understood at the wavefunction level, are accompanied by the emergence or elimination of inversion centers (alpha-beta, alpha-gamma, alpha-alpha + delta), structural anisotropy (alpha-gamma, gamma-delta) and chirality (alpha-alpha + delta), which could result in substantial changes in optical and other properties. In light of these findings, our work opens a new avenue for stabilizing different allotropes of layered materials; this is crucial for using their outstanding properties. This study also suggests the possibility of building mono-elemental electronic and optoelectronic heterostructures or devices, which are attractive for future applications in electronics. PMID- 30465585 TI - Identification of thienopyridine carboxamides as selective binders of HIV-1 trans Activation Response (TAR) and Rev Response Element (RRE) RNAs. AB - Small organic molecules that can selectively bind to RNA with specificity are relatively rare. Here we report the synthesis, biochemical and structural studies of thienopyridine carboxamide derivatives with the capacity of selectively recognizing and binding with HIV-1 TAR and RRE RNAs that are essential elements for viral replication. PMID- 30465586 TI - Experimental and theoretical investigations of regioselective functionalization of 3-hydroxy bisindoles with thiols. AB - An instant and efficient p-TSA.H2O-catalyzed sulfenylation reaction of 3-hydroxy bisindole derivatives is reported. This highly regioselective approach afforded C 3 functionalized products in excellent yield, and this methodology was found to be compatible with both aromatic and aliphatic thiols having electronic and steric divergence as well as diverse functional groups. The sulfenylation reaction was performed at room temperature with a green solvent with minimal catalyst loading and proceeded with the involvement of a quasi-antiaromatic-2H indol-2-one ring intermediate. Moreover, the experimental results obtained for the sulfenylation reaction of 3-hydroxy bisindoles were supported by theoretical calculations in order to comprehend the regioselectivity and chemical reactivity observed in the thiolation reaction of 3-hydroxy bisindoles. The protocol involved the SN1 pathway, as also demonstrated by theoretical calculations. PMID- 30465587 TI - A gold-catalyzed cycloisomerization/aerobic oxidation cascade strategy for 2-aryl indenones from 1,5-enynes. AB - A unique gold(i)-catalyzed 5-endo-dig cyclization/aerobic oxidation cascade strategy from 1,5-enyne substrates with molecular oxygen as the oxidant to yield the indenone was described. The reaction mechanism was studied by heavy atom labelling and some related experiments. This method was applied to the formal total synthesis of isoprekinamycin. PMID- 30465589 TI - Copper-catalyzed synthesis of 2,2,2-trifluoroethyl selenoethers and their insecticidal activities. AB - A simple and efficient protocol for the copper-catalyzed synthesis of aryl or alkyl 2,2,2-trifluoroethyl selenoethers has been developed. This reaction proceeded smoothly in the presence of CuI/phen as the catalyst, with elemental selenium, 1,1,1-trifluoro-2-iodoethane, and NaBH4 as reagents in DMF with a broad scope of functionalized (hetero)aryl or alkyl halides. Different functional groups were tolerated and moderate to excellent yields of 2,2,2-trifluoroethyl selenoethers were obtained. Some of the synthesized compounds exhibited promising insecticidal activities. PMID- 30465590 TI - Pediatric lupus nephritis. AB - Involvement of the kidneys by lupus nephritis (LN) is one of the most severe clinical manifestations seen in individuals with systemic lupus erythematosus (SLE). LN is more frequent and severe in pediatric patients and has been associated with higher morbidity and mortality rates. This narrative review aimed to describe the general aspects of LN and its particularities when affecting children and adolescents, while focusing on the disease's etiopathogenesis, clinical manifestations, renal tissue alterations, and treatment options. PMID- 30465591 TI - Acute Kidney Injury Epidemiology in pediatrics. AB - We performed a search in the MEDLINE database using the MeSH term: "Acute Kidney Injury", selecting the subtopic "Epidemiology", and applying age and year of publication filters. We also searched for the terms: "acute renal failure" and "epidemiology" "acute tubular necrosis" and "epidemiology" in the title and summary fields with the same filters. In a second search, we searched in the LILACS database, with the terms: "acute renal injury", or "acute renal failure" or "acute kidney injury" and the age filter. All abstracts were evaluated by the authors and the articles considered most relevant, were examined in their entirety. Acute Kidney Injury (AKI) -related mortality ranged from 3-63% in the studies included in this review. AKI etiology has marked regional differences, with sepsis being the main cause in developed countries. In developing countries, primary renal diseases and hypovolemia are still a common cause of AKI. PMID- 30465592 TI - Multidisciplinary approach for patients with nephropathic cystinosis: model for care in a rare and chronic renal disease. AB - Care for patients with chronic and rare diseases is complex, especially considering the lack of knowledge about the disease, which makes early and precise diagnosis difficult, as well as the need for specific tests, sometimes of high complexity and cost. Added to these factors are difficulties in obtaining adequate treatment when available, in raising patient and family awareness about the disease and treatment compliance. Nephropathic cystinosis is among these diseases. After more than 20 years as a care center for these patients, the authors propose a follow-up protocol, which has been used with improvement in the quality of care and consists of a multidisciplinary approach, including care provided by a physician, nurse, psychologist, nutritionist and social worker. In this paper, each field objectively exposes how to address points that involve the stages of diagnosis and its communication with the patient and their relatives or guardians, covering the particularities of the disease and the treatment, the impact on the lives of patients and families, the approach to psychological and social issues and guidelines on medications and diets. This protocol could be adapted to the follow-up of patients with other rare diseases, including those with renal involvement. This proposal is expected to reach the largest number of professionals involved in the follow-up of these patients, strengthening the bases for the creation of a national protocol, observing the particularities of each case. PMID- 30465593 TI - Parathyroidectomy in the treatment of BMD-DRC Brazil: many limitations, but still fundamental. PMID- 30465594 TI - Erratum. AB - [This corrects the article doi: 10.1590/2175-8239-JBN-2018-00030003] [This corrects the article doi: 10.1590/2175-8239-JBN-2018-00030002][This corrects the article doi: 10.1590/1678-4685-JBN-2018-00020001]. PMID- 30465596 TI - An Overview of the Management of Diabetic Foot Ulcers PMID- 30465595 TI - Localization of CGRP and VEGF mRNAs in the mouse superior cervical ganglion during pre- and postnatal development. AB - The neuropeptide calcitonin gene-related peptide (CGRP) mediates inflammation and head pain by influencing the functional vascular blood supply. CGRP is a well characterized mediator of receptor-regulated neurotransmitter release. However, knowledge regarding the role of CGRP during the development of the superior cervical ganglion (SCG) is limited. In the present study, we observed the localization of CGRP and vascular endothelial growth factor (VEGF-A) mRNAs during prenatal development at embryonic day 14.5 (E14.5), E17.5 and postnatal day 1 (P1) using in situ hybridization. The antisense probe for CGRP was detected by in situ hybridization at E14.5, E17.5, and P1, and the highest levels were detected at E17.5. In contrast, the antisense probe for VEGF-A was detected by in situ hybridization in gradually increasing intensity from E14.5 to P1. The differences in the expression of these two markers revealed specific characteristics related to CGRP concentration and release compared to those of VEGF-A during development. The correlation between CGRP and VEGF-A may influence functional stress and the vascular blood supply during prenatal and postnatal development. PMID- 30465597 TI - Is Helmet and Faceguard Modification Common in Hurling and Camogie and Why Is It Done? AB - AimsDespite no previous research, it is anecdotally reported that hurling and camogie players modify their helmet and faceguard, which is against GAA regulations and can potentially increase injury risk. This study aimed to establish the prevalence and rationale behind modifications in hurling and camogie.MethodsAn online questionnaire was completed by 304 players aged over 18 (62% hurlers, 38% camogie players) which consisted of 27 questions.ResultsAppearance (43%) was the primary reasons for helmet brand choice, with just 1.6% citing safety as a main reason for choice. Surprisingly, 8% of helmets were already modified when purchased and 31% of participants made further modifications, primarily switching faceguards and removal of bars. Restricted vision, comfort and perceived poor quality of the helmet/faceguard were the most common reasons for modification. Players predominantly (75.8%) agreed that further education on modifications is required.ConclusionFuture research on the relationship between helmet/faceguard modification and injury risk is required. PMID- 30465598 TI - Patient Texting in General Practice: Who, Why, Why Not? A National Survey of Text Messaging in Irish General Practice. AB - IntroductionThe benefits of text messaging patients are well documented. The General Medical Council recently published guidance endorsing text messaging. The use of text messaging by GPs in Ireland is currently unknown. The survey aims to address this knowledge deficit and ascertain the extent, benefits, risks, barriers and clinical role of text messaging in Irish general practice.MethodsAn online survey was emailed to 1,375 members of the Irish College of General Practitioners (ICGP).ResultsA total of 536 GPs completed the questionnaire; a response rate of 40%. Overall, 66% (n=353) of respondents text patients and 27% have a written policy for texting patients. Texting is used primarily to send test results (71%), to advise the patient to phone the practice (52%) and as appointment reminders (43%).DiscussionGPs text messaging patients is widespread. Complex issues to resolve include consent, confidentiality, children/young adults and the clinical content of text messages. Guidance is required to enable GPs and patients harness the benefits of text messaging, while minimising potential risks. PMID- 30465599 TI - Saving Blood and Reducing Costs: Updating Blood Transfusion Practice in Lower Limb Arthroplasty AB - AimOur aim was to quantify blood transfusion rates in lower limb arthroplasty following the introduction of a multimodal enhanced recovery programme (ERP). We then sought to update the maximum surgical blood ordering schedule (MSBOS) and calculate cost savings achieved.MethodsA retrospective cohort study was conducted of all patients who required blood transfusion following primary and revision total hip and knee arthroplasty in 2012 and 2015. A multimodal ERP was introduced in 2015. Cost savings were calculated following the introduction of a new MSBOS.ResultsDuring the two-year study period 1467 lower limb arthroplasty procedures were performed. The cross-match to transfusion ratio was 3.6:1 in 2012 and 9.9:1 in 2015. The updated MSBOS resulted in a 46% reduction of cross-matched blood and savings of ?54,375 per annum.ConclusionImproved perioperative management in lower limb arthroplasty has reduced blood transfusion rates. Updating blood transfusion practice can result in considerable savings in blood, resources and costs. PMID- 30465600 TI - Unsatisfactory Level of Dermatology Undergraduate Education in Newly Qualified Irish Doctors. PMID- 30465601 TI - Orthogonal Stimuli Trigger Self-Assembly and Phase Transfer of FeII4L4 Cages and Cargoes. AB - Two differently protected aldehydes, A and B, were demonstrated to deprotect selectively through the application of light and heat, respectively. In the presence of iron(II) and a triamine, two distinct FeII4L4 cages, 1 and 2, were thus observed to form from the deprotected A and B, respectively. The alkyl tails of B and 2 render them preferentially soluble in cyclopentane, whereas A and 1 remain in acetonitrile. The stimulus applied (either light or heat) thus determines the outcome of self-assembly and dictates whether the cage and its ferrocene cargo remain in acetonitrile, or transport into cyclopentane. Cage self assembly and cargo transport between phases can in this fashion be programmed using orthogonal stimuli. PMID- 30465602 TI - Highly sensitive air stable easily processable gas sensors based on Langmuir Schaefer monolayer organic field-effect transistors for multiparametric H2S and NH3 real-time detection. AB - A combination of low limit of detection, low power consumption and portability makes organic field-effect transistors (OFETs) chemical sensors promising for various applications in the areas of industrial safety control, food spoilage detection and medical diagnostics. However, the OFET sensors typically lack air stability and restoration capability at room temperature. Here we report on a new design of highly sensitive gas sensors based on Langmuir-Schaefer monolayer organic field-effect transistors (LS OFETs) prepared from organosilicon derivative of [1]benzothieno[3,2-b][1]-benzothiophene. The devices fabricated are able to operate in air and allows an ultrafast detection of different analytes at low concentrations down to tens ppb. The sensors are reusable and can be utilized in real-time air quality monitoring systems. We show that a direct current response of the LS OFET can be splitted into the alteration of various transistor parameters, responsible for the interactions with different toxic gases. The sensor response acquiring approach developed allows distinguishing two different gases, H2S and NH3, with a single sensing device. The results reported open new perspectives for the OFET-based gas-sensing technology and pave the way to easy detection of the other types of gases enabling the development of complex air analysis systems based on a single sensor. PMID- 30465603 TI - Cu-Fe-Se Ternary Nanosheet-Based Drug Delivery Carrier for Multimodal Imaging and Combined Chemo-photothermal Therapy of Cancer. AB - Ternary transition-metal chalcogenide nanosheets have shown great potential in diverse applications owing to their intrinsically amazing properties with broad tunable window. Direct preparation of water-soluble and biocompatible ternary chalcogenide nanosheets for theranostic application remains a challenge. In this article, we prepared Cu-Fe-Se nanosheets (CFS NSs) in an aqueous solution under ambient conditions by sequential coprecipitation method. They were functionalized with anticancer drug doxorubin (CFS@DOX) through electrostatic interactions, and labeled with radioactive isotope 99mTc through surface coordination effect. The resulting nanosheets have a size of 70 nm and a thickness of 5 nm, and can be well dispersed in water, PBS, 10% FBS, and 0.9% NaCl with an excellent colloidal stability. They also exhibit a high photothermal conversion efficiency of 78.9% for in vitro and in vivo photoacoustic imaging and photothermal therapy. The isotope-labelled nanosheets (99mTc-CFS NSs) were used for single photon emission computed tomography/computed tomography (SPECT/CT) imaging, and quantification of their blood circulation time (~4.7 h) and biodistributions in major organs, which follow an order of liver > bladder > lung > spleen > heart > kidney. The DOX functionalized nanosheets (CFS@DOX) were used for chemotherapy of cancer and exhibited excellent anti-cancer efficacy. Our research shows the great promise of ternary metal chalcogenide nanosheets for combined imaging and therapy of cancer. PMID- 30465604 TI - Strain Stiffening in Dynamic Supramolecular Fiber Networks. AB - The cytoskeleton is a highly adaptive network of filamentous proteins capable of stiffening under stress even as it dy-namically assembles and disassembles with time constants of minutes. Synthetic materials that combine reversibility and strain-stiffening properties remain elusive. Here, strain-stiffening hydrogels that have dynamic fibrous polymers as their main structural components are reported. The fibers form via self-assembly of bolaamphiphiles (BA) in water and have a well-defined cross-section of 9 to 10 molecules. Fiber length recovers after sonication, H/D exchange experiments, and rheology confirm the dynamic nature of the fibers. Crosslinking of the fibers yields strain-stiffening, self healing hydro-gels that closely mimic the mechanics of biological networks, with mechanical properties that can be tuned by chemical modification of the components. Comparison of the supramolecular networks with covalently fixated networks shows that the non-covalent nature of the fibers limits the maximum stress that fibers can bear, and hence limit the range of stiffening. PMID- 30465605 TI - Scalable Solvothermal Synthesis of Superparamagnetic Fe3O4 Nanoclusters for Bio separation and Theragnostic Probes. AB - Magnetic nanoparticles have had a significant impact on a wide range of advanced applications in the academic and industrial fields. In particular, in nanomedicine, the nanoparticles require specific properties, including hydrophilic behavior, uniform and tunable dimensions, and good magnetic properties, which are still challenging to achieve by industrial-scale synthesis. Here, we report a gram-scale synthesis of hydrophilic magnetic nanoclusters based on a one-pot solvothermal system. Using this approach, we achieved the nanoclusters with controlled size composed of magnetite nanocrystals in close packed superstructures that exhibited hydrophilicity, superparamagnetism, high magnetization, and colloidal stability. The proposed solvothermal method is found to be highly suitable for synthesizing industrial quantities (gram-per-batch level) of magnetic spheres with unchanged structural and magnetic properties. Furthermore, coating the magnetic spheres with an additional silica layer provided further stability and specific functionalities favorable for biological applications. Using in vitro and in vivo studies, we successfully demonstrated both positive and negative separation, and the use of the magnetic nanoclusters as a theragnostic nanoprobe. This scalable synthetic procedure is expected to be highly suitable for widespread use in biomedical, energy storage, photonics, and catalysis fields, among others. PMID- 30465606 TI - Why Does RNA Collapse? The Importance of Water in a Simulation Study of Helix Junction-Helix Systems. AB - Using computer simulations, we consider the balance of thermodynamic forces that collapse RNA. A model helix-junction-helix (HJH) construct is used to investigate the transition from an extended to a collapsed conformation. Conventional Molecular Dynamics and Milestoning Simulations are used to study the free energy profile of the process for two ion concentrations. We illustrate that HJH folds to a collapsed state with two types of counterions (Mg2+ and K+). By dissecting the free energy landscape into energetic and entropic contributions, we illustrate that the electrostatic forces between the RNA and the mobile ions do not drive the RNA to a collapsed state. Instead, entropy gains from water expulsion near the neighborhood of the RNA provide the stabilization free energy that tilt HJH into more compact structures. Further simulations of a three-helix hammerhead ribozyme show a similar behavior and support the idea of collapse due to increased gain in water entropy. PMID- 30465607 TI - Allosteric Control of Photofoldamers for Selecting between Anion Regulation and Double-to-Single Helix Switching. AB - Allosteric regulation of protein structure and function is a hallmark of biology. The structures of protein-like abiological foldamers have been subject to allosteric control, however, regulation of their function is rare. We report this behavior using a photoactive foldamer following the discovery that small and large anions select between single and double helical structures, respectively. Correspondingly, these anions activate different functions in the photofoldamer; small anions turn on photoregulation of anion concentrations while large anions turn on chiroptical switching of quaternary structure. For this demonstration, we used an aryl-triazole based photofoldamer in which the light-driven trans-cis isomerization of azobenzenes alters intrastrand pi-pi contacts while the triazoles define the anion-binding allosteric site. Binding to eleven anions of increasing size was quantified (Cl-, Br-, NO2-, I-, NO3-, SCN-, BF4-, ClO4-, ReO4 , PF6-, SbF6-). Contrary to expectations that single helices will expand to accommodate larger and larger guests, this behavior only occurs for smaller anions (Cl- - NO3-; < 45 A3) beyond which the larger anions form double helices (SCN!!- - SbF6-; > 45 A3). With small anions, the single helix regulates anion concentrations when the azobenzenes are photoswitched. The binding of large anions favors a chiral double helix and activates light-driven switching into racemic single helices thereby modulating the quaternary structure and chiroptical activity. This work shows how complex multifunctional outcomes emerge when allosteric changes in structure are expressed in intrinsically functional foldamers. PMID- 30465608 TI - Recombinant Newcastle disease virus (NDV) La Sota expressing the hemagglutinin neuraminidase protein of genotype VII NDV shows improved protection efficacy against NDV challenge. AB - Intensive vaccination strategies against Newcastle disease (ND) have been implemented in many countries for a long time, but ND outbreaks still occur frequently, with most isolates belonging to VII genotype of Newcastle disease virus (NDV). Many researchers have revealed that vaccines closely matched to epidemic viruses provide better protection. Therefore, using a previously established reverse genetics system, we generated a recombinant NDV vaccine strain (rLa Sota-HN) based on the La Sota vaccine strain expressing the hemagglutinin-neuraminidase (HN) protein of genotype VII NDV. The pathogenicity of the recombinant virus was confirmed by the mean death time in 9-day-old specific-pathogen-free (SPF) embryonated chicken eggs and the intracerebral pathogenicity index in 1-day-old SPF chickens. Subsequently, 1-day-old chickens were immunized with commercial vaccine La Sota and recombinant virus rLa Sota-HN and then challenged with virulent genotype VII NDV strain. The results indicated that recombinant virus rLa Sota-HN provided increased protection of vaccinated chickens from morbidity and mortality, and inhibited the shedding of virulent virus after challenging with genotype VII virus, compared with the conventional vaccine La Sota. Our findings indicated that rLa Sota-HN is a promising vaccine candidate to improve the protection efficiency against ND in chickens, thereby preventing frequent outbreaks of this disease. PMID- 30465609 TI - The Use of Occupational Adaptation in Research: A Scoping Review. AB - The aim of this scoping review was to identify and describe how occupational adaptation has been used in different research studies published from 1992 to 2015 and to identify possible gaps in study design. Four categories of studies were identified: those focused on understanding how occupational adaptation occurs in different life situations and different health conditions, those focused on the use of occupational adaptation as a guide or model in organizing the occupational therapy process, and those using occupational adaptation as a part of instrument development. Several gaps in research are evident including updating the theory development on occupational adaptation, types of maladaptation, studies conducted in less affluent countries, quantitative studies with robust designs, inclusion of men and younger persons as subjects, vulnerable groups, health promotion, and community settings. PMID- 30465610 TI - Obstructive sleep apnea during REM sleep and daytime cerebral functioning: A regional cerebral blood flow study using high-resolution SPECT. AB - Obstructive sleep apnea (OSA) predominantly during rapid eye movement (REM) sleep may have impacts on brain health, even in milder OSA cases. Here, we evaluated whether REM sleep OSA is associated with abnormal daytime cerebral functioning using high-resolution single-photon emission computed tomography (SPECT). We tested 96 subjects (25 F, age: 65.2 +/- 6.4) with a wide range of OSA severity from no OSA to severe OSA (apnea-hypopnea index: 0-97 events/h). More respiratory events during REM sleep were associated with reduced daytime regional cerebral blood flow (rCBF) in the bilateral ventromedial prefrontal cortex and in the right insula extending to the frontal cortex. More respiratory events during non REM (NREM) sleep were associated with reduced daytime rCBF in the left sensorimotor and temporal cortex. In subjects with a lower overall OSA severity (apnea-hypopnea index<15), more respiratory events during REM sleep were also associated with reduced daytime rCBF in the insula and extending to the frontal cortex. Respiratory events that characterized OSA during NREM versus REM sleep are associated with distinct patterns of daytime cerebral perfusion. REM sleep OSA could be more detrimental to brain health, as evidenced by reduced daytime rCBF in milder forms of OSA. PMID- 30465611 TI - Pharmacogenetics of treatments for inflammatory bowel disease. AB - INTRODUCTION: Inflammatory bowel diseases is a chronic inflammation of the gut whose pathogenesis is still unclear. Although no curative therapy is currently available, a number of drugs are used in induction and maintenance therapy; however, for most of these drugs, a high inter-individual variability in response is observed. Among the factors of this variability, genetics plays an important role. Areas covered: This review summarizes the results of pharmacogenetic studies, considering the most important drugs used and in particular aminosalycilates, glucocorticoids, thiopurines, monoclonal antibodies and thalidomide. Most studies used a candidate gene approach, even if significant breakthroughs have been obtained recently from applying genome-wide studies. When available, also investigations considering epigenetics and pharmacogenetic dosing guidelines have been included. Expert opinion: Only for thiopurines, genetic markers identified as predictors of efficacy or adverse events have allowed the development of dosing guidelines. For the other drugs, encouraging results are available and great expectations rely on the study of epigenetics and integration with pharmacokinetic information, especially useful for biologics. However, to improve therapy of IBD patients with these drugs, for implementation in the clinics of pharmacogenetics, informatic clinical decision support systems and training about pharmacogenetics of health providers are needed. PMID- 30465612 TI - Inflammatory responses mediate brain-heart interaction after ischemic stroke in adult mice. AB - Stroke induces cardiac dysfunction which increases post stroke mortality and morbidity particularly in aging population. Here, we investigated the effects of inflammatory responses as underlying mediators of cardiac dysfunction after stroke in adult mice. Adult (eight-to-nine months) male C57BL/6 mice were subjected to photothrombotic stroke. To test whether immunoresponse to stroke leads to cardiac dysfunction, splenectomy was performed with stroke. Immunohistochemistry, flow cytometry, PCR, ELISA and echocardiography were performed. We found marginal cardiac dysfunction at acute phase and significant cardiac dysfunction at chronic phase of stroke as indicated by significant decrease of left ventricular ejection fraction (LVEF) and shortening fraction (LVSF). Stroke significantly increases macrophage infiltration into the heart and increases IL-1beta, IL-6, MCP-1, TGF-beta and macrophage-associated inflammatory cytokine levels in the heart as well as induces cardiac-fibrosis and hypertrophy. Splenectomy with stroke significantly reduces macrophage infiltration into heart, decreases inflammatory factor expression in the heart, decreases cardiac hypertrophy and fibrosis, as well as significantly improves cardiac function compared to non-splenectomized adult stroke mice. Therefore, cerebral ischemic stroke in adult mice induces chronic cardiac dysfunction and secondary immune response may contribute to post stroke cardiac dysfunction. PMID- 30465613 TI - Trabectedin for reversing platinum resistance and resensitization to platinum in patients with recurrent ovarian cancer. AB - AIMS: We evaluated trabectedin in patients with platinum-resistant/refractory and partially platinum-sensitive recurrent ovarian cancer and the outcomes after reintroduction of platinum. METHODS: Twenty-seven patients (platinum resistant/refractory n = 24/PPS; n = 3) treated with trabectedin were retrospectively analyzed. RESULTS: Trabectedin resulted in an objective response rate (ORR) of 18.2% with a 59.1% of disease control rate (ORR plus stable disease). The median progression-free and overall survival were 3.0 and 21.3 months, respectively. Subsequently, 17 patients were retreated with platinum and yield an ORR of 41.2% and DCR of 47.0%. The median progression-free and overall survival after platinum rechallenge were 5.0 and 14.7 months, respectively. CONCLUSION: Our results suggest that trabectedin may contribute to resensitize tumor cells to platinum rechallenge. PMID- 30465614 TI - Older Adults' Parasocial Relationships with Favorite Television Characters and Depressive Symptoms. AB - Older adults can form parasocial relationships with favorite television characters, and these relationships often serve as sources of companionship. Using the selection, optimization, and compensation model as a guiding framework, this study explored whether or not attachment anxiety and relationship quality with romantic partners and children moderate the associations between parasocial relationships and depressive symptoms. A series of three-way interactions emerged in predicting depressive symptoms. Among other findings, stronger parasocial relationships predicted an increase in depressive symptoms for anxious older adults in low-quality parent-child relationships. Older adults' individual characteristics and family relationships may qualify how they experience parasocial relationships with favorite television characters. PMID- 30465615 TI - Inter-rater and inter-device reliability of mechanical thresholds measurement with the Electronic von Frey Anaesthesiometer and the SMALGO in healthy cats. AB - OBJECTIVES: The aim of this study was to compare the Electronic von Frey Anaesthesiometer (EVF) and the Small Animal ALGOmeter (SMALGO), used to measure sensory thresholds in 13 healthy cats at both the stifle and the lumbosacral joint, in terms of inter-rater and inter-device reliability. METHODS: Two independent observers carried out the sets of measurements in a randomised order, with a 45 min interval between them, in each cat. The inter-rater and inter device reliability were evaluated by calculating the inter-rater correlation coefficient (ICC) for each pair of measurements. The Bland-Altman method was used as an additional tool to assess the level of agreement between the two algometers. RESULTS: The mean +/- SD sensory thresholds measured with the EVF were 311 +/- 116 g and 378 +/- 178 g for the stifle and for the lumbosacral junction, respectively, whereas those measured with the SMALGO were 391 +/-172 g and 476 +/- 172 g. The inter-rater reliability was fair (ICC >0.4) for each pair of measurements except those taken at the level of the stifle with the SMALGO, for which the level of agreement between observer A and B was poor (ICC = 0.01). The inter-device reliability was good (ICC = 0.73; P = 0.001). The repetition of the measurements affected reliability, as the thresholds obtained after the 45 min break were consistently lower than those measured during the first part of the trial ( P = 0.02). CONCLUSIONS AND RELEVANCE: The EVF and the SMALGO may be used interchangeably in cats, especially when the area to be tested is the lumbosacral joint. However, when the thresholds are measured at the stifle, the inter-observer reliability is better with the EVF than with the SMALGO. The reliability decreases when the measurements are repeated within a short time interval, suggesting a limited clinical applicability of quantitative sensory testing with both algometers in cats. PMID- 30465616 TI - Feline upper respiratory tract infection and disease in Australia. AB - OBJECTIVES: The aim of this study was to conduct a comprehensive assessment of feline infectious upper respiratory tract infection (URTI) and disease (URTD) in Australian cats. METHODS: Laboratory data demonstrating URTI from feline URTD multiplex PCR panel (feline Herpesvirus 1 [FHV-1], feline calicivirus [FCV], Bordetella bronchiseptica, Chlamydophila felis, Mycoplasma felis and H1N1 influenza) submissions in Australia (2013-2015) were obtained. For comparison, reports of feline URTD during the same time period were sourced from a voluntary companion animal disease surveillance system. RESULTS: A total of 3126 samples were submitted for testing; 1533 (49%) were positive. Of these, the most commonly detected agents were M felis (21.5%) and FCV (16.0%) alone, followed by FCV and M felis (13.4%) together as a respiratory infection complex, then FHV-1 (7.0%) alone. During the study period, there were 262 reports of 320 clinical feline URTD cases. Most cases (69%) were reported from New South Wales, <1 year of age (41%) and equally distributed between the sexes. Infection was more common in entire cats (69%) and most cases (55%) involved domestic shorthair cats. Of the 90 reports that had a known vaccination status, 63 had a vaccination history, 40 of which were recently vaccinated. Most (72%) feline URTD cases recovered from clinical disease. Both feline URTI and URTD were more common during winter months. CONCLUSIONS AND RELEVANCE: Feline URTI and URTD cause substantial impact in Australia, being most commonly associated with M felis and FCV infection. This information can be used by veterinarians to educate clients about prevention and management of this important infectious disease of cats. PMID- 30465617 TI - Antioxidant activity of alpha and beta-amyrin isolated from Myrcianthes pungens leaves. AB - Brazil has a great variety of native plants which could be explored and among them guabiju (Myrcianthes pungens) stands out. Thus, this study consisted of isolating pentacyclic triterpenes, alpha and beta-amyrin from guajibu leaves, and determine the antioxidant activity.The leaves were dried, pulverized and submitted to a dynamic maceration process with ethanol 96 degrees GL, concentrated to obtain crude leaf extract (CLE). CLE was eluted with dichloromethane until total depletion, resulting in a dichloromethane fraction (FRDicl) which was concentrated and analyzed by GC/MS and NMR. The result of the chemical analysis revealed the presence of pentacyclic triterpenes of oleanane (beta-amyrin), and ursane (alpha-amyrin) groups. The beta-carotene bleaching method revealed a high antioxidant activity for the CLE as well as for FRDicl. The antioxidant protection equivalent to the trolox was of 137 and 129%, respectively at 500 ug/mL. The antioxidant potential of FRDicl can be explained by the presence of alpha and beta-amyrins. PMID- 30465619 TI - News, Announcements, Reviewers, and IASP. PMID- 30465618 TI - Preventing Suicide - What Precedes Us Will Propel Us. PMID- 30465620 TI - Intratympanic methylprednisolone administration promotes the recovery of idiopathic sudden sensorineural hearing loss: a retrospective case-control study. AB - BACKGROUND: Efficacy of current treatment methods in idiopathic sudden sensorineural hearing loss (ISSNHL) is still unsatisfactory. OBJECTIVE: This study aimed to discover in differences in effect between steroid applications responsible for promoting the prognosis in ISSNHL. MATERIALS AND METHODS: A study was conducted to diagnose ISSNHL patients in our hospital from January 2014 to September 2016. All patients accepted treatments including intravenous injection (intravenous dexamethasone, [IV DXM]), intratympanic injection (intratympanic methylprednisolone [IT MP], intratympanic dexamethasone [IT DXM]) or combined injections with steroids (IV + IT DXM). Patients were divided into groups according to treatment outcomes and clinical characteristics of each group were compared for univariate comparison. Logistic regression was utilized to verify screening factors from univariate comparison for exclude biases. RESULTS: There were 313 patients with ISSNHL enrolled in the study. Logistic regression verified that vertigo (p = .023), severity of hearing loss (p=.969), pattern of hearing loss (p = .03), and the treatment method (p < .001) were statistically related to the patients' prognosis based on the condition all biases had been excluded as possible. IT MP showed a better prognosis of hearing improvement compared to treatment with IT DXM (OR = 0.5), IV DXM (OR =0.226), and IV DXM + IV DXM (OR = 0.320). CONCLUSIONS AND SIGNIFICANCE: IT MP treatment could be utilized as initial treatment in ISSNHL and might promote outcomes. PMID- 30465621 TI - Endovascular treatment of carotid-cavernous sinus fistulas: ophthalmic and visual outcomes. AB - PURPOSE: The main objective was to report the epidemiology, clinical manifestations, angiography features, treatment modality and post-treatment outcomes in patients diagnosed with carotid cavernous fistulas (CCF). METHODS: A retrospective review of the medical imaging database in conjunction with medical records from 2004 to 2017 at the Royal Brisbane and Women's Hospital (RBWH) was conducted.We identified 39 patients with CCF (16 direct, 23 indirect). A total of 37 diagnoses were confirmed by direct catheter angiography. The remaining two cases were diagnosed using magnetic resonance imaging/magnetic resonance angiography. RESULTS: Coils were deployed in 100% of direct and 83% of treated indirect fistulas that were treated. Other embolic agents were deployed alone or in combination with coils. Successful angiographic closure was achieved in 93% of direct and 92% of indirect fistulas. Multiple treatments were required in 33% of direct and 16% of indirect fistulas. Visual acuity improved in patients with direct fistulae(p = 0.02) and was preserved in those with indirect fistulae. Post treatment diplopia persisted in six patients with direct fistulas and three patients with indirect fistulas. Four patients with indirect fistulas experienced persistent ocular hypertension post-treatment compared to two patients with direct fistulas. CONCLUSIONS: Endovascular coils are the most commonly deployed treatment for CCF. Both indirect and direct fistulas achieved high rates of closure; however, indirect fistulas were less likely to require multiple treatments. Good post-procedural vision was achieved for both groups. PMID- 30465622 TI - Association between IL1A and IL1B polymorphisms and primary open angle glaucoma in a Brazilian population. AB - Abstract: The aim of this study was to investigate the association of five polymorphisms in the IL1A and IL1B genes in Brazilian patients with primary open angle glaucoma (POAG). A case-control study, including 214 unrelated POAG patients and 187 healthy individuals, was conducted to evaluate the frequency of polymorphisms in the IL1A and IL1B genes. Ophthalmic evaluation was performed and genomic DNA was obtained from all participants. Five single nucleotide polymorphisms (SNPs): IL1A (-889C/T: rs1800587:C > T, +4845G/T:rs17561G>T) and IL1B (-31C/T:rs1143627:T > C, -511C/T:rs16944C>T and +3954C/T:rs1143634:C > T) were genotyped through direct sequencing. The association of individual SNPs was tested using logistic regression. There was an association between the -31C/T and -511 C/T polymorphisms in the IL1B gene with POAG (p = 0.002 and p = 0.009, respectively). High linkage disequilibrium was observed between the -31C/T and 511C/T polymorphisms. The statistical analysis showed that the T/C haplotype ( 31/-511) in the IL1B gene is more frequent in controls (p = 0.011) and the C/T haplotype (-31/-511) is more common in POAG patients (p = 0.018). Among POAG cases, the genotypic distribution of the -31C/T and -511 C/T SNPs was significantly different in patients who underwent anti-glaucomatous surgery compared to patients without surgery (p = 0.016 and 0.023, respectively). There was no statistically significant difference for the remaining SNPs between POAG patients and controls. In conclusion, the C allele of the -31C/T and the T allele of the -511C/T polymorphisms in the IL1B gene may represent a "risk haplotype" for the development of POAG in Brazilian individuals. Further studies with larger cohorts of patients are necessary to substantiate these findings. PMID- 30465623 TI - Perceived Influence on Service Goals Among Community-Working Occupational Therapists in Norway. AB - AIM: This study aimed to assess the perceived influence that community-working occupational therapists in Norway have on the service goals of their respective organizations. In addition, we aimed to assess sociodemographic and work-related factors associated with the perceived level of influence. METHODS: A cross sectional survey was distributed to occupational therapists in community-based services in Norway (n = 1767), to which 561 (32%) responded. By multivariate regression analysis, factors associated with "self-perceived influence" were assessed. RESULTS: After controlling for all variables, having a master's degree ( beta = 0.09, P < .05), being involved in a research and development project ( beta = 0.25, P < .001), and not working with assistive technology ( beta = -0.19, P < .001) were associated with higher perceived influence. CONCLUSIONS: For occupational therapy to reach its potential in Norwegian community-based health care, the profession needs to establish itself more firmly and increase its influence within the health care services. To do so, it appears important to support occupational therapists' educational aspirations, their participation in research and development projects, and their autonomous role in relation to the provision of assistive technology equipment. PMID- 30465624 TI - N6-isopentenyladenosine a new potential anti-angiogenic compound that targets human microvascular endothelial cells in vitro. AB - N6-isopentenyladenosine is an anti-proliferative and pro-apoptotic atypical nucleoside for normal and tumor cells. Considering the role of angiogenesis in various diseases, we investigated the cytotoxic effect of N6-isopentenyladenosine on human microvascular endothelial cells, protagonists in angiogenesis. Our results show that N6-isopentenyladenosine induced a significant reduction of cell viability, upregulated p21 and promoted caspase-3 cleavage in a dose dependent manner leading to apoptotic cell death as detected by FACS analysis. To understand structure-function relationship of N6-isopentenyladenosine, we investigated the effect of some N6-isopentenyladenosine analogs. Our results suggest that N6-isopentenyladenosine and some of its derivatives are potentially novel angiostatic agents and might be associated with other anti-angiogenic compounds for a better outcome. PMID- 30465625 TI - Intimate Partner Violence and Controlling Behaviors Experienced by Emergency Department Patients: Differences by Sexual Orientation and Gender Identification. AB - The objective of this study was to estimate the prevalence of intimate partner violence (IPV) in an emergency department (ED) by sexual orientation and gender identification. We conducted a cross-sectional survey of adult patients ( n = 1,136) presenting to a Level I Trauma Center ED from November 2015 to November 2016. Multivariable logistic regression analysis was used to estimate the adjusted odds ratio (aOR) of reporting any IPV or IPV subtypes (physical or sexual IPV or battering) by sexual orientation and gender identification, controlling for confounders. Overall, 11.6% (132 / 1,136) of those surveyed were IPV positive. The prevalence of IPV was significantly higher in lesbian, gay, bisexual, transgender, and questioning (LGBTQ) patients than in heterosexuals (18.3% vs. 10.8%, p = .0151); prevalence was highest among bisexuals (21.6%) and gay men (18.5%). IPV prevalence did not differ significantly in females versus males (13.5% vs. 9.2%, p = .0872). After controlling for age, the odds of reporting any IPV was highest among females (aOR = 1.67; 95% confidence interval [CI] = [1.10, 2.53]); no significant differences were found by sexual orientation. Gay patients (aOR = 5.50; 95% CI = [1.60, 18.94]) and females (aOR = 2.70; 95% CI = [1.46, 9.99]) had significantly higher odds of reporting physical or sexual IPV than heterosexuals and males, respectively. The study is among the first to report IPV prevalence by sexual orientation in an ED patient population. The reported IPV was higher among LGBTQ patients than heterosexual patients although this relationship diminished when controlling for covariates. These data begin to define the scope of IPV among LGBTQ ED patients and may be used to inform brief interventions to reduce the IPV-related morbidity experienced by ED patients. PMID- 30465626 TI - Are Changes in Medical Group Practice Characteristics Over Time Associated With Medicare Spending and Quality of Care? AB - Physician practices have been growing in size, and becoming more commonly owned by hospitals, over time. We use survey data on physician practices surveyed at two points in time, linked to Medicare claims data, to investigate whether changes in practice size or ownership are associated with changes in the use of care management, health information technology (HIT), or quality improvement processes. We find that practice growth and becoming hospital-owned are associated with adoption of more quality improvement processes, but not with care management or HIT. We then investigate whether growth or becoming hospital-owned are associated with changes in Medicare spending, 30-day readmission rates, or ambulatory care sensitive admission rates. We find little evidence for associations with practice size and ownership, but the use of care management practices is associated with lower rates of ambulatory care sensitive admissions. PMID- 30465627 TI - An unusual traumatic delivery malpractice: a case report. AB - Head trauma may occur during delivery and can lead to a number of conditions. When an infant is injured during birth, the cause of injury is generally due to mechanical forces, such as compression, excessive or abnormal traction during delivery, and the use of forceps. A 39-year-old woman who was a primagravida (first pregnancy) with a gestational age of 26 weeks premature pregnancy was referred to a hospital in Tehran due to premature rupture of membranes (PROM) and fever. She arrived 2 h after rupture (noting that the rupture lasted for one week and then the baby was delivered). Antibiotics were given early on. After weak labour pain, vaginal examination revealed that the cervix was fully dilated and one of the feet of the foetus had come out of the cervix and was seen in the vagina. The foetus had died. The delivery staff used traction with force. Due to the age of the foetus, the head was relatively big and could not be delivered; the neck was thin and broken and the head separated from the body. The mother underwent a caesarean section to deliver the head of the foetus a week after PROM. The father of the dead newborn foetus sued the hospital and the staff responsible for the delivery. When medical professionals damage the trust between patients and their families and babies are injured children, they should be held accountable. PMID- 30465628 TI - Steam Explosion in alkaline medium for gelatine extraction from chromium-tanned leather wastes: time reduction and process optimization. AB - Alkaline hydrolysis of chromium-tanned leather wastes (CTLW) is a well-known process that allows the extraction of its most valuable portion: the protein. However, alkaline hydrolysis is time-consuming. It usually takes from 2 to 10 h to be completed. In this work, alkaline hydrolysis was performed in a steam explosion reactor, using CaO as the alkalinizing agent and aiming at a short-time process. Three different temperatures and residence times were tested: 130, 140, and 150 degrees C; 5, 10, and 15 min. When performed at 140 degrees C for 10 min, the steam explosion in alkaline medium resulted in the optimum combination of protein extraction yield (30%) and gelatine quality (viscosity of 2.4 cP at 25 degrees C in a 24.6 g/L protein solution - 39 kDa of molecular mass [Formula: see text]w). Not only a high extraction yield was achieved, but when compared to traditional methods, steam explosion in alkaline medium reduced the process time by a factor that varied from 12 to 36 times. It also reduced chromium content in the gelatine by a factor that varied from 16 to 96 times. Finally, to produce a high quality product, the ash content of the gelatine was reduced from 11.8% (dry basis) to 1.2% (dry basis) through diafiltration. This purification allows the application of the gelatine, for example, in the production of polymeric films. PMID- 30465629 TI - Effects of national smoke-free legislation on the rates of preterm births and low birthweights in Taiwan. AB - This study evaluated the effects of partial and complete island-wide smoking bans on perinatal outcomes in Taiwan. Trends were determined in the yearly prevalence rates for preterm births and low birth weight (LBW) for a 1978 to 1997 pre-ban period, a 1998 to 2008 Phase 1 partial ban period, and a 2009 to 2016 Phase 2 complete ban period. Poisson regression with a yearly time-series model was employed to determine alterations in trends in prevalence rates for preterm births and LBW. Compared with pre-ban period, the rate ratio (RR) for Phase 1 preterm births was 0.969 (95% confidence interval [CI] = 0.968-0.971) and Phase 2 0.995 (95% CI = 0.992-0.998). The Phase 1 RR LBW fell 0.4% (95% CI = 0.2%-0.5%), but Phase 2 RR rose 1.7% (95% CI = 1.4%-2.1%). Data indicated that the risk of preterm births and LBW in Taiwan was reduced significantly after implementation of the smoking ban. These findings are in agreement with growing evidence suggesting that smoke-free legislation exerted a beneficial health effect on pregnant women and their newborn infants. PMID- 30465630 TI - Phone-based intervention for blood pressure control among Ghanaian stroke survivors: A pilot randomized controlled trial. AB - BACKGROUND: The potential of mobile-health (mHealth) technology for the management of hypertension among stroke survivors in Africa remains unexplored. We assessed whether an mHealth technology-enabled, nurse-guided intervention initiated among stroke patients within one month of symptom onset is effective in improving their blood pressure (BP) control. METHODS: A two-arm pilot cluster randomized controlled trial involving 60 stroke survivors, >=18 years, with BP >=140/90 mmHg at screening/enrollment visit at a medical center in Ghana. Participants in the intervention arm (n = 30) received a Blue-toothed BP device and smartphone with an App for monitoring BP measurements and medication intake under nurse guidance for three months after which intervention was withdrawn. Control arm (n = 30) received usual care. Primary outcome measure was proportion with clinic BP < 140/90 mmHg at month 9; secondary outcomes included medication adherence. FINDINGS: Mean +/- SD age was 55 +/- 13 years, 65% males. Two participants on intervention and three in control group were lost to follow-up. At month 9, proportion on the intervention versus controls with BP < 140/90 mmHg was 14/30 (46.7%) versus 12/30 (40.0%), p = 0.79 by intention-to-treat; systolic BP < 140 mmHg was 22/30 (73.3%) versus 13/30 (43.3%), p = 0.035. Mean +/- SD medication possession ratio was 0.95 +/- 0.16 on intervention versus 0.98 +/- 0.24 in the control arm, p = 0.56. INTERPRETATION: We demonstrate feasibility and signal of improvement in BP control among stroke survivors in a resource-limited setting via an mHealth intervention. Larger scale studies are warranted. TRIAL REGISTRATION: NCT02568137. Registered on 13 July 2015 at ClinicalTrials.gov. PMID- 30465631 TI - Enablers and barriers in accessing sexual and reproductive health services among visually impaired women in the Ashanti and Brong Ahafo Regions of Ghana. AB - The need to improve the sexual and reproductive health (SRH) and rights of women with disabilities is increasingly acknowledged. Unfortunately, women with disabilities in low- and middle-income settings, including Ghana, face several barriers (including structural, financial, physical, social and attitudinal) to accessing SRH services and care. This paper explores the enablers and barriers to accessing SRH services and care among visually impaired women in the Ashanti and Brong Ahafo Regions of Ghana. Qualitative data from in-depth interviews and focus group discussions were collected from 21 visually impaired women, selected through purposive and snowballing sampling techniques. Thematic analysis was used to develop codes, and data were further grouped into emerging themes. The barriers to accessing SRH services and care were financial difficulties and lack of preferential treatment. The enablers which facilitated access to SRH services and care were the support provided by caregivers and friendly relationships with health providers. To address these challenges and promote access, SRH related policies, services and programmes should be inclusive of the needs of visually impaired women, and measures to remove financial challenges to service utilisation and foster positive relationships with health workers, church and community members should be adopted. PMID- 30465632 TI - Knowledge about cochlear implantation: A parental perspective. AB - OBJECTIVES: Cochlear implantation (CI) is used for children with severe to profound hearing loss who show little or no improvement using hearing aids. This study explored parental knowledge of their children's CI. METHODS: A cross sectional study involving the parents of 115 pediatric CI patients was conducted at King Abdullah Specialized Children's Hospital in Riyadh, Saudi Arabia. Parents were interviewed by telephone using a 50-question validated questionnaire. RESULTS: Most parents of children with CI reported being comfortable in using the internet (68.7%) and social media (40.9%) to obtain information regarding CI. Although most parents of children with CI relied on health professionals and websites as their main sources of information, they were also able to obtain necessary information at meetings for CI patients and health professionals. Parents of children with CI felt they had sufficient information regarding the impact of hearing loss (78%) and CI (71%) on speech understanding and language development; however, they had insufficient information regarding criteria for CI candidacy, available brands of CI devices, and the advantages and disadvantages of each. CONCLUSION: Parents reported that health professionals were the ideal source of information regarding hearing loss and CI. Moreover, our study showed that parents should learn more about cochlear implant devices, the post implantation process, and candidacy criteria. PMID- 30465633 TI - Rural and urban differences in prenatal exposure to essential and toxic elements. AB - Excess or inadequate levels of inorganic ions may induce significant acute and long-term irreversible dysfunction in humans. The fetus and placenta are particularly vulnerable to toxins due to the immaturity of the blood-brain barrier and diminished biotransformation enzymatic activity. A comparative cross sectional study was conducted on 172 pregnant women, 79 rural, and 93 urban. Umbilical cord blood was collected at the time of delivery and analyzed for 20 inorganic elements. Significant differences were found between urban and rural samples for two elements where copper (Cu) and molybdenum (Mo) were higher in urban samples. No marked differences between groups occurred for: arsenic, barium, cadmium, calcium, cobalt, lead, lithium, magnesium, manganese, mercury, selenium, strontium, or zinc. All samples were devoid of platinum, silver, thallium or uranium. Data demonstrated significant differences in urban and rural prenatal exposure to Cu and Mo. Further study is needed to determine if there is a causal link between neonatal outcomes and prenatal exposure to these elements. PMID- 30465634 TI - Use of MRI to determine cochlear duct length in patients undergoing cochlear implantation. AB - OBJECTIVES: It is recognised that CT can be used to determine the cochlear duct length (CDL) when selecting an electrode for cochlear implantation. It is the practice of our institution to routinely use MRI as the sole modality of pre operative imaging in the assessment of children referred for consideration of cochlear implantation. We therefore wanted to determine whether MRI could be reliably used to determine cochlear duct length. METHODS: An analysis of 40 ears that had undergone MRI and CT of the temporal bones was undertaken. The diameter of the basal turn was independently measured for each ear using the two modalities, and CDL was then calculated. RESULTS: The mean error of measurement was 0.26 mm (range 0-0.8 mm), leading to a difference in calculated CDL of 0.96 mm (range 0-2.92 mm). CDL did not predict full insertion of 28 mm cochlear implant electrodes in 30 ears. CONCLUSIONS: MRI can be used to reliably determine cochlear duct length. PMID- 30465635 TI - Exercise training in thermo-mineral spring water has beneficial effects on hemodynamic and health-related factors in young-older hypertensive women: A randomized control trial. AB - The aim of the study was to evaluate the effects of an 8-week aerobic training in mineral geothermal water on hemodynamic variables, VO2max, and body composition in sedentary hypertensive women. Twenty postmenopausal women (58.55 +/- 3.28 years) were divided into an exercise group (2 days/week, 30-40 minutes, 60%-75% of HRmax) and control group. Compared to the control group, a significant reduction in systolic blood pressure, heart rate, rate pressure product, body fat percent, and a significant improvement in VO2max values was found. Aerobic training in thermo-mineral spring water is a safe and effective training modality in the young-older hypertensive population. PMID- 30465636 TI - Prefrontal Transcranial Direct Current Stimulation (tDCS) Enhances Behavioral and EEG Markers of Proactive Control. AB - This study examined the effects of stimulation targeting dorsolateral prefrontal cortex (DLPFC) on behavioral and neural oscillatory markers of proactive cognitive control in healthy adults. We hypothesized that active stimulation targeting the DLPFC would enhance proactive control compared to sham, leading to changes in the pattern of error rates and gamma-band power on the Dot Pattern Expectancy (DPX) task. We recorded EEG while participants completed the DPX, after receiving either 20 minutes of active DLPFC stimulation at 2 mA or sham stimulation in a counterbalanced within-participants design. The results showed significant tDCS-induced changes in the pattern of error rates on the DPX task indicative of enhanced proactive control, as well as predicted increases in gamma power associated with the engagement of proactive control. These results provide support for the role of DLPFC-mediated gamma activity in proactive cognitive control, and further, indicate that proactive control can be enhanced with non invasive neurostimulation. PMID- 30465637 TI - Objective, audiological and quality of life measures with the CI532 slim modiolar electrode. AB - OBJECTIVES: To report on electrode array measurements for the Nucleus(r) CI532 Slim Modiolar Electrode device including: ECAP thresholds, electrode impedances, and psychophysical comfort levels, as well as speech perception results pre- and post-operatively and standardized evaluations of quality of life. METHODS: Forty four subjects were implanted with the CI532. Electrically evoked compound action potential (ECAP) thresholds and impedances were measured using automatic Neural Response Telemetry intra-operatively, at activation and at six months post implant. Pre- and post-operative measures of words in quiet and sentences in noise were made in multiple languages. Quality of life was assessed using The Speech Spatial Qualities questionnaire (SSQ) and Glasgow Benefit Inventory (GBI). RESULTS: Intra-operative ECAP thresholds were recorded successfully from 90% of electrodes tested. ECAP thresholds varied across the array and a post-hoc Dunn's test showed that median thresholds for electrodes E1-E13 were significantly greater than those for E17-E22 (all P < 0.001). Impedances increased significantly between surgery and activation. Speech recognition scores for words in quiet and sentences in noise showed a significant improvement for the group at six months, when using the cochlear implant, compared with pre-operative performance (P < 0.001). There was a significant increase compared to pre operative ratings for all sections of the SSQ at six months post activation (P < 0.001). The GBI gave scores significantly above zero for the 'general' subscale and total score. CONCLUSION: Objective ECAP and impedance measures for this new electrode array were as expected and similar to results reported for other array types. Speech perception and quality of life improved significantly following implantation. (Registered as NCT02392403 on ClinicalTrials.gov PRS). PMID- 30465638 TI - Molecular characterization of Corynebacterium diphtheriae isolates in Malaysia between 1981 and 2016. AB - Sporadic diphtheria cases in Malaysia have remained low in number since the 1990s. However, in 2016 a total of 31 cases were reported nationwide and to investigate this we performed molecular characterization of 30 Corynebacterium diphtheriae isolates collected from 1981 to 2016 using multilocus sequence typing (MLST). C. diphtheriae isolates were identified and biotyped using the API Coryne kit, while the toxigenicity was determined by PCR and the Elek test. All of the 2016 isolates belonged to biotype mitis, caused respiratory diphtheria and were toxigenic strains. MLST analysis identified 17 sequence types (STs), including 11 new ones. ST453 was the most common clone (7/30, 23.3 %), followed by ST141 (5/30, 16.7 %), ST451 (3/30, 10.0 %) and ST248 (2/30, 6.7 %). The clones identified in 2016 had not been detected in previous isolations and they were phylogenetically distinct. Our results suggest that the diphtheria cases in 2016 were caused by the emergence and spread of new clones in Malaysia. PMID- 30465639 TI - Paraburkholderia phosphatilytica sp. nov., a phosphate-solubilizing bacterium isolated from forest soil. AB - A novel Gram-stain-negative, aerobic, non-spore-forming, non-motile and rod shaped bacterial strain, 7QSK02T, was isolated from forest soil of Dinghushan Biosphere Reserve, Guangdong Province, China. It grew at 12-37 degrees C, at pH 4.0-7.5 and in the presence of 0-1.0 % (w/v) NaCl on R2A agar medium, with optimum growth at 28 degrees C, pH 5.5 and 0 % NaCl. Strain 7QSK02T was closely related to members of the genus Paraburkholderia: P. acidipaludis NBRC 101816T (98.1 % 16S rRNA gene sequence similarity), P. piptadeniae STM 7183T (97.6 %), P. kururiensis JCM 10599T (97.3 %), P. caballeronis TNe-841T (97.3 %) and P. diazotrophica JPY461T (97.1 %). 16S rRNA gene sequence analysis showed that strain 7QSK02T and two closely strains, P. kururiensis JCM 10599T and P. caballeronis TNe-841T, formed a clade within the genus Paraburkholderia, but was clearly separated from the established species. The genomic G+C content of strain 7QSK02T was 64.9 mol% based on total genome calculations. The average nucleotide identity and digital DNA-DNA hybridization value for the complete genomes were 79.2-81.5 and 23.2-24.9 % between strain 7QSK02T and its closely related species listed above. Strain 7QSK02T contained ubiquinone 8 as the major respiratory quinone. Major fatty acids were C16 : 0, C17 : 0 cyclo and C19 : 0 cyclo omega8c. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylmethylethanolamine, one unidentified aminophospholipid, aminolipid and polar lipid. The phenotypic, chemotaxonomic and phylogenetic properties, and genome analysis suggest that strain 7QSK02T represents a novel species of the genus Paraburkholderia, for which the name Paraburkholderia phosphatilytica sp. nov. is proposed. The type strain is 7QSK02T (=GDMCC 1.1283T=CGMCC 1.15470T=KCTC 62473T). PMID- 30465640 TI - Marinobacter maroccanus sp. nov., a moderately halophilic bacterium isolated from a saline soil. AB - During the taxonomic investigation of exopolymer-producing halophilic bacteria, a rod-shaped, motile, Gram-stain-negative, halophilic bacterium, designated strain N4T, was isolated from a saline soil located in northern Morocco. Optimal growth of the isolate was at 30-37 oC and at pH 7.0-8.0, in the presence of 5-7 % (w/v) NaCl. Useful characteristics for the phenotypic differentiation of strain N4T from other Marinobacter species included alpha-chymotrypsin and alpha-glucosidase activities and the carbohydrate assimilation profile. The major fatty acids detected in strain N4T were C16:0 and C18:1omega9c and the predominant respiratory quinone was ubiquinone-9. Sequence analysis of the 16S rRNA gene indicated that strain N4T belonged to the genus Marinobacter and was closely related to the type strains of Marinobacter adhaerens (99.04 % similarity), Marinobacter salsuginis (98.97 %) and Marinobacter flavimaris (98.36 %). Phylogenetic analysis of the rpoD gene sequence also showed that the nearest neighbours of strain N4T were M. salsuginis (91.49 % similarity), M. adhaerens and M. flavimaris (90.63 %). Strain N4T showed 87.98 % average nucleotide identity with M. flavimaris and M. salsuginis, and 87.47 % with M. adhaerens. Regarding in-silico genome-to-genome distance, strain N4T showed DNA-DNA hybridization values of 33.30 % with M. adhaerens, 34.60 % with M. flavimaris and 34.70 % with M. salsuginis. The DNA G+C content of strain N4T was 57.3 mol%. Based on the results of phenotypic characterization, phylogenetic analysis and genome comparison, strain N4T represents a novel species of the genus Marinobacter, for which the name Marinobacter maroccanus sp. nov. is proposed. The type strain is N4T (=CECT 9525T=LMG 30466T). PMID- 30465641 TI - Paracandidimonas caeni sp. nov., isolated from sludge. AB - A beige-pigmented, Gram-stain-negative, aerobic, non-motile, rod-shaped bacterium, named 24T, was isolated from sludge of a pesticide manufacturing factory in Nantong, Jiangsu Province, China. 16S rRNA gene sequence analysis revealed that strain 24T shared highest similarity with Parapusillimonas granuli Ch07T (98.20 %), followed by Candidimonas nitroreducens SC-089T (98.07 %) and Paracandidimonas soli IMT-305T (98.03 %). Phylogenetic trees showed that strain 24T formed a distinct clade with Paracandidimonas soli IMT-305T. The results of DNA-DNA hybridization tests showed that reassociation values were less than 45 % with respect to these closely related type strains. Strain 24T contained Q-8 and putrescine as the major respiratory quinone and polyamine, respectively. The main cellular fatty acids were summed feature 3 (C16 : 1omega7c/C16 : 1omega6c), summed feature 2 (iso-C16 : 1 I/C14 0 3-OH/C12 : 0 aldehyde), summed feature 8 (C18 : 1omega7c/C18 : 1omega6c) and C12 : 0. The polar lipid profile included phosphatidylmethylethanolamin, phosphatidylethanolamine, phosphatidylglycerol, one unidentified phospholipid and one unidentified aminolipid. The G+C content was 56.83 mol%. Combined data from phenotypic, phylogenetic and DNA-DNA relatedness studies demonstrated that strain 24T represents a novel species of the genus Paracandidimonas, for which the name Paracandidimonas caeni sp. nov. is proposed. The type strain is 24T (=CCTCC AB 2018057T=KACC 19692T). PMID- 30465642 TI - PANINI: Pangenome Neighbour Identification for Bacterial Populations. AB - The standard workhorse for genomic analysis of the evolution of bacterial populations is phylogenetic modelling of mutations in the core genome. However, a notable amount of information about evolutionary and transmission processes in diverse populations can be lost unless the accessory genome is also taken into consideration. Here, we introduce panini (Pangenome Neighbour Identification for Bacterial Populations), a computationally scalable method for identifying the neighbours for each isolate in a data set using unsupervised machine learning with stochastic neighbour embedding based on the t-SNE (t-distributed stochastic neighbour embedding) algorithm. panini is browser-based and integrates with the Microreact platform for rapid online visualization and exploration of both core and accessory genome evolutionary signals, together with relevant epidemiological, geographical, temporal and other metadata. Several case studies with single- and multi-clone pneumococcal populations are presented to demonstrate the ability to identify biologically important signals from gene content data. panini is available at http://panini.pathogen.watch and code at http://gitlab.com/cgps/panini. PMID- 30465643 TI - Polynucleobacter paneuropaeus sp. nov., characterized by six strains isolated from freshwater lakes located along a 3000 km north-south cross-section across Europe. AB - Six Polynucleobacter (Burkholderiaceae, Betaproteobacteria) strains isolated from different freshwater lakes located across Europe were taxonomically investigated. Phylogenetic analyses based on 16S rRNA gene sequences assigns all six strains to the cryptic species complex PnecC within the genus Polynucleobacter. Analyses of partial glutamine synthetase (glnA) genes suggests that all six strains belong to the species-like taxon designated F15 in previous papers. Comparative genome analyses reveal that the six strains form a genomically coherent group characterized by whole-genome average nucleotide identity (gANI) values of >98 % but separated by gANI values of <88 % from the type strains and representatives of the 16 previously described Polynucleobacter species. In phylogenetic analyses based on nucleotide sequences of 319 orthologous genes, the six strains represent a monophyletic cluster that is clearly separated from all other described species. Genome sizes of the six strains range from 1.61 to 1.83 Mbp, which is smaller than genome sizes of the majority of type strains representing previously described Polynucleobacter species. By contrast, the G+C content of the DNA of the strains is well in the range of 44.8-46.6 mol% previously found for other type strains of species affiliated with the subgroup PnecC. Variation among the six strains representing the new species is evident in a number of traits. These include gene content differences, for instance regarding a gene cluster encoding anoxygenic photosynthesis, as well as phenotypic traits. We propose to name the new species represented by the six strains Polynucleobacter paneuropaeus sp. nov. and designate strain MG-25-Pas1-D2T (=DSM 103454T =CIP 111323T) as the type strain. PMID- 30465644 TI - Nakamurella deserti sp. nov., isolated from rhizosphere soil of Reaumuria in the Taklamakan desert. AB - A Gram-stain-positive, aerobic, non-motile, non-spore-forming, coccus-shaped actinobacterium, designated strain 12Sc4-1T, was isolated from a soil sample collected in the Taklamakan desert in Xinjiang Uygur Autonomous Region, China. Strain 12Sc4-1T grew at 8-35 degrees C (optimum, 28-30 degrees C), pH 6.0-9.0 (optimum, pH 7.0) and in the presence of 0-3 % (w/v) NaCl (optimum, 0 %). Phylogenetic analysis based on 16S rRNA gene sequence suggested that strain 12Sc4 1T belonged to the genus Nakamurella and shared the highest 16S rRNA gene sequence similarity to Nakamurella silvestris S20-107T (96.94 %). Strain 12Sc4-1T showed <96.0 % 16S rRNA gene sequence similarities to all other recognized members of the genus Nakamurella. Chemotaxonomic analyses showed that the isolate possessed meso-diaminopimelic acid as the diagnostic diamino acid of the peptidoglycan, glucose, mannose and galactose as whole-cell sugars, and MK-8(H4) as the predominant menaquinone. The polar lipids comprised diphosphatidylglycerol, phosphatidylethanolamine, an unidentified aminophospholipid, phosphatidylinositol, an unidentified phospholipid, an unidentified phosphoglycolipid and an unidentified glycolipid. The major fatty acids were C16 : 0 and anteiso-C15 : 0. The DNA G+C content was 72.1 mol% (draft genome sequence). On the basis of phylogenetic, phenotypic and chemotaxonomic analyses, strain 12Sc4-1T represents a novel species of the genus Nakamurella, for which the name Nakamurelladeserti sp. nov. is proposed. The type strain is 12Sc4-1T (=KCTC 49114T=CGMCC 1.16555T). PMID- 30465645 TI - The quantity and distribution of biofilm growth of Escherichia coli strain ATCC 9723 depends on the carbon/energy source. AB - Escherichia coli strain 15 (ATCC 9723) formed robust biofilms of two distinct forms on glass tubes. In rich, low-osmolarity medium, the biofilms were restricted to the air/liquid interface, resulting in rings attached to the glass. As it was not evident that these biofilms extended across the liquid surface, we termed them 'ring' rather than 'pellicle' biofilms. In minimal medium supplemented with a non-fermentable substrate as the carbon/energy source, we observed either robust ring biofilms or little biofilm of any type, depending on the substrate. In contrast, fermentable substrates (sugars and sugar derivatives) supported robust biofilms covering most of the solid/liquid interface, which we termed 'tube-covering biofilms'. Maximal biofilm growth was observed when the sugar was a relatively poor substrate, supporting slow growth and known to cause minimal dephosphorylation of regulatory protein Enzyme IIAGlucose of the phosphotransferase system. Compounds found to be inhibitors of biofilm growth, such as lactate, caused a shift from tube-covering to ring form at low concentration and complete loss of biofilm growth at high when added to minimal medium supplemented with a fermentable substrate. Exogenous cAMP activated biofilm growth under all conditions tested, leading to more intense ring or tube covering biofilms and/or to a shift from ring to tube-covering form. PMID- 30465646 TI - TETyper: a bioinformatic pipeline for classifying variation and genetic contexts of transposable elements from short-read whole-genome sequencing data. AB - Much of the worldwide dissemination of antibiotic resistance has been driven by resistance gene associations with mobile genetic elements (MGEs), such as plasmids and transposons. Although increasing, our understanding of resistance spread remains relatively limited, as methods for tracking mobile resistance genes through multiple species, strains and plasmids are lacking. We have developed a bioinformatic pipeline for tracking variation within, and mobility of, specific transposable elements (TEs), such as transposons carrying antibiotic resistance genes. TETyper takes short-read whole-genome sequencing data as input and identifies single-nucleotide mutations and deletions within the TE of interest, to enable tracking of specific sequence variants, as well as the surrounding genetic context(s), to enable identification of transposition events. A major advantage of TETyper over previous methods is that it does not require a genome reference. To investigate global dissemination of Klebsiella pneumoniae carbapenemase (KPC) and its associated transposon Tn4401, we applied TETyper to a collection of over 3000 publicly available Illumina datasets containing blaKPC. This revealed surprising diversity, with over 200 distinct flanking genetic contexts for Tn4401, indicating high levels of transposition. Integration of sample metadata revealed insights into associations between geographic locations, host species, Tn4401 sequence variants and flanking genetic contexts. To demonstrate the ability of TETyper to cope with high-copy-number TEs and to track specific short-term evolutionary changes, we also applied it to the insertion sequence IS26 within a defined K. pneumoniae outbreak. TETyper is implemented in python and is freely available at https://github.com/aesheppard/TETyper. PMID- 30465647 TI - Acute postoperative pain after arthroscopic rotator cuff surgery: A review of methods of pain assessment. AB - INTRODUCTION: Pain can be severe during the first days after arthroscopic surgery, and acute pain is an important outcome in clinical trials of surgical technique or anaesthetic strategy. A standardized, validated method of assessing acute postoperative pain would improve the quality of clinical studies, and facilitate systematic reviews and meta-analyses. A step on the way towards this standard is to investigate the methods most commonly used in recent literature. METHODS: PubMed and CINAHL databases were searched, including studies of arthroscopic rotator cuff surgery with a primary pain-related outcome during the first postoperative week, published in English from 2012 to 2017. RESULTS: A total of 47 studies were included, all measuring pain intensity using a pain rating scale. Most frequently used was the visual analogue scale using the anchors "no pain" and "worst pain imaginable", with recordings at 1, 2, 4, 6, 8, 12, and 24 hours postoperatively. A total of 34 studies recorded analgesic consumption, usually as average cumulated consumption in mg. Time to first analgesic request or first pain were recorded in 11 studies, and 4 different starting points were used. DISCUSSION: This review describes the currently most common methods of assessing acute postoperative pain in clinical trials of arthroscopic shoulder surgery involving rotator cuff repair, and the large variety of methods applied. Based on this study and international guidelines, several recommendations on how to measure and report postoperative pain outcomes in future trials are proposed. PMID- 30465648 TI - All-endoscopic management of benign bone lesions; a case series of 26 cases with minimum of 2 years follow-up. AB - PURPOSE: Assessment of the functional and oncologic outcomes regarding endoscopic curettage of different benign bone tumor types within variable anatomic locations. PATIENTS AND METHODS: During the period between February 2012 and December 2016, 26 patients with symptomatic intra-osseous benign bony lesions were included. The age ranged from 3 up to 49 years (mean 20), of 14 females and 12 males. The follow-up duration ranged from 26 up to 58 months (mean 41). Functional scoring was done according to the Revised Musculoskeletal Tumour Society Rating Scale. Anatomic locations of the lesions included: 6 cases in the proximal tibia, 6 cases in the distal femur, 4 cases in the calcaneus, 3 cases in the proximal humerus, 3 cases in the distal tibia, 2 cases in the talus, 1 case in the proximal femur, and 1 case in the distal fibula. The procedure used 4 mm 30 degrees scope for endoscopy, and high speed burrs 3.5-5 mm for extended curettage. Autogenous bone grafting was done in 5 cases, and adjuvant material (polymethylmethacrylate) was needed in 7 cases. RESULTS: After exclusion of one case that was lost in the follow-up, the remaining 25 cases showed full functional recovery at a period of 8-12 weeks, and improved mean functional scores from 20.2 to 28.6/30 post-operatively, with p value <0.001 which was considered as a statistically significant result. The oncologic outcome showed 24 cases with adequate healing, while 1 case developed recurrence (aneurysmal bone cyst in the proximal tibia) for which, an open revision surgery was performed. Intra-operative fracture occurred in another case with aneurysmal bone cyst of the proximal femur, which was fixed by flexible nails with complete healing. CONCLUSION: Endoscopic curettage of different types of intra-osseous benign bony lesions proved to be an effective treatment modality with promising oncologic outcome, improved functional scores, and fast functional recovery. PMID- 30465649 TI - When do patients drive after minimally invasive anterior hip replacements? A single surgeon experience of 212 hip arthroplasties. AB - INTRODUCTION: Patients desire to return to normal activities soon after hip arthroplasty, with driving often being an integral component. We aimed to determine when patients resumed driving following a minimally invasive anterior bikini hip replacement and when they returned to work. METHODOLOGY: All consecutive patients undergoing elective primary bikini hip replacements between January 2017 and April 2018 were included in the study. Patients who did not drive were excluded. A detailed questionnaire was sent to patients 3-6 weeks after surgery to record their driving status. Fifty patients were randomly selected to assess flexion at the hip, knee and ankle joints while seated in the driver's seat of their own vehicle. RESULTS: Altogether 212 anterior bikini total hip replacements (L = 102, R = 108 and 1 bilateral one stage) were performed in 198 patients (F = 129 and M = 69) with a mean age of 69 years. A total of 76% patients returned to driving within the first 3 weeks after surgery, of which 25 (14%) resumed driving within the first post-operative week, 71 (39%) in the second week and 42 (23%) in the third week. Among them, 98.4% stated they were confident when they first started driving and 90.66% stated they were more comfortable driving after surgery than before. Employed patients returned to work within 1-79 days (mean = 24 days). CONCLUSION: Surgeons may allow patients to resume driving within 1 week after anterior hip replacement and return to work within 3 weeks if they are medically fit and deemed safe. PMID- 30465651 TI - ATRX promotes maintenance of herpes simplex virus heterochromatin during chromatin stress. AB - The mechanisms by which mammalian cells recognize and epigenetically restrict viral DNA are not well defined. We used herpes simplex virus with bioorthogonally labeled genomes to detect host factors recruited to viral DNA shortly after its nuclear entry and found that the cellular IFI16, PML, and ATRX proteins colocalized with viral DNA by 15 min post infection. HSV-1 infection of ATRX depleted fibroblasts resulted in elevated viral mRNA and accelerated viral DNA accumulation. Despite the early association of ATRX with vDNA, we found that initial viral heterochromatin formation is ATRX-independent. However, viral heterochromatin stability required ATRX from 4-8 h post infection. Inhibition of transcription blocked viral chromatin loss in ATRX-knockout cells; thus, ATRX is uniquely required for heterochromatin maintenance during chromatin stress. These results argue that the initial formation and the subsequent maintenance of viral heterochromatin are separable mechanisms, a concept that likely extrapolates to host cell chromatin and viral latency. PMID- 30465652 TI - Multi-protein Bridging Factor 1(Mbf1), Rps3 and Asc1 prevent stalled ribosomes from frameshifting. AB - Reading frame maintenance is critical for accurate translation. We show that the conserved eukaryotic/archaeal protein Mbf1 acts with ribosomal proteins Rps3/uS3 and eukaryotic Asc1/RACK1 to prevent frameshifting at inhibitory CGA-CGA codon pairs in the yeast Saccharomyces cerevisiae. Mutations in RPS3 that allow frameshifting implicate eukaryotic conserved residues near the mRNA entry site. Mbf1 and Rps3 cooperate to maintain the reading frame of stalled ribosomes, while Asc1 also mediates distinct events that result in recruitment of the ribosome quality control complex and mRNA decay. Frameshifting occurs through a +1 shift with a CGA codon in the P site and involves competition between codons entering the A site, implying that the wobble interaction of the P site codon destabilizes translation elongation. Thus, eukaryotes have evolved unique mechanisms involving both a universally conserved ribosome component and two eukaryotic-specific proteins to maintain the reading frame at ribosome stalls. PMID- 30465650 TI - Sensorimotor pathway controlling stopping behavior during chemotaxis in the Drosophila melanogaster larva. AB - Sensory navigation results from coordinated transitions between distinct behavioral programs. During chemotaxis in the Drosophila melanogaster larva, the detection of positive odor gradients extends runs while negative gradients promote stops and turns. This algorithm represents a foundation for the control of sensory navigation across phyla. In the present work, we identified an olfactory descending neuron, PDM-DN, which plays a pivotal role in the organization of stops and turns in response to the detection of graded changes in odor concentrations. Artificial activation of this descending neuron induces deterministic stops followed by the initiation of turning maneuvers through head casts. Using electron microscopy, we reconstructed the main pathway that connects the PDM-DN neuron to the peripheral olfactory system and to the pre-motor circuit responsible for the actuation of forward peristalsis. Our results set the stage for a detailed mechanistic analysis of the sensorimotor conversion of graded olfactory inputs into action selection to perform goal-oriented navigation. PMID- 30465653 TI - Relevance of healthcare-associated pneumonia for empirical antibiotic therapy in the Netherlands. AB - BACKGROUND: There is no consensus whether patients with healthcare-associated pneumonia (HCAP) should be considered as a patient with hospital-acquired pneumonia (HAP) and treated with broad-spectrum antibiotics, or as a patient with community-acquired pneumonia (CAP), and treated with narrow-spectrum antibiotics. HCAP research has focused mostly on the predictive value for non-susceptibility to broad-spectrum antibiotics and multi-drug resistant pathogens, in settings with moderate to high levels of antibiotic resistance. We investigated whether HCAP criteria predicts non-susceptibility to different empirical strategies, including narrow-spectrum antibiotics in the Dutch setting. METHODS: In a post hoc analysis of patients with moderate-severe CAP in seven Dutch hospitals, we compared in vitro antibiotic susceptibilities of definite and possible causative pathogens of CAP and HCAP to amoxicillin and broader antibiotic regimens. In a sensitivity analysis, pathogens with missing susceptibilities were assumed susceptible (best-case scenario) or non-susceptible (worst-case scenario). RESULTS: Among 2,283 patients with moderate-severe CAP, 23.1% (n = 527) were classified as HCAP. Non-susceptibility to amoxicillin ranged from 11.3% (95% CI 9.9-12.8%; best-case) to 14.4% (95% CI 12.8-16.1%; worst-case) in CAP patients and from 16.7% (95% CI 13.8-20.1%; best-case) to 19.7% (95% CI 16.6-23.3%; worst case) in HCAP patients. The largest reduction in non-susceptibility was achieved by adding ciprofloxacin to amoxicillin treatment in both CAP patients (10% absolute risk reduction) and HCAP patients (11-16% reduction). CONCLUSIONS: In the Netherlands, HCAP criteria predict higher amoxicillin non-susceptibility in patients hospitalized with moderate-severe CAP. Although broadening the antibiotic spectrum of empiric treatment reduced the likelihood of non susceptibility, absolute reductions of non-susceptibility in HCAP patients were too low to justify the universal use of broad-spectrum empirical therapy.No abstract available. PMID- 30465654 TI - Secondary care experiences of patients with multiple chronic conditions. AB - BACKGROUND: This study aimed to investigate patients' experiences, beliefs and understandings of the current secondary care of patients with multiple chronic conditions (MCC) in the Netherlands. METHODS: A qualitative, interpretative description design was used. We conducted semi-structured, in-depth interviews with patients with MCC, who visited at least two physicians in Gelre Hospitals for at least two appointments in the previous year. After eight interviews data saturation was achieved. RESULTS: Being a patient with MCC in the hospital can be complex and keeping an overview required effort, according to the participants. Most participants would appreciate more coordination and communication. However, the exact needs seemed to differ. The multiple visits transformed them into experienced patients: based on their experiences and observations they developed strategies to sustain themselves in the hospital. Different types of communication (an important, overarching theme) evoked specific feelings and expectations that were important for the patients' care experiences as well. CONCLUSION: An overview of patient care seems an essential element for a more coordinated, individualised approach to care. Future research might focus on ways to engage both healthcare professionals and patients in the improvement of care. It could aim to find ways to create an overview and coordination, and define responsibilities, but also to clarify which groups of patients need assistance. It might also investigate the effect of good and clear communication on reducing obstacles that patients perceive when dealing with healthcare situations. Overall, also in the future, patients' care experiences could play an important role in determining the direction of new interventions. PMID- 30465655 TI - Taking care of the multimorbid patient, a primary task of the internist. PMID- 30465656 TI - Progressive kidney failure in chronic myelomonocytic leukaemia: don't forget lysozyme damage. AB - Kidney failure is common in haematologic malignancies. However, the nephrotoxic effect of lysozyme is seldom recognized. We present a 78-year-old male with chronic myelomonocytic leukaemia who developed progressive kidney failure due to increased production of lysozyme. PMID- 30465657 TI - Allergic acute coronary syndrome in exercise-induced anaphylaxis. AB - In this case report we present a 49-year-old male who was seen in the emergency department after collapsing due to anaphylactic shock, with ECG findings suggesting myocardial ischaemia. We linked both diagnoses to Kounis syndrome, which describes an acute coronary syndrome due to an allergic event. His circulatory collapse was explained by exercise-induced anaphylaxis. PMID- 30465658 TI - Itching dermatitis on the leg of a 46-year-old HIV-positive man from Jamaica. PMID- 30465659 TI - Answer to Photo Quiz: Itching dermatitis on the leg of a 46-year-old HIV-positive man from Jamaica. PMID- 30465660 TI - Out of pace: An uncommon cause of atrioventricular block. PMID- 30465661 TI - Answer to Photo Quiz: Out of pace: An uncommon cause of atrioventricular block. PMID- 30465662 TI - A woman with a purplish-red skin lesion on the neck. PMID- 30465663 TI - Answer to Photo Quiz: A woman with a purplish-red skin lesion on the neck. PMID- 30465664 TI - Assessment of physicians' cognitive biases. PMID- 30465665 TI - The effect of 3d-electron configuration entropy on the temperature coefficient of redox potential in Co1-zMnz Prussian blue analogues. AB - Recently, it was reported that a thermocell can convert temperature into electrical energy by using the difference in the thermal coefficient (alpha = dV/dT) of the redox potential (V) between the cathode and anode materials. Here, we systematically investigated alpha of NaxCo1-zMnz[Fe(CN)6]y (Co1-zMnz-PBA) against Mn concentration (z). The z-dependence of alpha is interpreted in terms of the 3d-electron configuration entropy (DeltaS3d) of the redox site. Utilization of S3d is a strategy effective for the design of high-|alpha| materials for energy harvesting thermocells. PMID- 30465666 TI - Investigations of the capacity fading mechanism of Na0.44MnO2via ex situ XAS and magnetization measurements. AB - Na-ion batteries represent a promising complementary alternative to Li-ion batteries due to their high energy density and natural abundancy of Na. However, these batteries have short cycle life and extensive research activities on these batteries are required to understand the mechanism of such drawbacks. In this report, we investigate the capacity fading mechanism of Na0.44MnO2via ex situ X ray diffraction, X-ray absorption spectroscopy, Fourier transform infrared spectroscopy and magnetization measurements. Our results show that the unit cell volume, the effective mass of Mn-O bonds, the number of Mn4+ ions and the effective magnetic moment decrease upon repeated cycling. We propose that some Mn4+ ions in the octahedral environment become Mn3+ ions in a square pyramidal environment, causing oxygen release upon cycling. Any free oxygen in the battery is expected to react with the electrolyte and cause capacity fade. PMID- 30465667 TI - Schiff-base macrocyclic ZnII complexes based upon flexible pendant-armed extended dialdehydes. AB - This Frontier article reviews diverse structures of Schiff-base macrocyclic ZnII complexes derived from a family of flexible pendant-armed extended dialdehydes via a preorganized synthetic strategy and the corresponding structure-determining factors, including primary cationic template effects and secondary complementary template effects. In addition, further post-modification and supramolecular self assembly of Schiff-base ZnII macrocycles and their possible applications in a variety of areas have been discussed. PMID- 30465668 TI - Multiple coordination modes of a new ditopic bis(pyrazolyl)methane-based ligand. AB - A new ditopic ligand, N-(2,2-bis(pyrazolyl)ethyl)-2,2-bis(pyrazolyl)acetamide ((pz)2CH-C(O)-NH-CH2-CH(pz)2, L4Pz, pz = pyrazolyl ring), comprising two bis(pyrazolyl)methane donor groups linked via an amide bridge, has been prepared from the reaction of HOOCCH(pz)2 and H2NCH2CH(pz)2. The ligand coordinates to various metallic salts (i.e. AgO3SCF3, PdCl2, Re(CO)5Br, and Fe(BF4)2), in either a kappa2-MU-kappa2 or a kappa3-MU-kappa2 fashion, depending on the coordination preferences of the metallic center. These compounds were characterized by NMR, UV Vis and IR spectroscopy, and in solid state by single crystal X-ray diffraction. In the case of silver(i), a mono-dimensional coordination polymer was obtained, while the others were found to be discrete complexes. The synthesis and characterization of a heterobimetallic complex is also described. In solid state, all compounds are associated into supramolecular architectures via hydrogen bonding and pyrazolyl embrace interactions. PMID- 30465669 TI - Nanomedicine and macroscale materials in immuno-oncology. AB - Immunotherapy is revolutionizing the treatment of cancer. It can achieve unprecedented responses in advanced-stage patients, including complete cures and long-term survival. However, immunotherapy also has limitations, such as its relatively low response rates and the development of severe side effects. These drawbacks are gradually being overcome by improving our understanding of the immune system, as well as by establishing combination regimens in which immunotherapy is combined with other treatment modalities. In addition to this, in recent years, progress made in chemistry, nanotechnology and materials science has started to impact immuno-oncology, resulting in more effective and less toxic immunotherapy interventions. In this context, multiple different nanomedicine formulations and macroscale materials have been shown to be able to boost anti cancer immunity and the efficacy of immunomodulatory drugs. We here review nanotechnological and materials chemistry efforts related to endogenous and exogenous vaccination, to the engineering of antigen-presenting cells and T cells, and to the modulation of the tumor microenvironment. We also discuss limitations, current trends and future directions. Together, the insights provided and the evidence obtained indicate that there is a bright future ahead for engineering nanomedicines and macroscale materials for immuno-oncology applications. PMID- 30465670 TI - A single-atom Fe-N4 catalytic site mimicking bifunctional antioxidative enzymes for oxidative stress cytoprotection. AB - Atomically dispersed Fe-N4 sites anchored on N-doped porous carbon materials (Fe SAs/NC) can mimic two antioxidative enzymes of catalase (CAT) and superoxide dismutase (SOD), and therefore serves as a bifunctional single-atom-based enzyme (SAzyme) for scavenging reactive oxygen species (ROS) to remove excess ROS generated during oxidative stress in cells. PMID- 30465671 TI - Characterization of the metal status of natively purified alpha-synuclein from human blood, brain tissue, or recombinant sources using size exclusion ICP-MS reveals no significant binding of Cu, Fe or Zn. AB - Abnormal protein structure and function have been implicated as the toxic species in many diseases including neurodegenerative diseases, such as Parkinson's. One key pathological hallmark in Parkinson's disease is the formation of Lewy bodies, of which alpha-synuclein is the major component. These Lewy bodies are formed by the aggregation and oligomerization of alpha-synuclein. The oligomeric form of the protein is suspected to be the main contributor to the neurotoxicity seen in the disease. The formation of toxic oligomers has been shown to occur through reactions with lipids, dopamine, hydrogen peroxide as well as metals. The interplay between metals and alpha-synuclein has also been proposed to cause oxidative stress, which promotes the formation of protein aggregates. Most studies investigating the relationship of Cu, Fe and Zn with alpha-synuclein have relied on the use of recombinant protein and there is little evidence that the interaction between metals and alpha-synuclein are physiologically relevant. To address this gap in our knowledge we have characterized the metal content and metal binding capacity of alpha-synuclein purified from human erythrocytes and brain tissue. In addition, we examined the ability of dityrosine cross-linked alpha-synuclein oligomers to bind Cu, Fe and Zn. Using size exclusion chromatography-inductively coupled plasma-mass spectrometry we demonstrated that native human alpha-synuclein, recombinant familial mutants and oligomers do not bind to significant amounts of metal even when they are added to the protein in excess. PMID- 30465672 TI - Organic semiconducting nanoprobe with redox-activatable NIR-II fluorescence for in vivo real-time monitoring of drug toxicity. AB - An activatable organic semiconducting nanoprobe that specifically turns on its second near-infrared window fluorescence upon being exposed to nitric oxide stimuli was developed for in vivo, in situ, real-time and high-spatial-resolution mapping of drug-induced hepatotoxicity. PMID- 30465673 TI - Facile synthesis of aquo-cisplatin arsenite multidrug nanocomposites for overcoming drug resistance and efficient combination therapy. AB - Cisplatin (CDDP) and arsenic trioxide (ATO), two representative inorganic anticancer drugs, have been successful in the treatment against several kinds of malignancies. However, combination therapy with these two drugs in clinical application suffers from poor pharmacokinetics, serious side effects, and drug resistance of the tumor. Herein, we report a carrier-free aquo-cisplatin arsenite multidrug nanocomposite loaded with cisplatin and arsenic trioxide prodrugs simultaneously. This nanocomposite achieves a high loading capacity and pH dependent controlled release of the drugs. Because of these features, this nanocomposite shows better in vitro toxicity against various carcinoma cell lines than either the single drug or free drug combination, promotes the synergistic effect of cisplatin and arsenic trioxide, and significantly inhibits the growth of tumors in vivo. Furthermore, cisplatin and arsenic trioxide in this nanocomposite can realize a coordination of both enhanced DNA damage and DNA repair interference within cisplatin-resistant cells, which results in overcoming the drug resistance effectively. Gene expression profiles demonstrate the reduced expression of proto-oncogenes and DNA damage repair related genes MYC, MET, and MSH2, along with the increase of tumor suppressor genes PTEN, VHL, and FAS after the nanocomposite treatment. This type of multidrug nanocomposite offers an alternative and promising strategy for combination therapy and overcoming drug resistance. PMID- 30465674 TI - Local crystal structure and mechanical properties of sputtered Ti-doped AlN thin films. AB - In this article, we predominantly report the investigation of the local crystal structure around a Ti dopant by X-ray absorption spectroscopy (XAS) and the nano mechanical properties of co-sputtered Al1-xTixN (x = 0 to 4%) thin films. Grazing incidence X-ray diffraction (GIXRD) results show that these films are crystallized with the hexagonal wurtzite structure of AlN. Surface chemical analysis and morphology analysis of Al1-xTixN films are executed using X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM) techniques, respectively. X-ray absorption near-edge structure (XANES) shows that a Ti atom replaces Al in the AlN crystal and forms localized distorted tetrahedral TiN species, leading to a tensile strain. The bond lengths (Ti-N)ax and (Ti-N)bs are found to be moderately decreased with increasing Ti concentration, which is extracted from the extended X-ray absorption fine structure (EXAFS) analysis. However, the Ti-Al bond length in the second coordination sphere having Al vacancies is unaffected by Ti concentration. The hardness (H) and modulus (E) of Al1-xTixN films are measured by the nano-indentation technique, and increase from 17.5 to 27.6 GPa and 231 to 293 GPa, respectively with x = 0 to 4 at% because of the improvement of p-d hybridization between the Ti and N atoms. PMID- 30465675 TI - An overview on enhancing the stability of lead halide perovskite quantum dots and their applications in phosphor-converted LEDs. AB - Beyond the unprecedented success achieved in photovoltaics (PVs), lead halide perovskites (LHPs) have shown great potential in other optoelectronic devices. Among them, nanometer-scale perovskite quantum dots (PQDs) with fascinating optical properties including high brightness, tunable emission wavelength, high color purity, and high defect tolerance have been regarded as promising alternative down-conversion materials in phosphor-converted light-emitting diodes (pc-LEDs) for lighting and next-generation of display technology. Despite the promising applications of perovskite materials in various fields, they have received strong criticism for the lack of stability. The poor stability has also attracted much attention. Within a few years, numerous strategies towards enhancing the stability have been developed. This review summarizes the mechanisms of intrinsic- and extrinsic-environment-induced decomposition of PQDs. Simultaneously, the strategies for improving the stability of PQDs are reviewed in detail, which can be classified into four types: (1) compositional engineering; (2) surface engineering; (3) matrix encapsulation; (4) device encapsulation. Finally, the challenges for applying PQDs in pc-LEDs are highlighted, and some possible solutions to improve the stability of PQDs together with suggestions for further improving the performance of pc-LEDs as well as the device lifetime are provided. PMID- 30465676 TI - An ultrasensitive electrochemical immunoassay based on a proximity hybridization triggered three-layer cascade signal amplification strategy. AB - In this paper, an ultrasensitive electrochemical immunoassay was constructed for the determination of carcinoembryonic antigen (CEA) based on a proximity hybridization-triggered three-layer cascade signal amplification strategy. In the presence of CEA and two antibody-labeled DNA strands (Ab-DNA1 and Ab-DNA2), a sandwich proximate complex was formed which could hybridize with the hairpin DNA (HP1) and open it, initiating the degradation process of exonuclease III (Exo III) accompanied by the release of a sandwich proximate complex used for Cycle I and autogenous yield of a DNA fragment. The fragment was then employed as a ST DNA (secondary target DNA fragment) for the subsequent binding to the other hairpin DNA (HP2) on the gold (Au) electrode surface to trigger the catalytic hairpin assembly (CHA, Cycle II) and rolling circle amplification (RCA). After the immersion of the above final electrode into methylene blue (MB) solution, an amplified signal was obtained. The proposed electrochemical immunoassay had a good linear relationship in the CEA concentration from 10 fg mL-1 to 100 ng mL-1, and the limit of detection (LOD) was found to be 4.2 fg mL-1. Moreover, with the excellent sensitivity and selectivity based on a three-layer cascade signal amplification strategy, the developed electrochemical immunoassay can pave the way for analysis of other biomarkers. PMID- 30465677 TI - Comparing sulfidation kinetics of silver nanoparticles in simulated media using direct and indirect measurement methods. AB - Reported reaction kinetics of metal nanoparticles in natural and engineered systems commonly have used proxy measurements to infer chemical transformations, but extension of these methods to complex media has proven difficult. Here, we compare the sulfidation rate of AgNPs using two ion selective electrode (ISE) based methods, which rely on either (i) direct measurement of free sulfide, or (ii) monitor the free Ag+ available in solution over time in the presence of sulfide species. Most experiments were carried out in moderately hard reconstituted water at pH 7 containing fulvic acid or humic acid, which represented a broad set of known interferences in ISE. Distinct differences in the measured rates were observed between the two proxy-based methods and details of the divergent results are discussed. The two ISE based methods were then compared to direct monitoring of AgNP chemical conversion to Ag2S using synchrotron-based in situ X-ray diffraction (XRD). Using XRD, distinct rates from both ISE-based technique were observed, which demonstrated that ISE measurements alone are inadequate to discriminate both the rate and extent of AgNP sulfidation. XRD rate data elucidated previously unidentified reaction regimes that were associated with AgNP coating (PVP and citrate acid) and NOM components, which provided new mechanistic insight into metallic NP processing. In general, the extent of Ag2S formation was inversely proportional to surface coverage of the initial AgNP. Overall, methods to determine reaction kinetics of nanomaterials in increasingly complex media and heterogeneous size distributions to improve NP-based design and performance will require similar approaches. PMID- 30465678 TI - Changes in the nutrients of camels' milk alter the functional features of the intestine microbiota. AB - Heat treatment alters the nutritive quality of camels' milk and thus the intestine microbiota, but the effect of heat treatment-induced nutrient loss on the functional features of the intestine microbiota is unknown. In this study, the influence of two heat treatments of camels' milk on the intestine microbiota was investigated to establish the correlations between milk nutrients and the functional features of the intestine microbiota. Camels' milk, heat treated at low (65 degrees C) or high (100 degrees C) temperatures, was administered to mice (LM = low; HM = high); control mice received sterile distilled water (CW = control). Intestine microbiota were compared in the three groups using metagenomic-based 16S rRNA gene high throughput sequencing. The results showed that the relative abundance of probiotic genera (Akkermansia, Bifidobacterium and Lactobacillus) was significantly higher in the LM group mice than in the HM group mice, due to the high-temperature degradation of the nutrients of camels' milk. The diversity of the intestine microbiota in mice receiving milk was lower than in the control group because of the intrinsically high antimicrobial components (lactoferrin and lysozyme) detected in camels' milk. Carbohydrate digestion/absorption, and cysteine and methionine metabolism were significantly higher in the intestine microbiota of the LM group mice than in the HM group mice owing to the corresponding degradation of lactose, cysteine and methionine in camels' milk at high temperatures. Changes in the nutrients of camels' milk affected the changes in the functional features of the intestine microbiota. This research suggests that low temperature heat treatment achieves nutrient preservation, but also encourages probiotic genera. PMID- 30465679 TI - Feature optimization for atomistic machine learning yields a data-driven construction of the periodic table of the elements. AB - Machine-learning of atomic-scale properties amounts to extracting correlations between structure, composition and the quantity that one wants to predict. Representing the input structure in a way that best reflects such correlations makes it possible to improve the accuracy of the model for a given amount of reference data. When using a description of the structures that is transparent and well-principled, optimizing the representation might reveal insights into the chemistry of the data set. Here we show how one can generalize the SOAP kernel to introduce a distance-dependent weight that accounts for the multi-scale nature of the interactions, and a description of correlations between chemical species. We show that this improves substantially the performance of ML models of molecular and materials stability, while making it easier to work with complex, multi component systems and to extend SOAP to coarse-grained intermolecular potentials. The element correlations that give the best performing model show striking similarities with the conventional periodic table of the elements, providing an inspiring example of how machine learning can rediscover, and generalize, intuitive concepts that constitute the foundations of chemistry. PMID- 30465680 TI - Six-coordinate [CoIII(L)2]z (z = 1-, 0, 1+) complexes of an azo-appended o aminophenolate in amidate(2-) and iminosemiquinonate pi-radical (1-) redox levels: the existence of valence-tautomerism. AB - Aerobic reaction of the ligand H2L1, 2-(2-phenylazo)-anilino-4,6-di-tert butylphenol, CoCl2.6H2O and Et3N in MeOH under refluxing conditions produces, after work-up and recrystallization, black crystals of [Co(L1)2] (1). When examined by cyclic voltammetry, 1 displays in CH2Cl2 three one-electron redox responses: two oxidative, E11/2 = 0.30 V (peak-to-peak separation, DeltaEp = 100 mV) and E21/2 = 1.04 V (DeltaEp = 120 mV), and one reductive E1/2 = -0.27 V (DeltaEp = 120 mV) vs. SCE. Consequently, 1 is chemically oxidized by 1 equiv. of [FeIII(eta5-C5H5)2][PF6], affording the isolation of deep purple crystals of [Co(L1)2][PF6].2CH2Cl2 (2), and one-electron reduction with [CoII(eta5-C5H5)2] yielded bluish-black crystals of [CoIII(eta5-C5H5)2][Co(L1)2].MeCN (3). A solid sample of 1 exhibits temperature-independent (50-300 K) magnetism, revealing the presence of a free radical (S = 1/2), which exhibits an isotropic EPR signal (g = 2.003) at 298 K and at 77 K an eight-line feature characteristic of hyperfine interaction of the radical with the Co (I = 7/2) nucleus. Based on X-ray structural parameters of 1-3 at 100 K, magnetic and EPR spectral behaviour of 1, and variable-temperature (233-313 K) 1H NMR spectral features of 1-3 and 13C NMR spectra at 298 K of 2 and 3 in CDCl3 point to the electronic structure of the complexes as either [CoIII{(LAP)2-}{(LISQ)}-] or [CoIII{(L1)2}3-] (delocalized nature favours the latter description) (1), [CoIII{(LISQ)-}2][PF6].2CH2Cl2 (2) and [CoIII(eta5-C5H5)2][CoIII{(LAP)2-}2].MeCN (3) [(LAP)2- and (LISQ)- represent the redox-level of coordinated ligands o-amidophenolate(2-) ion and o iminobenzosemiquinonate(1-) pi-radical ion, respectively]. Notably, all the observed redox processes are ligand-centred. To the best of our knowledge, this is the first time that six-coordinate complexes of a common tridentate o aminophenolate-based ligand have been structurally characterized for the parent 1, its monocation 2 and the monoanion 3 counterparts. Temperature-dependent 1H NMR spectra reveal the existence of valence-tautomeric equilibria in 1-3. Density Functional Theory (DFT) calculations at the B3LYP-level of theory corroborate the electronic structural assignment of 1-3 from experimental data. The origins of the observed UV-VIS-NIR absorptions for 1-3 have been assigned, based on time dependent (TD)-DFT calculations. PMID- 30465681 TI - Multicomponent reactions: a sustainable tool to 1,2- and 1,3-azoles. AB - Multicomponent reactions (MCRs) have emerged as an efficient and eco-safe approach in organic synthesis. The influential nature of this approach has been well established in the fields of drug discovery, catalysis, materials science, and pharmaceutical and combinatorial chemistry. Not surprisingly, the development of multicomponent reactions leading to 1,2/1,3-azoles has expanded rapidly over the last few years. Despite their myriad synthetic applications, there is yet no exclusive review on the MCRs concerning the synthesis of 1,2/1,3-azoles. Therefore, this critical review covers the journey of MCRs to 1,2/1,3-azoles including the synthetic strategies, scope, reaction conditions, rationale behind the choice of catalyst and the proposed mechanism. PMID- 30465682 TI - Correction: Self-adaptive multiscaling algorithm for efficient simulations of many-protein systems in crowded conditions. AB - Correction for 'Self-adaptive multiscaling algorithm for efficient simulations of many-protein systems in crowded conditions' by Sergio A. Hassan et al., Phys. Chem. Chem. Phys., 2018, DOI: 10.1039/c8cp05517c. PMID- 30465683 TI - Direct halosulfenylation of benzo[b]furans: a metal-free synthesis of 3-halo-2 thiobenzo[b]furans. AB - The first example of the direct halosulfenylation of benzo[b]furans with commercially available disulfides and N-halosuccinimides has been achieved, providing an efficient metal-free synthetic pathway to access diverse 3-halo-2 thiobenzo[b]furans in moderate to excellent yields. In particular, a halogen (e.g., bromo or iodo) substituent on the benzo[b]furan ring is amenable for further synthetic elaborations thereby broadening the diversity of the products. PMID- 30465684 TI - Synthesis of organic-inorganic hybrids via a high-pressure-ramp process: the effect of inorganic nanoparticle loading on structural and photochromic properties. AB - Organic polymerization remains a limiting step in the preparation of organic inorganic hybrid materials with a strong concentration of the inorganic component. In this work, a high-pressure-ramp process was applied to achieve pHEMA-TiO2 nanoparticulate solids with an unprecedentedly high concentration (12 mol l-1) of the inorganic component, which is four times higher than that obtained after radical polymerization induced thermally or by photons. The inorganic nanoparticles underwent morphological and structural changes with an increase of Ti concentration above 1.5 mol l-1: they slightly coarsen and crystallize into an anatase polymorph. The material possesses a strong photochromic response related to the electron-hole separation at the organic inorganic interface and can store 1e- per 5 Ti atoms. The electron storage capacity of the titania nanoparticles decreases upon crystallization. PMID- 30465685 TI - Significantly enhanced magnetoresistance in monolayer WTe2via heterojunction engineering: a first-principles study. AB - The large non-saturating magnetoresistance (MR) of bulk WTe2 is known to be greatly reduced in thin films with decreasing thickness. In this study, based on first-principles calculations, we demonstrate that 2D WTe2 bonded to graphene, through a WTe2/graphene van der Waals (vdW) heterojunction, can exhibit a significantly enhanced MR, which can be even larger than that of bulk WTe2. Moreover, the MR shows a strong stacking-orientation-dependent behavior, which facilitates a tunable MR effect. Our findings illustrate a new route to enhancing the MR of WTe2 and other 2D semimetals via heterojunction engineering, which is useful for a range of applications in information technology. PMID- 30465686 TI - Ferromagnetism in magnesium chloride monolayer with an unusually large spin-up gap. AB - The primary research target of the rapidly evolving spintronic industry is to design highly efficient novel materials that consume very low power and operate with high speed. Main group based ferromagnetic half-metallic materials are very promising due to their long spin-relaxation time. In recent years, the discovery of superconducting state with high critical temperature in a magnesium based system (MgB2) invigorated researchers due to its simple crystal structure and intriguing results, leading to its use as a good material for large scale application in electronic devices. Here, we report ferromagnetism and strong half metallicity in another Mg-based system, which can be a promising material for spintronics based devices rather than for electronic devices (such as MgB2). Based on the first principle calculations, we report here a series of magnetic half-metallic magnesium chloride based monolayers [Mg0.89delta0.11Cl2, Mg0.78delta0.22Cl2, and Mg0.67delta0.33Cl2 (MgCl3)]. This MgCl3 phase has a similar pattern as that in CrI3, which has drawn remarkable attention worldwide as the first intrinsic 2D magnet. These magnesium chloride monolayer based systems are 100% spin-polarized, and promising for scattering-less transport due to strong half-metallicity and large spin-up gap (~6.135-6.431 eV). The unusually large spin-up gap in our proposed system may shield spin current leakage even in nanoscale device. Further investigation explores a ferromagnetic ordering in Mg0.89delta0.11Cl2 with a Curie temperature of 250 K, which makes the system viable for operation at temperatures slightly lower than the room temperature. High magnetic anisotropy energy (MAE) in Mg0.89delta0.11Cl2 (452.84 MUeV) indicates that the energy required to flip the spin is high, and therefore inhibits spin fluctuation. These results suggest a promising way to discover MgCl2-based 2D spin valves, GMR, TMR and other spintronics devices. PMID- 30465687 TI - The structure-property relationship in LAPONITE(r) materials: from Wigner glasses to strong self-healing hydrogels formed by non-covalent interactions. AB - Rheology, small-angle X-ray scattering (SAXS), and dynamic light scattering (DLS) analysis, zeta potential measurement, scanning electron microscopy (SEM), and micro-FTIR and absorbance spectroscopy were used to enlighten the controversial literature about LAPONITE(r) materials. Our data suggest that pristine LAPONITE(r) in water does not form hydrogels induced by the so-called "house of cards" assembly, but rather forms Wigner glasses governed by repulsive forces. Ionic interactions between anisotropic LAPONITE(r) nanodiscs, sodium polyacrylate and inorganic salts afforded hydrogels that were transparent, self-standing, moldable, strong, and biocompatible with shear-thinning and self-healing behavior. An extensive study on the role of salts in the gelification process dictates a trend that relates the valence of cations with the viscoelastic properties of the bulk material (G' values follow the trend, monovalent < divalent < trivalent). These hydrogels present G' values up to 5.1 * 104 Pa, which are considered high values for non-covalent hydrogels. Hydrogels crosslinked with sodium phosphate salts are biocompatible, and might be valid candidates for injectable drug delivery systems due to their shear-thinning behavior with rapid self-healing after injection. PMID- 30465688 TI - An in vitro exploratory study of dietary strategies based on polyphenol-rich beverages, fruit juices and oils to control trimethylamine production in the colon. AB - Trimethylamine-N-oxide (TMAO) has been described as a new biomarker of cardiovascular disease (CVD), derived from gut microbial biotransformation of dietary choline and l-carnitine into trimethylamine (TMA) and subsequent hepatic oxidation. (Poly)phenols are among the dietary factors able to interfere with microbial enzymatic activity, possibly modulating TMA biotransformation at the gut level. The aim of this work was to investigate the in vitro biotransformation of choline and carnitine using faecal starters obtained from omnivorous and vegetarian subjects and the effect of (poly)phenol-rich foods on TMA production. Choline and l-carnitine were fermented with vegetarian or omnivorous faecal slurries, alone or in combination with 10 (poly)phenol-rich food items. TMA production from carnitine, but not from choline, was significantly lower when vegetarian faecal starters were used and, among the tested food items, blonde orange juice significantly reduced TMA formation during faecal biotransformation. Consequently, the main compounds of orange juice, namely phenolic compounds, terpenes, limonoids, organic acids and sugars, were tested individually. Sugars exerted the highest inhibitory effect on TMA production. Despite some limitations deriving from the applied in vitro model, this is the first work describing a possible role of some (poly)phenol-rich dietary products on the modulation of TMA colonic production. Free sugars were the main factor responsible for TMA inhibition, suggesting a potential beneficial role of colonic fermentation of carbohydrates in reducing TMA formation from its precursor molecules. This work opens new research directions to evaluate the effect of dietary fermentable fibre on TMA production and, potentially, on circulating TMAO levels. PMID- 30465689 TI - 90-90-90 by 2020? Estimation and projection of the adult HIV epidemic and ART programme in Zimbabwe - 2017 to 2020. AB - INTRODUCTION: The 90-90-90 targets set by the United Nations aspire to 73% of people living with HIV (PLHIV) being virally suppressed by 2020. Using the HIV Synthesis Model, we aim to mimic the epidemic in Zimbabwe and make projections to assess whether Zimbabwe is on track to meet the 90-90-90 targets and assess whether recently proposed UNAIDS HIV transition metrics are likely to be met. METHODS: We used an approximate Bayesian computation approach to identify model parameter values which result in model outputs consistent with observed data, evaluated using a calibration score. These parameter values were then used to make projections to 2020 to compare with the 90-90-90 targets and other key indicators. We also calculated HIV transition metrics proposed by UNAIDS (percentage reduction in new HIV infections and AIDS-related mortality from 2010 to 2020, absolute rate of new infections and AIDS-related mortality, incidence mortality ratio and incidence-prevalence ratios). RESULTS: After calibration, there was general agreement between modelled and observed data. The median predicted outcomes in 2020 were: proportion of PLHIV (aged 15 to 65) diagnosed 0.91 (90% uncertainty range 0.87, 0.94) (0.84 men, 0.95 women); of those diagnosed, proportion on treatment 0.92 (0.90, 0.93); of those receiving treatment, proportion with viral suppression 0.86 (0.81, 0.91). This results in 72% of PLHIV having viral suppression in 2020. We estimated a percentage reduction of 36.5% (13.7% increase to 67.4% reduction) in new infections from 2010 to 2020, and of 30.4% (9.7% increase to 56.6% reduction) in AIDS-related mortality (UNAIDS target 75%). The modelled absolute rates of HIV incidence and AIDS-related mortality in 2020 were 5.48 (2.26, 9.24) and 1.93 (1.31, 2.71) per 1000 person-years respectively. The modelled incidence-mortality ratio and incidence-prevalence ratios in 2020 were 1.05 (0.46, 1.66) and 0.009 (0.004, 0.013) respectively. CONCLUSIONS: Our model was able to produce outputs that are simultaneously consistent with an array of observed data and predicted that while the 90-90-90 targets are within reach in Zimbabwe, increased efforts are required in diagnosing men in particular. Calculation of the HIV transition metrics suggest increased efforts are needed to bring the HIV epidemic under control. PMID- 30465690 TI - Fast and Furious: A neglected issue in health promotion among young drivers. AB - ISSUES ADDRESSED: This paper investigates the influence of mood while driving, advocates for identifying high-risk groups, and detects associations between mood while driving and risky driving behaviours. While commensurate studies regarding aggressive driving have confirmed significant detriments in driving performance, little scholarly research has studied the gaps and opportunities at the intersection of mood and risky driving in young drivers. METHODS: A cross sectional design was implemented using 660 young drivers (17-25 years) from Australia (34.7%) and Colombia (65.3%), who completed the Behaviour of Young Novice Drivers Scale (BYNDS). Cluster analysis differentiated young drivers across two groups: high risk and low risk driving whilst influenced by mood. Hierarchical segmentation analysis explored the relationship between driver mood and self-reported risky driving behaviour. RESULTS: Young drivers reported frequent driving whilst influenced by mood. The typical risky driving behaviours of young drivers who are emotion-affected are transient violations (e.g., speeding) and risky exposure (e.g., driving tired). CONCLUSIONS: Risky driving behaviours that have been found to increase the risk of road injury (speeding, fatigued driving) and to decrease the survivability of road crashes (speeding) are inextricably intertwined with the influence of driver mood upon driving behaviour at an international level. Driver mood is a neglected issue in health promotion programs for young drivers. SO WHAT?: Current health promotion interventions for young drivers safety such as Graduated Driver Licensing (GDL) may not prevent driving whilst influenced by mood. Additional strategies are required to minimise the exposure to driving whilst affected by negative mood. This article is protected by copyright. All rights reserved. PMID- 30465691 TI - Database establishment for the secondary fungal DNA barcode -Translational Elongation Factor 1alpha (TEF1alpha). AB - With new or emerging fungal infections, human/animal fungal pathogens are a growing threat worldwide. Current diagnostic tools are slow, non-specific at the species and subspecies levels, and require specific morphological expertise to accurately identify pathogens from pure cultures. DNA barcodes are easily amplified, universal, short species-specific DNA sequences, which enable rapid identification by comparison with a well-curated reference sequence collection. The primary fungal DNA barcode, ITS region, was introduced in 2012 and is now routinely used in diagnostic laboratories. However, the ITS region only accurately identifies around 75% of all medically relevant fungal species, which has prompted the development of a secondary barcode to increase the resolution power and suitability of DNA barcoding for fungal disease diagnostics. The translational elongation factor 1alpha (TEF1alpha) was selected in 2015 as a secondary fungal DNA barcode, but has not been implemented into practice, due to the absence of a reference database. Here, we have established a quality controlled reference database for the secondary barcode which together with the ISHAM-ITS database, forms the "ISHAM BARCODE DATABASE", available online at: http://its.mycologylab.org/. We encourage the mycology community for active contributions. The application of a dual DNA barcoding system enables accurate identification of all clinically important fungal pathogens. PMID- 30465692 TI - Long-acting reversible contraception in adolescents in Sub-Saharan Africa: evidence from demographic and health surveys. AB - OBJECTIVE: To explore (1) long-acting reversible contraception (LARC) use and (2) future contraceptive preferences in Sub-Saharan African adolescents as undesired pregnancies in Sub-Saharan African adolescents are associated with significant maternal/neonatal morbidity. METHODS: Nationally-representative Demographic and Health Surveys (USAID) obtained informed consent and interviewed 45,054 adolescents, including 19,561 (43.4% of total) sexually active adolescents (aged 15-19) from 18 least developed Sub-Saharan African nations regarding contraception (years 2005-2011, response rate 89.8-99.1% for all women interviewed). Frequencies and percentages of contraceptive use, prior pregnancies, and unwanted births were reported. Categorical variables were analyzed through chi2 and unadjusted and binary logistic regression, adjusted for confounders, evaluated LARC use. RESULTS: A majority of sexually active adolescents were not using contraception (n = 16,165 non-users; 82.6% of all sexually active adolescents). Many (n = 8465, 43.3% of sexually active adolescents) interviewed already had at least one child, with 31.5% (n = 2646) of those with previous children reporting the pregnancy was not wanted at the time it occurred. Sexually active adolescents using contraception (n = 3384) used LARCs (injectable contraception, implants, or intrauterine devices; 29.8%, n = 1007) barrier contraceptives (31.9%), oral contraceptives (10.9%), and other methods (27.4%). Adolescents using LARCs were more likely to be urban [OR 1.76 (95% CI 1.39-2.22)], to have been visited by a family planning worker in the last 12 months [OR1.62 (95% CI 1.24-2.11)], and to have visited a health facility in the past 12 months [OR1.84 (95% CI 1.53-2.21)]. Injectable contraception was the most preferred (39.9%, n = 3036) future method by sexually-active non contracepting adolescents who were asked about future methods (n = 7605) compared to other methods. An unfortunate percentage of adolescents surveyed cannot read (35.7%, n = 16,084). CONCLUSION: A majority of sexually-active adolescents in Sub Saharan Africa are not using contraception and are desirous of doing so. Offering LARCs during post-abortive or postpartum care with particular focus on rural adolescents may reduce undesired pregnancy and subsequent morbidity/mortality. Educational materials should limit printed information as many teens are unable to read. PMID- 30465693 TI - An orthotopic non-small cell lung cancer model for image-guided small animal radiotherapy platforms. AB - METHODS:: An orthotopic non-small cell lung cancer model in NMRI-nude mice was established to investigate the complementary information acquired from 80 kVp microcone-beam CT (micro-CBCT) and bioluminescence imaging (BLI) using different angles and filter settings. Different micro-CBCT-based radiation-delivery plans were evaluated based on their dose-volume histogram metrics of tumor and organs at risk to select the optimal treatment plan. RESULTS:: H1299 cell suspensions injected directly into the lung render exponentially growing single tumor nodules whose CBCT-based volume quantification strongly correlated with BLI-integrated intensity. Parallel-opposed single angle beam plans through a single lung are preferred for smaller tumors, whereas for larger tumors, plans that spread the radiation dose across healthy tissues are favored. CONCLUSIONS:: Closely mimicking a clinical setting for lung cancer with highly advanced preclinical radiation treatment planning is possible in mice developing orthotopic lung tumors. ADVANCES IN KNOWLEDGE:: BLI and CBCT imaging of orthotopic lung tumors provide complementary information in a temporal manner. The optimal radiotherapy plan is tumor volume-dependent. PMID- 30465694 TI - Elucidating performance failures in use of granular sludge for nutrient removal from domestic wastewater in a warm coastal climate region. AB - The effects of domestic wastewater and a coastal warm climate on granular sludge and biological nutrient removal were evaluated using a pilot-scale sequencing batch reactor (SBR). The reactor operation employed two different operational strategies (OS) based on up-flow feeding regimes, defined as fast (OS1, flow rate = 18.0 L min-1 and flow velocity = 22.0 m h-1) and slow (OS2, flow rate = 3.5 L min-1 and flow velocity = 4.3 m h-1). Under slow feeding, larger (OS1: 290 um; OS2: 450 um) and faster settling granules were obtained (OS1: 109; OS2: 74 mL g-1 TSS). The slow feeding regime was also advantageous for the hydrolysis of particulate organic matter (OS1: 1.3; OS2: 3.1 g CODtot g-1 VSS d-1) and for phosphorus removal (OS1: <33%; OS2: >97.5%). Neither strategy resulted in substantial biomass accumulation in the reactor (OS1: 0.7; OS2: 1.5 g VSS L-1), and high concentrations of nitrite were observed in the effluent (9-27 mg NO2--N L-1). Ordinary heterotrophic organisms dominated the granular sludge developed under both feeding regimes (OS1: 30% of Thauera; OS2: 56% of Comamonas), while polyphosphate-accumulating organisms (PAOs) were only detected during OS2 (2.3 3.4% of total bacteria). A successful granular sludge process should be able to cope with high fluctuations in wastewater loads caused by rain events (82-182 mm month-1 in Florianopolis, Brazil). In order to achieve higher water quality, strategies identified for an efficient granular sludge SBR operation included (i) management of an anaerobic phase for PAO selection, and (ii) aeration control for successful nitrification/denitrification. PMID- 30465695 TI - A low cost stereophotogrammetric system for the evaluation of tridimensional head translations during visual tasks. AB - A simple, low cost and easy-to-operate 3D stereophotogrammetry system was developed to measure the kinematic pattern of head stabilisation during visual tasks. The system differs from commercially available ones since it: (a) takes into account the gaze motor coordination characteristics and measures the head translations quantified at the point that best represents the translations caused by the eyes' movement during visual tasks, that is, the midpoint between the eyes; (b) offers minimum restriction to the head movement and minimum interference with it; (c) innovates when using the position coordinates produced by a free-online tracker software. The system was effective in recording the head movements and its RMS total error was 0.705 mm with +/-0.808 mm standard deviation. This represents an RMS total error of 3.5%, considered satisfactory because it provided results with a confidence level higher than 95%. The system was effective to record differences in head movements of 11 individuals in open and closed eyes conditions and revealed the direction-specific feature of the head displacements size. The results showed that the system is a cost-effective and accurate alternative for studies needing to accurately measure head movements during visual tasks. PMID- 30465697 TI - For Science, King and Country: The Life and Legacy of Henry Moseley. PMID- 30465696 TI - Functional interplay between ribosomal protein paralogues in the eRpL22 family in Drosophila melanogaster. AB - Duplicated ribosomal protein (RP) genes in the Drosophila melanogaster eRpL22 family encode structurally-divergent and differentially-expressed rRNA-binding RPs. eRpL22 is expressed ubiquitously and eRpL22-like expression is tissue restricted with highest levels in the adult male germline. We explored paralogue functional equivalence using the GAL4-UAS system for paralogue knockdown or overexpression and a conditional eRpL22-like knockout in a heat- shock flippase/FRT line. Ubiquitous eRpL22 knockdown with Actin-GAL4 resulted in embryonic lethality, confirming eRpL22 essentiality. eRpL22-like knockdown (60%) was insufficient to cause lethality; yet, conditional eRpL22-like knockout at one hour following egg deposition caused lethality within each developmental stage. Therefore, each paralogue is essential. Variation in timing of heat-shock-induced eRpL22-like knockout highlighted early embryogenesis as the critical period where eRpL22-like expression (not compensated for by eRpL22) is required for normal development of several organ systems, including testis development and subsequent sperm production. To determine if eRpL22-like can substitute for eRpL22, we used Actin-GAL4 for ubiquitous eRpL22 knockdown and eRpL22-like-FLAG (or FLAG-eRpL22: control) overexpression. Emergence of adults demonstrated that ubiquitous eRpL22 like-FLAG or FLAG-eRpL22 expression eliminates embryonic lethality resulting from eRpL22 depletion. Adults rescued by eRpL22-like-FLAG (but not by FLAG-eRpL22) overexpression had reduced fertility and longevity. We conclude that eRpL22 paralogue roles are not completely interchangeable and include functionally diverse roles in development and spermatogenesis. Testis-specific paralogue knockdown revealed molecular phenotypes, including increases in eRpL22 protein and mRNA levels following eRpL22-like depletion, implicating a negative crosstalk mechanism regulating eRpL22 expression. Paralogue depletion unmasked mechanisms, yet to be defined that impact paralogue co-expression within germ cells. PMID- 30465698 TI - Treatment continuation and satisfaction in women using combined oral contraception with nomegestrol acetate and oestradiol: a multicentre, prospective cohort study (BOLERO). AB - OBJECTIVE: The aim of the study was to examine treatment continuation and satisfaction over 1 year among women receiving nomegestrol acetate (NOMAC)/oestradiol (E2) combined oral contraception (COC) in real-world clinical practice. METHODS: The 17beta-Estradiol and Nomegestrol Acetate (BOLERO) Study is an observational, non-interventional, prospective, multicentre cohort study of premenopausal women (aged 18-50 years) who received prescription NOMAC/E2 (2.5 mg/1.5 mg) for contraception during routine clinical practice. Assessments were carried out at enrolment and at 3, 6 and 12 months. Probability of treatment continuation through 12 months (primary outcome) was examined using Kaplan-Meier survival analysis. Secondary outcomes included treatment satisfaction, menstrual cycle-related symptoms, libido and adverse events (AEs). RESULTS: Of 298 enrolled women, 292 were evaluable. The probability of NOMAC/E2 continuation through 12 months was 73.7% (95% confidence interval [CI] 68.0%, 78.5%). Satisfaction with NOMAC/E2 increased from 56.9% (37/65) of women at initial evaluation to 89.2% (58/65) of women at 12 months. Physician ratings at 12 months showed satisfactory to very satisfactory in 84.0% (168/200) of women. Libido was not affected. Menstrual cycle-related symptoms significantly declined from enrolment (6.04 +/- 4.32) to 3 months (3.25 +/- 3.05) and 12 months (2.62 +/- 2.74; p < .0001). Treatment-related AEs were reported by 38.7% (113/292) of women. CONCLUSION: The real-world experience of women receiving NOMAC/E2 indicated very good treatment continuation, high satisfaction and significantly improved menstrual cycle related symptoms. PMID- 30465699 TI - Neuropsychological Evaluation of Somatoform and Other Functional Somatic Conditions. PMID- 30465700 TI - Epilepsy detection from EEG signals: a review. AB - Over many decades, research is being attempted for the detection of epileptic seizure to support for automatic diagnosis system to help clinicians from burdensome work. In this respect, an enormous number of research papers is published for identification of epileptic seizure. It is difficult to present a detailed review of all these literature. Therefore, in this paper, an attempt has been made to review the detection of an epileptic seizure. More than 100 research papers have been discussed to discern the techniques for detecting the epileptic seizure. Further, the literature survey shows that the pattern recognition required to detect epileptic seizure varies with different conditions of EEG datasets. This is mainly due to the fact that EEG detected under different conditions has different characteristics. This is, in turn, necessitates the identification of pattern recognition technique to effectively distinguish EEG epileptic data from a various condition of EEG data. PMID- 30465701 TI - Not All Clots Are Created Equal: A Review of Deficient Thrombolysis with Tissue Plasminogen Activator (tPA) in Patients with Metabolic Syndrome. AB - Metabolic syndrome is a cluster of cardiovascular risk factors associated with a prothrombotic, proinflammatory and hypofibrinolysis state. Although resistance to tissue plasminogen activator (tPA) in metabolic syndrome patients has been associated with a defective fibrinolytic system, the factors and mechanisms underlining such resistance is unclear. While there is a great debate on proposed mechanisms, fundamental questions regarding resistance to tPA in metabolic syndrome patients with ischemic stroke remain unanswered. This paper reviews articles and documents published between 2001 to 2017, and provides an overview of metabolic syndrome, factors associated with tPA resistance in metabolic syndrome, conflicting evidence of insufficient dosing of tPA in overweight/obese patients and future directions for research. PMID- 30465702 TI - A Prospective Study of Environmental Exposures and Early Biomarkers in Autism Spectrum Disorder: Design, Protocols, and Preliminary Data from the MARBLES Study. AB - BACKGROUND: Until recently, environmental factors in autism spectrum disorder (ASD) were largely ignored. Over the last decade, altered risks from lifestyle, medical, chemical, and other factors have emerged through various study designs: whole population cohorts linked to diagnostic and/or exposure-related databases, large case-control studies, and smaller cohorts of children at elevated risk for ASD. OBJECTIVES: This study aimed to introduce the MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) prospective study and its goals, motivate the enhanced-risk cohort design, describe protocols and main exposures of interest, and present initial descriptive results for the study population. METHODS: Families having one or more previous child with ASD were contacted before or during a pregnancy, and once the woman became pregnant, were invited to enroll. Data and biological samples were collected throughout pregnancy, at birth, and until the child's third birthday. Neurodevelopment was assessed longitudinally. The study began enrolling in 2006 and is ongoing. RESULTS: As of 30 June 2018, 463 pregnant mothers have enrolled. Most mothers ([Formula: see text]) were thirty years of age or over, including 7.9% who are fourty years of age or over. The sample includes 22% Hispanic and another 25% nonHispanic Black, Asian, or multiracial participants; 24% were born outside the United States. Retention is high: 84% of participants whose pregnancies did not end in miscarriage completed the study or are still currently active. Among children evaluated at 36 months of age, 24% met criteria for ASD, and another 25% were assessed as nonASD nontypical development. CONCLUSION: Few environmental studies of ASD prospectively obtain early-life exposure measurements. The MARBLES study fills this gap with extensive data and specimen collection beginning in pregnancy and has achieved excellent retention in an ethnically diverse study population. The 24% familial recurrence risk is consistent with recent reported risks observed in large samples of siblings of children diagnosed with ASD. https://doi.org/10.1289/EHP535. PMID- 30465703 TI - Assessment of the environmental impact and economic benefits of the adoption of cleaner production in a Brazilian metal finishing industry. AB - The Metal Finishing Industry (MFI) use water and several chemicals in its production chain, which generatesboth liquid and solid hazardous waste. The present study evaluatesthe economic and environmental advantages of implementing cleaner production (CP) in a Brazilian MFI specialized in chrome and zinc. For the economic assessment, we adopted the measures of return on investment and internal rate of return. In order to measure the environmental impact, we used the Mass Intensity Factor. A case study methodology was adopted, with datacollectedthrough observation and semi-structured interviews. The findings indicate that the adoption of CPin this sector encourages the deployment of a Rising Cascades System in Counterflow (RCSC) to minimize water consumption through the reuse and segregation of hazardous solid waste (sludge). The sludge generated may be sold as a byproduct for the production of ceramics. We identifiedopportunities to reduce costs by minimizing waste, although this does require investment. However, the return on such investments mayenable the implementation of CP. The reduction in environmental impact on the ecosystem was significant, with large reductions in hazardous components contained in the sludge being dumped in the environment. The results may guide the development of public policies in Brazil, particularly in the adoption of CP in MFI to disseminate environmental education and increase governmental control. PMID- 30465704 TI - A novel EOG-based wireless rapid communication device for people with motor neuron diseases. AB - In this study, a new electrooculography (EOG) based system that provides efficient communication for people suffered from motor neuron diseases is presented. The system consists of two distinct devices. The first device operates as a main unit that is activated by the subject's eye movements. This unit is capable of transmitting 10 different command/state messages. These messages enable subject to choose his/her situation such as "I'm fine", "I feel bad", "I'm hungry" and "I'm thirsty". Commands such as "Come", "Go". The number of messages can be increased. The main unit acquires the EOG signal from the subject. Newly developed analogue and digital signal conditioning interprets the eye movements as specific messages and transmits them to the second unit (receiver) using radio frequency transmitter. The messages related to the subject's demands and situation can be heard from both main and receiver unit speakers. The wireless receiver unit is capable of notifying the patient's command by auditory and visual indicators. The realised device was tested by 2 healthy and 2 ALS patients and confirmed to be successful with 100% performance for sending correct messages. PMID- 30465705 TI - Review of the therapeutic neurofeedback method using electroencephalography: EEG Neurofeedback. AB - Electroencephalographic neurofeedback (EEG-NFB) represents a broadly used method that involves a real-time EEG signal measurement, immediate data processing with the extraction of the parameter(s) of interest, and feedback to the individual in a real-time. Using such a feedback loop, the individual may gain better control over the neurophysiological parameters, by inducing changes in brain functioning and, consequently, behavior. It is used as a complementary treatment for a variety of neuropsychological disorders and improvement of cognitive capabilities, creativity or relaxation in healthy subjects. In this review, various types of EEG-NFB training are described, including training of slow cortical potentials (SCPs) and frequency and coherence training, with their main results and potential limitations. Furthermore, some general concerns about EEG NFB methodology are presented, which still need to be addressed by the NFB community. Due to the heterogeneity of research designs in EEG-NFB protocols, clear conclusions on the effectiveness of this method are difficult to draw. Despite that, there seems to be a well-defined path for the EEG-NFB research in the future, opening up possibilities for improvement. PMID- 30465706 TI - Future of assisted dying reform in Australia. AB - The Voluntary Assisted Dying Act 2017 (Vic) will come into force in June 2019, becoming the first law in Australia in 20 years to permit voluntary assisted dying (VAD). This paper considers how other Australian states and territories are likely to respond to this development. It analyses three key factors that suggest that law reform is likely to occur in other parts of Australia: (1) the growing international trend to permit VAD; (2) social science evidence about how VAD regimes operate; and (3) changes to the local political environment. The paper argues that these three factors, coupled with the effect of Victoria changing its law, suggest that other VAD law reform is likely to occur in Australia. It also considers the different types of laws that may be adopted, including whether other states and territories will follow the very conservative Victorian approach or adopt more liberal models.What is known about the topic? Despite sustained law reform efforts in parliaments across the country, Victoria is the first Australian jurisdiction to pass a law permitting VAD in 20 years.What does this paper add? This paper addresses likely future trends in VAD law reform in Australia. Drawing on international developments, a growing body of social science evidence about how VAD regimes work in practice, and evidence about a changing local political environment, the paper argues that other states and territories in Australia will also enact laws about VAD.What are the implications for practitioners? The legalisation of VAD has significant implications for health professionals, health administrators and health systems. Understanding how reform may occur and what legal models may be considered supports participation in the law reform process and preparation for likely change. PMID- 30465707 TI - Progress on Active Analgesic Components and Mechanisms of Commonly Used Traditional Chinese Medicines: A Comprehensive Review. AB - Many clinical diseases are accompanied by the symptoms of pain, and the degree of pain is closely related to the patients' suffering. Therefore, effectively relieving pain has become one of the vital concerns of clinical treatment and analgesic drug research. Non-opioid drugs are mainly used for the clinical treatment of mild to moderate pain, whereas opioid drugs are mainly used for treating moderate to severe pain. However, opioid drugs easily elicit adverse reactions, such as gastrointestinal discomfort, addiction, dependence, and so on. Traditional Chinese medicine and its active ingredients have unique advantages in the treatment of pain for quite a long time, and many analgesic drugs directly or indirectly were isolatiedfrom Chinese medicine or natural products, such as Liu Suan Yan Hu Suo Yi Su Pian and aspirin. With the development and modernization of research on herbal medicine more and more studies have been conducted on the active ingredients and mechanisms of traditional Chinese medicine analgesics. However, no review has been done on analgesic active components and their mechanisms. In this paper, 81 active components with clear chemical structure and definite analgesic effects in vivo and in vitro of traditional Chinese medicine and mechanisms of action reported in recent literatures are reviewed and summarized to provide reference for clinical analgesia and analgesics research. PMID- 30465708 TI - STAT3 is involved in IL-6-Mediated Downregulation of Hepatic Transporters in Mice. AB - : Interleukin (IL)-6 decreases hepatic expression of numerous transporters. Although IL-6 signaling occurs through STAT3, the extent of the involvement of the STAT3 signaling pathway has not been elucidated. PURPOSE: Our objective was to investigate whether IL-6-mediated effects occur through STAT3, and whether PXR plays a role in this regulation. METHOD: PXR null (-/-) or wild-type (+/+) male mice were pre-dosed with a selective STAT3 inhibitor S3I-201 (7.5 mg/kg ip) or vehicle (n=5-8/group) 30 minutes before receiving a single dose of IL-6 (1 ug ip) or saline. Animals were sacrificed after 6 hours and liver samples were analyzed using qRT-PCR and western blotting. RESULTS: As compared to saline controls, IL-6 decreased the expression of Cyp3a, Abcb1a, Abcc3, and Slco1a4 20-70% similarly in PXR (+/+) and (-/-) mice at 6 hr, while downregulation of Abcb11, Abcc2, Slc10a1and Slco2b1 was only seen in PXR (+/+). Pre-administration of S3I-201 attenuated IL-6-mediated changes of most transporters in PXR (+/+) and PXR (-/-) mice. At early times after IL-6 administration (10-120 minutes), transcript levels of Socs3, PXR, Abcb1a, Abcc3, Abcb11, Slco1a4 and Slco2b1were increased in PXR (+/+) mice. CONCLUSIONS: Our findings demonstrate that IL-6 imposes a significant downregulation of numerous ABC and SLC transporters in liver primarily through activation of the STAT3 signaling pathway. Based on time dependent changes in transporter expression, downregulation likely occurs downstream of STAT3 activation. As IL-6 is elevated in many diseases, understanding the underlying mechanism(s) involved in transporter dysregulation will allow us to predict potential drug-disease interactions. PMID- 30465709 TI - An Unsupervised Smart App-Optimized HIV Self-Testing Program in Montreal, Canada: Cross-Sectional Study. AB - BACKGROUND: Although HIV self-testing strategies have been recommended by the World Health Organization, HIV self-tests are not yet approved in Canada. Currently approved HIV self-tests offer toll-free lines that are insufficient for initiating expedited linkages to counseling and care, accurate interpretation, and support during HIV self-testing. We developed an innovative, multilingual software app called HIVSmart! to plug these gaps. OBJECTIVE: This study aimed to test our app-optimized oral HIV self-testing strategy for feasibility in men who have sex with men (MSM) who presented to test at a large sexual health clinic (Clinique Medicale L'Actuel) in Montreal. METHODS: Between July 2016 and February 2017, we offered a strategy consisting of the OraQuick In-Home HIV Test (an investigational device) and a tablet installed with the HIVSmart! app to study participants, who presented at a private office in the clinic, mimicking an unsupervised home environment. We evaluated the strategy for its feasibility, acceptability, and preference. Using the HIVSmart! app, participants were guided through the self-testing process. We determined feasibility with a metric defined as the completion rate, which consisted of the following 3 steps: (1) self-test conduct; (2) self-test interpretation; and (3) linkages to care. Participants independently performed, interpreted, recorded their self-test and result, engaged in pre- and posttest counseling, and sought linkages to care. Laboratory tests (p24, Western Blot, and RNA), as per country algorithms, were expedited, and linkages based on the rapid test status were arranged. RESULTS: Mean age of the 451 participants enrolled was 34 (range, 18-73) years. Of all participants, 97.1% (438/451) completed and submitted the survey through the HIVSmart! app. In total, 84.7% (371/438) of the participants were well educated (beyond high school) and 52.5% (230/438) had been tested within the past 6 months. Of the 451, 11.5% (52/451) were on pre-exposure prophylaxis. Feasibility (completion rate), an average proportion of the 3 steps, was computed to be 96.6% (419/451). The acceptability of the strategy was high at 98.5% (451/458). A majority of the participants (448/451, 99.3%) were found to be self-tested and lab-confirmed negative and were counseled after self- and rapid tests. In total, 0.7% (3/451) of the participants who self-tested positive and were lab-confirmed positive were linked to a physician within the same day. Furthermore, 98.8% (417/422) of the participants found the app to be useful and 94.0% (424/451) were willing to recommend it to a friend or partner. CONCLUSIONS: The HIVSmart! app-optimized strategy was feasible, accepted, and preferred by an educated, urban MSM population of Montreal. With the app, participants were able to perform, interpret, store results, and get rapidly linked to care. The HIVSmart! optimized, self-testing strategy could be adapted and contextualized to many at risk populations within Canada and worldwide, thereby maximizing its public health impact. PMID- 30465710 TI - Synthetic biology of B cell activation: understanding signal amplification at the B cell antigen receptor using a rebuilding approach. AB - Upon activation of the B cell antigen receptor (BCR), the spleen tyrosine kinase (Syk) and the Src family kinase Lyn phosphorylate tyrosines of the immunoreceptor tyrosine-based activation motif (ITAM) of Igalpha and Igbeta which further serve as binding sites for the SH2 domains of these kinases. Using a synthetic biology approach, we dissect the roles of different ITAM residues of Igalpha in Syk activation. We find that a leucine to glycine mutation at the Y+3 position after the first ITAM tyrosine prevents Syk binding and activation. However, a preactivated Syk can still phosphorylate this tyrosine in trans. Our data show that the formation of a Syk/ITAM initiation complex and trans-ITAM phosphorylation is crucial for BCR signal amplification. In contrast, the interaction of Lyn with the first ITAM tyrosine is not altered by the leucine to glycine mutation. In addition, our study suggests that an ITAM-bound Syk phosphorylates the non-ITAM tyrosine Y204 of Igalpha only in cis. Collectively, our reconstitution experiments suggest a model whereby first trans phosphorylation amplifies the BCR signal and subsequently cis-phosphorylation couples the receptor to downstream signaling elements. PMID- 30465711 TI - Unforgettable force - crosstalk and memory of mechanosensitive structures. AB - The ability of cells to sense and respond to mechanical stimuli is crucial for many developmental and homeostatic processes, while mechanical dysfunction of cells has been associated with numerous pathologies including muscular dystrophies, cardiovascular defects, and epithelial disorders. Yet, how cells detect and process mechanical information is still unclear. In this review, we outline major mechanisms underlying cellular mechanotransduction and we summarize the current understanding of how cells integrate information from distinct mechanosensitive structures to mediate complex mechanoresponses. We also discuss the concept of mechanical memory and describe how cells store information on previous mechanical events for different periods of time. PMID- 30465712 TI - Facile generation of antibody heavy and light chain diversities for yeast surface display by Golden Gate Cloning. AB - Antibodies can be successfully engineered and isolated by yeast or phage display of combinatorial libraries. Still, generation of libraries comprising heavy chain as well as light chain diversities is a cumbersome process involving multiple steps. Within this study, we set out to compare the output of yeast display screening of antibody Fab libraries from immunized rodents that were generated by Golden Gate Cloning with the conventional three step method of individual heavy- and light chain sub-library construction followed by chain combination via yeast mating. We demonstrate that the Golden Gate Cloning-based one-step process delivers libraries and antibodies from heavy- and light chain diversities with similar quality to the traditional method while being significantly less complex and faster. Additionally, we show that this method can also be used to successfully screen and isolate chimeric chicken/human antibodies following avian immunization. PMID- 30465713 TI - Conversion of chenodeoxycholic acid to cholic acid by human CYP8B1. AB - The human cytochrome P450 enzyme CYP8B1 is a crucial regulator of the balance of cholic acid (CA) and chenodeoxycholic acid (CDCA) in the liver. It was previously shown to catalyze the conversion of 7alpha-hydroxycholest-4-en-3-one, a CDCA precursor, to 7alpha,12alpha- dihydroxycholest-4-en-3-one, which is an intermediate of CA biosynthesis. In this study we demonstrate that CYP8B1 can also convert CDCA itself to CA. We also show that five derivatives of luciferin are metabolized by CYP8B1 and established a rapid and convenient inhibitor test system. In this way we were able to identify four new CYP8B1 inhibitors, which are aminobenzotriazole, exemestane, ketoconazole, and letrozole. PMID- 30465714 TI - Liquid biopsy: novel technologies and clinical applications. AB - "Liquid biopsy" was introduced as a new diagnostic concept in 2010 for the analysis of circulating tumor cells (CTCs) and has been now extended to material (in particular DNA) released by tumor cells in the peripheral blood of cancer patients. Over the past decade, various methods have been developed to detect CTCs and ctDNA in the peripheral blood of cancer patients. PMID- 30465715 TI - The long way to standardization of practices: HbA1c as archetypal example. PMID- 30465716 TI - Gerard Siest Prize awarded to Alzbeta Hlavackova at the 9th Santorini Conference. PMID- 30465717 TI - Willingness-to-pay threshold for preventing spurious hemolysis during blood sample collection. PMID- 30465718 TI - A Serious Flaw in Nutrition Epidemiology: A Meta-Analysis Study. AB - Background Many researchers have studied the relationship between diet and health. Specifically, there are papers showing an association between the consumption of sugar sweetened beverages and Type 2 diabetes. Many meta-analyses use individual studies that do not attempt to adjust for multiple testing or multiple modeling. Hence the claims reported in a meta-analysis paper may be unreliable as the base papers do not ensure unbiased statistics. Objective Determine (i) the statistical reliability of 10 papers and (ii) indirectly the reliability of the meta-analysis study. Method We obtained copies of each of the 10 papers used in a metaanalysis paper and counted the numbers of outcomes, predictors, and covariates. We estimate the size of the potential analysis search space available to the authors of these papers; i. e. the number of comparisons and models available. The potential analysis search space is the number of outcomes times the number of predictors times 2 c , where c is the number of covariates. This formula was applied to information found in the abstracts (Space A) as well as the text (Space T) of each base paper. Results The median and range of the number of comparisons possible across the base papers are 6.5 and (2 12,288), respectively for Space A, and 196,608 and (3072-117,117,952), respectively for Space T. It is noted that the median of 6.5 for Space A may be misleading as each study has 60-165 foods that could be predictors. Conclusion Given that testing is at the 5% level and the number of comparisons is very large, nominal statistical significance is very weak support for a claim. The claims in these papers are not statistically supported and hence are unreliable so the meta-analysis paper is also unreliable. PMID- 30465719 TI - Assessment of dental caries and gingival status among a group of type 1 diabetes mellitus and healthy children of South India - a comparative study. AB - Background Diabetes mellitus is a metabolic disorder. However, dental caries and periodontal health have not attracted much interest in diabetic patients. This study was carried out to assess the dental caries status and gingival health status in children with type 1 diabetes mellitus (T1DM). Methods The study group consisted of 80 children, aged 6-18 years, with T1DM. The dental caries status was recorded using the World Health Organisation (WHO) criteria. Gingival health was assessed using the Loe and Silness gingival index (GI). Data obtained were subjected to statistical analysis. Results The mean dental caries status for primary (decayed, extracted, filled teeth [deft]) and permanent dentition (decayed, missing, filled teeth [DMFT]) scores in diabetic children were 0.44+/ 1.28 and 1.26+/-2.49, respectively. The GI scores of diabetic children were 0.33+/-0.48. GI in the study group significantly correlated with DMFT (p<0.001) and deft (p<=0.05). Conclusions Dental caries in primary dentition was lower in diabetic children but was not statistically significant, whereas dental caries in permanent dentition was significantly higher. The gingival condition of diabetic children was healthy. PMID- 30465720 TI - Chronic Widespread Pain in a tertiary pain clinic: classification overlap and use of a patient generated quality of life instrument. AB - Background and aims This study has two main aims: (1) To explore the overlap between classification criteria in patients with Chronic Widespread Pain (CWP) and (2) To explore the use of the Patient Generated Index (PGI) as a quality of life (QoL) measure in this patient group. Methods Patients with Widespread Pain (ICD-11: pain in four or more out of five bodily regions, i.e. the four quadrants and axially) in a tertiary pain outpatient clinic were assessed according to classification criteria for Fibromyalgia [FM, American College of Rheumatology (ACR) criteria of 1990, 2010, 2011 and 2016], Chronic Fatigue Syndrome [CFS, Fukuda, Canada and International Consensus Criteria (ICC)] and Bodily Distress Syndrome (BDS). Furthermore, patients completed the PGI to assess QoL, and electronic questionnaires including demographic variables and standardised patient-reported outcome measures (PROMs). Results All patients (n=33) fulfilled the criteria for musculoskeletal type single-organ BDS, 81.8% met the 2016 modified criteria for FM, 30.3% met the Canada criteria for CFS and 24.2% met the criteria for multi-organ type BDS. There was substantial agreement between the 2016 and the 2011 and 2010 criteria sets for FM compared to the 1990 criteria (kappa=0.766 and 0.673 compared to 0.279). Patients generally scored low on the PGI, indicating poor QoL (mean PGI 28.9, SD 19.8, range 0-100). Conclusions Our findings support the use of the term musculoskeletal type single-organ BDS to describe patients with CWP and the 2016 revision of the FM criteria. The PGI provides useful clinical information which is not captured by standardised PROMs. Implications The terminology of CWP has become less ambiguous as the new ICD-11 is closely related to the generalised pain criterion of the modified 2016 FM definition. Studies based on the 1990 classification criteria for FM should not be directly compared to studies based on later criteria set. The PGI may be a supplement to other measurements to portray patients' individual concerns in patients with complex symptom disorders. PMID- 30465721 TI - Quantifying ventilatory control stability from spontaneous sigh responses during sleep: a comparison of two approaches. AB - RATIONALE: Ventilatory control instability is an important factor contributing to the pathogenesis of periodic breathing (PB) and other forms of sleep-related breathing disorders (SRBD). The development of tools for the quantification of such instabilities from non-invasive respiratory measurements during sleep could be useful to clinicians in identifying subjects that are at risk of developing SRBD. OBJECTIVES: To present and compare two different mathematical modeling approaches that allow the quantification of ventilatory control stability from the ventilatory responses to spontaneous sighs. MEASUREMENTS AND METHODS: Breath by-breath measurements of normalized ventilation were derived from respiratory inductance plethysmography (RIP) traces collected during sleep from a cohort of 19 preterm infants with various degrees of periodic breathing. A hypothesis-based minimal closed-loop model consisting of a gain, time-constant and time delay; and a data-driven autoregressive model with time delay were used to fit the ventilatory responses to the spontaneous sighs. Loop gain, a quantitative measure of ventilatory control stability, was extracted from both models. RESULTS AND DISCUSSION: Both approaches accurately described the ensuing responses to the sighs. Significant and robust correlations were found in the loop gain estimates extracted with the two models in the frequency range spanning 2-8 cycles min-1, which corresponds to PB cycling oscillations in infants. In addition, the hypothesis-based model showed a decreased within-subject variability of the estimated stability quantifiers, while the data-driven better resembled the experimental data. There are advantages and limitations associated with each of the modeling approaches which are discussed in the paper. CONCLUSIONS: The agreement found between the two mathematical models indicates that either methodology can be used indistinctively providing reliable results and their application can expand to sigh data from other clinical cohorts of preterm infants. PMID- 30465722 TI - Dexamethasone Reduces the Incidence of Postoperative Nausea and Vomiting in Children Undergoing Endoscopic Adenoidectomy under General Anesthesia Without Increasing the Risk of Postoperative Hemorrhage. AB - BACKGROUND Postoperative nausea and vomiting (PONV) is a common complication of pediatric anesthesia, but the overall incidence of PONV in patients undergoing adenoidectomy is unknown. The aim of this controlled study was to compare the effect of dexamethasone administration with placebo to reduce PONV in children undergoing endoscopic adenoidectomy under general anesthesia. MATERIAL AND METHODS A randomized placebo-controlled study included 118 pediatric patients who underwent elective endoscopic adenoidectomy under general anesthesia. A dexamethasone-treated (0.15 mg/kg) group (Group D) (n=56) and a placebo group (Group C) (n=62) were randomly assigned. The incidence of nausea and vomiting was recorded on the day of surgery. Postoperative nausea was assessed according to illustrated Baxter Animated Retching Faces (BARF) scale. The Face, Legs, Activity, Cry, and Consolability (FLACC) scale (scores between 0-10) was used to assess pain. Follow-up was performed on the 14th postoperative day by a telephone call. RESULTS Overall prevalence of postoperative nausea was 25% (30/118) and postoperative vomiting was 14% (17/118). In the first 24 hours following surgery, in Group D, the incidence of nausea and vomiting was 13% and 7%, respectively; in Group C, without pharmacological prophylaxis, the incidence of postoperative nausea and vomiting was 37%, and 21%, respectively. CONCLUSIONS A prospective controlled study in children undergoing endoscopic adenoidectomy under general anesthesia showed that dexamethasone (0.15 mg/kg) significantly reduced the incidence of PONV without increasing the risk of postoperative hemorrhage. Dexamethasone is a safe method for the prevention of PONV that may be recommended in pediatric anesthesiology. PMID- 30465723 TI - Aquaporins in human platelets: intracellular localization and possible role in granule and lysosome secretion. AB - This study was undertaken to establish the presence and the role of aquaporins (AQPs) in human platelets. Immunodetection with polyclonal antibodies and fluorescent microscopy suggest the presence of AQP isoforms - 0-7 and 9-12 - localized (in resting platelets) in the plasma membrane and in the dense and alpha granules. In thrombin- or monensin-treated platelets, the granules' AQPs become visible in the whole cell body, indicating the granules' swelling. In our studies on the role of AQPs in platelet responses we used tetrachloroauric acid (HAuCl4), a classical water channel blocker. We found that 10-100 uM of Au(III) inhibited the hypotonicity-, monensin (simulating the action of Na+/H+ exchanger) , and collagen-evoked platelet swelling and reduced tritiated water uptake by platelets treated by collagen or monensin, indicating its ability to block water channels in these cells. HAuCl4, at the concentrations reducing water influx, did not induce cell lysis, alter the plasma membrane shape or the -SH group content. The inhibitor also failed to affect Na+ and Cl--related osmotic gradient formation and protein kinase D2 phosphorylation. In platelets activated by threshold concentrations of collagen, the thrombin receptor activating peptide, ADP, calcium ionophore A23187, phorbol ester and arachidonic acid, HAuCl4 (100 uM) completely inhibited secretion of ATP from dense granules but failed to reduce platelet aggregation. In collagen-stimulated platelets, HAuCl4 (10-100 uM) reduced secretion from dense and alpha granules, as well as lysosomes, in a dose dependent manner. We conclude that human platelets possess numerous AQPs subtypes localized in the plasma and granule membranes. AQP-mediated water fluxes may be crucial for platelet volume regulation as well as secretion from dense and alpha granules and lysosomes. PMID- 30465724 TI - Collection planning for the next 100 years: What will we commit to save in zoos and aquariums? AB - The "sustainability crisis" in zoos and aquariums has been a sobering reminder of how limited our resources are for maintaining viable populations of species threatened with extinction. This, combined with increasing concern among the public about the value of zoos and aquariums, suggests that the zoological profession should engage in a thorough re-examination of our guiding principles, philosophies, and practices with regard to collection planning at global, regional, and institutional scales. An analysis of AZA cooperative breeding programs reveals that in order to make these populations viable, many more founders and tens of thousands more spaces for animals, either in existing facilities or new ones, are necessary if we want to maintain all of the species that are covered by cooperative breeding programs currently. Regional zoological associations and their associated cooperative breeding programs must be more strategic and make more scientifically defensible decisions about which species to try and safeguard in zoos and aquariums. This would enable the zoological profession to give society a "Promise List" of species that we will commit to save from total extinction. Developing such a list will require a collaborative, inclusive process that transcends zoological regions. Regional association leaders, zoo & aquarium directors, and curators must make commitments to safeguard the species on the Promise List regardless of other interests. As our profession re-examines its philosophies and practices and finds ways to increase its capacity to provide refuge for species facing extinction in the wild, it may be possible to expand the Promise List. PMID- 30465725 TI - Approaches to studying behavior in captive sloth bears through animal keeper feedback. AB - Animal keepers at zoos and wildlife rescue centers often possess in-depth knowledge of the health and behavior of the individuals under their care. While it is often not feasible for keepers to regularly collect behavior data through formal scientific methods, efforts should be made to find alternative means to capture this knowledge. We investigated the use of keeper feedback to study the behavior of sloth bears at the Agra Bear Rescue Facility (ABRF; Agra, India). We prepared a survey with 5 questions focused on behaviors indicative of playfulness, boldness, aggressiveness, and the tendency to express self-directed behaviors (SDB). We asked keepers to rate bears on a Likert scale from 1 (least likely to exhibit a behavior) to 5 (most likely) for 44 adult female bears (5-21 years of age). We validated this method by comparing keeper ratings of SDB with formal behavior observations, finding that time of day had an influence on the accuracy of keeper assessments. We found a significant negative correlation between housing bears in larger groups (>15) and SDB. In addition, we correlated ratings given by keepers for all study behaviors. Social play had significant negative correlation with aggression toward people. There was no correlation between social play and aggression toward other bears, possibly due to the existence of cohesive social groups in group housing or high dimensionality of the data. We found that keeper feedback is an efficient tool to gather behavior data on captive sloth bears and recommend its use in future studies. PMID- 30465726 TI - Use of molecular data in zoo and aquarium collection management: Benefits, challenges, and best practices. AB - The global zoo and aquarium community widely recognizes that its animal collections and cooperative breeding programs are facing a sustainability crisis. It has become commonly accepted that numerous priority species cannot be maintained unless new management strategies are adopted. While molecular data have the potential to greatly improve management across a range of scenarios, they have been generally underutilized by the zoo and aquarium community. This failure to effectively apply molecular data to collection management has been due, in part, to a paucity of resources within the community on which to base informed decisions about when the use of such data is appropriate and what steps are necessary to successfully integrate data into management. Here, we identify three broad areas of inquiry where molecular data can inform management: 1) taxonomic identification; 2) incomplete or unknown pedigrees; and 3) hereditary disease. Across these topics, we offer a discussion of the advantages, limitations, and considerations for applying molecular data to ex situ animal populations in a style accessible to zoo and aquarium professionals. Ultimately, we intend for this compiled information to serve as a resource for the community to help ensure that molecular projects directly and effectively benefit the long term persistence of ex situ populations. PMID- 30465727 TI - Oral reserpine administration in horses results in low plasma concentrations that alter platelet biology. AB - BACKGROUND: Reserpine is a popular drug in the equine industry for long-term tranquilisation. Clinical observations revealed that blood from horses receiving oral reserpine was hypercoagulable. No studies have documented the pharmacokinetics of orally administered reserpine nor the effects of reserpine on platelets in horses. OBJECTIVES: To evaluate the pharmacokinetics of oral reserpine in horses and the effects of clinically relevant concentrations of reserpine on platelet functionality in vitro. STUDY DESIGN: Experimental controlled study. METHODS: The pharmacokinetics of oral reserpine (2.5 mg/horse, once) were determined in six healthy adult horses. Plasma samples were collected and concentrations of reserpine determined by UPLC-MS/MS. Using this data, the in vitro effects of reserpine on platelets were examined. Aggregation, adhesion, and releasate assays for serotonin and thromboxane B2 were performed on platelets exposed to varying concentrations of reserpine (0.01-10 ng/mL), aspirin (negative control) and saline (unexposed control). RESULTS: Oral reserpine administration demonstrated low plasma concentrations with a Cmax of 0.2 +/- 0.06 ng/mL and a prolonged half-life of 23.6 +/- 6.24 h. Simulations over a dose range of 2-8 MUg/kg predicted Cmax at steady state between 0.06-0.9 ng/mL. Platelets exposed to these reserpine concentrations in vitro displayed increased aggregation and adhesion compared to unexposed or aspirin-exposed platelets as well as compared to higher concentrations of reserpine. These functional changes correlated with lower concentrations of serotonin and higher concentrations of thromboxane B2 in the platelet suspension supernatant. MAIN LIMITATIONS: This study used a small number of horses and only in vitro platelet experiments. CONCLUSIONS: Oral reserpine demonstrates low plasma concentrations and a prolonged half-life in horses. At these concentrations, reserpine causes significant changes in platelet function, most likely due to serotonin release and re-uptake which primes platelets for activation and thromboxane B2 release. These findings suggest that clinicians should harvest blood for biological processing prior to the onset of reserpine administration. This article is protected by copyright. All rights reserved. PMID- 30465728 TI - CTLA-4 polymorphism rs231775: influence on relapse and survival after allogeneic hematopoietic stem cell transplantation in childhood. AB - OBJECTIVE: Relapse following allogeneic hematopoietic stem cell transplantation (HSCT) is still linked to a poor prognosis. Mainly, donor's T-cells mediate the graft-versus-leukemia effect. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is an inhibitory molecule which down-regulates T-cell activation. Single nucleotide polymorphism (SNP) in CTLA-4 may have an effect on immune response. METHODS: Eighty-eight children with acute leukemia and their donors were genotyped of CTLA 4 gene for rs231775. We searched for an association of CTLA-4 SNP with relapse and survival after allogeneic HSCT. RESULTS: We identified a significantly reduced relapse rate in children who received a transplant from a donor with the CTLA-4 genotypes AG or GG in comparison to genotype AA of rs231775 (19% versus 40%, P =.026). In addition, we observed a significant difference in event-free survival (EFS) depending on the donor's genotype. The EFS was 70% or 46% if the patient was transplanted from a donor with CTLA-4 genotype AG/GG or AA, respectively (P =.025). In multivariate analysis, CTLA-4 genotype was an independent risk factor for relapse rate (P = .028). CONCLUSION: This study suggests that CTLA-4 polymorphism rs231775 is relevant for relapse and survival after allogeneic HSCT in childhood and should be further investigated in clinical trials. This article is protected by copyright. All rights reserved. PMID- 30465729 TI - Atomically Well-Ordered Structure at Solid Electrolyte and Electrode Interface Reduces the Interfacial Resistance. AB - Using synchrotron surface X-ray diffraction, we investigated the atomic structures of the interfaces of a solid electrolyte (Li3PO4) and electrode (LiCoO2). We prepared two types of interfaces with high and low interface resistances; the low-resistance interface exhibited a flat and well-ordered atomic arrangement at the electrode surface, whereas the high-resistance interface showed a disordered interface. These results indicate that the crystallinity of LiCoO2 at the interface has a significant impact on interface resistance. Furthermore, we reveal that the migration of Li ions along the interface and into grain boundaries and antiphase domain boundaries is a critical factor reducing interface resistance. PMID- 30465730 TI - Preparation and Characterization of Solid Supported Lipid Bilayers Formed by Langmuir-Blodgett Deposition - a Tutorial. AB - The structure, phase behavior and properties of cellular membranes are derived from their composition, which includes phospholipids, sphingolipids, sterols, and proteins with various levels of glycosylation. Due to the intricate nature of cellular membranes, a plethora of in vitro studies have been carried out with model membrane systems that capture particular properties such as fluidity, permeability, or protein binding, but vastly simplify the membrane composition in order to focus in detail on a specialized property or function. Supported lipid bilayers (SLB) are widely used as archetypes for cellular membranes and this instructional review primarily focuses on the preparation and characterization of SLB systems formed by Langmuir deposition methods. Typical characterization methods, which take advantage of the planar orientation of SLBs, are illustrated and references that go into more depth are included. The instructional review is written so that non-experts can quickly gain an in-depth knowledge regarding the preparation and characterization of SLBs. In addition, this work goes beyond traditional instructional reviews to provide expert readers with new results that cover a wider range of SLB systems than those previously reported in the literature. The quality of an SLB is frequently not well described and details, such as topological defects, can influence the results and conclusions of an individual study. This paper quantifies and compares the quality of SLBs fabricated from a variety of gel and fluid compositions, in correlation with preparation techniques and parameters, to generate general rules of thumb to guide construction of designed SLB systems. PMID- 30465731 TI - Mineral pollutants removal through immobilized microalgae-bacterial flocs in a multitrophic microreactor. AB - Microalgae-bacterial flocs (MaB-flocs) immobilization technique using polyvinyl alcohol (PVA) crosslinked with sodium alginate represent a novel approach for sustainable pollutants removal. The present work was performed to evaluate the performance of a multitrophic batch reactor at microscale for treating two synthetic wastewater solutions prepared with two different initial Chemical Oxygen Demand (COD): 200 mg.L-1 and 450 mg.L-1, respectively. Three MaB-flocs concentrations were entrapped into PVA-alginate beads: C1 (2%, v/v), C2 (5%, v/v) and C3 (10%, v/v), without O2 supply, during three periods 2, 4 and 6 days of batch incubation. PVA-alginate beads containing the highest concentration C3 of MaB-flocs improved the performance of the microreactor to remove significantly NH4+ and PO43- of about 61% and 82%, respectively, from wastewater more than two other concentrations used. This result confirms that C3 of MaB-flocs displays not only a good potential for nutrients removals but also the highest MaB-flocs morphological progression after 6 days of treatment with the highest COD of 450 mg.L-1. The feasibility of the PVA-alginate for cells immobilization, investigated through microscopy analysis, reveals that the evolution of multicellularity in MaB-flocs, for all experiments. PMID- 30465732 TI - L4 stage Heligmosomoides polygyrus prevents the maturation of dendritic JAWS II cells. PMID- 30465733 TI - Side population cells in anaplastic thyroid cancer and normal thyroid. AB - Comparison of studies of cells derived from normal and pathological tissues of the same organ can be fraught with difficulties, particular with cancer where a number of different diseases are considered cancer within the same tissue. In the thyroid, there are 4 main types of cancer, three of which arise from follicular epithelial cells; papillary and follicular which are classified as differentiated, and anaplastic which is classified as undifferentiated. One assay that can be utilised for isolation of cancer stem cells is the side population (SP) assay. However, SP studies have been limited in part due to lack of optimal isolation strategies and in the case of anaplastic thyroid cancer (ATC) are further compounded by lack of access to ATC tumors. We have used thyroid cell lines to determine the optimal conditions to isolate viable SP cells. We then compared SP cells and NSP cells (bulk tumour cells without the SP) of a normal thyroid cell line N-thy ori-3-1 and an anaplastic thyroid cancer cell line SW1736 and showed that both SP cell populations displayed higher levels of stem cell characteristics than the NSP. When we compared SP cells of the N-thy ori-3-1 and the SW1736, the SW1736 SP had a higher colony forming potential, expressed higher levels of stem cell markers and CXCR4 and where more migratory and invasive, invasiveness increasing in response to CXCL12. This is the first report showing functional differences between ATC SP and normal thyroid SP and could lead to the identification of new therapeutic targets to treat ATC. PMID- 30465734 TI - Significance of Postinfectious Irritable Bowel Syndrome? PMID- 30465735 TI - Significance of post-infectious Irritable Bowel Syndrome? PMID- 30465736 TI - Fluorescent peptides for imaging of fungal cells. AB - Fungal infections, especially with the advent of antimicrobial resistance, represent a major burden to our society. As a result, there has been an increasing interest in the development of new probes that accelerate the study of fungi-related biological processes and facilitate novel clinical diagnostic and treatment strategies. Fluorescence-based reporters can provide dynamic information at the molecular level with high spatial resolution. However, conventional fluorescent probes for microbes often suffer from low specificity. In the last decade, numerous studies have been reported on the chemical design and application of fluorescent peptides for both in vitro and in vivo imaging of fungal cells. In this article, we review different strategies used in the preparation of fluorescent peptides for pathogenic fungi as well as some of their applications in medical imaging and in mode-of-action mechanistic studies. PMID- 30465737 TI - Cleavage of loops 1 and 2 in skeletal muscle heavy meromyosin (HMM) leads to a decreased function. AB - BACKGROUND: The mechanical work and the actin-activated ATP kinetics in skeletal muscles are closely associated with two surface loops that are present in the myosin molecule: loop 1 and loop 2. They are located close to the ATP-loop (loop 1), and the actin binding domain (loop 2). In this study we investigated the roles of loops 1 and 2 in the regulation of the load-dependent velocity of actin sliding and ATPase activity. METHODS: Heavy meromyosin (HMM) from rabbit skeletal muscle was subjected to limited tryptic proteolysis to obtain fragments containing different amounts of loops 1 and 2. The amino-acid sequences of these fragments were confirmed with quantitative mass-spectrometry. The velocity of actin motility propelled by the HMM fragments was measured using in-vitro motility assays, with varying loads induced by the addition of different concentrations of alpha-actinin. RESULTS: The load-dependent velocity of the myosin-propelled actin motility, and the fraction of actin filaments motility, were decreased in close association with the depletion of loop 1 in the HMM. The ATPase activity was decreased in close association with depletion of loops 1 and 2. CONCLUSIONS: Loop 1 is responsible for regulating the load-dependent velocity of actin motility. GENERAL SIGNIFICANCE: Myosin-actin interaction is closely regulated by two flexible loops in the structure of myosin. The results of this study are important for the understanding of the molecular mechanisms of contraction, and therefore the most basic functions of life, such as locomotion, heart beating, and breathing. PMID- 30465738 TI - Pyrrolizidine alkaloid-induced alterations of prostanoid synthesis in human endothelial cells. AB - Pyrrolizidine alkaloids (PA) are a group of secondary plant metabolites belonging to the most widely distributed natural toxins. PA intoxication of humans leads to severe liver damage, such as hepatomegaly, hepatic necrosis, fibrosis and cirrhosis. An acute consequence observed after ingestion of high amounts of PA is veno-occlusive disease (VOD) where the hepatic sinusoidal endothelial cells are affected. However, the mechanisms leading to VOD after PA intoxication remain predominantly unknown. Thus, we investigated PA-induced molecular effects on human umbilical vein endothelial cells (HUVEC). We compared the effects of PA with the effects of PA metabolites obtained by in vitro metabolism using liver homogenate (S9 fraction). In vitro-metabolized lasiocarpine and senecionine resulted in significant cytotoxic effects in HUVEC starting at 300 MUM. Initial molecular effect screening using a PCR array with genes associated with endothelial cell biology showed PA-induced upregulation of the Fas receptor, which is involved in extrinsic apoptosis, and regulation of a number of interleukins, as well as of different enzymes relevant for prostanoid synthesis. Modulation of prostanoid synthesis was subsequently studied at the mRNA and protein levels and verified by increased release of prostaglandin I2 as the main prostanoid of endothelial cells. All effects occurred only with in vitro metabolically activated PA lasiocarpine and senecionine. By contrast, no effect was observed for the PA echimidine, heliotrine, lasiocarpine, senecionine, senkirkine and platyphylline in the absence of an external metabolizing system up to the highest tested concentration of 500 MUM. Overall, our results confirm the metabolism-dependent toxification of PA and elucidate the involved pathways. These include induction of inflammatory cytokines and deregulation of the prostanoid synthesis pathway in endothelial cells, linking for the first time PA dependent changes in prostanoid release to distinct alterations at the mRNA and protein levels of enzymes of prostanoid synthesis. PMID- 30465739 TI - From Hospital to Home to Participation: A Position Paper on Transition Planning after Stroke. AB - Based on a review of the evidence, members of the American Congress of Rehabilitation Medicine Stroke Group's Movement Interventions Task Force offer these five recommendations to help improve transitions of care for patients and their caregivers: (1) improving communication processes, (2) utilizing transition specialists, (3) implementing a patient-centered discharge checklist, (4) utilizing standardized outcome measures, and (5) establishing partnerships with community wellness programs. Due to changes in healthcare policy, there are incentives to improve transitions during stroke rehabilitation. Although transition management programs often include multidisciplinary teams, medication management, caregiver education, and follow-up care management, there is a lack of a comprehensive and standardized approach to implement transition management protocols during post-stroke rehabilitation. This article uses the Transitions of Care (TOC) model to conceptualize how to facilitate a comprehensive patient centered hand-off at discharge to maximize patient functioning and health. Specifically, this article reviews current guidelines and provides an evidence summary of several commonly cited approaches (early supported discharge, planned pre-discharge home visits, discharge checklists) to manage TOC, followed by a description of documented barriers to effective transitions. Patient-centered and standardized transition management may improve community integration, activities of daily living performance, and quality of life for stroke survivors while also decreasing hospital readmission rates during the transition from hospital to home to community. PMID- 30465740 TI - Efficacy of ivermectin to control Strongyloides stercoralis infection in sheltered dogs. AB - In dogs, information on treatments against S. stercoralis infection is rare and anecdotal. The aim of the present work was to evaluate the treatment outcome of S. stercoralis natural infection in sheltered dogs. Furthermore, based on the potential risk of infection, people working in the infected shelter were also tested. Seventeen sheltered dogs positive to S. stercoralis using the Baermann test were treated with ivermectin 200 MUg/kg/sid/os for two consecutive days. Only two dogs showed clinical signs suggestive of strongyloidiasis (diarrhea, weigh loss) at diagnosis. All dogs showed consistently negative results for S. stercoralis at weekly monitoring after treatment using both the direct microscopy and Baermann test. Real-time PCR confirmed negative results at the last follow up 2 months after treatment. Serology performed at the first diagnosis showed that 82% and 41% of dogs were positive for S. stercoralis using an IFAT (titres ranging from 1:40 to 1:320) and ELISA, respectively. Two months after treatment, IFAT titres were strongly reduced in all animals. The results of clinical pathological laboratory tests at diagnosis in the positive dogs were within normal ranges, except for the two symptomatic dogs. Serum collected from two out of 14 shelter workers tested positive with titres 1:20 and 1:40 for S. stercoralis using an IFAT. Results of the study confirm that ivermectin was an effective treatment option to control S. stercoralis infection in dogs. Shelter workers are at risk of infection with S. stercoralis, thus the application of correct deworming protocols to reduce the environmental infective larval burden is essential to protect dogs and probably also shelter workers from the risk of infection. PMID- 30465741 TI - How rational drug use reduces trypanosome infections in cattle in chemo resistance hot-spot villages of northern Togo. AB - The study assessed an integrated trypanosomosis control strategy in drug resistant hotspot villages of northern Togo. This strategy comprised (i) rational trypanocidal drug use in symptomatic cattle, (ii) vectors and ticks control by targeted bi-monthly insecticidal spraying of the lower body parts of cattle and (iii) strategic deworming with Albendazole in the beginning and the end of the rainy season. The program was implemented between June 2014 and October 2015 in four villages in northern Togo, which had been previously identified as drug resistant hotspots for diminazene diaceturate (DA) and isometamidium chloride (ISM). The integrated control strategy was implemented in eight cattle herds at risk of the disease from two villages. Twelve herds from two other villages served as controls where trypanosomosis management and deworming remained under control of the farmers. Trypanocidal drug use during the study period was recorded by the intervention team based on the farmers' reports and own observations. Cattle herds were followed-up for trypanosomosis symptoms which were recorded at 3 to 4-month intervals, while extensive trypanosome diagnostics and recording of the packed cell volume were done before and after the intervention. Intervention herds had a significantly lower risk of trypanosome infection with a risk ratio of 0.18 (95% CI: 0.04, 0.91; p = 0.03), but no significant effect on mean packed cell volume was observed. However, trypanocidal treatments per animal per year were lower in intervention herds compared to control herds (0.3 vs 5 for DA and 0.8 vs 2 for ISM). This study demonstrates that the implementation of an integrated best-bet strategy leads to a reduced trypanosome prevalence under lowered trypanocidal use. PMID- 30465742 TI - Peridomestic small Indian mongoose: An invasive species posing as potential zoonotic risk for leptospirosis in the Caribbean. AB - In this study, we investigated Leptospira infection and exposure in small Indian mongoose (Herpestes auropunctatus), an invasive animal species, in two different sites in the Caribbean island of Saint Kitts. Overall a low seroprevalence (12/148; 8.1%: 95%CI: 3.7-12.5) was observed. Agglutinating antibodies to serovars Mankarso (3.4%), Copenhageni (2.7%), Icterohemorrhagiae (1.4%), Bratislava (1.4%), Canicola (1.4%), Autumnalis (0.7%), Alexi (0.7%), Pomona (0.7%) and Grippotyphosa (0.7%) was observed on the microscopic agglutination test. The seroprevalence observed in mongooses trapped from peridomestic sites was significantly higher compared to the arid and less inhabited site (p = 0.0268). The real time PCR targeting lipL32 gene was positive for 9 out of 146 mongooses. Bacterial culture of kidneys resulted in two Leptospira isolates. Whole genome sequencing and analysis suggested that these isolates are closely related to L. interrogans serovar Copenhageni. We observed mild to severe chronic renal lesions in 20.2% of mongooses in the absence of an antibody response or active infection. Our findings emphasize the need to investigate other infectious etiologies or atypical outcomes and potential chronic long-term impact of Leptospira infection in animals and people living in an endemic area. In addition, our data reinforces the need for including locally prevalent Leptospira isolates rather than representative members of a serogroup in the microscopic agglutination test panel in epidemiologic and diagnostic investigations. In conclusion, mongoose inhabiting the island are exposed to and harbor pathogenic Leptospira and hence may play a role in the transmission. The invasive nature of the species highlights their presence as a potential risk factor for this widespread zoonotic disease. PMID- 30465743 TI - Novel herpesviruses in riverine and marine cetaceans from South America. AB - Herpesvirus (HV) infections in cetaceans are frequently associated with skin and mucosal lesions. Although HV infections have been reported worldwide, their occurrence in southern Atlantic marine mammals is still poorly understood. We tested skin, oral and genital mucosal beta-actin PCR-positive samples from 109 free-ranging Brazilian cetaceans using a universal herpesvirus DNA polymerase PCR. Herpesvirus-positive skin samples from a Guiana dolphin (Sotalia guianensis), a dwarf sperm whale (Kogia sima), a Bolivian river dolphin (Inia boliviensis), and a lingual sample from an Atlantic spotted dolphin (Stenella frontalis) were histologically evaluated. Additional tissue samples from these animals were also PCR-positive for HV, including a novel sequence obtained from the dwarf sperm whale's stomach and mesenteric lymph node. Four novel HV species were detected in the Guiana dolphin (one), the dwarf sperm whale (two) and the Bolivian river dolphin (one). The cutaneous lesions (marked, focally extensive, chronic proliferative dermatitis) of the Guiana dolphin and the Bolivian river dolphin were similar to previous HV reports in cetaceans, despite the absence of intranuclear inclusion bodies. This is the largest HV survey in South American cetaceans and the first detection of HV infection in riverine dolphins worldwide. PMID- 30465744 TI - Rainfall as a driver of epidemic cholera: Comparative model assessments of the effect of intra-seasonal precipitation events. AB - The correlation between cholera epidemics and climatic drivers, in particular seasonal tropical rainfall, has been studied in a variety of contexts owing to its documented relevance. Several mechanistic models of cholera transmission have included rainfall as a driver by focusing on two possible transmission pathways: either by increasing exposure to contaminated water (e.g. due to worsening sanitary conditions during water excess), or water contamination by freshly excreted bacteria (e.g. due to washout of open-air defecation sites or overflows). Our study assesses the explanatory power of these different modeling structures by formal model comparison using deterministic and stochastic models of the type susceptible-infected-recovered-bacteria (SIRB). The incorporation of rainfall effects is generalized using a nonlinear function that can increase or decrease the relative importance of the large precipitation events. Our modelling framework is tested against the daily epidemiological data collected during the 2015 cholera outbreak within the urban context of Juba, South Sudan. This epidemic is characterized by a particular intra-seasonal double peak on the incidence in apparent relation with particularly strong rainfall events. Our results show that rainfall-based models in both their deterministic and stochastic formulations outperform models that do not account for rainfall. In fact, classical SIRB models are not able to reproduce the second epidemiological peak, thus suggesting that it was rainfall-driven. Moreover we found stronger support across model types for rainfall acting on increased exposure rather than on exacerbated water contamination. Although these results are context-specific, they stress the importance of a systematic and comprehensive appraisal of transmission pathways and their environmental forcings when embarking in the modelling of epidemic cholera. PMID- 30465745 TI - Vector and reservoir surveillance study in a canine and human leishmaniasis endemic area in most western part of Turkey, Karaburun. AB - Leishmaniasis is an arthropod borne disease that is endemic in 102 countries and one and half million new cases are reported each year. Sand flies are the one and only proven vectors of the disease and dogs are the main reservoirs in urban areas. Karaburun peninsula is located in most western part of Turkey and is reported to be an endemic area for human and canine leishmaniasis. The most recent study was undertaken more than 15 years ago in The peninsula and no clear data available for vectors or reservoirs. Thus, we aimed to update the information regarding sand fly diversity, infection status of reservoirs and vectors in the study area. Sand flies were collected using CDC light traps at 13 different sites of Karaburun and species identification was made using previously published keys. Monospecific pools were generated using midguts with blood retention and were screened for the presence of Leishmania spp. DNA by molecular techniques. A non-invasive conjunctival swab sampling was performed to identify the infection status among reservoirs and species typing of the causative agent was also undertaken using ITS1 PCR. Three out of 30 pools were found positive for Leishmania infantum that were generated using guts of Phlebotomus tobbi (n:36). Among all sampled dogs (44) and cats (19), 11 and one of them were found positive for L. infantum, respectively. There was a decrease in the number of P. papatasi during the study period, while increase was observed in the number of P. tobbi. The presence of proven vectors and reservoirs as well as Leishmania DNA in cats was shown in the present study. Sand fly fauna is updated and Leishmania DNA presence in cats was reported in the study area for the first time. PMID- 30465746 TI - Early Detection of Glaucomatous Visual Field Progression Using Pointwise Linear Regression with Binomial Test in the Central 10 Degrees. AB - PURPOSE: We previously reported that it was beneficial to apply binomial pointwise linear regression (PLR) to detect 24-2 glaucomatous visual field (VF) progression, compared to mean deviation (MD) trend analysis and permutation analysis of PLR (PoPLR). The purpose of the current study was to validate the usefulness of the binomial PLR method to detect VF progression in the central 10 degrees in glaucoma patients. DESIGN: Reliability assessment. METHODS: A series of 15 VFs (Humphrey Field Analyzer 10-2 SITA-standard) from 97 eyes in 69 primary open-angle glaucoma, obtained over 8.5 +/- 1.3 years (mean +/- SD), were investigated. PLR was performed by regressing the total deviation of all test points on the series of 15 VFs. VF progression was determined from the analyses of VF test points using the binomial test (one-side, p < 0.025). The time needed to detect VF progression was also investigated. The results were compared with PoPLR and MD trend analyses. RESULTS: The binomial PLR was comparable to PoPLR and MD trend analyses in the positive predictive value (0.19 to 0.80), the negative predictive value (0.86 to 1.0), and the false positive rate (0.0 to 0.13) to evaluate glaucomatous VF progression. The time needed to detect VF progression (4.2 +/- 1.8 years) was significantly shorter with the binomial PLR method compared with PoPLR and MD trend analysis (p = 0.04, p = 0.012, respectively). CONCLUSIONS: The binomial PLR method detected glaucomatous VF progression in the central 10 degrees significantly earlier than PoPLR and MD trend analyses. PMID- 30465747 TI - Translating chemometric analysis into physiological insights from in vivo confocal Raman spectroscopy of the human stratum corneum. AB - The superficial layer of the skin, the stratum corneum (SC), consists of corneocytes surrounded by lipid regions and acts as a protective barrier for the body against water loss, toxic agents and microorganisms. As most substances permeate the stratum corneum through the lipid regions, lipid organization is considered crucial for the skin barrier function. Here, we investigate the potential of in vivo confocal Raman spectroscopy to describe the composition and organization of the SC. Confocal Raman spectroscopy is finding increasing use in the characterization of skin in biomedical, pharmaceutical and cosmetic applications. In this work, we analyze the spectra using chemometric methods and obtain principal components that correspond to the primary skin constituents: protein (keratin), natural moisturizing factor (NMF), water and lipid contributions in both ordered (orthorhombic) and disordered structural organization. By identifying these important components of the SC, these results highlight the utility of this in vivo, non-invasive, and depth resolved tool at the forefront of skin research. PMID- 30465748 TI - Trial of labor after cesarean delivery in twin gestations: Systematic review and meta-analysis. AB - BACKGROUND: Trial of labor after cesarean is offered as a routine option for singleton gestations with previous cesarean delivery. However, adequate data are not available to determine if the approach is equally valid in women with twin gestation. OBJECTIVE: This systematic review and meta-analysis aimed to assess maternal morbidities associated with trial of labor after cesarean in twin gestations. STUDY DESIGN: Electronic databases were searched for cohort studies and randomized controlled trials evaluating the association between trial of labor after cesarean delivery in twin gestations and pregnancy outcomes. Maternal mortality and severe morbidities, such as uterine rupture and hysterectomy, were compared between women who had trial of labor and women who had a planned repeat cesarean delivery. Pooled odds ratios (ORs) were calculated using a random effects model. Additional analyses were performed to compare trial of labor after cesarean outcomes in singleton and twin gestations. RESULTS: Eleven cohort studies including a total of 8209 twin gestations with previous cesarean delivery were included in the present study. Of these gestations, 2484 were intended for planned vaginal birth, and 5725 were intended for planned repeat cesarean delivery. The rate of uterine rupture in twin gestations was higher in the trial of labor after cesarean group than the elective cesarean group (OR 10.09, 95% CI 4.30-23.69, I2=68%). However, no statistically significant difference was found in the rate of uterine rupture between twin and single gestations attempting trial of labor after cesarean (OR 1.34, 95% CI 0.54 -3.31, I2=0%). Women who attempted trial of labor after cesarean with twins did not have an increased risk of uterine scar dehiscence, hemorrhage, blood transfusion, or neonatal morbidity and mortality compared to elective repeat cesarean delivery. Patients with twins had similar rates of successful vaginal delivery as patients with singletons (OR 0.85, 95% CI 0.61 -1.18, I2=36%). CONCLUSION: This meta-analysis demonstrates that, although trial of labor with twins after previous cesarean delivery is associated with higher rates of uterine rupture compared to elective cesarean delivery, pregnancy outcomes and success rates are similar to a trial of labor after previous cesarean delivery in singleton gestations. Planned vaginal birth for women with twin gestation and previous cesarean delivery may be a safe alternative to a planned repeat cesarean. PMID- 30465749 TI - Fasting promotes functional changes in liver mitochondria. AB - Overnight fasting of rodents is commonly adopted in protocols to obtain isolated liver mitochondria, but the effects of fasting itself on mitochondrial function are poorly characterized. In this study we show that overnight fasting (15 h) promotes a shift in the liver mitochondrial bioenergetic profile, with a reduction in ADP-stimulated and maximal respiration, lower membrane potentials and lower resistance to Ca2+-induced mitochondrial permeability transition. Short term fasting (4 h) promoted similar changes, suggesting that this is a physiological shift in mitochondrial function associated with fasting, but not torpor. Our results suggest that the widely adopted liver mitochondrial isolation technique using fasted animals should be reconsidered, and also uncover physiological changes in bioenergetic function associated to nutritional status. PMID- 30465750 TI - Radioprotective role of cyanobacterial phycobilisomes. AB - Cyanobacteria are thought to be responsible for pioneering dioxygen production and the so-called "Great Oxygenation Event" that determined the formation of the ozone layer and the ionosphere restricting ionizing radiation levels reaching our planet, which increased biological diversity but also abolished the necessity of radioprotection. We speculated that ancient protection mechanisms could still be present in cyanobacteria and studied the effect of ionizing radiation and space flight during the Foton-M4 mission on Synechocystis sp. PCC6803. Spectral and functional characteristics of photosynthetic membranes revealed numerous similarities of the effects of alpha-particles and space flight, which both interrupted excitation energy transfer from phycobilisomes to the photosystems and significantly reduced the concentration of phycobiliproteins. Although photosynthetic activity was severely suppressed, the effect was reversible, and the cells could rapidly recover from the stress. We suggest that the actual existence and the uncoupling of phycobilisomes may play a specific role not only in photo-, but also in radioprotection, which could be crucial for the early evolution of Life on Earth. PMID- 30465751 TI - Lysine Methylation: Implications in Neurodegenerative Disease. AB - Lysine methylation is well-documented and relatively well-understood with respect to histone modification and the epigenetic regulation of gene expression. Enzymes called lysine methyltransferases (KMTs) are capable of methylating lysine residues on histone tails, while the opposing lysine demethylases (KDMs) are capable of removing the methyl groups. This balance of dynamic methylation of histone proteins effectively alters gene expression, and has been widely studied with many applications in neurological disease. While histone methylation is an extensive field of research, lysine methylation has received considerable attention in recent years, following the discovery of a handful of non-histone substrates for KMTs. With the expanding repertoire of non-histone substrates, exploration into the cellular functions regulated by this dynamic post translational modification has become an intriguing research question. Recent studies have implicated non-histone methylation in many crucial cell processes, such as signal transduction, apoptosis, and proliferation. Although most of the current research in this emerging field is streamlined for applications in cancer, it seems that lysine methylation of non-histone proteins could also be relevant in neurodegenerative disease. This review will summarize what is known about the role of histone lysine methylation in neurodegenerative diseases, and explore the links between recently identified non-histone methylated proteins, and the brain. Our goal is to connect the emerging field of non-histone protein methylation with neurodegenerative research. PMID- 30465752 TI - Early postnatal tobacco smoke exposure triggers anxiety-like behavior and decreases synaptic proteins even after a long exposure-free period in mice. AB - Although environmental tobacco smoke (ETS) is mainly associated to cardiorespiratory disease, clinical and preclinical studies have showed that ETS induces behavioral disorders and deleterious effects in the brain. Our aim was to investigate the effects of ETS during the early postnatal period on locomotor activity and anxiety and in the presynaptic proteins and brain-derived neurotrophic factor (BDNF) in distinct brain regions. BALB/c mice were exposed to ETS generated from 3R4F reference research cigarettes from the third to the fourteenth days of life. Behavioral and biochemical analyzes were performed during infancy, adolescence, and adulthood. ETS exposure induced a decrease in the locomotor activity in both female and male mice during infancy and in male mice during adolescence. Mice exposed to ETS showed lower distance traveled in the open arms of the elevated plus maze than control group. We also observed a decrease in synapsin levels in the cerebellum and striatum during infancy and adolescence, which persisted during the adulthood only in the cerebellum. Synaptophysin levels were low in all brain regions studied during the infancy, which remained reduced in the cerebellum and prefrontal cortex during adolescence and in the prefrontal cortex during adulthood. BDNF levels were reduced in the striatum and prefrontal cortex during infancy. These behavioral and biochemical data indicate that exposure to ETS during a critical development period leads to anxiety-like behavior and blunted synaptic proteins levels in different regions of the brain. More important, several of these effects were not reversed even after a long exposure-free period. PMID- 30465753 TI - Barriers and outcomes associated with unfulfilled requests for permanent contraception following vaginal delivery. AB - OBJECTIVES: To identify barriers to postpartum permanent contraception procedures after vaginal delivery and to explore contraceptive and reproductive outcomes of women who experience unfulfilled requests. STUDY DESIGN: We performed a retrospective cohort study of women requesting postpartum permanent contraception after vaginal delivery from 7/1/11-6/30/14 at Strong Memorial Hospital in Rochester, NY. We ascertained patient characteristics and outcomes through electronic medical records and birth certificate data search. RESULTS: Of 189 women in our sample, 78 (41.3%) had a postpartum permanent contraception procedure. Factors associated with unfulfilled requests in adjusted analysis included BMI >=40 (OR 3.71, 95%CI 1.46-9.48 compared to BMI<35), federal sterilization consent signed >=36 weeks (OR 5.10, 95%CI 1.64-15.86 compared to <36 weeks), and delivery in the latter half of the week (Wednesday-Saturday) (OR 2.02, 95%CI 1.08-3.79). Documented reasons for unfulfilled permanent contraception requests included patient changing her mind related to procedural issues (21, 18.9%), invalid consent (20, 18.0%), maternal obesity (17, 15.3%), lack of operating room availability (14, 12.6%) and ambivalence about permanent contraception (5, 4.5%). Of 57 women who planned for interval permanent contraception and had institutional follow-up over the subsequent year, 14 (24.6%) had a procedure, 8 (14.0%) initiated long-acting reversible contraception, and 13 (22.8%) became pregnant. CONCLUSIONS: Fewer than half of women obtained desired postpartum permanent contraception after vaginal delivery, with logistical issues and obesity being the most common reported barriers. Health care providers should advocate for access to postpartum permanent contraception, as well as discussing prenatally the individualized probability of non-fulfillment and importance of alternative contraceptive plans. Implications Logistical barriers and inappropriate antenatal preparation contribute to the fact that over half of women don't obtain desired postpartum permanent contraception after vaginal delivery. To respect reproductive autonomy and improve care, clinicians and other health officials should eliminate barriers to immediate postpartum permanent contraception while increasing access to alternative options. PMID- 30465754 TI - Neuropathologic, genetic, and longitudinal cognitive profiles in primary age related tauopathy and Alzheimer's disease. AB - INTRODUCTION: Primary age-related tauopathy (PART) is a recently described entity that can cause cognitive impairment in the absence of Alzheimer's disease (AD). Here, we compared neuropathological features, tau haplotypes, apolipoprotein E (APOE) genotypes, and cognitive profiles in age-matched subjects with PART and AD pathology. METHODS: Brain autopsies (n = 183) were conducted on participants 85 years and older from the Baltimore Longitudinal Study of Aging and Johns Hopkins Alzheimer's Disease Research Center. Participants, normal at enrollment, were followed with periodic cognitive evaluations until death. RESULTS: Compared with AD, PART subjects showed significantly slower rates of decline on measures of memory, language, and visuospatial performance. They also showed lower APOE epsilon4 allele frequency (4.1% vs. 17.6%, P = .0046). DISCUSSION: Our observations suggest that PART is separate from AD and its distinction will be important for the clinical management of patients with cognitive impairment and for public health care planning. PMID- 30465755 TI - Knockdown on aPKC-iota inhibits epithelial-mesenchymal transition, migration and invasion of colorectal cancer cells through Rac1-JNK pathway. AB - BACKGROUND: Atypical protein kinase C-iota (aPKC-iota) is an oncogenic factor, and required for the epithelial-mesenchymal transition (EMT) of different types of cancer. Our study aimed to investigate the role of aPKC-iota in the EMT, migration and invasion of colorectal cancer (CRC) cells. METHODS: Expression of aPKC-iota was evaluated in CRC cell lines treated with TGF-beta1 using qPCR and western blot. After aPKC-iota was knocked down using shRNA, migration and invasion abilities of CRC cell lines were evaluated by wound healing assay and transwell assay, respectively. Activation status of downstream signaling factors of aPKC-iota, including Rac1, JNK, STAT3 and beta-catenin, was measured using western blot. Furthermore, auranofin, an aPKC-iota inhibitor, was used to treat CRC cell lines to investigate its possible inhibition on the EMT of CRC cell lines, as well as on the expression of aPKC-iota and its downstream signaling factors. RESULTS: TGF-beta1 induced the expression of aPKC-iota in CRC cells, and knockdown on aPKC-iota inhibited the TGF-beta1-induced EMT, migration and invasion of CRC cells. Interestingly, Rac1 GTPase level was decreased when aPKC iota was knocked down, and overexpression of Rac1G12V rescued the cell EMT, migration and invasion in CRC cells as inhibited by sh-aPKC-iota. Moreover, knockdown on aPKC-iota suppressed the phosphorylation of JNK and STAT3, and nuclear translocation of beta-catenin. The aPKC- iota inhibitor, Auranofin, showed similar inhibitory effects as aPKC-iota knockdown. CONCLUSION: Knockdown on aPKC-iota inhibited the EMT, migration and invasion of CRC cells through suppressing of Rac1-JNK pathway. Those findings indicate that aPKC-iota may serve as a novel therapeutic target for CRC. PMID- 30465756 TI - Molecular and cellular genetics of non-Hodgkin lymphoma: Diagnostic and prognostic implications. AB - Non-Hodgkin lymphoma (NHL) is a diverse collection of malignant neoplasms with lymphoid-cell origin which includes all the malignant lymphomas that are not classified as Hodgkin lymphoma. NHL is one of the most common types of cancer diagnosed in men and women in the developed world. In the United States of America, the past few decades have seen a significant rise in the incidence of NHL and it accounts for about 4% of all cancers now. The overall survival of NHL has improved drastically over the past ten years. This can be attributed to better understanding of pathogenesis, refined classification, enhanced supportive care, and data from collaborative clinical trials. The prognosis of a newly diagnosed NHL patient depends, among other factors, on the specific subtype of lymphoma, stage of the disease, and age of the patient. Advances in the fields of molecular biology and innovations in cytogenetic techniques have led to the discovery of several oncogenic pathways involved in lymphomagenesis, which in turn has amplified the diagnostic and therapeutic approaches available for NHL. Our comprehension of the genetic features that determine the character of NHL, and ultimately guide the therapy, has undergone significant shift and it is essential that scientists as well as clinicians stay in tune with this rapidly evolving knowledge. In this review we have summarized the current concepts about cellular and molecular genetics of the common subtypes of NHL and their clinical implications. PMID- 30465757 TI - Fatal Neurologic Dysfunction During Continuous-flow Left Ventricular Assist Device Support. AB - BACKGROUND: During continuous-flow left ventricular assist device (CF-LVAD) support, neurologic dysfunction (ND) is a common complication and can be fatal. Few reports provide detailed data on neurological mortality in such patients. Therefore, we examined ND-related mortality during CF-LVAD support. METHODS: Between November 2003 and March 2016, 526 patients underwent implantation of a CF LVAD (403 HeartMate II and 123 HVAD) at our center. We categorized ND as hemorrhagic or ischemic and recorded resulting deaths. Records were reviewed to determine preoperative demographics, perioperative variables, prevalence and causes of post-implantation ND, duration of support until ND, time from ND to death, laboratory data and medications at the time of ND, post-ND treatment procedures, and causes of hemorrhagic ND. We also performed Cox multivariable logistic regression analysis to identify predictors of ND-related mortality by calculating odds ratios and confidence intervals. RESULTS: Neurologic dysfunction occurred in 141 (26.8%) patients, 48 (9.1%) of whom subsequently died. Median duration of LVAD support before ND was 230 days (range 3-2422 d), and median time from ND to death was 3.5 days (range 0-55 d). Parenchymal hemorrhage was the most frequent cause of early conversion (76.7%). In the Cox multivariable regression analysis, predictors of fatal ND were age, ischemic cause of heart failure, history of stroke, and longer intraoperative aortic cross-clamp time. CONCLUSIONS: Our study elucidates the characteristics and risk factors of patients who died of ND during CF-LVAD support. Further studies are required to find ways to decrease the incidence of fatal ND during CF-LVAD support. PMID- 30465758 TI - Unlocking the Dangers of a Stiffening Brain. AB - Mechanical cues regulate neuronal function and reactivity of glial cells, the origin of gliomas. In this issue of Neuron, Chen et al. (2018) uncover a feedforward loop mediated by the mechanosensitive ion channel Piezo1 and tissue stiffness that drives glioma aggression. PMID- 30465759 TI - Remembering a Bad Taste. AB - The phenomenon of conditioned taste aversion (CTA) is generated after ingestion of a specific food is associated with an adverse outcome, i.e., sickness. In this issue of Neuron, Chen et al. (2018) interrogate the pivotal role of PBNCGRP neurons in both the acquisition and the expression of CTA. PMID- 30465760 TI - The Theta Rhythm Mixes and Matches Gamma Oscillations Cycle by Cycle. AB - In the hippocampus, gamma power modulation by the theta rhythm is interpreted as the signature of temporally coordinated inputs that reflect ongoing processing. In this issue of Neuron, Lopes-Dos-Santos et al. (2018) develop a new methodology demonstrating that theta cycles can be viewed as individual computational units characterized by typical gamma profiles. PMID- 30465761 TI - Adapting Fine with a Little Help from the Null Space. AB - During motor adaptation, the brain must learn to produce new muscle outputs without disrupting the intricate coordination between numerous motor areas. A new paper (Perich et al., 2018) shows how adaptation can occur in a subset of neural dimensions and avoid muddling inter-area communication. PMID- 30465762 TI - The Big Reveal: Precision Mapping Shines a Gigantic Floodlight on the Cerebellum. AB - The cerebellum, a brain structure historically considered to be important for motor coordination, is often overlooked in terms of its role in higher-order control processing. Using resting-state functional connectivity and precision mapping, Marek et al. (2018) illuminate the cerebellum as an important source of individual variation in brain function and cognition. PMID- 30465763 TI - Getting Too Old Too Quickly for Their Job: Senescent Glial Cells Promote Neurodegeneration. AB - In a provocative study recently published in Nature, Bussian et al. (2018) report that in tauopathies, glial cells, but not neurons, may be prone to enter cell senescence. Importantly, eliminating senescent glial cells preserves neuronal functions and prevents cognitive decline. PMID- 30465764 TI - A Pathway to Avoiding Threats? AB - How does our brain give rise to passive or active defensive responses when we are confronted with threats? In a recent study in Cell, Terburg, Scheggia and colleagues (Terburg et al., 2018) show that, in both humans and rats, a pathway originating from the amygdala can help suppress passive responses, thereby facilitating active responses to imminent threats. PMID- 30465765 TI - Best Practices for Translational Disease Modeling Using Human iPSC-Derived Neurons. AB - From the beginning, induced pluripotent stem cell (iPSC) technology was touted as a path to improve our understanding of disease biology and enable drug discovery. Advances in iPSC culture, genome engineering, and differentiation protocols have rapidly expanded the use of iPSC-derived disease models from the specialized work of stem cell biology into the mainstream toolkit of cellular neuroscience. Here we provide guidance for using iPSC-derived neurons for disease modeling with a focus on enabling screening platforms amenable to therapeutic drug discovery. We also highlight the potential for incorporating three-dimensional systems that may create more translational in vitro models. PMID- 30465766 TI - Attenuating Neural Threat Expression with Imagination. AB - Imagination is an internal simulation of real-life events and a common treatment tool for anxiety disorders; however, the neural processes by which imagination exerts behavioral control are unclear. This investigation tests whether and how imagined exposures to a threatening stimulus, conditioned in the real world, influence neural and physiological manifestations of threat. We found that imagined and real extinction are equally effective in the reduction of threat related neural patterns and physiological responses elicited upon re-exposure to real-world threatening cues. Network connectivity during the extinction phase showed that imagined, like real, extinction engaged the ventromedial prefrontal cortex (vmPFC) as a central hub. vmPFC, primary auditory cortex, and amygdala activation during imagined and real extinction were predictive of individual differences in extinction success. The nucleus accumbens, however, predicted extinction success in the imagined extinction group alone. We conclude that deliberate imagination can attenuate reactions to threat through perceptual and associative learning mechanisms. PMID- 30465767 TI - Sex hormone binding globulin during an annual reproductive cycle in the hepatopancreas and ovary of pejerrey (Odontesthes bonariensis). AB - In the present study, we determined the hepatopancratic shbg transcript abundance and ovarian immunoreactive Shbg (ir-Shbg) localization in pejerrey females at different gonadal stages during an annual ovarian cycle. In the hepatopancreas, shbg expression remains was constant in pre-vitellogenic stages, decreased at final vitellogenesis to increase again in final maturation and atretic stages to previous levels at post-vitellogenic stages. Related to this, also we found a negative significant relation between sex steroid and shbg expression. On the other hand, in the ovary we found ir-Shbg inside of cortical alveoli, from previtellogenic stages to final maturation. This localization of Shbg in a teleost fish ovary suggests a new role for Shbg in oocytes, that may also extend the oocyte fertilization/development process. PMID- 30465768 TI - Recent studies of LPXRFa receptor signaling in fish and other vertebrates. AB - The hypothalamo-pituitary-gonadal (HPG) axis plays a major role in coordinating the reproduction of fish and other vertebrates. Gonadotropin-releasing hormone (GnRH) is the primary stimulatory factor responsible for the hypothalamic control of gonadotropin secretion. In 2000, a previously unidentified hypothalamic neuropeptide was isolated from the brain of Japanese quail and termed gonadotropin-inhibitory hormone (GnIH) based on its ability to directly inhibit gonadotropin release from the cultured quail anterior pituitary gland. One year later, the cDNA sequence that encodes the quail GnIH precursor polypeptide was cloned and was found to encompass two further peptides (GnIH-related peptide (RP) 1 and GnIH-RP-2) besides GnIH. To date, GnIH orthologous have been detected in a variety of vertebrates from fish to humans. These peptides possess a characteristic-LPXRFa (X = L or Q) motif at the C-terminus and are designated as LPXRFa peptides. It is generally accepted that LPXRFa peptides act on GnRH neurons in the hypothalamus to inhibit gonadotropin synthesis and release in addition to affecting the pituitary function in birds and mammals. However, the exact physiological role of LPXRFa is still uncertain in fish and dual actions of LPXRFa on the HPG axis have been observed. Research aiming to elucidate the detailed signaling pathways mediating the actions of LPXRFa on target cells may contribute to understanding the functional divergence of the LPXRFa system in teleosts. Accordingly, this review will discuss the recent advances in LPXRFa receptor signaling, as well as the potential interactions on cell signaling induced by other factors, such as GnRH and kisspeptin. PMID- 30465769 TI - Different risk factors between early and late cancer recurrences in patients without additional surgery after noncurative endoscopic submucosal dissection for early gastric cancer. AB - BACKGROUND AND AIMS: Cancer recurrence is observed in some patients without additional radical surgery after endoscopic submucosal dissection (ESD) that does not fulfill the curability criteria for early gastric cancer (EGC), categorized as "noncurative resection" or "curability C-2" in the guidelines. However, time to cancer recurrence is different in such patients. Thus, we aimed to identify the risk factors of early and late cancer recurrences in these patients. METHODS: Between 2000 and 2011, this multicenter study analyzed 905 patients who were followed up without additional radical surgery after ESD for EGC categorized as curability C-2. We evaluated the risk factors for early and late cancer recurrences, separately, after ESD. Their cut-off value was defined at 2 years. RESULTS: Time to cancer recurrence in the enrolled patients showed a bimodal pattern, and the 5-year cancer recurrence rate was 3.2%. Multivariate Cox analyses revealed that lymphatic invasion (hazard ratio [HR], 8.56; P = 0.003) was the sole independent risk factor for early cancer recurrence. Regarding late cancer recurrence, vascular invasion (HR, 4.50; P = 0.039) was an independent risk factor, and lymphatic invasion tended to be a risk factor (HR, 3.63; P = 0.069). CONCLUSIONS: This multicenter study with the largest cohort demonstrated that lymphatic invasion is mainly associated with early cancer recurrence; however, vascular invasion was a risk only for late recurrence in patients without additional treatment after ESD for EGC categorized as curability C-2. This finding may contribute to the decision making for treatment strategies after ESD, especially in patients with a relatively short life expectancy. PMID- 30465770 TI - Preoperative Predictors of Choledocholithiasis in Patients Presenting with Acute Calculous Cholecystitis. AB - BACKGROUND AND AIMS: Markedly elevated liver chemistries in patients presenting with acute calculous cholecystitis (AC) often prompt an evaluation for concomitant choledocholithiasis (CDL). However, current guidelines directing the workup for CDL fail to address this unique population. The aims of this study are to define the range of presenting lab values and imaging findings in AC, develop a model to predict the presence of concurrent CDL, and develop a management algorithm that can be easily applied on presentation. METHODS: We conducted a retrospective review of patients presenting with AC to a large tertiary hospital over a 3.5-year period. CDL was defined as common bile duct (CBD) stone(s), sludge, or debris seen on any of the following studies: US, CT, MRI/MRCP, EUS, ERCP, or intraoperative cholangiogram. A multivariable model to predict CDL was developed on 70% of the patients and validated on the remaining 30%. RESULTS: 366 patients were identified, with 65 (17.8%) having concurrent CDL. Univariable analysis was used to predict CDL and demonstrated statistically significant odds ratios for transaminases >3-times upper limit of normal, alkaline phosphatase (AlkPhos) above normal, lipase >3-times upper limit of normal, total bilirubin >1.8 mg/dL, and CBD diameter >6 mm. In the validation cohort, an optimal model containing ALT >3-times upper limit of normal, abnormal AlkPhos and CBD diameter >6 mm was found to have an AUROC of 0.91. When 0 or 1 risk factors were present, 98.6% of patients did not have CDL. When all 3 risk factors were present, 77.8% were found to have CDL. CONCLUSIONS: Patients with AC have a high prevalence of choledocholithiasis. When a validated model is used, application of cutoffs for ALT, AlkPhos, and CBD diameter can effectively triage low and high likelihood patients for CDL to surgery or ERCP, respectively. PMID- 30465771 TI - Endoscopic control of polyp burden and expansion of surveillance intervals in serrated polyposis syndrome. AB - INTRODUCTION: Serrated polyposis syndrome (SPS) increases colorectal cancer (CRC) risk. We describe the numbers of colonoscopies and polypectomies performed to achieve and maintain low polyp burdens, and the feasibility of expanding surveillance intervals in patients who achieve endoscopic control. METHODS: We retrospectively evaluated a prospectively collected database on 115 SPS patients undergoing surveillance at Indiana University Hospital between June 2005 and May 2018. The endoscopist provided surveillance interval recommendations based on polyp burden. Endoscopic control was considered successful if surveillance examinations exhibited fewer polyps and if no or only an occasional polyp >=1 cm in size was present at follow-up. Initial control was designated the clearing phase and the maintenance phase was surveillance after control was established. RESULTS: In total, 87 patients (75.7%) achieved endoscopic control, with some others in the clearing phase at this writing. Achieving control required a mean of 2.84 colonoscopies (including the baseline) over 20.4 months and a mean total 27.9 polyp resections. After establishing control, 71 patients were recommended to receive >=24-month follow-up. Of those, 60 patients (69.0% of patients with initial control) continued surveillance at our center. The mean interval between colonoscopies during maintenance was 19.3 months with 6.74 mean polypectomies per procedure on polyps primarily <1 cm. There were no incident cancers or colon surgeries during maintenance. CONCLUSION: Most patients achieved control of polyp burden with 2 to 3 colonoscopies over 1 to 2 years. After reaching control, 60 patients returned at intervals up to 24 months with no incident cancers and no surgeries required. Expansion of surveillance intervals to 24 months is effective and safe for many SPS patients who reach control of polyp burden. PMID- 30465772 TI - Effects of adolescent Bisphenol-A exposure on memory and spine density in ovariectomized female rats: Adolescence vs adulthood. AB - The endocrine disruptor, Bisphenol-A (BPA), alters many behavioral and neural parameters in rodents. BPA administration to gonadally intact adolescent rats increases anxiety, impairs spatial memory, and decreases dendritic spine density when measured in adulthood. Since BPA's action seems to be mediated through gonadal steroid receptors, the current experiments were done in ovariectomized (OVX) female rats to examine the effects on behavior and spine density of adolescent BPA exposure under controlled hormone conditions. OVX (postnatal day, PND, 21) female Sprague-Dawley rats (n = 66) received subcutaneous injections of BPA (40 MUg/kg/bodyweight), 17beta-Estradiol (E2, 50 MUg/kg/bodyweight), or saline during adolescence (PND 38-49). Following the last injection brains were processed for Golgi impregnation (Exp1), behavioral and spine density in adolescence (Exp2), or in adulthood (Exp3). In Exp1, E2 increased spine density in CA1 pyramidal cells and BPA decreased spine density in granule cells of the dentate gyrus (DG). In Exp2, BPA impaired spatial memory on the object placement (OP) task, E2 increased spine density in CA1, BPA decreased spine density in the DG and the medial prefrontal cortex (mPFC). When measured in adulthood (Exp3), BPA impaired OP and object recognition (OR) performance, E2 increased spine density in CA1, and BPA decreased spine density in CA1, the mPFC and the DG. Results provide novel data on the effects of adolescent BPA in an OVX model and are compared to data in intact animals and within the context of understanding the importance of the profound neuronal alterations occurring during adolescent development. PMID- 30465773 TI - Echocardiography in Transcatheter Structural Heart Disease Interventions. AB - Interventional echocardiography is an emerging field with growing interest and applications as therapeutic procedures to address structural heart disease (SHD) continue to evolve and expand. As opposed to coronary interventions, in which the course of catheter movement is constrained within the artery, percutaneous procedures for SHD entail free catheter movement within the heart and great vessels. Imaging guidance in 3-dimensional space is therefore of critical importance to the successful performance of these procedures. The complexity of these procedures requires an imager with a complete knowledge of ultrasound instrumentation and technique, an in-depth knowledge of cardiac anatomy, understanding of the procedural steps involved, and an awareness of potential complications that may arise perioperatively. Echocardiography, especially 3 dimensional transesophageal echocardiography, plays a crucial role in every aspect of percutaneous interventions, from patient selection to final device assessment. This review will focus on the role of echocardiography and the echocardiographer with respect to transcatheter guidance for the spectrum of SHD interventions that have gained worldwide application in recent years. PMID- 30465774 TI - Role of Transesophageal Echocardiography in Patients with Ischemic Stroke. AB - Acute ischemic stroke is a condition with considerable mortality and morbidity. When used appropriately, Transesophageal Echocardiography (TEE) can be an incredibly useful tool to identify potential causes of stroke and guide management. The crucial distinction in this modality lies in separating common incidental findings from those likely to have contributed to ischemic stroke. Furthermore, the management of identified intracardiac causes varies widely from open surgery to antiplatelet therapy. This review seeks to discuss the role of TEE in identifying common etiologies of cardioembolic stroke, review the clinical entities, and the highlight the most recent management recommendations. PMID- 30465775 TI - Grand Round: Autoimmune Hepatitis. AB - Autoimmune hepatitis (AIH) is a corticosteroid responsive, autoimmune liver disease arising consequent to immunogenetic and environmental risk factors. The clinical course reflects relapsing and remitting, hepatocyte targeted, immunologic damage, countered by reparative responses to cell injury. Appropriate and timely immunosuppressive therapy drives disease into remission, albeit accompanied by inevitable side effects. Many challenges faced in the clinic reflect practice that must capture a heterogeneous disease presentation, course, and treatment response, as well as treatment tolerability. In this grand round we appraise the evidence supporting currently applied treatment approaches, address the impact of autoimmune liver disease 'crossover or overlap' presentations, explore important clinical correlates to immune-serological classifiers, and discuss the factors influencing choice of alternative therapy in difficult-to treat situations. PMID- 30465776 TI - First reported case of thrombocytopenia from a Heterodon nasicus envenomation. AB - CONTEXT: The vast majority of the 2.5 million annual worldwide venomous snakebites are attributed to Viperidae or Elapidae envenomations. Of the nearly 2000 Colubridae species described, only a handful are known to cause medically significant envenomations. Considered medically insignificant, Heterodon nasicus (Western Hognose Snake) is a North American rear-fanged colubrid common in the legal pet trading industry. Previously reported cases of envenomations describe local pain, swelling, edema, and blistering. However, there are no reported cases of systemic or hematologic toxicity. CASE DETAILS: A 20-year-old female sustained a bite while feeding a captive H. nasicus causing local symptoms and thrombocytopenia. On day three after envenomation, the patient was seen in the emergency department for persistent pain, swelling, and blistering. At that time, she was found to have a platelet count of 90 * 109/L. Previous routine platelet counts ranged from 315 to 373 * 109/L during the prior two years. Local symptoms peaked on day seven post envenomation. Her local symptoms and thrombocytopenia improved on evaluation four months after envenomation. DISCUSSION: We report the first Heterodon nasicus envenomation causing both local toxicity and thrombocytopenia. Potential mechanisms based on H. nasicus venom composition are discussed in detail. Treatment is largely supportive. Bites by H. nascius should be evaluated by a toxicologist familiar with Colubridae species. This represents the first reported case of hematologic toxicity from envenomation by a North American colubrid snake. PMID- 30465777 TI - Boundary behaviours of Leishmania mexicana: A hydrodynamic simulation study. AB - It is well established that the parasites of the genus Leishmania exhibit complex surface interactions with the sandfly vector midgut epithelium, but no prior study has considered the details of their hydrodynamics. Here, the boundary behaviours of motile Leishmania mexicana promastigotes are explored in a computational study using the boundary element method, with a model flagellar beating pattern that has been identified from digital videomicroscopy. In particular a simple flagellar kinematics is observed and quantified using image processing and mode identification techniques, suggesting a simple mechanical driver for the Leishmania beat. Phase plane analysis and long-time simulation of a range of Leishmania swimming scenarios demonstrate an absence of stable boundary motility for an idealised model promastigote, with behaviours ranging from boundary capture to deflection into the bulk both with and without surface forces between the swimmer and the boundary. Indeed, the inclusion of a short range repulsive surface force results in the deflection of all surface-bound promastigotes, suggesting that the documented surface detachment of infective metacyclic promastigotes may be the result of their particular morphology and simple hydrodynamics. Further, simulation elucidates a remarkable morphology dependent hydrodynamic mechanism of boundary approach, hypothesised to be the cause of the well-established phenomenon of tip-first epithelial attachment of Leishmania promastigotes to the sandfly vector midgut. PMID- 30465778 TI - Analysing single-molecule trajectories to reconstruct free-energy landscapes of cyclic motor proteins. AB - Stochastic trajectories measured in single-molecule experiments have provided key insights into the microscopic behaviour of cyclic motor proteins. However, the fundamental free-energy landscapes of motor proteins are currently only able to be determined by computationally intensive numerical methods that do not take advantage of available single-trajectory data. In this paper we present a robust method for analysing single-molecule trajectories of cyclic motor proteins to reconstruct their free-energy landscapes. We use simulated trajectories on model potential landscapes to show the reliable reconstruction of the potentials. We determine the accuracy of the reconstruction method for common precision limitations and show that the method converges logarithmically. These results are then used to determine the experimental precision required to reconstruct a potential with a desired accuracy. The key advantages of the method are that it is simple to implement, is free of numerical difficulties that plague existing methods and is easily generalizable to higher dimensions. PMID- 30465779 TI - Zinc transporter 8 autoantibodies (ZnT8-ab) are associated with higher prevalence of multiple diabetes-related autoantibodies in adults with type 1 diabetes. AB - AIM: The study aimed to assess the prevalence of zinc transporter 8 autoantibodies (ZnT8-ab), other diabetes-related autoantibodies and clinical manifestation of type 1 diabetes in adults, depending on age of the onset of disease. METHODS: 119 patients with type 1 diabetes, 66 at age <35 years (T1DM < 35) and 53 T1DM at age >=35 years (T1DM >= 35). We assessed clinical features, GAD-ab, IA2-ab, ICA, ZnT8-ab and thyroid peroxidase antibodies (ATPO). RESULTS: In T1DM < 35 lower initial serum C-peptide concentration was observed and diabetes ketoacidosis (DKA) was more common. ATPO positivity was more prevalent in T1DM >= 35 (35.8 vs 21.2%, p = 0.04). The prevalence of GAD-ab, IA2-ab and ZnT8-ab was similar in both groups, the titres of IA2-ab and ICA were higher in T1DM < 35 but titre of ZnT8-ab was higher in T1DM >= 35. The majority of T1DM < 35 patients were positive for three autoantibodies (40.9%), while T1DM >= 35 subjects most often presented with only one (30.2%) antibody, most commonly GAD ab (81.2%). 45% T1DM < 35 and 34% T1DM >= 35 subjects were positive for ZnT8-ab. ZnT8-ab positive patients had higher titre and more frequent occurrence of multiple diabetes-related autoantibodies than ZnT8-ab negative patients. CONCLUSIONS: Adults with T1DM < 35 and T1DM >= 35 differ in the severity of autoimmune response at diagnosis. ZnT8-ab positivity is related to higher titre and more frequent occurrence of multiple diabetes-related autoantibodies. PMID- 30465780 TI - Disposable otoscope specula cryotherapy for lesions in convoluted or sensitive locations. PMID- 30465781 TI - Human stimulus factor is a promising peptide for delivery of therapeutics. AB - Fluticasone (FP) uptake in the presence of a proprietary cell penetrating peptide (Human stimulus factor-HSF) based on the N-terminal domain of lactoferrin was studied, alone and in combination with salmeterol, using an air-interface Calu-3 epithelial model. The HSF enhanced uptake and transport of FP across the epithelial barrier when alone and in presence of salmeterol. This was attributed to transcellular-mediated uptake. This HSF is a promising peptide for delivery of therapeutics where enhanced epithelial penetrating is required. PMID- 30465782 TI - Biotherapeutic Antibody Subunit LC-MS and Peptide Mapping LC-MS Measurements to Study Possible Biotransformation and Critical Quality Attributes In Vivo. AB - Biotransformation monitoring involves tracking drug modification occurring during in-life studies. Critical Quality Attribute (CQA) monitoring from forced degraded drug material or in-life sample sets can provide an in-depth assessment of product quality for support in early or late stage drug development. For CQA analysis, biotherapeutic mAb subunit analysis and peptide mapping liquid chromatography-mass spectrometry (LC-MS) approaches are utilized, although typically from an in vitro setting (e.g. formulation buffer) not involving biological samples or material. Here, samples from a high-dose rat study (in vivo) are subjected to analysis by ligand binding assay, mAb subunit LC-MS, and peptide mapping by LC-MS. Taken together, data from the three analytical approaches provide information regarding drug concentration in circulation, biotransformation, and biotherapeutic drug product quality. The concept of a multi-tier workflow for pre-clinical or clinical sample sets can be applied to other biotherapeutic mAb products such as bi-specific mAbs, fusions proteins, or antibody-drug conjugates. PMID- 30465783 TI - The mouse posterior parietal cortex: Anatomy and functions. AB - In recent years, the number of studies on decision-making in mice has increased dramatically. Many of these studies focus on the posterior parietal cortex (PPC), an area that has been implicated in sensory and multisensory processing, navigation, motion planning, and decision-making. In this review we summarize recent anatomical and functional studies of mouse PPC. First, we make a note of the existing variability in the nomenclature and its anatomical localization. Based on the commonalities across different studies we then describe the connectivity of PPC and discuss its place within several functional brain networks. In view of the examined connectivity, we go on to discuss the role of PPC for the encoding of single-modality and multimodal stimuli as well as its role in navigation. Finally, we summarize the literature on the choice-related activity: we discuss the variety of behavioral protocols and sensory modalities used in these studies, and we note that the response properties of PPC and its causal involvement in decision-making may depend substantially on these conditions. We conclude that, although more research should be devoted to creating a more complete and consistent image of the mouse PPC, this area should rightfully be considered a convenient model system for a circuit-level understanding of the mammalian parietal cortex. PMID- 30465784 TI - RA-839, a selective agonist of Nrf2/ARE pathway, exerts potent anti-rotaviral efficacy in vitro. AB - Acute watery diarrhea due to Rotavirus (RV) infection is associated with high infantile morbidity and mortality in countries with compromised socio-economic backgrounds. Although showing promising trends in developed countries, the efficacy of currently licensed RV vaccines is sub-optimal in socio-economically poor settings with high disease burden. Currently, there are no approved anti rotaviral drugs adjunct to classical vaccination program. Interestingly, dissecting host-rotavirus interaction has yielded novel, non-mutable host determinants which can be subjected to interventions by selective small molecules. The present study was undertaken to evaluate the anti-RV potential of RA-839, a recently discovered small molecule with potent and highly selective agonistic activity towards cellular redox stress-sensitive Nuclear factor erytheroid-derived-2-like 2 (Nrf2)/Antioxidant Response Element (ARE) pathway. In vitro studies revealed that RA-839 inhibits RV RNA and protein expression, viroplasm formation, yield of virion progeny and virus-induced cytopathy independent of RV strains, RV-permissive cell lines and without bystander cytotoxicity. Anti-RV potency of RA-839 was subsequently identified to be independent of stochastic Interferon (IFN) stimulation but to be dependent on RA 839's ability to stimulate Nrf2/ARE signaling. Interestingly, anti-rotaviral effects of RA-839 were also mimicked by 2-Cyano-3, 12-dioxo-oleana-1, 9(11)-dien 28-oic acid methyl ester (CDDO-Me) and Hemin, two classical pharmacological activators of Nrf2/ARE pathway. Overall, this study highlights that RA-839 is a potent antagonist of RV propagation in vitro and can be developed as anti rotaviral therapeutics. PMID- 30465785 TI - Systems biology and gene networks in Alzheimer's disease. AB - Gene mining has been a fruitful approach in the study of Alzheimer's disease (AD). As a new starting point for studying AD, genetic and genomic investigations consistently strive to discover causative variants that are related to disease pathophysiology. Currently, genetic and genomic approaches have identified numerous loci. However, the elaboration of AD mechanism lagged behind gene discovery. The extensive use of parallel, high-throughput, next-generation sequencing techniques has improved our understanding of the roles of genetic variants in the brain at the highest level of functional hierarchy. We highlight three molecular systems (the transcriptome, proteome and epigenome) in this review to ascertain whether the methods used in systems biology studies of AD are useful. Here, we present many advantages of the high-throughput molecular, integrative and network methods, which may provide a good reference for future studies employing network biology approaches and large datasets. PMID- 30465786 TI - Polymorphisms in genes related to the hypothalamic-pituitary-adrenal axis and antidepressant response - systematic review. AB - OBJECTIVE: Around 50% of depressed patients do not respond to antidepressants. Evidence from familial studies suggests a genetic component to this. This study investigated whether patients with polymorphisms in genes related to the hypothalamic-pituitary-adrenal (HPA) axis were less likely to respond to antidepressants. METHOD: EMBASE, MEDLINE, PsycINFO, and the Cochrane Library were searched. Inclusionary criteria were: 1) patients with depression, 2) study of HPA axis-related candidate genes, 3) at least four weeks of antidepressants, and 4) assessment of depressive symptoms dividing patients into non-responders and responders. RESULTS: Nineteen studies were identified. Non-responders and responders did not differ in single nucleotide polymorphisms (SNPs) in genes encoding arginine vasopressin. Findings were equivocal regarding genes encoding the FK506 binding protein 5 and glucocorticoid and mineralocorticoid receptors. Specific SNPs and haplotypes within genes related to corticotropin-releasing hormone (CRHBP, CRHR1) and melanocortins (POMC) predicted non-responder status. CONCLUSIONS: Replication studies and additional investigations exploring gene x environment and drug x environment interactions are necessary before pharmacological treatments may be adjusted based on a patient's genetic profile. PMID- 30465787 TI - Clozapine-induced reduction of l-carnitine reabsorption via inhibition/down regulation of renal carnitine/organic cation transporter 2 contributes to liver lipid metabolic disorder in mice. AB - Clozapine, an atypical antipsychotic drug, is widely utilized for the treatment of schizophrenia; however, clozapine-induced metabolic disorders, such as fatty liver and weight gain, warrant increased attention. Considering the crucial role of l-carnitine (L-Car) in fatty acid oxidation and carnitine/organic cation transporter (OCTN) 2 in renal reabsorption of L-Car, we aimed to study whether clozapine-induced liver lipid metabolic disorder is associated with L-Car dysregulation via inhibition/down-regulation of renal OCTN2. Our results reveal that clozapine inhibits L-Car uptake in MDCK-hOCTN2 cells with an IC50 value of 1.78 MUM. Additionally, clozapine significantly reduces the uptake of L-Car in HK 2 cells, mouse primary cultured proximal tubular (mPCPT) cells and HepG2 cells. Acute (intraperitoneal injection) and 21-day successive oral administration of clozapine at 12.5, 25, and 50 mg/kg to mice resulted in 2-3-fold greater renal excretion of L-Car than in the vehicle group, and the concentration of L-Car in plasma and liver was significantly decreased. Concomitantly, mRNA and protein levels of mOctn2 in the kidney were markedly down regulated. Additionally, 28-day oral administration of clozapine induced increased triglyceride (TG) and total cholesterol (TCHO) levels in mouse livers, while L-Car (40 mg/kg - 1 g/kg) attenuated clozapine-induced liver TG and TCHO increase in a dose-dependent manner. These results indicate that clozapine-induced reduction of L-Car reabsorption via inhibition/down-regulation of renal OCTN2 contributes to liver lipid metabolic disorder. L-Car supplementation is probably an effective strategy to attenuate clozapine-induced abnormal lipid metabolism. PMID- 30465788 TI - Plant lipids: Key players of plasma membrane organization and function. AB - The plasma membrane (PM) is the biological membrane that separates the interior of all cells from the outside. The PM is constituted of a huge diversity of proteins and lipids. In this review, we will update the diversity of molecular species of lipids found in plant PM. We will further discuss how lipids govern global properties of the plant PM, explaining that plant lipids are unevenly distributed and are able to organize PM in domains. From that observation, it emerges a complex picture showing a spatial and multiscale segregation of PM components. Finally, we will discuss how lipids are key players in the function of PM in plants, with a particular focus on plant-microbe interaction, transport and hormone signaling, abiotic stress responses, plasmodesmata function. The last chapter is dedicated to the methods that the plant membrane biology community needs to develop to get a comprehensive understanding of membrane organization in plants. PMID- 30465789 TI - Histone deacetylase 2 regulates the doxorubicin (Dox) resistance of hepatocarcinoma cells and transcription of ABCB1. AB - Histone deacetylases (HDACs) can regulate cell-cycle, differentiation, and apoptosis of hepatocarcinoma (HCC) cells, while their roles in drug sensitivity remain unclear. Our results showed that the expression of HDAC2 was significantly increased in HCC doxorubicin (Dox) resistant cells as compared with their corresponding control cells. Over expression of HDAC2 can increase the cell viability and decrease the Dox sensitivity. Kaplan-Meier Plotter assay revealed that HCC patients with higher levels of HDAC2 had significantly poor prognosis than that of the lower expression patients. Mechanistically studies revealed that HDAC2 can regulate the transcription of ABCB1 via directly binding with its promoter and increasing its expression in Dox resistant HCC cells. Knockdown of HDAC2 significantly inhibited the expression of ABCB1. Co-immunoprecipitation revealed that HDAC2 can bind with c-fos, an important transcription factor of ABCB1, in HCC/Dox cells. Knockdown of c-Fos decreased the binding between HDAC2 and promoter of ABCB1 in HCC/Dox cells. Collectively, our data revealed that HDAC2 can regulate Dox sensitivity of HCC cells and the transcription of ABCB1. PMID- 30465790 TI - Study of the immunomodulatory effects of osteogenic differentiated human dental pulp stem cells. AB - BACKGROUND AND AIMS: Dental pulp stem cells (DPSC) are promising tools in regenerative medicine due to their differentiation potential and immunomodulatory properties. However, it is not clearly known whether or not DPSCs maintain their immunosuppressive effects after differentiation. In the present study, we examined the immunomodulatory effects of osteogenic differentiated DPSCs (OD DPSCs). METHODS: OD-DPSCs and undifferentiated DPSCs were co-cultured with allogenic PBMCs in different ratios and the proliferation of the PBMCs was measured. The concentration of IL-10, TGF-beta, PGE2, IL-6, and NO were then examined. Moreover, the expression of IDO, HLAG, and HGF genes were determined in undifferentiated and OD-DPSCs. FINDINGS: The results showed that OD-DPSCs could inhibit the proliferation of allogenic PBMCs. The levels of PGE2, IL-6, and TGF beta anti-inflammatory cytokines increased after the co-culture. Moreover, the levels of NO increased during the differentiation process and the expression of IDO, HLAG, and HGF genes remained unchanged after osteogenic differentiation. SIGNIFICANCE: Although, there were some differences between the OD-DPSCs and undifferentiated DPSCs in terms of their cytokine and NO production, undifferentiated DPSCs maintained their immunomodulatory activities upon differentiation. PMID- 30465791 TI - Development of host strains and vector system for an efficient genetic transformation of filamentous fungi. AB - An ability to synthesize extracellular enzymes degrading a wide spectrum of plant and algae polymeric substrates makes many fungi relevant for biotechnology. The terrestrial thermophilic and marine fungal isolates capable of plant and algae degradation have been tested for antibiotic resistance for their possible use in a new genetic transformation system. Plasmids encoding the hygromycin B phosphotransferase (hph) under the control of the cauliflower mosaic virus 35S promoter, the trpC gene promoter of Aspergillus nidulans, and the Aureobasidium pullulans TEF gene promoter were delivered into the fungal cells by electroporation. The effectiveness of different promoters was compared by transformation and growth of Thermothelomyces thermophila (formerly Myceliophthora thermophila) on the selective medium and by real-time PCR analysis. A highly efficient transformation was observed at an electric-pulse of 8.5 kV/cm by using 10 MUg of DNA per 1 * 105 conidia. Although all promoters were capable of hph expression in the Th. thermophila cells, the trpC promoter provided the highest level of hygromycin resistance. We further successfully applied plant binary vector pPZP for co-transformation of hph gene and enhanced green fluorescent protein gene that confirmed this transformation system could be used as an appropriate tool for gene function studies and the expression of heterologous proteins in micromycetes. PMID- 30465792 TI - Biocatalyst Engineering of Thermomyces Lanuginosus Lipase Adsorbed on Hydrophobic Supports: Modulation of Enzyme Properties for Ethanolysis of Oil in Solvent-Free Systems. AB - Different immobilized biocatalysts of Thermomyces lanuginosus lipase (TLL) exhibited different properties for the ethanolysis of high oleic sunflower oil in solvent-free systems. TLL immobilized by interfacial adsorption on octadecyl (C 18) supports lost its 1,3-regioselectivity and produced more than 99% of ethyl esters. This reaction was influenced by mass-transfer limitations. TLL adsorbed on macroporous C-18 supports (616 A of pore diameter) was 10-fold more active than TLL adsorbed on mesoporous supports (100-200 A of pore diameter) in solvent free systems. Both derivatives exhibited similar activity when working in hexane in the absence of diffusional limitations. In addition, TLL adsorbed on macroporous Purolite C-18 was 5-fold more stable than TLL adsorbed on mesoporous Sepabeads C-18. The stability of the best biocatalyst was 20-fold lower in anhydrous oil than in anhydrous hexane. Mild PEGylation of immobilized TLL greatly increased its stability in anhydrous hexane at 40 degrees C, fully preserving the activity after 20 days. In anhydrous oil at 40 degrees C, PEGylated TLL-Purolite C-18 retained 65% of its initial activity after six days compared to 10% of the activity retained by the unmodified biocatalyst. Macroporous and highly hydrophobic supports (e.g., Purolite C-18) seem to be very useful to prepare optimal immobilized biocatalysts for ethanolysis of oils by TLL in solvent-free systems. PMID- 30465793 TI - Exploring anti-MRSA activity of chitosan-coated liposomal dicloxacillin. AB - One of the greatest disturbing global health problems is antibiotic-resistant bacterial infections, which have rendered numerous currently used antibiotics ineffective. Thus, the feasibility of chitosan-coated deformable liposomes (C Lips) containing dicloxacillin (DLX) were evaluated for their efficacy against methicillin-resistant Staphylococcus aureus (MRSA) strains, which are resistant to beta lactam antibiotics. DLX-loaded liposomes (DLX-Lip) were prepared by a lipid film hydration method and then chitosan (CS) coated (C-DLX-Lip) by the electrostatic deposition method. Both DLX-Lips and C-DLX-Lips showed a particle size distribution with a nano-range and a narrow polydispersity index (PDI). After CS coating, the zeta potential was shifted from negative to positive value. The DLX entrapment efficiency (EE) and drug loading (DL) were 62% and 5.6% for C DLX-Lips compared to 38% and 3.1% for DLX-Lip, respectively. The in vitro release profile of C-DLX-Lips possessed a slow release behavior. Moreover, the DLX-Lips and C-DLX-Lips demonstrated an enhanced anti-MRSA activity. These results revealed that DLX-Lips and C-DLX-Lips may serve as promising carriers for DLX to increase the efficacy against MRSA, which offers considerably clinical value for long-term use of DLX. PMID- 30465794 TI - Actin dynamics during Ca2+-dependent exocytosis of endothelial Weibel-Palade bodies. AB - Weibel-Palade bodies (WPBs) are specialized secretory organelles of endothelial cells that serve important functions in the response to inflammation and vascular injury. WPBs actively respond to different stimuli by regulated exocytosis leading to full or selective release of their contents. Cellular conditions and mechanisms that distinguish between these possibilities are only beginning to emerge. To address this we analyzed dynamic rearrangements of the actin cytoskeleton during histamine-stimulated, Ca2+-dependent WPB exocytosis. We show that most WPB fusion events are followed by a rapid release of von-Willebrand factor (VWF), the large WPB cargo, and that this occurs concomitant with a softening of the actin cortex by the recently described Ca2+-dependent actin reset (CaAR). However, a considerable fraction of WPB fusion events is characterized by a delayed release of VWF and observed after the CaAR reaction peak. These delayed VWF secretions are accompanied by an assembly of actin rings or coats around the WPB post-fusion structures and are also seen following direct elevation of intracellular Ca2+ by plasma membrane wounding. Actin ring/coat assembly at WPB post-fusion structures requires Rho GTPase activity and is significantly reduced upon expression of a dominant-active mutant of the formin INF2 that triggers a permanent CaAR peak-like sequestration of actin to the endoplasmic reticulum. These findings suggest that a rigid actin cortex correlates with a higher proportion of fused WPB which assemble actin rings/coats most likely required for efficient VWF expulsion and/or stabilization of a WPB post-fusion structure. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech. PMID- 30465795 TI - Vertical and oblique cultural transmission fluctuating in time and in space. PMID- 30465796 TI - Mass synaptometry: High-dimensional multi parametric assay for single synapses. AB - BACKGROUND: Synaptic alterations, especially presynaptic changes, are cardinal features of neurodegenerative diseases and strongly correlate with cognitive decline. NEW METHOD: We report "Mass Synaptometry" for the high-dimensional analysis of individual human synaptosomes, enriched nerve terminals from brain. This method was adapted from cytometry by time-of-flight mass spectrometry (CyTOF), which is commonly used for single-cell analysis of immune and blood cells. RESULT: Here we overcome challenges for single synapse analysis by optimizing synaptosome preparations, generating a 'SynTOF panel,' recalibrating acquisition settings, and applying computational analyses. Through the analysis of 390,000 individual synaptosomes, we also provide proof-of principle validation by characterizing changes in synaptic diversity in Lewy Body Disease (LBD), Alzheimer's disease and normal brain. COMPARISON WITH EXISTING METHOD(S): Current imaging methods to study synapses in humans are capable of analyzing a limited number of synapses, and conventional flow cytometric techniques are typically restricted to fewer than 6 parameters. Our method allows for the simultaneous detection of 34 parameters from tens of thousands of individual synapses. CONCLUSION: We applied Mass Synaptometry to analyze 34 parameters simultaneously on more than 390,000 synaptosomes from 13 human brain samples. This new approach revealed regional and disease-specific changes in synaptic phenotypes, including validation of this method with the expected changes in the molecular composition of striatal dopaminergic synapses in Lewy body disease and Alzheimer's disease. Mass synaptometry enables highly parallel molecular profiling of individual synaptic terminals. PMID- 30465797 TI - Inter- and intra-rater reliability of computer-assisted planimetry in experimental stroke research. AB - BACKGROUND: Computer-assisted planimetry is widely used in experimental stroke research to assess the size of the ischemic lesion or hemispheric volume. NEW METHOD: Only insufficient data exist on the training required to achieve sufficient reliability in planimetry. Therefore, planimetry was performed over 15 months by two blinded raters who were initially inexperienced in the method. For inter-rater reliability, the hemispheric and lesional volume of 227 male Wistar Unilever rats subjected to middle cerebral artery occlusion were determined in diffusion- and T2-weighted sequences. For the intra-rater agreement, one investigator assessed the hemispheric and lesional volume in 87 T2-weighted sequences twice within a six-week interval. The correlation was calculated using Krippendorff's alpha and Bland-Altman plots illustrated the agreement. RESULTS: Inter-rater agreement increased during the first seven weeks and remained at high values (Krippendorff's alpha > 0.88). For intra-rater agreement, Krippendorff's alpha was 0.84 for hemispheric and 0.85 for lesional volume. The Bland-Altman plot indicated solid agreement between raters in the absence of systematic errors. COMPARISON WITH EXISTING METHODS: Simplified geometrical models or automated methods for planimetry can be used to determine lesional volume, but both approaches are inappropriate to assess hemispheric volume. CONCLUSION: Computer-assisted planimetry can be an appropriate method to determine hemispheric or ischemic lesion volume in rodents but requires a sufficiently long learning period of approximately two months. Even an experienced investigator can generate data with serious variation. Inter- and intra-rater-dependent bias should be considered during the design and performance of respective studies. PMID- 30465798 TI - Driver mutation profiles and clinicopathological correlation in pulmonary adenocarcinoma with a micropapillary component. AB - Pulmonary adenocarcinoma (PA) with a micropapillary component (PA-MPC) is considered a highly aggressive neoplasm. The molecular profile of PA-MPC has not yet been clearly elucidated. Based on these, we performed next-generation sequencing and quantitative real-time polymerase chain reaction to detect the driver mutation profiles of fifty PA-MPC cases and confirmed the results by Sanger sequencing. Additionally, in 10 selected MPC-predominant cases, we captured the MPC and non-MPC by laser capture microdissection and sequenced them separately to investigate the differences in driver mutation profiles between MPC and non-MPC. In fifty PA-MPC cases, the prevalence rates of EGFR, KRAS, and PIK3CA somatic mutations were 76.0%, 6.0%, and 2.0%, respectively; no BRAF, NRAS, ALK, PDGFRA, or other mutations were found. With regard to the MPC, EGFR mutation was more frequent in MPC-predominant cases (18/20, 90%) than in non-MPC predominant cases (20/30, 66.7%). The overall survival of the MPC-predominant group was significantly worse than that of the non-MPC-predominant group. In the 10 microdissected MPC-predominant cases, the EGFR mutation was identical in both components and was consistent with previous results without microdissection. In conclusion, our study indicated that EGFR mutations were frequent in PA-MPC. Paired MPC and non-MPC from the same cases had the same driver mutation profiles. PMID- 30465799 TI - Cathepsin K-deficiency impairs mouse cardiac function after myocardial infarction. AB - BACKGROUND: Extracellular matrix metabolism and cardiac cell death participate centrally in myocardial infarction (MI). This study tested the roles of collagenolytic cathepsin K (CatK) in post-MI left ventricular remodeling. METHODS AND RESULTS: Patients with acute MI had higher plasma CatK levels (20.49 +/- 7.07 pmol/L, n = 26) than those in subjects with stable angina pectoris (8.34 +/- 1.66 pmol/L, n = 28, P = .01) or those without coronary heart disease (6.63 +/- 0.84 pmol/L, n = 93, P = .01). CatK protein expression increases in mouse hearts at 7 and 28 days post-MI. Immunofluorescent staining localized CatK expression in cardiomyocytes, endothelial cells, fibroblasts, macrophages, and CD4+ T cells in infarcted mouse hearts at 7 days post-MI. To probe the direct participation of CatK in MI, we produced experimental MI in CatK-deficient mice (Ctsk-/-) and their wild-type (Ctsk+/+) littermates. CatK-deficiency yielded worsened cardiac function at 7 and 28 days post-MI, compared to Ctsk+/+ littermates (fractional shortening percentage: 5.01 +/- 0.68 vs. 8.62 +/- 1.04, P < .01, 7 days post-MI; 4.32 +/- 0.52 vs. 7.60 +/- 0.82, P < .01, 28 days post-MI). At 7 days post-MI, hearts from Ctsk-/- mice contained less CatK-specific type-I collagen fragments (10.37 +/- 1.91 vs. 4.60 +/- 0.49 ng/mg tissue extract, P = .003) and more fibrosis (1.67 +/- 0.93 vs. 0.69 +/- 0.20 type-III collagen positive area percentage, P = .01; 14.25 +/- 4.12 vs. 6.59 +/- 0.79 alpha-smooth muscle actin positive area percentage, P = .016; and 0.82 +/- 0.06 vs. 0.31 +/- 0.08 CD90 positive area percentage, P = .008) than those of Ctsk+/+ mice. Immunostaining demonstrated that CatK-deficiency yielded elevated cardiac cell death but reduced cardiac cell proliferation. In vitro studies supported a role of CatK in cardiomyocyte survival. CONCLUSION: Plasma CatK levels are increased in MI patients. Heart CatK expression is also elevated post-MI, but CatK-deficiency impairs post-MI cardiac function in mice by increasing myocardial fibrosis and cardiomyocyte death. PMID- 30465800 TI - Role of Chemokine Receptor CCR4 and Regulatory T Cells in Wound Healing of Diabetic Mice. AB - Wound healing is a well-coordinated process that involves inflammatory mediators and cellular responses; however, if any disturbances are present during this process, tissue repair is impaired. Chronic wounds are one of the serious long term complications associated with diabetes mellitus (DM). The chemokine receptor CCR4 and its respective ligands, CCL17 and CCL22, are involved in regulatory T cell (Treg) recruitment and activation in inflamed skin; however, the role of Treg in wounds is still not clear. Our aim was to investigate the role of CCR4 and Treg in cutaneous wound healing in diabetic mice. Alloxan-induced diabetic wild- type mice (diabetic) developed wounds that were difficult to heal, differently from CCR4-/- diabetic mice (CCR4-/- diabetic), and also from anti CCL17/22 or anti-CD25 injected diabetic mice that presented with accelerated wound healing and less Treg in the wound bed. Consequently, CCR4-/- diabetic mice also presented with alteration on T cells population in the wound and draining lymph nodes; on the 14th day, these mice also displayed an increase of collagen fiber deposition. Still, cytokine levels were decreased in the wounds of CCR4-/- diabetic mice on the 2nd day. Our data suggest that the receptor CCR4 and Treg negatively affect wound healing in diabetic mice. PMID- 30465801 TI - Presynaptic regulation of dopamine release: Role of the DAT and VMAT2 transporters. AB - The signaling dynamics of the neurotransmitter dopamine has been established to have an important role in a variety of behavioural processes including motor control, cognition, and emotional processing. Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles. This review provides an overview of how these transporter proteins are involved in molecular regulation and function together to govern the dynamics of vesicular release with opposing effects on the quantal size and extracellular concentration of dopamine. These transporter proteins are both focal points of convergence for a variety of regulatory molecular cascades as well as targets for many pharmacological agents. The ratio between these transporters is argued to be useful as a molecular marker for delineating dopamine functional subsystems that may differ in transmitter release patterns. PMID- 30465802 TI - A serial mediation model of the relationship between alexithymia and BMI: The role of negative affect, negative urgency and emotional eating. AB - Difficulty identifying and describing emotions (alexithymia) has been related to impulsiveness and negative affect, emotional eating and obesity. However, previous research findings concerning the relationship between alexithymia and obesity have been mixed and inconsistent, raising the possibility that the relationship is indirect and mediated by multiple unknown factors. The aim of the study was to comprehensively explore the potential pathways between alexithymia and obesity via a novel theoretical model, and for the first time, incorporate negative affect, impulsiveness (negative urgency) and emotional eating as potential mediating factors. Two questionnaire-based studies were conducted; the first as an exploratory analysis within a student sample (N = 125), and the second as a self-replication within a more representative general population sample (N = 342). Study One revealed that difficulty identifying feelings predicted Body Mass Index (BMI) both directly (B = 0.1694, CI = 0.0194-0.3194) and indirectly via negative urgency and emotional eating (B = 0.0074, CI = 0.0001 0.0315). In contrast, Study Two revealed that alexithymia predicted BMI indirectly via negative affect (when depression was included in the model; B = 0.0335, CI = 0.0019-0.0660) or negative urgency (when anxiety was included in the model; B = 0.0021, CI = 0.0001-0.0066). Our findings provide partial support for the hypothesised model and offer original insight into the relationship between alexithymia and obesity. Additionally, our findings highlight important methodological considerations for future research and suggest that ways to address an individual's ability to identify, describe and regulate emotions should be considered when designing interventions to assist weight loss and management. PMID- 30465803 TI - Acute and 28-days repeated dose sub-acute toxicity study of gallic acid in albino mice. AB - Gallic acid is a phenolic acid ubiquitously present in numerous medicinal plants and food beverages. Gallic acid is also a potent anti-oxidant phytochemical possessing numerous medicinal potentials against various ailments such as diabetes, hypercholesterolemia and other life-threatening diseases including malignancy. Present study was aimed to evaluate acute and sub-acute toxicity of gallic acid in albino mice. The primary aim of the study was to investigate gallic acid prompted PPAR-alpha/gamma activation associated adverse events. Acute toxicity of gallic acid was determined in albino mice and 28-days sub-acute toxicity study was carried out in male and female albino mice at three dose levels, 100, 300 and 900 mg/kg/day, p.o. LD50 of gallic acid was found to be greater than 2000 mg/kg in mice. Hematological investigation did not show any alteration in transaminases and other blood homeostasis parameters. Gross necropsy showed non-significant alteration upon gallic acid administration. Histopathological finding suggested no significant alteration in tissue histology with slight fatty cells in bone marrow indicating non-significant bone marrow suppression, also no obvious effect was observed on hematological parameters. High dose of gallic acid (900 mg/kg/day) for 28 days did not produce any significant alteration in morphological and behavioral parameters. Histopathological finding also supports safety of gallic acid in mice. PMID- 30465804 TI - In further defense of nonclinical abuse liability testing of biologics. AB - Risk assessment is not a choice. Drug Abuse Liability (DAL) is mandated under international and national drug control statutes for all drugs targeting the CNS. Once administered to humans many biologics may have long-lived or permanent physiological effects that make DAL testing arduous. We respond to premises of a recently published position on DAL testing of biologics by de Zafra et al. (2018). We propose that, at a minimum, Sponsors submitting a Biologics Licensure Application (BLA) must think "outside the box" and include differential study designs for the same three core small NME assays detailed in the current DAL guidelines (self-administration, drug discrimination, and dependence liability). Abuse liability testing for drug scheduling decisions for marketing approval are not excluded or limited from risk assessment analysis simply because the entity is a biologic. In fact, more robust study designs may be necessary to address alterations in the reinforcing and discriminative stimulus effects of common drugs of abuse, as well as the dependence liability of the biologic, itself. PMID- 30465805 TI - Behavioral, hormonal, and neurochemical outcomes of neonatal repeated shaking brain injury in male adult rats. AB - It is well known that an abusive environment in childhood is related to individual anxiety behavior in adulthood. Though an imbalance of adrenocorticosteroid receptors and a dysfunction of monoaminergic neuron systems have been proposed, the underlying mechanisms are not fully understood. To address these problems, we recently developed a new model of shaking brain injury (SBI) in neonatal rats. These model rats showed transient microhemorrhages in the gray matter of the cerebral cortex and hippocampus. Using this model, we assessed the effects of neonatal repeated mild SBI on subsequent behavior and the stress response, and we further examined the possible contribution of adrenocorticosteroid receptors in the hippocampus and central monoaminergic neuron systems mediating such abnormalities. Behavioral screening examination with a novel open-field test showed that the rats with postnatal day (P) 3-7 shaking had significantly reduced locomotor activity and exploration behaviors than those with late (P8-14) shaking periods, indicating a critical period for neonatal SBI. In the elevated plus maze (EPM) and the light/dark transition (L/D) tests, the model rats spent less time in the open arm of the EPM and the light box of the L/D test, indicating anxiety-like behavior as adults. In adults, the novel EPM-induced adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) responses were significantly increased by neonatal SBI. Further experiments showed that the expression of mineralocorticoid receptor (MR), but not glucocorticoid receptor (GR), was significantly downregulated in the hippocampus of this model rat. These results suggest that neonatal SBI-induced downregulation of MRs in the hippocampus attenuates negative feedback of the hypothalamic pituitary-adrenal (HPA) axis, which results in abnormal secretion of ACTH and CORT. Furthermore, the neurochemical analysis showed that shaken rats had higher dopamine (DA), serotonin (5-HT), 5-hydroxyindolacetic acid (5-HIAA), and noradrenaline (NA) levels in the dorsal part of the medial prefrontal cortex (dmPFC). In the amygdala, higher 5-HIAA and lower NA levels were observed. Both areas are known to be anxiety and stress-related. Taken together, the effects of neonatal SBI on the monoaminergic systems may also be involved in the changes of behavioral and hormonal responses in this model. PMID- 30465806 TI - A rat model to study maternal depression during pregnancy and postpartum periods, its comorbidity with cardiovascular diseases and neurodevelopmental impact in the offspring. AB - This study aimed to develop an animal model of human depression during pregnancy and lactation to examine the effect of maternal, perinatal depression on offspring development. Maternal depression during pregnancy affects up to 20% of women and is a risk factor for both the developmental and long-term health issues. It is often comorbid with the cardiovascular disease (CVD) that affects the uteroplacental circulation and impacts offspring development. More than half of the expecting mothers with depression use antidepressants that cross the placenta and may interfere with the neurodevelopmental programming. Thus, depressed pregnant mothers face a difficult choice whether "to use or not to use" antidepressant therapy, since both untreated depression and antenatal antidepressant exposure present increased risks of neurodevelopmental pathologies. The ongoing clinical debate presents inconclusive data, while the existing animal models of maternal depression do not include early gestational periods, and, do not monitor depressive-like behavior nor address the cardiovascular abnormalities. The presented model includes pregestational depressive behavior extending into pregnancy and lactation, periods that have not been previously examined. Rat dams exposed to pre-gestational chronic mild stress (CMS) developed a sustained decrease in self-grooming behavior, correlated with hormonal, behavioral, and cardiac changes persisting through the postpartum period. Preliminary data indicate neurodevelopmental delays, behavioral and cardiac abnormalities, and altered levels of both the brain and the heart markers in the offspring of stressed dams. Furthermore, the preliminary data predict that maternal pregnancy during the perinatal period is likely to impact the neurodevelopmental process in a sex-dependent manner. Thus the presented here model (PG-LAC CMS) fulfills both the face and the construct validity criteria for maternal stress-induced depression during pregnancy and postpartum that may facilitate further studies of the relative risks of untreated vs. antidepressant treated maternal depression during pregnancy to the mother and her offspring. PMID- 30465807 TI - Proposition for a shortened version of the Leeds Food Preference Questionnaire (LFPQ). AB - The Leeds Food Preference Questionnaire (LFPQ) assesses, among other components, food preference (FP) using a procedure that requires both time and concentration. Its use may therefore be difficult in a complex protocol. In this article, we assessed the suitability of two shorter versions: 1) the LFPQ-S2, using two instead of four foods per group, and 2) the food preference questionnaire (FPQ S16), using the 16 same foods as the LFPQ, displayed simultaneously, that have to be ranked in order of preference. We assessed the reliability of these short versions using correlations and interchangeability (Bland and Altman) analyses. Sixty-nine healthy French adults completed the original LFPQ using foods adapted to the French context, and then the FPQ-S16 procedure before (hungry state) and after (satiated state) a classic lunch. Finally, they had to select the two foods that best depict the characteristics of each group. The two foods receiving the most votes were used to calculate FP scores with the LFPQ-S2 procedure. The FP scores were no different between the three questionnaires and were modified similarly by lunch intake. The FP scores also highly correlated between the two short versions and the LFPQ (mean r = 0.83 and 0.88 in the hungry state and r = 0.86 and 0.87 in the satiated state for LFPQ-S2 and FPQ-S16, respectively). Finally, the FPQ-S16 was considered to be a better surrogate of the LFPQ than the LFPQ-S2. Scores of specific categories (groups of foods categorized by one property; e.g. high-fat foods) showed modest-to-good agreement, whereas scores of combined categories (groups of foods categorized by combined properties, e.g. high-fat and sweet foods) showed poor-to-modest agreement. Overall, the two short versions of the LFPQ could replace it to assess FP in a protocol in which time is limited. The FPQ-S16 appears to be a better solution than the LFPQ-S2, based on interchangeability analyses. PMID- 30465808 TI - Energy metabolism and personality in wild-caught fall field crickets. AB - Standard metabolic rate (SMR) is known to be highly variable across levels of biological organisation (e.g., species, populations, among individuals, within individuals). Some of the variation in SMR can be attributed to factors such as diet, temperature, and body mass, yet much of the residual variation in SMR remains unexplained. Intuitively, we can expect SMR to co-vary with "personality", but the rapidly accumulating empirical evidence on this topic remains equivocal. The goal of this study was to test for a link between SMR and a behavioural syndrome at the among-individual level in wild-caught fall field crickets (Gryllus pennsylvanicus). Paired measurements of SMR and two behavioural traits were repeatedly taken over a two-month period, thus allowing to estimate the among-individual correlations (rind) separately from the residual (within individual) correlations. The two behavioural traits (latency to exit a refuge in a novel environment and "freezing" time following a stressful stimulus) were significantly and moderately repeatable and were found to be part of a syndrome, as indicated by a strong and positive among-individual correlation (rind = 0.82 +/- 0.27). Yet, only latency to exit was significantly and positively correlated with SMR (rind = 0.45 +/- 0.21), suggesting that the link between boldness and SMR may be driven by individual differences in responses to novelty and not to simulated predatory cues. Since we found that bold individuals (short latency to exit) consistently had a lower SMR than shy individuals (long latency to exit), our results go against the pace-of-life syndrome hypothesis. Instead, our results suggest the presence of constrains in the energy budgets of crickets, which generated an allocation trade-off between energy spent on physical activity vs. maintenance costs (SMR). PMID- 30465809 TI - Proposed study designs for approval based on a surrogate endpoint and a post marketing confirmatory study under FDA's accelerated approval regulations for disease modifying osteoarthritis drugs. AB - In 1992, the Food and Drug Administration (FDA) instituted the accelerated approval regulations that allow drugs or biologics for serious conditions that fill an unmet medical need to be approved on the basis of a surrogate endpoint or an intermediate clinical endpoint. The current definition of a serious condition includes chronic disabling conditions, such as osteoarthritis (OA), and thereby provides expanded opportunities for the use of biomarkers for regulatory approval of drugs for OA. The use of surrogates or intermediate clinical endpoints for initial regulatory approval of a drug or biologic requires confirmation in a post marketing study of a drug effect on a clinically relevant outcome, such as on how a patient feels, functions or survives. Current FDA guidance requires that the post-marketing approval (PMA) study be ongoing during the time of initial drug approval. This white paper arose out of the need to brainstorm trial designs that might be suitable for PMA of drugs initially approved, on the basis of a surrogate or intermediate clinical endpoint, for treatment of OA to alter disease progression, abnormal function or pathological changes in the morphology of the joint. In this white paper we define the concept and regulations regarding accelerated approval and propose two major study design scenarios for PMA trials in OA. The long-term goal is to discuss and refine these designs in consultation with regulatory agencies in order to facilitate development of drugs to fill the large unmet need in OA. PMID- 30465810 TI - Cytotoxicity of new psychoactive substances and other drugs of abuse studied in human HepG2 cells using an adopted high content screening assay. AB - New psychoactive substances (NPS) are still an emerging issue in clinical and forensic toxicology. Information about their cytotoxic potential is limited or even unavailable before distribution and thus their intake can be of high risk for consumers. The aim of the presented study was to develop a strategy to identify cytotoxic potential of NPS based on a high content screening assay (HCSA) using HepG2 cell line and four fluorescent dyes, namely Hoechst33342, TMRM, CAL-520, and TOTO-3. The HCSA was optimized to work without an automated analyzer by using the model compounds fluvastatin, paracetamol, propranolol, and simvastatin. The following parameters were monitored: stained nuclei as a measure for cell count as well as nuclear size and nuclear intensity (all Hoechst33342), mitochondrial membrane potential (TMRM), cytosolic calcium level (CAL-520), and plasma membrane integrity (TOTO-3). The present study showed strong cytotoxic potential for the NPS 5F-PB-22 and MDAI, moderate effects for MDMA, MDPV, methylone, cathinone, 4-MEC, and mephedrone, and no toxic effects for methamphetamine. To assess the metabolic suitability of HepG2 cells under the chosen conditions, cell culture supernatants were analyzed by liquid chromatography-high resolution-tandem mass spectrometry. Metabolites were merely detected for lipophilic drugs such as 5F-PB-22 and MDPV and in addition with a much lower abundance in comparison to the parent compound but the study only allowed a qualitative look for metabolites and the used liver cell line might not ideal when considering metabolism. PMID- 30465811 TI - Molecular basis involved in the blocking effect of antidepressant metergoline on C-type inactivation of Kv1.4 channel. AB - Voltage-gated potassium channels (VGKCs) are transmembrane ion channels specific for potassium. Currently there are nine kinds of VGKCs. Kv1.4 is one of shaker related potassium channels. It is a representative alpha subunit of potassium channels that can inactivate A type-currents, leading to N pattern inactivation. Inactivation of Kv channels plays an important role in shaping electrical signaling properties of neuronal and muscular cells. The shape of N pattern inactivation can be modified by removing the N-terminal (NT) domain which results in non-inactivated currents and C pattern inactivation. In a previous work, we have reported the regulatory effect of metergoline on Kv1.4 and Nav1.2 channel activity. In the present study, we constructed a mutant of deleted 61 residues from NT of Kv1.4 channels (Kv1.4 Delta2-61) and found that it induced an outward peak and steady-state currents We also studied the modulation effect of metergoline on the activity of this Kv1.4 Delta2-61 mutant channel without having the N-terminal quick inactivation domain. Our results revealed that treatment with metergoline inhibited NT deleted Kv1.4 mutant channel activity in a concentration-dependent manner which was reversible. Interestingly, metergoline treatment induced little effects on the outward peak current in the deleted Kv1.4 mutant channel. However, metergoline treatment conspicuously inhibited steady state currents of Kv1.4 Delta2-61 channels with acceleration current mode. The acceleration of steady-state current of deleted Kv1.4 mutant channel occurred in a concentration-dependent manner. This means that metergoline can accelerate C pattern inactivation of Kv1.4 Delta2-61 channel by acting as an open state dependent channel blocker. We also performed site-directed mutations in V561A and K532Y, also known as C-type inactivation sites. V561A, K532Y, and V561A + K532Y substitution mutants significantly attenuated the acceleration effect of metergoline on C pattern inactivation of hKv1.4 channel currents. In docking modeling study, predicted binding residues for metergoline were analyzed for six amino acids. Among them, the K532 residue known as the C-type inactivation site was analyzed to be a major site of action. Then various mutants were constructed. K532 substitution mutant significantly abolished the effect of metergoline on Kv1.4 currents among various mutants whereas other changes had slight inhibitory effects. Furthermore, we found that metergoline had specificity for Kv1.4, but not for Kv1.5 currents. In addition, the A type current in rat neuronal cell was inhibited and accelerated of inactivation. This result further shows that metergoline might interact with Lys532 residue and then accelerate C pattern inactivation of Kv1.4 channels with channel type specificity. Taken together, these results demonstrate the molecular basis involved in the effect of metergoline, an ergot alkaloid, on human Kv1.4 channel, providing a novel interaction ligand. PMID- 30465812 TI - Differential effect of amphetamine over the corticotropin-releasing factor CRF2 receptor, the orexin OX1 receptor and the CRF2-OX1 heteroreceptor complex. AB - Stress is one of the factors underlying drug seeking behavior that often goes in parallel with loss of appetite. We here demonstrate that orexin 1 receptors (OX1R) may form complexes with the corticotropin releasing factor CRF2 receptor. Two specific features of the heteromer were a cross-antagonism and a blockade by CRF2 of OX1R signaling. In cells expressing one of the receptors, agonist mediated signal transduction mechanisms were potentiated by amphetamine. Sigma 1 (sigma1) and 2 (sigma2) receptors are targets of drugs of abuse and, despite sharing a similar name, the two receptors are structurally unrelated and their physiological role is not known. We here show that sigma1 receptors interact with CRF2 receptors and that sigma2 receptors interact with OX1R. Moreover, we show that amphetamine effect on CRF2 receptors was mediated by sigma1R whereas the effect on OX1 receptors was mediated by sigma2R. Amphetamine did potentiate the negative cross-talk occurring within the CRF2-OX1 receptor heteromer context, likely by a macromolecular complex involving the two sigma receptors and the two GPCRs. Finally, in vivo microdialysis experiments showed that amphetamine potentiated orexin A-induced dopamine and glutamate release in the ventral tegmental area (VTA). Remarkably, the in vivo orexin A effects were blocked by a selective CRF2R antagonist. These results show that amphetamine impacts on the OX1R-, CRF2R- and OX1R/CRF2R-mediated signaling and that cross-antagonism is instrumental for in vivo detection of GPCR heteromers. PMID- 30465813 TI - Purple sweet potato color improves hippocampal insulin resistance via down regulating SOCS3 and galectin-3 in high-fat diet mice. AB - Hippocampal insulin resistance is the key factor in cognitive deficits. The obesity induces chronic inflammation and the inflammation molecules suppressors of cytokine signaling3 (SOCS3) and galectin-3 directly impair the insulin signaling. The anti-inflammation properties of purple sweet potato color (PSPC) prompted us to investigate the effect of PSPC on cognitive impairment associated with obesity. 60 C57BL/6 mice were randomly divided into four groups: normal, high fat diets (HFD), HFD+PSPC and PSPC. The mice were fed with the HFD or normal diet for 32 weeks. The PSPC (500 mg/kg/day) was administered via oral gavage from 21 to 32 weeks. The results showed the PSPC rectified the abnormal metabolism indexes induced by HFD, including ameliorated obesity, decreased the concentration of fasting blood glucose and improved the glucose tolerance. The Morris water maze test showed the PSPC alleviated the cognitive impairment in HFD mice. The PSPC decreased the expression of Iba1, tumor necrosis factor-alpha, interleukin-1beta, SOCS3 and galectin-3 in hippocampus of HFD mice. The insulin signaling molecules including the p-IRS1 (Tyr608), PI3K p110alpha and p-AKT (Ser473) were detected and the PSPC treatment improved the insulin resistance in hippocampus of HFD mice. Furthermore, the PSPC increased Bcl-2, diminished the Bak and the cleaved-caspase3 in HFD mice hippocampus. These findings indicated that PSPC could be a potential treatment to improve the cognitive impairment associated with obesity. PMID- 30465814 TI - Sex differences in hedonic and homeostatic aspects of palatable food motivation. AB - Feeding behaviors can be modified via homeostatic and hedonic mechanisms. Homeostasis, while primarily concerned with maintaining energy balance via food consumption and energy expenditure, can alter food reward and motivation in response to food deprivation. Alternatively, reward and motivation of food is also driven by its palatability or hedonic nature, and this process can be augmented by opioid receptor activation. The present study examined sex differences in the motivational properties of sucrose pellets through manipulation of homeostatic and hedonic processes via acute food deprivation and acute systemic administration of morphine, respectively. The results showed that regardless of sex, systemic injections of morphine did not alter the motivation to obtain a sucrose pellet on a progressive ratio schedule of reinforcement but does significantly increase consumption of sucrose pellets when freely available. Male and female rats demonstrated similar increased consumption of sucrose pellets under free feeding conditions following acute (24-hours) food deprivation, compared to the non-deprived conditions. Overall, the findings from these experiments indicate that female rats work harder in order to obtain a sucrose pellet (under a Progressive Ratio (PR) schedule of reinforcement) and consume more sucrose pellets than males. However, while acute morphine administration causes similar increases on feeding in males and females, it does not alter motivation as measured by breakpoint on a PR schedule of reinforcement. PMID- 30465815 TI - Beneficial effects of acute high-intensity exercise on electrophysiological indices of attention processes in young adult men. AB - BACKGROUND: Emerging research suggests that a single bout of aerobic exercise can improve cognition, brain function and psychological health. Our aim was to examine the effects of high-intensity exercise on cognitive-performance and brain measures of attention, inhibition and performance-monitoring across a test battery of three cognitive tasks. METHOD: Using a randomised cross-over design, 29 young men completed three successive cognitive tasks (Cued Continuous Performance Task [CPT-OX]; Eriksen Flanker Task; four-choice reaction-time task [Fast Task]) with simultaneous electroencephalogram (EEG) recording before and after a 20-min high-intensity cycling exercise and resting control session. Cognitive-performance measures, EEG power and event-related potential measures, were obtained during the tasks. Random-intercept linear models were used to investigate the effects of exercise, compared to rest, on outcomes. RESULTS: A single bout of exercise significantly (p < 0.05) increased the amplitude of the event-related potential Go P3, but had no effect on the contingent negative variation (CNV), Cue P3 or NoGo P3, during the CPT-OX. Delta power, recorded during the CPT-OX, also significantly increased after exercise, whereas there was no effect on cognitive-performance in this task. Exercise did not influence any cognitive-performance or brain measures in the subsequent Flanker or Fast Tasks. CONCLUSION: Acute high-intensity exercise improves brain-indices reflecting executive and sustained attention during task performance (Go P3 and delta activity), in the CPT-OX, but not anticipatory attention (Cue P3 and CNV) or response inhibition (NoGo P3) in young-adult men. Exercise had no effect on cognitive-performance or brain measures in the subsequent Flanker and Fast tasks, which may potentially be explained by the time delay after exercise. PMID- 30465816 TI - Sp140 is a multi-SUMO-1 target and its PHD finger promotes SUMOylation of the adjacent Bromodomain. AB - BACKGROUND: Human Sp140 protein is a leukocyte-specific member of the speckled protein (Sp) family (Sp100, Sp110, Sp140, Sp140L), a class of multi-domain nuclear proteins involved in intrinsic immunity and transcriptional regulation. Sp140 regulates macrophage transcriptional program and is implicated in several haematologic malignancies. Little is known about Sp140 structural domains and its post-translational modifications. METHODS: We used mass spectrometry and biochemical experiments to investigate endogenous Sp140 SUMOylation in Burkitt's Lymphoma cells and Sp140 SUMOylation sites in HEK293T cells, FLAG-Sp140 transfected and His6-SUMO-1T95K infected. NMR spectroscopy and in vitro SUMOylation reactions were applied to investigate the role of Sp140 PHD finger in the SUMOylation of the adjacent BRD. RESULTS: Endogenous Sp140 is a SUMO-1 target, whereby FLAG-Sp140 harbors at least 13 SUMOylation sites distributed along the protein sequence, including the BRD. NMR experiments prove direct binding of the SUMO E2 ligase Ubc9 and SUMO-1 to PHD-BRDSp140. In vitro SUMOylation reactions show that the PHDSp140 behaves as SUMO E3 ligase, assisting intramolecular SUMOylation of the adjacent BRD. CONCLUSIONS: Sp140 is multi SUMOylated and its PHD finger works as versatile protein-protein interaction platform promoting intramolecular SUMOylation of the adjacent BRD. Thus, combinatorial association of Sp140 chromatin binding domains generates a multifaceted interaction scaffold, whose function goes beyond the canonical histone recognition. GENERAL SIGNIFICANCE: The addition of Sp140 to the increasing lists of multi-SUMOylated proteins opens new perspectives for molecular studies on Sp140 transcriptional activity, where SUMOylation could represent a regulatory route and a docking surface for the recruitment and assembly of leukocyte-specific transcription regulators. PMID- 30465817 TI - Development of a joint population pharmacokinetic model of ezetimibe and its conjugated metabolite. AB - Ezetimibe (EZE) is an extensively used antihyperlipidemic drug with an important cholesterol lowering activity. It undergoes extensive first-pass metabolism to form its active glucuronide metabolite (EZEG). Both drugs exhibit complex pharmacokinetic profiles attributed mainly to repetitive enterohepatic kinetics. The aim of the present study was the investigation of EZE and EZEG pharmacokinetics (PK), through the development of a joint population pharmacokinetic model able to characterize their kinetic processes and enterohepatic recirculation simultaneously. Concentration-time data derived from a bioequivalence study in 28 healthy subjects were used for the analysis. Population PK modeling was performed on the obtained data using nonlinear mixed effect modeling approach, where different methodologies were applied for the description of the complex metabolism and recirculation processes of the two compounds. EZE and EZEG concentrations were best described by a population PK model incorporating first-pass metabolism and an enterohepatic recirculation loop, accounting for the recycling process of the two moieties. This is the first joint population pharmacokinetic model describing the kinetics of both EZE and EZEG. PMID- 30465818 TI - Nanomedicines: The magic bullets reaching their target? AB - Nanomedicines, since the approval of the first one in the 1950s, have been accompanied by expectations of higher efficiency and efficacy, compared to less complex drugs. The fulfilment of those expectations has been slower than anticipated, due to the high complexity of nanomedicine drugs combined with a lack of scientific understanding of nanomedicine interactions with biological systems. The unique properties of their size and their surface composition create difficulties in their physicochemical characterization, and as a consequence, difficulty in assessing the similarity of follow-on products (nanosimilars) to originator nanomedicines. During the 2018 European Federation for Pharmaceutical Sciences (EUFEPS) annual meeting "Crossing the barrier for future medicines" in Athens, there were several sessions on nanomedicines organised by the EUFEPS Nanomedicine Network. This review focuses on the session "Nanomedicines and nanosimilars: how to assess similar?", discussing the nature of nanomedicines, the regulatory aspects of the topic and the impact of practical use and handling of such medicinal products. Emphasis is put on the consequences their nanosize related properties have on the establishment of their critical quality attributes and how this affects the demonstration of bioequivalence of nanosimilars to their originator products. The lack of an appropriate and harmonized regulatory evaluation procedure and the absence of corresponding education are also discussed, especially the uncertainty surrounding the practical use of nanosimilars, including the higher healthcare cost due to less than satisfactory number of safe and efficacious nanosimilars in the market. PMID- 30465819 TI - Structural networks analysis for depression combined with graph theory and the properties of fiber tracts via diffusion tensor imaging. AB - Previous studies have suggested that major depressive disorder was associated with topological properties of impaired white matter. However, most related studies only use one property of nerve fibers to construct whole-brain structural brain network. Considering white matter changes variously, We hypothesized whether the alternations of white matter topological properties could reflect different impairment of white matter integrity. In addition, it is still unknown whether impaired integrity of the white matter fiber tracts has relationship with abnormal topological properties in MDD. This study investigated the impaired white matter by using graph theoretic analyses in a cohort of 37 MDD patients and 38 matched control subjects. In addition, we further investigated fiber tracts differences in three interregional connectivity matrixes of significant different topological regions in MDD. Our graph theoretic analyses demonstrated that 7 different regions were observed for the local measures in patients with MDD compared with control groups. These regions were the central nodes of cortical limbic network, frontal-cingulate network, default mode network (DMN), cognitive control network(CCN)and affective network (AN). In addition, two impaired white matter pathways which included inferior longitudinal fasciculus (ILF) and cingulum were observed in MDD using fiber tracts analysis. We speculate impaired integrity of ILF is due to the alternations in the number of axons or myelination. The results further demonstrated that the number of fiber tracts of anterior cingulum was associated with the depression scores in MDD. PMID- 30465820 TI - Computational approaches for detection and quantification of A-to-I RNA-editing. AB - Adenosine deaminases that act on RNA (ADARs) catalyze adenosine-to-inosine (A-to I) RNA editing in double-stranded RNA. Such editing is important for protection against false activation of the immune system, but also confers plasticity on the transcriptome by generating several versions of a transcript from a single genomic locus. Recently, great efforts were made in developing computational methods for detecting editing events directly from RNA-sequencing (RNA-seq) data. These efforts have led to an improved understanding of the makeup of the editome in various genomes. Here we review recent advances in editing detection based on the data available to the researcher, with emphasis on the principles underlying the various methods and the limitations they were designed to overcome. We also discuss the available various methods for analyzing and quantifying editing levels. This review collects and organizes the available approaches for analyzing RNA editing and discuss the current status of the different A-to-I detection methods with possible directions for extending these approaches. PMID- 30465821 TI - Pharmacokinetics of topically applied tacrolimus dissolved in Marinosolv, a novel aqueous eye drop formulation. AB - Corticosteroids and macrolide immunomodulators such as tacrolimus are effective drugs for the topical treatment of inflammatory eye diseases like allergic conjunctivitis or dry eye. However, tacrolimus is practically insoluble in aqueous solutions and is therefore currently formulated as dispersion. This leads to low bioavailability. Here, we present a novel pharmacologically acceptable, aqueous formulation of tacrolimus based on the "Marinosolv formulation platform". Marinosolv allows the solubilization and thereby improvement of the bioavailability of many otherwise practically insoluble drugs, since dissolved drugs permeate faster into tissues, including ocular tissues. To visualize the benefits of Marinosolv in ophthalmic formulations, we investigated the permeation of a fluorescently labeled estradiol dissolved in Marinosolv compared to a formulation containing the compound as dispersion. Permeation was studied ex-vivo and in-vivo in porcine eyes. Further, we evaluated the improved permeation of topically applied tacrolimus dissolved in Marinosolv compared to a commercially available topically applied tacrolimus dispersion. The Marinosolv formulation was also compared to oral tacrolimus treatment, the standard application route for this drug in case of severe posterior uveitis. Finally, the ocular tissue levels of tacrolimus in all groups were determined using HPLC/MS. We demonstrated that tacrolimus dissolved in Marinosolv reached significantly higher levels in ocular tissues compared to the marketed topical product or after oral application and thus may be a suitable novel option for the treatment of several eye diseases, such as allergic conjunctivitis or uveitis. Thus, Marinosolv may be considered as a new vehicle for tacrolimus eye drops. PMID- 30465822 TI - Drug-free albumin-triggered sensitization of cancer cells to anticancer drugs. AB - Chemosensitization strategies have been used to sensitize cancer cells to conventional drugs, but their utility is often obstructed by additional off target toxicity, limited access to intracellular targets and heterogeneous tumor pathogenesis. To address these challenges, we rationally developed a drug-free human serum albumin (HSA)-based therapeutic (KH-1) that functions extracellularly and exhibits pleiotropic effect on multiple intracellular signaling pathways. It is a two-step touch-trigger system that consists of a pretargeting anchor on surface receptor CD20 (anti-CD20 Fab' conjugated with a morpholino oligonucleotide 1) and a CD20 clustering actuator (HSA grafted with multiple copies of complementary morpholino oligonucleotide 2). The extracellular actuation by surface CD20 crosslinking boosts robust activations of numerous intracellular responses, and promotes cancer cell susceptibility to various anticancer drugs, including docetaxel (microtubule stabilizer), gemcitabine (nucleoside analogue) and GDC-0980 (PI3K/mTOR inhibitor). The broad applicability of KH-1 is demonstrated to result from simultaneous inhibition of survival pathways and augmentation of apoptotic pathways. In addition, KH-1 covalently conjugated with anthracycline anticancer agent, epirubicin, integrates the advantages of both chemosensitization function and improved intracellular drug delivery in a single system and takes effect on the same cell. Therefore, in the present study, we have provided mechanistic demonstration that crosslinking of surface receptors can be leveraged to elicit chemosensitization. PMID- 30465823 TI - Antimicrobial synergy of monolaurin lipid nanocapsules with adsorbed antimicrobial peptides against Staphylococcus aureus biofilms in vitro is absent in vivo. AB - Bacterial infections are mostly due to bacteria in their biofilm-mode of growth, while penetrability of antimicrobials into infectious biofilms and increasing antibiotic resistance hamper infection treatment. In-vitro, monolaurin lipid nanocapsules (ML-LNCs) carrying adsorbed antimicrobial peptides (AMPs) displayed synergistic efficacy against planktonic Staphylococcus aureus, but it has not been demonstrated, neither in-vitro nor in-vivo, that such ML-LNCs penetrate into infectious S. aureus biofilms and maintain synergy with AMPs. This study investigates the release mechanism of AMPs from ML-LNCs and possible antimicrobial synergy of ML-LNCs with the AMPs DPK-060 and LL-37 against S. aureus biofilms in-vitro and in a therapeutic, murine, infected wound-healing model. Zeta potentials demonstrated that AMP release from ML-LNCs was controlled by the AMP concentration in suspension. Both AMPs demonstrated no antimicrobial efficacy against four staphylococcal strains in a planktonic mode, while a checkerboard assay showed synergistic antimicrobial efficacy when ML-LNCs and DPK 060 were combined, but not for combinations of ML-LNCs and LL-37. Similar effects were seen for growth reduction of staphylococcal biofilms, with antimicrobial synergy persisting only for ML-LNCs at the highest level of DPK-060 or LL-37 adsorption. Healing of wounds infected with bioluminescent S. aureus Xen36, treated with ML-LNCs alone, was faster when treated with PBS, while AMPs alone did not yield faster wound-healing than PBS. Faster, synergistic wound-healing due to ML-LNCs with adsorbed DPK-060, was absent in-vivo. Summarizing, antimicrobial synergy of ML-LNCs with adsorbed antimicrobial peptides as seen in vitro, is absent in in-vivo healing of infected wounds, likely because host AMPs adapted the synergistic role of the AMPs added. Thus, conclusions regarding synergistic antimicrobial efficacy, should not be drawn from planktonic data, while even in-vitro biofilm data bear little relevance for the in-vivo situation. PMID- 30465824 TI - Prolonged PM2.5 exposure elevates risk of oxidative stress-driven nonalcoholic fatty liver disease by triggering increase of dyslipidemia. AB - An increasing number of studies have shown that air pollution containing particulate matter (PM) <= 2.5 um (PM2.5) plays a significant role in the development of metabolic disorder and other chronic diseases. Inflammation and oxidative stress caused by metabolic syndrome are widely determined to be critical factors in the development of nonalcoholic fatty liver disease (NAFLD) pathogenesis. However, there is no direct evidence of this, and the underlying molecular mechanism is still not fully understood. In this study, we investigated the role of inflammation and oxidative stress caused by prolonged PM2.5 exposure in dyslipidemia-associated chronic hepatic injury, and further determined whether an increase in hepatic inflammation and oxidative stress promoted lipid accumulation in the liver, ultimately increasing the risk of NAFLD. Therefore, we studied changes in indicators of metabolic disorder and in symbolic indices of NAFLD. We confirmed increases in insulin resistance, glucose tolerance, peripheral inflammation and dysarteriotony in PM2.5-induced mice. Oxidative stress and inflammatory response in the liver caused by PM2.5 inhalation contributed to abnormal hepatic function, further promoting lipid accumulation in the liver. Moreover, we observed inhibition of oxidative stress and inflammatory response by pyrrolidine dithiocarbamate (PDTC) and N-acetyl-L-cysteine (NAC) in vitro, suggesting that oxidative stress and inflammatory in liver cells aggravated by PM2.5 contributed to hepatic injury by altering normal lipid metabolism. These results indicate a new goal for preventing and treating air pollution-induced diseases: suppression of oxidative stress and inflammatory response. PMID- 30465825 TI - Effect of antioxidant supplements on lipid peroxidation levels in primary cortical neuron cultures. AB - Oxidative stress, specifically lipid peroxidation, is a major driving force in neurodegenerative processes. However, the exact role of lipid peroxidation remains elusive as reliable real-time detection and quantification of lipid peroxyl radicals proves to be challenging in vitro and in vivo. Motivated by this methodological limitation, we have optimized conditions for real-time imaging and quantification of lipid peroxyl radical generation in primary neuron cultures using the lipophilic fluorogenic antioxidant H4BPMHC (8-((6-hydroxy-2,5,7,8 tetramethylchroman-2-yl)-methyl)-1,5-di(3-chloropropyl)-pyrromethene fluoroborate), an alpha-tocopherol analog probe. By subjecting neurons to different antioxidant conditions in the presence and absence of lipid peroxidation inducing stressors (Haber-Weiss reagents), we maximized H4BPMHC sensitivity and confirmed its potential to temporally resolve subtle and marked differences in lipid peroxidation levels in real-time. Herein we report imaging and quantification of homeostatic and induced lipid peroxidation in primary neuron cultures, supporting the use of this probe for investigating healthy and diseased states. Overall these results provide the necessary foundation and impetus towards using H4BPMHC for elucidating and mapping lipid peroxyl radical contributions to ROS-associated pathological processes in neurons. PMID- 30465826 TI - Low expression of PDK1 inhibits renal cell carcinoma cell proliferation, migration, invasion and epithelial mesenchymal transition through inhibition of the PI3K-PDK1-Akt pathway. AB - As the most commonly occurring form of primary renal tumor, renal cell carcinoma (RCC) is a malignancy accompanied by a high mortality rate. 3-phosphoinositide dependent protein kinase 1 (PDK1) has been established as a protein target and generated considerable interest in both the pharmaceutical and academia industry. The aim of the current study was to investigate the effect of si-PDK1 on the RCC cell apoptosis, proliferation, migration, invasion and epithelial mesenchymal transition (EMT) in connection with the PI3K-PDK1-Akt pathway. Microarray analysis from the GEO database was adopted to identify differentially expressed genes (DEGs) related to RCC, after which the positive expression of the PDK1 protein in tissue was determined accordingly. The optimal silencing si-RNA was subsequently selected and RCC cell lines 786-O and A498 were selected and transfected with either a si-PDK1 or activator of the PI3K-PDK1-Akt pathway for grouping purposes. The mRNA and protein expressions of PDK1, the PI3K-PDK1-Akt pathway-, EMT- and apoptosis-related genes were then evaluated. The effect of si PDK1 on cell proliferation, apoptosis, invasion and migration was then analyzed. Through microarray analysis of GSE6344, GSE53757, GSE14762 and GSE781, PDK1 was examined. PDK1 was determined to be highly expressed in RCC tissues. Si-PDK1 exhibited marked reductions in relation to the mRNA and protein expression of PDK1, PI3K, AKT as well as Vimentin while elevated mRNA and protein expressions of E-cadherin were detected, which ultimately suggested that cell migration, proliferation and invasion had been inhibited coupled with enhanced levels of cell apoptosis. While a notable observation was made highlighting that the PI3K PDK1-Akt pathway antagonized the effect of PDK1 silencing. Taken together, the key observations of this study provide evidence suggesting that high expressions of PDK1 are found in RCC, while highlighting that silencing PDK1 could inhibit RCC cell proliferation, migration, invasion and EMT by repressing the PI3K-PDK1 Akt pathway. PMID- 30465827 TI - How do chemokines navigate neutrophils to the target site: Dissecting the structural mechanisms and signaling pathways. AB - Chemokines play crucial roles in combating microbial infection and initiating tissue repair by recruiting neutrophils in a timely and coordinated manner. In humans, no less than seven chemokines (CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8) and two receptors (CXCR1 and CXCR2) mediate neutrophil functions but in a context dependent manner. Neutrophil-activating chemokines reversibly exist as monomers and dimers, and their receptor binding triggers conformational changes that are coupled to G-protein and beta-arrestin signaling pathways. G protein signaling activates a variety of effectors including Ca2+ channels and phospholipase C. beta-arrestin serves as a multifunctional adaptor and is coupled to several signaling hubs including MAP kinase and tyrosine kinase pathways. Both G-protein and beta-arrestin signaling pathways play important non-overlapping roles in neutrophil trafficking and activation. Functional studies have established many similarities but distinct differences for a given chemokine and between chemokines at the level of monomer vs. dimer, CXCR1 vs. CXCR2 activation, and G-protein vs. beta-arrestin pathways. We propose that two forms of the ligand binding two receptors and activating two signaling pathways enables fine-tuned neutrophil function compared to a single form, a single receptor, or a single pathway. We summarize the current knowledge on the molecular mechanisms by which chemokine monomers/dimers activate CXCR1/CXCR2 and how these interactions trigger G-protein/beta-arrestin-coupled signaling pathways. We also discuss current challenges and knowledge gaps, and likely advances in the near future that will lead to a better understanding of the relationship between the chemokine CXCR1/CXCR2-G-protein/beta-arrestin axis and neutrophil function. PMID- 30465828 TI - Application of polymerized multiporous nanofiber of SnO2 for designing a bienzyme glucose biosensor based on HRP/GOx. AB - This work reports on a novel glucose biosensor based on co-immobilization of glucose oxidase (GOx) and horseradish peroxidase with polymerized multiporous nanofiber (MPNFs) of SnO2 onto glassy carbon electrode with chitosan. Multiporous nanofibers of SnO2 were synthesized by electrospinning method from the tin precursor which possesses high surface area good electrical conductivity, and the nanofibers were polymerized with polyaniline (PANI). GOx and HRP were then co immobilized with the nanofibers on the surface of the glassy carbon electrode by using chitosan. The polymerized nanofibers play a significant role in facilitating the direct electron transfer between the electroactive center of the immobilized enzyme and the electrode surface. The morphology of the nanofiber and polymerized nanofiber has been evaluated by field emission scanning electron microscopy (FESEM). Cyclic Voltammetry and amperometry were employed to study and optimize the performance of the fabricated biosensor. The PANI/SnO2-NF/GOx HRP/Ch/GC biosensor displayed a linear amperometric response towards the glucose concentration range from 5 to 100 MUM with a detection limit of 1.8 MUM (S/N = 3). Also, the anti-interference study and real sample analysis was investigated. Furthermore, the biosensor reported in this work exhibited excellent stability, reproducibility, and repeatability. PMID- 30465829 TI - Functional substitution of domain 3 (T1 copper center) of a novel laccase with Cu ions. AB - A bacterial laccase having potential to work in industry without mediator is of special interest. In this work, gene (1.83kb) encoding a novel laccase from Rheinheimera sp., having potential to deink waste paper without mediator, was cloned, over-expressed and the induced 69kDa protein (RhLacc) was purified and characterized. rhlacc gene was mutated by error prone PCR and mutants were sequenced. One mutant showed protein truncation resulting in the absence of domain 3 that contains T1 copper center. It is known that redox potential of T1 is the key parameter for substrate oxidation. Overexpression of this mutant gene showed induced 41.1kDa protein (?RhLacc) that exhibited laccase activity but in the presence of added copper, compared to RhLacc which showed activity without added copper ions. Optimum temperature for both was 55 degrees C. However, optimum pH varied with substrates. Kinetic studies showed ?RhLacc had lower affinity for substrates except for guaiacol and reduced kcat in comparison to RhLacc. Both were able to deink old newspaper and degrade indigo carmine without mediator. The study suggests that the novel property to deink waste paper without mediator may not depend on the redox potential of T1 but other mechanisms using domains 1 and 2 may be involved. PMID- 30465830 TI - Isolation, cloning and characterization of an azoreductase and the effect of salinity on its expression in a halophilic bacterium. AB - Understanding the molecular mechanisms of azo dye decolorization is important for the development of effective bioremediation for textile-colored wastewater. A halophilic bacterium Halomonas sp. strain GT was isolated, which could degrade the azo dye Acid Brilliant Scarlet GR at 10% NaCl. The complete genome sequence of this strain was obtained using the PacBio RS II platform. Genome annotation revealed that four proteins are related to decolorization of azo dyes, such as azoreductase, laccases, benzene 1,2-dioxygenase, and catechol 1,2-dioxygenase. The putative azoreductase gene of Halomonas sp. strain GT responsible for the decolorization of azo dye in high salt environment was isolated. Phylogenetic tree analysis showed that the azoG (azoreductase gene of Halomonas sp. strain GT) and its homologs constituted a new branch of the NADH depending azoreductases, with all the homologous sequence of the protein from halophilic bacteria. At high NaCl concentrations, azoreductase gene expression and azoreductase activity were restrained in Halomonas sp. strain GT, which resulted in low a decolorization rate. PMID- 30465831 TI - Polysaccharide fractions from Fortunella margarita affect proliferation of Bifidobacterium adolescentis ATCC 15703 and undergo structural changes following fermentation. AB - In this study, the relationships between the proliferation effect of polysaccharide fractions from the citrus shrub Fortunella margarita on Bifidobacterium adolescentis ATCC 15703 and their resulting structural changes were investigated. Four polysaccharide fractions, FP20, FP40, FP60, and FP80, were obtained by graded precipitation at ethanol concentrations of 20%, 40%, 60% and 80%, respectively. The results showed that polysaccharide fractions, especially FP20, FP40, and FP60, enhanced the proliferation of B. adolescentis ATCC 15703 and their effects were better than those of FP80, inulin or glucose. Moreover, acetic acid was mainly produced during fermentation. After fermentation, the molecular weight of polysaccharide fractions decreased and the tightly structural chain conformations of FP20, FP40, and FP60 changed to highly branched structures. The prebiotic effect of these polysaccharide fractions might be related to their molecular weight and chain conformation. Thus, these polysaccharides could be used as potential prebiotics. PMID- 30465832 TI - Dissolution, derivatization, and functionalization of chitin in ionic liquid. AB - In this article, a review of the researches, which endeavor concerning ionic liquids, used as media for dissolution, derivatization, and functionalization of chitin is presented. Although chitin has been noted to show poor solubility and processability, leading to mostly an unutilized biomass resource, some ionic liquids have been found to dissolve chitin. For example, an ionic liquid, 1-allyl 3-methylimidazolium bromide (AMIMBr), was reported to dissolve chitin in concentrations up to 4.8 wt% and to form ion gels at higher contents of chitin. A cellulose/chitin binary ion gel was fabricated from the individually prepared cellulose/chitin solutions with ionic liquids, which was further converted into a binary film by regeneration. The binary ion gel was applied as a novel electrolyte for an electric double layer capacitor. Acetylation of chitin using acetic anhydride in AMIMBr gave chitin acetates with high degrees of substitution. The acetylation method has been extended to synthesize several chitin acylates using acyl chlorides after optimization of the conditions. The derivatization technique of chitin in AMIMBr was applied to the synthesis of a chitin macroinitiator for atom transfer radical polymerization (ATRP). Grafting of styrene by ATRP from the resulting macroinitiator was thus conducted to give chitin-graft-polystyrene. PMID- 30465833 TI - Physiochemical characterization, antioxidative, anticancer cells proliferation and food pathogens antibacterial activity of chitosan nanoparticles loaded with Cyperus articulatus rhizome essential oils. AB - Essential oil of Cyperus articulatus have known bioactivities, the qualitative chemical composition analysis of the Essential Oils (EOs) by Gas Chromatography Mass Spectrometry (GC-MS) revealed the presence of new compounds not previously known to the plant rhizome which includes, sesquiterpenes, monoterpenes, nootkatone, 6-methyl-3,5-heptadien-2-one, retinene, nopinone, cycloeucalenol, anozol, toosendanin, furanone, ethanone and vitamin A. Cyperus articulatus Essential Oils (CPEOs) loaded Chitosan Nanoparticles (CSNPs) was successful synthesized using an oil-in-water mixture and ionic gelation method and were characterized by Scanning Electron Microscopy (SEM), Fourier Transform Infrared Spectroscopy (FTIR) and UV-Vis spectrophotometry. CPEOs had more radical scavenging bioactivity in vitro than CSNPs and CPEO-CSNPs at initial storage times. CPEO-CSNPs showed the highest (P < 0.05) antioxidant activity over a prolonged period of time. Antimicrobial activity of two strains of bacteria, Staphylococcus aureus (ATCC6538), and Escherichia coli (ATCC 8739) showed that all CPEO-loaded chitosan nanoparticle inhibited bacterial growth at lower (P < 0.05) CPEO-CSNP concentration (5 mg/mL MIC) compared to free CPEOs (10 mg/mL MIC). Trypan blue in vitro exclusion assay showed CPEO-CSNPs to be more cytotoxic against MDA-MB-231 breast cancer cells after 48 h. The bioactivity and physiochemical properties of CPEO-CSNPs have shown promising applications in food and pharmaceutical industries. PMID- 30465834 TI - Immune-enhancing effects of polysaccharides from purple sweet potato. AB - Immune-enhancing effects of three kinds of purple sweet potato polysaccharides (PSPPs) including water-soluble polysaccharide (WSP), dilute alkali-soluble polysaccharide (DASP) and concentrated alkali-soluble polysaccharide (CASP) were evaluated. Scanning electron microscope analysis showed that all PSPPs could stimulate the formation of microvilli-like structures in cellular surfaces, which was possibly related to activation of macrophages. Neutral red uptake assay showed that PSPPs could increase the phagocytic activity of cells. High dose (400 MUg/mL) of PSPPs could notably augment the level of nitric oxide (NO). ELISA analysis revealed that 200 and 400 MUg/mL of PSPPs distinctly elevated the production of IL-1beta. Cells received 200 and 400 MUg/mL of WSP as well as 400 MUg/mL of DASP exhibited higher level of IL-6. Results of animal experiments showed that WSP treatment (400 mg/kg) could promote the secretions of IgA, IgG, IgM and sIgA in both normal and immunosuppressed mice. Moreover, CASP treatment (400 mg/kg) elevated the production of IgM in the serum of normal and immunosuppressive mice, while DASP (400 mg/kg) only improved the secretion of IgM in normal mice. In summary, all three polysaccharides can stimulate immune responses of macrophages and positively regulate adaptive immunity by enhancing the production of immunoglobulins in mice. PMID- 30465835 TI - Novel cellulose-gelatin composite films made from self-dispersed microgels: Structure and properties. AB - A series of epichlorohydrin-couple-linked cellulose-gelatin composite films (ECGF) was fabricated in NaOH/urea aqueous solution using a process involving homogenous blending, coupling, dialysis, self-dispersion, microgel solution casting, and evaporation. Their structure and properties were characterized with elemental analysis, Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (1H NMR), gel permeation chromatography (GPC), scanning electron microscope (SEM), atomic force microscopy (AFM), ultraviolet visible (UV-vis) spectroscopy, water vapor permeability, and mechanical testing. The results showed that the self-dispersed cellulose-gelatin microgels were successfully prepared and the coupling interactions existed in the inter- and intra-molecules of the corresponding composite films during the fabrication process. The water vapor permeability of the ECGF films was improved when the protein content was higher than 30 wt% in composite films at 75% relative humidity. Interestingly, compared with the cellulose/protein composite films prepared via phase separation method, ECGF films exhibited more homogeneous surface and compact cross-section structures, as well as presented higher light transmittance at 400 nm of about 88% and relative lower swelling ratio. Moreover, ECGF films displayed higher tensile strength compared with that of water-soluble cellulose derivatives/protein composite films in dry and wet states. PMID- 30465836 TI - Evaluation of modified hyaluronic acid in terms of rheology, enzymatic degradation and mucoadhesion. AB - PURPOSE: This study aimed to investigate the properties of modified hyaluronic acid in terms of rheological properties, enzymatic degradation and mucoadhesiveness. METHODS: Hyaluronic acid (HA) was chemically modified with sulfhydryl ligand cysteine ethyl ester (C) in order to immobilize sulfhydryl groups on the polymeric backbone. MTT assay was performed to evaluate the safety of hyaluronic acid-cysteine ethyl ester (HAC). Rheological and enzymatic degradation studies were accomplished by preparing hydrogels of HA and HAC, respectively. HA served as control. Enzymes such as lysozyme, amylase and hyaluronidase were chosen to perform degradation studies. To study mucoadhesiveness, hydrogels of HA and HAC, respectively, were mixed with mucus and evaluated by rheology. RESULTS: MTT assay indicated no toxicity at all. The rheological assay showed 2.2-fold increase in gelling properties in case of HAC in comparison to HA. Furthermore, it could be shown that HAC was degraded by amylase to a lesser extent of 11.5-fold than HA. After 2 h, HA showed a higher degradation by lysozyme with 67.97% than HAC. Adhesion studies exhibited a 2.17 fold higher mucoadhesion of HAC with mucus compared to HA. CONCLUSION: These results will open the door for high efficient drug delivery systems based on hydrogels for mucosal application. PMID- 30465837 TI - Mathematical modeling and experimental study of mechanical properties of chitosan based polyurethanes: Effect of diisocyanate nature by mixture design approach. AB - This research work has been done to investigate the influence of the geometry of aliphatic diisocyanate (hexamethylene diisocyanate, HDI), cycloaliphatic diisocyanate (isophorone diisocyanate, IPDI) and aromatic diisocyanate (2,4 toluene diisocyanate, TDI) on the tensile strength and hardness of chitosan based polyurethane biomaterials. For this purpose, chitosan (CS) and polycaprolactone diol (PCL) based polyurethanes have been synthesized with above mentioned diisocyanates following statistical design (mixture design). Simplex mixture design was used for analysis and totally 10 experiments were generated by the software. Samples were tested based on the portions of mixture components. Fourier transform Infrared attenuated total reflection (FTIR-ATR) and nuclear magnetic resonance (NMR) spectroscopic techniques confirmed the synthesis of chitosan based polyurethanes. This biomaterial has been established as an innovative and promising strategy to improve the mechanical strength of chitosan based polyurethanes. PMID- 30465838 TI - Characterization and assessment of antioxidant and antibacterial activities of sulfated polysaccharides extracted from cuttlefish skin and muscle. AB - In this study, novel polysaccharides extracted from cuttlefish skin (CSP) and muscle (CMP), by precipitation with cetylpyridinium, were characterized and their antioxidant and antibacterial activities were investigated. CMP showed the highest amounts of sulfated groups (6.6%), uronic acids (9.2%) and proteins (3.7%). Infrared spectroscopic analysis indicated the presence of sulfonyl (OSO) and acetyl (CH3CO-) groups for both CSP and CMP. In addition, CSP showed the presence of glucuronic acid (GlcA) and galacturonic acid (GalA) as major components, while CMP showed highest amount of GalA in its monosaccharide composition. Sulfated polysaccharides were found to display important antibacterial activity against several Gram+ and Gram- bacteria. In addition, they exhibited strong antioxidant activities as showed by various in vitro tests. Fractionation of cuttlefish polysaccharides, by DEAE-cellulose column showed one peak during the buffer elution phase and three major fractions for CMP and two peaks for CSP during the linear gradient of NaCl. The last eluting sulfated fraction from each sample, characterized by the highest negative charge, was found to exhibit the best antioxidant and antibacterial activities. The obtained results demonstrated that cuttlefish polysaccharides and their fractions could serve as natural antioxidant and antibacterial agents. PMID- 30465839 TI - Identification of differences in the formation of plasma glycated proteins between dogs and humans under diabetes-like glucose concentration conditions. AB - Dogs have been proposed as a translational model and used for studying aging, diabetes, and diabetes-related complications in humans. However, no studies have ever compared the glycation of plasma proteins between dogs and humans under similar experimental conditions. Thus, the aim of this study was to fill this gap by comparing the plasma protein glycation patterns of dogs and humans in an ex vivo system. Canine and human plasma samples were incubated with glucose at concentrations comparable to those observed in diabetic patients. The final glucose plasma concentration resulted in similar glucose:albumin ratios in both species. Glycated proteins were evaluated by measuring the content of fructosamine, protein carbonyls, and the formation of advanced glycation end products (AGEs). The concentrations of fructosamine and protein carbonyls in canine and human plasma increased in a glucose concentration-dependent manner (P < 0.0001). Of note, the relative increment of fructosamine and protein carbonyl content and AGE formation was always higher in human than in dog plasma. Our results reveal that the plasma glycation processes in dogs and humans are not similar. These novel findings could contribute to improve our understating about canine and human diabetes as well as other condition associated in the glycation of proteins. PMID- 30465840 TI - Cell behavior on the alginate-coated PLLA/PLGA scaffolds. AB - Here, we investigated the effect of preparation temperature and alginate-coating on L929 fibroblast behavior on lyophilized microporous PLLA/PLGA (95:5, w/w) scaffolds. The lower freezing temperature used during lyophilization (-80 degrees C) resulted in smaller pores (around 50 MUm) and higher compressive modulus (1500 kPa) than those prepared at the higher temperature (-20 degrees C) (pore size: 120 MUm, compressive modulus: 600 kPa) (p < 0.01). Cell proliferation was significantly lower on the alginate-coated scaffolds (p < 0.05), probably due to weak cell adhesion on alginate, rapid degradation/dissolution of the alginate hydrogel (40% weight loss after 2 weeks of incubation) (p < 0.05), which resulted in loss of material and cells, and the decrease in the pH (p < 0.05), which probably resulted in decreased cell metabolic activity. Cells tended to get less round on the scaffolds prepared at -20 degrees C, which had lower compressive modulus and larger pores, and upon coating with alginate, which resulted in a hydrophilic surface that had lower stiffness. When the scaffolds had closer stiffness to the cells, the cells tended to get more branched. The most branched morphology of the fibroblasts was obtained in the presence of alginate, a natural polymer having a similar stiffness with that of the L929 fibroblasts (4 kPa). PMID- 30465841 TI - Investigation of potential biomarkers for thrombosis related diseases in Turkish Cypriot population. AB - Genetic and environmental factors are involved in development of many diseases. The allelic frequencies may differ in different populations and in different ethnic groups. The aim of this study was to investigate the genotypes of MTHFR and factor VII polymorphisms and to identify biomarkers for thrombosis related diseases in Turkish Cypriot population. The lipid profiles and genotypes of MTHFR polymorphisms (rs1801133, rs1801131) and factor VII (rs6046) genes were investigated for the first time in the Turkish Cypriot population. The heterozygosity for MTHFR (rs1801133, rs1801131) and FVII (rs6046) polymorphisms is high in Turkish Cypriot population. The heterozygosity for MTHFR C677T was 38%, MTHFR A1298C was 40% and factor VII G353A was 37%, respectively. Allelic frequencies between males and females were similar. There were no correlations between the genotypes of polymorphisms and the lipid profiles. This study is the first genetic epidemiology study that investigated the allelic frequencies of MTHFR and FVII polymorphisms associated with metabolic syndromes. This study proves to be a crucial analysis in order to use these polymorphisms as a predictor of disease development in the Turkish Cypriot community. PMID- 30465842 TI - Effect of enzyme-assisted extraction on the physicochemical properties of mucilage from the fronds of Asplenium australasicum (J. Sm.) Hook. AB - Enzyme-assisted extraction (EAE) possesses the advantages of being environmentally friendly and easily operated owing to relatively mild reaction conditions. Thus, mucilage from Asplenium australasicum was extracted with xylanase, glucanase and simultaneous application of both enzymatic preparations then investigated for their physicochemical properties. It was observed that compared to the control, the yield of mucilage increased significantly by EAE (from 3.64% to 6.04-6.86%), while the average molecular weight also increased slightly. SEM results showed that enzymes can erode the raw material which contributed to the higher extraction efficiency of polysaccharide. Furthermore, EAE modified the monosaccharide composition profile of A. australasicum mucilage considerably, especially there was a significant increase in glucose and galacturonic acid content. Although the FT-IR fingerprint did not change pronouncedly due to the action of the enzymes, but the degree of polysaccharide branching seemed to be more complicated, thus significantly reducing the intrinsic viscosity and water holding capacity of mucilage. PMID- 30465843 TI - Bio-inspired keratin-based core-crosslinked micelles for pH and reduction dual responsive triggered DOX delivery. AB - Facile bio-inspired approach has been developed to prepare novel DOX-loaded chicken feather keratin-based core-crosslinked micelles (DOX/Ker-PEG CCMs) for pH and reduction dual-responsive tumor-specific intracellular triggered DOX delivery, by oxidation crosslinking the DOX/Ker-PEG micelles which were simply self-assembled by adjusting solution pH value to 10. The final DOX/Ker-PEG CCMs with a mean hydrodynamic diameter of 152 nm were obtained with a drug loading capacity (DLC) of 24.8%. The in vitro controlled release profiles demonstrated the pH and reduction dual-responsive triggered release of DOX from the developed bio-inspired drug delivery system (DDS), with a cumulative release of 58% within 3 days in a sustained release manner in the stimulated tumor intracellular microenvironment, while a low premature drug leakage of 14% occurred in the normal physiological medium. Furthermore, the MTT assays demonstrated that the graft copolymer Ker-PEG58 possessed excellent cytocompatibility, while the DOX/Ker-PEG CCMs exhibited an enhanced anti-tumor efficacy on the HepG2 cells than the free DOX. PMID- 30465844 TI - Fucosylated chondroitin sulfate from Isostichopus badionotus alleviates metabolic syndromes and gut microbiota dysbiosis induced by high-fat and high-fructose diet. AB - Fucosylated chondroitin sulfate from Isostichopus badionotus (fCS-Ib) is a kind of sulfated polysaccharides with well-repeated structure. In our former publications, fCS-Ib has been reported to be a functional food ingredient with hypoglycemic and antilipemic activities. However, there is no systematic study to investigate the effects of fCS-Ib on metabolic syndromes. In the present study, C57BL/6 mice fed on a high-fat and high sucrose diet (HFSD) for 6 weeks was used to cause metabolic syndromes. The final results showed that fCS-Ib alleviated obesity, hyperlipidemia, hyperglycemia, inflammation, liver steatosis, and adipocyte hypertrophy caused by HFSD. Meanwhile, fCS-Ib showed powerful effects on moderating gut microbiota dysbiosis in the HFSD-fed mice. Supplement of fCS-Ib could reduce ratio of Firmicutes to Bacteroidetes by decreasing abundance of Lachnospiraceae and Allobaculum while increasing abundance of Porphyromonadaceae, Barnesiella, and Bacteroides. Our results showed that fCS-Ib could be further developed as a potential pharmaceutical agent to prevent metabolic syndromes and gut microbiota dysbiosis. PMID- 30465845 TI - Effect of functionalized gold nanoparticle on collagen stabilization for tissue engineering application. AB - Functionalization of nanoparticle with specific groups is one of the most straightforward strategies to induce structural stability and specific cell responses from collagen based biomaterials. The effect of functionalised nanoparticles on triple helical conformational changes in collagen has not been understood well. For understanding the role of functionalization on collagen conformation, gold nanoparticles (Au NPs) prepared through wet chemical methods and functionalized with organic molecules (F-AuNPs) such as self-assembled monolayer (SAM), (3-aminopropyl) triethoxysilane (APTES), Polysaccharides (pectin and chitosan) and Poly(amido amine) PAMAM dendrimer (G0), were characterised and their interaction with collagen was studied. Protein conformational changes assessed by circular dichroism spectroscopy (CD) reveals that triple helical conformation of collagen was retained in presence of functionalized gold nanoparticle. The biocompatibility of functionalized gold nanoparticle was analysed against keratinocytes (HaCaT) cell by using (3-(4,5-dimethylthiazol-2 yl)-2, 5-diphenyltetrazolium bromide) MTT assay. The result suggested that dendrimer functionalized gold nanoparticle exhibited higher cell viability when compared to other molecules functionalized gold nanoparticles studied. Based on the outcome of this study it can be envisioned that dendrimer functionalized gold nanoparticle mediated collagen materials are highly suitable for tissue engineering and cosmetic application. PMID- 30465846 TI - Enhanced production, overexpression and characterization of a hyperthermophilic multimodular GH family 2 beta-glucuronidase (TpGUS) cloned from Thermotoga petrophila RKU-1T in a mesophilic host. AB - A multimodular hyperthermophilic beta-glucuronidase (TpGUS) from Thermotoga petrophila RKU-1T, belongs to glycoside hydrolase family 2 (GH2), was cloned and overexpressed in Escherichia coli BL21 CodonPlus (DE3)-RIPL. Expression and production of extracellular TpGUS was enhanced through various specific cultivation and induction strategies. Extracellular TpGUS activity was improved by 3.44 and 7 fold in 4 * ZB medium induced with 0.5 mM IPTG and 100 mM lactose, respectively. The enzyme was purified to homogeneity with a single band of 65.6 kDa on SDS-PAGE, using two subsequent steps of anion exchange and hydrophobic interaction chromatography after heat precipitation (70 degrees C, 1 h). Optimal activity of TpGUS was observed at 95 degrees C and pH 6.0; and it displayed prodigious thermal stability over a temperature range of 50-85 degrees C for 12 h at pH 6.0-7.5. Km, Vmax, VmaxKm-1, kcat, and kcatKm-1 were calculated to be 0.7 mM, 227 mmol mg-1 min-1, 324.3 min-1, 164,492.7 s-1 and 234,989.6 mM-1 s-1, respectively using pNPGU as a substrate. Recombinant TpGUS exhibited favorable properties which make this a promising candidate for various biotechnological and pharmacological applications. PMID- 30465847 TI - Pectic oligosaccharides hydrolyzed from citrus canning processing water by Fenton reaction and their antiproliferation potentials. AB - Citrus canning processing water contains a valuable and renewable source of biopolymers and bioactive compounds including pectic polysaccharides. Upgrading these processing wastes can not only alleviate environmental pollution but also add value to the commodity's production. In a previous study we recovered pectic polysaccharides from citrus canning processing water. In the present study, pectic polysaccharides recycled from citrus canning processing water was depolymerized by an optimized Fenton system. The hydrolyzate was fractionated via size-exclusion chromatography into six fractions: 500 Da < LMP1 < 3 kDa; 3 kDa < LMP2 < 5 kDa; 5 kDa < LMP3 < 12 kDa; 12 kDa < LMP4 < 25 kDa; 25 kDa < LMP5 < 100 kDa and LMP6 > 10 wDa. Structure analyses showed that LMP1 were homogalacturonans enriched non-esterified polysaccharides. While LMP2 contained both HG and rhamnogalacturonan-I (RG-I). Further antitumor assay showed that in comparison with the native pectic polysaccharide with moderate antitumor activity, both LMP1 and LMP2 possessed significant antitumor activity, while the inhibitory effect of LMP1 was higher than that of LMP2, suggesting that the biological properties of LMPs was influenced by structural characteristics, including molecular weight and monosaccharide composition. PMID- 30465848 TI - Continued citation of retracted radiation oncology literature - Do we have a problem? AB - PURPOSE: The purpose of this study was to quantify the number and explore the nature of citations of retracted articles in the radiation oncology literature occurring after publication of the retraction note. METHODS: A list of previously identified retracted articles within the field of radiation oncology was updated in June 2017. The number of publications citing retracted articles was quantified using Google Scholar, Web of Science and Scopus. Citing studies occurring after publication of the retraction note were individually assessed to determine the nature of the reference. RESULTS: Forty-seven retracted articles were identified for this study. Thirty-seven studies (79%) received 1,017 citations prior to retraction, and 34 articles (72%) received 407 English and 169 foreign-language citations afterwards. The average number of citations dropped from 22 to 11 following publication of the retraction note (95% CI: 0.3 to 21.0, p = 0.043). Most post-retraction citations occurred during the second year after the article's retraction, originated from North America and Asia (each N = 124, 31%) and Europe (N = 122, 30%), and featured in original articles (N = 254, 62%) and reviews (N = 73, 18%). Of the 358 individually evaluable citing studies, 92% referenced the retracted article as legitimate work. Three guidelines and fifteen systematic reviews and meta-analyses were also identified that cited retracted articles as valid work. CONCLUSIONS: Post-retraction citations are an avoidable phenomenon. The results of the study emphasise the need for adherence to good research practices by investigators to mitigate the influence and propagation of flawed and unethical research. Journal editors, peer reviewers and the broader radiation oncology readership should remain diligent in ensuring that citations of retracted work are identified and removed prior to, during, and possibly even after publication. PMID- 30465849 TI - Introducing a cost-effective method for purification of bioactive flagellin from several flagellated gram-negative bacteria. AB - The objective of this study was to introduce a simple and cheap method for purification of flagellin. So, flagellin proteins of Salmonella typhimurium (S. typhimurium), Escherichia coli (E. coli), Citrobacter freundii (C. freundii) and Salmonella typhi (S. typhi) were purified by a modified simple method. Bacterial cultures were precipitated by centrifugation. Precipitates were washed twice and flagellin proteins were detached by shaking vigorously (in PBS pH = 2), and then flagellin proteins were precipitated by ammonium sulfate saturation. Evaluation of purification efficiency and concentration were examined by SDS-PAGE and Bradford assay. Polyclonal antibodies were produced against S. typhimurium FliC and cross-reactivity of anti-S. typhimurium was assessed against other flagellins. Bioactivity of flagellins was evaluated by cell proliferation and IL 8 protein expression assay in HEK293 cells, and also, IL-6 and TNF-alpha genes expression in chicken cells. Results showed a single band for flagellin proteins of all bacteria on %10 SDS-PAGE, which concentration ranged from 150 to 400 MUg/mL. All flagellin proteins increased cell proliferation, and IL-8 levels were increased after treatment by flagellins and levels of IL-6 and TNF-alpha were increased after treatment with S. typhimurium FliC. All flagellin proteins showed cross-reactivity with antibodies. Findings showed that application of our method, not only reduced time and cost, but also, the purified flagellin proteins had acceptable bioactivity. PMID- 30465850 TI - Prefrontal-accumbens opioid plasticity: Implications for relapse and dependence. AB - In addiction, an individual's ability to inhibit drug seeking and drug taking is thought to reflect a pathological strengthening of drug-seeking behaviors or impairments in the capacity to control maladaptive behavior. These processes are not mutually exclusive and reflect drug-induced modifications within prefrontal cortical and nucleus accumbens circuits, however unlike psychostimulants such as cocaine, far less is known about the temporal, anatomical, and cellular dynamics of these changes. We discuss what is known regarding opioid-induced adaptations in intrinsic membrane physiology and pre-/postsynaptic neurotransmission in principle pyramidal and medium spiny neurons in the medial prefrontal cortex and nucleus accumbens from electrophysiological studies and explore how circuit specific adaptations may contribute to unique facets of opioid addiction. PMID- 30465851 TI - Synaptic structural protein dysfunction leads to altered excitation inhibition ratios in models of autism spectrum disorder. AB - Genetics is believed to play a key role in the development of Autism Spectrum Disorder (ASD) and a plethora of potential candidate genes have been identified by genetic characterization of patients, their family members and controls. To make sense of this information investigators have searched for common pathways and downstream properties of neural networks that are regulated by these genes. For instance, several candidate genes encode synaptic proteins, and one hypothesis that has emerged is that disruption of the synaptic excitation and inhibition (E/I) balance would destabilize neural processing and lead to ASD phenotypes. Some compelling evidence for this has come from the analyses of mouse and culture models with defects in synaptic structural proteins, which influence several aspects of synapse biology and is the subject of this review. Remaining challenges include identifying the specifics that distinguish ASD from other psychiatric diseases and designing more direct tests of the E/I balance hypothesis. PMID- 30465852 TI - Application of biorelevant saliva-based dissolution for optimisation of orally disintegrating formulations of felodipine. AB - The oral cavity is of great importance to the performance of orally retained formulations, including: orally disintegrating tablets, taste-masked formulations, and buccal/sublingual delivery systems. With regards to in vitro dissolution assessment of these dosage forms, human saliva should be represented by the dissolution media. Currently there is no general consensus regarding oral cavity dissolution. In this study pooled human saliva was characterised and utilised as dissolution media for biorelevant oral cavity dissolution studies and to assess drug release. Lipophilic drug felodipine with challenging biopharmaceutical properties was selected for assessment in oral cavity dissolution studies. These saliva dissolution studies investigated for the first time how biorelevant dissolution can be implemented as a screening tool to guide the formulation development process and to predict dosage form performance within the mouth. In this study a combination of three dissolution enhancement strategies (cryomilling, solid dispersion, and inclusion complexation) were employed to eventually increase the concentration of felodipine in saliva 150 fold. Using this successful formulation strategy orally disintegrating tablets of felodipine were produced. Interestingly, the percentage release of felodipine in compendial dissolution apparatus was shown to be over 80% after 10 min. On the other hand, saliva-based dissolution showed that percentage release of felodipine was only 0.2% after 10 min using the same formulation. This discrepancy in drug release between dissolution media highlights the need for biorelevant dissolution apparatus for the oral cavity to reliably assess performance of relevant dosage forms in vitro. PMID- 30465853 TI - Pigmented contact lenses for managing ocular disorders. AB - Blocking a selected wavelength range from the light spectrum can have multiple benefits. Ultra-violet (UV) radiation is detrimental to the retina, necessitating its blocking through sunglasses and contact lenses. The near-visible light also has enough energy to cause damage but, is typically not blocked by commercial lenses. Filtering light can also be useful to patients with migraines, amblyopia, and color blindness. Here, to achieve blocking, incorporation of pigments extracted from colored agro-products into contact lenses is explored. Pigment extraction from food powders including turmeric, spinach, paprika, and woad powders in ethanol is demonstrated. Lens immersion in pigment concentrated ethanol is done to facilitate swelling, allowing rapid pigment uptake. Pigment incorporation ensures the absence of visible light scattering, lens opacity, and leaching. The characterization of pigmented lenses is done through absorptivity and transmittance measurements. Degradation measurements investigate the stability of the green pigment extract from spinach powder with time. p-HEMA and silicone hydrogels loaded with >400 ug/g turmeric pigment act as class 1 UV blockers retaining >90% visible light transparency and screening >95% of the UVR spectra. Spinach, paprika, and woad powder loaded silicone lenses mitigate >20% visible light transmission from selective wavelengths finding applications in photophobia, amblyopia treatment, and color vision deficiency management. PMID- 30465854 TI - Endocrine disruption through membrane estrogen receptors and novel pathways leading to rapid toxicological and epigenetic effects. AB - Estrogen binding to estrogen receptors (ESR) triggers signaling cascades within cells. Historically, a major emphasis has been characterizing estrogen-induced genomic actions resulting from binding to nuclear estrogen receptor 1 (nESR1). However, recent evidence indicates the first receptors estrogens encounter as they enter a cell, membrane ESR1 (mESR1), also play crucial roles. Membrane and nuclear ESR are derived from the same transcripts but the former are directed to the membrane via palmitoylation. Binding and activation of mESR1 leads to rapid fluctuations in cAMP and Ca+2 and stimulation of protein kinase pathways. Endocrine disrupting chemicals (EDC) that mimic 17beta-estradiol can signal through mESR1 and elicit non-genomic effects. Most current EDC studies have focused on genomic actions via nESR1. However, increasing number of studies have begun to examine potential EDC effects mediated through mESR1, and some EDC might have higher potency for signaling through mESR1 than nESR1. The notion that such chemicals might also affect mESR1 signaling via palmitoylation and depalmitoylation pathways has also begun to gain currency. Recent development of transgenic mice that lack either mESR1 or nESR1, while retaining functional ESR1 in the other compartment, will allow more precise in vivo approaches to determine EDC effects through nESR1 and/or mESR1. It is increasingly becoming apparent in this quickly evolving field that EDC directly affect mESR and estrogen signaling, but such chemicals can also affect proportion of ESR reaching the membrane. Future EDC studies should be designed to consider the full range of effects through mESR alone and in combination with nESR. PMID- 30465855 TI - Vitamin D inhibits the epithelial-mesenchymal transition by a negative feedback regulation of TGF-beta activity. AB - Vitamin D and TGF-beta exert opposite effects on epithelial-mesenchymal EMT transition. Here we report a novel mechanism of action of TGF-beta that promotes the counteracting activity of vitamin D; in two models of human epithelial mesenchymal EMT transition we demonstrated for the first time that TGF-beta strongly induced the expression of vitamin D receptor (VDR) and that 1,25(OH)2D3 was able to contrast the TGF-beta-driven EMT transition by transcriptional modulation. In human bronchial epithelial cells the effects of TGF-beta on EMT transition markers (E-Cadherin expression and cell motility) were reversed by pre treatment and co-treatment with 1,25(OH)2D3, but not when the hormone was given later. Silencing experiments demonstrated that the inhibition of TGF-beta activity was VDR-dependent. 1,25(OH)2D3 abrogated the mitochondrial stimulation triggered by TGF-beta. In fact we showed that 1,25(OH)2D3 repressed the transcriptional induction of respiratory complex, limited the enhanced mitochondrial membrane potential and restrained the increased levels of mitochondrial ATP; 1,25(OH)2D3 also decreased the production of reactive oxygen species promoted by TGF-beta. Overall, our study suggests that the overexpression and activity of VDR may be a regulatory response to TGF-beta signaling that could be exploited in clinical protocols, unraveling the therapeutic potentiality of 1,25(OH)2D3 in the prevention of cancer metastasis. PMID- 30465856 TI - Immediate-hypersensitivity reactions to proton pump inhibitors - experience in a medical department. PMID- 30465857 TI - Asthma in the Melting Pot. PMID- 30465858 TI - Implementation of the NIAID Peanut Allergy Guidelines: Outcomes and Experience. PMID- 30465859 TI - Racial differences in Atopic Dermatitis. PMID- 30465860 TI - Inpatient Beta-lactam test-dose Protocol promotes Antimicrobial Stewardship in Patients with History of Penicillin Allergy. AB - BACKGROUND: Penicillin allergy is the most commonly reported drug allergy in hospitalized patients, resulting in increased second-line antibiotic use, nosocomial infections, and healthcare utilization. Given that the vast majority of patients are not truly allergic, a safe strategy that empowers the admitting physician is needed. OBJECTIVE: To assess the impact on antibiotic prescribing practices for hospitalized patients with penicillin allergy using a validated intervention. METHODS: An intervention was implemented to educate providers on management of patients with penicillin allergy using a validated risk stratification algorithm to guide testing and antibiotic use. 30 days of control data using current standard of care was compared with 60 days of post intervention data measuring documentation of penicillin allergy history and antibiotic selection. RESULTS: The relative use of cephalosporin and penicillin antibiotics increased by 121.2% (p=0.027) and 256% (p=0.043) respectively without an increase in adverse drug reactions. There was a decrease in the use of broad spectrum antibiotics; vancomycin 67.2% (p=0.036), quinolones 33.3% (p=0.31), carbapenems 81.9% (p=0.080), and aztreonam 73.8% (p=0.180). CONCLUSION: The antibiotic choice in patients admitted to the hospital with a reported penicillin allergy can be improved by better evaluation of the allergy history and the use of a risk stratification guideline. PMID- 30465861 TI - The Glycerin Associated Pain (GAP) Study. PMID- 30465862 TI - AllergyWatch - Feb-19. PMID- 30465863 TI - "Drug Allergy in children and adults: is it the double X chromosome?" PMID- 30465864 TI - The role of dopamine in the brain - lessons learned from Parkinson's disease. AB - Parkinson's disease causes a characteristic combination of motor symptoms due to progressive neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta. The core impairment of dopaminergic neurotransmission has motivated the use of functional magnetic resonance imaging (fMRI) in patients with Parkinson's disease to elucidate the role of dopamine in motor control and cognition in humans. Here we review the main insights from functional brain imaging in Parkinson's disease. Task-related fMRI revealed many disease-related alterations in brain activation patterns. However, the interpretation of these findings is complicated by the fact that task-dependent activity is influenced by complex interactions between the amount of dopaminergic neurodegeneration in the task-relevant nuclei, the state of medication, genetic factors and performance. Despite these ambiguities, fMRI studies in Parkinson's disease demonstrated a central role of dopamine in the generation of movement vigour (bradykinesia) and the control of excessive movements (dyskinesia), involving changes of both activity and connectivity of the putamen, premotor and motor regions, and right inferior frontal gyrus (rIFG). The fMRI studies addressing cognitive flexibility provided convergent evidence for a non-linear, U-shaped, relationship between dopamine levels and performance. The amount of neurodegeneration in the task relevant dopaminergic nuclei and pharmacological dopamine replacement can therefore move performance either away or towards the task-specific optimum. Dopamine levels also strongly affect processing of reward and punishment for optimal learning. However, further studies are needed for a detailed understanding of the mechanisms underlying these effects. PMID- 30465865 TI - Flexible proton density (PD) mapping using multi-contrast variable flip angle (VFA) data. AB - Quantitative proton density (PD) maps measure the amount of free water, which is important for non-invasive tissue characterization in pathology and across lifespan. PD mapping requires the estimation and subsequent removal of factors influencing the signal intensity other than PD. These factors include the T1, T2* relaxation effects, transmit field inhomogeneities, receiver coil sensitivity profile (RP) and the spatially invariant factor that is required to scale the data. While the transmit field can be reliably measured, the RP estimation is usually based on image post-processing techniques due to limitations of its measurement at magnetic fields higher than 1.5 T. The post-processing methods are based on unified bias-field/tissue segmentation, fitting the sensitivity profile from images obtained with different coils, or on the linear relationship between T1 and PD. The scaling factor is derived from the signal within a specific tissue compartment or reference object. However, these approaches for calculating the RP and scaling factor have limitations particularly in severe pathology or over a wide age range, restricting their application. We propose a new approach for PD mapping based on a multi-contrast variable flip angle acquisition protocol and a data-driven estimation method for the RP correction and map scaling. By combining all the multi-contrast data acquired at different echo times, we are able to fully correct the MRI signal for T2* relaxation effects and to decrease the variance and the entropy of PD values within tissue class of the final map. The RP is determined from the corrected data applying a non-parametric bias estimation, and the scaling factor is based on the median intensity of an external calibration object. Finally, we compare the signal intensity and homogeneity of the multi-contrast PD map with the well-established effective PD (PD*) mapping, for which the RP is based on concurrent bias field estimation and tissue classification, and the scaling factor is estimated from the mean white matter signal. The multi-contrast PD values homogeneity and accuracy within the cerebrospinal fluid (CSF) and deep brain structures are increased beyond that obtained using PD* maps. We demonstrate that the multi-contrast RP approach is insensitive to anatomical or a priori tissue information by applying it in a patient with extensive brain abnormalities and for whole body PD mapping in post mortem foetal imaging. PMID- 30465866 TI - Simultaneous acquisition of magnetic resonance elastography of the supraspinatus and the trapezius muscles. AB - We developed a Magnetic Resonance elastography (MRE) technique using a conventional magnetic resonance imaging (MRI), which allows a simultaneous elastography of the supraspinatus and trapezius muscles, by designing a new wave transducer (vibration pad) and optimizing the mechanical vibration frequency. Five healthy volunteers underwent an MRE. In order to transmit the mechanical vibration (pneumatic vibration) to the supraspinatus and trapezius muscles, a new vibration pad was designed using a three-dimensional (3D) printer. The vibration pad was placed on the skin 2 cm medial and 2 cm cephalad the deltoid tubercle. MRE acquisition was performed with a multi-slice gradient-echo type multi-echo MR sequence, which allows MREs even in a conventional MRI; two oblique axial images of the supraspinatus and trapezius muscles were obtained simultaneously. Vibration frequencies were set at 50-150 Hz, with a 25 Hz step. Wave image quality in each frequency was analyzed using a phase-to-noise ratio (PNR) and clarity of propagating wave that was assessed by two readers qualitatively. In the supraspinatus muscle, the wave images were of good quality especially at frequencies >75 Hz. In the trapezius muscle, the wave images were of better quality at low frequencies (50 and 75 Hz) compared with high frequencies (100-150 Hz). The PNR of both muscles were higher at low frequencies. The mean stiffness in the trapezius muscle (7.26 +/- 2.13 kPa at 75 Hz) was larger than those in the supraspinatus muscle (4.16 +/- 0.50 kPa at 75 Hz). The results demonstrated that our MRE technique allows simultaneous assessment of the stiffness in the supraspinatus and trapezius muscles using a conventional MRI, and that optimal vibration frequency for simultaneous MRE of these muscles is 75 Hz. This technique provides a new means for early detection of abnormality in the shoulder. PMID- 30465867 TI - Evaluation of hepatic function using dynamic contrast-enhanced magnetic resonance imaging in melanocortin 4 receptor-deficient mice as a model of nonalcoholic steatohepatitis. AB - INTRODUCTION: Melanocortin 4 receptor-deficient (MC4R-KO) mice fed a high-fat diet (HFD) develop liver pathology similar to human nonalcoholic steatohepatitis (NASH). However, although liver histology and blood biochemistry have been reported, hepatic function has not been evaluated. In the present study, we evaluated hepatic function in MC4R-KO mice fed an HFD using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) with gadolinium-ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA). MATERIALS AND METHODS: Wild type (WT) mice and MC4R-KO mice were fed a standard diet (SD) or an HFD for 20 weeks. The hepatic signal intensity was obtained from DCE-MRI images, and relative enhancement (RE), the time to maximum RE (Tmax), and the half-life of RE elimination (T1/2) were calculated. Histopathological analysis was then performed. RESULTS: Histological analysis with nonalcoholic fatty liver disease activity score (NAS) revealed that MC4R-KO mice fed an HFD achieved the NAS of 5. There was moderate fibrosis in MC4R-KO mice fed an HFD. DCE-MRI with Gd-EOB-DTPA showed that Tmax and T1/2 were significantly longer in MC4R-KO mice fed an HFD compared with wild type (WT) mice (Tmax, WT, 3.9 +/- 0.4 min; MC4R-KO, 7.4 +/- 1.5 min; T1/2, WT, 23.7 +/- 1.9 min; MC4R-KO, 62.5 +/- 18.5 min). Tmax and T1/2 were significantly correlated with histopathologic score (steatosis vs. Tmax, rho = 0.48, P = 0.04; steatosis vs. T1/2, rho = 0.50, P = 0.03; inflammation vs. Tmax, rho = 0.55, P = 0.02; inflammation vs. T1/2, rho = 0.61, P < 0.01; ballooning vs. T1/2, rho = 0.51, P = 0.03;fibrosis vs Tmax, rho = 0.72, P < 0.01; fibrosis vs T1/2, rho = 0.75, P < 0.01). CONCLUSIONS: MC4R-KO mice fed an HFD developed obesity and NASH. The liver kinetics of Gd-EOB-DTPA were significantly different in MC4R-KO mice fed an HFD from WT mice, and correlated with the histopathologic score. These results suggest that MC4R-KO mice fed an HFD mimic the hepatic pathology and liver function of human NASH, and therefore might be useful for the study of hepatic dysfunction during the fibrotic stage of NASH. PMID- 30465868 TI - MRI based texture analysis to classify low grade gliomas into astrocytoma and 1p/19q codeleted oligodendroglioma. AB - PURPOSE: Texture analysis performed on MR images can detect quantitative features that are imperceptible to human visual assessment. The purpose of this study was to evaluate the feasibility of texture analysis on preoperative conventional MRI to discriminate between histological subtypes in low-grade gliomas (LGGs), and to determine the utility of texture analysis compared to histogram analysis alone. METHODS: A total of 41 patients with LGG, 21 astrocytoma and 20 1p/19q codeleted oligodendroglioma were included in this study. Patients were randomly divided into training (60%) and testing (40%) sets. Texture analysis was performed on conventional MRI sequences to obtain the most discriminant factor (MDF) values for both the training and testing data. Receiver operating characteristic (ROC) curve analyses were then performed using the MDF values and 9 histogram parameters in the training data to obtain cut-off values for determining the correct rate of discriminating between astrocytoma and oligodendroglioma in the testing data. RESULTS: The ROC analyses using MDF values resulted in an area under the curve (AUC) of 0.91 (sensitivity 86%, specificity 87%) for T2w FLAIR, 0.94 (87%, 89%) for ADC, 0.98 (93%, 95%) for T1w, and 0.88 (78%, 86%) for T1w + Gd sequences. Using the best cut-off values, MDF correctly discriminated between the two groups in 94%, 82%, 100%, and 88% of cases in the testing data, respectively. The MDF outperformed all 9 of the histogram parameters. CONCLUSION: Texture analysis performed on conventional preoperative MRI images can accurately predict histological subtype of LGGs, which would have an impact on clinical management. PMID- 30465869 TI - Reproducibility of inhomogeneous magnetization transfer (ihMT): A test-retest, multi-site study. AB - BACKGROUND: Inhomogeneous magnetization transfer (ihMT) has been reported to feature superior sensitivity and specificity for myelin imaging. However, the reproducibility on ihMT has yet been rarely investigated up to date. The purpose of the present study is to assess the multi-center reproducibility and test retest variability of ihMT in central nervous system. METHODS: 5 volunteers were recruited and scanned twice on three 3.0 T magnetic resonance imaging (MRI) scanners using ihMT with identical scan parameters. The maps of quantitative ihMT (qihMT) and ihMT ratio (ihMTR) for each scan were calculated. Voxel based analysis then was performed to generate qihMT and ihMTR values for major white matter fibers. The intra- and inter-scanner reliability and reproducibility was assessed with intraclass correlation coefficients (ICCs). Bland-Altman method was used to show the level of agreement between two measurement types. Paired t-test and one-way ANOVA test were also used to compare the difference between inter- and intra-scanner, respectively. RESULTS: In the 10 major white matter tracts areas, the ICCs indicated high intra- and inter-scanner measurement reliability and reproducibility. The Bland-Altman plots together with 95% confidence interval (CI) across all ROIs in the five volunteers also demonstrated good repeatability. No significant inter- and intra-scanner differences were found in Paired t-test and one-way ANOVA tests. CONCLUSION: Good inter- and intra-scanner reliability and reproducibility of ihMT measurements were observed in this study. These findings support the use of ihMT measurements as biomarkers in multicenter and/or longitudinal studies. PMID- 30465870 TI - Comparison of dynamic contrast-enhanced magnetic resonance imaging and contrast enhanced ultrasound for evaluation of the effects of sorafenib in a rat model of hepatocellular carcinoma. AB - OBJECTIVES: To compare the accuracy of contrast-enhanced ultrasound (CEUS) and Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for the assessment of changes in tissue vascularization as result of sorafenib treatment in a rat model of hepatocellular carcinoma (HCC). METHODS: Male Buffalo rats with orthotopic liver tumors treated daily with 7.5 mg/kg sorafenib via oral gavage for 2 weeks (n = 9) were subject to DCE-MRI and CEUS 2 weeks after tumor implantation - right before treatment initiation - and also after treatment completion - right before tumor harvest. Untreated animals (n = 10) were used as control. Tumor tissue sections were stained for hematoxylin-eosin, pimonidazole, and CD34 for quantitative assessment of necrosis, hypoxia, and microvessel density (MVD), respectively. RESULTS: Of all the DCE-MRI parameters that were evaluated, only volume transfer constant (Ktrans) measurements were significantly lower in sorafenib-treated tumors (0.18 vs 0.33 min-1, p < 0.01), indicating a substantial decrease in vascular permeability caused by the therapy. This reduction was associated with decreased MVD (3.9 vs 10.8% CD34+ cells, p < 0.01), higher tumor necrosis (31.9 vs 21.8%, p < 0.001) and hypoxia (19.7 vs 10.5% pimonidazole binding, p < 0.01). Moreover, statistical analysis demonstrate significant correlation of DCE-MRI Ktrans with histopathologic tissue necrosis (r = -0.537, p < 0.05) and MVD (r = 0.599, p < 0.05). Interestingly, none of the CEUS measurements were significantly different between the control and treatment groups, and did not show statistical correlation with any of the histopathological parameters assessed (p > 0.05). CONCLUSIONS: Sorafenib-induced reduction in vascular permeability in this preclinical model of HCC is detected more accurately through DCE-MRI than CEUS, and DCE-MRI parameters strongly correlate with histopathological changes in tissue vascularization and tissue necrosis. PMID- 30465872 TI - Nerve cells developmental processes and the dynamic role of cytokine signaling. AB - The stunning diversity of neurons and glial cells makes possible the higher functions of the central nervous system (CNS), allowing the organism to sense, interpret and respond appropriately to the external environment. This cellular diversity derives from a single primary progenitor cell type initiating lineage leading to the formation of both differentiated neurons and glial cells. The processes governing the differentiation of the progenitor pool of cells into mature nerve cells will be here briefly reviewed. They involve morphological transformations, specialized modes of cell division, migration, and controlled cell death, and are regulated through cell-cell interactions and cues provided by the extracellular matrix, as well as by humoral factors from the cerebrospinal fluid and the blood system. In this respect, a quite large body of studies have been focused on cytokines, proteins representing the main signaling network that coordinates immune defense and the maintenance of homeostasis. At the same time, they are deeply involved in CNS development as regulatory factors. This dual role in the nervous system appears of particular relevance for CNS pathology, since cytokine dysregulation (occurring as a consequence of maternal infection, exposure to environmental factors or prenatal hypoxia) can profoundly impact on neurodevelopment and likely influence the response of the adult tissue during neuroinflammatory events. PMID- 30465871 TI - Placental Macrophages: A Window Into Fetal Microglial Function in Maternal Obesity. AB - Fetal placental macrophages and microglia (resident brain macrophages) have a common origin in the fetal yolk sac. Yolk-sac-derived macrophages comprise the permanent pool of brain microglia throughout an individual's lifetime. Inappropriate fetal microglial priming may therefore have lifelong neurodevelopmental consequences, but direct evaluation of microglial function in a living fetus or neonate is impossible. We sought to test the hypothesis that maternal obesity would prime both placental macrophages and fetal brain microglia to overrespond to an immune challenge, thus providing a window into microglial function using placental cells. Obesity was induced in C57BL/6 J mice using a 60% high-fat diet. On embryonic day 17.5, fetal brain microglia and corresponding CD11b + placental cells were isolated from fresh tissue. Cells were treated with media or lipopolysaccharide (LPS). Tumor necrosis factor-alpha (TNF-alpha) production by stimulated and unstimulated cells was quantified via ELISA. We demonstrate for the first time that the proinflammatory cytokine production of CD11b + placental cells is strongly correlated with that of brain microglia (Spearman's rho = 0.73, p = 0.002) in the setting of maternal obesity. Maternal obesity-exposed CD11b + cells had an exaggerated response to LPS compared to controls, with a 5.1-fold increase in TNF-alpha production in placentas (p = 0.003) and 3.8-fold increase in TNF-alpha production in brains (p = 0.002). In sex-stratified analyses, only male obesity-exposed brains and placentas had significant increase in TNF-alpha production in response to LPS. Taken together, these data suggest that maternal obesity primes both placental macrophages and fetal brain microglia to overproduce a proinflammatory cytokine in response to immune challenge. Male brain and placental immune response is more marked than female in this setting. Given that fetal microglial priming may impact neuroimmune function throughout the lifespan, these data could provide insight into the male predominance of certain neurodevelopmental morbidities linked to maternal obesity, including cognitive dysfunction, autism spectrum disorder, and ADHD. Placental CD11b+ macrophages may have the potential to serve as an accessible biomarker of aberrant fetal brain immune activation in maternal obesity. This finding may have broader implications for assaying the impact of other maternal exposures on fetal brain development. PMID- 30465873 TI - Reply to letter by B. D. McCullough regarding Kernan, Walter N., Catherine M. Viscoli, Robert W. Makuch, Lawrence M. Brass, and Ralph I. Horwitz (1999), "Stratified Randomization for Clinical Trials," Journal of Clinical Epidemiology 52(1), 19-26. PMID- 30465874 TI - Moderate intensity continuous training reverses the detrimental effects of ovariectomy on RyR1 phosphorylation in rat skeletal muscle. AB - High 17beta-Estradiol (E2) concentrations in isolated ventricular myocytes as well as a lack of ovarian hormones in cardiac muscle of ovariectomized (OVX) rodents has been shown to lead to arrhythmogenic effects by inducing post translational modifications, including phosphorylation of the sarcoplasmic reticulum (SR) Ca2+ release channel ryanodine receptor-2 (RyR2). The effects of estrogens on the phosphorylation status of the RyR1 in skeletal muscle have not been investigated before. Furthermore, while high intensity exercise has been shown to increase RyR phosphorylation, there is no data on the effects of moderate intensity continuous training (MICT). The aims of the study were to investigate the effects of a 3-day treatment with low (1 nM, moderate (5 nM) and high (10 nM, 100 nM) E2 concentrations on RyR1 mRNA and protein expression and phosphorylation status (pRyRSer2844) in cultured C2C12 myotubes and to study the effects of OVX on RyR1 expression and phosphorylation in rat skeletal muscle in combination with 3 weeks of MICT. Treatment with low, physiological E2 concentrations reduced dihydropyridine receptor (DHPR) and RyR1 mRNA content in C2C12 myotubes compared to untreated control cells, whereas RyR1 protein phosphorylation (pRyRSer2844) was significantly increased after treatment with high, non-physiological E2 concentrations (p <= 0.05). RyR1 protein content (p <= 0.05) and pRyRSer2844 (p <= 0.05) were significantly elevated in skeletal muscle of OVX vs. sham-operated rats. Importantly, pRyRSer2844 levels were similar to sham-operated controls in OVX rats after MICT (OVX vs. OVX + MICT, p <= 0.05). Our results indicate, that one of the actions of estrogens is to alter skeletal muscle Ca2+ homeostasis by modulating the expression and phosphorylation of the RyR1 in skeletal muscle. Notably, regular MICT was able to counteract RyR1 phosphorylation in skeletal muscle of OVX rats. PMID- 30465875 TI - Identifying symptom clusters among people living with HIV on antiretroviral therapy in China: A network analysis. AB - CONTEXT: There exists a research interest shift from separate symptoms to symptom clusters among people living with HIV (PLWH), which may provide a better understanding of symptom management in HIV/AIDS care. However, the symptom clusters among Chinese PLWH is still unknown. OBJECTIVES: The aim of our study is to identify symptom clusters and to examine demographic and health related factors associated with these symptom clusters among PLWH prescribing antiretroviral therapy (ART) in China. METHODS: From April to September 2017, we recruited 1116 participants through a convenience sampling in five HIV/AIDS designated facilities in the eastern, middle, and southwest regions of China. The Principal Component Analysis was used to identify the symptom clusters. Association network was adopted to describe the relationships among symptoms and clusters. A multiple linear model were used to investigate the associated factors for the severity of overall symptoms and the prevalence of each symptom clusters. RESULTS: Five symptom clusters were identified, including cognitive dysfunction, mood disturbance, wasting syndrome, dizziness/headache, and skin-muscle-joint disorder. Cognitive dysfunction was the most central symptom cluster. Variables including primary caregiver during ART treatment, years of HIV diagnosis and ART use, having comorbidity, self-rated health, and quality of life were associated with the prevalence of these five symptom clusters. CONCLUSION: Our study suggests that there is a need to evaluate symptom clusters for the improvement of symptom management among PLWH. It is particularly important to include assessment and treatment of cognitive symptoms as an essential component of the HIV care. PMID- 30465876 TI - Recent advancements in the mechanism of nitric oxide signaling associated with hydrogen sulfide and melatonin crosstalk during ethylene-induced fruit ripening in plants. AB - The current review focuses on the significant role of nitric oxide (NO) in modulating ethylene-induced fruit ripening responses in plants. In this context, hydrogen sulfide (H2S) and melatonin mediated crosstalk mechanisms have been discussed with recent updates. Physiological and biochemical events associated with climacteric fruit ripening involves a plethora of effects mediated by these biomolecules. In the last few years of progress in fruit ripening physiology, the involvement of hydrogen sulfide in relation to NO remains as a nascent field of research. The importance of nitric oxide as a freely diffusible and membrane permeable biomolecule leads to its applications in post-harvest fruit storage. The process of field to market transition of edible fruits involves various intermediate stages of post-harvest storage and transport. Fruits harvested in the pre-climacteric stage are intended to be stored and transported for longer durations. However, this does not confer proper development of aroma and flavor in the post-harvest stages. Nitric oxide and ethylene crosstalk is mediated by hydrogen sulfide and melatonin activity which regulate various metabolic pathways associated with fruit ripening. A surge in the reactive nitrogen species (RNS), sugar metabolism, and plastid biogenesis are the plausible effects of NO-ethylene crosstalk. NO-mediated regulations of carbon metabolism and phytohormone levels are essential components of fruit ripening process. Melatonin by the virtue of its functional group possesses strong anti-oxidative properties. Recent updates suggest crosstalk mechanisms associated with melatonin-ethylene and nitric oxide in plants. The present review briefly summarizes the current understandings of fruit ripening physiology manifested by the effects of NO, H2S and melatonin signaling. The agri-horticultural applications of exogenous NO/H2S donors and melatonin treatment impose major benefits for delaying postharvest fruit senescence. PMID- 30465877 TI - A review of non-invasive insulin delivery systems for diabetes therapy in clinical trials over the past decade. AB - At present, the main form of insulin administration is the invasive subcutaneous (s.c.) route and, for many patients, this means managing their glucose levels with multiple daily injections, which is both painful and difficult to administer chronically. To increase patient compliance, products are slowly reaching the market that are more patient friendly, such as the insulin patch-pump systems, including Omnipod and V-Go, but also the inhaled-insulin Afrezza(r) and the buccal insulin Oral-lynTM. In this review, we outline the history of insulin, the various options that are currently available in practice for insulin delivery, and the non-invasive delivery systems that have entered the different stages of clinical trials over the past decade. PMID- 30465878 TI - The role of Th17 cells in the pathophysiology of pregnancy and perinatal mood and anxiety disorders. AB - T cells play a key role in adaptive immune responses, and shifts among T cell classes occur in normal pregnancy. There is evidence for the role of TH17 cells and dysregulation of the TH17/Treg cell balance in morbidities and autoimmune diseases during pregnancy. Because TH17 responses may play a role in depression and anxiety outside of pregnancy, we hypothesize that TH17 responses and the balance of TH17/Treg activity may also contribute to the development of depression and anxiety during pregnancy. To explore this hypothesis, this review has three main aims: 1) to evaluate systematically the role of TH17 cells and cytokines during pregnancy; 2) to compare changes in the ratio of TH17/Treg cells during pregnancy morbidities with the changes that occur in depression and anxiety outside of pregnancy; and 3) to provide a basis for further research on TH17 cells in perinatal mood and anxiety disorders, with an eye toward the development of novel therapeutics. We also review the limited literature concerning perinatal mood and anxiety disorders, and hypothesize about the potential role of TH17 cells in these illnesses. Understanding the pathophysiology of perinatal mood and anxiety disorders will aid development of novel therapeutics that address immunological mechanisms, in addition to the serotonin system, which are targetable molecules in treating depression and anxiety during pregnancy. PMID- 30465879 TI - The lack of association between herpes simplex virus 1 or Toxoplasma gondii infection and cognitive decline in the general population: An 11-year follow-up study. AB - BACKGROUND: Inflammation has been suggested to be one, possibly treatable, cause of cognitive decline and dementia. The purpose of the present article was to investigate whether the herpes simplex virus 1 (HSV-1) or Toxoplasma gondii (T. gondii) infections are related to cognitive decline or dementia. METHOD: The Health 2000 survey, conducted 2000-2001, is a population-representative sample of people over 30 years old that involved 7112 participants. The sample was followed up in the year 2011, in the Health 2011 study. At both time points, cognitive performance was assessed with two tests from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) assessing verbal fluency and verbal learning. In addition, the abbreviated Mini-Mental State Examination was administered to people aged over 55. In addition, tests assessing reaction and movement time were performed at baseline. Dementia diagnoses from nationwide health care registers were followed up until the end of year 2013. The presence of HSV-1 and T. gondii immunoglobulin G (IgG) was determined by solid-phase immunoassay at baseline. RESULTS: HSV-1 or T. gondii seropositivity, or IgG antibody levels, were not associated with cognitive decline when investigated as infection * time interactions. In addition, the infections were not associated with the risk of dementia. CONCLUSIONS: In a large sample of participants that is representative of the whole country and with a long follow-up, the results suggest that latent HSV-1 or T. gondii infections are not related to either decline in cognitive performance or dementia risk. PMID- 30465880 TI - Neuraxial TNF and IFN-beta co-modulate persistent allodynia in arthritic mice. AB - In rheumatoid arthritis, joint pain can persist despite resolution of swelling. Similarly, in the murine K/BxN serum transfer model, a persistent tactile allodynia is observed after the resolution of joint inflammation (post inflammatory pain) in male mice. Here, we found female wild type (WT) mice show inflammatory, but reduced post-inflammatory tactile allodynia. The transition to the post-inflammatory phenotype is dependent on TLR4 signaling. At the spinal level, we found differences in TNF and IFNbeta mRNA expression in WT and TLR4 deficient males. In wild type male and female mice, there is differential temporal spinal expression of TNF and IFNbeta. In WT males, blockade of TNF or administration of IFNbeta was insufficient to affect the persistent allodynia. However, co-administration of intrathecal (IT) IFNbeta and anti-TNF antibodies in male WT mice permanently reversed tactile allodynia. IT IFNbeta treatment induces expression of anti-inflammatory proteins, contributing to the beneficial effect. Together, these experiments illustrated differences in the transition to chronic tactile allodynia in male and female animals and the complexities of effective pharmacologic interventions. PMID- 30465881 TI - Activation of GPR55 induces neuroprotection of hippocampal neurogenesis and immune responses of neural stem cells following chronic, systemic inflammation. AB - New neurons are continuously produced by neural stem cells (NSCs) within the adult hippocampus. Numerous diseases, including major depressive disorder and HIV 1 associated neurocognitive disorder, are associated with decreased rates of adult neurogenesis. A hallmark of these conditions is a chronic release of neuroinflammatory mediators by activated resident glia. Recent studies have shown a neuroprotective role on NSCs of cannabinoid receptor activation. Yet, little is known about the effects of GPR55, a candidate cannabinoid receptor, activation on reductions of neurogenesis in response to inflammatory insult. In the present study, we examined NSCs exposed to IL-1beta in vitro to assess inflammation caused effects on NSC differentiation and the ability of GPR55 agonists to attenuate NSC injury. NSC differentiation and neurogenesis was determined via immunofluorescence and flow cytometric analysis of NSC markers (Nestin, Sox2, DCX, S100beta, betaIII Tubulin, GFAP). GPR55 agonist treatment protected against IL-1beta induced reductions in neurogenesis rates. Moreover, inflammatory cytokine receptor mRNA expression was down regulated by GPR55 activation in a neuroprotective manner. To determine inflammatory responses in vivo, we treated C57BL/6 and GPR55-/- mice with LPS (0.2 mg/kg/day) continuously for 14 days via osmotic mini-pump. Reductions in NSC survival (as determined by BrdU incorporation), immature neurons, and neuroblast formation due to LPS were attenuated by concurrent direct intrahippocampal administration of the GPR55 agonist, O-1602 (4 ug/kg/day). Molecular analysis of the hippocampal region showed a suppressed ability to regulate immune responses by GPR55-/- animals manifesting in a prolonged inflammatory response (IL-1beta, IL-6, TNFalpha) after chronic, systemic inflammation as compared to C57BL/6 animals. Taken together, these results suggest a neuroprotective role of GPR55 activation on NSCs in vitro and in vivo and that GPR55 provides a novel therapeutic target against negative regulation of hippocampal neurogenesis by inflammatory insult. PMID- 30465882 TI - Fusarium graminearum KP4-like proteins possess root growth-inhibiting activity against wheat and potentially contribute to fungal virulence in seedling rot. AB - The virally encoded KP4 killer toxin protein was first identified from Ustilago maydis (Um), and its homologues are present in diverse fungi and in one species of moss. No KP4-like (KP4L) proteins have been functionally characterized. Here, we report the identification and functional analysis of four KP4L proteins from Fusarium graminearum (Fg), the primary causal pathogen of Fusarium head blight (FHB), which is also known to associate with seedling rot of wheat. The four FgKP4L proteins (FgKP4L-1, -2, -3 and -4) are encoded by small open reading frames (378-825 bp) located on chromosome 1 with the FgKP4L-1, -2 and -3 genes clustering together. Sequence analysis indicated that FgKP4L proteins have conserved domains predicted to form a three-dimensional alpha/beta-sandwich structure as first reported for UmKP4, with FgKP4L-4 featuring double Kp4 domains. Further analyses revealed that the FgKP4L genes are expressed in vitro under certain stress conditions, and all up-regulated during FHB and/or seedling rot development, the recombinant FgKP4L-2 protein does not induce cell death in wheat leaves or spikelets, but inhibits root growth of young seedlings, and the elimination of the FgKP4L-1/-2/-3 gene cluster from the fungal genome results in reduced virulence in seedling rot but not in FHB. Database searches revealed KP4L proteins from ~80 fungal species with more than half from human/animal pathogens. Phylogenetic analysis suggested that UmKP4 and the moss KP4L proteins are closely related to those from a zygromycete and Aspergillus, respectively, implying cross kingdom horizontal gene transfer. PMID- 30465883 TI - Effects of Paraoxonase-1 variants on course of severity and mortality of Crimean Congo hemorrhagic fever. AB - Crimean-Congo hemorrhagic fever (CCHF) is an acute viral hemorrhagic fever caused by Crimean Congo hemorrhagic fever virus (CCHFV). Paraoxonase-1 (PON1) is a high density lipoprotein (HDL)-binding protein which defense the body against oxidative stress. To investigate the role of the PON1 gene in CCHF, we screened the genotypes of two single nucleotide polymorphisms (Q192R [rs662] and L55M [rs854560]) in CCHF patients stratified according to course of severity and mortality by using PCR-based RFLP assay. Overall, 132 patients diagnosed as CCHF were enrolled in this study. The frequencies of the three genotypes and two alleles of Q192R and L55M polymorphisms didn't show any statistically significant differences in terms of mortality and disease severity (p > 0.05). Any statistically significant differences were not found between severe and mild and fatal and non-fatal CCHF patients according to seven composite genotypes (p > 0.05). When we analyzed the clinical characteristics of CCHF patients stratified according to PON1gene polymorphisms, any statistically significant differences were not also observed (p > 0.05). Our study showed no possible association between genotypes of PON1 gene Q192R and L55M polymorphisms and CCHF. PMID- 30465884 TI - Toll-like receptor 9 gene in Periodontal Disease - A promising biomarker. AB - Periodontal Disease is an infectious and inflammatory disorder triggered mainly by periodontopathogenic bacteria, however, as a multifactorial disease, several factors modulate its progression, namely, genetic factors. Toll-like receptors (TLR) recognize molecular patterns present in pathogens and trigger an immune response against them. Thus, sequences variants in TLR genes seem to have the potential to modify the predisposition to Periodontal Disease and its progression. Based on this fact, TLR9 gene were analysed in a case-control study. DNA was obtained from 90 dogs (50 control and 40 cases) and a fragment of TLR9 gene was amplified by PCR and sequenced. The variants were identified by comparison with the dog wild type sequences. Our results suggest that rs375556098 and rs201959275 polymorphisms in the TLR9 gene are good candidates to become biomarkers of the canine predisposition to Periodontal Disease. It's important to notice that these polymorphic sites exist in Human exactly in the same codon. Since the dog is the best animal model to replicate the pathophysiological mechanisms of human Periodontal Disease, these results can potentially be extrapolated to humans. PMID- 30465885 TI - Changes in Fluorescence Recovery After Photobleaching (FRAP) as an indicator of SOX9 transcription factor activity. AB - Cells respond to their environment via an intricate cellular signaling network, directing cell fate. Changes in cell fate are characterized by changes in gene transcription, dictated by (master) transcription factor activity. SOX9 is the master transcription factor for chondrocyte development. Its impaired function is implicated in osteoarthritis and growth disorders, such as dwarfism. However, the factors regulating SOX9 transcriptional activity are not yet fully mapped. Current methods to study transcription factor activity are indirect and largely limited to quantification of SOX9 target gene and protein expression levels after several hours or days of stimulation, leading to poor temporal resolution. We used Fluorescence Recovery After Photobleaching (FRAP) to study the mobility of SOX9 and correlated the changes in mobility to changes in its transcriptional activity by cross-validating with chromatin immunoprecipitation and qPCR. We show that using FRAP, we can quantify the changes in SOX9 mobility on short time scales as an indication of transcriptional activity, which correlated to changes of SOX9 DNA-binding and long-term target gene expression. PMID- 30465886 TI - Pre-operative Evaluation for Minimally Invasive Gynecologic Surgery: What is the best evidence and recommendations for clinical practice. AB - Preoperative evaluation for elective benign gynecologic procedures is a necessary step in reducing perioperative complications. While a thorough history and physical exam is the foundation of this assessment, much evidence exists that physicians rely on unnecessary laboratory and diagnostic testing. Our goal was to perform a systematic review of the available literature regarding preoperative evaluation to better inform preoperative test selection and to identify deficiencies in current literature. There is very limited data specific preoperative testing for patients undergoing gynecologic surgeries. Abnormal test results are common when routine, unselected testing is applied. Employing a protocol to guide preoperative testing improves patient care by eliminating unnecessary tests without compromising the efficacy of predicting adverse perioperative events or case cancellation and modifications. PMID- 30465887 TI - Footedness in Steppe Buzzards (Buteo vulpinus). AB - Asymmetries in handedness/footedness has been demonstrated in many vertebrate and invertebrate species, including humans, but its role and origins are still debated. We studied the ratio of footedness in migratory Steppe Buzzards (Buteo vulpinus). We hypothesized that during our raptor banding program we could observe the preferred foot used by the raptor when trying to access the lure in a bal-chatri trap, and that if there was no preference in the population then it would show a 50:50 use of the right or left foot. A total of 367 different Steppe Buzzards were identified and their footedness analyzed. Of these 196 (53.4%) preferentially hit the trap first with the right foot, 148 (40.3%) with the left foot, and 23 (6.3%) appeared to be ambidextrous. In the avian world, predominance is considered to be species specific but mostly right-footed. The migratory Steppe Buzzards also show a predominantly right-sided lateralization. This result could be due to the task/situation that was analyzed; perhaps in a different more tool-like manipulation activity lateralization could be different. We recommend all future researchers that deal in wildlife trapping to also pay attention to this very interesting aspect of wildlife biology. PMID- 30465888 TI - Comparing the critical features of e-applications for three-dimensional anatomy education. AB - Anatomical e-applications are increasingly being created and used in medical education and health care for the purpose of gaining anatomical knowledge. Research has established their superiority over 2D methods in the acquisition of spatial anatomy knowledge. Many different anatomy e-applications have been designed, but a comparative review is still lacking. We aimed to create an overview for comparing the features of anatomy e-applications in order to offer guidance in selecting a suitable anatomy e-application. A systematic search was conducted. Data were retrieved from the 3D model designs (realism), software aspects and program functionality. The non-commercial e-applications focused on small body regions and received an average score of 3.04 (range 1-5) for model realism. Their average score on program functionality was 8.8 (range 0-14). The commercial e-applications covered the entire human body and received an average score of 2.85 (range 1-5) for model realism. Their average score on program functionality was 10.4 (range 0-14). Non-commercial anatomy e-applications received higher scores on realism and facilities like performing a virtual dissection, while the commercial anatomy e-applications offer a much wider range of anatomical structures available and they showed higher scores on program functionality. These scores gave good insight of the e-applications' possibilities, and may help future users to make an informed choice among the large number of available e-applications. PMID- 30465889 TI - Comprehensive study of pulmonary hilam with its clinical correlation. AB - INTRODUCTION: Awareness of pulmonary hilar variations is essential for lobectomy of lung. MATERIALS AND METHODS: We studied 54 left and 49 right hilum of formalin fixed adult cadaveric lungs. Morphologic and mophometric details were recorded and variations were noted. RESULTS: Classical picture of hilum was found in 35.19% left lung and 40.82% right lung. Morphological variations were more on left side (64.81%) than right side (59.18%) in terms of numbers of structures. On the left side, highest percentage of variable structure was bronchus (46.3%) followed by pulmonary artery (37.31%) and lowest by pulmonary vein (31.48%) whereas on right side, percentage for variable pulmonary artery and vein were same (36.73%) followed by bronchi (20.41%). Maximum number of pulmonary veins was five, pulmonary artery was three and accessory bronchus was two on both side hila. In morphometric measurement, mean vertical length of hilum was more on right side whereas anteroposterior length was more on left side. Right hilum is slightly lower and anteriorly placed than left hilum in the mediastinal surface of lung. Significant correlations between vertical length of lung and hilum and antero-postero length of lung and hilum of left and right sides were found. CONCLUSIONS: By analysis and comparison with previous studies, present study concludes that morphology of pulmonary hila is extremely variable which contributes significant consequences in the field of pulmonary resection. PMID- 30465890 TI - Prenatal imaging features suggestive of liver gestational allo immune disease. AB - We report prenatal imaging features of four cases of neonatal hemochromatosis due to an alloimmune disease. All cases exhibited intra uterine growth restriction (IUGR) without arguments for a vascular etiology, associated with oligohydramnios. Placental hydrops was present in 75% of cases. Splenomegaly was identified in one case. Other causes of NH have been ruled out during diagnostic workup including karyotype, detection of IGFBP-1 to evaluate a premature rupture of membranes, maternal serologic tests. MRI was performed in two cases and showed an atrophic liver associated with a low signal intensity on T2-sequence in one case. Prenatal NH was suspected in this later case and the fetus was successfully treated with two IVIG (intravenous immunoglobulins) perfusions performed during pregnancy followed by exchange transfusion and IVIG after birth. The child is doing well with normal liver function tests after 17 months of follow up. Our aim was to highlight the importance of suggesting NH-GALD when facing IUGR with oligohydramnios, ascites, placental hydrops, splenomegaly on prenatal ultrasound with negative work up for placental vascular pathologies and infectious fetopathies. MRI might be of a good help, showing an atrophic liver but enhancing iron overload in hepatic and extrahepatic tissue is helpful but not constant. PMID- 30465891 TI - Fatal orbital necrotizing fasciitis secondary to stenotrophomonas maltophilia associated stomatitis. AB - An 81-year-old woman with diabetes mellitus presented with signs of orbital cellulitis and a gangrenous ulcer on the right palate. Biopsy analysis confirmed a diagnosis of necrotizing fasciitis. Surgical debridement of necrotic tissues and enucleation of the right eye were performed. Stenotrophomonas maltophilia was isolated from the specimens. The patient remained stable under antibiotic therapy and underwent reconstructive surgery. To the best of our knowledge, this represents a rare case of orbital necrotizing fasciitis developing secondary to S. maltophilia infection. Orbital necrotizing fasciitis is rare; the early clinical features may be similar to those of cellulitis. To prevent devastating complications, the former condition must be kept in mind, particularly in immunocompromised patients. PMID- 30465892 TI - Clinical Study on Hemoporfin PDT for Infant Facial Port-Wine Stains. AB - OBJECTIVE: To observe the clinical efficacy and therapeutic response of Hemoporfin photodynamic therapy (PDT) for infant facial port-wine stains (PWS). METHOD: Hemoporfin PDT was used to treat 100 cases of infant facial PWS. After receiving Hemoporfin skin test, the cases with a negative skin test result were intravenously injected with Hemippofen (5 mg/kg) and irradiated under 532 nm LED green light. After treatment, a follow-up visit was paid through WeChat and Dermlink PWS consulting platform, in order to observe the therapeutic response and clinical efficacy. RESULT: The follow-up visit showed an effective rate of 98%, including 85 cases of itching (85%), 100 cases of edema (100%), 89 cases of purpura-like change (89%), 33 cases of crust (33%), 2 cases of hyperpigmentation (2%) and 2 cases of scars (2%), with no allergy and other systematic adverse reaction. CONCLUSION: Hemoporfin PDT has a high clinical efficacy and response rate in treating infant facial PWS, with slight adverse reactions. PMID- 30465893 TI - Risk indicators for acute kidney injury in cardiogenic shock. AB - PURPOSE: In critical illness, the relation between the macrocirculation, microcirculation and organ dysfunction, such as acute kidney injury (AKI), is complex. This study aimed at identifying predictors for AKI in patients with cardiogenic shock. MATERIALS AND METHODS: Thirty-nine adult cardiogenic shock patients, with an admission creatinine <200 MUmol l-1, and whose microcirculation was measured within 48 h were enrolled. Patient data were analyzed if AKI stage >=1 developed according to the Kidney Disease/Improving Outcomes classification within 48 h after admission. Variables with a p < .05 in the univariate analysis were considered for analysis with logistic regression. RESULTS: Twenty-four patients (61.5%) developed AKI within 48 h. The group that developed AKI had higher central venous pressures (CVP), lower diastolic arterial blood pressures and mean perfusion pressures, higher maximum ventilator pressures as well as positive end expiratory pressures and were treated with higher dosages of dobutamine. There was no difference of the microcirculation. In the multivariate logistic regression analysis, CVP was the only independent predictor for AKI (OR 1.241; 95% CI 1.030-1.495; p = .023). CONCLUSIONS: In this population of patients with cardiogenic shock, CVP was associated with the development of AKI. PMID- 30465894 TI - Mutations in glucokinase and other genes detected in neonatal and type 1B diabetes patient using whole exome sequencing may lead to disease-causing changes in protein activity. AB - Monogenic diabetes is caused by mutations that reduce beta-cell function. While Sanger sequencing is the standard method used to detect mutated genes. Next generation sequencing techniques, such as whole exome sequencing (WES), can be used to find multiple gene mutations in one assay. We used WES to detect genetic mutations in both permanent neonatal (PND) and type 1B diabetes (T1BD). A total of five PND and nine T1BD patients were enrolled in this study. WES variants were assessed using VarioWatch, excluding those identified previously. Sanger sequencing was used to confirm the mutations, and their pathogenicity was established via the literature or bioinformatic/functional analysis. The PND and T1BD patients were diagnosed at 0.1-0.5 and 0.8-2.7 years of age, respectively. Diabetic ketoacidosis was present at diagnosis in 60% of PND patients and 44.4% of T1BD patients. We found five novel mutations in five different genes. Notably, patient 602 had a novel homozygous missense mutation c.1295C > A (T432 K) in the glucokinase (GCK) gene. Compared to the wild-type recombinant protein, the mutant protein had significantly lower enzymatic activity (2.5%, p = 0.0002) and Vmax (1.23 +/- 0.019 vs. 0.33 +/- 0.016, respectively; p = 0.005). WES is a robust technique that can be used to unravel the etiologies of genetically heterogeneous forms of diabetes. Homozygous inactivating mutations of the GCK gene may have a significant role in PND pathogenesis. PMID- 30465895 TI - Evidence of metabolic memory-induced neurodegeneration and the therapeutic effects of glucagon-like peptide-1 receptor agonists via Forkhead box class O. AB - Metabolic memory, which refers to diabetic stresses that persist after glucose normalization, is considered a major factor in addition to hyperglycaemia for diabetes complications, including dementia. We previously reported that glucagon like peptide-1 receptor agonist (GLP-1RA) alleviated neuronal injury in diabetes related dementia models. However, our understanding of the effects and mechanisms of GLP-1RA on metabolic memory-induced neurodegeneration are limited. The present study mainly focuses on the mechanisms of action of GLP-1RA on metabolic memory induced neurotoxicity in vivo and in vitro. Thus, in this study, aiming at mimicking metabolic memory phenomena, in vivo and in vitro models were exposed to high glucose first and then normal glucose. We also used advanced glycation end products, which are key metabolic memory-related factors, to induce neuronal injury in vitro. Based on the models, here, we report that GLP-1RA alleviated neurodegeneration in db/db mice with normalized blood glucose levels controlled with metformin and neuronal damage induced by high glucose treatment followed by withdrawal. GLP-1RA ameliorated metabolic memory-induced amyloid-beta and tau pathologies in vivo and in vitro. Furthermore, the data suggested that GLP-1RA can protect neurons against metabolic memory via Forkhead box class O (FoxO) pathways, and silent information regulator 2 homolog 1-dependent deacetylation and protein kinase B-dependent phosphorylation of FoxO1 were involved in the mechanisms underlying protective effects. This study provides evidence of the beneficial effects of GLP-1RA on neuronal cell metabolic memory, as well as GLP-1 analogues and metformin combination therapy efficiency on cognitive impairment. PMID- 30465896 TI - RIFM fragrance ingredient safety assessment, 2-methylbutyl butyrate, CAS Registry Number 51115-64-1. PMID- 30465897 TI - Ganoderma tsugae induced ROS-independent apoptosis and cytoprotective autophagy in human chronic myeloid leukemia cells. AB - The medicinal fungus Ganoderma, known in Chinese as Lingzhi or Reishi, traditionally has various medicinal uses and has been employed in cancer treatment in Asia for centuries. This study used ethanol-extracted Ganoderma tsugae (GT) and examined its antitumor activities on human chronic myeloid leukemia cells as well as its molecular mechanism of action. Treatment with GT (200-400 MUg/mL) significantly reduced cell viability and caused G2/M arrest in K562 cells. In addition, GT induced mitochondrial and death receptor mediated apoptosis, correlated with DNA fragmentation, followed by cytochrome c release, caspase-3/8/9 activation, PARP cleavage, Fas activation, Bid cleavage, and Bax/Bcl-2 dysregulation. Cytoprotective autophagy was found to be induced by GT, as was revealed by increased LC3-II accumulation, Beclin-1/Bcl-2 dysregulation, acidic vesicular organelle formation, and p62/SQSTM1 activation. Notably, pretreatment of cells with the autophagy inhibitors 3-MA and CQ enhanced GT induced apoptosis. Interestingly, reactive oxygen species production in cells was not triggered by GT administration; equally, the antioxidant N-acetylcysteine was found to be incapable of preventing apoptosis and autophagy induced by GT treatment. Finally, this study discovered that cytoprotective autophagy induced by GT was associated with EGFR and PI3K/AKT/mTOR signaling cascade suppression. In summary, GT demonstrated antitumor activity against human chronic myeloid leukemia. PMID- 30465898 TI - Preventive role of Pycnogenol(r) against the hyperglycemia-induced oxidative stress and DNA damage in diabetic rats. AB - Diabetes mellitus, a complex progressive metabolic disorder, leads to some oxidative stress related complications. Pycnogenol(r) (PYC), a plant extract obtained from Pinus pinaster, has been suggested to be effective in many diseases including diabetes, cancer, inflammatory and immune system disorders. The mechanisms underlying the effects of PYC in diabetes need to be elucidated. The aim of this study was to determine the effects of PYC treatment (50 mg/kg/day, orally, for 28 days) on the DNA damage and biochemical changes in the blood, liver, and kidney tissues of experimental diabetic rats. Changes in the activities of catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase enzymes, and the levels of 8-hydroxy-2' deoxyguanosine, total glutathione, malondialdehyde, insulin, total bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, high density lipoprotein, low density lipoprotein, total cholesterol, and triglyceride were evaluated. DNA damage was also determined in the whole blood cells and the liver and renal tissue cells using the alkaline comet assay. PYC treatment significantly ameliorated the oxidative stress, lipid profile, and liver function parameters as well as DNA damage in the hyperglycemic rats. The results show that PYC treatment might improve the hyperglycemia-induced biochemical and physiological changes in diabetes. PMID- 30465899 TI - RIFM fragrance ingredient safety assessment, linalyl phenylacetate, CAS Registry Number 7143-69-3. PMID- 30465900 TI - Safety assessment of EPA+DHA canola oil by fatty acid profile comparison to various edible oils and fat-containing foods and a 28-day repeated dose toxicity study in rats. AB - The omega-3 long-chain polyunsaturated fatty acids (LC-PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are recognized for their health promoting qualities. Marine fish and fish oil currently provide the main sources of EPA and DHA for human consumption. An alternative plant-based source of EPA and DHA is provided by EPA + DHA canola event LBFLFK (LBFLFK). A comparative analysis and a 28-day toxicity study assessed the safety of LBFLFK refined, bleached, and deodorized (RBD) oil. Thirty-one different commercially-obtained fat and oil samples were tested, and principal component analysis showed that the overall fatty acid profile of LBFLFK RBD oil was most similar to Mortierella alpina oil and salmon flesh. Samples with the fewest differences in the presence or absence of individual fatty acids compared to LBFLFK RBD oil were menhaden oil and some other fish oils. In a 28-day toxicity study, LBFLFK RBD oil was administered by oral gavage to male and female Wistar rats. No signs of toxicity were evident and no adverse effects were noted in clinical observations, clinical pathology, or histopathology. Overall, these studies support the safety of LBFLFK RBD oil as a source of EPA and DHA for human consumption. PMID- 30465901 TI - Blood magazines. PMID- 30465902 TI - A Novel Pacing Maneuver to Verify the Post-Pacing Interval Minus the Tachycardia Cycle Length While Adjusting for Decremental Conduction: Using 'Dual Chamber Entrainment' for Improved Supraventricular Tachycardia Discrimination. AB - BACKGROUND: The post-pacing interval (PPI) minus the tachycardia cycle length (TCL) is frequently used to investigate tachycardias. However, a variety of issues (e.g. failure to entrain, decremental conduction, and oscillating TCLs) can make interpretation of the PPI-TCL challenging. OBJECTIVES: To investigate a novel maneuver to confirm the PPI-TCL value without using either the ventricular PPI or the TCL interval. To assess the ability of this maneuver to identify decremental conduction and differentiate supraventricular tachycardias. METHODS: We analyzed 77 intracardiac recordings from patients [age 25+/-20 years, 40 female] who underwent catheter ablation of AVNRT or orthodromic reciprocating tachycardia (ORT) with a concealed pathway. We calculated the PPI-TCL, the AH corrected PPI-TCL, and estimated the PPI-TCL using "dual chamber entrainment" calculated as: [PPIV-TCL=Stim(AoV)+Stim(VoA)-PPIA]. RESULTS: The PPI-TCL calculated by dual chamber entrainment highly correlated with the observed and AH corrected PPI-TCL [R2=0.79 and 0.96, respectively, p<0.001]. A dual chamber entrainment PPI-TCL value of 80ms correctly differentiated all AVNRT from septal ORT cases, whereas the standard PPI-TCL and AH-corrected PPI-TCL methods were incorrect in 14% and 6% of cases, respectively. Dual chamber entrainment identified 3+/-10ms of additional decremental conduction beyond AH-prolongation, including four pathways with significant (>10ms) decrement. CONCLUSION: Dual chamber entrainment estimates the PPI-TCL value without using either the ventricular PPI or the TCL interval. This maneuver adjusts for all decremental conduction, including within concealed pathways, where a dual chamber entrainment PPI-TCL value >80ms favors AVNRT over ORT. This maneuver can be used to verify the observed PPI-TCL value in challenging cases. PMID- 30465903 TI - Predictability in Complex Atrial Arrhythmias: the N/N-1 Algorithm to Guide Ablation of Atrial Tachycardias. PMID- 30465904 TI - Ventricular Tachycardia induced by Antitachycardia Pacing for Ventricular Tachycardia: Not so Pain Free? PMID- 30465905 TI - Epicardial connection between the right-sided pulmonary venous carina and right atrium in patients with atrial fibrillation: A possible mechanism for preclusion of pulmonary vein isolation without carina ablation. AB - BACKGROUND: Ablation of the pulmonary venous (PV) carina is occasionally required for PV isolation (PVI) despite its non-essential role in ipsilateral PVI from the anatomical (endocardial) viewpoint. Although Bachmann's bundle (BB) is a common and main interatrial band, local variations of small tongues of muscular fibers were frequently found in autopsy studies. OBJECTIVE: We sought to clarify the impact of the electrical conduction pattern from right atrium (RA) to left atrium (LA) during sinus rhythm on the necessity of performing right-sided PV carina ablation to achieve PVI. METHODS: Study subjects comprised 37 consecutive patients undergoing initial catheter ablation of lone AF. During sinus rhythm, RA and LA activation maps were acquired using the CARTO ConfiDENSE module in the auto-freeze mode. LA breakthroughs were classified into 3 sites: BB, fossa ovalis (FO), and right-sided PV carina. Patients were divided into the carina-ABL (ablation) or non-carina-ABL group based on the necessity of PV carina ablation to achieve PVI. RESULTS: Patients were classified in the non-carina-ABL group (n=26, 70%) and carina-ABL group (n=8, 22%) after excluding 3 patients (8%) because of their complex ablation lesion sets. Breakthrough occurred in the BB (n=21 patients, 62%), FO (n=7, 21%), carina (n=1, 3%), carina+BB (n=3, 9%), and carina+FO (n=2, 6%). Carina breakthrough occurred in 6 (75%) patients in the carina-ABL group but in no patients in the non-carina-ABL group (P<0.0001) CONCLUSIONS: PVI was not achievable without carina ablation in one-fifth of patients probably because of epicardial connections present between the right sided PV carina and RA. PMID- 30465906 TI - Infero-lateral J wave Syndromes: A Reflection of Abnormal Repolarization, Depolarization, or Both? PMID- 30465907 TI - Sustainable PHA production in integrated lignocellulose biorefineries. AB - In emerging bioeconomies, the compostable biopolymers polyhydroxyalkanoates (PHAs) are desirable products due to their similarity to petropolymers. While industrial PHA production has been growing rapidly, obtaining a cheap and sustainable carbon source is still a challenge. Among biobased feedstocks, lignocellulose is a cheap, abundant and potentially sustainable carbon source. However, because of its recalcitrance, separation and depolymerization processes that have not reached industrial maturity are usually required. Integrated biorefineries utilize a holistic approach to conversion processes to minimize feedstock price and maximize resource use. This review examines the technical feasibility of merging PHA production and lignocellulose biorefining in integrated processing facilities. Among lignocellulosic feedstocks, wood is a promising carbon source due to its mature industrial infrastructure. Among the lignocellulose components, the hemicellulose fraction is the most promising feedstock for PHA production since it is underutilized and can be combined with bioethanol production from the cellulose fraction. Fractionation processes allow separate recovery of cellulose, hemicellulose and lignin, to which PHA can be added as a co-product. PMID- 30465908 TI - Four types of human platelet lysate, including one virally inactivated by solvent detergent, can be used to propagate Wharton jelly mesenchymal stromal cells. AB - There is accumulating experimental evidence that human platelet lysate (HPL) made from platelet concentrates can replace fetal bovine serum (FBS) as a xeno-free clinical-grade supplement of growth media to expand mesenchymal stromal cells (MSCs). However, uncertainties exist in regard to impacts that various manufacturing methods of HPL can exert on the expansion and differentiation capacity of MSCs. In particular, there is a need to evaluate the possibility of implementing virus-inactivation treatment during HPL production to ensure optimal safety of industrial HPL pools. Expired human platelet concentrates from four different donors were pooled and subjected to freeze-thaw cycles (-80/+37 degrees C), followed or not by serum-conversion by calcium chloride, heat treatment at 56 degrees C for 30 min, or solvent-detergent (S/D) virus inactivation. The concentrations of total proteins, growth factors and fibrinogen, and the chemical compositions of the HPLs were characterized. The impact of HPL supplementation on the cell morphology, doubling time, immunophenotype and trilineage differentiation capacity of Wharton jelly MSCs (WJMSCs) were compared over five passages, using FBS as a control and normalizing the protein content. Data showed that WJMSCs expanded equally well, exhibited a typical fibroblast morphology, had short doubling times, maintained their immunophenotypes, and differentiated into chondrocyte, osteocyte, and adipocyte lineages in all HPL-supplemented media, all of which were more effective than FBS. In conclusion, we found minimal detectable impact of the HPL manufacturing process, including S/D virus inactivation, on the suitability of expanding WJMSCs in vitro. PMID- 30465909 TI - A novel and simple method to produce large amounts of recombinant soluble peptide/major histocompatibility complex monomers for analysis of antigen specific human T cell receptors. AB - Soluble peptide/major histocompatibility complex (p/MHC) tetramers that directly bind to T cell receptors (TCRs) allow the direct quantification, phenotypic characterization and isolation of antigen-specific T cells. Conventionally, soluble p/MHC tetramers have been produced using Escherichia coli, but this method requires refolding of the recombinant proteins. Here, a novel and technically simple method that does not require protein refolding in vitro has been developed for the high-throughput generation of soluble and functional p/MHC single chain trimer (SCT) monomers and tetramers in a mammalian cell system. The p/MHC-SCT tetramers generated by this method bound to the corresponding antigen specific TCRs. Moreover, the immobilized p/MHC-SCT monomers effectively activated antigen-specific T cell lines as well as primary T cells in an antigen-specific manner. This technique provides a robust improvement in the technology, such that recombinant soluble p/MHC monomers and tetramers can be produced more readily and which enables their use in analysis of antigen-specific T cells in basic and clinical studies. PMID- 30465910 TI - Left ventricular diastolic function influences right ventricular - Pulmonary vascular coupling in premature infants. AB - INTRODUCTION: Reduced left ventricular (LV) diastolic function can exert significant load to the right ventricle (RV) that can affect RV-pulmonary vasculature (PV) coupling. RV-PV can be assessed with the RV length-force relationship (tricuspid annular plane systolic excursion [TAPSE] to pulmonary artery acceleration time [PAAT] ratio). We aimed to determine the association between LV diastolic function measured using tissue Doppler imaging (TDI) and TAPSE/PAAT. METHODS: A study of premature infants <29 weeks gestation. TAPSE/PAAT, LV e' and a' waves were measured on Day 1 following birth. Correlation between diastolic indices and TAPSE/PAAT was performed. The independent effect of LV diastolic function and TAPSE/PAAT was assessed using linear regression. RESULTS: One hundred and sixty-two infants with a mean +/- SD gestation & birthweight of 26.6 +/- 1.5 weeks & 938 +/- 241 g. There was a significant positive correlation between LV e' (r = 0.44, p < 0.01)/LV a' (r = 0.44, p < 0.01) and TAPSE/PAAT. This relationship remained significant when adjusting for important confounders (all p < 0.01). Infants with LV a' values in the lowest quartile had lower TAPSE values (4.2 +/- 1.2 vs. 5.1 +/- 1.1 mm, p < 0.01) without a difference in PAAT (41 +/- 8 vs. 41 +/- 10 ms, p = 0.97). CONCLUSIONS: We observed a direct correlation between LV diastolic function and RV-PV coupling in the first day of age, highlighting the importance ventricular interdependence in premature infants. TAPSE/PAAT, as the index of the RV-PV interaction may be further explored for its potential to assess RV reserve under stress with preterm infants in health and disease. PMID- 30465911 TI - A novel genetic lineage of Tula orthohantavirus in Altai voles (Microtus obscurus) from Turkey. AB - Orthohantaviruses (family Hantaviridae order Bunyavirales) are emerging pathogens with a significant impact on human health. They are transmitted via aerosolized excreta of rodents which also act as reservoir hosts, constituting a unique route for dispersion. Dobrava-Belgrade and Puumala orthohantaviruses have been previously reported from Anatolia, in rodents, case reports and occasional outbreaks. We have collected rodents at several locations during a surveillance study in eastern Anatolia. The specimens were morphologically-identified and various tissues were screened via a generic orthohantavirus reverse transcription polymerase chain reaction assay. DNA barcoding via mitochondrial cytochrome b sequencing was performed in rodents with detectable orthohantavirus sequences. High throughput sequencing was performed for viral genome characterization. Fifty rodents were collected and identified morphologically as Microtus spp. (96%) and Apodemus spp. (4%). Orthohantavirus sequences were detected in lung and spleen or liver tissues of 4 voles (8%), barcoded as Microtus obscurus. The virus sequences were identified as Tula orthohantavirus (TULV) and near-complete genomic segments of the prototype viral genome, tentatively named as the Tula orthohantavirus Turkey (TULV-T), could be characterized. Putative open reading frames for viral nucleocapsid and a nonstructural protein on the S segment, glycoproteins G1 and G2 on the M segment and viral replicase on the L segment were identified on the TULV-T. Several minor sequence variants were further characterized. No evidence of recombination could be detected and pairwise comparisons displayed over 95% amino acid sequence identities to various Eurasian TULV strains. Phylogenetic analyses revealed distinct clustering of all genome segments from previously characterized TULV strains via various approaches and models. Here, TULV-T constituted a novel lineage, forming an intermediate among Asian and European TULV lineages. This report describes the initial documentation of TULV circulation and its potential reservoir in Anatolia. The extent of virus dispersion, alternate hosts or outcomes of human exposure require elucidation. PMID- 30465912 TI - Aedes aegypti vector competence studies: A review. AB - Aedes aegypti is the primary transmitter of the four viruses that have had the greatest impact on human health, the viruses causing yellow fever, dengue fever, chikungunya, and Zika fever. Because this mosquito is easy to rear in the laboratory and these viruses grow in laboratory tissue culture cells, many studies have been performed testing the relative competence of different populations of the mosquito to transmit many different strains of viruses. We review here this large literature including studies on the effect of the mosquito microbiota on competence. Because of the heterogeneity of both mosquito populations and virus strains used, as well as methods measuring potential to transmit, it is very difficult to perform detailed meta-analysis of the studies. However, a few conclusions can be drawn: (1) almost no population of Ae. aegypti is 100% naturally refractory to virus infection. Complete susceptibility to infection has been observed for Zika (ZIKV), dengue (DENV) and chikungunya (CHIKV), but not yellow fever viruses (YFV); (2) the dose of virus used is directly correlated to the rate of infection; (3) Brazilian populations of mosquito are particularly susceptible to DENV-2 infections; (4) the Asian lineage of ZIKV is less infective to Ae. aegypti populations from the American continent than is the African ZIKV lineage; (5) virus adaptation to different species of mosquitoes has been demonstrated with CHIKV; (6) co-infection with more than one virus sometimes causes displacement while in other cases has little effect; (7) the microbiota in the mosquito also has important effects on level of susceptibility to arboviral infection; (8) resistance to virus infection due to the microbiota may be direct (e.g., bacteria producing antiviral proteins) or indirect in activating the mosquito host innate immune system; (9) non-pathogenic insect specific viruses (ISVs) are also common in mosquitoes including genome insertions. These too have been shown to have an impact on the susceptibility of mosquitoes to pathogenic viruses. One clear conclusion is that it would be a great advance in this type of research to implement standardized procedures in order to obtain comparable and reproducible results. PMID- 30465913 TI - Early transcriptome changes in response to chemical long-term potentiation induced via activation of synaptic NMDA receptors in mouse hippocampal neurons. AB - Long term potentiation (LTP) is a form of synaptic plasticity. In the present study LTP was induced via activation of synaptic NMDA receptors in primary hippocampal neuron cultures from neonate mice and RNA was isolated for RNA sequencing at 20 min following LTP induction. RNA sequencing and differential expression testing was performed to determine the identity and abundance of protein-coding and non-coding RNAs in control and LTP induced neuron cultures. We show that expression levels of a small group of transcripts encoding proteins involved in negative regulation of gene expression (Adcyap1, Id3), protein translation (Rpl22L1), extracellular structure organization (Bgn), intracellular signalling (Ppm1H, Ntsr2, Cldn10) and protein citrullination (PAD2) are downregulated in the stimulated neurons. Our results suggest that the early stages of LTP are accompanied by the remodelling of the biosynthetic machinery, interactions with the extracellular matrix and intracellular signalling pathways at the transcriptional level. PMID- 30465914 TI - Deciphering mixotrophic Clostridium formicoaceticum metabolism and energy conservation: Genomic analysis and experimental studies. AB - Clostridium formicoaceticum, a Gram-negative mixotrophic homoacetogen, produces acetic acid as the sole metabolic product from various carbon sources, including fructose, glycerol, formate, and CO2. Its genome of 4.59-Mbp contains a highly conserved Wood-Ljungdahl pathway gene cluster with the same layout as that in other mixotrophic acetogens, including Clostridium aceticum, Clostridium carboxidivorans, and Clostridium ljungdahlii. For energy conservation, C. formicoaceticum does not have all the genes required for the synthesis of cytochrome or quinone used for generating proton gradient in H+-dependent acetogens such as Moorella thermoacetica; instead, it has the Rnf system and a Na+-translocating ATPase similar to the one in Acetobacterium woodii. Its growth in both heterotrophic and autotrophic media were dependent on the sodium concentration. C. formicoaceticum has genes encoding acetaldehyde dehydrogenases, alcohol dehydrogenases, and aldehyde oxidoreductases, which could convert acetyl CoA and acetate to ethanol and butyrate to butanol under excessive reducing equivalent conditions. PMID- 30465915 TI - Transcriptome sequencing of the gill and barbel of Southern catfish (Silurus meridionalis) revealed immune responses and novel rhamnose-binding lectins (RBLs). AB - Southern catfish (Silurus meridionalis) is an economically important species widely cultured in China. It is well known for its fast growth, strong resistance to diseases and euryphage. However, little is known about the mechanisms for its powerful immune systems. Our Fish-T1K project has finished its first phase of 200 fish transcriptomes, with sequencing of gills in most examined fishes. In this study, we performed transcriptome sequencing of the gill and the maxillary barbel of Southern catfish, with the latter as a control. High expression of immune related transcripts were observed in these two tissues. We observed that genes in the T cell receptor signaling pathway had higher transcription values in the gill than in the barbel. In addition, eight new rhamnose-binding lectins (RBLs) were identified and their carbohydrate recognition domains (CRDs) were classified according to the eight conserved cysteine residues and two conserved motifs (-YGR and -DPC-). This is the first transcriptome report by high-throughput sequencing of the Southern catfish. Our genomic data and discovery of novel RBLs in this project should be able to promote better understandings of the roles of gills in immune responses and disease prevention for further aquaculture. PMID- 30465916 TI - Transcriptome analysis of differential expressed genes in hepatopancreas of Procambarus clarkii challenged with peptidoglycan. AB - Procambarus clarkii is one of the most economically important species in Chinese aquaculture, and is widely cultured. Infection of P. clarkii populations with bacterial pathogens causes high mortality and great economic loss, therefore disease control is of significant economic importance. P. clarkii is a model system for studying immune responses in invertebrates, and its immune system consists solely of the innate response. In the present study, we examined gene expression related to immune function in P. clarkii in response to pathogen challenge. The transcriptome of hepatopancreas tissue from P. clarkii challenged with peptidoclycan (PGN) was analyzed and compared to control specimens. After assembly and annotation, 48,661 unigenes were identified with an average length of 671.54 bp. A total of 2533 differentially expressed genes (DEGs) were obtained, including 765 significantly up-regulated unigenes and 1757 significantly down-regulated unigenes. Gene ontology (GO) analysis demonstrated 19 biological process subcategories, 16 cellular component subcategories, and 17 molecular function subcategories that were enriched among these DEGs. Enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database revealed enrichment among immune responses pathways. Taken together, this study not only enriches the existing P. clarkii transcriptome database, but also elucidates immune responses of crayfish that are activated in response to PGN challenge. PMID- 30465917 TI - Pregnancy supplementation of Gambian mothers with calcium carbonate alters mid childhood IGF1 in a sex-specific manner. AB - CONTEXT: Sex-specific effects of pregnancy calcium carbonate supplementation have been reported in 8-12 year old Gambian children, indicating faster growth in boys but slower growth in girls born to calcium-supplemented mothers. OBJECTIVE: To determine whether the pregnancy supplement resulted in sex-specific effects on offspring IGF1 and other growth-related indices in mid-childhood. DESIGN: Analysis of archived data obtained in mid-childhood from the children of rural Gambian mothers who had been randomised to 1500 mgCa/d (Ca) or placebo (P) from 20 weeks pregnancy to delivery (ISRCTN96502494). PARTICIPANTS AND METHODS: Of the 526 children born and followed in infancy, 290 had early-morning, fasting plasma assayed for IGF1, IGFBP3, leptin, insulin and calcium-related indices and had anthropometry performed at age 7.5 (SD1.2) years (N/group: Males(M)-Ca = 64, Females(F)-Ca = 77; M-P = 76, F-P = 73). Sex-specific effects of maternal supplementation were considered using regression with sexes separated and together to test for sex * supplement interactions. RESULTS: Boys had lower IGF1, IGFBP3, leptin and insulin than girls (P <= 0.004). IGF1 was higher in M-Ca than M-P (+14.2 (SE7.7)%, P = 0.05) but lower in F-Ca than F-P (-17.8 (SE7.4)%, P = 0.01); sex * supplement interaction P = 0.001. IGF1 concentrations (ng/ml, geometric mean [-1SE,+1SE]) were M-Ca = 78.1[4.3,4.5], M-P = 67.8[3.4,3.6]; F-Ca = 99.5[4.8,5.1], F-P = 118.9[6.4,6.8]. Similar sex * supplement interactions were seen for IGFBP3 and IGF1-adjusted-for-IGFBP3 but group differences were smaller. There were no significant supplement effects on the other biochemical indices. CONCLUSIONS: Calcium carbonate supplementation of pregnant Gambian mothers resulted in higher IGF1 in boys and lower IGF1 in girls during mid-childhood, consistent with the reported maternal supplement effects on growth of the offspring in later childhood. PMID- 30465918 TI - Skeletal Manifestations of Hypoparathyroidism. AB - Chronic PTH deficiency has a marked effect on the skeleton, leading to characteristic decreases in bone remodeling and increases in bone mass. An effect on fracture risk has not been demonstrated, although biochemical, imaging, and histomorphometric data indicate abnormalities in skeletal properties1,21,21,21,2. Replacement with PTH leads to a new skeletal state that is maintained with long term treatment. PMID- 30465919 TI - The Body Appreciation Scale-2: Item interpretation and sensitivity to priming. AB - The Body Appreciation Scale-2 (BAS-2) is a widely-used measure of positive body image. Items are worded ambiguously to allow reference to any aspect of the body during measure completion. We examined (a) how BAS-2 items are interpreted and whether this interpretation is influenced by the content of measures administered prior to it, (b) whether measures administered prior to the BAS-2 alter its scores or (c) the correlation between BAS-2 scores and scores on a measure of body dissatisfaction, (d) how BAS-2 item interpretation relates to total scores, and (e) whether BAS-2 scores are associated with investment in appearance for aesthetic purposes. Canadian female undergraduates (N = 392) completed one of four priming questionnaires, followed by the BAS-2, and then indicated how they interpreted each BAS-2 item. Most items were interpreted in terms of appearance, with the primes having no impact on item interpretation, scores, or the magnitude of the correlation with body dissatisfaction. BAS-2 scores were highest among women interpreting a moderate number of items in terms of appearance and negatively correlated with investment for aesthetic purposes. Thus, the BAS-2 is not vulnerable to priming, but among young Western women, items are likely to be interpreted in terms of appearance. PMID- 30465920 TI - Dual-ion delivery for synergistic angiogenesis and bactericidal capacity with silica-based microsphere. AB - Inhibition of bacterial growth with the simultaneous promotion of angiogenesis has been challenging in the repair and regeneration of infected tissues. Here, we aim to tackle this issue through the use of cobalt-doped silicate microspheres that can sustainably release dual ions (silicate and cobalt) at therapeutically relevant doses. The cobalt was doped up to 2.5 wt% within a sol-gel silicate glass network, and microspheres with the size of ~300 MUm were generated by an emulsification method. The cobalt and silicate ions released were shown to synergistically upregulate key angiogenic genes, such as HIF1-alpha, VEGF and the receptor KDR. Moreover, the incorporation of ions promoted the polarization, migration, homing and sprouting angiogenesis of endothelial cells. Neo-vascular formation was significantly higher in the dual-ion delivered microspheres, as evidenced in a chicken chorioallantoic membrane model. When cultured with bacterial species, the cobalt-doped microspheres effectively inhibited bacteria growth in both indirect or direct contacts. Of note, the bacteria/endothelial cell coculture model proved the efficacy of dual-ion releasing microcarriers for maintaining the endothelial survivability against bacterial contamination and their cell-cell junction. The current study demonstrates the multiple actions (proangiogenic and antibacterial) of silicate and cobalt ions released from microspheres, and the concept provided here can be extensively applied to repair and regenerate infected tissues as a growth factor- or drug-free delivery system. STATEMENT OF SIGNIFICANCE: While several ions have been introduced to biomaterials for therapeutic purposes, relaying the effects of antibacterial into tissue regenerative (e.g., angiogenesis) has been a significant challenge. In this study, we aim to develop a biomaterial platform that has the capacity of both 'antibacterial' and 'proangiogenic' from a microsphere sustainably releasing multiple ions (herein cobalt and silicate). Here, dual-actions of the microspheres revealed the stimulated endothelial functions as well as the inhibited growth of different bacterial species. In particular, protecting endothelial survivability against bacterial contamination was reported using the bacterial/endothelial co-culture model. The current concept of drug-free yet multiple-ion delivery biomaterials can be applicable for the repair and regeneration of infected tissues with dual actions of angiogenesis and suppressing bacterial activity. PMID- 30465921 TI - A dual-targeted hyaluronic acid-gold nanorod platform with triple-stimuli responsiveness for photodynamic/photothermal therapy of breast cancer. AB - Multi-stimuli-responsive theranostic nanoplatform integrating functions of both imaging and multimodal therapeutics holds great promise for improving diagnosis and therapeutic efficacy. In this study, we reported a pH, glutathione (GSH) and hyaluronidase (HAase) triple-responsive nanoplatform for HER2 and CD44 dual targeted and fluorescence imaging-guided PDT/PTT dual-therapy against HER2 overexpressed breast cancer. The nanoplatform was fabricated by functionalizing gold nanorods (GNRs) with hyaluronic acid (HA) bearing pendant hydrazide and thiol groups via Au-S bonds, and subsequently chemically conjugating 5 aminolevulinic acid (ALA), Cy7.5 and anti-HER2 antibody onto HA moiety for PDT, fluorescence imaging and active targeting, respectively. The resulting versatile nanoplatform GNR-HA-ALA/Cy7.5-HER2 had uniform sizes, favorable dispersibility, as well as pH, GSH and HAase triple-responsive drug release manner. In vitro studies demonstrated that HER2 and CD44 receptor-mediated dual-targeting strategy could significantly enhance the cellular uptake of GNR-HA-ALA/Cy7.5-HER2. Under near-infrared (NIR) irradiation, MCF-7 cells could efficiently generate reactive oxygen species (ROS) and heat, and be more efficiently killed by a combination of PDT and PTT as compared with individual therapy. Pharmacokinetic and biodistribution studies showed that the nanoplatform possessed a circulation half life of 1.9 h and could be specifically delivered to tumor tissues with an accumulation ratio of 12.8%. Upon the fluorescence imaging-guided PDT/PTT treatments, the tumors were completely eliminated without obvious side effects. The results suggest that the GNR-HA-ALA/Cy7.5-HER2 holds great potential for breast cancer therapy. STATEMENT OF SIGNIFICANCE: A combination of photodynamic therapy (PDT) and photothermal therapy (PTT) is emerging as a promising cancer treatment strategy. However, its therapeutic efficacy is compromised by the nonspecific delivery and unintended release of photo-responsive agents. Herein, we developed a multifunctional theranostic nanoplatform GNR-HA-ALA/Cy7.5-HER2 with pH, glutathione and hyaluronidase triple-responsive drug release for HER2 and CD44 dual-targeted and fluorescence imaging-guided PDT/PTT therapy against breast cancer. We demonstrated that HER2 and CD44 receptors-mediated dual targeting strategy significantly enhanced the cellular uptake of GNR-HA-ALA/Cy7.5 HER2. We also demonstrated that the combined PDT/PTT treatment had significantly superior antitumor effect than PDT or PTT alone both in vitro and in vivo. Therefore, GNR-HA-ALA/Cy7.5-HER2 could serve as a promising nanoplatform for HER2 positive breast cancer therapy. PMID- 30465922 TI - A new glioblastoma cell trap for implantation after surgical resection. AB - Glioblastoma (GB) is a highly infiltrative tumor, recurring, in 90% of cases, within a few centimeters of the surgical resection cavity, even with adjuvant chemo/radiotherapy. Residual GB cells left in the margins or infiltrating the brain parenchyma shelter behind the extremely fragile and sensitive brain tissue and may favor recurrence. Tools for eliminating these cells without damaging the brain microenvironment are urgently required. We propose a strategy involving the implantation, into the tumor bed after resection, of a scaffold to concentrate and trap these cells, to facilitate their destruction by targeted therapies, such as stereotactic radiosurgery. We used bacterial cellulose (BC), an easily synthesized and modifiable random nanofibrous biomaterial, to make the trap. We showed that the structure of BC membranes was ideal for trapping tumor cells and that BC implants were biocompatible with brain parenchyma. We also demonstrated the visibility of BC on magnetic resonance imaging, making it possible to follow its fate in clinical situations and to define the target volume for stereotactic radiosurgery more precisely. Furthermore, BC membranes can be loaded with chemoattractants, which were released and attracted tumor cells in vitro. This is of particular interest for trapping GB cells infiltrating tissues within a few centimeters of the resection cavity. Our data suggest that BC membranes could be a scaffold of choice for implantation after surgical resection to trap residual GB cells. STATEMENT OF SIGNIFICANCE: Glioblastoma is a highly infiltrative tumor, recurring, in 90% of cases, within a few centimeters of the surgical resection cavity, even with adjuvant chemo/radiotherapy. Residual tumor cells left in the margins or infiltrating the brain parenchyma shelter behind the extremely fragile and sensitive brain tissue and contribute to the risk of recurrence. Finding tools to eliminate these cells without damaging the brain microenvironment is a real challenge. We propose a strategy involving the implantation, into the walls of the surgical resection cavity, of a scaffold to concentrate and trap the residual tumor cells, to facilitate their destruction by targeted therapies, such as stereotactic radiosurgery. PMID- 30465923 TI - Methods for producing microstructured hydrogels for targeted applications in biology. AB - Hydrogels have been broadly studied for applications in clinically motivated fields such as tissue regeneration, drug delivery, and wound healing, as well as in a wide variety of consumer and industry uses. While the control of mechanical properties and network structures are important in all of these applications, for regenerative medicine applications in particular, matching the chemical, topographical and mechanical properties for the target use/tissue is critical. There have been multiple alternatives developed for fabricating materials with microstructures with goals of controlling the spatial location, phenotypic evolution, and signaling of cells. The commonly employed polymers such as poly(ethylene glycol) (PEG), polypeptides, and polysaccharides (as well as others) can be processed by various methods in order to control material heterogeneity and microscale structures. We review here the more commonly used polymers, chemistries, and methods for generating microstructures in biomaterials, highlighting the range of possible morphologies that can be produced, and the limitations of each method. With a focus in liquid-liquid phase separation, methods and chemistries well suited for stabilizing the interface and arresting the phase separation are covered. As the microstructures can affect cell behavior, examples of such effects are reviewed as well. STATEMENT OF SIGNIFICANCE: Heterogeneous hydrogels with enhanced matrix complexity have been studied for a variety of biomimetic materials. A range of materials based on poly(ethylene glycol), polypeptides, proteins, and/or polysaccharides, have been employed in the studies of materials that by virtue of their microstructure, can control the behaviors of cells. Methods including microfluidics, photolithography, gelation in the presence of porogens, and liquid-liquid phase separation, are presented as possible strategies for producing materials, and their relative advantages and disadvantages are discussed. We also describe in more detail the various processes involved in LLPS, and how they can be manipulated to alter the kinetics of phase separation and to yield different microstructured materials. PMID- 30465924 TI - Insights into the structure and tubulin-targeted anticancer potential of N-(3 bromobenzyl) noscapine. AB - BACKGROUND: Noscapine is a non-narcotic, antitussive alkaloid isolated from plants of Papaveraceae family. This benzylisoquinoline alkaloid and its synthetic derivatives, called noscapinoids, are being evaluated for their anticancer potential. METHODS: The structure of a novel analogue, N-(3-bromobenzyl) noscapine (N-BBN) was elucidated by X-ray crystallography. Effect of N-BBN on cancer cell proliferation and cellular microtubules were studied by sulphorhodamine B assay and immunofluorescence, respectively. Binding interactions of the alkaloid with tubulin was studied using spectrofluorimetry. RESULTS: N-BBN, synthesized by introducing modification at site B ('N' in isoquinoline unit) and a bromo group at the 9th position of the parent compound noscapine, was found to be superior to many of the past-generation noscapinoids in inhibiting cancer cell viability and it showed a strong inhibition of the clonogenic potential of an aggressively metastatic breast tumour cell line, MDA MB-231. The compound perturbed the tertiary structure of purified tubulin as indicated by an anilinonaphthalene sulfonic acid-binding assay. However, substantiating the common feature of noscapinoids, it did not alter microtubule polymer mass considerably. In cells, the drug-treatment showed a peculiar type of disruption of normal microtubule architecture. CONCLUSION: N-BBN may be considered for further investigations as a potent antiproliferative agent. PMID- 30465925 TI - Amygdaloid administration of tetrapentylammonium attenuates development of pain and anxiety-like behavior following peripheral nerve injury. AB - BACKGROUND: The central amygdaloid nucleus (CeA) is involved in processing and descending regulation of pain. Amygdaloid mechanisms underlying pain processing and control are poorly known. Here we tested the hypothesis that perioperative CeA administration of tetrapentylammonium (TPA), a non-selective THIK-1 channel blocker and thereby inhibitor of microglia, attenuates development of chronic neuropathic pain and comorbid anxiety-like behavior. METHODS: Rats with a spared nerve injury (SNI) model of neuropathy or sham operation had a chronic cannula for drug microinjections into the CeA or a control injection site. Monofilament test was used to evaluate pain, and light-dark box (LDB) to assess anxiety. RESULTS: Perioperative CeA treatment with TPA (30 MUg/day up to the third postoperative day, D3) significantly attenuated the development of pain and anxiety-like behavior. In the late phase (> D14), CeA administration of TPA (3-30 MUg) failed to influence pain. Perioperative minocycline (microglia inhibitor; 25 MUg), MK-801 (an N-Methyl-D-aspartate receptor antagonist; 0.1 MUg), vehicle or TPA in a control injection site failed to attenuate pain development. CONCLUSIONS: Perioperative treatment of the CeA with TPA delayed development of neuropathic pain and comorbid anxiety-like behavior, while TPA treatment failed to influence maintenance of established neuropathic pain. The failures to attenuate pain development with CeA administrations of minocycline or MK-801 do not support the hypothesis that the TPA-induced prophylactic effect was due to inhibition of amygdaloid microglia or N-methyl-D-aspartate receptors. While TPA in the CeA proved to have a prophylactic effect on SNI-induced pain behavior, the underlying mechanism still remains to be studied. PMID- 30465927 TI - Induction chemotherapy in borderline (non-)resectable pancreatic cancer: a unique window of opportunity for understanding pancreatic cancer. PMID- 30465926 TI - Serum gamma-glutamyl transferase is associated with silent brain infarcts in a healthy population. AB - BACKGROUND AND AIMS: Although there is substantial evidence that serum gamma glutamyl transferase (GGT) is associated with cerebrovascular diseases, its role in silent brain infarcts (SBIs) has not been addressed. In this study, we evaluated the relationship between serum GGT and the presence of SBI in a neurologically healthy population. METHODS: We evaluated a consecutive series of healthy volunteers recruited between January 2006 and December 2013. We conducted broad examinations in the form of health check-ups, which included brain magnetic resonance imaging and laboratory examinations including assessment of GGT levels. SBI was defined as asymptomatic, well-defined lesions with a dimeter of >=3 mm with the same signal characteristics as cerebrospinal fluid on T1- or T2-weighted images. RESULTS: A total of 3145 healthy subjects were assessed, and 260 SBI cases were identified. In multivariate analysis, the highest GGT tertile was independently associated with SBI [adjusted OR (aOR) = 1.48, 95% confidence interval (CI) = 1.02 to 2.15, p = 0.040] in a dose-response manner (p for trend = 0.037). Age and hypertension were also found to be significant factors for SBI. In a stratified analysis by sex, these positive associations of GGT levels with SBI became more prominent in the male group (aOR = 2.14, 95% CI = 1.15 to 4.00, p = 0.017), with a significantly increasing trend (p for trend = 0.028), while there was no association among female participants. CONCLUSIONS: Increased serum GGT levels were found to be associated with higher SBI prevalence in a neurologically healthy population. PMID- 30465928 TI - Pregestational diabetes and fetal heart rate in the first trimester of pregnancy. AB - OBJECTIVE: The aim of our study is to evaluate if pregestational diabetes affects fetal heart rate (FHR) readings at 11-14 weeks of pregnancy. STUDY DESIGN: For each patient, we recorded age, body mass index (BMI), presence of pregestational diabetes, nuchal translucency (NT), FHR, crown-rump length (CRL), biparietal diameter (BPD) and gestational age. Pregnancies were grouped according to the presence or absence of pregestational diabetes and maternal and fetal variables were compared. Ordinal regression analysis was performed to assess the influence of maternal and fetal variables on the FHR. RESULTS: We included 994 pregnancies from 2009 to 2016. Kruskal-Wallis test showed that median FHR was higher in women with pregestational diabetes than in controls (161; IQR 11 vs. 158; IQR 10, chi2 = 5.13, p = 0.02). Ordinal regression analysis showed that differences in FHR were significantly correlated with the presence of pregestational diabetes (p = 0.007) and the CRL (p = 0.042) but not with the maternal BMI, maternal age, gestational age, BPD and NT. CONCLUSIONS: First trimester FHR is higher in diabetic pregnancies than in non-diabetic pregnancies. Therefore, further research is needed to assess whether these pregnancies may benefit from a correction of FHR for a better estimation of the chromosomal abnormalities risk. PMID- 30465929 TI - Long-term (8.5 years) analysis of the type and rate of reoperation after transvaginal mesh repair (Prolift(r)) in 349 patients. AB - OBJECTIVE: Polypropylene meshes have specific complications, and in 2016 the Food and Drug Administration required a Premarket Approval for their use in pelvic prolapse repair, as there was a lack of long-term data. Our objectives were to determine the long-term reoperation rates and type in our patients after transvaginal mesh repair and to study their risk factors. STUDY DESIGN: We were able to follow up with 349 patients from a single University Hospital, with phone calls, after a median time of 8,5 years. The 8.5-year reoperation rates were derived from Kaplan-Meier survival curves. RESULTS: Our global, long-term reoperation rate, including mesh complications, prolapse recurrence and urinary incontinence after a median follow-up of 8.5 years, was 14.5%. The mesh-related complication rate (including mesh exposures, infections, and retractions requiring surgery) was 4.3%, the urinary incontinence rate was 5.7%. The prolapse recurrence rate was 7.2%; mainly found with posterior mesh only (18.5% of reoperations). For total Prolift, the reoperation rate for prolapse recurrence was only 4%. Moreover, 867% of the patients who had an anterior Prolift only or a posterior Prolift only and who were re-operated for prolapse recurrence showed recurrence exclusively in another compartment. In bivariate analysis, only the posterior mesh type was significantly associated with prolapse recurrence versus total meshes. CONCLUSION: Despite their market withdrawal, the transvaginal meshes are a safe and efficient option for pelvic organ prolapse surgical management. Low rates of mesh complications can be achieved with cautious dissection and adequate training of surgeons. PMID- 30465930 TI - Glycoprotein D of HSV-1 is dependent on tegument protein UL16 for packaging and contains a motif that is differentially required for syncytia formation. AB - Glycoprotein D (gD) of herpes simplex virus type 1 (HSV-1) plays a key role in multiple events during infection including virus entry, cell-to-cell spread, and virus-induced syncytia formation. Here, we provide evidence that an arginine/lysine cluster located at the transmembrane-cytoplasm interface of gD critically contributes to viral spread and cell-cell fusion. Our studies began with the discovery that packaging of gD into virions is almost completely blocked in the absence of tegument protein UL16. We subsequently identified a novel, direct, and regulated interaction between UL16 and gD, but this was not important for syncytia formation. However, a mutational analysis of the membrane-proximal basic residues of gD revealed that they are needed for the gBsyn phenotype, salubrinal-induced fusion of HSV-infected cells, and cell-to-cell spread. Finally, we found that these same gD tail basic residues are not required for cell fusion induced by a gKsyn variant. PMID- 30465931 TI - Induction of immune responses by a novel recombinant fusion protein of enterovirus A71 in BALB/c mice. AB - Fusion protein technology is used in biotechnology and medical developments. In this study, recombinant fusion proteins from enterovirus A71 (EV-A71) subgenotype B5, Thailand were designed based two surface proteins (VP1 and VP2) and an internal protein (VP4), and named "VP0" (consisting of VP4-VP2) and "EV71" (consisting of VP4-VP2-VP1), respectively. The recombinant fusion proteins VP0 and EV71 were expressed in insect cells and successfully produced and secreted into the media. Both recombinant fusion proteins were shown to have immunogenic properties in BALB/c mice when formulated with Freund's complete/incomplete adjuvant (FA). Interestingly, EV71 formulated with FA- induced a level of IgG antibodies level similar to that induced by the recombinant protein VP1 formulated with FA (the positive control). Our results showed that VP1 alone is better at eliciting a strong cell-mediated immune response. Nontheless, EV71 formulated with FA was capable of inducing lymphocyte proliferation and increasing the cytokine-related mRNA expression levels of interferon-gamma (IFN gamma), interleukin-2 (IL-2), and IL-10 in mice after immunization. Additionally, the number of CD4+ and CD8+ T lymphocyte cells after stimulation with purified EV71 in splenic cell culture showed highly specific CD4+ and CD8+ T-cell production. We suggest that EV71, which consists of VP4-VP2-VP1, could be used as the foundation for developing a novel recombinant fusion protein-based vaccine for EV-A71. PMID- 30465932 TI - Healthcare underutilization in middle-aged and elderly adults in China. AB - OBJECTIVES: This article investigates the prevalence of, illness conditions associated with, and reasons for healthcare underutilization among middle-aged and elderly adults in China. It also identifies participants' characteristics associated with healthcare underutilization. STUDY DESIGN: A cross-sectional survey was conducted in Beijing and Henan in August 2016. METHODS: The survey was questionnaire-based. It focused on middle-aged and elderly persons aged 45 years and older. A total of 1778 people were surveyed. RESULTS: In the end, 243 participants (30.11%) and 312 participants (32.13%) displayed signs of healthcare underutilization in Beijing and Henan, respectively. The disease conditions and reasons for underutilization were different in these two areas. Age group, marital status, education level, occupation, and chronic disease were found to be associated with healthcare underutilization in Beijing, whereas gender, age group, marital status, education level, and chronic disease were associated with healthcare underutilization in Henan. CONCLUSIONS: Illness conditions, reasons for underutilization, and risk factors associated with healthcare underutilization were different in developed areas compared with developing areas of China. Further reforms and interventions are needed to consider these problems. PMID- 30465933 TI - Physical activity of university students with disabilities: accomplishment of recommendations and differences by age, sex, disability and weight status. AB - OBJECTIVES: This article aims to study physical activity and the achievement of World Health Organization physical activity recommendations in university students with disabilities, and to examine differences by sex, age, disability characteristics and weight status. STUDY DESIGN: Cross-sectional data from a wider research project conducted at the Spanish universities from Autumn 2016 to Autumn 2017 were analysed. METHODS: The International Physical Activity Questionnaire-Short Form was administered to 1103 Spanish university students with different disabilities. Nonparametric tests were performed to examine the differences in physical activity based on the interest variables. RESULTS: The mean metabolic equivalent (MET)-minutes/week was 1772.75 (+/-2161.00) for total physical activity, 642.93 (+/-1303.08) for vigorous physical activity, 344.31 (+/ 699.53) for moderate physical activity and 785.50 (+/-1053.31) for walking intensity physical activity. Overall, 72.2% of the participants did not meet the recommendation of 75 min/week of vigorous physical activity, 80.3% did not meet the recommendation of 150 min/week of moderate physical activity and 63.1% did not meet any of these recommendations. Nonparametric tests revealed that students with multiple disabilities, chronic illnesses, acquired disabilities, older students, obese students and women were less active than their counterparts. CONCLUSIONS: A high number of participants did not meet the World Health Organization physical activity recommendations, and some subgroups were especially inactive. Public health policies should implement interventions to encourage people with disabilities to engage in physical activity, paying extra attention to the most inactive subgroups. PMID- 30465934 TI - Enhanced basal autophagy supports ameloblastoma-derived cell survival and reactivation. AB - OBJECTIVES: Ameloblastoma is an aggressive odontogenic jaw neoplasm. Its unlimited growth confers high potential for malignant transformation and recurrence. It is unclear why ameloblastoma is highly recurrent despite surgical resection with a wide margin of normal tissue. While canonical autophagy can be used to degrade and eliminate damaged cellular components, it is also a protective mechanism that provides energy and vital metabolites for cell survival. We used ameloblastoma-derived cells to test the hypothesis that autophagic processes play a role in survival and reactivation of ameloblastoma. METHODS: Primary epithelial (EP-AMCs) and mesenchymal (MS-AMCs) ameloblastoma derived cells were established from tissue samples of solid multicystic ameloblastoma. Clonogenic capacity and basal autophagic capacity were assessed in ameloblastoma-derived cells relative to human odontoma-derived cells (HODCs) and maxilla-mesenchymal stem cells (MX-MSCs). Ability of ameloblastoma-derived cells to survive and form new ameloblastoma was assessed in mouse tumor xenografts. RESULTS: EP-AMCs were highly clonogenic (p < 0.0001) and demonstrated enhanced basal levels of autophagic proteins microtubule-associated protein 1-light chain 3 (LC3) (p < 0.01), p62 (Sequestosome 1, SQSTM1) (p < 0.01), and the LC3-adapter, melanoregulin (MREG) (p < 0.05) relative to controls. EP-AMCs xenografts regenerated solid ameloblastoma-like tumor with histological features of columnar ameloblast-like cells, loose stellate reticulum-like cells and regions of cystic degeneration characteristic of follicular variant of solid multicystic ameloblastoma. The xenografts also displayed stromal epithelial invaginations strongly reactive to LC3 and p62 suggestive of epithelial-mesenchymal transition and neoplastic odontogenic epithelium. CONCLUSIONS: EP-AMCs exhibit altered autophagic processes that can support survival and recurrence of post-surgical ameloblastoma cells. PMID- 30465935 TI - Development and use of a mouth gag for oral experiments in rats. AB - OBJECTIVE: Rodent models such as mice and rats are often used in investigations of the oral cavity in the fields of periodontology and dental anesthesiology. When various treatments are performed in the oral cavity, it is very important to secure the visual field while keeping the animal's mouth fully opened, in order to ensure the consistency of experimental procedures. Therefore, we developed a standardized gag conforming to various degrees of oral cavity size of different aged rats. DESIGN: The gag was composed of a rectangular incisor-opening frame constructed from a stainless steel wire with retractors and a dial to alter the opening amounts. Wistar rats (n = 5) aged 4, 8, and 12 weeks were used to evaluate the suitability of the gag in oral cavity. As tests for application of gag in intraoral experiments, the ligature placement around the molars, drug injection into the gingiva, measurement of gingival blood flow rate, and installation of stimulation an electrode for somatosensory-evoked potentials into the molar were performed. RESULTS: Adjusting the opening dial enabled both the maintenance of open state and more favorable intraoral observation compared with tweezers as a control device in all different types of rats. Furthermore, our gag made it possible to facilitate the insertion of diverse instruments into the oral cavity and to achieve various experimental purposes. The stainless-steel gag can also be autoclaved and dry-heat sterilized. CONCLUSION: It was revealed that our mouth gag can be widely applied to various oral experiments in different old aged rats. PMID- 30465936 TI - High molecular weight hyaluronic acid regulates P. gingivalis-induced inflammation and migration in human gingival fibroblasts via MAPK and NF-kappaB signaling pathway. AB - Chronic periodontitis is associated with Porphyromonas gingivalis (P. gingivalis) infection. Hyaluronic Acid (HA), a critical component of the extracellular matrix, exhibits anti-inflammatory and wound-healing properties. This study aimed to investigate the effect of various molecular weights of HA (30, 300 and 1300 kDa) on P. gingivalis-induced inflammatory and wound-healing responses in human gingival fibroblasts (HGFs). Cell cytotoxicity and proliferation were assessed by Lactate dehydrogenase and MTT assays, respectively. An enzyme linked immunosorbent assay was used to detect the levels of interleukin (IL) -1beta, IL 6, IL-8, IL-4 and IL-10. Cell migration was evaluated with a scratch wound healing assay. The expression of nuclear factor kappa B (NF-kB), IkBalpha, p38 and extracellular signal-regulated kinase (ERK) were analyzed with Western blotting. The results showed that P. gingivalis (1.6 * 106 CFU/mL) and HA (1, 2, 5 and 10 mg/mL) exhibited no toxicity to the HGFs. The 1300 kDa HA inhibited P. gingivalis-induced IL-1beta, IL-6, IL-8, IL-4 and IL-10 production in a dose dependent manner, while the 30 and 300 kDa HA did not have an effect. Meanwhile, cell migration was significantly promoted by the 30 and 1300 kDa HA. Furthermore, the 1300 kDa HA inhibited NF-kappaB expression, IkappaBalpha degradation and P. gingivalis-induced ERK and P38 activation. Therefore, our study suggests that high molecular weight HA may have beneficial effects on periodontal inflammation and oral wounds. PMID- 30465937 TI - Antinociceptive effects of the adenylyl cyclase inhibitor ST034307 on tooth movement-induced nociception in rats. AB - OBJECTIVE: This study aimed to investigate the antinociceptive effects of the selective adenylyl cyclase type 1 (AC1) inhibitor ST034307 on tooth movement nociception through orofacial nociceptive behavior tests and molecular examination. METHODS: We placed fixed nickel-titanium alloy closed-coil springs around the incisors of male Sprague-Dawley rats to induce tooth movement. We subsequently administered ST034307 (3 mg/kg), for 2 days, intraperitoneally, and then subjected the rats to a battery of behavioral tests (n = 10/group) to assess orofacial nociception. The changes in the expression of key molecules in the anterior cingulate cortex were measured by ELISA (n = 8/group) and Western blotting (n = 8/group). RESULTS: Tooth movement increased face-grooming activities and rat grimace scale scores. Tooth movement was also associated with enhanced cyclic adenosine monophosphate (cAMP) generation as well as protein kinase A (PKA) activation. Moreover, the phosphorylation of alpha-amino-3-hydroxy 5-methyl-4-isoxazolepropionic acid (AMPA) receptors and expression of N-methyl-d aspartate (NMDA) receptors in the anterior cingulate cortex increased during tooth movement. ST034307 significantly decreased mouth wiping and rat grimace scale scores, accompanied by reductions in cAMP generation, PKA activation, AMPA receptor phosphorylation, and NMDA receptor expression in the anterior cingulate cortex. CONCLUSIONS: These results suggest that adenylyl cyclase type 1 plays an important role in the development of orthodontic tooth movement nociception. Furthermore, ST034307 can be used as an effective pharmacotherapy for orthodontic nociception. PMID- 30465938 TI - The modulation of the evaluative priming effect by phasic affect. AB - Previous research suggests that affect modulates the sequential priming effect such that positive affect yields robust sequential priming effects, whereas negative affect inhibits them. Although this observation has received substantial empirical support for semantic priming effects (i.e., faster responding to a target word following the earlier presentation of a meaningfully related prime), the evidence is rather scant concerning evaluative priming effects (i.e., faster and/or more accurate evaluative responding to a target word when it is preceded by an evaluatively consistent rather than an evaluatively inconsistent prime). The present research aimed at filling this gap, demonstrating the impact of phasic (temporally short-lived) affect on evaluative priming effects. In doing so, we addressed the shortcomings of previous research as we implemented affective contexts that changed from trial to trial in a within-participants design. In Experiments 1 and 2, brief positive music excerpts yielded a reliable evaluative priming effect, whereas brief negative excerpts inhibited it. In Experiment 3, we replicated and generalized these findings using a proprioceptive facial feedback procedure. Our results corroborate and extend previous research by showing that brief negative affect inhibits priming effects as compared to brief positive affect or a control condition. These findings attest to the flexibility of the evaluative priming effect and suggest it is permeable to subtle affective contexts that influence its magnitude. PMID- 30465939 TI - Hepatic transcriptome of the euryhaline teleost Japanese seabass (Lateolabrax japonicus) fed diets characterized by alpha-linolenic acid or linoleic acid. AB - To investigate the different effects of dietary alpha-linolenic acid (ALA) and linoleic acid (LA) on the euryhaline fish Japanese seabass, a feeding trial followed by hepatic transcriptome assay was conducted. Two experimental diets containing 10% LA-rich sunflower seed oil (diet LA) or 10% ALA-rich perilla oil (diet ALA) were used in the feeding trial. LA and ALA in diets were characteristically incorporated into fish tissues while no significant difference was observed in growth performance and body proximate composition between groups LA and ALA. Compared to LA, ALA up-regulated transcription of 49 unigenes and down-regulated those of 311 unigenes. Quantitative RT-PCR studies on eight lipid metabolism-related genes and seven randomly selected genes were conducted to validate the transcriptomic results. Lipid metabolism-related genes ApoA1, ApoA4, ApoE, FABP1, FABP3, FABP4, FATP6, and DGAT1, as well as ribosomal proteins L9e, L13e, and S4e, were transcriptionally down-regulated by ALA. The differentially expressed genes (DEGs) were primarily enriched in Gene Ontology terms such as Lipid transport, Protein metabolic process, and Ribosome biogenesis, as well as in KEGG pathways such as Complement and coagulation cascades and Ribosome. The Protein-Protein Interaction (PPI) network based on the peptide biosynthesis related DEGs showed that ribosomal proteins such as SAe, L4e, S4e, L15e, L9e, and L13Ae had high betweenness centrality in the dietary regulation of peptide biosynthetic processes. In conclusion, under the present experimental conditions, a high level of dietary alpha-linolenic acid tended to suppress lipid transport and protein biosynthetic processes in the liver of Japanese seabass at the gene expression level. PMID- 30465940 TI - Candidate olfactory genes identified in Heortia vitessoides (Lepidoptera: Crambidae) by antennal transcriptome analysis. AB - Heortia vitessoides Moore is the most severe defoliating pest of Aquilaria sinensis (Lour.) Gilg (Thymelaeaceae) forests. Olfaction in insects is essential for host identification, mating, and oviposition, in which olfactory proteins, including odorant-binding proteins (OBPs), chemosensory proteins (CSPs), olfactory receptors (ORs), ionotropic receptors (IRs), and sensory neuron membrane proteins (SNMPs), are responsible for chemical signaling. Here, we determined the transcriptomes of male and female adult antennae of H. vitessoides. We assembled 52,383 unigenes and annotated their putative gene functions based on the gene ontology (GO), eukaryotic ortholog groups (KOG), and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Overall, 61 olfactory related transcripts, including nine OBPs, 10 CSPs, 28 ORs, 12 IRs, and two SNMPs, were identified. Expression patterns of OBPs and CSPs in the female antennae, male antennae, and legs were performed using reverse transcription quantitative PCR (RT-qPCR). The results revealed that HvitOBP1, HvitOBP6, and HvitGOBP1 were enriched in the female antennae, while HvitOBP2, HvitOBP3, HvitOBP5, HvitGOBP2, and HvitPBP1 were enriched in the male antennae. HvitOBP4 was expressed at nearly the same level in the antennae of both males and females. Four CSPs (HvitCSP3, HvitCSP5, HvitCSP7, and HvitCSP10) and two CSPs (HvitCSP1 and HvitCSP4) were expressed at higher levels in the female and male antennae, respectively. HvitCSP6 was expressed at higher levels both in the female antennae and legs. Three CSP genes (HvitCSP2, HvitCSP8, and HvitCSP9) were expressed at higher levels in the legs. These results provide a basis for further studies on the molecular olfactory mechanisms of H. vitessoides. PMID- 30465941 TI - Rational cyclization-based minimization of entropy penalty upon the binding of Nrf2-derived linear peptides to Keap1: A new strategy to improve therapeutic peptide activity against sepsis. AB - Nrf2 is a critical regulator of innate immune response and survival during sepsis, which is constitutively degraded through binding to the Keap1 adapter protein of E3 ubiquitin ligase. Two linear peptides DLG and ETG derived from, respectively, the low-affinity and high-affinity motifs of Nrf2 binding site exhibit self-binding affinity to Keap1 central hole (active pocket); they can be exploited as therapeutic self-inhibitory peptides to disrupt the Nrf2-Keap1 interaction. Molecular dynamics simulation and binding energetics decomposition reveal that the two peptides possess large flexibility and intrinsic disorder in unbound free state, and thus would incur a considerable entropy penalty upon binding to Keap1. In order to improve Keap1-peptide binding affinity (or free energy DeltaG), instead of traditionally increasing favorable enthalpy contribution (DeltaH) we herein describe a rational peptide cyclization strategy to minimize unfavorable entropy penalty (DeltaS) upon the binding of Nrf2-derived linear peptides to Keap1. Crystal structure analysis impart that the native active conformations of DLG and ETG peptides bound with Keap1 are folded into U shape and hairpin configurations, respectively, and adopt their turning head to insert into the central hole of Keap1. Here, cyclization is designed by adding a disulfide bond across the two arms of DLG U-shape or ETG hairpin, which would not influence the direct intermolecular interaction between Keap1 and peptide as well as desolvation effect involved in the interaction, but can effectively constrain the conformational flexibility and disorder of the two peptides in free state, thus largely minimizing entropy penalty upon the binding. Both free energy calculation and binding affinity assay substantiate that the cyclization, as might be expected, can moderately or considerably enhance peptide binding potency to Keap1, with affinity (dissociation constant Kd) increase by 1.4-7.5-fold for designed cyclic peptides relative to their linear counterparts. PMID- 30465942 TI - Comparison of neural excitation measures from the surface electromyogram during rate-dependent muscle contractions. AB - Peak power and peak rate of isometric force development (RFD) predict performance and functional mobility. Surface electromyography (EMG) is used to quantify the amplitude and rate of neuromuscular excitation. To inform the selection of EMG measures in research on rate-dependent muscle contractions, this methodological study compared amplitude-, area- and rate-based measures based on their correlations with RFD. Considering populations in whom a quiet EMG baseline is challenging, we included measures that do not require the determination of EMG onset. Twenty-one young adults performed isometric dorsiflexion contractions to 40% of their maximal force at increasing RFD. EMG was recorded from tibialis anterior. Relationships between EMG measures and RFD were quantified with Spearman's rho. RMS amplitude of the initial 75 ms of EMG had the strongest correlation with peak RFD (rho = 0.80) among measures computed from EMG onset. Peak rate of EMG rise (RER) had the strongest relationship with peak RFD (rho = 0.69) among measures that did not require determination of EMG onset. The strength of the relationship between RER and RFD and the strong correlation between RER and RMS75 during rapid contractions (rho = 0.86) supports the use of RER in experiments where neural excitation might not be initiated from a quiet baseline. PMID- 30465943 TI - Spending too little in hard times. AB - People's decisions to consume and save resources are critical to their wellbeing. Previous experiments find that people typically spend too much because of how they discount the future. We propose that people's motive to preserve their savings can instead cause them to spend too little in hard times. We design an economic game in which participants can store resources for the future to survive in a harsh environment. A player's income is uncertain and consumption yields diminishing returns within each day, creating tradeoffs between spending and saving. We compare participants' decisions to a heuristic that performed best in simulations. We find that participants spent too much after windfalls in income, consistent with previous research, but they also spent too little after downturns, supporting the resource preservation hypothesis. In Experiment 2, we find that by varying the income stream, the downturn effect can be isolated from the windfall effect. In Experiments 3-4, we find the same downturn effect in games with financial and political themes. PMID- 30465944 TI - How does the slope gradient affect spatiotemporal parameters during running? Influence of athletic level and vertical and leg stiffness. AB - BACKGROUND: The current evidence leaves certain questions unanswered, including whether well-trained athletes adapt to different slope gradients in the same way as amateurs, and whether stiffness influences spatiotemporal adaptations during uphill running. RESEARCH QUESTION: This study aimed to determine the effect of different slope gradients (0%-11%) on spatiotemporal gait characteristics during running, taking into account the influence of athletic level, vertical and leg stiffness. METHODS: Male endurance runners (12 amateurs, 10 highly-trained) performed a running test on a motorized treadmill. The running velocity was set at 12 km/h, and participants completed six different running conditions (0, 3, 5, 7, 9 and 11% gradients). Spatiotemporal parameters were measured using the OptoGait system. Vertical (Kvert) and leg (Kleg) stiffness were calculated according to the sine-wave method. RESULTS: A 2 (amateur; highly-trained) * 6 (running conditions) ANOVA found no significant between-group differences in spatiotemporal parameters at any gradient (P >= 0.05); however, significant Kvert and Kleg differences (P < 0.05) were found within both groups with increasing gradients. Stepwise linear regression analysis showed that Kleg was strongly associated with contact time (R2 = 0.797, P < 0.001), whereas Kvert was associated with spatiotemporal adaptations to different slope gradients (R2 = 0.547, P = 0.002). SIGNIFICANCE: An increased slope gradient (0-11%) at a given running velocity (12 km.h-1) caused spatiotemporal adaptations (i.e., increased CT and SF and decreased FT, SL and SA) regardless of the athletic level of the runner, although a non-significant trend differentiated the adaptations between the amateur and highly-trained groups. The results also indicated that leg stiffness plays a key role in the characteristics of spatiotemporal gait during level running, whereas vertical stiffness is strongly associated with spatiotemporal adaptations when running uphill. PMID- 30465945 TI - Self-Selected walking speed increases when individuals are aware of being recorded. AB - BACKGROUND: Typical gait data collections consist of discrete walking trials where participants are aware when data are being recorded. Anecdotally, some investigators have reported that participants often walk differently between trials or before or after data collection compared to when they know they are being recorded. In addition, walking speed, which affects a number of gait variables, is known to be different when individuals complete discrete and continuous walking trials. RESEARCH QUESTION: The purpose of this study was to determine whether changes in walking speed occurred as a result of participants being aware, versus unaware that data were being recorded, during both discrete and continuous walking trials. METHODS: Kinematic data were collected for twenty two individuals walking continuous trials or discrete trials, while they were both aware and unaware of being recorded. Comparisons of walking speeds were made between groups (continuous walking; discrete trials) and awareness of being recorded (aware; unaware) using a two way ANOVA. RESULTS: The results indicated that participants walked significantly faster during discrete trials when they were aware that data were being recorded compared to when they were unaware. However, when they walked continuously their walking speed was not affected by their awareness. SIGNIFICANCE: The results suggest that awareness of data collection, and the type of protocol used during data collection, affect an individual's walking speed during gait analysis. Therefore, care should be taken when determining gait analysis protocols where variables are sensitive to walking speeds. PMID- 30465946 TI - Age-related changes in upper body contribution to braking forward locomotion in women. AB - INTRODUCTION: Gait termination is a transitory task that requires the lower body to produce braking forces and inhibit forward propulsion. However, it is still unknown whether the upper body plays an active role in braking of gait and whether this mechanism is impaired with ageing. RESEARCH QUESTION: Do older women exhibit an impaired control of upper body segments during gait termination with respect to young women? METHODS: Ten young and 10 older women performed three gait termination trials at comfortable speed while fixing the gaze on a visual target. A 3D motion analysis system was used to measure head, trunk and pelvis angular displacement and velocity, and estimate neck, waist and hip moments through Plug-in Gait modeling. Cross-correlation analysis of kinematic waveforms between paired adjacent segments (head-trunk and trunk-pelvis) was performed to investigate upper body coordination. Surface EMG activity of erector spinae (L3), sternocleidomastoid and neck extensor muscles was recorded. Statistics was carried out by MANOVA. RESULTS: Older participants exhibited delayed peak extensor torques of neck, waist and hip compared to young participants, along with lower progression speed. Both groups showed a slight flexion of the trunk counteracted by a backward tilt of head and pelvis during braking. In addition, older women displayed a peculiar upper body coordination pattern, with the head coupling with trunk motion, as shown by cross-correlation. Older women displayed shorter lumbar erector spinae onset latency relative to last heel contact than young (16 +/- 68 ms vs 92 +/- 37 ms). SIGNIFICANCE: The upper body plays an active role in the braking of gait and this mechanism is impaired in older women. Moreover, the age-related coupling of head and trunk motion may produce an unbalancing effect on whole-body stability during the braking mechanism, thus leading to a higher risk of falls. PMID- 30465947 TI - Treatment of single-level thoracic tuberculosis by percutaneous endoscopic debridement and allograf via the transforaminal approach combined with percutaneous pedicle screw fixation: a multicenter study with a median follow-up of 36 months. PMID- 30465948 TI - Predictors of Venous Thromboembolism After Non-Emergent Craniotomy: A Nationwide Readmission Database Analysis. AB - BACKGROUND: Venous thromboembolism is responsible for a significant number of hospital readmissions each year, particularly among post-surgical cohorts. Because early and indiscriminate VTE prophylaxis carries catastrophic consequences in post-craniotomy cohorts, identifying factors associated with a high risk for thromboembolic complications is important for guiding postoperative management. OBJECTIVE: To determine VTE incidence in patients undergoing non emergent craniotomy and to evaluate for factors, which predict 30- and 90-day readmission with VTE. METHODS: The 2010-2014 cohorts of the Nationwide Readmissions Database were employed to generate a large heterogeneous craniotomy sample. RESULTS: There were 89,450 non-emergent craniotomies that met inclusion criteria. Within 30-days, 1513 patients (1.69%) were readmitted with VTE diagnoses; among them 678 (44.8%) had a diagnosis of DVT alone, 450 (29.7%) had PE alone and 385 (25.4%) had both. The corresponding 30-day DVT and PE incidences were 1.19% and 0.93%, respectively. In multivariate analysis, several factors were significantly associated with VTE readmission namely, craniotomy for tumor, corticosteroids, advanced age, greater length of stay and discharge to institutional care. CONCLUSIONS: Craniotomies for tumor, corticosteroids, advanced age, prolonged length of stay and discharge to institutional care are significant predictors of VTE readmission. The implication of steroids, coupled with their ubiquity in neurosurgery, makes them a potentially modifiable risk factor and a prime target for VTE reduction in craniotomy cohorts. Furthermore, the fact that dose is proportional to VTE risk in the literature suggests that careful consideration should be given towards lowering regimens in situations where use of a lower dose might prove equally sufficient. PMID- 30465949 TI - Down-regulation of miR-145 improves learning and memory abilities in epileptic rats by regulating hippocampal neuron apoptosis. AB - OBJECTIVES: The aim of this study was to investigate effect of miR-145 on learning and memory ability in epileptic rats. METHODS: Epileptic rats were induced by lithium chloride-pilocarpine. miR-145 antagomir and antagomir-control were injected into epileptic brain by stereotactic technique, respectively. Then rats were divided into normal group (N), epilepsy group (Ep), miR-145 antagomir group (A) and antagomir-control group (C). After 1 d and 7d treatment, the expression of miR-145 and Caspase-9 were detected, and the apoptosis of hippocampal neurons in CA1 of hippocampus was detected. After 7d treatment, the learning and memory abilities of rats was measured by Morris water maze test. RESULTS: The rat epilepsy model was successfully constructed. Compared with N group, the target quadrant time and platform crossing times were reduced, and the expression of miR-145 and Caspase-9 were increased in epilepsy groups (P < 0.05). Compared with Ep and C groups, the target quadrant time and platform crossing times were increased, and the expression of miR-145 and Caspase-9 were down regulated in A group (P < 0.05). The number of apoptotic hippocampal neuron in hippocampal CAl area of Ep group was more than that in N group, and it in A group was less than that in C group at 1 d and 7d after modeling respectively (P < 0.05). CONCLUSIONS: Down-regulated miR-145 improved the apoptosis of hippocampal neurons by reducing the Caspase-9 expression in hippocampus, and further affected learning and memory abilities of epileptic rats. PMID- 30465950 TI - Intracranial Low Grade Fibromyxoid Sarcoma with an Atypical Radiology. AB - BACKGROUND: Low grade fibromyxoid sarcoma (LGFMS), an uncommon soft tissue tumor generally occurs in extremities and is characterized by aggressive clinical course with frequent recurrences. Primary intracranial occurrence of LGFMS is rare. The few existing descriptions deal with the clinico-pathological aspects of LGFMS and lack information from a radiologic perspective. In these reports, the lesions appeared solid on imaging. CASE DESCRIPTION: We describe a falx-based lesion with solid-cystic radiologic appearance that turned out to be LGFMS on histopathology in a 45-year-old woman. The patient's clinical follow-up (2 years) along with literature review of such cases has also been presented. CONCLUSION: The report emphasizes on the radiologic aspect as well as describes an atypical (solid-cystic) appearance of this uncommon central nervous system tumor. Thus, it adds another facet to the imaging of LGFMS. Although rare, LGFMS can form a differential of dural-based lesions. PMID- 30465951 TI - The Effectiveness of Antiepileptic Medications as Prophylaxis of Early Seizure in Traumatic Brain Injury Patients Compared to Placebo or No Treatment: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The use of antiepileptic drugs (AEDs) to prevent early post-traumatic seizure (PTS) for patients with severe traumatic brain injury (TBI) is currently recommended, although published studies present contradictory results concerning the protective effect of AEDs. OBJECTIVE: The purpose of this study was to quantify the association between the use of prophylactic AEDs, particularly of the four main drugs of interest (phenytoin, levetiracetam, valproate, or carbamazepine) versus placebo or no treatment, and risk of early seizures following TBI. METHODS: A comprehensive search was performed on PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. The selection criteria were English written randomized controlled trials (RCTs) and observational studies, comparing AEDs with placebo or no treatment, for prevention of early PTS. Random-effects models were used to calculate pooled relative risk (RR). Subgroup analysis and meta-regression were used to assess heterogeneity sources. RESULTS: This research included three RCTs (750 patients) and six observational studies (3,362 patients), analyzing the efficacy of phenytoin, levetiracetam, and valproate. The pooled RR estimate across RCTs trended towards a protective effect (RR=0.50; 95% CI 0.24-1.03; I2=59.5%); a significant protective association was demonstrated when pooling the results across all six observational studies (RR=0.43; 95% CI 0.26-0.71; I2= 0%). When stratifying the observational studies by drug, no significant difference was observed (P-interaction=0.85). Begg's and Egger's tests indicated no publication bias among observational studies. CONCLUSION: Only modest evidence suggested effectiveness of AEDs as prophylaxis of early PTS. Phenytoin was the most studied drug; more prospective studies are needed to assess the efficacy of other AEDs. PMID- 30465952 TI - Microsurgical treatment of cerebral aneurysms after prior endovascular therapy: single center series and systematic review. AB - BACKGROUND: Since its introduction in the early 90s, endovascular treatment of cerebral aneurysms has had a steady upward trend and is currently the primary mode of treatment for most intracranial aneurysms. Concurrently, the need for retreatment of aneurysms after prior endovascular treatment has continued to grow, some of which can only be treated with microsurgical techniques. The factors that dictate outcomes in this group of patients are incompletely understood. OBJECTIVE: To study factors contributing to patient outcomes after microsurgical treatment of aneurysms with prior endovascular treatment. METHODS: The senior author's (DLB) records since 2002 were retrospectively reviewed for aneurysms treated after prior endovascular treatment. Demographics, treatment details and imaging were reviewed for all patients. A systematic review of the literature on microsurgical treatment of aneurysms previously treated by endovascular therapy was also conducted. RESULTS: A total of 91 patients were identified from the retrospective review. Mean age at the time of initial treatment was 49 +/- 12.68 years. Most patients initially presented with subarachnoid hemorrhage prior to initial endovascular treatment, with only 11 (12%) patients presenting with incidentally discovered lesions. mRS at discharge after initial treatment was good (0-3) in 81.4% of cases. Functional outcomes at the last known follow-up revealed a mRS of 0-3 in 74 (81.3%) patients. Only aneurysm neck size was found to be a significant predictor of surgical complications (Wald chi2=10.79, p=0.0010) with an odds ratio of 2.32 (95% CI: 1.40 , 3.83) for a 2mm increase in neck size. Systematic review identified 37 studies that were used to pool data on 370 total patients. Although type of surgery was identified as a predictor of poor outcomes this was significantly confounded by Hunt and Hess grade in the systematic review. CONCLUSION: Favorable outcomes can be obtained even for highly complex cerebral aneurysms that have failed endovascular treatment at high volume cerebrovascular centers. Initial presentation grade and aneurysm size are important predictors of final patient outcomes. PMID- 30465953 TI - Two-nation comparison of classification and treatment of subaxial cervical spine fractures: An internet-based multicenter study among spine surgeons. AB - BACKGROUND: To date, there is no evidence-based treatment algorithm for fractures of the subaxial spine, and an international controversy concerning optimal surgical care exists. The aim of this study was to assess and compare the management strategy for traumatic subaxial fractures among German and Dutch spine surgeons. METHODS: In this web-based-multicenter study (www.umfrageonline.com) CT scans of traumatic subaxial fractures (C3-C7) were evaluated by German and Dutch spine surgeons. Supplementary case-specific information as age, gender, neurological status, and injury mechanism were provided. By use of a questionnaire, fractures were classified according to the AOSpine subaxial cervical spine injury classification system, followed by nine questions concerning treatment algorithm. Data were analyzed using SPSS (Version 21, 76 Chicago IL, USA). The interobserver agreement was determined by Cohens' kappa. Statistical significance was defined as p< 0.05. RESULTS: Ten surgeons (five/country) evaluated each 31 cases (310 votes). The fractures were classified as AO type A in 37% (114 votes), type B in 50% (155 votes) and type C in 13% (41 votes). In general, German spine surgeons had a lower threshold concerning the indication for surgical treatment (Ger 94.2% vs. NL 58.1%; p<0.05). There was consensus about operative stabilization for AO type B and type C injuries, whereas a discrepancy in the therapeutic algorithm for AO type A fractures was observed. The most significant difference was seen in the treatment of type A2 and A3 fractures (Surgery in type A2/A3 fracture: Ger 92.9%; NL 5.3 %; p< 0.05). CONCLUSION: There is consensus to stabilize AO type B and C fractures, whereas country-specific differences in the treatment of AO type A fractures, especially in case of A2 and A3 fractures, were noted. Further clinical controlled studies will be needed to gather more evidence for the best therapeutic approach of especially type A2 and A3 subaxial cervical spine fractures to ensure more consistent international treatment strategies. PMID- 30465954 TI - Detection of Hemodynamic Characteristics Before Growth in Growing Cerebral Aneurysms by Analyzing Time-of-Flight Magnetic Resonance Angiography Images Alone - Preliminary results. AB - OBJECTIVE: Cerebral aneurysm growth often precedes rupture. Definite contributors to aneurysm growth have not been determined even by means of recently developed commercially available computational fluid dynamics (CFD) software. We developed an original CFD tool that can analyze data from time-of-flight magnetic resonance angiography (TOF-MRA) prior to growth in the growing aneurysms and investigate possible factors for aneurysm growth in the near future. METHODS: We retrospectively reviewed unruptured aneurysms that were treated at our institute because of aneurysm growth (growing group) between April 2013 and March 2017. Stable aneurysms that had demonstrated no growth for more than five years were selected (stable group). TOF-MRA data of these aneurysms were retrospectively converted to three-dimensional vessel geometric data; three hemodynamic indices including streamline, wall shear stress (WSS), and oscillatory shear index were calculated by our original CFD tool using the lattice Boltzmann method to quantitatively compare the two groups. RESULTS: Six growing aneurysms and 6 stable aneurysms were analyzed. Of the 6 growing aneurysms, WSS on the focal aneurysmal sac increased temporally in the vicinity of the constant low WSS area at the peak systolic phase. By contrast, WSS did not increase during any part of the cardiac cycle in three of the six stable aneurysms. The peak values of WSS were significantly different between the two groups. CONCLUSION: A focal increase in WSS in the peak systolic phase may be a risk factor for aneurysm enlargement in the near future. PMID- 30465955 TI - Percutaneous vertebral augmentation for osteoporotic vertebral compression fracture in the mid-thoracic vertebrae (T5-T8): a retrospective study of 101 Patients with 111 fractured segments. AB - OBJECTIVE: Data reporting PVP or PKP application to the mid-thoracic vertebrae remains limited. This study aimed to summarize our experiences and explore the efficacy and the safety of the PVP or PKP in dealing with OVCF in the mid thoracic vertebrae. METHODS: Patients receiving PVP or PKP for mid-thoracic OVCF in our institution from January 2015 to January 2018 were retrospectively enrolled. All patients were grouped according to the cement augmentation procedure types, surgical approaches, and puncture routes. All patients underwent a postoperative follow-up of 2-36 months. VAS and ECOG scores were evaluated pre- and postoperatively. The cement distribution and rate of cement leakage were assessed by radiographs. Associations of these variables, and clinical scores and radiographic indices were analyzed. RESULTS: A total of 101 consecutive patients with 111 fractured centrums were enrolled. Both VAS and ECOG scores of all patients decreased significantly after the operation, and progressively decreased at the final follow-up. The cement distribution of the bipedicular group was significantly better than the unipedicular group, but the total leakage rate of the former (71.7%) was significantly higher than the latter (43.1%). The rate of epidural cement leakage in PKP group (5.4%) was significantly lower than that of PVP group (20.3%), while the left puncture group (28.6%) was significantly higher than that of the right group (2.7%). CONCLUSION: PKP and bipedicular approach can help improve the cement distribution and reduce the epidural cement leakage rate, thus should preferred over PVP or unipedicular approach in OVCF of the mid thoracic vertebrae. PMID- 30465956 TI - First Carpometacarpal Joint Denervation for Primary Osteoarthritis: Technique and Outcomes. AB - BACKGROUND: First carpometacarpal (CMC) joint osteoarthritis is commonly encountered in clinical practice. The preferred surgical option when conservative therapy fails varies with the stage and nature of the disease. Denervation of the first CMC joint is a relatively new procedure for managing stable thumb CMC joint osteoarthritis. Our objective was to review our experience and surgical technique with first CMC joint denervation surgery. METHODS: The authors retrospectively identified all patients who underwent first CMC joint denervation surgery from January 2015 through September 2017. Before undergoing surgical CMC denervation, patients received a joint block at the first CMC joint with 0.25% bupivacaine. Only those with a good response to the injection were selected for surgical denervation. Patients' demographics, pre- and postoperative pain score using the Numerical Rating Scale (NRS), and grip strength using the Jamar Hydraulic Hand Dynamometer were analyzed. RESULTS: Of the 10 patients (13 hands) with CMC joint osteoarthritis, only 8 patients (11 hands) met the inclusion criteria. Patients' average grip strength improved significantly after the procedure (38.4+/-26.7 foot/lbs to 50.2+/-27.6; p=0.007). Similarly, the NRS pain score improved significantly from 7.8+/-2.4 to 2.4+/-1.8 (p<0.001). Seven of eight patients reported satisfaction with surgery. There were 2 complications in the series. CONCLUSIONS: First CMC joint denervation provided good pain relief and improvement in grip strength in patients with thumb CMC joint osteoarthritis. This minimally invasive technique proved to be a good option for providing optimal pain control, improvement in strength, with minimal and mild complications. PMID- 30465957 TI - Correlation Studies and Literature Review of Medullary Artery Occlusion after Intracranial Vertebral Artery Stenting. AB - BACKGROUND: Stenosis of the target intracranial vertebral artery is one of the major causes of posterior circulation ischemic stroke. The objective of this paper is to explore methods for reducing the occurrence of medullary artery occlusion after intracranial vertebral artery stenting. CASE DESCRIPTION: The current research presents a retrospective analysis of 48 patients who received Gateway-Wingspan stent angioplasty to treat severe stenosis of the intracranial vertebral artery, evaluates the results of stenosis remission and perfusion improvement after stent angioplasty, and explores the causes of postoperative medullary artery occlusion. A total of 49 Wingspan stents were implanted in the 48 patients, with a surgical success rate of 100%. After stent implantation, the patients' rates of intracranial vertebral artery stenosis dropped from (75.9+/ 6.3)% to (28.4+/-5.1)%. Transcranial Doppler (TCD) or cranial CT angiography 3 months after surgery showed that none of the patients suffered from in-stent restenosis. Within 24 hours after surgery, medullary perforating artery occlusion occurred in two patients, probably because atherosclerotic plaques in the stenotic area became less stable and displaced under the mechanical action of postoperative saccule and stent. As a result, the medullary artery was blocked. After drug and rehabilitation therapies, the patients' symptoms were alleviated. CONCLUSIONS: Perforating artery occlusion after intracranial vertebral artery stenting can be prevented by strict assessment and preparation before surgery, correct choices of saccule and stent during operation, and other measures. However, large sample data are needed for verification. PMID- 30465958 TI - Delayed recurrent laryngeal nerve palsy following anterior cervical discectomy and fusion: A case report. AB - Vocal cord dysfunction as a result of recurrent laryngeal nerve palsy (RLNP) is a known complication following anterior cervical discectomy and fusion (ACDF). RLNP occurs typically due to neuropraxia caused by intraoperative compression or traction on the nerve, and less commonly from direct nerve injury intraoperatively in the setting of anterior cervical spine surgery. Patients with RLNP typically present with hoarseness immediately after surgery due to unilateral vocal cord paralysis. However, in rare cases there is a late-onset, progressive development of RLNP that may potentially lead to permanent vocal cord paralysis or respiratory failure. We report a 75-year-old woman presenting with myeloradiculopathy and chronic urinary incontinence. Imaging revealed severe foraminal and central stenosis with T2 cord signal change. A C4-7 ACDF was successful performed without immediate complications following surgery. The patient had a normal voice and was tolerating regular diet well. However, on post operative day three, the patient developed new hoarseness and dysphagia. Otolaryngology was consulted and a flexible nasolaryngoscopy examination revealed left vocal cord paralysis consistent with left RLN palsy. The patient was treated with a course of steroids, and her hoarseness and dysphagia had resolved at the six-month follow-up visit. To our best knowledge, this is the first report of delayed RLN palsy in patients undergoing ACDF. This rare complication should be discussed during pre-operative patient counselling. Previous literature points towards the underlying pathophysiology for delayed onset of RLNP as being small vessel ischemia, vasospasm, or even viral resurgence that leads to RLN dysfunction. PMID- 30465959 TI - Apoplectic Silent Crooke's Cell Adenoma with Adjacent Pseudoaneurysms: Causation or Bystander? AB - BACKGROUND: Crooke's cell adenomas (CCAs) are rare and potentially aggressive pituitary tumors that often invade the cavernous sinuses. Although clinical presentations of pituitary tumors may include the development of accompanying intracranial aneurysms, there are no documented cases of coexistent intracranial aneurysms and CCAs to date. Herein we describe an apoplectic silent CCA that presented with adjacent cavernous internal carotid artery (ICA) aneurysms. CASE DESCRIPTION: A 45-year old male patient presented for evaluation of headaches and diplopia. Subsequent imaging series revealed a hemorrhagic pituitary macroadenoma that had invaded the left cavernous sinus and circumferentially involved the ICA. Two pseudoaneurysms were visualized along regions of the ICA directly attached to the tumor. A transnasal transsphenoidal endoscopic approach was utilized for resection of the tumor, which was identified histologically as a CCA. Endocrine evaluations characterized the tumor as nonfunctional. The patient experienced an excellent recovery with resolution of related symptoms. A pseudoaneurysm was treated with a Pipeline embolization device, however, it persisted at last follow up. CONCLUSIONS: CCAs are a poorly characterized and rare pituitary tumor type. In this case, an apoplectic silent CCA invaded the left cavernous sinus and presented with pseudoaneurysms along its involvement of the ICA. Accordingly, the authors speculated that the invasive qualities of this silent corticotroph adenoma may have directly contributed to the development of these aneurysms. PMID- 30465960 TI - Direct Carotid Cavernous Fistula Due to Rupture of a Cavernous Carotid Aneurysm Embedded within a Prolactinoma after Cabergoline Administration. AB - BACKGROUND: A small number of reports have discussed subarachnoid hemorrhage from a ruptured aneurysm embedded within a prolactinoma. To the best of our knowledge, however, no reports have discussed an embedded carotid cavernous fistula (CCF). We report a patient with CCF secondary to a ruptured internal carotid artery (ICA) aneurysm embedded within a prolactinoma. CASE DESCRIPTION: A 61-year-old woman was referred to our hospital with sudden headache, vomiting, and dizziness. Magnetic resonance imaging revealed a small acute subdural hematoma, recurrent prolactinoma, and left cavernous carotid aneurysm. Conservative therapy was initiated. Her serum prolactin level at hospitalization was 11 300 MUg/L; therefore, we initiated cabergoline therapy. Twenty days after cabergoline administration, she suddenly presented with left conjunctival injection and pulsatile tinnitus. Angiography revealed a left direct CCF with a connection between the cavernous ICA and the cavernous sinus via the aneurysm, and venous congestion. To prevent hemorrhagic stroke, we scheduled staged surgery. First, we urgently performed embolization of the cavernous sinus and fistula. One month later, to prevent aneurysm re-rupture, we performed a radical operation with superficial temporal artery-middle cerebral artery double anastomosis with proximal occlusion of the left ICA at the cervical portion. The patient was discharged 2 weeks after surgery without neurological deficits. Follow-up angiography revealed complete occlusion of the aneurysm 2 months postoperatively. CONCLUSIONS: An aneurysm embedded within a prolactinoma, as in our patient, should be closely observed when cabergoline administration is started. PMID- 30465961 TI - Predictive factors for delayed hyponatremia after endoscopic transsphenoidal surgery in patients with non-functioning pituitary tumors: a retrospective observational study. AB - OBJECTIVE: Delayed hyponatremia can occur after transsphenoidal pituitary tumor surgery, resulting in unexpected readmission. Predictive factors for delayed hyponatremia after this type of surgery are not well established. In this retrospective study, predictive factors for delayed hyponatremia were investigated in patients undergoing transsphenoidal pituitary tumor surgery. METHODS: Preoperative data (demographics, comorbidities, and hormonal assessment), pre-, intra-, and immediate postoperative sodium concentrations, the nadir sodium concentration on postoperative day (POD) 1-2, characteristics of pituitary tumor (size, cell type, optic chiasm compression, and cavernous sinus invasion), and intraoperative data (operation time and fluid balance) were retrospectively collected from 234 patients undergoing endoscopic transsphenoidal surgery for removal of non-functioning pituitary tumors. Delayed hyponatremia was defined as serum sodium concentration < 135 mEq/L on POD 3 or later, and after discharge, postoperative sodium concentration was measured on POD 7-10. RESULTS: Delayed hyponatremia was observed in 53 (22.6%) patients. Of these, five (9.4%) were readmitted due to delayed hyponatremia. In binary logistic regression analysis, age > 60 years (OR [95% CI] 2.22 [1.16-4.26], P=0.017), the nadir sodium concentration on POD 1-2 (0.88 [0.77-0.99], P=0.034), and operation time (1.01 [1.00-1.02], P=0.018) were independent risk factors for delayed hyponatremia after endoscopic transsphenoidal pituitary surgery. CONCLUSIONS: The incidence of delayed hyponatremia in patients with non-functioning pituitary tumor who underwent endoscopic transsphenoidal surgery was 22.6%. Old age, low sodium concentration on POD 1-2, and long operation time were associated with the development of delayed hyponatremia in such patients. PMID- 30465962 TI - Atypical Intracranial Meningioma with Metastasis to C-7 Vertebral Body: A Case Report. AB - Extracranial metastasis, mainly a feature of WHO grade III meningiomas, is only rarely reported in grade II meningiomas. We report a case of a 48-year-old man who was initially diagnosed in 2010 with an occipital convexity meningioma based on CT/MRI and treated with surgical therapy + gamma knife. The first operation achieved a macroscopically complete resection. The tumor was histologically classified as an atypical meningioma. Patient had a recurrence in 2014 on the left tentorial leaflet as noted on post-contrast MRI. Patient was asymptomatic, without focal neurological deficits. In 2016, patient reported new onset pain in the neck and left upper extremity. MRI indicated complete replacement of the C7 vertebral marrow, with a soft tissue component extending posteriorly into the epidural space that appeared to be flattening the thecal sac but without evidence of abnormal cord signal. Histopathology of resection confirmed atypical meningioma. This case represents a rare instance of intra-osseous spine as the first site of metastasis of WHO grade II atypical meningioma, and is the first reported case of extracranial metastasis of a meningioma to the C-7 vertebral body. PMID- 30465963 TI - S1 pedicle subtraction osteotomy in sagittal balance correction. A feasibility study on human cadaveric specimens. AB - STUDY DESIGN: Cadaveric feasibility study. BACKGROUND: Osteotomies to correct fixed sagittal imbalance are usually performed at L3/ L4. AIM: To investigate the feasibility of S1 pedicle subtraction osteotomy to correct spinal deformity and spinopelvic parameters, achieving better results with a more limited exposure. The data obtained will allow designing a fixation construct specific for this osteotomy. MATERIAL AND METHODS: S1 pedicle subtraction osteotomy was performed on twelve cadaveric specimens. Baseline and post-procedural CT-scan and biomechanical studies were performed. Data analyzed with a fixation system SolidWorks model, describing and analyzing the re-designed fixation construct with an ANSYS model. RESULTS: The S1 pedicle subtraction osteotomy is technically feasible. The fixation can be achieved with L4, L5 and iliac screws connected with bars. The system can be reinforced with a PEEK cage placed anteriorly in the S1 body osteotomy site, a cross-connecting bar, a double iliac screw or an anterior interbody cage placed at the L5-S1 disc. The fixation strength is improved by angulating 10o the iliac rod channel, adding a semi-sphere to the locking screw contact surface and two fins to its saddle. The re-designed construct showed suitable stress and deformation levels, achieving the expected biomechanical requirements. DISCUSSION: Comparing to surgery on higher levels, the S1 pedicle subtraction osteotomy allows a greater correction with a shorter fixation, as the osteotomy is performed at a more the caudal level modifying the spino-pelvic parameters. CONCLUSIONS: The S1 pedicle subtraction osteotomy is technically feasible. Finite element analysis results indicate that it has appropriate biomechanical properties. PMID- 30465964 TI - Percutaneous endoscopic lumbar discectomy in treating calcified lumbar intervertebral disc herniation. PMID- 30465965 TI - Routine postoperative CT is not helpful after elective craniotomy. AB - BACKGROUND: Next-day postoperative computed tomography (CT) imaging is routinely used to obtain radiographic "clearance" for transferring patients after elective craniotomy to the ward. The value of this traditional policy, however, has repeatedly been questioned. Limited patient numbers may underestimate very rare, but catastrophic events. OBJECTIVE: The aim of our study therefore was to analyze the value of routine postoperative CT imaging in a larger cohort of elective tumor, epilepsy and vascular cases. METHODS: All patients who underwent elective craniotomy were included in our study. Routine postoperative CT imaging of patients was analyzed by a neuroradiologist blinded to the clinical data. Charts were retrospectively reviewed for events of arterial hypertension and clinical deterioration. RESULTS: A total of 660 patients with mostly tumor resections (n=393, 59.5%), aneurysms (n=107, 16.2%) and skull base lesions were evaluated. In nearly half of the patients (n=264, 45.8%) CT depicted presence of blood, not associated with symptoms. Twenty-one patients (3.6%) showed a mass effect radiographically, 11 of which were taken to revision surgery. Arterial hypertension was documented in only 8 patients (1.3%) and was related to revision (p=0.018). Overall revision rate was 2.7% (n=18). All patients revised for a postoperative hematoma presented with a new neurologic deficit immediately prior to imaging. CONCLUSION: Routine postoperative CT imaging did not reveal one patient with serious hematoma, that would not have been identified by clinical examination. Patients could be transferred safely from the ICU, if the weaning process and clinical observation was uneventful, without deterioration of neurological symptoms or consciousness. PMID- 30465966 TI - Intimate partner violence and receptive syringe sharing among women who inject drugs in Indonesia: A respondent-driven sampling study. AB - BACKGROUND: Intimate partner violence (IPV) and HIV are overlapping public health problems that disproportionately affect women who inject drugs. Little is known about the relationship between IPV and HIV-related unsafe injecting practices among women in low- and middle-income settings. This study investigated whether IPV victimisation was associated with receptive syringe sharing among women who inject drugs in Indonesia. METHODS: Respondent-driven sampling (RDS) was used to recruit 731 women aged 18+ years, injecting drugs in the preceding 12 months, and residing in Greater Jakarta or Bandung, West Java. Population estimates were derived using the RDS-II estimator. Multivariate logistic regressions assessed relationships between different forms of past-year IPV (i.e. psychological abuse, physical and/or injurious assault, forced sex) and receptive syringe sharing, controlling for city differences and sociodemographic cofactors. RESULTS: Overall, 21.1% of participants reported engaging in past-month receptive syringe sharing. In multivariate analyses controlling for all forms of IPV, receptive syringe sharing was significantly positively associated with experiencing psychological abuse (OR = 1.86; 95% CI = 1.06,3.24; p = 0.030), physical and/or injurious assault (OR = 1.73; 95% CI = 1.04,2.89; p = 0.034), and several covariates: injecting pharmaceuticals only (versus heroin only) (OR = 3.58; 95% CI = 1.66,7.69; p = 0.001), experiencing unstable housing and/or homelessness (OR = 2.89; 95% CI = 1.41,5.95; p = 0.004), and residing in Bandung, West Java (versus Greater Jakarta) (OR = 2.33; 95% CI = 1.40,3.90; p = 0.001). CONCLUSION: IPV is a significant risk factor for HIV-related injecting risk among women who inject drugs in Indonesia. These findings indicate the urgent need to scale up harm reduction interventions and align existing programs with IPV prevention and support services, with specific efforts targeting the needs of female injectors. PMID- 30465967 TI - Postural control of individuals with spinal fusion for adolescent idiopathic scoliosis. AB - BACKGROUND: The purpose of the study was to assess the postural stability and complexity of postural control for moderately physically active individuals with spinal fusion for adolescent idiopathic scoliosis at two years post-operation. METHODS: Limit of stability test and sensory organization test were conducted for 10 moderately physically-active participants with spinal fusion and 10 controls pair-matched for mass, height and physical activity level. During the limit of stability test, participants were instructed to lean the center of gravity as far as possible toward 8 predetermined directions and the maximum excursion and direction control were analyzed. During the sensory organization test, participants were instructed to maintain as still as possible in six test conditions and equilibrium scores and sway area of center of pressure were analyzed. Multi-scale entropy of center of pressure was calculated to quantify sway complexity. FINDINGS: Most postural stability outcomes of spinal fusion participants were comparable to controls except for significantly reduced equilibrium scores (p = 0.039, partial eta2 = 0.217). Moreover, spinal fusion participants exhibited tendencies of reduced direction control (p = 0.053) during the limit of stability test and greater sway area (p = 0.052) during the sensory organization test. INTERPRETATION: Although the center of gravity control might be affected, spinal fusion individuals who were moderately physically active likely progressively learned to adapt postoperatively to their fused spine to meet the postural demands required when performing physical movements. We suggest that spinal fusion is a satisfactory treatment in regard to the recovery of postural stability. PMID- 30465968 TI - Epigenetics of the molecular clock and bacterial diversity in bipolar disorder. AB - Objectives The gut microbiome harbors substantially more genetic material than our body cells and has an impact on a huge variety of physiological mechanisms including the production of neurotransmitters and the interaction with brain functions through the gut-brain-axis. Products of microbiota can affect methylation according to preclinical studies. The current investigation aimed at analyzing the correlation between gut microbiome diversity and the methylation of the clock gene ARNTL in individuals with Bipolar Disorder (BD). Methods Genomic DNA was isolated from fasting blood of study participants with BD (n = 32). The methylation analysis of the ARNTL CG site cg05733463 was performed by bisulfite treatment of genomic DNA with the Epitect kit, PCR and pyrosequencing. Additionally, DNA was extracted from stool samples and subjected to 16S rRNA sequencing. QIIME was used to analyze microbiome data. Results Methylation status of the ARNTL CpG position cg05733463 correlated significantly with bacterial diversity (Simpson index: r= -0.389, p = 0.0238) and evenness (Simpson evenness index: r= -0.358, p = 0.044). Furthermore, bacterial diversity differed significantly between euthymia and depression (F(1,30) = 4.695, p = 0.039). Discussion The results of our pilot study show that bacterial diversity differs between euthymia and depression. Interestingly, gut microbiome diversity and evenness correlate negatively with methylation of ARNTL, which is known to regulate monoamine oxidase A transcription. We propose that alterations in overall diversity of the gut microbiome represent an internal environmental factor that has an epigenetic impact on the clock gene ARNTL which is thought to be involved in BD pathogenesis. PMID- 30465969 TI - Chronic dysfunction of blood-brain barrier in patients with post encephalitic/encephalopathic epilepsy. AB - PURPOSE: This study aimed to elucidate the characteristics and effects of chronic blood-brain barrier (BBB) dysfunction in patients with post encephalitic/encephalopathic epilepsy (PEE), using brain images and the cerebral spinal fluid (CSF)/serum albumin ratio (albumin quotient, QAlb) as a marker of BBB function. METHODS: We examined the albumin levels in CSF and serum samples from 312 patients with refractory epilepsy in our center between 2004 and 2015. Sixty samples from patients with PEE and 97 samples from age- and sex-matched disease controls (DC) were evaluated. We classified PEE patients into a widespread lesion group and a focal lesion group by severity on brain magnetic resonance images in the chronic phase after acute encephalitis/encephalopathy. RESULTS: Median QAlb was higher in PEE than in DC [median (range) *103: PEE 3.6 (1.0-10.3) versus DC 2.7 (1.0-6.7), p = 0.007]. In a linear regression analysis of the relationship between QAlb and patient's age at CSF examination or duration of epilepsy, the slope of the regression line was greater in PEE than in DC. Furthermore, in patients under ten years of age, linear regression analysis of QAlb versus seizure frequency showed a weak but positive correlation. Among PEE patients, seizure frequency was higher in the widespread lesion group than in the focal lesion group [300 (4-3000) versus 30 (1-1500) seizures/month, p < 0.001]. CONCLUSION: Our study suggests that patients with PEE have more severe BBB dysfunction, and that the BBB dysfunction is associated with refractory epilepsy. PMID- 30465970 TI - Evidence of congenital block vertebra in Pleistocene Cave Bear (Ursus spelaeus) from Cueva de Guantes (Palencia, Spain). AB - OBJECTIVE: This work provides a detailed description and differential diagnosis of a Pleistocene cave bear (Ursus spelaeus). MATERIALS: The specimen was recovered at the Cueva de Guantes archaeo- paleontological site, located in the North of the Iberian Peninsula and dated to more than 30k yr BP. METHODS: The study was carried out by macroscopic and radiological analysis. RESULTS: The specimen has unusual morphology, with two vertebrae (C6-C7) connected in the ventrodorsal projection by osseous tissue, without a space or disruption between them. However, a separation is visible in the dorsoventral projection. Moreover, C7 shows a "wedge-shape" conformation. CONCLUSIONS: The lack of clear radiological and macroscopic evidence of degenerative processes and trauma suggests a congenital anomaly or pathology. The short height of the ventral margin of the block and evidence of a radiological 'waist' lead us to propose congenital block vertebra (CBV) as the most likely diagnosis. SIGNIFICANCE: The Cueva de Guantes specimen would be the first reported evidence of CBV in a Pleistocene cave bear (Ursus spelaeus). LIMITATIONS: All diagnosis of archaeological animal remains should be undertaken with caution, especially when based on partial remains, as in this case. Moreover, this specimen lacks the neural arches of C6 and C7, preventing evaluation of the vertebral foramina. SUGGESTIONS FOR FURTHER RESEARCH: Intensive review of cave bear skeletal collections is advised to find new cases and perform an epidemiological approach to the palaeopathology of cave bears. PMID- 30465971 TI - Testicular transcriptome alterations in zebrafish (Danio rerio) exposure to 17beta-estradiol. AB - The hormone 17beta-estradiol (E2) can be found in rivers, effluents, and even drinking water. Researches have demonstrated that E2 affects various metabolic pathways through gene activation and may cause reproductive toxicity in fish. Therefore, the aim of this study was to evaluate E2-induced toxicity via testicular transcriptome of zebrafish (Danio rerio) exposed to different concentrations (10 ng L-1, and 100 ng L-1) of E2. A total of >600 significant differentially expressed genes (DEGs) were enriched among the three treatments. Short time-series expression miner analysis revealed five KEGG pathways including drug metabolism, other enzymes, calcium signaling pathway, ECM-receptor interaction, gap junction, and cell adhesion molecules. Twenty genes were selected to verify the accuracy of RNA-Seq. Other reported genes related to sex differentiation, development, energy metabolism, and other processes were found. One set of genes significantly increased/decreased/fluctuated over time, especially 12 h after E2 exposure. Genes associated with ovaries (zp3c), and development (bmp15, gdf9, and sycp2l) were significantly upregulated with increasing E2 concentration. E2 and testosterone was significantly decreased by 10 (except for T) and 100 ng L-1 E2 exposure at 12 h. The current study demonstrated that sex differentiation, development, energy metabolism, immunity, and ribosome biogenesis in male zebrafish were all significantly affected by 17beta-estradiol exposure through transcriptional alterations. PMID- 30465972 TI - The dissipation of cyazofamid and its main metabolite in soil response oppositely to biochar application. AB - Biochars derived from rice straw (RS), corn straw (CS), chicken manure (CM) and tire rubber (TR) were applied to soil to investigate their effects on the dissipation of cyazofamid and its metabolite CCIM (4-chloro-5-p-tolylimidazole-2 carbonitrile), with high acute toxicity compared to cyazofamid. The enhancement of cyazofamid dissipation followed the order of CS > RS > CM, whereas TR depressed the cyazofamid dissipation. Adsorption, hydrolysis and microbial degradation were all involved in cyazofamid dissipation. CM and CS enhanced the contribution of biodegradation to cyazofamid dissipation, which might be related with the shifted microbial community. More importantly, CCIM residual was drastically increased by 8-15 times after biochar application, regardless of biochar type. In total, this study shed light on the issue of build-up of metabolites in biochar-amended soil, especially for metabolites having higher toxicities than parent compounds, providing new insights into potential risk of biochar application for soil remediation. PMID- 30465973 TI - Erythrocyte-cancer hybrid membrane-camouflaged melanin nanoparticles for enhancing photothermal therapy efficacy in tumors. AB - Cell membrane coating has emerged as an intriguing biomimetic strategy to endow nanomaterials with functions and properties inherent to source cells for various biomedical applications. Hybrid membrane of different types of cells could be coated onto nanoparticle surface to achieve additional functions. Herein, we fused red blood cell (RBC) membrane together with MCF-7 cell membrane and fabricated an erythrocyte-cancer (RBC-M) hybrid membrane-camouflaged melanin nanoparticle (Melanin@RBC-M) platform for enhancing therapeutic efficacy of photothermal therapy (PTT). The fused RBC-M hybrid membrane vesicles retained both RBC and MCF-7 cell membrane proteins and the resultant Melanin@RBC-M exhibited prolonged blood circulation and homotypic targeting to source MCF-7 cells simultaneously. Interestingly, increasing MCF-7 membrane components in RBC M significantly enhanced the homotypic targeting function of Melanin@RBC-M while increasing RBC membrane components in RBC-M effectively reduced the cellular uptake of Melanin@RBC-M by macrophages and improved their circulation time in the blood. After intravenous injection into MCF-7 tumor-bearing athymic nude mice, Melanin@RBC-M with 1:1 membrane protein weight ratio of RBC to MCF-7 exhibited significantly higher tumor accumulation and better PTT efficacy compared with other Melanin@RBC-M with different membrane protein weight ratios as well as pristine melanin nanoparticles, due to the optimal balance between prolonged blood circulation and homotypic targeting. In addition, in vitro photoacoustic results revealed that Melanin@RBC-M had a photoacoustic signal enhancement with the increase of nanoparticle size (64 -> 148 nm) and the photoacoustic amplitudes increased linearly with nanoparticle concentration at the excitation wavelength ranged from 680 nm to 800 nm, which could be used for quantification of Melanin@RBC-M in vivo. Looking forward, coating hybrid membrane onto nanoparticles could add flexibility and controllability in enhancing nanoparticles functionality and offer new opportunities for biomedical applications. PMID- 30465974 TI - Development of a composite membrane with underwater-oleophobic fibrous surface for robust anti-oil-fouling membrane distillation. AB - Membrane fouling caused by non-polar foulants is a challenging problem for hydrophobic membranes, which hinders the industrial implementation of membrane distillation (MD). The hydrophilic coating can create a hydration layer at solid water interface, thereby the hydrophilic surfaces are expected to supply a barrier inhibiting adhesion of hydrophobic foulants. Hence, it should be possible to develop anti-fouling composite membranes through constructing a hydrophilic skin layer onto hydrophobic MD membranes. Herein, we fabricated a novel composite membrane for excellent anti-oil-fouling performance in MD process by electrospinning polyetherimide (PEI) nanofibers on the hydrophobic polyvinylidene fluoride (PVDF) membrane surface, followed by cross-linking with ethanediamine (EDA). The membrane morphology and structure properties, surface zeta potential and wettability, thermal stability were all systematically characterized, and force spectroscopy was used to quasi-quantitatively evaluate oil-membrane adhesion force. Compared with the PVDF membrane, the PVDF/PEI-EDA composite membrane exhibited strong resistance to crude oil with underwater oil contact angle of about 145 degrees and low oil-membrane adhesion force, which contributed to the stable performance during MD desalinating an oily and saline solution. The fabricated composite membrane with underwater-oleophobic fibrous surface can effectively mitigate oil-fouling in MD and promote MD to treat highly saline wastewater with high concentration of hydrophobic foulants. PMID- 30465975 TI - Mesoporous matrices for the delivery of the broad spectrum bacteriocin, nisin A. AB - Mesoporous matrices of different pore size and chemical composition were explored as potential delivery matrices for the broad spectrum bacteriocin, nisin A. The adsorption of nisin A onto two mesoporous silicates (MPS - SBA-15, MCM-41) and two periodic mesoporous organosilanes (PMO - MSE, PMO-PA) was examined. It was found that hydrophobic interactions dominated in the adsorption of this peptide to the matrices, lending the highest adsorption to MCM-41 with a small pore size of 2.8 nm. The hydrophobic ethylene-bridged MSE (6 nm pore) improved the loading and protection of nisin A from degradation by a non-specific protease pepsin, over un-functionalised SBA-15 which had a slightly larger pore size and less hydrophobic moieties. Nisin A did not adsorb onto an amine-functionalised PMO. Upon suspension in modified fasted state simulated gastric fluid (pH 1.6), the highest release of nisin A was observed from MCM-41, with a lower release from SBA-15 and MSE, with release following Higuchi release kinetics. No release was detected into modified fasted state simulated intestinal fluid (pH 6.5) but despite this, the suspended matrices loaded with nisin A remained active against Staphylococcus aureus. PMID- 30465976 TI - Investigation of antisolvent effect on gold nanoparticles during postsynthesis purification. AB - Gold nanoparticles (Au NPs) were synthesized by reducing HAuCl4 using borane tert butylamine complex in the presence of alkylamine (dodecylamine, hexadecylamine, and octadecylamine) and didodecyldimethylammonium bromide. Ethanol was used as an antisolvent for the postsynthesis purification of Au NPs. Au NPs had uniform size distribution after first wash with ethanol and the aggregation and growth of Au NPs happened after second wash with ethanol. The Au NPs were characterized by TEM, SEM, XRD, 1H NMR, UV-vis absorption and FTIR spectroscopy. The aggregated mechanism after the second wash with ethanol was proposed. Au NPs still retained their monodispersity after second wash compared with after first wash using the antisolvents, such as acetonitrile, dimethyl sulfoxide and acetone. The presented results suggest that the good choice of antisolvent is critical for the postsynthesis purification of Au NPs. PMID- 30465977 TI - Chiral beta-HgS quantum dots: Aqueous synthesis, optical properties and cytocompatibility. AB - beta-HgS quantum dots (QDs) have drawn enormous attention due to the size-tunable bandgap and the lowest quantum state in conduction band which have been applied to semiconductor transistor and photodetector. Though beta-HgS is the essential component of Tibetan medicine, the potential toxicity of beta-HgS limits its applications, especially in bio-application. Herein, chiral biomolecule enantiomers N-isobutyryl-L(D)-cysteine (L(D)-NIBC) and L(D)-cysteine (L(D)-Cys) were introduced into HgCl2 and Na2S aqueous solution to synthesize chiral beta HgS QDs in one-pot, which significantly improved their water-solubility and cytocompatibility. Notably, all chiral beta-HgS QDs showed none cytotoxicity even at high concentration (20 mg.L-1), and the cytocompatibility of D-beta-HgS QDs was better than corresponding L-beta-HgS QDs at the concentration of 20 mg.L-1. This cytotoxicity discrimination was associated with the chirality inversion of chiral beta-HgS QDs compared with the corresponding chiral ligands. In-situ real time circular dichroism (CD) monitoring indicated that the chirality of beta-HgS QDs originated from the asymmetrical arrangement of chiral ligands on the achiral core surface. Their chiroptical activity, near-infrared optical absorption (800 nm), fluorescence emission (900-1000 nm), high-performance photothermal conversion and good cytocompatibility, implied chiral beta-HgS QDs could be used as a candidate material for photothermal therapy or a near-infrared fluorescent probe in organism, which brings a novel insight for bio-application of beta-HgS QDs. PMID- 30465978 TI - On the growth of argon clusters on a weak adsorbent decorated with patches. AB - Much attention has been paid to understanding the clustering mechanism of water adsorbed on carbonaceous adsorbents. Adsorbed water forms clusters around strong sites, such as functional groups and surface defects, and these clusters then coalesce if the strong sites are sufficiently close to each other. Simulations of water adsorption are notoriously time consuming because of the slow relaxation of the strongly-directional hydrogen bonds. Our objective in this paper is to gain a better insight into clustering and coalescence of water, without incurring large computing overheads. To this end we have chosen argon as an adsorbate, and a substrate that is a very weak adsorbent for argon. To mimic functional groups, the substrate surface is decorated with strongly adsorbing patches. The adsorbate forms nano-clusters with convex surfaces at pressures greater than the saturation vapour pressure. When these clusters are sufficiently close to each other, they coalescence to form larger fused clusters, and there is a decrease in the equilibrium pressure. The relationship between the radius of curvature of the developed nano-clusters and the equilibrium pressure follows the functional form of the Kelvin equation, but the energy parametergammavM is smaller than the bulk value, implying that the clusters have a smaller cohesive energy. PMID- 30465979 TI - Palygorskite-template amorphous carbon nanotubes as a superior adsorbent for removal of dyes from aqueous solutions. AB - The carbon-coated palygorskite (Pal@C) was prepared by impregnation and carbonization using modified palygorskite (Pal) as a hard template and glucose as the carbon source. The amorphous carbon nanotubes (ACNTs) could be finally obtained by removing Pal template using acid and alkali treatment. In comparison with pure Pal@C nanocomposite, the maximum adsorption capacity of Congo red dye onto the ACNTs could be improved by over 13-fold (467.97 mg/g vs. 34.40 mg/g, ACNTs vs. Pal@C), which was attributed to the larger specific surface area (877.09 m2/g) and more mesoporous pores (average pore diameter is 7.62 nm) that ACNTs possess. The effects of different dyes molecules such as Congo red and methyl orange on the adsorption properties of ACNTs were investigated. The maximum adsorption capacity of Congo red was 467.97 mg/g more than that of methyl orange (253.26 mg/g) due to differences in molecular structure and size. Furthermore, Langmuir model can be used to predict the adsorption isotherm of Congo red dye by ACNTs. Our kinetic study showed that the quasi-second-order kinetic model could describe the adsorption behavior of ACNTs for Congo red. In particular, the ACNTs presented a higher adsorption capacity for adsorption of Congo red, regardless of pH. PMID- 30465980 TI - The correlation between the quality of life and clinical variables among outpatients with schizophrenia. AB - The study identifies the correlation between the quality of life (QoL) among outpatients with schizophrenia and clinical outcomes. A cross-sectional study design was used with 157 people with schizophrenia treated in outpatient clinics. Demographic, clinical and psychosocial variables were examined for their influence on QoL. Data were analysed with descriptive statistics, Pearson product moment correlation and stepwise forward multiple linear regression. The majority of the study participants were female, single, unemployed, had secondary level of education or less and were being supported financially by family members. QoL correlated negatively with advanced age, male gender, longer duration of illness, high body mass index and prescribed typical anti-psychotic medication. However, it was related positively with employment and being married. Illness duration, recurrent hospitalisation, knowledge level about schizophrenia, psychiatric symptoms and coping mechanisms were found to be key significant predictors of QoL among participants. The study findings enhance our understanding of socio demographic, clinical and psychosocial characteristics influencing the QoL in people with schizophrenia. Involvement of families in the management process may improve patients' ability to be integrated in the community and be more socially active. PMID- 30465981 TI - Physical effort exertion and pain: Links with trait-based risk for psychopathology. AB - People with serious mental illness (SMI) are at an increased risk for physical health complications, such as cardiovascular disease and obesity. Low levels of physical activity is a major contributor to these health complications. One factor associated with limited physical activity in the broader sedentary population is pain. While preliminary findings suggest an association between lack of physical activity and pain in SMI, conclusions are still unclear. Thus, the goal of this correlational study was to examine associations between trait based risk for psychopathology (hypomanic personality, schizotypy, and anhedonic depression) and the experience of pain following a physical endurance/effort task. Healthy participants (N = 43; 18 females) completed self-report measures of trait-based risk for psychopathology. They also reported on the experience of pain before and after the Time To Exhaustion (TTE) test. Findings revealed that risk for psychosis and anhedonic depression were associated with increases in pain following the TTE test, accounting for other key variables, such as age and self-reported physical exercise. Risk for mania was unrelated to changes in pain. These results suggest that the experience of pain in relation to physical endurance/effort may contribute to diminished physical activity among people at risk for SMI. PMID- 30465982 TI - Higher transcription alleles of the MAOA-uVNTR polymorphism are associated with higher seizure frequency in temporal lobe epilepsy. AB - BACKGROUND: There is evidence of an imbalance in the neuromodulatory system mediated by serotonin (5-HT) in patients with drug-resistant temporal lobe epilepsy (TLE). This study analyzed the monoamine oxidase A promoter variable number of tandem repeats (MAOA-uVNTR) polymorphism in patients with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). Therefore, we assessed the association between this genetic variant and seizure predisposition and severity in patients with TLE-HS. METHODS: One hundred nineteen patients with TLE-HS and 113 healthy volunteers were assessed. First, we genotyped all individuals for the MAOA-uVNTR genetic polymorphism. Second, we compared patients and controls and evaluated clinical variants of epilepsy. RESULTS: There was no difference between the TLE-HS and control groups regarding genotypic and allelic distributions of MAOA-uVNTR polymorphism (p = 1.000). Higher transcription alleles of the MAOA uVNTR were associated with higher seizure frequency (p = 0.032) and bilateral tonic-clonic seizures (p = 0.016). CONCLUSIONS: In a selected group of patients with TLE-HS, the polymorphism MAOA-uVNTR was associated with some aspects of epilepsy severity, namely seizure frequency and bilateral tonic-clonic seizures. PMID- 30465983 TI - Immunization against Kisspeptin-54 perturb hypothalamic-pituitary-testicular signaling pathway in ram lambs. AB - Kisspeptin, a peptide product of KISS1 gene, recently identified as essential upstream gatekeeper in hypothalamic-pituitary-gonadal (HPG) axis. This study was designed to investigate the effect of immunization against kisspeptin-54 on hypothalamic-pituitary-testicular signaling pathway. A total of ten intact 56 days-old ram lambs were used and randomized into the treatment and control groups, which were, respectively immunized by kisspeptin-54 based vaccine and the empty plasmid via intramuscular route. We employed indirect enzyme-linked immunosorbent assay and quantitative real-time PCR to characterize the difference in serum kisspeptin, luteinizing hormone, testosterone hormone concentration and mRNA expression of reproductive-related genes in HPG axis across kisspeptin-54 immunized and control ram lambs. Serum kisspeptin, luteinizing hormone and testosterone concentration in the treatment group was lower (p < 0.05) than that of the control group. Compared with the control group, the mRNA expression of the hypothalamic androgen receptor (AR), KISS1, G protein-coupled receptor (GPR54) and gonadotropin-releasing hormone (GnRH) was altered in the immunized group (p < 0.05). Moreover, mRNA expression of pituitary luteinizing hormone beta (LHbeta), follicle stimulating hormone beta (FSHbeta), and GnRH receptor as well as, testicular LH receptor and FSH receptor, were remarkably lower (P < 0.05) in the treatment group. We concluded that immunization against kisspeptin-54 reduced serum kisspeptin levels thereby, the normal hypothalamic-pituitary-testicular signaling pathway disrupted. This data provides a great insight for the use of kisspeptin to regulate reproduction. PMID- 30465984 TI - Pomegranate seed in diet, affects sperm parameters of cloned goats following freezing-thawing. AB - Semen cryopreservation is affected by individual differences and use of cloned animal from the same source is the main tool to eliminate genetic variation. Pomegranate seed (PS) contains fatty acids and phenolic compounds which have antioxidant properties. Essential fatty acids and antioxidants are vital for production of healthy sperm by improving sperm membrane integrity and protecting sperm from oxidative stress. In this study, the effect of dietary supplementation of PS on some blood metabolites and sperm parameters following freezing-thawing of semen of cloned goats were investigated. 5-6 years cloned male goats (N = 9, 50 +/- 2 kg) were randomly assigned to three different isocaloric and isonitogenous diet groups: supplemented with 0 (control), 30 and 60% (g/100 g of barley) replaced with PS for a total of 9 weeks. Sperm collection was carried out within 10-14 weeks. Semen samples were diluted whit cryo-protectant and frozen in liquid nitrogen. Sperm parameters, reactive oxygen species (ROS) as well as, ability to induce fertilization were evaluated following freezing/thawing. According to the results of our study, treatment with PS induce higher plasma cholesterol production compared to control group at 8th week. However, testosterone and MDA (malondialdehyde) level of blood plasma were not significantly affected by PS treatment. In comparison to control group, PS supplementation significantly improved total sperm motility and viability in both 30 and 60% PS groups and reduced ROS production. Cleavage rate and developmental competency to blastocyst stage were similar to fresh sperm. In conclusion, dietary supplementation with PS can improve sperm motility and viability following freezing-thawing and maintain developmental competency. PMID- 30465985 TI - Tertiary treatment of urban wastewater by solar and UV-C driven advanced oxidation with peracetic acid: Effect on contaminants of emerging concern and antibiotic resistance. AB - Photo-driven advanced oxidation process (AOP) with peracetic acid (PAA) has been poorly investigated in water and wastewater treatment so far. In the present work its possible use as tertiary treatment of urban wastewater to effectively minimize the release into the environment of contaminants of emerging concern (CECs) and antibiotic-resistant bacteria was investigated. Different initial PAA concentrations, two light sources (sunlight and UV-C) and two different water matrices (groundwater (GW) and wastewater (WW)) were studied. Low PAA doses were found to be effective in the inactivation of antibiotic resistant Escherichia coli (AR E. coli) in GW, with the UV-C process being faster (limit of detection (LOD) achieved for a cumulative energy (QUV) of 0.3 kJL-1 with 0.2 mg PAA L-1) than solar driven one (LOD achieved at QUV = 4.4 kJL-1 with 0.2 mg PAA L-1). Really fast inactivation rates of indigenous AR E. coli were also observed in WW. Higher QUV and PAA initial doses were necessary to effectively remove the three target CECs (carbamazepine (CBZ), diclofenac and sulfamethoxazole), with CBZ being the more refractory one. In conclusion, photo-driven AOP with PAA can be effectively used as tertiary treatment of urban wastewater but initial PAA dose should be optimized to find the best compromise between target bacteria inactivation and CECs removal as well as to prevent scavenging effect of PAA on hydroxyl radicals because of high PAA concentration. PMID- 30465986 TI - Antibiotic-resistance gene transfer in antibiotic-resistance bacteria under different light irradiation: Implications from oxidative stress and gene expression. AB - Due to the significant public health risks, there is substantial scientific interest in the increasing abundance of antibiotic-resistance bacteria (ARB) and the spread of antibiotic-resistance genes (ARGs) in aquatic environments. To clearly understand the mechanism of ARG transfer, this study examined the conjugative transfer of genes encoding resistance to cephalosporin (blaCTX) and polymyxin (mcr-1) from two antibiotic-resistant donor strains, namely E. coli DH5alpha (CTX) and E. coli DH5alpha (MCR), and to a streptomycin-resistant receptor strain (E. coli C600 (Sm)). Conjugative transfer was specifically studied under different light irradiation conditions including visible light (VL), simulated sunlight (SS) and ultraviolet light (UV254nm). Results show that the conjugative transfer frequency was not affected by VL irradiation, while it was slightly improved (2-10 fold) by SS irradiation and extremely accelerated (up to 100 fold) by UV irradiation. Furthermore, this study also explored the link between ARG transfer and stress conditions. This was done by studying physiological and biochemical changes; oxidative stress response; and functional gene expression of co-cultured AR-E. coli strains under stress conditions. When correlated with the transfer frequency results, we found that VL irradiation did not affect the physiological and biochemical characteristics of the bacteria, or induce oxidative stress and gene expression. For SS irradiation, oxidative stress occurred slowly, with a slight increase in the expression of target genes in the bacterial cells. In contrast, UV irradiation, rapidly inactivated the bacteria, the degree of oxidative stress was very severe and the expression of the target genes was markedly up-regulated. Our study could provide new insight into the underlying mechanisms and links between accelerated conjugative transfer and oxidative stress, as well as the altered expression of genes relevant to conjugation and other stress responses in bacterial cells. PMID- 30465987 TI - Oil-in-water emulsion breaking marine bacteria for demulsifying oily wastewater. AB - Oily wastewater is a large waste stream produced by a number of industries. This wastewater often forms stable oil-in-water (O/W) emulsion. These emulsions require demulsification in order to effectively treat the water prior to release. Although biological demulsification of O/W emulsion has advantages over traditional approaches, its development is at a preliminary stage with few demulsifying bacteria reported and a need for effective screening methods for such bacteria. In this study, thirty-seven marine O/W emulsion demulsifying bacterial strains belonging to 5 genera and 15 species were reported. Cell hydrophobicity and interfacial activity played key roles in the emulsion breaking. One of the highly effective demulsifying bacteria, Halomonas venusta strain N3-2A was identified and characterized. Both its extracellular biosurfactant and cell surface contributed to demulsification resulting in breaking of 92.5% of the emulsion within 24 h. A high throughput and effective screening strategy targeting O/W emulsion breaking bacteria using oil spreading test coupled with cell hydrophobicity test was proposed. In addition, the 37 demulsifying bacteria showed a certain degree of species/genus specific patterns of surface activity and cell hydrophobicity. The reported bacteria and the screening strategy have promising potential for the biological demulsification of O/W emulsions and oily wastewater treatment. PMID- 30465988 TI - Stoichiometric mechanisms of regime shifts in freshwater ecosystem. AB - Catastrophic regime shifts in shallow lakes are hard to predict due to a lack of clear understanding of the associate mechanisms. Theory of alternative stable states suggests that eutrophication has profound negative effects on the structure, function and stability of freshwater ecosystems. However, it is still unclear how eutrophication destabilizes ecosystems stoichiometrically before a tipping point is reached. The stoichiometric homeostasis (H), which links fine scale process to broad-scale patterns, is a key parameter in ecological stoichiometry. Based on investigation of 97 shallow lakes on the Yangtze Plain, China, we measured nitrogen (N) and phosphorus (P) concentrations of the aboveground tissues of common submerged macrophyte species and their corresponding sediments. We found submerged macrophytes showed significant stoichiometric homeostasis for P (HP) but not for N (HN). Furthermore, HP was positively correlated with dominance and stability at the species level, and community production and stability at the community level. Identifying where macrophyte community collapse is a fundamental way to quantify their resilience. Threshold detection showed that macrophyte community dominated by high-HP species had a higher value of tipping point (0.08 vs. 0.06 mg P L-1 in lake water), indicating their strong resilience to eutrophication. In addition, macrophytes with high HP were predominant in relative oligotrophic sediments and have higher ability in stabilizing the water environment compared to those low-HP ones. Our results suggested that ecosystem dominated by homeostatic macrophyte communities was more productive, stable and resilient to eutrophication. Eutrophication induced stoichiometric imbalance may destabilize the ecosystem by altering the community structure from high-to low-HP species. Efforts should be focused on maintaining and restoration of high homeostatic communities to make ecosystem more resilient, which can significantly improve our understanding of the critical transition mechanisms. PMID- 30465989 TI - Real-time prediction of rain-impacted sewage flow for on-line control of chemical dosing in sewers. AB - Chemical dosing is a commonly used strategy for mitigating sewer corrosion and odour problems caused by sulfide production. Prediction of sewage flow variation in real-time is critical for the optimization of chemical dosing to achieve cost effective mitigation of hydrogen sulfide (H2S). Autoregressive (AR) models have previously been used for real-time sewage prediction. However, the prediction showed significant delays in wet weather conditions. In this paper, autoregressive with exogenous inputs (ARX) models are employed to reduce the delays with rainfall data used as model inputs. The model is applied to predicting sewage flows at two real-life sewage pumping stations (SPSs) with different hydraulic characteristics and climatic conditions. The calibrated models were capable of predicting flow rates in both cases, much more accurately than previously developed AR models under wet weather conditions. Simulation of on-line chemical dosing control based on the predicted flows showed excellent sulfide mitigation performance at reduced cost. PMID- 30465990 TI - Development of crash modification factors of horizontal curve design features for single-motorcycle crashes on rural two-lane highways: A matched case-control study. AB - Single-motorcycle crashes are overrepresented on horizontally curved segments of rural, two-lane, undivided (RTU) highways. However, the relationship between single-motorcycle crash risk and the design features of horizontal curves on RTU highways is not well-studied in existing literature. This study aims to quantify the effect of horizontal curve type and radius on the risk of single-motorcycle crashes with a matched case-control study that can address the issues of the low sample mean, aggregation bias, and uncontrolled confounders existing in the traditional cross-sectional study. In the matched case-control study, three matching factors-year, annual average daily traffic (AADT), and segment length were selected to match controls (RTU segments without crash records) with cases (RTU segments with crash records). A total of 1601 cases and 16,010 matched controls over 11 years (2005-2015) were identified as matched-strata. A conditional logistic model was fitted on the matched-strata data to estimate the crash modification factors (CMFs) of horizontal curve design features for single motorcycle crashes. The modeling results highlighted the interaction effects between curve type and radius on the risk of single-motorcycle crashes. Sharp (radius <= 1500 ft) non-reverse curves were identified as the riskiest curve design for motorcyclists, followed by sharp reverse curves and moderate (1500 ft < radius <= 3000 ft) reverse curves. The study also revealed that motorcyclists might take safety-compensation behaviors on sharp curves, narrow shoulders, and poor pavement conditions. Engineering and education countermeasures are suggested for comprehending curve presence and associated risk level, reducing curve entry speed, and improving safety awareness. Finally, the limitations of the study and possible solutions are discussed. PMID- 30465991 TI - Synergistic effects of fast-neutron dose per epithermal neutron and 10B concentration on relative-biological-effectiveness dose for accelerator-based boron neutron capture therapy. AB - The efficacy of accelerator-based boron neutron capture therapy was examined through relative-biological-effectiveness dose calculations with the fast-neutron dose per epithermal neutron (FNR) and the 10B concentration as parameters. In the case of a tumor 10B concentration of 65 ppm, the treatment efficacy depended more strongly on the FNR when the normal-tissue 10B concentration was 0.65 ppm, which would be brought about by the administration of an advanced chemical compound, than when the 10B concentration was 18 ppm, which is attainable by the use of boronophenylalanine. PMID- 30465992 TI - Comparison of post-mortem ethanol level in blood and bone marrow. PMID- 30465993 TI - Eradicating the legacy of Othello: Western Sydney University's attempt to raise awareness of intimate partner violence. AB - In Australia scant attention is given to teaching medical students how to identify and manage intimate partner violence (IPV) and sexual assault (SA). In Australia one woman dies weekly from IPV and the prevalence of IPV in Australian women is 29 percent. The Australian Prime Minister labelled it a 'national disgrace' and yet, of the five World Health Organisation (WHO) regions, the Western Pacific Region has the lowest rates in the world.1 Since 2015 reducing IPV has become a national strategy. In undergraduate medicine the obstetric and gynaecological curriculum is a logical and appropriate place for such education given the predominance of female victims. Western Sydney University (WSU) commenced this training as a 1 day practical multidisciplinary workshop on IPV and Management of Sexual Assault in 2017. Prior to that time the University provided less than 2 h of training in IPV or SA in a 5 year undergraduate degree course. The preliminary results suggest that medical students are predominantly positive towards developing skills in dealing with IPV and their enthusiasm and knowledge increases after the workshop. PMID- 30465994 TI - A novel pharmacological approach of herbal mediated cerium oxide and silver nanoparticles with improved biomedical activity in comparison with Lawsonia inermis. AB - Diabetes mellitus is one of the threatening, non-communicable and chronic ailments worldwide since ancient times to the current stage of human existence. The utilization of nanoparticles as a medicine in the treatment of diabetes is an attractive proposition. In the present study, herbal mediated cerium oxide nanoparticles (HMCeO2 NPs), herbal mediated silver nanoparticles (HMAg NPs) and Lawsonia intermix extract (LIE) was evaluated for them for in-vivo hypoglycemic effect and compared the potency. The resulting HMCeO2 NPs, HMAg NPs and Lawsonia inermis have been characterized by different analytical equipments such as X-ray Diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Particle size analyzer (PSA), Field emission scanning electron microscope (FESEM) and High resolution transmission electron microscope (HRTEM). The synthesized NPs and Lawsonia inermis extract were assessed for toxicity by using acute oral toxicity using female albino mice (s) model by following OECD-425 guidelines. In in-vivo hypoglycemic animal model, the male wistar rats with weight varying between 180 200 gms were grouped as: normal control: did not receive any treatment, diabetic control (saline): received a single intraperitoneal dose of Streptozotocin (40 mg/kg), standard: received a single daily oral dose of 50 mg/kg body weight, HMCeO2 NPs: received single daily oral dose of 100 mg/kg, 200 mg/kg, HMAg NPs: received a single daily oral dose of 100 mg/kg, 200 mg/kg, and Lawsonia inermis: received a single daily oral dose of 100 mg/kg, 200 mg/kg. The herbal mediated NPs were considered safe as they have not shown toxic effects. From the current study results, it may conclude that, due to the advanced biological and pharmacological characters, the HMAg NPs depicted more potent hypoglycemic activity than that of LIE and CeO2 NPs. PMID- 30465995 TI - Influences of tantalum pentoxide and surface coarsening on surface roughness, hydrophilicity, surface energy, protein adsorption and cell responses to PEEK based biocomposite. AB - Polyetheretherketone (PEEK) biomaterial has become increasingly popular in orthopedic applications due to its favorable biocompatibility, biostability, mechanical strength and elastic modulus similar to natural bones. In this research, in order to improve the biological performances of PEEK, tantalum pentoxide (Ta2O5) was incorporated into PEEK to fabricate PEEK/Ta2O5 composites (PTC) using a method of cold press-sintering, and surface coarsening of PTC was prepared by sand blasting. The results showed that the Ta2O5 particles were uniformly disperse into PEEK, and thermal and mechanical properties of PTC were enhanced with the increase of Ta2O5 content. In addition, incorporating Ta2O5 into PEEK and surface coarsening could improve surface roughness, hydrophilicity, surface energy and protein absorption of PTC. Furthermore, the adhesion and proliferation as well as osteogenic differentiation of BMSCs on PTC were significantly promoted and regulated by Ta2O5 content and surface coarsening. The results indicated that surface coarsening of PTC (PTCS) with high surface roughness, hydrophilicity and surface energy could induce positive cellular responses, showing good cytocompatibility. PTCS might have a great potential as implants for bone repair. PMID- 30465996 TI - Delivery of proteins encapsulated in chitosan-tripolyphosphate nanoparticles to human skin melanoma cells. AB - We have successfully encapsulated two proteins, bovine serum albumin (BSA) and p53, in chitosan-tripolyphosphate (TPP) nanoparticles at various pH values from 5.5 to 6.5 and delivered the particles to human melanoma cells. The particles have diameters ranging from 180 nm to 280 nm and a zeta potential of +15 to + 40 mV. Cellular uptake of the particles by human skin melanoma cells was evaluated by: (i) fluorescence microscopy and (ii) gel electrophoresis showing that FITC labeled BSA and p53 could be recovered in the soluble cell fraction after lysis of the cells. Our data also show that the highest cellular uptake takes place at the lowest pH as the particles have the highest positive charge under these conditions. The method we describe appears to be a general method for delivery of proteins to cells using chitosan-TPP nanoparticles as a drug delivery system, since structurally unrelated proteins such as BSA and p53 with different isoelectrical points can be encapsulated in the chitosan-TPP nanoparticles and be effectively internalized by the cells. PMID- 30465997 TI - Antibiofilm effect of chlorhexidine-carrier nanosystem based on iron oxide magnetic nanoparticles and chitosan. AB - This study synthesized and characterized a chlorhexidine (CHX)-carrier nanosystem based on iron oxide magnetic nanoparticles (IONPs) and chitosan (CS), and evaluated its antimicrobial effect on mono- and dual-species biofilms of Candida albicans and Streptococcus mutans. CHX was directly solubilized in CS-coated IONPs and maintained under magnetic stirring for obtaining the IONPs-CS-CHX nanosystem. Antimicrobial susceptibility testing for planktonic cells was performed by determining the minimum inhibitory concentration (MIC) of the nanosystem and controls. The effects of the IONPs-CS-CHX nanosystem on the formation of mono- and dual-species biofilms, as well as on pre-formed biofilms were assessed by quantification of total biomass, metabolic activity and colony forming units. Data were analyzed by the Kruskal-Wallis' test or one-way analysis of variance, followed by the Student-Newman-Keuls' or Holm-Sidak's tests (alpha = 0.05), respectively. Physico-chemical results confirmed the formation of a nanosystem with a size smaller than 40 nm. The IONPs-CS-CHX nanosystem and free CHX showed similar MIC values for both species analyzed. In general, biofilm quantification assays revealed that the CHX nanosystem at 78 MUg/mL promoted similar or superior antibiofilm effects compared to its counterpart at 39 MUg/mL and free CHX at 78 MUg/mL. These findings highlight the potential of CS-coated IONPs as preventive or therapeutic agents carrying CHX to fight biofilm associated oral diseases. PMID- 30465998 TI - pH Responsive 5-Fluorouracil Loaded Biocompatible Nanogels For Topical Chemotherapy of Aggressive Melanoma. AB - Combating melanoma via topical route is a highly challenging task due to low selectivity, poor efficacy and impeding biological environment of the skin. In the present study, we engineered a chitosan based pH responsive biodegradable nanogel (FCNGL), encapsulated with 5-FU that was effective even at very low drug doses (0.2% w/v) against melanoma. The FCNGL was synthesized by ion gelation technique exhibited nano-size particle distribution and sustained drug release kinetics. Hemolysis and coagulation analysis revealed high safety whereas MTT and apoptosis assays exhibited the efficacy of FCNGL. DMBA-Croton oil Swiss albino mice model was employed for in vivo assessment followed by gamma scintigraphic screening. Tumor burden and pharmacokinetic antioxidant stress levels along with whole-body gamma scintigraphy imaging using 99 mTc labelled nanogel exhibited selective accumulation in melanoma tumor nodules. The pH responsive behaviour of the nanogels resulted in triggered release of 5-FU in slightly acidic microenvironment, resulting in selective drug accumulation at the melanoma site. Immunohistochemistry (IHC) analysis of tumor showed improvement of subcutaneous layer alignment and regeneration of the epithelial skin layer when compared with standard 5% 5-FU and control mice group. Overall our preclinical data using the FCNGL portends to be a promising platform for efficient and sustained delivery of 5-FU for topical chemotherapy that can result in high efficacy, patient compliance and safety in the clinical set up. PMID- 30465999 TI - Therapeutic and preventative effects of ankaferd blood stopper in an experimental necrotizing enterocolitis model. AB - Necrotizing enterocolitis (NEC) is a major neonatal health problem that especially affects preterm infants and causes severe morbidity and mortality. Although its pathogenesis is not fully understood, important risk factors include prematurity, oxidative stress, inflammation, and apoptosis. Ankaferd Blood Stopper(r) (ABS) has antioxidant, antiinflammatory, antimicrobial, antiapoptotic, and wound healing accelerant properties. In this study, we aimed to investigate whether treatment with ABS reduced the severity of NEC in rat pups in an experimental NEC model. Thirty-six newborn Wistar albino rat pups were randomly assigned to the control, NEC + saline, or NEC + ABS groups. NEC was induced by intraperitoneal injection of lipopolysaccharide, feeding with hyperosmolar enteral formula, and exposure to hypoxia/hyperoxia and cold stress. ABS was administered intraperitoneally to the pups in the NEC + ABS group daily starting on day 1 of the study at a dose of 2 ml/kg by diluting 2 ml with saline at a ratio of 1:3. All pups were sacrificed on day 4. The terminal ileum including the proximal colon was removed for histopathological and immunohistochemical examination and biochemical analysis. Macroscopic assessment and intestinal injury scores were lower in NEC + ABS group compared to the NEC + saline group (p < 0.05). Immunohistochemical evaluations of caspase-3, -8, and -9 revealed significantly reduced apoptosis in the NEC + ABS group compared to the NEC + saline group (p = 0.001). Total oxidant status, oxidative stress index, tumor necrosis factor alpha and interleukin-1beta levels, and lipid, protein, and deoxyribonucleic acid oxidation products were significantly lower in the NEC + ABS group compared to NEC + saline group (p < 0.001 for all), while total antioxidant status, glutathione, and superoxide dismutase levels were higher in the NEC + ABS group (p < 0.001, p < 0.001, p = 0.01, respectively). ABS treatment has the potential to effectively reduce the severity of intestinal damage in NEC due to its antioxidant, antiinflammatory, and antiapoptotic properties. Therefore, NEC may be an alternative option for treatment. PMID- 30466000 TI - Metabolic interactions of rosmarinic acid with human cytochrome P450 monooxygenases and uridine diphosphate glucuronosyltransferases. AB - In light of the widespread use of herbal medicines containing rosmarinic acid (RA) and limited literature available thereon, we investigated the metabolic interactions of RA with human cytochrome P450 monooxygenases (CYPs) and uridine diphosphate glucuronosyltransferases (UGTs). The involvement of selected enzymes (CYP1A2, CYP2C19, CYP2E1, CYP3 A4, UGT1A1, UGT1A6, and UGT2B7) in the metabolism of RA and the inhibitory effect of RA on the enzyme activity were comprehensively evaluated using human recombinant isozyme system. Additionally, concentration dependent RA metabolism mediated by phase I enzymes (including CYPs) or UGT was investigated in human liver microsome (HLM) system. A significant disappearance of RA was observed in the seven CYP and UGT isoforms studied, indicating their possible involvement in the metabolism of RA. Based on Michaelis-Menten kinetics, the metabolism study using HLM suggests that the UGT system may have a higher capacity and lower affinity for the metabolism of RA than phase I enzyme (including CYP) systems. Moreover, RA weakly inhibited CYP2C9 and 2E1 activities with IC50 values of 39.6 and 61.0 MUM, respectively, while moderately inhibiting UGT1A1, 1A6, and 2B7 with IC50 values of 9.24, 19.1, and 23.4 MUM, respectively. By constructing Line weaver-Burk plots, the type of inhibition exhibited by RA on CYP and UGT activities was determined as follows: CYP2C19, mixed inhibition; CYP2E1, UGT1A1, UGT1A6, and UGT2B7, competitive inhibition. Based on the comparison of the IC50 and Ki values obtained in the current study with the previously reported plasma concentrations of RA after oral dosing in humans, it is suggested that RA may significantly inhibit the activities of the tested UGTs, rather than CYPs, in clinical settings. Thus, the present study could provide a basis for further studies on clinically significant interactions between UGT substrate drugs and herbal medicines containing RA. PMID- 30466001 TI - Multi-targeting aurones with monoamine oxidase and amyloid-beta inhibitory activities: Structure-activity relationship and translating multi-potency to neuroprotection. AB - Previously, a series of aurones bearing amine and carbamate functionalities was synthesized and evaluated for their cholinesterase inhibitory activity and drug like attributes. In the present study, these aurones were evaluated for their multi-targeting properties in two Alzheimer's disease (AD)-related activities namely, monoamine oxidase (MAO) and amyloid-beta (Abeta) inhibition. Evaluation of the aurones for MAO inhibitory activity disclosed several potent selective inhibitors of MAO-B, particularly those with 6-methoxyl group attached at ring A. Of the different amine moieties attached as side chains, pyrrolidine-bearing aurones were prominent as represented by 2-2, the most potent inhibitor. Evaluation on the Abeta aggregation inhibition identified 4-3 as the best inhibitor with a percentage inhibition comparable to that of a known Abeta inhibitor curcumin. Examination on the neuroprotective ability of the more drug like aurone 4-3 in two Caenorhabditis elegans neurodegeneration models showed 4-3 to protect the nematodes against both Abeta- and 6-hydroxydopamine-induced toxicities. These new activities further support 4-3 as a promising lead to develop the aurones as potential multipotent agents for neurodegenerative diseases. PMID- 30466002 TI - Chemical profile, liver protective effects and analgesic properties of a Solanum paniculatum leaf extract. AB - BACKGROUND/AIM: Solanum paniculatum L. (Solanaceae) is a plant native to South America where it is used in traditional medicine for different therapeutic indications. This study evaluated the chemical composition and the hepatoprotective and analgesic activities of S. paniculatum leaf extracts. MATERIAL AND METHODS: The chemical profile of an ethyl acetate partition (SPOE) of a S. paniculatum leaf infusion (SPAE) was analysed by high performance liquid chromatography coupled to high-resolution electrospray mass spectrometry (HPLC ESIMS). Liver protective effects of SPAE (600 and 1200 mg/kg bw, po), or SPOE (300 mg/kg bw, po) were evaluated in a C57BL/6 mouse model of acetaminophen (AP, 600 mg/kg bw, ip) hepatotoxicity by measuring alanine (ALT) and aspartate (AST) aminotransferase activity in the serum, and reduced glutathione (GSH), and thiobarbituric acid reactive species (TBARs) levels in the hepatic tissue. RESULTS: HPLC-ESIMS analysis of the SPOE fraction tentatively identified 35 flavonoids, esters of hydroxycinnamic acid and isomers of chlorogenic acid. SPAE (600 and 1200 mg/kg bw) and SPOE (300 mg/kg bw) antagonized the rise in ALT and AST, and the depletion of GSH, and elevation of TBARs levels in the liver caused by AP. The liver protective effects of SPOE (300 mg/kg bw) against AP-induced liver toxicity mimicked those of N-acetyl-cysteine (NAC 300 or 600 mg/kg bw ip). The mouse writhing assay showed that SPOE (300 mg/kg bw po) has anti-nociceptive effects comparable to those of AP (180 mg/kg bw po). CONCLUSION: This study suggests that an extract of S. paniculatum leaves (SPOE), rich in phenolic compounds, is a promising herbal drug to prevent and treat AP poisoning and presents analgesic properties as well. PMID- 30466003 TI - Inhibition of pyruvate dehydrogenase kinase-4 by l-glutamine protects pregnant rats against fructose-induced obesity and hepatic lipid accumulation. AB - OBJECTIVE: Accumulation of lipids in non-adipose tissues particularly the liver is a feature of tissue insulin resistance. Hepatic glycogen depletion reflects counter glucoregulation in an insulin-resistant state and/or obesity. The effect of l-glutamine on fructose-induced increased hepatic lipid accumulation and depleted glycogen content, particularly in pregnancy, is not known. We therefore aimed at investigating the effect of glutamine on fructose-induced weight gain, hepatic lipids and glycogen contents in pregnant rats and also tested the hypothesis that hepatoprotective role of l-glutamine is through suppression of PDK-4. METHODS: Eleven-week-old pregnant Wistar rats were allotted into the Control, Glutamine, Fructose and Fructose plus Glutamine groups (6 rats/group). The groups received distilled water (vehicle, p.o.), 1 g/kg bwl-glutamine (p.o.), 10% Fructose (w/v) and 10% Fructose (w/v) plus 1 g/kg bwl-glutamine (p.o.) respectively, daily for 19 days. Biochemical analysis and histology of the liver were performed. RESULTS: Data showed that fructose intake caused insulin resistance, hyperglycemia, hyperlipidemia, increased body weight gain, visceral fat mass, hepatic mass, lactate production, uric acid production, lipid peroxidation and decreased pancreatic beta-cell function and hepatic glycogen synthesis. These alterations were accompanied by elevated pyruvate dehydrogenase kinase-4 (PDK-4). However, the fructose-induced dysmetabolism were improved by l glutamine. CONCLUSION: Our results demonstrate that obesity and hepatic lipid accumulation induced by fructose in pregnant rats is accompanied by increased PDK 4. The findings also suggest that l-glutamine would protect against obesity and hepatic lipid accumulation by suppression of PDK-4. PMID- 30466004 TI - Toxicological evaluation of the biflavonoid, agathisflavone in albino Swiss mice. AB - Agathisflavone (AGF) is a biflavonoid with a number of important biological and pharmacological activities, such as antioxidant, antimicrobial, and neuroprotective effects. However, its toxicological effects have not been fully investigated. Accordingly, the aim of this study was to investigate the toxicological effects of AGF in mice. For this purpose, the median lethal dose 50% (LD50) was determined along with the anatomic and histopathological parameters (weight, alimentation, excretion, biochemical, and hematological) in fertile untouched female Swiss mice. Results suggest that during the treatment, no deaths were reported at 300 and 2000 mg/kg (n = 03/group, p.o.). Moreover, AGF did not cause significant change in the above mentioned parameters in test animals when compared with the control group (0.05% Tween 80 dissolved in 0.9% saline). Taken all together, this non-clinical toxicological study revealed that AGF has an LD50 larger than 2000 mg/kg and did not change significantly the hematological, biochemical, histopathological, behavioral, as well as physiological parameters in the female mice. PMID- 30466005 TI - Leea macrophylla root extract upregulates the mRNA expression for antioxidative enzymes and repairs the necrosis of pancreatic beta-cell and kidney tissues in fructose-fed Type 2 diabetic rats. AB - This research investigated the functional food effect of Leea macrophylla (Roxb.) ex Hornem root extract on pancreatic necrosis in Streptozotocin-induced type-2 diabetes. Prior to animal intervention, Leea macrophylla root extract (LMR) was subjected to GC-MS analysis. Across a three-week intervention of fructose-fed albino model with LMR50, LMR100 and LMR200, the fluid & food intake, body weight changes, weekly blood glucose concentrations and oral glucose tolerance (OGT) were recorded. The animals were sacrificed after intervention and serum was analyzed for insulin, ALT, AST, LDH, CK-MB, creatinine, uric acid and lipid profile and liver section was used for glycogen estimation. Changes of pancreas and kidney architecture were evaluated by histopathology. Relative mRNA for superoxide dismutase 1 (SOD1), glutathione peroxidase (GPx) and catalase (CAT) were quantitated using assay kits. Results showed that fluid and food intake, weekly blood glucose level, ALT, AST, LDH, CK-MB level were significantly (p < 0.05) decreased in LMR50 group. Conversely, the glucose tolerance ability, liver glycogen level, serum insulin, organ weight and pancreatic morphology were improved significantly in this group. Diameter of islet of Langerhans (MUm), area occupied by beta-cell/ islet of Langerhans (MUm2) and number of beta-cells/islet of Langerhans were amazingly improved to the NC animals. Expressions of mRNA for SOD1 and CAT from liver tissue have been found to be increased multifold while GPx was remained unchanged. The data suggests that L. macrophylla root extract could be very potential as functional food to modulate pancreatic action. PMID- 30466006 TI - Ellagic acid ameliorates oxidative stress and insulin resistance in high glucose treated HepG2 cells via miR-223/keap1-Nrf2 pathway. AB - As a promising new target, miR-233 may regulate oxidative stress by targeting keap1-Nrf2 system to affect the pathological process of liver injury in T2DM. Ellagic acid (EA) is versatile for protecting oxidative stress damage and metabolic disorders. In the present study, we investigated the effect of EA on oxidative stress and insulin resistance in high glucose-induced T2DM HepG2 cells and examined the role of miR-223/keap1-Nrf2 pathway in system. HepG2 cells were incubated in 30 mM of glucose, with or without EA (15 and 30 MUM) or metformin (Met, 150 MUM) for 12 h. Glucose consumption, phosphorylation of IRS1, Akt and ERK under insulin stimulation, ROS and O2- production, MDA level, SOD activity and miR-223 expression, as well as protein levels of keap1, Nrf2, HO-1, SOD1 and SOD2 were analyzed. Furthermore, dual luciferase reporter assay, miR-223 mimic and inhibitor were implemented in cellular studies to explore the possible mechanism. EA upregulated glucose consumption, IRS1, Akt and ERK phosphorylation under insulin stimulation, reduced ROS and O2- production and MDA level, and increased SOD activity in high glucose-exposed HepG2 cells. In addition, EA elevated miR-223 expression level, downregulated mRNA and protein levels of keap1, and upregulated Nrf2, HO-1, SOD1 and SOD2 protein levels in this cell model. What's more, dual luciferase reporter assay, miR-223 mimic and inhibitor transfection confirmed that EA activated keap1-Nrf2 system via elevating miR-223. The miR-223, a negative regulator of keap1, represents an attractive therapeutic target in hepatic injury in T2DM. EA ameliorates oxidative stress and insulin resistance via miR-223-mediated keap1-Nrf2 activation in high glucose-induced T2DM HepG2 cells. PMID- 30466007 TI - Herb-drug interaction: A case study of effects and involved mechanisms of cisplatin on the pharmacokinetics of ginsenoside Rb1 in tumor-bearing mice. AB - Ginseng is often prescribed together with cisplatin for treatment of cancer, but the interaction between ginseng and cisplatin is still unknown. This study employed ginsenoside Rb1 (Rb1), one of the major components in ginseng, to explore the effects and involved mechanisms of cisplatin on the pharmacokinetics of ginseng. The effects of cisplatin on the pharmacokinetics of Rb1 and its bioactive metabolites Rd, Rg3, and F2 were investigated by using A549-bearing mice with and without cisplatin intervention. Our data showed that cisplatin could significantly decrease the AUC(0-t) and Cmax of Rd, Rg3, and F2, except Rb1. To evaluate the involved mechanisms, feces and intestinal mucosa were collected to explore the effects of cisplatin on the gut metabolism of Rb1 in vitro; meanwhile, Caco-2 cell model and small intestine histological characters were examined to evaluate the effects of cisplatin on the gut absorptive areas and permeability. The mechanisms involved may be mainly related to the comprehensive contributions of inhibited intestinal bacteria and mucosa metabolisms, narrowed intestinal absorptive area, increased efflux ratio of intestinal absorption and enhanced intestinal permeability. All these findings suggested that the dosage of ginseng traditionally used for health protection should be adjusted when it was prescribed together with cisplatin in the treatment of cancer. PMID- 30466008 TI - Thymol exposure mediates pro-oxidant shift by regulating Nrf2 and apoptotic events in zebrafish (Danio rerio) embryos. AB - The biochemical process of oxidative stress is an integral mechanism of chemical toxicity, contributing to complex pathological disorders. Thymol (THY) has a wide range of therapeutic applications for several ailments, although a better understanding of signaling cues regulated by this compound is needed to address the mechanism of its action. To better perceive the mode of action, we investigated the potential impact of THY on zebrafish embryos, with special emphasis on ROS biogenesis. In this study, we exposed the zebrafish embryos to 25, 50 and 100MUM of THY for 96 hours post fertilization (hpf). Noticeable teratogenic effects were observed upon assessing the survival rate (LC50 = 42.35MUM), hatching process, morphological exam and cardiac functions, thereby verifying the toxicity of THY on zebrafish embryos. Furthermore, we analyzed the effect of THY on the levels of ROS, mitochondrial membrane potential (DeltaPsim) and immunofluorescence by DCFH-DA, JC-1, Casp-3-FITIC staining, respectively. Furthermore, we preformed the expressional analysis of Nrf2, superoxide dismutase 1 (SOD-1), catalase (CAT), Cytochrome P450 (CYP450) and apoptotic marker proteins (AIF, p53, Bax, Bcl-2, Casp-3 and Casp-9) in zebrafish embryos. As expected, we noticed a significant modulatory effect on the above-mentioned activities by THY. Collectively, our findings suggest that ROS might be the prime mediator responsible for THY-induced oxidative damage, thereby affecting the cellular defense mechanism and apoptotic events in zebrafish embryos. PMID- 30466009 TI - Evaluation of watershed health using Fuzzy-ANP approach considering geo environmental and topo-hydrological criteria. AB - Assessment of watershed health and prioritization of sub-watersheds are needed to allocate natural resources and efficiently manage watersheds. Characterization of health and spatial prioritization of sub-watersheds in data scarce regions helps better comprehend real watershed conditions and design and implement management strategies. Previous studies on the assessment of health and prioritization of sub-watersheds in ungauged regions have not considered environmental factors and their inter-relationship. In this regard, fuzzy logic theory can be employed to improve the assessment of watershed health. The present study considered a combination of climate vulnerability (Climate Water Balance), relative erosion rate of surficial rocks, slope weighted K-factor, topographic indices, thirteen morphometric characteristics (linear, areal, and relief aspects), and potential non-point source pollution to assess watershed health, using a new framework which considers the complex linkage between human activities and natural resources. The new framework, focusing on watershed health score (WHS), was employed for the spatial prioritization of 31 sub-watersheds in the Khoy watershed, West Azerbaijan Province, Iran. In this framework, an analytical network process (ANP) and fuzzy theory were used to investigate the inter relationships between the above mentioned geo-environmental factors and to classify and rank the health of each sub-watershed in four classes. Results demonstrated that only one sub-watershed (C15) fell into the class that was defined as 'a potentially critical zone'. This article provides a new framework and practical recommendations for watershed management agencies with a high level of assurance when there is a lack of reliable hydrometric gauge data. PMID- 30466010 TI - Biochar amendment improves crop production in problem soils: A review. AB - Problem soils are referred to as those with poor physical, chemical, and biological properties that inhibit or prevent plant growth. These poor properties may be a result of soil formation processes but are largely due to inappropriate farming practices or anthropogenic pollution. The world has lost a third of its arable land due to erosion and pollution in the past 40 years. Thus, there is an urgent need for improving and remediating problem soils. As a novel multifunctional carbon material, biochar has been widely used as a soil amendment for improving soil quality. Previous reviews have summarized the characteristics of biochar, the interactions with various soil contaminants, and the effects on soil quality, soil productivity, and carbon sequestration. Relatively limited attention has been focused on the effects of biochar amendment on plant growth in problem soils. As a result, a comprehensive review of literature in the Web of Science was conducted with a focus on the effects of biochar amendment on plant growth in problems soils. The review is intended to present an overview about problem soils, biochars as functional materials for soil amendment, how amended biochars interact with soils, soil microbes, and plant roots in remediation of problem soil and improve plant growth. Additionally, existing knowledge gaps and future directions are discussed. Information gathered from this review suggests that biochar amendment is a viable way of improving the quality of problem soils and enhancing crop production. It is anticipated that further research on biochar amendment will increase our understanding on the interactions of biochar with components of problem soils, speed up our effort on soil remediation, and improve crop production in problem soils. PMID- 30466011 TI - Associations between blood cadmium concentration and kidney function in the U.S. population: Impact of sex, diabetes and hypertension. AB - BACKGROUND: Exposure to cadmium has been associated with nephropathy and implicated in the development of diabetes and hypertension. The role of environmental metal exposure may be an underexplored risk factor for decreased kidney function among people with diabetes and/or hypertension. The objective of this study was to examine the association of blood concentration of cadmium with kidney function parameters and evaluate sex, diabetes, and hypertension as effect modifiers of the association. METHODS: This study used data from 12,577 adult participants in the National Health and Nutrition Examination Survey (NHANES) 2007-2012 cycles. We used multivariable linear and logistic regression models to conduct a cross-sectional analysis of the association between cadmium exposure quartiles and estimated glomerular filtration rate (eGFR), urine albumin to creatinine ratio (UACR), low eGFR (defined as eGFR <60 mL/minute/1.73 m2), and albuminuria (defined as UACR >= 30 mg/g). Models were adjusted for confounders and interaction terms were evaluated for cadmium concentration and sex, diabetes, and hypertension. Final models were stratified by sex and indices of existing diabetes and hypertension status. RESULTS: The mean eGFR was 94.3 mL/minute/1.73 m2 (SD 21.5) and the geometric mean of UACR was 7.9 mg/g (95% CI 7.6-8.2 mg/g). Blood cadmium concentration was inversely associated with eGFR and positively associated with UACR. We found significant effect modification of the association of eGFR with cadmium, predominantly for sex and hypertension. The strength of the association between cadmium quartiles and eGFR was more pronounced among females compared to males. Among females with hypertension and diabetes, eGFR was lower on average by 4.9 mL/minute/1.73 m2 (95% CI -10.1 to 0.29) in the highest versus lowest cadmium quartile, and in females with hypertension alone, eGFR was lower on average by 5.8 mL/minute/1.73 m2 (95% CI -8.2 to -3.3) in the highest versus lowest cadmium quartile. Among those in the highest exposure quartile, higher mean UACR was observed among participants with hypertension compared to those without. CONCLUSIONS: Our results confirm that cadmium exposure is associated with decreased glomerular filtration and increased urine protein excretion, and provide evidence that the magnitude of these associations differ by sex and may vary based on preexisting diabetes and hypertension. Future prospective sex specific investigations are necessary to address concerns of reverse causality and efforts should be made to reduce smoking and environmental contamination from cadmium to protect human health. PMID- 30466012 TI - Pesticides Exposure by Air in Vineyard Rural Area and Respiratory Health in Children: A pilot study. AB - RATIONALE: Asthma, frequently associated with rhinitis, is the most common chronic disease in children, and a significant role is played by a range of environmental exposures. Among them, air pollution is of foremost concern. However, little is known about the impact of airborne pesticide exposure on children's respiratory health in rural areas. The objective of this study was to analyze the association between airborne pesticide exposure and asthma and rhinitis in children. METHODS: In a French vineyard rural area, children (3-10 years old) from 4 selected schools were invited to participate in this study over two periods: winter, with no or low air pesticide levels, and summer when fields are frequently treated with pesticides. Two health outcomes were considered: asthma and rhinitis symptoms (ISAAC questionnaire), and peak expiratory flow (PEF). A quantitative score of symptoms was built. Exposure to pesticides was evaluated 1) by measuring 56 pesticides in the ambient outdoor air around schools in the two periods and building a cumulative exposure index, and 2) by measuring ethylenethiourea (ETU) concentrations in urine in a subsample of children (n = 96), ETU being a urine biomarker of exposure to dithiocarbamates fungicides. Next, the association between pesticide exposure and respiratory health was studied using a logistic regression model, adjusted for confounders and respiratory status at baseline. RESULTS: 281 children participated in the study (47% girls, mean age: 7.5 yrs). 25% of the children were living on a farm. 22% had experienced wheezing at least once. 15.8% had asthma diagnosed by a doctor, 12% had current asthma and 35% had allergic rhinitis. The main pesticides detected in the ambient outdoor air around schools were fungicides (89,3%; mainly folpet and dithiocarbamates) and insecticides (10.6%). No association was found between the symptom score and pesticides in the outdoor air around schools during summer, when pesticides were applied to vineyards. However, an association was found between ETU urinary concentration (>0.974 MUg/g creatinine) and asthma and rhinitis symptoms (OR=3.56; IC 95% 1.04-12.12). This result could be explained by extracurricular exposure, which was not considered in our air measurements in the schools. No association was found between peak expiratory flow and exposure to pesticides in the air. CONCLUSIONS: Children living in vineyard rural areas are at a higher risk of airborne dithiocarbamates exposure during the summer period. Despite the limited size of our sample, our results suggest possible links between some pesticide measurements and respiratory and allergic symptoms such as rhinitis. PMID- 30466013 TI - Impact of heatwaves on daily outpatient visits of respiratory disease: A time stratified case-crossover study. AB - OBJECTIVES: This study aims to estimate the impact of heatwaves from July 2010 to October 2012 on daily outpatient visits for respiratory disease (RD) in Cangnan, China and identify vulnerable populations. METHODS: The definition of heatwave was a period at least 3 consecutive days with maximum temperature exceeding 35 degrees C in this study. A time-stratified case-crossover design was conducted to examine the relationship between heatwaves and outpatient visits for RD. Patient data for the period from 2010 to 2012 were collected from the Third People's Hospital of Cangnan and daily meteorological data for the same period were collected from the China Meteorological Data Service Center. Data regarding the air pollution index (API), a composite indicator of air pollution, were collected from the Data Center of the Chinese Ministry of Environmental Protection. RD were identified based on the 10th revision International Classification of Diseases (ICD-10) codes (J00-J99). A conditional Poisson regression model was applied to examine the heatwave-RD association using the Relative Risk (RR) while adjusting for meteorological and air pollution factors including temperature, rainfall, wind speed, pressure, humidity, sunshine hours and API. RESULTS: During the study period, 4 heatwaves occurred and a total of 1732 outpatient visits for RD were reported. Heatwaves increased the frequency of RD outpatient visits and the highest RR of total RD was 1.155% and 95% Confidence Intervals (95% CI) was 1.084 1.232 at Lag 0. For subcategories, heatwaves increased the risk of infectious RD (Lag 0: RR =1.182, 95% CI: 1.106-1.263) and decreased the risk of non-infectious RD ((Lag 6: RR =0.750, 95% CI: 0.568-0.990). Moreover, heatwaves showed adverse effects on acute upper respiratory infection (Lag 0: RR =1.306, 95% CI: 1.177 1.450). The RR of outpatient visits for RD was statistically significant in females (Lag 0: RR =1.161, 95% CI: 1.046-1.298), males (Lag 4: RR =1.161, 95% CI: 1.096-1.261), young people aged 4-17 years (Lag 0: RR =1.741, 95% CI: 1.524 1.990) and elders aged 65 years or older (Lag 5: RR =1.412, 95% CI: 1.111-1.794) during heatwaves. CONCLUSIONS: Heatwaves had a significant harmful impact on daily outpatient visits for RD in Cangnan, especially for vulnerable population identified. These results can be used not only to strengthen the health education and protection of these vulnerable populations, but also to assist relevant organizations with developing intervention programmes and improving disease prevention and community care. PMID- 30466014 TI - Self-assessment of negative symptoms - Critical appraisal of the motivation and pleasure - Self-report's (MAP-SR) validity and reliability. AB - OBJECTIVE: The negative symptom domain remains a major challenge concerning treatment. A valid self-report measure could assist clinicians and researchers in identifying patients with a relevant subjective burden. The Motivation and Pleasure - Self Report (MAP-SR) derives from the CAINS and is supposed to reflect the "amotivation" factor of negative symptoms. We evaluated different aspects of the scale's reliability and validity. This is the first factorial analysis as well as the first analysis of test-retest reliability. METHODS: We assessed three samples of subjects with schizophrenia or schizoaffective disorder (n = 93) and a broad spectrum of related domains. RESULTS: We explored a 3-, 2- and 1-factor solution (explaining 50.93, 44.85 and 36.18% of variance, respectively). The factor "pleasure and hedonic activity" consists of eight items and was most robust; the factors "social motivation" and "motivation for work" were problematic. Test-retest reliability of the scale was adequate (rS = 0.63, p = .005). Neither the MAP-SR nor the "pleasure and hedonic activities" factor are associated with the PANSS negative symptom scale. There are significant associations with the observer-rated CAINS-MAP scale, experiences of pleasure, and social cognition but none with functional outcome. Discriminant validity could not be established with regards to depression and extrapyramidal symptoms. CONCLUSIONS: We found that the MAP-SR is adequate to assess anhedonia but is less suitable when assessing motivation. Therefore, we propose using the "pleasure and hedonic activity scale" to cover the "anhedonia" subdomain. We think the "motivation" part of the instrument requires reconstruction. PMID- 30466015 TI - Developmental influences on stress response systems: Implications for psychopathology vulnerability in adolescence. AB - The adolescent transition is marked by increases in stress exposure and significant maturation of neural and hormonal stress processing systems. Variability in the development of these systems during adolescence may influence the risk for stress-related psychopathology. This paper aims to review the developmental maturation of the HPA axis and related stress regulation systems, and demonstrate how interference in this adaptive developmental process may increase the risk for negative outcomes. We argue that the developmental maturation of the HPA axis aims to improve the regulatory capacity of the axis in order to more adaptively respond to these increases in stress reactivity. Additionally, we review evidence that sex differences in the development of the HPA and related axes may contribute to sex differences in the risk for stress related psychopathology. Finally, we discuss how contextual factors, such as early trauma and obesity may alter the development of HPA axis during the adolescence transition and how alterations of normative development increase the risk for stress-related disorders. PMID- 30466016 TI - Is the side effect profile of protons really safer than photons for intracranial disease? PMID- 30466017 TI - Persistent DNA methylation changes in zebrafish following graphene quantum dots exposure in surface chemistry-dependent manner. AB - Modified nano-graphene quantum dots (M-GQDs) are widely used in bioimaging, drug delivery, and chemical engineering. Because M-GQDs could induce reactive oxygen species and DNA damage, we hypothesized that M-GQDs modulate DNA methylation. To test this hypothesis, zebrafish were exposed to reduced, hydroxylated, or aminated GQDs (graphene quantum dots) at different concentrations for 7 days; global DNA methylation in liver, gill, and intestine was then studied. M-GQDs induced global DNA hypermethylation in various tissues in a dose-dependent manner. The global DNA methylation of reduced and aminated GQDs exposure showed a significant increase in intestines even at low concentrations (2 mg/L), suggesting that intestines are the main target for these two M-GQDs. The effects of global DNA methylation were evaluated 14 days after exposure had ceased. DNA methylation in the livers of exposure groups was significantly higher than in control zebrafish. Global DNA methylation increased in livers of zebrafish even after exposure to aminated GQDs (2 mg/L) had ceased, indicating a more complex mechanism of DNA methylation deregulation. The present results showed that chemical groups in the surface of GQDs are a critical factor for modulating DNA methylation. PMID- 30466018 TI - Evaluation of uptake, translocation, and accumulation of arsenic species by six different Brazilian rice (Oryza sativa L.) cultivars. AB - Rice is a significant source of arsenic (As) exposure. The accumulation of the plant depends on several factors, including environmental conditions and genetic factors. The differences in As uptake, translocation, and grains filling in different cultivars are a focus on studies to mitigate the grains contamination. This study assessed the pattern of As species accumulation in different Brazilian rice cultivars (Oryza sativa L.). Thus, pot experiments were conducted with 6 different cultivars (white rice: EPAGRI 109, EPAGRI 108, BRS Tiotaka SCS, and SCS 114 Andosan and red rice: Maranhao and Caqui) cultivated in soils at low (As-) (0.65 mg kg-1) and high (As+) (12.1 mg kg-1) As levels. All cultivars in As+ group presented total As (t-As) in grains more elevated than the maximum limit of inorganic arsenic (i-As) recommended by Codex Alimentarius Commission. The As speciation disclose that Maranhao, Caqui, and SCS 114 Andosan cultivars presented the lowest % i-As (27%, 25% and 31%, respectively) at the highest As exposure condition. On the other hand, higher i-As concentration and % i-As (91%) were observed in EPAGRI 108. Moreover, EPAGRI 108 and EPAGRI 109 had the highest transference factor soil-to-grain (TFsoil-grain = 0.22 and 0.20, respectively). Interestingly, for the cultivars EPAGRI 108 and Maranhao, the levels of some essential elements (Co and Mn) in grains were modulated by the levels of As in the soil. This study shows that levels of i-As were modulated by the type of Brazilian rice cultivar, the range of As levels in soil, As phytotoxicity and the transference factor of As from soil to root straw and grains. Moreover, SCS 114 Andosan is the promising cultivar that exhibits low t-As and % i-As in grains and low TF soil-grain. PMID- 30466019 TI - Presence and human exposure assessment of organophosphate flame retardants (OPEs) in indoor dust and air in Beijing, China. AB - In this study, levels of 14 organophosphate flame retardants (OPEs) were measured in 101 indoor dust samples collected from dormitories, residential homes, and offices in Beijing, China. In addition, paired air samples were also analyzed to evaluate any correlation between OPE levels in air and that in corresponding dust samples. The Sigma14OPEs levels substantially varied between individual samples. Thereinto, significantly higher OPE levels were found in dust samples from office (mean value: 14 MUg g-1), comparing to that in dust samples from residential homes (mean value: 5.9 MUg g-1) and dormitories (mean value: 6.9 MUg g-1). Congener profiles of OPEs in dust samples from different microenvironments indicated that tris (2-chloroethyl) phosphate (TCEP) was the dominant OPE in the office samples, followed by tris (2-chloroisopropyl) phosphate (TCPP). In contrast, TCPP was the dominant OPE in the residential home and dormitory samples, followed by TCEP. The mean concentration (range) of Sigma14OPEs in the 15 air samples was 5.2 (1.0-20) ng m-3, and TCPP was the dominated congener in these samples. The concentration of TCEP and TCPP in air was positively correlated with that in corresponding indoor dust, and OPEs with highly saturated vapor pressures have higher fractions in the air than that in the dust. The estimated daily intakes through dust ingestion, dermal absorption, and inhalation indicated that the exposure to OPEs in indoor environments do not result in significant health risk for the general population in Beijing. PMID- 30466020 TI - Enhancing methane production of excess sludge and dewatered sludge with combined low frequency CaO-ultrasonic pretreatment. AB - Methane production of excess sludge (ES) and dewatered sludge (DS) were investigated with low frequency CaO-ultrasonic pretreatment. The results showed that the concentrations of SCOD and VFAs in pretreated ES (P-ES) and DS (P-DS) were 212.11% and 75.26%, 270.30% and 159.52% higher than those of untreated ES and DS, respectively. The contents of acetic acid and ethanol comprised 83.87% 92.88% of the total VFAs. The cumulative methane production (CMP) of P-ES and P DS were 167.08 and 162.96 mL/g.VS, respectively, which resulted in 40.45% and 36.94% higher than those of untreated ones. The biodegradability of P-ES was 87.65%, which was close to theoretical value. Low frequency CaO-ultrasonic pretreatment could not only improve the performance of anaerobic digestion (AD), but also accelerate the decomposition rate of two kinds of sludge. Therefore, this study provided meaningful insight for exploring efficient pretreatment strategy to stabilize and enhance AD performance for practical application. PMID- 30466021 TI - Turbo thin film continuous flow production of biodiesel from fungal biomass. AB - Direct biodiesel production from wet fungal biomass may significantly reduce production costs, but there is a lack of fast and cost-effective processing technology. A novel thin film continuous flow process has been applied to study the effects of its operational parameters on fatty acid (FA) extraction and FA to fatty acid methyl ester (FAME) conversion efficiencies. Single factor experiments evaluated the effects of catalyst concentration and water content of biomass, while factorial experimental designs determined the interactions between catalyst concentration and biomass to methanol ratio, flow rate, and rotational speed. Direct transesterification (DT) of wet Mucor plumbeus biomass at ambient temperature and pressure achieved a FA to FAME conversion efficiency of >90% using 3 wt/v % NaOH concentration, if the water content was <=50% (w/w). In comparison to existing DT methods, this continuous flow processing technology has an estimated 90-94% reduction in energy consumption, showing promise for up scaling. PMID- 30466022 TI - A pilot-scale biomass pyrolytic poly-generation plant performance study and self sufficiency assessment. AB - This work studied the influence of pyrolysis temperature on the energy and mass balance of pyrolysis of rice husk (RH), cotton stalk (CS) and fruit branch (FB) in a pilot-scale biomass pyrolytic poly-generation plant. The paper presents energy balance and self-sufficiency assessment of pilot-scale pyrolysis plant processing different types of biomass. The results also include characterization of the pyrolysis products. The volatile matter varied from 6.5 to 25.8% at different temperatures for the three feed stocks, which can be used as indexes for the degree of carbonization of biochar. The yield of pyrolysis gases enriched with H2, CH4 and other alkanes, and olefins increased significantly with increasing pyrolysis temperature from 550 to 650 degrees C. With a lower heating value >17.1 MJ/m3, an energy self-sufficient system is possible using only the pyrolysis gas. Biomass pyrolytic poly-generation technology offers a promising means of converting abundant agricultural residues into energy and added-value products. PMID- 30466023 TI - Improving liquid chromatography-tandem mass spectrometry determination of polycarboxylic acids in human urine by chemical derivatization. Comparison of o benzyl hydroxylamine and 2-picolyl amine. AB - Due to its high sensitivity and specificity, liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS) could be considered as the gold-standard in targeted metabolomics. Although LC-MS/MS allows for the direct detection of a large number of molecules, the proper quantification of highly polar compounds such as poly-carboxylic acids in complex matrices like urine is still a challenge. Chemical derivatization offers a suitable way to improve chromatographic behavior and sensitivity for these compounds. Several derivatizing agents have been proposed for the LC-MS/MS determination of carboxylic acids but studies dealing with their comparison in challenging scenarios are scarce. Here we present the evaluation of two different derivatization agents; o-benzylhydroxyl amine (oBHA) and 2-picolyl amine (2-PA); for the quantification of the (poly)-carboxylic acids belonging to the tricarboxylic acid cycle in urine. The suitability of both derivatizating agents was compared by validation of the two approaches. Derivatization with oBHA showed important advantages against 2-PA derivatization such as (i) providing better sensitivity, (ii) more stable derivatives and (iii) allowing for the proper validation of a larger number of analytes. Moreover, while 2-PA derivatization failed in the determination of the target analytes in some stored urine samples, oBHA derivatization successfully allowed for their appropriate determination in the same samples. A comparison between the concentrations obtained using oBHA derivatization and those provided by an external laboratory using UV and GC-MS detection revealed a satisfactory agreement between both results. Additionally, the concentrations obtained by the oBHA method for a set of 38 urines are in agreement with those previously reported in the literature. As a conclusion, our results show that the use of oBHA is preferred against 2-PA for the detection and quantification of (poly)-carboxylic acids in urine. PMID- 30466024 TI - X-ray irradiation effects on nuclear and membrane regions of single SH-SY5Y human neuroblastoma cells investigated by Raman micro-spectroscopy. AB - Raman micro-spectroscopy was performed in vitro on nuclear and membrane regions of single SH-SY5Y human neuroblastoma cells after irradiation by graded X-ray doses (2, 4, 6, 8 Gy). The acquired spectra were analyzed by principal component analysis (PCA) and interval-PCA (i-PCA) methods. Biochemical changes occurring in the different regions of single cells as a consequence of the radiation exposure were observed in cells fixed immediately after the irradiation. The most relevant effects arose from the analysis of the spectra from the cell nucleus region. The observed changes were discussed in terms of the modifications in the cell cycle, resulting in an increase in the DNA-related signal, a protein rearrangement and changes in lipid and carbohydrates profiles within the nucleus. Potential markers of an apoptotic process in cell population irradiated with 6 and 8-Gy X-ray doses could have been singled out. No significant effects were found in spectra from cells fixed 24 h after the irradiation, thus suggesting the occurrence of repairing processes of the X-ray induced damage. PMID- 30466025 TI - A case study demonstrating the migration of diethyl phthalate from an ancillary component to the drug product. AB - Phthalates are chemical compounds employed as plasticizers in the plastic industry and have been reported to migrate into drug products. The extent of their migration into the drug product depends upon various factors including the chemical nature of the migrant and the permeability of its packaging container. Migration of semi-volatile phthalates such as Diethyl phthalate (DEP) into drug products is often related to the primary and secondary packaging but due to its chemical nature, it could also migrate from an ancillary component. Therefore, it is not only important to screen the primary and secondary components, but also the ancillary materials that are used during the handling of drug products. In our study, we discovered an ancillary material (scotch tape) to be the source of DEP found in an ophthalmic drug product using orthogonal mass spectroscopy techniques (GC-MS and LC-MS). It is evident from our data that DEP migrated from the scotch tape into the drug product crossing the physical barriers provided by the primary (LDPE container closure system) and secondary packaging (carton and label). The tape was used as an ancillary material to wrap the packaged drug product units together for storage in the stability chamber. The primary and the secondary packaging of the drug product did not exhibit any traces of DEP. The aim of this report is to demonstrate how a chemical compound can migrate into the drug product from an ancillary source (which is not a part of its packaging) and adulterate a drug product. The impact of ancillary materials on drug products should be evaluated appropriately prior to their implementation. PMID- 30466026 TI - A comprehensive appraisal on Crocus chrysanthus (Herb.) Herb. flower extracts with HPLC-MS/MS profiles, antioxidant and enzyme inhibitory properties. AB - In the quest for new drugs of herbal origin, the ethyl acetate (EAE), methanol (ME), and water (WE) extracts of Crocus chrysanthus (Herb.) Herb. flowers were analyzed for their polyphenolic composition, antioxidant, and enzyme inhibitory potential. WE showed the highest antioxidant activities in all assays including metal chelating, phosphomolybdenum, FRAP, CUPRAC, ABTS and DPPH. EAE was the most effective enzyme inhibitor, exhibiting the highest inhibition against some enzymes linked to Alzheimer's disease (cholinesterases), diabetes mellitus (alpha glucosidase and alpha-amylase) and hyperpigmentation problems (tyrosinase). The highest total phenolics (34.99 mg GAE/g) and flavonoids content (77.58 mg RE/g) were observed in WE and ME, respectively. Eight compounds were identified in EAE, 24 in ME, and 15 in WE. Kaempferol 3-O glucoside was found in all extracts. In conclusion, C. chrysanthus flowers can be suggested as a source of bioactive components with potential use against chronic disorders caused by oxidative stress. Future in-depth studies are recommended to determine the biological effects of isolated compounds from C. chrysanthus to identify the main compounds modulating the observed activities. PMID- 30466027 TI - Agreement between digital breast tomosynthesis and pathologic tumour size for staging breast cancer, and comparison with standard mammography. AB - PURPOSE: Tomosynthesis is proposed to improve breast cancer assessment and staging. We compared tomosynthesis and mammography in estimating the size of newly-diagnosed breast cancers. METHODS: All pathologically-confirmed cancers detected in the STORM-2 trial (90 cancers, 85 women) were retrospectively measured on tomosynthesis by two independent readers. One reader also measured cancers on mammography. Relative mean differences (MDs) and 95% limits of agreement (LOA) with pathology were estimated for tomosynthesis and mammography within a single reader (Analysis 1) and between two readers (Analysis 2). RESULTS: Where cancers were detected and hence measured by both tests, tomosynthesis overestimated pathologic size relative to mammography (Analysis 1: MD 5% versus 1%, Analysis 2: 7% versus 3%; P = 0.10 both analyses). There was similar, large measurement variability for both tests (LOA range: -60% to +166%). Overestimation by tomosynthesis was attributable to the subgroup with dense breasts (MDs = 12-13% versus 4% for mammography). There was low average bias for both tests in the low-density subgroup (MDs = 0-4%). LOA were larger in dense breasts for both tomosynthesis and mammography (P <= 0.02 all comparisons). Cancers detected only by tomosynthesis were more frequently in dense breasts (60 68%): for those tumours size was estimated with increased measurement variability (LOA ranging from -75% to +293%). CONCLUSIONS: On average, tomosynthesis overestimates pathologic tumour size in women with dense breasts; that difference is more likely to impact management in women with larger tumours. The main advantage of tomosynthesis appears to be detecting mammographically-occult cancers; however tomosynthesis less accurately measured those cancers in dense breasts (large measurement variability). PMID- 30466028 TI - Vascular protection of DPP-4 inhibitors in retinal endothelial cells in in vitro culture. AB - People with diabetes are at high risk of developing diabetes-related eye disease, termed as diabetic retinopathy, due damage being caused to the blood vessels in the retina. An efficient medical treatment to reduce diabetic retinopathy can improve the quality of life for diabetes patients. In our study, we show that linagliptin, a commercially available DPP-4 inhibitor, plays a protective role in retinal vascular endothelial cells. The presence of linagliptin protects retinal endothelial cells against TNF-alpha-induced cytotoxicity and enhances their viability. Linagliptin treatment suppresses TNF-alpha-induced production of reactive oxygen species and improves mitochondrial membrane potential. Moreover, linagliptin suppresses TNF-alpha-induced production of pro-inflammatory and pro adhesive vascular cytokines including IL-6, IL-8, ICAM-1, and VCAM-1. The presence of linagliptin in cell media can reduce the number of THP-1 cells that adhere to retina endothelial cells. Mechanistically, linagliptin potently suppresses TNF-alpha-induced accumulation of NF-kappaB nuclear protein p65 and activation of NF-kappaB promoter. Our data indicate that linagliptin is an anti inflammatory diabetic agent, with the potential to be applied as a treatment for diabetic retinopathy. PMID- 30466029 TI - Chicoric acid alleviates lipopolysaccharide-induced acute lung injury in mice through anti-inflammatory and anti-oxidant activities. AB - Acute lung injury (ALI) is a severe clinical disease with high mortality rates. Chicoric acid (CA), an active component extracted from traditional Chinese medicine, was suggested to have anti-inflammatory and anti-oxidant activities. Inflammation and oxidative damage are implicated in the pathogenesis of ALI. In this study, we explored the protection effect of CA on LPS-induced ALI, and further discussed the possible molecular mechanisms. The results showed that CA could significantly improve the histological changes of LPS-induced acute lung injury. In addition, CA not only decreased LPS-stimulated protein leakage and lung wet/dry ratio but also reduced inflammatory cell infiltration, myeloperoxidase (MPO) activity and the generation of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF). Meanwhile, CA lessened the reactive oxygen species (ROS) generation, and malondialdehyde (MDA) formation, and decreased glutathione (GSH) and superoxide dismutase (SOD) depletion, which were caused by LPS challenge. Furthermore, CA dramatically inhibited LPS-stimulated MAPK and NLRP3 activation and increased the expression of NAD (P) H: quinone oxidoreductase (NQO1), and dismutase (SOD), glutamate-cysteine ligase catalytic/modifier (GCLC/GCLM) subunit and heme oxygenase-1 (HO-1), as well as its upstream genes nuclear factor-erythroid 2-related factor 2 (Nrf2), which might be central to the protective effects of CA. In conclusion, these data indicated that the protective effects and mechanisms of CA on LPS-induced ALI and provided new insights for its application. PMID- 30466030 TI - Repetitive negative thinking predicts eating disorder behaviors: A pilot ecological momentary assessment study in a treatment seeking eating disorder sample. AB - BACKGROUND: Repetitive negative thinking is a transdiagnostic process that occurs across several psychological disorders, including eating disorders. Individuals with eating disorders have higher levels of repetitive negative thinking than controls, and repetitive negative thinking is associated with eating disorder behaviors. However, no study has measured how momentary repetitive negative thinking may subsequently impact daily eating disorder behaviors and vice-versa. METHOD: In the current study (N = 66, recently treated individuals recruited from an eating disorder treatment center), we examined the relationship between repetitive negative thinking and subsequent eating disorder behaviors and vice versa using ecological momentary assessment. RESULTS: We found that higher momentary repetitive negative thinking predicted higher subsequent weighing and body checking. We also found that higher momentary meal-specific repetitive negative thinking predicted higher subsequent weighing and lower subsequent compensatory behavior. We also found that higher repetitive negative thinking predicted higher eating disorder symptoms at one-month follow-up. CONCLUSION: There are short-term and long-term negative effects of repetitive negative thinking in the eating disorders. Targeting repetitive negative thinking may be important for decreasing eating disorder behaviors. PMID- 30466031 TI - Self-critical perfectionism, experiential avoidance, and depressive and anxious symptoms over two years: A three-wave longitudinal study. AB - This three-wave longitudinal study examined the relations among perfectionism, experiential avoidance, and depressive and anxious symptoms over two years. Community adults (N = 173) completed self-report questionnaires assessing two higher-order perfectionism dimensions (self-critical [SC], personal standards [PS]), neuroticism, experiential avoidance, and depressive and anxious symptoms at Time 1, Time 2 one year later, and Time 3 two years later. Cross-lagged path analyses demonstrated that SC perfectionism predicted increases in experiential avoidance from Time 1 to Time 2 and again from Time 2 to Time 3. Experiential avoidance predicted increases in both depressive and anxious symptoms from Time 1 to Time 2 and again from Time 2 to Time 3. Time 2 experiential avoidance mediated the relation between Time 1 SC perfectionism and both depressive and anxious symptoms over two years, controlling for the effects of Time 1 neuroticism and prior symptom levels. Experiential avoidance did not mediate the relations between PS perfectionism and depressive/anxious symptoms over two years. These findings highlight the importance of targeting experiential avoidance in reducing vulnerability to depressive and anxious symptoms over the long-term in individuals with higher SC perfectionism. PMID- 30466032 TI - A dual-function probe based on naphthalene for fluorescent turn-on recognition of Cu2+ and colorimetric detection of Fe3+ in neat H2O. AB - A simple naphthalene derivative, 6-hydroxy-2-naphthohydrazide (NAH), was designed and synthesized through two facile steps reactions with the 6-hydroxy-2-naphthoic acid (NCA) as the starting material. In neat H2O (10% 0.01 M HEPES buffer, v/v, pH = 7.4), probe NAH showed a highly selective and sensitive response towards Fe3+ via perceptible color change and displayed "turn-on" dual-emission fluorescence response for Cu2+. The binding stoichiometry ratio of NAH/Cu2+ and NAH/Fe3+ were all confirmed as 1:1 by the method of fluorescence job's plot and UV-Vis job's plot, respectively. Probe NAH can be used over a wide pH range for the determination of Fe3+ (2.0-10.0) and Cu2+ (6.0-10.0) without interference from other co-existing metal ions. A possible detection mechanism was the hydrolysis of NAH upon the addition of Fe3+ or Cu2+, thereby leading to the formation of 6-hydroxy-naphthalene-2-carboxylic acid (NCA) which was further confirmed by the various spectroscopic techniques including FT-IR, 1H NMR titration and HRMS. Moreover, NAH was successfully applied to the detection of Cu2+ and Fe3+ in tap water, ultrapure water and BSA. PMID- 30466033 TI - Study of the H2O dipole moment and polarisability vibrational dependence by the analysis of rovibrational line shifts. AB - The study of the H2O dipole moment MU and polarisability alpha vibrational dependence is based on the comparison of experimental and calculated line shifts induced by argon, nitrogen, and air pressure in different H2O vibrational bands. Obtained dependence alpha on the stretching vibrations is in good agreement with the existing ab initio calculations in the literature, but the dependence alpha on the bending vibration is quite different. To clarify the dependence of MU and alpha on the bending vibration, the shifts of selected H2O lines of the 4nu2, 5nu2, and 6nu2 bands induced by argon, hydrogen and helium pressure are measured with the help of a Bruker IFS HR 125 spectrometer at room temperature with a spectral resolution of 0.01 cm-1. The comparison of experimental and calculated results with different values of MU and alpha line shifts is given. PMID- 30466034 TI - A novel isophorone-based red-emitting/NIR probe for thiophenol and its application in real water sample and vivo. AB - Fast, highly selective and sensitive thiophenol probes are highly desirable in the field of bioimaging and environmental monitoring. For that, based on the mechanism that thiophenol can effectively cleave the sulfonamide bond selectively, we herein report a dicyanoisophorone-based Red-emitting/NIR probe for thiophenol detection. This probe had some desirable properties such as rapid response, high selectivity and sensitivity, remarkable large Stokes shift (181 nm), Red-emitting/NIR fluorescence region and low LOD value (80 nM, according to 3sigma/s). Moreover, this novel Red-emitting/NIR probe can potentially be applied to the detection of thiophenols in real water samples quantitatively and fluorescent imaging in living cells and zebrafishes. PMID- 30466035 TI - Corrigendum to "Detection of adulterants in dietary supplements with Ginkgo biloba extract by attenuated total reflectance Fourier transform infrared spectroscopy and multivariate methods PLS-DA and PCA" [Spectrochim. Acta A Mol. Biomol. Spectrosc. 208 (2019) 222-228]. PMID- 30466036 TI - Psychological adjustment of young subjects with Mobius sequence and their primary caregivers' strain and life satisfaction: First longitudinal data. AB - AIMS/METHODS: At present, there is no information about the course of psychological adjustment in young subjects with Mobius sequence (MS) and their parents' strain and life satisfaction. To fill this gap, we performed a four-year follow-up study. Parents were anonymously asked to fill out the Child Behavior Checklist 4-18 [CBCL/ 4-18] or the Young Adult Behavior Checklist 18-30 [YABCL/ 18-30] and the Freiburger Personality Inventory-Revised [FPI-R], subscales strain and life satisfaction. RESULTS: 12 males and 14 females (mean: 15.20 years, standard deviation: 3.48 years) could be included in the follow-up (response rate: 83.9%).Compared to the general population, subjects with MS showed significantly higher scores on almost all CBCL scales (exception: externalizing problems) at T1 and T2. At both study times, parental strain and life satisfaction were not significantly different from findings in the general population. No significant longitudinal changes could be found for CBLC scales, parental strain and life satisfaction. CONCLUSIONS: Problems with psychological adjustment seem to be frequent among younger subjects with MS. Therefore, careful monitoring as well as early and adequate interventions, if indicated, are crucial for subjects with MS, not only with regard to somatic complaints but also to aspects of adjustment. PMID- 30466037 TI - Posterior bi-parietal decompressive craniectomy in refractory intracranial hypertension secondary to civilian gunshot wound. Case report and review of literature. AB - BACKGROUND: Decompressive craniectomy is recommended as second tier therapy for unresponsive intracranial hypertension in Traumatic Brain Injury. There have been reports of a Bi-Occipital craniectomy in cases where the focal injury is posterior. CASE DESCRIPTION: The work has been reported in line with the SCARE criteria. There is a 56-year-old male with Traumatic brain injury secondary to gunshot and intracranial hypertension, managed with biparietal craniectomy, after place a intracranial pressure monitor, whit good response to surgical and medical treatment, even with good outcome after hospitalization. CONCLUSIONS: In selected cases a posterior bi-parietal craniectomy can be performed in a safe way with acceptable results to treat refractory Intracranial hypertension. We propose that this neurosurgical technique can be used in patients with posterior focal injuries. PMID- 30466038 TI - A case report: Feasibility of a near infrared ray vision system (Photo dynamic eye(r)) for the postoperative ischemic complication of gallbladder carcinoma. AB - INTRODUCTION: Radical resection with or without preserving extra-hepatic bile duct has shown similar prognoses for gallbladder carcinoma (GB ca), although aggressive resection is essential. In preserving bile duct, ischemic complications are serious, life-threatening serious problems. Correct evaluation of the blood flow to the biliary tract is crucial. CASE PRESENTATION: A case of gallbladder ca in a 62-year-old man was reported. The patient was diagnosed with stage II GB ca (T2, N0, M0) by ultrasonography, computed tomography, magnetic resonance imaging, and endoscopic ultrasonography. Cholecystectomy and intraoperative frozen section examination were planned. After recognition of invasion to subserosa and negative cystic duct margin, radical dissection of the lymph nodes in the hepatoduodenal ligament with preserving biliary tract was performed. Three days after the operation, biliary peritonitis was revealed. Emergency laparotomy showed ischemic bile leakage. Proper blood flow of the biliary system was realized by a near-infrared ray vision system (Photo Dynamic Eye(r): HAMAMATSU Photonics) using indocyanine green. Primary suture of the extra hepatic biliary duct and T-tube drainage were selected. No stricture of the bile system nor recurrence was recognized for two years after surgery. DISCUSSION: In the case of ischemic biliary complications, whether to preserve the extrahepatic bile duct is a critical issue for the surgeons. In this case study, the feasibility of authentic indocyanine green near-infrared imaging was shown for postoperative ischemic biliary situations. CONCLUSIONS: Authentic indocyanine green near-infrared imaging was feasible for the estimation of the blood flow to the postoperative ischemic biliary complication. PMID- 30466039 TI - Implementing a competency-based midwifery programme in Lesotho: A gap analysis. AB - Global reforms in health professions education, including midwifery, support the transformation of education programmes to adopt competency-based models. Lesotho, a small sub-Saharan African country, with perennially high maternal and neonatal mortality, adopted a competency-based education model in the design and subsequent implementation of a one-year post-basic midwifery programme. Through a gap analysis involving administrators, educators and students in all the nursing education institutions in Lesotho, we explored their experiences related to the implementation of a competency-based midwifery programme after three years of continuous implementation. The findings revealed a vast gap between the described curriculum, and what was enacted in the nursing education institutions. The essential components of the midwifery programme had not been transformed to accommodate competency-based education. We argue that structural and operational elements of a programme should be adjusted before and during the implementation of such a curriculum innovation to enhance a positive teaching and learning experience, further sustaining the programme. Therefore, contextually relevant frameworks aimed at supporting the implementation and sustainability of the entire programme should be developed. PMID- 30466040 TI - Randomized controlled trial of telephone monitoring with psychiatry inpatients with co-occurring substance use and mental health disorders. AB - Background Psychiatry inpatients frequently have co-occurring substance use and mental health disorders, which are related to poor post-discharge outcomes. Telephone monitoring is effective in specialty substance use disorder treatment settings in increasing continuing care and 12-step program utilization and improving substance use outcomes. This study examined the effectiveness of telephone monitoring among psychiatry inpatients with co-occurring substance use and mental health disorders. Methods This randomized controlled trial (n = 406) compared usual care to usual care plus telephone monitoring (one in-person session during the inpatient stay, followed by weekly telephone contact for three months post-discharge). Follow-ups were conducted at end-of-intervention (three months post-baseline) and nine and 15 months post-baseline (73% followed). Primary outcomes were number of days out of the past 30 of drinking alcohol, using drugs, and experiencing psychological problems. Secondary outcomes were outpatient substance use treatment, and 12-step group, utilization. Results Longitudinal modeling found that patients in both conditions improved over time on each primary outcome. Improvement was comparable between conditions on alcohol and drug use and psychological problems. Receipt of outpatient treatment decreased over the follow-up period and was not related to condition. Likelihood of attending 12-step group meetings did not change over follow-ups, and was not related to condition. Conclusions Improvement over time was evident regardless of condition assignment. Patients maintained attendance at 12-step groups from pre- to post-discharge. Short-term telephone monitoring in addition to usual care for patients with co-occurring substance use and mental health disorders may not be sufficiently intensive to achieve additional improvements on outcomes. PMID- 30466041 TI - Comparison of age of first drink and age of first intoxication as predictors of substance use and mental health problems in adulthood. AB - BACKGROUND: International public policy on age of first alcoholic drink (AFD) has emphasised the long-term benefits of delaying AFD. This study aimed to compare AFD to age of first intoxication (AFI) as predictors of substance use disorder and mental disorder outcomes in adulthood. METHODS: Data were obtained from a longitudinal birth cohort in Christchurch, New Zealand. Participants were born in 1977. Analysis samples ranged from n = 1025 (age 18) to n = 962 (age 35). Measures of AFD and AFI were generated using parental- and self-report data collected from age 11. Outcomes at age 18-35 were alcohol quantity consumed, DSM IV alcohol use disorder (AUD) and AUD symptoms, major depression, anxiety disorder, and nicotine, cannabis, and other illicit drug dependence. Covariate factors measured during childhood included family socioeconomic status, family functioning, parental alcohol-related attitudes/behaviours, and individual factors. RESULTS: There was a significant unadjusted association between AFD and symptoms of AUD (p < .001) and nicotine dependence (p < .05) but not other outcomes. AFI was significantly (p < .05) associated with all outcomes. After adjustment for covariates, the association between AFD and outcomes was not statistically significant. Conversely, in adjusted models, statistically significant (p < .05) associations remained between AFI and all AUD and substance use disorder outcomes but not alcohol consumption or mental disorder outcomes. CONCLUSIONS: AFI was a more robust predictor of adult substance use disorder outcomes than AFD. Public health and policy interventions aimed at prevention of long term harms from alcohol should therefore focus on AFI rather than AFD. PMID- 30466042 TI - Calcium interactions with Cx26 hemmichannel: Spatial association between MD simulations biding sites and variant pathogenicity. AB - Connexinophaties are a collective of diseases related to connexin channels and hemichannels. In particular many Cx26 alterations are strongly associated to human deafness. Calcium plays an important role on this structures regulation. Here, using calcium as a probe, extensive atomistic Molecular Dynamics simulations were performed on the Cx26 hemichannel embedded in a lipid bilayer. Exploring different initial conditions and calcium concentration, simulation reached ~4 MUs. Several analysis were carried out in order to reveal the calcium distribution and localization, such as electron density profiles, density maps and distance time evolution, which is directly associated to the interaction energy. Specific amino acid interactions with calcium and their stability were capture within this context. Few of these sites such as, GLU42, GLU47, GLY45 and ASP50, were already suggested in the literature. Besides, we identified novel calcium biding sites: ASP2, ASP117, ASP159, GLU114, GLU119, GLU120 and VAL226. To the best of our knowledge, this is the first time that these sites are reported within this context. Furthermore, since various pathologies involving the Cx26 hemichannel are associated with pathogenic variants in the corresponding CJB2 gene, using ClinVar, we were able to spatially associate the 3D positions of the identified calcium binding sites within the framework of this work with reported pathogenic variants in the CJB2 gene. This study presents a first step on finding associations between molecular features and pathological variants of the Cx26 hemichannel. PMID- 30466043 TI - Mutations and functional analysis of 14-3-3 stress response protein from Triticum aestivum: An evolutionary analysis through in silico structural biochemistry approach. AB - Wheat (Triticum aestivum), having high nutritional values is one of the staple food of most of the countries in the world. The productivity of the crop decreases drastically when it encounters various abiotic stresses, most common of which are heat, drought, flood and salinity. There is a crucial role of stress response proteins for the survival of the crops in stress conditions. So the study of wheat stress response proteins is of great importance to raise wheat production in different stress conditions. In this study, we analysed 14-3-3 protein, a stress response protein that is expressed in three major stresses, for example heat, drought and salinity and helps the plants to survive in those conditions. Effect of mutations in the 14-3-3 sequence was predicted using its domain, secondary structure and multiple sequence alignment of amino acid sequences from wheat and its related species. The functional diversity of the protein in different species was correlated with mutations, change in secondary structure and the evolutionary relatedness of the protein in different species. This is the first novel work for analysing the mutational effect on the structure and function of a stress response protein (14-3-3) from Triticum aestivum and its related species. PMID- 30466044 TI - Ant colony optimization with an automatic adjustment mechanism for detecting epistatic interactions. AB - Single Nucleotide polymorphisms (SNPs) are usually used as biomarkers for research and analysis of genome-wide association study (GWAS). Moreover, the epistatic interaction of SNPs is an important factor in determining the susceptibility of individuals to complex diseases. Nowadays, the detection of epistatic interactions not only attracts attention of many researchers but also brings new challenges. It is of great significance to mine epistatic interactions from large-scale data for the combinatorial explosion problem of loci. Hence, it is necessary to improve an efficient algorithm for solving the problem. In this article, a novel ant colony optimization based on automatic adjustment mechanism (AA-ACO) is proposed. The mechanism automatically adjusts the behaviour of artificial ants according to the real-time feedback information so that the algorithm can run at its best. This study also compares AA-ACO with ACO, AntEpiSeeker, AntMiner, MACOED and epiACO in a set of simulated data sets and a real genome-wide data. As shown by the experimental results, the proposed algorithm is superior to the other algorithms. PMID- 30466045 TI - Schistosomiasis: Snail-vector control, molecular modelling and dynamic studies of bioactive N-acetylglycoside saponins from Tetrapleura tetraptera. AB - Schistosomiasis, a chronic neglected tropical disease caused by the Schistosoma spp. parasite, is associated with disabling patient symptoms. The new focus of the WHO roadmap on 'transmission control, wherever possible' offers drug development opportunities for intermediate-host control to prevent human-to-snail to-human parasite transmission. Reports on the analysis of the impact of 'chemical-based mollusciciding' have concluded that constant application of molluscicides may contribute significantly towards the elimination of schistosomiasis in endemic areas. In South-Western Nigeria, Tetrapleura tetraptera is a tree whose fruit has been widely used in snail vector control. The presence of molluscicidal N-acetyl triterpene glycosides in the fruit has been reported. In this study, a bioactivity-directed fractionation of the fruit extract was performed to isolate the most potent molluscicidal saponin from the fruit. In an attempt to provide mechanistic insight into the observed activity, in silico screening was performed, profiling the molluscicidal N-acetyl triterpene glycosides reported from the fruit against two potential therapeutic targets in the mollusk used, NADH-ubiquinone oxidoreductase (NAD1) and retinoid X receptor. The docking predicted binary complexes of the saponins, which were subjected to explicit solvent conformational sampling from which patterns of structural stability were obtained. The binding energies alone did not account for the potency of the saponins indicating the influence of other factor like pharmacokinetic parameters. The study concluded that there is a preferential suitability of ND1's MWFE site for the rational design and development of novel molluscicidal agents. PMID- 30466046 TI - Intrinsic-overlapping co-expression module detection with application to Alzheimer's Disease. AB - Genes interact with each other and may cause perturbation in the molecular pathways leading to complex diseases. Often, instead of any single gene, a subset of genes interact, forming a network, to share common biological functions. Such a subnetwork is called a functional module or motif. Identifying such modules and central key genes in them, that may be responsible for a disease, may help design patient-specific drugs. In this study, we consider the neurodegenerative Alzheimer's Disease (AD) and identify potentially responsible genes from functional motif analysis. We start from the hypothesis that central genes in genetic modules are more relevant to a disease that is under investigation and identify hub genes from the modules as potential marker genes. Motifs or modules are often non-exclusive or overlapping in nature. Moreover, they sometimes show intrinsic or hierarchical distributions with overlapping functional roles. To the best of our knowledge, no prior work handles both the situations in an integrated way. We propose a non-exclusive clustering approach, CluViaN (Clustering Via Network) that can detect intrinsic as well as overlapping modules from gene co expression networks constructed using microarray expression profiles. We compare our method with existing methods to evaluate the quality of modules extracted. CluViaN reports the presence of intrinsic and overlapping motifs in different species not reported by any other research. We further apply our method to extract significant AD specific modules using CluViaN and rank them based the number of genes from a module involved in the disease pathways. Finally, top central genes are identified by topological analysis of the modules. We use two different AD phenotype data for experimentation. We observe that central genes, namely PSEN1, APP, NDUFB2, NDUFA1, UQCR10, PPP3R1 and a few more, play significant roles in the AD. Interestingly, our experiments also find a hub gene, PML, which has recently been reported to play a role in plasticity, circadian rhythms and the response to proteins which can cause neurodegenerative disorders. MUC4, another hub gene that we find experimentally is yet to be investigated for its potential role in AD. A software implementation of CluViaN in Java is available for download at https://sites.google.com/site/swarupnehu/publications/resources/CluViaN Software.rar. PMID- 30466047 TI - Bio-inspired hollow PDMS sponge for enhanced oil-water separation. AB - Oil spills from disasters such as the sinking of ships and the discharge of oily wastes cause serious environmental problems. Polydimethylsiloxane(PDMS) sponges are valuable tools for isolating spilled oil. Here, we propose new PDMS sponges with bio-inspired design and enhanced absorption capacities. 3D printing was used to produce templates having negative designs, and after being filled with PDMS, the templates were selectively dissolved. Through this, PDMS sponges with well interconnected and controlled porosities were produced within 10% error. The wettability of sponges with various pore sizes and line widths was investigated. The surfaces were found to be highly hydrophobic, with water contact angles of 100-143 degrees , and oleophilic, with oil contact angles of ~0 degrees . The sponge fabricated with line width of 200 MUm and pore size of 400 MUm showed the highest hydrophobicity and oleophilicity. These parameters were used to produce the surfaces of hollow sponges having bio-inspired design that mimics the water absorption and storage functions of cactus. Repeated oil-water separation testing was conducted, and the absorption capacities were compared with those of non hollow and conventional sponges. The new design showed absorption capacity up to 3.7 times that of the sponges. The bio-inspired PDMS sponge provides a significant advance in oil-water separation ability. PMID- 30466048 TI - Nationwide reconnaissance of five parabens, triclosan, triclocarban and its transformation products in sewage sludge from China. AB - China's rapid growth of both population size and sanitation infrastructure have created a heightened need for responsible management of sewage sludge. We applied liquid chromatography in conjunction with isotope dilution tandem mass spectrometry to measure multiple endocrine disrupting antimicrobials and their transformation products in 100 sewage sludge samples collected across 21 Chinese provinces/districts. Occurrences (detection frequencies) and concentrations (ng/g dry weight) were as follows: triclosan (99%; <4-4870), triclocarban (95%; <3 43,300), 2'-hydroxy-triclocarban (94%; <1-2340), 3'-hydroxy-triclocarban (91%; <1 1250), 3,3',4,4'-tetrachlorocarbanilide (100%; 22-580), dichlorocarbanilide (94%; <2-23,890), monocarbanilide (92%; <2-120), carbanilide (90%; <3-1,340), and five parabens: methyl- (98%; <2-630), ethyl- (96%; <2-170), propyl- (99%; <2-27), butyl- (89%; <2-11) and benzyl-paraben (7%; <2-12). The transformation products of triclocarban were measured for the first time in Chinese wastewater system, and ratios of transformation products to parental triclocarban indicate ongoing triclocarban dechlorination during wastewater treatment. Contaminant profiles and concentrations differed by region, treatment capacity, and wastewater type. Extrapolation of collected data yielded an estimate for the total mass of 13 analytes sequestered in Chinese sewage sludge of 68 t/y with an upper bound of 400 t/y. This China-wide survey established baseline levels of selected antimicrobials in sludges whose current disposal is performed with little regulatory oversight and enforcement. PMID- 30466049 TI - Mechanistic reaction model for oxidation of sulfur mustard simulant by a catalytic system of nitrate and tribromide. AB - A new metal-free catalytic reaction system is developed to selectively oxidize 2 chloroethyl ethyl sulfide (CEES), a surrogate of sulfur mustard. The combination of two catalytic precursors, tribromide and nitrate, allows a rapid sulfoxidation of CEES even at ambient conditions. The kinetic behaviours at various reaction conditions are investigated to identify the most probable reaction pathways of the development of catalytic loop and the overall reaction steps of CEES sulfoxidation. The mechanistic study demonstrates that the catalytic loop does not require an addition of mineral acid or water, which is common in most other reaction systems. Incomplete catalytic systems with one precursor are also examined to uncover the complex network of sulfoxidation in the catalytic reaction system. The results reveal that the complex between CEES and bromine is a reactive intermediate, bromosulfonium, which can be further catalysed and converted into sulfoxide by nitrate. Based on the proposed reaction mechanism, a predictive kinetic model fully describing most reaction behaviours is developed. PMID- 30466050 TI - How cells exploit tubulin diversity to build functional cellular microtubule mosaics. AB - Cellular microtubules are mosaic polymers assembled from multiple alphabeta tubulin isoforms bearing chemically diverse posttranslational modifications. This tubulin diversity constitutes a combinatorial code that regulates microtubule interactions with cellular effectors and alters their intrinsic dynamic and mechanical properties. Cells generate stereotyped and complex tubulin modification patterns that are important for their specialized functions. Here we give a brief overview of the tubulin genetic and chemical diversity and highlight recent advances in our understanding of how the tubulin code regulates essential biological processes ranging from intracellular cargo transport, to cell division and cardiomyocyte contraction. Finally, we speculate on the molecular mechanisms for the generation and maintenance of the complex stereotyped modification patterns that form cellular microtubule mosaics. PMID- 30466051 TI - Auto-cleaning paper-based electrochemiluminescence biosensor coupled with binary catalysis of cubic Cu2O-Au and polyethyleneimine for quantification of Ni2+ and Hg2. AB - Inspired by the pop-up greeting cards, a 3D collapsible auto-cleaning paper-based electrochemiluminescence (ECL) biosensor (CAPEB) with different functions of signal collection and residual multiple cleaning, is developed for sensitive detection of Ni2+ and Hg2+ by simply regulating its 3D configurations. The multiple fluidic paths and the hollow-channel structure were firstly integrated into the paper substrate, realizing simultaneously repetitive auto-cleaning of the two working electrodes. For achieving ultrasensitive Ni2+ and Hg2+ monitoring, binary catalysis consisting of the intermolecular co-reaction (H2O2 and N-(4-Aminobutyl)-N-ethylisoluminol (ABEI)) and intramolecular catalysis (polyethyleneimine (PEI)-ABEI) w a s introduced. Specifically, silver nanospheres with a large specific surface area and excellent conductivity were grown on the paper working electrode and served as the sensor substrate for fixing PEI-ABEI and Ni2+-specific DNAzyme. With the assistance of DNAzyme, Cu2O-Au and ferrocene (Fc) labeled strand S2 were immobilized on electrode surface through the hybridization reaction, and catalyzed H2O2 to generate reactive oxygen species, promoting the luminescence of ABEI. In the existence of Ni2+, DNAzyme was activated followed by cleavage of strand S2 to induce the release of Fc, which quenched the ECL signal of ABEI, eventually realizing the detection of Ni2+. Similarly, for sensitive quantification of Hg2+, full thymine (T) bases strand S3 was modified on surface of Cu2O-Au and anchored Hg2+ by T-Hg2+-T pairing interaction. The ECL intensity was decreased along with increasing of Hg2+ due to the quenching effect of Hg2+ on ECL emission of ABEI. Based on this ingenious system, the detection of Ni2+ and Hg2+ had high sensitivity, wide linear ranges, and low detection limits. The results indicated that the integration of a multi channel structure into a paper device chips opened new opportunities for designing promising paper-based devices for metal ions diagnosis. PMID- 30466052 TI - Origami multiple paper-based electrochemical biosensors for pesticide detection. AB - Herein, we propose the first three-dimensional origami paper-based device for the detection of several classes of pesticides by combining different enzyme inhibition biosensors. This device was developed by integrating two different office paper-based screen-printed electrodes and multiple filter paper-based pads to load enzymes and enzymatic substrates. The versatile analysis of different pesticides was carried by folding and unfolding the filter paper-based structure, without any addition of reagents and any sample treatment (i.e. dilution, filtration, pH adjustment). The paper-based platform was employed to detect paraoxon, 2,4-dichlorophenoxyacetic acid, and atrazine by exploiting the capability of these different types of pesticides (i.e. organophosphorus insecticides, phenoxy-acid herbicides, and triazine herbicide) to inhibit butyrylcholinesterase, alkaline phosphatase, and tyrosinase, respectively. The degree of inhibition correlating to the quantity of pesticides was evaluated by chronoamperometrically monitoring the enzymatic activity in the absence and in the presence of pesticides by using a portable potentiostat. To improve the sensitivity, the paper-based electrodes were modified with carbon black alone in the case of platforms for 2,4-dichlorophenoxyacetic acid and atrazine detection, or decorated with Prussian blue nanoparticles for the detection of paraoxon. The paper-based device was applied for the detection of paraoxon, 2,4 dichlorophenoxyacetic acid, and atrazine at ppb level in both standard solutions and river water sample. The accuracy of this origami multiple paper-based electrochemical biosensor was evaluated in river water by recovery studies, obtaining satisfactory values (e.g. for paraoxon 90 +/- 1% and 88 +/- 2%, for 10 and 20 ppb, respectively). The proposed three-dimensional origami paper device allows for rapid, cost-effective and accurate pesticide detection in surface water as a result of combining filter and office papers, screen-printing, wax printing and nanomaterial technology. PMID- 30466053 TI - SiNAPS: An implantable active pixel sensor CMOS-probe for simultaneous large scale neural recordings. AB - Large-scale neural recordings with high spatial and temporal accuracy are instrumental to understand how the brain works. To this end, it is of key importance to develop probes that can be conveniently scaled up to a high number of recording channels. Despite recent achievements in complementary metal-oxide semiconductor (CMOS) multi-electrode arrays probes, in current circuit architectures an increase in the number of simultaneously recording channels would significantly increase the total chip area. A promising approach for overcoming this scaling issue consists in the use of the modular Active Pixel Sensor (APS) concept, in which a small front-end circuit is located beneath each electrode. However, this approach imposes challenging constraints on the area of the in-pixel circuit, power consumption and noise. Here, we present an APS CMOS probe technology for Simultaneous Neural recording that successfully addresses all these issues for whole-array read-outs at 25 kHz/channel from up to 1024 electrode-pixels. To assess the circuit performances, we realized in a 0.18 MUm CMOS technology an implantable single-shaft probe with a regular array of 512 electrode-pixels with a pitch of 28 MUm. Extensive bench tests showed an in-pixel gain of 45.4 +/- 0.4 dB (low pass, F-3 dB = 4 kHz), an input referred noise of 7.5 +/- 0.67 MUVRMS (300 Hz to 7.5 kHz) and a power consumption <6 MUW/pixel. In vivo acute recordings demonstrate that our SiNAPS CMOS-probe can sample full-band bioelectrical signals from each electrode, with the ability to resolve and discriminate activity from several packed neurons both at the spatial and temporal scale. These results pave the way to new generations of compact and scalable active single/multi-shaft brain recording systems. PMID- 30466054 TI - The effect of varying the number of contributors in the prosecution and alternate propositions. AB - Using a simplified model, we examine the effect of varying the number of contributors in the prosecution and alternate propositions for a number of simulated examples. We compare the Slooten and Caliebe [1] solution, with several existing practices. Our own experience is that most laboratories, and ourselves, assign the number of contributors, N = n, by allele count and a manual examination of peak heights. The LRn for one or a very few values is calculated and typically one of these is presented, usually the most conservative. This gives an acceptable approximation. Reassessing the number of contributors if LR = 0 and adding one to N under both Hp and Ha to "fit" the POI may lead to a substantial overstatement of the LR. A more reasonable option is to allow optimisation of the assignment under Hp and Ha separately. We show that an additional contributor explained the single locus profile better when PHR>=0.51. This is pleasingly in line with current interpretation approaches. Collectively these trials, and the solid theoretical development, suggest that the Slooten and Caliebe approach preforms well. PMID- 30466055 TI - Postpartum obsessive-compulsive symptoms in a case of peripartum-onset depression and infanticide. PMID- 30466056 TI - Do comorbidities among patients with mental retardation differ across various age groups? AB - Distribution of comorbidities in patients with mental retardation or intellectual disabilities (MR/ID) across various age groups is not recognized adequately. Data from 426 patients diagnosed with MR/ID was collected out of 546 samples referred for intelligence assessment. 42.3% had psychiatric comorbidities. The prevalence ratio of psychiatric comorbidity associated with MR/ID was 2.11. Frequency of comorbidities in the order of occurrence was "behavioral impairment > Epilepsy > autism/ADHD" for age-groups 10years and below, and "behavioral impairment > Epilepsy > depression/anxiety" for age-groups 11years and above. We conclude that irrespective of age distribution, behavioral impairment followed by epilepsy are found to be the most common comorbidities. PMID- 30466057 TI - A case of autoimmune autonomic ganglionopathy with prolonged delirium. AB - Autoimmune autonomic ganglionopathy (AAG) is a rare acquired immune-mediated disorder that leads to autonomic failure. It is sometimes complicated by mental and behavioral symptoms. We report a case of 72-year-old male with AAG who was admitted to the psychiatric department for prolonged severe delirium. Repeated loss of consciousness attributed to severe orthostatic hypotension disturbed recovery from delirium. In addition, intracerebral hemorrhage occurred during hospitalization, and this cerebrovascular event may have been substantially affected by unstable blood pressure due to AAG. This case suggests importance of differential diagnosis of AAG in patients with mental and behavioral symptoms accompanying severe autonomic failure. PMID- 30466058 TI - Decomposition of dissolved organic contaminants by combining a boron-doped diamond electrode, zero-valent iron and ultraviolet radiation. AB - This study presents the results of a research project dealing with the degradation of dissolved tetrachloroethene, MTBE and clopyralid by using a boron doped diamond electrode, zero-valent iron in a fluidized bed reactor and ultraviolet radiation. These treatment methods were tested alone, in any combination of two as well as in combination of all three of them to identify emerging synergy effects. Additionally, the influence of adding H2O2 or H2O2 + H2SO4 is investigated. The experiments revealed that the treatment methods alone were able to decrease the organic contaminant concentrations, yet, the decomposition rate was not very sufficient. Applying the BDD yielded the highest decomposition rates, however, this degradation was accompanied by metabolite production. By combining two methods and adding H2O2, the decomposition was enhanced significantly for any combination. These removal rates were further increased by using the combination of the three treatment methods and adding H2O2 or H2O2 + H2SO4. These high removal rates were not achieved by solely using the combination of the three methods without further addition of chemicals. This research demonstrates the potential, but also the limitations of the investigated system. PMID- 30466059 TI - Exposure to aflatoxin B1 interferes with locomotion and neural development in zebrafish embryos and larvae. AB - Aflatoxin B1 (AFB1) is the major mycotoxin that contaminates aquafeeds and regarded as a causative agent in illnesses and the mortality of aquacultural species. However, the effects of AFB1 on developing fish and associated toxic mechanism are still unknown. This study examines the behavioral changes, neuronal morphology and gene expression in zebrafish embryos and larvae upon exposure to aflatoxin solutions. Treatment of 6 h post fertilization (hpf) embryos with AFB1 at 15-75 ng/mL significantly changed the swimming patterns of seven days post fertilization (dpf) zebrafish larvae. Larvae in the 15 ng/mL group demonstrated a hypolocomotor activity in free swimming, but hyperlocomotion was observed in the larvae exposed to 30-75 ng/mL AFB1. AFB1 at 75 ng/mL also significantly reduced the startle response of 7 dpf larvae after tapping stimulus. Exposure to AFB1 resulted in an aberrant morphology of trigeminal ganglion and hindbrain neurons in transgenic embryos (HuC:eGFP); this finding was supported by acetylated alpha tubulin staining in wild-type fish. Additionally, AFB1 altered the levels of neurotoxic markers, including gfap and huC. The transcriptomic profile of AFB1 treated embryos revealed several differentially expressed genes that are related to neuroactivity and neurogenesis. PCR analysis verified that AFB1 significantly down-regulated the expression of ngfa and atp1b1b genes and increased that of prtga gene. The results herein indicate the toxicological impacts of AFB1 on the behaviors and neurodevelopment of fish in the early embryonic stage. Disruption of neural formation and synapse dysfunction may be responsible for the behavioral alteration. PMID- 30466060 TI - A novel role for NUPR1 in the keratinocyte stress response to UV oxidized phospholipids. AB - Ultraviolet light is the dominant environmental oxidative skin stressor and a major skin aging factor. We studied which oxidized phospholipid (OxPL) mediators would be generated in primary human keratinocytes (KC) upon exposure to ultraviolet A light (UVA) and investigated the contribution of OxPL to UVA responses. Mass spectrometric analysis immediately or 24 h post UV stress revealed significant changes in abundance of 173 and 84 lipid species, respectively. We identified known and novel lipid species including known bioactive and also potentially reactive carbonyl containing species. We found indication for selective metabolism and degradation of selected reactive lipids. Exposure to both UVA and to in vitro UVA - oxidized phospholipids activated, on transcriptome and proteome level, NRF2/antioxidant response signaling, lipid metabolizing enzyme expression and unfolded protein response (UPR) signaling. We identified NUPR1 as an upstream regulator of UVA/OxPL transcriptional stress responses and found this protein to be expressed in the epidermis. Silencing of NUPR1 resulted in augmented expression of antioxidant and lipid detoxification genes and disturbed the cell cycle, making it a potential key factor in skin reactive oxygen species (ROS) responses intimately involved in aging and pathology. PMID- 30466062 TI - High-Resolution Plasma Membrane-Selective Imaging by Second Harmonic Generation. AB - The plasma membrane is the site of intercellular communication and subsequent intracellular signal transduction. The specific visualization of the plasma membrane in living cells, however, is difficult using fluorescence-based techniques owing to the high background signals from intracellular organelles. In this study, we show that second harmonic generation (SHG) is a high-resolution plasma membrane-selective imaging technique that enables multifaceted investigations of the plasma membrane. In contrast to fluorescence imaging, SHG specifically visualizes the plasma membrane at locations that are not attached to artificial substrates and allows high-resolution imaging because of its subresolution nature. These properties were exploited to measure the distances from the plasma membrane to subcortical actin and tubulin fibers, revealing the precise cytoskeletal organization beneath the plasma membrane. Thus, SHG imaging enables the specific visualization of phenomena at the plasma membrane with unprecedented precision and versatility and should facilitate cell biology research focused on the plasma membrane. PMID- 30466061 TI - Mitochondria can act as energy-sensing regulators of hydrogen peroxide availability. AB - Mitochondria are widely recognized as sources of reactive oxygen species in animal cells, with H2O2 being of particular note because it can act not only in oxidative stress but also is important to several signalling pathways. Lesser recognized is that mitochondria can have far greater capacity to consume H2O2 than to produce it; however, the consumption of H2O2 may be kinetically constrained by H2O2 availability especially at the low nanomolar (or lower) concentrations that occur in vivo. The production of H2O2 is a function of many factors, not the least of which are respiratory substrate availability and the protonmotive force (Deltap). The Deltap, which is predominantly membrane potential (DeltaPsi), can be a strong indicator of mitochondrial energy status, particularly if respiratory substrate supply is either not meeting or exceeding demand. The notion that mitochondria may functionally act in regulating H2O2 concentrations may be somewhat implicit but little evidence demonstrating this is available. Here we demonstrate key assumptions that are required for mitochondria to act as regulators of H2O2 by an integrated system of production and concomitant consumption. In particular we show the steady-state level of H2O2 mitochondria approach is a function of both mitochondrial H2O2 consumption and production capacity, the latter of which is strongly influenced by DeltaPsi. Our results are consistent with mitochondria being able to manipulate extramitochondrial H2O2 as a means of signalling mitochondrial energetic status, in particular the Deltap or DeltaPsi. Such a redox-based signal could operate with some independence from other energy sensing mechanisms such as those that transmit information using the cytosolic adenylate pool. PMID- 30466063 TI - A Proteomics Approach to Profiling the Temporal Translational Response to Stress and Growth. AB - To quantify dynamic protein synthesis rates, we developed MITNCAT, a method combining multiplexed isobaric mass tagging with pulsed SILAC (pSILAC) and bio orthogonal non-canonical amino acid tagging (BONCAT) to label newly synthesized proteins with azidohomoalanine (Aha), thus enabling high temporal resolution across multiple conditions in a single analysis. MITNCAT quantification of protein synthesis rates following induction of the unfolded protein response revealed global down-regulation of protein synthesis, with stronger down regulation of glycolytic and protein synthesis machinery proteins, but up regulation of several key chaperones. Waves of temporally distinct protein synthesis were observed in response to epidermal growth factor, with altered synthesis detectable in the first 15 min. Comparison of protein synthesis with mRNA sequencing and ribosome footprinting distinguished protein synthesis driven by increased transcription versus increased translational efficiency. Temporal delays between ribosome occupancy and protein synthesis were observed and found to correlate with altered codon usage in significantly delayed proteins. PMID- 30466065 TI - Single-Cell ID-seq Reveals Dynamic BMP Pathway Activation Upstream of the MAF/MAFB-Program in Epidermal Differentiation. AB - Epidermal homeostasis requires balanced and coordinated adult stem cell renewal and differentiation. These processes are controlled by both extracellular signaling and by cell intrinsic transcription regulatory networks, yet how these control mechanisms are integrated to achieve this is unclear. Here, we developed single-cell Immuno-Detection by sequencing (scID-seq) and simultaneously measured 69 proteins (including 34 phosphorylated epitopes) at single-cell resolution to study the activation state of signaling pathways during human epidermal differentiation. Computational pseudo-timing inference revealed dynamic activation of the JAK-STAT, WNT, and BMP pathways along the epidermal differentiation trajectory. We found that during differentiation, cells start producing BMP2-ligands and activate the canonical intracellular effectors SMAD1/5/9. Mechanistically, the BMP pathway is responsible for activating the MAF/MAFB/ZNF750 transcription factor network to drive late-stage epidermal differentiation. Our work indicates that incorporating signaling pathway activation into this transcription regulatory network enables coordination of transcription programs during epidermal differentiation. PMID- 30466064 TI - PAQR3 Regulates Endoplasmic Reticulum-to-Golgi Trafficking of COPII Vesicle via Interaction with Sec13/Sec31 Coat Proteins. AB - Endoplasmic reticulum (ER)-to-Golgi anterograde transport is driven by COPII vesicles mainly composed of a Sec23/Sec24 inner shell and a Sec13/Sec31 outer cage. How COPII vesicles are tethered to the Golgi is not completely understood. We demonstrated here that PAQR3 can facilitate tethering of COPII vesicles to the Golgi. Proximity labeling using PAQR3 fused with APEX2 identified that many proteins involved in intracellular transport are in close proximity to PAQR3. ER to-Golgi trafficking of N-acetylgalactosaminyltransferase-2 on removal of brefeldin A is delayed by PAQR3 deletion. RUSH assay also revealed that ER-to Golgi trafficking is affected by PAQR3. The N-terminal end of PAQR3 can interact with the WD domains of Sec13 and Sec31A. PAQR3 enhances Golgi localization of Sec13 and Sec31A. Furthermore, PAQR3 is localized in the ERGIC and cis-Golgi structures, the acceptor sites for COPII vesicles. Taken together, our study uncovers a role for PAQR3 as a player in regulating ER-to-Golgi transport of COPII vesicles. PMID- 30466066 TI - Highly Selective 5-Formyluracil Labeling and Genome-wide Mapping Using (2 Benzimidazolyl)Acetonitrile Probe. AB - Chemical modifications to nucleobases have a great influence on various cellular processes, by making gene regulation more complex, thus indicating their profound impact on aspects of heredity, growth, and disease. Here, we provide the first genome-wide map of 5-formyluracil (5fU) in living tissues and evaluate the potential roles for 5fU in genomics. We show that an azido derivative of (2 benzimidazolyl)acetonitrile has high selectivity for enriching 5fU-containing genomic DNA. The results have demonstrated the feasibility of using this method to determine the genome-wide distribution of 5fU. Intriguingly, most 5fU sites were found in intergenic regions and introns. Also, distribution of 5fU in human thyroid carcinoma tissues is positively correlated with binding sites of POLR2A protein, which indicates that 5fU may distributed around POLR2A-binding sites. PMID- 30466067 TI - Cystine-thiamin-containing hair-growth formulation modulates the response to UV radiation in an in vitro model for growth-limiting conditions of human keratinocytes. AB - BACKGROUND: Ultraviolet radiation (UVR) is known to be harmful to normal human epidermal keratinocytes (NHEKs) of the epidermal skin layer, as well as to hair follicle-associated keratinocytes. An oral formulation containing l-cystine, thiamin, calcium d-pantothenate, medicinal yeast, keratin and p-aminobenzoic acid (Panto[vi]gar(r)) has demonstrated clinical efficacy for the treatment of diffuse telogen effluvium; however, its mode of action at the cellular level, and in particular whether protective mechanisms are involved, has yet to be elucidated. OBJECTIVES: To assess the capacity of ingredients of this oral formulation, both separately and in combination, to modulate the effects of UVR in growth-limited NHEKs in vitro. METHODS: NHEKs were incubated in keratinocyte basal medium, keratinocyte basal medium lacking cystine, thiamin, calcium d-pantothenate, folic acid and biotine (minimal growth medium [MGM]) or MGM plus test compound. Test compounds comprised the following four ingredients related to the oral formulation: l-cystine, thiamin, calcium d-pantothenate and folic acid (a proposed metabolite of p-aminobenzoic acid), and a combination of these (Panto[vi]gar(r)-in vitro correlate; P-IC). The effect of different doses of these compounds on the metabolic activity and proliferation of NHEKs was tested, as well as their influence on the impact of UV light on NHEKs assessed by monitoring metabolic activity, cell number and apoptosis induction. RESULTS: Compared with basal medium, MGM reduced the proliferation of NHEKs in a time dependent manner. Reduced proliferation is a characteristic of the multifactorial and complex phenotype associated with diffuse hair loss. l-cystine (50 MUM) increased metabolic activity and proliferation 3-fold versus MGM (p < 0.05). Thiamin also had a significant effect (p < 0.05) on proliferation and metabolic activity of NHEKs, but calcium d-pantothenate and folic acid did not when tested individually in this in vitro model. In the presence of P-IC, metabolic activity increased 4-fold and proliferation 3-fold compared with MGM alone (p < 0.05 for both). Following UV irradiation, cells in MGM showed a 72% reduction in metabolic activity, while P-IC-treated cells showed only a 12-18% reduction. The observed prevention of the UV-induced reduction in metabolic activity was not simply due to filtering UVR by the P-IC components, as P-IC-mediated reduction of this effect persisted even when P-IC was washed out during UV irradiation. CONCLUSION: This study demonstrated that l-cystine and thiamin are essential for proliferation of epidermal keratinocytes and suggests a novel, UV-protective potential of formulations combining l-cystine and thiamin in growth-limited inter follicular NHEKs in vitro. PMID- 30466068 TI - CO2-related vasoconstriction superimposed on ischemic medullary brain autonomic nuclei may contribute to sudden death. AB - INTRODUCTION: In 2015, a multinational randomized controlled phase IV clinical trial of adaptive servoventilation for the management of heart failure with central sleep apnea was halted in progress because more patients in the study group were dying than in the control group. One year later, another large clinical trial reported results on the effectiveness of continuous positive airway pressure (CPAP) in preventing sudden death and other cardiovascular events such as heart attack and stroke in patients with preexisting vascular disease as well as obstructive sleep apnea. BACKGROUND: Sudden unexpected death has been associated with many types of small and nonmalignant medullary brain lesions, like demyelination plaques - largely asymptomatic until they caused sudden death. Many such medullary lesions, typically without hemorrhage or mass effect, have in themselves been previously considered relatively harmless - in cases where they have been known to be present. DISCUSSION: Why did not the improved pulmonary ventilation and subsequently improved gas exchange provided during the CPAP and servoventilation clinical trials help to resolve any ischemic lesions that may have been present both in the heart and in the medulla, thereby tending to normalize interactions between the vagal neural structures and the heart? CO2 is a potent dilator of brain vasculature, thereby increasing blood flow to the brain. When ventilation is increased, even if only to improve it back toward normal from a depressed steady-state level, the alveolar partial pressure of carbon dioxide is decreased, likely resulting in a converse relative vasoconstriction in the brain, thereby reducing blood flow in the brain, especially in watershed areas like the solitary tract nucleus. In normal physiology, this is demonstrated impressively by the ability of hyperventilation to induce loss of consciousness. CONCLUSIONS: The findings of several clinical trials recently reported, taken together with neuropathology case studies reported elsewhere, suggest that additional research is warranted in regard to the mechanisms by which focal medullary autonomic brain ischemia may be related to sudden death in general medical illnesses - and how it may additionally be influenced by changes in arterial CO2 levels. PMID- 30466069 TI - Telomere shortening in alcohol dependence: Roles of alcohol and acetaldehyde. AB - Heavy drinking leads to premature aging and precipitates the onset of age-related diseases. Acetaldehyde (AcH), a toxic metabolite of ethanol, has been implicated in various types of cancer. However, whether alcohol accelerates biological aging at a cellular level is controversial and the mechanism involved is unclear. We addressed these questions by measuring telomere length (TL) in peripheral blood leukocytes of Japanese patients with alcohol dependence (AD) and examined the association between TL, genetic variants of alcohol dehydrogenase (ADH)1B and aldehyde dehydrogenase (ALDH)2, and other clinical characteristics. A total of 134 male AD patients and 121 age- and sex-matched healthy controls were evaluated. All patients received endoscopic screening for cancer of the upper aerodigestive tract (UADT). TL was almost 50% shorter in AD patients relative to controls. There were no significant differences in TL between AD patients with and without UADT cancer, and no associations between ADH1B and ALDH2 genotypes and TL. AD patients with thiamine (vitamin B1) deficiency at admission had significantly shorter TL than those with normal thiamine status. Although the exact mechanism underlying the shorter TL in AD patients remain unclear, our findings suggest that alcohol rather than AcH is associated with telomere shortening in AD, which may be accelerated by thiamine deficiency. Future studies should also focus on the association between telomere shortening and TD in the context of oxidative stress. PMID- 30466070 TI - Lupus anticoagulant identifies two distinct groups of patients with different antibody patterns. AB - BACKGROUND: Whether antibodies directed to beta2-Glycoprotein I (abeta2GPI) are responsible for LA activity is not well defined. However, in the absence of such antibodies the molecule responsible for LA phenomenon is unknown. OBJECTIVE: The aim of this study was the biochemical identification of the target antigen epitope of aPL responsible of LA activity in the absence of abeta2GPI antibodies together with the biological and clinical characteristics of these patients in comparison with classical triple positive patients. PATIENTS/METHODS: A comparison of patients with LA without (LA+/abeta2GPI-) and those with (LA+/abeta2GPI+) associated abeta2GPI antibodies was performed. Size exclusion chromatography and analytical chromatography were used to identify the molecule with LA activity in patients LA+/abeta2GPI-. RESULTS AND CONCLUSIONS: Analytical size-exclusion chromatography revealed a peak of 996Kd with LA activity perfectly overlapping that of IgM anti phosphatidylserine/prothrombin (aPS/PT) antibodies. Similarly, all the 25 LA+/abeta2GPI- patients were positive for aPS/PT antibodies. LA+/abeta2GPI- compared to 33 LA+/abeta2GPI+ patients turned out to be significantly older, with a lower rate of previous thromboembolic events and a weaker LA activity. Search for aPS/PT and abeta2GPI antibodies in patients with LA is useful to identify two subgroups of LA at different risk of thromboembolic events. PMID- 30466071 TI - Vital contribution of residential emissions to atmospheric fine particles (PM2.5) during the severe wintertime pollution episodes in Western China. AB - To mitigate severe wintertime pollution events in Western China, identifying the source of atmospheric fine particles with an aerodynamic diameter of <=2.5 MUm (PM2.5) is a crucial step. In this study, we first analyzed the meteorological and emission factors that caused a considerable increase in the PM2.5 concentration in December 2016. This severe pollution episode was found to be related with unfavorable meteorological conditions and increased residential emissions. The WRF-Chem simulations were used to calculate the residential contribution to PM2.5 through a hybrid source apportionment method. From the validation that used grid data and in situ observations in terms of meteorological elements, PM2.5 and its compounds, the simulated results indicated that the residential sector was the largest single contributor to the PM2.5 concentration (60.2%), because of its predominant contributions to black carbon (BC, 62.1%) and primary organic aerosol (POA, 86.5%), with these two primary components accounting for 70.7% of the PM2.5 mass. Compared with the remote background (RB) region covering the central part of the Tibetan Plateau, the residential sector contributed 11.3% more to PM2.5 in the highly populated mega city (HM) region, including the Sichuan and Guanzhong Basins, due to greater contribution to the concentrations of primary PM2.5 components. As the main emission source of sulfur dioxide (SO2), nitrogen oxides (NOx), and secondary organic aerosol (SOA), the industrial sector was the second largest contributor to the PM2.5 concentration in the HM region. However, in the RB region, the dominating emissions of NOx, SOA, and BC were from the transport sector; thus, it was the next largest contributor to total PM2.5. An evaluation of the emission control experiment suggested that mitigation strategies that reduce emissions from residential sources can effectively reduce the PM2.5 concentration during heavy pollution periods. PMID- 30466072 TI - Negative bottom-up effects of sulfadiazine, but not penicillin and tetracycline, in soil substitute on plants and higher trophic levels. AB - Veterinary antibiotics are widely used in livestock production and can be released to the environment via manure, affecting non-target organisms. Recent studies provide evidence that antibiotics can adversely affect both plants and insects but whether antibiotics in soil also affect trophic interactions is unknown. We tested whether antibiotics grown in sand as soil substitute with environmentally relevant concentrations of penicillin, sulfadiazine and tetracycline affect the survival of aphids feeding on plants (two crop and one non-crop plant species). Apera spica-venti, Brassica napus, and Triticum aestivum individuals were infested with aphids that were monitored over four weeks. We did not observe effects of penicillin or tetracycline on plants or aphids. However, sulfadiazine treatments reduced plant growth and increased mortality in the two tested grass species, but not in B. napus. Sulfadiazine subsequently decreased aphid density indirectly through reduced host plant biomass. We thus show that an antibiotic at realistic concentrations in a soil substitute can affect several trophic levels, i.e. plants and herbivores. This study contributes to the environmental risk assessment of veterinary antibiotics as it implies that their use potentially affects plant-insect interactions at environmentally relevant concentrations. PMID- 30466073 TI - Novel Magnified Single-Balloon Enteroscopy Enables Observation of Jejunal White Spots Associated with Lymphangiectasia. AB - A 59-year-old woman was diagnosed with primary intestinal lymphangiectasia (PIL), with characteristic findings on capsule enteroscopy and confirmation by histopathological examination of biopsy specimens. We viewed the abnormal jejunal mucosa using a newly developed magnifying single-balloon enteroscope (SIF-Y0007). Conventional observation showed leakage of chyle. However, using this new scope, we could see scattered white villi, representing dilated lymphatic vessels within the intestinal villi protruding from the dilated submucosal lymphoid vessels (D2 40 positive) within an edematous jejunal lesion. This report is the first to describe the white villi in a patient with PIL observed clearly using a newly developed magnifying enteroscope. Technological advancements and the accumulation of reported pathological data would further improve our understanding of the pathophysiological aspects of this disease entity, even in the jejunum. PMID- 30466074 TI - Repeated Pediatric Concussions Evoke Long-Term Oligodendrocyte and White Matter Microstructural Dysregulation Distant from the Injury. AB - Concussion or mild traumatic brain injury (mTBI) is often accompanied by long term behavioral and neuropsychological deficits. Emerging data suggest that these deficits can be exacerbated following repeated injuries. However, despite the overwhelming prevalence of mTBI in children due to falls and sports-related activities, the effects of mTBI on white matter (WM) structure and its development in children have not been extensively examined. Moreover, the effect of repeated mTBI (rmTBI) on developing WM has not yet been studied, despite the possibility of exacerbated outcomes with repeat injuries. To address this knowledge gap, we investigated the long-term effects of single (s)mTBI and rmTBI on the WM in the pediatric brain, focusing on the anterior commissure (AC), a WM structure distant to the injury site, using diffusion tensor imaging (DTI) and immunohistochemistry (IHC). We hypothesized that smTBI and rmTBI to the developing mouse brain would lead to abnormalities in microstructural integrity and impaired oligodendrocyte (OL) development. We used a postnatal day 14 Ascl1 CreER: ccGFP mouse closed head injury (CHI) model with a bilateral repeated injury. We demonstrate that smTBI and rmTBI differentially lead to myelin-related diffusion changes in the WM and to abnormal OL development in the AC, which are accompanied by behavioral deficits 2 months after the initial injury. Our results suggest that mTBIs elicit long-term behavioral alterations and OL-associated WM dysregulation in the developing brain. These findings warrant additional research into the development of WM and OL as key components of pediatric TBI pathology and potential therapeutic targets. PMID- 30466075 TI - miR-33a Mediates the Anti-Tumor Effect of Lovastatin in Osteosarcoma by Targeting CYR61. AB - BACKGROUND/AIMS: Preventing cell metastasis is an effective therapeutic strategy to treat osteosarcoma and improve prognosis. Statins have been found to have anticancer effects in addition to their cholesterol-lowering action. As a new target of statins, cysteine-rich 61 (CYR61) was recently identified to promote cell migration and metastasis in osteosarcoma. However, the underlying mechanisms mediating the regulation of CYR61 expression by statins remain unknown. METHODS: Human osteosarcoma cell lines MG63 and SaOS2 were used to clarify the effect of lovastatin on CYR61 expression. Real-time PCR was performed to detect mRNA or microRNA (miRNA) levels and western blot was performed to detect protein levels. Cell invasive ability was determined using Transwell assays. Lentivirus encoding CYR61 cDNA or sterol regulatory element-binding protein 2 (SREBP-2) shRNA was used to upregulate CYR61 expression or downregulate SREBP-2 expression. Binding of the CYR61 3' untranslated region (UTR) and miR-33a was analyzed by luciferase reporter assay. RESULTS: We found that lovastatin treatment decreased CYR61 expression, inhibited cell invasion and altered epithelial-to-mesenchymal transition (EMT)-related protein expression, while CYR61 overexpression abolished the effect of lovastatin. Moreover, lovastatin increased the expression of SREBP 2 and miR-33a, which were then downregulated by SREBP-2 silencing. Bioinformatics analysis indicated that the CYR61 3'UTR harbored a potential miR-33a binding site and luciferase reporter assay demonstrated that CYR61 was a target of miR-33a in osteosarcoma cells. Furthermore, miR-33a could inhibit cell invasion and alter EMT-related protein expression. SREBP-2 silencing or miR-33a inhibitor upregulated CYR61 expression and reversed the effects of lovastatin on cell invasion and EMT-related proteins. CONCLUSION: Our findings suggest lovastatin suppresses osteosarcoma cell invasion through the SREBP-2/miR-33a/CYR61 pathway. PMID- 30466076 TI - 4-Octyl Itaconate Activates Nrf2 Signaling to Inhibit Pro-Inflammatory Cytokine Production in Peripheral Blood Mononuclear Cells of Systemic Lupus Erythematosus Patients. AB - BACKGROUND/AIMS: Increased production of multiple pro-inflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6, plays an essential pathogenic role in the progression of systemic lupus erythematosus (SLE). Recent studies have characterized itaconate as a novel and potent nuclear-factor-E2-related factor 2 (Nrf2) activator that activates Nrf2 signaling by alkylating cysteine residues on Keap1 (Kelch-like ECH-associated protein 1). METHODS: THP-1 human macrophages and peripheral blood mononuclear cells (PBMCs) of SLE patients were treated with 4-octyl itaconate (OI). Nrf2 signaling activation was tested by qPCR assay and western blotting. mRNA expression and the production of multiple pro-inflammatory cytokines were tested by qPCR and enzyme-linked immunosorbent assays, respectively. Nuclear factor (NF) kappaB activation was tested by the p65 DNA-binding assay. RESULTS: We demonstrated that OI, the cell-permeable derivative of itaconate, induced Keap1 Nrf2 dissociation, Nrf2 protein accumulation, and nuclear translocation, which enabled the transcription and expression of multiple Nrf2-dependentantioxidant enzymes (heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, and glutamate cysteine ligase modifier subunit) in THP-1 human macrophages. OI also induced significant Nrf2 activation in SLE patient-derived PBMCs. OI pretreatment inhibited mRNA expression and the production of multiple pro-inflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) in SLE patient-derived PBMCs and lipopolysaccharide (LPS)-activated THP-1 cells. OI potently inhibited NF-kappaB activation in SLE patient-derived PBMCs and LPS-activated THP-1 cells. Importantly, Nrf2 silencing (by targeted short hairpin RNA) or knockout (by CRISPR/Cas9 gene-editing method) almost abolished OI-induced anti-oxidant and anti-inflammatory actions in SLE patient-derived PBMCs and LPS-activated THP-1 cells. CONCLUSION: OI activates Nrf2 signaling to inhibit the production of pro inflammatory cytokines in human macrophages and SLE patient-derived PBMCs. OI and itaconate could have important therapeutic value for the treatment of SLE. PMID- 30466077 TI - Increased Frequency of In-Center Hemodialysis as Rescue Therapy: Impact on Hospitalization for Acute Cardiovascular Events. AB - BACKGROUND: The intermittency of conventional hemodialysis (HD) leads to an increase in cardiovascular events. OBJECTIVE: We aimed to evaluate the effect of in-center frequent HD (FHD, 4-6 times a week) as a rescue option for cardiovascular events. METHOD: Patients who failed to achieve fluid volume control with conventional HD (thrice a week) were administered FHD. A total of 52 patients were divided into 2 groups by left ventricular ejection fraction (LVEF): low ejection fraction (LEF [n = 26], LVEF < 55%) and normal ejection fraction (NEF [n = 26], LVEF >=55%). Mortality and hospitalization rates were evaluated. RESULTS: All-cause mortality tended to be higher in the LEF than in the NEF group (p = 0.09). The 1-year hospitalization rate for acute cardiovascular events decreased in both LEF (1.24-0.89; p = 0.049) and NEF (0.36-0.16; p = 0.01) groups. In Cox regression models, LVEF < 55% (hazard ratio 3.81; 95% CI 1.15 12.66; p = 0.03) was identified as the risk factor for hospitalization for acute cardiovascular events. CONCLUSION: In-center FHD may decrease acute cardiovascular events. PMID- 30466078 TI - Trends in Post-Therapeutic Endoscopic Retrograde Cholangiopancreatography Gastrointestinal Hemorrhage, Perforation and Mortality from 2000 to 2012: A Nationwide Study. AB - BACKGROUND/AIMS: Recent trends in complications following inpatient therapeutic Endoscopic Retrograde Cholangiopancreatography (ERCP) remain poorly defined. We studied trends of gastrointestinal (GI) hemorrhage, perforation, and mortality following inpatient therapeutic ERCPs from 2000 to 2012 with the hypothesis that ERCPs would have down trending complication rates. METHODS: First, we isolated therapeutic ERCPs in patients 18 years or older using the International Classification of Diseases, Ninth Edition in the 2000 to 2012 National Inpatient Sample databases. Procedures complicated by hemorrhage, perforation, and mortality were identified. Multivariate logistic regressions were used to calculate trends in complication rates and secondary variables, including hospital and patient demographics. Time series regressions were then built for each complication to assess for trends from 2000 to 2012. RESULTS: The mortality rate decreased from 1.77 to 1.24%, a trend that was confirmed by time series regression. Perforation rates increased from 0.07 to 0.10% for therapeutic ERCPs. However, time series regression did not show a significant trend. GI hemorrhage rates increased from 1.36 to 1.57% and this uptrend was confirmed by our time series regression. CONCLUSION: Therapeutic ERCPs have become safer, as demonstrated by a down trending mortality rate. Over the same time, GI hemorrhage rates trended upwards, while no change was noted in perforation rates. PMID- 30466079 TI - Systematic Review and Meta-Analysis of the Impact of Hypoxia on Infarcted Myocardium: Better or Worse? AB - BACKGROUND/AIMS: Patients with myocardial infarction and hypoxemia require supplemental oxygen. However, the current therapeutic paradigm is contradicted by several recent studies in which the post-infarcted heart appears to benefit from systemic hypoxia. With this systematic review and meta-analysis, we aimed to discover whether systemic hypoxia is beneficial or detrimental to the infarcted myocardium. METHODS: We conducted an electronic search of the PubMed, EMBASE, and Web of Science databases and extracted the outcomes of cardiac function, geometry, and hemodynamics. A random-effect model was applied when the I2 value of greater than 50%. The sensitivity analysis was performed by omitting one study at a time, and publication bias was assessed using Egger's test. In addition, the quality of studies was evaluated using the risk of bias tool devised by the Systematic Review Centre for Laboratory Animal Experimentation. RESULTS: Six reports comprising 14 experiments were ultimately screened from among 10,323 initially identified preclinical studies. Few studies reported the method of randomization and none described allocation concealment, random outcome assessment or blinding. Overall, chronic hypoxia was found to have a beneficial effect on the ejection fraction (standard mean difference [SMD] = 5.39; 95% confidence interval [CI], 3.83 to 6.95; P < 0.001) of the infarcted heart, whereas acute hypoxia significantly improved hemodynamics, as indicated by an increase in the maximal rate of rise of left ventricular pressure (SMD = 1.27; 95% CI, 0.27 to 2.28; P = 0.013) and cardiac output (SMD = 1.26; 95% CI, 0.34 to 2.18; P = 0.007) and a decrease in total systematic vascular resistance (SMD = 0.89; 95% CI, -1.24 to -0.53; P < 0.001). Furthermore, a reduced oxygen content increased the stroke volume (P = 0.010). However, hypoxia reduced the end systolic (SMD = -2.67; 95% CI, -4.09 to -1.26; P < 0.001) and end-diastolic (SMD = -3.61; 95% CI, -4.65 to -2.57; P < 0.001) left ventricular diameters and increased the total pulmonary resistance (SMD = 0.76; 95% CI, 0.20 to 1.33; P = 0.008), pulmonary arterial mean pressure (SMD = 2.02; 95% CI, 0.23 to 3.81; P = 0.027), and left atrial pressure (SMD = 1.20; 95% CI, 0.57 to 1.82; P < 0.001). CONCLUSION: Hypoxia significantly improved heart function after infarction, with particular beneficial effects on systolic function and hemodynamics. However, it had slightly adverse effects on pulmonary circulation and left ventricular geometry. A lower inspired oxygen concentration may improve cardiac function, although further research is needed to determine the optimum level of hypoxia. Finally, more studies of hypoxia and myocardial infarction in larger species are required before these findings can be incorporated into therapeutic guidelines. PMID- 30466080 TI - Effects of Migration on Allergic Diseases. AB - Studies in migrant populations provide vital opportunities to investigate the role of environmental factors in the pathogenesis of allergic disorders. Differences in allergy prevalence have been observed between migrants and native born subjects living in the same geographical location. Immigrants who migrate from less affluent countries with lower allergy prevalence tend to have a lower prevalence of allergic disorders compared to native-born residents of the more affluent host country. The patterns of allergic disease prevalence also differ between first- and second-generation migrants. The timing of migration in relation to birth, age at migration, and duration of residence in the host country also influence one's atopic risk. A complex interplay of multiple environmental, socioeconomic, and cultural factors is likely responsible for these observed differences. Further research into the roles of various risk factors in modulating differences in allergic disease prevalence between migrant and native populations will enhance our understanding of the complex gene environment interactions involved in the pathogenesis of allergic disorders. PMID- 30466081 TI - Arterial Wall Stress Induces Phenotypic Switching of Arterial Smooth Muscle Cells in Vascular Remodeling by Activating the YAP/TAZ Signaling Pathway. AB - BACKGROUND/AIMS: Increasing wall stress or biomechanical stretch experienced by arteries influences the initiation of atherosclerotic lesions. This initiation is mediated by Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which are both effectors of the Hippo pathway. In this study, the functional roles of YAP/TAZ proteins in the regulation of the stretch mediated programing of human umbilical arterial smooth muscle cells (HUASMCs) to a proliferative phenotype were examined. METHODS: HUASMCs were seeded on a Matrigel-coated silicone chamber and subjected to biomechanical stretch for 24 h after 48 h of growth. YAP/TAZ small interfering RNA was used to specifically knockdown YAP/ TAZ expression in HUASMCs. RESULTS: We observed that YAP/TAZ activation via biomechanical stretching is involved in the regulation of critical aspects of the HUASMC phenotypic switch. YAP/TAZ knockdown significantly attenuated the stretch-induced proliferative and pro-inflammatory phenotypes in HUASMCs. Furthermore, treatment with atorvastatin, an anti-atherosclerotic drug, attenuated the stretch-induced phenotypic switch of HUASMCs from the contractile to synthetic state by suppressing YAP/TAZ expression. Additional investigations demonstrated the role of stretch in inhibiting the Hippo pathway, leading to the activation of PI3-kinase (PI3K) and phosphoinositide dependent kinase (PDK1); the key molecule for the regulation of the PDK1 and Hippo complex interaction was Sav1. These results showed the importance of YAP/TAZ activation, induced by biomechanical stretch, in promoting atheroprone phenotypes in HUASMCs. CONCLUSION: Taken together, our findings revealed a mechanism by which YAP/TAZ activation contributes to the pathogenesis of atherosclerosis. PMID- 30466083 TI - We Need a New Narrative: Agents instead of Patients. PMID- 30466082 TI - Short-Term Progression of Diabetic Hard Exudates Monitored with High-Resolution Camera. AB - PURPOSE: To assess the progression of diabetic hard exudates over an 8-week period, using a high-resolution adaptive optics camera. DESIGN: Prospective observational study. METHODS: Five eyes of three patients presenting diabetic maculopathy with hard exudates were studied. An area of clinically visible exudates was imaged sequentially using SD-OCT and high-resolution flood illumination adaptive optics for 2 months, on a weekly basis. A time-lapse video was obtained for each eye studied. Changes in terms of surface, number of free elements (foci), and central macular thickness were recorded. RESULTS: Short-term modifications in terms of disposition, size, and number of exudates were observed. Two patterns of progression were identified: two eyes showed exudate dislocation concomitant with the regression of the underlying macular edema, with hard exudates being progressively replaced by a multitude of smaller foci. These exudates were labeled resorption exudates. In three other eyes with persistent diabetic macular edema, foci aggregated into larger exudates. CONCLUSION: Diabetic hard exudate changes occurred over a short period of time but were not assessable clinically. Adaptive optics was able to document these subtle changes precisely. Further studies using this imaging modality may improve our understanding of the natural history of exudates and eventually help assess the efficacy of the various treatments available such as lipid-lowering drugs and anti-VEGFs injections. PMID- 30466084 TI - Microsurgical Technique of Locoregional Injection into the Hepatic Artery in Tumor-Bearing Mice. AB - BACKGROUND: Intraarterial injection into the hepatic artery represents an important route for locoregional administration for the treatment of hepatic tumors. In the present work, we describe microsurgical methodology for injection into the hepatic artery in mice. The technique was recently used for analysis of the phenomenon of endothelial capture in liver tumors. METHODS: Two different models of hepatic tumors in C57BL/6 mice were used. Tumors were induced by intrahepatic cell inoculation. The preferential blood supply of tumors was studied using blocking of bioavailability of nontumoral endothelial epitope and the subsequent injection of fluorescent endothelium-specific antibody. The selective intraarterial injection of labeled antibody was performed in tumor bearing mice. The procedure addressed variations of vascular anatomy of the hepatic artery in mice and used direct intraarterial injection with dispensable catheterization. RESULTS: Both experimental tumor models showed preferential blood supply from the hepatic artery. The technique of hepatic arterial injection was adapted and performed according to two major anatomic variations of the hepatic artery. Using this technique, the selective enrichment of labeled antibody to tumor and liver blood vessels, which were perfused during the first intravascular passage, was demonstrated. CONCLUSIONS: The experimental hepatic arterial injection in mice is a feasible but demanding microsurgical procedure. The choice of subsequent operation steps is dependent on the vascular anatomy of the hepatic artery which has two major variations in mice. PMID- 30466085 TI - CDK6 and miR-320c Co-Regulate Chondrocyte Catabolism Through NF-kappaB Signaling Pathways. AB - BACKGROUND/AIMS: Cyclin-dependent kinase 6 (CDK6) regulates inflammatory response and cell differentiation. This study sought to determine whether CDK6 and miR 320c co-regulate chondrogenesis and inflammation. METHODS: Utilizing quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC), CDK6 and miR-320c expression were assessed in a micromass culture of human bone mesenchymal stem cells that underwent chondrogenesis in vitro as well as in chondrocytes from E16.5 mouse forelimbs. Normal chondrocytes were transfected with miR-320c mimic, miR-320c inhibitor, or CDK6-siRNA. Luciferase reporter assay results confirmed that miR-320c directly targets CDK6 by interacting with the 3'-untranslated region (3'-UTR) of its mRNA. qRT-PCR, Western blotting, and Cell Counting Kit-8 were subsequently used to evaluate the effects of miR-320c overexpression and CDK6 inhibition on inflammatory factor expression, as well as to investigate the effects of NF-kB and MAPK signaling pathway activation on IL-1beta-induced chondrocyte inflammation. RESULTS: Our results show that miR-320c expression increased during the middle stage and decreased during the late stage of hBMSC chondrogenic differentiation. In contrast, CDK6 expression decreased during the middle stage and increased during the late stage of hBMSC chondrogenic differentiation. Moreover, CDK6 expression increased in severe OA cartilage and in hypertrophic chondrocytes of mouse forelimbs at E16.5. Results of the luciferase reporter assay showed that miR-320c modulated CDK6 expression by binding to the 3'-UTR of its mRNA. miR-320c overexpression and CDK6 inhibition repressed IL-1beta-induced expression of inflammatory factors and regulated the NF-kB signaling pathway. CONCLUSION: CDK6 and miR-320c co-regulate hBMSC chondrogenesis and IL-1beta-induced chondrocyte inflammation through the NF-kB signaling pathway, suggesting that miR-320c and CDK6 inhibitors can be used to repress catabolism in human chondrocytes. PMID- 30466086 TI - Localization of the SRY Gene on Chromosome 3 in a Patient with Azoospermia and a Complex Karyotype 45,X/46,X,i(Y)(q10)/46,XX/ 47,XX,i(Y)(q10). AB - This study aimed to identify the cause of azoospermia in a 38-year-old infertile man who was referred for genetic testing. Cytogenetic evaluation was performed by G-banding, C-banding, and FISH using centromeric probes for chromosomes X and Y and showed the presence of a monocentric isochromosome Y with a complex, mosaic karyotype 45,X/46,X,i(Y)(q10)/46,XX/47,XX,i(Y)(q10). Multiplex PCR for the commonly deleted genes in the AZFa, AZFb, and AZFc regions of the Y chromosome was performed and indicated the presence of all 3 regions. Further, PCR amplification followed by DNA sequencing of the SRY gene was done, which ruled out mutations in that gene. To identify the position of the SRY gene, FISH using a locus-specific probe was used and showed that the gene had been translocated to chromosome 3. Subtelomere FISH for 3q and Yp evidenced that the subtelomeric region of the Y chromosome was found on the terminal region of 3q. The clinical symptoms of the patient can be attributed to this abnormal genotype. The importance of genetic testing in infertile patients and the need for genetic counselling to prevent the transmission of the defect are emphasized. PMID- 30466088 TI - Small-Cell Lung Cancer Comorbid with Pulmonary Mycobacterium avium Infection: A Case Report. AB - BACKGROUND: Small-cell lung cancer (SCLC) rarely coexists with pulmonary Mycobacterium avium intracellular complex (MAC) infection. The key drug for SCLC treatment is etoposide, which is metabolized by cytochrome P-450 (CYP) 3A4. Meanwhile, the key drugs for pulmonary MAC infection are clarithromycin (CAM) and rifampicin (RFP), and their metabolism influences CYP3A4. Therefore, treatment of concurrent SCLC and pulmonary MAC infection is difficult, and to the best of our knowledge, no report of treatments for concurrent SCLC and pulmonary MAC infection has been published. Patient Concerns and Diagnoses: A 65-year-old man presented to our hospital with abnormal findings of chest computed tomography: (1) a hilar region nodule in the left lung and mediastinal lymphadenopathy and (2) a thick-walled cavity lesion in the right upper lobe of the lung. After further examinations, the former lesions were diagnosed as SCLC, cT4N3M0, stage IIIC and the latter as pulmonary MAC infection, fibrocavitary disease. INTERVENTIONS AND OUTCOMES: Concurrent treatment was conducted with discontinuation of CAM and RFP before and after etoposide administration. Specifically, intravenous cisplatin and etoposide were administered on day 1 and days 1-3, respectively, and CAM, RFP, and ethambutol (EB) were administered orally on days 6-22 every 4 weeks. Concurrent radiotherapy was added to the drug administration on days 1-27 of the first cycle. The chemotherapy was continued for 4 cycles, followed by continuation of CAM and RFP administration. EB was discontinued because of optic nerve disorder. The treatments were conducted completely and safely, and both of the SCLC lesions and the MAC lesion were improved. CONCLUSIONS: Treatments for concurrent SCLC and pulmonary MAC infection may be successfully conducted with discontinuation of CAM and RFP before and after etoposide administration. PMID- 30466089 TI - Hyperoside Protects Against Pressure Overload-Induced Cardiac Remodeling via the AKT Signaling Pathway. AB - BACKGROUND/AIMS: Cardiac hypertrophy is a major predisposing factor for heart failure and sudden cardiac death. Hyperoside (Hyp), a flavonoid isolated from Rhododendron ponticum L., is a primary component of Chinese traditional patent medicines. Numerous studies have shown that Hyp exerts marked anti-viral, anti inflammatory, anti-oxidant, anti-cancer, anti-ischemic, and particularly cardio protective effects. However, the effects of Hyp on cardiac hypertrophy have not been explored. The aims of this study were to determine whether Hyp could protect against cardiac remodeling and to clarify the potential molecular mechanisms. METHODS: Neonatal rat cardiac myocytes were isolated and treated with different concentrations of Hyp, then cultured with angiotensin II for 48 h. Mice were subjected to either aortic banding or sham surgery (control group). One week after surgery, the mice were treated with Hyp (20 mg/kg/day) or vehicle by oral gavage for 7 weeks. Hypertrophy was evaluated by assessing morphological changes, echocardiographic parameters, histology, and biomarkers. RESULTS: Hyp pretreatment suppressed angiotensin II-induced hypertrophy in cardiomyocytes. Hyp exerted no basal effects but attenuated cardiac hypertrophy and dysfunction, fibrosis, inflammation, and oxidative stress induced by pressure overload. Both in vivo and in vitro experiments demonstrated that the effect of Hyp on cardiac hypertrophy was mediated by blocking activation of the AKT signaling pathway. CONCLUSION: Hyp improves cardiac function and prevents the development of cardiac hypertrophy via AKT signaling. Our results suggest a protective effect of Hyp on pressure overload-induced cardiac remodeling. Taken together, Hyp may have a role in the pharmacological therapy of cardiac hypertrophy. PMID- 30466090 TI - Evaluation of 2 ex vivo Bovine Cornea Storage Protocols for Drug Delivery Applications. AB - The use of corneal tissue for ex vivo therapeutic evaluations is limited due to its rapid loss of viability after excision. Optimization of storage conditions may allow prolonged retention of physical tissue properties. In this study, we evaluated how storage in optimized organ culture (OC) medium at 37 degrees C or phosphate-buffered saline (PBS) at 2-8 degrees C impacted physical properties of bovine corneas. Tissue hydration, permeability and histology were monitored at baseline and following 1, 4 and 7 days of storage. Corneas stored in OC demonstrated significantly higher hydration and permeability when compared to those stored in PBS. Histology revealed that storage in OC consistently caused detachment of the epithelial layer by day 4 of storage, whereas both storage conditions caused a significant increase in stromal thickness and tissue vacuolation. This study highlights the limitations of currently available corneal tissue storage approaches for ex vivo drug permeation studies. PMID- 30466091 TI - Irisin Ameliorates Glucolipotoxicity-Associated beta-Cell Dysfunction and Apoptosis via AMPK Signaling and Anti-Inflammatory Actions. AB - BACKGROUND/AIMS: Islet metabolic disorder and inflammation contribute to the pathogenesis and progression of type 2 diabetes mellitus (T2DM). Irisin is a recently identified adipomyokine with protective effects on metabolic homeostasis and inflammation-suppressing effects in hepatic and vascular cells. The present study examined the effects of irisin on lipid metabolism and inflammation in beta cells under glucolipotoxic conditions. METHODS: Rat INS-1E beta cells and islets isolated from C57BL/6 mice were incubated in glucolipotoxic conditions with or without irisin. Intracellular lipid contents and lipogenic gene expression were determined by enzymatic colorimetric assays and real-time PCR, respectively. Inflammatory status was evidenced by Western blot analysis for the phosphorylation of nuclear factor-kappaB (NF-kappaB) p65 and real-time PCR analysis for the expression of pro-inflammatory genes. RESULTS: Irisin reversed glucolipotoxicity-induced intracellular non-esterified fatty acid (NEFA) and triglyceride accumulation, suppressed associated elevations in lipogenic gene expression, and phosphorylated acetyl-CoA-carboxylase (ACC) in INS-1E cells. These demonstrated effects were dependent on irisin-activated adenosine monophosphate-activated protein kinase (AMPK). Meanwhile, AMPK signaling mediated the protective effects of irisin on INS-1E cell insulin secretory ability and survival as well. Additionally, irisin inhibited phosphorylation of NF-kappaB p65 while decreasing the expression of pro-inflammatory genes in INS-1E cells under glucolipotoxic conditions. Moreover, irisin also improved insulin secretion, inhibited apoptosis, and restored beta-cell function-related gene expression in isolated mouse islets under glucolipotoxic conditions. CONCLUSION: Irisin attenuated excessive lipogenesis in INS-1E cells under glucolipotoxic state through activation of AMPK. Irisin also suppressed overnutrition-induced inflammation in INS-1E cells. Our findings implicate irisin as a promising therapeutic target for the treatment of islet lipid metabolic disorder and islet inflammation in T2DM. PMID- 30466092 TI - A Familial Small Supernumerary Marker Chromosome 15 Associated with Cryptic Mosaicism with Two Different Additional Marker Chromosomes Derived de novo from Chromosome 9: Detailed Case Study and Implications for Recurrent Pregnancy Loss. AB - We report a case of familial small supernumerary marker chromosome 15 in a phenotypically normal female with 4 recurrent spontaneous abortions and a healthy child. The initial karyotype showed a small, bisatellited, apparently metacentric marker chromosome, 47,XX,+idic(15)(q11.1), maternally inherited. The proband's mother was mosaic for the idic(15)(q11.1) without pregnancy loss. Reexamination of the proband's karyotype revealed cryptic mosaicism for 1 ring and 1 minute chromosome derived de novo from chromosome 9 in 2% of the metaphases. In FISH analysis, the patient's karyotype was mos 47,XX,+idic(15)(q11.1)mat[100]/49,XX,+idic(15)(q11.1)mat,+r(9;9;9;9),+der(9)dn[2] The second spontaneous abortion had trisomy 9 (47,XX,+9); the third had mosaic trisomy 9 in 21% of the nuclei and isodicentric chromosome 15 in 36% of the nuclei (mos 48,XN,+9,+idic(15)(q11.1)/47,XN,+9/47,XN,+idic(15)(q11.1)/46,XN). The first and fourth abortions were not cytogenetically studied. The cause of the spontaneous abortions in this patient is likely the cryptic mosaicism for ring and minute chromosomes 9, and gonadal mosaicism is most probable, due to the 2 abortions. PMID- 30466093 TI - Facial and Extrafacial Lesions in an Ethnically Diverse Series of 91 Patients with Frontal Fibrosing Alopecia Followed at a Single Center. AB - BACKGROUND: Various facial and extrafacial lesions have been reported in frontal fibrosing alopecia (FFA). Facial papules have been associated with worse prognosis. OBJECTIVES: We sought to detect the prevalence of facial and extrafacial lesions and to analyze their relation to demographic and clinical variables in a large and ethnically diverse series of patients with FFA. METHODS: Charts of patients diagnosed with FFA between January 1, 2015, and December 31, 2017, at the Department of Dermatology, University of Miami, were reviewed retrospectively. RESULTS: 91 patients (87 women and 4 men) met inclusion criteria: 45% (n = 41) were of Hispanic/Latino ethnicity, and 34% (n = 30) were premenopausal. Facial papules were most commonly detected (41% among Hispanic/Latino patients). Significant associations were found between: (1) Hispanic/Latino ethnicity and any FFA-associated facial lesions, facial papules alone, or lichen planus pigmentosus alone, as well as premenopausal status; (2) any FFA-associated facial lesions or facial papules alone and premenopausal status; and (3) Hispanic/Latino ethnicity and simultaneous presence of facial and extrafacial lesions. CONCLUSIONS: There is a significant association among Hispanic/Latino ethnicity, facial papules, and premenopausal status, which may portend a susceptibility to severer disease and prompt early and aggressive treatment in this group. PMID- 30466094 TI - Advanced Maternal Age and the Future Health of the Offspring. AB - OBJECTIVE: We aimed to evaluate the association between advanced maternal age and the long-term health of the offspring. METHODS: In this population-based cohort study, hospitalizations of offspring up to the age of 18 years were compared according to maternal age. The incidence of long-term hospitalizations of the offspring due to cardiovascular, endocrine, neurological, hematological, respiratory and gastro-intestinal morbidities was evaluated. Deliveries occurred between the years 1991 and 2014 in a tertiary medical center. Kaplan-Meier survival curves were used to compare cumulative morbidity incidence. Cox regression models were performed to control for confounders. RESULTS: During the study period, 202,709 deliveries were included, of which 26,287 (12.9%) were in women aged 35-39 years, and 6,718 (3.3%) in women aged 40-50 years. Children born to older mothers did not have a significantly different cumulative incidence of long-term pediatric morbidities evaluated, as compared with the comparison group, using Kaplan-Meier survival analyses. In the Cox regression analyses, advanced maternal age did not exhibit an independent association with long-term morbidities of the offspring. CONCLUSION: Despite the association of advanced maternal age with adverse maternal and immediate neonatal outcomes, there does not seem to be an association with the long-term morbidity of the offspring. PMID- 30466096 TI - Aneurysms and Diabetes Mellitus: A Strange Symbiosis? PMID- 30466095 TI - Knockdown of Long Noncoding RNA HOXA-AS2 Suppresses Chemoresistance of Acute Myeloid Leukemia via the miR-520c-3p/S100A4 Axis. AB - BACKGROUND/AIMS: Among different molecular candidates, there is growing data to support that long noncoding RNAs (lncRNAs) play a significant role in acute myeloid leukemia (AML). HOXA-AS2 is significantly overexpressed in a variety of tumors and associated with anti-cancer drug resistance, however, little is known regarding the expression and function of HOXA-AS2 in the chemoresistance of AML. In this study, we aimed to determine the role and molecular mechanism of HOXA-AS2 in adriamycin-based chemotherapy resistance in AML cells. METHODS: Quantitative real-time PCR was used to detect HOXA-AS2 expression in the BM samples and ADR cell lines, U/A and T/A cells. Furthermore, the effects of HOXA-AS2 silencing on cell proliferation and apoptosis were assessed in vitro by CCK8 and flow cytometry, and on tumor growth in vivo. Furthermore, bioinformatics online programs predicted and luciferase reporter assay were used to validate the association of HOXA-AS2 and miR-520c-3p in AML. RESULTS: In this study, we showed that HOXA-AS2 is significantly upregulated in BM samples from AML patients after treatment with adriamycin-based chemotherapy and in U/A and T/A cells. Knockdown of HOXA-AS2 inhibited ADR cell proliferation in vitro and in vivo and promoted apoptosis. Bioinformatics online programs predicted that HOXA-AS2 sponge miR-520c 3p at 3'-UTR with complementary binding sites, which was validated using luciferase reporter assay and anti-Ago2 RIP assay. HOXA-AS2 could negatively regulate the expression of miR-520c-3p in ADR cells. S100A4 was predicted as a downstream target of miR-520c-3p, which was confirmed by luciferase reporter assay. CONCLUSION: Our results suggest that HOXA-AS2 plays an important role in the resistance of AML cells to adriamycin. Thus, HOXA-AS2 may represent a therapeutic target for overcoming resistance to adriamycin-based chemotherapy in AML. PMID- 30466097 TI - Growing Human Parathyroids in a Microphysiological System: A Novel Approach to Understanding and Developing New Treatments for Hyperparathyroidism. AB - We developed a novel model for studying hyperparathyroidism by growing ex vivo 3 dimensional human parathyroids as part of a microphysiological system (MPS) that mimics human physiology. The purpose of this study was to validate the parathyroid portion of the MPS. We prospectively collected parathyroid tissue from 46 patients with hyperparathyroidism for growth into pseudoglands. We evaluated pseudogland architecture and calcium responsiveness. Following 2 weeks in culture, dispersed cells successfully coalesced into pseudoglands ~500-700 um in diameter that mimicked the appearance of normal parathyroid glands. Functionally, they also appeared similar to intact parathyroids in terms of organization and calcium-sensing receptor expression. Immunohistochemical staining for calcium-sensing receptor revealed 240-450/cell units of mean fluorescence intensity within the pseudoglands. Finally, the pseudoglands showed varying levels of calcium responsiveness, indicated by changes in parathyroid hormone (PTH) levels. In summary, we successfully piloted the development of a novel MPS for studying the effects of hyperparathyroidism on human organ systems. We are currently evaluating the effect of PTH on adverse remodeling of tissue engineered cardiac, skeletal, and bone tissue within the MPS. PMID- 30466098 TI - Screening for Common Fetal Trisomies in Twin Pregnancies: First-Trimester Combined, Cell-Free DNA, or Both? AB - OBJECTIVE: To examine the distribution of risks for fetal trisomies after first trimester combined screening in twins and to investigate different strategies for clinical implementation of cell-free DNA (cfDNA) testing. METHODS: We retrospectively analyzed all twin pregnancies undergoing first-trimester combined screening over a 10 years' period. The population was stratified according to various risk cut-offs, and we examined different screening strategies for implementation of cfDNA testing in terms of impact on invasive testing rate, cfDNA test failure rate, and economic costs. RESULTS: We included 572 twin pregnancies: 480 (83.92%) dichorionic and 92 (16.08%) monochorionic. Performing a first-line combined screening and offering cfDNA testing to the group with a risk between 1 in 10 and 1 in 1,000, would lead to an invasive testing rate of 2.45%, and cfDNA testing would be performed in 22.20% of the population. This strategy would be cost-neutral compared to universal combined screening alone. CONCLUSIONS: First-trimester combined screening results can be used to stratify twin pregnancies into different risk categories and select those that could be offered cfDNA testing. A contingent screening strategy would substantially decrease the need for invasive testing in twins and it would be cost-neutral compared to combined testing alone. PMID- 30466099 TI - Association Between Pretreatment Serum Apolipoprotein A1 and Prognosis of Solid Tumors in Chinese Population: A Systematic Review and Meta-Analysis. AB - BACKGROUND/AIMS: Serum apolipoprotein A1 (apoA1) has been reported to be abnormally expressed in several malignancies. However, the prognostic role of apoA1 in solid tumors is still controversial. We conducted this meta-analysis to obtain a more accurate evaluation of prognostic significance of apoA1 in Chinese patients with solid tumors. METHODS: A comprehensive literature search of electronic databases was carried out up to August 2018. We included studies investigating the association between pretreatment serum apoA1 level and clinicopathological features, including survival outcomes, in solid tumors. Hazard ratios (HRs) and odds ratio (ORs) with 95% confidence intervals (CIs) were applied as effect size estimates. RESULTS: A total of 13 studies and 8052 patients were included in our meta-analysis. Elevated level of pretreatment serum apoA1 was markedly associated with an improved OS (pooled HR = 0.608, 95% CI = 0.557 - 0.665, P < 0.001). The statistical significances were observed in all cancer types, including digestive system malignancies (pooled HR = 0.633; 95% CI = 0.550-0.727; P < 0.001), urinary system cancers (pooled HR = 0.471; 95% CI = 0.352-0.630; P < 0.001), nasopharyngeal cancer (pooled HR = 0.642; 95% CI = 0.538 0.766; P < 0.001) and non-small cell lung cancer (pooled HR = 0.526; 95% CI = 0.329-0.841; P = 0.007), but not in breast cancer (pooled HR = 0.573; 95% CI = 0.266-1.246; P = 0.155). Meanwhile, cancer patients with a low level of serum apoA1 suffered an unfavorable DFS (pooled HR = 0.714, 95% CI = 0.603 - 0.845, P < 0.001). Moreover, abnormal serum apoA1 was significantly correlated to tumor size (pooled OR = 0.640, 95% CI = 0.475 - 0.863, P = 0.003), tumor differentiation (pooled HR = 0.724, 95% CI = 0.565 - 0.929, P = 0.011), and tumor stage (pooled HR = 0.493, 95% CI = 0.384 - 0.633, P < 0.001). CONCLUSION: Elevated level of pretreatment serum apoA1 was significantly associated with longer survival in patients with solid tumors. Pretreatment serum apoA1 could serve as a novel positive factor for malignant patient prognosis in Chinese population. PMID- 30466100 TI - Glomerular Hyperfiltration: An Early Marker of Nephropathy in Fabry Disease. AB - BACKGROUND AND OBJECTIVES: Progressive nephropathy is one of the main features of Fabry disease (FD). It has been supposed that an early phase, clinically silent disease occurs in childhood and adolescence and is characterized by glomerular hyperfiltration (HF). Surprisingly, although HF has been reported in several studies, its prevalence is at present unknown. The focus of our study was to determine the prevalence of HF in a cohort of patients with FD and to identify the factors associated with a high risk of HF. METHODS: To address this issue, a retrospective observational study of 87 patients with genetically confirmed FD was performed. HF was defined as an estimated glomerular filtration rate (eGFR) > 130 mL/min/1.73 m2 corrected for age (> 40 years: -1 mL/min/1.73 m2/year). RESULTS: HF occurred in 21 patients (24% of our population), and increased to 50% when only young adults were considered. Hyperfiltrating patients were younger and had lower proteinuria levels than those without HF. The prevalence of cardiovascular and other manifestations of FD was significantly lower in hyperfiltering patients. CONCLUSIONS: Our study showed a negative correlation between eGFR and age, and with proteinuria levels and the presence of cardiovascular and other manifestations of FD. These data favor the view that HF in Fabry patients could be related predominantly to a predisease state. Even in the absence of a "measured" GFR, HF should be regarded as an early marker of Fabry nephropathy, and its recognition and confirmation by true GFR seems a relevant feature to address the issue of the potential benefit of nephroprotective treatments at the early stage of Fabry nephropathy. PMID- 30466101 TI - Articulatory Contact Pressure during Bilabial Plosive Production in Esophageal and Tracheoesophageal Speech. AB - OBJECTIVES: The present study investigated the articulatory contact pressure during the production of bilabial plosives by esophageal (ES), tracheoesophageal (TE), and laryngeal speakers. METHODS: The peak contact pressure (PCP) during bilabial plosive production of /CVCVCVCVCV/ syllable strings of /p/ and /ph/ was obtained from 10 ES, 10 TE, and 10 laryngeal speakers of Cantonese. PCP values were obtained by using a pressure transduction system (Iowa Oral Performance Instrument) during speech production. RESULTS: The results showed that ES speakers exhibited a significantly greater PCP value than TE and laryngeal speakers, as revealed by cheek muscle compression force. In addition, the unaspirated bilabial plosive /p/ was associated with a greater PCP than its aspirated counterpart /ph/. CONCLUSION: The current findings might support the hypothesis of over-exaggerated speech for better intelligibility among alaryngeal speakers. In addition, the increased oral muscular effort could be associated with a compensatory strategy for maintaining a high intraoral pressure or the unique air intake by ES speakers. PMID- 30466102 TI - Is Liver Ultrasound Useful as Part of the Surveillance Strategy following Potentially Curative Colorectal Cancer Resection? AB - BACKGROUND: Optimal surveillance monitoring following curative resection of colorectal cancer remains unclear. Guidelines recommend computed tomography (CT) based imaging for the initial 3 years following surgical intervention due to the high rates of local and distant recurrence. However, there is currently limited supporting evidence for this strategy. Our current follow-up practice is to offer annual interval abdominal ultrasound and abdominal/pelvis CT scans starting at 6 and 12 months with the sequence of radiological follow-up remaining at the discretion of each clinician. We aim to establish the additional diagnostic benefit of abdominal ultrasound to CT scans in colorectal cancer surveillance follow-up. METHODS: All patients who underwent colorectal resection with curative intent in our region during a single year were included. Patients were detected from a prospectively collected pathology database and supplemented retrospectively with patient demographics, imaging reports, and mortality data. RESULTS: A total of 243 patients (male n = 135, 55.6%) were included. There was a mortality rate of 31.3% over the study period. Patients who received abdominal ultrasound as their initial imaging modality (n = 64, 26.3%) were significantly older, had less severe disease, and a significantly lower mortality rate when compared to CT -patients (n = 148, 60.9%). All patients with new hepatic disease detected by ultrasound scans had their management discussed in multi-disciplinary team meetings before their next scheduled CT. CONCLUSION: In an era where cross sectional imaging of colorectal cancer is commonplace, abdominal ultrasound offers additional benefit to CT as a postoperative imaging adjunct for the detection of hepatic disease recurrence. PMID- 30466103 TI - Arginine-Depleting Enzymes - An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies. AB - Arginine auxotrophy occurs in certain tumor types and is usually caused by the silencing of argininosuccinate synthetase 1 or arginine lyase genes. Such tumors are often associated with an intrinsic chemoresistance and thus a poor prognosis. Arginine auxotrophy however renders these tumors vulnerable to treatment with arginine-degrading enzymes. Among the most frequently applied arginine-degrading agents are bacterial arginine deiminases (ADI). The anti-cancerous effects of ADI derived from different bacteria were extensively studied in numerous preclinical cell culture and xenograft models. Mycoplasma-derived ADI-PEG20 is most commonly used and is currently under clinical investigation as a single agent therapeutic as well as in combination with different antineoplastic compounds. Mechanistically, ADI is capable of reducing metabolic activity in tumor cells, contributing to autophagy, senescence and apoptosis in arginine auxotrophic cells. Although clinical trials are promising, the resistance development upon initial treatment response is an increasing challenge. Furthermore, interference of ADI with the tumor microenvironment is poorly understood. In the present review, we outline recent experimental ADI-based treatment approaches and their translation into the clinic. Furthermore, we summarize new insights into the molecular mechanisms underlying the anti-cancer effects of ADI that might facilitate the refinement of ADI-based combination therapy approaches. PMID- 30466104 TI - Methyl Helicterate Inhibits Hepatic Stellate Cell Activation Through Modulation of Apoptosis and Autophagy. AB - BACKGROUND/AIMS: Activated hepatic stellate cells (HSCs) are the major source of extracellular matrix (ECM). Therefore inhibiting HSC activation is considered as an effective strategy to inhibit the process of liver fibrosis. This study aimed to investigate the underlying mechanism of methyl helicterate (MH) isolated from Helicteres angustifolia on the activation of HSCs. METHODS: HSC-T6 cells were treated with various concentration of MH and autophagy was inhibited by 3-Methyl adenine (3-MA) or RNA interference. Cell viability was observed by MTT assay and cell colony assay. Cell cycle and apoptosis were analyzed using flow cytometry. Autophagic vacuoles were observed by transmission electron microscopy and monodansyl cadaverine (MDC) staining. Moreover, autophagy-related genes and proteins were detected using real-time PCR and Western blot assays, respectively. RESULTS: MH significantly inhibited HSC activation, as evidenced by the inhibition of cell viability, colony formation and the expression of alpha-SMA and collagen I. MH caused cell cycle arrest in G2/M phase. Moreover, MH significantly induced apoptosis through regulating the mitochondria-dependent pathway and the activity of caspases. MH treatment significantly increased lysosomes and autophagosomes, and enhanced the formation of autophagic vacuoles and autophagic flux. Interestingly, inhibiting autophagy by 3-MA or RNA interference abolished the ability of MH in inhibiting HSC activation. On the other hand, induction of autophagy promoted MH-induced HSC apoptosis. Further study showed that MH-induced HSC apoptosis and autophagy was mediated by the JNK and PI3K/Akt/mTOR pathways. CONCLUSION: Our results demonstrate that MH-induced HSC apoptosis and autophagy may be one of the important mechanisms for its anti fibrosis effect. PMID- 30466105 TI - Current Social Media Conversations about Genetics and Genomics in Health: A Twitter-Based Analysis. AB - BACKGROUND: The growing availability of genomic information to the public may spur discussion about genetics and genomics on social media. Sites, including Twitter, provide a unique space for the public to access and discuss health information. The objective of this study was to better understand how social media users are sharing information about genetics and genomics in health and healthcare and what information is most commonly discussed among Twitter users. METHODS: We obtained tweets with specific genetics- and genomics-related keywords from Crimson Hexagon. We used Boolean logic to collect tweets containing chosen keywords within the timeframe of October 1, 2016, to October 1, 2017. Features of the software were used to identify salient themes in conversation, conduct an emergent content analysis, and gather key demographic information. RESULTS: We obtained 347,196 tweets from our search. There was a monthly average volume of 28,432 tweets. The five categories of tweets included: genetic disorders/disease (45.3%), health (15.6%), genomics (8%), and genetic testing (7.3%). Top influencers in the conversation included news outlets and universities. CONCLUSIONS: This content analysis provides insight about the types of conversation related to genomics and health. Conversations about genomics are occurring on Twitter, and they frequently emphasize rare genetic diseases and genetic disorders. These discussions tend to be driven by key influencers who primarily include news media outlets. Further understanding of the discussions related to genomics and health in social media may offer insight about topics of importance to the public. PMID- 30466106 TI - Interferon Consensus Sequence-Binding Protein 8, a Tumor Suppressor, Suppresses Tumor Growth and Invasion of Non-Small Cell Lung Cancer by Interacting with the Wnt/beta-Catenin Pathway. AB - BACKGROUND/AIMS: Interferon consensus sequence-binding protein 8 (IRF8) belongs to a family of interferon (IFN) regulatory factors that modulates various important physiological processes including carcinogenesis. As reported by others and our group, IRF8 expression is silenced by DNA methylation in both human solid tumors and hematological malignancies. However, the role of IRF8 in lung carcinoma remains elusive. In this study, we determined IRF8 epigenetic regulation, biological functions, and the signaling pathway involved in non-small cell lung cancer (NSCLC). METHODS: IRF8 expression were determined by Q- PCR. MSP and A+T determined promotor methylation. MTS, clonogenic, Transwell assay, Flow cytometry, three-dimensional culture and AO/EB stain verified cell function. In vivo tumorigenesis examed the in vivo effects. By Chip-QPCR, RT-PCR, Western blot and Immunofluorescence staining, the mechanisms were studied. RESULTS: IRF8 was significantly downregulated in lung tumor tissues compared with adjacent non cancerous tissues. Furthermore, methylation-specific PCR analyses revealed that IRF8 methylation in NSCLC was a common event, and demethylation reagent treatment proved that downregulation of IRF8 was due to its promoter CpG hypermethylation. Clinical data showed that the IRF8 methylation was associated with tumor stage, lymph node metastasis status, patient outcome, and tumor histology. Exogenous expression of IRF8 in the silenced or downregulated lung cancer cell lines A549 and H1299 at least partially restored the sensitivity of lung cancer cells to apoptosis, and arrested cells at the G0/G1 phase. Cell viability, clonogenicity, and cell migration and invasive abilities were strongly inhibited by restored expression of IRF8. A three-dimensional culture system demonstrated that IRF8 changed the cells to a more spherical phenotype. Moreover, ectopic expression of IRF8 enhanced NSCLC chemosensitivity to cisplatin. Furthermore, as verified by Chip-qPCR, immunofluorescence staining, and western blotting, IRF8 bound to the T cell factor/lymphoid enhancer factor (TCF /LEF) promoter, thus repressing beta catenin nuclear translocation and its activation. IRF8 significantly disrupted the effects of Wnt agonist, bml284, further suggesting its involvement in the Wnt/beta-catenin pathway. CONCLUSION: IRF8 acted as a tumor suppressor gene through the transcriptional repression of beta-catenin-TCF/LEF in NSCLC. IRF8 methylation may serve as a potential biomarker in NSCLC prognosis. PMID- 30466107 TI - MTHFD2 Overexpression Predicts Poor Prognosis in Renal Cell Carcinoma and is Associated with Cell Proliferation and Vimentin-Modulated Migration and Invasion. AB - BACKGROUND/AIMS: To investigate the role of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in the clinical prognosis and cell biology of renal cell carcinoma (RCC). METHODS: A total of 137 RCC tissues were evaluated by immunohistochemistry. The relationship between MTHFD2 overexpression and clinical parameters and vimentin expression was assessed. Kaplan-Meier curves and the log rank test were applied for survival analysis according to MTHFD2 and vimentin expression in RCC tissues. The expression of MTHFD2 mRNA and protein was examined by quantitative reverse transcription PCR and western blotting, respectively. To determine further the biological activity of MTHFD2 in RCC, 786-O cells were transfected with short hairpin RNA specifically targeting MTHFD2 (shMTHFD2) with or without tumor necrosis factor (TNF)-alpha stimulation. Cell proliferation, cell migration and invasion and drug sensitivity were subsequently assessed using Cell Counting Kit-8, wound healing, and Transwell assays. RESULTS: Immunohistochemical analysis demonstrated that both MTHFD2 and vimentin overexpression was positively associated with clinical staging, pathological grade, and poor overall survival (all P < 0.05). MTHFD2 expression was closely correlated with vimentin overexpression in RCC (r = 0.402, P < 0.001). After knocking down MTHFD2 expression in 786-O cells, decreased cell proliferation, migration, and invasion were observed and accompanied by the reduced expression of vimentin. The effects of MTHFD2 down-regulation could be partially restrained by TNF-alpha treatment. Vimentin expression and cell migration and invasion, but not cell proliferation, were reversed by TNF-alpha stimulation. Furthermore, treatment of 786-O cells with shMTHFD2 increased their sensitivity to chemotherapy drugs. CONCLUSION: The current results demonstrated that MTHFD2 was overexpressed in RCC and associated with poor clinical characteristics, vimentin expression, and cellular features connected to malignant disease, thus, implicating MTHFD2 as a potential target for RCC therapy. PMID- 30466108 TI - The LASSO Program in Oslo: Harm Reduction Using Buprenorphine-Naloxone (Suboxone(r)) in a Low Threshold Setting. AB - BACKGROUND: This is a 6-year retrospective quality control study of the LASSO Program (Low Threshold Substitution Treatment in Oslo), using exclusively Suboxone(r) (buprenorphine-naloxone [BPNX]) in out-patient settings. Adequate abstinence prior to induction is necessary to avoid acute onset opioid withdrawal symptoms; thus, its use in low threshold settings is far less common than methadone. OBJECTIVES: The aim of this study was to determine if BPNX is a safe and feasible medication to use in a low threshold setting. METHODS: The analysis is based on daily supervised BPNX medication. The standardized induction regime started with 4-mg BPNX increasing by 4 mg daily until 16 mg, with individual adjustments based on clinical status. Treatment effect was evaluated by the number of medication induction attempts, treatment length and lag time between initial contact and medication start. Statistical computations were performed with SPSS(r). RESULTS: There were 331 out of 394 registered patient inquires that started on BPNX. Two hundred fifty-three patients (76.4%) completed induction on first attempt with 95% Wilson score CIs of (0.716-0.807). The accumulated percentage increased to 85.2% during successive inductions. No significant association was found between lag time and (i) the number of days on medication during the first induction; or (ii) total treatment length. Patients had a median lag time of 5 days, remained in treatment a median of 52.0 days with an average of 3.9 inductions. There were no cases of severe precipitated withdrawal and only 2 cases of adverse reactions among the 1,293 inductions and 25,544 administered dosages. CONCLUSION: This study shows that BPNX is highly effective in treating marginalized heroin addicts in low threshold settings. Even during their first attempt, 76.4% completed induction. There were no cases of severe precipitated withdrawal. Prolonged lag time affected neither the length of first treatment nor the total treatment length. Individualized induction readiness approach and motivation were central to the above results. PMID- 30466109 TI - The Effect of Scraping Therapy on Perimenopausal Syndrome: A Synthesis of Evidence. PMID- 30466110 TI - ATP Citrate Lyase and LncRNA NONMMUT010685 Play Crucial Role in Nonalcoholic Fatty Liver Disease Based on Analysis of Microarray Data. AB - BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease with unclear molecular mechanisms. Our study intended to identify potential long non-coding RNAs (lncRNAs) and genes, and to determine the potential molecular mechanisms of NAFLD pathogenesis. METHODS: The microarrays of GSE24031 and GSE57425 were downloaded from the Gene Expression Omnibus database. GSE24031 included 4 control and 4 model mice and GSE57425 included 3 control and 3 model mice on the basis of GPL1261 platform. Differentially expressed lncRNAs and mRNAs between control and NAFLD liver tissue were calculated. Gene ontology (GO), pathway enrichment analyses, co-expression network and PPI were performed to analyze the biological roles and pathways for the differentially expressed lncRNAs and mRNAs. Non-alcoholic steatohepatitis (NASH) rats were further chosen to investigate the key protein identified based on co-expression network and protein-protein interaction (PPI) network data. RESULTS: A total of 6 significantly up-regulated and 39 down-regulated lncRNAs, 340 up-regulated and 281 down-regulated mRNAs were identified. LncRNA-mRNA co-expression network were analyzed to show a total of 16 key lncRNAs (node degree > 10) in NAFLD samples compared to control tissues. Three key protein identified on co-expression network and protein-protein interaction (PPI) network data were verified in NASH in vivo. The protein level of ATP-citrate lyase (Acly) was significantly increased while lncNONMMUT010685 and NONMMUT050689 in NAFLD samples, whose regulator gene was x-box binding protein 1 (XBP1) and receptor-interacting protein 1 kinase (RIPK1) respectively, were gradually reduced in NASH. CONCLUSION: In summary, we found a set of lncRNAs and mRNAs differentially expressed in the development of NAFLD. LncRNA Ttc39aos1 and Acly, may be crucial biomarkers for NAFLD. LncRNA NONMMUT010685 and NONMMUT050689, the regulator of XBP1 gene and RIPK1 gene respectively, played important roles in the development of NAFLD. PMID- 30466111 TI - Health Outcomes for Definite Concurrent Chemoradiation in Locally Advanced Non Small Cell Lung Cancer: A Prospective Study. AB - BACKGROUND: In patients with locally advanced lung cancer treated with concurrent chemoradiation, outcome measurements have been mostly limited to survival. OBJECTIVES: We aimed to measure outcomes that matter to these patients beyond survival in a general clinical practice. METHODS: In a prospective single-centre study, consecutive patients with locally advanced non-small cell lung cancer reported their own outcomes using the EORTC Quality of Life Questionnaire Core 30 at baseline, during therapy, at therapy stop and till 1 year after therapy end every 3 months. Survival, complications, quality of death and case-mix variables were measured. RESULTS: There were 32 consecutive patients included prospectively from June 2013 until September 2016. Median overall survival was 24.3 months (95% CI 12.7-35.9). Severe toxicity (grade III-IV) was frequent (haematologic toxicity III-IV in 59%). Patient-reported outcomes (PROs) documented the burden on global health status and on functional domains (physical, role, social, emotional and cognitive functioning). Deterioration was pronounced during and after treatment with drops over 20 up to 40% points from baseline for physical, role and social functioning. Clinically meaningful negative effects did persist up to 6 and 9 months for physical and role functioning. Fifty-six percent of the deceased patients died in hospital. CONCLUSIONS: The assault on health-related quality of life during concurrent chemoradiation for locally advanced lung cancer is considerable. Loss of physical and role functioning persists up to 6 and 9 months after therapy end, respectively. Measuring PROs can help to identify issues for improvement of the value of care delivered. PMID- 30466123 TI - ? PMID- 30466122 TI - Primary Sclerosing Cholangitis and Psychological Wellbeing: A Scoping Review. AB - Primary sclerosing cholangitis (PSC) is a chronic liver disease resulting from the inflammation and scarring of an individual's hepatic bile ducts. With no curative treatment available and a risk of potentially severe complications and death, it is likely that those diagnosed with the illness may experience impairments in their psychological wellbeing. The aim of this scoping review is to locate, chart, and summarize all available literature on how PSC affects mental health and psychological wellbeing, as well as the factors that may or may not impact on the psychological wellbeing of those who have this diagnosis. This exercise identified five key themes within the literature: prevalence and characteristics of mental health problems, quality of life, unmet needs, medical treatment, and biomarkers. Three key recommendations for clinical practice emerge from this review. PMID- 30466124 TI - ? PMID- 30466125 TI - ? PMID- 30466126 TI - ? PMID- 30466127 TI - ? PMID- 30466128 TI - ? PMID- 30466129 TI - ? PMID- 30466130 TI - ? PMID- 30466131 TI - [Alginate on demand as add-on for patients with gastro-oesophageal reflux disease and insufficient PPI effect]. AB - BACKGROUND: Chronic reflux patients with long-term PPI therapy frequently have persistent symptoms. A critical source of the persistent acid reflux is the acid pocket, which can be treated effectively by the non-systemic reflux suppressing action of alginates. METHODS: GERD patients with at least one year of PPI long term therapy, who were dissatisfied with their therapy, were treated over a period of 14 days with alginate as add-on and when required (up to 4 times daily) in a prospective, multi-centre, non-randomised, non-interventional and uncontrolled study in GP practices. The frequency of symptoms in the week before treatment was recorded, as well as in the second week of the study phase and the consumption of alginate. The validated GERD Q score was also applied. The patients assessed satisfaction with the therapy on a five-point Likert scale (very unhappy - happy) before the beginning and at the end of the study. The primary endpoint of the study was improvement in satisfaction with the therapy by >= 1 point. RESULTS: 155 patients (54 % women, median age 57 (18 - 85) years) entered the study. Six patients had to be excluded from the final efficacy analysis (no intake of study drug, lost to follow-up). The median duration of GORD was 8 (1 - 50) years and the median time on PPI therapy was 6 years. On average the patients took 3 sachets of alginate per day. The alginate therapy led to an improvement by at least 1 point on the Likert scale in 72 % of patients (1 step n = 45, 2 steps n = 41, 3 steps n = 16, 4 steps n = 5). Patients with a Gerd Q score > 8 showed a higher response rate at 81 %. There was improvement in all typical reflux symptoms and sleep disorders. The treatment was generally well tolerated. CONCLUSIONS: A reflux blocking alginate taken on demand is an effective and safe option for the treatment of breakthrough symptoms in GERD patients on PPI. PMID- 30466132 TI - Anti-inflammatory and Quinone Reductase-Inducing Compounds from Beilschmiedia mannii. AB - Previous studies on the therapeutic potential of plant species found in the diet of chimpanzees living in Tai National Park have shown that they could be potential candidates for the search of new molecules useful for humans. Based on the screening of some of these plants, the fruits of Beilschmiedia mannii, whose dichloromethane extract showed cancer chemopreventive properties, were selected. Bioactivity-guided fractionation of the extract resulted in the isolation and identification of two gamma-pyrones, including desmethoxydihydromethysticin (1: ), found in a natural source for the first time, and a new congener, beilschmiediapyrone (2: ), as well as five known alkamides (3: - 7: ). Their structures were established by using nuclear magnetic resonance spectroscopy and mass spectrometry methods. The isolated compounds were evaluated for their cancer chemopreventive potential by using quinone reductase induction and nuclear factor kappa B inhibition tests in Hepa 1c1c7 and HEK-293/NF-kappaB-Luc cells, respectively. Among them, compounds 1: and 2: were the most active. The concentrations to double the quinone reductase activity were 7.5 uM for compound 1: and 6.1 uM for compound 2: . Compounds 1: and 2: inhibited nuclear factor kappa B with IC50 values of 2.1 and 3.4 uM, respectively. These results are promising with regard to cancer chemoprevention, especially because this plant is also used for cooking by the local population around the Tai forest. PMID- 30466133 TI - [Chronic granulomatous disease as a rare differential diagnosis of inflammatory bowel disease]. AB - BACKGROUND: Chronic granulomatous disease is a rare disease with a prevalence of approximately 150 cases in Germany. An intestinal manifestation that mimics chronic inflammatory bowel disease (IBD) has only been described in a few cases. As a result of a deficient superoxide-synthesis, frequent and recurrent infections caused by rare pathogens have been described. We present the case of a 28-year old patient who has been diagnosed with IBD at the age of 2 years. He showed recurrent liver abscesses and the picture of a chronic IBD. METHODS: Clinical and laboratory data was obtained and endoscopic, radiologic and histologic examinations, tests for granulocytic functions as well as a genetic analysis were performed. Literature of the PubMed database and recent literature were analyzed. CASE: Under immunosuppressive therapy, with TNF -blocker Adalimumab followed by therapy with integrin-receptor antagonist Vedolizumab, the patient developed recurrent abscesses of the liver. Those were the result of infection with a sensitive Staphylococcus aureus strain. Colonoscopy showed stenosis of the rectum and some inflammatory activity. Intestinal symptoms were unresponsive to all therapies for IBD. Furthermore, there was a presence of active acne and recurrent liver abscesses due to bacteria not typical for intestinal infections. Consequently, we considered a granulocyte dysfunction as the underlying cause. Diagnosis of a chronic granulomatous disease was confirmed by flow cytometry and oxidative burst test. Genetic analysis showed a homozygote mutation of the p47phox (NCF1) gene located on chromosome 7, which represents the most common autosomal recessive form with 20 - 25 % of cases. RESULTS: In light of recent literature, this case report shows that chronic granulomatous disease should be considered as a differential diagnosis to therapy refractory IBD. This is the case, especially in young patients, when recurrent bacterial lesions caused by intestine-atypical pathogens appear. PMID- 30466134 TI - Colorectal cancer stage at diagnosis in migrants and non-migrants: a cross sectional analysis of the KoMigra Study in Germany. AB - BACKGROUND: Colorectal cancer is one leading cause of cancer-related morbidity and mortality. Its prognosis depends largely on tumour stage at diagnosis. Migration status was associated with late stage at diagnosis in some studies, yet results are inconsistent. METHODS: The cross-sectional study "The Diagnostics of Colorectal Carcinoma in Migrants and Non-Migrants in Germany" (KoMigra) investigated the association between migration background and tumour stage of colorectal cancer at diagnosis in a large German urban area. Patient variables were collected via a survey translated into nine languages. Data on tumour stage were extracted from medical records. RESULTS: 437 patients could be recruited for analysis. Explorative logistic regression yielded no significant difference for tumour stage "I" versus "II-IV" according to the tumour classification "Union Internationale Contre le Cancer" (UICC) between migrants and non-migrants. Although the odds of a higher tumour stage were consistently higher in migrants than non-migrants, the effect estimates had wide confidence intervals. In descriptive analyses, migrants reported symptoms more often and for longer time than non-migrants. This was especially true for patients with poor proficiency of German. CONCLUSIONS: Migration background was not significantly associated with advanced tumour stage at diagnosis. However, the effect of poor language proficiency should be explored further. PMID- 30466135 TI - Never seen before? Opisthorchiasis and Clonorchiasis. AB - Parasitic diseases are relatively rarely diagnosed and treated in Europe. Therefore, European clinicians are not familiar with their clinical and imaging features. In an era of increased human migration, it is fundamental for clinicians to be able to identify such diseases. We have recently described the features of cystic echinococcosis, schistosomiasis, fascioliasis and ascariasis. Here, we report on the clinical and imaging features as well as on the current therapy options of infections by the small liver flukes: Clonorchis sinensis, Opisthorchis viverrini (Southeast Asian liver fluke) and Opisthorchis felineus (cat liver fluke) and other Opisthorchis species prevalent in South Asia. PMID- 30466136 TI - Presence of Zearalenone in Cereal Grains and Its Exposure Risk Assessment in Indian Population. AB - Zearalenone (ZEA) is a toxic metabolite of Fusarium genera that frequently contaminates cereal grains. India being a tropical country provides suitable conditions for fungal invasion to the cereals. In the absence of any regulatory limits for ZEA in India, the present study was carried out to analyze the contamination levels of ZEA in different cereal samples consumed by Indian population and its exposure assessment through intake. Out of 117 cereal samples comprising of wheat, rice, corn, and oats, 70 (84%) were found to be positive for ZEA contamination, among which 24 (33%) samples exceeded the permissible limits proposed by European Union when analyzed by high-performance liquid chromatography. The positive samples were further validated by Liquid Chromatography-Mass Spectroscopy (LC-MS) analysis. Based on the quantitative estimation of ZEA contamination in cereals and their daily consumption values, the probable daily intake of ZEA was found to be 16.9- and 7.9-fold higher in rice and wheat samples, respectively, than the tolerable daily intake prescribed by European Food Safety Authority. The presence of ZEA at high levels indicates a higher exposure risk for Indian population as wheat and rice are staple foods in India. Thus, there is an immediate need to set the permissible levels of ZEA in India to safeguard the health of 1.34 billion people. PRACTICAL APPLICATION: High levels of ZEA contaminated wheat and rice samples suggest that the consumers are at a greater exposure risk. The study will help the Indian regulatory bodies to set the permissible level of ZEA in different cereal grains so as to safeguard the health of common masses. This can happen by simply adopting to European Food Safety Authority standards or depending on the consumption pattern of food and its occurrence, the new safe limit can be prescribed in India like in other Asian countries. PMID- 30466137 TI - Predictors of hospital discharge in cancer patients with pericardial effusion undergoing surgical pericardial drainage. AB - INTRODUCTION: Pericardial effusion (PE) is a complication of late-stage cancer and some patients never leave the hospital despite drainage. The main objective of this study was to identify predictors of hospital discharge in cancer patients with (PE) who underwent pericardial drainage. We also report the occurrence of paradoxical hemodynamic instability (PHI). METHODS AND MATERIALS: A retrospective study was carried out in a cancer center. Patients included had malignancy, PE, and underwent surgical drainage. An institutional database was reviewed for preoperative variables, analyzed for hospital discharge. RESULTS: One-hundred and thirteen patients were included, with a mean age of 54 years old (SD 14.3). Sixty three patients were discharged from hospital (55.7%). Age (odds ratio [OR], 1.04; P = 0.004), higher ECOG status (OR, 0.63; P = 0.019), recent chemotherapy (OR, 3.40; P = 0.007), and renal failure (OR, 0.14; P = 0.002) were associated with hospital discharge. Median survival was 43 days (IQ 25%-75%; 15-162). Patients with pulmonary embolism or neutropenia were at greater risk of developing PHI (OR, 10.11; P = 0.009 and OR, 12.13; P = 0.015, respectively). CONCLUSION: Almost half of the patients never left the hospital. Patients with no chemotherapy within 45 days of procedure, patients with renal failure and higher ECOG status are at greater risk of not getting discharged. PHI remains a serious condition with high mortality. PMID- 30466138 TI - The rich are different: Unravelling the perceived and self-reported personality profiles of high-net-worth individuals. AB - Beyond money and possessions, how are the rich different from the general population? Drawing on a unique sample of high-net-worth individuals from Germany (>=1 million Euro in financial assets; N = 130), nationally representative data (N = 22,981), and an additional online panel (N = 690), we provide the first direct investigation of the stereotypically perceived and self-reported personality profiles of high-net-worth individuals. Investigating the broad personality traits of the Big Five and the more specific traits of narcissism and locus of control, we find that stereotypes about wealthy people's personality are accurate albeit somewhat exaggerated and that wealthy people can be characterized as stable, flexible, and agentic individuals who are focused more on themselves than on others. PMID- 30466139 TI - Modularity in the intact and spinal cat: methods, issues and questions for the future. AB - The paper of Etienne Desrochers and colleagues in the Frigon lab (Desrochers et al., this volume) is an important contribution. They provide a clear demonstration of a synergy organization in the spinal cord of the cat that is closely similar before and after spinal transection, using the methods of Krouchev and colleagues (2006) of 'Direct Component Analysis' (DCA). PMID- 30466140 TI - Daily Maximum Erythemal Dose Rates in the Tropics. AB - The maximum erythemal dose rate (EDRmax ) at the Earth's surface tends to occur at local noon. However, clouds can make the timing of EDRmax significantly away from local noon. In fact, EDRmax and its time of occurrence depend mainly on the solar zenith angle at noon (SZAn ), site's altitude, the total ozone column (TOC), cloud cover, cloud genera and aerosols. This work depicts the daily incidence of EDRmax for Belo Horizonte (19.92 degrees S, 43.94 degrees W, 858 m a.s.l.) in the Southern Hemisphere tropics for a period of five years (2005 2010). Daily values of EDRmax ranged from 0.063 W m-2 (1sigma > 6.9%, Moderate UV Index of 3, winter) to 0.486 W m-2 (Extreme UVI of 19, summer). Indicative values of EDRmax for cloudless days were 0.336 W m-2 (summer, TOC = 258 Dobson Units), 0.311 W m-2 (fall, 260 DU), 0.253 W m-2 (spring, 274 DU) and 0.143 W m-2 (winter, 246 DU). Radiation enhancement events by clouds made EDRmax up to 45% higher than the reference EDRmax for cloudless summer skies at a time resolution of a few minutes. The main cloud genera to be associated with such events are Cumulus, Altocumulus, Altostratus and Stratocumulus. The EDR can also be significantly affected by aerosols, which attenuated on average 0.031 W m-2 (22%) of the erythemal UV in a case study at the site. PMID- 30466141 TI - Effective filter screening approach with fractionation for enabling inline filtration of protein A eluate. AB - Filtration of protein A eluates inline with a chromatography column is a common challenge for monoclonal antibody (mAb) purification due to the high system backpressure during elution, which can result in system shut down or require a decreased elution flow rate. The inability to filter inline not only poses a risk for process deviations, but can also lead to tank constraints and microbial ingress risk. Here, we evaluated and described a novel approach for identifying filters for inline filtration of protein A eluates at pilot scale. We fractionated the protein A eluates into 0.25 column volume fractions to screen filters under constant pressure or constant flow conditions. We observed that filtration properties for eluate fractions are significantly different from the offline eluate, and the conventional filter sizing study using elution pool is not able to predict inline filtration behavior. Through the submicron particle counts and size distribution in pre- and post-filtration samples, we determined that both attributes contribute to the high pressure across the filters. A successful proof-of-concept experiment on a column 10 cm in diameter inline with the filter train selected validated this fractionation method, and the approach was applied to a different mAb molecule to confirm effectiveness. PMID- 30466142 TI - Preliminary results show that males born with hypospadias from 1959-1994 had the same psychiatric morbidity as population-based controls. AB - AIM: Population studies have shown an increased risk of neurodevelopmental disorders in males born with the congenital condition hypospadias, where the opening of the urethra is on the underside of the penis. We investigated overall psychiatric morbidity in cases and matched controls. METHODS: This study compared 167 men born with hypospadias from 1959-1994 in Stockholm or Gothenburg in Sweden using hospital registers. They were compared with controls from the Swedish population registry, who were contacted by regular mail and students who were recruited by local advertisements. The total sample had a mean age of 33.5 years (range 19-54). They completed self-rating scales for depressive, anxiety and obsessive-compulsive symptoms and symptoms of attention deficit hyperactivity disorder. In addition, 33 cases and 47 controls underwent psychiatric morbidity interviews that covered the 17 most common psychiatric diagnoses. RESULTS: A fifth (21%) of both the cases and controls reported current or previous psychiatric symptoms. There were no significant differences in self-rated depression, anxiety or obsessive-compulsive disorder symptoms between the patients or controls or between the different phenotype groups. The distribution was not significantly affected by the severity of hypospadias. CONCLUSION: Psychiatric morbidity was no higher in men with hypospadias than population-based controls. This article is protected by copyright. All rights reserved. PMID- 30466143 TI - Synthesis of highly potent Lymphocyte Function-Associated Antigen-1 Antagonists Labeled with Carbon-14 and with Stable Isotopes, Part 3. AB - The drug candidates (2) and (3) are highly potent LFA-1 inhibitors. They were efficiently prepared labeled with carbon-14 using a palladium-catalyzed carboxylation of an iodo-precursor (5) and sodium formate-14 C to afford acid [14 C]-(6), which was coupled via an amide bond to chiral amines (7) and (8) in 52% and 48% overall yield respectively and with specific activities higher than 56 mCi/mmol and radiochemical purities of 99%. For stable isotopes synthesis, the amine [2 H8 ]-(7) was synthesized in three steps from 2-cyanopyridine-2 H4 using Kulinkovich-Szymonik aminocyclopropanation, followed by coupling to L-alanine 2,3,3,3-2 H4 -N-t-BOC, and then removal of the BOC-protecting group. Amide bond formation with acid (6) gave [2 H8 ]-(2) in 36% overall yield. The amine [13 C4 ,15 N]-(8) was obtained in two steps using L-threonine-14 C4 ,15 N and then coupled to acid [13 C]-(6) to give [13 C5 ,15 N]-(3) in 56% overall yield. PMID- 30466144 TI - Soap Bubbles as a Distraction Technique in the Management of Pain, Anxiety and Fear in Children at the Pediatric Emergency Room: A pilot study. AB - BACKGROUND: Hospitals can cause anxiety, pain and fear in children perceiving medical procedures as intrusive and painful. Among the non-pharmacological strategies, distraction techniques have proved to be effective in the management of pain and distress. METHODS: The aim of the present study is to assess the effectiveness of soap bubbles as a distraction technique for the management of anxiety, fear and pain in children waiting for a medical examination at the pediatric emergency room. We employed a parallel trial design with a sample consisting of 74 children (M = 9.30; SD = 1.10; 50% female) randomly assigned to either a control or experimental group. The children in the experimental group underwent the soap bubble protocol while waiting for a medical examination at the pediatric emergency room. Anxiety, Fear and Pain were assessed by self-report administered to the children before the TRIAGE and the application of the soap bubbles (baseline), after the application of the soap bubbles (T1) and after the medical examination (T2). RESULTS: The children in the experimental group showed a significant reduction of perceived pain while waiting for the medical examination (T1) while no difference was found after the medical examination (T2). Furthermore, the children in the experimental group showed a significant reduction in fear (T1 and T2) while no difference was found in the Anxiety scores measured by the Child Anxiety. CONCLUSION: The use of soap bubbles is a good distraction technique in the reduction of fear and the perception of pain in children awaiting a medical examination at the pediatric emergency room. PMID- 30466145 TI - Synthesis, Structure, Photophysical Properties, and Photostability of Benzodipyrenes. AB - We explored the syntheses, structure, photophysical properties, and photostability of benzodipyrenes (BDPs). BDPs were synthesized through an InCl3 AgNTf2 catalyzed, four-fold alkyne benzannulation reaction. The structures of BDP 4a and its corresponding endoperoxide product were unambiguously confirmed by X ray crystallography. The BDPs reported here can also be recognized as peri- and cata-benzannulated pentacenes with a non-functionalized central ring. Unlike the previous reported pentacene-based polycyclic aromatic hydrocarbons, the absorbance of the BDPs was blue-shifted by ca. 40 nm relative to pentacene, even after extension of pi-conjugation. The newly synthesized BDP products exhibit good relative stability with half-lives as high as 4612 min in THF. PMID- 30466146 TI - Oncologist Recommendation Matters! - Predictors of Psycho-Oncological Service Uptake in Oncology Outpatients. AB - OBJECTIVE: Highly distressed cancer patients often do not use psycho-oncological services (POS). Research on predictors of POS uptake has mainly focused on patient-related variables and less on communication variables, so we examined the link between patient-oncologist communication (i.e., talking about psychosocial distress, providing detailed information, and recommending POS) and POS uptake. METHODS: We conducted a prospective, observational study in an Oncology Outpatient Clinic in Switzerland. Predictors (i.e., patient-related variables and patient's reports of the patient-oncologist communication) were assessed via semi structured interviews and information on outpatient POS uptake was prospectively assessed. For statistical analysis a multivariate logistic regression was performed. RESULTS: Of 333 participants (mean age 61 years; 55% male; 54% Distress Thermometer >=5), 77 (23%) had used POS during a 4-month period. Patients who reported an oncologist recommended POS (odds ratio [OR])=6.27, 95% confidence interval [CI]=3.14-12.85) and those who were not sure if they had received a recommendation (OR=4.64, 95% CI=1.83-11.97) were more likely to attend POS than those who reported receiving no recommendation. Talking about psychosocial distress (OR=0.74, 95% CI=0.38-1.46) and providing detailed information about POS did not predict POS uptake (OR=1.06, 95% CI=0.46-2.38). CONCLUSIONS: Oncologists' expert recommendations to attend POS were strongly associated with patients' uptake of POS. The central role played by oncologists should be accounted for in stepped psycho-oncological care when POS referral pathways are defined. PMID- 30466147 TI - Effects of livestock grazing on grassland carbon storage and release override impacts associated with global climate change. AB - Predicting future carbon (C) dynamics in grassland ecosystems requires knowledge of how grazing and global climate change (e.g., warming, elevated CO2 , increased precipitation, drought and N fertilization) interact to influence C storage and release. Here, we synthesized data from 223 grassland studies to quantify the individual and interactive effects of herbivores and climate change on ecosystem C pools and soil respiration (Rs). Our results showed that grazing overrode global climate change factors in regulating grassland C storage and release (i.e., Rs). Specifically, grazing significantly decreased aboveground plant C pool (APCP), belowground plant C pool (BPCP), soil C pool (SCP), and Rs by 19.1%, 6.4%, 3.1%, and 4.6%, respectively, while overall effects of all global climate change factors increased APCP, BPCP and Rs by 6.5%, 15.3%, and 3.4% but had no significant effect on SCP. However, the combined effects of grazing with global climate change factors also significantly decreased APCP, SCP and Rs by 4.0%, 4.7% and 2.7%, respectively, but had no effect on BPCP. Most of the interactions between grazing and global climate change factors on APCP, BPCP, SCP and Rs were additive instead of synergistic or antagonistic. Our findings highlight the dominant effects of grazing on C storage and Rs when compared with the suite of global climate change factors. Therefore, incorporating the dominant effect of herbivore grazing into Earth System Models is necessary to accurately predict climate-grassland feedbacks in the Anthropocene. This article is protected by copyright. All rights reserved. PMID- 30466148 TI - Consistency of trajectories of suicidal ideation and depression symptoms: Evidence from a randomized controlled trial. AB - BACKGROUND: Depression is a risk factor for suicidal ideation. However, suicidal ideation can occur in the absence of depression and treating depression may not reduce suicidal thinking. This study tested whether trajectories of suicidal thinking are concordant with trajectories of depressive symptoms and sought to identify factors associated with these trajectories. METHODS: Participants were community-based Australian adults (N = 418, 77% female) enrolled in a randomized controlled trial evaluating the effectiveness of an online cognitive-behavioral intervention for suicidal ideation. Separate linear growth mixture models were estimated across 12 months of follow-up to identify longitudinal trajectories of suicidal ideation and depression symptoms. Predictors of latent class membership were tested using logistic regression models. RESULTS: Two-class models were found to have optimal fit for both suicidal thinking and depressive symptoms. Trajectory classes of suicidal ideation were: (1) moderate severity decreasing over time; and (2) high severity remaining stable over time. Depression trajectories were: (1) moderate severity with a small decrease over time; and (2) high severity that decreased moderately over time. Lower perceived burdensomeness was associated with having a greater decrease in both suicidal thinking and depression. More severe mental health symptoms were associated with less decrease in depression symptoms but not with suicidal ideation trajectory. CONCLUSION: Class membership across the two outcomes and predictors of class membership were found to be largely independent. The lack of coupling in trajectories and predictors suggests that changes in suicidal thinking may occur independently of changes in depression. PMID- 30466150 TI - Bilateral facial circumscribed morphea: The first case report. PMID- 30466149 TI - NRT1.1B Improves Selenium Concentrations in Rice Grains by Facilitating Selenomethinone Translocation. AB - Selenium (Se) is an essential trace element for humans and other animals, yet approximately one billion people worldwide suffer from Se deficiency. Rice is a staple food for over half of the world's population that is a major dietary source of Se. In paddy soils, rice roots mainly take up selenite. Se speciation analysis indicated that most of the selenite absorbed by rice is predominantly transformed into selenomethinone (SeMet) and retained in roots. However, the mechanism by which SeMet is transported in plants remains largely unknown. In this study, SeMet uptake was found to be an energy-dependent symport process involving H+ transport, with neutral amino acids strongly inhibiting SeMet uptake. We further revealed that NRT1.1B, a member of rice peptide transporter (PTR) family which plays an important role in nitrate uptake and transport in rice, displays SeMet transport activity in yeast and Xenopus oocyte. The uptake rate of SeMet in the roots and its accumulation rate in the shoots of nrt1.1b mutant were significantly repressed. Conversely, the overexpression of NRT1.1B in rice significantly promoted SeMet translocation from roots to shoots, resulting in increased Se concentrations in shoots and rice grains. With vascular-specific expression of NRT1.1B, the grain Se concentration was 1.83-fold higher than that of wild type. These results strongly demonstrate that NRT1.1B holds great potential for the improvement of Se concentrations in grains by facilitating SeMet translocation, and the findings provide novel insight into breeding of Se enriched rice varieties. This article is protected by copyright. All rights reserved. PMID- 30466151 TI - Impact of microvascular invasion on clinical outcomes after curative-intent resection for intrahepatic cholangiocarcinoma. AB - BACKGROUND: Microvascular invasion (MiVI) is a histological feature of intrahepatic cholangiocarcinoma (ICC) that may be associated with biological behavior. We sought to investigate the impact of MiVI on long-term survival of patients undergoing curative-intent resection for ICC. METHODS: A total of 1089 patients undergoing curative-intent resection for ICC were identified. Data on clinicopathological characteristics, disease-free survival (DFS), and overall survival (OS) were compared among patients with no vascular invasion (NoVI), MiVI, and macrovascular invasion (MaVI). RESULTS: A total of 249 (22.9%) patients had MiVI, while 149 (13.7%) patients had MaVI (+/-MiVI). MiVI was associated with higher incidence of perineural, biliary and adjacent organ invasion, and satellite lesions (all P < 0.01). On multivariable analysis, MiVI was an independent risk factor of DFS (hazard ratios [HR] 1.5; 95%confidence intervals [CI], 1.3-1.9; P < 0.001), but not OS (HR 1.1; 95%CI, 0.9-1.3; P = 0.379). While MiVI and MaVI patients had similar DFS (median, MiVI 14.0 vs MaVI 12.0 months, HR 0.9; 95%CI, 0.7-1.2; P = 0.377), OS was better among MiVI patients (median, MiVI 39.0 vs MaVI 21.0 months, HR 0.7; 95%CI, 0.5-0.8; P = 0.002). Whereas nodal metastasis, R1 margin, and postoperative morbidity were associated with early death (<=18 months) among patients with MiVI, only nodal metastasis was associated with late (>18 months) prognosis. CONCLUSIONS: Roughly 1 out of 5 patients with resected ICC had MiVI. MiVI was associated with advanced tumor characteristics and a higher risk of tumor recurrence. PMID- 30466152 TI - Genome-Wide Association studies on the phyllosphere microbiome: embracing complexity in host-microbe interactions. AB - Environmental sequencing shows that plants harbor complex communities of microbes that vary across environments. However, many approaches for mapping plant genetic variation to microbe-related traits were developed in the relatively simple context of binary host-microbe interactions under controlled conditions. Recent advances in sequencing and statistics make genome-wide association studies (GWAS) an increasingly promising approach for identifying the plant genetic variation associated with microbes in a community context. This review discusses early efforts at GWAS of the plant phyllosphere microbiome and the outlook for future studies based on human microbiome GWAS. A workflow for GWAS of the phyllosphere microbiome is then presented, with particular attention to how perspectives on the mechanisms, evolution, and environmental dependence of plant-microbe interactions will influence the choice of traits to be mapped. This article is protected by copyright. All rights reserved. PMID- 30466153 TI - c-Rel is a cell cycle modulator in human melanoma cells. AB - Melanoma progression and resistance to therapy is associated with faulty regulation of signaling molecules including the central transcription factor NF kappaB. Increased expression of the c-Rel subunit of NF-kappaB has been described in progressing melanoma, though mechanistic implications of this up-regulation remain unclear. To elucidate the functional role of c-Rel in melanoma biology, we have assessed its expression in human melanoma as well as in melanoma cell lines. Suppression of c-Rel expression in four melanoma cell lines resulted in reduced growth and altered cell cycle regulation, namely G2/M and polyploid phase induction. Moreover, mitotic spindle morphology was profoundly altered in three of the cell lines with a predominance of monopolar structures. These findings suggest that c-Rel is involved in G2/M phase regulation, prevention of polyploidy and, consequently, in chromosomal stability. Our results highlight a novel tumor promoting function of c-Rel in human melanoma cells through governing cell cycle regulation. This article is protected by copyright. All rights reserved. PMID- 30466154 TI - Interdisciplinary Research as an Iterative Process to Build Disaster Systems Knowledge. AB - Disasters occur at the intersections of social, natural, and built environments, and robust understanding of these interactions can only occur through insight generated from different disciplines. Yet, there are cultural, epistemological, and methodological differences across the many disciplines concerned with hazards and disasters that can make conducting interdisciplinary research difficult. Approaches are needed to overcome these challenges. This article argues that interdisciplinary disaster research can be successful when it entails an iterative process in which researchers from different disciplines work collaboratively and exert reciprocal influence to generate disaster systems knowledge. Disaster systems knowledge is interdisciplinary and is defined as a comprehensive understanding of the intersections of built, natural, and human environmental factors and their interplay in hazards and disasters. The iterative process can reduce disciplinary biases and privileges by encouraging collaboration among researchers to help ensure disciplinary knowledge complements other disciplinary knowledge, to ultimately generate interdisciplinary disaster systems knowledge. The article concludes by illustrating the process by analyzing a research case study of an interdisciplinary approach to volcanic risk reduction. PMID- 30466155 TI - Three-dimensional finite element stress analysis of teeth adjacent to a traumatized incisor. AB - BACKGROUND/AIMS: Dental trauma is the cause of several consequences to the injured tooth, however, the stresses and strains at adjacent teeth non-directly impacted as a possible cause of sequelaes are still unknown. The aim of this study was to evaluate the stress distribution in incisors adjacent to an upper central incisor when it suffers a frontal impact, in order to identify a potential explanation for sequelae in non-traumatized teeth. MATERIALS AND METHODS: A three-dimensional (3D) finite element model of the maxillary central incisors, lateral incisors and canines was created from a cone-beam scan of a patient with normal occlusion. Non-linear dynamic impact analysis was performed, simulating the right central incisor being impacted by a steel ball with a velocity of 10 m/s. A functional chewing load (100N) on the palatal surface of the central incisor was simulated for comparison. Displacements, strains, and modified von Mises stresses were calculated for the adjacent teeth. RESULTS: During impact on the central incisor, the adjacent teeth showed root displacement. Considerable stress concentrations were observed on the palatal surfaces and proximal and labial surfaces of teeth adjacent to the traumatized incisor. Stresses in the adjacent teeth were higher than stresses calculated during functional biting. Compressive stresses were concentrated at the proximal areas of the adjacent incisors. High levels of deformation were found in the root dentin of adjacent teeth during the traumatic event. CONCLUSIONS: A frontal impact on an anterior tooth generated stresses at the roots of adjacent teeth. These stresses may play a role in clinically observed sequelae of teeth adjacent to traumatized teeth. This article is protected by copyright. All rights reserved. PMID- 30466156 TI - Tissue-engineered nanoclay based 3D in vitro breast cancer model for studying breast cancer metastasis to bone. AB - Breast cancer (BrCa) preferentially spreads to bone and colonizes within the bone marrow to cause bone metastases. To improve the outcome of patients with breast cancer bone metastasis, we need to understand better the mechanisms underlying bone metastasis. Researchers have relied heavily upon in vivo xenografts due to limited availibility of human bone metastasis samples. A significant limitation of these is that they do not have a human bone microenvironment. To address this issue, we have developed a nanoclay based 3D in vitro model of breast cancer bone metastasis using human breast cancer cells mimicking late stage of breast cancer pathogenesis at the metastatic site. This 3D model can provide a microenvironment suitable for cell-cell, and cell-matrix interactions while retaining the behavior of BrCa cells with different metastasis potential (i.e., highly metastatic MDA-MB 231, and low metastatic MCF-7) as shown by the production of alkaline phosphatase (ALP) and matrix metalloproteinase-9 (MMP-9). The sequential culture of mesenchymal stem cells (MSCs) with MCF-7 exhibited 3D tumoroids formation and also occurrence of mesenchymal to epithelial transition of cancer metastasis as evidenced by gene expression and immunocytochemistry. The unique and distinct behavior of highly metastatic MDA-MB-231 and the low metastatic MCF-7 was observed at the bone metastasis site. The changes to migratory capabilities and invasiveness in MDA-MB-231 in comparison to tumor growth with MCF-7 was observed. Together, a novel bone-mimetic 3D in vitro breast cancer model has been developed that could be used to study mechanisms governing the later stage of cancer pathogenesis in bone. PMID- 30466157 TI - Effects of Ultraviolet Radiation (UVA + UVB) on Germination of Carpospores of the Red Macroalga Pyropia acanthophora var. brasiliensis (Rhodophyta, Bangiales): Morphological Changes. AB - Carpospores of Pyropia acanthophora var. brasiliensis are dispersion and reproduction units responsible for giving rise to the diploid filamentous structure of this alga's life cycle. The present study assesses the anthropogenic impact of ultraviolet radiation (UVR) on morphology and ultrastructure, spore viability, autofluorescence of chloroplasts and the amount of intensity of ROS during the germination of carpospores. Carpospores were cultivated at 24 +/- 1 degrees C, 40 +/- 10 MUmol photons m-2 s-1 with photoperiod of 12 h and exposed to UVAR + UVBR for 3 h a day for 2 days with a daily dose of 5.05 J cm-2 for UVAR and 0.095 J cm-2 for UVBR. Samples were cultured for another five days exposed only to PAR in order to confirm their viability after the initial 2-day exposure. Carpospores showed significant sensitivity to UVR exposure after only 48 h, including changes in developmental rate, overall morphology, cell organization and chloroplast autofluorescence. UVR exposure inhibited germ tube formation in carpospores, which were mostly nonviable and/or altered, showing retracted cytoplasm and disorganized cytoplasmic content. Even in the absence of UVR exposure, carpospores remained collapsed, indicating irreversible damage. It can be concluded that UVR is a limiting factor for the development of P. acanthophora. PMID- 30466158 TI - Replication fork collapse at a protein-DNA roadblock leads to fork reversal, promoted by the RecQ helicase. AB - Proteins that bind DNA are the cause of the majority of impediments to replication fork progression and can lead to subsequent collapse of the replication fork. Failure to deal with fork collapse efficiently leads to mutation or cell death. Several models have been proposed for how a cell processes a stalled or collapsed replication fork; eukaryotes and bacteria are not dissimilar in terms of the general pathways undertaken to deal with these events. This study shows that replication fork regression, the combination of replication fork reversal (RFR) leading to formation of a Holliday Junction (HJ) along with exonuclease digestion, is the preferred pathway for dealing with a collapsed fork in Escherichia coli. Direct endo-nuclease activity at the replication fork was not observed. The protein that had the greatest effect on these fork processing events was the RecQ helicase, while RecG and RuvABC, which have previously been implicated in this process, were found to play a lesser role. Eukaryotic RecQ homologues, BLM and WRN, have also been implicated in processing events following replication fork collapse and may reflect a conserved mechanism. Finally, the SOS response was not induced by the protein-DNA roadblock under these conditions, so did not affect fork processing. This article is protected by copyright. All rights reserved. PMID- 30466159 TI - Lung inflammation and disease: A perspective on microbial homeostasis and metabolism. AB - It is now well appreciated that the human microbiome plays a significant role in a number of processes in the body, significantly affecting its metabolic, inflammatory, and immune homeostasis. Recent research has revealed that almost every mucosal surface in the human body is associated with a resident commensal microbiome of its own. While the gut microbiome and its role in regulation of host metabolism along with its alteration in a disease state has been well studied, there is a lacuna in understanding the resident microbiota of other mucosal surfaces. Among these, the scientific information on the role of lung microbiota in pulmonary diseases is currently severely limited. Historically, lungs have been considered to be sterile and lung diseases have only been studied in the context of bacterial pathogenesis. Recently however, studies have revealed a resilient microbiome in the upper and lower respiratory tracts and there is increased evidence on its central role in respiratory diseases. Knowledge of lung microbiome and its metabolic fallout (local and systemic) is still in its nascent stages and attracting immense interest in recent times. In this review, we will provide a perspective on lung-associated metabolic disorders defined for lung diseases (e.g., chronic obstructive pulmonary disease, asthma, and respiratory depression due to infection) and correlate it with lung microbial perturbation. Such perturbations may be due to altered biochemical or metabolic stress as well. Finally, we will draw evidence from microbiome and classical microbiology literature to demonstrate how specific lung morbidities associate with specific metabolic characteristics of the disease, and with the role of microbiome in this context. (c) 2018 IUBMB Life, 1-14, 2018. PMID- 30466160 TI - Perforating dermatosis associated with multikinase inhibitors: report of two cases, including one associated with lenvatinib. PMID- 30466161 TI - A Bayesian Approach for Extracting Fluorescence Lifetimes from Sparse Data Sets and Its Significance for Imaging Experiments. AB - The measurement of fluorescence lifetimes, especially in small sample volumes, presents the dual challenge of probing a small number of fluorophores and fitting the concomitant sparse data set to the appropriate excited-state decay function. A common method of analysis, such as the Maximum Likelihood (ML) technique, assumes a uniform probability distribution of the parameters describing the fluorescence decay function. An improvement is thus suggested by implementing a suitable nonuniform distribution, as is provided by a Bayesian framework, where the distribution of parameters is obtained from both their prior knowledge and the evidence-based likelihood of an event for a given set of parameters. We have also considered the Dirichlet prior distribution, whose form enables analytical solutions of the fitting parameters to be rapidly obtained. If Gaussian and exponential prior distributions are judiciously chosen, they reproduce the experimental target lifetime to within 20% with as few as 20 total photon counts for the data set, as does the Dirichlet prior distribution. But because of the analytical solutions afforded by the Dirichlet prior distribution, it is proposed to employ a Dirichlet prior to search parameter space rapidly to provide, if necessary, appropriate parameters for subsequent employment of a Gaussian or exponential prior distribution. This article is protected by copyright. All rights reserved. PMID- 30466162 TI - Cracking the Combination: Gut Hormones for the Treatment of Obesity and Diabetes. AB - Obesity and type 2 diabetes are a veritable global pandemic. There is an imperative to develop new therapies for these conditions that can be delivered at scale to patients, which deliver effective and titratable weight loss, amelioration of diabetes, prevention of diabetic complications and improvements in cardiovascular health. Although agents based on glucagon-like peptide-1 (GLP 1) are now in routine use for diabetes and obesity, the limited efficacy of such drugs means that newer agents are required. By combining the effects of GLP-1 with other gut and metabolic hormones such as glucagon (GCG), oxyntomodulin, glucose-dependent insulinotropic peptide (GIP) and peptide YY, we may obtain improved weight loss, increased energy expenditure and improved metabolic profiles. Drugs based on dual agonism of GLP1R/GCGR and GLP1R/GIPR are being actively developed in clinical trials. Triple agonism, for example with GLPR1/GCGR/GIPR unimolecular agonists or using GLP-1/oxyntomodulin/peptide YY, is also being explored. Multi-agonist drugs seem set to deliver the next generation of therapies for diabetes and obesity soon. This article is protected by copyright. All rights reserved. PMID- 30466163 TI - Implementation Quality: Implications for Intervention and Translational Science. AB - PURPOSE: Implementation quality (IQ), a critical concept for translational science, measures the discrepancy between an intervention's intended design and its implementation. Quantifying the impact of IQ on intervention outcomes informs efforts to improve intervention translatability. The purpose of this article is to define and describe IQ and its dimensions (content adherence, quality of delivery, and engagement) with a focus on individualized interventions being delivered in research and practice settings. APPROACH: We apply IQ concepts from intervention science in two contexts: (a) an intervention currently being investigated in an efficacy trial, and (b) a practice situation involving the application of evidence-based practice guidelines during clinic visits. IQ measurement approaches are presented using a study protocol, progress notes, interdisciplinary meeting notes, or clinical guidelines, depending upon whether the intervention is delivered during a research study or a clinical encounter. CONCLUSIONS: The investigators describe the necessary infrastructure and support for capturing IQ data and the subsequent complexities and challenges of collecting, measuring, and analyzing these data. Understanding IQ is critical to advancing translational science. Such understanding informs application of appropriate IQ measures, and promotes effective translation of evidence-based interventions into practice. Policy changes are needed to promote IQ assessment to ensure high-quality clinical encounters during which interventions are effectively delivered. CLINICAL RELEVANCE: In both research and practice settings, the conceptualization and measurement of IQ will improve patient outcomes by advancing translational science and integrating evidence-based interventions into nursing practice. PMID- 30466164 TI - Oral health is a mediator for disease severity in patients with behcet's disease: a multiple mediation analysis study. AB - OBJECTIVES: The aim of the study was to examine whether oral health as an infection focus could mediate disease course in patients with Behcet's disease (BD). METHODS: In the study, oral health of 194 BD patients was examined at baseline and follow-up periods. The reasons for last dental visits were recorded as tooth extraction or regular control visits/planned treatments at the end of follow-up period. The Behcet's disease severity score was calculated with higher scores indicating a more severe course. Mediation analysis was carried out to assess the effects of oral health on disease severity score at follow-up period in the study. RESULTS: Dental and periodontal indices were found to be higher at follow-up visit compared to those of baseline (p<0.05). Disease severity score was found to be higher in males (5.3+/-2.4) compared to females (4.4+/-2.5) in the whole group (p=0.005). Moreover, patients having tooth extraction at their last dental visit and patients with dental caries had a more severe disease course (5.4+/-2.4; 5.5+/-2.5) compared to others (4.2+/-2.3; 4.4+/ 2.4)(p<0.0001). In multiple mediation analysis, disease severity score was a dependent variable and was directly mediated by male gender (B=-0.8822, p=0.0145) and indirectly mediated through the presence of dental caries (B=0.9509 p=0.0110) and need of tooth extraction (B=0.8758 p=0.0128). CONCLUSION: Both presence of dental caries and need of tooth extraction were observed to be effective mediators for a more severe disease course in BD. Therefore, better oral health should be aimed to eliminate microbial factors, which are a part of pathogenic processes. This article is protected by copyright. All rights reserved. PMID- 30466165 TI - Predicting Genes in Single Genomes with AUGUSTUS. AB - AUGUSTUS is a tool for finding protein-coding genes and their exon-intron structure in genomic sequences. It does not necessarily require additional experimental input, as it can be applied in so-called ab initio mode. However, extrinsic evidence from various sources such as transcriptome sequencing or the annotations of closely related genomes can be integrated in order to improve the accuracy and completeness of the annotation. AUGUSTUS can be applied to single genomes, or simultaneously to several aligned genomes. Here, we describe steps required for training AUGUSTUS for the annotation of individual genomes and the steps to do the actual structural annotation. Further, we describe the generation and integration of evidence from various sources of extrinsic evidence. (c) 2018 by John Wiley & Sons, Inc. PMID- 30466166 TI - Comparing Kadish, TNM, and the modified Dulguerov staging systems for esthesioneuroblastoma. AB - BACKGROUND: Esthesioneuroblastoma (ENB) is a rare neuroendocrine tumor. The purpose of this study was to compare the Kadish, tumor-node-metastasis (TNM), and Dulguerov's modified TNM staging in order to determine the impact of the stage on primary surgical treatment selection, margin status, and survival. METHODS: The National Cancer Database (NCDB) was used to identify patients diagnosed with ENB between 2004 to 2015. Patients were excluded based on the ability to properly stage their disease as well as the availability of treatment data. RESULTS: Eight hundred eighty-three patients had sufficient data for analysis. On multivariate analysis, age and government insurance were associated with primary surgical treatment, whereas tumor stage, gender, race, hospital type and volume, and comorbidity score were not. Age, charlson-deyo comorbidity (CDCC) score, hospital volume, and nodal status were found to be predictors of survival. Multivariate analysis controlling for stage failed to demonstrate clear survival differences between staging in both TNM and Kadish systems. T-stage and the presence of regional nodal metastasis were associated with an increased risk of positive margins on multivariate analysis. CONCLUSION: Although primary surgical management and positive margins can be predicted by certain patient and tumor factors, clinical staging systems for ENB poorly predict prognosis over a 10-year horizon. PMID- 30466167 TI - Lipid lowering in dialysis patients with cardiovascular disease who are awaiting kidney transplantation. AB - Dyslipidemias are highly prevalent in chronic kidney disease, end-stage renal disease and kidney transplant patients. These dyslipidemias are associated with high cardiovascular risk and mortality. Many clinical trials have shown that statin therapy can significantly reduce adverse cardiovascular events in chronic kidney disease patients and kidney transplant recipients. However, three major trials did not show a benefit of statin therapy in end-stage renal disease patients on dialysis. Major guidelines either recommend against the use of statins in patients on dialysis or provide no recommendations about statin use for this complex patient population. As a result, we suspect many patients on dialysis are not on statins, even if they have known atherosclerotic cardiovascular disease. When these patients receive kidney transplants, the risk of adverse cardiovascular events increases in the peri-operative period. Although, there are no randomized clinical trials looking at statin use in these patients, we suggest that statin use be considered in patients with a history of atherosclerotic cardiovascular disease, to potentially minimize peri-operative cardiovascular complications. We also recommend further research to determine whether statin therapy in dialysis patients awaiting kidney transplant is associated with better survival. This article is protected by copyright. All rights reserved. PMID- 30466168 TI - Key amino acid residues of the AGT1 permease required for maltotriose consumption and fermentation by Saccharomyces cerevisiae. AB - AIMS: The AGT1 gene encodes for a general alpha-glucoside-H+ symporter required for efficient maltotriose fermentation by Saccharomyces cerevisiae. In the present study we analyzed the involvement of four charged amino acid residues present in this transporter that are required for maltotriose consumption and fermentation by yeast cells. METHODS AND RESULTS: By using a knowledge-driven approach based on charge, conservation, location, 3D structural modeling and molecular docking analysis, we identified four amino acid residues (Glu-120, Asp 123, Glu-167 and Arg-504) in the AGT1 permease that could mediate substrate binding and translocation. Mutant permeases were generated by site-directed mutagenesis of these charged residues, and expressed in a yeast strain lacking this permease (agt1?). While mutating the Arg-504 or Glu-120 residues into alanine totally abolished (R504A mutant) or greatly reduced (E120A mutant) maltotriose consumption by yeast cells, as well as impairing the active transport of several other alpha-glucosides, in the case of the Asp-123 and Glu-167 amino acids it was necessary to mutate both residues (D123G/E167A mutant) in order to impair maltotriose consumption and fermentation. CONCLUSIONS: Based on the results obtained with mutant proteins, molecular docking and the localization of amino acid residues, we propose a transport mechanism for the AGT1 permease. SIGNIFICANCE AND IMPACT OF THE STUDY: Our results present new insights into the structural basis for active alpha-glucoside-H+ symport activity by yeast transporters, providing the molecular bases for improving the catalytic properties of this type of sugar transporters. This article is protected by copyright. All rights reserved. PMID- 30466169 TI - Proteomic analysis of dentin-enamel junction and adjacent protein-containing enamel matrix layer of healthy human molar teeth. AB - The dentin-enamel junction (DEJ) is the border where two different mineralized structures - enamel and dentin - meet. The protein-rich DEJ, together with the inner enamel region of mature teeth, is known to exhibit higher fracture toughness and crack growth resistance than bulk phase enamel. However, an explanation for this behavior has been hampered by the lack of compositional information for the DEJ and the adjacent enamel organic matrix (EOM). We studied proteomes of the DEJ and EOM of healthy human molars and compared them with dentin and enamel proteomes from the same teeth. These tissues were cut out of tooth sections by laser capture microdissection, proteins were extracted and cleaved by trypsin, then processed by liquid chromatography coupled to tandem mass spectrometry to analyze the proteome profiles of these tissues. This study identified 46 proteins in DEJ and EOM. The proteins identified have a variety of functions, including calcium ion-binding, formation of extracellular matrix, formation of cytoskeleton, cytoskeletal protein binding, cell adhesion, and transport. Collagens were identified as the most dominant proteins. Tissue specific proteins, such as ameloblastin and amelogenin, were also detected. Our findings reveal new insight into proteomics of DEJ and EOM, highly mineralized tissues that are obviously difficult to analyze. PMID- 30466170 TI - Intermetallic electride catalyst as a new platform for ammonia synthesis. AB - Electrides loaded with transition-metal (TM) nanoparticles have recently attracted attentions as emerging materials for catalytic NH3 synthesis. However, they suffer from the disadvantages of the growth and aggregation of the nanoparticles. TM-containing intermetallic electrides appear to be promising catalysts with the advantages of both electride features and transition metals in a single phase. Here we show that LaRuSi is an intermetallic electride showing a superior activity for NH3 synthesis and report direct evidence of electride character-induced catalytic performance. The discussion is made mainly based on the contrasting synthesis rates over the isostructural compounds, LaRuSi, CaRuSi and LaRu2Si2 and the N2 isotope-exchange reactions over these compounds. We show that lattice hydride ions, which can reversibly exchange with anionic electrons, are indispensable in the promotion of NHx formation. The mechanism derived from the present findings provides new guidelines for NH3 synthesis. PMID- 30466171 TI - USP14 promotes K63-linked RIG-I deubiquitination and suppresses antiviral immune responses. AB - Retinoic acid-inducible gene I (RIG-I) is a critical RNA virus sensor that initiates antiviral immune response through K63-linked ubiquitination. In this study, we demonstrated USP14, a deubiquitinating enzyme, as a negative regulator in antiviral responses by directly deubiquitinating K63-linked RIG-I. USP14 knockdown significantly enhanced RIG-I-triggered type I IFN signaling and inhibited vesicular stomatitis virus (VSV) replication both in mouse peritoneal macrophages and THP1 cells. USP14 overexpression in HeLa cells attenuated RIG-I triggered IFN-beta expression and promoted VSV replication. Besides, USP14 specific inhibitor, IU1, increased RIG-I-mediated type I IFN production and antiviral responses in vitro and in vivo. In addition, USP14 could interact with RIG-I and remove RIG-I K63-linked polyubiquitination chains. This article is the first to report that USP14 acts as a negative regulator in antiviral response through deubiquitinating K63-linked RIG-I. These findings provide insights into a potential new therapy targeting USP14 for RNA virus-related diseases. PMID- 30466172 TI - James Lind Alliance research priorities: how do we identify people at high risk of Type 2 diabetes and help prevent the condition from developing? AB - AIMS: To review the evidence regarding the identification of those at high risk of Type 2 diabetes and the conceptual and clinical criteria defining high risk, the prevention or delay of onset of Type 2 diabetes through lifestyle interventions, and the evolution of evidence from efficacy trials, through effectiveness trials in real-world settings, to implementation programmes at scale. METHOD: The wide scope of this review precluded a systematic approach, therefore, we present a narrative review that highlights key themes and contemporary developments, drawing on landmark studies, previous systematic and expert reviews, and previous meta-analyses. RESULTS: While the diagnostic thresholds for Type 2 diabetes are accepted, international consensus on whether, and how, to classify those at high risk of Type 2 diabetes has not been achieved. There is ongoing debate about which laboratory test to use and each test's corresponding inclusion threshold, about where the balance of clinical benefits and harms sit when defining thresholds, and about how affordability of subsequent preventative interventions might influence the derivation of such thresholds within any particular population. A remarkable international effort has seen the evolution of interventions for those at high risk move from efficacy trials, through effectiveness trials, to implementation at scale, and the evidence supporting each stage is reviewed. CONCLUSIONS: To achieve healthcare system sustainability, many countries are now focusing on disease prevention. To complement population-level interventions that address the obesogenic environment, lifestyle interventions that empower individuals at high risk of Type 2 diabetes to modify this risk beneficially are now being implemented at scale. This article is protected by copyright. All rights reserved. PMID- 30466173 TI - Effects of 7 T static magnetic fields on the expression of biological markers and the formation of bone in rats. AB - In this study, we aimed to evaluate the effects of 7 T static magnetic fields (SMFs) on rat mesenchymal stem cells (MSCs) in order to determine whether strong SMFs affected the osteogenesis of MSCs. MSCs were prepared from bone marrow cells obtained from the femurs of 7-week-old male Fischer 344 rats. MSCs were then combined with beta-tricalcium phosphate (beta-TCP), yielding two types of TCP/MSC constructs (TCP/P-1 and P-2) on day 0. Exposure was performed for 3 h/day for 6 days, and the experiments were performed twice using different exposure apparatus (cryovials or 4-well chambers) for each experiment. The results from gene expression, protein expression, and histological analyses showed no reproducible effects on both TCP/P-1 and TCP/P-2 MSC constructs, although osteocalcin levels for TCP/P-1 MSC constructs increased significantly once after 7 T exposure in two experiments. These findings contribute to understanding the effects of strong SMFs on MSC and osteoblasts. Bioelectromagnetics. (c) 2018 Wiley Periodicals, Inc. PMID- 30466174 TI - Enabling Directional Sequence-Control via Step-Growth Polymerization of Heterofunctionalized Precision Macromonomers. AB - The synthesis of periodic copolymers with a regularly recurring sequence in one direction along the polymeric backbone is presented, applying a step-growth polymerization of heterofunctionalized precision macromonomers derived from solid phase synthesis (SPS) via photoinduced thiol-ene coupling (TEC). Heterofunctional macromonomers with monomer sequence-control of the AB type present a terminal alkene and a terminal thiol group carrying a photolabile protecting group to avoid uncontrolled polymerization by self-initiation. As protecting group, 3,4 methylenebisoxy-6-nitrobenzyl is attached onto the thiol via its bromide derivative directly on solid support. The protected heterofunctionalized macromonomer is polymerized in a two-step procedure, first cleaving the photolabile group and subsequent polymerization of the macromonomer via TEC, giving a high molecular weight polymer with M-n of 23.8 kDa corresponding to a X n of 10 with one directional sequence-control due to their consistent head-to tail linkage. PMID- 30466175 TI - Diagnosis, anatomy, and electromyography profiles of 73 nonrecurrent laryngeal nerves. AB - BACKGROUND: The purpose of this work was to compare methods of detecting nonrecurrent laryngeal nerves (NRLNs). METHODS: Specificity and sensitivity were compared in three NRLN detection methods: CT, electromyography (EMG), and A-B point comparison. RESULTS: A total of 73 intraoperative pictures and 36 CT details of NRLNs are presented. Incidence of NRLN was 0.39%. Type I NRLN accounted for 50.7%, type IIA 45.2%, type IIB 4.1%. The NRLN median latency was 2.13 ms vs 3.00 ms median in an RLN control group (P < .001). When the threshold was set to 2.5 ms, EMG latency detection had 96.7% sensitivity and 91.6% specificity for detecting NRLN, and the A-B point comparison algrithm had 97.3% sensitivity and 92.5% specificity. Combining EMG latency detection with A-B point comparison achieved 100% sensitivity and specificity for detecting NRLN. CONCLUSION: This is the largest series of NRLN presented in the literature. Latency shorter than 2.50 ms combined with the A-B point comparison method is the ideal algorithm procedure for early NRLN identification. PMID- 30466176 TI - Size-Exclusion Borane Catalyzed Domino 1,3-Allylic/Reductive Ireland-Claisen Rearrangements. Impact of the Electronic and Structural Parameters on the 1,3 Allylic Shift Aptitude. AB - The reductive Ireland-Claisen rearrangement via borane mediated hydrosilylation is reported. The method employs borane catalyst with a special structural design and affords access to synthetically relevant product with high diastereoselectivity. Depending on electronic and structural parameter, the reaction can be coupled with a 1,3-allylic shift, thus the valence isomer of the Ireland-Claisen product is formed. PMID- 30466177 TI - Assembling a Hybrid Pd-Catalyst from Chiral Anionic Co(III)-Complex and Ligand for Asymmetric C(sp3)-H Functionalization. AB - An unusual hybrid palladium catalyst containing an anionic chiral Co(III) complex and a chiral phosphoramidite ligand shows high capacity of catalyzing the asymmetric thioamide-directed C(sp3)-H arylation and delivers excellent levels of yield and enantioselectivity (up to 99% yield, 99% ee). A significant synergy of chiral ligand and anion in the stereochemical control has been observed. Mechanistic investigations have revealed both the nature of the C-H activation and the origin of the enantioselectivity. PMID- 30466178 TI - Hydrogen Peroxide Enhances the Antibacterial Effect of Methylene Blue-based Photodynamic Therapy on Biofilm-forming Bacteria. AB - Recently, increased attention has been focused on endoscopic disinfection after outbreaks of drug resistant infections associated with gastrointestinal endoscopy. The aims of this study were to investigate the bactericidal efficacy of methylene blue (MB)-based photodynamic therapy (PDT) on Pseudomonas aeruginosa (P. aeruginosa), which is the major cause of drug resistant post-endoscopy outbreak, and to assess the synergistic effects of hydrogen peroxide addition to MB-based PDT on biofilms. In planktonic state of P. aeruginosa, the maximum decrease was 3 log10 and 5.5 log10 at 20 and 30 J / cm2 , respectively, following MB-based PDT. However, the maximum reduction of colony forming unit (CFU) was decreased by 2.5 log10 and 3 log10 irradiation on biofilms. The biofilm formation was significantly inhibited upon irradiation with MB-based PDT. When the biofilm state of P. aeruginosa was treated with MB-based PDT with hydrogen peroxide, the CFU was significantly decreased by 6 log10 after 20 J / cm2 , by 7 log10 after 30 J / cm2 irradiation, suggesting significantly higher efficacy than MB-based PDT alone. The implementation of the combination of hydrogen peroxide with MB-based PDT through working channels might be appropriate for preventing early colonization and biofilm formation in the endoscope and post-endoscopy outbreak. This article is protected by copyright. All rights reserved. PMID- 30466179 TI - Prophages in Salmonella enterica: a driving force in reshaping the genome and physiology of their bacterial host? AB - Thanks to the exponentially increasing number of publicly available bacterial genome sequences, one can now estimate the important contribution of integrated viral sequences to the diversity of bacterial genomes. Indeed, temperate bacteriophages are able to stably integrate the genome of their host through site specific recombination and transmit vertically to the host siblings. Lysogenic conversion has been long acknowledged to provide additional functions to the host, and particularly to bacterial pathogen genomes where prophages contribute important virulence factors. This review aims particularly at highlighting the current knowledge and questions about lysogeny in Salmonella genomes where functional prophages are abundant, and where genetic interactions between host and prophages are of particular importance for human health considerations. This article is protected by copyright. All rights reserved. PMID- 30466180 TI - Psychological Work Environment and Suicidal Ideation Among Nurses in Taiwan. AB - PURPOSE: Nurses are exposed to a poor psychological work environment; this may cause poor mental health, which is a risk factor for suicidal ideation. We investigated the association between psychological work environment and suicidal ideation among hospital nurses in Taiwan. DESIGN: We conducted a cross-sectional survey in Taiwan female nurses using stratified sampling by region (north, central, south, and east) to select representative centers for this study. METHODS: A self-report questionnaire including items on demographic data, the psychological work environment, and suicidal ideation was sent to nurses working in hospitals. Multiple logistic regression and population attributable risk analyses were performed to assess the effect of the psychological work environment on suicidal ideation. FINDINGS: A total of 2,734 eligible questionnaires (76.8%) were returned. The prevalence of suicidal ideation was 18.3%, and higher risk was found to be associated with the educational level of junior college or below, higher personal burnout, higher client-related burnout, and always feeling stressed at work. Estimation of population attributable risk showed that higher personal burnout, client-related burnout, and always feeling stressed at work were the most crucial factors among nurses, accounting for 19.4%, 8.6%, and 10.5% of suicidal ideation, respectively. CONCLUSIONS: A considerable proportion of nurses developed suicidal ideation. A poor psychological work environment was a relevant factor for suicidal ideation. CLINICAL EVIDENCE: This study provides relevant knowledge for nursing management levels in preventing the development of suicidal ideation among nurses. Not only for nurses' mental health, but for patient safety and care quality, further studies in improving nurses' psychological work environment are warranted. PMID- 30466181 TI - Displacement of mandibular dentition during total arch distalization according to locations and types of TSADs: 3D Finite element analysis. AB - OBJECTIVE: The aim of this study was to evaluate the biomechanical effects of temporary skeletal anchorage devices (TSADs) on the mandibular dentition and mandible during total arch distalization according to locations and types of the TSADs using finite element (FE) analysis. SETTING AND SAMPLE POPULATION: A model of the mandible and teeth were used to build an FE analysis model. MATERIALS AND METHODS: Four FE models were constructed: Ramal plate (Type A) Sugawara plate (Type B), buccal shelf miniscrew (Type C), and interradicular miniscrew (Type D). A retraction force of 300g per side was applied to the mandibular arch wire. RESULTS: In the sagittal plane, the plates Type A and B showed more distal displacement than the miniscrew Types C and D, especially in the posterior teeth. Type A presented the greatest amount of distal displacement, followed by Types B, C and D. Type A was closest to the line of occlusion, which showed the lowest degree of buccolingual angulations of the molar crowns. Vertically, Type A showed a greater amount of extrusive displacement of the posterior teeth than the other types of TSADs, while Type B showed intrusive displacement of the molars. CONCLUSIONS: The ramal plate showed a greater amount of distal and extrusive displacement of the posterior teeth than the miniscrews. Therefore, clinicians should consider the displacement of mandibular dentition during total arch distalization according to types of the TSADs. This article is protected by copyright. All rights reserved. PMID- 30466182 TI - The Ability of Functionalized Fullerenes and Surface Modified TiO2 Nanoparticles to Photosensitize Peroxidation of Lipids in Selected Model Systems. AB - Photochemical properties of a new class of inorganic nanoparticles, namely a cationic C60 fullerene substituted with three quaternary pyrrolidinium groups (BB6) and a surface modified nanocrystalline TiO2 with bromopyrogallol red (Brp@TiO2 ) were examined for their effectiveness in photogenerating singlet oxygen and free radicals. In particular, their ability to photosensitize peroxidation of unsaturated lipids was analyzed in POPC:cholesterol liposomes and B16 mouse melanoma cells employing a range of spectroscopic and analytical methods. Because melanoma cells typically are pigmented, we examined the effect of melanin on the photosensitized peroxidation of lipids in liposomes and B16 melanoma cells, mediated by BB6 and Brp@TiO2 nanoparticles. The obtained results suggest that peroxidation of unsaturated lipids, photosensitized by BB6 occurs mainly, although not exclusively, via Type II mechanism involving singlet oxygen. On the other hand, if surface modified TiO2 is used as a photosensitizer, Type I mechanism of lipid peroxidation dominates, as indicated by the predominant formation of the free-radical dependent cholesterol oxidation products. The protective effect of melanin was particularly evident when BB6 was used as a photosensitizer, suggesting that melanin could efficiently interfere with Type II processes. This article is protected by copyright. All rights reserved. PMID- 30466183 TI - A Hexavalent Basket for Bottom-Up Construction of Functional Soft Materials and Polyvalent Drugs via "Click" Reaction. AB - Inspired by polyvalency and its prevalence in nature, we developed an efficient synthetic route for accessing a large variety of multivalent and dual-cavity baskets from inexpensive and abundant starting materials. First, the cycloaddition of vinyl acetate to anthracene was optimized to, upon hydrolysis, give dibenzobarrelene derivative 6, which after five functional group transformations and then cyclotrimerization gave heptiptycene dodecaester 4 in an overall 17% yield. Following, compound 4 was converted into D3h symmetric 1, composed of two fused cavitands each holding three terminal alkynes at the rim for conjugation to functional molecules using the highly efficient CuAAC reaction. To survey the reactivity of hexavalent 1, we "clicked" 2-acetamido-2 deoxy-beta-D-glucopyranosyl azide 3,4,6-triacetate (carbohydrate), methoxypolyethylene glycol azide (PEG, Mn = 2000; polymer) and benzyl azide (aromatic) to obtain hexavalent conjugates 12-14 in 50-79% yields. In summary, dual-cavity 1 is an accessible, topologically-unique and hexavalent host that can be "clicked" to a variety of functional molecules for (a) combinatorial lead identification of drugs, (b) preparation of hierarchical soft materials and (c) design of selective chemosensors, scavengers or supramolecular catalysts. PMID- 30466184 TI - A new coupling of an acid-base transporter to PKD and cyst formation. AB - Autosomal dominant polycystic kidney disease (ADPKD) is a devastating disease that affects millions of people, and often leads to renal failure, kidney dialysis, and transplantation (Ghata & Cowley Jr, 2017). PMID- 30466185 TI - Review and meta-analysis found that prenatal folic acid was associated with a 58% reduction in autism but had no effect on mental and motor development. AB - AIM: The impact of prenatal folic acid on children's neurodevelopment and the risk of autism spectrum disorder (ASD) remain unclear and this review and meta analysis aimed to quantify any associations. METHODS: We systematically searched PubMed, Scopus and The Cochrane Library until June 2018 with no language restrictions. Standardised mean differences and odds ratio with 95% confidence intervals are used to describe any associations between folic acid and mental development, motor development and ASD. RESULTS: The search strategy identified 647 papers and 16 were finally included in the meta-analysis after the application of the exclusion criteria. These provided a total cohort size of 756,365 children aged 11 months to 15 years from 10 countries. The main finding was that prenatal use of folic acid was associated with a 58% reduction in the risk of ASD in children. We were surprised that better scores for mental development were associated with low prenatal exposure to folic acid. CONCLUSION: Although the results should be interpreted with caution, they showed that routine prenatal supplements of folic acid were associated with significantly lower levels of ASD. Further studies are needed to reach a firm conclusion, given the multifactorial aetiology of neurodevelopment. This article is protected by copyright. All rights reserved. PMID- 30466186 TI - Role of melanocortin 4 receptor in hypertension induced by chronic intermittent hypoxia. AB - AIM: We previously demonstrated that central nervous system (CNS) melanocortin 4 receptors (MC4R) play a key role in regulating blood pressure (BP) in some conditions associated with increased SNS activity, including obesity. In this study we examined if activation of CNS MC4R contributes to chronic intermittent hypoxia (CIH)-induced hypertension and ventilatory responses to hypercapnia. METHODS: Rats were instrumented with an intracerebroventricular (ICV) cannula in the lateral cerebral ventricle for continuous infusion of MC4R antagonist (SHU 9119) and telemetry probes for measuring mean arterial pressure (MAP) and heart rate (HR). Untreated and SHU-9119 treated rats as well as obese and lean MC4R deficient rats were exposed to CIH for 7 to 18 consecutive days. RESULTS: CIH reduced cumulative food intake by 18+/-5 g while MAP and HR increased by 10+/-3 mmHg and 9+/-5 bpm in untreated rats. SHU-9119 increased food intake (from 15+/-1 to 46+/-3 g) and prevented CIH-induced reduction in food intake. CIH-induced hypertension was not attenuated by MC4R antagonism (average increase of 10+/-1 vs. 9+/-1 mmHg for untreated and SHU-9119 treated rats). In obese MC4R deficient rats CIH for 7 days raised BP by 11+/-4 mmHg. However, when MC4R deficient rats were food restricted to prevent obesity, CIH-induced hypertension was attenuated by 32%. We also found that MC4R deficiency was associated with impaired ventilatory responses to hypercapnia independently of obesity. CONCLUSION: These results show that obesity and the CNS melanocortin system interact in complex ways to elevate BP during CIH and that MC4R may be important in the ventilatory responses to hypercapnia. This article is protected by copyright. All rights reserved. PMID- 30466187 TI - Risk of psychiatric disorders in rosacea: A nationwide, population-based, cohort study in Taiwan. AB - Rosacea has been reported to be associated with psychiatric disorders. Nevertheless, a nationwide study of the relationship between rosacea and comorbid psychiatric diseases in an Asian population has not been conducted. The aim of this study was to clarify the role of rosacea in the various psychiatric disorders by using a nationwide database in Taiwan. Data were obtained from the National Health Insurance Research Database of Taiwan from 2000 to 2013. In total, 7881 patients with rosacea and 31 524 age- and sex-matched controls were enrolled. Patients with rosacea tended to have more coexisting psychiatric disorders. After adjusting for age, sex, comorbidity and residence/regions, the adjusted hazard ratio (HR) of psychiatric disorders for patients with rosacea was 2.761 (95% CI = 2.650-2.877, P < 0.001). Among them, the highest adjusted HR are phobic disorder and obsessive-compulsive disorder of 7.841 (95% CI = 7.526-8.170, P < 0.001) and 6.389 (95% CI = 6.132-6.657, P < 0.001), respectively. The National Health Insurance Research Database of Taiwan does not include the information about rosacea subtypes, severity and laboratory parameters. In conclusion, rosacea is related to various psychiatric disorders. In addition to anxiety and depression, patients are also at increased risk of phobic disorder and obsessive-compulsive disorder. PMID- 30466189 TI - Cost-effectiveness of panel tests for multiple pharmacogenes associated with adverse drug reactions: An evaluation framework. AB - The cost-effectiveness of testing for multiple genes implicated in adverse drug reactions requires the simultaneous assessment of all actionable information, including future prescribing decisions based on incidental findings. We developed methodology for determining the value of pharmacogenetic panel tests, illustrated with a multi-gene panel including HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, HLA B*58:01, HLA-B (158T) and HLA-DQB1 (126Q). If the findings for all alleles are acted upon, regardless of their individual cost-effectiveness, the HLA panel resulted in cost savings of L378 (US$491), and a QALY gain of 0.0069. Based on a stratified analysis and compared with no testing, initial use of the panel was cost-effective in patients eligible for abacavir (HLA-B*57:01), carbamazepine (HLA-A*31:01) and clozapine (HLA-B (158T) and HLA-DQB1 (126Q)) but not for carbamazepine (HLA-B*15:02) or allopurinol (HLA-B*58:01). The methods presented allow for the assessment of the cost-effectiveness of multiple-gene panels. This article is protected by copyright. All rights reserved. PMID- 30466188 TI - The International Childhood Cancer Cohort Consortium (I4C): A research platform of prospective cohorts for studying the aetiology of childhood cancers. AB - BACKGROUND: Childhood cancer is a rare but leading cause of morbidity and mortality. Established risk factors, accounting for <10% of incidence, have been identified primarily from case-control studies. However, recall, selection and other potential biases impact interpretations particularly, for modest associations. A consortium of pregnancy and birth cohorts (I4C) was established to utilise prospective, pre-diagnostic exposure assessments and biological samples. METHODS: Eligibility criteria, follow-up methods and identification of paediatric cancer cases are described for cohorts currently participating or planning future participation. Also described are exposure assessments, harmonisation methods, biological samples potentially available for I4C research, the role of the I4C data and biospecimen coordinating centres and statistical approaches used in the pooled analyses. RESULTS: Currently, six cohorts recruited over six decades (1950s-2000s) contribute data on 388 120 mother-child pairs. Nine new cohorts from seven countries are anticipated to contribute data on 627 500 additional projected mother-child pairs within 5 years. Harmonised data currently includes over 20 "core" variables, with notable variability in mother/child characteristics within and across cohorts, reflecting in part, secular changes in pregnancy and birth characteristics over the decades. CONCLUSIONS: The I4C is the first cohort consortium to have published findings on paediatric cancer using harmonised variables across six pregnancy/birth cohorts. Projected increases in sample size, expanding sources of exposure data (eg, linkages to environmental and administrative databases), incorporation of biological measures to clarify exposures and underlying molecular mechanisms and forthcoming joint efforts to complement case-control studies offer the potential for breakthroughs in paediatric cancer aetiologic research. PMID- 30466190 TI - Outcome after reconstruction of proximal femoral tumors: A systematic review. AB - Tumor resection followed by reconstruction with a proximal femoral endoprosthesis or an allograft-prosthesis composite are the two main alternatives for treatment of proximal femoral malignancies. This review describes the revision rate, implant survival, limb salvage rate, and function. Overall revision rates are high and reasons for failure differ between treatment modalities. Rate and reasons for amputation are comparable between both methods. Functional outcome was reasonable to good on average for both treatment modalities. Level of evidence: IV, systematic review and meta-analysis. PMID- 30466191 TI - Mealtime fast-acting insulin aspart versus insulin aspart for controlling postprandial hyperglycaemia in people with insulin-resistant Type 2 diabetes. AB - AIM: This post hoc analysis explored whether mealtime fast-acting insulin aspart treatment provided an advantage in postprandial plasma glucose (PPG) control vs. insulin aspart in people with Type 2 diabetes receiving high doses of bolus insulin. METHODS: A post hoc, post-randomization, subgroup analysis of a 26-week, randomized, double-blind, treat-to-target trial (onset 2) that compared mealtime fast-acting insulin aspart vs. mealtime insulin aspart, both in a basal-bolus regimen, in people with Type 2 diabetes uncontrolled on basal insulin therapy and metformin. At the end of trial, the impact of fast-acting insulin aspart and insulin aspart on PPG control was assessed with a standard liquid meal test and participants were grouped into three post-randomization subgroups: meal test bolus insulin dose <= 10 units per dose (n = 171), > 10-20 units per dose (n = 289) and > 20 units per dose (n = 146). RESULTS: A statistically significant treatment difference in favour of fast-acting insulin aspart vs. insulin aspart was observed for the change in PPG increment at all post-meal time points (from 1 to 4 h) for those in the > 20 units bolus insulin subgroup. There was no difference in the magnitude of change from baseline in HbA1c level between fast acting insulin aspart and insulin aspart in any of the bolus insulin dose subgroups (data herein). CONCLUSION: Fast-acting insulin aspart may hold promise as a more effective treatment compared with insulin aspart for controlling PPG in people with insulin-resistant Type 2 diabetes. PMID- 30466192 TI - Titanium dental implants with different collar design and surface modifications: a systematic review on survival rates and marginal bone levels. AB - AIM: To compare clinical and radiographic outcomes of dental implants with different neck characteristics. METHODS: A protocol-oriented search aimed at the question: "In patients subjected to tooth replacement with screw-type dental implants does the modification of the implant neck macro or micro-geometry contribute to the improvement of survival rates and maintenance of the peri implant marginal bone levels?" Primary outcomes were survival and marginal bone level (MBL) changes evaluated on randomized controlled trials with >10 participants and follow-up >1 year. Risk of bias was evaluated using the Cochrane Collaboration's tool. The review follows the PRISMA statement. RESULTS: Forty three studies compared: 1. One- versus two-piece implants (N=7); 2. Two-piece implants with different neck characteristics (machined and rough collars, microthreads, LASER microtexturing) (N=21); 3. Two-piece implants with macrogeometry modifications (tapering, back-tapering and scalloping) (N=6). One- and two-piece implants showed similar survival (RR= 0.45, 95% CI: [0.12, 1.66], p=0.23) and MBL changes (WMD=0.09mm, 95% CI: [-0.27, 0.45], p=0.64) at 1-year post-loading. Machined collar implants have higher risk of early failure than rough collar implants (RR= 3.96, 95% CI: [1.12, 13.93], p=0.03) and 0.43mm higher bone resorption (95% CI: [0.0, 0.86], p=0.05). Microthreads (WMD= 0.07mm, 95% CI: [-0.01, 0.15], p=0.10) and LASER microtexturing (WMD=0.15mm, 95% CI: [-0.35, 0.65], p=0.56) do not reduce bone resorption. Scalloped implants have 1.26mm higher resorption (95% CI: [0.72, 2.00], p<0.001). CONCLUSIONS: One- and two piece implants have similar survival and MBL changes. Rough collar implants have lower MBL changes than machined collar implants. Additional modifications to rough collars are irrelevant. This article is protected by copyright. All rights reserved. PMID- 30466193 TI - Advanced Polymers for Reduced Energy Consumption in Architecture. AB - In an effort to slow the progress of climate change, the current scientific community has focused on the reduction of greenhouse gases in order to limit the global average temperature inflation to less than 2 degrees C. The improvement of thermally controlled construction materials can potentially result in lower energy homes/reduced emissions, and lowering the thermal conductivity of insulation materials improves home energy efficiency. Nanoporous insulation foams impart a drastic decrease in thermal conductivity but many polymer properties must be assessed to produce these materials. Passive phase-change materials also represent another key energy-saving device to control heat flux within a living space. Research into unique polymeric systems provides a novel means of encapsulation or creating polymeric cross-linked matrices to prevent leakage and improve mechanical robustness. These two areas of polymer research in architecture represent key advancements for construction materials aimed toward energy savings and energy-related emissions control. PMID- 30466194 TI - Decolonial Pedagogy in Community Psychology: White Students Disrupting White Innocence via a Family Portrait Assignment. AB - A decolonizing standpoint in community psychology is discussed in relation to the Family Portrait Assignment-a pedagogical tool developed and implemented to facilitate white students' decolonial thinking. The Family Portrait Assignment contributes to the limited of decolonial pedagogical tools in community psychology. Through a critical discourse analysis of student's essays, I discuss how decolonial thinking, including a critical sociohistorical examination of colonialism, racism and whiteness, was facilitated. Decoloniality as the disruption of white innocence, an ideological construct embedded within systems of power that sustain structures of whiteness, guides the analysis of student's essays. The purpose of this paper is to demonstrate how the Family Portrait Assignment facilitated white student's decolonial thinking, specifically their process of engaging with and disrupting white innocence. A discussion of decoloniality in community psychology pedagogy, theory, research and action concludes this paper. PMID- 30466195 TI - A wheat dominant dwarfing line with Rht12 which reduces stem cell length and affects GA synthesis, is a 5AL terminal deletion line. AB - Dwarfing and semi-dwarfing are important agronomic traits that have great potential for the improvement of wheat yields. Rht12, a dominant GA(gibberellic acid, GA)-responsive dwarfing gene from the gamma-ray induced wheat mutant Karcagi 522M7K, is located in the long arm of chromosome 5A, which is closely linked with the locus Xwmc410. Rht12 is likely an ideal gene for GA biosynthesis and deactivation research in common wheat. However, information on the Rht12 locus and sequence is lacking. In this study, Rht12 significantly shortened stem cell length and decreased GA biosynthetic components. Using bulked segregant RNA Seq, wheat 660k single nucleotide polymorphism chip detection, and newly developed simple sequence repeat markers, Rht12 was mapped to a 11.21 Mb region at the terminal end of chromosome 5AL, and was found to be closely linked with the Xw5ac207 SSR marker with a 10.73 Mb fragment deletion in all of the homologous dwarfing plants. Transcriptome analyses of the remaining 483 Kb region identified significantly higher expression of the TraesCS5A01G543100 gene encoding the GA deactivation enzyme GA 2-beta-dioxygenase 8 in the dwarfing plants than in the high stalk plants, suggesting that Rht12 reduces plant height by activating TaGA2ox8. Taken together, our findings will promote cloning and functional studies of Rht12 in common wheat. This article is protected by copyright. All rights reserved. PMID- 30466196 TI - A bioactive collagen membrane that enhances bone regeneration. AB - Membranes are an integral component of guided bone regeneration protocols. This pre-clinical study was aimed at enhancing the bioactivity of collagen membranes by incorporating plasmid DNA (pDNA) or chemically modified RNA (cmRNA) encoding bone morphogenetic protein-9 (BMP-9). In addition, we also endeavored to harness the regenerative potential of the periosteum by creating perforations in the membrane. Nanoplexes of polyethylenimine (PEI)-nucleic acids (PEI-pDNA or PEI cmRNA encoding BMP-9) were incorporated into commercially obtained and perforated collagen membranes (PCM) to produce PCM-pDNA(BMP-9) or PCM-cmRNA(BMP-9). After structural characterization, the biodegradation kinetics of PCM, PCM-pDNA(BMP-9) and PCM-cmRNA(BMP-9) were assessed in simulated body fluid in vitro. Using a 24 well transwell plate system with bone marrow stromal cells (BMSCs) in the lower chamber and the PCM to be tested in the upper chamber, the in vitro bioactivity of different PCMs was evaluated by measuring various markers for osteogenesis in BMSCs. Alkaline phosphatase activity was assessed in BMSCs, after 7 and 11 days of exposure to PCM, PCM-pDNA(BMP-9), or PCM-cmRNA(BMP-9). Similarly, calcium deposition and Alizarin red staining in BMSCs were assessed after 14 days of exposure to the three different types of PCM. PCMs were then tested in vivo using the calvarial defect model in rats. After 4 weeks, animals were euthanized and bone specimens were harvested for micro-computed tomography and histological assessments. Incorporation of pDNA or cmRNA did not alter the biodegradation profile of PCMs. Alkaline phosphatase activity trended toward being higher in BMSCs exposed to PCM-cmRNA(BMP-9) or PCM-pDNA(BMP-9), when compared to BMSCs alone. Similar trends were observed when calcium deposition and alizarin red staining was evaluated. Calvarial bone defects treated with PCM-cmRNA(BMP-9) resulted in significantly higher bone volume/total volume % (BV/TV%), when compared to empty defects and trended toward being higher than defects treated with PCM-pDNA(BMP-9) and PCM alone. We demonstrate for the first time that resorbable PCM can be utilized to efficiently deliver pDNA and cmRNA of interest. The released pDNA and cmRNA encoding BMP-9 in this assessment was shown to be functional in vitro as well as in vivo. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 00B: 000-000, 2018. PMID- 30466197 TI - High-voltage electrostatic field-induced oxidative stress: Characterization of the physiological effects in Sitobion avenae (Hemiptera: Aphididae) across multiple generations. AB - In recent decades, man-made electric fields have greatly increased the intensity of electrostatic fields that are pervasively present in the environment. To better understand the physiological alterations exhibited by herbivorous insects in response to changing electric environments, we determined the activities of anti-oxidative enzymes and the metabolic rate of Sitobion avenae Fabricius (Hemiptera: Aphididae) over multiple generations in response to direct and host seed exposure to a high-voltage electrostatic field (HVEF) of varying strength for different durations. Under controlled greenhouse conditions, 20-min direct exposure of S. avenae and wheat seeds to a 2- or 4-kV/cm HVEF resulted in significantly increased superoxide dismutase (SOD) activity in the sixth, 11th, 16th, and 21st generations relative to the control activities, whereas significantly decreased SOD activity was detected in the second generation. In addition, the activities of catalase (CAT) and peroxidase (POD) in S. avenae showed significant decreases over multiple generations. We also examined the suppressive effects of the duration of 4-kV/cm treatment on aphid physiology. The results showed that exposure to the 4-kV/cm HVEF for 20 min exerted adverse effects on CAT and POD activities and significantly decreased the metabolic rates of S. avenae, as demonstrated through evaluations of CO2 production rate, and these parameters were not significantly affected by higher HVEF durations. Overall, these findings increase our understanding of plant-pest interactions under novel HVEF environments and provide information that can improve integrated management strategies for S. avenae. Bioelectromagnetics. (c) 2018 Wiley Periodicals, Inc. PMID- 30466198 TI - Na+ /Ca2+ Exchanger 1 is a Key Mechanosensitive Molecule of the Esophageal Myenteric Neurons. AB - AIM: Our earlier studies showed that mechanical stretch activates inhibitory motor neurons of the esophagus; however, the underlying molecular mechanisms are unclear. Here, we sought to examine if Na+ /Ca2+ exchanger 1 (NCX1) is responsible for the mechanosensitivity in the esophageal myenteric neurons (EMN) of rats and humans. METHODS: The function of NCX1 in primary culture of neurons was determined using calcium imaging, and mechanosensitivity was tested using osmotic stretch and direct mechanical stretch. Axial stretch-induced relaxation of the lower esophageal sphincter (LES) was also studied in vivo in rats. RESULTS: The expression and co-localization of NCX1 with nNOS were identified in the EMN from both rats and humans. The extracellular Ca2+ entry caused by ATP through purinergic signaling in the rat EMN was significantly inhibited by selective NCX blockers. Removal of extracellular Na+ to activate the Ca2+ entry mode of NCX1 induced an increase in the cytoplasmic calcium ([Ca2+ ]cyt ), which was attenuated by NCX blockers. Osmotic stretch and mechanical stretch-induced [Ca2+ ]cyt signaling in the rat and human EMN were attenuated by NCX blockers as well as specific NCX1 knockdown. Osmotic stretch and mechanical stretch also induced [Ca2+ ]cyt signaling in the Chinese hamster ovary (CHO) cells with NCX1 over-expression, which was attenuated by NCX blockers. Finally, NCX blockade inhibited axial stretch-activated LES relaxation in-vivo experiments in the rats. CONCLUSIONS: We demonstrate a novel NCX1/Ca2+ pathway in the mechanosensitive neurons of rat and human esophagus, which may provide a potential therapeutic target for the treatment of esophageal motility disorders. This article is protected by copyright. All rights reserved. PMID- 30466199 TI - Weight Management as a Treatment Option for Gastroesophageal Reflux Disease: A Mechanical or Metabolic Rescuer? PMID- 30466200 TI - Efficacy of Direct-Acting Antivirals in Patients with Hepatitis C Virus/Human Immunodeficiency Virus Coinfection: A Gap between Clinical Trial and Real Practice. PMID- 30466201 TI - The Choice of Interventional Treatment of Gastric Variceal Hemorrhage: What Is Better? PMID- 30466202 TI - The More, the Better? Predicting Prognosis in Primary Biliary Cholangitis. PMID- 30466203 TI - Association between Physical Fitness and Cardiometabolic Risk of Children and Adolescents in Korea. AB - Background: This study aimed to investigate the association between physical fitness and cardiometabolic health of Korean children and adolescents. Methods: In total, 168 participants (89 boys and 79 girls) aged 10-16 years were recruited for the Intervention for Childhood and Adolescent Obesity via Activity and Nutrition Study in 2016. The subjects were categorized into two groups using the definition of metabolic syndrome by the International Diabetes Federation: metabolically unhealthy (with at least two of the five criteria) and healthy groups (with less than one criterion). Correlation analysis of the participants' general characteristics was performed. Odds ratios (ORs) of physical fitness for cardiometabolic risk were evaluated via logistic regression. Results: Metabolically unhealthy children showed greater weight, height, and body mass index, higher Children's Depression Inventory score, and longer screen time than did the metabolically healthy children. Metabolically healthy children showed greater upper and lower extremity muscular strength than did the metabolically unhealthy children (P=0.04 and P<0.001, respectively). In the multiple logistic regression analysis, lower extremity muscle strength was inversely related to the clustered cardiometabolic risk of the children and adolescents with or without adjustment for confounders (OR, 4.32; 95% confidence interval [CI], 1.87-9.97; OR, 7.64; 95% CI, 1.55- 37.74, respectively). Conclusion: Physical fitness, especially lower extremity muscle strength, is significantly inversely associated with individual and clustered cardiometabolic risks in Korean children and adolescents. PMID- 30466204 TI - Will New Instruments for Endoscopic Ultrasound-Guided Tissue Acquisition Make Us Happy? PMID- 30466205 TI - Bright Light Therapy in the Morning or at Mid-Day in the Treatment of Non Seasonal Bipolar Depressive Episodes (LuBi): Study Protocol for a Dose Research Phase I / II Trial. AB - Objective: This study protocol aims to determine, using a rigorous approach in patients with bipolar disorder (BD) and non-seasonal major depressive episode (MDE), the characteristics of bright light therapy (BLT) administration (duration, escalation, morning and mid-day exposures) depending on the tolerance (hypomanic symptoms). Methods: Patients with BD I or II and treated by a mood stabilizer are eligible. After 1 week of placebo, patients are randomized between either morning or mid-day exposure for 10 weeks of active BLT with glasses using a dose escalation at 7.5, 10, 15, 30 and 45 minutes/day. A further follow-up visit is planned 6 months after inclusion. Patients will be included by cohorts of 3, with at least 3 days of delay between them, and 1 week between cohorts. If none meet a dose limiting toxicity (DLT; i.e hypomanic symptoms), the initiation dose of the next cohort will be increased. If one patient meet a DLT, an additionnal cohort will start at the same dose. If 2 or 3 patients meet a DLT, from the same cohort or from two cohorts at the same dose initiation, the maximum tolerated dose is defined. This dose escalation will also take into account DLTs observed during the intra-subject escalation on previous cohorts, with a "Target Ceiling Dose" defined if 2 DLTs occured at a dose. Discussion: Using an innovative and more ergonomic device in the form of glasses, this study aims to better codify the use of BLT in BD to ensure a good initiation and tolerance. PMID- 30466206 TI - Relationship of Working Memory, Processing Speed, and Fluid Reasoning in Psychiatric Patients. AB - OBJECTIVE: The present study aimed to investigate relationship among cognitive factors (working memory and processing speed) and fluid reasoning (Gf) in psychiatric patients using a standardized clinical tool. METHODS: We included the responses of 115 heterogeneous patients who were diagnosed with the MINI-Plus 5.0 and WAIS-IV/WMSIV was administered. For our analysis, structured equation modeling (SEM) was conducted to evaluate which cognitive variables are closely related to the Gf. RESULTS: The results showed that the visual working memory was the strongest predictor of the Gf compared to other cognitive factors. CONCLUSION: Processing speed was capable of predicting the Gf, when visual working memory was controlled. The inter-relationship among the Gf and other cognitive factors and its clinical implications were further discussed. PMID- 30466207 TI - Subcortical Ischemic Change as a Predictor of Driving Cessation in the Elderly. AB - OBJECTIVE: Motor, perceptual, and cognitive functions are known to affect driving competence. Subcortical ischemic changes on brain magnetic resonance imaging (MRI) can reflect reduction in cognitive and motor performance. However, few studies have reported the relationship between subcortical ischemic changes and driving competence of the elderly. Thus, the objective of this study was to investigate the association between subcortical ischemic changes on MRI and driving abilities of the elderly. METHODS: Participants (n=540) were drawn from a nationwide, multicenter, hospital-based, longitudinal cohort. Each participant underwent MRI scan and interview for driving capacity categorized into 'now driving' and 'driving cessation (driven before, not driving now)'. Participants were divided into three groups (mild, n=389; moderate, n=116; and severe, n=35) depending on the degree of white matter hyperintensity (WMH) on MRI at baseline. Driving status was evaluated at follow-up. Statistical analyses were conducted using chi2 test, analysis of variance (ANOVA), structured equation model (SEM), and generalized estimating equation (GEE). RESULTS: In SEM, greater baseline degree of WMH was directly associated with driving cessation regardless of cognitive or motor dysfunction (beta=-0.110, p<0.001). In GEE models after controlling for age, sex, education, cognitive, and motor dysfunction, more severe change in the degree of WMH was associated with faster change from 'now driving' state to 'driving cessation' state over time in the elderly (beta= 0.508, p<0.001). CONCLUSION: In both cross-sectional and longitudinal results, the degree of subcortical ischemic change on MRI might predict driving cessation in the elderly. PMID- 30466208 TI - Comparative Efficacy and Safety of Long-acting Injectable and Oral Second generation Antipsychotics for the Treatment of Schizophrenia: A Systematic Review and Meta-analysis. AB - We aimed to compare the efficacy and safety of long-acting injectable (LAI) and oral second-generation antipsychotics (SGAs) in treating schizophrenia by performing a systematic review and meta-analysis. MEDLINE, EMBASE, PsycINFO, CINAHL, and the Cochrane Library, as well as five Korean databases, were systemically searched to identify studies published from 2000 to 16 April 2015, which compared the efficacy and safety of LAI and oral SGAs. Using data from randomized controlled trials (RCTs), meta-analyses were conducted. In addition, the GRADE (the Grading of Recommendations, Assessment, Development and Evaluation) approach was applied to explicitly assess the quality of the evidence. A total of 30 studies including 17 RCTs and 13 observational studies were selected. The group treated with LAI SGAs was characterized by significantly lower relapse rates, longer times to relapse and fewer hospital days, but also by a higher occurrence of extrapyramidal syndrome and prolactin-related symptoms than that in the group treated with oral SGAs. Our findings demonstrate that there is moderate to high level of evidence suggesting that in the treatment of schizophrenia, LAI SGAs have higher efficacy and are associated with higher rates of extrapyramidal syndrome and prolactin-related symptoms. Additionally, the use of LAI SGAs should be combined with appropriate measures to reduce dopamine D2 antagonism-related symptoms. PMID- 30466209 TI - Pharmacological Treatment of Major Depressive Episodes with Mixed Features: A Systematic Review. AB - We reviewed clinical studies investigating the pharmacological treatment of major depressive episodes (MDEs) with mixed features diagnosed according to the dimensional criteria (more than two or three [hypo]manic symptoms+principle depressive symptoms). We systematically reviewed published randomized controlled trials on the pharmacological treatment of MDEs with mixed features associated with mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD). We searched the PubMed, Cochrane Library, and ClinicalTrials.gov databases through December 2017 with the following key word combinations linked with the word OR: (a) mixed or mixed state, mixed features, DMX, mixed depression; (b) depressive, major depressive, MDE, MDD, bipolar, bipolar depression; and (c) antidepressant, antipsychotic, mood stabilizer, anticonvulsant, treatment, medication, algorithm, guideline, pharmacological. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We found few randomized trials on pharmacological treatments for MDEs with mixed features. Of the 36 articles assessed for eligibility, 11 investigated MDEs with mixed features in mood disorders: six assessed the efficacy of antipsychotic drugs (lurasidone and ziprasidone) in the acute phase of MDD with mixed features, although four of these were post hoc analyses based on large randomized controlled trials. Four studies compared antipsychotic drugs (olanzapine, lurasidone, and ziprasidone) with placebo, and one study assessed the efficacy of combination therapy (olanzapine+fluoxetine) in the acute phase of BD with mixed features. Pharmacological treatments for MDEs with mixed features have focused on antipsychotics, although evidence of their efficacy is lacking. Additional well-designed clinical trials are needed. PMID- 30466210 TI - The Levels of Vitamin D, Vitamin D Receptor, Homocysteine and Complex B Vitamin in Children with Autism Spectrum Disorders. AB - Objective: Autism spectrum disorder (ASD) is a complex neurodevelopmental syndrome with an increasingly prevalent etiology, yet not fully understood. It has been thought that vitamin D, complex B vitamin levels and homocysteine are associated with environmental factors and are important in ASD. The aim of this study was to examine serum vitamin D, vitamin D receptor (VDR), homocysteine, vitamin B6, vitamin B12 and folate levels in ASD. Methods: In this study, serum vitamin D and VDR, homocysteine, vitamins B6, B12 and folate levels were determined in 60 patients with ASD (aged 3 to 12 years) and in 45 age-gender matched healthy controls. In addition, calcium, phosphorus and alkaline phosphatase, which are associated with vitamin D metabolism, were measured from serum in both groups. ASD severity was evaluted by the Childhood Autism Rating Scale (CARS). Results: Serum vitamin D and VDR were substantially reduced in patients with ASD in comparision to control group. However, homocysteine level was significantly higher and vitamin B6, vitamin B12 and folate were also reduced in patients with ASD. Total CARS score showed a positive association with homocysteine and a negative correlation with vitamins D,B6, B12, folate and VDR. Conclusion: This comprehensive study, which examines many parameters has shown that low serum levels of vitamins D, B6, B12, folate and VDR as well as high homocysteine are important in the etiopathogenesis of ASD. However, further studies are required to define the precise mechanism(s) of these parameters and their contributions to the etiology and treatment of ASD. PMID- 30466211 TI - In-Depth Relationships between Emotional Intelligence and Personality Traits in Meditation Practitioners. AB - Objective: Meditation can elicit trait-like changes in psychological and social styles, as well as enhancement of emotional regulatory capacity. We investigated the relation between personality traits and emotional intelligence in meditation practitioners. Methods: Seventy-two long-term practitioners of mind-body training (MBT) and 62 healthy comparative individuals participated in the study. The participants completed emotional intelligence questionnaires and the Myers-Briggs Type Indicator (MBTI). Results: The MBT group revealed higher scores on all five emotional intelligence factors than did those in the control group, such as emotional awareness and expression, empathy, emotional thinking, emotional application, and emotional regulation (all p<=0.001). MBT practitioners also had higher scores on the intuition of perceiving function (t =-2.635, p =0.010) and on the feeling of the judging function (t =-3.340, p =0.001) of the MBTI compared with those in the control group. Only the MBT group showed a robust relationship with every factor of emotional intelligence and MBTI-defined intuitive styles, indicating that higher scores of emotional intelligence were related to higher scores for intuition. Conclusion: Emotional intelligence of meditation practitioners showed notable relationships with some features of personality trait. In-depth associations between emotional intelligence and personality traits would help to foster psychological functions in meditation practitioners. PMID- 30466212 TI - Increased Readmission Risk and Healthcare Cost for Delirium Patients without Immediate Hospitalization in the Emergency Department. AB - Objective: Hospitalization of patients with delirium after visiting the emergency department (ED) is often required. However, the readmission risk after discharge from the ED should also be considered. This study aimed to explore whether (i) immediate hospitalization influences the readmission risk of patients with delirium; (ii) the readmission risk is affected by various risk factors; and (iii) the healthcare cost differs between groups within 28 days of the first ED visit. Methods: Using the National Health Insurance Research Database, the data of 2,780 subjects presenting with delirium at an ED visit from 2000 to 2008 were examined. The readmission risks of the groups of patients (i.e., patients who were and were not admitted within 24 hours of an ED visit) within 28 days were compared, and the effects of the severities of different comorbidities (using Charlson's comorbidity index, CCI), age, gender, diagnosis and differences in medical healthcare cost were analyzed. Results: Patients without immediate hospitalization had a higher risk of readmission within 3, 7, 14, or 28 days of discharge from the ED, especially subjects with more severe comorbidities (CCI>=3) or older patients (>=65 years). Subjects with more severe comorbidities or older subjects who were not admitted immediately also incurred a greater healthcare cost for re-hospitalization within the 28-day follow-up period. Conclusion: Patients with delirium with a higher CCI or of a greater age should be carefully considered for immediate hospitalization from ED for further examination in order to reduce the risk of re-hospitalization and cost of healthcare. PMID- 30466213 TI - Trait Anxiety as a Mediator of the Association between Attention Deficit Hyperactivity Disorder Symptom Severity and Functional Impairment. AB - Objective: Anxiety has been shown to influence functional impairment in patients with attention deficit hyperactivity disorder (ADHD). This study aimed to compare functional impairment in subjects with and without adult ADHD and to investigate the associations among trait anxiety, functional impairment, and ADHD symptom severity. Moreover, the effects of ADHD symptom subtypes on trait anxiety and functional impairment were also examined. Methods: The sample included 209 adults between the ages of 20 and 31 years. Fifty-one adults received a diagnosis of ADHD, and an additional age, sex-matched group of 51 adults comprised the adult control. Participants were assessed with Conners' Adult ADHD Rating Scales (CAARS), the Beck Depression Inventory (BDI), the Spielberg Trait Anxiety Inventory (STAI-T), and the Sheehan Disability Scale (SDS). The relationships among ADHD severity, anxiety, and functional impairment were investigated using Pearson's correlation analysis. Subtypes of ADHD symptoms that predicted anxiety and functional impairment were investigated using regression analyses. Results: Adult ADHD patients significantly differed from normal control subjects according to BDI, STAI-T, and SDS assessment. Significant positive correlations were noted between ADHD severity, anxiety, and functional impairment. Multiple linear regression analysis confirmed anxiety as a mediator between functional impairment and ADHD CAARS symptom subscales. Conclusion: Patients with adult ADHD showed higher levels of anxiety, depression, and functional impairment. Additionally, ADHD symptoms and anxiety impacted subject functional impairment. Our results suggest that anxiety may be a strong mediator between ADHD severity and functional impairment. PMID- 30466214 TI - No Association between Polymorphisms of Vitamin D and Oxytocin Receptor Genes and Autistic Spectrum Disorder in a Sample of Turkish Children. AB - Objective: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in social skills and communication with repetitive behaviors. Etiology is still unclear although it is thought to develop with interaction of genes and environmental factors. Oxytocin has extensive effects on intrauterine brain development. Vitamin D, affects neural development and differentiation and contributes to the regulation of around 900 genes including oxytocin receptor gene. In the present study, the contribution of D vitamin receptor and oxytocin receptor gene polymorphisms in the development of ASD in Turkish community was investigated. To our knowledge, this is the first study examining these two associated genes together in the literature. Methods: Eighty five patients diagnosed with ASD according to DSM-5 who were referred to outpatient clinics of Child and Adolescent Psychiatry of Baskent University and Mersin University and 52 healthy, age and gender-matched controls were included in the present study. Vitamin D receptor gene rs731236 (Taq1), rs2228570 (Fok1), rs1544410 (Bsm1), rs7975232 (Apa1) polymorphisms and oxytocin receptor gene rs1042778 and rs2268493 polymorphisms were investigated using real time polymerase chain reaction method. Results: No significant difference between groups in terms of distribution of genotype and alleles in each of polymorphisms for these genes could be found. Conclusion: Knowledge of genes and polymorphisms associated with the development of ASD may be beneficial for early diagnosis and future treatment. Further studies with larger populations are required to demonstrate molecular pathways which may play part in the development of ASD in Turkey. PMID- 30466215 TI - From Gut to Brain: Alteration in Inflammation Markers in the Brain of Dextran Sodium Sulfate-induced Colitis Model Mice. AB - Objective: Neuropsychiatric manifestations like depression and cognitive dysfunction commonly occur in inflammatory bowel disease (IBD). In the context of the brain-gut axis model, colitis can lead to alteration of brain function in a bottom-up manner. Here, the changes in the response of the hypothalamic-pituitary adrenal axis and inflammation-related markers in the brain in colitis were studied. Methods: Dextran sodium sulfate (DSS) was used to generate a mouse model of colitis. Mice were treated with DSS for 3 or 7 days and sacrificed. We analyzed the gene expression of brain-derived neurotrophic factor (BDNF), cyclooxygenase 2 (COX-2), and glial fibrillary acidic protein (GFAP), and the expression of GFAP, in the hippocampus, hypothalamus, and amygdala. Additionally, the levels of C-reactive protein (CRP) and serum cortisol/corticosterone were measured. Results: Alteration of inflammatory-related markers varied depending on the brain region and exposure time. In the hippocampus, COX-2 mRNA, GFAP mRNA, and GFAP expression were upregulated during exposure to DSS. However, in the hypothalamus, COX-2 mRNA was upregulated only 3 days after treatment. In the amygdala, BDNF and COX-2 mRNAs were downregulated. CRP and corticosterone expression increased with DSS treatment at day 7. Conclusion: IBD could lead to neuroinflammation in a bottom-up manner, and this effect varied according to brain region. Stress-related hormones and serum inflammatory markers, such as CRP, were upregulated from the third day of DSS treatment. Therefore, early and active intervention is required to prevent psychological and behavioral changes caused by IBD, and region-specific studies can help understand the precise mechanisms by which IBD affects the brain. PMID- 30466216 TI - Korean Medication Algorithm Project for Bipolar Disorder 2018 (KMAP-BP 2018): Fourth Revision. AB - Objective: The Korean Medication Algorithm Project for Bipolar Disorder (KMAP-BP) was first published in 2002 through an expert consensus of opinion, and updated in 2006, 2010, and 2014. This study constitutes the fourth revision of the KMAP BP. Methods: A 50-item questionnaire was used to obtain the consensus of experts regarding pharmacological treatment strategies for various phases of adult bipolar disorder and six items for pediatric bipolar disorder. The review committee included 84 Korean psychiatrists and 43 child and adolescent psychiatry experts. Results: The preferred first-step strategies for acute mania were the combination of a mood stabilizer (MS) and an atypical antipsychotic (AAP), MS monotherapy, and AAP monotherapy. A combination of a MS and an AAP, and AAP monotherapy were preferred for psychotic mania. The first-step strategies for mild to moderate bipolar depression were monotherapy with MS, AAP, or lamotrigine (LMT), and the combination of a MS and an AAP or LMT, or a combination of an AAP and LMT. The combination of two among a MS, AAP, and LMT were preferred for non psychotic severe depression. A combination of a MS and an AAP or the combination of an AAP with an antidepressant or LMT were the first-line options for psychotic severe depression. Conclusion: The recommendations of the KMAP-BP 2018 have changed from the previous version by reflecting recent developments in pharmacotherapy for bipolar disorder. KMAP-BP 2018 provides clinicians with a wealth of information regarding appropriate strategies for treating patients with bipolar disorder. PMID- 30466217 TI - Dysfunctional Social Reinforcement Processing in Disruptive Behavior Disorders: An Functional Magnetic Resonance Imaging Study. AB - Objective: Prior functional magnetic resonance imaging (fMRI) work has revealed that children/adolescents with disruptive behavior disorders (DBDs) show dysfunctional reward/non-reward processing of non-social reinforcements in the context of instrumental learning tasks. Neural responsiveness to social reinforcements during instrumental learning, despite the importance of this for socialization, has not yet been previously investigated. Methods: Twenty-nine healthy children/adolescents and 19 children/adolescents with DBDs performed the fMRI social/non-social reinforcement learning task. Participants responded to random fractal image stimuli and received social and non-social rewards/non rewards according to their accuracy. Results: Children/adolescents with DBDs showed significantly reduced responses within the caudate and posterior cingulate cortex (PCC) to non-social (financial) rewards and social non-rewards (the distress of others). Connectivity analyses revealed that children/adolescents with DBDs have decreased positive functional connectivity between the ventral striatum (VST) and the ventromedial prefrontal cortex (vmPFC) seeds and the lateral frontal cortex in response to reward relative to non-reward, irrespective of its sociality. In addition, they showed decreased positive connectivity between the vmPFC seed and the amygdala in response to non-reward relative to reward. Conclusion: These data indicate compromised reinforcement processing of both non-social rewards and social non-rewards in children/adolescents with DBDs within core regions for instrumental learning and reinforcement-based decision- making (caudate and PCC). In addition, children/adolescents with DBDs show dysfunctional interactions between the VST, vmPFC, and lateral frontal cortex in response to rewarded instrumental actions potentially reflecting disruptions in attention to rewarded stimuli. PMID- 30466218 TI - Predictors of Cognitive Improvement during 12 Weeks of Antidepressant Treatment in Patients with Major Depressive Disorder. AB - Objective: Cognitive disturbance is one of the major symptoms of depression and may be improved by treatment with antidepressants. This study aimed to investigate the predictors of cognitive improvement in patients with major depressive disorder (MDD) who were taking antidepressants. Methods: This study included 86 patients with MDD who completed 12 weeks of antidepressant monotherapy. Cognitive symptoms were assessed using the Perceived Deficits Questionnaire-Korean version (PDQ-K), which addresses four domains of cognitive functioning (attention/concentration, retrospective memory, prospective memory, and organization/planning) and was administered at study entry and at the 12-week end point. A variety of demographic, clinical, and treatment-related variables were evaluated as predictors of changes in total and domain scores. Results: All PDQ-K domains showed significant improvement after 12 weeks of antidepressant treatment. More severe initial depressive symptoms, fewer sick-leave days at study entry, and reduced use of concomitant anxiolytics/hypnotics during treatment were significantly associated with greater cognitive improvement. Conclusion: Cognitive symptoms are more responsive to antidepressant treatment in patients with severe MDD. Reduced use of anxiolytics and hypnotics could improve the cognitive functioning of patients with MDD taking antidepressants. PMID- 30466219 TI - A Pharmacogenomic-based Antidepressant Treatment for Patients with Major Depressive Disorder: Results from an 8-week, Randomized, Single-blinded Clinical Trial. AB - Objective: Pharmacogenomic-based antidepressant treatment (PGATx) may result in more precise pharmacotherapy of major depressive disorder (MDD) with better drug therapy guidance. Methods: An 8-week, randomized, single-blind clinical trial was conducted to evaluate the effectiveness and tolerability of PGATx in 100 patients with MDD. All recruited patients were randomly allocated either to PGATx (n=52) or treatment as usual (TAU, n=48) groups. The primary endpoint was a change of total score of the Hamilton Depression Rating Scale-17 (HAMD-17) from baseline to end of treatment. Response rate (at least 50% reduction in HAMD-17 score from baseline), remission rate (HAMD-17 score <=7 at the end of treatment) as well as the change of total score of Frequency, Intensity, and Burden of Side Effects Ratings (FIBSER) from baseline to end of treatment were also investigated. Results: The mean change of HAMD-17 score was significantly different between two groups favoring PGATx by -4.1 point of difference (p=0.010) at the end of treatment. The mean change in the FIBSER score from baseline was significantly different between two treatment groups favoring PGATx by -2.5 point of difference (p=0.028). The response rate (71.7 % vs. 43.6%, p=0.014) were also significantly higher in PGATx than in TAU at the end of treatment, while the remission rate was numerically higher in PGATx than in TAU groups without statistical difference (45.5% vs. 25.6%, p=0.071). The reason for early drop-out associated with adverse events was also numerically higher in TAU (n=9, 50.0%) than in PGATx (n=4, 30.8%). Conclusion: The present study clearly demonstrate that PGATx may be a better treatment option in the treatment of MDD in terms of effectiveness and tolerability; however, study shortcomings may limit a generalization. Adequately powered, well-designed, subsequent studies should be mandatory to prove its practicability and clinical utility for routine practice. PMID- 30466220 TI - Neuro-cognitive Ramifications of Fasting and Feeding in Obese and Non-obese Cases. AB - Preliminary studies have claimed that short term fasting would negatively affect school performance and cognition. In contrast some other studies have reported not important decline in cognition and executive function as a result of fasting. Also limited attention was generally devoted to dietetic regimens, nutritional status and body weight. Yet neuroscience and neuro-cognitive aspects of acute hunger on the electroencephalogram and differences between obese and non-obese cases is not well understood. Hence, we decided to design and perform a case study in a more controlled situation similar to reality. Therefore, we performed several examinations including subjective tests (for eating status) and objective tests (cognitive tests such as Stroop effect and Sternberg search and electroencephalogram measures such as steady-state visual evoked potential and auditory steady-state responses) for an obese and a non-obese academic case before and after a simple breakfast. The results showed that the breakfast effects on the neuro-cognitive functions depend on either obesity status, nutritional status of the case or the type of cognitive task (visual or auditory). This paper would open a new insight to answer some important questions about the neuro-cognitive implications of fasting and feeding in obese and non obese human cases. PMID- 30466221 TI - Modality-Specific Working Memory Systems Verified by Clinical Working Memory Tests. AB - Objective: This study was to identify whether working memory (WM) can be clearly subdivided according to auditory and visual modality. To do this, we administered the most recent and universal clinical WM measures in a mixed psychiatric sample. Methods: A total of 115 patients were diagnosed on the basis of DSM-IV diagnostic criteria and with MINI-Plus 5.0, a structured diagnostic interview. WM subtests of Korean version of Wechsler Adult Intelligence Scale-IV and Korean version of Wechsler Memory Scale-IV were administered to assess WM. Confirmatory factor analysis (CFA) was used to observe whether WM measures fit better to a one-factor or two-factor model. Results: CFA results demonstrated that a two factor model fits the data better than one-factor model as expected. Conclusion: Our study supports a modality model of WM, or the existence of modality-specific WM systems, and thus poses a clinical significance of assessing both auditory and visual WM tests. PMID- 30466222 TI - Turning on the Left Side Electrode Changed Depressive State to Manic State in a Parkinson's Disease Patient Who Received Bilateral Subthalamic Nucleus Deep Brain Stimulation: A Case Report. AB - No previous reports have described a case in which deep brain stimulation elicited an acute mood swing from a depressive to manic state simply by switching one side of the bilateral deep brain stimulation electrode on and off. The patient was a 68-year-old woman with a 10-year history of Parkinson's disease. She underwent bilateral subthalamic deep brain stimulation surgery. After undergoing surgery, the patient exhibited hyperthymia. She was scheduled for admission. On the first day of admission, it was clear that resting tremors in the right limbs had relapsed and her hyperthymia had reverted to depression. It was discovered that the left-side electrode of the deep brain stimulation device was found to be accidentally turned off. As soon as the electrode was turned on, motor impairment improved and her mood switched from depression to mania. The authors speculate that the lateral balance of stimulation plays an important role in mood regulation. The current report provides an intriguing insight into possible mechanisms of mood swing in mood disorders. PMID- 30466223 TI - Clinical Usefulness of Aripiprazole Treatment in a Girl with Prader-Willi Syndrome and Psychosis. AB - Prader-Willi syndrome (PWS) is a quite rare multi-systemic genetic disorder strongly associated with psychiatric illness in adults, especially psychosis. This report presents a 16-year-old female with PWS and symptoms of brief psychotic disorder with a complete resolution of symptoms under aripiprazole medication. However, an exacerbation occurred after aripiprazole reduction. Apart from a weight gain of about 2 kg over the course of two years, no adverse effects could be found. This first report on the use of aripiprazole in a subject with PWS and psychosis suggests that aripiprazole might be a promising treatment approach in this distinct group of patients. PMID- 30466224 TI - Quetiapine Induced Autoimmune Hemolytic Anemia in a Child Patient: A Case Report. AB - Autoimmune hemolytic anemia is a disease characterized with destruction of erythrocytes as a result of antibody produce against patient's own erythrocytes and anemia. Autoimmune hemolytic anemia can be roughly stratified into two groups according to serological features and secondary causes including drugs induced hemolytic anemia. Drugs induced autoimmune hemolytic anemia is very rare in pediatric patients. Even though hematological side effects such as leucopenia, agranulocytosis, eosinophilia, thrombocytopenic purpura and aplastic anemia might occur due to psychotropic drug use; to the best of our knowledge there is no autoimmune hemolytic anemia case due to quetiapine, an atypical antipsychotics, in literature. We hereby describe the first child case of autoimmune hemolytic anemia during quetiapine treatment.We also are pointing out that one should keep in mind serious hematological side effects with atypical antipsychotic drug use with this case report. PMID- 30466225 TI - Clozapine-related Sudden Pericarditis in a Patient Taking Long Acting Aripiprazole and Valproate: A Case Report. AB - Clozapine may be associated with cardiovascular adverse effects including QTc prolongation and, more rarely, with myocarditis and pericarditis. Although rare, these latter cardiovascular adverse effects may be life-threatening and must be immediately recognized and treated. Several cases of clozapine related pericarditis have been described and often it has a subtle and insidious onset with symptoms that may be often misdiagnosed with psychiatric manifestations (e.g. anxiety, panic or somatization) leading to a delayed correct diagnosis with potential fatal consequences. In the present report we describe the case of a 27 year-old girl with schizoaffective disorder taking long acting aripiprazole and valproate who developed a sudden onset clozapine-related pericarditis during titration phase that resolved with immediate clozapine discontinuation and indomethacin administration. We underline the importance of an early diagnosis of clozapine-related pericarditis and the need to have monitoring protocols to prevent this potentially fatal adverse effect especially when polypharmacy is administered to patients taking clozapine. PMID- 30466226 TI - Striatum Involvement in LGI1 Limbic Encephalitis. PMID- 30466227 TI - Establishment of an article transfer service for Archives of Plastic Surgery. PMID- 30466228 TI - Osteocutaneous flaps for head and neck reconstruction: A focused evaluation of donor site morbidity and patient reported outcome measures in different reconstruction options. AB - With significant improvements in success rates for free flap reconstruction of the head and neck, attention has turned to donor site morbidity associated with osteocutaneous free flaps. In this review, we address the morbidity associated with harvest of the four most commonly used osteocutaneous flaps; the free fibula flap, the scapula flap, the iliac crest flap and the radial forearm flap. A comprehensive literature search was performed to identify articles relevant to donor site morbidity for these flaps. We assessed morbidity in terms of incidence of delayed healing, chronic pain, aesthetic outcomes, site specific complications and patient satisfaction/quality of life. Weighted means were calculated when sufficient studies were available for review. The radial forearm and free fibula flaps are associated with high rates of delayed healing of approximately 20% compared to the scapular (<10%) and iliac flaps (5%). The radial forearm flap has higher rates of chronic pain (16.7%) and dissatisfaction with scar appearance (33%). For the majority of these patients harvest of one of these four osteocutaneous does not limit daily function at long-term follow-up. The scapular osteocutaneous flap is associated with the lowest relative morbidity and should be strongly considered when the recipient defect allows. The radial forearm is associated with higher morbidity in terms of scarring, fractures, chronic pain and wrist function and should not be considered as first choice when other flap options are available. PMID- 30466229 TI - Wound healing effects of paste type acellular dermal matrix subcutaneous injection. AB - BACKGROUND: Acellular dermal matrix (ADM) helps wound healing by stimulating angiogenesis, acting as a chemoattractant for endothelial cells, providing growth factors, and permitting a substrate for fibroblasts to attach. The current standard for using paste-type ADM (CG Paste) in wound healing is direct application over the wounds. The major concerns regarding this method are unpredictable separation from the wounds and absorption into negativepressure wound therapy devices. This study aimed to investigate the effects of subcutaneous injection of paste-type ADM on wound healing in rats. METHODS: Full thickness skin defects were created on the dorsal skin of rats. Eighteen rats were randomly divided into three groups and treated using different wound coverage methods: group A, with a saline dressing; group B, standard application of CG Paste; and group C, injection of CG Paste. On postoperative days 3, 5, 7, 10, and 14, the wound areas were analyzed morphologically. Histological and immunohistochemical tissue analyses were performed on postoperative days 3 and 7. RESULTS: Groups B and C had significantly less raw surface than group A on postoperative days 10 and 14. Collagen fiber deposition and microvessel density were significantly higher in group C than in groups A and B on postoperative days 3 and 7. CONCLUSIONS: This study showed comparable effectiveness between subcutaneous injection and the conventional dressing method of paste-type ADM. Moreover, the injection of CG Paste led to improved wound healing quality through the accumulation of collagen fibers and an increase in microvessel density. PMID- 30466230 TI - Dermoid cysts: Epidemiology and diagnostic approach based on clinical experiences. AB - BACKGROUND: Dermoid cysts are congenital tumors that are benign. Dermoid cysts with intracranial extension can cause serious neurological complications. It is important, therefore, to determine whether a patient has a dermoid cyst when their chief concern at a doctor's visit is a mass in the head or neck area. In this study, we present a literature review of dermoid cysts and an analysis of the authors' experiences, with the goal of providing guidance useful for the diagnosis and treatment of dermoid cysts. METHODS: This study retrospectively analyzed the medical records of 62 patients who visited the two medical clinics with which the authors are affiliated. The patients were enrolled between October 2003 and January 2017. RESULTS: Of the 62 patients analyzed in this study, 32 were 0 to 5 years of age (52%) and 23 were 17 years of age or older (37%). Forty seven patients underwent 1 or more imaging study during the process of diagnosis. Thirty-two patients were suspected to have a dermoid cyst. Forty-nine patients were analyzed to determine the depth of the cyst. Bone was seen in 43 patients through imaging tests or during actual surgery, and nine of the 43 had bony problems (21%). CONCLUSIONS: This study found that dermoid cysts were present in many adults, and that a high rate of deep lesions was observed, as well as many cases in which even the bone was affected. These results suggest, therefore, that dermoid cysts should be considered, and medical professionals should actively conduct imaging studies. PMID- 30466231 TI - Oral propranolol therapy in 23 infants with infantile hemangioma. AB - BACKGROUND: Infantile hemangioma (IH) is a common vascular tumor in pediatric patients, and is commonly treated with propranolol. We describe our experiences with dosage, response to treatment, and side effects in 23 IH patients treated with propranolol. METHODS: For this nonrandomized comparative cohort study, the authors enrolled 23 patients treated with propranolol. Photographs were taken before propranolol administration and at 3, 6, 9, and 12 months after treatment. Treatment responses were objectively analyzed with a computer program. RESULTS: There were three male and 20 female patients. Common tumor locations were the head and neck (13 cases, 56.5%), trunk (four cases, 17.4%), extremities (three cases, 13.0%), and combined locations (three cases, 13.0%). The response to propranolol was significantly lower in patients with two or more lesions than in patients with a single lesion in terms of both color fading (P<0.001) and size reduction (P<0.001). In male patients (42.2+/-3.9), the change in a-values, indicating coloration, was higher than in female patients (19.8 +/-13.8) (P<0.001). In patients who started treatment before 6 months after birth, the size reduction was greater than in their counterparts (62.3%; range, 3.0%-93.0% vs. 15.8%; range, 1.0%-79.0%; P<0.001). CONCLUSIONS: Propranolol is an efficacious treatment with a good safety profile. In patients with a single lesion, the response to treatment was better in terms of color fading and size reduction. Furthermore, male patients responded better to propranolol treatment in terms of color fading than female patients, and starting treatment before 6 months after birth was more advantageous for size reduction. PMID- 30466232 TI - Algorithm for the management of ectropion through medial and lateral canthopexy. AB - BACKGROUND: Patients with ectropion experience devastating symptoms. Therefore, the prevention and management of this condition are of utmost importance. To treat ectropion, it is important to perform medial and lateral canthopexy in an effective way. In this study, we propose a comprehensive algorithm for the prevention and management of ectropion based on a new classification of ectropion according to its signs and causes. METHODS: Canthopexy was performed in 68 cases according to the proposed algorithm, which starts with a categorization of the types of ectropion and ends with the recommended operative technique. To assess the results, we reviewed clinical preoperative and postoperative photographs. To evaluate improvements in patients' symptoms, we conducted a survey with responses scored on a Likert scale. RESULTS: None of the patients had scleral show postoperatively. The average patient satisfaction score was satisfied or higher for all symptoms, and the most improved symptom was aesthetic appearance. No major complications were reported. CONCLUSIONS: For the comprehensive management of ectropion, it is crucial to consider both treatment and prevention. Through the simple surgical algorithm proposed in this study, both medically acceptable results and high levels of patient satisfaction were achieved without significant postoperative complications. We recommend using this algorithm for the comprehensive management of ectropion. PMID- 30466233 TI - Skin-sparing mastectomy with immediate nipple reconstruction during autologous latissimus dorsi breast reconstruction: A review of patient satisfaction. AB - BACKGROUND: Nipple-areolar complex (NAC) reconstruction following curative mastectomy is traditionally performed as a second-stage procedure several months after initial breast reconstruction. The recent literature has documented the increasing popularity of immediate nipple reconstruction carried out simultaneously during autologous reconstruction. The aim of this study was to evaluate the surgical outcomes and patient satisfaction with immediate breast and nipple reconstruction performed in a single stage after skin-sparing mastectomy. METHODS: All patients who underwent a skin-sparing mastectomy with immediate latissimus dorsi flap breast and NAC reconstruction as a single-stage procedure from 2007 to 2015 were included. Patient demographics, oncologic details, and surgical outcomes were recorded. The BREAST-Q questionnaire was administered to patients to assess the impact and effectiveness of this reconstructive strategy. RESULTS: During the study period, 34 breast and NAC reconstructions in 29 patients were performed at Cork University Hospital. The majority of our patient cohort were non-smokers (93.1%) and did not receive adjuvant radiotherapy. Postoperative complications were infrequent, with no cases of partial necrosis or complete loss of the nipple. The response rate to the BREAST-Q was 62% (n=18). Patients reported high levels of satisfaction with the reconstructed breast (62+/ 4), nipple reconstruction (61+/-4.8), overall outcome (74.3+/-5), and psychosocial well-being (77.7+/-3.2). CONCLUSIONS: Skin-sparing mastectomy with immediate nipple reconstruction during autologous latissimus dorsi reconstruction was demonstrated to be a safe and aesthetically reliable procedure in our cohort, yielding high levels of psychological and physical well-being. A single-stage procedure promotes psychosocial well-being involving issues that are intrinsically linked with breast cancer surgery. PMID- 30466234 TI - Bacterial profile of suction drains and the relationship thereof to surgical-site infections in prosthetic breast reconstruction. AB - BACKGROUND: Despite the increasing popularity of prosthetic breast reconstruction, scant data exist on the microbiological profile of drainage fluid from closed-suction drains and the relationship thereof to surgical-site infections (SSIs) in breast reconstruction surgery. This study aimed to determine whether bacteria isolated from drainage fluid were associated with the development of SSIs, and whether the bacterial profile of drainage fluid could be a clinically useful predictor of SSIs. METHODS: We performed a retrospective chart review of 61 women who underwent tissue expander/implant or direct-to implant reconstructions. Patient demographics and culture studies of drainage fluid from suction drains collected on postoperative day 7 were evaluated. RESULTS: Sixteen patients (26.23%) were culture-positive, and 45 patients (73.77%) were culture-negative. The most frequently isolated bacteria were coagulase-negative staphylococci, followed by Staphylococcus aureus. SSIs were diagnosed in seven patients and were mostly resolved by systemic antibiotics; however, the tissue expander or implant was explanted in two patients. Positive culture of drainage fluid from closed-suction drains was significantly associated with the development of SSIs (P<0.05). The positive predictive value was 37.50%, and the negative predictive value was 97.78%. CONCLUSIONS: To our knowledge, this study is the first to demonstrate a significant association between the microbiological profile of drainage fluid from closed-suction drains and the development of SSIs in patients with prosthetic breast reconstructions. The high negative predictive value suggests that microbial testing of drainage fluid from closed-suction drains may have clinical utility. Further prospective studies with larger sample sizes are required to confirm our findings. PMID- 30466235 TI - Analysis of gluteal subcutaneous and muscle thickness in infants and children for application to intramuscular injection, autologous fat grafting, and gluteal artery perforator flaps. AB - BACKGROUND: To achieve improvements in intramuscular injection, autologous fat grafting, and gluteal artery perforator flaps in infants and children, the relationships of computed tomography (CT)-determined gluteal muscle thickness (MT) and subcutaneous tissue thickness (SCT) with age and body mass index (BMI) were analyzed. METHODS: Gluteal SCT and MT at ventrogluteal (VG) and dorsogluteal (DG) sites were measured in a standardized manner in 350 patients aged 0 to 6 years who had visited a tertiary hospital and had undergone abdominopelvic CT between January 2005 and December 2016. Recorded measurements were analyzed using one-way analysis of variance and stepwise multiple regression to identify the factors that were most closely related to MT and SCT. RESULTS: Subcutaneous tissue at VG sites was thinner than at DG sites, but not significantly so in any age group. Muscles tended to be thinner at VG sites in 4 to 7-year-old, but thicker at VG sites in 1 to 3-year-old, though the differences were not significant. MT in the VG and DG regions was found to be related to age, and SCT in these regions to be related to age and BMI. CONCLUSIONS: The VG and DG sites should be considered as alternatives for intramuscular injection in infants and children when the anterolateral site is problematic. In addition, considering the gluteal MT and SCT of infants and children should help produce good results in autologous fat grafting and gluteal artery perforator flap harvesting. PMID- 30466236 TI - 3-Dimensional fasciectomy: A highly efficacious common ground approach to Dupuytren's surgery. AB - BACKGROUND: Numerous Dupuytren's fasciectomy techniques have been described, each associated with unique surgical challenges, complications and recurrence rates. We describe a common ground surgical approach to Dupuytren's disease; 3 dimensional fasciectomy (3DF). 3DF aims to address the potential contributors to the high recurrence rate of Dupuytren's disease and unite current limited fasciectomy practice that varies considerably between surgeons. METHODS: We describe the 3DF principles; raising thin skin flaps (addressing dermal involvement), excising diseased palmar fascia with a 3-5 mm clearance margin (treating highly locally recurrent conditions) and excising the vertical septae of Legueu and Juvara (providing deep clearance, hence addressing all potentially involved pathological tissue). The surgical outcomes between traditional limited fasciectomy (LF) and 3DF are compared. RESULTS: From the 786 operations included (n=585), postoperative recurrence rates were significantly lower for the 3DF group (2/145, 1.4%) than the LF group (72/641, 11.2%) (P=0.001), and the time to recurrence was significantly longer (5.0+/-0 years vs. 4.0+/-0.2 years; P<0.0001). With recurrence excluded, there were no differences between the postoperative complication rates for 3DF (5/145, 3.5%) and LF (41/641, 6.4%) (P=0.4). CONCLUSIONS: Our results suggest that 3DF leads to lower recurrence rates and a longer disease-free period for patients, without increasing complications. 3DF provides a safe, efficacious, common ground surgical approach in the treatment of Dupuytren's flexion deformity. PMID- 30466237 TI - Application of a paste-type acellular dermal matrix for coverage of chronic ulcerative wounds. AB - BACKGROUND: Chronic wounds occur due to failure of the normal healing process, associated with a lack of deposition of cellular components and a suitable microenvironment such as the extracellular matrix (ECM). Acellular dermal matrix (ADM) is viewed as an ECM substitute, and a paste-type ADM has recently been introduced. We hypothesized that CGPaste, an injectable paste-type ADM, could serve as a scaffold and promote wound healing. METHODS: We retrospectively studied seven patients in whom CGPaste was applied between 2017 and 2018, who had pressure ulcers, necrotizing fasciitis, diabetic foot ulcers, traumatic defects, and osteomyelitis. The goal of applying CGPaste was to achieve complete wound healing with re-epithelialization or growth of granulation tissue, depending upon the wound bed status. CGPaste was injected based on the wound size along with the application of a dressing. RESULTS: Four of the seven patients showed granulation tissue on their wound bed, while the other three patients had a bony wound bed. The mean wound area was 453.57 mm2 and the depth was 10.71 mm. Wound healing occurred in five of the seven patients (71.43%). The mean duration of complete healing was 2.4 weeks. Two patients showed failure due to paste absorption (29.57%); these patients had wound beds comprising bone with relatively large and deep wounds (40*30 and 30*20 mm2 in area and 15 and 10 mm in depth). CONCLUSIONS: CGPaste is an effective option for coverage of small and deep chronic wounds for which a flap operation or skin grafting is unfeasible. PMID- 30466238 TI - Lower facial contouring surgery using a novel method: M-genioplasty. AB - BACKGROUND: Mandibular contouring surgery to produce a more slender and small face has become popular, especially in East Asia. Narrowing genioplasty should be simultaneously performed with mandibular angle resection to achieve satisfactory results. In Korea, T-genioplasty has been frequently performed for chin narrowing. The authors developed a new, safe, and reliable method, termed M genioplasty, that can provide a more slender and attractive lower face. METHODS: From June 2013 to December 2017, 36 patients underwent M-genioplasty with mandibular angle resection for lower facial contouring. Horizontal and vertical osteotomies were performed obliquely. The resected bone segments were wedge shaped. The remaining two bone segments were rotated and approximated centrally. The lateral mandible bony stepoff was trimmed off for mandibular angle resection. RESULTS: In all patients, the facial contour sufficiently improved, and most patients were satisfied with the outcome. No severe complications took place during postoperative follow-up. CONCLUSIONS: M-genioplasty can provide more mandibular angle resection and can create a more acute chin angle without bone resorption than other methods, including T-genioplasty. M-genioplasty with mandibular angle resection is a safer, more accurate, and more reliable method for lower facial contouring. PMID- 30466239 TI - Proboscis lateralis: A case report of a rare giant craniofacial teratoma in an infant. AB - Teratomas can occur in almost any region of the body and are the most common extragonadal germ cell childhood tumors. However, craniofacial teratomas are rare. Craniofacial teratomas can present unique features and cause significant functional and aesthetic concerns. There are complex lesions that can have components intra-cranially and extra-cranially. Therefore, their management requires significant multi-stage multidisciplinary surgical procedures. Herein, we present a case of craniofacial teratoma in a child with the phenotype of proboscis lateralis that highlights some of the pertinent point of the diagnosis and management of congenital neonatal teratomas. PMID- 30466240 TI - Adult-onset kaposiform hemangioendothelioma with neurofibromatosis type 1: A case report and literature review. AB - Kaposiform hemangioendothelioma (KHE) is a very rare, locally aggressive vascular neoplasm. It occurs mostly in children and is rarely observed in adults. It typically originates on the skin, later affecting the deep soft tissue of the extremities, head or neck, and retroperitoneum by infiltrative growth. It is locally aggressive, does not regress spontaneously, and tends to metastasize locally as well as to the regional lymph nodes. In this article, we report a case of adult-onset KHE with neurofibromatosis type 1. The patient presented to our department with a 2-month history of a painful ulceration in her left popliteal area. Since KHE had not previously been reported in patients with neurofibromatosis, the diagnosis was difficult due to the similarity of the skin manifestation to neurofibromatosis-associated lesions. We share our experience of diagnosing and treating this rare case of adult-onset KHE. PMID- 30466241 TI - Eruption of a venous malformation through an iliac bone harvesting site after trauma. AB - Harvesting grafts from the anterior iliac bone has been associated with various complications. A 50-year-old woman presented to our department with a chief complaint of right inguinal swelling and pain. Autologous bone grafts had been harvested on two previous occasions from the right anterior iliac crest for use in the reconstruction of multiple facial fractures. Computed tomography and magnetic resonance imaging revealed a full-thickness bone defect in the right anterior iliac crest. A mass was noted in the right gluteus minimus, while a multilocular cystic mass extended from the right iliac crest defect to the right inguinal region. Both the inguinal mass and gluteal mass were removed under general anesthesia. Following histopathological analysis, the gluteal mass was diagnosed as a venous malformation(VM). Based on the patient's clinical course, iliac bone graft harvesting and trauma to the gluteal region triggered hemorrhaging from the VM. Blood components leaked out from the fragile portion of the iliac bone defect, forming a cystic lesion that developed into the inguinal mass. In this case, a coincidental VM resulted in a rare complication of iliac bone graft harvesting. These sequelae could have been avoided by planning for more appropriate ways to collect the grafts. PMID- 30466242 TI - Complex sternal and rib reconstruction with allogeneic material. AB - Sternal malunion, or loss, developed after a median sternotomy cannot only be difficult to manage and treat, but also may diminish one's quality-of-life drastically. The technique presented here represents a multispecialty approach in one stage for the reconstruction of an unstable thoracic cage. The procedure utilized a donated sternum and ribs. The sternum with ribs harvested from a single donor included adipose derived stromal vascular fraction (ADSVF) cells with marrow also from the same donor. Autologous muscle flaps, stabilized with acellular dermal matrix were utilized to provide a robust blood supply to the ADSVF cells and bone grafts. Acellular dermal matrix was used to construct the ribs and stabilize the plugs of stem cells and bone. These procedures, in the hands of multispecialty physicians, have led to several successful reconstructions involving complex chest wall deformities. This surgical intervention was performed in a one stage operation. This represents the first successful complete sternal transplant in a patient with return to normal activities and increased quality-of-life. PMID- 30466243 TI - Upper eyelid platinum weight placement for the treatment of paralytic lagophthalmos: A new plane between the inner septum and the levator aponeurosis. PMID- 30466244 TI - Response to Letter: Upper eyelid platinum weight placement for the treatment of paralytic lagophthalmos: A new plane between the inner septum and the levator aponeurosis. PMID- 30466245 TI - Epithelial-mesenchymal transition in keloid tissue. PMID- 30466246 TI - Versatility of the reverse sural fasciocutaneous flap for the reconstruction of lower leg defects caused by chronic osteomyelitis. PMID- 30466247 TI - Vastus intermedius-anterolateral thigh chimeric free flap for lower extremity reconstruction. PMID- 30466248 TI - Some Considerations in High Tibial Osteotomy. PMID- 30466249 TI - Open Posterior Approach versus Arthroscopic Suture Fixation for Displaced Posterior Cruciate Ligament Avulsion Fractures: Systematic Review. AB - Purpose: To compare the clinical outcomes between the open posterior approach and arthroscopic suture fixation for displaced posterior cruciate ligament (PCL) avulsion fractures. Methods: A literature search was performed on MEDLINE, EMBASE, and the Cochrane Library databases. The inclusion criteria were as follows: papers written in English on displaced PCL avulsion fractures, clinical trial(s) with clear description of surgical technique, adult subjects, a follow up longer than 12 months and modified Coleman methodology score (CMS) more than 60 points. Results: Twelve studies were included with a mean CMS value of 72.4 (standard deviation, 7.6). Overall, 134 patients underwent the open posterior approach with a minimum 12-month follow-up, and 174 patients underwent arthroscopic suture fixation. At final follow-up, the range of Lysholm score was 85-100 for the open approach and 80-100 for the arthroscopic approach. Patients who were rated as normal or nearly normal in the International Knee Documentation Committee subjective knee assessment were 92%-100% for the open approach and 90% 100% for the arthroscopic approach. The range of side-to-side difference was 0-5 mm for both approaches. Conclusions: Both arthroscopic and open methods for the treatment of PCL tibial-side avulsion injuries resulted in comparably good clinical outcomes, radiological healing, and stable knees. PMID- 30466250 TI - Short-Term Results of Hybrid Closed-Wedge High Tibial Osteotomy: A Case Series with a Minimum 3-Year Follow-up. AB - Purpose: High tibial valgus osteotomy (HTO) is a well-established surgical procedure for patients with medial compartment osteoarthritis (OA) of the knee. The hybrid closed-wedge HTO (CWHTO) procedure permits extensive correction in patients with severe deformities or patellofemoral joint OA. The aim of this study was to report the short-term results in a consecutive series of patients treated with hybrid CWHTO. Materials and Methods: We retrospectively evaluated the clinical outcomes and radiographic parameters in 29 consecutive knees that underwent hybrid CWTHO to correct medial compartment OA at an average follow-up of 52.6 months. Clinical outcomes were assessed using the Lysholm score and knee scoring system of the Japanese Orthopedic Association (JOA). The Kellgren Lawrence grading system and pre- and postoperative mechanical axis (MA), femorotibial angle (FTA), posterior tibial slope, and patella height were assessed. Results: The FTA and MA significantly changed from 180.7 degrees to 170.4 degrees and from 22.0 degrees to 60.2 degrees , respectively. No significant differences were observed between the mean pre- and postoperative posterior tibial slope, Insall-Salvati ratio, or Caton-Deschamps index. The postoperative JOA and Lysholm scores significantly improved from 76.7 to 95.8 and from 58.8 to 90.2, respectively. Conclusions: Satisfactory outcomes can be achieved with hybrid CWHTO in patients with medial OA. PMID- 30466251 TI - Does Coronal Knee and Ankle Alignment Affect Recurrence of the Varus Deformity after High Tibial Osteotomy? AB - Purpose: The purpose of this study was to evaluate changes in the coronal alignment of the knee and ankle joints after open wedge high tibial osteotomy (OWHTO) to determine factors related to the recurrence (R) of the varus deformity by serial analysis. Materials and Methods: Sixty-four OWHTOs were enrolled in this study. The weight bearing line (WBL) ratio, joint line convergence angle (JLCA), knee joint inclination, mechanical axis-tibial plateau angle, talar inclination (TI), and distal tibia articular angle (DTAA) were serially assessed. Serial correlation analysis between all parameters was performed. Patients were divided into R group and no recurrence (NR) group according to the WBL ratio (55%) at postoperative one year. Results: The preoperative WBL ratio showed significantly negative correlation with serial changes of JLCA, TI, and DTAA (p<0.05). The JLCA, TI, and DTAA as well as WBL ratio showed a significantly larger degree of varus alignment in the R group than in NR group at postoperative 6 weeks and 1 year after OWHTO (p<0.05). Conclusions: Sufficient correction of the WBL and restoration of the JLCA during OWHTO are essential to prevention of the R of varus deformity after the surgery because they are the only modifiable factors during surgery. Level of Evidence: IV, Case series. PMID- 30466252 TI - Prospective Study of Central versus Peripheral Obesity in Total Knee Arthroplasty. AB - Purpose: Body mass index (BMI) is often used to predict surgical difficulty in patients receiving total knee arthroplasty (TKA); however, BMI neglects variation in the central versus peripheral distribution of adipose tissue. We sought to examine whether anthropometric factors, rather than BMI alone, may serve as a more effective indication of surgical difficulty in TKA. Materials and Methods: We prospectively enrolled 67 patients undergoing primary TKA. Correlation coefficients were used to evaluate the associations of tourniquet time, a surrogate of surgical difficulty, with BMI, pre- and intraoperative anthropometric measurements, and radiographic knee alignment. Similarly, Knee Injury and Osteoarthritis Outcome Score (KOOS) was compared to BMI. Results: Tourniquet time was significantly associated with preoperative inferior knee circumference (p=0.025) and ankle circumference (p=0.003) as well as the intraoperative depth of incision at the quadriceps (p=0.014). BMI was not significantly associated with tourniquet time or any of the radiographic parameters or KOOS scores. Conclusions: Inferior knee circumference, ankle circumference, and depth of incision at the quadriceps (measures of peripheral obesity) are likely better predictors of surgical difficulty than BMI. Further study of alternative surgical indicators should investigate patients that may be deterred from TKA for high BMI, despite relatively low peripheral obesity. PMID- 30466253 TI - Reliability and Validity of the Femorotibial Mechanical Axis Angle in Primary Total Knee Arthroplasty: Navigation versus Weight Bearing or Supine Whole Leg Radiographs. AB - Purpose: To evaluate the reliability and validity of the femorotibial mechanical axis angle from radiographs in the weight bearing (WB) and supine positions compared with navigation-measured values. Materials and Methods: Sixty-eight cases of navigation-assisted total knee arthroplasty (TKA) were included. The pre and postoperative whole leg radiographs (WLRs) in WB and supine positions were compared with the initial and final navigation values. Results: The mean mechanical axis angle from the preoperative WBWLR and navigation were not statistically different (p=0.079) and were correlated strongly with each other (intraclass correlation [ICC], 0.818). However, on postoperative measurements, although the WBWLR and navigation values were not different (p=0.098), they were not correlated with each other (ICC, 0.093). The standard error of measurement was 1.8 degrees +/-3.6 degrees for the preoperative WBWLR and 2.5 degrees +/-4.8 degrees for the postoperative WBWLR. The validity that was determined by the Bland-Altman plot was not acceptable for both pre- and postoperative measurements. Conclusions: The preoperative WBWLR could provide accurate but not precise measurement value of the femorotibial mechanical axis angle for navigation-assisted TKA, and postoperative measurements in navigation were not comparable with radiographic measurements. The lack of agreement was found between the radiographic and navigation measurements of the coronal alignment regardless of pre- or postoperative evaluation although the accuracy was found acceptable. Level of Evidence: Level 4. PMID- 30466254 TI - Does Second-Generation Suspensory Implant Negate Tunnel Widening of First Generation Implant Following Anterior Cruciate Ligament Reconstruction? AB - Purpose: Tunnel widening following anterior cruciate ligament (ACL) reconstruction is commonly observed. Graft micromotion is an important contributing factor. Unlike fixed-loop devices that require a turning space, adjustable-loop devices fit the graft snugly in the tunnel. The purpose of this study is to compare tunnel widening between these devices. Our hypothesis is that the adjustable-loop device will create lesser tunnel widening. Materials and Methods: Ninety-eight patients underwent ACL reconstruction from January 2013 to December 2014. An adjustable-loop device was used in 54 patients (group 1) and a fixed-loop device was used in 44 patients (group 2). Maximum tunnel widening at 1 year was measured by the L'Insalata's method. Functional outcome was measured at 2-year follow-up. Results: The mean widening was 4.37 mm (standard deviation [SD], 2.01) in group 1 and 4.09 mm (SD, 1.98) in group 2 (p=0.511). The average International Knee Documentation Committee score was 78.40 (SD, 9.99) in group 1 and 77.11 (SD, 12.31) in group 2 (p=0.563). The average Tegner-Lysholm score was 87.25 (SD, 3.97) in group 1 and 87.29 in group 2 (SD, 4.36) (p=0.987). There was no significant difference in tunnel widening and functional outcome between the groups. Conclusions: The adjustable-loop device did not decrease the amount of tunnel widening when compared to the fixed-loop device. There was no significant difference in outcome between the two fixation devices. Level of Evidence: Level 3, Retrospective Cohort. PMID- 30466255 TI - Minimal Ablation of the Tibial Stump Using Bony Landmarks Improved Stability and Synovial Coverage Following Double-Bundle Anterior Cruciate Ligament Reconstruction. AB - Purpose: To evaluate the clinical effects of using anatomical bony landmarks (Parsons' knob and the medial intercondylar ridge) and minimal ablation of the tibial footprint to improve knee anterior instability and synovial graft coverage after double-bundle anterior cruciate ligament reconstruction. Materials and Methods: We performed a retrospective comparison of outcomes between patients who underwent reconstruction with minimal ablation of the tibial footprint, using an anatomical tibial bony landmark technique, and those who underwent reconstruction with wide ablation of the tibial footprint. Differences between the two groups were evaluated using second-look arthroscopy, radiological assessment of the tunnel position, postoperative anterior knee joint laxity, and clinical outcomes. Results: Use of the anatomical reference and minimal ablation of the tibial footprint resulted in a more anterior positioning of the tibial tunnel, with greater synovial coverage of the graft postoperatively (p=0.01), and improved anterior stability of the knee on second-look arthroscopy. Both groups had comparable clinical outcomes. Conclusions: Use of anatomical tibial bony landmarks that resulted in a more anteromedial tibial tunnel position improved anterior knee laxity, and minimal ablation improved synovial coverage of the graft; however, it did not significantly improve subjective and functional short term outcomes. PMID- 30466256 TI - Arthroscopic Excision of Medial Knee Plica: A Meta-Analysis of Outcomes. AB - Purpose: A meta-analysis was performed to assess the outcomes following surgical intervention for medial knee plica. Materials and Methods: A literature search of Medline, EMBASE, CINAHL and Cochrane CENTRAL was performed using relevant key words. The primary outcome was patient-reported postoperative scores of "good" and "excellent". Meta-analyses were performed using a random effects model. Results: The literature search identified 731 articles. After removing duplicates and those not meeting the inclusion criteria, 12 articles reporting on a total of 643 knees were included for analysis, and of these, 7 articles including 235 knees were used for meta-analysis. The overall rate of good and excellent outcomes following surgery was estimated at 84.2% (95% confidence interval [CI], 72.8-91.4). In those cases that had non-surgical therapy prior to surgery, the rate of good and excellent outcomes of surgery was estimated at 76.1% (95% CI, 60.1-87). Conclusions: Arthroscopic surgical management of symptomatic medial knee plica results in favourable outcomes. Our results suggest that arthroscopic surgical excision should be considered as a treatment modality in patients with pathological medial plica disease of the knee either as a first-line treatment or when symptoms have not responded to non-surgical interventions. Level of Evidence: IV. PMID- 30466257 TI - Pseudoaneurysm Formation due to Popliteal Artery Injury Caused by Drilling during Medial Opening Wedge High Tibial Osteotomy. AB - We report a case of 53-year-old woman with an injured popliteal artery due to excessive drilling with a drill bit during medial opening wedge high tibial osteotomy (MOWHTO). Pseudoaneurysm was diagnosed three days after surgery and confirmed by urgent computed tomography (CT) angiography. Open vascular surgery with resection of the perivascular hematoma and end-to-end anastomosis using ipsilateral saphenous vein interposition graft was performed. CT angiography at 8 months postoperatively showed that blood flow was maintained without obstruction of the graft site and active dorsiflexion of the foot was possible. To reduce neurovascular injury during MOWHTO, it is important not to drill the far cortex at the proximal part of the osteotomy site when using a drill bit, and the metal should be positioned posteromedially as much as possible. PMID- 30466258 TI - Enantioselective Conversion of Oligoprenol Derivatives to Macrocycles in the Germacrene, Cembrene, and 18-Membered Cyclic Sesterterpene Series. AB - A new enantio-and diastereoselective process has been developed for the efficient conversion of farnesol and other oligoprenyl alcohols to chiral 10-, 14-, and 18 membered cyclization products, including germacrenol, (+)-costunolide, 3-beta elemol, and epi-mukulol. The key cyclization reaction utilizes omega-bromo aldehyde substrates, a chiral ligand, and indium powder as the reagent at -78 degrees C and generates 10-, 14-, and 18-membered cyclic products in 70-74% yield and 94-95% ee. PMID- 30466259 TI - Valence and Inner Electronic Excitation, Ionization and Fragmentation of Perfluoropropionic Acid. AB - The photoexcitation, photoionization and photofragmentation of gaseous CF3CF2C(O)OH were studied by means of synchrotron radiation in the valence and inner energy regions. Photofragmentation events were detected from 11.7 eV through formation of COH+, C2F4+ and the parent species M+. Since the vertical ionization potential has been reported at 11.94 eV, the starting energy used in this study, 11.7 eV, falls just inside the tale of the ionization band in the photoelectron spectra. Together, therefore, with the foremost ionization process, autoionization or adiabatic ionization cannot be discounted in order to explain the observed production of ions. The information from the Total Ion Yield spectra around the C 1s, O 1s and F 1s ionization potentials allows the energies at which different resonance transitions take place in the molecule to be determined. These transitions have been assigned by comparison with the results of the analysis of similar compounds. In the inner energy region both kinetic energy release (KER) values and the slope and shape of double coincidence islands obtained from PhotoElectron-PhotoIon-PhotoIon-Coincidence (PEPIPICO) spectra allow different photofragmentation mechanisms to be elucidated. PMID- 30466260 TI - Associations of Water-Soluble Macrocyclic Hosts with 4-aminoazobenzene: Impact of the pH. AB - An investigation of the pH effect on the inclusion complexes of ?-Cyclodextrins and calixarenesulfonates with 4-aminoazobenzene was conducted both by experiments and molecular simulations. The whole thermodynamic characterizations of the association between hosts and 4-aminoazobenzene (K, ?rG0, ?rH0 and T?rS0) were determined by UV-visible spectroscopy. ?-Cyclodextrin inclusion complexes are not affected by pH change unlike those obtained with calixarenes. All the studied systems were enthalpically favoured. Nevertheless, the entropic behavior is different depending on the host. In order to interpret these experimental results, molecular simulations were used to calculate the number of atoms inserted into the cage-like host compounds and the number of water molecules expelled from the cavity. Finally, we have also shown that the cis-trans isomerization of 4-aminoazobenzene depends on both the pH and the nature of the host molecules. PMID- 30466261 TI - Matrix product state formulation of the multiconfiguration time-dependent Hartree theory. AB - A matrix product state formulation of the multiconfiguration time-dependent Hartree (MPS-MCTDH) theory is presented. The Hilbert space that is spanned by the direct products of the phonon degree of freedoms, which is linearly parameterized in the MCTDH ansatz and thus results in an exponential increase in the computational cost, is parametrized by the MPS form. Equations of motion based on the Dirac-Frenkel time-dependent variational principle is derived by using the tangent space projection and the projector-splitting technique for the MPS, which have been recently developed. The mean-field operators, which appear in the equation of motion of the MCTDH single particle functions, are written in terms of the MPS form and efficiently evaluated by a sweep algorithm that is similar to the density-matrix renormalized group sweep. The efficiency and convergence of the MPS approximation to the MCTDH are demonstrated by quantum dynamics simulations of extended excitonic molecular systems. PMID- 30466262 TI - Incremental embedding: A density matrix embedding scheme for molecules. AB - The idea of using fragment embedding to circumvent the high computational scaling of accurate electronic structure methods while retaining high accuracy has been a long-standing goal for quantum chemists. Traditional fragment embedding methods mainly focus on systems composed of weakly correlated parts and are insufficient when division across chemical bonds is unavoidable. Recently, density matrix embedding theory and other methods based on the Schmidt decomposition have emerged as a fresh approach to this problem. Despite their success on model systems, these methods can prove difficult for realistic systems because they rely on either a rigid, non-overlapping partition of the system or a specification of some special sites (i.e., "edge" and "center" sites), neither of which is well-defined in general for real molecules. In this work, we present a new Schmidt decomposition-based embedding scheme called incremental embedding that allows the combination of arbitrary overlapping fragments without the knowledge of edge sites. This method forms a convergent hierarchy in the sense that higher accuracy can be obtained by using fragments involving more sites. The computational scaling for the first few levels is lower than that of most correlated wave function methods. We present results for several small molecules in atom-centered Gaussian basis sets and demonstrate that incremental embedding converges quickly with fragment size and recovers most static correlation in small basis sets even when truncated at the second lowest level. PMID- 30466263 TI - Phase-field method for epitaxial kinetics on surfaces. AB - We present a procedure for simulating epitaxial growth based on the phase-field method. We consider a basic model in which growth is initiated by a flux of atoms onto a heated surface. The deposited atoms diffuse in the presence of this flux and eventually collide to form islands which grow and decay by the attachment and detachment of migrating atoms at their edges. Our implementation of the phase field method for this model includes uniform deposition, isotropic surface diffusion, and stochastic nucleation (in both space and time), which creates islands whose boundaries evolve as the surface atoms "condense" into and "evaporate" from the islands. Computations using this model in the submonolayer regime, prior to any appreciable coalescence of islands, agree with the results of kinetic Monte Carlo (KMC) simulations for the coverage-dependence of adatom and island densities and island-size distributions, for both reversible and irreversible growth. The scaling of the island density, as obtained from homogeneous rate equations, agrees with KMC simulations for irreversible growth and for reversible growth for varying deposition flux at constant temperature. For reversible growth with varying temperature but constant flux, agreement relies on an estimate of the formation energy of the critical cluster. Taken together, our results provide a comprehensive analysis of the phase-field method in the submonolayer regime of epitaxial growth, including the verification of the main scaling laws for adatoms and island densities and the scaling functions for island-size distributions, and point to the areas where the method can be extended and improved. PMID- 30466264 TI - Curing basis-set convergence of wave-function theory using density-functional theory: A systematically improvable approach. AB - The present work proposes to use density-functional theory (DFT) to correct for the basis-set error of wave-function theory (WFT). One of the key ideas developed here is to define a range-separation parameter which automatically adapts to a given basis set. The derivation of the exact equations are based on the Levy-Lieb formulation of DFT, which helps us to define a complementary functional which corrects uniquely for the basis-set error of WFT. The coupling of DFT and WFT is done through the definition of a real-space representation of the electron electron Coulomb operator projected on a one-particle basis set. Such an effective interaction has the particularity to coincide with the exact electron electron interaction in the limit of a complete basis set, and to be finite at the electron-electron coalescence point when the basis set is incomplete. The non diverging character of the effective interaction allows one to define a mapping with the long-range interaction used in the context of range-separated DFT and to design practical approximations for the unknown complementary functional. Here, a local-density approximation is proposed for both full-configuration-interaction (FCI) and selected configuration-interaction approaches. Our theory is numerically tested to compute total energies and ionization potentials for a series of atomic systems. The results clearly show that the DFT correction drastically improves the basis-set convergence of both the total energies and the energy differences. For instance, a sub kcal/mol accuracy is obtained from the aug-cc-pVTZ basis set with the method proposed here when an aug-cc-pV5Z basis set barely reaches such a level of accuracy at the near FCI level. PMID- 30466265 TI - Non-adiabatic mass correction to the rovibrational states of molecules: Numerical application for the H2+ molecular ion. AB - General transformation expressions of the second-order non-adiabatic Hamiltonian of the atomic nuclei, including the kinetic-energy correction terms, are derived upon the change from laboratory-fixed Cartesian coordinates to general curvilinear coordinate systems commonly used in rovibrational computations. The kinetic-energy or so-called "mass-correction" tensor elements are computed with the stochastic variational method and floating explicitly correlated Gaussian functions for the H2+ molecular ion in its ground electronic state. {Further numerical applications for the 4 He2+ molecular ion are presented in the forthcoming paper, Paper II [E. Matyus, J. Chem. Phys. 149, 194112 (2018)]}. The general, curvilinear non-adiabatic kinetic energy operator expressions are used in the examples, and non-adiabatic rovibrational energies and corrections are determined by solving the rovibrational Schrodinger equation including the diagonal Born-Oppenheimer as well as the mass-tensor corrections. PMID- 30466266 TI - Global elucidation of broken symmetry solutions to the independent particle model through a Lie algebraic approach. AB - Broken symmetry solutions-solutions to the independent particle model that do not obey all symmetries required by the Hamiltonian-have attracted significant interest for capturing multireference properties with mean-field scaling. However, identification and optimization of broken-symmetry solutions is difficult owing to the non-linear nature of the self-consistent field (SCF) equations, particularly for solutions belonging to low-symmetry subgroups and where multiple broken symmetry solutions are sought. Linearization of SCF solution space results in the Lie algebra, which this work utilizes as a framework for elucidation of the set of solutions that exist at the desired symmetry. To demonstrate that searches constructed in the Lie algebra yield the set of broken symmetry solutions, a grid-based search of real-restricted, real unrestricted, complex-restricted, paired-unrestricted, and real-general solutions of the C2v (nearly D 4h ) H4 molecule is performed. PMID- 30466267 TI - Heterogeneous reactions of SO2 on the hematite(0001) surface. AB - Heterogeneous reactions at the surfaces of mineral dusts represent a key process in the formation of atmospheric aerosols. To quantify the rate of aerosol formation in climate modeling as well as combat hazardous aerosols, a deep understanding of the mechanisms of these reactions is essential. In the present work, density functional theory calculations, including a Hubbard-like +U correction, were employed to elucidate the reaction between SO2 and the hematite(0001) surface. Three reaction conditions are considered: dry, wet, and aerobic. In the absence of water and oxygen, adsorption energies of SO2 on the clean Fe-O3-Fe-termination were found to be about -0.8 to -1.0 eV and resulted in the formation of an adsorbed SO3-like species. The addition of water leads to surface hydroxylation and has little effect on promoting the SO2 adsorption. Under such circumstances, an HSO3-like species was formed with a smaller adsorption energy of about -0.5 eV. By contrast, the presence of molecular oxygen enhances the SO2 adsorption significantly as the two species combine to form sulfate SO4 2-, with adsorption energies of -1.31 to -1.64 eV. The calculated vibrational frequencies of the adsorbate species provide insight into the surface bonding and a useful spectral fingerprinting for experimental measurements. These results elucidate the atomistic mechanism of the reaction between SO2 and hematite and highlight the important role of atmospheric O2 in the formation of sulfates. PMID- 30466268 TI - A transport model and constitutive equation for oppositely charged polyelectrolyte mixtures with application to layer-by-layer assembly. AB - We develop a general framework for transport of polyions, solvent and salt, with intended application to Layer-by-Layer (LbL) assembly of polyelectrolyte monolayers (PEMs). The formulation for the first time includes electrostatics, chemical potential gradients, and mechanical stress gradients as driving forces for mass transport. The general model allows all species to be mobile throughout the process and avoids the assumptions of stepwise instantaneous equilibrium and/or immobilized structures typical of previous approaches, while reducing to these models in appropriate limits. A simple constitutive equation is derived for a mixture of oppositely charged polyelectrolytes that accounts for network strand dilution and cross-chain ion pairing by appending reactive terms to the Smoluchowski probability diffusion equation for network strand end-to-end vectors. The resulting general framework encompasses the Poisson equation describing the electrostatic potential distribution, an osmotic pressure balance, a stress constitutive equation, and a generalized flux law of polymer transport. The computational domain is split into a PEM phase and an external solution phase with an appropriate boundary condition derived for the interface between the two. The mobile species (water and small salt ions) are taken to be in a state of dynamic equilibrium with their distributions enslaved to the perturbations in the two polyion compositions. The proposed model captures the swelling response of PEM films to external solutions. For the first time, we studied the effects of the temporal evolution of electrostatic and stress distribution on the rate of chain loss and absorption during rinsing and dipping of an idealized and arbitrarily selected and rigid brush layer into external solutions. The temporal evolution provides a kinetic basis for the ability of LbL films to grow under conditions that thermodynamics alone suggests would cause them to be washed away and to account for partial desorption during washing. The proposed transport framework constitutes a solid basis for eventual quantitative modeling of LbL assembly and transport in polyion networks more generally. PMID- 30466269 TI - Plasmon excitation and subsequent isomerization dynamics in naphthalene and azulene under fast proton interaction. AB - The interaction of fast protons (velocity between 1.41 and 2.4 a.u.) with naphthalene and azulene is investigated as a model of an ion-polycyclic aromatic hydrocarbon interaction system. Production of various intact and fragment ions in coincidence with electron emission, electron transfer to projectile, or both is analyzed. The two targets being isomers, the rather obvious similarity in the fundamental ion-molecule collision energetics is quantitatively verified. The fast isomerization processes of cationic azulene are observed to be influencing its further dissociation channels such as C2H2 and H eliminations. A first ever attempt is presented here wherein single plasmon excitation in conjunction with isomerization dynamics is reported. Evidence from dication evaporation energetics is used to invoke the double plasmon excitation model. A model based on the multiplasmon resonance explains the observed proton velocity dependence of double to single ionization cross sections. Moreover an attempt is made to reinforce the proposition of double plasmon excitation by explaining the observed suppression of neutral H loss from dications as opposed to monocations. PMID- 30466270 TI - Comprehensive classical analysis of partition function and some observables for weakly interacting polyatomic dimers. AB - This paper presents the systematic classical consideration of a statistical averaging procedure that permits the calculation of partition function, equilibrium constant, and some observables for polyatomic dimers composed of weakly interacting rigid monomers. It was shown that the number of independent internal coordinates in a body-fixed frame is a crucial parameter that largely determines the temperature dependence of the partition function irrespective of the kinematic coupling within various degrees of freedom. The kinetic energy was derived for the molecular pair of arbitrary complexity in the body-fixed frame. Rigorous expression was obtained for the partition function over a pre-selected domain in the phase space. A similar expression was applicable to perform statistical averaging of some observables. Taking a linear molecule-atom as an example, it was shown how the suggested general approach permits the calculation of the equilibrium constant for true bound dimer formation or zeroth spectral moment of a collision-induced absorption band. PMID- 30466271 TI - A transferable artificial neural network model for atomic forces in nanoparticles. AB - We have designed a new method to fit the energy and atomic forces using a single artificial neural network (SANN) for any number of chemical species present in a molecular system. The traditional approach for fitting the potential energy surface for a multicomponent system using artificial neural network (ANN) is to consider n number of networks for n number of chemical species in the system. This shoots the computational cost and makes it difficult to apply to a system containing more number of species. We present a new strategy of using a SANN to compute energy and forces of a chemical system. Since atomic forces are significant for geometry optimizations and molecular dynamics simulations for any chemical system, their accurate prediction is of utmost importance. So, to predict the atomic forces, we have modified the traditional way of fitting forces from underlying energy expression. We have applied our strategy to study geometry optimizations and dynamics in gold-silver nanoalloys and thiol protected gold nanoclusters. Also, force fitting has made it possible to train smaller sized systems and extrapolate the parameters to make accurate predictions for larger systems. This proposed strategy has definitely made the mapping and fitting of atomic forces easier and can be applied to a wide variety of molecular systems. PMID- 30466272 TI - Communication: Constrained molecular dynamics for polarizable models. AB - A new algorithm to solve numerically the evolution of empirical shell models of polarizable systems is presented. It employs constrained molecular dynamics to satisfy exactly, at each time step, the crucial condition that the gradient of the potential with respect to the shell degrees of freedom is null. The algorithm is efficient, stable, and, contrary to the available alternatives, it is symplectic and time reversible. A proof-of-principle calculation on a polarizable model for NaCl is presented to illustrate its properties in comparison with the current method, which employs a conjugate-gradient procedure to enforce the null gradient condition. The proposed algorithm is applicable to other cases where a minimum condition on a function of an auxiliary set of driven dynamical variables must be satisfied. PMID- 30466273 TI - Variational reduced density matrix method in the doubly occupied configuration interaction space using three-particle N-representability conditions. AB - Ground-state energies and two-particle reduced density matrices (2-RDMs) corresponding to N-particle systems are computed variationally within the doubly occupied configuration interaction (DOCI) space by constraining the 2-RDM to satisfy a complete set of three-particle N-representability conditions known as three-positivity conditions. These conditions are derived and implemented in the variational calculation of the 2-RDM with standard semidefinite programming algorithms. Ground state energies and 2-RDMs are computed for N2, CO, CN-, and NO+ molecules at both equilibrium and nonequilibrium geometries as well as for pairing models at different repulsive interaction strengths. The results from the full three-positivity conditions are compared with those from the exact DOCI method and with approximated 2-RDM variational ones obtained within two positivity and two-positivity plus a subset of three-positivity conditions, as recently reported [D. R. Alcoba et al., J. Chem. Phys. 148, 024105 (2018) and A. Rubio-Garcia et al., J. Chem. Theory Comput. 14, 4183 (2018)]. The accuracy of these numerical determinations and their low computational cost demonstrate the usefulness of the three-particle variational constraints within the DOCI framework. PMID- 30466274 TI - Communication: Gas phase vibrational spectroscopy of the azide-water complex. AB - The vibrational spectra of the azide-water complex, N3 -(H2O), and its fully deuterated isotopologue are studied using infrared photodissociation (IRPD) spectroscopy (800-3800 cm-1) and high-level ab initio computations. The IRPD spectrum of the H2-tagged complex exhibits four fundamental transitions at 3705, 3084, 2003, and 1660 cm-1, which are assigned to the free OH stretching, the hydrogen-bonded O-H stretching, the antisymmetric N3 stretching, and the water bending mode, respectively. The IRPD spectrum is consistent with a planar, singly hydrogen-bonded structure according to an MP2 and CCSD(T) anharmonic analysis via generalized second-order vibrational perturbation theory. The red-shift of the hydrogen-bonded OH stretching fundamental of 623 cm-1 associated with this structure is computed within 6 cm-1 (or 1%) and is used to estimate the proton affinity of azide (1410 kJ mol-1). Born-Oppenheimer molecular dynamics simulations show that large amplitude motions are responsible for the observed band broadening at cryogenic temperature. Temperature-dependent (6-300 K) IR multiphoton dissociation spectra of the untagged complex are also presented and discussed in the context of spectral diffusion observed in the condensed phase. PMID- 30466275 TI - Amplitude of jump motion signatures in classical vibration-jump dynamics. AB - The classical Langevin dynamics of a particle in a periodic potential energy landscape are studied via the intermediate scattering function (ISF). By construction, the particle performs coupled vibrational and activated jump motion with a wide separation of the vibrational period and the mean residence time between jumps. The long time limit of the ISF is a decaying tail proportional to the function that describes ideal jump motion in the absence of vibrations. The amplitude of the tail is unity in idealized jump dynamics models but is reduced from unity by the intra-well motion. Analytical estimates of the amplitude of the jump motion signature are provided by assuming a factorization of the conditional probability density of the particle position at long times, motivated by the separation of time scales associated with inter-cell and intra-cell motion. The assumption leads to a factorization of the ISF at long correlation times, where one factor is an ideal jump motion signature and the other component is the amplitude of the signature. The amplitude takes the form of a single-particle anharmonic Debye-Waller factor. The factorization approximation is exact at the diffraction conditions associated with the periodic potential. Numerical simulations of the Langevin equation in one and two spatial dimensions confirm that for a strongly corrugated potential the analytical approximation provides a good qualitative description of the trend in the jump signature amplitude, between the points where the factorization is exact. PMID- 30466276 TI - Unsupervised machine learning for detection of phase transitions in off-lattice systems. II. Applications. AB - We outline how principal component analysis can be applied to particle configuration data to detect a variety of phase transitions in off-lattice systems, both in and out of equilibrium. Specifically, we discuss its application to study (1) the nonequilibrium random organization (RandOrg) model that exhibits a phase transition from quiescent to steady-state behavior as a function of density, (2) orientationally and positionally driven equilibrium phase transitions for hard ellipses, and (3) a compositionally driven demixing transition in the non-additive binary Widom-Rowlinson mixture. PMID- 30466277 TI - Simulating vibronic spectra via Matsubara-like dynamics: Coping with the sign problem. AB - Measuring vibronic spectra probes dynamical processes in molecular systems. When interpreted via suitable theoretical tools, the experimental data provides comprehensive information about the system in question. For complex many-body problems, such an approach usually requires the formulation of proper classical like approximations, which is particularly challenging if multiple electronic states are involved. In this work, we express the imaginary-time shifted time correlation function and, thus, the vibronic spectrum in terms of the so-called Matsubara dynamics, which combines quantum statistics and classical-like dynamics. By applying the Matsubara approximation in the adiabatic limit, we derive a formal generalization of the existing Matsubara dynamics formalism to multiple potential energy surfaces (PESs), which, however, does not feature all the defining properties of its single-PES counterpart though suffering equally from the sign problem. The mathematical analysis for two shifted harmonic oscillators suggests a new modified method to practically simulate the standard correlation function via Matsubara-like dynamics. Importantly, this modified method samples the thermal Wigner function without suffering from the sign problem and yields an accurate approximation to the vibronic absorption spectrum, not only for the harmonic system but also for the anharmonic one. PMID- 30466278 TI - Refining evERdock: Improved selection of good protein-protein complex models achieved by MD optimization and use of multiple conformations. AB - A method for evaluating binding free energy differences of protein-protein complex structures generated by protein docking was recently developed by some of us. The method, termed evERdock, combined short (2 ns) molecular dynamics (MD) simulations in explicit water and solution theory in the energy representation (ER) and succeeded in selecting the near-native complex structures from a set of decoys. In the current work, we performed longer (up to 100 ns) MD simulations before employing ER analysis in order to further refine the structures of the decoy set with improved binding free energies. Moreover, we estimated the binding free energies for each complex structure based on an average value from five individual MD snapshots. After MD simulations, all decoys exhibit a decrease in binding free energy, suggesting that proper equilibration in explicit solvent resulted in more favourably bound complexes. During the MD simulations, non native structures tend to become unstable and in some cases dissociate, while near-native structures maintain a stable interface. The energies after the MD simulations show an improved correlation between similarity criteria (such as interface root-mean-square distance) to the native (crystal) structure and the binding free energy. In addition, calculated binding free energies show sensitivity to the number of contacts, which was demonstrated to reflect the relative stability of structures at earlier stages of the MD simulation. We therefore conclude that the additional equilibration step along with the use of multiple conformations can make the evERdock scheme more versatile under low computational cost. PMID- 30466279 TI - Detecting the undetectable: The role of trace surfactant in the Jones-Ray effect. AB - The surface tension of dilute salt water is a fundamental property that is crucial to understanding the complexity of many aqueous phase processes. Small ions are known to be repelled from the air-water surface leading to an increase in the surface tension in accordance with the Gibbs adsorption isotherm. The Jones-Ray effect refers to the observation that at extremely low salt concentration, the surface tension decreases. Determining the mechanism that is responsible for this Jones-Ray effect is important for theoretically predicting the distribution of ions near surfaces. Here we use both experimental surface tension measurements and numerical solution of the Poisson-Boltzmann equation to demonstrate that very low concentrations of surfactant in water create a Jones Ray effect. We also demonstrate that the low concentrations of the surfactant necessary to create the Jones-Ray effect are too small to be detectable by surface sensitive spectroscopic measurements. The effect of surface curvature on this behavior is also examined, and the implications for unexplained bubble phenomena are discussed. This work suggests that the purity standards for water may be inadequate and that the interactions between ions with background impurities are important to incorporate into our understanding of the driving forces that give rise to the speciation of ions at interfaces. PMID- 30466280 TI - On the calculation of the stress tensor in real-space Kohn-Sham density functional theory. AB - We present an accurate and efficient formulation of the stress tensor for real space Kohn-Sham density functional theory calculations. Specifically, while employing a local formulation of the electrostatics, we derive a linear-scaling expression for the stress tensor that is applicable to simulations with unit cells of arbitrary symmetry, semilocal exchange-correlation functionals, and Brillouin zone integration. In particular, we rewrite the contributions arising from the self-energy and the nonlocal pseudopotential energy to make them amenable to the real-space finite-difference discretization, achieving up to three orders of magnitude improvement in the accuracy of the computed stresses. Using examples representative of static and dynamic calculations, we verify the accuracy and efficiency of the proposed formulation. In particular, we demonstrate high rates of convergence with spatial discretization, consistency between the computed energy and the stress tensor, and very good agreement with reference planewave results. PMID- 30466281 TI - A TPD-based determination of the graphite interlayer cohesion energy. AB - Temperature Programmed Desorption (TPD) spectroscopy was used to determine the binding energies of polycyclic aromatic hydrocarbons C n H m (22 <= n <= 60) with highly oriented pyrolytic graphite. These energies were then used to estimate the dispersive graphite interlayer cohesion by means of a refined extrapolation method proposed by Bjork et al. This yields a cohesion energy of 44.0 +/- 3.8 meV per carbon atom. We discuss some limits of the TPD-based approach and contrast our values with previous determinations of the interlayer cohesion energy of graphite. PMID- 30466282 TI - The interplay of structure and dynamics at grain boundaries. AB - Molecular simulations are carried out to address the structure and atomic diffusion at grain boundaries. We use an inherent structure approach, which maps each configuration in a molecular dynamics trajectory to the potential energy minimum ("inherent structure") it would reach by a steepest descent quench. Dynamics are then decomposed into a combination of displacements within an inherent structure and transitions between inherent structures. The inherent structure approach reveals a simple structural picture of the grain boundary that is normally obscured by the thermal motion. We apply our methodology to polycrystalline MgO. Grain boundary atoms are identified as atoms that are undercoordinated in the inherent structure, relative to those in the perfect crystal. Our method enables the calculation of grain boundary diffusion coefficients without arbitrary assumptions about which atoms or spatial regions belong to the grain boundary, and the results are shown to be consistent with estimates from experiments. The inherent structure approach also enables the elementary steps in the diffusion process to be elucidated. We show that the process in MgO grain boundaries primarily involves vacancy hops, but that there is also significant motion of other nearby atoms during such a hop. PMID- 30466283 TI - Interatomic potentials for ground and excited states of Ar+He. AB - The potential energy curves (PECs) of the ground and excited states that correlate in the atomic limit with Ar([Ne]3s 23p 6,1S), Ar([Ne]3s 23p 54s 1, 3P, 1P), and Ar([Ne]3s 23p 54p 1, 3D, 3P, 3S, 1D, 1P, 1S) are calculated at the multireference configuration interaction (MRCI+Q) theoretical level with extrapolations to the complete basis set limit using all-electron correlation consistent triple-, quadruple-, and quintuple-zeta basis sets. Scalar relativistic corrections are calculated using second-order Douglas-Kroll-Hess Hamiltonian with the corresponding basis sets contracted for scalar relativistic Hamiltonians. For these calculations, the 3s orbitals of the Ar atom are not included in the active space but are correlated through single and double excitations. Spin-orbit eigenstates are computed by diagonalizing the Breit-Pauli matrix between internal configurations with no electrons in external orbitals and added to the scalar relativistic results. A total of 32 molecular PECs are computed with spin-orbit contributions, which correlate with 1s1, 1s5-2, and 2p10 1 atomic Ar energies in Paschen notation. Important features of the PECs and system crossings are discussed. PMID- 30466284 TI - New compact density matrix averaged ANO basis sets for relativistic calculations. AB - When including relativistic effects in quantum chemical calculations, basis sets optimized for relativistic Hamiltonians such as the atomic natural orbital relativistic core-correlated (ANO-RCC) basis set have to be used to avoid large errors that appear upon contraction of the basis set. While the large size of the ANO-RCC basis set in terms of primitive basis functions allows for highly accurate calculations, it also hinders its applicability to large sized systems due to the computational costs. To tackle this problem, a new compact relativistic ANO basis set, the ANO-eXtra Small (XS) basis set, is introduced for elements H-Ca. The number of primitive basis functions in ANO-XS is about half that of the ANO-RCC basis set. This greatly reduces the computational costs in the integral calculations especially when used in combination with Cholesky decomposition. At the same time, the ANO-XS basis set is able to predict molecular properties such as bond lengths and excitation energies with reasonable errors compared to the larger ANO-RCC basis set. The main intention for the ANO XS basis set is to be used in conjunction with the ANO-RCC basis set for large systems that can be divided with regions demanding different qualities of basis sets. This is exemplified in CASPT2 calculations for an Ir(C3H4N)3 complex, where substituting the larger ANO-RCC for the compact ANO-XS basis set at the ligand atoms yields only minor differences for a large number of excited states compared to calculations employing the ANO-RCC basis set on all atoms. Thus, accurate calculations including relativistic effects for large systems become more affordable with the new ANO-XS basis set. PMID- 30466285 TI - Unsupervised machine learning for detection of phase transitions in off-lattice systems. I. Foundations. AB - We demonstrate the utility of an unsupervised machine learning tool for the detection of phase transitions in off-lattice systems. We focus on the application of principal component analysis (PCA) to detect the freezing transitions of two-dimensional hard-disk and three-dimensional hard-sphere systems as well as liquid-gas phase separation in a patchy colloid model. As we demonstrate, PCA autonomously discovers order-parameter-like quantities that report on phase transitions, mitigating the need for a priori construction or identification of a suitable order parameter-thus streamlining the routine analysis of phase behavior. In a companion paper, we further develop the method established here to explore the detection of phase transitions in various model systems controlled by compositional demixing, liquid crystalline ordering, and non-equilibrium active forces. PMID- 30466286 TI - Folding a small protein using harmonic linear discriminant analysis. AB - Many processes of scientific importance are characterized by time scales that extend far beyond the reach of standard simulation techniques. To circumvent this impediment, a plethora of enhanced sampling methods has been developed. One important class of such methods relies on the application of a bias that is a function of a set of collective variables specially designed for the problem under consideration. The design of good collective variables can be challenging and thereby constitutes the main bottle neck in the application of these methods. To address this problem, recently we have introduced Harmonic Linear Discriminant Analysis, a method to systematically construct collective variables as linear combinations of a set of descriptors. The method uses input information that can be gathered in short unbiased molecular dynamics simulations in which the system is trapped in the metastable states. Here, to scale up our examination of the method's efficiency, we applied it to the folding of chignolin in water. Interestingly, already before any biased simulations were run, the constructed one-dimensional collective variable revealed much of the physics that underlies the folding process. In addition, using it in metadynamics, we were able to run simulations in which the system goes from the folded state to the unfolded one and back, where to get fully converged results, we combined metadynamics with parallel tempering. Finally, we examined how the collective variable performs when different sets of descriptors are used in its construction. PMID- 30466287 TI - Random sequential adsorption of cuboids. AB - The subject of this study was random sequential adsorption of cuboids of axes length ratio of a : 1 : b for a ? [0.3, 1.0] and b ? [1.0, 2.0], and the aim of this study was to find a shape that provides the highest packing fraction. The obtained results show that the densest packing fraction is 0.401 87 +/- 0.000 97 and is reached for axes ratios near cuboids of 0.75:1:1.30. Kinetics of packing growth was also studied, and it was observed that its power-law character seems not to be governed by the number of cuboid degrees of freedom. The microstructural properties of obtained packings were studied in terms of density correlation function and propagation of orientational ordering. PMID- 30466288 TI - Non-adiabatic mass-correction functions and rovibrational states of 4 He2+ ( X 2Sigmau+ ). AB - The mass-correction functions in the second-order non-adiabatic Hamiltonian are computed for the 4 He2+ molecular ion using the variational method, floating explicitly correlated Gaussian functions, and a general coordinate-transformation formalism. When non-adiabatic rovibrational energy levels are computed using these (coordinate-dependent) mass-correction functions and a highly accurate potential energy and diagonal Born-Oppenheimer correction curve, significantly improved theoretical results are obtained for the nine rotational and two rovibrational intervals known from high-resolution spectroscopy experiments. PMID- 30466289 TI - Establishing a microscopic model for nonfullerene organic solar cells: Self accumulation effect of charges. AB - A one-dimensional many-body tight-binding model is established to mimic the charge distribution and dynamics in nonfullerene organic solar cells. Two essential issues are taken into account in the model: the alternating donor and acceptor structure, which is beneficial for the direct generation of charge transfer state, and the local imbalance of the intrinsic electrons and holes. The most remarkable outcome of the model is that, due to the strong Coulomb attractive potential energy, the intrinsic charges in the cells are self accumulated in a small spatial region and outside the self-accumulation region the charge density vanishes so that the recombination is regarded to be largely suppressed. The photogenerated electrons are subsequently observed to spread freely outside the self-accumulation region, implying that the Coulomb attraction does not matter in the ultrafast charge separation dynamics. These findings enable the understanding of the high performance of emerging nonfullerene cells, and the designing rules of molecules and devices are then comprehensively discussed. PMID- 30466291 TI - Cholangioscopy: seeing to believe, seeing to know, seeing to cure. AB - Endoscopic retrograde cholangiopancreatography (ERCP) remains the gold standard for the diagnosis and treatment of biliopancreatic disorders, and over one million ERCP procedures are performed each year worldwide. ERCP has always been performed by a group of courageous endoscopists who on a daily basis managed to develop its full diagnostic and therapeutic potential over the technique's 50 years of lifespan, always making the most of radiographic images, ever secretly dreaming of directly viewing the banned, consigned-to-oblivion territory. PMID- 30466290 TI - Is prophylactic gastrectomy indicated for healthy carriers of CDH1 gene mutations associated with hereditary diffuse gastric cancer? AB - INTRODUCTION: hereditary diffuse gastric cancer (HDGC) is a recently reported hereditary cancer syndrome. Patients with suspected HDGC must be under surveillance via endoscopy and multiple biopsies. As an alternative, some studies suggest prophylactic gastrectomy (PG) for disease carriers. The goal of this article was to report our experience with a CDH1 mutation positive family who underwent PG. PATIENTS AND METHODS: the index case was a 34-year-old female diagnosed with diffuse gastric adenocarcinoma and massive carcinomatosis. There was a family history of gastric adenocarcinoma in seven family members. A genetic study identified the c.1577G>A mutation, in exon 11 of the CDH1 gene via sequencing analysis. RESULTS: this mutation was also present in other six family members, who subsequently underwent prophylactic gastrectomy. The pathology study of resected gastric segments revealed multiple microscopic foci of adenocarcinoma in five of these individuals. These foci were not detected in the multiple endoscopies performed before surgery. CONCLUSIONS: we recommend prophylactic gastrectomy for CDH1 mutation carriers even in the absence of lesions during endoscopic screening. PMID- 30466292 TI - What is the value of Forensic Orders? PMID- 30466293 TI - Association Between Depression and Metabolic Syndrome in Korean Adults: Data From the 2014 and 2016 Korea National Health and Nutrition Examination Survey. AB - This study aimed to examine the association of depression with metabolic syndrome and to investigate levels of awareness and treatment of depression in Korean adults. We analyzed data extracted from the Korea National Health and Nutrition Examination Survey (2014 and 2016) using the Patient Health Questionnaire-9 depression screening instrument. Among the survey participants, 10 459 were selected for data analysis. Of them, 7.2% had depression, 24.4% had metabolic syndrome, and 10.0% had both depression and metabolic syndrome. Among those with depression, 33.1% were aware of their condition and 25.7% received treatment, with significant differences found between those with and without metabolic syndrome. The mean Patient Health Questionnaire-9 scores significantly increased with the number of metabolic syndrome components ( F = 6.06, P = <.001). In logistic regression analysis, the odds ratio (OR) for depression with metabolic syndrome was 1.41 (95% confidence interval [CI] = 1.12-1.76). For the number of metabolic syndrome components, having 2 (OR = 1.37, 95% CI = 1.01-1.86), 3 (OR = 1.57, 95% CI = 1.12-2.21), 4 (OR = 1.95, 95% CI = 1.32-2.87), and 5 (OR = 2.18, 95% CI = 1.38-3.46) conditions significantly increased the OR for depression. Including depression in the management of metabolic syndrome could help make people with depression more aware of their condition. PMID- 30466294 TI - Leisure time and family functioning in families living with autism spectrum disorder. AB - Family leisure can provide opportunities for both enjoyment and family growth. However, families of children with autism spectrum disorder experience multiple barriers to engaging in satisfying family leisure activities. This study surveyed parents of children with autism spectrum disorder ( n = 112) and parents of children with typical development ( n = 123) to examine relationships among family leisure involvement, leisure satisfaction, family functioning, and satisfaction with family life. Parents of children with autism spectrum disorder reported a similar amount of leisure involvement as families of typically developing children. However, they reported lower leisure satisfaction, poorer family functioning, and less satisfaction with family life. Mediation models suggested that low leisure satisfaction was related to less effective family communication, which in turn led to poorer family functioning and less satisfaction with family life. Amount of time spent in leisure made relatively small contributions to predicting other family variables. These results suggest that leisure-focused interventions for families of children with autism spectrum disorder should focus on improving quality, rather than quantity, of family leisure time. PMID- 30466295 TI - Inside OUES: fact or fiction? PMID- 30466296 TI - Correlations between methylenetetrahydrofolate reductase gene polymorphisms and venous thromboembolism: A meta-analysis of 99 genetic association studies. AB - We performed this meta-analysis to better assess the relationship between methylenetetrahydrofolate reductase gene ( MTHFR) polymorphisms and the risk of venous thromboembolism. Eligible studies were searched in PubMed, Medline, Embase, and Web of Science. Odds ratios with 95% confidence intervals were used to assess associations of MTHFR polymorphisms with venous thromboembolism. A total of 99 genetic association studies were enrolled for analyses. Although no positive results were detected in overall analyses for the rs1801131 polymorphism. Further subgroup analyses according to ethnicity of participants and type of disease revealed that the rs1801131 polymorphism was significantly correlated with the risk of pulmonary embolism. For the rs1801133 polymorphism, significant association with the risk of venous thromboembolism was found in the dominant, recessive, and allele models. Further subgroup analyses according to ethnicity of participants revealed that the rs1801133 polymorphism was significantly associated with the risk of venous thromboembolism in Caucasians, East Asians, and West Asians. When we stratified available data according to type of disease, we found that the rs1801133 polymorphism was also significantly correlated with the risk of deep vein thrombosis and pulmonary embolism. In conclusion, our findings indicate that the MTHFR rs1801133 polymorphism may serve as a potential biological marker for venous thromboembolism in Caucasians, East Asians, and West Asians. Moreover, the MTHFR rs1801133 polymorphism may be implicated in the development of deep vein thrombosis and pulmonary embolism, while the MTHFR rs1801131 polymorphism may contribute to the development of pulmonary embolism. PMID- 30466297 TI - Exercise training for chronic heart failure (ExTraMATCH II): Why all data are not equal. PMID- 30466298 TI - Infant Feeding Guidelines for the Asia Pacific Region. AB - Good nutrition for infants, during the first 1000 days from conception, is one of the most important determinants of a healthy long life. Breastfeeding is the most important component of infant nutrition and reduces morbidity and mortality. With the changes to the climate currently occurring, issues of nutrition and food supply are only going to increase in importance. The Sustainable Development Goals of the United Nations, place nutrition at the forefront of world development and a sustainable planet. The vision of Asia-Pacific Academic Consortium for Public Health (APACPH) is to "achieve the highest possible level of health of all the people of the nations of the Asia-Pacific region." Much of the burden of disease, early deaths, and disability in the Asia Pacific region could be reduced with public health efforts to address the major risk factors, including nutrition-related causes and smoking. The United Nations Decade of Action on Nutrition 2016-2025 has recently been launched with the aim of reducing the global burden of inappropriate nutrition. The goals include increasing rates of exclusive breastfeeding to 6 months, reducing wasting and stunting, and reducing the rates of low birthweight. This is the position endorsed in these guidelines along with the principles of the Baby Friendly Hospital Initiative. These guidelines expand the information on infants that was included in the 2016 APACPH Dietary Guidelines. APACPH covers many different environments, geographical areas, cultures, and socioeconomic groups. These guidelines are generally applicable to all infants in our region, specific local advice may sometimes be needed. PMID- 30466299 TI - Women's Employment and Well-Being of Children Under 5 Years in Vietnam. AB - This study investigates the impact of women's employment in the manufacturing sector and in the services sector on the well-being of children aged 0 to 5 years in Vietnam. Our findings show that women's employment decreases the quantity of time that mothers spend with their children. At the same time, women's employment increases their income. The magnitude of the impact of women's employment in the services sector on child nutrition is greater than that of women's employment in manufacturing. This may be because of the higher income of mothers working in the service sector when compared to those working in manufacturing. PMID- 30466300 TI - Somatic delusions as motivated beliefs? PMID- 30466301 TI - Activity of enisamium, an isonicotinic acid derivative, against influenza viruses in differentiated normal human bronchial epithelial cells. AB - AIMS: New therapeutics for the control of influenza virus infections are needed to alleviate the burden caused by seasonal epidemics and occasional pandemics, and to overcome the potential risk of drug-resistance emergence. Enisamium iodide (Amizon(r), Farmak) is currently approved for clinical use for the treatment of influenza in 11 countries which includes Ukraine, Russia, Belarus, Kazakhstan, and Uzbekistan. However, experimental evidence of the antiviral activity of enisamium has not been reported. METHODS: Antiviral activity of enisamium was assessed by virus yield reduction assays using differentiated normal human bronchial epithelial cells. Permeability of enisamium into differentiated normal human bronchial epithelial cells and its cytotoxicity were also assessed, and comparisons with other cell lines were made. RESULTS: Enisamium inhibited replication of multiple subtypes of influenza A viruses, including seasonal H1N1, 2009 pandemic H1N1, seasonal H3N2, the zoonotic H5N1 and H7N9, neuraminidase inhibitor-resistant variant carrying the H275Y NA substitution (N1 numbering), and influenza B virus at doses 23- to 64-fold lower than cytotoxic concentrations. The permeability of enisamium in Madin-Darby canine kidney cells (where no antiviral activity was found) was less than 0.08%, while higher permeability was observed in differentiated normal human bronchial epithelial cells (1.9%). The kinetics of enisamium intracellular uptake in differentiated normal human bronchial epithelial cells was concentration dependent. In time-of addition experiments in differentiated normal human bronchial epithelial cells, enisamium treatment within 4 h after A(H1N1) virus inoculation resulted in 100 fold or greater reductions in virus titers, suggesting that it affects an early stage of the virus life cycle. CONCLUSIONS: Enisamium exhibits antiviral activity against influenza viruses in vitro, supporting the reported clinical efficacy against influenza virus infections. PMID- 30466302 TI - Negative associations between general self-efficacy and anxiety/depression among newly HIV-diagnosed men who have sex with men in Beijing, China. AB - To evaluate the association between general self-efficacy and depression/anxiety among newly HIV-diagnosed Chinese men who have sex with men (MSM) in Beijing, our study evaluated the baseline survey data of MSM taking part in a clinical trial among Chinese MSM in Beijing. The baseline survey of the trial was conducted between March 2013 and March 2014. General self-efficacy and depression/anxiety were measured using standard scales. Logistic regression and cumulative logistic regression were used to evaluate the associations between general self-efficacy and depression/anxiety. A total of 367 newly HIV-diagnosed Chinese MSM in Beijing were recruited. There were negative associations between general self-efficacy and depression/anxiety among the study population. As general self-efficacy increased by one unit, the odds of "likely" or "borderline" depression versus normal, or "likely" depression versus "borderline" depression or normal decreased by 12% [adjusted odds ratio (AOR): 0.88, 95% confidence interval (CI): 0.85-0.92] after adjusting for potential confounders. Similarly, general self-efficacy was negatively associated with anxiety (AOR: 0.89, 95% CI: 0.86-0.93). A higher level of general self-efficacy was associated with lower levels of depression and anxiety among newly HIV-diagnosed Chinese MSM. Interventions promoting overall health and wellness should address self-efficacy, depression and anxiety. PMID- 30466303 TI - Factors associated with delayed and late ART initiation among people living with HIV in BC: results from the engage study. AB - We examined correlates of late and delayed initiation of antiretroviral therapy (ART) in British Columbia, Canada. From December 2013 to December 2015 we recruited treatment-naive people living with HIV who initiated ART within the previous year. 'Late initiation' was defined as CD4 cell count <=500 cells/uL at ART initiation and 'delayed initiation' as >=1 year between HIV diagnosis and initiation. Multivariable logistic regression assessed independent correlates of late and delayed initiation. Of 87 participants, 44 (51%) initiated late and 22 (26%) delayed initiation. Delayed initiation was positively associated with older age (adjusted odds ratio [AOR]: 1.06 per year, 95% confidence interval [95% CI]: 1.01-1.12) and inversely associated with wanting to start ART at diagnosis (AOR: 0.06, 95% CI: 0.02-0.21). Variables associated with late initiation were older age (AOR: 1.09 per year, 95% CI: 1.03-1.15) and medical reason(s) for initiation (AOR: 5.00, 95% CI: 1.41-17.86). Late initiation was less likely among those with greater perceived ART efficacy (AOR 0.94, 95% CI: 0.90-0.98) and history of incarceration (AOR: 0.12, 95% CI: 0.03-0.56). Disparities in timing of initiation were observed for age, perceived ART efficacy, and history of incarceration. Enhanced health services that address these factors may facilitate earlier treatment initiation. PMID- 30466304 TI - Predictors of postpartum HIV care engagement for women enrolled in prevention of mother-to-child transmission (PMTCT) programs in Tanzania. AB - Prevention of mother-to-child transmission of HIV (PMTCT) is a foundational component of a comprehensive HIV treatment program. In addition to preventing vertical transmission to children, PMTCT is an important catch-point for universal test-and-treat strategies that can reduce community viral load and slow the epidemic. However, systematic reviews suggest that care engagement in PMTCT programs is sub-optimal. This study enrolled a cohort of 200 women initiating PMTCT in Kilimanjaro, Tanzania, and followed them to assess HIV care engagement and associated factors. Six months after delivery, 42/200 (21%) of participants were identified as having poor care engagement, defined as HIV RNA >200 copies/mL or, if viral load was unavailable, being lost-to-follow-up in the clinical records or self-reporting being out of care. In a multivariable risk factor analysis, younger women were more likely to have poor postpartum care engagement; with each year of age, women were 7% less likely to have poor care engagement (aRR: 0.93; 95% CI: 0.89, 0.98). Additionally, women who had told at least one person about their HIV status were 47% less likely to have poor care engagement (aRR: .53; 95% CI: 0.29, 0.97). Among women who entered antenatal care with an established HIV diagnosis, those who were pregnant for the first time had increased risk of poor care engagement (aRR 4.16; 95% CI 1.53, 11.28). The findings suggest that care engagement remains a concern in PMTCT programs, and must be addressed to realize the goals of PMTCT. Comprehensive counseling on HIV disclosure, along with community-based stigma reduction programs to provide a supportive environment for people living with HIV, are crucial to address barriers to care engagement and support long-term treatment. Women presenting to antenatal care with an established HIV status require support for care engagement during the crucial period surrounding childbirth, particularly those pregnant for the first time. PMID- 30466305 TI - Insulin Pumping Patches: Emerging Insulin Delivery Systems. AB - In this special section of JDST, patch-pump delivery systems ("patch pumps") are discussed. Patch pumps are novel insulin delivery systems that have emerged on the market; offering flexible insulin delivery options. These systems offer several advantages over conventional insulin pump delivery systems and are gaining popularity. Patch pumps are free of tubing, small, and lightweight. In this special section, the authors discuss both the simple and complex patch pumps currently available on the US market as well as those that are currently under development. Current technologies used to operate these pumps are discussed in detail, and potential promising technologies are presented. Available data on patient preferences, clinical trial data, and the future of patch pumps are discussed. PMID- 30466306 TI - Superficial Peroneal Nerve Injury Risk During a Semiblind Fasciotomy for Anterior Chronic Exertional Compartment Syndrome of the Leg: An Anatomical and Clinical Study. AB - BACKGROUND:: Up to 8% of patients who underwent a fasciotomy for leg anterior chronic exertional compartment syndrome (ant-CECS) report sensory deficits suggestive of iatrogenic superficial peroneal nerve (SPN) injury. In the current study we aimed to thoroughly assess the risk of SPN injury during a semiblind fasciotomy of the anterior compartment using 2 separate approaches. METHODS:: A modified semiblind fasciotomy of the anterior compartment was performed via a longitudinal 2-cm skin incision 2 cm lateral of the anterior tibial crest halfway along the line fibular head-lateral malleolus both in cadaver legs and in patients with ant-CECS. In the cadaver legs, the skin was removed after the procedure and possible SPN injuries and spatial relationships between the SPN and the opened fascia were studied. Between January 2013 and December 2016, 64 ant CECS patients who underwent a fasciotomy of the anterior compartment were prospectively followed. Iatrogenic SPN injuries were assessed using questionnaires and physical examinations. RESULTS:: Macroscopic SPN nerve injury was not observed in any of the 9 cadaver legs. In 8 specimens, the SPN was located at least 5 mm posterolateral to the opened fascia. In 1 specimen, an undamaged SPN branch crossed the operative field in a ventral plane. De novo sensory deficits suggestive for iatrogenic SPN injury were not observed in any of the 64 patients (120 legs; 36 females; median age, 22 years) who underwent a fasciotomy of the anterior compartment. CONCLUSION:: The proposed semiblind fasciotomy for treatment of ant-CECS was not associated with SPN injury in either the cadaveric study or our clinical series. LEVEL OF EVIDENCE:: Level IV, case series. PMID- 30466307 TI - Results of Peroneal Tendoscopy With a Technical Modification. AB - BACKGROUND:: The aim of this study was to evaluate the role of tendoscopy in the diagnosis and treatment of peroneal tendon (PT) pathologies, and to evaluate the results of our technical modification. METHODS:: Twenty ankles of 18 patients with retrofibular pain, operated on between 2006 and 2012, were included in this study. Peroneal tendoscopy was performed diagnostically for the patients who were diagnosed as having "peroneal tendinopathy" with physical examination, x-ray, or magnetic resonance imaging (MRI). After being diagnosed by peroneal tendoscopy, patients were definitively treated with either tendoscopy or open surgery. RESULTS:: Thirteen of 20 ankles had accompanying ankle pathology with PT pathology, and the other 7 ankles had no concomitant pathology. We detected peroneal tenosynovitis (PTS) in 13 patients, PT tear in 7 patients, and vincula thickening in 1 patient. The American Orthopaedic Foot & Ankle Society (AOFAS) score was 76 preoperatively, and after 2 years' follow-up the AOFAS score was 96. CONCLUSION:: Tendoscopy is a useful method for the diagnosis and treatment of PT pathologies. The patients with clinical suspicion of PT pathology were treated or diagnosed by peroneal tendoscopy with our technical modification. LEVEL OF EVIDENCE:: Level IV, retrospective case series. PMID- 30466308 TI - A Simple Risk Scoring System to Estimate Adverse Cardiovascular Outcomes in Patients Undergoing Percutaneous Coronary Intervention: CHA2DS2-VASc. PMID- 30466309 TI - Connecting Child Maltreatment Risk With Crime and Neighborhood Disadvantage Across Time and Place: A Bayesian Spatiotemporal Analysis. AB - Child maltreatment is a major public health problem. Although maltreatment rates vary over time and are influenced by neighborhood characteristics, the unique effects of crime and disadvantage on risk are not well understood. This study utilized a Bayesian spatiotemporal approach to examine risk factors for substantiated child abuse and neglect over a 9-year period across zip codes in Davidson County, TN. Risk of child sexual and physical abuse decreased from 2008 to 2016. In contrast, risk of child neglect increased from 2011 to 2014, followed by a rapid decrease in risk. Whereas higher percentages of families living in poverty were associated with higher risk of all maltreatment subtypes, higher unemployment rates were uniquely associated with risk of child neglect. Crime rates were positively associated with risk of child physical and sexual abuse but not neglect. Results have implications for tailoring prevention strategies according to geographic area and maltreatment subtype. PMID- 30466311 TI - Commentary on Hay et al.: Can clinical trials data collection be improved by administrative data elements? PMID- 30466310 TI - Pilot study of the ability to probabilistically link clinical trial patients to administrative data and determine long-term outcomes. AB - BACKGROUND: Clinical trials are important but extremely costly. Utilization of routinely collected administrative data may simplify and enhance clinical trial data collection. PURPOSE: The aim of this study was to test the feasibility of use of administrative databases in Ontario, Canada, for long-term clinical trial follow-up, specifically (a) to determine whether limited patient identifiers held by the Canadian Cancer Trials Group can be used to probabilistically link with individuals in the Institute for Clinical Evaluative Sciences databases and if so, (b) the level of concordance between the two data sets. METHODS: This retrospective study was conducted through collaboration of established health service (Institute for Clinical Evaluative Sciences) and clinical trial (Canadian Cancer Trials Group) research groups in the province of Ontario, Canada, where healthcare is predominantly funded by the government. Adults with pre-treated metastatic colorectal cancer previously enrolled in the Canadian Cancer Trials Group CO.17 and CO.20 randomized phase III trials were included, limited to those in Ontario. The main outcomes were rate of successful probabilistic linkage and concordance of survival data, stated a priori. RESULTS: Probabilistic linkage was successful in 266/293 (90.8%) participants. In those patients for whom linkage was successful, the Canadian Cancer Trials Group (trial) and the Institute for Clinical Evaluative Sciences (administrative) data sets were concordant with regard to the occurrence of death during the period of clinical trial follow-up in 206/209 (98.6%). Death was recorded in the Institute for Clinical Evaluative Sciences, but not the Canadian Cancer Trials Group, for 57 cases, where the event occurred after the clinical trial cut-off dates. The recorded date of death matched closely between both databases. During the period of clinical trial conduct, administrative databases contained details of hospitalizations and emergency room visits not captured in the clinical trial electronic database. CONCLUSION: Prospective use of administrative data could enhance clinical trial data collection, both for long-term follow-up and resource utilization for economic analyses and do so less expensively than current primary data collection. Recording a unique identifier (e.g. health insurance number) in trial databases would allow deterministic linkage for all participants. PMID- 30466312 TI - An Anatomic Study of the Naviculocuneiform Ligament and Its Possible Role Maintaining the Medial Longitudinal Arch. AB - BACKGROUND:: Weight-bearing radiographic analysis of pes planus deformities show, with varying degree of severity, a break in the Meary line. The break in the Meary line occurs not only at the talonavicular joint but also distal to the spring ligament and reported tibialis posterior insertion. Our aim in this study was to investigate the distal plantar ligaments of the medial longitudinal arch, to try to identify other areas where deformity correction could be affected. METHODS:: We examined 11 cadaveric lower limbs that had been preserved for dissection in a solution of formaldehyde. The lower limbs were carefully dissected to identify the plantar aspect of the medial longitudinal arch. RESULTS:: In all specimens, the tibialis posterior tendon inserted into the plantar medial aspect of the navicular with separate slips to the intermediate and lateral cuneiform. The navicular cuneiform ligament extended from the navicular to medial cuneiform. This structure was statically inserted between the navicular and medial cuneiform, which would allow the pull of the tibialis posterior to act on the navicular and medial cuneiform in tandem. The average width of the naviculocuneiform ligament was 15.2 mm (range 12.4-18.0) compared to 9.5 mm (range 7.6-11.4) for the tibialis posterior tendon. CONCLUSION:: The tibialis posterior tendon inserted into the navicular and continued onto the medial cuneiform to provide a static restraint between 2 bony insertions, thus supporting the distal aspect of the medial longitudinal arch. CLINICAL RELEVANCE:: We are confident that it is a structure of importance in maintaining the distal aspect of the medial longitudinal arch and may therefore have significant clinical and surgical implications when treating the pes planus deformity. PMID- 30466314 TI - Trends in provider-advised HIV antiretroviral therapy deferral in the United States, 2009-2014. AB - Since 2012, U.S. clinical guidelines for antiretroviral therapy (ART) initiation have recommended universal ART prescription barring patient contraindications. Although ART prescription has significantly increased among U.S. HIV patients in recent years, the reasons for this increase, and why some patients are still not taking ART, are not well characterized. To fill these gaps, we analyzed data from the Medical Monitoring Project (MMP), to assess the proportion of persons who reported provider-advised ART deferral during 2009-2014, and used bivariate linear regression to estimate linear trends in provider-advised ART deferral over time by patient characteristics and clinical setting. During this period, the proportion of patients reporting provider-advised ART deferral decreased from 67% to 40%. Significant decreases were observed in all patient subgroups and clinical settings. Patients recently reporting non-provider-advised reasons for ART deferral were significantly less likely to be virally suppressed and more likely to have inconsistent care, be depressed, binge drink, and use illicit drugs. This work suggests that U.S. providers are recommending ART deferral for fewer patients, consistent with increasing adoption of 2012 universal prescribing guidelines. Addressing patients' financial, mental health, and substance use barriers may be needed to achieve universal ART prescription in the United States. PMID- 30466313 TI - Sweet Solutions for Analgesia in Neonates in China: A Systematic Review and Meta Analysis. AB - INTRODUCTION: High-quality synthesized evidence of sweet taste analgesia in neonates exists. However, Chinese databases have never been included in previous systematic reviews of sweet solutions for procedural pain. OBJECTIVE: To conduct a systematic review of Chinese literature evaluating analgesic effects of sweet solutions for neonates. Data sources: Wang Fang, China National Knowledge Infrastructure and Chinese Biomedical Literature Database. Data extraction and analysis: Two authors screened studies for inclusion and conducted risk of bias ratings and data extraction. A third author resolved any conflicts. Meta-analyses were performed using RevMan 5.2 software, on mean differences in pain outcomes using random effects models. RESULTS: Thirty-one trials (4999 neonates) were included; 26 trials used glucose, 4 used sucrose, and 1 trial evaluated both solutions. Sweet solutions reduced standardized mean pain scores (n = 21 studies; -1.68, 95% confidence interval -2.08, -1.27) and cry duration (n = 6 studies; 25.60, 95% confidence interval -36.47, -14.72 s) but not heart rate change (n = 7 studies; -17.64, 95% confidence interval -52.71, 17.43). No included studies cited the previously published systematic reviews of sweet solutions. CONCLUSIONS: This systematic review of Chinese databases showed the same results as previously published systematic reviews. No trials included in this review cited the English systematic reviews, highlighting a parallel research agenda. PMID- 30466315 TI - Comprehensive Health Literacy and Health-Related Behaviors Within a General Japanese Population: Differences by Health Domains. AB - The present study aimed to explore how different health-related domains of health literacy, as measured by the European Health Literacy Survey Questionnaire, were associated with health-related behaviors among a general population in Japan. We conducted a cross-sectional observational study of 1002 Japanese residents. Our questionnaire addressed socioeconomic status, health status, health-related behaviors, and health literacy. Among the 3 health-related domains of health literacy (health care, disease prevention, and health promotion), a multivariate model revealed that the disease prevention domain was associated with exercise behavior and alcohol consumption. The health promotion domain was associated with dietary behavior and exercise behavior. There were strong correlations among all health-related domains of health literacy; however, there were different associations between health literacy and health-related behaviors depending on those domains. Additional research is needed to determine how and to what extent each domain of health literacy is related to what health behaviors and outcomes. PMID- 30466316 TI - Brief iPad-Based Assessment of Cognitive Functioning with ImPACT(r) Pediatric. AB - ImPACT(r) Pediatric is an examiner-administered iOS-based battery of neuropsychological tests designed to measure neurocognitive functioning in children ages 5-11. This study documented Multivariate Base Rates (prevalence of low scores when multiple test scores are considered simultaneously) in the ImPACT(r) Pediatric standardization sample (N = 892). In the total sample, it was common for children to obtain at least one low factor score using the 25th percentile [T 43; base rate (BR) = 54.2%], 16th percentile (T40, BR = 38.1%), and the 10th percentile (T37, BR = 31.1%). However, it was uncommon for children to obtain two (or more) low factor scores using any of the above-listed cutoff score. PMID- 30466317 TI - Long-Term Cancer Survivors' Everyday Embodiment. AB - Long-term survivors of cancer (LTS) face daunting challenges to their physical, emotional, and cognitive well-being in the years following completion of cancer treatment. Most LTS face a new reality shaped by chronic "late effects" of treatments, or illnesses and conditions caused by chemotherapy, radiation, surgery, medications, and other treatments. Copious biomedical research explores the health challenges of patients undergoing cancer treatment, yet relatively little investigates the lived experience of LTS from a health communication perspective. Using Managing Meaning of Embodied Experience Theory (Field-Springer & Striley, 2018 ) as a critical embodiment lens, this study describes LTS' embodiment of health and illness. Critical qualitative analyses produced three themes: Bodies-in-relation, bodies entangled with biomedical actants, and dynamic embodiment. We discuss implications for health communication research and theorizing and for healthcare practice. PMID- 30466318 TI - Deaths of Despair in Florida: Assessing the Role of Social Determinants of Health. AB - Deaths of despair (DOD) is a new term appearing in public health literature to describe deaths attributable to suicide, liver disease, and drug overdose. In Florida, suicide and liver disease are the 8th and 10th leading causes of death, respectively. Additional mortality data show that the rate of drug overdose deaths in Florida is 12.5% higher than the suicide death rate. Some have hypothesized that economic social determinants of health (SDH) may be responsible for the recent increase in DOD. The current study, using secondary data, sought to identify what county-level SDH were significantly associated with county-level DOD. Using backward regression methodology, the results of the analysis indicate that 44% of the variance in county-level DOD is significantly associated with six county-level SDH: (a) Recent Medical Checkup, (b) Income, (c) Education Level, (d) Age, (e) Mental Health Professionals, and (f) the Income * Age interaction term. Higher than average income, age, and mental health professionals in a Florida county was associated with significantly higher rates of DOD. Higher than average levels of education and recent checkups in a Florida county were associated with a significant decrease in DOD. Possible explanations and implications are discussed. PMID- 30466319 TI - Factors associated with social deprivation among older persons living with HIV. AB - Aging persons living with HIV may develop multiple health problems, including comorbidities, and altered physical and mental health, earlier than non-infected people. They may also experience social deprivation. We assessed the prevalence of social deprivation and its relationship with health indicators in older persons living with HIV. An 18-month, multicenter, cross-sectional study was carried out between 2013 and 2014 focusing on patients >=50-years of age followed up in 12 dedicated HIV medical hospital units located in the South of France and involved the VISAGE study group. Social deprivation was measured with the EPICES (Evaluation of Deprivation and Inequalities in Health Examination Centers) score (ES) and defined as ES >=30.17. The following data were recorded: health indicators (gender, age, body mass index), comorbidities, frailty markers, socioeconomic, behavioral and age-related variables. Among 509 patients recruited, 494 completed the ES social deprivation evaluation. Mean age was 58.5 +/- 7.0 years and 72.9% were male. The prevalence of social deprivation was 49.0%. Multivariable logistic regression analysis showed that higher social deprivation was significantly linked to alcohol consumption (OR = 4.07 [95%CI: 1.23-13.48]), risk of depression (OR = 3.59 [95%CI: 2.26-5.70]), chronic obstructive pulmonary disease (OR = 3.10 [95%CI: 1.36-7.09]), hepatitis C (OR = 1.96 [95%CI: 1.10-3.52]), and chronic pain (OR = 1.11 [95%CI: 1.01-1.21]). Social deprivation was not related to HIV status. Our study showed that not only did older patients with HIV suffer from social deprivation, but they also received little support from social workers. Physicians should be aware of this situation and should systematically evaluate social deprivation in order to provide comprehensive targeted care involving global, social, and psychological support to reduce the burden of social deprivation. PMID- 30466320 TI - A immunosuppressive triterpenoid saponin from the stems of Epigynum griffithianum. AB - Chemical investigation of the stems of Epigunum griffithianum led to the isolation and identification of a new triterpenoid saponin (1) and two known compounds (epigynosides A (2) and B (3)). These structures were elucidated by means of spectroscopic analysis (1D and 2D NMR, MS, UV, IR) as well as comparison with the reported data. Compound 1 was evaluated in vitro for the immunosuppressive activities on proliferation of mice splenocyte and displayed significant immunosuppressive activities compared to the positive control (dexamethasone) with the concentration at 25 MUM. PMID- 30466322 TI - Editor's presentation. PMID- 30466321 TI - Development and validation of RP-HPLC method for the determination of stigmasterol in the botanical extract of Ficus deltoidea. AB - A simple, rapid, accurate and precise RP-HPLC method was developed for the determination of stigmasterol in botanical extract of Ficus deltoidea. Separation was achieved with acetonitrile and acetic acid in water (75:25% v/v) in isocratic mode at 210 nm. Single sharp peak of standard stigmasterol was detected at retention time 3.17 min which overlay with the peak of plant extract at 3.14 min. The calibration curve was found to be linear in a concentration range of 2-10 MUg/ml with correlation coefficient of 0.998. The LOD and LOQ were found to be 1.50 MUg/ml and 4.55 MUg/ml respectively. Accuracy and precision was determined with overall recovery of 99.6-100.1% for stigmasterol and RSD values in both intra-day and inter-day repeatability assay lesser than 0.340%, respectively. The robustness study also indicated that there is no influence of minor changes in detecting wavelength and flow rate of mobile phase on the response. PMID- 30466323 TI - Analysis of the influence of modelling assumptions on the prediction of the elastic properties of cardiac fibres. AB - Although several numerical models of the human heart have been proposed in the literature, there are still several discrepancies among the results predicted by each model. These discrepancies can be attributed to the fact that each model has a number of assumptions and simplifications, which can limit the scope and precision of the numerical predictions obtained. Moreover, none of the works reported in the literature have assessed the influence of modelling assumptions on the predicted cardiac fiber elastic properties. In this paper a new passive mechanical model that combines the left ventricular (LV) pressure-volume in-vivo measurements with an indirect approach based on the finite element method (FEM), is proposed and used to analyze the influence of different modelling assumptions on the estimated elastic properties of the cardiac fiber. This analysis is carried out by varying modelling assumptions that are common to existing passive mechanical models. The results have shown that although the different modelling assumptions have a significant effect on the predicted value of the fiber elastic properties, they tend to lead to the same results. This suggests that simplified passive numerical models in combination with adjustment factors, are valid in comparison with more refined and complex LV passive models. PMID- 30466324 TI - Validation of a model-based inverse kinematics approach based on wearable inertial sensors. AB - Wearable inertial measurement units (IMUs) are a promising solution to human motion estimation. Using IMUs 3D orientations, a model-driven inverse kinematics methodology to estimate joint angles is presented. Estimated joint angles were validated against encoder-measured kinematics (robot) and against marker-based kinematics (passive mechanism). Results are promising, with RMS angular errors respectively lower than 3 and 6 deg over a minimum range of motion of 50 deg (robot) and 160 deg (passive mechanism). Moreover, a noise robustness analysis revealed that the model-driven approach reduces the effects of experimental noises, making the proposed technique particularly suitable for application in human motion analysis. PMID- 30466325 TI - Polymyxin B and colistin - the economic burden of nephrotoxicity against multidrug resistant bacteria. AB - INTRODUCTION: Polymyxin B and colistin are nephrotoxic drugs used in the treatment of carbapenem-resistant Enterobacteriaceae. The aim of this study is to evaluate the burden of costs due to polymyxin associated AKI and propose a simulated break-even price for new therapies. METHODS: The pharmacoeconomic model is based on two large cross-sectional studies of polymyxin nephrotoxicity. Total direct costs in patients with and without renal failure were compared. Direct cost of each hemodialysis section (USD82.94) and daily hospital charges (USD934.85) were based on the values used in a major public hospital in the city where the clinical study was performed. The break-even price of new drugs was simulated considering eventual new drugs as effective as polymyxins, but less nephrotoxic in different percentages. Outcomes of patients after hospital discharge were not evaluated. RESULTS: Total direct cost of the group of patients who survived without AKI was significantly lower than total direct cost of the groups either with AKI or the group who died without AKI. There was a tendency of even higher costs in those who died with AKI and dialysis. Direct cost of hemodialysis was not as important as the longer hospitalization after sepsis. Considering daily cost of polymyxin is USD60, drugs with 50% less AKI could be considered cost-beneficial if the daily cost is lower than USD160. CONCLUSIONS: AKI in patients with carbapenem-resistant Enterobacteriaceae treated with polymyxin increases both length of stay in hospital and total costs. PMID- 30466326 TI - Steps to address anti-microbial drug resistance in today's drug discovery. PMID- 30466327 TI - Safety concerns of biosimilar hormone products. AB - Currently, biotherapeutic medicines are the most effective options for the treatment of many severe and chronic diseases. For faster market entry of biotherapeutic products and their cost reduction, the principles of "biosimilarity" have been developed. Development and licensing of biosimilars is allowed only after the end of patent exclusivity of the original preparation period. Biosimilar medicines of human growth hormones, follicle stimulating hormones and insulins were registered in EMA. During development of biosimilar hormone medicines, differences in the profile of glycosylation between biosimilar and reference preparations were revealed. As biotherapeutical preparations are produced by cells, the differences in glycosylation profile between biosimilar and referent preparation are predictable. While carrying out clinical studies, a high similarity of biosimilar and reference products effectiveness is shown, but some differences between them in the safety profile are revealed. The study of biosimilar products safety has shown the necessity of the further improvement of safety and standard approaches assessment for characteristic of biosimilar products immunogenicity. PMID- 30466328 TI - Patients' experiences of unilateral spatial neglect between stroke onset and discharge from inpatient rehabilitation: a thematic analysis of qualitative interviews. AB - PURPOSE: The purpose of this qualitative study was to explore how stroke patients with unilateral spatial neglect experience; (a) performance in activities of daily living; (b) alterations in bodily perceptions; and (c) personal hopes and expectations, looking at the period between stroke onset and discharge from inpatient rehabilitation. MATERIALS AND METHODS: We conducted individual semi structured interviews with 7 (5 men, 2 women, mean age 69 years) consecutively sampled participants. All interviews were transcribed verbatim and analyzed using thematic analysis. FINDINGS: Participants' experiences were captured in three over-arching themes: "unawareness of neglect," "emergent awareness for neglect related difficulties," and "comparing the new life with the old one." Findings showed that participants progressed from initial unawareness to emergent awareness for their neglect-related difficulties over the course of rehabilitation. Comparing their current life situation with the one before their stroke triggered feelings of uncertainty and regret, with associated decreased pleasure in meaningful activities. CONCLUSIONS: This study informs health professionals regarding personal experiences of orientation in and reorganization of life of stroke patients with unilateral spatial neglect. The findings highlight that being aware of neglect-related deficits is a prerequisite for using coping strategies and incorporating them in daily life. Possible therapeutic strategies that fit the current stage of recovery and level of awareness are discussed. IMPLICATIONS FOR REHABILITATION Symptoms of unilateral spatial neglect and anosognosia are most common after right hemispheric stroke, both being predictors of poorer functional outcome during rehabilitation. Patients' regaining some awareness of their impairments is a prerequisite for successful treatment and for engagement in neglect-specific interventions. Health care providers should carefully examine the "state of awareness" of the patient and adapt their therapeutic approach accordingly. This check should frequently be repeated over the course of rehabilitation, as awareness changes at different paces for each patient. PMID- 30466329 TI - Resources to Reduce Underage Drinking Risks and Associated Harms: Social Ecological Perspectives. AB - Underage college student alcohol consumption results in adverse consequences for students, colleges, and communities. Unfortunately, college health practitioners have invested time and effort implementing interventions that either fail to account for the complexity of this public health problem or are not evidence based. Consequently, in September 2015, the National Institute on Alcohol Abuse and Alcoholism published CollegeAIM, which was developed to support higher education administrators and campus health/wellness professionals in selecting appropriate interventions for reducing harmful and underage drinking. CollegeAIM is a user-friendly, matrix-based tool that evaluates and synthesizes the peer reviewed literature associated with nearly 60 campus and community interventions. This review uses the social ecological model to highlight individual- and environmental-level strategies evaluated in CollegeAIM matrices and is intended to be a tool in determining how best to implement resources to reduce college student alcohol use and associated harms. While CollegeAIM outlines strategies to be implemented among currently enrolled college students, it is important to note drinking behaviors for some students are established prior to entering college. Thus, interventions prior to enrolling in higher education are needed. As a resource for parents and for practitioners to use and share, the "Talk. They Hear You." mobile health (mHealth) app is also discussed and recommended. PMID- 30466330 TI - A clinical perspective on escalating or de-escalating adjuvant therapy in HER2+ breast cancer. AB - INTRODUCTION: Patients with early HER2-positive breast cancer (BC) benefit from HER2-targeted systemic therapy. The endorsed standard adjuvant treatment for patients with early HER2-positive breast cancer is chemotherapy plus trastuzumab administered for 1 year. Areas covered: Several trials have investigated modifications of the standard treatment in terms of de-escalation by either shortening the duration or giving less resource-demanding regimens and in terms of escalation by either adding a second anti-HER2 agent or extending the duration of HER2-targeted treatment for more than 12 months. In this perspective, we would offer a comprehensive view of these trials and discuss their findings. Expert commentary: At the current state of knowledge, there are still open questions regarding the management of HER2+ BC patients, such as the most adequate duration of trastuzumab therapy, the optimal chemotherapy regimen that should be combined with trastuzumab, and the addition of a second anti-HER2 agent. Growing evidences suggest that some HER2+ BC patients may not need chemotherapy. If these patients could be recognized upfront, optimal response could potentially be reached with HER2-targeted therapy alone. PMID- 30466331 TI - Participant-Driven Health Education Workshops With Men Transitioning From Prison to Community. AB - As part of a participatory health research project seeking to support men in achieving their health goals during the transition from prison to community, a workshop program was developed and piloted in a Community Residential Facility in British Columbia, Canada. The pilot program was evaluated through feedback surveys at each of the 16 workshops and a focus group interview at the end of the program. Workshops were highly valued by participants and seen as a means for (1) building skills relevant to their health and wellness, (2) working toward changing attitudes and behaviors adopted in prison, and (3) helping others and accepting help from others. Similar programs may be an effective support for men working to achieve their health goals during other transitions (e.g., bereavement, cancer patients, returning soldiers, and veterans). PMID- 30466332 TI - Current approaches towards identifying a correlate of immune protection from tuberculosis. AB - INTRODUCTION: Mycobacterium tuberculosis kills more people than any other pathogen. Vaccination is the most cost-effective control measure for any infectious disease. Development of an effective vaccine against tuberculosis is hindered by the uncertain predictive value of preclinical animal models, incomplete understanding of protective immunity and lack of validated immune correlates of protection (COP). Areas covered: Here we review what is known about protective immunity against Mycobacterium tuberculosis, the preclinical and clinical cohorts that can be utilized to identify COP, and COP that have been identified to date. Expert commentary: The identification of COP would allow the rational design and development of vaccine candidates which can then be optimised and prioritised based on the induction of these immune responses. Once validated in field efficacy trials, such COP could potentially facilitate the development and licensure of vaccines, in combination with human efficacy data. The identification and validation of COP would represent a very significant advance in TB vaccine development. Every opportunity to collect samples and cohorts on which to cross- validate pre-existing COP and identify novel COP should be exploited. Furthermore, global cooperation and collaboration on such samples will ensure that the utility of such precious samples is fully exploited. PMID- 30466333 TI - Inferred systolic blood pressure levels to switch from lifestyle modifications to antihypertensive medications: a success-rate oriented simulation. AB - OBJECTIVE: This simulation study attempted to infer the systolic blood pressure (SBP) levels at which subjects with hypertension, health nurses, and primary physicians should switch their preference of their treatment policies from lifestyle modifications to antihypertensive medications in virtual Japanese sample populations. METHODS: We assumed that SBP levels were normally distributed and that the incidence rate of cardiovascular disease (IRCVD, events/year) increased exponentially according to SBP. The total IRCVD was calculated by the definite integral for the product of the distribution of SBP multiplied by IRCVD at each SBP level. The success rates were calculated according to SBP and metabolic risk profiles in the two approaches, respectively. We deduced the hypothetical SBP levels by solving differential equations of ?(IRCVD)/ ?(SBP) = 0 using numerical analysis. RESULTS: In the realistic situations where the subjects were not affirmative to antihypertensive medications, the inferred SBP level to switch from lifestyle modifications to antihypertensive medications should be around 150 mmHg. If the subjects are affirmative to antihypertensive medications, the SBP level should be lowered to 140 mm Hg. CONCLUSION: This success rate oriented simulation proposes that the SBP level to switch from lifestyle modifications to antihypertensive medications can be modulated according to the behavioral propensity for taking antihypertensive medications. ABBREVIATIONS: The following abbreviations are used in this manuscript: CVD: cardiovascular disease; LM: lifestyle modifications; AM: antihypertensive medications; IRCVD: incidence rate of cardiovascular disease (events/year); SBP: systolic blood pressure; ?IRCVD: the improvements in the incidence rate of cardiovascular disease by lifestyle modifications and/or by antihypertensive medications. PMID- 30466334 TI - Age Moderates the Effect of Self-Paced Exercise on Exercise Adherence among Overweight Adults. AB - OBJECTIVE: The present study tested the hypothesis that the effect of self-paced exercise on adherence to exercise programs is more pronounced with increasing age. METHOD: Fifty-nine low-active overweight adults (18-65 years) were encouraged to walk 30 to 60 min/day and randomized to either self-paced ( n = 30) or prescribed moderate-intensity ( n = 29) conditions. RESULTS: The effect of study condition was moderated by age (main effect: b = 6.14, SE = 2.54, p = .02; Condition * Age: b = -11.55, SE = 3.77, p < .01), such that among participants >50 years, those in the self-paced condition exercised 6 more min/day than participants in the prescribed moderate-intensity condition ( p = .02), whereas among participants <50 years, those in the self-paced condition exercised 5.4 fewer min/day compared with those in the moderate-intensity condition ( p = .05). Affective response to physical activity did not mediate the moderating effect of age. DISCUSSION: As age increases, adults may be more likely to adhere to self paced versus prescribed moderate-intensity exercise. PMID- 30466335 TI - Gait-training devices in the treatment of lower extremity injuries in sports medicine: current status and future prospects. AB - INTRODUCTION: This review seeks to provide synthesized information on gait training techniques and devices applied, in four of the most prevalent chronic lower extremity injuries seen in sports medicine. Areas Covered: Comprehensive searches were performed in CINAHL and PubMed databases in April 2018 to identify gait-training articles in Chronic Ankle Instability (CAI), Exercise-Related Lower Leg Pain (ERLLP), Patellofemoral Pain (PFP), and Anterior Cruciate Ligament with Reconstruction (ACLR) populations. An investigator reviewed the articles and extracted data including study demographics, gait-training techniques, devices used, and primary gait-training outcomes. Fifty-eight articles were included in this review (9 CAI, 19 ERLLP, 17 PFP, 13 ACLR). Pooled analyses were performed for common outcomes within each injury category. Current evidence supports destabilization training and pressure medialization tactics for CAI (n=9), footstrike/loading and cadence interventions for ERLLP (n=11) and PFP (n=7), and limb off-loading techniques for ACLR (n=4). Commonly-used devices included accelerometers (n=6), custom gait-training footwear (n=9), metronomes (n=14), and pressure sensors (n=5). Expert Commentary: Although there are commonalities among gait-training interventions for chronic pathologies, more uniform approaches and clinical predictor rules would help identify the most appropriate interventions. Wearable sensors will continue to revolutionize gait-training and allow for ecologically valid gait-training interventions. PMID- 30466336 TI - Homicide Illustrated Across the Ages: Graphic Depictions of Victim and Offender Age, Sex, and Relationship. AB - OBJECTIVE: A total of 34 years of FBI Supplementary Homicide Reports were examined using statistical graphics to illustrate patterns across ages, by sex, and victim/offender relationships (intimate partner [IP], other family, acquaintance, or stranger). METHOD: An innovative fourfold display and victim/sex specific scatterplots with overlaid deviation ellipses determine the age/sex patterns for each relationship. RESULTS: We illustrate numerous acquaintance killings among young men and improve our understanding of predictors by sex, relationship, and circumstances in mid/later life. Male victims of strangers are either older with young male offenders or vice versa. Female acquaintance and stranger homicides are rare. Within families, older male parents are killed by adult offspring, but rarely by IP. The majority of elder femicide is perpetrated by IP or other family. DISCUSSION: U.S. murder rates are rising, and we found children from 6 to 12 years were least likely to die by homicide. Elder femicide risk from IP and other kin indicated danger from within the home. PMID- 30466337 TI - The Relationship Between Sleep Characteristics and Unmet Physical Activity Need in Older Women. AB - OBJECTIVE: We examined among older women the association of sleep quality, daytime tiredness, and sleep duration with unmet physical activity need, that is, wishing to be more physically active but perceiving no opportunity for it. METHOD: Cross-sectional logistic regression analyses among women aged 74 to 86 years (Finnish Twin Study on Aging, third wave, n = 302). RESULTS: Thirty-one participants reported unmet physical activity need. Short sleepers had fivefold and long sleepers threefold odds for unmet physical activity need compared with normative sleepers, while for daytime tiredness the odds were double. Presence of daytime tiredness and unmet physical activity coincided with higher prevalence of chronic diseases, depressive symptoms and walking difficulties, which partly explains the observed associations. Poor sleep quality was not associated with unmet physical activity need. DISCUSSION: Older women with nonoptimal sleep characteristics who perceive unmet physical activity need may benefit from solutions that improve their perceived opportunities for physical activity. PMID- 30466338 TI - Behind the Wheel: Process Evaluation of a Safe-Transport Program for Older Drivers Delivered in a Randomized Controlled Trial. AB - This process evaluation explores relationships between program outcomes and intervention implementation in a trial evaluating "Behind the Wheel," an education-based safe-transport program for older drivers. Participants (intervention group) were 190 Sydney drivers aged ?75 years ( M = 80 +/- 4years). Process measures included fidelity, dose delivered, and received. Outcomes were self-reported driving regulation and objectively measured driving exposure. Relationships were explored using regression models. Older drivers who took ownership of driving retirement and self-regulation by developing plans were more likely to reduce their weekly driving, (beta = 38 km, 95% confidence interval (CI) = [7.5,68.7]), and night driving (beta = 7 km, 95% CI = [3.5, 10.4]). Drivers of older age (odds ratio [ OR] = 1.1/year older, 95% CI = [1.05, 1.3]) had greater odds of developing driving retirement plans. Female drivers ( OR = 2.7,95% CI = [1.1, 6.9]), drivers with poorer function ( OR = 1.2/5-point decrease on DriveSafe, 95% CI = [1.04, 1.4]), and worse health ( OR = 1.2/additional medication, 95% CI = [1.02, 1.5]) had greater odds of developing safe mobility plans. This program had greatest impact with older, lower functioning drivers. A stronger message was delivered and received, as intended, to older drivers with lower function and poorer health. Our logic model can help channel resources to drivers who benefit most. PMID- 30466339 TI - Measurable residual disease in acute myeloid leukemia using flowcytometry: approaches for harmonization/standardization. AB - INTRODUCTION: Measurable Residual Disease (MRD) in acute myeloid leukemia (AML) is a rapidly evolving area with many institutes embarking on it, both in academical and pharmaceutical settings. However, there is a multitude of approaches to design, perform and report flow cytometric MRD. Together with the long-term experience needed, this makes flow cytometric MRD in AML non standardized and time-consuming. Areas covered: This paper briefly summarizes critical issues, like sample preparation and transport, markers and fluorochromes of choice, but in particular focuses on the main issues, which includes specificity and sensitivity, hereby providing a new model that may circumvent the main disadvantages of the present approaches. New approaches that may add to the value of flow cytometric MRD includes assessment of leukemia stem cells, MRD in peripheral blood and approaches to use multi-dimensional image analysis. Expert Commentary: MRD in AML requires standardization/harmonization on many aspects, for which the present paper offers possible guidelines. PMID- 30466340 TI - Electrophysiological verification of enhanced S-cone syndrome caused by a novel c.755T>C NR2E3 missense variant. AB - BACKGROUND: Nuclear hormone receptor gene, NR2E3, plays a critical role in retinogenesis and determination of the rod photoreceptor phenotype. Mutations in NR2E3 typically lead to recessive enhanced S-cone syndrome (ESCS), where affected individuals show higher sensitivity to short wavelength light and early onset rod dysfunction. Patients with ESCS present in early childhood with nyctalopia, enhanced sensitivity to blue light and display a very heterogeneic retinal phenotype with varying degrees of clumped pigmentation and occasional retinoschisis. PURPOSE: To confirm the pathogenicity of a novel mutation in NR2E3 using electrophysiological studies. MATERIALS AND METHODS: Patient underwent detailed clinical evaluation and ophthalmic imaging followed by next generation sequencing analysis and electrophysiological studies. RESULTS: We describe a case of a young man of Greek descent with a family history of retinal degeneration. His fundal features at presentation were atypical of ESCS, with striking macular involvement in both eyes, including fibrotic subretinal material overlying the pigment epithelial detachment in one eye and schisis in the other. Genetic testing revealed a novel homozygous variant in NR2E3 gene of uncertain pathogenicity. Instead of performing further genetic analyses, electrophysiological studies showed pathognomonic changes in the S-cone response. CONCLUSIONS: With the recent clinical endorsement of a gene therapy for RPE65 related-inherited retinal degeneration it is of paramount importance to correctly identify the pathogenic genetic mutation. In this particular syndrome, we highlight the value of electrophysiology to confirm the pathogenicity of a novel mutation in NR2E3 and aid the diagnosis of ESCS, with potential for gene therapy in the future. PMID- 30466341 TI - XAV939, a Wnt/beta-catenin pathway modulator, has inhibitory effects on LPS induced inflammatory response. AB - AIM: In this study, we report the anti-inflammatory activity of XAV939, a modulator of the Wnt/beta-catenin pathway. METHODS: WNT/beta-catenin pathway and NF-kappaB signaling pathway were examined in LPS-stimulated human bronchial epithelial cells and effects of XAV939 on these pathways were analyzed. The effect of XAV939 was confirmed in human umbilical vein endothelial cells. RESULTS: LPS-induced expressions of pro-inflammatory genes IL-6, IL-8, TNF-alpha, IL-1beta, MCP-1, MMP-9, iNOS and COX-2 were significantly and dose-dependently suppressed by XAV939. LPS-induced NF-kappaB signaling, such as IkappaB phosphorylation and degradation as well as nuclear translocation of NF-kappaB, was also suppressed by XAV939. Target DNA binding of NF-kappaB was significantly and dose-dependently suppressed by XAV939 during LPS-induced inflammatory response. The suppressive effects of XAV939 on NF-kappaB signaling, target DNA binding of NF-kappaB and pro-inflammatory gene expression were all rescued by over expression of beta-catenin, which shows that the anti-inflammatory effect of XAV939 is mediated by the modulation of beta-catenin, a central component of the WNT/beta-catenin pathway. CONCLUSION: The findings of this study showed that XAV939 exerts anti-inflammatory effects through the modulation of the Wnt/beta catenin pathway. PMID- 30466342 TI - Cohort by Education Interactions in Longitudinal Changes in Functional Abilities. AB - OBJECTIVE: Investigations of cohort differences in relationships between education and health tend to focus on mortality or self-reported health. We report one of the first analyses of cohort differences in relationships between education and objective measures of functional abilities across the lifespan. METHOD: Up to 26 years of follow-up data were available from 859 adults from the Swedish Adoption/Twin Study of Aging. The sample was divided into two cohorts by birth year: 1900-1924 and 1925-1948. Latent growth curve models (LGCM) were compared across cohort and educational levels. RESULTS: LGCM indicated divergence between adults with lower and higher educational attainment in longitudinal trajectories of change with age in the Balance and Flexibility factors for the later born cohort only. DISCUSSION: Results support the cumulative advantage theory and suggest that education-health disparities are increasing in recent cohorts, even in counties with national health care systems and strong support of education. PMID- 30466343 TI - Gendered "Long Arm" of Parental Education? Life Course Influences on Later Life Functional Limitations in India. AB - OBJECTIVE: We adopt a novel approach to mediation analysis to account for interrelated life course social processes that constitute later life health disparities. We examine gender-specific direct effect of parental education on functional limitations in later life. METHOD: Based on the first wave (2007-2010; n = 7,150) of the Study on Global Ageing and Adult Health (SAGE), we estimate both (natural) direct and indirect effects of parental education on functional limitations in later life. RESULTS: We observed a significant indirect and positive effect of parental education on functional health. Contrary to prior literature, we documented adverse direct effect of parental education on later life functional health. The direct effect is statistically significant only for father's education, and is greater, though not statistically significantly so, for women than men. DISCUSSION: The intersection of gender status and interrelated social stratification documented by this study highlights the need for gender-sensitive life course research. Such research can enhance our understanding of the ways patriarchal social systems produce heterogeneous effects of interrelated structural factors on later life health for men and women. PMID- 30466344 TI - Metformin Promotes Regeneration of the Injured Endometrium Via Inhibition of Endoplasmic Reticulum Stress-Induced Apoptosis. AB - Intrauterine adhesion (IUA) is now recognized as one of the most common diseases in reproductive-age women. Metformin, a well-known frontline oral antidiabetic drug, has been found effective in numerous different diseases. The aim of this study was to determine the effect of metformin on reducing adhesions in an animal model of IUA. Sprague-Dawley rats were randomized into 4 groups: sham operation, control, metformin-treated for 7 days, and metformin-treated for 14 days. To establish the IUA model, mechanical injury to the endometria of rats was induced with a mini curette. Metformin was injected intraperitoneally after surgery. A significant amelioration in both the number of glands and the fibrotic area, compared to those of the control group, was detected 14 days after metformin intervention. The expression levels of antigen KI-67 and vascular endothelial growth factor were increased at 7 and 14 days after treatment. However, the transforming growth factor-beta expression was decreased at 14 days after treatment. Endoplasmic reticulum stress-related apoptosis proteins (glucose regulated protein 78, caspase-12, and CCAAT/enhancer binding protein (EBP) homologous protein) were downregulated after metformin treatment. Moreover, we determined that the effect of metformin was related to the inhibition of endoplasmic reticulum stress-induced apoptosis via the Phosphatidylinositol 3 kinase (PI3K)/Protein kinase B (AKT) and Extracellular regulated protein kinases1/2 pathways. In conclusion, metformin can attenuate the adhesion and promote the regeneration of the endometrium of the IUA rat, and metformin may serve as a novel therapeutic strategy for IUA patients. PMID- 30466345 TI - Multisectoral (in)action: towards effective mainstreaming of HIV in public sector departments in South Africa. AB - Whilst progress has been made, evidence of effective approaches to improve action on addressing the social and structural drivers of the HIV epidemic remains a priority, to meet the 2030 sustainable development agenda, and to achieve key HIV targets, including the 90-90-90 target and the Treatment as Prevention (TasP) intervention. With a focus on the public sector in South Africa, we critically reflect on the HIV mainstreaming approach, assessing its ability to augment multisectoral action on the response to HIV. We reflect on progress made in mainstreaming HIV in non-health sector departments, exploring factors that have enabled and hindered the process. We also highlight limitations in the adopted approach to mainstreaming HIV in non-health sector departments in South Africa; which currently promotes working in silos and does not encourage collaboration and partnerships. We propose a three-step approach to effective mainstreaming of HIV that will augment multisectoral action. The approach also contributes towards realising the sustainable development agenda of "leaving no one behind" and achieving the national and global targets on HIV that are embedded in collaborative efforts. PMID- 30466346 TI - Nanobodies reveal an extra-synaptic population of SNAP-25 and Syntaxin 1A in hippocampal neurons. AB - Synaptic vesicle fusion (exocytosis) is a precisely regulated process that entails the formation of SNARE complexes between the vesicle protein synaptobrevin 2 (VAMP2) and the plasma membrane proteins Syntaxin 1 and SNAP-25. The sub-cellular localization of the latter two molecules remains unclear, although they have been the subject of many recent investigations. To address this, we generated two novel camelid single domain antibodies (nanobodies) specifically binding to SNAP-25 and Syntaxin 1A. These probes penetrated more easily into samples and detected their targets more efficiently than conventional antibodies in crowded regions. When investigated by super-resolution imaging, the nanobodies revealed substantial extra-synaptic populations for both SNAP-25 and Syntaxin 1A, which were poorly detected by antibodies. Moreover, extra-synaptic Syntaxin 1A molecules were recruited to synapses during stimulation, suggesting that these are physiologically-active molecules. We conclude that nanobodies are able to reveal qualitatively and quantitatively different organization patterns, when compared to conventional antibodies. PMID- 30466347 TI - Influence of N-glycosylation on effector functions and thermal stability of glycoengineered IgG1 monoclonal antibody with homogeneous glycoforms. AB - Glycosylation of the conserved asparagine residue in each heavy chain of IgG in the CH2 domain is known as N-glycosylation. It is one of the most common post translational modifications and important critical quality attributes of monoclonal antibody (mAb) therapeutics. Various studies have demonstrated the effects of the Fc N-glycosylation on safety, Fc effector functions, and pharmacokinetics, both dependent and independent of neonatal Fc receptor (FcRn) pathway. However, separation of various glycoforms to investigate the biological and functional relevance of glycosylation is a major challenge, and existing studies often discuss the overall impact of N-glycans, without considering the individual contributions of each glycoform when evaluating mAbs with highly heterogeneous distributions. In this study, chemoenzymatic glycoengineering incorporating an endo-beta-N-acetylglucosaminidase (ENGase) EndoS2 and its mutant with transglycosylation activity was used to generate mAb glycoforms with highly homogeneous and well-defined N-glycans to better understand and precisely evaluate the effect of each N-glycan structure on Fc effector functions and protein stability. We demonstrated that the core fucosylation, non-reducing terminal galactosylation, sialylation, and mannosylation of IgG1 mAb N-glycans impact not only on FcgammaRIIIa binding, antibody-dependent cell-mediated cytotoxicity, and C1q binding, but also FcRn binding, thermal stability and propensity for protein aggregation. PMID- 30466348 TI - Prevention of Chlamydia Infections With Theater in School Sex Education. AB - The aim of the study was to evaluate if an intervention including theater in school sex education affects students' knowledge, attitudes, and behavior regarding condom use in Sweden. The study was a cluster randomized controlled trial. The intervention group got a play, value exercises, chlamydia games, condom school, and interactive replay with professional actors and staff from a youth guidance center. The control group got standard sex education from school staff. Students in both groups answered web surveys on knowledge, attitudes, and behavior regarding condom use. Posteducation, knowledge on condom use, chlamydia, and protection had increased in both groups. However, students in the intervention group showed higher levels of knowledge, improved attitudes, and less risky behavior in regard to condom use compared to the control group. The intervention titled SAFETY seemed to be a beneficial supplement to standard sex education and more effective with regard to knowledge of condom use. PMID- 30466349 TI - Mussel-inspired in situ forming adhesive hydrogels with anti-microbial and hemostatic capacities for wound healing. AB - All kinds of commercially available wound dressings are clinically used as fleshly obstacles and therapeutic materials in opposition to microbial incursion. Few researches focused on effective-bleeding and anti-bacteria at the same time. In order to better solve this problem, two hydrogels were synthetized in this study. One is phosphate buffer solution-activated dopamine-modified-gamma-poly glutamic acid (PBS-PD) hydrogel, the other one is cirsium setosum extracts activated dopamine-modified-gamma-poly glutamic acid (CSE-PD) hydrogel. The two hydrogels are prepared by applying an enzyme-catalyzed crosslinking means in the presence of horseradish peroxidase (HRP) and hydrogen peroxide (H2O2). The chemical structures were characterized through 1H-NMR and FT-IR. In conclusion, both PBS-PD and CSE-PD hydrogels exhibit superior tissue adhesion properties, and remarkable anti-infection quality. In addition, these two hydrogels manifest prominent hemostatic efficiency. The bio adhesion performance can achieve 30 kPa, meanwhile the CSE-PD hydrogels show good germicidal properties, and the antibacterial rate can reach 98%. The hydrogels could reduce blood loss without any obvious side effect, and present a new prospect in the field of hemostasis rapidly. PMID- 30466350 TI - Employees' experiences of the stigma of HIV in a retail organisation: secrecy, privacy or trust? AB - This study unveiled the participants' experiences of HIV-related stigma in a retail organisation located in the Western Cape province of South Africa. A qualitative approach was adopted because of its appropriateness for unravelling subjective phenomena such as employees' experiences of HIV-related stigma. In depth interviews were conducted with 10 HIV-positive employees who volunteered to participate. The findings reveal that the participants concealed their HIV positive status because they feared that the co-workers and managers might stigmatise them and breach confidentiality. The results also revealed that despite being HIV-positive, the participants seemed not to experience a lower work-related self-concept as they said that they are as competent as other employees. The study draws on these empirical findings to theorise about whether concealment of an HIV-positive status is symptomatic of secrecy, the desire for privacy or low levels of trust. PMID- 30466351 TI - A Longitudinal Study of Allostatic Load in Later Life: The Role of Sex, Birth Cohorts, and Risk Accumulation. AB - Are challenging life courses associated with more wear and tear on the biological level? This study investigates this question from a life-course perspective by examining the influence of life-course risk accumulation on allostatic load (AL), considering the role of sex and birth cohorts. Using biomarker data collected over three waves (2004, 2008, and 2012) of the English Longitudinal Study of Ageing ( N = 3,824) in a growth curve framework, AL trajectories over a period of 8 years are investigated. Our results illustrate that AL increases substantially in later life. Men have higher AL than women, but increases are similar for both sexes. Older cohorts have both higher levels and a steeper increase of AL over time. Higher risk accumulation over the life course goes hand in hand with higher AL levels and steeper trajectories, contributing to the body of evidence on cumulative (dis)advantage processes in later life. PMID- 30466352 TI - Use of the Worklife and Levels of Burnout Surveys to Assess the School Nurse Work Environment. AB - Previous research regarding burnout in acute care settings revealed that positive work environments increase job satisfaction, decrease staff turnover, and improve patient outcomes. However, few studies address burnout among school nurses. The purpose of this study was to describe the relationship between the school nurse practice environment, school nurses' levels of burnout, and perceived sources of work stress. A cross-sectional sample of 100 registered nurses completed a web based version of the Maslach Burnout Inventory and Areas of Worklife Survey. Identified stressors were entered into regression models to determine associations with levels of burnout. Burnout is significantly associated with all Areas of Worklife subscales. School nurses who reported satisfactory work environments experienced little to no burnout. This study provides insights into the domains of work that can cause burnout among school nurses and provides evidence that can inform school leadership and policy makers on ways to promote healthy work environments. PMID- 30466353 TI - Evaluation of Choroidal Thickness, Choroidal Vascularity Index and Peripapillary Retinal Nerve Fiber Layer in Patients with Juvenile Systemic Lupus Erythematosus. AB - OBJECTIVE: The aim of this study was to conduct a detailed ophthalmological examination in children with systemic lupus erythematosus (jSLE), including choroidal thickness (ChT), choroidal vascularity index (CVI) and peripapillary retinal nerve fiber layer (RNFL). METHODS: The study included all jSLE patients ( n = 21) diagnosed according to the Systemic Lupus International Collaborating Clinics classification criteria between January 2017 and April 2017, and an age- and gender-matched control group ( n = 21). The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) was used to assess disease activity. After routine eye examinations, ChT at five points (750 u and 1500 u from the center of the fovea both in the temporal and nasal quadrants and under the fovea), total subfoveal choroidal area (TCA), luminal area (LA), stromal area (SA), CVI and RNFL thickness at the optic disc were evaluated. RESULTS: One patient had active ocular involvement in the form of episcleritis. Another patient had corticosteroid-induced cataract. The median age of the patients was 16 years (6 19 years). ChT at five points, TCA, LA and SA were found to be higher in patients with jSLE, whereas RNFL thickness and CVI were similar to those of the healthy control individuals. No correlation was determined between optical coherence tomography findings, SLEDAI and the immunological parameters (antinuclear antibodies, anti-double-stranded DNA, complements 3 and 4, extracted nuclear antigen antibody, antiphospholipid antibody). Intraretinal and subretinal fluid was not present in any of the patients. CONCLUSION: The choroid was thicker in patients with jSLE than in the control group. The study results suggest that jSLE may affect the choroid. Ophthalmological evaluation is important in SLE patients, even in the absence of relevant complaints. PMID- 30466354 TI - Patient-reported outcomes of endovenous superficial venous ablation for lower extremity swelling. AB - OBJECTIVE: To evaluate the effect of endovenous ablation in patients presenting with leg swelling. METHODS: We identified Clinical, Etiology, Anatomy, Pathophysiology (CEAP) clinical class 3 (C3) patients undergoing endovenous ablation from 21 January 2005 to 19 March 2015 with an 810-nm or 1470-nm laser. Patients were surveyed regarding the degree of edema, use of compression stockings, and satisfaction with the procedure. RESULTS: A total of 1634 limbs were treated by endovenous ablation for incompetent saphenous veins with or without adjunctive segmental varicose vein microphlebectomy. Of these, 528 limbs were treated for CEAP C3. The average time period from the procedure date until the survey date was 1494 days (range, 562-2795 days). Ninety-two respondents accounted for 130 ablations in 128 limbs with an average venous segmental disease score of 2.7. Ninety-seven limbs (75.8%) had reduced or resolved swelling, 29 limbs (22.6%) were unchanged, and 2 limbs (1.6%) had increased swelling. The vast majority (81%) were satisfied with their decision to have the procedure. CONCLUSIONS: Endovenous ablation for edema secondary to superficial venous insufficiency is effective and has high patient satisfaction. Further investigation is needed regarding risk factors for immediate failure and delayed recurrence of edema. PMID- 30466355 TI - Socio-demographic, marital and psychosocial predictors of safe sex behaviour among Mozambican women at risk for HIV/AIDS. AB - Heterosexual encounters remain the primary route for HIV transmission in Africa. Safer sex behaviour is not adopted by many women due to several social and psychological factors. This paper aims to identify socio-demographic, marital and psychosocial predictors associated with current sexual activity and condom use in Mozambican women at sexual risk for HIV/AIDS. Women (173), patients at a public hospital and at risk for HIV infection, completed measures of condom use negotiation self-efficacy, perceived barriers against safer sex, current sexual activity and condom use. Having more than 6 years of education and being younger and single were significant predictors for current sexual activity and condom use. Regarding psychosocial factors, talking about AIDS with partners, condom use negotiation self-efficacy and fewer perceived barriers to safer sex were significant predictors for current sexual activity (intention to use and buy/get condoms). Condom use negotiation self-efficacy is a significant predictor for condom use. These results should be considered in new HIV prevention intervention design in Mozambique. PMID- 30466356 TI - Competence and Satisfaction in Occupational Performance Among a Sample of University Students: An Exploratory Study. AB - Success at university may be influenced by concerns with occupation and occupational performance. To understand occupations of concern and occupational performance among a sample ( N = 144) of university students in the Midwest United States, the Canadian Occupational Performance Measure was administered. Socially related ( n = 103), academic-related ( n = 75), and work-related ( n = 64) occupations were the three most frequently reported occupational concerns. Time management ( n = 79) was the most frequent person-level concern. Mean self perceived competence in occupations was 29.83 ( SD = 7.18) out of 50 and mean performance satisfaction was 26.80 ( SD = 8.01) out of 50. There were no differences in occupational performance across gender, race/ethnicity, class standing, living environment, or work status. However, within participants, there was a significant and clinically relevant difference between performance satisfaction and self-perceived competence in occupation, t(143) = 7.052, p < .0005, d = 0.58. Students have varied occupations that they find important, and future research should explore how occupational performance and performance satisfaction influence university success. PMID- 30466357 TI - Hispanic Families' Action Plans for a Healthier Lifestyle for Diabetes Management. AB - PURPOSE: The purpose of this study was to conduct focus groups with Hispanic patients with type 2 diabetes and their family members who participated in a culturally tailored, family-based diabetes intervention about their action plans for a healthier lifestyle. METHODS: Five separate focus groups were led in Spanish by an experienced bicultural/bilingual moderator. The audiotaped sessions occurred at the end of the 8-week diabetes educational program. Data were transcribed in Spanish and translated into English. Qualitative content analysis was used to analyze the findings. RESULTS: Eighty-four Hispanic adults participated with an equal representation of patients with diabetes and family members. Most persons were female (63.1%) and the majority of persons were born in Mexico. The mean (SD) age of participants was 44.2 (14.3) years. Six themes emerged from the data: healthier eating habits, increasing physical activity, taking care of my sugar, coping with emotions, for the family, and empowerment and increased self-efficacy. CONCLUSIONS: Hispanics created action plans that promoted healthier lifestyle behaviors individually and as a family. This type of behavior change may result in better diabetes management and fewer complications. Research studies are needed to assess the sustainability of action plans and their impact on glycemic control and diabetes risk factors. Additional studies are needed to address emotional eating and mental health factors. PMID- 30466358 TI - Molecular dynamics analysis of the effects of GTP, GDP, and benzimidazole derivative on structural dynamics of a cell division protein FtsZ from Mycobacterium tuberculosis. AB - The prevailing multi-drug resistance in Mycobacterium tuberculosis continues to remain one of the main challenges to combat tuberculosis. Hence, it becomes imperative to focus on novel drug targets. Filamenting temperature-sensitive mutant Z (FtsZ) is an essential cell division protein, a eukaryotic tubulin homologue and a promising drug target. During cytokinesis, FtsZ polymerises in the presence of GTP to form Z-ring and recruits other proteins at this site that eventually lead to the formation of daughter cells. Benzimidazoles were experimentally shown to inhibit Mtb-FtsZ, with one of the benzimidazole derivatives, M1, being reported to have the minimum inhibitory concentration (MIC) value of 3.13ug/ml. In the present study, mechanism of destabilization of FtsZ in the presence of M1 was computationally investigated in the presence of its substrate GTP/GDP employing Molecular dynamics (MD) simulation analysis, principal component analysis (PCA), molecular mechanics combined with the generalized Born and surface area continuum salvation (MM-GBSA), and density functional theory (DFT). From the analyses it is proposed that binding of M1 in the inter-domain cleft induces structural changes in the GTP binding region that affect GTP binding, thus switching the preference of this protein towards depolymerised state and eventually inhibiting the cell division. Hence, this study provides mechanistic insights into the design of novel benzimidazole inhibitors against Mtb-FtsZ. PMID- 30466359 TI - Socio-economic status and the developing brain in adolescence: A systematic review. AB - Socioeconomic status is associated with differences in social, cognitive, and behavioral outcomes for adolescents. Correspondingly, the period reflects continued dynamic, complex, and adaptive brain development. Research demonstrates associations between the developing adolescent brain and SES; however, such research has not been systematically integrated. We undertook a systematic search of studies and review 21 papers that examined both SES and brain development or functioning as measured during adolescence or young adulthood in nonclinical populations (13-25 years old). Few studies focused on architecture and such findings were varied. The majority of studies focused on functioning with two themes emerging. First, studies demonstrate different activation in regions of interest to cognitive and behavioral tasks relative to SES. Second, when similar neurological activation is evident, they can be related to different behavioral observations relative to SES. There is also evidence of different neurological functioning associated with SES with regard to different conceptualizations and coding of SES. Further, some of the reviewed studies identified potential mediators to the relationship, such as parenting practices, stress, and IQ. Overall, the findings suggest it is important to consider SES and neighborhood context within neuroscience research and practice. PMID- 30466360 TI - Occupational manganese exposure, reproductive hormones, and semen quality in male workers: A cross-sectional study. AB - It has been found that exposure to manganese (Mn) could induce reproductive dysfunction, but its occupational risk in male workers is unclear. This study aims to assess the association of occupational Mn exposure with reproductive hormones and semen quality in a cross-sectional study. Urinary Mn, semen quality, and reproductive hormones were explored in 84 male workers occupationally exposed to Mn and 92 referents. Multiple linear regression analyses were used to assess the relationship. Urinary Mn levels in Mn-exposed workers ranged from 0.56 to 34.25 ug/L, and the average level was 15.92 +/- 8.49 ug/L. Compared with the control group, gonadotropin-releasing hormone (GnRH) levels and luteinizing hormone (LH) levels increased significantly and the levels of testosterone (TSTO) decreased significantly in the Mn-exposed group. There was a significant positive linear association between urinary Mn and GnRH and LH, while the linear association between urinary Mn and TSTO was negative. Sperm progressive motility and total motility decreased significantly in the Mn-exposed group. There was a significantly negative linear association between urinary Mn and sperm progressive motility and total motility. In conclusion, occupational Mn exposure was inversely associated with reproductive health of male workers, resulting in the abnormality of hormones secretion and decrease of sperm motility. PMID- 30466361 TI - Memory Decline and Depression Onset in U.S. and European Older Adults. AB - OBJECTIVES: We explore the association between different patterns of change in depressive symptoms and memory trajectories in US and European Mediterranean (Spain, France, Italy, and Israel) and non-Mediterranean (Sweden, Denmark, Netherlands, Germany, Belgium, Switzerland, and Austria) older adults. METHODS: Samples consisted of 3,466 participants from the Health Retirement Study (HRS) and 3,940 participants from the Survey of Health, Aging and Retirement (SHARE). Individuals were grouped as follows: non-case depression (NO DEP), persistent depression (DEP), depression onset (ONSET), depression recovery (RECOV), and fluctuating (FLUCT). Memory was measured using immediate and delayed recall tests. Linear mixed models were used. RESULTS: DEP and RECOV had significantly lower baseline memory scores compared to NO DEP, at intercept level. At slope level, ONSET had a significantly faster decline in both tasks compared to NO DEP. DISCUSSION: Cross-cohort robust and consistent new empirical evidence on the association between depression onset and faster decline in memory scores is provided. PMID- 30466362 TI - Self-Control, Opportunity, and College Students' Bystander Intervention in Sexually Coercive Situations. AB - This study examines students' bystander intervention opportunities and behaviors using survey data from a convenience sample of 226 college students from a university in the United States. We approach this study with theoretical concepts from the criminological literature on positive peer influence, self-control theories, and social control theories. Bivariate correlations and logistic analysis reveal, contrary to our predictions, that social and self-control have only minor predictive power on the likelihood of witnessing and intervening in sexually coercive events. However, we find strong support for some demographic characteristics, peer relationships, and behavioral characteristics (such as binge drinking) as predictive of witnessing a sexually coercive event and intervening in an event. Our study adds to the literature on bystander intervention behavior and aims to inform bystander intervention programming efforts by identifying student populations that are more likely to have the opportunity to intervene in sexually coercive situations and sexual assaults. PMID- 30466363 TI - Does the peptide backbone unit interact with gold nanoclusters? Insights from computational modeling. PMID- 30466364 TI - The relationship between social support and anxiety amongst children living with HIV in rural northern Namibia. AB - This study examined how HIV-related stigma and social support are related to anxiety among children living with HIV in rural northern Namibia. This is a cross sectional exploratory study with a sample of 132 caregiver-child dyads. Our study found that higher levels of social support was correlated with lower levels of anxiety among children living with HIV, but higher levels of HIV-related stigma was not correlated with higher levels of anxiety. These findings point to the need for the development of more culturally and age specific interventions that enhance social support among children living with HIV, especially those in high prevalence and socio-economically deprived settings. PMID- 30466365 TI - Social engagement and survival in people aged 50 years and over living with HIV and without HIV in Uganda: a prospective cohort study. AB - This study examined the association between social engagement and survival in people with or without HIV aged 50 years and over in Uganda. We analysed two waves of a survey from two sites in Uganda to assess predictors of mortality between waves. The first wave was conducted between 2009 and 2010 while the second wave was conducted between 2012 and 2013. A standardised questionnaire adapted from the World Health Organization study on global AGEing and adult health (SAGE) was administered through face-to-face interviews at both survey waves. Cox proportional hazards models and Nelson-Aalen cumulative hazards functions were used to investigate associations between the strength of participants' social ties, using distance and intimacy metrics, and their social engagement with mortality between waves. Of the original 510 participants, 63 (12.3%) died between waves. Being more socially engaged and able to provide in kind or financial contributions to family or friends were protective. After adjusting for covariates neither social tie measure was predictive of mortality. There were no significant differences in social engagement and survival by HIV status. Further research is needed in African settings on the relationship between social relationships and subsequent mortality in older adults to assess if improved social relationships could moderate mortality. PMID- 30466366 TI - Identification of a gene cluster for biosynthesis of the sesquiterpene antibiotic, heptelidic acid, in Aspergillus oryzae. AB - Heptelidic acid (HA), a sesquiterpene lactone, is a known inhibitor of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Recently, we found that HA was produced by Aspergillus oryzae RIB40 and acted as the growth inhibitor of the salt-tolerant lactic acid bacteria in soy sauce brewing. Although several decades have passed since the discovery of HA, the genes involved in its biosynthesis and biosynthetic pathway have not yet been fully identified. In this study, we identified the HA biosynthetic gene cluster (HA cluster) using gene disruption and expression analysis. We also revealed that two transcription regulatory genes adjacent to the HA cluster were responsible for the expression of HA biosynthetic genes in A. oryzae. Interestingly, the HA cluster contained a gene encoding GAPDH (gpdB), which showed much higher resistance to HA than the GAPDH gene (gpdA) located at the other locus, but which did not seem to act as a self-resistant gene. PMID- 30466367 TI - Heavy metals in spices commonly consumed in Republic of Korea. AB - Levels of lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg) were evaluated in 359 samples of commonly consumed spices (cinnamon, parsley, basil, oregano, coriander seed, nutmeg, cumin, bay leaf, fenugreek, rosemary, thyme, fennel, sage, clove, marjoram, tarragon, caraway, dill seed, pepper, and turmeric) from the market in the Republic of Korea. The content of Pb, Cd, and As was assessed by acid wet digestion using a microwave oven and inductively coupled plasma mass spectrometry (ICP-MS). The content of Hg was analysed using a direct mercury analyzer (DMA). Pb, Cd, As, and Hg mean content in spices ranged from 0.039-0.972 mg kg-1, 0.013-0.315 mg kg-1, 0.121-0.861 mg kg-1, and 0.001-0.025 mg kg-1, respectively. PMID- 30466368 TI - Overexpression of Collapsin Response Mediator Protein 1 Inhibits Human Trophoblast Cells Proliferation, Migration, and Invasion. AB - Collapsin response mediator protein 1 (CRMP-1) is widely expressed in the nervous system and has tumor suppressive effects. Our previous studies have demonstrated that CRMP-1 was expressed in the trophoblasts of the whole stage of pregnancy with significantly increasing expression in the placenta of early-onset preeclampsia. Preeclampsia, especially early onset, is strongly associated with the dysfunction of trophoblast including proliferation, apoptosis, migration, and invasion. In this study, we found an inhibitory effect of CRMP-1 on proliferation, migration, invasion, and an enhanced effect on apoptosis in human trophoblast cell lines HTR-8/SVneo and JEG-3 by MTT assay, colony formation assay, cell viability assay, caspase 3/7 activity assay, scratch wound assay, and Matrigel Transwell assay. Overexpression of CRMP-1 in trophoblast cells led to downregulate expression of matrix metalloproteinase 2 and 9. The expression of CRMP-1 was detected by real-time quantitative polymerase chain reaction and Western blot analysis. Thus, we suggested that CRMP-1 might have implications for the pathogenesis of preeclampsia by regulating the biological behavior of trophoblast cells. PMID- 30466369 TI - Infrarenal Aortic Endograft Infection: A Single-Center Experience. AB - PURPOSE:: Endograft infection is an infrequent but one of the most serious and challenging complications after endovascular aortic repair. The aim of this study was to assess the management of this complication in a tertiary center. CASE SERIES:: A retrospective analysis of a prospective database was performed including all patients who underwent elective endovascular abdominal aortic repair (EVAR) from 2003 to 2016 in a tertiary center. Seven cases of endograft infection were identified during the follow-up period from a total of 473 (1.48%) EVAR. Most frequent symptoms at presentation were fever (71.4%) and lumbar pain (57.1%). One case developed an early infection, while 6 cases were diagnosed as late infections. Mean time from endograft placement to symptom presentation was 28.3 months (2-91.5 months). Gram-positive cocci were the microorganisms most commonly isolated in blood cultures (66%). Two cases were managed with endograft removal and aortic reconstruction with a cryopreserved allograft, 2 cases with surgical drainage, and 2 cases exclusively with antibiotic therapy. In 1 case, the diagnosis was performed postoperatively based on intraoperative findings associated with positive graft cultures; and graft explantation was performed with "in situ" reconstruction using a Dacron graft. Perioperative mortality was 42.9%. One-year mortality was 57.1%. Mean follow-up was 21.5 months. CONCLUSION:: Endograft explantation is the gold standard of treatment; however, given the overall high morbi-mortality rates of this pathology, a tailored approach should always be offered depending on the patient's overall condition. Conservative management can be an acceptable option in those patients with short life expectancy and high surgical risk. PMID- 30466370 TI - Cooking Data: Culture and Politics in an African Research World. PMID- 30466371 TI - Balloon Angioplasty Versus Bailout Stenting for Isolated Chronic Total Occlusions in the Popliteal Artery. AB - AIMS:: Stenting of the popliteal artery (PA) is generally considered inappropriate due to the high mechanical stress and bending of the artery during knee flexion. Nevertheless, vessel recoil remains problematic following angioplasty procedure for chronic total occlusions (CTOs) and adjunctive stenting may be required. The purpose of this study is to compare balloon angioplasty alone versus bailout stenting for isolated CTO of the PA. MATERIALS AND METHODS:: Between March 2012 and October 2016, 43 patients were treated with percutaneous transluminal angioplasty with balloon alone (PTA, n = 16) or bailout stenting percutaneous transluminal angioplasty and stenting (PTAS, n = 27) for de novo CTO of PA. There was no statistically significant difference between both groups with regard to patient demographics and lesions characteristics (calcification severity and lesion length). The median lesion lengths were 67 mm (39.5-78.5) in the PTA group and 94 mm (50-114) in the PTAS group ( p = 0.14). The primary outcome measure was primary patency; secondary outcomes were technical success, primary assisted patency, major amputation, and increased Rutherford classification. RESULTS:: Technical success rate was 37% and 96.3% in the PTA and PTAS groups, respectively. There was no statistical difference in 12-month primary patency rate (65.8% versus 58.7%; p = 0.15) and primary assisted patency at 12 months (75.2 versus 69.2; p = 0.47) between the 2 groups. Freedom from target lesion revascularization at 12 months was not significantly different, with 85.7% and 81.6% ( p = 0.2) in the PTA and PTAS groups, respectively. One amputation occurred in the PTA group. CONCLUSION:: This small cohort suggests that stenting as a bailout procedure in CTO of the PA provides similar results to successful balloon angioplasty. Stenting should only be performed after suboptimal balloon angioplasty with vessel recoil. Due to the large lost to follow-up, strong evidence of a therapy over the other cannot be formulated. Larger studies with longer and stronger follow-up are needed to confirm those results. PMID- 30466372 TI - An intermittent hypercaloric diet alters gut microbiota, prefrontal cortical gene expression and social behaviours in rats. AB - OBJECTIVES: Excessive consumption of high fat and high sugar (HFHS) diets alters reward processing, behaviour, and changes gut microbiota profiles. Previous studies in gnotobiotic mice also provide evidence that these gut microorganisms may influence social behaviour. To further investigate these interactions, we examined the impact of the intermittent access to a HFHS diet on social behaviour, gene expression and microbiota composition in adolescent rats. METHODS: Male rats were permitted intermittent daily access (2 h / day) to a palatable HFHS chow diet for 28 days across adolescence. Social interaction, social memory and novel object recognition were assessed during this period. Following testing, RT-PCR was conducted on hippocampal and prefrontal cortex (PFC) samples. 16S ribosomal RNA amplicon sequencing was used for identification and relative quantification of bacterial taxa in faecal samples. RESULTS: We observed reduced social interaction behaviours, impaired social memory and novel object recognition in HFHS diet rats compared to chow controls. RT-PCR revealed reduced levels of monoamine oxidase A (Maoa), catechol-O-methyltransferase (Comt) and brain derived neurotrophic factor (Bdnf) mRNA in the PFC of HFHS diet rats. Faecal microbiota analysis demonstrated that the relative abundance of a number of specific bacterial taxa differed significantly between the two diet groups, in particular, Lachnospiraceae and Ruminoccoceae bacteria. DISCUSSION: Intermittent HFHS diet consumption evoked physiological changes to the brain, particularly expression of mRNA associated with reward and neuroplasticity, and gut microbiome. These changes may underpin the observed alterations to social behaviours. PMID- 30466373 TI - A mixed methods study: Midlife African American women's knowledge, beliefs, and barriers to well-woman visit, flu vaccine, and mammogram use. AB - African American women (AAW) are particularly at risk for deleterious health outcomes that might be mitigated through increased preventive care use. A mixed methods study that examined relationships between knowledge of, beliefs about, and barriers to well-woman visits, flu vaccines, and mammograms was conducted with midlife AAW who participated in an online survey (n = 124) and in-depth interviews (n = 19). Findings showed that greater knowledge of preventive service recommendations and positive patient-provider relationships were associated with greater preventive service use. Flu vaccines were significantly underused. Study implications inform strategies to increase preventive care utilization among AAW and increase capacities to improve health disparities. PMID- 30466375 TI - Intraoperative Probe-Based Confocal Endomicroscopy to Histologically Differentiate Thyroid From Parathyroid Tissue Before Resection. AB - BACKGROUND: Frozen section is the standard method to histologically distinguish parathyroid tissue from thyroid tissue during endocrine neck surgery. Frozen section can be time-consuming and costly. Its drawback is that it is to be performed only after the removal of a suspected pathological tissue. This study demonstrates the use of probe-based confocal laser endomicroscopy (pCLE) to confirm histology prior to tissue resection. DESIGN: A prospective, single institution, nonrandomized study was conducted. No sample size calculation was performed for this observational trial. The primary objective was the description of histological rendering of normal and pathological tissues through pCLE. Real time in vivo fluorescence microscopy imaging was performed with the CystoFlex UHD probe after intravenous injection of 2.5 mL of 10% fluorescein sodium. RESULTS: Eleven patients with hyperparathyroidism and thyroid conditions were included. A total of 104 videos showing thyroid, parathyroid, adipose tissue, muscle, laryngeal nerve, and lymph nodes were recorded. Videos were compared with visual information and pathological samples (when sampling was indicated). Thyroid tissue could be identified based on the presence of colloid follicles (intensely fluorescent area surrounded by a small ridge of low-fluorescence epithelial cells) including the pathognomonic aspect of resorption vacuole. Parathyroid tissue could be identified based on a regular, "diamond-shaped" capillary network encompassing parathyroid chief cells. Blinded reinterpretation of pCLE videos demonstrated an 89.3% sensitivity and a 90% specificity as compared with histology in tissue recognition. CONCLUSION: This pilot study describes representative renderings of intraoperative pCLE to nontraumatically differentiate thyroid, parathyroid, and lymph nodes before surgical removal. PMID- 30466376 TI - Aortic Thrombosis in a Patient With Malignant Disease: A Literature Review and Case Presentation. AB - INTRODUCTION:: Aortic mural thrombosis associated with a malignant disease is rare, and whether anticoagulation therapy or surgical treatment is the more definitive primary treatment remains uncertain. This study aims to determine the best treatment strategy for aortic thrombosis in a patient with a malignant disease. METHODS:: We reviewed medical literature using the PubMed database and present a case of aortic thrombosis due to a hypercoagulable state related to sigmoid colon adenocarcinoma. RESULTS:: Of the 18 patients from 14 articles included in this study, 13 received simple anticoagulation as a primary treatment (anticoagulation group), while 5 underwent surgical treatment (surgical treatment group). Recurrence or exacerbation of embolism was found in 2 (15.4%) of the 13 patients and in 1 (20.0%) of the 5 patients ( P = 1.0). Major complications were observed in 1 (7.7%) of the patients in the anticoagulation group and in 1 (20.0%) of the 5 patients in the surgical treatment group ( P = .49). No significant differences between the groups were found. CONCLUSIONS:: A simple anticoagulation therapy may be as effective as surgical treatment in patients with aortic thrombosis associated with malignancy. PMID- 30466377 TI - Glenohumeral fusion in adults with sequelae of obstetrical brachial plexus injury: a report of eight cases. AB - The purpose of this study was to assess the outcomes of glenohumeral fusion performed in adulthood in patients with poor recovery after obstetric brachial plexus injury. We reviewed eight patients with obstetrical brachial plexus injury who had undergone shoulder arthrodesis. The mean age was 28 years (range 16 to 55). All of the patients had active periscapular and elbow flexor muscles. At an average follow-up of 20 months, the active range of abduction and external rotation of the affected shoulder was 67 degrees (range 50 degrees to 85 degrees ) and 21 degrees (range 0 degrees to 40 degrees ), respectively. All of the patients were satisfied with the outcome of the intervention. Fusion was obtained between 3 and 6 months, and none of the patients experienced residual pain. Shoulder fusion improved the active shoulder abduction and external rotation in adults with residual obstetrical brachial plexus paralysis. Level of evidence: IV. PMID- 30466378 TI - Prognostic factors for return to work and resumption of other daily activities after traumatic hand injury. AB - The purpose of this study was to investigate prognostic factors for the time off work, the time to resumption of activities of daily living and hobbies, and duration of complaints in patients with a traumatic hand or wrist injury. In a 10 month longitudinal prospective cohort study, 383 patients were included and interviewed in person every 2 to 3 months. Several sociodemographic, psychological and work-related prognostic factors were investigated. For the time off work, job type, diagnosis, complication, blaming someone else for the trauma and gender were all found to be individual prognostic factors in Cox regression. For the time to resumption of activities of daily living and hobbies, and duration of complaints, gender, diagnosis, treatment and complications were found to be prognostic factors in univariate analysis. Age was solely correlated with resumption of activities of daily living and the duration of complaints. Considering these prognostic factors can help predict a patient's recovery more accurately. Level of evidence: II. PMID- 30466380 TI - ? PMID- 30466379 TI - Amputation-Free Survival in Patients With Diabetes Mellitus and Peripheral Arterial Disease With Heel Ulcer: Open Versus Endovascular Surgery. AB - BACKGROUND:: Heel ulcers in patients with diabetes mellitus (DM) and peripheral arterial disease (PAD) are hard to heal. The aim of the present study was to evaluate the difference in amputation-free survival (AFS) between open and endovascular revascularization in patients with DM, PAD, and heel ulcers. METHODS:: Retrospective comparative study of results of open versus endovascular surgery in patients with DM, PAD, and heel ulcer presented at the multidisciplinary diabetes foot clinic between 1983 and 2013. RESULTS:: Patients with heel ulcers were treated with endovascular intervention (n = 97) and open vascular surgery (n = 30). Kaplan-Meier analysis showed that the AFS was higher in patients undergoing open vascular surgery compared to the endovascular group ( P = .009). Multivariate analysis showed that open vascular surgery versus endovascular therapy (hazard ratio 2.1, 95% confidence interval 1.1-3.9; P = .025) was an independent factor associated with higher AFS. The proportion of patients undergoing endovascular therapy in the former (1983-2000) time period was 47% compared to 89% in the latter (2001-2013) time period ( P < .001). CONCLUSION:: The AFS was higher after open than endovascular surgery among patients with DM and PAD with heel ulcer. These results suggest that open vascular surgery should be offered more often as opposed to current practice. PMID- 30466382 TI - ? PMID- 30466381 TI - ? PMID- 30466383 TI - A Piece of the ROCK: A Critical Role for Rho Kinases in the Nervous System. PMID- 30466384 TI - Lifestyle modifications as therapy for medication refractory post-traumatic headache (PTHA) in the military population of Okinawa. AB - OBJECTIVE: Our aim was 1) to reduce disability, as characterized by headache frequency, duration and severity in patients with post-traumatic headache (PTHA), 2) to reduce the number of medical boards and work limitations in patients with post traumatic headache, and 3) to reduce use of medical resources and clinic visits related to headache or migraine. BACKGROUND: Modifiable risk factors for PTHA include stressful life event, sleep disturbances, and medication overuse. Cognitive-behavioral strategies, biofeedback, and relaxation therapy may have an important role in treatment and preventing progression to chronic post-traumatic headache (CPTHA). There is limited literature and a known practice gap for implementation of these techniques. DESIGN/METHODS: An IRB approved project focused on patients who were seen for PTHA and CPTHA. 1) Intervention consisted of lifestyle teaching, cognitive-behavioral therapy and biofeedback, supplemented by decreasing polypharmacy. 2) Patients were followed for 2 years and a retrospective review was conducted for 2 years prior to presentation. 3) Outcome measures included reduction in migraine intensity or frequency, improved quality of life, duty status, and decreased utilization of clinic visits. RESULTS: Over the course of one year, 221 patients were treated for migraines in the Naval Okinawa Neurology Clinic. Of these, 22 active duty service members and 3 Dependents suffered a mild TBI prior to onset. After intervention, there was a 36% decrease in PTHA frequency, 56% decrease in headache severity and 60% of patients had improved quality of life as compared to the 2 years prior to intervention. Twenty-four percent had reduction in polypharmacy. Appointment frequency for migraine decreased from an average of 6.8 to 2.6 per year. CONCLUSIONS: An implemented program geared towards reducing polypharmacy was shown to improve safety, quality of life and reduce hospitalizations from the burden of migraines. Our systematic approach resulted in quality of life improvements and decreased use of medical resources. TRIAL REGISTRATION: Authors received the approval of NAVMED West, Okinawa Naval Hospital Institutional Review Board on January 13th, 2016. QI.2016.0021. PMID- 30466385 TI - A statistical method to identify recombination in bacterial genomes based on SNP incompatibility. AB - BACKGROUND: Phylogeny estimation for bacteria is likely to reflect their true evolutionary histories only if they are highly clonal. However, recombination events could occur during evolution for some species. The reconstruction of phylogenetic trees from an alignment without considering recombination could be misleading, since the relationships among strains in some parts of the genome might be different than in others. Using a single, global tree can create the appearance of homoplasy in recombined regions. Hence, the identification of recombination breakpoints is essential to better understand the evolutionary relationships of isolates among a bacterial population. RESULTS: Previously, we have developed a method (called ACR) to detect potential breakpoints in an alignment by evaluating compatibility of polymorphic sites in a sliding window. To assess the statistical significance of candidate breakpoints, we propose an extension of the algorithm (ptACR) that applies a permutation test to generate a null distribution for comparing the average local compatibility. The performance of ptACR is evaluated on both simulated and empirical datasets. ptACR is shown to have similar sensitivity (true positive rate) but a lower false positive rate and higher F1 score compared to basic ACR. When used to analyze a collection of clinical isolates of Staphylococcus aureus, ptACR finds clear evidence of recombination events in this bacterial pathogen, and is able to identify statistically significant boundaries of chromosomal regions with distinct phylogenies. CONCLUSIONS: ptACR is an accurate and efficient method for identifying genomic regions affected by recombination in bacterial genomes. PMID- 30466386 TI - "Expression of genes encoding protein disulfide isomerase (PDI) in cultivars and lines of common wheat with different baking quality of flour". AB - BACKGROUND: The subject of this research was to investigate the level of expression of genes encoding protein disulfide isomerase (PDI) in cultivars and lines of wheat with different baking value of flour. PDI plays a key role in the formation of disulfide bonds in newly formed proteins. Each of cultivars and lines had a specific set of high molecular weight glutenin subunits (HMW-GS). Based on the presence of individual subunits, the potential baking value is predicted. Sometimes this value is not confirmed during technological analysis. Since there are cases where flour has a better or worse value than expected on the basis of the genotype, the expression of PDI genes was considered as a potential cause for discrepancies mentioned. RESULTS: Analysis focused on three stages of grain development. The expression level of PDI genes was compared between wheat cultivars and lines with different genotype-phenotype combinations, which means diversified sets of HMW-GS combined with diversified qualitative classification. The highest expression level of PDI was noticed at early stage of grain development, which is consistent with the function of PDI. The expression level was evaluated by the real-time PCR technique. CONCLUSION: Results obtained in this work did not allow for a clear statement of decisive significance of PDI in the context of shaping the final baking value. The results of this work contribute to an ever more in-depth understanding of the mechanisms governing baking value, and thus to the progress of the selection of new varieties with more beneficial properties. PMID- 30466387 TI - AL amyloidosis with non-amyloid forming monoclonal immunoglobulin deposition; a case mimicking AHL amyloidosis. AB - BACKGROUND: Immunoglobulin heavy-and-light-chain amyloidosis (AHL amyloidosis) is a newly established disease entity where both the immunoglobulin heavy-chain and light-chain compose amyloid fibrils. The immunoglobulins responsible for the amyloid fibrils are generally identified by immunostaining and/or laser microdissection-liquid chromatography-tandem mass spectrometry (LMD-LC-MS/MS). However, both techniques do not biochemically differentiate immunoglobulins that formed amyloid fibrils from non-responsible immunoglobulins. CASE PRESENTATION: We herein report a case of 67-year-old female patient with renal amyloidosis due to lymphoplasmacytic lymphoma secreting monoclonal immunoglobulin M (IgM)-kappa. Renal immunostaining monotypically positive for IgM-kappa and LMD-LC-MS/MS identification of mu heavy-chain and kappa light-chain were consistent with the diagnosis of AHL amyloidosis. In order to confirm that both the immunoglobulin heavy-chain and light-chain were forming amyloid fibrils, we performed LC-MS/MS of renal amyloid fibrils isolated by the traditional amyloid purification method. The additional LC-MS/MS identified kappa light-chain only without any heavy-chain component. These results were suggestive that amyloid fibrils were composed by kappa light-chain only and that the mu heavy-chain identified by immunostaining and LMD-LC-MS/MS was derived from the non-specific co-deposition of monoclonal IgM-kappa. CONCLUSION: The case was AL amyloidosis with non-amyloid forming monoclonal immunoglobulin deposition. While immunostaining and LMD-LC-MS/MS are irreplaceable techniques to classify amyloidosis, confident exclusion of the present condition should be required to diagnose AHL amyloidosis. PMID- 30466388 TI - Screening, purification and characterization of thermostable, protease resistant Bacteriocin active against methicillin resistant Staphylococcus aureus (MRSA). AB - BACKGROUND: The emergence of serious issues of multidrug resistance in the past few years have enforced the use of bacteriocins for combating infections. Threat posed to public health by various multidrug resistant (MDR) organisms can be resolved by discovering new antimicrobial proteins with broad spectrum of inhibition. RESULTS: In the current study, Bacteriocin (BAC-IB17) produced by Bacillus subtilis KIBGE-IB17 is found to be effective against different strains of methicillin resistant Staphylococcus aureus (MRSA). The approximate molecular mass of BAC-IB17 is 10.7 kDa. This unique bacteriocin is found to be highly thermostable and pH stable in nature. It also showed its stability against various heavy metals, organic solvents, surfactants and proteolytic enzymes. Amino acid profile of BAC-IB17 clearly showed that this protein mainly consists of non-polar and basic amino acids whereas; some acidic amino acids were also detected. Sequence of first 15 amino acid residues obtained from N-terminal sequencing of BAC-IB17 were NKPEALVDYTGVXNS. CONCLUSIONS: The anti-MRSA property of purified bacteriocin may be used to prevent the spread of MRSA infections. Remarkable features of BAC-IB17 suggests its applications in various pharmaceutical and food industries as it can function under a variety of harsh environmental conditions. PMID- 30466389 TI - Multi-drug resistant Enterobacter bugandensis species isolated from the International Space Station and comparative genomic analyses with human pathogenic strains. AB - BACKGROUND: The antimicrobial resistance (AMR) phenotypic properties, multiple drug resistance (MDR) gene profiles, and genes related to potential virulence and pathogenic properties of five Enterobacter bugandensis strains isolated from the International Space Station (ISS) were carried out and compared with genomes of three clinical strains. Whole genome sequences of ISS strains were characterized using the hybrid de novo assembly of Nanopore and Illumina reads. In addition to traditional microbial taxonomic approaches, multilocus sequence typing (MLST) analysis was performed to classify the phylogenetic lineage. Agar diffusion discs assay was performed to test antibiotics susceptibility. The draft genomes after assembly and scaffolding were annotated with the Rapid Annotations using Subsystems Technology and RNAmmer servers for downstream analysis. RESULTS: Molecular phylogeny and whole genome analysis of the ISS strains with all publicly available Enterobacter genomes revealed that ISS strains were E. bugandensis and similar to the type strain EB-247T and two clinical isolates (153_ECLO and MBRL 1077). Comparative genomic analyses of all eight E. bungandensis strains showed, a total of 4733 genes were associated with carbohydrate metabolism (635 genes), amino acid and derivatives (496 genes), protein metabolism (291 genes), cofactors, vitamins, prosthetic groups, pigments (275 genes), membrane transport (247 genes), and RNA metabolism (239 genes). In addition, 112 genes identified in the ISS strains were involved in virulence, disease, and defense. Genes associated with resistance to antibiotics and toxic compounds, including the MDR tripartite system were also identified in the ISS strains. A multiple antibiotic resistance (MAR) locus or MAR operon encoding MarA, MarB, MarC, and MarR, which regulate more than 60 genes, including upregulation of drug efflux systems that have been reported in Escherichia coli K12, was also observed in the ISS strains. CONCLUSION: Given the MDR results for these ISS Enterobacter genomes and increased chance of pathogenicity (PathogenFinder algorithm with > 79% probability), these species pose important health considerations for future missions. Thorough genomic characterization of the strains isolated from ISS can help to understand the pathogenic potential, and inform future missions, but analyzing them in in-vivo systems is required to discern the influence of microgravity on their pathogenicity. PMID- 30466391 TI - Variable participation of knowledge users in cancer health services research: results of a multiple case study. AB - BACKGROUND: Integrated knowledge translation (IKT) is a research approach in which knowledge users (KUs) co-produce research. The rationale for IKT is that it leads to research that is more relevant and useful to KUs, thereby accelerating uptake of findings. The aim of the current study was to evaluate IKT activities within a cancer health services research network in Ontario, Canada. METHODS: An embedded multiple case study design was used. The cases were 5 individual studies within an overarching cancer health services research network. These studies focused on one of the following topics: case costing of cancer treatment, lung cancer surgery policy analysis, patient and provider-reported outcomes, colorectal cancer screening, and a team approach to women's survivorship. We conducted document reviews and held semi-structured interviews with researchers, KUs, and other stakeholders within a cancer system organization. The analysis examined patterns across and within cases. RESULTS: Researchers and their respective knowledge users from 4 of the 5 cases agreed to participate. Eighteen individuals from 4 cases were interviewed. In 3 of 4 cases, there were mismatched expectations between researchers and KUs regarding KU role; participants recommended that expectations be made explicit from the beginning of the collaboration. KUs perceived that frequent KU turnover may have affected both KU engagement and the uptake of study results within the organization. Researchers and KUs found that sharing research results was challenging because the organization lacked a framework for knowledge translation. Uptake of research findings appeared to be related to the researcher having an embedded role in the cancer system organization and/or close alignment of the study with organizational priorities. Document reviews found evidence of planned IKT strategies in 3 of 4 cases; however, actual KU role/engagement on research teams was variable. CONCLUSIONS: Barriers to KU co-production of cancer health services research include mismatched expectations of KU role and frequent KU turnover. When a research study directly aligns with organizational priorities, it appears more likely that results will be considered in programming. Research teams that take an IKT approach should consider specific strategies to address barriers to KU engagement. PMID- 30466390 TI - knnAUC: an open-source R package for detecting nonlinear dependence between one continuous variable and one binary variable. AB - BACKGROUND: Testing the dependence of two variables is one of the fundamental tasks in statistics. In this work, we developed an open-source R package (knnAUC) for detecting nonlinear dependence between one continuous variable X and one binary dependent variables Y (0 or 1). RESULTS: We addressed this problem by using knnAUC (k-nearest neighbors AUC test, the R package is available at https://sourceforge.net/projects/knnauc/ ). In the knnAUC software framework, we first resampled a dataset to get the training and testing dataset according to the sample ratio (from 0 to 1), and then constructed a k-nearest neighbors algorithm classifier to get the yhat estimator (the probability of y = 1) of testy (the true label of testing dataset). Finally, we calculated the AUC (area under the curve of receiver operating characteristic) estimator and tested whether the AUC estimator is greater than 0.5. To evaluate the advantages of knnAUC compared to seven other popular methods, we performed extensive simulations to explore the relationships between eight different methods and compared the false positive rates and statistical power using both simulated and real datasets (Chronic hepatitis B datasets and kidney cancer RNA-seq datasets). CONCLUSIONS: We concluded that knnAUC is an efficient R package to test non linear dependence between one continuous variable and one binary dependent variable especially in computational biology area. PMID- 30466392 TI - Lack of association between single-nucleotide polymorphisms of pro- and anti inflammatory cytokines and HTLV-1-associated myelopathy / tropical spastic paraparesis development in patients from Rio de Janeiro, Brazil. AB - BACKGROUND: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive neurological and inflammatory disease, associated with HTLV-1 infection. HAM/TSP neurological disease is a consequence of an inflammatory reaction, and adaptive immune responses, through the secretion of anti inflammatory and pro-inflammatory cytokines, play an important role in the outcome of infection and disease progression. Studies addressing the association between cytokines functional single nucleotide polymorphisms and HAM/TSP development are scarce. METHODS: The genetic polymorphisms of cytokine genes were evaluated in HAM/TSP patients (n = 68) and in asymptomatic HTLV-1 positive carriers (n = 83) from Rio de Janeiro, Brazil, in a case-control study. HTLV-1 infected patients were genotyped for SNPs in five cytokine genes: TNFA-308G/A, IL6-174G/C, IFNG + 874 T/A, TGFB at the codons + 10 T/C and + 25G/C, IL10-592C/A and -819C/T, and -1082A/G and proviral load (PVL) was quantified. Associations between genotypes, haplotypes, clinical outcome and pro viral load were evaluated. RESULTS: Lack of association between the cytokine polymorphisms and disease outcome was observed. The genotypes TNFA-308GG, IL6-174GG/GC, IL10-592AA and -819CC and TGFb1 high producers phenotypes were correlated with higher PVL in HAM/TSP patients versus asymptomatic carriers. CONCLUSIONS: We did not observe association between cytokine polymorphisms and risk for HAM/TSP development in Brazilian HTLV-1 infected individuals, regardless of differences in PVL between HAM/TSP versus asymptomatic carriers in specific cytokine polymorphisms. PMID- 30466393 TI - Glomerular filtration rate: new age- and gender- specific reference ranges and thresholds for living kidney donation. AB - BACKGROUND: There is a need for a large, contemporary, multi-centre series of measured glomerular filtration rates (mGFR) from healthy individuals to determine age- and gender-specific reference ranges for GFR. We aimed to address this and to use the ranges to provide age- and gender-specific advisory GFR thresholds considered acceptable for living kidney donation. METHODS: Individual-level data including pre-donation mGFR from 2974 prospective living kidney donors from 18 UK renal centres performed between 2003 and 2015 were amalgamated. Age- and gender specific GFR reference ranges were determined by segmented multiple linear regression and presented as means +/- two standard deviations. RESULTS: Males had a higher GFR than females (92.0 vs 88.1 mL/min/1.73m2, P < 0.0001). Mean mGFR was 100 mL/min/1.73m2 until 35 years of age, following which there was a linear decline that was faster in females compared to males (7.7 vs 6.6 mL/min/1.73m2/decade, P = 0.013); 10.5% of individuals aged > 60 years had a GFR < 60 mL/min/1.73m2. The GFR ranges were used along with other published evidence to provide advisory age- and gender-specific GFR thresholds for living kidney donation. CONCLUSIONS: These data suggest that GFR declines after 35 years of age, and the decline is faster in females. A significant proportion of the healthy population over 60 years of age have a GFR < 60 mL/min/1.73m2 which may have implications for the definition of chronic kidney disease. Age and gender differences in normal GFR can be used to determine advisory GFR thresholds for living kidney donation. PMID- 30466394 TI - Analysis of a novel mutant allele of GSL8 reveals its key roles in cytokinesis and symplastic trafficking in Arabidopsis. AB - BACKGROUND: Plant cell walls are mainly composed of polysaccharides such as cellulose and callose. Callose exists at a very low level in the cell wall; however, it plays critical roles at different stages of plant development as well as in defence against unfavorable conditions. Callose is accumulated at the cell plate, at plasmodesmata and in male and female gametophytes. Despite the important roles of callose in plants, the mechanisms of its synthesis and regulatory properties are not well understood. RESULTS: CALLOSE SYNTHASE (CALS) genes, also known as GLUCAN SYNTHASE-LIKE (GSL), comprise a family of 12 members in Arabidopsis thaliana. Here, we describe a new allele of GSL8 (named essp8) that exhibits pleiotropic seedling defects. Reduction of callose deposition at the cell plates and plasmodesmata in essp8 leads to ectopic endomitosis and an increase in the size exclusion limit of plasmodesmata during early seedling development. Movement of two non-cell-autonomous factors, SHORT ROOT and microRNA165/6, both required for root radial patterning during embryonic root development, are dysregulated in the primary root of essp8. This observation provides evidence for a molecular mechanism explaining the gsl8 root phenotype. We demonstrated that GSL8 interacts with PLASMODESMATA-LOCALIZED PROTEIN 5, a beta-1,3-glucanase, and GSL10. We propose that they all might be part of a putative callose synthase complex, allowing a concerted regulation of callose deposition at plasmodesmata. CONCLUSION: Analysis of a novel mutant allele of GSL8 reveals that GSL8 is a key player in early seedling development in Arabidopsis. GSL8 is required for maintaining the basic ploidy level and regulating the symplastic trafficking. Callose deposition at plasmodesmata is highly regulated and occurs through interaction of different components, likely to be incorporated into a callose biosynthesis complex. We are providing new evidence supporting an earlier hypothesis that GSL8 might have regulatory roles apart from its enzymatic function in plasmodesmata regulation. PMID- 30466396 TI - Which ICD-9-CM codes should be used for bronchiolitis research? AB - BACKGROUND: Bronchiolitis is a common respiratory disorder in children. Although there are specific ICD-9-CM diagnosis codes for bronchiolitis, the illness is often coded using broader diagnosis codes. This creates the potential for subject misclassification if researchers rely on specific diagnosis codes when assembling retrospective cohorts. Here we challenge the common research practice of relying on specific diagnosis codes for bronchiolitis. METHODS: We examined the use of diagnosis codes for the first episode of bronchiolitis, bronchitis, acute asthma, and bronchospasm and wheezing, in children younger than six and 24 months in the State of California Medic-Aid database. We categorized codes as narrow or broad diagnosis codes. We compared patient, geographic, and temporal characteristics of the different diagnoses codes. RESULTS: We identified visits from 48,732 children for first episode of wheezing illness. We retained 48,269 who had the diagnosis codes and data of interest. Diagnosis codes for acute asthma were widely used, even in children younger than six months in whom a diagnosis code for bronchiolitis would have been anticipated. The temporal pattern was similar across all diagnoses. Antipyretics were prescribed more often in those with diagnosis codes for bronchiolitis and bronchitis. Other statistically significant differences were too small to usefully distinguish the groups. There was substantial geographic variability in the diagnosis codes selected. CONCLUSION: Users of Medic-Aid administrative data should generally favor broad rather than narrow definitions of bronchiolitis and should perform sensitivity analysis comparing broad and narrow definitions. PMID- 30466395 TI - Dialogue between Staphylococcus aureus SA15 and Lactococcus garvieae strains experiencing oxidative stress. AB - BACKGROUND: Staphylococcus aureus is an important foodborne pathogen. Lactococcus garvieae is a lactic acid bacterium found in dairy products; some of its strains are able to inhibit S. aureus growth by producing H2O2. Three strains of L. garvieae from different origins were tested for their ability to inhibit S. aureus SA15 growth. Two conditions were tested, one in which H2O2 was produced (high aeration) and another one in which it was not detected (low aeration). Several S. aureus genes related to stress, H2O2-response and virulence were examined in order to compare their level of expression depending on the inoculated L. garvieae strain. Simultaneous L. garvieae H2O2 metabolism gene expression was followed. RESULTS: The results showed that under high aeration condition, L. garvieae strains producing H2O2 (N201 and CL-1183) inhibited S. aureus SA15 growth and impaired its ability to deal with hydrogen peroxide by repressing H2O2-degrading genes. L. garvieae strains induced overexpression of S. aureus stress-response genes while cell division genes and virulence genes were repressed. A catalase treatment partially or completely restored the SA15 growth. In addition, the H2O2 non-producing L. garvieae strain (Lg2) did not cause any growth inhibition. The SA15 stress-response genes were down-regulated and cell division genes expression was not affected. Under low aeration condition, while none of the strains tested exhibited H2O2-production, the 3 L. garvieae strains inhibited S. aureus SA15 growth, but to a lesser extent than under high aeration condition. CONCLUSION: Taken together, these results suggest a L. garvieae strain specific anti-staphylococcal mechanism and an H2O2 involvement in at least two of the tested L. garvieae strains. PMID- 30466397 TI - Bone marrow mesenchymal stem cells attenuate the progression of focal segmental glomerulosclerosis in rat models. AB - BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is the most common glomerular etiology of end-stage kidney disease (ESKD). Increasing evidence has indicated the reparative potential of mesenchymal stem cells (MSCs) in damaged diseased kidneys. However, the effect of bone marrow mesenchymal stem cells (BMSCs) on the FSGS progression remains unclear. This study aimed to investigate the protective effects of BMSCs on FSGS progression. METHODS: A rat model of FSGS was generated via unilateral nephrectomy plus adriamycin injection. Rat BMSCs were isolated and characterized on the basis of their differentiative potential towards adipocytes and osteoblasts and via flow cytometry analysis. Thereafter, rat BMSCs were transplanted into FSGS recipients through the caudal vein. After 8 weeks, 24-h proteinuria, serum creatinine, and urea nitrogen levels were determined. Renal morphology was assessed using a light and transmission electron microscope. MMP9 and TIMP-1 positive cells were detected via immunohistochemical analysis. Expression levels of proinflammatory cytokines IL-6 and TNF-alpha were examined via RT-PCR. RESULTS: The isolated adherent cells from the bone marrow of rats were phenotypically and functionally equivalent to typical MSCs. Clinical examination revealed that BMSC transplantation reduced the 24-h urinary protein excretion, and serum creatinine and urea nitrogen levels. Renal morphology was ameliorated in BMSCs-transplanted rats. Mechanistically, BMSC transplantation significantly downregulated TIMP-1 and upregulated MMP9, thereby increasing the renal MMP9/TIMP-1 ratio. Moreover, BMSC transplantation also downregulated IL-6 and TNF-alpha. CONCLUSIONS: BMSC transplantation can attenuate FSGS progression in a rat model of FSGS, thereby providing a theoretical foundation for the application of autologous BMSCs in clinical FSGS therapy. PMID- 30466398 TI - PCRdrive: the largest qPCR assay archive to date and endless potential for lab workflow revitalization. AB - BACKGROUND: Primer design is a crucial step in establishing specific and sensitive qPCR assays. Even though numerous tools for primer design exist, the majority of resulting assays still requires extensive testing and optimisation or does not allow for high quality target amplification. We developed a workflow for designing qPCR assays. Unlike other tools, we compute a PCR assay including primer design, concentrations and the optimal PCR program. RESULTS: Gene expression assays were already generated in a total of 283,226 genes from three species and are continued for all genes of the major model species. The results are available online at https://pcrdrive.com/lab#/assay-database . The workflow involves filtering Primer3-generated primers by considering diverse parameters including specificity, single-nucleotide polymorphisms (SNPs), secondary structure as well as compatibility with standard qPCR assay conditions. The resulting assays consist of transcript-specific primer sequences, a reagents protocol as well as instrument settings which are provided in a web-based tool called PCRdrive. PCRdrive was designed to support PCR users in their PCR-related tasks and is equipped with handy functions, components of an electronic lab notebook (ELN) as well as teamworking opportunities. CONCLUSION: High quality ready to use qPCR assays for gene expression analysis are provided within the online platform PCRdrive. A built-in primer designer enables easy generation of assays which is not supported by any other tool. The wet lab optimisation of new assays can be transparently documented and shared within the team. PCRdrive also contains an archive of public PCRs which is updated regularly. Users may use the archive to publish their PCR to the community which makes it easy for other researchers worldwide to reproduce and validate the PCR. PCRdrive is a growing network of PCR users, simplifying and streamlining research through its useful existing features and continuous developments from the active development team. PMID- 30466399 TI - The geographic variation and spatiotemporal distribution of hepatitis C virus infection in Libya: 2007-2016. AB - BACKGROUND: Hepatitis C Virus infection has been considered an important hidden pandemic in developing countries, particularly in Africa. It varies greatly from one region to another and even within districts of the same region. Macroscopic geospatial analysis has become an important scientific tool for identifying the density and clustering of HCV infection and provides epidemiological information for planning interventions and control strategies. The application of these parameters provides a better knowledge of the hepatitis C virus infection prevalence at the national level and can help to implement pertinent strategies to address the HCV-related burdens. This study aims to determine the geographical variability of HCV infection in Libya and to identify the hot spots within regions and districts of the country, and to analyze the population-based demographic determinants involved and outline the intervention programs needed. METHODS: Disease mapping and spatial analysis were conducted using geographic information data available on all documented cases of HCV infections in Libya between 2007 and 2016. Spatial autocorrelation was tested using Moran's Index, which determines and measures the degree of clustering and dispersion of HCV infection in a country. RESULTS: A total 114,928 HCV infection cases during a ten year period with accurate geographic information were studied. Ages ranged between 16 and 50 years and the male to female ratio was 2:1. HCV infection was unevenly distributed in Libya, and its incidence increased steadily over the study period. Several hot spots and cold spots were found mainly in the southern and eastern regions of the country. CONCLUSION: HCV infection in Libya was geographically variable, with several hot spots particularly in eastern and southern Libya associated with different demographic determinants. Future intervention planning should consider the geospatial variability and risk factors involved. PMID- 30466400 TI - Significance of histological crescent formation in patients with IgA vasculitis (Henoch-Schonlein purpura)-related nephritis: a cohort in the adult Chinese population. AB - BACKGROUND: IgA vasculitis (IgAV, formerly Henoch-Schonlein purpura) is a type of systemic vasculitis. This study aimed to explore the clinicopathological features, treatment and renal outcomes of adult IgAV-related nephritis (Henoch Schonlein purpura nephritis) patients with different degrees of crescent formation. METHODS: Adult patients with biopsy-proven IgAV-related nephritis in Nanjing Jinling Hospital were enrolled and divided into three groups as follows: control (no crescents, n = 257), group 1 (crescents < 25%, n = 381), and group 2 (crescents >=25%, n = 60). The clinicopathological features, treatment and renal outcomes were compared among the three groups. RESULTS: There were no significant differences in gender and age at biopsy among the three groups. Groups with more crescents had shorter renal durations and higher prevalence of macroscopic hematuria, proteinuria and nephrotic syndrome than the control group. The presence of renal insufficiency at biopsy was similar, whereas laboratory findings indicated that patients with >=25% crescents had higher levels of serum creatinine and blood urea nitrogen than the control and group 1. Histologically, the incidence of glomeruli-Bowman's capsule adhesion and capillary necrosis were proportional to the degree of crescent formation. Patients with more crescents received more positive immunosuppressive therapies. During follow-up, the levels of proteinuria and hematuria were in remission after treatment, and patients without crescents had lower levels of proteinuria. At the last follow-up, the renal function had deteriorated in the control and group 1, whereas the levels of serum creatinine at biopsy and last follow-up were similar in group 2. There was a significant difference in renal survival from end-stage renal disease (ESRD) or 50% decline in renal function among the three groups (log-rank, P = 0.030). However, no association between crescent formation and renal outcomes was found after adjusting potential confounders. CONCLUSIONS: Adult IgAV-related nephritis patients with more crescents had more-severe renal manifestations and worse treatment responses, whereas the proportions of crescents were not associated with higher risks for ESRD or 50% decline in renal function. A more suitable pathological classification standard is needed to predict renal prognosis. PMID- 30466401 TI - Identification of a SiCL1 gene controlling leaf curling and capsule indehiscence in sesame via cross-population association mapping and genomic variants screening. AB - BACKGROUND: Leaf shape can affect plantlet development and seed yield in sesame. The morphological, histological and genetic analyses of a sesame mutant cl1 (cl) with curly leaf and indehiscent capsule traits were performed in this study. In order to clone the cl1 gene for breeding selection, genome re-sequencing of the 130 individuals of cl1 * USA (0)-26 F2 population and a bulked segregation analysis (BSA) pool was carried out. The genome re-sequencing data of the 822 germplasm with normal leaf shape were applied. RESULTS: For cl1 mutant, the adaxial/abaxial character of the parenchyma cells in the leaf blades is reduced. Results proved that the leaf curling trait is controlled by a recessive gene (Sicl1). Cross- population association of the F2 population of cl1 * USA (0)-26 indicated that the target cl locus was located on the interval C29 between C29_6522236 and C29_6918901 of SiChr. 1. Further regional genome variants screening determined the 6 candidate variants using genomic variants data of 822 natural germplasm and a BSA pool data. Of which, 5 markers C29_6717525, C29_6721553, C29_6721558, C29_6721563, and C29_6721565 existed in the same gene (C29.460). With the aid of the validation in the test F2 population of cl1 * Yuzhi 11 and natural germplasm, the integrated marker SiCLInDel1 (C29: 6721553 6721572) was determined as the target marker, and C29.460 was the target gene SiCL1 in sesame. SiCL1 is a KAN1 homolog with the full length of 6835 bp. In cl1, the 20 nucleic acids (CAGGTAGCTATGTATATGCA) of SiCLInDel1 marker were mutagenized into 6 nucleic acids (TCTTTG). The deletion led to a frameshift mutation and resulted in the earlier translation termination of the CL gene. The Sicl1 allele was shortened to 1829 bp. SiCL1 gene was expressed mainly in the tissues of stem, leaf, bud, capsule and seed. CONCLUSIONS: SiCL1 encodes a transcription repressor KAN1 protein and controls leaf curling and capsule indehiscence in sesame. The findings provided an example of high-efficient gene cloning in sesame. The SiCL1 gene and the cl1 mutant supply the opportunity to explore the development regulation of leaf and capsule, and would improve the new variety breeding with high harvest mechanization adaption in sesame. PMID- 30466402 TI - Effects of oxytocin and anaesthesia on vascular tone in pregnant women: a randomised double-blind placebo-controlled study using non-invasive pulse wave analysis. AB - BACKGROUND: Oxytocin is an uterotonic drug with profound cardiovascular effects, which in compromised patients could lead to serious events. The objective was to investigate whether oxytocin affects cardiac function and vascular tone in large and small arteries. We hypothesized that oxytocin decreases arterial vascular tone and elevates cardiac output. METHODS: 51 pregnant women were randomised to treatment with 8.3 MUg (5 U) oxytocin or placebo injection during first trimester surgical evacuation of the gravid uterus under general anaesthesia. Oxytocin or placebo was administered once either early or late in the procedure, in a double blind fashion. Digital photoplethysmography pulse wave analysis variables, heart rate, mean arterial blood pressure and electrocardiographic ST index were recorded before and after anaesthesia and after each injection. Non-parametric statistics were used with a two-sided P value < 0.05 considered significant. RESULTS: Anaesthesia induced a significant fall in blood pressure, heart rate and vascular tone in small and peripheral arteries. Oxytocin had a vasodilatory effect on small and peripheral arteries and increased the left cardiac ventricular ejection time. The ST index decreased. CONCLUSIONS: Pulse wave analysis indicated peripheral vasodilation and increased cardiac output after oxytocin, implying increased myocardial oxygen demand. These effects might have been enhanced by the vasodilating effects of anaesthesia. Previous studies have demonstrated myocardial ischaemia after oxytocin, as reflected by a decrease in ST index in the present study. TRIAL REGISTRATION: Trial registration number ISRCTN17860978 , 2018/03/14, Retrospectively registered. PMID- 30466403 TI - The role of intention and self-efficacy on the association between breastfeeding of first and second child, a Danish cohort study. AB - BACKGROUND: The impact of parity on breastfeeding duration may be explained by physiological as well as psychosocial factors. The aim in the present study was to investigate the mediating influence of intention and self-efficacy on the association between the breastfeeding duration of the first and the following child. METHODS: A 5-year Danish cohort study with data from online questionnaires was used. Data came from 1162 women, who participated in the "Ready for child" trial in 2006-7 and gave birth to their second child within 5 years in 2011-3. Analysis included multiple regression models with exclusive/any breastfeeding duration of first child as the exposure variables, intention and self-efficacy measured as mediators, and exclusive/any breastfeeding duration of the second child as the outcome variables. RESULTS: Duration of exclusive breastfeeding of the first child was significantly associated with exclusive breastfeeding duration of the second child (p < 0.001) and with the self-reported intention and self-efficacy in the ability to breastfeed the second child (p < 0.001). The exclusive breastfeeding period was slightly longer for the second child. Self efficacy and intention mediated the association between breastfeeding duration in the first and second child. Together the two factors explained 48% of the association in exclusive breastfeeding and 27% of the association in any breastfeeding between the first and second child. CONCLUSION: Due to a reinforcing effect of intention and self-efficacy, breastfeeding support should focus on helping the first time mothers to succeed as well as to identify the second time mother with low self-efficacy and additional need for support. PMID- 30466404 TI - Novel role of O-glycosyltransferases GALNT3 and B3GNT3 in the self-renewal of pancreatic cancer stem cells. AB - BACKGROUND: Glycosylation plays a critical role in the aggressiveness of pancreatic cancer (PC). Emerging evidences indicate significant involvement of cancer stem cells (CSCs) in PC aggressiveness. However, the importance of glycosylation in pancreatic cancer stem cells (PCSCs) is yet to be addressed. Hence, we evaluated the potential role of glycosylation in maintenance of stemness of PCSCs. METHODS: Effect of glycosylation specific inhibitors on growth and PCSCs of PC cells was assessed by MTT assay and Side Population (SP) analysis. Isolated PCSCs/SP were characterized using molecular and functional assays. Expression of tumor-associated carbohydrate antigens (TACAs) was analyzed in PCSCs by western blotting. Effect of tunicamycin on PCSCs was analyzed by tumorsphere, clonogenicity, migration assay and immunoblotting for CSCs markers. The differential expression of glycogenes in PCSCs compared to non-CSCs were determined by RT-qPCR, immunoblotting and immunofluorescence. Co-expression of GALNT3 and B3GNT3 with CD44v6 was assessed in progression stages of KrasG12D; Pdx 1-Cre (KC) and KrasG12D; p53R172H; Pdx-1-Cre (KPC) tumors by immunofluorescence. Transient and CRISPR/Cas9 silencing of GALNT3 and B3GNT3 was performed to examine their effect on CSCs maintenance. RESULTS: Inhibition of glycosylation decreased growth and CSCs/SP in PC cells. PCSCs overexpressed CSC markers (CD44v6, ESA, SOX2, SOX9 and ABCG2), exhibited global expressional variation of TACAs and showed higher self-renewal potential. Specifically, N-glycosylation inhibition, significantly decreased tumorsphere formation, migration, and clonogenicity of PCSCs, as well as hypo-glycosylated CD44v6 and ESA. Of note, glycosyltransferases (GFs), GALNT3 and B3GNT3, were significantly overexpressed in PCSCs and co expressed with CD44v6 at advanced PDAC stages in KC and KPC tumors. Further, GALNT3 and B3GNT3 knockdown led to a decrease in the expression of cell surface markers (CD44v6 and ESA) and self-renewal markers (SOX2 and OCT3/4) in PCSCs. Interestingly, CD44v6 was modified with sialyl Lewis a in PCSCs. Finally, CRISPR/Cas9-mediated GALNT3 KO significantly decreased self-renewal, clonogenicity, and migratory capacity in PCSCs. CONCLUSIONS: Taken together, for the first time, our study showed the importance of glycosylation in mediating growth, stemness, and maintenance of PCSCs. These results indicate that elevated GALNT3 and B3GNT3 expression in PCSCs regulate stemness through modulating CSC markers. PMID- 30466405 TI - RNA-based analysis of ALK fusions in non-small cell lung cancer cases showing IHC/FISH discordance. AB - BACKGROUND: Rearrangements of the anaplastic lymphoma kinase (ALK) belong to the promising targets in the therapy of advanced non-small cell lung cancer (NSCLC) and are predominantly detected by immunohistochemistry (IHC) and/or fluorescence in-situ hybridization (FISH). However, both methods occasionally produce discordant results, especially in so-called borderline (BL) cases, showing ALK FISH-positive signals in 10-20% of the tumor nuclei around the cutoff (15%). This leads to a diagnostic and thus to a therapeutic dilemma. METHODS: We selected 18 unequivocal (12 ALK IHC/FISH-negative; 6 ALK IHC/FISH-positive) and 15 equivocal samples with discordant results between FISH (Abbott, Vysis LSI ALK Dual Color) and IHC (Ventana, D5F3), including cases with FISH-BL results, for further RNA based-analysis. To detect ALK rearrangement at the transcriptional level, RNA was analyzed using a targeted multiplex-PCR panel followed by IonTorrent sequencing and by direct transcript counting using a digital probe-based assay (NanoString). Sensitivity of both methods was defined using RNA obtained from an ALK-positive cell line dilution series. RESULTS: Cases with unequivocal IHC/FISH results showed concordant data with both RNA-based methods, whereas the three IHC negative/FISH-positive samples were negative. The four IHC-negative/FISH-BL negative cases, as well as the five IHC-negative/FISH-BL-positive samples showed negative results by massive parallel sequencing (MPS) and digital probe-based assay. The two IHC-positive/FISH-BL-positive cases were both positive on the RNA level, whereas a tumor with questionable IHC and FISH-BL-positive status displayed no ALK fusion transcript. CONCLUSIONS: The comparison of methods for the confirmation of ALK rearrangements revealed that the detection of ALK protein by IHC and ALK fusion transcripts on transcriptional level by MPS and the probe based assay leads to concordant results. Only a small proportion of clearly ALK FISH-positive cases are unable to express the ALK protein and ALK fusion transcript which might explain a non-responding to ALK inhibitors. Therefore, our findings led us to conclude that ALK testing should initially be based on IHC and/or RNA-based methods. PMID- 30466406 TI - A systematic review of non-standard dosing of oral anticancer therapies. AB - BACKGROUND: The use of oral systemic anticancer therapies (SACT) has increased and led to improved cancer survival outcomes, particularly with the introduction of small molecule targeted agents and immunomodulators. Oral targeted SACT are, however, associated with toxicities, which might result in reduced quality of life and non-adherence. To reduce treatment-related toxicity, the practice of non standard dosing is increasing; however guidance to govern this practice is limited. A systematic review was conducted to identify evidence of, and outcomes from, non-standard dosing of oral SACT in oncology and malignant haematology. METHODS: A comprehensive search of 78 oral SACT was conducted in the following databases: MEDLINE(r), EMBASE(r), Cochrane Library(c), and Cumulative Index to Nursing and Allied Health Literature (CINAHL(c)). Studies were selected based on predefined inclusion/exclusion criteria, and were critically appraised. Extracted data were tabulated to summarise key findings. Due to diversity of study designs and heterogeneity of reported outcomes, studies were categorised and evidence was synthesised in three main themes: dose interruption; dose reduction; and other dosing strategies. RESULTS: Thirty-four studies were eligible for inclusion: four clinical trials, fifteen cohort studies and fifteen case reports. Evidence for non-standard dosing was reported for eleven oral SACT. Dose interruptions were the most commonly reported strategy (14 studies); nine studies reported dose reductions; and eleven reported other dosing strategies. Eight retrospective cohort studies reported dose interruption of sunitinib in renal cell carcinoma and showed either similar or improved responses and survival outcomes, and fewer or equivalent high grade toxicities, compared to the standard schedule. Four cohort studies retrospectively evaluated dose reductions of imatinib, gefitinib or erlotinib, for chronic myeloid leukaemia and non-small cell lung cancer, respectively. Other dosing strategies included alternate-day dosing. The quality of the evidence was limited by the small sample size in many studies, retrospective study designs, and lack of reported toxicity and/or QoL outcomes. CONCLUSIONS: This review identified limited evidence to support current non standard dosing strategies, but some of findings, e.g. dose interruption of sunitinib, warrant further investigation in large-scale prospective clinical trials. PMID- 30466407 TI - Differential distribution of IgA-protease genotypes in mucosal and invasive isolates of Haemophilus influenzae in Sweden. AB - BACKGROUND: Several different IgA-proteases exist in Haemophilus influenzae. The variants have been suggested to play differential roles in pathogenesis, but there is limited information on their distribution in clinical isolates. The objective of this study was to investigate the distribution of IgA-protease genotypes in H. influenzae and assess the association between IgA-protease genotype and type of clinical infection. METHODS: We performed PCR-screening of the IgA-protease gene variants in two cohorts of clinical H. influenzae. The first cohort consisted of 177 isolates from individuals with respiratory tract infection in January 2010, 2011 and 2012. Information on age, gender and clinical infection was available in this cohort. The second cohort comprised 53 isolates, including NTHi from bloodstream, cerebrospinal fluid (CSF) and urogenital origin as well as encapsulated isolates respresenting all capsule types. We assessed associations between IgA protease genotype and clinical predictors using basic statistical tests of association as well as regression analysis. RESULTS: The igaB gene was found in 46% of isolates in the respiratory tract cohort, and no evident trend could be seen during the study years. However, the igaB gene was significantly less common among invasive isolates (19%), p = 0.003 (Fischer's exact test), even when encapsulated isolates were excluded (21%), p = 0.012. A significantly negative association between bacteraemia and igaB genotype remained after adjusting for covariates. We did not identify a significant association between IgA-protease gene variants and type of respiratory tract infection, but isolates with an igaA2 genotype were overrepresented in pre-school children. CONCLUSIONS: The distribution of IgA-protease gene variants in Swedish H. influenzae highlighted the widespread abundance of the igaB in isolates from cases of respiratory tract infection, but the igaB gene variant was significantly less common in invasive (bloodstream and CSF) isolates of H. influenzae compared with respiratory tract isolates. PMID- 30466409 TI - EpiViewer: an epidemiological application for exploring time series data. AB - BACKGROUND: Visualization plays an important role in epidemic time series analysis and forecasting. Viewing time series data plotted on a graph can help researchers identify anomalies and unexpected trends that could be overlooked if the data were reviewed in tabular form; these details can influence a researcher's recommended course of action or choice of simulation models. However, there are challenges in reviewing data sets from multiple data sources - data can be aggregated in different ways (e.g., incidence vs. cumulative), measure different criteria (e.g., infection counts, hospitalizations, and deaths), or represent different geographical scales (e.g., nation, HHS Regions, or states), which can make a direct comparison between time series difficult. In the face of an emerging epidemic, the ability to visualize time series from various sources and organizations and to reconcile these datasets based on different criteria could be key in developing accurate forecasts and identifying effective interventions. Many tools have been developed for visualizing temporal data; however, none yet supports all the functionality needed for easy collaborative visualization and analysis of epidemic data. RESULTS: In this paper, we present EpiViewer, a time series exploration dashboard where users can upload epidemiological time series data from a variety of sources and compare, organize, and track how data evolves as an epidemic progresses. EpiViewer provides an easy-to-use web interface for visualizing temporal datasets either as line charts or bar charts. The application provides enhanced features for visual analysis, such as hierarchical categorization, zooming, and filtering, to enable detailed inspection and comparison of multiple time series on a single canvas. Finally, EpiViewer provides several built-in statistical Epi-features to help users interpret the epidemiological curves. CONCLUSION: EpiViewer is a single page web application that provides a framework for exploring, comparing, and organizing temporal datasets. It offers a variety of features for convenient filtering and analysis of epicurves based on meta-attribute tagging. EpiViewer also provides a platform for sharing data between groups for better comparison and analysis. Our user study demonstrated that EpiViewer is easy to use and fills a particular niche in the toolspace for visualization and exploration of epidemiological data. PMID- 30466408 TI - Health-related quality of life in long-term survivors of colorectal cancer and its association with all-cause mortality: a German cohort study. AB - BACKGROUND: The group of colorectal cancer (CRC) survivors continues to grow worldwide. Understanding health-related quality of life (HRQOL) determinants and consequences of HRQOL impairments in long-term CRC survivors may help to individualize survivorship care plans. We aimed to i) examine the HRQOL status of CRC long-term survivors, ii) identify cross-sectional sociodemographic and clinical correlates of HRQOL, and iii) investigate the prospective association of HRQOL after CRC diagnosis with all-cause mortality. METHODS: We assessed HRQOL within a Northern German cohort of 1294 CRC survivors at a median of 6 years after CRC diagnosis using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Cross-sectional correlates of different HRQOL dimensions were analyzed using multivariable adjusted logistic regression models with HRQOL as a binary variable. With multivariable-adjusted Cox proportional hazards regression models, hazard ratios (HR) of all-cause mortality were estimated per 10-point-increments of an HRQOL summary score, a global quality of life scale, and HRQOL functioning and symptom domains. RESULTS: The median HRQOL summary score was 87 (interquartile range: 75 94). Sex, age, education, tumor location, metastases, other cancers, type of therapy, and current stoma were identified as correlates of different HRQOL scales. After a median follow-up time of 7 years after HRQOL assessment, 175 participants had died. Nearly all HRQOL domains, except for cognitive functioning and diarrhea, were significantly associated with all-cause mortality. A 10-point increment in the summary score decreased the risk of death by 24% (HR: 0.76; 95% CI: 0.70-0.82). CONCLUSIONS: HRQOL in CRC survivors appeared to be relatively high in the long term. Various clinical and sociodemographic factors were cross sectionally associated with HRQOL in long-term CRC survivors. Lower HRQOL was associated with increased all-cause mortality. Individualized healthcare programs for CRC survivors (including psychosocial screening and interventions) are needed to detect decreased HRQOL and to further improve long-term HRQOL and survival. PMID- 30466410 TI - Long-term efficacy of crizotinib in a metastatic papillary renal carcinoma with MET amplification: a case report and literature review. AB - BACKGROUND: Papillary renal cell carcinoma (pRCC) is the 2nd most frequent histological type of kidney cancer and accounts for approximately 15% of all renal cell carcinoma. It has a poorer prognosis than clear cell RCC (ccRCC) with a lack of standard treatments. CASE PRESENTATION: We report the case of a 51 year old man with a metastatic pRCC (hepatic dome and left colonic peritoneal carcinomatosis) progressive after sunitinib, with a MET amplification. The patient was enrolled in the UNICANCER-sponsored AcSe crizotinib trial (NCT02034981), designed to give an access to crizotinib for patients with tumors harboring a genomic alteration on one of the biological targets of the drug. With 2nd line crizotinib (250 mg twice/day), the patient had a very good tolerance, a partial response in the target lesions using RECIST 1.1, and a 19 months' clinical efficacy. CONCLUSIONS: In metastatic pRCC with a MET amplification, crizotinib maybe a potential met-inhibitory therapeutic option. PMID- 30466411 TI - Correction to: Supporting Aboriginal and Torres Strait islander cultural educators and cultural mentors in Australian general practice education. AB - Following publication of the original article [1], the author reported that Fig. 1 was missing. PMID- 30466412 TI - Retained gastric band port and tube 5 years after gastric band removal and laparoscopic Roux-en-Y gastric bypass: a case report. AB - BACKGROUND: While LAGB has become uncommon in the bariatric surgery practice, band removal with or without revision surgery is still common. Retained postoperative foreign body, of which surgical sponges are the most common, is a rare condition. We report a rare case of retained gastric band port and the attached tube. CASE PRESENTATION: A 31-year-old Caucasian female presented to the outpatient clinic, 5 years after her last surgery, complaining of a left upper quadrant abdominal mass over the last 2 years. She had a history of 2 weight loss operations. She had no significant family history nor smoking. CT of the abdomen and pelvis revealed a retained foreign body. On exploration, the port with 10 cm of the connected tube was found and removed through a small incision without laparotomy. The patient made an uneventful recovery. CONCLUSION: A bariatric surgeon should be involved in the evaluation of any patient who complains of abdominal pain and/or palpable mass if she/he has a previous weight loss procedure because the bariatric surgeon is fully aware of the possible complications of the bariatric surgeries. PMID- 30466413 TI - Efficacy of hearing conservation education programs for youth and young adults: a systematic review. AB - BACKGROUND: Many youth and young adults experience high noise exposure compounded by lack of access to hearing health education. Although the need for hearing health education programs is evident, the efficacy of these programs for youth is unclear. We evaluated the literature for efficacy of various hearing conservation programs aimed at youth and young adults, and analyzed their strengths and limitations. METHODS: Studies reporting results of hearing conservation or hearing loss prevention programs with youth or young adults, using randomized controlled trials, quasi-experimental designs, experimental design, or qualitative research, and published in peer-reviewed journals in English between 2001 and 2018 were included. Studies were found through searches of selected literature databases (i.e., PubMed, Google Scholar, NIOSH Toxline, and Scopus). Identified publications were assessed for relevance, and data were extracted from the studies deemed relevant. RESULTS: A total of 10 studies were included. Very little evidence of efficacy of hearing conservation educational programs was found in these studies. Several methodological limitations including lack of rigorous study designs, inadequate power, and application of inappropriate statistical analysis were noted. Some use of technology in programs (e.g., smartphone apps, mobile phone text messages, and computers) was observed, but conclusions as to the effectiveness of these tools were limited by the small number of studies and small sample sizes. CONCLUSIONS: The number of studies of educational hearing conservation programs for youth and young adults was low. The efficacy of the program was not reported in most studies, and it is difficult to draw public health conclusions from these studies due to their multiple methodological limitations. While use of technology in hearing conservation educational programs offers promise, its effectiveness has not been studied. PMID- 30466414 TI - Stroke units, certification, and outcomes in German hospitals: a longitudinal study of patient-based 30-day mortality for 2006-2014. AB - BACKGROUND: Treatment of stroke patients in stroke units has increased and studies have shown improved outcomes. However, a large share of patients in Germany is still treated in hospitals without stroke unit. The effects of stroke unit service line, and total hospital quality certification on outcomes remain unclear. METHODS: We employ annual hospital panel data for 1100-1300 German hospitals from 2006 to 2014, which includes structural data and 30-day standardized mortality. We estimate hospital- and time-fixed effects regressions with three main independent variables: (1) stroke unit care, (2) stroke unit certification, and (3) total hospital quality certification. RESULTS: Our results confirm the trend of decreasing stroke mortality ratios, although to a much lesser degree than previous studies. Descriptive analysis illustrates better stroke outcomes for non-certified and certified stroke units and hospitals with total hospital quality certification. In a fixed effects model, having a stroke unit has a significant quality-enhancing effect, lowering stroke mortality by 5.6%, while there is no significant improvement effect for stroke unit certification or total hospital quality certification. CONCLUSIONS: Patients and health systems may benefit substantially from stroke unit treatment expansion as installing a stroke unit appears more meaningful than getting it certified or obtaining a total hospital quality certification. Health systems should thus prioritize investment in stroke unit infrastructure and centralize stroke care in stroke units. They should also prioritize patient-based 30-day mortality data as it allows a more realistic representation of mortality than admission-based data. PMID- 30466415 TI - Navigating conflict and difference in medical education: insights from moral psychology. AB - Medical students and educators face a myriad of complex moral disagreements and conflicts both in preclinical and clinical training environments. Inability to deal with these conflicts effectively and compassionately can lead to undesirable consequences and threaten important relationships in high-stakes healthcare environments. We suggest that the integration of moral psychology into medical education can help trainees and faculty constructively respond to behavior they may find immoral or misguided. Here we focus on the application of Moral Foundations Theory (MFT), which demonstrates how the instantaneous gut reactions which guide reactionary behavior can be categorized into six foundational categories. These categories offer psychological explanations for human behavior which can help medical trainees and professionals navigate challenging moral conflicts. PMID- 30466416 TI - Prevalence of drug-drug interactions in oncology patients enrolled on National Clinical Trials Network oncology clinical trials. AB - BACKGROUND: Drug-drug interactions (DDIs) in subjects enrolling in clinical trials can impact not only safety of the patient but also study drug outcomes and data validity. This makes it critical to adequately screen and manage DDIs. The study objective was to determine the prevalence of DDIs involving study medications in subjects enrolling in National Clinical Trials Network (NCTN) clinical trials at a single institution. DDIs were evaluated based on study protocol recommendations for concomitant medication use (i.e. exclude, avoid or use caution), screening via DDI tool, and pharmacist review. METHODS: Subjects enrolled in NCTN trials of commercially available agents between January 2013 and August 2017 were included if a complete medication list was available. Complete medication lists were collected from the date of enrollment or the next available date then screened utilizing protocol guidance and the DDI screening tool, Lexicomp(r) Drug Interactions (Wolters Kluwer, Hudson, OH). Interactions were reviewed for clinical relevance: defined as a DDI that would require a medication change to ensure study agent safety and efficacy at enrollment. RESULTS: One hundred and twenty-eight subjects enrolled in 35 clinical trials were included. Protocol guidance detected 15 unique DDI pairs that should be avoided or used with caution in 10.2% (13/128) of subjects. The majority of these subjects did not have a clinically relevant DDI (69.2%, 9/13) based on pharmacist review. Lexicomp(r) detected moderate to major DDIs in 24.2% (31/128) of subjects, with 9.4% (12/128) having a clinically relevant DDI. CONCLUSIONS: This study confirms a high prevalence of DDIs present in subjects enrolling in oncology clinical trials. Further efforts should be made to improve methods to detect and manage DDIs in patients enrolling on clinical trials to ensure patient safety and trial data validity. PMID- 30466418 TI - A rodent model of anterior ischemic optic neuropathy (AION) based on laser photoactivation of verteporfin. AB - BACKGROUND: A rodent model of photodynamic AION resulting from intravenous verteporfin is presented. The analysis of the morphological function, the pathological changes and the potential mechanism of action were further investigated. METHODS: Photodynamic treatment was conducted on the optic nerve head (ONH) following administration of the photosensitizer. The fellow eye was considered as sham control. Fundus Fluorescein angiography (FFA), spectral domain optical coherence tomography (SD-OCT) and Flash-visual evoked potential (F-VEP) recordings were conducted at different time points. Immunohistochemistry was used to observe apoptotic cell death (TUNEL) and macrophage infiltration (ED-1/Iba-1). Retrograde labeling of retinal ganglion cells (RGCs) was used to evaluate the loss of RGCs. RESULTS: After laser treatment, SD-OCT indicated optic nerve edema, while FFA indicated late leakage of the ONH. F-VEPs were distinctly reduced compared to control eyes. The number of apoptotic RGCs peaked on day 14 (5.71 +/- 0.76, p < 0.01). The infiltration of ED-1 and Iba-1 increased on the 3rd day following PDT, while it peaked on day 14 (67.5 +/- 9.57 and 77.5 +/- 12.58 respectively, p < 0.01). Following 3 weeks of AION, the densities of RGCs in the central retinas of the normal and AION eyes were 3075 +/- 298/mm2 and 2078 +/- 141/mm2 (p < 0.01), respectively. CONCLUSIONS: Verteporfin photodynamic treatment on rodents ONH can lead to functional, histological, and pathological changes. This type of animal model of AION is easy to establish and stable. It can be used for studying the mechanism and neuroprotective medicine of AION injury. PMID- 30466417 TI - Healthcare utilization and cost trajectories post-stroke: role of caregiver and stroke factors. AB - BACKGROUND: It is essential to study post-stroke healthcare utilization trajectories from a stroke patient caregiver dyadic perspective to improve healthcare delivery, practices and eventually improve long-term outcomes for stroke patients. However, literature addressing this area is currently limited. Addressing this gap, our study described the trajectory of healthcare service utilization by stroke patients and associated costs over 1-year post-stroke and examined the association with caregiver identity and clinical stroke factors. METHODS: Patient and caregiver variables were obtained from a prospective cohort, while healthcare data was obtained from the national claims database. Generalized estimating equation approach was used to get the population average estimates of healthcare utilization and cost trend across 4 quarters post-stroke. RESULTS: Five hundred ninety-two stroke patient and caregiver dyads were available for current analysis. The highest utilization occurred in the first quarter post stroke across all service types and decreased with time. The incidence rate ratio (IRR) of hospitalization decreased by 51, 40, 11 and 1% for patients having spouse, sibling, child and others as caregivers respectively when compared with not having a caregiver (p = 0.017). Disability level modified the specialist outpatient clinic usage trajectory with increasing difference between mildly and severely disabled sub-groups across quarters. Stroke type and severity modified the primary care cost trajectory with expected cost estimates differing across second to fourth quarters for moderately-severe ischemic (IRR: 1.67, 1.74, 1.64; p = 0.003), moderately-severe non-ischemic (IRR: 1.61, 3.15, 2.44; p = 0.001) and severe non-ischemic (IRR: 2.18, 4.92, 4.77; p = 0.032) subgroups respectively, compared to first quarter. CONCLUSION: Highlighting the quarterly variations, we reported distinct utilization trajectories across subgroups based on clinical characteristics. Caregiver availability reducing hospitalization supports revisiting caregiver's role as potential hidden workforce, incentivizing their efforts by designing socially inclusive bundled payment models for post-acute stroke care and adopting family-centered clinical care practices. PMID- 30466419 TI - Prevalence and factors associated with modern contraceptive discontinuation among reproductive age group women, a community based cross-sectional study in Humera town, northern Ethiopia. AB - BACKGROUND: Contraceptive prevalence rate (CPR) for married women aged 15-49 in Ethiopia is 36%, with 35% using modern methods and 1% using traditional methods. However, the discontinuation rate is fairly high. Women usually discontinue contraception use for fertility and method related reasons without adopting an alternate method which in turn leads to many health risks such as unwanted pregnancy, unplanned childbearing, miscarriage, abortion, leads to morbidity and mortality among mothers and newborns. The purpose of this study was to determine the prevalence of modern contraceptive discontinuation and to identify predicting factors. METHODS: A community- based cross- sectional study was conducted in Humera town among 321 married women of reproductive age (15-49 yrs.) who had a history of modern contraceptive use. Systematic sampling technique was employed to select study participants and data was collected by BSc health extension workers using interviewer -administered questionnaire. EPI-INFO (V-7) and SPSS (V 23) software were used for entry and analysis respectively. Descriptive statistics and logistic regression analysis were used to present results accordingly. P- Value < 0.05 was used as a cut point for statistical significance. RESULTS: The magnitude of modern contraceptive discontinuation was 27.1%. Number of desired children (AOR = 2.83 95% CI = 1.16, 6.89), experience of side effects (AOR = 3 95% CI = 1.2, 7.58), discussion with female friend (AOR = 3.26 95% CI = 1.27, 8.36), counseled on side effects (AOR = 6.55 95% CI = 2.21, 19.39), number of male children (AOR = 2.51 95% CI = 1.06, 5.96), absence of husband support (AOR = 12.99 95% CI = 4.59, 36.78) and presence of community prohibition (AOR = 6.88 95% CI = 3.05, 15.51) were identified as predicting factors for modern contraceptive discontinuation. CONCLUSION: Magnitude of modern contraceptive discontinuation among reproductive age group women in Humera was relatively high. Increasing community awareness, involving partners and pre dispensation counseling might help to reduce discontinuation and its consequences. Various targeted messages are also needed to dispel misconception at community level. PMID- 30466420 TI - Suitability of nutrients removal from brewery wastewater using a hydroponic technology with Typha latifolia. AB - BACKGROUND: This study aims to assess suitability of hydroponic technology for treatment of brewery wastewater in a hydroponic bioreactor using Typha latifolia. Triplicated hydroponic bioreactor treatment units were designed, constructed and operated at a hydraulic retention time of 5 days with different surface loadings and mean hydraulic loading rate 0.023 m3 m-2d- 1. Young T. latifolia shoots were collected in the vicinity of study site. Wastewater characteristics, plant growth and nutrient accumulation during experiment were analyzed as per APHA standard methods and nutrient removal efficiency was evaluated based on inlet and outlet values. RESULTS: T. latifolia established and grew well in the hydroponics under fluctuations of wastewater loads and showed a good phytoremedial capacity to remove nutrients. Significant removal efficiencies (p < 0.05) varied between 54 and 80% for Total Kjeldahl Nitrogen, 42 and 65% for NH4+ -N, 47 and 58% for NO3- N, and 51 and 70% for PO43--P. The system improved the removal up to 29% compared to control and produced biomass of 0.61-0.86 kg dry weight (DW) m- 2. Nutrients retained were up to 21.17 g N kg- 1 DW and 2.87 g P kg- 1 DW. CONCLUSION: The significant nutrients reduction obtained and production of biomass led us to conclude that hydroponics technology using T. latifolia has suitability potential for treatment of brewery wastewater and similar agro-industrial wastewaters. Thus it could be considered as a promising eco-friendly option for wastewater treatment to mitigate water pollution. Integration of treatment and production of biomass needs further improvement. PMID- 30466421 TI - Optimal cut-off for obesity and markers of metabolic syndrome for Ethiopian adults. AB - BACKGROUND: Metabolic syndrome (MetS) is defined as the presence of central obesity plus any two of the following markers: high triglycerides (> 150 mg/dl), low high density lipoprotein (HDL) cholesterol < 40 mg/dl in men and < 50 mg/dl in women, hypertension (blood pressure > 130/85 mmHg or use of antihypertensive medication), high fasting blood glucose (> 100 mg/dl or use of treatment for diabetes mellitus). Since recently, metabolic syndrome and obesity have become emerging problems of both low and middle income countries, although they have been the leading cause of morbidity and mortality in high income countries for the past decades. It has been indicated that the international anthropometric cut off for detecting obesity is not appropriate for Ethiopians. This study developed optimal cut off values for anthropometric indicators of obesity and markers of metabolic syndrome for Ethiopian adults to enhance preventive interventions. METHODS: A total of 704 employees of Jimma University were randomly selected using their payroll as a sampling frame. Data on socio-demographic, anthropometry, clinical and blood samples were collected from February to April 2015. Receiver Operating Characteristic Curve analyses were used to determine optimal anthropometric cut-off values for obesity and markers of the metabolic syndrome. WHO indicators of obesity based on body fat percent (> 25% for males and > 35% for females) were used as binary classifiers for developing anthropometric cut-offs. Optimal cut-off values were presented using sensitivity, specificity and area under the curve. RESULTS: The optimal cut-off for obesity using body mass index was 22.2 k/m2 for males and 24.5 kg/m2 for females. Similarly, the optimal waist circumference cut-off for obesity was 83.7 cm for males and 78.0 cm for females. The cut-off values for detecting obesity using waist to hip ratio and waist to height ratio were: WHR (0.88) and WHtR (0.49) for males, while they were 0.82 and 0.50 for females, respectively. Anthropometric cut-off values for markers of metabolic syndrome were lower compared to the international values. For females, the optimal BMI cut-offs for metabolic syndrome markers ranged from 24.8 kg/m2 (triglycerides) to 26.8 kg/m2 (fasting blood sugar). For WC the optimal cut-off ranged from of 82.1 cm (triglyceride) to 96.0 cm(HDL); while for WHtR the optimal values varied from 0.47(HDL) to 0.56(fasting blood sugar). Likewise, the optimal cut-offs of WHR for markers of metabolic syndrome ranged from 0.78(fasting blood sugar) to 0.89(HDL and blood pressure). For males, the optimal BMI cut-offs for metabolic syndrome markers ranged from 21.0 kg/m2 (HDL) to 23.5 kg/m2 (blood pressure). For WC, the optimal cut-off ranged from 85.3 cm (triglyceride) to 96.0 cm(fasting blood sugar); while for WHtR the optimal values varied from 0.47(BP, FBS and HDL) to 0.53(Triglyceride). Similarly, the optimal cut-offs of WHR form markers of metabolic syndrome ranged from 0.86(blood pressure) to 0.95(fasting blood sugar). CONCLUSION: The optimal anthropometric cut-offs for obesity and markers of metabolic syndrome in Ethiopian adults are lower than the international values. The findings imply that the international cut-off for WC, WHtR, WHR and BMI underestimate obesity and metabolic syndrome markers among Ethiopian adults, which should be considered in developing intervention strategies. It is recommended to use the new cut-offs for public health interventions to curb the increasing magnitude of obesity and associated metabolic syndrome and diet related non-communicable diseases in Ethiopia. PMID- 30466422 TI - Operationalizing the 'pragmatic' measures construct using a stakeholder feedback and a multi-method approach. AB - CONTEXT: Implementation science measures are rarely used by stakeholders to inform and enhance clinical program change. Little is known about what makes implementation measures pragmatic (i.e., practical) for use in community settings; thus, the present study's objective was to generate a clinical stakeholder-driven operationalization of a pragmatic measures construct. EVIDENCE ACQUISITION: The pragmatic measures construct was defined using: 1) a systematic literature review to identify dimensions of the construct using PsycINFO and PubMed databases, and 2) interviews with an international stakeholder panel (N = 7) who were asked about their perspectives of pragmatic measures. EVIDENCE SYNTHESIS: Combined results from the systematic literature review and stakeholder interviews revealed a final list of 47 short statements (e.g., feasible, low cost, brief) describing pragmatic measures, which will allow for the development of a rigorous, stakeholder-driven conceptualization of the pragmatic measures construct. CONCLUSIONS: Results revealed significant overlap between terms related to the pragmatic construct in the existing literature and stakeholder interviews. However, a number of terms were unique to each methodology. This underscores the importance of understanding stakeholder perspectives of criteria measuring the pragmatic construct. These results will be used to inform future phases of the project where stakeholders will determine the relative importance and clarity of each dimension of the pragmatic construct, as well as their priorities for the pragmatic dimensions. Taken together, these results will be incorporated into a pragmatic rating system for existing implementation science measures to support implementation science and practice. PMID- 30466423 TI - Inflammation and lung injury in an ovine model of fluid resuscitated endotoxemic shock. AB - BACKGROUND: Sepsis is a multi-system syndrome that remains the leading cause of mortality and critical illness worldwide, with hemodynamic support being one of the cornerstones of the acute management of sepsis. We used an ovine model of endotoxemic shock to determine if 0.9% saline resuscitation contributes to lung inflammation and injury in acute respiratory distress syndrome, which is a common complication of sepsis, and investigated the potential role of matrix metalloproteinases in this process. METHODS: Endotoxemic shock was induced in sheep by administration of an escalating dose of lipopolysaccharide, after which they subsequently received either no fluid bolus resuscitation or a 0.9% saline bolus. Lung tissue, bronchoalveolar fluid (BAL) and plasma were analysed by real time PCR, ELISA, flow cytometry and immunohistochemical staining to assess inflammatory cells, cytokines, hyaluronan and matrix metalloproteinases. RESULTS: Endotoxemia was associated with decreased serum albumin and total protein levels, with activated neutrophils, while the glycocalyx glycosaminoglycan hyaluronan was significantly increased in BAL. Quantitative real-time PCR studies showed higher expression of IL-6 and IL-8 with saline resuscitation but no difference in matrix metalloproteinase expression. BAL and tissue homogenate levels of IL-6, IL-8 and IL-1beta were elevated. CONCLUSIONS: This data shows that the inflammatory response is enhanced when a host with endotoxemia is resuscitated with saline, with a comparatively higher release of inflammatory cytokines and endothelial/glycocalyx damage, but no change in matrix metalloproteinase levels. PMID- 30466424 TI - Polyhedrocytes in blood clots of type 2 diabetic patients with high cardiovascular risk: association with glycemia, oxidative stress and platelet activation. AB - BACKGROUND: Little is known about factors that affect the composition of contracted blood clots in specific diseases. We investigated the content of polyhedral erythrocytes (polyhedrocytes) formed in blood clots and its determinants in type 2 diabetes (T2D) patients. METHODS: In 97 patients with long standing T2D [median HbA1c, 6.4% (interquartile range 5.9-7.8)], we measured in vitro the composition of blood clots, including a clot area covered by polyhedrocytes using scanning electron microscopy and the erythrocyte compression index (ECI), defined as a ratio of the mean polyhedrocyte area to the mean native erythrocyte area. Moreover, plasma fibrin clot permeability (Ks), clot lysis time (CLT), thrombin generation, oxidative stress [total protein carbonyl (total PC), total antioxidant capacity and thiobarbituric acid reactive substances (TBARS)], and platelet activation markers were determined. The impact of glucose concentration on polyhedrocytes formation was assessed in vitro. RESULTS: Polyhedrocytes content in contracted clots was positively correlated with glucose (r = 0.24, p = 0.028), glycated hemoglobin (r = 0.40, p = 0.024), total cholesterol (r = 0.22, p = 0.044), TBARS (r = 0.60, p = 0.0027), P-selectin (r = 0.54, p = 0.0078) and platelet factor-4, PF4 (r = 0.59, p = 0.0032), but not with thrombin generation, platelet count, Ks or CLT. Patients who formed more polyhedrocytes (>= 10th percentile) (n = 83, 85.6%) had higher glucose (+ 15.7%, p = 0.018), fibrinogen (+ 16.6%, p = 0.004), lower red blood cell distribution width (RDW, - 8.8%, p = 0.034), reduced plasma clot density (- 21.8% Ks, p = 0.011) and impaired fibrinolysis (+ 6.5% CLT, p = 0.037) when compared to patients with lesser amount of polyhedrocytes (< 10th percentile). ECI and the content of polyhedrocytes were strongly associated with total PC (r = 0.79, p = 0.036 and r = 0.67, p = 0.0004, respectively). In vitro an increase of glucose concentration by 10 mmol/L was associated with 94% higher polyhedrocytes content (p = 0.033) when compared to the baseline (7.1 mM). After adjustment for age, sex and fibrinogen, multiple regression analysis showed that RDW was the only independent predictor of polyhedrocytes content in T2D (OR = 0.61, 95% CI 0.39 0.92). CONCLUSIONS: Poor glycemic control, together with enhanced platelet activation and oxidative stress, increase the content of polyhedrocytes in blood clots generated in T2D patients. PMID- 30466425 TI - HIV diagnosis disclosure to infected children and adolescents; challenges of family caregivers in the Central Region of Ghana. AB - BACKGROUND: Disclosure of Human Immunodeficiency Virus (HIV) to infected older children and adolescents is essential for both personal health maintenance and HIV prevention within the larger population. Non-disclosure of HIV status has been identified as one of the potential barriers to optimum adherence especially in children and adolescents. Like many other countries in the SSA region, Ghana has significant number of children and adolescents infected by HIV, who have increased survival times, due to increased access to ART. However, both family caregivers and healthcare workers face an array of challenges with the disclosure process, including the timing, what information about the child's HIV status should be shared with him/her and how to go about it. The aim of the study was to identify family caregiver factors associated with non-disclosure of HIV status to infected children and adolescents accessing Antiretroviral Therapy (ART) at the three main ART sites within the Central Region of Ghana. METHODS: A quantitative analytical survey was conducted among 103 family caregivers of HIV infected children (aged 6-17 years) assessing ART services in the Central Region of Ghana. Data were analyzed using SSPS version 21. RESULTS: The age range of caregivers was 20-69 years. The study found a low disclosure rate (23.3%) among caregivers. Majority of the caregivers (80.6%) lacked knowledge on the process of disclosure (how and what to tell child), and majority (64%) also had never received guidance about the disclosure process from their healthcare providers. The main barriers to disclosure were caregiver lack of knowledge regarding the disclosure process and when to disclose, the fear of child's reaction, and fear of stigmatization and associated negative social consequences. CONCLUSION: These findings suggest a lesser involvement of health care providers in preparing caregivers for the disclosure process. This therefore highlight the need for the National HIV/AIDS/STI Control Program to strengthen the involvement and training of healthcare providers in HIV diagnosis disclosure to infected children, based on context-specific policy guidelines informed by the WHO recommendations. PMID- 30466426 TI - Quality of perinatal depression care in primary care setting in Nigeria. AB - BACKGROUND: Even though integrating mental health into maternal and child health (MCH) is widely accepted as a means of closing the treatment gap for maternal mental health conditions in low- and middle-income countries (LMIC), there are not many studies on the quality of the currently available mental health care for mothers in these countries. This study assessed the existing organization of service for maternal mental health, the actual care delivered for perinatal depression, as well as the quality of the care received by affected women presenting to primary care clinics in Ibadan, Nigeria. METHODS: The Assessment of Chronic Illness Care (ACIC) tool was administered to the staff in 23 primary maternal care clinics and key informant interviews were conducted with 20 facility managers to explore organizational and administrative features relevant to the delivery of maternal mental health care in the facilities. Detection rate of perinatal depression by maternal care providers was assessed by determining the proportion of depressed antenatal women identified by the providers. The women were then followed up from the antenatal period up until 6 months after childbirth to track their experience with care received. RESULTS: All the facilities had ACIC domain scores indicating poor capacity to offer quality chronic care. Emerging themes from the interviews included severe manpower shortage and absence of administrative and clinical support for manpower training and care provision. Only 31 of the 218 depressed women had been identified by the maternal care providers as having a psychological problem throughout the follow up period. In spite of the objective evidence of inadequate care, most of the perinatal women rated the service provided in the facilities as being of good quality (96%) and reported being satisfied with the care received (98%). CONCLUSION: There are major inadequacies in the organisational and administrative profile of these primary maternal care facilities that militate against the provision of quality chronic care. These inadequacies translate to a large treatment gap for women with perinatal depression. Lack of awareness by service users of what constitutes good quality care, indicative of low service expectation, may hamper user-driven demand for quality improvement. PMID- 30466427 TI - Measuring medical students' reflection on their learning: modification and validation of the motivated strategies for learning questionnaire (MSLQ). AB - BACKGROUND: Reflection on learning is an essential component of effective learning. Deconstructing the components of reflection on learning using a self regulated learning (SRL) framework, allows the assessment of students' ability to reflect on their learning. The aim of this study was to validate an instrument to measure medical students' reflection on their learning. METHODS: A systematic search was conducted to identify the most suitable instrument to measure students' reflection on their learning based on the theoretical framework of SRL. The search identified the Motivated Strategies for Learning Questionnaire (MSLQ) which contained five subscales: internal goal orientation, self-efficacy, critical thinking, metacognitive/self-regulation, help seeking and peer learning. Using the original MSLQ as the foundation, we carried out three phases of a research program to develop a useful set of items: an expert panel's review of items, a substantial pilot study, and a factor analysis of ratings of a modified set of items by preclinical and final year medical students. RESULTS: The factor analysis of the Modified MSLQ extracted four subscales with reasonable internal consistency: self-orientation, critical thinking, self-regulation and feedback seeking. Each subscale correlates highly with the Modified MSLQ score, with modest inter-correlations between the subscales suggesting that they are measuring different components of the total score. CONCLUSION: Medical students and their educators need to be able to monitor their learning in their complex academic and clinical environments. The Modified MSLQ provides a means of investigating and tracking individual medical students' reflections on their learning. PMID- 30466428 TI - Using a GIS to support the spatial reorganization of outpatient care services delivery in Italy. AB - BACKGROUND: Studying and measuring accessibility to care services has become a major concern for health care management, particularly since the global financial collapse. This study focuses on Tuscany, an Italian region, which is re organizing its inpatient and outpatient systems in line with new government regulations. The principal aim of the paper is to illustrate the application of GIS methods with real-world scenarios to provide support to evidence-based planning and resource allocation in healthcare. METHODS: Spatial statistics and geographical analyses were used to provide health care policy makers with a real scenario of accessibility to outpatient clinics. Measures for a geographical potential spatial accessibility index using the two-step floating catchment area method for outpatient services in 2015 were calculated and used to simulate the rationalization and reorganization of outpatient services. Parameters including the distance to outpatient clinics and volumes of activity were taken into account. RESULTS: The spatial accessibility index and the simulation of reorganization in outpatient care delivery are presented through three cases, which highlight three different managerial strategies. The results revealed the municipalities where health policy makers could consider a new spatial location, a shutdown or combining selected outpatient clinics while ensuring equitable access to services. CONCLUSIONS: A GIS-based approach was designed to provide support to healthcare management and policy makers in defining evidence-based actions to guide the reorganization of a regional health care delivery system. The analysis provides an example of how GIS methods can be applied to an integrated framework of administrative health care and geographical data as a valuable instrument to improve the efficiency of healthcare service delivery, in relation to the population's needs. PMID- 30466429 TI - Somatic experiencing(r) for patients with low back pain and comorbid posttraumatic stress disorder - protocol of a randomized controlled trial. AB - BACKGROUND: Research has almost exclusively focused on the neck in order to explain the mechanisms of persistent pain after motor vehicle collisions (MVC). However, studies have shown that low back pain after MVC is as common as neck pain. Also, posttraumatic stress disorder (PTSD) is common after MVCs, and evidence indicate that PTSD may be linked to the development of pain and disability. PTSD has even been proposed as "the missing link" for some in the development of chronic low back pain. Unfortunately, PTSD often goes unattended in low back pain rehabilitation and very few randomized controlled studies exists targeting both conditions. Hence, the aim of the present study is to investigate the potential additional effect of the trauma therapy "Somatic Experiencing(r)" (SE) in addition to physiotherapy (PT) compared to PT alone for patients with chronic low back pain and comorbid PTSD. METHODS: The study is a two-group randomized controlled clinical trial in which participants (n = 140) are recruited consecutively from a large Danish spine center in the Region of Southern Denmark, between January 2016 and December 2017. Patients are randomly allocated to one of the two conditions: SE + PT or PT alone. Measurements of effect are carried out at baseline before randomization, post-intervention, 6 and 12 months post-randomization. The primary outcome is a 20% reduction in disability (Rolland Morris Disability Questionnaire) at 6 months post randomization. Secondary outcomes are: PTSD symptoms, pain intensity, pain catastrophizing, fear of movement, anxiety and depression. DISCUSSION: Comorbid PTSD is currently not targeted in back pain rehabilitation although highly prevalent. If the SE intervention shows to have an additional effect on disability and pain, the study is likely to have a positive impact on the management of chronic low back pain and will have immediate clinical applicability. TRIAL REGISTRATION: Current Controlled Trials Registration August 4, 2017: NCT03244046 . Retrospectively registered. PMID- 30466430 TI - Initiation of LPS-induced pulmonary dysfunction and its recovery occur independent of T cells. AB - BACKGROUND: The acute respiratory distress syndrome (ARDS) is a serious disease in critically ill patients that is characterized by pulmonary dysfunctions, hypoxemia and significant mortality. Patients with immunodeficiency (e.g. SCID with T and B cell deficiency) are particularly susceptible to the development of severe ARDS. However, the role of T cells on pulmonary dysfunctions in immune competent patients with ARDS is only incompletely understood. METHODS: Wild-type (wt) and RAG2-/- mice (lymphocyte deficient) received intratracheal instillations of LPS (4 mg/kg) or saline. On day 1, 4 and 10 lung mechanics and bronchial hyperresponsiveness towards acetylcholine were measured with the flexiVent ventilation set-up. The bronchoalveolar lavage fluid (BALF) was examined for leukocytes (FACS analysis) and pro-inflammatory cytokines (ELISA). RESULTS: In wt mice, lung mechanics, body weight and body temperature deteriorated in the LPS group during the early phase (up to d4); these alterations were accompanied by increased leukocyte numbers and inflammatory cytokine levels in the BALF. During the late phase (day 10), both lung mechanics and the cell/cytokine homeostasis recovered in LPS-treated wt mice. RAG2-/- mice experienced changes in body weight, lung mechanics, BAL neutrophil numbers, BAL inflammatory cytokines levels that were comparable to wt mice. CONCLUSION: Following LPS instillation, lung mechanics deteriorate within the first 4 days and recover towards day 10. This response is not altered by the lack of T lymphocytes suggesting that T cells play only a minor role for the initiation, propagation or recovery of LPS-induced lung dysfunctions or function of T lymphocytes can be compensated by other immune cells, such as alveolar macrophages. PMID- 30466432 TI - Methionine to cystine ratio in the total sulfur amino acid requirements and sulfur amino acid metabolism using labelled amino acid approach for broilers. AB - BACKGROUND: Assuming that part of Methionine (Met) is converted into Cystine (Cys), but ignoring the rates with which such phenomenon occurs may lead to an excessive supply of Met in poultry diets. Such inconvenient could be easily avoided with the knowledge of the ideal Met:Cys/Total sulfur amino acids (TSAA) ratio and the rates of Met conversion into Cys. RESULTS: Met sources did not affect performance. Met:Cys/TSAA ideal ratio was determined using curvilinear plateau regression model. Both optimum body weight gain and feed conversion ratio were estimated in 1007 g/day and 1.49, respectively, at 52% Met/TSAA ratio. Feed intake was not affected by Met:Cys/TSAA ratios. In the labelled amino acid assay, the rates with which Met was converted into Cys ranged from 27 to 43% in response to changes in Met:Cys/TSAA ratios, being higher at 56:44. CONCLUSION: Based on performance outcomes, the minimum concentration of Met relative to Cys in diets for broilers from 14 to 28 d of age based on a TSAA basis, is 52% (52:48 Met:Cys/TSAA). The outcomes from labelled amino acid assay indicate that highest the Met supply in diets, the highest is its conversion into Cys. PMID- 30466431 TI - Co-existence of physical activity and sedentary behavior among children and adolescents in Shanghai, China: do gender and age matter? AB - BACKGROUND: There is limited evidence for the prevalence of the co-existence of physical activity (PA) and sedentary behavior (SED), and its correlates among children and adolescents. This study has two aims: 1) to investigate the prevalence of PA and SED, and their co-existence, and 2) to examine the associations between PA or SED, or both with gender and age among children and adolescents in Shanghai, China. METHODS: Using a cross-sectional study design (conducted from September to December 2014), 50,090 children and adolescents (10 18 years old, 50.4% boys) were included in this study. A self-reporting questionnaire was used to measure participants' sociodemographic characteristics, PA, and SED. Descriptive statistics were used to describe sample characteristics, the prevalence of PA and SED, and their co-existence. A Generalized Linear Model was conducted to explore the associations between the prevalence of PA and SED, and their co-existence with gender and age separately. RESULTS: Of the children and adolescents studied, only 18.4% met the guidelines for PA, 25.5% met the guidelines for SED, and 5.7% met the guidelines for both. Boys were more physically active (aOR = 1.43, 95% CI: 1.36-1.50), and girls were less sedentary (aOR = 1.29, 95%CI: 1.24-1.34). The prevalence of PA, SED, or both all declined as age increased (p < 0.001). Stratified analysis by gender revealed greater declining trends of meeting the PA or SED guidelines, or both in girls (all p < 0.005). CONCLUSION: Very few children and adolescents showed active lifestyles, and this was significantly related to age. Effective interventions aiming to promote PA and concurrently to limited SED among children and adolescents should be implemented as early as possible. PMID- 30466433 TI - Roles of mitochondrial ROS and NLRP3 inflammasome in multiple ozone-induced lung inflammation and emphysema. AB - BACKGROUND: Mitochondrial damage leading to oxidant stress may play an important role in the pathogenesis of airflow obstruction and emphysema. NLPR3 inflammasome can be activated by mitochondrial ROS (mtROS) and other stimuli. We examined the importance of mtROS and NLRP3 inflammasome and their interactions in multiple ozone-induced lung inflammation and emphysema. METHODS: C57/BL6 mice were exposed to ozone (2.5 ppm, 3 h) or filtered air twice a week over 6 weeks. MitoTEMPO (20 mg/kg), an inhibitor of mtROS, and VX765 (100 mg/kg), an inhibitor of caspase-1 activity, were administered by intraperitoneal or intragastric injection respectively 1 h prior to each ozone exposure for 6 weeks. RESULTS: Ozone-exposed mice had increased bronchoalveolar lavage (BAL) total cells and levels of IL 1beta, KC and IL-6, augmented lung tissue inflammation scores, enhanced oxidative stress with higher serum 8-OHdG concentrations, emphysema with greater mean linear intercept (Lm), airway remodeling with increased airway smooth muscle mass and airflow limitation as indicated by a reduction in the ratio of forced expiratory volume at 25 and 50 milliseconds to forced vital capacity (FEV25/FVC, FEV50/FVC). Both MitoTEMPO and VX765 reduced lung inflammation scores, cytokine levels, oxidative stress and increased mitochondrial fission proteins. VX765 also attenuated emphysema, airway remodeling and airflow limitation. MitoTEMPO inhibited the increased expression of mitochondrial complex II and IV and of NLPR3 while VX765 inhibited the expression and activity of NLRP3 and caspase-1 pathway in the lung. CONCLUSIONS: Both mtROS and NLRP3 inflammasome play a role in ozone-induced lung inflammation while only NLRP3 is involved in ozone-induced emphysema. PMID- 30466434 TI - Evolution of mitochondrial TAT translocases illustrates the loss of bacterial protein transport machines in mitochondria. AB - BACKGROUND: Bacteria and mitochondria contain translocases that function to transport proteins across or insert proteins into their inner and outer membranes. Extant mitochondria retain some bacterial-derived translocases but have lost others. While BamA and YidC were integrated into general mitochondrial protein transport pathways (as Sam50 and Oxa1), the inner membrane TAT translocase, which uniquely transports folded proteins across the membrane, was retained sporadically across the eukaryote tree. RESULTS: We have identified mitochondrial TAT machinery in diverse eukaryotic lineages and define three different types of eukaryote-encoded TatABC-derived machineries (TatAC, TatBC and TatC-only). Here, we investigate TatAC and TatC-only machineries, which have not been studied previously. We show that mitochondria-encoded TatAC of the jakobid Andalucia godoyi represent the minimal functional pathway capable of substituting for the Escherichia coli TatABC complex and can transport at least one substrate. However, selected TatC-only machineries, from multiple eukaryotic lineages, were not capable of supporting the translocation of this substrate across the bacterial membrane. Despite the multiple losses of the TatC gene from the mitochondrial genome, the gene was never transferred to the cell nucleus. Although the major constraint preventing nuclear transfer of mitochondrial TatC is likely its high hydrophobicity, we show that in chloroplasts, such transfer of TatC was made possible due to modifications of the first transmembrane domain. CONCLUSIONS: At its origin, mitochondria inherited three inner membrane translocases Sec, TAT and Oxa1 (YidC) from its bacterial ancestor. Our work shows for the first time that mitochondrial TAT has likely retained its unique function of transporting folded proteins at least in those few eukaryotes with TatA and TatC subunits encoded in the mitochondrial genome. However, mitochondria, in contrast to chloroplasts, abandoned the machinery multiple times in evolution. The overall lower hydrophobicity of the Oxa1 protein was likely the main reason why this translocase was nearly universally retained in mitochondrial biogenesis pathways. PMID- 30466435 TI - Dieting is associated with reduced bone mineral accrual in a longitudinal cohort of girls. AB - BACKGROUND: Peak bone mass accrual occurs during adolescence, a time when dieting and related eating behaviors are common. Impaired bone mineral accrual is a known consequence of eating disorders in adolescents, but the effects of subclinical dieting behaviors on bone mineral content (BMC) have not been described in this age group. The goal of this analysis was to determine whether dieting behavior in preadolescence and adolescence is associated with bone mineral accrual in adolescent girls. METHODS: Non-Hispanic white girls (n = 139) were followed in a longitudinal cohort study. BMC was assessed at ages 9 and 15y. Dieting to lose weight was reported every 2 years, and dietary restraint and disinhibition, eating attitudes, weight concerns, and body esteem were assessed at age 11y. Girls were classified as "early dieters" if they first dieted by age 11y (31.7%), "adolescent dieters" if they first dieted after 11y (46.8%), or non-dieters if they did not report dieting by 15 y (21.6%). The effect of dieting related variables on BMC at 15y and change in BMC from 9 to 15y was assessed using linear regression, controlling for height, weight, BMI, physical activity, and pubertal status. RESULTS: Girls who first reported dieting to lose weight by age 11y had a 4.2% lower bone mineral accrual across adolescence (p = 0.02) and 3.1% lower BMC at age 15y (p = 0.005) than girls who first reported dieting after 11y or not at all. Number of weight control behaviors used, dietary restraint, and weight concerns were also negatively associated with BMC (p < 0.05). CONCLUSIONS: Dieting behavior in preadolescence is associated with reduced bone mineral accrual. Strategies to promote optimal bone development should include prevention of dieting. TRIAL REGISTRATION: Clinicaltrials.gov NCT03342430, November 17, 2017. Retrospectively registered. PMID- 30466436 TI - Assessment of patient safety culture: a nationwide survey of community pharmacists in Kuwait. AB - BACKGROUND: Medication errors have been the largest component of medical errors threatening patient safety worldwide. Several international health bodies advocate measuring safety culture within healthcare organizations as an effective strategy for sustainable safety improvement. To the best of our knowledge, this is the first study conducted in a Middle Eastern country at the level of community pharmacy, to examine safety culture and to evaluate the extent to which patient safety is a strategic priority. METHODS: A descriptive cross-sectional study was conducted. The Pharmacy Survey on Patient Safety Culture (PSOPSC), developed by the Agency for Healthcare Research and Quality (AHRQ), was used to collect data. PSOPSC is a self-administered questionnaire which was previously tested for validity and reliability. The questionnaire was distributed among pharmacists who work in community pharmacies from the five governorates of Kuwait (Capital, Hawalli, Farwaniya, Jahra, and Ahmadi). The Statistical Package for Social Science (SPSS) software, version 24 was used for analysing data. RESULTS: A total of 255 community pharmacists from the five governorates were approached to participate in the study, of whom 253 returned a completed questionnaire, with the response rate of 99%. Results from the study showed that patient safety is a strategic priority in many aspects of patient safety standards at the level of community pharmacies. This was reflected by the high positive response rate (PRR) measures demonstrated in the domains of "Teamwork" (96.8%), "Organizational Learning-Continuous Improvement" (93.2%) and "Patient Counselling" (90.9%). On the other hand, the lowest PRR was given to the "Staffing, Work Pressure, and Pace" domain which scored 49.7%. CONCLUSIONS: Understanding community pharmacists' perspectives of patient safety culture within their organization is critical. It can help identify areas of strength and those that require improvement, which can help support decision about actions to improve patient safety. The current study showed that urgent attention should be given to the areas of weakness, mainly in the dimension of "Staffing, Work Pressure and Pace." The pharmacists pointed the need for adequate breaks between shifts and less distractible work environment to perform their jobs accurately. PMID- 30466437 TI - Association between patient-reported HIV status and provider recommendation for screening in an opportunistic cervical Cancer screening setting in Jos, Nigeria. AB - BACKGROUND: Cervical cancer screening (CCS) is an important health service intervention for prevention of morbidity and mortality from invasive cervical cancer. The role of provider recommendation and referral is critical in utilization of this services particularly in settings where screening is largely opportunistic. We sought to understand how patient-reported human immunodeficiency virus (HIV) infection status is associated with provider referral in an opportunistic screening setting. METHODS: We performed a cross sectional analysis of data on a sample of women who had received a CCS at the "Operation Stop" cervical cancer (OSCC) screening service in Jos, Nigeria over a 10-year time period (2006-2016). We used the de-identified records of women who had their first CCS to analyze the association between patient-reported HIV and likelihood of provider-referral at first CCS. We performed descriptive statistics with relevant test of association using Student t-test (t-test) for continuous variables and Pearson chi square or Fisher exact test where applicable for categorical variables. We also used a bivariable and multivariable logistic regression models to estimate the independent association of patient-reported HIV on provider referral. All statistical tests were performed using STATA version 14.1, College Station, Texas, USA. Level of statistical significance was set at 0.05. RESULTS: During the 10-year period, 14,088 women had their first CCS. The reported HIV prevalence in the population was 5.0%; 95% CI: 4.6, 5.4 (703/14,088). The median age of women who were screened was 37 years (IQR; 30 45). Women who were HIV infected received more referrals from providers compared to women who were HIV uninfected (68.7% versus 49.2%), p-value < 0.001. Similarly, we found an independent effect of patient-reported HIV infection on the likelihood for provider-referral in the screened sample (aOR = 2.35; 95% CI: 1.95, 2.82). CONCLUSION: Our analysis supports the design of health systems that facilitates providers' engagement and provision of necessary counseling for CCS in the course of routine clinical care. The practice of offering recommendation and referrals for CCS to women at high risk of cervical cancer, such as HIV infected women should be supported. PMID- 30466438 TI - Using neuroimaging to investigate the impact of Mandolean(r) training in young people with obesity: a pilot randomised controlled trial. AB - BACKGROUND: Slowing eating rate using the Mandolean(r) previously helped obese adolescents to self-select smaller portion sizes, with no reduction in satiety, and enhanced ghrelin suppression. The objective of this pilot, randomised trial was to investigate the neural response to food cues following Mandolean(r) training using functional Magnetic Resonance Imaging (fMRI), and measures of ghrelin, PYY, glucose and self-reported appetite. METHOD: Twenty-four obese adolescents (11-18 years; BMI >= 95th centile) were randomised (but stratified by age and gender) to receive six-months of standard care in an obesity clinic, or standard care plus short-term Mandolean(r) training. Two fMRI sessions were conducted: at baseline and post-intervention. These sessions were structured as an oral glucose tolerance test, with food cue-reactivity fMRI, cannulation for blood samples, and appetite ratings taken at baseline, 30 (no fMRI), 60 and 90 min post-glucose. As this was a pilot trial, a conservative approach to the statistical analysis of the behavioural data used Cliff's delta as a non parametric measure of effect size between groups. fMRI data was analysed using non-parametric permutation analysis (RANDOMISE, FSL). RESULTS: Following Mandolean(r) training: (i) relatively less activation was seen in brain regions associated with food cue reactivity after glucose consumption compared to standard care group; (ii) 22% reduction in self-selected portion size was found with no reduction in post-meal satiety. However, usage of the Mandolean(r) by the young people involved was variable and considerably less than planned at the outset (on average, 28 meals with the Mandolean(r) over six-months). CONCLUSION: This pilot trial provides preliminary evidence that Mandolean(r) training may be associated with changes in how food cues in the environment are processed, supporting previous studies showing a reduction in portion size with no reduction in satiety. In this regard, the study supports targeting eating behaviour in weight-management interventions in young people. However, given the variable usage of the Mandolean(r) during the trial, further work is required to design more engaging interventions reducing eating speed. TRIAL REGISTRATION: ISRCTN, ISRCTN84202126 , retrospectively registered 22/02/2018. PMID- 30466439 TI - Development and validation of a quantitative choline food frequency questionnaire for use with drinking and non-drinking pregnant women in Cape Town, South Africa. AB - BACKGROUND: Although animal and human studies have demonstrated interactions between dietary choline and fetal alcohol spectrum disorders, dietary choline deficiency in pregnancy is common in the US and worldwide. We sought to develop and validate a quantitative food frequency questionnaire (QFFQ) to estimate usual daily choline intake in pregnant mothers. METHODS: A panel of nutrition experts developed a Choline-QFFQ food item list, including sources with high choline content and the most commonly consumed choline-containing foods in the target population. A data base for choline content of each item was compiled. For reliability and validity testing in a prospective longitudinal cohort, 123 heavy drinking Cape Coloured pregnant women and 83 abstaining/light-drinking controls were recruited at their first antenatal clinic visit. At 3 prenatal study visits, each gravida was interviewed about alcohol, smoking, and drug use, and administered a 24-hour recall interview and the Choline-QFFQ. RESULTS: Across all visits and assessments, > 78% of heavy drinkers and controls reported choline intake below the Dietary Reference Intakes adequate intake level (450 mg/day). Women reported a decrease in choline intake over time on the QFFQ. Reliability of the QFFQ across visits was good-to-acceptable for 2 of 4 group-level tests and 4 of 5 individual-level tests for both drinkers and controls. When compared with 24 hr recall data, validity of the QFFQ was good-to-acceptable for 3 of 4 individual level tests and 3 of 5 group-level tests. For controls, validity was good-to acceptable for all 4 individual-level tests and all 5 group-level tests. CONCLUSIONS: To our knowledge, this is the first quantitative choline food frequency screening questionnaire to be developed and validated for use with both heavy and non-drinking pregnant women and the first to be used in the Cape Coloured community in South Africa. Given the high prevalence of inadequate choline intake and the growing evidence that maternal choline supplementation can mitigate some of the adverse effects of prenatal alcohol exposure, this tool may be useful for both research and future clinical outreach programs. PMID- 30466440 TI - Dairy intake revisited - associations between dairy intake and lifestyle related cardio-metabolic risk factors in a high milk consuming population. AB - BACKGROUND: The association between milk and dairy intake and the incidence of cardiometabolic diseases, cancer and mortality has been evaluated in many studies, but these studies have had conflicting results with no clear conclusion on causal or confounding associations. The present study aims to further address this association by cross-sectional and longitudinal evaluation of the associations between exposure to various types of dairy products and metabolic risk markers among inhabitants in northern Sweden while taking other lifestyle factors into account. METHODS: Respondents in the Vasterbotten Intervention Programme with complete and plausible diet data between 1991 and 2016 were included, yielding 124,934 observations from 90,512 unique subjects. For longitudinal analysis, 27,682 participants with a visit 8-12 years after the first visit were identified. All participants completed a validated Food Frequency Questionnaire. Metabolic risk markers, including body mass index (BMI), blood pressure, serum (S) cholesterol and triglycerides, and blood glucose, were measured. Participants were categorized into quintiles by intake of dairy products, and risk (odds ratios, OR) of undesirable levels of metabolic risk markers was assessed in multivariable logistic regression analyses. In longitudinal analyses, intake quintiles were related to desirable levels of metabolic risk markers at both visits or deterioration at follow-up using Cox regression analyses. RESULTS: The OR of being classified with an undesirable BMI decreased with increasing quintiles of total dairy, cheese and butter intake but increased with increasing non-fermented milk intake. The OR of being classified with an undesirable S-cholesterol level increased with increasing intake of total dairy, butter and high fat (3%) non-fermented milk, whereas an undesirable S triglyceride level was inversely associated with cheese and butter intake in women. In longitudinal analyses, increasing butter intake was associated with deterioration of S-cholesterol and blood glucose levels, whereas increasing cheese intake was associated with a lower risk of deterioration of S triglycerides. CONCLUSIONS: Confounding factors likely contribute to the demonstrated association between dairy intake and mortality, and other medical conditions and analyses should be stratified by dairy type. PMID- 30466441 TI - Rapid virulence prediction and identification of Newcastle disease virus genotypes using third-generation sequencing. AB - BACKGROUND: Newcastle disease (ND) outbreaks are global challenges to the poultry industry. Effective management requires rapid identification and virulence prediction of the circulating Newcastle disease viruses (NDV), the causative agent of ND. However, these diagnostics are hindered by the genetic diversity and rapid evolution of NDVs. METHODS: An amplicon sequencing (AmpSeq) workflow for virulence and genotype prediction of NDV samples using a third-generation, real time DNA sequencing platform is described here. 1D MinION sequencing of barcoded NDV amplicons was performed using 33 egg-grown isolates, (15 NDV genotypes), and 15 clinical swab samples collected from field outbreaks. Assembly-based data analysis was performed in a customized, Galaxy-based AmpSeq workflow. MinION based results were compared to previously published sequences and to sequences obtained using a previously published Illumina MiSeq workflow. RESULTS: For all egg-grown isolates, NDV was detected and virulence and genotype were accurately predicted. For clinical samples, NDV was detected in ten of eleven NDV samples. Six of the clinical samples contained two mixed genotypes as determined by MiSeq, of which the MinION method detected both genotypes in four samples. Additionally, testing a dilution series of one NDV isolate resulted in NDV detection in a dilution as low as 101 50% egg infectious dose per milliliter. This was accomplished in as little as 7 min of sequencing time, with a 98.37% sequence identity compared to the expected consensus obtained by MiSeq. CONCLUSION: The depth of sequencing, fast sequencing capabilities, accuracy of the consensus sequences, and the low cost of multiplexing allowed for effective virulence prediction and genotype identification of NDVs currently circulating worldwide. The sensitivity of this protocol was preliminary tested using only one genotype. After more extensive evaluation of the sensitivity and specificity, this protocol will likely be applicable to the detection and characterization of NDV. PMID- 30466443 TI - Spillover benefit of improved access to healthcare on reducing worry about housing and meal affordability. AB - BACKGROUND: The Affordable Care Act Medicaid expansion improved access to health insurance among low-income populations. We sought to examine the spillover benefits of the ACA Medicaid expansion on ability to afford rent/mortgage and purchase of nutritious meals. METHODS: Using data from the Behavioral Risk Factor Surveillance System (BRFSS) we analyzed individuals aged 18-64 years residing in 12 U.S. states (including five ACA Medicaid expansion states) in 2015. Our treatment of interest was access to health insurance, instrumented by the ACA Medicaid expansion. Our outcome variables were: worry or stress about having sufficient money to pay the rent or mortgage and to purchase nutritious meals. We conducted a two-stage least squares instrumental variables regression. RESULTS: A 10%-point increase in the proportion of those who obtained health insurance following the ACA Medicaid expansion reduced the probability of being worried and stressed related to purchasing nutritious meals by 7.2% points (95% CI: 1.3-13.2) as well as paying the rent or mortgage by 8.6% points (95% CI: 2.5-14.7) among people living below 138% of the federal poverty level (FPL). The ACA Medicaid expansion was not associated with access to health insurance among those living over 138% of FPL, and obtaining health insurance did not influence stress or worry in relation to affording rent/mortgage or meals in this income group. CONCLUSIONS: Improved access to health insurance contributed to reducing worry and stress associated with paying rent/mortgage or purchasing meals among low income people. Expanding health insurance access may have contributed to increasing the disposable income of low income groups. PMID- 30466442 TI - BRD4 and Cancer: going beyond transcriptional regulation. AB - BRD4, member of the Bromodomain and Extraterminal (BET) protein family, is largely acknowledged in cancer for its role in super-enhancers (SEs) organization and oncogenes expression regulation. Inhibition of BRD4 shortcuts the communication between SEs and target promoters with a subsequent cell-specific repression of oncogenes to which cancer cells are addicted and cell death. To date, this is the most credited mechanism of action of BET inhibitors, a class of small molecules targeting BET proteins which are currently in clinical trials in several cancer settings.However, recent evidence indicates that BRD4 relevance in cancer goes beyond its role in transcription regulation and identifies this protein as a keeper of genome stability.Indeed, a non-transcriptional role of BRD4 in controlling DNA damage checkpoint activation and repair as well as telomere maintenance has been proposed, throwing new lights into the multiple functions of this protein and opening new perspectives on the use of BETi in cancer. Here we discuss the current available information on non-canonical, non transcriptional functions of BRD4 and on their implications in cancer biology. Integrating this information with the already known BRD4 role in gene expression regulation, we propose a "common" model to explain BRD4 genomic function. Furthermore, in light of the transversal function of BRD4, we provide new interpretation for the cytotoxic activity of BETi and we discuss new possibilities for a wide and focused employment of these drugs in clinical settings. PMID- 30466444 TI - Chronic non bacterial osteitis- a multicentre study. AB - OBJECTIVE: To understand the demographics, clinical features and treatment outcomes of Chronic Non-bacterial Osteitis (CNO) from three tertiary paediatric rheumatology services in the United Kingdom. METHODS: Children less than 18 years of age diagnosed with CNO between 2001 to 2016 from one tertiary service and between 2001 to 2017 from two tertiary services were included. Clinical notes were reviewed and all pertinent data were collected on a pre-defined proforma. One hundred and thirty one patients were included in the study. The Bristol diagnostic criteria were applied retrospectively. RESULTS: Retrospective analysis of the data showed that the disease was more common in girls than boys (2.5:1), median age at onset of symptoms was 9.5 years (IQR 8 to 11 years). Bone pain was the predominant symptom in 118/129 (91.4%) followed by swelling in 50/102 (49.01%). Raised inflammatory markers were present in 39.68% of the patients. Whole body Magnetic Resonance Imaging (MRI) was a useful diagnostic tool. Metaphyses of long bones were most often involved and the distal tibial metaphyses 65/131 (49.6%) was the most common site. Non-steroidal anti inflammatory drugs were used as first line (81.67%) followed by bisphosphonates (61.79%). Treatment was escalated to a TNF blocker when response to bisphosphonates was suboptimal. The disease was in remission in 82.4% of the patients during the last follow up. CONCLUSION: Our multicentre study describes features and outcomes of CNO in a large number of patients in the United Kingdom. SIGNIFICANCE AND INNOVATION: Raised inflammatory markers were present in 39.68% of our patients. Whole body MRI is useful for diagnosis and also determining response to treatment. A greater number of lesions were detected on radiological imaging compared to clinical assessment. Metaphyses of long bones were most often involved and the distal tibial metaphyses (49.6%) were the most common site. Non steroidal anti-inflammatory drugs were used as first line (81.67%) followed by bisphosphonates (61.79%). There was no difference in number of medications used for management in unifocal versus multifocal disease. TNF blockers were used with good effect in our cohort. PMID- 30466445 TI - Imprinted and ancient gene: a potential mediator of cancer cell survival during tryptophan deprivation. AB - BACKGROUND: Depletion of tryptophan and the accumulation of tryptophan metabolites mediated by the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1), trigger immune cells to undergo apoptosis. However, cancer cells in the same microenvironment appear not to be affected. Mechanisms whereby cancer cells resist accelerated tryptophan degradation are not completely understood. We hypothesize that cancer cells co-opt IMPACT (the product of IMPrinted and AnCienT gene), to withstand periods of tryptophan deficiency. METHODS: A range of bioinformatic techniques including correlation and gene set variation analyses was applied to genomic datasets of cancer (The Cancer Genome Atlas) and normal (Genotype Tissue Expression Project) tissues to investigate IMPACT's role in cancer. Survival of IMPACT-overexpressing GL261 glioma cells and their wild type counterparts cultured in low tryptophan media was assessed using fluorescence microscopy and MTT bio-reduction assay. Expression of the Integrated Stress Response proteins was measured using Western blotting. RESULTS: We found IMPACT to be upregulated and frequently amplified in a broad range of clinical cancers relative to their non-malignant tissue counterparts. In a subset of clinical cancers, high IMPACT expression associated with decreased activity of pathways and genes involved in stress response and with increased activity of translational regulation such as the mTOR pathway. Experimental studies using the GL261 glioma line showed that cells engineered to overexpress IMPACT, gained a survival advantage over wild-type lines when cultured under limiting tryptophan concentrations. No significant difference in the expression of proteins in the Integrated Stress Response pathway was detected in tryptophan-deprived GL261 IMPACT-overexpressors compared to that in wild-type cells. IMPACT-overexpressing GL261 cells but not their wild-type counterparts, showed marked enlargement of their nuclei and cytoplasmic area when stressed by tryptophan deprivation. CONCLUSIONS: The bioinformatics data together with our laboratory studies, support the hypothesis that IMPACT mediates a protective mechanism allowing cancer cells to overcome microenvironmental stresses such as tryptophan deficiency. PMID- 30466446 TI - Treatment of hepatitis C virus genotype 4 in the DAA era. AB - The recently approved interferon-free DAA (direct antiviral agents) regimens have shown not only to be effective in terms of sustained virological response (SVR) rates (> 90%) but also well tolerated in most hepatitis C virus (HCV) infected patients. Nevertheless HCV genotypes are different and only a small percentage of trials consider genotype 4 (GT4), which was associated with lower rates of SVR compared with other genotypes before the arrival of the DAA's. In this review, we discuss the efficacy of DAA therapy in GT4 HCV infection with specific reference to more recent studies, including those conducted in a 'field-practice' scenario. Overall, DAA-based regimens appear more effective also in the poorly-explored setting of patients with HCV GT4 infection. Despite an overall limited number of patients was evaluated, favorable results are being derived from studies on ombitasvir/paritaprevir/ritonavir, sofosbuvir and velpatasvir, whether or not in association with voxilaprevir, and with the new combined therapy glecaprevir + pibentasvir. PMID- 30466447 TI - Antinuclear antibody and rheumatoid factor positivity in temporomandibular disorders. AB - BACKGROUND: To investigate the differences in clinical characteristics and long term treatment outcomes according to antinuclear antibody(ANA) and rheumatoid factor(RF) positivity and the correlation between pain-related and hematological indices in temporomandibular disorders(TMD) patients. METHODS: Clinical examinations were done following the Research Diagnostic Criteria for TMD in 257 patients. Comprehensive screening along with psychological and hematological evaluations (ANA, RF, complete blood cell count, C-reactive protein[CRP] and erythrocyte sedimentation rate[ESR]) were conducted. Clinical characteristics and treatment outcomes were statistically compared between ANA/RF positive and negative groups. RESULTS: Thirty-nine patients showed ANA/RF positivity. Male patients had smaller comfortable mouth opening(CMO)(p = 0.033) and maximum mouth opening(MMO)(p = 0.016) ranges with more painful neck muscles on palpation when RF/ANA positive. Pain duration, intensity, disability days and psychological distress levels were also higher in RF/ANA positive male patients. Significant correlation was shown in ESR with pain duration(p < 0.05) and numeric rating scale(NRS) before treatment(p < 0.05), CRP with NRS before treatment(p < 0.01), and red blood cell (RBC) with pain intensity(p < 0.05), NRS before treatment(p < 0.01), CMO(p < 0.01), pain on palpation of cervical muscles(p < 0.01), CMO(p < 0.05), and MMO(p < 0.05) 6 months after treatment. CONCLUSIONS: These results may point towards a nonspecific autoimmune disposition in a subgroup of TMD patients. RF and ANA could be considered as a screening test for the detection of autoimmune phenomena in TMD. PMID- 30466448 TI - Isolated ovarian tuberculosis in an Immuno- competent woman in the post partum period: case report. AB - BACKGROUND: Pelvic tuberculosis is a rare form of extrapulmonary tuberculosis. It commonly involves the fallopian tubes and the uterus from a lympho-hematogeneous spread. The presentation of pelvic tuberculosis as an isolated ovarian abscess is extremely rare and is reported only twice. CASE PRESENTATION: a 25 yrs. old para III mother in the post partum period undergone laparotomy for suspected tuboovarian abscess/ovarian tumor after presenting with abdominal pain, pelvic mass and fever. Intra-operatively, Isolated right ovarian mass with caseation in the cavity but no significant pelvic adhesions was detected and right oophorectomy was done. Post operative Histopathology of surgical specimens revealed tuberculous leision and patient recovered well after anti-tuberculosis treatment. CONCLUSION: Isolated ovarian tuberculosis is a very rare form of Genital Tuberculosis which should always be considered in the evaluation of a woman presenting with any adnexal mass in highly prevalent areas. PMID- 30466449 TI - Feasibility of a musculoskeletal ultrasound intervention to improve adherence in juvenile idiopathic arthritis: a proof-of concept trial. AB - BACKGROUND: Non-adherence is a prevalent and modifiable issue in juvenile idiopathic arthritis (JIA) that currently lacks provider-based intervention. Education surrounding disease status is one way in which families remain engaged in their care. Musculoskeletal ultrasound is one such form of demonstrative, real time education that may impact the way patients and caregivers self-manage their disease. The aims of this study are to 1) assess the feasibility, acceptability and perceived usefulness of musculoskeletal ultrasound as a non-adherence intervention tool and 2) to examine changes in methotrexate adherence in adolescents with JIA following the ultrasound. METHODS: Eight adolescents with polyarticular or extended oligoarticular JIA and their caregivers completed this 12 week study. A within subject design was used to compare baseline and post intervention adherence, quality of life and disease activity indices. Adherence measures included electronic measurement of methotrexate in addition to self reported adherence questionnaires. The ultrasound intervention included a one time, rheumatologist provided, educational examination of three or more currently or historically active joints. RESULTS: The ultrasound intervention was found to be both feasible and acceptable. One hundred percent of eligible participants completed the ultrasound intervention. The ultrasound was well received by patients and caregivers, with most believing this to be a helpful tool. Baseline adherence was 75.3% among participants, with half of the participants being classified as non-adherent. Electronically measured and self-reported adherence measures did not show significant changes during the post-intervention period. Two participants improved, four participants maintained, and two participants decreased adherence. On ultrasound, 18/27 (66.7%) of the examined joints displayed abnormalities, with 63% being discrepant and additive to the rheumatologist's physical examination. CONCLUSIONS: While our intervention did not show any changes in adherence, quality of life or disease activity indices in this proof-of-concept trial, the intervention does show promise in acceptability measures and merits future study in a more robust trial design. An additional study benefit was that the musculoskeletal ultrasound intervention was able to demonstrate subclinical disease, leading to clinically impactful therapeutic changes in several participants. PMID- 30466451 TI - The inequality of inpatient care net benefit under integration of urban-rural medical insurance systems in China. AB - BACKGROUND: China has recently made efforts to integrate urban and rural basic medical insurance systems in order to ensure both urban and rural enrollees obtain unified benefits. However, whether the distribution of government healthcare subsides has become more equitable remains unknown. The purpose of this study was to analyze determinants of and inequality in net inpatient care benefits under the integration of urban-rural medical insurance systems in China. METHODS: Data were obtained from a nationally representative household survey, the Fifth National Health Services Survey (2013), conducted in Anhui province. A multiple regression model and concentration index (CI) was used to estimate related factors and inequality of inpatient care net benefits. RESULTS: Findings indicated that individuals received more inpatient care benefits when urban and rural social healthcare systems were integrated. Factors associated with net benefits included gender, age, marital status, retirement, educational level, history of chronic diseases, health status, willingness to seek inpatient care and per capita income. The rich were found to disproportionately benefit from inpatient care, and the CI of net benefits for integrated insurance enrollees was the lowest among all three available health insurance schemes. These findings indicate that the recent unification of urban-rural social health insurances reduces inequality in net benefits from government subsidies. Some socioeconomic factors, such as per capita income, 60 years of age and over, history of chronic disease and high educational level positively influence inequality. CONCLUSION: In China, accelerating the integration of urban and rural medical insurance systems is an effective way to increase equity of benefit in urban and rural areas. Strategies aimed at reducing inpatient benefit inequality must address socioeconomic factors influencing healthcare outcomes. PMID- 30466450 TI - T-CaST: an implementation theory comparison and selection tool. AB - BACKGROUND: Theories, models, and frameworks (TMF) are foundational for generalizing implementation efforts and research findings. However, TMF and the criteria used to select them are not often described in published articles, perhaps due in part to the challenge of selecting from among the many TMF that exist in the field. The objective of this international study was to develop a user-friendly tool to help scientists and practitioners select appropriate TMF to guide their implementation projects. METHODS: Implementation scientists across the USA, the UK, and Canada identified and rated conceptually distinct categories of criteria in a concept mapping exercise. We then used the concept mapping results to develop a tool to help users select appropriate TMF for their projects. We assessed the tool's usefulness through expert consensus and cognitive and semi-structured interviews with implementation scientists. RESULTS: Thirty-seven implementation scientists (19 researchers and 18 practitioners) identified four criteria domains: usability, testability, applicability, and familiarity. We then developed a prototype of the tool that included a list of 25 criteria organized by domain, definitions of the criteria, and a case example illustrating an application of the tool. Results of cognitive and semi-structured interviews highlighted the need for the tool to (1) be as succinct as possible; (2) have separate versions to meet the unique needs of researchers versus practitioners; (3) include easily understood terms; (4) include an introduction that clearly describes the tool's purpose and benefits; (5) provide space for noting project information, comparing and scoring TMF, and accommodating contributions from multiple team members; and (6) include more case examples illustrating its application. Interview participants agreed that the tool (1) offered them a way to select from among candidate TMF, (2) helped them be explicit about the criteria that they used to select a TMF, and (3) enabled them to compare, select from among, and/or consider the usefulness of combining multiple TMF. These revisions resulted in the Theory Comparison and Selection Tool (T-CaST), a paper and web-enabled tool that includes 16 specific criteria that can be used to consider and justify the selection of TMF for a given project. Criteria are organized within four categories: applicability, usability, testability, and acceptability. CONCLUSIONS: T-CaST is a user-friendly tool to help scientists and practitioners select appropriate TMF to guide implementation projects. Additionally, T-CaST has the potential to promote transparent reporting of criteria used to select TMF within and beyond the field of implementation science. PMID- 30466452 TI - Health care expenditure and health outcome nexus: new evidence from the SAARC ASEAN region. AB - BACKGROUND: The total health expenditure (as a percentage of GDP) and health outcomes in the region of South Asian Association for Regional Cooperation (SAARC) and Association for South East Asian Nations (ASEAN) are lower than that of the OECD region and the world. This study investigated the relationship between different types of healthcare expenditures (public, private and total) and three main health status outcomes - life expectancy at birth, crude death rate and infant mortality rate - in the region. METHODOLOGY: Using the World Bank data set for 15 countries over a 20-year period (1995-2014), a panel data analysis was conducted where relevant fixed and random effect models were estimated to determine the effects of healthcare expenditure on health outcomes. The main variables studied were total health expenditure, public health expenditure, private health expenditure, GDP per capita, improved sanitation, life expectancy at birth, crude death rate and infant mortality rate. RESULTS: Total health expenditure, public health expenditure and private health expenditure significantly reduced infant mortality rates, and, the extent of effect of private health expenditure was greater than that of public health expenditure. Private health expenditure also had a significant role in reducing the crude death rate. Per capita income growth and improved sanitation facilities also had significant positive roles in improving population health in the region. CONCLUSIONS: Health expenditure in the SAARC-ASEAN region should be increased as our results indicated that it improved the health status of the population in the region. Public sector health funds must be appropriately and efficiently used, and accountability and transparency regarding spending of public health funds should be ensured. Finally, government and private institutes should implement appropriate strategies to improve sanitation facilities. PMID- 30466453 TI - Does short message service improve focused antenatal care visit and skilled birth attendance? A systematic review and meta-analysis of randomized clinical trials. AB - BACKGROUND: In low resource circumstances, non-adherence for available health services is a major cause of inefficiency in health care delivery. MHealth has been projected as a possible solution to support women during pregnancy, birth and puerperium period, to increase the uptake of essential maternal services. OBJECTIVES: This systematic review and meta-analysis study was aimed to determine the effectiveness of short message services (SMS)on Focused Antenatal Care (FANC) visits and the attendance of skilled birth professionals in Low and Middle Income Countries (LMICs). METHODS: We searched a broad body of literature from electronic databases-Cochrane review, CINAHL, PsycINFO, PubMed and Google Scholar to collect comprehensive evidence on the role of SMS on FANC visits and skilled birth attendance. We extracted data from randomized clinical trials (RCTs) only. Meta-analyses were conducted using random-effects models with inverse variance method in Review Manager (RevMan) computer software. Qualities of the included studies were determined by GRADEpro, and risk of bias was assessed using Cochrane Collaboration risk of bias tool. RESULTS: Of the 1224 non-duplicated articles screened, only 7 RCT studies representing 8324 participants met eligibility criteria and included in this synthesis. On aggregate, there were statistically significant associations in experimental group in that pregnant mothers who received text messaging had a 174% increase in FANC visits (OR = 2.74 (95% CI: 1.41, 5.32) and 82% in skilled birth attendance (OR = 1.82 (95% CI; 1.33, 2.49). The I2 test result indicated high heterogeneity I2 = 78% (P < .001). The overall qualities of included studies were moderate, and had low risk of bias. CONCLUSIONS: SMS has positive effects for the uptake of FANC visits and skilled birth attendance in LMICs. A short messaging service targeting pregnant woman is an invaluable, affordable intervention to improve maternal healthcare seeking behaviors. PMID- 30466454 TI - Dosimetric comparison of different radiation techniques (IMRT vs. 3-dimensional) of the "true" (deep) ano-inguinal lymphatic drainage of anal cancer patients. AB - INTRODUCTION: The ano-inguinal lymphatic drainage (AILD) is located in the subcutaneous adipose tissue of the proximal medial thigh. Currently, there are no recommendations for an inclusion of the 'true' AILD in the clinical target volume (CTV) of definitive chemoradiation for anal cancer patients. To estimate the relevance of inguinal recurrence, we compared the incidental dose to the AILD in anal cancer (AC) patients who were treated either with Volumetric Arc Therapy - Intensity Modulated Radiation Therapy (VMAT-IMRT) or conventional 3D-radiation technique. METHODS: One VMAT-IMRT-plans and one 3D-plans were calculated on the same target volumes and identical dose prescription in ten patients. We defined the volume of the AILD on the planning CT-scans based on the information of new fluorescence methods. Furthermore, we defined several anatomical subvolumes of interest inside the AILD. We examined and compared absolute and relative dosimetric parameters of the AILD and different anatomical subunits. RESULTS: The Dmean of the AILD was 40 Gy in the 3D-group and 38 Gy in the IMRT-group. Dmean and Dmedian as well as the V30Gy of the AILD and all subvolumes of the caudal AILD were significant higher using 3D-RT compared to IMRT. Even though the absolute differences were small, in the caudal aspect of the ano-inguinal lymphatic drainage the V30Gy could be more than 10% less with VMAT-IMRT. CONCLUSIONS: 3D-RT was slightly superior to IMRT in terms of dose coverage of the AILD. However, the absolute differences were very small. Some relevant caudal parts of the AILD received an insufficient dose for treating potential micrometastases. Particularly in high-risk situations, this may lead to inguinal recurrence and therefore the true deep AILD should be included into the target volume in high risk patients. PMID- 30466455 TI - Accelerated FRET-PAINT microscopy. AB - Recent development of FRET-PAINT microscopy significantly improved the imaging speed of DNA-PAINT, the previously reported super-resolution fluorescence microscopy with no photobleaching problem. Here we try to achieve the ultimate speed limit of FRET-PAINT by optimizing the camera speed, dissociation rate of DNA probes, and bleed-through of the donor signal to the acceptor channel, and further increase the imaging speed of FRET-PAINT by 8-fold. Super-resolution imaging of COS-7 microtubules shows that high-quality 40-nm resolution images can be obtained in just tens of seconds. PMID- 30466457 TI - Toward a global health approach: lessons from the HIV and Ebola epidemics. AB - BACKGROUND: The imposing burden of non-communicable diseases, emerging infectious diseases, climate change, environmental consequences, migrations, urbanization, and other challenges, faced in a context that strives to make universal health coverage (UHC) a reality, compels global health professionals to ask: how do we construct a "global" roadmap that is both realistic and effective? To move forward and begin to answer this question, we draw on lessons and experiences gained during the "global" health crises triggered by the HIV and Ebola pandemics. MAIN TEXT: Improving the early response and committing to the long haul; developing inter-disciplinary and inter-sectoral responses; designing comprehensive and versatile interventions; and, most importantly, to work closely and effectively with civil society and communities are some of the critical elements that were identified. The health sector has changed dramatically in recent years; new tools and innovative technologies are transforming the culture and practice of public health. This calls for a new vision. Reprioritizing primary health care and community engagement, repositioning approaches to meet people's needs, applying integrated disease management to respond to problems caused by the silo approach, implementing UHC, and ensuring equity are some of the new strategies. CONCLUSION: These strategies must all undergo a mandatory revolution in health governance-locally and globally. It should be obvious that nothing can be improved on a global or sustainable scale without re-examining the architecture and governance of major funding and international organizations dedicated to health. Pressing economic, demographic, and climate issues related to health underscore the urgent need for these changes. PMID- 30466458 TI - Clinical and structural outcomes after arthroscopic rotator cuff repair: a comparison between suture bridge techniques with or without medial knot tying. AB - PURPOSE: To compare arthroscopic suture bridge (SB) techniques with medial tying to those without tying, considering clinical and structural outcomes. METHODS: We included 124 patients with rotator cuff tears after arthroscopic rotator cuff repair (ARCR). Fifty-three patients with clinical and structural evaluations 3, 12, and 24 months postoperatively were included and divided into 29 patients with medial tying (WMT group) and 24 without tying (WOMT group). Clinical outcomes comprised the University of California Los Angeles (UCLA) and Japanese Orthopaedic Association (JOA) scores. Structural outcomes were evaluated with magnetic resonance images (MRI) using Sugaya classifications. RESULTS: JOA and UCLA scores in the WMT and WOMT groups improved significantly from before surgery to 24 months after surgery (P < 0.01, respectively). No significant difference was noted between groups. No significant postoperative retears (Sugaya types 4 and 5) between WMT and WOMT groups were noted at 3 months (5 vs 3 cases), 12 months (6 vs 5 cases), and 24 months (7 vs 6 cases) postoperatively. Complete healing (Sugaya type 1) was noted at 3 months (8 vs 11 cases), 12 months (10 vs 10 cases), and 24 months (8 vs 13 cases, P = 0.024) postoperatively. Incomplete healing (Sugaya types 2 and 3) were noted at 3 months (16 vs 10 cases), 12 months (13 vs 9 cases), and 24 months (14 vs 5 cases, P = 0.024) postoperatively. CONCLUSION: Clinical outcomes for both techniques were comparable, but the number of incompletely healed tendons in SB with medial tying was significantly larger at 24 months after surgery. LEVEL OF EVIDENCE: This study is a level III, case control study. CLINICAL RELEVANCE: This study revealed the influence of medial tying in rotator cuff repair. PMID- 30466456 TI - Long non-coding RNAs in hematological malignancies: translating basic techniques into diagnostic and therapeutic strategies. AB - Recent studies have revealed that non-coding regions comprise the vast majority of the human genome and long non-coding RNAs (lncRNAs) are a diverse class of non coding RNAs that has been implicated in a variety of biological processes. Abnormal expression of lncRNAs has also been linked to different human diseases including cancers, yet the regulatory mechanisms and functional effects of lncRNAs are still ambiguous, and the molecular details also need to be confirmed. Unlike protein-coding gene, it is much more challenging to unravel the roles of lncRNAs owing to their unique and complex features such as functional diversity and low conservation among species, which greatly hamper their experimental characterization. In this review, we summarize and discuss both conventional and advanced approaches for the identification and functional characterization of lncRNAs related to hematological malignancies. In particular, the utility and advancement of clustered regularly interspaced short palindromic repeats (CRISPR) Cas system as gene-editing tools are envisioned to facilitate the molecular dissection of lncRNAs via different knock-in/out strategies. Besides experimental considerations specific to lncRNAs, the roles of lncRNAs in the pathogenesis and progression of leukemia are also highlighted in the review. We expect that these insights may ultimately lead to clinical applications including development of biomarkers and novel therapeutic approaches targeting lncRNAs. PMID- 30466459 TI - SOX2 as a novel contributor of oxidative metabolism in melanoma cells. AB - BACKGROUND: Deregulated metabolism is a hallmark of cancer and recent evidence underlines that targeting tumor energetics may improve therapy response and patient outcome. Despite the general attitude of cancer cells to exploit the glycolytic pathway even in the presence of oxygen (aerobic glycolysis or "Warburg effect"), tumor metabolism is extremely plastic, and such ability to switch from glycolysis to oxidative phosphorylation (OxPhos) allows cancer cells to survive under hostile microenvironments. Recently, OxPhos has been related with malignant progression, chemo-resistance and metastasis. OxPhos is induced under extracellular acidosis, a well-known characteristic of most solid tumors, included melanoma. METHODS: To evaluate whether SOX2 modulation is correlated with metabolic changes under standard or acidic conditions, SOX2 was silenced and overexpressed in several melanoma cell lines. To demonstrate that SOX2 directly represses HIF1A expression we used chromatin immunoprecipitation (ChIP) and luciferase assay. RESULTS: In A375-M6 melanoma cells, extracellular acidosis increases SOX2 expression, that sustains the oxidative cancer metabolism exploited under acidic conditions. By studying non-acidic SSM2c and 501-Mel melanoma cells (high- and very low-SOX2 expressing cells, respectively), we confirmed the metabolic role of SOX2, attributing SOX2-driven OxPhos reprogramming to HIF1alpha pathway disruption. CONCLUSIONS: SOX2 contributes to the acquisition of an aggressive oxidative tumor phenotype, endowed with enhanced drug resistance and metastatic ability. PMID- 30466460 TI - A retrospective analysis of health care utilization for patients with mitochondrial disease in the United States: 2008-2015. AB - BACKGROUND: Mitochondrial disease (MD) is a heterogeneous group of disorders characterized by impaired energy production caused by abnormal oxidative phosphorylation. Diagnosis of MD is challenging given the variability in how the disease can affect an individual's neurologic, cardiovascular, ophthalmologic, or gastroenterological systems. This study describes the health care utilization and cost in patients diagnosed with MD. METHODS: This study was a retrospective claims analysis based on data from the Truven Health Analytics MarketScan Database and Milliman's Consolidated Health Cost Guidelines Sources Database. For the purpose of this study the diagnosis of MD was defined by ICD-9-CM (prior to October 2015), and ICD-10-CM (October 2015 or later), and included patients identified between January 1, 2008 to December 31, 2015. ICD-9-CM code of 277.87 (disorders of mitochondrial metabolism) and the ICD-10-CM codes of E88.40, E88.41, E88.42 and E88.49 (mitochondrial metabolism disorders) were used as inclusive criteria. Patients were included if they had at least six months of exposure after the first MD-related claim occurrence, and either one MD claim in the inpatient setting OR two MD claims in an outpatient setting. Claims of MD patients are compared to those of a general insured total member population, as well as to those from multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) patients. RESULTS: During the study period, 3825 patients between the ages of 0 and 15 (pediatric) and 4358 patients 16 years of age and greater (adult) were identified. Total allowed per member per month (PMPM) cost for pediatric patients was $4829 and $3100 for adults, compared with an average of $202 and $486, respectively, for the total member population. The greatest drivers of costs based on allowed claims came from inpatient, surgery, and prescription medications. In the adult population, MD imposes a PMPM cost burden that was comparable to that observed for multiple sclerosis ($3518) and ALS ($3460) patients. CONCLUSIONS: This retrospective claim study highlights the significant differences in the cost of medical care for MD patients compared to those of a general population. Mitochondrial disorders are associated with multisystem disease manifestations and a greater care and cost burden similar to other devastating neuromuscular diseases. PMID- 30466461 TI - Presence and diagnostic value of circulating tsncRNA for ovarian tumor. AB - tRNA-derived small non-coding RNAs (tsncRNAs), a class of newly defined small non coding RNA, have been considered to be involved in various cellular biological processes through regulating gene expression at both transcriptional and post transcriptional level. However, the presence of circulating tsncRNAs and their diagnostic potential is largely unclear. In this study, we investigate the serum derived public transcriptome data from ovarian tumor patients and non-cancer controls, and find that circulating tsncRNAs cover a high proportion of total small RNA and are non-random degradation products in serum (ranging from 2.5 29.4%), which are enriched in several specific types of related tRNA (e.g., Gly tRNA). Particularly, four tsncRNAs are differentially expressed in serum from cancer patients compared to those from healthy controls, and can predict abnormal cell proliferation with high accuracy. Our results reveal the ubiquitous presence of circulating tsncRNAs in serum, and diagnostic potential of specific tsncRNAs for ovarian tumor. PMID- 30466462 TI - Is unilateral pedicle screw fixation superior than bilateral pedicle screw fixation for lumbar degenerative diseases: a meta-analysis. AB - BACKGROUND: To investigate whether unilateral pedicle screw fixation is superior than bilateral pedicle screw fixation for lumbar degenerative diseases. METHODS: Electronic databases including PubMed, Embase, and the Cochrane Library up to August 2018 were searched. All the high-quality randomized controlled trials (RCTs) and prospective clinical controlled studies comparing the unilateral pedicle screw fixation and bilateral pedicle screw fixation for lumbar degenerative diseases were enrolled in this study. Fusion rate was the main outcome. Stata 12.0 was used for the meta-analysis. RESULTS: Twelve RCTs including 808 patients (unilateral pedicle screw fixation = 393, bilateral pedicle screw fixation = 415) were included in our meta-analysis. There was a significant difference between unilateral pedicle screw fixation and bilateral pedicle screw fixation in terms of the fusion rate (risk ratio (RR) = 0.96, 95%CI [0.92, 1.00], P = 0.073), visual analog scale (VAS) at final follow-up, Oswestry Disability Index (ODI), Japanese Orthopedic Association scores (JOA), short-form health survey (SF-36), and length of hospital stay. Compared with bilateral pedicle screw fixation, unilateral pedicle screw fixation was associated with a reduction of the total blood loss and operation time (P < 0.05). Unilateral pedicle screw fixation was associated with an increase of the cage migration than bilateral pedicle screw fixation (17.1% vs 7.1%, RR = 2.40, 95% CI = 1.17 to 4.93; P = 0.017). CONCLUSIONS: Unilateral pedicle screw fixation and bilateral pedicle screw fixation has similar fusion rate when treating for lumbar degenerative diseases. Our meta-analysis suggested that compared with bilateral pedicle screw fixation, unilateral pedicle screw fixation significantly reduced total blood loss and operation time for lumbar degenerative diseases. The use of unilateral pedicle screw for lumbar degenerative diseases increases the cage migration. PMID- 30466463 TI - Factors affecting the use of medicinal plants by migrants from rural areas of Brazilian Northeast after moving to a metropolitan region in Southeast of Brazil. AB - BACKGROUND: Ethnopharmacological studies about migrants reveal a dynamic process of knowledge and use of medicinal plants. In this study, we sought to elucidate quantitative and qualitatively the main factors influencing the use of medicinal plants by migrants from rural areas to an urban region in Brazil with traces of remnant natural vegetation. METHODS: Seven Northeastern individuals who migrated to the Southeastern Region of Brazil (Borore Peninsula, in the city of Sao Paulo) were selected to participate in semi-structured interviews regarding the use of medicinal plants throughout their lives, and indicated an inhabitant in their hometown that would be able to accompany the field collections in each area. Socioeconomic, educational, family structure, and use of Western medicine data were provided during interviews with the individuals from their hometowns. Plant samples cited by the interviewees were collected both at the current place of residence and in their hometowns. RESULTS: The participants cited 131 plants and 315 recipes, being the main indications related to the gastrointestinal system, respiratory problems, and pain and inflammatory processes. We observed that most plant uses were maintained after migration. Higher percentages of maintenances and incorporations in plant uses occurred to exotic species, while replacements happen mainly to native plants. The introduction of new species into the migrants' therapeutics occurred mainly by observations of organoleptic similarities between the substituted plant and the incorporated species, conversations with neighbors, and contact with the television and print media. In addition, the public health system allowed the interviewees access to prophylactic drugs, leading to the discontinuation of certain recipes used in endemic diseases. CONCLUSION: Migrants were exposed to information about new plants and their uses, new diseases, and socioeconomic and cultural differences that impacted their use of medicinal plants. Although migration to a more developed city facilitated access to public health and education, on the other hand, it made access to fresh medicinal plants difficult, causing some medicinal plants to be replaced or ceased to be used. PMID- 30466464 TI - GSK3beta-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions. AB - BACKGROUND: Although diabetic retinopathy (DR) has long been considered as a microvascular disorder, mounting evidence suggests that diabetic retinal neurodegeneration, in particular synaptic loss and dysfunction of retinal ganglion cells (RGCs) may precede retinal microvascular changes. Key molecules involved in this process remain poorly defined. The microtubule-associated protein tau is a critical mediator of neurotoxicity in Alzheimer's disease (AD) and other neurodegenerative diseases. However, the effect of tau, if any, in the context of diabetes-induced retinal neurodegeneration has yet to be ascertained. Here, we investigate the changes and putative roles of endogeneous tau in diabetic retinal neurodegeneration. METHODS: To this aim, we combine clinically used electrophysiological techniques, i.e. pattern electroretinogram and visual evoked potential, and molecular analyses in a well characterized high-fat diet (HFD)-induced mouse diabetes model in vivo and primary retinal ganglion cells (RGCs) in vitro. RESULTS: We demonstrate for the first time that tau hyperphosphorylation via GSK3beta activation causes vision deficits and synapse loss of RGCs in HFD-induced DR, which precedes retinal microvasculopathy and RGCs apoptosis. Moreover, intravitreal administration of an siRNA targeting to tau or a specific inhibitor of GSK3beta reverses synapse loss and restores visual function of RGCs by attenuating tau hyperphosphorylation within a certain time frame of DR. The cellular mechanisms by which hyperphosphorylated tau induces synapse loss of RGCs upon glucolipotoxicity include i) destabilizing microtubule tracks and impairing microtubule-dependent synaptic targeting of cargoes such as mRNA and mitochondria; ii) disrupting synaptic energy production through mitochondria in a GSK3beta-dependent manner. CONCLUSIONS: Our study proposes mild retinal tauopathy as a new pathophysiological model for DR and tau as a novel therapeutic target to counter diabetic RGCs neurodegeneration occurring before retinal vasculature abnormalities. PMID- 30466466 TI - Culture- and PCR-based detection of BV associated microbiological profile of the removed IUDs and correlation with the time period of IUD in place and the presence of the symptoms of genital tract infection. AB - OBJECTIVES: The long-term use of intrauterine devices (IUDs) may lead to biofilm formation on the surface. The aim of this study was to perform the culture- and PCR-based detection of bacteria/fungi from the biofilm of the removed IUDs with different time periods in place. METHODS: For a 2-year period, 100 IUD users were involved in the study. In the majority of the cases, IUDs were removed because of the patients' complaints. Beside the aerobic and anaerobic culture, species specific PCR was carried out to detect Chlamydia trachomatis Neisseria gonorrhoeae and the "signalling" bacteria of bacterial vaginosis (BV) in the biofilm removed by vortexing. RESULTS: Sixty-eight percent of IUDs were used for more than 5 years, 32% were removed after 10 years in place. In 28% of the IUDs >= 3 different anaerobic species typically found in BV with or without other aerobic bacteria were found by culture method. Streptococcus agalactiae (14%) and Actinomyces spp. (18%) were also isolated frequently. The PCR detection of Gardnerella vaginalis, Atopobium vaginae, Mobiluncus spp. and Ureaplasma urealyticum were 62%, 32%, 23% and 16%, respectively. Seventy-six percent of the IUDs were PCR positive at least for one "signalling" bacterium of BV. C. trachomatis was detected by PCR only in one IUD together with other aerobic and anaerobic bacteria, while the presence of N. gonorrhoeae could not be confirmed from the biofilm of these removed devices. CONCLUSION: Sexually transmitted infections (STI)-related bacteria-except for one patient-were not detected on the IUDs removed due to different reasons including clinical symptoms of infection. Presence of any BV "signaling" anaerobic bacteria were detected in a much higher number in the biofilm of the removed IUDs by PCR-based method compared to use culture method (76 versus 28 samples). Different aerobic and anaerobic bacteria colonized an equal number of IUDs, independent of the time-period in place, which may be relevant, if the IUD is removed due to planned pregnancy or due to a fear from upper genital tract infection caused by anaerobic bacteria including Actinomyces spp. PMID- 30466465 TI - Nanomaterial enabled sensors for environmental contaminants. AB - The need and desire to understand the environment, especially the quality of one's local water and air, has continued to expand with the emergence of the digital age. The bottleneck in understanding the environment has switched from being able to store all of the data collected to collecting enough data on a broad range of contaminants of environmental concern. Nanomaterial enabled sensors represent a suite of technologies developed over the last 15 years for the highly specific and sensitive detection of environmental contaminants. With the promise of facile, low cost, field-deployable technology, the ability to quantitatively understand nature in a systematic way will soon be a reality. In this review, we first introduce nanosensor design before exploring the application of nanosensors for the detection of three classes of environmental contaminants: pesticides, heavy metals, and pathogens. PMID- 30466467 TI - Helicobacter pylori CagA promotes epithelial mesenchymal transition in gastric carcinogenesis via triggering oncogenic YAP pathway. AB - BACKGROUND: Helicobacter pylori (H. pylori) delivers oncoprotein CagA into gastric epithelial cells via the T4SS and drives activation of multiple oncogenic signalling pathways. YAP, a core effector of the Hippo tumour suppressor pathway, is frequently overexpressed in human cancers, suggesting its potential tumor promoting role. Although CagA is a casual factor in H. pylori induced gastric carcinogenesis, the link between CagA and YAP pathway has not been identified. In this work, we investigated the regulation of oncogenic YAP pathway by H. pylori CagA. METHODS: Expression of YAP and E-cadherin protein in human gastric biopsies were assessed by immunohistochemistry. H. pylori PMSS1 cagA- isogenic mutant strains were generated. Gastric epithelial cells were co-cultured with H. pylori wild-type cagA+ strains or isogenic mutants and were also treated by recombinant CagA expression. Immunofluorescence was performed for YAP localization. Immunoblot and quantitative PCR were performed for examining levels of YAP, downstream effectors and markers of epithelial-mesenchymal transition. Verteporfin and siRNA silencing were used to inhibit YAP activity. RESULTS: YAP is significantly upregulated in human gastric carcinogenesis. We generated PMSS1 CagA isogenic mutant strains with chloramphenicol resistance successfully. Our analysis indicated that H. pylori infection induced YAP and downstream effectors in gastric epithelial cells. Importantly, knockout of CagA in 7.13 and PMSS1 strains reduced the expression of YAP by H. pylori infection. Moreover, Inhibition of YAP suppressed H. pylori infection-induced Epithelial-mesenchymal transition (EMT). CONCLUSION: Our results indicated that H. pylori CagA as a pathogenic protein promotes oncogenic YAP pathway, which contributes to EMT and gastric tumorigenesis. This study provided a novel mechanistic insight into why cagA+ H. pylori infection is associated with a higher risk for the development of gastric cancer. PMID- 30466468 TI - Comparison of different treatment planning approaches for intensity-modulated proton therapy with simultaneous integrated boost for pancreatic cancer. AB - BACKGROUND: Neoadjuvant radio(chemo)therapy of non-metastasized, borderline resectable or unresectable locally advanced pancreatic cancer is complex and prone to cause side-effects, e.g., in gastrointestinal organs. Intensity modulated proton therapy (IMPT) enables a high conformity to the targets while simultaneously sparing the normal tissue such that dose-escalation strategies come within reach. In this in silico feasibility study, we compared four IMPT planning strategies including robust multi-field optimization (rMFO) and a simultaneous integrated boost (SIB) for dose-escalation in pancreatic cancer patients. METHODS: For six pancreatic cancer patients referred for adjuvant or primary radiochemotherapy, four rMFO-IMPT-SIB treatment plans each, consisting of two or three (non-)coplanar beam arrangements, were optimized. Dose values for both targets, i.e., the elective clinical target volume [CTV, prescribed dose Dpres = 51Gy(RBE)] and the boost target [Dpres = 66Gy(RBE)], for the organs at risk as well as target conformity and homogeneity indexes, derived from the dose volume histograms, were statistically compared. RESULTS: All treatment plans of each strategy fulfilled the prescribed doses to the targets (Dpres(GTV,CTV) = 100%, D95%,(GTV,CTV) >= 95%, D2%,(GTV,CTV) <= 107%). No significant differences for the conformity index were found (p > 0.05), however, treatment plans with a three non-coplanar beam strategy were most homogenous to both targets (p < 0.045). The median value of all dosimetric results of the large and small bowel as well as for the liver and the spinal cord met the dose constraints with all beam arrangements. Irrespective of the planning strategies, the dose constraint for the duodenum and stomach were not met. Using the three-beam arrangements, the dose to the left kidney could be significant decreased when compared to a two beam strategy (p < 0.045). CONCLUSION: Based on our findings we recommend a three beam configuration with at least one non-coplanar beam for dose-escalated SIB with rMFO-IMPT in advanced pancreatic cancer patients achieving a homogeneous dose distribution in the target while simultaneously minimizing the dose to the organs at risk. Further treatment planning studies on aspects of breathing and organ motion need to be performed. PMID- 30466469 TI - Comparison of enzyme-linked immunosorbent assay systems using rift valley fever virus nucleocapsid protein and inactivated virus as antigens. AB - BACKGROUND: Rift Valley Fever (RVF) is a mosquito-borne viral zoonosis. To detect RVF virus (RVFV) infection, indirect immunoglobulin G (IgG) and immunoglobulin M (IgM) enzyme linked immunosorbent assays (ELISAs) which utilize recombinant RVFV nucleocapsid (RVFV-N) protein as assay antigen, have reportedly been used, however, there is still a need to develop more sensitive and specific methods of detection. METHODS: RVFV-N protein was expressed in Escherichia coli (E. coli) and purified by histidine-tag based affinity chromatography. This recombinant RVFV-N (rRVFV-N) protein was then used as antigen to develop an IgG sandwich ELISA and IgM capture ELISAs for human sera. Ninety six serum samples collected from healthy volunteers during the RVF surveillance programme in Kenya in 2013, and 93 serum samples collected from RVF-suspected patients during the 2006-2007 RVF outbreak in Kenya were used respectively, to evaluate the newly established rRVFV-N protein-based IgG sandwich ELISA and IgM capture ELISA systems in comparison with the inactivated virus-based ELISA systems. RESULTS: rRVFV-N protein-based-IgG sandwich ELISA and IgM capture ELISA for human sera were established. Both the new ELISA systems were in 100% concordance with the inactivated virus-based ELISA systems, with a sensitivity and specificity of 100%. CONCLUSIONS: Recombinant RVFV-N is a safe and affordable antigen for RVF diagnosis. Our rRVFV-N-based ELISA systems are safe and reliable tools for diagnosis of RVFV infection in humans and especially useful in large-scale epidemiological investigation and for application in developing countries. PMID- 30466470 TI - ECMO improves survival following cardiogenic shock due to carbon monoxide poisoning - an experimental porcine model. AB - BACKGROUND: Severe intoxication with carbon monoxide (CO) is extremely lethal and causes numerous deaths due to cardiac or respiratory failure. Conventional intensive treatment may not be sufficient. The aim of this study was to investigate the treatment effect of extracorporeal veno-arterial extracorporeal membrane oxygenation (ECMO) following severe CO poisoning in an experimental porcine model. METHODS: A total of twelve pigs were anaesthetized, routinely monitored and intoxicated by inhalation of CO until the beginning of cardiac failure and randomized to a treatment (ventilator using an FiO2 of 100% or ECMO). In the case of cardiac arrest, advanced resuscitation using standard guidelines was performed for at least 10 min. ECMO was also initiated in the ventilation group if the return of spontaneous circulation did not occur within 10 min. Lung tissue biopsies were obtained before and after CO intoxication. RESULTS: All animals in the ECMO group survived; however, one had to be resuscitated due to cardiac arrest. A single animal survived in the ventilator group, but five animals suffered from cardiac arrest at an average of 11.8 min after initiation of treatment. Conventional resuscitation failed in these animals, but four animals were successfully resuscitated after the establishment of ECMO. A significant decrease was noticed in PO2 with increasing HbCO, but there was no increase in pulmonary vascular resistance. No differences in H&E-stained lung tissue biopsies were observed. CONCLUSIONS: The use of ECMO following severe CO poisoning greatly improved survival compared with conventional resuscitation in an experimental porcine model. This study forms the basis for further research among patients. PMID- 30466471 TI - Intraoperative transit-time flowmetry in patients undergoing coronary surgery to determine relationships between graft flow and patency and prior coronary interventions and flow demand: a retrospective study. AB - BACKGROUND: The aim of this study was to delineate impacts of percutaneous coronary intervention (PCI), flow demand, and status of myocardium on graft flow. METHODS: We retrospectively assessed 736 individual coronary artery bypass grafts that had been created as the sole bypass graft for a vascular region in 405 patients. The grafts comprised 334 internal thoracic artery (ITA) to left anterior descending (LAD), 129 ITA and 65 saphenous vein grafts (SVG) to left circumflex (LCX), and 142 gastroepiploic artery (GEA) and 66 SVG to right coronary artery (RCA). Minimal luminal diameter, size of revascularized area, history of myocardial infarction, and PCI in the relevant area were examined to determine whether these factors are associated with flow insufficiency (FI), which was defined as <= 20 mL/min. RESULTS: FI developed in 123/736 grafts (16.7%) and correlated significantly with stenosis in the distal portion (23.0% vs. 12.8%, p = 0.0003). Prior myocardial infarction significantly correlated with FI in GEA-RCA (p = 0.002) and ITA-LCX grafts (p = 0.04). There was a history of PCI to the LAD (PCI group) in 54 ITA to LAD bypass grafts (16.2%), whereas the remaining 280 had no history of PCI to the LAD (no-PCI group). Graft flow was significantly greater in the no-PCI than in the PCI group (53 +/- 29 vs. 42 +/- 27; p = 0.006). The incidences of FI and graft failure were significantly higher in the PCI than the no-PCI group (22.2%, vs. 8.2%; p = 0.003; 9.2% vs. 1.8%; p = 0.003, respectively). CONCLUSIONS: Prior PCI has a negative impact on graft flow. The influences of small revascularized area, myocardial infarction, and PCI are greater, necessitating consideration of factors associated with flow demand or microvasculature when planning revascularization. PMID- 30466472 TI - Minimally invasive drainage in critically ill patients with severe necrotizing pancreatitis is associated with better outcomes: an observational study. AB - BACKGROUND: Infected pancreatic necrosis, which occurs in about 40% of patients admitted for acute necrotizing pancreatitis, requires combined antibiotic therapy and local drainage. Since 2010, drainage by open surgical necrosectomy has been increasingly replaced by less invasive methods such as percutaneous radiological drainage, endoscopic necrosectomy, and laparoscopic surgery, which proved effective in small randomized controlled trials in highly selected patients. Few studies have evaluated minimally invasive drainage methods used under the conditions of everyday hospital practice. The aim of this study was to determine whether, compared with conventional open surgery, minimally invasive drainage was associated with improved outcomes of critically ill patients with infection complicating acute necrotizing pancreatitis. METHODS: A single-center observational study was conducted in patients admitted to the intensive care unit for severe acute necrotizing pancreatitis to compare the characteristics, drainage techniques, and outcomes of the 62 patients managed between September 2006 and December 2010, chiefly with conventional open surgery, and of the 81 patients managed between January 2011 and August 2015 after the introduction of a minimally invasive drainage protocol. RESULTS: Surgical necrosectomy was more common in the early period (74% versus 41%; P <0.001), and use of minimally invasive drainage increased between the early and late periods (19% and 52%, respectively; P <0.001). The numbers of ventilator-free days and catecholamine free days by day 30 were higher during the later period. The proportions of patients discharged from intensive care within the first 30 days and from the hospital within the first 90 days were higher during the second period. Hospital mortality was not significantly different between the early and late periods (19% and 22%, respectively). CONCLUSION: In our study, the implementation of a minimally invasive drainage protocol in patients with infected pancreatic necrosis was associated with shorter times spent with organ dysfunction, in the intensive care unit, and in the hospital. Mortality was not significantly different. These results should be interpreted bearing in mind the limitations inherent in the before-after study design. PMID- 30466475 TI - Dynamic Notch signalling regulates neural stem cell state progression in the Drosophila optic lobe. AB - BACKGROUND: Neural stem cells generate all of the neurons and glial cells in the central nervous system, both during development and in the adult to maintain homeostasis. In the Drosophila optic lobe, neuroepithelial cells progress through two transient progenitor states, PI and PII, before transforming into neuroblasts. Here we analyse the role of Notch signalling in the transition from neuroepithelial cells to neuroblasts. RESULTS: We observed dynamic regulation of Notch signalling: strong activity in PI progenitors, low signalling in PII progenitors, and increased activity after neuroblast transformation. Ectopic expression of the Notch ligand Delta induced the formation of ectopic PI progenitors. Interestingly, we show that the E3 ubiquitin ligase, Neuralized, regulates Delta levels and Notch signalling activity at the transition zone. We demonstrate that the proneural transcription factor, Lethal of scute, is essential to induce expression of Neuralized and promote the transition from the PI progenitor to the PII progenitor state. CONCLUSIONS: Our results show dynamic regulation of Notch signalling activity in the transition from neuroepithelial cells to neuroblasts. We propose a model in which Lethal of scute activates Notch signalling in a non-cell autonomous manner by regulating the expression of Neuralized, thereby promoting the progression between different neural stem cell states. PMID- 30466473 TI - Methylome profiling of healthy and central precocious puberty girls. AB - BACKGROUND: Recent studies demonstrated that changes in DNA methylation (DNAm) and inactivation of two imprinted genes (MKRN3 and DLK1) alter the onset of female puberty. We aimed to investigate the association of DNAm profiling with the timing of human puberty analyzing the genome-wide DNAm patterns of peripheral blood leukocytes from ten female patients with central precocious puberty (CPP) and 33 healthy girls (15 pre- and 18 post-pubertal). For this purpose, we performed comparisons between the groups: pre- versus post-pubertal, CPP versus pre-pubertal, and CPP versus post-pubertal. RESULTS: Analyzing the methylome changes associated with normal puberty, we identified 120 differentially methylated regions (DMRs) when comparing pre- and post-pubertal healthy girls. Most of these DMRs were hypermethylated in the pubertal group (99%) and located on the X chromosome (74%). Only one genomic region, containing the promoter of ZFP57, was hypomethylated in the pubertal group. ZFP57 is a transcriptional repressor required for both methylation and imprinting of multiple genomic loci. ZFP57 expression in the hypothalamus of female rhesus monkeys increased during peripubertal development, suggesting enhanced repression of downstream ZFP57 target genes. Fourteen other zinc finger (ZNF) genes were related to the hypermethylated DMRs at normal puberty. Analyzing the methylome changes associated with CPP, we demonstrated that the patients with CPP exhibited more hypermethylated CpG sites compared to both pre-pubertal (81%) and pubertal (89%) controls. Forty-eight ZNF genes were identified as having hypermethylated CpG sites in CPP. CONCLUSION: Methylome profiling of girls at normal and precocious puberty revealed a widespread pattern of DNA hypermethylation, indicating that the pubertal process in humans is associated with specific changes in epigenetically driven regulatory control. Moreover, changes in methylation of several ZNF genes appear to be a distinct epigenetic modification underlying the initiation of human puberty. PMID- 30466476 TI - Marijuana and head and neck cancer: an epidemiological review. AB - BACKGROUND: Marijuana is the most widely used illicit substance in Canada. To date, no conclusive study has looked at the epidemiologic basis of marijuana use and head and neck cancer (HNC). Due to the imminent recreational legalization of marijuana in Canada, the epidemiologic relationship between marijuana use and HNC is becoming increasingly important. OBJECTIVE: To examine the epidemiologic characteristics of HNC patients who are recreational marijuana users. METHODS: This study was conducted at a single tertiary care centre from 2011 to 2014. Patients were enrolled consecutively at time of diagnosis of malignancy. Data was prospectively collected and included socioeconomic factors, alcohol/tobacco history, tumor characteristics, and treatment modality. Marijuana use was defined as current usage on an at least weekly basis. RESULTS: Eight hundred seventy-nine patients met inclusion and exclusion criteria. Seventy-four (8.4%) patients were classified as marijuana users. Compared to non-users, marijuana users were less likely to be married (p = 0.048) and had less significant tobacco smoking history (p = 0.004). There were no significant differences between other socioeconomic factors or local and regional disease (p > 0.05). Marijuana users differed in the proportion of cancers stratified by primary site (p < 0.0001), with higher rates of p16+ oropharyngeal cancers, and treatment modality (p < 0.0001), with more use of chemoradiation. CONCLUSIONS: HNC patients who were marijuana users were less likely to be married and smoke tobacco. They have a distinct cancer site prevalence and are more likely to be treated by chemoradiation. Understanding the epidemiological breakdown of marijuana users amongst HNC patients will be a useful adjunct for future studies. PMID- 30466477 TI - Prognostic value of computed tomography score in patients after extracorporeal cardiopulmonary resuscitation. AB - BACKGROUND: We evaluated whether Alberta Stroke Program Early Computed Tomography Score (ASPECTS) with some modifications could be used to predict neurological outcomes in patients after extracorporeal cardiopulmonary resuscitation (ECPR). METHODS: This was a retrospective, multicenter, observational study of adult unconscious patients who were evaluated by brain computed tomography (CT) within 48 hours after ECPR between May 2010 and December 2016. ASPECTS, bilateral ASPECTS (ASPECTS-b), and modified ASPECTS (mASPECTS) were assessed by ROC curves to predict neurological outcomes. The primary outcome was neurological status upon hospital discharge assessed with the Cerebral Performance Categories (CPC) scale. RESULTS: Among 58 unconscious patients, survival to discharge was identified in 25 (43.1%) patients. Of these 25 survivors, 19 (32.8%) had good neurological outcomes (CPC score of 1 or 2). Interrater reliability of CT scores was excellent. Intraclass correlation coefficients of ASPECTS, ASPECTS-b, and mASPECTS were 0.918 (95% CI, 0.865-0.950), 0.918 (95% CI, 0.866-0.951), and 0.915 (95% CI, 0.860-0.949), respectively. The predictive performance of mASPECTS for poor neurological outcome was better than that of ASPECTS or ASPECTS-b (C statistic for mASPECTS vs. ASPECTS, 0.922 vs. 0.812, p = 0.004; mASPECTS vs. ASPECTS-b, 0.922 vs. 0.818, p = 0.003). A cutoff of 25 for poor neurological outcome had a sensitivity of 84.6% (95% CI, 69.5-94.1%) and a specificity of 89.5% (95% CI, 66.9-98.7%) in mASPECTS. CONCLUSIONS: mASPECTS might be useful for predicting neurological outcomes in patients after ECPR. PMID- 30466474 TI - Tackling malignant melanoma epigenetically: histone lysine methylation. AB - Post-translational histone modifications such as acetylation and methylation can affect gene expression. Histone acetylation is commonly associated with activation of gene expression whereas histone methylation is linked to either activation or repression of gene expression. Depending on the site of histone modification, several histone marks can be present throughout the genome. A combination of these histone marks can shape global chromatin architecture, and changes in patterns of marks can affect the transcriptomic landscape. Alterations in several histone marks are associated with different types of cancers, and these alterations are distinct from marks found in original normal tissues. Therefore, it is hypothesized that patterns of histone marks can change during the process of tumorigenesis.This review focuses on histone methylation changes (both removal and addition of methyl groups) in malignant melanoma, a deadly skin cancer, and the implications of specific inhibitors of these modifications as a combinatorial therapeutic approach. PMID- 30466478 TI - Acquired mechanisms of immune escape in cancer following immunotherapy. AB - Immunotherapy has revolutionized the management of numerous cancers; however, a substantial proportion that initially respond subsequently acquire means of immune escape and relapse. Analysis of recent clinical trials permits us to preliminarily understand how immunotherapies exert evolutionary pressures: selecting cancer subclones deficient in antigenicity and/or immunogenicity, thereby facilitating immune escape. PMID- 30466479 TI - Induction of chronic destructive arthritis in SCID mice by arthritogenic fibroblast-like synoviocytes derived from mice with antigen-induced arthritis. AB - BACKGROUND: Fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA) are autonomously activated to maintain inflammation and joint destruction in co-transplantation models. To elucidate inducing mechanisms involved in this altered behavior, the arthritogenic potential of FLSs from murine antigen-induced arthritis (AIA) were investigated in a transfer model. METHODS: FLSs were isolated, expanded in vitro, and transferred into knee joint cavities of severe combined immunodeficient (SCID) mice. Their arthritogenic capacity was assessed by monitoring joint swelling and evaluation of histological parameters 70 to 100 days after transfer. RESULTS: FLSs from AIA mice were able to transfer arthritis into recipient SCID mice. FLS transfer induced a chronic arthritis with recruitment of inflammatory cells and marked cartilage destruction. Long-lasting inflammation was not required for imprinting of arthritogenicity in FLSs since cells isolated from acute arthritic joints were fully competent to transfer arthritis. We also observed arthritogenic potential in FLSs isolated from contralateral non-arthritic joints in our monoarticular arthritis model. CONCLUSIONS: We show that the transformation of FLSs into arthritogenic cells occurs early in arthritis development. This challenges current hypotheses on the role of these cells in arthritis pathogenesis and opens up the way for further mechanistic studies. PMID- 30466480 TI - Identification and characterization of early photoreceptor cis-regulatory elements and their relation to Onecut1. AB - BACKGROUND: Cone and rod photoreceptors are two of the primary cell types affected in human retinal disease. Potential strategies to combat these diseases are the use of gene therapy to rescue compromised photoreceptors or to generate new functional photoreceptors to replace those lost in the diseased retina. Cis regulatory elements specific to cones, rods, or both types of photoreceptors are critical components of successful implementation of these two strategies. The purpose of this study was to identify and characterize the cell type specificity and activity of cis-regulatory elements active in developing photoreceptors. METHODS: Cis-regulatory elements were introduced into the developing chicken and mouse retina by electroporation. Characterization of reporter activity in relation with cell type markers was determined using confocal microscopy. In addition, two high-throughput flow cytometry assay were developed to assess whether these elements were downstream of Onecut1 in the photoreceptor specification network. RESULTS: The majority of cis-regulatory elements were active in both cone and rod photoreceptors and were largely uninfluenced by a Onecut1 dominant-negative construct. Elements associated with the Thrb, Nr2e3, and Rhodopsin genes showed highly enriched activity in cones or rods, and were affected by interference in Onecut1 signaling. Rhodopsin promoter activity was the most highly influenced by Onecut1 activity and its induction could be modulated by the Maf family transcription factor L-Maf. Nr2e3 elements were observed to have activity in cone photoreceptors and Nr2e3 protein was expressed in developing cone photoreceptors, suggesting a role for this predominant rod gene in cone photoreceptor development. CONCLUSIONS: The analysis presented here provides an experimental framework to determine the specificity and strength of photoreceptor elements within specific genetic networks during development. The Onecut1 transcription factor is one such factor that influences the gene regulatory networks specific to cones and rods, but not those that are common to both. PMID- 30466481 TI - Early surgical management of traumatic dislocation of the tibialis posterior tendon: a case report and review of the literature. AB - BACKGROUND: Traumatic dislocation of the tibialis posterior tendon at the ankle is a rare injury. Some of these cases are misdiagnosed as ankle sprains and are not treated properly. In addition, because the conservative treatment is not as effective as the surgical treatment, it is essential that patients be diagnosed early so that proper surgical treatment can be performed. We report the early surgical management of traumatic dislocation of the tibialis posterior tendon. CASE PRESENTATION: A 44-year-old Japanese man, who was a karate coach, was injured while acting as an umpire in a karate competition. On the same day of his injury, he came to our hospital. He complained of swelling and pain in the medial malleolus. Anterior dislocation of the tibialis posterior tendon was detected upon palpation. Magnetic resonance imaging showed the presence of anterior dislocation of the tibialis posterior tendon with retinaculum injury. Four days after the injury, we performed the Das De procedure as the surgical treatment. Three months after the surgery, the patient was able to participate in karate again. CONCLUSIONS: Dislocation of the tibialis posterior tendon is likely to be misdiagnosed, thus delaying the start of proper treatment. It is essential to diagnose the patient accurately by carefully assessing the physical symptoms manifested. Moreover, magnetic resonance imaging can also be used for better diagnosis, thereby leading to an early and proper surgical treatment. PMID- 30466482 TI - Rural-urban difference in blood pressure measurement frequency among elderly with hypertension: a cross-sectional study in Shandong, China. AB - BACKGROUND: Blood pressure measurement is the first step in preventing and controlling hypertension. The objective of this study is to examine the rural urban difference towards blood pressure measurement among elderly with hypertension. METHODS: A total of 2007 elderly (65+) were selected from the fifth Health Service Survey of Shandong Province in 2013. A standardized questionnaire was used to investigate the demographic characters, socioeconomic status, self rated health, and blood pressure related index. Three logistic regression models were used to examine the difference in blood pressure measurement between rural and urban elderly. Unadjusted and adjusted logistic regression models were used to explore the associated factors of blood pressure measurement in both rural areas and urban areas. RESULTS: The prevalence of weekly blood pressure measurement in urban elderly was higher than that in rural elderly (63.9% vs 34.3%). The rural elderly had an odds ratio (OR) for weekly blood pressure measurement of 0.467 (95%CI = 0.380-0.575) compared with urban elderly. Binary logistic regression analysis showed that medication frequency and accepting health care professionals' guidance were common associated factors of blood pressure measurement among both rural and urban elderly; personal income was unique associated factor of blood pressure measurement among rural elderly; marital status, education level, self-rated health, and blood pressure level currently were unique associated factors of blood pressure measurement among urban elderly. CONCLUSIONS: There is a big difference in blood pressure measurement between rural and urban elderly. Interventions targeting identified at-risk subgroups, especially for those rural elderly, should be made to reduce such a gap. PMID- 30466483 TI - Specialisation events of fungal metacommunities exposed to a persistent organic pollutant are suggestive of augmented pathogenic potential. AB - BACKGROUND: The impacts of man-made chemicals, in particular of persistent organic pollutants, are multifactorial as they may affect the integrity of ecosystems, alter biodiversity and have undesirable effects on many organisms. We have previously demonstrated that the belowground mycobiota of forest soils acts as a buffer against the biocide pollutant pentachlorophenol. However, the trade offs made by mycobiota to mitigate this pollutant remain cryptic. RESULTS: Herein, we demonstrate using a culture-dependent approach that exposure to pentachlorophenol led to alterations in the composition and functioning of the metacommunity, many of which were not fully alleviated when most of the biocide was degraded. Proteomic and physiological analyses showed that the carbon and nitrogen metabolisms were particularly affected. This dysregulation is possibly linked to the higher pathogenic potential of the metacommunity following exposure to the biocide, supported by the secretion of proteins related to pathogenicity and reduced susceptibility to a fungicide. Our findings provide additional evidence for the silent risks of environmental pollution, particularly as it may favour the development of pathogenic trade-offs in fungi, which may impose serious threats to animals and plant hosts. PMID- 30466484 TI - mHealth smoking cessation intervention among high-school pupils (NEXit Junior): study protocol for a randomized controlled trial. AB - BACKGROUND: Mobile health (mHealth) interventions, using text messages to support high-school pupils to quit smoking, could be a novel and cost-effective approach. However, more research is needed, specifically to investigate long-term effectiveness. The study aims to evaluate the effectiveness of a newly developed mHealth intervention targeting smoking cessation among high-school pupils. METHODS: The study is a two-arm, randomized controlled trial with an intervention group (mHealth intervention) and a control group (treatment as usual: national smoking cessation help line). Outcome measures will be investigated at baseline and at 3, 6, and 12 months' follow-up. Primary outcome measures will be: prolonged abstinence and 4-week point prevalence of smoking abstinence. Secondary outcome measures will be: 7-day point prevalence of smoking abstinence; mean number of quit attempts since taking part in the study; number of uses of other smoking cessation services since first invitation to the study and number of cigarettes smoked weekly if still smoking. DISCUSSION: High schools in Sweden are bound by law to offer a smoke-free environment. However, little effort has been made to offer support to pupils who wish to quit smoking; rather the emphasis is on prevention of uptake. The study will examine the effectiveness of a stand alone mHealth intervention targeting smokers among high-school pupils. TRIAL REGISTRATION: The trial was not retrospectively registered and has been registered at ISRCTN with the unique identification number ISRCTN15396225 . The trial was registered on 13 October 2017. PMID- 30466486 TI - The paramount parameter: arterial oxygen tension versus arterial oxygen saturation as target in trials on oxygenation in intensive care. PMID- 30466485 TI - Anxiety, Depression and Post Traumatic Stress Disorder after critical illness: a UK-wide prospective cohort study. AB - BACKGROUND: Survivors of intensive care are known to be at increased risk of developing longer-term psychopathology issues. We present a large UK multicentre study assessing the anxiety, depression and post-traumatic stress disorder (PTSD) caseness in the first year following discharge from an intensive care unit (ICU). METHODS: Design: prospective multicentre follow-up study of survivors of ICU in the UK. SETTING: patients from 26 ICUs in the UK. INCLUSION CRITERIA: patients who had received at least 24 h of level 3 ICU care and were 16 years of age or older. INTERVENTIONS: postal follow up: Hospital Anxiety and Depression Score (HADS) and the Post-Traumatic Stress Disorder (PTSD) Check List-Civilian (PCL-C) at 3 and 12 months following discharge from ICU. MAIN OUTCOME MEASURE: caseness of anxiety, depression and PTSD, 2-year survival. RESULTS: In total, 21,633 patients admitted to ICU were included in the study. Postal questionnaires were sent to 13,155 survivors; of these 38% (4943/13155) responded and 55% (2731/4943) of respondents passed thresholds for one or more condition at 3 or 12 months following discharge. Caseness prevalence was 46%, 40% and 22% for anxiety, depression and PTSD respectively; 18% (870/4943 patients) met the caseness threshold for all three psychological conditions. Patients with symptoms of depression were 47% more likely to die during the first 2 years after discharge from ICU than those without (HR 1.47, CI 1.19-1.80). CONCLUSIONS: Over half of those who respond to postal questionnaire following treatment on ICU in the UK reported significant symptoms of anxiety, depression or PTSD. When symptoms of one psychological disorder are present, there is a 65% chance they will co-occur with symptoms of one of the other two disorders. Depression following critical illness is associated with an increased mortality risk in the first 2 years following discharge from ICU. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN69112866 . Registered on 2 May 2006. PMID- 30466487 TI - Adjuvant Vitamin C in critically ill patients undergoing renal replacement therapy: What's the right dose? PMID- 30466488 TI - Caregivers' knowledge and attitudes about childhood diarrhea among refugee and host communities in Gambella Region, Ethiopia. AB - BACKGROUND: Maternal knowledge, attitudes, and practices related to hygiene, breastfeeding, sanitary food preparation, and appropriate weaning practices are potentially important determinants in the occurrence of diarrhea in children. However, few studies have been carried out about the knowledge and attitudes about childhood diarrhea among parents in refugee camps and host communities. OBJECTIVE: This study aims at assessing the caregivers' knowledge and attitudes regarding acute diarrhea in under-five children among refugee and host communities in Gambella Region, Ethiopia. METHODOLOGY: This cross-sectional study, employing multistage sampling, was carried out from September to December 2016. Data was collected by a questionnaire-based interview, and 1667 caregivers were included in this study. A composite knowledge score was calculated, and a five-point Likert type of attitude scale was developed to assess the attitudes of the caregivers towards childhood diarrhea. Appropriate descriptive statistics and logistic regression models were used. Odds ratios (ORs) are presented with their 95% confidence intervals (CIs), and all analyses were performed at the 5% significance level (p < 0.05). RESULT: The study indicates that 633 (28.0%) of the caregivers had poor knowledge, while 393 (23.6%) of them had unfavorable attitudes towards childhood diarrhea. Knowledge of the caregivers was significantly associated with formal education (AOR, 1.3; 95% CI, 1.03-1.5) and health information obtained from a health care institution (AOR, 1.8; 95% CI, 1.28-2.3). Caregivers' knowledge is a single predictor of their attitude (p < 0.001), and Pearson's correlation coefficient revealed that there was a significant positive correlation (r = 0.2, p < 0.001) between knowledge and attitude scores. CONCLUSION: The study indicates that significant numbers of caregivers had inadequate knowledge and unfavorable attitudes about diarrhea in under-five children. Designing and implementing an inclusive health education intervention focusing on uneducated child caregivers may be beneficial for improving knowledge and attitudes towards reducing the incidence of acute childhood diarrhea in the region. PMID- 30466489 TI - Attitudes toward cost-conscious care among U.S. physicians and medical students: analysis of national cross-sectional survey data by age and stage of training. AB - BACKGROUND: The success of initiatives intended to increase the value of health care depends, in part, on the degree to which cost-conscious care is endorsed by current and future physicians. This study aimed to first analyze attitudes of U.S. physicians by age and then compare the attitudes of physicians and medical students. METHODS: A paper survey was mailed in mid-2012 to 3897 practicing physicians randomly selected from the American Medical Association Masterfile. An electronic survey was sent in early 2015 to all 5,992 students at 10 U.S. medical schools. Survey items measured attitudes toward cost-conscious care and perceived responsibility for reducing healthcare costs. Physician responses were first compared across age groups (30-40 years, 41-50 years, 51-60 years, and > 60 years) and then compared to student responses using Chi square tests and logistic regression analyses (controlling for sex). RESULTS: A total of 2,556 physicians (65%) and 3395 students (57%) responded. Physician attitudes generally did not differ by age, but differed significantly from those of students. Specifically, students were more likely than physicians to agree that cost to society should be important in treatment decisions (p < 0.001) and that physicians should sometimes deny beneficial but costly services (p < 0.001). Students were less likely to agree that it is unfair to ask physicians to be cost-conscious while prioritizing patient welfare (p < 0.001). Compared to physicians, students assigned more responsibility for reducing healthcare costs to hospitals and health systems (p < 0.001) and less responsibility to lawyers (p < 0.001) and patients (p < 0.001). Nearly all significant differences persisted after controlling for sex and when only the youngest physicians were compared to students. CONCLUSIONS: Physician attitudes toward cost-conscious care are similar across age groups. However, physician attitudes differ significantly from medical students, even among the youngest physicians most proximate to students in age. Medical student responses suggest they are more accepting of cost-conscious care than physicians and attribute more responsibility for reducing costs to organizations and systems rather than individuals. This may be due to the combined effects of generational differences, new medical school curricula, students' relative inexperience providing cost-conscious care within complex healthcare systems, and the rapidly evolving U.S. healthcare system. PMID- 30466490 TI - Improving redox sensitivity of roGFP1 by incorporation of selenocysteine at position 147. AB - OBJECTIVE: Redox-sensitive green fluorescent protein (roGFP) is a genetically encoded redox-sensitive protein used to detect cellular oxidative stress associated with reactive oxygen species production. Here we replaced the cysteine at position 147 of roGFP1 (variant of roGFP) with selenocysteine in order to increase redox sensitivity of the redox reporter. RESULTS: Expression of roGFP1 selenoprotein (roGFP1-Se147) in HEK293 cells required the presence of a selenocysteine insertion sequence and was augmented by co-expression with SBP2. roGFP1-Se147 demonstrated a similar excitation and emission spectra to roGFP1. Although expression of roGFP1-Se147 was limited, it was sufficient enough to perform live cell imaging to evaluate sensitivity to oxidation and reduction. roGFP1-Se147 exhibited a 100-fold increase in sensitivity to oxidation with H2O2 in comparison to roGFP1 as well as a 20-fold decrease in the EC50 of H2O2. Furthermore, roGFP1-Se147, unlike roGFP1, was able to detect oxidation caused by the mitochondrial electron transport complex III inhibitor antimycin A. Unfortunately roGFP-Se147 exhibited a diminished dynamic range and photoinstability. PMID- 30466491 TI - Gut microbiome composition is associated with spatial structuring and social interactions in semi-feral Welsh Mountain ponies. AB - BACKGROUND: Microbiome composition is linked to host functional traits including metabolism and immune function. Drivers of microbiome composition are increasingly well-characterised; however, evidence of group-level microbiome convergence is limited and may represent a multi-level trait (i.e. across individuals and groups), whereby heritable phenotypes are influenced by social interactions. Here, we investigate the influence of spatial structuring and social interactions on the gut microbiome composition of Welsh mountain ponies. RESULTS: We show that semi-feral ponies exhibit variation in microbiome composition according to band (group) membership, in addition to considerable within-individual variation. Spatial structuring was also identified within bands, suggesting that despite communal living, social behaviours still influence microbiome composition. Indeed, we show that specific interactions (i.e. mother offspring and stallion-mare) lead to more similar microbiomes, further supporting the notion that individuals influence the microbiome composition of one another and ultimately the group. Foals exhibited different microbiome composition to sub adults and adults, most likely related to differences in diet. CONCLUSIONS: We provide novel evidence that microbiome composition is structured at multiple levels within populations of social mammals and thus may form a unit on which selection can act. High levels of within-individual variation in microbiome composition, combined with the potential for social interactions to influence microbiome composition, suggest the direction of microbiome selection may be influenced by the individual members present in the group. Although the functional implications of this require further research, these results lend support to the idea that multi-level selection can act on microbiomes. PMID- 30466492 TI - Corporate political activity of major food companies in Thailand: an assessment and policy recommendations. AB - BACKGROUND: The food industry can influence individual and population level food consumption behaviours, shape public preferences and interfere with government policy on obesity prevention and NCDs. This paper identifies the Corporate Political Activity (CPA) of major food companies in Thailand which relate to obesity and NCDs. METHODS: Using the INFORMAS framework to classify CPA, we reviewed publicly available information by 12 food companies between August 2011 and July 2016 in order to identify, analyse and classify the CPA contents. Semi structured interviews with 17 key stakeholders who are experts in this field supplemented evidence from the document review. Data analysis applied a thematic approach. RESULTS: Food industry in Thailand applied a variety of CPA strategies and practices. The two most common strategies were constituency building and information and messaging. CONCLUSION: The diverse range of CPA strategies which influence government policy and public opinion can undermine efforts to prevent obesity and diet-related NCDs. We recommend systematic monitoring of their CPA, strengthening mechanisms to hold the food industry accountable for their role in protecting and promoting the nutrition and health of the population, introducing mandatory registration of lobbyists, mandatory disclosure of political donations, and stronger oversight of conflicts of interest among the government actors. PMID- 30466495 TI - Cost Analysis of Computerized Clinical Decision Support and Trainee Financial Incentive for Clostridioides difficile Testing. PMID- 30466496 TI - Compassion and the Uncertain Caregiver. PMID- 30466497 TI - Effects of l-carnitine in the distillers dried grains with solubles diet of sows on reproductive performance and antioxidant status of sows and their offspring. AB - Distillers dried grains with solubles (DDGS) are highly susceptible to lipid oxidation because DDGS contain about 10% crude fat, which is largely composed of polyunsaturated fatty acids. l-carnitine serves an important function in fatty acids beta-oxidation, and also has antioxidant properties. The objective of this study was to examine the effects of l-carnitine in the DDGS diet of gestating and lactating sows on reproductive performance, milk composition and antioxidant status of sows and their offspring. One hundred and twenty sows (Landrace*Large white, mean parity 4.2, initial BW 230 kg) were randomly allotted to 1 of 4 dietary treatments (n=30 sows/treatment). Treatments were arranged as a 2*2 factorial with two levels of dietary DDGS (0 v. 250 g/kg in gestating diets and 400 g/kg in lactating diets) and two levels of dietary l-carnitine (0 v. 100 mg/kg in gestating diets and 0 v. 200 mg/kg in lactating diets). Distillers dried grains with solubles had no significant effect on litter size but significantly reduced the birth weights and weaning weights of piglets (P0.05). Supplementing the diets with l-carnitine had no significant effect of total litter size (P>0.05) but increased the number of piglets born alive and piglets weaned, birth weight and weaning weight of piglets and litter weight at birth and weaning (P<0.05). l-carnitine supplementation also increased the concentration of l carnitine in milk and l-carnitine status of piglets (P<0.05). The antioxidant enzyme activities of new born and weaning piglets were increased (P<0.05) by maternal dietary l-carnitine but this did not extend to finishing pigs. In conclusion, including DDGS in the sows diet could induce oxidative stress, which may be associated with the reduced individual birth and weaning weight of piglets. Dietary l-carnitine supplementation improved the antioxidant and l carnitine status of sows, which may be associated with the improved reproduction and piglet performance and the antioxidant status of piglets at birth and weaning. There were no interactions between DDGS and l-carnitine. PMID- 30466498 TI - Attachment state of mind and childhood experiences of maltreatment as predictors of sensitive care from infancy through middle childhood: Results from a longitudinal study of parents involved with Child Protective Services. AB - The current longitudinal study examined whether attachment states of mind and childhood maltreatment predict sensitive caregiving during infancy, early childhood, and middle childhood among a sample of 178 parents who were involved with Child Protective Services. Nearly all the parents had themselves experienced childhood maltreatment based on their reports on the Childhood Trauma Questionnaire-Short Form (Bernstein et al., 2003) when their children were infants. Adult Attachment Interviews (George, Kaplan, & Main, 1985) were administered to parents when their children were infants (M = 10.92 months, SD = 8.66). Parental sensitivity was rated based on observations of parent-child interactions at three time points: infancy, early childhood, and middle childhood. During infancy, dismissing states of mind of parents predicted marginally lower sensitivity scores than autonomous states of mind. In early and middle childhood, dismissing states of mind of parents predicted significantly lower sensitivity ratings than autonomous states of mind. Unresolved states of mind of parents predicted significantly lower sensitivity scores than autonomous states of mind only during early childhood. Childhood maltreatment was not significantly associated with parents' sensitivity ratings at all three time points. Findings suggest that among parents with Child Protective Services involvement, most of whom had themselves experienced maltreatment, parents' unresolved states of mind predict insensitive caregiving in early childhood, and parents' dismissing states of mind predict insensitive caregiving from infancy through middle childhood. PMID- 30466494 TI - Dystrophin R16/17-syntrophin PDZ fusion protein restores sarcolemmal nNOSMU. AB - BACKGROUND: Loss of sarcolemmal nNOSMU is a common manifestation in a wide variety of muscle diseases and contributes to the dysregulation of multiple muscle activities. Given the critical role sarcolemmal nNOSMU plays in muscle, restoration of sarcolemmal nNOSMU should be considered as an important therapeutic goal. METHODS: nNOSMU is anchored to the sarcolemma by dystrophin spectrin-like repeats 16 and 17 (R16/17) and the syntrophin PDZ domain (Syn PDZ). To develop a strategy that can independently restore sarcolemmal nNOSMU, we engineered an R16/17-Syn PDZ fusion construct and tested whether this construct alone is sufficient to anchor nNOSMU to the sarcolemma in three different mouse models of Duchenne muscular dystrophy (DMD). RESULTS: Membrane-associated nNOSMU is completely lost in DMD. Adeno-associated virus (AAV)-mediated delivery of the R16/17-Syn PDZ fusion construct successfully restored sarcolemmal nNOSMU in all three models. Further, nNOS restoration was independent of the dystrophin associated protein complex. CONCLUSIONS: Our results suggest that the R16/17-Syn PDZ fusion construct is sufficient to restore sarcolemmal nNOSMU in the dystrophin-null muscle. PMID- 30466499 TI - Factors related to sense of competence in family caregivers of people living with dementia in the community: a narrative synthesis. AB - : ABSTRACTObjectives:Sense of competence defines a caregiver's feeling of being capable to manage the caregiving task and is an important clinical concept in the caregiving literature. The aim of this review was to identify the factors, both positive and negative, associated with a caregiver's perception of their sense of competence. DESIGN: A systematic review of the literature was conducted, retrieving both quantitative and qualitative papers from databases PsycINFO, CINAHL, EMBASE, and Medline. A quality assessment was conducted using the STROBE and CASP checklists, and the quality rating informed the inclusion of papers ensuring the evidence was robust. Narrative synthesis was employed to synthesize the findings and to generate an updated conceptual model of sense of competence. RESULTS: Seventeen papers were included in the review, all of which were moderate to high quality. These included 13 quantitative, three mixed-methods and one qualitative study. Factors associated with sense of competence included: behavioral and psychological symptoms of dementia (BPSD), caregiver depression, gratitude, and the ability to find meaning in caregiving. CONCLUSIONS: The results of this review demonstrate that both positive and negative aspects of caring are associated with caregiver sense of competence. Positive and negative aspects of caregiving act in tandem to influence caregiver perception of their competence. The proposed model of sense of competence aims to guide future research and clinical interventions aimed at improving this domain but requires further testing, as due to the observational nature of the include papers, the direction of causality could not be inferred. PMID- 30466493 TI - Characteristics, management, and in-hospital mortality among patients with severe sepsis in intensive care units in Japan: the FORECAST study. AB - BACKGROUND: Sepsis is a leading cause of death and long-term disability in developed countries. A comprehensive report on the incidence, clinical characteristics, and evolving management of sepsis is important. Thus, this study aimed to evaluate the characteristics, management, and outcomes of patients with severe sepsis in Japan. METHODS: This is a cohort study of the Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis, and Trauma (FORECAST) study, which was a multicenter, prospective cohort study conducted at 59 intensive care units (ICUs) from January 2016 to March 2017. We included adult patients with severe sepsis based on the sepsis-2 criteria. RESULTS: In total, 1184 patients (median age 73 years, interquartile range (IQR) 64-81) with severe sepsis were admitted to the ICU during the study period. The most common comorbidity was diabetes mellitus (23%). Moreover, approximately 63% of patients had septic shock. The median Sepsis-related Organ Failure Assessment (SOFA) score was 9 (IQR 6-11). The most common site of infection was the lung (31%). Approximately 54% of the participants had positive blood cultures. The compliance rates for the entire 3-h bundle, measurement of central venous pressure, and assessment of central venous oxygen saturation were 64%, 26%, and 7%, respectively. A multilevel logistic regression model showed that closed ICUs and non-university hospitals were more compliant with the entire 3-h bundle. The in-hospital mortality rate of patients with severe sepsis was 23% (21-26%). Older age, multiple comorbidities, suspected site of infection, and increasing SOFA scores correlated with in-hospital mortality, based on the generalized estimating equation model. The length of hospital stay was 24 (12-46) days. Approximately 37% of the patients were discharged home after recovery. CONCLUSION: Our prospective study showed that sepsis management in Japan was characterized by a high compliance rate for the 3-h bundle and low compliance rate for central venous catheter measurements. The in-hospital mortality rate in Japan was comparable to that of other developed countries. Only one third of the patients were discharged home, considering the aging population with multiple comorbidities in the ICUs in Japan. TRIAL REGISTRATION: UMIN-CTR, UMIN000019742 . Registered on 16 November 2015. PMID- 30466500 TI - Differences in Facial Emotional Recognition Between Patients With the First Episode Psychosis, Multi-episode Schizophrenia, and Healthy Controls. AB - OBJECTIVES: The aim of our study was to assess the differences in facial emotional recognition (FER) between patients with first-episode psychosis (FEP), patients with multi-episode schizophrenia (SCH), and healthy controls (HC) and to find possible correlations of FER with psychopathology in the two patient groups. METHODS: We performed a cross-sectional study enrolling 160 patients from two psychiatric hospitals in Croatia (80 FEP and 80 SCH) and 80 HC during the period from October 2015 until October 2017. Patients were assessed once during their hospital treatment, using the Penn Emotion Recognition Task for assessment of FER, rating scales for psychopathology and depression and self-reporting questionnaires for impulsiveness, aggression, and quality of life. RESULTS: The number of correctly identified emotions significantly decreased from HC to FEP [Delta -7%; 95% confidence interval (CI) [-12% to -3%], effect size r = 0.30] and more markedly in SCH (Delta -15%; 95% CI [-25% to -10%], effect size r = 0.59) after the adjustment for age and gender and correction for multiple testing. Correct FER for negative emotions, but not for happiness and neutral emotions, had a statistically significant negative correlation with some features on the scales of psychopathology, impulsivity and aggression in both patient groups. CONCLUSIONS: Impairment of FER is present from the first episode of schizophrenia and increases further with multiple psychotic episodes, but it may depend on or contribute to clinical symptoms. Therefore, assessment of FER should be included in the clinical assessment and integrated in the plan of treatment from the beginning of the illness. (JINS, 2018, 00, 1-9). PMID- 30466501 TI - CT evaluation of aberrant right subclavian artery: anatomy and clinical implications. AB - : PurposeThe aim of the study was to perform CT angiography-based evaluation of aberrant right subclavian artery prevalence, anatomy, and its influence on clinical symptoms. METHODS: A total of 6833 patients who underwent 64-slice or dual-source CT angiography and those who revealed aberrant right subclavian artery underwent evaluation of its anatomy and were interviewed for the presence of clinical symptoms. RESULTS: Aberrant right subclavian artery was found in 32 (0.47%) patients consisting of 13 males and 19 females, with mean age of 60.8+/ 13.4 years. Among the interviewed 30 (94%) patients, oesophageal compression was observed in 14 cases (47%) and tracheal compression in three cases (10%). None of the patients underwent surgery related to aberrant right subclavian artery. Dysphagia was the most common clinical symptom in nine cases (30%), and in those patients the median distance between aberrant right subclavian artery and trachea was lower (4 mm) than in individuals without dysphagia (7.5 mm) (p = 0.009). The median lumen area of the aberrant right subclavian artery at the level of oesophagus was higher in patients with dysphagia (208 mm2) compared with individuals without dysphagia (108 mm2) (p = 0.01). CONCLUSIONS: Aberrant right subclavian artery is a rare occurring abnormality in CT angiography. In the evaluated adult population, the most common symptom was dysphagia, which occurred in patients with decreased distance between aberrant right subclavian artery and trachea and increased lumen area of the aberrant artery at the level of compressed oesophagus. PMID- 30466502 TI - Goals of care and treatment in terminal delirium: A qualitative study of the views and experiences of healthcare professionals caring for patients with cancer. AB - OBJECTIVE: This study explores the views of healthcare professionals regarding care and treatment goals in irreversible terminal delirium and their effect on patients and caregivers. METHOD: We conducted a qualitative interview study of healthcare professionals (palliative care physician, oncologist, psycho oncologist, and clinical psychologist) engaged in the treatment of terminally ill cancer patients. We assessed the views of healthcare workers regarding treatment goals in terminal delirium and their effect on patients and their families.ResultOf the 21 eligible healthcare professionals, 20 agreed to participate in this study. Three of the professionals had experience with treating terminal delirium as family caregivers. We identified five important aspects of treatment goals in terminal delirium based on the views of healthcare professionals: (1) adequate management of symptoms/distress, (2) ability to communicate, (3) continuity of self, (4) provision of care and support to families, and (5) considering a balance (between symptom alleviation and maintaining communication; between symptom alleviation and family preparations for the death of patients; balance between specific treatment goals for delirium and general treatment goals).Significance of resultsAccording to the views of healthcare workers questioned in this study, goals of care and treatment in terminal delirium are multidimensional and extend beyond simply controlling patient symptoms. PMID- 30466503 TI - DOHaD in science and society: emergent opportunities and novel responsibilities. AB - The field of Developmental Origins of Health and Disease (DOHaD) has grown considerably in recent decades and is receiving increasing recognition from health policymakers. Today, DOHaD research aims to offer a comprehensive perspective on health and disease that traces how different life experiences shape health and disease risks over the entire life course. This integrative perspective opens up distinct possibilities for improving health. At the same time, it raises questions regarding the specific social responsibilities of DOHaD as a field and about possible pathways to a socially just and scientifically robust implementation of DOHaD knowledge in society. In this article, we review the history and key characteristics of DOHaD as a field of scientific knowledge production. We argue that based on its key assumptions - that life circumstances, health and disease are closely linked on a molecular scale - DOHaD is an inherently political research field. When tracing how life environments affect health and disease, it is of utmost social and political importance to specify how DOHaD understands and frames these life environments, which aspects of life worlds are included and which excluded, and how research results are interpreted and translated into health recommendations at individual, societal and policy levels. We suggest a number of ways by which the DOHaD community can constructively and responsibly meet the demands that these inherent characteristics place on knowledge production and dissemination in the field. PMID- 30466504 TI - 'We get so task orientated at times that we forget the people': staff communication experiences when caring for Aboriginal cardiac patients. AB - Objective The aim of this study was to describe the experiences of communication for staff providing cardiac care for Aboriginal and Torres Strait Islander patients in hospital and discuss potential improvements.Methods Focus group discussions were performed with 58 multidisciplinary staff who provide care for Aboriginal and Torres Strait Islander cardiac patients in two metropolitan and two regional hospitals in South Australia and Northern Territory. Inductive thematic analysis was undertaken to identify staff perceptions of communication challenges and strategies for improvement.Results There were five key themes: (1) communication is central to good care; (2) communication within busy clinical environments; (3) supporting a strong Aboriginal workforce; (4) a cultural as well as clinical focus; and (5) particular challenges working with patients from remote areas.Conclusions Providing effective communication that is both clinically and culturally appropriate is often challenging within a busy and non adaptive hospital environment. Moving beyond clinical tasks, increased Aboriginal and Torres Strat Islander health workforce and cultural competency, supporting coordinated care and improved skills are required to meet the communication needs of Aboriginal and Torres Strait Islander patients.What is known about this topic? Communication between patients, their families and hospital staff is crucial for health care quality and safety. There is little understanding of the challenges and opportunities for staff to meet the communication needs of Aboriginal and Torres Strait Islander cardiac patients to address disparities in acute care settings.What does this paper add? This paper discusses the barriers and potential improvements, as identified by hospital staff providing care to Aboriginal and Torres Strait Islander cardiac patients in both metropolitan and regional settings.What are the implications for practitioners? Practitioners should be trained and supported in providing both clinically and culturally safe care for Aboriginal and Torres Strait Islander patients. This requires adequate time, two-way communication and resources to support and facilitate effective communication. PMID- 30466505 TI - Persistence of Drug Memories: Melting Transcriptomes. PMID- 30466506 TI - Deconstructing and Reconstructing the Dichotomy That Is Dopamine Receptor-1- and Dopamine Receptor-2-Expressing Neurons. PMID- 30466507 TI - Activation of the Immune System During a Developmental Window May Provide a Link Between Early Life Stress and Future Susceptibility to Cocaine Abuse. PMID- 30466508 TI - Are We Ready for Individualized Target Planning of Ablative Procedures in Intractable Obsessive-Compulsive Disorder? PMID- 30466509 TI - Constitutional absence of epithelial integrin alpha3 impacts the composition of the cellular microenvironment of ILNEB keratinocytes. AB - Integrin alpha3beta1, a major epidermal adhesion receptor is critical for organization of the basement membrane during development and wound healing. Integrin alpha3 deficiency leads to interstitial lung disease, nephrotic syndrome and epidermolysis bullosa (ILNEB), an autosomal recessive multiorgan disease characterized by basement membrane abnormalities in skin, lung and kidney. The pathogenetic chains from ITGA3 mutation to tissue abnormalities are still unclear. Although integrin alpha3 was reported to regulate multiple extracellular proteins, the composition of the extracellular compartment of integrin alpha3 negative keratinocytes has not been resolved so far. In a comprehensive approach, quantitative proteomics of deposited extracellular matrix, conditioned cultured media as well as of the intracellular compartment of keratinocytes isolated from an ILNEB patient and from normal skin were performed. By mass spectrometry-based proteomics, 167 proteins corresponding to the GO terms "extracellular" and "cell adhesion", or included in the "human matrisome" were identified in the deposited extracellular matrix, and 217 in the conditioned media of normal human keratinocytes. In the absence of integrin alpha3, 33% and 26% respectively were dysregulated. Dysregulated proteins were functionally related to integrin alpha3 or were known interaction partners. The results show that in the absence of integrin alpha3 ILNEB keratinocytes produce a fibronectin-rich microenvironment and make use of fibronectin-binding integrin subunits alphav and alpha5. The most important results were validated in monolayer and organotypic coculture models. Finally, the in vivo relevance of the most dysregulated components was demonstrated by immunostainings of skin, kidney and lung samples of three ILNEB patients. PMID- 30466511 TI - Editorial: Drug delivery in older people - unique challenges and important opportunities. PMID- 30466510 TI - Puerarin alleviate radicular pain from lumbar disc herniation by inhibiting ERK dependent spinal microglia activation. AB - Lumbar disc herniation is a common cause of radicular pain, but the mechanism remains ambiguous and the treatment stays unsatisfied. Many studies revealed a traditional Chinese medicine puerarin may moderate chronic pain from diabetes and nerve injury. Thus far, the role and mechanism of puerarin in radicular pain is still unknown. In this study, by using a rat model of lumbar disc herniation, which was induced by autologous nucleus pulposus (NP) implantation, the analgesic effect of puerarin on radicular pain was tested. Puerarin was delivered intraperitoneally form 1 h before surgery, and once daily for 7 days. The results demonstrated that NP implantation induced long-lasting pain, characterized by decrease of paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in ipsilateral hindpaws, as long as day 20 after surgery. Spinal phosphorylated extracellular signal-regulated kinase (p-ERK) was up-regulated from day 5 to day 20 after surgery in ipsilateral but not contralateral side, and p-ERK was mainly co-localized with microglia. Puerarin decreased p-ERK expression from day 7 to day 20 after surgery. Puerarin or ERK inhibitor PD98059 alleviated pain behaviors, decreased expression of microglia marker ionized calcium-binding adaptor molecule 1 (Iba-1) in rats with NP implantation. The results suggested puerarin may alleviate radicular pain by inhibiting ERK-dependent or accompanied spinal microglia activation. PMID- 30466513 TI - Guiding Heart Failure Therapy After GUIDE-IT: Back to the Drawing Board. PMID- 30466512 TI - Economic and Quality-of-Life Outcomes of Natriuretic Peptide-Guided Therapy for Heart Failure. AB - BACKGROUND: The GUIDE-IT (GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) trial prospectively compared the efficacy of an N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided heart failure treatment strategy (target NT-proBNP level <1,000 pg/ml) with optimal medical therapy alone in high-risk patients with heart failure and reduced ejection fraction. When the study was stopped for futility, 894 patients had been enrolled. OBJECTIVES: The purpose of this study was to assess treatment-related quality-of-life (QOL) and economic outcomes in the GUIDE-IT trial. METHODS: The authors prospectively collected a battery of QOL instruments at baseline and 3, 6, 12, and 24 months post-randomization (collection rates 90% to 99% of those eligible). The principal pre-specified QOL measures were the Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and the Duke Activity Status Index (DASI). Cost data were collected for 735 (97%) U.S. PATIENTS: RESULTS: Baseline variables were well balanced in the 446 patients randomized to the NT-proBNP-guided therapy and 448 to usual care. Both the KCCQ and the DASI improved over the first 6 months, but no evidence was found for a strategy related difference (mean difference [biomarker-guided - usual care] at 24 months of follow-up 2.0 for DASI [95% confidence interval (CI): -1.3 to 5.3] and 1.1 for KCCQ [95% CI: -3.7 to 5.9]). Total winsorized costs averaged $5,919 higher in the biomarker-guided strategy (95% CI: -$1,795, +$13,602) over 15-month median follow up. CONCLUSIONS: A strategy of NT-proBNP-guided HF therapy had higher total costs and was not more effective than usual care in improving QOL outcomes in patients with heart failure and a reduced ejection fraction. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840). PMID- 30466514 TI - Left Ventricular Scar and Prognosis in Chronic Chagas Cardiomyopathy. AB - BACKGROUND: Patients with chronic Chagas cardiomyopathy (CCC) have pronounced myocardial fibrosis, which may predispose to sudden cardiac death, despite well preserved global left ventricular (LV) systolic function. Cardiac magnetic resonance can assess myocardial fibrosis by late gadolinium enhancement (LGE) sequences. OBJECTIVES: This prospective study evaluated if the presence of scar by LGE predicted hard adverse outcomes in a cohort of patients with CCC. METHODS: A prospective cohort of 140 patients with CCC (52.1% female; median age 57 years [interquartile range: 45 to 67 years]) were included. Cardiac magnetic resonance cine and LGE imaging were performed at enrollment with a 1.5-T scanner. The primary endpoint was the combination of cardiovascular death and sustained ventricular tachycardia. The secondary endpoint was the combination of cardiovascular death, sustained ventricular tachycardia, or cardiovascular hospitalization during follow-up. RESULTS: After a median of 34 months (interquartile range: 24 to 49 months) of follow-up, 11 cardiovascular deaths, 3 episodes of sustained ventricular tachycardia, and 20 cardiovascular hospitalizations were recorded. LGE scar was present in 71.4% of the patients, with the lateral, inferolateral, and inferior walls most commonly affected. Patients with positive LGE had lower LV ejection fraction and higher LV end diastolic volume and LV mass than patients without LGE. No difference in other cardiovascular risk factors was noted. Patients with scar had higher event rates compared with those without scar for the primary (p = 0.043) and the secondary (p = 0.016) endpoint. In multivariable analysis, age and LGE area were related to primary outcome; age and lower LV ejection fraction were related to the secondary outcome. The pattern of LGE myocardial fibrosis was transmural, focal, or diffuse scar in approximately one-third of patients with positive LGE, and no pattern was specifically related to outcomes. CONCLUSIONS: In patients with CCC, presence of scar by LGE is common and is strongly associated with major adverse outcomes. PMID- 30466515 TI - Long-Term Prognostic Value of Myocardial Fibrosis in Patients With Chagas Cardiomyopathy. AB - BACKGROUND: Myocardial fibrosis (MF) according to cardiac magnetic resonance (CMR) is a frequent finding in Chagas cardiomyopathy and has been associated with risk factors of poor outcome. OBJECTIVES: The goal of this study was to determine the prognostic value of MF in predicting combined hard events or all-cause mortality. METHODS: Patients with Chagas cardiomyopathy who had a previous CMR evaluation were included, and clinical follow-up was retrospectively obtained. The primary outcome was a combination of all-cause mortality, heart transplantation, antitachycardia pacing or appropriate shock from an implantable cardioverter-defibrillator, and aborted sudden cardiac death; the secondary outcome was all-cause mortality. RESULTS: A total of 130 patients were included; mean age was 53.6 +/- 11.5 years, and 53.9% were female. The majority of patients reported no symptoms of heart failure or arrhythmia, but electrocardiographic and echocardiographic abnormalities were common. On CMR, left ventricular dilatation and dysfunction were frequent, and MF was found in 76.1%, with a mean mass of 15.2 +/- 16.5 g. Over a median follow-up of 5.05 years, 58 (44.6%) patients reached the combined endpoint, and 45 (34.6%) patients died. MF was associated with the primary outcome as a continuous variable (adjusted hazard ratio: 1.031; 95% CI: 1.013 to 1.049; p = 0.001) and as a categorical variable (MF >=12.3 g) (adjusted hazard ratio: 2.107; 95% CI: 1.111 to 3.994; p = 0.022), independently from the Rassi risk score. MF expressed as a continuous variable was also associated with all-cause mortality (adjusted hazard ratio: 1.028; 95% CI: 1.005 to 1.051; p = 0.017) independently from the Rassi risk score. CONCLUSIONS: MF is an independent predictor of adverse outcome in Chagas cardiomyopathy. Our data may support the use of CMR in better risk-stratifying this population and possibly guiding therapy. PMID- 30466516 TI - Myocardial Delayed Enhancement in Chagas Heart Disease: Ready for the Clinical Arena? PMID- 30466517 TI - A Targeting Nanotherapy for Abdominal Aortic Aneurysms. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) is a leading cause of mortality and morbidity in the elderly. Currently, there remain no effective drugs that can prevent the growth of aneurysms and delay aneurysm rupture in the clinical setting. OBJECTIVES: The aim of this study was to develop a nanotherapy that can target aneurysms and release drug molecules in response to the inflammatory microenvironment. METHODS: Using a reactive oxygen species (ROS)-responsive nanoparticle and a candidate drug rapamycin, in combination with a peptide ligand for integrin and biomimetic cloaking with macrophage cell membrane, a nanotherapy was developed. Its effectiveness was demonstrated by in vitro and in vivo studies. RESULTS: Based on a facile and translational method, a rapamycin-loaded responsive nanotherapy was successfully prepared, which could release drug molecules upon triggering by the high level of ROS. In cells associated with the development of AAAs, the nanotherapy significantly inhibited calcification and attenuated ROS-mediated oxidative stress and apoptosis. By passively targeting aneurysms and releasing drug molecules in response to the inflammatory microenvironment, the intravenously injected ROS-responsive nanotherapy more effectively prevented aneurysm expansion in AAA rats than a nonresponsive control nanotherapy. After decoration with a peptide ligand cRGDfK and macrophage cell membrane, the aneurysmal targeting capability and therapeutic effects of a ROS responsive nanotherapy with a mean diameter of 190 nm were further enhanced. Moreover, the nanotherapy showed a good safety profile in a preliminary safety test. CONCLUSIONS: The multifunctional nanotherapy can be further studied as a promising targeted drug for treatment of aneurysms. The underlying design principles enable the development of a broad range of nanomedicines for targeted therapy of other vascular diseases. PMID- 30466518 TI - Engineered Nanoparticles Prevent Dilation of Abdominal Aortic Aneurysms. PMID- 30466520 TI - Renal Denervation Halts Left Ventricular Remodeling and Dysfunction in Heart Failure: New Shores Ahead. PMID- 30466519 TI - Renal Denervation Prevents Heart Failure Progression Via Inhibition of the Renin Angiotensin System. AB - BACKGROUND: Previously, we have shown that radiofrequency (RF) renal denervation (RDN) reduces myocardial infarct size in a rat model of acute myocardial infarction (MI) and improves left ventricular (LV) function and vascular reactivity in the setting of heart failure following MI. OBJECTIVES: The authors investigated the therapeutic efficacy of RF-RDN in a clinically relevant normotensive swine model of heart failure with reduced ejection fraction (HFrEF). METHODS: Yucatan miniswine underwent 75 min of left anterior descending coronary artery balloon occlusion to induce MI followed by reperfusion (R) for 18 weeks. Cardiac function was assessed pre- and post-MI/R by transthoracic echocardiography and every 3 weeks for 18 weeks. HFrEF was classified by an LV ejection fraction <40%. Animals who met inclusion criteria were randomized to receive bilateral RF-RDN (n = 10) treatment or sham-RDN (n = 11) at 6 weeks post MI/R using an RF-RDN catheter. RESULTS: RF-RDN therapy resulted in significant reductions in renal norepinephrine content and circulating angiotensin I and II. RF-RDN significantly increased circulating B-type natriuretic peptide levels. Following RF-RDN, LV end-systolic volume was significantly reduced when compared with sham-treated animals, leading to a marked and sustained improvement in LV ejection fraction. Furthermore, RF-RDN improved LV longitudinal strain. Simultaneously, RF-RDN reduced LV fibrosis and improved coronary artery responses to vasodilators. CONCLUSIONS: RF-RDN provides a novel therapeutic strategy to reduce renal sympathetic activity, inhibit the renin-angiotensin system, increase circulating B-type natriuretic peptide levels, attenuate LV fibrosis, and improve left ventricular performance and coronary vascular function. These cardioprotective mechanisms synergize to halt the progression of HFrEF following MI/R in a clinically relevant model system. PMID- 30466521 TI - Coronary Microvascular Disease Pathogenic Mechanisms and Therapeutic Options: JACC State-of-the-Art Review. AB - Coronary microvascular disease (CMD) refers to the subset of disorders affecting the structure and function of the coronary microcirculation, is prevalent in patients across a broad spectrum of cardiovascular risk factors, and is associated with an increased risk of adverse events. Contemporary evidence supports that most patients with CMD also have macrovessel atherosclerosis, which has important implications for their prognosis and management. In this state-of the-art review, the authors summarize the pathophysiology of CMD, provide an update of diagnostic testing strategies, and classify CMD into phenotypes according to severity and coexistence with atherosclerosis. They examine emerging data highlighting the significance of CMD in specific populations, including obesity and insulin resistance, myocardial injury and heart failure with preserved ejection fraction, and nonobstructive and obstructive coronary artery disease. Finally, they discuss the role of CMD as a potential target for novel interventions beyond conventional approaches, representing a new frontier in cardiovascular disease reduction. PMID- 30466522 TI - Coronary Physiology Beyond Coronary Flow Reserve in Microvascular Angina: JACC State-of-the-Art Review. AB - Angina with no angiographic stenosis, commonly called "microvascular angina," encompasses a wide continuum of coronary pathophysiology in conflicting published reports. Comprehensive quantitative myocardial perfusion offers new insights beyond overly simplistic coronary flow reserve. Integrating regional absolute stress flow, relative stress flow, coronary flow reserve, and qualitative subendocardial perfusion gradient on tomograms of relative images, provides correct diagnosis, quantitative physiological classification, and potential treatment. Angina without angiographic stenosis is associated with abnormal quantitative perfusion with rare, but instructive, exceptions. However, microvascular dysfunction without angina is common, particularly associated with risk factors. Reduced subendocardial/epicardial relative activity is common with diffuse coronary artery disease without focal stenosis with or without angina depending on the severity of reduced subendocardial perfusion. Precision quantitative myocardial perfusion in 5,900 cases objectively classifies angina with no angiographic stenosis into 4 categories: subendocardial ischemia due to diffuse coronary artery disease (most common), overlooked stenosis, diffuse microvascular dysfunction due to risk factors or specific microvasculopathies, and nonischemic cardiac pain mechanisms (rare), or some mix of these prototypes, of which 95% associate with risk factors, or subclinical or clinically manifest coronary atherosclerosis needing vigorous risk factor treatment. PMID- 30466523 TI - Women in Medicine: Addressing the Gender Gap in Interventional Cardiology. PMID- 30466524 TI - Translating the Translation: What Clinicians Should Know About the Fourth Universal Definition of Myocardial Infarction. PMID- 30466525 TI - In Memoriam: Professor Bongani Mayosi, 1967 to 2018. PMID- 30466526 TI - Low Serum Free Testosterone Association With Cardiovascular Mortality in Men With Stable CAD. PMID- 30466527 TI - Switching, Discontinuation, and Reinitiation of Statins Among Older Adults. PMID- 30466528 TI - 1-h Evaluation for Acute Myocardial Infarction Using the Generation 5 Cardiac Troponin T Assay. PMID- 30466529 TI - Stroke Risk Following Anaortic Off-Pump CABG Versus PCI. PMID- 30466530 TI - Reply: Stroke Risk Following Anaortic Off-Pump CABG Versus PCI. PMID- 30466531 TI - Optimal Dose of Rivaroxaban in Asians With Atrial Fibrillation: Further Studies Are Warranted. PMID- 30466532 TI - Reply: Optimal Dose of Rivaroxaban in Asians With Atrial Fibrillation: Further Studies Are Warranted. PMID- 30466533 TI - Concerns on the Effect of lncRNA CAREL on Cardiac Regeneration. PMID- 30466534 TI - Reply: The Effect of Targeting CAREL on Cardiac Regeneration. PMID- 30466535 TI - Collections-A New Feature of the JID Connector. PMID- 30466536 TI - Treatment with Modified Heat Shock Protein Repigments Vitiligo Lesions in Sinclair Swine. AB - HSP70i is secreted by stressed melanocytes, is associated with human vitiligo lesions, and functionally contributes to a mouse model of vitiligo. Henning et al. report that treatment with a modified version of the protein reversed depigmentation in Sinclair swine, a useful animal model of vitiligo. These studies provide the rationale for testing in human studies. PMID- 30466537 TI - NLRP1 Is the Key Inflammasome in Primary Human Keratinocytes. AB - The epidermis is the primary area of contact between the body and the environment, and it distinguishes between harmful exposures and those that should be tolerated. Discrimination between insults, and in particular the recognition of danger signals such as UVB, is mediated by innate immune receptors. Inflammasomes are one major innate mechanism that activate inflammatory caspases. In human keratinocytes, the importance of inflammasomes and the sensing of UVB and other danger signals are a matter of debate. Fenini et al. now provide evidence that the NLRP1 (rather than the NLRP3) inflammasome plays a key role in UVB sensing and subsequent IL-1beta and -18 secretion by human keratinocytes. PMID- 30466538 TI - SnapshotDx Quiz: December 2018. PMID- 30466539 TI - Cells to Surgery Quiz: December 2018. PMID- 30466540 TI - Progress in Understanding Atopic Dermatitis. PMID- 30466541 TI - Posttraumatic stress symptoms, shame, and substance use among Asian Americans. AB - BACKGROUND: To examine the association between posttraumatic stress symptoms (PTSS) and substance use among Asian Americans and the influence of a culturally relevant moderator, shame. METHODS: From 2016 to 2017, 199 participants from Amazon Mechanical Turk and a university subject pool completed an online survey. Chi-square and Kruskal-Wallis tests explored demographic and clinical differences among three Asian American ethnic subgroups (East Asians, South Asians, and Southeast Asians). Generalized linear models assessed the association between PTSS and substance use (alcohol, tobacco, and other drugs) and the moderation of this relationship by shame. RESULTS: Ethnic subgroups significantly differed on all three substance use variables. The severity in PTSS was significantly associated with hazardous drug use (IRR = 1.03, (1.01, 1.05), p = .003). The association between PTSS and days of tobacco use and binge drinking was significantly moderated by shame. Low levels of shame increased the effect of PTSS on binge drinking (IRR = 1.05, (1.00, 1.10), p = .035) and tobacco use (IRR = 1.15, (1.11, 1.19), p < .001). High levels of shame had no effect of PTSS on binge drinking (IRR = 1.01, (0.99, 1.03), p = .54) and a reduced effect on tobacco use (IRR = 1.07, (1.05, 1.09), p < .001). CONCLUSIONS: Among Asian Americans, the association of PTSS and substance use depends on shame. Lower levels of shame are a risk factor, increasing the effect of PTSS on substance use. Culturally-modified addiction treatments should assess for shame among Asian Americans and attend to ethnic sub-group diversity in substance use. PMID- 30466542 TI - The reality of drinking and drug using dreams: A study of the prevalence, predictors, and decay with time in recovery in a national sample of U.S. adults. AB - BACKGROUND: The meaning of unconscious dreaming has been assigned varying degrees of historical significance throughout the ages and across different cultures including in major psychological theories of psychopathology. While dreams' meaning and implications have remained controversial, not disputed is the occurrence of drinking/drug-using dreams (DDUD) when people enter recovery from a significant alcohol and other drug (AOD) problem. Typically taking the form of a relapse scenario followed by relief on awakening, such dreams can be profoundly unnerving. Beyond common anecdotal reports of these phenomena, however, very little is known about the prevalence, predictors, and decay of such dreams with time in recovery. Greater knowledge could help inform patients and providers about what to anticipate in recovery. METHOD: Nationally-representative cross sectional study of US adults (N = 39,093) who had resolved a significant AOD problem (weighted n = 2002). MEASURES: DDUD prevalence/time since last DDUD; demographics; measures of clinical history. RESULTS: Approximately one third (31.9%) reported experiencing DDUD which were predicted by more severe clinical history variables (earlier age of onset; prior treatment/mutual-help participation). A significant linear decay of DDUD occurrence was observed with time in recovery. CONCLUSIONS: DDUD appear to occur among a substantial minority of US adults resolving significant AOD problems and are related to a more pronounced and deleterious AOD history. DDUD attenuate in frequency over time in recovery which plausibly may be indicative of increased biopsychosocial stability that reduces neurocognitive reverberation and psychological angst regarding relapse risk. Further prospective research is needed to understand the frequency, topography, content variability, and influence such dreams may have on intermediate (e.g., abstinence self-efficacy) and ultimate (substance use) outcomes. PMID- 30466543 TI - Evidence-based treatment for opioid use disorders: A national study of methadone dose levels, 2011-2017. AB - The nation's methadone maintenance treatment (MMT) programs play a central role in addressing the current opioid epidemic. Considerable evidence documents the treatment effectiveness of MMT and, in turn, the importance of adequate dosing to MMT's effectiveness. Yet, as recently as 2011, 41% of patients received doses below the level of 80 mg/day. Using survey data from a nationally representative sample of MMT programs in 2011 and 2017, we examine (1) the extent to which the nation's MMT programs are meeting evidence-based standards for methadone dose level and (2) characteristics of MMT programs that are associated with variation in performance. Our results show that 43% of MMT patients receive <80 mg/day in 2017, and 23% of methadone maintenance patients receive daily doses below 60 mg. Results from multivariate regression analysis of the 2017 survey data show that private for-profit and public organizations significantly under-dosed patients compared to private nonprofit providers. Under-dosing also was more common in programs that serve high proportions of African-American patients. These results are concerning because MMT remains the medication of choice for vulnerable patients with the most severe opioid use disorders, and for-profit providers treat a growing proportion of MMT patients. PMID- 30466544 TI - Fentanyl exposure among patients seeking opioid treatment. AB - AIM: Overdoses attributed to the potent opioid agonist fentanyl have substantially increased in recent years. Despite these serious public health consequences, many opioid treatment providers do not currently include a fentanyl assay in their urine toxicology testing. As a result, extent of fentanyl exposure and related risks among individuals with opioid use disorder often remains unknown. We examined the prevalence of fentanyl exposure among patients seeking or enrolled in opioid agonist treatment. METHODS: Six hundred urine specimens were collected from adults entering (n = 100) or enrolled in (n = 500) opioid agonist treatment and analyzed using the clinic's standard opioid panel, supplemented with a 100 ng/ml fentanyl assay. RESULTS: Of the 100 specimens collected from patients at treatment intake, 19 (19%) tested positive for fentanyl. Importantly, 17 (90%) of those fentanyl-positive specimens were also positive for heroin. Of the 500 collected from patients in treatment, 17 (3%) of specimens tested positive for fentanyl. Of those, 11 (92%) were also positive for heroin. CONCLUSION: These data illustrate a concerning degree of fentanyl exposure among patients seeking treatment and suggest that much of this exposure may have stemmed from fentanyl-containing heroin. Given the unprecedented recent surges in fentanyl-related overdoses, efforts to identify fentanyl exposure are critical. In particular, the point of treatment entry permits a rare systematic opportunity for medical and clinical staff to address fentanyl use and risks with incoming patients. PMID- 30466545 TI - A randomized clinical trial of cue exposure treatment through virtual reality for smoking cessation. AB - INTRODUCTION: Cue-induced craving is a major motivator of smoking behavior, and, more importantly, a predictor of relapse. Previous studies demonstrated that cue exposure treatment (CET) reduces both cue-induced craving and daily nicotine intake in smokers. However, the efficacy of CET for smoking cessation has rarely been tested in controlled trials. This two-site randomized clinical trial explored the effectiveness of a CET procedure in combination with a Cognitive Behavioral Treatment (CBT) for smoking cessation among treatment-seeking patients from the general population. METHODS: One hundred and two smokers were randomly assigned to one of two treatment conditions: CBT (n = 52) or CBT + CET (n = 50). The CBT intervention involved group-based sessions over the course of 6 weeks. In addition to CBT, participants in the CBT + CET condition received 5 individual sessions of CET through virtual reality. RESULTS: The CBT + CET group showed a significant reduction in cue-induced craving. However, there were no significant differences in either retention nor abstinence rates between CBT and CBT + CET in any assessment period (end-of-treatment, 1-, 6-, and 12-month follow-up). Moreover, a higher rate of relapse over a 12-month follow-up period was found in the CBT + CET group compared to the CBT group (Wald chi2 = 4.796, p = .029). CONCLUSIONS: Findings support and expand previous evidence by showing that a CET protocol does not increase the effectiveness of a CBT intervention for smoking cessation among treatment-seeking smokers. Moreover, this study also reveals that CET may increase risk of relapse among nicotine-dependent individuals who successfully achieve abstinence. Until the mechanisms underlying the effect of CET are identified, researchers and clinicians should be cautious when utilizing this protocol. PMID- 30466546 TI - Specific aspects of cognitive impulsivity are longitudinally associated with lower treatment retention and greater relapse in therapeutic community treatment. AB - INTRODUCTION: Impulsivity has been consistently associated with poorer addiction treatment outcomes. However, impulsivity is a multifaceted construct and current evidence have failed to unravel which specific aspects explain this relationship. There is also limited research examining long-term outcomes. We aimed to examine the longitudinal association between baseline performance on a comprehensive battery of impulsivity measures and retention and relapse at the end of treatment. METHODS: The sample comprised 68 participants with miscellaneous diagnoses of substance use disorders and polysubstance use patterns, enrolled in public residential therapeutic communities in Andalusia (Spain). At baseline, we applied measures of selective attention (Stroop), response inhibition (Affective Go/No Go), delay discounting (Monetary Choice Questionnaire; MCQ), and decision making (Iowa Gambling Task; IGT). At the end of treatment (mean = 148.36 days, range = 22-289 days), we collected outcome measures of retention (coded by the clinical team as completion or dropout based on statewide practice guidelines) and relapse (defined as at least two separate alcohol/drug use episodes based on urine analyses). RESULTS: Cox regression models showed that poorer decision making in the IGT was associated with premature treatment dropout, whereas elevated commission errors in the Affective Go/No Go were associated with higher relapse rates. Selective attention and delay discounting were unrelated to outcomes. CONCLUSION: Long-term based decision-making skills are important to commit to the complex and intensive treatment programs of therapeutic communities. The ability to withhold behavioural responses under positive affect is relevant to prevent relapse. Both skills should be assessed and potentially trained during therapeutic community treatment. PMID- 30466547 TI - Examining the influence of active ingredients of motivational interviewing on client change talk. AB - Motivational Interviewing (MI) is an evidenced-based intervention designed to help clients explore and resolve ambivalence around substance use. MI combines a humanistic tradition with behavioral components to facilitate client decisions concerning behavior change. As such, there is marked interest in the relationship between the two active ingredients of MI - the relational, or person-centered, components and the technical, or directional, behavioral components - on client in-session language. Yet, few studies have examined how these active ingredients operate in concert. Therefore, the current study evaluated the constellation of relational skills associated with client language, as well as the influence of technical skills on the relationship between provider relational skills and client change language. Specifically, we tested a latent construct of relational skill and its direct association with the proportion of client change talk. We then explored the mediating role of reflections of change and sustain talk (RefCT and RefST) on this relationship. The data for this secondary analysis are from Project ELICIT (N = 131), a randomized control trial evaluating the effects of MI training on client change language. We found support for a latent construct of relational skill (i.e., empathy, acceptance, collaboration, and autonomy/support). However, the relational skill construct did not predict client change language. There was support for an indirect effect, such that relational skills predicted RefCT and RefST, and RefCT and RefST predicted client change language. These results suggest that the synergistic implementation of the relational and technical components of MI is critical to facilitating a higher percentage of change talk. PMID- 30466548 TI - Health literacy in substance use disorder treatment: A latent profile analysis. AB - INTRODUCTION AND AIMS: Health literacy refers to the degree to which people can access and understand health information, as well as communicate their health needs to service providers. Whilst health literacy is increasingly being examined within general community samples, there is limited research focused on substance use disorders where the need for health literacy is likely to be high. The aim of this study was to examine the health literacy profiles of people attending substance use disorder treatment and to examine how these profiles were related to measures of quality of life, mental health, and physical health. DESIGN AND METHODS: Participants were attending specialist non-government substance use disorder treatment across New South Wales, Queensland, and the Australia Capital Territory, Australia (N = 298). Participants completed the Health Literacy Questionnaire, a multi-dimensional measure of health literacy. Latent profile analysis was conducted to identify profiles of health literacy within the sample. RESULTS: Three distinct health literacy profiles were identified, and termed low (24.2%), moderate (62.8%) and high health literacy (13.1%). Participants with lower levels of health literacy had lower levels of social support in their home environment outside of treatment, as well as lower levels of quality of life, higher levels of psychological distress, and poorer mental health. There was no difference between the three profiles on measures of physical health. DISCUSSION AND CONCLUSION: The current study found that low to moderate health literacy levels were common for those attending residential substance abuse treatment. Participants with lower health literacy tended to have poorer quality of life and mental health. Future research should examine strategies to improve health literacy amongst people attending alcohol and other drug treatment. It may also be useful for service providers to consider ways to minimise the impact of low health literacy on the health needs and outcomes of this vulnerable population. PMID- 30466549 TI - Substance use outcomes in cocaine-dependent tobacco smokers: A mediation analysis exploring the role of sleep disturbance, craving, anxiety, and depression. AB - BACKGROUND: Sleep disturbance may play a role in cocaine use outcomes and, hence, may be a potential therapeutic target for cocaine use disorder (CUD). Research in this area, which has largely relied on resource-intensive polysomnography, would be facilitated by identifying a self-report sleep measure predictive of CUD outcomes and by a better understanding of the mechanisms by which sleep may impact CUD outcomes. This study tested the predictive validity of the Pittsburgh Sleep Quality Index (PSQI), a self-report assessment of past-month sleep quality. To better understand potential mechanisms, mediation models relating sleep disturbance to CUD outcomes were evaluated. METHODS: This is a secondary analysis of data from cocaine-dependent (n = 290) participants in a multi-site trial evaluating smoking-cessation treatment for stimulant-dependent patients. The PSQI was collected at baseline; the outcomes of interest were cocaine and drug abstinence at end-of-treatment (weeks 9-10). Potential mediators, measured in weeks 1-8, were: cocaine craving (Brief Substance Craving Scale); and anxiety and depression symptoms (Hospital Anxiety and Depression Scale). Mediation techniques were used to evaluate mediation effects separately and jointly. RESULTS: The majority of participants (58.3%) had baseline sleep disturbance. Sleep disturbance was not a significant predictor of end-of-treatment abstinence when regressed without consideration of mediators. Cocaine craving, anxiety, and depression were significant mediators, both separately and jointly, of an effect of baseline sleep disturbance on end-of-treatment abstinence. CONCLUSION: This exploratory analysis suggests that there may be an indirect relationship between self-reported sleep quality and substance use outcomes in cocaine-dependent patients, mediated by craving, anxiety, and depression. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01077024. PMID- 30466550 TI - Raja yoga meditation and medication-assisted treatment for relapse prevention: A pilot study. AB - The continued need for advancement in evidence-based SUD treatment, as well as increases in treatment expense and decline in support from insurance providers, suggest that brief, innovative, and affordable treatments are needed. Meditation, spirituality, and adherence to medication-assisted treatments have all been shown to support abstinence. The current trial assessed effects of spiritually-based meditation, versus relaxation or standard treatment, on substance abstinence and psychological distress and dysfunction in a partially buprenorphine-supported (41.5%) treatment sample. Participants (N = 40) were recruited from an intensive outpatient treatment program, in which three treatment locations acted as separate experimental conditions. Abstinence was measured through urinalyses at baseline and weekly thereafter for the duration of the intervention. Psychological distress and dysfunction were assessed with a Likert-scaled questionnaire measuring symptoms typically associated with SUD. Co-varying for buprenorphine use, participants in the Meditation condition had better odds of remaining abstinent than participants in the Treatment-as-Usual (TAU) and Relaxation conditions. There were no significant differences in substance abstinence between the Relaxation and TAU conditions. Further, co-varying out baseline there were no significant differences at post-course in psychological distress and dysfunction between the three conditions. Results from this pilot trial suggest that this spiritually-informed approach may offer additive support to individuals in SUD treatment, as an aid to the meditative aspect of the 12 steps, or a non-12-step alternative spiritual supplement to standard SUD treatment. PMID- 30466551 TI - Alcohol-related social and health service use patterns as predictors of death and remission in patients with AUD. PMID- 30466552 TI - Health insurance coverage is associated with access to substance use treatment among individuals with injection drug use: Evidence from a 12-year prospective study. AB - OBJECTIVE: Understand how insurance impacts access to services among people who have injected drugs. METHODS: 1748 adults who have injected drugs were assessed at twice-annual study visits between 2006 and 2017 (18,869 visits). Use of specialty substance use treatment, receipt of buprenorphine, and having a regular source of medical care were assessed for association with concurrent insurance coverage. Random intercept logistic regression was used to adjust for potential confounders. RESULTS: When participants acquired insurance, they were more likely to report specialty substance use treatment (aOR 2.0, 95% CI 1.6 to 2.5), a buprenorphine prescription (aOR 3.3, 95% CI 2.0 to 5.5), and a regular source of medical care (aOR 6.3, 95% CI 5.1 to 7.8). CONCLUSION: Insurance is associated with increased use of three important services for individuals who inject drugs. IMPLICATIONS: Expanding insurance may facilitate access to substance use treatment and other needed health services. PMID- 30466553 TI - Generational trends and patterns in readmission within a statewide cohort of clients receiving heroin use disorder treatment in Maryland, 2007-2013. AB - The recent rise in opioid-related overdose deaths stresses the importance of understanding how heroin use disorders persist and what interventions are best suited for treating these illnesses. Trends show that there are diverse pathways leading to heroin use disorder that span multiple generations, but little is known about how different generations utilize and respond to treatment. This study provides insight into treatment utilization for young, middle-aged, and older adults by examination of an unusually rich longitudinal dataset of substance use disorder clients in Maryland who were treated for heroin use. Results show that clear patterns of treatment readmission emerge across generations in treatment-naive clients with regard to gender, ethnicity, employment, geographical region, and treatment type/intensity. In particular, Millennials comprise the majority of the clients receiving heroin use disorder treatment and are the largest contributor to these readmission patterns. Millennials are also given opioid maintenance therapy (OMT) more frequently than other generations, while exhibiting a strong avoidance to treatment. Generational differences in treatment decisions and outcomes over the course of a treatment career are important for understanding the nature of the current opioid epidemic, and can play an important role in directing heroin use disorder treatment efforts and improving models of care. PMID- 30466554 TI - Genomic organization and role of SPI-13 in nutritional fitness of Salmonella. AB - Salmonella pathogenicity island 13 (SPI-13) contributes to the virulence of Salmonella. The majority of the SPI-13 genes encode proteins putatively involved in bacterial metabolism, however, their functions largely remain uncharacterized. It is currently unknown if SPI-13 contributes to metabolic fitness of Salmonella and, if so, what are the metabolic substrates for the protein encoded by genes within SPI-13. We employed Phenotype Microarray (Biolog, USA) to compare the metabolic properties of SPI-13 deficient mutant (DeltaSPI-13) and the WT parent strain of non-typhoidal Salmonella enterica sub sp. enterica serovar Enteritidis (S. Enteritidis). The results of Phenotype Microarray revealed that SPI-13 is required for efficient utilization of two micronutrients, namely, d-glucuronic acid (DGA) and tyramine (TYR), as sole sources of carbon and/or nitrogen. By systematic deletion of the individual gene(s), we identified specific genes within SPI-13 that are required for efficient utilization of DGA (SEN2977-80) and TYR (SEN2967 and SEN2971-72) as sole nutrient sources. The results show that SPI 13 mediated DGA and TYR metabolic pathways afford nutritional fitness to S. Enteritidis. Comparative genomics analysis of the SPI-13 locus from 247 Salmonella strains belonging to 57 different serovars revealed that SPI-13 genes specifically involved in the metabolism of DGA and TYR are highly conserved in Salmonella enterica. Because DGA and TYR are naturally present as metabolic byproducts in the gastrointestinal tract and other host tissues, we propose a metabolic model that shows that the role of SPI-13 mediated DGA and TYR metabolism in the nutritional fitness of Salmonella is likely linked to nutritional virulence of this pathogen. PMID- 30466557 TI - The Lasker Prize award 2018: histones "tail" the story. PMID- 30466555 TI - Case definitions of hemolytic uremic syndrome following Escherichia coli O157:H7 infection vary in validity. AB - BACKGROUND: Multiple case definitions for post-diarrheal hemolytic uremic syndrome (D+ HUS) associated with Shiga toxin-producing Escherichia coli (STEC) are used across public health, research, and clinical practice. METHODS: To identify a single definition of D+ HUS for standardized use, we evaluated the comparability and validity of four common, heterogeneous definitions: the Council of State and Territorial Epidemiologists (CSTE) definition, hematology-focused and age-focused definitions from the literature, and hospital diagnosis. We reviewed medical records from 471 hospitalized E. coli O157:H7 cases reported in Washington State, 2005-2014. We assessed 1) reliability across definitions, 2) comparability of temporal trends, and 3) sensitivity and specificity using an omnibus reference standard, developed using a combination of definition agreement and clinical outcomes. With the standard, we classified cases as definite, borderline, or unlikely/not post-diarrheal D+ HUS. RESULTS: Reliability was highest between the age-focused definition and hospital diagnosis (kappa = 0.84), and temporal trends were largely comparable across definitions. For definite D+ HUS cases, the age-focused definition had the highest overall validity [100% sensitivity, 95% confidence interval (CI): 94%, 100%; 96% specificity, 95% CI: 94%, 98%]. The CSTE definition had low specificity (75%, 95% CI: 70%, 79%). CONCLUSIONS: In this review, the CSTE definition overestimated the burden of D+ HUS, and the age-focused definition provided the best overall reliability and validity to define post-diarrheal D+ HUS. Disease monitoring and research activities should consider using the age-focused D+ HUS definition. PMID- 30466558 TI - Targeting oxidative stress in diabetic kidney disease: a novel drug in an old pathway. PMID- 30466559 TI - Kidney organoids-a new tool for kidney therapeutic development. AB - Kidney organoids, derived from human pluripotent stem cells, have the potential to greatly facilitate drug development. Borestrom et al. have used CRISPR/Cas9 to create kidney fluorescent lineage markers for SIX2 and NPHS1 to monitor the differentiation process to tubular and glomerular structures and optimize maturity. The convergence of "personalized" kidney organoids with genome editing and single-cell sequencing technology hold great promise to result in better insight to disease, better human cell disease models, more predictive toxicology, and potentially "clinical trials in a dish." PMID- 30466560 TI - Awakening the Bowman: inhibition of CXCL12 signaling activates parietal epithelial cells. AB - Glomerular podocytes are terminally differentiated cells, and podocyte loss is a common feature of progressive renal pathologies. In this issue, Romoli et al. focus on podocyte progenitors that were proposed to reside in the Bowman's capsule. They demonstrate that suppression of CXCL12/CXCR4 signaling activates parietal epithelial cells that integrate into glomeruli, express podocyte specific markers, and interdigitate with existing cells. The data may open new therapeutic avenues for the treatment of glomerular diseases. PMID- 30466561 TI - ANCA Renal Risk Score: is prediction of end-stage renal disease at baseline possible? AB - Despite improved overall prognosis of patients with ANCA-associated vasculitis (AAV), those presenting with impaired renal function remain at risk of developing end-stage renal disease (ESRD). In addition to its role in diagnosis, renal histology provides prognostic information that has permitted definition of subgroups with differing risks of ESRD. In this issue, Brix et al. have developed and validated a risk score to predict the probability of ESRD. Against a background of outcome prediction in AAV, this commentary assesses different approaches to histologic risk and to what extent they assist with decisions on patient management. PMID- 30466562 TI - Expanding the spectrum of APOL1-related renal disease: de novo collapsing glomerulopathy following kidney transplant. AB - Santoriello et al. report a series of 38 cases of de novo collapsing glomerulopathy following kidney transplant. Associations included acute rejection, viral infection, and APOL1 high-risk genotype (the latter in 9 cases). Risk factors for collapsing glomerulopathy included acute rejection, viral infection, acute vaso-occlusive disease, and an African American donor. The data are suggestive of, but do not directly establish, a role for interferon in these associations. PMID- 30466563 TI - Does alanyl-glutamine supplementation offer potential to improve peritoneal dialysate biocompatibility? AB - Peritoneal dialysis technique survival remains challenging due to peritonitis and long-term alterations to peritoneal membrane function and integrity. Up to now, the development of less bio-incompatible dialysis solutions have not had a major impact on these aspects of the therapy. A novel approach, supplementing dialysis solutions with a cytoprotective additive, alanyl-glutamine, has shown benefits to surrogate biomarkers of cell function in a randomized controlled study. PMID- 30466564 TI - Kidney disease in Latin America: current status, challenges, and the role of the ISN in the development of nephrology in the region. PMID- 30466565 TI - Extracellular traps in kidney disease. AB - During the past decade the formation of neutrophil extracellular traps (NETs) has been recognized as a unique modality of pathogen fixation (sticky extracellular chromatin) and pathogen killing (cytotoxic histones and proteases) during host defense, as well as collateral tissue damage. Numerous other triggers induce NET formation in multiple forms of sterile inflammation, including thrombosis, gout, obstruction of draining ducts, and trauma. Whether neutrophils always die along with NET release, and if they do die, how, remains under study and is most likely context dependent. In certain settings, neutrophils release NETs while undergoing regulated necrosis-for example, necroptosis. NETs and extracellular traps (ETs) released by macrophages also have been well documented in kidney diseases-for example, in various forms of acute kidney injury. Histones released from ETs and other sources are cytotoxic and elicit inflammation, contributing to necroinflammation of the early-injury phase of acute tubular necrosis in antineutrophil cytoplasmic antibody-related renal vasculitis, anti-glomerular basement membrane disease, lupus nephritis, and thrombotic microangiopathies. Finally, acute kidney injury-related releases of dying renal cells or ETs promote remote organ injuries-for example, acute respiratory distress syndrome. In this review, we summarize what is known about the release of ETs from neutrophils and macrophages in the kidney, the available experimental evidence, and ongoing discussions in the field. PMID- 30466566 TI - Clinical markers to predict progression from acute to chronic kidney disease in Mesoamerican nephropathy. AB - An epidemic of chronic kidney disease (CKD) of unknown etiology, known as Mesoamerican Nephropathy (MeN), has been ongoing in Latin America for at least two decades. MeN primarily affects young adults without traditional CKD risk factors, and agricultural workers are disproportionately afflicted. We previously identified an acute phase of MeN that involves acute kidney injury (AKI) with tubulointerstitial nephritis and systemic inflammation. Because clinical disease progression in MeN is not yet understood, we sought to determine clinical predictors for progression from acute MeN to CKD. Through ongoing surveillance in Nicaragua, local physicians reported cases of acute MeN and CKD among agricultural workers. We analyzed clinical data collected during the acute MeN encounter to identify factors associated with progression to CKD. From February 2015 to May 2017, 586 agricultural workers (median age 27.8 years, 90% male) presented with acute MeN. The majority had a normal baseline creatinine, and leukocyturia (98.8%) and peripheral leukocytosis (80.7%) were common. Ultimately, 49 (8.4%) progressed to CKD, the majority of those within 6 months. CKD was attributed to MeN in all cases, and none had diabetes or hypertension. The strongest predictors of CKD progression were anemia and paresthesias at presentation, while leukocytosis was associated with renal recovery. Clinical markers of acute MeN may help clinicians identify patients at high risk for rapid progression to CKD, which in turn can inform early clinical management. Future studies should seek to determine the underlying etiology of disease and identify optimal interventions to interrupt the pathophysiologic process of MeN. PMID- 30466567 TI - Screening for renal cell carcinoma in dialysis patients. PMID- 30466568 TI - The authors reply. PMID- 30466569 TI - Hemoperfusion for paraquat poisoning. PMID- 30466570 TI - Postpartum renal cortical necrosis. PMID- 30466571 TI - Acute page kidney phenomenon following renal allograft biopsy. PMID- 30466572 TI - The Case | A patient with acute tetraparesis. PMID- 30466573 TI - Epigenetic stability in Saffron (Crocus sativus L.) accessions during four consecutive years of cultivation and vegetative propagation under open field conditions. AB - Saffron (Crocus sativus L.) is a sterile species that is vegetatively propagated in the field, year by year, via the production of new corms. While Saffron's genetic variability is extremely low, phenotypic variation is frequently observed in the field and epigenetics could be a possible origin of these alternative phenotypes. Present day knowledge on Saffron epigenetics is very low or absent. In the present paper, to deepen existing knowledge, we focused on the epigenetic differences and stability among 17 Saffron accessions, of different geographic origin, during four consecutive years of vegetative propagation under open field conditions. Before the analysis, the selected accessions have been cultivated in the same field for at least three consecutive years. Despite the low genetic variability and the prolonged co-cultivation in the same environment, Methylation Sensitive Amplified Fragment Length Polymorphism (MS-AFLP) analysis revealed a very high epigenetic difference among accessions, making it possible to discriminate them based on the epigenetic profiles. During the four years of the study, a little variation has been observed within accessions following different patterns, slightly modifying the accession epigenotypes but not enough to even them to a more uniform profile. These results confirm that, under natural conditions, Saffron epigenotypes are highly stable, supporting a role for epigenetics in phenotypic variability. PMID- 30466574 TI - Overexpression of TaLEA3 induces rapid stomatal closure under drought stress in Phellodendron amurense Rupr. AB - Late embryogenesis abundant (LEA) proteins participate in drought stress responses in plants. In the present study, the gene TaLEA3 from the drought resistant plant Tamarix androssowii was transformed into Amur cork tree (Phellodendron amurense) via Agrobacterium tumefaciens to investigate the mechanism of stomatal closure in response to osmotic stress. Our results showed that P. amurense overexpressing TaLEA3 were resistant to drought stress by rapid stomatal closure. To study the stomatal movement regulated at the molecular level, a model system for stoma closure was established in in vitro P. amurense. In this work, we found that the increased Ca2+ accumulation in guard cells of transgenic plants caused stomatal closure and activated K+ efflux under polyethylene glycol (PEG) stress. Moreover, H+ changes might provide a needed pH condition for stomatal closure. Further, nitric oxide (NO) fluorescence was measured using an NO-specific fluorescent probe, diaminofluorescein-FM diacetate, which showed that guard cell NO fluorescence was stronger in transgenic plants compared with wild type plants. Additionally, five genes encoding nitrate reductase were up-regulated, indicating that TaLEA3 overexpression positively regulated NO biosynthesis and accumulation in the guard cells. This discovery will further our understanding of the LEA gene function and will help in engineering drought-resistant tree cultivars. PMID- 30466575 TI - Molecular and functional characterization of Arabidopsis thaliana VPNB1 gene involved in plant vascular development. AB - Armadillo (ARM) repeat containing proteins constitute a large family in plants and are involved in diverse cellular functions, like signal transduction, proliferation and differentiation. In animals, ARM repeat proteins have been implicated in cancer development. In this study, we aimed in characterizing the VPNB1 gene from Arabidopsis thaliana and its role in plant development, by implementing a number of genetic and molecular approaches. AtVPNB1 encodes for an ARM repeat protein of unknown function, exclusively expressed in the cambium as well as in the differentiating xylem and phloem cells of the vascular system. Subcellular localization experiments showed that VPNB is confined in nucleoplasmic speckle-like structures unrelated to cajal bodies. Transgenic VPNB impaired plants exhibit a slower growing phenotype and a non-canonical pattern of xylem tissue. On the contrary, VPNB overexpression lines display an inverted phenotype of increased growth, accompanied by an increased deposition of phloem and xylem cell layers. In line with the above data, qPCR analysis revealed a deregulation of several key master genes of secondary wall biosynthesis, underlining the involvement of VPNB1 in the regulation and differentiation of the root and shoot vascular tissue. PMID- 30466576 TI - Exogenous brassinosteroids altered cell length, gibberellin content, and cellulose deposition in promoting carrot petiole elongation. AB - Brassinosteroid (BR) is a predominant plant hormone in regulating cell elongation and cell size. BR-deficient mutants display reduced plant growth and dwarfism in Arabidopsis and rice. In carrot, BRs promote petiole elongation, but its underlying mechanism involving exogenous BR remains unknown. Here, weighted gene co-expression network analysis and promoter region analysis were adopted to identify the potential genes that interacted with DcBZR1/BES1. Bioactive gibberellin (GA) level and cellulose deposition were also determined in the control and treated plants. Quantitative real-time PCR was performed to detect the expression profiles of GA biosynthesis-related genes, GA signaling genes, and cellulose synthase genes. Bioactive GA level and cellulose deposition were upregulated after the petioles were treated with 24-epibrassinolide (24-EBL). The most putative DcBZR1/BES1 genes were clustered in yellow module. The expression level of DCAR_009411 (a GA5-like gene) was significantly induced after 3 h of treatment. The expression levels of DCAR_019754 and DCAR_013973 (CESA-like genes) were also significantly induced after 3 h of 24-EBL treatment. Our results suggested that the effect of BR on carrot petiole growth was quick. These results also provided potential insights into the mechanism by which BRs modulate GA and cellulose synthesis to promote cell elongation in carrot petioles. PMID- 30466577 TI - Overexpression of the CsFUS3 gene encoding a B3 transcription factor promotes somatic embryogenesis in Citrus. AB - In citrus, genetic improvement via biotechnology is challenging due to insufficient understanding of molecular barriers that prevent regeneration by somatic embryogenesis (SE). Our previous study indicated that LEC genes were involved in SE in citrus, but their regulatory roles remain to be elucidated. Here, we cloned one of the LEC genes, CsFUS3, and show that it is preferentially expressed during SE and in the embryogenic callus (EC) derived from citrus varieties with strong embryogenic competence. The overexpression of CsFUS3 in recalcitrant citrus callus restored embryogenic competence. Complementation of the loss-of-function Arabidopsis fus3 mutant with the CsFUS3 gene restored normal late embryogenesis, which is consistent with the CsFUS3 and AtFUS3 proteins contributing to the same regulatory network in Arabidopsis. Transcriptome profiling revealed that the expression of particular TFs that promote SE was up regulated in the citrus overexpression (OE) line. The 104 differentially expressed genes associated with hormone biosynthesis, catabolism, and signaling are particularly noteworthy. The dynamic change in the ratio of ABA to GA during SE in wild-type callus mirrored the expression pattern of CsFUS3. In contrast, in the OE line, the ratio of ABA to GA was higher and the capacity for SE was greater when the OE line was separately treated with ABA and GA biosynthesis inhibitors. Taken together, our results demonstrate that the overexpression of CsFUS3 appears to establish a cellular environment favorable to SE, at least in part by promoting a high ABA to GA ratio and by regulating the expression of TFs that promote SE. PMID- 30466578 TI - In vivo promoter engineering in plants: Are we ready? AB - Engineering plant promoter sequence for optimal expression of a gene has been a long standing goal for plant scientists. In recent times, Sequence Specific Nucleases (SSNs) like CRISPR/Cas9 are enabling researchers to achieve this goal, in vivo in the genome. It is well known that SSNs have met with unprecedented success in rapid transgene free crop improvement largely by targeting the coding sequence. Here, we discuss the strategies being employed by plant scientists in targeting SSNs to non-coding promoter regions/Cis Regulatory Elements (CRE). We collectively refer all such endeavors as in vivo promoter engineering (IPE). We further classify the IPE efforts into CRE addition, CRE deletion/disruption, promoter swap/insertion and targeted promoter polymorphism. Till date, IPE has proven useful in altering plant architecture in tomato, developing resistance against Xanthomonas sp in rice and citrus, and engineering drought tolerance in maize. However it is quite challenging to achieve predictable changes in gene expression using IPE at this point. In future years, data generated from high throughput techniques to investigate non coding genome may immensely augment the efforts in this direction. As IPE does not involve addition of the transgene for modifying crop traits, it will be relatively more conducive to public acceptance in crop improvement programs. PMID- 30466579 TI - On the mechanism of the cell cycle control of suspension-cultured tobacco cells after exposure to static magnetic field. AB - One of the main sites of the magnetic fields influence on living cells is the cell cycle. The intensity of this influence however, varies depending on the cell type and the duration of the treatment. Suspension of cultured tobacco cells (Nicotiana tabacum cv. Barley 21) were synchronized via sucrose starvation at their stationary growth phase. The cells were then exposed to 0.2 m T SMF up to 24 h. The progression of different cell cycle phases was monitored through flow cytometry in a time course manner. Expression of cell cycle controlling genes and amounts of certain signaling molecules were measured as well. Exposure to SMF delayed G1.S transition which was accompanied by decrease of cyclin-dependent kinases A (CDK A) and D-type cyclin, but an increase in the adenylyl cyclase (AC), transcription factor E2F, retinoblastoma protein (Rbp), and CDK-inhibitor protein 21 (p21) transcript accumulation. Exposure to SMF also increased the contents of nitric oxide (NO), hydrogen peroxide (H2O2), and salicylic acid (SA), compared to the control group. The results suggest a signaling pathway triggered by SMF starting from accumulation of NO and H2O2 followed by downstream events including the increase of cyclic nucleotides and subsequent decrease of both CDKA and CycD. PMID- 30466580 TI - OsPKS1 is required for sexine layer formation, which shows functional conservation between rice and Arabidopsis. AB - The sporopollenin precursors, as a general constituent of sexine, are synthesized in the tapetum and deposited on the pollen surface after transportation and processing. The polyketide synthase condenses the acyl-CoA into a hydroxyalkyl alpha-pyrone, which is predicted to be a component of the sporopollenin precursors. In this study, we found that the rice POLYKETIDE SYNTHASE 1 (OsPKS1) was the orthologue of Arabidopsis POLYKETIDE SYNTHASE A/LESS ADHESIVE POLLEN 6 (PKSA/LAP6) through sequence alignment. The OsPKS1 knockout mutants obtained by Crispr-Cas9-mediated editing exhibited a complete male sterile phenotype. Cytological observations revealed that abnormal bacula deposition and ubisch body structures for sexine formation led to pollen rupture in ospks1. The expression analysis showed that the OsPKS1 was highly expressed in tapetal cells and anther locules from stage 9 to stage 11 during anther development in rice. Subcellular localization demonstrated that the OsPKS1 protein was preferentially localized to the ER. The genomic sequence of OsPKS1 driven by the PKSA/LAP6 promoter restored the sexine pattern of Arabidopsis pksa/lap6. These results indicated that OsPKS1 is required for sexine layer formation in rice and functionally conserved in the sporopollenin synthesis pathway. PMID- 30466581 TI - Modulation of steroidal glycoalkaloid biosynthesis in tomato (Solanum lycopersicum) by jasmonic acid. AB - Jasmonic acid (JA) is a phytohormone involved in plant development and defense. A major role of JA is the enhancement of secondary metabolite production, such as response to herbivory. Systemin is a bioactive plant peptide of 18 amino acids that contributes to the induction of local and systemic defense responses in tomato (Solanum lycopersicum) through JA biosynthesis. The overexpression of systemin (PS-OE) results in constitutive JA accumulation and enhances pest resistance in plants. Conversely, mutant plants affected in linolenic acid synthesis (spr2) are negatively compromised in the production of JA which favors damage and oviposition by insect herbivores. With undirected mass fingerprinting analyses, we found global metabolic differences between genotypes with modified jasmonic acid production. The spr2 mutants were enriched in di-unsaturated fatty acids and generally showed more changes. The PS-OE genotype produced an unidentified compound with a mass-to-charge ratio of 695 (MZ695). Most strikingly, the steroidal glycoalkaloid biosynthesis was negatively affected in the spr2 genotype. Complementation with jasmonic acid could restore the tomatine pathway, which strongly suggests the control of steroidal glycoalkaloid biosynthesis by jasmonic acid. spr2 plants were more susceptible to fungal infection with Fusarium oxysporum f.sp. ciceris, but not to bacterial infection with Clavibacter michiganensis subsp. michiganensis which supports the involvement of steroidal glycoalkaloids in the plant response against fungi. PMID- 30466583 TI - Inhibition of starch branching enzymes in waxy rice increases the proportion of long branch-chains of amylopectin resulting in the comb-like profiles of starch granules. AB - Starches with comb-like profiles have been detected in some cereal endosperms with inhibiting expression of starch branching enzyme (SBE). Although amylose is considered to be an important factor in the formation of the comb-like profile, the details remain unclear. In this study, a transgenic rice line (GLXN-SBEI/IIb ) was derived from japonica waxy rice cultivar Guang-ling-xiang-nuo (GLXN) through antisense RNA inhibition of both SBEI and SBEIIb. The expression and activity of SBEI, SBEIIb and SBEIIa were declined. The GLXN-SBEI/IIb- endosperm contained large and small starch granules, and these starch granules had the comb like profiles. The comb-like profiles of starches were detected in GLXN-SBEI/IIb- endosperm after 10 days after flowering with gradually increasing proportion of long branch-chains of amylopectin. The long branch-chains of amylopectin were responsible for forming the comb-like profiles at the outer region of starch granules. The gradually decreasing expression of SBEs influenced the synthesis of amylopectin during endosperm development, resulting in different structure between the inner and outer regions of starch granules from GLXN-SBEI/IIb- endosperm. The above results indicated that the long branch-chains of amylopectin, not amylose, led to the formation of comb-like profiles of starch granules in cereal crops with inhibiting expression of SBEs. PMID- 30466582 TI - Datura innoxia plants hydroponically-inoculated with Agrobacterium rhizogenes display an enhanced growth and alkaloid metabolism. AB - BACKGROUND: The production of secondary metabolites through the culture of entire plants is of great interest. Soilless culture, such as hydroponics, enables the control of plant growth and metabolism. Specific environmental conditions must be developed to maximize the productivity of medicinal plants used as efficient natural bioreactors. METHODS: The nutrient solution of newly established hydroponic cultures ofDatura innoxia Mill. were inoculated with Agrobacterium rhizogenes (A.r.) wild strains (TR7, TR107, 11325 or 15834). Growth and the alkaloid contents of roots and aerial parts were analyzed. Axenic cultures were also performed with modified TR7 strains containing the egfp or gus reporter gene. In vitro isolated root cultures enabled the phenological and molecular demonstration of gene transfer. RESULTS: A.r.TR 7 led to a greater improvement in plant secondary metabolism and growth. Positive expression of the reporter genes occurred. Isolation and subculture of some of the roots of these plants showed a hairy root phenotype; molecular tests proved the transfer of bacterial genes into the roots isolated from the plants. CONCLUSIONS: Hyoscyamine and scopolamine productivity is enhanced after A.r. inoculation in the nutrient solution of hydroponic plants. Transformation events occur in the original roots of the plants. This leads to chimeric plants with a part of their roots harboring a hairy root phenotype. Such semi-composite plants could be used for successful specialized metabolite bioproduction in greenhouses. PMID- 30466584 TI - Greater emergence force and hypocotyl cross sectional area may improve wheat seedling emergence in sodic conditions. AB - Surface crusting of sodic soils is a major problem in the semi-arid tropics when rapid drying after sowing follows light showers, leading to reduced seedling emergence and grain yield. The magnitude of the force exerted by germinating seeds affects the ability of the seedlings to rupture the crust and emerge. This study aimed to determine whether the seed germination and seedling emergence force of wheat (Triticum aestivum L.) seedlings vary among different genotypes at different sodicity levels. Germination and emergence force of seedlings of four wheat genotypes was determined in assays using four solutions with sodium adsorption ratio (SAR) values ranging from 0 to 60. Seed germination and seedling emergence force varied between genotypes at different sodicity levels, with the emergence force of the coleoptile correlated to the cross sectional area of the hypocotyl. The results suggest that the selection of wheat genotypes with rapid germination, higher seedling emergence force and larger hypocotyl cross sectional area, offers a strategy to improve seedling emergence in crusted sodic soils. PMID- 30466585 TI - Cucumber Golgi protein CsMTP5 forms a Zn-transporting heterodimer with high molecular mass protein CsMTP12. AB - Heterodimeric complexes formed by members of the cation facilitator (CDF) family catalyse the import of Zn into the secretory pathway of yeast and vertebrate cells. Orthologous proteins AtMTP5 and AtMTP12 from Arabidopsis have also been shown to form a heterodimeric complex at the Golgi compartment of plant cells that possibly transport Zn. In this study we show that cucumber proteins CsMTP5 and CsMTP12 form a functional heterodimer that is involved in the loading of Zn into the ER lumen under low Zn, and not in the detoxification of yeast from Zn excess through vesicle-mediated exocytosis. Using specific antibodies, we demonstrate that CsMTP5 is localized at the Golgi compartment of cucumber cells and is markedly up-regulated upon Zn deficiency. The level of CsMTP5 transcript in cucumber is also significantly elevated in Zn-limiting conditions, whereas the expression of CsMTP12 is independent of the availability of Zn. Therefore we propose that the cucumber heterodimeric complex CsMTP5-CsMTP12 functions to deliver Zn to Zn-dependent proteins of the Golgi compartment and is regulated by zinc at the level of CsMTP5 transcription. PMID- 30466586 TI - OsMADS27 regulates the root development in a NO3--Dependent manner and modulates the salt tolerance in rice (Oryza sativa L.). AB - OsMADS27 is one of the ANR1-like homologues in rice, whreas its functions in plant growth and development as well as the abiotic stress responses remain unclear. Here we investigated the roles of OsMADS27 in the root development in response to NO3- availability. Constitutive expression of OsMADS27 significantly inhibited the elongation of primary root (PR), but enhanced lateral root (LR) formation in a NO3--dependent manner. Furthermore, OsMADS27 overexpression promoted NO3- accumulation as well as the expression of NO3- transporter genes. ABA is reported to play an important role in mediating the effects of NO3- on the root development, thus it is supposed that OsMADS27 might regulate the root growth and development by ABA pathway. The root growth and development in OsMADS27 overexpression lines was shown to be more sensitive to exogenous ABA than wild type. Moreover, under NO3- conditions, higher levels of ABA accumulates in OsMADS27 overexpression plants. Yeast two-hybrid and bimolecular fluorescence complementation (BiFC) assays showed that OsMADS27 physically interacts with ABA INSENSITIVE5 (OsABI5) via DELLA protein OsSLR1. More importantly, OsMADS27 overexpression could enhance the salt tolerance. Taken together, our findings suggested that OsMADS27 is an important regulator controlling the root system development and adaption to osmotic stress in rice. PMID- 30466587 TI - The contrasting response to drought and waterlogging is underpinned by divergent DNA methylation programs associated with transcript accumulation in sesame. AB - DNA methylation is a heritable epigenetic mechanism that participates in gene regulation under abiotic stresses in plants. Sesame (Sesamum indicum) is typically considered a drought-tolerant crop but highly susceptible to waterlogging, probably because of its origin in Africa or India. Understanding DNA methylation patterns under drought and waterlogging conditions can provide insights into the regulatory mechanisms underlying sesame contrasting responses to these abiotic stresses. We combined Methylation-Sensitive Amplified Polymorphism and transcriptome analyses to profile cytosine methylation patterns, transcript accumulation, and their interplay in drought-tolerant and waterlogging tolerant sesame genotypes. Drought stress strongly induced de novo methylation (DNM) whereas most of the loci were demethylated (DM) during the recovery phase. In contrast, waterlogging stress decreased the level of methylation but during the recovery phase, both DM and DNM were concomitantly deployed. In both stresses, the levels of the differentially accumulated transcripts (DATs) highly correlated with the methylation patterns. We observed that DM was associated with an increase of DAT levels while DNM was correlated with a decrease of DAT levels. Altogether, sesame has divergent epigenetic programs that respond to drought and waterlogging stresses and an interplay among DNA methylation and transcript accumulation may partly modulate the contrasting responses to these stresses. PMID- 30466588 TI - TaNAC6s are involved in the basal and broad-spectrum resistance to powdery mildew in wheat. AB - NACs are important transcriptional factors involved in growth and development as well as responses to abiotic and biotic stresses in plants. In this study, TaNAC6 was identified as a differentially expressed gene between two lines with broad spectrum resistance to powdery mildew, NAU9918 and OEStpk-V, and their corresponding susceptible isogenic lines, SM-1 and Yangmai158, after Bgt inoculation by transcriptome analysis. Then, three homoeologous genes of TaNAC6 were cloned and named as TaNAC6-A, TaNAC6-B and TaNAC6-D, respectively. Each member of TaNAC6s was subcellular localized to the nucleus and displayed the transcriptional activation activity. However, the responses of them to pathogens and phytohormones were different. Transient overexpression of each TaNAC6 reduced the haustorium index of Yangmai158, and stable transformation of TaNAC6-A enhanced its resistance against Bgt, implying that TaNAC6s play important roles in basal resistance. Silencing of TaNAC6s compromised the resistance of OEStpk-V and NAU9918 suggesting that TaNAC6s play positive roles in the broad-spectrum resistance against Bgt. TaNAC6s might be induced by JA and then feedback regulate the JA pathway leading to improved resistance to Bgt. The role of TaNAC6s and their orthologous genes HvNAC6 and ATAF1 in the powdery mildew resistance implied these NAC6 genes share a common signal pathway across species. PMID- 30466589 TI - Miscanthus NAC transcription factor MlNAC12 positively mediates abiotic stress tolerance in transgenic Arabidopsis. AB - NAC (NAM, ATAF1/2 and CUC2) transcription factors play critical roles in plant abiotic stress responses. However, knowledge regarding the functional roles of NACs in abiotic stress tolerance and its underlying mechanisms is relatively limited in Miscanthus. In this study, we functionally characterized a novel Miscanthus NAC gene MlNAC12 by ectopic expression in Arabidopsis. MlNAC12 was localized in the nucleus. It could specifically binds to the NAC recognition sequence (NACRS) and has a transactivation activity in the C-terminus. Overexpression of MlNAC12 in Arabidopsis conferred hypersensitivity to exogenous Abscisic acid (ABA) at seed germination and root elongation stages. In addition, MlNAC12 overexpression enhanced germination and root growth under salt (NaCl) stress. Furthermore, MlNAC12 overexpression lines exhibited significantly enhanced drought stress tolerance, which was evidenced by a higher survival rate and a lower water loss rate compared to the wild type (WT). Accordingly, the stomata aperture was remarkably reduced in MlNAC12 overexpression lines in comparison to the WT under drought stress. Furthermore, the accumulation of the reactive oxygen species (ROS) and malondialdehyde (MDA) under abiotic stresses was significantly decreased, accompanied by dramatically enhanced activities of several antioxidant enzymes including superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) in the transgenic plants. Correspondingly, the expression of six stress-responsive genes was significantly up-regulated in MlNAC12 overexpression lines. Together, our results indicate that MlNAC12 is a positive regulator of drought and salt stress tolerance through activating ROS scavenging enzymes. PMID- 30466590 TI - WRKY7, -11 and -17 transcription factors are modulators of the bZIP28 branch of the unfolded protein response during PAMP-triggered immunity in Arabidopsis thaliana. AB - Plants must defend themselves against pathogens. The defense response requires greater protein synthesis, which generates endoplasmic reticulum (ER) stress, yet failure to attenuate this stress has detrimental effects. WRKY7/11/17 transcription factors (TFs) are negative regulators of immunity since mutants are more resistant to Pseudomonas syringae pv tomato (Pst) infection. Here, we reveal a connection between ER-stress and the molecular mechanisms underlying the wrky mutant phenotype. The bZIP28 TF upregulates ER-chaperone expression (BiP1/2, ERdj3B, and SDF2) upon exposure of Arabidopsis to a bacterial defense elicitor, flagellin 22 (Flg22). Also, the activation of ER-chaperones is more sustained in double and triple wrky mutants treated with Flg22, suggesting that WRKY7/11/17 TFs downregulate these genes. Moreover, wrky mutants accumulate more bZIP28 transcripts in response to Flg22, indicating that WRKY7/11/17 transcriptionally repress this TF. Using Arabidopsis protoplasts, we also demonstrate that WRKYs bind to the bZIP28 promoter via W-box elements. Additionally, triple wrky mutants are more resistant, whilst bzip28 mutants are more susceptible, to Pst infection. Finally, we postulate a model of PAMP-Triggered Immunity regulation, where Flg22 activates bZIP28-signaling inducing the expression of ER-stress genes, as well as WRKY7/11/17 expression, which in turn inhibits PTI by downregulating bZIP28, controlling physiological responses in the Arabidopsis-Pst interaction. PMID- 30466591 TI - Natural variation in Brassica FT homeologs influences multiple agronomic traits including flowering time, silique shape, oil profile, stomatal morphology and plant height in B. juncea. AB - Natural structural variants of regulatory proteins causing quantitative phenotypic consequences have not been reported in plants. Herein, we show that 28 natural structural variants of FT homeologs, isolated from 6 species of Brassica, differ with respect to amino-acid substitutions in regions critical for interactions with FD and represent two evolutionarily distinct categories. Analysis of structural models of selected candidates from Brassica juncea (BjuFT_AAMF1) and Brassica napus (BnaFT_CCLF) predicted stronger binding between BjuFT and Arabidopsis thaliana FD. Over-expression of BjuFT and BnaFT in wild type and ft-10 mutant backgrounds of Arabidopsis validated higher potency of BjuFT in triggering floral transition. Analysis of gain-of-function and artificial miRNA mediated silenced lines of B. juncea implicated Brassica FT in multiple agronomic traits beyond flowering, consistent with a pleiotropic effect. Several dependent and independent traits such as lateral branching, silique shape, seed size, oil-profile, stomatal morphology and plant height were found altered in mutant lines. Enhanced FT levels caused early flowering, which in turn was positively correlated to a higher proportion of desirable fatty acids (PUFA). However, higher FT levels also resulted in altered silique shape and reduced seed size, suggesting trait trade-offs. Modulation of FT levels for achieving optimal balance of trait values and parsing pair-wise interactions among a reportoire of regulatory protein homeologs in polyploid genomes are indeed future areas of crop research. PMID- 30466592 TI - RAD7 homologues contribute to Arabidopsis UV tolerance. AB - Frequent exposure of plants to solar ultraviolet radiation (UV) results in damaged DNA. One mechanism of DNA repair is the light independent pathway Global Genomic Nucleotide Excision Repair (GG-NER), which repairs UV damaged DNA throughout the genome. In mammals, GG-NER DNA damage recognition is performed by the Damaged DNA Binding protein 1 and 2 (DDB1/2) complex which recruits the Xeroderma Pigmentosa group C (XPC) / RAD23D complex. In the yeast Saccharomyces cerevisiae, distinct proteins, Radiation sensitive 7 and 16 (Rad7p and Rad16p), recognize the damaged DNA strand and then recruit the XPC homologue, Rad4p, and Rad23p. The remainder of the proteins involved GG-NER are well conserved. DDB1, DDB2, XPC/RAD4, and RAD23 homologues have been described in the model plant Arabidopsis thaliana. In this study we characterize three Arabidopsis RAD7 homologues, RAD7a, RAD7b, and RAD7c. Loss of function alleles of each of the three RAD7 homologues result in increased UV sensitivity. In addition, RAD7b and RAD7c overexpression lines exhibited increased UV tolerance. Thus RAD7 homologues contribute to UV tolerance in plants as well as in yeast. This is the first time any system has been shown to utilize both the DDB1/2 and RAD7/16 damage recognition complexes. PMID- 30466593 TI - Identification and characterization of an Arabidopsis phosphate starvation induced secreted acid phosphatase as a vegetative storage protein. AB - Induction and secretion of acid phosphatases is an adaptive response of plants to phosphate starvation. The secreted acid phosphatases are believed to scavenge phosphate from organophosphate compounds in the rhizosphere, thereby increasing phosphate availability for plant absorption. To date, however, all of the characterized phosphate starvation-induced secreted acid phosphatases in plants belong to a unique acid phosphatases subfamily, called purple acid phosphatase. In this work, we identified a phosphate starvation-induced secreted acid phosphatase in Arabidopsis as a vegetative storage protein, AtVSP3. AtVSP3 exists as a monomer with molecular weight of 29 kDa. The activity of recombinant AtVSP3 protein is activated by Mg2+, Co2+, and Ca2+. AtVSP3 has an optimal pH of 6.5 for its APase activity and is relatively thermostable. The transcription of AtVSP3 is induced in roots by phosphate starvation, and the accumulation of AtVSP3 protein is high in roots and siliques. Additional research is needed to determine the function of AtVSP3 in plant responses to stress conditions. PMID- 30466594 TI - A cupin domain is involved in alpha-amylase inhibitory activity. AB - Proteinaceous alpha-amylase inhibitors have specialized activities that make some strong inhibition of alpha-amylases. New alpha-amylase inhibitors continue to be discovered so far. A proteinaceous alpha-amylase inhibitor CL-AI was isolated and identified from chickpea seeds. CL-AI, encoded by Q9SMJ4, was a storage legumin precursor containing one alpha-chain and one beta-chain, and each chain possessed a same conserved cupin domain. Amino acid mutation and deficiency of cupin domain would lead to loss of alpha-amylase inhibitory activity, indicating that it was essential for inhibitory activity. CL-AI(alpha + beta) in its single stranded state in vivo had inhibitory activity. After it was processed into one alpha chain and one beta-chain, the two chains were connected to each other via disulfide bond, which would cover the cupin domains and lead to the loss of inhibitory activity. The CL-AI(alpha + beta), alpha-chain and beta-chain could inhibit various alpha-amylases and delay the seed germination of wheat, rice and maize as well as the growth and development of potato beetle larva. Two cupin proteins, Glycinin G1 in soybean and Glutelinin in rice were also found to have inhibitory activity. Our results indicated that the cupin domain is involved in alpha-amylase inhibitory activity and the proteins with a cupin domain may be a new kind of proteinaceous alpha-amylase inhibitor. PMID- 30466595 TI - Genetic dissection of the mechanism of flowering time based on an environmentally stable and specific QTL in Brassica napus. AB - Flowering time is an important agronomic trait that is highly influenced by the environment. To elucidate the genetic mechanism of flowering time in rapeseed (Brassica napus L.), a genome-wide QTL analysis was performed in a doubled haploid population grown in winter, semi-winter and spring ecological conditions. Fifty-five consensus QTLs were identified after combining phenotype and genomic data, including 12 environment-stable QTLs and 43 environment-specific QTLs. Importantly, six major QTLs for flowering time were identified, of which two were considered environment-specific QTLs in spring ecological condition and four were considered environment-stable QTLs in winter and semi-winter ecological conditions. Through QTL comparison, 18 QTLs were colocalized with QTLs from six other published studies. Combining the candidate genes with their functional annotation, in 49 of 55 consensus QTLs, 151 candidate genes in B. napus corresponding to 95 homologous genes in Arabidopsis thaliana related to flowering were identified, including BnaC03g32910D (CO), BnaA02g12130D (FT) and BnaA03g13630D (FLC). Most of the candidate genes were involved in different flowering regulatory pathways. Based on re-sequencing and differences in sequence annotation between the two parents, we found that regions containing some candidate genes have numerous non-frameshift InDels and many non- synonymous mutations, which might directly lead to gene functional variation. Flowering time was negativly correlated with seed yield and thousand seed weight based on a QTL comparison of flowering time and seed yield traits, which has implications in breeding new early-maturing varieties of B. napus. Moreover, a putative flowering regulatory network was constructed, including the photoperiod, circadian clock, vernalization, autonomous and gibberellin pathways. Multiple copies of genes led to functional difference among the different copies of homologous genes, which also increased the complexity of the flowering regulatory networks. Taken together, the present results not only provide new insights into the genetic regulatory network underlying the control of flowering time but also improve our understanding of flowering time regulatory pathways in rapeseed. PMID- 30466596 TI - Different nitrogen (N) forms affect responses to N form and N supply of rootstocks and grafted grapevines. AB - Rootstocks play an important role in the cultivation of grapevines. In addition to the uptake and storage of nutrients, rootstocks and their root system affect the growth and metabolite composition of the berries. Nitrogen can be taken up in various forms, such as nitrate, ammonium or amino acids or even small peptides, and is of considerable importance in vigor control and in yield and berry quality. Amino acids in the must adjust fermentation kinetics, constitute a major source for yeast and affect vine metabolism. In the present study, two different experiments were undertaken; nitrate, ammonium, urea, arginine and glutamine at various doses (0; 0.5; 1.0; 3.0 g N/plant) were used to fertilize (i) two hydroponically grown rootstock varieties (Ru140 and SO4) and (ii) grafted grapevines of Vitis vinifera L cv. Regent (rootstock SO4) grown in pots. Accumulation capabilities, generative growth and berry quality were examined. It can be assed that the preferred N form is rootstock-variety-dependent. We demonstrated that grapevines were able to take up nitrogen in the form of amino acids; (arginine to a greater extent than glutamine). Although, growth was reduced, nitrogen content and nitrate reductase activity were comparable for nitrate, ammonium and urea nutrition. In terms of berry quality, only minor differences between the N forms applied were identified. An economic optimum in terms of vine and berry quality was detected. Excessive amounts of nitrogen seemed to lead to the increased growth of green plant tissue. Berry yield increased with increasing nitrogen supply but slightly decreased at the highest dosage, whereas quality parameters such as must pH increased and the total acid concentration was reduced. PMID- 30466597 TI - Dynamic transcriptome analysis of root nitrate starvation and re-supply provides insights into nitrogen metabolism in pear (Pyrus bretschneideri). AB - Pear (Pyrus bretschneideri) is a popular fruit worldwide, but the irrational utilization of nitrogen as a fertilizer not only greatly affects the fruit' quality, but also wastes resources and results in serious environmental pollution. To better understand the molecular mechanism in pear responsible for the regulation of nitrate transport and assimilation, RNA-seq was performed on samples collected in response to nitrate treatments. Here, 10,273 differentially expressed genes were obtained and annotated into 49 GO terms, 45 clusters having co-expression trends that involved 18 KEGG-defined significantly overrepresented pathways. The KEGG pathways revealed that 15 unigenes, including one NRT gene, two NR genes, one NiR gene, two GDH genes, six GS genes and three GOGAT genes, were related to nitrogen metabolism and significantly differentially expressed in response to nitrate starvation and a nitrate re-supply treatment. Furthermore, 449 transcription factors belonging to 35 different families were identified during the nitrate treatments. The expression patterns of 14 randomly selected differentially expressed genes were validated by qRT-PCR. This study provides valuable resources for investigating the genetics of the nitrogen metabolic pathways and improving nitrogen utilization efficiency in pear. PMID- 30466598 TI - The Arabidopsis DWARF27 gene encodes an all-trans-/9-cis-beta-carotene isomerase and is induced by auxin, abscisic acid and phosphate deficiency. AB - Strigolactones (SLs) are carotenoid-derived plant hormones that influence various aspects of plant growth and development in response to environmental conditions, especially nutrients deficiency. SLs are synthesized via a strict stereo-specific core pathway that leads to the intermediate carlactone, requiring the iron containing polypeptide DWARF27 (D27) and the carotenoid cleavage dioxygenases 7 (CCD7) and 8 (CCD8). It has been shown that the rice OsD27 is a beta-carotene isomerase catalyzing the interconversion of all-trans- into 9-cis-beta -carotene. However, data about the enzymatic activity of D27 from other species are missing. Here, we investigated the activity and substrate specificity of the Arabidopsis AtD27 by testing a broad range of carotenoid substrates. Both in vivo and in vitro assays show that AtD27 catalyzes the reverse isomerization of all-trans-/9 cis-beta-carotene. AtD27 did not isomerize 13-cis- or 15-cis-beta-carotene, indicating high specificity for the C9-C10 double bond. The isomerization reaction was inhibited in the presence of silver acetate, pointing to the involvement of an iron-sulfur cluster. We further investigated the expression of AtD27, using Arabidopsis transgenic lines expressing beta-glucuronidase (GUS) under the control of AtD27 native promoter. AtD27 is ubiquitously expressed throughout the plant with the highest expression in immature flowers. In lateral roots, AtD27 expression was induced by treatment with auxin and ABA, while the application of SL analogs did not show an effect. Lower ABA levels in atd27 mutant indicated an interference with the ABA pathway. Quantitative real-time RT PCR showed that transcript levels of AtD27 and other SL biosynthetic genes in roots are induced upon phosphate starvation. Taken together, our study on AtD27 confirms the postulated enzymatic function of this enzyme, shows its strict substrate- and regio-specificity and indicates an important role in response to multiple plant hormones and phosphate deficiency. PMID- 30466599 TI - Citrus sinensis MYB transcription factors CsMYB330 and CsMYB308 regulate fruit juice sac lignification through fine-tuning expression of the Cs4CL1 gene. AB - Lignin is one of the most important components of the plant cell wall, and the expression and transcriptional regulation of lignin biosynthesis-related genes have been studied widely in Arabidopsis and other plants. Citrus fruit juice sacs often undergo lignification, particularly during fruit ripening and storage periods; however, the underlying genetic mechanisms have been little investigated. In this study, we isolated and identified CsMYB330 and CsMYB308 transcription factors, and found that their expression levels are significantly altered during the lignification of citrus fruit juice sacs. We found that CsMYB330 and CsMYB308 can recognize and bind AC elements in the Cs4CL1 promoter and finely regulate expression of the Cs4CL1 gene. In this regulatory process, CsMYB330 was identified as a transcriptional activator, whereas CsMYB308 appears to be a transcriptional repressor. In addition, using a transient assay, we demonstrated that expression of the Cs4CL1 gene is significantly altered in fruit juice sacs overexpressing these two transcription factors. These results indicate that the transcription factors CsMYB330 and CsMYB308 play important roles in the lignification of citrus fruit juice sacs and provide novel insights into the transcriptional regulation associated with fruit juice sac lignification. PMID- 30466600 TI - The GDP-mannose transporter gene (DoGMT) from Dendrobium officinale is critical for mannan biosynthesis in plant growth and development. AB - Dendrobium officinale is a precious traditional Chinese medicinal herb because it is abundant in mannose-containing polysaccharides (MCPs). GDP-mannose transporter (GMT), which translocates GDP-mannose into the Golgi lumen, is indispensable for the biosynthesis of MCPs. In this study, we found that the dominant polysaccharides in D. officinale were MCPs in a range of varieties and different physiological phases. After a positive correlation between the accumulation of mannose and the transcript levels of candidate GMT genes was found, three GMT genes (DoGMT1-3) were identified in D. officinale. DoGMT1, DoGMT2 and DoGMT3 exhibited the highest transcript level in stem that an organ for MCPs storage. All three DoGMT proteins were targeted to Golgi apparatus, and had a GDP binding domain (GXL/VNK) that was homologous to a specially characterized GMT protein GONST1 in Arabidopsis thaliana. Moreover, DoGMT1, DoGMT2 and DoGMT3 complemented a GDP-mannose transport-defective yeast mutant (vrg4-2), meanwhile they also demonstrated a higher GDP-mannose uptake activity. Therefore, we conclude that DoGMT1, DoGMT2 and DoGMT3 are able to transport GDP-mannose while the expression patterns of these genes correspond to the accumulation of MCPs in D. officinale. These findings support the importance of GMT genes from D. officinale in the biosynthesis of MCPs. PMID- 30466601 TI - A novel cysteine-rich peptide regulates cell expansion in the tobacco pistil and influences its final size. AB - Plant morphogenesis is dependent on cell proliferation and cell expansion, which are responsible for establishing final organ size and shape during development. Several genes have been described as encoding components of the plant cell development machinery, among which are the plant peptides. Here we describe a novel cysteine-rich plant peptide (68 amino acids), encoded by a small open reading frame gene (sORF). It is specifically expressed in the reproductive organs of Nicotiana tabacum and is developmentally regulated. N- and C-terminal translational fusions with GFP in protoplasts have demonstrated that the peptide is not secreted. Knockdown transgenic plants produced by RNAi exhibited enlarged pistils due to cell expansion and the gene was named Small Peptide Inhibitor of Cell Expansion (SPICE). Estimation of nuclear DNA content using flow cytometry has shown that cell expansion in pistils was not correlated with endoreduplication. Decreased SPICE expression also affected anther growth and pollen formation, resulting in male sterility in at least one transgenic plant. Our results revealed that SPICE is a novel reproductive organ specific gene that controls cell expansion, probably as a component of a signal transduction pathway. PMID- 30466602 TI - Highlighting type A RRs as potential regulators of the dkHK1 multi-step phosphorelay pathway in Populus. AB - In previous studies, we highlighted a multistep phosphorelay (MSP) system in poplars composed of two hybrid-type Histidine aspartate Kinases, dkHK1a and dkHK1b, which interact with three Histidine Phosphotransfer proteins, dkHPt2, 7, and 9, which in turn interact with six type B Response Regulators. These interactions correspond to the dkHK1a-b/dkHPts/dkRRBs MSP. This MSP is putatively involved in an osmosensing pathway, as dkHK1a-b are orthologous to the Arabidopsis osmosensor AHK1, and able to complement a mutant yeast deleted for its osmosensors. Since type A RRs have been characterized as negative regulators in cytokinin MSP signaling due to their interaction with HPt proteins, we decided in this study to characterize poplar type A RRs and their implication in the MSP. For a global view of this MSP, we isolated 10 poplar type A RR cDNAs, and determined their subcellular localization to check the in silico prediction experimentally. For most of them, the in planta subcellular localization was as predicted, except for three RRAs, for which this experimental approach gave a more precise localization. Interaction studies using yeast two-hybrid and in planta BiFC assays, together with transcript expression analysis in poplar organs led to eight dkRRAs being singled out as partners which could interfere the dkHK1a-b/dkHPts/dkRRBs MSP identified in previous studies. Consequently, the results obtained in this study now provide an exhaustive view of dkHK1a-b partners belonging to a poplar MSP. PMID- 30466603 TI - Review: Functional linkages between amino acid transporters and plant responses to pathogens. AB - Upon infection, plant pathogens become dependent on their hosts for nutrition. Therefore, the interaction between the two organisms is tightly linked to the availability and flux of nutrients in the plant. The plant's nitrogen metabolism is reprogrammed during pathogen attack, likely reflecting plant's response to invasion by the pathogen and active modification by the pathogen to promote feeding. Several lines of evidence indicate that plant-derived amino acids are an important source of nitrogen for diverse pathogens. Moreover, amino acid homeostasis is interconnected with the plant's immune signaling pathways. Here, we critically examine the knowns and unknowns about connections between plant encoded amino acid transporters and resistance or susceptibility to pathogens and pests. We use recent insights into sugar transporters to frame a perspective with potential applicability to amino acids and other nutrients. We emphasize different approaches that have provided insight in this topic and we conclude with suggestions to fill gaps in foundational knowledge and explore new avenues for disease control. PMID- 30466604 TI - FLOURY ENDOSPERM11 encoding a plastid heat shock protein 70 is essential for amyloplast development in rice. AB - Mutations of stromal Hsp70 cause chloroplast developmental abnormalities and knockout mutants of stromal Hsp70 usually exhibit protein import deficiencies. However, their effects have not been studied in amyloplast development. Here, we identified an amyloplast abnormal development mutant, floury endosperm11 (flo11) that exhibited an opaque phenotype in the inner core and the periphery of grains. Semi-thin section revealed defective amyloplast development in the flo11 endosperm. Map-based cloning and subsequent complementation test demonstrated that FLO11 encoded a plastid-localized heat shock protein 70 (OsHsp70cp-2). OsHsp70cp-2 was abundantly expressed in developing endosperm, whereas its paralogous gene OsHsp70cp-1 was mainly expressed in photosynthetic tissues. Ectopic expression of OsHsp70cp-1 under the control of OsHsp70cp-2 promoter rescued the mutant phenotype of flo11. Moreover, simultaneous knockdown of both OsHsp70cp genes resulted in white stripe leaves and opaque endosperm. BiFC and Co IP assays revealed that OsHsp70cp-2 was associated with Tic complex. Taken together, OsHsp70cp-2 may regulate protein import into amyloplasts, which is essential for amyloplast development in rice. PMID- 30466605 TI - Microbial community response and migration of petroleum compounds during a sea ice oil spill experiment in Svalbard. AB - This paper concerns the migration of oil through sea-ice and the biodegradation of different hydrocarbons in sea-ice and seawater following in situ oil spills in megacosms exposed to winter and spring conditions in Svalbard (80 degrees N). Hydrocarbon-degrading microbes were detected in ice cores and the analysis of metabolically active bacterial populations in the different layers of sea-ice indicate significant population shifts following oil exposure, whether dispersant addition or oil burning was carried out or not. The presence of dispersant in the system was associated with the most pronounced and fastest population shifts out of all exposures, as well as lower bacterial diversity as measured by the Shannon index. Microorganisms were metabolically most active in the bottom layer of the sea ice and our data confirmed the predominance of Oleispira and Colwellia aestuarii in sea-ice. Migration of polycyclic aromatics through the sea-ice layer was observed when dispersant was added to the oil, and the presence of oil degrading organisms below the ice-layer was consistent with biodegradation taking place. Given the thickness and concentration of the oil-layer frozen into the ice, the bioavailability of the hydrocarbons was nevertheless limited. Consequently, much of the bulk of the oil remained intact. PMID- 30466606 TI - Rhein protects the myocardiac cells against hypoxia/reoxygention-induced injury by suppressing GSK3beta activity. AB - BACKGROUND: Rhein, an anthraquinone compound isolated from rhubarb, has been shown to protect the pancreatic beta cells from hyperglycemia induced apoptosis in our previous studies. PURPOSE: In the present study, we examined whether rhein can protect myocardial cells against ischemia reperfusion (I/R)-induced apoptosis and investigated the underlying mechanism. METHODS: We used an in vitro model of myocardial hypoxia/reoxygenation (H/R) injury. H9c2 cells were incubated with rhein for 1 h and then subjected to hypoxia for 6 h, followed by reoxygenation for 2 h. Cells viability, apoptosis and ROS were assayed for the treated cells. AKT, p-AKT, GSK3beta, p- GSK3beta, P38 and p-P38 proteins were analyzed using Western blotting. PI3K/AKT inhibitor, LY294002, and GSK3beta siRNA were also used to determine the signaling pathways involved in the protection by rhein. RESULTS: Rhein increased viability, decreased apoptosis and ROS production, of the cells that were exposed to H/R. Rhein also increased the phosphorylation of AKT and GSK3beta, an effect that was eliminated by LY294002. GSK3beta silencing by siRNA showed similar effect as LY294002. The p-P38 level was upregulated by H/R and downregulated in the presence of rhein; however, the p-P38 downregulation was completely abolished by GSK3beta silencing. CONCLUSION: Rhein protects myocardial H9c2 cells against hypoxia/reoxygenation induced injury via AKT/ GSK3beta/p38 pathway. PMID- 30466607 TI - Correlation between macroscopic characteristics and tissue-specific chemical profiling of the root of Salvia miltiorrhiza. AB - BACKGROUND: Macroscopic identification has been widely used as a convenient method for herbal authentication and quality assessment. However, sensory evaluation heavily relied on personal experience and lacked enough evidence-based validations. PURPOSE: We aim to reveal the correlation between macroscopic characteristics and tissue-specific chemical composition of the root of Salvia miltiorrhiza (SMR), and then develop a rapid method for quality assessment. METHODS: Thirty-two batches of SMR were collected and evaluated. The outer surface color and diameter as the representative tissue features of SMR were selected as the macroscopic indexes. SMR were then divided into three parts along transverse section as outer bark, middle part and central part, to explore the spatial distribution of chemicals. Outer-surface color information was converted into RGB values, while the diameter data were expressed by mean distance, respectively. Thirteen major components including eight salvianolic acids and five tanshinones in each part were determined by liquid chromatography tandem mass spectrometry. Finally, several mathematical models were established and optimized to evaluate the correlation between outer-surface color, size and chemical distribution. RESULT: All five tanshinones mainly distributed in the outer bark while salvianolic acids were averagely existed among three parts. Correlational studies revealed that the surface color depth was significantly and positively correlated with tanshinone contents in the outer bark, while the size showed poor correlation in any chemicals. A color-oriented model was thus developed for the prediction of tanshinone contents in SMR, and a 9 * 9 standard color chart was created for easily use. CONCLUSION: This study contributes an alternative method for macroscopic features-based quality evaluation of herbs, and also complements some scientific data for traditional knowledge. PMID- 30466608 TI - Epimagnolin A, a tetrahydrofurofuranoid lignan from Magnolia fargesii, reverses ABCB1-mediated drug resistance. AB - BACKGROUND: Epimagnolin A is an ingredient of the Chinese crude drug Shin-i, derived from the dried flower buds of Magnolia fargesii and Magnolia flos, which has been traditionally used for the treatment of allergic rhinitis and nasal congestion, empyema, and sinusitis. The pharmacokinetic activity of epimagnolin A remains to be evaluated. PURPOSE: In this study, we examined the possible interactions of epimagnolin A with human ATP-binding cassette (ABC) transporter ABCB1, a membrane protein vital in regulating the pharmacokinetics of drugs and xenobiotics. STUDY DESIGN/METHODS: The interaction of epimagnolin A with ABCB1 was evaluated in calcein, ATPase, and MTT assays by using Flp-In-293/ABCB1 cells and purified ABCB1 and simulated in molecular docking studies. RESULTS: Epimagnolin A inhibited calcein export by Flp-In-293/ABCB1 cells in a concentration-dependent manner in a calcein assay. ATPase assay revealed a concentration-dependent stimulation of the ATPase activity of ABCB1 by epimagnolin A. Epimagnolin A also showed saturation kinetics in the relationship between the compound-stimulated ATPase activity and the compound concentration, suggesting Michaelis-Menten kinetics similar to those of the control drug, verapamil. Km and Vmax values were calculated from Hanes-Woolf plots of (compound concentration) * (compound-stimulated ATPase activity)-1 vs. (compound concentration); the Km of epimagnolin and verapamil was 42.9 +/- 7.53 MUM and 12.3 +/- 4.79 MUM, respectively, and the corresponding Vmax values were 156 +/- 15.0 MUM and 109 +/- 3.18 MUM. Molecular docking studies on human ABCB1 showed that epimagnolin A docked to the same binding pocket as verapamil, and 3-(4,5 dimethyl-2-thiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays showed that the sensitivities of Flp-In-293/ABCB1 cells against anti-cancer drugs were enhanced upon exposure to 10 MUM epimagnolin A. CONCLUSION: These results strongly suggest that epimagnolin A affects the transport activity of ABCB1 as a substrate. PMID- 30466609 TI - Phytochemical constituents from Uncaria rhynchophylla in human carboxylesterase 2 inhibition: Kinetics and interaction mechanism merged with docking simulations. AB - BACKGROUND: Carboxylesterases (CEs) belong to the serine hydrolase family, and are in charge of hydrolyzing chemicals with carboxylic acid ester and amide functional groups via Ser-His-Glu. Uncaria rhynchophylla (Miq.) Miq. ex Havil. is a famous traditional Chinese medicine used in managing hyperpyrexia, epilepsy, preeclampsia, and hypertension in China. HYPOTHESIS/PURPOSE: To discover the potential natural human carboxylesterase 2 (hCE 2) inhibitors from U. rhynchophylla. METHODS: Compounds were obtained from the hooks of U. rhynchophylla by silica gel and preparative HPLC. Their structures were elucidated by using HRESIMS, 1D and 2D NMR spectra. Their inhibitory activeties and inhibition kinetics against hCE 2 were assayed by the fluorescent probe, and potential mechanisms were also investigated by molecular docking. RESULTS: Twenty three compounds, including a new phenolic acid uncariarhyine A (1), eight known triterpenoids (2-9), and ten known aromatic derivatives (10, 13-16, and 19-23), were isolated from U. rhynchophylla. Compounds 1-5, 7, 9, and 15 showed significant inhibitory activities against hCE 2 with IC50 values from 4.01 +/- 0.61 uM to 18.60 +/- 0.21 uM, and their inhibition kinetic analysis results revealed that compounds 1, 5, 9, and 15 were non-competitive; compounds 3 and 4 were mixed-type, and compounds 2 and 7 were uncompetitive. Molecular docking studies indicated inhibition mechanisms of compounds 1-5, 7, 9, and 15 against hCE 2. CONCLUSION: Our present findings highlight potential natural hCE 2 inhibitors from U. rhynchophylla. PMID- 30466610 TI - Improved protective effects of American ginseng berry against acetaminophen induced liver toxicity through TNF-alpha-mediated caspase-3/-8/-9 signaling pathways. AB - BACKGROUND: Similar to the leaves of P. Quinquefolius, American ginseng berry (AGB) is another important part of P. Quinquefolius with alternative therapeutic potential. The liver protection capabilities of the former have been demonstrated previously, however, the later has not yet been evaluated. PURPOSE: Based on our previous observation, the present work was designed to evaluate the hepatic protective effects for novel mechanisms of AGB in acetaminophen (APAP)-induced liver injury in vivo. STUDY DESIGN/METHODS: All mice were divided into four groups as follows: normal group, APAP group and APAP + AGB (150 mg/kg and 300 mg/kg) groups. AGB were orally administered for one week before exposure to APAP (250 mg/kg). Severe liver injury was observed and hepatotoxicity was evaluated after 24 h through evaluating the biochemical markers, protein expressions levels and liver histopathology. RESULTS: Our study results clearly demonstrated that AGB pretreatment ameliorated APAP-induced hepatic injury as evidenced by decreasing plasma alanine aminotransferase (ALT), aspartate transaminase (AST), tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) compared to the APAP group. Western blotting analysis showed that pretreatment with AGB decreased the expressions levels of TNF-alpha and nuclear transcription factor kappaB (NF-kappaB p65) in liver tissues. Meanwhile, the protein expression levels of caspases, cytochrome c, and Bax were elevated by AGB treatment for seven days, while the protein expression level of Bcl-2 was inhibited comparison with that in APAP group. Furthermore, supplement of AGB resulted in increase of superoxide dismutase (SOD) and glutathione (GSH), while decrease of malondialdehyde (MDA) content and the expression levels of 4-hydroxynonenal (4-HNE) and cytochrome P450 E1 (CYP2E1). The results of histopathological staining demonstrated that AGB pretreatment inhibited APAP-induced hepatocyte infiltration, congestion, and necrosis. CONCLUSION: The present study demonstrated that AGB pretreatment protected liver cells against APAP-induced hepatotoxicity through inhibition of oxidative stress, inflammation responses via TNF-alpha-mediated caspase-3/-8/-9 signaling pathways. PMID- 30466611 TI - Afrocyclamin A, a triterpene saponin, induces apoptosis and autophagic cell death via the PI3K/Akt/mTOR pathway in human prostate cancer cells. AB - BACKGROUND: Afrocyclamin A, an oleanane-type triterpene saponin, was isolated from Androsace umbellata which used as a traditional herbal medicine. PURPOSE: This study aimed to explore the anticancer activity of afrocyclamin A on human prostate cancer cells in vitro as well as in vivo. METHODS: Cytotoxicity, cell cycle distribution, apoptosis, and autophagic cell death were measured following exposure to afrocyclamin A. In vivo antitumor activity of afrocyclamin A was assessed in a xenograft model. The protein levels of p-Akt, p-mTOR, Bax, Bcl-2, caspase-3, and caspase-9 were quantified using western blot analysis. RESULTS: In DU145 cells, afrocyclamin A increased cytotoxicity, caused changes in cell morphology, and induced sub-G0/G1 phase indicating increased apoptosis. Afrocyclamin A robustly induced autophagic cell death as demonstrated by the conversion of LC3B-I to LC3B-II, and the formation of autophagic vacuoles as revealed by western blot analysis and fluorescence staining, respectively. Afrocyclamin A also inhibited the phosphorylation of PI3K, Akt, and mTOR, suggesting their role in afrocyclamin A induced cell death. In addition, afrocyclamin A inhibited cell migration and invasion in concentration and time dependent manners. In an in vivo xenograft model, afrocyclamin A inhibited the growth of DU145 cells. CONCLUSION: Afrocyclamin A has anticancer activity via the PI3K/Akt/mTOR pathway, which leads to cell death. PMID- 30466612 TI - Positive effects of alpha-asarone on transplanted neural progenitor cells in a murine model of ischemic stroke. AB - BACKGROUND: Some traditional Oriental herbal medicines, such as Acorus tatarinowii and Acorus gramineus, produce beneficial effects for cognition enhancement. An active compound in rhizomes and the bark of these plants is alpha asarone. PURPOSE: This study investigated the effects of alpha-asarone on the proliferation and differentiation of neural progenitor cells (NPCs) in a primary culture and a murine model of ischemic stroke. METHODS: NPCs were isolated from mouse fetal cerebral cortices on embryonic day 15, and all experiments were performed using passage 3 NPCs. We utilized a cell counting kit-8 assay, flow cytometry, western blot, and immunohistochemical analysis to assess proliferation and differentiation of NPCs and employed alpha-asarone in NPC transplanted ischemic stroke mice to evaluate stroke-related functional recovery using behavioral and immunohistochemical analysis. RESULT: Treatment with 1 uM, 3 uM, or 10 MUM alpha-asarone induced significant NPC proliferation compared to vehicle treatment. Induced NPCs expressed the neuronal marker neuronal nuclei (NeuN) or the astrocyte marker S100 calcium-binding protein B (S100beta). Both immunohistochemistry and flow cytometry revealed that treatment with alpha asarone increased the number of NeuN-immunoreactive cells and decreased the number of S100beta-immunoreactive cells. Treatment with alpha-asarone also increased the expression of beta-catenin, cyclin D1, and phosphorylated extracellular signal-regulated kinase (ERK) compared to vehicle treatment. In a murine model of ischemic stroke, treatment with alpha-asarone and transplanted NPCs alleviated stroke-related functional impairments. The corner and rotarod test results revealed that treatment with alpha-asarone in the NPC transplanted group had greater-than-additive effects on sensorimotor function and motor balance. Moreover, alpha-asarone treatment promoted the differentiation of transplanted NPCs into NeuN-, glial fibrillary acidic protein (GFAP)-, platelet derived growth factor-alpha (PDGFR-alpha)-, and 2', 3'-cyclic nucleotide 3' phosphodiesterase (CNPase)-immunoreactive cells. CONCLUSION: alpha-asarone may promote NPC proliferation and differentiation into neuron-lineage cells by activating beta-catenin, cyclin D1, and ERK. Moreover, alpha-asarone treatment facilitated neurofunctional recovery after NPC transplantation in a murine model of ischemic stroke. Therefore, alpha-asarone is a potential adjunct treatment to NPC therapy for functional restoration after brain injuries such as ischemic stroke. PMID- 30466613 TI - Periplocin, the most anti-proliferative constituent of Periploca sepium, specifically kills liposarcoma cells by death receptor mediated apoptosis. AB - BACKGROUND: During a screening of Chinese plants traditionally used for the treatment of cancer and related diseases, extracts of the root bark of Periploca sepium Bunge showed strong cytotoxic activity. PURPOSE: Isolate and identify cytotoxic compounds from P. sepium and investigate the effects and mechanism of action on different cancer cell lines. METHODS: Extracts obtained with solvents of different polarities of the root bark of P. sepium were tested for their anti proliferative effects. The most active extract was subjected to activity-guided fractionation using different chromatographic methods. The most active compound was further investigated on sarcoma cell lines regarding its effects concerning apoptosis, DNA damage and death receptor expression. RESULTS: We isolated the cardiac glycosides periplocin, glucosyl divostroside, periplogenin, periplocymarin and periplocoside M with periplocin exhibiting the lowest IC50 value against leukemia and liposarcoma cells. Liposarcomas are rare tumors within the heterogeneous group of soft tissue sarcomas and respond poorly to conventional treatments. Periplocin led to growth inhibition and apoptosis induction by changing the expression of death receptors and inducing DNA double strand breaks in SW-872 cells. CONCLUSION: Periplocin displays a promising mechanism of action in sarcoma cells because altering the death receptor expression is an interesting target in sarcoma treatment especially to overcome TRAIL resistance. PMID- 30466615 TI - Icariin abrogates osteoclast formation through the regulation of the RANKL mediated TRAF6/NF-kappaB/ERK signaling pathway in Raw264.7 cells. AB - BACKGROUND: Icariin is pharmacologically active prenylated flavonoid glycoside that has various biologic effects such as antioxidant, anticancer, and anti inflammatory activities. In addition, icariin has been used in Chinese medicine for thousands of years to treat osteoporosis and it is still being used today. However, direct mechanism of icariin in the treatment of bone disease is not understood. PURPOSE: The purpose of this study is to investigate whether icariin influences RANKL-induced osteoclast formation in murine macrophages. METHODS: Osteoclastogenesis was determined by TRAP staining and activity assay. Inhibition of signaling pathways and marker protein expression were evaluated by western blot analysis. The NF-kappaB (p65) nuclear localization was detected by immunofluorescence assay, and NF-kappaB/DNA-binding activity was detected by electrophoretic mobility shift assay (EMSA). RESULTS: In our study, icariin inhibited the differentiation of pre-osteoclast cells into osteoclasts and suppressed expression of various genes involved in osteoclast formation and bone resorption. Also, icariin blocked the osteoclastogenesis induced by MCF7 and MDA MB-231 breast cancer cells through inhibition of NF-kappaB activation. We found that icariin inhibited RANKL-stimulated TRAF-6 expression, and subsequently suppressed the phosphorylation of ERK, but icariin did not show an effect on p38, JNK, and Akt activation. CONCLUSION: These results indicate that icariin is likely to be a candidate for bone-related disease treatment and that icariin provides insights into the molecular mechanisms that influence RANKL-induced osteoclast differentiation. PMID- 30466614 TI - Anti-atherosclerosis of oligomeric proanthocyanidins from Rhodiola rosea on rat model via hypolipemic, antioxidant, anti-inflammatory activities together with regulation of endothelial function. AB - BACKGROUND: Rhodiola rosea has been used as a traditional medicine for a long history. Previous studies on oligomeric proanthocyanidins from Rhodiola rosea (OPCRR) have showed that it exhibited significant free radical-scavenging activities, antioxidant activities in aging mice and lipid lowering effects. HYPOTHESIS/PURPOSE: We hypothesized that OPCRR can improve the atherosclerosis pathological in rats. In the present study, we investigated the effects of OPCRR on the serum lipid profiles, oxidant stress status, inflammatory cytokines and atherosclerotic mediators, and endothelial dysfunction as well as changes in abdominal aorta of atherosclerosis rats. METHODS: The major components of OPCRR were analyzed by using infrared spectrum and HPLC-ESI-MS. The atherosclerosis rat model was induced by high fat and vitamin D3 feeding for 9 weeks and two OPCRR doses (60 and 120 mg/kg b.w.) were orally administered daily for 9 weeks. The rats were then sacrificed and the blood was collected via abdominal aorta and serum was separated by centrifugated for biochemical analysis. Part of the aorta tissues were excised immediately for histopathological examination and western blotting. RESULTS: Compared to model group, OPCRR treatments significantly decreased the serum lipid profiles including total cholesterol, total triglycerides, low-density lipoprotein cholesterol (LDL-C) and ox-LDL and increased the high-density lipoprotein cholesterol (HDL-C); significant increased serum antioxidant enzymes (SOD and GSH-Px) and decrease of MDA content as a product of lipid peroxidation; lowered serum levels of TNF-alpha, IL-1beta, IL-6, ICAM-1 and VCAM-1 and enhanced IL-10 level; increased the serum release of nitric oxide and expression of iNOS in aortic, whereas decreased the expression of eNOS. CONCLUSION: OPCRR can improve the progress of atherosclerosis by regulation of lipid metabolism, restoring of the antioxidant capacities, and attenuation of pro inflammatory cytokines and chemcytokines release, and improving the endothelial dysfunction indicated by nitric oxide system. PMID- 30466616 TI - Efficacy of linalool to ameliorate uremia induced vascular calcification in wistar rats. AB - BACKGROUND: Uremia is the condition generally associated with the last stage of chronic kidney disease (CKD) due to highly reduced glomerular filtration rate. Mortality of the patients diagnosed with Uremia generally occurs due to cardiovascular involvement. This occurs due to the transdifferentiation of vascular smooth muscle cells (VSMCs) into osteogenic cells in hyperphosphatemic condition that is associated with kidney failure promoting extra-osseous calcification. PURPOSE: Linalool is an essential oil that has been recently studied for its procardiovascular effects, thus the aim of the study involved to identify its potential role on vascular calcification (VC). METHODS: Uremia was induced in male wistar rats, weighing 250-350 gm by giving adenine diet for 4 weeks followed by phosphate diet for next 4 weeks. Linalool was given orally at two different doses (100 mg/kg bodyweight and 150 mg/kg bodyweight) daily for 4 weeks with phosphate diet. RESULTS: Linalool being a moderate antioxidant probably scavenged superoxide radicals (in vitro analysis). Deposition of calcium was observed by alizarin and von-kossa stains in aorta of uremic rats whereas linalool co-administration prevents calcium deposition in aorta of uremic rats. Elevated mRNA expression of calcification markers, increased lipid peroxidation levels and increased levels of catalase and superoxide dismutase (SOD) was found in aorta of uremic animals. However, with supplementation of linalool reduction in the mRNA expression of calcification markers, lipid peroxidation and antioxidant enzymes were observed. CONCLUSION: Therefore it can be concluded that linalool could be a promising therapeutic candidate for exploring its clinical application in VC. PMID- 30466617 TI - Protective effect of rutin isolated from Spermococe hispida against cobalt chloride-induced hypoxic injury in H9c2 cells by inhibiting oxidative stress and inducing apoptosis. AB - BACKGROUND: Cardiovascular disease and its related deaths are increasing in the modern world. Therefore, there is a need to identify a plant based nutraceutical supplement with potent activity. HYPOTHESIS/PURPOSE: Reportedly, the protective effect of the rutin in hypoxia-induced cardiomyocytes is due to the activation of molecular networks related to programmed cell death. STUDY DESIGN-METHODS: Phytochemical methods and advanced analytical methods were employed to isolate natural products from Spermococe hispida their effects in cardiomyocyets. RESULTS: We reports herein that CoCl2-induced hypoxic condition significantly decreased cell viability as evidenced by MTT assay and cell cycle analysis. Western blot studies revealed an up-regulation of HIF-1alpha, BAX and caspase and down-regulation of BCl-2 expression, followed by modulation of Akt, p-Akt, p38 and p-p38. The oxidative abnormalities were ameliorated by rutin pretreatment, as deduced by the reduced CoCl2-induced cytotoxicity, MDA concentration and LDH activity and the enhanced levels of GSH and SOD in a dose-dependent manner. Rutin protects H9c2 cells from CoCl2-induced hypoxic damage by mitigating oxidative stress and preserving cell viability by modulating the antiapoptotic proteins. CONCLUSION: The overall findings reinforce the cardioprotective action of rutin, a potential source of antioxidant of natural origin, which may help in mitigating the progress of oxidative stress in hypoxic conditions such as myocardial infarction and stroke. PMID- 30466618 TI - Intestinal, urinary and uterine antispasmodic effects of isoespintanol, metabolite from Oxandra xylopioides leaves. AB - BACKGROUND: Isoespintanol is a monoterpene isolated from the leaves of Oxandra xylopioides Diels. (Annonaceae) with antioxidant and antiinflammatory effects. It was of interest to know whether it has antispasmodic effects such as other known drugs, phloroglucinol and trimethoxybenzene, used in therapeutics for treating biliary, urinary and uterine spasms. PURPOSE: To assess whether isoespintanol possesses antispasmodic effects on intestine, uterus and bladder. STUDY DESIGN: A preclinical study was performed in which isoespintanol, phloroglucinol and trimethoxybenzene were evaluated with concentration-contractile response curves (CRC) of carbachol in isolated rat intestine and bladder, and with CRC of serotonin (5-HT) in rat uterus. Moreover, it was assessed whether isoespintanol interferes with Ca2+ influx by making CRC of Ca2+ in high-K+ medium in intestine and bladder. RESULTS: Isoespintanol non-competitively inhibited the CRC of carbachol with affinity constant (pK) of 4.78 +/- 0.09 in intestine and 4.60 +/- 0.09 in bladder. Phloroglucinol and trimethoxybenzene were also non-competitive antagonists, but isoespintanol was 8 times more potent than trimethoxybenzene and similarly potent than phloroglucinol in intestine. In bladder, isoespintanol resulted 8 times more potent than trimethoxybenzene. The maximal inhibition of contraction followed the order of isoespintanol > trimethoxybenzene > phloroglucinol in intestine, and isoespintanol > trimethoxybenzene in bladder. Moreover, isoespintanol also completely and non-competitively inhibited the CRC of Ca2+, with a pK of 5.1 +/- 0.1 in intestine, and 4.32 +/- 0.07 in bladder. In uterus isoespintanol reduced, completely and non-competitively, the contraction produced by 5-HT with pK of 5.05 +/- 0.07. CONCLUSION: Results demonstrate that isoespintanol is a very good intestinal, urinary and uterine antispasmodic, with higher potency than the other drugs used in therapeutics. The mechanism of action of isoespintanol is the interference with Ca2+ influx, at a difference of trimethoxybenzene and phloroglucinol. PMID- 30466619 TI - Magnolol ameliorates pneumonectomy and monocrotaline-induced pulmonary arterial hypertension in rats through inhibition of angiotensin II and endothelin-1 expression. AB - BACKGROUND: Magnolol, a major bioactive component extracted from Magnolia officinalis, exerts several beneficial effects, such as anti-inflammatory and anti-hypertensive activities. PURPOSE: In this study, we investigated whether magnolol has a protective effect on pneumonectomy and monocrotaline-induced pulmonary arterial hypertension (PAH) in rats. DESIGN/METHODS: The alterations of right ventricular (RV) hypertrophy, pulmonary vascular remodeling, histopathological parameters, and related gene expression and signaling pathways in lungs by magnolol treatment were studied in the PAH rats. RESULTS: Administration of magnolol greatly ameliorated the characteristic features of PAH, including increased pulmonary arterial pressure, RV hypertrophy, and pulmonary vascular remodeling. Moreover, magnolol inhibited angiotensin converting enzyme (ACE)/angiotensin II (Ang II)/Ang II type 1 receptor (AT-1R) cascade, whereas upregulates ACE2 in the lungs of PAH rats. The overexpression of endothelin-1 (ET-1) and ETA receptor occurred in the PAH rats was significantly attenuated by magnolol through inhibition of Akt/ERK1/2/GSK3beta/beta-catenin pathway. Compared with that of untreated PAH rats, higher expression of endothelial nitric oxide synthase, and lower expression of inducible nitric oxide synthase and O2- production in lungs were observed in magnolol-treated PAH rats. CONCLUSION: We demonstrated that treatment with magnolol reduces the development of PAH induced by pneumonectomy and monocrotaline in rats, and suppressing Ang II and ET-1-mediated processes may contribute to its protective effects. These findings suggest that magnolol may be a potential agent for PAH therapy. PMID- 30466620 TI - Matrine induces apoptosis in multiple colorectal cancer cell lines in vitro and inhibits tumour growth with minimum side effects in vivo via Bcl-2 and caspase-3. AB - BACKGROUND: The World Health Organization (WHO) reported that colorectal cancer (CRC) was the third most common cancer in men and the second in women, worldwide. Our previous meta-analysis found Sophora flavescens increased tumour response rate in randomised controlled trials of CRC. We hypothesised that its principal constituent matrine had exerted anti-tumour effects. PURPOSE: To elucidate its mechanisms of action we investigated the dose-related anti-tumour effects of matrine on four human CRC cell-lines: LS174T, Caco-2, SW1116 and RKO. In a LS174T xenografted tumour model in nude mice we assessed the effects of matrine and oxaliplatin on tumour volume, weight and morphology. Computer simulated dockings for target proteins were also conducted. METHODS AND DESIGN: Cell viability, cell cycle and apoptosis were measured by Cell Counting Kit-8 and flow cytometry, and Annexin V-FITC/PI double staining assay respectively. Western blot was performed to examine the expression of Bax, Bcl-2 and caspase-3 in the cells. The xenograft model and immunohistochemistry were used to investigate the effect of matrine in vivo. Oxaliplatin was set as positive control. Molecular docking was performed to predict the binding modes of matrine and oxaliplatin with target proteins using CDOCKER algorithm. RESULTS: Matrine inhibited proliferation of cancer cells in a dose- and time-dependent manner. Matrine induced cell-cycle arrest at G1/G0 phase, induced apoptosis and reduced expression of Bcl-2 and caspase-3 while up regulating Bax and cleaved caspase-3 in the four CRC cells. In vivo, matrine significantly inhibited tumour growth without side effects on physical health compared to the negative (vehicle) control group. Mice in the oxaliplatin group lost vigour, became frail and lost weight. Expression of Bcl-2 in tumour tissue was lower and Bax expression was higher in the matrine-treated groups compared to the negative control. In computer-simulated docking, matrine successfully docked into active sites of Bcl-2 and caspase-3. CONCLUSION: Matrine inhibited growth of colorectal cancer cells in vitro and in vivo. A molecular mechanism was apoptosis induction via effects on Bcl-2, Bax and caspase-3. Moreover, matrine showed minimum side effects and may provide a candidate for the development of new therapies for colorectal cancer. PMID- 30466621 TI - Andalucin from Artemisia lannta suppresses the neuroinflammation via the promotion of Nrf2-mediated HO-1 levels by blocking the p65-p300 interaction in LPS-activated BV2 microglia. AB - BACKGROUND: Neuroinflammation plays an important role in many neurodegenerative conditions such as Alzheimer's disease (AD) and Parkinson disease (PD). Andalucin (ADL), a sesquiterpene lactone from Artemisia lannta, has been reported to exhibit NO inhibition in vitro. However, the effect of ADL on microglia-mediated neuroinflammation has not been investigated. PURPOSE: This study was designed to determine the anti-neuroinflammatory effect of ADL against LPS-activated BV2 microglial cells and to explore the underlying mechanisms. METHODS: The production of pro-inflammatory mediators and cytokines were measured by ELISA. The relevant mechanisms were analyzed by qRT-PCR, Luciferase assay, Western blot and Co-immunoprecipitation Assay. RESULTS: ADL inhibited the LPS-induced release of NO, PGE2, TNF-alpha, IL-6 and IL-1beta. In addition, ADL reduced the mRNA and protein levels of iNOS and COX-2. Mechanism studies found that ADL activated Nrf2/HO-1 signaling pathway and suppressed NF-kappaB signaling pathway. Further investigation showed that the stimulative effect of ADL on Nrf2 transcriptional activity and the inhibitory effect of ADL on RelA transcriptional activity were due to its regulation on p300-Nrf2/p65 interaction. CONCLUSION: ADL displayed anti-neuroinflammatory activity in LPS-activated BV2 cells. The mechanism concerns its regulatory effect on the crosstalk between Nrf2 and p65. PMID- 30466622 TI - Effect of Artemisia annua and Artemisia afra tea infusions on schistosomiasis in a large clinical trial. AB - BACKGROUND AND OBJECTIVE: Schistosomiasis (bilharzia), a serious neglected tropical disease affecting millions, has few cost-effective treatments, so two Artemisia wormwood species, A. annua and A. afra, were compared with the current standard praziquantel (PZQ) treatment in an 800 patient clinical trial, August November of 2015. METHODS: The double blind, randomized, superiority clinical trial had three treatment arms: 400 for PZQ, 200 for A. annua, and 200 for A. afra. PZQ-treated patients followed manufacturer posology. Artemisia-treated patients received 1 l/d of dry leaf/twig tea infusions divided into 3 aliquots daily, for 7 days with 28-day follow-up. RESULTS: Of 800 enrolled patients having an average of >700 Schistosoma mansoni eggs per fecal sample, 780 completed the trial. Within 14 days of treatment, all Artemisia-treated patients had no detectable eggs in fecal smears, a result sustained 28 days post treatment. Eggs in fecal smears of PZQ-treated patients were undetectable after D21. More males than females who entered the trial had melena, but both genders responded equally well to treatment; by D28 melena disappeared in all patients. In all arms, eosinophil levels declined by about 27% from D0 to D28. From D0 to D28 hemoglobin increases were greater in PZQ and A. afra-treated patients than in A. annua treated patients. Hematocrit increases were greater from D0 to D28 for patients treated with either PZQ or A. annua compared to those treated with A. afra. Gender comparison showed that A. afra-treated males had significantly greater hemoglobin and hematocrit increases by D28 than either PZQ or A. annua-treated males. In contrast, PZQ and A. afra-treated females had greater hemoglobin and hematocrit increases than A. annua-treated females. Both adults and pediatric patients treated with A. annua responded better compared to PZQ treatment. CONCLUSION: Both A. annua and A. afra provided faster effective treatment of schistosomiasis and should be considered for implementation on a global scale. PMID- 30466623 TI - Allicin improves the function of cardiac microvascular endothelial cells by increasing PECAM-1 in rats with cardiac hypertrophy. AB - OBJECTIVE: Cardiac microvascular damage is significantly associated with the development of cardiac hypertrophy (CH). Researchers found that allicin could inhibit CH, but the relationship between cardiac microvessel and the inhibition of allicin on CH has not been reported. We aimed to investigate the effect of allicin on the function of cardiac microvascular endothelial cells (CMECs) in CH rat. MATERIALS AND METHODS: The hemodynamic parameters were measured by BL-420F biological function experimental system and the indicators of the ventricular structure and function were measured by echocardiographic system. MTT assay was performed to assess the cell viability. Nitrite detection was performed to detect nitric oxide content. The morphology and molecular characteristics were detected by electron micrographs, immunofluorescence, quantitative real-time polymerase chain reaction (qRT-PCR), western blot. Wound healing experiment, analysis of tube formation and shear adaptation were performed to assess CMECs migration ability, angiogenesis and shear-responsiveness respectively. RESULT: Our findings have identified that microvascular density was decreased by observing the expression of platelet endothelial cell adhesion molecule-1 (PECAM-1) in CH rats. Interestingly, allicin improved the distribution and expression of PECAM-1. Meanwhile, allicin enhanced the migration and angiogenesis ability of CMECs, activated PECAM-1-PI3K-AKT-eNOS signaling pathway, however, the role of allicin was disappear after PECAM-1 was silenced. Allicin decreased the expression of caspase-3 and receptor interacting protein 3 (RIP3), inhibited necroptosis, and increased the levels of Angiopoietin-2 (Ang-2) and platelet-derived growth factor receptor-beta (PDGFR-beta). Under 10 dyn/cm2 condition, allicin advanced the modification ability of CMECs's shear-adaptation by activating PECAM-1. CONCLUSION: Allicin provided cardioprotection for CH rats by improving the function of CMECs through increasing the expression of PECAM-1. PMID- 30466624 TI - Salvianolate reduces atrial fibrillation through suppressing atrial interstitial fibrosis by inhibiting TGF-beta1/Smad2/3 and TXNIP/NLRP3 inflammasome signaling pathways in post-MI rats. AB - BACKGROUND: Salvianolate is the main water-soluble bioactive compound of Salvia Miltiorrhiza Bunge and is now clinically used in the treatment of cardiovascular diseases in China. However, its applications in the prevention of atrial interstitial fibrosis (AIF) and atrial fibrillation (AF) are not fully revealed. PURPOSES: To investigate the preventive effect of salvianolate on the pathogenesis of AF in post-myocardial infarction (MI) rats and to elucidate the potential mechanisms. MATERIALS AND METHODS: Rats underwent left anterior descending coronary artery ligation were randomized into four groups and administered intraperitoneally with vehicle (MI group, n = 13), or 10, 20 and 40 mg/kg salvianolate (Sal-L, Sal-M and Sal-H group, n = 13, 14 and 13 respectively) for totally five weeks. Rats underwent sham operation was used as control group (Sham, n = 10). Then, echocardiography and AF inducibility test were detected. Tissues and serum were collected for Sirius red and fast green counter stain or hematoxylin-eosin to assess atrial interstitial fibrosis and hypertrophy, or for western blot and ELISA analysis. RESULTS: Salvianolate injection significantly improved cardiac function, reduced left atrial enlargement and P-wave duration, and decreased not only the vulnerability to AF but also AF duration. Histologic analysis showed that salvianolate mitigated AIF and atrial hypertrophy. Western blot analysis found that salvianolate inhibited the TGFbeta1/Smad2/3 mediated collagen deposition and inhibited the TXNIP/NLRP3 inflammasome /IL-1beta and IL 18 signal pathway. ELISA analysis showed that salvianolate significantly reduced the serum concentrations of BNP, IL-6, CRP and TGFbeta1. CONCLUSIONS: Salvianolate may constitute a novel upstream therapy for AF by suppressing AIF. The underlying mechanism may be attributable to its inhibitory effects on TGF beta1/Smad2/3 and TXNIP/NLRP3 inflammasome signaling pathway. PMID- 30466625 TI - Intranasal curcumin regulates chronic asthma in mice by modulating NF-KB activation and MAPK signaling. AB - BACKGROUND: Curcumin, a natural product found in the plant Curcuma longa, has been reported to have diverse range of molecular targets that influence numerous biochemical and molecular cascades including anti-inflammatory and antioxidant properties. PURPOSE: The aim of the study was to investigate the therapeutic potential of intranasal curcumin on ovalbumin (OVA)-induced chronic asthma and to elucidate underlying molecular mechanisms. STUDY DESIGN/METHOD: Mice were sensitized and exposed to 2% OVA aerosol for 2 times in a week for five consecutive weeks to study effect of intranasal curcumin on various MAPK pathway enzymes involved in chronic asthma and its effect on the activation of nuclear factor kB (NF-kB). RESULTS: Curcumin treatment decreased the ROS level in BALF and nitrite level in blood serum of chronic asthmatic mice. Curcumin treatment had significantly decreased the phosphorylation of JNK, ERK1/2, and p38 and COX-2 expression thereby nuclear factor kappaB (NF-kappaB) activation and expression in lung tissues. CONCLUSION: These results suggest that intranasal curcumin protects against asthma via action on mitogen-activated protein kinase (MAPK)/NF-kappaB signaling pathways. PMID- 30466626 TI - Ganoderma immunomodulatory protein and chidamide down-regulate integrin-related signaling pathway result in migration inhibition and apoptosis induction. AB - BACKGROUND: In terms of melanoma, recent advances have been made in target therapies and immune checkpoint inhibitors, but durable remission is rare. Ganoderma immunomodulatory proteins (GMI) induce a cytotoxic effect in cancer cells via autophagy. However, the role of GMI in melanoma is not clear. PURPOSE: The aims of this study are to investigate the inhibiting effects of GMI combined with chidamide on survival and metastases of melanoma cells via integrin-related signaling pathway and to propose strategies for combining GMI and chidamide using animal model. METHODS: Cell viability was measured by cell CCK-8. The activities of apoptosis- and migration-related proteins were detected on Western blot. Flow cytometry was used to analyze cell cycle distribution and sub-G1 fraction in treated melanoma cells. To evaluate the activity of combination GMI and chidamide treatment, an in vivo anti-tumor metastasis study was performed. RESULTS: GMI combined with chidamide additively induced apoptosis. GMI inhibited the expressions of Integrin alpha5, alphaV, beta1, and beta3. The level of p-FAK was inhibited by GMI. Combination treatment of GMI and chidamide decreased survivin and increased cleaved caspase-7 and LC3 II/I. Integrin-alphaV overexpression activated p-FAK pathways in A375.S2 cells. GMI significantly inhibited cell growth and migration of A375.S2 cells on wound healing assay. In vivo, GMI combined with chidamide suppressed distal tumor metastasis. CONCLUSION: GMI inhibits the migration and growth of melanoma cells via integrin-related signaling pathway. GMI and chidamide induces apoptosis. In vivo, GMI and chidamide additively reduce distant metastases. GMI and chidamide are potential immunotherapeutic adjuvant for metastatic melanoma. PMID- 30466627 TI - HMQ-T-F5 (1-(4-(2-aminoquinazolin-7-yl)phenyl)-3-(2-bromo-5- (trifluoromethoxy)phenyl) thiourea) suppress proliferation and migration of human cervical HeLa cells via inhibiting Wnt/beta-catenin signaling pathway. AB - BACKGROUND: Drug therapy plays an important role in the treatment of cervical cancer, which is one of the most common solid tumors in women. Therefore, it is important to seek more effective and less toxic therapies. PURPOSE: The aim of this study is to investigate the therapeutic potential of HMQ-T-F5 (1-(4-(2 aminoquinazolin-7-yl)phenyl)-3-(2-bromo-5-(trifluoromethoxy) phenyl)thiourea) (F5) for cervical cancer and explore the related mechanism. METHODS: By performing MTT assay, colony formation assay, flow cytometry, wound-healing assay, transwell assay, immunofluorescent staining and siRNA assay, we study the effect of F5 on human cervical HeLa cells. The mechanism of F5 was also investigated. RESULTS: We found that F5 significantly inhibited HeLa cell proliferation, led to accumulation of cells in the S phase, and induced apoptosis and inhibited migration. Mechanistically, F5 inhibited HeLa cell growth and migration through repressing the expression and nuclear translocation of beta catenin, enhancing Axin expression, inhibiting the phosphorylation of LRP5/6 and GSK3beta, as well as downregulating the Wnt downstream targeted proteins. Knockdown of a checkpoint beta-catenin by siRNA significantly attenuated HeLa cell proliferation. Furthermore, XAV939, an inhibitor of beta-catenin, was used to treat HeLa cells and the results demonstrated that F5 inhibited proliferation and migration via the inhibition of the Wnt/beta-catenin pathway. CONCLUSION: Our findings demonstrated that F5 can target beta-catenin potentially and is useful in the treatment of cervical cancer. PMID- 30466628 TI - Potentiation of the anticancer effect of doxorubicinin drug-resistant gastric cancer cells by tanshinone IIA. AB - BACKGROUND: Gastric cancer is the fifth commonest cancer and the third cause of cancer-related deaths all over the world. The effectiveness of chemotherapy is still limited by drug resistance in gastric cancer. Tanshinones, abietane diterpenes isolated from the traditional Chinese medicine Danshen (Salvia miltiorrhiza), have exhibited versatile anticancer activities in particular the ability to overcome drug resistance in different cancers. PURPOSE: The current study aimed to explore the capacity of tanshinone IIA, the most abundant tanshinone found in the plant Danshen, to overcome drug resistance of gastric cancer cells to a commonly used anticancer drug doxorubicin. STUDY DESIGN: Sensitivity of cell lines to doxorubicin was determined by MTT assay. Doxorubicin resistant gastric cancer cell lines was established by step selection with increasing concentrations of doxorubicin. Cell cycle arrest, apoptosis and doxorubicin efflux were analyzed by flow cytometry. The expression of MRP1 was determined by realtime PCR and western-blot. RESULTS: Based on the IC50 values of doxorubicin, we identified the doxorubicin-sensitive gastric cancer cell lines SNU-719 and SNU-610 as well as the cell lines relatively resistant to doxorubicin including SNU-638, SNU-668, SNU-216 and SNU-620. We also established two drug resistant cell lines SNU-719R and SNU-610R. Despite the fact that tanshinone IIA alone showed no cytotoxicity on these gastric cells, we found the potentiation of the anticancer effect of doxorubicin in drug-resistant gastric cancer cells by tanshinone IIA. Furthermore, using doxorubicin-sensitive cell line SNU-719 and doxorubicin-resistant cell lines SNU-719R and SNU-620, we revealed the pivotal roles of MRP1. Its overexpression impaired cell cycle arrest and suppressed apoptosis in the development of both intrinsic and acquired drug resistance in gastric cancer cells to doxorubicin. Importantly, inhibition of MRP1 function enhanced cell cycle arrest, increased apoptosis and induced autophagic cell death which contributed to the capability of tanshinone IIA to potentiate the anticancer effect of doxorubicin in drug-resistant gastric cancer cells. CONCLUSION: Tanshinone IIA is an interesting agent with potential to treat drug resistant gastric cancer in combination therapy. PMID- 30466629 TI - High-throughput metabolomics investigates anti-osteoporosis activity of oleanolic acid via regulating metabolic networks using ultra-performance liquid chromatography coupled with mass spectrometry. AB - BACKGROUND: Osteoporosis has brought about heavy socio-economic burden in the morbidity and medical expenses associated with osteoporosis treatment and various restrictions on behavior of their social roles. Oleanolic acid (OA) is an anti osteoporosis natural product, but molecular mechanisms of therapeutic effect are not still well known. PURPOSE: In this study, we explore anti-osteoporosis activity of oleanolic acid and predict the underlying mechanisms by metabolomics strategy. METHODS: SD rats were intraperitoneal injection with prednison for once to establish osteoporosis model. Using metabolomics strategy based on ultra performance liquid chromatography coupled with quadrupole time-of-flight/ mass spectrometry (UPLC-TOF/MS), serum samples of 24 rats were analyzed to seek differential metabolites and pathway associated with OA treatment of osteoporosis. In addition, the effect of OA on osteoporosis rats was also evaluated by clinical biochemistry indicators and bone density analysis. RESULTS: Clinical biochemistry indicators and bone density of lumbar and femur were reversed by OA treatment. A total of 25 potential biomarkers were identified in the rats model of glucocorticoid-induced osteoporosis, and oleanolic acid have a regulatory effect on 17 of them that related to some vital metabolic pathway such as linoleic acid metabolism, valine, leucine and isoleucine biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis as well as cysteine and methionine metabolism. The ingenuity pathway analysis (IPA) platform is applied to further understanding the relationship between metabolic changes and therapeutic effect of OA, which the disordered state carbohydrate metabolism, molecular transport and lipid metabolism in glucocorticoid-induced osteoporosis rats are mainly ameliorated by oleanolic acid. CONCLUSION: Metabolomics provides a novel method to investigate the anti-osteoporosis effects of OA and probe into the potential mechanisms, and will contributes to the development of new drugs. PMID- 30466630 TI - Redox regulation and NO/cGMP plus K+ channel activation contributes to cardiorenal protection induced by Cuphea carthagenensis (Jacq.) J.F. Macbr. in ovariectomized hypertensive rats. AB - BACKGROUND: One of the medicinal plants widely used by the population in the treatment of hypertension, atherosclerosis and circulatory disorders is Cuphea carthagenensis (Jacq.) J.F. Macbr. (Lythraceae), popularly known as 'sete sangrias', being found in Brazil, Hawaii and in South Pacific Islands. Despite the widespread use of this species by the population, its long-term antihypertensive and cardioprotective activities have not yet been scientifically evaluated. PURPOSE: To evaluate the possible cardioprotective effects of an ethanol-soluble fraction obtained from C. carthagenensis (ESCC) using ovariectomized hypertensive rats to simulate a broad part of the female population over 50 years of age affected by hypertension. In addition, the molecular mechanism that may be responsible for its cardiorenal protective effects was also explored. METHODS: Female Wistar rats were submitted to surgical procedures of bilateral ovariectomy and induction of renovascular hypertension (two-kidneys, one-clip model). The sham-operated group was used as negative control. ESCC was obtained and a detailed phytochemical investigation about its main secondary metabolites was performed. ESCC was orally administered at doses of 30, 100 and 300 mg/kg, daily, for 28 days, 5 weeks after surgery. Enalapril (15 mg/kg) was used as standard antihypertensive drug. Renal function was evaluated on days 1, 7, 14, 21 and 28. At the end of the experimental period, systolic, diastolic, mean arterial pressure and heart rate were recorded. The activity of the tissue enzymatic antioxidant system, thiobarbituric acid reactive substances, nitrotyrosine, nitrite, aldosterone and vasopressin levels, in addition to the activity of the angiotensin-converting enzyme were also evaluated. Additionally, vascular reactivity to acetylcholine, sodium nitroprusside, and phenylephrine, and the role of nitric oxide, prostaglandins, and K+ channels in the vasodilator response of ESCC on the mesenteric vascular bed were also investigated. RESULTS: ESCC-treatment induced an important cardiorenal protective response, preserving renal function and preventing elevation of blood pressure and heart rate in ovariectomized hypertensive rats. In addition, prolonged treatment with ESCC recovered mesenteric vascular reactivity at all doses used. This effect was associated with an important modulation of the antioxidant defense system with a possible increase in NO bioavailability. Additionally, NO/cGMP activation and K+ channel opening dependent vasodilator effect was observed on the mesenteric vascular bed, indicating a potential mechanism for the cardiovascular effects of ESCC. CONCLUSION: A 28-days ESCC treatment reduces the progression of the cardiorenal disease in ovariectomized hypertensive rats. These effects seem to be involved with an attenuation of oxidative and nitrosative stress, affecting endothelial nitric oxide production and K+ channel opening in smooth muscle cells. PMID- 30466631 TI - Ameliorative effects of protodioscin on experimental diabetic nephropathy. AB - BACKGROUND: Diabetic nephropathy is one of the most common and serious complications of diabetes mellitus. HYPOTHESIS/PURPOSE: The present study aimed to investigate the effects of protodioscin on renal damage in high-fat diet-fed and streptozotocin-induced diabetic rats. METHODS: After 4 weeks of feeding a high-fat diet, male Sprague-Dawley rats were injected 35 mg/kg streptozotocin intraperitoneally. The diabetic rats were divided into 4 groups, and treated orally with carboxymethylcellulose sodium, metformin, or protodioscin (20 or 40 mg/kg). After 12 weeks of treatment, blood, urine, and renal tissue were collected for biochemical and histological examination. RESULTS: Protodioscin significantly reduced the levels of blood glucose, serum creatinine, and blood urea nitrogen, and also the excretion of urinary protein and albumin in diabetic rats. Histological examinations showed that protodioscin ameliorated the diabetes induced glomerular and tubular pathological changes. Furthermore, protodioscin significantly reduced the renal concentrations of total cholesterol, triglycerides, free fatty acids, phospholipids, and TNF-alpha. CONCLUSION: These results indicate that protodioscin has ameliorative effects on diabetic nephropathy. PMID- 30466632 TI - Mechanistic insights to the cardioprotective effect of blueberry nutraceutical extract in isoprenaline-induced cardiac hypertrophy. AB - BACKGROUND: Lowbush blueberry extract (Vaccinium angustifolium) is abundant with polyphenols (such as chlorogenic acid) with high antioxidant profile. It has received great interest due to its protective role in many disorders such as heart diseases and neurological disorders. HYPOTHESIS: We hypothesized that blueberry leaf extract might have a protective effect against cardiac hypertrophy via suppressing oxidative stress, inflammation and fibrosis. METHOD: Blueberry leaf nutraceutical extract was administered orally to male albino rats at three different doses (25, 50 and 100 mg/kg/day of the extract, equivalent to 3.4, 6.8 and 13.6 mg of chlorogenic acid, respectively) once daily for 28 consecutive days against a dose of isoprenaline (ISO) (5 mg/kg) for 14 days. RESULTS: The results indicated that isoprenaline induced significant myocardial damage, characterized by conduction abnormalities, increased heart-to-body weight ratio, increased serum CKMB, AST, c-TnI and LDH. Pretreatment with blueberry extract at a dose of 50 mg/kg/day (equivalent to 6.8 mg chlorogenic acid) protected against ISO induced ECG changes, leakage of cardiac enzymes and histopathological changes. Also, ISO caused significant glutathione depletion, lipid peroxidation and reduction in activities of antioxidant catalase enzyme. These effects were prevented by pretreatment with blueberry extract. Additionally, ISO elicited inflammatory effects by increasing the expression of NF-kappaB, COX-2, TNF-alpha and IL-6 while pretreatment with blueberry extract significantly inhibited these inflammatory responses. Furthermore, ISO induced fibrosis by increasing the level of TGF-beta while pretreatment with blueberry extract significantly reduced it. CONCLUSION: These findings indicate that blueberry leaf extract possessed a potent protective effect against ISO-induced cardiac hypertrophy via suppressing oxidative stress, inflammation and fibrosis. PMID- 30466633 TI - Boswellia serrata oleo-gum-resin and beta-boswellic acid inhibits HSV-1 infection in vitro through modulation of NF-kB and p38 MAP kinase signaling. AB - BACKGROUND: Herpes Simplex Virus (HSV), a highly contagious pathogen, is responsible for causing lifelong oral to genital infection in human. Boswellia serrata oleo-gum-resin possesses a strong traditional background of treating diverse skin ailments including infection but its effect on HSV-1 has not been examined yet. PURPOSE: To exploit its potential, we aimed to explore the antiviral activity of methanol extract of B. serrata oleo-gum-resin (BSE) and one of its major constituent beta-boswellic acid (BA) against HSV-1 along with the underlying mechanism of action involved. METHODS: BSE was subjected to RP-HPLC analysis to quantify the active constituent. Cytotoxicity (CC50) and antiviral activity were evaluated by MTT and plaque reduction assay, followed by the determination of median effective concentration (EC50). The mode of antiviral activity was assessed by time-of-addition assay and confirmed by reverse transcriptase-PCR (RT-PCR). Further, the expressions of various cytokines were measured by RT-PCR, while the proteins by Western blot. RESULTS: BSE and BA potently inhibited wild-type and a clinical isolate of HSV-1 (EC50 5.2-6.2 and 12.1-14.63 MUg/ml), with nearly-complete inhibition (EC99) at 10 and 30 MUg/ml, respectively. The inhibitory effect was significant at 1 h post-infection and effective up to 4 h. Based on target analysis we examined the inhibition of NF kappaB, essential for virus replication, and observed significant down-regulation of NF-kappaB, and p38 MAP-kinase activation, with reduced expression of tumor necrosis factor (TNF)-alpha, Interleukin (IL)-1beta and IL-6, involved in scheming NF-kappaB signaling. CONCLUSION: Thus, our results support the ethnomedicinal use of BSE in skin infection by inhibiting HSV-1 through the modulation of NF-kappaB and p38 MAPK pathway. PMID- 30466634 TI - Inflammation of the Temporal Bone. AB - Temporal bone and ear structure inflammation is commonly due to infection. It can be associated with a variety of complications and postinflammatory sequelae. Where the ear is easily inspected, clinical evaluation suffices. At the deeper aspect of the temporal bone, clinical evaluation is limited. High-resolution computed tomography scanning is suited for temporal bone imaging and is the modality of choice. MR imaging is useful to characterize disease, define the extent and spread of disease, or as a surveillance tool. MR imaging can be used with high-resolution computed tomography scanning to give a comprehensive evaluation of a complex disease process. PMID- 30466635 TI - Imaging of Pediatric Hearing Loss. AB - Temporal bone high-resolution computed tomography (HRCT) and magnetic resonance (MR) imaging are valuable tools in the evaluation of pediatric hearing loss. Computed tomography is important in the evaluation of pediatric conductive hearing loss and is the imaging modality of choice for evaluation of osseous abnormalities. MR imaging is the modality of choice for evaluation of sensorineural hearing loss. A broad spectrum of imaging findings can be seen with hearing loss in children. HRCT and MR imaging provide complementary information and are often used in conjunction in the preoperative evaluation of pediatric candidates for cochlear implantation. PMID- 30466636 TI - Imaging Findings in Syndromes with Temporal Bone Abnormalities. AB - There is a wide variety of congenital syndromes that can involve the temporal bone. Many of these have overlapping features due to common embryologic abnormalities, such as first and second branchial anomalies. Diagnostic imaging is often important in the workup of hearing deficits related to congenital syndromes. This article reviews the imaging features of selected congenital syndromes with temporal bone abnormalities, including Treacher Collins syndrome, oculo-auriculo-vertebral dysplasia spectrum, Klippel-Feil syndrome, branchio-oto renal syndrome, Pierre Robin sequence, CHARGE syndrome, Pendred syndrome, Down syndrome, Trisomy 18, Turner syndrome, and neurofibromatosis type 2. PMID- 30466637 TI - Imaging of Temporal Bone Trauma: A Clinicoradiologic Perspective. AB - Imaging plays an important role in the evaluation of temporal bone trauma. Certain imaging findings can significantly change patient management or change surgical approach. Precise knowledge of clinical or surgical management can guide the review of imaging to detect these key findings. This article reviews the clinical and imaging findings as well as management of complications from temporal bone trauma, including hearing loss, vertigo, perilymphatic fistula, cerebrospinal fluid leak, facial nerve injury and vascular injury. PMID- 30466638 TI - Temporal Bone Tumors: An Imaging Update. AB - In their variety, temporal bone tumors mirror the complexity of the structure from which they arise. They include more familiar lesions, such as vestibular schwannomas and paragangliomas, and also rarer neoplasms, such as nonvestibular schwannomas, sarcomas, giant cell tumors, Schneiderian papillomas, and endolymphatic sac tumors. Diagnostic imaging is invaluable in evaluating such lesions because they are typically challenging to access surgically and monitor clinically. The ability to differentiate tumors from benign ('don't touch') or indolent lesions can prevent unnecessary morbidity. This article reviews a range of temporal bone neoplasms, focusing on imaging approaches and characteristic imaging findings. PMID- 30466639 TI - Management of Vestibular Schwannomas for the Radiologist. AB - Vestibular schwannomas are the most common tumor of the cerebellopontine angle. The history of their management has driven advances in imaging, lateral skull base surgery, as well as radiosurgery. With these advances, a shift has occurred from life-saving treatment for late-stage disease to quality of life focused management of smaller tumors. The complicated treatment paradigms involving observation, stereotactic radiosurgery and surgery require close communication between the treatment and neuroradiology teams. PMID- 30466640 TI - Common Otologic Surgical Procedures: Clinical Decision-Making Pearls and the Role of Imaging. AB - Neuro-otologists rely on the expertise and judgment of a skilled neuroradiologist to identify radiographic abnormalities in the complicated regional anatomy of the temporal bone and middle and posterior fossa, and more importantly, to alert the surgeon to potential operative pitfalls. This article highlights some of the common otologic surgical procedures that stress this important dynamic. The surgical perspective on quick and effective clinical decision-making pearls to keep in mind during a thorough radiographic analysis of the ear and lateral skull base is presented. PMID- 30466641 TI - Imaging of Meniere Disease. AB - Visualization of the morphologic substrate of Meniere disease, the endolymphatic hydrops, can be performed using noncontrast or contrast-enhanced MR imaging techniques. Noncontrast MR imaging uses a heavily T2-weighted sequence; however, its reproducibility remains to be confirmed. Contrast-enhanced MR imaging techniques mainly use a 3-dimensional fluid-attenuated inversion recovery sequence after intratympanic gadolinium administration or after a 4-hour delayed intravenous gadolinium administration. The latter technique is most frequently used and is able to detect and grade Meniere disease. It is a reliable technique with a high diagnostic accuracy, enabling visualization of endolymphatic hydrops. PMID- 30466642 TI - Advanced MR Imaging of the Temporal Bone. AB - Temporal bone pathologies are challenging to discern because of their small size and subtle contrast. MR imaging is one of the key modalities in evaluating otologic diseases. Current advancement in MR techniques provide multiparametric information for evaluation of these pathologies. The aim of this article is to review state-of-the-art 3-dimensional morphologic and diffusion sequences for otologic MR imaging. PMID- 30466643 TI - Otosclerosis and Dysplasias of the Temporal Bone. AB - Many bone dysplasias, some common and others rare, may involve the temporal bone causing conductive, sensorineural, or mixed hearing loss, vestibular dysfunction, or skull base foraminal narrowing, potentially affecting quality of life. Some conditions may affect only the temporal bone, whereas others may be more generalized, involving different regions of the body. High-resolution computed tomography may detect subtle osseous changes that can help define the type of dysplasia, and MR imaging can help define the degree of activity of lesions and potential associated complications. PMID- 30466644 TI - Imaging of Tinnitus. AB - Although not all patients with tinnitus require imaging, patients with tinnitus and asymmetric hearing loss, additional neurologic findings, or pulsatile tinnitus should be evaluated with an appropriately tailored imaging study. Choice of imaging study should be guided by type of hearing loss and additional physical examination findings, such as middle ear lesion, presence of carotid bruit, or pulsatile tinnitus extinguished by jugular compression. PMID- 30466645 TI - Third Window Lesions. AB - Third window abnormalities are bony defects of the inner ear that enable abnormal communication with the middle ear and/or cranial cavity. Vestibular symptoms include vertigo and nystagmus induced by loud noises or increases in pressure. Auditory symptoms involve "pseudo-conductive" hearing loss with a low-frequency air-bone gap at audiometry, resulting from decreased air and increased bone conduction. High-resolution temporal bone computed tomography is the first-line imaging modality for evaluation of third window pathology and is critical for accurate diagnosis and management. This article reviews the fundamental mechanisms of the third window phenomenon and describes imaging findings and differential diagnosis. PMID- 30466646 TI - Arterial Anomalies of the Middle Ear: A Pictorial Review with Clinical Embryologic and Imaging Correlation. AB - The differential diagnosis of a red and/or pulsatile retrotympanic mass includes aberrant internal carotid artery, persistent stapedial artery (PSA), glomus tympanicum, and dehiscent jugular bulb. By recognizing the features of aberrant internal carotid artery and PSA on high-resolution computed tomography, these entities can be assessed by the radiologist. PSA is further classified by type because each type demonstrates a unique set of imaging features in addition to features common to all types. Although rarely encountered, it is important to reliably and consistently detect these anomalies because failure to do so can lead to disastrous surgical outcomes. PMID- 30466647 TI - Update on Temporal Bone Imaging with Emphasis on Clinical and Surgical Perspectives. PMID- 30466648 TI - Hear and Now. PMID- 30466649 TI - Bovine cysticercosis and taeniosis: The effect of an alternative post-mortem detection method on prevalence and economic impact. AB - In Europe, bovine cysticercosis (BCC) is detected by routine meat inspection (MI) at the slaughterhouse. The prevalence of BCC in Belgium based on MI is estimated at 0.23%. MI has a known low sensitivity for animals with localised infections and alternative detection techniques should be considered. A mathematical scenario-analysis model was built to determine the current prevalence of BCC in Belgium based on MI results combined with results of dissection of the predilection sites (PS) and the B158/B60 Ag-ELISA on serum of 614 carcasses found negative on MI. Additionally, the impact of the introduction of the B158/B60 Ag ELISA at slaughter on the prevalence of BCC and taeniosis and on the economic impact related to Taenia saginata was estimated for Belgium. Data for estimating the economic impact were gathered from multiple sources within the meat and human health sectors and included value loss for infected carcasses, inspection costs, carcass destruction costs, cattle insurance costs and costs related to taeniosis (consultation physician, drugs and laboratory test). The model estimated the current prevalence of BCC to be 42.5% (95% CI: 32.4-60.7%) and the sensitivity of the MI for viable and degenerated cysticerci at only 0.54% (95% CI: 0.37-0.71%). A total of 213,344 viable cysticerci (95% CI: 122,962-386.249) were estimated to be present in the infected carcasses in one year and only 408 (95% CI: 356-464) of these were present in the carcasses detected at current MI. The annual number of human taeniosis cases is estimated at 11,000 by using the sale numbers of niclosamide in Belgium. Implementation of the Ag-ELISA at slaughter (Se = 36.37%; Sp = 99.36%) would greatly reduce the prevalence of BCC to 0.6% and the number of taeniosis cases to 89 in year 10. Unfortunately, the accompanying resulting increase in costs for the animal owners, slaughterhouses and the insurance company, would be extremely high in the first years. Cattle owners would suffer losses of up to ?21 million in the first year after implementation of the Ag ELISA (compared to an annual loss of ?3.5 million in the current situation), slaughterhouses of ?10 million (compared to ?200,000 currently) and the insurance company of almost ?6 million (compared to ?2.3 million profit currently). Therefore, implementation of the Ag-ELISA might not be feasible and other options for controlling T. saginata should be investigated. PMID- 30466650 TI - Associations between group sizes, serum protein levels, calf morbidity and growth in dairy-beef calves in a Finnish calf rearing unit. AB - Efficient dairy-beef production relies on good quality of purchased calves, defined by breed, health, and growth characteristics. Several management factors, such as commingling of calves and large group size, predispose calves to diseases. Acute phase proteins are sensitive detectors of calf diseases. We studied the associations between group size, serum acute phase proteins, immunoglobulin G (IgG), calf morbidity and growth of dairy-beef calves in a random field trial in a calf-rearing unit in Finland. The randomized trial was carried out at a calf rearing unit, where approximately 80 dairy or crossbred calves were allocated either into a single group of 40 calves or into four groups of 10 on arrival at the calf-rearing unit (at age 24.1 SD +/- 9.2 days). The study was carried out on 6 arrival batches: 476 calves. Calves were clinically examined and blood sampled on arrival (day 0), and haptoglobin (Hp), serum amyloid A (SAA), albumin and IgG were determined. Calves were weighed on arrival (day 0, average age 24.1 days), at the end of the milk feed period (day 49), at approximately 200 days of age and at slaughter (carcass weight) at 15-18 months of age. During the rearing calves were observed by the farm workers and treated, if necessary, according to predetermined instructions of the veterinary surgeon. All NSAID and antimicrobial treatments were recorded and used as morbidity indicators in statistical analysis. There were no differences in the numbers of antimicrobial treatments or growth among the groups. The majority (84.1%) of antimicrobial treatments were used against respiratory tract infections. Higher concentrations of albumin and IgG on arrival extended the time before the first and the second antimicrobial treatments. Complex relationships between group size, morbidity, concentrations of serum acute phase proteins and IgG at arrival, and growth of calves were explored. Group size of 10 calves did not protect calves from respiratory tract infections, when the small groups were sharing the air space with a large group. An increased SAA concentration on arrival was associated with poorer average daily gain at two rearing periods and with lower carcass weight at slaughter. Serum proteins could be valuable health indicators for purchased calves because they have numerous and variable associations with health and growth. The mechanisms that connect increased SAA concentration and poorer average daily gain over the long term remain unclear. PMID- 30466651 TI - A retrospective epidemiological analysis of shared risk factors for bovine trichomoniasis and bovine genital campylobacteriosis in La Pampa province (Argentina). AB - The venereal diseases bovine trichomoniasis (BT) and bovine genital campylobacteriosis (BGC) cause economic losses in endemic areas like La Pampa province in Argentina, where beef cattle are usually managed extensively. The eradication of both diseases is a priority in Argentine. The aim of this case control study was to identify shared and specific risk factors of both diseases from the data obtained from the Provincial Program for the Control and Eradication of BT and BGC in La Pampa (PCE). The study population included 5777 breeding beef herds tested for BT and BGC in 2013. The study comprised 3481 herds that were surveyed in situ by official PCE veterinarians, distributed as follows: 3159 negative herds (with no BT or BGC positive bulls), 121 BT case herds (with at least a BT positive bull), 170 BGC case herds (with at least a BGC positive bull) and 31 BT and BGC co-infected case herds (with at least a positive bull for each disease). Three multivariable analyses were performed in order to identify the risk factors using a logistic regression model. Results showed that the risk factors shared by both diseases were the number of bulls (OR for BT = 1.03, 95% CI: 1.02-1.04, p < 0.001; OR for BGC = 1.02, 95% CI: 1.01-1.03, p < 0.001; OR for BT and BGC co-infection = 1.02, 95% CI: 1.01-1.04, p = 0.003) and the presence in the previous year of each disease (OR for BT = 18.69, 95% CI: 11.82 29.57, p < 0.001; OR for BGC = 4.65, 95% CI: 3.18-6.81, p < 0.001; OR for BT and BGC co-infection = 39.18, 95% CI: 16.72-91.80, p < 0.001). Disease-specific risk factors were continuous breeding season for BT (OR = 1.59, 95% CI: 1.04 2.47, p = 0.034), and inadequate condition of the fences for BGC (OR = 1.51, 95% CI: 1.06-2.15, p = 0.022). An integrated approach to venereal disease management needs to consider the risk characteristics identified in this study. This could lead to reduce both diseases and improve the efficiency of BT and BGC control activities in La Pampa. PMID- 30466652 TI - Antimicrobial use practices, attitudes and responsibilities in UK farm animal veterinary surgeons. AB - Increasing levels of antimicrobial resistance in human and veterinary medicine have raised concerns around the issue of overprescribing and the indiscriminate use of antimicrobials. Their use in food producing animals is under scrutiny due to the perceived risk from the zoonotic transfer of resistant pathogens from animals to humans. This study aimed to explore UK veterinary surgeons antimicrobial prescribing behaviours, their attitudes to antimicrobial resistance and their perceptions of responsibility of antimicrobial use in pigs through a questionnaire study on a census sample of 261 veterinary surgeons in England, Wales and Scotland who had a clinical caseload which included commercial pigs. The questionnaire had a useable response rate of 34.1% (n = 61/179) in eligible veterinary surgeons. Overall, veterinary surgeons reported personal confidence that their prescribing decisions were responsible however, there was concern that the prescribing behaviours of other veterinary surgeons and physicians in human medicine may be less responsible; a sociological concept known as 'othering'. In parallel, veterinary surgeons seldom identified that treatment failure was a consequence of antimicrobial resistance in their own clinical caseload, however they considered it an issue for other veterinary surgeons and for human prescribers. Veterinary surgeons consulted a wide spectrum of resources on antimicrobial use in pigs which, on occasion, contained conflicting guidance on what was defined as responsible prescribing. The decision over whether or not to prescribe an antimicrobial was influenced by numerous factors relating to the veterinary surgeons' experience and the clinical situation presented, but maintaining pig welfare was a high priority. There was a shared desire to seek alternative methods to prevent disease to antimicrobial use, however the use of diagnostics to support prescribing decisions was an infrequently reported behaviour and could play a more significant role in prescriber decisions if more cost effective and rapid tests were available. Future interventions to optimise antimicrobial use in pigs needs to focus on the evolution of antimicrobial use practices in a changing political and scientific landscape whilst also considering individual motivations and justifications for use. PMID- 30466653 TI - Using beef-breed semen in seropositive dams for the control of bovine neosporosis. AB - A program for controlling bovine neosporosis based only on the use of beef semen, without culling seropositive animals, was evaluated in a closed dairy cattle herd over a 5-year period (2013-2017). The program was based on individual and periodic serological screenings to identify seropositive breeders. Seropositive cows were inseminated with beef-breed semen, thus excluding their descendants from the remount in order to prevent the vertical transmission of the disease. Seronegative animals, as well as heifers at first insemination, were tested before each insemination. Sera of 1097 cattle were examined by a commercial indirect ELISA for the detection of antibodies anti-Neospora caninum. To verify the difference in seropositivity values among years of sampling, statistical analysis through generalized estimation equations (GEEs) was performed, also considering the effects of age, lineages, and occurrence of abortion. A seroprevalence of 33.8% was found in the first screening. The prevalence and incidence of the infection within the herd decreased significantly in 2017 (P = 28.9%, I = 1.4%) (p-value = 0.0001). The family line investigation detected a higher risk of being seropositive for a cow born to a seropositive dam (p-value = 0.0001) than to a seronegative dam, decreasing both the apparently vertical and horizontal transmissions. The number of spontaneous abortions decreased after the first year of the study (23 in 2013 to 6 in 2017). Seropositive animals were associated with abortion events (p-value = 0.0001). Although an eradication of N. caninum was not achieved at the end of the study period, a significant reduction in prevalence and incidence of neosporosis in the herd and a reduction of the abortion rate was achieved with the application of this control plan in five years, without culling a high number of seropositive potential milk-producing animals. PMID- 30466654 TI - Prevalence of visceral leishmaniasis in A population of free-roaming dogs as determined by multiple sampling efforts: A longitudinal study analyzing the effectiveness of euthanasia. AB - Free-roaming dogs affected by visceral leishmaniasis (VL) contribute to the geographical expansion of the disease and require special attention from health authorities. The objectives of the present study were to determine the prevalences of VL in a population of free-roaming dogs in an endemic region of Brazil, to establish the spatial distribution of infected dogs, and to examine the effectiveness of euthanasia of infected dogs in controlling the disease in this particular population. Dogs were captured every two months during seven sampling efforts. Capture locations were georeferenced and captured dogs were assessed for the presence of anti-Leishmania antibodies using an enzyme-linked immunosorbent assay (ELISA) as a screening test and the indirect fluorescent antibody test (IFAT) as the confirmatory procedure. Dogs that were seropositive by both assays were considered infected and were submitted to immediate euthanasia. After the end of the collection period, stored sera were evaluated with the Dual-Path Platform test (DPP). Animals positive by this method and by ELISA were also considered infected as currently recommended by the Brazilian Ministry of Health. Spatial analysis was performed using the Kernel technique. A total of 328 dogs were captured at least once during the sampling period, 25 (7.6%) of them were seropositive by ELISA and IFAT and 27 (8.2%) by DPP and ELISA. The prevalence of VL showed an overall decreasing trend. However, even with periodical euthanasia, it was not possible to eliminate the infection and increased prevalences were observed in the fourth and seventh samplings. There was a high overall agreement between the two criteria for defining infection. None of the dogs that tested negative by IFAT at the first capture seroconverted in the subsequent captures but a number of dogs exhibited changes in serological status over time. From the three dogs initially tested negative by ELISA and IFAT, but tested positive by the protocol currently adopted in Brazil, two became negative in subsequent recaptures. Spatial analysis revealed that infected animals concentrated in areas with a high density of free-roaming dogs. The existence of VL among homeless dogs may contribute significantly in the persistence of the disease among the human population, despite the practice of periodical euthanasia. The operational and ethical implications associated with euthanasia of free-roaming dogs, and the failure to control the transmission of VL among this particular population, led us to conclude that interventions promoting responsible ownership of pets may be a more effective strategy. PMID- 30466655 TI - Seroprevalence and participatory epidemiology of camelpox in Afar region of Ethiopia. AB - Camelpox is endemic in most camel rearing regions of the world, causing significant economic losses. However, its epidemiology is not extensively investigated. We conducted a cross sectional seroprevalence study of camelpox in Amibara and Awash Fentale districts in Afar region of Ethiopia from November 2014 to May 2015. In addition, participatory epidemiology (PE) was conducted to identify seasonal occurrence of the disease in the study districts. Blood samples were collected from 384 dromedary camels from 31 herds distributed in five pastoral associations (PAs) in the two districts. Serum samples were separated from the blood samples and tested for the presence of viral antibodies using virus neutralization test. Seroprevalence data were analyzed using multilevel mixed effects logistic regression models accounting for the 4-level hierarchical data structure (camels nested in herds-herds in PA, and PA in district). For the participatory data, Kendall's coefficient of concordance was used to assess agreements between the informants in identifying seasonal occurrences of the top five camel diseases. Camelpox antibodies were detected in 19.3% of camels (n = 384), 81% of herds (n = 31), and in all five PAs from the two districts in the Gabi Rasu zone of Afar region, Ethiopia. The seroprevalence did not significantly vary between herds, PAs or districts suggesting the widespread occurrence of the disease. Estimated age stratified basic reproduction number (R0) was 1.25 (95% CI: 0.62-2.19). Camelpox was identified as one of the top five common camel diseases in the area. The widespread occurrence of the disease can be attributed mainly to the commingling of camels from many herds during seasonal migration in search of feed and water, a practice very common under pastoral production systems. Although the PE informants indicated the clinical disease to be more common in young animals, seropositivity was higher in older animals. Camelpox commonly occurs during the minor and major rainy seasons. In conclusion, camelpox is found to be endemic in Afar pastoral region with sporadic outbreaks occurring during rainy seasons. Vaccination and improved camel management practices particularly during the high-risk period can be viable strategies to reduce the burden of the disease. PMID- 30466656 TI - Breed-to-wean farm factors associated with influenza A virus infection in piglets at weaning. AB - Breed-to-wean pig farms play an important role in spreading influenza A virus (IAV) because suckling piglets maintain, diversify and transmit IAV at weaning to other farms. Understanding the nature and extent of which farm factors drive IAV infection in piglets is a prerequisite to reduce the burden of influenza in swine. We evaluated the association between IAV infection in piglets at weaning and farm factors including farm features, herd management practices and gilt- and piglet-specific management procedures performed at the farm. Voluntarily enrolled breed-to-wean farms (n = 83) agreed to share IAV diagnostic testing and farm data from July 2011 through March 2017 including data obtained via the administration of a survey. There were 23% IAV RT-PCR positive samples of the 12,814 samples submitted for IAV testing within 2989 diagnostic submissions with 30% positive submissions. Among all the factors evaluated (n = 24), and considering the season adjusted multivariable analysis, only sow IAV vaccination and gilt IAV status at entry significantly reduced (p-value<0.05) IAV infections in piglets at weaning. Results from this study indicate that veterinarians and producers could manage these identified factors to reduce the burden of influenza in piglets prior to wean and perhaps, reduce the spread of IAV to other farms and people. PMID- 30466657 TI - Temporal and geographic distribution of weather conditions favorable to airborne spread of foot-and-mouth disease in the coterminous United States. AB - Foot-and-mouth disease (FMD) is a highly infectious viral disease of cloven hoofed animals. FMD outbreaks have the potential to cause significant economic consequences, and effective control strategies are needed to minimize the damage to livestock systems and the economy. Although not the predominant route of infection, airborne transmission has been implicated in previous outbreaks. Under favorable weather conditions, airborne spread of FMD can make the rapid containment of an outbreak more difficult. Our objective was to identify seasonal and geographic differences in patterns of conditions favorable to airborne FMD spread in the United States. Data from a national network of surface weather stations were examined for three study years (December 2011-November 2012, December 2012-November 2013, December 2014-November 2015). Weather conditions were found to be most frequently favorable to airborne spread during the winter (December, January, February). Geographically, conditions were most frequently favorable to airborne FMD spread in the upper Midwestern United States, a region where swine and cattle populations are common. Across study years, conditions for airborne FMD spread were more frequently favorable when weather conditions were generally mild with few extremes with respect to temperature and precipitation (e.g., 2014-2015). However, national patterns in risk areas for airborne FMD spread were similar across study years even though the degree of risk differed based on variations in weather patterns among study years. Our findings suggest that airborne transmission could contribute to FMD spread between livestock premises in the event of an outbreak in the coterminous United States, and that some geographic areas are at an increased risk particularly in seasons with conducive weather conditions. To our knowledge, this is the first study to characterize the risk of airborne FMD spread on a national scale in the United States. The findings presented here can be used to enhance preparedness and surveillance activities by identifying specific geographic areas in the United States where airborne spread is most likely to be a risk factor for transmission during an outbreak. PMID- 30466658 TI - Assessment of systematic reviews and meta-analyses available for bovine and equine veterinarians and quality of abstract reporting: A scoping review. AB - OBJECTIVE: Evidence-based medicine (EBM) is used in various areas including veterinary medicine. The assessment of the quality of systematic review and meta analyses (SR-MA) despite their importance in the EBM process is uncommonly performed in veterinary medicine due to the absence of specific dedicated tools. The main objective of this observational study was to examine the extent and nature of SR-MA that can be available online to an equine or bovine veterinarian. Secondary objectives included: (1) to determine if A MeaSurement Tool to Assess systematic Reviews (AMSTAR) tool can be used for equine and bovine SR-MA methodological assessment and if it has a satisfactory interrater reliability in a subsample of these SR-MA and (2) to appraise the completeness of abstract reporting of this sample. STUDY DESIGN AND SETTING: A scoping review using equine and bovine medical science SR-MA retrieved from PubMed was performed. A sub sample of these reviews (n = 30) were independently assessed by 3 different raters using the AMSTAR tool validated for medical reviews. The completeness of abstract reporting was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. RESULTS: Ten and 168 SR MA were retrieved for equine and bovine species respectively. For bovine SR-MA, 93 reviews were about nutrition and metabolism topic. On the 30 SR-MA subsamples, with 10 equine and 20 bovine SR-MA randomly chosen for AMSTAR assessment, the median interrater agreement (Kappa) was 0.60 (interquartile range: 0.36-0.71) depending on AMSTAR item and pairs of raters. When focusing on the total score of AMSTAR, the inter-observer intra-class correlation coefficient was very good (0.85, 95% confidence interval (CI): 0.74-0.92). The AMSTAR items that were unfrequently reported (33% or less of reviews) were "a priori" protocol of SR-MA specification, complete report of the list of studies (included and excluded studies), quality assessment of the included studies, publication bias assessment and conflict of interest (reported either for included studies and for SR-MA authors). Abstracts reporting quality was low with a median percentage of complete reported items of 33% (range: 8-58%) CONCLUSIONS: In large animal veterinary medicine, SR-MA are uncommonly performed in equine and bovine medicine. The SR-MA can be assessed using AMSTAR with acceptable inter-rater reliability, which is helpful to assess SR-MA methodological quality. PMID- 30466659 TI - Animal and management factors associated with weight gain in dairy calves and heifers on smallholder dairy farms in Kenya. AB - Calf growth is an important determinant of dairy herd productivity, particularly in countries where the dairy industry is expanding, such as Kenya. Our objective was to determine factors associated with weight gain in randomly selected dairy calves and heifers in smallholder dairy farms (SDF) in Kenya. A cross-sectional study on a census of 321 calves and heifers (dairy calves and heifers up to 36 months of age), sampled from 200 randomly selected SDF in Naari, Kenya, formed the study population. Youngstock management was recorded using a questionnaire. Biodata were obtained through subsequent physical examination and heart girth measurement. Descriptive statistical analyses were conducted, and mixed model regression was used for identification of factors associated (p < 0.05) with the natural log transformation of estimated average daily weight gain (ADG). Median and mean ADG of the youngstock were 360 and 443 (s.d. = 375) g day-1, respectively. In the final model, ADG was highest in pre-weaned calves and declined with age. Supplementing with quality hay during the dry season at least weekly was associated with increased ADG. There was an interaction between breed and historical disease on ADG such that disease was associated with decreased ADG in Bos taurus breeds, while ADG in Bos indicus breeds was not affected by disease. There was a significant interaction between education levels of the husband and wife caretakers; when the man's education was low (having less than or equal to primary school), ADG was highest when the woman had not completed primary school, but was lower when the woman had completed primary, secondary or tertiary education, possibly because such women worked off-farm more often. General growth performance of animals on these farms was lower than benchmarked standards recommended for optimum dairy production but within previously reported ranges for the East African region. Supplementation of diets (with hay and/or concentrates) is recommended for optimum growth in calves and heifers, especially in the dry season. If nutritional management of Bos taurus youngstock is not improved, crosses of Bos indicus could be better suited for the current nutritional management systems in SDF in Meru having calf disease problems. Interventions to support educating women (the primary caretakers of the cattle) and men in the community on calf management should be initiated, preferably with shared on-farm responsibilities. Training in better management, even for learned farmers, would be critical to better calf growth. PMID- 30466661 TI - Using Bayesian network modelling to untangle farm management risk factors for bovine viral diarrhoea virus infection. AB - Understanding risk factors for bovine viral diarrhoea (BVD) transmission is important for planning national disease control programmes. However, traditional statistical approaches may miss important features of BVD epidemiology due to the highly correlated nature of many farm-level risk factors. In this cross-sectional study, we used data collected from 304 cattle herds in New Zealand during 2015/2016 to compare the results from multivariable logistic regression with Bayesian network (BN) analysis. Blood samples from 15 heifers from each farm were pooled and analysed with an antibody ELISA test to classify BVD virus exposure status. Farmers were surveyed about their general management practices, knowledge about BVD, and risk factors for disease transmission, including onto- and off farm movements, within- and between-farm contacts, and whether they implemented BVD control measures for their service bulls. Multiple imputation was used to infer missing values in the dataset prior to statistical analysis. The results showed that 57/116 (49.1%) beef farms and 95/188 (50.5%) dairy farms were likely to be actively infected with BVD virus. Almost 60% of farms had movements of heifers/cows onto the premises and 13.8% of farmers reported contact with cattle from other farms. The results of the multivariable logistic regression showed that farms where heifers/cows had been moved onto the premises during all or most of the past five years were at higher risk of being BVD seropositive than farms without those movements (OR 2.21, 95% CI 1.29-4.24). Farms where cattle had occasional or rare contacts with cattle on other farms were also at increased risk compared with farms without any animal contacts between farms (OR 2.63, 95% CI 1.33-5.41) although this association was not frequency-dependent. Only close animal contacts between farms was directly associated with BVD status in the BN model, however, this approach further untangled other complex associations between correlated management factors, and provided additional important insights into BVD epidemiology. Compared to other countries with intensive production systems, over the fence contact appeared to play a more important role in New Zealand pastoral-based production systems and should be considered when developing strategies for a national BVD control programme. PMID- 30466660 TI - Accuracy of qPCR and bacterial culture for the diagnosis of bovine intramammary infections and teat skin colonisation with Streptococcus agalactiae and Staphylococcus aureus using Bayesian analysis. AB - Streptococcus agalactiae (Strep. agalactiae) and Staphylococcus aureus (Staph. aureus) are originally regarded as contagious mastitis pathogens, however, both pathogens have recently been isolated from extramammary and environmental sites, indicating that other sites than the udder might contribute to the spread of these pathogens potentially causing intramammary infections. Diagnostic tools to identify pathogens at extramammary sites are available but still needs to be validated. The objective of this cross-sectional field study was to estimate the diagnostic sensitivity (Se) and specificity (Sp) of the commercially available Mastit4 qPCR assay and bacterial culture (BC) in identifying Strep. agalactiae and Staph. aureus from milk and teat skin samples. We randomly selected 30-40 cows with high somatic cell counts from eight Danish Strep. agalactiae-positive dairy herds with automatic milking systems. Teat skin samples and aseptic milk samples were collected from right rear quarters (n = 287) for BC and PCR analysis. Se and Sp were estimated in a Bayesian latent class analysis. For milk samples, the Se and Sp of qPCR for Strep. agalactiae were estimated to 0.97 and 0.99, respectively, whereas the Se and Sp of BC were 0.41 and 1.00, respectively. The Se and Sp of qPCR for Staph. aureus were estimated to 0.95 and 0.99, respectively, whereas the Se and Sp of BC were 0.54 and 0.77, respectively. For teat skin samples, the Se and Sp of qPCR for Strep. agalactiae were estimated to be 0.97 and 0.96, respectively, whereas the Se and Sp of BC were 0.33 and 1.00, respectively. The Se and Sp of qPCR for Staph. aureus were estimated to 0.94 and 0.98, respectively, whereas the Se and Sp of BC were 0.44 and 0.74, respectively. In conclusion, the Se for diagnosing Strep. agalactiae and Staph. aureus IMI was higher for qPCR than BC, suggesting that qPCR is a valuable method for detecting both pathogens from quarter-level milk samples. The performance of BC in the detection of Strep. agalactiae and Staph. aureus on teat skin was poor compared to qPCR, indicating that differences in the target condition of the two methods should be considered when implementing them as routine diagnostic tests for detecting teat skin colonisers. The low Se of BC may preclude the use of BC for skin testing, and qPCR is better for this task. PMID- 30466662 TI - An overview of claw disorders at slaughter in finishing beef cattle reared in intensive indoor systems through a cross-sectional study. AB - This cross-sectional study aimed to assess in post-mortem the prevalence of specific claw disorders and their location on the sole in hind feet of finishing beef cattle reared indoors under intensive production systems. Evaluation was made on animals that were introduced in the ordinary slaughterhouse planning, presumably with no signs of impaired locomotion or severe lameness. A total of 4292 hind feet (right and left) belonging to 153 batches were collected (average feet/batch 28.1 +/- 5.62 (SD)) in 3 abattoirs in Northern Italy at 3 time points (April-June and September-October 2016; February-March 2017). One veterinarian performed the claw trimming first and then scored the presence of specific claw disorders and their position on the sole considering 7 zones (in the digital and interdigital areas). All claw disorders in a specific zone were recorded as binary (presence/absence). Infectious (ILS), non-infectious (NILS), and global (GLS) scores were calculated considering both the type of claw disorder detected and the number of zones affected. Non-infectious disorders were the most common diagnoses among batches, mainly on the lateral claws and in the heel-sole junction area. In particular, white line abscesses and ulcers (sole and toe ulcers) were also found as two of the most debilitating and painful lesions with a non-negligible frequency. Infectious diseases, when occurring in a batch, spread to almost all feet. As expected, GLS distribution on the total feet inspected showed a non-harmful condition, given that the worst scores from 3 to 13 were assigned to a restricted sample of feet (15%) and were far from the maximum potential value of 50. However, the GLS of all batches monitored revealed 10 critical batches having no healthy feet or more than 50% of feet graded with the worst scores. Since right and left feet of the same animal showed similar clinical diagnoses, a more efficient claw health evaluation system should consider only one foot. Although all cattle inspected were supposed to have no evident locomotory problems before slaughter, the detection of several foot disorders and the considerable distribution in some batches might suggest poor conditions on farms affecting finishing beef cattle health, behaviour, and welfare. It is therefore advisable that possible predisposing factors of specific claw disorders on the farms of origin be investigated more deeply. PMID- 30466663 TI - Association of herd-level risk factors and incidence rate of clinical mastitis in 20 Brazilian dairy herds. AB - The objectives of this study were to characterize the pathogen frequency and severity of clinical mastitis (CM) in 20 dairy herds of southeastern Brazil; and to determine the incidence rate of clinical mastitis (IRCM; overall and based on specific-pathogen groups) based on quarter time at risk and its association with risk factors at the herd-level. Data were recorded in each herd for a period of 8 to 15 months. The association between herd-level risk factors and IRCM were determined by two groups of mixed regression models: one based on the overall IRCM, and five based on the following specific-pathogen groups: contagious, other Gram-positive, Gram-negative, other, and negative culture. The following herd level risk factors were evaluated: herd size, housing system, average daily milk yield per cow, bulk milk somatic cell count (BMSCC), and bulk milk total bacterial count (BMTBC). A total of 5957 quarter-cases of CM were recorded from 2637 cows, but only 4212 cases had milk samples collected for culture. The most frequently isolated pathogens were Escherichia coli (6.6% of total cultures), Streptococcus uberis (6.1%), and Streptococcus agalactiae (5.9%). The majority of CM cases were mild (60.3%), while 34.1% were moderate and 5.6% severe. The frequency of severe CM cases was lower for those with a Gram-positive result (4.6%) compared to a Gram-negative result (11.4%). Overall, monthly mean IRCM was 9.7 cases per 10,000 quarter-days at risk (QDAR). Herds with a geometric mean BMSCC >= 601 * 103 cell/mL had higher overall IRCM (16/10,000 QDAR) than those with BMSCC <= 600 * 103 cell/mL (<=7.7/10,000 QDAR). When the specific-pathogen groups were evaluated, for contagious pathogens, variables housing (free-stalls or compost-bedded pack barns), BMSCC (>=601 * 103 cells/mL), and average daily milk yield per cow (21 and 25 Kg/d) presented the highest IRCM. Furthermore, in Gram-negative group, herds with BMTBC >= 31 * 103 cfu/mL had higher IRCM compared with herds with BMTBC <= 30 * 103 cfu/mL. Although environmental pathogens were the most common cause of CM in this study, contagious pathogens (e.g., Strep. agalactiae and Staph. aureus) are still a concern in dairy herds of Brazil. Additionally, as there were some herd-level risk factors associated with the IRCM, there may be opportunity for management strategies aiming to improve the control of CM in dairy herds. PMID- 30466665 TI - Mediterranean Neuroscience Methods 2017. PMID- 30466664 TI - Bayesian estimation of sensitivity and specificity of culture- and PCR-based methods for the detection of six major non-O157 Escherichia coli serogroups in cattle feces. AB - Non-O157 Shiga toxin-producing Escherichia coli (non-O157 STEC, O26, O45, O103, O111, O121, and O145) are foodborne pathogens of public health importance. Culture and PCR-based methods have been developed for the detection of these serogroups in cattle feces. The objectives of this study were to evaluate diagnostic sensitivity and specificity of PCR- and culture-based methods for the detection of the six non-O157 serogroups, and to estimate their true prevalence in cattle feces, using a Bayesian latent class modeling approach that accounts for conditional dependence among the three methods. A total of 576 fecal samples collected from the floor of pens of finishing feedlot cattle during summer 2013 were used. Fecal samples, suspended in E. coli broth, were enriched and subjected to three detection methods: culture (involving immunomagnetic separation with serogroup specific beads and plating on a selective medium), conventional (cPCR), and multiplex quantitative PCR (mqPCR) assays. Samples were considered serogroup positive if the sample or the recovered isolate tested positive by PCR for an O gene of interest; neither Shiga toxin (stx) nor intimin (eae) genes were assessed. Prior information on the performance of the three methods was elicited from three subject experts. Culture was generally the least sensitive and most specific of the 3 tests across serogroups, mqPCR was generally the most sensitive test and cPCR more specific than mqPCR. Sensitivity analysis indicated that posterior inferences on test performance and prevalence were susceptible to prior specification in cases where few or no detections present in the data for selected combinations of diagnostic methods (i.e. extreme category problem). Our results characterize performance of detection methods and true prevalence of non O157 serogroups, thus informing necessary adjustments for test bias in risk modeling. PMID- 30466666 TI - Proton Pump Inhibitors: What the Internist Needs to Know. AB - This report reviews the physiology of gastric acid suppression by proton pump inhibitors (PPIs) and anti-inflammatory effects of PPIs that are independent of their acid-suppressive effects. Valid indications for PPI use are discussed, as are putative adverse effects of PPIs that have been identified through weak associations in observational studies that cannot establish cause-and-effect relationships. Although evidence supporting the validity of these adverse effects is weak, there is also insufficient evidence to dismiss the risks. The report emphasizes how PPIs frequently are prescribed inappropriately and encourages physicians to carefully consider the indication for PPI therapy in their patients. PMID- 30466667 TI - Diet and the Role of Food in Common Gastrointestinal Diseases. AB - Food plays an essential role in normal cellular processes; however, certain foods may also trigger or worsen certain disease states. This article focuses particularly on the role of food in common gastrointestinal and liver diseases, and discusses the current evidence that either supports or debunks common dietary recommendations. Nutrition topics discussed include the use of artificial sweetener for weight loss, avoidance of all dairy products in the setting of lactose intolerance, dietary recommendations for diverticular disease, and dietary management in cirrhotic patients with hepatic encephalopathy. PMID- 30466668 TI - Colorectal Cancer Screening: Is Colonoscopy the Best Option? AB - Colorectal cancer is the second leading cause of cancer death in the United States. Prospective studies demonstrate that colorectal cancer screening reduces incidence and mortality, but uptake remains suboptimal. More than a third of age eligible Americans are not up to date on screening. There are several available screening tests, which may cause primary care providers to ponder which is the best test. This article provides an overview of the available test options and the evidence for each; a summary of major guidelines; and a comparison of the two most widely used tests, colonoscopy and fecal immunochemical testing. PMID- 30466669 TI - Colonoscopy, Polypectomy, and the Risk of Bleeding. AB - Colonoscopy with polypectomy is the means by which the incidence of colon cancer may be reduced; however, polypectomy is not without risk. Physicians must carefully weigh the risks and benefits of colonoscopy, particularly when patients are given prescriptions for antiplatelet agents and anticoagulants. This article discusses the risks of colonoscopy and polypectomy and reviews the most recent data for managing antiplatelet agents and anticoagulants in the periendoscopic period. PMID- 30466670 TI - Irritable Bowel Syndrome: What Treatments Really Work. AB - Irritable bowel syndrome (IBS) is present in patients with symptoms of chronic abdominal pain and altered bowel habits but no identifiable organic etiology. Rome IV classification groups patients based on predominant stool pattern. Low FODMAP diets have been helpful in providing symptom relief, as have cognitive behavioral and mind-body techniques that help patients manage symptoms. Targeted symptomatic relief for the patient's predominant symptoms provides relief in addition to effective older medications that are inexpensive and reliable. Newer treatments for IBS-D, such as eluxadoline, and IBS-C, with linaclotide, lubiprostone, plecanatide, also can provide durable relief. PMID- 30466672 TI - The Management of Chronic Pancreatitis. AB - Chronic pancreatitis (CP) may remain undiagnosed for years until patients exhibit manifestations, such as pain and exocrine or endocrine insufficiency. Some patients with CP develop serious complications, such as malignancy or peripancreatic fluid collections. Considering CP in at-risk patients such as those with a long-standing history of alcohol or tobacco use is key to establishing the diagnosis. Management involves reducing and eliminating exposures, dietary modification, treatment of pancreatic insufficiency, assessing for complications, and surveillance for neoplasia. The management of CP is often multidisciplinary involving medical, endoscopic, and surgical options for therapy. PMID- 30466671 TI - Proton Pump Inhibitor-Refractory Gastroesophageal Reflux Disease. AB - Proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD) is defined by the presence of troublesome GERD symptoms despite PPI optimization for at least 8 weeks in the setting of ongoing documented pathologic gastroesophageal reflux. It arises from a dysfunction in protective systems to prevent reflux and as propagation of physiologic reflux events. Treatment possibilities include pharmacologic options, invasive management strategies, and endoluminal therapies. Management strategy should be personalized to the patient's needs and mechanistic dysfunction. This article reviews the definition, mechanisms, and management options for PPI-refractory GERD. PMID- 30466673 TI - Pancreatic Cysts: Sinister Findings or Incidentalomas? AB - Pancreatic cysts are common and are incidentally detected in up to 13.5% of individuals. Intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN) are precursors to pancreatic adenocarcinoma. Most will never develop into pancreatic cancer. Several types of pancreatic cysts have no malignant potential. Solid tumors can present as a pancreatic cysts. Guidelines recommend surveillance. Management includes differentiating IPMNs and MCNs from other types, identifying those at highest risk of harboring pancreatic cancer or high-grade dysplasia, and referral to a multidisciplinary group for evaluation and consideration of surgical resection. PMID- 30466675 TI - The Revolution in Treatment of Hepatitis C. AB - Treatment of hepatitis C with interferon therapy produced some cures early on, but was associated with significant side effects. Because of further advances in the molecular understanding of hepatitis C, by 2014 effective treatments became available that far surpassed all prior interferon-based regimens in efficacy, tolerability, and safety. This led to rapid transformation of a hard-to-treat disease to simple, safe, and effective treatment offered to anyone. This article focuses on hepatitis C epidemiology; the clinical impact and consequences; discussion of past hepatitis C treatments; and a review of current recommendations for screening, diagnosis, and treatment of this ubiquitous virus. PMID- 30466676 TI - The Future of Nonalcoholic Fatty Liver Disease Treatment. AB - Nonalcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver disease in the United States. The NAFLD subtype, nonalcoholic steatohepatitis, represents a progressive form of the disease that can lead to cirrhosis, portal hypertension, and hepatocellular carcinoma. NAFLD is a diagnosis of exclusion and is strongly related to obesity and the metabolic syndrome. Although there has been an explosion of exciting therapeutic avenues for NAFLD in recent years, the bedrock of management continues to be lifestyle modification, weight loss, and optimization of metabolic risk factors. PMID- 30466674 TI - Eosinophilic Esophagitis. AB - Eosinophilic esophagitis (EoE) is a chronic disorder characterized by symptoms of esophageal dysfunction and esophageal inflammation with intraepithelial eosinophils. EoE represents an important cause of upper gastrointestinal morbidity. Primary care providers are pivotal for timely and accurate recognition of symptoms of eosinophilic esophagitis, for facilitating diagnoses through specialist referrals, and for understanding management strategies. This process begins with a thorough understanding of the clinical features of EoE, its associated atopic conditions, and its evolving epidemiology. PMID- 30466677 TI - Helping Patients with Gastroparesis. AB - Gastroparesis is an increasing concern and options remain limited. Diagnosis hinges on recognition of delayed gastric emptying in the absence of mechanical obstruction. Nontransit studies evaluating gastric motility serve a complementary role and may help guide therapy. Treatment consists of a combination of lifestyle and dietary medication, medications (antiemetics, prokinetics, neuromodulators, and accommodation-enhancers), alternative and complementary therapy, endoscopic therapy (pyloric-directed therapy, temporary stimulation, jejunostomy, or venting gastrostomy) and surgical therapy (pyloroplasty, gastric electrical stimulation, gastrectomy). Treatment can be tailored to the individual needs and symptoms of the affected patient. PMID- 30466678 TI - Who Should Be Gluten-Free? A Review for the General Practitioner. AB - Historically, a gluten-free diet was recommended only for those with celiac disease or IgE-mediated wheat allergy. With changes in food allergy labeling in the United States and the publication of several best-selling books, gluten related disorders have come to the forefront of popular culture. As a result, there has been a dramatic increase in the number of gluten-free diet followers, many for nontraditional reasons. As "going gluten-free" has become mainstream, it is imperative that health care providers acquire the knowledge to identify true gluten-related disorders to effectively counsel their patients and minimize potential complications from following such a restrictive diet. PMID- 30466680 TI - Gastroenterology for the Internist. PMID- 30466679 TI - Gut Check. PMID- 30466681 TI - New Concepts, Concerns, and Creations in Acne. AB - Laboratory monitoring for patients on isotretinoin should include creatinine kinase in athletic males and the more liver-specific gamma glutamyltransferase. There is mounting evidence that acne pathophysiology includes a barrier defect and subsequent microbiome disruption. Avoidance of acne scars with early and aggressive treatment is a more efficient and cost-effective option than subsequent treatment. Laser and light treatments for acne and acne scars are plentiful but poorly supported by evidence-based medicine. The acne pipeline is rich with new chemical entities, new formulations, and combinations of older agents. The gold standard for acne therapy may be changing its face. PMID- 30466682 TI - Cosmeceuticals: What's Real, What's Not. AB - Cosmeceuticals are cosmetics that promise to deliver physiologically relevant benefits without the incorporation of prescription drugs. To entice consumers to purchase these premium priced products, a story must be told of how the cosmeceutical delivers on these appearance improvement promises. The backbone of any cosmeceutical skin care regimen is facial cleansing and moisturizing. This article reviews the novel ingredients and technologies used to achieve these benefits examining what is real and what is not. PMID- 30466683 TI - Atopic Dermatitis: New Developments. AB - Herein we review recent developments in our understanding and treatment of atopic dermatitis. Key insights from the recent literature are summarized, from findings on the pathogenesis of this multifactorial disease to a new and more nuanced understanding of its natural history. Therapeutic advances and new data on comorbidities are also discussed. PMID- 30466684 TI - What's New in Cosmetic Dermatology. AB - Topical silicone gel is more beneficial than petrolatum-based products as an all purpose wound dressing for granulating and sutured wounds, regardless of cause. Vaginal laser rejuvenation is effective in relieving genitourinary syndrome of menopause, stress urinary incontinence, vaginal relaxation syndrome, and related vulvar disorders. New cosmetic indications in the upper face for onabotulinumtoxinA have been approved by the Food and Drug Administration, whereas off-label treatments in the lower face increase in popularity. Clinical trials of uncomplexed daxibotulinumtoxinA demonstrate safety and efficacy lasting more than 6 months. PMID- 30466685 TI - Contact Dermatitis: Emerging Trends. AB - The field of contact dermatitis is constantly evolving. Trends in irritant and allergic contact dermatitis are shaped by the introduction of new chemicals, revival of older allergens, industrial practices, and consumer behaviors. This article discusses the most noteworthy trends within the field, organized by allergen category, with particular attention to newer and/or controversial allergens. PMID- 30466686 TI - Biologics and Psoriasis: The Beat Goes On. AB - Psoriasis is a chronic, immune-mediated, inflammatory skin disease that requires long-term therapy for disease control. This article reviews data presented in clinical trials to evaluate and compare various characteristics of biologics that are currently approved for the treatment of psoriasis. Attributes of biological agents that are examined in this article include efficacy, long-term maintenance, overall safety, median time to onset of efficacy, adjustment for body weight, frequency of injections, indication for psoriatic arthritis, and safety in pregnancy. Here, we evaluate what the ideal choice of biological therapy may be for psoriasis patients with specific needs. PMID- 30466687 TI - Connective Tissue Disease: Current Concepts. AB - Connective tissue diseases often prominently affect the skin, requiring dermatologists to play an important role in diagnosis and treatment of these patients. Herein we describe updates on the pathogenesis, clinical features, and treatment of 4 major connective tissue diseases: dermatomyositis, cutaneous lupus erythematosus, limited scleroderma (morphea), and cutaneous vasculitis. Many of these updates promise to improve clinical care of patients who suffer from dermatologic involvement of these diseases and are the result of research performed by dermatologists who have expertise in these conditions. PMID- 30466688 TI - Advances in Inflammatory Granulomatous Skin Diseases. AB - Inflammatory granulomatous dermatitides include cutaneous sarcoidosis, necrobiosis lipoidica, granuloma annulare, and reactive granulomatous dermatitis. The etiopathogenesis of these disorders is not well understood; but the T helper 1 response mediated by interferon-gamma, tumor necrosis factor-alpha, and interleukin (IL) 1, 2, and 6 and the T helper 17 response mediated by IL-17 play a role. These inflammatory granulomatous disorders often have cutaneous manifestations in addition to extracutaneous manifestations or associations with systemic diseases. The authors review these disorders, propose diagnostic and evaluative approaches to these diseases, and explore recent literature with regard to the etiopathogenesis and treatment of these entities. PMID- 30466689 TI - Comorbidities in Dermatology: What's Real and What's Not. AB - Comorbidities affecting dermatologic patients are of significant importance to providers and highly relevant for appropriate patient counseling, screening practices, prevention, and treatment. This article seeks to highlight several of the newest findings in the literature regarding comorbidities associated with dermatologic diseases including atopic dermatitis, hidradenitis suppurativa, alopecia areata, chronic urticaria, and the pemphigus family of immunobullous diseases. Further investigation is needed for associations between atopic dermatitis and pancreatic cancer and pemphigus family diseases and chronic obstructive pulmonary disease in order to better characterize the strength of these associations and clinical relevance. PMID- 30466690 TI - Updates in Melanoma. AB - Skin cancer is reaching epidemic levels in the United States. Recent advances in the understanding of the pathophysiology of melanoma have allowed improved risk stratification in the revised American Joint Committee on Cancer (AJCC) criteria, new tests to capture patients at higher risk than their stage may indicate, and new treatments to offer hope and cures to patients with advanced disease. PMID- 30466691 TI - Skin Cancer and Immunosuppression. AB - Immunosuppressed patients are at significantly increased risk of developing cutaneous malignancies. These malignancies are often more aggressive compared with the general population and require multidisciplinary care. This article highlights the incidence and risk factors of cutaneous malignancies in this cohort. The treatment and prevention strategies are discussed. There continues to be a need for evidence-driven guidelines regarding the management of skin cancers in these patients. PMID- 30466692 TI - Going Viral 2019: Zika, Chikungunya, and Dengue. AB - Chikungunya and Zika virus infections are emerging diseases in the Americas, and dengue continues to be the most prevalent arthropod-borne virus in the world. These arbovirus diseases may spread by endemic transmission or as travel-related infections and have rapidly expanded their geographic distribution secondary to vector spread. All 3 share a similar clinical picture that includes a maculopapular rash. Zika is characterized by pruritic rash, low-grade fever, and arthralgia. Congenital nervous system malformations are a growing public-health concern. Chikungunya distinctive dermatologic manifestations include facial melanosis and bullous eruption. Dengue bleeding complications may be life threatening and require inpatient management. PMID- 30466693 TI - Hot Topics in Dermatology. PMID- 30466694 TI - Injection of Urethral Bulking Agents. AB - Urethral injection is a safe and minimally invasive method of treating female stress urinary incontinence with multiple bulking agents currently commercially available. Although there are numerous studies that demonstrate efficacy, long term success is not yet proven. This article aims to describe the mechanism of action and properties of various agents, patient selection factors, available techniques for injection, outcomes of urethral injections, and complications associated with the procedure. PMID- 30466695 TI - Surgery for Apical Vaginal Prolapse after Hysterectomy: Transvaginal Mesh-Based Repair. AB - Several transvaginal mesh products have been marketed to address vaginal vault prolapse. Although data are limited, prolapse recurrence rates and subjective outcome measures seem to be equivalent for vaginal mesh compared with native tissue apical prolapse repair, and the different vaginal meshes have not proven superior to one another. Given the known unique complications specific to vaginal mesh with equivalent outcomes for the apical vaginal prolapse, it is reasonable to reserve mesh use for specific high-risk cases, such as patients with large apical prolapse recurrence after native tissue repair who are not candidates for sacrocolpopexy. PMID- 30466696 TI - Surgery for Apical Vaginal Prolapse After Hysterectomy: Abdominal Sacrocolpopexy. AB - The number of surgeries for pelvic organ prolapse in the United States is increasing. Abdominal sacrocolpopexy has become the gold standard for women desiring a restorative repair of their apical pelvic organ prolapse. Despite the associated morbidity of abdominal sacrocolpopexy, advances in minimally invasive approaches have safely increased the number of these surgeries performed, especially among urologists. Moreover, a number of studies have demonstrated superior objective outcomes after abdominal sacrocolpopexy when compared with vaginal approaches. Variations in the technique are described, but no consensus exists on a standard approach. PMID- 30466697 TI - Vaginal Approach to Vesicovaginal Fistula. AB - Vesicovaginal fistula is the most commonly encountered sequela of genitourinary trauma. Although the etiology differs between developed and developing countries, the principles of fistula repair must be strictly adhered to for success. Timing and route of repair remain contentious, because of a lack of randomized data. Evaluation and management is dictated by the surgeon's experience. Minimally invasive techniques with laparoscopy and robotic technology are generating wider interest with reduced postoperative morbidity, but a transvaginal technique should be in the arsenal of all pelvic reconstructive surgeons. More research is required to evaluate the optimal surgical route and technique for successful outcomes. PMID- 30466698 TI - Abdominal Approach to Vesicovaginal Fistula. AB - Principles of abdominal vesicovaginal fistula (VVF) repair include good exposure of the fistulous tract, double-layer bladder closure, retrograde fill of the bladder to ensure a water-tight seal, tension-free closure and continuous postoperative bladder drainage. Minimally invasive approaches, particularly robot assisted laparoscopy, have demonstrated shorter operative times, decreased blood loss, improved visibility, and similar cure rates without increased adverse events. These techniques are therefore rising in popularity among surgeons. Ultimately, surgical approach to VVF repair depends upon the individual characteristics of the patient and fistula, as well as the preference and experience of the surgeon. PMID- 30466699 TI - Synthetic Midurethral Slings: Roles, Outcomes, and Complications. AB - Synthetic midurethral sling placement is the most studied anti-incontinence procedure available. Multiple randomized trials demonstrate its safety and efficacy, with results out to 5 years. With long-term follow-up, it seems there may be some benefit in efficacy to retropubic sling placement compared with the transobturator approach. Single-incision slings are a newer modification to multi incision sling placement, and the data regarding safety and efficacy are not as mature as other forms of sling placement. Complications may occur with mesh midurethral sling placement and surgeons performing these procedures should be comfortable with the diagnosis and management of these issues. PMID- 30466700 TI - Management of the Exposed or Perforated Midurethral Sling. AB - The synthetic midurethral sling has become the gold standard for treatment of stress urinary incontinence since its introduction more than 20 years ago. With its utilization, the incidence of mesh-related complications has also increased. Mesh exposure and perforation are 2 common mesh complication scenarios that pelvic floor surgeons should be prepared to treat. This article highlights preoperative, perioperative, and postoperative factors to minimize the chance of vaginal wall mesh exposure or perforation of mesh into the lower urinary tract. It also summarizes common presenting symptoms, suggested evaluation and a range of treatment options. PMID- 30466701 TI - Surgery for Stress Urinary Incontinence: Autologous Fascial Sling. AB - This article describes the operative technique of autologous fascial pubovaginal sling (AFPVS) surgery, examines the senior author's outcomes with AFPVS, compares these outcomes with those of other large studies and meta-analyses, and compares the safety and efficacy of AFPVS with those of the synthetic midurethral sling (SMUS). Recently, the SMUS has become the treatment of choice for most surgeons. The efficacy of the SMUS remains unchallenged and comparable with that of AFPVS, but SMUS are associated with more severe complications. In the author's opinion, the AFPVS should remain the gold standard for treating SUI. PMID- 30466702 TI - Burch Colposuspension. AB - The Burch colposuspension has a 50-plus year history demonstrating strong long term outcomes with minimal complications. Iterations of the procedure, including laparoscopic, robotic, and mini-incisional approaches, appear to have equal efficacy to the open procedure. Although the current use of the Burch colposuspension has waned with the growing shift toward sling surgery, it continues to have a role in the treatment of stress urinary incontinence. Specifically, a Burch procedure should be considered when vaginal access is limited, concurrent intra-abdominal surgery is planned, or mesh is contraindicated. PMID- 30466703 TI - Surgery for Anterior Compartment Vaginal Prolapse: Suture-Based Repair. AB - Native tissue anterior compartment prolapse repair remains an important surgical procedure for pelvic prolapse. Native tissue repair has been well-studied and is successful in relieving vaginal bulge symptoms and reducing prolapse within the vagina. Native tissue cystocele repair has been performed safely since the advent to modern vaginal surgery for prolapse. Reoperation rates are low and the contribution of apical support in the durability of vaginal wall defect repair surgery has been well-established. Native tissue cystocele repair addresses symptom relief for women, and should continue to be a part of pelvic floor reconstructive surgery. PMID- 30466704 TI - Surgery for Anterior Compartment Prolapse Synthetic Graft-Augmented Repair. AB - Pelvic organ prolapse is a common and bothersome problem that affects women's work, traveling, physical exercise, sleep, and sexual function. Synthetic implants show superiority in reducing recurrence of pelvic organ prolapse. However, inserting foreign materials carries an increased risk of complications. In this article containing the most updated available literature, we look back at the history of synthetic mesh repair, examine its efficacy and advantages, assess common complications, review current opinions, and look at the future for ways to improve the use of mesh for better results and fewer complications in an attempt to improve women's quality of life. PMID- 30466705 TI - Posterior Vaginal Wall Prolapse: Suture-Based Repair. AB - Pelvic organ prolapse is common in parous women, although few report symptoms. The incidence of posterior compartment prolapse, or rectocele, is less well reported. Posterior vaginal wall prolapse is associated with pain, constipation, and splinting. Surgery is the mainstay of therapy for symptomatic rectoceles. Though several surgical techniques have been described, no clear indications for type of repair have emerged. This article reviews the management strategies and draws conclusions about suture-based and site-specific techniques. PMID- 30466706 TI - Surgery for Posterior Compartment Vaginal Prolapse: Graft Augmented Repair. AB - Posterior compartment vaginal prolapse can be approached with multiple surgical techniques, including transvaginally, transperineally, and transanally, repaired with either native tissue or with the addition of an augment. Augment material for posterior compartment prolapse includes biologic graft (dermal, porcine submucosal), absorbable mesh (Vicryl polyglactin), or nonabsorbable synthetic mesh (polypropylene). Anatomic success rates for posterior compartment repair with augment has ranged from 54% to 92%. Augmented posterior compartment repair has not been shown to have superior outcome to native tissue repair. The focus of this article is on the transvaginal approach comparing native tissue repair with graft or mesh augmented repair. PMID- 30466707 TI - Transvaginal Suture-Based Repair. AB - An estimated 300,000 women undergo pelvic organ prolapse (POP) surgery in the United States every year at a cost of more than 1 billion dollars per year. The prevalence of POP is approximately 2.9% to 8%, and increases with age. Apical support is required to achieve successful prolapse repair. As the search for the safest, most durable, surgical repair continues, transvaginal native tissue repairs have the advantage of providing minimally invasive surgical repairs without the added risk of abdominal, laparoscopic, or robotic surgery while avoiding the risk of mesh augmentation. PMID- 30466708 TI - Reconstruction of the Female Pelvis: A Fundamental Pillar of Urology. PMID- 30466710 TI - Corrigendumto "Transcranial magnetic stimulation in basic and clinical neuroscience: A comprehensive review of fundamental principles and novel insights" [Neurosci. Biobehav. Rev. 83 (2017) 381-404]. PMID- 30466712 TI - Precision medicine in head and neck cancer. AB - Head and Neck cancer is among the most common cancers worldwide, with a high prevalence in south East Asia, Brazil and central Europe. Head and Neck Squamous cell carcinoma (HNSCC) is associated with elevated mutational load but lacks specific genetic mutations. Exposure to carcinogens including tobacco and alcohol are the most dominant etiologic factors of HNSCC, while Epstein-Barr (HBV) and Human Papilloma Viruses (HPV) are associated with nasopharyngeal and oropharyngeal carcinoma, respectively. Surgery including open and minimally invasive procedures is considered the standard of care for the majority of oral cavity and early larynx cancers, while radiation therapy or concurrent chemoradiation are used for the other head and neck cancers. The treatment of patients with head and neck cancer is complex and has undergone considerable transformation in the last decade. These modalities include immunotherapy, targeted therapy (small molecule inhibitors or antibodies), or combined modality treatments. Emerging evidence supports a vital role of the immune system in eradicating HNSCC. Cancer cells express programmed death ligand 1 or 2 (PD-L1/2) which binds to the PD receptor on the T-cell, leading to an inactivation of the cytotoxic response of the T-cell. Cytotoxic T lymphocytes antigen-4 (CTLA-4) is another key player, expressed by cancer-activated T-cells, which binds to B7 ligand on the cancer cells, leading to inhibition of T-cells activation. Checkpoint inhibitors such as anti-PD-1 and anti-PD-L1 antibodies, were shown to significantly improve disease free survival and overall survival after failure of platinum-based chemotherapy. In addition, expression of HPV is associated with better response to single modality treatment (e.g. radiotherapy or surgery) and improved survival. In future years we expect to see the establishment of precision medicine modalities in an attempt to extend survival and improve quality of life of advanced stage HNSCC patients. Several phase III clinical trials are in progress to evaluate the utility of checkpoint inhibitors at different treatment settings, including combinations with adjuvant surgery, radiation therapy and chemotherapy. PMID- 30466711 TI - A close look onto structural models and primary ligands of metallo-beta lactamases. AB - beta-Lactamases are hydrolytic enzymes capable of opening the beta-lactam ring of antibiotics such as penicillin, thus endowing the bacteria that produce them with antibiotic resistance. Of particular medical concern are metallo-beta-lactamases (MBLs), with an active site built around coordinated Zn cations. MBLs are pan reactive enzymes that can break down almost all classes of beta-lactams, including such last-resort antibiotics as carbapenems. They are not only broad spectrum-reactive but are often plasmid-borne (e.g., the New Delhi enzyme, NDM), and can spread horizontally even among unrelated bacteria. Acquired MBLs are encoded by mobile genetic elements, which often include other resistance genes, making the microbiological situation particularly alarming. There is an urgent need to develop MBL inhibitors in order to rescue our antibiotic armory. A number of such efforts have been undertaken, most notably using the 3D structures of various MBLs as drug-design targets. Structure-guided drug discovery depends on the quality of the structures that are collected in the Protein Data Bank (PDB) and on the consistency of the information in dedicated beta-lactamase databases. We conducted a careful review of the crystal structures of class B beta lactamases, concluding that the quality of these structures varies widely, especially in the regions where small molecules interact with the macromolecules. In a number of examples the interpretation of the bound ligands (e.g., inhibitors, substrate/product analogs) is doubtful or even incorrect, and it appears that in some cases the modeling of ligands was not supported by electron density. For ten MBL structures, alternative interpretations of the original diffraction data could be proposed and the new models have been deposited in the PDB. In four cases, these models, prepared jointly with the authors of the original depositions, superseded the previous deposits. This review emphasizes the importance of critical assessment of structural models describing key drug design targets at the level of the raw experimental data. Since the structures reviewed here are the basis for ongoing design of new MBL inhibitors, it is important to identify and correct the problems with ambiguous crystallographic interpretations, thus enhancing reproducibility in this highly medically relevant area. PMID- 30466713 TI - Fractured pediatric central venous catheters - Repair or replace? AB - INTRODUCTION: Central venous catheter (CVC) fracture is a common complication. The aim of this study is to examine risk factors resulting in CVC fracture and compare outcomes of children undergoing CVC repair versus replacement. METHODS: A retrospective chart review was conducted from 2000 to 2016 for children with tunneled CVCs. Children with CVC fractures were compared to those without to identify risk factors resulting in fracture. Children with fractured CVCs were divided into repair or replacement treatment groups and outcomes compared. A logistic regression model determined independent predictors of CVC-associated bloodstream infections (CLABSI) after fracture. RESULTS: In the 236 children with CVCs, the fracture rate was 29.2%. Fractured CVCs were more common with double lumen CVC (p = 0.040) and children whose indication was total parenteral nutrition (p = 0.003). Given children often underwent multiple repairs or replacements. 98 CVC repairs and 41 replacements were analyzed. CVC replacements had longer durability than repair (181.98 vs. 98.9 days, p = 0.038). There were no differences in CLABSI incidence for repair vs. replacement (OR 0.5 CI 0.05 4.97) after controlling for other factors. CONCLUSIONS: CVC fracture is a frequent complication in children with tunneled CVCs. CVC repair has no increased incidence of CLABSI but eliminates the intraoperative and anesthetic risks of CVC replacement. TYPE OF STUDY: Retrospective cohort study. LEVEL OF EVIDENCE: Level III. PMID- 30466714 TI - Heart rate variability biofeedback increases sexual arousal among women with female sexual arousal disorder: Results from a randomized-controlled trial. AB - Low resting heart rate variability (HRV) has been associated with poor sexual arousal function in women. In a recent study, a single session of autogenic training increased HRV and facilitated improvements in both sexual arousal and perceived genital sensations among women experiencing decreased arousal. The current study expands upon these findings by examining the efficacy of HRV biofeedback, with and without autogenic training, as a treatment for sexual arousal dysfunction in an at-home setting. Participants (N = 78) were randomized into one of three conditions: HRV biofeedback, HRV biofeedback + autogenic training, or waitlist control. Each condition included three laboratory sessions; participants in the two active conditions completed 4-6 biofeedback sessions at home, and participants in the HRVB + A condition listened to a 14-min autogenic training recording before completing the biofeedback. Across the three laboratory visits, participants in the three conditions singficnatly differed in their genital arousal, subjective sexual arousal, and their perceived genital sensations. Compared to women in the control group, women who engaged in HRV biofeedback at home, with and without additional autogenic training, experienced increases in genital arousal, subjective sexual arousal, and perceived genital sensations. These results provide preliminary support for the contribution of heart rate variability level to female sexual arousal function and for the use of either of these interventions in the treatment of sexual arousal concerns. PMID- 30466716 TI - Corticosteroids and Hyaluronic Acid Injections. AB - Osteoarthritis is a common condition that affects many individuals resulting in pain, reduced mobility, and decreased function. Corticosteroids have been a mainstay of osteoarthritis treatment. Studies have shown that they provide short term pain improvement and can be used for osteoarthritis flares. Hyaluronic acid injections have extensively been studied in knee osteoarthritis but to a lesser degree in other joints. Despite some debate between societies, a large number of recent studies have shown hyaluronic acid to be a viable treatment option showing longer-term improvement in both pain and function. PMID- 30466715 TI - Applicability of trials in rheumatoid arthritis and osteoarthritis: A systematic review and meta-analysis of trial populations showing adequate proportion of women, but underrepresentation of elderly people. AB - OBJECTIVES: To evaluate whether elderly people and women are adequately represented in randomized controlled trials (RCT) in rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Four systematic searches in MEDLINE yielded RCT in RA and OA on any intervention published in 2016 and 2017 and population-based studies (PBS) in RA and OA published between 2013 and 2017. Random effects meta analyses estimated the pooled proportion of elderly people (defined as being >= 65 years old), the mean age, its standard deviation (SD), and the proportion of women stratified by disease (RA and OA) and study type (RCT and PBS). Stratified estimates were subsequently compared. RESULTS: 265 RCT comprising 51,240 participants and 53 PBS comprising 523,630 participants were included. In both RA and OA, RCT included lower proportions of elderly people than PBS: RA -0.18 (95% confidence interval -0.22 to -0.13); OA -0.20 (-0.30 to -0.09); had lower mean ages: RA -5.2 years (-6.8 to -3.5); OA -4.7 years (-7.5 to -2.0); and smaller SD: RA -1.9 years (-2.6 to -1.3); OA -2.7 years (-4.2 to -1.2); (all comparisons: p <= 0.001). Proportions of women were comparable in RCT compared to PBS in both RA and OA. CONCLUSIONS: While women are adequately represented in RA and OA trials, the elderly are underrepresented, probably limiting applicability of current evidence to this growing subgroup. It is urgent to improve the inclusion of elderly people in clinical trials and study age as a determinant for outcome. PMID- 30466717 TI - Orthobiologics for Focal Articular Cartilage Defects. AB - Focal chondral defects of the knee are extremely common and often result in pain, dysfunction, joint deterioration, and, ultimately, the development of osteoarthritis. Due to the limitations of conventional treatments for focal chondral defects of the knee, orthobiologics have recently become an area of interest. Orthobiologics used for cartilage defects include (but are not limited to) bone marrow aspirate concentrate, adipose-derived mesenchymal stem cells, platelet-rich plasma, and micronized allogeneic cartilage. Each of these products can be applied in the clinical setting, as an isolated surgical procedure, or as an augment to cartilage restoration surgery. PMID- 30466719 TI - Emerging Orthobiologic Techniques and the Future. AB - The future of orthopedic surgery appears to be intimately associated with the development of orthobiologics to facilitate healing and the treatment of multiple disease processes. The orthopedic community should understand developmental processes to ensure that products are adequately studied and the effects are fully known before widespread implementation in the clinical setting. Technologies that embrace this paradigm will impact the field the most. PMID- 30466718 TI - Ortho-Biologics for Osteoarthritis. AB - Osteoarthritis (OA) is a debilitation condition that affects millions of North Americans. Aside from weight loss, activity modification, and joint replacement, little else has been effective in delaying the progression of OA or treating the symptoms of OA. Ortho-biologics have become a popular treatment option in a variety of musculoskeletal conditions, including OA. In this article, the authors explore the use of 4 key ortho-biologics in the treatment of OA, all of which have shown promising results in the literature, despite the lack of large randomized controlled trials. PMID- 30466720 TI - Incorporating Ortho-Biologics into Your Clinical Practice. AB - The decision to incorporate ortho-biologics into a clinical practice will ultimately depend on physicians' preferences and the resources available to their practice. It is important to emphasize that different biologics are used for different pathologies/injuries and in different settings, such as the operating room or in the office. Physicians thinking about using biologics in their practices should consider the time commitment required to learn and use the technique, insurance coverage, and informed consent. The decision to treat patients with ortho-biologics should be a shared decision based on current literature, previous treatment regimen, and patients' goals. PMID- 30466721 TI - Platelet-Rich Plasma. AB - Platelet-rich plasma (PRP) is a promising treatment for musculoskeletal maladies and clinical data to date have shown that PRP is safe. However, evidence of its efficacy has been mixed and highly variable depending on the specific indication. Additional future high-quality large clinical trials will be critical in shaping our perspective of this treatment option. The heterogeneity of PRP preparations, both presently and historically, leads sweeping recommendations about its utility impossible to make. This heterogeneity has also made interpreting existing literature more complicated. PMID- 30466722 TI - Amniotic-Derived Treatments and Formulations. AB - In orthopedic sports medicine, amniotic-derived products have demonstrated promising preclinical and early clinical results for the treatment of tendon/ligament injuries, cartilage defects, and osteoarthritis. The amniotic membrane is a metabolically active tissue that has demonstrated anti inflammatory, antimicrobial, antifibrotic, and epithelialization-promoting features that make it uniquely suited for several clinical applications. Although the existing clinical literature is limited, there are several ongoing clinical trials aiming to elucidate the specific applications and benefits of these products. This article reviews the current amniotic-derived treatment options and the existing literature on outcomes, complications, and safety profile of these products for use in sports medicine. PMID- 30466723 TI - Adipose-Derived Stem Cell Treatments and Formulations. AB - This article analyzes the current literature on the use of adipose-derived stem cells (ASCs) to evaluate the available evidence regarding their therapeutic potential in the treatment of cartilage pathology. Seventeen articles were included and analyzed, showing that there is overall a lack of high-quality evidence concerning the use of ASCs. Most trials are case series with short-term evaluation. The most adopted approach consists of an intra-articular injection of the stromal vascular fraction (SVF) rather than the expanded cells. Based on the available data, no specific preparation method or formulation could be considered as the preferred choice in clinical practice. PMID- 30466724 TI - Orthobiologics for Bone Healing. AB - Orthobiologics are a group of biological materials and substrates that promote bone, ligament, muscle, and tendon healing. These substances include bone autograft, bone allograft, demineralized bone matrix, bone graft substitutes, bone marrow aspirate concentrate, platelet-rich plasma, bone morphogenetic proteins, platelet-derived growth factor, parathyroid hormone, and vitamin D and calcium. Properties of orthobiologics in bone healing include osteoconduction, osteoinduction, and osteogenesis. This article discusses the important properties of orthobiologics in bone healing, many of the orthobiologics currently available for bone healing, the related literature, their current clinical uses in sports medicine, and systemic factors that inhibit bone healing. PMID- 30466726 TI - OrthoBiologics: Science or Snake Oil? PMID- 30466725 TI - Ortho-Biologics for Ligament Repair and Reconstruction. AB - Biologics enhance tissue healing by stimulating the recovery processes for restoration of native or near-native tissue in addition to symptom management. The most popular biological modalities currently used include hyaluronic acid, growth factors therapy, platelet-rich plasma, and bone marrow aspirate concentrate. These treatment protocols are thought to facilitate and signal with cells or bioactive factors to improve ligament interventions by enhanced graft incorporation and strength, gene activation, and other mechanisms. Various growth factors regulate and improve cellular activities and proliferation, extracellular matrix deposition, and differentiation of mesenchymal stem cells into fibroblasts in the repair process of torn ligaments. PMID- 30466727 TI - OrthoBiologics in Sports Medicine: Real-Time Applications Are Here, and Future Developments Are Promising! PMID- 30466728 TI - Processing inflectional morphology: ERP evidence for decomposition of complex words according to the affix structure. AB - This study investigated the processing of inflectional morphology by registrating event-related brain potentials (ERPs) during sentence reading. In particular, we examined nouns combined with affixes that have distinct structural characteristics as proposed by morphological theory. Affixes were either complex consisting of functionally distinguishable subparts as occurring for German plural morphology, or simple consisting of one part only. To test possible differences in processing these affixes we compared grammatical nouns [e.g., Kartons (cartons)] to ungrammatical ones (e.g., *Kartonen) in two different syntactic contexts represented by a complex, or simple affix. The ERPs showed that ungrammatical nouns consisting of complex affixes elicited a left anterior negativity (LAN) reflecting enhanced morphosyntactic processing, which was absent for equivalent nouns consisting of simple affixes. This finding suggests that inflected words are decomposed dependent on the affix structure, whereby the affixes themselves seem to consist of morphological subparts in accordance with current morphological theories (Muller, 2007; Noyer, 1992). Moreover, ungrammatical nouns elicited early (reduced P200) and late (P600) ERP components relative to their grammatical equivalents, which implies an engagement of syntactic processes presumably based on intially enhanced pre-lexical processing of these irregularized nouns. The findings are discussed with respect to theoretical and neuropsychological accounts to inflectional morphology. PMID- 30466729 TI - RNA Splicing and Disease: Animal Models to Therapies. AB - Alternative splicing of pre-mRNA increases genetic diversity, and recent studies estimate that most human multiexon genes are alternatively spliced. If this process is not highly regulated and accurate, it leads to mis-splicing events, which may result in proteins with altered function. A growing body of work has implicated mis-splicing events in a range of diseases, including cancer, neurodegenerative diseases, and muscular dystrophies. Understanding the mechanisms that cause aberrant splicing events and how this leads to disease is vital for designing effective therapeutic strategies. In this review, we focus on advances in therapies targeting splicing, and highlight the animal models developed to recapitulate disease phenotypes as a model for testing these therapies. PMID- 30466730 TI - Knocking Out Enhancers to Enhance Epigenetic Research. PMID- 30466731 TI - GuttaFlow Bioseal promotes spontaneous differentiation of human periodontal ligament stem cells into cementoblast-like cells. AB - OBJECTIVES: To evaluate in vitro the cementogenic potential and the biological effects of GuttaFlow Bioseal, GuttaFlow 2, MTA Fillapex and AH Plus on human periodontal ligament stem cells (hPDLSCs). METHODS: Cell viability, cell migration and cell morphology assays were performed using eluates of each material. To evaluate cell attachment, hPDLSCs were directly seeded onto the material surfaces and analyzed by scanning electron microscopy (SEM). The effects of endodontic sealers on cementum protein 1 (CEMP1), cementum-derived attachment protein (CAP), bone sialoprotein (BSP), ameloblastin (AMBN), amelogenin (AMELX) and alkaline phosphatase (ALP) gene expression on hPDLSCs were investigated by qPCR and immunofluorescence (IF). Statistical analysis was performed with analysis of variance and Bonferroni or Tukey post-test (alpha<0.05). RESULTS: More than 90% of viable cells were obtained using extracts of GuttaFlow Bioseal and GuttaFlow2 after 72h of culture. By contrast, AH Plus and MTA Fillapex induced significantly lower levels of cell viability. GuttaFlow2 and GuttaFlow Bioseal promoted wound closure in a concentration-dependent manner, comparable to that observed with control extracts (*p<0.05). However, with AH Plus and MTA Fillapex, cell migration was significantly lower than in the control (***p<0.0001). SEM analysis pointed to an organized stress fiber assembly and high degree of cell adhesion on GuttaFlow Bioseal disks but low rates on GuttaFlow2, MTA Fillapex and AH Plus. When hPDLSCs were cultured with GuttaFlow Bioseal-conditioned media, qPCR assays and IF showed a higher level of AMELX, AMBN, CEMP1 and CAP expression than the control (*p<0.05)), whereas no such expression was observed in the other sealers. SIGNIFICANCE: Our results showed that GuttaFlow sealers were more cytocompatible than AH Plus and MTA Fillapex, while GuttaFlow Bioseal favored cementoblast differentiation of hPDLSCs in the absence of any growth factors. PMID- 30466732 TI - Open cornual resection versus laparoscopic cornual resection in patients with interstitial ectopic pregnancies. PMID- 30466733 TI - Corrigendum to "Mast cells improve functional recovery of transected peripheral nerve: A novel preliminary study" [Injury 48/7 (2017) 1480-1485]. PMID- 30466734 TI - A new classification of injury patterns of the medial patellofemoral ligament after acute lateral patella dislocation detected using magnetic resonance imaging studies. AB - INTRODUCTION: Acute lateral patellar dislocation is a very common condition in orthopedics, especially among adolescents and physically active patients. To evaluate distinct medial patellofemoral ligament (MPFL) injury patterns and the associated knee pathology after acute lateral patellar dislocation (ALPD) using magnetic resonance imaging (MRI) studies, which is essential for the development of treatment protocols. MATERIALS AND METHODS: MRI images of 74 ALPD patients were taken between January 2015 to December 2016. Images were evaluated using standardized protocols. RESULTS: The prevalence of MPFL injury following ALPD was 97.3% (72/74 patients). Among the 72 patients with MPFL, the prevalence of Type I injury was 26.4% (19/72). Since only bone marrow edema and a partial tear were showed on MRI of these patients, conservative treatment was given. Tear of the MPFL occurred at the patellar attachment (Type IIa) in 16 patients (16/72, 22.2%), at the middle area of the ligament (Type IIb) in 5 patients (5/72, 6.9%), and at the femoral attachment (Type IIc) in 27 patients (27/72, 37.5%). For Type II injuries, all patients had the surgery to reconstruct the MPFL. The prevalence of Type III MPFL injury was 6.9% (5/72) after the surgery. CONCLUSION: MPFL injury of is a common sequel following ALPD. We assessed the distinct injury pattern and associated pathology of MPFL using MRI studies. A good understanding of the injury pattern and associated knee pathology of MPFL is essential in managing patients with ALPD, especially if surgical intervention is considered. PMID- 30466735 TI - Pancreatic Stellate Cells Activation and Matrix Metallopeptidase 2 Expression Correlate With Lymph Node Metastasis in Pancreas Carcinoma. AB - BACKGROUND: This study aimed to investigate the correlation between pancreatic stellate cell activation, matrix metallopeptidase 2 (MMP2) expression and lymph node metastasis in pancreas carcinoma. METHODS: Alpha-smooth muscle actin (ACTA2), Desmin (DES) and MMP2 were detected in 40 pancreas carcinoma patients and 10 cases of normal pancreas tissues using immunohistochemistry. Then MMP2 and ACTA2 expression profiles in pancreatic cancer were obtained from UCSC (University of California, Santa Cruz) and SurvExpress. RESULTS: A total of 67.5% and 55.0% of cases positively expressed ACTA2 and DES in pancreas carcinoma, respectively. MMP2 in pancreas carcinoma was expressed in 55.0% of cases, and there were significant differences between the lymph node metastasis group and the lymph node nonmetastasis group, as well as invasion and noninvasion to the peripheral tissue group (P < 0.01). High throughput sequencing databases verified that ACTA2 and MMP2 gene expression were both upregulated in pancreatic carcinoma tissues. CONCLUSIONS: The coexpression of ACTA2 and DES was related to the expression of MMP2, and positively correlated with lymph node metastasis. Activation of pancreatic stellate cells may promote the expression of MMP2 and enhance the invasion and metastasis of pancreas carcinoma. PMID- 30466736 TI - Advanced Glycation End Products Stimulate Angiotensinogen Production in Renal Proximal Tubular Cells. AB - BACKGROUND: Elevated advanced glycation end products (AGE) in diabetes mellitus (DM) are implicated in the progression of DM-associated tissue injury, including diabetic nephropathy. The intrarenal renin-angiotensin system, in particular augmentation of angiotensinogen (AGT) in proximal tubular cells (PTC), plays a crucial role in the development of diabetic nephropathy. This study investigated hypothesis that AGE stimulates AGT production in PTC. MATERIALS AND METHODS: Urinary AGT and AGE levels in streptozotocin-induced DM mice were measured by enzyme-linked immunosorbent assays. AGT expression and secretion were evaluated in cultured rat PTC receiving 0-200 ug/ml AGE-BSA treatments for 24 hours. Furthermore, intracellular signaling pathways activated by AGE were elucidated. RESULTS: DM mice exhibited greater urinary AGT and AGE levels compared to control mice (AGT: 21.6 +/- 5.5 ng/day vs. 190.1 +/- 57.8 ng/day, AGE: 139.1 +/- 21.6 MUg/day vs. 332.8 +/- 102.7 MUg/day). In cultured PTC, treatment with AGE-BSA enhanced AGT mRNA expression (3.43 +/- 0.11-fold compared to control), intracellular AGT protein levels (3.60 +/- 0.38-fold), and secreted AGT levels (2.11 +/- 0.18-fold). On the other hand, AGT levels were not altered in PTC receiving nonglycated BSA. Recombinant soluble AGE receptor, which competes with endogenous AGE receptor, diminished the AGE-induced AGT upregulation, suggesting that AGE-BSA stimulates AGT expression via activation of the AGE receptor. Enhanced phosphorylation of ERK1/2 and c-Jun, but not p38 MAP kinase, were observed in AGE-BSA-treated PTC. AGE-induced AGT augmentation was attenuated by an ERK inhibitor. CONCLUSIONS: The findings indicate that AGE enhances proximal tubular AGT expression via ERK1/2, which can exacerbate the development of diabetic related kidney injury. PMID- 30466737 TI - Empyema Secondary to Transdiaphragmatic Extension of Pyogenic Liver Abscess. PMID- 30466738 TI - Long-term analysis of standard abdominal aortic endovascular repair using different grafts focusing on endoleak onset and its evolution. AB - OBJECTIVE: To report long-term results of standard EVAR focusing on endoleak onset (ELo) and its evolution. METHODS: 880 EVARs using different stentgrafts (1999-2015) were included. Primary outcomes were all-cause mortality and AAA related mortality. Timing of ELo after EVAR was categorized as follows: ELo1 = 0 2 years, ELo2 = 2-4 years, ELo3 = 4-6 years, ELo4 = 6-8 years, and ELo5 >= 8 years. The rate of sac shrinkage/sac expansion and the need to re-intervene were the variables considered to determine EL evolution. RESULTS: Median follow-up was 60 months (IQR: 36-84). Summary follow-up index was 0.99. Survival rate was 94.5% at 2 years, 57.7% at 10 years, 33.3% at 14 years. Freedom from AAA-related-death rate was 99.3% at 14 years. Freedom from endoleak was 86.4% at 2 years, 68.3% at 10 years, and 48.6% at 14 years. EL rate was 1.9% (n = 19),16.6% (n = 146), 0.8% (n = 7), and 0.4% (n = 4) for type I, II, III and IV, respectively. Only type II EL showed a significant difference in the ELo (Elo1 = 31%; ELo2 = 12.8%; ELo3 = 9.4%; Elo4 = 10.2%; Elo5 = 11.4%; P < .001). Sac shrinkage occurred in 791 (90%) patients while 89 (10%) had a persistent sac expansion at the last follow-up. Freedom from reintervention was 95.6% at 2 years, 86.4% at 10 years, and 80% at 14 years. 48 out of 176 (27.2%) patients with EL underwent reintervention. The re intervention rate was significantly higher within the first two years of follow up if compared to the following years (17.6% vs. <10%; P < .001). CONCLUSIONS: An active lifelong surveillance follow-up can guarantee good long-term EVAR outcomes. Reinterventions and type II EL were more frequent in the first two-year of follow-up. PMID- 30466739 TI - Patient-mediated interventions to improve professional practice: A summary of a Cochrane systematic review. AB - OBJECTIVE: To assess the effectiveness of patient-mediated interventions on healthcare professionals' performance. METHODS: We conducted a systematic Cochrane review according to established guidelines. We searched predefined databases in 2016 and 2017. Two review authors independently assessed studies for inclusion, extracted data, assessed risk of bias, performed meta-analyses, and assessed the certainty of the evidence (GRADE). RESULTS: We included 25 randomised studies with a total of 12 268 patients. We found that patient reported health information interventions and patient education interventions probably improve healthcare professionals' adherence to recommended clinical practice (moderate certainty evidence). We also found that patient information interventions may improve healthcare professionals' adherence to recommended clinical practice (low certainty evidence). Patient decision aids may make little or no difference to the number of healthcare professionals' adhering to recommended clinical practice (low-certainty evidence). CONCLUSION: Our findings strengthen the belief that patient-mediated interventions have the potential to improve professional practice, especially patient-reported health information interventions and patient education interventions. PRACTICE IMPLICATIONS: Our findings show that patient-reported health information interventions and patient education interventions are relevant approaches to improve professional practice. Thus, it seems reasonable to conclude that these types of patient-mediated interventions can contribute to improving the quality of healthcare services. PMID- 30466740 TI - The effect of freezing and thawing on water flow and MCPA leaching in partially frozen soil. AB - Limited knowledge and experimental data exist on pesticide leaching through partially frozen soil. The objective of this study was to better understand the complex processes of freezing and thawing and the effects these processes have on water flow and pesticide transport through soil. To achieve this we conducted a soil column irrigation experiment to quantify the transport of a non-reactive tracer and the herbicide MCPA in partially frozen soil. In total 40 intact topsoil and subsoil columns from two agricultural fields with contrasting soil types (silt and loam) in South-East Norway were used in this experiment. MCPA and bromide were applied on top of all columns. Half the columns were then frozen at 3 degrees C while the other half of the columns were stored at +4 degrees C. Columns were then subjected to repeated irrigation events at a rate of 5 mm artificial rainwater for 5 h at each event. Each irrigation was followed by 14 day periods of freezing or refrigeration. Percolate was collected and analysed for MCPA and bromide. The results show that nearly 100% more MCPA leached from frozen than unfrozen topsoil columns of Hov silt and Kroer loam soils. Leaching patterns of bromide and MCPA were very similar in frozen columns with high concentrations and clear peaks early in the irrigation process, and with lower concentrations leaching at later stages. Hardly any MCPA leached from unfrozen topsoil columns (0.4-0.5% of applied amount) and concentrations were very low. Bromide showed a different flow pattern indicating a more uniform advective dispersive transport process in the unfrozen columns with higher concentrations leaching but without clear concentration peaks. This study documents that pesticides can be preferentially transported through soil macropores at relatively high concentrations in partially frozen soil. These findings indicate, that monitoring programs should include sampling during snow melt or early spring in areas were soil frost is common as this period could imply exposure peaks in groundwater or surface water. PMID- 30466741 TI - Leaching and anaerobic digestion of poultry litter for biogas production and nutrient transformation. AB - Anaerobic digestion of poultry litter is a potentially sustainable means of stabilizing this waste while generating biogas. However, technical challenges remain including seasonality of litter production, low C/N ratios, limited digestibility of bedding, and questions about transformation of nutrients during digestion. This study investigated biogas production and nutrient transformations during anaerobic digestion of poultry litter leachate and whole litter. Use of fresh litter collected from within the house was also compared to waste litter cake that was stored outdoors on the farm. The results showed that litter leachates had higher biomethane potential (0.24-0.30 L/gVS) than whole litter (0.15-0.16 L/gVS) and the insoluble bedding material left after leaching (0.08 0.13 L/gVS). Leachates prepared from waste litter cake had lower uric acid and higher acetic acid concentrations than fresh litter indicating that decomposition had occurred during storage. Consequently, waste litter cake had faster initial biogas production but lower final biogas yields compared to fresh litter. In all reactors, uric and acetic acids were completely consumed during digestion, phosphate levels decreased but ammonium levels increased. The results demonstrate that poultry litter leachate is amenable to digestion despite a low C/N ratio and that the remaining insoluble bedding material has been partially stripped of its nutrients. Moreover, litter can be stored prior to digestion but some losses in biomethane potential should be expected due to decomposition of organics during storage. PMID- 30466742 TI - Mechanical properties and long-term durability of recycled polysulfone plastic. AB - In view of the recycling of PSU plastics has a good energy saving and environmental protection significance. This paper is concerned with the mechanical properties, and long-term durability of virgin and recycled polysulfone plastics (PSU) collected from wasted PSU nonwovens, the mechanical experiment of tensile test and Izod impact test are carried out to investigate the effect of cycle processing on the performance of PSU. The long-term durability of virgin and recycled PSU is studied base on time-temperature superposition by using a dynamic mechanical analysis (DMA). The thermal stability is evaluated by pyrolytic activation energy calculated by Iso-conversional kinetics method using a Thermogravimetric analysis (TGA). The results show that the recycled PSU exhibits the similar tensile property while lower impact strength than virgin PSU. The long-term durability and thermal stability of virgin PSU are better than recycled PSU and decreased with increasing the times of cycle processing, which is attributed to the mixing of impurities and degradation of the molecular structure in the recycling process. PMID- 30466743 TI - Progress and predictions: AML in 2018. AB - The FLT3 inhibitor midostaurin, the antibody-drug conjugate gemtuzumab ozogamicin, CPX-351 (liposomal daunorubicin and cytarabine), and the IDH2 inhibitor enasidenib are among the novel agents approved for use in the clinic this past year. This year, 2018, already has seen the regulatory approval of the BCL2 inhibitor venetoclax in the form of breakthrough designation and the IDH1 inhibitor ivosidenib received full FDA approval. Much remains to be learned about how best to use these drugs to improve patient outcomes and how best to employ and interpret next-generation sequencing to determine measurable residual disease (MRD) levels that can more accurately predict risk of relapse. PMID- 30466744 TI - What biologic factors predict for transformation to AML? AB - Transformation of myelodysplastic syndromes (MDS) into secondary acute myeloid leukemia (sAML) is defined by an arbitrary boundary of >=20% bone marrow blasts but does not necessarily reflect a defined biological transition. The more obvious distinction lies between MDS patients that have an isolated bone marrow failure phenotype and those with excess blasts. Subtyping of MDS might be more accurately stratified into clonal cytopenias and oligoblastic leukemias, using the degree of dysplasia and blast percentage as risk features, respectively, rather than as diagnostic criteria. Transformation from MDS to sAML often involves clonal evolution or expansion of existing subclones that can be assessed by changes in variant allele frequencies of the somatic mutations that define them. There are a number of predictors for transformation that have been identified: these include mutations of genes in growth signaling pathways (NRAS, KRAS, PTPN11, FLT3), mutations in genes more commonly observed in AML (NPM1, WT1, IDH2), certain cytogenetic abnormalities (monosomy 7, complex karyotype, loss of 17p). Gene expression profiles that divide MDS into two major categories identify a progenitor gene signature subtype associated with a high risk of AML transformation. Assessing for these genetic abnormalities may better identify MDS patients at greatest risk of transformation. PMID- 30466745 TI - The role of hypomethylating agents prior to hematopoietic cell transplantation in myelodysplastic syndromes. AB - Therapies for myelodysplastic syndromes (MDS) are chosen depending on whether a patient has lower- or higher-risk disease. Hypomethylating agents are recommended as up-front therapy for all higher-risk patients, and lower-risk patients with multiple cytopenias. This article reviews the rationale for hypomethylating agents, their use or intensive chemotherapy pre-transplant, and data supporting pre-transplant MDS treatment. PMID- 30466746 TI - Why and how to treat Ph-like ALL? AB - Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL), or BCR ABL1-like ALL, is a high-risk subtype of B-cell precursor ALL characterized by a gene expression profile similar to Ph-positive ALL, a high frequency of IKZF1 alterations, and poor outcome. The prevalence of Ph-like ALL is common among all ages, ranging from 10% to 15% in children to over 25% in young adults. Patients with Ph-like ALL harbor a diverse range of genetic alterations that activate cytokine receptor and kinase signaling and can be targeted with tyrosine kinase inhibitors. The majority of Ph-like ALL alterations are divided into two main groups based on activation of ABL-class or JAK-STAT alterations. Accordingly, preclinical studies and anecdotal reports suggest patients harboring ABL-class fusions are candidates for ABL1-inhibitors, whilst alterations activating the JAK STAT pathway may be amenable to treatment with JAK inhibitors. Diagnostic screening approaches and precision medicine trials are now being developed and implemented to test the efficacy of targeted therapy with a backbone of chemotherapy, similar to the treatment of Ph-positive ALL. PMID- 30466747 TI - Allogeneic transplantation for patients with Philadelphia chromosome positive acute lymphoblastic leukemia: Is it imperative in the tyrosine kinase inhibitor era? AB - Before the advent of tyrosine kinase inhibitors (TKIs), Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) was associated with dismal survival without allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recent evidence has demonstrated that the combination of TKI and chemotherapy can result in a high rate of complete remission, thereby enabling more patients to proceed to allo-HSCT. However, with more studies reporting non-inferior outcomes with TKI and chemotherapy combination without allo-HSCT, the need for allo-HSCT in Ph+ ALL has become less certain. This review summarizes evidence that will address the relevance of allo-HSCT in Ph+ ALL. PMID- 30466748 TI - Can one target T-cell ALL? AB - Progress in our understanding of the central genes, pathways, and mechanisms in the pathobiology of T-cell acute lymphoblastic leukemia (T-ALL) has identified key drivers of the disease, opening new opportunities for therapy. Drugs targeting highly prevalent genetic alterations in NOTCH1 and CDKN2A are being explored, and multiple other targets with readily available therapeutic agents, and immunotherapies are being investigated. The molecular basis of T-ALL is reviewed here and potential targets and therapeutic targets discussed. PMID- 30466749 TI - Should immunologic strategies be incorporated into frontline ALL therapy? AB - Survival rates in adult patients with acute lymphoblastic leukemia (ALL) have markedly improved during the past decade. The one-size-fits-all-ages approach has been replaced with adaptation of pediatric-inspired treatment protocols for younger adults. Yet different treatment strategies for older patients are needed due to chemotherapy-related toxicities. A new era of immunotherapy has arrived, offering opportunities for targeted treatments for ALL subtypes. While CD20 targeting with rituximab has been demonstrated to improve survival when combined with chemotherapy, it has little activity as a single agent in ALL. In contrast, antibody targeting of CD19 and CD22 with blinatumomab and inotuzumab ozogamicin, respectively, has had remarkable single-agent activity in the relapsed setting. Studies are now underway to test these agents in combination with chemotherapy in the frontline setting. The goal of these studies is to improve event-free survival and overall survival by using these approaches in the frontline to eradicate minimal residual disease and, particularly in older adults with ALL, to reduce treatment-related toxicity by limiting the exposure to traditional multi agent chemotherapy with its attendant toxicities. This review focuses on new immunotherapeutic treatment options and strategies for frontline treatment, including a brief discussion of the use of true immunotherapy, chimeric antigen receptor T-cells, for relapsed B-cell ALL, the potential for targeting CD38 in T cell ALL, and how these approaches are facilitating the next steps to improve survival for adult patients with ALL. PMID- 30466750 TI - Identifying patients with genetic predisposition to acute myeloid leukemia. AB - Germline syndromes in myeloid leukemias are being discovered increasingly in patients, and their identification is essential for proper medical management to yield positive health outcomes for patients and their families. There needs to be a greater appreciation of germline predisposition driving the development of hematologic malignancies within the field of myeloid malignancies. Characterization of the influence of germline mutations on the development of myeloid malignancies is ongoing by utilization of next generation sequencing data and prognostic panels. Here, we propose modifications to the utilization and analysis of genetic results, specifically to have a high index of clinical suspicion for germline predisposition, to use assays that are comprehensive for detection of these variants, and a few caveats to interpreting sequencing data. Presented are the benefits and shortcomings of prognostic panels and clinical examples of the utilization of the prognostic panel used within the Department of Pathology at The University of Chicago. The examples demonstrate that panels performed for prognostication on DNA derived from malignant cells are able to identify patients with germline syndromes, but they can lack coverage for genes that confer inherited susceptibility. Furthermore, the panels are often not designed to find duplication and deletion mutations, which calls for a need to improve assay design and bioinformatic approaches to interpret such variants using these data. PMID- 30466751 TI - Patterns of mutations in TP53 mutated AML. AB - TP53 mutated acute myeloid leukemia (AML) responds poorly to chemotherapy and has a short overall survival rate with a median of 5-9 months. Poor outcomes in TP53 mutated AML following chemotherapy have been observed and treatment options remain limited, although the presence of TP53 mutations alone should not be a barrier to therapy. Decitabine is emerging as an alternative treatment option for patients with TP53 mutated AML, although the agent has not been associated with deep molecular remissions and requires additional consolidation. The clinical and genomic characteristics of TP53 mutated AML are reviewed in this paper. PMID- 30466752 TI - Is there a standard of care for relapsed AML? AB - Despite advances in treatment for acute myeloid leukemia (AML), the prognosis for patients with relapsed disease is extremely poor. The median overall survival for patients with relapsed AML ranges from 4-6 months and long-term survival from the time of relapse ranges from 5%-20%. Much of the difficulty in establishing a standard of care for relapsed AML is that the disease is clinically and genomically diverse. Nevertheless, significant progress has been made over the past 12 months with the approval of several agents, and the expectation is that additional therapies will be available soon. A brief review follows on the progress made in establishing a standard of care for relapsed AML. PMID- 30466753 TI - Is the overall survival for older adults with AML finally improving? AB - Older adults with acute myeloid leukemia (AML) traditionally have very poor survival outcomes. Those who receive only supportive care have worse overall survival than those who undergo treatment, regardless of treatment type, and improvements in overall survival in the last several decades are largely attributable to the increasing decision to treat rather than offer only supportive care. However, there are a few newer agents that appear promising; these include CPX-351 (a liposomal product with cytarabine and daunorubicin), glasdegib (a selective Hedgehog signaling pathway inhibitor), and venetoclax (potent small molecule inhibitor of BCL2). A systematic review and meta-analysis is being completed to help clinicians optimize standard therapies for older AML patients. PMID- 30466754 TI - Which novel agents for acute myeloid leukemia are likely to change practice? AB - There has been little progress in drug development in acute myeloid leukemia (AML) in the recent past. This recently changed with the approval of several therapies for patients with this disease and prompts one to consider which therapies may change practice for patients with AML. To change practice, a therapy must be adopted as a standard of care intervention based on its efficacy and safety profile and must endure as the accepted treatment for a particular indication for a significant period of time. Here I attempt to determine which therapies, approved or in development, may change practice in the field of AML. PMID- 30466755 TI - Is it time to routinely incorporate MRD into practice? AB - Interest in detecting minimal/measurable residual disease (MRD) in acute myeloid leukemia (AML) has been increasing, but numerous issues need to be addressed if MRD assessment is to be routinely incorporated into practice. Assays, their reliability, standardization, and availability all must be considered, and a strategy developed to eradicate residual leukemia. This paper reviews some issues surrounding the routine incorporation of MRD assessment into practice. PMID- 30466756 TI - What FLT3 inhibitor holds the greatest promise? AB - Determining which FLT3 inhibitor holds the greatest promise is a difficult task, as the drugs vary according to potency, specificity, protein-binding, drug interactions, and side effect profile. The best choice depends on when in the course of the disease the inhibitor will be used. Moreover, as the results of ongoing trials become available, newer agents could supplant former 'best' drugs. This paper reviews FLT3 inhibitors in combination with chemotherapy early in the disease in FLT3 mutant patients, as single agents or in combination in advanced disease, or in the post-transplant setting to provide separate answers to the main question. PMID- 30466757 TI - Hematopoietic cell transplantation as treatment of patients with acute myeloid leukemia with measurable residual disease after consolidation therapy. AB - The persistence of measurable residual disease (MRD) following induction chemotherapy is the single most powerful prognostic factor available to clinicians treating patients with acute myeloid leukemia (AML). How to use this information to guide subsequent therapy is complex, and influenced by the category of AML being treated, the assays used to measure MRD, MRD levels and kinetics, and the spectrum of therapies available to the patient. In this literature-based review, each of these issues will be discussed, with a particular emphasis on the role of hematopoietic cell transplantation in the treatment of MRD-positive patients. PMID- 30466758 TI - Can haploidentical transplantation meet all patients' needs? AB - Allotransplantation in the absence of an HLA-matched sibling donor can offer numerous donor options including unrelated donor and umbilical cord blood grafting. Recently, haploidentical transplantation has exploded in popularity and worldwide use following the application of post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis. Various approaches, disease states, conditioning intensities and supportive care advances have improved all these choices without demonstrable superiority of one approach versus the others. However, PTCy limits risks of GVHD; bone marrow over peripheral blood stem cells limits risks of chronic GVHD, which suggests that both these promising techniques can inform these donor and graft choices. Formal and prospective data will answer whether situationally adapted best options-tailored to each patient's disease risk and comorbidity status-will help guide future decision-making to improve patient outcomes with the least cumulative morbidity. PMID- 30466759 TI - Why is a 3-year NRM following allogeneic transplantation still stuck at approximately 20%? AB - Whether and when to recommend an allogeneic stem cell transplant (SCT) for a patient with leukemia is a treatment decision that rests on determining whether the transplant or non-transplant option carries the greatest probability of 3-5 year survival. While SCT confers a greater possibility of leukemia cure, the decision to transplant has to be made in the light of the high chance of treatment-related mortality (TRM) that follows the allograft. Here we identify that current estimates of a 20% 3-year TRM hold largely true for a variety of leukemias, diverse types of conditioning regimen, and varied donor-recipient compatibility across a wide age-range. While there is a wide spectrum of causes of death in the first few months after SCT, they usually stem from a limited set of immediate post-transplant complications, including those induced by the conditioning regimen, post-transplant endovascular damage, gut dysbiosis, graft versus-host disease, and immunodeficiency causing viral reactivation. As we better understand and improve preventative treatments for these initiating events there is a real expectation that TRM will continue to fall to levels well below 10% within the next decade. PMID- 30466760 TI - Clinical features of poorly differentiated thyroid papillary carcinoma. AB - OBJECTIVE: To investigate the clinical feature of the poorly differentiated thyroid papillary carcinoma. METHODS: We investigate retrospectively 276 thyroid papillary carcinoma patients who underwent initial treatment at our Department who underwent initial treatment at our Department during the 13-year period from 2000 to 2012. We examine the pathological samples of papillary carcinoma retrospectively to investigate the prevalence of a poorly differentiated component in the tumor. Then the disease-specific survival rate, metastasis-free survival rate, and relapse-free survival rate were compared between patients with or without a poorly differentiated component. In addition, well differentiated carcinoma and poorly differentiated carcinoma were compared in relation to the age, sex, TNM stage, and recurrent laryngeal nerve infiltration. RESULTS: It was considered appropriate to define tumors with a poorly differentiated component of 10% or more as poorly differentiated carcinoma. There was a significant difference of the T classification but not the N classification between well and poorly differentiated thyroid papillary carcinomas. The disease-specific survival rate, metastasis-free survival rate, and relapse-free survival rate of patients with poorly differentiated carcinoma was significantly lower than that of patients with well differentiated carcinoma, and we considered that this might be due to the higher frequency of local infiltration in patients with poorly differentiated tumors. CONCLUSION: The higher relapse rate compared with well differentiated carcinoma suggests that careful postoperative follow-up of patients with poorly differentiated carcinoma is important, particularly surveillance of distant metastasis. PMID- 30466761 TI - Promoting a nursing team's ability to notice intent to communicate in lightly sedated mechanically ventilated patients in an intensive care unit: An action research study. AB - OBJECTIVES: This study aimed to examine changes in the practice of nurses who received an intervention designed to increase their awareness of endotracheally intubated, lightly sedated mechanically ventilated patients' intent to communicate. RESEARCH METHODOLOGY: Action research was applied. Specifically, three interventions promoting awareness of patients' intent to communicate were administered and pre- and post-intervention, observations of patient-nurse interactions, unstructured interviews with nurses and a patients' satisfaction survey were conducted. The pre- and post-intervention patient-nurse interactions and patients' survey results were then compared and a content analysis of the interviews and field notes was performed. SETTING: The intensive care unit of a university hospital. MAIN OUTCOME MEASURE: Nurses' awareness of lightly sedated mechanically ventilated patients' intent to communicate. FINDINGS: After the intervention, the incidence-rate ratios for nurses noticing of patients' intent to communicate were 1.53; there was no change in the frequency of patients' intent to communicate. Further, nurses became more aware of and reflected on their own practices, showed increased interest in co-workers' practices and considered their actions from patients' perspectives. Patients' satisfaction with nurses' respect for their wishes and dignity also increased. CONCLUSIONS: Action research can induce a change in intensive-care-unit-based nursing practice towards patient-centred care. PMID- 30466762 TI - Violence and aggression in the intensive care unit: What is the impact of Australian National Emergency Access Target? AB - INTRODUCTION: Violence in healthcare settings is a concern for healthcare professionals and patients. Media reports, and debate within the healthcare profession, and the academic literature infer that workplaces such as intensive care units are becoming exposed to increasing violence. Increases in the incidence of violent behaviour are sometimes attributed to the increased pressure on emergency departments to accelerate the throughput of patients to meet targets. To ensure the wellbeing of patients and staff, there is a need to evaluate the impact of such targets. The aim in this study was to evaluate the incidence and to describe the context in which patients' aggressive and violent behaviours occurred since the introduction of the National Emergency Access Target in a local tertiary Australian intensive care unit. METHODS: A retrospective examination of events triggering violence-related emergency codes from 12 months before the introduction of the National Emergency Access Target up until 12 months after its implementation (2011-2013). RESULTS: A small increase in the number of Code Grey/Code Black activation was identified after the introduction of the target (before = 18, after = 29). Admissions following drug overdoses, isolated head trauma, and cardiac arrest were the presentations most likely to have been associated with a violence-related emergency call. Female registered nurses, male critical care registered nurses, and clinical nurse specialists were the most at risk of occupational violence. Male nursing staff members were found to be more likely to be involved in incidences of verbal violence (p < 0.003). CONCLUSION: Although there was a minimal increase in the overall number of emergencies triggered by violent behaviour, valuable information on the type of occupational violence occurring towards healthcare professionals and patients in this setting was found. We suggest that these findings add further important detail to the existing understanding of the problem of occupational violence. These detailed insights can further inform policy development, professional education, and practice. PMID- 30466763 TI - Liposomal amphotericin B pharmacokinetics in a patient treated with extracorporeal membrane oxygenation. PMID- 30466764 TI - Expression and significance of CD47, PD1 and PDL1 in T-cell acute lymphoblastic lymphoma/leukemia. AB - Although dose intensification strategies achieve a favorable prognosis for pediatric patients of T-lmphoblastic lymphoma/leukemia (T-LBL/ALL), numerous side effects have been followed. Molecular targeted therapies will be needed to optimize the current treatment strategy for T-LBL/ALL. The aim of this study was to analyse expression and significance of CD47, PD1 and PDL1 in. T-LBL/ALL. We performed immunohistochemistry staining and real time fluorescence quantitative PCR (qRT-PCR) on FFPE tissues. Immunohistochemistry results showed that the high expression rate of CD47 protein was 46.4% (26/56) and the positive expression rate of PDL1 protein was 37.5% (21/56). PD1 expression was observed in tumor infiltrating lymphocytes in approximately 20% of T-LBL/ALL patients, but not expressed on tumor cells of T-LBL/ALL. And the results of qRT-PCR showed that the relative expression levels of CD47, PDL1 and PD1 mRNA in 56 cases of T LBL/ALL were significantly higher than those in control group (6.915 vs 4.050, 12.255 vs 2.575, 37.990 vs 3.615), and the differences were all statistically significant (p all <0.05). Univariate analysis showed that age, CD47 protein, CD47 mRNA,PDL1 protein and PDL1 mRNA expression were closely correlated with prognosis (P all <0.05). We found that the overall one-year survival rates of patients with a high expression (>=M) of CD47 and PDL1 mRNA were higher than in patients with low expression (=M) of CD47 and PDL1 protein were lower than in patients with low expression (25 years old. Multivariate Cox regression analysis showed that the high expression of CD47 and PDL1 protein were independent prognostic factors (both p < 0.05). In a word, PD1/PDL1 and CD47 may be involved in the disease progression and prognosis of T-LBL/ALL, and detection and targeting of CD47 and PD1/PDL1 may provide a rational basis to for treatment of T-LBL/ALL. PMID- 30466765 TI - The prognostic role of tumor associated glycoprotein 72 (TAG-72) in stage II and III colorectal adenocarcinoma. AB - Tumor associated glycoprotein 72 (TAG-72) is a membrane-bound glycoprotein complex that is overexpressed in many adenocarcinomas. Recently, monoclonal antibody targeting TAG72, minretumomab, have been introduced as a potential therapeutic target in colorectal cancers (CRC) as well as breast and lung cancers. However, the detailed expression profile of TAG72 and its prognostic effect in CRC are not clear yet. We investigated the relationship between tumor associated glycoprotein 72 (TAG-72) expression and clinicopathologic characteristics in CRC using 3E8 antibody, a fully humanized antibody with the highest affinity to TAG-72. Immunohistochemical staining for TAG-72 was performed in 578 CRC patients, and the results were analyzed using a modified Remmele scoring system (score: 0-12). Of the 578 patients, 144 (24.9%) composed the TAG 72 overexpression (TAG-72high) group. TAG-72high was significantly associated with microsatellite stable tumor (P = .002), lymphatic invasion (P = .001), venous invasion (P = .005), and high pN status (P < .001). In survival analyses, TAG-72high group showed shorter disease-free survival in univariate analysis (P = .001), and TAG-72high was found to be an independent prognostic factor in multivariate analysis (P = .028), in addition to TNM stage. In conclusion, TAG-72 is thought to be the factors involved in the progression of CRC and may be considered as one of the potential therapeutic target. PMID- 30466766 TI - Comprehensive analysis of tumor immune infiltration associated with endogenous competitive RNA networks in lung adenocarcinoma. AB - Cancer immunotherapy has achieved unprecedented success in the treatment of cancer. However, different patients have different responses to immunotherapy. More and more studies have shown that tumor immune heterogeneity has an important influence on the prognosis of cancer. Therefore, understanding the clinical impact of tumor immune infiltration and the regulatory mechanism of RNA molecules is crucial for exploring the pathogenesis of lung adenocarcinoma (LUAD) and the development of immunotherapy protocols.The endogenous competitive RNA hypothesis provides new ideas for studying immune heterogeneity. Therefore, by using the method of immune genomics, this article explores the relationship between immune infiltration and prognosis of patients with lung adenocarcinoma, and found that B cell immune infiltration highly affects the survival of patients. Through differential analysis, differential mRNAs, lncRNAs and miRNAs were extracted, and 318 differentially expressed mRNAs related to B cell immunity were screened by correlation analysis, and prognosis of patients with COX risk regression model was predicted and analyzed. Through multiple database searches, an immune-related ceRNA regulatory network was constructed, containing 3 key mRNAs, 4 miRNAs, and 50 lncRNAs. Three mRNAs and most miRNAs, lncRNAs, are significantly associated with LUAD prognosis. Bioinformatics analysis of the network showed that LINC00337 may up-regulate the expression of PBK and KIF23 through competitive binding of has-mir-373 and has-mir-519d. The competitive binding of has-mir-373 and has-mir 372 can up-regulate the expression of SLC7A11. The interaction between these RNAs may have an important regulatory role in the immune infiltration in lung adenocarcinoma, thereby affecting the patient's prognosis and immunotherapy efficacy. PMID- 30466767 TI - Newborn Screening for Severe Combined Immunodeficiency in the United States: Lessons Learned. AB - In the United States, significant improvement in diagnosis and outcomes for children affected with severe combined immunodeficiency has followed institution of newborn screening using an assay to measure T-cell receptor excision circles in newborn dried blood spot specimens. Key to this outcome is the avoidance of infectious complications in infants with severe combined immunodeficiency. PMID- 30466768 TI - Update on Advances in Hematopoietic Cell Transplantation for Primary Immunodeficiency Disorders. AB - Hematopoietic stem cell transplantation (HSCT) in patients with primary immunodeficiency disorders (PIDDs) is being increasingly used as a curative option. Understanding the critical components, such as disease's nature and activity and pre-HSCT and post-HSCT patient care is key to a successful outcome. HSCT should be tailored to the underlying PIDD, as different PIDDs, such as severe combined immune deficiency, Treg dysfunction, and phagocytic disorders, have different transplant approaches. Therefore, successful HSCT in patients with PIDDs requires teamwork between immunologists and transplant physicians. In this article, the authors elaborate on various aspects of PIDD-HSCT and highlight recent advances. PMID- 30466769 TI - Genetic Testing to Diagnose Primary Immunodeficiency Disorders and to Identify Targeted Therapy. AB - Since the first genes associated with primary immunodeficiency were described in the early 1990s, there has been an exponential increase the number of genes found to have pathologic variants in patients with symptoms of primary immunodeficiency. Genetic testing currently used clinically includes chromosomal microarray, Sanger sequencing, and next-generation sequencing techniques, including whole exome testing. With the knowledge of the underlying molecular pathways, biologic therapies have been used for treatment and efforts are underway to broaden the availability of gene therapy. PMID- 30466770 TI - Hereditary Autoinflammatory Disorders: Recognition and Treatment. AB - The autoinflammatory diseases encompass approximately 30 monogenic disorders in which inborn errors in the innate immune system lead to episodic systemic inflammation. Largely mediated by dysregulation of myeloid cells, interleukin (IL)-1beta, type I interferon, and NF-kappaB, these disorders have rapidly expanded over the past several years, and increasing numbers of patients identified. Crossover disorders, bridging autoinflammation and immunodeficiency, have recently been described. This article focuses on the clinical presentation of IL-1 and interferon-driven autoinflammatory disorders, and discusses novel diseases with features of immunodeficiency. Approaches to the clinical diagnosis, genetic testing, and treatment of these disorders are addressed. PMID- 30466771 TI - Secondary Hypogammaglobulinemia: An Increasingly Recognized Complication of Treatment with Immunomodulators and After Solid Organ Transplantation. AB - Secondary hypogammaglobulinemia is a common development in patients treated with immunomodulatory agents for autoimmune, connective tissue, and malignant diseases. It has been observed in the medical management of patients undergoing hematopoietic stem cell and solid organ transplantation. Some patients have preexisting immunodeficiency associated with these illnesses; immunosuppressive treatment magnifies their immune defect. This article reviews immunosuppressive medications, including biological treatments that cause secondary hypogammaglobulinemia. It summarizes risk factors for rituximab-induced hypogammaglobulinemia, such as preexisting low immunoglobulin G levels, CD19 levels, host factors, and additive effect of all immunomodulatory drugs used. The evaluation and management of secondary hypogammaglobulinemia are discussed. PMID- 30466772 TI - An Update on Syndromes with a Hyper-IgE Phenotype. AB - Improvement in genetic testing has allowed specific delineation of several distinct clinical causes characterized by the hyperimmunoglobulin E (IgE) phenotype of eczema, recurrent infections, and elevated serum IgE. Mutations in STAT3, DOCK8, PGM3, ERBIN, IL6ST, and CARD11 cause clinical phenotypes that can present in this manner. This article focuses on loss of function STAT3 mutations causing autosomal-dominant hyper-IgE syndrome and dedicator of cytokinesis 8 deficiency, with discussion of other more recently described diseases. PMID- 30466773 TI - Early-Onset Inflammatory Bowel Disease. AB - The epidemiology of inflammatory bowel disease has changed over the past 4 decades. The incidence is rising dramatically and the age of onset has become younger. This changing landscape of inflammatory bowel disease reflects the new recognition that the youngest children with inflammatory bowel disease are enriched in cases with underlying primary immunodeficiency and monogenic causes. The management of these cases can be quite different, with specific genetic etiologies supporting unique interventions and some requiring hematopoietic cell transplantation for effective treatment. PMID- 30466774 TI - Gastrointestinal Manifestations and Complications of Primary Immunodeficiency Disorders. AB - Gastrointestinal (GI) involvement can be the presenting disease manifestation in patients with primary immunodeficiency disorders (PIDs). Infections and noninfectious diarrhea are frequent manifestations; however, malignancy and inflammatory and autoimmune-related GI diseases are also described. GI symptoms and disease seen in association with PIDs can mimic other diseases but are often resistant to conventional treatments owing to alternate disease mechanisms. Despite the advances in treatments for these conditions, therapy for immunodeficiency-related GI disease is often empiric. PMID- 30466776 TI - Diagnosis and Management of Primary Immunodeficiency Disorders: The Pieces of the Puzzle Are Starting to Fit Together. PMID- 30466775 TI - Personalized Therapy: Immunoglobulin Replacement for Antibody Deficiency. AB - Immunoglobulin replacement therapy is the cornerstone of management for most primary immunodeficiency disease patients. The selection of a particular product, dose, and route of administration requires an understanding of the features of therapeutic immunoglobulin as well as patient-specific risk factors in order to maximize efficacy and tolerability and minimize risk. Individualizing therapy, taking into consideration the burdens of care, is necessary in order to optimize patient outcomes. PMID- 30466777 TI - Primary Immunodeficiency Disorders. PMID- 30466778 TI - [Aripiprazole as dopamine partial agonist model: Basic concepts and clinical impact]. AB - Aripiprazole may be viewed as the prototype of third-generation antipsychotics. This concept is based on the notion of D2 partial agonism, whereas all molecules of first-and second generation were D2 antagonists. After reviewing the basic pharmacological notions linked to such concepts, the mechanisms of action of these molecules are addressed, with a particular focus on functional selectivity and biased ligand. One of the essential pharmacological properties of D2 agonists, and particularity aripiprazole, is their ability to not induce D2 supersensitivity as well as to reverse this supersensitivity when it has been induced by D2 antagonists. In clinical practice, this impacts the choice of treatment in first episode psychosis as well as in refractory schizophrenia. Animal research shows that D2 supersensitivity could contribute to worsen addictive trends. The pharmacokinetic incidence of D2 supersensitivity tends to favour the long-acting forms of partial agonists. The notion of partial agonism could finally lead to design fourth-generation antipsychotics, on the basis on research focusing on functional selectivity. PMID- 30466779 TI - Indoor ozone levels, houseplants and peak expiratory flow rates among healthy adults in Taipei, Taiwan. AB - The association between houseplants and indoor air quality improvement has been reported in previous studies. However, the effect of houseplant-emitted isoprene on the association between ozone (O3) formation and respiratory health remains unclear. We recruited 60 adult subjects from 60 houses with or without houseplants (1:1) in Taipei; twelve house visits were conducted in each home throughout 2014. The indoor air pollutants that were measured consisted of particulate matter less than or equal to 2.5 MUm in diameter (PM2.5), O3 and isoprene. Peak expiratory flow rate (PEFR) was measured in each study subject during each house visit. Household information was collected by a questionnaire. Mixed-effects models were used to explore the association between indoor air pollution levels and PEFR. We found that the concentrations of O3 and isoprene in houses with houseplants were higher than those in houses without houseplants. In contrast, PM2.5 levels and % predicted PEFR were higher in houses without houseplants than in those with houseplants. Moreover, increased levels of O3 and PM2.5 in houses with houseplants were associated with a decreased % predicted PEFR, especially in the summer. We concluded that increased levels of indoor O3 and PM2.5 were associated with decreased PEFR. The presence of houseplants was associated with indoor O3, isoprene and PEFR variations in the summer. PMID- 30466780 TI - ECMO in severe trauma patient with intracranial bleeding requiring surgery. PMID- 30466781 TI - Attenuation of zinc-enhanced inflammatory M1 phenotype of microglia by peridinin protects against short-term spatial-memory impairment following cerebral ischemia in mice. AB - Activated microglia exhibit two opposite activation states, the inflammatory M1 and the anti-inflammatory M2 activation states. In the mammalian brain, ischemia elicits a massive release of zinc from hippocampal neurons, and the extracellular zinc primes M1 microglia-by inducing reactive oxygen species (ROS) generation-to enhance their production of proinflammatory cytokines, which ultimately results in short-term spatial memory impairment. Here, we examined how peridinin, a carotenoid in dinoflagellates, affects the zinc-enhanced inflammatory M1 phenotype of microglia. Treatment of microglia with 30-300 ng/mL peridinin caused a dose-dependent attenuation of zinc-enhanced interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNFalpha) secretion when M1 activation was induced by lipopolysaccharide exposure. Moreover, peridinin inhibited the increase in ROS levels in zinc-treated microglia without directly interacting with zinc. Notably, when mice were administrated peridinin (20-200 ng/animal) intracerebroventricularly 5 min before cerebral ischemia-reperfusion, the peridinin treatment not only suppressed the increase in expression of IL-1beta, IL-6, TNFalpha, and the microglial M1 surface marker CD16/32, but also protected the mice against ischemia-induced short-term spatial-memory impairment. Our findings suggest that peridinin prevents extracellular zinc-enhanced proinflammatory cytokine secretion from M1 microglia by inhibiting the increase in microglial ROS levels, and that this anti-inflammatory effect of peridinin might result in protection against deficits in short-term spatial memory. PMID- 30466782 TI - Prolonged MEK inhibition leads to acquired resistance and increased invasiveness in KRAS mutant gastric cancer. AB - Gastric cancer (GC) is one of the most common causes of cancer-associated death. However, traditional therapeutic strategies have failed to significantly improve the survival of patient with advanced GC. While KRAS mutations have been found in some patients with gastric cancer, an effective therapy to treat KRAS-driven gastric cancer has not been established yet. To provide a rationale for clinical application of kinase inhibitors targeting RAS pathways, we first determined the sensitivity of GC cell lines harboring KRAS mutations or amplification to RAS pathway inhibitors. We found that MAPK pathway inhibitors (MEKi and ERKi) were more effective than AKT inhibitor, suggesting that KRAS-driven gastric cancer cells are dependent on MAPK pathway for survival. Further, we established a KRAS mutant GC cell line with acquired resistance to MEK inhibitors in order to mimic clinical situation of kinase inhibitor resistance. A comprehensive analysis of tyrosine phosphorylation in receptor tyrosine kinases in combination with small molecule chemical library screening revealed upregulated c-MET phosphorylation in this resistance cell line with elevated sensitivity to c-MET TKI (crizotinib) and PI3K/mTOR dual inhibitor (BEZ235). We also showed that migration and invasion of resistant cells were promoted, and crizotinib and BEZ235 could inhibit this malignant phenotype. Overall, our results indicate that prolonged MAPK pathway inhibition could result in acquired resistance which is associated with increased malignant phenotype in KRAS mutant GC and pharmacological targeting c-MET and PI3K/mTOR could overcome this problem. PMID- 30466783 TI - Overexpression of sialidase NEU3 increases the cellular radioresistance potential of U87MG glioblastoma cells. AB - The plasma membrane-associated sialidase NEU3 is known to play important roles in different physiological and pathophysiological processes such as proliferation, cellular differentiation and tumorigenesis. Up-regulation of NEU3 has been associated to several tumors and recently it was demonstrated that its down modulation in glioblastoma cells promotes cell invasiveness. To date, no information concerning the possible role played by NEU3 in relation to tumor radioresistance is available. Here we show that overexpression of NEU3 in glioblastoma U87MG cells activates PI3K/Akt signaling pathway resulting in an increased radioresistance capacity and in an improved efficiency of double strand DNA-repair mechanisms after irradiation. Our results demonstrate for the first time that NEU3 contributes to the radioresistance features of U87MG cells, bringing to evidence a novel rand peculiar role of the enzyme in cancer biology. PMID- 30466784 TI - Effect of hypoxia/reoxygenation on the biological effect of IGF system and the inflammatory mediators in cultured synoviocytes. AB - Hypoxia/reoxygenation (H/R) plays an important role in the pathogenesis of osteoarthritis. Fibroblast-like synoviocytes (FLS), which are highly sensitive to H/R, are thought to be associated with cartilage degradation during osteoarthritis development. In this study, we investigated the biological effects of insulin-like growth factor (IGF) system and the expression of inflammatory mediators in FLS. We also pretreated FLS with tumor necrosis factor-alpha (TNF alpha) before H/R in order to observe the response of FLS with the background of inflammatory cytokines. H/R increased the levels of TNF-alpha-induced C-C chemokine ligand 5 (CCL5), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) in cell-free culture supernatants; H/R also increased the expression of TNF-alpha induced insulin-like growth factor binding protein 3 (IGFBP-3), downregulated the expression of insulin-like growth factor 1 (IGF-1), promoted the loss of mitochondrial membrane potential (MMP), the openness of mitochondrial permeability transition pore (MPTP), the release of intracellular reactive oxygen species (ROS), and mitochondrial matrix swelling, outer membrane rupture and decrease in cristae. Furthermore, H/R induced the expression of catabolic factors and activated the NF-kappaB signaling pathway in FLS. We therefore concluded that H/R may play a role in inducing inflammation and increase the TNF-alpha-induced inflammatory effect in FLS, contributing to osteoarthritis pathogenesis. PMID- 30466785 TI - Valproic acid suppresses Warburg effect and tumor progression in neuroblastoma. AB - Altered glucose metabolism is a hallmark for cancer, which is characterized by a unique metabolic phenotype known as Warburg effect or aerobic glycolysis. Emerging studies show that valproic acid (VPA), an established histone deacetylase inhibitor, possesses tumor suppressive properties. However, the effects of VPA on the regulation of Warburg effect in neuroblastoma (NB), the most common extracranial malignancy in childhood, still remain elusive. In this study, we show that VPA inhibits the aerobic glycolysis in NB cells by decreasing glucose uptake and reducing lactate and ATP production. Mechanistically, VPA suppresses aerobic glycolysis via reducing the levels of E2F transcription factor 1 (E2F1), resulting in repressed expression of glycolytic genes glucose-6 phosphate isomerase (GPI) and phosphoglycerate pinase 1 (PGK1). Rescue experiments show that VPA inhibits the aerobic glycolysis and NB progression through down-regulation of E2F1. These results demonstrate that VPA suppresses the Warburg effect and tumor progression, indicating a novel therapeutic strategy for NB. PMID- 30466786 TI - PKA-dependent phosphorylation of IP3K-A at Ser119 regulates a binding affinity with EB3. AB - Microtubule-associated end-binding protein 3 (EB3) accumulates asymmetrically at the tip-end of growing microtubules, providing a central platform for linking various cellular components. EB3 orchestrates microtubule dynamics and targeting, enabling diverse processes within neurons. Inositol 1, 4, 5-trisphosphate 3 kinase A (IP3K-A; also known as ITPKA) is a neuron-enriched protein that binds to microtubules by PKA-dependent manners. In this study, we found that IP3K-A binds to EB3 and their binding affinity is precisely regulated by protein kinase A (PKA)-dependent phosphorylation of IP3K-A at Ser119 (pSer119). We also revealed that the complex of IP3K-A and EB3 dissociates and reassociates rapidly during chemically induced LTP (cLTP) condition. This dynamic rearrangement of IP3K-A and EB3 complex will contribute remodeling of microtubule cytoskeleton allowing effective structural plasticity in response to synaptic stimulations. PMID- 30466787 TI - UGT76G1 polymorphism in Stevia rebaudiana: New variants for steviol glycosides conjugation. AB - Steviol glycosides (SVglys) are secondary metabolites derived from terpenoids exhibiting high-sweetening properties produced in Stevia rebaudiana leaves. Their great diversity is due to the number, the position and the nature of glycosylations on the steviol aglycone. Steviol conjugation is mediated by uridine-diphosphate glycosyltransferases (UGTs). Four UGTs have been clearly identified as involved in SVglys metabolism: UGT74G1, UGT85C2, UGT76G1 and UGT73E1. Natural non-functional mutants with nonsense codon have yet been observed for UGT76G1. To investigate the variability of UGT76G1 functionality, natural mutants with low or no content of rebaudioside A and C were identified in a germplasm collection of Stevia rebaudiana. These compounds are known to be the direct products of UGT76G1 and their biosynthesis is governed by a single gene at the locus Rae (Rebaudioside A enablement). Crosses were done with remarkable accessions including phenotypes with low (0-3%) and high proportions (70%) of rebaudioside A and C, to investigate the functionality of the Rae locus in the parents. Seven variants of UGT76G1 were found, among them 4 lead to a functional protein and 3 lead to non-functional isoforms. Five of these variants are new. We found that non-functionality of UGT76G1 towards SVglys is not due to a premature nonsense codon, which appears to be an extreme case to explain the loss of functionality of an UGT. Variations in steviol glycoside profile in stevia leaves is partly due to UGT76G1 polymorphism: amino acid substitutions in parts of the protein involved in the substrate specificity can be found by sequence comparison. PMID- 30466788 TI - Expression of immunoregulatory molecules PD-L1 and PD-1 in oral cancer and precancerous lesions: A cohort study of Japanese patients. AB - OBJECTIVE: An association of the programmed cell death-1 (PD-1) and its ligand PD L1 with various types of malignant tumors has been established. This study aimed to investigate the role of the PD-L1/PD-1 pathway in oral squamous cell carcinoma (OSCC) and oral epithelial precursor lesions (OEPL). MATERIALS AND METHODS: We examined 106 OSCC and 79 OEPL specimens for PD-L1 and PD-1 expression by immunohistochemistry. The results were compared with clinicopathological features of OSCC patients. RESULTS: In OSCC and OEPL specimens, PD-L1 expression was detected predominantly in epithelial or carcinoma cells, whereas PD-1 expression was found mainly in infiltrating or stromal lymphocytes. Seventy-two OSCC (67.9%) and 21 OEPL (26.6%) specimens were positive for PD-L1, and 73 OSCC (68.9%) and 23 OEPL (29.2%) specimens were positive for PD-1. PD-L1 and PD-1 expression levels were significantly different between OEPL and OSCC specimens (P < 0.001). There were significant positive correlations between PD-L1 and PD-1 expression in OEPL and OSCC specimens (P < 0.001). PD-L1 and PD-1 immunoreactivity was significantly associated with tumor size (P < 0.05). PD-L1 and PD-1 immunoreactivity in cases with advanced TNM staging was significantly higher than that in low staging cases (P < 0.01). There were significant correlations between PD-L1 and PD-1 expression in OSCC specimens and pathological variables such as stromal lymphocytic reaction (P < 0.05) and invasion depth (P < 0.01). CONCLUSION: PD-L1 and PD-1 immunohistochemical status may be related to carcinogenesis, tumor progression, and prognosis in oral epithelial lesions. Agents targeting PD-1 and PD-L1 might be useful for OSCC treatment. PMID- 30466789 TI - Korean Youth with Comorbid Allergic Disease and Obesity Show Heightened Psychological Distress. AB - OBJECTIVE: To explore psychological distress in Korean adolescents having allergic disease comorbid with obesity. STUDY DESIGN: A total of 703 869 adolescents who completed the Korean Youth Risk Behavior Web-based Survey between 2007 and 2016 were analyzed. Participants were divided into 4 groups-healthy control, allergic disease only, obesity only, and comorbidity of allergic disease and obesity-and compared them to determine whether they showed differences in mental health. RESULTS: Adolescents with both atopic dermatitis and obesity had significantly greater odds of experiencing unhappiness (OR, 1.17), stress (OR, 1.32), and suicidal ideation (OR, 1.25) than those without both conditions. The same was true of adolescents with obesity and allergic rhinitis (OR, 1.21, 1.37, and 1.27, respectively) or bronchial asthma (OR, 1.37, 1.39, and 1.37). The comorbidity groups also showed significantly greater odds of stress and suicidal ideation than the allergic disease-only (atopic dermatitis with obesity, 1.21 and 1.15, respectively; allergic rhinitis with obesity, 1.11 and 1.09; bronchial asthma with obesity, 1.17 and 1.14) and obesity-only groups (atopic dermatitis with obesity, 1.13 and 1.09; allergic rhinitis with obesity, 1.18 and 1.10; bronchial asthma with obesity, 1.18 and 1.21). CONCLUSIONS: Allergic disease and obesity negatively and additively influence mental health in adolescents. PMID- 30466790 TI - Mechanisms of Aerodigestive Symptoms in Infants with Varying Acid Reflux Index Determined by Esophageal Manometry. AB - OBJECTIVE: To test whether symptom generation in infants is related to the severity of gastroesophageal reflux disease (GERD) symptoms as determined by the Acid Reflux Index (ARI), stimulus media, and stimulus volume during provocative esophageal manometry. STUDY DESIGN: Symptomatic neonates (n = 74) born at a median of 28.9 weeks gestation (range, 23.4-39.4 weeks) were studied at a median of 41.0 weeks (range, 34.6-48.0 weeks) postmenstrual age using 24-hour pH impedance methods to determine ARI severity, followed by provocative esophageal manometry with graded mid-esophageal infusions (0.1-5.0 mL) of air, water, and apple juice. Peristaltic reflexes and symptom characteristics were compared among ARI severity categories using linear mixed models and generalized estimating equations. RESULTS: The effects of 2635 separate esophageal stimuli on reflexes and symptoms were analyzed. Peristaltic reflexes occurred in 1880 infusions (71%), and physical, cardiorespiratory, sensory symptoms were seen in 439 infusions (17%). Symptom prevalence did not differ across the ARI severity categories (ARI <3, 18%; ARI 3-7, 17%; ARI >7, 16%; P = 1.0). Symptom and peristaltic responses increased with incremental stimulus volumes (all media, P < .001). CONCLUSIONS: Symptoms and peristaltic reflexes are manifestations of the recruitment of several neurosensory and neuromotor pathways evoked by mid esophageal infusions. ARI severity grade plays no role in symptom generation, indicating that GERD should not be diagnosed and severity should not be assigned based on symptoms alone. An increase in symptom occurrence was noted with increasing stimulus volumes, which provided increased activation of receptors, afferents, and efferents in evoking peristaltic clearance reflexes. PMID- 30466791 TI - Caution Is Required When Using Non-Food and Drug Administration-Cleared Assays to Diagnose Sexually Transmitted Infections in Children. AB - Nucleic acid amplification testing is the gold-standard for Chlamydia trachomatis and Neisseria gonorrhoeae testing in adults. We present 3 pediatric cases in which testing resulted in probable false-positive results. Clinicians should avoid tests without clearance from a regulatory agency and should maintain consistent communication with laboratories. PMID- 30466792 TI - Pediatric Idiopathic Intervertebral Disc Calcification: Single-Center Series and Review of the Literature. AB - OBJECTIVE: To review pediatric idiopathic intervertebral disc calcification (PIIVDC) within a single center and within the literature to outline the disease course, management, and outcome. STUDY DESIGN: A retrospective chart review was performed spanning the period between January 2001 and February 2016 for diagnoses of PIIVDC. Patient age, sex, symptoms, and history and physical and neurologic findings were reviewed. Laboratory and imaging findings, management, follow-up, and outcome also were studied. RESULTS: Nine cases of PIIVDC were identified; they included 6 male and 3 female patients, with an age range of 23 months to 12 years. Two patients were asymptomatic, and PIIVDC was discovered incidentally. Of the remaining 7 patients, 5 presented with neck and/or back pain, 1 with painless torticollis, and 1 with painful torticollis. One patient reported neurologic symptoms of pain radiating along 1 dermatome. Disc spaces affected were 5 cervical, 4 thoracic, and 2 lumbar, with 2 patients having more than 1 space affected. All patients were managed conservatively. In 1 case, symptoms and lesions persisted after 5 years, but the remainder had complete symptom resolution, generally within 6 months. CONCLUSIONS: The etiology of PIIVDC remains unknown but appears to occur spontaneously, without preceding trauma or underlying medical condition. A conservative approach to patients without severe neurologic deficit with outpatient follow-up is supported. PMID- 30466793 TI - Social Cognition 2.0: An Interactive Memory Systems Account. AB - For 40 years, research on impression formation and attitudes has relied on dual process theories that represent knowledge in a single associative network. Although such models explain priming effects and some implicit responses, they are generally silent on other forms of learning and on the interface of social cognition with perception and action. Meanwhile, advances in cognitive neuroscience reveal multiple, interacting forms of learning and memory (e.g., semantic associative memory, Pavlovian conditioning, and instrumental learning), with detailed models of their operations, neural bases, and connections with perceptual and behavioral systems. This memory systems perspective offers a more refined, neurally plausible model of social cognition and attitudes that, I argue, provides a useful and generative account of human social behavior. PMID- 30466794 TI - Sleep Evaluation in the Assessment of Pediatric Attention Deficit Disorders. AB - INTRODUCTION: Examining the impact of appropriate sleep evaluation on diagnosis of attention deficit disorders can improve the standard of care in pediatrics. This quality improvement project examined current practice and subsequent implementation of a validated standardized sleep evaluation tool in the assessment of children with symptoms of attention deficit. METHODS: Retrospective chart review and implementation of the Children's Sleep Habits Questionnaire (CSHQ) for children 6 to 14 years old with attention deficit symptoms. MEASURES: Rates of sleep screening, sleep referrals, diagnosis of sleep and attention deficit disorders, Vanderbilt scores, CSHQ scores. RESULTS: In the retrospective group (n = 41), 76% of patients had attention deficit disorder/attention deficit hyperactivity disorder, 19.5% had sleeping disorders. There were significant provider differences in diagnosing sleep problems (p = .007). In the intervention group (n = 5), 60% had abnormal CSHQ scores. DISCUSSION: There was considerable incidence of sleeping problems in children with symptoms of attention deficit and provider variation in sleep evaluation and diagnosis, with minimal referral to specialist care. Our findings support a more comprehensive and standardized evaluation of sleep when assessing for attention deficit disorders to improve appropriate referrals, diagnosis, and treatment in pediatrics. PMID- 30466795 TI - Diagnostic and Interventional Imaging Services are Significant Sources of Medicare Revenue for Highly Reimbursed Nonradiologist Providers. AB - INTRODUCTION: Nonradiologist providers increasingly perform diagnostic imaging examinations and imaging-guided interventions traditionally performed by radiologists, which have raised concerns regarding appropriate utilization and self-referral. The purpose of this study was to assess the contribution of imaging studies to Medicare reimbursements for highly compensated nonradiologist providers in specialties often performing imaging studies. METHODS: The Medicare Provider Utilization and Payment Database was queried for provider information regarding overall reimbursement for providers in anesthesiology, cardiology, emergency medicine, neurology, obstetrics and gynecology, orthopedic surgery, neurology, and vascular surgery. Information regarding imaging studies reported and payment amounts were extracted for the 25 highest-reimbursed providers. Data were analyzed for relative contribution of imaging payments to overall medical Medicare payments. RESULTS: Significant differences between numbers of imaging studies, types of imaging, and payment amounts were noted based on provider specialty (p < 0.001). Highest-reimbursed cardiologists received the greatest percentage of Medicare payments from imaging (18.3%) followed by vascular surgery (11.6%), obstetrics and gynecology (10.9%), orthopedic surgery (9.6%), emergency medicine (8.7%), neurology (7.8%), and anesthesiology (3.2%) providers. Mean imaging payments amongst highly reimbursed nonradiologists were greatest for cardiology ($578,265), vascular surgery ($363,912), and orthopedic surgery ($113,634). Amongst highly reimbursed specialists, most common nonradiologist imaging payments were from ultrasound (45%) and cardiac nuclear medicine studies (40%). CONCLUSIONS: Nonradiologist performed imaging payments comprised substantial proportions of overall Medicare reimbursement for highly reimbursed physicians in several specialties, especially cardiology, vascular surgery, and orthopedic surgery. Further investigation is needed to better understand the wider economic implications of nonradiologist imaging study performance and self referral beyond the Medicare population. PMID- 30466796 TI - The Exon Junction Complex Undergoes a Compositional Switch that Alters mRNP Structure and Nonsense-Mediated mRNA Decay Activity. AB - The exon junction complex (EJC) deposited upstream of mRNA exon junctions shapes structure, composition, and fate of spliced mRNA ribonucleoprotein particles (mRNPs). To achieve this, the EJC core nucleates assembly of a dynamic shell of peripheral proteins that function in diverse post-transcriptional processes. To illuminate consequences of EJC composition change, we purified EJCs from human cells via peripheral proteins RNPS1 and CASC3. We show that the EJC originates as an SR-rich mega-dalton-sized RNP that contains RNPS1 but lacks CASC3. Sometime before or during translation, the EJC undergoes compositional and structural remodeling into an SR-devoid monomeric complex that contains CASC3. Surprisingly, RNPS1 is important for nonsense-mediated mRNA decay (NMD) in general, whereas CASC3 is needed for NMD of only select mRNAs. The switch to CASC3-EJC slows down NMD. Overall, the EJC compositional switch dramatically alters mRNP structure and specifies two distinct phases of EJC-dependent NMD. PMID- 30466797 TI - CA19.9 decrease >15% is a predictor of favourable outcome in patients treated for advanced pancreatic carcinoma: analysis of two independent cohorts. AB - BACKGROUND: Although carbohydrate antigen 19.9 (CA19.9) is widely used in pancreatic adenocarcinoma (PA), no consensual cut-off value of CA19.9 decrease has been established for treatment monitoring. METHODS: This was a retrospective study including patients with a baseline CA19.9 >= 37 UI/ml and with locally advanced or metastatic PA from two French centers. CA19.9 measurements were performed at baseline and first CT-scan evaluation. The aim was to use a training set to determine the best cut-off of CA19.9 decrease for predicting progressive disease (PD) and to analyze its performance in an independent validation cohort. RESULTS: A total of 95 and 93 patients were included in the training and validation sets, respectively. A <=15% CA19.9 decrease was the best cut-off for predicting PD with a sensitivity (Se) = 68% and a specificity (Sp) = 90%. In the validation set, this threshold was associated with Se = 76% and Sp = 83%. A >15% CA19.9 decrease was significantly associated with improved PFS (median 8.3 versus 3.1 months, p < 0.0001) and OS (median 14 versus 7.2 months, p < 0.0001). A >15% CA19.9 decrease was also identified as a factor independently associated with OS (HRa = 0.25, 95% CI:0.14-0.44). CONCLUSIONS: A CA 19.9 decrease >15% is a favourable predictor of outcome in patients treated for advanced PA. PMID- 30466798 TI - The presentation of proteinuria in an adolescent with new-onset diabetes after heart transplantation. PMID- 30466799 TI - Association between continuity of care and emergency department visits and hospitalization in senior adults with asthma-COPD overlap. AB - OBJECTIVE: To investigate associations between continuity of care (COC) and emergency department (ED) visits and hospitalization for chronic obstructive pulmonary disease (COPD) or asthma among elderly adults with asthma-COPD overlap (ACO). METHODS: A retrospective cohort study was performed using the Taiwan National Health Insurance research database. A total of 1141 ACO patients aged >=65 years during 2005-2011 were observed and followed for 2 years. The Bice and Boxerman COC index (COCI) was used to evaluate COC by considering ambulatory care visits duo to COPD or asthma in the first year; ED visits and hospitalization for COPD or asthma were identified in the subsequent year, respectively. The COCI was divided into three levels (COCI < 0.3= low, 0.3 <= COCI<1=medium, COCI = 1=high). The Cox model was used to estimate the hazard ratio (HR) for ED visits and hospital admissions due to COPD or asthma. RESULTS: The average COCI was 0.55. 21.3% patients received outpatient care from a single physician. Compared to patients with high COC, those with low and medium COC had a higher risk of ED visits (aHR = 2.80 and 2.69, P < .01) and admissions (aHR = 1.80 and 1.72, P < .05). CONCLUSION: Increasing COC is beneficial for elderly patients with ACO in disease management. Policymakers could create effective pay-for-performance programs for the elderly ACO population to enhance COC and improve care outcomes. PMID- 30466800 TI - Diagnostic biomarkers for Parkinson's disease: focus on alpha-synuclein in cerebrospinal fluid. AB - Diagnostic biomarkers are measures that detect or confirm the presence of a disease or identify individuals with a subtype of the disease. For Parkinson's disease, unlike other neurodegenerative diseases such as Alzheimer's disease and Creutzfeldt-Jakob disease, diagnostic biomarkers remain elusive as none are yet available or approved for clinical use. A biomarker to diagnose early or prodromal Parkinson's disease with high accuracy would significantly enhance clinical practice as well as advance clinical therapeutic trials. Multiple lines of evidence support a role of alpha-synuclein in the pathophysiology of Parkinson's disease and hence major ongoing efforts to identify biomarkers for Parkinson's disease are aimed at measuring alpha-synuclein in peripheral tissues and biofluids, including cerebrospinal fluid. This work is still in the early stages of biomarker development and has been accompanied by both losses and victories. Here, alpha-synuclein in cerebrospinal fluid as a diagnostic marker for Parkinson's disease is reviewed, including measures of total alpha-synuclein, oligomeric and phosphorylated alpha-synuclein, and seeding activity of alpha synuclein. PMID- 30466801 TI - Melatonin in sleep disorders. AB - Melatonin is the main hormone involved in the control of the sleep-wake cycle. It is easily synthesisable and can be administered orally, which has led to interest in its use as a treatment for insomnia. Moreover, as production of the hormone decreases with age, in inverse correlation with the frequency of poor sleep quality, it has been suggested that melatonin deficit is at least partly responsible for sleep disorders. Treating this age-related deficit would therefore appear to be a natural way of restoring sleep quality, which is lost as patients age. However, despite the undeniable theoretical appeal of this approach to insomnia, little scientific evidence is available that supports any benefit of this substitutive therapy. Furthermore, the most suitable dose ranges and pharmaceutical preparations for melatonin administration are yet to be clearly defined. This review addresses the physiology of melatonin, the different pharmaceutical preparations, and data on its clinical usefulness. PMID- 30466802 TI - Long-term outcomes after transplantation after support with a pulsatile pediatric ventricular assist device. AB - BACKGROUND: There has been increasing use of durable ventricular assist devices (VAD) in children as a bridge to transplantation (BTT). The Berlin Heart investigational device exemption (IDE) trial was the first pediatric VAD trial to demonstrate excellent survival outcomes as a BTT. OBJECTIVES: Our aim was to compare the expanded post-transplant outcomes for children enrolled in the Berlin Heart IDE trial to a matched Pediatric Heart Transplant Study (PHTS) cohort not requiring mechanical circulatory support (MCS). SETTING: University Hospitals. METHODS: This was a retrospective review of linked PHTS and Berlin Heart IDE databases for pediatric (<=18 years) recipients transplanted from 2007-2011. Subjects with <5 years of follow up were excluded. VAD supported patients were matched 1:2 to non-VAD supported controls from the PHTS database. RESULTS: Among 109 Berlin Heart IDE study enrollees, 83 were merged with the PHTS database and matched to 166 non-MCS supported patients. There was no difference in diagnosis, status at listing, and age between groups with the expected difference in inotrope use in the non-MCS supported patients. Compared to their matched cohort, there was no statistical difference in 5-year patient survival between VAD and non-VAD patients (81% vs 88%; p = 0.09) nor was there a difference in freedom from rejection or infection. CONCLUSIONS: This data suggests that children supported with a Berlin Heart VAD had similar survival, infection and rejection rates compared to those not requiring MCS support. Continued surveillance of the Berlin Heart IDE trial population post heart transplantation is warranted. PMID- 30466803 TI - Prognostic significance of early pulmonary function changes after onset of chronic lung allograft dysfunction. AB - BACKGROUND: Chronic lung allograft dysfunction (CLAD), including the phenotypes of bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (R-CLAD), represents the leading cause of late death after lung transplantation. Little is known, however, regarding the natural history or prognostic significance of pulmonary function changes after the onset of these conditions. We examined changes in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) over the first 18 months after CLAD. We also sought to determine whether lung function changes occurring early after CLAD impact longer term outcomes. METHODS: We performed a retrospective analysis of 216 bilateral lung recipients with CLAD, which included those with R-CLAD (n = 65) or BOS (n = 151). The course of FEV1 and FVC after CLAD was described. Cox proportional hazards models were used to evaluate the impact of a >=10% decline in FEV1 or FVC within the first 6 months of CLAD on graft loss after that time. RESULTS: Lung recipients with CLAD, whether BOS or R-CLAD, had the largest decreases in FEV1 and FVC within the first 6 months after onset. Moreover, a decline in FEV1 or FVC of >=10% within the first 6 months after CLAD was associated with a significantly increased hazard for graft loss after that time (hazard ratio [HR] = 3.17, 95% confidence interval [CI] 1.56 to 6.42, p = 0.001, and HR = 2.80, 95% CI 1.66 to 4.70, p <= 0.001, respectively), an effect observed in both BOS and R-CLAD patients. CONCLUSIONS: Early physiologic changes after CLAD were independently associated with graft loss. This suggests lung function changes after CLAD, specifically a >=10% decline in FEV1 or FVC, could be a surrogate measure of graft survival. PMID- 30466804 TI - Incidence of bacteremia and antimicrobial resistance, and associated factors among patients transferred from long-term care hospital. AB - OBJECTIVE: To evaluate the prevalence of bacteremia and antimicrobial resistance, and associated factors among infectious patients transferred from long-term care hospitals (LTCHs). METHODS: Consecutive adult patients who were transferred for suspected infection from affiliated LTCH's to study hospital emergency department (ED) over a 12 month period from January to December 2016 were included retrospectively. Patients with positive blood cultures (excluding contaminants as clinically determined) were defined as primary measure and subjected to further analysis according to antimicrobial resistance pattern. The latter was categorized into 4 subgroups based on groups of antimicrobial choices for empiric choices of suspected bloodstream infections. R-Group 0: bacteria susceptible to penicillin and amoxicillin; R-Group 1: bacteria resistant to penicillin/amoxicillin, first, second, or third generation cephalosporins. R Group 2: ESBL-producing bacteria or bacteria resistant methicillin, fourth generation cephalosporin, or fluoroquinolone. R-Group 3: highly resistant pathogens including vancomycin resistant enterococci, carbapenem or colistin resistant Gram negatives. Blood culture isolate could therefore be included in >1 group. RESULTS: Among 756 patients who were transferred from LTCHs, we excluded 278 patients who were not suspicious of infection and 65 patients who were not checked blood culture at ED. In total, 422 patients were enrolled. The incidence of bacteremia was 20.4% (n = 86). The most frequent pathogen was E. coli (n = 25) followed by S. aureus (n = 10), S. epidermidis (n = 8), and K. pneumonia (n = 6). The incidences of the R-Group 1, 2, and 3 groups were 16.8% (n = 71), 14.4% (n = 61), and 1.4% (n = 6), respectively. Of the Gram-positive pathogens (n = 44), the R-Group 1, 2, and 3 groups were 84.1% (n = 37), 75.0% (n = 33), and 9.1% (n = 4), respectively. Of the Gram-negative pathogens (n = 46), the R-Group 1, 2, and 3 groups were 82.6% (n = 38), 69.6% (n = 32), and 4.3% (n = 2), respectively. Among tested variables, initial serum procalcitonin level was significantly associated with the presence of bacteremia (AOR 1.03, 95% confidence interval 1.00-1.05), R Group 1 (1.04, 1.01-1.07) and the R-Group 2 (1.04, 1.00-1.06). CONCLUSIONS: The prevalence of bloodstream infections in patients admitted from LTCH was high (20.4%) with majority of these infections from resistant bacteria. Procalcitonin levels were significantly higher in bacteremic patients with an increasing trend towards bacteria in the antimicrobial resistant groups. PMID- 30466805 TI - Early tumor regrowth is a contributor to impaired survival in patients with completely resected advanced ovarian cancer. An exploratory analysis of the Intergroup trial AGO-OVAR 12. AB - OBJECTIVE: Surgical assessment of residual tumor provides the strongest prognostic information in advanced ovarian cancer (AOC), with the best outcome observed after complete resection. Postoperative radiological assessment before initiation of chemotherapy can supplement the information obtained by surgical assessment; however, it may also reveal conflicting findings. METHODS: Patients with AOC enrolled in the AGO-OVAR 12 trial underwent baseline imaging before the first chemotherapy cycle. The findings from surgical and radiologic assessment for disease extend were compared. Additionally, an integrated approach was assessed. RESULTS: Complete data from all 3 assessment methods were available for 1345 patients. Of 689 patients with complete resection, tumor was observed in 28% and 22% of patients undergoing radiologic and integrated assessment, respectively. Patients with surgical- radiological and surgical-integrated concordant findings showed a 5-year overall survival (5Y-OS) of 72% and 71%, whereas patients with surgical-radiological and surgical-integrated discordant results showed inferior 5Y-OS of 47% and 49%, respectively. Patients with surgically assessed residual disease had a 5-YOS of 37%. The interval between surgery and baseline assessment was independently associated with discordance between assessment methods, which might reflect early tumor regrowth. CONCLUSIONS: Baseline tumor assessment before chemotherapy provides information that stratifies patients with complete resection into different prognostic groups. Integrating the data from different assessment methods might lead to improved definitions of prognostic groups. Further investigation to determine if earlier initiation of chemotherapy after debulking surgery could increase survival of patients with early tumor regrowth is warranted. PMID- 30466806 TI - A clinical, biologic and mechanistic analysis of the role of ZNF692 in cervical cancer. AB - OBJECTIVE: Cervical cancer (CC) is the most common malignancy in women. The zinc finger protein 692 (ZNF692) has been identified as a transcription factor and its aberrant expression participates in tumorigenesis of various cancers. However, its biological function and molecular mechanisms in cervical cancer remain unclear. METHODS: Microarrays were analysed by immunohistochemistry (IHC) to investigate the expression of ZNF692 in cervical cancer and its relationship with clinicopathologic characteristics. siRNAs and expression plasmids were used to reveal the biological function of ZNF692 in CC and subcutaneous xenograft model to examine the role of ZNF692 in vivo. Chromatin Immunoprecipitation and luciferase reporter assay were performed to ascertain whether ZNF692 binds to the promoter region of p27kip1. RESULTS: By analyzing The Cancer Genome Atlas (TCGA) dataset, we confirmed ZNF692 as a potential oncogene in CC. ZNF692 expression was up-regulated in CC tissues compared with that in adjacent normal tissues, and its overexpression was correlated with poor clinicopathologic characteristics. Moreover, ZNF692 promoted the proliferation, migration and invasion of CC cells both in vitro and in vivo. Regarding molecular mechanisms, up-regulation of ZNF692 was found to enhance the G1/S transition via regulating the p27kip1/PThr160-CDK2 signal pathway in CC cells. CONCLUSION: ZNF692 promotes CC cells proliferation and invasion through suppressing p27kip1 transcription by directly binding its promoter region, which suggests that ZNF692 may serve as an underlying therapeutic target and prognostic marker in CC. PMID- 30466807 TI - Identifying the need to refine the potential patient risk factors for niraparib induced thrombocytopenia. AB - OBJECTIVE: Niraparib is a poly (ADP-ribose) polymerase inhibitor (PARP) approved for use in maintenance therapy for ovarian cancer that is associated with the unpredictable grade 3/4 thrombocytopenia. This study was conducted to refine patient dosing recommendations for niraparib based upon clinical practice observations of grade 3/4 thrombocytopenia. METHODS AND MATERIALS: Six patient cases were reviewed to identify similarities in patient factors. An in vitro study was conducted using healthy volunteer blood spiked with Niraparib concentrations ranging from 0 ng/mL to 5000 ng/mL. Manual platelet counts were evaluated at different time intervals for each concentration and compared to untreated controls. Data was then analyzed based on percent change in platelet count versus untreated control for each concentration/time point. RESULTS: In three patients with body weight > 80 kg and platelet count >200 * 109/L, decreased creatinine clearance (CrCl) <60 mL/min was identified as potential signal. An additional three patients with weights below 77 kg and/or baseline platelet counts <150 * 109/L were re-evaluated, and it was observed that all had decreased CrCl of <60 mL/min. Albumin <3.5 g/dL was also observed in some patients with thrombocytopenia. The in vitro study, observed a direct concentration-dependent relationship between niraparib and thrombocytopenia. CONCLUSION: The data suggests that renal insufficiency and hypoalbuminemia may be associated with the development of niraparib-induced thrombocytopenia. Moreover, the preliminary in vitro studies also demonstrated a concentration-dependent relationship between niraparib and direct toxicity to platelets. PMID- 30466808 TI - How many patients enter endometrial cancer surgery with psychotropic medication prescriptions, and how many receive a new prescription perioperatively? AB - OBJECTIVE: Psychotropic medications including antidepressants and anxiolytics are used to treat anxiety and depression in cancer patients; however, little is known about the prescription practices in endometrial cancer. This study aimed to determine the prevalence, type, dose, frequency and timing of psychotropic medications prescribed to endometrial cancer patients. A secondary aim was to study sociodemographic and clinical characteristics associated with receiving a psychotropic medication prescription. METHODS: Secondary data analysis of an international, multicentre, prospective randomised controlled trial was conducted. Patients aged >18 years diagnosed with Stage I endometrial cancer were included. Logistic regression models were fitted to estimate the association of receiving psychotropic medications with patient's socio-demographic and clinical characteristics. RESULTS: The overall prevalence of patients prescribed one or more psychotropic medications was 16.8% (n = 121/719) comprising antidepressants (12.6%, n = 91/719) and anxiolytics (5.8%, n = 42/719). The majority of patients (78.1%, n = 71/91) were already receiving antidepressants before cancer diagnosis, the remaining medications were newly prescribed perioperatively (21.9%, n = 20/91). Patients of younger age (18-50 years, OR (Odds Ratio): 2.61), who had hypertension (OR: 0.61), history of a previous cancer (OR: 1.96), and >=2 comorbidities (2-3, OR: 2.97; 4-5, OR: 7.85; >=6, OR: 9.13) were significantly (p < 0.05) more likely to receive a prescription of psychotropic medications. CONCLUSIONS: While one in eight patients already had psychotropic medications prescribed before surgery for early stage endometrial cancer, only few women received a new prescription after surgery. The overall prescription rates were similar to other patients with cancer, but higher than those observed in the general population, likely reflecting the comorbidity burden of patients who develop endometrial cancer. Qualitative data could be used in future research to explore the psychological and quality of life impacts of endometrial cancer. PMID- 30466809 TI - Chemical characterization of an Ayurvedic herbo-mineral preparation- Mahalaxmivilas Rasa through spectroscopic & chromatographic methods. AB - BACKGROUND: To protect the massive trust of patient in Ayurveda, a need aroused for the researches to ascertain the quality, safety & efficacy of herbo-mineral preparations on scientific lines. The rasa-aushadhis are having qualities such as instant effectiveness, requirement in very small dosage and ample therapeutic utility. Mahalaxmi Vilas Rasa [AFI, 20:27] has been used for treatment of a variety of ailments since time immemorial. OBJECTIVE: To prepare Mahalaxmi Vilas Rasa as per standard operating procedures (SoPs) mentioned in classical text and to characterize it chemically using modern analytical techniques. MATERIALS AND METHODS: The drug (Mahalaxmi Vilas Rasa) in three batches was prepared in GMP certified pharmacy. Physico-chemical analysis, HPTLC, Assay of elements by AAS & ICP-AES were carried out as per Ayurvedic Pharmacopoeia of India. Powder X-ray diffraction (XRD) was conducted using Rigaku Ultima-IV X-ray diffractometer. RESULTS: The elemental analysis shown the presence of Mercury, Sulphur, Calcium, Copper, Gold, Iron & Tin etc. and HPTLC revealed presence of organic constituents from plant material. The XRD had indicated that prepared drug contained free sulphur, cinnabar (mercury sulphide added as Kajjali), cassiterite (tin oxide, Vanga Bhasma), orpiment (Hartal, arsenic III sulphide) and mica (Leucite/ Zeolite, Abhrak Bhasma). The drug was also tested for residual pesticide and microbiological contamination which were found within permissible limits. CONCLUSION: Classical pharmaceutical procedures of Mahalaxmi Vilas Rasa showed converting the macro elements into therapeutically effective medicines of micro form. Standards laid down in this study certainly utilized as an important tool for standardization and quality assurance of this herbo-mineral formulation. PMID- 30466810 TI - Analysis of the anatomical features of pulmonary veins on pre-procedural cardiac CT images resulting in incomplete cryoballoon ablation for atrial fibrillation. AB - BACKGROUND: To investigate the anatomical features related to the failure of cryoballoon (CB) ablation for atrial fibrillation (AF) on pre-procedural CT images. METHODS: We retrospectively analyzed CT images of 100 patients with AF who had undergone a first CB ablation at our institution between June 2016 and April 2017. We measured the angle, short- and long axis length, and the area and ovality of 4 major pulmonary vein (PV) ostium on CT images. We performed logistic regression analysis to analyze the anatomical features related to the failure (incomplete CB ablation) of PV isolation. We also performed a receiver-operating characteristic (ROC) curve analysis to identify an appropriate cut-off value for anatomical features significantly associated with incomplete CB ablation. RESULTS: We analyzed 400 PVs in 100 patients [aged 64 (range, 27-82) years, 59% male]. The rate of incomplete CB ablation was significantly higher for right-than left-sided PVs (p < 0.001). The anatomical feature significantly associated with incomplete CB ablation was the angle at the right inferior PV (RIPV) (AOR: 1.17; 95% CI: 1.09-1.27, p < 0.001) and the right superior PV (RSPV) (AOR: 1.12; 95% CI: 1.01-1.23; p = 0.014). In the ROC analysis, the optimal cut-off value for RIPV and RSPV angle to discriminate an incomplete CB ablation were 40.1 degrees and 79.7 degrees , respectively. CONCLUSION: Our findings may help to select the appropriate ablation strategy to treat patients with AF. We show that the angle is an anatomical feature significantly related to failed CB ablation. PMID- 30466811 TI - Oral & Maxillofacial surgery is ready for patient-centred eHealth interventions - the outcomes of a scoping review. AB - Within the field of oral and maxillofacial (OMF) surgery, eHealth is expected to be a tool to improve quality of care. The aim of this study is to map the research of patient-centred eHealth interventions within OMF surgery by means of a scoping review. After a systematic literature search, relevant studies on patient-centred eHealth interventions for OMF-surgery patients were selected. The interventions were mapped based on their key components, target population and outcome measures. To gain insight in the research phase of evaluation, the framework of the Medical Research Council (MRC) was used. Forty-one papers were included, comprising 34 unique interventions. Nineteen interventions were designed for head and neck cancer patients, 11 interventions concernd video teleconsultation. According to the MRC framework, 26 papers fitted into the feasibility and piloting phase of research, 8 into the evaluation phase, 7 were in the development phase. No implementation studies were found. This scoping review can be a starting point for those who are interested in applying and evaluating eHealth in their practice. Since many feasibility and pilot studies were found on similar interventions, a more extensive collaboration with and connecting to each other is recommended to catalyze the implementation of eHealth in daily practice. Profound involvement of patients in developing and evaluating eHealth interventions is essential to achieve true patient-centred OMF surgery. PMID- 30466812 TI - How hospital pharmacists prioritise patients at high-risk for medication harm. AB - BACKGROUND: Medication harm is experienced by up to 30% of hospitalised patients, of which 7% experience severe harm. Pharmacist review can mitigate this harm. However, in increasingly busy hospitals, with high patient throughput, and scarce resources, there is a need to prioritise patients. Current methods are cumbersome, include many risk factors and are not evaluated in the clinical setting. OBJECTIVES: To determine key criteria used by hospital pharmacists and investigate perspectives related to patient prioritisation for potential medication harm in the hospital setting. METHODS: This study used two methods; focus groups and a cross-sectional survey of Australian hospital pharmacists. Focus groups were used to identify criteria and perspectives related to prioritisation and were analysed thematically. Criteria from focus groups, and a systematic review, were used to design the survey. The survey was distributed via the Society of Hospital Pharmacists of Australia. The top 10 prioritisation criteria, and associated sub-criteria selected by over 50% of respondents were ranked. Combination of criteria used most frequently on a day-to-day basis were identified. RESULTS: Twenty clinical pharmacists participated in four, one-hour, audio recorded focus groups. Using inductive thematic analysis of transcripts three themes were identified; 1) prioritisation criteria, 2) barriers to, and 3) facilitators of patient prioritisation, with five sub-themes and 26 codes. Pharmacists identified a number of barriers such as a lack of relevant handover information. Organisational demands, such as patient discharge and medications supply also influenced priority and could act as barriers to a pharmacist enacting their prioritisation plan. A total of 231 pharmacists completed the survey. High priority criteria included, renal impairment, use of high-risk medications and therapeutic drug monitoring. CONCLUSION: Pharmacists described prioritisation as a multifactorial process with a focus on high-risk medications and renal impairment. These findings will inform the development of a predictive risk score for patient prioritisation. PMID- 30466813 TI - Living 'in between' outside and inside: The forensic psychiatric unit as an impermanent assemblage. AB - This paper presents analysis from 'a study of staff and patient experiences of the restrictive environments of a forensic psychiatric unit. The paper conceptualises the forensic unit as an impermanent assemblage, enacted in and through practices that hold a future life outside the unit simultaneously near, yet far. We show how the near-far relations between life inside and outside the unit operate in three ways; 1) in relation to the 'care pathway', 2) practices of dwelling, and 3) creating and maintaining connections to life 'beyond' the unit. The paper concludes with a discussion about possible ways to overcome the limitations to recovery that can arise through practices of impermanence. PMID- 30466814 TI - Obtaining contextually relevant geographic data using Facebook recruitment in public health studies. AB - INTRODUCTION: Online participant recruitment for public health research studies has increased dramatically in recent years, particularly as traditional recruitment strategies have waned in efficiency. The emergence of e-epidemiology offers possibilities for reaching understudied populations as well as conducting large-scale studies. METHODS: We conducted a cross-sectional survey focused on self-reported neighborhood characteristics, perceived stress, and feasibility of obtaining work/residential addresses via online recruitment in St. Louis, Missouri, USA from February 2017 to December 2017. We report the process of using Facebook recruitment and demonstrate how this strategy can enhance collection of geospatial data to better understand context and spatial patterns of disease. RESULTS: A total of 425 participants were recruited via Facebook advertisements. All participants reported their residential and work ZIP codes, though only 64.7% and 45.6% provided their complete residential and work street addresses, respectively. Those who reported their complete residential street addresses were more likely to be female (69.8% vs. 56.1% of males, chi2 = 7.89, 1 df, p = 0.005), though no differences were observed by race, age, or employment status. DISCUSSION: These findings indicate that valuable location data can be successfully collected via Facebook recruitment - data that could potentially include residential history or prospective follow-up time or be combined with other emerging technologies for geographic data in order to better understand the context and the effects of place on health outcomes. CONCLUSIONS: Facebook recruitment may be an underutilized resource for obtaining accurate geospatial and contextually relevant health data and should be considered as a means for finding participants due to the cost-effectiveness, efficiency and flexibility of this recruitment approach. PMID- 30466815 TI - Cardiac computed tomography for atrial fibrillation ablation - a one-stop shop? PMID- 30466817 TI - Focus on spontaneous coronary artery dissection: Where are we now? PMID- 30466816 TI - Cardiac computed tomography previous to atrial fibrillation ablation - effects of technological improvements and protocol optimization. AB - BACKGROUND: Cardiac computed tomography (CT) can provide a precise tridimentional anatomic map and exclude intra-cardiac thrombus. We aimed to access the impact of CT protocol optimization and technological evolution on the contrast and radiation dose as well as on image quality previous to atrial fibrillation (AF) ablation. METHODS: From a prospective registry of consecutive patients who underwent cardiac CT in a single center, we selected 270 patients in whom the CT was done for evaluation prior to AF ablation and they were distributed in 3 groups: Group1: the first 150 patients included; Group2: the last 60 patients performed with the same CT scanner; Group3: the first 60 exams performed with the new CT scanner. Quality of the protocol was access based on radiation dose, contrast volume used, the use of a second (delayed) acquisition, and on quantitative image quality analisis (signal to noise and contrast to noise ratios; density homogeneity racio between LA and LAA). RESULTS: We found a significant radiation dose as well as contrast dose reduction between the first and last subgroups (G1: 5,6mSv and 100ml; G2: 1,3mSv and 90ml; G3: 0,6mSv and 65ml). Even though group 3 had less radiation and contrast used it still had better quantitative image quality (signal/noise of 13,5; contrast/noise 14,8; density homogeneity racio of 0,92). CONCLUSION: Protocol optimization and technology both contributed to significant lower radiation dose and contrast volume used on cardiac CTs prior to AF ablation, without compromising image quality. PMID- 30466818 TI - Timely recognition of total elbow and radial head arthroplasty adverse events: an analysis of reports to the US Food and Drug Administration. AB - BACKGROUND: Recent recalls of several commonly used elbow arthroplasty implants have prompted interest in the modes by which elbow implants fail and the timing of reports of these failures. METHODS: We reviewed the adverse event reports to the US Food and Drug Administration's Manufacturer and User Facility Device Experience (MAUDE) database from 2012 to 2015 regarding elbow arthroplasty to determine the event date and the type of each adverse event. RESULTS: Among 179 total elbow adverse event reports, the most common modes of failure were implant dissociation (23%), loosening (22%), and infection (16%). The most common modes of failure among 58 radial head replacement reports were component dissociation (19%) and linkage screw failure (19%). The percentage distribution of adverse event types differed among different arthroplasty systems and from that reported in published reviews of elbow arthroplasty. Three implant recalls were implemented 2, 5, and 9 years after the first adverse event report in the MAUDE database. For 2 of the recalls, the first reports of the device failures were published 2 and 5 years after the first MAUDE reports. CONCLUSIONS: The MAUDE database is a publicly funded and publicly available means by which surgeons can identify adverse events for the prostheses they use before such information becomes available through journal publication or recall notification. In this study, MAUDE data revealed a higher relative frequency of mechanical dissociation of elbow implants than what has been represented in the literature. Early identification of these adverse events may help surgeons by informing their implant selection and surgical technique. PMID- 30466819 TI - Comparison of two different superior capsule reconstruction methods in the treatment of chronic irreparable rotator cuff tears: a biomechanical and histologic study in rabbit models. AB - BACKGROUND: In the treatment of irreparable rotary cuff (RC) tears, the superior capsule of the shoulder is reconstructed using tensor fascia lata (TFL) or several allografts to prevent progressive joint degeneration. This study compared the healing qualities of acellular human dermal graft (HDG) and the TFL autograft in superior capsule reconstruction (SCR) from biomechanical and histologic perspectives. METHODS: Chronic retracted RC tear models were created bilaterally in 9 rabbits, and 7 rabbits with intact RC were used as a control group. SCR was performed 8 weeks after the tear using HDG in right shoulders and TFL in left shoulders. At 12 weeks after SCR, 2 shoulders from each experimental group were investigated for histologic healing, and 7 samples from the experimental and control groups were biomechanically tested. RESULTS: Complete healing was observed macroscopically in the glenoid and humeral sides of both groups. No difference was observed in the enthesis maturation scores between the experimental groups. Collagen fiber density was higher and the orientation was better in TFL group. Inflammatory cell infiltration was not seen in the TFL group, but inflammatory cell infiltration was pronounced in the HDG group. The mean pullout strengths of the TFL group, HDG group, and intact RC group were 139.7 +/- 40.5 N, 123.9 +/- 47.9 N, and 105.1 +/- 11.8 N (P = .187), respectively. The mean stiffness values (P = .711), yield forces (P = .404), and displacements (P = .135) were also statistically not different between the groups. CONCLUSION: In SCR, the healing qualities of HDG and TFL were similar in rabbit models. PMID- 30466820 TI - Sleep-disordered breathing, craniofacial development, and neurodevelopment in premature infants: a 2-year follow-up study. AB - INTRODUCTION: Sleep problems, neuro-developmental development, and sleep disordered-breathing (SDB), are reported as more prevalent in premature infants than in full-term infants. We investigated the relationship between neuro development, and SDB in preterm infants at 24 months corrected age (CA) with a narrow palatal presentation over time. METHODS: We enrolled infants 40 weeks or younger at birth collecting obstetric and birth data. Participants were followed up at 6, 12, 18, and 24 months CA. We evaluated craniofacial development by inspecting and photo documenting hard palate; sleep using sleep diary, actigraphy and night-time polysomnography-PSG-; and development using Bayley- Scales-of Infant-Development and Denver-Developmental-Screening-Test (DDST) at each visit and comparing results at six months and two years. RESULTS: 244 premature infants [139 (57.0%) boys, [at birth: mean gestational age-GA- 31.5 +/- 3.2 weeks, 1691.9 +/- 593.9 g, 40.2 +/- 5.2 cm], and 30 full term infants (50% boys), [mean GA 39.3 +/- 1.0 weeks, 3131.0 +/- 390.0 g, and 49.38 +/- 2.0 cm] were enrolled in the study. At 6 and 24 months, 65.2% premature infants had a narrow hard palate (NHP). At 24 months, 79% had an apnea-hypopnea- index (AHI) > 1 events/hour at PSG, with a mean AHI of 3.00 +/- 2.95. Only 10% of full term infants had NHP at birth and the mean AHI was 0.5 +/- 0.2 event/hour at 24 months. CONCLUSION: Preterm infants have a higher occurrence of NHP at birth. At two years of age they have more sleep problems, most commonly associated with obstructive-SDB, and a higher rate of development delays. Frequency of NHP is still abnormally high, suggesting not only abnormal orofacial growth over-time, but also impact of this abnormal growth in the genesis of the obstructive-SDB. PMID- 30466821 TI - Severe hypertriglyceridemia is primarily polygenic. AB - BACKGROUND: Hypertriglyceridemia (HTG) is a complex trait defined by elevated plasma triglyceride levels. Genetic determinants of HTG have so far been examined in a piecemeal manner; understanding of its molecular basis, both monogenic and polygenic, is thus incomplete. OBJECTIVE: The objective of this study was to characterize genetic profiles of patients with severe HTG, and quantify the genetic determinants and molecular contributors. METHODS: We concurrently assessed rare and common variants in two independent cohorts of 251 and 312 Caucasian patients with severe HTG. DNA was subjected to targeted next-generation sequencing of 73 genes and 185 SNPs associated with dyslipidemia. LPL, APOC2, GPIHBP1, APOA5, and LMF1 genes were screened for rare variants, and a polygenic risk score was used to assess the accumulation of common variants. RESULTS: As there were no significant differences in the prevalence of genetic determinants between cohorts, data were combined for all 563 patients: 1.1% had biallelic (homozygous or compound heterozygous) rare variants, 14.4% had heterozygous rare variants, 32.0% had an extreme accumulation of common variants (ie, high polygenic risk), and 52.6% remained genetically undefined. Patients with HTG were 5.77 times (95% CI [4.26-7.82]; P < .0001) more likely to carry one of these types of genetic susceptibility compared with controls. CONCLUSIONS: We report the most in-depth, systematic evaluation of genetic determinants of severe HTG to date. The predominant feature was an extreme accumulation of common variants (high polygenic risk score), whereas a substantial proportion of patients also carried heterozygous rare variants. Overall, 46.3% of patients had polygenic HTG, whereas only 1.1% had biallelic or homozygous monogenic HTG. PMID- 30466822 TI - Strategies to Reduce Acute Kidney Injury and Improve Clinical Outcomes Following Percutaneous Coronary Intervention: A Subgroup Analysis of the PRESERVE Trial. AB - OBJECTIVES: The aim of this study was to compare intravenous (IV) sodium bicarbonate with IV sodium chloride and oral acetylcysteine with placebo for the prevention of contrast-associated acute kidney injury (CAAKI) and intermediate term adverse outcomes. BACKGROUND: Data are conflicting on the optimal strategy to reduce CAAKI and related complications after percutaneous coronary intervention (PCI). METHODS: The PRESERVE (Prevention of Serious Adverse Events Following Angiography) trial used a 2 * 2 factorial design to randomize 5,177 patients with stage III or IV chronic kidney disease undergoing angiography to IV 1.26% sodium bicarbonate or IV 0.9% sodium chloride and 5 days of oral acetylcysteine or placebo. A subgroup analysis was conducted of the efficacy of these interventions in patients who underwent PCI during the study angiographic examination. The primary endpoint was a composite of death, need for dialysis, or persistent kidney impairment at 90 days; CAAKI was a secondary endpoint. RESULTS: A total of 1,161 PRESERVE patients (mean age 69 +/- 8 years) underwent PCI. The median estimated glomerular filtration rate was 50.7 ml/min/1.73 m2 (interquartile range: 41.7 to 60.1 ml/min/1.73 m2), and 952 patients (82%) had diabetes mellitus. The primary endpoint occurred in 15 of 568 patients (2.6%) in the IV sodium bicarbonate group and 24 of 593 patients (4.0%) in the IV sodium chloride group (odds ratio: 0.64; 95% confidence interval: 0.33 to 1.24; p for interaction = 0.41) and in 23 of 598 patients (3.8%) in the acetylcysteine group and 16 of 563 patients (2.8%) in the placebo group (odds ratio: 1.37; 95% confidence interval: 0.71 to 2.62; p for interaction = 0.29). There were no significant between-group differences in the rates of CAAKI. CONCLUSIONS: Among patients with CKD undergoing PCI, there was no benefit of IV sodium bicarbonate over IV sodium chloride or of acetylcysteine over placebo for the prevention of CAAKI or intermediate-term adverse outcomes. PMID- 30466823 TI - The Arc of the Research Universe Is Long, But it Bends Toward the Truth. PMID- 30466824 TI - Predictors and Outcomes of Staged Versus One-Time Multivessel Revascularization in Multivessel Coronary Artery Disease: Insights From the VA CART Program. AB - OBJECTIVES: The aim of this study was to determine predictors and outcomes associated with staged percutaneous coronary intervention (PCI) versus one-time multivessel revascularization (OTMVR) in patients with multivessel coronary artery disease. BACKGROUND: Prior observational studies have not evaluated predictors and outcomes of staged PCI versus OTMVR in a heterogenous population of patients with multivessel coronary artery disease who undergo multivessel revascularization. METHODS: Data from the Veterans Affairs (VA) CART (Clinical Assessment, Reporting, and Tracking) Program were used to evaluate patients who underwent PCI of >2 vessels between October 1, 2007, and September 3, 2014. Associations between individual factors and the decision to perform staged PCI were assessed. Additionally, the impact of measured patient and procedural factors, site factors, and unmeasured site factors on the decision to perform staged PCI was compared. Cox proportional hazards models were used to determine the association between staged PCI and mortality. RESULTS: A total of 7,599 patients at 61 sites were included. The decision to perform staged PCI was driven by procedural characteristics and unmeasured site factors. Staged PCI was associated with lower risk-adjusted mortality compared with OTMVR (adjusted hazard ratio [HR]: 0.78; 95% confidence interval [CI]: 0.72 to 0.84; p < 0.01). This mortality benefit was observed among the ST-segment elevation myocardial infarction (HR: 0.31; 95% CI: 0.21 to 0.47; p < 0.01), non-ST-segment elevation myocardial infarction (HR: 0.74; 95% CI: 0.64 to 0.87; p < 0.01), unstable angina (HR: 0.75; 95% CI: 0.64 to 0.89; p < 0.01) and stable angina (HR: 0.88; 95% CI: 0.77 to 1.00; p = 0.05) groups. CONCLUSIONS: The decision to pursue staged PCI was driven by procedural characteristics and unmeasured site variation and was associated with lower mortality compared with OTMVR. After adjustment, there was an association between staged PCI and reduced mortality. Given the observational nature of these findings, a randomized trial comparing the 2 is needed to guide practice. PMID- 30466825 TI - Nonculprit Lesion Intervention: 1 Step Closer to the COMPLETE Answer? PMID- 30466826 TI - Health Status Benefits of Successful Chronic Total Occlusion Revascularization Across the Spectrum of Left Ventricular Function: Insights From the OPEN-CTO Registry. AB - OBJECTIVES: This study sought to describe the association between chronic total occlusion (CTO) revascularization (CTO percutaneous coronary intervention [PCI]) and health status in patients with and without cardiomyopathy. BACKGROUND: Prior PCI trials for cardiomyopathy have excluded CTO patients. Whether patients with reduced left ventricular ejection fraction (LVEF) receive similar health status benefit from CTO-PCI compared with patients with normal LVEF is unclear. METHODS: We assessed health status change, using the Seattle Angina Questionnaire (SAQ) Summary, SAQ Angina Frequency, and Rose Dyspnea Scale scores, among patients undergoing successful CTO PCI in the OPEN-CTO (Outcomes, Patient Health Status, and Efficiency in Chronic Total Occlusion) Registry. Participants were classified by LVEF (normal, >=50%; mild-moderate, 30% to 49%; and severe, <30%), with higher SAQ and lower Rose Dyspnea Scale scores indicating better health status. Differences in 1-year outcomes were compared using hierarchical multivariable regression. RESULTS: Of 762 patients, 506 (66.4%), 193 (25.3%), and 63 (8.3%) had normal, mild-moderate, and severely reduced LVEF. SAQ Summary score improvements were observed in each group (27.1 +/- 20.4, 26.7 +/- 21.2, and 20.3 +/- 18.1, respectively). Compared with patients with LVEF >=50%, those with LVEF <30% had less improvement in SAQ Summary Score (-5.2 points; 95% confidence interval: -9.0 to -1.5; p = 0.01) and Rose Dyspnea Scale (+0.5 points; 95% confidence interval: 0.1 to 0.8; p = 0.01), with no difference in odds of angina (odds ratio: 1.3; 95% confidence interval: 0.6 to 3.0; p = 0.48). Health status improvement was similar between patients with LVEF >=50% and LVEF 30% to 49%. CONCLUSIONS: Although health status improvement was less in patients with severely reduced LVEF compared with those with normal LVEF, each group experienced large health status improvements after CTO-PCI. PMID- 30466827 TI - Chronic Total Occlusion Revascularization and Quality-of-Life Improvement Across All Levels of Left Ventricular Function: Many Questions Still Unanswered. PMID- 30466829 TI - Invasive Cardiac Procedures Increase Bleeding in Frail Patients With Acute Myocardial Infarction: A Call to Action. PMID- 30466828 TI - The Association of Frailty With In-Hospital Bleeding Among Older Adults With Acute Myocardial Infarction: Insights From the ACTION Registry. AB - OBJECTIVES: The aim of this study was to determine whether frailty is associated with increased bleeding risk in the setting of acute myocardial infarction (AMI). BACKGROUND: Frailty is a common syndrome in older adults. METHODS: Frailty was examined among AMI patients >=65 years of age treated at 775 U.S. hospitals participating in the ACTION (Acute Coronary Treatment and Intervention Outcomes Network) Registry from January 2015 to December 2016. Frailty was classified on the basis of impairments in 3 domains: walking (unassisted, assisted, wheelchair/nonambulatory), cognition (normal, mildly impaired, moderately/severely impaired), and activities of daily living. Impairment in each domain was scored as 0, 1, or 2, and a summary variable consisting of 3 categories was then created: 0 (fit/well), 1 to 2 (vulnerable/mild frailty), and 3 to 6 (moderate-to-severe frailty). Multivariable logistic regression was used to examine the independent association between frailty and bleeding. RESULTS: Among 129,330 AMI patients, 16.4% had any frailty. Frail patients were older, more often female, and were less likely to undergo cardiac catheterization. Major bleeding increased across categories of frailty (fit/well 6.5%; vulnerable/mild frailty 9.4%; moderate-to-severe frailty 9.9%; p < 0.001). Among patients who underwent catheterization, both frailty categories were independently associated with bleeding risk compared with the non-frail group (vulnerable/mild frailty adjusted odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.23 to 1.44; moderate-to-severe frailty adjusted OR: 1.40, 95% CI: 1.24 to 1.58). Among patients managed conservatively, there was no association of frailty with bleeding (vulnerable/mild frailty adjusted OR: 1.01, 95% CI: 0.86 to 1.19; moderate-to-severe frailty adjusted OR: 0.96, 95% CI: 0.81 to 1.14). CONCLUSIONS: Frail patients had lower use of cardiac catheterization and higher risk of major bleeding (when catheterization was performed) than nonfrail patients, making attention to clinical strategies to avoid bleeding imperative in this population. PMID- 30466830 TI - The Latest Evolution of the Medtronic CoreValve System in the Era of Transcatheter Aortic Valve Replacement: Matched Comparison of the Evolut PRO and Evolut R. AB - OBJECTIVES: The aim of this study was to investigate the hemodynamic and clinical performance of the Evolut PRO compared with its direct predecessor, the Evolut R. BACKGROUND: Recently, the newest commercially available generation of the self expandable Medtronic CoreValve prosthesis, the CoreValve Evolut PRO, was introduced to the market. This prosthesis is based on the previous Evolut R model and specifically designed to mitigate paravalvular leakage. Because of the design changes, the Evolut PRO needs a larger sheath size (16-F vs. 14-F). METHODS: Patients receiving either the Evolut R (n = 148) or the Evolut PRO (n = 74) from September 2015 to January 2018 were compared in a 2:1 fashion after propensity score matching. Baseline characteristics, cardiovascular imaging, and pre- and periprocedural outcomes were prospectively collected and assessed. RESULTS: Both cohorts represent a high-risk, real-world collective with increased perioperative mortality risk (logistic European System for Cardiac Operative Risk Evaluation score, Evolut R vs. Evolut PRO: 24.7 +/- 13.7% vs. 25.1 +/- 12.5%; p = 0.881). Procedural success was 100%, and the mean transvalvular pressure gradient was substantially reduced (Evolut R vs. Evolut PRO: 7.9 +/- 3.9 mm Hg vs. 7.5 +/- 3.5 mm Hg; p = 0.348). Mild paravalvular leakage was observed in 16.2% of Evolut R patients and in 14.9% of Evolut PRO patients (p = 0.794). In the Evolut R group, moderate aortic regurgitation was documented in 2 patients (Evolut R vs. Evolut PRO: 1.4% vs. 0%; p = 1.000). No differences regarding clinical parameters, such as major bleeding events (Evolut R vs. Evolut PRO: 1.4% vs.1.3%; p = 0.868) and vascular complications were observed. CONCLUSIONS: Both prostheses show excellent hemodynamic performance with a low incidence of paravalvular leakage and comparable clinical outcomes. PMID- 30466831 TI - Choosing a Self-Expanding Transcatheter Heart Valve in 2018: Is it Worth it to "Go PRO"? PMID- 30466832 TI - 1-Year Outcomes With the Evolut R Self-Expanding Transcatheter Aortic Valve: From the International FORWARD Study. AB - OBJECTIVES: This study sought to report the 1-year safety and efficacy outcomes in the FORWARD (CoreValve Evolut R FORWARD) study following transcatheter aortic valve replacement (TAVR) with the next-generation Evolut R device (Medtronic, Minneapolis, Minnesota) in routine clinical practice. BACKGROUND: The FORWARD study reported low incidences of mortality, disabling stroke, and significant paravalvular leak following TAVR in routine clinical practice at 30 days. Longer term results in large patient populations with the Evolut R self-expanding, repositionable transcatheter heart valve (THV) are lacking. METHODS: This was a prospective, single-arm, multinational, multicenter, observational study investigating efficacy and safety following TAVR with the next-generation self expanding THV. Between January and December 2016, 1,040 patients underwent attempted implant of the Evolut R self-expanding repositionable valve at 53 sites worldwide. An independent Clinical Events Committee adjudicated safety endpoints based on Valve Academic Research Consortium-2 definitions. An independent echocardiographic core laboratory evaluated all echocardiograms. RESULTS: The mean age was 81.8 +/- 6.2 years, 64.8% were women, and patients had a mean Society of Thoracic Surgeons Predicted Risk of Mortality score of 5.5 +/- 4.5% and EuroSCORE II of 5.7 +/- 5.0%. The 1-year all-cause mortality rate was 8.9%, with a cardiovascular mortality rate of 6.9%. At 1 year, the incidence of disabling stroke was 2.1%, and a pacemaker was implanted in 19.7% of patients. The incidence of more than mild paravalvular leak was 1.2%. CONCLUSIONS: The FORWARD study demonstrated good safety and efficacy profiles for the next generation Evolut R THV up to 1-year follow-up, with very low mortality and adverse events. (CoreValve Evolut R FORWARD Study [FORWARD]; NCT02592369). PMID- 30466833 TI - Newer Generation Transcatheter Heart Valve Devices: Moving FORWARD. PMID- 30466835 TI - The Wisdom of Restraint. PMID- 30466834 TI - Does the OPTALYSE PE Trial Cover Unmet Need in the Real-Life Practice of Pulmonary Embolism? PMID- 30466836 TI - Clinical Implications of Distal Vessel Stenosis After Successful Coronary Chronic Total Occlusion Recanalization. PMID- 30466837 TI - Repair pathway for PARP-1 DNA-protein crosslinks. AB - Poly(ADP-ribose) polymerase-1 (PARP-1) is a regulatory enzyme involved in many different processes of DNA and RNA metabolism, including DNA repair. Previously, PARP-1 was found capable of forming a covalent DNA-protein crosslink (DPC) at the apurinic/apyrimidinic (AP) site in double-stranded DNA. The C1' atom of the AP site participates in Schiff base formation with a lysine side chain in PARP-1, and a covalent bond is formed upon reduction of the Schiff base. The PARP-1 DPC is formed in vivo where DPC formation correlates with AP site induction by a monofunctional alkylating agent. Here, we examined repair of PARP-1 DPCs in mouse fibroblasts and found that a proteasome inhibitor, MG-132, reduces repair resulting in accumulation of PARP-1 DPCs and increased alkylating agent cytotoxicity. Using a model DNA substrate mimicking the PARP-1 DPC after proteasomal degradation, we found that repair is completed by a sub-pathway of base excision repair (BER). Tyrosyl-DNA phosphodiesterase 1 was proficient in removing the ring-open AP site sugar at the phosphodiester linkage, leaving an intermediate for processing by other BER enzymes. The results reveal proteasomal degradation of the PARP-1 DPC is active in mouse fibroblasts and that a model repair intermediate is processed by the BER machinery. PMID- 30466838 TI - Foreword: Contraceptive strategies for prevention of adolescent pregnancy. PMID- 30466839 TI - Contraception for adolescents with medically complex conditions. AB - Both the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) have developed, published, and updated evidence-based guidelines to support medical providers in the provision of contraceptives to patients with specific medical conditions or characteristics. The goal of these guidelines is to provide recommendations on the safe use of contraceptives with the goal of removing unnecessary medical barriers to access and use of contraceptives, thus decreasing the number of unintended pregnancies. Many medical conditions increase a patient's risk of venous thromboembolism; a risk that may also be increased with specific contraceptives. Specific conditions that require more enhanced contraceptive counseling due to their frequency in adolescence and their association either with adverse events during pregnancy or with increased risk for specific contraceptives are detailed by the WHO and CDC and are summarized herein. Adolescents with morbid obesity, migraine headache, cardiac conditions, hypertension, diabetes mellitus, hyperlipidemia, systemic lupus erythematosus, sickle cell anemia, cystic fibrosis, inflammatory bowel disease, or seizure disorders would benefit from greater attention to the urgency of exploring highly effective contraceptive methods. Details of the considerations that should be used in providing contraceptive care to adolescents with each of these medical conditions, as per WHO and CDC guidelines, are provided in this review. The ultimate goal in contraceptive counseling is the balancing of risk and benefit to arrive at the best therapeutic option, maintaining patient preference as a priority, as that will enhance adherence and comfort with the contraceptive method. Each patient must be assessed for pregnancy risk and be allowed full risk reduction and education regarding contraceptive options. PMID- 30466840 TI - Use of Long-Acting Reversible Contraception (LARC) and the Depo-Provera Shot in Adolescents. AB - The intrauterine devices (IUDs) and the subdermal implant, collectively known as long-acting reversible contraceptives (LARC), along with the Depo-Provera shot, represent highly efficacious methods of birth control for all reproductive-age women, including adolescents. They are also safe, private, and convenient, and can be used for their noncontraceptive benefits. Additionally, LARC and Depo Provera represent methods of contraception that do not contain estrogen and may be safely used in young women who have contraindications to estrogen-containing medications. The LARC methods have traditionally been underused by adolescents due to lack of knowledge and misperceptions about safety and effects on future fertility. However, studies have found that when barriers to the use of LARC are removed, adolescents have increasingly chosen the IUD and implant for birth control and most continue to use these methods with satisfaction. This chapter will provide an overview of IUDs, the subdermal implant and Depo-Provera, address barriers to care for adolescents, efficacy, continuation rates, common side effects and reasons for discontinuation, contraindications, and noncontraceptive benefits. PMID- 30466841 TI - Foreword. PMID- 30466842 TI - Current and Future Use of Insertable Cardiac Monitors. AB - Insertable cardiac monitors (ICMs) are small, subcutaneously implanted devices offering continuous ambulatory electrocardiogram monitoring with a lifespan up to 3 years. ICMs have been studied and proven useful in selected cases of unexplained syncope and palpitations, as well as in atrial fibrillation (AF) management. The use of ICMs has greatly improved our ability to detect subclinical AF after cryptogenic stroke, and application of this technology is growing. Despite this, current stroke and cardiology society guidelines are lacking in recommendations for monitoring of subclinical AF following cryptogenic stroke, including the optimal timing from stroke event, duration, and method of electrocardiogram monitoring. This focused review outlines the current society guidelines, summarizes the latest evidence, and describes current and future use of ICMs with an emphasis on detection of subclinical AF in patients with cryptogenic stroke. PMID- 30466843 TI - The Efficacy of His Bundle Pacing: Lessons Learned From Implementation for the First Time at an Experienced Electrophysiology Center. AB - OBJECTIVES: This study sought to evaluate the clinical and procedural characteristics impacting outcomes during implementation of a His bundle pacing (HBP) program in a real-world setting. BACKGROUND: Right ventricular pacing is associated with an elevated risk of heart failure, but device reprogramming and upgrades have significant challenges. HBP has emerged as an alternative and is reported to be highly successful in the hands of highly experienced centers. METHODS: All patients referred for permanent pacemaker implantation at the Valley Hospital (Ridgewood, New Jersey) between October 2015 and October 2017 were evaluated; a subset of 24% was selected for HBP. RESULTS: Permanent HBP was feasible with an acute implant success rate of 75%. HBP in the presence of bundle branch block (64% vs. 85%; p = 0.05) or complete heart block (56% vs. 83%; p = 0.03) was significantly less successful. The pattern of atrioventricular block in combination with bundle branch block (BBB) further affects outcomes. HBP is highly successful across the spectrum of atrioventricular block pattern severity in the absence of BBB. In the presence of BBB, Mobitz II AV block and complete heart block significantly attenuated HBP success compared with Mobitz I atrioventricular block (62% vs. 100%; p = 0.02). A rising threshold was observed in 30%, and 8% required lead intervention. CONCLUSIONS: HBP was feasible and readily learned with a high implant success in the hands of experienced electrophysiologists without prior exposure to the technique. BBB and atrioventricular block pattern appears to affect success. The technique is limited by a high rate of rising thresholds and lead intervention. These data have important implications for patient selection. PMID- 30466844 TI - His Bundle Pacing in the Real World: Encouraging Findings and Future Challenges. PMID- 30466845 TI - Left Ventricular Lead Location and Long-Term Outcomes in Cardiac Resynchronization Therapy Patients. AB - OBJECTIVES: The authors aimed to evaluate the association of left ventricular (LV) lead location and long-term outcomes in MADIT-CRT (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy). BACKGROUND: There is limited data on the association of lead location with long-term clinical outcomes in patients with cardiac resynchronization therapy with defibrillator (CRT-D). METHODS: The LV lead location was classified in 797 patients with CRT-D, in 569 patients with left bundle branch block (LBBB), in 228 patients with non LBBB, and in 505 patients with an implantable cardioverter-defibrillator (ICD) only. Leads were classified into apical (n = 83) and non-apical (n = 486); with the non-apical LV leads further categorized into anterior (n = 99) and posterior/lateral (n = 387) within LBBB. All-cause mortality and heart failure (HF) events were assessed using Kaplan-Meier and Cox analyses. RESULTS: In CRT-D patients with LBBB and posterior/lateral LV lead location, there was an association with a significant reduction in long-term all-cause mortality (hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.37 to 0.79; p = 0.001), and HF events (HR: 0.44, 95% CI: 0.33 to 0.60; p < 0.001) compared to an ICD only, accompanied with better LV reverse remodeling. CRT-D patients with LBBB and an anterior LV lead location were shown to be associated with a significant reduction in HF events compared to an ICD only (anterior HR: 0.50, 95% CI: 0.30 to 0.82; p = 0.006); however, no association with mortality reduction was observed from CRT-D versus an ICD only. CRT-D was not associated with improved outcomes in non-LBBB patients, regardless of LV lead location. CONCLUSIONS: In mild HF patients with LBBB and an implanted CRT-D, lateral/posterior, and anterior LV lead locations are similarly associated with reduction in the risk of HF or death events compared to ICD alone. Mortality benefit derived from CRT-D is associated only with patients with lateral/posterior LV lead location. An apical LV lead location should be avoided due to the early risk of death whenever possible. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy [MADIT-CRT], NCT00180271; Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy Post Approval Registry [MADIT-CRT-PAR], NCT01294449; and MADIT-CRT Long-Term International Follow-Up Registry - Europe, NCT02060110). PMID- 30466846 TI - Transvenous Extraction of Pacemaker and Defibrillator Leads and the Risk of Tricuspid Valve Regurgitation. AB - OBJECTIVES: The aims of this study were to detect and quantify acute increases in tricuspid regurgitation (TR) severity following transvenous lead extraction (TLE) and to evaluate the associated risk factors. BACKGROUND: Although established as a safe and effective method for lead removal, TLE is sometimes complicated by TR. METHODS: In 208 consecutive patients undergoing TLE, acute changes in TR severity were assessed by transesophageal echocardiography. A significant acute TR increase (TRI) was defined as a >=1 grade increase in TR severity and post extraction TR severity that was moderate or greater. RESULTS: Overall, 266 ventricular leads (mean lead age, 11.8 +/- 7.3 years) were extracted from the 208 patients. A significant acute TRI was observed in 24 (11.5%) of these patients. Acute TRI was associated with longer lead implant duration, extraction of pacemaker rather than defibrillator leads, anatomic injury to the tricuspid valve (TV), and longer post-extraction hospital stays. Multivariate analysis yielded only lead implant duration as an independent predictor of TLE-related acute TRI (odds ratio: 1.05; 95% confidence interval: 1.01 to 1.11; p = 0.046). When the patients were divided into 4 subgroups according to quartiles of lead age, there was a graded elevation in the rates of acute TRI (p trend = 0.048) and TV injury (p trend = 0.009) with lead implant duration. CONCLUSIONS: Following TLE, TV damage and acute TRI were commonly detected by transesophageal echocardiography, particularly in patients with advanced lead age. Lead abandonment strategies, which prolong implantation duration of future leads requiring extraction, should consider the potential long-term deleterious impact on TV function. PMID- 30466847 TI - Transvenous Extraction of Pacemaker and Defibrillator Leads and the Risk of Tricuspid Valve Regurgitation: Making a Case for Thoughtful Lead Management. PMID- 30466848 TI - Contribution of Cardiac Implantable Electronic Devices to Thrombus Formation in Patients With Chronic Thromboembolic Pulmonary Hypertension. AB - OBJECTIVES: This study aimed to identify the prevalence of cardiac implantable electronic devices (CIEDs) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and to describe the associated disease burden. BACKGROUND: CTEPH is a debilitating disease, now potentially curable with pulmonary thromboendarterectomy (PTE). The contribution of CIEDs to thrombosis in this patient population has not been previously studied. METHODS: The charts of 982 CTEPH patients, who underwent PTE between January 1, 2009, and December 31, 2015 at University of California-San Diego (UCSD) Medical Center, were reviewed for pacemakers or implantable cardioverter defibrillators (ICDs) implanted before surgery. RESULTS: Among 982 CTEPH patients who underwent PTE, 14 had pacemakers and 3 had ICDs, giving 17 CIEDs and a prevalence of 1.7%. Of these 17 CIEDs, 6 devices were extracted intraoperatively, and 5 of 6 devices were replaced with epicardial leads. Furthermore, of the 950 patients classified by intraoperative UCSD level, 12 of 17 (70.6%) patients with CIEDs had distal disease versus 241 of 933 (25.8%) patients without CIEDs (p = 0.0002). The prevalence of known venous thromboembolism (VTE) was 50% in CIED patients compared with 78.6% in patients without CIEDs (p = 0.018). CONCLUSIONS: At 1.7%, the prevalence of CIEDs in the PTE population was higher than previously reported values, which estimated CIED prevalence between 0.16% and 0.47% in the general population. Moreover, CTEPH patients with CIEDs were more strongly associated with distal disease burden and less likely to have had previous VTE, which suggested that CIEDs may be a nidus for small clots that embolize distally in the pulmonary vasculature. PMID- 30466849 TI - Cardiac Implantable Electronic Device Lead Thrombus as a Nidus for Pulmonary and Systemic Embolization. PMID- 30466851 TI - Cryo(Balloon) Ablation 4 Patients With Persistent Atrial Fibrillation: Is the Glass Half Full or Half Empty? PMID- 30466850 TI - Single-Procedure Outcomes and Quality-of-Life Improvement 12 Months Post Cryoballoon Ablation in Persistent Atrial Fibrillation: Results From the Multicenter CRYO4PERSISTENT AF Trial. AB - OBJECTIVES: The CRYO4PERSISTENT AF (Cryoballoon Ablation for Early Persistent Atrial Fibrillation) trial aims to report long-term outcomes after a single pulmonary vein isolation (PVI)-only ablation procedure using the second generation cryoballoon in persistent atrial fibrillation (PerAF) patients. BACKGROUND: Pulmonary vein isolation is recognized as the cornerstone of atrial fibrillation (AF) ablation, including ablation of PerAF. METHODS: The CRYO4PERSISTENT AF trial (NCT02213731) is a prospective, multicenter, single-arm trial designed to assess single-procedure outcomes of PVI using the cryoballoon. The primary endpoint was freedom from AF, atrial flutter, or atrial tachycardia >=30 s after a 90-day blanking period. After enrollment, but before ablation, patients without 100% AF burden (18-h Holter monitoring or 3 consecutive electrocardiograms in a time frame >=14 days) were excluded. Patients were followed at 3, 6, and 12 months, with 48-h Holter monitoring at 6 and 12 months. Quality of life and symptoms were evaluated at baseline and 12 months. Arrhythmia recurrence and adverse events were adjudicated by an independent committee. RESULTS: A total of 101 patients (62 +/- 11 years of age, 74% men, left ventricular ejection fraction 56 +/- 8%, left atrial diameter 43 +/- 5 mm) meeting criteria, undergoing cryoballoon-based PVI, with follow-up data, were included. Kaplan-Meier estimate of freedom from AF, atrial flutter, or atrial tachycardia recurrence was 60.7% at 12 months. Compared with baseline, there were significantly fewer patients with arrhythmia-related symptoms at 12 months (16% vs. 92%; p < 0.0001). The symptom reduction was supported by significant improvement in 36-Item Short Form Health Survey composite scores and European Heart Rhythm Association score at 12 months. The only device related event was transient phrenic nerve injury in 2 (2%) patients, with resolution pre-discharge. CONCLUSIONS: Cryoballoon ablation for treatment of PerAF demonstrated 61% single procedure success at 12 months post-ablation in addition to significant reduction in arrhythmia-related symptoms and improved quality of life. (Cryoballoon Ablation for Early Persistent Atrial Fibrillation [Cryo4 Persistent AF]; NCT02213731). PMID- 30466852 TI - Regular Alcohol Consumption Is Associated With Impaired Atrial Mechanical Function in the Atrial Fibrillation Population: A Cross-Sectional MRI-Based Study. AB - OBJECTIVES: This study sought to determine the impact of regular alcohol consumption on left atrial (LA) mechanical and reservoir function. BACKGROUND: Earlier studies suggest that regular alcohol intake is associated with increased atrial fibrillation (AF) and LA dilatation. METHODS: This study prospectively enrolled 160 patients with paroxysmal or persistent AF to undergo 3-T cardiac magnetic resonance (CMR) imaging in sinus rhythm. Patients self-reported alcohol consumption in standard drinks (~12 g alcohol) per week over the preceding 12 months and were categorized into 4 groups: 1) lifelong nondrinkers; 2) mild drinkers (3 to 10 standard drinks/week); 3) moderate drinkers (11 to 20 standard drinks/week); 4) heavy drinkers (>20 standard drinks/week). Permanent AF and cardiomyopathy were excluded. On CMR, maximum LA volume (LAmax) and minimum LA volume (LAmin), global LA emptying fraction (LAEF) as (LAmax - LAmin) / LAmax, and LA reservoir function as (LAmax - LAmin) / LAmin were calculated. RESULTS: Regular alcohol consumption (mean 15.8 +/- 6.9 standard drinks/week, n = 120) was associated with larger LA size (LA volume index 50 +/- 13 ml/m2 vs. 43 +/- 12 ml/m2; p = 0.005), reduction in LAEF (40 +/- 14% vs. 52 +/- 15%; p < 0.001), and reduction in reservoir function (77 +/- 48% vs. 119 +/- 63%; p < 0.001) compared with lifelong nondrinkers (n = 40). There were progressive dose-related impairments in LAEF (mild 45.4 +/- 13.5% vs. moderate 39.1 +/- 14.7% vs. heavy drinkers 35.6 +/- 12.6%; p < 0.01) and reservoir function (mild 95.8 +/- 55.6% vs. moderate 74.8 +/- 47.1% vs. heavy drinkers 61.7 +/- 34.4%; p < 0.01). Predictors of atrial mechanical dysfunction included weekly alcohol intake (p = 0.001), older age (p = 0.018), and persistent AF (p = 0.016), but not binge drinking or beverage type. CONCLUSIONS: In patients with AF, habitual alcohol consumption is associated with significantly increased LA size and atrial mechanical dysfunction compared with nondrinkers. PMID- 30466853 TI - Evaluation of Electrophysiological Mechanisms of Post-Surgical Atrial Tachycardias Using an Automated Ultra-High-Density Mapping System. AB - OBJECTIVES: This study aimed to evaluate the electrophysiological mechanisms of post-surgical atrial tachycardias (ATs) during mapping with an automated high resolution mapping system (Rhythmia, Boston Scientific, Marlborough, Massachusetts). BACKGROUND: Mapping and ablation of post-operative ATs following previous open-heart surgery is often challenging because the potential mechanisms remain incompletely understood. METHODS: Fifty-one consecutive patients underwent mapping and ablation of post-surgical ATs. RESULTS: A total of 64 ATs were identified, and the mechanism was macro re-entry in 58 of 63 (92.1%) ATs, focal in 4 ATs, localized micro re-entry in 1 AT, and undetermined in 1 AT. Of 11 patients who underwent surgical repair of congenital heart disease, 6 (54.5%) had peri-tricuspid re-entrant AT, 5 had either right atrial (RA) free-wall incisional ATs or figure-8 re-entrant ATs, with an isthmus between the tricuspid annulus and the RA free-wall incision or between the incisions, and none had left atrial (LA) or focal ATs. In 32 patients with valve replacement and 8 who underwent valvuloplasty, peri-tricuspid ATs were observed in 14 (43.4%) and 6 (75%) patients, RA free wall or septal incisions-related ATs were seen in 7 and 2 patients, and LA macro re-entrant ATs were observed in 12 patients and 1 patient, respectively. A macro pseudo re-entry pattern was identified in 8 of 51 patients (15.7%). All these activations could be easily excluded by manually moving the window of interest, except in 2 cases with a figure-8 re-entrant configuration. CONCLUSIONS: RA macro re-entrant ATs predominate, irrespective of the types of initial surgical procedures, but LA ATs occur more frequently in patients with valve replacement. Pseudo re-entry atrial activation is common and easily recognized by adjusting the mapping window. PMID- 30466854 TI - In Times of High-Density Mapping, How Much Electrophysiology Do We Still Need? PMID- 30466856 TI - Safety of Chronic Cardiac Ryanodine Receptor Modulation: A 10-Year Experience. PMID- 30466855 TI - Early Repolarization Pattern Inheritance in the Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER). AB - OBJECTIVES: This study explored early repolarization (ER) pattern inheritance between survivors of unexplained cardiac arrest (UCA) and their first-degree relatives. BACKGROUND: ER is considered a factor that confers an increased risk of sudden death. A monogenic explanation for ER is seldom evident after cascade screening. METHODS: UCA survivors and their first-degree relatives enrolled in the CASPER (Cardiac Arrest Survivors With Preserved Ejection Fraction Registry) were included in the study. ER was defined and characterized according to accepted criteria. Logistic regression was performed to explore the association between ER status in the UCA survivor and first-degree relative groups based on the presence of an ER pattern in their related family members after adjusting for age, sex, and ethnicity. RESULTS: A total of 289 patients from 14 Canadian sites were studied (age: 43.0 +/- 15.9 years; 148 women), and 945 electrocardiograms were analyzed. Seventy-five patients had the ER pattern. There was a significantly higher prevalence of the ER pattern in UCA survivors who had first degree relatives with the ER pattern (adjusted odds ratio: 5.79; 95% confidence intervals [CIs]: 1.79 to 18.7). There was also a nonsignificant higher prevalence of the ER pattern in first-degree relatives of UCA survivors with the ER pattern (OR: 2.43; 95% CI: 0.70 to 8.43). The highest prevalence of the ER pattern was seen in first-degree relatives of UCA survivors with ER syndrome (29%). CONCLUSIONS: The ER pattern appeared to be more common among UCA survivors and first-degree relatives whose related family members had similar changes on electrocardiography, which suggested that genetically complex factors contribute to electrocardiographic patterns that predispose to cardiac arrest. PMID- 30466857 TI - Cardiac Ablation by Electroporation. PMID- 30466858 TI - Reply: Cardiac Ablation by Electroporation. PMID- 30466859 TI - Split Intracardiac Potentials: Marker of Cardiac Inflammation. PMID- 30466860 TI - Dynamic Electrocardiographic Abnormalities Captured in Timothy Syndrome. PMID- 30466861 TI - Atrial Arrhythmias and Extensive Left Atrial Fibrosis as the Initial Presentation of MYH7 Gene Mutation. PMID- 30466862 TI - Novel rearrangements involving the RET gene in papillary thyroid carcinoma. AB - BACKGROUND: In the field of gene fusions driving tumorigenesis in papillary thyroid carcinoma (PTC), rearrangement of the proto-oncogene RET is the most frequent alteration. Apart from the most common rearrangement of RET to CCDC6, more than 15 partner genes are yet reported. The landscape of RET rearrangements in PTC ("RET-PTC") can notably be enlarged by modern targeted next-generation sequencing, indicating similarities between oncogenic pathways in other cancer types with identical genetic alterations. METHODS: Targeted next-generation sequencing was performed for two cases of BRAF-wild type PTC with confirmation of the results by Sanger sequencing. A "UniProt" database research was performed to assess protein alterations resulting from RET rearrangements. RESULTS: RUFY2-RET and KIAA1468-RET were detected. The fusion genes were not present in normal tissue of the index patients. The rearrangement RUFY2-RET lead to a fusion of the RET tyrosine kinase domain to a RUN domain and a coiled-coil domain. For KIAA1468 RET, a fusion to a LisH domain and two coiled-coil domains resulted. CONCLUSIONS: RUFY2-RET and KIAA1468-RET are novel RET/PTC rearrangements. The fusions were previously described in non-small cell lung cancer. The rearrangement results in a fusion of the RET tyrosine kinase to regulatory domains of RUFY2 and KIAA1468. PMID- 30466863 TI - Correction to Lancet Neurol 2018; 17: 1098-108. PMID- 30466864 TI - Countries must steer new response to turn the malaria tide. PMID- 30466865 TI - Take a pill for no more polyps: is it that simple? PMID- 30466866 TI - Eicosapentaenoic acid and aspirin, alone and in combination, for the prevention of colorectal adenomas (seAFOod Polyp Prevention trial): a multicentre, randomised, double-blind, placebo-controlled, 2 * 2 factorial trial. AB - BACKGROUND: The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) and aspirin both have proof of concept for colorectal cancer chemoprevention, aligned with an excellent safety profile. Therefore, we aimed to test the efficacy of EPA and aspirin, alone and in combination and compared with a placebo, in individuals with sporadic colorectal neoplasia detected at colonoscopy. METHODS: In a multicentre, randomised, double-blind, placebo controlled, 2 * 2 factorial trial, patients aged 55-73 years who were identified during colonoscopy as being at high risk in the English Bowel Cancer Screening Programme (BCSP; >=3 adenomas if at least one was >=10 mm in diameter or >=5 adenomas if these were <10 mm in diameter) were recruited from 53 BCSP endoscopy units in England, UK. Patients were randomly allocated (1:1:1:1) using a secure web-based server to receive 2 g EPA-free fatty acid (FFA) per day (either as the FFA or triglyceride), 300 mg aspirin per day, both treatments in combination, or placebo for 12 months using random permuted blocks of randomly varying size, and stratified by BCSP site. Research staff and participants were masked to group assignment. The primary endpoint was the adenoma detection rate (ADR; the proportion of participants with any adenoma) at 1 year surveillance colonoscopy analysed in all participants with observable follow-up data using a so-called at the-margins approach, adjusted for BCSP site and repeat endoscopy at baseline. The safety population included all participants who received at least one dose of study drug. The trial is registered with the International Standard Randomised Controlled Trials Number registry, number ISRCTN05926847. FINDINGS: Between Nov 11, 2011, and June 10, 2016, 709 participants were randomly assigned to four treatment groups (176 to placebo, 179 to EPA, 177 to aspirin, and 177 to EPA plus aspirin). Adenoma outcome data were available for 163 (93%) patients in the placebo group, 153 (85%) in the EPA group, 163 (92%) in the aspirin group, and 161 (91%) in the EPA plus aspirin group. The ADR was 61% (100 of 163) in the placebo group, 63% (97 of 153) in the EPA group, 61% (100 of 163) in the aspirin group, and 61% (98 of 161) in the EPA plus aspirin group, with no evidence of any effect for EPA (risk ratio [RR] 0.98, 95% CI 0.87 to 1.12; risk difference -0.9%, -8.8 to 6.9; p=0.81) or aspirin (RR 0.99 (0.87 to 1.12; risk difference -0.6%, 8.5 to 7.2; p=0.88). EPA and aspirin were well tolerated (78 [44%] of 176 had >=1 adverse event in the placebo group compared with 82 [46%] in the EPA group, 68 [39%] in the aspirin group, and 76 [45%] in the EPA plus aspirin group), although the number of gastrointestinal adverse events was increased in the EPA alone group at 146 events (compared with 85 in the placebo group, 86 in the aspirin group, and 68 in the aspirin plus placebo group). Six upper-gastrointestinal bleeding events were reported across the treatment groups (two in the EPA group, three in the aspirin group, and one in the placebo group). INTERPRETATION: Neither EPA nor aspirin treatment were associated with a reduction in the proportion of patients with at least one colorectal adenoma. Further research is needed regarding the effect on colorectal adenoma number according to adenoma type and location. Optimal use of EPA and aspirin might need a precision medicine approach to adenoma recurrence. FUNDING: Efficacy and Mechanism Evaluation Programme, a UK Medical Research Council and National Institute for Health Research partnership. PMID- 30466867 TI - Scholarly culture: How books in adolescence enhance adult literacy, numeracy and technology skills in 31 societies. AB - A growing body of evidence supports the contention of scholarly culture theory that immersing children in book-oriented environments benefits their later educational achievement, attainment and occupational standing. These findings have been interpreted as suggesting that book-oriented socialization, indicated by home library size, equips youth with life-long tastes, skills and knowledge. However, to date, this has not been directly assessed. Here, we document advantageous effects of scholarly culture for adult literacy, adult numeracy, and adult technological problem solving. Growing up with home libraries boosts adult skills in these areas beyond the benefits accrued from parental education or own educational or occupational attainment. The effects are loglinear, with greatest returns to the growth in smaller libraries. Our evidence comes from regressions with balanced repeated replicate weights estimated on data from 31 societies which participated in the Programme for the International Assessment of Adult Competencies (PIAAC) between 2011 and 2015. PMID- 30466868 TI - A multichannel typology of temporary employment careers in the Netherlands: Identifying traps and stepping stones in terms of employment and income security. AB - In this paper, we apply multichannel sequence analysis of labour market positions and incomes to create a typology of careers starting with temporary employment in the Netherlands. For this purpose, we use detailed register data from Statistics Netherlands for all workers who entered temporary employment in 2007 and were observed for 96 months. This approach leads to a typology of 17 different career types that shows a considerably larger variation - in terms of employment and income security - than previous research has shown. Specifically, the typology shows that 29.6% of the research population has a stepping stone career with high career and income security, while 39.7% has a dead-end career with low career and income security. However, a large part of careers - 24.7% - cannot be classified in this traditional distinction, as they combine high employment security and low incomes or high incomes and low employment security. PMID- 30466869 TI - Discrimination experience, family relations, and generalized trust in China. AB - Building upon how experiential learning theory explains sources of generalized trust, this study argues that discrimination experiences of others in individual's social network, especially those in close social ties, can have spillover influence on one's generalized trust. Empirically, this study focuses on family relations and examines whether another family member's discrimination experiences may shape an adult individual's generalized trust. Using husband-wife and parent-child linked data from the adult sample of China Family Panel Studies (CFPS) in 2012, this study confirms findings that an individual's discrimination experiences negatively impact their own level of generalized trust. Additionally, net of one's own experiences of discrimination, the disorder experienced by closely related others also affects generalized trust. This is true for effects that travel from husband to wife and wife to husband. However, these impacts are not found in parent-child relationships. The results of this study extend previous literature on sources of generalized trust by suggesting an additional mechanism whereby family members' experiences with discrimination spillover to affect generalized trust for closely related adults. PMID- 30466870 TI - Migration and children's psychosocial development in China: When and why migration matters. AB - Migration has affected a large number of children in many settings. Despite growing attention to these children, important gaps remain in our understanding of their psychosocial development, as well as the factors that mediate and moderate the impact of migration on children. The present study examines the influences of migration on children's psychosocial well-being in China using a new nationally representative survey. We compared different groups of children age 3-15, including migrant children, left-behind children, and rural and urban children in nonmigrant families. Results show that rural children left behind by both parents were significantly worse off in psychological and behavioral well being than rural nonmigrant children. By contrast, rural children left behind by one parent and migrant children were no worse off. The disadvantage of left behind children was mediated by their caregivers' emotional well-being and parenting practices. Frequent contact with migrant parents, but not receipt of remittances, helped ameliorate the vulnerability of left-behind children. These results add to our understanding of how migration affects child development in general. PMID- 30466871 TI - Personalized networks? How the Big Five personality traits influence the structure of egocentric networks. AB - In this paper, we expand previous research on the psychological foundations of social behavior by evaluating the role of the Big Five personality traits with regard to the formation of individual social networks. More precisely, we ask if personality traits significantly relate to individuals' social integration and position in their ego-network. While studies on both social capital formation and the impact of personality traits on social and political behavior have been flourishing in recent years, little is known about the main effects of personality traits, namely openness, agreeableness, conscientiousness, extraversion, and emotional stability, on the characteristics of social ties as well as the agency of egos in their networks. To test our research question, we rely on data from a Swiss population survey carried out in 2005 that combines detailed information on ties in egocentric networks and personality traits for about 1600 respondents. We show that neurotic persons have a tendency towards triad structures encompassing structural holes, whereas extroverted persons show a preference for networks with stronger ties. Moreover, our findings support the potential relationship between the three hitherto neglected personality traits - agreeableness, openness to experience, conscientiousness - with personal networks structures. PMID- 30466872 TI - Black-white differences in happiness, 1972-2014. AB - This paper examines the extent to which the black-white gap in happiness-an important indicator of subjective well-being-has narrowed over the 1972 to 2014 period. Analyzing data from the General Social Survey, we find that that the difference in levels of happiness between whites and blacks is substantial, but declined over time. Results from a decomposition analysis shed new light on the sources of change. We find that observable differences in characteristics of whites and blacks explain a significant and growing proportion of the happiness gap. The two most important characteristics are income and marital status, as both are strongly associated with race and happiness, and the proportion of the difference in the gap that they explain has generally increased over time. Overall, the declining gap in happiness is consistent with the moderate narrowing of substantial racial disparities in other realms, such as life expectancy, residential segregation, and neighborhood conditions, suggesting small steps toward equality in some realms, even as high levels of inequality persist in others. PMID- 30466873 TI - Concerted cultivation developed in a standardized education system. AB - Annette Lareau coined the term "concerted cultivation" to describe the cultural logic of a distinctive middle-class parenting pattern. I explore whether concerted cultivation as practiced in Japan exhibits unique patterns in response to distinctive characteristics of the nation's education system (i.e., standardized compulsory education with high-stakes educational selection in secondary education). Using nationally representative longitudinal data on third to sixth-grade children (N = 30187) through growth curve models, I show that college educated parents shift their focus of parenting practices (measured by four aspects) from providing diverse experiences to narrower academic preparation as the time for lower secondary education approaches. Using multivariate analyses with an additional wave of data in seventh grade, I further demonstrate that "unequal childhoods,"--the accumulated disparities in adult-led structured experiences--lead to unequal success in the transition to junior high school education, a critical period of preparation before the mass educational selection (i.e., high school admissions). PMID- 30466874 TI - Family fortunes: The persisting grandparents' effects in contemporary British society. AB - This study examines grandparents' effects on grandchildren in contemporary British society. We begin with grandchildren's occupational aspiration in their adolescent years and move on to assess their educational and class attainment in adulthood. Using the British Household Panel Survey and the UK Household Longitudinal Study, we find persisting grandparental effects in all three domains even after controlling for parents' socio-economic-cultural resources and other demographic and contextual factors. In addition, we find that self-employed grandparents have a strong impact on grandsons' (albeit not on granddaughters') likelihood of engagement in self-employment, a pattern that holds true even when parents are not self-employed. Our study shows that grandparents' class still affects grandchildren's life chances in contemporary UK society just as earlier research showed for mid-20th century Britain and that the effects are manifested at different stages of the life course, from occupational aspiration as teenagers to educational attainment as young adults to occupational destination as adults. PMID- 30466875 TI - Economic insecurity and the distribution of income volatility in the United States. AB - We examine inequalities in the distribution of income volatility in two ways using data from the Panel Study of Income Dynamics (PSID) in order to improve our understanding of economic insecurity. First, we use a variance function regression to jointly quantify the relationship between changes in average levels of volatility as they relate to changes in the distribution of volatility. The results indicate that inequalities in the distribution of volatility rise much faster than the overall level of volatility. Therefore, what are often perceived to be rising levels of volatility for everyone are better understood as rising levels of volatility for households at the top of the volatility distribution. Second, we use a linear probability model to better understand changes in who experiences high income volatility over time. Rising inequalities in the distribution of volatility turn out to be the result of a rising probability of experiencing high volatility among households that would not typically be classified as economically insecure. PMID- 30466876 TI - Pathways to retirement: Are they related to patterns of short- and long-term subjective well-being? AB - We examine the association between pathways to retirement and patterns of subjective well-being in Germany. We argue that short-term development of subjective well-being is related to social status changes while long-term development of subjective well-being is related to resources and changes in life circumstances. Importantly, we expect that how a person's social status changes and his/her access to resources post-retirement both depend on the person's specific pathway to retirement, resulting in distinct patterns of subjective well being post-retirement. Based on data from the German Socio-Economic Panel, we categorized people as retiring from employment, short- or long-term unemployment, labour market inactivity or due to disability. We then used dual-change score models to compare trajectories of life satisfaction ten years before to ten years after the retirement transition. For people retiring from employment, life satisfaction did not change in the short term but developed more positively in the long term. In comparison, people retiring from unemployment or due to disability experienced a short-term increase in life satisfaction but had more negative long-term trajectories of life satisfaction. We found no retirement related changes in life satisfaction for people retiring from inactivity. The findings suggest that different pathways to retirement are related to distinct patterns of subjective well-being and highlight the importance of late-life employment biographies for quality of life post-retirement. PMID- 30466877 TI - Fluctuating courses and constant challenges: The two trajectories of black-white earnings inequality, 1968-2015. AB - While rich literature exists on black-white earnings disparity, few studies differentiate the separate challenges facing different socioeconomic segments of the black population. Based on the Panel Study of Income Dynamics (PSID), this study explores the evolvement of black-white inequality in early-career earnings separately among college-educated and non-college-educated Americans from 1968 to 2015. The results indicate that while college-educated African Americans underwent fluctuating progress toward racial earnings equality, contingent on larger political and economic climates, African Americans of limited educational attainment experienced persistently wide earnings gaps with their white counterparts. By confirming the significance of social class on African-American economic outcomes, this study provides evidence in support of class-specific policy interventions toward racial equality. It also opens the door for subsequent research to explore specific mechanisms through which class-based racial disadvantages are operationalized. PMID- 30466878 TI - Wealth and health revisited: Economic growth and wellbeing in developing countries, 1970 to 2015. AB - Is wealthier always healthier, or are the health effects of economic growth trivial, irregular, or perhaps even detrimental? Using data for up to 134 developing countries between 1970 and 2015, this article revisits the effect of economic growth on health, focusing on infant mortality, life expectancy, and caloric consumption. The analysis enlarges the geographical and temporal scope of previous samples and attempts to isolate the causal effects of growth using two stage models with instrumental variables. Results show that five-year economic growth rates improve all three health outcomes, even after controlling for other important determinants and accounting for the possibility of reverse causality. Growth effects are largest for infant mortality rates. Nevertheless, there are diminishing returns to economic growth as a function of economic development: as countries become more affluent, the benefits of growth for health diminish. PMID- 30466879 TI - How great and how good?: Third places, neighbor interaction, and cohesion in the neighborhood context. AB - Though Ray Oldenburg's (1989) notion of "third places", or places conducive to sociality outside of the realms of home and work, has received both scholarly and popular attention over the past several decades, many of the author's central claims remain empirically untested. The present study considers the association between neighborhood third places, cohesion and neighbor interaction. Drawing on various literatures regarding interaction in public space and neighborhood use value, we consider how the role of third places might vary according to neighborhood socioeconomic context. Using data from Wave I of the Los Angeles Family and Neighborhood Study (LAFANS) and data on third places from the point based business data of ReferenceUSA, we test the effect of third places on cohesion and neighbor interaction across neighborhood poverty strata. We find support for the hypothesis that third places are associated with greater cohesion and neighbor interaction, and that neighbor interaction mediates the relationship between third places and cohesion in poor neighborhoods. PMID- 30466880 TI - Modeling the micro-macro link: Understanding macro-level outcomes using randomization tests on micro-level data. AB - Analytical sociology explains macro-level outcomes by referring to micro-level behaviors, and its hypotheses thus take macro-level entities (e.g. groups) as their units of analysis. The statistical analysis of these macro-level units is problematic, since macro units are often few in number, leading to low statistical power. Additionally, micro-level processes take place within macro units, but tests on macro-level units cannot adequately deal with these processes. Consequently, much analytical sociology focuses on testing micro-level predictions. We propose a better alternative; a method to test macro hypotheses on micro data, using randomization tests. The advantages of our method are (i) increased statistical power, (ii) possibilities to control for micro covariates, and (iii) the possibility to test macro hypotheses without macro units. We provide a heuristic description of our method and illustrate it with data from a published study. Data and R-scripts for this paper are available in the Open Science Framework (https://osf.io/scfx3/). PMID- 30466881 TI - Till multiculturalism do us part: Multicultural policies and the national identification of immigrants in European countries. AB - How do multicultural policies affect immigrants' identification with the country of destination? Theory suggests that these policies may have two opposite effects and either widen or diminish the gap between the national identification of natives and immigrants. In addition to these opposite effects, I expect that the effects of multicultural policies are also diverse depending on immigrants' cultural and social distance from the host society. In this study, immigrants are categorised based on generations and origins. Using newly constructed measurements for multicultural policies, as well as European Social Survey Round 7 with 20 European countries, I conduct a multilevel analysis. The results indicate that multicultural policies diminish the gap between the national identification of natives and immigrants. However, these effects are evident only for non-European immigrants and not for European immigrants. Furthermore, I find no evidence that the effects differ for the first and second generations. PMID- 30466883 TI - Injury Prevention in Medical Education: A Systematic Literature Review. AB - OBJECTIVE: Traumatic injury is the first cause of death for Canadians aged 1 to 44 years old. To reduce the global burden of injury, the need for healthcare professionals with injury prevention proficiency is growing. The aim of this study was to review the literature to identify and analyze current injury prevention curriculums amongst medical undergraduate and residency programs. DESIGN: A systematic literature review (no date restriction was used) was conducted using Embase, Medline, ERIC, and CINAHL. Three reviewers independently selected studies, extracted data, checked accuracy, assessed risk of bias, and assessed quality. The Preferred Reporting Items for Systematic Reviews and Meta Analysis guideline was followed. The study was registered with PROSPERO, #CRD42016048805. PARTICIPANTS: Articles were included if they were peer-reviewed, published in the English language, and reported data on injury prevention and control curriculum. RESULTS: Eight hundred and twenty-four articles were identified with the initial search strategy. Internal consistency reliability, generalizability, evidence for content, criterion-related and construct validity was performed. The systematic review synthesized the characteristics (population, intervention type, outcome measures) described in the literature. This review is the first step in identifying gaps in injury prevention teaching and curriculums for medical students and residents. CONCLUSION: The number of studies reporting the incidence and/or effectiveness of injury prevention and control curriculum is limited across the literature. Therefore, there is a knowledge gap in providing injury prevention education. Given that physicians play a vital role in the prevention or control of injuries, further development of medical undergraduate and residency programs to include core concepts of injury prevention would be unquestionably paramount. PMID- 30466882 TI - Early Correction of N-Methyl-D-Aspartate Receptor Function Improves Autistic-like Social Behaviors in Adult Shank2-/- Mice. AB - BACKGROUND: Autism spectrum disorder involves neurodevelopmental dysregulations that lead to visible symptoms at early stages of life. Many autism spectrum disorder-related mechanisms suggested by animal studies are supported by demonstrated improvement in autistic-like phenotypes in adult animals following experimental reversal of dysregulated mechanisms. However, whether such mechanisms also act at earlier stages to cause autistic-like phenotypes is unclear. METHODS: We used Shank2-/- mice carrying a mutation identified in human autism spectrum disorder (exons 6 and 7 deletion) and combined electrophysiological and behavioral analyses to see whether early pathophysiology at pup stages is different from late pathophysiology at juvenile and adult stages and whether correcting early pathophysiology can normalize late pathophysiology and abnormal behaviors in juvenile and adult mice. RESULTS: Early correction of a dysregulated mechanism in young mice prevents manifestation of autistic-like social behaviors in adult mice. Shank2-/- mice, known to display N-methyl-D aspartate receptor (NMDAR) hypofunction and autistic-like behaviors at postweaning stages after postnatal day 21 (P21), show the opposite synaptic phenotype-NMDAR hyperfunction-at an earlier preweaning stage (~P14). Moreover, this NMDAR hyperfunction at P14 rapidly shifts to NMDAR hypofunction after weaning (~P24). Chronic suppression of the early NMDAR hyperfunction by the NMDAR antagonist memantine (P7-P21) prevents NMDAR hypofunction and autistic-like social behaviors from manifesting at later stages (~P28 and P56). CONCLUSIONS: Early NMDAR hyperfunction leads to late NMDAR hypofunction and autistic-like social behaviors in Shank2-/- mice, and early correction of NMDAR dysfunction has the long-lasting effect of preventing autistic-like social behaviors from developing at later stages. PMID- 30466884 TI - Using Mobile Text and Media to Complement Teaching in a Facial Reconstruction Training Module in Haiti. AB - OBJECTIVES: (1) To describe electronic communication between global surgeons and trainees in a low-middle income country (LMIC) and to gauge appeal of the WhatsApp platform (2) To introduce a novel intensive ear reconstruction teaching module for surgical capacity building using simulation in a LMIC. DESIGN: Prospective cohort study. SETTING: University-based medical center in Haiti. PARTICIPANTS: Eleven otolaryngology trainees and faculty in Haiti. RESULTS: Three months prior to on-site arrival, a WhatsApp Messenger group was created for information-sharing and distribution of teaching materials. A surgical curriculum was created to incorporate didactics, cartilage framework simulation, and live surgery. During the intensive on-site week, WhatsApp was used to distribute materials and to recap learning points from each case, with pre- and postoperative surgical photographs circulated. Postmodule written, oral, and practical testing was conducted on the final day, and a postmodule survey was administered a month later. Post-tests scores were significantly improved from pretests scores. Initial scores on the written, oral, and practical tests averaged 24.6%. Postmodule scores averaged 86.9% (p < 0.001). Participants rated the use of WhatsApp to be highly important to their learning and requested further use of mobile health technology. CONCLUSIONS: WhatsApp Messenger technology complemented a reconstructive surgery education module in a LMIC. WhatsApp provides opportunities for premodule patient screening, real-time discussion, and postmodule review. Its usage was well-received by Haitian otolaryngology trainees and faculty. Our results suggest that the combination of didactic teaching, simulated surgery, and live surgery resulted in successful transfer of both skills and knowledge. PMID- 30466885 TI - Defining the Content for a Quality and Safety in Surgery Curriculum Using a Nominal Group Technique. AB - OBJECTIVE: There is growing awareness of the need to provide surgical residents with training in quality and safety. Previous studies have revealed a need for a formal curriculum, but the content and structure of such a curriculum has not been defined. Our objective was to develop a surgery resident curriculum using a consensus, team-building approach. DESIGN: This study consisted of moderated, structured focus groups using a nominal group technique to guide discussion. Participants generated rank lists of topics to be included and answered questions regarding structure and design of teaching and assessment modalities. SETTING: Two separate focus groups among 9 surgical residents and 10 faculty experts in quality and safety were held in conjunction with the American College of Surgeons Quality and Safety Conference in July 2017. A total of 16 institutions were represented. RESULTS: A total of 35 topics were initially proposed by the resident group and a total of 41 topics were proposed by the expert group. After discussion, each group reached consensus on a final list of 9 topics. Most topics in the final lists fell into the broad areas of improvement science and nontechnical skills. Residents indicated that most topics were, on average, poorly covered by their current training program, however, a wide range was noted within each topic. Faculty indicated a preference for didactic instructional methods and assessment using multiple-choice questions. CONCLUSIONS: Quality and safety are integral components of surgical training. Learners and experts agreed that topics within the domains of improvement science and nontechnical skills should be included in a formal curriculum. Learners reported wide variation on how well these topics are currently included in graduate medical education training programs. PMID- 30466886 TI - A Cross-Sectional Study of Emotional Intelligence in Military General Surgery Residents. AB - OBJECTIVE: Higher emotional Intelligence (EI) is linked to improved doctor patient relationships, empathy, teamwork, communication skills, stress management, and leadership in medicine. This study analyzes the effects of age, postgraduate year (PGY), gender, and prior military experience on EI in military general surgery residents, and compares these to the general population and civilian surgery residents. DESIGN: This is a retrospective, observational study. Results were analyzed using independent sample t test and linear regression to compare general surgery residents with the normative population and civilian general surgery residents. SETTING: The general surgery department at Walter Reed National Military Medical Center, a single-center, academic institution. PARTICIPANTS: All general surgery residents, PGY 1 to 6, were surveyed at the beginning of academic year, in June 2016. RESULTS: There were no statistically discernable differences in global EI between male (n = 27) and female residents (n = 19), PGY, or prior military experience. Female general surgery residents show higher global EI, and both males and females scored higher in the self control factor than the normative population. Mid-residency, there is a nonstatistically discernible dip in many factors and facets of EI. CONCLUSIONS: Gender differences in EI present in the general population were not appreciated in our cohort of surgery residents, which confirms the results of previous studies. This may be due to the fact that general surgery residents are a more uniform group than the population at large. Additionally, our cohort of military surgery residents demonstrated similar global EI to civilian surgery residents. While PGY had no statistically discernable affect on global, facet, or factor EI, more studies are needed to longitudinally follow changes in EI over the course of surgery residency. PMID- 30466887 TI - Immunoecology of the short neck clam Paphia malabarica (Chemnitz, 1782) in a tropical monsoon-influenced estuary. AB - Understanding the variability in organism's immunological response is crucial for predicting changes at population or community level. The present study investigated the immunoecology of a commercially valuable clam Paphia malabarica in a tropical monsoon-influenced estuary. Clams were collected monthly during a year cycle, which coincided with pre-monsoon (February-May), monsoon (June September) and post-monsoon seasons (October-January). For assessment of immune functioning, selected hemocyte parameters (total hemocyte concentration, hemocyte mortality, lysosomal content, esterase activity, reactive oxygen species production, and phagocytic activity) were analyzed using flow cytometry. Simultaneously, clam's condition index, nutrients, chlorophyll a, dissolved oxygen, pH, temperature and bacterial density were also measured at the sampling site. Our results exhibited seasonal patterns in hemocyte functioning with the highest activity during the pre-monsoon season (suggestive of a suitable harvesting period) and lowest during monsoon (suggestive of a critical biological period). The critical biological period for P. malabarica was marked with compromised immune parameters inflicted by low salinity, food availability, and possibly high bacterial abundance. Also, the involvement of reproductive stress altering the hematological functioning in P. malabarica cannot be ruled out. Nutrients, dissolved oxygen, pH and temperature could not explain much of the hemocyte variability. The present study has further validated the usefulness of hemocyte as a suitable marker for understanding immunoecology of P. malabarica which is of prime importance, especially in a monsoon-influenced tropical estuarine environment. The findings of our research will be constructive in monitoring natural as well as cultivated bivalve populations of economic and ecological relevance. PMID- 30466888 TI - Towards a New Classification for Metastatic Prostate Cancer. PMID- 30466889 TI - Re: Maxine Sun, Lorenzo Marconi, Tim Eisen, et al. Adjuvant Vascular Endothelial Growth Factor-targeted Therapy in Renal Cell Carcinoma: A Systematic Review and Pooled Analysis. Eur Urol 2018;74:611-20: Systematic Review Findings on the Role of Adjuvant Vascular Endothelial Growth Factor-targeted Therapy in Renal Cell Carcinoma. PMID- 30466890 TI - Aging in Place: Implications for Continence Care for Older People. PMID- 30466891 TI - Serum Free Methylated Glutathione S-transferase 1 DNA Levels, Survival, and Response to Docetaxel in Metastatic, Castration-resistant Prostate Cancer: Post Hoc Analyses of Data from a Phase 3 Trial. AB - BACKGROUND: Glutathione S-transferase 1 (GSTP1) expression is inactivated in >90% of all prostate cancers in association with aberrant DNA methylation. Detection of serum free methylated GSTP1 (mGSTP1) DNA is associated with overall survival (OS) and response to docetaxel in metastatic castration-resistant prostate cancer (mCRPC) in test and internal validation cohorts. OBJECTIVE: To assess the relationship between serum free mGSTP1 and treatment outcomes in SYNERGY, a phase 3 multicentre randomised trial testing the addition of custirsen to first-line chemotherapy with docetaxel in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: Serum free mGSTP1 DNA was measured by a sensitive methylation-specific polymerase chain reaction assay in paired samples (baseline and after two cycles of docetaxel) from 600 patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations between serum free mGSTP1 at baseline, change in mGSTP1 after docetaxel, OS, and time to prostate-specific antigen (PSA) progression were examined using Cox proportional hazards models and Kaplan-Meier methods. RESULTS AND LIMITATIONS: Serum free mGSTP1 was detectable at baseline in 458 (81%) patients. Of those with detectable mGSTP1 at baseline, mGSTP1 became undetectable after two cycles in 243 (53%). Undetectable mGSTP1 at baseline was associated with longer OS (hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.29-0.55; p<0.00001). The event of mGSTP1 becoming undetectable after two cycles of chemotherapy was associated with longer OS (HR 0.36, 95% CI 0.29-0.46; p<0.00001) and longer time to PSA progression (HR 0.44, 95% CI 0.35-0.56; p<0.00001). Associations between mGSTP1 and clinical outcomes were independent of other established prognostic variables. Analysis was limited by the lack of radiographic progression-free survival data. CONCLUSIONS: This is the first study to externally validate the prognostic role of a circulating epigenetic biomarker in mCRPC. Further studies are needed to validate serum free mGSTP1 as a surrogate endpoint for clinical trials and as a potential clinical decision tool. PATIENT SUMMARY: In this study, we confirmed that a blood marker predicted outcomes after chemotherapy for metastatic prostate cancer. This marker may accelerate future clinical trials of new therapies and be useful in the clinic to guide treatment decisions. PMID- 30466892 TI - Re: Radiotherapy to the Primary Tumour for Newly Diagnosed, Metastatic Prostate Cancer (STAMPEDE): A Randomised Controlled Phase 3 Trial. PMID- 30466893 TI - Knowledge and attitudes of nurses in a major public hospital in Cyprus towards pressure ulcer prevention. AB - STUDY AIM: The main aim of the study was to identify the knowledge and attitudes of nurses towards pressure ulcer prevention in a major public hospital in Cyprus. MATERIAL AND METHODS: A descriptive and cross-sectional study design was used to collect the data between December 2014 and February 2015, the sample consisted of n = 102 nurses employed in a major public hospital in Cyprus. Customised and standardised Pressure Ulcer Knowledge Test and an attitudes Likert questionnaire was used to investigate both parameters. Descriptive and inferential statistics, parametric (t-test), non-parametric tests (Mann-Whitney U) and Pearson test was applied. Statistical significance was set at p = 0.05. RESULTS: The majority of the participants (44.1%) n = 45 were employed in the intensive care unit, were female (61.8%) n = 63, registered nurses (93.1%) n = 95, had more than 5 years of experience (59.4%) n = 32 and 10.8% (n = 11) had a postgraduate title. The mean value regarding the knowledge questionnaire was 16.16, IQR: 17(15-18) correct answers 77%. In the attitudes questionnaire the median value was 41.82, IQR: 43 (40-46). Knowledge and attitudes correlated positively and statistically significantly (Pearson's R = 0,223, p = 0,019). CONCLUSION: The result suggests that nurses had relatively inadequate knowledge levels and positive attitudes, attitudes and knowledges correlated statistically significantly and positively. It is proposed that through the development of educational programs and the frequent measurement of the two parameters further improvement can be achieved. PMID- 30466894 TI - Heterotopic Ossification After Stroke: Clinical Profile and Severity of Ossification. AB - BACKGROUND AND PURPOSE: The aim of this study was to evaluate heterotopic ossification (HO) prevalence after stroke, describing clinical features and investigating predictors of HO and its severity. METHODS: A cross-sectional study was carried out in 7 rehabilitation centers (Sarah Network) from 2004 to 2013. RESULTS: Among 17,794 stroke cases, 235 patients (1.3%) presented clinical and radiological evidence of HO. A log-binomial model with robust variance estimated the prevalence ratio of 1.3% in 10 years. A multinomial logistic regression was performed to investigate the predictors of HO and its severity. The presence of hemorrhagic stroke (prevalence ratio [PR] = 4.75; 95% confidence interval [CI] PR = 3.38; 6.68) and ischemic stroke with hemorrhagic transformation (PR = 3.08; 95% CI PR = 1.63; 5.81), male sex (PR = 1.60; 95% CI PR = 1.16; 2.22), spasticity (PR = 13.78; 95% CI PR = 8.59; 22.10), and cognitive impairment (PR = 1.88; 95% CI PR = 1.36; 2.60) were independently associated with HO. Patients with HO were younger (P < .0001) and presented a shorter time of disease (P = .013). Young adult patients were more likely to develop severe HO (odds ratio = 2.80, 95% CI 1.09; 7.20) than were elderly patients. Severe HO was also related to heavy alcohol consumption (2.45; 1.03-5.84) and involved 2 or more joints (5.34; 1.85 15.36). There was an association with use of invasive ventilation (6.30; 2.13 18.63) at the acute stroke phase and patients were dependent on activities of daily living after stroke (3.90; 1.00-15.19). CONCLUSIONS: Despite the small prevalence of HO after stroke, this 10-year multicenter study was able to identify several associated factors related to the management and severity of stroke as well as the hemorrhagic subtype. PMID- 30466895 TI - Efficacy of a topical formulation of selamectin plus sarolaner against induced infestations of Amblyomma americanum on cats and prevention of Cytauxzoon felis transmission. AB - Cytauxzoonosis, caused by infection with Cytauxzoon felis, is the most severe tick-borne disease of cats. The purpose of our study was to determine the efficacy of selamectin (6.0 mg/kg) plus sarolaner (1.0 mg/kg) formulated in combination (Revolution(r) Plus / Stronghold(r) Plus, Zoetis) applied topically once a month on cats for three months against induced infestations of Amblyomma americanum adults and to evaluate the effectiveness of the product in preventing the transmission of C. felis. This study was conducted in two phases. Sixteen cats were dosed with selamectin/sarolaner or a placebo (vehicle control) on Days 0, 28, and 56. In phase 1, each cat was infested with 50 (+/-5) unfed adult A. americanum on Day 4 and tick counts were conducted on Day 6 (48 h post infestation) and Day 7 (72 h post infestation) to evaluate acaricidal efficacy. In phase 2, to confirm acaricidal efficacy and evaluate prevention of C. felis transmission, each cat was infested on Day 60 with 50 (+/-5) adult A. americanum acquisition fed as nymphs on two C. felis-infected donor cats. Tick counts were conducted on Day 62 (48 h post infestation) and Day 63 (72 h post infestation). Blood samples were collected on Days -9, 60, 70, 76, and 90 and tested for infection with C. felis. Placebo cats were adequately infested on all count days, with least squares (geometric) mean live tick counts ranging from 34.0 (28.8) to 46.1 (46.0). Treatment reduced the least squares (geometric) mean counts compared to placebo by 27.1 (32.1)% and 90.4 (96.8)% on Days 6 and 7, respectively. The corresponding percent reductions were 56.4 (60.6)% and 94.7 (97.3)% on Days 62 and 63, respectively. Least squares mean counts were significantly lower in the treated group compared with the placebo group on all count days (P <= 0.0286). All cats were negative for C. felis by PCR prior to study start. In phase 2, seven cats in the control group and no cats in the selamectin/sarolaner group became infected with C. felis (P = 0.0017). Topical treatment with selamectin/sarolaner was >90% effective in reducing A. americanum tick counts 72 h after infestation and prevented the transmission of C. felis from infected ticks following the third of three monthly treatments. Revolution(r) Plus / Stronghold(r) Plus offers an option for the control of A. americanum infestations on cats and for preventing the transmission of C. felis to cats. PMID- 30466896 TI - The development of myeloperoxidase inhibitors. AB - Myeloperoxidase (MPO), an abundant hemoprotein present in neutrophils and monocytes, plays a significant role in immune surveillance and host defense mechanisms. However, increased MPO activity has been linked to a number of pathologies with compelling evidence in initiation and progression of inflammatory events. As a result, search for active compounds that can efficiently inhibit MPO activity and subsequently decrease inflammatory events has been focus of the current research. This perspective provides an overview of the development of MPO inhibitors, their mechanism of action and the review of molecules that were in clinical trials as promising MPO inhibitors. PMID- 30466897 TI - Molecular features characterizing non-peptide selectivity to the human B1 and B2 bradykinin receptors. AB - Bradykinin is produced in response to inflammation, trauma, burns, shock, allergy and some cardiovascular diseases. Actions of this peptide are mediated through two different G-protein coupled receptors, named B1 and B2 that have different pharmacological characteristics. The former is up-regulated during inflammation episodes or tissue trauma whereas, the latter is constitutively expressed in a variety of cell types. In a previous work we have characterized the molecular features that explain the observed structure-activity results for both receptors by means of molecular modeling studies, using diverse ligands for both receptors. These results were summarized in the form of two different pharmacophores that provided new insights to be used for the design of novel molecules with antagonistic profile. In the present work, we compare these pharmacophores to understand the features that characterize ligand selectivity to the two bradykinin receptors. The study shows that most of the residues involved in the binding pocket are similar in both receptors and consequently are the pharmacophores obtained. The main difference between the two pharmacophores remains on point #5 that involves a polar moiety for the B1 receptor and an aromatic ring for the B2 receptor. Accordingly, analysis of the prospective bound conformation of several non-selective small molecule ligands of the bradykinin receptors permits to conclude that fulfilment of point#5 is a requirement to produce selective ligands. However, the study also shows that this is a necessary condition only, since ligands need also to be bulky enough to avoid binding to these receptors in diverse poses. These results provide new insights for a better understanding of the molecular features that ligands are required to exhibit to be selective bradykinin ligands. PMID- 30466898 TI - Cost-effectiveness analysis of hepatitis B vaccine booster in children born to HBsAg-positive mothers in rural China. AB - OBJECTIVE: In rural areas of China with highly endemic for hepatitis B virus (HBV) infection, protective efficacy was observed in adulthood when a one-dose HBV vaccine booster was administered to high-risk children born to mothers who were positive for hepatitis B surface antigen (HBsAg). The aim of this study was to estimate the cost-effectiveness of an HBV vaccine booster in this specific group of children when given at 10 years of age. METHODS: Two potential strategies were considered: strategy 1 was a one-dose booster given if the child was negative on HBsAg screening; strategy 2 was a one-dose booster given if the child was negative on both HBsAg plus anti-HBs screening. A decision tree combined with a Markov model was developed to simulate the booster intervention process and to simulate the natural history of HBV infection in a cohort of 10 year-old children who were born to HBsAg-positive mothers. The model was calibrated based on multiple selected outcomes. Costs and quality-adjusted life years (QALYs) were measured from a societal perspective. Cost-effectiveness ratios (CERs) of the different strategies were compared in both base-case and one way sensitivity analyses. RESULTS: Compared to the current practice of 'no screening and no booster', both strategy 1 and strategy 2 were cost-saving, with CERs estimated at US$ -6961 and US$ -6872 per QALY gained, respectively. In the one-way sensitivity analysis for strategy 1, all the CERs were found to be less than US$ -5000 per QALY gained after considering the uncertainty of all the variables, including vaccination protective efficacy, natural history, behavior, and various costs and utility weights. In a 'worst case' scenario (all parameter values simultaneously being at the worst), the CER of strategy 1 increased to US$ 3263 per QALY gained, which was still less than the GDP per capita of China in 2016 (US$ 8126). CONCLUSIONS: A hepatitis B vaccine booster given to children born to HBsAg-positive mothers in rural China would be cost-effective and could be considered in HBV endemic areas. PMID- 30466899 TI - Establishment of a Predictive Model for Surgical Resection of Ground-Glass Nodules. AB - PURPOSE: To establish a predictive model for surgical resection of invasive pulmonary adenocarcinoma (IPA) presenting as ground-glass nodules (GGNs) based on a radiomics nomogram. METHODS: The CT images of 239 patients with GGNs were collected, of which 160 cases were included in the training set to construct the predictive model and 79 cases were included in the validation set to verify the established predictive model. The least absolute shrinkage and selection operator algorithm was used to select the radiomic features and construct the radiomics tagging. The predictive model for the surgical resection of IPA was constructed using the radiomics nomogram. RESULTS: The presence of IPA showed significant correlations with seven radiomics features (P < .01), which were the independent predictors. The predictive model constructed using the radiomics features performed well on the training set (area under the curve [AUC] 0.792, 95% confidence interval [CI]: 0.720-0.864) and the validation set (AUC 0.773, 95% CI: 0.668-0.877). The predictive model constructed using the clinical information alone was relatively less effective (AUC 0.711, 95% CI: 0.634-0.787). The predictive model constructed by integrating the radiomics features into the clinical information using the radiomics nomogram showed the best predictive ability and calibration in the training set (AUC 0.831, 95% CI: 0.765-0.897) and the validation set (AUC 0.816, 95% CI: 0.724-0.909). Decision curve analysis showed that radiomics nomogram has a certain clinical value. CONCLUSION: The predictive model for surgical resection of IPA constructed by integrating the radiomics features and the clinical information based on the radiomics nomogram can help clinicians control the operative node and reduce the occurrence of overtreatment. PMID- 30466900 TI - Phage Therapy: Going Temperate? AB - Strictly lytic phages have been consensually preferred for phage therapy purposes. In contrast, temperate phages have been avoided due to an inherent capacity to mediate transfer of genes between bacteria by specialized transduction - an event that may increase bacterial virulence, for example, by promoting antibiotic resistance. Now, advances in sequencing technologies and synthetic biology are providing new opportunities to explore the use of temperate phages for therapy against bacterial infections. By doing so we can considerably expand our armamentarium against the escalating threat of antibiotic-resistant bacteria. PMID- 30466901 TI - Was the Mitochondrion Necessary to Start Eukaryogenesis? AB - Arguments based on cell energetics favour the view that a mitochondrion capable of oxidative phosphorylation was a prerequisite for the evolution of other features of the eukaryotic cell, including increased volume, genome size and, eventually, phagotrophy. Contrary to this we argue that: (i) extant amitochondriate eukaryotes possess voluminous phagotrophic cells with large genomes; (ii) picoeukaryotes demonstrate that phagotrophy is feasible at prokaryotic cell sizes; and (iii) the assumption that evolution of complex features requires extra ATP, often mentioned in this context, is unfounded and should not be used in such considerations. We claim that the diversity of cell organisations and functions observed today in eukaryotes gives no reason to postulate that a mitochondrion must have preceded phagocytosis in eukaryogenesis. PMID- 30466902 TI - Dengue Outbreak in Peshawar: Clinical Features and Laboratory Markers of Dengue Virus Infection. AB - BACKGROUND: Dengue is a tropical disease caused by dengue virus (DENV). It is one of the most significant arthropod-borne viral infection. OBJECTIVES: The aim of the current study was to characterize epidemiological, clinical features and laboratory markers of dengue infection during the recent epidemic in Peshawar, KP. METHODS: During the prospective hospital-based observational study, 2000 dengue suspected cases were serologically examined at Lady Reading Hospital (LRH) Peshawar. Dengue NS1 antigen and Dengue IgG and IgM antibody ELISA tests were conducted for the confirmation of dengue infection. Data regarding the clinical features, platelet count and liver function tests were also recorded for the dengue positive patients. RESULTS: Out of total samples 415 (21%) cases including 309 (74%) male and 106 (25%) female were detected positive for the dengue infection. In the dengue positive patients, the highest prevalence was observed in the age group of 21-40years with 160 (38%) followed by the age group of 1 20years with 89 (21%) patients. Fever was recorded in 100% of the dengue patients followed by a headache and fatigue in 73% and liver abnormality observed in 70% of the cases. During laboratory examinations IgM antibody was detected in 180 cases, followed by IgG antibody in 87, NS1 antigen in 43, NS1 antigen along with IgG and IgM antibodies in 41 dengue positive cases. Another combine detection of NS1 antigen with IgM antibody, NS1 antigen with IgG antibody and both IgG and IgM antibodies was observed in 21, 21, 22 dengue cases respectively. CONCLUSION: It was concluded that the dengue infection can be early diagnosed on the basis of described clinical features and with the detection of dengue-specific NS1 antigen along with antibodies such as IgG and IgM. PMID- 30466903 TI - Prevalence, serotypes, and drug resistance of nontyphoidal Salmonella among paediatric patients in a tertiary hospital in Guangzhou, China, 2014-2016. AB - PURPOSE: Nontyphoidal Salmonella (NTS) is a common pathogen responsible for acute gastroenteritis among all ages; however, information on the prevalence, serotypes, and antibiotic susceptibility of NTS isolates is limited. We aimed to explore the characteristics of NTS isolated from paediatric patients in Guangzhou, China. METHODS: This was a retrospective study of 4586 stool culture collected at Guangzhou Women and Children's Medical Center from 2014 to 2016. RESULTS: We identified 220 (4.80%) NTS isolates in stool samples. Fourteen serotypes were identified among the 220 NTS isolates. Salmonella serotype Typhimurium was the most common serotype, representing 69.09%. The highest rate of resistance was recorded in relation to AMP (76.61%), followed by SXT (29.95%), CTX (29.93%), CHL (29.77%), CAZ (23.20%), CIP (7.51%), and CFS (7.18%). The resistance rates of NTS and serotype Typhimurium to CAZ in 2015 were significantly higher than those in 2014. The average hospitalisation duration of inpatients infected by NTS resistant to three or more clinically important agents was significantly longer than that of patients infected with NTS with less antibiotic resistance. CONCLUSION: NTS represents a major cause of paediatric gastroenteritis in Guangzhou, China, and the high level of resistance to third generation cephalosporins coupled with increasing resistance to quinolones among isolated NTS from paediatric gastroenteritis is a serious public health concern that requires continued monitoring and rational usage of antibiotics. PMID- 30466904 TI - Radiomics in Kidney Cancer: MR Imaging. AB - Renal tumors encompass a heterogeneous disease spectrum, which confounds patient management and treatment. Percutaneous biopsy is limited by an inability to sample every part of the tumor. Radiomics may provide detail beyond what can be achieved from human interpretation. Understanding what new technologies offer will allow radiologists to play a greater role in caring for patients with renal cell carcinoma. In this article, we review the use of radiomics in renal cell carcinoma, in both the pretreatment assessment of renal masses and posttreatment evaluation of renal cell carcinoma, with special emphasis on the use of multiparametric MR imaging datasets. PMID- 30466905 TI - MR Imaging of the Urinary Bladder: Added Value of PET-MR Imaging. AB - MR imaging has been increasingly getting attention for the evaluation of bladder cancer. Recent studies have been promising for the staging performance of MR imaging in the bladder cancer, although its specific role has not been established yet. Additionally, the use of hybrid imaging combining PET with MR imaging could have the potential to increase its accuracy, although more research studies are needed. PMID- 30466906 TI - Future Perspectives in Multiparametric Prostate MR Imaging. AB - Multiparametric MR imaging is being used for prostate cancer diagnosis. However, many cancers are missed and the performance needs to improve before it can be used for population-level screening. We can expect standardization of multiparametric MR imaging and increased use of quantitative multiparametric MR imaging, which will lead to more reproducible results and improved interpretation. The development and integration of new acquisition techniques and use of artificial intelligence for image interpretation can lead to implementation of new clinical MR methods. These will lead to increased adoption of multiparametric MR imaging for prostate cancer diagnosis and for guiding intervention and follow-up. PMID- 30466907 TI - MR Imaging-Guided Focal Therapies of Prostate Cancer. AB - MR imaging-guided focal therapy is a viable treatment option for patients with localized prostate cancer. After the identification of a malignant focus in the prostate gland on multiparametric MR imaging, treatment can be directed in a precise fashion to the area of interest. The goal of focal therapy is to eradicate prostate cancer while minimizing complications that can affect quality of life. Currently, the most commonly used methods of focal treatment of prostate cancer are cryotherapy, high-intensity focused ultrasound, and laser ablation. PMID- 30466908 TI - MR Imaging of the Penis and Urethra. AB - MR imaging has been increasingly used as a problem-solving adjunct after an initial ultrasound examination for a variety of penile disorders, and is the best cross-sectional imaging modality for the assessment of urethra and periurethral disease. Critical advantages of MR imaging for penile and urethra imaging include high soft tissue contrast resolution providing detailed anatomic evaluation, which is important for the demonstration and assessment of critical structures such as tunica albuginea or walls of the urethra, larger field of view for better evaluation of extent of disease, and demonstration of proteinaceous material and varying ages of the blood products. PMID- 30466909 TI - Tumors of Renal Collecting Systems, Renal Pelvis, and Ureters: Role of MR Imaging and MR Urography Versus Computed Tomography Urography. AB - Hematuria evaluation remains a common problem, particularly in patients who smoke and are at risk for urothelial tumors. Lifetime surveillance of the urothelium is often required once urothelial cancer is diagnosed. Computed tomography urography (CTU) has exquisite sensitivity and specificity for identification of renal and urothelial lesions. The examination is well accepted by patients and physicians. Possible harms include radiation exposure and contrast-induced nephropathy. MR imaging is also an accurate test, but requires longer exam times, and may not demonstrate stones. We present the technical and interpretation skills required to use MR urography and CTU effectively. PMID- 30466910 TI - MR Imaging of the Testicular and Extratesticular Tumors: When Do We Need? AB - Testicular ultrasound is typically the first-line imaging examination in evaluating scrotal pathology. However, MR imaging can often provide valuable additional information, especially when ultrasound and/or clinical examinations are inconclusive. This is particularly evident when encountering testicular or paratesticular lesions, where accurate localization and characterization are paramount for management and prognosis. After reviewing normal scrotal anatomy as seen on MR imaging and offering a sample imaging protocol, the article describes specific indications for scrotal MR imaging and highlights imaging findings unique to various benign and malignant causes. PMID- 30466911 TI - Classification and Diagnosis of Cystic Renal Tumors: Role of MR Imaging Versus Contrast-Enhanced Ultrasound. AB - Superior soft tissue and contrast resolution of MR imaging benefits sensitivity to kidney cyst features and classification, which may have an impact on patient management and outcomes. Contrast-enhanced ultrasound (CEUS) may have nearly similar sensitivity for detection of cyst features yet is dependent on patient body habitus and adequacy of visualization windows for the kidneys, which does not have the same impact on MR imaging results. Both MR imaging and CEUS may provide superior kidney cyst assessment compared with contrast-enhanced CT; however, further research is needed, particularly for the identification of role of CEUS. PMID- 30466912 TI - MR Imaging Evaluation of the Kidneys in Patients with Reduced Kidney Function: Noncontrast Techniques Versus Contrast-Enhanced Techniques. AB - MR imaging has been optimized for the evaluation of a multitude of disease processes affecting the kidneys. A wide variety of noncontrast methods are available for the evaluation of both kidney structure and function, which are especially useful in clinical scenarios that obviate the use of intravenous contrast. Contrast-enhanced methods remain important, especially for tumor evaluation, and are used increasingly for functional analysis of quantitative biometrics, such as glomerular filtration rate and kidney blood flow. PMID- 30466913 TI - Infectious and Inflammatory Diseases of the Urinary Tract: Role of MR Imaging. AB - Urinary tract infection (UTI) is among the most common of bacterial infections. Imaging studies are only required in cases of complicated UTIs. Ultrasound remains the first-line imaging method; however, CT is the gold standard for evaluation of UTIs. MR imaging's improved contrast resolution and absence of ionizing radiation may recommend its use for assessment of lower UTIs. Furthermore, MR imaging performs with diagnostic accuracy at least similar to CT in complicated UTIs, except for the identification of calculi and emphysematous pyelonephritis. In this article, the role of MR imaging for the evaluation of infectious and inflammatory disease processes of the urinary tract is reviewed. PMID- 30466914 TI - Magnetic Resonance Imaging of the Perirenal Space and Retroperitoneum. AB - Retroperitoneal diseases are frequently a great clinical challenge because of their nonspecific presentation. Diseases may be asymptomatic with indolent biological behavior, and often show a large mass at initial imaging evaluation. Magnetic resonance (MR) imaging is a powerful diagnostic technique for assessment of detailed disease location and for characterization of tissue components and vascularization of lesions, with many advantages compared with computed tomography and ultrasonography. This article presents the MR imaging features of common retroperitoneal pathologic processes. PMID- 30466915 TI - Foreword. PMID- 30466916 TI - Update on Genitourinary MR Imaging. PMID- 30466917 TI - Aggregation of the diabetes-related peptide ProIAPP1-48 measured by dynamic light scattering. AB - Islet amyloid polypeptide (IAPP1-37) or amylin is implicated in the aetiology of diabetes. It is found as amyloid along with its precursor ProIAPP1-48 in the islets of Langerhans in the pancreas. Metals have been implicated in amyloidogenesis of both IAPP and ProIAPP. Herein we have used dynamic light scattering (DLS) to investigate how Al(III) and Cu(II) influence aggregation of ProIAPP1-48 under near-physiological conditions and in a biologically-relevant timeframe. ProIAPP1-48 formed primarily sub-micron particles within 5 min (e.g. 470 nm at 15MUM peptide) that grew to micron-sized particles (1310 nm) within a 30 min timeframe. Equimolar Al(III) had little influence upon particle size at either 5 (656 nm) or 30 min (1250 nm) while Cu(II) tended to increase particle size over the same time period (731-1300 nm). It is suggested that any effects of Al(III) and Cu(II) reflected their well known tendencies to support beta-sheet or amorphous aggregates of ProIAPP1-48 respectively. PMID- 30466918 TI - Selol (Se IV) modulates adhesive molecules in control and TNF-alpha-stimulated HMEC-1 cells. AB - Selol, an organic selenitetrigliceride formulation containing selenium at +4 oxidation level, has been suggested as anticancer drug. One of the causes of several diseases including cancer may be inflammation. This study aimed at determining the activity of Selol via measuring its effect on reactive oxygen species (ROS) generation, nuclear factor kappa B (NF-kappaB) activation, intercellular cell adhesion molecules-1 (ICAM-1), vascular cell adhesive molecule 1 (VCAM-1), and plateled-endothelial cell adhesive molecule-1 (PECAM-1) levels on control and on tumor necrosis factor-alpha (TNF-alpha)-stimulated human microvascular endothelial cells (HMEC-1). Cells were treated either with Selol 5% (4 or 8 MUgSe/mL) or TNF-alpha (10 ng/mL) alone or with Selol concomitant with TNF-alpha. Selol treatment resulted in ROS generation, activation of NF-kappaB, downregulation of PECAM-1, VCAM-1 and slight upregulation ICAM-1 expression on the cell surface. TNF-alpha treatment reflected in sharp NF-kappaB activation, upregulation of both ICAM-1 and VCAM-1 in parallel with the downregulation of PECAM-1 expression on cell surface. Exposure to both compounds upregulated ICAM-1 and VCAM-1, downregulated PECAM-1 level on cell surface in parallel with no changes in level of NF-kappaB activation as compared with effects mediated by TNF alpha alone. These results points to new look at Selol action since it shows a pro-inflammatory activity in parallel with effects on CAMs expression on the cell surface of human microvascular endothelial cells. However, since Selol enhances CAMs expression level when is present concomitantly with TNF-alpha this fact might suggest that selenium present in the condition of inflammation will make it worse. PMID- 30466919 TI - The influence of the place of residence, smoking and alcohol consumption on bone mineral content in the facial skeleton. AB - BACKGROUND: Environmental factors exert their influence on the living organism throughout ontogeny. More and more often, researchers find correlations between specific environmental factors and the so-called diseases of affluence. Deficits and excess of essential elements also leave their mark on the skeleton. AIM: To investigate the influence of alcohol consumption, tobacco smoking and place of residence, according to sex and calendar age, on the concentrations of micro-, macro- and toxic elements in human facial bones. MATERIAL & METHODS: Patients undergoing surgical treatment were examined for the mineral content in the collected bone material. The bone contents of the following elements were determined: Ca, K, Mg, Na, P, Fe, Zn, Mo, Ba, Mn, Li, Be, Co, B, Sr, Cr, Pb, Cd, Ni, and Al, depending on the type of facial bone, sex, calendar age, alcohol consumption, tobacco smoking and place of residence. RESULTS: Sex and alcohol consumption showed the highest degree of correlation with the content of the minerals included in the study. Alcohol drinking was found to exert the strongest influence on women's bodies, the highest number of statistically significant correlations was demonstrated between the content of minerals in the examined bones and alcohol drinking in women. Other factors included in the analysis had a different impact on men and women, the concentrations of elements included in the study differed depending on age, tobacco smoking and place of residence. CONCLUSIONS: The observed differences in the element mineral composition of the human facial skeleton may be explained by developmental specifics and functional adaptation. However, general biological characteristics (sex, age), environmental factors (place of residence), as well as smoking and alcohol use may exert significant influence on the concentrations of micro-, macro- and toxic elements in particular regions of the human skeleton. The impact of environmental factors is a very complex phenomenon, which may be stronger or more subtle, leaving its mark on the bone structure. The environmental factors included in the analysis had a different influence on men than women. PMID- 30466920 TI - The association between blood copper concentration and biomarkers related to cardiovascular disease risk - analysis of 206 individuals in the Northern Finland Birth Cohort 1966. AB - BACKGROUND: Copper is an abundant trace element in humans where alterations in the circulating concentration could inform on chronic disease aetiology. To date, data are lacking to study how copper may associate with cardiovascular disease (CVD) risk factors in young and healthy population. Molecular evidence suggests an important role of copper in liver metabolism, an essential organ in maintaining cardiovascular health and inflammation, therefore supporting copper as an associated biomarker of the risk. OBJECTIVE: We performed a cross-sectional analysis to examine the possible associations between blood copper levels and risk factors for CVD and pre-inflammatory process. DESIGN: The data has been collected from a sub-sample set of the Northern Finland Birth Cohort 1966 (NFBC1966) at 31 years. PARTICIPANTS: The study included 206 individuals, 116 men and 90 women. To reduce environmental individual variations affecting both copper and the metabolic profile in the study sample, the participants were selected as: i) being born in Finnish Lapland and ii) living in their birth place for the last five years preceding blood sampling. MAIN OUTCOME MEASURES: Fasting blood copper concentration was measured by inductively coupled plasma mass spectrometer. The CVD risk factors included 6 metabolic clusters (30 cardiovascular and pro inflammatory factors) assessed by nuclear magnetic resonance. Multivariate linear regression analysis was performed to test the linear association between blood copper and 6 metabolic clusters for CVD risk. Associations were assessed under correction for multiple testing. RESULTS: Copper (Cu) levels were comparable in men and women, with no difference between sexes (p-value <0.60). In multiple regression models, sex adjusted, copper was associated with 9 metabolites from 4 metabolic clusters. After adjustment with BMI, copper was associated with 4 metabolites from 3 metabolic clusters: glutamine, beta-hydroxybutyrate, alpha-1 acid glycoprotein (AGP) and high-sensitive C-reactive protein (hs-CRP). After correction for multiple testing, Cu was found positively associated with only 2 biomarkers of inflammation including AGP [p = 0.04] and hs-CRP [p = 0.0001]. CONCLUSIONS: Considering the strength and limitation of the study design, the present study does not support evidence for an independent role of copper on biomarkers for CVD risk. Nevertheless, we are reporting a robust association of copper with the inflammatory load that is important to consider in light with the inflammatory component of chronic health. In addition, the association of copper with metabolites may be attributable to BMI or environmental factors associated to it, and warrants further research in large population samples. PMID- 30466921 TI - Trace elements among a sample of prisoners with mental and personality disorders and aggression: correlation with impulsivity and ADHD indices. AB - OBJECTIVES: Mental, personality and substance use disorders are over represented among prisoners and aggressive individuals. The psychopathological and biological markers linked to mental functioning remain still unclear. In particular, the role of trace elements in mental illness is still matter of debate. Here, we investigated whether trace elements are correlated to specific psychopathological phenotype groups. METHODS: Axis I and II disorders, aggression, impulsivity, adult attention deficit/hyperactivity disorders (ADHD) indices and serum levels of zinc, copper and cadmium were evaluated in 160 male prisoners. RESULTS: Using latent class analysis we could subdivide prisoners into three distinct psychopathological classes: Class 1 characterized by low prevalence of aggression, personality disorders and substance abuse/dependence (alcohol, cannabis, cocaine); Class 2 represented by low prevalence of aggression and high prevalence of personality disorders and substance abuse/dependence; Class 3 defined by high prevalence of aggression, personality disorders and substance abuse/dependence. Serum levels of zinc were higher in Class 2 and 3 compared to Class 1. Moreover, Class 3 was associated with higher scores of impulsivity and ADHD indices. CONCLUSION: Our results suggest that impulsivity but also adult ADHD indices are related to aggressive behaviour, and higher zinc levels are linked to personality disorders and addictions, but not to aggression. PMID- 30466922 TI - The relationships between blood lead levels and serum thyroid stimulating hormone and total thyroxine in the third National Health and Nutrition Examination Survey. AB - Regression analysis was used to estimate and test for relationships between the blood lead concentration and the concentrations of serum thyroid stimulating hormone and serum total thyroxine in adults, 20 years and older, participating in the third National Health and Nutrition Examination Survey. No relationship was found between the blood lead level and the concentration of serum thyroid stimulating hormone. The serum total thyroxine concentration decreased as the blood lead level increased in women, but not in men. The lowest concentration of blood lead at which a relationship could be detected was 2.1 MUg/dL and 3.9 MUg/dL for the non-pregnant and pregnant women, respectively. Hypothetical mechanisms of the action of lead are discussed. PMID- 30466923 TI - Aluminium in brain tissue in autism. PMID- 30466924 TI - Relation of selenium status to neuro-regeneration after traumatic spinal cord injury. AB - INTRODUCTION: The trace element selenium (Se) is crucial for the biosynthesis of selenoproteins. Both neurodevelopment and the survival of neurons that are subject to stress depend on a regular selenoprotein biosynthesis and sufficient Se supply by selenoprotein P (SELENOP). HYPOTHESIS: Neuro-regeneration after traumatic spinal cord injury (TSCI) is related to the Se status. STUDY DESIGN: Single-centre prospective observational study. PATIENTS AND METHODS: Three groups of patients with comparable injuries were studied; vertebral fractures without neurological impairment (n = 10, group C), patients with TSCI showing no remission (n = 9, group G0), and patients with remission developing positive abbreviated injury score (AIS) conversion within 3 months (n = 10, group G1). Serum samples were available from different time points (upon admission, and after 4, 9 and 12 h, 1 and 3 days, 1 and 2 weeks, and 1, 2 and 3 months). Serum trace element concentrations were determined by total reflection X-ray fluorescence, SELENOP by ELISA, and further parameters by laboratory routine. RESULTS: Serum Se and SELENOP concentrations were higher on admission in the remission group (G1) as compared to G0. During the first week, both parameters remained constant in C and G0, whereas they declined significantly in the remission group. Similarly, the concentration changes between admission and 24 h were most pronounced in this group of recovering patients (G1). Binary logistic regression analysis including the delta of Se and SELENOP within the first 24 h indicated an AUC of 90.0% (CI: 67.4%-100.0%) with regards to predicting the outcome after TSCI. CONCLUSION: A Se deficit might constitute a risk factor for poor outcome after TSCI. A dynamic decline of serum Se and SELENOP concentrations after admission may reflect ongoing repair processes that are associated with higher odds for a positive clinical outcome. PMID- 30466925 TI - A spatial ecological study of selenoprotein P and Keshan disease. AB - Few spatial ecological studies on selenoprotein P (SePP) and Keshan disease (KD) have been reported. The main objective of this study is to investigate the relationships of SePP with KD, economic indicators and soil selenium and to visualize the evidence for KD precise prevention and control. An ecological study design was employed. The serum SePP of 2351 subjects living in rural areas, general cities and developed cities in 15 KD endemic provinces and 13 KD non endemic provinces in China were measured. Spatial description and spatial analysis of SePP were conducted. The subjects were adults aged. The mean serum SePP level of KD endemic area residents was 14.20 mg/L, significantly lower than that in non-endemic areas, 15.30 mg/L (t = - 3.19, P = 0.0010). Serum SePP levels were low among the people in the KD endemic provinces of Shandong, Inner Mongolia, Heilongjiang, etc. The mean serum SePP level of the 2351 people was 15.04 (95% CI: 14.76 and 15.31) mg/L. The mean serum SePP levels of residents in developed cities, general cities and rural areas were 16.54 mg/L, 14.98 mg/L and 14.44 mg/L, respectively, and were significantly different (F = 17.00, P < 0.0010). Spatial regression analysis showed that the spatial distribution of SePP was positively correlated with per capita consumption expenditure and soil selenium. Selenium deficiency may still exist among residents living in the KD endemic provinces. Shandong, Inner Mongolia, and Heilongjiang should be the target provinces, visualized by spatial analysis, for KD precise prevention and control. PMID- 30466926 TI - The effect of intake of sausages fortified with beta-CD-I2 complex on iodine status and thyroid function: A preliminary study. AB - The present study evaluated influence of boiled sausages consumption fortified with beta-CD-I2 on the urinary iodine excretion (UIE) level of volunteers. Median urinary UIE level was increased from 58.02 (24.0-175.4) MUg/L to 110.6 (20.5 231.6) MUg/L during 10 days. Thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were determined by radio immunoassay analysis. As it was expected, intake of sausages fortified with beta-CD-I2 resulted in rise of FT4 level from 1.1 (0.95-1.25) to 1.23 (1.07-1.63) ng/dL, whereas TSH level decreased from 1.53 (0.47-3.37) mIU/L to 1.1 (0.51-3.17) mIU/L. A dynamic gastrointestinal model in vitro was used in order to determine possibility of 3,5-diiodotyrosine (DIT) formation during consumption of the fortified sausages. The DIT concentration was determined by HPLC-MS method and was found to be 0.38 ng/mL in sausage dialyzate. These findings indicate that beta-CD-I2 introduction as an iodine carrier in boiled sausages may help to improve iodine status and to control organic iodine species concentration. PMID- 30466927 TI - Characterization of selenium speciation in selenium-enriched button mushrooms (Agaricus bisporus) and selenized yeasts (dietary supplement) using X-ray absorption near-edge structure (XANES) spectroscopy. AB - Selenium is an essential trace element for which dietary intake is not sufficient in many parts of the world such as in Europe. Yeast and mushrooms may accumulate considerable amounts of selenium, but the chemical form in mushrooms has not been elucidated yet. Thus, we determined the selenium speciation of selenium-enriched button mushrooms in comparison to that of selenized yeast via Se K-edge XANES spectroscopy. Quantitative analysis of the XANES spectra revealed that the selenium in selenized yeast is mainly present as seleno-methionine but that in selenium-enriched button mushrooms, it is present predominantly as Se-methyl-l selenocysteine. As this form is highly bioavailable and directly enters the selenium metabolic pool, selenium-enriched mushrooms may be a good food choice to improve selenium intake. PMID- 30466928 TI - Iron status at opposite ends of the menstrual function spectrum. AB - OBJECTIVES: Although exercising women are at high risk of poor iron status, it is unknown how non-pathological, physiological menstrual function affects iron status. As such, this study investigates the association between menstrual function and iron status in exercising women with amenorrhea and exercising women with ovulatory, eumenorrheic menstrual cycles. DESIGN: Cross-sectional analysis of iron depletion prevalence, iron status indices, exercise parameters, and diet composition. METHODS: Women aged 18-35 years performing at least 2 h per week of aerobic exercise were recruited. Women with amenorrhea (AMEN) were defined by the absence of menses for at least 90 days or less than 6 menses in the past 12 months (n = 82). Women with ovulatory, eumenorrheic menstrual cycles (OvEU) were defined by the presence of ovulatory cycles of 26-35 days in length for the past 6 months (n = 109). Group differences in serum ferritin (Ft), soluble transferrin receptor (sTfR), total body iron (TBI), hemoglobin (Hb), hematocrit (Hct), iron depletion prevalence (Ft <15 MUg/L), peak oxygen consumption (VO2peak), exercise minutes per week, and diet logs were assessed. RESULTS: The prevalence of iron depletion was greater in OvEU when compared to AMEN (26% vs. 15%, p = 0.04). No significant differences were observed between AMEN and OvEU in Ft (30.2 +/- 2.2 vs. 24.9 +/- 2.6 MUg/L; p = 0.62), sTfR (5.2 +/- 1.4 vs. 4.9 +/- 1.5 mg/L; p = 0.95), TBI (5.3 +/- 2.7 vs. 4.8 +/- 3.7 mg/kg; p = 0.42), Hb (13.2 +/- 0.4 vs. 13.4 +/- 0.6 g/dL; p = 0.80), Hct (39.5 +/- 0.8% vs. 39.8 +/- 4.1%; p = 0.93), or exercise parameters. AMEN consumed more vitamin C than OvEU (269 +/- 180 vs. 129 +/- 141 mg/day, p < 0.001), but all other dietary factors were similar between AMEN and OvEU. CONCLUSION: Exercising women with ovulatory, eumenorrheic cycles are at a greater risk of iron depletion than exercising, amenorrheic women. Thus, menstrual function must be considered when screening for poor iron status in exercising women. PMID- 30466929 TI - In vitro apoptosis-induction, antiproliferative and BSA binding studies of a oxidovanadium(V) complex. AB - In our ongoing efforts to develop novel trace metal complexes with therapeutically interesting properties, a neutral mono nuclear oxidomethoxidovanadium(V) complex, [VVO(OCH3)(hpdbal-sbdt)] (1) and a MU-O bridged dinuclear oxidovanadium(V) complex, [{VVO(hpdbal-sbdt)}2MU-O] (2) [H2hpdbal-sbdt (I) is a tridentate and dibasic ONS2- donor ligand obtained through the Schiff base reaction of 2-hydroxy-5-(phenyldiazenyl)benzaldehyde (Hhpdbal) and S-benzyldithiocarbazate (Hsbdt)] have been synthesized and characterized by various analytical techniques such as TGA, EDS, ATR-IR, UV-Vis, CV, 1H NMR, 13C NMR and 51V NMR. Single-crystal X-ray diffraction analysis of 1 confirms the coordination of phenolate oxygen, imine nitrogen and thioenolate sulfur of the ligand to the vanadium center with a distorted tetragonal-pyramidal geometry. The compound 2 triggered apoptotic and reproductive death of the cancer cells in vitro with 76% and 62% growth inhibition of human breast adenocarcinoma (MCF-7) and human lung carcinoma cells (A549) respectively. The compound 2 was found to be sufficiently stable over a wide window of physiological pH. The complex 2 was studied further for its interaction with a drug carrier protein BSA with the aid of spectroscopic techniques viz. fluorescence, temperature controlled UV-vis and deconvoluted IR techniques. PMID- 30466930 TI - Low doses of methylmercury exposure during adulthood in rats display oxidative stress, neurodegeneration in the motor cortex and lead to impairment of motor skills. AB - Despite the vast distribution among tissues, the central nervous system (CNS) represents the main target of methylmercury (MeHg) toxicity. However, few studies have evaluated the effects of MeHg exposure on the CNS at equivalent doses to human environmental exposure. In our study, we evaluated the motor cortex, an important area of motor control, in adult rats chronically exposed to MeHg in a concentration equivalent to those found in fish-eating populations exposed to mercury (Hg). The parameters evaluated were total Hg accumulation, oxidative stress, tissue damage, and behavioral assessment in functional actions that involved this cortical region. Our results show in exposed animals a significantly greater level of Hg in the motor cortex; increase of nitrite levels and lipid peroxidation, associated with decreased antioxidant capacity against peroxyl radicals; reduction of neuronal and astrocyte density; and poor coordination and motor learning impairment. Our data showed that chronic exposure at low doses to MeHg is capable of promoting damages to the motor cortex of adult animals, with changes in oxidative biochemistry misbalance, neurodegeneration, and motor function impairment. PMID- 30466931 TI - Crustin-capped selenium nanowires against microbial pathogens and Japanese encephalitis mosquito vectors - Insights on their toxicity and internalization. AB - Herein, we reported a method to synthesize selenium nanowires (Cr-SeNWs) relying to purified cysteine-rich antimicrobial peptide crustin in presence of ascorbic acid. Cr-SeNWs were characterized by UV-vis, XRD, FTIR and Raman spectroscopy, as well as SEM, HR-TEM and EDAX. The UV-vis spectroscopy peak was noted at 350 nm. XRD showed the crystalline nature of Cr-SeNWs through diffraction peaks observed 2theta at 12 degrees and 28 degrees corresponding to (020), and (241) lattice planes, respectively. HR-TEM results shed light on the size of Cr-SeNWs, ranging from 17 to 47 nm. Raman spectroscopy and EDAX analysis of Cr-SeNWs showed presence of 57% selenium element. Furthermore, Cr-SeNWs showed higher antimicrobial activity on Gram-positive bacteria (Staphylococcus aureus, Enterococcus faecalis) over Gram-negative ones (Pseudomonas aeruginosa, Escherichia coli). The zone of inhibition was larger on S. aureus (50 MUg/ml = 4.0 mm, 75 MUg/ml = 7.2 mm) and E. faecalis (50 MUg/ml = 3.1 mm, 75 MUg/ml = 5.1 mm), over P. aeruginosa (50 MUg/ml = 2.1 mm, 75 MUg/ml = 4.8 mm), E. coli (50 MUg/ml = 1.3 mm, 75 MUg/ml = 4.3 mm) bacteria. The antibiofilm activity of Cr SeNWs was also investigated and biofilm reduction was observed at 75 MUg/ml. In addition, Cr-SeNWs were highly effective as larvicides against Zika virus and Japanese encephalitis mosquito vectors, i.e., Culex quinquefasciatus and Culex tritaeniorhynchus, with LC50 values of 4.15 and 4.85 mg/l, respectively. The nanowire toxicity and internalization was investigated through confocal laser scanning microscopy and histological studies. To investigate the potential of Cr SeNWs for real-world applications, we also evaluated Cr-SeNWs in hemolytic assays, showing no cytotoxicity till 5 mg/ml. Besides, higher antioxidant activity at the concentration at 100 MUg/ml was noted, if compared with purified crustin. The strong antioxidant potential of this nanomaterial can be helpful to boost the shelf-life potential of Cr-SeNWs-based pesticides and antimicrobials. PMID- 30466932 TI - The reproducibility of urinary ions in manganese exposed workers. AB - PURPOSE: Manganese (Mn) is found in environmental and occupational settings, and can cause cognitive and motor impairment. Existing Mn exposure studies have not reached consensus on a valid and reproducible biomarker for Mn exposure. METHODS: Previously, global metabolomics data was generated from urine collected in October 2014 using mass spectrometry (MS). Nine ions were found to be different between persons exposed and unexposed to Mn occupationally, though their identity was not able to be determined. Here, we investigated these nine ions in a follow up set of urine samples taken from the same cohort in January 2015, and in urine samples from a separate Mn-exposed cohort from Wisconsin. We fit an elastic net model fit using the nine ions found in the October 2014 data. RESULTS: The elastic net correctly predicted exposure status in 72% of the follow-up samples collected in January 2015, and the area under the curve of the receiver operating characteristic (ROC) curve was 0.8. In the Wisconsin samples, the elastic net performed no better than chance in predicting exposure, possibly due to differences in Mn exposure levels, or unmeasured occupational or environmental co exposures. CONCLUSIONS: This work underscores the importance of taking repeat samples for replication studies when investigating the human urine metabolome, as both within- and between-person variances were observed. Validating and identifying promising results remains a challenge in harnessing global metabolomics for biomarker discovery in occupational cohorts. PMID- 30466933 TI - LA-ICP-MS/MS improves limits of detection in elemental bioimaging of gadolinium deposition originating from MRI contrast agents in skin and brain tissues. AB - A novel analytical method to detect the retention of gadolinium from contrast agents for magnetic resonance imaging (MRI) in tissue samples of patients is presented. It is based on laser ablation - inductively coupled plasma - triple quadrupole - mass spectrometry (LA-ICP-MS/MS). Both Gd and P were monitored with a mass shift of +16, corresponding to mono-oxygenated species, as well as Zn, Ca, and Fe on-mass. This method resulted in a significantly reduced background and improved limits of detection not only for phosphorus, but also for gadolinium. These improvements were essential to perform elemental bioimaging with improved resolution of 5 MUm x 5 MUm, allowing the detection of small Gd deposits in fibrotic skin and brain tumour tissue with diameters of approximately 50 MUm. Detailed analyses of these regions revealed that most Gd was accompanied with P and Ca, indicating co-precipitation. PMID- 30466934 TI - Testing new hypotheses of neurological and immunological outcomes with aluminum containing vaccines is warranted. PMID- 30466935 TI - Trace element profile in pemphigus foliaceus and in pemphigus vulgaris patients from Southeastern Brazil. AB - Pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are autoimmune bullous diseases; they are endemic in the northeastern region of the state of Sao Paulo, Southeastern Brazil. Patients' copper (Cu), zinc (Zn), and selenium (Se) metabolic deficiencies have already been associated with PV pathogenesis in the Middle East but not in Brazil. Lead (Pb), Cu, Zn, and Se concentrations were determined in whole blood or serum samples obtained from 56 PV patients, 62 PF patients, and 135 healthy controls from the endemic region and compared. The PV patients had higher (above the reference values) Pb and lower Zn levels as compared to controls. Both the PV and the PF patients presented decreased Se levels as compared to controls. The PV, PF, and control groups did not differ in terms of Cu concentration. These results indicate that high Pb blood levels are related with environmental contamination and consequently with PV pathogenesis. Moreover, Zn and Se depletion, observed in the PV patients and in the PV and the PF patients, respectively, may result from metabolic consumption verified in chronic diseases. PMID- 30466936 TI - Micronutrient content and antioxidant enzyme activities in human breast milk. AB - Breast milk contains micronutrients that function as cofactors of antioxidant enzymes. High concentrations of iron (Fe) and copper (Cu) can increase the production of reactive oxygen species (ROS). This study aimed to assess the relationship between the activity of antioxidant enzymes (superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST)) and the concentration of the micronutrients Fe, Cu and zinc (Zn) in breast milk. Breast milk samples were collected from 108 mothers (7-10 days postpartum, transitional milk). The samples were grouped into three groups according to the number of pregnancies (one, two and three or more pregnancies), also grouped according to the body mass index (BMI) suggested by the World Health Organization (WHO) in underweight, normal weight, overweight and obese. Breast milk Fe, Cu and Zn concentrations were determined by atomic absorption spectrophotometry and the activity of the antioxidant enzymes was determined by spectrophotometry. An increase in GPx, SOD and GST activities in relation to the number of pregnancies was found (p = 0.05, p = 0.04 and p < 0.01, respectively). An inverse relationship between GST activity and BMI was found (p = 0.05). A positive correlation was observed between Cu and Zn concentrations (r = 0.52, p < 0.05). A negative correlation was found between Cu concentration and catalase activity (r = -0.22, p < 0.05); Fe content was negatively correlated with GPx and GST activities (r = -0.32, r = -0.22, respectively, p < 0.05). The activities of antioxidant enzymes (GPx, SOD and GST) may be affected by the number of pregnancies and contribute to prevent oxidation of nutritional molecules in breast milk. PMID- 30466937 TI - Quantitative trace element mapping in liver tissue from patients with Wilson's disease determined by micro X-ray fluorescence. AB - AIMS: of this investigation were to quantify copper (Cu), iron (Fe) and zinc (Zn) along with sulphur (S) and phosphorus (P) in hepatocytes and connective tissue in liver section from patients with Wilson's disease (WD) by micro Synchrotron X-ray fluorescence (MU-SRXRF). Secondly to establish two-dimensional MU-SRXRF element mappings for comparison with histologically prepared slices, and thirdly to assess whether elemental distributions are associated. METHODS: Archival liver tissues from twelve patients with end-stage cirrhosis or fulminant WD were investigated. Mutations in ATP7B have been classified before. For control seven archived normal liver tissues were investigated. MU-SRXRF measurements were performed at the DORIS III storage ring at HASYLAB/DESY (Hamburg, Germany). Two dimensional element distribution were compared with histologically prepared slices about 20-30 MUm apart from those investigated by MU-SRXRF. RESULTS: Elementary copper (Cu) could be demonstrated in all investigated liver sections simultaneously with Fe, Zn, P and S. In WD mean Cu was 20 fold increased in hepatocytes and threefold in fibrotic areas in comparison with controls. In regeneration nodules Cu was strikingly inhomogeneous distributed. Cu concentrations measured by MU-SRXRF correlated with those measured by atom absorption spectroscopy. Strong associations in their regional distribution existed between Zn and Cu or Fe and S. Moreover, differences in Cu/S were found between hepatocytes and fibrotic areas. An increase of Fe could only be documented in hepatocytes compared to fibrotic areas. With a beam size of 15 x 15 MUm two-dimensional distributions of these elements are morphologically comparable with histological section with a magnification of about 25x optic microscope. CONCLUSIONS: MU-SRXRF investigations are a valuable tool for quantifying element concentrations in biological tissues and further provide 2 dimensional information of element distribution and elemental association in a biological tissues, thus speeding up basic knowledge in a synopsis with biological and clinical data. PMID- 30466938 TI - Quantitative dried blood spot analysis for metallodrugs by laser ablation inductively coupled plasma-mass spectrometry. AB - A quantitative dried blood spot (DBS) method based on direct sampling by means of laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) is presented. Gadolinium-based contrast agents were used as model metallodrugs with a significant relevance for pharmaceutical applications. Challenges regarding the ablation of the complex blood-filter matrix were characterized and successfully addressed by a thorough adaption of the laser ablation conditions. Especially the laser fluence was optimized with respect to the particle size distribution of the generated aerosol as monitored by an optical particle counter. Thus, generation of micrometer-sized particles could be minimized in favor of smaller particles increasing the transport efficiency of the DBS ablation aerosol to the plasma and the recorded signal stability. Inhomogeneous blood drying on the porous filter paper could be compensated by the addition of an internal standard prior to blood spotting. To preserve the advantages of DBS sampling, such as small blood volumes and minimal invasiveness, the combined use of DBS and a capillary blood sampling system is demonstrated. By placing the internal standard into the capillary prior to blood sampling, a simple workflow usable for clinical application was implemented. The applicability of the developed method, achieving limits of detection and quantification in the low MUg L-1 range and covering a linear range of over four orders of magnitude, was demonstrated for blood samples containing different concentrations of the gadolinium contrast agents gadopentetate and gadoterate. PMID- 30466939 TI - Selenium-biofortified corn peptides: Attenuating concanavalin A-Induced liver injury and structure characterization. AB - The relationship between hepatoprotective effects of selenium-biofortified corn (Zea mays Linn) peptides (SeCPs) and its antioxidant ability was evaluated and the structure of SeCPs was identified. SeCPs and corn peptides (CPs) both had good antioxidant ability, and the effect of SeCPs was significantly higher than CPs within a certain concentration range (P < 0.05). Additionally, animal experiments indicated that SeCPs (200 mg/kg) had a significantly protective effect against concanavalin A (Con A) induced hepatic lesions, as it significantly declined glutamic-pyruvic transaminase (AST), alanine transaminase (ALT) activities, tumor necrosis factor alpha (TNF-alpha), interferon (IFN)-gamma contents in serum, and malondialdehyde (MDA) contents in liver (P < 0.05). Superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in liver were also significantly increased by SeCPs (P < 0.05). The amino acid composition of SeCPs with Mw < 1 kDa was mainly glutamic acid (Glu, 31.18%), leucine (Leu, 21.06%) and alanine (Ala, 13.26%). According to the retention time, the amino acid sequences of 8 selenium-biofortified corn peptides and 29 selenium-free corn peptides were identified. Our results illustrated that the mechanisms of SeCPs against Con A induced hepatic injury in mice may be related to its antioxidant ability and reduction of lipid peroxidation, inhibiting the release of immune factors, such as TNF-alpha and IFN-gamma. PMID- 30466940 TI - A new ferrous diflunisal complex and its effects on biopools of labile iron. AB - Drugs bearing metal-coordinating moieties can alter biological metal distribution. In this work, a complex between iron(II) and diflunisal was prepared in the solid state, exhibiting the following composition: [Fe(diflunisal)2(H2O)2], (Fe(dif)2). The ability of diflunisal to alter labile pools of both plasmatic and cellular iron was investigated in this work. We found out that diflunisal does not increase the levels of redox-active iron in plasma of iron overloaded patients. However, diflunisal efficiently carries iron into HeLa or HepG2 cells, inducing an iron-catalyzed oxidative stress. PMID- 30466941 TI - The toxicological analysis of lead and cadmium in prescription food for special medical purposes and modified milk products for newborns and infants available in Polish pharmacies. AB - There is currently a lack of risk assessments around Pb and Cd in prescription food for special medical purposes (FSMPs) and modified milk products available in from pharmacies in Poland. This article describes and evaluates a toxicological analysis of lead and cadmium in prescription FSMPs (n = 6) and modified milk products (n = 6) available in Polish pharmacies. The metals were determined using electrothermal atomisation atomic absorption spectrometry. To make the appropriate risk assessment, we considered (1) the levels of lead and cadmium in a powdered product, (2) the amount of the metals consumed in one portion (single exposure), (3) the daily dose depending on age (months) and body weight and (4) the weekly intake of Pb and Cd in samples in comparison to provisional tolerable weekly intake (PTWI). The results demonstrated that the samples analysed do not represent a health hazard to newborns and infants. This study is important because of the concerns around the complex risk assessment of prescription FSMP's and modified milk products available in Polish pharmacies related to lead and cadmium. PMID- 30466942 TI - Comparison of serum essential trace metals between patients with schizophrenia and healthy controls. AB - Preclinical and clinical studies have suggested that essential trace metals (ETMs) play an important role in the pathophysiology of brain-based disorders, including schizophrenia. This case-control study aimed to evaluate the association between ETMs and schizophrenia, and to further examine the association between ETMs and clinical characteristics in schizophrenia. One hundred and five (n = 105) subjects who meet DSM-IV criteria for schizophrenia between the ages of 18 and 40 were recruited for the study. One hundred and six (n = 106) age- and sex-matched healthy controls (HCs) were recruited for comparison. Serum concentrations of seven ETMs [i.e. iron (Fe), zinc (Zn), copper (Cu), cobalt (Co), manganese (Mn), nickel (Ni) and molybdenum (Mo)] were evaluated using inductively coupled plasma mass spectrometry, which allows for the quantitative analysis of multiple ETMs at a single time point. Compared to HCs, serum concentrations of Mn and Mo were significantly lower in patients with schizophrenia. In contrast, serum concentrations of Fe and Ni were significantly higher in patients with schizophrenia. Additionally, correlations between specific ETMs and metabolic parameters (particularly those related to liver and renal function) were found in patients with schizophrenia, and the correlations between every two ETMs in HCs were widely interrupted. Differential levels of selected ETMs (i.e., Mn, Mo, and Ni) were identified between patients with schizophrenia and HCs following adjustment for potential confounders. The findings here should therefore be evaluated in future studies. PMID- 30466943 TI - The comparison of zinc, copper and iron levels in serum, aorta and left internal mammarian artery tissues in coronary by-pass graft surgery patients. AB - Trace elements are crucial for vital enzymatic reactions in all metabolic processes. Zinc (Zn) acts as a co-factor for many enzymes. Copper (Cu) and iron (Fe) have pro-atherogenic effects resulting in atherosclerosis. Aorta exposing high pulsatile pressure is sensitive for atherosclerosis because of its fast metabolism and poor nutrition by diffusion from vasa vasorum. We aimed to determine the relationship between serum Zn, Cu and Fe levels with aortic and left internal mammary artery (LIMA) tissues in 33 atherosclerotic individuals who inevitably underwent coronary artery by-pass graft (CBAG) surgery that is an end point treatment for atherosclerosis. Trace elements in serum and tissues were measured using inductively coupled plasma-optical emission spectrophotometer. Pre operative (Pre-op) serum Fe levels were statistically 46% higher than post operative (Post-op) values (p = 0.009). Aortic Fe level was 49.8% higher than LIMA Fe (p = 0.0001). Our study points out the tendency of aortic tissue to atherosclerosis via pro- atherogenic effect of Fe. LIMA, being a potential graft for CBAG, is resistant to atherosclerosis with its intimal specialty of graft patency. In conclusion, serum Zn, Cu and Fe levels in atherosclerotic CBAG patients might be monitored to reveal minor alterations pre-operatively and post operatively for ameliorating the treatment and life quality. PMID- 30466944 TI - Mercury in dental amalgams: A great concern for clinical toxicology in developing countries? PMID- 30466945 TI - Effects of green tea polyphenols on trace metals level of rats on food restriction and high-fat diet. AB - Little evidence showed the interplay between tea and diet in the regulation of trace metal. Here, we examined the effects of green tea polyphenols (GTPs) on the level of trace elements (TEs) in rats on food restriction or high-fat diet. Thirty-six rats (Wistar, male) were randomly divided into 6 groups and fed on standard diet, food restriction and high-fat diet with or without GTPs (200 mg/kg bw/day) supplementation, respectively. Levels of vanadium (V), manganese (Mn), iron (Fe), copper (Cu), zinc (Zn), selenium (Se), molybdenum (Mo) and cobalt (Co) in feed, whole blood, femur and urine were measured by inductively coupled plasma mass spectrometry (ICP-MS). Blood glucose, total cholesterol (TC), triglycerides (TG), high and low density lipoprotein-cholesterol (LDL-C, HDL-C) in serum were determined. Decreased daily intakes of TEs were observed in rats on food restriction and high-fat diet. Decreased whole blood level of Zn, femur level of Co and increase urinary excretion of Se were observed in rats fed on high-fat diet. GTPs altered the whole blood level of several TEs in rats on food restriction (V, Zn, Co) or high-fat diet (V, Se), respectively, but not in rats fed on standard diet. The level of several TEs in femur and the daily urinary excretion of V and Mo were altered by GTPs in rats on all of the three diets. In addition, rats fed on high-fat diet developed dyslipidemia, which was ameliorated by GTPs. The data indicated that diet status played a role in the effects of GTPs on TEs and lipid metabolism, and trace elements may play a role in the modulation of lipid metabolic disturbances by high-fat diet and GTPs. PMID- 30466946 TI - Use of Selenium-enriched olive leaves in the feed of growing rabbits: Effect on oxidative status, mineral profile and Selenium speciation of Longissimus dorsi meat. AB - In the present study the use of Selenium-fortified olive leaves as potential dietary source of Se in rabbit nutrition was evaluated. Sixty New Zealand White rabbits (35 days of age) were randomly assigned to the following dietary treatments: standard diet (C), and C supplemented with either 10% olive leaves (OL) or 10% Selenium-fortified olive leaves (SeOL; 100 mg/L of foliar spray sodium selenate solution). At 70 days of age, 10 rabbits per group were slaughtered and the oxidative status, mineral profile and Selenium speciation of Longissimus dorsi meat was analyzed. Meat of the SeOL group exhibited better oxidative status (lower TBARS, higher GPx and alpha-tocopherol values) and a 5 fold higher Se content compared to that of the other treatments. The main Se form was SeMet (7-fold higher in the SeOL group), followed by SeCys2. The present trial demonstrates the possibility of using agro-industrial by-products as ingredients in rabbit feeds, thereby enriching meat bioactive compound content. PMID- 30466947 TI - First report of homocystinuria-megaloblastic anaemia, cobalamin E complementation type, in an Indian child. PMID- 30466948 TI - Human telomerase reverse transcriptase protein expression predicts tumour aggressiveness and survival in patients with clear cell renal cell carcinoma. AB - Human telomerase reverse transcriptase (hTERT) is an active component of telomerase and responsible for its catalytic activity, associated with cell proliferation and differentiation. For the first time, the present study was conducted to evaluate the expression and prognostic significance of hTERT in different histological subtypes of renal cell carcinoma (RCC). Expression of hTERT was examined in 176 well-defined renal tumour samples including clear cell RCCs (ccRCCs), papillary and chromophobe RCCs using immunohistochemistry on tissue microarrays. The association between hTERT expression and clinicopathological parameters as well as survival outcomes were then analysed. There was a statistically significant difference in terms of hTERT expression among various RCC subtypes. In ccRCC, increased expression of hTERT was significantly associated with advanced stage, higher grade, presence of microvascular invasion, lymph node invasion, and metastasis. Moreover, in the multivariate analysis, tumour stage and tumour size were independent predictors of the disease-specific survival (DSS). Additionally, expression of hTERT was found to be a significant predictor of worse DSS (p = 0.012) in the univariate analysis. In papillary carcinoma samples (type I and II), significant association was detected between hTERT expression and the tumour stage (p = 0.010, p = 0.050), respectively. In chromophobe RCC, no significant association was detected between expression of hTERT and clinicopathological parameters and survival data. We showed that hTERT protein expression was associated with more aggressive tumour behaviour and more advanced disease in ccRCC patients. Also, hTERT may be a novel poor prognostic indicator of DSS, if the patients are followed for more prolonged time periods. PMID- 30466949 TI - Editorial Introduction. PMID- 30466950 TI - Apparent mass of the standing human body when using a whole-body vibration training machine: Effect of knee angle and input frequency. AB - Several studies have investigated the transmission of vibration from the vibrating plate of a whole-body vibration training machine (WBVTM) to different locations on the human body. No known work has investigated the interface force between the vibrating plate of the machine and the human body. This paper investigates the effect of bending the knees and the vibration frequency on the interface force (presented as apparent mass (AM)) between the vibrating plate and the body. Twelve male subjects stood with four different knee angles (180, 165, 150 and 135 degrees ) and were exposed to sinusoidal vertical vibration at eight frequencies in the range of 17-42 Hz. The vertical acceleration and the interface force between the body and the vibrating plate were measured and used to calculate the AM. The acceleration and force depended on the frequency and were found to vary with both the adopted posture and subject. The AM generally decreased with increasing the frequency but showed a peak at 24 Hz which was clearer when the knees were bent. Bending the knees showed an effect similar to increasing the damping of a system with base excitation; increasing the damping reduced the AM in the resonance region but increased the AM at higher frequencies. Users of WBVTMs have to be careful when choosing the training posture: although, as shown in previous studies, bending the knees reduces the transmission of vibration to the spine, it increases the interface forces which might indicate increased stresses on the lower legs and joints. PMID- 30466951 TI - Classification methods can identify external constrains in swimming. AB - The purpose of the present study is to examine whether the use of fins is identifiable based on swimmers' technique and to find out technique-related features that depict fins' influence. First, a number of features were extracted from kinematic data given by movement sensors attached to swimmers' bodies during butterfly swimming technique. Then, dimensionality reduction, feature selection and classification methods were applied to the extracted features. Two classification tasks were defined, one for the three classes of long, short and no fins, attaining accuracy up to 70, 62 and 70%, respectively, and the two-class simplified version (long fins, no fins) with accuracy up to 78%. These high accuracy levels were also found statistically significant and suggest that the use of fins influences swimming technique in a recognizable way and that the selected features that depict those differences are swimming type depended. PMID- 30466952 TI - Linking hyperelastic theoretical models and experimental data of vaginal tissue through histological data. AB - Mechanical characterization of living tissues and computer-based simulations related to medical issues, has become increasingly important to improve diagnostic processes and treatments evaluation. This work proposes a link between the mechanical testing and the material model predictions through histological data of vaginal tissue. Histological data was used to link tensile testing experiments with material-dependent parameters; the approach was adequate to capture the nonlinear response of ovine vaginal tissue over a large strain range. The experimental data obtained on a previous study, has two main components: tensile testing and histological analysis of the ovine vaginal tissue. Uniaxial tensile test data and histological data were collected from three sheep groups: virgins, pregnant and parous. The distal part of vaginal wall was selected since it is prone to tears induced by vaginal delivery. The HGO (Holzapfel-Gasser Ogden) model parameters were fitted using a stochastic approach, namely the Simple Genetic Algorithm (SGA). The SGA was able to fit the experimental data successfully (R2 > 0.986). The dimensionless coefficient xi, was highly correlated with histological data. The ratio was seen to increase linearly with increasing collagen content. Coefficient xi brings a new way of interpreting and understanding experimental data; it connects the nonlinear mechanical behaviour (tensile test) with tissue's morphology (histology). It can be used as an 'inverse' (approximate) method to estimate the mechanical properties without direct experimental measurements, through basic histology. In this context, the proposed methodology appears very promising in estimating the response of the tissue via histological information. PMID- 30466953 TI - The effect of Hispanic ethnicity on surgical outcomes: An analysis of the NSQIP database. AB - BACKGROUND: Existing literature has shown racial/ethnic disparities between white and black surgical populations, however, surgical outcomes for Hispanic patients are limited in both scope and quantity. METHODS: Data from the American College of Surgeons National Surgical Quality Improvement Program from 2007 to 2015 was used to analyze surgical outcomes in approximately 3.5 million patients. RESULTS: Overall, Hispanics experienced lower odds of mortality compared to non-Hispanic White, non-Hispanic Black, and non-Hispanic American Indian or Alaska Native patients (all P < 0.0001). No difference was found in mortality odds between Hispanics and non-Hispanic Asian or Native Hawaiian patients. Hispanics experienced minimal disparities in complications as compared to non-Hispanic White and non-Hispanic Black but had a higher rate of select complications when compared to Non-Hispanic Asian, Native Hawaiian, or Pacific Islander. CONCLUSION: Hispanics, in general, had lower odds of 30-day postoperative mortality and major morbidity compared to most of the races/ethnicities included in the ACS NSQIP database. PMID- 30466954 TI - Evolving window factor analysis-multivariate curve resolution with automated library matching for enhanced peak deconvolution in gas chromatography-mass spectrometry fuel data. AB - Fuel chromatography is inherently limited by the high complexity of petroleum fuel compositions. In practice, almost no fuel components are fully resolved in gas chromatography. This is due to both insufficient peak capacity for the large number of individual components within time and chromatographic efficiency constraints, and insufficient resolving power of the stationary phase in the gas chromatography column relative to the many structurally similar isomers or homologs present in petrochemical fuels. Multidimensional approaches, longer columns and slower heating rates can offer some benefits but will not necessarily fully resolve co-eluting fuel compounds, especially within reasonable analysis times. The following work details how deconvolved mass spectral loadings, combined with library matching, provide a quality metric against which to automatically evaluate results obtained from an experimental evolving window factor analysis-multivariate curve resolution deconvolution algorithm applied to gas chromatography-mass spectrometry data. This algorithm was evaluated in the context of trace component detection in synthetic fuel data sets, dodecane and tetradecane detection in petrochemical fuels, and the detection of natural products unlikely to be present in petrochemical fuels. In the case of the trace component detection challenge, the experimental algorithm outperformed a control algorithm that utilized a singular value-based quality metric. Meanwhile, when detecting dodecane, tetradecane, and natural products in petrochemical fuels, the experimental algorithm allowed for higher-quality compound identification results than could be obtained without peak deconvolution, thus reliably improving fuel component resolution in an automated fashion. PMID- 30466955 TI - A simple field method for the determination of sulfite in natural waters: Based on automated dispersive liquid-liquid microextraction coupled with ultraviolet visible spectrophotometry. AB - Sulfite is known to be harmful to human health and associated to sulfur related environmental effects and ideally should be analyzed onsite owing to its instability. Here we describe an automated, miniaturized, and highly efficient dispersive liquid-liquid microextraction (DLLME) system that seamlessly coupled to a UV-vis spectrophotometer for the trace analysis of sulfite in natural waters. The automated DLLME system was constructed by a single syringe pump that is coupled with a multiposition valve. Nanomolar levels of sulfite could be extracted from natural water samples and injected into the hyphenated spectrophotometer for quantification. The whole analytical procedures, including chromogenic reactions, DLLME, collecting and transferring of microvolume of extracts, and spectrophotometric quantification, were automatically carried out. Key parameters that affect the performance of the method were investigated. The method allows the determination of trace levels of sulfite in the range of 15 1500 nM with a detection limit of 1.2 nM. Good reproducibility and recoveries were obtained by analyzing a series of natural water samples that were spiked with different concentration levels. The method was successfully applied to real natural water samples with satisfactory results. The proposed analytical system is light (3.9 kg), simple to use, able to be applied in the field, and sensitive enough for fresh and saline waters analysis. PMID- 30466956 TI - Lean non-alcoholic fatty liver disease. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD), with its increasing prevalence and association with various co-morbidities, such as diabetes, cardiovascular disease and metabolic syndrome, is a growing concern. Previously thought to predominantly affect obese individuals, NAFLD has been shown to occur in non-obese subjects. This subset of individuals, known to have 'lean NAFLD' or 'non-obese NAFLD', is also growing increasingly prevalent. We summarize the clinical manifestations, pathophysiology and management of lean NAFLD in both adult and pediatric populations. METHODS: Two reviewers performed an independent, formal review and analysis of the literature (PubMed and EMBASE search until April 2018). RESULTS AND CONCLUSIONS: Patients with lean NAFLD share metabolic features of insulin resistance and dyslipidemia, similar to obese patients with NAFLD. Genetic predisposition, dietary and environmental factors may play a role in the pathogenesis of lean NAFLD. Genetic and metabolic conditions should be considered as well. Currently, there are no formal recommendations for the treatment of adult or pediatric lean NAFLD; however, lifestyle changes aimed at improving overall fitness are likely to have a favorable impact. PMID- 30466957 TI - [Subcutaneous administration of trastuzumab at home: Feedback of patients treated in 2016 by Sante service]. AB - In 2013, the European Medicines Agency authorized a new pharmaceutical formulation of the trastuzumab for breast cancer treatment. The latter allows a sub-cutaneous injection that reduces significantly the injection time and permits an administration at home. This study aims to assess the experience of patients treated by trastuzumab subcutaneously at home in 2016, and the experience of the nurses who performed these injections. In 2017, a retrospective survey by phone calls could gather the impressions from 84 patients on their treatment. And 60 nurses answered to a written survey. The whole treatment session is estimated to last 30minutes to one hour by most of the patients (60%) and the nurses (85%), with an injection duration below 5 minutes (according to 71% of patients and 77% of nurses). The main side effects described were: rash (reported by 40% of patients and 52% of nurses) and pain (32% of patients and 68% of nurses). Among patients feeling pain, it was estimated as brief and weak by two thirds of them. Eighty-six per cent of patients found the session pleasant. The general impression of the nurses was also satisfying for almost all of them (89%). Overall, the feedback about subcutaneous injections of trastuzumab at home is very positive, for patients as for nurses. This new formulation improves quality and comfort in patients' care. PMID- 30466958 TI - Basophil activation test in children with autoimmune chronic spontaneous urticaria: Is it ready for clinical practice? AB - INTRODUCTION: Chronic spontaneous urticaria (CSU) is characterized by recurrent itchy wheals, angioedema or both, that persist for longer than six weeks. In children, up to 40% of chronic spontaneous urticaria is due to mast cells and basophils-activating autoantibodies, mostly directed against the IgE high affinity receptor subunit (FcepsilonRI). Indirect basophil activation test (BAT) has been proposed in the diagnosis of autoimmune urticaria. MATERIALS AND METHODS: Sera from sixteen patients, aged from 2 to 15 yrs, with CSU were evaluated through indirect BAT by flow cytometry using a commercial kit (Flow CAST(r), BUHLMANN Laboratories, Schonenbuch, Switzerland) according to the manufacturer's instructions. RESULTS: Indirect BAT test gave a much better diagnosis in our cohort than the gold standard ASST. Six children (37.5%) showed a positive indirect BAT while we could perform ASST in only 3 patients with just one patients showing a positive ASST. The specificity of BAT positive results was confirmed by the absence of significant difference between the BAT results obtained from negative controls vs negative sera of the patient (p = 0.65) on the basophil donors, indicating that the serum is not activating basophil per se. CONCLUSIONS: This pilot study suggests the utility of BAT to identify the subtype of autoimmune CSU in children in clinical practice. PMID- 30466959 TI - WDR20 regulates shuttling of the USP12 deubiquitinase complex between the plasma membrane, cytoplasm and nucleus. AB - The human deubiquitinases USP12 and USP46 are very closely related paralogs with critical functions as tumor suppressors. The catalytic activity of these enzymes is regulated by two cofactors: UAF1 and WDR20. USP12 and USP46 show nearly 90% amino acid sequence identity and share some cellular activities, but have also evolved non-overlapping functions. We hypothesized that, correlating with their functional divergence, the subcellular localization of USP12 and USP46 might be differentially regulated by their cofactors. We used confocal and live microscopy analyses of epitope-tagged proteins to determine the effect of UAF1 and WDR20 on the localization of USP12 and USP46. We found that WDR20 differently modulated the localization of the DUBs, promoting recruitment of USP12, but not USP46, to the plasma membrane. Using site-directed mutagenesis, we generated a large set of USP12 and WDR20 mutants to characterize in detail the mechanisms and sequence determinants that modulate the subcellular localization of the USP12/UAF1/WDR20 complex. Our data suggest that the USP12/UAF1/WDR20 complex dynamically shuttles between the plasma membrane, cytoplasm and nucleus. This shuttling involved active nuclear export mediated by the CRM1 pathway, and required a short N terminal motif (1MEIL4) in USP12, as well as a novel nuclear export sequence (450MDGAIASGVSKFATLSLHD468) in WDR20. In conclusion, USP12 and USP46 have evolved divergently in terms of cofactor binding-regulated subcellular localization. WDR20 plays a crucial role in as a "targeting subunit" that modulates CRM1 dependent shuttling of the USP12/UAF1/WDR20 complex between the plasma membrane, cytoplasm and nucleus. PMID- 30466960 TI - Ketogenic diet prevents impaired prepulse inhibition of startle in an acute NMDA receptor hypofunction model of schizophrenia. AB - Recent transcriptomic, proteomic and metabolomics studies have highlighted an abnormal cerebral glucose and energy metabolism as one of the potential pathophysiological mechanisms of schizophrenia. This raises the possibility that a metabolically-based intervention might have therapeutic value in the management of schizophrenia, a notion supported by our recent results that a low carbohydrate/high-fat therapeutic ketogenic diet (KD) prevented a variety of behavioural abnormalities induced by pharmacological inhibition of NMDA glutamate receptors. Here we asked if the beneficial effects of KD can be generalised to impaired prepulse inhibition of startle (PPI), a translationally validated endophenotype of schizophrenia, in a pharmacological model in mice. Furthermore, we addressed the issue of whether the effect of KD is linked to the calorie restricted state typical of the initial phase of KD. We fed male C57BL/6 mice a KD for 7 weeks and tested PPI at 3 and 7 weeks, in the presence and absence of a significant digestible energy deficit, respectively. We used an NMDA receptor hypo-function model of schizophrenia induced by acute injection of dizocilpine (MK-801). We found that KD effectively prevented MK-801-induced PPI impairments at both 3 and 7 weeks, irrespective of the presence or absence of digestible energy deficit. Furthermore, there was a lack of correlation between PPI and body weight changes. These results support the efficacy of the therapeutic KD in a translational model of schizophrenia and furthermore provide evidence against the role of calorie restriction in its mechanism of action. PMID- 30466961 TI - Predicting Inpatient Status After Total Hip Arthroplasty in Medicare-Aged Patients. AB - BACKGROUND: The Centers for Medicare and Medicaid Services has solicited comments regarding the removal of total hip arthroplasty (THA) from its inpatient-only list. The goal of this study is to develop and internally validate a risk stratification nomogram to aid in the identification of optimal inpatient candidates in this patient population. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was utilized to identify all patients >65 years of age who underwent primary THA between 2006 and 2015. Inpatient stay was the primary outcome measure, as defined by stay >2 days in length. The impact of numerous demographic, comorbid, and perioperative variables was assessed through a multivariable logistic regression analysis to construct a predictive nomogram. RESULTS: In total, 30,587 inpatient THAs and 17,024 outpatient THAs were analyzed. Heart failure (odds ratio [OR] 2.11, P = .001), simultaneous bilateral THA (OR 2.47, P < .0001), age >80 years (OR 2.91, P < .0001), female gender (OR 1.90, P < .0001), and dependent functional status (OR 1.89, P < .0001) were the most influential determinants of inpatient status. The final prediction algorithm showed good accuracy, excellent calibration, and internal validation (bias-corrected concordance index of 0.69). CONCLUSION: Our model enabled accurate and simple identification of the best candidates for inpatient admission after THA in Medicare-aged patients. Given the increasing feasibility of outpatient THA coupled with the likelihood of THA being removed from the Centers for Medicare and Medicaid Services inpatient-only list, this model provides a framework to guide discussion and decision-making for stakeholders. PMID- 30466962 TI - Letter to the editor: Are thyroid function abnormalities only related to antipsychotic treatment in patients with severe mental disorders? PMID- 30466963 TI - Remembering. PMID- 30466964 TI - Mutational analysis of gene function in the Anaplasmataceae: Challenges and perspectives. AB - Mutational analysis is an efficient approach to identifying microbial gene function. Until recently, lack of an effective tool for Anaplasmataceae yielding reproducible results has created an obstacle to functional genomics, because surrogate systems, e.g., ectopic gene expression and analysis in E. coli, may not provide accurate answers. We chose to focus on a method for high-throughput generation of mutants via random mutagenesis as opposed to targeted gene inactivation. In our search for a suitable mutagenesis tool, we considered attributes of the Himar1 transposase system, i.e., random insertion into AT dinucleotide sites, which are abundant in Anaplasmataceae, and lack of requirement for specific host factors. We chose the Anaplasma marginale tr promoter, and the clinically irrelevant antibiotic spectinomycin for selection, and in addition successfully implemented non-antibiotic selection using an herbicide resistance gene. These constructs function reasonably well in Anaplasma phagocytophilum harvested from human promyelocyte HL-60 cells or Ixodes scapularis tick cells. We describe protocols developed in our laboratory, and discuss what likely makes them successful. What makes Anaplasmataceae electroporation competent is unknown and manipulating electroporation conditions has not improved mutational efficiency. A concerted effort is needed to resolve remaining problems that are inherent to the obligate intracellular bacteria. Finally, using this approach, we describe the discovery and characterization of a putative secreted effector necessary for Ap survival in HL-60 cells. PMID- 30466965 TI - Risk factors associated with the carriage of Ixodes scapularis relative to other tick species in a population of pet dogs from southeastern Ontario, Canada. AB - In eastern North America, the blacklegged tick, Ixodes scapularis, is the vector for Borrelia burgdorferi sensu stricto and Anaplasma phagocytophilum, the causal agents for human and canine Lyme disease and anaplasmosis, respectively. The extensive range expansion of I. scapularis in Ontario is a growing veterinary and public health concern. However, there is limited information on the risk factors associated with I. scapularis carriage on dogs. Within an emerging area for Lyme disease risk in southeastern Ontario, we identified the tick species carried by dogs; determined the prevalence of B. burgdorferi and A. phagocytophilum in I. scapularis; and examined associations between pet demographics, travel history, and geographical location and the odds of: a dog carrying I. scapularis relative to other tick species (i.e., case-case design), and a removed I. scapularis being infected with B. burgdorferi. Seven species of ticks were collected from 543 companion dogs at 20 participating veterinary hospitals from April to December 2015. Ixodes scapularis were detected on 85.6% of parasitized dogs, and 7.5% of these dogs were carrying at least one B. burgdorferi-positive tick. Based on a multivariable logistic regression model, the odds of I. scapularis infestation relative to other tick species was significantly higher in fall and spring compared to summer, with closer proximity to Lake Ontario, in female compared to male dogs, in dogs weighing over 30 kg compared to lighter dogs, and in dogs that had not visited a farm in the 7 days prior to tick removal. Based on univariable exact logistic regression models, the odds of B. burgdorferi-positive I. scapularis carriage relative to B. burgdorferi-negative I. scapularis were significantly higher for dogs that traveled in the 14 days prior to tick removal, for those dogs under 1 year of age, and for those weighing less than 10 kg. This case-case study provides information for veterinarians and public health practitioners to help protect dogs and their owners from Lyme disease in southeastern Ontario. PMID- 30466966 TI - The role of STAT3 protein as a prognostic factor in the clear cell renal carcinoma. Systematic review. AB - CONTEXT AND OBJECTIVE: There have been significant advances in the knowledge of renal carcinogenesis n the last years. Nowadays, renal tumors are classified according to their genetic profile and specific treatments based on the identification of therapeutic targets have also been developed. However, no prognostic markers have yet been identified. The aim of this review is to analyse literature that has evaluated the expression of the STAT3 protein as a molecular marker in clear cell renal carcinoma (ccRCC). EVIDENCE ACQUISITION: In January 2018 a systematic review was conducted in Pubmed, Cochrane library and Sciencedirect databases, from papers published from 1990. Search terms were"renal cell carcinoma"and"STAT3"or"STAT-3"and"prognostic factor. Following the principles of the PRISMA declaration and the PICO selection strategy, original articles with series of patients diagnosed with localized or metastatic ccRCC, and where the activity of STAT3 is analysed as a prognostic marker, were selected. A total of 132 publications were identified, of which 10 were finally revised, for they met the inclusion criteria. EVIDENCE SYNTHESIS: STAT3 activation (phosphorylation) through Ser727 is important during ccRCC development and progression. PSTAT3 expression seems to be a prognostic marker and an antiangiogenic-resistance marker in metastatic patients. There is little evidence as prognostic marker in patients with localized disease. CONCLUSIONS: STAT3 (Ser 727) expression in the nucleus of the ccRCC cells can be a prognostic marker and an antiangiogenic-resistance marker. Current scientific evidence is limited and more studies are needed to demonstrate its usefulness. PMID- 30466967 TI - Health and Access to Care among Reproductive-Age Women by Sexual Orientation and Pregnancy Status. AB - BACKGROUND: A large body of research has documented disparities in health and access to care among sexual minority populations, but very little population based research has focused on the health care needs among pregnant sexual minority women. METHODS: Data for this study came from 3,901 reproductive-age (18 44 years) women who identified as lesbian or bisexual and 63,827 reproductive-age women who identified as heterosexual in the 2014-2016 Behavioral Risk Factor Surveillance System. Logistic regression models were used to compare health care access, health outcomes, and health behaviors by sexual orientation and pregnancy status while controlling for demographic characteristics and socioeconomic status. RESULTS: Approximately 3% of reproductive-age sexual minority women were pregnant. Pregnant sexual minority women were more likely to have unmet medical care needs owing to cost, frequent mental distress, depression, poor/fair health, activity limitations, chronic conditions, and risky health behaviors compared with pregnant heterosexual women. Nonpregnant sexual minority women were more likely to report barriers to care, activity limitations, chronic conditions, smoking, and binge drinking compared with nonpregnant heterosexual women. Health outcomes were similar between pregnant and nonpregnant sexual minority women, but pregnant sexual minority women were more likely to smoke cigarettes every day compared with other women. CONCLUSIONS: This study adds new population-based research to the limited body of evidence on health and access to care for pregnant sexual minority women who may face stressors, discrimination, and stigma before and during pregnancy. More research and programs should focus on perinatal care that is inclusive of diverse families and sexual orientations. PMID- 30466968 TI - Flavonoids isolated from Tibetan medicines, binding to GABAA receptor and the anticonvulsant activity. AB - BACKGROUND: Our previous studies on Asterothamnus centrali-asiaticus Novopokr. (ACN) and Arenaria kansuensis Maxim. (AKM) had led to the isolation of some phytochemical constituents and evaluation of anticonvulsant effect based on their extracts. ACN and AKM have been widely used in traditional Tibetan herbs for neuropsychiatric diseases and cardiopulmonary disorders. PURPOSE: The purpose is to investigate structure-activity relationships of flavonoids isolated from ACN and AKM, for binding to the benzodiazepine site (BZ-S) of gamma-aminobutyric acid type A (GABAA) receptor complex, and to search for anticonvulsant compounds without undesirable effects such as myorelaxation and sedation. STUDY DESIGN AND METHODS: The affinities of these flavonoids for the BZ-S of GABAA receptors were determined by [3H]flunitrazepam binding to mouse cerebellum membranes in vitro. And the anticonvulsant, myorelaxant and sedative effects were determined by pentylenetetrazol (PTZ)-induced seizure and electrogenic seizure protection, rotarod test and locomotor activity test, respectively. RESULTS: Fifteen and thirteen flavonoids were isolated from ACN and AKM, respectively. Structure activity relationships analysis indicated that 6-and/or 8-OMe flavones exhibited the most potent binding affinity to GABAA receptors. Furthermore, 2',4',5,7 tetrahydroxy-5',6-dimethoxyflavone (DMF, IC50 value of 0.10 MUM), a flavone isolated from ACN, presented high anticonvulsant activity against chemical induced seizures and electrogenic seizures, without myorelaxation and sedation. CONCLUSION: This study suggested that these flavones, especially DMF, are new BZ receptor ligands and prospective therapeutic candidates for seizures. PMID- 30466969 TI - Immunometabolic regulation by triterpenes of Eucalyptus tereticornis in adipose tissue cell line models. AB - BACKGROUND: Eucalyptus tereticornis Sm (Myrtaceae) is a plant used in traditional medicine to control obesity, insulin resistance and diabetes. Chronic adipose tissue inflammation is involved in generating insulin resistance, the greatest risk factor in developing type 2 diabetes mellitus and cardiovascular disease. In the present study, a mixture of triterpenes, as obtained from the starting plant material, was evaluated in inflamed adipose tissue cells models. AIM: Our goal is to advance into the understanding, at the cellular level, of the immunometabolic effects of the triterpene mixes from Eucalyptus tereticornis in in vitro models of mouse and human adipose tissues. METHODS: Triterpene mixes were obtained from Eucalyptus tereticornis leaves by organic extraction. The major compounds of these mixes were identified by 1H NMR and 13C NMR in addition to HPLC using primary and secondary standards of ursolic acid, oleanolic acid and ursolic acid lactone. To provide an approach for evaluating the cellular and molecular mechanisms through which triterpene mixes act to modify the metabolic processes associated with obesity, mouse macrophage and adipocyte cell lines, human macrophage cell line and primary culture of human adipocytes were used as models. RESULTS: Adipocytes treated with the two natural chemically characterized triterpene mixes partially reduce lipogenesis and leptin expression. Additionally, an increase in the transcriptional expression of PPARgamma, and C/EBPalpha is observed. In macrophages, these triterpene mixes, decrease the transcriptional and translational expression of pro-inflammatory cytokines, such as interleukin-6 (IL-6), interleukin 1beta (IL-1beta) and tumoral necrosis factor alpha (TNFalpha). Conditioned medium of 3T3-L1 adipocytes treated with the triterpene mix shows a stronger anti-inflammatory response on activated J774A.1 macrophages. CONCLUSION: The mixtures of the three triterpenes in the proportions obtained from the plant material may act on different components of the cell, generating a different response, which, in some cases, is more powerful than that seen when exposure to only two triterpenes. It makes this three triterpenes mix a good phytotherapeutic prototype for pathologies as complex as those associated with obesity. PMID- 30466970 TI - Sesquiterpene lactones from Ambrosia arborescens Mill. inhibit pro-inflammatory cytokine expression and modulate NF-kappaB signaling in human skin cells. AB - BACKGROUND: Ambrosia arborescens has been used in Andean traditional medicine to reduce problems associated with various inflammatory diseases and conditions, although the underlying mechanism is unknown. HYPOTHESIS/PURPOSE: The sesquiterpene lactones (SLs) coronopilin and damsin, which are major secondary metabolites of A. arborescens, have anti-inflammatory activity by attenuation of IL-6 and MCP-1 expression and inhibition of NF-kappaB in human dermal fibroblasts (HDFa) and human keratinocytes (HaCaT). STUDY DESIGN: In order to confirm a high concentration of damsin and coronopilin in the plant material, a quantitative method was developed. The effect of the pure compounds on cytokine and NF-kappaB expression was examined, as well as their effects on HDFa and HaCaT cell morphology and viability. METHODS: Coronopilin and damsin were quantified by HPLC DAD analysis, from EtOAc extracts of the aerial parts of A. arborescens. Cell morphology was investigated by phase-contrast microscopy and cell viability by the MTT assay. IL-6 and MCP-1 cytokine gene expression was assessed by quantitative real-time RT-PCR in LPS stimulated cells. The NF-kappaB pathway was studied through western blotting of the phosphorylated forms of p65 and p50/p105, as well as the non-phosphorylated IkappaB. Dexamethasone was used as positive control. RESULTS: Dry aerial parts contained 12.3 mg/g and 13.4 mg/g of coronopilin and damsin, respectively. Treatment with either compound (1-10 uM) for 24 h attenuated LPS-induced mRNA expression of the pro-inflammatory cytokine IL-6 and the chemokine MCP-1 in HDFa cells. The down-regulation of MCP-1 mRNA induced by coronopilin and damsin was confirmed on the protein level. Damsin reduced phosphorylated p65 and p105 subunits in HDFa cells. Neither coronopilin nor damsin affected HDFa cell morphology and viability within the used concentration range (1-10 uM). Also, in HaCaT cells, treatment with damsin (1-10 uM) for 24 h inhibited the MCP-1 expression, and damsin thereby attenuated cytokine expression both in HDFa and HaCaT cells. CONCLUSION: We show that coronopilin and damsin from A. arborescens inhibit pro-inflammatory IL-6 and MCP 1 expression in human skin cells via NF-kappaB inhibition, suggesting that they may be useful for antagonizing inflammatory conditions of the human skin. PMID- 30466971 TI - Metabolomic and biotechnological approaches to determine therapeutic potential of Withania somnifera (L.) Dunal: A review. AB - BACKGROUND: Withania somnifera, a high value medicinal plant is a major source of pharmaceutically important active compounds withanolides. Withania somnifera has been used in ayurveda as health restorative and anabolic agent besides having anti-arthritic, antidepressant, anti-microbial, anti-inflammatory, anti-diabetic, anti-stress, neuroprotective and cardio-protective activities. HYPOTHESIS/PURPOSE: The mining of the compound(s) of interest offers opportunity to identify desired attributes in the therapeutic area of interest. Metabolomic has become an important tool in the field of pharmacological and functional genomics of medicinal plants. The analysis supports the information regarding differential outline of the gene expression for increasing important withanolides viz. withanolide A and withaferin A in W. somnifera. STUDY DESIGN: The bioinformatics and biotechnological approaches viz. tissue culture, genetic transformation, genomic, transcriptomic, proteomic, gene mining and metabolomic studies have opened new windows about engineering of withanolide production. METHODS: Target and network analysis for maximum therapeutic potential of Withania somnifera have been determined by employing Genemania software for finding interactions among various human genes that are being affected by active constituents. RESULTS: Some of the major bioactive compounds of Withania somnifera have been discussed on protein-protein, protein-DNA and genetic interactions with respect to gene and protein expression data, protein domains, metabolic profiling, root organ culture, genetic transformation and phenotypic screening profiles CONCLUSION: The implementation of latest bioinformatic tools in combination with biotechnological techniques for breeding platforms are important in conservation of medicinal plant species in danger. The current review is based on molecular and in vitro methodologies employed in W. somnifera for accepting their importance in the improvement of this valuable medicinal species. PMID- 30466972 TI - Phytochemical and pharmacological aspects of Cnidoscolus Pohl species: A systematic review. AB - BACKGROUND: Cnidoscolus is a genus belonging to the Euphorbiaceae family, distributed in South American countries, such as Mexico and Brazil, which includes several species widely used in folk medicine. However, the genus is not sufficiently exploited from a chemical and pharmacological point of view. HYPOTHESIS/PURPOSE: This paper aims to present a systematic review of known pharmacological and chemical aspects from Cnidoscolus, an important genus for South America research groups on medicinal plants. In this article, we highlight the importance of Cnidoscolus species in the search for new bioactive molecules. STUDY DESIGN: A systematic review was conducted in order to collect chemical and pharmacological information on species of this genus in the last 25 years. METHODS: Literature search was performed through specialized databases (PUBMED, LILACS, SCIELO, Science Direct and Web of Science) using different combinations of the following keywords: Cnidoscolus, phytochemistry, pharmacological activity. For the selection of the manuscripts, two independent investigators (RGOJ and CAAF) first selected the articles according to the title, then to the abstract and finally through an analysis of the full-text publication. All selected manuscripts were analyzed for year of publication, country where the research was performed, reported plant species, isolated chemical compounds and evaluated biological activities. RESULTS: Most of the studies involving Cnidoscolus were conducted by research groups located in Brazil, Nigeria and Mexico. Regarding the annual evolution of the publications, a larger number of articles published in 2014 were observed. Flavonoids, triterpenes and diterpenes represent the main classes of secondary metabolites that have been isolated from Cnidoscolus. In terms of the pharmacological investigations, C. aconitifolius, C. chayamansa and C. quercifolius are considered the most studied species, with different pharmacological activities. CONCLUSION: All findings indicate that Cnidoscolus is an important genus of the Euphorbiaceae family. However, considering its chemical and pharmacological importance, the studies developed with Cnidoscolus species are still limited, representing an opportunity to investigate new bioactive molecules. PMID- 30466973 TI - Metal-plant frameworks in nanotechnology: An overview. AB - BACKGROUND: Since ancient times, potential of plants in research and medicine have found pronounced applications, due to better therapeutic value. To meet the mounting demands for commercial nanoparticles, novel eco-friendly methods of synthesis has led to a remarkable progress via unfolding a green synthesis protocol towards metallic nanoparticles synthesis. HYPOTHESIS/PURPOSE: This review highlights the biological synthesis of various metallic nanoparticles as safe, cost effective process, where the phytochemicals present in extract such as flavonoid, phenols, terpenoids act as capping, reducing and stabilizing agents. Moreover, due to their nano size, the nanoparticles directly bind to bacterial strains leading to higher antimicrobial activity. CONCLUSION: Nano-sized dosage systems have a potential for enhancing the activity and overcoming problems associated with phyto medicines. Hence, synthesis of metallic nanoparticles using various plant extracts, emerge as safe alternative to conventional methods for biomedical applications. PMID- 30466974 TI - Eulophia macrobulbon extract relaxes rat isolated pulmonary artery and protects against monocrotaline-induced pulmonary arterial hypertension. AB - BACKGROUND: Extract of the wild orchid, Eulophia macrobulbon (EM) inhibits phosphodiesterase5 (PDE5) suggesting it could preferentially dilate the pulmonary vasculature. PURPOSE AND STUDY DESIGN: To pharmacologically characterize the vascular actions of EM ethanolic extract and its active compound, 1-(4' hydroxybenzyl)-4,8-dimethoxyphenanthrene-2,7-diol using isolated pulmonary arteries (PA) from rats having pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). PA were fixed and prepared for histology. RESULTS: EM extract relaxed PA (EC50 = 0.17 mg/ml, Emax ~ 94%) but less so for aorta (EC50 = 0.51 mg/ml, Emax ~ 62%), suggesting some selectivity towards the pulmonary circulation. PA vasorelaxation was reduced by endothelial removal or NG-nitro-L arginine methyl ester, but unaffected by indomethacin, apamin +charybdotoxin, 4 aminopyridine, glibenclamide, iberiotoxin, or 1H - [1,2,4]oxadiazolo[4,3 a]quinoxalin -1- one. Sodium nitroprusside-induced relaxation was enhanced by EM extract, probably via PDE5 inhibition. EM extract reduced contractions evoked by extracellular Ca2+application, and inhibited intracellular Ca2+release activated by phenylephrine. The phenanthrene relaxed PA independently of the endothelium. MCT thickened walls and decreased lumens of PA, and hypertrophied right ventricular myocytes, effects ameliorated by 3 weeks of oral sildenafil (20 mg/kg) or EM extract (15, 450 or 1000 mg/kg). CONCLUSION: PAH is improved by EM extract acting through PA relaxation mediated through endothelial NO, reduced Ca2+-mobilization, and reduced PA wall thickness and right ventricular hypertrophy. PMID- 30466975 TI - Pentacyclic triterpenes: New tools to fight metabolic syndrome. AB - BACKGROUND: Metabolic syndrome is a combination of dysregulated cardiometabolic risk factors characterized by dyslipidemia, impaired glucose tolerance, insulin resistance, inflammation, obesity as well as hypertension. These factors are tied to the increased risk for type-II diabetes and cardiovascular diseases including myocardial infarction in patients with metabolic syndrome. PURPOSE: To review the proposed molecular mechanisms of pentacyclic triterpenes for their potential use in the metabolic syndrome. METHODS: PubMed, Science Direct, and Google Scholar database were searched from commencement to April 2018. Following keywords were searched in the databases with varying combinations: "metabolic syndrome", "pentacyclic triterpenes", "transcription factors", "protein kinase", "lipogenesis", "adipogenesis", "lipolysis", "fatty acids", "gluconeogenesis", "cardiovascular", "mitochondria", "oxidative stress", "pancreas", "hepatic cells", "skeletal muscle", "3T3-L1", "C2C12", "obesity", "inflammation", "insulin resistance", "glucose uptake", "clinical studies" and "bioavailability". RESULTS: Pentacyclic triterpenes, such as asiatic acid, ursolic acid, oleanolic acid, 18beta-glycyrrhetinic acid, alpha,beta-amyrin, celastrol, carbenoxolone, corosolic acid, maslinic acid, bardoxolone methyl and lupeol downregulate several metabolic syndrome components by regulating transcription factors, protein kinases and enzyme involved in the adipogenesis, lipolysis, fatty acid oxidation, insulin resistance, mitochondria biogenesis, gluconeogenesis, oxidative stress and inflammation. CONCLUSION: In vitro and in vivo studies suggests that pentacyclic triterpenes effectively downregulate various factors related to metabolic syndrome. These phytochemicals may serve as promising candidates for clinical trials for the management of metabolic syndrome. PMID- 30466976 TI - DNA barcoding for specific and sensitive detection of Cuminum cyminum adulteration in Bunium persicum. AB - BACKGROUND: Bunium persicum commonly called as Kala zeera, a very high value herbaceous spice used for medicinal purposes is often adulterated with Cuminum cyminum or Safed zeera, a closely related species. Lack of distinctive morphological features makes the identification of genuine kala zeera from its adulterant difficult, the problem is even exaggerated in case of powdered material. METHODOLOGY: Genomic DNA was extracted from all the plant materials by using CTAB-SDS method (Moller et al., 1992) with slight modifications. On the basis of reproducibility and high amplification ability, four universal barcoding loci viz. ITS2, rbcL-a, mat K and psbA-trnH and a specific locus Cum were used in the present study. The amplified PCR products were sequenced bidirectionally and assembled to obtain contigs. The sequences thus obtained were aligned using MUSCLE algorithm (Edgar, 2004) and information pertaining to conserved/ variable/ parsimony informative sites, number of transitions, transversions and Indels was obtained after analyzing the sequences. RESULTS AND CONCLUSION: Among the tested barcoding loci, psbA-trnH has proven to be best barcode in authentication of kala zeera as its amplification and sequencing success was high and it showed the presence of polymorphic sites to detect interspecific variation. This barcode could differentiate between safed zeera and kala zeera in a single reaction, simultaneously. PMID- 30466977 TI - Induction of apoptosis by essential oil from P. missionis in skin epidermoid cancer cells. AB - BACKGROUND: The genus Pamburus (Rutaceae) comprises the only species, Pamburus missionis (Wight) Swingle. Pamburus missionis is traditionally used in the treatment of swellings, chronic rheumatism, paralysis and puerperal diseases. PURPOSE: The present study investigates the cancer chemotherapeutic potential of essential oil (EO) from P. missionis. METHODS: EO was isolated by steam distillation and chemical composition was determined by GC-MS. Cell viability was used to detect cytotoxic activity. Mechanism of cell death was studied using Annexin V-FITC/PI binding, cell cycle analysis, measurement of MMP and ROS generation by flow cytometry. Expression of apoptosis related proteins was investigated by western blot. RESULTS: GC-MS analysis of the essential oil revealed the presence of 51 components. The major components were beta Caryophyllene, 4(14),11-Eudesmadiene, Aromadendrene oxide-(2) and Phytol. EO inhibited the growth and colony formation ability of A431 and HaCaT cells. EO treatment induced nuclear condensation and loss of membrane integrity, DNA fragmentation, increase in sub-G1 DNA content and increase in intracellular ROS level. Inhibition of intracellular ROS by ascorbic acid and N-acetyl cysteine treatment blocked EO induced apoptosis, revealing that apoptotic activity was by ROS accumulation. EO induced apoptosis was found to be due to the loss of mitochondrial membrane potential (DeltaPsim), increase in Bax/Bcl-2 ratio, release of cytochrome c and activation of caspases (cleaved form of caspase-3, caspase-8, caspase-9) and by PARP cleavage. CONCLUSION: The present study revealed cancer chemotherapeutic potential of EO from P. missionis. EO induces cell death through intrinsic (mitochondrial) and extrinsic apoptotic pathway in A431 and HaCaT cells. These results suggest that EO could be used as a potential therapeutic agent for the treatment of skin epidermoid cancer. PMID- 30466978 TI - Indicaxanthin from Opuntia Ficus Indica (L. Mill) impairs melanoma cell proliferation, invasiveness, and tumor progression. AB - BACKGROUND: A strong, reciprocal crosstalk between inflammation and melanoma has rigorously been demonstrated in recent years, showing how crucial is a pro inflammatory microenvironment to drive therapy resistance and metastasis. PURPOSE: We investigated on the effects of Indicaxanthin, a novel, anti inflammatory and bioavailable phytochemical from Opuntia Ficus Indica fruits, against human melanoma both in vitro and in vivo. STUDY DESIGN AND METHODS: The effects of indicaxanthin were evaluated against the proliferation of A375 human melanoma cell line and in a mice model of cutaneous melanoma. Cell proliferation was assessed by MTT assay, apoptosis by Annexin V-Fluorescein Isothiocyanate/Propidium Iodide staining, protein expression by western blotting, melanoma lesions were subcutaneously injected in mice with B16/F10 cells, chemokine release was quantified by ELISA. RESULTS: Data herein presented demonstrate that indicaxanthin effectively inhibits the proliferation of the highly metastatic and invasive A375 cells as shown by growth inhibition, apoptosis induction and cell invasiveness reduction. More interestingly, in vitro data were paralleled by those in vivo showing that indicaxanthin significantly reduced tumor development when orally administered to mice. The results of our study also clarify the molecular mechanisms underlying the antiproliferative effect of indicaxanthin, individuating the inhibition of NF-kappaB pathway as predominant. CONCLUSION: In conclusion, we demonstrated that indicaxanthin represents a novel phytochemical able to significantly inhibit human melanoma cell proliferation in vitro and to impair tumor progression in vivo. When considering the resistance of melanoma to the current therapeutical approach and the very limited number of phytochemicals able to partially counteract it, our findings may be of interest to explore indicaxanthin potential in further and more complex melanoma studies in combo therapy, i.e. where different check points of melanoma development are targeted. PMID- 30466979 TI - Comparison of the anti-inflammatory effects of Sinapis alba and Brassica juncea in mouse models of inflammation. AB - BACKGROUND: Sinapis Semen is derived from the dried mature seeds of Sinapis alba L. or Brassica juncea (L.) Czern. et Coss. Traditionally, the seeds from S. alba are called "White Sinapis Semen" while those from B. juncea are called "Yellow Sinapis Semen". PURPOSE: The present study aimed to compare the chemical composition and the anti-inflammatory effects of 50% aqueous ethanol extracts of the White Sinapis Semen (EWSS) and Yellow Sinapis Semen (EYSS) using both acute (12-O-tetradecanoylphorbol-acetate (TPA)- and arachidonic acid (AA)-induced mouse ear edema) and chronic (multiple applications of croton oil (CO)) inflammatory models. METHODS: The anti-inflammatory effects of EWSS and EYSS were determined by measuring the ear thickness and myeloperoxidase (MPO) activity. The anti inflammatory mechanism was explored by measuring the protein and mRNA levels of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta and IL-6 in the ear of the TPA-treated mice. RESULTS: The results showed that both EWSS and EYSS significantly decreased the ear thickness in both the TPA- and AA-induced acute models, as well as in the CO-induced chronic model. In addition, EWSS and EYSS could markedly inhibit the MPO activity in the ears of TPA-, AA- or CO-treated mice. Moreover, EWSS and EYSS also remarkably inhibited the protein and mRNA levels of TNF-alpha and IL-6 in the ears of TPA-treated mice. Comparatively, EWSS exerted more potent anti-inflammatory effect than that of EYSS. CONCLUSION: Our results revealed that both EWSS and EYSS are effective anti-inflammatory agents against acute and chronic inflammatory processes, and EWSS possess more potent anti-inflammatory effect than EYSS. The anti-inflammatory effect of the two herbs may be mediated, at least in part, by suppressing the mRNA expression of a panel of inflammatory mediators including TNF-alpha, IL-6 and IL-1beta. PMID- 30466980 TI - Evaluations of the effect of HuangQi against heart failure based on comprehensive echocardiography index and metabonomics. AB - BACKGROUND: HuangQi (HQ) is a major medicinal herb commonly used as an ingredient of traditional Chinese medicine (TCM) formulas. It has been proved to be effective against heart failure (HF). However, its holistic therapeutic mechanism is not yet well explored. PURPOSE: The present study was designed to investigate the inhibitory effects and action mechanism of HQ in adriamycin (ADR)-induced HF rats. METHODS: An integrative approach combining comprehensive echocardiography index (CEI) and metabonomics was conducted to assess the integral efficacy of HQ against HF. CEI was constructed to comprehensively evaluate the protection of HQ through principal component analysis of eight echocardiography parameters. Meanwhile, NMR-based untargeted metabolomic studies were performed to investigate the regulative effects of HQ coupled with correlation analysis. RESULTS: HQ showed significant regulatory effects on four echocardiography parameters (left ventricular diastolic diameter, left ventricular systolic wall thickness, ejection fraction and fractional shortening). The effect on comprehensive CEI also demonstrated the efficacy of HQ against HF, especially on the first principal component (PC1). HQ could exert marked metabolic regulations on five key metabolites related to HF (NAG, 3-hydroxybutyrate, glutamine, succinate and acetoacetate), which were mainly involved into alterations of energy metabolism, oxidative stress, hypertrophy, as well as inflammatory. Their correlation analysis revealed the relationship between the metabolic profiles and cardiac function, which further authenticated the systemic regulation of HQ against HF. CONCLUSION: Current evidences revealed that HQ was effective in control of HF from cardiac dysfunction and metabolic alterations. This study provided a useful approach for evaluating the efficacy of TCMs against HF. PMID- 30466981 TI - Modulation of multidrug resistant in cancer cells by EGCG, tannic acid and curcumin. AB - BACKGROUND: Cancer is one of the most common life-threatening diseases worldwide; many patients develop multidrug resistance after treatment with anticancer drugs. The main mechanism leading to multidrug resistance is the overexpression of ABC transporters in cancer cells. Chemosensitizers are needed to inhibit the activity of ABC transporters, resulting in higer intracellular concentration of anticancer drugs. Some secondary metabolites have been reported to be chemosensitizers by inhibiting ABC transporters. Epigallocatechin gallate (EGCG), tannic acid, and curcumin were employed in this study. Different assays were used to detect whether they have the ability to inhibit P-gp activity and overcome multidrug resistance in cancer cells overexpressing P-gp. Hypothesis/Purpose: CEM/ADR 5000 and Caco-2 cell lines, which overexpress P-gp, are multidrug resistant cell lines. We first detected whether the combination of polyphenols (EGCG, tannic acid, curcumin) and doxorubicin, an anticancer drug, is synergistic or not. To further understand the potential mechanism, EGCG, tannic acid, and curcumin were tested to check whether they have the ability to inhibit P-gp activity. When P-gp activity is inhibited, the intracellular concentration of doxorubicin is higher, resulting in enhanced cytotoxicity of doxorubicin. STUDY DESIGN: The P-gp overexpressing human colon cancer cell line Caco-2 and human T-lymphoblastic leukemia cell line CEM/ADR 5000 were used in this study. Two-drug combinations (doxorubicin + polyphenol) and three-drug combinations (doxorubicin + polyphenol + digitonin) were tested to examine potential synergism. The potential mechanism leading to synergism would be the inhibition of P-gp activity. A Rhodamine 123 assay and Calcein-AM assay in Caco-2 and CEM/ADR 5000, respectively, were used to detect P-gp inhibition by EGCG, curcumin, and tannic acid. METHODS: MTT assay was used to determine the cytotoxicity of doxorubicin, polyphenols and digitonin alone, and then their combinations. Furthermore, Rhodamine 123 and Calcein-AM were used to detect the effects of polyphenols on the activity of P-gp. RESULTS: The results demonstrated that a combination of non-toxic concentrations of each polyphenol with doxorubicin synergistically sensitized Caco-2 and CEM/ADR 5000 cells. Furthermore, three-drug combinations (doxorubicin + polyphenol + digitonin) were much more effective. In addition, the activity of P-gp in Caco-2 and CEM/ADR 5000 cells was measured. Consistent with the combination results, tannic acid and curcumin decreased the activity of P-gp both in Caco-2 and CEM/ADR 5000. EGCG, which weakly affected the activity of P-gp in CEM/ADR 5000, only had an effect on P-gp under higher concentration in Caco-2 cells. CONCLUSION: Our results show that EGCG, curcumin, and tannic acid, when combined with doxorubicin, can exert synergism, mediated by a reduced activity of P-gp. This study suggests that polyphenols, by modulating the activity of P-gp, may be used as chemosensitisers. PMID- 30466982 TI - trans-3-Methoxy-5-hydroxystilbene (MHS) from the rhizome of Alpinia nantonensis inhibits metastasis in human lung cancer cells. AB - BACKGROUND: Alpinia nantoensis (Zingiberaceae) is an aromatic plant endemic to Taiwan, which is used as food flavoring and traditional herbal medicine. The biological activities of compounds isolated from this plant are rarely investigated. PURPOSE: The present study was aimed to investigate the anti metastatic potential of trans-3-methoxy-5-hydroxystilbene (MHS) a major stilbene isolated from the rhizomes of A. nantonensis. METHODS: We investigated the anti metastatic potential of MHS on human non-small cell lung carcinoma (A549) cell line using wound healing, trans-well, western blot, zymography and immunofluorescence assays. RESULTS: Initial cytotoxicity assay showed that treatment with MHS did not exhibit cytotoxicity to A549 cells up to the concentration of 40 uM. Further in vitro wound healing and transwell chamber assays revealed that MHS significantly inhibited tumor cell migration in a dose dependent manner, which is associated with inhibition of matrix mettalloprotinase 2 (MMP-2) and matrix mettalloprotinase-9 (MMP-9) at both enzyme and protein levels. The inhibition of MMPs activity by MHS was reasoned by suppression of their corresponding transcription factor, beta-catenin as indicated by reduced levels of beta-catenin in the nucleus. MHS also regulates epithelial-to mesenchymal transition (EMT) by increasing E-cadherin and occludin as well as decreasing N-cadherin levels in A549 cells. Furthermore, pre-treatment with MHS significantly inhibited A549 cells migration and EMT in TGF-beta induced A549 cells. CONCLUSION: To the best of our knowledge, this is the first report demonstrating that MHS, a plant-derived stilbene has a promising ability to inhibit lung cancer cell metastasis in vitro. PMID- 30466983 TI - Citrus peels prevent cancer. AB - BACKGROUND: Citrus comprises the largest fruit sector worldwide, and its fruit peels are the dominant 'residue' of the industry. Though not profitable, Citrus peels are industrially used for making some byproducts (cattle feed, molasses, ethanol, fiber) and for the extraction of bioactives (flavonoids, essential oils, d-limonene). Still huge amounts of peels are wasted by Citrus industries, juice and other vending sectors. PURPOSE: The biological potentials of these unutilized or 'wasted' Citrus peels are least exploited. Here we tested the anticancer potentials of Citrus medica (2 morphotypes), C. sinensis, C. maxima, C. limon and C. reticulata peels by in vitro assays and in vivo cancer models. METHODS: Chemical profiles of Citrus peel oils and peel extracts were analyzed by gas chromatographic techniques (GC-FID, GC-MS) and HPTLC-densitometry, respectively. Anticancer potentials of Citrus peels (Citrus medica 2 morphotypes, C. sinensis, C. maxima, C. limon and C. reticulata) were evaluated by various in vitro assays (MTT assay, morphological observations, fast halo assay, flow cytometric analysis) and in vivo cancer models. RESULTS: C. reticulata peels (extracts, essential oils) showed significant activity against DLA cell line in MTT assay. We found C. reticulata peel water extract inducing cell cycle arrest of DLA in G0/G1 phase followed by nuclear condensation, membrane blebbing, formation of apoptotic bodies and DNA damage leading to apoptosis. In in vivo experiments, C. reticulata peel extract pre-treated mice were significantly (50%) protected from DLA compared to post-treated mice (33%), without any conspicuous toxic symptoms. Citrus peels have volatiles (essential oils, limonoids) and non-volatiles (mainly polymethoxy flavones) as their bioactive/anticancer constituents. CONCLUSION: Our results encourage the use of Citrus peels, which is wasted in huge amounts, as cancer preventive food additives and as anticancer agents. PMID- 30466984 TI - Naringenin suppresses growth of human placental choriocarcinoma via reactive oxygen species-mediated P38 and JNK MAPK pathways. AB - BACKGROUND: Human placental choriocarcinoma is a gestational trophoblastic tumor with high rates of metastasis and reoccurrence. However, some patients with choriocarcinoma are chemoresistance to conventional chemotherapeutic agents. HYPOTHESIS: Naringenin increases apoptosis in human placental choriocarcinoma cells. METHODS: We investigated the effects of naringenin on proliferation and migration of JAR and JEG3 cells, and performed TUNEL and Annexin V/PI staining assays to examine apoptotic effects of naringenin on both cells. In addition, we studied the loss of mitochondrial membrane potential (MMP) and the production of mitochondrial reactive oxygen species (ROS) to determine the specific reason for apoptosis of choriocarcinoma cells being mediated via mitochondria. Consistent with the induction of production of ROS by naringenin in both choriocarcinoma cell lines, we investigated lipid peroxidation and glutathione levels in both JAR and JEG3 cells since both are affected by ROS. We next determined dose-dependent effects of naringenin and its pharmacological inhibitors on signal transduction pathways in JAR and JEG3 cells by western blot analyses. RESULTS: Naringenin reduced viability and migratory functions of both cell lines, and increased mitochondria related apoptosis induced by ROS and lipid peroxidation, decreased glutathione and decreased mitochondrial membrane potential MMP in a dose dependent manner. We also determined naringenin activated phosphorylation of ERK1/2, P38, JNK and P70S6K in JAR and JEG3 cells in a dose-response manner. Although naringenin induced phosphorylation of AKT proteins in JAR cells, it suppressed phosphorylation of the protein in JEG3 cells. In addition, we confirmed the mechanism of naringenin-induced cell signaling by using a combination of naringenin and pharmacological inhibitors of the PI3K and MAPK pathways, as well as a ROS inhibitor in JAR and JEG3 cell lines. CONCLUSIONS: Collectively, results of this study indicate that naringenin is a potential therapeutic molecule with anti-cancer effects on choriocarcinoma cells by inducing generation of ROS and activation of the MAPK pathways. PMID- 30466985 TI - Withania somnifera (Indian ginseng) in male infertility: An evidence-based systematic review and meta-analysis. AB - BACKGROUND: Withania somnifera Dunal, commonly known as Indian ginseng, has been in use since ancient times as anti-stress agent, aphrodisiac, for impotence and infertility treatment. PURPOSE: To evaluate the efficacy and safety of W. somnifera treatment in infertile men. STUDY DESIGN: An evidence-based systematic review and meta-analysis using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. METHODS: Published literature was searched in PubMed/MEDLINE, EMBASE, Scopus, the Cochrane Library, and DHARA. Grey literature was assessed from the WHO International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/) and the US National Institutes of Health (https://clinicaltrials.gov/). RESULTS: Four clinical trials (comprising 5 publications: observational, n = 4; randomized controlled trial [RCT], n = 1) were included in the study. As only one RCT included, meta-analysis of RCT was not performed; however, systematically reviewed data demonstrated statistical (p <= .002 versus baseline) increase in sperm concentration (167%), semen volume (59%), and sperm motility (57%) in oligospermic males after 90 days of W. somnifera treatment, as well, serum testosterone (17%) and luteinizing hormone (34%) levels. Meta-analysis of observational (versus pre-treatment) studies showed that W. somnifera treatment significantly improved semen parameters (semen volume: mean difference [MD], 0.28 ml; 95% confidence interval [CI], 0.12 to 0.43; p = .0004; sperm concentration: MD, 13.57 million/ml; 95% CI, 11.12 to 16.01; p < .00001; sperm motility: MD, 8.50%; 95% CI, 7.36 to 9.63; p < .00001) with 14% of pregnancy outcome success rate in normozoospermic men. Meta-analysis findings also evidenced significant improvement in serum hormonal profile, oxidative biomarkers and antioxidant vitamins in seminal plasma. No adverse effects were reported in infertile men taking W. somnifera treatment. CONCLUSION: Due to a small number of eligible studies, the available data, though promising, are too limited to provide novel and sufficiently robust evidence of the benefits of W. somnifera in male infertility. Additional RCTs of high quality with a larger sample size are warranted to further strength clinical use of W. somnifera in treating male factor infertility. Future research also needs to elucidate the molecular mechanism(s) of W. somnifera as well its active principles in male infertility. PMID- 30466986 TI - Efficacy and safety of berberine for dyslipidaemias: A systematic review and meta analysis of randomized clinical trials. AB - BACKGROUND: In recent years, berberine has become widely used as an effective alternative to treat dyslipidaemias; much clinical evidence has emerged. It is important to systematically and critically evaluate the existing evidence. PURPOSE: This study aims to evaluate the efficacy and safety of berberine in patients with dyslipidaemias. STUDY DESIGN: A systematic review and meta-analysis of randomized clinical trials. METHODS: Five electronic databases were searched up to Apr 15, 2018 to identify randomized controlled trials (RCTs) of berberine in treatment of dyslipidaemias. The outcomes were lipid profile parameters and adverse events. Study selection, data collection, risk of bias assessment, data analyses and interpretations were conducted according to the Cochrane handbook. RESULTS: Sixteen trials with total of 2147 participants were judged to be eligible and were included in the meta-analysis. The included trials were assessed to be of high clinical heterogeneity. The methodological quality of the majority of the trials was generally low in terms of random sequence generation, allocation concealment, blinding and incomplete outcome data. Thus, selection bias, performance bias, detection bias, attrition bias and confounding bias might exist. Meta-analysis showed that berberine significantly reduced levels of total cholesterol (TC) (MD = -0.47 mmol/l 95% CI [-0.64, -0.31], p < 0.00001), low density lipoprotein cholesterol (LDL-C) (MD =-0.38 mmol/l 95% CI [-0.53, -0.22], p < 0.00001) and triglycerides (TG) (MD = -0.28 mmol/l 95% CI [-0.46, -0.10], p = 0.002). Berberine also increased the level of high-density lipoprotein cholesterol (HDL-C) when used alone (MD = 0.08 mmol/l 95% CI [0.03, 0.12], p = 0.001). No significant differences were found between groups in terms of incidence of adverse events (RR = 0.64 95% CI [0.31, 1.30], p = 0.22). No severe adverse effects were reported in either group. CONCLUSION: Berberine improves lipid profiles in dyslipidaemias with satisfactory safety. Nevertheless, these findings should be interpreted with caution because of the high clinical heterogeneity and high risk of bias in the included trials. Rigorous clinical trials should be carried out to provide more reliable evidence. PMID- 30466987 TI - Novel molecular mechanisms for the adaptogenic effects of herbal extracts on isolated brain cells using systems biology. AB - INTRODUCTION: Adaptogens are natural compounds or plant extracts that increase adaptability and survival of organisms under stress. Adaptogens stimulate cellular and organismal defense systems by activating intracellular and extracellular signaling pathways and expression of stress-activated proteins and neuropeptides. The effects adaptogens on mediators of adaptive stress response and longevity signaling pathways have been reported, but their stress-protective mechanisms are still not fully understood. AIM OF THE STUDY: The aim of this study was to identify key molecular mechanisms of adaptogenic plants traditionally used to treat stress and aging-related disorders, i.e., Rhodiola rosea, Eleutherococcus senticosus, Withania somnifera, Rhaponticum carthamoides, and Bryonia alba. MATERIALS AND METHODS: To investigate the underlying molecular mechanisms of adaptogens, we conducted RNA sequencing to profile gene expression alterations in T98G neuroglia cells upon treatment of adaptogens and analyzed the relevance of deregulated genes to adaptive stress-response signaling pathways using in silico pathway analysis software. RESULTS AND DISCUSSION: At least 88 of the 3516 genes regulated by adaptogens were closely associated with adaptive stress response and adaptive stress-response signaling pathways (ASRSPs), including neuronal signaling related to corticotropin-releasing hormone, cAMP mediated, protein kinase A, and CREB; pathways related to signaling involving CXCR4, melatonin, nitric oxide synthase, GP6, Galphas, MAPK, neuroinflammation, neuropathic pain, opioids, renin-angiotensin, AMPK, calcium, and synapses; and pathways associated with dendritic cell maturation and G-coupled protein receptor mediated nutrient sensing in enteroendocrine cells. All samples tested showed significant effects on the expression of genes encoding neurohormones CRH, GNRH, UCN, G-protein-coupled and other transmembrane receptors TLR9, PRLR, CHRNE, GP1BA, PLXNA4, a ligand-dependent nuclear receptor RORA, transmembrane channels, transcription regulators FOS, FOXO6, SCX, STAT5A, ZFPM2, ZNF396, ZNF467, protein kinases MAPK10, MAPK13, MERTK, FLT1, PRKCH, ROS1, TTN), phosphatases PTPRD, PTPRR, peptidases, metabolic enzymes, a chaperone (HSPA6), and other proteins, all of which modulate numerous life processes, playing key roles in several canonical pathways involved in defense response and regulation of homeostasis in organisms. It is for the first time we report that the molecular mechanism of actions of melatonin and plant adaptogens are alike, all adaptogens tested activated the melatonin signaling pathway by acting through two G-protein-coupled membrane receptors MT1 and MT2 and upregulation of the ligand-specific nuclear receptor RORA, which plays a role in intellectual disability, neurological disorders, retinopathy, hypertension, dyslipidemia, and cancer, which are common in aging. Furthermore, melatonin activated adaptive signaling pathways and upregulated expression of UCN, GNRH1, TLR9, GP1BA, PLXNA4, CHRM4, GPR19, VIPR2, RORA, STAT5A, ZFPM2, ZNF396, FLT1, MAPK10, MERTK, PRKCH, and TTN, which were commonly regulated by all adaptogens tested. We conclude that melatonin is an adaptation hormone playing an important role in regulation of homeostasis. Adaptogens presumably worked as eustressors ("stress-vaccines") to activate the cellular adaptive system by inducing the expression of ASRSPs, which then reciprocally protected cells from damage caused by distress. Functional investigation by interactive pathways analysis demonstrated that adaptogens activated ASRSPs associated with stress-induced and aging-related disorders such as chronic inflammation, cardiovascular health, neurodegenerative cognitive impairment, metabolic disorders, and cancer. CONCLUSION: This study has elucidated the genome-wide effects of several adaptogenic herbal extracts in brain cells culture. These data highlight the consistent activation of ASRSPs by adaptogens in T98G neuroglia cells. The extracts affected many genes playing key roles in modulation of adaptive homeostasis, indicating their ability to modify gene expression to prevent stress-induced and aging-related disorders. Overall, this study provides a comprehensive look at the molecular mechanisms by which adaptogens exerts stress-protective effects. PMID- 30466988 TI - Curcumin downregulates expression of opioid-related nociceptin receptor gene (OPRL1) in isolated neuroglia cells. AB - BACKGROUND: Curcumin (CC) exerts polyvalent pharmacological actions and multi target effects, including pain relief and anti-nociceptive activity. In combination with Boswellia serrata extract (BS), curcumin shows greater efficacy in knee osteoarthritis management, presumably due to synergistic interaction of the ingredients. AIM: To elucidate the molecular mechanisms underlying the analgesic activity of curcumin and its synergistic interaction with BS. METHODS: We performed gene expression profiling by transcriptome-wide mRNA sequencing in human T98G neuroglia cells treated with CC (Curamed), BS, and the combination of CC and BS (CC-BS; Curamin), followed by interactive pathways analysis of the regulated genes. RESULTS: Treatment with CC and with CC-BS selectively downregulated opioid-related nociceptin receptor 1 gene (OPRL1) expression by 5.9 fold and 7.2-fold, respectively. No changes were detected in the other canonical opioid receptor genes: OPRK1, OPRD1, and OPRM1. Nociceptin reportedly increases the sensation of pain in supra-spinal pain transduction pathways. Thus, CC and CC BS may downregulate OPRL1, consequently inhibiting production of the nociception receptor NOP, leading to pain relief. In neuroglia cells, CC and CC-BS inhibited signaling pathways related to opioids, neuropathic pain, neuroinflammation, osteoarthritis, and rheumatoid diseases. CC and CC-BS also downregulated ADAM metallopeptidase gene ADAMTS5 expression by 11.2-fold and 13.5-fold, respectively. ADAMTS5 encodes a peptidase that plays a crucial role in osteoarthritis development via inhibition of a corresponding signaling pathway. CONCLUSION: Here, we report for the first time that CC and CC-BS act as nociceptin receptor antagonists, selectively downregulating opioid-related nociceptin receptor 1 gene (OPRL1) expression, which is associated with pain relief. BS alone did not affect OPRL1 expression, but rather appears to potentiate the effects of CC via multiple mechanisms, including synergistic interactions of molecular networks. PMID- 30466989 TI - Ginger causes subfertility and abortifacient in mice by targeting both estrous cycle and blastocyst implantation without teratogenesis. AB - BACKGROUND: Due to renowned medicinal properties, Ginger rhizomes (Zingiber officinale Roscoe) used traditionally in the treatment of arthritis, rheumatism, muscular aches, constipation, indigestion, hypertension, dementia, fever, and infectious diseases. As an antiemetic, Ginger is consumed by approximately 80% of pregnant women to treat nausea and vomiting of early pregnancy. PURPOSE: The aim of this study is to evaluate the impact of ginger extract on the oestrous cycle and implantation in female mice. STUDY DESIGN AND METHODS: Four experimental episodes were identified. One considered the main study of outcomes and lasted 90 days; one lasted 35 days and considered the oestrous cycle; while the third and fourth intended antifertility and abortifacient and continued 20 days for each. Mice dosed Ginger orally at 0, 250, 500, 1000 or 2000 mg/kgbw/day (GNC, GN1, GN2, GN3, GN4, respectively). RESULTS: GN3 and GN4 dams showed maternal toxicity. High dose significantly reduced the number of live fetuses and increased fetal death and resorption. Mice treated with 2000 mg/kgbw/day displayed significant decreases in implantation sites. At a dose of 2000 mg/kgbw/day, Ginger prolonged the length of oestrous cycle with a significant decrease in the duration of diestrous-metestrus (luteal) phase, prolonged proestrus-estrus (ovulatory) phase and reduced the number of cycles as well. Therefore, Ginger impairs the normal growth of corpus luteum because of progesterone insufficiency during early pregnancy. The observed-adverse-effect dose set at 2000 mg/kgbw, but no-observed adverse-effect dose set at 250 and 500 mg/kgbw. CONCLUSION: These findings suggest that Ginger can disrupt the oestrous cycle and blastocyst implantation without teratogenesis. PMID- 30466990 TI - Orientin inhibits invasion by suppressing MMP-9 and IL-8 expression via the PKCalpha/ ERK/AP-1/STAT3-mediated signaling pathways in TPA-treated MCF-7 breast cancer cells. AB - BACKGROUND: Orientin (luteolin 8-C-beta-D-glucopyranoside), a glycosyl dietary flavonoid, has therapeutic effects such as anti-inflammation and antiadipogenesis. However, there is little known about the antimigratory and anti invasive effects of orientin. Thus, we demonstrate the anti-invasive effects of orientin compared with well-known anticancer flavonoid, luteolin and luteolin 8-C beta-fucopyranoside (LU8C-FP). PURPOSE: We investigated whether orientin would inhibit the migration and invasion of 12-O-tetradecanoyl phorbol-13-acetate (TPA) induced MCF-7 breast cancer cells. METHODS: We investigated the anti-invasive mechanism of orientin by using wound-healing assay, Matrigel invasion assay, gelatin zymography, qRT-PCR, ELISA, western blotting, nuclear, membrane and cytosolic fractionations, and immunofluorescence staining in MCF-7 cell line. RESULTS: We demonstrated the antimigratory and anti-invasive effects of orientin in TPA-treated MCF-7 cells. TPA-induced membrane translocation of protein kinase C alpha (PKCalpha), phosphorylation of extracellular signal regulated kinase (ERK), and nuclear translocations of activator protein-1 (AP-1) and signal transducer and activator of transcription 3 (STAT3) were downregulated by orientin. In addition, orientin also inhibited matrix metalloproteinase-9 (MMP-9) and interleukin-8 (IL-8) expression. CONCLUSION: Orientin inhibits migratory and invasive responses by suppressing MMP-9 and IL-8 expression through mitigation of TPA-induced PKCalpha and ERK activation, as well as the nuclear translocation of AP-1 and STAT3. Therefore, orientin prevents tumor invasion and could be applied as a possible therapeutic agent for the treatment of cancer metastasis. PMID- 30466991 TI - Berberine down-regulates IL-8 expression through inhibition of the EGFR/MEK/ERK pathway in triple-negative breast cancer cells. AB - BACKGROUND: Interleukin-8 (IL-8) expression is associated with metastasis in a variety of cancer cells. PURPOSE: Here, we investigated the regulatory mechanism of IL-8 expression as well as the pharmacological effect of berberine (BBR) on IL 8 expression in triple-negative breast cancer (TNBC) cells. METHODS: The clinical value of IL-8 was analyzed by from a public database [Kaplan-Meier plotter database. IL-8 mRNA and protein expression was analyzed by real-time PCR and ELISA, respectively. Cell invasion was analyzed by Boyden chamber assay. Tumor cell growth was analyzed by colony forming assay. RESULTS: Clinically, we observed that breast cancer patients with highly expressed IL-8 are associated with poor outcomes in areas such as relapse-free, overall, and distant metastasis free survival. We showed that IL-8 expression is higher in TNBC cells than in non TNBC cells. In addition, the rates of cell invasion were significantly increased by IL-8 treatment. These IL-8 levels were decreased by EGFR (Neratinib and Afatinib) and MEK (PD98059) inhibitors in TNBC cells. Finally, we observed that BBR dramatically suppresses IL-8 expression. In addition, BBR also inhibited cell invasiveness and anchorage-independent growth. Interestingly, our results showed that BBR down-regulates EGFR protein expression and dose-dependently inhibits MEK and ERK phosphorylation. CONCLUSION: Here, we demonstrate that BBR may be a promising drug to suppress cell invasiveness and growth of TNBC through IL-8 related mechanisms. PMID- 30466992 TI - Natural products for the prevention and treatment of kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) is one of the common causes resulting in a high morbidity and mortality. Renal fibrosis is the main pathological features of CKD. Natural products have begun to gain widely popularity worldwide for promoting healthcare and preventing CKD, and have been used as a conventional or complementary therapy for CKD treatment. PURPOSE: The present paper reviewed the therapeutic effects of natural products on CKD and revealed the molecular mechanisms of their anti-fibrosis. METHODS: All the available information on natural products against renal fibrosis was collected via a library and electronic search (using Web of Science, Pubmed, ScienceDirect, Splinker, etc.). RESULTS: Accumulated evidence demonstrated that natural products exhibited the beneficial effects for CKD treatment and against renal fibrosis. This review presents an overview of the molecular mechanism of CKD and natural products against renal fibrosis, followed by an in-depth discussion of their molecular mechanism of natural products including isolated compounds and crude extracts against renal fibrosis in vitro and in vivo. A number of isolated compounds have been confirmed to retard renal fibrosis. CONCLUSION: The review provides comprehensive insights into pathophysiological mechanisms of CKD and natural products against renal fibrosis. Particular challenges are presented and placed within the context of future applications of natural products against renal fibrosis. PMID- 30466993 TI - Anti-inflammatory effects of Zhishi and Zhiqiao revealed by network pharmacology integrated with molecular mechanism and metabolomics studies. AB - BACKGROUND: The inflammatory response has a complex pathogenesis; thus, it is a critical contributor to the development and complication of many diseases. Zhishi and Zhiqiao are famous Citrus herbal medicines that are rich in bioactive phenolic constituents with multiple anti-inflammatory activities. PURPOSE: Establishment of a multi-component-target-pathway network strategy to investigate the usage of Zhishi and Zhiqiao on inflammatory diseases can provide a reference for mechanisms of traditional Chinese medicine (TCM). STUDY DESIGN: A multi component-target-pathway network strategy was constructed to elucidate the various antiinflammatory effects of Zhishi and Zhiqiao by integrating multi constituent determination, network pharmacology, molecular mechanisms in cells and integrated metabolomics in animals. METHODS: Based on the quantitatively determined global and characteristic chemical profiles of Zhishi and Zhiqiao, the component-target-pathway network was predicted by network pharmacology coupled with text mining and docking. The potential antiinflammatory mechanism of the various components in Zhishi and Zhiqiao were verified using LPS-induced inflammatory responses in RAW 264.7 cells. The different metabolic regulating effects of Zhishi and Zhiqiao against an LPS-induced inflammation model were investigated using a plasma metabolomics strategy. RESULTS: The molecular mechanism of Zhishi mainly suppressed the MAPK signaling pathway, whereas Zhiqiao emphasized the PPAR-AKT signaling pathways simultaneously to block the inflammatory process. Meanwhile, Zhishi and Zhiqiao both exhibited an anti inflammatory effect by inhibiting the NF-kappaB signaling pathway to reduce the production of inflammatory mediators. In the metabolomics study, Zhishi and Zhiqiao exhibited variant corrections of the disordered metabolic pathways through amino acid metabolism, glycometabolism and lipid metabolism. CONCLUSION: All of these results indicate that Zhishi and Zhiqiao, in a diversified mixture, exert their anti-inflammatory effect through variant pathways. These findings can assist in developing the use of Zhishi and Zhiqiao for inflammatory diseases. PMID- 30466994 TI - A comprehensive review and perspectives on pharmacology and toxicology of saikosaponins. AB - BACKGROUND: Radix Bupleuri (RB) has been widely used in Chinese Traditional Medicine for over 2000 years and is currently marketed in China as Chai-Hu-Shu Gan tablets and Xiao-Yao-Wan tablets. Saikosaponins (SSs, especially SSa, SSc and SSd), as the major bioactive compounds in RB, represent anti-inflammatory, anti tumor, anti-oxidant, anti-viral and hepatoprotective effects. PURPOSE: To summarize recent findings regarding to the extraction, detection, biosynthesis, metabolism, pharmacological/toxicological effects of SSs. METHODS: Online academic databases (including PubMed, Google Scholar, Web of Science and CNKI) were searched using search terms of "Saikosaponin", "Radix Bupleuri", "Bupleurum" and combinations to include published studies of SSs primarily from 2003 to 2018. Several critical previous studies beyond this period were also included. RESULTS: 354 papers were found and 165 papers were reviewed. SSs have drawn great attention for their anti-inflammation, anti-viral and anti-cancer effects and contradictory roles in the regulation of cell apoptosis, oxidative stress and liver fibrosis. Meanwhile, increased risks of overdose-induced acute or accumulation-related chronic hepatotoxicity of SSs and RB have also been reported. However, underlying mechanisms of SSs bioactivities, the metabolism of SSs and bioactivities of SSs metabolites are largely unknown. CONCLUSION: This comprehensive review of SSs provides novel insights and perspectives on the limitations of current studies and the importance of metabolism study and the dose-pharmacological/toxic relationship of SSs for the future discovery of SSs based therapeutic strategies and clinical safe practice. PMID- 30466995 TI - Ginger (Zingiber officinale): An alternative for the prevention of postoperative nausea and vomiting. A meta-analysis. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is a distressing outcome related to surgeries. Traditionally, ginger has been used in the treatment of nausea and vomiting for thousands of years. Recently, several randomized, placebo controlled clinical trials (RCTs) have been conducted to evaluate the efficacy of ginger in PONV. PURPOSE: To systematically evaluate the efficacy of ginger on postoperative nausea and vomiting (PONV) compared to placebo, based on RCTs. STUDY DESIGN: The meta-analysis was reported following the PRISMA guidelines using the PICO format, and it was registered with the PROSPERO register. METHODS: PubMed, Embase, the Cochrane Central Register of Controlled Trials and Web of Science were searched for relevant studies. Human, placebo-controlled clinical studies of patients undergoing any types of surgery, receiving pharmacological doses of ginger per os were included. Only clinical trials with explicit description of the ginger preparation used were analysed. No language or publication year restrictions was applied. RESULTS: Ten randomized trials including a total of 918 patients were pooled for the statistical analysis. The present meta-analysis supports that ginger has a significant effect on the severity of PONV based on visual analogue scale (VAS) results: in a fixed effects model the pooled standardized mean difference (SMD) was -0.247 (favouring ginger; [LL]: -0.455, [UL]: -0.040, p-value: 0.019). Moreover, our results suggest that ginger reduces the incidence of postoperative nausea and vomiting, as well antiemetic drug demand; however, these effects are not statistically significant compared to placebo, which may be explained by underdosing. CONCLUSIONS: According to our thorough meta-analysis ginger is safe and well tolerated, and decreases the severity of PONV, and may lower the incidence of postoperative nausea and vomiting, which in turn may reduce antiemetic drug demand, suggesting that ginger may be a useful alternative to antiemetic medications to alleviate PONV. PMID- 30466996 TI - Identification of amentoflavone as a potent highly selective PARP-1 inhibitor and its potentiation on carboplatin in human non-small cell lung cancer. AB - BACKGROUND: Nuclear protein poly (ADP-ribose) polymerase-1 (PARP-1) is a key enzyme in the repair of DNA and is a promising target in the development of chemosensitizers. This study first investigated the inhibitory effects of amentoflavone (AMF) and its derivatives on PARP-1 and the potentiation of AMF on carboplatin (CBP) in non-small cell lung cancer (NSCLC). PURPOSE: This study aims to evaluate the inhibitory effect of AMF against PARP-1 and its potentiation on CBP in lung cancer both in vitro and in vivo. STUDY DESIGN: The inhibitory effect of AMF on PARP-1 was investigated using molecular docking and cell-free model of PARP-1 assay. Its potentiation on CBP in lung cancer was also evaluated. METHODS: Fluorescence resonance energy transfer assay was used to detect the inhibitory effects of AMF and its analogues on PARP-1. Molecular docking was employed to predict the binding mode of AMF and PARP-1. MTT assay, isobologram analysis, Hoechst staining, and Annexin V-PI double staining were used to confirm the potentiation of AMF on CBP in vitro. siRNA (PARP-1)-A549 cells were used to reveal the action target of AMF. Western blot analysis, immunohistochemistry, and Tunnel assay were employed to evaluate the potentiation of AMF on CBP in A549 xenograft mice. RESULTS: AMF and its analogues exerted excellent inhibitory effects on PARP-1 with IC50 values ranging from 0.198 MUM to 0.409 MUM. Docking experiment showed that AMF can stably bind to PARP-1 with a comparable binding energy to olaparib. AMF can decrease the expression of PAR induced by H2O2in vitro. AMF synergistically increased the CBP anti-proliferative effect in A549. However, its potentiation nearly disappeared when the cells were transfected with siRNAs against PARP-1. Oral administration of AMF (100 mg/kg), combined with CBP, remarkably inhibited A549 tumor growth and ki67 expression, and increased apoptosis compared with CBP-alone group. CONCLUSION: All results suggest that AMF can be a potential PARP-1 inhibitor and a candidate adjuvant agent to boost the anticancer effect of CBP in NSCLC. PMID- 30466997 TI - Vasodilator and hypotensive effects of pure compounds and hydroalcoholic extract of Xenophyllum poposum (Phil) V.A Funk (Compositae) on rats. AB - BACKGROUND: Xenophyllum poposum is an endemic species of the Andes Cordillera, popularly known as Popusa. Popusa is widely used by mountain communities as a folk medicine to treat altitude sickness and hypertension. PURPOSE: The aim of this study is to evaluate the hypotensive effects and vascular reactivity of Popusa extracts and its pure isolated compounds. METHODS: Hydroalcoholic extract of Xenophyllum poposum (HAE X. poposum; 40 mg/kg dose) were administered to rats by gavage and mean arterial pressures were recorded. Organ bath studies were conducted in endothelium-intact and denuded rings, and the vascular reactivity of the HAE X. poposum extract and its isolated compounds were compared and analysed. Cytosolic Ca2+ was measured in vascular smooth muscle cell line A7r5 using Fura2 AM. RESULTS: HAE X. poposum significantly reduced the mean arterial blood pressure and heart rate in normotensive rats chronically treated with the extract, as well as mice acutely treated with the extract. A negative chronotropic effect was observed in the isolated rat heart. HAE X. poposum induced endothelial vasodilation mediated by nitric oxide (NO), reduced the contractile response to PE, and decreased PE-induced intracellular Ca2+ influx in vascular smooth muscle cells. Pure compounds isolated from HAE X. poposum such as 4-hydroxy-3-(3-methyl-2-butenyl) acetophenone, 5-acetyl-6-hydroxy-2-isopropenyl 2, and 3-dihydrobenzofurane (dihydroeuparin) also triggered endothelium-dependent vasodilation. CONCLUSION: HAE X. poposum decreases blood pressure, heart rate and vascular response. The vasodilation properties of HAE X. poposum extract and its isolated compounds may act through the endothelial nitric oxide synthase, as well as calcium channel blocker mechanisms. The results of the present study provide the first qualitative analysis that supports the use of X. poposum in traditional folk medicine for the treatment of altitude sickness and hypertension. PMID- 30466998 TI - Expression of Concern. PMID- 30466999 TI - [Epidemiology of invasive mycoses: A landscape in continuous change]. AB - The landscape of invasive mycoses is in a continuous evolution with important implications for their diagnosis and treatment. The overall burden remains high, particularly in neonates and the elderly, patients admitted to intensive care units, using prostheses, catheters or other intravenous devices, those receiving different immunosuppressant treatments or antineoplastic chemotherapy, or transplant recipients. In addition, opportunistic mycoses can be associated with HIV infection. Many fungal infections are acquired by inhalation, direct contact or ingestion, but fungi can also enter into the bloodstream through needles or catheters. Invasive candidiasis remains the most frequent mycosis, but its aetiology progressively shifts from Candida albicans to other species of Candida, such as Candida parapsilosis, Candida glabrata, or the multiresistant Candida auris. However, aspergillosis can be predominant in specific conditions, such as bone marrow transplant recipients. Moreover, Pneumocystis, Cryptococcus, Fusarium and Rhizopus can cause devastating illnesses. There are significant variations among hospitals and countries that are related to many factors, such as local characteristics of mycoses and patients, or different practices between medical and surgical wards. The attributed mortality remains high, ranging from 30% in invasive candidiasis to 90-100% in some clinical presentations of scedosporiosis and mucormycosis. The extremely complexity of patients and the growing diversity of pathogenic fungi are major challenges for improving diagnosis, creating surveillance networks, and implementing control measures for these invasive infections. PMID- 30467000 TI - [Invasive aspergillosis in solid organ transplantation]. AB - Solid organ transplant (SOT) recipients have a high risk for developing invasive fungal infections (IFI). Treatment is difficult due to the interaction between the antifungal and immunosuppressant drugs, as well as the risk of hepatotoxicity and kidney failure associated with voriconazole and amphotericinB, respectively. Isavuconazole is a new antifungal triazole agent with excellent oral bioavailability, predictable and linear pharmacokinetics, good tolerance and low adverse effects. It has been approved for the treatment of invasive aspergillosis and mucormycosis. A review is presented of the reported experience in the use of isavuconazole in SOT. According to the published studies, isavuconazole has a significantly lower risk of interaction with tacrolimus, and is less hepatotoxic than voriconazole. Nevertheless, there is a significant variability between patients, and between each type of SOT. Isavuconazole reduces the side effects associated with the treatment of IFI in SOT. It would be of great interest the implementation of future clinical trials with isavuconazole for the treatment and/or prophylaxis of IFI in these patients. PMID- 30467001 TI - Single use negative-pressure wound therapy: Are we being sucked in? PMID- 30467002 TI - A quantitative analysis of factors influencing lower lid retraction and involutional ectropion. PMID- 30467003 TI - Shear wave elastography of median nerve at wrist and forearm. Heterogeneity of normative values. PMID- 30467004 TI - A feasibility study of indocyanine green fluorescence mapping for sentinel lymph node detection in cutaneous melanoma. PMID- 30467005 TI - Reduction mammaplasty technique. The core and the master key of oncoplastic breast surgery. PMID- 30467006 TI - Achieving clear margins: Review of techniques to more accurately delineate basal cell carcinoma (BCC) macroscopic border prior to excision biopsy. PMID- 30467007 TI - Altered lymphatic drainage in malignant melanoma after previous sentinel node biopsy in the same nodal drainage basin. PMID- 30467008 TI - ALT vs. Jejunum: Have we found the ideal flap for circumferential pharyngoesophageal reconstruction? A meta-analysis of comparative studies. PMID- 30467009 TI - Editorial commentary: Pathophysiological effects of proton pump inhibitors in cardiac patients: Time for a critical reappraisal. PMID- 30467010 TI - Time to reconsider urate: Neuroprotective potential may prevail on cardiovascular risk in animal models and clinical trials. PMID- 30467011 TI - Increased urinary exosomal microRNAs in children with idiopathic nephrotic syndrome. AB - BACKGROUND: Urinary exosomal miRNAs are gaining increasing attention for their potential as ideal non-invasive biomarkers for kidney diseases; however, little is known about their diagnostic ability for paediatric nephrotic syndrome (NS). This study explored the clinical value of urinary exosomal miRNAs for paediatric idiopathic NS. METHODS: Urine samples were collected from 129 NS children and 126 age-/sex-matched healthy controls. The miRNA profile of urinary exosomes was analysed by high-throughput Illumina sequencing via synthesis (SBS) technology followed by verification with a quantitative reverse-transcription polymerase chain reaction (RT-qPCR) assay arranged in two independent cohorts. Additionally, paired urine samples from 65 of these patients were collected before and after treatment. FINDINGS: The Illumina SBS identified 30 markedly increased urinary exosomal miRNAs in NS children compared with controls (>= 5-fold, P < .05). Fifteen miRNAs were selected for further investigation, of which 5 (miR-194-5p, miR-146b-5p, miR-378a-3p, miR-23b-3p and miR-30a-5p) were verified by RT-qPCR to be significantly and steadily increased in NS (> 3-fold, P < .01) and markedly reduced during the clinical remission period (P < .001). Moreover, the concentrations of miR-194-5p and miR-23b-3p were significantly positively correlated with the urine protein content and were markedly higher in the high urine protein group than in the low urine protein group (P < .001 and P < .01, respectively). INTERPRETATIONS: We identified 5 altered urinary exosomal miRNAs in NS children with disease progression and treatment. These urinary exosomal miRNAs could be promising and non-invasive potential biomarker candidates for diagnosing, monitoring and stratifying paediatric NS. FUND: National Natural Science Foundation of China; Fund of State Key Laboratory of Analytical Chemistry for Life Science; National Basic Research Programme of China; Foundation of Jiangsu Provincial Medical Youth Talent. PMID- 30467012 TI - Pharmacovigilance Is Everyone's Concern: Let's Work It Out Together. AB - In recent decades, the field of drug safety/pharmacovigilance (PV) has advanced dramatically in some ways and yet has remained stagnant or progressed slowly in others. One way to assess the PV landscape is to view it through both a regulatory lens and a science and technology lens. This commentary highlights some of the current PV issues that can be resolved by sustained collaboration among all relevant stakeholders. PMID- 30467013 TI - Tacrolimus Concentrations Measured in Excreted Bile in Liver Transplant Recipients: The STABILE Study. AB - PURPOSE: Tacrolimus (TAC) is the main immunosuppressive drug in liver transplantation. Despite intensive therapeutic drug monitoring (TDM) that relies on whole blood trough concentration (TACblood), patients still present with acute cellular rejection or TAC-related toxic effects with concentrations within the therapeutic range. TAC concentration in peripheral blood mononuclear cells (TACPBMC) is considered as an efficient surrogate marker of TAC efficacy. However, it is still not applicable in daily practice. New TDM methods are therefore needed, especially during the early postoperative period. TAC is metabolized in the liver and eliminated through biliary excretion. We therefore hypothesised that TAC concentration measured in excreted bile (TACbileC) could be a relevant surrogate marker of its efficacy. METHODS: The Therapeutic Drug Monitoring of Tacrolimus Biliary Concentrations for Liver-Transplanted Patients (STABILE) study is a prospective monocentric trial. During the 7 first days after TAC therapy initiation, TACbileC was measured. The correlation between TACbileC and TACPBMC as well as between TACblood and TACPBMC was assessed. The correlations between TACbileC and liver graft function parameter or with occurrence of neurologic toxic effects were also evaluated. FINDINGS: Between May 2016 and April 2017, 41 patients were analyzed. TACbileC was significantly correlated with TACPBMC (r = 0.25, P = 0.007). However, a better correlation was found between TACPBMC and TACblood (r = 0.53, P < 0.001) and was confirmed in multivariate analysis. However, only TACbileC was significantly correlated with liver graft function, such as factor V (r = 0.40, P = 0.009) or bilirubin level (r = 0.21, P = 0.01), and significantly lower in patients presenting with neurologic toxic effects (P < 0.001). Receiver operating characteristic curve analysis found that a TACbileC level lower than 0.20 ng/mL on day 2 after TAC therapy initiation was a good predictive marker of occurrence of neurotoxic effects (AUC = 0.81). IMPLICATIONS: TACbileC is not a better surrogate maker of TAC activity than TACblood. However, TACbileC could help predict the occurrence of TAC toxic effects when a T-tube is inserted. ClinicalTrials.gov identifier: NCT02820259. PMID- 30467014 TI - Predictive factors of benefit from iodine-125 brachytherapy for hepatocellular carcinoma with portal vein tumor thrombosis. AB - PURPOSE: The aims of this study were to evaluate treatment responses and predictive factors for overall survival (OS) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) treated with iodine-125 (125I) brachytherapy. METHODS AND MATERIALS: Seventy-seven HCC patients with PVTT underwent 125I brachytherapy after transcatheter arterial chemoembolization. Clinical, laboratory, and radiological evaluation were performed before and after treatment, as well as at 4-6 weeks intervals for 7 years to assess the efficacy and toxicity of therapy. Treatment response was assessed using modified response evaluation criteria in solid tumors. OS and predictive factors for each subgroup were evaluated after treatment. RESULTS: In total, 11 patients (14.29%) achieved complete response, and 41 patients (53.25%) achieved partial response. The response rate (complete response + partial response) was 67.53% (52/77). The median OS was 9 months. The multivariable Cox regression model indicated that post-treatment tumor size with PVTT (p = 0.016, hazard ratio [HR] = 1.889, 95% confidence interval [CI]: 1.127 to 3.166) and baseline hemoglobin (p = 0.013, HR=0.518, 95% CI: 0.308 to 0.872) and alkaline phosphatase (p = 0.002, HR=2.275, 95% CI: 1.338 to 3.868) levels were significant independent predictors of OS. CONCLUSIONS: 125I brachytherapy results in favorable treatment responses in HCC patients with PVTT. Notably, post-treatment tumor size and baseline hemoglobin and alkaline phosphatase levels are significant independent predictive factors for OS and provide the most predictive information regarding OS. PMID- 30467015 TI - Initial collection of an inadequate 24-hour urine sample in children does not predict subsequent inadequate collections. AB - INTRODUCTION: Approximately half of adult stone formers submit specimens that are either under or over collections as determined by 24-h creatinine/kg. Previously identified predictors of inadequate collection in adults include female sex, older age, higher body mass index (BMI), vitamin D supplementation, and weekday collection. OBJECTIVE: The objective of this study is to determine risk factors for inadequate 24-h urinary specimen collection in the pediatric population. STUDY DESIGN: A retrospective analysis of all children (<18 years of age) with renal and/or ureteral calculi evaluated at the study tertiary care pediatric center from 2005 to 2015 was performed. Those who had at least one 24-h urinary metabolic profile after a clinical visit for kidney and/or ureteral stones were included; children with bladder stones were excluded. Adequate collections had a urine creatinine of 10-15 mg/kg/24 h. A bivariate analysis of potential factors associated with inadequate collection of the initial urinary metabolic profile, including child demographics, parental socio-economic factors, history of stone surgery, and weekday vs. weekend urine collection, was performed. A mixed-effects logistic regression, controlling for correlation of specimens from the same patient, was also performed to determine whether an initial inadequate collection predicted a subsequent inadequate collection. RESULTS: Of 367 patients, 80 had an adequate collection (21.9%): median age, 13 years (interquartile range, 8-16); 61.1% female; 93.5% white; 19.5% obese; and 13.0% overweight. No parental or child factors were associated with inadequate collection (Summary Table). Of inadequate collections, more than 80% were over collections. In the 175 patients with more than one 24-h urinary specimen collection, the effect of an initial inadequate collection on subsequent inadequate collections was not significant after controlling for the correlation of samples from the same patient (p = 0.8). DISCUSSION: Any parental or child factors associated with the collection of inadequate 24-h urine specimens in children were not found. An initial inadequate collection does not predict subsequent inadequate collections. It was surprising that >80% of the inadequate collections were over collections rather than under collections. Possible explanations are that children collected urine samples for longer than the 24-h period or that stone-forming children produce more creatinine per 24-h period than healthy children due to hyperfiltration. CONCLUSION: Inadequate collections are very common, and the risk factors for them are unclear. A repeat collection would be suggested if the first is inadequate. Further studies must be planned to explore barriers to accurate specimen collection using qualitative research methodology. PMID- 30467016 TI - Response to letter re 'Pneumovesical ureteric reimplantation using T-fastener: a modification for bladder wall anchorage'. PMID- 30467017 TI - Cancer screening in the pediatric cancer patient: a focus on genitourinary malignancies, and why does a urologist need to know about this? AB - INTRODUCTION: The long-term survival of a patient with childhood cancer now exceeds 80%. Unfortunately, as survivorship improves, the long-term consequences of the treatments used have become manifest. Specifically, the finding that development of a subsequent malignant neoplasm (SMN) is the leading cause of late mortality is concerning. In cancer survivors who are at high risk for developing an SMN, cancer screening protocols have well-documented survivorship benefits. Regrettably, 50% of these high-risk patients are non-compliant with these protocols, with studies revealing that inadequate patient compliance is in part because of insufficient knowledge of the physician regarding its need. DISCUSSION: Urologists are in a unique position to correct this deficiency. Characteristically, survivors of childhood cancer present to urologists as an adult with complaints of infertility, erectile dysfunction, androgen deprivation, lower urinary tract symptoms or for follow-up of a urinary diversion. The urologist because of their specialty should be able to treat the patients presenting complaint, identify the high-risk patient, and re-establish them on their surveillance protocol. SCREENING RECOMMENDATIONS FOR HIGH-RISK PATIENTS: The risk for developing an SMN is unequally expressed and is temporally biphasic. A minimal 10-year follow-up time span is recommended for patients who received alkylating agents or topoisomerase inhibitors. These agents can induce hematologic malignancies classically within the first 3-5 years after chemotherapy completion, with minimal risk existing after 10 years. Lifelong follow-up for SMN development is recommended under five distinct circumstances; if a genetic predisposition to tumor formation exists, a persistent post treatment non-malignant mass is present if chemotherapy was received before 2 years of age, if the initial type of tumor predisposes to SMN, or if the patient received radiation therapy. CONCLUSION: The urologists ability to identify the patient at high risk for developing an SMN and return them to a surveillance protocol is crucial for appropriate patient management. PMID- 30467018 TI - Diversity and abundance of denitrifiers during cow manure composting. AB - Diversity and abundance of the denitrifying genes nirK, nirS and nosZ were investigated in cow manure compost using polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) and real-time quantitative PCR (qPCR), respectively. These three genes were detected in all the stages of the composting process. Phylogenetic analysis showed that the nirK gene was closely related to Rhizobiales, Burkholderiales, the nirS gene was closely related to Pseudomonadales and Burkholderiales, and the nosZ gene was closely related to Rhodospirillales, Rhizobiales, Pseudomonadales, and Alteromonadales. qPCR results showed that the abundance of these three genes (nirK, nirS and nosZ) reached the peak value in the late thermophilic stage of composting and abundance of the nirK gene was higher than that of the nosZ gene and the nirS gene. Redundancy analysis (RDA) showed that the diversity of the nirK and nirS genes was significantly correlated with ammonium (p<0.05), the diversity of the nosZ gene was significantly correlated with pH (p<0.05) and the abundance of the nirK nirS and nosZ genes was significantly correlated with temperature (p<0.05). PMID- 30467019 TI - The effect of socioeconomic deprivation on the association between an extended measurement of unhealthy lifestyle factors and health outcomes: a prospective analysis of the UK Biobank cohort. AB - BACKGROUND: Combinations of lifestyle factors interact to increase mortality. Combinations of traditional factors such as smoking and alcohol are well described, but the additional effects of emerging factors such as television viewing time are not. The effect of socioeconomic deprivation on these extended lifestyle risks also remains unclear. We aimed to examine whether deprivation modifies the association between an extended score of lifestyle-related risk factors and health outcomes. METHODS: Data for this prospective analysis were sourced from the UK Biobank, a prospective population-based cohort study. We assigned all participants an extended lifestyle score, with 1 point for each unhealthy lifestyle factor (incorporating sleep duration and high television viewing time, in addition to smoking, excessive alcohol, poor diet [low intake of oily fish or fruits and vegetables, and high intake of red meat or processed meats], and low physical activity), categorised as most healthy (score 0-2), moderately healthy (score 3-5), or least healthy (score 6-9). Cox proportional hazards models were used to examine the association between lifestyle score and health outcomes (all-cause mortality and cardiovascular disease mortality and incidence), and whether this association was modified by deprivation. All analyses were landmark analyses, in which participants were excluded if they had an event (death or cardiovascular disease event) within 2 years of recruitment. Participants with non-communicable diseases (except hypertension) and missing covariate data were excluded from analyses. Participants were also excluded if they reported implausible values for physical activity, sleep duration, and total screen time. All analyses were adjusted for age, sex, ethnicity, month of assessment, history of hypertension, systolic blood pressure, medication for hypercholesterolaemia or hypertension, and body-mass index categories. FINDINGS: 328 594 participants aged 40-69 years were included in the study, with a mean follow-up period of 4.9 years (SD 0.83) after the landmark period for all-cause and cardiovascular disease mortality, and 4.1 years (0.81) for cardiovascular disease incidence. In the least deprived quintile, the adjusted hazard ratio (HR) in the least healthy lifestyle category, compared with the most healthy category, was 1.65 (95% CI 1.25-2.19) for all-cause mortality, 1.93 (1.16-3.20) for cardiovascular disease mortality, and 1.29 (1.10-1.52) for cardiovascular disease incidence. Equivalent HRs in the most deprived quintile were 2.47 (95% CI 2.04 3.00), 3.36 (2.36-4.76), and 1.41 (1.25-1.60), respectively. The HR for trend for one increment change towards least healthy in the least deprived quintile compared with that in the most deprived quintile was 1.25 (95% CI 1.12-1.39) versus 1.55 (1.40-1.70) for all-cause mortality, 1.30 (1.05-1.61) versus 1.83 (1.54-2.18) for cardiovascular disease mortality, and 1.10 (1.04-1.17) versus 1.16 (1.09-1.23) for cardiovascular disease incidence. A significant interaction was found between lifestyle and deprivation for all-cause and cardiovascular disease mortality (both pinteraction<0.0001), but not for cardiovascular disease incidence (pinteraction=0.11). INTERPRETATION: Wide combinations of lifestyle factors are associated with disproportionate harm in deprived populations. Social and fiscal policies that reduce poverty are needed alongside public health and individual-level interventions that address a wider range of lifestyle factors in areas of deprivation. FUNDING: None. PMID- 30467020 TI - Is an unhealthy lifestyle more harmful for poor people? PMID- 30467021 TI - Taking Malawi's option B+ programme from a B+ to an A. PMID- 30467022 TI - National estimates and risk factors associated with early mother-to-child transmission of HIV after implementation of option B+: a cross-sectional analysis. AB - BACKGROUND: Routine data from Malawi's prevention of mother-to-child transmission (MTCT) option B+ programme suggest high uptake of antiretroviral therapy (ART) among pregnant women. Malawi's Ministry of Health led the National Evaluation of Malawi's PMTCT Program to obtain nationally representative data on maternal ART coverage and prevention of MTCT effectiveness. Here, we present the early transmission data for infants aged 4-12 weeks. METHODS: We used a multistage cluster design to recruit a nationally representative sample of HIV-exposed infants and their mothers in Malawi. Between October 16, 2014, and May 17, 2016, we screened for HIV in all mothers attending an under-5 vaccination or outpatient sick-child clinic with infants aged 4-26 weeks at 54 health facilities selected across ten districts and four regional sampling zones. Infants with mothers identified as HIV-infected were enrolled in the cohort. We calculated weighted MTCT rates for only the subset of infants aged 4-12 weeks at screening, thereby capturing MTCT from early pregnancy, to delivery, and early breastfeeding. We collected data on maternal and infant demographics and self-reported use of HIV services, ART, and antenatal clinics. We tested HIV-exposed infants for the virus and assessed associations of certain variables with infant HIV status. FINDINGS: We confirmed HIV exposure in 3542 (10.4%) of 33 980 mother (guardian)-infant pairs with infants aged 4-26 weeks. Of those, 2530 (2514 mothers and 16 guardians) had infants aged 4-12 weeks at the time of screening (2498 singlets and 32 twins). We excluded 25 infants from the analysis because no information was available about their HIV status. 91.3% (95% CI 85.6-96.9) of mothers were on ART during pregnancy. The MTCT rate was 3.7% (2.3-6.0) overall and ranged from 1.4% (0.4-4.4) in women who initiated ART before pregnancy to 19.9% (13.4-28.6) in women not on ART. In multivariable logistic regression analysis, the odds of early MTCT were higher in mothers starting ART post partum (adjusted odds ratio 16.7, 95% CI 1.6-171.5; p=0.022) and in those not on ART with an unknown HIV status during pregnancy (19.1, 8.5-43.0; p<0.0001) than in mothers on ART before pregnancy. Among HIV-exposed infants, 98.0% (95% CI 96.9-99.1) were reported by the mother to have received infant nevirapine prophylaxis, and only 45.6% (34.8 56.4) were already enrolled in an exposed infant HIV care clinic at the time of study screening. INTERPRETATION: These data suggest that Malawi's decentralisation of ART services has resulted in higher ART coverage and lower early MTCT. However, the uptake of services for HIV-exposed infants remains suboptimal. FUNDING: President's Emergency Plan for AIDS Relief. PMID- 30467023 TI - The value of postoperative prosthesis alignment and patellar height measurements on standard X-rays after Total Knee Arthroplasty: Does it relate to knee function after 5 years? AB - BACKGROUND: The purpose of this retrospective cohort study was to investigate the influence of parameters of malalignment on knee function 5 years post TKA and, additionally, to explore alterations in patellar height after TKA. METHODS: All 661 patients undergoing TKA between 2010 and 2011 were considered for inclusion. Preoperative and 1-year postoperative short-leg radiographs were assessed for malalignment parameters: coronal tibial angle (cTA), sagittal tibial angle (sTA), femoral flexion angle (FFA) and mediolateral tibial mismatch. Patellar height was measured using the modified Insall-Salvati ratio. We determined improvements in knee function utilizing the Knee Society Score (Function score, KSS-F), Oxford Knee Score (OKS) and Algofunctional index (AI). Influences of malalignment parameters were analyzed univariate and selected (p < 0.10) for multivariate linear regression analysis. Inter-observer reproducibility was assessed by test retest analysis of 30 randomly selected radiographs and calculation of an intra class correlation coefficient (ICC) for all radiographic parameters. RESULTS: Three-hundred and four patients were included. Multivariate regression showed degrees of cTA malalignment to be significantly associated with only the KSS-F (beta = -3.52). Correction of coronal deformity was stronger associated with knee function (KSS-F beta = 2.81; AI beta = -0.36). Patellar height was significantly reduced after TKA (1.51 vs 1.44). Decrease of patellar height was weakly associated with the OKS (beta = 10.69). ICC scores were: cTA 0.81, sTA 0.57, IS 0.72, FFA 0.75. CONCLUSION: Postoperative coronal tibial plate alignment and correction of preoperative coronal deformity are associated with improved knee function 5 years post TKA. Decrease in patellar height was weakly associated with knee function. Short-leg radiography can be a sufficient screening tool for prosthesis alignment. PMID- 30467024 TI - Unraveling the Control of Cell Cycle Periods during Intestinal Stem Cell Differentiation. AB - During differentiation, intestinal stem cells (ISCs), a prototypical adult stem cell pool, become either secretory transit-amplifying cells, which give rise to all secretory cell types, or absorptive transit-amplifying cells, which give rise to enterocytes. These cells exhibit distinct cell cycle dynamics: ISCs cycle with a period of 24 h and absorptive transit-amplifying cells cycle with a period of ~12 h, whereas secretory transit-amplifying cells arrest their cycle. The cell cycle dynamics of ISCs and their progeny are a systems-level property that emerges from interactions between the cell cycle control machinery and multiple regulatory pathways. Although many mathematical models have been developed to study the details of the cell cycle and related regulatory pathways, few models have been constructed to unravel the dynamic consequences of their interactions. To fill this gap, we present a simplified model focusing on the interaction between four key regulatory pathways (STAT, Wnt, Notch, and MAPK) and cell cycle control. After experimentally validating a model prediction, which showed that the Notch pathway can fine-tune the cell cycle period, we perform further model analysis that reveals that the change of cell cycle period accompanying ISC differentiation may be controlled by a design principle that has been well studied in dynamical systems theory-a saddle node on invariant circle bifurcation. Given that the mechanisms that control the cell cycle are conserved in most eukaryotic cell types, this general principle potentially controls the interplay between proliferation and differentiation for a broad range of stem cells. PMID- 30467025 TI - MutSgamma-Induced DNA Conformational Changes Provide Insights into Its Role in Meiotic Recombination. AB - In many organisms, MutSgamma plays a role in meiotic recombination, facilitating crossover formation between homologous chromosomes. Failure to form crossovers leads to improper segregation of chromosomes and aneuploidy, which in humans result in infertility and birth defects. To improve current understanding of MutSgamma function, this study investigates the binding affinities and structures of MutSgamma in complex with DNA substrates that model homologous recombination intermediates. For these studies, we overexpressed and isolated from Escherichia coli the yeast MutSgamma protein Saccharomyces cerevisiae (Sc) Msh4-Msh5. Sc Msh4 Msh5 binds Holliday junction (HJ)-like substrates, 3' overhangs, single-stranded (ss) forks, and the displacement loop with nanomolar affinity. The weakest binding affinities are detected for an intact duplex and open-junction construct. Similar to the human protein, Sc Msh4-Msh5 exhibits the highest affinity for the HJ with a Kd < 0.4 nM in solution. Energy-transfer experiments further demonstrate that DNA structure is modulated by the binding interaction with the largest changes associated with substrates containing an ss end. Upon binding, Sc Msh4-Msh5 displaces the ss away from the duplex in most of the ss-containing intermediates, potentially enabling the binding of RPA and other proteins. In the case of the junction-like intermediates, Msh4-Msh5 binding either stabilizes the existing stacked structure or induces formation of the stacked X conformation. Significantly, we find that upon binding, Msh4-Msh5 stacks an open-junction construct to the same extent as the standard junction. Stabilization of the junction in the stacked conformation is generally refractory to branch migration, which is consistent with a potential role for MutSgamma to stabilize HJs and prevent branch migration until resolution by MutLgamma. The different binding modalities observed suggest that Msh4-Msh5 not only binds to and stabilizes stacked junctions but also participates in meiotic recombination before junction formation through the stabilization of single-end invasion intermediates. PMID- 30467026 TI - Targeting the Pentose Phosphate Pathway: Characterization of a New 6PGL Inhibitor. AB - Human African trypanosomiasis, or sleeping sickness, is a lethal disease caused by the protozoan parasite Trypanosoma brucei. However, although many efforts have been made to understand the biochemistry of this parasite, drug development has led to treatments that are of limited efficiency and of great toxicity. To develop new drugs, new targets must be identified, and among the several metabolic processes of trypanosomes that have been proposed as drug targets, carbohydrate metabolism (glycolysis and the pentose phosphate pathway (PPP)) appears as a promising one. As far as the PPP is concerned, a limited number of studies are related to the glucose-6-phosphate dehydrogenase. In this work, we have focused on the activity of the second PPP enzyme (6-phospho-gluconolactonase (6PGL)) that transforms 6-phosphogluconolactone into 6-phosphogluconic acid. A lactam analog of the natural substrate has been synthesized, and binding of the ligand to 6PGL has been investigated by NMR titration. The ability of this ligand to inhibit 6PGL has also been demonstrated using ultraviolet experiments, and protein-inhibitor interactions have been investigated through docking calculations and molecular dynamics simulations. In addition, a marginal inhibition of the third enzyme of the PPP (6-phosphogluconate dehydrogenase) was also demonstrated. Our results thus open new prospects for targeting T. brucei. PMID- 30467027 TI - Accuracy of 3D surface scanners for clinical torso and spinal deformity assessment. AB - Externally visible deformities are cosmetic features of great concern for Adolescent Idiopathic Scoliosis (AIS) patients. Current assessment techniques for AIS do not fully encompass the external deformity. A non-invasive method capable of capturing superficial anatomy, such as 3D scanning, would enable better qualitative and quantitative evaluation of cosmesis. This study aimed to quantify the accuracy of commonly available scanners, in assessing posterior asymmetry in AIS. The technique of 3D surface deviation analysis was proposed as a suitable method for comparing the models created by each scanner. Eight plaster cast moulds manufactured to create braces for AIS patients were used as test samples. Four 3D scanners were selected: Solutionix RexScan CS+; Artec Eva; Microsoft Kinect V1; iPhone with 123D Catch App. These scanners were selected from those available as representative of a range of scanning technologies. Each cast was scanned and 3D models created. A simulated rib hump measurement was obtained and the surface-to-surface deviations between the Solutionix scan and all other scans were determined. The Solutionix scanner is a metrology scanner of very high quality and so it was selected as the reference. Surface-to-surface deviations were calculated in the positive and negative directions separately to specifically identify size and volume inaccuracies created by the scans. Surface deviations showed excellent agreement between the Solutionix and the Eva with deviations of +0.17 +/- 0.17 mm (Eva regions larger) and -0.20 +/- 0.32 mm (Eva regions smaller) (mean+/-SD). The Kinect showed lower agreement (+1.58 +/- 1.50 mm and -0.58 +/- 0.58 mm). The iPhone scans were not able to be scaled to the correct size, so were excluded. Rib hump measurements with all scanners were within clinical measurement variability (+/-4.9 deg) of the known values. These commercially available 3D scanners are capable of imaging torso shape in 3D and deriving clinically relevant external deformity measures. The non-invasive 3D topographic information provided can be used to improve assessment of torso shape in spinal deformity patients. PMID- 30467028 TI - Color Doppler Artifact Masking Iatrogenic Aortic Valve Injury Related to an Impella Device. AB - The Impella (Abiomed, Danvers, MA) is a minimally invasive transvalvular left ventricular assist device (LVAD) that effectively unloads the left ventricle (LV), especially in patients with ventricular arrhythmias in the setting of a venous-arterial extracorporeal membrane oxygenator (VA ECMO).1,2 Utilization of the Impella device has increased significantly in the last few years for high risk percutaneous coronary intervention and cardiogenic shock because of its relatively easy implantation in the catheterization lab and the operating room. Although rare, iatrogenic injury of the aortic valve (AV) can be caused by placement of the device across the AV.3 This can lead to aortic regurgitation (AR) with significant clinical consequences in the setting of cardiogenic shock. This AR can be challenging to diagnose echocardiographically because of the artifacts generated by the device when using color-flow Doppler. In this E challenge, the authors emphasize the importance of recognizing these findings for accurate interpretation of the echocardiogram in the management of cardiogenic shock refractory to the Impella LVAD and the utility of transesophageal echocardiography (TEE). PMID- 30467029 TI - Intraoperative Transesophageal Echocardiography During Cardiovascular Surgery in China. AB - OBJECTIVE: To perform a comprehensive nationwide survey of more than 90% of all cardiovascular hospitals in China to assess the current 2018 status of transesophageal echocardiography (TEE) equipment, operating physicians, education, impact on surgery, and reimbursement. DESIGN: In this nationwide survey, 716 cardiovascular hospitals in mainland China were included. A 15 question electronic survey was sent to these hospitals and the data were received directly from the questionnaire website for analysis. SETTING: Cardiovascular hospitals in mainland China. PARTICIPANTS: Departments of anesthesiology in cardiovascular hospitals in mainland China. INTERVENTIONS: Answer a 15-question survey. MEASUREMENTS AND MAIN RESULTS: About 90% of hospitals have acquired machines to perform TEEs with most of the machines controlled by the ultrasound department. Anesthesiologists performed intraoperative TEEs in 45% of the hospitals, but only 15% of the hospitals have anesthesiologists who have met the basic TEE training requirements. Most anesthesiologists (68%) believed TEE significantly contributed to patient care during cardiovascular surgeries. The overwhelming majority of surveyed hospital staff (93%) stated that they were planning to continue or start intraoperative TEE examinations in the future. CONCLUSION: Many hospitals in China have acquired equipment to perform intraoperative TEE examinations during cardiovascular surgeries. However, the number of anesthesiologists who can perform TEEs independently still is not adequate. Standardized trainings, a formal certification process, and governmental payment model changes must be provided to ensure high-quality TEE services and better surgical outcomes in China. PMID- 30467030 TI - Management of Arteriovenous Fistulas in Cardiac Surgery. PMID- 30467032 TI - Transvaginal Ultrasound Vibro-elastography for Measuring Uterine Viscoelasticity: A Phantom Study. AB - The purpose of this research was to determine the feasibility of a transvaginal ultrasound vibro-elastography (TUVE) technique for generating and measuring shear wave propagation in the uterus. In TUVE, a 0.1-s harmonic vibration at a low frequency is generated on the abdomen of a subject via a handheld vibrator. A transvaginal ultrasound probe is used to measure the resulting shear wave propagation in the uterus. TUVE was evaluated on a female ultrasound phantom. The shear wave speeds in the region of interest of the uterus of the female ultrasound phantom were measured in the frequency range of 100-300 Hz. The viscoelasticity was analyzed based on the wave speed dispersion with frequency. The measurement of shear wave speed suggests that the uterus of this female ultrasound phantom is much stiffer than the human uterus. This research illustrates the feasibility of TUVE for generating and measuring shear wave propagation in the uterus of a female ultrasound phantom. We will further evaluate TUVE in patients, both normal controls and those with uterine diseases such as adenomyosis. PMID- 30467031 TI - The Impact of l-Thyroxine Treatment of Donors and Recipients on Postoperative Outcomes After Heart Transplantation. AB - OBJECTIVE: The effect of thyroid dysfunction on adverse outcomes has been studied in many different patient populations. The objective of this study was to investigate the effect of thyroid hormone supplementation of donors and recipients on postoperative outcomes after orthotopic heart transplantation. DESIGN: Retrospective. SETTING: Single center, university hospital. PARTICIPANTS: Two-hundred and sixty-six consecutive patients undergoing heart transplantation. INTERVENTIONS: No interventions. MEASUREMENTS AND MAIN RESULTS: Demographic, hemodynamic, and clinical characteristics; donor and recipient United Network for Organ Sharing scores; and information on thyroid hormone support of donors and recipients were recorded. During the median follow-up of 4.59 years (interquartile range 4.26-4.92 y), 70 patients (26.3%) died. After adjustments were made for the United Network for Organ Sharing score, recipients who were treated preoperatively with l-thyroxine had a lower risk for all-cause mortality (adjusted hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.06-0.98; p = 0.047) compared with recipients who were not treated with l-thyroxine. In addition, l-thyroxine treatment of donors was associated with a better recipient survival (HR 0.31, 95% CI 0.11-0.87; p = 0.025). CONCLUSIONS: Pretransplantation thyroid hormone supplementation of donors and recipients was associated with improved long-term survival after heart transplantation. PMID- 30467034 TI - Ventral hernia surgery in morbidly obese patients, immediate or after bariatric surgery preparation: Results of a case-matched study. AB - BACKGROUND: Obesity is a risk factor for the development of ventral hernia and increases the risk of recurrence and surgical site infection after hernia repair (HR). OBJECTIVES: We tested the hypothesis that bariatric surgery (BS) before HR would decrease these risks in patients with morbid obesity. SETTING: University hospital, France. METHODS: We retrospectively compared 2 groups of patients with morbid obesity in a case-matched study; 1 underwent immediate HR surgery (control), and the other initially underwent BS and then HR after weight loss (case). Patients were individually matched at a 2:1 ratio according to defect size (<7 or >=7 cm), obesity grade (<40 or >=40 kg/m2), American Society of Anesthesiologists score, sex, smoker status, and presence of chronic obstructive pulmonary disease. RESULTS: From 2000 to 2017, 41 patients underwent BS, in association with herniorrhaphy in 14 cases (34%). Initial body mass index was higher in the BS group (46.7 +/- 6.4 versus 42.4 +/- 7.2, P < .0001) but had decreased by the time of HR (34.1 +/- 6.5 versus 42.3 +/- 7.2, P < .0001). Prosthetic HR was performed after 21.5 months (range, 7-87); however, 7 patients did not receive HR at this time due to insufficient weight loss. Postoperative morbidity was similar in the 2 groups. Hospital stay was shorter in the BS group (6.2 +/- 2.6 versus 10.7 +/- 9.3 d, P = .002). After a median follow-up of 4.6 +/ 4.1 years, the recurrence rate was lower in the BS group (2/30, 6.7%) than in the control group (12/50, 24%; P = .048). CONCLUSION: For morbidly obese patients with ventral hernia, BS before HR surgery can decrease recurrence without increasing morbidity. PMID- 30467033 TI - Determinants of Myocardial Strain in Experimental Chronic Myocardial Infarction. AB - We evaluated the relationships between regional myocardial strain measured by speckle tracking echocardiography and viability, fibrosis, hypertrophy and oxygen consumption in the infarcted or remote myocardium in a pig model of chronic myocardial infarction (MI). Thirteen farm pigs with surgical occlusion of the left anterior descending coronary artery and five sham-operated pigs were studied 3 mo post-MI. Computed tomography revealed significant left ventricle remodeling. Reduced radial or circumferential strain identified areas of transmural infarction (area under the curve: 0.82 and 0.79, respectively). In the remote non infarcted area, radial strain correlated inversely with the amount of fibrosis (r = -0.66, p = 0.04) and myocyte hypertrophy (r = -0.68, p = 0.03). Radial strain rate inversely correlated with myocardial resting oxygen consumption assessed with 11C-labeled acetate positron emission tomography (r = -0.71, p = 0.006). In conclusion, myocardial strain and strain rate reflect fibrosis, hypertrophy and oxygen consumption of the remote areas after MI. PMID- 30467035 TI - Comment on: Midterm outcomes of sleeve gastrectomy in the elderly. PMID- 30467036 TI - Self-inflicted burn injuries: Etiologies, risk factors and impact on institutional resources. AB - INTRODUCTION: Self-inflicted burns are a rare cause of injury, accounting for only 1.0% of burns in the United States. While rare, the physical and psychosocial ramifications of these injuries are lasting. The goal of this study was to examine the etiologies, risk factors and outcomes of self-inflected burns in an urban setting. METHODS: Records of all patients presented to a regional burn center from July 2011 to June 2015 were reviewed. Those who sustained a self inflected burn were identified and included in this study. Demographic data, psychiatric history, previous self-harm records, insurance status, injury circumstance, burn characteristic [location and total body surface area (TBSA)], need for excision and grafting, graft-take and duration of hospital stay and costs were reviewed. This group was then compared to a cohort of 166 patients with non-intentional burn during the same time frame matched for age and TBSA%. RESULTS: There were 34 patients with a mean (SD) age of 31 (15.2) who sustained a self-inflicted burn during the study period. The mean TBSA% was 2.8 (SD=5.1), with most injuries in the upper and lower extremities. Fifty three percent of the patients presented with altered mental status secondary to either psychiatric illness or intoxication. Twenty-four percent of incidents were claimed as suicide attempts and suicidal ideation was present in 47% of cases. Twenty-six percent of patients with a previous psychiatric diagnosis were not on a psychiatric medication prior to incident. There was record of previous self-harm in 26% of patients. When compared to control group of 166 patient with non-intentional burn, patients with self-inflicted burn had higher rates of substance abuse (35% vs. 13%, p<0.05), longer stay in the hospital (11.3 vs. 5.3 days, p<0.01), longer stay in the intensive care unit (1.8 vs. 0.2 days, p<0.01), and lower rates of insurance (15% vs. 42%, p<0.001). These patients also exhibited a higher need for excision and grafting (41% vs. 20%, p<0.01). CONCLUSIONS: Patients with self inflected burn have a higher rate of previous self-harm behavior, psychiatric comorbidities and substance abuse. These patients are more likely to require surgical excision and grafting and expanded institutional resources compared to those with non-intentional burn with similar degree and size of burn. Increased counseling of at-risk populations may help to decrease this potentially preventable method of injury. PMID- 30467037 TI - Short-term outcomes after laparoscopic cytoreductive surgery in patients with limited peritoneal metastases from colorectal cancer. AB - BACKGROUND: The purpose of this study was to investigate the safety of laparoscopic cytoreductive surgery versus open surgery for patients with limited peritoneal metastases from colorectal cancer. METHODS: Laparoscopic surgery for patients with colorectal cancer with peritoneal metastases has been performed at our institution since December 2004. We retrospectively evaluated data from patients with colorectal cancer metastatic to the peritoneum, with a peritoneal cancer index <=10. We compared short-term operative and survival outcomes in the laparoscopic cytoreductive surgery group and open cytoreductive surgery group. RESULTS: A total of 21 patients underwent open cytoreductive surgery and 42 underwent laparoscopic cytoreductive surgery, of whom 6 (14%) required open conversion. Clinicopathologic characteristics and operative outcomes were comparable between the groups. Complete cytoreduction was achieved in all patients in the laparoscopic cytoreductive surgery group and in 19 patients (91%) in the open cytoreductive surgery group (P = .042). Both the mean hospital stay and use of postoperative narcotics were significantly less in the laparoscopic cytoreductive surgery group than in the open cytoreductive surgery group. The type of operation (open cytoreductive surgery versus laparoscopic cytoreductive surgery) was not related to survival outcomes. CONCLUSION: With careful selection by experienced laparoscopic surgeons, laparoscopic cytoreductive surgery was technically feasible and safe to treat colorectal cancer patients with limited peritoneal metastases. PMID- 30467038 TI - Enhanced readability of discharge summaries decreases provider telephone calls and patient readmissions in the posthospital setting. AB - INTRODUCTION: Hospital discharge instructions provide critical information necessary for patients to manage their own care; however, often they are written at a substantially higher readability level than recommended (ie, 6th-grade level) by the American Medical Association and the National Institutes of Health. We hypothesize that improving the reading level of discharge instructions will decrease the number of patient telephone calls and readmissions in the posthospital setting. METHODS: We conducted a prospective observational study. Patient discharge instructions were edited and incorporated to enhance the readability level in August 2015. Return telephone call and readmissions of patients admitted before the intervention from August 1, 2014, to January 31, 2015, were compared with the prospective cohort studied from September 1, 2015, to September 30, 2016. RESULTS: A total of 1,072 patients were included (preintervention: n = 493, postintervention: n = 579). Patient demographics, injury characteristics, and education level were similar among both groups. The median discharge instruction readability level in the postintervention group was significantly lower (10.0, 95% CI 10.0-10.2 vs 8.6, 95% CI 8.8-8.9; P < .0001). The proportion of patients calling after hospital discharge was significantly reduced after the intervention (21.9% vs 9.0%; P < .0001). Monthly hospital readmissions were decreased by 50% for every 100 patients discharged after the intervention (1.9% vs 0.9%; P = .002). The proportion of patients calling and readmissions for poor pain control significantly decreased after the intervention (7.1% vs 2.59%; P = .0005 and 2.8% vs 1.0%; P = .029, respectively). CONCLUSION: Enhanced readability of discharge instructions was associated with a decrease in the number of telephone calls and readmissions in the posthospital setting, enhancing health literacy and simultaneously reducing the burden on providers. Improved patient instructions written to an appropriate level may also allow for better pain control in the posthospital setting. PMID- 30467039 TI - Is disease progression a contraindication for the strategy of portal vein embolization followed by hepatectomy for hepatocellular carcinoma? AB - BACKGROUND: Portal vein embolization has been used worldwide to induce hypertrophy of the future liver remnant and to reduce the risk of hepatic insufficiency and death after major hepatectomy. However, whether disease progression after portal vein embolization can affect long-term oncologic outcomes in patients with hepatocellular carcinoma is uncertain. METHODS: From a total of 107 patients who underwent portal vein embolization and subsequent hepatectomy between 2000 and 2016, 57 patients with hepatocellular carcinoma were enrolled. We evaluated their long-term oncologic outcomes and investigated whether the disease progression between portal vein embolization and subsequent hepatectomy affected survival. RESULTS: The 5-year overall survival and disease free survival after hepatectomy were 74.5% and 31.7%, respectively. Multivariate analyses revealed that tumor number before hepatectomy >=3 (hazard ratio 3.59, P = .019), des-gamma-carboxy prothrombin >200 mAU/mL (hazard ratio 3.36, P = .045), and red blood cell transfusion (hazard ratio 11.03, P = .0008) were independent prognostic factors for overall survival. Male sex (hazard ratio 3.74, P = .029), bilobar tumor distribution (hazard ratio 3.65, P = .004), and red blood cell transfusion (hazard ratio 6.22, P = .0026) were independent prognostic factors for disease-free survival. Disease progressions after portal vein embolization, including increases in tumor size, tumor number, alpha-fetoprotein, lens culinaris agglutinin-reactive fraction of alpha-fetoprotein, and des-gamma carboxy prothrombin, were observed in 22.8%, 14.0%, 29.8%, 19.3%, and 47.4% of patients, respectively. Only an increase of tumor number significantly decreased the disease-free survival rate after hepatectomy in a univariate analysis, and none of the variables affected overall survival. CONCLUSION: Disease progression after portal vein embolization did not affect long-term survival in patients with hepatocellular carcinoma if the planned subsequent hepatectomy could be completed. PMID- 30467040 TI - Reply to: Insufficient number of examined lymph nodes may offset the survival benefit from neoadjuvant therapy in esophageal squamous cell carcinoma. PMID- 30467041 TI - The role of proportionate kinetic growth rate fraction in future remnant liver function over volume determined by 99mTc-Mebrofenin hepatobiliary scintigraphy including SPECT and computed tomography in the risk prediction of postoperative mortality in ALPPS. PMID- 30467042 TI - Systematic Review of the Role of Cytoreductive Nephrectomy in the Targeted Therapy Era and Beyond: An Individualized Approach to Metastatic Renal Cell Carcinoma. AB - CONTEXT: The role of cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) in the targeted therapy (TT) era is controversial. OBJECTIVE: To assess if CN versus no CN is associated with improved overall survival (OS) in patients with mRCC treated in the TT era and beyond, characterize the morbidity of CN, identify prognostic and predictive factors, and evaluate outcomes following treatment sequencing. EVIDENCE ACQUISITION: Medline, EMBASE, and Cochrane databases were searched from inception to June 4, 2018 for English-language clinical trials, cohort studies, and case control studies evaluating patients with mRCC who underwent and those who did not undergo CN. The primary outcome was OS. Risk of bias was evaluated using the Cochrane Collaborative tools. EVIDENCE SYNTHESIS: We identified 63 reports on 56 studies. Risk of bias was considered moderate or serious for 50 studies. CN was associated with improved OS among patients with mRCC in 10 nonrandomized studies, while one randomized trial (CARMENA) found that OS with sunitinib alone was noninferior to that with CN followed by sunitinib. The risk of perioperative mortality and Clavien >=3 complications ranged from 0% to 10.4% and from 3% to 29.4%, respectively, with no meaningful differences between upfront CN or CN after presurgical systemic therapy (ST). Notably, 12.9-30.4% of patients did not receive ST after CN. Factors most consistently prognostic of decreased OS were progression on presurgical ST, high C-reactive protein, high neutrophil lymphocyte ratio, poor International Metastatic renal cell carcinoma Database Consortium (IMDC)/Memorial Sloan Kettering Cancer Center (MSKCC) risk classification, sarcomatoid dedifferentiation, and poor performance status. At the same time, good performance status and good/intermediate IMDC/MSKCC risk classification were most consistently predictive of OS benefit with CN. In a randomized trial investigating the sequence of CN and ST (SURTIME), an OS trend was observed with CN after a period of ST in patients without progression compared with upfront CN. However, the study was underpowered and results are exploratory. CONCLUSIONS: Currently, ST should be prioritized in the management of patients with de novo mRCC who require medical therapy. CN maintains a role in patients with limited metastatic burden amenable to surveillance or metastasectomy, and may potentially be considered in patients with favorable response after initial ST or for symptom's palliation. PATIENT SUMMARY: In the contemporary era, receiving systemic therapy is the priority in metastatic kidney cancer. Nephrectomy still has a role in patients with limited burden of metastases, well-selected patients based on established prognostic and predictive factors, and patients with a favorable response after initial systemic therapy. PMID- 30467043 TI - Prognostic Models for Patient Selection in Postoperative Radiotherapy: Ready for Use? PMID- 30467044 TI - Checkpoint Inhibitor Pneumonitis - Real-World Incidence and Risk. PMID- 30467045 TI - Arterial Embolization During Programmed Death-1 Inhibitor Treatment: An Unexpected Finding. PMID- 30467046 TI - KRAS Mutation as a Resistance Mechanism to BRAF/MEK Inhibition in NSCLC. PMID- 30467047 TI - Osimertinib for Secondary T790M-Mutation-Positive Squamous Cell Carcinoma Transformation After Afatinib Failure. PMID- 30467048 TI - ARID1A Gene Driver Mutations in Lung Adenocarcinomas. PMID- 30467049 TI - Bilateral Vocal Cord Paralysis: Pembrolizumab-Induced Delayed-Onset Toxicity in a Patient with Lung Adenocarcinoma. PMID- 30467050 TI - An analysis of primary nurse consultation in the Community of Madrid. AB - OBJECTIVE: to analyse the characteristics of primary care nurse consultation and to identify the factors associated with different types of activity. METHOD: A cross-sectional multicentre observational study in 23 health centres (Community of Madrid), on 164 different nurses. The consultation was classified according to a consensus proposal in: "preventive activities" (PA), "self-care deficit" (SD), "coping and adaptation" (CA) and "diagnostic and therapeutic procedures" (DTP). Sociodemographic characteristics, health needs, and consultation characteristics were collected. A bivariate inferential analysis was made, and explanatory multivariate models were constructed. RESULTS: Of the total consultations 63.6% (95% CI: 59.9-67.3%) were classified as DTP. The consultation was directly requested by the patient in 24.3% (95% CI: 21.0- 27.7%) of the cases. There were no differences in the type of consultations by gender (P=.858), or for immigrants (P=.428). Subjects from higher social classes more frequently attended PA consultations (P=.007). There were no other differences in accessibility. The DTP consultations related to previous hospitalizations (OR: 1.191, 95% CI: 1.088 1.304), or the previous use of services (nurse consultation OR: 1.002, 95% CI: 1.000-1.003, medical consultation OR: 1.003, 95% CI: 1.000-1.006). CONCLUSIONS: The nurse consultation is mainly aimed at carrying out procedures and previously arranged consultation prevails over patient demanded consultation. No inequities in accessibility were detected, but the type of care for different social groups was not homogeneous. PMID- 30467051 TI - Positive clinical signs in neurological diseases - An observational study. AB - Many patients with organic neurological disease have symptoms and signs that are unexplained by their disease condition. We attempted to explore the prevalence of positive clinical signs in patients with various organic neurological diseases. We performed a prospective uncontrolled observational study on the presence of 7 positive signs in adults with various organic neurological diseases that were admitted to our tertiary care hospital. This observation was performed during their neurological examination in those who provided consent, could comprehend and lacked terminal illness or profound weakness that limited their ability to perform these tasks. We dichotomized them into two groups based on the presence of these signs. Out of 190 patients that were evaluated between 2014 and 2015, 37 patients had at least one positive sign. On univariate analysis: young age, female gender, prior anxiety, history of childhood abuse, identification of sensory deficits on examination and lack of imaging correlation with clinical localization were identified as risk factors for these positive signs. On multivariate analysis, anxiety (OR 2.88, 95% CI 1.11-7.49, p = 0.03) and presence of sensory deficits on examination (OR 5.81, 95% CI 2.36-14.32, p <= 0.001) were associated with these positive signs. Positive signs are common in patients with organic neurological diseases that have anxiety or sensory deficits and may imply a component of functional overlay. Large studies are required to understand its pathophysiology and impact on future outcomes. PMID- 30467052 TI - Outcomes of adjunctive steroid therapy in adult patients with bacterial meningitis in Taiwan: A nationwide population-based epidemiologic study. AB - BACKGROUND: Although corticosteroids are an effective anti-inflammatory adjuvant therapy, the role of adjunctive steroid therapy in treating adult bacterial meningitis in Taiwan remains controversial. METHODS: Cases of acute bacterial meningitis were identified from the annual hospitalization discharge claims of the National Health Insurance Research Database using International Classification of Diseases, Ninth Revision codes from January 2000 to December 2013. Patients were classified into two groups: (1) steroid group (adjunctive steroids and empirical antibiotics) and (2) placebo group (empirical antibiotics only). RESULTS: There were 15,037 patients enrolled in this study; of these, 57% (7175/15,037) and 52% (7862/15,037) were placed in the placebo and steroid groups, respectively. The case-fatality rates were 11.5% (826/7175) in the placebo group and 19.9% (1562/7862) in the steroid groups during hospitalization (P = 0.77). Further, the hazard ratio (relative to placebo group) of in-hospital and one-year case fatality rate were 0.923 (95% confidence interval [CI]: 0.846 1.007, P = 0.073) and 1.514 (95% CI: 1.425-1.608, P < 0.0001) according to the multivariate Cox model after adjustment for age and sex. CONCLUSION: On the basis of these results, steroid group had a more fulminant clinical course (e.g., acute respiratory failure and pneumonia, etc.), and unfavorable outcomes than placebo group. Therefore, more prospective, randomized, double-blind trials are warranted to evaluate the efficacy of adjunctive steroid therapy in treating adult bacterial meningitis in Taiwan. PMID- 30467053 TI - Deep cheek fat flap: new technique to augment the soft tissues of the mandibular alveolus. PMID- 30467054 TI - Incidence and predictors of early complications following primary and revision total ankle arthroplasty. AB - BACKGROUND: Total ankle arthroplasty (TAA) offers an effective option for end stage osteoarthritis. The incidence and preoperative risk factors for early adverse events (AEs) following primary and revision TAA may be useful information for providers. METHODS: A large database was queried from 2010 to 2016 to identify 905 patients of whom 818 underwent primary TAA (90.4%) and 87 underwent revision TAA (9.6%). Data on patient demographics, comorbidities, and hospital length of stay were analyzed as risk factors for reported 30-day AEs. RESULTS: The overall AE rate was 5.5% (50/905) for the entire cohort. AEs occurred more frequently for revision TAA (9/87) than primary TAA (41/818) cases (OR 2.43, p=0.022). Age (OR 1.03, p=0.045), BMI (OR 1.04, p=0.046), and revision TAA (OR 2.56, p=0.002) were independent risk factors for 30-day AEs in multivariate analysis. CONCLUSIONS: Older age, higher BMI, and revision cases are associated with a higher risk of AEs. PMID- 30467055 TI - Managing the open calcaneal fracture: A systematic review. AB - INTRODUCTION: Open fractures of the calcaneus are rare. They are mostly caused by high-energy trauma. There are several treatment options for calcaneal fractures. However, treatment of open calcaneal fractures might need a different approach, as open calcaneal fractures are associated with high rates of complications. The purpose of this study was to provide a literature overview on the management of open calcaneal fractures, and deduct a more standardized treatment algorithm. MATERIAL AND METHODS: A literature review was conducted in the databases of PubMed, EMBASE and the Cochrane Library for articles describing the management of open calcaneal fractures. Excluded were studies with less than 10 patients, studies describing combat injuries and reviews. Only articles published from 1998 to 2017 were included and there were no language restrictions. RESULTS: A total of 18 articles were included with 616 open calcaneal fractures in 598 patients. Most wounds were Gustilo grade III and most fractures were Sanders type III. Definitive surgery was performed after a mean of 9.8days and in most cases in the form of ORIF via ELA. The complication rate was 21% and the mean AOFAS score was 73.7 points. CONCLUSION: The complication rates of open calcaneal fractures are high and increase with the severity of the wound. A treatment algorithm is suggested. However, to produce a more evidence-based protocol and achieve consensus for treatment, additional research should be done, preferably in the form of a prospective multicenter database. PMID- 30467056 TI - Individualized treatment for allergic rhinitis based on key nasal clinical manifestations combined with histamine and leukotriene D4 levels. AB - INTRODUCTION: The types of allergic rhinitis are roughly classified based on the causative antigens, disease types, predilection time, and symptom severity. OBJECTIVE: To examine the clinical typing and individualized treatment approach for allergic rhinitis and to determine the optimal treatment method for this disease using various drug combination therapies. METHODS: A total of 108 participants with allergic rhinitis were divided into three groups based on symptoms. Subsequently, each group was further categorized into four subgroups based on the medications received. The efficacy of the treatments was evaluated using the visual analog scale VAS scores of the total and individual nasal symptoms, decline index of the symptom score, histamine and leukotriene levels, and mRNA and protein expression levels of histamine 1 and cysteinyl leukotriene 1 receptors. RESULTS: Loratadine+mometasone furoate and loratadine+mometasone furoate+montelukast significantly improved the sneezing symptom and reduced the histamine levels compared with the other combination therapies (p<0.05). Meanwhile, montelukast+mometasone furoate and montelukast+mometasone furoate+loratadine considerably improved the nasal obstruction symptom and decreased the leukotriene D4 levels compared with the other combination therapies (p<0.05). CONCLUSION: Clinical symptom evaluation combined with experimental detection of histamine and leukotriene levels can be an objective and accurate method to clinically classify the allergic rhinitis types. Furthermore, individualized treatment based on allergic rhinitis classification can result in a good treatment efficacy. PMID- 30467057 TI - Erratum: Survey of methicillin-resistant Staphylococcus aureus control measures in hospitals participating in the VINCat program [Enferm Infecc Microbiol Clin. 2016;34(7):409-414]. PMID- 30467058 TI - Patient from India with fever and uncommon findings. PMID- 30467059 TI - Epidemiology and current control of sexually transmitted infections. The role of STI clinics. AB - The burden of disease from sexually transmitted infections (STI) undermines sexual and reproductive health and the health of newborn infants. The presence of some STI facilitates the transmission of others, such as HIV, and cause cellular changes that precede some types of cancer. For all these reasons STIs are a first order uncontrolled public health problem. In Spain, gonococcal infection has been on rising since the beginning of 2000, while syphilis has remained stable at high levels since 2011. Both infections are more common in males. Chlamydia trachomatis is the most common STI, and principally affects females between the ages of of 20 and 40. STI units are an essential instrument to tackle this problem. They deal with populations that are particularly vulnerable to these infections and are essential for their control by means of interventions that reduce their transmission efficiency and infectivity duration. They are also the principal source of epidemiological information about these infections. PMID- 30467060 TI - A nationwide survey of the prevalence and psychosocial correlates of internet addictive disorders in Taiwan. AB - BACKGROUND AND PURPOSE: The American Psychiatric Association has published the diagnostic criteria of Internet Gaming Disorder (IGD) in the 5th Diagnostic and Statistical Manual of Mental Disorders (DSM-5) for further studies to clarify IGD and related concepts of internet addiction. The study aims to investigate the prevalence and psychosocial correlates of internet addictive disorder (IAD) in the general population using the framework of IGD criteria. METHODS: A nationwide survey was conducted using a computer-assisted telephone interview of residents aged 15 and older selected by a stratified proportional randomizing method. The questionnaire comprised socio-demographic information, 9-items IAD (IAD-9) for identification of IGD and non-gaming IAD, the 5-item Brief Symptom Rating Scale, and questions about internet use and suicidal ideation. RESULTS: Among 2147 respondents (50.4% females), the one-year prevalence of IAD was 1.9% (1.2% for IGD and 0.7% for non-gaming IAD). People with IAD were characterized as: younger, unemployed or students, under recent psychological distress, with recent and lifetime suicidal ideation, and engaging in regular multiple online activities including gaming, shopping or video-watching. Logistic regression revealed that age and psychopathology including insomnia, depression and inferiority were significant predictors of IAD. High prevalence of psychiatric morbidity (27.5%) and lifetime suicidal ideation (34.2%) accompanied with very low psychiatric treatment rate were also identified. CONCLUSION: Age and psychopathology were identified as major determinants of IAD. The IGD criteria in DMS-5 is applicable to identify the internet addictive problems that enhances early engagement for high-risk populations across the ages. PMID- 30467061 TI - Immunization with attenuated non-transformable pneumococcal pep27 and comD mutant provides serotype-independent protection against pneumococcal infection. AB - Streptococcus pneumoniae is a well-known pathogenic bacterium with a high mortality rate. Currently, a 23-valent pneumococcal polysaccharide vaccine (PPV23) and protein-conjugate vaccines (PCVs) are available on the market. However, both of these vaccines have limitations; specifically, PPV23 produces weak antibody responses in children younger than 2 years and PCVs only partially protect against secondary infection. Previously, we showed serotype-nonspecific protection by Deltapep27 vaccine, but the reversion of Deltapep27 to the wild type serotype during immunization cannot be excluded. To ensure the safety of the Deltapep27 vaccine, comD, an important protein that activates competence, was inactivated, and the transformability of the double mutant (Deltapep27DeltacomD) was determined. The transformation ability of this double mutant was successfully abolished. Deltapep27DeltacomD immunization significantly increased the survival time after heterologous challenge(s), and diminished colonization levels independent of serotype, including a non-typeable strain (NCC1). Moreover, the double mutant was found to be highly safe in both normal and immunocompromised mice. In conclusion, this pneumococcal Deltapep27DeltacomD vaccine appears to be a highly feasible and safe vaccine to prevent various types of pneumococcal infections. PMID- 30467062 TI - Evaluation of the genetic stability of Sabin strains and the consistency of inactivated poliomyelitis vaccine made from Sabin strains using direct deep sequencing. AB - Inactivated poliomyelitis vaccine made from Sabin strains (sIPV) has been encouraged to introduce in the "Global Polio Eradication & Endgame Strategic Plan" and increasingly used worldwide. Attenuated Sabin strains used in manufacture of oral poliovirus vaccine (OPV) and sIPV may regain full or partial neurovirulence during growth in vaccine recipients and the vaccine manufacturing processes. Ensuring the molecular consistency of sIPV batches and that no mutation accumulates beyond the level present in past batches are important for quality control of vaccine manufacture process. Direct deep-sequencing allows the construction of a library of virus RNA and the detection of genetic mutations throughout the viral genome. In the present study, direct deep-sequencing was conducted to detect molecular mutations in virus passages, multiple sIPV monovalent lots, and virus monovalent lots from different polio type III strains. The results indicated that direct deep-sequencing can be used to identify and quantify small amounts of mutant viruses in vaccine preparations, trace the source of a specific virus seed, and monitor the batch-to-batch consistency of vaccines, suggesting that this technique could be suitable for the quality control and consistency monitoring of sIPV production. PMID- 30467063 TI - Short-term safety of 4CMenB vaccine during a mass meningococcal B vaccination campaign in Quebec, Canada. AB - BACKGROUND: To address a high incidence of serogroup B invasive meningococcal disease (IMD-B) in the Saguenay-Lac-Saint-Jean region, Quebec, Canada, a mass vaccination campaign targeting nearly 60,000 individuals <=20 years old was launched in May 2014. Because of the limited clinical experience with the four component meningococcal B vaccine (4CMenB), active surveillance for adverse events following immunization (AEFI) was conducted. This paper reports 4CMenB AEFI surveillance findings. METHODS: Active surveillance assessed AEFIs with acute onset within 7-days post-immunization, AEFI-associated absenteeism and medical consultations, impact of antipyretic prophylaxis and coadministration of other vaccines. RESULTS: By July 17, 2015, 83% and 77% of the 59,098 individuals targeted by the campaign had received a first and a second dose of 4CMenB. The incidence of fever on days1-2 was highest in children <2 years old but only 0.6% reported a temperature >=40?C. Among children <10 years old, >=2doses of acetaminophen prophylaxis significantly reduced fever incidence on days1-2 after dose1&2. Absenteeism or a medical consultation during the 7 days following vaccination was reported by 6.2% of vaccinees post-dose1 and 9.2% post-dose2 and was most often reported in association with fever/malaise (4.2%) or injection site reactions (3.6%). CONCLUSION: Large-scale population-based surveillance identified a 7-day reactogenicity profile consistent with earlier clinical trials with the 4CMenB vaccine but indicating frequent AEFI-associated absenteeism and medical consultations affecting the societal cost of this vaccine. We conclude acceptable vaccine safety and risk-benefit profile overall on the short term, particularly as an intervention to address a high regional incidence of IMD-B. PMID- 30467065 TI - Author's reply : "It could have been much worse: The Minnesota measles outbreak of 2017". PMID- 30467064 TI - Humoral and cellular immune correlates of protection against bubonic plague by a live Yersinia pseudotuberculosis vaccine. AB - Immunization with the live-attenuated Yersinia pseudotuberculosis VTnF1 strain producing a Yersinia pestis F1 pseudocapsule efficiently protects mice against bubonic and pneumonic plague. In clinical trials, demonstration of a plague vaccine's efficacy in humans will not be feasible, and correlates of protection will be needed to bridge the immune response of protected animals to that of vaccinated humans. Using serum transfer and vaccination of antibody-deficient uMT mice, we established that both humoral and cellular responses elicited by VTnF1 independently conferred protection against bubonic plague. Thus, correlates were searched for in both responses, using blood only. Mice were vaccinated with increasing doses of VTnF1 to provide a range of immune responses and survival outcomes. The cellular response was evaluated using an in vitro IFNgamma release assay, and IFNgamma levels were significantly associated with protection, although some survivors were negative for IFNgamma, so that IFNgamma release is not a fully satisfactory correlate. Abundant serum IgG against the F1 capsule, Yop injectable toxins, and also non-F1 Y.pestis antigens were found, but none against the LcrV antigen. All readouts correlated to survival and to each other, confirming that vaccination triggered multiple protective mechanisms developing in parallel. Anti-F1 IgG was the most stringent correlate of protection, in both inbred BALB/c mice and outbred OF1 mice. This indicates that antibodies (Ab) to F1 play a dominant role for protection even in the presence of Ab to many other targets. Easy to measure, the anti-F1 IgG titer will be useful to evaluate the immune response in other animal species and in clinical trials. PMID- 30467066 TI - Molecular characterization of rotavirus diarrhea among children aged under five years in the Philippines, 2013-2015. AB - With the availability of new and existing rotavirus vaccines, credible and reliable data on burden of rotavirus-associated disease are needed to enable evidence-based decision making regarding the introduction of rotavirus vaccines. The national rotavirus surveillance program in the Philippines, a sentinel-based surveillance, was established in 2012 to determine the proportion of laboratory confirmed rotavirus cases among children under five years with acute gastroenteritis and to describe the geographic distribution and molecular epidemiology of rotavirus in the country. During 2013 to 2015, rotavirus infection was the cause of acute gastroenteritis among children under five years admitted to hospitals or evaluated in emergency rooms, constituting more than one third of gastroenteritis hospitalizations at the sentinel site hospitals. The predominant genotype observed was G1P[8]. Although a rotavirus surveillance network has been established, findings suggest the need to strengthen the network in the country and to continue monitoring prevalent rotavirus strains to help identify the possible emergence of new strains. PMID- 30467067 TI - Allogeneic hematopoietic cell transplantation; the current renaissance. AB - Allogeneic hematopoietic cell transplantation (HCT) provides the best chance for cure for many patients with malignant and nonmalignant hematologic disorders. Recent advances in selecting candidates and determining risk, procedure safety, utilization in older patients, use of alternative donors, and new or novel application of anti-cancer, immunosuppressive and antimicrobial agents have improved outcomes and expanded the role of HCT in hematologic disorders. Relapse remains the predominant cause of failure but enlightened use of new targeted and immunotherapeutic agents in combination with HCT promises to reduce relapse and further improve HCT outcomes. PMID- 30467068 TI - Targeting interferon activity to dendritic cells enables in vivo tolerization and protection against EAE in mice. AB - Type I Interferon (IFN) is widely used for multiple sclerosis (MS) treatment, but its side effects are limiting and its mechanism of action still unknown. Furthermore, 30-50% of MS patients are unresponsive, and IFN can even induce relapses. Fundamental understanding of the cellular target(s) of IFN will help to optimize treatments by reducing side effects and separating beneficial from detrimental effects. To improve clinical systemic IFN usage, we are developing AcTaferons (Activity-on-Target IFNs = AFNs), optimized IFN-based immunocytokines that allow cell-specific targeting. In experimental autoimmune encephalitis (EAE) in mice, high dose WT mIFNalpha could delay disease, but caused mortality and severe hematological deficits. In contrast, AFN targeted to dendritic cells (DC, via Clec9A) protected without mortality or hematological consequences. Conversely, CD8-targeted AFN did not protect and exacerbated weight loss, indicating the presence of both protective and unfavorable IFN effects in EAE. Comparing Clec9A-, XCR1-and SiglecH-targeting, we found that targeting AFN to plasmacytoid (p) and conventional (c) DC is superior and non-toxic compared to WT mIFN. DC-targeted AFN increased pDC numbers and their tolerogenic potential, evidenced by increased TGFbeta and IDO synthesis and regulatory T cell induction. In addition, both regulatory T and B cells produced significantly more immunosuppressive TGFbeta and IL-10. In conclusion, specific DC-targeting of IFN activity induces a robust in vivo tolerization, efficiently protecting against EAE, without noticeable side effects. Thus, dissecting positive and negative IFN effects via cell-specific targeting may result in better and safer MS therapy and response rates. PMID- 30467069 TI - Piezoelectric focal waves application in the treatment of plantar fascitis. AB - INTRODUCTION: Plantar fasciitis (PF) is one of the most frequent causes of thalalgia and disability. The effectiveness of extracorporeal shock wave therapy is an ideal alternative to conservative treatments. OBJETIVE: To evaluate the effectiveness of the treatment with Piezoelectric Focal Shock Waves with echographic support and maintenance of the effect at 3 and 6 months. MATERIALS AND METHODS: Causi-experimental, retrospective statistical study,June 2015 to June 2017, of 90 patients, 36.6% men and 63.3% women, with a mean age of 52 years, diagnosed with PF. Three sessions (one weekly for 3 weeks) of shock wave therapy (PiezoWave F10 G4 generator) were performed, with echographic support and weekly revision and at 3 and 6 months. MAIN VARIABLES: pain,using Visual Analog Scale before and after each session and at 3 and 6 months and Roles and Maudsley Scale at the end of treatment and at 3 and 6 months. RESULTS: 2000 pulses per session were applied, medium energy intensity 0.45 mJ /mm2, median frequency 8 MHz and median depth of focus of 15 mm. Statistically significant improvement was observed in the Visual Analog Scale between the 3 treatment sessions and after 3 and 6 months posttreatment,obtaining a statistically significant improvement in all values (p <0.05). CONCLUSION: Treatment with piezoelectric focal shock waves in PF may reduces pain from the first session and achieves a subjective perception of improvement, maintaining these results at 6 months post -treatment. PMID- 30467070 TI - Ethnic differences in metabolic cardiovascular risk among normal weight individuals: Implications for cardiovascular risk screening. The HELIUS study. AB - BACKGROUND AND AIMS: Cardiovascular disease (CVD) risk factors may occur among a substantial proportion of normal weight individuals, particularly among some ethnic minorities. It is unknown how many of these individuals would be missed by commonly applied eligibility criteria for cardiovascular risk screening. Thus, we aim to determine cardiovascular risk and eligibility for cardiovascular risk screening among normal weight individuals of different ethnic backgrounds. METHODS AND RESULTS: Using the HELIUS study (Amsterdam, The Netherlands), we determined cardiovascular risk among 6910 normal weight individuals of Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Moroccan and Turkish background. High cardiovascular risk was approximated by high metabolic risk based on blood pressure, HDL, triglycerides and fasting glucose. Eligibility criteria for screening were derived from Dutch CVD prevention guidelines and include age >= 50 y, family history of CVD, or current smoking. Ethnic group comparisons were made using logistic regression. Age-adjusted proportions of high metabolic risk ranged from 12.6% to 38.4% (men) and from 2.7% to 11.5% (women). This prevalence was higher among most ethnic minorities than the Dutch, especially among women. For most ethnic groups, 79.9%-86.7% of individuals with high metabolic risk were eligible for cardiovascular risk screening. Exceptions were Ghanaian women (58.8%), Moroccan men (70.9%) and Moroccan women (45.0%), although age-adjusted proportions did not differ between groups. CONCLUSION: Even among normal weight individuals, high cardiovascular metabolic risk is more common among ethnic minorities than among the majority population. Regardless of ethnicity, most normal weight individuals with increased risk are eligible for cardiovascular risk screening. PMID- 30467071 TI - Role of rs670 variant of APOA1 gene on metabolic response after a high fat vs. a low fat hypocaloric diets in obese human subjects. AB - BACKGROUND & AIMS: A common G-to-A transition located 75 base pairs upstream (rs670) from transcription start site of the APOA1 gene has been related with some metabolic parameters. Our aim was to analyze the effects of rs670 APOA1 gene polymorphism on lipid profile and metabolic changes after two different hypocaloric diets. METHODS: 282 obese subjects were randomly allocated during 12 weeks (Diet HF - high fat diet vs. Diet LF - low fat diet). Anthropometric and biochemical status were evaluated. RESULTS: Body mass index, weight, fat mass, waist circumference, systolic blood pressure, leptin levels and waist circumference decreased in all patients in average after both diets. In A allele carriers after 12 weeks with both diets, insulin levels (Delta diet HF: -5.3 + 1.2 UI/L; P = 0.02 and Delta diet LF: -5.8 + 1.3 UI/L; P = 0.02) and HOMA-IR (Delta diet HF: -2.9 + 0.8 units; P = 0.01 and Delta diet LF: -2.2 + 0.9 units; P = 0.03) improved in a significant way. With the low fat diet, A allele carriers showed a statistical improvement in HDL-cholesterol levels (Delta: 4 + 1 mg/dl; P = 0.03). CONCLUSIONS: Our study showed the association of rs670 ApoA1 polymorphism with a decrease of insulin resistance induced by both diets and provided additional evidence on HDL-cholesterol increase after a LF hypocaloric diet in A allele carriers. PMID- 30467072 TI - Usefulness of MR Arthrography of the Hip with and without leg Traction in Detection of Intra-articular Bodies. AB - RATIONALE AND OBJECTIVE: Although intra-articular bodies are a classic indication for MR arthrography and surgical removal, diagnostic studies are currently sparse. To assess the diagnostic performance of MR arthrography with and without leg traction in detection of intra-articular bodies in the hip joint. MATERIAL AND METHODS: The institutional hip arthroscopy data base (2009-2016: 631 hips) was retrospectively reviewed. Inclusion criteria were hips with and without intra articular bodies and direct MR arthrography performed with and without leg traction. Twenty-one hips with intra-articular bodies constituted the "disease positive" group. Seventy-nine randomly selected hips without intra-articular bodies constituted the "disease-negative" group. Images were reviewed independently for presence of intra-articular bodies by two blinded readers. Overall diagnosis and location of intra-articular bodies was recorded (peripheral or central). Arthroscopy served as goldstandard for diagnosis and location of intra-articular bodies. Diagnostic performance and kappa statistics of traction MR arthrography with and without traction were calculated. RESULTS: For both readers sensitivity/specificity of traction MR arthrography was 86%-95% respectively 90%-91% for overall diagnosis of intra-articular bodies and was 81% 86% respectively 90%-92%for MR arthrogrpahy without traction. For central intra articular bodies sensitivity was higher for both readers with traction (79%-89%) than without traction (74% each). CONCLUSION: MR arthrography with and without traction of the hip is highly accurate in identifying central and peripheral intra-articular bodies. Application of traction was further useful for visualization of centrally located intra-articular bodies. PMID- 30467073 TI - Selection of Fitting Model and Arterial Input Function for Repeatability in Dynamic Contrast-Enhanced Prostate MRI. AB - RATIONALE AND OBJECTIVES: Analysis of dynamic contrast-enhanced (DCE) magnetic resonance imaging is notable for the variability of calculated parameters. The purpose of this study was to evaluate the level of measurement variability and error/variability due to modeling in DCE magnetic resonance imaging parameters. MATERIALS AND METHODS: Two prostate DCE scans were performed on 11 treatment naive patients with suspected or confirmed prostate peripheral zone cancer within an interval of less than two weeks. Tumor-suspicious and normal-appearing regions of interest (ROI) in the prostate peripheral zone were segmented. Different Tofts Kety based models and different arterial input functions, with and without bolus arrival time (BAT) correction, were used to extract pharmacokinetic parameters. The percent repeatability coefficient (%RC) of fitted model parameters Ktrans, ve, and kep was calculated. Paired t-tests comparing parameters in tumor suspicious ROIs and in normal-appearing tissue evaluated each parameter's sensitivity to pathology. RESULTS: Although goodness-of-fit criteria favored the four-parameter extended Tofts-Kety model with the BAT correction included, the simplest two-parameter Tofts-Kety model overall yielded the best repeatability scores. The best %RC in the tumor-suspicious ROI was 63% for kep, 28% for ve, and 83% for Ktrans . The best p values for discrimination between tissues were p <10 5 for kep and Ktrans, and p = 0.11 for ve. Addition of the BAT correction to the models did not improve repeatability. CONCLUSION: The parameter kep, using an arterial input functions directly measured from blood signals, was more repeatable than Ktrans. Both Ktrans and kep values were highly discriminatory between healthy and diseased tissues in all cases. The parameter ve had high repeatability but could not distinguish the two tissue types. PMID- 30467074 TI - Antisense oligonucleotide eluforsen improves CFTR function in F508del cystic fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. In this study we assessed the effect of antisense oligonucleotide eluforsen on CFTR biological activity measured by Nasal Potential Difference (NPD) in patients with the most common mutation, F508del CFTR. METHODS: This multi-centre, exploratory, open-label study recruited adults with CF homozygous or compound heterozygous for the F508del-CFTR mutation. Subjects received intranasal eluforsen three times weekly for 4 weeks. The primary endpoint was the within-subject change from baseline in total chloride transport (Cl-free+iso), as assessed by NPD. Secondary endpoints included within subject change from baseline in sodium transport. RESULTS: In the homozygous cohort (n = 7; per-protocol population), mean change (90% confidence interval) in Cl-free+iso was -3.0 mV (-6.6; 0.6) at day 15, -4.1 mV (-7.8; -0.4, p = .04) at day 26 (end of treatment) and - 3.7 mV (-8.0; 0.6) at day 47. This was supported by improved sodium transport as assessed by an increase in average basal potential difference at day 26 of +9.4 mV (1.1; 17.7, p = .04). The compound heterozygous cohort (n = 7) did not show improved chloride or sodium transport NPD values. Eluforsen was well tolerated with a favourable safety profile. CONCLUSIONS: In F508del-CFTR homozygous subjects, repeated intranasal administration of eluforsen improved CFTR activity as measured by NPD, an encouraging indicator of biological activity. PMID- 30467075 TI - Natural course of asymptomatic walled off pancreatic necrosis. AB - INTRODUCTION: There is paucity of data on natural course of asymptomatic walled off necrosis (WON). OBJECTIVE: To study the natural course as well as outcome of conservative management in patients with asymptomatic WON. METHODS: Retrospective analysis of prospectively maintained data base of patients with asymptomatic WON presenting to us 4-6 weeks after an episode of acute necrotising pancreatitis (ANP). RESULTS: Forty three patients (37 M; mean age: 38.2 +/- 10.4 years) with asymptomatic WON were studied. The size of WON ranged from 5 to 16 cm (mean 8.2 +/- 2.2 cm). The site of WON was head, body and tail in 5 (11%), 34 (79%) and 4 (10%) patients respectively. Thirty of 43 patients (70%) patients did not have any complications during the expectant management period of 3 weeks-32 months with 13 (30%) patients having spontaneous resolution within 6.2 +/- 3.4 months. Thirteen (30%) patients became symptomatic or developed complication within 3.2 +/- 1.3 months. These were refractory pain (n = 7), infection (n = 4), spontaneous rupture into gastrointestinal tract (n = 5; stomach in 3, duodenum in 1 and colon in 1 patient respectively) and bleeding from splenic artery pseudoaneursym in 1 patient. CONCLUSIONS: Majority of patients with asymptomatic WON have an uneventful clinical course. However, one third patients will develop symptoms/complications requiring interventional treatment. PMID- 30467077 TI - Effect of probiotics on lipid profiles in hypercholesterolaemic adults: A meta analysis of randomized controlled trials. AB - BACKGROUND: Recent clinical studies have yielded controversial results regarding the effect of probiotics on lipid profiles. To assess the efficacy of probiotics in lowering serum lipid concentrations, we conducted a meta-analysis of randomized controlled trials (RCTs). METHODS: Literature from the PubMed, Embase and Cochrane databases were searched and screened. The effects of probiotics on lipid profiles were assessed by mean difference (MD) and 95% confidence interval (CI). All included studies were analyzed using Review Manager 5.3 (Cochrane Collaboration, 2014). RESULTS: A total of 19 RCTs, including 967 participants, met the inclusion criteria. Probiotic interventions reduced total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) compared to controls (placebo or no treatment) by -0.25mmol/L (95% CI: -0.39, -0.12) and -0.17mmol/L (95% CI: -0.25, -0.09), respectively. No significant effects of probiotics on triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels were found. The effects of probiotics on decreasing TC and LDL-C levels were greater for longer intervention times, certain probiotic strains, and in younger mildly hypercholesterolaemic subjects. CONCLUSION: This meta-analysis revealed that the use of probiotics can significantly lower TC and LDL-C levels in hypercholesterolaemic adults, which brings hope for reducing the risk factors for developing cardiovascular disease. PMID- 30467076 TI - Erectile dysfunction in compensated liver cirrhosis. AB - BACKGROUND: Data on erectile dysfunction (ED) in cirrhotic patients are limited as yet. Aim of this study was to investigate the prevalence of ED and the factors potentially involved in its development in compensated cirrhosis. METHODS: We prospectively enrolled 102 male (mean age 63 +/- 10 years) affected by cirrhosis in Child-Pugh Class A. The following questionnaires were used: simplified International Index of Erectile Function (IIEF-5) Questionnaire, Centre of Epidemiologic Studies Depression Scale and ANDROTEST. RESULTS: ED was found in 57/102(55.9%) patients, and was mild, moderate and severe in 21(36.8%), 6(10.5%) and 30(52.6%) subjects, respectively. ED patients were significantly older than those without (66 +/- 10 vs 60 +/- 10,p = 0.006); ED prevalence gradually increased with age. There was no statistically significant difference between patients with and without ED concerning the coexistence of diabetes, hypertension, and cardiovascular disease. Age(p = 0.040) and serum haemoglobin(p = 0.027) were identified as predictors of ED on multivariate analysis. Liver related factors and pharmacological treatment, including beta-blockers, were not associated with the presence of ED. CONCLUSIONS: In patients with compensated liver cirrhosis, even in concomitance with other chronic comorbidities, the prevalence of ED is not markedly different from the general population. Compensated cirrhosis per se is not a risk factor for ED occurrence. Older age and low haemoglobin values are significantly associated with ED in cirrhotics. PMID- 30467078 TI - High convective volumes are associated with improvement in metabolic profile in diabetic patients on online haemodiafiltration. AB - BACKGROUND AND OBJECTIVE: Online haemodiafiltration (OL-HDF) with high convective transport volumes improves patient survival in haemodialysis. Limiting the amount of convective volume has been proposed in patients with diabetes mellitus due to glucose load that is administered with replacement fluid. The objective of the study was to analyse the influence of substitution volume on the evolution of the metabolic profile and body composition of incident diabetic patients on OL-HDF. MATERIAL AND METHODS: Prospective observational study in 29 incident diabetic patients on postdilution OL-HDF. Baseline data included clinical and demographic data, laboratory parameters (metabolic, nutritional and inflammatory profile) and body composition with bioimpedance spectroscopy (BIS). Laboratory parameters and mean substitution volume per session were collected every 4 months, and in 23 patients a further BIS was performed after a minimum of one year. Variations in glycosylated haemoglobin (HbA1c), triglycerides, total cholesterol, LDL-c, HDL-c, albumin, prealbumin and C reactive protein (CRP) were calculated at one year, 2 years, 3 years, and at the end of follow-up. Quarterly and annual variations were calculated as independent periods, and changes in body composition were analysed. RESULTS: Age at baseline was 69.7+/-13.6 years, 62.1% were male, 72.3+/-13.9kg, 1.78+/-0.16m2, with 48 (35.5-76) months on dialysis. Approximately 81.5% received insulin, 7.4% antidiabetic drugs and 51.9% statins. Mean substitution volume was 26.9+/-2.9L/session and follow-up period (time on OL-HDF) was 40.4+/-26 months. A significant correlation was observed between mean substitution volume and the increase in HDL-c (r=0.385, p=0.039) and prealbumin levels (r=0.404, p=0.003) throughout follow-up. Moreover, substitution volume was correlated with a reduction in CRP levels at one year (r=-0.531, p=0.005), 2 years (r=-0.463, p=0.046), and at the end of follow-up (r=-0.498, p=0.007). Patients with mean substitution volume >26.9L/session had a higher reduction in triglycerides and CRP, and an increase in HDL-c levels. These patients with >26.9L/session finished the study with higher HDL-c (48.1+/-9.4mg/dL vs. 41.2+/-11.6mg/dL, p=0.025) and lower CRP levels (0.21 [0.1-2.22] mg/dL vs. 1.01 [0.15-6.96] mg/dL, p=0.001), with no differences at baseline. Quarterly comparisons between substitution volume and laboratory changes [n=271] showed a significant correlation with a reduction in HbA1c (r=-0.146, p=0.021). Similar findings were obtained with annual comparisons [n=72] (r=-0.237, p=0.045). An annual mean substitution volume over 26.6L/session (29.3+/-1.7L/session vs. 23.9+/-1.9L/session) was associated with a reduction in HbA1c (-0.51+/-1.24% vs. 0.01+/-0.88%, p=0.043). No correlation was observed between substitution volume and changes in weight, body mass index or BIS parameters. CONCLUSION: There is not enough evidence to restrict convective transport in diabetic patients on OL-HDF due to the glucose content of the replacement fluid. PMID- 30467079 TI - Interactions between the Ig-Superfamily Proteins DIP-alpha and Dpr6/10 Regulate Assembly of Neural Circuits. AB - Drosophila Dpr (21 paralogs) and DIP proteins (11 paralogs) are cell recognition molecules of the immunoglobulin superfamily (IgSF) that form a complex protein interaction network. DIP and Dpr proteins are expressed in a synaptic layer specific fashion in the visual system. How interactions between these proteins regulate layer-specific synaptic circuitry is not known. Here we establish that DIP-alpha and its interacting partners Dpr6 and Dpr10 regulate multiple processes, including arborization within layers, synapse number, layer specificity, and cell survival. We demonstrate that heterophilic binding between Dpr6/10 and DIP-alpha and homophilic binding between DIP-alpha proteins promote interactions between processes in vivo. Knockin mutants disrupting the DIP/Dpr binding interface reveal a role for these proteins during normal development, while ectopic expression studies support an instructive role for interactions between DIPs and Dprs in circuit development. These studies support an important role for the DIP/Dpr protein interaction network in regulating cell-type-specific connectivity patterns. PMID- 30467080 TI - Neuron-Subtype-Specific Expression, Interaction Affinities, and Specificity Determinants of DIP/Dpr Cell Recognition Proteins. AB - Binding between DIP and Dpr neuronal recognition proteins has been proposed to regulate synaptic connections between lamina and medulla neurons in the Drosophila visual system. Each lamina neuron was previously shown to express many Dprs. Here, we demonstrate, by contrast, that their synaptic partners typically express one or two DIPs, with binding specificities matched to the lamina neuron expressed Dprs. A deeper understanding of the molecular logic of DIP/Dpr interaction requires quantitative studies on the properties of these proteins. We thus generated a quantitative affinity-based DIP/Dpr interactome for all DIP/Dpr protein family members. This revealed a broad range of affinities and identified homophilic binding for some DIPs and some Dprs. These data, along with full length ectodomain DIP/Dpr and DIP/DIP crystal structures, led to the identification of molecular determinants of DIP/Dpr specificity. This structural knowledge, along with a comprehensive set of quantitative binding affinities, provides new tools for functional studies in vivo. PMID- 30467081 TI - Corrigendum to "Spatial analysis and high resolution mapping of the human whole brain transcriptome for integrative analysis in neuroimaging". PMID- 30467082 TI - A nonhuman primate model of early Alzheimer's disease pathologic change: Implications for disease pathogenesis. AB - INTRODUCTION: Nonhuman primates may serve as excellent models of sporadic age associated brain beta-amyloid deposition and Alzheimer's disease pathologic changes. We examined whether a vervet nonhuman primate model recapitulated pathologic, physiologic, and behavioral features of early Alzheimer's disease. METHODS: Nine middle-aged (mean = 11.2 years) and nine aged (mean = 21.7 years) female vervet/African green monkeys underwent cerebrospinal fluid collection, gait speed measurement, and neuroimaging before neuropathologic assessment. RESULTS: beta-amyloid plaques were identified in all aged vervets and paired helical filament tau immunoreactivity was observed in all animals. Cerebrospinal fluid beta-amyloid42 and gait speed correlated negatively with age and plaque density. Greater plaque and paired helical filament tau burden predicted reduced volumes and CMRg in several brain regions. DISCUSSION: We observed a coordinated set of relationships among neuropathologic, cerebrospinal fluid, imaging, and behavioral modalities consistent with early Alzheimer's disease. Our results support future use of the vervet model to explore disease mechanisms, biomarkers, and novel therapeutic strategies. PMID- 30467083 TI - Corrigendum to "The economic impact of agricultural pollutions in Iran, spatial distance function approach" [Sci. Total Environ. Volumes 616-617, March 2018, Pages 1656-1663]. PMID- 30467084 TI - Between orchestrated and organic: Accountability for loss and the moral landscape of childbearing in Malawi. AB - This paper explores loss in childbearing in Malawi (miscarriages, perinatal deaths and maternal mortality) as a lens to understand accountability and health system functioning. In low-income countries, maternal and perinatal mortality reflects poor health system functioning, to be improved in part through accountability. Understanding how accountability plays out on the ground requires examination of the existing, 'organic' accountability relationships and mechanisms. Thematic and discourse analysis of interviews and observations illuminates vocabularies of responsibility and practices of accountability concerning loss. Women are especially held accountable for loss, by a range of social actors. They use existing 'organic' accountability relationships and mechanisms to manage their own interests, but arguably also to care for pregnant women, even though negative birth experiences may ensue. Instances of disrespectful care appear a by-product of the convergence of organic and orchestrated, policy-driven accountability for numeric outcomes (deaths averted) rather than process (quality of care). Moreover, in the absence of essential physical resources, providers and relatives mobilize the social resources at their disposal to keep women and babies alive. Improving quality of care requires acknowledgment that providers' actions are both systemic and situational, and embedded in local moral landscapes and uneven webs of accountability. PMID- 30467086 TI - Retraction notice to: "Characteristics of recursive backstepping algorithm and active damping of oscillations in feedback linearization for electromechanical system with extended stability analysis and perturbation rejection" [ISA Trans. 64C (2016) 365-372]. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted by agreement between the authors and the Editor-in Chief. A request by the authors to add additional authors to the paper after publication resulted in an agreement to retract the paper by the Authors and Editor-in-Chief. PMID- 30467085 TI - Fetal stroke and cerebrovascular disease: Advances in understanding from lenticulostriate and venous imaging, alloimmune thrombocytopaenia and monochorionic twins. AB - Fetal stroke is an important cause of cerebral palsy but is difficult to diagnose unless imaging is undertaken in pregnancies at risk because of known maternal or fetal disorders. Fetal ultrasound or magnetic resonance imaging may show haemorrhage or ischaemic lesions including multicystic encephalomalacia and focal porencephaly. Serial imaging has shown the development of malformations including schizencephaly and polymicrogyra after ischaemic and haemorrhagic stroke. Recognised causes of haemorrhagic fetal stroke include alloimmune and autoimmune thrombocytopaenia, maternal and fetal clotting disorders and trauma but these are relatively rare. It is likely that a significant proportion of periventricular and intraventricular haemorrhages are of venous origin. Recent evidence highlights the importance of arterial endothelial dysfunction, rather than thrombocytopaenia, in the intraparenchymal haemorrhage of alloimmune thrombocytopaenia. In the context of placental anastomoses, monochorionic diamniotic twins are at risk of twin twin transfusion syndrome (TTTS), or partial forms including Twin Oligohydramnios Polyhydramnios Sequence (TOPS), differences in estimated weight (selective Intrauterine growth Retardation; sIUGR), or in fetal haemoglobin (Twin Anaemia Polycythaemia Sequence; TAPS). There is a very wide range of ischaemic and haemorrhagic injury in a focal as well as a global distribution. Acute twin twin transfusion may account for intraventricular haemorrhage in recipients and periventricular leukomalacia in donors but there are additional risk factors for focal embolism and cerebrovascular disease. The recipient has circulatory overload, with effects on systemic and pulmonary circulations which probably lead to systemic and pulmonary hypertension and even right ventricular outflow tract obstruction as well as the polycythaemia which is a risk factor for thrombosis and vasculopathy. The donor is hypovolaemic and has a reticulocytosis in response to the anaemia while maternal hypertension and diabetes may influence stroke risk. Understanding of the mechanisms, including the role of vasculopathy, in well studied conditions such as alloimmune thrombocytopaenia and monochorionic diamniotic twinning may lead to reduction of the burden of antenatally sustained cerebral palsy. PMID- 30467087 TI - Finite-time dissipative filtering for uncertain discrete-time systems with state and disturbance-dependent noise over fading channels. AB - This paper concerns with the finite-time exponential dissipative filtering problem for a class of discrete stochastic system subject to randomly occurring uncertainties and channel fadings. A modified Lth-order Rice fading model is presented to better characterize the multipath fading phenomena in real wireless communication environment. Our objective is to design a filter such that the filtering error system is finite-time stochastic bounded with a prespecified exponential dissipative performance. With the aid of the auxiliary function, a new set of sufficient conditions is derived for the existence of an acceptable filter which can degrade into the conditions for filtering with Hinfinity performance. Then, the filter gains are obtained by solving these inequality sufficient conditions. Finally, an illustrative example is given to demonstrate the validity of the proposed approach. PMID- 30467089 TI - Sexual Orientation Disparities in Prescription Opioid Misuse Among U.S. Adults. AB - INTRODUCTION: The opioid epidemic in the U.S. continues to increase in severity, and misuse of prescription opioids is of particular concern since it commonly precedes heroin use. This study examined whether sexual orientation (i.e., sexual identity and sexual attraction) is a risk factor for prescription opioid misuse and use disorder among a nationally representative sample of adults in the U.S. METHODS: This study used data from adult participants (ages >=18 years) in the 2015 National Survey on Drug Use and Health. Chi-square tests and logistic regression examined how sexual identity and sexual attraction relate to past-year and past-month prescription opioid misuse and past-year prescription opioid use disorder. Multivariable models examined associations controlling for demographic characteristics and other drug use. Gender-stratified analyses were also conducted. Data were analyzed in 2018. RESULTS: In multivariable analyses, compared with those identifying as heterosexual, bisexual individuals were at 1.53 (95% CI=1.20, 1.97) and 1.66 (95% CI=1.14, 2.42) higher odds of reporting past-year and past-month misuse, respectively. In stratified analyses, female bisexuals remained at high risk. Regarding sexual attraction, compared with being attracted to only the opposite sex, being attracted to mostly the opposite sex (AOR=2.15, 95% CI=1.77, 2.63) or being equally attracted to both sexes (AOR=1.78, 95% CI=1.38, 2.30) were associated with higher odds for past-year opioid misuse. In stratified analyses, these associations were limited to females. CONCLUSIONS: Sexual orientation disparities in opioid misuse and use disorder among a nationally representative sample of U.S. adults was found. PMID- 30467088 TI - Hepatitis C Testing and Patient Characteristics in Washington State's Prisons Between 2012 and 2016. AB - INTRODUCTION: There is no widely accepted testing approach for hepatitis C virus infection in correctional settings, and many U.S. prisons do not provide routine testing. The aim of this study was to determine the most effective hepatitis C virus testing strategy in one U.S. state prison and describe the population with reactive testing. METHODS: A retrospective analysis was performed using individuals entering the Washington State prison system, which routinely offers hepatitis C virus testing, to compare routine opt-out with current recommendations for risk-based and one-time testing for individuals born between 1945 and 1965. Additionally, liver fibrosis stage was characterized using aspartate aminotransferase to platelet ratio index and Fibrosis-4 index. Analyses were conducted in 2017. RESULTS: Between 2012 and 2016, a total of 24,567 (83%) individuals were tested for the hepatitis C virus antibody and 4,921 (20%) were reactive (test was positive). There were 2,403 (49%) that had hepatitis C virus RNA testing, with 1,727 (72%) showing chronic infection. Reactive antibody was more prevalent in individuals born between 1945 and 1965 compared with other years (44% vs 17%); however, most cases (72%) were outside of this cohort. Up to 35% of positive reactive tests would be missed with testing targeted by birth cohort and risk behavior. Of chronically infected individuals, 23% had at least moderate liver fibrosis. CONCLUSIONS: Targeted testing in the Washington State prison system missed a substantial proportion of hepatitis C virus cases; of those with reactive testing, a sizeable proportion of people had at least moderate liver disease, placing them at risk for complications. Routine testing at entry should be considered by U.S. state prisons. PMID- 30467090 TI - U.S. Adult Attitudes About Electronic Vapor Product Use in Indoor Public Places. AB - INTRODUCTION: The U.S. Surgeon General has concluded that aerosol from electronic vapor products, such as e-cigarettes, can contain harmful and potentially harmful constituents. This study assessed the prevalence and determinants of U.S. adult attitudes toward electronic vapor product use in indoor public places. METHODS: Data from 2017 Summer Styles, an Internet survey of U.S. adults aged >=18 years (n = 4,107) were analyzed in 2017. Respondents were asked, Do you favor or oppose allowing the use of electronic vapor products in indoor public places such as workplaces, restaurants, and bars? Responses were strongly favor, somewhat favor, somewhat oppose, and strongly oppose. Multivariate Poisson regression was used to determine sociodemographic correlates of opposition (somewhat or strongly). RESULTS: In 2017, a total of 82.4% of adults strongly or somewhat opposed the use of electronic vapor products in indoor public places, including 28.0% of current (past 30-day) electronic vapor product users and 52.7% of current cigarette smokers. After adjustment, opposition was significantly lower among current and former electronic vapor product users than never users, current cigarette smokers than never smokers, and people living with tobacco product users. Opposition was significantly higher among adults aged >=45 years than those aged 18-24 years and among adults who had rules prohibiting electronic vapor product use in their vehicles or homes than those without such rules. CONCLUSIONS: Approximately eight in ten U.S. adults, including more than one quarter of electronic vapor product users, opposed electronic vapor product use in indoor public places. Prohibiting electronic vapor product use in indoor public areas can protect bystanders from the health risks of secondhand electronic vapor product aerosol exposure. PMID- 30467091 TI - State Preemption of Food and Nutrition Policies and Litigation: Undermining Government's Role in Public Health. AB - INTRODUCTION: In the U.S., federal, state, and local governments have various legal tools to support public health and prevent diet-related disease, including enacting policy and bringing lawsuits against businesses that produce harm causing products. Yet, states preempt, or limit, government's authority to enact public health policies or initiate litigation. METHODS: In 2018, research was conducted to find state laws enacted through March 16, 2018, using state legislatures' websites, LexisNexis, UConn Rudd Center's Legislative Database, Centers for Disease Control and Prevention Chronic Disease State Policy Tracking System, and the Internet, that preempt local food and nutrition policies including their legislative histories; and preempt lawsuits related to food consumption and chronic disease (e.g., Commonsense Consumption Acts), including explicitly preempting government activity. RESULTS: Between 2008 and March 16, 2018, 12 states enacted 13 preemptive laws on nutrition labeling, content or "criteria"; consumer incentive items; "food-based health disparities"; sale, distribution, or serving of food and beverages; portion size; food safety; menus; taxes; and "marketing." Between 2003 and 2013, 26 states enacted laws preempting lawsuits claiming long-term food consumption causes obesity and diet-related disease; of these, ten states explicitly preempt such litigation by the government and five explicitly preempt laws providing litigation as a remedy. CONCLUSIONS: State preemption may hinder public health progress by impeding local food and nutrition policies and government-initiated litigation. Local governments are in a prime position to address fundamental concerns, such as reduction of health disparities, the provision of nutrition information, access to healthy food, and the cost of unhealthy food. Government-initiated litigation could potentially support broader policy changes. PMID- 30467092 TI - Lung Cancer Screening Inconsistent With U.S. Preventive Services Task Force Recommendations. AB - INTRODUCTION: Prior studies suggest overuse of nonrecommended lung cancer screening tests in U.S. community practice and underuse of recommended tests. METHODS: Data from the 2010 and 2015 National Health Interview Surveys was analyzed from 2016 to 2018. Prevalence, populations, and number of chest computed tomography (CT) and chest x-ray tests were estimated for people who did and did not meet U.S. Preventive Services Task Force (USPSTF) criteria for lung cancer screening, among people aged >=40 years without lung cancer. RESULTS: In 2015, among those who met USPSTF criteria, 4.4% (95% CI=3.0%, 6.6%), or 360,000 (95% CI=240,000, 535,000) people reported lung cancer screening with a chest CT; and 8.5% (95% CI=6.5%, 11.1%), or 689,000 (95% CI=526,000, 898,000) people reported a chest x ray. Among those who did not meet USPSTF criteria, 2.3% (95% CI=2.0%, 2.6%), or 3,259,000 (95% CI=2,850,000, 3,724,000) people reported a chest x ray; and 1.3% (95% CI=1.1%, 1.5%), or 1,806,000 (95% CI=1,495,000, 2,173,000) people reported a chest CT. The estimated population meeting USPSTF criteria for lung cancer screening in 2015 was 8,098,000 (95% CI=7,533,000, 8,702,000), which was smaller than the 9,620,000 people (95% CI=8,960,000, 10,325,000) in 2010. CONCLUSIONS: The number of adults inappropriately screened for lung cancer greatly exceeds the number screened according to USPSTF recommendations, the prevalence of appropriate lung cancer screening is low, and the population meeting USPSTF criteria is shrinking. To realize the potential benefits of screening, better processes to appropriately triage eligible individuals to screening, plus screening with a USPSTF-recommended test, would be beneficial. PMID- 30467093 TI - BAFF-R and TACI expression on CD3+ T cells: Interplay among BAFF, APRIL and T helper cytokines profile in systemic lupus erythematosus. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is the prototype of systemic autoimmune disease, characterized by loss of immune tolerance against self antigens where autoantibody production is the hallmark of disease. B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) are cytokines that promote autoreactive cell survival, immunoglobulin-class switching and autoantibody responses in human and mouse SLE models. BAFF and APRIL exert their functions through interactions with their receptors BAFF-R and TACI that are differentially expressed in B lymphocyte subsets, monocytes, dendritic cells and T lymphocytes. BAFF stimulation favors T lymphocyte activation and cytokine production through BAFF-R, which could contribute to the Th1, Th17 and/or Th2 response dysregulation observed in SLE patients. OBJECTIVE: To evaluate the expression of the cytokines BAFF and APRIL and their association with the receptors BAFF-R and TACI on CD3+ T cells and to evaluate Th1/Th2/Th17 cytokine profile in patients with SLE. METHODS: Fifteen healthy controls (HC) and 36 SLE patients were included, and their demographic and clinical data were assessed. The disease activity index (Mex-SLEDAI) and damage index (SLICC) were applied to the SLE patients. BAFF-R and TACI expression on CD3+ T cells were evaluated by flow cytometry. Serum BAFF and APRIL concentrations were measured by enzyme linked immunosorbent assays (ELISA). Cytokine levels of Th1 (IL-12, IL-2, IFN gamma, TNF-alpha), Th2 (IL-4, IL-6, IL-10, IL-13) and Th17 (IL-1beta e IL-17) were quantified with a multiplex assay (MAGPIX). Statistical analysis was performed using PASW Statistics v.20 and GraphPad Prism v.6 software. RESULTS: No differences in BAFF-R or TACI expression on the CD3+ T cells of SLE and HC were observed. BAFF-R expression correlates inversely with disease activity (r = 0.538, p < 0.01), while TACI correlates with disease activity (r = 0.530, p < 0.05). Serum BAFF and APRIL levels were high in SLE patients and correlated with the disease activity index Mex-SLEDAI (r = 0.621, p < 0.01 and r = 0.416, p < 0.05). SLE patients were found to have significantly higher levels of IL-12, IFN gamma, TNF-alpha, IL-6, IL-10, IL-13, IL-1beta and IL-17 compared to HC (p < 0.05). Cytokines IL-17 (r = 0.526) and TNF-alpha (r = 0.410) correlate with disease activity (p < 0.05), while APRIL (r = 0.477), IL-10 (r = 0.426) and IFN gamma (r = 0.440) levels were associated with organ damage (p < 0.01). Serum BAFF expression levels correlate with IL-4 (r = 0.424; p < 0.05), IL-6 (r = 0.420; p < 0.05) and IL-10 (r = 0.459; p < 0.01), whereas APRIL levels correlate with IL-2 (r = 0.666; p < 0.01), IL-12 (r = 0.611; p < 0.01) and TNF-alpha (r = 0.471; p < 0.05) cytokines. A subgroup of SLE patients with high serum BAFF levels (>2 ng/mL) also showed increased APRIL, IL-2, IL-6 and IL-10 levels (p < 0.05). Finally, BAFF, IL-4 and TNF-alpha serum levels were associated with high titers of antinuclear antibodies. CONCLUSIONS: The study demonstrates an imbalance in the Th1/Th2 cytokine profile, with increased proinflammatory cytokines, as well as BAFF and APRIL serum levels. Associations of BAFF with Th2 profile cytokines and disease activity, as well as APRIL with Th1 profile cytokines and organ damage, suggest that BAFF and APRIL generated in the autoimmunity context could through still unknown mechanisms, modulate the microenvironment, and perpetuate the inflammatory response, autoantibody production and organ damage observed in SLE patients. PMID- 30467094 TI - Functional MIF promoter haplotypes modulate Th17-related cytokine expression in peripheral blood mononuclear cells from control subjects and rheumatoid arthritis patients. AB - Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by elevated levels of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-17, and macrophage migration inhibitory factor (MIF). MIF induces IL-17 secretion and MIF promoter polymorphisms influence the expression of selected downstream mediators. The aim of this study was to investigate the relationship between known functional MIF haplotypes and Th17-related cytokine secretion profile in peripheral blood mononuclear cells (PBMC) from control subjects (CS) and RA patients stimulated with lipopolysaccharide (LPS) and recombinant human MIF (rhMIF). The -794 CATT5-8 and -173G > C polymorphisms of the MIF gene were determined by conventional PCR and PCR-RFLP, respectively. The most frequent haplotypes of the MIF polymorphism and PBMC were identified from three subjects homozygous for each haplotype and in both study groups, the PBMC were obtained and stimulated with LPS or rhMIF. The secretion of cytokines related to the Th17 profile was determined by a multiplex immunoassay (MAGPIX). LPS stimulation induced the secretion of cytokines related to the Th17 profile in PBMC from CS and RA patients, whereas, rhMIF only stimulated this response in PBMC from RA patients. PBMC from CS carriers of the MIF 7C haplotype showed more IL-17A, IL-17F, IL-22, and IL-23 secretion than non-7C carriers after LPS stimulation. In the case of rhMIF stimulation, the PBMC from CS carriers of the 7C haplotype secreted more IL-17A and IL-23 than non-7C carriers. In conclusion, genetic variants of the MIF promoter modulate the secretion of cytokines related to the Th17 profile in PBMC from CS inducing a differential response in comparison to PBMC from RA patients. PMID- 30467095 TI - Kinetics of cytokine mRNA and protein expression by plastic adherent cells in the thymus after split-dose irradiation. AB - Whole body irradiation causes significant apoptosis in various tissues such as the thymus. If apoptotic cells outnumber the phagocytic capacity of macrophages, apoptosis becomes secondary necrosis, inducing inflammatory cytokine expression in macrophages. Radiation also induces thymic lymphomas in C57BL/6 mice after four consecutive irradiations with 1.6 Gy X-rays with nearly 100% incidence. Since cancer development is modulated by a microenvironment involving macrophages, we examined the kinetics of thymocyte number and plastic adherent cell number in the thymus as well as cytokine mRNA expression by plastic adherent cells in the thymus after split-dose irradiation. Upon split-dose irradiation, thymocyte number changed dramatically, whereas plastic adherent cell number did not. Among cytokine mRNAs tested, IL-1beta, IL-11 and IL-12p40 mRNAs were up regulated 2 days after the 1st and 2nd, 3rd and 4th, and 2nd and 3rd irradiations, respectively. On the other hand, TNF-alpha mRNA was up regulated 2 days after the 3rd irradiation and 2 weeks after the 4th irradiation. The level of IL-11 protein was also increased 2 days after 3rd and 4th irradiations. These results suggest that, upon split-dose irradiation, macrophages in the thymus produce various cytokines in a time-dependent manner, thereby contributing to induction of thymic lymphomas. PMID- 30467096 TI - Molecular characterization of the 2',5'-oligoadenylate synthetase family in the Chinese tree shrew (Tupaia belangeri chinensis). AB - Virus infection induces type I interferons (IFNs) that in turn exert their pleiotropic effects through inducing a large number of interferon-stimulated genes (ISGs). The IFN-induced 2',5'-oligoadenylate synthetases (OASs) have been identified as a member of the ISGs family characterized by the ability to synthesize 2',5'-oligoadenylate (2-5A), which can induce the degradation of viral RNA by activating RNase L within the infected cells to block viral replications. In this study, we characterized the OASs of the Chinese tree shrew (Tupaia belangeri chinensis), a small mammal genetically close to primates and has the potential as animal model for viral infections. We identified 4 putative tree shrew OASs (tOASs, including tOAS1, tOAS2, tOASL1, and tOASL2) and characterized their roles in antiviral responses. Tree shrew lost tOAS3 that was presented in human and mouse. Phylogenetic analyses based on the protein sequences showed a close relationship of tOASs with those of mammals. Constitutive mRNA expression of tOASs was found in seven tissues (heart, liver, spleen, lung, kidney, small intestine and brain). Moreover, tOASs were significantly up-regulated upon various virus infections. Overexpression of tOASs significantly inhibited DNA virus and RNA virus replications in tree shrew primary renal cells. tOAS1 and tOAS2, but not tOASL1 and tOASL2, exerted their anti-HSV activity in an RNase L dependent pathway. Collectively, our results revealed the evolutionary conservation of tOASs in tree shrew and might offer helpful information for creating viral infection models using the Chinese tree shrew. PMID- 30467098 TI - For whom the bell tolled. PMID- 30467097 TI - Inflammasome and cytokine expression profiling in experimental periodontitis in the integrin beta6 null mouse. AB - Epithelial alphavbeta6 integrin participates in immune surveillance in many organs, including the gastrointestinal track. Expression of alphavbeta6 integrin is reduced in the junctional epithelium of the gingiva in periodontal diseases, and mutations in the ITGB6 gene are associated with these diseases in humans and mice. The aim of this study was to unravel potential differences in the inflammatory responses in the periodontal tissues of FVB wild-type (WT) and beta6 integrin-null (Itgb6-/-) mice, using a ligature-induced periodontitis model and assessing inflammation, bone loss and expression profiles of 34 genes associated with periodontal disease. Using micro-CT and histology, we demonstrated more advanced inflammation and bone loss in the control and ligatured Itgb6-/- mice compared to the WT animals. Neutrophil and macrophage marker genes were significantly upregulated by ligation in both WT and Itgb6-/- mice while the expression of T-cell and B-cell markers was downregulated, suggesting acute-type of inflammation. Expression of inflammasome NLRP3-related genes Nlpr3 and Il1b was also significantly increased in both groups. However, the expression of Il18 was significantly lower in non-ligatured Itgb6-/- mice than in the WT mice and was further downregulated in both groups by the ligatures. IL-18 mediates many effects of the AIM2 inflammasome, including regulation of the microbiome. Interestingly, expression of Aim2 was significantly lower in both control and ligatured Itgb6-/- mice than in WT animals. Overall, ligature-induced periodontitis was associated with increased expression of pro-inflammatory cytokines, chemokines and osteoclastogenic regulatory molecules. Another significant difference between the Itgb6-/- and WT mice was that mRNA expression of the anti-inflammatory cytokine IL-10 was increased in ligatured WT mice but reduced in the Itgb6-/- mice. In conclusion, alphavbeta6 integrin in junctional epithelium of the gingiva appears to positively regulate the expression of the AIM2 inflammasome and anti-inflammatory IL-10, thus providing protection against periodontal inflammation. PMID- 30467099 TI - Paediatric critical care survival: how to avoid bias. PMID- 30467100 TI - A Real-Time Autonomous Dashboard for the Emergency Department: 5-Year Case Study. AB - BACKGROUND: The task of monitoring and managing the entire emergency department (ED) is becoming more important due to increasing pressure on the ED. Recently, dashboards have received the spotlight as health information technology to support these tasks. OBJECTIVE: This study aimed to describe the development of a real-time autonomous dashboard for the ED and to evaluate perspectives of clinical staff on its usability. METHODS: We developed a dashboard based on three principles-"anytime, anywhere, at a glance;" "minimal interruption to workflow;" and "protect patient privacy"-and 3 design features-"geographical layout," "patient-level alert," and "real-time summary data." Items to evaluate the dashboard were selected based on the throughput factor of the conceptual model of ED crowding. Moreover, ED physicians and nurses were surveyed using the system usability scale (SUS) and situation awareness index as well as a questionnaire we created on the basis of the construct of the Situation Awareness Rating Technique. RESULTS: The first version of the ED dashboard was successfully launched in 2013, and it has undergone 3 major revisions since then because of geographical changes in ED and modifications to improve usability. A total of 52 ED staff members participated in the survey. The average SUS score of the dashboard was 67.6 points, which indicates "OK-to-Good" usability. The participants also reported that the dashboard provided efficient "concentration support" (4.15 points), "complexity representation" (4.02 points), "variability representation" (3.96 points), "information quality" (3.94 points), and "familiarity" (3.94 points). However, the "division of attention" was rated at 2.25 points. CONCLUSIONS: We developed a real-time autonomous ED dashboard and successfully used it for 5 years with good evaluation from users. PMID- 30467101 TI - Contextual Anonymization for Secondary Use of Big Data in Biomedical Research: Proposal for an Anonymization Matrix. AB - BACKGROUND: The current law on anonymization sets the same standard across all situations, which poses a problem for biomedical research. OBJECTIVE: We propose a matrix for setting different standards, which is responsive to context and public expectations. METHODS: The law and ethics applicable to anonymization were reviewed in a scoping study. Social science on public attitudes and research on technical methods of anonymization were applied to formulate a matrix. RESULTS: The matrix adjusts anonymization standards according to the sensitivity of the data and the safety of the place, people, and projects involved. CONCLUSIONS: The matrix offers a tool with context-specific standards for anonymization in data research. PMID- 30467102 TI - How Twitter Can Support the HIV/AIDS Response to Achieve the 2030 Eradication Goal: In-Depth Thematic Analysis of World AIDS Day Tweets. AB - BACKGROUND: HIV/AIDS is a tremendous public health crisis, with a call for its eradication by 2030. A human rights response through civil society engagement is critical to support and sustain HIV eradication efforts. However, ongoing civil engagement is a challenge. OBJECTIVE: This study aimed to demonstrate the use of Twitter data to assess public sentiment in support of civil society engagement. METHODS: Tweets were collected during World AIDS Days 2014 and 2015. A total of 39,940 unique tweets (>10 billion users) in 2014 and 78,215 unique tweets (>33 billion users) in 2015 were analyzed. Response frequencies were aggregated using natural language processing. Hierarchical rank-2 nonnegative matrix factorization algorithm generated a hierarchy of tweets into binary trees. Tweet hierarchy clusters were thematically organized by the Joint United Nations Programme on HIV/AIDS core action principles and categorized under HIV/AIDS Prevention, Treatment or Care, or Support. RESULTS: Topics tweeted 35 times or more were visualized. Results show a decrease in 2015 in the frequency of tweets associated with the fight to end HIV/AIDS, the recognition of women, and to achieve an AIDS free generation. Moreover, an increase in tweets was associated with an integrative approach to the HIV/AIDS response. Hierarchical thematic differences in 2015 included no prevention discussion and the recognition of the pandemic's impact and discrimination. In addition, a decrease was observed in motivation to fast track the pandemic's end and combat HIV/AIDS. CONCLUSIONS: The human rights based response to HIV/AIDS eradication is critical. Findings demonstrate the usefulness of Twitter as a low-cost method to assess public sentiment for enhanced knowledge, increased hope, and revitalized expectations for HIV/AIDS eradication. PMID- 30467103 TI - Rethinking Data Sharing at the Dawn of a Health Data Economy: A Viewpoint. AB - A health data economy has begun to form, but its rise has been tempered by the profound lack of sharing of both data and data products such as models, intermediate results, and annotated training corpora, and this severely limits the potential for triggering economic cluster effects. Economic cluster effects represent a means to elicit benefit from economies of scale from internal data innovations and are beneficial because they may mitigate challenges from external sources. Within institutions, data product sharing is needed to spark data entrepreneurship and data innovation, and cross-institutional sharing is also critical, especially for rare conditions. PMID- 30467104 TI - Lamotrigine Therapy for Bipolar Depression: Analysis of Self-Reported Patient Data. AB - BACKGROUND: Depression in people with bipolar disorder is a major cause of long term disability, possibly leading to early mortality and currently, limited safe and effective therapies exist. Although existing monotherapies such as quetiapine have limited proven efficacy and practical tolerability, treatment combinations may lead to improved outcomes. Lamotrigine is an anticonvulsant currently licensed for the prevention of depressive relapses in individuals with bipolar disorder. A double-blinded randomized placebo-controlled trial (comparative evaluation of Quetiapine-Lamotrigine [CEQUEL] study) was conducted to evaluate the efficacy of lamotrigine plus quetiapine versus quetiapine monotherapy in patients with bipolar type I or type II disorders. OBJECTIVE: Because the original CEQUEL study found significant depressive symptom improvements, the objective of this study was to reanalyze CEQUEL data and determine an unbiased classification accuracy for active lamotrigine versus placebo. We also wanted to establish the time it took for the drug to provide statistically significant outcomes. METHODS: Between October 21, 2008 and April 27, 2012, 202 participants from 27 sites in United Kingdom were randomly assigned to two treatments; 101: lamotrigine, 101: placebo. The primary variable used for estimating depressive symptoms was based on the Quick Inventory of Depressive Symptomatology-self report version 16 (QIDS-SR16). The original CEQUEL study findings were confirmed by performing t test and linear regression. Multiple features were computed from the QIDS-SR16 time series; different linear and nonlinear binary classifiers were trained to distinguish between the two groups. Various feature-selection techniques were used to select a feature set with the greatest explanatory power; a 10-fold cross-validation was used. RESULTS: From weeks 10 to 14, the mean difference in QIDS-SR16 ratings between the groups was -1.6317 (P=.09; sample size=81, 77; 95% CI -0.2403 to 3.5036). From weeks 48 to 52, the mean difference was -2.0032 (P=.09; sample size=54, 48; 95% CI -0.3433 to 4.3497). The coefficient of variation (sigma/MU) and detrended fluctuation analysis (DFA) exponent alpha had the greatest explanatory power. The out-of-sample classification accuracy for the 138 participants who reported more than 10 times after week 12 was 62%. A consistent classification accuracy higher than the no information benchmark was obtained in week 44. CONCLUSIONS: Adding lamotrigine to quetiapine treatment decreased depressive symptoms in patients with bipolar disorder. Our classification model suggested that lamotrigine increased the coefficient of variation in the QIDS-SR16 scores. The lamotrigine group also tended to have a lower DFA exponent, implying a substantial temporal instability in the time series. The performance of the model over time suggested that a trial of at least 44 weeks was required to achieve consistent results. The selected model confirmed the original CEQUEL study findings and helped in understanding the temporal dynamics of bipolar depression during treatment. TRIAL REGISTRATION: EudraCT Number 2007-004513-33; https://www.clinicaltrialsregister.eu/ctr search/trial/2007-004513-33/GB (Archived by WebCite at http://www.webcitation.org/73sNaI29O). PMID- 30467105 TI - Experience of Emergency Department Patients With Using the Talking Pole Device: Prospective Interventional Descriptive Study. AB - BACKGROUND: Patient engagement is important. However, it can be difficult in emergency departments (EDs). OBJECTIVE: The aim of this study was to evaluate the satisfaction of ED patients using a patient-friendly health information technology (HIT) device, the "Talking Pole," and to assess the factors relevant to their satisfaction. METHODS: This study was conducted in May 2017 at the ED of a tertiary hospital. The "Talking Pole" is a smartphone-based device attached to a intravenous infusion pole with sensors. It is capable of sensing patient movement and fluid dynamics. In addition, it provides clinical information from electronic medical records to patients and serves as a wireless communication tool between patients and nurses. Patients and caregivers who entered the observation room of the ED were selected for the study. The "Talking Pole" devices were provided to all participants, regardless of their need for an intravenous pole upon admittance to the ED. After 2 hours, each participant was given an 18-item questionnaire created for this research, measured on a 5-point Likert scale, regarding their satisfaction with "Talking Pole." RESULTS: Among 52 participants recruited, 54% (28/52) were patients and the remaining were caregivers. In total, 38% (20/52) were male participants; the average age was 54.6 (SD 12.9) years, and 63% (33/52) of the participants were oncology patients and their caregivers. The overall satisfaction rate was 4.17 (SD 0.79 ) points. Spearman correlation coefficient showed a strong association of "overall satisfaction" with "comparison to the previous visit" (rho=.73 ), "perceived benefit" (rho=.73), "information satisfaction" (rho=.70), and "efficiency" (rho=.70). CONCLUSIONS: In this study, we introduced a patient-friendly HIT device, the "Talking Pole." Its architecture focused on enhancing information delivery, which is regarded as a bottleneck toward achieving patient engagement in EDs. Patient and caregiver satisfaction with the "Talking Pole" was positive in the ED environment. In particular, correlation coefficient results improved our understanding about patients' satisfaction, HIT devices, and services used in the ED. PMID- 30467106 TI - Dynamics of Health Agency Response and Public Engagement in Public Health Emergency: A Case Study of CDC Tweeting Patterns During the 2016 Zika Epidemic. AB - BACKGROUND: Social media have been increasingly adopted by health agencies to disseminate information, interact with the public, and understand public opinion. Among them, the Centers for Disease Control and Prevention (CDC) is one of the first US government health agencies to adopt social media during health emergencies and crisis. It had been active on Twitter during the 2016 Zika epidemic that caused 5168 domestic noncongenital cases in the United States. OBJECTIVE: The aim of this study was to quantify the temporal variabilities in CDC's tweeting activities throughout the Zika epidemic, public engagement defined as retweeting and replying, and Zika case counts. It then compares the patterns of these 3 datasets to identify possible discrepancy among domestic Zika case counts, CDC's response on Twitter, and public engagement in this topic. METHODS: All of the CDC-initiated tweets published in 2016 with corresponding retweets and replies were collected from 67 CDC-associated Twitter accounts. Both univariate and multivariate time series analyses were performed in each quarter of 2016 for domestic Zika case counts, CDC tweeting activities, and public engagement in the CDC-initiated tweets. RESULTS: CDC sent out >84.0% (5130/6104) of its Zika tweets in the first quarter of 2016 when Zika case counts were low in the 50 US states and territories (only 560/5168, 10.8% cases and 662/38,885, 1.70% cases, respectively). While Zika case counts increased dramatically in the second and third quarters, CDC efforts on Twitter substantially decreased. The time series of public engagement in the CDC-initiated tweets generally differed among quarters and from that of original CDC tweets based on autoregressive integrated moving average model results. Both original CDC tweets and public engagement had the highest mutual information with Zika case counts in the second quarter. Furthermore, public engagement in the original CDC tweets was substantially correlated with and preceded actual Zika case counts. CONCLUSIONS: Considerable discrepancies existed among CDC's original tweets regarding Zika, public engagement in these tweets, and actual Zika epidemic. The patterns of these discrepancies also varied between different quarters in 2016. CDC was much more active in the early warning of Zika, especially in the first quarter of 2016. Public engagement in CDC's original tweets served as a more prominent predictor of actual Zika epidemic than the number of CDC's original tweets later in the year. PMID- 30467107 TI - The people behind the papers - Chaitanya Dingare and Virginie Lecaudey. AB - For the past 2 years, our community blog the Node has run a series of interviews with authors of exciting new papers in developmental biology. This series, 'The people behind the papers', aims to promote the faces and personalities behind research, and to hear more about how the work came about; you can see the back catalogue of over 50 interviews at thenode.biologists.com/tag/the-people-behind the-papers To extend the reach of these interviews, we will now publish them in Development, starting with a paper from our current issue that reveals an unexpected role for the Hippo pathway effector Taz in zebrafish fertilisation. First author and PhD student Chaitanya Dingare and his supervisor Virginie Lecaudey, Professor for Developmental Biology of Vertebrates at the Goethe University of Frankfurt in Germany, told us more about the story. PMID- 30467108 TI - Left-right asymmetry in heart development and disease: forming the right loop. AB - Extensive studies have shown how bilateral symmetry of the vertebrate embryo is broken during early development, resulting in a molecular left-right bias in the mesoderm. However, how this early asymmetry drives the asymmetric morphogenesis of visceral organs remains poorly understood. The heart provides a striking model of left-right asymmetric morphogenesis, undergoing rightward looping to shape an initially linear heart tube and align cardiac chambers. Importantly, abnormal left-right patterning is associated with severe congenital heart defects, as exemplified in heterotaxy syndrome. Here, we compare the mechanisms underlying the rightward looping of the heart tube in fish, chick and mouse embryos. We propose that heart looping is not only a question of direction, but also one of fine-tuning shape. This is discussed in the context of evolutionary and clinical perspectives. PMID- 30467109 TI - Are you well controlled? PMID- 30467110 TI - Probiotics for gastroenteritis in young children do not improve symptoms, studies find. PMID- 30467111 TI - Leukemia development initiated by deletion of RBP-J: mouse strain, deletion efficiency, and cell of origin. AB - Conditional deletion of RBP-J, the major transcriptional effector of Notch signaling, specifically within renin-expressing cells leads to the development of B cell leukemia. However, the influence of contributing factors such as mouse strain, cell of origin, and cre recombinase copy number are unknown. In this study, we compared RBP-J deletion efficiency using 1 versus 2 copies of cre recombinase. Further, we compared the incidence and timing of leukemia development in two unique strains of mice, C57BL/6 and 129/Sv, as well as at different B cell developmental stages. We found that animals expressing 2 copies of cre recombinase developed B cell leukemia at an earlier age and with more fulminant disease. In addition, we found a difference in leukemia incidence between C57BL/6 and 129/SV mouse strains. Whereas deletion of RBP-J in renin expressing cells of C57BL/6 mice leads to the development of B cell leukemia, 129/SV mice develop dermatitis with a reactive, myeloproliferative phenotype. The difference in phenotypes is explained in part by the differential expression of extra-renal renin; C57BL/6 mice have more renin-expressing cells within hematopoietic tissues. Finally, we found that deletion of RBP-J in Mb1- or CD19 expressing B lymphocytes does not result in leukemia development. Together, these studies establish that renin progenitors are vulnerable cells for neoplastic transformation and emphasize the importance of genetic background on the development of inflammatory and malignant conditions. PMID- 30467112 TI - A tired young man with a dysmorphic thumb. PMID- 30467114 TI - Demystifying surgery live on TV. PMID- 30467113 TI - Yemen: Number of children under 5 who have died from malnutrition may be as high as 85 000, says Save the Children. PMID- 30467115 TI - Reporting harms more transparently in trials of cancer drugs. PMID- 30467116 TI - Rebirth of a controversy: Damien Hirst sculptures go back on display. PMID- 30467117 TI - Optimising detection and prevention of prosthetic joint infections. PMID- 30467118 TI - Every patient should be enabled to stop the line. PMID- 30467119 TI - Parts list for a microtubule depolymerising kinesin. AB - The Kinesin superfamily is a large group of molecular motors that use the turnover of ATP to regulate their interaction with the microtubule cytoskeleton. The coupled relationship between nucleotide turnover and microtubule binding is harnessed in various ways by these motors allowing them to carry out a variety of cellular functions. The Kinesin-13 family is a group of specialist microtubule depolymerising motors. Members of this family use their microtubule destabilising activity to regulate processes such as chromosome segregation, maintenance of cilia and neuronal development. Here, we describe the current understanding of the structure of this family of kinesins and the role different parts of these proteins play in their microtubule depolymerisation activity and in the wider function of this family of kinesins. PMID- 30467120 TI - The role of LRRK2 in cytoskeletal dynamics. AB - Leucine-rich repeat kinase 2 (LRRK2), a complex kinase/GTPase mutated in Parkinson's disease, has been shown to physically and functionally interact with cytoskeletal-related components in different brain cells. Neurons greatly rely on a functional cytoskeleton for many homeostatic processes such as local and long distance vesicle transport, synaptic plasticity, and dendrites/axons growth and remodeling. Here, we will review the available data linking LRRK2 and the cytoskeleton, and discuss how this may be functionally relevant for the well established roles of LRRK2 in intracellular trafficking pathways and outgrowth of neuronal processes in health and disease conditions. PMID- 30467121 TI - LRRK2 and Rab GTPases. AB - Leucine-rich repeat kinase 2 (LRRK2) is mutated in familial Parkinson's disease, and pathogenic mutations activate the kinase activity. A tour de force screen by Mann and Alessi and co-workers identified a subset of Rab GTPases as bona fide LRRK2 substrates. Rab GTPases are master regulators of membrane trafficking and this short review will summarize what we know about the connection between LRRK2 and this family of regulatory proteins. While, in most cases, Rab GTPase phosphorylation is predicted to interfere with Rab protein function, the discovery of proteins that show preferential binding to phosphorylated Rabs suggests that more complex interactions may also contribute to mutant LRRK2 mediated pathology. PMID- 30467122 TI - Regulation of ATP-dependent chromatin remodelers: accelerators/brakes, anchors and sensors. AB - All ATP-dependent chromatin remodelers have a DNA translocase domain that moves along double-stranded DNA when hydrolyzing ATP, which is the key action leading to DNA moving through nucleosomes. Recent structural and biochemical data from a variety of different chromatin remodelers have revealed that there are three basic ways in which these remodelers self-regulate their chromatin remodeling activity. In several instances, different domains within the catalytic subunit or accessory subunits through direct protein-protein interactions can modulate the ATPase and DNA translocation properties of the DNA translocase domain. These domains or subunits can stabilize conformations that either promote or interfere with the ability of the translocase domain to bind or retain DNA during translocation or alter the ability of the enzyme to hydrolyze ATP. Second, other domains or subunits are often necessary to anchor the remodeler to nucleosomes to couple DNA translocation and ATP hydrolysis to DNA movement around the histone octamer. These anchors provide a fixed point by which remodelers can generate sufficient torque to disrupt histone-DNA interactions and mobilize nucleosomes. The third type of self-regulation is in those chromatin remodelers that space nucleosomes or stop moving nucleosomes when a particular length of linker DNA has been reached. We refer to this third class as DNA sensors that can allosterically regulate nucleosome mobilization. In this review, we will show examples of these from primarily the INO80/SWR1, SWI/SNF and ISWI/CHD families of remodelers. PMID- 30467123 TI - The role of the interleukin (IL)-6/IL-6 receptor axis in cancer. AB - Interleukin-6 (IL-6) is a pleiotropic cytokine that activates a classic signalling pathway upon binding to its membrane-bound receptor (IL-6R). Alternatively, IL-6 may 'trans-signal' in a manner that is facilitated by its binding to a soluble derivative of the IL-6 receptor (sIL-6R). Resultant signal transduction is, respectively, driven by the association of IL-6/IL-6R or IL 6/sIL-6R complex with the membrane-associated signal transducer, gp130 (Glycoprotein 130). Distinct JAK (Janus tyrosine kinase)/STAT (signal transducers and activators of transcription) and other signalling pathways are activated as a consequence. Of translational relevance, overexpression of IL-6 has been documented in several neoplastic disorders, including but not limited to colorectal, ovarian and breast cancer and several haematological malignancies. This review attempts to summarise our current understanding of the role of IL-6 in cancer development. In short, these studies have shown important roles for IL 6 signalling in tumour cell growth and survival, angiogenesis, immunomodulation of the tumour microenvironment, stromal cell activation, and ultimate disease progression. Given this background, we also consider the potential for therapeutic targeting of this system in cancer. PMID- 30467124 TI - Extra L3.5bn will fund community and care home services to reduce pressure on hospitals. PMID- 30467125 TI - Work of the BASHH Sexual Violence Special Interest Group. PMID- 30467126 TI - Tackling treatment burden at the system level. PMID- 30467128 TI - Coroners' reports should be published online. PMID- 30467127 TI - PARP-1 regulates DNA repair factor availability. AB - PARP-1 holds major functions on chromatin, DNA damage repair and transcriptional regulation, both of which are relevant in the context of cancer. Here, unbiased transcriptional profiling revealed the downstream transcriptional profile of PARP 1 enzymatic activity. Further investigation of the PARP-1-regulated transcriptome and secondary strategies for assessing PARP-1 activity in patient tissues revealed that PARP-1 activity was unexpectedly enriched as a function of disease progression and was associated with poor outcome independent of DNA double-strand breaks, suggesting that enhanced PARP-1 activity may promote aggressive phenotypes. Mechanistic investigation revealed that active PARP-1 served to enhance E2F1 transcription factor activity, and specifically promoted E2F1 mediated induction of DNA repair factors involved in homologous recombination (HR). Conversely, PARP-1 inhibition reduced HR factor availability and thus acted to induce or enhance "BRCA-ness". These observations bring new understanding of PARP-1 function in cancer and have significant ramifications on predicting PARP-1 inhibitor function in the clinical setting. PMID- 30467129 TI - Optical coherence tomography angiography in exudative age-related macular degeneration: a predictive model for treatment decisions. AB - AIMS: To evaluate on optical coherence tomography angiography (OCT-A), the predictive role of different qualitative findings of choroidal neovascularisations (CNV) in assessing the status of exudative age-related macular degeneration (eAMD) and to develop a potential model to predict the CNV activity. METHODS: Retrospective review of the multimodal imaging records of patients with eAMD obtained during treatment for type 1 or type 2 CNV. The qualitative analysis of CNVs on OCT angiograms assessed the presence or absence of tiny branching vessels, loops, peripheral anastomotic arcades and choriocapillaris hypointense halo. These findings were then correlated with those of structural OCT scans. A score forecast was built and validated. RESULTS: One hundred and twenty-six eAMD eyes were enrolled in the study. Exudation was observed in 90 eyes (71%) on structural OCT. The qualitative OCT-A analysis revealed: tiny branching vessels in 82.5% of the cases, vascular loops in 81.7%, peripheral anastomotic arcades in 66.7% and choriocapillaris hypointense halo in 54.8%. In the univariate analysis, each OCT-A parameter showed a statistically significant correlation with exudation on structural OCT (p<0.001). The overall analysis demonstrated a sensitivity of 96.7% and a positive predictive value of 87.9%. In the multivariate analysis, a model with four criteria predicted an exudative lesion in 97.6% of cases and one with two criteria (tiny branching vessels and peripheral anastomotic arcades) in 71.2%. CONCLUSIONS: The presence of tiny branching vessels and a peripheral anastomotic arcade appears to predict the lesion activity with a good accuracy and the model based on four criteria enables optimal decisions regarding retreatment in eAMD. PMID- 30467130 TI - Collateral vessels on optical coherence tomography angiography in eyes with branch retinal vein occlusion. AB - AIMS: To detect collateral vessels using optical coherence tomography angiography (OCTA) in eyes with branch retinal vein occlusion (BRVO) and to investigate the associations with visual outcomes and macular oedema. METHODS: Eyes with macular oedema secondary to BRVO that underwent OCTA at baseline and were followed up for more than 6 months were enrolled. The presence of collaterals, whether the collaterals were leaky or not, and the associations with visual outcomes and macular oedema were investigated. RESULTS: Twenty-eight eyes of 28 patients (8 men and 20 women; mean age, 68 years) were enrolled. Collaterals were detected in 23 eyes (82%) and already existed at the initial visit. Collaterals were more frequently detected in eyes with major BRVO or ischaemic type. One-third of the collaterals were leaky and all of the leaky collaterals had microaneurysms (MAs) inside. Macular oedema in eyes with collaterals was more quickly and frequently resolved than that in eyes without collaterals, but there were no significant differences. Collateral vessel formation did not seem to impact on visual outcomes, but the mean baseline central retinal thickness (CRT) was significantly higher in eyes with collaterals, and the mean CRT reduction at 6 months after treatments was significantly greater than in eyes without collaterals. CONCLUSIONS: These results suggest that collateral vessels are formed at the acute phase in eyes with BRVO. In addition, the presence of collaterals might be associated with absorption of macular oedema, but MAs formed in collaterals sometimes can cause macular oedema. PMID- 30467131 TI - Real-world persistence and adherence to oral antimuscarinics and mirabegron in patients with overactive bladder (OAB): a systematic literature review. AB - PURPOSE: To evaluate persistence and adherence of oral pharmacotherapy used in the treatment of overactive bladder (OAB) in a real-world setting. MATERIALS AND METHODS: Systematic literature searches of six electronic publication databases were performed to identify observational studies of patients with OAB treated with antimuscarinics and/or mirabegron. Studies obtaining persistence and adherence data from sources other than electronic prescription claims were excluded. Reference lists of identified studies and relevant systematic reviews were assessed to identify additional relevant studies. RESULTS: The search identified 3897 studies, of which 30 were included. Overall, persistence ranged from 5% to 47%. In studies reporting data for antimuscarinics and mirabegron (n=3), 1-year persistence was 12%-25% and 32%-38%, respectively. Median time to discontinuation was <5 months for antimuscarinics (except one study (6.5 months)) and 5.6-7.4 months for mirabegron. The proportion of patients adherent at 1 year varied between 15% and 44%. In studies reporting adherence for antimuscarinics and mirabegron, adherence was higher with mirabegron (mean medication possession ratio (MPR): 0.59 vs 0.41-0.53; mean proportion of days covered: 0.66 vs 0.55; and median MPR: 0.65 vs 0.19-0.49). Reported determinants of persistence and adherence included female (sex), older age group, use of extended-release formulation and treatment experience. CONCLUSION: Most patients with OAB discontinued oral OAB pharmacotherapy and were non-adherent 1 year after treatment initiation. In general, mirabegron was associated with greater persistence and adherence compared with antimuscarinics. Combined with existing clinical trial evidence, this real-world review merits consideration of mirabegron for first-line pharmacological treatment among patients with OAB. PROSPERO REGISTRATION NUMBER: CRD42017059894. PMID- 30467133 TI - Father's roles and perspectives on healthcare seeking for children with pneumonia: findings of a qualitative study in a rural community of the Philippines. AB - OBJECTIVES: Pneumonia remains a primary cause of death for under-five children. It is possible to reduce the mortality impact from childhood pneumonia if caregivers recognise the danger signs of pneumonia and obtain appropriate healthcare. Among caregivers, research on fathers' healthcare-seeking behaviours and perceptions are limited, whereas research on mothers is available. This study aims to reveal fathers' roles and perspectives with respect to the selection of care and treatment for children with pneumonia in a remote island of the Philippines. DESIGN: A qualitative research was carried out using semistructured interviews. SETTING AND PARTICIPANTS: The interviews were conducted with 12 fathers whose children had pneumonia-like episodes in the 6 months prior to the interview. Data analysis was performed using the concept analysis method to identify codes which were merged into subcategories and categories. Finally, the themes were identified. RESULTS: Three themes were identified as part of fathers' roles, and two were identified as fathers' perspectives on various treatment options. Fathers took care of their sick children by not entrusting care only to mothers because they considered this as part of their role. Notably, fathers considered that arranging money for the child's treatment was a matter of prime importance. They selected a particular treatment based on their experiences and beliefs, including herbal medicine, home treatment, and visiting traditional healers and health facilities. Their decision was influenced by not only their perception of the severity of illness but also cultural beliefs on the cause of illness. Visiting health facilities, particularly during hospital admissions, causes significant financial burden for the family which was the main concern of fathers. CONCLUSION: It is crucial to consider the cultural background and also imperative to address issues related to medical cost and the credibility of health facilities to improve fathers' healthcare-seeking behaviour. PMID- 30467132 TI - Reliability and accuracy of delirium assessments among investigators at multiple international centres. AB - INTRODUCTION: Delirium is a common, serious postoperative complication. For clinical studies to generate valid findings, delirium assessments must be standardised and administered accurately by independent researchers. The Confusion Assessment Method (CAM) is a widely used delirium assessment tool. The objective was to determine whether implementing a standardised CAM training protocol for researchers at multiple international sites yields reliable inter rater assessment and accurate delirium diagnosis. METHODS: Patients consented to video recordings of CAM delirium assessments for research purposes. Raters underwent structured training in CAM administration. Training entailed didactic education, role-playing with intensive feedback, apprenticeship with experienced researchers and group discussions of complex cases. Raters independently viewed and scored nine video-recorded CAM interviews. Inter-rater reliability was determined using Fleiss kappa. Accuracy was judged by comparing raters' scores with those of an expert delirium researcher. RESULTS: Twenty-seven raters from eight international research centres completed the study and achieved almost perfect agreement for overall delirium diagnosis, kappa=0.88 (95% CI 0.85 to 0.92). Agreement of the four core CAM features ranged from fair to substantial. The sensitivity and specificity for identifying delirium were 72% (95% CI 60% to 81%) and 99% (95% CI 96% to 100%), considering an expert rater's scores as the reference standard (delirious, n=3; non-delirious, n=6). Delirium severity ratings were tightly clustered, with most scores within 5% of the median. CONCLUSION: Our results demonstrate that, with appropriate training and ongoing scoring discussions, researchers at multiple sites can reliably detect delirium in postsurgical patients. These results support the premise that methodologically rigorous multi-centre studies can yield standardised and accurate determinations of delirium. PMID- 30467134 TI - Dynamic prediction of childhood high blood pressure in a population-based birth cohort: a model development study. AB - OBJECTIVES: To develop a dynamic prediction model for high blood pressure at the age of 9-10 years that could be applied at any age between birth and the age of 6 years in community-based child healthcare. DESIGN, SETTING AND PARTICIPANTS: Data were used from 5359 children in a population-based prospective cohort study in Rotterdam, the Netherlands. OUTCOME MEASURE: High blood pressure was defined as systolic and/or diastolic blood pressure >=95th percentile for gender, age and height. Using multivariable pooled logistic regression, the predictive value of characteristics at birth, and of longitudinal information on the body mass index (BMI) of the child until the age of 6 years, was assessed. Internal validation was performed using bootstrapping. RESULTS: 227 children (4.2%) had high blood pressure at the age of 9-10 years. Final predictors were maternal hypertensive disease during pregnancy, maternal educational level, maternal prepregnancy BMI, child ethnicity, birth weight SD score (SDS) and the most recent BMI SDS. After internal validation, the area under the receiver operating characteristic curve ranged from 0.65 (prediction at age 3 years) to 0.73 (prediction at age 5-6 years). CONCLUSIONS: This prediction model may help to monitor the risk of developing high blood pressure in childhood which may allow for early targeted primordial prevention of cardiovascular disease. PMID- 30467135 TI - Protocol for a phase II, open-label exploratory study investigating the efficacy of fesoterodine for treatment of adult patients with spinal cord injury suffering from neurogenic detrusor overactivity for amelioration of autonomic dysreflexia. AB - INTRODUCTION: Managing and preventing risk factors associated with cardiovascular and cerebrovascular impairment is well studied in able-bodied individuals. However, individuals with spinal cord injury (SCI) at or above the spinal segment T6 are prone to experience autonomic dysreflexia (AD) but also to suffer from neurogenic detrusor overactivity (NDO). Treatment of NDO would not only improve lower urinary tract function but could also reduce the severity and frequency of life-threatening episodes of AD. Fesoterodine, an antimuscarinic drug, has been successfully employed as a first-line treatment for detrusor overactivity in individuals without an underlying neurological disorder. Thus, our aim is to investigate the efficacy of fesoterodine to improve NDO and ameliorate AD in individuals with SCI. METHODS AND ANALYSIS: This phase II, open-label exploratory, non-blinded, non-randomised, single-centre study will investigate the efficacy of fesoterodine to improve NDO and ameliorate AD in individuals with chronic SCI at or above T6. During screening, we will interview potential candidates (with a previous history of NDO and AD) and assess their injury severity. At baseline, we will perform cardiovascular and cerebrovascular monitoring (blood pressure (BP), heart rate and cerebral blood flow velocity) during urodynamics (UDS) and 24-hour ambulatory BP monitoring (ABPM) during daily life to assess severity and frequency of AD episodes (ie, maximum increase in systolic BP). The primary outcome is a reduction of artificially induced (during UDS) and spontaneous (during daily life) episodes of AD as a display of treatment efficacy. To answer this, we will repeat UDS and 24-hour ABPM during the last cycle of the treatment phase (12 weeks overall, ie, three cycles of 4 weeks each). At the end of each treatment cycle, participants will be asked to answer standardised questionnaires (AD symptoms and quality of life) and present bladder and bowel diaries, which will provide additional subjective information. ETHICS AND DISSEMINATION: The University of British Columbia Research Ethics Boards (H15 02364), Vancouver Coastal Health Research Institute (V15-02364) and Health Canada (205857) approved this study. The findings of the study will be published in peer reviewed journals and presented at national and international scientific meetings. This protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials and CONsolidated Standards Of Reporting Trials statements. TRIAL REGISTRATION NUMBER: NCT02676154; Pre-results. PMID- 30467136 TI - Use of multiple antidiabetic medications in patients with diabetes and its association with hypoglycaemic events: a case-crossover study in Jordan. AB - OBJECTIVE: To assess whether the use of multiple antidiabetic medications is associated with an increased risk of hypoglycaemia in patients with type 2 diabetes mellitus. DESIGN: A case-crossover study. SETTING: Cases were enrolled from the National Center for Diabetes, Endocrinology and Genetics in Amman, Jordan. PARTICIPANTS: Patients were those with diabetes mellitus and reported incident of a hypoglycaemic event in their medical records during the period January 2007 to July 2017. Patients with multiple antidiabetic medications were those with at least two antidiabetic medications. PRIMARY OUTCOME: History of antidiabetic medication use was extracted from the pharmacy records. The use of multiple antidiabetic medications during the risk window (before hypoglycaemia) was compared with a control window(s) (earlier time) of the same length after a washout period. Conditional logistic regression was applied to evaluate the OR of hypoglycaemia between the treatment groups. A secondary analysis was performed in patients with a blood glucose measurement of <=70 mg/dL. RESULTS: 182 patients (106 females, 58.2%) were included in the study with an average age of 59.9 years (SD=9.9). The patients' average body mass index was 31.7 kg/m2 (SD=6.2). Compared with monotherapy, the OR of hypoglycaemic events for patients with multiple antidiabetic medications was 5.00 (95% CI 1.10 to 22.82). The OR was 6.00 (95% CI 0.72 to 49.84) for the secondary analysis patient group (n=94). Ten-fold increased risk was found in patients (n=155) with insulin and sulfonylurea-based combination therapy (OR 10.00;95% CI 1.28 to 78.12). CONCLUSION: This study shows that the use of multiple antidiabetic medications appears to increase the risk of hypoglycaemic events. Patients and healthcare professionals should be extra vigilant when patients are on multiple antidiabetic medications therapy, especially the combination of sulfonylurea and insulin. PMID- 30467137 TI - Rehabilitation via HOMe Based gaming exercise for the Upper-limb post Stroke (RHOMBUS): protocol of an intervention feasibility trial. AB - INTRODUCTION: Effective interventions to promote upper-limb recovery poststroke are characterised by intensive and repetitive movements. However, the repetitive nature of practice may adversely impact on adherence. Therefore, the development of rehabilitation devices that can be used safely and easily at home, and are motivating, enjoyable and affordable is essential to the health and well-being of stroke survivors.The Neurofenix platform is a non-immersive virtual reality device for poststroke upper-limb rehabilitation. The platform uses a hand controller (a NeuroBall) or arm bands (NeuroBands) that facilitate upper-limb exercise via games displayed on a tablet. The Rehabilitation via HOMe Based gaming exercise for the Upper-limb post Stroke trial aims to determine the safety, feasibility and acceptability of the Neurofenix platform for home-based rehabilitation of the upper-limb poststroke. METHODS AND ANALYSIS: Thirty people poststroke will be provided with a Neurofenix platform, consisting of a NeuroBall or NeuroBands (dependent on impairment level), seven specially designed games, a tablet and handbook to independently exercise their upper limb for 7 weeks. Training commences with a home visit from a research therapist to teach the participant how to safely use the device. Outcomes assessed at baseline and 8 weeks and 12 weeks are gross level of disability, pain, objectively measured arm function and impairment, self-reported arm function, passive range of movement, spasticity, fatigue, participation, quality of life (QOL) and health service use. A parallel process evaluation will assess feasibility, acceptability and safety of the intervention through assessment of fidelity to the intervention measured objectively through the Neurofenix platform, a postintervention questionnaire and semistructured interviews exploring participants' experiences of the intervention. The feasibility of conducting an economic evaluation will be determined by collecting data on QOL and resource use. ETHICS AND DISSEMINATION: Ethics approval granted from Brunel University London (10249-MHR-Mar/2018-12322 2). Trial results will be submitted for publication in journals, presented at national and international conferences and distributed to people with stroke. TRIAL REGISTRATION NUMBER: ISRCTN60291412; Pre-results. PMID- 30467139 TI - Emma Vaux: setting new standards. PMID- 30467138 TI - Functions of actin in mouse oocytes at a glance. AB - Gametes undergo a specialized and reductional cell division termed meiosis. Female gametes (oocytes) undergo two rounds of meiosis; the first meiotic division produces the fertilizable egg, while the second meiotic division occurs upon fertilization. Both meiotic divisions are highly asymmetric, producing a large egg and small polar bodies. Actin takes over various essential function during oocyte meiosis, many of which commonly rely on microtubules in mitotic cells. Specifically, the actin network has been linked to long-range vesicle transport, nuclear positioning, spindle migration and anchorage, polar body extrusion and accurate chromosome segregation in mammalian oocytes. In this Cell Science at a Glance article and the accompanying poster, we summarize the many functions of the actin cytoskeleton in oocytes, with a focus on findings from the mouse model system. PMID- 30467140 TI - The importance of ethical expertise. PMID- 30467141 TI - Seven days in medicine: 14-20 November 2018. PMID- 30467142 TI - Intensification for redesigned and sustainable agricultural systems. AB - Redesign of agricultural systems is essential to deliver optimum outcomes as ecological and economic conditions change. The combination of agricultural processes in which production is maintained or increased, while environmental outcomes are enhanced, is currently known as sustainable intensification (SI). SI aims to avoid the cultivation of more land, and thus avoid the loss of unfarmed habitats, but also aims to increase overall system performance without net environmental cost. For example, large changes are now beginning to occur to maximize biodiversity by means of integrated pest management, pasture and forage management, the incorporation of trees into agriculture, and irrigation management, and with small and patch systems. SI is central to the Sustainable Development Goals of the United Nations and to wider efforts to improve global food and nutritional security. PMID- 30467143 TI - Maternal Huluwa dictates the embryonic body axis through beta-catenin in vertebrates. AB - The vertebrate body is formed by cell movements and shape change during embryogenesis. It remains undetermined which maternal signals govern the formation of the dorsal organizer and the body axis. We found that maternal depletion of huluwa, a previously unnamed gene, causes loss of the dorsal organizer, the head, and the body axis in zebrafish and Xenopus embryos. Huluwa protein is found on the plasma membrane of blastomeres in the future dorsal region in early zebrafish blastulas. Huluwa has strong dorsalizing and secondary axis-inducing activities, which require beta-catenin but can function independent of Wnt ligand/receptor signaling. Mechanistically, Huluwa binds to and promotes the tankyrase-mediated degradation of Axin. Therefore, maternal Huluwa is an essential determinant of the dorsal organizer and body axis in vertebrate embryos. PMID- 30467145 TI - Fixing the internet. PMID- 30467144 TI - Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. AB - During tissue repair, myofibroblasts produce extracellular matrix (ECM) molecules for tissue resilience and strength. Altered ECM deposition can lead to tissue dysfunction and disease. Identification of distinct myofibroblast subsets is necessary to develop treatments for these disorders. We analyzed profibrotic cells during mouse skin wound healing, fibrosis, and aging and identified distinct subpopulations of myofibroblasts, including adipocyte precursors (APs). Multiple mouse models and transplantation assays demonstrate that proliferation of APs but not other myofibroblasts is activated by CD301b-expressing macrophages through insulin-like growth factor 1 and platelet-derived growth factor C. With age, wound bed APs and differential gene expression between myofibroblast subsets are reduced. Our findings identify multiple fibrotic cell populations and suggest that the environment dictates functional myofibroblast heterogeneity, which is driven by fibroblast-immune interactions after wounding. PMID- 30467146 TI - News at a glance. PMID- 30467148 TI - NASA to pay private space companies for moon rides. PMID- 30467147 TI - Luxe research ship to explore the deep ocean. PMID- 30467149 TI - Artificial cells gain communication skills. PMID- 30467150 TI - Asia set to take center stage in Higgs studies. PMID- 30467151 TI - Giant mammal cousin rivaled early dinosaurs. PMID- 30467152 TI - Cracking the Cambrian. PMID- 30467154 TI - How behavioral science can help conservation. PMID- 30467153 TI - Nurturing connections to the environment. PMID- 30467155 TI - Cellular networks in wound healing. PMID- 30467156 TI - The decline of Africa's largest mammals. PMID- 30467157 TI - The paradox of mutations and cancer. PMID- 30467159 TI - Thomas A. Steitz (1940-2018). PMID- 30467158 TI - Changing concepts in hematopoietic stem cells. PMID- 30467160 TI - Is it time for a universal genetic forensic database? PMID- 30467161 TI - Microbiome dynamics in obesity. PMID- 30467162 TI - The ecology of an olfactory trap. PMID- 30467163 TI - A key component of gene expression, revealed. PMID- 30467164 TI - Paring down to the essentials. PMID- 30467165 TI - Neutral mass spectrometry of virus capsids above 100 megadaltons with nanomechanical resonators. AB - Measurement of the mass of particles in the mega- to gigadalton range is challenging with conventional mass spectrometry. Although this mass range appears optimal for nanomechanical resonators, nanomechanical mass spectrometers often suffer from prohibitive sample loss, extended analysis time, or inadequate resolution. We report on a system architecture combining nebulization of the analytes from solution, their efficient transfer and focusing without relying on electromagnetic fields, and the mass measurements of individual particles using nanomechanical resonator arrays. This system determined the mass distribution of ~30-megadalton polystyrene nanoparticles with high detection efficiency and effectively performed molecular mass measurements of empty or DNA-filled bacteriophage T5 capsids with masses up to 105 megadaltons using less than 1 picomole of sample and with an instrument resolution above 100. PMID- 30467166 TI - Multicomponent intermetallic nanoparticles and superb mechanical behaviors of complex alloys. AB - Alloy design based on single-principal-element systems has approached its limit for performance enhancements. A substantial increase in strength up to gigapascal levels typically causes the premature failure of materials with reduced ductility. Here, we report a strategy to break this trade-off by controllably introducing high-density ductile multicomponent intermetallic nanoparticles (MCINPs) in complex alloy systems. Distinct from the intermetallic-induced embrittlement under conventional wisdom, such MCINP-strengthened alloys exhibit superior strengths of 1.5 gigapascals and ductility as high as 50% in tension at ambient temperature. The plastic instability, a major concern for high-strength materials, can be completely eliminated by generating a distinctive multistage work-hardening behavior, resulting from pronounced dislocation activities and deformation-induced microbands. This MCINP strategy offers a paradigm to develop next-generation materials for structural applications. PMID- 30467167 TI - Plio-Pleistocene decline of African megaherbivores: No evidence for ancient hominin impacts. AB - It has long been proposed that pre-modern hominin impacts drove extinctions and shaped the evolutionary history of Africa's exceptionally diverse large mammal communities, but this hypothesis has yet to be rigorously tested. We analyzed eastern African herbivore communities spanning the past 7 million years encompassing the entirety of hominin evolutionary history-to test the hypothesis that top-down impacts of tool-bearing, meat-eating hominins contributed to the demise of megaherbivores prior to the emergence of Homo sapiens We document a steady, long-term decline of megaherbivores beginning ~4.6 million years ago, long before the appearance of hominin species capable of exerting top-down control of large mammal communities and predating evidence for hominin interactions with megaherbivore prey. Expansion of C4 grasslands can account for the loss of megaherbivore diversity. PMID- 30467168 TI - Social network plasticity decreases disease transmission in a eusocial insect. AB - Animal social networks are shaped by multiple selection pressures, including the need to ensure efficient communication and functioning while simultaneously limiting disease transmission. Social animals could potentially further reduce epidemic risk by altering their social networks in the presence of pathogens, yet there is currently no evidence for such pathogen-triggered responses. We tested this hypothesis experimentally in the ant Lasius niger using a combination of automated tracking, controlled pathogen exposure, transmission quantification, and temporally explicit simulations. Pathogen exposure induced behavioral changes in both exposed ants and their nestmates, which helped contain the disease by reinforcing key transmission-inhibitory properties of the colony's contact network. This suggests that social network plasticity in response to pathogens is an effective strategy for mitigating the effects of disease in social groups. PMID- 30467170 TI - Molecular to organismal chirality is induced by the conserved myosin 1D. AB - The emergence of asymmetry from an initially symmetrical state is a universal transition in nature. Living organisms show asymmetries at the molecular, cellular, tissular, and organismal level. However, whether and how multilevel asymmetries are related remains unclear. In this study, we show that Drosophila myosin 1D (Myo1D) and myosin 1C (Myo1C) are sufficient to generate de novo directional twisting of cells, single organs, or the whole body in opposite directions. Directionality lies in the myosins' motor domain and is swappable between Myo1D and Myo1C. In addition, Myo1D drives gliding of actin filaments in circular, counterclockwise paths in vitro. Altogether, our results reveal the molecular motor Myo1D as a chiral determinant that is sufficient to break symmetry at all biological scales through chiral interaction with the actin cytoskeleton. PMID- 30467171 TI - ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation. AB - Pyroptosis is a lytic form of cell death that is induced by inflammatory caspases upon activation of the canonical or noncanonical inflammasome pathways. These caspases cleave gasdermin D (GSDMD) to generate an N-terminal GSDMD fragment, which executes pyroptosis by forming membrane pores. We found that calcium influx through GSDMD pores serves as a signal for cells to initiate membrane repair by recruiting the endosomal sorting complexes required for transport (ESCRT) machinery to damaged membrane areas, such as the plasma membrane. Inhibition of the ESCRT-III machinery strongly enhances pyroptosis and interleukin-1beta release in both human and murine cells after canonical or noncanonical inflammasome activation. These results not only attribute an anti-inflammatory role to membrane repair by the ESCRT-III system but also provide insight into general cellular survival mechanisms during pyroptosis. PMID- 30467172 TI - Finding my inner Wonder Woman. PMID- 30467169 TI - Egocentric coding of external items in the lateral entorhinal cortex. AB - Episodic memory, the conscious recollection of past events, is typically experienced from a first-person (egocentric) perspective. The hippocampus plays an essential role in episodic memory and spatial cognition. Although the allocentric nature of hippocampal spatial coding is well understood, little is known about whether the hippocampus receives egocentric information about external items. We recorded in rats the activity of single neurons from the lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC), the two major inputs to the hippocampus. Many LEC neurons showed tuning for egocentric bearing of external items, whereas MEC cells tended to represent allocentric bearing. These results demonstrate a fundamental dissociation between the reference frames of LEC and MEC neural representations. PMID- 30467174 TI - "2017 ERS/ATS standards for single-breath carbon monoxide uptake in the lung." Brian L. Graham, Vito Brusasco, Felip Burgos, Brendan G. Cooper, Robert Jensen, Adrian Kendrick, Neil R. MacIntyre, Bruce R. Thompson and Jack Wanger. Eur Respir J 2017; 49: 1600016. PMID- 30467173 TI - This is what's happening to NHS spending on public health. PMID- 30467175 TI - Happy ever after? A new assessment tool for long-term noninvasive ventilation: the S3-NIV questionnaire. PMID- 30467176 TI - Pirfenidone in the kaleidoscope: reflecting mechanisms through different angles. PMID- 30467177 TI - Type 2 diabetes: sweetened drinks pose greater risk than other sugary foods. PMID- 30467178 TI - Cap-specific terminal N 6-methylation of RNA by an RNA polymerase II-associated methyltransferase. AB - N 6-methyladenosine (m6A), a major modification of mRNAs, plays critical roles in RNA metabolism and function. In addition to the internal m6A, N 6, 2'-O dimethyladenosine (m6Am) is present at the transcription start nucleotide of capped mRNAs in vertebrates. However, its biogenesis and functional role remain elusive. Using a reverse genetics approach, we identified PCIF1, a factor that interacts with the Ser5-phosphorylated C-terminal domain of RNA polymerase II, as cap-specific adenosine methyltransferase (CAPAM) responsible for N 6-methylation of m6Am. Crystal structure of CAPAM in complex with substrates revealed the molecular basis of cap-specific m6A formation. A transcriptome-wide analysis revealed that N 6-methylation of m6Am promotes the translation of capped mRNAs. Thus, a cap-specific m6A writer promotes translation of mRNAs starting from m6Am. PMID- 30467179 TI - An elephant-sized Late Triassic synapsid with erect limbs. AB - Here, we describe the dicynodont Lisowicia bojani, from the Late Triassic of Poland, a gigantic synapsid with seemingly upright subcursorial limbs that reached an estimated length of more than 4.5 meters, height of 2.6 meters, and body mass of 9 tons. Lisowicia is the youngest undisputed dicynodont and the largest nondinosaurian terrestrial tetrapod from the Triassic. The lack of lines of arrested growth and the highly remodeled cortex of its limb bones suggest permanently rapid growth and recalls that of dinosaurs and mammals. The discovery of Lisowicia overturns the established picture of the Triassic megaherbivore radiation as a phenomenon restricted to dinosaurs and shows that stem-group mammals were capable of reaching body sizes that were not attained again in mammalian evolution until the latest Eocene. PMID- 30467180 TI - Structures and gating mechanism of human TRPM2. AB - Transient receptor potential (TRP) melastatin 2 (TRPM2) is a cation channel associated with numerous diseases. It has a C-terminal NUDT9 homology (NUDT9H) domain responsible for binding ADP-ribose (ADPR), and both ADPR and Ca2+ are required for TRPM2 activation. Here we report cryo-EM structures of human TRPM2, alone, with ADPR, and with ADPR and Ca2+ NUDT9H forms both intra- and inter subunit interactions with the N-terminal TRPM homology region (MHR1/2/3) in the apo state, but undergoes conformational changes upon ADPR binding, resulting in rotation of MHR1/2 and disruption of the inter-subunit interaction. Ca2+ binding further engages transmembrane helices and the conserved TRP helix to cause conformational changes at the MHR arm and the lower gating pore to potentiate channel opening. These findings explain the molecular mechanism of concerted TRPM2 gating by ADPR and Ca2+ and provide insights into the gating mechanism of other TRP channels. PMID- 30467181 TI - Correction: Tumour risks and genotype-phenotype correlations associated with germline variants in the succinate dehydrogenase subunit genes SDHB, SDHC, and SDHD. PMID- 30467182 TI - Healthcare staff need training in human factors. PMID- 30467183 TI - Artificial intelligence in sports medicine radiology: what's coming? PMID- 30467184 TI - Progress on children's mental health services is too slow, says commissioner for England. PMID- 30467185 TI - Is less equal with ibrutinib dose? PMID- 30467186 TI - gammadelta T cells for immunotherapy. PMID- 30467187 TI - A small change makes a big difference in Hodgkin lymphoma. PMID- 30467189 TI - Postthrombotic syndrome: simple prevention. PMID- 30467188 TI - Tfr2 suppression benefits beta-thalassemic erythropoiesis. PMID- 30467190 TI - Microgranular variant of acute promyelocytic leukemia with cytoplasmic projections resembling micromegakaryocytes. PMID- 30467192 TI - Type 2 diabetes affects 7000 young people in England and Wales, analysis shows. PMID- 30467191 TI - Functional Cardiac Orexin Receptors: Role of Orexin-B/Orexin 2 Receptor in Myocardial Protection. AB - Orexins/hypocretins exert cardiovascular effects which are centrally mediated. In this study we tested whether orexins and their receptors may also act in an autocrine/paracrine manner in the heart exerting direct effects. Quantitative RT PCR, immunohistochemical and Western blot analyses revealed that the rat heart expresses orexins and orexin receptors. In isolated rat cardiomyocytes, only orexin-B (OR-B) caused an increase in contractile shortening, independent of diastolic or systolic calcium levels. A specific orexin receptor-2 (OX2R) agonist ([Ala11, D-Leu15]-Orexin B) exerted similar effects as OR-B, whereas a specific OX1R antagonist (SB-408124) did not alter the responsiveness of OR-B. Treatment of the same model with OR-B resulted in a dose-dependent increase of myosin light chain and troponin-I phosphorylation. Following ischaemia/reperfusion in the isolated Langendorff perfused rat heart model, OR-B, but not OR-A, exerts a cardioprotective effect; mirrored in an in vivo model as well. Unlike OR-A, OR-B was also able to induce ERK1/2 and Akt phosphorylation in rat myocardial tissue and ERK1/2 phosphorylation in human heart samples. These findings were further corroborated in an in vivo rat model. In human subjects with heart failure, there is a significant negative correlation between the expression of OX2R and the severity of the disease clinical symptoms, as assessed by the New York Heart Association (NYHA) functional classification. Collectively, we provide evidence of a distinct orexin system in the heart that exerts a cardioprotective role via an OR-B/OX2R pathway. PMID- 30467193 TI - Fifty-seven-year-old man with progressive dyspnoea. AB - CLINICAL INTRODUCTION: A 57-year-old man from the USA with a history of atrial fibrillation and hypertension was evaluated for progressive dyspnoea and decreased energy. The patient denied a history of congestive heart failure, systemic symptoms or myocardial infarction. He was found to have a 3/6 holosystolic murmur radiating to the axilla. Transthoracic echocardiography (TTE) reported a reduced ejection fraction of 40%, mitral valve regurgitation and absence of interatrial shunts. The remaining cardiac valves were without abnormality. A nuclear stress test reported 18% fixed inferolateral defect. Subsequent coronary angiography was negative for obstructive coronary artery disease. To better evaluate the mitral valve apparatus, transoesophageal echocardiography (TEE) was performed. QUESTION: Which of the following best explains the TEE findings (figure 1) of the mitral valve?Carcinoid heart disease.Drug-induced valvular heart disease.Infective endocarditis.Ischaemic mitral regurgitation (MR).Rheumatic mitral valve disease. heartjnl;heartjnl-2018 314080v1/F1F1F1Figure 1(A) Transoesophageal echocardiography (TEE) mid oesophageal view at 94 degrees during diastole. (B) TEE mid-oesophageal view at 94 degrees during systole. (C) TEE mid-oesophageal view at 0 degrees with colour Doppler. (D) TEE 3D view of the mitral valve from the left atrium. PMID- 30467194 TI - Assessment of reversibility in pulmonary arterial hypertension and congenital heart disease. AB - Pulmonary arterial hypertension (PAH) in congenital heart disease (CHD) can be reversed by early shunt closure, but this potential is lost beyond a certain point of no return. Therefore, it is crucial to accurately assess the reversibility of this progressive pulmonary arteriopathy in an early stage. Reversibility assessment is currently based on a combination of clinical symptoms and haemodynamic variables such as pulmonary vascular resistance. These measures, however, are of limited predictive value and leave many patients in the grey zone. This review provides a concise overview of the mechanisms involved in flow dependent progression of PAH in CHD and evaluates existing and future alternatives to more directly investigate the stage of the pulmonary arteriopathy. Structural quantification of the pulmonary arterial tree using fractal branching algorithms, functional imaging with intravascular ultrasound, nuclear imaging, putative new blood biomarkers, genetic testing and the potential for transcriptomic analysis of circulating endothelial cells and educated platelets are being reviewed. PMID- 30467195 TI - Viagra for fetal growth restriction: STRIDER Consortium replies to letter by Symonds and Budge. PMID- 30467196 TI - Situating requests for medical aid in dying within the broader context of end-of life care: ethical considerations. AB - BACKGROUND: Medical aid in dying (MAiD) was introduced in Quebec in 2015. Quebec clinical guidelines recommend that MAiD be approached as a last resort when other care options are insufficient; however, the law sets no such requirement. To date, little is known about when and how requests for MAiD are situated in the broader context of decision-making in end-of-life care; the timing of MAiD raises potential ethical issues. METHODS: A retrospective chart review of all MAiD requests between December 2015 and June 2017 at two Quebec hospitals and one long term care centre was conducted to explore the relationship between routine end-of life care practices and the timing of MAiD requests. RESULTS: Of 80 patients requesting MAiD, 54% (43) received the intervention. The median number of days between the request for MAiD and the patient's death was 6 days. The majority of palliative care consults (32%) came less than 7 days prior to the MAiD request and in another 25% of cases occurred the day of or after MAiD was requested. 35% of patients had no level of intervention form, or it was documented as 1 or 2 (prolongation of life remains a priority) at the time of the MAiD request and 19% were receiving life-prolonging interventions. INTERPRETATION: We highlight ethical considerations relating to the timing of MAiD requests within the broader context of end-of-life care. Whether or not MAiD is conceptualised as morally distinct from other end-of-life options is likely to influence clinicians' approach to requests for MAiD as well as the ethical importance of our findings. We suggest that in the wake of the 2015 legislation, requests for MAiD have not always appeared to come after an exploration of other options as professional practice guidelines recommend. PMID- 30467197 TI - Bawa-Garba ruling is not good news for doctors. AB - Although some doctors celebrated when the Court of Appeal overturned Hadiza Bawa Garba's erasure from the medical register, it is argued here that in many ways the ruling is by no means good news for the medical profession. Doctors' interests are served by transparent professional tribunals but the Court of Appeal's approach to the GMC Sanctions Guidance risks increasing opacity in decision-making. Close attention to systemic factors in the criminal trial protects doctors yet the Court of Appeal states that the structural circumstances surrounding Bawa-Garba's failings were only of peripheral relevance to her conviction. Public confidence in the profession is undermined when convicted doctors return to work because the public de facto do not understand the nuance of gross negligence manslaughter law. Rather than changing the law to make the regulator more lenient towards doctors, it would be better to ensure that doctors are only convicted of gross negligence manslaughter when their conduct is so serious that they ought to be struck off. PMID- 30467198 TI - Computer knows best? The need for value-flexibility in medical AI. AB - Artificial intelligence (AI) is increasingly being developed for use in medicine, including for diagnosis and in treatment decision making. The use of AI in medical treatment raises many ethical issues that are yet to be explored in depth by bioethicists. In this paper, I focus specifically on the relationship between the ethical ideal of shared decision making and AI systems that generate treatment recommendations, using the example of IBM's Watson for Oncology. I argue that use of this type of system creates both important risks and significant opportunities for promoting shared decision making. If value judgements are fixed and covert in AI systems, then we risk a shift back to more paternalistic medical care. However, if designed and used in an ethically informed way, AI could offer a potentially powerful way of supporting shared decision making. It could be used to incorporate explicit value reflection, promoting patient autonomy. In the context of medical treatment, we need value flexible AI that can both respond to the values and treatment goals of individual patients and support clinicians to engage in shared decision making. PMID- 30467199 TI - Brexit fears: five minutes with . . . Matthew Shaw. PMID- 30467201 TI - The small-molecule compound AC-73 targeting CD147 inhibits leukemic cell proliferation, induces autophagy and increases the chemotherapeutic sensitivity of acute myeloid leukemia cells. AB - CD147 is a transmembrane glycoprotein with multiple functions in human healthy tissues and diseases, in particular in cancer. Overexpression of CD147 correlates with biological functions that promote tumor progression and confers resistance to chemotherapeutic drugs. In contrast to solid tumors, the role of CD147 has not been extensively studied in leukemia. Understanding whether CD147 represents a new hematological target and whether its inhibitor AC-73 may be used in leukemia therapy, may reveal an alternative treatment strategy in patients with acute myeloid leukemia. We analyzed CD147 expression and function in hematopoietic progenitor cells from normal cord blood, in several leukemic cell lines and in primary leukemic blasts obtained from patients with acute myeloid leukemia. We investigated the effects of AC-73, used alone or in combination with arabinosylcytosine (Ara-C) and arsenic trioxide (ATO), on leukemic cell proliferation. In our study, we demonstrated that CD147 overexpression promotes leukemic cell proliferation. We showed that AC-73 exhibits a potent growth inhibitory activity in leukemic cells, by inhibiting the ERK/STAT3 activation pathway and activating autophagy. We demonstrated that AC-73 exerts an anti proliferative effect additive to chemotherapy, by enhancing leukemic cells sensitivity to Ara-C-induced cytotoxicity or to ATO-induced autophagy. We also reported CD147 expression in the fraction of leukemic blasts expressing CD371, a marker of leukemic stem cells. Altogether, our study indicates CD147 as a novel potential target in the treatment of acute myeloid leukemia and AC-73 as an anti proliferative drug and an inducer of autophagy in leukemic cells to use in combination with chemotherapeutic agents. PMID- 30467202 TI - The population dynamics of haemoglobins A, A2, F and S in the context of the haemoglobinopathies HbS and alpha+thalassaemia in Kenyan infants. AB - Few studies have described the dynamics of haemoglobin production in African populations with a high prevalence of haemoglobinopathies. We have used the BioRad Variant ClassicTM HPLC method to document the production patterns of the common haemoglobin variants HbA, HbA2, HbF and HbS, stratified by a+thalassaemia genotype, among 15,301 infants recruited to a study on the Coast of Kenya. Notably, we confirm that HbA2 measurements determined using this instrument are unreliable in HbAS and HbSS subjects. Further, we showed that HbA2 exceeded 4.0%, a level consistent with the presence of a-thalassaemia, in 0.8% of infants of HbAA phenotype who participated in our study. a-thalassaemia, has not been widely reported in the East Africa region and, as such, this finding merits further study. PMID- 30467200 TI - Trypsin encoding PRSS1-PRSS2 variation influence the risk of asparaginase associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report. AB - Asparaginase-associated pancreatitis is a life-threatening toxicity to childhood acute lymphoblastic leukemia treatment. To elucidate genetic predisposition and asparaginase-associated pancreatitis pathogenesis, ten acute lymphoblastic leukemia trial groups contributed remission samples from patients aged 1.0-17.9 years and treated from 2000-2016. Cases were defined (n=244) by at least two of the following criteria: i) abdominal pain, ii) pancreatic enzymes >3 x upper normal limit, iii) imaging compatible with asparaginase-associated pancreatitis. Controls (n=1320) completed intended asparaginase therapy, 78% receiving >=8 pegylated-asparaginase injections, without developing aparaginase-associated pancreatitis. rs62228256 on 20q13.2 showed the strongest association (OR=3.75; P=5.2x10-8). Moreover, rs13228878 (OR=0.61; P=7.1x10-6) and rs10273639 (OR=0.62; P=1.1x10-5) on 7q34 showed significant association. A Dana Farber Cancer Institute ALL Consortium cohort consisting of patients treated protocols from 1987-2004 (controls=285, cases=33), and the Children's Oncology Group AALL0232 cohort (controls=2653, cases=76) were available as replication cohorts for the 20q13.2 and 7q34 variants, respectively. While rs62228256 was not validated (P=0.86), both rs13228878 (P=0.03) and rs10273639 (P=0.04) were. rs13228878 and rs10273639 are in high linkage disequilibrium (r2=0.94) and associated with elevated expression of the trypsinogen encoding PRSS1 gene and are known risk variants for alcohol-associated and sporadic pancreatitis in adults. Intra pancreatic trypsinogen cleavage to proteolytic trypsin induces autodigestion and pancreatitis. Asparaginase-associated pancreatitis and non-asparaginase associated pancreatitis shares genetic predisposition and targeting the trypsinogen activation pathway may enable identification of effective interventions towards asparaginase-associated pancreatitis. PMID- 30467203 TI - Extramedullary acute myeloid leukemia presenting in young adults demonstrates sensitivity to high dose anthracycline: subset analysis from ECOG-ACRIN 1900. PMID- 30467205 TI - First line therapy in chronic lymphocytic leukemia: a Swedish nation-wide real world study on 1053 consecutive patients treated between 2007 and 2013. AB - The aim of this study was to investigate long-term outcome following first line therapy in consecutive chronic lymphocytic leukemia patients in a well defined geographic area (Sweden). All patients diagnosed with chronic lymphocytic leukemia (2007-2013) (n=3672) were identified from national registries, screening of patient files identified all (100%) first line treated (n=1053) and for those, depth analysis was performed. Endpoints were overall response rate, progression free survival, overall survival and safety. Median age was 71 years, 53% had Rai stage III-IV and 97% had performance status grade 0-2. FISH was performed in 57% of patients: 15% had del(17p). Chlorambucil +/- prednisone was used in 39% (5% also received rituximab). Fludarabine+cyclophosphamide+rituximab or fludarabine+cyclophosphamide was used in 43% and bendamustine +/- rituximab in 6%. Overall response rate was 64%; chlorambucil 43%, fludarabine+cyclophosphamide+rituximab 84%, fludarabine+cyclophosphamide 75% and bendamustine +/- rituximab 75%. Median progression free survival and overall survival was 24 and 58 months, respectively; both significantly associated (multivariate analysis) with type of treatment, del(17p), performance status, sex, age and geographical region (overall survival only). Chlorambucil-treated patients had a median progression free survival and overall survival of only 9 and 33 months, respectively. Chlorambucil usage declined gradually throughout the study period, but one-third of patients still received chlorambucil +/- rituximab in 2013. Infections >=grade III were significantly associated with treatment; chlorambucil 19% vs fludarabine+cyclophosphamide+rituximab 30%. Richter transformation occurred in 5.5% of the patients, equally distributed across therapies. This is the largest retrospective, real-world cohort of consecutive first line treated chronic lymphocytic leukemia patients with a complete follow up. In elderly patients, an unmet need for more effective, well-tolerated therapies was identified. PMID- 30467204 TI - Sphingolipid dysregulation due to lack of functional KDSR impairs proplatelet formation causing thrombocytopenia. AB - Sphingolipids are fundamental to membrane trafficking, apoptosis and cell differentiation and proliferation. KDSR or 3-keto-dihydrosphingosine reductase is an essential enzyme for de novo sphingolipid synthesis, and pathogenic mutations in KDSR result in the severe skin disorder erythrokeratodermia variabilis et progressiva-4. Four of the eight reported cases also had thrombocytopenia but the underlying mechanism has remained unexplored. Here we expand upon the phenotypic spectrum of KDSR deficiency with studies in two siblings with novel compound heterozygous variants associated with thrombocytopenia, anemia and minimal skin involvement. We report a novel phenotype of progressive juvenile myelofibrosis in the propositus, with spontaneous recovery of anemia and thrombocytopenia in the first decade of life. Examination of bone marrow biopsies showed megakaryocyte hyperproliferation and dysplasia. Megakaryocytes obtained by culture of CD34+ stem cells confirmed hyperproliferation and showed reduced proplatelet formation. The effect of KDSR insufficiency on the sphingolipid profile was unknown, and was explored in vivo and in vitro by a broad metabolomics screen that indicated activation of an in vivo compensatory pathway that leads to normalisation of downstream metabolites such as ceramide. Differentiation of propositus-derived induced pluripotent stem cells to megakaryocytes followed by expression of functional KDSR showed correction of the aberrant cellular and biochemical phenotypes, corroborating the critical role of KDSR in proplatelet formation. Finally, Kdsr depletion in zebrafish recapitulated the thrombocytopenia and showed biochemical changes similar to those observed in the affected siblings. These studies support an important role for sphingolipids as regulators of cytoskeletal organisation during megakaryopoiesis and proplatelet formation. PMID- 30467207 TI - Autophagic degradation determines the fate of T315I-mutated BCR-ABL protein. PMID- 30467206 TI - Targeting intermediary metabolism enhances the efficacy of BH3 mimetic therapy in haematological malignancies. AB - BH3 mimetics are novel targeted drugs with remarkable specificity and potency and enormous potential to improve cancer therapy. However, acquired resistance is an emerging problem. We report the rapid development of resistance in chronic lymphocytic leukemia cells isolated from patients exposed to increasing doses of Navitoclax (ABT-263), a BH3 mimetic. To mimic such rapid development of chemoresistance, we have developed simple resistance models to three different BH3 mimetics, targeting BCL-2 (ABT-199), BCL-XL (A-1331852) or MCL-1 (A-1210477), in relevant haematological cancer cell lines. In these models, resistance could be attributed neither to consistent changes in expression levels of the anti apoptotic proteins nor interactions among different pro- and anti-apoptotic BCL-2 family members. Using genetic silencing, pharmacological inhibition and metabolic supplementation, we report that targeting of glutamine uptake and its downstream signalling pathways, namely glutaminolysis, reductive carboxylation, lipogenesis, cholesterogenesis and mTOR signalling result in marked sensitisation of the chemoresistant cells to BH3 mimetic-mediated apoptosis. Furthermore, our findings highlight the possibility of repurposing widely used drugs, such as statins, to target intermediary metabolism and improve the efficacy of BH3 mimetic therapy. PMID- 30467208 TI - In review. PMID- 30467209 TI - Neurochemical correlates of functional decline in amyotrophic lateral sclerosis. AB - OBJECTIVE: To determine whether proton magnetic resonance spectroscopy (1H-MRS) can detect neurochemical changes in amyotrophic lateral sclerosis (ALS) associated with heterogeneous functional decline. METHODS: Nineteen participants with early-stage ALS and 18 age-matched and sex ratio-matched controls underwent ultra-high field 1H-MRS scans of the upper limb motor cortex and pons, ALS Functional Rating Scale-Revised (ALSFRS-R total, upper limb and bulbar) and upper motor neuron burden assessments in a longitudinal observational study design with follow-up assessments at 6 and 12 months. Slopes of neurochemical levels over time were compared between patient subgroups classified by the rate of upper limb or bulbar functional decline. 1H-MRS and clinical ratings at baseline were assessed for ability to predict study withdrawal due to disease progression. RESULTS: Motor cortex total N-acetylaspartate to myo-inositol ratio (tNAA:mIns) significantly declined in patients who worsened in upper limb function over the follow-up period (n=9, p=0.002). Pons glutamate + glutamine significantly increased in patients who worsened in bulbar function (n=6, p<0.0001). Neurochemical levels did not change in patients with stable function (n=5-6) or in healthy controls (n=14-16) over time. Motor cortex tNAA:mIns and ALSFRS-R at baseline were significantly lower in patients who withdrew from follow-up due to disease progression (n=6) compared with patients who completed the 12-month scan (n=10) (p<0.001 for tNAA:mIns; p<0.01 for ALSFRS-R), with a substantially larger overlap in ALSFRS-R between groups. CONCLUSION: Neurochemical changes in motor areas of the brain are associated with functional decline in corresponding body regions. 1H-MRS was a better predictor of study withdrawal due to ALS progression than ALSFRS-R. PMID- 30467210 TI - Structural network disruption markers explain disability in multiple sclerosis. AB - OBJECTIVE: To evaluate whether structural brain network metrics correlate better with clinical impairment and information processing speed in multiple sclerosis (MS) beyond atrophy measures and white matter lesions. METHODS: This cross sectional study included 51 healthy controls and 122 patients comprising 58 relapsing-remitting, 28 primary progressive and 36 secondary progressive. Structural brain networks were reconstructed from diffusion-weighted MRIs and standard metrics reflecting network density, efficiency and clustering coefficient were derived and compared between subjects' groups. Stepwise linear regression analyses were used to investigate the contribution of network measures that explain clinical disability (Expanded Disability Status Scale (EDSS)) and information processing speed (Symbol Digit Modalities Test (SDMT)) compared with conventional MRI metrics alone and to determine the best statistical model that explains better EDSS and SDMT. RESULTS: Compared with controls, network efficiency and clustering coefficient were reduced in MS while these measures were also reduced in secondary progressive relative to relapsing-remitting patients. Structural network metrics increase the variance explained by the statistical models for clinical and information processing dysfunction. The best model for EDSS showed that reduced network density and global efficiency and increased age were associated with increased clinical disability. The best model for SDMT showed that lower deep grey matter volume, reduced efficiency and male gender were associated with worse information processing speed. CONCLUSIONS: Structural topological changes exist between subjects' groups. Network density and global efficiency explained disability above non-network measures, highlighting that network metrics can provide clinically relevant information about MS pathology. PMID- 30467211 TI - Practical approach to the diagnosis of adult-onset leukodystrophies: an updated guide in the genomic era. AB - Adult-onset leukodystrophies and genetic leukoencephalopathies comprise a diverse group of neurodegenerative disorders of white matter with a wide age of onset and phenotypic spectrum. Patients with white matter abnormalities detected on MRI often present a diagnostic challenge to both general and specialist neurologists. Patients typically present with a progressive syndrome including various combinations of cognitive impairment, movement disorders, ataxia and upper motor neuron signs. There are a number of important and treatable acquired causes for this imaging and clinical presentation. There are also a very large number of genetic causes which due to their relative rarity and sometimes variable and overlapping presentations can be difficult to diagnose. In this review, we provide a structured approach to the diagnosis of inherited disorders of white matter in adults. We describe clinical and radiological clues to aid diagnosis, and we present an overview of both common and rare genetic white matter disorders. We provide advice on testing for acquired causes, on excluding small vessel disease mimics, and detailed advice on metabolic and genetic testing available to the practising neurologist. Common genetic leukoencephalopathies discussed in detail include CSF1R, AARS2, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and mitochondrial and metabolic disorders. PMID- 30467212 TI - Brain Atrophy Is Associated with Disability Progression in Patients with MS followed in a Clinical Routine. AB - BACKGROUND AND PURPOSE: The assessment of brain atrophy in a clinical routine is not performed routinely in multiple sclerosis. Our aim was to determine the feasibility of brain atrophy measurement and its association with disability progression in patients with MS followed in a clinical routine for 5 years. MATERIALS AND METHODS: A total of 1815 subjects, 1514 with MS and 137 with clinically isolated syndrome and 164 healthy individuals, were collected retrospectively. Of 11,794 MR imaging brain scans included in the analysis, 8423 MRIs were performed on a 3T, and 3371 MRIs, on a 1.5T scanner. All patients underwent 3D T1WI and T2-FLAIR examinations at all time points of the study. Whole-brain volume changes were measured by percentage brain volume change/normalized brain volume change using SIENA/SIENAX on 3D T1WI and percentage lateral ventricle volume change using NeuroSTREAM on T2-FLAIR. RESULTS: Percentage brain volume change failed in 36.7% of the subjects; percentage normalized brain volume change, in 19.2%; and percentage lateral ventricle volume change, in 3.3% because of protocol changes, poor scan quality, artifacts, and anatomic variations. Annualized brain volume changes were significantly different between those with MS and healthy individuals for percentage brain volume change (P < .001), percentage normalized brain volume change (P = .002), and percentage lateral ventricle volume change (P = .01). In patients with MS, mixed-effects model analysis showed that disability progression was associated with a 21.9% annualized decrease in percentage brain volume change (P < .001) and normalized brain volume (P = .002) and a 33% increase in lateral ventricle volume (P = .004). CONCLUSIONS: All brain volume measures differentiated MS and healthy individuals and were associated with disability progression, but the lateral ventricle volume assessment was the most feasible. PMID- 30467213 TI - Long-Term Ultrasound Follow-Up of Incidentally Detected Thyroglossal Duct Cysts in Adults. AB - BACKGROUND AND PURPOSE: There has been no previous study that used ultrasonography for longitudinal changes of thyroglossal duct cysts, to our knowledge. We assessed the prevalence and interval changes in incidentally detected thyroglossal duct cysts in adults. MATERIALS AND METHODS: From January 2010 to December 2016, we identified 796 ultrasonography radiologic reports from 513 subjects that contained the words "thyroglossal" or "TGDC" among 54,369 participants. Of 513 subjects, 172 (M/F = 103:69, mean age, 53 +/- 11 years) who underwent >=2 sonography studies were enrolled. Two reviewers determined ultrasonography features, including maximal diameter, location, internal echogenicity, wall thickness, and the presence of posterior enhancement, internal septa, and solid components. RESULTS: The mean follow-up time of total 172 lesions was 2.01 +/- 1.13 years. Thyroglossal duct cysts ranged from 2 to 32 mm (mean, 8.77 +/- 3.83 mm) on the initial ultrasonography examination. On follow-up ultrasonography studies, 14 lesions (8.2%) increased by >2 mm, while most thyroglossal duct cysts (133 lesions, 77.3%) remained stable in size. During the follow-up period, 31 lesions (18.0%) showed interval changes in ultrasonography features. There was no significant relationship between the presence of ultrasonography feature changes and size changes (P = .12). CONCLUSIONS: On ultrasonography, 0.9% of adults had incidental thyroglossal duct cysts. Most did not increase in size with time despite changes in various ultrasonography features. Therefore, we recommend performing an observation at long intervals of 2-3 years for asymptomatic thyroglossal duct cysts, and we suggest that fine needle aspiration can be suspended unless suspicious findings of malignancy are detected. PMID- 30467214 TI - Does Phase-Contrast Imaging through the Cerebral Aqueduct Predict the Outcome of Lumbar CSF Drainage or Shunt Surgery in Patients with Suspected Adult Hydrocephalus? AB - BACKGROUND AND PURPOSE: Radiologic imaging plays a key role in diagnosing chronic adult hydrocephalus, but its role in predicting prognosis is still controversial. We sought to evaluate the effectiveness of cardiac-gated phase-contrast MR imaging through the cerebral aqueduct in predicting the clinical response to diagnostic lumbar puncture/lumbar drainage and shunt surgery in suspected adult hydrocephalus. MATERIALS AND METHODS: In this retrospective study, the phase contrast MR imaging of 185 patients with suspected chronic adult hydrocephalus was evaluated using the CSF Flow software package. Decision-making for shunt placement was performed in this cohort on the basis of clinical assessment alone without the availability of quantitative phase-contrast MR imaging results. We recorded the response to lumbar puncture or lumbar drainage and shunt surgery using quantitative tests such as the Tinetti Test, the Timed Up and Go, and the Mini-Mental State Examination and qualitative measures of gait, urinary, and cognitive symptom improvement before and after lumbar puncture/lumbar drainage and shunt surgery. Quantitative analysis of phase-contrast MR imaging was compared with clinical outcome measures. RESULTS: Both CSF stroke volume and flow rate overlapped between lumbar puncture/lumbar drainage responders and nonresponders. There was also a significant overlap between shunt responders and nonresponders. Aqueductal stroke volume or flow rate alone was a poor predictor of lumbar puncture/lumbar drainage and shunt surgery response. Quantitative clinical measures after lumbar puncture/lumbar drainage were better predictors of shunt response. CONCLUSIONS: This study suggests that the results of phase contrast MR imaging through the cerebral aqueduct alone should not be used to select patients for diagnostic or therapeutic CSF diversion. PMID- 30467215 TI - Women Rising to the Top: The Tipping Point for the ASNR. PMID- 30467216 TI - Neuropsychiatric Lupus with Antibody-Mediated Striatal Encephalitis. AB - Systemic lupus erythematosus is a chronic autoimmune disease characterized by the production of autoantibodies resulting in tissue injury across multiple organs; up to 50% of patients develop neurologic involvement, collectively referred to as neuropsychiatric systemic lupus erythematosus. The cases in this clinical report will highlight a subtype of neuropsychiatric systemic lupus erythematosus demonstrating imaging findings of striatal inflammation responsive to plasmapheresis similar to those in the subset of N-methyl-D-aspartate receptor autoimmune encephalitis that involves the striatum. Although the cause for this striking imaging appearance is not definitely known, literature will be presented supporting the hypothesis that it is due to peripheral anti-double-stranded DNA antibodies entering the central nervous system to cross-react with N-methyl-D aspartate receptor antigens. PMID- 30467217 TI - Retrospective Review of Otic Capsule Contour and Thickness in Patients with Otosclerosis and Individuals with Normal Hearing on CT. AB - BACKGROUND AND PURPOSE: Otosclerosis is commonly identified on CT as a focus of hypodensity in the otic capsule anterior to the oval window. However, otosclerosis can have a sclerotic phase approximating the density of normal bone, making diagnosis challenging. This study assesses differences in otic capsule contour and thickness anterolateral to the anterior margin of the oval window in patients with otosclerosis compared with individuals with normal hearing. MATERIALS AND METHODS: Axial CT of 104 ears with clinically diagnosed otosclerosis and 108 consecutive ears of audiometrically normal individuals were retrospectively reviewed. Two radiologists independently evaluated the pattern of otosclerosis, otic capsule contour, and bone thickness on standardized axial images at the level of the oval window and cochleariform process. Measurements were made from the posterolateral margin of the cochlea to the apex of the otic capsule convex contour just anterolateral to the anterior margin of the oval window. In the absence of a convex contour, the sulcus between the oval window and the cochleariform process was identified, and measurement to the depth of the sulcus was used. Receiver operating characteristic analysis determined the best cutoff value of otic capsule thickness. RESULTS: Mean otic capsule thickness (2 SDs) was 3.08 (0.93) mm and 1.82 (0.31) mm in patients with otosclerosis and individuals with normal hearing, respectively (P < .001), with excellent interobserver agreement. Otic capsule thickness of >2.3 mm had 96.2% sensitivity, 100% specificity, 100% positive predictive value, and 96.4% negative predictive value for otosclerosis. A bulging/convex contour of the otic capsule had 68.3% sensitivity, 98.1% specificity, 97.3% positive predictive value, and 76.3% negative predictive value. CONCLUSIONS: Patients with otosclerosis have significantly thicker bone abutting the oval window than individuals with normal hearing. PMID- 30467218 TI - Abnormal Cerebral Perfusion Profile in Older Adults with HIV-Associated Neurocognitive Disorder: Discriminative Power of Arterial Spin-Labeling. AB - BACKGROUND AND PURPOSE: The aging HIV-infected (HIV+) population has increased vascular comorbidities, including stroke, and increased cognitive deficits compared with the general population. Arterial spin-labeling is a technique to measure cerebral blood flow and is more sensitive than regional volume loss in assessing neurodegenerative diseases and cognitive aging. Previous studies have found global cerebral perfusion abnormalities in the HIV+ participants. In this study, we evaluated the specific regional pattern of CBF abnormalities in older HIV+ participants using quantitative whole-brain arterial spin-labeling. MATERIALS AND METHODS: CBF data from the UCSF HIV Over 60 Cohort and the Alzheimer Disease Neuroimaging Initiative were retrospectively evaluated to identify 19 HIV+ older adults, all with plasma viral suppression (including 5 with HIV-associated neurocognitive disorder); 13 healthy, age-matched controls; and 19 participants with early mild cognitive impairment. CBF values were averaged by ROI and compared among the 3 groups using generalized linear models. RESULTS: When we accounted for age, education, sex, and vascular risk factors, the HIV+ participants demonstrated alterations in regional cerebral perfusion, including hypoperfusion of bilateral temporal, parietal, and occipital brain regions compared with both clinically healthy participants and those with mild cognitive impairment. Arterial spin-labeling showed reasonable test characteristics in distinguishing those with HIV-associated neurocognitive disorder from healthy controls and participants with mild cognitive impairment. CONCLUSIONS: This study found specific CBF patterns associated with HIV status despite viral suppression-data that should animate further investigations into the pathobiologic basis of vascular and cognitive abnormalities in HIV-associated neurocognitive disorders. PMID- 30467220 TI - Differences in the Calculated Transvenous Pressure Drop between Chronic Hydrocephalus and Idiopathic Intracranial Hypertension. AB - BACKGROUND AND PURPOSE: Chronic hydrocephalus is associated with dilated ventricles despite a normal intracranial pressure. In idiopathic intracranial hypertension, the ventricles are normal despite an elevated intracranial pressure. This apparent paradox has largely remained unexplained. It is suggested that a pressure difference between the superficial and deep venous territories of the brain could account for the variation between the 2 diseases. The purpose of this paper is to investigate the cause of this pressure difference. MATERIALS AND METHODS: Using MR phase-contrast imaging, we calculated the hydraulic diameters of the sagittal and straight sinuses in 21 patients with hydrocephalus, 20 patients with idiopathic intracranial hypertension, and 20 age-matched controls. The outflow resistance of each sinus was estimated using the Poiseuille equation. The outflow pressure was estimated using the flow data. A smaller subset of the patients with hydrocephalus had these studies repeated after successful shunt insertion. RESULTS: In hydrocephalus, the sagittal sinuses were 21% smaller than those in controls (P < .001); the straight sinuses were not significantly different. In idiopathic intracranial hypertension, both sinuses were not significantly different from those of controls. The pressure drop from the sagittal sinus to the end of the straight sinus was elevated by 1.2 mm Hg in hydrocephalus (P = .001) but not significantly different from that in controls in idiopathic intracranial hypertension. Shunt insertion dilated the sagittal sinuses in hydrocephalus, leaving them 18% larger than normal and eliminating the transvenous pressure change. CONCLUSIONS: There is a transvenous pressure difference in hydrocephalus that is absent in idiopathic intracranial hypertension. This difference is eliminated by shunt insertion. The findings may have a bearing on ventricular dilation. PMID- 30467219 TI - Cesarean Delivery Impacts Infant Brain Development. AB - BACKGROUND AND PURPOSE: The cesarean delivery rate has increased globally in the past few decades. Neurodevelopmental outcomes associated with cesarean delivery are still unclear. This study investigated whether cesarean delivery has any effect on the brain development of offspring. MATERIALS AND METHODS: A total of 306 healthy children were studied retrospectively. We included 3 cohorts: 2-week old neonates (cohort 1, n = 32/11 for vaginal delivery/cesarean delivery) and 8 year-old children (cohort 2, n = 37/23 for vaginal delivery/cesarean delivery) studied at Arkansas Children's Hospital, and a longitudinal cohort of 3-month to 5-year-old children (cohort 3, n = 164/39 for vaginal delivery/cesarean delivery) studied independently at Brown University. Diffusion tensor imaging, myelin water fraction imaging, voxel-based morphometry, and/or resting-state fMRI data were analyzed to evaluate white matter integrity, myelination, gray matter volume, and/or functional connectivity, respectively. RESULTS: While not all MR imaging techniques were shared across the institutions/cohorts, post hoc analyses showed similar results of potential effects of cesarean delivery. The cesarean delivery group in cohort 1 showed significantly lower white matter development in widespread brain regions and significantly lower functional connectivity in the brain default mode network, controlled for a number of potential confounders. No group differences were found in cohort 2 in white matter integrity or gray matter volume. Cohort 3 had significantly different trajectories of white matter myelination between groups, with those born by cesarean delivery having reduced myelin in infancy but normalizing with age. CONCLUSIONS: Cesarean delivery may influence infant brain development. The impact may be transient because similar effects were not observed in older children. Further prospective and longitudinal studies may be needed to confirm these novel findings. PMID- 30467221 TI - The IkappaB kinase complex is a regulator of mRNA stability. AB - The IkappaB kinase (IKK) is considered to control gene expression primarily through activation of the transcription factor NF-kappaB. However, we show here that IKK additionally regulates gene expression on post-transcriptional level. IKK interacted with several mRNA-binding proteins, including a Processing (P) body scaffold protein, termed enhancer of decapping 4 (EDC4). IKK bound to and phosphorylated EDC4 in a stimulus-sensitive manner, leading to co-recruitment of P body components, mRNA decapping proteins 1a and 2 (DCP1a and DCP2) and to an increase in P body numbers. Using RNA sequencing, we identified scores of transcripts whose stability was regulated via the IKK-EDC4 axis. Strikingly, in the absence of stimulus, IKK-EDC4 promoted destabilization of pro-inflammatory cytokines and regulators of apoptosis. Our findings expand the reach of IKK beyond its canonical role as a regulator of transcription. PMID- 30467222 TI - Optogenetic control of morphogenesis goes 3D. PMID- 30467223 TI - Semiology, clustering, periodicity and natural history of seizures in an experimental occipital cortical epilepsy model. AB - Focal neocortical epilepsy is a common form of epilepsy and there is a need to develop animal models that allow the evaluation of novel therapeutic strategies to treat this type of epilepsy. Tetanus toxin (TeNT) injection into rat visual cortex induces focal neocortical epilepsy without preceding status epilepticus. The latency to first seizure ranged from 3 to 7 days. Seizure duration was bimodal, with both short (approximately 30s) and long-lasting (>100s) seizures occurring in the same animals. Seizures were accompanied by non-motor features such as behavioural arrest, or motor seizures with or without evolution to generalized tonic-clonic seizures. Seizures were commoner during the sleep phase of a light-dark cycle. Seizure occurrence was not random, and tended to cluster with significantly higher probability of recurrence within 24 hours of a previous seizure. Across animals, the number of seizures in the first week could be used to predict the number of seizures in the following 3 weeks. The TeNT model of occipital cortical epilepsy is a model of acquired focal neocortical epilepsy well suited for preclinical evaluation of novel anti-epileptic strategies. We provide here a detailed analysis of the epilepsy phenotypes, seizure activity, electrographic features, and the semiology. In addition we provide a predictive framework that can be used to reduce variation and consequently animal use in pre clinical studies of potential treatments. PMID- 30467224 TI - A New Formula for Predicting the Fraction of Delivered Oxygen During Low-Flow Oxygen Therapy. AB - BACKGROUND: During O2 therapy at low flow in patients who breathe spontaneously, the fraction of delivered O2 (FDO2 ) is unknown. In recent years, FDO2 prediction formulas have been proposed. However, they do not take into account the effect of inspiratory flow (VI) on the FDO2 . The aim of this study was to validate a new FDO2 prediction formula, which takes into account the VI and compares it with other FDO2 prediction formulas. METHODS: During a bench study, spontaneous breathing was generated with a mechanical test lung connected to a mechanical ventilator set to volume control mode. O2 flow from a wall-mounted tube was delivered through a heat-and-moisture exchanger filter. A flow sensor recorded each breath of the VI in ambient temperature and barometric pressure conditions. Three parameters [O2 flow at 2, 3, 4, 5, 6 L/min; minute ventilation at 5, 10, 15, 20 L/min; and ratio of the inspiratory time (TI) to the total breathing cycle time (Ttot) (TI/Ttot) of 0.33 (TI/Ttot value) and 0.50 (TI/Ttot value)] were modified to generate many ventilatory patterns. An O2 analyzer continuously examined the FDO2 . RESULTS: When the O2 flow and/or TI/Ttot increased, the FDO2 increased. When the minute ventilation increased, the FDO2 decreased. The results of the Bland-Altman method for the FDO2 , calculated by using our mathematical model and the measured FDO2 , showed that the mean +/- SD bias value was equal to 1.49 +/- 0.84%, and the limits of agreement ranged from -0.17% to 3.14%. The intraclass correlation coefficients were 0.991 for TI/Ttot = 0.33 and 0.994 for TI/Ttot = 0.50, and the coefficient of variation was 2.1% for TI/Ttot = 0.33 and 1.3% for TI/Ttot = 0.50. The results of the Bland-Altman method for the FDO2 calculated by using the Shapiro formula and the FDO2 measured on the bench indicated that the bias value was 0.075 +/- 8.66% and the limits of agreement ranged from -16.89% to 17.04%. For the Vincent formula, the bias value was 3.08% +/- 8.56% and the limits of agreement ranged from -13.69% to 19.84%. CONCLUSIONS: The VI has a major impact on FDO2 during O2 therapy at low flow. FDO2 comparisons between frequently used prediction formulas and FDO2 measured on the bench indicated greater differences. Uncritical use of these formulas should be used cautiously to predict FDO2 . In this study, our prediction formula indicated a good accuracy for predicting FDO2 during supplemental oxygenation through a heat and-moisture exchanger in patients who breathe spontaneously. PMID- 30467225 TI - Experiences of Individuals Awaiting Lung Transplantation. AB - Lung transplantation is an established intervention for patients with advanced and life-threatening respiratory disease. Unfortunately, the shortage of organ donors results in a need for organs that greatly exceeds availability. This narrative review aimed to investigate the experiences of patients with respiratory diseases who wait for lung transplantation. Articles were retrieved from medical literature databases. Thirteen qualitative studies were reviewed, one of them used a mixed method. We found that individuals faced varied and complex situations differently while waiting for lung transplantations, depending on physical, psychological, social, and existential factors. Waiting gives hope for a future without the limitations imposed by the disease but also causes great stress. Many individuals struggled with the existential guilt associated with the privilege of having access to transplantation. This review highlighted that support from health-care professionals, next of kin, patients who had previously received a transplantation, and close friends have a vital role to play for individuals waiting for a lung transplantation. PMID- 30467226 TI - The Impact of High-Flow Nasal Oxygen in the Immunocompromised Critically Ill: A Systematic Review and Meta-Analysis. AB - BACKGROUND: High-flow nasal-cannula (HFNC) may be an oxygen modality useful for preventing invasive mechanical ventilation and mortality; however, its role in acute hypoxemic respiratory failure is not clearly defined. We sought to evaluate the impact of HFNC on mortality across immunocompromised subjects compared to alternative noninvasive oxygen therapies, namely conventional oxygen therapy and noninvasive ventilation (NIV). METHODS: We systematically searched the major databases to identify randomized, controlled trials (RCTs) or observational studies (until May 2018). We included studies reporting the use of HFNC in immunocompromised subjects and evaluated its impact on mortality and invasive mechanical ventilation. RESULTS: Upon review of 6,506 titles, 13 studies (1,956 subjects) fulfilled our inclusion criteria (4 RCTs, 9 observational studies). The predominant cause of immunocompromised status was cancer. Bacterial pneumonia was the most common cause of acute hypoxemic respiratory failure with a median PaO2/FIO2 of 145 mm Hg (interquartile range 115-175). HFNC was used as the first oxygen strategy in 474 subjects compared to NIV (242 subjects) and conventional O2 therapy (703 subjects). There was a 46% rate of invasive mechanical ventilation and 36% mortality. Mortality at the longest available follow-up was lower with HFNC compared to the oxygen therapy controls (NIV or conventional O2 therapy) in 7 studies (1,429 subjects; relative risk 0.72, 95% CI 0.56-0.93, P = .01). There was a lower rate of invasive mechanical ventilation with HFNC compared to the oxygen therapy controls across 8 studies (1,529 subjects, relative risk 0.81, 95% CI 0.67-0.96, P = .02). These results were robust across a series of sensitivity analyses. CONCLUSIONS: There exists a need to develop a greater evidence base evaluating the utility of HFNC in immunocompromised subjects. In our exploratory analysis, HFNC was found to decrease mortality and use of invasive mechanical ventilation compared to alternative noninvasive oxygen controls. These results are meant to be exploratory. Higher-quality studies evaluating a more homogeneous population are needed to further elucidate its benefit. PMID- 30467227 TI - Supportive Care of Patients on Mechanical Ventilation. AB - The paradigm of supportive care of patients who are critically ill has changed significantly over the past 20 years. Patients on mechanical ventilation are no longer heavily sedated; the goal is a comfortable patient who can interact with health-care professionals and with their family members. Systematic, regular assessment of the patient for pain, anxiety, and sleep deprivation allows early recognition of these distressing symptoms. Appropriate treatment of patients' symptoms should be based on a multi-modal pharmacologic and non-pharmacologic approach. Early mobilization and avoidance of physical restraint are additional patient-centered goals. The presence of family members during daily rounds and at the bedside can reduce the distress of the patient and enhance communication with the health-care team. All of these changes have created new challenges and opportunities for the multidisciplinary health-care team. This review aimed to describe the main components of evidence-based supportive care of patients on mechanical ventilation, beyond the specific settings of the ventilator. PMID- 30467228 TI - Optoacoustic Evaluation of Endotracheal Tube Depth in Pediatrics. PMID- 30467229 TI - Mechanical Insufflation-Exsufflation to Improve Secretion Clearance During Invasive Ventilation. PMID- 30467230 TI - The Importance of Synchronization During Neonatal Noninvasive Ventilation. PMID- 30467231 TI - Weak Cough Strength and Secretion Retention in Mechanically Ventilated Patients: Is There a Role for Cough-Assist Devices? PMID- 30467233 TI - Editor's Commentary. PMID- 30467232 TI - Mechanical Insufflation-Exsufflation Is Safe in Mechanically Ventilated Patients. PMID- 30467234 TI - T time for ADAR: ADAR1 is required for T cell self-tolerance. PMID- 30467235 TI - You can't always sequence your way out of a tight spot: Next-generation sequencing holds great promise for pathogen detection, but the devil is in the details. PMID- 30467236 TI - Modulating the expression of long non-coding RNAs for functional studies. AB - Long non-coding RNAs (lncRNAs) have emerged as important regulators of cell biology. The mechanisms by which lncRNAs function are likely numerous, and most are poorly understood. Currently, the mechanisms of functional lncRNAs include those that directly involve the lncRNA transcript, the process of their own transcription and splicing, and even underlying transcriptional regulatory elements within the genomic DNA that encodes the lncRNA As our understanding of lncRNA biology evolves, so have the methods that are utilized to elucidate their functions. In this review, we survey a collection of different methods used to modulate lncRNA expression levels for the assessment of biological function. From RNA-targeted strategies, genetic deletions, to engineered gene regulatory systems, the advantages and caveats of each method will be discussed. Ultimately, the selection of tools will be guided by which potential lncRNA mechanisms are being investigated, and no single method alone will likely be sufficient to reveal the function of any particular lncRNA. PMID- 30467238 TI - Obesity in pregnancy needs specialist multidisciplinary care, says royal college. PMID- 30467237 TI - The human phosphatase CDC14A modulates primary cilium length by regulating centrosomal actin nucleation. AB - CDC14A codes for a conserved proline-directed phosphatase, and mutations in the gene are associated with autosomal-recessive severe to profound deafness, due to defective kinocilia. A role of CDC14A in cilia formation has also been described in other organisms. However, how human CDC14A impacts on cilia formation remains unclear. Here, we show that human RPE1 hCDC14APD cells, encoding a phosphatase dead version of hCDC14A, have longer cilia than wild-type cells, while hCDC14A overexpression reduces cilia formation. Phospho-proteome analysis of ciliated RPE1 cells identified actin-associated and microtubule binding proteins regulating cilia length as hCDC14A substrates, including the actin-binding protein drebrin. Indeed, we find that hCDC14A counteracts the CDK5-dependent phosphorylation of drebrin at S142 during ciliogenesis. Further, we show that drebrin and hCDC14A regulate the recruitment of the actin organizer Arp2 to centrosomes. In addition, during ciliogenesis hCDC14A also regulates endocytosis and targeting of myosin Va vesicles to the basal body in a drebrin-independent manner, indicating that it impacts primary cilia formation in a multilayered manner. PMID- 30467239 TI - Prognostic significance of tumour infiltration growth pattern in patients with advanced gastric cancer. AB - AIMS: The prognostic significance of infiltration growth pattern (INF) in patients with gastric cancer (GC) remains controversial. In the present study, we evaluated the impact of INF pattern on the prognosis of patients with advanced GC. METHODS: A total of 1455 patients with advanced GC who underwent curative gastrectomy in our institution were retrospectively analysed. All patients were histopathologically classified as INFa/b and INFc pattern according to the Japanese Classification of Gastric Cancer. The prognostic difference between two patterns was compared and clinicopathological features were analysed. RESULTS: The prognosis of the patients with INFc pattern was poorer than that of those with INFa/b pattern (5-year disease-free survival, INFa/b: 48.4% vs INFc: 33.5%, p < 0.001), even when they were stratified according to lymph node metastasis and the tumour, node, metastases stage. In addition, the subgroup analysis indicated that INFc pattern was significantly associated with poorer prognosis of T2-T3 stage patients (T2, INFa/b: 72.7% vs INFc: 55.4%; T3, INFa/b: 47.4% vs INFc: 33.5%; p<0.001). However, a similar result was not observed among T4a stage patients (INFa/b: 26.8% vs INFc: 24.8%, p>0.05). The prognosis of T2 stage patients with INFc pattern was similar to that of T3 stage patients with INFa/b pattern (p>0.05). Also, there was no significantly prognostic difference between T3 stage patients with INFc pattern and T4a stage patients (p>0.05). The multivariate analysis indicated that INF pattern was an independent prognostic factor for patients with advanced GC (HR 1.259, 95%CI 1.089 to 1.454). CONCLUSION: In view of its prognostic significance, histopathological evaluation of INF pattern in surgically resected specimens should be recommended in patients with advanced GC. PMID- 30467240 TI - Recurrent MED12 exon 2 mutations in benign breast fibroepithelial lesions in adolescents and young adults. AB - AIMS: Most benign breast fibroepithelial lesions (FEL) in adults harbour recurrent somatic MED12 exon 2 mutations and rare TERT promoter hotspot mutations. We sought to determine the frequency of MED12 exon 2 and TERT promoter hotspot mutations in fibroadenomas (FA) and benign phyllodes tumours (BePT) in adolescents and young adults. METHODS: DNA from 21 consecutive FAs and eight consecutive BePTs in adolescents and young adults was subjected to Sanger sequencing of the exon 2 of MED12 and the TERT promoter hotspot locus. RESULTS: We identified MED12 exon 2 mutations in 62% and 88% of FAs and BePTs, respectively, and no TERT promoter hotspot mutations. The majority of the MED12 exon 2 mutations identified were in-frame deletions (60%). CONCLUSIONS: As in adults, benign FELs in juvenile patients harbour recurrent MED12 exon 2 mutations. PMID- 30467241 TI - Circulating tumour DNA, microRNA and metabolites in cerebrospinal fluid as biomarkers for central nervous system malignancies. AB - Central nervous system (CNS) malignancies can be difficult to diagnose and many do not respond satisfactorily to existing therapies. Monitoring patients with CNS malignancies for treatment response and tumour recurrence can be challenging because of the difficulty and risks of brain biopsies, and the low specificity and sensitivity of the less invasive methodologies that are currently available. Uncertainty about tumour diagnosis or whether a tumour has responded to treatment or has recurred can cause delays in therapeutic decisions that can impact patient outcome. Therefore, there is an urgent need to develop and validate reliable and minimally invasive biomarkers for CNS tumours that can be used alone or in combination with current clinical practices. Blood-based biomarkers can be informative in the diagnosis and monitoring of various types of cancer. However, blood-based biomarkers have proven suboptimal for analysis of CNS tumours. In contrast, circulating biomarkers in cerebrospinal fluid (CSF), including circulating tumour DNA, microRNAs and metabolites, hold promise for accurate and minimally invasive assessment of CNS tumours. This review summarises the current understanding of these three types of CSF biomarkers and their potential use in neuro-oncologic clinical practice. PMID- 30467242 TI - Distinguishing thymoma from T-lymphoblastic leukaemia/lymphoma: a case-based evaluation. AB - T-lymphoblastic lymphoma and thymoma are distinct primary mediastinal neoplasms that can have similar clinical presentations and overlapping histological features. Microscopic distinction is occasionally difficult because the immature lymphocytes associated with thymoma may resemble T-lymphoblastic leukaemia/lymphoma cells, morphologically and immunohistochemically. An accurate diagnosis assumes particular importance since the treatment approaches for these two entities differ considerably. Multimodality diagnostic approaches incorporating histological, flow cytometry immunophenotypic' and molecular approaches are required. In this article, we describe four patients, each presenting with a mediastinal tumour in different clinicopathological settings. A detailed report of each case will follow, illustrating the challenges involved in the diagnosis in patients with these mediastinal neoplasms. PMID- 30467243 TI - Revitalising an academic pathology department: lessons learnt. AB - Pathology is a specialty that bridges basic medical science and clinical practice. In the era of personalised medicine, this specialty is facing unprecedented challenges. Some of these challenges are institution-specific, while many are shared worldwide at different magnitude. This review shares our team efforts in the past 5 years, 2012-2017, to revitalise a century-old academic pathology department in three aspects: administration, clinical service and academic development. The lessons learnt and insights gained from our experience may provide guidance to leaders in pathology or in other related specialties. PMID- 30467244 TI - TP53 and DNA-repair gene polymorphisms genotyping as a low-cost lung adenocarcinoma screening tool. AB - AIM: TP53 and DNA repair polymorphisms have been proposed as cancer risk factors. This study evaluated the usability of TP53 Arg72Pro single-nucleotide polymorphism, X RCC1 Arg399Gln and RAD51 G135C as a low-cost lung adenocarcinoma screening tool. PATIENTS AND METHODS: This case-control study included 78 atients with lung adenocarcinoma and 79 healthy matched controls. TP53, XRCC1 and RAD51 genotyping was done by PCR followed by restriction length polymorphism. Descriptive analyses included genotype and allelic frequencies and deviations of the frequencies from those expected under Hardy-Weinberg equilibrium were assessed using the chi2 test. The OR and 95% CIs were calculated as an estimate of relative risk, with significance set at p value <0.05. RESULTS: The TP53 codon 72 Pro allele and the XRCC1 codon 399 Arg allele in a homozygous state were associated with lung adenocarcinoma (p=0.037; OR (95% CI) 2.42 (1.10 to 5.31)), that is, p=0.037; OR (95% CI) 2.16 (1.08 to 4.33), respectively. Also, carriers of the TP53 codon 72 Pro allele and the XRCC1 codon 399 ArgArg genotype older than 50 showed an even higher risk of developing lung adenocarcinoma (p=0.03 in both cases). CONCLUSIONS: The TP53 codon 72 Arg allele and XRCC1 codon 399 Gln allele are likely to have a protective effect against lung adenocarcinoma, especially in individuals older than 50 years of age. XRCC1 and TP53 genotyping might be a useful low-cost tool for evaluating individual lung cancer risk, leading to earlier detection and management of this disease. PMID- 30467246 TI - Should we legitimise puppy farming? PMID- 30467245 TI - Potentially serious incidental findings on brain and body magnetic resonance imaging of apparently asymptomatic adults: systematic review and meta-analysis. AB - OBJECTIVES: To determine prevalence and types of potentially serious incidental findings on magnetic resonance imaging (MRI) in apparently asymptomatic adults, describe factors associated with potentially serious incidental findings, and summarise information on follow-up and final diagnoses. DESIGN: Systematic review and meta-analyses. DATA SOURCES: Citation searches of relevant articles and authors' files in Medline and Embase (from inception to 25 April 2017). REVIEW METHODS: Eligible studies included prevalence and types of incidental findings detected among apparently asymptomatic adults undergoing MRI of the brain, thorax, abdomen, or brain and body. Data on study population and methods, prevalence and types of incidental findings, and final diagnoses were extracted. Pooled prevalence was estimated by random effects meta-analysis, and heterogeneity by tau2 statistics. MAIN OUTCOME MEASURES: Prevalence of potentially serious incidental findings on MRI of the brain, thorax, abdomen, and brain and body. RESULTS: Of 5905 retrieved studies, 32 (0.5%) met the inclusion criteria (n=27 643 participants). Pooled prevalence of potentially serious incidental findings was 3.9% (95% confidence interval 0.4% to 27.1%) on brain and body MRI, 1.4% (1.0% to 2.1%) on brain MRI, 1.3% (0.2% to 8.1%) on thoracic MRI, and 1.9% (0.3% to 12.0%) on abdominal MRI. Pooled prevalence rose after including incidental findings of uncertain potential seriousness (12.8% (3.9% to 34.3%), 1.7% (1.1% to 2.6%), 3.0% (0.8% to 11.3%), and 4.5% (1.5% to 12.9%), respectively). There was generally substantial heterogeneity among included studies. About half the potentially serious incidental findings were suspected malignancies (brain, 0.6% (95% confidence interval 0.4% to 0.9%); thorax, 0.6% (0.1% to 3.1%); abdomen, 1.3% (0.2% to 9.3%); brain and body, 2.3% (0.3% to 15.4%)). There were few informative data on potential sources of between-study variation or factors associated with potentially serious incidental findings. Limited data suggested that relatively few potentially serious incidental findings had serious final diagnoses (48/234, 20.5%). CONCLUSIONS: A substantial proportion of apparently asymptomatic adults will have potentially serious incidental findings on MRI, but little is known of their health consequences. Systematic, long term follow-up studies are needed to better inform on these consequences and the implications for policies on feedback of potentially serious incidental findings. SYSTEMATIC REVIEW REGISTRATION: Prospero CRD42016029472. PMID- 30467248 TI - News section PDF. PMID- 30467247 TI - Stress levels for vets will lead to 'implosion'. PMID- 30467250 TI - 'Ethical puppy farming could fix smuggling crisis'. PMID- 30467249 TI - Gender pay gap will resolve in 2098, say experts. PMID- 30467251 TI - Intensive farms less likely to meet animals' needs. PMID- 30467252 TI - Celebrity vet visits Morocco to help horses in need. PMID- 30467254 TI - Antibiotic use targets: how is each sector doing? PMID- 30467253 TI - Ban must be enforced on preventive antibiotics. PMID- 30467255 TI - Why are we adopting so many dogs from abroad? AB - Josh Loeb reports on research from the University of Liverpool on the issues around rescuing dogs from overseas. PMID- 30467257 TI - Oral protection for cats against fleas and ticks. PMID- 30467258 TI - Bovine tuberculosis elimination: playing the long game. PMID- 30467259 TI - Selected highlights from other journals. PMID- 30467260 TI - Support needed to prepare clients for Brexit. PMID- 30467261 TI - Antimicrobial resistance is a shared global problem. PMID- 30467262 TI - Diagnostic technologies and antimicrobial use in livestock systems. PMID- 30467263 TI - Supporting student veterinary nurses. PMID- 30467264 TI - Julie Dugmore, director of veterinary nursing at the RCVS, responds. PMID- 30467265 TI - Effectiveness of badger culls. PMID- 30467266 TI - Effectiveness of badger culls. PMID- 30467268 TI - Time to stop accepting 'normal for the breed'. PMID- 30467267 TI - Alternative multi-dose TB testing gun. PMID- 30467269 TI - The strength of the vet and nurse bond. AB - Vet Louise Kelly and vet nurse Phyllis Pratt are joint owners of a practice. As they celebrate winning their first practice award, they explain how the partnership works. PMID- 30467271 TI - Postoperative outcomes in laparoscopic appendicectomies with histopathologically normal appendix. AB - AIM: Although still debatable, appendicectomy during laparoscopy in patients with abdominal pain is often performed even if the appendix seems normal. The study's aim is to compare the postoperative outcomes of laparoscopic appendicectomies with appendix proven to be histologically normal to those with proven appendicitis, adding evidence on whether a normal appendix should be removed. METHODS: All consecutive patients who underwent laparoscopic appendicectomy in a one-year period in a single centre were retrospectively studied. Comparison was attempted between patients with negative and positive histology with regards to their postoperative outcomes (length of stay and postoperative complications). RESULTS: Out of 134 patients included in the study, ten patients developed postoperative complications (7.5%), 42 patients had negative histology (31.3%), 92 patients had positive histology (68.7%) and six (14.3%) and four patients (4.3%) respectively from each group developed post-operative complications. No statistically significant difference was found regarding morbidity, length of stay and Clavien-Dindo grading of complications between the two groups. DISCUSSION: Morbidity and length of stay in laparoscopic appendicectomy with normal appendix are not inferior to those with histologically confirmed appendicitis and thus should not be disregarded when considering a routine appendicectomy. CONCLUSION: The final decision to remove a normal appendix in laparoscopy for abdominal pain should be based on the individual clinical scenario and surgeon's experience. KEY WORDS: Acute appendicitis, Histology, Length of Stay, Morbidity. PMID- 30467272 TI - Falknor's needling method as a potential immunotherapy in palmo-plantar warts. AB - Background and Aim: Treatment of palmoplantar warts is a challenge for dermatologists. We aimed to study the efficacy and safety of Falknor's needling method in palmoplantar warts. Methods: In an open, nonrandomized study, the index wart of eligible patients was punctured several times with a 26-gauge needle to produce a "beefy" red wound. Patients were followed up to 6 months. Results: Out of 82 patients, complete resolution occurred in 58 (70.7%) and partial response in 5 (6.1%) patients. Nine (10.9%) patients developed secondary infection. Limitations: Small sample size, No comparison group. Conclusion: Falknor's needling method provides a high rate of complete resolution after a single treatment session. It is easy to perform and is cost effective. PMID- 30467273 TI - A Fuzzy Comprehensive Assessment and Hierarchical Management System for Urban Lake Health: A Case Study on the Lakes in Wuhan City, Hubei Province, China. AB - Environmental assessment of eutrophication or heavy metals in urban lakes is an important reference for identifying the pollution degree and formulating pollution prevention strategies. At present, the most research on lake health states is often evaluated from a single angle for toxic metals pollution or eutrophication using the standard comparison method for both, the comprehensive trophic level index (TLI), and the health risk assessment for toxic metals. Moreover, the above deterministic methods probably lead to biased or unreliable assessment due to the randomness and fuzziness in environment system caused by natural change and human activities. In this paper, a fuzzy comprehensive lake health assessment method (FCLHAM) was established to evaluate comprehensive lake health states more comprehensively and accurately, which integrates quantitative eutrophication and health risk considerations. To test and verify FCLHAM, 21 lakes, scientifically selected from the total 143 lakes in the Chinese Wuhan city as study case, were investigated and analyzed for their state of eutrophication and the health risk posed by heavy metals. According to the FCLHAM, the average comprehensive lake health state decreased in the sequence of L20 (considerate risk level) > L1-L17, L19, L21 (moderate risk level) > L18 (low risk level). Based on the result, lakes were classified into three categories: general management (L18), enhanced management (L1-L17, L19, L21), and priority management (L20). If the 143 lakes in Wuhan were classified by the "area-region-function" classification, they would be assigned to the same category as the representative lakes of the same type. At this point, we will attribute all of Wuhan's lakes to the three types. Depending on the characteristics of each type, a targeted approach to different types of management for each type of lake is a more efficient way to manage many of Wuhan's lakes. This management mode also serves as an effective reference for the environmental management of urban lakes both at home and abroad. In other words, according to the FCLHAM, a hierarchical management system based on lake characteristics classification was obtained. PMID- 30467274 TI - AMP-activated Protein Kinase Controls Immediate Early Genes Expression Following Synaptic Activation Through the PKA/CREB Pathway. AB - Long-term memory formation depends on the expression of immediate early genes (IEGs). Their expression, which is induced by synaptic activation, is mainly regulated by the 3',5'-cyclic AMP (cAMP)-dependent protein kinase/cAMP response element binding protein (cAMP-dependent protein kinase (PKA)/ cAMP response element binding (CREB)) signaling pathway. Synaptic activation being highly energy demanding, neurons must maintain their energetic homeostasis in order to successfully induce long-term memory formation. In this context, we previously demonstrated that the expression of IEGs required the activation of AMP-activated protein kinase (AMPK) to sustain the energetic requirements linked to synaptic transmission. Here, we sought to determine the molecular mechanisms by which AMPK regulates the expression of IEGs. To this end, we assessed the involvement of AMPK in the regulation of pathways involved in the expression of IEGs upon synaptic activation in differentiated primary neurons. Our data demonstrated that AMPK regulated IEGs transcription via the PKA/CREB pathway, which relied on the activity of the soluble adenylyl cyclase. Our data highlight the interplay between AMPK and PKA/CREB signaling pathways that allows synaptic activation to be transduced into the expression of IEGs, thus exemplifying how learning and memory mechanisms are under metabolic control. PMID- 30467275 TI - Laboratory Automation in Clinical Microbiology. AB - Laboratory automation is currently the main organizational challenge for microbiologists. Automating classic workflows is a strenuous process for the laboratory personnel and a huge and long-lasting financial investment. The investments are rewarded through increases in quality and shortened time to report. However, the benefits for an individual laboratory can only be estimated after the implementation and depending on the classic workflows currently performed. The two main components of automation are hardware and workflow. This review focusses on the workflow aspects of automation and describes some of the main developments during recent years. Additionally, it tries to define some terms which are related to automation and specifies some developments which would further improve automated systems. PMID- 30467276 TI - Sensing Urban Transportation Events from Multi-Channel Social Signals with the Word2vec Fusion Model. AB - Social sensors perceive the real world through social media and online web services, which have the advantages of low cost and large coverage over traditional physical sensors. In intelligent transportation researches, sensing and analyzing such social signals provide a new path to monitor, control and optimize transportation systems. However, current research is largely focused on using single channel online social signals to extract and sense traffic information. Clearly, sensing and exploiting multi-channel social signals could effectively provide deeper understanding of traffic incidents. In this paper, we utilize cross-platform online data, i.e., Sina Weibo and News, as multi-channel social signals, then we propose a word2vec-based event fusion (WBEF) model for sensing, detecting, representing, linking and fusing urban traffic incidents. Thus, each traffic incident can be comprehensively described from multiple aspects, and finally the whole picture of unban traffic events can be obtained and visualized. The proposed WBEF architecture was trained by about 1.15 million multi-channel online data from Qingdao (a coastal city in China), and the experiments show our method surpasses the baseline model, achieving an 88.1% F1 score in urban traffic incident detection. The model also demonstrates its effectiveness in the open scenario test. PMID- 30467277 TI - Methyl and Total Mercury in Different Media and Associated Fluxes in a Watershed Forest, Southwest China. AB - Mercury (Hg) deposition in the forest ecosystem is a significant source of input for methyl Hg (MeHg) and total Hg (THg) to the subtropical forest field and downstream aquatic systems. Wet deposition, litterfall, runoff, and fluxes with forest soil percolate of MeHg and THg were sampled for two years in a watershed forest of southwest China. Results showed that the depositions of THg and MeHg through litterfall and throughfall were 86 ug m-2 yr-1 and 0.8 ug m-2 yr-1 respectively, with litterfall acting as a predominant route for the input of both THg and MeHg. The estimated fluxes of THg and MeHg in the throughfall and litterfall were 3 and 4 times greater than those in the precipitation. Methylmercury in the decomposed litter migrates during its erosion by surface runoff and the concentrations of MeHg were quite consistent with that in the surface runoff. Methylmercury mainly accumulated in the lower layer of the litter and upper layer of the soil (Oi), and its transfer through the soil cross-section was delayed. THg retention was not consistent with MeHg, probably with lower soil layers (Oe and Oa) storing and enriching THg in the forest ecosystem. The forest floor of the lower soil is an effective sink for THg but not for MeHg. Methylmercury accumulated in decomposing litter and upper soil layer might transfer with soil percolate, possessing potential ecological risks for residents living around the downstream aquatic systems. PMID- 30467278 TI - Natural Computing Applied to the Underground System: A Synergistic Approach for Smart Cities. AB - The management and proper use of the Urban Public Transport Systems (UPTS) constitutes a critical field that has not been investigated in accordance to its relevance and urgent idiosyncrasy within the Smart Cities realm. Swarm Intelligence is a very promising paradigm to deal with such complex and dynamic systems. It presents robust, scalable, and self-organized behavior to deal with dynamic and fast changing systems. The intelligence of cities can be modelled as a swarm of digital telecommunication networks (the nerves), ubiquitously embedded intelligence, sensors and tags, and software. In this paper, a new approach based on the use of the Natural Computing paradigm and Collective Computation is shown, more concretely taking advantage of an Ant Colony Optimization algorithm variation and Fireworks algorithms to build a system that makes the complete control of the UPTS a tangible reality. PMID- 30467279 TI - Iron Supplementation in Suckling Piglets: An Ostensibly Easy Therapy of Neonatal Iron Deficiency Anemia. AB - In pigs, iron deficiency anemia (IDA) is the most prevalent deficiency disorder during the early postnatal period, frequently developing into a serious illness. On the other hand, in humans, only low-birth-weight infants, including premature infants, are especially susceptible to developing IDA. In both human and pig neonates, the initial cause of IDA is low birth iron stores. In piglets this shortage of stored iron results mainly from genetic selection over the past few decades for large litter sizes and high birth weights. As a consequence, pregnant sows cannot provide a sufficient amount of iron to the increasing number of developing fetuses. Supplementation with iron is a common practice for the treatment of IDA in piglets. For decades, the preferred procedure for delivering iron supplements during early life stages has been through the intramuscular injection of a large amount of iron dextran. However, this relatively simple therapy, which in general, efficiently corrects IDA, may generate toxic effects, and by inducing hepcidin expression, may decrease bioavailability of supplemental iron. New iron supplements are considered herein with the aim to combine the improvement of hematological status, blunting of hepcidin expression, and minimizing the toxicity of the administered iron. We propose that iron-deficient piglets constitute a convenient animal model for performing pre-clinical studies with iron supplements. PMID- 30467280 TI - Erratum: Yamanis, T., et al. Legal Immigration Status is Associated with Depressive Symptoms among Latina Transgender Women in Washington, DC. Int. J. Environ. Res. Public Health 2018, 15, 1246. AB - The authors would like to update the "Acknowledgements" section of their previous paper [...]. PMID- 30467281 TI - Myosins in Osteoclast Formation and Function. AB - Skeletal quantity and quality are determined by processes of bone modeling and remodeling, which are undertaken by cells that build and resorb bone as they respond to mechanical, hormonal, and other external and internal signals. As the sole bone resorptive cell type, osteoclasts possess a remarkably dynamic actin cytoskeleton that drives their function in this enterprise. Actin rearrangements guide osteoclasts' capacity for precursor fusion during differentiation, for migration across bone surfaces and sensing of their composition, and for generation of unique actin superstructures required for the resorptive process. In this regard, it is not surprising that myosins, the superfamily of actin-based motor proteins, play key roles in osteoclast physiology. This review briefly summarizes current knowledge of the osteoclast actin cytoskeleton and describes myosins' roles in osteoclast differentiation, migration, and actin superstructure patterning. PMID- 30467282 TI - Untargeted Metabolomics of Extracts from Faecal Samples Demonstrates Distinct Differences between Paediatric Crohn's Disease Patients and Healthy Controls but No Significant Changes Resulting from Exclusive Enteral Nutrition Treatment. AB - Metabolomic profiling using high resolution mass spectrometry with hydrophilic interaction chromatography was applied to 11 faecal extracts from eleven healthy children and to 43 faecal extracts from eleven children undergoing exclusive enteral nutrition for the treatment of active Crohn's disease (CD) at timepoints before, during (15, 30, and 60 days), and after treatment. Differences between the control and CD samples were identified at each timepoint. An orthogonal partial least square-discriminant analysis (OPLS-DA) model identified eight metabolites that were normally distributed according to Q-Q plots. The OPLS-DA model was able to discriminate the CD samples from the controls at every timepoint, but the model was not able to differentiate the CD samples from one another at the different timepoints during treatment with exclusive enteral nutrition. The differentiated metabolites identified in the CD samples included tyrosine, an ornithine isomer, arachidonic acid, eicosatrienoic acid, docosatetraenoic acid, a sphingomyelin, a ceramide, and dimethylsphinganine. Despite successful treatment, underlying differences remained in the metabolome of the CD patients. These differences dominated the separation of the samples when multivariate methods were applied. PMID- 30467283 TI - Determination of Activation Overpotential during the Nucleation of Hcp-Cobalt Nanowires Synthesized by Potentio-Static Electrochemical Reduction. AB - The crystal growth process and ferromagnetic properties of electrodeposited cobalt nanowires were investigated by controlling the bath temperature and cathodic overpotential. The cathodic overpotential during electrodeposition of cobalt nanowire arrays, DeltaEcath, was theoretically estimated by the difference between the cathode potential, Ecath, and the equilibrium potential, Eeq, calculated by the Nernst equation. On the other hand, the activation overpotential, DeltaEact, was experimentally determined by the Arrhenius plot on the growth rate of cobalt nanowire arrays, Rg, versus (vs.) reciprocal temperature, 1/T. The ferromagnetic cobalt nanowire arrays with a diameter of circa (ca.) 25 nm had the preferred crystal orientation of (100) and the aspect ratio reached up to ca. 1800. The average crystal grain size, Ds, of (100) peaks was estimated by X-ray diffraction patterns and was increased by decreasing the cathodic overpotential for cobalt electrodeposition by shifting the cathode potential in the noble direction. Axial magnetization performance was observed in the cobalt nanowire arrays. With increasing Ds, coercivity of the film increased and reached up to ca. 1.88 kOe. PMID- 30467284 TI - Using Cross-Sectional Data to Identify and Quantify the Relative Importance of Factors Associated with and Leading to Food Insecurity. AB - Australian governments routinely monitor population household food insecurity (FI) using a single measure-'running out of food at least once in the previous year'. To better inform public health planning, a synthesis of the determinants and how they influence and modify each other in relation to FI was conducted. The analysis used data from the Health & Wellbeing Surveillance System cross sectional dataset. Weighted means and multivariable weighted logistic regression described and modelled factors involved in FI. The analysis showed the direction and strength of the factors and a path diagram was constructed to illustrate these. The results showed that perceived income, independent of actual income was a strong mediator on the path to FI as were obesity, smoking and other indicators of health status. Eating out three or more times a week and eating no vegetables more strongly followed FI than preceded it. The analysis identified a range of factors and demonstrated the complex and interactive nature of them. Further analysis using propensity score weighted methods to control for covariates identified hypothetical causal links for investigation. These results can be used as a proof of concept to assist public health planning. PMID- 30467285 TI - Modular Synthesis and Biological Investigation of 5-Hydroxymethyl Dibenzyl Butyrolactones and Related Lignans. AB - Dibenzyl butyrolactone lignans are well known for their excellent biological properties, particularly for their notable anti-proliferative activities. Herein we report a novel, efficient, convergent synthesis of dibenzyl butyrolactone lignans utilizing the acyl-Claisen rearrangement to stereoselectively prepare a key intermediate. The reported synthetic route enables the modification of these lignans to give rise to 5-hydroxymethyl derivatives of these lignans. The biological activities of these analogues were assessed, with derivatives showing an excellent cytotoxic profile which resulted in programmed cell death of Jurkat T-leukemia cells with less than 2% of the incubated cells entering a necrotic cell death pathway. PMID- 30467286 TI - miR-542-5p Attenuates Fibroblast Activation by Targeting Integrin alpha6 in Silica-Induced Pulmonary Fibrosis. AB - Silicosis is a very serious occupational disease and it features pathological manifestations of inflammatory infiltration, excessive proliferation of fibroblasts and massive depositions of the extracellular matrix in the lungs. Recent studies described the roles of a variety of microRNAs (miRNAs) in fibrotic diseases. Here, we aimed to explore the potential mechanism of miR-542-5p in the activation of lung fibroblasts. To induce a pulmonary fibrosis mouse model, silica suspension and the miR-542-5p agomir were administered to mice by intratracheal instillation and tail vein injection. We found that miR-542-5p was significantly decreased in mouse fibrotic lung tissues and up-regulation of miR 542-5p visually attenuated a series of fibrotic lesions, including alveolar structural damage, alveolar interstitial thickening and silica-induced nodule formation. The down-regulation of miR-542-5p was also observed in mouse fibroblast (NIH-3T3) treated with transforming growth factor beta1 (TGF-beta1). The proliferation and migration ability of NIH-3T3 cells were also inhibited by the transfection of miR-542-5p mimic. Integrin alpha6 (Itga6), reported as a cell surface protein associated with fibroblast proliferation, was confirmed to be a direct target of miR-542-5p. The knockdown of Itga6 significantly inhibited the phosphorylation of FAK/PI3K/AKT. In conclusion, miR-542-5p has a potential function for reducing the proliferation of fibroblasts and inhibiting silica induced pulmonary fibrosis, which might be partially realized by directly binding to Itga6. Our data suggested that miR-542-5p might be a new therapeutic target for silicosis or other pulmonary fibrosis. PMID- 30467287 TI - On the Mechanism of Action of Anti-Inflammatory Activity of Hypericin: An In Silico Study Pointing to the Relevance of Janus Kinases Inhibition. AB - St. John's Wort (Hypericum perforatum L.) flowers are commonly used in ethnomedical preparations with promising outcomes to treat inflammation both per os and by topical application. However, the underlying molecular mechanisms need to be described toward a rational, evidence-based, and reproducible use. For this purpose, the aptitude of the prominent Hypericum metabolite hypericin was assessed, along with that of its main congeners, to behave as an inhibitor of janus kinase 1, a relevant enzyme in inflammatory response. It was used a molecular modeling approach relying on docking simulations, pharmacophoric modeling, and molecular dynamics to estimate the capability of molecules to interact and persist within the enzyme pocket. Our results highlighted the capability of hypericin, and some of its analogues and metabolites, to behave as ATP-competitive inhibitor providing: (i) a likely mechanistic elucidation of anti inflammatory activity of H. perforatum extracts containing hypericin and related compounds; and (ii) a rational-based prioritization of H. perforatum components to further characterize their actual effectiveness as anti-inflammatory agents. PMID- 30467288 TI - Identification of Genes that Control Silk Yield by RNA Sequencing Analysis of Silkworm (Bombyx mori) Strains of Variable Silk Yield. AB - Silk is an important natural fiber of high economic value, and thus genetic study of the silkworm is a major area of research. Transcriptome analysis can provide guidance for genetic studies of silk yield traits. In this study, we performed a transcriptome comparison using multiple silkworms with different silk yields. A total of 22 common differentially expressed genes (DEGs) were identified in multiple strains and were mainly involved in metabolic pathways. Among these, seven significant common DEGs were verified by quantitative reverse transcription polymerase chain reaction, and the results coincided with the findings generated by RNA sequencing. Association analysis showed that BGIBMGA003330 and BGIBMGA005780 are significantly associated with cocoon shell weight and encode uridine nucleosidase and small heat shock protein, respectively. Functional annotation of these genes suggest that these play a role in silkworm silk gland development or silk protein synthesis. In addition, we performed principal component analysis (PCA) in combination with wild silkworm analysis, which indicates that modern breeding has a stronger selection effect on silk yield traits than domestication, and imply that silkworm breeding induces aggregation of genes related to silk yield. PMID- 30467289 TI - Structure of Active Sites of Fe-N-C Nano-Catalysts for Alkaline Exchange Membrane Fuel Cells. AB - Platinum group metal-free (PGM-free) catalysts based on transition metal-nitrogen carbon nanomaterials have been studied by a combination of ex situ and in situ synchrotron X-ray spectroscopy techniques; high-resolution Transmission Electron Microscope (TEM); Mobetabauer spectroscopy combined with electrochemical methods and Density Functional Theory (DFT) modeling/theoretical approaches. The main objective of this study was to correlate the HO2- generation with the chemical nature and surface availability of active sites in iron-nitrogen-carbon (Fe-N-C) catalysts derived by sacrificial support method (SSM). These nanomaterials present a carbonaceous matrix with nitrogen-doped sites and atomically dispersed and; in some cases; iron and nanoparticles embedded in the carbonaceous matrix. Fe-N-C oxygen reduction reaction electrocatalysts were synthesized by varying several synthetic parameters to obtain nanomaterials with different composition and morphology. Combining spectroscopy, microscopy and electrochemical reactivity allowed the building of structure-to-properties correlations which demonstrate the contributions of these moieties to the catalyst activity, and mechanistically assign the active sites to individual reaction steps. Associated with Fe-Nx motive and the presence of Fe metallic particles in the electrocatalysts showed the clear differences in the variation of composition; processing and treatment conditions of SSM. From the results of material characterization; catalytic activity and theoretical studies; Fe metallic particles (coated with carbon) are main contributors into the HO2- generation. PMID- 30467290 TI - Smartphone-Based Indoor Localization within a 13th Century Historic Building. AB - Within this work we present an updated version of our indoor localization system for smartphones. The pedestrian's position is given by means of recursive state estimation using a particle filter to incorporate different probabilistic sensor models. Our recently presented approximation scheme of the kernel density estimation allows to find an exact estimation of the current position, compared to classical methods like weighted-average. Absolute positioning information is given by a comparison between recent measurements of nearby access points and signal strength predictions. Instead of using time-consuming approaches like classic fingerprinting or measuring the exact positions of access points, we use an optimization scheme based on a set of reference measurements to estimate a corresponding model. This work provides three major contributions to the system. The most essential contribution is the novel state transition based on continuous walks along a navigation mesh, modeling only the building's walkable areas. The localization system is further updated by incorporating a threshold-based activity recognition using barometer and accelerometer readings, allowing for continuous and smooth floor changes. Within the scope of this work, we tackle problems like multimodal densities and sample impoverishment (system gets stuck) by introducing different countermeasures. For the latter, a simplification of our previous solution is presented for the first time, which does not involve any major changes to the particle filter. The goal of this work is to propose a fast to deploy localization solution, that provides reasonable results in a high variety of situations. To stress our system, we have chosen a very challenging test scenario. All experiments were conducted within a 13th century historic building, formerly a convent and today a museum. The system is evaluated using 28 distinct measurement series on four different test walks, up to 310 m length and 10 min duration. It can be shown, that the here presented localization solution is able to provide a small positioning error, even under difficult conditions and faulty measurements. The introduced filtering methods allow for a real fail-safe system, while the optimization scheme enables an on-site setup-time of less then 120 min for the building's 2500 m walkable area. PMID- 30467291 TI - Location-Based Lattice Mobility Model for Wireless Sensor Networks. AB - Significant research has been conducted for maintaining a high standard of communication and good coverage in wireless sensor networks (WSNs), but extra power consumption and mobility issues are not yet fully resolved. This paper introduces a memory-less location mobility-aware Lattice Mobility Model (LMM) for WSNs. LMM is capable of concurrently determining the node and sink mobility. LMM has a lower pause time, fewer control packets, and less node dependency (e.g., the energy consumed by each node in each cycle that is independent of the data traffic). LMM accurately determines a node's moving location, the distance from its previous location to its current location, and the distance from its existing location to its destination. Many existing mobility models only provide a model how nodes move (e.g., to mimic pedestrian behavior), but do not actually control the next position based on properties of the underlying network topology. To determine the strength of LMM, OMNet++ was used to generate the realistic scenario to safeguard the affected area. The operation in affected area comprises searching for, detecting, and saving survivors. Currently, this process involves a time-consuming, manual search of the disaster area. This contribution aims to identify an energy efficient mobility model for a walking pattern in this particular scenario. LMM outperforms other mobility models, including the geographic-based circular mobility model (CMM), the random waypoint mobility model (RWMM) and the wind mobility model (WMM), The simulation results also demonstrate that the LMM requires the least time to change the location, has a lower drop rate, and has more residual energy savings than do the WMM, RWMM, and CMM. PMID- 30467292 TI - Cuscuta chinensis and C. campestris Attenuate Scopolamine-Induced Memory Deficit and Oxidative Damage in Mice. AB - The seeds of Cuscuta chinensis Lam. and C. campestris Yuncker have been commonly used as Chinese medical material for preventing aging. Our previous studies have found that C. chinensis and C. campestris possess anti-inflammatory activities in rodents. However, their other biological activities, such as memory-improving properties, have not yet been explored. In the present study, we examined the memory-improving effects of the extracts of C. chinensis and C. campestris on scopolamine (SCOP)-induced memory deficit and explored their underlying mechanism in mice. Both Cuscuta species improved SCOP-induced memory deficits in the passive avoidance test, elevated plus-maze, and spatial performance test of the Morris water maze in mice. In addition, compared with mice injected with SCOP, mice pretreated with both Cuscuta species stayed for a longer time on the platform for the probe test of the Morris water maze. Moreover, both Cuscuta species reduced brain acetylcholinesterase activity and malondialdehyde levels that were increased by SCOP, and the species restored the activities of antioxidant enzymes (superoxide dismutase and catalase) and the levels of glutathione that were decreased by SCOP in the brains of mice. Both Cuscuta species further decreased brain interleukin-1beta and tumor necrosis factor-alpha levels that were elevated by SCOP. We demonstrated that both Cuscuta species exhibited a protective activity against SCOP-induced memory deficit, cholinergic dysfunction, oxidative damage, and neuroinflammation in mice, and C. campestris has better potential than C. chinensis. In addition, we provided evidence that the seeds of C. campestris can be used as Cuscutae Semen in Traditional Chinese Medicine. PMID- 30467293 TI - Cytisine-Pterocarpan-Derived Compounds: Biomimetic Synthesis and Apoptosis Inducing Activity in Human Breast Cancer Cells. AB - Cytisine-pterocarpan-derived compounds were biomimetically synthesized with (-) cytisine and (-)-maackiain via a N,N-4-dimethyl-4-aminopyridine (DMAP)-mediated synthetic strategy in a mild manner. In the present study, tonkinensine B (4) was elaborated in good and high yields with the optimized reaction conditions. The in vitro cytotoxicity of compound 4 was evaluated against breast cancer cell lines and showed that 4 had a better cytotoxicity against MDA-MB-231 cells (IC50 = 19.2 MUM). Depending on the research on cytotoxicities of 4 against RAW 264.7 and BV2 cells, it was suggested that 4 produced low cytotoxic effects on the central nervous system. Further study indicated that 4 demonstrated cytotoxic activity against MDA-MB-231 cells and the cytotoxic activity was induced by apoptosis. The results implied that the apoptosis might be induced by mitochondrion-mediated apoptosis via regulating the ratio of Bax/Bcl-2 and promoting the release of cytochrome c from the mitochondrion to the cytoplasm in MDA-MB-231 cells. PMID- 30467294 TI - Temporal Frame of Immune Cell Infiltration during Heart Failure Establishment: Lessons from Animal Models. AB - Heart failure (HF) is a cardiovascular syndrome characterized by maladaptive changes with an underlying inflammatory mediated pathogenesis. Nevertheless, current therapy is aimed at the heart workload and neurohormonal axis; thus, prognosis remains poor. To continue improving treatment, we rely on murine models for a better understanding of HF pathophysiology. Among them, pressure overload HF (PO-HF) animal models are a common strategy. Development of PO-HF is characterized by monocyte infiltration, which orchestrates a cascade of events leading to sustained inflammation and maladaptive changes. Here, we divide the PO HF model progression into four phases and describe the inflammatory, structural, and gene expression profiles. This division is relevant due to its similarities with clinical hypertensive heart disease progression to HF. Evidence shows improvement in hemodynamic and other local parameters by altering the inflammatory response in a specific immune response at a specific point of time. Thus, it is relevant to focus on the time-dependent immune response interaction in order to provide more effective therapy. This review summarizes the pathogenesis of PO-HF murine models, highlighting the inflammatory events in a time frame view. By this approach, we expect to provide researchers with a better understanding of the intertwining time-dependent events that occur in PO-HF. PMID- 30467295 TI - Causal Relationship between Diet-Induced Gut Microbiota Changes and Diabetes: A Novel Strategy to Transplant Faecalibacterium prausnitzii in Preventing Diabetes. AB - The incidence of metabolic disorders, including diabetes, has elevated exponentially during the last decades and enhanced the risk of a variety of complications, such as diabetes and cardiovascular diseases. In the present review, we have highlighted the new insights on the complex relationships between diet-induced modulation of gut microbiota and metabolic disorders, including diabetes. Literature from various library databases and electronic searches (ScienceDirect, PubMed, and Google Scholar) were randomly collected. There exists a complex relationship between diet and gut microbiota, which alters the energy balance, health impacts, and autoimmunity, further causes inflammation and metabolic dysfunction, including diabetes. Faecalibacterium prausnitzii is a butyrate-producing bacterium, which plays a vital role in diabetes. Transplantation of F. prausnitzii has been used as an intervention strategy to treat dysbiosis of the gut's microbial community that is linked to the inflammation, which precedes autoimmune disease and diabetes. The review focuses on literature that highlights the benefits of the microbiota especially, the abundant of F. prausnitzii in protecting the gut microbiota pattern and its therapeutic potential against inflammation and diabetes. PMID- 30467296 TI - Complementary Quantitative Structure-Activity Relationship Models for the Antitrypanosomal Activity of Sesquiterpene Lactones. AB - Three complementary quantitative structure-activity relationship (QSAR) methodologies, namely, regression modeling based on (i) "classical" molecular descriptors, (ii) 3D pharmacophore features, and (iii) 2D molecular holograms (HQSAR) were employed on the antitrypanosomal activity of sesquiterpene lactones (STLs) toward Trypanosoma brucei rhodesiense (Tbr), the causative agent of the East African form of human African trypanosomiasis. In this study, an extension of a previous QSAR study on 69 STLs, models for a much larger and more diverse set of such natural products, now comprising 130 STLs of various structural subclasses, were established. The extended data set comprises a variety of STLs isolated and tested for antitrypanosomal activity within our group and is furthermore enhanced by 12 compounds obtained from literature, which have been tested in the same laboratory under identical conditions. Detailed QSAR analyses yielded models with comparable and good internal and external predictive ability. For a set of compounds as chemically diverse as the one under study, the models exhibited good coefficients of determination (R2) ranging from 0.71 to 0.85, as well as internal (leave-one-out Q2 values ranging from 0.62 to 0.72) and external validation coefficients (P2 values ranging from 0.54 to 0.73). The contributions of the various tested descriptors to the generated models are in good agreement with the results of previous QSAR studies and corroborate the fact that the antitrypanosomal activity of STLs is very much dependent on the presence and relative position of reactive enone groups within the molecular structure but is influenced by their hydrophilic/hydrophobic properties and molecular shape. PMID- 30467297 TI - A Rapid Method for the Detection of Sarcosine Using SPIONs/Au/CS/SOX/NPs for Prostate Cancer Sensing. AB - BACKGROUND: Sarcosine is an amino acid that is formed by methylation of glycine and is present in trace amounts in the body. Increased sarcosine concentrations in blood plasma and urine are manifested in sarcosinemia and in some other diseases such as prostate cancer. For this purpose, sarcosine detection using the nanomedicine approach was proposed. In this study, we have prepared superparamagnetic iron oxide nanoparticles (SPIONs) with different modified surface area. Nanoparticles (NPs) were modified by chitosan (CS), and sarcosine oxidase (SOX). SPIONs without any modification were taken as controls. Methods and Results: The obtained NPs were characterized by physicochemical methods. The size of the NPs determined by the dynamic light scattering method was as follows: SPIONs/Au/NPs (100-300 nm), SPIONs/Au/CS/NPs (300-700 nm), and SPIONs/Au/CS/SOX/NPs (600-1500 nm). The amount of CS deposited on the NP surface was found to be 48 mg/mL for SPIONs/Au/CS/NPs and 39 mg/mL for SPIONs/Au/CS/SOX/NPs, and repeatability varied around 10%. Pseudo-peroxidase activity of NPs was verified using sarcosine, horseradish peroxidase (HRP) and 3,3',5,5'-tetramethylbenzidine (TMB) as a substrate. For TMB, all NPs tested evinced substantial pseudo-peroxidase activity at 650 nm. The concentration of SPIONs/Au/CS/SOX/NPs in the reaction mixture was optimized to 0-40 mg/mL. Trinder reaction for sarcosine detection was set up at 510 nm at an optimal reaction temperature of 37 degrees C and pH 8.0. The course of the reaction was linear for 150 min. The smallest amount of NPs that was able to detect sarcosine was 0.2 mg/well (200 uL of total volume) with the linear dependence y = 0.0011x - 0.0001 and the correlation coefficient r = 0.9992, relative standard deviation (RSD) 6.35%, limit of detection (LOD) 5 uM. The suggested method was further validated for artificial urine analysis (r = 0.99, RSD 21.35%, LOD 18 uM). The calculation between the detected and applied concentrations showed a high correlation coefficient (r = 0.99). NPs were tested for toxicity and no significant growth inhibition was observed in any model system (S. cerevisiae, S. aureus, E. coli). The hemolytic activity of the prepared NPs was similar to that of the phosphate buffered saline (PBS) control. The reaction system was further tested on real urine specimens. Conclusion: The proposed detection system allows the analysis of sarcosine at micromolar concentrations and to monitor changes in its levels as a potential prostate cancer marker. The whole system is suitable for low-cost miniaturization and point-of-care testing technology and diagnostic systems. This system is simple, inexpensive, and convenient for screening tests and telemedicine applications. PMID- 30467298 TI - Urbanization, Land Use Behavior and Land Quality in Rural China: An Analysis Based on Pressure-Response-Impact Framework and SEM Approach. AB - During the last 40 years, China has undergone rapid urbanization which has resulted in land degradation and a decrease in land. Cultivated land protection has thus become one of the most active and important aspects of land science. This study presents a pressure-response-impact (PRI) framework which may reveal the inter-correlations among households' land-use behavior and cultivated land quality change in the process of rapid urbanization in China. The structural equation model (SEM) has been applied using a household survey dataset collected in 2015 in Sujiatun district, Shenyang city, Liaoning province. The results show that: (1) there is a complex causal relationship between the latent variables urbanization, household land-use behavior and cultivated land quality (i.e., urbanization -> land-use behavior -> land quality), which supports our PRI conceptual framework; (2) the changes of external social-economic context stemming from urbanization are the major cause of land-use behavior variance; (3) land quality is mostly affected by farmers' land-use behavior including land-use pattern, land-use degree and land-input intensity, in particular the growing of cash crops (GCC, associated with land use pattern) and capital input per unit of farmland (LII, associated with land input intensity). These findings are of some theoretical and practical significance. Theoretically, they add to the current literature by identifying the roles of sociological factors and farmers' land-use behavior in the process of land quality protection using a PRI framework. Practically, measures should be taken to reasonably set the prices of agricultural products, promote the development of the land rental market and increase the comparative revenue of agricultural production, so as to stimulate incentives to farming and land quality protection. PMID- 30467299 TI - Development of Laser-Based Powder Bed Fusion Process Parameters and Scanning Strategy for New Metal Alloy Grades: A Holistic Method Formulation. AB - In spite of the fast growth of laser-based powder bed fusion (L-PBF) processes as a part of everyday industrial practice, achieving consistent production is hampered by the scarce repeatability of performance that is often encountered across different additive manufacturing (AM) machines. In addition, the development of novel feedstock materials, which is fundamental to the future growth of AM, is limited by the absence of established methodologies for their successful exploitation. This paper proposes a structured procedure with a complete test plan, which defines step-by-step the standardized actions that should be taken to optimize the processing parameters and scanning strategy in L PBF of new alloy grades. The method is holistic, since it considers all the laser/material interactions in different local geometries of the build, and suggests, for each possible interaction, a specific geometry for test specimens, standard energy parameters to be analyzed through a design of experiment, and measurable key performance indicators. The proposed procedure therefore represents a sound and robust aid to the development of novel alloy grades for L PBF and to the definition of the most appropriate processing conditions for them, independent of the specific AM machine applied. PMID- 30467300 TI - Proteome Investigation of Rat Lungs subjected to Ex Vivo Perfusion (EVLP). AB - Ex vivo lung perfusion (EVLP) is an emerging procedure that allows organ preservation, assessment and reconditioning, increasing the number of marginal donor lungs for transplantation. However, physiological and airflow measurements are unable to unveil the molecular mechanisms responsible of EVLP beneficial effects on lung graft and monitor the proper course of the treatment. Thus, it is urgent to find specific biomarkers that possess these requirements but also accurate and reliable techniques that identify them. The purpose of this study is to give an overview on the potentiality of shotgun proteomic platforms in characterizing the status and the evolution of metabolic pathways during EVLP in order to find new potential EVLP-related biomarkers. A nanoLC-MS/MS system was applied to the proteome analysis of lung tissues from an optimized rat model in three experimental groups: native, pre- and post-EVLP. Technical and biological repeatability were evaluated and, together with clustering analysis, underlined the good quality of data produced. In-house software and bioinformatics tools allowed the label-free extraction of differentially expressed proteins among the three examined conditions and the network visualization of the pathways mainly involved. These promising findings encourage further proteomic investigations of the molecular mechanisms behind EVLP procedure. PMID- 30467301 TI - The Risk of Mortality among Psoriatic Patients with Varying Severity: A Nationwide Population-Based Cohort Study in Taiwan. AB - Background: Previous studies showed conflicting results regarding the mortality risk in psoriasis patients with respect to disease severity and presence of psoriatic arthritis. This study aimed to determine the mortality risk in patients with mild and severe psoriasis and patients with psoriatic arthritis (PsA). Methods: A nationwide population-based cohort study was conducted based on data from the Taiwan National Health Insurance Research Database between 2002 and 2012. Incident psoriasis subjects were classified into two groups: psoriasis without arthritis and psoriasis with arthritis. Patients who had received systemic therapy and/or phototherapy were classified as having severe psoriasis; otherwise, patients were classified as having mild psoriasis. Control subjects without psoriasis were selected to match each psoriasis patient from the database within the same observational period. Cox proportional hazards analysis was used to compare the hazard ratio (HR) of time to death. Results: A total of 106,701 patients with psoriasis were included in this study. After controlling for demographics and comorbidities, psoriasis patients had a higher mortality risk compared with the control group (HR 1.41; 95% confidence interval (CI) 1.36 to 1.46). Compared with psoriasis alone, the mortality risk was not increased for PsA (HR = 1.01; 95% CI 0.93 to 1.10). Besides, severe psoriasis did not increase mortality risk compared with mild psoriasis (HR = 1.0; 95% CI 0.95 to 1.06). Conclusions: Patients with psoriasis had a higher mortality risk compared with control subjects, whereas psoriasis severity and presence of PsA had no impact on mortality risk in psoriasis patients. PMID- 30467302 TI - Mesenchymal Stem Cell-Derived Exosomes Ameliorated Diabetic Nephropathy by Autophagy Induction through the mTOR Signaling Pathway. AB - BACKGROUND: Diabetic nephropathy (DN) is a serious complication of diabetes mellitus and a common cause of end-stage renal disease. Autophagy has a defensive role against kidney damage caused by hyperglycemia. Mesenchymal stem cell (MSC) derived exosomes are currently considered as a new promising therapy for chronic renal injury. However, the renal-protective mechanism of exosomes on DN is not completely understood. We examined the potential role of MSC-derived exosomes for enhancement of autophagy activity and their effect on DN. In our study, we used five groups of rats: control; DN; DN treated with exosomes; DN treated with 3 methyladenine (3-MA) and chloroquine (inhibitors of autophagy); and DN treated with 3-methyladenine (3-MA), chloroquine, and exosome groups. We assessed renal function, morphology, and fibrosis. Moreover, ratios of the autophagy markers mechanistic target of rapamycin (mTOR), Beclin-1, light chain-3 (LC3-II), and LC3 II/LC3-I were detected. Additionally, electron microscopy was used for detection of autophagosomes. RESULTS: Exosomes markedly improved renal function and showed histological restoration of renal tissues, with significant increase of LC3 and Beclin-1, and significant decrease of mTOR and fibrotic marker expression in renal tissue. All previous effects were partially abolished by the autophagy inhibitors chloroquine and 3-MA. CONCLUSION: We conclude that autophagy induction by exosomes could attenuate DN in a rat model of streptozotocin-induced diabetes mellitus. PMID- 30467303 TI - Alleviating Distortion and Improving the Young's Modulus in Two-Photon Polymerization Fabrications. AB - Two-photon polymerization enables the extremely high resolution three-dimensional printing of micro-structures. To know the mechanical properties, and better still, to be able to adjust them is of paramount importance to ensuring the proper structural integrity of the printed products. In this work, the Young's modulus is measured on two-photon polymerized micro-cantilever bars. Optimizing the scanning trajectory of the laser focus points is important in alleviating distortion of the printed bars. By increasing the laser power and decreasing the inter-voxel distances we can double the Young's modulus. Post-curing with ultraviolet light can approximately quadruple the Young's modulus. However, the resulting modulus is still only about 0.3% of that of the bulk polymerized material. PMID- 30467304 TI - Enantioselective Drug Recognition by Drug Transporters. AB - Drug transporters mediate the absorption, tissue distribution, and excretion of drugs. The cDNAs of P-glycoprotein, multidrug resistance proteins (MRPs/ABCC), breast cancer resistance protein (BCRP/ABCG2), peptide transporters (PEPTs/SLC15), proton-coupled folate transporters (PCFT/SLC46A1), organic anion transporting polypeptides (OATPs/SLCO), organic anion transporters (OATs/SLC22), organic cation transporters (OCTs/SLC22), and multidrug and toxin extrusions (MATEs/SLC47) have been isolated, and their functions have been elucidated. Enantioselectivity has been demonstrated in the pharmacokinetics and efficacy of drugs, and is important for elucidating the relationship with recognition of drugs by drug transporters from a chiral aspect. Enantioselectivity in the transport of drugs by drug transporters and the inhibitory effects of drugs on drug transporters has been summarized in this review. PMID- 30467305 TI - Cytomegalovirus Pneumonia with Progressive Lung Volume Loss. AB - BACKGROUND Cytomegalovirus (CMV) pneumonia is common in immunocompromised patients with hematological malignancies. Although the spectrum of illness caused by CMV is well-documented in immunocompromised patients, the clinical course and evolution of lung changes after initiation of antiviral therapy remain unclear. CASE REPORT We present the cases of 3 patients with leukemia who developed CMV pneumonia following cord blood transplantation and who presented with distinctive features on chest computed tomography (CT). In all patients, chest CT showed central peribronchial changes with severe lung volume loss. Furthermore, the patients were refractory to high-dose steroids, and the lung volume loss rapidly progressed, leading to death from respiratory failure. CONCLUSIONS We observed central peribronchial changes with severe lung volume loss after the acute phase in 3 cases of CMV pneumonia. While our diagnosis was made on the basis of exclusion, it is important to bear in mind that lung involvement in CMV pneumonia may be refractory to various treatment modalities and can lead to a fatal clinical course. PMID- 30467306 TI - Protective Effects of Apoptosis of Kupffer Cells Induced by Zoledronate Liposomes Following Hepatic Ischemia-Reperfusion Injury. AB - BACKGROUND The goal of this study was to observe the effect of the apoptosis of Kupffer cells (KCs) selectively induced by zoledronate liposomes following the hepatic ischemia-reperfusion injury (IRI) in the rat liver transplantation model and to explore its mechanisms. MATERIAL AND METHODS The rat liver transplantation model was established using the improved Kamada method. Male Sprague Dawley rats were randomly divided into 3 groups: no liver transplantation or drug treatment (Group A); donor rats were injected with 1 mL normal saline through the tail vein for 3 continuous days before transplantation, and the donor liver was preserved in cold for 2 hours (Group B); donor rats were injected with 1 mL zoledronate liposomes (0.001 mg/mL) through the tail vein for 3 continuous days before transplantation, and the donor liver was preserved in cold for 2 hours (Group C). At 24 hours after transplantation, the receiving rats were sacrificed for sampling. RESULTS Compared with Group C and Group A, the bile secretion flow was dramatically decreased in Group B, whereas the serum liver function index [alanine aminotransferase (ALT), glutamate aminotransferase (AST), and gamma glutamyl transpeptidase (gamma-GT)] was significantly increased (P<0.01), and the pathological injury area was obviously increased. Compared with Group B, the levels of serum interleukin1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and the apoptotic index in Group C were significantly decreased (P<0.05), and Suzuki scores of congestion, vacuolar degeneration, and necrosis were all reduced (P<0.05). CONCLUSIONS The apoptosis of KCs selectively induced by zoledronate liposomes inhibited the inflammatory cascade reaction induced by KC activation and reduced the release of cytokines and decreased the extent of IRI in the liver transplantation in animal model. PMID- 30467307 TI - Efficacy and Safety of Treatment with Transcutaneous Vagus Nerve Stimulation in 17 Patients with Refractory Epilepsy Evaluated by Electroencephalogram, Seizure Frequency, and Quality of Life. AB - BACKGROUND This study aimed to investigate the efficacy and safety of treatment with transcutaneous vagus nerve stimulation (tVNS) for patients with refractory epilepsy by evaluation of the frequency of seizures, electroencephalogram (EEG) changes, and quality of life on follow-up at three months and six months. MATERIAL AND METHODS EEG evaluation followed baseline evaluation with EEG at three months and six months following tVNS treatment. The frequency of seizures was recorded during the six-month study period. Before and after tVNS treatment, patients completed the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS), the Liverpool Seizure Severity Scale (LSSS), the Quality of Life in Epilepsy Inventory (QOLIE-31), and the Pittsburg Sleep Quality Index (PSQI). RESULTS Seventeen patients completed six months of tVNS treatment. Following three months of tVNS therapy, the frequency of epileptic seizures decreased in 13/17 subjects, with an average reduced seizure rate of 31.3%. Following six months of tVNS treatment, the frequency of epileptic seizures decreased in 16/17 subjects, with an average reduced seizure rate of 64.4%. There were 14/17 cases with abnormal EEG at baseline; 2/17 patients had improved EEGs by three months, and 10/17 patients had improved EEGs by six months. During the study period, there were no adverse events associated with tVNS treatment, but the effects on sleep were inconclusive. CONCLUSIONS This preliminary study showed that tVNS was an effective and safe adjuvant treatment for refractory epilepsy that reduced seizure frequency and reduced abnormal EEG changes following clinical improvement. PMID- 30467308 TI - Upregulation of Ets1 expression by NFATc2 and NFKB1/RELA promotes breast cancer cell invasiveness. AB - Breast cancer is highly aggressive and is the leading cause of cancer-related mortality in women in developed countries. The ETS proto-oncogene 1 (Ets1) has versatile roles during the cellular processes of cancer development. It is often highly expressed in breast cancers and mediates migration and invasion of human breast cancer cells. However, underlying mechanisms of Ets1 gene expression is still ambiguous. Here, we identified a core-regulatory element (CRE) located in the Ets1 promoter region (-540/-80 bp from TSS) that contains elements responsible for associating with NFATs and NF-kappaBs. Compared with the less metastatic breast cancer cells, metastatic breast cancer cells (MDA-MB-231) show open chromatin configurations in the CRE, which facilitates direct binding of NFATc2 and/or NFKB1/RELA complex to trans-activate Ets1 transcription. Moreover, enhanced level of Nfatc2 and Nfkb1 positively correlated with Ets1 expression in the human breast cancer specimens. Deletion of the CRE region by CRISPR/Cas9 system resulted in significant reduction in Ets1 expression, which led to alterations of Ets1-mediated transcription programs including tumor invasiveness related genes. Proper regulation of Ets1 gene expression by targeting the NFATc2 and NFKB1/RELA interaction could be a potential therapeutic target for Ets1 mediated metastatic breast cancer. PMID- 30467310 TI - Coral-associated bacteria demonstrate phylosymbiosis and cophylogeny. AB - Scleractinian corals' microbial symbionts influence host health, yet how coral microbiomes assembled over evolution is not well understood. We survey bacterial and archaeal communities in phylogenetically diverse Australian corals representing more than 425 million years of diversification. We show that coral microbiomes are anatomically compartmentalized in both modern microbial ecology and evolutionary assembly. Coral mucus, tissue, and skeleton microbiomes differ in microbial community composition, richness, and response to host vs. environmental drivers. We also find evidence of coral-microbe phylosymbiosis, in which coral microbiome composition and richness reflect coral phylogeny. Surprisingly, the coral skeleton represents the most biodiverse coral microbiome, and also shows the strongest evidence of phylosymbiosis. Interactions between bacterial and coral phylogeny significantly influence the abundance of four groups of bacteria-including Endozoicomonas-like bacteria, which divide into host generalist and host-specific subclades. Together these results trace microbial symbiosis across anatomy during the evolution of a basal animal lineage. PMID- 30467311 TI - Air quality co-benefits for human health and agriculture counterbalance costs to meet Paris Agreement pledges. AB - Local air quality co-benefits can provide complementary support for ambitious climate action and can enable progress on related Sustainable Development Goals. Here we show that the transformation of the energy system implied by the emission reduction pledges brought forward in the context of the Paris Agreement on climate change (Nationally Determined Contributions or NDCs) substantially reduces local air pollution across the globe. The NDCs could avoid between 71 and 99 thousand premature deaths annually in 2030 compared to a reference case, depending on the stringency of direct air pollution controls. A more ambitious 2 degrees C-compatible pathway raises the number of avoided premature deaths from air pollution to 178-346 thousand annually in 2030, and up to 0.7-1.5 million in the year 2050. Air quality co-benefits on morbidity, mortality, and agriculture could globally offset the costs of climate policy. An integrated policy perspective is needed to maximise benefits for climate and health. PMID- 30467309 TI - Molecular insights into genome-wide association studies of chronic kidney disease defining traits. AB - Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning the associations uncovered in GWAS of CKD-dt. PMID- 30467312 TI - Vortex rectenna powered by environmental fluctuations. AB - A rectenna, standing for a rectifying antenna, is an apparatus which generates d.c. electricity from electric fluctuations. It is expected to realize wireless power transmission as well as energy harvesting from environmental radio waves. To realize such rectification, devices that are made up of internal atomic asymmetry such as an asymmetric junction have been necessary so far. Here we report a material that spontaneously generates electricity by rectifying environmental fluctuations without using atomic asymmetry. The sample is a common superconductor without lowered crystalline symmetry, but, just by putting it in an asymmetric magnetic environment, it turns into a rectifier and starts generating electricity. Superconducting vortex strings only annihilate and nucleate at surfaces, and this allows the bulk electrons to feel surface fluctuations in an asymmetric environment: a vortex rectenna. The rectification and generation can be switched on and off with only a slight change in temperature or external magnetic fields. PMID- 30467313 TI - Author Correction: Iron restriction inside macrophages regulates pulmonary host defense against Rhizopus species. AB - The original version of this Article contained an error in the spelling of the author Emilien Etienne, which was incorrectly given as Emilien Ettiene. These errors have now been corrected in both the PDF and HTML versions of the Article. PMID- 30467314 TI - Microwave emission from superconducting vortices in Mo/Si superlattices. AB - Most of superconductors in a magnetic field are penetrated by a lattice of quantized flux vortices. In the presence of a transport current causing the vortices to cross sample edges, emission of electromagnetic waves is expected due to the continuity of tangential components of the fields at the surface. Yet, such a radiation has not been observed so far due to low radiated power levels and lacking coherence in the vortex motion. Here, we clearly evidence the emission of electromagnetic waves from vortices crossing the layers of a superconductor/insulator Mo/Si superlattice. The emission spectra consist of narrow harmonically related peaks which can be finely tuned in the GHz range by the dc bias current and, coarsely, by the in-plane magnetic field value. Our findings show that superconductor/insulator superlattices can act as dc-tunable microwave generators bridging the frequency gap between conventional radiofrequency oscillators and (sub-)terahertz generators relying upon the Josephson effect. PMID- 30467315 TI - Frequency-dependent decoupling of domain-wall motion and lattice strain in bismuth ferrite. AB - Dynamics of domain walls are among the main features that control strain mechanisms in ferroic materials. Here, we demonstrate that the domain-wall controlled piezoelectric behaviour in multiferroic BiFeO3 is distinct from that reported in classical ferroelectrics. In situ X-ray diffraction was used to separate the electric-field-induced lattice strain and strain due to displacements of non-180 degrees domain walls in polycrystalline BiFeO3 over a wide frequency range. These piezoelectric strain mechanisms have opposing trends as a function of frequency. The lattice strain increases with increasing frequency, showing negative piezoelectric phase angle (i.e., strain leads the electric field), an unusual feature so far demonstrated only in the total macroscopic piezoelectric response. Domain-wall motion exhibits the opposite behaviour, it decreases in magnitude with increasing frequency, showing more common positive piezoelectric phase angle (i.e., strain lags behind the electric field). Charge redistribution at conducting domain walls, oriented differently in different grain families, is demonstrated to be the cause. PMID- 30467316 TI - Changes in short term river flow regulation and hydropeaking in Nordic rivers. AB - Quantifying short-term changes in river flow is important in understanding the environmental impacts of hydropower generation. Energy markets can change rapidly and energy demand fluctuates at sub-daily scales, which may cause corresponding changes in regulated river flow (hydropeaking). Due to increasing use of renewable energy, in future hydropower will play a greater role as a load balancing power source. This may increase current hydropeaking levels in Nordic river systems, creating challenges in maintaining a healthy ecological status. This study examined driving forces for hydropeaking in Nordic rivers using extensive datasets from 150 sites with hourly time step river discharge data. It also investigated the influence of increased wind power production on hydropeaking. The data revealed that hydropeaking is at high levels in the Nordic rivers and have seen an increase over the last decade and especially over the past few years. These results indicate that increased building for renewable energy may increase hydropeaking in Nordic rivers. PMID- 30467317 TI - High-throughput screens identify HSP90 inhibitors as potent therapeutics that target inter-related growth and survival pathways in advanced prostate cancer. AB - The development of new treatments for castrate resistant prostate cancer (CRPC) must address such challenges as intrinsic tumor heterogeneity and phenotypic plasticity. Combined PTEN/TP53 alterations represent a major genotype of CRPC (25 30%) and are associated with poor outcomes. Using tumor-derived, castration resistant Pten/Tp53 null luminal prostate cells for comprehensive, high throughput, mechanism-based screening, we identified several vulnerabilities among >1900 compounds, including inhibitors of: PI3K/AKT/mTOR, the proteasome, the cell cycle, heat shock proteins, DNA repair, NFkappaB, MAPK, and epigenetic modifiers. HSP90 inhibitors were one of the most active compound classes in the screen and have clinical potential for use in drug combinations to enhance efficacy and delay the development of resistance. To inform future design of rational drug combinations, we tested ganetespib, a potent second-generation HSP90 inhibitor, as a single agent in multiple CRPC genotypes and phenotypes. Ganetespib decreased growth of endogenous Pten/Tp53 null tumors, confirming therapeutic activity in situ. Fifteen human CRPC LuCaP PDX-derived organoid models were assayed for responses to 110 drugs, and HSP90 inhibitors (ganetespib and onalespib) were among the select group of drugs (<10%) that demonstrated broad activity (>75% of models) at high potency (IC50 <1 uM). Ganetespib inhibits multiple targets, including AR and PI3K pathways, which regulate mutually compensatory growth and survival signals in some forms of CRPC. Combined with castration, ganetespib displayed deeper PDX tumor regressions and delayed castration resistance relative to either monotherapy. In all, comprehensive data from near-patient models presents novel contexts for HSP90 inhibition in multiple CRPC genotypes and phenotypes, expands upon HSP90 inhibitors as simultaneous inhibitors of oncogenic signaling and resistance mechanisms, and suggests utility for combined HSP90/AR inhibition in CRPC. PMID- 30467318 TI - Genome-wide analysis of RNAs associated with Populus euphratica Oliv. heterophyll morphogenesis. AB - The desert plant Populus euphratica Oliv. has typical heterophylly; linear (Li), lanceolate (La), ovate (Ov) and broad-ovate (Bo) leaves grow in turn as trees develop to maturity. P. euphratica is therefore a potential model organism for leaf development. To investigate the roles of RNAs (including mRNAs, miRNAs, lncRNAs and circRNAs) in the morphogenesis of P. euphratica heterophylls, juvenile heterophylls were sampled individually, and then, the expression patterns of miRNAs, mRNAs, lncRNAs and circRNAs were analysed by small RNA sequencing and strand-specific RNA sequencing. We found that 1374 mRNAs, 19 miRNAs, 71 lncRNAs and 2 circRNAs were P. euphratica heterophyll morphogenesis associated (PHMA) RNAs; among them, 17 PHMA miRNAs could alter the expression of 46 PHMA mRNAs. Furthermore, 11 lncRNAs and 2 circRNAs interacted with 27 PHMA mRNAs according to the ceRNA hypothesis. According to GO and KEGG pathway analysis, PHMA RNAs were mainly involved in metabolism, response to stimulus and developmental processes. Our results indicated that external environmental factors and genetic factors in P. euphratica co-regulated the expression of PHMA RNAs, repressed cell division, reinforced cell growth, and ultimately resulted in the morphogenesis of P. euphratica heterophylls. PMID- 30467319 TI - Foxi3 transcription factor activity is mediated by a C-terminal transactivation domain and regulated by the Protein Phosphatase 2A (PP2A) complex. AB - The Forkhead box (FOX) family consists of at least 19 subgroups of transcription factors which are characterized by the presence of an evolutionary conserved 'forkhead' or 'winged-helix' DNA-binding domain. Despite having a conserved core DNA binding domain, FOX proteins display remarkable functional diversity and are involved in many developmental and cell specific processes. In the present study, we focus on a poorly characterized member of the Forkhead family, Foxi3, which plays a critical role in the development of the inner ear and jaw. We show that Foxi3 contains at least two important functional domains, a nuclear localization sequence (NLS) and a C-terminal transactivation domain (TAD), and that it directly binds its targets in a sequence specific manner. We also show that the transcriptional activity of Foxi3 is regulated by phosphorylation, and that the activity of Foxi3 can be attenuated by its physical interaction with the protein phosphatase 2A (PP2A) complex. PMID- 30467320 TI - Phase and structure engineering of copper tin heterostructures for efficient electrochemical carbon dioxide reduction. AB - While engineering the phase and structure of electrocatalysts could regulate the performance of many typical electrochemical processes, its importance to the carbon dioxide electroreduction has been largely unexplored. Herein, a series of phase and structure engineered copper-tin dioxide catalysts have been created and thoroughly exploited for the carbon dioxide electroreduction to correlate performance with their unique structures and phases. The copper oxide/hollow tin dioxide heterostructure catalyst exhibits promising performance, which can tune the products from carbon monoxide to formic acid at high faradaic efficiency by simply changing the electrolysis potentials from -0.7 VRHE to -1.0 VRHE. The excellent performance is attributed to the abundant copper/tin dioxide interfaces involved in the copper oxide/hollow tin dioxide heterostructure during the electrochemical process, decreasing the reaction free-energies for the formation of COOH* species. Our work reported herein emphasizes the importance of phase and structure modulating of catalysts for enhancing electrochemical CO2 reduction and beyond. PMID- 30467321 TI - Comparison of 1D and 3D Models for the Estimation of Fractional Flow Reserve. AB - In this work we propose to validate the predictive capabilities of one dimensional (1D) blood flow models with full three-dimensional (3D) models in the context of patient-specific coronary hemodynamics in hyperemic conditions. Such conditions mimic the state of coronary circulation during the acquisition of the Fractional Flow Reserve (FFR) index. Demonstrating that 1D models accurately reproduce FFR estimates obtained with 3D models has implications in the approach to computationally estimate FFR. To this end, a sample of 20 patients was employed from which 29 3D geometries of arterial trees were constructed, 9 obtained from coronary computed tomography angiography (CCTA) and 20 from intra vascular ultrasound (IVUS). For each 3D arterial model, a 1D counterpart was generated. The same outflow and inlet pressure boundary conditions were applied to both (3D and 1D) models. In the 1D setting, pressure losses at stenoses and bifurcations were accounted for through specific lumped models. Comparisons between 1D models (FFR1D) and 3D models (FFR3D) were performed in terms of predicted FFR value. Compared to FFR3D, FFR1D resulted with a difference of 0.00 +/- 0.03 and overall predictive capability AUC, Acc, Spe, Sen, PPV and NPV of 0.97, 0.98, 0.90, 0.99, 0.82, and 0.99, with an FFR threshold of 0.8. We conclude that inexpensive FFR1D simulations can be reliably used as a surrogate of demanding FFR3D computations. PMID- 30467323 TI - Pancreatic cancer arising in the remnant pancreas is not always a relapse of the preceding primary. AB - This study aimed to understand the biology of pancreatic ductal adenocarcinoma that arises in the remnant pancreas after surgical resection of a primary pancreatic ductal adenocarcinoma, using integrated histological and molecular analysis. Patients who underwent a completion pancreatectomy for local recurrence following resection of a primary pancreatic ductal adenocarcinoma were studied with histological analysis and next-generation sequencing of the primary and the recurrent cancer. Of six patients that met the inclusion criteria, three cases were classified as "true" recurrences, i.e., the primary and the cancer in the remnant pancreas shared both morphological features and molecular alterations. Two cases were identified as having independent cancers that exhibited different histological and molecular profiles. In the remaining case, the relationship could not be determined. Pancreatic ductal adenocarcinoma that arises in the remnant pancreas can be either a second primary or a "true" relapse of the preceding primary. The differentiation of second primaries from local recurrences may have important implications for patient management. PMID- 30467322 TI - Air trapping in usual interstitial pneumonia pattern at CT: prevalence and prognosis. AB - This study was conducted to evaluate the presence of air trapping in patients with idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases (ILDs) (non-IPF), showing the radiological pattern of usual interstitial pneumonia (UIP). Retrospectively, we included 69 consecutive patients showing the typical UIP pattern on computed tomography (CT), and 15 final diagnosis of IPF with CT pattern "inconsistent with UIP" due to extensive air trapping. Air trapping at CT was assessed qualitatively by visual analysis and quantitatively by automated-software. In the quantitative analysis, significant air trapping was defined as >6% of voxels with attenuation between -950 to -856 HU on expiratory CT (expiratory air trapping index [ATIexp]) or an expiratory to inspiratory (E/I) ratio of mean lung density >0.87. The sample comprised 51 (60.7%) cases of IPF and 33 (39.3%) cases of non-IPF ILD. Most patients did not have air trapping (E/I ratio <=0.87, n = 53, [63.1%]; ATIexp <=6%, n = 45, [53.6%]). Air trapping in the upper lobes was the only variable distinguishing IPF from non-IPF ILD (prevalence, 3.9% vs 33.3%, p < 0.001). In conclusion, air trapping is common in patients with ILDs showing a UIP pattern on CT, as determined by qualitative and quantitative evaluation, and should not be considered to be inconsistent with UIP. On subjective visual assessment, air trapping in the upper lobes was associated with a non-IPF diagnoses. PMID- 30467324 TI - Grail attenuates influenza A virus infection and pathogenesis by inhibiting viral nucleoprotein. AB - Grail is a well-characterized mediator of metabolic disease, tumour progression, and immune response. However, its role in influenza A virus (IAV) infection remains poorly understood. In this study, we demonstrated that Grail knockdown potentiates IAV infection, whereas Grail overexpression blocks IAV replication. The intranasal administration of IAV to Grail KO mice led to a lower survival rate than in similarly infected wild-type mice. Additionally, IAV-infected Grail KO mice had higher viral titres, greater immune cell infiltration, and increased expression of inflammatory cytokines in the lungs. Mechanistically, we showed that Grail interacts with viral nucleoprotein (NP), targeting it for degradation and inhibiting IAV replication. NP expression was increased in Grail knockdown cells and reduced in cells overexpressing Grail. Collectively, our results demonstrate that Grail acts as a negative regulator of IAV infection and replication by degrading viral NP. These data increase our understanding of the host antiviral response to infection with IAV. PMID- 30467325 TI - BET Inhibition Improves NASH and Liver Fibrosis. AB - Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease with large unmet need. Non-alcoholic steatohepatitis (NASH), a progressive variant of NAFLD, can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. To identify potential new therapeutics for NASH, we used a computational approach based on Connectivity Map (CMAP) analysis, which pointed us to bromodomain and extra-terminal motif (BET) inhibitors for treating NASH. To experimentally validate this hypothesis, we tested a small-molecule inhibitor of the BET family of proteins, GSK1210151A (I-BET151), in the STAM mouse NASH model at two different dosing timepoints (onset of NASH and progression to fibrosis). I BET151 decreased the non-alcoholic fatty liver disease activity score (NAS), a clinical endpoint for assessing the severity of NASH, as well as progression of liver fibrosis and interferon-gamma expression. Transcriptional characterization of these mice through RNA-sequencing was consistent with predictions from the CMAP analysis of a human NASH signature and pointed to alterations in molecular mechanisms related to interferon signaling and cholesterol biosynthesis, as well as reversal of gene expression patterns linked to fibrotic markers. Altogether, these results suggest that inhibition of BET proteins may present a novel therapeutic opportunity in the treatment of NASH and liver fibrosis. PMID- 30467326 TI - Author Correction: Sexual homomorphism in dioecious trees: extensive tests fail to detect sexual dimorphism in Populus. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30467327 TI - Reflections on the early years of neonatology. William Oh: neonatal pioneer devoted his career to groundbreaking research, expanding patient care, and mentoring others. PMID- 30467328 TI - Correspondence: "Effect of early treatment with zoledronic acid on prevention of bone loss in patients with acute spinal cord injury: a randomized controlled trial". PMID- 30467329 TI - Epidemiology of cardiovascular disease in China: current features and implications. AB - Cardiovascular disease (CVD) is the leading cause of death in China. To develop effective and timely strategies to cope with the challenges of CVD epidemics, we need to understand the current epidemiological features of the major types of CVD and the implications of these features for the prevention and treatment of CVD. In this Review, we summarize eight important features of the epidemiology of CVD in China. Some features indicate a transition in CVD epidemiology owing to interrelated changes in demography, environment, lifestyle, and health care, including the rising burden from atherosclerotic CVD (ischaemic heart disease and ischaemic stroke), declining mortality from haemorrhage stroke, varied regional epidemiological trends in the subtypes of CVD, increasing numbers of patients with moderate types of ischaemic heart disease and ischaemic stroke, and increasing ageing of patients with CVD. Other features highlight the problems that need particular attention, including the high proportion of out-of-hospital death of patients with ischaemic heart disease with insufficient prehospital care; the wide gaps between guideline-recommended goals and levels of lifestyle indicators; and the huge number of patients with undiagnosed, untreated, or uncontrolled hypertension, hypercholesterolaemia, or diabetes mellitus. PMID- 30467331 TI - The cost of antimicrobial resistance. PMID- 30467330 TI - Author Correction: Comparison of DNA-, PMA-, and RNA-based 16S rRNA Illumina sequencing for detection of live bacteria in water. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30467332 TI - A villain turns good. PMID- 30467334 TI - Publisher Correction: Does Predictive coding have a future? AB - This News & Views article should have been marked as a Historical News & Views and the supertitle was incorrect. PMID- 30467333 TI - Visible light-promoted CO2 fixation with imines to synthesize diaryl alpha-amino acids. AB - Light-mediated transformations with CO2 have recently attracted great attention, with the focus on CO2 incorporation into C-C double and triple bonds, organohalides and amines. Herein is demonstrated visible light -mediated umpolung imine reactivity capable of engaging CO2 to afford alpha-amino acid derivatives. By employing benzophenone ketimine derivatives, CO2 fixation by hydrocarboxylation of C=N double bonds is achieved. Good to excellent yields of a broad range of alpha,alpha-disubstituted alpha-amino acid derivatives are obtained under mild conditions (rt, atmospheric pressure of CO2, visible light). A procedure that avoids tedious chromatographic purification and uses sustainable sunlight is developed to highlight the simplicity of this method. PMID- 30467336 TI - Evidence for 'critical slowing down' in seagrass: a stress gradient experiment at the southern limit of its range. AB - The theory of critical slowing down, i.e. the increasing recovery times of complex systems close to tipping points, has been proposed as an early warning signal for collapse. Empirical evidence for the reality of such warning signals is still rare in ecology. We studied this on Zostera noltii intertidal seagrass meadows at their southern range limit, the Banc d'Arguin, Mauritania. We analyse the environmental covariates of recovery rates using structural equation modelling (SEM), based on an experiment in which we assessed whether recovery after disturbances (i.e. seagrass & infauna removal) depends on stress intensity (increasing with elevation) and disturbance patch size (1 m2 vs. 9 m2). The SEM analyses revealed that higher biofilm density and sediment accretion best explained seagrass recovery rates. Experimental disturbances were followed by slow rates of recovery, regrowth occurring mainly in the coolest months of the year. Macrofauna recolonisation lagged behind seagrass recovery. Overall, the recovery rate was six times slower in the high intertidal zone than in the low zone. The large disturbances in the low zone recovered faster than the small ones in the high zone. This provides empirical evidence for critical slowing down with increasing desiccation stress in an intertidal seagrass system. PMID- 30467337 TI - Encryption and steganography of synthetic gene circuits. AB - Synthetic biologists use artificial gene circuits to control and engineer living cells. As engineered cells become increasingly commercialized, it will be desirable to protect the intellectual property contained in these circuits. Here, we introduce strategies to hide the design of synthetic gene circuits, making it more difficult for an unauthorized third party to determine circuit structure and function. We present two different approaches: the first uses encryption by overlapping uni-directional recombinase sites to scramble circuit topology and the second uses steganography by adding genes and interconnections to obscure circuit topology. We also discuss a third approach: to use synthetic genetic codes to mask the function of synthetic circuits. For each approach, we discuss relative strengths, weaknesses, and practicality of implementation, with the goal to inspire further research into this important and emerging area. PMID- 30467335 TI - Topical Analgesia with Lidocaine Plus Diclofenac Decreases Pain in Benign Anorectal Surgery: Randomized, Double-blind, and Controlled Clinical Trial. AB - OBJECTIVE: The aim of this study is to evaluate the efficacy and safety of a topical formulation containing lidocaine plus diclofenac (CLIFE1) compared to lidocaine (CLIFE2), to decrease pain in benign anorectal surgery (BARS) to date not evaluated. More than 50% of patients undergoing BARS, especially hemorrhoidectomy, suffer from moderate and severe postoperative pain. This remains an unresolved problem that could be addressed with the new CLIFE1 topical treatment. METHODS: A multicenter, randomized double-blind, active-controlled parallel-group superiority trial, was conducted in two Spanish hospitals. Patients undergoing BARS (hemorrhoids, anal fistula and anal fissure) were randomized at the end of surgery at a 1:1 ratio to receive first dose either CLIFE1 (n = 60) or CLIFE2 (n = 60) anorectal topical treatment, and after every 12 h for the first three postoperative days and once a day from the fourth to sixth. The primary outcome was average of pain decrease after topical treatment, measured with visual analogue scale (VAS) by the patients themselves, the evening in the surgery day and four times daily for the first three postoperative days. RESULTS: The results of 120 patients included out of 150 selected undergoing BARS show a decrease in pain after CLIFE1 topical treatment (7.47 +/- 13.09) greater than with CLIFE2 (4.38 +/- 6.75), difference -3.21 95% CI (-5.75; -0.68), p = 0.008, decreasing significantly postoperative pain ( >= 9 mm, VAS) in 35% of patients undergoing benign anorectal surgery, compared to 18.33 % treated with lidocaine. CONCLUSIONS: The CLIFE1 topical treatment shows better analgesic efficacy than CLIFE2 in BARS. PMID- 30467338 TI - Sex-dependent regulation of social reward by oxytocin receptors in the ventral tegmental area. AB - Social reward is critical for social relationships, and yet we know little about the characteristics of social interactions that are rewarding or the neural mechanisms underlying that reward. Here, we investigate the sex-dependent role of oxytocin receptors within the ventral tegmental area (VTA) in mediating the magnitude and valence of social reward. Operant and classical conditioning tests were used to measure social reward associated with same-sex social interactions. The effects of oxytocin, selective oxytocin receptor agonists, antagonists, and vehicle injected into the VTA on social reward was determined in male and female Syrian hamsters. The colocalization of FOS and oxytocin in sites that project to the VTA following social interaction was also determined. Females find same-sex social interactions more rewarding than males and activation of oxytocin receptors in the VTA is critical for social reward in females, as well as males. These studies provide support for the hypothesis that there is an inverted U relationship between the duration of social interaction and social reward, mediated by oxytocin; and that in females the dose-response relationship is initiated at lower doses compared with males. Same-sex social interaction is more rewarding in females than in males, and an inverted U relationship mediated by oxytocin may have a critical role in assigning positive and negative valence to social stimuli. Understanding these sex differences in social reward processing may be essential for understanding the sex differences in the prevalence of many psychiatric disorders and the development of gender-specific treatments of neuropsychiatric disorders. PMID- 30467340 TI - Arming oncolytic reovirus with GM-CSF gene to enhance immunity. AB - Oncolytic reovirus administration has been well tolerated by cancer patients in clinical trials. However, its anti-cancer efficacy as a monotherapy remains to be augmented. We and others have previously demonstrated the feasibility of producing replication-competent reoviruses expressing a heterologous transgene. Here, we describe the production of recombinant reoviruses expressing murine (mm) or human (hs) GM-CSF (rS1-mmGMCSF and rS1-hsGMCSF, respectively). The viruses could be propagated up to 10 passages while deletion mutants occurred only occasionally. In infected cell cultures, the secretion of GM-CSF protein (up to 481 ng/106 cells per day) was demonstrated by ELISA. The secreted mmGM-CSF protein was functional in cell culture, as demonstrated by the capacity to stimulate the survival and proliferation of the GM-CSF-dependent dendritic cell (DC) line D1, and by its ability to generate DCs from murine bone marrow cells. Importantly, in a murine model of pancreatic cancer we found a systemic increase in DC and T-cell activation upon intratumoral administration of rS1-mmGMCSF. These data demonstrate that reoviruses expressing functional GM-CSF can be generated and have the potential to enhance anti-tumor immune responses. The GM CSF reoviruses represent a promising new agent for use in oncolytic virotherapy strategies. PMID- 30467341 TI - Mitochondrial dysfunction causes hyperexcitability of serotonergic neurons. PMID- 30467342 TI - Genetic variation in CRHR1 is associated with short-term respiratory response to corticosteroids in preterm infants at risk for bronchopulmonary dysplasia. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) is an orphan disease and advances in prevention and treatment are lacking. The clinical efficacy of systemic corticosteroid therapy to reduce the severity of lung disease and BPD is highly variable. Our objective was to assess whether candidate SNPs in corticosteroid metabolism and response genes are associated with short-term phenotypic response to systemic corticosteroids in infants at high risk for BPD. METHODS: Pharmacogenetic analysis of data from a large randomized controlled trial (TOLSURF) in infants treated with dexamethasone or hydrocortisone using multivariate linear regression. The primary outcome was a change in respiratory severity score (RSS, mean airway pressure x FiO2) at day 7 of corticosteroid treatment. RESULTS: rs7225082 in the intron of CRHR1 is significantly associated with the magnitude of decrease in RSS 7 days after starting treatment with systemic corticosteroid (meta-analysis P = 2.8 * 10-4). Each T allele at rs7225082 is associated with a smaller absolute change in RSS at day 7, i.e., less response to systemic corticosteroids. CONCLUSION: Genetic variability is associated with corticosteroid responsiveness with regard to respiratory status in preterm infants. Identification of genetic markers of corticosteroid responsiveness may allow for therapeutic individualization, with the goal of optimizing the risk-to-benefit ratio for an individual child. PMID- 30467339 TI - Effects of Low Intensity Focused Ultrasound on Liposomes Containing Channel proteins. AB - The ability to reversibly and non-invasively modulate region-specific brain activity in vivo suggests Low Intensity Focused Ultrasound (LIFU) as potential therapeutics for neurological dysfunctions such as epilepsy and Parkinson's disease. While in vivo studies provide evidence of the bioeffects of LIFU on neuronal activity, they merely hint at potential mechanisms but do not fully explain how this technology achieves these effects. One potential hypothesis is that LIFU produces local membrane depolarization by mechanically perturbing the neuronal cell membrane, or activating channels or other proteins embedded in the membrane. Proteins that sense mechanical perturbations of the membrane, such as those gated by membrane tension, are prime candidates for activating in response to LIFU and thus leading to the neurological responses that have been measured. Here we use the bacterial mechanosensitive channel MscL, which has been purified and reconstituted in liposomes, to determine how LIFU may affect the activation of this membrane-tension gated channel. Two bacterial voltage-gated channels, KvAP and NaK2K F92A channels were also studied. Surprisingly, the results suggest that ultrasound modulation and membrane perturbation does not induce channel gating, but rather induces pore formation at the membrane protein-lipid interface. However, in vesicles with high MscL mechanosensitive channel concentrations, apparent decreases in pore formation are observed, suggesting that this membrane-tension-sensitive protein may serve to increase the elasticity of the membrane, presumably because of expansion of the channel in the plane of the membrane independent of channel gating. PMID- 30467343 TI - Differentiation of esophageal pH-impedance characteristics classified by the mucosal integrity marker in human neonates. AB - BACKGROUND: In adults, distal baseline impedance (BI) is a determinant of esophageal mucosal integrity with values <900 Omega indicating inflammation. Relationships between acid gastroesophageal reflux (GER) and BI in neonates are unclear. METHODS: NICU infants (N = 198, 30.4 +/- 0.3 weeks gestation) were evaluated at 43 +/- 0.4 weeks postmenstrual age using 24-h pH-impedance. Ten randomly selected 1-min windows during rest from the distal impedance channel (Z6) were averaged. Chi-square, t-tests, and ANOVA were used to compare pH impedance and symptom characteristics by BI severity (BI < 900 Omega, BI 900-2000 Omega, BI > 2000 Omega). Regression analysis was used to identify potential contributing factors of BI. RESULTS: In BI < 900 Omega: (1) pH-impedance characteristics were increased (acid reflux event frequency, duration, and severity, all P < 0.05 vs. BI > 2000 Omega), and (2) positive symptom correlations were noted with bolus (73%) and acid events (55%). Significant predictors of BI included chronological age, acid reflux index, and BPD diagnosis (all P < 0.05). CONCLUSIONS: Low BI is associated with prolonged acid exposure, delayed clearance, and greater aerodigestive symptom prevalence, likely associated with inflammation and or increased mucosal permeability. BI > 2000 Omega likely involves little or no inflammation because acid exposure is minimal. Combination of SAP, pH-impedance metrics, and BI along with the clarification of dysmotility mechanisms provides the rationale for personalized anti-reflux therapies as needed. PMID- 30467345 TI - A clinically useful MRI marker of PD? PMID- 30467344 TI - Differential cell proliferation and cell death during the urethral groove formation in guinea pig model. AB - BACKGROUND: Urethral groove (UG) formation is an important step in penile formation. Because commonly used animal models do not have UG, the mechanisms of UG formation have never been discovered. We aim to discover the cellular mechanism of the UG formation using guinea pig model. METHODS: Histology was used to study the ontogeny of UG. BrdU immunofluorescence was used to label proliferating cells, cell death was determined using LysoTracker Red and TUNEL staining, and stereology was used for quantification. To reveal Shh mRNA expression patterns, in situ hybridization was performed in guinea pig genital tubercles (GTs) and ShhGFPcre-LacZ-reporter mice were used for comparison. RESULTS: Cell proliferation in the outer layers and programmed cell death in the inner layers of urethral epithelium play key roles during urethral canal movement from dorsal to ventral aspect and final opening to form UG. Shh mRNA expression domain shifts out to the ventral surface of GT from proximal throughout to distal in guinea pigs, but was excluded from the ventral surface epithelium in midshaft and distal of mouse GT. CONCLUSION: Differential cell proliferation and cell death in developing urethral epithelium led to UG formation and Shh expression in ventral surface epithelium of GT may play an important role. PMID- 30467346 TI - Wavelength-optimized Two-Photon Polymerization Using Initiators Based on Multipolar Aminostyryl-1,3,5-triazines. AB - Two-photon induced polymerization (2PP) based 3D printing is a powerful microfabrication tool. Specialized two-photon initiators (2PIs) are critical components of the employed photosensitive polymerizable formulations. This work investigates the cooperative enhancement of two-photon absorption cross sections (sigma2PA) in a series of 1,3,5-triazine-derivatives bearing 1-3 aminostyryl donor arms, creating dipolar, quadrupolar and octupolar push-pull systems. The multipolar 2PIs were successfully prepared and characterized, sigma2PA were determined using z-scan at 800 nm as well as spectrally resolved two-photon excited fluorescence measurements, and the results were compared to high-level ab initio computations. Modern tunable femtosecond lasers allow 2PP-processing at optimum wavelengths tailored to the absorption behavior of the 2PI. 2PP structuring tests revealed that while performance at 800 nm is similar, at their respective sigma2PA-maxima the octupolar triazine-derivative outperforms a well established ketone-based quadrupolar reference 2PI, with significantly lower fabrication threshold at exceedingly high writing speeds up to 200 mm/s and a broader window for ideal processing parameters. PMID- 30467348 TI - Machine learning analysis of extreme events in optical fibre modulation instability. AB - A central research area in nonlinear science is the study of instabilities that drive extreme events. Unfortunately, techniques for measuring such phenomena often provide only partial characterisation. For example, real-time studies of instabilities in nonlinear optics frequently use only spectral data, limiting knowledge of associated temporal properties. Here, we show how machine learning can overcome this restriction to study time-domain properties of optical fibre modulation instability based only on spectral intensity measurements. Specifically, a supervised neural network is trained to correlate the spectral and temporal properties of modulation instability using simulations, and then applied to analyse high dynamic range experimental spectra to yield the probability distribution for the highest temporal peaks in the instability field. We also use unsupervised learning to classify noisy modulation instability spectra into subsets associated with distinct temporal dynamic structures. These results open novel perspectives in all systems exhibiting instability where direct time-domain observations are difficult. PMID- 30467347 TI - Deep-subwavelength control of acoustic waves in an ultra-compact metasurface lens. AB - Space-coiling acoustic metasurfaces have been largely exploited and shown their outstanding wave manipulation capacity. However, they are complex in realization and cannot directly manipulate acoustic near-fields by controlling the effective path length. Here, we propose a comprehensive paradigm for acoustic metasurfaces to extend the wave manipulations to both far- and near-fields and markedly reduce the implementation complexity with a simple structure, which consists of an array of deep-subwavelength-spaced slits perforated in a thin plate. A semi-analytical approach for such a design is established using a microscopic coupled-wave model, which reveals that the acoustic diffractive pattern at every slit exit is the sum of the initial transmission and the secondary scatterings of the coupled fields from other slits. For proof-of-concept, we examine two metasurface lenses for sound focusing within and beyond the diffraction limit. This work provides a feasible strategy for creating ultra-compact acoustic components with versatile potentials. PMID- 30467349 TI - Locally anchoring enzymes to tissues via extracellular glycan recognition. AB - Success of enzymes as drugs requires that they persist within target tissues over therapeutically effective time frames. Here we report a general strategy to anchor enzymes at injection sites via fusion to galectin-3 (G3), a carbohydrate binding protein. Fusing G3 to luciferase extended bioluminescence in subcutaneous tissue to ~7 days, whereas unmodified luciferase was undetectable within hours. Engineering G3-luciferase fusions to self-assemble into a trimeric architecture extended bioluminescence in subcutaneous tissue to 14 days, and intramuscularly to 3 days. The longer local half-life of the trimeric assembly was likely due to its higher carbohydrate-binding affinity compared to the monomeric fusion. G3 fusions and trimeric assemblies lacked extracellular signaling activity of wild type G3 and did not accumulate in blood after subcutaneous injection, suggesting low potential for deleterious off-site effects. G3-mediated anchoring to common tissue glycans is expected to be broadly applicable for improving local pharmacokinetics of various existing and emerging enzyme drugs. PMID- 30467351 TI - The association between fibromyalgia and female sexual dysfunction: a systematic review and meta-analysis of observational studies. AB - Female sexuality in patients with fibromyalgia has received little attention in the literature, and published data have mainly relied upon a small sample size with evident heterogeneity. Our aim was to pool the observational studies on the association between fibromyalgia and sexual dysfunction in female patients to reach a more comprehensive and reliable result. The literature search comprised of Pubmed-Medline, Cochrane, and Embase databases. The relevant studies that met the inclusion criteria were gathered and the pooled effect size was calculated. The standard mean difference of the global sexual function score as well as the sub-items scores were calculated using the random-effect size model. Sensitivity analysis was conducted. Publication bias was assessed using Funnel plots and Begg and Mazumdar rank correlation tests. The meta-analysis was conducted in accordance with the MOOSE guideline. The six selected studies contained 919 participants (ranging from 51 to 362). Of those, 578 were patients with fibromyalgia, and 341 were the controls. While four studies evaluated the sexual function using the female sexual function index (FSFI) questionnaire, two used changes in the sexual functioning questionnaire (CSFQ). Patients with fibromyalgia had a decreased total sexual function score [(-5.02 (-7.58 to 2.46), p < 0.0001; Q = 664.28; p-value for heterogeneity = p < 0.0001; I2 = 99.24%)]. All sexual response cycle domains including desire, arousal, orgasm, pain, lubrication, and satisfaction were found detrimental in patients with fibromyalgia compared with the healthy controls. For the sensitivity analysis, omitting any one of the six studies did not produce a significant difference in the original pooled summary effect size. Our meta-analysis provided a clear association between female sexual dysfunction and fibromyalgia, suggesting patients with fibromyalgia should be assessed regarding sexual health, although further, well designed longitudinal studies are needed to establish the causality between fibromyalgia and female sexual dysfunction. PMID- 30467350 TI - Neuroprotection by Heat Shock Factor-1 (HSF1) and Trimerization-Deficient Mutant Identifies Novel Alterations in Gene Expression. AB - Heat shock factor-1 (HSF1) protects neurons from death caused by the accumulation of misfolded proteins by stimulating the transcription of genes encoding heat shock proteins (HSPs). This stimulatory action depends on the association of trimeric HSF1 to sequences within HSP gene promoters. However, we recently described that HSF-AB, a mutant form of HSF1 that is incapable of either homo trimerization, association with HSP gene promoters, or stimulation of HSP expression, protects neurons just as efficiently as wild-type HSF1 suggesting an alternative neuroprotective mechanism that is activated by HSF1. To gain insight into the mechanism by which HSF1 and HSF1-AB protect neurons, we used RNA-Seq technology to identify transcriptional alterations induced by these proteins in either healthy cerebellar granule neurons (CGNs) or neurons primed to die. When HSF1 was ectopically-expressed in healthy neurons, 1,211 differentially expressed genes (DEGs) were identified with 1,075 being upregulated. When HSF1 was expressed in neurons primed to die, 393 genes were upregulated and 32 genes were downregulated. In sharp contrast, HSF1-AB altered expression of 13 genes in healthy neurons and only 6 genes in neurons under apoptotic conditions, suggesting that the neuroprotective effect of HSF1-AB may be mediated by a non transcriptional mechanism. We validated the altered expression of 15 genes by QPCR. Although other studies have conducted RNA-Seq analyses to identify HSF1 targets, our study performed using primary neurons has identified a number of novel targets that may play a special role in brain maintenance and function. PMID- 30467352 TI - The influence of surface chemistry on the kinetics and thermodynamics of bacterial adhesion. AB - This work is concerned with investigating the effect of substrate hydrophobicity and zeta potential on the dynamics and kinetics of the initial stages of bacterial adhesion. For this purpose, bacterial pathogens Staphylococcus aureus and Escherichia coli O157:H7 were inoculated on the substrates coated with thin thiol layers (i.e., 1-octanethiol, 1-decanethiol, 1-octadecanethiol, 16 mercaptohexadecanoic acid, and 2-aminoethanethiol hydrochloride) with varying hydrophobicity and surface potential. The time-resolved adhesion data revealed a transformation from an exponential dependence to a square root dependence on time upon changing the substrate from hydrophobic or hydrophilic with a negative zeta potential value to hydrophilic with a negative zeta potential for both pathogens. The dewetting of extracellular polymeric substances (EPS) produced by E. coli O157:H7 was more noticeable on hydrophobic substrates, compared to that of S. aureus, which is attributed to the more amphiphilic nature of staphylococcal EPS. The interplay between the timescale of EPS dewetting and the inverse of the adhesion rate constant modulated the distribution of E. coli O157:H7 within microcolonies and the resultant microcolonial morphology on hydrophobic substrates. Observed trends in the formation of bacterial monolayers rather than multilayers and microcolonies rather than isolated and evenly spaced bacterial cells could be explained by a colloidal model considering van der Waals and electrostatic double-layer interactions only after introducing the contribution of elastic energy due to adhesion-induced deformations at intercellular and substrate-cell interfaces. The gained knowledge is significant in the context of identifying surfaces with greater risk of bacterial contamination and guiding the development of novel surfaces and coatings with superior bacterial antifouling characteristics. PMID- 30467354 TI - A novel homozygous mutation of the TFG gene in a patient with early onset spastic paraplegia and later onset sensorimotor polyneuropathy. AB - The tropomyosin-receptor kinase fused gene (TFG) has recently been implicated in several distinct hereditary disorders, including the autosomal-recessive form of complicated hereditary spastic paraplegia called SPG57. Previously, three homozygous variants of the TFG gene were reported in five families with SPG57, in which early onset spastic paraplegia, optic atrophy, and peripheral neuropathy were variably identified. Here, we present the first Japanese patient with SPG57, and have added a homozygous p.Ile66Thr variant as the fourth SPG57 genotype. PMID- 30467353 TI - Nezara viridula (Hemiptera: Pentatomidae) transcriptomic analysis and neuropeptidomics. AB - Stinkbugs (Hemiptera: Pentatomidae) are of major economic importance as pest of crops. Among the species composing the stinkbug complex, Nezara viridula is one of the most abundant in Brazil, Argentina and the Southern USA. However, this species has been poorly characterized at the genetic and physiological level. Here we sequenced and analyzed the complete transcriptome of N. viridula male and female adults. We identified neuropeptide precursor genes and G-protein coupled receptors for neuropeptides in this transcriptome. Mature neuropeptides were identified in N. viridula brain extracts by liquid chromatography-tandem mass spectrometry. We also analyzed the neuropeptide precursor complement in the genome sequence of Halyomorpha halys, another pentatomid of economic relevance. We compared the results in both pentatomids with the well-characterized neuropeptide repertoire from the kissing bug Rhodnius prolixus (Hemiptera: Reduviidae). We identified both group-specific features (which could be related to the different feeding habits) and similarities that could be characteristic of Heteroptera. This work contributes to a deeper knowledge of the genetic information of these pests, with a focus on neuroendocrine system characterization. PMID- 30467355 TI - Effects of Dynamic Perturbation-Based Training on Balance Control of Community Dwelling Older Adults. AB - Walking is one of the daily activities that may cause falling in older adults. We developed a novel dynamic balance training program using a perturbation-based training on a custom-made treadmill, which can generate forward, backward, and lateral sway perturbations during walking. The purpose of this study was to investigate the changes in the balance performance of community-dwelling older adults after 8-weeks of perturbation-based balance training. A three-dimensional motion analysis system was used to collect kinematic and kinetic data. Seventeen community-dwelling older adults performed quiet standing with and without the balance perturbation. Biomechanical parameters such as center of pressure (COP) and center of mass (COM) were calculated. A paired t-test was used to compare the difference in balance performance before and after the training. After training, the results showed that the COM control of the older adults was significantly improved during quiet standing with perturbation, while the COP control during quiet standing without perturbation was not changed. The perturbation-based balance training exerted a positive effect on dynamic balance control in older adults. This translational research offers a new paradigm of balance training and can be applied to patient populations who have a high risk of falling. PMID- 30467356 TI - Alleles of a gene differ in pleiotropy, often mediated through currency metabolite production, in E. coli and yeast metabolic simulations. AB - A major obstacle to the mapping of genotype-phenotype relationships is pleiotropy, the tendency of mutations to affect seemingly unrelated traits. Pleiotropy has major implications for evolution, development, ageing, and disease. Except for disease data, pleiotropy is almost exclusively estimated from full gene knockouts. However, most deleterious alleles segregating in natural populations do not fully abolish gene function, and the degree to which a polymorphism reduces protein function may influence the number of traits it affects. Utilizing genome-scale metabolic models for Escherichia coli and Saccharomyces cerevisiae, we show that most fitness-reducing full gene knockouts of metabolic genes in these fast-growing microbes have pleiotropic effects, i.e., they compromise the production of multiple biomass components. Alleles of the same metabolic enzyme-encoding gene with increasingly reduced enzymatic function typically affect an increasing number of biomass components. This increasing pleiotropy is often mediated through effects on the generation of currency metabolites such as ATP or NADPH. We conclude that the physiological effects observed in full gene knockouts of metabolic genes will in most cases not be representative for alleles with only partially reduced enzyme capacity or expression level. PMID- 30467357 TI - Redirecting Primary Metabolism to Boost Production of Tyrosine-Derived Specialised Metabolites in Planta. AB - L-Tyrosine-derived specialized metabolites perform many important functions in plants, and have valuable applications in human health and nutrition. A necessary step in the overproduction of specialised tyrosine-derived metabolites in planta is the manipulation of primary metabolism to enhance the availability of tyrosine. Here, we utilise a naturally occurring de-regulated isoform of the key enzyme, arogenate dehydrogenase, to re-engineer the interface of primary and specialised metabolism, to boost the production of tyrosine-derived pigments in a heterologous plant host. Through manipulation of tyrosine availability, we report a 7-fold increase in the production of tyrosine-derived betalain pigments, with an upper range of 855 mg.kg-1.FW, which compare favourably to many in vitro and commercial sources of betalain pigments. Since the most common plant pathway for tyrosine synthesis occurs via arogenate, the de-regulated arogenate dehydrogenase isoform is a promising route for enhanced production of tyrosine-derived pharmaceuticals in diverse plant hosts. PMID- 30467358 TI - Liquid-crystalline half-Skyrmion lattice spotted by Kossel diagrams. AB - Skyrmions are swirl-like topological entities that have been shown to emerge in various condensed matter systems. Their identification has been carried out in different ways including scattering techniques and real-space observations. Here we show that Kossel diagrams can identify the formation of a hexagonal lattice of half-Skyrmions in a thin film of a chiral liquid crystal, in which case Kossel lines appear as hexagonally arranged circular arcs. Our experimental observations on a hexagonal lattice of half-Skyrmions and other defect structures resembling that of a bulk cholesteric blue phase are perfectly accounted for by numerical calculations and a theoretical argument attributing strong reflections yielding Kossel lines to guided mode resonances in the thin liquid crystal film. Our study demonstrates that a liquid crystal is a model system allowing the investigation of topological entities by various optical means, and also that Kossel techniques are applicable to the investigation of thin systems with non-trivial photonic band structures including topologically protected optical surface states. PMID- 30467361 TI - Neonatal abstinence syndrome. PMID- 30467359 TI - Identifying the region responsible for Brucella abortus MucR higher-order oligomer formation and examining its role in gene regulation. AB - MucR is a member of the Ros/MucR family of prokaryotic zinc-finger proteins found in the alpha-proteobacteria which regulate the expression of genes required for the successful pathogenic and symbiotic interactions of these bacteria with the eukaryotic hosts. The structure and function of their distinctive zinc-finger domain has been well-studied, but only recently the quaternary structure of the full length proteins was investigated demonstrating their ability to form higher order oligomers. The aim of this study was to identify the region of MucR involved in higher-order oligomer formation by analysing deletion and point mutants of this protein by Light Scattering, and to determine the role that MucR oligomerization plays in the regulatory function of this protein. Here we demonstrate that a conserved hydrophobic region at the N-terminus of MucR is responsible for higher-order oligomer formation and that MucR oligomerization is essential for its regulatory function in Brucella. All these features of MucR are shared by the histone-like nucleoid structuring protein, (H-NS), leading us to propose that the prokaryotic zinc-finger proteins in the MucR/Ros family control gene expression employing a mechanism similar to that used by the H-NS proteins, rather than working as classical transcriptional regulators. PMID- 30467360 TI - Publisher Correction: Sensory attenuation in Parkinson's disease is related to disease severity and dopamine dose. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30467362 TI - The association between spirituality and religiousness and mental health. AB - The present study aims to investigate how different levels of spirituality and religiousness (high spirituality and high religiousness -S/R, high spirituality and low religiousness -S/r, low spirituality and high religiousness s/R and low spirituality and low religiousness - s/r) are associated with quality of life, depressive symptoms, anxiety, optimism and happiness among adults. A cross sectional study was carried out among 1,046 Brazilian adults. Concerning the different levels of spirituality and religiousness, 49.2% had s/r, 26.5% S/R, 17.2% S/r and 7.1% s/R. Participants with S/R had better outcomes as compared to those with s/r and those with S/r in WHOQOL Psychological, Social Relationship and Environment, Optimism and happiness. Participants with s/R had better outcomes as compared to those with s/r in WHOQOL Psychological and Social Relationship, Optimism and happiness. Participants with S/r were different from those with s/r, with higher levels of WHOQOL Environment and happiness but also anxiety. The results revealed that, having higher levels of both spirituality and religiousness were more correlated to better outcomes than having just one of them or none of them. Likewise, having higher levels of religiousness in detriment of higher levels of spirituality was also associated with better outcomes in comparison to others. PMID- 30467363 TI - Six years of grazing exclusion is the optimum duration in the alpine meadow steppe of the north-eastern Qinghai-Tibetan Plateau. AB - Grazing exclusion is an effective management strategy for restoring degraded grasslands worldwide, but the effects of different exclusion durations on vegetation structure and soil properties remain unclear. Therefore, we evaluated vegetation characteristics and soil properties in an alpine meadow-steppe under grazing exclusion of different lengths (with grazing and with 3-year, 6-year, 9 year and 11-year grazing exclusions) on the Qinghai-Tibetan Plateau (QTP). We also explored the relationships among above-ground biomass, biodiversity and soil properties to ascertain the mechanism underlying the impact of grazing exclusion on these factors. The results showed that the above- and below-ground biomass, total number of plant species, community density, Shannon-Wiener diversity index, evenness index, richness index, soil and vegetation carbon (C) and nitrogen (N) storage and ecosystem C and N storage exhibited a hump-shaped pattern in response to the length of grazing exclusion with a 6-year threshold. In addition, structural equation modelling showed that the bulk density, soil moisture content, micro sand content and clay and silt contents were the most important determining factors leading to an increase in above-ground biomass in the alpine meadow-steppe after grazing exclusion, whereas the soil total N, available N, available phosphate and soil organic C content were the most important determining factors leading to a decrease in biodiversity. Considering the stability of the plant community and the C and N pools, long-term grazing exclusion (>9 years) is unnecessary, and the optimum exclosure duration of the moderately degraded Elymus nutans - Kobresia humilis type alpine meadow-steppe is six years on the north-eastern QTP. PMID- 30467364 TI - Proximity-induced supercurrent through topological insulator based nanowires for quantum computation studies. AB - Proximity-induced superconducting energy gap in the surface states of topological insulators has been predicted to host the much wanted Majorana fermions for fault tolerant quantum computation. Recent theoretically proposed architectures for topological quantum computation via Majoranas are based on large networks of Kitaev's one-dimensional quantum wires, which pose a huge experimental challenge in terms of scalability of the current single nanowire based devices. Here, we address this problem by realizing robust superconductivity in junctions of fabricated topological insulator (Bi2Se3) nanowires proximity-coupled to conventional s-wave superconducting (W) electrodes. Milling technique possesses great potential in fabrication of any desired shapes and structures at nanoscale level, and therefore can be effectively utilized to scale-up the existing single nanowire based design into nanowire based network architectures. We demonstrate the dominant role of ballistic topological surface states in propagating the long range proximity induced superconducting order with high IcRN product in long Bi2Se3 junctions. Large upper critical magnetic fields exceeding the Chandrasekhar-Clogston limit suggests the existence of robust superconducting order with spin-triplet cooper pairing. An unconventional inverse dependence of IcRN product on the width of the nanowire junction was also observed. PMID- 30467366 TI - Author Correction: Single molecule localisation microscopy reveals how HIV-1 Gag proteins sense membrane virus assembly sites in living host CD4 T cells. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30467365 TI - A high-density genetic linkage map and QTL mapping for growth and sex of yellow drum (Nibea albiflora). AB - A high-density genetic linkage map is essential for the studies of comparative genomics and gene mapping, and can facilitate assembly of reference genome. Herein, we constructed a high-density genetic linkage map with 8,094 SNPs selected from 113 sequenced fish of a F1 family. Ultimately, the consensus map spanned 3818.24 cM and covered nearly the whole genome (99.4%) with a resolution of 0.47 cM. 1,457 scaffolds spanning 435.15 Mb were anchored onto 24 linkage groups, accounting for 80.7% of the draft genome assembly of the yellow drum. Comparative genomic analyses with medaka and zebrafish genomes showed superb chromosome-scale synteny between yellow drum and medaka. QTL mapping and association analysis congruously revealed 22 QTLs for growth-related traits and 13 QTLs for sex dimorphism. Some important candidate genes such as PLA2G4A, BRINP3 and P2RY1 were identified from these growth-related QTL regions. A gene family including DMRT1, DMRT2 and DMRT3 was identified from these sex-related QTL regions on the linkage group LG9. We demonstrate that this linkage map can facilitate the ongoing marker-assisted selection and genomic and genetic studies for yellow drum. PMID- 30467367 TI - Publisher Correction: Regional disparities in warm season rainfall changes over arid eastern-central Asia. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30467369 TI - CARD-BCL-10-MALT1 signalling in protective and pathological immunity. AB - CARD protein-BCL-10-MALT1 (CBM) signalosomes are multiprotein signalling platforms that control immune and inflammatory pathways in most tissues. After exposure to distinct immune triggers, these molecules form self-organizing filaments with MALT1 protease activity to regulate canonical nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) signalling pathways and the degradation of mRNA-binding proteins, which provides two layers of control of inflammatory gene expression. These CBM-regulated mechanisms are essential for host defence and tissue homeostasis, and numerous genetic alterations in CBM signalling components have been implicated in inherited and acquired immune-mediated diseases. This Review discusses the regulation and signalling of CBM complexes, their physiological roles and their pathophysiological functions in human immunodeficiency diseases, inflammatory disorders and cancers of the immune system. PMID- 30467370 TI - Neonatal abstinence syndrome. AB - Neonatal abstinence syndrome refers to the signs and symptoms attributed to the cessation of prenatal exposure (via placental transfer) to various substances. This Primer focuses on neonatal abstinence syndrome caused by opioid use during pregnancy - neonatal opioid withdrawal syndrome (NOWS). As the global prevalence of opioid use has alarmingly increased, so has the incidence of NOWS. NOWS can manifest with varying severity or not at all, for unknown reasons, but is likely to be associated with multiple factors, both maternal (for example, smoking and additional substance exposures) and neonatal (gestational age, sex and genetics). Care for the infant with NOWS begins with addressing the issues experienced by pregnant women with opioid use disorder. Co-occurring mental illness, economic hardship, intimate partner violence, infectious diseases and limited access to care are common in these women and can result in poor maternal and neonatal outcomes. Although there is no consensus regarding optimal NOWS management, non pharmacological interventions (such as breastfeeding and rooming-in of the mother and the baby) have become a priority, as they can ameliorate symptoms without the need for further opioid exposure. Untreated NOWS can be associated with morbidity in early infancy, and the long-term consequences of fetal opioid exposure are only beginning to be understood. PMID- 30467368 TI - A link between plasma membrane calcium ATPase 2 (PMCA2), estrogen and estrogen receptor alpha signaling in mechanical pain. AB - Earlier studies on genetically modified mice indicated that plasma membrane calcium ATPase 2 (PMCA2), a calcium extrusion pump, plays a novel and sex dependent role in mechanical pain responses: female, but not male, PMCA2+/- mice manifest increased mechanical pain compared to female PMCA2+/+ mice. The goal of the present studies was to determine the contribution of ovarian steroids to the genotype- and sex-dependent manifestation of mechanical pain in PMCA2+/+ versus PMCA2+/- mice. Ovariectomy increased mechanical pain sensitivity and 17beta estradiol (E2) replacement restored it to basal levels in PMCA2+/+ mice, but not in PMCA2+/- littermates. Intrathecal administration of an estrogen receptor alpha (ERalpha) agonist induced ERalpha signaling in the dorsal horn (DH) of female PMCA2+/+ mice, but was ineffective in PMCA2+/- mice. In male PMCA2+/+ and PMCA2+/ mice, E2 treatment following orchidectomy did not recapitulate the genotype dependent differential pain responses observed in females and the agonist did not elicit ERalpha signaling. These findings establish a novel, female-specific link between PMCA2, ERalpha and mechanical pain. It is postulated that PMCA2 is essential for adequate ERalpha signaling in the female DH and that impaired ERalpha signaling in the female PMCA2+/- mice hinders the analgesic effects of E2 leading to increased sensitivity to mechanical stimuli. PMID- 30467372 TI - Author Correction: Multiple sclerosis. AB - In the originally published version of this article, in Table 4, Ocrelizumab was incorrectly referred to as an anti-CD25 antibody. This has been corrected in the HTML and PDF versions of the article to an anti-CD20 antibody. PMID- 30467373 TI - Immunotherapy for lethal prostate cancer. PMID- 30467371 TI - Seabird-affected taluses are denitrification hotspots and potential N2O emitters in the High Arctic. AB - In High Arctic tundra ecosystems, seabird colonies create nitrogen cycling hotspots because of bird-derived labile organic matter. However, knowledge about the nitrogen cycle in such ornithocoprophilous tundra is limited. Here, we determined denitrification potentials and in-situ nitrous oxide (N2O) emissions of surface soils on plant-covered taluses under piscivorous seabird cliffs at two sites (BL and ST) near Ny-Alesund, Svalbard, in the European High Arctic. Talus soils at both locations had very high denitrification potentials at 10 degrees C (2.62-4.88 mg N kg-1 dry soil h-1), near the mean daily maximum air temperature in July in Ny-Alesund, with positive temperature responses at 20 degrees C (Q10 values, 1.6-2.3). The talus soils contained abundant denitrification genes, suggesting that they are denitrification hotspots. However, high in-situ N2O emissions, indicating the presence of both active aerobic nitrification and anaerobic denitrification, were observed only at BL (max. 16.6 ug N m-2 h-1). Rapid nitrogen turnover at BL was supported by lower carbon-to-nitrogen ratios, higher nitrate content, and higher delta15N values in the soils at BL compared with those at ST. These are attributed to the 30-fold larger seabird density at BL than at ST, providing the larger organic matter input. PMID- 30467375 TI - Association Between Serum Aluminum Level and Uremic Pruritus in Hemodialysis Patients. AB - Uremic pruritus (UP) is a common symptom in patients undergoing hemodialysis (HD). The pathogenesis of UP is complex. Aluminum (Al) is a common metal and is toxic to patients undergoing HD. Al is also a known human allergen which can induce immune reactions. However, the correlation between Al and UP remains unclear in dialysis patients. A total of 866 patients on maintenance HD were enrolled for analysis. The HD patients with higher serum Al levels had higher a prevalence of UP than those with lower serum Al levels. After adjusting for confounding variables, the serum Al level was significantly associated with UP. Overall, each 10-fold increase in serum Al level was associated with a 5.64-fold increase in the risk of developing UP in these subjects. The results of this cross-sectional study suggest that serum Al level may be associated with the development of UP in patients on maintenance HD. PMID- 30467374 TI - Pivotal role of bZIPs in amylose biosynthesis by genome survey and transcriptome analysis in wheat (Triticum aestivum L.) mutants. AB - Starch makes up 70% of the wheat grain, and is an important source of calories for humans, however, the overconsumption of wheat starch may contribute to nutrition-associated health problems. The challenge is to develop resistant starch including high amylose wheat varieties with health benefits. Adapting advance genomic approaches in EMS-induced mutant lines differing in amylose content, basic leucine zipper (bZIP) regulatory factors that may play role in controlling amylose biosynthesis were identified in wheat. bZIP transcription factors are key regulators of starch biosynthesis genes in rice and maize, but their role in regulating these genes in wheat is poorly understood. A genome-wide survey identified 370 wheat bZIPs, clustered in 11 groups, showing variations in amino acids composition and predicted physicochemical properties. Three approaches namely, whole transcriptome sequencing, qRT-PCR, and correlation analysis in contrasting high and low amylose mutants and their parent line identified 24 candidate bZIP (positive and negative regulators), suggesting bZIPs role in high amylose biosynthesis. bZIPs positive role in high amylose biosynthesis is not known. In silico interactome studies of candidate wheat bZIP homologs in Arabidopsis and rice identified their putative functional role. The identified bZIPs are involved in stress-related pathways, flower and seed development, and starch biosynthesis. An in-depth analysis of molecular mechanism of novel candidate bZIPs may help in raising and improving high amylose wheat varieties. PMID- 30467376 TI - Genetic variation is associated with PTSD risk and aversive memory: Evidence from two trauma-Exposed African samples and one healthy European sample. AB - The probability to develop posttraumatic stress disorder (PTSD), characterized by vivid, intrusive emotional memories of the encountered traumatic events, depends among other factors - on the number of previous traumatic experiences (traumatic load) and individual genetic vulnerability. So far, our knowledge regarding the biological underpinnings of PTSD is relatively sparse. Genome-wide association studies (GWAS) followed by independent replication might help to discover novel, so far unknown biological mechanisms associated with the development of traumatic memories. Here, a GWAS was conducted in N = 924 Northern Ugandan rebel war survivors and identified seven suggestively significant single nucleotide polymorphisms (SNPs; p <= 1 * 10-5) for lifetime PTSD risk. Of these seven SNPs, the association of rs3852144 on chromosome 5 was replicated in an independent sample of Rwandan genocide survivors (N = 370, p < .01). While PTSD risk increased with accumulating traumatic experiences, the vulnerability was reduced in carriers of the minor G-allele in an additive manner. Correspondingly, memory for aversive pictures decreased with higher number of the minor G-allele in a sample of N = 2698 healthy Swiss individuals. Finally, investigations on N = 90 PTSD patients treated with Narrative Exposure Therapy indicated an additive effect of genotype on PTSD symptom change from pre-treatment to four months after treatment, but not between pre-treatment and the 10-months follow-up. In conclusion, emotional memory formation seems to decline with increasing number of rs3852144 G-alleles, rendering individuals more resilient to PTSD development. However, the impact on therapy outcome remains preliminary and further research is needed to determine how this intronic marker may affect memory processes in detail. PMID- 30467378 TI - Conditional knockout of SHP2 in ErbB2 transgenic mice or inhibition in HER2 amplified breast cancer cell lines blocks oncogene expression and tumorigenesis. AB - Overexpression of the human epidermal growth factor receptor 2 (HER2) is the cause of HER2-positive breast cancer (BC). Although HER2-inactivating therapies have benefited BC patients, development of resistance and disease recurrence have been the major clinical problems, pointing to a need for alternative therapeutic strategies. For that to happen, proteins that play critical roles in the biology of HER2-induced tumorigenesis have to be identified and characterized. Here, we show that the Src homology phosphotyrosyl phosphatase 2 (Shp2) encoded by the Ptpn11 gene is a requisite for ErbB2-induced tumorigenesis. We report that conditional knockout of Shp2 alleles in the ErbB2 BC model mice abrogates mammary tumorigenesis by blocking the expression of the ErbB2 transgene. We also show that inhibition of SHP2 encoded by the PTPN11 gene in the HER2-amplified BC cells induces a normal-like cellular phenotype and suppresses tumorigenesis and metastasis by blocking HER2 overexpression. These findings demonstrate that ErbB2 induced tumors in mice or xenograft tumors induced by transplantation of HER2 amplified BC cells are vulnerable to SHP2 inhibition since it abrogates the expression of the very oncogene that causes of the disease. This report paves the way for developing SHP2-targeting therapies for BC treatment in the future. PMID- 30467377 TI - Mutation landscape in patients with myelofibrosis receiving ruxolitinib or hydroxyurea. AB - Refractoriness to ruxolitinib in patients with myelofibrosis (MF) was associated with clonal evolution; however, whether genetic instability is promoted by ruxolitinib remains unsettled. We evaluated the mutation landscape in 71 MF patients receiving ruxolitinib (n = 46) and hydroxyurea (n = 25) and correlated with response. A spleen volume response (SVR) was obtained in 57% and 12%, respectively. Highly heterogenous patterns of mutation acquisition/loss and/or changes of variant allele frequency (VAF) were observed in the 2 patient groups without remarkable differences. In patients receiving ruxolitinib, driver mutation type and high-molecular risk profile (HMR) at baseline did not impact on response rate, while HMR and sole ASXL1 mutations predicted for SVR loss at 3 years. In patients with SVR, a decrease of >= 20% of JAK2V617F VAF predicted for SVR duration. VAF increase of non-driver mutations and clonal progression at follow-up correlated with SVR loss and treatment discontinuation, and clonal progression also predicted for shorter survival. These data indicate that (i) ruxolitinib does not appreciably promote clonal evolution compared with hydroxyurea, (ii) VAF increase of pre-existing and/or (ii) acquisition of new mutations while on treatment correlated with higher rate of discontinuation and/or death, and (iv) reduction of JAK2V617F VAF associated with SVR duration. PMID- 30467379 TI - Loss of Par3 promotes prostatic tumorigenesis by enhancing cell growth and changing cell division modes. AB - Although cell polarity plays an important role in epithelial tumorigenesis, the consequence of polarity protein loss in prostatic tumorigenesis and the underlying mechanisms remain unclear. Using conditional knockout mouse models, we found in the current study that loss of polarity protein Par3 increases prostatic epithelial cell growth, elevates symmetrical cell divisions in basal cells, and randomizes spindle orientation in luminal cells, causing the development of high grade prostatic intraepithelial neoplasia (PIN). Mechanistically, loss of Par3 dissociates the Par3/merlin/Lats1 complex, consequently inhibiting phosphorylation of Lats1 to attenuate the Hippo pathway. Furthermore, attenuated Hippo pathway enhances nuclear translocation of Yes-associated protein (YAP), which promotes cell proliferation and symmetrical cell divisions through transcriptional activation of Ki-67 and Sox2. In addition, Lats1 dephosphorylation impairs its interaction with G protein signaling modulator 2 (GPSM2, which is also known as LGN) that causes randomization of spindle orientation in luminal cells. Interestingly, co-deletion of Par3 and Lats1 for complete blockade of the Hippo pathway in mice results in prostate tumor initiation, whereas co-deletion of Par3 and YAP for disrupting YAP nuclear translocation reverses the phenotypes to a relatively normal state. Therefore, our findings highlight combination of Par3 loss and blockade of the Hippo pathway as a novel mechanism for prostatic tumorigenesis. PMID- 30467380 TI - The lncRNA BORG facilitates the survival and chemoresistance of triple-negative breast cancers. AB - Disseminated breast cancer cells employ adaptive molecular responses following cytotoxic therapeutic insult which promotes their survival and subsequent outgrowth. Here we demonstrate that expression of the pro-metastatic lncRNA BORG (BMP/OP-Responsive Gene) is greatly induced within triple-negative breast cancer (TNBC) cells subjected to environmental and chemotherapeutic stresses commonly faced by TNBC cells throughout the metastatic cascade. This stress-mediated induction of BORG expression fosters the survival of TNBC cells and renders them resistant to the cytotoxic effects of doxorubicin both in vitro and in vivo. The chemoresistant traits of BORG depend upon its robust activation of the NF-kappaB signaling axis via a novel BORG-mediated feed-forward signaling loop, and via its ability to bind and activate RPA1. Indeed, genetic and pharmacologic inhibition of NF-kappaB signaling or the DNA-binding activity of RPA1 abrogates the pro survival features of BORG and renders BORG-expressing TNBCs sensitive to doxorubicin-induced cytotoxicity. These findings suggest that therapeutic targeting of BORG or its downstream molecular effectors may provide a novel means to alleviate TNBC recurrence. PMID- 30467381 TI - Mutant Kras-induced upregulation of CD24 enhances prostate cancer stemness and bone metastasis. AB - Prostate cancer (PCA), one of the most common malignant tumors in men, is the second leading cause of cancer deaths in males worldwide. We report here that PCA models harboring conditional LSL/KrasG12D or BRAFF-V600E allele with prostate specific abrogated p53 function recapitulate human PCA precursor lesions, histopathology, and clinical behaviors. We found that the development of reprogrammed EMT-like phenotypes and skeleton metastatic behavior requires concurrent activated Kras and p53 depletion in PCA. Microarray analyses of primary PCA cells derived from these models identified several cancer stemness genes including CD24, EpCAM, and CD133 upregulated by KRASG12D. Among these stemness markers, we identified CD24 as a key driver of tumorigenesis and metastasis in vivo. These data demonstrate that specific factors involved in cancer stemness are critical for metastatic conversion of PCA and may be ideal targets for therapeutic intervention. PMID- 30467382 TI - Evaluation of optic nerve head blood flow in response to increase of intraocular pressure. AB - The time course of the changes in the optic nerve head (ONH) blood flow in response to changes in the ocular perfusion pressure (OPP) induced by an artificial elevation of the intraocular pressure (IOP) has not been determined. We measured the blood flow, represented by the mean blur rate (MBR), on the ONH determined by laser speckle flowgraphy. The MBR was determined before, during, and after the IOP was elevated by 20 or 30 mmHg by pressure applied on the eye by an ophthalmodynamometer in a total of 27 healthy eyes. For an IOP elevation of 20 mmHg, the percentage reduction in the MBR-vessel was -24.7%, and in the MBR tissue was -16.0% (P < 0.001). For an IOP elevation of 30 mmHg, the percentage reduction of the MBR-vessel was -35.3% and the MBR-tissue was -24.7% (P < 0.001). During the 30 mmHg IOP elevation for 10 minutes, both the MBR-vessel and MBR tissue began returning to the baseline level from 1 minute after the beginning of the IOP elevation (P < 0.01, P < 0.05, respectively) and continued returning during the 10 minutes IOP elevation (P < 0.001, P < 0.01, respectively). We conclude that the ONH can autoregulate its blood flow in response to experimental changes in OPP induced by IOP elevations. PMID- 30467383 TI - An oviduct-on-a-chip provides an enhanced in vitro environment for zygote genome reprogramming. AB - Worldwide over 5 million children have been conceived using assisted reproductive technology, and research has concentrated on increasing the likelihood of ongoing pregnancy. However, studies using animal models have indicated undesirable effects of in vitro embryo culture on offspring development and health. In vivo, the oviduct hosts a period in which the early embryo undergoes complete reprogramming of its (epi)genome in preparation for the reacquisition of (epi)genetic marks. We designed an oviduct-on-a-chip platform to better investigate the mechanisms related to (epi)genetic reprogramming and the degree to which they differ between in vitro and in vivo embryos. The device supports more physiological (in vivo-like) zygote genetic reprogramming than conventional IVF. This approach will be instrumental in identifying and investigating factors critical to fertilization and pre-implantation development, which could improve the quality and (epi)genetic integrity of IVF zygotes with likely relevance for early embryonic and later fetal development. PMID- 30467385 TI - Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. AB - Apoptosis is crucial for the normal development of the nervous system, whereas neurons in the adult CNS are relatively resistant to this form of cell death. However, under pathological conditions, upregulation of death receptor family ligands, such as tumour necrosis factor (TNF), can sensitize cells in the CNS to apoptosis and a form of regulated necrotic cell death known as necroptosis that is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL). Necroptosis promotes further cell death and neuroinflammation in the pathogenesis of several neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease and Alzheimer disease. In this Review, we outline the evidence implicating necroptosis in these neurological diseases and suggest that targeting RIPK1 might help to inhibit multiple cell death pathways and ameliorate neuroinflammation. PMID- 30467384 TI - Arabidopsis thaliana DGAT3 is a [2Fe-2S] protein involved in TAG biosynthesis. AB - Acyl-CoA:diacylglycerol acyltransferases 3 (DGAT3) are described as plant cytosolic enzymes synthesizing triacylglycerol. Their protein sequences exhibit a thioredoxin-like ferredoxin domain typical of a class of ferredoxins harboring a [2Fe-2S] cluster. The Arabidopsis thaliana DGAT3 (AtDGAT3; At1g48300) protein is detected in germinating seeds. The recombinant purified protein produced from Escherichia coli, although very unstable, exhibits DGAT activity in vitro. A shorter protein version devoid of its N-terminal putative chloroplast transit peptide, Delta46AtDGAT3, was more stable in vitro, allowing biochemical and spectroscopic characterization. The results obtained demonstrate the presence of a [2Fe-2S] cluster in the protein. To date, AtDGAT3 is the first metalloprotein described as a DGAT. PMID- 30467387 TI - Free fatty acids clog up cytotoxic machinery. PMID- 30467386 TI - Analysis of regulator of G-protein signalling 2 (RGS2) expression and function during prostate cancer progression. AB - Prostate cancer (PC) represents the second highest cancer-related mortality among men and the call for biomarkers for early discrimination between aggressive and indolent forms is essential. Downregulation of Regulator of G-protein signaling 2 (RGS2) has been shown in PC, however the underlying mechanism has not been described. Aberrant RGS2 expression has also been reported for other carcinomas in association to both positive and negative prognosis. In this study, we assessed RGS2 expression during PC progression in terms of regulation and impact on tumour phenotype and evaluated its prognostic value. Our experimental data suggest that the RGS2 downregulation seen in early PC is caused by hypoxia. In line with the common indolent phenotype of a primary PC, knockdown of RGS2 induced epithelial features and impaired metastatic properties. However, increased STAT3, TWIST1 and decreased E-cadherin expression suggest priming for EMT. Additionally, improved tumour cell survival and increased BCL-2 expression linked decreased RGS2 levels to fundamental tumour advantages. In contrast, high RGS2 levels in advanced PC were correlated to poor patient survival and a positive metastatic status. This study describes novel roles for RGS2 during PC progression and suggests a prognostic potential discriminating between indolent and metastatic forms of PC. PMID- 30467388 TI - Development of whole brain versus targeted dentate gyrus irradiation model to explain low to moderate doses of exposure effects in mice. AB - Evaluation of the consequences of low to moderate doses of ionizing radiation (IR) remains a societal challenge, especially for children exposed to CT scans. Appropriate experimental models are needed to improve scientific understanding of how exposure of the postnatal brain to IR affects behavioral functions and their related pathophysiological mechanisms, considering brain complex functional organization. In the brain, the dorsal and ventral hippocampal dentate gyrus can be involved in distinct major behavioral functions. To study the long term behavioral effects of brain exposure at low to moderate doses of IR (doses range 0.25-1 Gy), we developed three new experimental models in 10-day-old mice: a model of brain irradiation and two targeted irradiation models of the dorsal and ventral dentate gyrus. We used the technological properties of the SARRP coupled with MR imaging. Our irradiation strategy has been twofold endorsed. The millimetric ballistic specificity of our models was first validated by measuring gamma-H2AX increase after irradiation. We then demonstrated higher anxiety/depressive-like behavior, preferentially mediate by the ventral part of the dentate gyrus, in mice after brain and ventral dentate gyrus IR exposure. This work provides new tools to enhance scientific understanding of how to protect children exposed to IR. PMID- 30467389 TI - Tunneling time probed by quantum shot noise. AB - In typical metallic tunnel junctions, the tunneling events occur on a femtosecond timescale. An estimation of this time requires current measurements at optical frequencies and remains challenging. However, it has been known for more than 40 years that as soon as the bias voltage exceeds one volt, the junction emits infrared radiation as an electrically driven optical antenna. We demonstrate here that the photon emission results from the fluctuations of the current inside the tunneling barrier. Photon detection is then equivalent to a measurement of the current fluctuations at optical frequencies, allowing to probe the tunneling time. Based on this idea, we perform optical spectroscopy and electronic current fluctuation measurements in the far from equilibrium regime. Our experimental data are in very good agreement with theoretical predictions based on the Landauer Buttiker scattering formalism. By combining the optics and the electronics, we directly estimate the so-called traversal time. PMID- 30467390 TI - A robust zirconium amino acid metal-organic framework for proton conduction. AB - Proton conductive materials are of significant importance and highly desired for clean energy-related applications. Discovery of practical metal-organic frameworks (MOFs) with high proton conduction remains a challenge due to the use of toxic chemicals, inconvenient ligand preparation and complication of production at scale for the state-of-the-art candidates. Herein, we report a zirconium-MOF, MIP-202(Zr), constructed from natural alpha-amino acid showing a high and steady proton conductivity of 0.011 S cm-1 at 363 K and under 95% relative humidity. This MOF features a cost-effective, green and scalable preparation with a very high space-time yield above 7000 kg m-3 day-1. It exhibits a good chemical stability under various conditions, including solutions of wide pH range and boiling water. Finally, a comprehensive molecular simulation was carried out to shed light on the proton conduction mechanism. All together these features make MIP-202(Zr) one of the most promising candidates to approach the commercial benchmark Nafion. PMID- 30467391 TI - Interconvertible vanadium-seamed hexameric pyrogallol[4]arene nanocapsules. AB - Research into stimuli-responsive controlled self-assembly and reversible transformation of molecular architectures has received much attention recently, because it is important to understand and reproduce this natural self-assembly behavior. Here, we report two coordination nanocapsules with variable cavities: a contracted octahedral V24 capsule and an expanded ball-shaped V24 capsule, both of which are constructed from the same number of subcomponents. The assemblies of these two V24 capsules are solvent-controlled, and capable of reversible conversion between contracted and expanded forms via control of the geometries of the metal centers by association and dissociation with axial water molecules. Following such structural interconversions, the magnetic properties are significantly changed. This work not only provides a strategy for the design and preparation of coordination nanocapsules with adaptable cavities, but also a unique example with which to understand the transformation process and their structure-property relationships. PMID- 30467392 TI - The role of mid-insula in the relationship between cardiac interoceptive attention and anxiety: evidence from an fMRI study. AB - Interoception refers to the perception of the internal bodily states. Recent accounts highlight the role of the insula in both interoception and the subjective experience of anxiety. The current study aimed to delve deeper into the neural correlates of cardiac interoception; more specifically, the relationship between interoception-related insular activity, interoceptive accuracy, and anxiety. This was done using functional magnetic resonance imaging (fMRI) in an experimental design in which 40 healthy volunteers focused on their heartbeat and anxious events. Interoceptive accuracy and anxiety levels were measured using the Heartbeat Perception Task and State Trait Anxiety Inventory, respectively. The results showed posterior, mid and anterior insular activity during cardiac interoception, whereas anxiety-related activation showed only anterior insular activity. Activation of the anterior insula when focused on cardiac interoception was positively correlated to state and trait anxiety levels, respectively. Moreover, the mid-insular activity during the cardiac attention condition not only related to individuals' interoceptive accuracy but also to their levels of state and trait anxiety, respectively. These findings confirm that there are distinct neural representations of heartbeat attention and anxious experience across the insular regions, and suggest the mid-insula as a crucial link between cardiac interoception and anxiety. PMID- 30467393 TI - Indoxyl Sulphate is Associated with Atrial Fibrillation Recurrence after Catheter Ablation. AB - Renal dysfunction results in the accumulation of various uremic toxins, including indoxyl sulphate (IS), and is a major risk factor for atrial fibrillation (AF). Experimental studies have demonstrated that IS exacerbates atrial remodelling via oxidative stress, inflammation, and fibrosis. However, its clinical impact on AF promoting cardiac remodelling has not been described. Therefore, the purpose of this study was to clarify the relationship between basal IS levels and the 1-year outcomes after catheter ablation for the treatment of AF. Our prospective observational study included data from 125 patients with AF who underwent catheter ablation. Over a 1-year follow-up period, AF recurrence was identified in 21 patients. The 1-year AF-free survival was significantly lower in patients with high serum IS levels (>=0.65 MUg/mL) than in those with low IS levels (60.1 +/- 10.4% versus 85.2 +/- 3.9%, P = 0.007). Univariable analysis identified that an IS concentration >= 0.65 MUg/mL was associated with AF recurrence (hazard ratio [HR] = 3.10 [1.26-7.32], P = 0.015), and this association was maintained in multivariate analysis (HR = 3.67 [1.13-11.7], P = 0.031). Thus, in patients undergoing AF ablation, serum IS levels at baseline independently predict the recurrence of arrhythmia. PMID- 30467394 TI - Comparative analysis of nucleus-encoded plastid-targeting proteins in Rafflesia cantleyi against photosynthetic and non-photosynthetic representatives reveals orthologous systems with potentially divergent functions. AB - Parasitic plants are known to discard photosynthesis thus leading to the deletion or loss of the plastid genes. Despite plastid genome reduction in non photosynthetic plants, some nucleus-encoded proteins are transported back to the plastid to carry out specific functions. In this work, we study such proteins in Rafflesia cantleyi, a member of the holoparasitic genus well-known for producing the largest single flower in the world. Our analyses of three transcriptome datasets, two holoparasites (R. cantleyi and Phelipanche aegyptiaca) and one photosynthetic plant (Arabidopsis thaliana), suggest that holoparasites, such as R. cantleyi, retain some common plastid associated processes such as biosynthesis of amino acids and lipids, but are missing photosynthesis components that can be extensions of these pathways. The reconstruction of two selected biosynthetic pathways involving plastids correlates the trend of plastid retention to pathway complexity - transcriptome evidence for R. cantleyi suggests alternate mechanisms in regulating the plastidial heme and terpenoid backbone biosynthesis pathways. The evolution to holoparasitism from autotrophy trends towards devolving the plastid genes to the nuclear genome despite the functional sites remaining in the plastid, or maintaining non-photosynthetic processes in the plastid, before the eventual loss of the plastid and any site dependent functions. PMID- 30467395 TI - Historical translocations by Maori may explain the distribution and genetic structure of a threatened surf clam in Aotearoa (New Zealand). AB - The population genetic structure of toheroa (Paphies ventricosa), an Aotearoa (New Zealand) endemic surf clam, was assessed to determine levels of inter population connectivity and test hypotheses regarding life history, habitat distribution and connectivity in coastal vs. estuarine taxa. Ninety-eight toheroa from populations across the length of New Zealand were sequenced for the mitochondrial cytochrome c oxidase I gene with analyses suggesting a population genetic structure unique among New Zealand marine invertebrates. Toheroa genetic diversity was high in Te Ika-a Maui (the North Island of New Zealand) but completely lacking in the south of Te Waipounamu (the South Island), an indication of recent isolation. Changes in habitat availability, long distance dispersal events or translocation of toheroa to southern New Zealand by Maori could explain the observed geographic distribution of toheroa and their genetic diversity. Given that early-Maori and their ancestors, were adept at food cultivation and relocation, the toheroa translocation hypothesis is plausible and may explain the disjointed modern distribution of this species. Translocation would also explain the limited success in restoring what may in some cases be ecologically isolated populations located outside their natural distributions and preferred niches. PMID- 30467396 TI - Effects of Modulating Actin Dynamics on HER2 Cancer Cell Motility and Metastasis. AB - Amplification of HER2 leads to development of HER2-positive (HER2+) cancers with high rates of metastasis compared to other cancer subtypes. The goal of this study was to probe the vulnerability of HER2+ cancer cells to a filamentous actin (F-actin) severing and capping toxin. The growth and viability of human HER2+ breast cancer (HCC1954) and ovarian cancer (SKOV3) cell lines were significantly impaired upon treatment with the marine macrolide mycalolide B (Myc B) at doses above 100 nanomolar. Further testing of Myc B in combination with the antibody drug conjugate Trastuzumab-emtansine (T-DM1) led to improved killing of SKOV3 cells compared to either treatment alone. At sub-lethal doses, treatment of HER2+ cancer cells with Myc B resulted in rapid loss of leading edge protrusions and formation of aggresomes containing F-actin and the actin regulatory protein Cortactin. This correlated with robust inhibition of HER2+ cancer cell motility and invasion with Myc B treatment. In SKOV3 tumor xenograft assays, intratumoral injections of Myc B impaired HER2+ tumor growth and metastasis, with maximal effects observed in combination with systemic delivery of Trastuzumab. Metastasis of SKOV3 cells to the lungs following tail vein injection was also reduced by Myc B. Together, these findings provide rationale for targeting F-actin in combination with existing therapies for HER2+ cancers to reduce metastasis. PMID- 30467397 TI - Guided-mode resonant narrowband terahertz filtering by periodic metallic stripe and patch arrays on cyclo-olefin substrates. AB - We experimentally and theoretically demonstrate a class of narrowband transmissive filters in the terahertz spectrum. Their operation is based on the excitation of guided-mode resonances in thin films of the low-loss cyclo-olefin polymer Zeonor, upon which aluminum stripe and patch arrays are patterned via standard photolithography. The filters are engineered to operate in low atmospheric loss THz spectral windows, they exhibit very high transmittance and quality factors, compact thickness, and mechanical stability. The dependence of their filtering properties on the geometrical parameters, the substrate thickness and the angle of incidence is investigated, discussing the physical limitations in their performance. This class of filters provides a cost-effective solution for broadband source or channel filtering in view of emerging terahertz wireless communication systems. PMID- 30467399 TI - Adsorption characteristics of organics in the effluent of ultra-short SRT wastewater treatment by single-walled, multi-walled, and graphitized multi-walled carbon nanotubes. AB - With a conceptual shift in sewage treatment from 'waste pollution' to 'vehicle of resource and energy recovery' and the further intensification of the energy crisis, the separation and recovery of carbon resources from discharged sewage has gained increasing recent attention in the field of water treatment. The ultra short Solids Retention Time (SRT) activated sludge process (SRT <= 4 d) is highly efficient for separating organic matter and improving the energy recovery rate in wastewater treatment plants, but the effluent quality is relatively poor. If organics in the ultra-short SRT effluent can be reduced further to separate and recover carbon resources, the process may soon replace the traditional activated sludge process. We conducted physical adsorption carbon recovery experiments in an ultra-short SRT (SRT = 2 d) activated sludge system using three carbon nanotubes. Considering that Chemical Oxygen Demand (COD) arises from a mixture of organic compounds, and because humic acid (HA) makes up a large fraction of the effluent and can cause great environmental harm, further experiments were conducted on the adsorption of HA in the effluent COD to three nanotubes. This study proposes a novel method to completely remove organics from the effluent from ultra-short SRT activated sludge processes and reveals nanotube adsorption properties and mechanisms. PMID- 30467398 TI - In-depth analysis of Bacillus subtilis proteome identifies new ORFs and traces the evolutionary history of modified proteins. AB - Bacillus subtilis is a sporulating Gram-positive bacterium widely used in basic research and biotechnology. Despite being one of the best-characterized bacterial model organism, recent proteomics studies identified only about 50% of its theoretical protein count. Here we combined several hundred MS measurements to obtain a comprehensive map of the proteome, phosphoproteome and acetylome of B. subtilis grown at 37 degrees C in minimal medium. We covered 75% of the theoretical proteome (3,159 proteins), detected 1,085 phosphorylation and 4,893 lysine acetylation sites and performed a systematic bioinformatic characterization of the obtained data. A subset of analyzed MS files allowed us to reconstruct a network of Hanks-type protein kinases, Ser/Thr/Tyr phosphatases and their substrates. We applied genomic phylostratigraphy to gauge the evolutionary age of B. subtilis protein classes and revealed that protein modifications were present on the oldest bacterial proteins. Finally, we performed a proteogenomic analysis by mapping all MS spectra onto a six-frame translation of B. subtilis genome and found evidence for 19 novel ORFs. We provide the most extensive overview of the proteome and post-translational modifications for B. subtilis to date, with insights into functional annotation and evolutionary aspects of the B. subtilis genome. PMID- 30467401 TI - Ejaculate sperm number compensation in stalk-eyed flies carrying a selfish meiotic drive element. AB - Meiotic drive genes cause the degeneration of non-carrier sperm to bias transmission in their favour. Males carrying meiotic drive are expected to suffer reduced fertility due to the loss of sperm and associated harmful side-effects of the mechanisms causing segregation distortion. However, sexual selection should promote adaptive compensation to overcome these deleterious effects. We investigate this using SR, an X-linked meiotic drive system in the stalk-eyed fly, Teleopsis dalmanni. Despite sperm destruction caused by drive, we find no evidence that SR males transfer fewer sperm to the female's spermathecae (long term storage organs). Likewise, migration from the spermathecae to the ventral receptacle for fertilisation is similar for SR and wildtype male sperm, both over short and long time-frames. In addition, sperm number in storage is similar even after males have mated multiple times. Our study challenges conventional assumptions about the deleterious effects of drive on male fertility. This suggests that SR male ejaculate investment per ejaculate has been adjusted to match sperm delivery by wildtype males. We interpret these results in the light of recent theoretical models that predict how ejaculate strategies evolve when males vary in the resources allocated to reproduction or in sperm fertility. Adaptive compensation is likely in species where meiotic drive has persisted over many generations and predicts a higher stable frequency of drive maintained in wild populations. Future research must determine exactly how drive males compensate for failed spermatogenesis, and how such compensation may trade-off with investment in other fitness traits. PMID- 30467400 TI - Development of a multi-locus CRISPR gene drive system in budding yeast. AB - The discovery of CRISPR/Cas gene editing has allowed for major advances in many biomedical disciplines and basic research. One arrangement of this biotechnology, a nuclease-based gene drive, can rapidly deliver a genetic element through a given population and studies in fungi and metazoans have demonstrated the success of such a system. This methodology has the potential to control biological populations and contribute to eradication of insect-borne diseases, agricultural pests, and invasive species. However, there remain challenges in the design, optimization, and implementation of gene drives including concerns regarding biosafety, containment, and control/inhibition. Given the numerous gene drive arrangements possible, there is a growing need for more advanced designs. In this study, we use budding yeast to develop an artificial multi-locus gene drive system. Our minimal setup requires only a single copy of S. pyogenes Cas9 and three guide RNAs to propagate three gene drives. We demonstrate how this system could be used for targeted allele replacement of native genes and to suppress NHEJ repair systems by modifying DNA Ligase IV. A multi-locus gene drive configuration provides an expanded suite of options for complex attributes including pathway redundancy, combatting evolved resistance, and safeguards for control, inhibition, or reversal of drive action. PMID- 30467402 TI - Qualitative study of system-level factors related to genomic implementation. AB - PURPOSE: Research on genomic medicine integration has focused on applications at the individual level, with less attention paid to implementation within clinical settings. Therefore, we conducted a qualitative study using the Consolidated Framework for Implementation Research (CFIR) to identify system-level factors that played a role in implementation of genomic medicine within Implementing GeNomics In PracTicE (IGNITE) Network projects. METHODS: Up to four study personnel, including principal investigators and study coordinators from each of six IGNITE projects, were interviewed using a semistructured interview guide that asked interviewees to describe study site(s), progress at each site, and factors facilitating or impeding project implementation. Interviews were coded following CFIR inner-setting constructs. RESULTS: Key barriers included (1) limitations in integrating genomic data and clinical decision support tools into electronic health records, (2) physician reluctance toward genomic research participation and clinical implementation due to a limited evidence base, (3) inadequate reimbursement for genomic medicine, (4) communication among and between investigators and clinicians, and (5) lack of clinical and leadership engagement. CONCLUSION: Implementation of genomic medicine is hindered by several system level barriers to both research and practice. Addressing these barriers may serve as important facilitators for studying and implementing genomics in practice. PMID- 30467403 TI - Experiences and perspectives on the return of secondary findings among genetic epidemiologists. AB - PURPOSE: While there has been a recent increase in scholarship around developing policies for the return of results from genetic sequencing, it is not clear whether these approaches are appropriate for genetic epidemiology studies. Because genetic epidemiological research increasingly utilizes genome sequencing methods, particularly in large data sets where researchers did not directly ascertain the subjects, it is important to understand researchers' perspectives on the return of results. METHODS: We conducted an online survey of members of the International Genetic Epidemiology Society to document the diversity of experiences and impressions regarding return of results. The survey contained both closed and open-ended questions. RESULTS: Among our respondents who enroll their own research participants, only 21% return secondary findings. Most respondents do not search their sequence data for clinically actionable findings not associated with their disease of interest. Many feel that genetic epidemiologists have a unique perspective on the return of results and that research studies should not follow the same procedures as clinical sequencing studies. CONCLUSION: Precision medicine initiatives that rely on both clinical and "big data" genomic research should account for variation in researcher perspectives and study design limitations when developing policies and standard practices regarding the return of results. PMID- 30467404 TI - RNA sequencing solved the most common but unrecognized NEB pathogenic variant in Japanese nemaline myopathy. AB - PURPOSE: The diagnostic rate for Mendelian diseases by exome sequencing (ES) is typically 20-40%. The low rate is partly because ES misses deep-intronic or synonymous variants leading to aberrant splicing. In this study, we aimed to apply RNA sequencing (RNA-seq) to efficiently detect the aberrant splicings and their related variants. METHODS: Aberrant splicing in biopsied muscles from six nemaline myopathy (NM) cases unresolved by ES were analyzed with RNA-seq. Variants related to detected aberrant splicing events were analyzed with Sanger sequencing. Detected variants were screened in NM patients unresolved by ES. RESULTS: We identified a novel deep-intronic NEB pathogenic variant, c.1569+339A>G in one case, and another novel synonymous NEB pathogenic variant, c.24684G>C (p.Ser8228Ser) in three cases. The c.24684G>C variant was observed to be the most frequent among all NEB pathogenic variants in normal Japanese populations with a frequency of 1 in 178 (20 alleles in 3552 individuals), but was previously unrecognized. Expanded screening of the variant identified it in a further four previously unsolved nemaline myopathy cases. CONCLUSION: These results indicated that RNA-seq may be able to solve a large proportion of previously undiagnosed muscle diseases. PMID- 30467405 TI - Personalized medicine: paradigm shift or revolution. PMID- 30467406 TI - Author Correction: Magnetic Resonance Imaging for tracking cellular patterns obtained by Laser-Assisted Bioprinting. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30467407 TI - Non-contact Quantification of Jugular Venous Pulse Waveforms from Skin Displacements. AB - The jugular venous (JV) pressure waveform is a non-invasive, proven indicator of cardiovascular disease. Conventional clinical methods for assessing these waveforms are often overlooked because they require specialised expertise, and are invasive and expensive to implement. Recently, image-based methods have been used to quantify JV pulsation waveforms on the skin as an indirect way of estimating the pressure waveforms. However, these existing image-based methods cannot explicitly measure skin deformations and rely on the use of photoplethysmography (PPG) devices for identification of the pulsatile waveforms. As a result, they often have limited accuracy and robustness and are unsuitable in the clinical environment. Here, we propose a technique to directly measure skin deformations caused by the JV pulse using a very accurate subpixel registration algorithm. The method simply requires images obtained from the subject's neck using a commodity camera. The results show that our measured waveforms contained all of the essential features of diagnostic JV waveforms in all of 19 healthy subjects tested in this study, indicating a significantly important capability for a potential future diagnostic device. The shape of our measured JV displacement waveforms was validated using waveforms measured with a laser displacement sensor, where the average correlation score between the two waveforms was 0.93 +/- 0.05. In addition, synchronously recorded ECG signals were used to verify the timings of diagnostic features of the measured waveforms. To our knowledge, this is the first use of image registration for direct measurement of JV displacement waveforms. Significant advantages of our novel method include the high precision of our measurements, and the ability to use ordinary cameras, such as those in modern mobile phones. These advantages will enable the development of affordable and accessible devices to measure JV waveforms for cardiac diagnostics in the clinical environment. Future devices based on this technology may provide viable options for telemedicine applications, point of care diagnostics, and mobile-based cardiac health monitoring systems. PMID- 30467408 TI - The timing and widespread effects of the largest Holocene volcanic eruption in Antarctica. AB - The caldera collapse of Deception Island Volcano, Antarctica, was comparable in scale to some of the largest eruptions on Earth over the last several millennia. Despite its magnitude and potential for far-reaching environmental effects, the age of this event has never been established, with estimates ranging from the late Pleistocene to 3370 years before present. Here we analyse nearby lake sediments in which we identify a singular event produced by Deception Island's caldera collapse that occurred 3980 +/- 125 calibrated years before present. The erupted tephra record the distinct geochemical composition of ejecta from the caldera-forming eruption, whilst an extreme seismic episode is recorded by lake sediments immediately overlying the collapse tephra. The newly constrained caldera collapse is now the largest volcanic eruption confirmed in Antarctica during the Holocene. An examination of palaeorecords reveals evidence in marine and lacustrine sediments for contemporaneous seismicity around the Antarctic Peninsula; synchronous glaciochemical volcanic signatures also record the eruption in ice cores spread around Antarctica, reaching >4600 km from source. The widespread footprint suggests that this eruption would have had significant climatic and ecological effects across a vast area of the south polar region. PMID- 30467409 TI - North-South Asymmetry in the Geographic Location of Auroral Substorms correlated with Ionospheric Effects. AB - Energetic particles of magnetospheric origin constantly strike the Earth's upper atmosphere in the polar regions, producing optical emissions known as the aurora. The most spectacular auroral displays are associated with recurrent events called magnetospheric substorms (aka auroral substorms). Substorms are initiated in the nightside magnetosphere on closed magnetic field lines. As a consequence, it is generally thought that auroral substorms should occur in both hemispheres on the same field line (i.e., magnetically conjugated). However, such a hypothesis has not been verified statistically. Here, by analyzing 2659 auroral substorms acquired by the Ultraviolet Imager on board the NASA satellite "Polar", we have discovered surprising evidence that the averaged location for substorm onsets is not conjugate but shows a geographic preference that cannot be easily explained by current substorm theories. In the Northern Hemisphere (NH) the auroral substorms occur most frequently in Churchill, Canada (~90 degrees W) and Khatanga, Siberia (~100 degrees E), up to three times as often as in Iceland (~22 degrees W). In the Southern Hemisphere (SH), substorms occur more frequently over a location in the Antarctic ocean (~120 degrees E), up to ~4 times more than over the Antarctic Continent. Such a large difference in the longitudinal distribution of north and south onset defies the common belief that substorms in the NH and SH should be magnetically conjugated. A further analysis indicates that these substorm events occurred more frequently when more of the ionosphere was dark. These geographic areas also coincide with regions where the Earth's magnetic field is largest. These facts suggest that auroral substorms occur more frequently, and perhaps more intensely, when the ionospheric conductivity is lower. With much of the magnetotail energy coming from the solar wind through merging of the interplanetary and Earth's magnetic field, it is generally thought that the occurrence of substorms is externally controlled by the solar wind and plasma instability in the magnetotail. The present study results provide a strong argument that the ionosphere plays a more active role in the occurrence of substorms. PMID- 30467410 TI - Engineering the hinge region of human IgG1 Fc-fused bispecific antibodies to improve fragmentation resistance. AB - Fc domain fusion can improve the therapeutic effects of relatively small biological molecules such as peptides, cytokines, and antibody fragments. Fc fusion proteins can also be used to enhance the cytotoxic effects of small bispecific antibodies (bsAbs). However, fragmentation of Fc fusion proteins, which mainly occurs around the hinge regions during production, storage, and circulation in the blood, is a major issue. In this study, we first investigated the mechanisms of fragmentation around the hinge region during storage using Fc fused bsAbs with specificity for epidermal growth factor receptor and CD3 as a model. The fragmentation peaks generated by gel filtration analysis indicated that both contaminating proteases and dissolved active oxygen should be considered causes of fragmentation. We designed and constructed variants by introducing a point mutation into the upper hinge region, which reduced the cleavage caused by dissolved active oxygen, and shortened the hinge region to restrict access of proteases. These hinge modifications improved fragmentation resistance and did not affect the biological activity of the bsAbs in vitro. We confirmed the versatility of the hinge modifications using another Fc-fused bsAb. Our results show that hinge modifications to the Fc fusion protein, especially the introduction of a point mutation into the upper hinge region, can reduce fragmentation substantially, and these modifications can be used to improve the fragmentation resistance of other recombinant Fc fusion proteins. PMID- 30467411 TI - Prospective multicenter real-world RAS mutation comparison between OncoBEAM-based liquid biopsy and tissue analysis in metastatic colorectal cancer. AB - BACKGROUND: Liquid biopsy offers a minimally invasive alternative to tissue-based evaluation of mutational status in cancer. The goal of the present study was to evaluate the aggregate performance of OncoBEAM RAS mutation analysis in plasma of colorectal cancer (CRC) patients at 10 hospital laboratories in Spain where this technology is routinely implemented. METHODS: Circulating cell-free DNA from plasma was examined for RAS mutations using the OncoBEAM platform at each hospital laboratory. Results were then compared to those obtained from DNA extracted from tumour tissue from the same patient. RESULTS: The overall percentage agreement between plasma-based and tissue-based RAS mutation testing of the 236 participants was 89% (210/236; kappa, 0.770 (95% CI: 0.689-0.852)). Re analysis of tissue from all discordant cases by BEAMing revealed two false negative and five false positive tumour tissue RAS results, with a final concordance of 92%. Plasma false negative results were found more frequently in patients with exclusive lung metastatic disease. CONCLUSIONS: In this first prospective real-world RAS mutation performance comparison study, a high overall agreement was observed between results obtained from plasma and tissue samples. Overall, these findings indicate that the plasma-based BEAMing assay is a viable solution for rapid delivery of RAS mutation status to determine mCRC patient eligibility for anti-EGFR therapy. PMID- 30467412 TI - The role of matrilineality in shaping patterns of Y chromosome and mtDNA sequence variation in southwestern Angola. AB - Southwestern Angola is a region characterized by contact between indigenous foragers and incoming food-producers, involving genetic and cultural exchanges between peoples speaking Kx'a, Khoe-Kwadi, and Bantu languages. Although present day Bantu speakers share a patrilocal residence pattern and matrilineal principle of clan and group membership, a highly stratified social setting divides dominant pastoralists from marginalized groups that subsist on alternative strategies and have previously been thought to have pre-Bantu origins. Here, we compare new high resolution sequence data from 2.3 Mb of the male-specific region of the Y chromosome (MSY) from 170 individuals with previously reported mitochondrial DNA (mtDNA) genomes, to investigate the population history of seven representative southwestern Angolan groups (Himba, Kuvale, Kwisi, Kwepe, Twa, Tjimba, !Xun), and to study the causes and consequences of sex-biased processes in their genetic variation. We found no clear link between the formerly Kwadi-speaking Kwepe and pre-Bantu eastern African migrants, and no pre-Bantu MSY lineages among Bantu speaking groups, except for small amounts of "Khoisan" introgression. We therefore propose that irrespective of their subsistence strategies, all Bantu speaking groups of the area share a male Bantu origin. Additionally, we show that in Bantu-speaking groups, the levels of among-group and between-group variation are higher for mtDNA than for MSY. These results, together with our previous demonstration that the matriclanic systems of southwestern Angolan Bantu groups are genealogically consistent, suggest that matrilineality strongly enhances both female population sizes and interpopulation mtDNA variation. PMID- 30467413 TI - Author Correction: Mitochondrial DNA synthesis fuels NLRP3 inflammasome. AB - In the initial published version of this article, there was a mistake in the title. The correct title should be "Mitochondrial DNA synthesis fuels NLRP3 activation". This correction does not affect the description of the results or the conclusions of this work. PMID- 30467415 TI - TB's Chinese travels. PMID- 30467414 TI - Migratory coupling between predators and prey. AB - Animal migrations act to couple ecosystems and are undertaken by some of the world's most endangered taxa. Predators often exploit migrant prey, but the movements taken by these consumers are rarely studied or understood. We define such movements, where migrant prey induce large-scale movements of predators, as migratory coupling. Migratory coupling can have ecological consequences for the participating prey, predators and the communities they traverse across the landscape. We review examples of migratory coupling in the literature and provide hypotheses regarding conditions favourable for their occurrence. We also provide a framework for interactions induced by migratory coupling and demonstrate their potential community-level impacts by examining other forms of spatial shifts in predators. Migratory coupling integrates the fields of landscape, movement, food web and community ecologies, and represents an understudied frontier in ecology. PMID- 30467416 TI - Challenging climate. PMID- 30467417 TI - Neuroendocrine control of natural killer cell function through the checkpoint molecule PD-1. PMID- 30467418 TI - Kinetics of the accumulation of group 2 innate lymphoid cells in IL-33-induced and IL-25-induced murine models of asthma: a potential role for the chemokine CXCL16. AB - ILC2s are implicated in asthma pathogenesis, but little is known about the mechanisms underlying their accumulation in airways. We investigated the time course of ILC2 accumulation in different tissues in murine models of asthma induced by a serial per-nasal challenge with ovalbumin (OVA), house dust mice (HDM), IL-25 and IL-33 and explored the potential roles of ILC2-attracting chemokines in this phenomenon. Flow cytometry was used to enumerate ILC2s at various time points. The effects of cytokines and chemokines on ILC2 migration were measured in vitro using a chemotaxis assay and in vivo using small animal imaging. Compared with saline and OVA challenge, both IL-25 and IL-33 challenge alone induced significant accumulation of ILC2s in the mediastinal lymph nodes, lung tissue and bronchoalveolar lavage fluid of challenged animals, but with a distinct potency and kinetics. In vitro, IL-33 and CXCL16, but not IL-25 or CCL25, directly induced ILC2 migration. Small animal in vivo imaging further confirmed that a single intranasal provocation with IL-33 or CXCL16 was sufficient to induce the accumulation of ILC2s in the lungs following injection via the tail vein. Moreover, IL-33-induced ILC2 migration involved the activation of ERK1/2, p38, Akt, JNK and NF-kappaB, while CXCL16-induced ILC2 migration involved the activation of ERK1/2, p38 and Akt. These data support the hypothesis that epithelium-derived IL-25 and IL-33 induce lung accumulation of ILC2s, while IL-33 exerts a direct chemotactic effect in this process. Although ILC2s express the chemokine receptors CXCR6 and CCR9, only CXCL16, the ligand of CXCR6, exhibits a direct chemoattractant effect. PMID- 30467419 TI - Distinct editing functions of natural HLA-DM allotypes impact antigen presentation and CD4+ T cell activation. AB - Classical human leukocyte antigen (HLA) molecules of the major histocompatibility class II (MHCII) complex present peptides for the development, surveillance and activation of CD4+ T cells. The nonclassical MHCII-like protein HLA-DM (DM) catalyzes the exchange and loading of peptides onto MHCII molecules, thereby shaping MHCII immunopeptidomes. Natural variations of DM in both chains of the protein (DMA and DMB) have been hypothesized to impact peptide presentation, but no evidence for altered function has been reported. Here we define the presence of DM allotypes in human populations covered by the 1000 Genomes Project and probe their activity. The functional properties of several allotypes are investigated and show strong enhancement of peptide-induced T cell activation for a particular combination of DMA and DMB. Biochemical evidence suggests a broader pH activity profile for the new variant relative to that of the most commonly expressed DM allotype. Immunopeptidome analysis indicates that the compartmental activity of the new DM heterodimer extends beyond the late endosome and suggests that the natural variation of DM has profound effects on adaptive immunity when antigens bypass the canonical processing pathway. PMID- 30467420 TI - TLR9 agonist enhances radiofrequency ablation-induced CTL responses, leading to the potent inhibition of primary tumor growth and lung metastasis. AB - Radiofrequency ablation (RFA) is the most common approach to thermal ablation for cancer therapy. Unfortunately, its efficacy is limited by incomplete ablation, and further optimization of RFA is required. Here, we demonstrate that incubation at 65 degrees C triggers more EG7 tumor cell death by necrosis than treatment at 45 degrees C, and the 65 degrees C-treated cells are more effective at inducing antigen-specific CD8+ cytotoxic T lymphocyte (CTL) responses after injection in mice than the 45 degrees C-treated ones. Dendritic cells (DCs) that phagocytose 65 degrees C-treated EG7 cells become mature with upregulated MHCII and CD80 expression and are capable of efficiently inducing effector CTLs in mouse tumor models. RFA (65 degrees C) therapy of EG7 tumors induces large areas of tumor necrosis and stimulates CTL responses. This leads to complete regression of small (~100 mm3) tumors but fails to suppress the growth of larger (~350 mm3) tumors. The administration of the Toll-like receptor-9 (TLR9) agonist unmethylated cytosine-phosphorothioate-guanine oligonucleotide (CpG) to DCs phagocytosing 65 degrees C-treated EG7 cells enhances the expression of MHCII and CD40 on DCs as well as DC-induced stimulation of CTL responses. Importantly, the intratumoral administration of CpG following RFA also increases the frequencies of tumor associated immunogenic CD11b-CD11c+CD103+ DC2 and CD11b+F4/80+MHCII+ M1 macrophages and increases CD4+ and CD8+ T-cell tumor infiltration, leading to enhanced CD4+ T cell-dependent CTL responses and potent inhibition of primary RFA treated or distant untreated tumor growth as well as tumor lung metastasis in mice bearing larger tumors. Overall, our data indicate that CpG administration, which enhances RFA-induced CTL responses and ultimately potentiates the inhibition of primary tumor growth and lung metastasis, is a promising strategy for improving RFA treatment, which may assist in optimizing this important cancer therapy. PMID- 30467423 TI - Macular microvasculature features before and after vitrectomy in idiopathic macular epiretinal membrane: an OCT angiography analysis. AB - PURPOSE: To evaluate pre-operative and post-operative morphologic characteristics in idiopathic macular epiretinal membrane (ERM) by optical coherence tomography angiography (OCTA). METHODS: Thirty-three subjects with unilateral idiopathic ERM were enrolled and the contralateral eyes served as controls. Vascular parameters including superficial capillary plexus (SCP), deep capillary plexus (DCP), outer capillary plexus (OCP), and choroidal capillary plexus (CCP) were evaluated by OCTA. RESULTS: The superficial foveal avascular zone (FAZ) was significantly smaller in eyes with ERM (P < 0.0001). The vessel densities (VDs) were significantly increased in the fovea but dramatically decreased in the parafovea in SCP and DCP of ERM eyes (all P < 0.0001), in contrast to those in OCP and CCP. The blood flow was augmented in OCP but declined in choroid compared with the controls. In CCP, the mean foveal VD in ERM was significantly smaller (P = 0.023), whereas parafoveal VD did not significantly change (P = 0.66). At 6 months after surgery, flow area was decreased in OCP (P = 0.0007), and foveal and parafoveal VDs were significantly altered in all layers except the foveal VD in OCP and the choroid (all P < 0.05). The total and inner retinal thickness of the fovea and parafovea were correlated with pre-operative and post-operative visual outcomes, respectively. Smaller FAZ and greater interocular differences between post-operative and fellow eyes in FAZ were associated with worse post-operative visual outcomes. CONCLUSIONS: OCTA provides a better display of the vascular network of the retina and choroid to evaluate the severity and surgical prognosis of ERM patients. PMID- 30467422 TI - Defining Coronary Flow Patterns: Comprehensive Automation of Transthoracic Doppler Coronary Blood Flow. AB - The coronary microcirculation (CM) plays a critical role in the regulation of blood flow and nutrient exchange to support the viability of the heart. In many disease states, the CM becomes structurally and functionally impaired, and transthoracic Doppler echocardiography can be used as a non-invasive surrogate to assess CM disease. Analysis of Doppler echocardiography is prone to user bias and can be laborious, especially if additional parameters are collected. We hypothesized that we could develop a MATLAB algorithm to automatically analyze clinically-relevant and non-traditional parameters from murine PW Doppler coronary flow patterns that would reduce intra- and inter-operator bias, and analysis time. Our results show a significant reduction in intra- and inter observer variability as well as a 30 fold decrease in analysis time with the automated program vs. manual analysis. Finally, we demonstrated good agreement between automated and manual analysis for clinically-relevant parameters under baseline and hyperemic conditions. Resulting coronary flow velocity reserve calculations were also found to be in good agreement. We present a MATLAB algorithm that is user friendly and robust in defining and measuring Doppler coronary flow pattern parameters for more efficient and potentially more insightful analysis assessed via Doppler echocardiography. PMID- 30467421 TI - The prevalence and transcriptional activity of the mucosal microbiota of ulcerative colitis patients. AB - Active microbes likely have larger impact on gut health status compared to inactive or dormant microbes. We investigate the composition of active and total mucosal microbiota of treatment-naive ulcerative colitis (UC) patients to determine the microbial picture at the start-up phase of disease, using both a 16S rRNA transcript and gene amplicon sequencing. DNA and RNA were isolated from the same mucosal colonic biopsies. Our aim was to identify active microbial members of the microbiota in early stages of disease and reveal which members are present, but do not act as major players. We demonstrated differences in active and total microbiota of UC patients when comparing inflamed to non-inflamed tissue. Several taxa, among them the Proteobacteria phyla and families therein, revealed lower transcriptional activity despite a high presence. The Bifidobacteriaceae family of the Actinobacteria phylum showed lower abundance in the active microbiota, although no difference in presence was detected. The most abundant microbiota members of the inflamed tissue in UC patients were not the most active. Knowledge of active members of microbiota in UC patients could enhance our understanding of disease etiology. The active microbial community composition did not deviate from the total when comparing UC patients to non-IBD controls. PMID- 30467424 TI - Acute primary angle closure-treatment strategies, evidences and economical considerations. AB - Acute primary angle closure requires emergency management that involves a rapid lowering of the intraocular pressure and resolution of relative pupil block - the most common mechanism of angle closure. Emergency strategies for lowering intraocular pressure include medical treatment and argon laser peripheral iridoplasty. Anterior chamber paracentesis and diode laser transcleral cyclophotocoagulation may be considered in special situations. Relative pupil block can be relieved by peripheral laser iridotomy and primary lens extraction; the latter is a more effective treatment according to the results of clinical trials. However, primary lens extraction can be technically demanding in the acute setting. Peripheral laser iridotomy has a role in relieving pupil block and should also be considered in most cases. Lens extraction may be combined with procedures such as goniosynechialysis, trabeculectomy or endoscopic cyclophotocoagulation. In this review, we aim to discuss the available evidence regarding the different treatment modalities. We also discuss the economic consideration, including cost-effectiveness and life expectancy, in the management of acute primary angle closure. PMID- 30467425 TI - Longitudinal single-cell RNA sequencing of patient-derived primary cells reveals drug-induced infidelity in stem cell hierarchy. AB - Chemo-resistance is one of the major causes of cancer-related deaths. Here we used single-cell transcriptomics to investigate divergent modes of chemo resistance in tumor cells. We observed that higher degree of phenotypic intra tumor heterogeneity (ITH) favors selection of pre-existing drug-resistant cells, whereas phenotypically homogeneous cells engage covert epigenetic mechanisms to trans-differentiate under drug-selection. This adaptation was driven by selection induced gain of H3K27ac marks on bivalently poised resistance-associated chromatin, and therefore not expressed in the treatment-naive setting. Mechanistic interrogation of this phenomenon revealed that drug-induced adaptation was acquired upon the loss of stem factor SOX2, and a concomitant gain of SOX9. Strikingly we observed an enrichment of SOX9 at drug-induced H3K27ac sites, suggesting that tumor evolution could be driven by stem cell-switch mediated epigenetic plasticity. Importantly, JQ1 mediated inhibition of BRD4 could reverse drug-induced adaptation. These results provide mechanistic insights into the modes of therapy-induced cellular plasticity and underscore the use of epigenetic inhibitors in targeting tumor evolution. PMID- 30467426 TI - In-depth validation of total HIV-1 DNA assays for quantification of various HIV-1 subtypes. AB - HIV-1 DNA quantification serves as an important reservoir biomarker in HIV cure trials. However, the high genetic diversity of HIV-1 represented by different subtypes may bring inaccuracy in quantifying HIV-1 DNA and a sensitive and validated assay covering diverse HIV-1 subtypes is lacking. Therefore, we cross validated total HIV-1 DNA assays described in literature using a three-step comparative analysis. First, a bioinformatics tool was developed in-house to perform an in silico evaluation of 67 HIV-1 DNA assays. Secondly, these selected assays were in vitro validated using a panel of different HIV-1 subtypes and, finally, ex vivo assessed on selected patient samples with different HIV-1 subtypes. Our results show that quantification of HIV-1 DNA substantially differs between assays and we advise five best performing HIV-1 DNA assays for ddPCR and qPCR (Schvachsa_2007, Viard_2004, Heeregrave_2009, Van_der_Sluis_2013, Yu_2008 and Yun_2002). This in-depth analysis of published HIV-1 DNA assays indicates that not all assays guarantee an optimal measurement of HIV-1 DNA, especially when looking across subtypes. Using an in-depth cross-validation, we were able to validate HIV-1 DNA assays that are suitable for quantification of HIV-1 DNA in a wide variety of HIV-1 infected patients. PMID- 30467427 TI - Functions and mechanisms of non-histone protein acetylation. AB - Nepsilon-lysine acetylation was discovered more than half a century ago as a post translational modification of histones and has been extensively studied in the context of transcription regulation. In the past decade, proteomic analyses have revealed that non-histone proteins are frequently acetylated and constitute a major portion of the acetylome in mammalian cells. Indeed, non-histone protein acetylation is involved in key cellular processes relevant to physiology and disease, such as gene transcription, DNA damage repair, cell division, signal transduction, protein folding, autophagy and metabolism. Acetylation affects protein functions through diverse mechanisms, including by regulating protein stability, enzymatic activity, subcellular localization and crosstalk with other post-translational modifications and by controlling protein-protein and protein DNA interactions. In this Review, we discuss recent progress in our understanding of the scope, functional diversity and mechanisms of non-histone protein acetylation. PMID- 30467428 TI - Ribosome assembly coming into focus. AB - In the past 25 years, genetic and biochemical analyses of ribosome assembly in yeast have identified most of the factors that participate in this complex pathway and have generated models for the mechanisms driving the assembly. More recently, the publication of numerous cryo-electron microscopy structures of yeast ribosome assembly intermediates has provided near-atomic resolution snapshots of ribosome precursor particles. Satisfyingly, these structural data support the genetic and biochemical models and provide additional mechanistic insight into ribosome assembly. In this Review, we discuss the mechanisms of assembly of the yeast small ribosomal subunit and large ribosomal subunit in the nucleolus, nucleus and cytoplasm. Particular emphasis is placed on concepts such as the mechanisms of RNA compaction, the functions of molecular switches and molecular mimicry, the irreversibility of assembly checkpoints and the roles of structural and functional proofreading of pre-ribosomal particles. PMID- 30467429 TI - [Authors' response (September 26, 2018) to the letter to the Editor concerning the paper "The prophylactic operational model integrated with occupational healthcare - Prophylactic of some types of cancers among women"]. PMID- 30467430 TI - Predictive factors of complications post intracranial meningioma surgery leading to early unplanned reoperations - a single center study. AB - INTRODUCTION: Complications occurring after neurosurgical procedures which lead to reoperations are associated with poor treatment outcomes. The aim of our study was to establish predictive factors of unplanned early reoperations after intracranial meningioma removal. MATERIALS AND METHODS: We retrospectively analyzed 177 patients who underwent craniotomy due to an intracranial meningioma. Early reoperation was de ned as reoperation during the same hospital stay. We used a chi2 test for proportional values and t-test and Mann-Whitney U tests as appropriate for continuous variables. To determine the potential predictors of early reoperation we used univariate and multivariate logistic regression analyses. RESULTS: A total of 13 (7.34%) patients underwent unplanned early reoperation. These patients underwent retrosigmoid craniotomies (25.00% vs. 6.40%; p = 0.047), suffered from ischemic heart disease (66.67% vs. 6.64%; p <0.01) and atrial fibrillation (60.00% vs. 6.25%; p <0.01), were receiving heparin (50.00% vs. 6.74%; p <0.01) and anticoagulants (66.67% vs. 6.21%; p <0.01) significantly more often than the general study population. In multivariate logistic regression analysis anticoagulant use (OR: 31.463; 95% CI: 1.139-868.604; p = 0.04) and retrosigmoid craniotomy (OR: 6.642; 95% CI: 1.139 38.73; p = 0.034) remained independently associated with a higher risk of early reoperation. CONCLUSIONS: Patients who underwent retrosigmoid craniotomy, those with a history of ischemic heart disease or atrial fibrillation and those who take heparin or anticoagulants are more likely to require early reoperation. Retrosigmoid craniotomy and anticoagulant use are independent risk factors for early reoperation. PMID- 30467431 TI - Triggering Receptor Expressed on Myeloid Cells-1 (TREM-1) and its soluble in the plasma form (sTREM-1) as a diagnostic biomarker in neonatal sepsis. AB - Neonatal sepsis, defined as sepsis occurring within the first 28 days of life, is associated with significant morbidity and mortality. It is undeniable that finding and appliance of biomarkers in clinical practice is of great importance, aiming at the early recognition of the impending clinical deterioration and the prompt and targeted therapeutic intervention. A er systematic and thorough research of the limited relevant literature, we attempt to present a documented point-of-view on the diagnostic value of TREM-1 and its soluble form both in early and late onset neonatal sepsis. PMID- 30467432 TI - Autonomic nervous system of the pelvis - general overview. AB - Autonomic nervous system of the pelvis is still poorly understood. Every year more and more pelvic procedures are carried out on patients suffering from different pelvic disorders what leads to numerous pelvic dysfunctions. Authors tried to review, starting from historical and clinical background, the most important reports on anatomy of the pelvic autonomic plexuses. We also pay attention to complete lack of knowledge of students of medicine on the autonomic nervous structures in the area studied. We present anatomical description of the pelvic plexuses including their visceral branches and anatomy of surrounding pelvic tissues which still remains unclear. More and more attention is paid to the topography of the plexuses specially because of new pain releasing techniques - neurolysies. PMID- 30467433 TI - Association between low-grade chronic inflammation and depressed left atrial compliance in heart failure with preserved ejection fraction: A retrospective analysis. AB - BACKGROUND: A novel paradigm of diastolic heart failure with preserved ejection fraction (HFpEF) proposed the induction of coronary microvascular dysfunction by HFpEF comorbidities via a systemic pro-inflammatory state and associated oxidative stress. The consequent nitric oxide deficiency would increase diastolic tension and favor fibrosis of adjacent myocardium, which implies not only left ventricular (LV), but all-chamber myocardial stiffening. Our aim was to assess relations between low-grade chronic systemic inflammation and left atrial (LA) pressure-volume relations in real-world HFpEF patients. METHODS: We retrospectively analyzed medical records of 60 clinically stable HpEFF patients in sinus rhythm with assayed high-sensitive C-reactive protein (CRP) during the index hospitalization. Subjects with CRP >10 mg/L or coexistent diseases, including coronary artery disease, were excluded. LV and LA diameters and mitral E/E' ratio (an index of LA pressure) were extracted from routine echocardiographic records. A surrogate measure of LA stiffness was computed as the averaged mitral E/e' ratio divided by LA diameter. RESULTS: With ascending CRP tertiles, we observed trends for elevated mitral E/e' ratio (p <0.001), increased relative LV wall thickness (p = 0.01) and higher NYHA functional class (p = 0.02). The LA stiffness estimate and log-transformed CRP levels (log-CRP) were interrelated (r = 0.38, p = 0.003). On multi- variate analysis, the LA stiffness index was independently associated with log-CRP (beta +/- SEM: 0.21 +/- 0.07, p = 0.007) and age (beta +/- SEM: 0.16 +/- 0.07, p = 0.03), which was maintained upon adjustment for LV mass index and relative LV wall thickness. CONCLUSIONS: Low-grade chronic inflammation may contribute to LA stiffening additively to age and regardless of the magnitude of associated LV hypertrophy and concentricity. LA stiffening can exacerbate symptoms of congestion in HFpEF jointly with LV remodeling. PMID- 30467434 TI - Initial experience with intracorporeal continuous ow LVAD in pediatric patients in Poland. AB - THE AIM: The aim of the study is to present the initial experience with continuous flow left ventricle assist device (CF-LVAD) in pediatric patients with BSA below 1.5 m2. MATERIAL AND METHODS: Between 2016 and 2017, CF-LVAD (the Heartware System) have been implanted in three pediatric patients in the Department of Pediatric Cardiac Surgery, Jagiellonian University, Krakow, Poland. The indications for initiating CF-LVAD were end-stage congestive heart failure due to dilated cardiomyopathy in all children. RESULTS: Implanted patients have had BSA of 1.09, 1.42, 1.2 m2, and 37, 34, 34 kg of body weight and the age 12, 11, 12 years, respectively. The time of support was 550 days in two patients and 127 in another one, and is ongoing. The main complication has been driveline infection. CONCLUSION: The outcomes from our single-center experience using the HeartWare CF-LVAD have been excellent with a low incidence of complication and no necessity to reoperation in our patients. Children could be successfully and safely discharged home. PMID- 30467435 TI - Optic nerve disc veins inflammation (papillophlebitis) - case report. AB - Papillophlebitis is an uncommon disease in clinical practice. We would like to present a case of a 29-year-old patient with atypical orbital pain and flashings, presenting relative afferent pupillary defect and already typical of the disease entity: ophthalmoscopic picture of the fundus and big blind spot in perimetry. We present a complex and interdisciplinary diagnostic process that excludes general diseases such as hypertension, diabetes, coagulation disorders and neurological causes. We leave the only identifiable abnormality and potential source in the inflammatory process of periodontal inflammation and sinus jaw changes. We also describe the process of remitting the changes and finally a favorable end result of the primarily a very disturbing clinical picture that this disease may present. PMID- 30467436 TI - Serum omentin-1 and chemerin concentrations in pancreatic cancer and chronic pancreatitis. AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by very poor prognosis. It is caused by asymptomatic course of the disease at early stage. Symptomatic PDAC means usually advanced stage of the disease, making radical treatment impossible. Finding of biological PDAC marker could improve PDAC treatment through early diagnosis. In our study, we investigated two adipokines: omentin and chemerin concentration in PDAC, chronic pancreatitis (CP) and healthy individuals. We examined 27 PDAC patients, 10 CP patients and 36 controls. To determine concentration of adipokines we used ELISA immunoenzymatic assay. Level of both adipokines was increased when comparing control group to PDAC patients. Additionally, chemerin concentration in CP group was elevated comparing to control. To evaluate both adipokines as potential PDAC biomarkers we performed ROC analysis. Chemerin (AUC = 0.913) displayed better discriminant ability than omentin-1 (AUC = 0.73). Some authors believe that chemerin may promote tumour growth by stimulating angiogenesis and is supposed to be a factor recruiting mesenchymal stroma cells (MSC) in tumour regions. Omentin-1 can inhibit tumourigenesis by TP53 stimulation. On the other hand, according to some studies, omentin-1 may promote cancer proliferation via Akt signalling pathway. Results from our study showed significantly elevated level of chemerin and omentin-1 in PDAC patients. Therefore, we believe that both investigated adipokines may provide promising and novel pharmacological insights for oncological diagnosis in the near future. PMID- 30467437 TI - Component-resolved diagnosis (CRD) of food anaphylaxis AB - Anaphylaxis is an increasing problem in public health. The food allergens (mainly milk, eggs, and peanuts) are the most frequent cause of anaphylaxis in children and youth. In order to define the cause of anaphylaxis, skin tests, the determination of the concentration of specific IgE in the blood and basophil activation test are conducted. In vitro tests are preferred due to the risk of allergic response during in vivo tests. Component-resolved diagnosis (CRD) is an additional tool in allergology, recommended in the third level of diagnostics when there are diagnostic doubts after the above mentioned tests have been carried out. The paper presents 3 cases of patients with anaphylactic response, and the application of CRD in these patients helped in planning the treatment. Patient 1 is a 4-year-old boy with diagnosed atopic dermatitis and bronchial asthma reported an anaphylactic shock at the age of seven months caused by cow's milk and the exacerbation of bronchial asthma after eating some fruit. Patient 2 is a 35-year-old woman who has had anaphylactic shock three times: in June 2015, 2016, and 2017 and associates these episodes with the consumption of dumplings with a caramel, bun, and the last episode took place during physical exertion few hours after eating waffle. Patient 3 is a 26-year-old man with one-time loss of consciousness after eating mixed nuts and drinking beer. CRD offers the possibility to conduct a detailed diagnostic evaluation of patients with a history of anaphylactic reaction. PMID- 30467438 TI - The role of vitamin D in the pathogenesis of ocular diseases. AB - The prevalence of vitamin D deficiency in the American and European population is estimated to be extremely high. Although fewer people today su er from serious health problems related to calcium and phosphate metabolism resulting from vitamin D deficiency, there are more and more studies suggesting that calcitriol may play an important role in the pathogenesis of other diseases in virtually every body system. A growing body of research shows that through its ubiquitously expressed receptor, calcitriol displays potent anti-angiogenic an anti inflammatory activity. This review summarizes recent discoveries regarding these non-classical effects of vitamin D and their clinical implications. Data collection focused on the prevention and treatment of ocular diseases as well as on the underlying mechanisms. PMID- 30467439 TI - Evaluation of plasma concentrations of selected antioxidant parameters in patients with active Crohn's disease. AB - Oxidative stress (OxS) has been implicated in the pathogenesis of Crohn's disease (CD). The aim of this study was to examine whether nonenzymatic antioxidants are associated with active CD, by using the FRAP and GSH assay in plasma. Additionally, we measured bilirubin and albumin levels as two individual components of the plasma antioxidant system. A total of 55 patients with established CD, 30 with active CD and 25 with inactive disease, and 25 healthy individuals were prospectively enrolled in this study. We evaluated CD activity index, BMI and blood morphology, platelet count, serum CRP level, and bochemical parameters of OxS: ferric reducing ability of plasma (FRAP), reduced glutathione (GSH) in plasma and bilirubin and albumin levels in serum. Plasma FRAP and GSH concentrations were decreased in both CD groups compared to controls and negatively correlated with CDAI values (FRAP: r = -0.572, p = 0.003; GSH: r = 0.761, p = 0.001), CRP and platelet count. Bilirubin and albumin levels were lower in the serum of active CD patients than inactive CD patients and controls and negatively correlated with the CD activity index (r = -0328, p = 0.036, r = 0.518, p = 0.002) and CRP (r = -0.433, p = 0.002). e decreased FRAP and GSH levels in plasma and bilirubin and albumin levels in serum of patients with active CD compared to inactive CD and controls underlines the importance of OxS in the pathophysiology and activity of CD. PMID- 30467440 TI - Obesity related adipokines release in rat adipose derived stem cell cultures influenced by pulsed electromagnetic field. AB - OBJECTIVE: The main goal of our studies was to investigate the effect exerted by pulsed electromagnetic led (PEMF) on adipocytokines secretion in cell culture supernatants from rat adipose derived stem cells (ADSCs) grown on varied energy rich diet. O spring and adult animals were randomly selected for two types of experimental diets: low (LF) or high fat (HF) diet for 7 weeks. A er the diet period, serum glucose level was measured, ADSCs were isolated from adipose tissues from different locations. ADSCs from all experimental groups were exposed to PEMF, supernatants collected and adipokines level was determined. RESULTS: HF diet feed in pups/adult animals elevated blood glucose level and increased the level of adiponectin (Apn) and leptin of both genders and age measured in serum. ADSCs cell cultures originated from female pups on LF diet and exposed to PEMF released large amounts of Apn. PEMF effect exerted on Apn release was also observed in ADSCs isolated from male pups HF diet. ADSCs from female pups on LF diet exposed to PEMF released smaller amounts of leptin in comparison to cell cultures without PEMF treatment. PEMF exposure of ADSCs cell cultures originated from female adults on LF diet decreased release of Apn, contrary adult male on LF diet ADSCs under PEMF treatment produced more leptin. PEMF treated male HF diet originated ADSCs cultures released significantly more leptin than controls. CONCLUSION: Our results suggest that PEMF exposure is responsible for metabolic physiological balance effects obtained in ADSCs cultures originating from adult animals on HF diet. PMID- 30467441 TI - Pool boiling in deep and shallow vessels and the effect of surface nano-texture and self-rewetting. AB - Pool boiling of ethanol and self-rewetting fluids on bare copper surface and copper surface with polymer nanofibers were studied experimentally. No significant effect of the depths of ethanol layer on the heat removal rate was found. That indicates that only the heat transfer in the liquid microlayer near the heater surface is a dominant factor. As a result, one can expect that self rewetting fluids can significantly affect boiling performance. Accordingly, several alcohol solutions including the self-rewetting ones were investigated as working fluids in the boiling chamber. It was found that at the 0.1% (v/v) concentration, only the high carbon-alcohol, n-heptanol in aqueous solution, improved boiling heat transfer considerably. Furthermore, the experimental study of the effect of surface nano-texture on boiling characteristics was undertaken. For that aim, polyacrylonitrile (PAN) nanofibers were deposited onto the copper heater surface. Measurements of the boiling curve revealed a detrimental effect of such nano-texture in the case of such working fluids as ethanol and self rewetting n-heptanol solutions. On the other hand, when polystyrene (PS) nanofibers were deposited onto the copper heater surface instead of PAN nanofibers, a significant improvement in boiling heat transfer was observed. The more hydrophobic nature of PS compared to copper is responsible for this effect, i.e. is the reason of the heat transfer enhancement on such a nano-textured surface compared to the pure copper one. In addition, the critical heat flux in the case of n-heptanol solution was found to be reduced considerably on the PS nano-textured surface compared to the pure copper one. This stems from the increased propensity of the heater surface to be covered by vapor, while the rewetting is insufficiently effective at high heat fluxes in presence of PS nanofibers. PMID- 30467442 TI - Vertical Profile of Cloud Optical Parameters Derived from Airborne Measurements Above, Inside and Below Clouds. AB - Past strategies for retrieving cloud optical properties from remote sensing assumed significant limits for desired parameters such as semi-infinite optical thickness, single scattering albedo equaling unity (non-absorbing scattering), absence of spectral dependence of the optical thickness, etc., and only one optical parameter could be retrieved (either optical thickness or single scattering albedo). Here, we demonstrate a new method based on asymptotic theory for thick atmospheres, and the presence of a diffusion domain within the clouds that does not put restrictions and makes it possible to get two or even three optical parameters (optical thickness, single scattering albedo and phase function asymmetry parameter) for every wavelength independently. We applied this method to measurements of angular distribution of solar radiation above, inside and below clouds, obtained with NASA's Cloud Absorption Radiometer (CAR) over two cases of marine stratocumulus clouds; first case, offshore of Namibia and the second case, offshore of California. The observational and retrieval errors are accounted for by regularization, which allows stable and smooth solutions. Results show good potential for parameterization of the shortwave radiative properties (reflection, transmission, radiative divergence and heating rate) of water clouds. PMID- 30467443 TI - A context-sensitive deep learning approach for microcalcification detection in mammograms. AB - A challenging issue in computerized detection of clustered microcalcifications (MCs) is the frequent occurrence of false positives (FPs) caused by local image patterns that resemble MCs. We develop a context-sensitive deep neural network (DNN), aimed to take into account both the local image features of an MC and its surrounding tissue background, for MC detection. The DNN classifier is trained to automatically extract the relevant image features of an MC as well as its image context. The proposed approach was evaluated on a set of 292 mammograms using free-response receiver operating characteristic (FROC) analysis on the accuracy both in detecting individual MCs and in detecting MC clusters. The results demonstrate that the proposed approach could achieve significantly higher FROC curves when compared to two MC-based detectors. It indicates that incorporating image context information in MC detection can be beneficial for reducing the FPs in detections. PMID- 30467444 TI - Synthesis of the hexacyclic triterpene core of the jujuboside saponins via tandem Wolff rearrangement-intramolecular ketene hetero-Diels-Alder reaction. AB - The jujubosides are saponin natural products reported to have immunoadjuvant, anticancer, antibacterial, antifungal, and antisweet activities. The triterpene component, jujubogenin contains a unique tricyclic ketal motif comprising the DEF ring system. Herein, we describe our efforts toward the total synthesis of jujubogenin, using a sterically-demanding intermolecular Diels-Alder reaction to assemble the C-ring and a tandem Wolff rearrangement-intramolecular ketene hetero Diels-Alder reaction to form the DF-ring system. Acid-catalyzed cyclization of the resulting bicyclic enol ether then closes the E-ring to provide the hexacyclic core of jujubogenin. PMID- 30467445 TI - Limnological Characteristics and Rotifer Community Composition of Northern Mexico Chihuahuan Desert Springs. AB - Desert springs are critical for wildlife and human subsistence, but poorly studied. The springs in the northern Chihuahuan Desert region of Mexico are no exception. While groundwater overexploitation and other anthropogenic activities have endangered these waters, little is known about their water quality or biodiversity. We monitored five springs on a monthly basis for one year, and two others sporadically, to determine their physicochemical characteristics and to study rotifer community composition as an assessment of biodiversity. Seasonal variation in temperature, dissolved oxygen (DO), and conductivity was observed in the five springs. DO was occasionally below the criterion for aquatic life (<4mg/L) in some springs. Ca2+ (468-775.2 mg/L) was the dominant ion in all springs except Ojo de Santa Maria where Na+ (180-290 mg/L) dominated. Of 57 rotifer species identified, Lepadella patella (Muller, 1786), Lepadella triptera (Ehrenberg, 1830), and Philodina megalotrocha, Ehrenberg, 1832 were present in most springs. The rotifer community exhibited nestedness among the sites (supported by four null modes, p<0.05) and was correlated with fall season, DO, and nitrate concentration. This work provides information that will aid in management practices and provide important baseline data on water quality and regional diversity of a major component of the zooplankton. PMID- 30467446 TI - Assessing Time-Varying Causal Effect Moderation in Mobile Health. AB - In mobile health interventions aimed at behavior change and maintenance, treatments are provided in real time to manage current or impending high risk situations or promote healthy behaviors in near real time. Currently there is great scientific interest in developing data analysis approaches to guide the development of mobile interventions. In particular data from mobile health studies might be used to examine effect moderators-individual characteristics, time-varying context or past treatment response that moderate the effect of current treatment on a subsequent response. This paper introduces a formal definition for moderated effects in terms of potential outcomes, a definition that is particularly suited to mobile interventions, where treatment occasions are numerous, individuals are not always available for treatment, and potential moderators might be influenced by past treatment. Methods for estimating moderated effects are developed and compared. The proposed approach is illustrated using BASICS-Mobile, a smartphone-based intervention designed to curb heavy drinking and smoking among college students. PMID- 30467447 TI - EDGE EXCHANGEABLE MODELS FOR INTERACTION NETWORKS. AB - Many modern network datasets arise from processes of interactions in a population, such as phone calls, email exchanges, co-authorships, and professional collaborations. In such interaction networks, the edges comprise the fundamental statistical units, making a framework for edge-labeled networks more appropriate for statistical analysis. In this context we initiate the study of edge exchangeable network models and explore its basic statistical properties. Several theoretical and practical features make edge exchangeable models better suited to many applications in network analysis than more common vertex-centric approaches. In particular, edge exchangeable models allow for sparse structure and power law degree distributions, both of which are widely observed empirical properties that cannot be handled naturally by more conventional approaches. Our discussion culminates in the Hollywood model, which we identify here as the canonical family of edge exchangeable distributions. The Hollywood model is computationally tractable, admits a clear interpretation, exhibits good theoretical properties, and performs reasonably well in estimation and prediction as we demonstrate on real network datasets. As a generalization of the Hollywood model, we further identify the vertex components model as a nonparametric subclass of models with a convenient stick breaking construction. PMID- 30467448 TI - The Relationship Between Intimate Partner Violence and Suicidal Ideation among Young Chinese, Korean, and Vietnamese American Women. AB - High depression and suicide rates are critical problems that have a significant impact on the lives of young Asian American women. Intimate partner violence (IPV) has been identified as a predictor of suicidality in general female samples, but no research study has examined the relationship between IPV and suicidality in a sample of 1.5 and second-generation Chinese, Korean, and Vietnamese American women. We used data collected from 173 women (aged 18-35 years) who were screened for eligibility to participate in the development and efficacy study of Asian American Women's Action for Resilience and Empowerment (AWARE). We measured the prevalence of (a) IPV, (b) lifetime suicidal ideation/intent, and (c) childhood abuse and tested the association between IPV and lifetime suicidal ideation/intent among study participants who completed the clinical screening assessments. The results indicated that seven out of 10 women in our sample experienced lifetime suicidal ideation/intent, psychological aggression was the most commonly reported form of IPV during the last six months, followed by sexual coercion, and history of physical and/or sexual partner violence had the most robust association with lifetime suicidal ideation/intent after controlling for demographic factors and childhood abuse. Our study suggests that suicide prevention and intervention programs for young 1.5 and second generation Asian American women should not only address experiences of childhood abuse, but also incorporate culturally adapted behavioral health approaches to identify and target physical and sexual partner violence. Furthermore, any such programs need to integrate a systemic approach in addressing IPV within the context of various marginalized experiences of Asian American women. PMID- 30467449 TI - Combined Effects of Backbone and N-Substituents on Structure, Bonding, and Reactivity of Alkylated Iron(II)-NHCs. AB - Iron and N-heterocyclic carbenes (NHCs) have proven to be a successful pair in catalysis, with reactivity and selectivity being highly dependent on the nature of the NHC ligand backbone saturation and N-substituents. Four (NHC)Fe(1,3-dioxan 2-ylethyl)2 complexes have been isolated and spectroscopically characterized to correlate their reactivity to steric effects of the NHC from both the backbone saturation and N-substituents. Only in the extreme case of SIPr where NHC backbone and N-substituent steric effects are the largest is there a major structural perturbation observed crystallographically. The addition of only two hydrogen atoms is sufficient for a drastic change in product selectivity in the coupling of 1-iodo-3-phenylpropane with (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide due to resulting structural perturbations to the precatalyst. Mossbauer spectroscopy and magnetic circular dichroism enabled the correlation of covalency and steric bulk in the SIPr case to its poor selectivity in alkyl-alkyl cross coupling with iron. Density functional theory calculations provided insight into the electronic structure and molecular orbital effects of ligation changes to the iron center. Finally, charge donation analysis and Mayer bond order calculations further confirmed the stronger Fe-ligand bonding in the SIPr complex. Overall, these studies highlight the importance of considering both N-substituent and backbone steric contributions to structure, bonding, and reactivity in iron-NHCs. PMID- 30467450 TI - A Structural Connectivity Approach to Validate a Model-based Technique for the Segmentation of the Pulvinar Complex. AB - The pulvinar of the thalamus is a higher-order thalamic nucleus that is responsible for gating information flow to the cortical regions of the brain. It is involved in several cortico-thalamocortical relay circuits and is known to be affected in a number of neurological disorders. Segmenting the pulvinar in clinically acquired images is important to support studies exploring its role in brain function. In recent years, we have proposed an active shape model method to segment multiple thalamic nuclei, including the pulvinar. The model was created by manual delineation of high resolution 7T images and the process was guided by the Morel stereotactic atlas. However, this model is based on a small library of healthy subjects, and it is important to validate the reliability of the segmentation method on a larger population of clinically acquired images. The pulvinar is known to have particularly strong white matter connections to the hippocampus, which allows us to identify the pulvinar from thalamic regions of high hippocampal structural connectivity. In this study, we obtained T1-weighted and diffusion MR data from 43 healthy volunteers using a clinical 3T MRI scanner. We applied the segmentation method to the T1-weighted images to obtain the intrathalamic nuclei, and we calculated the connectivity maps between the hippocampus and thalamus using the diffusion images. Our results show that the shape model segmentation consistently localizes the pulvinar in the region with the highest hippocampal connectivity. The proposed method can be extended to other nuclei to further validate our segmentation method. PMID- 30467451 TI - Tests of clustering thalamic nuclei based on various dMRI models in the squirrel monkey brain. AB - Background: Clustering thalamic nuclei is important for both research and clinical purposes. For example, ventral intermediate nuclei in thalami serve as targets in both deep brain stimulation neurosurgery and radiosurgery for treating patients suffering from movement disorders (e.g., Parkinson's disease and essential tremor). Diffusion magnetic resonance imaging (dMRI) is able to reflect tissue microstructure in the central nervous system via fitting different models, such as, the diffusion tensor (DT), constrained spherical deconvolution (CSD), neurite orientation dispersion and density imaging (NODDI), diffusion kurtosis imaging (DKI) and the spherical mean technique (SMT). Purpose: To test which of the above-mentioned dMRI models is better for thalamic parcellation, we proposed a framework of k-means clustering, implemented it on each model, and evaluated the agreement with histology. Method: An ex vivo monkey brain was scanned in a 9.4T MRI scanner at 0.3mm resolution with b values of 3000, 6000, 9000 and 12000 s/mm2. K-means clustering on each thalamus was implemented using maps of dMRI models fitted to the same data. Meanwhile, histological nuclei were identified by AChE and Nissl stains of the same brain. Overall agreement rate and agreement rate for each nucleus were calculated between clustering and histology. Sixteen thalamic nuclei on each hemisphere were included. Results: Clustering with the DKI model has slightly higher overall agreement rate but clustering with other dMRI models result in higher agreement rate in some nuclei. Conclusion: dMRl models should be carefully selected to better parcellate the thalamus, depending on the specific purpose of the parcellation. PMID- 30467452 TI - TRMM MICROWAVE IMAGER (TMI) ALIGNMENT AND ALONG-SCAN BIAS CORRECTIONS. AB - The Tropical Rainfall Measuring Mission (TRMM) Microwave Imager (TMI) dataset released by the Precipitation Processing System (PPS) has been updated to a final version following the decommissioning of the TRMM satellite in April 2015. The updates are based on increased knowledge of radiometer calibration and sensor performance issues. In particular, the Global Precipitation Measurement (GPM) Microwave Imager (GMI) is used as a model for many of the TMI updates. This paper discusses two aspects of the TMI data product that have been reanalyzed and updated: alignment and along-scan bias corrections. The TMI pointing accuracy is significantly improved over prior PPS versions, which used at-launch alignment values. ATMI instrument mounting offset is discovered as well as new alignment offsets for the two TMI feedhorns. The original TMI along-scan antenna temperature bias correction is found to be generally accurate over-ocean, but a scene temperature-dependent correction is needed to account for edge-of-scan obstruction. These updates are incorporated into the final TMI data version, improving the quality of the data product and ensuring accurate geophysical parameters can be derived from TMI. PMID- 30467453 TI - Addressing Reproducibility in Cryopreservation, and Considerations Necessary for Commercialization and Community Development in Support of Genetic Resources of Aquatic Species. AB - For the past six decades a repeated cycle of developing new cryopreservation protocols or simply reinventing them to counteract a lack of reproducibility has led to hundreds of published studies that have offered little to the establishment of a genetic resources community for aquatic species. This has hampered repository development and inhibited industrial application. Most protocols were developed without standardized approaches, leading to irreproducible studies and questionable or meaningless comparisons. Thus cryopreservation of germplasm in aquatic species would greatly benefit from strategies to facilitate reproducibility. Our objectives were to: (1) identify major sources of irreproducibility across research, small-scale, repository, and commercial-scale development levels, (2) provide recommendations to address reproducibility challenges, and (3) offer suggestions on how researchers can directly influence commercial development and application of cryopreservation research. Sources of irreproducibility include lack of standardized procedural approaches, lack of standardized terminology, and lack of reporting guidelines. To address these challenges, we propose implementation of standard operating procedures (SOP), support of stock centers and internet content for development of training programs, and strengthening of the role of scientific journals and reviewers in reducing the frequency of irreproducible outcomes. Reproducibility is the foundation for quality management programs and product reliability, and therefore standardization is necessary to assure efficient transition to commercial-scale application and repository development. Progress can only be possible through community-based approaches focused on coalescence and consensus of disparate groups involved in aquatic species cryopreservation and management of genetic resources. PMID- 30467454 TI - Multivariate left-censored Bayesian model for predicting exposure using multiple chemical predictors. AB - Environmental health exposures to airborne chemicals often originate from chemical mixtures. Environmental health professionals may be interested in assessing exposure to one or more of the chemicals in these mixtures, but often exposure measurement data are not available, either because measurements were not collected/assessed for all exposure scenarios of interest or because some of the measurements were below the analytical methods' limits of detection (i.e. censored). In some cases, based on chemical laws, two or more components may have linear relationships with one another, whether in a single or in multiple mixtures. Although bivariate analyses can be used if the correlation is high, often correlations are low. To serve this need, this paper develops a multivariate framework for assessing exposure using relationships of the chemicals present in these mixtures. This framework accounts for censored measurements in all chemicals, allowing us to develop unbiased exposure estimates. We assessed our model's performance against simpler models at a variety of censoring levels and assessed our model's 95% coverage. We applied our model to assess vapor exposure from measurements of three chemicals in crude oil taken on the Ocean Intervention III during the Deepwater Horizon oil spill response and clean-up. PMID- 30467455 TI - Metal-free Chlorothiolation of Alkenes using HCl and Sulfoxides. AB - We report a novel method for the chlorothiolation of alkenes using HCl and sulfoxides to achieve the 1,2-difunctionalization of unactivated alkenes. The combination of our new HCl reagent (HCl/DMPU) with sulfoxides forms a unique chlorothiolation system. Both terminal and internal alkenes are suitable substrates. This method works at gram scale and is applicable in further synthetic elaborations. PMID- 30467457 TI - Aging and Informed Financial Decision Making: New Tools for the Professional Working With Older Adults. PMID- 30467456 TI - Functional limitation trajectories and their determinants among women in the Philippines. AB - BACKGROUND: Limited evidence exists regarding how functional limitation patterns of women in developing countries unfold through midlife and into old age, a critical period during which the tendency to develop severe problems is fomented. OBJECTIVE: Functional limitation prevalence and patterns through midlife into early old age, and their determinants, are examined among women in the Philippines. METHODS: Data from the Cebu Longitudinal Health and Nutrition Study are monitored from 1994 to 2015. Patterns are categorized using group-based trajectory modeling. Predictors of group membership are modeled. RESULTS: About half responding to all survey waves report functional limitation at least once over the study period. Movements in and out of functional limitation states are common. Between age 30 and 70, trajectories are categorized into four groups: 1) robust, 2) late onset, 3) early onset, and 4) recovery. Being married, living in a nuclear household, higher successful birth ratio, and higher education associate with favorable trajectories. More births, higher age at first birth, wealth, and urbanicity associate with less favorable trajectories. CONCLUSION: Many possible routes into and out of functional limitation exist. The manifold patterns can be grouped into common trajectories. A number of earlier life characteristics associate with these trajectories. CONTRIBUTION: This is the first analysis to ascertain common functional limitation trajectories and earlier life predictors among women as they age in a high fertility developing country setting. Recognizing these is an important step toward understanding global health given aging of the population and the likelihood of functional problems developing in women as they move into old age. PMID- 30467458 TI - Augmentation of Physician Assessments with Multi-Omics Enhances Predictability of Drug Response: A Case Study of Major Depressive Disorder. AB - This work proposes a "learning-augmented clinical assessment" workflow to sequentially augment physician assessments of patients' symptoms and their socio demographic measures with heterogeneous biological measures to accurately predict treatment outcomes using machine learning. Across many psychiatric illnesses, ranging from major depressive disorder to schizophrenia, symptom severity assessments are subjective and do not include biological measures, making predictability in eventual treatment outcomes a challenge. Using data from the Mayo Clinic PGRN-AMPS SSRI trial as a case study, this work demonstrates a significant improvement in the prediction accuracy for antidepressant treatment outcomes in patients with major depressive disorder from 35% to 80% individualized by patient, compared to using only a physician's assessment as the predictors. This improvement is achieved through an iterative overlay of biological measures, starting with metabolites (blood measures modulated by drug action) associated with symptom severity, and then adding in genes associated with metabolomic concentrations. Hence, therapeutic efficacy for a new patient can be assessed prior to treatment, using prediction models that take as inputs, selected biological measures and physician's assessments of depression severity. Of broader significance extending beyond psychiatry, the approach presented in this work can potentially be applied to predicting treatment outcomes for other medical conditions, such as migraine headaches or rheumatoid arthritis, for which patients are treated according to subject-reported assessments of symptom severity. PMID- 30467460 TI - Electrically Controlled Neurochemical Release from Dual-Layer Conducting Polymer Films for Precise Modulation of Neural Network Activity in Rat Barrel Cortex. AB - Implantable microelectrode arrays (MEAs) are important tools for investigating functional neural circuits and treating neurological diseases. Precise modulation of neural activity may be achieved by controlled delivery of neurochemicals directly from coatings on MEA electrode sites. In this study, a novel dual-layer conductive polymer/acid functionalized carbon nanotube (fCNT) microelectrode coating is developed to better facilitate the loading and controlled delivery of the neurochemical 6,7-dinitroquinoxaline-2,3-dione (DNQX). The base layer coating is consisted of poly(3,4-ethylenedioxythiophene/fCNT and the top layer is consisted of polypyrrole/fCNT/DNQX. The dual-layer coating is capable of both loading and electrically releasing DNQX and the release dynamic is characterized with fluorescence microscopy and mathematical modeling. In vivo DNQX release is demonstrated in rat somatosensory cortex. Sensory-evoked neural activity is immediately (<1s) and locally (<446 um) suppressed by electrically triggered DNQX release. Furthermore, a single DNQX-loaded, dual-layer coating is capable of inducing effective neural inhibition for at least 26 times without observable degradation in efficacy. Incorporation of the novel drug releasing coating onto individual MEA electrodes offers many advantages over alternative methods by increasing spatial-temporal precision and improving drug selection flexibility without increasing the device's size. PMID- 30467462 TI - Multiple Sclerosis Identification by 14-Layer Convolutional Neural Network With Batch Normalization, Dropout, and Stochastic Pooling. AB - Aim: Multiple sclerosis is a severe brain and/or spinal cord disease. It may lead to a wide range of symptoms. Hence, the early diagnosis and treatment is quite important. Method: This study proposed a 14-layer convolutional neural network, combined with three advanced techniques: batch normalization, dropout, and stochastic pooling. The output of the stochastic pooling was obtained via sampling from a multinomial distribution formed from the activations of each pooling region. In addition, we used data augmentation method to enhance the training set. In total 10 runs were implemented with the hold-out randomly set for each run. Results: The results showed that our 14-layer CNN secured a sensitivity of 98.77 +/- 0.35%, a specificity of 98.76 +/- 0.58%, and an accuracy of 98.77 +/- 0.39%. Conclusion: Our results were compared with CNN using maximum pooling and average pooling. The comparison shows stochastic pooling gives better performance than other two pooling methods. Furthermore, we compared our proposed method with six state-of-the-art approaches, including five traditional artificial intelligence methods and one deep learning method. The comparison shows our method is superior to all other six state-of-the-art approaches. PMID- 30467463 TI - The Hazard Perception for the Surrounding Shape of Warning Signs: Evidence From an Event-Related Potentials Study. AB - Surrounding shape is a very important component of warning signs. Unlike colors, signal words, and pictorials that can directly convey the surface meaning, the surrounding shapes of warning signs convey warning information somewhat obscurely. Most of the researchers who studied this topic investigated the individuals' hazard perception of the surrounding shapes of warning signs by using questionnaires. In addition, the scholars' points about the role of the surrounding shapes are inconsistent. This study, therefore, decided to use Event Related Potentials (ERP) technology to explore the impact of the shapes on the perception of warning signs to find the evidences of the hazard perception of the shapes from the electrophysiological perspective. Using the Oddball paradigm, we found four components caused by different shapes of warning signs. Specifically, P200 amplitude characterizes the attraction to attention of surrounding shapes in the early automatic perception stage, the N300 components represented the emotional valance and arousal level, the P300 and the LPP connoted uneasy/unsafe information and reflected the inhibition strength on the uneasy/unsafe information. Experimental data indicated that the shape of UPRIGHT TRIANGLE had larger arousal strength and more negative valence than the shape of CIRCLE. People get stronger negative information from the UPRIGHT TRIANGLE shapes than from the CIRCLE. This finding might be helpful for designing the surrounding shapes of warning signs. PMID- 30467461 TI - Behavioral Outcomes Following Brain-Computer Interface Intervention for Upper Extremity Rehabilitation in Stroke: A Randomized Controlled Trial. AB - Stroke is a leading cause of persistent upper extremity (UE) motor disability in adults. Brain-computer interface (BCI) intervention has demonstrated potential as a motor rehabilitation strategy for stroke survivors. This sub-analysis of ongoing clinical trial (NCT02098265) examines rehabilitative efficacy of this BCI design and seeks to identify stroke participant characteristics associated with behavioral improvement. Stroke participants (n = 21) with UE impairment were assessed using Action Research Arm Test (ARAT) and measures of function. Nine participants completed three assessments during the experimental BCI intervention period and at 1-month follow-up. Twelve other participants first completed three assessments over a parallel time-matched control period and then crossed over into the BCI intervention condition 1-month later. Participants who realized positive change (>=1 point) in total ARAT performance of the stroke affected UE between the first and third assessments of the intervention period were dichotomized as "responders" (<1 = "non-responders") and similarly analyzed. Of the 14 participants with room for ARAT improvement, 64% (9/14) showed some positive change at completion and approximately 43% (6/14) of the participants had changes of minimal detectable change (MDC = 3 pts) or minimally clinical important difference (MCID = 5.7 points). Participants with room for improvement in the primary outcome measure made significant mean gains in ARATtotal score at completion (DeltaARATtotal = 2, p = 0.028) and 1-month follow-up (DeltaARATtotal = 3.4, p = 0.0010), controlling for severity, gender, chronicity, and concordance. Secondary outcome measures, SISmobility, SISadl, SISstrength, and 9HPTaffected, also showed significant improvement over time during intervention. Participants in intervention through follow-up showed a significantly increased improvement rate in SISstrength compared to controls (p = 0.0117), controlling for severity, chronicity, gender, as well as the individual effects of time and intervention type. Participants who best responded to BCI intervention, as evaluated by ARAT score improvement, showed significantly increased outcome values through completion and follow-up for SISmobility (p = 0.0002, p = 0.002) and SISstrength (p = 0.04995, p = 0.0483). These findings may suggest possible secondary outcome measure patterns indicative of increased improvement resulting from this BCI intervention regimen as well as demonstrating primary efficacy of this BCI design for treatment of UE impairment in stroke survivors. Clinical Trial Registration: ClinicalTrials.gov, NCT02098265. PMID- 30467464 TI - Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant neurogenetic disorder affecting the brain and other vital organs. Neurological symptoms include epilepsy, intellectual disability, and autism. TSC is caused by a loss-of function mutation in the TSC1 or TSC2 gene. These gene products form a protein complex and normally suppress mammalian target of rapamycin (mTOR) activity. mTOR inhibitors have been used to treat subependymal glioma (SEGA) that is a brain tumor characteristic of TSC. However, neuropathology of TSC also involves dysregulated cortical circuit formation including neuronal migration, axodendritic differentiation, and synapse formation. It is currently unknown to what extent mTOR signaling inhibitors correct an alteration in neuronal morphology that have already formed prior to the treatment. Here, we address the efficacy of rapamycin treatment on neuronal migration and dendrite formation. Using in utero electroporation, we suppressed Tsc1 expression in a fraction of neuronal progenitor cells during the fetal period. In embryonic brain slices, we found that more Tsc1-suppressed cells remained within the periventricular zone, and rapamycin treatment facilitated neuronal migration. Postnatally, Tsc1 suppressed pyramidal neurons showed more complex branching of basal dendrites and a higher spine density at postnatal day (P) 28. Aberrant arborization was normalized by rapamycin administration every other day between P1 and P13 but not P15 and P27. In contrast, abnormal spine maturation improved by rapamycin treatment between P15 and P27 but not P1 and P13. Our results indicate that there are multiple critical windows for correcting different aspects of structural abnormalities in TSC, and the responses depend on the stage of neuronal circuit formation. These data warrant a search for an additional therapeutic target to treat neurological symptoms of TSC. PMID- 30467459 TI - Machine Learning for Integrating Data in Biology and Medicine: Principles, Practice, and Opportunities. AB - New technologies have enabled the investigation of biology and human health at an unprecedented scale and in multiple dimensions. These dimensions include myriad properties describing genome, epigenome, transcriptome, microbiome, phenotype, and lifestyle. No single data type, however, can capture the complexity of all the factors relevant to understanding a phenomenon such as a disease. Integrative methods that combine data from multiple technologies have thus emerged as critical statistical and computational approaches. The key challenge in developing such approaches is the identification of effective models to provide a comprehensive and relevant systems view. An ideal method can answer a biological or medical question, identifying important features and predicting outcomes, by harnessing heterogeneous data across several dimensions of biological variation. In this Review, we describe the principles of data integration and discuss current methods and available implementations. We provide examples of successful data integration in biology and medicine. Finally, we discuss current challenges in biomedical integrative methods and our perspective on the future development of the field. PMID- 30467465 TI - Heterogeneity and Diversity of Striatal GABAergic Interneurons: Update 2018. AB - Our original review, "Heterogeneity and Diversity of Striatal GABAergic Interneurons," to which this is an invited update, was published in December, 2010 in Frontiers is Neuroanatomy. In that article, we reviewed several decades' worth of anatomical and electrophysiological data on striatal parvalbumin (PV)-, neuropeptide Y (NPY)- and calretinin(CR)-expressing GABAergic interneurons from many laboratories including our own. In addition, we reported on a recently discovered novel tyrosine hydroxylase (TH) expressing GABAergic interneuron class first revealed in transgenic TH EGFP reporter mouse line. In this review, we report on further advances in the understanding of the functional properties of previously reported striatal GABAergic interneurons and their synaptic connections. With the application of new transgenic fluorescent reporter and Cre driver/reporter lines, plus optogenetic, chemogenetic and viral transduction methods, several additional subtypes of novel striatal GABAergic interneurons have been discovered, as well as the synaptic networks in which they are embedded. These findings make it clear that previous hypotheses in which striatal GABAergic interneurons modulate and/or control the firing of spiny neurons principally by simple feedforward and/or feedback inhibition are at best incomplete. A more accurate picture is one in which there are highly selective and specific afferent inputs, synaptic connections between different interneuron subtypes and spiny neurons and among different GABAergic interneurons that result in the formation of functional networks and ensembles of spiny neurons. PMID- 30467466 TI - The Varieties of the Psychedelic Experience: A Preliminary Study of the Association Between the Reported Subjective Effects and the Binding Affinity Profiles of Substituted Phenethylamines and Tryptamines. AB - Classic psychedelics are substances of paramount cultural and neuroscientific importance. A distinctive feature of psychedelic drugs is the wide range of potential subjective effects they can elicit, known to be deeply influenced by the internal state of the user ("set") and the surroundings ("setting"). The observation of cross-tolerance and a series of empirical studies in humans and animal models support agonism at the serotonin (5-HT)2A receptor as a common mechanism for the action of psychedelics. The diversity of subjective effects elicited by different compounds has been attributed to the variables of "set" and "setting," to the binding affinities for other 5-HT receptor subtypes, and to the heterogeneity of transduction pathways initiated by conformational receptor states as they interact with different ligands ("functional selectivity"). Here we investigate the complementary (i.e., not mutually exclusive) possibility that such variety is also related to the binding affinity for a range of neurotransmitters and monoamine transporters including (but not limited to) 5-HT receptors. Building on two independent binding affinity datasets (compared to "in silico" estimates) in combination with natural language processing tools applied to a large repository of reports of psychedelic experiences (Erowid's Experience Vaults), we obtained preliminary evidence supporting that the similarity between the binding affinity profiles of psychoactive substituted phenethylamines and tryptamines is correlated with the semantic similarity of the associated reports. We also showed that the highest correlation was achieved by considering the combined binding affinity for the 5-HT, dopamine (DA), glutamate, muscarinic and opioid receptors and for the Ca+ channel. Applying dimensionality reduction techniques to the reports, we linked the compounds, receptors, transporters and the Ca+ channel to distinct fingerprints of the reported subjective effects. To the extent that the existing binding affinity data is based on a low number of displacement curves that requires further replication, our analysis produced preliminary evidence consistent with the involvement of different binding sites in the reported subjective effects elicited by psychedelics. Beyond the study of this particular class of drugs, we provide a methodological framework to explore the relationship between the binding affinity profiles and the reported subjective effects of other psychoactive compounds. PMID- 30467467 TI - An Automated Water Task to Test Visual Discrimination Performance, Adaptive Strategies and Stereotyped Choices in Freely Moving Mice. AB - We describe an automated training/testing system for adult mice that allows reliable quantification of visual discrimination capacities, adaptive swimming strategies, and stereotyped choices with minimal human intervention. The experimental apparatus consists of a hexagonal swimming pool with an internal decision zone leading to three interior arms with two software-controlled platforms inside of each arm. Each experimental trial consists in projecting a "positive" conditioned discriminative stimulus (SD) in one randomly chosen arm, whereas the other two arms project non-reinforced stimuli (the delta stimuli, SDelta). By employing a classical behavioral training schedule, the mice learn to swim toward the arm that displays the SD, because it predicts the presence of two elevated platforms located symmetrically to the left and right side of the projecting monitor. Separate behavioral components for discriminative and stereotyped choice behavior can be identified through this geometric arrangement. In addition, the projection in real-time of either static or dynamic visual stimuli allows the usage of training programs contingent on current behavioral performance. We validated the system by characterizing the visual acuity and contrast sensitivities in a group of trained mice. By employing pharmacological manipulations, we found that the mice required an intact functioning of the primary visual cortex (V1) to solve the hexagonal pool. Overall, the automated training system constitutes a reliable, rapid, and inexpensive method to quantify visual capacities of mice. It can be used to characterize visual and non-visual factors of choice behavior. It can also be combined with manipulations of visual experience and pharmacological micro-infusions to investigate integrated brain function and learning processes in adult mice over consecutive days. PMID- 30467468 TI - Comparison of Resting-State Brain Activation Detected by BOLD, Blood Volume and Blood Flow. AB - Resting-state brain activity has been widely investigated using blood oxygenation level dependent (BOLD) contrast techniques. However, BOLD signal changes reflect a combination of the effects of cerebral blood flow (CBF), cerebral blood volume (CBV), as well as the cerebral metabolic rate of oxygen (CMRO2). In this study, resting-state brain activation was detected and compared using the following techniques: (a) BOLD, using a gradient-echo echo planar imaging (GE-EPI) sequence; (b) CBV-weighted signal, acquired using gradient and spin echo (GRASE) based vascular space occupancy (VASO); and (c) CBF, using pseudo-continuous arterial spin labeling (pCASL). Reliable brain networks were detected using VASO and ASL, including sensorimotor, auditory, primary visual, higher visual, default mode, salience and left/right executive control networks. Differences between the resting-state activation detected with ASL, VASO and BOLD could potentially be due to the different temporal signal-to-noise ratio (tSNR) and the short post labeling delay (PLD) in ASL, along with differences in the spin-echo readout of VASO. It is also possible that the dynamics of spontaneous fluctuations in BOLD, CBV and CBF could differ due to biological reasons, according to their location within the brain. PMID- 30467470 TI - Editorial: Neural & Bio-inspired Processing and Robot Control. PMID- 30467469 TI - VIOLA-A Multi-Purpose and Web-Based Visualization Tool for Neuronal-Network Simulation Output. AB - Neuronal network models and corresponding computer simulations are invaluable tools to aid the interpretation of the relationship between neuron properties, connectivity, and measured activity in cortical tissue. Spatiotemporal patterns of activity propagating across the cortical surface as observed experimentally can for example be described by neuronal network models with layered geometry and distance-dependent connectivity. In order to cover the surface area captured by today's experimental techniques and to achieve sufficient self-consistency, such models contain millions of nerve cells. The interpretation of the resulting stream of multi-modal and multi-dimensional simulation data calls for integrating interactive visualization steps into existing simulation-analysis workflows. Here, we present a set of interactive visualization concepts called views for the visual analysis of activity data in topological network models, and a corresponding reference implementation VIOLA (VIsualization Of Layer Activity). The software is a lightweight, open-source, web-based, and platform-independent application combining and adapting modern interactive visualization paradigms, such as coordinated multiple views, for massively parallel neurophysiological data. For a use-case demonstration we consider spiking activity data of a two population, layered point-neuron network model incorporating distance-dependent connectivity subject to a spatially confined excitation originating from an external population. With the multiple coordinated views, an explorative and qualitative assessment of the spatiotemporal features of neuronal activity can be performed upfront of a detailed quantitative data analysis of specific aspects of the data. Interactive multi-view analysis therefore assists existing data analysis workflows. Furthermore, ongoing efforts including the European Human Brain Project aim at providing online user portals for integrated model development, simulation, analysis, and provenance tracking, wherein interactive visual analysis tools are one component. Browser-compatible, web-technology based solutions are therefore required. Within this scope, with VIOLA we provide a first prototype. PMID- 30467471 TI - Neural-Dynamic Based Synchronous-Optimization Scheme of Dual Redundant Robot Manipulators. AB - In order to track complex-path tasks in three dimensional space without joint drifts, a neural-dynamic based synchronous-optimization (NDSO) scheme of dual redundant robot manipulators is proposed and developed. To do so, an acceleration level repetitive motion planning optimization criterion is derived by the neural dynamic method twice. Position and velocity feedbacks are taken into account to decrease the errors. Considering the joint-angle, joint-velocity, and joint acceleration limits, the redundancy resolution problem of the left and right arms are formulated as two quadratic programming problems subject to equality constraints and three bound constraints. The two quadratic programming schemes of the left and right arms are then integrated into a standard quadratic programming problem constrained by an equality constraint and a bound constraint. As a real time solver, a linear variational inequalities-based primal-dual neural network (LVI-PDNN) is used to solve the quadratic programming problem. Finally, the simulation section contains experiments of the execution of three complex tasks including a couple task, the comparison with pseudo-inverse method and robustness verification. Simulation results verify the efficacy and accuracy of the proposed NDSO scheme. PMID- 30467472 TI - Herbal Medicine Formulas for Parkinson's Disease: A Systematic Review and Meta Analysis of Randomized Double-Blind Placebo-Controlled Clinical Trials. AB - Background: Parkinson's disease (PD) is a debitlitating, chronic, progressive neurodegenerative disorder without modifying therapy. Here, we aimed to evaluate the available evidence of herbal medicine (HM) formulas for patients with PD according to randomized double-blind placebo-controlled clinical trials. Methods: HM formulas for PD were searched in eight main databases from their inception to February 2018. The methodological quality was assessed using Cochrane Collaboration risk of bias tool. Meta-analysis was performed using RevMan 5.3 software. Results: Fourteen trials with Seventeen comparisons comprising 1,311 patients were identified. Compared with placebo groups, HM paratherapy (n = 16 comparisons) showed significant better effects in the assessments of total Unified Parkinson's Disease Rating Scale (UPDRS) (WMD: -5.43, 95% CI:-8.01 to 2.86; P < 0.0001), UPDRS I (WMD: -0.30, 95% CI: -0.54 to -0.06; P = 0.02), UPDRS II (WMD: -2.21, 95% CI: -3.19 to -1.22; P < 0.0001), UPDRS III (WMD: -3.26, 95% CI:-4.36 to -2.16; P < 0.00001), Parkinson's Disease Quality of Life Questionnaire (p < 0.01) and Parkinson's Disease Questionnaire-39 (WMD: -7.65, 95% CI: -11.46 to -3.83; p < 0.0001), Non-motor Symptoms Questionnaire (p < 0.01) and Non-Motor Symptoms Scale (WMD: -9.19, 95% CI: -13.11 to -5.28; P < 0.00001), Parkinson's Disease Sleep Scale (WMD: 10.69, 95% CI: 8.86 to 12.53; P < 0.00001), and Hamilton depression rating scale (WMD: -5.87, 95% CI: -7.06 to -4.68; P < 0.00001). The efficiency of HM monotherapy (n = 1 comparison) was not superior to the placebo according to UPDRS II, UPDRS III and total UPDRS score in PD patients who never received levodopa treatment, all P > 0.05. HM formulas paratherapy were generally safe and well tolerated for PD patients (RR: 0.41, 95% CI: 0.21 to 0.80; P = 0.009). Conclusion: The findings of present study supported the complementary use of HM paratherapy for PD patients, whereas the question on the efficacy of HM monotherapy in alleviating PD symptoms is still open. PMID- 30467473 TI - Pre-aging of the Olfactory Bulb in Major Depression With High Comorbidity of Mental Disorders. AB - Recent studies suggest that accelerated aging of the brain is a neuroanatomical signature of the state of mental diseases. In major depression, this pre-aging effect is negatively associated with the duration since the first onset of the disease. The olfactory bulb (OB) shrinks with age in healthy subjects and patients with mental diseases show reduced OB volumes, especially those with major depression. It is unclear whether this OB reduction in mental diseases resembles a pre-aging process and whether it is associated to the duration since the onset of the mental disease. To this aim, we investigated OB volume in 73 patients (mean-age 40.4 years, SD = 12.1 years, 57 women) with major depression and mixed comorbid mental diseases (diagnoses ranged from 1 to 6, median: 3) and 51 healthy controls (mean-age 39.2 years, SD = 13.0 years, 26 women) matched for age and sex. Patient's first onset of disease ranged from 15 to 53 years (mean 24.2 years). All participants underwent structural MR imaging with a spin-echo T2 wheighted sequence covering the anterior and middle segments of the skull base. All results were corrected for total intracranial volume (TIV) and sex. Individual OB volume was calculated by planimetric manual contouring and the pronounced diameter change in transition from bulb to tract was used as the distal demarcation of the OB. Inter-rater correlation between two independent persons analyzing the data was high (IRC = 0.81, p < 0.005). An age-dependent decline of the OB volume was confirmed in healthy controls (r = -0.34, p < 0.05). However, this pattern was altered in patients where the OB volume was not related to age, but to the duration since the onset of the mental disease (r = -0.25, p < 0.05). This association remained stable when controlling for age. Additionally, analyses of age sub-groups revealed that the association between duration since the onset of the mental disease and OB volume was mainly driven by the group aged 50 years and above (r = -0.68; p < 0.01). We conclude that there are time windows where the OB volume is susceptible for the effects of a mental disease, e.g., depression. These effects result in cumulative pre-aging in the OB in older patients with mental diseases. PMID- 30467474 TI - Effects of Inter-Stimulus Interval on Speech-Evoked Frequency-Following Response in Elderly Adults. AB - Background: The speech-evoked frequency following response (FFR) has shown to be useful in assessing complex auditory processing abilities and in different age groups. While many aspects of FFR have been studied extensively, the effect of timing, as measured by inter-stimulus-interval (ISI), especially in the older adult population, has yet to be thoroughly investigated. Objective: The purpose of this study was to examine the effects of different ISIs on speech evoked FFR in older and younger adults who speak a tonal language, and to investigate whether the older adults' FFR were more susceptible to the change in ISI. Materials and Methods: Twenty-two normal hearing participants were recruited in our study, including 11 young adult participants and 11 elderly participants. An Intelligent Hearing Systems Smart EP evoke potential system was used to record the FFR in four ISI conditions (40, 80, 120 and 160 ms). A recorded natural speech token with a falling tone /yi/ was used as the stimulus. Two indices, stimulus-to-response correlation coefficient and pitch strength, were used to quantify the FFR responses. Two-way analysis of variance (ANOVA) was used to analyze the differences in different age groups and different ISI conditions. Results: There was no significant difference in stimulus-to-response correlation coefficient and pitch strength among the different ISI conditions, in either age groups. Older adults appeared to have weaker FFR for all ISI conditions when compared to their younger adult counterparts. Conclusion: Shorter ISIs did not result in worse FFRs from older adults or younger adults. For speech-evoked FFR using a recorded natural speech token that is 250 ms in length, an ISI of as short as 40 ms appeared to be sufficient and effective to record FFR for elderly adults. PMID- 30467475 TI - Educational Attainment Moderates the Association Between Hippocampal Volumes and Memory Performances in Healthy Older Adults. AB - Objective: To examine whether educational attainment, as a proxy of cognitive reserve, moderated the association between hippocampal volumes and episodic verbal memory performances in healthy older adults. Methods: Data from 76 community dwelling older adults were included in the present study. Measures of hippocampal volumes (total, left, and right) were obtained using FreeSurfer software. Immediate and delayed verbal recall scores were derived from performances on the California Verbal Learning Test-Second Edition and the Wechsler Memory Scale- Third Edition. Educational attainment was defined by years of education. Linear regression analyses were performed using immediate and delayed recall as dependent variables and hippocampal volumes, years of education, and their interaction terms as independent variables. All analyses were controlled for age, sex, depression, and health status. Results: Total and left Hippocampal volumes had a positive main effect on delayed recall only. Additionally, the interaction between total, left, and right hippocampal volumes and education was a significant predictor for delayed recall performance but not for immediate recall performance. The positive association between hippocampal volumes and delayed recall was greatest in those with more years of education. Conclusion: Larger hippocampal volumes were associated with better delayed verbal recall and the effect on delayed recall was greatest in those with more years of education. Having higher levels of education, or cognitive reserve, may enable individuals to capitalize on greater structural integrity in the hippocampus to support delayed recall in old age. However, longitudinal research is needed to investigate the directionality of these associations. PMID- 30467476 TI - Correspondence Between Resting-State and Episodic Memory-Task Related Networks in Elderly Subjects. AB - Resting-state fMRI studies demonstrated temporally synchronous fluctuations in brain activity among ensembles of brain regions, suggesting the existence of intrinsic functional networks. A spatial match between some of the resting-state networks and regional brain activation during cognitive tasks has been noted, suggesting that resting-state networks support particular cognitive abilities. However, the spatial match and predictive value of any resting-state network and regional brain activation during episodic memory is only poorly understood. In order to address this research gap, we obtained fMRI acquired both during rest and a face-name association task in 38 healthy elderly subjects. In separate independent component analyses, networks of correlated brain activity during rest or the episodic memory task were identified. For the independent components identified for task-based fMRI, the design matrix of successful encoding or retrieval trials was regressed against the time course of each of the component to identify significantly activated networks. Spatial regression was used to assess the match of resting-state networks against those related to successful memory encoding or retrieval. We found that resting-state networks covering the medial temporal, middle temporal, and frontal areas showed increased activity during successful encoding. Resting-state networks located within posterior brain regions showed increased activity during successful recognition. However, the level of resting-state network connectivity was not predictive of the task related activity in these networks. These results suggest that a circumscribed number of functional networks detectable during rest become engaged during successful episodic memory. However, higher intrinsic connectivity at rest may not translate into higher network expression during episodic memory. PMID- 30467477 TI - Identification of Glycine Receptor alpha3 as a Colchicine-Binding Protein. AB - Colchicine (Col) is considered a kind of highly effective alkaloid for preventing and treating acute gout attacks (flares). However, little is known about the underlying mechanism of Col in pain treatment. We have previously developed a customized virtual target identification method, termed IFPTarget, for small molecule target identification. In this study, by using IFPTarget and ligand similarity ensemble approach (SEA), we show that the glycine receptor alpha 3 (GlyRalpha3), which play a key role in the processing of inflammatory pain, is a potential target of Col. Moreover, Col binds directly to the GlyRalpha3 as determined by the immunoprecipitation and bio-layer interferometry assays using the synthesized Col-biotin conjugate (linked Col and biotin with polyethylene glycol). These results suggest that GlyRalpha3 may mediate Col-induced suppression of inflammatory pain. However, whether GlyRalpha3 is the functional target of Col and serves as potential therapeutic target in gouty arthritis requires further investigations. PMID- 30467478 TI - Selective Blockade of HCN1/HCN2 Channels as a Potential Pharmacological Strategy Against Pain. AB - A prominent role of hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels has been suggested based on their expression and (dys)function in dorsal root ganglion (DRG) neurons, being likely involved in peripheral nociception. Using HCN blockers as antinociceptive drugs is prevented by the widespread distribution of these channels. However, tissue-specific expression of HCN isoforms varies significantly, HCN1 and HCN2 being considered as major players in DRG excitability. We characterized the pharmacological effect of a novel compound, MEL55A, able to block selectively HCN1/HCN2 isoforms, on DRG neuron excitability in-vitro and for its antiallodynic properties in-vivo. HEK293 cells expressing HCN1, HCN2, or HCN4 isoforms were used to verify drug selectivity. The pharmacological profile of MEL55A was tested on mouse DRG neurons by patch-clamp recordings, and in-vivo in oxaliplatin-induced neuropathy by means of thermal hypersensitivity. Results were compared to the non-isoform-selective drug, ivabradine. MEL55A showed a marked preference toward HCN1 and HCN2 isoforms expressed in HEK293, with respect to HCN4. In cultured DRG, MEL55A reduced I h amplitude, both in basic conditions and after stimulation by forskolin, and cell excitability, its effect being quantitatively similar to that observed with ivabradine. MEL55A was able to relieve chemotherapy-induced neuropathic pain. In conclusion, selective blockade of HCN1/HCN2 channels, over HCN4 isoform, was able to modulate electrophysiological properties of DRG neurons similarly to that reported for classical I h blockers, ivabradine, resulting in a pain-relieving activity. The availability of small molecules with selectivity toward HCN channel isoforms involved in nociception might represent a safe and effective strategy against chronic pain. PMID- 30467480 TI - Spectral and Multifractal Signature of Cortical Spreading Depolarisation in Aged Rats. AB - Cortical spreading depolarisation (CSD) is a transient disruption of ion balance that propagates along the cortex. It has been identified as an important factor in the progression of cerebral damage associated with stroke or traumatic brain injury. We analysed local field potential signals during CSD in old and young rats to look for age-related differences. We compared CSDs elicited under physiological conditions (baseline), during ischaemia and during reperfusion. We applied short-time Fourier transform and a windowed implementation of multifractal detrended fluctuation analysis to follow the electrophysiological signature of CSD. Both in the time-dependent spectral profiles and in the multifractal spectrum width, CSDs appeared as transient dips, which we described on the basis of their duration, depression and recovery slope and degree of drop and rise. The most significant age-related difference we found was in the depression slope, which was significantly more negative in the beta band and less negative in the delta band of old animals. In several parameters, we observed an attenuation-regeneration pattern in reaction to ischaemia and reperfusion, which was absent in the old age group. The age-related deviation from the pattern took two forms: the rise parameter did not show any attenuation in ischaemic conditions for old animals, whilst the depression slope in most frequency bands remained attenuated during reperfusion and did not regenerate in this age group. Though the multifractal spectrum width proved to be a reliable indicator of events like CSDs or ischaemia onset, we failed to find any case where it would add extra detail to the information provided by the Fourier description. PMID- 30467481 TI - Editorial: The Red Cell Life-Cycle From Erythropoiesis to Clearance. PMID- 30467479 TI - Bile Acids and Their Derivatives as Potential Modifiers of Drug Release and Pharmacokinetic Profiles. AB - Bile acids have received considerable interest in the drug delivery research due to their peculiar physicochemical properties and biocompatibility. The main advantage of bile acids as drug absorption enhancers is their ability to act as both drug solubilizing and permeation-modifying agents. Therefore, bile acids may improve bioavailability of drugs whose absorption-limiting factors include either poor aqueous solubility or low membrane permeability. Besides, bile acids may withstand the gastrointestinal impediments and aid in the transporter-mediated absorption of physically complexed or chemically conjugated drug molecules. These biomolecules may increase the drug bioavailability also at submicellar levels by increasing the solubility and dissolution rate of non-polar drugs or through the partition into the membrane and increase of membrane fluidity and permeability. Most bile acid-induced effects are mediated by the nuclear receptors that activate transcriptional networks, which then affect the expression of a number of target genes, including those for membrane transport proteins, affecting the bioavailability of a number of drugs. Besides micellar solubilization, there are many other types of interactions between bile acids and drug molecules, which can influence the drug transport across the biological membranes. Most common drug bile salt interaction is ion-pairing and the formed complexes may have either higher or lower polarity compared to the drug molecule itself. Furthermore, the hydroxyl and carboxyl groups of bile acids can be utilized for the covalent conjugation of drugs, which changes their physicochemical and pharmacokinetic properties. Bile acids can be utilized in the formulation of conventional dosage forms, but also of novel micellar, vesicular and polymer-based therapeutic systems. The availability of bile acids, along with their simple derivatization procedures, turn them into attractive building blocks for the design of novel pharmaceutical formulations and systems for the delivery of drugs, biomolecules and vaccines. Although toxic properties of hydrophobic bile acids have been described, their side effects are mostly produced when present in supraphysiological concentrations. Besides, minor structural modifications of natural bile acids may lead to the creation of bile acid derivatives with the reduced toxicity and preserved absorption-enhancing activity. PMID- 30467482 TI - Identification of 10 SUMOylation-Related Genes From Yellow Catfish Pelteobagrus fulvidraco, and Their Transcriptional Responses to Carbohydrate Addition in vivo and in vitro. AB - SUMOylation is a kind of important post-translational modification. In the present study, we identified 10 key genes involved in SUMOylation and deSUMOylation (sumo1, sumo2, sumo3, sae1, uba2, ubc9, pias1, senp1, senp2, and senp3) in yellow catfish Pelteobagrus fulvidraco, investigated their tissue expression patterns and transcriptional responses to carbohydrate addition both in vivo and in vitro. All of these members shared similar domains to their orthologous genes of other vertebrates. Their mRNAs were widely expressed in all the tested tissues, but at variable levels. Dietary carbohydrate levels differentially influenced the mRNA levels of these genes in liver, muscle, testis, and ovary of yellow catfish. Their mRNA levels in primary hepatocytes were differentially responsive to glucose addition. Our study would contribute to our understanding into the molecular basis of SUMOylation modification and into the potential SUMOylation function in the carbohydrate utilization in fish. PMID- 30467483 TI - Psychological Burden in Female, Iraqi Refugees Who Suffered Extreme Violence by the "Islamic State": The Perspective of Care Providers. AB - Introduction: A large number of refugees suffer from mental disorders such as post-traumatic stress disorder (PTSD). In the context of a special quota project, 1100 Yazidi women from Northern Iraq who had suffered extreme violence by the so called Islamic State (IS) were brought to Germany to receive specialized treatment. This study aims to investigate the psychological burden and trauma related symptoms of these female IS-victims from the perspectives of their care providers. Material and methods: Care providers with various professional backgrounds (N = 96) were asked to complete a self-developed questionnaire on a Likert-type scale ranging from 1 (very low) to 7 (very high) analyzing the psychological burden and trauma-related symptoms of the IS-traumatized women since their arrival in Germany. We controlled for potential confounders, namely the care providers' personal experiences of trauma and flight, by using chi square tests. Results: The mean psychological burden for the whole period in Germany as perceived by care providers was M = 5.51 (SD = 0.94). As the main factors of distress the care providers reported: worries about family members in Iraq (M = 6.69; SD = 0.69), worries about relatives' possibilities to be granted asylum in Germany (M = 6.62; SD = 0.68), and uncertainties regarding their future (M = 5.89; SD = 1.02). The most prominent trauma-related psychological symptoms were nightmares (M = 6.43; SD = 0.54). The care providers reported that somatic complaints have been present among the refugees in the following manifestation: pain (M = 6.24; SD = 1.08), gastrointestinal complaints (M = 4.62; SD = 1.62), and dizziness (M = 4.40; SD = 1.59). The care providers' personal experiences of trauma and flight had no significant influence on their response behavior. Discussion: Care providers working with IS-traumatized female refugees evaluate the psychological burden and trauma-related somatic and psychological symptom loads of their clients as very high. The results of this study provide important information about the perceptions of care providers working in a refugee-services context and may provide insights for the progression of specialized treatment programs and interventions for highly traumatized refugees and culture-sensitive training programs for their care providers. PMID- 30467484 TI - The Body as Evidence for the Nature of Language. AB - Taking its cue from sign languages, this paper proposes that the recruitment and composition of body actions provide evidence for key properties of language and its emergence. Adopting the view that compositionality is the fundamental organizing property of language, we show first that actions of the hands, face, head, and torso in sign languages directly reflect linguistic components, and illuminate certain aspects of compositional organization among them that are relevant for all languages, signed and spoken. Studies of emerging sign languages strengthen the approach by showing that the gradual recruitment of bodily articulators for linguistic functions directly maps the way in which a new language increases in complexity and efficiency over time. While compositional communication is almost exclusively restricted to humans, it is not restricted to language. In the spontaneous, intense emotional displays of athletes, different emotional states are correlated with actions of particular face and body features and feature groupings. These findings indicate a much more ancient communicative compositional capacity, and support a paradigm that includes visible body actions in the quest for core linguistic properties and their origins. PMID- 30467486 TI - Creativity in the Here and Now: A Generic, Micro-Developmental Measure of Creativity. AB - Creativity is a relevant yet elusive concept, and consequently there is a large range of methods to assess creativity in many different contexts. Broadly speaking, we can differentiate between creativity measures on the level of the person (such as the Torrance tests), the level of the creative product (consensual assessment), and the level of the creative process. In the recent literature on children's creativity, 80% of the studies employed measures on either the person or the product level (Kupers et al., submitted). However, for parents, teachers, and employers who wish to stimulate creativity, insight in the (often socially embedded) creative process is badly needed. This move from the inter-individual to the intra-individual level of assessment is furthermore in line with research in many other domains in psychology. Although there is some research focusing more on detailed descriptions of creative processes, the studies are usually purely qualitative and therefore highly context-specific, making generalization difficult. In this paper, we present a newly developed coding frame as a systematic, generic, micro-level measure of creativity. What is unique about this coding frame is that it can be applied to observations of creative processes in many different contexts, and for different kinds of creative tasks. The core of the instrument is that it allows us to assess the two core components of creativity - novelty and appropriateness on an ordinal 4-point scale, at each moment during the creative process. The coding frame can be applied in three steps. The first step is to determine the unit of analysis, that is, the level of detail in which the creative process is assessed. The second step and third steps are coding the units on two ordinal scales of novelty and appropriateness, respectively. In order to illustrate the versatility of our instrument, we apply it to two cases of very different creative processes: a musical composition task (open-ended) and a scientific reasoning task (closed- ended). Last, we demonstrate the possibilities for analyzing this type of dense intra-individual measurements of creativity (time series analysis and state space grids) and discuss the future research that is needed to fully validate the instrument. PMID- 30467485 TI - Satisfaction With the Self-Assessment of University Students Through e-Coping With Academic Stress Utility TM. AB - The general purpose of this report is: (1) research was to check whether the degree of satisfaction with the self-assessment activity of university students was related to the scores obtained and the degree of different variables, associated with level of Self-Regulation; (2) to present the online utility, e Coping with Academic Stress TM, as a technological development in Educational Psychology; (3) analyze the possibilities of transfer of this technological innovation. A total of 929 university students, coming from a public university, participated in the use of this online utility. University students can use the tool's online inventories to make self-assessments in the different variables of Studying, Learning and Performing under Stress (SLPS Competency Model). Descriptives, correlational and inferential analyzes (ANOVAs and MANOVAs) were carried out. The results allowed to know the profile of competences of the analyzed university students, in addition to the degree of satisfaction with the self-evaluation. Finally, we communicate possible actions and options available for transfer of this resulting technology, through RD transfer contracts arranged directly or with other universities. PMID- 30467487 TI - Determining the Types of Contrasts: The Influences of Prosody on Pragmatic Inferences. AB - This study explores the issues involving pragmatic inferences with prosodic cues. Although there is a well-established literature from multiple languages demonstrating how different pragmatic inferences can be applied to the same syntactic structure, few studies discuss whether prosody can determine types of alternative sets based on the same syntactic structure. In Mandarin Chinese, the same sentence containing a numeral-classifier phrase as a negative polarity item can be employed for two types of scalar inferences based on either the numeral or the noun. The sentence wo yi zhi mayi dou mei kan dao ("I didn't even see one ant") can induce two different scalar inferences: Quantity-contrast ('I did not see one ant, much less two ants, three ants, and so on' by drawing a contrast against the minimal quantity of one), and Type-contrast ('I did not see an ant, much less a dog, a cat, a human being, and so on' by drawing a contrast against the minimally surprising type, that of ants). Taking advantage of similar sentences with the syntactic structure and lexical items, our study examines whether prosodic conditions can guide people to choose pragmatic inferences from a set of options based on the same syntactic structure. The experiments of this study are designed to answer whether prosody interacts with contextual information in this grammatical structure. The results suggest that Mandarin speakers can use sentence prosody to determine which inference is intended, at least in experimental contexts that directly probe explicit awareness of prosody. Prosody does play a role in inducing scalar inferences, but contextual information can override the effects of prosody. Each prosodic pattern can evoke a specific set of scalar inferences, but quantity-contrast inferences are favored over type-contrast inferences. Our experiments show that prosodic prominence can serve as a linguistic cue to pragmatic inferences. PMID- 30467488 TI - The Mediating Role of Health Consciousness in the Relation Between Emotional Intelligence and Health Behaviors. AB - The goals of this study were to identify groups of health-related behaviors among young adults (N = 314, Mage = 21.94, SD = 6.53), gauge the relation between emotional intelligence and health behaviors in this population, and assess health consciousness as mediator of said relation. Latent class analysis identified two mutually exclusive health behavior groups, which according to response patterns were labeled as Healthy and Unhealthy. The Healthy group (56%) was composed of individuals who had a healthy diet (i.e., low fat and high fiber), exercised regularly, and who frequently engaged in behaviors that prevent oral and skin related diseases. In contrast, the Unhealthy group (44%) rarely engaged in these health-promoting behaviors. Using structural equation modeling we found a negative relation between emotional intelligence and unhealthy behaviors relative to health-promoting ones. Mediation analyses indicated that the mechanism explaining said relation was through increments in health consciousness, with large standardized indirect effects ranging between -0.52 and -0.78. As health behaviors during early adulthood are salient predictors of health outcomes in old age, the results have clear implications for the inclusion of emotional intelligence training in programs seeking to raise health awareness and cultivate health promoting behaviors in young adults, in so much as to seek to reduce the risk of chronic ailments later in life. PMID- 30467489 TI - Early Detection of Cerebral Infarction With Middle Cerebral Artery Occlusion With Functional Near-Infrared Spectroscopy: A Pilot Study. AB - Background: NIRSIT, a functional near-infrared spectroscopy (fNIRS) device with 204 channels, can measure oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR) in non pulsatile blood flow non-invasively using the absorption difference between HbO2 and HbR at a wavelength of 700-1,000 nm and can display the perfusion status in real time. Objective: We applied NIRSIT to patients with stroke to evaluate the usefulness of NIRSIT as an fNIRS device for the early detection of stroke. Methods: We performed a prospective pilot study in an emergency department (ED). Adult patients who had suspected symptoms and signs of stroke within 12 h of the first abnormal time and who underwent intravenous thrombolysis (IVT) or intra arterial thrombectomy with acute middle cerebral artery (MCA) or internal carotid artery (ICA) infarction were enrolled. NIRSIT was applied to the patients before the imaging study, and the perfusion status of the brain was displayed in real time at the bedside. We compared the NIRSIT results with the mean transit time (MTT) map from perfusion computed tomography (PCT) and the time-to-peak (TTP) map from perfusion-weighted magnetic resonance imaging (PWI). Results: Six male and three female patients were enrolled, and the median age was 74 years. The most common symptom was unilateral extremity weakness (77.8%), followed by dysarthria (33.3%) and aphasia (11.1%). The median National Institutes of Health Stroke Scale (NIHSS) score was 17. All cases of MCA infarction showed different cerebral oxygen saturation values between bilateral lobes of the brain in fNIRS imaging, and these values matched the PCT and PWI results. Conclusions: The brain hemisphere with low oxygen saturation on fNIRS showed hypoperfusion on PCT or PWI. The fNIRS device could be useful in assessing the perfusion status of the brain and detecting MCA or ICA infarction in real time at the bedside. PMID- 30467490 TI - GNE Myopathy With Novel Mutations and Pronounced Paraspinal Muscle Atrophy. AB - GNE myopathy is characterized by distal muscle weakness, and caused by recessive mutations in GNE. Its onset is characteristically in young adulthood, although a broad spectrum of onset age is known to exist. A large number of mutations in GNE are pathogenic and this clinical phenotype can be difficult to differentiate clinically from other late-onset myopathies. We describe two families with novel mutations in GNE, and describe their clinical and MRI features. We also describe the presence of striking paraspinal muscle involvement on MRI of the lumbar spine, which is an under-recognized feature of GNE myopathy. PMID- 30467491 TI - Machine Learning in Acute Ischemic Stroke Neuroimaging. AB - Machine Learning (ML) through pattern recognition algorithms is currently becoming an essential aid for the diagnosis, treatment, and prediction of complications and patient outcomes in a number of neurological diseases. The evaluation and treatment of Acute Ischemic Stroke (AIS) have experienced a significant advancement over the past few years, increasingly requiring the use of neuroimaging for decision-making. In this review, we offer an insight into the recent developments and applications of ML in neuroimaging focusing on acute ischemic stroke. PMID- 30467493 TI - Levothyroxine Replacement Improves Oxidative Status in Primary Hypothyroidism. AB - Objective: Although hypothyroidism has been linked to oxidative stress, data regarding the relationship between thyroid hormone levels and oxidative stress is still inconsistent. This study was designed to evaluate the effect of levothyroxine replacement on oxidative stress in women with primary hypothyroidism. Design: A total of 25 female patients with primary hypothyroidism were included. Oxidative stress markers were measured before and after levothyroxine replacement treatment in all patients. Methods: Oxidative stress was evaluated through the measurement of oxidants (thiobarbituric acid reactive substances [TBARS] and nitrite/nitrate levels), and antioxidants (superoxide dismutase and catalase activity). Results: Antioxidant catalase activity (63.77 +/- 23.8 vs. 50.12 +/-12.75 atv/min; p = 0.03) was significantly increased and the levels of TBARS (3.02 +/- 0.86 vs. 3.55 +/- 0.87 MUM; p = 0.03) were significantly decreased in the state of euthyroidism after levothyroxine replacement compared to the hypothyroidism before levothyroxine treatment. No significant change in neither nitrite/nitrate concentration (p = 0.18) nor in superoxide dismutase activity (p = 0.93) after L-T4 adjustment was found. Conclusions: Our data demonstrate that levothyroxine replacement improved oxidative status in patients with primary hypothyroidism, indexed by the significantly decreased levels of malonaldehyde (MDA) and increased catalase (CAT) activity. PMID- 30467492 TI - Lipid Metabolism Alteration by Endocrine Disruptors in Animal Models: An Overview. AB - Exposure to potential Endocrine Disrupting Chemicals (EDCs) pose a documented risk to both wildlife and human health. Many studies so far described declining sperm counts, genital malformations, early puberty onset, highlighting the negative impact on reproduction caused by the exposure to many anthropogenic chemicals. In the last years, increasing evidence suggested that these compounds, other than altering reproduction, affect metabolism and induce the onset of obesity and metabolic disorders. According to the "environmental obesogens" hypothesis, evidence exists that exposure to potential EDCs during critical periods when adipocytes are differentiating, and organs are developing, can induce diseases that manifest later in the life. This review summarizes the effects occurring at the hepatic level in different animal models, describing morphological alterations and changes of molecular pathways elicited by the toxicant exposure. Results currently available demonstrated that these chemicals impair normal metabolic processes via interaction with members of the nuclear receptor superfamily, including steroid hormone receptors, thyroid hormone receptors, retinoid X receptors, peroxisome proliferator-activated receptors, liver X receptors, and farnesoid X receptors. In addition, novel results revealed that EDC exposure can either affect circadian rhythms as well as up-regulate the expression of signals belonging to the endocannabinoid system, in both cases leading to a remarkable increase of lipid accumulation. These results warrant further research and increase the interest toward the identification of new mechanisms for EDC metabolic alterations. The last part of this review article condenses recent evidences on the ability of potential EDCs to cause "transgenerational effects" by a single prenatal or early life exposure. On this regard, there is compelling evidence that epigenetic modifications link developmental environmental insults to adult disease susceptibility. This review will contribute to summarize the mechanisms underlying the insurgence of EDC induced metabolic alterations as well as to build integrated strategies for their better management. In fact, despite the large number of results obtained so far, there is still a great demand for the development of frameworks that can integrate mechanistic and toxicological/epidemiological observations. This would increase legal and governmental institution awareness on this critical environmental issue responsible for negative consequences in both wild species and human health. PMID- 30467494 TI - 25(OH)D Concentration in Neonates, Infants, and Toddlers From Poland-Evaluation of Trends During Years 1981-2011. AB - Introduction: The numerous evidence showing spectrum of vitamin D effects on human health resulted in both updates of vitamin D supplementation guidelines for general population and concerns on potential risk of hypercalcaemia. The aim of this study was to analyse trends in serum 25-hydroxyvitamin D concentration (25(OH)D) change over the 30 years of operation of a single pediatric diagnostic unit. Materials and methods: Calcium-phosphate metabolism markers and 25(OH)D concentrations were analyzed in a group that consisted of newborns and infants commissioned for diagnostics due to suspected calcium-phosphate metabolic disturbances (n = 3,163; mean age 8.0 +/- 3.0 months). Results: 25(OH)D < 10 ng/ml was noted in 4.5% of patients (n = 163), 10-20 ng/ml in 14.7% (n = 465), 20 30 ng/ml in 23.9% (n = 756) and 30-50 ng/ml in 35.9% (n = 1,136). The mean 25(OH)D concentration in analyzed group was 37.5 +/- 24.5 ng/ml. In patients with 25(OH)D concentration < 10 ng/ml a normal calcaemia (2.25-2.65 mmol/l) was noted in 83.4% cases (n = 136). Eighty one patients had 25(OH)D concentrations above 100 ng/ml with co-existing calcaemia in range of 2.6-4.38 mmol/l (mean Ca = 2.69 mmol/l). Hypocalcaemia (Ca < 2.25 mmol/l) was observed in 0.54%, (n = 17). 13.8% patients revealed calcium levels >2.65 mmol/l (n = 435). In general, the mean calcium-phosphate markers values were within the reference range for age. The highest mean 25(OH)D concentration of 51.8 ng/ml +/- 38.8 was noted in years 1981 1999 (n = 305). The lowest mean 25(OH)D value was observed in years 2010-2011 (29.0 ng/ml +/- 13.6; n = 412). The trend of decreasing 25(OH)D concentration during analyzed time period was significant (r = -0.29, p < 0.0001). Conclusions: Eighty percentage of children aged 0-36 months had 25(OH)D concentration >20 ng/ml, however, during 3 decades a mean 25(OH)D concentrations trended significantly to decrease. A direct relationship between low 25(OH)D concentration and hypocalcaemia was not observed nor between high 25(OH)D concentration and hypercalcemia. PMID- 30467495 TI - Purification and Characterization of an Active Principle, Lawsone, Responsible for the Plasmid Curing Activity of Plumbago zeylanica Root Extracts. AB - Plasmid curing is the process of obviating the plasmid encoded functions such as antibiotic resistance, virulence, degradation of aromatic compounds, etc. in bacteria. Several plasmid curing agents have been reported in literature, however, no plasmid curing agent can eliminate all plasmids from different hosts. Hence, there is always a need for novel plasmid curing agents that can be effectively used for reversal of plasmid encoded functions such as virulence, antibiotic resistance, etc. In the present study, an active principle responsible for the plasmid curing activity was purified from roots of Plumbago zeylanica by bioassay guided fractionation and identified as 2-hydroxy-1,4-naphthoquinone (lawsone), on the basis of spectral and analytical data such as NMR, GCMS, FTIR. Plasmid curing activity of lawsone was observed against reference as well as wild plasmids (pBR322, pRK2013, R136, pUPI281, and pUPI282) residing in a range of hosts. Curing of plasmid was confirmed by agarose gel electrophoresis. MICs of antibiotics against A. baumannii A24 (pUPI281) and E. coli (pRK2013) decreased significantly in presence of lawsone suggesting synergy between lawsone and antibiotics. Lawsone also inhibited transfer of plasmid pRK2013 to E. coli either by transformation or conjugation. Viability assays (MTT) revealed that lawsone was not toxic to mammalian cells. Thus, the present investigation has revealed lawsone as an effective plasmid curing agent capable of suppressing development and spread of antibiotic resistance. Further, lawsone has important application in basic research to identify phenotypes encoded by the plasmids in plasmid curing experiments. To the best of our knowledge this is the first report of plasmid curing activity of lawsone isolated from roots of P. zeylanica. PMID- 30467496 TI - A Bridge Too Far? An Integrative Framework Linking Classical Protist Taxonomy and Metabarcoding in Lower Termites. PMID- 30467498 TI - Functional Analysis of the Melanin-Associated Gene CmMR1 in Coniothyrium minitans. AB - Coniothyrium minitans is a sclerotial parasite, which has been investigated for commercial control of crop diseases caused by Sclerotinia sclerotiorum. Previously, we obtained a T-DNA insertional mutant, ZS-1TN24363, which did not produce melanin during conidiation. To understand the function of melanin in C. minitans, we cloned the gene that was disrupted by the T-DNA insertion, and found that this gene, called CmMR1, encoded a putative protein of 1,011 amino acids, which is a homolog of the transcription factor MR. Full-length CmMR1 contains 3,167 bp, with three exons and two introns. To confirm that the disrupted gene is responsible for the melanin-deficiency of the mutant, CmMR1 was disrupted and three targeted knockout mutants were obtained. Biological assays showed that the phenotype of the targeted knockout mutants was similar to that of the T-DNA insertional mutant. Furthermore, gene complementation confirmed that CmMR1 is responsible for the mutant phenotype. CmMR1 disruption did not affect hyphal growth, conidiation, and parasitization of C. minitans, however, the ROS accumulation increased and tolerance to UV light decreased significantly in the mutants. Our result may enhance the understanding of melanin in the ecology of C. minitans on molecular level. PMID- 30467497 TI - Effects of Monolaurin on Oral Microbe-Host Transcriptome and Metabolome. AB - The aim of this in vitro study was to evaluate the effects of monolaurin against Aggregatibacter actinomycetemcomitans (Aa) and determine their effects on the host transcriptome and metabolome, using an oral cell/bacteria co-culture dual chamber model to mimic the human periodontium. For this, the Aa, was applied to cross the monolayer of epithelial keratinocytes (OBA-9) to reach the fibroblasts layer (HGF-1) in the basal chamber. The Monolaurin treatments (25 or 50 MUM) were added immediately after the inoculation of the dual-chamber with Aa. After 24 h, the transcriptional factors and metabolites produced were quantified in the remaining cell layers (insert and basal chamber) and in supernatant released from the cells. The genes IL-1alpha, IL-6, IL-18, and TNF analyzed in HGF-1 concentrations showed a decreased expression when treated with both concentration of Monolaurin. In keratinocytes, the genes IL-6, IL-18, and TNF presented a higher expression and the expression of IL-1alpha decreased when treated with the two cited concentrations. The production of glycerol and pyruvic acid increased, and the 2-deoxytetronic acid NIST, 4-aminobutyric acid, pinitol and glyceric acid, presented lower concentrations because of the treatment with 25 and/or 50 MUM of Monolaurin. Use of monolaurin modulated the immune response and metabolite production when administered for 24 h in a dual-chamber model inoculated with A. actinomycetemcomitans. In summary, this study indicates that monolaurin had antimicrobial activity and modulated the host immune response and metabolite production when administered for 24 h in a dual-chamber model inoculated with A. actinomycetemcomitans. PMID- 30467499 TI - Improving Iturin A Production of Bacillus amyloliquefaciens by Genome Shuffling and Its Inhibition Against Saccharomyces cerevisiae in Orange Juice. AB - Genome shuffling is an effective method for the rapid improvement of the production of secondary metabolites. This study used the principle of gene shuffling to enhance the yield of iturin A produced by Bacillus amyloliquefaciens LZ-5. Improvements in lipopeptide yield were evident among four strains subjected to recursive protoplast fusion. The four strains were obtained through mutagenesis processes: nitrosoguanidine, ultraviolet irradiation, and atmospheric and room temperature plasma. A high yield strain with 179.22 mg/l of iturin A was obtained after two rounds of genome shuffling, which was a 2.03-fold increase compared with the wild strain. To evaluate the efficacy of iturin A for control of spoilage yeast in food, the anti-yeast efficacy of iturin A was evaluated in orange juice incubated with Saccharomyces cerevisiae. The juice treated with 0.76 mg/ml iturin A showed a significant (p < 0.05) control on yeast population during the storage, similar to that of the 0.30 mg/ml natamycin. In addition, iturin A showed a tiny effect on chemical-physical characteristics of orange juice. Our results provide a basis for the application of antimicrobial lipopeptide in juice products. PMID- 30467500 TI - Programming Bacteria With Light-Sensors and Applications in Synthetic Biology. AB - Photo-receptors are widely present in both prokaryotic and eukaryotic cells, which serves as the foundation of tuning cell behaviors with light. While practices in eukaryotic cells have been relatively established, trials in bacterial cells have only been emerging in the past few years. A number of light sensors have been engineered in bacteria cells and most of them fall into the categories of two-component and one-component systems. Such a sensor toolbox has enabled practices in controlling synthetic circuits at the level of transcription and protein activity which is a major topic in synthetic biology, according to the central dogma. Additionally, engineered light sensors and practices of tuning synthetic circuits have served as a foundation for achieving light based real time feedback control. Here, we review programming bacteria cells with light, introducing engineered light sensors in bacteria and their applications, including tuning synthetic circuits and achieving feedback controls over microbial cell culture. PMID- 30467501 TI - A Recombinant Subunit Based Zika Virus Vaccine Is Efficacious in Non-human Primates. AB - Zika Virus (ZIKV), a virus with no severe clinical symptoms or sequelae previously associated with human infection, became a public health threat following an epidemic in French Polynesia 2013-2014 that resulted in neurological complications associated with infection. Although no treatment currently exists, several vaccines using different platforms are in clinical development. These include nucleic acid vaccines based on the prM-E protein from the virus and purified formalin-inactivated ZIKV vaccines (ZPIV) which are in Phase 1/2 clinical trials. Using a recombinant subunit platform consisting of antigens produced in Drosophila melanogaster S2 cells, we have previously shown seroconversion and protection against viremia in an immunocompetent mouse model. Here we demonstrate the efficacy of our recombinant subunits in a non-human primate (NHP) viremia model. High neutralizing antibody titers were seen in all protected macaques and passive transfer demonstrated that plasma from these NHPs was sufficient to protect against viremia in mice subsequently infected with ZIKV. Taken together our data demonstrate the immunogenicity and protective efficacy of the recombinant subunit vaccine candidate in NHPs as well as highlight the importance of neutralizing antibodies in protection against ZIKV infection and their potential implication as a correlate of protection. PMID- 30467502 TI - A Co-culture Model of PBMC and Stem Cell Derived Human Nasal Epithelium Reveals Rapid Activation of NK and Innate T Cells Upon Influenza A Virus Infection of the Nasal Epithelium. AB - Background: We established an in vitro co-culture model involving H3N2-infection of human nasal epithelium with peripheral blood mononuclear cells (PBMC) to investigate their cross-talk during early H3N2 infection. Methods: Nasal epithelium was differentiated from human nasal epithelial stem/progenitor cells and cultured wtih fresh human PBMC. PBMC and supernatants were harvested after 24 and 48 h of co-culture with H3N2-infected nasal epithelium. We used flow cytometry and Luminex to characterize PBMC subpopulations, their activation and secretion of cytokine and chemokines. Results: H3N2 infection of the nasal epithelium associated with significant increase in interferons (IFN-alpha, IFN gamma, IL-29), pro-inflammatory cytokines (TNF-alpha, BDNF, IL-3) and viral associated chemokines (IP-10, MCP-3, I-TAC, MIG), detectable already after 24 h. This translates into rapid activation of monocytes, NK-cells and innate T-cells (MAIT and gammadelta T cells), evident with CD38+ and/or CD69+ upregulation. Conclusions: This system may contribute to in vitro mechanistic immunological studies bridging systemic models and possibly enable the development of targeted immunomodulatory therapies. PMID- 30467504 TI - The Influence of Parasite Infections on Host Immunity to Co-infection With Other Pathogens. AB - Parasites have evolved a wide range of mechanisms that they use to evade or manipulate the host's immune response and establish infection. The majority of the in vivo studies that have investigated these host-parasite interactions have been undertaken in experimental animals, especially rodents, which were housed and maintained to a high microbiological status. However, in the field situation it is increasingly apparent that pathogen co-infections within the same host are a common occurrence. For example, chronic infection with pathogens including malarial parasites, soil-transmitted helminths, Mycobacterium tuberculosis and viruses such as HIV may affect a third of the human population of some developing countries. Increasing evidence shows that co-infection with these pathogens may alter susceptibility to other important pathogens, and/or influence vaccine efficacy through their effects on host immune responsiveness. Co-infection with certain pathogens may also hinder accurate disease diagnosis. This review summarizes our current understanding of how the host's immune response to infection with different types of parasites can influence susceptibility to infection with other pathogenic microorganisms. A greater understanding of how infectious disease susceptibility and pathogenesis can be influenced by parasite co-infections will enhance disease diagnosis and the design of novel vaccines or therapeutics to more effectively control the spread of infectious diseases. PMID- 30467505 TI - Making CAR T Cells a Solid Option for Solid Tumors. AB - Adoptive cell therapy with chimeric antigen receptor (CAR) T cells aims to redirect the patient's own immune system to selectively attack cancer cells. To do so, CAR T cells are endowed with specific antigen recognition moieties fused to signaling and costimulatory domains. While this approach has shown great success for the treatment of B cell malignancies, response rates among patients with solid cancers are less favorable. The major challenges for CAR T cell immunotherapy in solid cancers are the identification of unique tumor target antigens, as well as improving CAR T cell trafficking to and expansion at the tumor site. This review focuses on combinatorial antigen targeting, regional delivery and approaches to improve CAR T cell persistence in the face of a hostile tumor microenvironment. PMID- 30467503 TI - Tumor Microenvironment-Induced Immunometabolic Reprogramming of Natural Killer Cells. AB - Energy metabolism is key to the promotion of tumor growth, development, and metastasis. At the same time, cellular metabolism also mediates immune cell survival, proliferation and cytotoxic responses within the tumor microenvironment. The ability of natural killer cells to eradicate tumors relies on their ability to functionally persist for the duration of their anti-tumor effector activity. However, a tumor's altered metabolic requirements lead to compromised functional responses of cytokine-activated natural killer cells, which result in decreased effectiveness of adoptive cell-based immunotherapies. Tumors exert these immunosuppressive effects through a number of mechanisms, a key driver of which is hypoxia. Hypoxia also fuels the generation of adenosine from the cancer-associated ectoenzymes CD39 and CD73. Adenosine's immunosuppression manifests in decreased proliferation and impaired anti-tumor function, with adenosinergic signaling emerging as an immunometabolic checkpoint blockade target. Understanding such immunometabolic suppression is critical in directing the engineering of a new generation of natural killer cell-based immunotherapies that have the ability to more effectively target difficult-to treat solid tumors. PMID- 30467506 TI - CCL22-Producing Resident Macrophages Enhance T Cell Response in Sjogren's Syndrome. AB - Macrophages (MPhis) are critical regulators of immune response and serve as a link between innate and acquired immunity. The precise mechanism of involvement of tissue-resident MPhis in the pathogenesis of autoimmune diseases is not clear. Here, using a murine model for Sjogren's syndrome (SS), we investigated the role of tissue-resident MPhis in the onset and development of autoimmunity. Two unique populations of CD11bhigh and CD11blow resident MPhis were observed in the target tissue of the SS model. Comprehensive gene expression analysis of chemokines revealed effective production of CCL22 by the CD11bhigh MPhis. CCL22 upregulated the migratory activity of CD4+ T cells by increasing CCR4, a receptor of CCL22, on T cells in the SS model. In addition, CCL22 enhanced IFN-gamma production of T cells of the SS model, thereby suggesting that CCL22 may impair the local immune tolerance in the target organ of the SS model. Moreover, administration of anti CCL22 antibody suppressed autoimmune lesions in the SS model. Finally, histopathological analysis revealed numerous CCL22-producing MPhis in the minor salivary gland tissue specimens of the SS patients. CCL22-producing tissue resident MPhis may control autoimmune lesions by enhancing T cell response in the SS model. These results suggest that specific chemokines and their receptors may serve as novel therapeutic or diagnostic targets for SS. PMID- 30467507 TI - Modification of Growth, Yield, and the Nutraceutical and Antioxidative Potential of Soybean Through the Use of Synthetic Biostimulants. AB - Improvement of crop cultivation technologies is focused on increasing crop productivity and improving yield quality, and at the same time on minimizing risks posed to the natural environment. The use of biostimulants contributes to the increase in the productivity of plants, especially under their exposure to stress induced by negative environmental stimuli. A field experiment was conducted in three growing seasons (2014-2016). Seeds of soybean of the Atlanta cultivar were sown in the third decade of April. Two synthetic biostimulants were used in the growing period in the form of single (stage BBCH 13-15) or double (stage BBCH 13-15, BBCH 61) spraying: Atonik (in concentrations of 0.1 and 0.2%) and Tytanit (in concentrations of 0.07 and 0.13%). Atonik, the first tested biostimulant, contained three phenolic compounds: sodium p-nitrophenolate, sodium o-nitrophenolate, and sodium 5-nitroguaiacolate. The Tytanit preparation contained a titanium complex, magnesium oxide, and sulfur (VI) oxide. This work presents a complex study addressing the action of the biostimulants Atonik and Tytanit and demonstrates their effect on the physiological traits, plant productivity, and seed yield quality of Glycine max L. The conducted experiment proved that the biostimulant type, as well as the number of its applications and its concentration, modified the biometric traits, crop productivity, as well as yield quality and the nutraceutical and antioxidative potential of soybean seeds. It was also found that by positively affecting plant growth and seed yield, the Atonik and Tytanit also resulted biostimulants decreased the protein and lipid contents in seeds. A double application of these preparations in their higher concentrations had a more positive impact on soybean seed number and soybean seed yield. The use of both Atonik and Tytanit resulted also in an increased antioxidative activity of soybean seeds. The greatest increase in this activity was observed after the application of the Tytanit preparation. Dietary fiber fraction analysis demonstrated an increase in the acid-detergent fiber, lignin, and cellulose contents in soybean seeds as a result of biostimulant application; however, the increase was greater upon the use of Tytanit. In contrast, the neutral-detergent fiber, cellulose, and hemicellulose contents were observed to decrease in all analyzed combinations of crops treated with the tested preparations. PMID- 30467508 TI - Climate Regimes Override Micro-Site Effects on the Summer Temperature Signal of Scots Pine at Its Northern Distribution Limits. AB - Tree growth at northern boreal treelines is generally limited by summer temperature, hence tree rings serve as natural archives of past climatic conditions. However, there is increasing evidence that a changing summer climate as well as certain micro-site conditions can lead to a weakening or loss of the summer temperature signal in trees growing in treeline environments. This phenomenon poses a challenge to all applications relying on stable temperature growth relationships such as temperature reconstructions and dynamic vegetation models. We tested the effect of differing ecological and climatological conditions on the summer temperature signal of Scots pine at its northern distribution limits by analyzing twelve sites distributed along a 2200 km gradient from Finland to Western Siberia (Russia). Two frequently used proxies in dendroclimatology, ring width and maximum latewood density, were correlated with summer temperature for the period 1901-2013 separately for (i) dry vs. wet micro sites and (ii) years with dry/warm vs. wet/cold climate regimes prevailing during the growing season. Differing climate regimes significantly affected the temperature signal of Scots pine at about half of our sites: While correlations were stronger in wet/cold than in dry/warm years at most sites located in Russia, differing climate regimes had only little effect at Finnish sites. Both tree-ring proxies were affected in a similar way. Interestingly, micro-site differences significantly affected absolute tree growth, but had only minor effects on the climatic signal at our sites. We conclude that, despite the treeline-proximal location, growth-limiting conditions seem to be exceeded in dry/warm years at most Russian sites, leading to a weakening or loss of the summer temperature signal in Scots pine here. With projected temperature increase, unstable summer temperature signals in Scots pine tree rings might become more frequent, possibly affecting dendroclimatological applications and related fields. PMID- 30467510 TI - Policy and Governance Perspectives for Regulation of Genome Edited Crops in the United States. AB - Genome editing for crop improvement lies at the leading edge of disruptive bioengineering technologies that will challenge existing regulatory paradigms for products of biotechnology and which will elicit widespread public interest. Regulation of products of biotechnology through the US Coordinated Framework for Biotechnology is predicated on requiring burden of proof that regulation is warranted. Although driven by considerations of newly emerging processes for product development, regulation has, for the most part, focused on characteristics of the biotechnology product itself and not the process used for its development per se. This standard of evidence and product focus has been maintained to date in regulatory considerations of genome edited crops. Those genome edited crops lacking recombinant DNA (rDNA) in the product intended for environmental release, lacking plant pest or pesticidal activity, or showing no food safety attributes different from those of traditionally bred crops are not deemed subject to regulatory evaluation. Regardless, societal uncertainties regarding genome editing are leading regulators to seek ways whereby these uncertainties may be addressed through redefinition of those products of biotechnology that may be subject to regulatory assessments. Within US law prior statutory history, language and regulatory action have significant influence on decision making; therefore, the administrative law and jurisprudence underlying the current Coordinated Framework strongly inform policy and governance when considering new plant breeding technologies such as genome editing. PMID- 30467509 TI - Transcriptional Reprogramming of Legume Genomes: Perspective and Challenges Associated With Single-Cell and Single Cell-Type Approaches During Nodule Development. AB - Transcriptomic approaches revealed thousands of genes differentially or specifically expressed during nodulation, a biological process resulting from the symbiosis between leguminous plant roots and rhizobia, atmospheric nitrogen fixing symbiotic bacteria. Ultimately, nodulation will lead to the development of a new root organ, the nodule. Through functional genomic studies, plant transcriptomes have been used by scientists to reveal plant genes potentially controlling nodulation. However, it is important to acknowledge that the physiology, transcriptomic programs, and biochemical properties of the plant cells involved in nodulation are continuously regulated. They also differ between the different cell-types composing the nodules. To generate a more accurate picture of the transcriptome, epigenome, proteome, and metabolome of the cells infected by rhizobia and cells composing the nodule, there is a need to implement plant single-cell and single cell-types strategies and methods. Accessing such information would allow a better understanding of the infection of plant cells by rhizobia and will help understanding the complex interactions existing between rhizobia and the plant cells. In this mini-review, we are reporting the current knowledge on legume nodulation gained by plant scientists at the level of single cell-types, and provide perspectives on single cell/single cell-type approaches when applied to legume nodulation. PMID- 30467511 TI - Molecular and Cytogenetic Characterization of Six Wheat-Aegilops markgrafii Disomic Addition Lines and Their Resistance to Rusts and Powdery Mildew. AB - Aegilops markgrafii (Greuter) Hammer is an important source of genes for resistance to abiotic stresses and diseases in wheat (Triticum aestivum L.). A series of six wheat 'Alcedo'-Ae. markgrafii chromosome disomic addition lines, designated as AI(B), AII(C), AIII(D), AV(E), AIV(F), and AVIII(G) carrying the Ae. markgrafii chromosomes B, C, D, E, F, and G, respectively, were tested with SSR markers to establish homoeologous relationships to wheat and identify markers useful in chromosome engineering. The addition lines were evaluated for resistance to rust and powdery mildew diseases. The parents Alcedo and Ae. markgrafii accession 'S740-69' were tested with 1500 SSR primer pairs and 935 polymorphic markers were identified. After selecting for robust markers and confirming the polymorphisms on the addition lines, 132 markers were considered useful for engineering and establishing homoeologous relationships. Based on the marker analysis, we concluded that the chromosomes B, C, D, E, F, and G belong to wheat homoeologous groups 2, 5, 6, 7, 3, and 4, respectively. Also, we observed chromosomal rearrangements in several addition lines. When tested with 20 isolates of powdery mildew pathogen (Blumeria graminis f. sp. tritici) from five geographic regions of the United States, four addition lines [AIII(D), AV(E), AIV(F), and AVIII(G)] showed resistance to some isolates, with addition line AV(E) being resistant to 19 of 20 isolates. The addition lines were tested with two races (TDBJ and TNBJ) of the leaf rust pathogen (Puccinia triticina), and only addition line AI(B) exhibited resistance at a level comparable to the Ae. markgrafii parent. Addition lines AII(C) and AIII(D) had been previously identified as resistant to the Ug99 race group of the stem rust pathogen (Puccinia graminis f. sp. tritici). The addition lines were also tested for resistance to six United States races (PSTv-4, PSTv-14, PSTv-37, PSTv-40, PSTv 51, and PSTv-198) of the stripe rust pathogen (Puccinia striiformis f. sp. tritici); we found no resistance either in Alcedo or any of the addition lines. The homoeologous relationships of the chromosomes in the addition lines, molecular markers located on each chromosome, and disease resistance associated with each chromosome will allow for chromosome engineering of the resistance genes. PMID- 30467512 TI - Ethylene Receptors, CTRs and EIN2 Target Protein Identification and Quantification Through Parallel Reaction Monitoring During Tomato Fruit Ripening. AB - Ethylene, the plant ripening hormone of climacteric fruit, is perceived by ethylene receptors which is the first step in the complex ethylene signal transduction pathway. Much progress has been made in elucidating the mechanism of this pathway, but there is still a lot to be done in the proteomic quantification of the main proteins involved, particularly during fruit ripening. This work focuses on the mass spectrometry based identification and quantification of the ethylene receptors (ETRs) and the downstream components of the pathway, CTR-like proteins (CTRs) and ETHYLENE INSENSITIVE 2 (EIN2). We used tomato as a model fruit to study changes in protein abundance involved in the ethylene signal transduction during fruit ripening. In order to detect and quantify these low abundant proteins located in the membrane of the endoplasmic reticulum, we developed a workflow comprising sample fractionation and MS analysis using parallel reaction monitoring. This work shows the feasibility of the identification and absolute quantification of all seven ethylene receptors, three out of four CTRs and EIN2 in four ripening stages of tomato. In parallel, gene expression was analyzed through real-time qPCR. Correlation between transcriptomic and proteomic profiles during ripening was only observed for three of the studied proteins, suggesting that the other signaling proteins are likely post-transcriptionally regulated. Based on our quantification results we were able to show that the protein levels of SlETR3 and SlETR4 increased during ripening, probably to control ethylene sensitivity. The other receptors and CTRs showed either stable levels that could sustain, or decreasing levels that could promote fruit ripening. PMID- 30467514 TI - PIB: A Score to Select Sorafenib Treatment Candidates for Hepatocellular Carcinoma in Resource-Limited Settings. PMID- 30467515 TI - Oxygen Evolution Reaction on Nitrogen-Doped Defective Carbon Nanotubes and Graphene. AB - The realization of a hydrogen economy would be facilitated by the discovery of a water-splitting electrocatalyst that is efficient, stable under operating conditions, and composed of earth-abundant elements. Density functional theory simulations within a simple thermodynamic model of the more difficult half reaction, the anodic oxygen evolution reaction (OER), with a single-walled carbon nanotube as a model catalyst, show that the presence of 0.3-1% nitrogen reduces the required OER overpotential significantly compared to the pristine nanotube. We performed an extensive exploration of systems and active sites with various nitrogen functionalities (graphitic, pyridinic, or pyrrolic) obtained by introducing nitrogen and simple lattice defects (atomic substitutions, vacancies, or Stone-Wales rotations). A number of nitrogen functionalities (graphitic, oxidized pyridinic, and Stone-Wales pyrrolic nitrogen systems) yielded similar low overpotentials near the top of the OER volcano predicted by the scaling relation, which was seen to be closely observed by these systems. The OER mechanism considered was the four-step single-site water nucleophilic attack mechanism. In the active systems, the second or third step, the formation of attached oxo or peroxo moieties, was the potential-determining step of the reaction. The nanotube radius and chirality effects were examined by considering OER in the limit of large radius by studying the analogous graphene-based model systems. They exhibited trends similar to those of the nanotube-based systems but often with reduced reactivity due to weaker attachment of the OER intermediate moieties. PMID- 30467516 TI - BgeeDB, an R package for retrieval of curated expression datasets and for gene list expression localization enrichment tests. AB - BgeeDB is a collection of functions to import into R re-annotated, quality controlled and reprocessed expression data available in the Bgee database. This includes data from thousands of wild-type healthy samples of multiple animal species, generated with different gene expression technologies (RNA-seq, Affymetrix microarrays, expressed sequence tags, and in situ hybridizations). BgeeDB facilitates downstream analyses, such as gene expression analyses with other Bioconductor packages. Moreover, BgeeDB includes a new gene set enrichment test for preferred localization of expression of genes in anatomical structures ("TopAnat"). Along with the classical Gene Ontology enrichment test, this test provides a complementary way to interpret gene lists. Availability: http://www.bioconductor.org/packages/BgeeDB/. PMID- 30467513 TI - Hotspots for Initiation of Meiotic Recombination. AB - Homologous chromosomes must pair and recombine to ensure faithful chromosome segregation during meiosis, a specialized type of cell division that occurs in sexually reproducing eukaryotes. Meiotic recombination initiates by programmed induction of DNA double-strand breaks (DSBs) by the conserved type II topoisomerase-like enzyme SPO11. A subset of meiotic DSBs are resolved as crossovers, whereby reciprocal exchange of DNA occurs between homologous chromosomes. Importantly, DSBs are non-randomly distributed along eukaryotic chromosomes, forming preferentially in permissive regions known as hotspots. In many species, including plants, DSB hotspots are located within nucleosome depleted regions. DSB localization is governed by interconnected factors, including cis-regulatory elements, transcription factor binding, and chromatin accessibility, as well as by higher-order chromosome architecture. The spatiotemporal control of DSB formation occurs within a specialized chromosomal structure characterized by sister chromatids organized into linear arrays of chromatin loops that are anchored to a proteinaceous axis. Although SPO11 and its partner proteins required for DSB formation are bound to the axis, DSBs occur preferentially within the chromatin loops, which supports the "tethered-loop/axis model" for meiotic recombination. In this mini review, we discuss insights gained from recent efforts to define and profile DSB hotspots at high resolution in eukaryotic genomes. These advances are deepening our understanding of how meiotic recombination shapes genetic diversity and genome evolution in diverse species. PMID- 30467517 TI - Advances in prostate cancer imaging. AB - Many exciting advances in medical imaging have been made in recent years that will alter the way we diagnose, stage, and treat patients with prostate cancer. Multiparametric magnetic resonance imaging (MRI) is emerging as the main modality for prostate cancer imaging. Contrast-enhanced ultrasound and shear wave elastography may be strong alternatives in patients who cannot undergo MRI. Prostate-specific membrane antigen-directed positron emission tomography/computed tomography has proven to be valuable in the primary staging of high-risk disease and for detecting disease in patients with biochemical recurrence. As more studies continue to emerge, it is becoming clear that the standard algorithm for diagnosing and staging prostate cancer will undergo significant changes in the near future. PMID- 30467518 TI - Recent advances in understanding and preventing peanut and tree nut hypersensitivity. AB - Peanut allergy, the most persistent and deadly of the food allergies, has become more prevalent worldwide in recent decades. Numerous explanations have been offered for the rise in peanut allergy, which has been more pronounced in Western, industrialized nations. In infants who are at increased risk of peanut allergy, new evidence indicates that early introduction of peanuts can help prevent allergy development. This counterintuitive finding directly contradicts the previously established practice of peanut avoidance for high-risk infants but is supported by clinical and basic science evidence. Here, we review the literature contributing to our evolving understanding of nut allergy, emphasizing the translation of this work to clinical practice. PMID- 30467520 TI - Status of drowning in Nepal: A study of central police data. AB - Background: Drowning is a serious and mostly preventable injury-related cause of death. Low-and-middle income countries represent 90% of total drowning deaths worldwide. There is lack of epidemiological studies of drowning in Nepal. The aim of this paper is to describe the status of drowning in Nepal. Methods: Cases of drowning, occurring between January 2013 and December 2015 were extracted from the Daily Incident Recording System of Nepal Police. Variables on age, sex of the deceased, types of water bodies, places, season when drowning occurred and activities of deceased were extracted and descriptive analysis was done. Results: A total of 1,507 drowning cases were recorded over a 3 year period. The rate of drowning was 1.9 per 100,000 (2.95 for males and 0.92 for females). Majority of drowning occurred among males (76%) and more than half were (53%) under 20 years of age. Mostly drowning occurred in rivers (natural water bodies). The findings provide strong indication that drowning occurs throughout the year in Nepal. Children were highly vulnerable to drowning. The magnitude of drowning was found to be lower than estimated by global burden of disease (GBD) study. Conclusion: The burden of drowning in Nepal is considerable, but mostly unknown to the public. Despite only having access to a limited data source, this study provides useful evidence that comprehensive research in Nepal is needed urgently. PMID- 30467519 TI - Metabolic interactions between Toxoplasma gondii and its host. AB - Toxoplasma gondii is an obligate intracellular parasite belonging to the phylum Apicomplexa that infects all warm-blooded animals, including humans. T. gondii can replicate in every nucleated host cell by orchestrating metabolic interactions to derive crucial nutrients. In this review, we summarize the current status of known metabolic interactions of T. gondii with its host cell and discuss open questions and promising experimental approaches that will allow further dissection of the host-parasite interface and discovery of ways to efficiently target both tachyzoite and bradyzoite forms of T. gondii, which are associated with acute and chronic infection, respectively. PMID- 30467521 TI - The Congress Impact Factor: A proposal from board members of the World Society of Emergency Surgeons.it (WSES) and Academy of Emergency Medicine and Care (AcEMC). AB - Many scientific congresses and conferences are held every year around the world. The aim of the World Society of Emergency Surgeons.it (WSES) and Academy of Emergency Medicine and Care (AcEMC) was to develop a simple mathematical parameter as an indicator of academic quality and scientific validity of a congress. In this opinion article, a new metric, the Congress Impact Factor (IFc), is proposed taking into consideration the widely used Impact Factor as an indicator of journals' prestige and using H-index analysis. The IFc is derived from the mathematical ratio between the mean H-index of invited lecturers normalized for lecture topic and number of lectures in the conference. In case of multiple sessions, the mean of all IFc is calculated along with its standard deviation. We conclude that the IFc can be a useful measure for evaluating and comparing congress prestige, and may also represent a potentially useful parameter for improving academic curriculum and helping participants to choose the more prestigious meetings for their education. PMID- 30467522 TI - Using Lamin B1 mRNA for the early diagnosis of hepatocellular carcinoma: a cross sectional diagnostic accuracy study. AB - Background : Hepatocellular carcinoma (HCC) is vital medical issue in Egypt. It accounts for 70.48% of all liver tumors among Egyptians. The aim of this study was to determine the diagnostic role of plasma levels of mRNA of lamin B1 by RT qPCR as an early marker of HCC. Methods: This study was conducted at the Clinical Pathology Department in collaboration with the Department of Tropical Medicine and Infectious Diseases at Ain Shams University Hospitals. It included 30 patients with primary HCC and viral cirrhosis (all were hepatitis C virus positive) (Group I), in addition to 10 patients with chronic liver diseases (Group II) and 10 healthy age- and sex-matched subjects (Group III). Group I was further classified according to the Barcelona-Clinic Liver Cancer Staging System. Serum alpha-fetoprotein (AFP) chemiluminescent-immunoassays and RT-qPCR analysis of plasma lamin B1 mRNA levels were performed for all participants. Results: AFP and lamin B1 significantly elevated in patients with HCC compared to those in the other studied groups. AFP and lamin B1 status could discriminate group I from group II and III. A significant increase was found among the three Barcelona stages with regards to AFP and lamin B1 levels. A significant decrease was found between group II and stage 0, A and B with regards to AFP and lamin B1. Lamin B1 and AFP could both differentiate HCC patients with one tumor nodule (T1) from those with two or more tumor nodules (T2&Tm), as well as between those with tumor sizes >3 cm and <=3 cm. Conclusion: Measurement of lamin B1 mRNA is recommended in patients with chronic liver disease with normal serum AFP, especially in known cirrhotic patients that deteriorate rapidly without any apparent etiology. PMID- 30467523 TI - gganatogram: An R package for modular visualisation of anatograms and tissues based on ggplot2. AB - Displaying data onto anatomical structures is a convenient technique to quickly observe tissue related information. However, drawing tissues is a complex task that requires both expertise in anatomy and the arts. While web based applications exist for displaying gene expression on anatograms, other non genetic disciplines lack similar tools. Moreover, web based tools often lack the modularity associated with packages in programming languages, such as R. Here I present gganatogram, an R package used to plot modular species anatograms based on a combination of the graphical grammar of ggplot2 and the publicly available anatograms from the Expression Atlas. This combination allows for quick and easy, modular, and reproducible generation of anatograms. Using only one command and a data frame with tissue name, group, colour, and value, this tool enables the user to visualise specific human and mouse tissues with desired colours, grouped by a variable, or displaying a desired value, such as gene-expression, pharmacokinetics, or bacterial load across selected tissues. I hope that this tool will be useful by the wider community in biological sciences. Community members are welcome to submit additional anatograms, which can be incorporated into the package. A stable version gganatogram has been deposited to neuroconductor, and a development version can be found on github/jespermaag/gganatogram. PMID- 30467524 TI - Unraveling the Molecular Mechanisms of Thermo-responsive Properties of Silk Elastin-Like Proteins by Integrating Multiscale Modeling and Experiment. AB - Adaptive hydrogels tailor-made from silk-elastin-like proteins (SELPs) possess excellent biocompatibility and biodegradability with properties that are tunable and responsive to multiple simultaneous external stimuli. To unravel the molecular mechanisms of their physical response to external stimuli in tandem with experiments, here we predict and measure the variation in structural properties as a function of temperature through coarse-grained (CG) modeling of individual and crosslinked SE8Y and S4E8Y molecules, which have ratios of 1:8 and 4:8 of silk to elastin blocks respectively. Extensive structural reshuffling in single SE8Y molecules led to the increased compactness of the structure, whereas S4E8Y molecules did not experience any significant changes as they already adopted very compact structures at low temperatures. Crosslinking of SE8Y molecules at high concentrations impeded their structural transition at high temperatures that drastically reduced the degree of deswelling through extensive suppression of the structural shuffling and the trapping of the molecules in high potential energy states due to inter-molecular constraints. This integrative experimental and computational understanding of the thermal response in single molecules of SELPs and their crosslinked networks should lead to further improvements in the properties of SELP hydrogels through predictive designs and their wider applications in biomaterials and tissue engineering. PMID- 30467525 TI - Annual Performance Reviews Of, For and By Faculty: A Qualitative Analysis of One Department's Experiences. AB - Purpose: Although annual performance reviews and feedback are recommended for faculty development, best practices and faculty perceptions have not been documented. The authors sought to evaluate the process in one medical school department that established and has sustained an innovative review tradition for 25 years. Method: Content analysis of faculty reports and immersion/crystallization to analyze interviews. Results: Faculty reports described satisfaction and dissatisfaction; facilitators and barriers to goals; and requests for feedback, with community, collaboration and mentorship integral to all three. Interviewees emphasized practical challenges, the role of the mentor and the power of the review to establish community norms. Conclusion: Respondents generally found reviews constructive and supportive. The process informs departmental expectations and culture. PMID- 30467526 TI - Site-Specific Insulin-Trehalose Glycopolymer Conjugate by Grafting From Strategy Improves Bioactivity. AB - Insulin is an important therapeutic protein for the treatment of diabetes, but it is unstable and aggregates upon exposure to environmental stressors encountered during storage and transport. To prevent degradation of the protein in this manner and retain as much in vivo bioactivity as possible, a well-defined insulin trehalose glycopolymer conjugate was synthesized. To accomplish this, a strategy was employed to site-specifically modify insulin with a polymerization initiator at a particular conjugation site; this also facilitated purification and characterization. Lysine of the B chain was preferentially modified by conducting the reaction at high pH, taking advantage of its higher nucleophilicity than the N-terminal amines. Trehalose monomer was polymerized directly from this macroinitiator to form a well-defined conjugate. Bioactivity of the site-specific conjugate was shown to be higher compared to the non-specific conjugate and the same as the analogous site-specific polyethylene glycol (PEG) conjugate as confirmed by the insulin tolerance test (ITT) in mice. The conjugated trehalose glycopolymer also stabilized insulin to heat as measured by high-performance liquid chromatography (HPLC). PMID- 30467527 TI - Implementing a Pre-Exposure Prophylaxis Intervention for Safer Conception among HIV Serodiscordant Couples: Recommendations for Health Care Providers. AB - Couples in HIV serodiscordant relationships frequently desire children. Although partners who are virally suppressed pose almost no risk of transmitting HIV to their partners, partners who are inconsistently on therapy may transmit HIV to their partners when attempting to conceive. Pre-exposure prophylaxis (PrEP) is an available safer conception strategy for these couples but is not consistently offered. We sought to better understand barriers to PrEP implementation for couples seeking conception and patient perceptions on what providers could do to encourage use. We conducted in-depth, qualitative interviews with 11 participants representing six couples taking PrEP for safer conception in a safety-net hospital in New England. Semi-structured qualitative interviews assessed the following: Relationship nature and contextual factors; attitudes and perceptions regarding PrEP for safer conception; experience within health care systems related to HIV and PrEP; and facilitators, barriers, and other experiences using PrEP for safer conception. Four key themes have important implications for implementation of PrEP for safer conception: Knowledge and understanding gaps regarding HIV and PrEP among both members of the couple, role of insurance and financing in decision-making, learning to manage and adhere to a treatment plan, and the need for providers to enhance knowledge and offer further support. Addressing barriers to safer conception strategies at multiple levels is needed to prevent HIV transmission within serodiscordant couples who desire children. Providers can play an important role in lowering these barriers through the use of multiple strategies. PMID- 30467528 TI - Exercise in African American and White Colorectal Cancer Survivors: A Mixed Methods Approach. AB - Background: African-American (AA) colorectal cancer (CRC) survivors tend to be more obese and less physically active compared to white survivors. Purpose/Objective: To test the feasibility of an aerobic exercise program as well as explore perceptions about supervised exercise among AA CRC survivors. Methods: A prospective supervised exercise intervention performed on a cycle ergometer 2 days/week for 12 weeks. Peak (VO2peak) and sub-maximal exercise (6MWT) along with questionnaires (SF-36, Memorial Sloan Kettering Cancer Center Bowel Function Instrument (BFI), Functional Assessment of Cancer Therapy Scale-Colorectal (FACT C) and Fatigue (FACIT-F), Brief Symptom Inventory (BSI). A second group of survivors participated in an interview evaluating perceptions regarding exercise. Design: Prospective case series and qualitative interview. Setting: Research university and academic medical center. Patients: African American and white colorectal cancer survivors. Results: Quantitative: A total of 237 letters were mailed to CRC survivors (112 white, 126 AAs). From the letters, 25 white and 15 AAs expressed interest; only five white (4.5%) and four AAs (3.2%) enrolled. Two AAs and five white survivors (7/9) finished the program. There was an improvement in peak exercise (p=0.011) and quality of life (QoL) (SF-36 total, p=0.035) post training. Qualitative: 30 CRC survivors (12 AA and 18 white) participated in qualitative interviews and selected co-morbidity, motivation and location as primary barriers to exercise. Limitations: Small sample size. Conclusions: Recruiting CRC survivors (regardless of race) into an exercise program is challenging, however, there are exercise and QoL benefits associated with participation. Barriers to exercise are similar between AA and white CRC survivors. PMID- 30467529 TI - Tracking the Strength of the Walker Circulation with Stable Isotopes in Water Vapor. AB - General circulation models (GCMs) predict that the global hydrological cycle will change in response to anthropogenic warming. However, these predictions remain uncertain, in particular for precipitation [IPCC, 2013]. Held and Soden [2006] suggest that as lower-tropospheric water vapor concentration increases in a warming climate, the atmospheric circulation and convective mass fluxes will weaken. Unfortunately, this process is difficult to constrain, as convective mass fluxes are poorly observed and incompletely simulated in GCMs. Here, we demonstrate that stable hydrogen isotope ratios in tropical atmospheric water vapor can trace changes in temperature, atmospheric circulation and convective mass flux in a warming world. We evaluate changes in temperature, the distribution of water vapor, vertical velocity (omega) and advection, and water isotopes in vapor (deltaD V ) in water isotopeenabled GCM experiments for modern vs. high CO 2 atmospheres to identify spatial patterns of circulation change over the tropical Pacific. We find that slowing circulation in the tropical Pacific moistens the lower troposphere and weakens convective mass flux, both of which impact the deltaD of water vapor in the mid-troposphere. Our findings constitute a critical demonstration of how water isotope ratios in the tropical Pacific respond to changes in radiative forcing and atmospheric warming. Moreover, as changes in deltaD V can be observed by satellites, our results develop new metrics for the detection of global warming impacts to the hydrological cycle and, specifically, the strength of the Walker Circulation. PMID- 30467530 TI - On the forward modeling of radar Doppler spectrum width from LES: Implications for model evaluation. AB - Large-eddy simulations of an observed single-layer Arctic mixed-phase cloud are analyzed to study the value of forward modeling of profiling millimeter-wave cloud radar Doppler spectral width for model evaluation. Individual broadening terms and their uncertainties are quantified for the observed spectral width and compared to modeled broadening terms. Modeled turbulent broadening is narrower than the observed values when the turbulent kinetic energy dissipation rate from the subgrid-scale model is used in the forward model. The total dissipation rates, estimated with the subgrid-scale dissipation rates and the numerical dissipation rates, agree much better with both the retrieved dissipation rates and those inferred from the power spectra of the simulated vertical air velocity. The comparison of the microphysical broadening provides another evaluative measure of the ice properties in the simulation. To accurately retrieve dissipation rates as well as each broadening term from the observations, we suggest a few modifications to previously presented techniques. First, we show that the inertial subrange spectra filtered with the radar sampling volume is a better underlying model than the unfiltered -5/3 law for the retrieval of the dissipation rate from the power spectra of the mean Doppler velocity. Second, we demonstrate that it is important to filter out turbulence and remove the layer mean reflectivity-weighted mean fall speed from the observed mean Doppler velocity to avoid overestimation of shear broadening. Finally, we provide a method to quantify the uncertainty in the retrieved dissipation rates, which eventually propagates to the uncertainty in the microphysical broadening. PMID- 30467532 TI - Collagen-based sponge hastens wound healing via decrease of inflammatory cytokines. AB - The objective of this study was to compare and evaluate the efficacy of collagen based sponge compared to commercial collagen sponge as a potent open wound dressing material. In this study, 10 mm diameter skin incision was made on lateral side of rats. The wound was monitored regularly until day 12. Histopathology results revealed the faster re-epithelialization and lesser inflammatory cells, and also masson's trichrome staining showed that collagen fibrils were horizontal and interwoven in collagen-based sponge group. The expression of growth factors such as VEGF and TGF-beta1 was found to be upregulated in transcriptional and translational levels, suggesting the importance of collagen-based sponge as a potent wound-healing material. Furthermore, IL-6 and TNF-alpha in the wound tissue were significantly down regulated in 2 and 6 days in collagen-based sponge group and anti-inflammatory cytokine IL-10 level was found to be upregulated throughout 12 days. These results cumulatively revealed that collagen-based sponge may serve as novel material for wound healing in the animal model. PMID- 30467531 TI - Transient expression of anti-VEFGR2 nanobody in Nicotiana tabacum and N. benthamiana. AB - In human, the interaction between vascular endothelial growth factor (VEGF) and its receptor (VEGFR2) is critical for tumor angiogenesis. This is a vital process for cancer tumor growth and metastasis. Blocking VEGF/VEGFR2 conjugation by antibodies inhibits the neovascularization and tumor metastasis. This investigation designed to use a transient expression platform for production of recombinant anti-VEGFR2 nanobody in tobacco plants. At first, anti-VEGFR2 specific nanobody gene was cloned in a Turnip mosaic virus (TuMV)-based vector, and then, it was expressed in Nicotiana benthamiana and Nicotiana tabacum cv. Xanthi transiently. The expression of nanobody in tobacco plants were confirmed by reverse transcription-polymerase chain reaction (RT-PCR), dot blot, enzyme linked immunosorbent assays (ELISA), and Western blot analysis. It was shown that tobacco plants could accumulate nanobody up to level 0.45% of total soluble protein (8.3 ug/100 mg of fresh leaf). This is the first report of the successful expression of the camelied anti-VEFGR2 nanobody gene in tobacco plants using a plant viral vector. This system provides a fast solution for production of pharmaceutical and commercial proteins such as anti-cancer nanobodies in tobacco plants. PMID- 30467533 TI - Principles of designing a clinical trial: optimizing chances of trial success. AB - Purpose of Review: Clinical trials are essential to advance health care and develop new therapies. In this review we discuss the underlying principles of clinical trial design with an emphasis on assessing design risks that lead to trial failure as well as negative trials. While of general interest, this is perhaps particularly timely for the neuromodulation community, given the paucity of well-designed trials in the field. We give some examples from the phantom limb pain (PLP) literature. Recent Findings: It is critical to gather as much preliminary data as possible and to know how to interpret it in order to choose an appropriate trial design. Therefore, the investigator needs to effectively assess the likely trial design risk/benefit ratio with a view to maximizing the chance of a meaningful outcome, whether this outcome rejects or fails to reject the null hypothesis. This analysis is especially important in a complex and heterogeneous disorder such as PLP, which has had many negative trials. Summary: We discuss the factors pertaining to a strong trial design benefit/risk assessment, how late trial phases require greater support from preliminary data, how to design trials to minimize risks, maximize benefits, and optimize internal validity as well as the chances of a positive outcome. We highlight the need for investigators to incorporate best practice in trial design to increase the chances of success, to always anticipate unexpected challenges during the trial. PMID- 30467534 TI - Terrorism, geopolitics, and oil security: Using remote sensing to estimate oil production of the Islamic State. AB - As the world's most traded commodity, oil production is typically well monitored and analyzed. It also has established links to geopolitics, international relations, and security. Despite this attention, the illicit production, refining, and trade of oil and derivative products occur all over the world and provide significant revenues outside of the oversight and regulation of governments. A prominent manifestation of this phenomenon is how terrorist and insurgent organizations-including the Islamic State group, also known as ISIL/ISIS or Daesh-use oil as a revenue source. Understanding the spatial and temporal variation in production can help determine the scale of operations, technical capacity, and revenue streams. This information, in turn, can inform both security and reconstruction strategies. To this end, we use satellite multi spectral imaging and ground-truth pre-war output data to effectively construct a real-time census of oil production in areas controlled by the ISIL terrorist group. More broadly, remotely measuring the activity of extractive industries in conflict-affected areas without reliable administrative data can support a broad range of public policy and decisions and military operations. PMID- 30467535 TI - Amphiregulin (AREG) and Epiregulin (EREG) Gene Expression as Predictor for Overall Survival (OS) in Oxaliplatin/Fluoropyrimidine Plus Bevacizumab Treated mCRC Patients-Analysis of the Phase III AIO KRK-0207 Trial. AB - Background: The EGFR (epithelial growth factor receptor) ligands amphiregulin (AREG) and epiregulin (EREG) have been considered as predictors for EGFR-antibody efficacy. The effect of AREG and EREG expression levels in primary tumor samples on the outcome of bevacizumab-treated patients is unknown. Patients and Methods: Formalin-fixed paraffin-embedded (FFPE) tumor samples from surgically removed primaries of the AIO KRK-0207 trial have been tested for AREG and EREG expression. The AIO KRK-0207 trial was a randomized phase-3 study to investigate the best maintenance strategy after oxaliplatin/fluoropyrimidine plus bevacizumab induction treatment in patients with mCRC. Association of AREG and EREG levels with outcome parameters were investigated, taking into account RAS and BRAF mutations. Results: A total of 331 tumor samples had measurable AREG and EREG tissue levels. In the total cohort using continuous expression levels, higher logAREG and logEREG levels were associated with a significant longer overall survival (OS) (HR 0.80; p = 0.003 and HR 0.78; p = 0.001, respectively). The subgroup of BRAF mutant tumors displayed significantly lower AREG and EREG levels compared to wild-type tumors. The prognostic effect of AREG and EREG expression was limited to the double wild-type subpopulation, whereas in the RAS mutant and BRAF mutant subgroups no prognostic effect was detected. Conclusion: Low logAREG and logEREG levels are associated with a shorter OS in oxaliplatin/fluoropyrimidine plus bevacizumab treated patients. As low AREG and EREG level are associated with BRAF mutations, the prognostic value of EREG and AREG levels is limited to the RAS and BRAF wild-type subpopulation. PMID- 30467537 TI - The 9H-Fluoren Vinyl Ether Derivative SAM461 Inhibits Bacterial Luciferase Activity and Protects Artemia franciscana From Luminescent Vibriosis. AB - Vibrio campbellii is a major pathogen in aquaculture. It is a causative agent of the so-called "luminescent vibriosis," a life-threatening condition caused by bioluminescent Vibrio spp. that often involves mass mortality of farmed shrimps. The emergence of multidrug resistant Vibrio strains raises a concern and poses a challenge for the treatment of this infection in the coming years. Inhibition of bacterial cell-to-cell communication or quorum sensing (QS) has been proposed as an alternative to antibiotic therapies. Aiming to identify novel QS disruptors, the 9H-fluroen-9yl vinyl ether derivative SAM461 was found to thwart V. campbellii bioluminescence, a QS-regulated phenotype. Phenotypic and gene expression analyses revealed, however, that the mode of action of SAM461 was unrelated to QS inhibition. Further evaluation with purified Vibrio fischeri and NanoLuc luciferases revealed enzymatic inhibition at micromolar concentrations. In silico analysis by molecular docking suggested binding of SAM461 in the active site cavities of both luciferase enzymes. Subsequent in vivo testing of SAM461 with gnotobiotic Artemia franciscana nauplii demonstrated naupliar protection against V. campbellii infection at low micromolar concentrations. Taken together, these findings suggest that suppression of luciferase activity could constitute a novel paradigm in the development of alternative anti-infective chemotherapies against luminescent vibriosis, and pave the ground for the chemical synthesis and biological characterization of derivatives with promising antimicrobial prospects. PMID- 30467539 TI - Big Potential From Silicon-Based Porous Nanomaterials: In Field of Energy Storage and Sensors. AB - Silicon nanoparticles (SiNPs) are the promising materials in the various applications due to their unique properties like large surface area, biocompatibility, stability, excellent optical and electrical properties. Surface, optical and electrical properties are highly dependent on particle size, doping of different materials and so on. Porous structures in silicon nanomaterials not only improve the specific surface area, adsorption, and photoluminescence efficiency but also provide numbers of voids as well as the high surface to volume ratio and enhance the adsorption ability. In this review, we focus on the significance of porous silicon/mesoporous silicon nanoparticles (pSiNPs/mSiNPs) in the applications of energy storage, sensors and bioscience. Silicon as anode material in the lithium-ion batteries (LIBs) faces a huge change in volume during charging/discharging which leads to cracking, electrical contact loss and unstable solid electrolyte interphase. To overcome challenges of Si anode in the LIBs, mSiNPs are the promising candidates with different structures and coating of different materials to enhance electrochemical properties. On the basis of optical properties with tunable wavelength, pSiNPs are catching good results in biosensors and gas sensors. The mSiNPs with different structures and modified surfaces are playing an important role in the detection of biomarkers, drug delivery and diagnosis of cancer and tumors. PMID- 30467538 TI - A Chiral Bipyrimidine-Bridged Dy2 SMM: A Comparative Experimental and Theoretical Study of the Correlation Between the Distortion of the DyO6N2 Coordination Sphere and the Anisotropy Barrier. AB - Chiral bipyrimidine-bridged dinuclear LnIII complexes of general formula [(MU bipym){((+)-tfacam)3Ln}2] and [(MU-bipym){((-)-tfacam)3Ln}2], have been prepared from the assembly of Ln(AcO)3.nH2O (LnIII = Dy, Gd), (+)/(-)-3 (trifluoroacetyl)camphor enantiopure ligands ((+)/(-)-Htfacam) and bipyrimidine (bipym). The structure and chirality of these complexes have been supported by single-crystal X-Ray diffraction and circular dichroism. The study of the magnetic properties of the GdIII complexes revealed a very weak antiferromagnetic interaction between the GdIII ions through the bipyrimidine bridging ligand. Ab initio CASSCF calculations indicated that the ground Kramers doublet (KD) of both DyIII centers is almost purely axial with the anisotropy axis located close to the two tfacam-ligands at opposite sides of each DyIIIatom, which create an axial crystal field. In keeping with this, ac dynamic measurements indicated slow relaxation of the magnetization at zero field with U eff = 55.1 K, a pre exponential factor of tauo = 2.17.10-6 s and tauQTM = 8 MUs. When an optimal dc field of 0.1 T is applied, QTM is quenched and U eff increases to 75.9 K with tauo = 6.16 * 10-7 s. The DyN2O8 coordination spheres and SMM properties of [(MU bipym){((+)-tfacam)3Ln}2] and their achiral [(Dy(beta-diketonate)3)2(MU bpym)]analogous have been compared and a magneto-structural correlation has been established, which has been supported by theoretical calculations. In contrast to the GdIII compounds, the magnetic exchange interaction between the DyIII ions has been calculated to be very weak and, generally, ferromagnetic in nature. Relaxation mechanisms for [(MU-bipym){((+)-tfacam)3Ln}2] and previously reported analogous have been proposed from ab initio calculations. As the magnetic exchange interaction found to be very weak, the observed magnetization blockade in these systems are primarily dictated by the single ion anisotropy of DyIII ions. PMID- 30467540 TI - Analysis of Interaction Between Interfacial Structure and Fibrinogen at Blood Compatible Polymer/Water Interface. AB - The correlation between the interfacial structure and protein adsorption at a polymer/water interface was investigated. Poly(2-methoxyethyl acrylate)(PMEA), which is one of the best blood compatible polymers available, was employed. Nanometer-scale structures generated through the phase separation of polymer and water were observed at the PMEA/phosphate buffered saline interface. The interaction between the interfacial structures and fibrinogen (FNG) was measured using atomic force microscopy. Attraction was observed in the polymer-rich domains as well as in the non-blood compatible polymer. In contrast, no attractive interactions were observed, and only a repulsion occurred in the water rich domains. The non-adsorption of FNG into the water rich domains was also clarified through topographic and phase image analyses. Furthermore, the FNG molecules adsorbed on the surface of PMEA were easily desorbed, even in the polymer-rich domains. Water molecules in the water-rich domains are anticipated to be the dominant factor in preventing FNG adsorption and thrombogenesis on a PMEA interface. PMID- 30467536 TI - Radiation-Induced Alterations in the Recurrent Glioblastoma Microenvironment: Therapeutic Implications. AB - Glioblastoma (GBM) is uniformly fatal with a median survival of just over 1 year, despite best available treatment including radiotherapy (RT). Impacts of prior brain RT on recurrent tumors are poorly understood, though increasing evidence suggests RT-induced changes in the brain microenvironment contribute to recurrent GBM aggressiveness. The tumor microenvironment impacts malignant cells directly and indirectly through stromal cells that support tumor growth. Changes in extracellular matrix (ECM), abnormal vasculature, hypoxia, and inflammation have been reported to promote tumor aggressiveness that could be exacerbated by prior RT. Prior radiation may have long-term impacts on microglia and brain infiltrating monocytes, leading to lasting alterations in cytokine signaling and ECM. Tumor-promoting CNS injury responses are recapitulated in the tumor microenvironment and augmented following prior radiation, impacting cell phenotype, proliferation, and infiltration in the CNS. Since RT is vital to GBM management, but substantially alters the tumor microenvironment, we here review challenges, knowledge gaps, and therapeutic opportunities relevant to targeting pro-tumorigenic features of the GBM microenvironment. We suggest that insights from RT-induced changes in the tumor microenvironment may provide opportunities to target mechanisms, such as cellular senescence, that may promote GBM aggressiveness amplified in previously radiated microenvironment. PMID- 30467541 TI - Energy Storage and Thermostability of Li3VO4-Coated LiNi0.8Co0.1Mn0.1O2 as Cathode Materials for Lithium Ion Batteries. AB - The electrochemical performances and thermostability of LiNi0.8Co0.1Mn0.1O2 is affected by temperature. High ambient temperature or irregular heat distribution accelerates the decline of LiNi0.8Co0.1Mn0.1O2 performance, shortens cathode material life. In this work, the energy storage and thermostability of the Li3VO4 coated LiNi0.8Co0.1Mn0.1O2 cathode material were studied for the first time by electrochemical calorimetry methode at different temperatures and rates. Results show that Li3VO4-coated LiNi0.8Co0.1Mn0.1O2 cathode material has excellent rate and cycle performance. The thermal electrochemical experiments further show that the thermal stability of Li3VO4-coated LiNi0.8Co0.1Mn0.1O2 cathode material in charge-discharge energy storage and conversion system is better than LiNi0.8Co0.1Mn0.1O2 at 30, 40, and 50 degrees C. The enhanced performance can be attributed to the fact that Li3VO4 coating promotes the transmission of lithium ions and protects the active material from electrolyte corrosion at different temperature, as well as reduces side reaction, electrode polarization and heat generation of cathode materials. The Li3VO4-coated LiNi0.8Co0.1Mn0.1O2 cathode material has excellent energy storage properties and thermostability, which are beneficial to the development of electronic equipment. PMID- 30467543 TI - Editorial: The European Patients Academy on Therapeutic Innovation (EUPATI) Guidelines on Patient Involvement in Research and Development. PMID- 30467542 TI - Perspective From the 5th International Pemphigus and Pemphigoid Foundation Scientific Conference. AB - The 5th Scientific Conference of the International Pemphigus and Pemphigoid Foundation (IPPF), "Pemphigus and Pemphigoid: A New Era of Clinical and Translational Science" was held in Orlando, Florida, on May 15-16, 2018. Scientific sessions covered recent, ongoing, and future clinical trials in pemphigus and bullous pemphigoid, disease activity and quality of life instruments, and the IPPF Natural History Study. Furthermore, the meeting provided an opportunity to hear firsthand from patients, investigators, and industry about their experience enrolling for clinical trials. PMID- 30467544 TI - Postpolypectomy Bleeding Prevention and More Complete Precancerous Colon Polyp Removal With Endoscopic Mucosal Stripping (EMS). AB - Background and Aims: Postpolypectomy bleeding and incomplete polyp removal are important complication and quality concerns of colonoscopy for colon cancer prevention. We investigated if endoscopic mucosal stripping (EMS) as a technical modification of traditional cold snare polypectomy to avoid submucosal injury during removal of non-pedunculated colon polyps could prevent postpolypectomy bleeding and facilitate complete polyp removal. Methods: This is an Internal Review Board exemption-granted retrospective analysis of 5,142 colonoscopies with snare polypectomy performed by one of the authors (ZJC) at Minnesota Gastroenterology ambulatory endoscopy centers during a 12-year period divided into pre-EMS era (2005-2012, n = 2,973) and EMS era (2013-2016, n = 2169) with systemic adoption of EMS starting 2013. Change in postpolypectomy bleeding rate before and after EMS adoption and EMS polypectomy completeness were evaluated. Results: Zero postpolypectomy bleeding case was found during EMS era (rate 0%) compared with 10 bleeding cases during pre-EMS era (rate 0.336%). This difference was statistically significant (P = 0.0055) and remained so after excluding 2 bleeding cases of pedunculated polyps (P = 0.012). All bleeding cases involved hot snare polypectomy. Histological examination of the involved polyps showed substantial submucosal vascular damage in contrast to a remarkable paucity of submucosa in comparable advanced polyps removed using EMS. Both biopsy and follow up colonoscopy examination of the polypectomy sites confirmed that EMS more completely removed non-pedunculated advanced polyps. Conclusions: EMS polypectomy was effective in preventing postpolypectomy bleeding and facilitated complete polyp removal. PMID- 30467545 TI - Mass Spectrometry-Based Proteomics to Unveil the Non-coding RNA World. AB - The interaction between non-coding RNAs (ncRNAs) and proteins is crucial for the stability, localization and function of the different classes of ncRNAs. Although ncRNAs, when embedded in various ribonucleoprotein (RNP) complexes, control the fundamental processes of gene expression, their biological functions and mechanisms of action are still largely unexplored. Mass Spectrometry (MS)-based proteomics has emerged as powerful tool to study the ncRNA world: on the one hand, by identifying the proteins interacting with distinct ncRNAs; on the other hand, by measuring the impact of ncRNAs on global protein levels. Here, we will first provide a concise overview on the basic principles of MS-based proteomics for systematic protein identification and quantification; then, we will recapitulate the main approaches that have been implemented for the screening of ncRNA interactors and the dissection of ncRNA-protein complex composition. Finally, we will describe examples of various proteomics strategies developed to characterize the effect of ncRNAs on gene expression, with a focus on the systematic identification of microRNA (miRNA) targets. PMID- 30467546 TI - Millisecond Timescale Motions Connect Amino Acid Interaction Networks in Alpha Tryptophan Synthase. AB - Tryptophan synthase is a model system for understanding allosteric regulation within enzyme complexes. Amino acid interaction networks were previously delineated in the isolated alpha subunit (alphaTS) in the absence of the beta subunit (betaTS). The amino acid interaction networks were different between the ligand-free enzyme and the enzyme actively catalyzing turnover. Previous X-ray crystallography studies indicated only minor localized changes when ligands bind alphaTS, and so, structural changes alone could not explain the changes to the amino acid interaction networks. We hypothesized that the network changes could instead be related to changes in conformational dynamics. As such, we conducted nuclear magnetic resonance relaxation studies on different substrate- and products-bound complexes of alphaTS. Specifically, we collected 15N R2 relaxation dispersion data that reports on microsecond-to-millisecond timescale motion of backbone amide groups. These experiments indicated that there are conformational exchange events throughout alphaTS. Substrate and product binding change specific motional pathways throughout the enzyme, and these pathways connect the previously identified network residues. These pathways reach the alphaTS/betaTS binding interface, suggesting that the identified dynamic networks may also be important for communication with the betaTS subunit. PMID- 30467548 TI - Reliability and Validity Assessment of the Observation of Human-Animal Interaction for Research (OHAIRE) Behavior Coding Tool. AB - The Observation of Human-Animal Interaction for Research (OHAIRE) is a coding tool developed to capture the behavior of children when interacting with social partners and animals in naturalistic settings. The OHAIRE behavioral categories of focus are emotional displays, social communication behaviors toward adults and peers, behaviors directed toward animals or experimental control objects, and interfering behaviors. To date, the OHAIRE has been used by 14 coders to code 2,732 min of video across four studies with a total of 201 participants ages 5 to 18 years (M = 10.1, SD = 2.5). Studies involved animal-assisted intervention with three species (i.e., dogs, horses, and guinea pigs) and three populations (i.e., autism spectrum disorder, attention-deficit hyperactivity disorder, and typically developing children) in a school, a therapeutic horseback riding program, a group therapy program, and the hospital setting. We explored the psychometric properties of the OHAIRE through analyses of its inter-rater reliability, intra rater reliability, convergent and divergent validity, and internal structure, using data from these four human-animal interaction studies. The average inter rater reliability was excellent (kappa = 0.81), with good reliability in most of the behavioral categories coded. Intra-rater reliability was consistently excellent (0.87 <= kappa <=0.96). Internal structure analyses with Cronbach's alpha supported the exploratory use of subscales to measure social communication behaviors toward peers (alpha = 0.638) and adults (alpha = 0.605), and interactions experimental control objects (alpha = 0.589), and the use of a subscale to measure interactions with animals (alpha = 0.773). Correlation analyses with multiple questionnaires showed a convergence between positive emotional display and social behaviors as assessed by the OHAIRE and social skills as assessed by the Social Skills Rating System (SSRS) and the Social Communication Questionnaires (SCQ). Little concordance was found between the OHAIRE and the Social Responsiveness Scale (SRS) or the Aberrant Behavior Checklist-Community (ABC). The OHAIRE shows promise for wider use in the field of Human-Animal Interaction, with a need for generalization across more settings and ages. PMID- 30467547 TI - S100/RAGE-Mediated Inflammation and Modified Cholesterol Lipoproteins as Mediators of Osteoblastic Differentiation of Vascular Smooth Muscle Cells. AB - Arterial calcification is a feature of atherosclerosis and shares many risk factors including diabetes, dyslipidemia, chronic kidney disease, hypertension, and age. Although there is overlap in risk factors, anti-atherosclerotic therapies, including statins, fail to reduce arterial, and aortic valve calcifications. This suggests that low density lipoprotein (LDL) may not be the main driver for aortic valve disease and arterial calcification. This review focuses on modified LDLs and their role in mediating foam cell formation in smooth muscle cells (SMCs), with special emphasis on enzyme modified non-oxidized LDL (ELDL). In vivo, ELDL represents one of the many forms of modified LDLs present in the atherosclerotic vessel. Phenotypic changes of macrophages and SMCs brought about by the uptake of modified LDLs overlap significantly in an atherosclerotic milieu, making it practically impossible to differentiate between the effects from oxidized LDL, ELDL, and other LDL modification. By studying in vitro-generated modifications of LDL, we were able to demonstrate marked differences in the transcriptome of human coronary artery SMCs (HCASMCs) upon uptake of ELDL, OxLDL, and native LDL, indicating that specific modifications of LDL in atherosclerotic plaques may determine the biology and functional consequences in vasculature. Enzyme-modified non-oxidized LDL (ELDL) induces calcification of SMCs and this is associated with reduced mRNA levels for genes protective for calcification (ENPP1, MGP) and upregulation of osteoblastic genes. A second focus of this review is on the synergy between hyperlipidemia and accelerated calcification In vivo in a mouse models with transgenic expression of human S100A12. We summarize mechanisms of S100A12/RAGE mediated vascular inflammation promoting vascular and valve calcification in vivo. PMID- 30467549 TI - Nuclear/Cytoplasmic Fractionation of Proteins from Caenorhabditis elegans. AB - C. elegans is widely used to investigate biological processes related to health and disease. To study protein localization, fluorescently-tagged proteins can be used in vivo or immunohistochemistry can be performed in whole worms. Here, we describe a technique to localize a protein of interest at a subcellular level in C. elegans lysates, which can give insight into the location, function and/or toxicity of proteins. PMID- 30467550 TI - Electroporation of Labeled Antibodies to Visualize Endogenous Proteins and Posttranslational Modifications in Living Metazoan Cell Types. AB - The spatiotemporal localization of different intracellular factors in real-time and their detection in live cells are important parameters to understand dynamic protein-based processes. Therefore, there is a demand to perform live-cell imaging and to measure endogenous protein dynamics in single cells. However, fluorescent labeling of endogenous protein in living cells without overexpression of fusion proteins or genetic tagging has not been routinely possible. Here we describe a versatile antibody-based imaging approach (VANIMA) to be able to precisely locate and track endogenous proteins in living cells. The labeling is achieved by the efficient and harmless delivery of fluorescent dye-conjugated antibodies or antibody fragments (Fabs) into living cells and the specific binding of these antibodies to the target protein inside of the cell. Our protocol describes step by step the procedure from testing of the suitability of the desired antibody, over the digestion of the antibody to Fabs until the labeling and the delivery by electroporation of the antibody or Fab into the cells. VANIMA can be adapted to any monoclonal antibody, self-produced or commercial, and many different metazoan cell lines. Additionally, our method is simple to implement and can be used not only to visualize and track endogenous factors, but also to specifically label posttranslational modifications, which cannot be achieved by any other labeling technique so far. PMID- 30467551 TI - Sex differences in motivated behaviors in animal models. AB - Sex differences exist in the motivation for sexual behavior, food, parental care and motivation to take drugs. There are also sex differences in the likelihood of exhibiting motivational disorders such as anhedonia, depression, addictive behavior, and eating disorders. This brief review summaries recent studies on sex differences in all motivated behaviors in social and non-social contexts, focusing on animal models. We also discuss the roles of gonadal hormones and the nonapeptides (nine amino acid peptides) in modulating sex differences in motivation. We propose that sex differences in the neural mechanisms mediating endogenous motivation for food, sex, partners and care of offspring underlie sex differences in all motivated behaviors. PMID- 30467552 TI - Longitudinal serological measures of common infection in the Avon Longitudinal Study of Parents and Children cohort. AB - Antibodies against pathogens provide information on exposure to infectious agents and are meaningful measures of past and present infection. Antibodies were measured in the plasma of children that are the offspring in a population-based birth cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC). Plasma was collected during clinics at age 5, 7, 11 and 15 years. The antigens examined include: fungal ( Saccharomyces cerevisiae); protozoan ( Toxoplasma gondii and surface antigen 1 of T. gondii); herpes viruses (cytomegalovirus, Epstein-Barr virus, herpes simplex virus type 1); common colds (influenza virus subtypes H1N1 and H3N2); other antigens (measles); animal (feline herpes virus, Theiler's virus); bacteria ( Helicobacter pylori); dietary antigens (bovine casein alpha protein, bovine casein beta protein). Alongside the depth of data available within the ALSPAC cohort, this longitudinal resource will enable the investigation of the association between infections and a wide variety of outcomes. PMID- 30467553 TI - Cardiac-specific research platforms engender novel insights into mitochondrial dynamism. AB - Cardiac myocyte-specific gene manipulation is facilitated by reagents permitting temporal control over transgene expression or gene ablation, and by physiological phenotyping platforms that complement post-mortem cellular and pathological analyses. The ease of creating cardiac-specific gene modified mice may have contributed to genetic mouse models lacking strong underlying mechanistic rationales; this was argued for genetic ablation of mitochondrial dynamics factors in cardiac myocytes that exhibit little evidence for mitochondrial dynamism. Here, I review recent published studies in which experimental in vivo manipulation of mitochondrial fusion and fission genes has revealed non-canonical functioning dynamics factors in mitochondrial quality and quantity control. Targeting mitochondrial dynamics proteins in the cardiac system, where mitochondrial dynamism is barely observed, was essential to uncovering novel functioning of these factors in other pathways. PMID- 30467554 TI - Species-Specific Transcriptional Regulation of Genes Involved in Nitric Oxide Production and Arginine Metabolism in Macrophages. AB - Activated mouse macrophages metabolize arginine via NO synthase (NOS2) to produce NO as an antimicrobial effector. Published gene expression datasets provide little support for the activation of this pathway in human macrophages. Generation of NO requires the coordinated regulation of multiple genes. We have generated RNA-sequencing data from bone marrow-derived macrophages from representative rodent (rat), monogastric (pig and horse), and ruminant (sheep, goat, cattle, and water buffalo) species, and analyzed the expression of genes involved in arginine metabolism in response to stimulation with LPS. In rats, as in mice, LPS strongly induced Nos2, the arginine transporter Slc7a2, arginase 1 (Arg1), GTP cyclohydrolase (Gch1), and argininosuccinate synthase (Ass1). None of these responses was conserved across species. Only cattle and water buffalo showed substantial NOS2 induction. The species studied also differed in expression and regulation of arginase (ARG2, rather than ARG1), and amino acid transporters. Variation between species was associated with rapid promoter evolution. Differential induction of NOS2 and ARG2 between the ruminant species was associated with insertions of the Bov-A2 retrotransposon in the promoter region. Bov-A2 was shown to possess LPS-inducible enhancer activity in transfected RAW264.7 macrophages. Consistent with a function in innate immunity, NO production and arginine metabolism vary greatly between species and differences may contribute to pathogen host restriction. PMID- 30467555 TI - Analyzing Goals of Care in Advanced Cancer Patients and Their Family Caregivers: Evidence-based Research. AB - Objective: The study objective was to determine concordance between patients and family caregivers' preferences for quality or length of life over time. Background: Patients with advanced cancer are confronted with difficult decisions throughout their course of treatment and at end of life (EOL). These decisions can be influenced by their family caregivers' preferences for the patient's cancer treatment. Methods: Using a longitudinal, descriptive study design from an on-going study, data were collected on an adult sample of patients with advanced stage GI or lung cancers and their family caregivers (n=237). Using a one item visual analog scale (0-100 with higher number indicating a preference for length of life over quality of life), patients and family caregivers were asked "regarding your/your loved one's care, what is most important to you right now?" Data were collected every 3 months until 15 months or patient's death. Results: At enrollment, the preference scores between patients (48.5) and family caregivers (42.6) were closely aligned. At the last assessment prior to death, these scores diverged with the caregivers favoring goals associated with quality of life over length of life (p=.02). Discussion: Patients and family caregivers have differing preferences and these goals of care can change over time. Attention to these differences could be used to guide conversations between patients and family caregivers regarding preferences at EOL. PMID- 30467557 TI - UArizona at the MADE1.0 NLP Challenge. AB - MADE1.0 is a public natural language processing challenge aiming to extract medication and adverse drug events from Electronic Health Records. This work presents NER and RI systems developed by UArizona team for the MADE1.0 competition. We propose a neural NER system for medical named entity recognition using both local and context features for each individual word and a simple but effective SVM-based pairwise relation classification system for identifying relations between medical entities and attributes. Our system achieves 81.56%, 83.18%, and 59.85% F1 score in the three tasks of MADE1.0 challenge, respectively, ranked amongst the top three teams for Task 2 and 3. PMID- 30467556 TI - Patient-derived Models Reveal Impact of the Tumor Microenvironment on Therapeutic Response. AB - Background: Androgen deprivation therapy is a first-line treatment for disseminated prostate cancer (PCa). However, virtually all tumors become resistant and recur as castration-resistant PCa, which has no durable cure. One major hurdle in the development of more effective therapies is the lack of preclinical models that adequately recapitulate the heterogeneity of PCa, significantly hindering the ability to accurately predict therapeutic response. Objective: To leverage the ex vivo culture method termed patient-derived explant (PDE) to examine the impact of PCa therapeutics on a patient-by-patient basis. Design setting and participants: Fresh PCa tissue from patients who underwent radical prostatectomy was cultured as PDEs to examine therapeutic response. Outcome measurements and statistical analysis: The impact of genomic and chemical perturbations in PDEs was assessed using various parameters (eg, AR levels, Ki67 staining, and desmoplastic indices). Results and limitations: PDE maintained the integrity of the native tumor microenvironment (TME), tumor tissue morphology, viability, and endogenous hormone signaling. Tumor cells in this model system exhibited de novo proliferative capacity. Examination of the native TME in the PDE revealed a first-in-field insight into patient-specific desmoplastic stromal indices and predicted responsiveness to AR-directed therapeutics. Conclusions: The PDE model allows for a comprehensive evaluation of individual tumors in their native TME to ultimately develop more effective therapeutic regimens tailored to individuals. Discernment of novel stromal markers may provide a basis for applying precision medicine in treating advanced PCa, which would have a transformative effect on patient outcomes. Patient summary: In this study, an innovative model system was used to more effectively mimic human disease. The patient-derived explant (PDE) system can be used to predict therapeutic response and identify novel targets in advanced disease. Thus, the PDE will be an asset for the development of novel metrics for the implementation of precision medicine in prostate cancer.The patient-derived explant (PDE) model allows for a comprehensive evaluation of individual human tumors in their native tumor microenvironment (TME). TME analysis revealed first-in-field insight into predicted tumor responsiveness to AR-directed therapeutics through evaluation of patient-specific desmoplastic stromal indices. PMID- 30467558 TI - Objective Food Intake in Night and Day Shift Workers: A Laboratory Study. AB - Night shift work is associated with risk of overweight and obesity. In night shift workers, short sleep duration combined with circadian misalignment may contribute to altered food intake regulation, favoring positive energy balance and weight gain. Prior work investigating food intake in shift workers has suffered methodologically due to reliance on subjective self-report for dietary assessment. No study has yet been done to examine the impact of night shift work on food intake in real-life shift workers using objective measures. Female day (n = 12) and night (n = 12) shift workers from a hospital setting participated in a laboratory-based objective food intake assessment. Participants entered the laboratory in the fasted state after awakening from the sleep episode following a final work shift, and underwent an ad libitum 14-item test meal buffet to objectively quantify food choice/intake. Sleep duration (measured via wrist accelerometry) during the sleep episode before laboratory assessment was significantly longer in day vs. night workers (373.9 +/- 127.5 vs. 260.6 +/- 102.9 min, p = 0.03). No significant group difference was observed in calories consumed during the test meal (943.08 +/- 469.55 vs. 878.58 +/- 442.68 kcal, p = 0.74). When expressed as percent of energy consumed, day workers had higher protein consumption vs. night workers (16.03 +/- 5.69 vs. 11.82 +/- 4.05%; p = 0.05). To our knowledge, this is the first laboratory-based behavioral assessment of food choice/intake in actual night and day shift workers. Although not studied here, work by others has linked protein intake to satiety. This may be a potential pathway placing shift workers at risk for overweight and obesity. PMID- 30467559 TI - A 'burning opportunity' for human rights: using human rights as a catalyst for policies to mitigate the health risk of household air pollution. AB - With over 3 billion people dependent on traditional cooking and heating technologies, efforts to address the health burden of exposure to household air pollution (HAP), as well as other sociodemographic impacts associated with energy poverty, are central to sustainable development objectives. Yet despite overwhelming scientific consensus on the health burden of HAP exposure, particularly harms to impoverished women and children in developing countries, advocates currently lack a human rights framework to mitigate HAP exposure through improved access to cleaner household energy systems. This article examines the role of human rights in framing state obligations to mitigate HAP exposure, supporting environmental health for the most vulnerable through intersectional obligations across the human right to health, the collective right to development, and women's and children's rights. Drawing from human rights advocacy employed in confronting the public health harms of tobacco, we argue that rights-based civil society advocacy can structure the multi-sectoral policies necessary to address the impacts of HAP exposure and energy poverty, facilitating accountability for human rights implementation through international treaty bodies, national judicial challenges and local political advocacy. We conclude that there is a pressing need to build civil society capacity for a rights-based approach to cleaner household energy policy as a means to alleviate the environmental health effects of energy poverty. PMID- 30467561 TI - Enhancing the antimicrobial and antifungal activities of a coloring extract agent rich in betacyanins obtained from Gomphrena globosa L. flowers. AB - Although less explored than beetroot (Beta vulgaris L.), the flowers of Gomphrena globosa L. are a very suitable source of betacyanins with strong pigmentation features, together with many other desirable bioactive properties. Thus, the aim of this study was to enhance the antimicrobial and antifungal activities of a pigmented extract obtained from G. globosa flowers by ultrasound assisted extraction (UAE). The procedure was supported with the application of the response surface methodology, a robust optimization technique that allows to study jointly the effects of several variables and responses. To enhance the antimicrobial (Bacillus cereus, Listeria monocytogenes, Escherichia coli and Salmonella typhimurium) and antifungal (Aspergillus flavus, Aspergillus niger, Penicillium ochrochloron and Penicillium verrucosum) activities, the responses were evaluated in terms of the concentrations needed to obtain minimum inhibitory (MIC), minimum bactericidal (MBC) and minimum fungicidal (MFC) concentrations. It was found that the optimal UAE conditions were 10.8 min, 410.5 W, 57.8% of ethanol, and 5 g L-1 of the solid-liquid ratio providing the following response values: (1) from the studied species of bacteria, the MIC ranged from ~0.15 to 0.35 g L-1 and the MBC ranges were ~0.30 to 0.65 g L-1; and (2) from the studied fungus species, the MIC ranged from ~0.20 to 0.30 g L-1 and the MFC ranges were ~0.40 to 0.65 g L-1. The antibacterial activity dose levels were lower than the antifungal ones. In conclusion, the results obtained in this study highlight extracts from G. globosa flowers as natural sources of betacyanins with application as food colorants with important antimicrobial and antifungal activities. PMID- 30467560 TI - Axonal Transport: A Constrained System. AB - Long-distance intracellular axonal transport is predominantly microtubule-based, and its impairment is linked to neurodegeneration. Here we review recent theoretical and experimental evidence that suggest that near the axon boundaries (walls), the effective viscosity can become large enough to impede cargo transport in small (but not large) caliber axons. Theoretical work suggests that this opposition to motion increases rapidly as the cargo approaches the wall. However, having parallel microtubules close enough together to enable a cargo to simultaneously engage motors on more than one microtubule dramatically enhances motor activity, and thus decreases the effects due to such opposition. Experimental evidence supports this hypothesis: in small caliber axons, microtubule density is higher, increasing the probability of having parallel microtubules close enough that they can be used simultaneously by motors on a cargo. For transport toward the minus-end of microtubules, e.g., toward the cell body in an axon, a recently discovered force adaptation system can also contribute to overcoming such opposition to motion. PMID- 30467562 TI - Aminoluciferin 4-hydroxyphenyl amide enables bioluminescence detection of endogenous tyrosinase. AB - Tyrosinase, a copper-containing enzyme existing widely in plants, animals and microorganisms, usually serves as an important biomarker in melanoma, and is also related to hyperpigmentation of the skin, melasma, age spots and albinism. At present, only one bioluminescent probe has been applied to image tyrosinase in cells. Thus, it's of great significance to develop a new bioluminescent probe that can detect tyrosinase in living cells and in live animals. In the current work, we report a new BL probe, TyrBP-3, which not detect tyrosinase in vitro and in living cells, but can also visualize the level of tyrosinase activity in tumors of living animals. In summary, TyrBP-3 is the first bioluminescent probe that can image tyrosinase on a cellular level. Hence, we anticipate that TyrBP-3 can be a good tool to monitor tyrosinase in complex biosystems in the future. PMID- 30467563 TI - A high performance asymmetric supercapacitor based on in situ prepared CuCo2O4 nanowires and PPy nanoparticles on a two-ply carbon nanotube yarn. AB - One-dimensional supercapacitors (SCs) are of great interest for future wearable electronics, but improvement in both high capacitance and high flexibility is still a challenge. Herein, we fabricate a high performance yarn asymmetric SC (ASC) using in situ prepared CuCo2O4 nanowires and polypyrrole (PPy) nanoparticles on the surface of a two-ply carbon nanotube (CNT) yarn. The parallel-shaped yarn ASC not only shows outstanding redox pseudocapacitance, including a high areal capacitance (59.55 mF cm-2), specific energy density (20 MUW h cm-2) and power density (5.115 mW cm-2), but also exhibits good flexibility because of its well maintained capacitance during repeated dynamic bending states. The capacitance retention still remains 80.1% under 8000 cycles, suggesting relatively good reversibility and stability. PMID- 30467564 TI - Hypoglycemic mechanisms of Ganoderma lucidum polysaccharides F31 in db/db mice via RNA-seq and iTRAQ. AB - Our team has previously demonstrated that Ganoderma lucidum polysaccharides F31 have hypoglycemic effects on diabetic mice. This study provides insight into the system-level hypoglycemic mechanisms of F31 by the integrative analysis of transcriptomics and proteomics data. To explore the omics perspective for the mechanisms of action, the protein and gene expression in the liver from the normal control (NC), diabetic db/db control mice (DC) and F31-treated db/db mice (F31) were analyzed by iTRAQ and RNA-Seq. The differential expression proteins (DEPs) and differential expression genes (DEGs) were analyzed based on their gene ontology (GO) annotations and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and the expression of DEGs and DEPs was verified by quantitative polymerase chain reaction (qPCR) and western blotting (WB). We identified sixty-five DEGs and sixty-two DEPs in the F31-treated group as compared with the DC. Integrated analysis of the RNA-Seq data and proteomics data indicated that the two DEGs/DEPs-Gck [glucokinase (GCK)] and Cyp4a12a [cytochrome P450, family 4, subfamily a, polypeptide 12a (CYP4A12A)]-showed the same trend in mRNA and protein expression levels in the comparison of F31-VS-DC. KEGG analysis revealed that the peroxisome proliferator-activated receptors (PPARs) signaling pathway was enriched in both of the comparisons of NC-VS-DC and F31-VS-DC at the protein expression level. In the analysis of the gene and protein expression of candidate proteins targeting diabetes, we found that three genes [Gck, glucose-6 phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK)] and three proteins [GCK, glucose transporter type 2 (GLUT2), pyruvate kinase (PYK) ] in the glycolysis and gluconeogenesis pathways, proteins of the Janus-activated kinase 2 (JAK2) in the insulin pathway, and two genes [Cyp4a12a and stearoyl-CoA desaturase 2 (SCD2)] in the lipid metabolism were expressed significantly differently in the F31-treated group as compared with the DC group, which played important roles in the hypoglycemic activity of F31. Cluster analysis demonstrated that microRNAs probably participated in the regulation of the genes involved the glucose metabolism. These results provide theoretical evidence for F31 as a potential functional food ingredient for the prevention and treatment of type 2 diabetes. PMID- 30467565 TI - pH-Dependent growth of atomic Pd layers on trisoctahedral gold nanoparticles to realize enhanced performance in electrocatalysis and chemical catalysis. AB - In this work, the controlled epitaxial growth of ultrathin Pd shells of a few atomic layers (denoted as nL) on the surfaces of gold nanoparticle (Au NP) cores of different morphologies (trisoctahedral, cubic, and spherical shapes) in the presence of cetyltrimethylammonium chloride (CTAC) was achieved by regulating the pH value of the aqueous CTAC solution and finely tuning the amount of the Pd precursor. It was found that the critical shell thickness for epitaxial Pd growth at the optimal pH value was 4 atomic layers, taking {331}-faceted trisoctahedral (TOH) Au@PdnL NPs as an example, on the basis of the results of atomic-resolution high-angle annular dark-field scanning transmission electron microscopy (HAADF STEM) images. Moreover, the resulting TOH Au@Pd1L NPs (100.9 m2 g-1, 13.2 A mgPd 1 and 13.1 mA cm-2) exhibited excellent electrocatalytic performance and long term electrocatalytic activity for ethanol oxidation, around 4.8-fold, 66-fold, and 21.8-fold better than commercial Pd/C catalysts (31 m2 g-1, 0.2 A mgPd-1, and 0.6 mA cm-2). Furthermore, the resulting TOH Au@Pd1L NPs not only markedly enhance the chemical catalytic activity for the reduction of 4-nitrophenol (4 NP), but also allow the in situ surface-enhanced Raman spectroscopy (SERS) monitoring of the reaction process of the Pd-catalyzed reduction of 4-NTP. Thus, our work may provide a new way to fabricate core-shell (CS) bimetallic NPs with the merits of both metal outer shells (excellent catalytic performance in electrocatalysis and chemical catalysis) and Au NP cores (reaction process by in situ SERS monitoring). PMID- 30467566 TI - Halogen-free GeO2 conversion: electrochemical reduction vs. complexation in (DTBC)2Ge[Py(CN)n] (n = 0...2) complexes. AB - 3,5-di-tert-Butylcatecholate (DTBC) germanium complexes (DTBC)2Ge[Py(CN)n]2 (n = 0...2) have been synthesized from GeO2, 3,5-di-tert-butylcatechol and cyano substituted pyridines Py(CN)n and characterized by elemental analysis, NMR, IR and UV-VIS spectroscopy. The structure of 1 (with 4-cyanopyridine) has been determined by X-ray single crystal analysis. UV-VIS spectra have shown that these complexes are stable in CH3CN, toluene and CH2Cl2 solutions; in contrast, they are rapidly decomposed by dimethylformamide and tetrahydrofuran. Complexes 1 and 2 (with 4-cyano and 3-cyanopyridine) are electrochemically reducible in toluene/1 M Bu4NPF6 at E = -1.3...-1.7 V vs. AgCl. The quantum-chemical study of these complexes is in accordance with the unsuccessful attempts to obtain analogous derivatives with 2-cyanopyridine and 2,6-dicyanopyridine. PMID- 30467567 TI - Continuous processing of phase-change materials into uniform nanoparticles for near-infrared-triggered drug release. AB - We report a method based on interfacial, anti-solvent-induced precipitation in a fluidic device for the continuous and scalable processing of phase-change materials (PCMs) into uniform nanoparticles with controlled diameters in the range of 10-100 nm. A eutectic mixture of lauric acid and stearic acid, with a well-defined melting point at 39 degrees C, serves as an example to demonstrate the concept. In the fluidic device, a coaxial flow is created by introducing a PCM solution in ethanol and a lipid solution in water (the anti-solvent) as the focused and focusing phases, respectively. The formation of lipid-capped PCM nanoparticles is governed by diffusion-controlled mixing of ethanol and water. During the production, both doxorubicin (DOX, an anticancer drug) and indocyanine green (ICG, a near-infrared dye) can be readily loaded into the PCM nanoparticles to give a smart drug release system. Upon irradiation with near-infrared light, the photothermal heating caused by ICG can melt the PCM and thereby trigger the release of DOX. This work not only provides a new technique for the continuous processing of PCMs and other soft materials into uniform nanoparticles with controlled sizes but also demonstrates a biocompatible system for controlled release and related applications. PMID- 30467569 TI - Regenerating infected bone defects with osteocompatible microspheres possessing antibacterial activity. AB - Treatment of infected bone defects still remains a formidable clinical challenge, and the design of bone implants with both anti-bacterial activity and osteogenesis effects is nowadays regarded as a powerful strategy for infection control and bone healing. In the present study, bioresorbable porous-structured microspheres were fabricated from an amphiphilic block copolymer composed of poly(l-lactide) and poly(ethyl glycol) blocks. After being surface coated with mussel-inspired polydopamine, the microspheres were loaded with nanosilver via the reduction of silver nitrate and apatite via biomineralization in sequence. At optimized loading amounts, the nanosilver-loaded microspheres showed no unfavorable effects on the proliferation and differentiation of bone marrow mesenchymal stem cells despite preserving strong antibacterial activity in in vitro evaluations. For the critical-sized defects (phi = 8 mm) in the rat cranium that was pre-infected with Staphylococcus aureus, the filling of the dual-purpose microspheres demonstrated an effective way to kill bacteria in vivo, and in the meantime, it promoted new bone formation efficiently alongside the degradation of microspheres. Thus, the results suggested that bioresorbable microspheres with both osteoconductive and antibacterial activities were a good choice for treating infected bone defects. PMID- 30467568 TI - Synthesis, characterization, and catalytic application in aldehyde hydrosilylation of half-sandwich nickel complexes bearing (kappa1-C)- and hemilabile (kappa2-C,S)-thioether-functionalised NHC ligands. AB - Neutral nickel-N-heterocyclic carbene complexes, (kappa1-C)-[NiCpBr{R-NHC (CH2)2SR'}] [Cp = eta5-C5H5; R-NHC-(CH2)2SR' = 1-mesityl-3-[2-(tert butylthio)ethyl]- (1a), 1-mesityl-3-[2-(phenylthio)ethyl]- (1b), 1-benzyl-3-[2 (tert-butylthio)ethyl]- (1c), 1-benzyl-3-[2-(phenylthio)ethyl]-imidazol-2-ylidene (1d)], which bear a N-bound thioether side arm, were prepared by the reaction of nickelocene with the corresponding imidazolium bromides [R-NHC-(CH2)2SR'.HBr] (a d), via conventional or microwave heating. The 1H NMR spectra of the benzyl substituted species 1c and 1d showed signals for diastereotopic NCH2CH2S protons at room temperature. However, structural studies established the absence of coordination of the sulphur atom in the solid state, and solvent DFT calculations showed that bromide displacement by sulphur is an unfavourable process (DeltaG = +13.5 kcal mol-1 for 1d), thereby suggesting that the observed disatereotopicity is more likely due to significant steric congestion rather than to a possible C,S chelation in solution. Treatment of these complexes with KPF6 in tetrahydrofuran (THF) led to bromide abstraction to afford the cationic complexes [NiCp{R-NHC (CH2)2SR'}](PF6) (2a-c). Alternatively, 2a-c could also be prepared by the direct reaction of nickelocene with the corresponding imidazolium hexafluorophosphate salts [R-NHC-(CH2)2SR'.HPF6]. Inversely to the neutral species, whereas X-ray crystallography established C,S-chelation in the solid state, the 1H NMR spectra (CDCl3, CD2Cl2, or thf-d8) at room temperature showed no diastereotopic NCH2CH2S protons, thus suggesting the possible displacement of the sulphur atom by the respective solvents and/or very fast sulphur inversion. DFT calculations established a low energy inversion process in all cases (+9 <=DeltaG?<= +13 kcal mol-1) as well as a favourable solvent coordination process (DeltaG?~ +11 kcal mol-1; DeltaG~-7 kcal mol-1) with a solvent such as THF, thus suggesting that sulphur inversion and/or solvent coordination can both account for the absence of diastereotopy at room temperature, depending on the solvent. While all complexes catalysed the hydrosilylation of benzaldehyde in the absence of any additive, the cationic C,S-chelated complexes 2 proved more active than the sterically constrained neutral species 1. In particular, 2c proved to be the most active pre catalyst and its catalytic charge could be lowered down to 2 mol% with PhSiH3 as the hydrogen source. PMID- 30467570 TI - Spin-orbit coupling prevents spin channel suppression of transition metal atoms on armchair graphene nanoribbons. AB - We investigate the spin-dependent electronic and transport properties of armchair graphene nanoribbons including spin-orbit coupling due to the presence of nickel and iridium adatoms by using ab initio calculations within the spin-polarized density functional theory and non-equilibrium Green's function formalism. Our results indicate that the intensity of the spin-flip precession is a direct consequence of the relaxed adsorption sites of the adatoms. We point out that d orbitals of Ni and Ir result in strong dependence on the spin-conserved and spin flip transmission probabilities. In particular, we show that the presence of spin orbit coupling can lead to an enhancement of the transmission probabilities especially around resonances arising due to weak coupling with specific orbitals. PMID- 30467571 TI - From oxide to a new type of molecular tungsten compound: formation of bitetrahedral cluster complexes [{W6(MU4-O)2(MU3-CCN)4}(CN)16]10- and [{W6(MU4 O)2(MU3-As)4}(CN)16]10. AB - Tungsten trioxide has been found to be a convenient precursor for the synthesis of metal cluster compounds with new types of cluster cores. The reaction between WO3 and KCN led to the formation of the cluster complex [{W6(MU4-O)2(MU3 CCN)4}(CN)16]10-. Unexpectedly, it includes the fully deprotonated form of acetonitrile, the CCN3- anion, as a MU3-bridging ligand coordinated to the trigonal faces of the bitetrahedral W6 metallocluster. A similar complex [{W6(MU4 O)2(MU3-As)4}(CN)16]10- containing MU3-As3- ligands instead of MU3-CCN3- ones has been synthesized by the reaction between WO3, As and KCN. PMID- 30467572 TI - Designing air-stable cyclometalated Fe(ii) complexes: stabilization via electrostatic effects. AB - Designing efficient Fe(ii) chromophores requires optimization of numerous, at times conflicting, properties. It has been suggested that replacement of polypyridine ligands with cyclometalated analogs will be effective at destabilizing the quintet state and therefore extending the lifetime of photoactive metal-to-ligand charge transfer states. However, cyclometalated Fe(ii) complexes are not oxidatively stable due to the strong electron-donating nature of this ligand, which limits their applicability. Here we use density functional theory calculations to show how simple addition of nitro and carboxylic acid groups to these cyclometalated complexes can engender a less oxidizable Fe(ii) center while maintaining, or even improving, the favorable ligand field strength. PMID- 30467573 TI - The in vivo effects of silver nanoparticles on terrestrial isopods, Porcellio scaber, depend on a dynamic interplay between shape, size and nanoparticle dissolution properties. AB - The present work aims to study the effects that acute exposure to low concentrations of silver nanoparticles (AgNPs) cause in digestive glands of terrestrial isopods (Porcellio scaber). The experiments were designed to integrate different analytical techniques, such as transmission electron microscopy, atomic absorption spectroscopy, proton induced X-ray emission, and Fourier transform IR imaging (FTIRI), in order to gain a comprehensive insight into the process from the AgNPs' synthesis to their interaction with biological tissues in vivo. To this aim, terrestrial isopods were fed with AgNPs having different shapes, sizes, and concentrations. For all the tested conditions, no toxicity at the whole organism level was observed after 14 days of exposure. However, FTIRI showed that AgNPs caused detectable local changes in proteins, lipids, nucleic acids and carbohydrates at the tissue level, to an extent dependent on the interplay of the AgNPs' properties: shape, size, concentration and dissolution of ions from them. PMID- 30467574 TI - Development of a Hg-free UV light source and its performance in photolytic and photocatalytic applications. AB - Constraints on light sources that use mercury (arc lamps) are evolving with the establishment of the Minamata Convention, which has led to the proliferation of LEDs. However, no LED light source emits intense ultraviolet radiation at wavelengths below 300 nm for photolytic applications. Thus, it is necessary to develop suitable UV light sources for the decontamination of wastewater and water sterilization processing. Herein, we explore various substitute gases (e.g., N2, Ar, He and SF6) to replace mercury, which is commonly employed in arc lamps, using an EL (electroluminescence) quartz assembly platform similar to microwave discharge electrodeless lamps. Although nitrogen is an inexpensive and safe gas, it cannot generate significant UV radiation in the UVC region of 200-300 nm. This problem in the Hg-free light source was resolved by mixing a very small quantity of sulfur hexafluoride (SF6) as an additive filler gas in a nitrogen-, argon- or helium-filled assembly. The low-pressure mercury lamp consisting of Hg/Ar filler gases is ca. 25% more efficient than the novel N2/SF6 lamp toward the photolytic decomposition of Rhodamine-B (RhB) dye-contaminated wastewater (1.66 * 10-4 mM min-1 versus 1.22 * 10-4 mM min-1). Nonetheless, the latter has proven far more efficient than an LED source emitting 365 nm radiation (0.057 * 10-4 mM min-1). The addition of TiO2 to RhB-contaminated wastewater demonstrated that this Hg free N2/SF6 light source is as efficient as the corresponding Hg/Ar electroluminescent lamp toward the photocatalytic decomposition of the RhB dye pollutant. PMID- 30467575 TI - Hydride transfer initiated ring expansion of pyrrolidines toward highly functionalized tetrahydro-1-benzazepines. AB - A novel hydride transfer initiated ring expansion of 4-pyrrolidinyl isatins to synthesize tetrahydro-1-benzazepines has been developed. This methodology represents an atom- and step-economical protocol to assemble seven-membered polycyclic amines from pyrrolidine derivatives in one step. PMID- 30467576 TI - What role do family composition and functioning play in emotional and behavioural problems among adolescent boys and girls? AB - OBJECTIVES: The aim was to explore the associations of family composition, family support and communication with emotional and behavioural problems among adolescents as well as a possible moderating effect of gender on these associations. METHODS: Data from the Health Behaviour in School-aged Children study conducted in 2014 in Slovakia were used. The final sample consisted of 2908 students (mean age 14.36; 49.7% boys). We explored the association using generalized linear models. RESULTS: We found that non-intact family was significantly associated with a higher score in emotional and behavioural problems. Family support and communication were found to be significantly associated with a lower score in emotional and behavioural problems. Significant interactions of gender and family communication with emotional and behavioural problems were found, showing that family communication decreased emotional and behavioural problems only in girls. CONCLUSIONS: Family composition, family support and communication play an important role in the occurrence of emotional and behavioural problems in adolescence. Family communication lowers these problems only in girls. Prevention and intervention programmes could be focused on parent-child communication strategies with the importance of differences in the needs of boys and girls. PMID- 30467577 TI - Socioeconomic gradients in chronic disease risk behaviors in a population-based study of older adults in rural South Africa. AB - OBJECTIVES: To investigate the associations between household wealth, household consumption, and chronic disease risk behaviors among older adults in rural South Africa. METHODS: Data were from baseline assessments of 5059 adults aged >= 40 in the population-based "Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa" in 2015. Confounder-adjusted prevalence ratios were estimated for the associations between each of household wealth and household consumption quintiles with low moderate-to-vigorous physical activity (MVPA), current smoking, frequent alcohol intake, and overweight/obese body mass index (BMI). RESULTS: Low MVPA and overweight/obese BMI were common (57% and 58%, respectively), and linearly increased in prevalence across household wealth quintiles. Low MVPA decreased and overweight/obese BMI increased in prevalence across household consumption quintiles. Smoking and frequent alcohol intake were rare (9% and 6%, respectively); they decreased in prevalence across wealth quintiles, but did not vary by consumption quintile. CONCLUSIONS: Chronic disease risk behaviors are socioeconomically graded among older, rural South African adults. The high prevalence of overweight and obesity in rural South Africa is a public health concern requiring urgent attention. PMID- 30467578 TI - Efficacy of liraglutide intervention in myocardial infarction : A meta-analysis of randomized controlled trials. AB - INTRODUCTION: The efficacy of liraglutide intervention for myocardial infarction (MI) remains controversial. We conducted a systematic review and meta-analysis to explore the influence of liraglutide intervention versus placebo on cardiac function for MI. METHODS: We searched PubMed, Embase, Web of science, EBSCO, and Cochrane library databases through April 2018 for randomized controlled trials (RCTs) assessing the effect of liraglutide intervention versus placebo on MI. This meta-analysis was performed using the random-effect model. RESULTS: Four randomized controlled trials involving 469 patients were included in the meta analysis. Overall, compared with control group for MI, liraglutide intervention significantly improved left ventricular ejection fraction (mean difference [MD] = 4.42; 95% confidence interval [CI] =1.71 to 7.14; P = 0.001), superoxide dismutase (MD = 6.89; 95% CI = 1.80 to 11.98; P = 0.008), and decreased high sensitivity C-reactive protein (MD = -0.21; 95% CI = -0.33 to -0.09; P = 0.0006), but had no remarkable influence on major adverse cardiovascular events (risk ratio = 0.56; 95% CI = 0.28-1.09; P = 0.09), recurrence of MI (risk ratio = 0.50; 95% CI = 0.19-1.30; P = 0.16), repeated revascularization (risk ratio = 0.49; 95% CI = 0.17-1.42; P = 0.19), and cardiac death (risk ratio = 0.57; 95% CI = 0.12 2.73; P = 0.48). CONCLUSIONS: Liraglutide intervention is associated with significantly improved left ventricular ejection fraction and superoxide dismutase, reduced high-sensitivity C-reactive protein in patients with MI, but has no remarkable impact on major adverse cardiovascular events, recurrence of MI, repeated revascularization or cardiac death. PMID- 30467579 TI - Non-operative treatment of ACL injury is associated with opposing subjective and objective outcomes over 20 years of follow-up. AB - PURPOSE: The aim of this study was the evaluation of long-term clinical and radiological outcomes of non-operative treatment of anterior cruciate ligament (ACL) deficiency. The hypothesis was that conservative treatment would be associated with a deterioration of subjective and objective measures of joint health and disability over time. METHODS: From an initial sample of 41 patients conservatively treated for ACL rupture, 10 received secondary ACL reconstruction, 1 was excluded due to contralateral ACL injury, and 1 patient required total knee replacement and a high tibial osteotomy. Seven further patients were lost to follow-up. The remaining 21 patients (15 male, 6 female, mean age 53.1 +/- 9.2 years at the last follow-up) were evaluated by the same two examiners 5-7, 10-13 and 20-22 years after the injury. The evaluation was based on objective and subjective scores, instrumented testing, radiographic examination and assessment of sports activity. RESULTS: While subjective patient satisfaction improved over time, objective scores stayed constant or deteriorated (radiologic evaluation). Instrumented knee laxity testing showed an initial tendency to increasing instability, followed by a decrease in anterior tibial translation in the second half of the observation period. Physical activity levels, particularly in high risk sports, decreased significantly (p < 0.05) compared to preinjury levels. All patients developed significant arthritic degenerative changes over time compared to the uninjured contralateral knee. No correlation to activities in high- or low risk pivoting sports was found. CONCLUSIONS: Patient satisfaction with conservative treatment of ACL injuries is good in spite of objective measures indicating increasing degenerative changes. LEVEL OF EVIDENCE: IV. PMID- 30467580 TI - Survey results from an international hip course: comparison between experts and non-experts on hip arthroscopy clinical practice and post-operative rehabilitation. AB - PURPOSE: The purpose of this study was to compare the clinical practices between expert and non-expert arthroscopy hip surgeons. METHODS: Registered orthopedic surgeons completed anonymous surveys during a hip arthroscopy meeting. The survey included 60 questions on physician's level of expertise, surgical anesthesia, procedures performed, hospital stay, pain control, rehabilitation and socioeconomic parameters, and the results are presented. Comparisons were made between hip arthroscopy experts (> 500 cases performed) and non-experts (<= 500 cases performed) on aspects of patient care. RESULTS: Forty-eight (74%) surgeons responded. Forty-four questionnaires were filled out completely. There were no significant differences in recommendations between 15 (34%) hip arthroscopy experts and 29 (66%) non-experts on hip capsular management and cartilage repair techniques, use of antithrombotic prophylaxis and opioid analgesics, time of rehabilitation initiation and patient compliance factors, use of hip brace and CPM, and patient evaluation to return to sports following surgery. Surgical expertise was significantly associated with the performance of hip labral reconstruction (p = 0.016), subspine decompression (p = 0.039) and recommendation of a longer period of restricted weight bearing following the performance of microfractures (p = 0.011). There were no significant differences in clinical practice between surgeons who performed hip arthroscopy exclusively versus those who did not. CONCLUSIONS: Hip arthroscopy is a relatively new field, and clinical practice may vary among physicians based on the surgical expertise. In this study, hip arthroscopy experts agree with non-experts on most aspects of patient care. Surgical expertise was associated with performance of advanced techniques and recommendation of longer period of restricted weight bearing following performance of microfractures. This study highlights different care patterns that need to be investigated to determine which treatment results in improved patient care. LEVEL OF EVIDENCE: V. PMID- 30467581 TI - Complications and technical failures are rare in knee ligament reconstruction: analyses based on 31,326 reconstructions during 10 years in Denmark. AB - PURPOSE: Knowledge about treatment injuries (technical failures and complications) in relation to knee ligament reconstructions is sparse. Our purpose was to describe treatment injuries to knee ligament reconstruction in Denmark during a 10-year period and to suggest initiatives to reduce the risk for treatment injuries. METHODS: Treatment injuries after knee ligament reconstructions reported to the Danish Patient Compensation Association (DPCA) 2005-2014 were analyzed and compared to information from the Danish Kneeligament Reconstruction Register and Danish National Patient Register. RESULTS: The number of knee ligament reconstructions in Denmark 2005-2014, including revisions, was 31,326. Of the 704 cases claimed to DPCA, 371 were approved as treatment injuries (1.42% of all operations). Tunnel malpositioning (135 = 0.43% of all operations), deep infection (0.27%), nerve injury (0.17%), pain (0.12%) and unrecognized combined instability (0.11%) were the most common. Patients operated with anteromedial technique for femoral tunnel placement had a lower incidence (p < 0.0001) of tunnel malpositioning compared to other techniques. Public and private hospitals had the same risk of treatment injures. Hospitals that performed the largest number of reconstructions/year had the smallest risk of a treatment injury (p < 0.001). The total compensation was 7.6 m EURO, which equals 243 EURO/performed knee ligament reconstruction. CONCLUSION: Treatment injuries as defined in this study were rare, with tunnel malpositioning being the most common. Analyses of the results indicate that it may be clinically relevant to reduce the number of treatment injures that knee ligament reconstructions are concentrated in clinics with high volume. Also, malpositioning might be reduced by routine documentation of K-wire position before tunnels are drilled. LEVEL OF EVIDENCE: III. PMID- 30467582 TI - The dangers of preemptive obedience to political pressure and media campaigns in science. PMID- 30467583 TI - In vitro proteomic analysis of methapyrilene toxicity in rat hepatocytes reveals effects on intermediary metabolism. AB - The antihistaminic drug methapyrilene was withdrawn from the market in 1979 because of hepatocarcinogenicity in rats. Since then, the drug has been used as a model hepatotoxin especially for transcriptomic analyses using material from in vivo studies. Much less transcriptomics data are available from in vitro studies, and no studies have investigated proteomic effects of methapyrilene in vitro. Thus, the present study was aimed to characterize the proteomic response of primary rat hepatocytes to methapyrilene, to broaden our knowledge on the molecular mechanisms of methapyrilene toxicity, and to compare the results of collagen sandwich-cultured hepatocytes to in vivo data. In vitro methapyrilene concentrations (0.39 uM, 6.25 uM, and 100 uM) were chosen to cover an in vivo relevant range. Based on published pharmacokinetic data they correspond to concentrations in portal vein blood for previously in vivo-tested doses of methapyrilene, up to a concentration showing slight cytotoxicity. Analysis of proteomic alterations by two-dimensional gel electrophoresis and mass spectrometric protein identification demonstrated consistent and concentration dependent effects of methapyrilene, in particular on mitochondrial proteins. Data suggest substantial deregulation of amino acid and ammonia metabolism and effects on mitochondrial energy supply pathways. The effects identified in vitro concur well with into previous in vivo observations. Several effects, for example, the influence of methapyrilene on S-adenosylmethionine metabolism, have not been described previously. The data suggest that already non-toxic concentrations of methapyrilene alter components of the intermediary metabolism, such as branched chain amino acid metabolism, as well as urea and tricarboxylic cycle enzymes. In summary, data substantially add to our knowledge on molecular mechanisms of methapyrilene hepatotoxicity at the protein level. PMID- 30467584 TI - Highlight report: New applications of chimeric mice with humanized livers. PMID- 30467585 TI - Highlight report the food additive dammar resin is a rat hepatocarcinogen. PMID- 30467586 TI - [PAPA syndrome with Crohn's disease and primary sclerosing cholangitis/autoimmune hepatitis overlap syndrome]. AB - BACKGROUND: The PAPA syndrome, an acronym for pyogenic sterile arthritis, pyoderma gangraenosum and acne, is an autosomal dominant hereditary disease which is caused by a mutation in the PSTPIP1 ("proline-serine-threonine phosphatase interacting protein 1") gene located on chromosome 15 and encodes the proline serine-threonine phosphatase-interacting protein 1. An association with Crohn's disease (CD), autoimmune diseases of the liver and PAPA syndrome has not yet been reported in the literature. OBJECTIVE: To thoroughly investigate a family with three affected members (mother and 2 children) with newly diagnosed PAPA syndrome and intestinal and hepatobiliary symptoms. MATERIAL AND METHODS: We performed an in-depth phenotyping, dermatologic, radiologic, rheumatologic, gastroenterologic, histologic and genetic analysis in this family. RESULTS: All three family members could be newly diagnosed as suffering from PAPA syndrome and carried the known disease-causing mutation c.688G > A (p.Ala230Thr) in the PSTPIP1 gene. The younger son suffered from CD in addition to PAPA syndrome. The mother additionally suffered from ulcerative colitis (UC) and an overlap syndrome between autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). A mutation in in the NOD2 ("nucleotide binding oligomerization domain containing protein 2") gene could not be detected in any of the three persons affected. CONCLUSION: We extended the symptoms of PAPA syndrome to CD and autoimmune liver disease. These different disease entities might share a similar pathogenetic mechanism or even represent a new syndrome. This can be clarified in the future by screening patients with PAPA syndrome for intestinal and also hepatobiliary diseases. PMID- 30467587 TI - [Alternative therapy option for plastic-aesthetic treatment of defects after resection in the upper third of the facial region in the sense of subtotal scalping instead of local flap plastics]. AB - In the presented case, the resulting defect size after resection of a dermatofibrosarcoma protuberans exceeded the treatment capability with local flaps in the region of the exposed facial skin. Through the use of conventional wound healing in combination with a meshed split-thickness skin graft, plastic aesthetic soft tissue treatment with an aesthetically satisfactory result was possible. PMID- 30467588 TI - The rural children's loneliness and depression in Henan, China: the mediation effect of self-concept. AB - OBJECTIVE: This research explored the relationship among loneliness, depression and self-concept of rural children in China. METHODS: Seven hundred and twenty four children (Mage = 9.15 years) from two rural primary schools were selected as respondents to participate in this study. Piers-Harris Children's Self-concept Scale, Asher Loneliness Scale and the Center for Epidemiologic Studies Depression Scale for Children were used. RESULTS: Of the rural children surveyed, 14.50% and 10.22%, respectively, experienced strong loneliness and severe depression, and 28.52% had low self-concept. There was a significant positive relationship of moderate level between loneliness and depression, and significant negative relationships between total self-concept and depression, and between total self concept and loneliness. Moreover, a partial mediation role of self-concept was found in the relationship between loneliness and depression. CONCLUSION: Children's loneliness was not only directly related to depression, but also was indirectly mediated by self-concept, which demonstrated a partial mediation role in the relationship between loneliness and depression. PMID- 30467589 TI - A review of the 10/66 dementia research group. AB - BACKGROUND: In this review we discuss how the study of dementia epidemiology in Low- and Middle-Income Countries (LMICs) has changed in the last 20 years, and specifically to review the evidence created by the 10/66 Dementia Research Group (DRG) and discuss future directions for research. METHODS: We identified and collated all the papers related to the 10/66 Dementia Research Group, including papers from groups who adopted the 10/66 methodology, that have been published in peer-reviewed journals. RESULTS: Over 200 papers including data from Africa, Asia, Europe and Latin America and the Caribbean were identified by this review. Many of the findings revolved around the epidemiology of dementia, mental health and non-communicable diseases, including the cross-cultural development and validation of measurement tools of cognition and functioning, need for care, care arrangements and mental health. Social ageing, care dependence and caregiver interventions were also topics that the group had published on. DISCUSSION: A body of evidence has been generated that has challenged the view, prevalent when the group started, that dementia is comparatively rare in LMICs. The experience of the 10/66 DRG has shown that descriptive epidemiological research can be important and impactful, where few data exist. Monitoring population trends in the prevalence and incidence of dementia may be our best chance to confirm hypotheses regarding modifiable risk factors of dementia. PMID- 30467590 TI - [Development and validation of a hospital frailty risk score for older people]. PMID- 30467591 TI - Population pharmacokinetic and covariate analyses of intravenous trastuzumab (Herceptin(r)), a HER2-targeted monoclonal antibody, in patients with a variety of solid tumors. AB - PURPOSE: The aim of the study was to characterize the population pharmacokinetics (PK) of the intravenous formulation of trastuzumab, assess the impact of patient and pathological covariates on trastuzumab PK, and perform simulations to support dosing recommendations in special situations. METHODS: Serum trastuzumab concentrations were obtained from 1582 patients with metastatic breast cancer (MBC), early breast cancer (EBC), advanced gastric cancer (AGC), or other tumor types/healthy volunteers in 18 phase I, II, and III trials and analyzed by nonlinear mixed-effects modeling. RESULTS: A two-compartment model with parallel linear and nonlinear elimination best described the data. During treatment, linear clearance (CL) dominated, resulting in a total CL of 0.173-0.337 L/day, which is similar to other IgG1 monoclonal antibodies. Covariates influencing CL were baseline body weight, aspartate aminotransferase, albumin, gastric cancer, and the presence of liver metastases. MBC and EBC had similar PK parameters, while CL was higher in AGC. Simulations indicated that at least 95% of patients with BC reach concentrations < 1 ug/mL (~ 97% washout) by 7 months. A dose delay in BC or AGC patients of > 1 week would take approximately 6 weeks to get back within steady-state exposure range. CONCLUSIONS: Trastuzumab PK for the intravenous formulation was well-described across cancer types, disease status, and regimens. No dose adjustment is required for any of the identified patient covariates. A 7-month serum washout period for trastuzumab is recommended. A reloading dose is required if a maintenance dose is missed by > 1 week. PMID- 30467592 TI - Differential expression of heat shock and floral regulatory genes in pseudocarpel initials of mantled female inflorescences from Elaeis guineensis Jacq. AB - KEY MESSAGE: Transcriptomes generated by laser capture microdissected abnormal staminodes revealed adoption of carpel programming during organ initiation with decreased expression of numerous HSPs, EgDEF1, EgGLO1 but increased LEAFY expression. The abnormal mantled phenotype in oil palm involves a feminization of the male staminodes into pseudocarpels in pistillate inflorescences. Previous studies on oil palm flowering utilized entire inflorescences or spikelets, which comprised not only the male and female floral organs, but the surrounding tissues as well. Laser capture microdissection coupled with RNA sequencing was conducted to investigate the specific transcriptomes of male and female floral organs from normal and mantled female inflorescences. A higher number of differentially expressed genes (DEGs) were identified in abnormal versus normal male organs compared with abnormal versus normal female organs. In addition, the abnormal male organ transcriptome closely mimics the transcriptome of abnormal female organ. While the transcriptome of abnormal female organ was relatively similar to the normal female organ, a substantial amount of female DEGs encode HEAT SHOCK PROTEIN genes (HSPs). A similar high amount (20%) of male DEGs encode HSPs as well. As these genes exhibited decreased expression in abnormal floral organs, mantled floral organ development may be associated with lower stress indicators. Stamen identity genes EgDEF1 and EgGLO1 were the main floral regulatory genes with decreased expression in abnormal male organs or pseudocarpel initials. Expression of several floral transcription factors was elevated in pseudocarpel initials, notably LEAFY, FIL and DL orthologs, substantiating the carpel specification programming of abnormal staminodes. Specific transcriptomes thus obtained through this approach revealed a host of differentially regulated genes in pseudocarpel initials compared to normal male staminodes. PMID- 30467593 TI - Pulmonary and respiratory muscle function in response to 10 marathons in 10 days. AB - PURPOSE: Marathon and ultramarathon provoke respiratory muscle fatigue and pulmonary dysfunction; nevertheless, it is unknown how the respiratory system responds to multiple, consecutive days of endurance exercise. METHODS: Nine trained individuals (six male) contested 10 marathons in 10 consecutive days. Respiratory muscle strength (maximum static inspiratory and expiratory mouth pressures), pulmonary function (spirometry), perceptual ratings of respiratory muscle soreness (Visual Analogue Scale), breathlessness (dyspnea, modified Borg CR10 scale), and symptoms of Upper Respiratory Tract Infection (URTI), were assessed before and after marathons on days 1, 4, 7, and 10. RESULTS: Group mean time for 10 marathons was 276 +/- 35 min. Relative to pre-challenge baseline (159 +/- 32 cmH2O), MEP was reduced after day 1 (136 +/- 31 cmH2O, p = 0.017), day 7 (138 +/- 42 cmH2O, p = 0.035), and day 10 (130 +/- 41 cmH2O, p = 0.008). There was no change in pre-marathon MEP across days 1, 4, 7, or 10 (p > 0.05). Pre marathon forced vital capacity was significantly diminished at day 4 (4.74 +/- 1.09 versus 4.56 +/- 1.09 L, p = 0.035), remaining below baseline at day 7 (p = 0.045) and day 10 (p = 0.015). There were no changes in FEV1, FEV1/FVC, PEF, MIP, or respiratory perceptions during the course of the challenge (p > 0.05). In the 15-day post-challenge period, 5/9 (56%) runners reported symptoms of URTI, relative to 1/9 (11%) pre-challenge. CONCLUSIONS: Single-stage marathon provokes acute expiratory muscle fatigue which may have implications for health and/or performance, but 10 consecutive days of marathon running does not elicit cumulative (chronic) changes in respiratory function or perceptions of dyspnea. These data allude to the robustness of the healthy respiratory system. PMID- 30467594 TI - Ageing affects the balance between central and peripheral mechanisms of cerebrovascular regulation with increasing influence of systolic blood pressure levels. AB - BACKGROUND: Arterial baroreflex (BR) and cerebral autoregulation (CA) are two major regulatory mechanisms that maintain constant cerebral perfusion. Little is known about the interplay between these mechanisms, particularly when considering the effects of ageing or sex. PURPOSE: We studied the relationship between dynamic CA and BR sensitivity (BRS) in healthy subjects by sex and in different age strata. METHODS: 95 healthy adults (52% female), 20-80 years-old, were recruited. Arterial blood pressure (Finometer), 3-lead electrocardiogram and cerebral blood flow velocity in middle cerebral arteries (transcranial Doppler) were monitored. We assessed CA by transfer function analysis and BRS in frequency and time domain. RESULTS: With increasing age, BRS diminished (ANCOVA R2 = 0.281, p < 0.001) but CA parameters did not change significantly (p > 0.05). Overall, there was an inverse relationship between the efficacy of BRS and CA low frequency gain [multivariate linear regression beta = 0.41 (0.31; 0.61), p < 0.001]. However, this association suffers changes with ageing: in older subjects BRS and CA were not correlated [beta = 0.10 (- 0.41; 0.62), p = 0.369]. Instead, decreasing systolic blood pressure correlated with less efficient CA [lower CA low-frequency gain beta = - 0.02 (- 0.03; - 0.02), p = 0.003]. Sex did not affect BRS and CA relationship. CONCLUSIONS: Cerebral blood supply is governed by a tuned balance between BR and CA which is lost with age as BRS decreases dramatically. Low systolic blood pressure values might be harmful to older subjects as they might reduce the ability to keep cerebral blood flow tightly controlled. PMID- 30467595 TI - Genetic imprints of domestication for disease resistance, oil quality, and yield component traits in groundnut (Arachis hypogaea L.). AB - Ploidy difference between wild Arachis species and cultivated genotypes hinder transfer of useful alleles for agronomically important traits. To overcome this genetic barrier, two synthetic tetraploids, viz., ISATGR 1212 (A. duranensis ICG 8123 * A. ipaensis ICG 8206) and ISATGR 265-5A (A. kempff-mercadoi ICG 8164 * A. hoehnei ICG 8190), were used to generate two advanced backcross (AB) populations. The AB-populations, namely, AB-pop1 (ICGV 91114 * ISATGR 1212) and AB-pop2, (ICGV 87846 * ISATGR 265-5A) were genotyped with DArT and SSR markers. Genetic maps were constructed for AB-pop1 and AB-pop2 populations with 258 loci (1415.7 cM map length and map density of 5.5 cM/loci) and 1043 loci (1500.8 cM map length with map density of 1.4 cM/loci), respectively. Genetic analysis identified large number of wild segments in the population and provided a good source of diversity in these populations. Phenotyping of these two populations identified several introgression lines with good agronomic, oil quality, and disease resistance traits. Quantitative trait locus (QTL) analysis showed that the wild genomic segments contributed favourable alleles for foliar disease resistance while cultivated genomic segments mostly contributed favourable alleles for oil quality and yield component traits. These populations, after achieving higher stability, will be useful resource for genetic mapping and QTL discovery for wild species segments in addition to using population progenies in breeding program for diversifying the gene pool of cultivated groundnut. PMID- 30467596 TI - Diagnostic biomarkers in non-muscle invasive bladder cancer. AB - Successful treatment of non-muscle invasive bladder cancer (NMIBC) relies heavily on our ability to accurately detect disease typically in the presence of hematuria as well as to detect the early recurrent tumors in patients with a history of NMIBC. Unfortunately, the current biomarker landscape for NMIBC is a work in progress. Cystoscopy continues to be the gold standard, but can still miss 10% of tumors. Therefore, physicians frequently use additional tools to aid in the diagnosis of bladder cancer, such as urinary cytology. The urinary cytology is a good option for high-grade disease; however, it is limited by low sensitivity in detecting low-grade disease, as well as variable interpretation among cytopathologists. Thus, the limitations of cystoscopy and urinary cytology have brought to light the need for more robust diagnostic assays. In this non systematic review, we discuss the performance, potential advantages or disadvantages of these tests, and the future direction of biomarkers in NMIBC. PMID- 30467597 TI - Geographic location, local environment, and individual size mediate the effects of climate warming and neighbors on a benefactor plant. AB - Predictions of plant responses to global warming frequently ignore biotic interactions and intraspecific variation across geographical ranges. Benefactor species play an important role in plant communities by protecting other taxa from harsh environments, but the combined effects of warming and beneficiary species on their performance have been largely unexamined. We analyzed the joint effects of elevated temperature and neighbor removal on the benefactor plant Silene acaulis, in factorial experiments near its low- and high-latitude range limits in Europe. We recorded growth, probability of reproduction and fruit set during 3 years. The effects of enhanced temperature were positive near the northern limit and negative in the south for some performance measures. This pattern was stronger in the presence of neighbors, possibly due to differential thermal tolerances between S. acaulis and beneficiary species in each location. Neighbors generally had a negative or null impact on S. acaulis, in agreement with previous reviews of overall effects of plant-plant interactions on benefactors. However, small S. acaulis individuals in the north showed higher growth when surrounded by neighbors. Finally, the local habitat within each location influenced some effects of experimental treatments. Overall, we show that plant responses to rising temperatures may strongly depend on their position within the geographic range, and on species interactions. Our results also highlight the need to consider features of the interacting taxa, such as whether they are benefactor species, as well as local-scale environmental variation, to predict the joint effects of global warming and biotic interactions on species and communities. PMID- 30467598 TI - Adolescent social instability stress alters markers of synaptic plasticity and dendritic structure in the medial amygdala and lateral septum in male rats. AB - Much evidence indicates that experiences in adolescence can alter the development of social behaviour. We previously demonstrated that male rats exposed to social instability stress in adolescence (SS; 1 h isolation and return to an unfamiliar cagemate daily from postnatal day [PND] 30-45) had reduced social interaction, impaired social recognition, reduced sexual performance, and increased aggression in competition for food reward compared with non-stressed control (CTL) rats. Here, we investigated whether SS affects stellate neuron morphology using the Golgi-Cox method and several markers of synaptic plasticity using western blotting in the medial amygdala (MeA) and lateral septum (LS), sites involved in social behaviour. On PND 46, 24 h after the last stress exposure, SS rats had increased dendritic arborisation, a greater number of dendrite terminals, and a higher average dendrite branch order in the anterodorsal MeA compared with CTL rats. SS rats had reduced dendritic arborization and a reduced total length of dendrite matter in the anteroventral MeA and a reduced number of dendrite terminals in the posterodorsal MeA compared with CTL rats. Moreover, SS rats had a reduced number of dendritic spines in the dorsal LS compared with CTL rats. SS rats had less synaptophysin in the MeA and more CaMKII in the LS than did CTL rats, and did not differ in spinophilin, PSD95, or glucocorticoid receptor protein expression in the MeA and LS. We discuss how changes in neural structure and in markers of synaptic plasticity the MeA and LS of adolescent SS rats compared with CTL rats may underlie their differences in social behaviour. PMID- 30467599 TI - Eccrine ductal and acrosyringeal metaplasia in breast carcinomas: report of eight cases. AB - Eccrine ductal and acrosyringeal metaplasia was described in 2006 as the presence of tumor structures that resemble the epithelium of the eccrine skin ducts and their opening within the epidermis, the acrosyringeum. Here, we report the clinical, morphological, and phenotypic characteristics of eight breast carcinomas that we collected over the past years showing this metaplasia. Unlike squamous metaplasia, acrosyringeal and eccrine ductal metaplasia are luminated structures comprising cells with eosinophilic cytoplasm that are easily detectable in routine histological slides. These lesions invariably appeared in triple-negative carcinomas, but the cases differed in their clinical, radiological, and histological manifestations. Correct interpretation of these changes may facilitate identification of some metaplastic carcinomas. PMID- 30467600 TI - Expression and clinical role of the dipeptidyl peptidases DPP8 and DPP9 in ovarian carcinoma. AB - Dipeptidyl peptidase 9 (DPP9) was recently identified as fusion gene in ovarian high-grade serous carcinoma (HGSC). The aim of this study was to analyze the expression and clinical relevance of DPP8 and DPP9 in ovarian carcinoma, with focus on HGSC. mRNA expression by qRT-PCR of DPP8 and DPP9 was analyzed in 232 carcinomas, including 114 effusions and 118 surgical specimens (89 ovarian, 29 solid metastases). DPP8 and DPP9 protein expression was analyzed in 92 effusions. DPP8 and DPP9 mRNA was overexpressed in effusions compared to solid lesions in analysis of all histotypes (p < 0.001 both), as well as in analysis limited to HGSC (p < 0.001 for DPP9, p = 0.002 for DPP8). DPP9 mRNA was additionally overexpressed in HGSC compared to other histotypes (p = 0.021). DPP8 and DPP9 protein was expressed in carcinoma cells in 31/92 (37%) and 81/92 (88%) effusions, respectively. DPP8 protein expression in HGSC effusions was significantly related to better (complete) chemoresponse at diagnosis (p = 0.005). DPP8 and DPP9 mRNA and protein expression was unrelated to survival in analysis of the entire effusion cohort. However, higher DPP9 mRNA levels were significantly related to longer overall survival in pre-chemotherapy effusions (p = 0.049). In conclusion, DPP8 and DPP9 mRNA is frequently expressed in ovarian carcinoma, whereas DPP9 is more frequently expressed at the protein level. DPP8 and DPP9 may be related to less aggressive disease in advanced-stage HGSC. PMID- 30467601 TI - Alcohol-related peripheral neuropathy: a systematic review and meta-analysis. AB - The primary aim of this systematic review was to establish the prevalence, character, and risk factors of peripheral neuropathy amongst chronic alcohol abusers and to identify the most appropriate management strategies. In this review, possible pathogenetic mechanisms are also discussed. A systematic, computer-based search was conducted using the PubMed database. Data regarding the above parameters were extracted. 87 articles were included in this review, 29 case-control studies, 52 prospective/retrospective cohort studies and 2 randomised control trials, 1 cross sectional study, and 3 population-based studies. The prevalence of peripheral neuropathy amongst chronic alcohol abusers is 46.3% (CI 35.7- 57.3%) when confirmed via nerve conduction studies. Alcohol related peripheral neuropathy generally presents as a progressive, predominantly sensory axonal length-dependent neuropathy. The most important risk factor for alcohol-related peripheral neuropathy is the total lifetime dose of ethanol, although other risk factors have been identified including genetic, male gender, and type of alcohol consumed. At present, it is unclear what the pathogenetic mechanisms for the development of neuropathy amongst those who chronically abuse alcohol are, and therefore, it is unknown whether it is attributed to the direct toxic effects of ethanol or another currently unidentified factor. There is presently sparse data to support a particular management strategy in alcohol related peripheral neuropathy, but the limited data available appears to support the use of vitamin supplementation, particularly of B-vitamin regimens inclusive of thiamine. PMID- 30467602 TI - Urinary symptoms, quality of life, and patient satisfaction in genetic and sporadic hereditary spastic paraplegia. AB - BACKGROUND: Urinary involvement is common in hereditary spastic paraplegias (HSPs), but has rarely been assessed systematically. METHODS: We characterized urinary complaints in 71 German HSP patients (mean age 55.4 +/- 13.9 years; mean disease duration 20.7 +/- 14.3 years; 48% SPG4-positive) using validated clinical rating scales (SCOPA-AUT, ICIQ-SF, ICIQ-LUTSqol). Treatment history and satisfaction with medical care was also assessed. RESULTS: 74.6% of patients had one or more urological problems, most commonly nocturia and urgency. Incontinence was more severe in women, correlating with SCOPA-AUT. Female gender and SPG4 mutations were associated with higher urinary frequency and severity of urological involvement. QoL was overall reduced, more in women and in SPG4 mutation carriers. Almost 90% consulted a medical specialist; more than half were largely satisfied. 43.4% received oral medication and 5.7% received intravesical botulinum toxin. However, more than one-third of patients remained untreated. CONCLUSION: Urinary complaints are common in HSP and should be addressed and treated. PMID- 30467603 TI - Structural network topology relates to tissue properties in multiple sclerosis. AB - OBJECTIVE: Abnormalities in segregative and integrative properties of brain networks have been observed in multiple sclerosis (MS) and are related to clinical functioning. This study aims to investigate the micro-scale correlates of macro-scale network measures of segregation and integration in MS. METHODS: Eight MS patients underwent post-mortem in situ whole-brain diffusion tensor (DT) imaging and subsequent brain dissection. Macro-scale structural network topology was derived from DT data using graph theory. Clustering coefficient and mean white matter (WM) fiber length were measures of nodal segregation and integration. Thirty-three tissue blocks were collected from five cortical brain regions. Using immunohistochemistry micro-scale tissue properties were evaluated, including, neuronal size, neuronal density, axonal density and total cell density. Nodal network properties and tissue properties were correlated. RESULTS: A negative correlation between clustering coefficient and WM fiber length was found. Higher clustering coefficient was associated with smaller neuronal size and lower axonal density, and vice versa for fiber length. Higher whole-brain WM lesion load was associated with higher whole-brain clustering, shorter whole brain fiber length, lower neuronal size and axonal density. CONCLUSION: Structural network properties on MRI associate with neuronal size and axonal density, suggesting that macro-scale network measures may grasp cortical neuroaxonal degeneration in MS. PMID- 30467604 TI - Blockchain-Based Medical Records Secure Storage and Medical Service Framework. AB - Accurate and complete medical data are one valuable asset for patients. Privacy protection and the secure storage of medical data are crucial issues during medical services. Secure storage and making full use of personal medical records has always been a concern for the general population. The emergence of blockchain technology brings a new idea to solve this problem. As a hash chain with the characteristics of decentralization, verifiability and immutability, blockchain technology can be used to securely store personal medical data. In this paper, we design a storage scheme to manage personal medical data based on blockchain and cloud storage. Furthermore, a service framework for sharing medical records is described. In addition, the characteristics of the medical blockchain are presented and analyzed through a comparison with traditional systems. The proposed storage and sharing scheme does not depend on any third-party and no single party has absolute power to affect the processing. PMID- 30467605 TI - Theoretical Study on Carrier Mobility of Hydrogenated Graphene/Hexagonal Boron Nitride Heterobilayer. AB - Hydrogenated graphene (HG)/hexagonal boron nitride (h-BN) heterobilayer is an ideal structure for the high-performance field effect transistor. In this paper, the carrier mobilities of HG/h-BN heterobilayer are investigated based on the first-principles calculations by considering the influence of stacking pattern between HG and h-BN, hydrogen coverage and hydrogenation pattern. With the same hydrogenation pattern, the electron mobility monotonously decreases when the hydrogen coverage increases. With the same hydrogen coverage, different hydrogenation patterns lead to significant changes of mobility. For 25% and 6.25% HGs, the MUe (GammaK) of 25% pattern I is 8985.85 cm2/(V s) and of 6.25% pattern I is 23,470.98 cm2/(V s), which are much higher than other patterns. Meanwhile, the h-BN substrate affects the hole mobilities significantly, but it has limit influences on the electron mobilities. The hole mobilities of stacking patterns I and II are close to that of HG monolayer, but much lower than that of stacking patterns III and IV. PMID- 30467606 TI - Nematic-isotropic transition in a density-functional theory for hard spheroidal colloids. AB - We introduce a density-functional formalism based on the Parsons-Lee and the generalized van der Waals theories in order to describe the thermodynamics of anisotropic particle systems with steric interactions. For ellipsoids of revolution, the orientational distribution function is obtained by minimizing the free energy functional and the equations of state are determined. The system exhibits a nematic-isotropic discontinuous transition, characterized by a phase separation between nematic and isotropic phases at finite as well low packing fractions. The model presents a phase behavior which is in good agreement with Monte Carlo simulations for finite aspect ratios. PMID- 30467607 TI - Surface swimmers, harnessing the interface to self-propel. AB - In the study of microscopic flows, self-propulsion has been particularly topical in recent years, with the rise of miniature artificial swimmers as a new tool for flow control, low Reynolds number mixing, micromanipulation or even drug delivery. It is possible to take advantage of interfacial physics to propel these microrobots, as demonstrated by recent experiments using the proximity of an interface, or the interface itself, to generate propulsion at low Reynolds number. This paper discusses how a nearby interface can provide the symmetry breaking necessary for propulsion. An overview of recent experiments illustrates how forces at the interface can be used to generate locomotion. Surface swimmers ranging from the microscopic scale to typically the capillary length are covered. Two systems are then discussed in greater detail. The first is composed of floating ferromagnetic spheres that assemble through capillarity into swimming structures. Two previously studied configurations, triangular and collinear, are discussed and contrasted. A new interpretation for the triangular swimmer is presented. Then, the non-monotonic influence of surface tension and viscosity is evidenced in the collinear case. Finally, a new system is introduced. It is a magnetically powered, centimeter-sized piece that swims similarly to water striders. PMID- 30467608 TI - Novel amphiphilic pyridinium ionic liquids-supported Schiff bases: ultrasound assisted synthesis, molecular docking and anticancer evaluation. AB - BACKGROUND: Pyridinium Schiff bases and ionic liquids have attracted increasing interest in medicinal chemistry. RESULTS: A library of 32 cationic fluorinated pyridinium hydrazone-based amphiphiles tethering fluorinated counteranions was synthesized by alkylation of 4-fluoropyridine hydrazone with various long alkyl iodide exploiting lead quaternization and metathesis strategies. All compounds were assessed for their anticancer inhibition activity towards different cancer cell lines and the results revealed that increasing the length of the hydrophobic chain of the synthesized analogues appears to significantly enhance their anticancer activities. Substantial increase in caspase-3 activity was demonstrated upon treatment with the most potent compounds, namely 8, 28, 29 and 32 suggesting an apoptotic cellular death pathway. CONCLUSIONS: Quantum-polarized ligand docking studies against phosphoinositide 3-kinase alpha displayed that compounds 2-6 bind to the kinase site and form H-bond with S774, K802, H917 and D933. PMID- 30467609 TI - The Effect of an Electronic Dynamic Cognitive Aid Versus a Static Cognitive Aid on the Management of a Simulated Crisis: A Randomized Controlled Trial. AB - The aim of this study was to assess the effect of a dynamic electronic cognitive aid with embedded clinical decision support (dCA) versus a static cognitive aid (sCA) tool. Anesthesia residents in clinical anesthesia years 2 and 3 were recruited to participate. Each subject was randomized to one of two groups and performed an identical simulated clinical scenario. The primary outcome was task checklist performance with a secondary outcome of performance using the Anesthesia Non-technical skills (ANTS) scoring system. 34 residents were recruited to participate in the study. 19 residents were randomized to the sCA group and 15 to the dCA group. Overall inter-rater agreement for total checklist, malignant hyperthermia, hyperkalemia and ventricular fibrillation was 98.9%, 97.8%, 99.5% and 99.5% respectively with similar Kappa coefficient. Inter-rater agreement for ANTS partial ratings, however, was only 53.5% with a similar Kappa of 0.15. Mean performance was statistically higher in the dCA group versus the sCA group for total check list performance (15.70 +/- 1.93 vs 12.95 +/- 2.16, p < 0.0001). The difference in performance between dCA and sCA is most notable in dose-dependent related checklist items (4.60 +/- 1.3 vs 1.89 +/- 1.23, p < 0.0001), while the performance score for dose-independent checklist items was similar between the two groups (p = 0.8908). ANTS ratings did not differ between groups. In conclusion, we evaluated the use of a sCA versus a dCA with embedded decision support in a simulated environment. The dCA group was found to perform more checklist items correctly.Clinical Trial Registration: Clinicaltrials.gov study #: NCT02440607. PMID- 30467610 TI - Amperometric Biosensor of Matrix Metalloproteinase-7 Enhanced by Pd Functionalized Carbon Nanocomposites. AB - Matrix metalloproteinase-7 plays a pivotal role in tumour progression and metastasis as an enzyme that can degrade the cell-matrix composition and cleave peptides between alanine and leucine in various biomolecular activation processes. In this work, a Pd-functionalised carbon nanocomposite was designed as a new impedance enhancer for an amperometric sensor of MMP-7. Pd nanoparticles in the enhancer can catalyse the oxidation of 4-chloro-1-naphthol with H2O2 to generate insoluble precipitation in situ, forming high-resistance precipitation on electrodes. In addition, poorly conductive carbon nanospheres of the nanocomposite increased the precipitation resistance, further causing a dramatic increase in resistivity of the enhancer and, subsequently, a significant decrease in current. This can significantly promote the current signal difference between the biosensor treated with and without the target analyte, which is directly related to the sensitivity of the amperometric biosensor. Overall, electrochemical biosensor can sensitively detect MMP-7 in the range of 100 fg mL 1 to 100 ng mL-1 with a limit of detection for MMP-7 of 17.38 fg mL-1. PMID- 30467611 TI - Independent activation of the BoMYB2 gene leading to purple traits in Brassica oleracea. AB - KEY MESSAGE: Transposon insertion and point mutation independently activated the BoMYB2 gene in three purple cultivars of Brassica oleracea including kale, kohlrabi, and cabbage. Several varieties of B. oleracea have both green and purple cultivars. In this study, the causal genes for the purple traits in kale, kohlrabi and cabbage were cloned using map-based cloning approach. The purple traits in all three varieties were mapped to the same locus as the BoMYB2 gene in cauliflower. Surprisingly, the insertion of Harbinger transposon of BoMYB2 in cauliflower was not found in purple kale, kohlrabi and cabbage. Sequencing of the BoMYB2 gene in purple kale and purple kohlrabi discovered a 7606 bp CACTA-like transposon in its promoter region. Transient assay and promoter activity study showed that the insertion upregulated the expression of the BoMYB2 gene. On the other hand, the activation of the BoMYB2 gene in purple cabbage was caused by point mutation and/or 1-bp insertion in its promoter region. Sequence analysis of the BoMYB2 gene in different varieties suggested that the activating events most likely occurred independently after the divergence of cabbage, cauliflower, and kale/kohlrabi. Our results not only contribute to a better understanding of anthocyanin inheritance in B. oleracea, but also provide useful information for future hybrid breeding of purple cultivars through combination of different functional alleles of the BoMYB2 gene. PMID- 30467612 TI - Health-related quality of life, culture and communication: a comparative study in children with cancer in Argentina and Sweden. AB - BACKGROUND: Malignant disorders in childhood are life-threatening conditions, and issues regarding the children's health-related quality of life (HRQOL) are crucial in paediatric oncology. The overall aim of this study was to explore HRQOL in children with cancer in two countries, Argentina and Sweden, which have different cultural contexts. The specific aims were: to determine HRQOL by gender, age, diagnosis, treatment modality, time since diagnosis, and parental education/employment across cultures. Further aims were to assess the child/parent relationship in HRQOL and the influence of demographic variables in psychosocial and physical HRQOL in each country. METHODS: A cross-sectional study was performed in 2014, including 58 children (24 females, 34 males) and 62 parents/guardians. The instrument, the Pediatric Quality of Life InventoryTM (PedsQLTM, generic, cancer and fatigue modules), and medical records were used. The response rate was 97%. RESULTS: The mean age of the children was 8.67 years (SD 5.1, range 2-18 years) and the mean time on treatment was 10.7 months (SD 8.7, range 1-30 months). The most common diagnosis was leukaemia (57%). In Argentina, in comparison with Sweden, a higher estimation of generic HRQOL was reported among adolescents (p = 0.022) and more cancer-related problems among school-age children (p < 0.0001). Children and parents in both countries confirmed the major problem with fatigue and multimodality therapy regimes, but lower levels of fatigue were reported in Argentina. Adolescents and children with solid tumours appeared as vulnerable groups. In Sweden, children whose mothers had post-secondary education reported less cancer-related problems (p = 0.031). Good relationships were found between child/parent reports in Argentina regarding the fatigue module (p = 0.034) and physical subscale (p = 0.014), and in Sweden regarding generic health (p = 0.004), including psychosocial (p = 0.006) and physical subscales (p = 0.042), and cancer (p = 0.001), and fatigue (p < 0.0001) modules. In Sweden, psychosocial health (OR 7.5; p = 0.007) and physical health (OR 6.2; p = 0.011) were positively influenced by being a school-age child. CONCLUSIONS: Fatigue is as a major problem across cultures. Still, being in school facilitates recovery. Good relationships in psychosocial HRQOL highlight professional challenges regarding severe issues and open communication, and the need of performing comparative studies of HRQOL of children with cancer from different cultural backgrounds. PMID- 30467613 TI - Evaluation of graft anastomosis using time-intensity curves and quantitative near infrared fluorescence angiography during peripheral arterial bypass grafting. AB - Near-infrared fluorescence angiography (NIR) visualizes blood perfusion using the fluorescence property of indocyanine green (ICG). This study aimed to retrospectively determine the usefulness of a quantitative analysis using NIR to predict the patency of peripheral arterial bypass grafts by measuring their fluorescence luminance intensities (FLIs).Thirteen grafts in 11 patients who underwent peripheral arterial bypass grafting were divided into a patent graft group (n = 7) and a failed graft group (n = 6). The changes in the FLIs of ICG opacification through the graft and distal host artery were retrospectively analyzed using stored NIR data. The time-intensity curves (TICs) of ICG opacification through the graft (Qgraft) and distal host artery (Qdistal) were measured. Two parameters, Delta(Qgraft - Qdistal) and integral(Qgraft - Qdistal), were also analyzed.Although not significant, decreases in Qgraft were observed in the failed graft groups. The Qdistal of the failed graft group was significantly attenuated as compared with that of the patent graft group. Delta(Qgraft - Qdistal) increased only in the failed graft group, which indicates widening of the gap in FLI. Integral(Qgraft - Qdistal) was higher in the failed graft group, as it reflects the accumulation of ICG opacification.The TICs were influenced by anastomotic stenosis in the distal site of the host arteries. Our results indicate that the comparison of Delta(Qgraft - Qdistal) and integral (Qgraft - Qdistal) quantitatively analyzed using NIR can potentially predict anastomotic stenosis. PMID- 30467614 TI - Aerobic vaginitis in late pregnancy and outcomes of pregnancy. AB - The purpose of this study was to investigate the risk factors and pregnancy outcomes for aerobic vaginitis (AV) in late pregnancy. A total of 624 pregnant women who were treated in the perinatal unit at Tianjin Medical University General Hospital and 365 nonpregnant women who were evaluated at a health management center from January 2015 to June 2016 were recruited for this case control study. A questionnaire covering personal hygiene habits and sociodemographic factors was administered to pregnant women to analyze risk factors for AV. Bacterial vaginosis, AV, vulvovaginal candidiasis, and Trichomonas vaginitis were scored according to standardized definitions. Pregnancy outcomes were followed up and recorded. The chi-square test and univariate and multivariate logistic regression analyses were used for statistical evaluation. The prevalence of vaginal infection in pregnant and nonpregnant women were 27.9% and 15.3%, respectively (P < 0.05). AV was identified more frequently in pregnant women than in nonpregnant women (4.2% vs. 1.4%; P < 0.05). A history of vaginal infection within 1 year (odds ratio [OR] = 3.219, 95% confidence interval [CI] 1.103-9.346) and external hemorrhoids (OR = 11.233, 95% CI 4.647-27.155) were independent risk factors for AV during pregnancy. A higher incidence of premature rupture of membranes (PROM) was significantly associated with AV (P < 0.05). AV is common in late pregnancy. Clinicians should pay more attention to vaginal microbiota evaluations during pregnancy. PMID- 30467615 TI - Patient centered research to improve community involvement (PaRTICIpate) in diabetes self-management: a conference series for developing collaborations between researchers, stakeholders, and patients. AB - BACKGROUND: A patient-centered approach to research development is important to the creation of research evidence that is meaningful and beneficial to patients. Collaboration between patients, stakeholders, and researchers, where patients serve an integral role in all aspects of the research development process, is integral to achieving these twin objectives. RESULTS: This paper presents a unique approach to engaging patients and stakeholders in research by describing a conference series focused on meaningfully integrating patients in each phase of the project. Through three meeting phases, patients were not only introduced to patient-centered research (PCR) concepts, but they also led discussions about diabetes self-management and developed PCR questions. A total of 17 questions were developed represented by four main themes: communication, patient knowledge and perceptions, diabetes prevention, and diabetes management. Through patient feedback, three research questions were each identified as immediate priorities for development into research project proposals. CONCLUSION: To our knowledge, the use of a conference series designed to teach patients about research, encourage collaboration across stakeholder groups, and write research questions has not been described in the literature. Moreover, this approach has proven successful in recruiting and retaining patient participation through the life of the project. This project has also identified a number of issues for consideration by future researchers looking to meaningfully engage patients in the development of research proposals. PMID- 30467616 TI - Comparison of different staining methods for determination of viability on Mesocestoides vogae tetrathyridia. AB - Mesocestoides vogae is widely employed as a model for studying the biology, differentiation, and experimental chemotherapy of cestodes. Currently, there are few techniques to measure the viability of M. vogae metacestodes during pharmacological experiments. The aim of the present work was to evaluate and compare different staining techniques to determine objectively the viability of M. vogae tetrathyridia. Eosin (0.05% w/v), methylene blue (0.01% w/v), propidium iodide (PI, 2 MUg/ml), and fluorescein diacetate (FDA, 0.5 MUg/ml) solutions were tested against live, heat-killed (cultivated at 65 degrees C for 2 h) and thymol treated tetrathyridia (50 and 250 MUg/ml). Parasites were counted under a dissecting microscope or a fluorescence compound microscope, as appropriate. Studies by scanning electron microscope were performed to compare the ultrastructural damage with the viability of parasites. After comparing the performance of different dyes, we chose the eosin staining technique because its simplicity, rapidity, sensitivity, low cost and fidelity. PMID- 30467617 TI - Can peri-ovulatory putrescine supplementation improve egg quality in older infertile women? AB - The aging-related decline in fertility is an increasingly pressing medical and economic issue in modern society where women are delaying family building. Increasingly sophisticated, costly, and often increasingly invasive, assisted reproductive clinical protocols and laboratory technologies (ART) have helped many older women achieve their reproductive goals. Current ART procedures have not been able to address the fundamental problem of oocyte aging, the increased rate of egg aneuploidy, and the decline of developmental potential of the eggs. Oocyte maturation, which is triggered by luteinizing hormone (LH) in vivo or by injection of human chorionic gonadotropin (hCG) in an in vitro fertilization (IVF) clinic, is the critical stage at which the majority of egg aneuploidies arise and when much of an egg's developmental potential is established. Our proposed strategy focuses on improving egg quality in older women by restoring a robust oocyte maturation process. We have identified putrescine deficiency as one of the causes of poor egg quality in an aged mouse model. Putrescine is a biogenic polyamine naturally produced in peri-ovulatory ovaries. Peri-ovulatory putrescine supplementation has reduced egg aneuploidy, improved embryo quality, and reduced miscarriage rates in aged mice. In this paper, we review the literature on putrescine, its occurrence and physiology in living organisms, and its unique role in oocyte maturation. Preliminary human data demonstrates that there is a maternal aging-related deficiency in ovarian ornithine decarboxylase (ODC), the enzyme responsible for putrescine production. We argue that peri ovulatory putrescine supplementation holds great promise as a natural and effective therapy for infertility in women of advanced maternal age, applicable in natural conception and in combination with current ART therapies. PMID- 30467618 TI - Religious Attendance, Healthy Lifestyles, and Perceived Health: A Comparison of Baby Boomers with the Silent Generation. AB - Baby boomers are aging, and their health is an important concern. Research has suggested that (1) aging boomers are more vulnerable to mental and physical health problems than their parents' generation; (2) adoption of healthy lifestyles is critically important for the health of the aging population; and (3) religious attendance, often found to be associated with health-related outcomes, is lower among aging boomers than their parents' generation. In this research, we use a large national dataset to examine (1) whether the baby boom generation lags behind their parents' generation in adoption of healthy lifestyles and perceived health; and (2) if it does, whether the lag might possibly be attributed to lower religious attendance. We analyzed data collected by University of Michigan's Health and Retirement Study from the silent generation in 1994 and from the baby boom generation in 2010 when both generation cohorts were at about the same age (age 49-64 years). The results indicated that (1) the baby boom generation lagged behind the silent generation in adoption of three healthy lifestyles (not smoking, not drinking excessively, and not being overweight or obese) and in perceived health; (2) the lag may be partially attributed to lower religious attendance in the baby boom generation. We also discuss implications for the health of the baby boom generation and for promoting healthy lifestyles and health to the baby boom generation. PMID- 30467619 TI - A Data Mining and Data Visualization Approach to Examine the Interrelationships Between Life Satisfaction, Secularization and Religiosity. AB - Previous studies have suggested a positive relationship between secularization and happiness, as well as a geographical, cultural and development pattern, primarily based on data gathered in Europe and the USA. To gain a more holistic view on the interrelationships between secularization, religiosity and subjective perception of well-being, this study utilized the Wave 6 archival data set (2010 2014) of World Values Survey, which contains 74,042 observations from 60 countries. In this study, the rating of satisfaction with life was treated as the dependent variable. Four secular value indices and 12 variables related to religiosity were extracted from the data set for predictive analysis. Data mining tools, such as the partition tree and bootstrap forest approaches, suggested that only secular values were influential. Specifically, secular values had a negative relationship with satisfaction. In addition, hierarchical clustering based on secularization and satisfaction did not suggest a meaningful pattern. For example, the dendrogram showed that South Korea, Lebanon, Estonia and Algeria were grouped together. This implies that secularization and satisfaction could vary from country to country, regardless of their geographical location, culture and development status. Specifically, countries that are similar in terms of satisfaction and secularization are not necessarily culturally similar or geographically clustered. This discourages the idea that these factors (e.g., location, development status, culture) play a role in mediating the relationship between secularization and religiosity. By directly contradicting previous work showing a pattern based on Europe and the USA, this finding challenges the existing understanding of the relationship between these factors. By expanding the scope of study to the whole world, the current analysis suggested that the existing view regarding the positive relationship between secularization and well being might be oversimplified. PMID- 30467620 TI - Stress as an immunomodulator: liver X receptors maybe the answer. AB - Stress is a reflex response, both psychological and physiological, of the body to a difficult situation that requires adaptation. Stress is at the intersection of the objective event and the subjective event. The physiological mechanisms involved in chronic stress are numerous and can contribute to a wide variety of disorders, in all systems including the immune system. Stress modifies the Th1/Th2 balance via the HPA axis and a set of immune mediators. This will make the body more vulnerable to external infections in a scientific way while others claim the opposite, stress could be considered immune stimulatory. The development of synthetic LXR ligands such as T0901317 and GW3965 as well as an understanding of the direct involvement of these receptors in the regulation of proopiomelanocortin (POMC) gene expression and indirectly by producing a variety of cytokines in a stressor response, will open in the near future new therapeutic methods against the undesirable effects of stress on the behavior of the immune system. PMID- 30467621 TI - Effects of Human Interleukin-10 on Ventilator-Associated Lung Injury in Rats. AB - Ventilator-induced lung injury (VILI) is one of the most serious complications of mechanical ventilation (MV) and can increase the mortality of patients with acute respiratory distress syndrome (ARDS). This work aimed to test the hypothesis that the anti-inflammatory properties of human interleukin-10 (hIL-10) can reduce VILI. Thirty-six healthy male Sprague-Dawley rats were randomly assigned into three groups (n = 12) as follows: a control group, a VILI group, and a hIL-10 group. Lung function was evaluated by oxygenation index and pulmonary edema, and morphological changes associated with lung injury were assessed by HE staining and quantitative histological lung injury score. Malondialdehyde (MDA) and Superoxide dismutase (SOD) were measured, and the levels of various inflammatory cytokines were assessed in BALF and plasma. The oxygenation index in the VILI group decreased significantly relative to the control group and improved substantially in the hIL-10 group (P < 0.01). Compared to the control group, MDA production was stimulated (P < 0.01), and SOD activity rapidly declined (P < 0.01) in the VILI group. After hIL-10, MDA content was lower than that seen in the VILI group (P < 0.01), and SOD activity was enhanced (P < 0.01). The VILI group had the highest cytokine levels, compared to either the hIL-10 group or the control group (P < 0.05). High tidal volume MV can induce VILI. hIL-10 may regulate the inflammatory response in the lung tissue, improve lung tissue oxygenation, and inhibit oxidative stress, therefore reducing VILI in rats. These experiments reveal a potential new treatment option for VILI. PMID- 30467622 TI - The Expression of CXCL10/CXCR3 and Effect of the Axis on the Function of T Lymphocyte Involved in Oral Lichen Planus. AB - The etiology of oral lichen planus (OLP) is still not clear. The purpose of this study was to explore the role of CXC chemokine receptor 3(CXCR3) and its ligand CXC motif chemokine 10(CXCL10) in the pathogenesis of OLP. We examined the expression of CXCR3 and CXCL10 in OLP patients and healthy controls by quantitative real-time PCR, Western blotting, ELISAs, and immunohistochemistry, respectively. Moreover, we detected the effects of CXCL10/CXCR3 axis on T lymphocyte migration, proliferation and apoptosis by Transwell assays, CCK8 assays, and flow cytometry. We found that the expression of CXCR3 and CXCL10 was significantly increased in OLP patients. In addition, T lymphocyte migration rate of CXCL10 stimulation group was significantly higher than that of control and CXCR3 antagonist groups. After antagonizing CXCR3, the migration ability of T lymphocytes was significantly decreased, and regardless of whether CXCL10 was added in the upper chamber culture medium, the number of migrating cells was similar. The addition of CXCL10 stimulant could stimulate the proliferation of T lymphocytes, but there was no significant difference compared with control group. After antagonizing CXCR3, the proliferation rate of T lymphocytes was significantly reduced. However, there were no significant differences in the apoptosis rates of T lymphocytes between CXCL10 stimulation group, antagonist CXCR3 group, and control group. Due to the change of expression in CXCR3 and CXCL10, and its interaction in mediating the directional migration of peripheral blood T lymphocytes, affecting the proliferation of T lymphocytes, it suggests that CXCL10/CXCR3 axis may be related to the immune mechanism of OLP. PMID- 30467623 TI - [S3 guideline breast cancer: update on early detection, and mammography screening]. AB - Based on the update of the S3-Guideline Early Detection, Diagnosis, Treatment and Follow-up Care of Breast Cancer (Version 4.0, December 2017, AWMF registry number 032-045OL, www.leitlinienprogramm-onkologie.de ), evolving topics and relevant changes to the former 2012 version concerning early detection and mammography screening are presented. The outline and figures follow the original text. PMID- 30467624 TI - Activity of IL-12/15/18 primed natural killer cells against hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is common, but remains difficult to treat. Natural killer (NK) cells are cells of the innate immune system that have potent anti-cancer activity. Recent work has shown that stimulation with IL 12/15/18 leads to the generation of NK cells with enhanced functional and putative "memory" properties. We have investigated the activity of these NK cells against HCC cell lines in vitro and in a mouse model. METHODS: NK cells from healthy donors or individuals with HCC were activated with IL-12/15/18 in vitro and tested for cytotoxic activity against a panel of human HCC cell lines. IL 12/15/18 primed murine NK cells were then infused into a murine model of spontaneously arising HCC to test for anti-tumor activity. RESULTS: NK cells from patients and healthy controls had similar expression levels of activating and inhibitory NK cell receptors. However, proliferation of NK cells from HCC patients was weaker than healthy controls in response to IL-12/15/18 and IL-2 (p < 0.001 at day 9). In vitro, NK cells from both groups of individuals killed HCC targets to similar levels and this was unrelated to NKG2D expression. In a spontaneous model of HCC, IL-12/15/18 activated NK cells trafficked to the liver and resulted in lower levels of spontaneous HCC formation (p < 0.01). CONCLUSION: Cytokine-primed NK cells from patients with HCC have similar levels of activity against HCC cell lines as those from healthy controls. This type of activated NK cell has immunotherapeutic potential against hepatocellular carcinoma. PMID- 30467625 TI - Correction to: Different apoptotic effects of saxifragifolin C in human breast cancer cells. AB - The authors regret that incorrect western band of Bax (MDA-MB-231) in Fig. 6a (right panel) was mistakenly uploaded in the original publication. The correct Fig. 6a is shown below. This correction does not change the conclusions of this manuscript. The authors would like to apologize for any inconvenience caused. PMID- 30467627 TI - Factors predicting long-term comorbidities in patients with Cushing's syndrome in remission. AB - PURPOSE: In Cushing's syndrome, comorbidities often persist after remission of glucocorticoid excess. Here, we aim to identify factors predicting long-term comorbidities in patients with Cushing's syndrome in remission. METHODS: In a retrospective cross-sectional study, 118 patients with Cushing's syndrome in remission (52 pituitary, 58 adrenal, 8 ectopic) were followed for a median of 7.9 years (range 2-38) after the last surgery. Associations between baseline anthropometric, metabolic, hormonal parameters at diagnosis, and comorbidities (obesity, diabetes, hyperlipidemia, hypertension, osteoporosis, depression) at last follow-up, were tested by uni- and multivariate regression analysis. RESULTS: In patients with manifest comorbidities at diagnosis, remission of Cushing's syndrome resolved diabetes in 56% of cases, hypertension in 36% of cases, hyperlipidaemia in 23%, and depression in 52% of cases. In a multivariate regression analysis, age, fasting glucose, BMI, and the number of comorbidities at diagnosis were positive predictors of the number of long-term comorbidities, while baseline 24-h urinary free cortisol (UFC) negatively correlated with the persistence of long-term comorbidities. The negative relationship between baseline UFC and long-term comorbidities was also found when pituitary and adrenal Cushing's cases were analyzed separately. Baseline UFC was negatively related to the time of exposure to excess glucocorticoids. CONCLUSIONS: Long-term comorbidities after remission of Cushing's syndrome depend not only on the presence of classic cardiovascular risk factors (age, hyperglycemia, BMI), but also on the extent of glucocorticoid excess. Lower baseline UFC is associated with a higher number of long-term comorbidities, possibly due to the longer exposure to excess glucocorticoids in milder Cushing's syndrome. PMID- 30467626 TI - Limited scope for reproductive senescence in wild populations of a short-lived fish. AB - Senescence in wild populations was long considered negligible but current evidence suggests that it is widespread in natural populations of mammals and birds, affecting the survival and reproductive output of older individuals. In contrast, little is known about reproductive senescence in species with asymptotic growth that can keep increasing their reproductive output as they grow older and larger. Using a cross-sectional study, we tested age-related decline in fecundity and relative allocation to reproduction in five wild populations of an annual killifish, Nothobranchius furzeri (Cyprinodontiformes). We did not detect any decline in absolute female egg production over their short lifespan in the wild. Relative fecundity (egg production controlled for female body mass) tended to decrease with age. This effect was driven primarily by a single population that survived 17 weeks, almost twice as long as the median persistence of the other four study populations. There was no decrease in relative ovary mass while in males, relative testes mass actually increased with age. Intra-population variation in relative ovary mass increased in older females suggesting heterogeneity in individual trajectories of female reproductive allocation. Overall, we demonstrate that annual killifish do not experience significant age related decline in reproductive functions during their very short lifespan in the wild despite the marked deterioration of gonad tissue detected in captivity. PMID- 30467628 TI - The Impact of Trace Minerals on Bone Metabolism. AB - Bone is a metabolically active tissue that responds to alterations in dietary intake and nutritional status. It is ~ 35% protein, mostly collagen which provides an organic scaffolding for bone mineral. The mineral is the remaining ~ 65% of bone tissue and composed mostly of calcium and phosphate in a form that is structurally similar to mineral within the apatite group. The skeletal tissue is constantly undergoing turnover through resorption by osteoclasts coupled with formation by osteoblasts. In this regard, the overall bone balance is determined by the relative contribution of each of these processes. In addition to macro minerals such as calcium, phosphorus, and magnesium which have well-known roles in bone health, trace elements such as boron, iron, zinc, copper, and selenium also impact bone metabolism. Effects of trace elements on skeletal metabolism and tissue properties may be indirect through regulation of macro mineral metabolism, or direct by affecting osteoblast or osteoclast proliferation or activity, or finally through incorporation into the bone mineral matrix. This review focuses on the skeletal impact of the following trace elements: boron, iron, zinc, copper, and selenium, and overviews the state of the evidence for each of these minerals. PMID- 30467629 TI - Eukaryotic microalgae as hosts for light-driven heterologous isoprenoid production. AB - MAIN CONCLUSIONS: Eukaryotic microalgae hold incredible metabolic potential for the sustainable production of heterologous isoprenoid products. Recent advances in algal engineering have enabled the demonstration of prominent examples of heterologous isoprenoid production. Isoprenoids, also known as terpenes or terpenoids, are the largest class of natural chemicals, with a vast diversity of structures and biological roles. Some have high-value in human-use applications, although may be found in their native contexts in low abundance or be difficult to extract and purify. Heterologous production of isoprenoid compounds in heterotrophic microbial hosts such as bacteria or yeasts has been an active area of research for some time and is now a mature technology. Eukaryotic microalgae represent sustainable alternatives to these hosts for biotechnological production processes as their cultivation can be driven by light and freely available CO2 as a carbon source. Their photosynthetic lifestyles require metabolic architectures structured towards the generation of associated isoprenoids (carotenoids, phytol) which participate in photon capture, energy dissipation, and electron transfer. Eukaryotic microalgae should, therefore, contain inherently high capacities for the generation of heterologous isoprenoid products. Although engineering strategies in eukaryotic microalgae have lagged behind the more genetically tractable bacteria and yeasts, recent advances in algal engineering concepts have demonstrated prominent examples of light-driven heterologous isoprenoid production from these photosynthetic hosts. This work seeks to provide practical insights into the choice of eukaryotic microalgae as biotechnological chassis. Recent reports of advances in algal engineering for heterologous isoprenoid production are highlighted as encouraging examples that promote their expanded use as sustainable green-cell factories. Current state of the art, limitations, and future challenges are also discussed. PMID- 30467630 TI - From plant physiology to pharmacology: fusicoccin leaves the leaves. AB - MAIN CONCLUSION: This review highlights 50 years of research on the fungal diterpene fusicoccin, during which the molecule went from a tool in plant physiology research to a pharmacological agent in treating animal diseases. Fusicoccin is a phytotoxic glycosylated diterpene produced by the fungus Phomopsis amygdali, a pathogen of almond and peach plants. Widespread interest in this molecule started when it was discovered that it is capable of causing stomate opening in all higher plants, thereby inducing wilting of leaves. Thereafter, FC became, and still is, a tool in plant physiology, due to its ability to influence a number of fundamental processes, which are dependent on the activation of the plasma membrane H+-ATPase. Molecular studies carried out in the last 20 years clarified details of the mechanism of proton pump stimulation, which involves the fusicoccin-mediated irreversible stabilization of the complex between the H+-ATPase and activatory 14-3-3 proteins. More recently, FC has been shown to influence cellular processes involving 14-3-3 binding to client proteins both in plants and animals. In this review, we report the milestones achieved in more than 50 years of research in plants and highlight recent advances in animals that have allowed this diterpene to be used as a 14-3-3 targeted drug. PMID- 30467631 TI - Terpenes and isoprenoids: a wealth of compounds for global use. AB - MAIN CONCLUSION: Role of terpenes and isoprenoids has been pivotal in the survival and evolution of higher plants in various ecoregions. These products find application in the pharmaceutical, flavor fragrance, and biofuel industries. Fitness of plants in a wide range of environmental conditions entailed (i) evolution of secondary metabolic pathways enabling utilization of photosynthate for the synthesis of a variety of biomolecules, thereby facilitating diverse eco interactive functions, and (ii) evolution of structural features for the sequestration of such compounds away from the mainstream primary metabolism to prevent autotoxicity. This review summarizes features and applications of terpene and isoprenoid compounds, comprising the largest class of secondary metabolites. Many of these terpene and isoprenoid biomolecules happen to be high-value bioproducts. They are essential components of all living organisms that are chemically highly variant. They are constituents of primary (quinones, chlorophylls, carotenoids, steroids) as well as secondary metabolism compounds with roles in signal transduction, reproduction, communication, climatic acclimation, defense mechanisms and more. They comprise single to several hundreds of repetitive five-carbon units of isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP). In plants, there are two pathways that lead to the synthesis of terpene and isoprenoid precursors, the cytosolic mevalonic acid (MVA) pathway and the plastidic methylerythritol phosphate (MEP) pathway. The diversity of terpenoids can be attributed to differential enzyme and substrate specificities and to secondary modifications acquired by terpene synthases. The biological role of secondary metabolites has been recognized as pivotal in the survival and evolution of higher plants. Terpenes and isoprenoids find application in pharmaceutical, nutraceutical, synthetic chemistry, flavor fragrance, and possibly biofuel industries. PMID- 30467632 TI - Isoprenyl diphosphate synthases: the chain length determining step in terpene biosynthesis. AB - MAIN CONCLUSION: This review summarizes the recent developments in the study of isoprenyl diphosphate synthases with an emphasis on analytical techniques, product length determination, and the physiological consequences of manipulating expression in planta. The highly diverse structures of all terpenes are synthesized from the five carbon precursors dimethylallyl diphosphate and a varying number of isopentenyl diphosphate units through 1'-4 alkylation reactions. These elongation reactions are catalyzed by isoprenyl diphosphate synthases (IDS). IDS are classified depending on the configuration of the ensuing double bond as trans- and cis-IDS. In addition, IDS are further stratified by the length of their prenyl diphosphate product. This review discusses analytical techniques for the determination of product length and the factors that control product length, with an emphasis on alternative mechanisms. With recent advances in analytics, multiple IDS of Arabidopsis thaliana have been recently reinvestigated and demonstrated to yield products of different lengths than originally reported, which is summarized here. As IDS dictate prenyl diphosphate length and thereby which class of terpenes is ultimately produced, another focus of this review is the impact that altering IDS expression has on terpenoid natural product accumulation. Finally, recent findings regarding the ability of a few IDS to not catalyze 1'-4 alkylation reactions, but instead produce irregular products, with unusual connectivity, or act as terpene synthases, are also discussed. PMID- 30467634 TI - Correction to: Long-term treatment of endometriosis with dienogest: retrospective analysis of efficacy and safety in clinical practice. AB - In the original publication of the article, the word laparotomy has been presented in the proofs instead of laparoscopy in the below places. PMID- 30467633 TI - Non-invasive profiling of protease-specific elastin turnover in lung cancer: biomarker potential. AB - PURPOSE: Elastin is a signature protein of lungs. Increased elastin turnover driven by altered proteolytic activity is an important part of lung tumorigenesis. Elastin-derived fragments have been shown to be pro-tumorigenic, however, little is known regarding the biomarker potential of such elastin fragments. Here, we present an elastin turnover profile by non-invasively quantifying five specific elastin degradation fragments generated by different proteases. METHODS: Elastin fragments were assessed in serum from patients with stage I-IV non-small cell lung cancer (NSCLC) (n = 40) and healthy controls (n = 30) using competitive ELISAs targeting different protease-generated fragments of elastin: ELM12 (generated by matrix metalloproteinase MMP-9 and -12), ELM7 (MMP 7), EL-NE (neutrophil elastase), EL-CG (cathepsin G) and ELP-3 (proteinase 3). RESULTS: ELM12, ELM7, EL-NE and EL-CG were all significantly elevated in NSCLC patients (n = 40) when compared to healthy controls (n = 30) (ELM12, p = 0.0191; ELM7, p < 0.0001; EL-NE, p < 0.0001; EL-CG, p < 0.0001). ELP-3 showed no significant difference between patients and controls (p = 0.8735). All fragments correlated positively (Spearman, r: 0.69-0.81) when compared pairwise, except ELM12 (Spearman, r: 0.042-0.097). In general, all fragments were detectable across all stages of the disease. CONCLUSIONS: Elastin fragments generated by different proteases are elevated in lung cancer patients compared to healthy controls but differ in their presence. This demonstrates non-invasive biomarker potential of elastin fragments in serum from lung cancer patients and suggests that different pathological mechanisms may be responsible for the elastin turnover, warranting further validation in clinical trials. PMID- 30467635 TI - The preferred mode of delivery of medical professionals and non-medical professional mothers-to-be and the impact of additional information on their decision: an online questionnaire cohort study. AB - PURPOSE: It was the aim to evaluate the personal preference of mode of delivery and to analyze differences between medical professionals and non-medical professionals. Interest in participating in a risk stratification system was evaluated. We hypothesized that gaining information about risk stratification provided in the survey could potentially change participants' decision regarding the preferred mode of delivery; therefore, subjects were asked twice (before and after providing information). METHODS: Five cohorts [four professionals (MP) including participants of the German Urogynecology Congress 2017, employees of two major university hospitals in Germany, and members of the German Society of Gynecology and Obstetrics, and one non-professional group (NP) including pregnant women] were invited online to participate in this survey. RESULTS: Vaginal delivery was the preferred mode of delivery in both groups (MP 90.4% vs. NP 88.8%; p = 0.429). MP are more likely to opt for CS due to concerns regarding pelvic floor disorders (MP 56.6% vs. NP 9.1%; p < 0.001). Likewise, parity and prior experienced CS (pCS) had a significant impact on the decision towards vaginal delivery (parity MP OR 7.5 95% CI 4.6-12.3, NP OR 9.3 95% CI 1.9-44.2; (pCS) MP OR 0.12 95% CI 0.07-0.19, NP OR 0.05 95% CI 0.01-0.25). There is great interest in participating in risk stratification systems in the majority of participants (68.9%). CONCLUSIONS: MP and NP prefer vaginal birth for themselves or their partners. Within the group that opted for CS, MP were significantly more often concerned about pelvic floor disorders. Future prevention aspects might include education about pelvic floor disorders. PMID- 30467636 TI - Analysis of clinical and electrophysiological characteristics of 150 patients with amyotrophic lateral sclerosis in China. AB - OBJECTIVE: To explore the relationship between the clinical onset locations and the electrophysiological characteristics of different spinal segments in amyotrophic lateral sclerosis (ALS) patients. To develop a rapid examination method using electromyographs (EMGs) for the diagnosis of ALS. METHODS: The clinical symptoms and electrodiagnostic examination results of 150 patients with definite or probable ALS were retrospectively analyzed. The patients were divided into four groups according to the primary onset locations (arms and legs onset, arms onset, legs onset, and bulbar onset groups). The differences between the onset locations and the electrophysiological characteristics revealed the lower motor neuron dysfunction in EMGs. RESULTS: The most affected onset location was the lower limbs (36.7%), particularly in the distal muscles. Nerve conduction showed that the sensory system was damaged in 22 patients (14.7%). The positive diagnostic rate of EMGs varied due to different onset locations. EMG abnormalities were seen in approximately 40% of asymptomatic limb muscles. Distal limb muscles showed higher electrodiagnostic sensitivity (78.4%) than proximal limb muscles. Cervical muscles showed the highest electrodiagnostic sensitivity (86.3%). CONCLUSIONS: The sensory system in ALS patients was commonly impaired. Cervical muscles showed the highest electrodiagnostic sensitivity. The highest positive rate was generated from detecting the spinal segment onset and the special distal muscles onset ALS in our optimized test method. Through this improved examination based on the most affected individual muscles, physicians can greatly optimize the test duration and significantly reduce patient discomfort. PMID- 30467637 TI - Effect of Primary Hypertension on Treatment Outcomes of Patients with Postmenopausal Osteoporosis: A 5 Year Follow Up Retrospective Study. AB - AIM: To investigate the efficacy of primary hypertension (HTN) on the treatment prognosis of patients with postmenopausal osteoporosis (PMOP). METHODS: 45 patients who were diagnosed as PMOP with lumbar and/or femur neck bone mineral density screening (BMD) but have no history of PMOP treatment including calcium and vitamin D, have comorbid primary HTN and treated with a vasodilator antihypertensive drug at least a year were included to the study. Control group was constituted with 44 patients with PMOP at same age but have no comorbidity. Demographic features including age, height, weight, occupation, educational level menarche and menopause age, clothing style, daily intake of calcium, smoking and/or alcohol consumption, daily physical activity level, personal history of fragility fracture or in mother and duration of primary HTN diagnosis were recorded. Biochemical parameters were also recorded. Patients were treated with bisphosphonate, calcium and vitamin D and same parameters were evaluated at the end of first and fifth year. RESULTS: Demographic and disease characteristics were not different between groups before treatment (p > 0.05). In group analysis, there was significant improvement in lumbar and femur neck T scores of PMOP + HT and PMOP groups after 1 and 5 years of treatment compared to baseline (p < 0.05) Lumbar and femur neck T score variations between the baseline, first and fifth years of treatment were not significantly different in PMOP + HT and PMOP groups (p < 0.05). CONCLUSIONS: Although the results vary between populations, primary HTN does not have an impact on the prognosis of PMOP treatment in Turkish population. PMID- 30467638 TI - Hypertension Management at Older Age: An Update. AB - Hypertension is a risk factor for cardiovascular morbidity and mortality with increasing prevalence with age, whose treatment is associated with benefits over fatal and non-fatal cardiovascular events even later in life. However, there are persistent concerns on the short- and long-term weighted benefits of treating hypertension in the very old, particularly in those with specific clinical features. In fact, a broad range of clinical scenarios can be observed at older ages, spanning from the healthy to the frailest patient, and hypertension clinical trials have traditionally excluded the latter, thus preventing the unconditioned application to these patients of the same recommendations as in younger ages. Persistent issues regarding high blood pressure management in the very old adult are mainly related to treatment threshold and targets, which have been differently addressed by American and European guidelines. Herein, we will examine the challenges related to high blood pressure treatment in healthy and frail older and very old adults. We will discuss the evidence behind current recommendations. Finally, we will recapitulate the recommended treatment options for high blood pressure in these patients in the light of the most recent guidelines. PMID- 30467640 TI - Animal life and mind in Hobbes's philosophy of nature. AB - This paper explores Thomas Hobbes's account of animal life and mind. After a critical examination of Hobbes's mechanistic explanation of operations of the mind such as perception and memory, I argue that his theory derives its strength from his idea of the dynamic interaction of the body with its surroundings. This dynamic interaction allows Hobbes to maintain that the purposive disposition of the animal is not merely an upshot of its material configuration, but an expression of its distinctive bodily history. In support of Hobbes, I show how this is complemented by his account of the unity and continuity of the animal body in terms of a unification through the self-preserving drive that originates in perception. Nonetheless, I argue that Hobbes's philosophy of animal life and mental faculties is hindered by a kind of epiphenomenalist perspective that is embedded in his materialist framework, and this perspective leaves the status of ideas and mental content unclear. I explain why Hobbes's dynamic theory, founded upon the reciprocal determination of moving bodies, supports his idea of animal development and habituation while failing to account for the reflexivity of the mind. PMID- 30467639 TI - The dynamics of electron beam scattering on metal membranes: nanopore formation in metal membranes using transmission electron microscopy. AB - The dynamics of nanopore formation in metal membranes using the highly focused and high energy electron beams (e-beams) of transmission electron microscopy instruments was investigated. Various metals such as Al, Ti, Cr, Cu, and Au were selected to investigate the effect of the atomic mass of the metal on nanopore drilling, namely, elastic versus inelastic scattering. We demonstrated that the effect of elastic scattering (pore formation by sputtering) decreased as the atomic mass of the metal increased. Furthermore, experimental cross-sections obtained from normalized drilled volume vs. electron dose curves (characteristic contrast curves) matched well the calculated atomic displacement cross-sections determined from elastic scattering data. The sputtering energies of Ti, Cr, and Cu were determined to be approximately 10, 9, and 7 eV, respectively, which were in good agreement with the reported range of sputtering energy values. PMID- 30467641 TI - Educating about radiation risks in high schools: towards improved public understanding of the complexity of low-dose radiation health effects. AB - The levels of stochastic health effects following exposure to low doses of ionising radiation are not well known. A consequence of the uncertainty is that any radiation exposure is met with deep concern-both by the public and by scientists who disagree about how the partly conflicting results from low-dose studies should be interpreted. The concern is not limited to ionising radiation but is inherent to other areas of modern technologies such as biotechnology or electromagnetic fields. The everyday presence of advanced technologies confronts people with the necessity to take decisions and there is an ongoing debate regarding both the nature and magnitude of potential risks and how education efforts may empower peoples' decision-making. In the field of radiation research there are different opinions regarding the optimal education methods, spanning from the idea that peoples' fears will be eliminated by introducing dose thresholds below which the risk is assumed to be zero, to suggestions of concentrating research efforts in an attempt to eliminate all uncertainties regarding the effects of low doses. The aim of this paper was to present our approach which is based on developing an education program at the secondary school level where students learn to understand the role of science in society. Teaching about radiation risk as a socio-scientific issue is not based on presenting facts but on showing risks in a broader perspective aiming at developing students' competency in making decisions based on informed assessment. We hope to stimulate and encourage other researchers to pursue similar approaches. PMID- 30467642 TI - Measurement of gamma-H2AX foci, miRNA-101, and gene expression as a means to quantify radiation-absorbed dose in cancer patients who had undergone radiotherapy. AB - Radiological accidents and nuclear terrorism pose an increased threat to members of the public who, following such an event, would need to be assessed for medical care by fast triage. Assay methods such as chromosome aberrations (CA), cytokinesis-block micronucleus (CBMN) and fluorescence in situ hybridization (FISH) techniques have been well established for dose estimation and their potential for handling more samples has also been proved with automation. However, culturing of lymphocytes is an inevitable step, which limits the potential of these markers for triage. In vitro analysis of gamma-H2AX (gamma H2AX), gene and microRNA (miRNA) markers do not require culturing of lymphocytes, and as such have been suggested as attractive tools for triage. Despite studies reporting in vitro dose-response curves, limited evidence is available evaluating the suitability of these assays in real situations. In this study, we have measured the absorbed dose using gamma-H2AX, gene (GADD45A, FDXR, and CDKN1A) and miRNA-101 expression in blood samples of cancer patients (n = 20) who had undergone partial-body radiotherapy and compared with the derived equivalent whole-body doses (EWBD). The obtained results from all patients showed a significant (p < 0.05) increase of gamma-H2AX foci in post-irradiated as compared to pre-irradiated samples. Moreover, estimated doses using gamma-H2AX foci showed a correlation with the derived EWBD (r2 = 0.60, p = 0.0003) and was also shown to be dependent on the irradiated body volume. Consistent with gamma-H2AX foci frequency, an increase in fold change expression of genes and miRNA-101 was observed. However, the estimated dose significantly varied among the subjects and showed poor correlation (r2 = 0.09, 0.04, 0.01 and 0.03 for GADD45A, FDXR, CDKN1A and miRNA-101, respectively) with EWBD. The overall results suggest that the established in vitro gamma-H2AX assay is suitable for the detection of radiation exposure and can also provide an estimate of the dose in in vivo irradiated samples. The genes and miRNA-101 markers showed increased expression; nevertheless, there is a need for further improvements to measure doses accurately using these markers. PMID- 30467643 TI - Gravity effects on mixing with magnetic micro-convection in microfluidics. AB - Mixing remains an important problem for the development of successful microfluidic and lab-on-a-chip devices, where simple and predictable systems are particularly interesting. One is magnetic micro-convection, an instability happening on the interface of miscible magnetic and non-magnetic fluids in a Hele Shaw cell under applied field. Previous work proved that the Brinkman model quantitatively explains the experiments. However, a gravity-caused convective motion complicated the tests. Here we first improve the experimental system to exclude the parasitic convection. Afterwards, we experimentally observe the magnetic micro-convection, by finding and quantifying how gravity and laminar flow stabilizes the perturbations that create it. Accordingly, we improve our theoretical model for a zero-flow condition and perform a linear analysis. Two dimensionless quantities --magnetic and gravitational Rayleigh numbers-- are used to compare the experimental observations and theoretical predictions for the critical field of instability and the characteristic size of the emerging pattern. Finally, we discuss the conditions at which gravity plays an important role in microfluidic systems. PMID- 30467644 TI - Landscape perceptions and social representations of Fallopia spp. in France. AB - Choices have to be made to manage invasive species because eradication often is not possible. Both ecological and social factors have to be considered to improve the efficiency of management plans. We conducted a social study on Fallopia spp., a major invasive plant taxon in Europe, including (1) a survey on the perception of a landscape containing Fallopia spp. using a photoquestionnaire and (2) an analysis of the social representations of Fallopia spp. of managers and users in one highly invaded area and one less invaded area. The respondents to the photoquestionnaire survey appreciated the esthetics of the landscapes less when tall Fallopia spp. were present. Few people were able to identify and name the plant, and this knowledge negatively affected the appreciation of the photos containing Fallopia spp. The central core of the social representation of Fallopia spp. was composed of the invasive status of the plant, its density, and its ecological impacts. The peripheral elements of the representation depended on the people surveyed. The users highlighted the natural aspect whereas the managers identified the need for control. In the invaded area, the managers qualified the species as "unmanageable," whereas the species was qualified as "foreign" in the less invaded area. Those results provide insights that have to be included when objectives of management plans of these species are selected. PMID- 30467646 TI - Three-dimension-printed custom-made prosthetic reconstructions: from revision surgery to oncologic reconstructions. AB - BACKGROUND: The use of custom-made 3D-printed prostheses for reconstruction of severe bone defects in selected cases is increasing. The aims of this study were to evaluate (1) the feasibility of surgical reconstruction with these prostheses in oncologic and non-oncologic settings and (2) the functional results, complications, and outcomes at short-term follow-up. METHODS: We analyzed 13 prospectively collected patients treated between June 2016 and January 2018. Diagnoses were primary bone tumour (7 patients), metastasis (3 patients), and revision of total hip arthroplasty (3 patients). Pelvis was the most frequent site of reconstruction (7 cases). Functional results were assessed with MSTS score and complications according to Henderson et al. Statistical analysis was performed using Kaplan-Meier and log-rank test curves. RESULTS: At a mean follow up of 13.7 months (range, 6-26 months), all patients except one were alive. Oncologic outcomes show seven patients NED (no evidence of disease), one NED after treatment of metastasis, one patient died of disease, and another one was alive with disease. Overall survival was 100% and 80% at one and two years, respectively. Seven complications occurred in five patients (38.5%). Survival to all complications was 62% at two years of follow-up. Functional outcome was good or excellent in all cases with a mean score of 80.3%. CONCLUSION: 3D-printed custom-made prostheses represent a promising reconstructive technique in musculoskeletal oncology and challenging revision surgery. Preliminary results were satisfactory. Further studies are needed to evaluate prosthetic design, fixation methods, and stability of the implants at long-term. PMID- 30467645 TI - Functionalized microneedles for continuous glucose monitoring. AB - Microneedles (MNs) have been established as promising medical devices as they are minimally invasive, cause less pain, and can be utilized for self-administration of drugs by patients. There has been rapid development in MNs for transdermal monitoring and diagnostic systems, following the active research on fabrication methods and applications for drug delivery. In this paper, recent investigations on bio-sensing using MNs are reviewed in terms of the applicability to continuous glucose monitoring system (CGMS), which is one of the main research focuses of medical engineering technologies. The trend of the functionalized MNs can be categorized as follows: (i) as a sensing probe, and (ii) as a biological fluid collector. MNs as in vivo sensors are mainly integrated or coated with conductive materials to have the function as electrodes. MNs as fluid collectors are given a certain geometrical design, such as a hollow and porous structure aided by a capillary action or negative pressure, to extract the interstitial fluids or blood for ex vivo analysis. For realization of CGMS with MNs, a long-term accurate measurement by the MN-based sensing probe or a fluidic connection between the MN-based fluid collector and the existing microfluidic measurement systems should be investigated. PMID- 30467648 TI - Barriers to and Facilitators of Implementing Programs for Return to Work (RTW) of Cancer Survivors in Four European Countries: A Qualitative Study. AB - Purpose Implementation of return to work (RTW) programs for cancer survivors has proved to be challenging. The purpose of our study was to gather experiences about barriers to and facilitators of implementing RTW programs for cancer survivors in four European countries. Methods Separate multidisciplinary focus groups were held in Belgium (n = 8), the Netherlands (n = 8), Ireland (n = 6), and UK (n = 4) in 2017 and included among others a physician, and a representative of an employer, a cancer society, and the government. Primary focus of thematic analysis was what could be done to improve the implementation of RTW programs for cancer survivors. Analysis used the 'Arena in work disability prevention model' as the conceptual framework. Results Many barriers to and facilitators of implementing RTW programs for cancer survivors were described including the personal, workplace, healthcare and legislative system as well as the overall societal and political context. That is, for example cooperation between stakeholders, time, money and ability issues at the workplace, and insufficient/inadequate legislation. Insufficient knowledge of cancer and its implications for work was identified as an overarching theme in all countries leading to stigma, misconceptions and lack of communication. This was mentioned in relation to the workplace, personal and healthcare system, and in the overall societal context. Conclusions Results indicate that a prerequisite for implementing RTW programs is raising sufficient knowledge regarding cancer and its implications for work. Greater knowledge could be a first step to better implement RTW programs which may result in better supporting cancer survivors with their RTW . PMID- 30467647 TI - Synthesis of 2D transition metal dichalcogenides by chemical vapor deposition with controlled layer number and morphology. AB - Two-dimensional (2D) transition metal dichalcogenides (TMDs) have stimulated the modern technology due to their unique and tunable electronic, optical, and chemical properties. Therefore, it is very important to study the control parameters for material preparation to achieve high quality thin films for modern electronics, as the performance of TMDs-based device largely depends on their layer number, grain size, orientation, and morphology. Among the synthesis methods, chemical vapor deposition (CVD) is an excellent technique, vastly used to grow controlled layer of 2D materials in recent years. In this review, we discuss the different growth routes and mechanisms to synthesize high quality large size TMDs using CVD method. We highlight the recent advances in the controlled growth of mono- and few-layer TMDs materials by varying different growth parameters. Finally, different strategies to control the grain size, boundaries, orientation, morphology and their application for various field of are also thoroughly discussed. PMID- 30467649 TI - Triad-based screening risk assessment of the agricultural area exposed to the long-term PAHs contamination. AB - The aim of the study was ecological risk assessment (ERA) of the agricultural soils located in the vicinity of the highly industrialized area and exposed to different emission sources of polycyclic aromatic hydrocarbons (PAHs). In this study, we demonstrated the combination of generic and site-specific ERA approach for screening assessment and delineation of the area of a high ecological risk. Generic approach was based on a hazard quotient and indicated that 62% of the research area needs further assessment. For site-specific evaluation, the Triad approach was utilized. Information from three lines of evidence (LoE): chemical, ecotoxicological and ecological, was integrated into one environmental risk (EnvRI) index. The chemical risk was derived from toxic pressure coefficients based on the total PAHs concentration. The ecotoxicological LoE included an acute toxicity testing: the luminescent bacteria Aliivibrio fischeri activity in both liquid- and solid-phase samples and the ability of crustacean Thamnocephalus platyurus to food uptake. The ecological LoE comprised microbial parameters related to soil respiration and enzymatic activity. Integrated EnvRI index ranged from 0.44 to 0.94 and was mainly influenced by high values of chemical LoE risk, while the ecotoxicological and ecological LoE indicated no or low risk. Due to the relatively high uncertainty associated with the contradictory information given by LoEs, there is the need to confirm potential risk in a tier 2 analysis. PMID- 30467650 TI - How do depressed patients evaluate their quality of life? A qualitative study. AB - BACKGROUND: This is a qualitative study that aims to investigate the effect of depressive status on responses to items on the WHO quality of life assessment instrument (WHOQOL-Bref), comparing which aspects of the individual's life he or she takes into account in responding to the items related to quality of life when depressed and when euthymic. RESULTS: Six adult women were interviewed prior to initiating treatment for a depressive episode and were then interviewed again six months later when in remission from the episode. The 'think aloud' method of cognitive interviewing was used. Based on the Wilcoxon test, the seven items that exhibited a significant change with the improvement of the depressive condition were examined in depth, and the think aloud method was used to reveal the subjects' cognitive processes. Depressive symptoms were associated with different interpretations of some items and the response scale. Also, for some items, patients chose the same response for the item both times but justified their choice differently during the depressive episode and in euthymia. CONCLUSIONS: We found that, in addition to the impact caused by depression on quality of life, there are peculiarities in the way the depressed individual makes subjective assessments. We believe that qualitative studies such as the present one may provide important support in the interpretation of quantitative results. PMID- 30467652 TI - Fast and simple method for screening of single-stranded DNA breaking photosensitizers using graphene oxide. AB - A fast and simple method for screening of ssDNA-breaking photosensitizers was developed using graphene oxide. The ultraviolet light-induced DNA breaks are one of the most harmful DNA damages and cause skin cancer if they are left unrepaired. Since graphene oxide showed relatively strong affinity to the broken DNA than intact DNA, and it quenched fluorescence of the DNA labeling dye effectively, the degree of ultraviolet light-induced broken DNAs could be analyzed by measuring decreased fluorescence after mixing the DNA with graphene oxide. The decrease of fluorescence was highly correlated with the ultraviolet light-irradiating time and concentration of the added drugs. As a result, it was possible to evaluate the efficacy of different ssDNA-breaking photosensitizers in a high-throughput manner. However, conventional methods for the damaged-DNA analysis are time-consuming and require additional manipulations such as purification, radio-labeling, enzymatic digestion, or chemical modification of DNA. The phototoxicity of five drugs such as benzophenone, ketoprofen, indomethacin, naproxen, and norfloxacin was tested using the proposed method. The ssDNA-breaking efficiency of the drugs was well matched with reported efficiency of the tested drugs. In contrast to naked gold nanoparticles, graphene oxide is stably dispersed in the presence of salt, the phototoxicity of the drugs could be successfully tested at a physiological condition using the graphene oxide based method. PMID- 30467653 TI - The diversity of finfish population in Poonthura estuary, south-west coast of India, Kerala. AB - Quantitative measures of diversity are the ideal tools to reveal the community differences that are due to changes in the relative taxon abundance. The present study is an attempt to investigate the measures of finfish diversity of the Poonthura estuary, located in Thiruvananthapuram district of Kerala, India. Samples were collected using gill nets from three stations. Biodiversity indices such as Margalef's richness (d), Pielou's evenness (J'), Shannon diversity (H') loge(2), Simpson diversity (1-lambda), Simpson dominance (lambda), average taxonomic distinctness (?+), and variation in taxonomic distinctness (lambda+) were worked out for monthly and seasonal data (pre-monsoon, monsoon, and post monsoon). The ranges of species richness, evenness, Shannon diversity, and Simpson diversity and dominance were 2.30 to 4.51, 0.79 to 0.92, 2.52 to 3.42, 0.76 to 0.91, and 0.11 to 0.23 respectively. Considering the lacuna in information on this estuary, the results of the present study provide reference points for the measures of fish diversity for future studies. Non-metric multidimensional scaling (NMDS) plotted to understand the seasonal and monthly variation of diversity. The clusters showed 40% similarity in the monthly samples, with the post-monsoon season showing the highest number of species. Various physicochemical parameters influenced the temporal fluctuations in diversity including seasons, river runoff, sewage discharge, and intrusion of saline water. Moreover, higher values of chlorophyll a is an indicator of eutrophication. Proper management inputs are necessary to sustain the resources along with pollution abatement measures for improving the livelihood support from this estuary. PMID- 30467654 TI - Environmental enrichment influences spatial learning ability in captive-reared intertidal gobies (Bathygobius cocosensis). AB - Behavioural plasticity is an advantageous trait for animals living in dynamic environments, and can be induced through learning. While some behavioural traits are innate, others are framed by experience and learning during an individual's lifetime. Many studies have investigated cognitive abilities in fish species from contrasting environments, but the relative contribution of natural selection versus behavioural plasticity in cognitive variability remains equivocal. Furthermore, rearing conditions in laboratories are often mundane, failing to encourage natural behaviour in the species used in these studies. Here, we captured juvenile gobies (Bathygobius cocosensis) from intertidal rockpools, and raised them in captivity under varied environmental enrichment treatments that mimic variation observed in coastal habitats. When tested in a simple spatial learning task, individuals from complex rearing treatments (rock or oyster substrate) reached learning criteria faster than those reared in less complex (seagrass) and homogenous environments (sand substrate). Interestingly, gobies reared in complex environments demonstrated longer latencies to start the task than gobies in homogeneous treatments. Our results indicate that cognitive ability is strongly shaped by individual experience during ontogeny, and exposure to reduced environmental complexity in early life leads to reduced cognitive abilities in intertidal gobies. PMID- 30467655 TI - Developmental history and stress responsiveness are related to response inhibition, but not judgement bias, in a cohort of European starlings (Sturnus vulgaris). AB - Judgement bias tasks are designed to provide markers of affective states. A recent study of European starlings (Sturnus vulgaris) demonstrated modest familial effects on judgement bias performance, and found that adverse early experience and developmental telomere attrition (an integrative marker of biological age) both affected judgement bias. Other research has shown that corticosterone levels affect judgement bias. Here, we investigated judgement bias using a modified Go/No Go task in a new cohort of starlings (n = 31) hand-reared under different early-life conditions. We also measured baseline corticosterone and the corticosterone response to acute stress in the same individuals. We found evidence for familial effects on judgement bias, of a similar magnitude to the previous study. We found no evidence that developmental treatments or developmental telomere attrition were related to judgement bias per se. We did, however, find that birds that experienced the most benign developmental conditions, and birds with the greatest developmental telomere attrition, were significantly faster to probe the learned unrewarded stimulus. We also found that the birds whose corticosterone levels were faster to return towards baseline after an acute stressor were slower to probe the learned unrewarded stimulus. Our results illustrate the potential complexities of relationships between early-life experience, stress and affectively mediated decision making. For judgement bias tasks, they demonstrate the importance of clearly distinguishing factors that affect patterns of responding to the learned stimuli (i.e. response inhibition in the case of the Go/No Go design) from factors that influence judgements under ambiguity. PMID- 30467656 TI - Psychosocial factors associated with treatment outcomes in women with obesity and major depressive disorder who received behavioral activation for depression. AB - Behavioral activation is an empirically supported treatment for depression, but much is unknown about factors associated with treatment response. The present study aimed to determine whether baseline levels and subsequent changes in psychosocial factors were associated with improvement in depression in women with comorbid obesity who received behavioral activation treatment for depression and a lifestyle intervention. Multilevel modeling was used to estimate the associations between psychosocial factors and change in depression scores during the first 10 weeks of treatment and associations between changes in psychosocial factors from baseline to 6-month follow-up and change in depression over the same time period. No baseline psychosocial factors were associated with depression improvement during treatment (p = 0.110-0.613). However, greater improvement in hedonic capacity (p = 0.001), environmental reward (p = 0.004), and social impairment (p = 0.012) were associated with greater reductions in depression over 6 months. Findings highlight the differential relationship specific psychosocial factors have with depression treatment outcomes. PMID- 30467657 TI - Transcranial Doppler sonography reveals sustained attention deficits in young adults diagnosed with ADHD. AB - The National Institute of Mental Health has recently launched the Research Domain Criteria framework that seeks to inform clinical classification schemes by elevating the status of neuroscience research in the diagnosis of mental disorders. The current research seeks to contribute to that initiative by using a neurophysiological measure, transcranial Doppler sonography that has been shown to be sensitive to decrements in sustained attention and may provide an additional biomarker of executive dysfunction in ADHD. Twenty-seven participants performed a 12-min vigilance task while cerebral blood flow velocity (CBFV) was recorded. Thirteen participants were included in an ADHD condition if they had been formally diagnosed with ADHD. The remaining 14 participants who had never been formally diagnosed with ADHD were included in the control condition. Participants that had been diagnosed with ADHD demonstrated a steeper decrement in performance accuracy, a steeper decrement in perceptual sensitivity, and employed a more liberal response bias over time as compared to the control participants. Critically, the decrement in CBFV was steeper for participants previously diagnosed with ADHD than those who were not. Moreover, CBFV was found to better predict decreases in sensitivity and hit rate, as well as increases in liberal responding above and beyond self-reported ADHD symptoms. Results suggest that CBFV can be used to index failures of executive control in ADHD and can predict response strategy, and that the measure may provide an additional index of the sustained attention deficits associated with ADHD compared to traditional diagnostic methods. PMID- 30467659 TI - Safety of 5alpha-reductase inhibitors and spironolactone in breast cancer patients receiving endocrine therapies. AB - PURPOSE: To provide dermatologists and oncologists with a foundation for practical understanding and uses of 5alpha-reductase inhibitors and spironolactone for breast cancer patients and survivors receiving endocrine therapies (ETs), including the effect of these treatments on sex hormone levels, any reported drug interactions, and any risk of malignancy. METHODS: All published studies from January 1978 through April 2018 were considered, using databases such as PubMed, Google Scholar, and Science Direct. Forty-seven studies were included in this review. RESULTS: There is no evidence of interactions between 5alpha-reductase inhibitors and spironolactone with ETs used in breast cancer. Sex hormone alteration with 5alpha-reductase inhibitor or spironolactone use is variable. Three randomized controlled trials, 1 case-control study, and 6 retrospective cohort studies, including 284 female patients, studied the effects of 5alpha-reductase inhibitors on serum estrogen levels. Levels were increased in 97 of 284 (34%) patients, decreased in 15 of 284 (5.3%) patients, and unchanged in 162 of 284 (57%) patients. Four retrospective cohort studies, 1 case study, and 1 double-blinded crossover study, including 95 female patients, assessed the effect of spironolactone on estrogen levels. Levels were increased in 25 of 95 (26%) patients, decreased in 6 of 95 (6.3%) patients, and unchanged in 64 of 95 (67%) patients. Ultimately, most patients did not have a significant alteration in the level of estrogen when using 5alpha-reductase inhibitors or spironolactone. No consistent evidence of increased risk of female breast cancer while on spironolactone was reported in 3 studies including 49,298 patients; the risk of breast cancer with the use of 5alpha-reductase inhibitors has not been studied. CONCLUSIONS: Most patients did not show increased estrogen levels with spironolactone and there were no data suggesting increased risk of breast cancer. Based on hormonal and pharmacological activity, spironolactone may be considered for further research on alopecia and hirsutism in breast cancer patients. PMID- 30467658 TI - Application of ferroelectric materials for improving output power of energy harvesters. AB - In terms of advances in technology, especially electronic devices for human use, there are needs for miniaturization, low power, and flexibility. However, there are problems that can be caused by these changes in terms of battery life and size. In order to compensate for these problems, research on energy harvesting using environmental energy (mechanical energy, thermal energy, solar energy etc.) has attracted attention. Ferroelectric materials which have switchable dipole moment are promising for energy harvesting fields because of its special properties such as strong dipole moment, piezoelectricity, pyroelectricity. The strong dipole moment in ferroelectric materials can increase internal potential and output power of energy harvesters. In this review, we will provide an overview of the recent research on various energy harvesting fields using ferroelectrics. A brief introduction to energy harvesting and the properties of the ferroelectric material are described, and applications to energy harvesters to improve output power are described as well. PMID- 30467660 TI - A phase II study investigating the acute toxicity of targeted intraoperative radiotherapy as tumor-bed boost plus whole breast irradiation after breast conserving surgery in Korean patients. AB - BACKGROUND: There are concerns regarding local toxicity when IORT is applied in Asian women with a smaller breast volume than that of Western women. Trials are required to develop safety profiles for this technique. The aim of this trial was to evaluate acute toxicity after intra-operative radiotherapy (IORT) with low energy X-ray plus whole breast irradiation (WBI) in Asian patients with breast cancer. METHODS: This single-arm, single-institute, phase II trial investigated acute toxicity after completion of radiotherapy (targeted IORT followed by WBI) in Korean patients treated with breast-conserving surgery (BCS). In the conventional WBI arm from the TARGIT-A trial, the incidence of acute toxicity within 6 months was 15%. To prove the non-inferiority of the acute toxicity rate, 215 patients were required. This trial is registered with ClinicalTrials.gov (NCT02213991). RESULTS: Two-hundred and fifteen women were enrolled, and 198 underwent IORT. In 33 patients, clinically significant complications during the acute period were noted. The incidence of acute toxicity was 16.7% (95% CI 11.5 21.9%). There were 29 patients with seroma needing more than 3 aspirations, 4 with wound infection, and 2 with skin breakdown. There was no difference in the rate of complications according to the tumor volume or the tumor-breast volume ratio. Advanced age and high BMI were risk factors for acute complications. CONCLUSIONS: Targeted intra-operative radiotherapy using Intrabeam(r) is a safe procedure for Korean patients with breast cancer with an acceptable toxicity profile in the acute period. PMID- 30467661 TI - Increase of positive supercoiling in a hyperthermophilic archaeon after UV irradiation. AB - Diverse DNA repair mechanisms are essential to all living organisms. Some of the most widespread repair systems allow recovery of genome integrity in the face of UV radiation. Here, we show that the hyperthermophilic archaeon Thermococcus nautili possesses a remarkable ability to recovery from extreme chromosomal damage. Immediately following UV irradiation, chromosomal DNA of T. nautili is fragmented beyond recognition. However, the extensive UV-induced double-stranded breaks (DSB) are repaired over the course of several hours, allowing restoration of growth. DSBs also disrupted plasmid DNA in this species. Similar to the chromosome, plasmid integrity was restored during an outgrowth period. Intriguingly, the topology of recovered pTN1 plasmids differed from control strain by being more positively supercoiled. As reverse gyrase (RG) is the only enzyme capable of inducing positive supercoiling, our results suggest the activation of RG activity by UV-induced stress. We suggest simple UV stress could be used to study archaeal DNA repair and responses to DSB. PMID- 30467663 TI - Inactivation of ahpC renders Stenotrophomonas maltophilia resistant to the disinfectant hydrogen peroxide. AB - Inactivation of ahpC, encoding alkyl hydroperoxide reductase, rendered Stenotrophomonas maltophilia more resistant to H2O2; the phenotype was directly correlated with enhanced total catalase activity, resulting from an increased level of KatA catalase. Plasmid-borne expression of ahpC from pAhpCsm could complement all of the mutant phenotypes. Mutagenesis of the proposed AhpC peroxidactic and resolving cysteine residues to alanine (C47A and C166A) on the pAhpCsm plasmid diminished its ability to complement the ahpC mutant phenotypes, suggesting that the mutagenized ahpC was non-functional. As mutations commonly occur in bacteria living in hostile environment, our data suggest that point mutations in ahpC at codons required for the enzyme function (such as C47 and C166), the AhpC will be non-functional, leading to high resistance to the disinfectant H2O2. PMID- 30467662 TI - Rhodococcus daqingensis sp. nov., isolated from petroleum-contaminated soil. AB - A novel Gram-stain positive, aerobic, non-motile bacterial strain, designated Z1T, was isolated from a sample of petroleum-contaminated soil collected in Daqing, Heilongjiang province, China and characterised with a series of taxonomic approaches. The morphological and chemotaxonomic properties of the isolate were typical of those of members of the genus Rhodococcus. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain Z1T belongs to the genus Rhodococcus and clustered with Rhodococcus maanshanensis DSM 44675T (99.2%, sequence similarity) and Rhodococcus tukisamuensis JCM 11308T (97.9%), respectively. However, the DNA-DNA hybridizations between strain Z1T and R. maanshanensis DSM 44675T and R. tukisamuensis JCM 11308T were both less than 70%. The optimal growth temperature and pH for strain Z1T were found to be at 28 degrees C and at pH 7.0. The peptidoglycan was found to contain meso diaminopimelic acid; arabinose, galactose and glucose were detected as diagnostic sugars. The main polar lipids were identified as diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannoside and an unidentified lipid; MK-8(H2) was found as the major menaquinone. The major fatty acids were identified as C16:0, 10-methyl C18:0 and C18:1 omega9c. Mycolic acids were found to be present. The G + C content of the genomic DNA was determined to be 66.7 mol%. Based on a comparative analysis of phenotypic and genotypic characteristics, in combination with DNA-DNA hybridization results, strain Z1T can be distinguished from the type strains of its two close neighbours as a novel species of the genus Rhodococcus, for which the name Rhodococcus daqingensis sp. nov. is proposed. The type strain is Z1T (= CGMCC 1.13630T = DSM 107227T). PMID- 30467664 TI - A practical and easy surgical technique for recovery of an incarcerated haptic. AB - PURPOSE: To present a surgical intervention for a posterior haptic trapped between the cartridge and plunger during intraocular lens (IOL) implantation. MATERIALS AND METHODS: Posterior haptic incarceration was detected in 36 cases during implantation of a one-piece foldable IOL during cataract surgery with phacoemulsification. In 11 of the patients (Group 1), recovery was achieved by forcibly pulling out the incarcerated posterior haptic. In 25 cases (Group 2), the haptic was recovered by using an MVR knife to cut the cartridge tip from the bottom up parallel to the trapped haptic. RESULTS: In Group 1, tears were seen on the incarcerated haptic in all cases (100%). In Group 2, the procedure was successful in all 25 cases and there was no accidental cutting of the haptic. In all cases, the surgeries were completed with the recovered IOL in Group 2. CONCLUSIONS: Posterior haptic incarceration in cataract surgery can be solved by the simple and easy method of cutting the cartridge tip from the bottom upwards and releasing the haptic. PMID- 30467665 TI - Efficacy of fixation of the amniotic membrane on a symblepharon ring with continuous suturing in acute ocular chemical burn patients. AB - PURPOSE: To describe a modified non-traumatic amniotic membrane transplantation (AMT) technique and evaluating its efficiency for the ocular surface injury after chemical burn were aimed. METHODS: Twenty eyes of 20 patients (F: 6, M: 14) with acute chemical burn for whom modified non-traumatic AMT was utilized were evaluated retrospectively. In this technique, amniotic membrane (AM) was fixated onto a symblepharon ring with continuous suturing. The healing time of the corneal epithelial defect due to ocular surface chemical injury and melting duration of AM were evaluated. Development of infection or symblepharon, recurrence or persistence of epithelial defect, corneal perforation and the ring falling out with AM were evaluated as complications. RESULTS: Mean age of the patients was 24.7 +/- 11.7 years old (14 months-40 years). Mean duration of applying the non-traumatic AMT after contact with the chemical agent was 8.4 +/- 6.2 days (2-21 days). The mean duration of the epithelial defect healing was 27.8 +/- 8.8 days (11-40 days) in the grade II, III, and IV (n = 12) cases, while in the grade V and VI (n = 8) cases, a persistent epithelial defect developed, and the mean duration of the epithelial defect healing was 83 +/- 23.1 days (42-120 days) (p = 0.0002). The mean melting duration of the AM was 22.7 +/- 10 days (10 42 days). CONCLUSION: By using this modified AMT technique, AM can be utilized efficiently, easily, and non-traumatically in every center for the treatment of the ocular surface injury due to chemical burn. PMID- 30467666 TI - Phylogenetic analysis of upland cotton MATE gene family reveals a conserved subfamily involved in transport of proanthocyanidins. AB - The multidrug and toxic compound extrusion (MATE) protein belongs to a secondary transporter family, which plays a role in transporting different kinds of substrates like phytohormones and secondary metabolites. In plant, MATE transporters related to the endogenous and exogenous mechanisms of detoxification for secondary metabolites such as alkaloids, flavonoids, anthocyanins and other secondary metabolites have been studied. However, a genome-wide analysis of the MATE family is rarely reported in upland cotton (Gossypium hirsutum L.). In the study, a total of 72 GhMATEs were identified from the genome of upland cotton, which were classified into four subfamilies with possible diverse functions such as transport of proanthocyanidins (PAs), accumulation of alkaloids, extrusion of xenobiotic compounds, regulation of disease resistance and response to abiotic stresses. Meanwhile, the gene structure, evolutionary relationship, physical location, conservative motifs, subcellular localization and gene expression pattern of GhMATEs have been further analysed. Three of these MATE genes (GhMATE12, GhMATE16 and GhMATE38) were identified as candidate genes due to their functions in transport of PA similar to GhTT12. These results provide a new perspective on upland cotton MATE gene family for their potential roles in transport of PA and a theoretical basis for further analyzing the function of MATE genes and improving the fiber quality of brown cotton. PMID- 30467668 TI - Interpreting Behavior Genetic Models: Seven Developmental Processes to Understand. AB - Behavior genetic findings figure in debates ranging from urgent public policy matters to perennial questions about the nature of human agency. Despite a common set of methodological tools, behavior genetic studies approach scientific questions with potentially divergent goals. Some studies may be interested in identifying a complete model of how individual differences come to be (e.g., identifying causal pathways among genotypes, environments, and phenotypes across development). Other studies place primary importance on developing models with predictive utility, in which case understanding of underlying causal processes is not necessarily required. Although certainly not mutually exclusive, these two goals often represent tradeoffs in terms of costs and benefits associated with various methodological approaches. In particular, given that most empirical behavior genetic research assumes that variance can be neatly decomposed into independent genetic and environmental components, violations of model assumptions have different consequences for interpretation, depending on the particular goals. Developmental behavior genetic theories postulate complex transactions between genetic variation and environmental experiences over time, meaning assumptions are routinely violated. Here, we consider two primary questions: (1) How might the simultaneous operation of several mechanisms of gene-environment (GE)-interplay affect behavioral genetic model estimates? (2) At what level of GE interplay does the 'gloomy prospect' of unsystematic and non-replicable genetic associations with a phenotype become an unavoidable certainty? PMID- 30467667 TI - Curcumin prevented human autocrine growth hormone (GH) signaling mediated NF kappaB activation and miR-183-96-182 cluster stimulated epithelial mesenchymal transition in T47D breast cancer cells. AB - Autocrine growth hormone (GH) signaling is a promoting factor for breast cancer via triggering abnormal cell growth, proliferation, and metastasis, drug resistance. Curcumin (diferuloylmethane), a polyphenol derived from turmeric (Curcuma longa), has anti-proliferative, anti-carcinogenic, anti-hormonal effect via acting on PI3K/Akt, NF-kappaB and JAK/STAT signaling. Forced GH expression induced epithelial mesenchymal transition (EMT) through stimulation of miR-182-96 183 cluster expression in breast cancer cells. This study aimed to investigate the role of NF-kappaB signaling and miR-182-96-183 cluster expression profile on autocrine GH-mediated curcumin resistance, which was prevented by time-dependent curcumin treatment in T47D breast cancer cells. Dose- and time-dependent effect of curcumin on T47D wt and GH+ breast cancer cells were evaluated by MTT cell viability and trypan blue assay. Apoptotic effect of curcumin was determined by PI and Annexin V/PI FACS flow analysis. Immunoblotting performed to investigate the effect of curcumin on PI3K/Akt/MAPK, NF-kappaB signaling. miR182-96-183 cluster expression profile was observed by qRT-PCR. Overexpression of GH triggered resistant profile against curcumin (20 uM) treatment for 24 h, but this resistance was accomplished following 48 h curcumin exposure. Concomitantly, forced GH induced invasion and metastasis through EMT and NF-kappaB activation were prevented by long-term curcumin exposure in T47D cells. Moreover, 48 h curcumin treatment prevented the autocrine GH-mediated miR-182-96-183 cluster expression stimulation in T47D cells. In consequence, curcumin treatment for 48 h, prevented autocrine GH-triggered invasion-metastasis, EMT activation through inhibiting NF-kappaB signaling and miR-182-96-183 cluster expression and induced apoptotic cell death by modulating Bcl-2 family members in T47D breast cancer cells. PMID- 30467669 TI - Clinical Utility of In Situ Hybridization Assays in Head and Neck Neoplasms. AB - Head and neck pathology present a unique set of challenges including the morphological diversity of the neoplasms and presentation of metastases of unknown primary origin. The detection of human papillomavirus and Epstein-Barr virus associated with squamous cell carcinoma and newer entities like HPV-related carcinoma with adenoid cystic like features have critical prognostic and management implications. In salivary gland neoplasms, differential diagnoses can be broad and include non-neoplastic conditions as well as benign and malignant neoplasms. The detection of specific gene rearrangements can be immensely helpful in reaching the diagnosis in pleomorphic adenoma, mucoepidermoid carcinoma, secretory carcinoma, hyalinizing clear cell carcinoma and adenoid cystic carcinoma. Furthermore, molecular techniques are essential in diagnosis of small round blue cell neoplasms and spindle cell neoplasms including Ewing sarcoma, rhabdomyosarcoma, synovial sarcoma, biphenotypic sinonasal sarcoma, dermatofibrosarcoma protuberans, nodular fasciitis and inflammatory myofibroblastic tumor. The detection of genetic rearrangements is also important in lymphomas particularly in identifying 'double-hit' and 'triple-hit' lymphomas in diffuse large B cell lymphoma. This article reviews the use of in situ hybridization in the diagnosis of these neoplasms. PMID- 30467671 TI - [Influence of dual-tasking on straight ahead and curved walking in older adults]. AB - BACKGROUND: Walking is not an automatic movement task but requires continuous attention resources. While walking and undertaking an additional task (dual tasking), gait changes occur which are associated with falls in older adults. To date, the evaluation of gait characteristics under dual task conditions is typically performed during walking straight ahead (SW); however, everyday life also requires more complex walking maneuvers such as walking in a curve (CW). Complex walking maneuvers may require higher attentional resources and thus might have a greater impact on the gait under dual task conditions. OBJECTIVE: The aim was to compare the gait characteristics under dual task conditions during SW and CW. MATERIAL AND METHODS: In 30 community-dwelling older adults (mean age: 71.6 +/- 6.6 years) gait parameters including single leg support phase, velocity, cadence, step length and width were measured by electronic gait analysis (GAITRite(r), CIR Systems Inc., Franklin, New Jersey, USA) during SW and CW under single and dual task conditions. For each gait parameter the relative change from single to dual task condition was calculated as dual task costs (DTC) and compared using paired t-tests. RESULTS: For the single leg support phase, velocity, cadence and step width, descriptive results showed increased DTC during CW (2.08-23.74%) as compared to SW (1.39-12.90%). For cadence (DTC: SW 6.81 +/- 12.58%, CW 10.54 +/- 13.46%, p = 0.026) and step width (DTC: SW -12.90 +/- 18.01%, CW -23.74 +/- 56.37%, p = 0.004) the differences were statistically significant. CONCLUSION: The relative decline in gait performance under dual task conditions is greater during CW than during SW. The results suggest that CW requires greater attentional resources as compared to SW. In turn, the risk of falling might be increased during CW under dual task conditions. The present findings may contribute to the development of new, ecologically valid assessment and training strategies taking complex walking maneuvers into account. PMID- 30467672 TI - The use of end-tidal argon to detect venous air embolism: foiled by "fake oxygen!" AB - Venous air-embolism (VAE) potentially catastrophic complication surgery. Based on previous data using changes in end-tidal nitrogen as an indicator of VAE, we surmised that changes in end-tidal argon (EtAr) may be an indicator of VAE. We sought to determine if a commercial mass-spectrometer (PCT Proline Analyzer 61700 8 Class 85, Ametek, Pittsburgh, PA 15238) could be used to detect changes in EtAr in an invitro model. A Drager ApolloTM (Drager, Lubeck, Germany) anesthesia machine was used to ventilate a dummy lung (2 L bag) with a minute ventilation of 6 L/min in 100% oxygen. The quadrupole mass-spectrometer (sampling at 0.0004 atm cc/sec) was attached to the end-tidal inlet of the machine. Room air (1-60 mL) was injected into the dummy lung to simulate VAE. A strong baseline ion-current (1.2 * 10-12 amps) of argon was noted. Due to this contamination we were unable to detect "VAE" events of injected air. Argon represents approximately 0.93% of room air, or about 9300 parts per million (ppm). We detected about 2000 ppm argon in medical-grade oxygen (or 0.2%), limiting our ability to detect changes in EtAr. This is a USP-accepted contaminant, rendering this technology is insensitive for early, rapid detection of VAE. We assumed medical grade oxygen was pure and were surprised to learn otherwise. We want to share this likely largely unknown finding with the medical community. PMID- 30467673 TI - The focus of temperature monitoring with zero-heat-flux technology (3M Bair Hugger): a clinical study with patients undergoing craniotomy. AB - In the noninvasive zero-heat-flux (ZHF) method, deep body temperature is brought to the skin surface when an insulated temperature probe with servo-controlled heating on the skin creates a region of ZHF from the core to the skin. The sensor of the commercial Bair-Hugger ZHF device is placed on the forehead. According to the manufacturer, the sensor reaches a depth of 1-2 cm below the skin. In this observational study, the anatomical focus of the Bair-Hugger ZHF sensor was assessed in pre- and postoperative CT or MRI images of 29 patients undergoing elective craniotomy. Assuming the 2-cm depth from the forehead skin surface, the temperature measurement point preoperatively reached the brain cortex in all except one patient. Assuming the 1-cm depth, the preoperative temperature measurement point did not reach the brain parenchyma in any of the patients and was at the cortical surface in two patients. Corresponding results were obtained postoperatively, although either sub-arachnoid fluid or air was observed in all CT/MRI images. Craniotomy did not have a detectable effect on the course of the ZHF temperatures. In Bland-Altman analysis, the agreement of ZHF temperature with the nasopharyngeal temperature was 0.11 (95% confidence interval - 0.54 to 0.75) degrees C and with the bladder temperature - 0.14 (- 0.81 to 0.52) degrees C. As conclusions, within the reported range of the Bair-Hugger ZHF measurement depth, the anatomical focus of the sensor cannot be determined. Craniotomy did not have a detectable effect on the course of the ZHF temperatures that showed good agreement with the nasopharyngeal and bladder temperatures. PMID- 30467674 TI - Standard setting for a novel esophageal conduit questionnaire: CONDUIT Report Card. AB - BACKGROUND: The purpose of this study was to establish the clinical thresholds for five domains (dysphagia, reflux, dumping-hypoglycemia, dumping-GI symptoms, pain) to support the use of the CONDUIT questionnaire as a screening tool to identify patients who might benefit from an educational or clinical intervention. METHODS: A panel of 16 experts met to develop descriptions of "poor," "moderate," and "good" conduit performance. They were trained to use the modified and extended Angoff standard-setting method. Each judge provided item ratings that reflected borderline good and borderline moderate patients. The average item ratings were summed and transformed to a 0-100 scale to derive final cut scores. Panelist evaluation of the process and confidence with the rating tasks were collected. RESULTS: Panelists expressed that the training on the method gave them information they needed to complete their assignment. Among other factors, their experience with patients was most influential on their ratings. On the 0-100 score scale, good/moderate cuts ranged from 7.2 to 20.8, and moderate/poor cuts ranged from 37.9 to 64.3, depending on domains and weights. Standard errors of one or both cut scores increased for dysphagia and dumping-GI with weighting. CONCLUSIONS: We described the selection and training of panelists and panelists' evaluations of the processes they were asked to follow in detail to defend the cut scores. Further prospective validation studies are underway to compare cut scores from this study and clinicians' judgments and further refine the categorization. PMID- 30467675 TI - Maintaining Intestinal Mucosal Integrity by Plugging Leaks with Homoectoine. PMID- 30467676 TI - Sakuranetin downregulates inducible nitric oxide synthase expression by affecting interleukin-1 receptor and CCAAT/enhancer-binding protein beta. AB - Pruni Cortex is a herbal drug from the bark of the Japanese flowering cherries, Prunus jamasakura or Prunus verecunda, and is included in the traditional Japanese herbal (Kampo) formula Jumihaidokuto, which is administered orally to patients suffering from inflammatory skin diseases. The flavanones contained in Pruni Cortex (e.g., sakuranetin and naringenin) have potent anti-inflammatory, anti-allergic, and anti-microbial activities. Although the effects of Pruni Cortex on skin disease have been well studied, reports regarding its pharmacological effects on the liver are limited. In this study, we extracted the bark of Prunus jamasakura and purified it to isolate the pharmacologically active constituents by monitoring nitric oxide (NO) production in rat hepatocytes that were treated with the pro-inflammatory cytokine, interleukin (IL)-1beta. Sakuranetin and (-)-naringenin, which were present in an ethyl acetate-soluble fraction of the bark extract, significantly inhibited NO induction and inducible nitric oxide synthase (iNOS) expression. These two flavanones decreased the expression of type 1 IL-1 receptor gene and phosphorylation of Akt, also known as protein kinase B, which is regulated by phosphatidylinositol-4,5-bisphosphate 3 kinase (PI3K). Furthermore, sakuranetin decreased the phosphorylation of the activator isoforms of CCAAT/enhancer-binding protein beta (C/EBPbeta), which synergistically activates the transcription of the iNOS gene with nuclear factor kappaB (NF-kappaB). Therefore, sakuranetin inhibited the co-activating activity of C/EBPbeta with NF-kappaB, leading to the suppression of iNOS gene expression in hepatocytes. Taken together, sakuranetin in Pruni Cortex downregulated the iNOS gene by inhibiting PI3K/Akt signal transduction and the phosphorylation of C/EBPbeta. These results imply that sakuranetin may be primarily responsible for the anti-inflammatory effects of Pruni Cortex in the liver. PMID- 30467677 TI - Diminazene aceturate (Berenil) downregulates Trypanosoma congolense-induced proinflammatory cytokine production by altering phosphorylation of MAPK and STAT proteins. AB - Diminazene aceturate (Berenil) is the most commonly used trypanolytic agent in livestock. We previously showed that Berenil downregulates Trypanosoma congolense (T. congolense)-induced cytokine production in macrophages both in vitro and in vivo. Here, we investigated the molecular mechanisms through which the drug alters T. congolense-induced cytokine production in macrophages. We show that pretreatment of macrophages with Berenil significantly downregulated T. congolense-induced phosphorylation of mitogen-activated protein kinase (p38), signal transducer and activator of transcription (STAT) proteins including STAT1 and STAT3, and NFkappaB activity both in vitro and in vivo. Collectively, our results reveal a mechanistic insight through which Berenil downregulates T. congolense-induced cytokine production in macrophages by inhibiting key signaling molecules and pathways associated with proinflammatory cytokine production. PMID- 30467679 TI - Focus on ventilation management. PMID- 30467678 TI - Development of an ICU discharge instrument predicting psychological morbidity: a multinational study. AB - PURPOSE: To develop an instrument for use at ICU discharge for prediction of psychological problems in ICU survivors. METHODS: Multinational, prospective cohort study in ten general ICUs in secondary and tertiary care hospitals in Sweden, Denmark and the Netherlands. Adult patients with an ICU stay >= 12 h were eligible for inclusion. Patients in need of neurointensive care, with documented cognitive impairment, unable to communicate in the local language, without a home address or with more than one limitation of therapy were excluded. Primary outcome was psychological morbidity 3 months after ICU discharge, defined as Hospital Anxiety and Depression Scale (HADS) subscale score >= 11 or Post traumatic Stress Symptoms Checklist-14 (PTSS-14) part B score > 45. RESULTS: A total of 572 patients were included and 78% of patients alive at follow-up responded to questionnaires. Twenty percent were classified as having psychological problems post-ICU. Of 18 potential risk factors, four were included in the final prediction model after multivariable logistic regression analysis: symptoms of depression [odds ratio (OR) 1.29, 95% confidence interval (CI) 1.10 1.50], traumatic memories (OR 1.44, 95% CI 1.13-1.82), lack of social support (OR 3.28, 95% CI 1.47-7.32) and age (age-dependent OR, peak risk at age 49-65 years). The area under the receiver operating characteristics curve (AUC) for the instrument was 0.76 (95% CI 0.70-0.81). CONCLUSIONS: We developed an instrument to predict individual patients' risk for psychological problems 3 months post ICU, http://www.imm.ki.se/biostatistics/calculators/psychmorb/ . The instrument can be used for triage of patients for psychological ICU follow-up. TRIAL REGISTRATION: The study was registered at clinicaltrials.gov, NCT02679157. PMID- 30467680 TI - Long-term outcomes in surgically ineligible patients managed with percutaneous coronary revascularization or medical therapy. AB - The objective of the study was to report clinical outcomes of patients unsuitable for surgical coronary revascularization (CABG) treated with percutaneous revascularization (PCI) or medical therapy alone (MT). The decision to revascularize patients referred for CABG but who are unsuitable should be made at Heart Team meetings. The clinical outcomes in this important patient subset are not known, and while cases are considered individually, these decisions are not guided by robust data. Clinical data were analyzed for patients referred to the Heart Team for consideration of CABG over a 4-year period in a UK tertiary referral center. Outcome data for those managed with urgent PCI or MT were considered over a further 3-year period. 133 patients were treated with PCI and 117 with MT. MACE at 30 days were no different between groups (MT 10.3% versus PCI 12.2%); however, at 1 year MACE were higher in the MT group (MT 39.3% versus PCI 26.7%, P < 0.01). Log rank for MACE-free survival to 1 and 3 years was significantly lower in the MT group [HR 1.77 (0.60-1.11); P < 0.001]. Residual SYNTAX was an independent predictor of death. MT [OR 1.75 (1.03-2.99); P = 0.04] and a residual SYNTAX score [OR 6.45 (2.53-16.45); P < 0.001] were independent predictors of MACE at 1 year in the whole group. Our data reveal better outcomes in patients treated with PCI over MT at 1-3 years in CABG-ineligible patients. Patients without complete revascularization have worse outcomes. PMID- 30467682 TI - The logic of the interaction between beneficence and respect for autonomy. AB - Beneficence and respect for autonomy are two of the most fundamental moral duties in general and in bioethics in particular. Beyond the usual questions of how to resolve conflicts between these duties in particular cases, there are more general questions about the possible forms of the interactions between them. Only recognition of the full spectrum of possible interactions will ensure optimal moral deliberation when duties potentially conflict. This paper has two simultaneous objectives. The first is to suggest a typological scheme of all possible modes of interaction; these will be classified under the "discrete," "semi-discrete," and "non-discrete" categories, according to whether the meaning and/or forms of expression of each duty are treated as independent from or rather as constrained by the other. The second objective is to show that all logical possibilities of interaction indeed have real expressions in medical ethics, to provide clear illustrations of each, and in particular to stress those that have usually escaped recognition. PMID- 30467681 TI - Directed self-assembly of a two-state block copolymer system. AB - In this work, ladder-shaped block copolymer structures consisting of parallel bars, bends, and T-junctions are formed inside square confinement. We define binary states by the two degenerate alignment orientations, and study properties of the two-state system. We control the binary states by creating openings around the confinement, changing the confinement geometry, or placing lithographic guiding patterns inside the confinement. Self-consistent field theory simulations show templating effect from the wall openings and reproduce the experimental results. We demonstrate scaling of a single binary state into a larger binary state array with individual binary state control. PMID- 30467683 TI - Early detection of elevated lactate levels in a mitochondrial disease model using chemical exchange saturation transfer (CEST) and magnetic resonance spectroscopy (MRS) at 7T-MRI. AB - This study aimed to use chemical exchange saturation transfer (CEST) and magnetic resonance spectroscopy (MRS) at 7T-MRI for early detection of intracerebral lactate in a mitochondrial disease model without brain lesions. We considered Ndufs4-knockout (KO) mice as Leigh syndrome models and wild-type (WT) mice as control mice. Brain MRI and 1H-MRS were performed. T2WI data acquired with the Rapid Acquisition with Refocused Echoes (RARE) sequence were used for evaluation of brain lesions. CEST imaging of mice brains was performed using RARE with a magnetization transfer (MT) pulse. The MT ratio (MTR) asymmetry curves and five MTR asymmetry maps at 0.5, 1.0, 2.0, 3.0, and 3.5 ppm were calculated using these CEST images. Metabolite concentrations were measured by MRS. T2WI MRI revealed no obvious abnormal findings in KO and WT mice brains at 6 weeks of age. The MTR asymmetry maps at 0.5 ppm, 1.0 ppm, and 2.0 ppm of the KO mice were higher than those of the control mice. Brain 1H MRS revealed a significant increase in lactate levels in all KO mice in comparison with those in the control mice. Additionally, creatine levels in the KO mice were slightly higher than those in the control mice. The levels of the other four metabolites-mIns, NAA + NAAG, GPC + PCh, and Glu + Gln-did not change significantly. We propose that CEST imaging can be used as a biomarker of intracerebral elevated lactate levels in mitochondrial disease. PMID- 30467684 TI - Implicit-descriptor ligand-based virtual screening by means of collaborative filtering. AB - Current ligand-based machine learning methods in virtual screening rely heavily on molecular fingerprinting for preprocessing, i.e., explicit description of ligands' structural and physicochemical properties in a vectorized form. Of particular importance to current methods are the extent to which molecular fingerprints describe a particular ligand and what metric sufficiently captures similarity among ligands. In this work, we propose and evaluate methods that do not require explicit feature vectorization through fingerprinting, but, instead, provide implicit descriptors based only on other known assays. Our methods are based upon well known collaborative filtering algorithms used in recommendation systems. Our implicit descriptor method does not require any fingerprint similarity search, which makes the method free of the bias arising from the empirical nature of the fingerprint models. We show that implicit methods significantly outperform traditional machine learning methods, and the main strengths of implicit methods are their resilience to target-ligand sparsity and high potential for spotting promiscuous ligands. PMID- 30467685 TI - Noggin levels in nonalcoholic fatty liver disease: the effect of vitamin E treatment. AB - AIM: The evaluation of (a) noggin levels in patients with simple steatosis (SS) vs. nonalcoholic steatohepatitis (NASH) vs. controls, and (b) the effect of combined spironolactone plus vitamin E vs. vitamin E monotherapy on noggin levels in biopsy-proven patients with nonalcoholic fatty liver disease (NAFLD). METHODS: In the case-control study, 15 patients with SS, 16 with NASH, and 24 controls were included. In the randomized controlled trial, NAFLD patients were assigned to vitamin E (400 IU/d) or spironolactone (25 mg/d) plus vitamin E for 52 weeks. RESULTS: Noggin levels were lower in SS (5.8 +/- 1.5 pmol/l) and NASH (8.7 +/- 2.4 pmol/l) patients than in controls (13.7 +/- 2.7 pmol/l; p for trend = 0.040), but were similar in SS and NASH patients. After adjustment for potential cofounders, log(noggin) remained different between groups. Log(noggin) levels similarly increased post-treatment in both groups: log(noggin) was not different between groups (p = 0.20), but increased within groups over time (p < 0.001), without a significant group * time interaction (p = 0.62). Log(noggin) significantly increased at month 2 post-treatment (p = 0.008 vs. baseline) and remained stable thereafter. CONCLUSIONS: Lower noggin levels were observed in NAFLD patients than in controls. Noggin levels increased similarly by either combined low-dose spironolactone plus vitamin E or vitamin E monotherapy. TRIAL REGISTRATION: NCT01147523. PMID- 30467686 TI - DAPT Plus Cilostazol is Better Than Traditional DAPT or Aspirin Plus Ticagrelor as Elective PCI for Intermediate-to-Highly Complex Cases: Prospective, Randomized, PRU-Based Study in Taiwan. AB - PURPOSE: Current treatment guidelines do not recommend different antiplatelet treatments for patients in different coronary risk categories; nor do they consider ethnic differences in responses to individual drugs. OBJECTIVES: We performed a prospective, single-blind, randomized, comparative study of Taiwanese patients with stable angina and scheduled stent implantation for intermediate-to highly complex coronary lesions and compared the platelet reactivity unit (PRU) levels and 24-month outcomes of groups receiving three different antiplatelet treatments. METHODS: Patients (N = 334) were randomized into three treatment groups (aspirin + clopidogrel, aspirin + ticagrelor, or aspirin + clopidogrel + cilostazol) for 6 months of treatment and were then switched to aspirin only. PRU levels were determined 24 h, 7 days, and 1 month after stent implantation. Clinical outcomes and adverse events were recorded over 24 months. RESULTS: Clopidogrel treatment reached full effect after 1 month. Ticagrelor decreased PRU levels more than did clopidogrel but often to levels that increased the risk of hemorrhage. The addition of cilostazol to clopidogrel decreased PRU levels earlier and more strongly than clopidogrel alone but not as strongly as did ticagrelor. Ticagrelor treatment caused fewer major adverse cardiovascular events (MACEs) and more episodes of minor bleeding than the other two treatments. CONCLUSIONS: Clopidogrel appears safer than ticagrelor in Taiwanese patients with stable angina after stent implantation for intermediate-to-highly complex coronary lesions. The addition of cilostazol to clopidogrel may provide a more rapid decrease in PRU to therapeutic levels without increasing the risk of hemorrhage. CLINICAL TRIAL REGISTRATION NUMBER: NCT02101411. PMID- 30467687 TI - Effects of carrier frequency mismatch on frequency-selective spectral editing. AB - OBJECTIVES: This study sought to investigate the effects of carrier frequency mismatch on spectral editing and its correction by frequency matching of basis functions. MATERIALS AND METHODS: Full density matrix computations and Monte Carlo simulations based on magnetic resonance spectroscopy (MRS) data collected from five healthy volunteers at 7 T were used to analyze the effects of carrier frequency mismatch on spectral editing. Relative errors in metabolite quantification were calculated with and without frequency matching of basis functions. The algorithm for numerical computation of basis functions was also improved for higher computational efficiency. RESULTS: We found significant errors without frequency matching of basis functions when carrier frequency mismatch was generally considered negligible. By matching basis functions with the history of frequency deviation, the mean errors in glutamate, glutamine, gamma-aminobutyric acid, and glutathione concentrations were reduced from 3.90%, 1.85%, 11.53%, and 3.43% to 0.18%, 0.34%, 0.40%, and 0.51%, respectively. CONCLUSION: Matching basis functions to frequency deviation history was necessary even when frequency deviations during frequency-selective spectral editing were fairly small. Basis set frequency matching significantly improved accuracy in the quantification of glutamate, glutamine, gamma-aminobutyric acid, and glutathione concentrations. PMID- 30467688 TI - Low extracellular vesicle-associated tissue factor activity in patients with persistent lupus anticoagulant and a history of thrombosis. AB - Lupus anticoagulants (LA) are a heterogeneous group of antiphospholipid antibodies (aPLAs) that promote thrombosis. Tissue factor (TF)-bearing extracellular vesicles (EVs) might contribute to the prothrombotic state of patients with persistent LA and a history of thrombosis. To investigate if EV associated TF activity is elevated in a well-defined group of LA-positive patients with a history of thrombosis in comparison to that of healthy controls. Adult patients (n = 94, median age 40.1 years, interquartile range (IQR) 29.9 53.4; 87% females) positive for LA and a history of thrombosis (78% venous thrombosis, 17% arterial thrombosis, 5% venous thrombosis and arterial thrombosis) and healthy age- and sex-matched controls (n = 30, median age 42.9 years, IQR 38.6-45.8, 77% females) were included in this study. EV-TF activity was determined with a factor Xa generation assay and anti-beta2-glycoprotein (anti-beta2GPI) and anticardiolipin (aCL) antibodies by enzyme-linked immunoassays. EV-TF activity did not differ between 94 LA-positive patients with a history of thrombosis (median 0.05 pg/mL, IQR 0.00-0.14) and 30 healthy controls (median 0.06, IQR 0.00-0.11, p = 0.7745). No correlation was found between EV-TF activity and lupus-sensitive activated partial thromboplastin time (aPTT-LA) (rho = 0.034), Rosner index (rho = - 0.056), anti-beta2GPI IgG (rho = 0.05), anti-beta2GPI IgM (rho = - 0.08), aCL IgG (rho = 0.12), and aCL IgM (rho = - 0.11) in LA-positive patients. We found low EV-TF activity levels in LA positive patients and a history of thrombosis and no correlation with analyzed aPLAs. Our data indicate that circulating TF-bearing EVs do not contribute to the prothrombotic state of patients with LA. PMID- 30467689 TI - Synthesis of Fucose-Containing Disaccharides by Glycosylhydrolases from Various Origins. AB - Glycosylhydrolases of various origins were used to produce fucose-containing disaccharides with prebiotic potential using different donor substrates and L fucose as the acceptor substrate. Eight different disaccharides were synthesized as follows: three beta-D-galactosyl-L-fucosides with glycosidase CloneZyme Gly 001-02 using D-lactose as a donor substrate, two with a structure similar to prebiotics; one beta-D-galactosyl-L-fucose with beta-D-galactosidase from Aspergillus oryzae using D-lactose as a substrate donor; and four alpha-D glucosyl-L-fucosides with alpha-D-glucosidase from Saccharomyces cerevisiae using D-maltose as a donor substrate. All disaccharides were purified and hydrolyzed. In all cases, an L-fucose moiety was present, and it was confirmed for beta-D galactosyl-L-fucose by mass spectrometry. High concentrations of L-fucose as the acceptor substrate enhanced the synthesis of the oligosaccharides in all cases. The three enzymes were able to synthesize fucose-containing disaccharides when L fucose was used as the acceptor substrate, and the highest yield was 20% using beta-D-galactosidase from Aspergillus oryzae. PMID- 30467690 TI - Co-ordination of health care: the case of hospital emergency admissions. AB - The recognition that chronic care delivery is suboptimal has led many health authorities around the world to redesign it. In Norway, the Department of Health and Care Services implemented the Coordination Reform in January 2012. One policy instrument was to build emergency bed capacity (EBC) as an integrated part of primary care service provided by municipalities. The explicit aim was to reduce the rate of avoidable admissions to state-owned hospitals. Using five different sources of register data and a quasi-experimental framework-the "difference-in differences" regression approach-we estimated the association between changes in EBC on changes in aggregate emergency hospital admissions for eight ambulatory care sensitive conditions (ACSC). The results show that EBC is negatively associated with changes in aggregate ACSC emergency admissions. The associations are largely consistent with alternative model specifications. We also estimated the relationship between changes in EBC on changes in each ACSC condition separately. Our results are mixed. EBC is negatively associated with emergency hospital admissions for asthma, angina and chronic obstructive pulmonary disease but not congestive heart failure and diabetes. The main implication of the study is that EBC within primary care is potentially a sensible way of redesigning chronic care. PMID- 30467692 TI - Autophagosomal Sperm Organelle Clearance and mtDNA Inheritance in C. elegans. AB - The nematode C. elegans represents a powerful experimental system with key properties and advantages to study the mechanisms underlying mitochondrial DNA maternal inheritance and paternal components sorting. First, the transmission is uniparental and maternal as in many animal species; second, at fertilization sperm cells contain both mitochondria and mtDNA; and third, the worm allows powerful genetics and cell biology approaches to characterize the mechanisms underlying the uniparental and maternal transmission of mtDNA. Fertilization of C. elegans oocyte occurs inside the transparent body when the mature oocyte resumes meiosis I and passes through the spermatheca. One amoeboid sperm cell fuses with the oocyte and delivers its whole content. Among the structures entering the embryo, the sperm mitochondria and a fraction of the nematode specific membranous organelles are rapidly degraded, whereas others like centrioles and sperm genomic DNA are transmitted. In this chapter, we will review the knowledge acquired on sperm inherited organelles clearance during the recent years using C. elegans. PMID- 30467691 TI - Insomnia symptoms combined with nocturnal hypoxia associate with cardiovascular comorbidity in the European sleep apnea cohort (ESADA). AB - PURPOSE: The aim of the current study was to further investigate the concept of previously reported high occurrence of comorbidities in obstructive sleep patients (OSA) with insomnia-like symptoms. We hypothesized that this finding at least partly is mediated by nocturnal hypoxia. Moreover, we speculated that the spectrum of the clinical OSA phenotypes differs between European geographical regions. METHODS: Cohort of the European Sleep Apnea Database (n = 17,325; 29.9% females) was divided into five subcohorts according to geographical region (North, East, South, West, Central) and further into four clinical presentation phenotypes based on daytime symptoms (EDS) and characteristics suggestive of insomnia. RESULTS: The insomnia phenotype (alone or together with EDS) dominated in all European regions. Isolated insomnia, however, was less common in the West. Insomnia phenotype was associated with the highest proportion of cardiovascular comorbidity (51.7% in the insomnia vs. 43.9% in the EDS type). Measures of nocturnal hypoxemia were independently associated with cardiovascular comorbidity in phenotypes with insomnia-like symptoms. The burden of comorbidities was high across all geographical regions and clinical phenotypes. Regional differences were clinically relevant for age (48 vs. 54 years), BMI (29 vs. 34 kg/m2), and ODI (15 vs. 32/h). CONCLUSION: High prevalence of particularly cardiovascular comorbidity among patients with insomnia-like symptoms was linked to nocturnal hypoxemia. Considerable differences in clinical presentation were found among OSA patients across Europe. Our data underline that physicians should ask their patients with suspected OSA also for insomnia symptoms. It remains to be explored if a reduction of nocturnal hypoxemia predicts the improvement of insomnia symptoms. PMID- 30467693 TI - Exogenous Factors May Differentially Influence the Selective Costs of mtDNA Mutations. AB - In this review, we provide evidence to suggest that the cost of specific mtDNA mutations can be influenced by exogenous factors. We focus on macronutrient mitochondrial DNA interactions as factors that may differentially influence the consequences of a change as mitochondria must be flexible in its utilization of dietary proteins, carbohydrates, and fats. To understand this fundamental dynamic, we briefly discuss the energy processing pathways in mitochondria. Next, we explore the mitochondrial functions that are initiated during energy deficiency or when cells encounter cellular stress. We consider the anterograde response (nuclear control of mitochondrial function) and the retrograde response (nuclear changes in response to mitochondrial signaling) and how this mito nuclear crosstalk may be influenced by exogenous factors such as temperature and diet. Finally, we employ Complex I of the mitochondrial electron transport system as a case study and discuss the potential role of the dietary macronutrient ratio as a strong selective force that may shape the frequencies of mitotypes in populations and species. We conclude that this underexplored field likely has implications in the fundamental disciplines of evolutionary biology and quantitative genetics and the more biomedical fields of nutrigenomics and pharmacogenomics. PMID- 30467694 TI - Anti-fibrotic Effects and Mechanism of Shengmai Injection () on Human Hepatic Stellate Cells LX-2. AB - OBJECTIVE: To investigate the effects of Shengmai Injection (, SMI) on the proliferation, apoptosis and N-myc downstream-regulated gene 2 (NDRG2, a tumour suppressor gene) expression in varying densities of human hepatic stellate cells LX-2. METHODS: LX-2 cells were cultured in vitro. Then, cells were plated in 96 well plates at an approximate density of 2.5*104 cells/mL and cultured for 48, 72, 96 or 120 h followed by the application of different concentrations of SMI (0.6, 1.2, 2.4, 4.8 or 6 MUL/mL). Cell proliferation was measured after an additional 24 or 48 h using the 3(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The effects of SMI on different cell growth states (cultured for 48, 72, 96, or 120 h) were observed by light microscopy at 24 h after treatment. When the cells reached 80% confluence, apoptosis was detected by flow cytometry after 24 h. Lastly, LX-2 cells were treated with different concentrations of SMI and extracted with protein lysis buffer. The levels of NDRG2 were measured by Western blot. RESULTS: When the LX-2 cells grew for 48, 72, 96 and 120 h, 4.8 and 6 MUL/mL of SMI significantly inhibited cell proliferation at 24 and 48 h after treatment (P<0.05). And 2.4 MUL/mL of SMI also inhibited cell proliferation at 24 h after treatment when cell growth for 48 h (P<0.05) and at 48 h after treatment when cell growth for 72, 96 and 120 h (P<0.05). The NDRG2 expression level in the LX-2 cell was significantly increased when treated with SMI at concentrations of 1.2, 2.4, 4.8 or 6 MUL/mL (P<0.05). CONCLUSIONS: The inhibitory effects of SMI on the proliferation of LX-2 cells were related to not only concentration dependent but also cell density. In addition, SMI (2.4, 4.8 and 6 MUL/mL) could accelerate apoptosis in LX-2 cells, and the mechanism might be associated with NDRG2 over-expression. PMID- 30467696 TI - Low-Frequency Electroacupuncture Alleviates Chronic Constrictive Injury-Induced Mechanical Allodynia by Inhibiting NR2B Upregulation in Ipsilateral Spinal Dorsal Horn in Rats. AB - OBJECTIVE: To study the effects of electroacupuncture (EA) in chronic constrictive injury (CCI) rat model and the expression of N-methyl-D-aspartate receptor type 2B (NR2B) in ipsilateral spinal dorsal horn in rats to explore the analgesic mechanisms of EA. METHODS: According to the random number table, totally 180 rats were evenly divided into a sham group, a CCI group, and an EA group. CCI model was conducted with four 4-0 chromic gut ligatures loosely ligated around the left sciatic nerve 1 cm above the trifurcation. Rats in the EA group received 2 Hz EA therapy bilaterally at acupoints of Zusanli (ST 36) and Sanyinjiao (SP 6) once daily (30 min/d) for 30 days after surgery. Paw withdrawal thresholds (PWTs) were measured on 0 (baseline), 1, 3, 7, 15, 30 days after surgery. Rats were sacrificed on 0, 1, 3, 7, 15 and 30 days after surgery, and the L4-5 segments of spinal cord were removed to detect the expression of NR2B by immunohistochemistry and quantitative polymerase chain reaction. RESULTS: PWTs in the CCI group were significantly lower than the sham group at Day 1-30 after surgery, and reached its lowest at Day 1 (P<0.01). After EA treatment, the PWTs recovered rapidly and were significantly higher than those in the CCI group on 3, 7, 15 and 30 days after surgery (P<0.01). The numbers of NR2B-immunoreactive cells of the CCI group significantly increased after CCI surgery compared with the sham group (P<0.01). Compared with the CCI group, stimulation of EA markedly decreased the numbers of NR2B-immunoreactive cells at Day 3, 7, 15 and 30 (P<0.05). In the sham group, NR2B mRNA was expressed at a low level. It increased after CCI surgery, which increased rapidly at Day 7 (P<0.01) and reached its peak value at Day 15 (P<0.01). After EA stimulation, relative quantity of NR2B mRNA expression was less than that in the CCI group at Day 15 and 30 (P<0.05). CONCLUSIONS: Low frequency of EA had antinociceptive effect in CCI rat model. The analgesic effects of EA might be through the inhibition of NR2B. PMID- 30467695 TI - Effects of Niaoduqing Particles () on Delaying Progression of Renal Dysfunction: A Post-trial, Open-Label, Follow-up Study. AB - OBJECTIVE: To follow up the participants of the randomized clinical trial "Efficacy and Safety of Niaoduqing Particles () for Delaying Moderate-to-Severe Renal Dysfunction", and assess the long-term effects of Niaoduqing Particles on delaying the progression of renal dysfunction. METHODS: Participants, who had previously been randomly assigned to receive Niaoduqing Particles or placebo for 24 weeks (146 cases in each group), were invited to follow-up and all were administered Niaoduqing Particles 5 g thrice daily and 10 g before bedtime for 24 weeks. The primary endpoints were changes in baseline serum creatinine (Scr) and estimated glomerular filtration rate (eGFR) after completion of the open-label treatment period. RESULTS: After the double-blind period, the median (interquartile range) changes in Scr were 1.1 (-13.0-24.1) and 11.7 (-2.6-42.9) MUmol/L for the Niaoduqing Particle and placebo groups, respectively (P=0.008), and the median changes in eGFRs were-0.2 (-4.3-2.7) and-2.21 (-5.7-0.8) mL*min 1*1.73 m-2, respectively (P=0.016). There were significant differences in the double-blind period changes in renal function between groups. After the open label period, the median changes in Scr were 9.0 (-10.0-41.9) and 17.5 (-6.0 50.0) MUmol/L for the Niaoduqing Particle and placebo groups according to baseline grouping, respectively (P=0.214), and the median changes in eGFRs were 2.3 (-6.4-1.9) and-3.7 (-7.5-1.1) mL*min-1*1.73 m-2, respectively (P=0.134). There were no statistical differences in the open-label period changes in renal function between groups. The eGFR reduction of participants who accepted Niaoduqing Particle treatment for 48 weeks was projected to 2.5 mL*min-1*1.73 m-2 per year. CONCLUSIONS: Niaoduqing Particles appear to have long-term efficacy for patients with moderate-to-severe renal dysfunction. Although there was no statistical difference, the early use of Niaoduqing Paticles seems to ameliorate the worsening of renal function. (Trial registration No. ChiCTR-TRC-12002448). PMID- 30467697 TI - Correlation Analysis of Rubella Incidence and Meteorological Variables Based on Chinese Medicine Theory of Yunqi. AB - OBJECTIVE: To analyze the correlations between the incidence of rubella and meteorological factors over the same period and previous periods including 1, 2, 3 and 4 year ago (defined according to Chinese medicine Yunqi theory of "pestilence occurring after 3 years") and establish the rubella-meteorological forecast models for Beijing area, China. METHODS: Data regarding the incidence of rubella between 1990 and 2004 from Beijing Center for Disease Control and Prevention, and the meteorological variables including daily average temperatures, daily average wind speeds, average precipitations, average relative humidity, average vapor pressures and average low cloud covers between 1986 and 2004 were collected from the Beijing Meteorological Observatory. Descriptive statistics and back-propagation artificial neural network for forecast model's establishment were adopted for data analysis. RESULTS: The average temperature and relative humidity have a great contribution (100%) to the rubella morbidity. But the combination of other meteorological factors contributed to improve the accuracy of rubella-meteorological forecast models. The forecast accuracy could be improved by 76% through utilizing a combination of meteorological variables spanning from 3 years ago to the present rather than utilizing data from a single year or dating back to more earlier time than 3 years. CONCLUSIONS: There is a close relationship between the incidence of rubella and meteorological variables in current year and previous 3 years. This finding suggests that rubella prediction would benefit from consideration to previous climate changes. PMID- 30467698 TI - RET/PTC Gene Rearrangements in Thyroid Carcinogenesis: Assessment and Clinico Pathological Correlations. AB - Rearranged during transfection (RET) is a proto oncogene implicated in thyroid carcinogenesis of papillary type (PTC). The RET proto-oncogene in PTC is constitutively activated by fusion of its tyrosine kinase domain with the 5 'region of another gene thereby generating chimeric products collectively named RET/PTCs. RET/PTC1 and RET/PTC3 are best characterized among all RET/PTC rearrangements. Kashmir valley has witnessed an alarming increase in thyroid cancer incidence in young women. Therefore, we investigated the occurrence of RET/PTC 1 & 3 rearrangements by semi quantitative and qPCR in thyroid cancer patients (n = 48) of Kashmiri population and interrelated results with various clinicopathological characteristics. We observed that all the RET/PTC rearrangements were confined to PTC cases (10/40). Presence of RET/PTC rearrangement significantly correlated with gender, elevated TSH levels and lymph node metastasis. Overall, our study advocates that RET/PTC3 rearrangement is a frequent event in the carcinogenesis of thyroid gland in Kashmiri population although a study with a larger sample size is needed to get a clear scenario. PMID- 30467699 TI - Assessment of Gastritis and Gastric Cancer Risk in the Chilean Population Using the OLGA System. AB - Gastric cancer (GC) is the first cancer-related cause of death in Chile; however, no plan for GC early detection has been implemented in this country. The OLGA system characterizes gastritis from stages 0 to IV according to the risk of developing GC based on H. pylori infection, atrophy, metaplasia and GC. In this study, the performance of the OLGA system was evaluated in 485 Chilean patients receiving routine endoscopy to improve the detection of early GC or preneoplastic lesions. The results showed that OLGA scores, atrophy, metaplasia and GC increased significantly with age (p < 0.001). Conversely, H. pylori infection was higher in younger groups (p < 0.05). All gastric lesions were more frequent in men than women. The majority of patients with atrophy also had metaplasia (99%, p < 0.0001). Patients with H. pylori infection had more gastric atrophy and metaplasia than those without infection (p < 0.05). Of the 485 patients, 21 (4.3%) had GC, being 2.3 times more frequent among men than women and about 2/3 (14) were in OLGA stage >=2. In addition, 19 (90%) GC patients had atrophy and 18 (85%) had metaplasia (p < 0.001). In conclusion, the OLGA system facilitated the evaluation of GC precursor lesions particularly in patients with an OLGA score > 2 between 45 and 56 years old, because this group showed atrophy and intestinal metaplasia more frequently. Therefore, biennial endoscopic surveillance of patients with an OLGA >2 can be an important health policy in Chile for diagnosing GC in its early stages and reducing mortality over the next two decades. PMID- 30467700 TI - Caspase 3 as a Novel Marker to Distinguish Chromophobe Renal Cell Carcinoma from Oncocytoma. AB - Despite advances in our understanding of the biology of chromophobe renal cell carcinoma (ChRCC) and renal oncocytoma (RO), the differential diagnosis among these tumors remains one of the most problematic in renal pathology. Today, CK7 is the most recommended marker to distinguish these entities, however it appears insufficiently accurate by itself. This study aimed to find an easily accessible IHC stain that might out-compete CK7 in this field. Expressions of CK7, cyclin D1, p16, survivin, CD138, Ki-67 and caspase 3 (CASP3) were analyzed in a total of 27 cases (20 ROs and 7 ChRCCs). Immunoreactivity was assessed based on a combined score of the extent and intensity of staining. Compared to RO, a higher percentage of the total ChRCCs stained positive for CK7 (67% vs. 22%, respectively) and CASP3 (86% vs. 25%) (P < 0.005). The differences in staining with cyclin D1, p16, survivin, CD138 and Ki-67 turned out to be statistically insignificant in differentiating ChRCC from RO. CASP3 is a promising marker in distinguishing ChRCC from RO and may represent an alternative for CK7. Cyclin D1, p16, survivin, CD138 and Ki-67 cannot be used to distinguish these neoplasms. PMID- 30467701 TI - Economic Burden of Renal Cell Carcinoma-Part I: An Updated Review. AB - BACKGROUND: The economic burden of renal cell carcinoma (RCC) had been reported to be significant in a previous review published in 2011. OBJECTIVE: The objective of this study was to perform an updated review by synthesizing economic studies related to the treatment of RCC that have been published since the previous review. METHODS: We performed a literature search in PubMed, EMBASE, and the Cochrane Library, covering English-language studies published between June 2010 and August 2018. We categorized these articles by type of analyses [cost effectiveness analysis (CEA), cost analysis, and cost of illness (COI)] and treatment setting (cancer status and treatment), discussed findings from these articles, and synthesized information from each article in summary tables. RESULTS: We identified 52 studies from 2317 abstracts/titles deemed relevant from the initial search, including 21 CEA, 23 cost analysis, and 8 COI studies. For localized RCC, costs were found to be positively associated with the aggressiveness of the local treatment. For metastatic RCC (mRCC), pazopanib was reported to be cost effective in the first-line setting. We also found that the economic burden of RCC has increased over time. CONCLUSION: RCC continues to impose a substantial economic burden to the healthcare system. Despite the large number of treatment alternatives now available for advanced RCC, the cost effectiveness and budgetary impact of many new agents remain unknown and warrant greater attention in future research. PMID- 30467703 TI - Robotic resection of the uncinate process of the pancreas. AB - Since the development of the robotic platform, the number of robotic-assisted surgeries has significantly increased. Robotic surgery has gained growing acceptance in recent years, expanding to pancreatic resection. Here, we report a total robotic resection of the uncinate process of the pancreas performed in a patient with a cystic neuroendocrine tumor. To our knowledge, this is the first report of a robotic resection of the uncinate process of the pancreas. A 46-year old man with no specific medical history was diagnosed with a neuroendocrine tumor after undergoing routine imaging. Biopsy guided by echoendoscopy revealed a well-differentiated neuroendocrine tumor. We decided to perform a robotic resection of the uncinate process of the pancreas after obtaining informed consent for the procedure. According to preoperative echoendoscopy and magnetic resonance imaging, there was a safe margin between the neoplasm and the main pancreatic duct. The technique uses five ports. The duodenum is fully mobilized, and Kocher maneuver is carefully performed. The uncinate process of the pancreas is then identified. The resection of the uncinate process begins with the division of small arterial branches from the inferior pancreaticoduodenal artery in its inferior portion, followed by control of venous tributaries to the superior mesenteric vein. Intraoperative localization of the ampulla of Vater is performed using indocyanine green enhanced fluorescence, thus defining the superior margin of the uncinate process. The pancreatic division is made about 5 mm below its upper margin for safety. Surgical specimen is then retrieved through the umbilical port inside a plastic bag. The raw pancreatic area is covered with hemostatic tissue and drained. The total operation time was 215 min. The docking time was 8 min and console time was 180 min. Blood loss was minimum, estimated at less than 50 mL. The postoperative period was uneventful, except for hyperamylasemia in the drain fluid. The patient was discharged on the 3rd postoperative day. The final pathological report confirmed well-differentiated pancreatic neuroendocrine tumor. Robotic resection of the uncinate process of the pancreas is safe and feasible, providing parenchymal conservation in a minimally invasive setting. Robotic resection should be considered for patients suffering from low-grade pancreatic neoplasms located in this part of the pancreas. PMID- 30467702 TI - The value of a 1-day multidisciplinary robot surgery training for novice robot surgeons. AB - INTRODUCTION: To fulfil the need for a basic level of competence in robotic surgery (Brinkman et al., Surg Endosc Other Interv Tech 31(1):281-287, 2017; Dutch Health inspectorate (Inspectie voor de gezondheidszorg), Insufficient carefulness at the introduction of surgical robots (in Dutch: Onvoldoende zorgvuldigheid bij introductie van operatierobots), Igz, Utrecht, 2010), the NIVEL (Netherlands Institute for Healthcare Research) developed the 'Basic proficiency requirements for the safe use of robotic surgery' (BPR). Based on the BPR a 1-day robotic surgery training was organised to answer the following research questions: (1) Are novice robot surgeons able to accurately self-assess their knowledge and dexterity skills? (2) Is it possible to include the teaching of all BPRs in a 1-day training? MATERIALS AND METHODS: Based on the BPR, a robot surgery course was developed for residents and specialists (surgery, gynaecology and urology). In preparation, the participants completed an online e-module. The 1-day training consisted of a practical part on robot set-up, a theoretical section, and hands-on exercises on virtual reality robot simulators. Multiple online questionnaire was filled out by the participants at the end of the training to evaluate the perceived educational value of the course and to self assess the degree to which BPRs were reached. RESULTS: 20 participants completed the training during the conference of the Dutch Association for Endoscopic Surgery (NVEC) in 2017. Participants indicated nearly all competency requirements were mastered at the end of the training. The competency requirements not mastered were, however, critical requirements for the safe use of the surgical robot. Skill simulation results show a majority of participants are unable to reach a proficient simulation score in basic skill simulation exercises. CONCLUSION: Results show novice robot surgeons are too positive in the self assessment of their own dexterity skills after a 1-day training. Self-assessment revealed uncertainty of the obtained knowledge level on requirements for the safe use of the surgical robot. Basic courses on robotic training should inform trainees about their results to enhance learning and inform them of their competence levels. PMID- 30467704 TI - New Species, New Records, and Distribution of Smicridea Mclachlan 1871 in Bolivia (Trichoptera: Hydropsychidae). AB - During various studies of freshwater quality, twenty-four species of Smicridea were collected in Bolivia. This brings to thirty-one the number of Smicridea species present in this country. Four belong to the subgenus Smicridea Mclachlan J Linnean Soc London Zool 11: 98-141, 1871, which is recorded for the first time for the country. Additionally, 16 species in the subgenus Rhyacophylax Muller Zool Anzeiger 2: 38-40, 1879, are also registered for the first time. Three species are new and described from males: Smicridea (Rhyacophylax) molinai sp. nov., Smicridea (Rhyacophylax) ruedamartinae sp. nov., and Smicridea (Smicridea) moyai sp. nov. PMID- 30467705 TI - A recombinant multi-epitope peptide vaccine based on MOMP and CPSIT_p6 protein protects against Chlamydia psittaci lung infection. AB - Chlamydia psittaci is an obligate intracellular pathogen with a broad host range that can lead to severe infectious disease by transferring from birds to humans. Vaccination has been considered the best way to prevent chlamydial infection; nevertheless, there is currently still no commercially available vaccine that can inhibit the spread of C. psittaci. In previous study, major outer membrane protein (MOMP) of C. psittaci was confirmed to be an appropriate candidate antigen for limiting C. psittaci respiratory infections in a murine model, and plasmid-encoded CPSIT_p6 also has functions similar to those of MOMP in our study. Therefore, according to bioinformatics analysis, we developed a recombinant peptide containing multiple antigenic epitopes from MOMP (24-32, 262 272) and CPSIT_p6 protein (109-119, 173-181) and evaluated the efficacy of peptide immunization. BALB/c mice were inoculated intraperitoneally with the recombinant multi-epitope antigens three times at 2-week intervals and subsequently intranasally infected with C. psittaci. We found that the recombinant multi-epitope antigens induced strong humoral and Th1 cellular immune responses by producing meaningfully high levels of antigen-specific antibodies, interferon-gamma (IFN-gamma), or interleukin-2 (IL-2). Vaccination significantly reduced the bacterial burden and the degree of inflammation in the infected lungs and led to lower levels of IFN-gamma and IL-6. Furthermore, adoptive transfer of CD4+ splenocytes harvested from the vaccinated mice produced a significantly lower chlamydial load, indicating the importance of the cellular immune response. Therefore, the recombinant multi-epitope antigens may provide the basis for a new peptide-based vaccine against C. psittaci infection. PMID- 30467707 TI - Revisional Roux-en-Y Gastric Bypass: a Safe Surgical Opportunity? Results of a Case-Matched Study. AB - OBJECTIVE: To evaluate the safety and efficacy of revisional Roux-en-Y gastric bypass (RYGB) after adjustable gastric banding (AGB) or sleeve gastrectomy (SG) compared with primary RYGB, in regard to early and late morbidity, weight, and resolution of obesity-related comorbidities. METHODS: The group of patients undergoing revisional RYGB was matched in a 1:1 ratio with control patient who underwent a primary RYGB, based on age, gender, American Society of Anesthesiologist (ASA) score, preoperative body mass index (BMI), and diabetes mellitus. Demographics, anthropometrics, preoperative work-up, and perioperative data were retrieved. RESULTS: One hundred fifteen patients (16 males and 99 females) with a mean age of 45.5 +/- 1.5 years underwent revisional RYGB following either LAGB in 82 patients (71.3%) or laparoscopic sleeve gastrectomy (LSG) in 33 patients (28.7%). There was no conversion and no mortality in either group. Revisional RYGB was associated with similar early (16.5 vs 15.6%, ns) and late (42.6% vs 32.2%, ns) morbidity rates with a mean follow-up of 25.3 +/- 16.6 months compared to primary laparoscopic Roux-en-Y gastric bypass. The revisional RYGB group had significantly less weight loss (mean %EWL 67.4 +/- 20.7 vs 72.7 +/ 22.9, p = 0.023 and mean %EBMI 68.1 +/- 22 vs 78.3 +/- 25.7, p = 0.01) at the time of 1 year. Improvement of comorbidities including hypertension (62.5 vs 70.5%; p > 0.05), diabetes (73.7 vs 79%; p > 0.05), and obstructive sleep apnea syndrome (100 vs 97%; p > 0.05) was similar. CONCLUSION: This large case-matched study suggests that conversion of SG or AGB to RYGB is feasible with early and late comparable morbidity in an accredited center; even weight results might be inferior. PMID- 30467708 TI - Prediction of Long-Term Diabetes Remission After RYGB, Sleeve Gastrectomy, and Adjustable Gastric Banding Using DiaRem and Advanced-DiaRem Scores. AB - PURPOSE: DiaRem is a clinical scoring system designed to predict diabetes remission (DR) 1-year post-Roux-en-Y gastric bypass (RYGB). We examined long-term (2- and 5-year) postoperative DR prediction by DiaRem and an advanced-DiaRem (Ad DiaRem) score following RYGB, sleeve gastrectomy (SG), and gastric banding (GB). METHODS: We accessed data from a computerized database of persons with type 2 diabetes and BMI >= 30 kg/m2 who underwent RYGB, SG, or GB, and determined DR status 2- and 5-year postoperative according to preoperative DiaRem and the Ad DiaRem calculated scores. RESULTS: Among 1459 patients with 5-year postoperative diabetes status data, 53.6% exhibited DR. For RYGB, Ad-DiaRem trended to exhibit mildly improved predictive capacity 5-year postoperatively compared to DiaRem: Areas under receiver operating characteristic [AUROC] curves were 0.85 (0.76 0.93) and 0.78 (0.69-0.88), respectively. The positive predictive values (PPVs) detecting > 80% of those achieving DR (i.e., sensitivity >= 0.8) were 78.2% and 73.2%, respectively, and higher Ad-DiaRem scores more consistently associated with decreased DR rates. Following SG, both scores had an AUROC of 0.82, but Ad DiaRem still had a higher PPV for predicting > 80% of those with 5-year postoperative DR (76.2% and 71.0%). Predictive capacity parameters were comparatively lower, for both scores, when considering DR 5-year post-GB (AUROC: 0.73 for both scores, PPV: 66.3% and 64.3%, respectively). CONCLUSIONS: Ad-DiaRem provides modest improvement compared to DiaRem in predicting long-term DR 5-years post-RYGB. Both scores similarly provide fair predictive capacity for 5-year postoperative DR after SG. PMID- 30467706 TI - Biological tissue sample preparation for time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging. AB - Time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging is an analytical technique rapidly expanding in use in biological studies. This technique is based on high spatial resolution (50-100 nm), high surface sensitivity (1-2 nm top-layer), and statistical analytic power. In mass spectrometry imaging (MSI), sample preparation is a crucial step to maintaining the natural state of the biomolecules and providing accurate spatial information. However, a number of problems associated with temperature changes in tissue samples such as loss of original distribution due to undesired molecular migration during the sample preparation or reduced ionization efficiency make it difficult to accurately perform MSI. Although frozen hydrate analysis is the ideal sample preparation method to eliminate the effects of temperature, this approach is hindered by mechanical limitations. Alternatively, an adhesive-tape supported mounting and freeze-drying preparation has been proposed. This paper provides a concise review of the sample preparation procedures, a review of current issues, and proposes efficacious solutions for ToF-SIMS imaging in biological research. PMID- 30467709 TI - Relationships of endocrine cells to each other and to other cell types in the human gastric fundus and corpus. AB - Gastric endocrine cell hormones contribute to the control of the stomach and to signalling to the brain. In other gut regions, enteroendocrine cells (EECs) exhibit extensive patterns of colocalisation of hormones. In the current study, we characterise EECs in the human gastric fundus and corpus. We utilise immunohistochemistry to investigate EECs with antibodies to ghrelin, serotonin (5 HT), somatostatin, peptide YY (PYY), glucagon-like peptide 1, calbindin, gastrin and pancreastatin, the latter as a marker of enterochromaffin-like (ECL) cells. EECs were mainly located in regions of the gastric glands populated by parietal cells. Gastrin cells were absent and PYY cells were very rare. Except for about 25% of 5-HT cells being a subpopulation of ECL cells marked by pancreastatin, colocalisation of hormones in gastric EECs was infrequent. Ghrelin cells were distributed throughout the fundus and corpus; most were basally located in the glands, often very close to parietal cells and were closed cells i.e., not in contact with the lumen. A small proportion had long processes located close to the base of the mucosal epithelium. The 5-HT cells were of at least three types: small, round, closed cells; cells with multiple, often very long, processes; and a subgroup of ECL cells. Processes were in contact with their surrounding cells, including parietal cells. Mast cells had very weak or no 5-HT immunoreactivity. Somatostatin cells were a closed type with long processes. In conclusion, four major chemically defined EEC types occurred in the human oxyntic mucosa. Within each group were cells with distinct morphologies and relationships to other mucosal cells. PMID- 30467710 TI - Catestatin regulates vesicular quanta through modulation of cholinergic and peptidergic (PACAPergic) stimulation in PC12 cells. AB - We have previously shown that the chromogranin A (CgA)-derived peptide catestatin (CST: hCgA352-372) inhibits nicotine-induced secretion of catecholamines from the adrenal medulla and chromaffin cells. In the present study, we seek to determine whether CST regulates dense core (DC) vesicle (DCV) quanta (catecholamine and chromogranin/secretogranin proteins) during acute (0.5-h treatment) or chronic (24-h treatment) cholinergic (nicotine) or peptidergic (PACAP, pituitary adenylyl cyclase activating polypeptide) stimulation of PC12 cells. In acute experiments, we found that both nicotine (60 MUM) and PACAP (0.1 MUM) decreased intracellular norepinephrine (NE) content and increased 3H-NE secretion, with both effects markedly inhibited by co-treatment with CST (2 MUM). In chronic experiments, we found that nicotine and PACAP both reduced DCV and DC diameters and that this effect was likewise prevented by CST. Nicotine or CST alone increased expression of CgA protein and together elicited an additional increase in CgA protein, implying that nicotine and CST utilize separate signaling pathways to activate CgA expression. In contrast, PACAP increased expression of CgB and SgII proteins, with a further potentiation by CST. CST augmented the expression of tyrosine hydroxylase (TH) but did not increase intracellular NE levels, presumably due to its inability to cause post-translational activation of TH through serine phosphorylation. Co-treatment of CST with nicotine or PACAP increased quantal size, plausibly due to increased synthesis of CgA, CgB and SgII by CST. We conclude that CST regulates DCV quanta by acutely inhibiting catecholamine secretion and chronically increasing expression of CgA after nicotinic stimulation and CgB and SgII after PACAPergic stimulation. PMID- 30467711 TI - Effect of an Educational Video to Increase Calls and Screening into an Anal Cancer Clinical Trial Among HIV+ Hispanics in PR: Results from a Randomized Controlled Behavioral Trial. AB - Anal cancer incidence is higher in persons living with HIV/AIDS (PLWHA) than in the general population. Participation of PLWHA in anal cancer clinical trials (CTs) is essential; Hispanic PLWHA are underrepresented in CTs. We conducted a behavioral CT among 305 PLWHA in Puerto Rico to measure the efficacy of an educational video in increasing calls and screening into an anal cancer CT. Participants received printed educational materials on anal cancer and CTs; the intervention group also received an educational video. Outcome assessment based on follow-up interviews showed that printed materials increased awareness about CTs and high-resolution anoscopy (HRA), and willingness to participate in an anal cancer CT in both groups. However, the addition of the video increased the likelihood of participants to call the CT for orientation (RRadjusted = 1.66, 95% CI 1.00-2.76; p = 0.05) and pre-screening evaluation (RRadjusted = 1.70, 95% CI 0.95-3.03; p = 0.07). This intervention could help increase participation of Hispanics into anal cancer-related CTs. PMID- 30467712 TI - Unintended Pregnancy in Women Living with HIV in Sub-Saharan Africa: A Systematic Review and Meta-analysis. AB - In 2014, about 1.5 million pregnancies occurred among HIV-positive women in low and middle-income countries. To pool magnitude and factors associated with unintended pregnancy in women living with HIV in sub-Saharan Africa, a systematic search of electronic databases was undertaken in November 2016. Pooling the magnitude of unintended pregnancy reported by 14 studies yielded a crude summary prevalence of 55.9%. The magnitude of unwanted pregnancy and mistimed pregnancy in six studies ranged from 14 to 59 and 9 to 47.2%, respectively. Contraceptive failure was an important factor for many unintended pregnancies. The magnitude of unintended pregnancy was significantly higher in HIV-positive women than for HIV negative women in three out of six studies. The available evidence suggests that there is a high magnitude of unintended pregnancy in this population. Improving effective contraceptive utilization is thus a priority to address unintended pregnancies and to prevent mother to child transmission of HIV. PROSPERO Number: CRD42016051310. PMID- 30467713 TI - Gut and Whole-Body Microbiota of the Honey Bee Separate Thriving and Non-thriving Hives. AB - The recent worldwide decline of honey bee colonies is a major ecological problem which also threatens pollinated crop production. Several interacting stressors such as environmental pressures and pathogens are suspected. Recently, the gut microbiota has emerged as a critical factor affecting bee health and fitness. We profiled the bacterial communities associated with the gut and whole body of worker bees to assess whether non-thriving colonies could be separated from thriving hives based on their microbial signature. The microbiota of thriving colonies was characterised by higher diversity and higher relative abundance of bacterial taxa involved in sugar degradation that were previously associated with healthy bees (e.g. Commensalibacter sp. and Bartonella apis). In contrast, the microbiota of non-thriving bees was depleted in health-associated species (e.g. Lactobacillus apis), and bacterial taxa associated with disease states (e.g. Gilliamella apicola) and pollen degradation (e.g. G. apicola and Bifidobacterium asteroides) were present in higher abundance compared to thriving colonies. Gut and whole-body microbiota shared a similar dominant core but their comparison showed differences in composition and relative abundance. More differences in taxon relative abundance between gut and whole body were observed in non-thriving bees, suggesting that microbiota associated with other bee organs might also be different. Thus, microbiota profiling could be used as a diagnostic tool in beekeeping practices to predict hive health and guide hive management. PMID- 30467714 TI - The Influence of Habitat and Phylogeny on the Skin Microbiome of Amphibians in Guatemala and Mexico. AB - Microbial symbionts are increasingly recognized as playing a critical role in organismal health across a wide range of hosts. Amphibians are unique hosts in that their skin helps to regulate the exchange of water, ions, and gases, and it plays an active role in defense against pathogens through the synthesis of anti microbial peptides. The microbiome of amphibian skin includes a diverse community of bacteria known to defend against pathogens, including the global pandemic lineage of Batrachochytrium dendrobatidis associated with mass amphibian die offs. The relative influence of host phylogeny and environment in determining the composition of the amphibian skin microbiome remains poorly understood. We collected skin swabs from montane amphibians in Mexico and Guatemala, focusing on two genera of plethodontid salamanders and one genus of frogs. We used high throughput sequencing to characterize the skin bacterial microbiome and tested the impact of phylogeny and habitat on bacterial diversity. Our results show that phylogenetic history strongly influences the diversity and community structure of the total bacterial microbiome at higher taxonomic levels (between orders), but on lower scales (within genera and species), the effect of habitat predominates. These results add to a growing consensus that habitat exerts a strong effect on microbiome structure and composition, particularly at shallow phylogenetic scales. PMID- 30467715 TI - Soil Properties and Multi-Pollution Affect Taxonomic and Functional Bacterial Diversity in a Range of French Soils Displaying an Anthropisation Gradient. AB - The intensive industrial activities of the twentieth century have left behind highly contaminated wasteland soils. It is well known that soil parameters and the presence of pollutants shape microbial communities. But in such industrial waste sites, the soil multi-contamination with organic (polycyclic aromatic hydrocarbons, PAH) and metallic (Zn, Pb, Cd) pollutants and long-term exposure may induce a selection pressure on microbial communities that may modify soil functioning. The aim of our study was to evaluate the impact of long-term multi contamination and soil characteristics on bacterial taxonomic and functional diversity as related to the carbon cycle. We worked on 10 soils from northeast of France distributed into three groups (low anthropised controls, slag heaps, and settling ponds) based on their physico-chemical properties (texture, C, N) and pollution level. We assessed bacterial taxonomic diversity by 16S rDNA Illumina sequencing, and functional diversity using Biolog(r) and MicroRespTM microtiter plate tools. Although taxonomic diversity at the phylum level was not different among the soil groups, many operational taxonomic units were influenced by metal or PAH pollution, and by soil texture and total nitrogen content. Functional diversity was not influenced by PAH contamination while metal pollution selected microbial communities with reduced metabolic functional diversity but more tolerant to zinc. Limited microbial utilisation of carbon substrates in metal polluted soils was mainly due to the nitrogen content. Based on these two observations, we hypothesised that reduced microbial activity and lower carbon cycle-related functional diversity may have contributed to the accumulation of organic matter in the soils that exhibited the highest levels of metal pollution. PMID- 30467716 TI - Co-evolution of spliceosomal disassembly interologs: crowning J-protein component with moonlighting RNA-binding activity. AB - Spliceosome disassembly is catalyzed by the NineTeen-related (NTR) complex, which is constituted by several proteins, including Cwc23, Ntr1, and Ppr43. Cwc23 is an essential J-protein in Saccharomyces cerevisiae that recruits Ntr1, an NTC related G-patch protein, to the spliceosome. Ntr1 interacts with Prp43, a DExD/H box RNA helicase protein, which facilitates the disassembly of spliceosomal intermediates. The interaction between Ntr1 and Prp43 is conserved and crucial for the disassembly process. However, the J-protein component of this complex is not studied in other eukaryotes. In silico analysis supported by results of yeast complementation and two-hybrid studies suggests that while Prp43 is highly conserved, both Ntr1 and Cwc23 are co-evolving components of the disassembly triad. The J-domain of Cwc23, which is otherwise dispensable for its function, is highly conserved, whereas the functionally critical C-terminus has significantly diverged in Cwc23 orthologs. Some eukaryotic orthologs of Cwc23 contain a distinct RNA recognition motif at their C-terminus and are able to bind RNA in vitro. Based on the results presented in this study, we propose that RNA-binding activity in some eukaryotic orthologs of Cwc23 might provide additional functional diversity or robustness to the J-protein/Hsp70 machine in spliceosomal remodelling processes. PMID- 30467717 TI - DDR Inc., one business, two associates. AB - Eukaryotic cells activate cell cycle checkpoints in response to DNA damage. In Saccharomyces cerevisiae, the DNA damage response is achieved by the activation of the sensor kinases Mec1 and Tel1 and transmitted to the effector kinase Rad53. Rad9 and Mrc1 are thought to differentially mediate the activation of Rad53 depending on the cell cycle phase. Rad9 can respond to DNA lesions throughout the cell cycle, whereas Mrc1 responds to replication impediments in S phase. It was not clear if Rad9 and Mrc1 were triggering the same response to DNA damage occurring in S phase. By carefully studying the kinetics of activation of Rad53 by different types of replication stresses, we recently showed that Rad9 and Mrc1 cooperate in time and space to trigger a unique response to DNA damage in S phase. This primarily includes the control of both DNA replication initiation and elongation. After showing that Rad9 plays a preponderant role during S phase, the data presented here provocatively suggest that Mrc1 could also mediate the activation of Rad53 outside of S phase. PMID- 30467718 TI - Laparoscopic versus open distal pancreatectomy for benign and low-grade malignant lesions of the pancreas: a single-center comparative study. AB - PURPOSE: The purpose of the study was to compare the outcomes of laparoscopic distal pancreatectomy (LDP) and open distal pancreatectomy (ODP) for benign and low-grade malignant lesions to determine the safety and efficacy of LDP. METHODS: This retrospective comparative study included 67 consecutive patients who underwent LDP (n = 32) and ODP (n = 35) for benign or low-grade malignant lesions of the pancreas from January 2012 to March 2017. Thirty-five patients who were eligible for LDP in the ODP group were carefully selected. The clinical outcomes were compared in an intention-to-treat analysis. RESULTS: LDP was associated with significantly less operative blood loss (182 +/- 232 vs. 505 +/- 376 ml, P < 0.001) but a longer operation time (327 +/- 89 vs. 173 +/- 48 min, P < 0.001), than ODP. There were no significant differences between the 2 groups in the overall morbidity rates defined by Clavien-Dindo classification >= grade II (13% vs. 11%), clinically relevant postoperative pancreatic fistula rates (6% vs. 9%), and lengths of postoperative hospital stay (11 vs. 11 days). CONCLUSION: The study showed that LDP was safe and feasible. LDP should be considered as the first-line treatment for benign and low-grade malignant lesions in the left side of the pancreas. PMID- 30467719 TI - Preoperative lymph node status on computed tomography influences the survival of pT1b, T2 and T3 esophageal squamous cell carcinoma. AB - PURPOSE: The preoperative lymph node status is critical for tailoring optimal treatments for esophageal squamous cell carcinoma (ESCC). This study aimed to evaluate the prognostic impact of a diagnostic criterion based solely on the short-axis diameters of lymph nodes depicted on computed tomography (CT) in ESCC patients undergoing upfront esophagectomy. METHODS: We retrospectively reviewed 246 pT1b-T3 ESCC patients undergoing upfront esophagectomy. Clinically positive lymph node metastasis (cN+) was defined as nodes with a short-axis diameter of at least 8 mm on CT. RESULTS: Ninety-three patients had a cN+ status according to this criterion. The overall and recurrence-free survival rates were significantly lower in the cN+ group than in the cN- group (P < 0.001). The overall survival rate was markedly lower in the "pN2/3 and cN+" group than in the other groups (vs. pN0: P < 0.001, vs. pN1: P = 0.002, vs. "pN2/3 and cN-": P < 0.001). However, the overall survival rate of the "pN2/3 and cN-" group was similar to that of the pN0-1 groups. A multivariate analysis showed that cN+ (P = 0.002), major complications (P = 0.001), and pT3 (P = 0.021) were independently associated with a poor prognosis. CONCLUSION: A diagnostic criterion based solely on the short-axis diameters of lymph nodes depicted on CT was useful for stratifying the survival in ESCC patients. PMID- 30467720 TI - "Flip-flop enhancement" in renal infarction. PMID- 30467721 TI - The "linguine" sign. PMID- 30467722 TI - Quantification of fat deposition in the testis and epididymis using mDIXON Quant sequence: correlation with age and ejaculation. AB - PURPOSE: The objective of this study was to quantitatively assess fat deposition in the testis and epididymis by measuring the fat/water signal ratios with mDIXON Quant and to investigate its correlation with age and ejaculation. MATERIALS AND METHODS: Routine pelvic magnetic resonance imaging and mDIXON Quant were performed on 120 subjects. The fat/water signal ratios of the testis and epididymis were measured based on the fat/water signal intensity on mDIXON Quant. RESULTS: The fat/water signal ratio values of the testis and epididymis in the early adulthood group (0.952-3.550%, p < 0.05, and 5.182-12.725%, p < 0.05, respectively) were significantly higher than those in the late childhood group (0.611-2.198% and 1.310-4.520%) and in the youth group (0.659-2.360% and 1.568 4.469%), and they were lower than those in the middle adulthood group (1.538 4.249%, p < 0.05, and 5.830-19.002%, p < 0.05). The fat deposition decreased in the testis of the youth group, who ejaculated more than ten times per month (0.750-2.022%, p < 0.05), and the fat/water signal ratios of the epididymis decreased in one subject in the early adulthood group who had three ejaculations within 12 h. CONCLUSION: The findings of this study suggest that mDIXON Quant may be useful as a noninvasive, quantitative, and objective method for evaluating the fat deposition of the testis and epididymis. This method can provide guidance for fat deposition in the testis and epididymis in different age groups with varying ejaculation experiences. Additionally, our findings may facilitate more accurate diagnosis and monitoring of the reproductive function of the testis and epididymis by quantitatively measuring their fat deposition with age. PMID- 30467723 TI - Early response evaluation of neoadjuvant therapy with PET/MRI to predict resectability in patients with adenocarcinoma of the esophagogastric junction. AB - STUDY DESIGN AND PURPOSE: Positron emission tomography (PET)/magnetic resonance imaging (MRI) is a new modality that has showed promising results for various clinical indications. Currently, evaluation of neoadjuvant therapy (NT) among patients with adenocarcinoma of the esophagogastric junction has primarily been reserved for PET/computed tomography. Our aim was to evaluate if early response evaluation by PET/MRI is a feasible method to predict resectability. METHODS AND MATERIALS: Patients with untreated adenocarcinoma of the esophagogastric junction (Siewert types I/II) and fit for NT with no contraindications for PET/MRI were considered eligible. A baseline scan was performed prior to NT induction and an evaluation scan 3 weeks later. For histopathological response evaluation, the Mandard tumor regression grade score was applied. Response on PET/MRI was evaluated with Response Evaluation Criteria in Solid Tumors (RECIST 1.1), and change in ADC and SUVmax values. RESULTS: Twenty-eight patients were enrolled, and 22 completed both scans and proceeded to final analyses. Seventeen patients were found resectable versus five who were found unresectable. PET/MRI response evaluation had a sensitivity 94%, specificity 80%, and AUC = 0.95 when predicting resectability in patients with adenocarcinoma of the esophagogastric junction. No association with histopathological response (tumor regression grade) was found nor was RECIST correlated with resectability. CONCLUSION: Response evaluation using PET/MRI was a feasible method to predict resectability in patients with adenocarcinoma of the esophagogastric junction in this pilot study. However, larger studies are warranted to justify the use of the modality for this indication. PMID- 30467724 TI - Multimodality imaging of the Meso-Rex bypass. AB - Extrahepatic portal vein obstruction (EHPVO) is the most common cause of upper gastrointestinal bleeding in children. It is defined as thrombosis of the extrahepatic portal vein with or without extension to the intrahepatic portal veins. The Meso-Rex shunt is the gold standard treatment in children with favorable anatomy since it restores physiological portal liver reperfusion. This is achieved by rerouting the splanchnic venous blood through an autologous graft from the superior mesenteric vein (SMV) into the Rex recess of the left portal vein, curing portal hypertension by doing so. General and hepatobiliary radiologists must be familiar with multimodality imaging appearances of EHPVO and with the role of imaging in identifying suitable candidates for Meso-Rex bypass surgery. Imaging might also detect complications of this procedure, some of which might be treated via interventional radiology. PMID- 30467725 TI - Current and Future Treatment Options for Myelodysplastic Syndromes: More Than Hypomethylating Agents and Lenalidomide? AB - Myelodysplastic syndromes are a heterogeneous group of bone marrow disorders that result in cytopenias and a propensity to develop secondary leukemia. While allogeneic transplantation still remains the only potential curative treatment option, it can only be offered to a limited number of patients. For the majority, who are not transplant candidates, treatment strategies cover iron chelation, growth factors, lenalidomide, and hypomethylating agents to improve cytopenia and potentially delay disease progression. These limited options underpin the urgent need for more translational research-based clinical trials in well-defined subgroups of patients with myelodysplastic syndromes. Indeed, myelodysplastic syndromes are a moving target with maximum innovation in the understanding of the complex molecular pathways during the last decade. Compared with other hematological diseases such as myeloma, this has unfortunately not yet translated into approval of novel treatment options. Given the current developments in the field, we are optimistic that recent frustrations will be overcome shortly and this will pave the way for exciting opportunities, especially for patients not responding to first-line therapeutic options. PMID- 30467726 TI - Doxorubicin-Loaded PEG-CdTe Quantum Dots as a Smart Drug Delivery System for Extramedullary Multiple Myeloma Treatment. AB - New drug treatments still do not improve the prognosis of extramedullary multiple myeloma (EMM) patients. Luckily, high-dose chemotherapy can raise the prognosis, but is intolerant to most patients because of drug cytotoxicity. Nanoparticles (NPs) are used as drug carriers to prolong drug circulation time, control drug release, reduce drug toxicity and bioavailability, and target specific sites. In this work, doxorubicin (DOX) was loaded in polyethylene glycol-modified cadmium telluride quantum dots (PEG-CdTe QDs). PEG-CdTe-DOX facilitated intracellular drug accumulation through polyethylene organizational compatibility and released DOX into the microenvironment in a pH-controlled manner, which enhanced the therapeutic efficacy and the apoptosis rate of myeloma cells (PRMI8226). PEG-CdTe DOX improved the anti-tumor activity of DOX by regulating the protein expressions of apoptosis-associated genes. In summary, PEG-CdTe-DOX provides a specific and effective clinical treatment for EMM patients. PMID- 30467728 TI - Serum bilirubin concentrations, type 2 diabetes and incident coronary heart disease. PMID- 30467727 TI - Reply to comment: Serum bilirubin concentrations, type 2 diabetes, and incident coronary heart disease. PMID- 30467729 TI - Comparison of correlations of equation-derived body fat percentage and body mass index with carotid intima-media thickness. PMID- 30467731 TI - Sequential Treatment with Eldecalcitol After PTH Improves Bone Mechanical Properties of Lumbar Spine and Femur in Aged Ovariectomized Rats. AB - Parathyroid hormone (PTH) analogs have a powerful anabolic effect on bone and are used in the treatment of patients with severe osteoporosis. However, there are limitations to how long they can be safely administered. Withdrawal of PTH results in the cancelation of its effects, necessitating subsequent treatment to maintain the bone quantity and quality. This study assessed the effects of Eldecalcitol (ELD), an active vitamin D3 derivative, after PTH in estrogen deficient osteoporotic rats. Six-month-old female rats were ovariectomized, and PTH administration was started 7 weeks later. After 4 weeks of PTH treatment, the animals were divided into three groups and either continued to receive PTH (PTH PTH), or were switched to ELD (PTH-ELD) or vehicle (PTH-Veh) for an additional 4 weeks. In the femur, increased BMD by 4 weeks treatment of PTH was significantly reduced in PTH-Veh but not in PTH-PTH and PTH-ELD. The same tendency was observed in the lumbar vertebrae. MicroCT imaging and histomorphometry analysis revealed that the favorable bone structure changes by PTH administration were also maintained in the femurs and tibias of the PTH-PTH and PTH-ELD groups. Increased bone strength by 4-week treatment of PTH in lumber also maintained in PTH-ELD. Furthermore, minimodeling was observed in the PTH-ELD group. These results demonstrate that treatment with ELD sequentially following PTH prevented the bone quantity and strength reduction that accompanies PTH withdrawal in estrogen deficient rats. PMID- 30467732 TI - Comment on: "Does MCDA Trump CEA?" PMID- 30467730 TI - Expression and regulation of phenol-soluble modulins and enterotoxins in foodborne Staphylococcus aureus. AB - Although high levels of staphylococcal phenol-soluble modulins (PSMs) in clinical methicillin-resistant Staphylococcus aureus (MRSA) has been shown to correlate with bacterial virulence, the PSMs expression in foodborne Staphylococcus aureus (S. aureus), as well as its association with staphylococcal food poisoning (SFP) was not yet clear. We collected a panel of 350 foodborne and 127 clinic-derived S. aureus strains and compared their PSMs expression. Overall, foodborne strains exhibited higher PSMs than clinical isolates, indicating a potential pathological significance of PSMs in staphylococcal food contamination. Furthermore, PSMs expression and staphylococcal enterotoxins (SEs) levels in relation to antibiotic sensitive and resistant strains were analysed. While the co-expression of PSMs and SEs was confirmed, one typical foodborne strain simultaneously yielding PSMs, SEB and SED was selected. By comparing this wildtype strain to a series of gene deficient mutants, we concluded that PSMs and SEs expressions both relied on staphylococcal accessory regulator A initiation in the early stage of accessory gene regulator control, yet their succedent regulations differentiated to RNAIII dependent and independent, respectively. These data provided preliminary insight into PSMs and SEs expression in foodborne S. aureus, and may guide the further studies on PSMs effects in SFP. PMID- 30467734 TI - Treatment of small and medium-sized vestibular schwannoma-a need for better evidence. PMID- 30467733 TI - Impact of functional inorganic nanotubes f-INTs-WS2 on hemolysis, platelet function and coagulation. AB - Inorganic transition metal dichalcogenide nanostructures are interesting for several biomedical applications such as coating for medical devices (e.g. endodontic files, catheter stents) and reinforcement of scaffolds for tissue engineering. However, their impact on human blood is unknown. A unique nanomaterial surface-engineering chemical methodology was used to fabricate functional polyacidic polyCOOH inorganic nanotubes of tungsten disulfide towards covalent binding of any desired molecule/organic species via chemical activation/reactivity of this former polyCOOH shell. The impact of these nanotubes on hemolysis, platelet aggregation and blood coagulation has been assessed using spectrophotometric measurement, light transmission aggregometry and thrombin generation assays. The functionalized nanotubes do not induce hemolysis but decrease platelet aggregation and induce coagulation through intrinsic pathway activation. The functional nanotubes were found to be more thrombogenic than the non-functional ones, suggesting lower hemocompatibility and increased thrombotic risk with functionalized tungsten disulfide nanotubes. These functionalized nanotubes should be used with caution in blood-contacting devices. PMID- 30467735 TI - Development and validation of a TaqMan RT-PCR method for identification of mayonnaise spoilage yeast Pichia kudriavzevii. AB - Food spoilage and its contamination with yeast and mold is a serious problem of food industry. Despite the high fat content, mayonnaise is an attractive substrate for food spoilage microorganisms. The aim of this study was to develop a method for yeast identification in mayonnaise and to test commercially available mayonnaises for the presence of these contaminating microorganisms. Based on the sequencing of intergenic regions ITS1 and ITS2, we identified a yeast microorganism that causes mayonnaise spoilage. We found that DNA sequences were more than 99% identical to the GenBank DNA sequences from Pichia kudriavzevii. We developed a specific to P. kudriavzevii TaqMan probe and primers. The reaction conditions were optimized regarding to the components concentration and temperature cycle. The minimum amount of P. kudriavzevii DNA that could be detected by developed method was 50 fg. The minimal number of P. kudriavzevii cells that could be detected by developed method without pre enrichment was 50. We tested verified method with DNAs from microorganisms of different taxonomic groups that were obtained from three collections of microorganisms. Finally, we analyzed 20 different brands of mayonnaise from 14 producers and 10 different brands of mayonnaise sauce from seven producers. We determined the Cq parameter that characterizes transition of the fluorescence curve to the logarithmic phase and, therefore, correlates with the extent of sample contamination with P. kudriavzevii yeast. P. kudriavzevii was detected in six analyzed samples of mayonnaise and one sample of mayonnaise sauce. PMID- 30467736 TI - Potential intraoperative factors of screw-related complications following posterior transarticular C1-C2 fixation: a systematic review and meta-analysis. AB - PURPOSE: This study aimed to evaluate the impact of several factors, including patients' intraoperative position, intraoperative visualization technique, fixation method, and type of screws and their parameters, on the frequency of intraoperative screw-associated complications in posterior transarticular C1-C2 fixation. METHODS: A systematic review of the PubMed database between January 1986 and March 2018 was performed. The key inclusion criteria comprised detailed descriptions of the surgical technique and post-operative screw-associated complications. RESULTS: The initial search resulted in 1041 abstracts, and a total of 54 abstracts were included in the present study. The overall number of operated patients was 2306. In this group, 4439 screws were inserted. The rate of screw-associated complications during the different time periods was estimated upon meta-analysis. Statistical analysis of the screw malposition rate, vertebral artery injury rate, screw breakage rate based on patients' intraoperative position, intraoperative visualization technique, fixation method, and type of implants and their parameters was also performed. CONCLUSIONS: The factors that help reduce the rate of screw-associated complications include the intraoperative application of biplanar fluoroscopy or neuronavigation system, the use of 4 mm or thicker lag screws, and screw insertion through contraincisions using cannulated ported instruments. On the other hand, the potential risk factors of screw associated complications include inadequate intraoperative head fixation using skeletal traction, uniplanar fluoroscopy-guided screw insertion, screw insertion using the posterior midline approach, and the use of 3.5 mm or thinner full threaded screws. These slides can be retrieved under Electronic Supplementary Material. PMID- 30467737 TI - Correction to: Clinical significance of intratumoral HER2 heterogeneity on trastuzumab efficacy using endoscopic biopsy specimens in patients with advanced HER2 positive gastric cancer. AB - In the original publication of this article, Table 4 was published incorrectly. The correct Table 4 is given below. PMID- 30467738 TI - Comprehensive cancer control in the US: 20 years of progress. PMID- 30467739 TI - Barriers and facilitators to implementing an urban co-responding police-mental health team. AB - BACKGROUND: In an effort to reduce the increasing number of persons with mental illness (PMI) experiencing incarceration, co-responding police-mental health teams are being utilized as a way to divert PMI from the criminal justice system. Co-response teams are typically an inter-agency collaboration between police and mental health professionals, and in some cases include emergency medical personnel. These teams are intended to facilitate emergency response by linking patients to mental health resources rather than the criminal justice system, thus reducing burdens on both the criminal justice systems as well as local healthcare systems. The current study examines the barriers and facilitators of successfully implementing the Mobile Crisis Assistance Team model, a first-responder co response team consisting of police officers, mental health professionals, and paramedics. Through content analysis of qualitative focus groups with team members and interviews with program stakeholders, this study expands previous findings by identifying additional professional cultural barriers and facilitators to program implementation while also exploring the role of clear, systematic policies and guidelines in program success. RESULTS: Findings demonstrate the value of having both flexible and formal policies and procedures to help guide program implementation; ample community resources and treatment services in order to successfully refer clients to needed services; and streamlined communication among participating agencies and the local healthcare community. A significant barrier to successful program implementation is that of role conflict and stigma. Indeed, members of the co-response teams experienced difficulty transitioning into their new roles and reported negative feedback from other first responders as well as from within their own agency. Initial agency collaboration, information sharing between agencies, and team building were also identified as facilitators to program implementation. CONCLUSION: The current study provides a critical foundation for the implementation of first-responder police-mental health co-response teams. Cultural and systematic barriers to co response team success should be understood prior to program creation and used to guide implementation. Furthermore, attention must be directed to cultivating community and professional support for co-response teams. Findings from this study can be used to guide future efforts to implement first-response co-response teams in order to positively engage PMI and divert PMI from the criminal justice system. PMID- 30467740 TI - Statistical-based database fingerprint: chemical space dependent representation of compound databases. AB - BACKGROUND: Simplified representation of compound databases has several applications in cheminformatics. Herein, we introduce an alternative and general method to build single fingerprint representations of compound databases. The approach is inspired on the previously published modal fingerprints that are aimed to capture the most significant bits of a fingerprint representation for a compound data set. The novelty of the herein proposed statistical-based database fingerprint (SB-DFP) is that it is generated based on binomial proportions comparisons taking as reference the distribution of "1" bits on a large representative set of the chemical space. RESULTS: To illustrate the Method, SB DFPs were constructed for 28 epigenetic target data sets retrieved from a recently published epigenomics database of interest in probe and drug discovery. For each target data set, the SB-DFPs were built based on two representative fingerprints of different design using as reference a data set with more than 15 million compounds from ZINC. The application of SB-DFP was illustrated and compared to other methods through association relationships of the 28 epigenetic data sets and similarity searching. It was found that SB-DFPs captured overall, the common features between data sets and the distinct features of each set. In similarity searching SB-DFP equaled or outperformed other approaches for at least 20 out of the 28 sets. CONCLUSIONS: SB-DFP is a general approach based on binomial proportion comparisons to represent a compound data set with a single fingerprint. SB-DFP can be developed, at least in principle, based on any fingerprint and reference data set. SB-DFP is a good alternative for exploration of relationships between targets through its associated compound data sets and performing similarity searching. PMID- 30467741 TI - Correction to: A study on the role of articular cartilage soft tissue constitutive form in models of whole knee biomechanics. AB - Based on a reader comment, it has become clear that, in the originally published version of the article, Fig. 1 was published with incorrect anatomical labels. PMID- 30467742 TI - Pharmacokinetic and Pharmacodynamic Modeling to Optimize the Dose of Vestronidase Alfa, an Enzyme Replacement Therapy for Treatment of Patients with Mucopolysaccharidosis Type VII: Results from Three Trials. AB - INTRODUCTION: Mucopolysaccharidosis type VII (MPS VII, Sly Syndrome) is a progressive, debilitating, ultra-rare lysosomal storage disorder caused by the deficiency of beta-glucuronidase (GUS), an enzyme required for breakdown of glycosaminoglycans (GAGs). Vestronidase alfa, a recombinant human GUS, is an enzyme replacement therapy approved in the US and EU for the treatment of MPS VII. METHODS: The pharmacokinetics (PK) and pharmacodynamics (PD) of vestronidase alfa were evaluated in 23 adult and pediatric subjects with MPS VII enrolled in phase I-III clinical trials to optimize the clinical dosing regimen of vestronidase alfa. The serum concentration-time profiles were adequately described by a two-compartment population PK model incorporating subjects' body weight as the only significant covariate. RESULTS: Model-based simulations predicted a substantially decreased time duration of serum exposures exceeding the level of Kuptake (the in vitro determined vestronidase alfa concentration corresponding to 50% maximum rate of cellular uptake) for 4 or 8 mg/kg once every 4 weeks dosing, compared with 4 mg/kg once every other week (QOW) dosing by intravenous infusion, suggesting that given the same total monthly dose, the QOW dosing frequency should result in more efficient delivery to the GUS-deficient tissue cells, and therefore superior treatment efficacy. A standard inhibitory maximal effect model reasonably explained the observed pharmacological PD responses of reduction in urinary GAGs from pretreatment baseline, which appeared to have reached the plateau of maximal effect at the 4 mg/kg QOW dose. CONCLUSION: The modeling results, together with the clinical evidence of safety and efficacy, supported the recommended 4 mg/kg QOW dosing regimen of vestronidase alfa for pediatric and adult patients with MPS VII. CLINICAL TRIAL REGISTRATION: NCT01856218, NCT02418455, NCT02230566. PMID- 30467743 TI - fMRI data processing in MRTOOL: to what extent does anatomical registration affect the reliability of functional results? AB - Spatial registration is an essential step in the analysis of fMRI data because it enables between-subject analyses of brain activity, measured either during task performance or in the resting state. In this study, we investigated how anatomical registration with MRTOOL affects the reliability of task-related fMRI activity. We used as a benchmark the results from two other spatial registration methods implemented in SPM12: the Unified Segmentation algorithm and the DARTEL toolbox. Structural alignment accuracy and the impact on functional activation maps were assessed with high-resolution T1-weighted images and a set of task related functional volumes acquired in 10 healthy volunteers. Our findings confirmed that anatomical registration is a crucial step in fMRI data processing, contributing significantly to the total inter-subject variance of the activation maps. MRTOOL and DARTEL provided greater registration accuracy than Unified Segmentation. Although DARTEL had superior gray matter and white matter tissue alignment than MRTOOL, there were no significant differences between DARTEL and MRTOOL in test-retest reliability. Likewise, we found only limited differences in BOLD activation morphology between MRTOOL and DARTEL. The test-retest reliability of task-related responses was comparable between MRTOOL and DARTEL, and both proved superior to Unified Segmentation. We conclude that MRTOOL, which is suitable for single-subject processing of structural and functional MR images, is a valid alternative to other SPM12-based approaches that are intended for group analysis. MRTOOL now includes a normalization module for fMRI data and is freely available to the scientific community. PMID- 30467744 TI - Regulatory and Health Technology Assessment Considerations for Disease-Modifying Drugs in Alzheimer's Disease. AB - Although there are a growing number of well-reported, late-stage clinical trial failures in Alzheimer's disease, the introduction of a disease-modifying therapy within the next 5 years may be anticipated. These treatments are likely to target Alzheimer's disease in the earlier disease stages, unlike drugs that are currently available that treat symptoms of moderate-to-severe dementia. Therefore, there is a need to establish a consensus on regulatory and health technology assessment requirements for Alzheimer's disease, as a new drug will need to undergo regulatory and health technology assessments before it becomes available to patients. This article reports the discussions and activities of the regulatory and health technology assessment expert advisory group of the 2-year ROADMAP (real-world outcomes across the Alzheimer's disease spectrum: a multimodal data access platform) project. The expert advisory group discussions identified a lack of consensus on validated outcomes in the earliest Alzheimer's disease stages, the need for filling gaps between outcomes used across clinical trials and real-world settings, and the role that real-world evidence might have in characterising the impact of a possible disease-modifying therapy on caregivers, resource use and long-term outcomes. PMID- 30467745 TI - Computational investigations on the HO2 + CHBr2O2 reaction: mechanisms, products, and atmospheric implications. AB - Using quantum chemistry methods, mechanisms and products of the CHBr2O2 + HO2 reaction in the atmosphere were investigated theoretically. Computational result indicates that the dominant product is CHBr2OOH + O2 formed on the triplet potential energy surface (PES). While CBr2O + OH + HO2 produced on the singlet PES is subdominant to the overall reaction under the typical atmospheric condition below 300 K. Due to higher energy barriers surmounted, other products including CBr2O2 + H2O2, CBr2O + HO3H, CH2O + HO3Br, CHBrO + HO3 + Br, and CHBr2OH + O3 make minor contributions to the overall reaction. In the presence of OH radical, CHBr2OOH generates CHBr2O2 and CBr2O2 + H2O subsequently, which enters into new Br-cycle in the atmosphere. The substitution effect of alkyl group and halogens plays negligible roles to the dominant products in the RO2 + HO2 (X = H, CH3, CH2OH, CH2F, CH2Cl, CH2Br, CH2Cl, and CH2Br) reactions in the atmosphere. PMID- 30467746 TI - The impact of livestock farming activity on the quality of surface water. AB - The most dangerous pollution sources are intensive agricultural activity and livestock farming, whose production waste has a negative impact on soil and water quality. Livestock farming is separated into two systems: indoor (pigs and poultry) and pasture-based (livestock and sheep). Numerous studies aimed at elucidating how different systems affect the environment have been performed. In Lithuania, the biggest environmental problems are caused by 24 farms with more than 5000 pigs, 21 poultry farm with more than 1000 chickens, 2179 cow-cattle farms larger than 50 places, and about 200,000 sheep. We aimed to assess the quality of surface water in the Kaunas region next to the pig and livestock farms. In 2008-2017, seven livestock agricultural companies and seven larger farmers were regarded as potential sources of pollution in the Kaunas region. Half of these sources were pig farms, and the rest were livestock farms. Locations next to potential agricultural pollution sources were chosen to monitor the surface water. The results indicated that although the agricultural areas, number of livestock units, and nitrogen rate per 1 ha were similar between the pig and livestock farms, the activity on the pig farms affected the surface water quality more than that on livestock farms. As the number of livestock units (LU) increased on the farms, the pH decreased and the suspended materials, nitrates, and phosphates increased in the surface water. With increasing nitrogen kg/ha, the pH values decreased, thereby yielding more acidic water. The intensity of agricultural activity did not affect the water quality near the livestock farms, except for livestock units (LU), which affected the pH. PMID- 30467747 TI - The modulatory role of low concentrations of bisphenol A on tamoxifen-induced proliferation and apoptosis in breast cancer cells. AB - Selective estrogen receptor modulators such as tamoxifen (TAM) significantly reduce the risks of developing estrogen receptor-positive (ER+) breast cancer. Low concentrations (nanomolar range) of bisphenol A (BPA) shows estrogenic effects and further promotes the proliferation of hormone-dependent breast cancer cells. However, whether or not BPA can influence TAM-treatment resistance in breast cancer has not drawn much attention. In the current study, low concentrations of BPA reduced TAM-induced cytotoxicity of MCF-7 cells, which was proved by the suppression of cell apoptosis, transition of cell cycle from G1 to S phase, and upregulation of cyclin D1 and ERalpha. Simultaneously, the mRNA levels of estrogen-related receptor gamma (ERRgamma) and its coactivators, peroxisome proliferation-activated receptor gamma coactivator-1alpha (PGC 1alpha), and PGC-1beta, were increased. However, the similar effects were not observed in MDA-MB-231 cells. Our results indicated that low concentrations of BPA decreased the sensitivity of TAM in MCF-7 cells rather than in MDA-MB-231 cells. These different actions likely involved the interaction of relative receptors and coactivators. This study provided a possible support that the exposure of BPA in environmental media may potentially induce TAM resistance to breast cancer treatment. PMID- 30467748 TI - Research on the nitrogen transformation in rhizosphere of winter wheat (Triticum aestivum) under molybdenum addition. AB - Molybdenum (Mo), an essential microelement for plants, animals, and microorganisms, is reported can reduce soil nitrogen (N) residues and regulate plant root growth, but little is known about its effect on soil N transformation in plant-root region. A specially designed rhizobox was used in the present study to investigate the N processes in rhizosphere and non-rhizosphere soils of winter wheat applied with different rates of Mo fertilizer. (1) In the rhizosphere soil, pH values increased with increasing rates of Mo application, nitrate (NO3--N) accumulated at the rates of 0.15 and 0.3 mg Mo kg-1, potential denitrification activity (PDA) was significantly reduced by application of 0.15-1 mg Mo kg-1, and the copy numbers of narG and nosZ genes were increased by application of 0.15-1 mg Mo kg-1. (2) In the non-rhizosphere soil, NO3--N content decreased by application of 0.15-0.3 mg Mo kg-1, and narG gene abundance increased obviously by application of 0.3-1 mg Mo kg-1. (3) Soil pH, NO3--N, apparent nitrification rate (ANR), and nosZ gene abundance were significantly higher in rhizosphere than in non-rhizosphere soil. On the contrary, NH4+-N and total N, PDA, the abundance of AOB, and nirK and nirS genes were significantly higher in non-rhizosphere soil. The results indicated that the N transformations in rhizosphere and non rhizosphere soils were differently affected by soil application of Mo fertilizer, and rhizosphere played a more important role in soil N cycle processes. The regulatory effects of Mo on these processes were to increase plant biomass and N uptake, promote the NO3--N accumulation in rhizosphere soil, and weaken the denitrification in both rhizosphere and non-rhizosphere soils. PMID- 30467749 TI - Polychlorinated biphenyl 126 exposure in rats alters skeletal muscle mitochondrial function. AB - In the past few years, polychlorinated biphenyls (PCBs), a class of environmental pollutants, have been associated with metabolism dysregulation. Muscle is one of the key regulators of metabolism because of its mass and its important role in terms of glucose consumption and glucose storage. It has been shown that muscle alterations, such as oxidative stress and mitochondrial dysfunction, contribute significantly to the development of metabolic diseases. No study has yet investigated the toxicological effect of PCBs on muscle mitochondrial function and oxidative stress in vivo. The aim of this study was to assess the effect of PCB126 in vivo exposure (single dose of 1.05 MUmol/kg) on muscle mitochondrial function and oxidative stress in rats. PCB126-treated rats showed a marked increase in Cyp1a1 mRNA levels in skeletal muscles in association with a 40% reduction in state 3 oxygen consumption rate measured with complex I substrates in permeabilized muscle fibers. Furthermore, PCB126 exposure altered the expression of some enzymes involved in ROS detoxification such as catalase and glutaredoxin 2. Our results highlight for the first time a toxic effect of coplanar PCBs on skeletal muscle mitochondrial function and oxidative stress. This suggests that acute PCB exposure, by affecting muscle metabolism, could contribute to the development of metabolic disorders. Studies are needed to determine if lower-level but longer-term PCB exposure exhibits the same effect. PMID- 30467750 TI - Efficient removal of ethidium bromide from aqueous solution by using DNA-loaded Fe3O4 nanoparticles. AB - Ethidium bromide (EtBr) is widely used as DNA-staining dyes for the detection of nucleic acids in laboratories and known to be powerful mutagens and carcinogens. In the present paper, the removal of EtBr from aqueous solutions in a batch system using DNA-loaded Fe3O4 nanoparticles as a simple and efficient method was investigated. DNA was covalently loaded on the surface of Fe3O4 magnetic nanoparticles, which was confirmed by FT-IR analysis and zeta potential measurements. The morphology and crystal structure were characterized by SEM, TEM, and XRD. The influence factors on the removal efficiency such as initial EtBr concentration, contact time, adsorbent dose, pH, and temperature were also studied. The removal process of EtBr can be completed quickly within 1 min. The removal efficiency was more than 99% while the EtBr concentration was routinely used (0.5 mg L-1) in biology laboratories and the dosages of nanoparticles were 1 g L-1. For the different EtBr concentrations from 0.5 to 10 mg L-1 in aqueous solution, the goal of optimized removal was achieved by adjusting the dosage of DNA-loaded Fe3O4 nanoparticles. The optimum pH was around 7 and the operational temperature from 4 to 35 degrees C was appropriate. Kinetic studies confirmed that the adsorption followed second-order reaction kinetics. Thermodynamic data revealed that the process was spontaneous and exothermic. The adsorption of EtBr on DNA-loaded Fe3O4 nanoparticles fitted well with the Freundlich isotherm model. These results indicated that DNA-loaded Fe3O4 nanoparticles are a promising adsorbent for highly efficient removal of EtBr from aqueous solution in practice. PMID- 30467751 TI - Outdoor air pollution pregnancy exposures are associated with behavioral problems in China's preschoolers. AB - There are mounting evidences indicated that maternal exposure to outdoor air pollutants in pregnancy affects children's neural development, but the researches on children's behavioral difficulties are seldom. We explored the association between maternal exposure to outdoor air pollution during different trimesters of pregnancy and the prevalence of behavioral difficulties among 657 preschool children aged 3-4 from three kindergartens in Wuhan, China. This is a cross sectional study. Children's behavioral difficulties were assessed by the Strengths and Difficulties Questionnaire (SDQ) (reported by parents). Maternal exposure to outdoor air pollutants during pregnancy were estimated based on the daily average measured concentration levels from ground monitoring stations. Potential confounding factors including children-related, maternal, and socio economic status (SES) were adjusted in the study. We calculated the prevalence of each type of behavioral difficulties and used binary logistic regression method to estimate the crude odds ratio (cOR), adjusted odds ratio (aOR), and corresponding 95% confidence intervals (95% CIs) for 1 MUg/m3 increase in each air pollutant during every exposure window in single- and two-pollutant models. The prevalence of participants' total behavioral difficulties was 9.6%. In single pollutant models, during full gestation, positive associations were observed between exposure to NO2 (aOR = 1.204, 95% CI 1.042, 1.392), particle matter (PM)10 (aOR = 1.070, 95% CI 1.018, 1.125), PM2.5 (aOR = 1.095, 95% CI 1.021, 1.176) and total difficulties, exposure to PM10 (aOR = 1.040, 95% CI 1.001, 1.081), PM2.5 (aOR = 1.053, 95% CI 1.000, 1.109) and prosocial behavior, respectively. In the first trimester, exposure to SO2 (aOR = 1.047, 95% CI 1.009, 1.086), NO2 (aOR = 1.039, 95% CI 1.013, 1.066), PM10 (aOR = 1.013, 95% CI 1.004, 1.023), and PM2.5 (aOR = 1.016, 95% CI 1.004, 1.028) were all positively associated with total difficulties. The associations between second and third trimesters' exposure to all pollutants and outcomes were not statistically significant. However, in the two-pollutant models, second trimester exposure to PM2.5 (aOR = 1.078, 95%CI 1.023, 1.137) was positively associated with total behavioral difficulties after adjusting for PM10. Exposure to outdoor air pollutants SO2, NO2, PM10, and PM2.5 during pregnancy may be associated with behavioral difficulties, especially in the first trimester. PMID- 30467752 TI - Endocrine disruption as an adverse effect of non-endocrine targeting pharmaceuticals. AB - Endocrine disruptors have gained widespread attention owing to their severe adverse health impacts. These produce enormous burden of disease and are associated with high economic cost especially in developed countries. Environmental pollutants causing endocrine disruption include pesticides, industrial wastes, packaging materials, food constituents, plastics, and cosmetic products. Likewise, pharmaceutical drugs have the endocrine disrupting potential through a wide array of mechanisms. Antipsychotic, antiepileptic, antihypertensive, antiviral, antidiabetic, and anticancer drugs are among the foremost non-hormonal endocrine disruptors. Several drugs affect thyroid hormone synthesis via interaction with iodine uptake to the release of T3 and T4 by thyrocytes. Prolonged use of some drugs increase susceptibility to diabetes mellitus either by direct destruction of beta cells or enhanced insulin resistance. Other drugs may cause serious developmental defects in male or female reproductive system. Appropriate understanding of the mechanisms of endocrine disruption associated with non-hormonal drugs will guide future drug development and help us prevent and cure endocrine-related toxicity of pharmaceuticals. Therefore, this review focuses on endocrine disruption by pharmaceutical drugs as their side effect. PMID- 30467753 TI - RR2 dye adsorption to Hymenaea courbaril L. bark activated carbon associated with biofilm. AB - This study addressed the removal performance of RR2 from aqueous solutions in adsorption columns experiments by comparing the potential of activated carbon alone (ACA) and microbially inoculated (MIAC), prepared from barks of a largely available tree in Brazilian Cerrado biome, Hymenaea courbaril L. or "Jatoba," presenting the kinetics, isotherms, breakthrough curves, and dissolved organic carbon removal. ACA presented strong interaction to RR2 dye, evidenced at the first 20 min when absorbance already attained 66.4%. The removal percentage gradually increased with time and the equilibrium occurred around 91.7% within 120 min. Langmuir model best fitted the isotherm data, indicating a maximum adsorption capacity of 4.068 mg g-1 for the amount of 0.5 g of adsorbent. The Langmuir's model parameters KL, RL, and R2 corresponded to 0.0234 L mg-1, 0.4159, and 0.9663, respectively, indicating a favorable adsorption process (0 < RL < 1). The experiments in adsorption columns revealed maximum adsorption capacities of 14.38 and 11.43 mg g-1 for MIAC and ACA, respectively, where the microbial activity favorably retarded the adsorption breakpoint in approximately 20 min and enhanced the RR2 consumption in 25.8%. Effectiveness of DOC removal attained above 90% for both ACA and MIAC, reducing the content from 86.1 to 7.84 mg L-1 and 4.82 mg L-1, respectively. PMID- 30467754 TI - The impact of morphology and size of zinc oxide nanoparticles on its toxicity to the freshwater microalga, Raphidocelis subcapitata. AB - Microalgae are key test organisms to assess the effects of chemicals on aquatic ecosystems. Zinc oxide nanoparticles (ZnO NPs) as a widely used metal oxide is considered a potential threat to these primary producers at the base of the food chain. This study investigates the toxicity of ZnO NPs, bulk ZnO, and Zn2+ to the representative of freshwater microalgae, Raphidocelis subcapitata. To examine the effect of shape and size of nanoparticles, two types of spherical ZnO NPs with different sizes (20 and 40 nm) and two types of rod-shaped ZnO NPs with different lengths (100 and 500 nm) were synthesized. Microalgal cells were exposed to eight concentrations of each ZnO NP type from 0.01 to 0.7 mg/L for 96 h. The results showed that 0.7 mg/L of ZnO NP could completely inhibit algal growth. Size did not interfere with toxicity in spherical ZnO NPs, but the toxicity decreased by increasing the size of rod-shaped ZnO NPs. Spherical ZnO NPs acted more destructive to microalgal cells than nanorod shape. The addition of 0.7 mg/L of ZnO nanorods to samples caused 30% cell death, while 50% cell death was observed by adding the same concentration of nanospherical ZnO. Nano ZnO revealed to be more toxic than bulk ZnO and Zn2+. The Zn2+ released from dissolution of ZnO NPs was one of the sources of toxicity, but the ZnO nanostructures were also an important factor in the toxicity. PMID- 30467755 TI - Kinetic and equilibrium adsorption of two post-harvest fungicides onto copper exchanged montmorillonite: synergic and antagonistic effects of both fungicides' presence. AB - The simultaneous adsorption of both imazalil (IMZ) and thiabendazole (TBZ) fungicides in a Cu2+-exchanged Mt was studied in this work. Kinetic studies were used to determine the rate law which describes the adsorption of individual fungicides onto the adsorbent. Adsorption isotherm of individual and combined fungicides was done to evaluate synergic or antagonistic effects. The Mt-Cu material considerably improved TBZ and/or IMZ adsorption from aqueous suspensions with respect to raw Mt, leading to removal efficiencies higher than 99% after 10 min of contact time for TBZ and IMZ Ci = 15 and 40 mg/L, respectively, when a solid dosage = 1 g/L was used. The adsorption sites involved were determined by a combination of X-ray diffraction (XRD) determinations and electron paramagnetic resonance (EPR), indicating that fungicides were bonded to Cu2+ cations, while the rate limiting step was the formation of coordination bonds. The adsorption mechanism proposed is that of ligand exchange between water and fungicide molecules in the metal coordination sphere. The single-crystal structure for the IMZ-Cu2+ complex indicated that four molecules were bounded to the copper centers, while two molecules of TBZ are bounded to copper explaining the higher IMZ uptake capacity for the Mt-Cu material. Graphical abstract. PMID- 30467756 TI - An integrated process for struvite electrochemical precipitation and ammonia oxidation of sludge alkaline hydrolysis supernatant. AB - This study reported two-phase electrochemical processes, including struvite electrochemical precipitation and ammonia electrooxidation, for the treatment of supernatant from the hydrolysis sludge. The results showed that in phase I, the removal efficiencies of 92.3% PO43--P and 50.1% NH4+-N could be achieved in electrochemical precipitation with magnesium sacrificial anode at pH 9.0 and 40 mA after 120-min electrolysis, and slightly increased to 95.1% and 57.3%, respectively, when current further increased to 120 mA, while the energy consumption (ECS, from 0.6 to 6.7 kWh m-3) and specific energy consumption [SECS, from 2.7 to 29.9 Wh g (PO43--P)-1] sharply increased. In phase II, the residual NH4+-N is further indirectly electrooxidized to nitrogen with modified Ti anode (Ti/SnO2-Sb-Pd). With the generation of active chloride, about 83.2% NH4+-N was removed with the molar ratio of Cl/N 5:1 at 50 mA after 120-min treatment, and slightly increased to 92.2%, when current increased to 125 mA, while SECS significantly increased [from 0.027 to 0.117 kWh g (NH4+-N)-1]. The results indicated that current were the crucial factors; meanwhile, lower current and longer reaction time may be the optimal options in electrochemical process with higher efficiency and lower energy consumption. Finally, the integrated process was conducted at the optimal conditions (pH = 9.0, I = 40 mA in phase I; Cl/N = 5, I = 50 mA in phase II) with the supernatant of the alkaline hydrolysis sludge. Removal of ammonia nitrogen (79.3%) and removal of phosphorus (94.3%) were achieved, confirming the feasibility of practical application for the simultaneous phosphorus recovery and ammonia removal. PMID- 30467757 TI - Metal oxide modified ZnO nanomaterials for biosensor applications. AB - Advancing as a biosensing nanotechnology, nanohybrids present a new class of functional materials with high selectivity and sensitivity, enabling integration of nanoscale chemical/biological interactions with biomedical devices. The unique properties of ZnO combined with metal oxide nanostructures were recently demonstrated to be an efficient approach for sensor device fabrication with accurate, real-time and high-throughput biosensing, creating new avenues for diagnosis, disease management and therapeutics. This review article collates recent advances in the modified ZnO nanostructured metal oxide nanohybrids for efficient enzymatic and non-enzymatic biosensor applications. Furthermore, we also discussed future prospects for nanohybrid materials to yield high performance biosensor devices. PMID- 30467758 TI - Central-variant posterior reversible encephalopathy syndrome in a young patient with systemic lupus erythematosus. PMID- 30467759 TI - Adrenergic hyperactivity: a missing link between multiple sclerosis and cardiovascular comorbidities? AB - The aim of the study is to investigate differences in non-standard adrenergic baroreflex sensitivity (BRS) indices in patients with different phenotypes of multiple sclerosis (pwMS) and healthy controls (HC). Retrospective analysis of types of systolic blood pressure (BP) curves during Valsalva maneuver (VM) [balanced (BAR), augmented (AAR) and suppressed (SAR) autonomic responses] and adrenergic baroreflex sensitivity (BRSa) measured with BRSa1, alpha-BRSa and beta BRSa in patients with clinically isolated syndrome (CIS), relapsing remitting multiple sclerosis (RRMS), progressive multiple sclerosis (PMS) and HC. We also investigated correlations between BRSa1, alpha-BRSa, beta-BRSa and resting catecholamine levels. pwMS had higher alpha-BRSa compared to HC (p = 0.02). There was no difference in BRSa1, s and beta-BRSa between patients with CIS, RRMS and PMS. There was no association between pwMS and HC, and the type of sBP curve [chi2 = 4.332, p = 0.114]. pwMS and BAR or AAR had higher supine systolic and diastolic BP compared to pwMS and SAR. There was a significant correlation between alpha-BRSa and upright systolic BP (rp =0.194, p = 0.017), alpha-BRSa and norepinephrine (rs =0.228, p = 0.021), and BRSa1 and epinephrine (rs = 0.226, p = 0.040). pwMS and HC exhibit different alpha-adrenergic response to Valsalva maneuver. These results may explain the connection between MS and increased cardiovascular risk. PMID- 30467760 TI - Evaluation of direct oral anticoagulants for the treatment of cancer-associated thrombosis: an update. AB - Cancer is associated with an increased risk of venous thromboembolism of four to sixfold. Cancer-related interventions such as chemotherapy, hormonal therapy and indwelling central venous catheters also increase the risk of venous thromboembolism. Low molecular weight heparin for at least 3-6 months is the current standard of care for the treatment of cancer associated venous thromboembolism. Anticoagulation should be continued as long as the cancer is active. Over the past few years, direct oral anticoagulants have emerged, including one direct thrombin inhibitor (dabigatran etexilate) and three factor Xa inhibitors (apixaban, edoxaban and rivaroxaban). In the randomized controlled trials comparing direct oral anticoagulants with vitamin K antagonists, the direct oral anticoagulants all provide non-inferior in prevention of thromboembolic events in patients with atrial fibrillation, for the prevention and treatment of venous thromboembolism and in acute coronary syndrome. In people with cancer, these drugs have emerged as attractive alternatives for the treatment of venous thromboembolism with the potential to overcome the limitations of low molecular weight heparin. Randomized controlled studies comparing direct oral anticoagulants to low molecular weight heparin in cancer patients are still limited and direct oral anticoagulants are not recommended for the treatment of cancer associated venous thromboembolism yet. However, new emerging data are supporting the use of direct oral anticoagulants in cancer associated thrombosis. Here, we review recent data on the evidence related to the efficacy and safety of direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer. PMID- 30467761 TI - Surgical repair of vesico-vaginal fistula: the need for an evidence-based approach. PMID- 30467762 TI - Pelvic floor symptoms 5 to 14 years after total versus subtotal hysterectomy for benign conditions: a systematic review and meta-analysis. AB - INTRODUCTION AND HYPOTHESIS: We aim to compare total versus subtotal abdominal hysterectomy regarding urinary and bowel symptoms and pelvic organ prolapse at long-term follow-up. METHODS: A systematic literature search was performed on the MEDLINE, LILACS, Cochrane CENTRAL and SCOPUS databases and conference abstracts (AAGL, AUGS, ICS) from inception up to November 2017. We included randomized trials comparing total versus subtotal hysterectomy for benign conditions that evaluated pelvic floor symptoms over 5 years of follow-up. Risk of bias and GRADE assessment for quality of evidence were performed. RESULTS: We included four studies involving 566 participants with follow-up ranging from 5 to 14 years. Women who underwent total hysterectomy presented lower risk of reported urinary incontinence [RR 0.74 (CI = 0.58, 0.94) i2 0%; p = 0.02] and stress urinary incontinence [RR 0.84 (CI = 0.71, 0.99) i2 0%; p = 0.04] than those who had subtotal hysterectomy. The events urinary frequency, urge incontinence, incomplete bladder emptying, pelvic organ prolapse, incontinence of stool and constipation did not favor one procedure over another in the long term (P > 0.05). CONCLUSIONS: Patient-reported urinary incontinence and stress urinary incontinence events favored total hysterectomy over subtotal hysterectomy up to 14-year long-term follow-up. PMID- 30467763 TI - Subjective and objective responses to PTNS and predictors for success: a retrospective cohort study of percutaneous tibial nerve stimulation for overactive bladder. AB - INTRODUCTION AND HYPOTHESIS: We investigated the objective improvements in overactive bladder (OAB) symptoms in patients undergoing percutaneous tibial nerve stimulation (PTNS) and predictive factors of patient satisfaction. METHODS: In this single-center retrospective cohort study at a tertiary urogynecology center, we identified all female patients who underwent PTNS therapy from 1 October 2007 - 1 January 2016 and followed them from their initial visit through medication therapy and PTNS treatments. Patients who tried at least one medication prior to starting PTNS therapy and completed at least one PTNS visit were included. Baseline demographic data, urinary data, and details of medication and PTNS therapy sessions were collected from records through chart review. Paired or two-sample t-tests were used to compare changes over time or groups. Bivariate and multivariable logistic regression were performed. RESULTS: Two hundred thirteen patients underwent PTNS therapy and 183 patients met the criteria. Overall patients were able to decrease voiding frequency by 1 h, decrease nocturia episodes by 0.8, and decrease urge incontinence episodes with PTNS therapy by ten episodes per week (p = 0.02). Patients who continued OAB medications did not have additional improvements compared with patients who did not continue OAB medications during PTNS. Overall, 25.4% (43/169) patients reported >= 75% improvement during PTNS therapy, and 61.5% (104/169) reported >= 50% improvement. When evaluating predictive factors of >= 50% overall improvement, the number of PTNS sessions increased odds of subjective success (OR = 1.8, p = 0.004). Other factors were not significant predictors of subjective PTNS success. CONCLUSIONS: PTNS can provide both objective and subjective improvements for patients who do not respond to OAB medication therapy. PMID- 30467765 TI - Demographic characteristics and population projection of Phytonemus pallidus fragariae reared on different strawberry cultivars. AB - The strawberry mite, Phytonemus pallidus fragariae (Banks) (Acari: Tarsonemidae), is one of the most important pests of greenhouse grown strawberry plants. Field grown strawberries may also be infested by the pest in high humid conditions. Life tables give the most comprehensive description of the development, survival, stage differentiation, reproduction and consequently population growth of a population, and thus it is an important base of population ecology and pest management. In this study, to provide a comprehensive evaluation of an ecology based and cost-effective control program, life history and demographic parameters of the strawberry mite were studied. The experiment was conducted under laboratory conditions providing 20 +/- 1 degrees C, 80 +/- 10% RH and L16:D8 photoperiod. The data were analyzed based on the age-stage, two-sex life table theory. The population parameters net reproduction rate (R0 = 6.14 offspring), intrinsic rate of increase (r = 0.1317 day-1), and finite rate of increase (lambda = 1.1407 day-1) on cv. Aromas were lower than those on the other cultivars tested. Based on the population characteristics, Aromas is a less favorable cultivar for the population growth of strawberry mite. PMID- 30467764 TI - Pelvic floor muscle knowledge and relationship with muscle strength in Brazilian women: a cross-sectional study. AB - INTRODUCTION AND HYPOTHESIS: There seems to be little knowledge about pelvic floor muscles (PFMs) in the general population; however, literature confirming this assertion is scarce, especially in developing countries. The present study hypothesized a low level of knowledge about PFMs in a sample of Brazilian women and a positive relationship between that knowledge and the ability to contract the PFMs, strength, and urinary continence. METHODS: This was a cross-sectional study including 133 women. A questionnaire assessing knowledge about PFMs and the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-UI-SF) were applied. Vaginal palpation and manometry were used to assess PFM condition. Pearson's correlation coefficient was used to test the association between PFM knowledge and continuous variables, and Fisher's exact test was used to compare the women's PFM knowledge with the categorical variables. RESULTS: A low level of PFM knowledge was observed in this sample, with a mean total score of 0.48 (+/ 0.97). Vaginal manometry peak, mean, and duration values were 39.1 cmH2O (+/ 23.7), 25.5 cmH2O (+/-16.1), and 21.1 s (+/-20.8) respectively. The ICIQ-UI-SF mean score was 7.1 (+/- 6.8). There were weak correlations between PFM knowledge and age (r -0.2044/ p = 0.01), and parity (r -0.19568/p = 0.02). PFM knowledge was higher among women with higher education levels (p = 0.0012) and those who had previously performed PFM training (p <0.001). CONCLUSION: The participants showed a low level of PFM knowledge. No relationship between PFM knowledge and ability to contract or prevalence of UI was observed. PMID- 30467766 TI - Application of central composite design for the optimization of electrode surface composition for glucose biosensor fabrication. AB - The use of a central composite design (CCD) for the optimization of electrode surface composition and its application to develop an amperometric glucose biosensor as a model system are described. A five-level three-factorial CCD was applied to determine the optimum electrode surface composition for three critical variables: amounts of carboxylated multiwall carbon nanotubes (c-MWCNT), titanium dioxide nanoparticles (TiO2NP), and glucose oxidase (GOx). The statistical significance of the model and factors were evaluated using the variance analysis (ANOVA) at 95% of confidence level. The optimized electrode surface composition was used for the fabrication of the glucose biosensor. The resulting biosensor showed linear response to glucose from 2.0 * 10-5 to 1.9 * 10-3 M with a detection limit of 2.1 * 10-6 M and sensitivity of 168.5 MUA mM-1 cm-2 under optimal experimental conditions. Analytical performance parameters of the biosensor were also compared with those obtained with the glucose biosensors fabricated using the electrode compositions optimized by conventional one factor at-a-time method and 22 CCD (for c-MWCNT and TiO2NP amounts). The optimization of the critical variables, achieved by CDD, leads us to fabricate the glucose biosensor in the best electrode surface composition which was promoted by the improved analytical performance. The proposed biosensor was applied to the analysis of glucose in serum samples and the obtained results were well correlated with the results of reference method. Graphical abstract ?. PMID- 30467767 TI - A new analytical framework for multi-residue analysis of chemically diverse endocrine disruptors in complex environmental matrices utilising ultra performance liquid chromatography coupled with high-resolution tandem quadrupole time-of-flight mass spectrometry. AB - This manuscript presents a comprehensive analytical framework for identification and quantification of chemically diverse endocrine disrupting chemicals (EDCs) used in personal care and consumer products in diverse solid and liquid environmental matrices with an ultimate goal of evaluating public exposure to EDCs via water fingerprinting. Liquid chromatography coupled with tandem quadrupole time-of-flight mass spectrometry (UHPLC-ESI-MS/MS) was used for targeted analysis of selected EDCs as well as to identify and quantify a few metabolites using post-acquisition data mining. Solid-phase extraction (SPE) was applied to liquid matrices in order to reduce matrix effects and provide required sample concentration and ultimately, high sensitivity and selectivity of measurements. SPE recoveries in liquid samples ranged from 49 to 140% with method quantification limits not exceeding 1 ng L-1 for the majority of EDCs. Microwave assisted extraction (MAE) was applied to solid samples and when followed by SPE, it permitted the analysis of EDCs in digested sludge. MAE/SPE recoveries varied from 11 to 186% and MQLs between 0.03 and 8.1 ng g-1 with the majority of compounds showing MQLs below 2 ng g-1. Mass error for quantifier and qualifier ions was below 5 ppm when analysing river water and effluent wastewater and below 10 ppm when analysing influent wastewater and solid samples. The method was successfully applied to environmental samples, with 33 EDCs identified and quantified in wastewater and receiving waters. In addition, several EDCs were found in digested sludge, which confirms that for a more comprehensive understanding of exposure patterns and environmental impact, analysis of solids cannot be neglected. Finally, post-acquisition data mining permitted the identification and quantification of a metabolite of BPA and the identification of a metabolite of 4-Cl-3-methylphenol. Graphical abstract ?. PMID- 30467769 TI - Simultaneous determination of lactic acid and pyruvic acid in tissue and cell culture media by gas chromatography after in situ derivatization-ultrasound assisted emulsification microextraction. AB - Lactic acid and pyruvic acid are important metabolites in the tricarboxylic acid cycle that can reflect the cytoplasmic redox state and mitochondrial respiratory chain function. The combination of these acids is considered as a screening index for mitochondrial disorders. Due to their biological effects, a derivatization method was developed to simultaneously detect pyruvic acid and lactic acid in tissue and cell culture media using gas chromatography. In this work, the combined derivatization method with methoxyamine hydrochloride and isobutyl chloroformate was first proposed. To improve the efficiency of derivatization, in situ derivatization-ultrasound-assisted emulsification microextraction (USAEME) was used in this study. After optimizing the volume of reagents and reaction times, good linearity values were obtained from 50 to 1000 MUmol/L and 1 to 100 MUmol/L for lactic acid and pyruvic acid, respectively. The limits of detection (LODs) were 0.12 MUmol/L for lactic acid and 0.29 MUmol/L for pyruvic acid. The recoveries of the two analytes were between 93.60 and 102.80%, and the precisions were less than 6.20%. This method was successfully applied to quantify pyruvic acid and lactic acid in the animal and cellular hypoxia models which provided an auxiliary means for the diagnosis of mitochondrial diseases. Graphical abstract ?. PMID- 30467768 TI - A new anion exchange purification method for Cu stable isotopes in blood samples. AB - The isotopic composition of iron, zinc, copper, and cadmium (delta56Fe, delta66Zn, delta65Cu, and delta114Cd) are novel and promising tools to study the metabolism and homeostasis of trace metals in the human body. Serum delta65Cu has been proposed as a potential tool for diagnosis of cancer in liquid biopsy, and other metals may have similar utility. However, accurate analysis of trace metal isotopes is challenging because of the difficulties in purifying the metals from biological samples. Here we developed a simple and rapid method for sequential purification of Cu, Fe, Zn, and Cd from a single blood plasma sample. By using a combination of 11 M acetic acid and 4 M HCl in the first steps of column chemistry on AG-MP1 resin, we dramatically improve the separation of Cu from matrix elements compared to previous methods which use concentrated HCl alone. Our new method achieves full recovery of Cu, Fe, Zn, and Cd to prevent column induced isotope fractionation effects, and effectively separates analytes from the matrix in order to reduce polyatomic interferences during isotope analysis. Our methods were verified by the analysis of isotope standards, a whole blood reference material, and a preliminary sample set including five plasma samples from healthy individuals and five plasma samples from cancer patients. This new method simplifies preparation of blood samples for metal isotope analysis, accelerating multi-isotope approaches to medical studies and contributing to our understanding of the cycling of Fe, Zn, Cu, and Cd in the human body. Graphical abstract ?. PMID- 30467770 TI - Alpha-lipoic acid in the treatment of psychiatric and neurological disorders: a systematic review. AB - Despite the existence of many preclinical studies, scientific evidence is lacking on the clinical use of alpha-lipoic acid (ALA) for central nervous system disorders. Therefore, we aimed at revising the literature concerning the use of ALA for the treatment of psychiatric and neurological conditions and to point out what is missing for the introduction of this antioxidant to this purpose. For this systematic review we performed a search using PubMed and SCOPUS databases with the following keywords: "alpha-Lipoic Acid AND central nervous system OR psychiatric disorders OR neurological disorders OR mood disorders OR anxiety OR psychosis OR Alzheimer OR Parkinson OR stroke". The total number of references found after automatically and manually excluding duplicates was 1061. After primary and secondary screening 32 articles were selected. Regarding psychiatric disorders, the studies of ALA in schizophrenia are advanced being ALA administration related to the improvement of schizophrenia symptoms and side effects of antipsychotic medication. In neurological disorders, ALA as a supplement was effective in the prevention of Alzheimer disease progression. For stroke, the use of the supplement ALAnerv(r) (containing 300 mg ALA) presented important results, since it was observed a reversal of clinical parameters and oxidative imbalance in these patients. For other neurological conditions, such as encephalopathy, multiple sclerosis, traumatic brain injury, mitochondrial disorders and migraine, the results are still preliminary. Overall, there is a need of well-designed clinical trials to enhance the clinical evidences of ALA effects for the treatment of neurological and psychiatric conditions. PMID- 30467771 TI - Supervised machine learning to decipher the complex associations between neuro immune biomarkers and quality of life in schizophrenia. AB - Stable phase schizophrenia is characterized by altered patterning in tryptophan catabolites (TRYCATs) and memory impairments, which are associated with PHEMN (psychosis, hostility, excitation, mannerism and negative) and DAPS (depression, anxiety and physio-somatic) symptoms. This study was carried out to examine the association between TRYCAT patterning, memory impairments, psychopathological features and health-related quality of life (HR-QoL) in schizophrenia. The World Health Organization (WHO) QoL instrument-Abbreviated version (WHO-QoL-BREF), IgA/IgM responses to TRYCATs, cognitive tests, Scale for the Assessment of Negative Symptoms (SANS), Hamilton and Depression (HAMD) and Anxiety (HAMA) Rating Scales and the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale (FF) were measured in 80 schizophrenia patients and 40 controls. Neural Network analysis shows that the total HR-Qol score is best predicted by (in descending order) HAMA, FF, HAMD, and psychosis. Partial least Squares (PLS) analysis shows that 56.7% of the variance in the WHO-QoL scores is explained by PHEMN / DAPS symptoms, while 64.3% of the variance in those symptoms is explained by TRYCAT patterning and episodic/semantic memory impairments. IgA responses to picolinic acid, xanthurenic acid and 3-hydroxy-kynurenine (all negatively) and anthranilic acid (positively) have highly significant indirect effects on WHO-QoL scores, which are completely mediated by cognitive impairments and PHEMN / DAPS symptoms. The results show that lowered HR-Qol in schizophrenia is strongly associated with noxious TRYCATs and that these effects are mediated by impairments in episodic / semantic memory and schizophrenia phenomenology, especially physio-somatic and anxiety symptoms. Mucosal activation of the TRYCAT pathway combined with a deficit in natural IgM isotype antibodies to TRYCATs determine cognitive impairments and DAPS/PHEMN symptoms, which together determine to a large extent lowered HR-QoL in schizophrenia. PMID- 30467772 TI - Strategies related to light quality and temperature to improve lutein production of marine microalga Chlamydomonas sp. AB - The marine microalga Chlamydomonas sp. JSC4 was examined for its potential as a lutein producer. Environmental conditions, including light quality, temperature and light wavelength mixing ratio, were individually altered to enhance the cell growth rate and lutein production in strain JSC4. Results showed that optimal cell growth was obtained under white light and a temperature of 35 degrees C, while the optimal lutein content was obtained under blue light and a lower temperature of 20-25 degrees C. The best lutein production occurred when using a mixing ratio of 3:1 (white light: blue light). Strategies related to light quality and temperature (namely, temperature-gradient and two-stage strategies) were then used to further improve lutein production. Among them, the two-stage strategy proved to be effective markedly improving lutein content from 2.52 to 4.24 mg/g and resulting in the highest lutein productivity of 3.25 mg/L/day. PMID- 30467773 TI - Estimation of the minimum detectable phase change of surface coil for neural current MRI. AB - Neuronal current magnetic resonance imaging (NC-MRI) is a new method in functional imaging of the brain that could cause the alteration in the phase of magnetic resonance signal. The phase variance is defined as the inverse of the signal to noise ratio (SNR). The intrinsic SNR of the MRI signal is characterized by the coil performance. We evaluated the relation between the geometry and the shape of coils in order to find the minimum detectable change in the signal phase and the possibility of direct detection of neuronal activity by MRI. Full wave equations were solved by the finite element method to calculate the SNR for circular, elliptical, and square shape surface coils. The simulation was repeated for Larmor frequencies of 64 MHz and 85.2 MHz and the coil sizes between 1.5 and 7.5 cm. Relative intrinsic signal to noise ratio (rISNR) of coils with a respect to a selected reference coil and a reference point in the sample was estimated. The circular coil had higher rISNR than other shapes. The increase of the strip width in the coils raised the rISNR 5-20%. For typical imaging parameters, rISNR reference was about 66 which led to a minimum detectable change in MRI signal phase of 0.87 degrees (11.4 nT). It may also be reduced up to tenfold in a 1.5 cm circular coil. Detection of subtle phase signal change due to neuronal activity in surface coils needs a large amount of data acquisition and averaging, but it is intrinsically feasible. PMID- 30467774 TI - Radiotherapy for Hepatocellular Carcinoma in Russia: a Survey-Based Analysis of Current Practice and the Impact of an Educational Workshop on Clinical Expertise. AB - Radiation therapy (RT) is an effective treatment modality for hepatocellular carcinoma (HCC), but globally, it is underutilized. In Russia, practice patterns with regard to liver-directed radiation are unknown. Under the auspices of Russian Society of Clinical Oncology (RUSSCO), our team conducted an IRB-approved contouring workshop for Russian radiation oncologists. Pre- and post-workshop surveys were analyzed to determine baseline clinical experience and patterns of care for liver-directed RT among Russian providers. The effect of the contouring workshop on participants' knowledge was tested using mixed effects model. Forty pre-workshop and 24 post-workshop questionnaires were analyzable with a 100% response rate. Sixty percent of respondents had never evaluated a patient with HCC and only 8% (3 out of 40) reported treating an HCC patient with liver directed RT. Nonetheless, 73% of respondents were comfortable offering liver directed RT prior to the workshop. After the workshop, 85% of respondents felt comfortable treating a patient with HCC with liver-directed RT and 50% were comfortable recommending stereotactic body radiation therapy (SBRT). Measures of knowledge pertaining to evaluation of HCC patients and selection for appropriate liver-directed therapies were dramatically improved after the workshop. Liver directed RT is not commonly used in Russia in the management of patients with HCC, and few centers are equipped for motion management. Our contouring workshop resulted in dramatically improved understanding of the evaluation and management of HCC patients. We recommend starting with a more protracted fractionated RT and building experience through attendance of additional educational activities, participation in multidisciplinary liver tumor boards, and prospective analysis of treatment toxicity and outcomes. PMID- 30467775 TI - Caring for Family Caregivers: a Pilot Test of an Online COMFORTTM SM Communication Training Module for Undergraduate Nursing Students. AB - Family caregivers who provide care and support to cancer patients experience distress, burden, and decreased quality of life as a result of caregiving. Caregivers often turn to nurses for support; however, there is little training available for nurses on how to care for the family caregiver. Undergraduate nursing students have a high need to learn about engaging caregivers in care, but little content is presented to fulfill that need. Derived from the COMFORTTM SM communication curriculum, we developed a 1-h online educational module specifically addressing communication with family caregivers of cancer patients. Undergraduate nursing students (n = 128) from two accredited nursing programs completed a survey at the beginning and end of the module, in addition to answering unfolding response opportunities within the module. There was a significant increase in communication knowledge, attitude, and behaviors (p < .000) in post-test responses for students across all years of study. Knowledge based on responses to case study scenarios was more than 75% correct. Student open-ended responses to case-based scenarios featured in the module revealed student mastery and ability to apply module content (range, 40-56% across four scenarios). This online COMFORTTM SM communication training module is an innovative online cancer education tool for teaching about communication with family caregivers. This study finds the module effective for teaching undergraduate nursing students about communication with family and shows promise in interprofessional curricula as well. PMID- 30467776 TI - Downregulation of lncRNA CASC2 promotes the postoperative local recurrence of early oral squamous cell carcinoma. AB - PURPOSE: LncRNA CASC2 plays a role as tumor suppressor gene in different types of human malignancies, while its involvement in oral squamous cell carcinoma (OSCC) is unknown. The present study aimed to investigate the involvement of lncRNA CASC2 in OSCC. METHODS: In this study, the expression of lncRNA CASC2 in tumor tissues, adjacent healthy tissues, and plasma of 122 OSCC patients as well as in plasma of 52 healthy controls was detected by RT-qPCR. Diagnostic value of lncRNA CASC2 for OSCC was evaluated by ROC curve analysis. Patients were followed up for 5 years to record recurrence. LncRNA CASC2 expression vectors were transfected into cells of human OSCC cell lines, and the effects on cancer cell proliferation and miRNA-21 expression were analyzed by CCK-8 assay and RT-qPCR, respectively. RESULTS: We found that CASC2 was significantly downregulated in OSCC patients than in healthy controls. Downregulation of CASC2 distinguished OSCC patients from healthy controls. Local recurrence was observed in 26 out of 122 patients and no distant recurrence was observed during follow-up. Compared with pretreatment levels, plasma levels of CASC2 were significantly increased in patients with local recurrence than in patients without recurrence. Transfection of CASC2 expression vectors led to significantly inhibited tumor cell proliferation and reduced miRNA-21 expression levels. CONCLUSIONS: We, therefore, conclude that downregulation of lncRNA CASC2 may participate in the postoperative local recurrence of early OSCC through miRNA-21. PMID- 30467777 TI - Olfactory function and olfactory bulb volume in Wilson's disease. AB - PURPOSE: To evaluate the olfactory function and the olfactory bulb (OB) volume changes in Wilson's Disease (WD) patients. METHODS: A prospective, controlled, single-blinded study was planned. 12 patients with WD (Group 1) and 12 healthy subjects (Group 2) were included in the study. Connecticut Chemosensory Clinical Research Center (CCCRC) test was applied to evaluate olfactory functions. OB volumes were measured with a 1.5 T General Electric Signa Excite MRI scanner. RESULTS: There was a significant difference between the CCCRC scores of the two groups (p < 0.05). The difference of the OB volumes of the two groups was insignificant (p > 0.05). CONCLUSIONS: WD patients are likely to experience olfactory dysfunction, so its assessment may be a useful tool to the follow-up care of these patients, although further studies are needed to evaluate correlations in WD evolution. PMID- 30467778 TI - Cone beam versus multi-detector computed tomography for detecting hearing loss. AB - OBJECTIVE: To determine whether the diagnostic value of cone-beam computed tomography (CBCT) is equivalent or superior to that of multi-detector computed tomography (MDCT) for the radiological assessment of conductive hearing loss with intact tympanic membrane in adults. Evaluation of inter- and intraobserver variability and measurement of the radiation dosimetry associated with each technique were secondary objectives. STUDY DESIGN: Prospective, single-center study. METHODS: Ten adults were included from April to June 2013. All patients underwent MDCT and CBCT with reconstruction of temporal bones. Two radiologists with ENT experience reviewed the results twice. Diagnostic agreement between MDCT and CBCT and inter- and intraobserver agreement was evaluated with the kappa statistic. Comparisons of dosimetry were evaluated by calculating the ratio of the CT dose index (CTDI) between MDCT and CBCT. RESULTS: Diagnostic agreement between MDCT and CBCT was satisfactory (kappa = 0.69). Inter- and intraobserver agreement was also acceptable, and the average ratio of the CTDI of MDCT and CBCT was 4.01. CONCLUSION: CBCT is a reliable method that uses a low dose of radiation to investigate conductive hearing loss with intact tympanic membrane in adults. Its relevance and potential superiority to MDCT in diagnosing middle ear pathologies such as otosclerosis remain to be demonstrated, but the preliminary data are promising. PMID- 30467779 TI - Assessing the relationship between adverse childhood experiences and life satisfaction, psychological well-being, and social well-being: United States Longitudinal Cohort 1995-2014. AB - BACKGROUND: More than half of the U.S. population has experienced adverse childhood experiences (ACE), which are linked to physical and mental health issues. This study examines the relationship between ACEs and life satisfaction, psychological well-being, and social well-being. METHODS: Data of 6323 participants from three waves of the Midlife Development in the United States (1995-1996, 2004-2006, and 2011-2014) were used. Repeated measures models were used to test the associations between ACEs and all three psychosocial scales. Generalized estimating equations (GEE) were used to account for multiple survey measures. Adjusting for demographics and survey wave, GEE models were run for each ACE construct. RESULTS: After controlling for demographic covariables, those reporting an ACE had significantly lower levels of life satisfaction (beta = - 0.20, 95% CI - 0.26 to - 0.15) compared to those without an ACE. Those reporting higher ACE counts were associated with lower life satisfaction compared to those with no ACE (beta = - 0.38, 95% CI - 0.56 to - 0.20; beta = - 0.36, 95% CI - 0.46 to - 0.27; and beta = - 0.13, 95% CI - 0.19 to - 0.08 for ACE counts of 3, 2, and 1, respectively). Abuse (beta = - 0.41, 95% CI - 0.48 to - 0.33) and household dysfunction (beta = - 0.18, 95% CI - 0.25 to - 0.10) were associated with significantly lower life satisfaction. Overall, those exposed to ACEs had significantly lower sense of social well-being. CONCLUSION: In this sample of adults, ACEs were significantly associated with lower life satisfaction, lower psychological well-being, and lower social well-being, especially for those who report abuse and household dysfunction during childhood. PMID- 30467780 TI - Validation of the Patient-Reported Outcomes Measurement Information System (PROMIS)-57 and -29 item short forms among kidney transplant recipients. AB - OBJECTIVE: The Patient-Reported Outcomes Measurement Information System (PROMIS) aims to address the lack of generalizable and universal measure of patient reported outcomes to assess health-related quality of life. It has not been validated for patients with chronic kidney disease. We aim to validate the PROMIS 57 and PROMIS-29 questionnaires among kidney transplant recipients. METHODS: A cross-sectional sample of stable kidney transplant recipients was recruited. Each participant completed PROMIS-57, a 57-question instrument covering seven domains physical function, anxiety, depression, fatigue, pain, sleep disturbance, and social functioning-alongside validated legacy questionnaires [Patient Health Questionnaire (PHQ9), General Anxiety Disorder (GAD7), Edmonton Symptom Assessment Scale revised (ESASr), and Kidney Disease Quality of Life (KDQoL-36)]. PROMIS-29, a 29-question instrument, is nested within PROMIS-57 and measures the same domains. Structural validity of PROMIS was assessed with confirmatory factor analysis, reported using the Comparative Fit Index (CFI). Construct validity was assessed with known-groups comparisons. Internal consistency was evaluated with Cronbach's alpha and convergent validity was assessed with Spearman's Rho. Test retest reliability was assessed through the intraclass correlation coefficient (ICC). RESULTS: Mean (+/- SD) age of the 177 participants was 50 (+/- 17), 57% were male and 55% Caucasian. Internal consistency of each domain was high (Cronbach's alpha > 0.88). Confirmatory factor analysis showed good structural validity for most domains (CFI > 0.95, RMSEA < 0.05). Test-retest reliability indicated good agreement (ICC > 0.6). Known-groups comparisons by clinical and socio-demographic differences were found as hypothesized. CONCLUSIONS: Our results provide evidence that PROMIS-57 and PROMIS-29 are highly reliable and valid instruments among kidney transplant recipients. We propose it as a valuable tool to assess important domains of the illness experience. PMID- 30467781 TI - Guselkumab: A Review in Moderate to Severe Plaque Psoriasis. AB - Guselkumab (Tremfya(r)) is a human immunoglobulin G1 lambda (IgG1lambda) monoclonal antibody (mAb) that blocks the interleukin-23 (IL-23)-mediated signalling pathway and is the first in its class to be approved in adults with moderate to severe plaque psoriasis in several countries, including the USA and EU. In the VOYAGE trials, guselkumab was superior to placebo and to adalimumab at week 16 in terms of the proportion of patients achieving an Investigator Global Assessment (IGA) score of 0/1 and >= 90% improvement from baseline in Psoriasis Area and Severity index score (PASI 90 response), with benefits of guselkumab over adalimumab maintained at week 24. To date, the beneficial effects of guselkumab treatment in these trials were maintained for up to 2 years. Inadequate responders to ustekinumab who were then randomized to guselkumab in NAVIGATE showed better responses than those randomized to ustekinumab between weeks 28-40, with a significantly greater mean number of visits at which patients had IGA 0/1 and >= 2-grade improvement in IGA score, as well as higher proportions of patients achieving PASI 90 and PASI 100 at week 52. Treatment with guselkumab improved health-related quality of life (HR-QOL) and patient-reported outcomes in all trials and was generally well tolerated. Guselkumab, administered by subcutaneous injection, is a useful new option for patients with moderate to severe plaque psoriasis. PMID- 30467782 TI - Hydrothermal Synthesis and Upconversion Properties of About 19 nm Sc2O3: Er3+, Yb3+ Nanoparticles with Detailed Investigation of the Energy Transfer Mechanism. AB - The Sc2O3: Er3+, Yb3+ nanoparticles (NPs) with the size of about 19 nm were synthesized by a simple oleic acid-mediated hydrothermal (HT) process. X-ray diffraction (XRD), transmission electron microscopy (TEM), upconversion luminescence (UCL) spectra, and decay curves were used to characterize the resulting samples. The Sc2O3: Er3+, Yb3+ NPs made by HT method exhibit the stronger UCL, of which the red UCL are enhanced by a factor of 4, in comparison with those samples prepared by solvothermal (ST) method at the same optimized lanthanide ion concentrations. The UCL enhancement can be attributed to the reduced surface groups and longer lifetimes. Under 980 nm wavelength excitation, the decay curves of Er3+: (2H11/2, 4S3/2) -> 4I15/2 and 4F9/2 -> 4I15/2 emissions for Sc2O3: Er3+, Yb3+ NPs samples are both close to each other, resulting from the cross relaxation energy transfer from Er3+ to Yb3+, followed by an energy back transfer within the same Er3+-Yb3+ pair. Also, under the relatively low power density, the slopes of the linear plots of log(I) vs. log(P) for red and green emissions are 2.5 and 2.1, implying the existence of three-photon processes. Our results indicate that Sc2O3: Er3+, Yb3+ NPs is an excellent material for achieving intense UCL with small size in the biological fields. PMID- 30467783 TI - A glassy carbon electrode with electrodeposited silver nanoparticles for aptamer based voltammetric determination of trinitrotoluene using riboflavin as a redox probe. AB - An electrochemical nanoaptasensor is described that is based on the use of a glassy carbon electrode (GCE) modified with electrodeposited silver nanoparticles (AgNPs). An aptamer (Apt) against trinitrotoluene (TNT) was then immobilized on the AgNPs. The addition of TNT to the modified GCE leads to decrease in peak current (typically measured at a potential of -0.45 V vs. Ag/AgCl) of riboflavin which acts as an electrochemical probe. Even small changes in the surface (as induced by binding of Apt to TNT) alter the interfacial properties. As a result, the LOD is lowered to 33 aM, and the dynamic range extends from 0.1 fM to 10 MUM without sacrificing specificity. Graphical abstract Schematic presentation of a nanoaptasensor which is based on a glassy carbon electrode (GCE) modified with electrodeposited silver nanoparticles (AgNPs) and aptamer (Apt). It was applied to the detection of 2,4,6-trinitrotoluene (TNT) with the help of riboflavin (RF) as a redox probe. PMID- 30467784 TI - Effects of sleep disorders and sedative-hypnotic medications on health-related quality of life in dialysis patients. AB - PURPOSE: Sleep disorders are very common among dialysis patients, leading patients to frequently take sedative-hypnotic medications; however, the effects of sleep disorders and the use of such drugs on health-related quality of life (HRQOL) have rarely been investigated. METHODS: The Pittsburgh Sleep Quality Index and Short Form-12 were used to assess sleep quality and patient health situations, respectively. Logistic regression was employed to identify factors associated with deterioration of the mental component summary (MCS) score and the physical component summary (PCS) score. RESULTS: A total of 461 patients undergoing dialysis were recruited. The prevalence of sleep disorders was 67.0%. Among the study population, 30.4% of patients took sedative-hypnotic medications to improve their sleep quality. Both the PCS (81.25 vs. 71.88, p < 0.001) and MCS scores (78.63 vs. 74.63, p < 0.001), which indicate HRQOL, were decreased among patients with sleep disorders compared with good sleepers. However, neither the PCS nor MCS scores showed any significant difference between patients with sleep disorders who used sedative-hypnotic medications and those who did not. CONCLUSION: Sleep disorders were closely associated with deterioration of both mental HRQOL and physical HRQOL. Sedative-hypnotic medication use did not affect HRQOL among patients with sleep disorders undergoing dialysis. PMID- 30467785 TI - Genetic Mutations in jamb, jamc, and myomaker Revealed Different Roles on Myoblast Fusion and Muscle Growth. AB - Myoblast fusion is a vital step for skeletal muscle development, growth, and regeneration. Loss of Jamb, Jamc, or Myomaker (Mymk) function impaired myoblast fusion in zebrafish embryos. In addition, mymk mutation hampered fish muscle growth. However, the effect of Jamb and Jamc deficiency on fish muscle growth is not clear. Moreover, whether jamb;jamc and jamb;mymk double mutations have stronger effects on myoblast fusion and muscle growth remains to be investigated. Here, we characterized the muscle development and growth in jamb, jamc, and mymk single and double mutants in zebrafish. We found that although myoblast fusion was compromised in jamb and jamc single or jamb;jamc double mutants, these mutant fish showed no defect in muscle cell fusion during muscle growth. The mutant fish were able to grow into adults that were indistinguishable from the wild-type sibling. In contrast, the jamb;mymk double mutants exhibited a stronger muscle phenotype compared to the jamb and jamc single and double mutants. The jamb;mymk double mutant showed reduced growth and partial lethality, similar to a mymk single mutant. Single fiber analysis of adult skeletal myofibers revealed that jamb, jamc, or jamb;jamc mutants contained mainly multinucleated myofibers, whereas jamb;mymk double mutants contained mostly mononucleated fibers. Significant intramuscular adipocyte infiltration was found in skeletal muscles of the jamb;mymk mutant. Collectively, these studies demonstrate that although Jamb, Jamc, and Mymk are all involved in myoblast fusion during early myogenesis, they have distinct roles in myoblast fusion during muscle growth. While Mymk is essential for myoblast fusion during both muscle development and growth, Jamb and Jamc are dispensable for myoblast fusion during muscle growth. PMID- 30467786 TI - First steps in an uncharted territory by WFNMB. PMID- 30467787 TI - Implant therapy for a patient with osteogenesis imperfecta type I: review of literature with a case report. AB - Bone fragility and skeletal irregularities are the characteristic features of osteogenesis imperfecta (OI). Many patients with OI have weakened maxillary and mandibular bone, leading to poor oral hygiene and subsequent loss of teeth. Improvements in implant therapy have allowed for OI patients to achieve dental restoration. However, there is limited available literature on implant therapy for patients with OI. The greatest challenge in the restoration process for OI patients in an outpatient setting is ensuring primary stability and osseointegration. Improvements in synthetic grafts improve successful implant placement and prevent predisposing patients to unnecessary procedures. This report details the successful restoration process of an OI type I patient's maxillary arch in addition to a review of the currently available literature. PMID- 30467788 TI - Transcription factors involved in basal immunity in mammals and plants interact with the same MAMP-responsive cis-sequence from Arabidopsis thaliana. AB - KEY MESSAGE: WRKY and NF-kappaB transcription factors, involved in innate immunity in plants and mammals, interact with the same cis-sequence. Novel microbe-associated molecular pattern (MAMP)-responsive cis-sequences, designated type II WT-boxes, are required for flg22-responsive gene expression in Arabidopsis thaliana protoplasts. While type I WT-boxes like TGACTTTT and CGACTTTT interact with WRKY transcription factors (TFs), the question remained which TFs bind to the type II WT-boxes GGACTTTC, GGACTTTT, and GGACTTTG. Surprisingly, a bioinformatic analysis predicts mouse (Mus musculus) NF-kappaB p65 as a TF interacting with type II WT-boxes. NF-kappaB p65, like WRKY factors in plants, plays a role in innate immunity in mammals. Therefore, the interaction of NF-kappaB p65 with type II WT-boxes was tested experimentally. NF-kappaB p65 requires the WT-boxes GGACTTTC, GGACTTTT, and GGACTTTG for activating reporter gene expression in plant cells. NF-kappaB p65 directly binds to WT-box containing synthetic promoters in vitro and requires the WT-box for binding. Earlier studies indicate that the sequence GGACTTTC is also required for WRKY26 mediated reporter gene activation. Here it is shown that WRKY26, like NF-kappaB p65, binds to the sequence GGACTTTC. Consistent with other recent studies, type II WT boxes are WRKY binding sites and the distinction between type I and type II no longer applies. PMID- 30467789 TI - Safety of one-stage conversion surgery after failed gastric band: our experience and review of the literature. AB - The laparoscopic adjustable gastric band (AGB) has fallen out of favor due to poor long-term weight loss and frequent complications. Many patients stand to benefit from elective conversion of AGB to more durable procedures such as sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB). Whether it is safer to perform this conversion in one or two stages, however, remains controversial. We performed an IRB-approved review of prospectively collected data from all one stage band conversions performed at our institution from January 2012 to December 2017. Patients were separated into two groups: those who underwent conversion to either a RYGB or SG. Demographics, indications, and outcomes of each group were compared using Fisher's exact test, Mann-Whitney rank sums, and chi-squared tests. Outcomes were recorded within a 1-year follow-up period and compared to published outcomes for one-stage band conversions. Thirty-eight patients were included for analysis. Average age and BMI were was 50.8 years and 41.1 kg/m2, respectively. The average operative time (164 min, 105-258 min) and length of stay (2.2 days, 1-5 days) did not differ between indication and procedure performed. Overall, early (< 30 day) and late (> 30 day) major complication rates were 7.9% and 5.3%, respectively. There were no leaks and no deaths. Within a 1 year postoperative period, seven re-interventions were performed. Elective one stage band conversion to RYGB or SG can be performed safely. PMID- 30467790 TI - Chemical characterization of the milk oligosaccharides of some Artiodactyla species including giraffe (Giraffa camelopardalis), sitatunga (Tragelaphus spekii), deer (Cervus nippon yesoensis) and water buffalo (Bubalus bubalis). AB - Mammalian milk/colostrum usually contains oligosaccharides along with the predominant disaccharide lactose. It has been found that the number and identity of these milk oligosaccharides varies among mammalian species. Oligosaccharides predominate over lactose in the milk/colostrum of Arctoidea species (Carnivora), whereas lactose predominates over milk oligosaccharides in Artiodactyla including cow, sheep, goat, camel, reindeer and pig. To clarify whether heterogeneity of a variety of milk oligosaccharides is found within other species of Artiodactyla, they were studied in the milk of giraffe, sitatunga, deer and water buffalo. The following oligosaccharides were found: Neu5Ac(alpha2-3)[GalNAc(beta1-4)]Gal(beta1 4)Glc (GM2 tetrasaccharide), and Gal(alpha1-3)Gal(beta1-4)Glc (isoglobotriose) in giraffe milk; Neu5Ac(alpha2-3)Gal(beta1-4)Glc (3'-SL), Neu5Ac(alpha2-6)Gal(beta1 4)Glc (6'-SL), Gal(alpha1-4)Gal(beta1-4)Glc (globotriose) and isoglobotriose in sitatunga colostrum; Gal(beta1-3)Gal(beta1-4)Glc (3'-GL), Gal(beta1-6)Gal(beta1 4)Glc (6'-GL), isoglobotriose, Gal(beta1-4)GlcNAc(beta1-3)Gal(beta1-4)Glc (lacto N-neotetraose, LNnT), Gal(beta1-4)Glc-3'-O-SO3 (3'-O-lactose sulphate) in deer milk; 3'-GL, isoglobotriose and Gal(beta1-3)Gal(beta1-3)Gal(beta1-4)Glc (3',3" digalactosyllactose, DGL) in water buffalo colostrum. Thus it was shown that the milk oligosaccharides are heterogeneous among these Artiodactyla species. PMID- 30467792 TI - The experience of providing hospice care concurrent with cancer treatment in the VA. AB - PURPOSE: Veterans with advanced cancer can receive hospice care concurrently with treatments such as radiation and chemotherapy. However, variations exist in concurrent care use across Veterans Affairs (VA) medical centers (VAMCs), and overall, concurrent care use is relatively rare. In this qualitative study, we aimed to identify, describe, and explain factors that influence the provision of concurrent cancer care (defined as chemotherapy or radiation treatments provided with hospice) for veterans with terminal cancer. METHODS: From August 2015 to April 2016, we conducted six site visits and interviewed 76 clinicians and staff at six VA sites and their contracted community hospices, including community hospices (n = 16); VA oncology (n = 25); VA palliative care (n = 17); and VA inpatient hospice and palliative care units (n = 18). RESULTS: Thematic qualitative content analysis found three themes that influenced the provision of concurrent care: (1) clinicians and staff at community hospices and at VAs viewed concurrent care as a viable care option, as it preserved hope and relationships while patient goals are clarified during transitions to hospice; and (2) the presence of dedicated liaisons facilitated care coordination and education about concurrent care; however, (3) clinicians and staff concerns about Medicare guideline compliance hindered use of concurrent care. CONCLUSIONS: While concurrent care is used by a small number of veterans with advanced cancer, VA staff valued having the option available and as a bridge to hospice. Hospice staff felt concurrent care improved care coordination with VAMCs, but use may be tempered due to concerns related to Medicare compliance. PMID- 30467793 TI - Clinical utility of portable electrophysiology to measure fatigue in treatment naive non-small cell lung cancer. AB - PURPOSE: Cancer-related fatigue (CRF) biology remains poorly understood. Responsible mechanisms may be central or peripheral and originate anywhere from the brain to muscle fiber. Objective measurement is complex and previously limited to specialized laboratories. Portable electroencephalography (EEG) and electromyography (EMG) may enhance objective measurement. This study evaluated the feasibility and acceptability of portable EMG-EEG in CRF assessment. METHODS: A prospective observational feasibility study compared ten outpatients with inoperable, treatment-naive non-small cell lung cancer and CRF to ten healthy volunteers. All completed a sustained isometric hand-grip contraction at 30% maximal level until self-perceived exhaustion. 128-channel EEG and 2-channel EMG signals of forearm muscles were recorded. Device acceptability was evaluated by questionnaire. RESULTS: The task was evaluated in two stages; first and last 20 s. CRF cohort perceived exhaustion earlier than volunteers (mean 137 +/- 76 s vs 208 +/- 51 s). As fatigue progressed, EMG amplitude increased significantly (CRF p = 0.02; volunteers: p = 0.04) in both groups as did EMG beta band power (CRF p = 0.008; volunteers: p = 0.006). The increase was significantly less in CRF (amplitude p = 0.032; beta power: p = 0.014). EEG beta band power in the contralateral motor cortex increased significantly (CRF p = 0.03; volunteers: p = 0.019) in both cohorts but to greater extent (p = 0.024) in CRF. One hundred percent device acceptability was reported. CONCLUSIONS: A laboratory-based evaluation was successfully adapted to the outpatient setting during routine visits. High acceptability supports clinical utility. In CRF, a higher degree of cortical activation was required to drive a much lower level of muscle performance. This suggests impairment of both central and peripheral mechanisms in CRF. PMID- 30467794 TI - Documentation and incidence of late effects and screening recommendations for adolescent and young adult head and neck cancer survivors treated with radiotherapy. AB - PURPOSE: A retrospective review of adolescent and young adult (AYA) head and neck cancer (HNC) patients treated with radiation therapy (RT) at British Columbia Cancer was performed to determine the incidence of late toxicities, the documented late side effects discussed and the screening recommendations provided at the time of transfer of care to primary care providers (PCPs). METHODS: Charts (n = 162) were reviewed for all patients 15 to 35 years at diagnosis with HNC treated with RT from 1960 to 2010 who survived > 5 years after diagnosis. RESULTS: A discussion regarding the risk of long-term side effects was documented in the initial consultation for 85% of patients. The majority of patients (78%) developed > 1 documented late effect. The most common were xerostomia (44%), skin changes (28%), neck fibrosis (22%), nasal crusting (16%), epistaxis (16%), and dental decay (14%). In all, 20% were currently followed or were followed until they died. Of the 80% transferred to their PCP, 14% had a formal discharge summary. For those discharged from British Columbia Cancer, documented recommendations included regular dental care (34%) and screening for hypothyroidism (5%) and second malignancy (4%). CONCLUSIONS: The majority of AYA HNC patients treated with RT developed late side effects, and most PCPs were not sent a discharge summary outlining screening recommendations for delayed late effects. IMPLICATIONS FOR CANCER SURVIVORS: AYA HNC survivors treated with RT are at high risk for late effects and would benefit from a survivorship care plan outlining these risks and screening recommendations. PMID- 30467796 TI - ? PMID- 30467791 TI - Improvement of electrospray stability in negative ion mode for nano-PGC-LC-MS glycoanalysis via post-column make-up flow. AB - Analysis of glycans via a porous graphitized carbon liquid chromatography (PGC LC) coupled with electrospray ionization (tandem) mass spectrometry (ESI-MS(/MS)) is a powerful analytical method in the field of glycomics. Isobaric glycan structures can be identified reliably with the help of PGC-LC separation and subsequent identification by ESI-MS(/MS) in negative ion mode. In an effort to adapt PGC-LC-ESI-MS(/MS) to the nano-scale operation, spray instability along the nano-PGC-LC gradient was repeatedly observed on an LTQ Orbitrap Elite mass spectrometer equipped with a standard nano-electrospray ionization source. A stable electrospray was achieved with the implementation of a post-column make-up flow (PCMF). Thereby, acetonitrile was used to supplement the eluate from the nano-PGC-LC column. The improved spray stability enhanced detection and resolution of glycans during the analysis. This was in particular the case for smaller O-glycans which elute early in the high aqueous content regime of the nano-PGC-LC elution gradient. This study introduces PCMF as an easy-to-use instrumental adaptation to significantly improve spray stability in negative ion mode nano-PGC-LC-ESI-MS(/MS)-based analysis of glycans. PMID- 30467795 TI - [The MDK community appraisal guideline for the German procedure classification code 8-918 : Notification by the ad hoc commission for interdisciplinary multimodal pain therapy]. PMID- 30467797 TI - ? PMID- 30467799 TI - Energetic Al/Ni Superlattice as a Micro-Plasma Generator with Superb Performances. AB - In this study, energetic Al/Ni superlattice was deposited by magnetron sputtering. A micro-plasma generator was fabricated using the energetic Al/Ni superlattice. The cross-sectional micro-structure of the energetic Al/Ni superlattice was scanned by transmission electron microscopy. Results show that the superlattice is composed of Al layer and Ni layers, and its periodic structure is clearly visible. Moreover, the bilayer thickness is about 25 nm, which consists of about 15 nm Al layer and 10 nm Ni layer. The micro initiator was stimulated using a 0.22 MUF capacitor charged at 2900-4100 V. The electrical behaviors were investigated by testing the current-voltage waveform, and the plasma generation was explored by ultra-high-speed camera and photodiode. The integrated micro generator exhibited remarkable electrical exploding phenomenon, leading to plasma generations at a small timescale. The plasma outputs reflected by flyer velocities were superior to that with a much thicker bilayer of 500 nm Al/Ni multilayer. The higher flyer velocity combined with Gurney energy model confirmed the chemical reaction of the Al/Ni superlattice structure contributed to plasma production in comparison with the Al/Ni multilayers. Overall, the energetic Al/Ni superlattice was expected to pave a promising avenue to improve the initiator efficiency at a lower energy investment. PMID- 30467800 TI - Interleukin-33/ST2 signaling contributes to the severity of hemolytic uremic syndrome induced by enterohemorrhagic Escherichia coli. AB - OBJECTIVES: Interleukin (IL)-33 plays an important role in host defense, immune regulation, and inflammation. This study assessed IL-33's role in the pathogenesis of severe hemolytic uremic syndrome (HUS) induced by enterohemorrhagic Escherichia coli (EHEC). We also investigated the clinical significance of IL-33 and soluble ST2 (soluble form of IL-33 receptor) serum levels in patients with EHEC-induced HUS. METHODS: The role of IL-33 in Shiga toxin (STx)-2-induced endothelial injury was studied in human umbilical vein endothelial cells (HUVECs) in vitro. Blood samples were obtained from 21 HUS patients and 15 healthy controls (HC). The IL-33 and sST2 serum levels were quantified using an enzyme-linked immunosorbent assay. The results were compared to HUS' clinical features. RESULTS: Cytotoxic assays indicated that IL-33 enhanced STx2 toxicity in HUVECs. Serum IL-33 levels in most HUS patients were below the lowest detection limit. On the other hand, serum sST2 levels in patients during the HUS phase were significantly higher than those in HC and showed a correlation with disease severity. Serum sST2 levels in patients with encephalopathy were significantly higher than those in patients without it. A serum sST2 level > 63.2 pg/mL was associated with a high risk of encephalopathy. Serum sST2 levels significantly correlated with serum levels of inflammatory cytokines related to the development of HUS. CONCLUSIONS: Our results indicate that IL-33 contributes to the severity of EHEC-induced HUS. Serum sST2 level in HUS patients correlated with disease activity, which suggests its potential role as a marker for disease activity and development of encephalopathy in patients with EHEC-induced HUS. PMID- 30467798 TI - Diagnostic performance of abdominal point of care ultrasound performed by an emergency physician in acute right iliac fossa pain. AB - BACKGROUND: Right iliac fossa abdominal pain is a common reason for emergency ward admissions, its etiology is difficult to diagnose. It can be facilitated by an imaging examination, such as a Computerized Tomography scan which exposes the patient to ionizing radiation and implies delays. A bedside ultrasound performed by emergency physicians could avoid these issues. The aim of our study was to assess the performance of ultrasound carried out at the patient's bedside by an emergency physician compared with a clinical-laboratory examination for the diagnosis of a surgical pathology in right iliac fossa pain. METHODS: This is a single-center prospective cohort study conducted in an Emergency Department receiving 19,000 patients per year. All patients presenting pain in the right iliac fossa were included by four (out of ten) emergency physicians certified in an ultrasound examination. A full grid pattern scan ultrasound of the abdominal cavity with analysis of the right iliac fossa was performed. The primary outcome was to compare the diagnosis performance of bedside ultrasound and clinical laboratory examination to detect a surgical pathology. Two emergency physicians who did not participate in the study made the final diagnosis (i.e., surgical or non-surgical pathology) by reviewing the entire medical chart of each patient. RESULTS: From January 2011 to July 2013, 158 patients with a median age of 17 [13 32] years were analyzed. The diagnosed cases were: appendicitis (53), non specific abdominal pain (48), lymphadenitis (22), ileitis (11), complicated ovarian cysts (7), neoplasias (5), inflammatory or infectious colitis (5), inguinal herniations (3), bowel obstructions (2), and salpingitis (2). The accuracy of ultrasound diagnoses was 0.89 (95% CI 0.84-0.94) versus 0.70 (95% CI 0.57-0.82) for diagnoses based on clinical-laboratory examination only (p < 0.001). CONCLUSION: Bedsides, ultrasound allows an accurate diagnosis of a surgical pathology in 89% of cases, which is more efficient than the clinical laboratory examination. PMID- 30467801 TI - Glomerular basement membrane duplication is a predictor of the prognosis of diabetic nephropathy in patients with type 2 diabetes. AB - BACKGROUND: Several clinical parameters and pathological findings are known to be predictors of the deterioration of diabetic nephropathy (DN). Glomerular basement membrane duplication (GBM-DP) is a pathological feature representing endothelial injury, which is commonly observed in DN. In the present study, we investigated the association between GBM-DP and the renal prognosis in DN. METHODS: The study enrolled 80 patients with renal biopsy-proven DN who were managed at Chiba-East Hospital from 2005 to 2012. We confirmed the pathological findings according to the Renal Pathology Society classifications, and we further evaluated the GBM-DP, which was defined as double contours of the GBM that expanded more than 10% of capillary loops in the most affected nonsclerotic glomerulus. We used Cox regression models to estimate hazard ratios (HRs) for end-stage renal disease (ESRD), with adjustment for age, sex, systolic blood pressure, HbA1c, estimated glomerular filtration rate (eGFR), and urinary protein excretion (UP) at baseline. RESULTS: Of the 80 patients, 56 were male (70.0%) and the mean age was 59.1 years. The median eGFR and UP were 42 ml/min/1.73 m2 (IQR 30, 59) and 3.1 g/gCr (IQR 1.2, 5.2). Twenty-seven patients progressed to ESRD and one patient died during the median observational period of 2.9 years (IQR 1.5, 4.3). The multivariable analyses showed that GBM-DP was significantly associated with ESRD (HR 3.18 [95% confidence interval (CI): 1.02-9.87], p = 0.045). CONCLUSION: We newly identified GBM-DP as a strong prognostic predictor in DN patients. Further study is needed to clarify the pathogenic mechanism of GBM-DP in DN. PMID- 30467802 TI - Deciphering the transcriptome of prepubertal buffalo mammary glands using RNA sequencing. AB - Although water buffaloes are the main milk-producing animals in Indian subcontinent, only limited attempts have been made to identify canonical pathways and gene regulatory networks operating within the mammary glands of these animals. Such information is important for identifying unique transcriptome signatures in the mammary glands of diseased animals. In this report, we analyzed the transcription profile of 3 prepubertal buffalo mammary glands and identified common genes (mean FPKM > 0.2 in all samples) operating in the glands. Among 19,994 protein coding genes, 14,678 genes expressed and 5316 unique genes did not express in prepubertal buffalo mammary glands. Of these 14,678 expressed genes, 79% comprised a ubiquitous transcriptome that was dominated by very lowly expressed genes (51%). The percentage of rarely, moderately, and abundantly expressed genes was 25%, 2%, and 1%, respectively. Gene Ontology (GO) terms reflected in the expression of common genes (mean FPKM > 5.0) for molecular function were related to binding and catalytic activity. Products of these genes were involved in metabolic and cellular processes and belong to nucleic acid binding proteins. The canonical pathways for growth of mammary glands included integrin signaling, inflammation, GnRH and Wnt pathways. KEGG enriched pathways revealed many pathways of cancer including ribosome, splisosome, endocytosis, and ubiquitin-mediated proteolysis, pathways for viral infection, and bacterial invasion of epithelial. Highly expressed genes (mean FPKM > 500 included beta actin (ACTB), beta-2 microglobulin (B2M), caseins (CSN2, CNS3), collagens (COL1A1, COL3A1), translation elongation factors (EEF1A1, EEF1G, EEF2), keratins (KRT15, KRT19), major histocompatibility complex genes (CD74, JSP.1), vimentin (VIM), and osteopontin (SPP1). Interestingly, expression of milk protein genes in prepubertal glands opens possible roles of these genes in development of mammary glands. We report the whole transcriptomic signature of prepubertal buffalo mammary gland and indicated its molecular signature is similar to cancer type. PMID- 30467803 TI - Synthesis and characterization of Ni(II) complex functionalized silica-based magnetic nanocatalyst and its application in C-N and C-C cross-coupling reactions. AB - A new magnetically recoverable silica-based nickel(II) nanocatalyst was synthesized by a simple cost-effective procedure, which was characterized by TEM, SEM, XRD, VSM analysis, and FT-IR spectrophotometry. The catalytic activity of the prepared Ni(II) nanocatalyst was tested in two complementary reactions: C-N Chan-Lam cross-coupling of phenylboronic acid with aryl amines and C-C Suzuki Miyaura cross-coupling reaction of phenylboronic acid with aryl halides. The catalyst was easily recovered by magnetic separation and reused for five times. It demonstrated better catalytic activity in the C-N Chan-Lam reaction compared to C-C Suzuki-Miyaura reaction. Ease of recovery and reusability up to five cycles without noticeable loss of performance in the C-N cross-coupling reaction make the present protocol beneficial both industrially and environmentally. In this paper, a new magnetically recoverable silica-based nickel(II) nanocatalyst was synthesized and applied in two complementary reactions: C-C Suzuki-Miyaura reaction and C-N Chan-Lam reaction. The difference in catalytic activity makes it possible to use this catalyst for cases that are prone to both reactions and selectively create the desired product. PMID- 30467804 TI - The non-drug costs associated with the administration of an intravenous biologic treatment in the hospital setting. AB - BACKGROUND: In Ireland, over 20,000 people are affected by inflammatory bowel disease (IBD). The licenced biologic therapies to treat moderate to severe IBD are reported to have similar effectiveness levels but differ in their methods of delivery. Certain therapies are administered by intravenous (IV) infusion in the hospital setting, others are delivered by subcutaneous injection in the community. AIM: To determine the non-drug costs involved in administering an IV biologic infusion in the hospital setting. METHODS: This time-and-motion study was conducted at an Infusion Day Unit (IDU) in an Irish teaching hospital. The sequence and duration of each patient's use of resources was recorded and costed. Bootstrap methods were applied to ensure that robust estimates of the accuracy of the non-parametric population statistics were reliably estimated. RESULTS: The mean time the patient spent at the IDU was 143.78 mins with a mean treatment time of 129.81 min. The main driver of patient time was the drug infusion time (39%), followed by the monitoring period (25%). The mean cost was ?224.54 per treatment. Nurse time was the main expenditure driver (37%), followed by laboratory costs (27%) and other healthcare professional's costs (14%). CONCLUSIONS: The study confirms that the non-drug costs associated with the delivery of an IV biologic in the hospital setting are non-trivial. Given the current budgetary climate of health systems, the compounding prevalence of IBD and the expected increase in patient numbers, it is imperative that physicians also consider the opportunity costs associated with the method of treatment delivery. PMID- 30467805 TI - EU anti-smoking graphic warnings on cigarette packets: semiotics and the issue of gender under-representation. PMID- 30467806 TI - Dietary patterns were not associated with age-related macular degeneration: a cross-sectional analysis in the Irish Nun Eye Study. AB - BACKGROUND: Analysing dietary patterns (DP) evaluates overall dietary intake, taking account of its complexity, quality, variance and the interaction between different foods, providing an alternative approach for the evaluation of nutritional influences on age-related macular degeneration (AMD) risk. AIMS: To evaluate the relationship between DP and AMD in an older female population. METHODS: Data was analysed from the cross-sectional Irish Nun Eye Study involving 1233 older women with a restricted lifestyle (mean age 76.3 years [range, 56-100 years). The Wisconsin Age-related Maculopathy Grading System was used to classify digital colour macular fundus images and dietary intake was assessed using a food frequency questionnaire (n = 1033). A posteriori DP were derived using principal component analysis. Logistic regression models examined associations between DP and AMD risk with adjustment for confounders. RESULTS: Two DP were identified: a 'healthy' pattern characterised by a high intake of oily fish, wholegrains, vegetables and fruit; and an 'unhealthy' pattern characterised by high-fat dairy products, sugar, sweets and chips. Of the participants included within the analysis, AMD status were categorised as controls (n = 818, 86.9%), early AMD (n = 83, 8.8%) and late AMD (n = 21, 2.2%). Regression analysis failed to identify any significant associations between healthy or unhealthy DP and AMD risk, in unadjusted and adjusted models. CONCLUSION: No evidence of an association between the DP identified and AMD risk was detected in this well-characterised population. Further research is required to determine the overall dietary influences on AMD risk in general population cohorts. PMID- 30467807 TI - Development and performance of a novel vasopressor-driven mortality prediction model in septic shock. AB - BACKGROUND: Vasoactive medications are essential in septic shock, but are not fully incorporated into current mortality prediction risk scores. We sought to develop a novel mortality prediction model for septic shock incorporating quantitative vasoactive medication usage. METHODS: Quantitative vasopressor use was calculated in a cohort of 5352 septic shock patients and compared using norepinephrine equivalents (NEE), cumulative vasopressor index and the vasoactive inotrope score models. Having best discrimination prediction, log10NEE was selected for further development of a novel prediction model for 28-day and 1 year mortality via backward stepwise logistic regression. This model termed 'MAVIC' (Mechanical ventilation, Acute Physiology And Chronic Health Evaluation III, Vasopressors, Inotropes, Charlson comorbidity index) was then compared to Acute Physiology And Chronic Health Evaluation-III (APACHE-III) and Sequential Organ Failure Assessment (SOFA) scores in an independent validation cohort for its accuracy in predicting 28-day and 1-year mortality. MEASUREMENTS AND MAIN RESULTS: The MAVIC model was superior to the APACHE-III and SOFA scores in its ability to predict 28-day mortality (area under receiver operating characteristic curve [AUROC] 0.73 vs. 0.66 and 0.60) and 1-year mortality (AUROC 0.74 vs. 0.66 and 0.60), respectively. CONCLUSIONS: The incorporation of quantitative vasopressor usage into a novel 'MAVIC' model results in superior 28-day and 1 year mortality risk prediction in a large cohort of patients with septic shock. PMID- 30467808 TI - Safety and Efficacy of Bupivacaine HCl Collagen-Matrix Implant (INL-001) in Open Inguinal Hernia Repair: Results from Two Randomized Controlled Trials. AB - INTRODUCTION: Surgical site infiltration with bupivacaine results in short-lived analgesia. The MATRIX-1 and MATRIX-2 studies examined the efficacy and safety of the bioresorbable bupivacaine HCl collagen-matrix implant (INL-001) for postsurgical pain after open inguinal hernia repair. INL-001, designed to provide early and extended delivery of bupivacaine, provides prolonged duration of perioperative analgesia. METHODS: In two phase 3 double-blind studies [MATRIX-1 (ClinicalTrials.gov identifier, NCT02523599) and MATRIX-2 (ClinicalTrials.gov identifier, NCT02525133)], patients undergoing open tension-free mesh inguinal hernia repair were randomized to receive 300-mg bupivacaine (three INL-001 100-mg bupivacaine HCl collagen-matrix implants) (MATRIX-1 n = 204; MATRIX-2 n = 213) or three placebo collagen-matrix implants (MATRIX-1 n = 101; MATRIX-2 n = 106) during surgery. Postsurgical medication included scheduled acetaminophen and as needed opioids. RESULTS: Patients who received INL-001 in both studies reported statistically significantly lower pain intensity (P <= 0.004; primary end point) and opioid analgesic use (P < 0.0001) through 24-h post-surgery versus those who received a placebo collagen-matrix. Patients who received INL-001 reported lower pain intensity through 72 h (P = 0.0441) for the two pooled studies. In both studies, more of the patients (28-42%) who received INL-001 used no opioid medication 0-24, 0-48, and 0-72 h post-surgery versus those who received a placebo collagen-matrix (12-22%). Among patients who needed opioid medication, patients receiving INL-001 used fewer opioids than those who received a placebo collagen-matrix through 24 h in both studies (P < 0.0001) and through 48 h in MATRIX-2 (P = 0.0003). Most adverse events were mild or moderate, without evidence of bupivacaine toxicity or deleterious effects on wound healing. CONCLUSION: These findings indicate that INL-001 results in post-inguinal hernia repair analgesia that is temporally aligned with the period of maximal postsurgical pain and may reduce the need for opioids while offering a favorable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT02523599; NCT02525133. FUNDING: Innocoll Pharmaceuticals. Plain language summary available for this article. PMID- 30467809 TI - Methoxyflurane Versus Standard of Care for Acute Trauma-Related Pain in the Emergency Setting: Protocol for a Randomised, Controlled Study in Italy (MEDITA). AB - INTRODUCTION: Low-dose methoxyflurane, administered via a hand-held inhaler, has been used for short-term pain relief in emergency medicine in Australia and New Zealand for over 40 years, and was recently approved in Europe for the rapid relief of moderate-to-severe trauma-related pain in adults. There is currently a lack of data for methoxyflurane versus active comparators, therefore this trial will investigate the efficacy and safety of inhaled methoxyflurane compared with standard of care (SoC) in the treatment of acute trauma-related pain in pre hospital and ED settings in Italy. METHODS: MEDITA (Methoxyflurane in Emergency Department in ITAly) is a Phase IIIb, prospective, randomised, active-controlled, parallel-group, open-label, multicentre trial. A total of 272 adult patients with moderate-to-severe pain [score >= 4 on the Numerical Rating Scale (NRS)] due to limb trauma will be randomised 1:1 to receive 3 mL methoxyflurane (self administered by the patient via inhalation under supervision of a trained person) or medications that currently comprise the SoC in Italy [intravenous (IV) morphine for severe pain (NRS >= 7); IV paracetamol or ketoprofen for moderate pain (NRS 4-6)], administered as soon as possible after randomisation. PLANNED OUTCOMES: Pain intensity will be measured using a 100-mm visual analogue scale (VAS) at baseline (time of randomisation) and at intervals up to 30 min. Time of onset of pain relief as reported by the patient and use of rescue medication will be recorded. The patient will rate the efficacy and the healthcare professional will rate the practicality of study treatment at 30 min after randomisation using a 5-point Likert scale. Adverse events will be recorded until safety follow-up at 14 +/- 2 days. Vital signs will be measured at baseline, 10 and 30 min. The primary aim is to demonstrate non-inferiority of methoxyflurane versus SoC for the change in VAS pain intensity from baseline (randomisation) to 3, 5 and 10 min. TRIAL REGISTRATION: EudraCT number: 2017-001565-25. Clinicaltrials.gov identifier: NCT03585374. FUNDING: Mundipharma Pharmaceuticals srl. PMID- 30467810 TI - Demineralized enamel reduces margin integrity of self-etch, but not of etch-and rinse bonded composite restorations. AB - The aim of this study was to investigate margin integrity of Class V composite restorations in demineralized and sound enamel after bonding with different etch and-rinse and self-etch adhesive systems. Out of a total of 60 specimens from bovine incisors, 30 specimens were demineralized (21 days, acid buffer, pH 4.95) to create artificial enamel lesions. Circular Class V cavities were prepared in all 60 specimens and treated with either an unfilled etch-and-rinse adhesive (Syntac Classic; Ivoclar Vivadent), a filled etch-and-rinse adhesive (Optibond FL; Kerr), or a self-etch adhesive (iBond Self Etch; Heraeus) (n = 10 per group). The cavities were restored with a nanofilled resin composite and thermocycled (5000*, 5-55 degrees C). Scanning electron microscopy was used to evaluate margin integrity of the composite restorations, and the percentage of continuous margin was statistically analyzed (alpha = 0.05). Demineralized enamel led to a significantly lower margin integrity when the self-etch adhesive iBond Self Etch was applied, but did not affect margin integrity when the etch-and-rinse adhesives Optibond FL (filled) or Syntac Classic (unfilled) were used. No significant differences in margin integrity in sound and demineralized enamel were observed between the different adhesives. Demineralized enamel reduces margin integrity of composite restorations when bonded with a self-etch adhesive, but does not affect margin integrity when an etch-and-rinse approach is used. PMID- 30467811 TI - Neuropsychological outcomes of patients with low-grade glioma diagnosed during the first year of life. AB - PURPOSE: Low-grade gliomas (LGG) are a heterogeneous group of brain tumors, which are often assumed to have a benign course. Yet, children diagnosed and treated for LGG in infancy are at increased risk for neurodevelopmental disruption. We sought to investigate neuropsychological outcomes of infants diagnosed with LGG. METHODS: Between 1986 and 2013, 51 patients were diagnosed with LGG before 12 months of age and managed at St. Jude Children's Research Hospital. Twenty-five of the 51 patients received a cognitive assessment (68% male; 6.8 +/- 3.3 months at diagnosis; 10.5 +/- 4.8 years at latest assessment). Approximately half the patients received radiation therapy (n = 12; aged 4.0 +/- 3.0 years at radiation therapy), with a median of 2 chemotherapy regimens (range = 0-5) and 1 tumor directed surgery (range = 0-5). RESULTS: The analyses revealed performance below age expectations on measures of IQ, memory, reading, mathematics, and fine motor functioning as well as parent-report of attention, executive, and adaptive functioning. Following correction for multiple comparisons, a greater number of chemotherapy regimens was associated with lower scores on measures of IQ and mathematics. More tumor directed surgeries and presence of visual field loss were associated with poorer dominant hand fine motor control. Radiation therapy exposure was not associated with decline in neuropsychological performance. CONCLUSIONS: Children diagnosed with LGG in infancy experience substantial neuropsychological deficits. Treatment factors, including number of chemotherapy regimens and tumor directed surgeries, may increase risk for neurodevelopmental disruption and need to be considered in treatment planning. PMID- 30467812 TI - Computerized assessment of cognitive impairment among children undergoing radiation therapy for medulloblastoma. AB - PURPOSE: Advantages to computerized cognitive assessment include increased precision of response time measurement and greater availability of alternate forms. Cogstate is a computerized cognitive battery developed to monitor attention, memory, and processing speed. Although the literature suggests the domains assessed by Cogstate are areas of deficit in children undergoing treatment for medulloblastoma, the validity of Cogstate in this population has not been previously investigated. METHODS: Children participating in an ongoing prospective trial of risk-adapted therapy for newly diagnosed medulloblastoma (n = 73; mean age at baseline = 12.1 years) were administered Cogstate at baseline (after surgery, prior to adjuvant therapy) and 3 months later (6 weeks after completion of radiation therapy). Gold-standard neuropsychological measures of similar functions were administered at baseline. RESULTS: Linear mixed models revealed performance within age expectations at baseline across Cogstate tasks. Following radiation therapy, there was a decline in performance on Cogstate measures of reaction time (Identification and One Back). Females exhibited slower reaction time on One Back and Detection tasks at baseline. Higher-dose radiation therapy and younger age were associated with greater declines in performance. Pearson correlations revealed small-to-moderate correlations between Cogstate reaction time and working memory tasks with well-validated neuropsychological measures. CONCLUSIONS: Cogstate is sensitive to acute cognitive effects experienced by some children with medulloblastoma and demonstrates associations with clinical predictors established in the literature. Correlations with neuropsychological measures of similar constructs offer additional evidence of validity. The findings provide support for the utility of Cogstate in monitoring acute cognitive effects in pediatric cancer. PMID- 30467813 TI - Surgical management of lower-grade glioma in the spotlight of the 2016 WHO classification system. AB - PURPOSE: According to the 2016 WHO classification lower-grade gliomas consist of three groups: IDH-mutated and 1p/19q co-deleted, IDH-mutated and IDH-wildtype tumors. The aim of this study was to evaluate the impact of surgical therapy for lower-grade gliomas with a particular focus on the molecular subgroups. METHODS: This is a bi-centric retrospective analysis including 299 patients, who underwent treatment for lower-grade glioma between 1990 and 2016. All tumors were re classified according to the 2016 WHO classification. Data concerning baseline and tumor characteristics, overall survival, different treatment modalities and functional outcome were analyzed. RESULTS: A total of 112 (37.5%) patients with IDH-mutation and 1p/19q co-deletetion, 86 (28.8%) patients with IDH-mutation and 101 (33.8%) patients with IDH-wildtype tumors were identified. The median overall survival (mOS) differed significantly between the groups (p < 0.001). Surgical resection was performed in 226 patients and showed significantly improved mOS compared to the biopsy group (p = 0.001). Gross total resection (GTR) was associated with better survival (p = 0.007) in the whole cohort as well as in the IDH-mutated and IDH-wildtype groups compared to partial resection or biopsy. IDH wildtype patients presented a significant survival benefit after combined radio chemotherapy compared to radio- or chemotherapy alone (p = 0.02). Good clinical status (NANO) was associated with longer OS (p = 0.001). CONCLUSION: The impact of surgical treatment on the outcome of lower-grade gliomas depends to a great extent on the molecular subtype of the tumors. Patients with more aggressive tumors (IDH-wildtype) seem to profit from more intensive treatment like GTR, multiple resections and combined radio-/chemotherapy. PMID- 30467814 TI - Prevalence and distribution pattern of intestinal helminths in chicken and pigeons in Aswan, Upper Egypt. AB - There is scarce data available on helminth infection of poultry in the region of Aswan province, Upper Egypt. A total of 276 poultry (156 baladi chickens and 120 domestic pigeons) were collected from different villages in Aswan province to screen the presence of intestinal helminths during the period from April 2016 to March 2017. The current investigation revealed that the overall prevalence was 55.79% (154/276). Additionally, 59.09% baladi chickens had mixed infections with four cestodes and three nematodes. Among cestodes, Raillietina tetragona was the most prevalent species (16.02%) followed by Raillietina echinobothrida (10.98%), Cotugnia digonopora (6.41%), and Raillietina cesticillus (1.28%). The most prevalent nematodal species were Heterakis gallinarum (15.38%), Ascaridia galli (8.97%), and Subulura brumpti (1.28%). In pigeons, 52.5% were found to be infected by four cestodes: Raillietina echinobothrida (22.5%), Cotugnia digonopora (13.33%), Raillietina tetragona (9.16%), and Raillietina cesticillus (3.33%) as well as one species of nematodes, Ascaridia columbae (9.16%). There was a close relationship between the occurrence of intestinal helminths and the age of domestic birds revealing that the high prevalence was found in adults rather than young birds. Meanwhile, it has been found that the highest prevalence was found in summer, while the lowest infection rate was recorded in winter. Further studies are needed to determine the effects of the parasites on the health and productivity of poultry in such area. PMID- 30467815 TI - The role of goats as reservoir hosts for bovine herpes virus 1 under field conditions. AB - Bovine herpesvirus 1 (BoHV1) is the cause of economically significant viral infections in cattle. Respiratory symptoms associated with the infection are known as Infectious Bovine Rhinotracheitis (IBR). Sheep and goats are less sensitive to the infection although their role in inter-species viral transmission under field conditions is subject to controversy. The objective of this study was to investigate seroprevalence of BoHV1 infections in cattle, sheep, and goats raised together for at least a year. Blood serum samples were taken from 226 cattle, 1.053 sheep, and 277 goats from 17 small- to medium-scale farms. BoHV1-specific antibody presence and titers were determined using virus neutralization test. In total, 73 of the 226 cattle (32.3%) were seropositive. The infection was detected in 13 of the 17 farms. Infection rates ranged from 5.8 to 88.8%. Only one of the 1053 sheep (0.09%) was seropositive. However, 58 of the 277 (20.9%) goats were seropositive. Goat samples taken from 8 of the 17 farms were seropositive with infection rates ranging from 17 to 38.9%. Statistical analysis showed a significant correlation in infection rates between cattle and goats but not sheep. These results suggest that goats may be more sensitive to the BHV1 infection than sheep and the role of goats as possible reservoirs for BoHV1 in the control and eradication of BHV1 in cattle should be considered in future studies. PMID- 30467816 TI - The Contractile Apparatus Is Essential for the Integrity of the Blood-Brain Barrier After Experimental Subarachnoid Hemorrhage. AB - Development of vasogenic brain edema is a key event contributing to mortality after subarachnoid hemorrhage (SAH). The precise underlying mechanisms at the neurovascular level that lead to disruption of the blood-brain barrier (BBB) are still unknown. Activation of myosin light chain kinases (MLCK) may result in change of endothelial cell shape and opening of the intercellular gap with subsequent vascular leakage. Male C57Bl6 mice were subjected to endovascular perforation. Brain water content was determined by wet-dry ratio and BBB integrity by Evans-Blue extravasation. The specific MLCK inhibitor ML-7 was administered to the mice to determine the role of the contractile apparatus of the neurovascular unit in determining brain water content, BBB integrity, neurofunctional outcome, brain damage, and survival at 7 days after SAH. Inhibition of MLCK significantly reduced BBB permeability (Evans Blue extravasation - 28%) and significantly decreased edema formation in comparison with controls (- 2%). MLCK-treated mice showed reduced intracranial pressure (- 53%), improved neurological outcome at 24 h and 48 h after SAH, and reduced 7-day mortality. Tight junction proteins claudin-5 and zonula occludens-1 levels were not influenced by ML-7 at 24 h after insult. The effect of ML-7 on pMLC was confirmed in brain endothelial cell culture (bEnd.3 cells) subjected to 4-h oxygen-glucose deprivation. The present study indicates that MLCK contributes to blood-brain barrier dysfunction after SAH by a mechanism that does not involve modulation of tight junction protein levels, but via activation of the contractile apparatus of the endothelial cell skeleton. This underlying mechanism may be a promising target for the treatment of SAH. PMID- 30467817 TI - [Self-help friendliness in ambulatory care, hospital care and rehabilitation services : Is collaboration with self-help structures being recognised in quality management systems?] AB - BACKGROUND: The "self-help friendliness" concept means the sustainably institutionalised collaboration of health services with self-help groups, led by criteria defining good collaboration. It aims to improve patient-centeredness. Therefore self-help friendliness should be taken into account in quality management systems (QMSs). OBJECTIVE: The objective is an analysis of whether and to what degree criteria of good collaboration have been introduced into the most widespread quality management systems in Germany. MATERIAL AND METHODS: Overall, 17 QMSs were analysed: hospital care (3), outpatient care (8), rehabilitation (6, the quantitatively most important ones). METHODS: analysis of websites, supplemented by a qualitative email survey with five to seven short questions building on our knowledge from websites and a previous survey. RESULTS: Criteria for good collaboration are well represented within QMSs for inpatient care and within the most widespread ones for doctors in ambulatory care (seven of seven relevant sector-specific QMSs). This is not the case in the quality management system based on DIN EN ISO 9001-2000 and three lesser used ones in ambulatory care. All six researched QMSs for rehabilitation services contain some (between one and four) tips for collaboration with self-help groups, however they are not very visible. DISCUSSION: The German network "Self-help friendliness and patient centeredness in health services" tries to improve the overall unsatisfactory situation through closer collaboration with QMSs. The recently started discussion on quality premiums for good healthcare services may be favourable for future development, if patient-centeredness is recognised as a crucial quality goal. PMID- 30467818 TI - Thinner than yourself: self-serving bias in body size estimation. AB - The self-serving bias is the tendency to consider oneself in unrealistically positive terms. This phenomenon has been documented for body attractiveness, but it remains unclear to what extent it can also emerge for own body size perception. In the present study, we examined this issue in healthy young adults (45 females and 40 males), using two body size estimation (BSE) measures and taking into account inter-individual differences in eating disorder risk. Participants observed pictures of avatars, built from whole body photos of themselves or an unknown other matched for gender. Avatars were parametrically distorted along the thinness-heaviness dimension, and individualised by adding the head of the self or the other. In the first BSE task, participants indicated in each trial whether the seen avatar was thinner or fatter than themselves (or the other). In the second BSE task, participants chose the best representative body size for self and other from a set of avatars. Greater underestimation for self than other body size emerged in both tasks, comparably for women and men. Thinner bodies were also judged as more attractive, in line with standard of beauty in modern western society. Notably, this self-serving bias in BSE was stronger in people with low eating disorder risk. In sum, positive attitudes towards the self can extend to body size estimation in young adults, making own body size closer to the ideal body. We propose that this bias could play an adaptive role in preserving a positive body image. PMID- 30467819 TI - Gluing life together. Computer simulation in the life sciences: an introduction. AB - Over the course of the last three decades, computer simulations have become a major tool of doing science and engaging with the world, not least in an effort to predict and intervene in a future to come. Born in the context of the Second World War and the discipline of physics, simulations have long spread into most diverse fields of enquiry and technological application. This paper introduces a topical collection focussing on simulations in the life sciences. Echoing the current state of tinkering, fast developments, segmentation of knowledge and interdisciplinary collaboration, and in an effort to bridge the science humanities divide, the contributors to this collection come from multiple disciplinary backgrounds, including information studies, cognitive sciences, philosophy and biology. The ambiguous character of simulations, their cutting across scientific disciplines, analysis and prediction, understanding and doing, gave rise to their success in contemporary life sciences and has been the object of much scientific debate. One of the main aims of this topical collection, by contrast, is to call into question the assumption of an obvious use and easy transfer of methods between fields of knowledge as diverse as, e.g. physics and biology. The collection presents historical case studies from various biological sub-fields. The articles study how simulations are used and the ways they contribute specifically to our understanding of life. Taking up Sergio Sismondo's description of simulations as "compromises" and "glue", they also critically engage with the question of what exactly the life sciences have been gluing together over the last two decades. PMID- 30467821 TI - Sex Differences in Social Attention in Infants at Risk for Autism. AB - We studied visual attention to emotional faces in 10-month-old infant siblings of children with ASD (ASD-sibs; N = 70) and a siblings of typically developing children (N = 29) using static stimuli. Contrary to our predictions, we found no evidence for atypical gaze behavior in ASD-sibs when boys and girls were analyzed together. However, a sex difference was found in ASD-sibs' visual attention to the mouth. Male ASD-sibs looked more at the mouth across emotions compared to male controls and female ASD-sibs. In contrast, female ASD-sibs looked less at the mouth compared to female controls. These findings suggest that some aspects of early emerging atypical social attention in ASD-sibs may be sex specific. PMID- 30467820 TI - Feasibility of collecting retrospective patient reported outcome measures (PROMs) in emergency hospital admissions. AB - INTRODUCTION: Outcome of emergency admissions is usually limited to mortality with little attempt to capture the views of health status of survivors. This is because of the challenge of determining patient reported outcome measures (PROMs) for the period before their emergency admission. The aim was to assess the feasibility of collecting retrospective PROMs to capture the pre-admission health status of patients admitted as emergencies. METHODS: Prospective study of two cohorts: patients undergoing primary coronary angioplasty for acute ST elevation myocardial infarction (STEMI) in five hospitals and emergency laparotomy (EL) for gastro-intestinal conditions in 11 hospitals. Three rates were calculated: proportion of patients eligible for inclusion; proportion of eligible patients invited to participate; proportion of invitees who participated. Staff views were thematically analysed to understand factors that affected recruitment. RESULTS: About 85% of patients were eligible of whom most were invited to participate (84% EL; 79% STEMI). The proportions of invitees agreeing to participate differed between STEMI (92%) and EL (72%), probably reflecting greater post-intervention morbidity in the latter. Variation between hospitals was observed in the proportion deemed eligible (EL 72-97%; STEMI 63-100%), proportion invited (EL 60 93%; STEMI 71-96%) and the proportion of invitees agreeing to participate (EL 55 92%; STEMI 67-100%). While this might reflect case-mix differences between hospitals, it suggests there is scope for less well performing hospitals to improve their recruitment processes. The extent to which this initial feasibility study was able to assess selection bias was limited to the age and sex of patients. There was no bias evident for EL patients but for STEMI, younger men were more likely to participate. CONCLUSION: It appears to be feasible to collect retrospective PROMs from patients admitted unexpectedly as emergencies for the two conditions studied. The relevance of these findings to other causes of emergency admissions needs to be established. In addition, these findings justify the case for a large, multi-site study that could explore unresolved concerns about selection bias, particularly those arising from the clinical characteristics of patients. It would also enable estimates of the extent of variation in PROMs between hospitals to determine the usefulness of using PROMs in emergency admissions. PMID- 30467822 TI - Apolipoprotein D Upregulation in Alzheimer's Disease but Not Frontotemporal Dementia. AB - Frontotemporal dementia (FTD) and Alzheimer's disease (AD) are the two common forms of dementia. FTD syndromes are characterized by lobar atrophy (frontotemporal lobar degeneration or FTLD) and the presence of either cellular TDP43 (FTLD-TDP), tau (FTLD-tau), or FUS aggregates, while extracellular beta amyloid plaques and hyperphosphorylated tau tangles develop in AD. Oxidative stress can induce these pathological modifications in disease models, and is thought to play a role in these syndromes. Apolipoprotein D (apoD) is a glial expressed lipocalin known to protect against oxidative stress, with increased levels in AD, supporting a protective role. The expression of apoD has not been studied in FTLD. This study assesses apoD expression in FTLD-TDP and FTLD-tau in comparison to AD and controls. It also analyzes the effect of apoD on TARDBP (TDP43 gene) and beta-amyloid precursor protein (APP). The expression of apoD was analyzed by Western blotting in FTLD-TDP, FTLD-tau, AD, and control post-mortem brain tissue. An apoD-overexpressing cell model was used to study the impact of increased apoD on APP and TARDBP expression. We confirm that apoD expression was increased in AD but surprisingly it was not affected in either of the two main pathological forms of FTLD. Under oxidative stress conditions, apoD had no effect on TDP43 expression but it did decrease APP expression. This suggests that apoD does not act as a neuroprotective factor in FTLD in the same way as in AD. This could contribute to the more rapid degeneration observed in FTLD. PMID- 30467823 TI - Mesenchymal Stem Cells from Nucleus Pulposus and Neural Differentiation Potential: a Continuous Challenge. AB - Mesenchymal stem cells (MSCs) are well-characterized adult stem cells, recently isolated from human nucleus pulposus of degenerate and non-degenerate intervertebral disc. The attention to this source is linked to its embryologic history and cells may conserve a stronger aptitude to neuronal differentiation than other MSCs. Here, MSCs from nucleus pulposus (NP-MSCs) were successfully isolated and characterized for morphology, proliferation, and expression of selected genes. Subsequently, the neuronal differentiation was induced by 10 days of culture with a neuronal medium. NP-MSCs subjected to neural differentiation media (NP-MSCs-N) showed a morphological and biochemical modifications. NP-MSCs-N displayed elongated shape with protrusion, intermediate filaments, microtubules, and electron dense granules and the ability to form neurospheres. Even if they expressed neural markers such as NESTIN, beta-TUBULIN III, MAP-2, GAP-43, and ENOLASE-2, the neural differentiated cells did not show neither spontaneous nor evoked intracellular calcium variations compared to the undifferentiated cells, suggesting that cells do not have electric functional properties. Further studies are required in order to get a better understanding and characterization of NP MSCs and analyzed the molecular mechanisms that regulate their neural differentiation potential. PMID- 30467824 TI - Next-generation sequencing-based characterization of the invasion by anatomical contiguity in a primary osseous diffuse large B-cell lymphoma. Correlation between the genetic profile of the malignancy and the clinical outcome of the patient. AB - Primary bone lymphoma is now a well-described entity in the World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone as a malignancy of the lymphoid tissue, with at least one mass within bone, without involvement of supraregional lymph nodes or other extranodal sites. In the current paper, we describe the complete characterization of the mutational landscape of a diffuse large B cell non-Hodgkin's lymphoma (DLBLCL) of the tibial plateau. Currently, there is very little data about the genetic landscape of primary osseous lymphomas and about the genetic background of this type of malignancy, resistant to chemotherapy and invading the surrounding tissues. In the current paper, we describe the complete characterization of the mutational landscape of a DLBCL of the tibial plateau. Our data is consistent with already published data, that have shown that MKI67 activation is correlated with lymphoma progression. Along with a high Ki67 index, resistance to chemotherapy occurs with neurogenic locus notch homolog protein 1 (Notch) and KRAS activation. This is the first molecular characterization for the invasion by anatomical contiguity for a primary bone lymphoma and while we only characterized one case and further deep sequencing analyses are required, we can explain the clinical dismal evolution of the patient by correlating them with the genetic landscape of this type of lymphoma. PMID- 30467825 TI - Nonspecific Symptoms Lack Diagnostic Accuracy for Infection in Older Patients in the Emergency Department. AB - OBJECTIVES: To determine if nonspecific symptoms and fever affect the posttest probability of acute bacterial infection in older patients in the emergency department (ED). DESIGN: Preplanned, secondary analysis of a prospective observational study. SETTING: Tertiary care, academic ED. PARTICIPANTS: A total of 424 patients in the ED, 65 years or older, including all chief complaints. MEASUREMENTS: We identified presence of altered mental status, malaise/lethargy, and fever, as reported by the patient, as documented in the chart, or both. Bacterial infection was adjudicated by agreement among two or more of three expert reviewers. Odds ratios were calculated using univariable logistic regression. Positive and negative likelihood ratios (PLR and NLR, respectively) were used to determine each symptom's effect on posttest probability of infection. RESULTS: Of 424 subjects, 77 (18%) had bacterial infection. Accounting for different reporting methods, presence of altered mental status (PLR range, 1.40-2.53) or malaise/lethargy (PLR range, 1.25-1.34) only slightly increased posttest probability of infection. Their absence did not assist with ruling out infection (NLR, greater than 0.50 for both). Fever of 38 degrees C or higher either before or during the ED visit had moderate to large increases in probability of infection (PLR, 5.15-18.10), with initial fever in the ED perfectly predictive, but absence of fever did not rule out infection (NLR, 0.79 0.92). Results were similar when analyzing lower respiratory, gastrointestinal, and urinary tract infections (UTIs) individually. Of older adults diagnosed as having UTIs, 47% did not complain of UTI symptoms. CONCLUSIONS: The presence of either altered mental status or malaise/lethargy does not substantially increase the probability of bacterial infection in older adults in the ED and should not be used alone to indicate infection in this population. Fever of 38 degrees C or higher is associated with increased probability of infection. PMID- 30467826 TI - Using predicted Spanish preference to target bilingual mailings in a mail survey with telephone follow-up. AB - OBJECTIVE: Spanish-preferring Medicare beneficiaries are underrepresented in national patient experience surveys. We test a method for improving their representation via higher response rates. DATA SOURCES/STUDY SETTING: 2009-2010 Medicare CAHPS surveys; Medicare population. STUDY DESIGN: We used surname and address to predict Spanish-language preference for a national sample of 177 139 beneficiaries. We randomized half of the 10 000 non-Puerto Rico beneficiaries with the highest predicted probabilities of Spanish preference (>10 percent) to bilingual mailings (intervention) and half to standard English-only mailings (control). DATA COLLECTION: Medicare CAHPS Survey data were collected through mail surveys with telephone follow-up of nonrespondents. PRINCIPAL FINDINGS: Mail response rate was higher for intervention (28.7 percent) than control (23.9 percent) (P < 0.0001); phone response rates among mail nonrespondents were similar in intervention and control arms (15.8 percent vs 15.7 percent, P = 0.90). Targeted bilingual mailings induced 6.5 percent of those who would not have responded to respond by mail and 54.0 percent of those who would have responded in English to respond in Spanish. Beneficiaries with greater Spanish probabilities showed greater increases in response rates, a higher proportion of responses in Spanish, and lower control response rates among. CONCLUSIONS: Targeted bilingual mailing of mixed-mode surveys using commonly available surname and address information can efficiently increase representation of this underrepresented group. PMID- 30467827 TI - Fibreoptic-guided tracheal intubation through i-gel(r) and LMA(r) ProtectorTM supraglottic airway devices - a randomised comparison. AB - Fibreoptic-guided tracheal intubation using a supraglottic airway device as a conduit is a technique that can be used in anticipated and unanticipated difficult airway management. Although the i-gel(r) supraglottic airway device has been examined for this purpose, the LMA(r) ProtectorTM , a recently introduced second-generation supraglottic airway device, has not been evaluated for this use in clinical trials. This prospective, randomised clinical trial compared fibreoptic-guided tracheal intubation via i-gel and LMA Protector supraglottic airway devices in two UK hospitals. Patients who were ASA physical status 1 or 2 and undergoing elective surgery requiring tracheal intubation were recruited to the study. A block randomisation list was generated for each study site. The primary outcome measure was time to successful tracheal intubation and secondary outcomes were tracheal intubation success rate, glottic view through flexible fibrescope, ease of tracheal intubation using operator visual analogue score, supraglottic airway device insertion time and insertion success rate. Ninety patients were randomly allocated to each device, and final data analysis was carried out for 92 patients in the i-gel group and 86 patients in the LMA Protector group. Mean (SD) tracheal intubation time in the i-gel and LMA Protector groups were 54.3 (13.8) s and 52.0 (13.0) s, respectively (p = 0.240). There were no significant differences in tracheal intubation success rate, glottic view and ease of tracheal intubation between the two groups. This study demonstrates that the LMA Protector supraglottic airway device is comparable to the i-gel supraglottic airway device as a conduit for fibreoptic-guided tracheal intubation. PMID- 30467828 TI - Evolution of multiple myeloma treatment practices in Europe from 2014 to 2016. PMID- 30467829 TI - Fibrinogen concentrate vs. fresh frozen plasma for the management of coagulopathy during thoraco-abdominal aortic aneurysm surgery: a pilot randomised controlled trial. AB - Major vascular surgery is frequently associated with significant blood loss and coagulopathy. Existing evidence suggests hypofibrinogenaemia develops earlier than other haemostatic deficiencies during major blood loss. The purpose of this study was to assess whether the use of an infusion of fibrinogen concentrate to prevent and treat hypofibrinogenaemia during surgery resulted in satisfactory haemostasis, removing or reducing the need for blood component transfusion. Twenty patients undergoing elective extent-4 thoraco-abdominal aortic aneurysm repair were randomly allocated to receive either fresh frozen plasma or fibrinogen concentrate to treat hypofibrinogenaemia during surgery. Coagulation was assessed during and after surgery by point-of-care and laboratory testing, respectively, and treatment was guided by pre-defined transfusion triggers. Despite blood losses of up to 11,800 ml in the patients who received the fibrinogen concentrate, none required fresh frozen plasma during surgery, and only two required platelet transfusions. The median (IQR [range]) allogeneic blood component administration during surgery and in the first 24 h postoperatively was 22.5 (14-28 [2-41]) units in patients allocated to fresh frozen plasma vs. 4.5 (3-11[0-17]) in patients allocated to fibrinogen concentrate (p = 0.011). All patients in both groups were assessed by the surgeon to have satisfactory haemostasis at the end of surgery. Mean (SD) postoperative fibrinogen concentrations were similar in patients allocated to fresh frozen plasma and fibrinogen concentrate (1.6 (0.3) g.l-1 vs. 1.6 (0.2) g.l-1 ; p = 0.36) but the mean (SD) international normalised ratio and activated partial thromboplastin time ratio were lower in patients allocated to fresh frozen plasma (1.1 (0.1) vs. 1.8 (0.3); p < 0.0001 and 1.1 (0.2) vs. 1.7 (0.5); p = 0.032, respectively). Fibrinogen concentrate may be used as an alternative to fresh frozen plasma in the treatment of coagulopathy during thoraco-abdominal aortic aneurysm repair. PMID- 30467830 TI - The Case for Pharmacogenetics-Guided Prescribing of Codeine in Children. PMID- 30467831 TI - Geographic context of black-white disparities in Medicare CAHPS patient experience measures. AB - OBJECTIVE: To examine whether black-white patient experience disparities vary by geography and within-county contextual factors. DATA SOURCES: 321 300 Medicare beneficiaries responding to the 2015-2016 Medicare Consumer Assessment of Health care Providers and Systems (MCAHPS) Surveys; 2010 Census data for several within county contextual factors. STUDY DESIGN: Mixed-effects regression models predicted three MCAHPS patient experience measures for black and white beneficiaries from geographic random effects, contextual fixed effects, and beneficiary-level case-mix adjustors. PRINCIPAL FINDINGS: Black-white disparities in patient experiences were smaller in counties with higher average patient experiences. Black-white disparities in patient experiences were not associated with county-level poverty or racial segregation. However, county racial segregation and some measures of poverty were significantly associated with all beneficiaries' level of health care access. Getting Needed Care scores were higher with greater racial segregation, while Getting Care Quickly scores were lower with higher poverty and racial segregation. CONCLUSIONS: Efforts to reduce black-white disparities in patient experiences should focus on areas with low average patient experiences. Attempts to reduce disparities in timely access to health care should target primarily black, low-income, and racially and economically segregated areas. Positive associations of racial segregation with accessing needed care were unexpected. PMID- 30467832 TI - Prevalence and Associated Phenotypes of PLXNA1 Variants in Normosmic and Anosmic Idiopathic Hypogonadotropic Hypogonadism. AB - Idiopathic Hypogonadotropic Hypogonadism (IHH) can be divided into two major forms, normosmic IHH and Kallmann syndrome (KS). Genetic mutations are responsible for the majority of IHH. PLXNA1 has recently been implicated in the GnRH neuron migration and the etiology of KS. We aimed to investigate the prevalence and associated phenotypes of PLXNA1 variants in a large cohort of IHH patients. We screened the whole exome data of 215 IHH patients in a single center for causative PLXNA1 variants. Our studies revealed eight novel (p.Arg836His, p.Lys1451Arg, p.Val287Met, p.Val536Ile, p.Ser1850Arg, p.Ile1701Val, p.Arg319Trp, and p.Pro485Leu) and two previously described (p.Arg528Trp and p.Gly720Glu) heterozygous PLXNA1 variants in 9 affected individuals from 7 unrelated families. Only three of nine patients were anosmic (KS) while the remaining patients showed normal olfactory function (nIHH). Seven of nine patients (77.7%) harbored additional one or two variants in other nIHH/KS-associated genes, including PROKR2, IGSF10, HS6ST1, SEMA3E, CCDC141, FGFR1, NRP1, POLR3A, and SRA1. Our findings indicate that PLXNA1 variants cause not only anosmic but also normosmic IHH with a relatively high prevalence (3.9%). Heterozygous missense PLXNA1 variants appear to be involved together with other IHH gene variants in bringing about the IHH disease phenotype. This article is protected by copyright. All rights reserved. PMID- 30467833 TI - Clinical features and outcomes of spitzoid proliferations in children and adolescents. AB - BACKGROUND: Spitzoid proliferations range from Spitz nevi to melanomas, and there are few studies describing clinical features and outcomes in the pediatric population. OBJECTIVES: Determine clinical features and outcomes of a large pediatric cohort with histopathologically-confirmed Spitz tumors. METHODS: Retrospective cohort study of Boston Children's Hospital patients younger than 20 years with a histopathologic diagnosis of spitzoid proliferation from 1/1/1994 - 10/23/2012. RESULTS: Five hundred ninety-five patients with 622 spitzoid proliferations were identified [median age = 7.4 years, (25th , 75th ) quartiles = (4.6, 11.7) years]. Five hundred twelve (82.3%) proliferations were typical, 107 (17.2.%) were atypical, and 3 (0.5%) were melanomas. Median age at biopsy was 7.4, 7.2, and 17.2 years, respectively, and there was a significant difference in age at biopsy for patients with typical or atypical proliferations versus melanoma (p<0.01). Among samples with positive margins (n = 153), 55.1% (54/98) of typical proliferations, 77.4% (41/53) of atypical proliferations, and 100.0% (2/2) of melanomas were re-excised. Six patients had sentinel lymph node biopsy performed, with 3 patients demonstrating nodes positive for melanocytic cells. With median follow-up of 4.1 years for the full cohort, there were no related deaths. CONCLUSION: Spitz tumors have strikingly benign outcomes in the pediatric population, though this study is limited by low number of melanomas and restriction to a single pediatric institution. Aggressive management recommendations should be reconsidered for children and adolescents with banal appearing Spitz nevi, based upon the clinically indolent behavior in this cohort. This article is protected by copyright. All rights reserved. PMID- 30467834 TI - Juvenile hormone as a physiological regulator mediating phenotypic plasticity in pancrustaceans. AB - Phenotypic plasticity and polyphenism, in which phenotypes can be changed depending on environmental conditions, are common in insects. Several studies focusing on physiological, developmental, and molecular processes underlying the plastic responses have revealed that similar endocrine mechanisms using juvenile hormone (JH) are used to coordinate the flexible developmental processes. This review discusses accumulated knowledge on the caste polyphenism in social insects (especially termites), the wing and the reproductive polyphenisms in aphids, and the nutritional polyphenism and sexual dimorphism in stag beetles. For the comparison with non-insect arthropods, extensive studies on the inducible defense (and reproductive polyphenism) in daphnids (crustacean) are also addressed. In all the cases, JH (and methyl farnesoate in daphnids) plays a central role in mediating environmental stimuli with morphogenetic processes. Since the synthetic pathways for juvenoids, i.e., the mevalonate pathway and downstream pathways to sesquiterpenoids, are conserved across pancrustacean lineages (crustaceans and hexapods including insects), the evolution of developmental regulation by juvenoids that control molting (ecdysis) and metamorphosis is suggested to have occurred in the ancestral arthropods. The discontinuous postembryonic development (i.e., molting) and the regulatory physiological factors (juvenoids) would have enabled plastic developmental systems observed in many arthropod lineages. PMID- 30467835 TI - Photoperiod-temperature phase lag: A universal environmental context of seasonal developmental plasticity. AB - Seasonal developmental plasticity, which consists of season-dependent alternations of developmental processes, has evolved to produce optimal phenotypes depending on specific periods in a year. For example, many phenological events in plants, such as flowering, fruiting, bud blast, bud formation, and growth cessation, are often controlled seasonally. Although temperature and photoperiod are the two major seasonal cues for such responses, the importance of phase lag between annual oscillations of the two signals has been unexplored, despite its universal nature in the context of seasonal environments. In this article, the phase-lag calendar hypothesis (New Phytologist, 210, 2016, 399), especially the one between temperature and photoperiod, is explained using meteorological data obtained from central Japan as an example. We set forth to show how, for a narrow window in time of a couple of weeks in a year, simple threshold responses to these two signals that differ in annual oscillation phases are enough to make developmental plasticity to be expressed as phenological events. The properties of the underlying mechanisms of the events in different seasons are further predicted, and the responses are compared with reported empirical examples. Because many organisms have evolved under the phase lag between photoperiod and temperature, the developmental plasticity in response to the phase lag should be evaluated for diverse organisms. PMID- 30467837 TI - Movement responses to environment: fast inference of variation among southern elephant seals with a mixed effects model. AB - Like many species, movement patterns of southern elephant seals (Mirounga leonina) are being influenced by long-term environmental change. These seals migrate up to 4000 km from their breeding colonies, foraging for months in a variety of Southern Ocean habitats. Understanding how movement patterns vary with environmental features and how these relationships differ among individuals employing different foraging strategies can provide insight into foraging performance at a population level. We apply new fast-estimation tools to fit mixed effects within a random walk movement model, rapidly inferring among individual variability in southern elephant seal environment-movement relationships. We found that seals making foraging trips to the sea-ice on or near the Antarctic continental shelf consistently reduced speed and directionality (move persistence) with increasing sea-ice coverage but had variable responses to chlorophyll a concentration, whereas seals foraging in the open ocean reduced move persistence in regions where circumpolar deep water shoaled. Given future climate scenarios, open-ocean foragers may encounter more productive habitat but sea-ice foragers may see reduced habitat availability. Our approach is scalable to large telemetry data sets and allows flexible combinations of mixed effects to be evaluated via model selection, thereby illuminating the ecological context of animal movements that underlie habitat usage. This article is protected by copyright. All rights reserved. PMID- 30467836 TI - JNK2 modulates the CD1d-dependent and -independent activation of iNKT cells. AB - Invariant natural killer T (iNKT) cells play critical roles in autoimmune, anti tumor, and anti-microbial immune responses, and are activated by glycolipids presented by the MHC class I-like molecule, CD1d. How the activation of signaling pathways impacts antigen (Ag)-dependent iNKT cell activation is not well-known. In the current study, we found that the MAPK JNK2 not only negatively regulates CD1d-mediated Ag presentation in APCs, but also contributes to CD1d-independent iNKT cell activation. A deficiency in the JNK2 (but not JNK1) isoform enhanced Ag presentation by CD1d. Using a vaccinia virus (VV) infection model known to cause a loss in iNKT cells in a CD1d-independent, but IL-12-dependent manner, we found the virus-induced loss of iNKT cells in JNK2 KO mice was substantially lower than that observed in JNK1 KO or wild-type (WT) mice. Importantly, compared to WT mice, JNK2 KO mouse iNKT cells were found to express less surface IL-12 receptors. As with a VV infection, an IL-12 injection also resulted in a smaller decrease in JNK2 KO iNKT cells as compared to WT mice. Overall, our work strongly suggests JNK2 is a negative regulator of CD1d-mediated Ag presentation and contributes to IL-12-induced iNKT cell activation and loss during viral infections. PMID- 30467838 TI - Impact of graft-versus-lymphoma effect on outcomes after reduced intensity conditioned-alemtuzumab allogeneic haematopoietic stem cell transplantation for patients with mature lymphoid malignancies. AB - Allogeneic haematopoietic stem cell transplant (allo-HSCT) offers potentially curative therapy for patients with relapsed/refractory lymphoid malignancies. Reduced-intensity conditioning (RIC) with Alemtuzumab reduces transplant-related mortality and graft-versus-host disease (GvHD), but may be associated with increased risk of relapse. With the aim of studying the effect of GVHD and donor lymphocyte infusions (DLI) on relapse, we performed a retrospective study of 288 patients (57% non-Hodgkin lymphoma, 24% Hodgkin lymphoma and 19% chronic lymphocytic leukaemia; 58% were relapsed/refractory) who underwent RIC Alemtuzumab-HSCT between 2000 and 2012. Median follow-up time for survivors was 64 months. Five-year overall survival, relapse incidence, GvHD/relapse-free survival and non-relapse mortality were 47%, 33%, 37% and 28% respectively. Cumulative incidence of grade II-IV acute and extensive chronic GvHD was 22% and 21% at 100 days and 5 years respectively. On multivariate analysis, presence of GvHD (P = 0.03) and unrelated donor type (P = 0.03) were protective of relapse. 62/288 patients received DLI for either mixed donor chimerism (prophylactic DLI, n = 37) or clinical relapse (therapeutic DLI, n = 25). Prophylactic and therapeutic DLI successfully converted the patient to full or stable mixed donor chimerism in 78% and 56% of patients respectively. These data demonstrate good long-term outcomes and support the concept of the graft-vs-lymphoma effect as a key protective factor against relapse following RIC-Alemtuzumab allo-HSCT for patients with mature lymphoid malignancies. PMID- 30467839 TI - Prophylactic donor lymphocyte infusion after allogeneic stem cell transplantation in acute leukaemia - a matched pair analysis by the Acute Leukaemia Working Party of EBMT. AB - Strategies for relapse prevention after allogeneic transplantation in acute leukaemia are warranted. A registry-based matched-pair analysis evaluated the efficacy of prophylactic donor lymphocyte infusion (proDLI). Adults receiving proDLI in complete remission (CR) and controls were pair-matched for age, diagnosis, cytogenetics, stage, donor, gender, conditioning and T-cell depletion. Eighty-nine pairs were identified (median follow-up: 6.9 years). Within the entire cohort, no difference was observed. However, among patients with high-risk acute myeloid leukaemia (AML) (unfavourable cytogenetics and/or transplanted beyond first CR), proDLI recipients had improved overall survival (69.8% vs. 40.2% in controls, P = 0.027). ProDLI has moderate efficacy, but can contribute to improved outcome in high-risk AML. PMID- 30467841 TI - Atopic dermatitis at preschool age and contact allergy in adolescence: a population-based cohort study. AB - BACKGROUND: Atopic dermatitis (AD) is characterized by an impaired skin barrier that can allow enhanced penetration of allergens. It is not clear whether AD influences the risk of developing contact allergy. OBJECTIVES: To examine the association between AD at preschool age and contact allergy at 16 years of age. METHODS: At 16 years of age, 2215 adolescents from the population-based cohort BAMSE were included. These adolescents had been followed with repeated questionnaires regarding AD throughout childhood, and contact allergy was assessed by skin patch test at 16 years. RESULTS: AD at preschool age was associated with contact allergy to at least one of the tested substances at 16 years of age among boys (adjusted odds ratio [OR] 1.51, 95% confidence interval 1.03-2.20), but not among girls (adjusted OR 0.77, 95% CI 0.54-1.10). AD at preschool age was not associated with contact allergy to nickel in either boys or girls. In contrast, AD at preschool age was associated with contact allergy to fragrance mix I (adjusted OR 3.10, 95% CI 1.66-5.80). This association was observed especially for AD at preschool age in combination with immunoglobulin E (IgE) sensitization to airborne or food allergens (adjusted OR 3.80, 95% CI 1.67 8.61). CONCLUSIONS: The results suggest that AD in early childhood may be associated with contact allergy to fragrances, but not to nickel, in adolescence. This article is protected by copyright. All rights reserved. PMID- 30467840 TI - New insights into red cell rheology and adhesion in patients with sickle cell anaemia during vaso-occlusive crises. PMID- 30467842 TI - Cancer specific survival in patients with sickle cell disease. AB - Sickle cell disease (SCD) patients have a higher incidence of certain cancers, but no studies have determined the impact of cancer on survival among SCD patients. SCD patients (n = 6423), identified from state-wide hospitalisation data, were linked to the California Cancer Registry (1988-2014). Multivariable Cox proportional hazards regression was used to examine survival. Among SCD patients, a cancer diagnosis was associated with a 3-fold increased hazard of death. Compared to matched cancer patients without SCD, SCD was associated with worse overall survival, but not cancer-specific survival, suggesting that SCD cancer patients should be treated with similar therapeutic intent. PMID- 30467843 TI - Prevalence and correlates of growth failure in young African patients with sickle cell disease. AB - Growth failure (GF) in children with sickle cell disease (SCD) tends to decline in high-income countries, but data are lacking in sub-Saharan Africa. We performed a cross-sectional study nested in the CADRE (Coeur, Arteres et DREpanocytose) cohort in Mali, Senegal, Cameroon, Gabon and the Ivory Coast. SCD patients and healthy controls aged 5-21 years old were recruited (n = 2583). Frequency of GF, defined as a height, weight or body mass index below the 5th percentile on World health Organization growth charts, was calculated. We assessed associations between GF and SCD phenotypic group, clinical and biological characteristics and history of SCD-related complications. GF was diagnosed in 51% of HbSS, 58% of HbSbeta0 , 44% of HbSC, 38% of HbSbeta+ patients and 32% of controls. GF in patients was positively associated with parents' lower education level, male sex, age 12-14 years, lower blood pressure, HbSS or HbSbeta0 phenotypes, icterus, lower haemoglobin level, higher leucocyte count and microalbuminuria. No association was found between GF and clinical SCD-related complications. In sub-Saharan Africa, GF is still frequent in children with SCD, especially in males and during adolescence. GF is associated with haemolysis and microalbuminuria, but not with the history of SCD-related clinical complications. PMID- 30467844 TI - Exome analysis of treatment-related AML after APL suggests secondary evolution. PMID- 30467845 TI - Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma. PMID- 30467846 TI - Impact of stratification on the effectiveness of a comprehensive patient-centered strategy for multimorbid patients. AB - OBJECTIVE: The objective of this work was to assess the effectiveness of a population-level patient-centered intervention for multimorbid patients based on risk stratification for case finding in 2014 compared with the baseline scenario in 2012. DATA SOURCE: Clinical and administrative databases. STUDY DESIGN: This was an observational cohort study with an intervention group and a historical control group. A propensity score by a genetic matching approach was used to minimize bias. Generalized linear models were used to analyze relationships among variables. DATA COLLECTION: We included all eligible patients at the beginning of the year and followed them until death or until the follow-up period concluded (end of the year). The control group (2012) totaled 3558 patients, and 4225 patients were in the intervention group (2014). PRINCIPAL FINDING: A patient centered strategy based on risk stratification for case finding and the implementation of an integrated program based on new professional roles and an extensive infrastructure of information and communication technologies avoided 9 percent (OR: 0.91, CI: 0.86-0.96) of hospitalizations. However, this effect was not found in nonprioritized groups whose probability of hospitalization increased (OR: 1.19, CI = 1.09-1.30). CONCLUSIONS: In a before-and-after analysis using propensity score matching, a comprehensive, patient-centered, integrated care intervention was associated with a lower risk of hospital admission among prioritized patients, but not among patients who were not prioritized to receive the intervention. PMID- 30467847 TI - TNF-alpha-TNFR signal pathway inhibits autophagy and promotes apoptosis of alveolar macrophages in coal worker's pneumoconiosis. AB - OBJECTIVE: Exposure to coal dust causes the development of coal worker's pneumoconiosis (CWP), which is associated with accumulating macrophages in the lower respiratory tract. This study was performed to investigate the effect of tumor necrosis factor-alpha (TNF-alpha)-tumor necrosis factor receptor (TNFR) signal pathway on autophagy and apoptosis of alveolar macrophages (AMs) in CWP. METHODS: AMs from controls exposed to coal dust and CWP patients were collected, in which expressions of TNF-alpha and TNFR1 were determined. Autophagy was observed by transmission electron microscopy, and apoptosis by light microscope and using terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. AMs in CWP patients were treated with TNF-alpha or anti-TNF-alpha antibody. Besides, expressions of autophagy marker proteins, apoptosis-related factors, FAS, caspase-8, and receptor-interacting serine-threonine-protein kinase 3 (RIPK3) were determined by western Blot. Activities of caspase-3 and caspase-8 were determined by a fluorescence kit. Flow cytometry was applied to measure the expression of TNFR1 on the surface of the AM. RESULTS: TNF-alpha expression and TNFR1 expression on the surface of AM, as well as autophagy and apoptotic index were significantly increased in AMs of CWP patients. In response to the treatment of TNF-alpha, TNF-alpha expression and TNFR1 expression on the surface of AM as well as LC3I expression were increased, autophagy was decreased, and LC3, LC3II, Beclin1 and B-cell lymphoma 2 expressions decreased, whereas FAS expression and activity and expression of caspase-3 and caspase-8 increased, and apoptotic index increased. Moreover, the situations were reversed with the treatment of anti-TNF alpha antibody. CONCLUSION: TNF-alpha-TNFR signal pathway was involved in the occurrence and development of CWP by activating FAS-caspase-8 and thus inhibiting autophagy while promoting apoptosis of AM. PMID- 30467848 TI - Risk-based approach versus culture-based screening for identification of group B streptococci among women in labor. AB - OBJECTIVE: To compare a risk-based and culture-based screening approach for identification of group B streptococci (GBS) vaginal colonization using an intrapartum rectovaginal culture as the reference standard. METHODS: Pregnant women attending the prenatal clinic at Lillebaelt Hospital, Kolding, Denmark, between April 1, 2013, and June 30, 2014, were invited to participate in a prospective observational study. For prepartum culture-based screening, vaginal and rectal culture samples were obtained and, for reference, standard, paired vaginal and rectal culture samples were collected during labor. Risk factors for risk-based screening were previous early-onset GBS, GBS bacteriuria during pregnancy, maternal temperature >=38.0 degrees C intrapartum, and rupture of membranes for more than 18 hours. RESULTS: The intrapartum rectovaginal GBS colonization rate was 30% (32/108) among participants with risk factors and 15% (123/794) among participants without risk factors. Culture-based screening demonstrated a sensitivity, specificity, positive predictive value, negative predictive value, and positive likelihood ratio in predicting intrapartum GBS carriage of 78% (95% confidence interval [CI] 71-84), 95% (94-97), 78% (70-84), 95% (94-97), and 17 (12-23), respectively; for risk-based screening, these values were 21% (15-28), 90% (87-92), 30% (22-38), 85% (83-86), and 2 (1-3), respectively. CONCLUSIONS: Culture-based screening performed considerably better than a risk-based approach in identifying intrapartum GBS colonization. PMID- 30467849 TI - Cardiac biomarkers and health-related quality of life in patients with light chain (AL) amyloidosis. PMID- 30467851 TI - Should the Contralateral Tonsil Be Removed in Cases of HPV-Positive Squamous Cell Carcinoma of the Tonsil? PMID- 30467850 TI - Donor-type fresh frozen plasma is effective in preventing hemolytic reaction in major ABO incompatible allogeneic stem cell transplant. AB - BACKGROUND: Hemolysis at the time of graft infusion is one of the immediate complications in major ABO-incompatible allogeneic hematopoietic stem cell transplants (HSCTs). We conducted a retrospective analysis to evaluate the efficacy of donor-type fresh frozen plasma (FFP) in reducing isohemagglutinin titer and preventing hemolysis, as well as its effect on delayed red cell engraftment. MATERIALS AND METHODS: This is a single-center study on a series of 380 allogeneic HSCT between 2005 and 2015; of which 99 were either major (n = 74) or bidirectional (n = 25) ABO mismatched. Pre-transplant infusion of FFP, post transplant complications and transfusion requirements were determined by retrospective review of individual medical records. Laboratory results were also reviewed for evidence of hemolysis and pure red cell aplasia (PRCA). RESULTS: Clinical manifestation of hemolysis attributable to ABO mismatch was present in one recipient of major ABO-incompatible peripheral blood stem cell (PBSC) with a titer of 64. Another recipient of major ABO-incompatible PBSC with a titer of 64 showed biochemical evidence of hemolysis. Both patients recovered with supportive treatment. Hemolysis did not occur in any patients with titer of 32 or less at the time of stem cell infusion. We were unable to demonstrate the influence of any variables on the incidence of PRCA. CONCLUSION: Our experience demonstrated that donor-type FFP is safe and effective in preventing acute hemolysis in major ABO-mismatched HSCT. We have also established the titer of 64 as the threshold that may cause hemolysis and therefore efforts should be made to reduce titer to below this level. PMID- 30467852 TI - A metabolomic strategy revealed the role of JA and SA balance in Clematis terniflora DC. response to UVB radiation and dark. AB - Clematis terniflora DC. is a valuable resource with potential high pharmaceutical value. Proteomic, transcriptomic, and metabolomic analyses of C. terniflora that has been exposed to high levels of UVB irradiation and dark conditions (HUVB + D) have revealed the mechanisms underlying its medicinal potential. However, the signal transduction pathways and the mechanisms of regulation for the accumulation of secondary metabolites remain unclear. In this study, we show that the jasmonic acid (JA) and salicylic acid (SA) signals were activated in C. terniflora in response to HUVB + D. Metabolomic analysis demonstrated that the perturbation in JA and SA balance led to additional reallocation of carbon and nitrogen resources. Evaluating the fold change ratios of differentially changed metabolites proved that JA signal enhanced the transformation of nitrogen to carbon through the 4-aminobutyric acid (GABA) shunt pathway, which increased the carbon reserve to be utilized in the production of secondary metabolites. However, SA signal induced the synthesis of proline, while avoiding the accumulation of secondary metabolites. Over all, the results indicate that the co increase of JA and SA reconstructed the dynamic stability of transformation from nitrogen to carbon, which effectively enhanced the oxidative defense to HUVB + D in C. terniflora by increasing the secondary metabolites. This article is protected by copyright. All rights reserved. PMID- 30467853 TI - Stillbirths and neonatal deaths surveillance during the 2014-2015 Ebola virus disease outbreak in Sierra Leone. AB - OBJECTIVE: To determine rates of stillbirth and neonatal mortality in Sierra Leone during the 2014-2015 Ebola virus disease (EVD) outbreak. METHODS: A cross sectional study was performed using information from the Sierra Leone National Ebola Laboratory database to identify stillbirths and neonatal deaths that had been tested for Ebola virus from July 2, 2014, to October 18, 2015. Outcomes included the annualized rate of stillbirths and neonatal deaths; the percentage of all tested deaths attributable to stillbirths and neonatal deaths; and the proportion of stillbirths and neonatal deaths attributable to Ebola virus. RESULTS: In total, 1726 stillbirths and 4708 neonatal deaths were tested for Ebola virus, representing 2.6% and 7.2% of the total deaths tested (n=65 585), respectively. Of these, 25 stillbirths and neonatal deaths tested positive, accounting for 0.3% of EVD cases. In 2015, the annualized total number of reported stillbirths was higher than expected (3079 vs 1634), whereas reported neonatal deaths were lower (6351 vs 7770). CONCLUSIONS: Stillbirth and neonatal death reporting and testing improved over time. Systematic recording of these indicators might be used alongside retrospective surveillance to respond to the adverse effects of EVD on maternal and child health and guide response efforts for subsequent outbreaks. This article is protected by copyright. All rights reserved. PMID- 30467854 TI - Validation of a septoplasty deformity grading system for the evaluation of nasal obstruction. AB - OBJECTIVES/HYPOTHESIS: We developed and validated a septal deformity grading (SDG) system that accounts for anatomic location and grading of deformity severity. STUDY DESIGN: Retrospective cohort study. METHODS: Subjects were patients with nasal obstruction presenting to University of California, Irvine Medical Center. Subjects were given pre- and postoperative Nasal Obstruction Symptom Evaluation (NOSE) questionnaires and were evaluated by a facial plastic surgeon using our septal deformity grading (SDG) system. Validity and reliability analyses were conducted on the SDG results. Statistical analyses were conducted on SDG and NOSE data to assess and compare instruments, and to validate the SDG instrument using the NOSE instrument. RESULTS: One hundred thirty-five patients met inclusion criteria. Cronbach's alpha was >= 0.7 for SDG and pre- and postoperative NOSE scores. There was a significant difference in pre- and postoperative NOSE scores (Z score = -7.21, P < .001). Correlations between postoperative NOSE and SDG scores were significant (P = .014), and convergent construct validity was achieved. There was a significant difference in SDG scores between primary versus revision operations (P < .001), history versus no history of nasal trauma, and nasal/septal surgery (P = .025, P = .003, respectively). The odds of having a revision operation were 2.3 times higher for high SDG scores (P < .001), of having a history of nasal trauma were 1.33 times higher for high SDG scores (P = .014), and of having a history of nasal/septal surgery were 2.9 times higher for low SDG scores. CONCLUSIONS: Our SDG system addresses the challenge of providing objective anatomic information on the severity of nasal septal deformities, and may be valuable when used in conjunction with subjective data gathered from the NOSE questionnaire. LEVEL OF EVIDENCE: 4 Laryngoscope, 2018. PMID- 30467855 TI - Morphology of GNAT3-immunoreactive chemosensory cells in the rat larynx. AB - The upper airways play important roles in respiratory defensive reflexes. Although solitary chemosensory cells and chemosensory cell clusters have been reported in the laryngeal mucosa of mammalian species, the distribution and cellular morphology of chemosensory cells remain unclear. In the present study, the distribution and morphology of solitary chemosensory cells and chemosensory cell clusters were examined by immunofluorescence for GNAT3 on whole-mount preparations of the rat laryngeal mucosa. Electrophysiological experiments were performed to analyze the respiratory reflexes evoked by bitter stimuli to the laryngeal cavity. In the whole area of the laryngeal mucosa, the numbers of GNAT3 immunoreactive solitary chemosensory cells and chemosensory clusters were 421.0 +/- 20.3 and 62.7 +/- 6.9, respectively. GNAT3-immunoreactive solitary chemosensory cells were mainly distributed in the mucosa overlying epiglottic and arytenoid cartilage, and chemosensory clusters were mainly distributed on the edge of the epiglottis and aryepiglottic fold. GNAT3-immunoreactive solitary chemosensory cells were slender with elongated processes or had a flask like/columnar shape. The number of GNAT3-immunoreactive cells in chemosensory clusters was 6.1 +/- 0.4, ranging between 2 and 14 cells. GNAT3-immunoreactive cells in the cluster were variform and the tips of apical processes gathered at one point at the surface of the epithelium. The tips of apical cytoplasmic processes in solitary chemosensory cells and cells in the cluster were immunoreactive for espin, and faced the laryngeal cavity. Physiological experiments showed that the application of 10 mm quinine hydrochloride to the laryngeal cavity decreased respiratory frequency. The present results revealed the chemosensory field of the larynx and the morphological characteristics of the laryngeal chemosensory system for respiratory depression. PMID- 30467856 TI - Molecular identification and functional characterization of GhAMT1.3 in ammonium transport with a high affinity from cotton (Gossypium hirsutum L.). AB - Ammonium (NH4 + ) represents a primary nitrogen source for many plants, its effective transport into and between tissues and further assimilation in cells determine greatly plant nitrogen use efficiency. However, biological components involved in NH4 + movement in woody plants are unclear. Here, we report kinetic evidence for cotton NH4 + uptake and molecular identification of certain NH4 + transporters (AMTs) from cotton (Gossypium hirustum). A substrate-influx assay using 15 N-isotope revealed that cotton possessed a high-affinity transport system with a Km of 58 MUM for NH4 + . Sequence analysis showed that GhAMT1.1-1.3 encoded respectively a membrane protein containing 485, 509 or 499 amino acids. Heterologous functionality test demonstrated that GhAMT1.1-1.3 expression mediated NH4 + permeation across the plasma membrane (PM) of yeast and/or Arabidopsis qko-mutant cells, allowing a growth restoration of both mutants on NH4 + . Quantitative PCR measurement showed that GhAMT1.3 was expressed in roots and leaves and markedly upregulated by N-starvation, repressed by NH4 + resupply and regulated diurnally and age-dependently, suggesting that GhAMT1.3 should be a N-responsive gene. Importantly, GhAMT1.3 expression in Arabidopsis improved plant growth on NH4 + and enhanced total nitrogen accumulation (~50% more), conforming with the observation of 2-fold more NH4 + absorption by GhAMT1.3-transformed qko plant roots during a 1-h root influx period. Together with its targeting to the PM and saturated transport kinetics with a Km of 72 MUM for NH4 + , GhAMT1.3 is suggested to be a high-affinity NH4 + permease that may play a significant role in cotton NH4 + acquisition and utilization, adding a new member in the plant AMT family. This article is protected by copyright. All rights reserved. PMID- 30467857 TI - Solving periprosthetic leakage with a novel prosthetic device. PMID- 30467858 TI - Acute inflammatory response to contrast agent aspiration and its mechanisms in the rat lung. AB - OBJECTIVES/HYPOTHESIS: Contrast agent (CA) aspiration is an established complication of upper gastrointestinal and videofluoroscopic swallow studies. The underlying molecular biological mechanisms of acute response to CA aspiration in the respiratory organs remain unclear. The aims of this study were to elucidate the histological and biological influences of three kinds of CAs on the lung and to clarify the differences in acute responses. STUDY DESIGN: Animal model. METHODS: Eight-week-old male Sprague Dawley rats were divided into five groups (n = 6 in each group). Three groups underwent tracheal instillation of one of three different CAs: barium (Ba) sulfate, nonionic contrast agents (NICAs), and ionic contrast agents (ICAs). A control group was instilled with saline and a sham group was instilled with air. All animals were euthanized on day 2 after treatment and histological and gene analysis was performed. RESULTS: No animal died after CA or control/sham aspiration. Ba caused severe histopathologic changes and more prominent inflammatory cell infiltration in the lungs compared with the two other iodinated contrast agents. Increases in expressions of inflammatory cytokines (tumor necrosis factor [Tnf], interleukin-1beta [Il1b], and interferon-gamma [Ifng]) were observed in Ba aspiration rats, and upregulation of Il1b was seen in ICA aspiration rats. NICA did not cause obvious histologic changes or expressions of inflammatory cytokines and fibrosis-related genes in the lungs. CONCLUSIONS: Ba caused significantly more acute lung inflammation in a rodent model than did ioinic and nonionic iodinated CAs. Nonionic contrast did not cause any discernible inflammatory response in the lungs, suggesting that it may be the safest contrast for videofluoroscopic swallow studies. LEVEL OF EVIDENCE: NA. PMID- 30467859 TI - Signaling interactions between mitochondria and chloroplasts in Nicotiana tabacum leaf. AB - Research has begun to elucidate the signal transduction pathway(s) that control cellular responses to changes in mitochondrial status. Important tools in such studies are chemical inhibitors used to initiate mitochondrial dysfunction. This study compared the effect of different inhibitors and treatment conditions on the transcript amount of nuclear genes specifically responsive to mitochondrial dysfunction in leaf of Nicotiana tabacum L. cv. Petit Havana. The Complex III inhibitors antimycin A (AA) and myxothiazol (MYXO), and the Complex V inhibitor oligomycin (OLIGO) each increased the transcript amount of the mitochondrial dysfunction genes. Transcript responses to OLIGO were greater during treatment in the dark than in the light, and the dark treatment resulted in cell death. In the dark, transcript responses to AA and MYXO were similar to one another, despite MYXO leading to cell death. In the light, transcript responses to AA and MYXO diverged, despite cell viability remaining high with either inhibitor. This divergent response may be due to differential signaling from the chloroplast since only AA also inhibited cyclic electron transport, resulting in a strong acceptor-side limitation in photosystem I. In the light, chemical inhibition of chloroplast electron transport reduced transcript responses to AA, while having no effect on the response to MYXO, and increasing the response to OLIGO. Hence, when studying mitochondrial dysfunction signaling, different inhibitor and treatment combinations differentially affect linked processes (e.g. chloroplast function, cell fate) that then contribute to measured responses. Therefore, inhibitor and treatment conditions should be chosen to align with specific study goals. This article is protected by copyright. All rights reserved. PMID- 30467860 TI - Medialization laryngoplasty/arytenoid adduction: U.S. outcomes, discharge status, and utilization trends. AB - OBJECTIVES/HYPOTHESIS: To evaluate trends, outcomes, and healthcare utilization following medialization laryngoplasty (ML) with or without arytenoid adduction (AA) over 10 years. STUDY DESIGN: Retrospective observational study. METHODS: Using OptumLabs Data Warehouse, trends, outcomes, and healthcare utilization from 2006 to 2015 were examined with a focus on discharge type (same day or not). Predictors of postoperative emergency department (ED) use and hospitalization were determined by multivariable logistic regression. RESULTS: Overall rate of ML was 1.09 per 100 thousand enrollees per year. Of these, 7.8% ML were combined with an AA. Outpatient same-day discharge represented 62.0% (1,142 of 1,843) of total patients, steadily increasing over the 10-year period (P < 0.01). There was a 5.9% revision ML rate and 1.0% rate of tracheotomy within 1 day of ML. A total of 5.6% visited an ED, and 5.4% were admitted to a hospital following initial discharge within 30 days. Same-day discharge was found to be a predictor of hospitalization within 30 days after ML (odds ratio [OR] 1.74, P = 0.0452), along with Elixhauser comorbidity index of 4 + (OR 5.74, P = 0.0001). Pulmonary embolism, pulmonary hypertension, and weight loss were top predictors of ED visit or hospitalization. CONCLUSION: To our knowledge, this is the first search evaluating national claims data for ML with or without AA. Overall rate of ML is low, and same-day discharge has become more common over a 10-year period, with an associated higher 30-day hospital admission risk. Correct patient selection criteria for disposition status cannot be fully determined based on current data, but a high Elixhauser comorbidity index clearly carries increased risk for hospitalization after initial discharge. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018. PMID- 30467861 TI - Physician impact on the patient and family experience in a pediatric otolaryngology practice. AB - OBJECTIVE: On the Press Ganey (PG) survey, the item "likelihood of recommending practice" is a proxy for patient satisfaction because only the most satisfied patients will recommend a practice to friends and family. The objective of this study is to determine which other items on the PG survey best correlate with "likelihood of recommending practice" as a measure of patient satisfaction in pediatric otolaryngology. STUDY DESIGN: Retrospective analysis of a survey database. METHODS: The PG survey, consisting of 24 questions scaled from 1 to 5 representing (1) very poor, (2) poor, (3) fair, (4) good, and (5) very good, was sent to 28 different pediatric otolaryngology practices. Using the Pearson correlation coefficient, the statistical relationship of each PG survey question was analyzed in its association to the PG question "likelihood of recommending practice." Factors with a correlation coefficient greater than 0.65 were considered significant. RESULTS: Ten of 24 questions on the PG survey correlated with a top "likelihood of recommending practice" score. Eight of these 10 items were from the Care Provider category and were related to the physician patient/family interaction. CONCLUSION: Patient satisfaction surveys are utilized as a quality metric of the patient and family experience. These scores serve as one of several measures that affect reimbursement. The results demonstrate that most of the factors correlated with "likelihood of recommending practice" are provider-based. In conclusion, the physician-patient interaction strongly influences the potential for a practice to earn top box scores on the PG item "likelihood of recommending practice" and thereby achieve the highest patient satisfaction. LEVEL OF EVIDENCE: NA. Laryngoscope, 2018. PMID- 30467862 TI - The 3D imaging of mesenchymal stem cells on porous scaffolds using high contrasted x-ray computed nanotomography. AB - This study presents an X-ray computed nanotomography (nano-CT) based, high resolution imaging technique. Thanks to a voxel resolution of 540 nm, this novel technique is suitable for observing the 3D morphology of soft biopolymeric scaffolds seeded with stem cells. A sample of highly porous collagen scaffold seeded with contrasted mesenchymal stem cells (MSC) was investigated by using lab based nano-CT. The whole volume of the sample was analysed without its destruction. To evaluate the potential of nano-CT, a comparison measurement was done using a standard microscopy technique. Scanning electron microscopy (SEM) combined with energy dispersive X-ray analysis (EDX) established an extension and local accumulation of the contrasting agent - heavy metallic osmium tetroxide. The presented imaging technique is novel as it will help to understand better the behaviour of cells while interacting with three-dimensional biomaterials. This is crucial for both experimental and clinical tissue engineering applications in order to limit the risk of uncontrolled cell growth, and potentially tumour formation. LAY DESCRIPTION: Biomaterials play a crucial role in tissue engineering by serving as 3D scaffolds for cellular attachment, proliferation, and in growth ultimately leading to new tissue formation. Cell morphology and proliferation inside the 3D scaffold are necessary to know for assessing cell viability. However, these studies are usually negatively affected by the limitations of imaging techniques. We demonstrate that X-ray computed nanotomography (nano-CT), based on high-resolution imaging technique providing voxel resolution of 540 nm, is a suitable method for observing the 3D morphology of soft biopolymeric scaffolds seeded with stem cells. A sample of highly porous collagen scaffold seeded with contrasted mesenchymal stem cells (MSC) was investigated by using a lab-based nano-CT. The whole volume of the sample was analysed without its destruction. To evaluate the potential of nano-CT, a comparison measurement was done using a standard microscopy technique. Scanning electron microscopy in a combination with energy dispersive X-ray analysis established an extension and local accumulation of the contrasting agent - heavy metallic osmium tetroxide. The presented imaging technique is novel as it will help to understand better the behaviour of cells while interacting with three dimensional biomaterials. This is crucial for both experimental and clinical tissue engineering applications in order to limit the risk of uncontrolled cell growth, and potentially tumour formation. PMID- 30467863 TI - Analysis of patient factors associated with 30-day mortality after tracheostomy. AB - OBJECTIVE: Mortality has been reported to be 22% to 45% in patients with a tracheostomy. To better counsel patients and families, we aimed to determine the effect of body mass index (BMI), socioeconomic status (SES), and the 17 conditions of the Charlson comorbidity index (CCI) on 30-day survival posttracheostomy. METHODS: This retrospective cohort study identified adult patients enrolled from our institution in the Global Tracheostomy Collaborative database from March 2014 to June 2015. Data collected included age, BMI, residential zip code, and comorbidities. Cox proportionate univariate and multivariate analyses were used to measure the impact of BMI, SES, and CCI variables with 30-day posttracheostomy survival. We used geocoding as a surrogate for patients' SES. We used Deyo's modification of the CCI, which utilized International Classification of Diseases, 9th Revision, codes to identify comorbidities. RESULTS: Of 326 tracheostomies identified, the 30-day mortality rate was 15.6%. No significant differences were noted in BMI or in any of the SES categories between survivors and nonsurvivors. CCI was significantly higher in the 30-day mortality group. Congestive heart failure (hazard ratio [HR] = 2.39), severe liver disease (HR = 3.15), and peripheral vascular disease (HR = 2.62) were found to significantly impact 30-day survival. CONCLUSION: Higher CCI and specifically severe liver disease, congestive heart failure, and peripheral vascular disease were associated with increased 30-day mortality posttracheostomy. No association was found between BMI or SES and 30-day survival. This study identified three comorbidities that independently affect mortality in tracheostomy patients, which should be discussed with patients and families before tracheostomy. LEVEL OF EVIDENCE: 3. Laryngoscope, 2018. PMID- 30467865 TI - First confirmed record of the Critically Endangered green sawfish Pristis zijsron from Bangladeshi waters. AB - In a study identifying the species composition of illegally traded elasmobranch products, evidence was collected of the presence of green sawfish Pristis zijsron in Bangladeshi waters of the Bay of Bengal. This is the first confirmed record of Pristis zijsron from this region, extending its known range >1000 km to the north west. This is an important record in a region where sawfish have declined significantly and are now rarely sighted; it highlights the urgency of further regional species-specific studies within the Indian Ocean. PMID- 30467864 TI - Effect of an anxiolytic botanical containing Souroubea sympetala and Platanus occidentalis on in-vitro diazepam human cytochrome P450-mediated metabolism. AB - OBJECTIVES: A novel anxiolytic natural health product (NHP) containing Souroubea sympetala and Platanus occidentalis is available for the companion animal market and is currently being developed for clinical evaluation. Addressing the risk of potential NHP-drug interactions, this study investigated S. sympetala and P. occidentalis plant extracts, and their identified bioactive compounds, for effects on the activity of cytochrome P450 (CYP) isozymes and the metabolism of the conventional anti-anxiety medication diazepam. METHODS: Souroubea sympetala and P. occidentalis extracts, a 1 : 1 blend of the two extracts, and five triterpenes were tested for inhibitory effects on human recombinant CYP3A4, CYP2D6, CYP2C9 and CYP2C19 activity using a fluorometric plate assay. Direct effects on the metabolism of diazepam were evaluated using human liver microsomes with drug and metabolite quantification by ultra-high-pressure liquid chromatography and mass spectroscopy. KEY FINDINGS: The active substances betulinic acid (BA) and ursolic acid (UA) strongly inhibited CYP3A4 activity while UA and lupeol moderately inhibited CYP2C19. All extracts exhibited strong activity against the tested isozymes at 50-100 MUg/ml. BA and all plant extracts blocked the formation of major diazepam metabolites. CONCLUSIONS: Betulinic acid, UA and both the extracts and blended product are expected to affect the metabolism of diazepam when given in high dose. PMID- 30467866 TI - Contrasting thermal acclimation of leaf dark respiration and photosynthesis of Antarctic vascular plant species exposed to nocturnal warming. AB - Leaf respiration and photosynthesis will respond differently to an increase in temperature during night, which can be more relevant in sensitive ecosystems such as Antarctica. We postulate that the plant species able to colonize the Antarctic Peninsula -Colobanthus quitensis (Kunth) Bartl. and Deschampsia antarctica Desv- are able to acclimate their foliar respiration and to maintain photosynthesis under nocturnal warming to sustain a positive foliar carbon balance. We conducted a laboratory experiment to evaluate the effect of time of day (day and night) and nocturnal warming on dark respiration. Short (E0 and Q10 ) and long-term acclimation of respiration, leaf carbohydrates, photosynthesis (Asat ) and foliar carbon balance (R/A) were evaluated. The results suggest that the two species have differential thermal acclimation respiration, where D. antarctica showed more thermosensitivity to short-term changes in temperature than C. quitensis. Experimental nocturnal warming affected respiration at daytime differentially between the two species, with a significant increase of R10 and Asat in D. antarctica while no changes on respiration were observed in C. quitensis. Long thermal treatments of the plants indicated that nocturnal but not diurnal respiration could acclimate in both species, and to a greater extent in C. quitensis. Non-structural carbohydrates were related with respiration in C. quitensis but not in D. antarctica, suggesting that respiration in the former species is likely controlled by TSS and starch during day and night, respectively. Finally, foliar carbon balance was differentially improved under warming conditions in Antarctic plants by different mechanisms, with C. quitensis deploying respiratory acclimation while D. antarctica increased its Asat. This article is protected by copyright. All rights reserved. PMID- 30467867 TI - Two cases of occupational allergic contact dermatitis caused by abacavir. PMID- 30467868 TI - Do steroids improve recovery in vestibular neuritis? PMID- 30467869 TI - The protective role of melatonin and curcumin in the testis of young and aged rats. AB - We aimed to investigate the effect of melatonin and curcumin treatment on oxidative stress, apoptosis, and histology of testicular tissue in our study. Four groups were formed using young (4 months old, n = 6) and aged (20-22 months old, n = 18) male Wistar albino rats: (a) Young control (1% ethanol:phosphate buffered saline [PBS], subcutaneously [s.c.]); (b) Aged control (CTL; n = 6, 1% ethanol:PBS, s.c.); (c) Aged Melatonin (MLT; n = 6, 10 mg/kg, s.c.); (d) Aged Curcumin (CUR; n = 6, 30 mg/kg, i.p.). At the end of 21 days, the rats were sacrificed, and testicular tissues were removed. Malondialdehyde (MDA) in the testicular tissue was determined with thiobarbituric acid reactive substances formation, and glutathione (GSH) was determined with modified Ellman method; testosterone level was determined with chemiluminescence method and histologic changes were determined with Haematoxylin-Eosin and Johnsen's scoring; Apoptotic cell counts were made with TUNEL staining of seminiferous tubule in testis. With ageing, MDA level increased in testicular tissue, but GSH and blood testosterone levels decreased. Melatonin treatment for aged rats significantly decreased Paired total testicular/body weight ratio compared to aged control group (p < 0.05). Curcumin treatment for aged rats significantly increased GSH level compared to the aged control group (p < 0.05). Besides, melatonin and curcumin treatment significantly decreased the number of apoptotic cells and significantly increased Johnsen's score (p < 0.05). PMID- 30467870 TI - Lateral manus translation for limb-sparing surgery in 18 dogs with distal radial osteosarcoma in dogs. AB - OBJECTIVE: To describe and report outcomes after lateral translation of the manus for limb-sparing management of distal radial osteosarcoma in dogs. STUDY DESIGN: Retrospective case series. STUDY POPULATION: Eighteen client-owned dogs. METHODS: The distal aspect of the affected radius and associated neoplastic tissues were excised. The distal aspect of the ulna was preserved except for its medial cortex, which was removed en bloc with the radial segment. The manus was translated laterally to place the radial carpal bone in contact with the distal aspect of the ulna. A limb-sparing or locking compression plate was placed on the remaining proximal radius and the 3rd metacarpal bone. A 3.5-mm SOP (string of pearls) plate was placed on the lateral aspect of the proximal ulna and the 4th metacarpal bone. Dogs were administered chemotherapy. Data were collected to assess surgical and oncologic outcomes. Limb function was subjectively assessed. RESULTS: The percentage of radius removed ranged from 43% to 94% (median 54%). Complications developed in 12 limbs, with infection in 10, biomechanical complications in 6, and local recurrence in 4. Limb function was subjectively assessed as acceptable. Median disease-free interval was 219 days, and median survival time was 370 days. CONCLUSION: Outcomes after lateral translation of the manus compared favorably to other limb-sparing techniques for dogs with distal radial osteosarcoma, particularly in dogs requiring excision of a large segment of the radius. CLINICAL SIGNIFICANCE: The lateral manus translation provides an alternative limb-sparing technique that does not require an allograft, endoprosthesis, or autograft. PMID- 30467871 TI - Review article: the pharmacological causes of colon ischaemia. AB - BACKGROUND: Colon ischaemia is the most common ischaemic disorder of the gastrointestinal system, can affect any segment of the colon, and may present with a range of symptoms. Diagnosis can be challenging due to symptom overlap with other conditions, varied aetiology, and often rapid and self-resolving course. AIM: To review comprehensively the literature regarding the pharmacological aetiologies of colonic ischaemia to enhance the understanding of the various mechanisms of disease, presentations, distribution, and outcomes. METHODS: A PubMed search for "colon ischaemia" and "ischaemic colitis" alone as well as in combination with various known pharmacologic causes was performed. Only the highest quality and relevant literature was included in this review. The quality of the literature for each association was rated by the authors and a consensus was made when discrepancies were encountered. Only associations that were deemed "moderate" or "strong" were included. RESULTS: The literature considering pharmacologically associated colonic ischaemia is diverse, lacks codification and is characterised by numerous case reports and case series. Constipation-inducing drugs, digoxin, hormonal therapies, illicit drugs, immunomodulators, laxatives, and NSAIDs were strongly associated with colonic ischaemia. Antimicrobials, appetite suppressants, chemotherapies, decongestants, diuretics, ergot alkaloids, serotonin agents, statins, and vasopressor agents were moderately associated. CONCLUSIONS: Patients presenting with abdominal pain, diarrhoea, or bloody stool need to be evaluated for the possibility of this condition and treated accordingly. Timely diagnosis is necessary to improve patient outcomes. This review aims to increase awareness among clinicians regarding the presentation of pharmacologically induced colonic ischaemia. PMID- 30467872 TI - Effect of platelet-derived growth factor-BB on gap junction and connexin43 in rat penile corpus cavernosum smooth muscle cells. AB - We explored whether platelet-derived growth factor (PDGF)-BB regulates corpus cavernosum smooth muscle cell gap junctions and can ameliorate erectile dysfunction and how it modulates connexin43 (CX43) after bilateral cavernous neurectomy. Primary cultured rat corpus cavernosum smooth muscle cells were treated with PDGF-BB with or without a PDGFR inhibitor, Akt siRNA or the depletion or promotion of beta-catenin. PDGF-BB improved CCSMCs gap junction coupling and increased CX43 and PDGFRbeta expression; inhibition of PDGFR activity down-regulated CX43 and decreased Akt and nuclear beta-catenin. Knockdown or promotion of beta-catenin down-regulated and up-regulated CX43 expression respectively. Moreover, beta-catenin activation induced CX43 nuclear accumulation, which impeded CX43 down-regulation induced by PDGFR inhibition, suggesting that CX43 expression is positively correlated with nuclear beta catenin expression. Furthermore, CX43 promoter luciferase and chromatin immunoprecipitation assays indicated that beta-catenin regulates CX43 transcription by directly interacting with its promoter. Male rats underwent bilateral cavernous neurectomy. After 12 weeks, they were injected with PDGF-BB, CX43 and PDGFRbeta expression was significantly lower than in the control group, which was reversed by PDGF-BB injection. These results suggested that PDGF-BB contributed to the improvement of gap junction intracellular communication among corpus cavernosum smooth muscle cells, increased CX43 through PDGFRbeta/Akt/nuclear beta-catenin signalling, and ameliorated cavernous nerve injury-induced erectile dysfunction. PMID- 30467873 TI - Population level changes in schistosome specific antibody levels following chemotherapy. AB - AIMS: Previous studies have reported that chemotherapy of schistosomiasis by praziquantel in humans boosts protective antibody responses against S. mansoni and S. haematobium. A number of studies have reported schistosome-specific antibody levels before and after chemotherapy. Using these reports, a meta analysis was conducted to identify predictors of population level change in schistosome-specific antibody levels after chemotherapy. METHODS AND RESULTS: Following a systematic review, 92 observations from 26 articles published between 1988-2013 were included in this study. Observations were grouped by antigen type and antibody isotypes for the classification and regression tree (CART) analysis. The study showed that the change in antibody levels was variable: 1) between different human populations; and 2) according to the parasite antigen and antibody isotypes. Thus, while anti-worm responses predominantly increased after chemotherapy, anti-egg responses decreased or did not show a significant trend. The change in antibody levels depended on a combination of age and infection intensity for anti-egg IgA, IgM, IgG1, IgG2 and anti-worm IgM and IgG. CONCLUSION: The study results are consistent with praziquantel treatment boosting anti-worm antibody responses. However, there is considerable heterogeneity in post-treatment changes in specific antibody levels that is related to host age and pre-treatment infection intensity. This article is protected by copyright. All rights reserved. PMID- 30467874 TI - Suspicious index in Lyme carditis: Construction of a new risk model in the absence of guidelines. PMID- 30467875 TI - Qualitative and quantitative determination of Atractylodes rhizome using ultra performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometry with data-dependent processing. AB - A quick and effective workflow based on ultra-performance liquid chromatography coupled with electron spray ionization and LTQ-Orbitrap mass spectrometry (UPLC- LTQ-Orbitrap MS) was established for compositional analysis and screening the characteristic compounds of three species of Atractylodes rhizome for quality evaluation. This technique was employed to determine the seven main components in Atractylodes rhizome samples. Ultimately, seventy-eight constituents were identified; of these, seven characteristic compounds were selected for species discrimination, including atractylodin (63), atractylenolide I (43), atractylenolide II (49), atractylenolide III (53), atractylon (69), methyl atractylenolide II (54), and (4E,6E,12E)-tetradecadecatriene-8,10-diyne-1,3 diacetate (59). The seven main compounds, including six characteristic compounds, were simultaneously determined in twenty-nine batches of Atractylodes rhizome samples. Thus, the method validation showed acceptable results. Quantitative analysis showed significantly different contents of the seven main components among the three species of Atractylodes rhizome, which indicates possible distinctions in the pharmacological effects. This established method can simultaneously provide qualitative and quantitative results, for compositional characterization of Atractylodes rhizomes and for quality control. PMID- 30467876 TI - TIRADS Interobserver Variability Among Indeterminate Thyroid Nodules: A Single Institution Study. AB - OBJECTIVES: A high proportion of cytologically indeterminate, Afirma Gene Expression Classifier "suspicious" thyroid nodules are benign. The Thyroid Imaging Reporting and Data System (TIRADS), was proposed by the American College of Radiology in 2017 to help classify thyroid nodules based on ultrasound characteristics in a standardized fashion to guide management. We aim to determine the interobserver variability of TIRADS classification among cytologically indeterminate and Afirma suspicious nodules. METHODS: We retrospectively queried cytopathology archives for thyroid fine-needle aspiration specimens obtained between February 2012 and September 2016 with associated (1) indeterminate diagnosis, (2) ultrasound imaging at our institution, (3) Afirma suspicious result, and (4) surgery at our institution. We compared the TIRADS variability of the 3 blinded radiologists using intraclass correlation coefficients. RESULTS: Our cohort consisted of 127 nodules. Intraclass correlation coefficients can be interpreted as follows: less than 0.4, poor; 0.4 to 0.59, fair; 0.6 to 0.74, good; 0.75 to 1.00, excellent. The intraclass correlation coefficients of the raw TIRADS score and category variability was 0.561 (95% confidence interval [CI]: 0.464-0.651) or fair and 0.547 (95% CI, 0.449-0.640) or fair, respectively. When analyzing composition, echogenicity, shape, margin, and echogenic foci, the ICCs were 0.552 (95% CI, 0.454-0.643), fair; 0.533 (95% CI, 0.432-0.627), fair; 0.359 (95% CI, 0.248-0.469), poor; 0.192 (95% CI, 0.084-0.308), poor; and 0.549 (95% CI, 0.451- 0.641), fair, respectively. CONCLUSIONS: Our results show that among the subset of cytologically indeterminate and Afirma suspicious nodules, TIRADS interobserver variability was fair. Shape and margin criteria were the biggest sources of disagreement. Large prospective studies are needed to evaluate the interobserver variability of TIRADS in this subset of thyroid nodules. PMID- 30467877 TI - Sustained virologic response rates in patients with chronic hepatitis C genotype 6 treated with ledipasvir+sofosbuvir or sofosbuvir+velpatasvir. AB - BACKGROUND: Hepatitis C virus (HCV) genotype 6 (GT 6) is the predominant genotype among certain Asian populations. The availability of newer DAA options is limited in many parts of Asia. AIM: To compare sustained virologic response (SVR-12) rates between ledipasvir and sofosbuvir (LDV+SOF) and velpatasvir+SOF (SOF+VEL) for patients with HCVGT6 infection. METHOD: Retrospective study of consecutive adult HCVGT6 patients identified via ICD 9 code: 070.5 from United States treatment centers. Treatment was LDV+SOF or SOF+VEL for 8-24 weeks. A 1:1 propensity score matching (PSM) on HCV RNA, cirrhosis, alanine aminotransferase, aspartate aminotransferase, platelets, and fibrosis score was conducted among the treatment-naive HCVGT6 patients to balance groups and isolate treatment effects. RESULTS: After exclusion criteria, 149 patients remained (n = 135 treatment naive; n = 14 treatment-experienced). The mean age was 63.8 +/- 10.2 years, 66.9% male, and 93.9% Vietnamese. In treatment-naive arm, 52.2% LDV+SOF cohort were cirrhotic compared to 11.6% SOF+VEL cohort (P < 0.0001). SVR-12 for LDV+SOF was 96.4% and 100% for the SOF+VEL cohort (P = 0.22). SVR-12 for cirrhotic patients was 95.4% (n = 41/43) for LDV+SOF and 100.0% (n = 5/5) for SOF+VEL (P = 0.62). After PSM (n = 33 per group), LDV+SOF SVR-12 rate was 97.0% compared to SOF+VEL SVR-12 of 100% (P = 0.31). The treatment-experienced group (n = 14), were all treated with LDV+SOF-SVR-12 of 92.3%. CONCLUSION: Whether treatment-naive, treatment-experienced, or cirrhotic patients with HCV GT 6 residing in the US had excellent outcomes when treated with SOF+VEL or LDV+SOF. Since LDV+SOF is more readily available globally, our results may provide clinicians with a treatment option when cost and availability limit the treatment choice. PMID- 30467878 TI - Estimating the receiver operating characteristic curve in matched case control studies. AB - The matched case-control design is frequently used in the study of complex disorders and can result in significant gains in efficiency, especially in the context of measuring biomarkers; however, risk prediction in this setting is not straightforward. We propose an inverse-probability weighting approach to estimate the predictive ability associated with a set of covariates. In particular, we propose an algorithm for estimating the summary index, area under the curve corresponding to the Receiver Operating Characteristic curve associated with a set of pre-defined covariates for predicting a binary outcome. By combining data from the parent cohort with that generated in a matched case control study, we describe methods for estimation of the population parameters of interest and the corresponding area under the curve. We evaluate the bias associated with the proposed methods in simulations by considering a range of parameter settings. We illustrate the methods in two data applications: (1) a prospective cohort study of cardiovascular disease in women, the Women's Health Study, and (2) a matched case-control study nested within the Nurses' Health Study aimed at risk prediction of invasive breast cancer. PMID- 30467880 TI - Are you an expert? PMID- 30467879 TI - Fast screening of aflatoxins in dairy cattle feeds with CE-LIF method combined with preconcentration technique of vortex assisted low density solvent microextraction. AB - Aflatoxin contamination in agricultural products poses a great threat to humans and livestock. The aim of this study was to establish a simple, rapid, highly sensitive, and inexpensive method for the simultaneous detection of aflatoxin B1 , B2 , G1 , and G2 in agricultural products. We used a vortex assisted low density solvent-microextraction (VALDS-ME) technique for sample preconcentration and sample detection was achieved with a CE-LIF method. Aflatoxins were separated in an uncoated fused-silica capillary with the MEKC mode and were excited by a 355 nm UV laser to produce native fluorescence for detection. The obtained LOD and LOQ for the four aflatoxins were in the range of 0.002-0.075 and 0.007-0.300 MUg/L, respectively, and the analysis time was within 6.5 min. Using the established method, aflatoxins were screened in naturally contaminated dairy cattle feed samples including alfalfa, bran, and corn kernel. The result shows that the alfalfa and bran samples were contaminated with aflatoxins to varying degrees. Compared with other analytical techniques for aflatoxin screening in agricultural products, this CE-LIF method combined with VALDS-ME preconcentration technique is simple, rapid, highly efficient, and inexpensive. PMID- 30467882 TI - Continuing Professional Development Quiz. PMID- 30467883 TI - Discrepancy between true distance of tibial tuberosity advancement and cage size: An ex vivo study. AB - OBJECTIVE: To determine the discrepancy between true distance of tibial tuberosity advancement (tTTA) and the most commonly used cages. The null hypothesis was that tTTA would be within 1.5 mm difference of the cage size. STUDY DESIGN: Ex vivo study. SAMPLE POPULATION: Eight foam cortical shell specimens modeled from canine tibias. METHODS: Modified tibial tuberosity advancement (TTA) was performed to allow repeated measurement of the tTTA. The Pearson correlation test was used to evaluate the relationships of tTTA and cage sizes (P < .05). The difference between tTTA and cage size was calculated to establish the degree of underadvancement during the TTA. RESULTS: Two hundred forty tTTA measurements were recorded. The tTTA was less than each corresponding cage size (P < .001). Four cage sizes resulted in a difference greater than 1.5 mm (P < .001-.04). The 6-mm cage resulted in median tTTA of 4.3 mm, which did not differ significantly from 4.5 mm (range, 3.2-6.65). The median underadvancement ranged from 1.7 to 2.5 mm for the tested cage sizes. The percentage underadvancement ranged from 21% to 28% for the tested cage sizes. CONCLUSION: The tTTA was less than the corresponding cage sizes by at least 1.5 mm in all except the 6-mm cage. CLINICAL SIGNIFICANCE: Selection of a larger cage size during the TTA may be advantageous to compensate for underadvancement and to minimize the risk of residual cranial tibial translation. PMID- 30467884 TI - Letter to the editor on "Suspicious Index in Lyme Carditis (SILC): Systematic review and proposed new risk score". PMID- 30467885 TI - Increased Marginal Stiffness Differentiates Infiltrative From Noninfiltrative Cutaneous Basal Cell Carcinomas in the Facial Area: A Prospective Study. AB - OBJECTIVES: Basal cell carcinoma (BCC) is the most common dermatologic malignant skin cancer. Infiltrative histologic variants are more aggressive and require wider surgical margins or Mohs surgery, in contrast with noninfiltrative variants, which are commonly treated with standard surgical excision. Elastography has not been used to date to differentiate between the histologic variants of BCC. The purpose of this study was to differentiate infiltrative from noninfiltrative BCCs on elastography. METHODS: A total of 31 facial BCCs were studied. Preoperatively, color Doppler ultrasound and strain elastographic examinations of the lesions were performed. The size, intralesional vascularization, and presence of hyperechoic dots were considered relevant B-mode and color Doppler variables. Strain ratios of the tumors were obtained with respect to adjacent healthy tissue. Increased marginal stiffness, which was considered hardness in greater than 50% of the tumor margin, was also blindly evaluated. Histologic confirmation and subtyping (infiltrative or noninfiltrative) were performed in all cases. RESULTS: Infiltrative BCCs did not differ in the size, presence or absence of hyperechoic dots, or vascularization from noninfiltrative BCCs. Strain ratios were similar in both infiltrative and noninfiltrative BCCs (mean +/- SD, 1.82 +/- 0.879 versus 2.2 +/- 1.11). However, infiltrative BCCs had statistically increased marginal stiffness in comparison with noninfiltrative BCCs (88.0% versus 18.8%). Increased marginal stiffness had sensitivity and specificity of 0.89 and 0.82 respectively, with a positive predictive value of 0.67 for infiltrative BCCs and a negative predictive value of 0.95 for noninfiltrative BCCs. CONCLUSIONS: Histologic variants of BCC have different elastographic patterns. These differences may be of help in preoperative assessments of the BCC subtype and specific surgical planning, avoiding unnecessary skin biopsies. PMID- 30467886 TI - Response to Cardiac Resynchronization Therapy in Non-ischemic Cardiomyopathy is Unrelated to Medical Therapy. AB - INTRODUCTION: Current guidelines recommend at least three months of guideline directed medical therapy (GDMT) for patients with a new onset of nonischemic cardiomyopathy (NICM) and left bundle branch block (LBBB) prior to cardiac resynchronization therapy (CRT). For patients who do not receive optimal GDMT, response to CRT is unknown. MATERIALS AND METHODS: Patients with NICM and LBBB with QRS > 120 ms were identified among all patients who underwent CRT. Patients who received GDMT for > three months before CRT were compared to those who did not. Among 38 patients who met inclusion criteria, 24 received optimal GDMT prior to implantation (Group 1) and 14 did not (Group 2). RESULTS: QRS narrowing occurred in Group 1 (160 +/- 9 ms to 138 +/- 20 ms, P=0.001) and Group 2 (160 +/- 17 ms to 139 +/- 30 ms, P=0.021). LVEF improvement occurred in Group 1 (21.3 +/- 5.9% to 34.4 +/- 13.9%, P<0.001) and Group 2 (18.8 +/- 4.7% to 31.1 +/- 13%, P=0.010). QRS interval and LVEF changes were similar between groups (P=NS). There was a trend towards greater CRT response in women than in men, although differences did not reach statistical significance. CONCLUSIONS: In patients with NICM and LBBB, CRT is associated with improvements in LV size and function independent of prior GDMT. The ability of resynchronization to improve LVEF without GDMT suggests that CRT without waiting three months for GDMT optimization may benefit some patients with NICM and LBBB. This article is protected by copyright. All rights reserved. PMID- 30467887 TI - Household self-blame for disasters: responsibilisation and (un)accountability in decentralised participatory risk governance. AB - The most important theoretical argument concerning decentralised participatory governance is that it can make a government more accountable for the needs of the governed. Key to this process are participatory spaces that act as mechanisms for dialogue between citizens and local government. However, within Cochabamba, a city in the centre of Bolivia, South America, 'at-risk' citizens engage minimally with disaster risk issues in participatory spaces, despite high levels of civic participation. This is because 'at-risk' populations view disasters as a private/household problem that is symptomatic of household error, rather than seeing them as a broader public problem due to wider structural inequalities. Consequently, they redistribute responsibility for disaster risk reduction towards households, which (re)produces the absolution of government authorities as guarantors of disaster risk reduction. This paper challenges the normative assumption that participatory spaces facilitate democratic deliberation of disaster risk reduction and the downward accountability of local government for disaster risk reduction. PMID- 30467888 TI - The development of multiple ocular complications in a patient with Parry-Romberg syndrome. PMID- 30467889 TI - Understanding tailored PHN interventions and outcomes of Latina mothers. AB - OBJECTIVE: To examine associations of data-driven intervention approaches (IAs) with the outcomes of adolescent or adult Latina mothers with or without the Mental health problem. DESIGN AND SAMPLE: Retrospective observational study using public health nurse (PHN)-generated data for 676 Latina mothers aged 14-52. MEASURES: Mothers' age, having the Mental health problem, number of problems and interventions, and Knowledge, Behavior, and Status scores using the Omaha System. Mother-specific percentages of interventions to the total number received were calculated. Visualizations and statistical tests were used to analyze the association of IAs relating mothers' characteristics, problems, interventions, and outcomes. RESULTS: Four IAs were discovered. Sample characteristics differed significantly among IAs by age and having the Mental health problems. There was a small effect of age on outcomes (<0.10). PHNs differentially addressed problems in IA1-IA4 compared with IA2-IA3 (p < 0.001). Mothers who received IA3 had the most improvement and highest scores in Knowledge and Behavior (all p < 0.001). Mothers who received IA2 had the most improvement and highest scores in Status (both p < 0.001). CONCLUSIONS: The IAs were associated with outcomes differentially among Latina mothers, depending on multiple complex factors. These methods may be useful in understanding intervention tailoring and should be replicated with other populations and datasets. PMID- 30467890 TI - Lichen sclerosus et atrophicus diagnosed in a child accompanied with local periodontal attachment loss and maxillary deficiency: A rare case report. PMID- 30467891 TI - Emotion recognition in medical students: effects of facial appearance and care schema activation. AB - CONTEXT: Identifying the factors that may interfere with or sharpen the ability to recognise emotions when observing patients is a critical goal in medical education. This study addressed these issues by investigating the effects of facial appearance bias on medical students' emotion recognition (Experiment 1) and whether such bias is modulated by the activation of relational caregiving schema (Experiment 2). METHODS: In Experiment 1, medical students were asked to recognise the emotions expressed by individuals differing in facial appearance (trustworthy, neutral and untrustworthy). In Experiment 2, they completed the same type of emotion recognition task after activating and anchoring themselves to the representation of the relational/human competences typical of a competent professional caregiver or after a control non-representation condition. RESULTS: In both experiments, emotion recognition was affected by facial appearance bias: medical students were less accurate and slower in their recognition of emotions displayed by untrustworthy-looking individuals than in their recognition of emotions exhibited by individuals evoking more positive inferences. In Experiment 2, the activation of care schema enhanced medical students' emotion recognition ability regardless of facial appearance-based inferences. CONCLUSIONS: Medical students' emotion recognition is affected by appearance-based bias, but such bias may be weakened by techniques that harness medical students' personal affective/relational and representational resources. Thus, the results provide a basis for designing curricula aimed at challenging implicit negative bias and promoting medical students' emotion recognition ability starting in the early stages of their education. PMID- 30467892 TI - Cerebral embolic protection systems for transcatheter aortic valve replacement. AB - In the recent years, ischemic brain injury related to embolization after transcatheter aortic valve replacement (TAVR) has received increased attention as new embolic protection strategies emerged to protect the brain. Diverse cerebral protection devices have been developed to reduce cerebral embolization during TAVR. These devices work through various mechanisms and are in different stages of clinical translation. This review provides the evidence-based review of peri procedural stroke prevention during TAVR and summarizes currently available cerebral embolic protection devices. PMID- 30467893 TI - Impact of anemia on percutaneous coronary intervention in Chinese patients: A large single center data. AB - OBJECTIVES: To investigate the impact of anemia on 2-year outcomes in patients undergoing contemporary percutaneous coronary intervention (PCI). BACKGROUND: Whether anemia is an independent predictor of adverse outcomes after PCI is under debate. METHODS: A total of 10 717 consecutive patients who underwent PCI with available hemoglobin values at Fuwai Hospital were collected. Clinical outcomes were compared between patients with and without anemia both before and after PCI procedure. RESULTS: Totally, 1348 (12.5%) and 3111 (29.0%) patients presented with pre- and post-PCI anemia according to World Health Organization criteria (hemoglobin level <120 g/L for women or <130 g/L for men), respectively. Anemic patients presented with more baseline clinical risks and more extensive coronary disease than those without anemia. During 2-year follow-up, patients with pre-PCI anemia had higher incidence of bleeding and stroke than those without pre-PCI anemia. Patients with post-PCI anemia experienced higher incidence of all-cause death, myocardial infarction (MI), target vessel revascularization (TVR), bleeding, and major adverse cardiovascular events (MACE) than those without post PCI anemia. Survival analyses were performed using multivariable Cox proportional hazards models both before and after propensity score matching. Pre-PCI anemia was not an independent risk factor of any adverse clinical events. Post-PCI anemia was not an independent risk factor of all-cause death, but was an independent risk factor of MI, TVR, and MACE. CONCLUSIONS: Pre-PCI anemia was not an independent risk factor of any adverse clinical events, while post-PCI anemia had a predictable value of MI, TVR, and MACE after PCI. PMID- 30467894 TI - Embolization of an iliac vein stent to the right atrium. PMID- 30467895 TI - Synovial sarcoma of the aortopulmonary window. PMID- 30467896 TI - Hepatobiliary and Pancreatic: Pyoderma gangrenosum of the pancreas successfully treated with infliximab. PMID- 30467897 TI - Oral Health Literacy and Outcomes in Rural Wisconsin Adults. AB - PURPOSE: Low oral health literacy (OHL) is an emerging risk factor for several oral health outcomes, but there are very few studies of OHL overall and no studies of OHL in the rural United States. The purpose of this study was to examine the association between OHL and sociodemographic factors, as well as several oral health outcomes, in rural adults served by an integrated medical and dental care system in Wisconsin. METHODS: A cross-sectional survey was administered to a stratified random sample of patients from 2 rural communities. Survey data were linked to local electronic health records. Multivariable regression was used to identify sociodemographic determinants of low OHL, as well as associations between OHL and: oral hygiene, oral health quality of life, dentist visits, and emergency/urgent care visits for nontraumatic dental conditions. FINDINGS: Among the 164 respondents, OHL scores were generally high but were significantly lower among nonwhite participants (P < .001), as well as those without a college degree (P < .001) and those with an annual household income under $40,000 (P = .029). Lower OHL scores were significantly associated with lower quality of life scores (P = .005), fewer visits to the dentist (P = .007), and more emergency room visits for nontraumatic dental conditions (P = .021). CONCLUSION: In rural Wisconsin, low OHL tracked closely with markers of socioeconomic status and appeared most influential in the context of appropriate dental care utilization. Future research should consider longitudinal explorations of how OHL influences preventive and emergency dental visits over time. PMID- 30467898 TI - Using the Omaha System to determine health problems of urban Syrian immigrants. AB - OBJECTIVE(S): This study assessed the health problems of Syrian immigrants living in urban areas using the Omaha System. DESIGN: A descriptive and observational study was conducted in Istanbul. SAMPLE: The sample included 51 Syrian immigrant families and 248 Syrian refugees. MEASURES: Data were collected using the Omaha System-Problem Classification List and a sociodemographic questionnaire. RESULTS: The average household size was 6.36; 71% of those over the age of 18 were not employed. Only 8.5% of children aged 0-15 were vaccinated; 15 nursing problems and 46 signs and symptoms were diagnosed using the Problem Classification List scale. Personal care was the most frequently diagnosed problem, followed by Sanitation, Communication with community resources, Mental health, and Residence. CONCLUSIONS: Health and social problems are common Syrian immigrants living in urban areas. The Omaha System-Problem Classification List can be used as a tool by public health nurses to identify health problems encountered by immigrants. PMID- 30467899 TI - Living libraries: Nurse integration in interprofessional homeless health care team. AB - BACKGROUND: Despite an increase in national health care service utilization, entry into the health care system remains inequitable. This disparity in health care access disproportionately affects those experiencing homelessness. Because the homeless population faces significant financial and nonfinancial barriers, health care system engagement with these individuals must be reconsidered. OBJECTIVE: This article will describe the piloting of an interprofessional model within an urban library to address barriers to health care access that homeless individuals face. DESIGN: The library's unique status as a community hub presents an opportunity for partnership in addressing this population's health care access issues. This community-based model is the first recorded to utilize three distinct professions-nursing, social work, and library science-in a public library. RESULTS AND CONCLUSIONS: The implementation of this pilot project resulted in a high retention rate of referrals to community health services for those unstably housed and facilitated a system of warm transfers. Although opportunities to improve generalizability exist, this initiative sets the stage for discussion around co-location of health and social services in a nontraditional community-based setting to achieve equitable access to health care. PMID- 30467900 TI - Disseminated dermatophytosis due to Nannizzia gypsea (Microsporum gypseum) in an elderly patient. PMID- 30467901 TI - Urinary aquaporin 1 and perilipin 2: Can these novel markers accurately characterize small renal masses and help guide patient management? AB - OBJECTIVE: To evaluate the role of urine aquaporin 1 and perilipin 2 as biomarkers adjunct to renal mass biopsy in guiding the management of patients with small renal masses. METHODS: Preoperative aquaporin 1 and perilipin 2 levels in 57 patients with small renal masses undergoing partial nephrectomy were analyzed and compared with postoperative tumor histology. An algorithm was created utilizing aquaporin 1 and perilipin 2 in conjunction with renal mass biopsy. Cut-off values were implemented to maximize biomarker sensitivity and specificity. Renal mass biopsy utilization and intervention were then compared with rates in traditional renal mass biopsy algorithms. RESULTS: All clear cell and papillary renal cell carcinomas were correctly identified and assigned to the treatment path. All benign lesions were correctly sorted to a confirmatory renal mass biopsy path. Two chromophobe masses did not have elevated aquaporin 1 and perilipin 2, and would require renal mass biopsy. Compared with protocols that call for all small renal masses to be biopsied, confirmatory renal mass biopsy could have been safely avoided in 74% of patients with elevated aquaporin 1 and perilipin 2. Compared with protocols that do not utilize renal mass biopsy, surgical intervention would have been avoided in 23% of patients with benign masses. CONCLUSIONS: Aquaporin 1 and perilipin 2 possess high sensitivity and specificity for detecting clear cell and papillary renal cell carcinoma. Use of these markers might compliment renal mass biopsy in the characterization of small renal masses. PMID- 30467903 TI - Estimation of the standardized ileal digestible lysine requirement and optimal sulphur amino acids to lysine ratio for 30-50 kg pigs. AB - Two experiments were conducted to determine the standardized ileal digestible (SID) lysine (Lys) requirement and the ideal SID sulphur amino acids (SAA) to Lys ratio for 30-50 kg crossbred pigs. In experiment 1, a total of 72 crossbred pigs with an average initial body weight (BW) of 28.9 kg were allotted to one of six dietary treatments in a randomized complete block design. Each diet was assigned to six pens containing two pigs each. Six diets were obtained by supplementing graded levels of L-Lysine?HCl to create six dietary levels of SID Lys (0.70%, 0.80%, 0.90%, 1.00%, 1.10% and 1.20%). Responses of weight gain (ADG) and gain:feed (G:F) to increasing the SID Lys content of the diet fitted well with the curvilinear-plateau model; whereas, for plasma urea nitrogen (PUN) two-slope linear broken-line model was well fitted. The optimal SID Lys requirement for the pigs of this period was 1.10%. Experiment 2 was a dose-response study using SID Met+Cys to Lys ratios of 50%, 55%, 60%, 65%, 70% and 64%. A total of 72 crossbred pigs with initial BW of 32.9 kg were randomly allotted to receive one of the six diets. Diets 1-5 were formulated to contain 1.0% SID Lys to be second limiting in Lys and diet 6 contained 1.11% SID Lys to be adequate in Lys. The average optimal SID SAA:Lys ratio for maximal ADG and G:F and minimal PUN was 65.2% using curvilinear-plateau and linear broken-line models. PMID- 30467902 TI - Incidence and predictive factors of hypoglycemia after pheochromocytoma resection. AB - OBJECTIVES: To determine the incidence and preoperative risk factors of post excisional hypoglycemia in patients undergoing pheochromocytoma resection. METHODS: Patients who underwent surgical resection of pheochromocytoma at a single institution were retrospectively enrolled in the present study. The primary end-point was the development of post-excisional hypoglycemia; that is, a serum glucose level <70 mg/dL. The serum levels of immunoreactive insulin and glucose levels during the preoperative oral glucose-tolerance test and surgery were analyzed to elucidate the mechanism of hypoglycemia. RESULTS: A total of 49 patients underwent surgical resection of pheochromocytoma, of which 21 patients (43%) developed post-excisional hypoglycemia. The incidence of hypoglycemia was not statistically different between patients with adrenal tumors and those with extra-adrenal tumors (18/41 [44%] vs 3/8 [38%], respectively, P = 0.73). There was no difference in the immunoreactive insulin/glucose ratio during the preoperative oral glucose-tolerance test between patients with and those without post-excisional hypoglycemia. The intraoperative immunoreactive insulin/glucose ratio was significantly higher in patients with hypoglycemia than in those without hypoglycemia. A higher 24-h urinary epinephrine level, but not norepinephrine level, was a predictive factor for post-excisional hypoglycemia. CONCLUSIONS: Post-excisional hypoglycemia is a frequent complication of pheochromocytoma resection, irrespective of the tumor location, and might be common in patients with epinephrine-predominant tumors. All patients undergoing resection of adrenal and extra-adrenal pheochromocytoma require intensive monitoring of serum glucose levels during and after surgery. PMID- 30467904 TI - Effects of supplementation of chromium histidinate on glucose, lipid metabolism and oxidative stress in cats. AB - In recent years, two meta-analyses of chromium (Cr) supplementation have shown beneficial effects on glucose metabolism. Chromium histidinate (CrHis) reduces serum glucose levels in rats fed a high-fat diet but no study has been conducted on cats until now. The aim of this study was to examine the effects of CrHis on glucose and lipid metabolism in cats. To challenge the glucose metabolism, 16 cats were fed a high-carbohydrate high-fat diet for three months. One group (n = 8) received 800 ug CrHis per day for two months, while the other group (n = 8) served as control group. An oral glucose tolerance test was conducted, blood samples were taken, and biochemical parameters and oxidative stress were measured. CrHis serum levels were significantly increased (p = 0.027) in the treatment group, while fructosamine levels were significantly lower (p = 0.029) in the control group. In both groups, glucose (p < 0.01), b-hydroxy-butyrate (p = 0.024) and 8-hydroxy-deoxyguanosine (p = 0.028) levels decreased significantly and cholesterol levels increased significantly (p < 0.01). In conclusion, CrHis did not improve glucose or lipid metabolism and did not affect oxidative stress in healthy cats. PMID- 30467905 TI - An ultrafast molecular rotor based fluorescent turn-on sensor for perrhenate anion in aqueous solution. AB - Devising sensors for perrhenate anion in aqueous media is extremely challenging, and is seldom reported in literature. Herein, we report a fluorescence turn-on sensor for perrhenate anion in aqueous medium based on the aggregation induced emission of a popular ultrafast molecular rotor dye, Thioflavin-T. The selective response towards perrhenate anion has been rationalized in terms of matching water affinity, where the weakly hydrated perrhenate anion spontaneously forms a contact ion-pair with the weakly hydrated ultrafast molecule rotor based organic cation, Thioflavin-T, which in turn leads to an aggregate assembly which provides a fluorescence turn-on response towards perrhenate. The sensing response of Thioflavin-T is found to be quite selective towards perrhenate anion, when tested against the anions which are ubiquitously present in the environment such as chloride, nitrate, sulphate etc. The formation of self-assembled ThT aggregates has been also investigated by time-resolved emission and temperature dependent measurements. PMID- 30467906 TI - Commentary on Graydon et al. (2018): Realistic simulations and nudging gambling policy. PMID- 30467907 TI - Effect of margin design on fracture load of zirconia crowns. AB - Zirconia-based restorations are showing an increase as the clinicians' preferred choice at posterior sites because of the strength and esthetic properties of such restorations. However, all-ceramic restorations fracture at higher rates than do metal-based restorations. Margin design is one of several factors that can affect the fracture strength of all-ceramic restorations. The aim of this study was to assess the effect of preparation and crown margin design on fracture resistance. Four groups of bilayer zirconia crowns (with 10 crowns in each group) were produced by hard- or soft-machining technique, with the following four different margin designs: chamfer preparation (control); slice preparation; slice preparation with an additional cervical collar of 0.7 mm thickness; and reduced occlusal thickness (to 0.4 mm) on slice preparation with an additional cervical collar of 0.7 mm thickness. Additionally, 10 hard-machined crowns with slice preparation were veneered and glazed with feldspathic porcelain. In total, 90 crowns were loaded centrally in the occlusal fossa until fracture. The load at fracture was higher than clinically relevant mastication loads for all preparation and margin designs. The crowns on a chamfer preparation fractured at higher loads compared with crowns on a slice preparation. An additional cervical collar increased load at fracture for hard-machined crowns. PMID- 30467908 TI - Practical measurement of body composition using bioelectrical impedance, air displacement plethysmography and ultrasound in stable outpatients with short bowel syndrome receiving home parenteral nutrition: comparison of agreement between the methods. AB - BACKGROUND: People diagnosed with intestinal failure (IF) as a result of short bowel syndrome are dependent on home parenteral nutrition (HPN). Measuring nutritional status is essential for monitoring treatment. The present study aimed to determine the agreement and feasibility of three methods bioelectrical impedance analysis (BIA), ultrasound and air displacement plethysmography (ADP) for measuring body composition in people receiving HPN. METHODS: Body composition data were collected from patients attending an IF clinic. RESULTS: There were 50 participants recruited and data were collected for BIA (n = 46), ultrasound (n = 49) and ADP (n = 9). Numbers for ADP were much lower because of a lack of participant uptake. Fat-free mass (FFM) measured by BIA and ultrasound in comparison to ADP was found to have good intraclass correlation (ICC) 0.791 (95% confidence interval (CI) CI -0.21 to 0.96) and a moderate ICC 0.659 [95% (CI) 0.27 to 0.92], respectively. Fat mass (FM) measured by both BIA and ultrasound in comparison to ADP was found to have moderate ICC 0.660 (95% CI -0.28 to 0.92) and poor ICC -0.005 (95% CI -0.73 to 0.65), respectively. CONCLUSIONS: Compared to ADP, BIA indicated moderate to good agreement for measuring body composition, whereas ultrasound indicated far less agreement, particularly when measuring FM. The lack of uptake of ADP suggests that participants found the Bodpod (COSMED Srl, Shepperton, UK) unfavourable. Considering that ultrasound has limited agreement and ADP was not the preferred option for participants, BIA shows some potential. However, the difference between ADP and BIA was larger for FM compared to FFM, which needs to be considered in the clinical setting. PMID- 30467909 TI - A descriptive epidemiological study on the treatment options for head and neck cancer: Transition before and after approval of cetuximab. AB - PURPOSE: Chemoradiotherapy is among the effective treatment modalities for head and neck cancer (HNC). We aimed to elucidate the factors affecting drug selection by describing the actual situation of chemoradiotherapy for HNC in Japan and the transition in treatment selection before and after the approval of cetuximab. METHOD: We used a claims database involving multiple hospitals nationwide. The study included patients diagnosed with HNC between April 2008 and August 2015 who underwent chemoradiotherapy. The anticancer drugs used were categorized into four groups, namely, cetuximab, cisplatin, other platinum agents, and other agents. After assessing patient background and transition in concomitant drugs, we performed multinomial logistic regression analysis to determine factors that affect patient drug selection. RESULTS: This study analyzed 2777 patients whose median age was 66 years. A cisplatin-based regimen remained the most commonly used concomitant drug even after cetuximab approval. In multinomial logistic regression analysis, the odds ratio and 95% confidence interval (CI) in terms of age (66 y or older vs less than 65 y) relative to the cisplatin group were 3.01 (95% CI, 2.26-4.02) for the cetuximab group; 1.76 (95% CI, 1.22-2.48) for the other platinum agent group; and 3.09 (95% CI, 2.39-3.99) for the other agent group. CONCLUSION: This study showed the current practices in concomitant medication used in chemoradiotherapy for HNC patients in Japan, the transition in anticancer drugs used before and after cetuximab approval, and the factors affecting the selection of concomitant drugs. PMID- 30467910 TI - Iridium(III) Complex-based Activatable Probe for Phosphorescent/Time-gated Luminescent Sensing and Imaging of Cysteine in Mitochondria of Live Cells and Animals. AB - This study reports an activatable iridium(III) complex probe for phosphorescence/time-gated luminescence detection of cysteine (Cys) in vitro and in vivo. The probe, [Ir(ppy)2(NTY-bpy)](PF6), is developed by incorporating a strong electron withdrawing group, nitroolefin, into a bipyridine ligand of the Ir(III) complex. The luminescence of the probe is quenched due to the intramolecular charge transfer (ICT) process, but switched on by a specific recognition reaction between the probe and Cys. [Ir(ppy)2(NTY-bpy)](PF6) shows high sensitivity and selectivity for Cys detection and good biocompatibility. The long-lived emission of [Ir(ppy)2(NTY-bpy)](PF6) allows time-gated luminescence analysis of Cys in cells and human sera. These properties make it convenient for the phosphorescence and time-gated luminescence imaging and flow cytometry analysis of Cys in live samples. The Cys images in cancer cells and inflamed macrophage cells reveal that [Ir(ppy)2(NTY-bpy)](PF6) is distributed in mitochondria after cellular internalization. Visualizations and flow cytometry analysis of mitochondrial Cys levels and Cys-mediated redox activities of live cells are achieved. Using [Ir(ppy)2(NTY-bpy)](PF6) as a probe, in vivo sensing and imaging of Cys in D. magna, zebrafish, and mice are then demonstrated. PMID- 30467912 TI - Extended Open-Chain Polyenides as Versatile Delocalized Anion Ligands for Metal Chain Clusters. AB - Although small cyclic- and open-chain unsaturated hydrocarbon anions such as cyclopentadienide and open-chain pentadienide are used as the strongly electron donating auxiliary ligands for metal complexes, more extended pi-conjugated unsaturated hydrocarbon anions have rarely been used in coordination chemistry, despite their potential ability to serve as the multiply bridging pi-ligands for metal clusters. Here we report isolation of metal chain clusters bearing the multi-dentate, open-chain extended unsaturated hydrocarbon anion ligands. The open-chain pi-conjugated polyenyl ligands effectively stabilized an oxidized palladium chain such as an unprecedented [Pd4]4+ chain. PMID- 30467911 TI - The top-down regulation from the prefrontal cortex to insula via hypnotic aversion suggestions reduces smoking craving. AB - Hypnosis has been shown to have treatment effects on nicotine addiction. However, the neural basis of these effects is poorly understood. This preliminary study investigated the neural mechanisms of hypnosis-based treatment on cigarette smoking, specifically, whether the hypnosis involves a top-down or bottom-up mechanism. Two groups of 45 smokers underwent a smoking aversion suggestion and viewed smoking-related pictures and neutral pictures. One group underwent functional magnetic resonance imaging scanning twice (control and hypnotic states), whereas the other group underwent two electroencephalograph sessions. Our study found that self-reported smoking craving decreased in both groups following hypnosis. Smoking cue-elicited activations in the right dorsal lateral prefrontal cortex (rDLPFC) and left insula (lI) and the functional connectivity between the rDLPFC and lI were increased in the hypnotic state compared with the control state. The delta band source waveforms indicated the activation from 390 to 862 ms at the rDLPFC and from 490 to 900 ms at the lI was significantly different between the smoking and neutral conditions in the hypnotic state, suggesting the activation in the rDLPFC preceded that in the lI. These results suggest that the decreased smoking craving via hypnotic aversion suggestions may arise from the top-down regulation of the rDLPFC to the lI. Our findings provide novel neurobiological evidence for understanding the therapeutic effects of hypnosis on nicotine addiction, and the prefrontal-insula circuit may serve as an imaging biomarker to monitor the treatment efficacy noninvasively. PMID- 30467913 TI - Interaction between PLA2R1 and HLA-DQA1 Variants contributes to the increased genetic susceptibility to membranous nephropathy in Western China. AB - AIM: Recent studies showed that single nucleotide polymorphisms (SNPs) within the phospholipase A2 receptor (PLA2R1) and HLA-DQA1 genes were associated with the susceptibility to patients with primary membranous nephropathy (PMN). However, the results of previous research have not been always consistent. METHODS: We performed a case-control study including 314 patients with PMN and 354 healthy subjects in Western China. Eight SNPs in PLA2R1 and one SNP in HLA -DQA1 were genotyped and association between PLA2R1 and HLA -DQA1 was investigated. 120 patients were detected anti-PLA2R antibodies to analyze the association between genotype and anti-PLA2R antibody. RESULTS: We found A allele of rs2715918 (OR=1.66, Pc=7.9*10-3 ), A allele of rs4665143 (OR=1.76, Pc=2.7*10-6 ) and A allele of rs2187668 (OR=3.29, Pc=8.0*10-11 ) were associated with PMN. Susceptibility of PMN was significantly increased with rs2715918 in recessive model (OR=3.114, Pc=0.16), rs4665143 in recessive model (OR=2.134, Pc=1.4*10-4 ) and rs2187668 in dominant model (OR=3.961, Pc=4.1*10-11 ). The haplotype ATAC of rs2715918, rs6757188, rs4665143, rs3749119 was associated with the high risk of PMN (OR=1.453, P=3.0*10-4 ). Interaction of rs2715918 GA/AA, rs4665143 GA/AA and rs2187668 GA/AA could significantly increase the 10.61-fold higher risk for the development of PMN (OR=10.61, P=4.0*10-10 ). Patients who carried with risk genotypes for both HLA-DQA1 and PLA2R1, (87.8%) had antibodies positivity. However, patients who carried low-risk genotypes, (41.6%) had antibodies positivity (P=0.001). CONCLUSION: There are some differences in PLA2R1 distributions in PMN patients between previous literature and our study. Our results showed that interactions between PLA2R1 and HLA-DQA1 alleles increased genetic susceptibility to PMN in Western China. This article is protected by copyright. All rights reserved. PMID- 30467914 TI - Retracted: Salem, A. M., Ahmed, H. H., Atta, H. M., Ghazy, M. A. and Aglan, H. A. (2014), Potential of bone marrow mesenchymal stem cells in management of Alzheimer's disease in female rats. Cell Biol Int, 38: 1367-1383. doi:10.1002/cbin.10331. AB - The above article, published online on 07 July 2014 in the Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief (Sergio Schenkman) and John Wiley & Sons Ltd. The retraction has been agreed due to the overlap of data, figures and tables published in the following paper: Ahmed HH, Shousha WG, El-Sayed Mahdy, Rashed LA, Abdo SM. Influence of adipose tissue derived mesenchymal stem cells in combination with injectable bone substitute on osteoclastogenesis in osteoporotic rats. Journal of Applied Pharmaceutical Science, 2013 3(8):46-56. http://www.japsonline.com/admin/php/uploads/995_pdf.pdf Reference Salem, A. M., Ahmed, H. H., Atta, H. M., Ghazy, M. A. and Aglan, H. A. (2014), Potential of bone marrow mesenchymal stem cells in management of Alzheimer's disease in female rats. Cell Biol Int, 38: 1367-1383. doi:10.1002/cbin.10331. PMID- 30467915 TI - A revised model of uncertainty in complex healthcare settings: A scoping review. AB - BACKGROUND: Uncertainty is a ubiquitous and dynamic presence throughout healthcare systems and encounters, affecting the quality and safety of care. Although previous research has attempted to categorize varieties of uncertainty, it is not clear if these classifications are applicable across various healthcare settings. OBJECTIVE: The purpose of this review was to examine the applicability of the issues of uncertainty delineated in an established taxonomy across diverse healthcare domains, professions, and countries and to consider the complexity of these issues. METHODS: Drawing on empirical research from three databases, we conducted a scoping review of the literature to identify types of uncertainty experienced by healthcare professionals. A framework synthesis design was employed to review and synthesize the literature across multiple healthcare settings. RESULTS: The search identified 2285 articles, of which 94 met the inclusion criteria. Findings from included studies suggested professional uncertainty in healthcare is complex and pervasive. On the basis of our inability to categorize some studies in the issues of uncertainty outlined in the existing taxonomy, we proposed a revised model of uncertainty for healthcare professionals. CONCLUSIONS: The revised model of uncertainty, the model of uncertainty in complex healthcare settings (MUCH-S), is applicable to various healthcare ecosystems and proposes a reflexive archetype that recognizes different issues of uncertainty while establishing that these are often interrelated in healthcare systems. This review offers healthcare professionals greater levels of understanding of this complex phenomenon and may support more informed and reflective decision-making, assisting them to better navigate uncertainties experienced in healthcare workplaces. PMID- 30467916 TI - Resuscitative hysterotomy in a patient with peripartum cardiomyopathy. AB - Resuscitative hysterotomy (RH) is a resuscitation technique, allowing the restoration of a pregnant patient's heartbeat. Here, we reported a case of RH performed in a patient with cardiac arrest as a complication of a peripartum cardiomyopathy. A 29-year-old woman with suspected hemolysis, elevated liver enzymes, low platelet syndrome was admitted to the hospital. Cardiopulmonary resuscitation and RH were initiated at 30 weeks of gestation. The infant was successfully delivered 2 min after the mother's cardiac arrest, weighting 1388 g. At the first minute, the Apgar score was 3 and the 5th minute was 6. After delivery, defibrillation was performed on the mother and restoration of spontaneous circulation was observed. However, she was hemodynamically unstable and approximately 2 months later she died. After cardiac arrest, it is possible that RH could improve the hemodynamic status. The opportunity of performing a RH is rare; however, it is necessary to be familiarized with the technique as a resuscitation method. PMID- 30467917 TI - A longitudinal study on the association between facets of mindfulness and eating disorder symptoms in individuals diagnosed with eating disorders. AB - Mindfulness-based treatments for eating disorders could be improved by understanding how facets of mindfulness predict eating disorder symptoms over time. We examined whether facets of mindfulness predict eating disorder symptoms over time and vice versa. Individuals with an eating disorder diagnosis (N = 124; 87.9% diagnosed with anorexia nervosa) and an undergraduate sample (N = 290) completed measures of mindfulness at baseline. The clinical sample also completed these measures 1 month later. Individuals in the clinical sample had lower acting with awareness and higher observing than individuals in the undergraduate sample (ps < 0.002). In the clinical sample, higher body dissatisfaction prospectively predicted lower acting with awareness (p = 0.02). Lower acting with awareness prospectively predicted higher drive for thinness (p < 0.01) and bulimic symptoms (p < 0.01). Acting with awareness shows potential as a process that can be altered to effect positive outcomes on drive for thinness and bulimic symptoms. PMID- 30467918 TI - Remarkable progress in cystic fibrosis-But why? PMID- 30467919 TI - Synthesis, in vitro stability, and antiproliferative effect of d-cysteine modified GnRH-doxorubicin conjugates. AB - Overexpression of gonadotropin-releasing hormone (GnRH) receptor in many tumors but not in normal tissues makes it possible to use GnRH analogs as targeting peptides for selective delivery of cytotoxic agents, which may help to enhance the uptake of anticancer drugs by cancer cells and reduce toxicity to normal cells. The GnRH analogs [d-Cys6 , desGly10 , Pro9 -NH2 ]-GnRH, [d-Cys6 , desGly10 , Pro9 -NHEt]-GnRH, and [d-Cys6 , alpha-aza-Gly10 -NH2 ]-GnRH were conjugated with doxorubicin (Dox), respectively, through N-succinimidyl-3 maleimidopropionate as a linker to afford three new GnRH-Dox conjugates. The metabolic stability of these conjugates in human serum was determined by RP-HPLC. The antiproliferative activity of the conjugates was examined in GnRH receptor positive MCF-7 human breast cancer cell line by MTT assay. The three GnRH-Dox conjugates showed improved metabolic stability in human serum in comparison with AN-152. The antiproliferative effect of conjugate II ([d-Cys6 , desGly10 , Pro9 NHEt]-GnRH-Dox) on MCF-7 cells was higher than that of conjugate I ([d-Cys6 , desGly10 , Pro9 -NH2 ]-GnRH-Dox) and conjugate III ([d-Cys6 , alpha-aza-Gly10 NH2 ]-GnRH-Dox), and the cytotoxicity of conjugate II against GnRH receptor negative 3T3 mouse embryo fibroblast cells was decreased in comparison with free Dox. GnRH receptor inhibition test suggested that the antiproliferative activity of conjugate II might be due to the cellular uptake mediated by the targeting binding of [d-Cys6 -des-Gly10 -Pro9 -NHEt]-GnRH to GnRH receptors. Our study indicates that targeting delivery of conjugate II mediated by [d-Cys6 -des-Gly10 Pro9 -NHEt]-GnRH is a promising strategy for chemotherapy of tumors that overexpress GnRH receptors. PMID- 30467920 TI - Persistent restoration to the immunosupportive tumor microenvironment in glioblastoma by bevacizumab. AB - Although vascular endothelial growth factor (VEGF) promotes the immunosuppressive microenvironment, the efficacy of bevacizumab (Bev) on tumor immunity has not been fully investigated. The present study used 47 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naive Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory Bev group). The paired samples of the initial and post Bev recurrent tumors from 9 patients were included. The expression of PD-1/PD-L1, CD3, CD8, Foxp3, and CD163 was analyzed by immunohistochemistry. The PD-L1+ tumor cells significantly decreased in the effective or refractory Bev group compared with the naive Bev group (P<0.01 for each). PD-1+ cells significantly decreased in the effective or refractory Bev group compared with the naive Bev group (P<0.01 for each). The number of CD3+ and CD8+ T cell infiltration increased in the refractory Bev group compared with the naive Bev group (CD3: P<0.01, CD8: P=0.06). Both Foxp3+ Tregs and CD163+ TAMs significantly decreased in the effective or refractory Bev group compared with the naive Bev group (Foxp3: P<0.01 for each, CD163: P<0.01 for each). These findings were largely confirmed by comparing paired initial and post-Bev recurrent tumors. Bev restores the immunosupportive tumor microenvironment in glioblastomas, and this effect persists during long-term Bev therapy. This article is protected by copyright. All rights reserved. PMID- 30467921 TI - Proposed revision of N categories to the 8th edition AJCC-TNM staging system for non-surgical esophageal squamous cell cancer. AB - The 8th edition of the American Joint Committee on Cancer Tumor-Node-Metastasis (AJCC-TNM) staging system for esophageal cancer (EC) retained the definition of N categories based on the number of metastatic lymph nodes (LNs). However, it is difficult to accurately determine the number of metastatic LNs without surgery. This study aimed to propose a revision to the N categories of the 8th edition AJCC-TNM staging system that is easier to perform and better represents the prognosis of non-surgical esophageal squamous cell cancer (ESCC). We retrospectively reviewed the data of 336 patients with ESCC. The revised N categories were based on the anatomic regions of LN metastasis (cervix, thorax, and abdomen). Survival was analyzed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analyses were performed using the Cox proportional hazard model. Survival differences were adequately discriminated when the revised N categories were used. Subgroup analyses by T stage showed significant difference in overall survival between the revised N categories. Multivariate analyses demonstrated that T stage, revised N category, age, sex, and treatment modality were independent risk factors, with the revised N category being the most significant variable. The revised N categories determined in this study can be used to fill gaps in the staging system for patients with non surgical ESCC, which can help clinicians to make better treatment decisions and more effectively predict patient prognoses. Future large-scale studies are required to validate these results. This article is protected by copyright. All rights reserved. PMID- 30467922 TI - Supervised machine learning quality control for magnetic resonance artifacts in neonatal data sets. AB - Quality control (QC) of brain magnetic resonance images (MRI) is an important process requiring a significant amount of manual inspection. Major artifacts, such as severe subject motion, are easy to identify to naive observers but lack automated identification tools. Clinical trials involving motion-prone neonates typically pool data to obtain sufficient power, and automated quality control protocols are especially important to safeguard data quality. Current study tested an open source method to detect major artifacts among 2D neonatal MRI via supervised machine learning. A total of 1,020 two-dimensional transverse T2 weighted MRI images of preterm newborns were examined and classified as either QC Pass or QC Fail. Then 70 features across focus, texture, noise, and natural scene statistics categories were extracted from each image. Several different classifiers were trained and their performance was compared with subjective rating as the gold standard. We repeated the rating process again to examine the stability of the rating and classification. When tested via 10-fold cross validation, the random undersampling and adaboost ensemble (RUSBoost) method achieved the best overall performance for QC Fail images with 85% positive predictive value along with 75% sensitivity. Similar classification performance was observed in the analyses of the repeated subjective rating. Current results served as a proof of concept for predicting images that fail quality control using no-reference objective image features. We also highlighted the importance of evaluating results beyond mere accuracy as a performance measure for machine learning in imbalanced group settings due to larger proportion of QC Pass quality images. PMID- 30467923 TI - Morphological and genetic diversity of Pura Raza Espanol horse with regard to the coat colour. AB - Gene mutations influencing melanocytes also impact on physiological and behavioural functions. In this study, we investigated their association with four different coat colours in the Pura Raza Espanol (PRE) horse using morphological traits and molecular datasets. Four different subpopulations were identified according to individual coat colour: grey, bay, chestnut and black. Coat colour significantly associated with morphological measurements. Observed and expected heterozygosity values were low in grey compared with the other three subpopulations, suggesting the presence of unique ancestral alleles probably arisen by genetic drift and selection mechanism effects. Nei's distance demonstrated a clear division among subpopulations, the grey being the most divergent group. Gene flow estimates were similar, showing the lowest values in grey. Divergence times among subpopulations assessed with the average square distance suggested that grey was the original PRE population which diverged from bay, chestnut and black. Our results also demonstrated a clear morphological differentiation according to coat colour. The close genetic structure of bay and chestnut PRE subpopulations and the clear differences in most morphological traits of grey and chestnut PRE mares would suggest the pleiotropic effect of genomic regions determining coat colour in horses. However, further analysis including genomic information would be necessary to elucidate the mechanisms involved. PMID- 30467924 TI - Prevalence and correlates of depression among older urban community-dwelling adults in Sri Lanka. AB - AIM: As the population ages, mental health issues among the elderly are becoming a major concern worldwide, including in Sri Lanka. With rapid globalization, the coping and adapting skills of elderly individuals are tested, potentially revealing predisposition to psychological disturbances. Previous studies have indicated a higher risk of depression among the elderly. The current study attempts to quantify the prevalence and associated factors of depression in a highly urbanized setting within Sri Lanka. METHODS: A community-based, cross sectional analytical study was carried out in the urban areas of Colombo District. The subjects were young elders (60-74 years) who permanently reside in the area. Depression was assessed by the item Geriatric Depression Scale Sinhalese version (cut-off score >=8) among 1283 subjects. Logistic regression analysis was used to assess the association of depression with sociodemographic and health-related variables. RESULTS: The prevalence of depression in the sample was 13.9% (mild depression: 11.2%; moderate to severe depression: 2.7%). Among the sociodemographic predictors, female sex (odds ratio (OR) = 10.60), being 60 64 years old (OR = 1.61), being unmarried, separated, divorced, or widowed (OR = 3.73), income <=20 000 Sri Lankan rupees (OR = 2.27), and perceived financial burden (OR = 3.15) were significantly associated with clinically significant depression. Among the health-related variables, smoking (OR = 2.18), alcohol use (OR = 7.58), presence of chronic disease (OR = 1.51), limitation in performing one or more instrumental activities of daily living (OR = 1.73), unsatisfactory partner relationship (OR = 2.94), perceived inadequate social support (OR = 2.47), experiencing abuse (OR = 3.90), and experiencing major life events (OR = 2.11) were significantly related with depression. CONCLUSION: Depression is an important issue among the elderly living in an urbanized environment in Sri Lanka. PMID- 30467925 TI - The role of inhibitor of YAP1 in triple negative breast cancer with taxol-based chemoresistance. AB - The Triple negative breast cancer (TNBC) associates with high aggressive clinical behavior, and the taxol-based chemo-resistance remains a big TNBC therapeutic problem to be solved. Verteporfin, a small molecular The Yes-associated protein 1 (YAP1) inhibitor, is little known to be a anti-tumor drug for TNBC. Our data showed that the YAP1 expression was associated with early relapse in tissue sample of patients with TNBC taxol chemoresistance (P<0.001). Verteporfin, the inhibitor of YAP1, reduced migration and enhanced apoptosis or autophagy of taxol resistance MDA-MB-231 cell line in vitro. Knockdown of YAP1 increased EMT response in taxol resistant TNBC cell line. In the in vivo experiment, we found that Verteporfin is able to shrink the tumor weight and volume and decreased the Ki67 expression in taxol-resistance mouse model. Our results provide the evidence for Verteporfin could be a chemo-sensitizer for TNBC patients with taxol-based treatment. This article is protected by copyright. All rights reserved. PMID- 30467926 TI - Acute respiratory distress syndrome and the promise of driving pressure. PMID- 30467927 TI - Pulmonary rehabilitation for chronic obstructive pulmonary disease: Has it peaked? PMID- 30467928 TI - Clinical Outcomes of Carbon-Ion Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer. AB - Efficacy and safety of carbon-ion radiotherapy (CIRT) for locally advanced non small-cell lung cancer (LA-NSCLC) remain unclear. We reported the clinical outcomes of CIRT for LA-NSCLC. Data of 141 eligible patients who received CIRT between 1995 and 2015 were retrospectively analyzed. Local control (LC), locoregional control (LRC), progression-free survival (PFS), and OS were calculated using Kaplan-Meier method. The median age was 75.0 years. Overall, 21, (14.9%), 57 (40.4%), 43 (30.5%), and 20 (14.2%) patients had T1, T2, T3, and T4 disease, respectively. Moreover, 51 (36.2%), 45 (31.9%), 40 (28.4%), and 5 (3.5%) patients had N0, N1, N2, and N3 disease, respectively. Furthermore, 34 (24.1%), 42 (29.8%), 45 (31.9%), and 20 (14.2%) patients had stages IIA, IIB, IIIA, and IotaIotaIotaB disease, respectively. Overall, 62 (44.0%), 60 (42.6%), 8 (5.7%), and 11 (7.8%) patients had adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and others, respectively. The median dose was 72.0 Gy (relative biological effectiveness). No patient received concurrent chemotherapy. Median follow-up periods were 29.3 (1.6-207.7) and 40.0 (10.7-207.7) months for all patients and survivors, respectively. Two-year LC, PFS, and OS rates were 80.3%, 40.2%, and 58.7%, respectively. Overall, 1 (0.7%), 5 (3.5%), and 1 (0.7%) patient developed Grades 4 (mediastinal hemorrhage), 3 (radiation pneumonitis), and 3 (bronchial fistula) toxicities, respectively. Multivariate analysis showed adenocarcinoma and N2/3 classification as significant poor prognosticators of PFS. CIRT is an effective treatment with acceptable toxicity for LA-NSCLC, especially for elderly patients or patients with severe comorbidities who cannot be treated with surgery or chemoradiotherapy. This article is protected by copyright. All rights reserved. PMID- 30467929 TI - Individual glucose responses to prolonged moderate intensity aerobic exercise in adolescents with type 1 diabetes: The higher they start, the harder they fall. AB - OBJECTIVE: To evaluate the pattern of change in blood glucose concentrations and hypoglycemia risk in response to prolonged aerobic exercise in adolescents with type 1 diabetes (T1D) that had a wide range in pre-exercise blood glucose concentrations. RESEARCH DESIGN AND METHODS: Individual blood glucose responses to prolonged (~60 min) moderate-intensity exercise were profiled in 120 youth with T1D. RESULTS: The mean pre-exercise blood glucose concentration was 178+/-66 mg/dL, ranging from 69 to 396 mg/dL, while the mean change in glucose during exercise was -76+/-55 mg/dL (mean+/-SD), ranging from +83 to -257 mg/dL. Only 4 of 120 youth (3%) had stable glucose levels during exercise (i.e. +/- <=10 mg/dL), while 4 (3%) had a rise in glucose >10 mg/dL, and the remaining (93%) had a clinically significant drop (i.e. >10 mg/dL). A total of 53 youth (44%) developed hypoglycemia (<=70 mg/dL) during exercise. The change in glucose was negatively correlated with the pre-exercise glucose concentration (R2 =0.44, P<0.001), and tended to be greater in those on MDI vs. CSII (-98+/-15 vs. -65+/-7 mg/dL, P=0.05). No other collected variables appeared to predict the change in glucose including age, weight, height, body mass index, disease duration, daily insulin dose, HbA1c , or sex. CONCLUSION: Youth with T1D have variable glycemic responses to prolonged aerobic exercise, but this variability is partially explained by their pre-exercise blood glucose levels. When no implementation strategies are in place to limit the drop in glycemia, the incidence of exercise associated hypoglycemia is ~44% and having a high pre-exercise blood glucose concentration is only marginally protective. This article is protected by copyright. All rights reserved. PMID- 30467931 TI - Mechanisms of seed mass variation along resource gradients. AB - The enormous variation in seed mass along gradients of soil resources has fascinated plant ecologists for decades. However, so far, this research has focused on the description of such variation, rather than its underlying mechanisms. Here we experimentally test a recent model relating such variation to two fundamental properties of plant growth: allometry of biomass growth and size asymmetry of light competition. According to the model, mean seed mass should increase, and the variance of seed mass should show a unimodal response, to increasing soil resource availability (productivity). We test these predictions and their underlying assumptions using a combination of field observations, mesocosm experiments and greenhouse experiments focusing on Mediterranean annual plants. Our results support the predictions and assumptions of the model, and allow us to reject alternative models of seed mass variation. We conclude that growth-allometry and size-asymmetric light competition are key drivers of seed mass variation along soil resource gradients. PMID- 30467930 TI - Emerging threats and persistent conservation challenges for freshwater biodiversity. AB - In the 12 years since Dudgeon et al. (2006) reviewed major pressures on freshwater ecosystems, the biodiversity crisis in the world's lakes, reservoirs, rivers, streams and wetlands has deepened. While lakes, reservoirs and rivers cover only 2.3% of the Earth's surface, these ecosystems host at least 9.5% of the Earth's described animal species. Furthermore, using the World Wide Fund for Nature's Living Planet Index, freshwater population declines (83% between 1970 and 2014) continue to outpace contemporaneous declines in marine or terrestrial systems. The Anthropocene has brought multiple new and varied threats that disproportionately impact freshwater systems. We document 12 emerging threats to freshwater biodiversity that are either entirely new since 2006 or have since intensified: (i) changing climates; (ii) e-commerce and invasions; (iii) infectious diseases; (iv) harmful algal blooms; (v) expanding hydropower; (vi) emerging contaminants; (vii) engineered nanomaterials; (viii) microplastic pollution; (ix) light and noise; (x) freshwater salinisation; (xi) declining calcium; and (xii) cumulative stressors. Effects are evidenced for amphibians, fishes, invertebrates, microbes, plants, turtles and waterbirds, with potential for ecosystem-level changes through bottom-up and top-down processes. In our highly uncertain future, the net effects of these threats raise serious concerns for freshwater ecosystems. However, we also highlight opportunities for conservation gains as a result of novel management tools (e.g. environmental flows, environmental DNA) and specific conservation-oriented actions (e.g. dam removal, habitat protection policies, managed relocation of species) that have been met with varying levels of success. Moving forward, we advocate hybrid approaches that manage fresh waters as crucial ecosystems for human life support as well as essential hotspots of biodiversity and ecological function. Efforts to reverse global trends in freshwater degradation now depend on bridging an immense gap between the aspirations of conservation biologists and the accelerating rate of species endangerment. PMID- 30467932 TI - Environmental filtering explains a U-shape latitudinal pattern in regional beta deviation for eastern North American trees. AB - The underlying drivers of beta-diversity along latitudinal gradients have been unclear. Previous studies have focused on beta-diversities calculated at a local scale and shed limited light on regional beta-diversity. We tested the much debated effects of range size vs. environmental filtering on the beta-gradient using data from the US Forest Inventory Analysis Program. We showed that the drivers of the beta-gradient were scale dependent. At the local scale species spatial patterns contributed little to the beta-gradient, whereas at the regional scale spatial patterns dominated the gradient and a U-shape latitudinal relationship for the standardised beta-diversity deviation was revealed. The relationship can be explained by spatial variation in climate and soil texture, thus supporting the environmental filtering hypothesis. But it is inconsistent with Rapoport's rule about the effect of range size on beta-gradient. These results resolve the debate on whether species spatial distributions contribute to beta-gradient and attest the importance of environmental filtering in determining regional beta-diversity. PMID- 30467933 TI - A mechanistic theory of personality-dependent movement behaviour based on dynamic energy budgets. AB - Consistent between-individual differences in movement are widely recognised across taxa. In addition, foraging plasticity at the within-individual level suggests a behavioural dependency on the internal energy demand. Because behaviour co-varies with fast-slow life history (LH) strategies in an adaptive context, as theoretically predicted by the pace-of-life syndrome hypothesis, mass/energy fluxes should link behaviour and its plasticity with physiology at both between- and within-individual levels. However, a mechanistic framework driving these links in a fluctuating ecological context is lacking. Focusing on home range behaviour, we propose a novel behavioural-bioenergetics theoretical model to address such complexities at the individual level based on energy balance. We propose explicit mechanistic links between behaviour, physiology/metabolism and LH by merging two well-founded theories, the movement ecology paradigm and the dynamic energetic budget theory. Overall, our behavioural-bioenergetics model integrates the mechanisms explaining how (1) behavioural between- and within-individual variabilities connect with internal state variable dynamics, (2) physiology and behaviour are explicitly interconnected by mass/energy fluxes, and (3) different LHs may arise from both behavioural and physiological variabilities in a given ecological context. Our novel theoretical model reveals encouraging opportunities for empiricists and theoreticians to delve into the eco-evolutionary processes that favour or hinder the development of between-individual differences in behaviour and the evolution of personality-dependent movement syndromes. PMID- 30467934 TI - Biophysical factors in the regulation of asymmetric division of stem cells. AB - Stem cells are a promising cell source for regenerative medicine due to their characteristics of self-renewal and differentiation. The intricate balance between these two cell fates is maintained by precisely controlled symmetric and asymmetric cell divisions. Asymmetric division has a fundamental importance in maintaining tissue homeostasis and in the development of multi-cellular organisms. For example, during development, asymmetric cell divisions are responsible for the formation of the body axis. Mechanistically, mitotic spindle dynamics determine the assembly and separation of chromosomes and regulate the orientation of cell division. Interestingly, symmetric and asymmetric cell division is not mutually exclusive and a range of factors are involved in such cell-fate decisions, the measurement of which can provide efficient and reliable information on the regenerative potential of a cell. The balance between self renewal and differentiation in stem cells is controlled by various biophysical and biochemical cues. Although the role of biochemical factors in asymmetric stem cell division has been widely studied, the effect of biophysical cues in stem cell self-renewal is not comprehensively understood. Herein, we review the biological relevance of stem-cell asymmetric division to regenerative medicine and discuss the influences of various intrinsic and extrinsic biophysical cues in stem-cell self-renewal. This review particularly aims to inform the clinical translation of efforts to control the self-renewal ability of stem cells through the tuning of various biophysical cues. PMID- 30467935 TI - Mechanism of the Water-Gas Shift Reaction Catalyzed by Efficient Ruthenium Based Catalysts. AB - Supported ionic liquid phase (SILP) catalysis enables a highly efficient, Ru based, homogeneously catalyzed water-gas shift reaction (WGSR) between 100 degrees C and 150 degrees C. The active Ru-complexes have been found to exist in imidazolium chloride melts under operating conditions in a dynamic equilibrium, which is dominated by the [Ru(CO)3Cl3]- complex. We here present state-of-the-art theoretical calculations to elucidate the reaction mechanism in more detail. We show that the mechanism includes the intermediate formation and degradation of hydrogen chloride, which effectively reduces the high barrier for the formation of the requisite dihydrogen complex. The hypothesis that the rate-limiting step involves water is supported by using D2O in continuous catalytic WGSR experiments. The resulting mechanism constitutes a highly competitive alternative to earlier reported generic routes involving nucleophilic addition of hydroxide in the gas phase and in solution. PMID- 30467936 TI - Non-alcoholic fatty liver disease in pediatric type 2 diabetes: metabolic and histologic characteristics in 38 subjects. AB - BACKGROUND: Obesity and type 2 diabetes (T2D) are risk factors for non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). In children with T2D and liver biopsies we investigated correlations between NAFLD/NASH and transaminase activity, A1c, lipids, and histologic changes in repeat biopsies. METHODS: Liver histology of children with T2D was evaluated using the NASH CRN scoring system and NAFLD activity score (NAS). We included results <= 6 months from biopsy and A1c nearest biopsy. RESULTS: 38 subjects (21F,17M, 63.2% Hispanic, 15.8% Caucasian) had T2D diagnosed at 13.4 +/- 2.7 years, 78.9% using metformin, 50% on insulin. Histological diagnosis of NAFLD occurred at mean age 14.3 +/- 2.3, notable for NASH in 61%. Steatosis grade was higher in children with NASH than those without (mean 2.6+/- 0.7 vs. 2.1 +/- 0.5 (p < 0.001). Stage 3 fibrosis was noted only in subjects with NASH (26%). ALT was higher in NASH versus those without (112 +/- 56 vs. 85+/-112, p = 0.016). NAS correlated with A1c (r=0.51, p<0.01) and triglycerides (r=0.5, p <0.01), and inversely with HDL (r= -0.42, p = 0.04). Males had lower HDL and higher triglycerides (p <0.04). In 8 subjects with repeat biopsies, NAS was equal (37.5%) or improved (62.5%), and steatosis decreased (68.1% to 32.8%, p = 0.027). CONCLUSIONS: In children with type 2 diabetes and NAFLD, NASH is common. Having advanced fibrosis in 26% of NASH cases at this age is concerning. Better control of lipids, weight and diabetes may help avoid worsening in NAS. This article is protected by copyright. All rights reserved. PMID- 30467937 TI - Lacrimal gland choristoma in lacrimal sac as a probable cause of nasolacrimal duct obstruction. PMID- 30467938 TI - Colour pattern divergence in reef fish species is rapid and driven by both range overlap and symmetry. AB - Signal divergence is an important process underpinning the diversification of lineages. Research has shown that signal divergence is greatest in species pairs that possess high geographic range overlap. However, the influence of range-size differences within pairs is less understood. We investigated how these factors have shaped signal divergence within brightly coloured coral reef butterflyfishes (genus: Chaetodon). Using a novel digital imaging methodology, we quantified both colouration and pattern using 250 000 sample points on each fish image. Surprisingly, evolutionary age did not affect colour pattern dissimilarity between species pairs, with average differences arising in just 300 000 years. However, the effect of range overlap and range symmetry was significant. Species pair colour patterns become more different with increasing overlap, but only when ranges are similar in size. When ranges differ markedly in area, species-pair colour patterns become more similar with increasing overlap. This suggests that species with small ranges may maintain non-colour-based species boundaries. PMID- 30467939 TI - Seeing the impact of the Glaucoma Inheritance Study in Tasmania (GIST) after 25 years. PMID- 30467940 TI - Microreview: Mutual interplay between phytopathogenic powdery mildew fungi and other microorganisms. AB - Powdery mildew is a common and widespread plant disease of considerable agronomic relevance. It is caused by obligate biotrophic fungal pathogens that in most cases epiphytically colonize aboveground plant tissues. The disease has been typically studied as a binary interaction of the fungal pathogen with its plant hosts, for the most part neglecting the mutual interplay with the wealth of other microorganisms residing in the phyllo- and/or rhizosphere and roots. However, the establishment of powdery mildew disease can be impacted by the presence/absence of host-associated microbiota (epi- and endophytes), and conversely, plant colonization by powdery mildew fungi might disturb indigenous microbial community structures. In addition, other (foliar) phytopathogens could interact with powdery mildews and mycoparasites may affect the outcome of plant-powdery mildew interactions. In this review, we discuss the current knowledge regarding the intricate and multifaceted interplay of powdery mildew fungi, host plants and other microorganisms and outline current gaps in our knowledge, thereby setting the basis for potential future research directions. This article is protected by copyright. All rights reserved. PMID- 30467941 TI - Reconstituting the genome of a young allopolyploid crop, Brassica napus, with its related species. AB - Brassica napus (An An Cn Cn ) is an important worldwide oilseed crop, but it is a young allotetraploid with a short evolutionary history and limited genetic diversity. To significantly broaden its genetic diversity and create a novel heterotic population for sustainable rapeseed breeding, this study reconstituted the genome of B. napus by replacing it with the subgenomes from 122 accessions of B. rapa (Ar Ar ) and 74 accessions of B. carinata (Bc Bc Cc Cc ) and developing a novel gene pool of B. napus through five rounds of extensive recurrent selection. When compared with traditional B. napus using SSR markers and high-throughput SNP/Indel markers through genotyping by sequencing, the newly developed gene pool and its homozygous progenies exhibited a large genetic distance, rich allelic diversity, new alleles, and exotic allelic introgression across all 19 AC chromosomes. In addition to the abundant genomic variation detected in the AC genome, we also detected considerable introgression from the eight chromosomes of the B genome. Extensive trait variation and some genetic improvements were present from the early recurrent selection to later generations. This novel gene pool produced equally rich phenotypic variation and should be valuable for rapeseed genetic improvement. By reconstituting the genome of B. napus by introducing subgenomic variation within and between the related species using intense selection and recombination, the whole genome could be substantially reorganized. These results serve as an example of the manipulation of the genome of a young allopolyploid and provide insights into its rapid genome evolution affected by interspecific and intraspecific crosses. This article is protected by copyright. All rights reserved. PMID- 30467942 TI - Identifying Terminal Assembly Propensity of Amyloidal Peptides by Scanning Tunneling Microscopy. AB - The abnormal accumulation of beta-amyloids (Abeta) in brain is considered as a key initiating cause for Alzheimer's disease (AD) due to their richness in plaques and self-aggregate propensity. In recent studies, N-terminally extended Abeta peptides (NTE-Abeta) with the N-terminus originating prior to the canonical beta-secretase cleavage site were found in humans and suggested to have possible relevance to AD. However, the effects of the extended N-terminus on the amyloidegenic structure and aggregation propensity have not been fully elucidated. Herein, we characterized the assembly structures of Abeta1-42, Abeta( 5)-42, Abeta(-10)-42 and Abeta(-15)-42 with both normal and reversed sequences on highly oriented pyrolytic graphite (HOPG) surfaces with scanning tunneling microscopy (STM). The molecularly resolved surface-mediated peptide assemblies enable identification of amyloidegenic fragments. The observations reveal that the assembly propensity of the C-terminal strand of Abeta1-42 is highly conserved and insensitive to N-terminal extensions. In contrast, different assembly structures of the N-terminal strand of Abeta variants can be observed with possible assignment of varied amyloidegenic fragments in the extended N-termini, which may contribute to the varied aggregation propensities of Abeta42 species. PMID- 30467943 TI - An Idea to Explore: Understanding Redox Reactions in Biochemistry. AB - Understanding redox reactions in biochemistry requires a clear grasp of three definitions: electron exchange, oxidation number, and oxygen atom insertion. Here, the electrochemical cell is explained for redox-active ions, introducing a new comparison between the measurement of midpoint potential and the measurement of initial velocity for enzymes. Oxygen atom insertion is shown to be of use in readily classifying oxidation states. Finally, the use of several of these ideas is combined into an explanation of proton motive force development in the mitochondrial respiratory chain. (c) 2018 International Union of Biochemistry and Molecular Biology, 2018. PMID- 30467944 TI - Development of a novel convenient Alzheimer's disease assessment scale, the ABC Dementia Scale, using item response theory. AB - AIM: The present study aimed to assess the interrater reliability and construct the validity of a novel, convenient informant-based Alzheimer's disease assessment scale to prepare its final version. METHODS: For the assessment, site investigators, co-medicals and, if available, medical staff other than doctors or co-medicals interviewed study informants to assess individuals using this scale. We then analyzed the interrater reliability and construct validity using factor analysis and item response characteristics. RESULTS: In this study, 427 eligible participants were enrolled. We first examined the interrater reliability, and found that the lower limit of the confidence interval of each item was never <0.4 (except for the item "delusion of theft"). After deleting this item, the 14 items of this scale were organized into three domains (activities of daily living, behavioral and psychological symptoms of dementia, and cognitive function) through factor analysis. After discussion of the similarity of two items and their integration into one item, we confirmed that the final version of the 13 item scale showed almost the same degree of interrater reliability and construct validity as the former version of this scale. CONCLUSIONS: The final version of this novel Alzheimer's disease assessment scale had high interrater reliability and construct validity. We named it the ABC (activities of daily living, behavioral and psychological symptoms of dementia, and cognitive function) Dementia Scale. Further studies on its validation are required. Geriatr Gerontol Int 2018; **: **-**. PMID- 30467946 TI - Synzoochory: the ecological and evolutionary relevance of a dual interaction. PMID- 30467945 TI - Evaluation of serum exosomal LncRNA-based biomarker panel for diagnosis and recurrence prediction of bladder cancer. AB - Exosomes are small membrane vesicles released by many cells. These vesicles can mediate cellular communications by transmitting active molecules including long non-coding RNAs (lncRNAs). In this study, our aim was to identify a panel of lncRNAs in serum exosomes for the diagnosis and recurrence prediction of bladder cancer (BC). The expressions of 11 candidate lncRNAs in exosome were investigated in training set (n = 200) and an independent validation set (n = 320) via quantitative real-time PCR. A three-lncRNA panel (PCAT-1, UBC1 and SNHG16) was finally identified by multivariate logistic regression model to provide high diagnostic accuracy for BC with an area under the receiver-operating characteristic curve (AUC) of 0.857 and 0.826 in training set and validation set, respectively, which was significantly higher than that of urine cytology. The corresponding AUCs of this panel for patients with Ta, T1 and T2-T4 were 0.760, 0.827 and 0.878, respectively. In addition, Kaplan-Meier analysis showed that non muscle-invasive BC (NMIBC) patients with high UBC1 expression had significantly lower recurrence-free survival (P = 0.01). Multivariate Cox analysis demonstrated that UBC1 was independently associated with tumour recurrence of NMIBC (P = 0.018). Our study suggested that lncRNAs in serum exosomes may serve as considerable diagnostic and prognostic biomarkers of BC. PMID- 30467947 TI - Effects of brown rice particle size on energy and nutrient digestibility in diets for young pigs and adult sows. AB - The objective of this study was to evaluate the effects of brown rice particle size on the apparent total tract digestibility (ATTD) of energy and nutrients in diets fed to pigs at four different stages and determine the optimal particle size (OPS) of brown rice for young pigs and adult sows. Eighteen weanling piglets (initial body weight (BW): 10.2 +/- 0.4 kg), 18 growing barrows (initial BW: 35.6 +/- 1.5 kg), 24 gestating sows (initial BW: 220 +/- 2.8 kg), and 24 lactating sows (initial BW: 208 +/- 3.8 kg) were allotted to 1 of 3 or 4 diets based on completely randomized design with six replicates per diet. Within each stage, brown rice-soybean meal diets were formulated, and the only difference among diets was the brown rice used was ground to the specified particle size. Each stage lasted 19 days, including 7 days for cage adaptation, 7 days for diet adaptation, and 5 days for total feces and urine collection. For weanling and growing pigs, the results showed that pigs fed brown rice milled to 600 MUm had a greater ATTD of dry matter (DM), gross energy (GE), and crude protein (CP) than pigs fed brown rice ground to 800 MUm. However, there was no improvement in the ATTD of energy and nutrients for pigs fed brown rice milled to 600 MUm versus 400 MUm. The concentration of nitrogen (N) in feces significantly reduced (p < 0.01) as brown rice particle size decreased from 800 to 400 MUm. However, there were no differences in phosphorus (P) output and absorbed P among diets. For gestating and lactating sows, a reduction in particle size from 1,000 to 800 MUm significantly improved (p < 0.01) the ATTD of DM, GE, and CP in diets. However, there was also no improvement in the ATTD of energy and nutrients for pigs fed brown rice milled from 800 to 400 MUm. In conclusion, considering the energy required for milling and nutrient digestibility, milling brown rice to 600 and 800 MUm are recommended in diets for young pigs and adult sows, respectively. The OPS of brown rice for pigs at different physiological stages should be considered to economically and accurately formulate diets. PMID- 30467948 TI - Plate-shape carbonated hydroxyapatite/collagen nanocomposite hydrogel via in situ mineralization of hydroxyapatite concurrent with gelation of collagen at pH = 7.4 and 37 degrees C. AB - The objective of this study was to develop a collagen/hydroxyapatite (HA) nanocomposite scaffold for bone tissue engineering applications. For this purpose, in situ mineralization of HA was accompanied with formation of collagen hydrogel at condition similar to the physiological condition, pH = 7.4, and 37 degrees C. The physicochemical and biological properties of the in situ scaffold were compared with nanocomposite fabricated by mixing HA powder and collagen hydrogel (powder-mixed scaffold). The HA in this method was formed in the same condition as the in situ method. X-ray diffraction and FTIR analysis of in situ scaffold showed the formation of carbonated HA, similar to bone, while the HA powder in powder-mixed scaffold showed non-carbonated structure. Scanning electron microscopy revealed the formation of fibrillated collagen in both composites. HA was observed in both scaffolds, but with different morphology. The in situ formed HA had a plate-like morphology while the preformed HA showed spherical morphology in the powder-mixed scaffold. The in-vitro cytocompatibility and osteogenesis activity of scaffolds using osteoblast-like cells (MG-63) showed higher cytocompatibility and more osteogenesis capability of the in situ scaffold in comparison with the powder-mixed scaffold. The results suggest the in situ method as a proper approach for fabrication of HA/collagen scaffolds with similar properties like bone. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res B Part B: Appl Biomater, 2018. PMID- 30467949 TI - Cross-sectional survey of workplace stressors associated with physician burnout measured by the Mini-Z and the Maslach Burnout Inventory. AB - Rising physician burnout has adverse effects on healthcare. This study aimed to identify remediable stressors associated with burnout using the 10-item Mini-Z and the Maslach Burnout Inventory (MBI), and to compare performance of the Mini Z's single-item burnout metric against the 22-item MBI. Surveys were emailed to 4118 clinicians affiliated with an academic health system; 1252 clicked the link, and 557 responded (completion rate 44%). Four hundred seventy-five practicing physicians were included: academic faculty (372), hospital employed (52), and private practitioners (81). Prevalence of burnout via the MBI was 56.6%. Predictors of burnout were poor control over workload (OR 8.24, 95% CI 4.81 14.11), inefficient teamwork (OR 7.61, 95% CI 3.28-17.67), insufficient documentation time (OR 5.83, 95% CI 3.35-10.15), hectic-chaotic work atmosphere (OR 3.49, 95% CI 2.12-5.74), lack of value-alignment with leadership (OR 3.27, 95% CI 2.12-5.74), and excessive electronic medical record time at home (OR 1.99, 95% CI 1.21-3.27). Academic faculty experienced more burnout than private practitioners (59.9% vs. 42.0%, p=0.013). Odds of burnout associated with stressors were generally concordant via Mini-Z's burnout metric versus the MBI. The Mini-Z is a brief, valid method to identify stressors associated with burnout and guide interventions. PMID- 30467950 TI - Sequence variants in muscle tissue-related genes may determine the severity of muscle contractures in cerebral palsy. AB - Muscle contractures are a common complication to cerebral palsy (CP). The purpose of this study was to evaluate whether individuals with CP carry specific gene variants of important structural genes that might explain the severity of muscle contractures. Next-generation-sequencing (NGS) of 96 candidate genes associated with muscle structure and metabolism were analyzed in 43 individuals with CP (Gross Motor Function classification system [GMFCS] I, n=10; GMFCS II, n=14; GMFCS III, n=19) and four control participants. In silico analysis of the identified variants was performed. The variants were classified into four categories ranging from likely benign (VUS0) to highly likely functional effect (VUS3). All individuals with CP were classified and grouped according to their GMFCS level: Statistical comparisons were made between GMFCS groups. Kruskal Wallis tests showed significantly more VUS2 variants in the genes COL4 (GMFCS I III; 1, 1, 5, respectively [p < .04]), COL5 (GMFCS I-III; 1, 1, 5 [p < .04]), COL6 (GMFCS I-III; 0, 4, 7 [p < .003]), and COL9 (GMFCS I-III; 1, 1, 5 [p < .04]), in individuals with CP within GMFCS Level III when compared to the other GMFCS levels. Furthermore, significantly more VUS3 variants in COL6 (GMFCS I-III; 0, 5, 2 [p < .01]) and COL7 (GMFCS I-III; 0, 3, 0 [p < .04]) were identified in the GMFCS II level when compared to the other GMFCS levels. The present results highlight several candidate gene variants in different collagen types with likely functional effects in individuals with CP. PMID- 30467951 TI - What the neighbors say. PMID- 30467952 TI - Relationship of mildly increased albuminuria and coronary artery revascularization outcomes in patients with diabetes. AB - BACKGROUND: The aim of this study was to examine the relationship of albuminuria to cardiovascular disease outcomes in diabetic patients undergoing treatment for stable coronary artery disease. METHODS AND RESULTS: We analyzed data from 2176 participants of the Bypass Angioplasty Revascularization Investigation in type-2 diabetes (BARI-2D) trial, a randomized clinical trial comparing Percutaneous coronary intervention/Coronary artery bypass grafting (PCI/CABG) to medical therapy for people with diabetes. The population was stratified by baseline spot urine albumin-creatinine ratio (uACR) into normal (uACR <10 mg/g), mildly (uACR >=10 mg/g < 30 mg/g), moderately (uACR >=30 mg/g < 300 mg/g) and severely increased (uACR >=300 mg/g) groups, and outcomes compared between groups. Death, myocardial infarction (MI) and/or stroke were experienced by 489 patients at a mean follow-up of 4.3 +/- 1.5 years. Compared with normal uACR, mildly increased uACR was associated with a 1.4 times (P = 0.042) increase in all-cause mortality. Additionally, nonwhites with type-II diabetes and stable coronary artery disease who had mildly increased albuminuria had a Hazard ratio (HR) of 3.3 times (P = 0.028) for cardiovascular death, 3.1 times for (P = 0.002) all-cause mortality, and two times for (P = 0.015) MI during follow-up. CONCLUSIONS: Mildly increased albuminuria is a significant predictor of all-cause mortality in those with type II diabetes mellitus and stable coronary artery disease, as well as for cardiovascular events those who are nonwhites. PMID- 30467953 TI - Testin protects against cardiac hypertrophy by targeting a calcineurin-dependent signalling pathway. AB - Multiple organs express testin (TES), including the heart. Nevertheless, current understanding of the influence of TES on cardiovascular diseases, especially on cardiac hypertrophy and its etiology, is insufficient. This study investigated the influence of TES on cardiac hypertrophy and its etiology. Murine models with excessive TES expression specific to the heart were constructed with an adeno associated virus expression system. Cardiac hypertrophy was stimulated through aortic banding (AB). The severity of cardiac hypertrophy was evaluated through molecular, echocardiographic, pathological, and hemodynamic examination. The findings of our study revealed that TES expression was remarkably suppressed not only in failing human hearts but also in mouse hearts with cardiac hypertrophy. It was discovered that excessive TES expression driven by an adeno-associated viral vector noticeably inhibited hypertrophy triggered by angiotensin II (Ang II) in cultivated cardiomyocytes from newborn rats. It was also revealed that TES knockdown via AdshTES caused the reverse phenotype in cardiomyocytes. Furthermore, it was proved that excessive TES expression attenuated the ventricular dilation, cardiac hypertrophy, dysfunction, and fibrosis triggered by AB in mice. It was discovered that TES directly interacted with calcineurin and suppressed its downstream signalling pathway. Moreover, the inactivation of calcineurin with cyclosporin A greatly offset the exacerbated hypertrophic response triggered by AB in TES knockdown mice. Overall, the findings of our study suggest that TES serves as a crucial regulator of the hypertrophic reaction by hindering the calcineurin-dependent pathway in the heart. PMID- 30467954 TI - Sustaining patient and public involvement and engagement in research. PMID- 30467955 TI - MiR-15a/16-1 deficiency induces IL-10-producing CD19+ TIM-1+ cells in tumor microenvironment. AB - IL-10-producing B cells (B10) are associated with autoimmune diseases, infection and tumours. MiR-15a/16 as a tumour-suppressive gene is down-regulated in several tumours, such as chronic lymphocytic leukaemia, pituitary adenomas and prostate carcinoma. Here, increased frequency of IL-10-producing CD19+ Tim-1+ cells was seen in both aged miR-15a/16-/- mice (15-18 months) with the onset of B cell leukaemia and young knockout mice (8-12 weeks) transplanted with hepatic cancer cells. CD19+ Tim-1+ cells down-regulated the function of effector CD4+ CD25low T cells ex vivo dependent on IL-10 production, and adoptive transfer of CD19+ Tim 1+ cells promoted tumour growth in mice. IL-10 production by CD19+ Tim-1+ cells was involved with the STAT3 activation. Bioinformatics analysis shows that miR-16 targets the 3'-untranslating region (3'-UTR) of STAT3 mRNA. Overexpression of miR 16 in CD19+ Tim-1+ cells inhibited STAT3 transcription and its protein expression. Thus, the loss of miR-15a/16 promoted induction of regulatory CD19+ Tim-1+ cells in tumour microenvironment. These results confirmed that miR-15a/16 could be used in tumour therapy due to its inhibition of tumour and regulatory B cells. PMID- 30467956 TI - Engineering "designer" glycomodules for boosting recombinant protein secretion in tobacco hairy root culture and studying hydroxyproline-O-glycosylation process in plants. AB - The key technical bottleneck for exploiting plant hairy root cultures as a robust bioproduction platform for therapeutic proteins has been low protein productivity, particularly low secreted protein yields. To address this, we engineered novel hydroxyproline (Hyp)-O-glycosylated peptides (HypGPs) into tobacco hairy roots to boost the extracellular secretion of fused proteins and to elucidate Hyp-O-glycosylation process of plant cell wall Hyp-rich glycoproteins. HypGPs representing two major types of cell wall glycoproteins were examined: an extensin module consisting of 18 tandem repeats of "Ser-Hyp-Hyp-Hyp-Hyp" motif or (SP4)18 and an arabinogalactan protein module consisting of 32 tandem repeats of "Ser-Hyp" motif or (SP)32 . Each module was expressed in tobacco hairy roots as a fusion to the enhanced green fluorescence protein (EGFP). Hairy root cultures engineered with a HypGP module secreted up to 56-fold greater levels of EGFP, compared with an EGFP control lacking any HypGP module, supporting the function of HypGP modules as a molecular carrier in promoting efficient transport of fused proteins into the culture media. The engineered (SP4)18 and (SP)32 modules underwent Hyp-O-glycosylation with arabino-oligosaccharides and arabinogalactan polysaccharides, respectively, which were essential in facilitating secretion of the fused EGFP protein. Distinct non-Hyp-O-glycosylated (SP4)18 -EGFP and (SP)32 EGFP intermediates were consistently accumulated within the root tissues, indicating a rate-limiting trafficking and/or glycosylation of the engineered HypGP modules. An updated model depicting the intracellular trafficking, Hyp-O glycosylation and extracellular secretion of extensin-styled (SP4)18 module and AGP-styled (SP)32 module is proposed. This article is protected by copyright. All rights reserved. PMID- 30467957 TI - DIABETES PHARMACOTHERAPY AND EFFECTS ON THE MUSCULOSKELETAL SYSTEM. AB - Persons with type 1 or type 2 diabetes (T1D, T2D) have a significantly higher fracture risk than age-matched persons without diabetes, attributed to disease specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin-based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall-related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in T2D, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium-dependent glucose co-transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes-related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes. PMID- 30467958 TI - Algorithmic solutions to common problems encountered during chronic total occlusion angioplasty: The algorithms within the algorithm. AB - Improved technical equipment, dissemination of best practices, and the importance of complete coronary revascularization have led to a renewed interest in coronary chronic total occlusion (CTO) PCI. In particular, the hybrid algorithm has been associated with increasing procedural success rates in the US. However, the hybrid algorithm only covers overarching strategies in the overall approach to these lesions. Several technical challenges can occur during execution of these approaches, each of which has several potential solutions. A systematic or algorithmic approach to dealing with these challenges could contribute to improved procedural efficiency and higher procedural success. While there have been isolated attempts in the past to codify approaches to each of these situations, there has not been a contemporary, comprehensive review of the potential solutions to these problems. We present 10 common problems encountered during CTO PCI and a consensus hierarchical approach to them. PMID- 30467959 TI - Genes regulating gland development in the cotton plant. AB - In seeds and other parts of cultivated, tetraploid cotton (Gossypium hirsutum L.), multicellular groups of cells lysigenously form dark glands containing toxic terpenoids such as gossypol that defend the plant against pests and pathogens. Using RNA-seq analysis of embryos from near-isogenic glanded (Gl2 Gl2 Gl3 Gl3 ) versus glandless (gl2 gl2 gl3 gl3 ) plants, we identified 33 genes that expressed exclusively or at higher levels in embryos just prior to gland formation in glanded plants. Virus Induced Gene Silencing against three gene pairs led to significant reductions in the number of glands in the leaves, and significantly lower levels of gossypol and related terpenoids. These genes encode transcription factors and have been designated the "Cotton Gland Formation" (CGF) genes. No sequence differences were found between glanded and glandless cotton for CGF1 and CGF2 gene pairs. The glandless cotton has a transposon insertion within the coding sequence of the GoPGF (synonym CGF3) gene of the A subgenome and extensive mutations in the promoter of D subgenome homeolog. Overexpression of GoPGF (synonym CGF3) led to a dramatic increase in gossypol and related terpenoids in cultured cells, while CRISPR/Cas9 knockout of GoPGF (synonym CGF3) genes resulted in glandless phenotype. Taken collectively, the results show that the GoPGF (synonym CGF3) gene plays a critical role in the formation of glands in the cotton plant. Seed-specific silencing of CGF genes, either individually or in combination, could eliminate glands, thus gossypol, from the cottonseed to render it safe as food or feed for monogastrics. This article is protected by copyright. All rights reserved. PMID- 30467960 TI - MicroRNA let-7a regulates angiogenesis by targeting TGFBR3 mRNA. AB - Angiogenesis has a great impact on human health, owing to its participation in development, wound healing and the pathogenesis of several diseases. It has been reported that let-7a is a tumour suppressor, but whether it plays a role in angiogenesis is unclear. Here we showed that let-7a, a microRNA conserved in vertebrates, regulated angiogenesis by concomitantly down-regulating TGFBR3. Overexpression of let-7a or knockdown of TGFBR3 in cell culture inhibited the tube formation and reduced migration rate. Moreover, xenograft experiments showed that overexpression of let-7a or knockdown of TGFBR3 had smaller tumour size. Downstream genes, such as VEGFC and MMP9, were also down-regulated in let-7a overexpression or TGFBR3 knockdown groups. Therefore, our results revealed a novel mechanism that let-7a regulate angiogenesis through post-transcriptional regulation of TGFBR3. PMID- 30467961 TI - Gliomasphere marker combinatorics: multidimensional flow cytometry detects CD44+/CD133+/ITGA6+/CD36+ signature. AB - Glioblastoma is the most dangerous brain cancer. One reason for glioblastoma's aggressiveness are glioblastoma stem-like cells. To target them, a number of markers have been proposed (CD133, CD44, CD15, A2B5, CD36, CXCR4, IL6R, L1CAM, and ITGA6). A comprehensive study of co-expression patterns of them has, however, not been performed so far. Here, we mapped the multidimensional co-expression profile of these stemness-associated molecules. Gliomaspheres - an established model of glioblastoma stem-like cells - were used. Seven different gliomasphere systems were subjected to multicolor flow cytometry measuring the nine markers CD133, CD44, CD15, A2B5, CD36, CXCR4, IL6R, L1CAM, and ITGA6 all simultaneously based on a novel 9-marker multicolor panel developed for this study. The viSNE dimensionality reduction algorithm was applied for analysis. All gliomaspheres were found to express at least five different glioblastoma stem-like cell markers. Multi-dimensional analysis showed that all studied gliomaspheres consistently harbored a cell population positive for the molecular signature CD44+/CD133+/ITGA6+/CD36+. Glioblastoma patients with an enrichment of this combination had a significantly worse survival outcome when analyzing the two largest available The Cancer Genome Atlas datasets (MIT/Harvard Affymetrix: P = 0.0015, University of North Carolina Agilent: P = 0.0322). In sum, we detected a previously unknown marker combination - demonstrating feasibility, usefulness, and importance of high-dimensional gliomasphere marker combinatorics. PMID- 30467962 TI - Inflammatory potential of cotton-based surgically invasive devices: Implications for cardiac surgery. AB - Cotton-based surgical invasive devices with their desired hemostyptic properties have been used for decades in the surgical field. However, in cardiac surgery using the heart-lung machine with direct retransfusion of suction blood, activated blood may re-enter the circulation without filtration and may trigger a cascade reaction leading to systemic inflammation and thrombosis. We therefore set out to evaluate the inflammatory potential of untreated and pyrogen impregnated cotton-based surgical invasive medical devices. After incubation of the swabs with whole blood or PBMC, the cell-free supernatant was investigated for IL1beta and IL6. While the reaction of human whole blood toward cotton swabs could not be influenced by any sterilization technique, dry heat and gamma irradiation were able to diminish the inflammatory reaction of PBMC toward the material and the used pyrogens. In conclusion, using PBMC in direct contact to cotton we are the first to establish a suitable test method for quantification of the pyrogenic/inflammatory activity of this material. The unaltered reaction of whole blood, however, suggests a crosstalk of cells and plasma proteins in the inflammation activation that is not prevented by sterilization of the swabs. This new in vitro testing methodology may help to better display the clinical situation during development of new materials. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res B Part B: Appl Biomater, 2018. PMID- 30467963 TI - Routine postprocedure ultrasound increases rate of detection of femoral arterial thrombosis in infants after cardiac catheterization. AB - OBJECTIVES: To examine the effect of implementing postcatheterization ultrasound (US) on femoral arterial thrombosis detection rates and factors associated with thrombosis in infants. BACKGROUND: Although femoral arterial thrombosis is an uncommon complication of cardiac catheterization, it can cause limb threatening complications. Previous studies assessing the utility of postprocedure US to detect thrombosis in infants have utilized US as an adjunct to standard clinical detection methods, are small scale, or include small cohorts of infants within older populations. METHODS: We reviewed institutional records of patients 0-12 months undergoing catheterization from 2007 to 2016. Demographics and procedural data were compared between the thrombosis and non-thrombosis group. Pre- and post US groups were compared for detected thrombosis rate. Using univariate and multivariable analyses, we identified factors associated with thrombosis. RESULTS: In total, 270 patients underwent 509 catheterizations, with 40 (7.9%) documented thromboses. The rate of thrombus detection in patients younger than 6 months increased from 8.3% to 23.4% (P = 0.006) after implementing routine US. On multivariable analysis, lower weight (P < 0.001), larger arterial sheath size (P < 0.001), and longer procedure duration (P = 0.003) were independently associated with higher odds of thrombosis. CONCLUSIONS: Higher rates of femoral arterial thrombosis detection were observed since implementing an US screening program. Further studies are needed to evaluate age-related changes in hemostasis in this population and how advanced screening methods and anticoagulation protocols may help improve short-term and long-term sequelae of femoral arterial thrombosis. PMID- 30467964 TI - Single-molecule real-time (SMRT) sequencing reveals diverse allelic variations in carotenoid biosynthetic genes in pepper (Capsicum spp.). AB - The diverse colors of mature pepper (Capsicum spp.) fruit result from the accumulation of different carotenoids. The carotenoid biosynthetic pathway has been well elucidated in Solanaceous plants, and analysis of candidate genes involved in this process has revealed variations in carotenoid biosynthetic genes in Capsicum spp. However, the allelic variations revealed by previous studies could not fully explain the variation in fruit color in Capsicum spp. due to technical difficulties in detecting allelic variation in multiple candidate genes in numerous samples. In this study, we uncovered allelic variations in six carotenoid biosynthetic genes, including phytoene synthase (PSY1, PSY2), lycopene beta-cyclase (Lcyb), beta-carotene hydroxylase (CrtZ-2), zeaxanthin epoxidase (ZEP), and capsanthin-capsorubin synthase (CCS) genes, in 94 pepper accessions by single-molecule real-time (SMRT) sequencing. To investigate the relationship between allelic variations in the candidate genes and differences in fruit color, we performed ultra-performance liquid chromatography (UPLC) analysis using 43 accessions representing each allelic variation. Different combinations of dysfunctional mutations in PSY1 and CCS could explain variation in the compositions and levels of carotenoids in the accessions examined in this study. Our results demonstrate that SMRT sequencing technology can be used to rapidly identify allelic variation of target genes in various germplasms. The newly identified allelic variants will be useful for pepper breeding and for further analysis of carotenoid biosynthesis pathways. This article is protected by copyright. All rights reserved. PMID- 30467965 TI - Case reports of coronary fibromuscular dysplasia and spontaneous coronary artery dissections. AB - Spontaneous coronary artery dissection (SCAD) is an important cause of acute coronary syndrome especially in women. The most common underlying predisposing cause of SCAD is fibromuscular dysplasia (FMD), a non-inflammatory arteriopathy that results in weakening of the affected arteries, and can cause dissection or aneurysm. Coronary FMD (CFMD) was described as rare, and was shown to cause SCAD in histopathological case reports. Unfortunately, CFMD is challenging to diagnose on coronary angiography, as the findings can be similar to other causes of coronary artery disease. Therefore, we illustrate two case examples of CFMD on coronary angiography, and highlight findings on optical coherence tomography to aid diagnosis. PMID- 30467966 TI - Impact of prosthesis-iteration evolution and sizing practice on the incidence of prosthesis-patient mismatch after transcatheter aortic valve replacement. AB - OBJECTIVES: To investigate the impact of the introduction of the next generation self-expanding (SE) and balloon-expandable (BE) transcatheter heart valves (THVs) on the incidence of prosthesis-patient mismatch (PPM) after transcatheter aortic valve replacement (TAVR). BACKGROUND: PPM is a risk factor for accelerated degeneration of bioprosthetic aortic valves. Data on PPM after TAVR are derived mainly from studies of older generation THVs. METHODS: PPM was assessed at 30 days post-TAVR with the older generation (Medtronic CoreValve, n = 120 and Edwards Sapien XT, n = 121) and the next generation THVs (Medtronic Evolut R/Pro, n = 136 and Edwards Sapien 3, n = 363). RESULTS: The incidence of any and severe PPM was 15.1% and 0.0% for the older generation THVs, and 42.8% and 12.1% for the next generation THVs. The incidence of moderate and severe PPM was 23.3% and 3.5% in patients who received an Evolut R/Pro vs. 33.1% and 14.7% in those who received a Sapien 3 (P < 0.001). On multivariable analysis, TAVR with the Sapien 3 THV was not associated with PPM, while left ventricular ejection fraction (0.97 [0.95-0.99], P = 0.002), history of myocardial infarction (2.09 [1.00-4.34], P = 0.049), annulus maximum diameter (0.84 [0.77-0.92], P < 0.001), and THV oversizing (0.90 [0.87-0.94], P < 0.001) were independently associated with PPM. In Sapien 3, the risk of any and severe PPM was higher in those with no oversizing (odds ratio: 3.25 [1.23-8.53], P = 0.017 and 5.79[2.33-14.36], P < 0.001). CONCLUSIONS: The incidence of PPM in contemporary TAVR is significant, especially with the next generation BE THV without adequate oversizing. PMID- 30467968 TI - Antibacterial Activity and Structure-Activity Relationship of a Series of Newly Synthesized Pleuromutilin Derivatives. AB - A series of novel thioether or sulfoxide-type pleuromutilin derivatives containing heteroaromatic substituents at the end of C14 side chain were designed and synthesized. All of the derivatives were evaluated for their anti gram positive bacteria activity in vitro. And some of them show good to excellent anti bacterial activity comparable to retapamulin and azamulin in most of the tested gram-positive pathogens. In this work, a five-membered heterocyclic moiety, a pyrimidine-membered heterocyclic moiety or a benzoheterocyclic moiety was introducted in the C14 side chain to increase the structural diversity of the pleuromutilin derivatives. The anti-bacterial result reveal that the thioether containing pleuromutilin derivatives exert a more potency activity than the sulfoxide-type derivatives against gram-positive pathogens. The structure activity relationship summarized in this work may provide some interesting clues as to which functionalities are beneficial for high antimicrobial activity of the pleuromutilin derivatives. PMID- 30467967 TI - An overview of percutaneous coronary intervention in dialysis patients: Insights from a Japanese nationwide registry. AB - OBJECTIVES: This study sought to provide an overview of percutaneous coronary intervention (PCI) in dialysis patients from a Japanese nationwide registry. BACKGROUND: Little is known about dialysis patients undergoing PCI because few are enrolled in clinical trials. METHODS: We analyzed 624,900 PCI cases including 41,384 dialysis patients (6.6%) from 1,017 Japanese hospitals between 2014 and 2016. We investigated differences in characteristics and in-hospital outcomes between dialysis and nondialysis patients, and assessed factors associated with an increased risk of adverse outcomes. RESULTS: Dialysis patients had more comorbidities than nondialysis patients and higher rates of complications including in-hospital mortality (3.3% vs. 1.5%, respectively, in the acute coronary syndrome [ACS] cohort, 0.2% vs. 0.1% in the non-ACS cohort) and bleeding complications requiring blood transfusion (1.1% vs. 0.4% in ACS, 0.5% vs. 0.2% in non-ACS). Dialysis was significantly associated with an increased risk of in hospital mortality (odds ratio [OR]: 1.42, 95% confidence interval [CI]: 1.24 1.62 in ACS, OR: 2.25, 95% CI: 1.66-3.05 in non-ACS) and bleeding (OR: 1.60, 95% CI: 1.30-1.96 in ACS, OR: 1.55, 95% CI: 1.27-1.88 in non-ACS). For dialysis patients, age, acute heart failure, and cardiogenic shock were associated with an increased risk of in-hospital mortality in the ACS cohort, whereas age, female gender, and history of heart failure were associated with higher in-hospital mortality in the non-ACS cohort. CONCLUSIONS: PCI was widely performed for dialysis patients with either ACS or non-ACS in Japan. Dialysis patients had a greater risk of adverse outcomes than nondialysis patients after PCI. PMID- 30467969 TI - The LepRdb/db mice model for studying glycation in the context of diabetes. AB - BACKGROUND: Early (furosine) and advanced (carboxymethyllysine, CML) products of glycation (AGEs) have been reported as increased in plasma, tissues and organs of diabetic people, indicating a direct link between glycation and type 2 diabetes (T2D). While murine models present some of the characteristics observed in diabetic humans, their pertinence as models of glycation, particularly for T2D, remains poorly described. The aim of this study was to characterize and compare glycation in several organs of two commonly-studied murine models of T2D using stable isotope dilution liquid chromatography tandem mass spectrometry (LC MS/MS). METHODS: Defining parameters of diabetes including body weight, fasting glycaemia and glucose intolerance were measured in three different C57BL6 mouse models of T2D (the genetic LepRdb/db (db/db) model and two diet-induced obesity (DIO) models) and their respective controls. Furosine, free and protein-bound CML were quantified in kidneys, lungs, heart and liver by LC-MS/MS. RESULTS: The obesity, hyperglycaemia and glucose intolerance in db/db mice was accompanied by an increase of furosine and protein-bound CML levels in all organs relative to controls. The DIO models took several months to become obese, exhibited less severe hyperglycaemia and glucose intolerance, while glycation products were not significantly different between these groups (with the exception of furosine in liver and CML in lungs). CONCLUSIONS: The db/db model better reflected the characteristics of human T2D compared with the DIO models, and exhibited greater formation and accumulation of both furosine and protein-bound CML in all of the organs tested here. PMID- 30467970 TI - MicroRNA-296-5p promotes healing of diabetic wound by targeting sodium-glucose transporter 2 (SGLT2). AB - BACKGROUND: Diabetic wounds are refractory and very difficult to heal. We aimed to use miRNA to identify novel and specific molecular markers for diabetes mellitus (DM) diagnosis and treatment. METHODS: The expression level of miR-296 5p was determined in tissue samples of 12 DM patients. The effect of miR-296-5p on proliferation of beta-cells was examined using CCK-8 and colony formation assay. The effect of miR-296-5p on cell cycle progression was analyzed using flow cytometry. The target gene was verified using luciferase reporter assay. A rat diabetes model was used to assess the effect of miR-296-5p in vivo. RESULTS: Overexpression of miR-296-5p suppressed cell proliferation, arrested cell cycle progression and increased the healing rate of diabetic wounds both in vivo and in vitro. TargetScan analysis results showed that miR-296-5p is a direct regulator of SGLT2. CONCLUSIONS: miR-296-5p can increase the healing rate of diabetic wounds and may be an effective molecular tool in DM diagnosis and therapy. PMID- 30467971 TI - Plasma levels of miR-29b and miR-200b in type 2 diabetic retinopathy. AB - MicroRNAs (miRNAs/miRs) are involved in the pathogenesis of diabetes mellitus and its chronic complications, and their circulating levels have emerged as potential biomarkers for the development and progression of diabetes. However, few studies have examined the expression of miRNAs in diabetic retinopathy (DR) in humans. This case-control study aimed to investigate whether the plasma levels of miR-29b and miR-200b are associated with DR in 186 South Brazilians with type 2 diabetes (91 without DR, 46 with non-proliferative DR and 49 with proliferative DR). We also included 20 healthy blood donors to determine the miRNA expression in the general population. Plasma levels of miR-29b and miR-200b were quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Proliferative DR was inversely associated with plasma levels of miR-29b (unadjusted OR = 0.694, 95% CI: 0.535-0.900, P = 0.006) and miR-200b (unadjusted OR = 0.797, 95% CI: 0.637-0.997, P = 0.047). However, these associations were lost after controlling for demographic and clinical covariates. In addition, patients with type 2 diabetes had lower miR-200b levels than blood donors. Our findings reinforce the importance of addressing the role of circulating miRNAs, including miR-29 and miR-200b, in DR. PMID- 30467972 TI - Self-Standing 3D Cathodes for All-Solid-State Thin Film Lithium Batteries with Improved Interface Kinetics. AB - 3D all-solid-state thin film batteries (TFBs) are proposed as an attractive power solution for microelectronics. However, the challenge in fabricating self supported 3D cathodes constrains the progress in developing 3D TFBs. In this work, 3D LiMn2 O4 (LMO) nanowall arrays are directly deposited on conductive substrates by magnetron sputtering via controlling the thin film growth mode. 3D TFBs based on the 3D LMO nanowall arrays and 2D TFBs based on the planar LMO thin films are successfully fabricated using a lithium phosphorous oxynitride (LiPON) electrolyte and Li anode. In comparison, the 3D TFB significantly outperforms the 2D TFB, exhibiting large specific capacity (121 mAh g-1 at 1 C), superior rate capability (83 mAh g-1 at 20 C), and good cycle performance (over 90% capacity retention after 500 cycles). The superior electrochemical performance of the 3D TFB can be attributed to the 3D architecture, which not only greatly increases the cathode/electrolyte interface and shortens the Li+ diffusion length, but also effectively enhances the structural stability. Importantly, the vertically aligned nanowall array architecture of the cathode can significantly mitigate disordered LMO formation at the cathode surface compared to the 2D planar thin film, resulting in a greatly reduced interface resistance and improved rate performance. PMID- 30467973 TI - Delayed aortic dissection and valve thrombosis after transcatheter aortic valve implantation. AB - We report a case of a 78-year-old female who presented with type A aortic dissection 22 months following transcatheter aortic valve implantation (TAVI). In addition, preoperative echocardiogram showed high gradients across the aortic prosthesis which was found to be thrombosed. At surgery, the intimal tear appeared to be non-acute and anatomically related to the rim of the valve cage. The thrombosed valve was not replaced and the patient received anticoagulation therapy following surgery with significant improvement in valve gradients. PMID- 30467974 TI - Take to the high seas: microbiology labs below the ocean surface. PMID- 30467975 TI - ADIPOQ, KCNJ11 and TCF7L2 polymorphisms in type 2 diabetes in Kyrgyz population: A case-control study. AB - The aim of this study was to ascertain the polymorphic markers profile of ADIPOQ, KCNJ11 and TCF7L2 genes in Kyrgyz population and to analyze the association of polymorphic markers and combinations of ADIPOQ gene's G276T locus, KCNJ11 gene's Glu23Lys locus and TCF7L2 gene's VS3C>T locus with type two diabetes (T2D) in Kyrgyz population. In this case-control study, 114 T2D patients 109 non-diabetic participants were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Two individual polymorphisms (ADIPOQ rs1501299, KCNJ11 rs5219) were found to be associated with T2D. We found two (Lys23Lys/CC and Glu23Lys/CT) of the overall nine combinations, which were more prevalent in T2D group compared to controls (chi2 = 4.21, P = 0.04). Lys23Lys/CC combination was associated with a 2.65-fold increased likelihood of T2D (OR = 2.65, 95% CI 1.12-6.28), whereas the Glu23Lys/CT combination also increased such likelihood (OR = 3.88, 95% CI 1.27-11.91). This study demonstrated some association of 276T allele and ADIPOQ gene G276T heterozygous genotype as well as KCNJ11 gene 23Lys allele with T2D in ethnic Kyrgyz, but study results should be interpreted with caution because of the limited statistical power. PMID- 30467976 TI - Spontaneous middle lobe torsion in a patient with multicentric Castleman disease: A case report. AB - We describe a rare case of middle lobe lung torsion in a patient with a tension hydrothorax secondary to multicentric Castleman disease. The case demonstrates the difficulty of diagnosing torsion prospectively, and the possible sequelae of delayed detection. Although imaging features can be confusing, an awareness of this condition and careful image interpretation by radiologists could facilitate early recognition and management of a torted lobe. PMID- 30467977 TI - Differential clustering of faecal and mucosa-associated microbiota in healthy individuals. AB - BACKGROUND: Faecal samples are often used to characterise gut microbiota, since they are easily collected. However, whether or not the faecal microbiota differ from the mucosa-associated microbiota remains largely unknown. This may be specifically relevant in conditions that are characterised by complex mucosal microbe-host interactions, such as Crohn's disease. We aimed to determine the degree of agreement between faecal and mucosal microbiota profiles in healthy individuals, using two commonly used collection procedures. MATERIAL AND METHODS: The gut microbiota composition of faecal samples (sent at ambient temperature before storage at -70 degrees C) and of colonic biopsies (obtained at endoscopy and immediately stored at -70 degrees C) was determined by sequencing the 16S rRNA gene. Thirty-one randomly selected healthy individuals from the population based colonoscopy (Popcol) study were included. RESULTS: Faecal samples were characterised by a reduced degree of richness (p<0.0001) and diversity (p=0.016), and also differences in several phyla, including a lower relative abundance of Proteobacteria (p<0.0001) and Verrucomicrobia (p=0.008) than in biopsies. Only 3 of 30 individuals had a similar faecal and mucosal microbiota profile, based on weighted UniFrac analysis. A difference in Crohn's disease dysbiosis-associated bacteria was observed, including a lower relative abundance of Faecalibacterium (p=0.004) and a higher relative abundance of Ruminococcus (p=0.001) in faeces than in biopsies. CONCLUSIONS: Analysis of faecal samples that have been transported at ambient temperature does not adequately reflect the colonic mucosa associated microbiota in healthy individuals. These findings have implications for the interpretation of the previous literature, and may be specifically relevant to studies on Crohn's disease. This article is protected by copyright. All rights reserved. PMID- 30467978 TI - Do pre-haemodialysis estimates of extracellular volume excess using bioimpedance and N terminal brain natriuretic peptide correlate with cardiac chamber size measured by magnetic resonance imaging ? AB - BACKGROUND: Bioimpedance can be used to measure extracellular water (ECW) and total body water (TBW) in haemodialysis (HD) patients and estimate ECW excess. However, ECW excess potentially includes both an increase in the plasma volume and also the extravascular volume. Overestimating the amount of fluid to be removed during HD risks intra-dialytic hypotension. We wished to determine the association between estimates of ECW excess comparing several different equations using bioimpedance, brain N-terminal pro-brain natriuretic peptide (NT-proBNP) with cardiac chamber volumes and function as determined by cardiac magnetic resonance imaging (MRI) METHODS: Pre-HD measurements of ECW and TBW were made using multi-frequency bioimpedance and cardiac chamber sizes and functionwere determined by MRI . RESULTS: 30 patients, 20 males (66.7%), mean age 64.4+/-15.3 years were studied. ECW and ECW/height were positively associated with indexed right ventricular end-systolic (RVESVi) and end-diastolic volume (RVEDVi) (RVESi r=0.46, r=0.43; RVEDi r=0.50, r=0.44, all p<0.05), but not with left sided cardiac volumes. Whereas NT-proBNP was associated with indexed left atrial and ventricular size (r= 0.47, r=0.58, p<0.05), but not right sided cardiac volumes. CONCLUSION: Pre-HD NT-proBNP was associated with left sided cardiac chamber sizes, but not with right sided chamber sizes, whereas ECW/height was associated with right sided cardiac chamber sizes. As right sided cardiac chamber size is more responsive to and reflective of changes in intravascular volume than the left atrium and ventricle, then bioimpedance measured ECW is potentially more reliable in estimating plasma volume expansion. This article is protected by copyright. All rights reserved. PMID- 30467979 TI - Carboxytherapy: Controls the inflammation and enhances the production of fibronectin on wound healing under venous insufficiency. AB - To examine the influence of carboxytherapy on wound healing under venous insufficiency, full-thickness excisional wounds were created on Wistar rats. We used three groups with 32 rats each: Group (I): daily cleaning with 0.9% saline solution; Group Sulfadiazine (II): 1% silver sulfadiazine; and Carboxytherapy (III): subcutaneous application of 0.3 mL of carbon dioxide. The predetermined periods of analysis were the 3rd, 7th, 14th, and 30th day. The slides were stained with haematoxylin and eosin and Picrosirius red and submitted for immunohistochemistry. Groups II and III presented a statistically significant decrease in relation to the presence of neutrophilic and lymphocytic infiltrates. The presence of collagen significant increased in groups II and III. However, group III presented better organisation. Only group I maintained the neovascularisation until the 30th day. The new epithelium statistically significantly increased in groups II and III. On immunohistochemistry, regarding fibronectin expression, only group III demonstrated a statistically significant increase since the beginning of the healing process. Thus, the use of carboxytherapy promotes the formation of a tissue better structured and that may be an important resource for the treatment of wounds under venous insufficiency, especially those of recurrent re-openings. PMID- 30467980 TI - Stacking three late blight resistance genes from wild species directly into African highland potato varieties confers complete field resistance to local blight races. AB - Considered responsible for one million deaths in Ireland and widespread famine in the European continent during the 1840s, late blight, caused by Phytophthora infestans, remains the most devastating disease of potato (Solanum tuberosum L.) with about 15-30% annual yield loss in sub-Saharan Africa, affecting mainly smallholder farmers. We show here that the transfer of three resistance (R) genes from wild relatives [RB, Rpi-blb2 from Solanum bulbocastanum and Rpi-vnt1.1 from S. venturii] into potato provided complete resistance in the field over several seasons. We observed that the stacking of the three R genes produced a high frequency of transgenic events with resistance to late blight. In the field, 13 resistant transgenic events with the 3R-gene stack from the potato varieties 'Desiree' and 'Victoria' grew normally without showing pathogen damage and without any fungicide spray, whereas their non-transgenic equivalent varieties were rapidly killed. Characteristics of the local pathogen population suggest that the resistance to late blight may be long-lasting because it has low diversity, and essentially consists of the single lineage, 2_A1, which expresses the cognate avirulence (Avr) effector genes. Yields of two transgenic events from 'Desiree' and 'Victoria' grown without fungicide to reflect small-scale farm holders were estimated to be 29 t/ha and 45 t/ha, respectively. This represents a three to four-fold increase over the national average. Thus, these late blight resistant potato varieties, which are the farmers' preferred varieties, could be rapidly adopted and bring significant income to smallholder farmers in sub Saharan Africa. This article is protected by copyright. All rights reserved. PMID- 30467981 TI - The Role of Affect on Physical Health Over Time: A Cross-Lagged Panel Analysis Over 20 Years. AB - BACKGROUND: While previous studies have investigated the interplay between affect and health (1) over an extended period of time, (2) in a representative population, and (3) while modelling positive and negative affect simultaneously, no single study has done all three at once. METHODS: The present study accomplishes this by sampling adults from the Midlife Development in the US study who completed affect (Mroczek & Kolarz, 1998) and health measures (chronic conditions, Charlson, Szatrowski, Peterson, & Gold, 1994; functional limitations, McHorney, Ware, Lu, & Sherbourne, 1994; self-reported health) measured three times over 20 years. We ran three (one per health metric) random-intercept cross lagged panel models, where positive and negative affect were modelled simultaneously. RESULTS: Results indicated that positive and negative affect significantly predicted future heath (functional limitations/self-reported health) and that this relationship was reciprocal (i.e. health measures predicted future affect). However, there were no significant cross-lagged relations between affect and chronic conditions. CONCLUSION: Our results suggest that both positive and negative affect play an equal role in predicting future health for functional limitations and self-reported health as well as highlight the bi-directionality of this relationship. Additionally, the degree to which affect predicts future health may be moderated by the type of health outcome. PMID- 30467982 TI - Application of Extracellular Vesicles Proteomics to Cardiovascular Disease: Guidelines, Data Analysis, and Future Perspectives. AB - Extracellular vesicles (EVs) are a heterogeneous population of vesicles composed of a lipid bilayer that carry a large repertoire of molecules including proteins, lipids and nucleic acids. In this review, we provide some guidelines for plasma derived EVs isolation, characterization, and proteomic analysis, and the application of the above to cardiovascular disease studies. For EVs analysis, blood samples should be collected using a 21-gauge needle, preferably in citrate tubes, and plasma stored for up to one year at -80 degrees , using a single freeze-thaw cycle. For proteomic applications, differential centrifugation (including ultracentrifugation steps) is a good option for EVs isolation. EVs characterization can be done by transmission electron microscopy, particle enumeration techniques (nanoparticle-tracking analysis, dynamic light scattering), and flow cytometry. Regarding the proteomics strategy, a label-free gel-free quantitative method is a good choice due to its accuracy and because it minimizes the amount of sample required for clinical applications. Besides the above, main EVs proteomic findings in cardiovascular-related diseases are presented and analyzed in this review, paying especial attention to overlapping results between studies. The latter might offer new insights into the clinical relevance and potential of novel EVs biomarkers identified to date in the context of cardiovascular disease. This article is protected by copyright. All rights reserved. PMID- 30467984 TI - Transforming traditional shadowing: engaging millennial learners through the active apprenticeship. PMID- 30467983 TI - N-Upsilon-(l-Glutamyl)-l-Selenomethionine Inhibits Fat Storage via the Stearoyl CoA Desaturases FAT-6 and FAT-7 and the Selenoprotein TRXR-1 in Caenorhabditis elegans. AB - SCOPE: Selenium is an important nutrient for human health. The influence of dietary selenium on lipid metabolism remains largely unknown. N-gamma-(l glutamyl)-l-selenomethionine (Glu-SeMet) on inhibition of fat accumulation and its underlying mechanisms in the nematode Caenorhabditis elegans are investigated. METHODS AND RESULTS: Triacylglyceride quantification and post-fixed Nile red staining methods are conducted to evaluate fat accumulation in wild-type N2 worms in normal or high-glucose diet. Glu-SeMet (0.01 um) treatment effectively reduces fat storage in wild-type N2 C. elegans in both a normal and high-glucose diet. Further evidence shows that Glu-SeMet (0.01 um) decreases the ratio of oleic acid/stearic acid (C18:1Delta9/C18:0) using gas chromatography mass spectrometry analysis. The mRNA levels of fatty acid stearoyl-CoA desaturases, FAT-6 and FAT-7, and the mediator-15 (MDT-15) are downregulated while the wild-type N2 worms are co-treated with high glucose and Glu-SeMet (0.01 um). The effect of reduced fat accumulation is absent in fat-6, fat-7, and trxr-1 mutant worms under high glucose and Glu-SeMet (0.01 um) co-treatment. CONCLUSIONS: This study demonstrates that Glu-SeMet inhibiting fat accumulation may be associated with FAT-6 and FAT-7 and the selenoprotein TRXR-1 in C. elegans. This study implies a potential for Glu-SeMet as a new treatment for obesity or its complications. PMID- 30467985 TI - An Experimental Test of the Effects of a Target Person's Body Weight and Engagement with Health Behaviours on Perceptions of Overall Health. AB - BACKGROUND: Public health campaigns commonly emphasise the association between excess weight and poor health. The present study aimed to examine the effect of information about weight and engagement with health behaviours on judgements of a person's health. METHOD: In two experimental studies, participants were asked to evaluate a target person's health and to make recommendations about that person's health-related behaviours. In Study 1 (n = 306), we manipulated the target's behaviours (healthy, unhealthy) and body weight (normal, overweight, obese); in Study 2 (n = 192), we manipulated the behaviour of an overweight target (healthy, unhealthy). RESULTS: Study 1 found that the obese target was consistently rated as less healthy than the normal-weight target, whereas the overweight target was only rated as less healthy when her behaviours were unhealthy. Study 2 found that the overweight target's weight was viewed as being more harmful to her health when she engaged in unhealthy behaviours. Recommendations to lose weight were most common for the obese targets (with healthy or unhealthy behaviours), and for the overweight target with unhealthy behaviours. CONCLUSIONS: Whereas obesity appears to be viewed as harmful to health independent of health behaviours, the extent to which overweight is perceived as harmful depends on the overweight individual's diet and exercise behaviours. PMID- 30467986 TI - Intraoperative radiotherapy with image guidance: Mix and match. PMID- 30467987 TI - The clinician educator as qualitative researcher. PMID- 30467988 TI - Thymic inflammatory pseudotumor with multilocular thymic cyst caused by immunoglobulin G4-related disease. AB - A 44-year-old man was referred to our hospital after an anterior mediastinal tumor was noted on computed tomography during follow-up observation after left testicular seminoma resection. Chest computed tomography revealed an enhanced mass measuring 33 x 16 x 15 mm at the anterior mediastinum. Chest magnetic resonance imaging revealed high signal intensity on T2-weighted imaging, and F18 fluorodeoxyglucose-positron emission tomography showed a maximum standardized uptake of 12.45. Laboratory tests revealed no elevated tumor markers, except for mildly elevated interleukin-2. Based on these results, complete resection was performed under suspicion of a malignant tumor, mediastinal metastasis of seminoma, or malignant lymphoma. An extended thymectomy with partial merger pericardial resection was performed using a subxiphoid approach. Small nodules and multiple thymic cysts were observed the thymus in addition to the main mass. Microscopic examination of the tumor revealed fibrosis, lymphocyte infiltration with lymphoid follicular hyperplasia, and hyperplasia of the thymus. Numerous immunoglobulin G4 (IgG4)-positive plasma cells were found on immunohistochemical staining. The ratio of IgG4 to total IgG was approximately 60%. We ultimately diagnosed the patient with a thymic inflammatory pseudotumor with multilocular cyst caused by IgG4-related disease. PMID- 30467989 TI - Proteomic signature of mesenchymal stromal cell-derived small extracellular vesicles. AB - Small extracellular vesicles are 50-200 nm vesicles secreted by most cells. They are considered as mediators of intercellular communication, and EVs from specific cell types, in particular mesenchymal stem/stromal cells (MSCs), offer powerful therapeutic potential, and could provide a novel therapeutic strategy. They appear promising and safe (as EVs are non-self-replicating), and eventually MSC derived EVs (MSC-EVs) may be developed to standardized, off-the-shelf allogeneic regenerative and immunomodulatory therapeutics. Promising pre-clinical data have been achieved using MSCs from different sources as EV-producing cells. Similarly, a variety EV isolation and characterization methods have been applied. Interestingly, MSC-EVs obtained from different sources and prepared with different methods show in vitro and in vivo therapeutic effects, indicating that isolated EVs share a common potential. Here, we compare well-characterized and controlled publicly available proteome profiles of MSC-EVs to identify a common MSC-EV protein signature that might be coupled to the MSC-EVs' common therapeutic potential. This protein signature may be helpful in developing MSC-EV quality control platforms required to confirm the identity and test for the purity of potential therapeutic MSC-EVs. This article is protected by copyright. All rights reserved. PMID- 30467990 TI - Tumour-derived extracellular vesicles as a novel source of protein biomarkers for cancer diagnosis and monitoring. AB - "Liquid biopsies" have received attention as a complementary tool for traditional tissue biopsies that may enhance the spectrum of analysis for tumour-derived factors. One such factor gaining prominence in the liquid biopsy field are extracellular vesicles (EVs), membrane-bound nanovesicles which are secreted by cells into biofluids such as blood, urine and saliva. EVs are released in both physiological and pathological conditions and can transport a variety of molecules, including proteins, metabolites, RNA, microRNAs and DNA, to distant sites throughout the body. As such, they are emerging as a promising source of tumour biomarkers for the non-invasive diagnosis, prognosis and monitoring of cancer patients. In particular, the wealth of tumour-related information that can be gleaned from the EV proteomic cargo has become apparent through mass spectrometric analysis, which has provided new benchmarks for clinically-focused biomarker research. In this review, we have explored the current achievements in the use of mass spectrometry for identifying potential EV-derived protein biomarkers of cancer, and summarised the techniques and challenges involved in this pursuit. This article is protected by copyright. All rights reserved. PMID- 30467991 TI - A student's advice on scholarly letter writing. PMID- 30467993 TI - Uterine natural killer cells: To protect and to nurture. AB - During the course of pregnancy, the maternal-fetal interface is tightly regulated and undergoes dynamic changes that promote the successful development of the semi allogeneic fetus. In response to embryo implantation, the uterus remodels with maternal immune cells occupying the maternal-fetal interface and uterine natural killer (uNK) cells becoming the most prominent leukocyte. Recently, uNK cells have been discovered to be heterogeneous, including conventional NK and tissue resident NK cells. Here, we will review the recent advances in uNK cell biology and discuss their functional mechanisms which protect and nurture the growing fetus. PMID- 30467992 TI - Laparoscopic repair of secondary perineal hernia with coverage by the mobilized cecum. AB - The incidence of secondary perineal hernia (SPH) has increased since the introduction of extralevator abdominoperineal resection and laparoscopic abdominoperineal resection. Currently, laparoscopic mesh repair is the usual procedure. Here, we demonstrate a repair of SPH without mesh that uses the mobilized cecum to cover the pelvic hernial orifice. An 83-year-old man complained of discomfort when sitting for long periods. He was status post laparoscopic abdominoperineal resection and was diagnosed with SPH. Hernia repair was performed. After transperitoneal adhesiolysis in the inferior pelvis, the right colon was laparoscopically mobilized, and the pelvic orifice was covered by suturing the cecum to the pelvic brim. The perineal skin was managed with negative pressure wound therapy. The postoperative course was uneventful. There has been no sign of recurrent herniation for 12 months. This method of SPH repair is simple to perform and avoids mesh-related complications. PMID- 30467995 TI - Identification of the novel HLA-B*18:01:01:17 allele in a Saudi individual. AB - HLA-B*18:01:01:17 differs from HLA-B*18:01:01:01 by a single nucleotide substitution (A?T) at position 3956. This article is protected by copyright. All rights reserved. PMID- 30467994 TI - Outcome after new generation single-layer polytetrafluoroethylene-covered stent implantation for the treatment of coronary artery perforation. AB - AIMS: Coronary artery perforation (CAP) is a rare but severe complication during percutaneous coronary intervention (PCI). Implantation of covered stents (CS) represents a potentially life-saving treatment. Concerns exist regarding limited efficacy and high stent thrombosis (ST) rates related to early generation CS. The aim of this study was to evaluate angiographic and clinical outcomes of patients with CAP treated with a new generation single-layer polytetrafluoroethylene (PTFE)-CS. METHODS: Between May 2013 and November 2017, we identified a total of 61 patients who underwent implantation of 71 single layer PTFE-CS after CAP. We analyzed angiographic results at follow up (including binary angiographic restenosis [BAR] and late-lumen-loss [LLL]) and clinical outcomes in hospital and at follow up, including target lesion revascularization (TLR), cardiovascular-, and all-cause mortality, myocardial infarction (MI) and stent thrombosis (ST). RESULTS: Procedural success was achieved in all but two patients (96.7%). Procedure related MI, occurred in 19 cases (31.1%), in hospital death occurred in five cases (8.2%). At follow-up, TLR occurred in 11 cases (18.0%), two patients (3.3%) died from non-cardiovascular cause, there was no case of MI or ST. CONCLUSIONS: In this retrospective analysis, implantation of a new generation PTFE-CS, for the treatment of CAP showed high technical success rates. Although, periprocedural MI-and in-hospital-death rates remain not inconsiderable, new generation PTFE-CS showed favorable angiographic and clinical efficacy and high safety profile, especially with regard to thrombotic events. PMID- 30467996 TI - "The epidemiology of chronic kidney disease in Australian general practice:NPS MedicineWise MedicineInsight dataset". AB - AIM: To describe sociodemographic characteristics and comorbidities of a large cohort of Australian general practice-based patients identified as having chronic kidney disease (CKD), using data from NPS MedicineWise's MedicineInsight dataset, and compare this dataset to the 2011-12 Australian Health Survey's (AHS) CKD prevalence estimates. METHODS: This was a cohort study using deidentified, longitudinal, electronic health record (EHR) data collected from 329 practices and 1,483,416 patients distributed across Australia, from 1 June 2013 until 1 June 2016. Two methods were used to calculate the CKD prevalence. One used the same method as used by the 2011-12 AHS, based on one estimate of the electronic glomerular filtration (eGFR) or albumin/creatinine ratios (ACR). The other defined CKD more rigorously using eGFR or ACR results at least 90 days apart. RESULTS: In 2016, of 1,310,602 active patients, 710,674 (54.2%) did not have an eGFR or ACR test, while 524,961 (40.1%) had an eGFR or ACR test but did not meet AHS criteria for CKD. Age-sex adjusted rates of CKD (compared to AHS) were CKD 1 0.45% (3.9%), CKD 2 - 0.62% (2.5%), CKD 3a - 3.1% (2.7%), CKD 3b - 1.14% (0.6%), CKD 4-5 - 0.41% (0.3%). The CKD cohort, defined more rigorously using eGFR and ACR measures > 90 days apart, had comorbidities of atrial fibrillation (30.5%), cardiovascular disease (25.0%), diabetes mellitus (17.1%), and hypertension (14.8%). CONCLUSIONS: The MedicineInsight dataset contains valuable and timely information about Australian patients with CKD, and provides prevalence estimates similar to those from AHS data. This article is protected by copyright. All rights reserved. PMID- 30467997 TI - Identification of the novel HLA-A*29:02:01:06 allele in a Saudi individual. AB - HLA-A*29:02:01:06 differs from HLA-A*29:02:01:01 by a single nucleotide substitution (T?C) at position 2471. This article is protected by copyright. All rights reserved. PMID- 30467999 TI - An official nomenclature for the Major Histocompatibility Complex allele sequences from the domestic goat (Capra hircus). AB - Official allelic nomenclature and corresponding databases of validated MHC alleles from most of the major species of farmed livestock are now represented on the IPD-MHC Database. The major exception is the domestic goat (Capra hircus) which can lead to confusion in the research community. Here we propose to start the process of developing such a resource which will support the research community's interests in livestock population genetics, infectious disease research, vaccine development and comparative studies. In this manuscript, we assign the official nomenclature for the major transcribed and highly polymorphic MHC class II DRB1 locus. Additional class II loci including DRA and DQ and MHC class I loci will be added in the future. This article is protected by copyright. All rights reserved. PMID- 30467998 TI - Colocalization of A2a but not A1 adenosine receptors with GABA-ergic neurons in cardiopulmonary chemoreflex network in the caudal nucleus of the solitary tract. AB - Adenosine operating in the nucleus of the solitary tract (NTS) may inhibit or facilitate neurotransmitter release from nerve terminals and directly inhibit or facilitate central neurons via A1 and A2a pre- and postsynaptic receptors, respectively. However, adenosine A2a receptors, may also activate GABA-ergic neurons/terminals which in turn inhibit glutamatergic transmission in the NTS network. Our previous studies showed that adenosine operating via both A1 (inhibitor) and A2a (activator) receptors powerfully inhibits the cardiopulmonary chemoreflex (CCR) at the level of the caudal NTS. A1 receptors most likely inhibit glutamate release in the CCR network, whereas A2a receptors facilitate NTS GABA-ergic mechanisms which in turn inhibit CCR glutamatergic transmission. Therefore, we hypothesized that A2a receptors are located on NTS GABA-ergic neurons/terminals whereas A1 receptors may be located on NTS glutamatergic neurons/terminals. We investigated this hypothesis using double immunofluorescent staining for A2a or A1 adenosine receptors and GABA synthesizing enzyme, GAD67, in 30 MUm thick, floating, medullary rat sections. We found that A2a adenosine receptors are localized within the GABA-ergic cells in the caudal NTS, whereas A1 adenosine receptors are absent from these neurons. Instead, A1 receptors were located on non-GABA-ergic (likely glutamatergic) neurons/terminals in the caudal NTS. These data support our functional findings and the hypothesis that adenosine A2a, but not A1 receptors are located on GABA-ergic neurons. PMID- 30468000 TI - Effect of elderly status on postoperative complications in patients with sinonasal cancer. AB - BACKGROUND: Elderly patients with multiple comorbidities may be at higher risk of postoperative complications. With an increasingly aging population, more data assessing for predisposing factors are needed in this at-risk group. In this study, we analyzed the effect of elderly status on relative comorbidities and complications of sinonasal cancer (SNC) patients receiving surgery. METHODS: A retrospective database analysis was performed using cases from the Nationwide Inpatient Sample (NIS) from 2003 to 2012. Patients with a diagnosis of malignant neoplasm of the nasal cavity or paranasal sinuses, who received surgery for sinonasal malignancy, including neck dissections, were selected. Demographics of interest included age, sex, race, type of admission, mean length of stay, and median hospital charges. Elderly and nonelderly patients were compared for differences in rates of acute medical complications, acute surgical complications, and relevant procedures during hospitalization. RESULTS: Of the 920 cases identified in the NIS, 382 (41.5%) were elderly (>=65 years). Cases of SNC were more frequently seen in males than females (p < 0.001). Elderly patients had significantly higher comorbidity rates compared with nonelderly patients, which included congestive heart failure, hypertension, diabetes, chronic pulmonary disease, and chronic renal failure (p < 0.001 for all). Elderly patients more frequently had postoperative cardiac complications (6.0% vs 0.5%, p < 0.001), but this finding was not statistically significant on multivariate analysis when controlling for race, sex, and comorbidities. CONCLUSION: Elderly status is not an independent factor for postoperative complications in patients undergoing surgery for sinonasal malignancy. PMID- 30468001 TI - Regression of peripheral subclinical enthesopathy in therapy-naive patients treated with Ustekinumab for moderate-to-severe chronic plaque psoriasis. AB - OBJECTIVE: This study investigated whether sonographically determined subclinical enthesopathy in patients with moderate-to-severe psoriasis regressed under therapy with ustekinumab, initiated for skin disease. METHODS: Seventy-three systemic therapy-naive patients with moderate-to-severe psoriasis and without symptoms of PsA, and 23 healthy volunteers, were screened using ultrasound for subclinical enthesitis. Subsequently, 23 psoriasis patients with "inflammatory changes" on ultrasound were treated with ustekinumab for 52 weeks. The evolution of sonographic abnormalities was assessed using an extensive grey scale (GS) and power Doppler (PD) ultrasound protocol of the upper and lower limb entheses at weeks 0, 12, 24 and 52. For each parameter, a GS or PD score >0 was taken as abnormal and a summative score (based on the GUESS) calculated. RESULTS: 49.3% of screened patients with psoriasis had at least one inflammatory entheseal abnormality on ultrasound. Mean inflammation scores were higher in psoriasis patients compared with healthy volunteers: 9.9 (6.6) vs. 1.0 (1.4). With treatment, mean (95% C.I.) inflammation scores reduced significantly from week 0 by 42.2% to week 24 (-4.2 (-6.3,-2.1), p<0.001) and by 47.5% (-4.7 (-7.1,-2.3), p=0.001) to week 52. Entheseal structural abnormalities did not significantly change during treatment. CONCLUSION: IL-12/23 inhibition for psoriasis appears to suppress subclinical enthesopathy within 12 weeks of treatment, maintained to week 52. Further longitudinal studies are needed to see whether therapy initiated for skin disease may prevent PsA development. This article is protected by copyright. All rights reserved. PMID- 30468003 TI - Now is the time for evidence-generating practice in gerontological nursing. PMID- 30468002 TI - Cost-effective and fast KIR gene-content genotyping by multiplex melting curve analysis. AB - Killer cell immunoglobulin-like receptor (KIR) genes encode cell surface molecules that recognize human leukocyte antigen (HLA) molecules and modulate the activity of natural killer (NK) cells. KIR genes exhibit presence and absence polymorphism, which generates a variety of gene-content haplotypes in worldwide populations. KIR gene-content variation is implicated in many diseases and is also important for placentation and transplantation. Due the complexity of KIR polymorphism, variation in this family is still mostly studied at the gene content level, even with the advent of next generation sequencing methods. Gene content determination is generally expensive and/or time-consuming. To overcome these difficulties, we developed a method based on multiplex polymerase chain reaction with specific sequence primers (PCR-SSP) followed by melting curve analysis that allows cost-effective, precise and fast generation of results. Our method was 100% concordant with a gel-based method and 99.9% concordant with presence and absence determination by next generation sequencing. The limit of detection for accurate typing was 30 ng of DNA (0.42 MUM) with 260/230 and 260/280 ratios as low as 0.19 and of 0.44. In addition, we developed a user friendly Java-based computational application called killerPeak that interprets the raw data generated by Viia7 or QuantStudio 7 quantitative PCR machines and reliably exports the final genotyping results in spreadsheet file format. The combination of a reliable method that requires low amount of DNA with an automated interpretation of results allows scaling the KIR genotyping in large cohorts with reduced turnaround time. This article is protected by copyright. All rights reserved. PMID- 30468004 TI - The complexity and diversity of mhc challenge disease association studies. AB - The Major Histocompatibility Complex (MHC; 6p21.3) contains the most polymorphic genes, the most gene dense parts and the highest diversity of functional gene clusters of the human genome. The clusters form haplotypes, which differ in linkage disequilibrium and show large variations in strength and extent between populations. Haplotype cis- and trans-eQTL have increased the knowledges of regulatory interactions between multiple MHC genes. The detailed haplotype data offers a reference for future studies in immune-mediated diseases and may unravel disease associations in conditions traditionally considered not to be immunologic. This article aims to describe the structural and functional variations of the MHC genes and haplotypes and their role on selected immune mediated diseases. In immune/inflammation-mediated complex diseases hundreds of common variants influence the development of the disease trait but the individual variants have small effects on the disease phenotypes as seen in genome-wide association studies. The genetic influence may still be significant on the cellular or molecular level. Nonetheless, the HLA alone is not sufficient as a susceptible genetic background to deduce the disease. For a comprehensive insight of the disease mechanisms both immunological and genome assays methods are required. This article is protected by copyright. All rights reserved. PMID- 30468005 TI - Nationwide analysis of unplanned 30-day readmissions after transsphenoidal pituitary surgery. AB - BACKGROUND: Transsphenoidal pituitary surgery has evolved into a safe procedure with shorter hospitalizations, yet unplanned readmissions remain a quality measure for which there is a paucity of data. We sought to examine rates, timing, etiologic factors, and costs surrounding readmission after transsphenoidal pituitary surgery. METHODS: The Nationwide Readmissions Database (NRD) was queried for patients who underwent transsphenoidal pituitary between January 2013 and November 2013. Patient, procedure, admission, and hospital-level characteristics were compared for patients with and without unplanned 30-day readmission. Multivariate logistic regression was used to identify readmission predictors. A total of 8546 patients were included in this retrospective study. RESULTS: A total of 8546 patients with a median age of 54 years and female predominance were identified, with 742 patients experiencing at least 1 unplanned readmission within 30 days of index admission. Hypertension, hypothyroidism, diabetes, and obesity were common comorbidities among readmitted patients. Readmission was most frequently because of nervous system complications, followed by neurohypophyseal or electrolyte disorders, cerebrospinal fluid leak, hemorrhage, and meningitis. Median length and cost of stay of index admission was greater in the readmission group (p < 0.001). Fluid and electrolyte disorders as well as neurologic disease (most commonly epilepsy or convulsions) present on initial admission were predictive of length of initial stay and readmission (p < 0.001). Median readmission cost was $7723 and was expected to occur within 7 days. CONCLUSION: Approximately 8.7% of patients undergoing transsphenoidal pituitary surgery experience an unplanned readmission within 30 days of discharge. Risk factors identified should be considered to reduce preventable readmissions and identify medically complex patients. PMID- 30468006 TI - Evaluation of NSE and S100B in patients with tick-borne encephalitis. AB - INTRODUCTION: The aim of this study was the assessment of neuron-specific enolase (NSE) and S-100 concentration in serum and cerebrospinal fluid (CSF) in patients with different clinical forms of tick-borne encephalitis (TBE). MATERIAL AND METHODS: The serum and CFS concentrations of S100B and NSE of 43 patients with TBE were measured with ELISA method using commercial kits: NSE and S100B Elisa Kit (DRG, Germany). Subjects were divided into: Group I-patients with meningoencephalitis (n = 17) and Group II-patients with meningitis (n = 26). None of the patients reported any neurodegenerative disorder that could affect the results of the study. The control group (CG) consisted of 13 patients. These patients were admitted to the hospital because of headache, and the CSF examination excluded inflammatory process. Samples were collected on admission (sample 1) and after treatment (sample 2). RESULTS: Neuron-specific enolase concentration in CSF was higher in group I than in group II (p = 0.0002) and controls (p = 0.04). NSE concentration was higher in the second serum and CSF sample in both groups. S100B concentration did not differ between TBE patients and controls. NSE concentration in serum after 14 days was higher in the sequelae group (34.3 +/- 9.7 vs. 16.7 +/- 15, p = 0.04). Also, NSE serum sample 2/serum sample 1 ratio was significantly higher in the sequelae group (3.57 +/- 0.92 vs. 1.53 +/- 1.99, p = 0.04). Receiver Operating Characteristic curve analysis indicated that NSE concentration in serum II differentiates sequelae group from other meningoencephalitis patients (p = 0.0001). S100B serum sample 2/CSF sample 2 ratio was lower in the sequelae group (0.05 +/- 0.1 vs. 0.37 +/- 0.28, p = 0.02). CONCLUSIONS: (a) Neurodegeneration process is present in TBE encephalitis. (b) NSE concentration correlates with inflammatory parameters in CSF in TBE. (c) Neurodegeneration is present even after clinical recovery of TBE. (d) NSE could be used in the prediction of TBE course. (e) S-100 did not differ between TBE patients and controls. PMID- 30468007 TI - The effect of infertility-related stress on Chinese infertile females' mental health: The moderating role of marital adjustment. AB - Although the impacts of infertility-related stress on mental health have been testified in the literature, the underlying mechanism between them is still not clear. In response to this issue, 286 Chinese women who were pursuing medical treatment for fertility problems in two state-owned hospitals were invited to complete the survey, including the 7-item Dyadic Adjustment Scale (DAS), the Fertility Problem Inventory (FPI), the 5-item Mental Health Inventory (MHI-5), and demographic variables (e.g., age). The multiple linear regression method (SPSS 16) was used to investigate the impact of infertility-related stress and marital satisfaction on infertile women's mental health. Results showed that the total FPI score-and the specific domains of Social Concern, Relationship Concern, and Rejection of Child-Free Lifestyle in particular-had a significant negative relation with infertile women's mental health and marital satisfaction as a moderator between them. Therefore, the core of marital relationship and specific infertility-related stress should be addressed in psychological intervention programs for people facing infertility in mainland China. PMID- 30468008 TI - Identification of the novel HLA-DQB1*05:01:01:05 allele in a Saudi individual. AB - HLA-DQB1*05:01:01:05 differs from HLA-DQB1*05:01:01:01 by a single nucleotide substitution (G?A) at position 1062. This article is protected by copyright. All rights reserved. PMID- 30468009 TI - Bacterial leakage and marginal adaptation of various bioceramics as apical plug in open apex model. AB - AIM: The aim of the present study was to investigate bacterial leakage and marginal adaptation of bioceramic apical plugs. METHODS: Extracted human mandibular premolars were prepared to simulate open apex using No. 4 Peeso reamer in retrograde direction. In total, 150 specimens were divided into 10 groups by obturation with five bioceramics in two thicknesses. Groups 1, 3, 5, 7, and 9 were obturated with ProRootMTA, Biodentine, TotalFill BC RRM paste, TotalFill BC RRM putty, and RetroMTA at 3 mm, and groups 2, 4, 6, 8, and 10 were obturated with the same materials at 4 mm. Ten specimens in each group were evaluated for bacterial leakage of Enterococcus faecalis for 75 days. Five specimens from each group were sectioned to investigate the gap area under scanning electron microscope. RESULTS: The 3- and 4-mm Biodentine and TotalFill BC RRM putty groups and the 4-mm ProRootMTA group exhibited less bacterial leakage and lower mean percentage of gap area than those of the other groups. TotalFill BC RRM paste showed the highest leakage for both the 3- and 4-mm groups. CONCLUSION: The 3- and 4-mm Biodentine and TotalFill BC RRM putty groups and the 4-mm ProRootMTA group exhibited the best sealing ability and marginal adaptation of apical plugs. PMID- 30468010 TI - Multifunctional Coatings and Nanotopographies: Toward Cell Instructive and Antibacterial Implants. AB - In biomaterials science, it is nowadays well accepted that improving the biointegration of dental and orthopedic implants with surrounding tissues is a major goal. However, implant surfaces that support osteointegration may also favor colonization of bacterial cells. Infection of biomaterials and subsequent biofilm formation can have devastating effects and reduce patient quality of life, representing an emerging concern in healthcare. Conversely, efforts toward inhibiting bacterial colonization may impair biomaterial-tissue integration. Therefore, to improve the long-term success of medical implants, biomaterial surfaces should ideally discourage the attachment of bacteria without affecting eukaryotic cell functions. However, most current strategies seldom investigate a combined goal. This work reviews recent strategies of surface modification to simultaneously address implant biointegration while mitigating bacterial infections. To this end, two emerging solutions are considered, multifunctional chemical coatings and nanotopographical features. PMID- 30468011 TI - Investigating the role of attachment styles, dysfunctional attitudes, and spirituality in predicting membership in addicted and non-addicted groups. AB - Drug addiction as a biological, psychological, and social issue affects all dimensions of one's life. The purpose of this study was to determine the role of attachment styles, dysfunctional attitudes, and spirituality in predicting membership in addicted and non-addicted groups. This was a cross-sectional study conducted on 60 addicted people and 60 non-addicted people. The Adult Attachment Scale of Hazan and Shaver, Allport Religious Orientation Scale, and the 26-item Dysfunctional Attitude Scale (DAS-26) were used to measure the variables. Based on the results, which were analyzed by logistic regression analysis, the variables of attachment style and dysfunctional attitude can significantly predict drug addiction (p < .001). However, avoidant attachment style and spirituality cannot predict readiness for addiction. The results of this study indicate the importance of safe and ambivalent attachment styles and dysfunctional attitudes. Thus, attending to these factors in studies and interventions related to the treatment of substance abuse disorders is essential. PMID- 30468012 TI - The influence of cardiorespiratory fitness on clustered cardiovascular disease risk factors and the mediator role of BMI in youth: The UP&DOWN study. AB - BACKGROUND: The combined effect of cardiorespiratory fitness (CRF) and body mass index (BMI) on cardiovascular disease (CVD) risk in young people remains to be fully determined. We examined the individual and combined associations of CRF and BMI with clustered CVD risk factors, and the mediator role of BMI in the association between CRF and clustered CVD risk factors in children and adolescents. RESEARCH DESIGN AND METHODS: 237 children (111 girls) and 260 adolescents (120 girls) were included in this cross-sectional study. Height and weight were assessed and BMI was calculated. A CVD risk factor index (CVDRF-I) was computed from: waist circumference, systolic blood pressure, triglycerides, high-density lipoprotein cholesterol and glucose. CRF was assessed using the 20-m shuttle run test. Regression analysis, analysis of covariance and mediation analysis (Baron and Kenny procedures) were used to test the independent and combined effect of CRF and BMI on CVDRF-I, and to test mediation hypothesis, respectively. RESULTS: CRF was negatively associated with CVDRF-I (all p<0.05); however, after adjusting for BMI the associations were no longer significant in children and adolescents of both sex groups. Contrary, the association between BMI and CVDRF-I was independent of CRF (all p<0.001). The effect of CRF on CVDRF I was mediated by BMI. The percentage of the total effect of CRF on CVDRF-I mediated by BMI for boys and girls children and boys and girls adolescents were 79.5%, 100%, 81.2% and 55.7%, respectively. CONCLUSIONS: BMI is an independent predictor of CVDRF-I and a mediator of the association between CRF and CVDRF-I in children and adolescents. These results help to clarify the associations between CRF, weight status and cardiovascular health, suggesting that future CVD health would benefit from maintaining an optimal weight status. This article is protected by copyright. All rights reserved. PMID- 30468013 TI - Rapamycin improves healthspan but not inflammaging in nfkappab1-/- mice. AB - Increased activation of the major pro-inflammatory NF-kappaB pathway leads to numerous age-related diseases, including chronic liver disease (CLD). Rapamycin, an inhibitor of mTOR, extends lifespan and healthspan, potentially via suppression of inflammaging, a process which is partially dependent on NF-kappaB signalling. However, it is unknown if rapamycin has beneficial effects in the context of compromised NF-kappaB signalling, such as that which occurs in several age-related chronic diseases. In this study, we investigated whether rapamycin could ameliorate age-associated phenotypes in a mouse model of genetically enhanced NF-kappaB activity (nfkappab1-/- ) characterized by low-grade chronic inflammation, accelerated aging and CLD. We found that, despite showing no beneficial effects in lifespan and inflammaging, rapamycin reduced frailty and improved long-term memory, neuromuscular coordination and tissue architecture. Importantly, markers of cellular senescence, a known driver of age-related pathology, were alleviated in rapamycin-fed animals. Our results indicate that, in conditions of genetically enhanced NF-kappaB, rapamycin delays aging phenotypes and improves healthspan uncoupled from its role as a suppressor of inflammation. PMID- 30468014 TI - Comparative nuclear proteomics analysis provides insight into the mechanism of signaling and immune response to blast disease caused by Magnoporthe oryzae in rice. AB - Modulation of plant immune system by extrinsic/intrinsic factors and host specific determinants fine-tunes cellular components involving multiple organelles, particularly nucleus to mount resistance against pathogen attack. Rice blast, caused by hemibiotrophic fungus Magnaporthe oryzae, is one of the most devastating diseases that adversely affect rice productivity. However, the role of nuclear proteins and their regulation in response to M. oryzae remains unknown. Here, we elucidate the nucleus-associated immune pathways in blast resistant rice genotype. Temporal analysis of nuclear proteome was carried out using 2-DE coupled MS/MS analysis. A total of 140 immune responsive proteins (IRPs) were identified associated with nuclear reorganization, cell division, energy production/deprivation, signaling and gene regulation. We interrogated the proteome data using correlation network analysis that identified significant functional modules pointing towards immune related coinciding processes through a common mechanism of remodelling and homeostasis. Novel clues regarding blast resistance include nucleus associated redox homeostasis and glycolytic enzyme mediated chromatin organization which manipulates cell division and immunity. Taken together, our study provides evidence that coordination of nuclear function and reprogramming of host translational machinery regulate resistance mechanism against blast disease. This article is protected by copyright. All rights reserved. PMID- 30468015 TI - Neighborhood disadvantage and chronic disease management. AB - OBJECTIVE: To assess the relationship between a composite measure of neighborhood disadvantage, the Area Deprivation Index (ADI), and control of blood pressure, diabetes, and cholesterol in the Medicare Advantage (MA) population. DATA SOURCES: Secondary analysis of 2013 Medicare Healthcare Effectiveness Data and Information Set, Medicare enrollment data, and a neighborhood disadvantage indicator. STUDY DESIGN: We tested the association of neighborhood disadvantage with intermediate health outcomes. Generalized estimating equations were used to adjust for geographic and individual factors including region, sex, race/ethnicity, dual eligibility, disability, and rurality. DATA COLLECTION: Data were linked by ZIP+4, representing compact geographic areas that can be linked to Census block groups. PRINCIPAL FINDINGS: Compared with enrollees residing in the least disadvantaged neighborhoods, enrollees in the most disadvantaged neighborhoods were 5 percentage points (P < 0.05) less likely to have controlled blood pressure, 6.9 percentage points (P < 0.05) less likely to have controlled diabetes, and 9.9 percentage points (P < 0.05) less likely to have controlled cholesterol. Adjustment attenuated this relationship, but the association remained. CONCLUSIONS: The ADI is a strong, independent predictor of diabetes and cholesterol control, a moderate predictor of blood pressure control, and could be used to track neighborhood-level disparities and to target disparities-focused interventions in the MA population. PMID- 30468017 TI - Nomenclature for factors of the HLA system, update July 2018. PMID- 30468016 TI - Nomenclature for factors of the HLA system, update August 2018. PMID- 30468018 TI - Nomenclature for factors of the HLA system, update September 2018. PMID- 30468019 TI - Sensitivity to imidazoles/nitroimidazoles in subjects sensitized to methylchloroisothiazolinone/methylisothiazolinone: A simple coincidence? PMID- 30468020 TI - Disseminated Trichosporonosis with Atypical Histology Findings in a Patient with Acute Lymphocytic Leukemia. AB - We report a case of disseminated Trichosporon asahii in a patient on systemic anti-fungal therapy who presented with multiple cutaneous nodules suggestive of fungal infection. Histologic features resembled neutrophilic eccrine hidradenitis but staining with periodic acid-Schiff and Gomori methenamine silver confirmed the clinical diagnosis. This case highlights the importance of maintaining suspicion for trichosporonosis and contextualizing histologic findings within the underlying clinical picture. This article is protected by copyright. All rights reserved. PMID- 30468021 TI - Buccal epithelium Expanded and Encapsulated in Scaffold-Hybrid Approach to Urethral Stricture (BEES-HAUS) procedure: A novel cell therapy-based pilot study. AB - OBJECTIVES: To describe the feasibility of a novel cell-based endoscopic technique using buccal epithelium, expanded and encapsulated in a thermoreversible gelation polymer scaffold for the treatment of urethral stricture. METHODS: Six male patients with bulbar urethral stricture ranging from 2.0 to 3.5 cm in length were included in this pilot study. Autologous buccal epithelial cells from a small buccal mucosal biopsy were isolated, cultured and encapsulated in thermoreversible gelation polymer scaffold, and were implanted at the stricture site after a wide endoscopic urethrotomy. RESULTS: All the patients voided well, with a mean peak flow rate of 24 mL/s. Urethroscopy carried out at 6 months showed healthy mucosa at the urethrotomy site. However, two of the six patients had recurrence at 18 and 24 months, respectively. CONCLUSIONS: This endoscopic-based Buccal epithelium Expanded and Encapsulated in Scaffold-Hybrid Approach to Urethral Stricture (BEES-HAUS) technique is a promising alternative for the open substitution buccal graft urethroplasty. It is possible to achieve the benefits of open substitution buccal urethroplasty with this endoscopic technique. PMID- 30468022 TI - Universal neural basis of structure building evidenced by network modulations emerging from Broca's area: The case of Chinese. AB - The basic steps in building up language involve binding words of different categories into a hierarchical structure. To what extent these steps are universal or differ across languages is an open issue. Here we examine the neural dynamics of phrase structure building in Chinese-a language that in contrast to other languages heavily depends on contextual semantic information. We used functional magnetic resonance imaging and dynamic causal modeling to identify the relevant brain regions and their dynamic relations. Language stimuli consisted of syntax-driving determiners, semantics-embedded classifiers, and nonverbal symbols making up for two-component sequences manipulated by the factors structure (phrase/list) and number of words (2-word/1-word). Processing phrases compared with word lists elicited greater activation in the anterior part of Broca's area, Brodmann area (BA) 45, and the left posterior superior/middle temporal gyri (pSTG/pMTG), while processing two words against one word led to stronger involvement of the left BA 45, BA 44, and insula. Differential network modulations emerging from subparts of Broca's area revealed that phrasal construction in particular highly modulated the direct connection from BA 44 to left pMTG, suggesting BA 44's primary role in phrase structure building. Conversely, the involvement of BA 45 rather appears sensitive to the reliance on lexico-semantic information in Chinese. Against the background of previous findings from other languages, the present results indicate that phrase structure building has a universal neural basis within the left fronto-temporal network. Most importantly, they provide the first evidence demonstrating that the structure-building network may be modulated by language-specific characteristics. PMID- 30468023 TI - Cost-effective production of tag-less recombinant protein in Nicotiana benthamiana. AB - Plants have recently received a great deal of attention as a means of producing recombinant proteins. Despite this, a limited number of recombinant proteins are currently on the market and, if plants are to be more widely used, a cost effective and efficient purification method is urgently needed. Although affinity tags are convenient tools for protein purification, the presence of a tag on the recombinant protein is undesirable for many applications. A cost-effective method of purification using an affinity tag and the removal of the tag after purification has been developed. The family 3 cellulose-binding domain (CBM3), which binds to microcrystalline cellulose, served as the affinity tag, and the small ubiquitin-related modifier (SUMO) and SUMO-specific protease were used to remove it. This method, together with size-exclusion chromatography, enabled purification of human interleukin-6 (hIL6) with a yield of 18.49 mg/kg fresh weight from leaf extracts of Nicotiana benthamiana following Agrobacterium mediated transient expression. Plant-produced hIL6 (P-hIL6) contained less than 0.2 EU/MUg (0.02 ng/mL) endotoxin. P-hIL6 activated the Janus kinase-signal transducer and activator of transcriptional pathways in human LNCaP cells, and induced expression of IL-21 in activated mouse CD4+ T cells. This approach is thus a powerful method for producing recombinant proteins in plants. This article is protected by copyright. All rights reserved. PMID- 30468024 TI - Iridoid Derivatives from Pedicularis uliginosa Bunge and Their Cytotoxic Activity. AB - Three new iridoids, (rel-4aS,7S,7aS)-1,4a,5,6,7,7a-hexahydro-7-hydroxyl-7-methyl cyclopenta[c]pyran-4-carboxaldehyde (1), 1,3,5,6-tetrahydro-1-methoxyl-7-methyl cyclopenta[c]pyran-4-carboxaldehyde (2), and (rel-1R,4S,4aS,7R,7aR)-7 methylhexahydro-1,4-(epoxymethano)cyclopenta[c]pyran-3(1H)-one(3), together with seven known analogues, were isolated from the 95% EtOH extract of the whole plant of Pedicularis uliginosa Bunge.Their structures were elucidated via their extensive NMR spectroscopy and mass spectral data. In terms of inhibitory effects on human tumor cells, compounds 1, 2, 6, 7and 8 exhibited better inhibitory activities against ACHN cells than the positive control (vinblastine). PMID- 30468025 TI - Intrapulmonary lymph node metastasis is common in clinically staged IA adenocarcinoma of the lung. AB - BACKGROUND: Intrapulmonary lymph nodes (LNs, stations 11-14) are usually omitted in postoperative pathological examination. Some non-small cell lung cancer (NSCLC) patients with intrapulmonary LN metastasis are incorrectly diagnosed as N0 cases. Furthermore, underestimation of intrapulmonary LN involvement in clinically early stage NSCLC may lead to the incorrect choice of surgical procedure: lobectomy or sublobar resection. This study was conducted to determine the status of intrapulmonary LN involvement in clinically staged IA (c-T1N0M0) peripheral adenocarcinoma of the lung. METHODS: Seventy-five lobectomy specimens of c-T1N0M0 peripheral adenocarcinoma of the lung were carefully dissected to find intrapulmonary LNs. The longest diameter of each intrapulmonary LN was measured and sent for pathological examination, together with hilar and mediastinal LNs, to investigate the relationship between LN metastasis and primary tumor size. RESULTS: Intrapulmonary LN metastasis was detected in 22.7%(17/75) of patients. Positive LNs were detected in 21.7% (10/46) of T1b patients and 45% (11/24) of T1c patients, while no metastasis (0/5) was observed in T1a patients (P = 0.036). The mean longest diameter of the 17 involved intrapulmonary LNs was only 6.5 +/- 2.1 mm, which was not significantly different to the size of negative intrapulmonary LNs (5.2 +/- 1.4 mm). CONCLUSIONS: Intrapulmonary LN metastasis is common in clinically staged IA peripheral adenocarcinoma of the lung. LN metastasis is related to tumor size, and this should be taken into account to determine appropriate surgical procedures and postoperative treatment. Computed tomography is not a reliable method to judge LN metastasis, particularly intrapulmonary LN metastasis. PMID- 30468026 TI - Gastric band migration to gastrointestinal lumen and possibilities of its surgical treatment. AB - BACKGROUND: Due to numerous late complications after laparoscopic adjustable gastric banding (LAGB), leading to band removal, a significant decrease of its application has been observed. OBJECTIVES: The objective of this study was to present complications after LAGB in our own material. MATERIAL AND METHODS: The study included 152 obese patients who underwent LAGB between 2005 and 2012. The group of women consisted of 91 patients (60%) with the following preoperative parameters: average body mass index (BMI) 42 +/-3.66 kg/m2 and average body mass 122 +/-12.8 kg. The group of men included 61 patients (40%) with a preoperative average BMI 43 +/-3.81 kg/m2 and average body mass 125 +/-13.02 kg. The average age of women was 35.02 +/-11.6 years and of men 36.18 +/-10.5 years. RESULTS: Among 152 patients after LAGB due to morbid obesity, in 7 (4.6%) migration of the band to the stomach lumen was observed, in 4 port wound purulence occurred, in 3 stomach mucosa ulceration was diagnosed in the band pressure area, 3 reported heartburn and hyperacidity, and 4 suffered from emesis. In all aforementioned patients, body mass loss stopped and they reported lack of restriction after last band regulation. CONCLUSIONS: Surgical or endoscopic treatment in patients with a migrated band is an individual matter depending on the type and size of band dislocation, its clinical symptoms and the general state of the patient, but also on the experience of the operating team and the quality of the equipment. PMID- 30468027 TI - Does the transplantation of keratinocytes really reduce the risk of death? Survival analysis of patients hospitalized at the Dr Stanislaw Sakiel Centre for Burns Treatment in 2008-2015. AB - BACKGROUND: Keratinocyte transplantation is an adjuvant procedure in the extensive burn therapy method. However, it must be taken into consideration that clinical results of keratinocyte transplantation are ambiguous and progress achieved in this method is still being verified, especially due to the high cost of cultured epithelial autograft (CEA) transplants. OBJECTIVES: The aim of this study was to verify the impact of cultured keratinocyte application on patients' survival. This study included a group of patients with the highest chance for a successful outcome of the therapy and excluded patients with no compelling reason to apply for such an expensive therapy. MATERIAL AND METHODS: This study included all the patients with burns diagnosed between January 1, 2008 and January 1, 2016, who were treated with cultured skin cells. Patients' age and gender, percentage of total body surface area (TBSA) affected, percentage of burn depth of the 3rd/4th degree, number of days between admission and surgery, and need for rehabilitation were analyzed. RESULTS: The cultured cell application did not significantly affect the risk of death (p > 0.05). CONCLUSIONS: Keratinocytes should be applied as an adjunctive method for the treatment of burns with at least 40% TBSA affected, but with a maximal burn depth of the 2nd degree. In the group of patients below 50 years of age, a higher number of transplants with a cell population above 20 million/mL and a significantly lower mortality rate were observed, which means that in the mentioned age group, this graft was more effective. It has been suggested that patients older than 50 years of age with burns deeper than of the 2nd degree should be treated with more advanced methods like, e.g., the application of stem cells. PMID- 30468028 TI - The Accuracy and Clinical Applicability of a Sensor Based Electromagnetic Non fluoroscopic Catheter Tracking System. AB - BACKGROUND AND OBJECTIVES: The differences between electromagnetic-based mapping (EM) and impedance-based mapping (IM) in 3D anatomical reconstruction have not been fully clarified. We aimed to investigate the anatomical accuracy between EM (MediGuideTM) and IM (EnSite VelocityTM) systems. METHODS: We investigated 15 consecutive patients (10 males, mean age 58+/-9 years) who underwent pulmonary veins (PVs) isolation for paroxysmal atrial fibrillation (PAF). Contrast-enhanced computed tomography (CT) image of the left atrium (LA) was acquired before ablation and the 3D geometry of the LA was constructed using EM during ablation procedure. We measured the 4 PV angles between the main trunk of each PV and the posterior LA after field scaling. Additionally, the posterior LA surface area was measured. The variables were compared to those of CT-based geometry. A control group of 40 patients who underwent conventional PVs isolation using IM were also evaluated. RESULTS: The actual and relative changes of EM and CT-based geometry in all PV angles and posterior LA were significantly smaller compared to those of IM and CT-based geometry. Intraclass correlation coefficient (ICC) between EM and CT-based geometry were 0.871 (right superior pulmonary vein [RSPV]), 0.887 (right inferior pulmonary vein [RIPV]), 0.853 (left superior pulmonary vein [LSPV]), 0.911 (left inferior pulmonary vein [LIPV]), and 0.833 (posterior LA). On the other hand, ICC between IM and CT-based geometry were 0.548 (RSPV), 0.639 (RIPV), 0.691 (LSPV), 0.706 (LIPV), and 0.568 (posterior LA). CONCLUSIONS: Image integration with EM enables high accurate visualization of cardiac anatomy compared to IM in PAF ablation. PMID- 30468029 TI - Assessment of the Clinical Heterogeneity of Kawasaki Disease Using Genetic Variants of BLK and FCGR2A. AB - BACKGROUND AND OBJECTIVES: Patients with Kawasaki disease (KD) are clinically heterogeneous because its diagnosis is based solely on clinical observation and there are no definitive biomarkers. We dissected the clinical heterogeneity of KD patients using the KD-associated genetic variants. METHODS: We performed a genetic association analysis in several KD subgroups categorized by clinical characteristics using the KD-associated variants of the B lymphoid tyrosine kinase (BLK; rs6993775) and Fc gamma receptor II a (FCGR2A; rs1801274) in a large number of case (n=1,011) and control (n=4,533) samples. RESULTS: BLK and FCGR2A were very significantly associated with KD in Korean KD patients (odds ratio [OR],1.48; p=4.63*10-11 for BLK, and OR, 1.26; p=1.42*10-4 for FCGR2A). However, in KD subgroup analysis, we found that neither BLK nor FCGR2A were associated with either incomplete Kawasaki disease (iKD) type patients or those older than 5 years of age (p>0.2), suggesting that patients with iKD or those older than 5 years of age are a unique subgroup of KD. In genetic association analysis after excluding iKD patients and those older than 5 years old, we found that BLK was associated with all KD subgroups, whereas FCGR2A was specifically associated with male KD patients younger than 1 year of age (OR, 2.22; p=2.35*10-5). CONCLUSIONS: KD is a clinically and genetically heterogeneous disease. These findings will provide new insights into the clinical and genetic heterogeneity of KD. PMID- 30468030 TI - Long-term Survival in Korean Elderly Patients with Symptomatic Severe Aortic Stenosis Who Refused Aortic Valve Replacement. AB - BACKGROUND AND OBJECTIVES: Aortic valve replacement (AVR) is the treatment of choice in severe symptomatic aortic stenosis (AS) patients. However, a substantial number of elderly patients refuse AVR and treated medically. We investigated their long-term prognosis. METHODS: From January 2005 to December 2016, we analyzed elderly patients with severe symptomatic AS who refused to have AVR. RESULTS: After screening of total 534 patients, we analyzed total 180 severe symptomatic AS patients (78+/-7 years old, 96 males). Hypertension was the most common cardiovascular risk factor (72%) and the most common symptom was dyspnea (66%). Calculated aortic stenosis area was 0.73+/-0.20 cm2 and mean left ventricular ejection fraction (LVEF) was 57.8+/-12.2%. Total 102 patients died during follow-up period (39.1+/-31.0 months). One-, 3-, and 5-year all-cause mortality rate was 21.1+/-3.0%, 43.1+/-3.8%, and 56.5+/-4.2%, respectively. Of them, 87 died from cardiac causes, and 1-, 3-, and 5-year cardiac mortality rate was 18.0+/-2.9%, 38.2+/-3.8%, and 50.7+/-4.3%, respectively. Their all-cause mortality and cardiac mortality were significantly higher than those of controls. Univariate analysis showed that age, anemia, LVEF, and Log N-terminal pro B-type natriuretic peptide (NT-proBNP) were significant parameters in all-cause mortality (p<0.001, p=0.001, p=0.039, and p=0.047, respectively) and in cardiac mortality (p<0.001, p<0.001, p=0.046, and p=0.026, respectively). Multivariate analysis showed that age and anemia were significant prognostic factors for cardiac and all-cause mortality. CONCLUSIONS: In elderly severe symptomatic AS patients who treated medically, their 1-, 3- and 5-year all-cause mortality rate was 21.1+/-3.0%, 43.1+/-3.8%, and 56.5+/-4.2%, respectively. Age and anemia were significant prognostic factors for cardiac and all-cause mortality. PMID- 30468031 TI - Benefit of Four-Dimensional Computed Tomography Derived Ejection Fraction of the Left Atrial Appendage to Predict Thromboembolic Risk in the Patients with Valvular Heart Disease. AB - BACKGROUND AND OBJECTIVES: Decreased left atrial appendage (LAA) emptying velocity in transesophageal echocardiography (TEE) is related with higher incidence of thrombus and increased risk of stroke. Patients with valve disease are at higher risk of thrombus formation before and after surgery. The aim of this study was to investigate the role of 4-dimensional cardiac computed tomography (4DCT) to predict the risk of thrombus formation. METHODS: Between March 2010 to March 2015, total of 62 patients (mean 60+/-15 years old, male: 53.2%) who underwent 4DCT and TEE for cardiac valve evaluation before surgery were retrospectively included in the current study. Fractional area change in TEE view and emptying velocity at left atrial appendage in TEE view (VeTEE) were measured. Ejection fraction (EF) of left atrial appendage in computed tomography (EFCT) was calculated by 4DCT with full volume analysis. The best cut-off value of EFCT predicting presence of spontaneous echo contrast (SEC) or thrombus was evaluated, and correlation between the parameters were also estimated. RESULTS: SEC or thrombus was observed in 45.2%. EFCT and VeTEE were significantly correlated (r=0.452, p<0.001). However, fractional area change measured by TEE showed no correlation with VeTEE (r=0.085, p=0.512). EFCT <37.5% best predicted SEC or thrombus in the patients with valve disease who underwent 4DCT and TEE (area under the curve, 0.654; p=0.038). CONCLUSIONS: In the patients who underwent 4DCT for cardiac valve evaluation before surgery, EFCT by volume analysis might have additional role to evaluate LAA function and estimate the risk of thrombus. PMID- 30468032 TI - Infliximab Treatment for Intravenous Immunoglobulin-resistant Kawasaki Disease: a Multicenter Study in Korea. AB - BACKGROUND AND OBJECTIVES: We investigated the status of infliximab use in intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) patients and the incidence of coronary artery aneurysms (CAAs) according to treatment regimens. METHODS: Between March 2010 and February 2017, 16 hospitals participated in this study. A total of 102 (32.3+/-19.9 months, 72 males) who received infliximab at any time after first IVIG treatment failure were enrolled. Data were retrospectively collected using a questionnaire. RESULTS: Subjects were divided into two groups according to the timing of infliximab administration. Early treatment (group 1) had shorter fever duration (10.5+/-4.4 days) until infliximab infusion than that in late treatment (group 2) (16.4+/-4.5 days; p<0.001). We investigated the response rate to infliximab and the incidence of significant CAA (z-score >5). Overall response rate to infliximab was 89/102 (87.3%) and the incidence of significant CAA was lower in group 1 than in group 2 (1/42 [2.4%] vs. 17/60 [28.3%], p<0.001). CONCLUSIONS: This study suggests that the early administration of infliximab may reduce the incidence of significant CAA in patients with IVIG-resistant KD. However, further prospective randomized studies with larger sample sizes are required. PMID- 30468033 TI - Non-fluoroscopic Catheter Tracking System for Atrial Fibrillation Ablation. PMID- 30468034 TI - Comparison between Right and Left Upper Arms in Detection of Hypertension. AB - BACKGROUND AND OBJECTIVES: This study aimed to investigate the right-left arm difference in detection of hypertension in the general Korean population. METHODS: This study analyzed data from the Cardiovascular and Metabolic Disease Etiology Research Center cohort. Study population was 2,103 people who were aged 30 to 64 years old, without history of major cardiovascular diseases, and did not use antihypertensive medication. Brachial blood pressures (BPs) were measured for both arms using an automated oscillometric device equipped with 2 cuffs for simultaneous double-arm measurements. Systolic and diastolic blood pressures (SBP and DBP) were measured 3 times, and the average value was used in the analysis. Overall hypertension was defined as elevated blood pressure (SBP/DBP >=140/90 mmHg) at the arm with higher value, while right-arm or left-arm hypertension was defined as elevated BP at each arm. Sensitivity was calculated as the number of each-arm hypertension divided by the number of overall hypertension. RESULTS: Overall 8.6% of the population had hypertension at either arm, while 7.8% had right-arm hypertension, 7.2% had left-arm hypertension, and 6.4% had both arms hypertension. The sensitivity for the detection of hypertension was 90.6% when BP was measured only at right arm, and 83.4% when measured only at left arm. Corresponding sensitivity were 87.9% and 87.1% in men, and 95.4% and 76.9% in women. CONCLUSIONS: Single-arm measurements, compared to double-arm measurements, may underestimate the prevalence of hypertension. However, if double-arm measurements are unavailable, right arm is preferred for measurement of BP, especially in women. PMID- 30468036 TI - Stent Selection in Complex Coronary Interventions: Thinking Complex? PMID- 30468035 TI - Safety and Efficacy of Biodegradable Polymer-biolimus-eluting Stents (BP-BES) Compared with Durable Polymer-everolimus-eluting Stents (DP-EES) in Patients Undergoing Complex Percutaneous Coronary Intervention. AB - BACKGROUND AND OBJECTIVES: There are no data comparing clinical outcomes of complex percutaneous coronary intervention (PCI) between biodegradable polymer biolimus-eluting stents (BP-BES) and durable polymer-everolimus-eluting stents (DP-EES). We sought to evaluate the safety and efficacy of BP-BES compared with DP-EES in patients undergoing complex PCI. METHODS: Patients enrolled in the SMART-DESK registry were stratified into 2 categories based on the complexity of PCI. Complex PCI was defined as having at least one of the following features: unprotected left main lesion, >=2 lesions treated, total stent length >40 mm, minimal stent diameter <=2.5 mm, or bifurcation as target lesion. The primary outcome was target lesion failure (TLF), defined as a composite of cardiac death, target vessel-related myocardial infarction (TV-MI), or target lesion revascularization (TLR) at 2 years of follow-up. RESULTS: Of 1,999 patients, 1,145 (57.3%) underwent complex PCI: 521 patients were treated with BP-BES and 624 with DP-EES. In propensity-score matching analysis (481 pairs), the risks of TLF (3.8% vs. 5.2%, adjusted hazard ratio [HR], 0.578; 95% confidence interval [CI], 0.246-1.359; p=0.209), cardiac death (2.5% vs. 2.5%, adjusted HR, 0.787; 95% CI, 0.244-2.539; p=0.689), TV-MI (0.5% vs. 0.4%, adjusted HR, 1.128; 95% CI, 0.157-8.093; p=0.905), and TLR (1.1% vs. 2.9%, adjusted HR, 0.390; 95% CI, 0.139 1.095; p=0.074) did not differ between 2 stent groups after complex PCI. CONCLUSIONS: Clinical outcomes of BP-BES were comparable to those of DP-EES at 2 years after complex PCI. Our data suggest that use of BP-BES is acceptable, even for complex PCI. PMID- 30468037 TI - Natural History Data in Symptomatic Severe Aortic Stenosis Alerts Cardiologists to the Dangers of No Action. PMID- 30468038 TI - Computed Tomography for Assessment of Left Atrial Appendage Function. PMID- 30468039 TI - Ovoid-shaped Left Main Coronary Calcified Aneurysm Leading to Unstable Angina Requiring Surgical Intervention. PMID- 30468040 TI - Recent Advances in Cardiac Magnetic Resonance Imaging. AB - Cardiac magnetic resonance (CMR) imaging provides accurate anatomic information and advanced soft contrast, making it the reference standard for assessing cardiac volumes and systolic function. In this review, we summarize the recent advances in CMR sequences. New technical development has widened the use of CMR imaging beyond the simple characterization of myocardial scars and assessment of contractility. These novel CMR sequences offer comprehensive assessments of coronary plaque characterization, myocardial fiber orientation, and even metabolic activity, and they can be readily applied in clinical settings. CMR imaging is able to provide new insights into understanding the pathophysiologic process of underlying cardiac disease, and it can help physicians choose the best treatment strategies. Although several limitations, including the high cost and time-consuming process, have limited the widespread clinical use of CMR imaging so far, recent advances in software and hardware technologies have made the future more promising. PMID- 30468041 TI - Cost-Effectiveness of Rivaroxaban Compared to Warfarin for Stroke Prevention in Atrial Fibrillation. AB - BACKGROUND AND OBJECTIVES: Rivaroxaban is noninferior to warfarin for preventing stroke or systemic embolism in patients with high-risk atrial fibrillation (AF) and is associated with a lower rate of intracranial hemorrhage (ICH). We assessed the cost-effectiveness of rivaroxaban compared to adjusted-dose warfarin for the prevention of stroke in patients with nonvalvular AF. METHODS: We built a Markov model using the Korean Health Insurance Review & Assessment Service database. The base-case analysis assumed a cohort of patients with prevalent AF who were aged 18 years or older without contraindications to anticoagulation. RESULTS: Number of patients with CHA2DS2-VASc scores 0, 1 and >=2 were 56 (0.2%), 1,944 (6.3%) and 28,650 (93.5%), respectively. In patients with CHA2DS2-VASc scores >=2, the incidence rate of ischemic stroke was 3.11% and 3.76% in warfarin and rivaroxaban groups, respectively. The incidence rates of ICH were 0.42% and 0.15%, and those of gastrointestinal bleeding were 0.32% and 0.15% in warfarin and rivaroxaban, respectively. Patients with AF treated with rivaroxaban lived an average of 11.8 quality-adjusted life years (QALYs) at a lifetime treatment cost of $20,886. Those receiving warfarin lived an average of 11.4 QALYs and incurred costs of $17,151. Patients with rivaroxaban gained an additional 0.4 QALYs over a lifetime with an additional cost of $3,735, resulting in an incremental cost-effectiveness ratio of $9,707 per QALY. CONCLUSIONS: Patients who had been treated with rivaroxaban may be a cost-effective alternative to warfarin for stroke prevention in Korean patients with AF. PMID- 30468042 TI - Beta-Blockers in Patients with Heart Failure with Preserved Ejection Fraction: Results from The Korea Acute Heart Failure (KorAHF) Registry. AB - BACKGROUND AND OBJECTIVES: Beta-blockers are indicated in patients with heart failure (HF) with reduced ejection fraction. However, their efficacy in patients with HF with preserved ejection fraction (HFpEF) is uncertain. We investigated the hypothesis that beta-blockers are associated with reduced adverse events in patients with HFpEF. METHODS: The Korea Acute Heart Failure (KorAHF) is a prospective observational multicentre cohort study. The 5,625 patients hospitalized for acute HF syndrome in 10 tertiary university hospitals across the country have been consecutively enrolled between March 2011 and February 2014. Of these patients, 2,152 patients with HFpEF (ejection fraction >=40%) were investigated. The primary outcome was all-cause mortality according to beta blocker use. RESULTS: During a median follow-up duration of 807 days, 702 patients died. In Cox proportional hazards model beta-blocker use was associated with a 14% reduced all-cause death (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.98), but not with reduce rehospitalization (HR, 1.03; 95% CI, 0.85-1.27). In the propensity-score matched population, beta-blockers were also associated with reduced all-cause death (HR, 0.80; 95% CI, 0.69-0.94) but not with reduced rehospitalization (HR, 1.08; 95% CI, 0.87-1.33). CONCLUSIONS: In Korean patients with HFpEF, use of beta-blockers is associated with reduced all cause death but not with reduced rehospitalization. PMID- 30468043 TI - New Insight to the Pathogenetic Mechanism of Kawasaki Disease (KD): the Relationship between Clinical Diversity and Genetic Heterogeneity. PMID- 30468044 TI - Cherenkov excited short-wavelength infrared fluorescence imaging in vivo with external beam radiation. AB - Cherenkov emission induced by external beam radiation therapy from a clinical linear accelerator (LINAC) can be used to excite phosphors deep in biological tissues. As with all luminescence imaging, there is a desire to minimize the spectral overlap between the excitation light and emission wavelengths, here between the Cherenkov and the phosphor. Cherenkov excited short-wavelength infrared (SWIR, 1000 to 1700 nm) fluorescence imaging has been demonstrated for the first time, using long Stokes-shift fluorophore PdSe quantum dots (QD) with nanosecond lifetime and an optimized SWIR detection. The 1 / lambda2 intensity spectrum characteristic of Cherenkov emission leads to low overlap of this into the fluorescence spectrum of PdSe QDs in the SWIR range. Additionally, using a SWIR camera itself inherently ignores the stronger Cherenkov emission wavelengths dominant across the visible spectrum. The SWIR luminescence was shown to extend the depth sensitivity of Cherenkov imaging, which could be used for applications in radiotherapy sensing and imaging in human tissue with targeted molecular probes. PMID- 30468045 TI - Simultaneous infrared thermal imaging and laser speckle imaging of brain temperature and cerebral blood flow in rats. AB - Infrared thermal imaging of brain temperature changes is useful for evaluating cortical activity and disease states, such as stroke. However, the changes depend on a balance between changes in heat generation from metabolism and in heat convection related to blood flow. To discriminate between these effects and gain a clearer understanding of neurovascular metabolic coupling, brain temperature imaging must be improved to measure temperature and blood flow simultaneously. We develop an imaging technique that shows a two-dimensional (2-D) distribution of absolute brain temperature and relative cerebral blood flow changes in anesthetized rats by combining infrared thermal imaging with laser speckle imaging. The changes in brain metabolism and cerebral blood flow are achieved using two different anesthetics (isoflurane and alpha-chloralose) to evaluate our system. Isoflurane increased cerebral blood flow but decreased metabolism, whereas alpha-chloralose decreased both parameters. This technique enables simultaneous visualization of brain surface changes in temperature and cerebral blood flow in the same regions. This imaging system will permit further study of neurovascular metabolic coupling in normal and diseased brains. PMID- 30468046 TI - Current Research and Prospects on Postmortem Interval Estimation. AB - The researches on postmortem interval (PMI) estimation are very important and meaningful in forensic science. PMI estimation is also an important issue that must be solved in practice of forensic pathology. There are many defects existing in traditional methods for PMI estimation, so it is imperative to introduce new pathways. With the emergence of various new technologies, the researches on PMI estimation have a tendency from simple to complex with a growth of data. The present review firstly summarizes a series of methods used for PMI estimation, and then gives an outlook for the application of artificial intelligence algorithms in this field. PMID- 30468047 TI - Standardized Application of Forensic Entomology and Application Data of Sarcosaprophagous Insects in China. AB - Postmortem interval (PMI) estimation is a major problem in forensic medicine and a vital indicator of crime investigations. Forensic entomology provides a new way to the PMI estimation, and its superiority has been confirmed through many cases, especially in relation to the cadaver at the stage of advanced decomposition even skeleton. The technologies of forensic entomology have become more mature. This review describes the mechanism of forensic entomology used for PMI estimation, emphasizes the standardized application of technology, and lists the data for the reference of forensic experts in China. PMID- 30468048 TI - Application of High-throughput Sequencing in Researches of Cadaveric Microorganisms and Postmortem Interval Estimation. AB - Necrobiome is the main factor causing the cadaver decomposition. Studying the microbial succession during decomposition is one of the main tasks of forensic microbiology. The interactive relationships among cadaver, environment and microorganisms are complicated. The microbial succession study relies on macroscopic monitoring of community composition and the diversity change in each decomposition stage. With the maturity and development of high-throughput sequencing (HTS), the structure and diversity of microbial communities in different environments have been successively revealed. A new breakthrough to explore the cadaveric microorganisms has been opened as well. It has become the research hotspots in forensic microbiology to reveal the microbial succession in the process of cadaver decomposition and to interpret the essence of various decomposition phenomena by using HTS, which can provide a new reference for postmortem interval (PMI) estimation. The present paper reviews studies on PMI estimation by using cadaveric microorganism. Problems and application prospects of forensic microbiology studies are discussed on the basis of the current application of HTS technology in the exploration of microbial succession. PMID- 30468049 TI - Succession Law of Intestinal Flora after Death in SD Rats. AB - OBJECTIVES: To initially explore the sequential changes in the intestinal flora of corpse for the estimation of postmortem interval (PMI). METHODS: Rats were sacrificed by cervical dislocation, and samples were taken from their intestines using cotton swab to extract the DNA of intestinal flora. The 16S rRNA V3 universal primers were selected for PCR, and the PCR products were used for denatured gradient gel electrophoresis. The diversity and similarity analysis of intestinal flora were analyzed between groups, and the bands were cut from denaturing gradient gel electrophoresis. After purification, PCR and sequencing, the percentage of major bacteria in each group was obtained. RESULTS: The flora diversity showed a reduced tendency from 1st to 30th day after death ( P<0.05), while the intra-group similarity showed a downward trend ( P<0.05). The number of bands and intra-group similarity coefficient (Cs) on the first day was higher than that of other groups ( P<0.05). The intra-group Cs of the 25th and 30th day had a significant difference compared with the 5th day ( P<0.05). At the genus level, the intestinal flora was mainly composed of Enterococcus sp. on the 1th and 5th day after death, Bacillus thuringienssis was the dominant species on the 10th, 15th and 20th day, and Enterococcus faecalis became the dominant species on the 25th and 30th day. CONCLUSIONS: The composition and structure of intestinal flora change significantly in rats with the time after death, which indicates that the succession of intestinal flora is related to the postmortem interval. PMID- 30468050 TI - Homogeneity of Different Functional mRNA Indicators for Wound Age Estimation. AB - OBJECTIVES: To explore the homogeneity level of four different functional mRNA (PUM2, TAB2, Cx45 and CHRNA1) expressions in rats with skeletal muscle contusion. METHODS: The relative expressions of PUM2, TAB2, Cx45 and CHRNA1 mRNAs were detected by quantitative real-time reverse transcription-polymerase chain reaction (RT-qPCR). The coefficient of variation (CV) of the relative expressions for different individuals in each injury group was calculated. The extreme value of CV, cumulative variability, and CVCV were compared. RESULTS: A high CV of PUM2 and TAB2 mRNAs appeared on several different time points. However, the CV of Cx45 and CHRNA1 mRNAs was relatively low. The cumulative variability from high to low was PUM2, CHRNA1, TAB2 and Cx45 mRNAs. The relative expression of PUM2 mRNA was significantly higher than that of TAB2, Cx45 and CHRNA1 mRNAs ( P<0.05). There was no statistical significance (P>0.05) in the CVCV of the relative expression of TAB2, CHRNA1 and Cx45 mRNAs. CONCLUSIONS: As the mRNAs involving in biological process regulation, PUM2 and CHRNA1 mRNAs show a lowest individual homogeneity of the relative expression followed by TAB2 mRNA. As the mRNAs participating in the composition of cellular structure, Cx45 and CHRNA1 mRNAs show a high individual homogeneity of the relative expressions. The functional classification should be considered for the screening of the mRNA indicators used for wound age estimation. PMID- 30468051 TI - Relationship between Early Postmortem Interval and Electrical Conductivity of Rat Liver, Spleen and Kidney after Death in Rats. AB - OBJECTIVES: To determine the electrical conductivity (EC) of the liver, spleen and kidney of rats at different postmortem intervals (PMIs) within 24 hours for investigating the relationship between EC of different organs and early PMI. METHODS: Totally 45 SD rats were sacrificed by cervical dislocation and kept at a constant temperature of 25 C. Tissues were taken from the liver, spleen, and kidney of rats at 0, 3, 6, 9, 12, 15, 18, 21 and 24 h. Impregnating solution with a mass concentration 0.1 g/mL was prepared using deionized water. The EC value of impregnating solution with different organs was separately determined. The regression equations of EC and PMI for different organs were established, respectively. The relationship between EC of different organs and early PMI was analysed in deceased rats. RESULTS: The relationship between PMI and EC of the liver and spleen was well fitted with the linear equation. The liver showed the best fitting degree followed by the spleen, while the EC of the kidney showed no significant changes within 24 h. There was a good linear relationship between early PMI and the EC of the liver and spleen. CONCLUSIONS: A good linear relationship between early PMI and the EC of the liver and spleen can be found in rats after death, which can be used for the early PMI estimation. PMID- 30468052 TI - Estimation of Lung Volume in Normal Population Using MSCT. AB - OBJECTIVES: To estimate lung volume in normal population by a combination of multi-slice spiral CT and Pulmo software. METHODS: Scans of the lung were performed on 45 normal individuals using Emotion 16-slice spiral CT and Pulmo software. A measurement instrument of work station was used to measure the vertical diameter of left and right lungs, the maximum anteroposterior and transverse diameters at the layers of apex pulmonis 1 cm below, arcus aortae, subcarinal and diaphragmatic dome, and the lung volume. Regression analysis was performed on normal lung volume and each measured parameter by SPSS 20.0 and an optimal model was selected. RESULTS: The goodness of fit between the best curvilinear equations of the normal bilateral lung volumes was 0.981. The goodness of fit between the curvilinear equations of the normal bilateral lung volume and the product of the vertical diameter and the maximum transverse diameter of diaphragmatic dome were 0.977 and 0.972, respectively. Fifteen cases were selected to make a retrospective test on the 3 models. No significant difference was found between the estimated and measured with Pulmo software lung volumes. CONCLUSIONS: The normal lung volume before injury can be estimated by the curvilinear equations established in this study. The percentage of lung compression can be measured based on the volume of compressed lung, which can provide a reference for the identification of lung compression degree. PMID- 30468053 TI - Analysis on Forensic Expertise of 49 Medical Disputes in Prenatal Examination. AB - OBJECTIVES: To analyze the cases of medical disputes involving prenatal examination from a point of view of forensic expertise, and to discuss the risk of medical disputes and the preventive measures. METHODS: A retrospective analysis was conducted on 49 forensic expertise cases of medical disputes in prenatal examination which were identified in Academy of Forensic Science and Shanghai Di'an Forensic Science Limited Company from 2010 to 2017. RESULTS: In recent years, the number of medical disputes involving prenatal examination showed an increasing trend year by year. The common causes of medical disputes were: uninformed or insufficiently informed disclosure (20 cases); the propaganda and application of three-dimensional, four-dimensional ultrasound were not standardized (14 cases); ultrasound examination and serological screening process were not standardized (12 cases); no antenatal counseling (2 cases), etc. CONCLUSIONS: In order to minimize the occurrence of such medical disputes, hospitals or related associations should avoid the risk of prenatal examination through the standardization of management and operation. PMID- 30468054 TI - Inference on Injury Mechanism of Ankle Fracture by Lauge-Hansen Classification. AB - OBJECTIVES: To explore the injury mechanism of ankle fracture inferred by the Lauge-Hansen classification with the application of medical imageology and its application value in forensic medicine. METHODS: A total of 32 ankle fracture cases with known injury mechanism were collected from January 2013 to May 2018, which were identified in Yongkang Public Security Bureau, Zhejiang Province. The Lauge-Hansen classification of ankle fracture was performed by three forensic experts based on the data of X-ray and CT image. Fisher's exact test and Kappa consistency analysis were performed by SPSS 20.0 statistical software to compare the results of the Lauge-Hansen classification with the injury mechanism of ankle fracture obtained through the criminal evidence. RESULTS: In 32 cases, 84.4% (27/32) ankle fractures were classified according to the Lauge-Hansen classification based on medical imaging. The mechanism of ankle fracture identified by the Lauge-Hansen classification was consistent with that obtained through the criminal evidence. CONCLUSIONS: Based on medical imaging, the Lauge Hansen classification can be well applied to infer the injury mechanism of ankle fracture in part cases, and provide objective evidence for the crime scene reconstruction of criminal cases. PMID- 30468055 TI - Application of Specific Fragment Length Polymorphism of Algae rDNA in Identification of Drowning Cases. AB - OBJECTIVES: To identify the drop-off location of victims in drowning cases, and confirm whether it is a fatal drowning or the victim is thrown into the water after death by detecting part of 5.8S sequence and second internal transcribed spacer (ITS2) (5.8S+ITS2) of diatom rDNA in water and organs. METHODS: Two cases identified by diatom examination, which received by Nanjing Municipal Public Security Bureau Forensic Center, were taken as the research objects. The difference of the population structure of algae in water and human tissue was analysed by length polymorphism of 5.8S+ITS2 marker. RESULTS: In case 1, similar species of diatom were detected from victim's lung and liver tissues and the water sample. Two kinds of DNA fragments with length of 330 bp and 376 bp were detected from victim's lung tissue and the water sample using 5.8S+ITS2 marker, which could confirm the victim was drowning before death. In case 2, there was no diatom found in victim's lung and liver tissues. Only one kind of DNA fragment with length of 331 bp and low relative fluorescence unit (RFU) was obtained from victim's lung tissue using 5.8S+ITS2 marker, thus the victim was thrown into the water after death. CONCLUSIONS: The experimental results of the two cases in present study are consistent with the actual facts and the result of the diatom microscopic examination. The difference of population structure of specific microorganism in water and human tissue can be detected by 5.8S+ITS2 marker, which can help to identify the drop-off location of victims in drowning cases, and confirm whether it is a fatal drowning or the victim is thrown into the water after death. PMID- 30468056 TI - Analysis of CSF1PO and D18S51 Loci Based on Ion Torrent PGMTM Platform. AB - OBJECTIVES: To analyse and detect CSF1PO and D18S51 loci by next generation sequencing (NGS) technology for the study on their sequence polymorphism. METHODS: The peripheral blood samples were collected from 165 unrelated individuals of Chinese Han population. DNA samples were obtained by QIAamp DNA Mini kit. The library was constructed by Ion Plus Fragment Library. DNA sequencing analysis was performed on Ion Torrent PGMTM Platform. The newfound alleles were verified by Sanger sequencing. Data were analysed by Torrent SuiteTM v5.0.2 and Integrative Genomics Viewer for the genotype identification and frequency count. The data were analysed statistically by PowerState v12. RESULTS: The length and sequence polymorphisms of CSF1PO and D18S51 loci were simultaneously obtained by NGS technology. A new genotype was found on CSF1PO locus, and two new genotypes on D18S51 locus. Sanger sequencing was used to verify the newfound alleles found by NGS technology, and the results of verification showed consistency. CONCLUSIONS: The structure of core repeats on CSF1PO and D18S51 loci was detected by NGS in this study for the improvement of the identifying performance of locus. PMID- 30468057 TI - Genetic Polymorphisms of 18 Autosomal STR loci in Changsha Han Population. AB - OBJECTIVES: To investigate the genetic polymorphisms of 18 autosomal short tandem repeats (STR) loci in Changsha Han population, and explore the population genetic relationships and evaluate its application value in forensic medicine. METHODS: The DNA of 2 004 unrelated individuals in Changsha Han population were amplified using Goldeneye(r)DNA ID System BASIC, and the PCR products were analyzed by electrophoresis using 3130xl genetic analyzer. The fragment sizes of alleles were analyzed subsequently by GeneMapper(r) ID v3.2. The frequency data and forensic genetic parameters [observed heterozygosity (Ho), expected heterozygosity (He), power of discrimination (DP) and polymorphic information content (PIC)] of 18 STR loci were statistically analyzed. Total probability of discrimination (TDP), probability of exclusion in trio cases (PEtrio) and probability of exclusion in duo cases (PEduo) were calculated by Cervus 3.0. Hardy-Weinberg equilibrium and linkage disequilibrium of the loci were detected by Arlequin v3.5. The results were compared with the available data of other populations from different races and regions. RESULTS: The power of discrimination (DP), and the polymorphic information content (PIC) of each locus of Changsha Han population ranged from 0.783 6 to 0.987 9 and 0.549 4 to 0.914 5, respectively. The TDP, cumulative probability of exclusion in trio cases (CPEtrio) and cumulative probability of exclusion in duo cases (CPEduo) were 0.999 999 999 999 999 999 999 865 2, 0.999 999 979 and 0.999 988 325, respectively. According to the Nei's DA genetic distance, the genetic distance between Changsha Han and Hunan Han populations was the smallest (0.014 1), while it was the largest (0.041 8) between Changsha Han and Xinjiang Kazakh populations. CONCLUSIONS: The 18 STR loci shows abundant genetic polymorphisms in Changsha Han population. The study of genetic diversity among different populations has an important meaning for the research of their origins, migrations and their relationships. PMID- 30468058 TI - Application of miniSTR Loci and Its Detection System for Degraded Materials in Forensic Medicine. AB - OBJECTIVES: To establish multiplex system of 16 miniSTR loci, and explore its application value for the degraded materials in forensic medicine. METHODS: The multiplex system of 16 miniSTR loci was established using a six-dye fluorescence labeling technology and its application value in forensic medicine was assessed. RESULTS: A six-dye fluorescence labeling miniSTR amplification kit was developed, which enabled 15 autosomal STR loci, Amelogenin locus and DYS391 to be typed simultaneously. This method showed good specificity and could provide stable and accurate typing results with a sensitivity of 50 pg. This system also provided a good test result for the normal biological sample of actual cases. CONCLUSIONS: The multiplex system of 16 miniSTR loci has application value for degraded and trace materials with the advantages of high sensitivity and database compatibility, which can be used for forensic casework. PMID- 30468059 TI - Forensic Pathological Identification and Antidiastole of Commotio Cordis. AB - Commotio cordis (CC) is the acute death caused by the cardiac rhythm disorder after a sudden blunt external force to the precordium of a healthy person without previous heart disease. As one type of violent heart damage, CC is rare with relatively small external force and sudden death, therefore causing disputes. This paper reviews the epidemiology, mechanisms and the key points in forensic identification of CC, discusses the identification and antidiastole of CC, myocardial contusion, sudden cardiac death and death from inhibition, and provides assistance to forensic pathologists to identify such causes of death. PMID- 30468061 TI - Tricuspid regurgitation: from physiopathology to transcatheter interventions. PMID- 30468060 TI - Progress in the 16S rRNA Gene Sequencing in Forensic Science. AB - Forensic microorganism is one of the hotspots of forensic science research. Due to its conservatism and specificity, the 16S rRNA gene is found to be an ideal marker for forensic identification. With the rapid development of high throughput sequencing technology, the research on microorganisms has been gradually applied to many fields such as environment and health care. In the field of forensic science, the results of forensic microbiology research, represented by 16S rRNA gene sequencing, are also gradually applied to forensic practice, such as biological samples identification, individual identification, postmortem interval estimation, and regional inference, which not only provide clues for the investigation of cases but also complement and assist traditional methods. This paper describes the research methods and related sequencing technologies of 16S rRNA gene sequencing, summarizes its research progress, and discusses the application value and potential of 16S rRNA in forensic science. PMID- 30468062 TI - Update on cardiac implantable electronic devices: from the injectable loop recorder to the leadless pacemaker, to the subcutaneous defibrillator. AB - A very fast-paced improvement of technology in the field of cardiac implantable devices has been observed in the last ten years. The aim of this review is to highlight the most important innovations which have been recently introduced in this field, such as the leadless pacemaker (a heart stimulator without intracardiac leads), the subcutaneous defibrillator (a completely extracardiac defibrillator device), the injectable loop recorder (a miniaturized subcutaneous continuous echocardiographic monitor provided by alarms and telephonic transmission) and many other new devices which will completely change the clinical practice in this field over the next decade. PMID- 30468063 TI - Left ventricular rotational abnormalities in chloroquine-induced cardiomyopathy (from the MAGYAR-Path Study). PMID- 30468064 TI - Atomic Platinum Skin under Synergy of Cobalt for Enhanced Methanol Oxidation Electrocatalysis. AB - To reduce the cost of the catalyst and the consumption of Pt, a facile electrochemical displacement preparation method is proposed, and the nanostructures can be easily controlled by a strong reducing agent and a surfactant. Two distinct Pt-Co spheres, Pt-Co core-shell spheres (CSSs) and Pt-Co hollow alloy spheres (HASs) are successfully synthesized by changing the introduction of N2. Interestingly, the Pt-Co CSSs possess a Pt-rich shell with 7 atomic layer thicknesses, which promotes efficient utilization of Pt atoms. Pt-Co HASs have a highly open structure and a single alloy phase. For methanol oxidation reaction (MOR), the Pt-Co CSSs and Pt-Co HASs exhibit enhanced catalytic performances. Compared with commercial Pt/C catalyst, the mass activity of Pt-Co CSSs catalyst is increased by 4 times and have better stability. More importantly, the current work opens a door to batch preparation of Pt-based catalysts and synthesis of shell nanostructures. PMID- 30468065 TI - A Cosmetically Adaptable Transparent Strain Sensor for Sensitively Delineating Patterns in Small Movements of Vital Human Organs. AB - Monitoring live movements of human body parts is becoming increasingly important in the context of biomedical and human machine technologies. The development of wearable strain sensors with high sensitivity and fast response is critical to addressing this need. In this article, we describe the fabrication of a wearable strain sensor made of a Au micromesh partially embedded in polydimethylsiloxane (PDMS) substrate. The sensor exhibits a high optical transmittance of 85%. The effective strain range for stretching is 0.02% to 4.5% for a gauge factor of over 108. In situ scanning electron imaging and infrared thermal microscopy analysis have revealed that nanometric break junctions form throughout the wire network under strain; strain increases the number of such junctions, leading to a large change in the sheet resistance of the mesh. This aspect has been examined computationally with the findings that wire segments break successively with increasing strain and resistance increases linearly for lower values of strain and non-linearly at higher values of strain due to formation of current bottlenecks. The semi-embedded nature of these Au microwires allow the broken wires to retract to the original positions, thus closing the nanogaps and regaining the original low resistance state. High repeatability as well as cyclic stability. have been demonstrated in live examples involving human body activity, importantly while mounting the sensor in strategic remote locations away from the most active site where strains are highest. PMID- 30468066 TI - Enhanced Detectivity and Suppressed Dark Current of Perovskite-InGaZnO Phototransistor via PCBM Interlayer. AB - Hybrid phototransistors based on InGaZnO (IGZO) metal oxide thin film transistor (TFT) and photoabsorbing capping layer such as perovskite (MAPbI3) is a promising low-cost device for developing advanced X-ray and UV flat panel imager. However, it is found that the introduction of MAPbI3 inevitably damages the IGZO channel layer during fabrication, leading to deteriorated TFT characteristics such as off current rising and threshold voltage shift. Here, we report an effective approach for improving the performance of the perovskite-IGZO phototransistor by inserting a PCBM or PCBM:PMMA interlayer between the patterned MAPbI3 and the IGZO. The interlayer effectively prevents the IGZO from damaging by the perovskite fabrication process, while allowing efficient charge transfer for photo sensing. In this configuration, we have achieved a high detectivity (1.35 * 10^12 Jones) perovskite-IGZO phototransistor with suppressed off-state drain current (~10 pA) in the dark. This work points out the importance of interface engineering for realizing higher performance and reliable heterogeneous phototransistors. PMID- 30468067 TI - Hybrid magneto-dynamical modes in a single magnetostrictive nanomagnet on a piezoelectric substrate arising from magneto-elastic modulation of precessional dynamics. AB - Magneto-elastic (or "straintronic") switching has emerged as an extremely energy efficient mechanism for switching the magnetization of magnetostrictive nanomagnets in magnetic memory, logic and non-Boolean circuits. Here, we investigate the ultrafast magneto-dynamics associated with straintronic switching in a single quasi-elliptical magnetostrictive Co nanomagnet deposited on a piezoelectric Pb(Mg1/3Nb2/3)O3-PbTiO3 (PMN-PT) substrate using time-resolved magneto-optical Kerr effect (TR-MOKE) measurements. The pulsed laser pump beam in the TR-MOKE plays a dual role: it causes precession of the nanomagnet's magnetization about an applied bias magnetic field and it also generates surface acoustic waves (SAWs) in the piezoelectric substrate that produce periodic strains in the magnetostrictive nanomagnet and modulate the precessional dynamics. This modulation gives rise to intriguing hybrid magneto-dynamical modes in the nanomagnet, with rich spin wave texture. The characteristic frequencies of these modes are 5-15 GHz, indicating that strain can affect magnetization in a magnetostrictive nanomagnet in time scales much smaller than 1 ns (~100 ps). This can enable ~10 GHz-range magneto-elastic nano-oscillators that are actuated by strain instead of a spin-polarized current. PMID- 30468068 TI - Morphotropic Phase Boundary of Hf1-xZrxO2 Thin Films for Dynamic Random Access Memories. AB - The utilization of the morphotropic phase boundary (MPB) between the newly found ferroelectric orthorhombic phase and the tetragonal phase in a HfO2-ZrO2 solid solution is suggested for high capacitance dielectric capacitor. Being different from other high-k dielectrics, where the k value decreases with the decreasing film thickness, these films (Hf:Zr ratio = 6:4, 5:5, 3:7) showed increasing k values with decreasing film thicknesses in the ~5-20 nm range. Among them, the Hf0.5Zr0.5O2 and Hf0.3Zr0.7O2 films showed 47 and 43 peak k values at the 6.5 and 9.2 nm thicknesses, respectively, suggesting the involvement of the MPB phenomenon. For the systematic understanding of this peculiar phenomenon, the phase evolution of the HfO2-ZrO2 solid solution is presented based on experimental observations. The detailed electrical tests of the films with different compositions and thicknesses demonstrated that the characteristic feature of this material system is consistent with the involvement of the MPB depending on the composition and thickness. Through the optimization of the annealing process for crystallization, a 0.62 nm minimum equivalent oxide thickness was reported for the 6.5-nm-thick Hf0.5Zr0.5O2 film, which is highly promising for the future dynamic random access memories. This work provided a breakthrough method for overcoming the fundamental limitation of a decreasing k value with a decreasing film thickness of other high-k dielectrics. PMID- 30468069 TI - Metal-Free Oxidative Thioesterification of Methyl Ketones with Thiols/Disulfides for the Synthesis of alpha-Ketothioesters. AB - A direct Csp3-H bond oxidative thioesterification of methyl ketones with aromatic thiols/disulfides promoted by TBAI/K2S2O8 has been developed. The reaction provides successfully a simple and efficient method for the synthesis of functionalized alpha-ketothioesters of aromatic thiols. This practical methodology exhibits readily available starting materials, large-scale applicability, synthetic application, and broad functional group tolerance. A possible mechanism for the transformation is proposed. PMID- 30468070 TI - Synthesis of CMe2CF3-Containing Heteroarenes via Tandem 1,1 Dimethyltrifluoroethylation and Cyclization of Isonitriles. AB - A tandem 1,1-dimethyltrifluoroethylation and cyclization of isonitriles with 3,3,3-trifluoro-2,2-dimethylpropanoic acid (TFDMPA) was developed. This protocol provides the efficient synthesis of a series of previously unknown CMe2CF3 containing heteroarenes, which are potentially useful in the drug discovery process. PMID- 30468071 TI - [3 + 4] Annulation of Bromoenals and 1,2-Benzenedithiol: Base-Promoted [2 + 4] Reaction and N-Heterocyclic Carbene-Catalyzed Ring-Expansion. AB - The [3 + 4] and [2 + 4] annulations of bromoenals and 1,2-benzenedithiol were developed in the presence or absence of N-heterocyclic carbene, respectively. Control experiment and kinetic investigation revealed the [3 + 4] annulation involves the base-promoted [2 + 4] annulation and the following carbene-catalyzed ring-expansion. PMID- 30468072 TI - Photochemical Preparation of 1,2-Dihydro-3H-indazol-3-ones in Aqueous Solvent at Room Temperature. AB - o-Nitrosobenzaldehyde is a reactive intermediate useful in the synthesis of nitrogen heterocycles. Previous strategies for using o-nitrosobenzaldehyde involve its isolation via chromatography and/or formation under harsh conditions. Herein, this intermediate was photochemically generated in situ from o nitrobenzyl alcohols in a mild, efficient manner for the construction of 1,2 dihydro-3H-indazol-3-ones using an aqueous solvent at room temperature. This convenient reaction offers several advantages over reported methods. The commercially available photoreactor employed 3x18W bulbs outputting broad emission above 365 nm. PMID- 30468073 TI - Amplified Split Aptamer Sensor Delivered Using Block Copolymer Nanoparticles for Small Molecule Imaging in Living Cells. AB - We develop a novel amplified split aptamer sensor for highly sensitive detection and imaging of small molecules in living cells by using cationic block copolymer nanoparticles (BCNs) with entrapped fluorescent conjugated polymer as a delivery agent. The design of split aptamer as the initiator of hybridization chain reaction (HCR) affords the possibility of enhancing the signal-to-background ratio and thus allows high-contrast imaging for small molecules with relatively weak interactions with their aptamers. The novel design of using fluorescent cationic BCNs as the nanocarrier enables efficient and self-tracking transfection of DNA probes. Results reveal that BCNs exhibit high fluorescence brightness allowing direct tracking of the delivery location. The developed amplified split aptamer sensor is shown to have high sensitivity and selectivity for in vitro quantitative detection of ATP with a detection limit of 30 nM. Live cell studies show that the sensor provides a "signal on" approach for specific, high-contrast imaging of ATP. The DNA sensor based HCR system may provide a new generally applicable platform for detection and imaging of low-abundance biomarkers. PMID- 30468074 TI - Enantioselective N-Heterocyclic Carbene Catalyzed Synthesis of Spirocyclic Oxindole-benzofuroazepinones. AB - Herein, we report an enantioselective synthesis of azepinones via the N heterocyclic carbene (NHC) catalyzed [3 + 4] annulation reaction of isatin derived enals and aurone-derived azadienes. The corresponding spirocyclic oxindole-benzofuroazepinones were obtained in good yields, with excellent diastereo- and enantioselectivities. The resulted azepinones were evaluated for their in vitro cytotoxic activities against six human tumor cell lines, with two compounds showing significant inhibitory activity in comparable with that of cisplatin. PMID- 30468075 TI - Vinyl-1,2,4-oxadiazoles Behave as Nucleophilic Partners in Morita-Baylis-Hillman Reactions. AB - We describe that vinyl-oxadiazoles function as a new and efficient nucleophilic partner for the Morita-Baylis-Hillman (MBH) reaction. The reaction between 5 vinyl-3-aryl-1,2,4-oxadiazoles and aromatic and aliphatic aldehydes, catalyzed by DABCO in absence of solvent, showed high efficiently to afford a new class of heterocyclic MBH adducts with potential biological activity on yields up to 99% and short reaction times. These synthetically attractive adducts bear a heterocyclic scaffold of large pharmaceutical and commercial interest associated to a plethora of biological effects and technological applications. We also demonstrate their synthetic usefulness by a photo-induced addition reaction to a poly-functionalized amino-alcohol. PMID- 30468076 TI - Collagenase Encapsulated pH-Responsive Nanoscale Coordination Polymers for Tumor Microenvironment Modulation and Enhanced Photodynamic Nanomedicine. AB - The abundant tumor extracellular matrix (ECM) could result in the insufficient tumor retention and ineffective intra-tumor penetration of therapeutic agents, as well as acidic & hypoxic tumor microenvironment (TME), further leading to the unsatisfactory therapeutic outcomes for many types of therapies. Therefore, developing strategies to modulate the TME by selectively degrading the condensed ECM may be helpful to improve existing cancer therapies. Herein, collagenase (CLG) encapsulated nanoscale coordination polymers (NCPs) are synthesized based on Mn2+ and an acid-sensitive benzoic-imine organic linker, and then modified by polyethylene glycol (PEG). Upon intravenous (i.v.) injection, these CLG@NCP-PEG nanoparticles show efficient accumulation within the tumor, in which CLG would be released due to the collapse of NCP structures within the acidic TME. The released CLG enzyme could then specifically degrade collagens, the major component of ECM, leading to loosened ECM structure, enhanced tumor perfusion and relieved hypoxia. As the results, the second-wave of nanoparticles, chlorin e6 (Ce6)-loaded liposomes (Liposome@Ce6), would exhibit enhanced retention and penetration within the tumor. Such phenomena together with relieved tumor hypoxia could then lead to greatly enhanced photodynamic therapeutic effect of Liposome@Ce6 for mice pretreated with CLG@NCP-PEG. Our work thus presents a unique strategy for TME modulation using pH-responsive NCPs as smart enzyme carriers. PMID- 30468077 TI - Effectiveness and safety of micronized purified flavonoid fraction for the treatment of concomitant varicose veins of the pelvis and lower extremities. AB - OBJECTIVE: Concomitant varicose veins of the pelvis (VVP) and lower extremities (VVLE) frequently coexist. This study evaluated the effectiveness and safety of micronized purified flavonoid fraction (MPFF) in the treatment of patients with both conditions. METHODS: Female outpatients with concomitant VVP and VVLE received MPFF 1000 mg once daily for 2 months (Group 1), or 1000 mg twice daily for 1 month followed by 1000 mg once daily for 1 month (Group 2), based on pelvic pain intensity. Change in pain intensity during treatment was evaluated on a 10 cm Visual Analog Scale. All patients underwent transvaginal and transabdominal duplex ultrasound scanning, radionuclide phlebography of the lower extremities, and emission computer tomography of the pelvic veins at inclusion and end of treatment. RESULTS: In Group 1 (N = 35), MPFF was associated with a twofold reduction in pain syndrome severity (pelvic, perineal and lower leg pain) in all patients after 1 month, and a reduction in chronic pelvic pain (CPP) from 3.4 +/- 1.2 to 0.83 +/- 0.18 cm at 2 months. Leg pain significantly decreased from 2.8 +/ 0.6 at baseline to 0.94 +/- 0.11 after 2 months. In Group 2 (N = 30), MPFF decreased CPP severity from 6.3 +/- 0.8 to 1.2 +/- 0.12, perineal pain from 3.6 +/- 0.9 to 0.88 +/- 0.22, and leg pain from 4.6 +/- 0.5 to 0.9 +/- 0.1. Radionuclide phlebography confirmed the clinical improvement in both treatment groups, with a substantial increase in linear blood flow velocity in the internal iliac veins (~10% in Group 1 and 35% in Group 2), and a reduction in mean transit times of the radiopharmaceutical. MPFF also reduced blood stasis in the pelvic venous plexuses. Gastralgias were reported in two patients but resolved rapidly and did not lead to treatment withdrawal. CONCLUSION: Phlebotropic treatment with MPFF is an effective and safe method of conservative therapy in patients with concomitant VVP and VVLE. PMID- 30468078 TI - New iridoid glycosides from Anarrhinum pubescens. AB - Six metabolites (1-6) were isolated from the aerial parts of Anarrhinum pubescens Fresen. (Plantaginaceae) growing in Saint Catherine region in Egypt; two of them (1 and 4) are here reported to be newly identified naturally occurring iridoids. The isolated metabolites were identified as 6-O-foliamenthoyl-(6'-O-cinnamoyl) antirrhinoside (1), 6'-O-cinnamoyl-antirrhinoside (2), the iridoid dimer, pubescensoside (4), antirrhinoside (5), 10-hydroxy-antirrhinoside (6), and the flavonoid, diosmin (3). Identification of the new metabolites was based on analysis of their collected spectroscopic data (NMR and HR-ESI-MS). Furthermore, compounds (1, 4, and 5) were subjected to cytotoxic testing against the human lung carcinoma cell line (A-549); compound 4 showed better cytotoxic activity as indicated by the obtained (IC50). PMID- 30468079 TI - Urinary levels of 1-hydroxypyrene and health risk assessment in children living in Mexican communities with a high risk of contamination by polycyclic aromatic hydrocarbons (PAHs). AB - Health complications have been associated with polycyclic aromatic hydrocarbons (PAHs) exposure, a widespread environmental pollutants family. Therefore, the objective of this investigation was to develop a probabilistic health risk evaluation (using Monte-Carlo simulation) in an infantile population living in areas with a high risk of pollution by PAHs (indoor wood combustion, brick kiln industry, municipal landfill, and low and high vehicular traffic) in Mexico. Urine samples were obtained from Mexican children (n = 135) and urinary 1-OHP concentrations (used as a PAHs biomarker) were quantified. Highest urinary 1-OHP concentrations were detected in children living in areas that use wood combustion as the principal indoor fuel (3.50 +/- 0.95 ug/L). Nevertheless, estimated hazard quotients (HQ) lower than 1 were found in all assessed sites after Monte-Carlo analysis. Although HQ <1.0 (a toxic effect is not expected), more data are necessary to determine the real impact of PAHs exposure on children health status. PMID- 30468080 TI - Ways to increase adherence to allergen immunotherapy. AB - Adherence to allergen immunotherapy (AIT) is crucial for its efficacy. Subcutaneous AIT requires monthly visits (or more extended in the case of venom immunotherapy), while sublingual is performed with a daily intake of allergen drops. Non-adherence to an AIT schedule and premature discontinuation are common problems. Results from various studies have concluded to controversial results on the rate of AIT adherence. The aim of this review was to describe the problem of non-adherence and to offer some evidence-based advice to allergologists, on how to increase it. Better patient education at the beginning of treatment, sharing with patient the decision on which type of immunotherapy to select, and showing sincere interest on their treatment concerns are some tips that can help to increase adherence. A well-organized allergologist time schedule not only increases safety but also offers the possibility of close follow-up and an increase in patient loyalty. PMID- 30468081 TI - 1H NMR-based metabonomics of the hypoglycemic effect of polysaccharides from Cordyceps militaris on streptozotocin-induced diabetes in mice. AB - The crude polysaccharide was extracted from Cordyceps militaris. Material ratio of powder and water was 1:10. The polysaccharide was successively purified by Sevag and chromatography on Sephadex G-100 column to produce a polysaccharide fraction termed CBPS-II. The average molecular weight of CBPS-II was 1.273 * 103 kDa. The study was conducted to investigate the hypoglycemic effect of Cordyceps militaris polysaccharide on diabetic mice. Analysis of the clinical chemistry of the serum samples included serum creatinine (CRE), urea nitrogen (BUN), triglyceride (TG) and total cholesterol (TC). Results revealed that a certain dose of polysaccharide can alleviate the symptoms of metabolic disorders of diabetes, contributing to the body to restore the normal levels. The metabolic profiling method was adopted to find the related biomarkers and the metabolic pathway of diabetes. Moreover, results showed that 100 mg.kg-1 of Cordyceps polysaccharides can effectively reduce the blood glucose level of diabetic mice, thus regulating the metabolism of their energy, amino acids and intestinal microbes. The biomarkers noted in their metabolism were glucose, lactic acid, 3 hydroxy butyric acid, creatine, glutamate, valine, leucine, isoleucine and very low density lipoprotein (VLDL). PMID- 30468082 TI - Long noncoding RNAs as biotargets in cisplatin-based drug resistance. AB - Since its discovery, cisplatin has become the key drug in chemotherapy for cancers. Nevertheless, chemoresistance in cancers has become an impediment in using cisplatin for cancer treatment. The resistance toward cisplatin is multifaceted as it involves multiple cellular pathways. Ever since the knowledge of long noncoding RNAs as modulators of various molecular pathways came to light, the interest in the biological function of lncRNAs as biomarkers has increased dramatically. Numerous studies have reported the link between the dysregulation of lncRNAs and drug resistance in cancers. More importantly, several lncRNAs were found to be vital in regulating cisplatin resistance. Therefore, this review summarizes the recent efforts in linking between cisplatin resistance and different types of lncRNAs. PMID- 30468083 TI - An epidemiologic investigation of amyotrophic lateral sclerosis in Thrace, Turkey, 2006-2010. AB - OBJECTIVE: The aim of the study was to investigate the incidence and prevalence of amyotrophic lateral sclerosis (ALS) in Thrace, Turkey in a five-year time period (2006-2010). METHODS: Study population included residents of three provinces (Edirne, Tekirdag, Kirklareli) in the Thrace region. Cases were ascertained from all of the neurologic centers and hospitals of these provinces. Demographic and clinical information was collected for each patient. Newly diagnosed ALS patients who are fulfilling the El Escorial revised diagnostic criteria were enrolled into the study. RESULTS: We identified a total of 145 patients (93 males, 52 females). The mean age at diagnosis was 57.0 +/- 13.6. According to El Escorial criteria, 60.0% of the cases were definite ALS, 24.8% were probable, and 15.2% were possible ALS. Thirty-two cases were bulbar (22.1%), 113 cases (77.9%) were spinal onset. Mean time delay from onset to diagnosis was 12.0 +/- 11.2 months. Age-gender standardized incidence rates with reference to Turkey, USA 2008 census were 1.9 (95% confidence interval (CI), 1.8-2.1), 1.9 (95%CI, 1.8-2.2) for overall. There were 112 living ALS patients at the end of the study. Crude point prevalence was calculated as 7.3 per 100,000 population (95%CI, 5.9-8.7). CONCLUSIONS: This is the first study to provide fundamental data about demographic and clinical characteristics about ALS in Thrace region of Turkey. Incidence and prevalence of ALS in Thrace region of Turkey appear to be comparable with European countries. PMID- 30468084 TI - Role of Stem Cells in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Pulmonary Emphysema. AB - There are only few human translational studies performed in the area of stem cell research in patients with chronic obstructive pulmonary disease (COPD) and/or pulmonary emphysema. Before progress to clinical trials with stem cells we strongly believe that more human translational studies are essential, otherwise, the clinical rationale would be solely based on limited in vitro and animal studies. In the future, stem cell therapy could be a treatment for this incurable disease. As of now, stem cell therapy is still to be considered as an area of active research, lacking any strong rationale for performing clinical trials in COPD. Although stem cells would be likely to represent a heterogeneous population of cells, the different cell subsets and their importance in the pathogenesis of the different clinical phenotypes need to be fully characterised before progressing to clinical trials. Moreover, the potential side effects of stem cell therapy are underestimated. We should not ignore that some of the most deadly neoplasms are arising from stem cells. PMID- 30468085 TI - Cold stress modulates redox signalling in murine fresh bone marrow cells and promotes osteoclast transformation. AB - CONTEXT: Alteration of redox signalling and RANK-L expression in FBMCs of mice exposed to different intensities of cold stress (15 degrees C, 8 degrees C and 4 degrees C) were studied. OBJECTIVE: To understand the effects of varying intensities of cold stress on murine FBMCs and its impact on osteoclastogenesis. MATERIALS AND METHODS: FBMCs were isolated from mice exposed to different intensities of cold stress and used for immunoblotting and biochemical assays. Bone histometry was also done. RESULTS: Different intensities of cold stress perturb redox signalling in FBMCs and alters bone histometry. Higher RANK-L expressions were noted in FBMCs of mice exposed to 8 degrees C and 4 degrees C as compared with 15 degrees C. DISCUSSION AND CONCLUSION: Cold stress boosts free radical production in FBMC's, which might enhance RANK-L expression, an indicator of osteoclastogenesis. Thus, we speculate that stronger cold stress (8 degrees C and 4 degrees C) contributes to the development of early bone loss. PMID- 30468086 TI - Myristigranol, a new diarylpropane derivative from the wood of Myristica fragrans. AB - Myristigranol, a new diarylpropane derivative, was isolated from the methanol extract of Myristica fragrans wood along with one diarylpropanoid and three stilbenoids. The isolated constituents were exhaustingly identified using the analyses of 1D and 2D NMR spectroscopic techniques and comparison of the literatures reported as well. The antioxidant activity was also determined. [Formula: see text]. PMID- 30468087 TI - Predicament and Pilgrimage: Hearing Families of Deaf Children in Mexico City. AB - In this article, I trace the most salient features of Mexican families' complex journeys as they coped with the "predicament" of childhood deafness. Framing support seeking through the theoretical lens of pilgrimage brings into focus family introspection and captures their tenacity while facing culture-specific obstacles. Ultimately, families realized their quests were not about "fixing" their children's hearing, but finding more reliable communication in sign language. Pilgrimage, as a metaphor for the journeys described by participants, helps us understand families' realizations that the biomedical options most commonly available in Mexico City were of limited efficacy, and reveals collective desire for alternatives to these options. PMID- 30468090 TI - The humanistic burden of postpartum depression: a systematic literature review. AB - OBJECTIVE: Postpartum depression (PPD) is the most common medical complication of childbirth. PPD can be disabling, with potential negative effects on maternal health-related quality of life (HRQoL) as well as on children and partners. The objective of this study was to systematically review and summarize recently published literature describing the humanistic burden of PPD on affected women, their children, and partners. METHODS: Databases including Embase, MEDLINE, and PsycINFO as well as conference proceedings were searched for keywords related to PPD. Searches were initially conducted in February 2017 and restricted to the prior 5 years for databases and the prior 2 years for conference proceedings. Searches were updated in February 2018. Two researchers independently reviewed 1154 unique records according to predefined inclusion and exclusion screening criteria. RESULTS: 48 studies were identified; over 40 studies assessed the effects of PPD on children of affected mothers, with many demonstrating a negative association with elements of parenting and childhood development. Furthermore, five studies that evaluated the effects of PPD symptoms on partners suggested that certain aspects of their relationships were negatively affected. Partners of affected women also experienced greater levels of their own stress, anxiety, and depression compared with partners of women without PPD symptoms. Despite limited data on HRQoL among women with PPD symptoms (four studies), a negative impact on physical and mental subscales was observed. CONCLUSIONS: Findings suggest that PPD symptoms have a substantial humanistic burden on affected mothers as well as on their children and partners. PMID- 30468091 TI - COPD Assessment Test (CAT) is a Valid and Simple Tool to Measure the Impact of Bronchiectasis on Affected Patients. AB - The COPD assessment test (CAT) is a short questionnaire developed to help patients and clinicians to assess the impact of symptoms in routine clinical practice. We aimed to validate and to test the reproducibility of CAT in patients with bronchiectasis and correlate with the severity of dyspnea, aerobic and functional capacity, and physical activity in daily life. This is a cross sectional study, patients with bronchiectasis underwent spirometry, cardiopulmonary exercise test (CPET), incremental shuttle walk test (ISWT), Saint George's Respiratory Questionnaire (SGRQ), and received pedometer. CAT was applied twice (CAT-1 and CAT-2, 7 to 10 days apart). The severity of bronchiectasis was assessed by E-FACED and bronchiectasis severity index (BSI). A total of 100 patients were evaluated (48 +/- 14 years, 59 women, FVC: 67 +/- 22% pred, FEV1: 52 +/- 25% pred). According to CAT, 14% patients presented low, 40% medium, 32% high, and 14% very high impact. The higher the CAT, the worse the severity of bronchiectasis, dyspnea, quality of life, performance on the CPET, and smaller the distance walked (DW) on the ISWT and number of steps (NS) per day. There was significant correlation between CAT and SGRQ, E-FACED, BSI, NS, ISWT, oxygen uptake, and workload at CPET. CAT-1 and CAT-2 presented similar values: 21 (13-26) and 19 (13-26), respectively. The CAT is a valid and reproducible instrument in patients with bronchiectasis presenting good correlation with clinical, functional, and quality of life measurements. This easy-to-use, easy-to-understand, quick, and useful tool may play an important role to assess the impact of bronchiectasis on both daily medical practice and clinical trial settings. PMID- 30468092 TI - Potential molecular targets of peroxynitrite in mediating blood-brain barrier damage and haemorrhagic transformation in acute ischaemic stroke with delayed tissue plasminogen activator treatment. AB - Tissue plasminogen activator (t-PA) remains to be the only FDA-approved drug for ischaemic stroke, but it has a restrictive therapeutic window with 4.5 hours. Beyond the golden time window, thrombolytic treatment carries the risk of haemorrhagic transformation (HT). The blood-brain barrier (BBB) disruption is a critical step in the t-PA-mediated HT. Although large efforts are made to explore the mechanisms of the BBB disruption and HT, the underlying mechanisms are largely unknown. Thrombolytic treatment for recanalization could produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) and mediate cerebral ischaemia-reperfusion injury. RNS, including nitric oxide (NO) and peroxynitrite (ONOO-), are important players in cerebral ischaemia-reperfusion injury. In particular, ONOO- and its derivatives could mediate neurovascular unit damages and induce the BBB disruption and HT possibly through interacting with different cellular signalling pathways including matrix metalloproteinase (MMPs), high mobility group Box 1 (HMGB1), toll-like receptor2/4, poly(ADP-ribose) polymerase, Src, ROCK, and GSK-3beta. Herein, we review current progress about the roles of ONOO- in mediating those signalling pathways and their impacts on the t-PA induced BBB disruption and HT. Subsequently, we discuss the values of natural compounds with the properties of scavenging ONOO- as adjunctive therapies to extend the therapeutic window of t-PA and attenuate haemorrhage transformation in ischaemic stroke. PMID- 30468093 TI - The role of decorin in cardiovascular diseases: more than just a decoration. AB - Decorin (DCN) is a proteoglycan constituent of the extracellular matrix (ECM) possessing powerful antifibrotic, anti-inflammation, antioxidant, and antiangiogenic properties. By attaching to receptors in the cell surface or to several ECM molecules, it regulates plenty of cellular functions, consequently influencing cell differentiation, proliferation, and apoptosis. These processes are dependent on cell types, biological contexts, and interfere with pathological processes such as cardiovascular diseases. In this review, we briefly discuss the potential of DCN targeting in addressing cardiovascular diseases (CVD). We dive into its interactome and discuss how its interaction with the proteins can affect disease progression, and how DCN can be a possible target for CVD therapeutics. PMID- 30468094 TI - LPS-induced MMP-9 expression is mediated through the MAPKs-AP-1 dependent mechanism in BEAS-2B and U937 cells. AB - AIM OF THE STUDY: Matrix metalloproteinases (MMPs) play a critical role in chronic obstructive pulmonary disease (COPD). This study investigated the role of mitogen-activated protein kinases (MAPKs) in MMP-9 secretion of BEAS-2B cells, a human bronchial epithelial cell line and U937 cells, a human myeloid leukaemia cell line, which could differentiate into macrophage, after LPS stimulation, and some details of involved signaling. MATERIALS AND METHODS: MTT assay was used to measure cell viability. U937 cells were incubated for 48h with 100ng/ml PMA, and had a resting period of 24h with culture medium without PMA for differentiation of U937 cells into macrophages. For the experiments, U937 cells or BEAS-2B cells were pretreated with several inhibitors and then stimulated by LPS. Western blotting, quantitative real-time PCR, enzyme-linked immunosorbent assay (ELISA) and DNA binding activity assay were used for measuring the protein expression, RNA expression, cytokine production and DNA binding activity, respectively. RESULTS: We found LPS induced MMP-9 expression and secretion were completely blocked by stress-activated protein kinase/jun kinase (SAPK/JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitors but not by p38 inhibitor. LPS-induced transactivation of AP-1 was also inhibited by JNK inhibitor SP600125 and ERK1/2 inhibitor PD98059. CONCLUSIONS: The present study suggests that in BEAS-2B cells and U937 cells, LPS probably activates ERK1/2 pathway and JNK pathway, which in turn initiate AP-1 activity, and leading to MMP 9 expression. Thus the ERK1/2 inhibitor and JNK inhibitor may have potential clinical value in treating COPD. PMID- 30468095 TI - Consumer willingness to pay for a hypothetical zika vaccine in Brazil and the implications. AB - BACKGROUND: Zika virus is a newly emerging infection, associated with increasingly large outbreaks especially in tropical countries such as Brazil. A future Zika vaccine can contribute to decreasing the number of cases and associated complications. Information about consumers' willingness to pay (WTP) for a hypothetical Zika vaccine can help price setting discussions in the future in Brazil, starting with the private market. METHODS: A cross-sectional study conducted among residents of Minas Gerais, Brazil, regarding their WTP for a hypothetical Zika Vaccine. The mean effective protection was 80%, with the possibility of some local and systemic side-effects. RESULTS: 517 people were interviewed. However, 30 would not be vaccinated even if the vaccine was free. Most of the resultant interviewees (489) were female (58.2%), had completed high school (49.7%), were employed (71.2%), had private health insurance (52.7%) and did not have Zika (96.9%). The median individual maximum willingness to pay for this hypothetical Zika vaccine (one dose) was US$31.34 (BRL100.00). CONCLUSION: Such discussions can contribute to decision-making about prices once a Zika vaccine becomes available in Brazil alongside other ongoing programmes to control the virus. PMID- 30468096 TI - A computational investigation of the reactions of tyrosyl, tryptophanyl, and cysteinyl radicals with nitric oxide and molecular oxygen. AB - Proteins are main targets of oxidants in biological systems. This oxidation may occur in the protein backbone as well as in certain amino acid side chains, depending on the oxidant and amino acid intrinsic reactivity. Moreover, many enzymes are capable of generating stable amino acid radicals, such as tyrosyl, tryptophanyl and cysteinyl radicals. These species react very rapidly (many times as diffusion-controlled reactions) with relevant cellular open-shell species such as nitric oxide (.NO) or molecular oxygen (O2). The exception to this apparent rule is tyrosyl radical, that reacts at diffusion rates with .NO, but shows very slow reactivity towards O2 (rate constant <103 M-1 s-1). In this work, we provide a comparative molecular-level description of the reaction mechanisms involved in the reactions of tyrosyl, tryptophanyl and cysteinyl radicals towards .NO and O2, through quantum mechanics simulations which allow us to obtain relevant energetic and structural parameters, proposing a molecular explanation to this tyrosyl discrimination capability, namely, its marginal reactivity with O2. PMID- 30468097 TI - Review of studies reporting actual prices for medicines. AB - BACKGROUND: Medicine purchasing and pricing decisions usually rely on officially published prices. Literature has reported evaluations of publicly stated prices. However, due to the frequent use of confidential price arrangements there are indications for paucity of data on actual medicine prices. Therefore, the study aimed to systematically review literature with regard to availability of information on actual medicine prices. Areas covered: The Medline database was searched systematically to identify studies addressing actually paid prices of medicines used in-patient or out-patient care from the health care payer, health provider or patient perspective, published during 2007-2017. Thirty-three observational studies were included in the analysis. Expert commentary: The review confirmed the paucity of studies on actual medicine prices, with only few studies evaluating differences between official and actually paid prices. The included studies are heterogeneous and differ in their design and focus. Non availability of actual price data in several non-European countries results from lack of price regulation, which usually coincides with variation in actual prices for the same medicines between different dispensaries. In high-income, mostly European countries, transparency of actual prices is limited due to increased use of confidential medicine price arrangements. PMID- 30468098 TI - Challenges to the improvement of Colombian medical brigades aimed at the diagnosis of congenital heart disease: A qualitative approach. AB - Qualitative research of brigades and the family experience of congenital heart disease is of current interest and has been previously neglected. This study aimed to explore the social factors conditioning outcomes of paediatric cardiology care in the setting of Colombian medical brigades and to identify feasible strategies to improve the experience of the beneficiary populations. Participants were selected using purposeful sampling. Semi-structured interviews were conducted with members of logistic and health care teams, caregivers and custodians of beneficiary children of the Programme. The data collected provided an understanding of the health culture, social background, household and intrafamily dynamics. The outcomes of the Programme are influenced by sociocultural dynamics such as communication gaps and the socioeconomic status of the beneficiary populations. Findings may be specific to brigades, but also cross relevant to any family experience of a new diagnosis of Congenital Heart Disease (CHD) communicating with healthcare professionals. It is important to foresee the role and further development of the Programme. Recommendations are provided suggesting innovative work by means of telemedicine and other sociocultural measures to reduce healthcare inequity and strengthen comprehensive healthcare programmes. PMID- 30468099 TI - Echocardiographic evaluation of prevalence of pulmonary hypertension in beta thalassemia major: A cross sectional study. AB - INTRODUCTION: Pulmonary hypertension is a common complication associated with thalassemia syndromes and it may play an important role in the pathogenesis of right ventricle failure. The true prevalence of pulmonary hypertension in patients with thalassemia major remains unclear and has been reported to be between 2 and 79%. MATERIALS AND METHODS: In total, 70 patients with thalassemia major were initially examined. Patients with valvular left heart disease, congenital heart diseases such as atrial septal defect (ASD) and ventricular septal defect (VSD), left heart failure, and chronic embolism were excluded. All patients with thalassemia major underwent echocardiography. Based on tricuspid regurgitation velocity (TRV), the patients were divided into the following three groups: low, medium, and high risk of pulmonary hypertension. RESULTS: The mean age of the subjects was 24 y; 60.6% of the subjects were males and 39.4% of the subjects were females. Overall, three (4.5%) subjects were considered at a high risk of pulmonary hypertension. The mean hemoglobin level in the patients with a high probability of pulmonary hypertension was 8.2 g/dL and that in the patients with a low or medium probability of pulmonary hypertension was 9.1 g/dL. No significant difference was observed between the groups (p = .059). CONCLUSION: This study showed that, based on new echocardiography criteria, the prevalence of pulmonary hypertension secondary to beta-thalassemia was 4.5% and there was no correlation between TRV and the number of received blood units or disease duration. PMID- 30468100 TI - Providing mental health care in the context of online mental health notes: advice from patients and mental health clinicians. AB - BACKGROUND: The OpenNotes initiative provides patients online access to their clinical notes. Mental health clinicians in the Veterans Health Administration report a need for guidance on how to provide care, write notes, and discuss them in the context of OpenNotes. AIM: To provide mental health clinicians recommendations identified by patients and clinicians that help them effectively practice in the context of OpenNotes. METHOD: Twenty-eight mental health clinicians and 28 patients in mental health care participated in semi-structured interviews about their experiences and perceptions with OpenNotes. A rapid review approach was used to analyze transcripts. RESULTS: Analysis of interviews identified three domains of advice for mental health clinicians: writing notes that maintain the therapeutic relationship, communicating with patients about their notes and utilizing clinical notes as a patient resource to enhance care. Specific recommendations are provided. CONCLUSION: Findings provide mental health clinicians with guidance from service users and clinicians on how to leverage clinical notes to maintain - and potentially enhance -therapeutic relationships in a healthcare system in which patients are able to read their mental health notes online. PMID- 30468101 TI - Physical activity may compensate for prolonged TV time regarding pulse rate-a cross-sectional study. AB - BACKGROUND: Regular exercise reduces pulse rate, but it is less clear how prolonged sitting time affects pulse rate. Our hypothesis was that high physical activity could compensate for prolonged sitting time regarding the pulse rate. METHODS: Regression analysis was performed on cross-sectional data including 47,457 men and women based on two Swedish cohort studies, EpiHealth (18-45 years) and LifeGene (45-75 years). Self-reported leisure time physical activity was given in five levels, from low (level 1) to vigorous (level 5), and television time was used as a proxy of sitting time. RESULTS: A higher physical activity (level 4 compared to level 1) was associated with a lower pulse rate in middle aged females (-2.7 beats per minute [bpm]; 95% CI -3.3 to -2.2) and males (-4.0 bpm; 95% CI -4.7 to -3.4). The relationship between physical activity and pulse rate was strongest in the young. A prolonged television time (3 h compared to 1 h per day) was associated with a slightly higher pulse rate in middle-aged females (+0.6 bpm; 95% CI +0.3 to +0.8) and males (+0.9 bpm; 95% CI +0.7 to +1.2). Among participants with a prolonged television time (3 h), those with a high physical activity (level 4) had a lower pulse rate compared to those with a low physical activity (level 1). CONCLUSIONS: A prolonged television time was associated with a high pulse rate, while high physical activity was associated with a low pulse rate. The results suggest that a high physical activity could compensate for a prolonged television time regarding pulse rate. PMID- 30468102 TI - Use of Alcohol Protective Behavioral Strategies as a Moderator of the Alcohol Use Consequences Relationship: Evidence from Multiple Replications. AB - BACKGROUND: The use of protective behavioral strategies (PBS) has been found to attenuate the relationship between alcohol use and related consequences. OBJECTIVES: The current study examined PBS use as a moderator of the association between alcohol use and consequences in multiple samples (N = 9) of college students with different sample sizes (e.g., ns 125-736). We also examined sex as a moderator of the PBS moderation analyses. Across all samples, we predicted that the use of more PBS would attenuate the use-consequences relation. METHODS: In total, 3,524 college students completed online measures of alcohol use, consequences, and PBS use (i.e., PBSS) across two sites. Conclusions/importance: In the analyses, 3 two-way interactions were consistent with the literature (i.e., use-consequences relation weakest among those with high PBS use), 6 were opposite of what was reported in the literature (i.e., use-consequences relation strongest among those with high PBS use), and 39 were not statistically significant. These results corroborate, contradict, and extend the current body of knowledge in the extant alcohol PBS literature. In the examination of three way interactions in the combined sample, serious harm reduction (SHR) PBS was found to moderate the use-consequences relation among female, but not among male students. Specifically, the use-consequences relation was weakest among female students who used more SHR PBS indicating that SHR PBS may be an important intervention target for female college students. Additional experimental and longitudinal studies are needed to examine the effects of PBS use on the use consequences relation. PMID- 30468103 TI - Atypical non-progressive semantic impairment following allogeneic bone marrow transplantation in a patient with Waldenstrom's macroglobulinemia: a case report. AB - OBJECTIVE: A case report of a 74-year-old male presenting with an atypical multimodal semantic impairment. The patient was diagnosed with Waldenstrom macroglobulinemia (WM) for which he received allogeneic bone marrow transplantation (BMT) due to disease progression. Following BMT, he developed a sudden onset of semantic difficulties that have remained unchanged for eight years. No other cognitive functions have been affected and his activities of daily living remain fully preserved. METHOD: The patient was assessed at our neuropsychology unit with six neuropsychological evaluations over an 8-years follow-up period following BMT. Additional semantic tests were administered during the last three evaluations. Four MRI scans (at age 62, 66, 69 and 74) and 18F-FDG PET (at age 74) were obtained. RESULTS: The patient presents a multimodal semantic impairment, including naming impairment, visual agnosia, prosopoanomia, associative prosopagnosia, topographical disorientation and impaired retrograde memory for public events. MRI scans and 18F-FDG PET revealed bilateral symmetrical atrophy (temporal > frontal) and inferior bilateral temporal lobe hypometabolism, respectively. Neuroradiological examination was unremarkable prior to BMT. CONCLUSION: Clinical diagnosis remains a challenge given the focal and stable nature of his deficits. We hypothesize that the BMT procedure might have resulted in the temporal lobe damage and subsequent semantic impairment. We recommend obtaining a thorough neuropsychological evaluation of patients who receive allogenic BMT, both prior to and following transplant. PMID- 30468104 TI - Latest developments in the field of stem cell research and regenerative medicine compiled from publicly available information and press releases from non-academic institutions 1 July-31 August 2018. PMID- 30468105 TI - Thoracic epidural anaesthesia reduces insulin resistance and inflammatory response in experimental acute pancreatitis. AB - AIMS: The activity of the sympathetic nervous system (SNS) is crucial at an early stage in the development of an inflammatory reaction. A study of metabolic events globally and locally in the early phase of acute pancreatitis (AP), implying hampered SNS activity, is lacking. We hypothesized that thoracic epidural anaesthesia (TEA) modulates the inflammatory response and alleviates the severity of AP in pigs. MATERIAL AND METHODS: The taurocholate (TC) group (n = 8) had only TC AP. The TC + TEA group (n = 8) had AP and TEA. A control group (n = 8) underwent all the preparations, without having AP or TEA. Metabolic changes in the pancreas were evaluated by microdialysis and by histopathological examination. RESULTS: The relative increase in serum lipase concentrations was more pronounced in the TC group than in TC + TEA and control groups. A decrease in relative tissue oxygen tension (PtiO2) levels occurred one hour later in the TC + TEA group than in the TC group. The maintenance of normoglycaemia in the TC group required a higher glucose infusion rate than in the TC + TEA group. The relative decrease in serum insulin concentrations was most pronounced in the TC + TEA group. CONCLUSION: TEA attenuates the development of AP, as indicated by changes observed in haemodynamic parameters and by the easier maintenance of glucose homeostasis. Further, TEA was associated with attenuated insulin resistance and fewer local pathophysiological events. PMID- 30468106 TI - Regulation of Mcl-1 alternative splicing by hnRNP F, H1 and K in breast cancer cells. AB - Myeloid cell leukemia-1 (Mcl -1) is one of the most frequently amplified genes in cancer, and its overexpression is associated with poor prognosis and drug resistance. As a member of the Bcl-2 family it is involved in the control of the mitochondrial (intrinsic) cell death pathway. Alternative splicing of the (Mcl-1) gene results in the expression of two functionally distinct proteins, the anti apoptotic Mcl-1L (exon 2 included) and the pro-apoptotic Mcl-1S (exon 2 skipped). Our data shows that transfecting siRNAs that target hnRNP K and the hnRNP F/H family result in a switch in splicing towards the pro-apoptotic Mcl-1S. Specific binding sites for these and other Mcl-1 splicing factors were investigated and identified by RNA immunoprecipitation and through construction of a Mcl-1 minigene construct. Moreover, this study shows up to a 30 fold change in the levels of Mcl-1S can be achieved through double and triple knockdowns of the most significant RNA binding proteins involved in Mcl-1 splicing, as well as activation of the mitochondrial cell death pathway. Targeting the splicing process of Mcl-1 along with other apoptotic regulators provides an exciting new therapeutic target in cancer cells, and may provide a way to overcome therapy resistance. PMID- 30468107 TI - Is self-report a valid measure of unimanual object-based task performance? AB - Hand preference is commonly measured via self-report using instruments known as handedness inventories. These instruments query which hand subjects use to perform unimanual object-based tasks and also the consistency of usage. Scores reveal which hand people report using most (i.e., which hand is preferred). Some people report highly consistent usage of their preferred hand while others report relatively inconsistent usage. These reports are often assumed to be accurate descriptions of people's actual behavior, but empirical evidence concerning their validity is surprisingly scant. In the present research, subjects completed a handedness inventory on which higher scores indicated more consistent usage of the preferred hand. After a brief filled interval, subjects performed tasks listed on the inventory, spontaneously choosing which hand to use for each task. Subjects who scored higher on the inventory used the preferred hand more often. Subjects were then timed while performing the tasks as fast as they could with each hand. Subjects were faster when using their preferred hand and the magnitude of the preferred hand advantage was positively correlated with self-reported consistency. These results support the validity of inventory scores by showing that they are related to spontaneous hand choice and manual fluency when performing inventory tasks. PMID- 30468108 TI - Health needs and risky behaviours among inmates in the largest prison of eastern Nepal. AB - PURPOSE: The purpose of this paper is to assess the health status and risky behaviours of inmates in Nepal. DESIGN/METHODOLOGY/APPROACH: This cross-sectional study was conducted in Jhumka Regional Prison, the largest male prison in eastern Nepal from September 2014 to August 2015. Data were collected through face-to face interviews from 434 randomly selected incarcerated participants using semi structured questionnaires. FINDINGS: The mean age of 434 participants was 35.7 years (SD 13.3). The majority (84 per cent) had at least one current health problem, of which the commonest were respiratory (50 per cent), skin (38 per cent) and digestive (26 per cent). Alcohol (73 per cent) and cigarettes (71 per cent) were the most commonly used substances prior to imprisonment. Approximately, 27 and 11 per cent reported illicit drug use and injectable drug use prior to incarceration, respectively. A total of 204 inmates reported having intercourse with sex workers. Of these, 49 per cent did not use a condom in their last intercourse with a sex worker. RESEARCH LIMITATIONS/IMPLICATIONS: This paper illustrates that a wide range of physical and mental health problems exist among incarcerated people in Nepal. The study may lack generalisability, however, as it was conducted in a single male prison. PRACTICAL IMPLICATIONS: The paper suggests a need for medical, psychiatric and substance abuse care in correctional settings to improve the health status of the prison population. It is also important to develop screening policies for blood-borne viral and other infectious diseases in the prison. ORIGINALITY/VALUE: This is the first study of its kind drawn from prisons in Nepal. PMID- 30468109 TI - Australian Aboriginal women prisoners' experiences of being a mother: a review. AB - PURPOSE: The rise in the incarceration of Aboriginal and Torres Strait Islander mothers is a major public health issue with multiple sequelae for Aboriginal children and the cohesiveness of Aboriginal communities. The purpose of this paper is to review the available literature relating to Australian Aboriginal women prisoners' experiences of being a mother. DESIGN/METHODOLOGY/APPROACH: The literature search covered bibliographic databases from criminology, sociology and anthropology, and Australian history. The authors review the literature on: traditional and contemporary Aboriginal mothering roles, values and practices; historical accounts of the impacts of white settlement of Australia and subsequent Aboriginal affairs policies and practices; and women's and mothers' experiences of imprisonment. FINDINGS: The review found that the cultural experiences of mothering are unique to Aboriginal mothers and contrasted to non Aboriginal concepts. The ways that incarceration of Aboriginal mothers disrupts child rearing practices within the cultural kinship system are identified. PRACTICAL IMPLICATIONS: Aboriginal women have unique circumstances relevant to the concept of motherhood that need to be understood to develop culturally relevant policy and programs. The burden of disease and cycle of incarceration within Aboriginal families can be addressed by improving health outcomes for incarcerated Aboriginal mothers and female carers. ORIGINALITY/VALUE: To the authors' knowledge, this is the first literature review on Australian Aboriginal women prisoners' experiences of being a mother. PMID- 30468110 TI - Non-cancer pain clinic in three English prisons: understanding prisoner needs and prescribing practice in relation to chronic non-cancer pain (CNCP). AB - PURPOSE: Prisoner access to opiate-based analgesics and gabapentinoids is a concern to prisons through illicit trading. The purpose of this paper is to describe patient needs following introduction of nine pilot chronic non-cancer pain (CNCP) clinics for chronic pain in three prisons (two male and one female) in the South of England. The study evaluated the effectiveness of this model and assessed the wider practical implementation issues. DESIGN/METHODOLOGY/APPROACH: Clinical notes were reviewed for 63 consultations, anonymised and recorded for secondary analysis. FINDINGS: Alongside CNCP, high levels of substance misuse, physical and mental health histories were noted, especially for female patients. Amitriptyline, pregabalin, gabapentin were the main frontline analgesics prescribed prior to assessment. A total of 41 per cent of patients did not change their medication following the consultation; 25 per cent had their medication increased or reintroduced (greater for women prisoners); with one-third (33 per cent) of patients reducing the prescription of strong opioids and gabapentinoids. Significant differences were noted between male and female patients. Prisoners were amenable to changes in medication to facilitate access to work and other therapeutic interventions. SOCIAL IMPLICATIONS: The prescribing of analgesics has largely been couched in terms of disruption to the prison regime through illicit trading. This study highlights the need to place CNCP within wider contexts of substance misuse, physical and emotional health. There is an opportunity to develop a rehabilitative rather than palliative approach to pain management. Gender specific approaches for female patients should be considered. ORIGINALITY/VALUE: Few studies of CNCP have been conducted within a prison environment. PMID- 30468111 TI - A novel care pathway for prisoners with intellectual disability designed through a Delphi process. AB - PURPOSE: Individuals with an intellectual disability (ID) form a significant minority in the Irish prison population and worldwide prison populations. There is growing recognition that specialist services for such individuals are in need of development. The purpose of this paper is to propose a care pathway for the management of individuals with an ID who present in prison, based on expert elicitation and consensus. DESIGN/METHODOLOGY/APPROACH: A convenience sample of professionals with a special interest in forensic intellectual disabilities was invited to participate in a Delphi exercise. In total, 12 agreed to participation and 10 subsequently completed the study (83.3 per cent). Expert views were elicited using a semi-structured questionnaire. Content analysis was completed using NVivo 11 software. A care pathway was subsequently proposed, based on the outcomes of the analysis, and circulated to participants for debate and consensus. A consensus was reached on management considerations. FINDINGS: Ten experts across a range of disciplines with a combined experience of 187 years participated in the study. Current provision of care was seen as limited and geographically variable. The vulnerability of prisoners with ID was highlighted. The need for equivalence of care with the community through multidisciplinary input and development of specialist secure and residential placements to facilitate diversion was identified. Consensus was achieved on a proposed care pathway. ORIGINALITY/VALUE: This study proposes a care pathway for the assessment and management of prisoners with an ID and is, therefore, potentially relevant to those interested in this topic internationally who may similarly struggle with the current lack of decision-making tools for this setting. Although written from an Irish perspective, it outlines key considerations for psychiatrists in keeping with international guidance and, therefore, may be generalisable to other jurisdictions. PMID- 30468112 TI - Impact of a nature-based intervention on incarcerated women. AB - PURPOSE: The purpose of this paper is to understand the impact of a short-term nature-based intervention on the social-emotional well-being of women incarcerated on a mental health unit in a state prison. DESIGN/METHODOLOGY/APPROACH: This research used a mixed method approach with individual interviews, a focus group and a visual analog scale (VAS). FINDINGS: Qualitative results found that women appreciated the planting party and the way the plants improved the physical environment. Women were also emotionally and relationally impacted by their participation and practiced skills related to planting and working with people. Quantitative results indicate that women were happier, calmer, and more peaceful after the intervention than before. RESEARCH LIMITATIONS/IMPLICATIONS: Study limitations include sample size, self-report data and use of a scale not yet tested for reliability and validity. PRACTICAL IMPLICATIONS: Findings suggest that nature-based interventions can serve as an adjunct to traditional mental health therapies in correctional settings. Nature based interventions can support women's goals to improve their mental health. SOCIAL IMPLICATIONS: Findings suggest that nature-based interventions can serve to improve relationships among incarcerated women, which may make a positive impact on the prison community. Such interventions may also assist them in developing relational and technical skills that are useful upon release. ORIGINALITY/VALUE: To date, there is limited knowledge about the impact of nature based interventions on incarcerated individuals coping with mental health concerns. PMID- 30468113 TI - Contraceptive needs among newly incarcerated women in a county jail in the United States. AB - PURPOSE: The purpose of this paper is to examine the risk of unintended pregnancy among women during Cook County Jail intake by assessing basic contraceptive history, the need for emergency contraception (EC) at intake, and contraception at release. DESIGN/METHODOLOGY/APPROACH: This is a cross-sectional study of women 18-50 years old at Cook County Jail in Chicago, Illinois from June 2011 through August 2012. The authors administered the survey at the time of intake on 33 convenient evenings. Surveys consisted of multiple-choice close-ended questions administered via interview. Topics included contraceptive use, pregnancy risk and pregnancy desire. The authors computed frequencies to describe the distribution of question responses and used logistic regression modeling to identify factors significantly related to the use of contraception at intake and to the acceptance of contraception at release. FINDINGS: Overall, 194 women participated. Excluding women not at risk for pregnancy (4.6 percent currently pregnant, 17.5 percent surgically sterilized/postmenopausal and 4.6 percent using long-acting reversible contraceptives), 73.2 percent of women were at risk for pregnancy ( n = 142) and, therefore, had a potential need for contraception. Among these women at risk for unintended pregnancy, 68 (47.9 percent) had unprotected intercourse within five days prior to survey administration. When asked about EC, most women (81.4 percent) would be interested if available. Additionally, 141 (72.7 percent) of women would be interested in contraceptive supplies if provided free at release. ORIGINALITY/VALUE: Newly incarcerated women are at high risk for unintended pregnancy. Knowledge about EC and ability to access birth control services are both significantly limited. These conclusions support providing an intake screening in jails to identify women at risk for unintended pregnancy. PMID- 30468114 TI - ? PMID- 30468115 TI - [Hemochromatosis related Arthropathy]. AB - Hemochromatosis related Arthropathy Abstract. Hemochromatosis is an autosomal recessive disease that is caused by an HFE gene mutation (High Iron Fe) in most patients. Pathophysiologically, the effect of the mutation is an increased iron absorption in the gut. It is a systemic disorder which, in addition to the involvement of the musculoskeletal system (MSK), can lead to a diabetic metabolic state, liver cirrhosis and skin discoloration, as well as other organ manifestations such as cardiopathy or hypogonadism in the late stages. MSK complications include arthropathy in the form of osteoarthritis, typically of the MCP 2 and 3 joints, and calcium pyrophosphate-associated (CPPD) arthritis. Osteoporosis, as a further complication, is multifactorial. The therapy of hemochromatosis consists of phlebotomy, oral therapy with iron chelators is also possible. Although, these measures have a positive effect on the development of organ complications such as liver cirrhosis, they show little effect on the MSK manifestations, which are treated in analogy to the idiopathic osteoarthritis or pseudogout. The same is true for osteoporosis. PMID- 30468116 TI - [Porphyria - when to think about how to clarify and treat?] AB - Porphyria - when to think about how to clarify and treat? Abstract. Porphyrias are a group of metabolic disorders that are mostly hereditary. They manifest either as abdominal colic or as skin changes at light-exposed areas. During the symptomatic phase the diagnosis of porphyria can be made by cost-effective screening tests. If the screening gives a positive result, further testing is required to determine the exact type of porphyria and to establish the best therapeutic option for the patient in a specialized porphyria center. PMID- 30468117 TI - [Wilson's disease or hepatolenticular degeneration]. AB - Wilson's disease or hepatolenticular degeneration Abstract. Wilson's disease, or hepatolenticular degeneration, is a rare inherited disorder of copper metabolism. The most common clinical presentations are liver disease and / or neuro psychiatric manifestations. Pathophysiologically, Wilson's disease is caused by mutations in the ATP7B gene, which lead to defective biliary excretion of copper and subsequent accumulation of copper in the liver and in other organs. Its prevalence is approximately 1:30 000, however its penetrance, clinical presentation and disease severity vary widely, ranging from asymptomatic elevation of liver enzymes to cirrhosis or acute liver failure with or without neuro-psychiatric symptoms. For this reason, Wilson's disease should be suspected and ruled out in cases of indeterminate liver disease or neuropsychiatric disturbances. The diagnostic algorithms are complex and involve clinical tests, ophthalmologic examination (Kayser-Fleischer rings in split-lamp examination), blood and urine tests, genetic testing, imaging and histology. In compensated liver disease, treatment of Wilson's disease by copper depletion (chelators, zinc) is usually effective. In case of liver failure liver transplantation may be needed, which corrects the underlying error of copper metabolism. New drugs with improved efficacy and tolerability are in clinical development. PMID- 30468118 TI - [The basics of lysosomal storage diseases]. AB - The basics of lysosomal storage diseases Abstract. Lysosomal storage diseases are comprised of a group of more than 50 genetic disorders which are characterized by a defective lysosomal function. The lysosome is the recycling plant of the cell. Most of the lysosomal storage diseases are caused by a deficient hydrolase. The disturbed metabolism leads to accumulation of complex molecules. The classic classification is by the main storage molecule: Sphingolipidoses, Mucopolysaccharidoses and Glycoproteinosis. The modern classification stretches the definition and includes every disease that has a defect in a lysosomal component, which is needed for the normal function of the lysosome. That component includes lysosomal membrane proteins, activator proteins, transport proteins or non-lysosomal proteins. Lysosomal storage disease are rare diseases with a total incidence of 16 cases in 100'000 live births. Results of screening studies are hinting an underestimation of the real incidence. The most frequent lysosomal storage diseases are Gaucher's disease and Fabry's disease, two Sphingolipidoses. The similarity respective the symptoms of lysosomal storage diseases are the systemic manifestations and common cerebral involvement. The occurrence of the symptoms in the different lysosomal storage diseases are very different. The pathophysiological processes are versatile, the simple concept of overload and consecutive destruction of the cell is overdue. Over time a number of therapeutic approaches have been introduced: the substitution of the enzyme by enzyme replacement therapy, gene therapy or hematopoietic stem cell transplantation, stabilizing of the defective enzyme by pharmacologic chaperone or the decrease of the substrate by substrate reduction therapy. PMID- 30468119 TI - [Gaucher's disease - an overview about a sphingolipidosis]. AB - Gaucher's disease - an overview about a sphingolipidosis Abstract. Gaucher's disease is a sphingolipidosis which results from an insufficient production of the enzyme glucocerebrosidase, a lysosomal hydrolase. Glucocerebrosides accumulate particularly in macrophages. There are three types of Gaucher's disease: type 1 shows primarily visceral, hematological and skeletal manifestations. It is the most common type. The types 2 and 3 are rarer and more associated with additional neurologic symptoms. The typical findings are hepatosplenomegaly, hematopoietic diseases and skeletal dysfunctions, caused by the infiltration of the spleen and bone marrow by the glucocerebrosid - loaded macrophages. Dependending on the disease progression, the first symptoms arise in childhood or in adulthood. For the diagnostic of Gaucher's disease, the glucocerebrosidase activity in white blood cells is measured. The intravenous enzyme replacement therapy is effective. PMID- 30468120 TI - [Fabry disease - the profile of an orphan disease]. AB - Fabry disease - the profile of an orphan disease Abstract. Fabry disease is a lysosomal storage disease, characterized by a deficient lysosomal function. The main pathophysiological mechanism is the deficiency of the enzyme alpha galactosidase A. As a result, an accumulation of the substrate globotriaosylceramide occurs in tissues of affected patients. Fabry disease is a X chromosome-linked disease, hence women with one allele often show only mild symptoms. Frequent and unspecific initial symptoms in childhood include acroparesthesias, hypo- and anhidrosis, and angiokeratoma. Life-threatening complications such as progressive kidney insufficiency, cardiomyopathy, and cerebrovascular insult manifest only in later adulthood. The diagnosis requires the measurement of the alpha-galactosidase A activity in blood plasma or white blood cells. Approved therapeutic methods are the enzyme-replacement therapy and pharmacologic chaperone. PMID- 30468121 TI - Cold Atmospheric Plasma Activated Solution: A New Approach for Cancer Treatment. PMID- 30468122 TI - Anti-inflammatory, antioxidant and antiproliferative activities from Trichilia silvatica (C.DC). AB - The aim of this research was to investigate the anti-inflammatory, antiproliferative and antioxidant activities of the leaves (MEL-TS) and bark (MEB TS) from T. silvatica. We evaluated the concentrations of phenolic compounds, condensed tannins, flavonoids, flavonols and HPLC/PDA analysis. MEL-TS and MEB-TS were analysed by LC-PDA, and the results revealed the presence of caffeic acid in both extracts. It showed high total phenolics concentrations (270.8 +/- 17.10 mg GAE/ g extract and 278.8 +/- 25.13 mg GAE/g extract, respectively), and content of flavonoids in MEL-TS (209.30 +/- 2.91 mg QE/g extract). In the antioxidant tests, MEL-TS and MEB-TL exhibited moderate scavenging activities with IC50 values <= 35.32 MUg/mL in lipoperoxidation. Both extracts (30-300 mg/kg) inhibited oedema induced by carrageenan at 2 h and 4 h after carrageenan induction and inhibited leukocyte migration at 6 h post administration. MEL-TS and MEB-TL (100 and 300 mg/kg) did not impact zymosan-induced arthritis in the treated animals. Finally, MEL-TS were particularly effective against VERO and PC 3 cell line resulting in GI50 <= 0.22 MUg/mL. The results indicated that the leaves and bark from T. silvatica has contributed in part to the traditional use of this genus for the treatment of rheumatism/arthritis. PMID- 30468123 TI - Functional diversity of quorum sensing receptors in pathogenic bacteria: Interspecies, intraspecies and interkingdom level. AB - Biofilm formation by pathogenic bacteria is considered as one of the most powerful mechanisms/modes of resistance against the action of several antibiotics. Biofilm is formed as a structural adherent over the surfaces of host, food and equipments etc. and are further functionally coordinated by certain chemicals produced by them. These chemicals are known as quorum sensing (QS) signaling molecules and are involved in the cross talk at inter species, intra-species and interkingdom levels that results in the production of virulence factors involved in pathogenesis. Bacteria possess receptor to sense these chemicals, which interact with the incoming QS molecules. It is followed by the secretion of virulence molecules, regulation of bioluminescence, biofilm formation, antibiotic resistance development and motility behavioral responses. In the natural environment different bacterial species (Gram-positive and Gram negative), produce QS signaling molecules that are structurally and functionally different. Recent and past researches show that various antagonistic molecules (naturally and chemically synthesized) have been characterized to inhibit biofilm formation and attenuation of bacterial virulence by blocking the QS receptors. This review article describes about the diverse QS receptors at their structural, functional and production levels. Thus by blocking these receptors with inhibitory molecules can be potential therapeutic approach to control pathogenesis. Furthermore, these receptors can also be used as structural platform to screen the most potent inhibitors with the help bioinformatics approaches. PMID- 30468124 TI - Investigational Hypoxia-Activated Prodrugs: Making Sense of Future Development. AB - Hypoxia, which occurs in most cancer cases, disrupts the efficacy of anticarcinogens. Fortunately, hypoxia itself is a potential target for cancer treatment. Hypoxia-activated prodrugs (HAPs) can be selectively activated by reductase under hypoxia. Some promising HAPs have been already achieved, and many clinical trials of HAPs in different types of cancer are ongoing. However, none of them has been approved in clinic to date. From the studies on HAPs began, some achievements are gotten but more challenges are put forward. In this paper, we reviewed the research progress of HAPs to discuss the strategies for HAPs development. According to the research status and results of these studies, administration pattern, reductase activity, and patient selection need to be taken into consideration to further improve the efficacy of existing HAPs. As the requirement of new drug research and development, design of optimal preclinical models and clinical trials are quite important in HAPs development, while different drug delivery systems and anticancer drugs with different mechanisms can be sources of novel HAPs. PMID- 30468125 TI - Are cerebral perfusion and atrophy linked in multiple sclerosis? Evidence for a multifactorial approach to assess neurodegeneration. AB - Background Grey matter (GM) atrophy has been extensively described in Multiple Sclerosis (MS) patients, while cerebral hypoperfusion has been less consistently reported. Since hypoperfusion might be related to atrophy, we evaluated the presence of both damages. Objective We aimed to assess if the regions of altered perfusion and atrophy overlapped with one another and if the two parameters were locally related. Method 3D-T1 weighted and arterial spin labelling sequences were acquired using a 1.5T Magnetic Resonance Imaging scanner from 26 relapsing remitting MS patients and 26 healthy controls (HC). GM volume and cerebral blood flow (CBF) differences and their correlation were tested with a voxel-wise approach. Results MS patients (41.4+/-12.5 years; 14 females) had a median [25th 75th percentile range] Expanded Disability Status Scale of 1.0[1.0-2.4] and a median [25th - 75th percentile range] disease duration of 8.0 [4.0 - 16.5] years. HC were age- and sex-matched (43.9+/-17.4 years; 11 females). GM atrophy was detected for MS group in the right parahippocampal gyrus, thalami and left caudate (pFWE<=0.05). Areas of significant (after family wise error -FWE- correction for multiple comparisons) (pFWE<=0.05) hypoperfusion were found for MS in the anterior cingulate and paracingulate gyri, supplementary motor cortex, precentral and superior frontal gyrus. GM volume and CBF showed a significant correlation (pFWE<=0.05) in the right lateral occipital cortex and precuneus in the MS group. Conclusions GM atrophy and hypoperfusion in MS were located in different areas. Perfusion estimate might be used as a further marker of tissue damage, in addition to GM volume. PMID- 30468126 TI - ERK/MAP Kinase activation is evident in activated microglia of the striatum and substantia nigra in an acute and chronically-induced mouse model of Parkinson's Disease. AB - BACKGROUND: Parkinson disease (PD) is one of the most debilitating disorder of the elderly where dopaminergic neurons of the midbrain especially in the substantia nigra (SNc) are damaged. Dopaminergic neurons are synthesized in the midbrain project to the striatum (Caudate-putamen-CPU). Few evidence have suggested that the extracellular signal-regulated kinase 1/2 (ERK 1/2) in the brain is activated after 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure, to our knowledge no study has yet been done to demonstrate whether such activation occurs in neurons or in glia. METHODS: In the current study, we utilized both an acute and chronic model of PD using the neurotoxicant MPTP as the causative agent. Both single and double immunolabeling method as Western Blot methods were employed. RESULTS: Immunohistochemical studies using anti-phospho ERK 1/2 antibodies suggested that ERK 1/2 activation takes place in the striatum (CPU) and SNc of both animal models. Moreover, double immunolabeling studies using phosphor-ERK 1/2 and the microglial marker, CD11b or the astrocyte marker, glial fibrillary acidic protein (GFAP), suggested that the phospho ERK 1/2 was present exclusively in the microglia and not in the astrocytes. Western-blot results suggested that there were no alterations in ERK in either MPTP-treated animals or in control animals; however, phospho ERK 1/2 was found to be significantly increased in the striatum and SNc in both acute chronic mouse PD models. Tyrosine hydroxylase (TH) immunolabeling revealed significant decreases in dopaminergic neurons in the SNc in both animal models' concomitant with activation of microglia and ERK activation. CONCLUSION: These observations suggest that ERK activation takes place following MPTP treatment and that activation of ERK occurs primarily in the microglia. The data provided also suggest that ERK activation may be involved in transcriptional activation of microglia following neurotoxicant insults. PMID- 30468127 TI - NLRP3 Inflammasome Activation Leads to Epileptic Neuronal Apoptosis. AB - BACKGROUND: While the NOD-like receptor protein-3 (NLRP3) inflammasome is involved in a variety of nervous system diseases, its role in epilepsy still needs to be further investigated.

METHODS: The expressions of NLRP3 inflammasome and apoptosis related proteins were examined by Western blot. MTT was used to assess cell viability. The role of NLRP3 inflammasome in epileptic neuronal apoptosis was further validated in NLRP3 knockout (KO) mice by Nissl staining.

RESULTS: Exposure of SH-SY5Y cells to free-Mg2+ solutions increased the expression of NLRP3 inflammasome with a concomitant increase in neuronal apoptosis. This effect was inhibited in cells treated with MCC950 as a common NLRP3 inhibitor, thereby implicating the role of NLRP3 inflammasome in epileptic neuronal apoptosis. In vivo relevance of this finding was further corroborated in the NLRP3 KO mice. Compared with the wild type mice, neuronal loss induced by pentylenetetrazole was significantly inhibited in the NLRP3 KO mice.

CONCLUSION: The study presented herein demonstrates the interaction between NLRP3 inflammasome and epilepsy progression. In addition, MCC950 might represent an important therapeutic drug for the treatment of NLRP3 inflammasome driven epileptogenic activity. PMID- 30468128 TI - Bradykinin Receptors in Ischemic Injury. AB - Bradykinin(BK) is a major kinin substance in the kallikrein-kinin system (KKS) that acts in conjunction with target cell bradykinin receptors and is involved in a variety of systems and organs. Functional regulation and pathophysiological processes such as cardiovascular, renal, central nervous system regulation, glucose metabolism, cell proliferation, smooth muscle contraction, inflammation, pain, shock, and tissue damage processes, etc. The role and mechanism of receptors in the mediation of ischemic injury in tissues was reviewed. PMID- 30468129 TI - Elevated serum human cytomegalovirus IgM levels in the acute phase of ischemic stroke are associated with increased risk of death and major disability. AB - BACKGROUND: There was a lack of studies on the association between human cytomegalovirus (HCMV) infection and prognosis of ischemic stroke, although it was indicated that human cytomegalovirus DNA has played a role in several cardiovascular disorders. OBJECTIVE: To examine the association between HCMV IgM levels in the acute phase and death and major disability after 2 weeks of acute ischemic stroke. METHODS: Serum HCMV IgM levels were measured in 1150 participants in China. Study outcome data on major disability and combined outcome of death and major disability were collected at 2 weeks after stroke onset or hospital discharge. RESULTS: After 2 weeks of follow-up, 351 participants (30.52%) were suffering major disability or died. Serum HCMV IgM was correlated with combined outcome of death and major disability significantly after adjustment confounding factors. For example, the highest quartile of HCMV IgM was related to an odds ratio (95% confidence interval) of 1.84 (1.12-3.11) for the combined outcome. Risk prediction of the combined outcome was improved by the addition of serum HCMV IgM to conventional risk factors (net reclassification index 25.41%, p=0.0002; integrated discrimination improvement 0.70%, p=0.04377). CONCLUSIONS: Elevated serum HCMV IgM levels in the acute phase of ischemic stroke were correlated with increased risk of combined outcome of death and major disability, indicating that serum HCMV IgM could be an important predictive factor for poor prognosis of ischemic stroke. PMID- 30468130 TI - The causative organisms of bacterial meningitis and their antimicrobial resistance profiles in Iranian children in 2011-2016. AB - OBJECTIVES: To describe the identity and antimicrobial resistance patterns of the causative agents of bacterial meningitis in children referred to Children's Medical Center (CMC) Hospital, Tehran, Iran. METHODS: This retrospective study was performed at CMC Hospital during a six year period from 2011 to 2016. The microbiological information of the patients with a diagnosis of bacterial meningitis was collected and the following data were obtained: patients' age, sex, hospital ward, the results of CSF and blood cultures, and the antibiotic susceptibility profiles of isolated organisms. RESULTS: A total of 118 patients with bacterial meningitis were admitted to CMC hospital. Sixty-two percent (n=73) of the patients were male. The median age of the patients was 10 months (interquartile range [IQR]: 2 months-2 years) and the majority of them (n=92, 80%) were younger than 2 years of age. The highest number of patients (n=47, 40%) were admitted to the surgery department. Streptococcus epidermidis was the most frequent isolated bacteria, accounted for 21% of pathogens (n=27/127), followed by Klebsiella pneumoniae (n=20/127, 16%), and Staphylococcus aureus (n=16/127, 12.5%). Blood culture was positive in 28% (n=33/118) of patients. Ampicillin sulbactam and imipenem were the most effective antibiotics against Gram-negative bacteria isolated from CSF cultures. In the case of Gram-positive organisms, ampicillin-sulbactam, vancomycin, and linezolid were the best choices. Imipenem was the most active drug against Gram-negative blood pathogens. Also, ampicillin and vancomycin had the best effect on Gram-positive bacteria isolated from blood cultures. CONCLUSION: Results of this study provide important information about the antibiotic resistance profiles of the etiologic agents of childhood meningitis, which can be used for prescription of more effective empirical therapies. Regarding the variable nature of causative agents of bacterial meningitis and their antibiotic resistance patterns, continuous updating of information on the most common pathogens responsible for meningitis in children and their drug resistance patterns in each region is highly recommended. PMID- 30468131 TI - Insights into Ebola Virus VP35 and VP24 Interferon inhibitory functions and their initial exploitation as drug targets AB - Upon viral infection, the interferon (IFN) system triggers potent antiviral mechanisms limiting viral growth and spread. Hence, to sustain their infection, viruses evolved efficient counteracting strategies to evade IFN control. Ebola virus (EBOV), member of the family Filoviridae, is one of the most virulent and deadly pathogen ever faced by humans. Etiological agent of the Ebola virus disease (EVD), EBOV can be undoubtedly considered the perfect example of a powerful inhibitor of the host organism immune response activation. Particularly, the efficacious suppression of the IFN cascade contributes to disease progression and severity. Among the EBOV-encoded proteins, the viral proteins 35 (VP35) and 24 (VP24) are responsible for the EBOV extreme virulence, representing the core of such inhibitory function through which EBOV determines its very effective shield to the cellular immune defenses. VP35 inhibits the activation of the cascade leading to IFN production, while VP24 inhibits the activation of the IFN stimulated genes. A number of studies demonstrated that both VP35 and VP24 are validated target for drug development. Insights of the structural characteristics of VP35 and VP24 domains revealed crucial pockets exploitable for drug development. Considered the lack of therapy for EVD, restoring the immune activation is a promising approach for drug development. In the present review we summarize the importance of VP35 and VP24 proteins in counteracting the host IFN cellular response and discuss their potential as druggable viral targets as a promising approach toward attenuation of EBOV virulence. PMID- 30468132 TI - Low prevalence of the mcr-1 gene among carbapenemase-producing clinical isolates of Enterobacterales. PMID- 30468134 TI - Culturally Relevant Meanings of the Protestant Work Ethic and Attitudes towards Poor Persons - CORRIGENDUM. PMID- 30468133 TI - Multimorbidity is associated with more subsequent depressive symptoms in three months: a prospective study of community-dwelling adults in Hong Kong. AB - ABSTRACTMultimorbid adults are more likely to have depression. However, existing data are mostly cross-sectional or retrospective with poor control of baseline depressive symptoms and a focus on long-term effects. This prospective study examined the short-term independent predictive association of multimorbidity with depressive symptoms. We collected baseline and three-month follow-up data from a population-based sample of 300 community-dwellers (aged 18-77) in Hong Kong. Multiple regression was used to examine the predictive association of baseline multimorbidity (two or more physical chronic conditions), relative to having one or zero conditions, with depressive symptoms in three months measured by the Center for Epidemiological Studies-Depression (CES-D, out of 60) scale. Multivariable adjustments were made for socio-demographics, baseline CES-D scores, and baseline self-perceived physical health status. A sub-analysis was conducted to compare multimorbid participants with monomorbid (one condition) ones. In our sample, 48 participants (16%) had multimorbidity. Adjusted analysis showed that on average, multimorbid participants had 2.71 (95% CI, 0.36-5.06, Cohen's d = 0.128) more points in the CES-D scale at three-month follow-up than non-multimorbid participants (zero or one condition) did, which was independent of baseline CES-D scores, self-perceived physical health status, and socio demographics. Compared with monomorbid participants, multimorbidity was associated with a similar difference of 2.92 (95% CI, 0.81-5.66, Cohen's d = 0.220) points. Incremental R-square changes associated with the inclusion of multimorbidity were significant (P < 0.05). In conclusion, the effect of multimorbidity on depressive symptoms may take a shorter period to manifest than previously assumed. The mental health of adults with multimorbidity warrants more attention. PMID- 30468135 TI - Cognitive impairment in major depressive disorder. AB - Cognitive dysfunction is a symptomatic domain identified across many mental disorders. Cognitive deficits in individuals with major depressive disorder (MDD) contribute significantly to occupational and functional disability. Notably, cognitive subdomains such as learning and memory, executive functioning, processing speed, and attention and concentration are significantly impaired during, and between, episodes in individuals with MDD. Most antidepressants have not been developed and/or evaluated for their ability to directly and independently ameliorate cognitive deficits. Multiple interacting neurobiological mechanisms (eg, neuroinflammation) are implicated as subserving cognitive deficits in MDD. A testable hypothesis, with preliminary support, posits that improving performance across cognitive domains in individuals with MDD may improve psychosocial function, workplace function, quality of life, and other patient-reported outcomes, independent of effects on core mood symptoms. Herein we aim to (1) provide a rationale for prioritizing cognitive deficits as a therapeutic target, (2) briefly discuss the neurobiological substrates subserving cognitive dysfunction, and (3) provide an update on current and future treatment avenues. PMID- 30468136 TI - Economic evaluation of mindfulness group therapy for patients with depression, anxiety, stress and adjustment disorders compared with treatment as usual. AB - BACKGROUND: A randomised controlled trial found that a structured mindfulness group therapy (MGT) programme was as effective as treatment as usual (mostly cognitive-behavioural therapy) for patients with a diagnosis of depression, anxiety or stress and adjustment disorders in Sweden (ClinicalTrials.gov: NCT01476371).AimsTo perform a cost-effectiveness analysis of MGT compared with treatment as usual from both a healthcare and a societal perspective for the trial duration (8 weeks). METHOD: The costs from a healthcare perspective included treatment as usual, medication and costs for providing MGT. The societal perspective included costs from the healthcare perspective plus savings from productivity gains for the trial duration. The effectiveness was measured as quality-adjusted life-years (QALY) using the EQ-5D-5L questionnaire and the UK value set. Uncertainty surrounding the incremental costs and effects were estimated using non-parametric bootstrapping with 5000 replications and presented with 95% confidence intervals and cost-effectiveness acceptability curves. RESULTS: The MGT group had significantly lower healthcare and societal costs (mean differences -?115 (95% CI -193 to -36) and -?112 (95% CI -207 to -17), respectively) compared with the control group. In terms of effectiveness, there was no significant difference in QALY gain (mean difference -0.003, 95% CI 0.0076 to 0.0012) between the two groups. CONCLUSIONS: MGT is a cost-saving alternative to treatment as usual over the trial duration from both a healthcare and a societal perspective for patients with a diagnosis of depression, anxiety or stress and adjustment disorders in Sweden.Declaration of interestNone. PMID- 30468137 TI - Genome-wide association study of treatment-resistance in depression and meta analysis of three independent samples. AB - BACKGROUND: Treatment-resistant depression (TRD) is the most problematic outcome of depression in terms of functional impairment, suicidal thoughts and decline in physical health.AimsTo investigate the genetic predictors of TRD using a genome wide approach to contribute to the development of precision medicine. METHOD: A sample recruited by the European Group for the Study of Resistant Depression (GSRD) including 1148 patients with major depressive disorder (MDD) was characterised for the occurrence of TRD (lack of response to at least two adequate antidepressant treatments) and genotyped using the Infinium PsychArray. Three clinically relevant patient groups were considered: TRD, responders and non responders to the first antidepressant trial, thus outcomes were based on comparisons of these groups. Genetic analyses were performed at the variant, gene and gene-set (i.e. functionally related genes) level. Additive regression models of the outcomes and relevant covariates were used in the GSRD participants and in a fixed-effect meta-analysis performed between GSRD, STAR*D (n = 1316) and GENDEP (n = 761) participants. RESULTS: No individual polymorphism or gene was associated with TRD, although some suggestive signals showed enrichment in cytoskeleton regulation, transcription modulation and calcium signalling. Two gene sets (GO:0043949 and GO:0000183) were associated with TRD versus response and TRD versus response and non-response to the first treatment in the GSRD participants and in the meta-analysis, respectively (corrected P = 0.030 and P = 0.027). CONCLUSIONS: The identified gene sets are involved in cyclic adenosine monophosphate mediated signal and chromatin silencing, two processes previously implicated in antidepressant action. They represent possible biomarkers to implement personalised antidepressant treatments and targets for new antidepressants.Declaration of interestD.S. has received grant/research support from GlaxoSmithKline and Lundbeck; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen and Lundbeck. S.M. has been a consultant or served on advisory boards for: AstraZeneca, Bristol Myers Squibb, Forest, Johnson & Johnson, Leo, Lundbeck, Medelink, Neurim, Pierre Fabre, Richter. S.K. has received grant/research support from Eli Lilly, Lundbeck, Bristol-Myers Squibb, GlaxoSmithKline, Organon, Sepracor and Servier; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Lundbeck, Pfizer, Organon, Schwabe, Sepracor, Servier, Janssen and Novartis; and has served on speakers' bureaus for AstraZeneca, Eli Lily, Lundbeck, Schwabe, Sepracor, Servier, Pierre Fabre, Janssen and Neuraxpharm. J.Z. has received grant/research support from Lundbeck, Servier, Brainsway and Pfizer, has served as a consultant or on advisory boards for Servier, Pfizer, Abbott, Lilly, Actelion, AstraZeneca and Roche and has served on speakers' bureaus for Lundbeck, Roch, Lilly, Servier, Pfizer and Abbott. J.M. is a member of the Board of the Lundbeck International Neuroscience Foundation and of Advisory Board of Servier. A.S. is or has been consultant/speaker for: Abbott, AbbVie, Angelini, Astra Zeneca, Clinical Data, Boehringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi and Servier. C.M.L. receives research support from RGA UK Services Limited. PMID- 30468138 TI - Growth performance and carcass traits of steers finished on three different systems including legume-grass pasture and grain diets. AB - Inclusion of legume in grass pastures optimizes protein values of the forage and promotes improved digestibility. Therefore, we hypothesized that finishing steers on a novel combination of legumes and grass pasture would produce carcasses with acceptable traits when compared to carcasses from steers finished in feedlot systems. In this study, we evaluated the effects of finishing steers on three systems including: grazing legume-grass pasture containing oats, ryegrass, white and red clover (PAST), grazing PAST plus supplementation with whole corn grain (14 g/kg BW (SUPP)), and on a feedlot-confined system with concentrate only (28 g/kg BW, consisting of 850 g/kg of whole corn grain and 150 g/kg of protein mineral-vitamin supplement (GRAIN)) on growth performance of steers, carcass traits and digestive disorders. Eighteen steers were randomly assigned to one of three dietary treatments and finished for 91 days. Data regarding pasture and growth performance were collected during three different periods (0 to 28, 29 to 56 and 57 to 91 days). Subsequently, steers were harvested to evaluate carcass traits, presence of rumenitis, abomasitis and liver abscesses. The legume-grass pasture provided more than 19% dry matter of protein. In addition, pasture of paddocks where steers were assigned to SUPP and PAST treatments showed similar nutritional quality. When compared to PAST, finishing on SUPP increased total weight gain per hectare, stocking rate, daily and total weight gains. The increase of weight gain was high to GRAIN than SUPP and PAST. Steers finished on GRAIN had high hot carcass weight, fat thickness and marbling score when compared to PAST. However, these attributes did not differ between GRAIN and SUPP. Abomasum lesions were more prevalent in steers finished on GRAIN when compared to PAST. Results of this research showed that it is possible to produce carcasses with desirable market weight and fat thickness by finishing steers on legume grass pasture containing oats, ryegrass, white and red clover. Moreover, supplementing steers with corn when grazing on legume-grass pasture produced similar carcass traits when compared to beef fed corn only. PMID- 30468139 TI - The return of investment of hospital-based surgical quality improvement programs in reducing surgical site infection at a Canadian tertiary-care hospital. AB - OBJECTIVE: We performed a return-on-investment analysis comparing the investment in surgical site infection (SSI) prevention programs in a hospital setting to the savings from averted SSI cases. DESIGN: A retrospective case costing study using aggregated patient data to determine the incidence and costs of SSI infection in surgical departments over time. We calculated return on investment to the hospital and conducted several sensitivity and scenario analyses. SETTING: Data were compiled for the Ottawa Hospital (TOH), a Canadian tertiary-care teaching institution.PatientsWe used aggregated records for all hospital patients who underwent surgical procedures between April 2010 and January 2015.InterventionWe estimated the potential cost savings of the hospital's surgical quality improvement program, namely the Surgeons National Surgical Quality Improvement Program (NSQIP) and the Comprehensive Unit-based Safety Program (CUSP). RESULTS: From 2010 to 2016, TOH invested C$826,882 (US$624,384) in surgical quality improvement programs targeting SSI incidence and accrued C$1,885,110 (US$1,423,460) in cumulative savings from averted SSI cases, generating a return of $2.28 (US$3.02) per dollar invested (95% confidence interval [CI], -0.67 to 7.37). The study findings are sensitive to the estimated cost to the hospital per SSI case and the rate reduction attributable to the prevention program. CONCLUSIONS: The NSQIP and CUSP have produced a positive return on investment at TOH; however, the result rests on several assumptions. This positive return on investment is expected to continue if the hospital can continue to reduce SSI incidence at least 0.25% annually without new investments. Findings from this study highlight the need for continuous program evaluation of the quality improvement initiatives. PMID- 30468140 TI - Top food sources of percentage of energy, nutrients to limit and total gram amount consumed among US adolescents: National Health and Nutrition Examination Survey 2011-2014. AB - OBJECTIVE: To identify most commonly consumed foods by adolescents contributing to percentage of total energy, added sugars, SFA, Na and total gram intake per day. DESIGN: Data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. SETTING: NHANES is a cross-sectional study nationally representative of the US population.ParticipantsOne 24 h dietary recall was used to assess dietary intake of 3156 adolescents aged 10-19 years. What We Eat in America food category classification system was used for all foods consumed. Food sources of energy, added sugars, SFA, Na and total gram amount consumed were sample-weighted and ranked based on percentage contribution to intake of total amount. RESULTS: Three-highest ranked food subgroup sources of total energy consumed were: sugar-sweetened beverages (SSB; 7.8 %); sweet bakery products (6.9 %); mixed dishes - pizza (6.6 %). Highest ranked food sources of total gram amount consumed were: plain water (33.1 %); SSB (15.8 %); milk (7.2 %). Three highest ranked food sources of total Na were: mixed dishes - pizza (8.7 %); mixed dishes - Mexican (6.7 %); cured meats/poultry (6.6 %). Three highest ranked food sources of SFA were: mixed dishes - pizza (9.1 %); sweet bakery products (8.3 %); mixed dishes - Mexican (7.9 %). Three highest ranked food sources of added sugars were: SSB (42.1 %); sweet bakery products (12.1 %); coffee and tea (7.6 %). CONCLUSIONS: Identifying current food sources of percentage energy, nutrients to limit and total gram amount consumed among US adolescents is critical for designing strategies to help them meet nutrient recommendations within energy needs. PMID- 30468141 TI - Memory of Medical Scenarios for End-of-Life Support Preferences. AB - We studied memory of health scenarios for end-of-life support decisions and stability of life support preferences. Psychology students (n = 36, age M = 27.25, SD = 6.21, 64% females) were administered the Life Support Preferences Questionnaire to assess their memory of six medical scenarios with different prognoses, care treatment, and end-of-life support choices. Recall, recognition, confidence and decision stability were assessed immediately and one month later. Correct recall decreased and incorrect recall increased from immediate to long term recall, F(2, 68) = 74.38, p < .001, eta2p = .69. In recall, participants spontaneously gave false information consistent with prior knowledge of illnesses and medical scenarios. Participants who had suffered a disease or serious accident did worse on correct recall, F(1, 34) = 6.59, p = .015, eta2p = .16, and had more errors, F(1, 34) = 4.68, p = .038, eta2p = .12, than participants who had not. In the recognition test there were no differences between hits and false alarms, showing the difficulty in discriminating between true and false contents. Confidence was greater for hits than for false alarms, F(1, 34) = 10.86, p = .002, eta2p = .24, but this subjective measure did not seem to be a good predictor of accuracy because confidence was greater than the mean value for hits (p = .001, d = 1.74) and for false alarms (p = .001, d = 0.96). Long-term memory was quite poor and biased, but life support preferences did not change much. PMID- 30468142 TI - Early-life adversity, later-life mental health, and resilience resources: a longitudinal population-based birth cohort analysis. AB - : ABSTRACTBackground:Robust and persistent links between early-life adversities and later-life mental distress have previously been observed. Individual and social resources are associated with greater mental health and resilience. This study aimed to test these resources as moderators and mediators of the association between childhood psychosocial adversity and later-life mental distress. METHODS: Participant data came from the Medical Research Council National Survey of Health and Development, a nationally-representative birth cohort study. The General Health Questionnaire-28 (GHQ-28) captured mental distress at ages 53, 60-64, and 68-69. An eight-item cumulative psychosocial adversity score was created (0, 1, 2, >=3 adversities). Individual (i.e., education, occupational status, physical activity) and social (i.e., social support, neighborhood cohesion) resources were examined as mediators and moderators of CPA and GHQ-28 in longitudinal multilevel models. FINDINGS: Greater adversity was associated with an average GHQ-28 score increase of 0.017, per unit adversity (beta = 0.017, p < 0.001, 95% CI 0.011, 0.022). Lower mental distress was associated with higher levels of physical activity, occupational status, education, social support, and neighborhood cohesion. There was no evidence that resources moderated the relationship between GHQ-28 and adversity. All resources, save for physical activity and occupational status, partly mediated this relationship. CONCLUSIONS: Individual and social resources were associated with lower mental distress. They did not modify, but partly mediated the association between childhood adversity and adult mental distress. Social support was the most important mediator, suggesting that interventions to promote greater social support may offset psychosocial adversities experienced in childhood to foster better mental health in older adults. PMID- 30468143 TI - Mediators of increased self-harm and suicidal ideation in sexual minority youth: a longitudinal study. AB - BACKGROUND: Sexual minority youth have elevated suicidal ideation and self-harm compared with heterosexual young people; however, evidence for mediating mechanisms is predominantly cross-sectional. Using a longitudinal design, we investigated self-esteem and depressive symptoms as mediators of increased rates of suicidal ideation or self-harm (SISH) among sexual minority youth, and the roles of childhood gender nonconformity (CGN) and sex as moderators of these relationships. METHOD: In total, 4274 youth from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort reported sexual orientation at age 15 years, and past-year SISH at age 20 years. Self-esteem and depressive symptoms were assessed at ages 17 and 18 years, respectively. CGN was measured at 30-57 months. Covariates included sociodemographic variables and earlier measures of mediator and outcome variables. Mediation pathways were assessed using structural equation modelling. RESULTS: Sexual minority youth (almost 12% of the sample) were three times more likely than heterosexual youth to report past-year SISH (95% confidence interval 2.43-3.64) at 20 years. Two mediation pathways were identified: a single mediator pathway involving self-esteem and a multiple mediated pathway involving self-esteem and depressive symptoms. Although CGN was associated with past-year SISH, it did not moderate any mediation pathways and there was no evidence for moderation by sex. CONCLUSIONS: Lower self-esteem and increased depressive symptoms partly explain the increased risk for later suicidal ideation and self-harm in sexual minority youth. Preventive strategies could include self-esteem-enhancing or protecting interventions, especially in female sexual minority youth, and treatment of depression. PMID- 30468144 TI - Sow environment during gestation: part I. Influence on maternal physiology and lacteal secretions in relation with neonatal survival. AB - In pig husbandry, pregnant females are often exposed to stressful conditions, and their outcomes on maternal and offspring health have not been well evaluated. The present study aimed at testing whether improving the welfare of gestating sows could be associated with a better maternal health during gestation, changes in the composition of lacteal secretions and improvement in piglet survival. Two contrasted group-housing systems for gestating sows were used, that is, a French conventional system on slatted floor (C, 49 sows) and an enriched system using larger pens on deep straw (E, 57 sows). On the 105th days of gestation (DG105), sows were transferred into identical farrowing crates on slatted floor. Saliva was collected from all sows on DG35, DG105 and DG107. Blood samples were collected on DG105 from all sows and on the 1st day of lactation (DL1) from a subset of them (C, n=18; E, n=19). Colostrum and milk samples were collected from this subset of sows at farrowing (DL0) and DL4. Saliva concentration of cortisol was greater in C than in E sows at DG35 and DG105, and dropped to concentrations comparable to E sows after transfer into farrowing crates (DG107). On DG105, plasma concentrations of haptoglobin, immunoglobulins G (IgG) and A (IgA), blood lymphocyte counts and plasma antioxidant potential did not differ between groups (P > 0.10), whereas blood granulocyte count, and plasma hydroperoxide concentration were lower in E than in C sows (P < 0.05). Concentrations of IgG and IgA in colostrum and milk did not differ between the two groups. The number of cells did not differ in colostrum but was greater in milk from E than C sows (P < 0.05). Pre-weaning mortality rates were lower in E than C piglets (16.7% v. 25.8%, P < 0.001), and especially between 12 and 72 h postpartum (P < 0.001). Plasma concentration of IgG was similar in E and C piglets on DL4. In conclusion, differences in salivary cortisol, blood granulocyte count and oxidative stress markers between groups suggested improved welfare and reduced immune solicitation during late gestation in sows of the E compared with the C system. However, the better survival observed for neonates in the E environment could not be explained by variations in colostrum composition. PMID- 30468145 TI - Combining mirtazapine with SSRIs or SNRIs for treatment-resistant depression: the MIR RCT. AB - BACKGROUND: Depression is usually managed in primary care and antidepressants are often the first-line treatment, but only half of those treated respond to a single antidepressant. OBJECTIVES: To investigate whether or not combining mirtazapine with serotonin-noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressants results in better patient outcomes and more efficient NHS care than SNRI or SSRI therapy alone in treatment resistant depression (TRD). DESIGN: The MIR trial was a two-parallel-group, multicentre, pragmatic, placebo-controlled randomised trial with allocation at the level of the individual. SETTING: Participants were recruited from primary care in Bristol, Exeter, Hull/York and Manchester/Keele. PARTICIPANTS: Eligible participants were aged >= 18 years; were taking a SSRI or a SNRI antidepressant for at least 6 weeks at an adequate dose; scored >= 14 points on the Beck Depression Inventory-II (BDI-II); were adherent to medication; and met the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, criteria for depression. INTERVENTIONS: Participants were randomised using a computer-generated code to either oral mirtazapine or a matched placebo, starting at a dose of 15 mg daily for 2 weeks and increasing to 30 mg daily for up to 12 months, in addition to their usual antidepressant. Participants, their general practitioners (GPs) and the research team were blind to the allocation. MAIN OUTCOME MEASURES: The primary outcome was depression symptoms at 12 weeks post randomisation compared with baseline, measured as a continuous variable using the BDI-II. Secondary outcomes (at 12, 24 and 52 weeks) included response, remission of depression, change in anxiety symptoms, adverse events (AEs), quality of life, adherence to medication, health and social care use and cost-effectiveness. Outcomes were analysed on an intention-to-treat basis. A qualitative study explored patients' views and experiences of managing depression and GPs' views on prescribing a second antidepressant. RESULTS: There were 480 patients randomised to the trial (mirtazapine and usual care, n = 241; placebo and usual care, n = 239), of whom 431 patients (89.8%) were followed up at 12 weeks. BDI-II scores at 12 weeks were lower in the mirtazapine group than the placebo group after adjustment for baseline BDI-II score and minimisation and stratification variables [difference -1.83 points, 95% confidence interval (CI) 3.92 to 0.27 points; p = 0.087]. This was smaller than the minimum clinically important difference and the CI included the null. The difference became smaller at subsequent time points (24 weeks: -0.85 points, 95% CI -3.12 to 1.43 points; 12 months: 0.17 points, 95% CI -2.13 to 2.46 points). More participants in the mirtazapine group withdrew from the trial medication, citing mild AEs (46 vs. 9 participants). CONCLUSIONS: This study did not find convincing evidence of a clinically important benefit for mirtazapine in addition to a SSRI or a SNRI antidepressant over placebo in primary care patients with TRD. There was no evidence that the addition of mirtazapine was a cost-effective use of NHS resources. GPs and patients were concerned about adding an additional antidepressant. LIMITATIONS: Voluntary unblinding for participants after the primary outcome at 12 weeks made interpretation of longer-term outcomes more difficult. FUTURE WORK: Treatment-resistant depression remains an area of important, unmet need, with limited evidence of effective treatments. Promising interventions include augmentation with atypical antipsychotics and treatment using transcranial magnetic stimulation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN06653773; EudraCT number 2012-000090-23. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 63. See the NIHR Journals Library website for further project information. PMID- 30468146 TI - Decision and navigation in mouse parietal cortex. AB - Posterior parietal cortex (PPC) has been implicated in navigation, in the control of movement, and in visually-guided decisions. To relate these views, we measured activity in PPC while mice performed a virtual navigation task driven by visual decisions. PPC neurons were selective for specific combinations of the animal's spatial position and heading angle. This selectivity closely predicted both the activity of individual PPC neurons, and the arrangement of their collective firing patterns in choice-selective sequences. These sequences reflected PPC encoding of the animal's navigation trajectory. Using decision as a predictor instead of heading yielded worse fits, and using it in addition to heading only slightly improved the fits. Alternative models based on visual or motor variables were inferior. We conclude that when mice use vision to choose their trajectories, a large fraction of parietal cortex activity can be predicted from simple attributes such as spatial position and heading. PMID- 30468147 TI - Markers of Atherosclerosis: Part 1 - Serological Markers. AB - Atherosclerosis is a major contributor to morbidity and mortality worldwide. With therapeutic consequences in mind, several risk scores are being used to differentiate individuals with low, intermediate or high cardiovascular (CV) event risk. The most appropriate management of intermediate risk individuals is still not known, therefore, novel biomarkers are being sought to help re-stratify them as low or high risk. This narrative review is presented in two parts. Here, in Part 1, we summarise current knowledge on serum (serological) biomarkers of atherosclerosis. Among novel biomarkers, high sensitivity C-reactive protein (hsCRP) has emerged as the most promising in chronic situations, others need further clinical studies. However, it seems that a combination of serum biomarkers offers more to risk stratification than either biomarker alone. In Part 2, we address genetic and imaging markers of atherosclerosis, as well as other developments relevant to risk prediction. PMID- 30468149 TI - Perinatal form hypophosphatasia caused by a novel large duplication of ALPL gene and one year follow-up under enzyme replacement therapy; a case report. AB - Hypophosphatasia is a rare disease caused by mutations in the gene encoding tissue-nonspecific isoenzyme of alkaline phosphatase. Duplications of the ALPL gene account for fewer than 1% of the mutations causing HPP. It has been shown that asfotase alfa treatment mineralizes the skeleton and improves respiratory function and survival in severe forms of hypophosphatasia. The newborn was evaluated for respira!tory failure and generalized hypotonia after birth. Diagnosis of HPP was based on low-serum ALP activity, high levels of substrates of tissue-nonspecific isoenzyme of alkaline phosphatase and radiologic findings. On day 21 after birth, enzyme replacement therapy using asfotase alfa (2 mg/kg three times per week, subcutaneous injection) was started. We were able to discharge our patient when he was 7 months old. His respiratory support was gradually reduced and skeletal mineralization improved during treatment. No mutation was detected in the ALPL gene by all exon sequencing, and additional analysis was done by quantitative polymerase chain reaction. As a result, a novel homozygote duplication encompassing exons 2 to 6 was detected. Early diagnosis and rapid intervention with enzyme replacement therapy is life-saving in the severe form of hypophosphatasia. Quantitative polymerase chain reaction can detect duplications if a mutation cannot be detected by sequence analysis in patients with hypophosphatasia. PMID- 30468148 TI - A Cleidocranial Dysplasia Case with a Novel Mutation and Growth Velocity Gain with Growth Hormone Treatment. AB - Cleidocranial dysplasia (CCD) is a rare congenital autosomal dominant skeletal disorder that is characterized by hypoplasia or aplasia of clavicles, failure of cranial suture closure, dental anomalies, short stature and other changes in skeletal patterning and growth. The gene responsible for pathogenesis has been mapped on the short arm of chromosome 6p21, Core Binding Factor Alpha-1 (CBFA1) or Runt Related Transcription Factor 2 (RUNX2). Here we describe a CCD patient with a novel mutation in the RUNX2 gene. An eight-and-a-half years old girl presented with severe short stature, dysmorphic facial appearance (hypertelorism, prominent forehead, high palate, midfacial hypoplasia), macrocephaly, large anterior fontanel, increased anteroposterior chest diameter when she was five-and a-half years old. Her shoulders were close to each other and her bilateral clavicles seemed too short on physical examination. Bilateral hypoplastic clavicles, coxa valga, hypoplasia of iliac bones wide symphysis pubis and phalangeal dysplastic features were detected on her skeletal x-ray examination. She was diagnosed as having CCD. Molecular analysis detected a novel heterozygous mutation 'NM_001024630.3 p. T155P(c.463A>C)' in the RUNX2 gene. Because of her severe short stature growth hormone (GH) treatment was started and she responded well to this one-year therapy with no adverse effects. In conclusion hypoplasia or aplasia of the clavicles, failure of cranial suture closure, dental anomalies, and short stature should bring CCD to mind. We present a novel mutation in the RUNX2 gene for CCD. We obtained growth velocity gain with GH treatment in our patient. PMID- 30468150 TI - Theory for the negative longitudinal magnetoresistance in the quantum limit of Kramers Weyl semimetals. AB - Negative magnetoresistance is rare in non-magnetic materials. Recently, negative magnetoresistance has been observed in the quantum limit of beta-Ag2Se, where only one band of Landau levels is occupied in a strong magnetic field parallel to the applied current. beta-Ag2Se is a material that hosts a Kramers Weyl cone with band degeneracy near the Fermi energy. Kramers Weyl cones exist at time-reversal invariant momenta in all symmorphic chiral crystals, and at a subset of these momenta, including the Gamma point, in non-symmorphic chiral crystals. Here, we present a theory for the negative magnetoresistance in the quantum limit of Kramers Weyl semimetals. We show that, although there is a band touching similar to those in Weyl semimetals, negative magnetoresistance can exist without a chiral anomaly. We find that it requires screened Coulomb scattering potentials between electrons and impurities, which is naturally the case in beta-Ag2Se. PMID- 30468151 TI - A definition of bioinks and their distinction from biomaterial inks. AB - Biofabrication aims to fabricate biologically functional products through bioprinting or bioassembly (Groll et al 2016 Biofabrication 8 013001). In biofabrication processes, cells are positioned at defined coordinates in three dimensional space using automated and computer controlled techniques (Moroni et al 2018 Trends Biotechnol. 36 384-402), usually with the aid of biomaterials that are either (i) directly processed with the cells as suspensions/dispersions, (ii) deposited simultaneously in a separate printing process, or (iii) used as a transient support material. Materials that are suited for biofabrication are often referred to as bioinks and have become an important area of research within the field. In view of this special issue on bioinks, we aim herein to briefly summarize the historic evolution of this term within the field of biofabrication. Furthermore, we propose a simple but general definition of bioinks, and clarify its distinction from biomaterial inks. PMID- 30468152 TI - Special issue on bioinks. PMID- 30468153 TI - Porous tissue strands: avascular building blocks for scalable tissue fabrication. AB - The scalability of cell aggregates such as spheroids, strands, and rings has been restricted by diffusion of nutrient and oxygen into their core. In this study, we introduce a novel concept in generating tissue building blocks with micropores, which represents an alternative solution for vascularization. Sodium alginate porogens were mixed with human adipose-derived stem cells, and loaded into tubular alginate capsules, followed by de-crosslinking of the capsules. The resultant cellular structure exhibited a porous morphology and formed cell aggregates in the form of strands, called 'porous tissue strands (pTSs).' Three dimensional reconstructions show that pTSs were able to maintain ~25% porosity with a high pore interconnectivity (~85%) for 3 weeks. Owing to the porous structure, pTSs showed up-regulated cell viability and proliferation rate as compared to solid counterparts throughout the culture period. pTSs also demonstrated self-assembly capability through tissue fusion yielding larger-scale patches. In this paper, chondrogenesis and osteogenesis of pTSs were also demonstrated, where the porous microstructure up-regulated both chondrogenic and osteogenic functionalities indicated by cartilage- and bone-specific immunostaining, quantitative biochemical assessment and gene expression. These findings indicated the functionality of pTSs, which possessed controllable porosity and self-assembly capability, and had great potential to be utilized as tissue building blocks in distinct applications such as cartilage and bone regeneration. PMID- 30468154 TI - ARPES studies on new types of electron-doped cuprate superconductors. AB - For more than thirty years since the discovery of superconductivity in cuprates, it has been widely agreed that the superconductivity is realized by doping a charge-transfer insulator with charge carriers through chemical substitution. For electron-doped cuprates, however, the recent development of reduction annealing methods has enabled superconductivity for a very small amount of or even without chemical substitution. In this article, we review recent angle-resolved photoemission spectroscopy studies on the new types of electron-doped cuprates with particular emphasis on the effect of reduction annealing. The presented results provide us with renewed insight into the phase diagram and the nature of the pseudogap not only on the electron-doped side but also in the entire doping range including hole doping. PMID- 30468155 TI - Peculiar covalent bonding of C60/6H-SiC(0 0 0 1)-(3 * 3) probed by photoelectron spectroscopy. AB - High resolution photoemission with synchrotron radiation was used to study the interface formation of a thin layer of C60 on 6H-SiC(0 0 0 1)-(3 * 3), characterized by protruding Si-tetramers. The results show that C60 is chemisorbed by orbital hybridization between the highest-occupied molecular orbital (HOMO) and the p z orbital of Si adatom at the apex of the tetramers. The covalent nature of the bonding was inferred from core level as well as valence band spectra. The Si 2p spectra reveal that a large fraction (at least 45%) of the Si adatoms remain unbound despite the reactive character of the associated dangling bonds. This is consistent with a model in which each C60 is attached to the substrate through a single covalent C60-Si bond. A binding energy shift of the core levels associated with sub-surface Si or C atoms indicates a decrease of the SiC band bending caused by a charge transfer from the C60 molecules to the substrate via the formation of donor-like interface states. PMID- 30468156 TI - High-accuracy large-scale DFT calculations using localized orbitals in complex electronic systems: the case of graphene-metal interfaces. AB - Over many years, computational simulations based on density functional theory (DFT) have been used extensively to study many different materials at the atomic scale. However, its application is restricted by system size, leaving a number of interesting systems without a high-accuracy quantum description. In this work, we calculate the electronic and structural properties of a graphene-metal system significantly larger than in previous plane-wave calculations with the same accuracy. For this task we use a localised basis set with the Conquest code, both in their primitive, pseudo-atomic orbital form, and using a recent multi-site approach. This multi-site scheme allows us to maintain accuracy while saving computational time and memory requirements, even in our exemplar complex system of graphene grown on Rh(1 1 1) with and without intercalated atomic oxygen. This system offers a rich scenario that will serve as a benchmark, demonstrating that highly accurate simulations in cells with over 3000 atoms are feasible with modest computational resources. PMID- 30468157 TI - Lysozyme-Antimicrobial Peptide Fusion Protein Promotes the Diabetic Wound Size Reduction in Streptozotocin (STZ)-Induced Diabetic Rats. AB - BACKGROUND Lysozymes and antibacterial peptides have been confirmed to protect humans against viral and bacterial infection, and accelerate wound healing. The study aimed to evaluate the effect of lysozyme-antimicrobial peptide fusion protein on the diabetic wound size reduction in streptozotocin (STZ)-induced diabetic rats. MATERIAL AND METHODS Diabetic rats were prepared via intraperitoneal injection of STZ, 70 mg/kg. A 2-cm circular incision with full thickness was made on the dorsum skin of the rats for preparation of diabetic wound model. The wounds were treated with the fusion protein or phosphate buffer saline. RESULTS The fusion protein markedly accelerated wound healing, decreased levels of proinflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha, lipid peroxide (LPO) content, and expression of cyclooxygenase-2 (COX-2), and increased activities of antioxidant enzyme including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in serum, levels of pro-angiogenic cytokines such as vascular endothelial growth factor (VEGF) and intercellular adhesion molecule (ICAM-1), and expression of VEGF, FGF-2, p-ERK, and p-Akt protein in granulation. CONCLUSIONS The results of the present study suggested that the fusion protein accelerated wound healing by improving anti-inflammation and antioxidant, and increasing angiogenesis in granulation tissues of diabetic rats. PMID- 30468158 TI - Publisher Correction: Single-cell RNA-seq reveals cell type-specific transcriptional signatures at the maternal-foetal interface during pregnancy. AB - This corrects the article DOI: 10.1038/ncomms11414. PMID- 30468159 TI - Strong protection for restorative work. PMID- 30468160 TI - Mouthwash and diabetes - a cause for concern? AB - Mouthwash use and risk of diabetes. PMID- 30468161 TI - Finding the perfect match. PMID- 30468163 TI - Security that can't be beaten. PMID- 30468162 TI - ADI Team Congress 2019 - Speakers announced. PMID- 30468164 TI - Ideal practice handpiece cover. PMID- 30468165 TI - Help on hand for struggling dentists. PMID- 30468166 TI - Use of safety syringes for administration of local anaesthesia among a sample of UK primary care dental professionals. PMID- 30468168 TI - Budget will mean less spending on workforce training. PMID- 30468167 TI - Human papillomavirus (HPV) and its vaccine: awareness and opinions of clinical dental students in a UK dental school. PMID- 30468170 TI - Support you can rely on. PMID- 30468169 TI - The difference between using a device or investing in a philosophy. PMID- 30468171 TI - Connected toothbrushes: Bridging the gap to personalized oral health. PMID- 30468172 TI - Effect of a single-tufted toothbrush on the control of dental biofilm in orthodontic patients: A randomised clinical trial. PMID- 30468173 TI - Study authors call on NICE to change guidelines on antibiotic prophylaxis. PMID- 30468174 TI - Are we letting neglect infect? AB - Paediatric dento-facial infections - a potential tool for identifying children at risk of neglect? PMID- 30468175 TI - Are bristle stiffness and bristle end-shape related to adverse effects on soft tissues during toothbrushing? A systematic review. PMID- 30468176 TI - Sugar; tax and reformulation. PMID- 30468177 TI - AI software traces a perfect ID nerve in 4.5 seconds - a first in dental history. PMID- 30468179 TI - Library retirement. PMID- 30468178 TI - Dental professionals' opinions and knowledge of smoking cessation and electronic cigarettes: a cross-sectional survey in the north of England. PMID- 30468180 TI - Orthodontics course on offer. PMID- 30468181 TI - Jonathan Shepherd: 'People are entitled to their own opinions but not their own facts'. PMID- 30468183 TI - Mind the gap. AB - This article looks at the provision of professional indemnity in the UK, what the different products are and the importance of making choices appropriate to your needs to fulfil the statutory and ethical obligation to have appropriate indemnity as a registered dentist. PMID- 30468182 TI - Complete dentures: an update on clinical assessment and management: part 2. AB - The ability to provide high quality complete dentures remains an important skill for general dental practitioners. The prevalence of edentulism is increasingly concentrated within an older patient cohort and general dental practitioners may face challenges associated with providing care for these patients. This two-part series explores various aspects of complete denture provision and is designed to act as a refresher on the management of edentulous patients. This second part focuses on the copy denture technique as well as discussing strategies for assessing and managing gag reflexes, prominent palatal and lingual tori and microstomia. PMID- 30468184 TI - David Robert Stevenson. PMID- 30468185 TI - Oral health waits another seven UN years. AB - An opportunity for oral health to be placed on the agendas of world leaders and policy makers arose and was then omitted at a recent meeting of the General Assembly of the United Nations (UN). The opening arose during a high-level meeting (27 Sept 2018) that was convened to discuss the global impact of non communicable diseases. However, in the event, oral health was never singled out during the presentations nor was it included in the final political declaration committing signatories to take action on its 34 clauses. Sadly, the next opportunity is not until 2025. PMID- 30468186 TI - The secret to a new smile. PMID- 30468187 TI - A heavenly practice. PMID- 30468188 TI - Health secretary's 'prevention drive' plan underwhelms. PMID- 30468190 TI - CDO issues advice following EpiPen supply disruption. PMID- 30468189 TI - Pharmacology: Dangerous interactions. PMID- 30468191 TI - Mouthwash use and risk of diabetes. AB - Many people in the UK use mouthwash on a regular basis. Recently, a longitudinal study conducted in Puerto Rico that monitored overweight and obese adults over a three-year period (which included periodontal and oral hygiene assessments) concluded that those using mouthwash twice daily or more at baseline had an approximately 50% increased risk of developing prediabetes/diabetes combined, compared to those who used mouthwash less than twice daily or not at all. The proposed mechanism to explain this is that mouthwash has antibacterial effects in the oral cavity, yet oral bacteria play an important role in the salivary nitrate nitrite-nitric oxide pathway, and reduced levels of nitric oxide are associated with insulin resistance as well as adverse cardiovascular effects such as hypertension and impaired vascular function. However, methodological limitations in the study bring into question the generalisability of the findings. In this article, the important role of oral bacteria in the production of nitric oxide is discussed, and the findings of the Puerto Rican study are considered in detail. It is important that dental professionals are aware of emerging research on this topic as patients frequently ask for advice on use of mouthwash as part of their oral hygiene regime. PMID- 30468193 TI - Dentists face 13% fee hike for care inspection. PMID- 30468192 TI - Two major breakthroughs in composite technology. PMID- 30468194 TI - Urgent action on HPV vaccine needed to protect boys. PMID- 30468195 TI - Proven alternatives. PMID- 30468196 TI - Treating gum disease could help manage type 2 diabetes. PMID- 30468197 TI - Effective implant imaging. PMID- 30468199 TI - Oral health gap in rich and poor areas is worsening. PMID- 30468198 TI - Dental trauma: Better communication between hospital and primary dental services. PMID- 30468200 TI - Leslie John Brinton. PMID- 30468201 TI - The effect of toothbrushing and flossing sequence on interdental plaque reduction and fluoride retention: A randomised controlled clinical trial. PMID- 30468202 TI - The ultimate guide to restoration longevity in England and Wales. Part 9: incisor teeth: restoration time to next intervention and to extraction of the restored tooth. PMID- 30468204 TI - Oral health left out of global health goals. PMID- 30468203 TI - The world of capitation. PMID- 30468205 TI - Mouth cancer: Dentists central to fight against oral cancer in new action plan. PMID- 30468206 TI - 90 second working time and 10 second cure. PMID- 30468207 TI - [Psychological examinations in occupational health services: Legal regulations. Part II]. AB - This paper constitutes a continuation of the critical analysis of legal aspects of psychological examinations in some group of workers. In this part the appeal procedure, documentation, costs of examinations and supervision are discussed. The analysis has shown many deficiencies in regulations related to all aspects of psychological examinations. They arise from incoherence of legal regulations and the lack of regulations of some questions. This legal standing is restricted to occupational work and adversely affects the quality of supplied services. Therefore acts of law and regulations relevant to psychological examinations for the purpose of fitness-to-work certification need necessary adjustments. According to authors it is desirable to end the legal procedure amending the act of law on a profession of psychology and the self-government of psychologists, as well as to develop and implement executive regulations. Med Pr 2018;69(6). PMID- 30468209 TI - Findings of Research Misconduct. PMID- 30468208 TI - Polish infection control nurses - Self-assessment of their duties and professional autonomy in different types of hospitals. AB - BACKGROUND: The objective of the study is self-assessment of Polish infection control nurses (ICNs) in terms of the structure of professional tasks and autonomy of decision-making. MATERIAL AND METHODS: A questionnaire survey was filled out by 208 ICNs (around 21% of all Polish ICNs) in 15 provinces located in Poland. The research encompassed ICNs surveillance healthcare-associated infections (HAIs) in 2014. RESULTS: The work time that ICNs devote to professional tasks and decision autonomy on the scale of 1-100% was as follows: 34% (67% of decision autonomy) was dedicated to detecting and registering HAIs, 12% (71%) to internal control, 10% (58%) to devising and implementing infection prevention practices, 10% (68%) - staff trainings, 8% (65%) - identification and study of outbreaks, 7% (58%) - promoting hand hygiene, 6% (51%) - consults with infected patients, 4% (57%) - consults on decontamination, 4% (54%) - consults on maintaining cleanliness, 3% (51%) - isolation and application of personal protective measures, 2% - other tasks. Infection prevention and control nurses estimated, on average, that their autonomy of decisions concerning the professional tasks performed amounted to 60%. CONCLUSIONS: Infection control nurses in Poland have difficulty in achieving balance between tasks they perform and the authority they exercise. The ICN professional task structure is dominated by duties associated with monitoring hospital infections, however, the greatest decision autonomy is visible regarding internal control. Decision-making concentrated on internal control may hinder building a positive image of an ICN. We should strive to firmly establish professional tasks and rights of ICNs in legislation concerning performing the duties of a nurse and midwife. Med Pr 2018;69(6). PMID- 30468210 TI - Phenyl-gamma-valerolactones and phenylvaleric acids, the main colonic metabolites of flavan-3-ols: synthesis, analysis, bioavailability, and bioactivity. AB - Covering: 1958 to June 2018Phenyl-gamma-valerolactones (PVLs) and their related phenylvaleric acids (PVAs) are the main metabolites of flavan-3-ols, the major class of flavonoids in the human diet. Despite their presumed importance, these gut microbiota-derived compounds have, to date, in terms of biological activity, been considered subordinate to their parent dietary compounds, the flavan-3-ol monomers and proanthocyanidins. In this review, the role and prospects of PVLs and PVAs as key metabolites in the understanding of the health features of flavan 3-ols have been critically assessed. Among the topics covered, are proposals for a standardised nomenclature for PVLs and PVAs. The formation, bioavailability and pharmacokinetics of PVLs and PVAs from different types of flavan-3-ols are discussed, taking into account in vitro and animal studies, as well as inter individual differences and the existence of putative flavan-3-ol metabotypes. Synthetic strategies used for the preparation of PVLs are considered and the methodologies for their identification and quantification assessed. Metabolomic approaches unravelling the role of PVLs and PVAs as biomarkers of intake are also described. Finally, the biological activity of these microbial catabolites in different experimental models is summarised. Knowledge gaps and future research are considered in this key area of dietary (poly)phenol research. PMID- 30468211 TI - [Ge(TenBu)4] - a single source precursor for the chemical vapour deposition of germanium telluride thin films. AB - Reaction of activated germanium with nBu2Te2 in THF solution was shown to be more effective for the preparation of the germanium(iv) tellurolate compound, [Ge(TenBu)4], than reaction of GeCl4 with LiTenBu in a 1 : 4 molar ratio in THF. The product was characterised by 1H, 13C{1H} NMR spectroscopy and microanalysis and evaluated as a single source precursor for the low pressure chemical vapour deposition of GeTe thin films. Depending upon deposition conditions, either dull grey films (predominantly elemental Te) or highly reflective (GeTe) films were obtained from the pure precursor. Grazing incidence X-ray diffraction shows that the highly reflective films are comprised of the rhombohedral alpha-GeTe phase, while scanning electron microscopy and energy dispersive X-ray analysis reveal rhomb-shaped crystallites with a 49(1) : 51(1)% Ge : Te ratio. This structure is also confirmed from Raman spectra. Van der Pauw measurements show rho = 3.2(1) * 10-4 Omega cm and Hall electrical measurements indicate that the GeTe thin films are p-type, with a mobility of 8.4(7) cm2 V-1 s-1 and carrier concentration of 2.5(2) * 1021 cm-3. The high p-type concentration is most likely a result of the substantial Ge vacancies in its sub-lattice, in line with the EDX elemental ratios. PMID- 30468212 TI - Reduction of double manganese-cobalt oxides: in situ XRD and TPR study. AB - The work reported here was aimed at determining differences in redox properties of simple and double oxides. Comparison between the reduction of double oxides (Mn,Co)3O4 and simple oxides Co3O4 and Mn3O4 was performed using in situ X-ray diffraction (XRD), temperature-programmed reduction (TPR) and transmission electron microscopy (TEM). The double oxides with a ratio of cations Mn : Co = 1 : 1 were prepared by the coprecipitation method and contained a mixture of 50% MnCo2O4 and 50% CoMn2O4. It was shown that the mechanism of reduction of double oxides with hydrogen differs significantly from the processes occurring on simple oxides. For simple cobalt and manganese oxides, transformations Co3O4-> CoO -> Co and Mn3O4-> MnO are observed under a hydrogen atmosphere. The reduction of mixed metal oxides occurs in two steps. In the first step, at 300-450 degrees C, (Mn,Co)3O4 transforms to (Mn,Co)O solid solutions. In situ XRD under isothermal conditions illustrates that Co-rich Co2MnO4 oxide starts to be reduced to Co0.6Mn0.4O first, and then Mn-rich Mn2CoO4 passes into Mn0.6Co0.4O. In the second step, at 450-700 degrees C, the reduction of solid solutions (Mn,Co)O to metallic cobalt Co and MnO proceeds. Again, the reduction begins with transformation of Co-rich oxide with the Co0.6Mn0.4O structure. The temperature of appearance of the intermediate phase (Mn,Co)O shifts to the higher values as compared to those observed for CoO, and to lower temperatures as compared to MnO during simple oxide reduction. PMID- 30468213 TI - Photoactivatable platinum anticancer complex can generate tryptophan radicals. AB - l-Tryptophan (Trp), melatonin (MLT) and the Trp-peptide pentagastrin quenched the formation of azidyl radicals generated on irradiation of the anticancer complex trans,trans,trans-[Pt(pyridine)2(N3)2(OH)2] with visible light, giving rise to C3 centred indole radicals which were characterized for Trp and MLT using an EPR spin-trap; indole, together with azidyl and hydroxyl radicals, have potential roles in a multitargeting mechanism of action against resistant cancers. PMID- 30468214 TI - Polymer-antibiotic conjugates as antibacterial additives in dental resins. AB - Affecting the vast majority of human beings, dental caries is a premier concern of worldwide dental health. As the most commonly used restorative material to treat dental caries, resin-based composites (RBCs) lack antibacterial properties leading to quite limited restoration lifetimes. The objective of this study is to develop a polymer-antibiotic conjugate (PAC) as an effective antibacterial additive for RBCs. A monomer-antibiotic conjugate (MAC) with significant solubility was prepared by an esterification reaction of tert-butyloxycarbonyl (Boc)-protected ciprofloxacin (Cip) and 2-hydroxyethyl methacrylate (HEMA). The Cip-containing PAC with well-controlled molecular weight and composition was synthesized by reversible addition-fragmentation chain transfer (RAFT) copolymerization of the MAC with HEMA (1 : 3 molar ratio), followed by the removal of Boc from the resulting copolymer. The antibacterial dental resin was then prepared by incorporating the PAC into a commercial resin, and their properties and antibacterial performance against Streptococcus mutans were tested. In vitro experiments revealed a very slow release of Cip, which resulted in significant killing effectiveness against Streptococcus mutans nonetheless, as observed through zone of inhibition assessment and SEM imaging. The promising antibacterial properties of these resins indicate that incorporating a PAC as an additive is a valid strategy to generate antibacterial materials for dental applications. PMID- 30468215 TI - Optimum driving energy for achieving balanced open-circuit voltage and short circuit current density in organic bulk heterojunction solar cells. AB - Organic bulk heterojunction solar cells generally suffer from a trade-off between the open circuit voltage (Voc) and the short circuit current density (Jsc) under a given donor/acceptor (D/A) interfacial energetic offset (or the so-called driving force). Here we theoretically investigate the optimum driving energy required for achieving the balanced Jsc and Voc simultaneously. To this end, the Jscversus the driving force DeltaE curves are calculated under two different charge separation mechanisms by employing the drift-diffusion method. For the Marcus incoherent mechanism, the curve features a high plateau in a broad range of DeltaE starting from 0.2 eV, which is due to the accumulation of undissociated excitons within their lifetime and signifies the possibility of obtaining a sizable Jsc under a DeltaE value much smaller than the reorganization energy. After incorporating both the electron and hole transfer pathways into the device model, the calculated J-V curves are comparable to experimentally measured ones foractual blended systems of different driving forces. For the coherent mechanism, it is demonstrated that the maximum Jsc can also be achieved under the DeltaE of 0.2 eV if a large proportion of the high-lying delocalized states are harvested through tuning the density of states for the charge transfer excitons to reduce the sub-gap states. This theoretical work revealed quantitatively the relationship between the interfacial energy offsets and device performance, and also provides some guidelines for identifying the macroscopic features of the actual charge separation mechanisms in bulk heterojunction solar cells. PMID- 30468216 TI - Membrane-mediated transport in a non-equilibrium hybrid protocell based on coacervate droplets and a surfactant. AB - A hybrid protocell is constructed to investigate the membrane transport of neutral, cationic, and anionic molecules under non-equilibrium conditions. Each model molecule follows a specific pathway to be internalized and generates different distributions in the droplets. This work provides a step towards functionalization of synthetic protocells capable of biomimetic operations. PMID- 30468217 TI - A review of methods for the detection of pathogenic microorganisms. AB - The testing and rapid detection of pathogenic organisms is a crucial protocol in the prevention and identification of crises related to health, safety and wellbeing. Pathogen detection has become one of the most challenging aspects in the food and water industries, because of the rapid spread of waterborne and foodborne diseases in the community and at significant costs. With the prospect of inevitable population growth, and an influx of tourism to certain water bodies testing will become a requirement to control and prevent possible outbreaks of potentially fatal illnesses. The legislation is already particularly rigorous in the food industry, where failure to detect pathogenic materials represents a catastrophic event, particularly for the elderly, very young or immune compromised population types. In spite of the need and requirement for rapid analytical testing, conventional and standard bacterial detection assays may take up to seven days to yield a result. Given the advent of new technologies, biosensors, chemical knowledge and miniaturisation of instrumentation this timescale is not acceptable. This review presents an opportunity to fill a knowledge gap for an extremely important research area; discussing the main techniques, biology, chemistry, miniaturisation, sensing and the emerging state of-the-art research and developments for detection of pathogens in food, water, blood and faecal samples. PMID- 30468218 TI - Dual enzyme-assisted one-step isothermal real-time amplification assay for ultrasensitive detection of polynucleotide kinase activity. AB - A novel, simple, one-step and one-tube detection method was developed for ultrasensitive detection of polynucleotide kinase (PNK) activity on the basis of dual enzyme-synergistic signal amplification. This method was also demonstrated to work well for PNK inhibitor screening and endogenous PNK detection in cell lysates at a single-cell level. PMID- 30468219 TI - Probing the binding mode and unbinding mechanism of LSD1 inhibitors by combined computational methods. AB - Lysine specific demethylase 1 (LSD1) has emerged as a potential drug target in cancer therapy and a variety of inhibitors have been reported. We have recently reported the discovery of a series of triazole-dithiocarbamate based compounds, which were basically confirmed as cofactor flavin adenine dinucleotide (FAD) competing inhibitors by experiments. However, the binding modes of the inhibitors to the binding site were undetermined. Here, we employed computational methods including molecular docking, classical molecular dynamics (MD) and steered molecular dynamics (SMD) simulations to investigate the potential binding modes of these inhibitors to LSD1. Based on the high correlation between the mean non equilibrium pulling work W and experimental binding affinity, we identified the optimal binding modes of this class of compounds with LSD1. Using the optimal inhibitor binding conformation, we then performed SMD to study the ligand unbinding mechanism with a lower pulling velocity at 0.0005 nm ps-1. We found that residue Arg316 plays a crucial role in the binding/unbinding process. Furthermore, a gatekeeper residue Trp756 influences the ligand unbinding process by acting like a switch via steric hindrance but can enhance the hydrophobic interaction with the inhibitor. Hydrophobic interaction also dominated the interaction between LSD1 and the inhibitors. The pivotal residues and interactions between LSD1 and inhibitors determined from this study can be used to improve the inhibition activity of this series of inhibitors in development and to discover new scaffolds as FAD-competing inhibitors in compound screening. PMID- 30468220 TI - Repurposing antitubercular agent isoniazid for treatment of prostate cancer. AB - The development of versatile antitumor agents with tumor-imaging, targeting and therapeutic activity is promising for clinical cancer therapy. Prostate cancer is still the one of the leading threats to males. Current therapies have restricted clinical efficiency for patients with advanced and metastatic prostate cancer. Recent studies demonstrate that monoamine oxidase A (MAOA) levels elevate with prostate cancer aggression and metastasis. In addition, MAOA inhibitor therapies have been reported as an effective means to reduce the metastasis of prostate cancer and extend mouse survival. Thus, these findings provide evidence that MAOA is promising for the treatment of metastatic and advanced prostate cancer. Herein, three isoniazid (INH)-dye conjugates were synthesized by conjugating MAOA inhibitor INH with mitochondria-targeting NIRF heptamethine dyes to improve the therapeutic efficacy of prostate cancer. These INH-dye conjugates could accumulate in PC-3 cellular mitochondria via organic anion transport peptide (OATP), increase ROS generation, and induce cancer cells apoptosis. In prostate cancer bearing xenografts, INH-dye conjugates showed significantly improved tumor homing characteristics, resulting in potent antitumor activity via a reduction in MAOA activity. These results suggest that INH-dye conjugates have great potential to be used as versatile antitumor agents with prostate cancer targeting, NIR imaging, and potent antitumor efficacy. PMID- 30468221 TI - Insights into the reaction mechanism of n-hexane dehydroaromatization to benzene over gallium embedded HZSM-5: effect of H2 incorporated on active sites. AB - The catalytic dehydroaromatization of alkanes to aromatics has attracted considerable attention from the scientific community, because it can be used for the upgrading of low-cost alkanes into high added-value aromatics, such as benzene, toluene, and xylene (BTX). In this context, we report the reaction mechanism of n-hexane dehydroaromatization to benzene over two different reduced gallium species embedded in HZSM-5, including univalent Ga+ embedded in HZSM-5 (Ga/HZSM-5) and dihydrido gallium complex (GaH2+) embedded in HZSM-5 (GaH2/HZSM 5) by using the M06-2X/6-31G(d,p) level of calculation. The reaction proceeds by following two main steps: (i) the dehydrogenation of hexane to haxa-1,3,5-triene; (ii) the dehydroaromatization of haxa-1,3,5-triene to benzene. For the univalent Ga+ embedded in HZSM-5, the first step of the hexane dehydrogenation is considered to be the rate-determining step, which requires a high activation energy of 76.6 kcal mol-1. In strong contrast to this, in the case of the GaH2/HZSM-5 catalyst the rate determining step is found to be the second hydrogen abstraction from n-hexane with a lower activation barrier of 11.1 kcal mol-1. The reaction is therefore preferentially taking place over the GaH2/HZSM-5 catalyst. These observations clearly confirm the existence of a dihydrido gallium complex (GaH2+) as one of the most active species for the dehydroaromatization of alkanes and it is obtained in the presence of hydrogen in the catalytic system. This example opens up perspectives for a better understanding of the effect of active species on the catalytic reaction. PMID- 30468222 TI - Regioselective 5'-position phosphorylation of ribose and ribonucleosides: phosphate transfer in the activated pyrophosphate complex in the gas phase. AB - Herein, we present a rapid, efficient and regioselective phosphorylation method at the 5'-position of unprotected ribose and ribonucleosides with pyrophosphate in the gas phase, which involves the formation of anionic complexes via electrospray ionization and collisional activation to induce phosphorylation within the complexes. PMID- 30468223 TI - Molecular dynamics study on the heterogeneous nucleation of liquid Al-Cu alloys on different kinds of copper substrates. AB - Al-Cu alloys are widely used in aeronautics and aerospace engineering because they exhibit outstanding performance. However, their casting characteristics are poor. Heterogeneous nucleation plays a significant role in controlling crystal growth. MD simulations are performed to explore the heterogeneous nucleation of liquid Al-Cu on a copper substrate including the heat-up process, preservation process, and freezing process. The simulation results show that the Al-Cu melt becomes layered at the liquid-solid interface and tends to be ordered in the structure because of the induced effect from the substrate. The crystal structure information is found to be gradually delivered from the substrate to the liquid, and this transmission capacity of information decays with increasing distance from the substrate. The liquid Al-Cu alloy with high copper content frozen on the single substrate tends to form a perfect crystal structure more easily, but the Al-Cu melt with low copper content between two copper substrates tends to form an arch-shaped structure, which can disappear when the copper content reaches a specific proportion. Moreover, different angles of the grooved substrates also affect the heterogeneous nucleation of the Al-Cu melt and its solidified structure. Our findings provide new insights into the defect and structural changes during heterogeneous nucleation, and our findings also promote leading edge studies, which can provide new ideas to mechanical research. PMID- 30468224 TI - Significant enhancement of conductance of a hybrid layered molybdate semiconductor by light or heat. AB - Introduction of the viologen cation, a well-known electron acceptor, into molybdate layers led to a dramatic change in the conductance of the 2D hybrid material in the process of photo-induced or thermo-induced coloration, which provides an alternative approach to manipulate the electronic properties of 2D semiconductors via external optical/thermal stimuli. PMID- 30468225 TI - Ultra-small Mo2N on SBA-15 as a highly efficient promoter of low-loading Pd for catalytic hydrogenation. AB - Decreasing Pd usage whilst maintaining a superior performance is promising, but remains a challenge in the catalytic field. Herein, we have demonstrated the highly efficient promotion of Mo2N with a reduced amount of Pd for the liquid phase hydrogenation reaction. The Mo2N (2-3 nm) was uniformly anchored onto mesoporous SBA-15 by using PMo12 as the Mo source. The small size and good dispersion of Mo2N is favourable for allowing their effective contact with post loading Pd. This good contact is conducive to developing a synergistic catalyst, which was verified by studying the liquid-phase hydrogenation of p-nitrophenol (PNP) to p-aminophenol (PAP) with NaBH4 as the H source. The conversion ability of PNP to PAP on 1 wt% Pd-Mo2N/SBA-15 was vastly superior to 1 wt% Pd/SBA-15 and even better than 20 wt% Pd/SBA-15. The low-Pd, highly efficient catalysis is ascribed to the transfer of the electrons from Mo2N to Pd for the easy activation of H. The synergy can be affected by the type of support used. SBA-15 is superior to SiO2 and the other supports, which could be related to the large surface area and the plentiful number of pores on SBA-15, which is favourable to the dispersion of Pd and Mo2N, and the transfer/diffusion of the reactants. In particular, a highly efficient catalyst can be achieved at an even more reduced Pd loading (0.05 wt%). The current method describes the design of a highly efficient catalyst for the hydrogenation reaction using low amounts of noble metals. PMID- 30468226 TI - Fluorescent peptide displacement as a general assay for screening small molecule libraries against RNA. AB - A prominent hurdle in developing small molecule probes against RNA is the relative scarcity of general screening methods. In this study, we demonstrate the application of a fluorescent peptide displacement assay to screen small molecule probes against four different RNA targets. The designed experimental protocol combined with statistical analysis provides a fast and convenient method to simultaneously evaluate small molecule libraries against different RNA targets and classify them based on affinity and selectivity patterns. PMID- 30468227 TI - Correction: Rewritable full-color computer-generated holograms based on color selective diffractive optical components including phase-change materials. AB - Correction for 'Rewritable full-color computer-generated holograms based on color selective diffractive optical components including phase-change materials' by Chi Young Hwang et al., Nanoscale, 2018, DOI: 10.1039/c8nr04471f. PMID- 30468228 TI - Optical radiation stability of ZnO hollow particles. AB - Zinc oxide has multifunctional physical properties depending on its microstructure and morphology. Herein, we reported the in situ investigations of the radiation stability of ZnO particles with hollow, ball, star and flower shapes under electron and proton irradiation. 100 keV protons with a fluence of 5 * 1015 cm-2 and 50 keV electrons with fluence ranging from 0.5 to 7 * 1016 cm-2 are employed to investigate the radiation stability of nanostructured ZnO particles. In situ reflectance, X-ray photoelectron spectra and photoluminescence were characterized in the irradiation environment to avoid the effects of the atmospheric environment on radiation induced defects. The experimental results reveal that, compared to the other shapes, the hollow structure with the best radiation stability due to the hollow structure facilitates the decrease of the accumulation of radiation defects. This study clearly demonstrates the promise of ZnO hollow particles as a plasmonic nanostructure for achieving high radiation stability, and they could be easily employed to serve as the radiation stability pigment for coatings. PMID- 30468229 TI - Hydroximoyl fluorides as the precursors of nitrile oxides: synthesis, stability and [3 + 2]-cycloaddition with alkynes. AB - The transformation of hydroximoyl fluorides to nitrile oxides for [3 + 2] cycloaddition with alkynes has been achieved for the first time. The hydroximoyl fluorides used in this work appeared to be not stable, which was proved by a series of experiments. A DFT calculation was performed to better understand the properties of hydroximoyl fluorides. Although not stable, the hydroximoyl fluorides could be successfully converted to the corresponding nitrile oxides for in situ [3 + 2]-cycloaddition with alkynes to yield the isoxazoles. Furthermore, it was feasible to conduct [3 + 2]-cycloaddition reaction without purification after the synthesis of hydroximoyl fluorides from gem-difluoroalkenes. By investigating a class of interesting yet previously rarely explored fluorinated compounds, this work sheds new light on the stability and reactivity of a C-F bond on a C[double bond, length as m-dash]N double bond. PMID- 30468230 TI - Reliability of rare-earth-doped infrared luminescent nanothermometers. AB - The use of infrared-emitting rare-earth-doped luminescent nanoparticles as nanothermometers has attracted great attention during the last few years. The scientific community has identified rare-earth-doped luminescent nanoparticles as one of the most sensitive and versatile systems for contactless local temperature sensing in a great variety of fields, but especially in nanomedicine. Researchers are nowadays focused on the design and development of multifunctional nanothermometers with new spectral operation ranges, outstanding brightness, and enhanced sensitivities. However, no attention has been paid to the assessment of the actual reliability of the measurements provided by rare-earth-doped luminescent nanothermometers. In fact, it is assumed that they are ideal temperature sensors. Nevertheless, this is far from being true. In this work we demonstrate that the emission spectra of rare-earth-doped nanothermometers can be affected by numerous environmental and experimental factors. These include the numerical aperture of the optical elements used for their optical excitation and luminescence collection, the local concentration of nanothermometers, optical length variations, self-absorption of the luminescence by the nanothermometers themselves, and solvent optical absorption. This work concludes that rare-earth doped luminescent nanothermometers are not as reliable as thought and, consequently, special care has to be taken when extracting temperature estimations from the variation of their emission spectra. PMID- 30468231 TI - 'Nano on micro' hierarchical porous all carbon structures: an insight into interfacial interactions with bacteria. AB - Micron long carbon nanofibers (CNFs) were grown on porous carbon beads to give an active surface for rapid immobilization of guest molecules. The fabrication of nanostructures using a catalytic route involving chemical vapour deposition on a porous substrate was accomplished by the controlled synthesis of iron nanoclusters on the surface of porous carbon beads. The challenge of catalyst nanoparticle diffusion into the porous substrate was addressed by using iron coordinated ligand complexes and optimizing the loading percentage of metal salts onto beads. The effect of using tethered bottom up surface processed CNFs on the porous beads' morphologies was established using structural characterization. The protruding architecture of CNFs on the porous carbon surface was subjected to bacterial colonisation in order to determine the efficiency of cell conjugation onto hairy structures, particularly at a low concentration. The interfaces of immobilized bacteria on the textured surface were studied by varying the pH and external physical stimuli to check the biofilm formation. The strategy of fabricating all carbon porous beads, which had topologically controlled 'nano on micro' geometries, to give fast immobilization of guest molecules could be useful in the future for developing an active disinfectant surface. PMID- 30468232 TI - A dynamic stretchable and self-healable supercapacitor with a CNT/graphene/PANI composite film. AB - Conventional flexible supercapacitors can work under consecutive bending, folding and even twisting without performance degradation. Nevertheless, these devices can hardly be used under large tensile strain. Flexible stretchable and healable supercapacitors are highly desired due to their many potential applications in electric devices. However, it is challenging to fabricate supercapacitors that can withstand stretchability and self-healability. Herein, we report a stretchable and self-healable supercapacitor based on a carbon nanotube@graphene@PANI nanowire film. The supercapacitor possesses high energy density from 36.3 to 29.4 MUW h cm-2 with the corresponding power density changing from 0.17 to 5 mW cm-2 at a current from 0.1 to 3 mA, and the highest capacitive performance can reach up to 261.5 mF cm-2. In terms of the bending test, the supercapacitor can operate under different static bending angles and dynamic bending conditions with different bending frequencies, and the capacitance was merely affected. Moreover, the supercapacitor can sustain a tensile strain up to 180% and 80.2% capacitance retention after the 10th healing cycle. This novel design integrating all stretchable and healable components provides a pathway toward the next generation of wearable energy devices in modern electronics. PMID- 30468233 TI - Correction: Conceptual design and analysis of ITM oxy-combustion power cycles. AB - Correction for 'Conceptual design and analysis of ITM oxy-combustion power cycles' by N. D. Mancini et al., Phys. Chem. Chem. Phys., 2011, 13, 21351-21361. PMID- 30468234 TI - Tandem fluorescence and Raman (fluoRaman) characterisation of a novel photosensitiser in colorectal cancer cell line SW480. AB - The development of new imaging tools, molecules and modalities is crucial to understanding biological processes and the localised cellular impact of bioactive compounds. A small molecule photosensitiser, DC473, has been designed to be both highly fluorescent and to exhibit a strong Raman signal in the cell-silent region of the Raman spectrum due to a diphenylacetylene structure. DC473 has been utilised to perform a range of novel tandem fluorescence and Raman (fluoRaman) imaging experiments, enabling a thorough examination of the compound's cellular localisation, exemplified in colorectal cancer cells (SW480). This multifunctional fluoRaman imaging modality revealed the presence of the compound in lipid droplets and only a weak signal in the cytosol, by both Raman and fluorescence imaging. In addition, Raman microscopy detected the compound in a cell compartment we labelled as the nucleolus, whereas fluorescence microscopy did not detect the fluoRaman probe due to solvatochromatic effects in a local polar environment. This last finding was only possible with the use of tandem confocal Raman and fluorescence methods. By following the approach detailed herein, incorporation of strong Raman functional groups into fluorophores can enable a plethora of fluoRaman experiments, shedding further light on potential drug compound's cellular behaviour and biological activity. PMID- 30468236 TI - Characterization of inflammatory breast cancer: a vibrational microspectroscopy and imaging approach at the cellular and tissue level. AB - Inflammatory breast cancer (IBC) has a poor prognosis because of the lack of specific biomarkers and its late diagnosis. An accurate and rapid diagnosis implemented early enough can significantly improve the disease outcome. Vibrational spectroscopy has proven to be useful for cell and tissue characterization based on the intrinsic molecular information. Here, we have applied infrared and Raman microspectroscopy and imaging to differentiate between non-IBC and IBC at both cell and tissue levels. Two human breast cancer cell lines (MDA-MB-231 and SUM-149), 20 breast cancer patients (10 non-IBC and 10 IBC), and 4 healthy volunteer biopsies were investigated. Fixed cells and tissues were analyzed by FTIR microspectroscopy and imaging, while live cells were studied by Raman microspectroscopy. Spectra were analyzed by hierarchical cluster analysis (HCA) and images by common k-means clustering algorithms. For both cell suspensions and single cells, FTIR spectroscopy showed sufficient high inter group variability to delineate MDA-MB-231 and SUM-149 cell lines. Most significant differences were observed in the spectral regions of 1096-1108 and 1672-1692 cm-1. Analysis of live cells by Raman microspectroscopy gave also a good discrimination of these cell types. The most discriminant regions were 688 992, 1019-1114, 1217-1375 and 1516-1625 cm-1. Finally, k-means cluster analysis of FTIR images allowed delineating non-IBC from IBC tissues. This study demonstrates the potential of vibrational spectroscopy and imaging to discriminate between non-IBC and IBC at both cell and tissue levels. PMID- 30468237 TI - Integrated nanoscale deterministic lateral displacement arrays for separation of extracellular vesicles from clinically-relevant volumes of biological samples. AB - Extracellular vesicles (EVs) offer many opportunities in early-stage disease diagnosis, treatment monitoring, and precision therapy owing to their high abundance in bodily fluids, accessibility from liquid biopsy, and presence of nucleic acid and protein cargo from their cell of origin. Despite their growing promise, isolation of EVs for analysis remains a labor-intensive and time consuming challenge given their nanoscale dimensions (30-200 nm) and low buoyant density. Here, we report a simple, size-based EV separation technology that integrates 1024 nanoscale deterministic lateral displacement (nanoDLD) arrays on a single chip capable of parallel processing sample fluids at rates of up to 900 MUL h-1. Benchmarking the nanoDLD chip against commonly used EV isolation technologies, including ultracentrifugation (UC), UC plus density gradient, qEV size-exclusion chromatography (Izon Science), and the exoEasy Maxi Kit (QIAGEN), we demonstrate a superior yield of ~50% for both serum and urine samples, representing the ability to use smaller input volumes to achieve the same number of isolated EVs, and a concentration factor enhancement of up to ~3* for both sample types, adjustable to ~60* for urine through judicious design. Further, RNA sequencing was carried out on nanoDLD- and UC-isolated EVs from prostate cancer (PCa) patient serum samples, resulting in a higher gene expression correlation between replicates for nanoDLD-isolated EVs with enriched miRNA, decreased rRNA, and the ability to detect previously reported RNA indicators of aggressive PCa. Taken together, these results suggest nanoDLD as a promising alternative technology for fast, reproducible, and automatable EV-isolation. PMID- 30468238 TI - Could resistant starch supplementation improve inflammatory and oxidative stress biomarkers and uremic toxins levels in hemodialysis patients? A pilot randomized controlled trial. AB - An imbalance of gut microbiota is considered a new cardiovascular risk factor for chronic kidney disease (CKD) patients, since it is directly associated with increased uremic toxin production, inflammation and oxidative stress. Strategies such as prebiotic supplementation have been suggested to mitigate these complications. We hypothesized that prebiotic-resistant starch could ameliorate uremic toxins levels, oxidative stress, and inflammatory states in hemodialysis (HD) patients. This pilot study evaluated 31 HD patients assigned to either resistant starch (16 g of resistant starch Hi-Maize(r) 260) or placebo (manioc flour) supplementation, which they received for 4 weeks on alternate days through cookies on dialysis days and powder in a sachet on non-dialysis days. Levels of interleukin (IL)-6, high-sensitive C-reactive protein, thiobarbituric acid reactive substances plasma (TBARS), protein carbonylation, indoxyl sulfate (IS) and p-cresyl sulfate were measured. Anthropometric and biochemical parameters, as well as, food intake were also evaluated. As expected, resistant starch group increased fiber intake (p > 0.01), in addition the prebiotic supplementation reduced IL-6 (p = 0.01), TBARS (p > 0.01), and IS (p > 0.01) plasma levels. No significant differences were evident in the placebo group. Prebiotic-resistant starch supplementation seems to be a promising nutritional strategy to improve inflammation, oxidative stress and to reduce IS plasma levels in CKD patients on HD. PMID- 30468239 TI - Overcoming the Challenging Cervix: Identification and Techniques to Access the Uterine Cavity. AB - Importance: Cervical stenosis is a challenging clinical entity that requires prompt identification and management in order to avoid iatrogenic injury at the time of endocervical canal cannulation. Objective: The aim of this study was to identify cervical stenosis and discuss associated etiologies, risk factors, and review medical and surgical approaches for overcoming cervical stenosis. Evidence Acquisition: Computerized searches of MEDLINE and PubMed were conducted using the key words "cervix", "cervical stenosis," "embryo transfer," "hysteroscopy complications," "misoprostol," and "ultrasound." References from identified sources were manually searched to allow for a thorough review. Data from relevant sources were compiled to create this review. Results: Transcervical access to the uterine cavity is frequently required for procedures such as hysteroscopy, dilation and curettage, endometrial biopsy, sonohysterogram, hysterosalpingogram, intrauterine insemination, embryo transfer in those undergoing in vitro fertilization, and insertion of intrauterine devices. These procedures can become complicated when difficult cannulation of the endocervical canal is encountered. Management strategies include preprocedural use of cervical-ripening agents or osmotic dilators, ultrasound guidance, no-touch vaginoscopy, manual dilatation, and hysteroscopic resection of the obstructed endocervical canal. Conclusions and Relevance: Cervical stenosis is associated with iatrogenic complications that can result in significant patient morbidity. In patients undergoing in vitro fertilization, difficult embryo transfer is associated with lower pregnancy rates. The clinician should carefully consider the patient's menopausal status, risk factors, and symptoms in order to anticipate difficult navigation of the endocervical canal. Various medical and surgical management strategies, including hysteroscopic resection, can be used to overcome the stenotic cervix. PMID- 30468240 TI - Current First-line Therapy for Ovarian Cancer: A Comprehensive Review. AB - Importance: Ovarian, fallopian tube, and primary peritoneal cancers constitute the deadliest gynecologic malignancies. After primary cytoreductive surgery, there are several standard first-line cytotoxic treatments for providers to consider. Newer molecular targeted therapies are becoming more common and may have a role as first-line therapy in the future. Objective: This article provides an evidence-based review of all approved standard therapies for first-line treatment of advanced-stage, high-grade serous ovarian cancer. Treatment schedules, dose modifications, and drug substitutions are reviewed. Ongoing trials and pending approvals for newer molecular therapies are discussed. Evidence Acquisition: A comprehensive primary literature review was performed using MEDLINE, the Cochrane Collaborative Database, and PubMed. Guidelines from the National Comprehensive Cancer Network and the Society for Gynecologic Oncology were also reviewed. Results: Seven different approved first-line regimens for high-grade serous ovarian cancer are available based on literature review. These vary in route of administration, dose intensity, drug combinations, and treatment schedules. Molecular targeted therapies, including antiangiogenic drugs and poly(ADP-ribose) polymerase inhibitors, have also been studied in multiple randomized controlled trials in the first-line setting. Conclusions and Relevance: Cytotoxic regimens remain the foundation of first-line treatment for high-grade serous ovarian cancer. Choosing which regimen is best for a patient depends on both patient and disease factors. Molecular therapies in first-line treatment are a promising and exciting possibility, with regulatory approval pending. PMID- 30468235 TI - Correction: The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research. AB - Correction for 'The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research' by James B. McAlpine et al., Nat. Prod. Rep., 2018, DOI: 10.1039/c7np00064b. PMID- 30468241 TI - Predictive data mining for diagnosing periodontal disease: the Korea National Health and Nutrition Examination Surveys (KNHANES V and VI) from 2010 to 2015. AB - OBJECTIVES: This study aimed to identify patients with the highest risk of periodontal disease (PD), and to provide recommendations for the effective use and application of data mining (DM) techniques when establishing evidence-based dental-care policies for vulnerable groups at a high risk of PD. METHODS: This study used the SEMMA (Sample, Explore, Modify, Model, and Assess) methodology to construct DM models based on data acquired from the fifth and sixth Korea National Health and Nutrition Examination Surveys (2000-2015). We analyzed the sociodemographic and comorbidity variables that influence PD by applying the popular DM techniques of decision-tree, neural-network, and regression models, and also attempted to improve the predictive power and reliability by comparing the results obtained by these three models. RESULTS: Our comparisons of the three DM algorithms confirmed that the average squared error, misclassification rate, receiver operating characteristic index, Gini coefficient, and Kolmogorov-Smirnov test results were the most appropriate for the decision-tree model. The analysis of the decision-tree model revealed that age and smoking status exert major effects on the risk of PD, and that stress and education level exert effects in rural areas, whereas education level, sex, hyperlipidemia, and alcohol intake exert effects in urban areas. CONCLUSIONS: We demonstrated that the decision-tree model is an effective DM technique for identifying the complex risk factors for PD. These results are expected to be helpful in improving the equality and efficacy of dental-care policies for vulnerable groups at a high risk of PD. PMID- 30468242 TI - The effects of cryotherapy on vocal fold healing in a rabbit model. AB - OBJECTIVES/HYPOTHESIS: Cryotherapy has been shown to be a scarless treatment modality for dermal lesions; however, there are limited data addressing the effect of cryotherapy on vocal fold tissue. The aim of this study was to clarify the effectiveness of cryotherapy for prevention of postsurgical vocal fold scarring. STUDY DESIGN: Prospective animal study in rabbits. METHODS: The lamina propria of 20 rabbit vocal folds was bilaterally stripped, followed by randomized unilateral cryotherapy. Five larynges were harvested for real-time polymerase chain reaction (RT-PCR) analysis at 1 day, 3 days, and 7 days postinjury. The remaining five were harvested for histologic analysis at 3 months. Images of the healing phase were recorded by laryngoscopy. Analyses of RT-PCR for cyclooxygenase (COX)-2, interleukin (IL)-6, collagen I, collagen III, matrix metallopeptidase 1 (MMP1), transforming growth factor beta (TGFbeta1), alpha smooth muscle actin (alpha-SMA), and hyaluronan synthase 1 (HAS1) were completed. Histological samples were completed for collagen and hyaluronic acid analysis. RESULTS: RT-PCR results revealed that higher expressions of HAS1 and MMP1 and lower expressions of COX-2, IL-6, collagen I, collagen III, TGFbeta1, and alpha SMA were observed, and histological examination showed significantly increased hyaluronic acid, decreased deposition, and more organized configuration of collagen in injury with the cryotherapy cohort compared with the injury cohort. CONCLUSIONS: Cryotherapy can inhibit the inflammatory reaction and simulate a fetal healing environment in extracellular matrix synthesis to regenerate vocal fold tissue with less fibrosis. Histological results showed that cryotherapy achieves a mature healing result with less scar, which tends to return to normal. In summary, the findings of this study suggest that administration of cryotherapy at the time of injury has the potential to minimize vocal fold scarring. LEVEL OF EVIDENCE: NA Laryngoscope, 2018. PMID- 30468243 TI - A controlled trial of HNSCC patient-derived xenografts reveals broad efficacy of PI3Kalpha inhibition in controlling tumor growth. AB - Head and neck squamous cell carcinomas (HNSCCs) frequently harbor alterations in the PI3K/AKT/mTOR signalling axis, particularly in the PIK3CA gene. PI3K-targeted agents have therefore gained considerable preclinical and clinical interest as emerging therapies for HNSCC. Identification of predictive biomarkers of response would advance the clinical application of PI3K-targeted drugs for patients in order to achieve maximal benefit. To date, studies of drug biomarkers have largely focused on screening cell lines, with much more limited in vivo testing, usually only as validation. This approach has rarely enabled accurate predictions of clinical efficacy. Recently, clinical trials of PDX models (PDX clinical trials) have been introduced as a preclinical approach to interrogate interpatient response heterogeneity. Already, PDX clinical trial responses have been demonstrated to correlate closely with patient outcomes. Here, using both an HNSCC specific, 28-cell line panel and a PDX clinical trial of 80 xenografts derived from 20 unique HNSCC tumors, we systematically examine patterns of response to PI3K inhibition in HNSCC. We find EGFR, AKT1 and CSMD1 copy number aberrations, but not PIK3CA mutations, to be associated with responsiveness to PI3K-targeted drugs. Further, we reveal PI3Kalpha inhibition to be almost globally tumoristatic in HNSCC xenografts regardless of PIK3CA mutational status, emphasizing its potential as a stabilizing neoadjuvant therapy for HNSCC patients. PMID- 30468244 TI - Relative preferences for edible and leisure stimuli in children with autism. AB - Prior researchers have reported a tendency for individuals with developmental disabilities to select edible items more often than leisure items when those items are presented together in stimulus preference assessments. However, children with autism spectrum disorders (ASD), with whom many behavior analysts currently practice, are underrepresented in this body of literature. We conducted a replication of prior research with 26 children with ASD. Results indicated that edible items were more likely than leisure items to rank highly in our preference assessments, in concurrence with prior research. However, leisure items were also selected more often overall than in prior research, and significant individual variation was observed. These results suggest that preference assessments containing both edible and leisure stimuli can yield useful information for behavior analysts providing services to children with ASD, and the degree of preference for edible items noted in prior work may not be reflected in this contemporary population. PMID- 30468245 TI - Strong associations of a healthy lifestyle with all stages of colorectal carcinogenesis: results from a large cohort of participants of screening colonoscopy. AB - The risk of developing colorectal cancer (CRC) is associated with a wide range of dietary and lifestyle factors. The individual contribution of single modifiable factors, such as alcohol consumption, physical activity, smoking, body mass index (BMI) or dietary components, to the development of CRC has been investigated extensively, but evidence on their combined effect at various stages of colorectal carcinogenesis is sparse. The aim of this study was to analyze the association of a healthy lifestyle pattern with prevalence of early and advanced colorectal neoplasms. A total of 13,600 participants of screening colonoscopy in Saarland/Germany (mean age 62.9 years) who were enrolled in the KolosSal study (Effektivitat der Fruherkennungs-Koloskopie: eine Saarland-weite Studie) from 2005 until 2013 were included in this cross-sectional analysis. Dietary and lifestyle data were collected and colonoscopy results were extracted from physicians' reports. The association of an a priori defined healthy lifestyle score - including dietary intake, alcohol consumption, physical activity, smoking and BMI - with early and advanced colorectal neoplasms was assessed by multiple logistic regression analyses with comprehensive adjustment for potential confounders. Strong inverse dose-response relationships were observed between an overall healthier lifestyle pattern and presence of advanced colorectal neoplasms, non-advanced adenomas and hyperplastic polyps (p value <0.0001 in all cases), with adjusted odds ratios (95% CI) for the highest compared to the lowest category of the healthy lifestyle score of 0.41 (0.30-0.56), 0.42 (0.33-0.54) and 0.39 (0.29-0.54) respectively. A healthy lifestyle is strongly associated with lower risk of all stages of colorectal neoplasms. This article is protected by copyright. All rights reserved. PMID- 30468247 TI - Robust regression: Testing global hypotheses about the slopes when there is multicollinearity or heteroscedasticity. AB - A well-known concern regarding the usual linear regression model is multicollinearity. As the strength of the association among the independent variables increases, the squared standard error of regression estimators tends to increase, which can seriously impact power. This paper examines heteroscedastic methods for dealing with this issue when testing the hypothesis that all of the slope parameters are equal to zero via a robust ridge estimator that guards against outliers among the dependent variable. Included are results related to leverage points, meaning outliers among the independent variables. In various situations, the proposed method increases power substantially. PMID- 30468246 TI - Clinical Features Contributing to Cortical Thickness Changes in Chronic Migraine A Pilot Study. AB - OBJECTIVES: The objectives of this cross-sectional pilot study were threefold: to identify regions of cortical thickness that differentiate chronic migraine (CM) from controls, to assess group differences in interregional cortical thickness covariance, and to determine group differences in associations between clinical variables and cortical thickness. BACKGROUND: Cortical thickness alterations in relation to clinical features have not been adequately explored in CM. Assessment of this relationship can be useful to describe cortical substrates for disease progression in migraine and to identify clinical variables that warrant management emphasis. METHODS: Thirty CM cases (mean age 40 years; male-to-female 1:4) and 30 sex-matched healthy controls (mean age 40 years) were enrolled. Participants completed self-administered and standardized questionnaires assessing headache-related clinical features and common psychological comorbidities. T1-weighted brain images were acquired on a 3T MRI. A whole-brain cortical thickness analysis was performed. Additionally, correlations between all brain regions were assessed to examine interregional cortical thickness covariance. Interactions were analyzed to identify clinical variables that were significantly associated with cortical thickness. RESULTS: The whole brain cortical thickness analysis revealed no significant differences between CM patients and controls. However, significant associations between clinical features and cortical thickness were observed for the patients only. These associations included the right superior temporal sulcus (R2 = 0.72, P = .001) and the right insula (R2 = 0.71, P = .002) with distinct clinical variables ie, longer history of CM, posttraumatic stress disorder (PTSD), sleep quality, pain self-efficacy, and somatic symptoms. Higher interregional cortical covariance was found in CM compared to controls (OR = 3.1, CI 2.10-4.56, P < .0001), such that cortical thickness between regions tended to be more correlated in patients, particularly in the temporal and frontal lobes. CONCLUSION: CM patients have significantly greater cortical covariance compared to controls. Cortical thickness in CM patients was predominantly accounted for by CM duration, PTSD, and poor sleep quality, while improved pain self-efficacy buffered cortical thickness. While it is important to address all CM features and comorbidities, it may be useful to emphasize optimizing the management of certain clinical features that contribute to cortical abnormalities including managing PTSD, early management to shorten duration of CM, and improving pain self-efficacy and sleep quality. PMID- 30468248 TI - A study on preganglionic connections and possible viscerofugal projections from urinary bladder intramural ganglia to the caudal mesenteric ganglion in the pig. AB - The present study was designed to (1) ascertain the distribution and immunohistochemical characteristics of sympathetic preganglionic neurons supplying the caudal mesenteric ganglion (CaMG) and (2) verify the existence of viscerofugal projections from the urinary bladder trigone intramural ganglia (UBT IG) to the CaMG in female pigs (n = 6). Combined retrograde tracing and immunofluorescence methods were used. Injections of the neuronal tracer Fast Blue (FB) into the right CaMG revealed no retrogradely labelled (FB-positive; FB+ ) nerve cells in the intramural ganglia; however, many FB+ neurons were found in the spinal cord sympathetic nuclei. Double-labelling immunohistochemistry revealed that nearly all (99.4 +/- 0.6%) retrogradely labelled neurons were cholinergic (choline acetyltransferase-positive; ChAT+ ) in nature. Many FB+ /ChAT+ perikarya stained positive for vesicular acetylcholine transporter (63.11 +/- 5.34%), neuronal nitric oxide synthase (53.48 +/- 9.62%) or cocaine- and amphetamine-regulated transcript peptide (41.13 +/- 4.77%). A small number of the retrogradely labelled cells revealed immunoreactivity for calcitonin gene-related peptide (7.60 +/- 1.34%) or pituitary adenylate cyclase-activating polypeptide (4.57 +/- 1.43%). The present study provides the first detailed information on the arrangement and chemical features of preganglionic neurons projecting to the porcine CaMG and, importantly, strong evidence suggesting the absence of viscerofugal projections from the UBT-IG. PMID- 30468249 TI - A review of error correction procedures during instruction for children with developmental disabilities. AB - Error correction procedures are remedial strategies presented following an incorrect response that increases the probability that a correct response will occur in the future. Error correction is commonly used during skill acquisition programs for children with developmental disabilities; however, the specific strategy used may differ considerably. Recent comparative studies have examined the effect of numerous error correction procedures on the efficiency of acquisition for children with developmental disabilities. Despite considerable merit, minor procedural differences and unique terms for similar procedures likely affect comparisons across studies. Here, we clarify the procedures and findings of these studies and suggest areas of future research. PMID- 30468250 TI - Assessing the risk of violence in a psychiatric clinic: the Broset Violence Checklist (BVC) Turkish version-validity and reliability study. AB - PURPOSE: This study was conducted for the purpose of adapting the Broset Violence Checklist (BVC) for Turkish patients and testing its validity and reliability in measuring and predicting the risk of violence psychiatric in patients. DESIGN AND METHODS: The BVC and the Overt Aggression Scale (OAS) were used in the study. The BVC was distributed to 126 patients at the psychiatric clinic. The receiver operating characteristic (ROC), the Mann-Whitney U test and chi 2 analysis were carried out. FINDINGS: With a BVC total score cutoff of two points, 52% sensitivity and 100% specificity were found. A total of 47 violent episodes were observed in 25 patients. PRACTICE IMPLICATIONS: These results support the validity and reliability of the BVC. The Turkish version of the BVC was found to be a reliable and valid tool suitable for use in psychiatric inpatients. PMID- 30468251 TI - CLPTM1L/CRR9 Ectodomain Interaction with GRP78 at the Cell Surface Signals for Survival and Chemoresistance upon ER Stress in Pancreatic Adenocarcinoma Cells. AB - Altered regulation of endoplasmic reticulum (ER) homeostasis has been implicated in many cancers and has recently become a therapeutic and chemosensitization target of interest. We have identified Cleft Lip and Palate Transmembrane 1-Like (CLPTM1L)/Cisplatin Resistance Related Protein 9 (CRR9) as an ER stress related mediator of cytoprotection in pancreatic cancer. We recently demonstrated that CLPTM1L is highly expressed in pancreatic ductal adenocarcinoma and associated with poor outcome. Furthermore, we have discovered that CLPTM1L interacts with phosphoinositol-3-kinase-alpha at the tumor cell surface and causes up-regulation of Bcl-xL and pAkt mediated survival signaling. Here, we demonstrate surface relocalization and survival signaling by CLPTM1L triggered by endoplasmic reticular (ER) stress. We demonstrate the interaction of with CLPTM1L with the central ER stress survival mediator, Glucose Regulated Protein 78 (GRP78)/Binding Immunoglobulin Protein (BiP) and PI3K-alpha /p110alpha. This interaction and surface relocalization of CLPTM1L and GRP78 is induced by ER stress, including that caused by treatment with gemcitabine. We demonstrate that the extracellular loop of CLPTM1L is required for gemcitabine resistance and interaction with GRP78. This interaction and the chemoresistance effect conferred by this pathway is targetable with our recently developed inhibitory CLPTM1L antibodies, which may represent novel modalities of chemosensitization and treatment of pancreatic adenocarcinoma. Anchorage independent growth, GRP78-mediated chemoresistance, and Akt phosphorylation were abrogated by inhibition of CLPTM1L. These findings demonstrate a novel and potentially targetable mechanism of cytoprotection and chemoresistance in pancreatic tumors. This article is protected by copyright. All rights reserved. PMID- 30468252 TI - Occurrence of Cronobacter Spp. in Ready-to-Eat Vegetable Products, Frozen Vegetables, and Sprouts Examined Using Cultivation and Real-Time PCR Methods. AB - Environmental matrices and food products are hypothesized to be sources of Cronobacter spp. The severity of neonatal infections, increasing number of cases in elderly and immunocompromised individuals, as well as isolation of Cronobacter spp. from clinical materials demands that more attention should be paid to Cronobacter spp. detection and occurrence of the bacteria in food products. Here, a total of 175 samples of ready-to-eat vegetables, frozen vegetables, and sprouted seeds were collected during a period of 1 year and examined for the presence of Cronobacter spp. using a cultivation method with two different sample preparations and real-time polymerase chain reaction (qPCR). In total, Cronobacter spp. were detected in 22.3% of tested samples using cultivation. In comparison, direct qPCR detected Cronobacter spp. in 37.7% of these samples (p < 0.01; Fisher's exact test) and the numbers of genome equivalents per gram reached 108 in some samples of sprouts. Cronobacter spp. were isolated from 51.4%, 37.2%, and 5.2% samples of sprouts, frozen vegetables, and cut green leaves/salads, respectively. Using qPCR, the most frequently contaminated sample types were sprouts (91.4%) and frozen vegetables (60.5%), whereas the rate of positivity for cut green leaves/salads was, in comparison, only 8.2% (p < 0.01; chi2 -test for independence). PRACTICAL APPLICATION: This study provided valuable information on the occurrence of Cronobacter spp. in ready-to-eat vegetables using cultivation and qPCR. Cronobacter spp. are emerging opportunistic pathogens that can be present in food of plant origin. Cronobacter spp. were isolated from sprouts, frozen vegetables, and cut green leaves/salads, and the numbers of genome equivalents per gram reached 108 in some samples of sprouts. PMID- 30468253 TI - Discrimination of the Sicilian Prickly Pear (Opuntia Ficus-Indica L., CV. Muscaredda) According to the Provenance by Testing Unsupervised and Supervised Chemometrics. AB - Different multivariate techniques were tested in an attempt to build up a statistical model for predicting the origin of prickly pears (Opuntia ficus indica L., cv. Muscaredda) from several localities within the Sicilian region. Specifically, two areas known for producing fruits marked respectively by TAP (traditional agri-food product) and PDO (protected designation of origin) brands, and three sites producing non-branded fruits, were considered. A validated inductively coupled plasma mass spectrometry (ICP-MS) method allowed to obtain elemental fingerprints of prickly pears, which were subsequently elaborated by unsupervised tools, such as hierarchical clustering analysis (HCA) and principal component analysis (PCA), and supervised techniques, such as stepwise-canonical discriminant analysis (CDA) and partial least squares-discriminant analysis (PLS DA). With the exception of HCA, which was not enough powerful to correctly cluster all selected samples, PCA successfully investigated the effect of subregional provenance on prickly pears, thus, differentiating labeled products from the non-labeled counterpart. Also, stepwise CDA and PLS-DA allowed to build up reliable models able to correctly classify 100% of fruits on the basis of the production areas, by exploiting a restricted pool of metals. Both statistical models, including unsupervised (PCA) and supervised techniques (stepwise CDA or PLS-DA), may guarantee the provenance of prickly pears protected by quality labels and safeguard producers and consumers. PRACTICAL APPLICATION: Based on elemental analysis and chemometrics, the reliable traceability models herein proposed, could be applied to commercial Sicilian prickly pears protected by TAP and PDO logos to guarantee their provenance and, at the same time, to safeguard producers and consumers. PMID- 30468255 TI - Minimal risk of tilapia lake virus transmission via frozen tilapia fillets. AB - Recent outbreaks of a novel tilapia lake virus (TiLV) have raised concerns regarding the international spread of TiLV in frozen tilapia products. This study investigated the potential risks of frozen tilapia fillet as a source of TiLV transmission. It revealed that TiLV genomic RNA could be detected in tilapia fillet and the virus isolated from non-frozen and frozen fillets with clinical TiLV infection stored up to 28 days caused a cytopathic effect (CPE) formation in the susceptible cell line in vitro. However, frozen fillets from clinical TiLV infection stored for 90 and 120 days did not cause CPE in the susceptible cell line. Similarly, CPE was not observed in TiLV isolated from subclinically TiLV infected fish fillets. In addition, in vivo bioassay revealed that despite the presence of TiLV isolated from subclinically TiLV-infected fillet stored at -20 degrees C for 14 days, there was no evidence of TiLV disease in naive red hybrid tilapia based on the absence of clinical signs and mortality and without the detection of TiLV genomic RNA using reverse transcription-quantitative polymerase chain reaction assay. Collectively, these findings suggested minimal risk of transmission of TiLV via frozen tilapia fillets. PMID- 30468254 TI - Selective BTK inhibition improves bendamustine therapy response and normalizes immune effector functions in chronic lymphocytic leukemia. AB - The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been shown to be highly effective in patients with chronic lymphocytic leukemia (CLL) and is approved for CLL treatment. Unfortunately, resistance and intolerance to ibrutinib has been observed in several studies, opening the door for more specific BTK inhibitors. CC-292 (spebrutinib) is a BTK inhibitor with increased specificity for BTK and less inhibition of other kinases. Our in vitro studies showed that CC-292 potently inhibited B-cell receptor signaling, activation, proliferation and chemotaxis of CLL cells. In in vivo studies using the adoptive transfer TCL1 mouse model of CLL, CC-292 reduced tumor load and normalized tumor associated expansion of T cells and monocytes, while not affecting T cell function. Importantly, the combination of CC-292 and bendamustine impaired CLL cell proliferation in vivo and enhanced the control of CLL progression. Our results demonstrate that CC-292 is a specific BTK inhibitor with promising performance in combination with bendamustine in CLL. Further clinical trials are warranted to investigate the therapeutic efficacy of this combination regimen. This article is protected by copyright. All rights reserved. PMID- 30468256 TI - Baicalin, Baicalein, and Lactobacillus Rhamnosus JB3 Alleviated Helicobacter pylori Infections in Vitro and in Vivo. AB - Helicobacter pylori infection is associated with chronic gastritis, peptic ulcers, and gastric cancer. The flavonoid compounds baicalin and baicalein found in many medicinal plants exhibit an anti-inflammatory effect. The administration of Lactobacillus strains reducing the risk of H. pylori infection is well accepted. In this study, the therapeutic effects against H. pylori infection of baicalin, baicalein, and L. rhamnosus JB3 (LR-JB3), isolated from a dairy product, were investigated. Compared to baicalin, baicalein exhibited stronger anti-H. pylori activity and cytotoxicity on human gastric cancer epithelial AGS cells. Baicalin and baicalein both suppressed the vacA gene expression of H. pylori and interfered with the adhesion and invasion ability of H. pylori to AGS cells, as well as decreased H. pylori-induced interleukin (IL)-8 expression. In the mice infection model, high dosages of baicalin and baicalein inhibited H. pylori growth in the mice stomachs. Serum IL-1beta levels and H. pylori-specific serum IgM and IgA levels in mice treated with baicalin and baicalein were decreased. Moreover, a synergistic therapeutic effect of baicalein and LR-JB3 on eradicating H. pylori infections was observed. Thus, administrating baicalin, baicalein, or LR-JB3 for an H. pylori infection could offer similar therapeutic effects to administering antibiotics while not disturbing the balance of gut microbiota. This study revealed the effects of baicalin, baicalein, and LR-JB3 on attenuating the virulence of H. pylori. The synergistic effect with baicalein and LR-JB3 provides the experimental rationale for testing the reliability, safety, and efficacy of this approach in higher animals and perhaps ultimately in humans to eradicate H. pylori infections. PRACTICAL APPLICATION: Baicalin and baicalein exert health promotion and avoidance of H. pylori infections by interfering with H. pylori growth and virulence. Lactobacillus rhamnosus JB3 was used to reduce the gastric inflammation caused by H. pylori infection. PMID- 30468257 TI - #WEWANTSPACE: Developing Student Activism Through a Decolonial Pedagogy. AB - This article explores how decolonial pedagogy can develop a sense of student activism (Portillo, 2013; Tejada & Espinoza, 2003; Villanueva, 2013). Decolonality in the classroom requires decentering dominant groups to make space for marginalized voices and experiences (Cruz & Sonn, 2011, American Journal of Community Psychology, 47, 203). Aligned with community psychology values (Amer, Mohammed, & Ganzon, 2013), this paper argues for the importance of employing decolonial pedagogy in undergraduate learning through praxis projects. Centering the analysis on one college course in United States, the author showcases how a large-scale class project can engage students in decolonial thinking and foster an interest in social action. The Practical Activism Project, a 45 student collaborative project, explores how class projects can work to decolonize the classroom environment and further push students toward social action and activism. Co-authored with some undergraduate students from this course, this article will examine how decolonizing-informed class projects can lead to campus activism that has spearheaded institutional change for marginalized students. Integrating both perspectives, the authors conclude with lessons learned from this project and advice for future educators. PMID- 30468258 TI - Assessing Risk for Adverse Outcomes in Older Adults: The Need to Include Both Physical Frailty and Cognition. AB - BACKGROUND: Physical frailty is a powerful tool for identifying nondisabled individuals at high risk of adverse outcomes. The extent to which cognitive impairment in those without dementia adds value to physical frailty in detecting high-risk individuals remains unclear. OBJECTIVES: To estimate the effects of combining physical frailty and cognitive impairment without dementia (CIND) on the risk of basic activities of daily living (ADL) dependence and death over 8 years. DESIGN: Prospective cohort study. SETTING: The Health and Retirement Study (HRS). PARTICIPANTS: A total of 7338 community-dwelling people, 65 years or older, without dementia and ADL dependence at baseline (2006-2008). Follow-up assessments occurred every 2 years until 2014. MEASUREMENTS: The five components of the Cardiovascular Health Study defined physical frailty. A well-validated HRS method, including verbal recall, series of subtractions, and backward count task, assessed cognition. Primary outcomes were time to ADL dependence and death. Hazard models, considering death as a competing risk, associated physical frailty and CIND with outcomes after adjusting for sociodemographics, comorbidities, depression, and smoking status. RESULTS: The prevalence of physical frailty was 15%; CIND, 19%; and both deficits, 5%. In unadjusted and adjusted analyses, combining these factors identified older adults at an escalating risk for ADL dependence (no deficit = 14% [reference group]; only CIND = 26%, sub-hazard ratio [sHR] = 1.5, 95% confidence interval [CI] = 1.3-1.8; only frail = 33%, sHR = 1.7, 95% CI = 1.4-2.0; both deficits = 46%, sHR = 2.0, 95%CI = 1.6-2.6) and death (no deficit = 21%; only CIND = 41%, HR = 1.6, 95% CI = 1.4-1.9; only frail = 56%, HR = 2.2, 95% CI = 1.7-2.7; both deficits = 66%, HR = 2.6, 95% CI = 2.0-3.3) over 8 year follow-up. Adding the cognitive measure to models that already included physical frailty alone increased accuracy in identifying those at higher risk of ADL dependence (Harrell's concordance [C], 0.74 vs 0.71; P < .001) and death (Harrell's C, 0.70 vs 0.67; P < .001). CONCLUSION: Physical frailty and CIND are independent predictors of incident disability and death. Because together physical frailty and CIND identify vulnerable older adults better, optimal risk assessment should supplement measures of physical frailty with measures of cognitive function. PMID- 30468259 TI - Effect size, statistical power, and sample size for assessing interactions between categorical and continuous variables. AB - The reporting and interpretation of effect size estimates are widely advocated in many academic journals of psychology and related disciplines. However, such concern has not been adequately addressed for analyses involving interactions between categorical and continuous variables. For the purpose of improving current practice, this article presents fundamental features and theoretical developments for the variance of standardized slopes as a desirable standardized effect size measure for the degree of disparity between several slope coefficients. To estimate the effect size, a consistent and nearly unbiased estimator is described and a simple refinement is emphasized for extreme situations whenever appropriate. The essential problems of power and sample size calculations for testing the equality of slope coefficients are also considered. According to the analytic justification and empirical assessment, the exact approach has a clear advantage over the approximate methods. Both SAS and R computer codes are provided to facilitate practical accessibility of the proposed techniques in interaction studies. PMID- 30468260 TI - Foodborne Bacterial, Viral, and Protozoan Pathogens in Field and Market Strawberries and Environment of Strawberry Farms. AB - Field-grown strawberries, the environment of strawberry farms and fresh strawberries from marketplaces were examined for bacterial, viral, and protozoan pathogens. The presence of bacteria was determined using culture and real-time PCR (qPCR), presence of protozoa and viruses using qPCR and reverse transcription qPCR, respectively. The highest proportion of positivity was observed for Escherichia coli both in field and purchased strawberries (up to 48.6%). Finding of Cronobacter ranged from 0.6% to 9% both for field and market strawberries. The prevalence of other pathogens (Listeria monocytogenes, Giardia intestinalis, Cryptosporidium sp., and Norovirus) in strawberries was below 4.5%; HAV was not detected at all. Positivity of the environment was determined to be lower than 2.1% for all microorganisms, except for E. coli. The concentration of pathogens in most samples did not exceed 100 CFU/g using culture and 1.8 * 102 GE/g of strawberries or swabbing area 6.1 * 102 GE/mL or swabbing area of environmental samples using qPCR. All studied farms applied preventive measures such as drip irrigation, avoidance of organic fertilizers, and use of mulch foils or gloves for workers to decrease contamination of strawberries. Despite this, certain pathogens were found in fresh strawberries. Even at low concentrations, these pathogens can be a source of infection for consumers. Thus, their presence in strawberries is of particular significance as these are mostly consumed fresh and without any thermal processing. PRACTICAL APPLICATION: Nonlegislatively monitored pathogens of bacterial, viral and parasitic origin were found in strawberries. Monitoring the presence of these pathogens in ready-to-eat food is therefore meaningful and important in terms of food safety, especially in relation to pathogens with low infectious dose (for example, viruses, parasites). PMID- 30468261 TI - Contextual and individual determinants of non-utilization of dental services among Brazilian adults. AB - OBJECTIVES: To examine the association of contextual and individual determinants with non-utilization of dental services among Brazilian adults. METHODS: Data were from adults aged 35-44 years (N = 7,265) from the 2010 Brazilian Oral Health Survey (SB Brasil Project). Non-utilization of dental services was assessed whether the individual has never had a dental visit over the whole life time. Independent variables were selected according to Andersen's behavioral model. Contextual variables included Human Development Index-longevity (HDI-Longevity) (predisposing demographic), HDI-Education and Gini index (predisposing social), integration of oral health teams into Primary Care (enabling health policy), and HDI-Income (enabling financing). Individual data were age and sex (predisposing demographic), ethnicity and schooling (predisposing social), family monthly income (predisposing enabling), perceived dental treatment (perceived need), and decayed teeth (evaluated need). The relationship of contextual and individual variables with non-utilization of dental services was assessed through multilevel logistic regression analysis to estimate odds ratios (ORs) and 95% confidence intervals (95% CI). RESULTS: The prevalence of non-utilization of dental services was 4.7 percent. Adults living in cities with high HDI-Income were less likely to never have a dental visit. The odds of non-utilization of dental services were lower for adults living in cities with high HDI-Longevity. Sex, skin color, dental treatment needs, poor socioeconomic characteristics, perceived dental treatment needs, and decayed teeth were also associated with non-utilization of dental services. CONCLUSIONS: The results suggest that contextual enabling and predisposing factors, individual sociodemographic, and needs-related characteristics influence non-utilization of dental services by Brazilian adults. PMID- 30468262 TI - Femoral Neuropathy Following Transfemoral Neuroendovascular Procedures. An Analysis of a Prospective Registry. AB - BACKGROUND AND PURPOSE: Although femoral neuropathy is recognized as an adverse consequence following transfemoral neuroendovascular procedures, no reliable estimates are available. We analyzed data from a prospective registry to ascertain the frequency and characteristics of femoral neuropathy following transfemoral neuroendovascular procedures. METHODS: Consecutive patients who underwent neuroendovascular procedures through the transfemoral route were included. Detailed assessment was performed if any patient reported occurrence of sensory or motor symptoms in the femoral or lower extremity region including neurological examination (sensory/motor deficits) and femoral region ultrasound. RESULTS: Femoral neuropathy was diagnosed following 4 of 270 neurovascular procedures with an occurrence rate of 1.5% (95% confidence intervals = .4-3.7%). The symptoms were exclusively sensory without any motor involvement. The femoral neuropathy appeared to involve anterior femoral cutaneous nerves in all and medial cutaneous branches in 2 patients, and more than one nerve distribution in 1 patient in whom lateral cutaneous nerve appeared to be involved. All patients reported resolution of symptoms within a period ranging from 1 week to 2 months. No local hematoma or arterial pseudoaneurysm was identified at femoral region ultrasound. CONCLUSIONS: Femoral neuropathy is a rare occurrence following transfemoral neuroendovascular procedures and it usually occurs with pure sensory manifestations with complete resolution. PMID- 30468263 TI - Social-emotional processing in nonverbal individuals with Angelman syndrome: evidence from brain responses to known and novel names. AB - BACKGROUND: The combination of intellectual, communicative and motor deficits limits the use of standardised behavioural assessments in individuals with Angelman syndrome (AS). The current study aimed to objectively evaluate the extent of social-emotional processing in AS using auditory event-related potentials (ERPs) during passive exposure to spoken stimuli. METHODS: Auditory ERP responses were recorded in 13 nonverbal individuals with the deletion subtype of AS, age 4-45 years, during the name recognition paradigm, in which their own names and names of close others (relative or friend) were presented among novel names. No behavioural responses were required. RESULTS: Contrary to findings in typical children and adults, there was no significant evidence of differential neural response to known vs. novel names in participants with AS. Nevertheless, greater amplitude differences between known and unknown names demonstrated the predicted association with better interpersonal relationships and receptive communication abilities. CONCLUSIONS: These findings indicate good tolerability of ERP procedures (85% success rate). The lack of own name differentiation is consistent with increased incidence of the autism-related symptoms in AS. Strong associations between the caregiver reports of adaptive functioning and neural indices of known name recognition support the utility of brain-based measures for objectively evaluating cognitive and affective processes in nonverbal persons with neurodevelopmental disorders. PMID- 30468264 TI - Determination of Nutrition Risk and Status in Critically Ill Patients: What Are Our Considerations? AB - The stress catabolism state predisposes critically ill patients to a high risk of malnutrition. This, coupled with inadequate or delayed nutrition provision, will lead to further deterioration of nutrition status. Preexisting malnutrition and iatrogenic underfeeding are associated with increased risk of adverse complications. Therefore, accurate detection of patients who are malnourished and/or with high nutrition risk is important for timely and optimal nutrition intervention. Various tools have been developed for nutrition screening and assessment for hospitalized patients, but not all are studied or validated in critically ill populations. In this review article, we consider the pathophysiology of malnutrition in critical illness and the currently available literature to develop recommendations for nutrition screening and assessment. We suggest the use of the (modified) Nutrition Risk in the Critically Ill (mNUTRIC) for nutrition risk screening and the subjective global assessment (SGA) together with other criteria relevant to the critically ill patients, such as gastrointestinal function, risk of aspiration, determination of sarcopenia and frailty, and risk of refeeding syndrome for nutrition assessment. Further research is needed to identify suitable nutrition monitoring indicators to determine the response to the provision of nutrition. PMID- 30468265 TI - Long-range molecular dynamics show that inactive forms of Protein Kinase A are more dynamic than active forms. AB - Many protein kinases are characterized by at least two structural forms corresponding to the highest level of activity (active) and low or no activity, (inactive). Further, protein dynamics is an important consideration in understanding the molecular and mechanistic basis of enzyme function. In this work, we use Protein kinase A (PKA) as the model system and perform microsecond range molecular dynamics (MD) simulations on 6 variants which differ from one another in terms of active and inactive form, with or without bound ligands, C terminal tail and phosphorylation at activation loop. We find that the root mean square fluctuations in the MD simulations are generally higher for the inactive forms than the active forms. This difference is statistically significant. The higher dynamics of inactive states has significant contributions from ATP binding loop, catalytic loop and alphaG helix. Simulations with and without C-terminal tail show this differential dynamics as well, with lower dynamics both in the active and inactive forms if C-terminal tail is present. Similarly, the dynamics associated with the inactive form is higher irrespective of the phosphorylation status of Thr 197. A relatively stable stature of active kinases may be better suited for binding of substrates and detachment of the product. Also, phosphoryl group transfer from ATP to the phosphosite on substrate requires precise transient coordination of chemical entities from 3 different molecules, which may be facilitated by the higher stability of the active state. This article is protected by copyright. All rights reserved. PMID- 30468266 TI - Andre Goffeau: from proteins to genes to genomes: the Goffeaumic approach to life sciences. PMID- 30468267 TI - Texting for Help: Processes and Impact of Text Counseling with Children and Youth with Suicide Ideation. AB - OBJECTIVE: To explore: (1) how children contacting a child helpline with suicide ideation differ from children discussing other topics, (2) whether text messaging effectively helps, and (3) which counselor behaviors are most effective. METHOD: Of 6,060 text sessions at the Danish national child helpline, 444 concerned suicidality, of which the 102 sessions that included self-rated, end Session ratings were selected for content analysis. RESULTS: Twenty-six percentage of suicidal children had severe suicidality. The suicide sample had significantly more girls, was older than the nonsuicide sample, and more often recontacted the helpline in the 2 weeks prior to follow-up. 35.9% of suicidal children felt better immediately and over half ended the session with a plan of action. At follow-up, 23.9% of suicidal children reported feeling better; however, 37.0% reported feeling worse. Talking about emotions, expressing empathy, and encouraging the child to talk to someone were associated with positive impacts. Setting boundaries was associated with negative impacts. CONCLUSIONS: Texting with suicidal children can be helpful, but should be considered a first step toward obtaining more sustainable help. Research is needed to determine how to better help children who felt worse or did not improve in the 2 weeks after contacting the helpline. Suggestions to further training of counselors are discussed. PMID- 30468268 TI - Impact of Intraoperative Hyperglycemia on Brain Structures and Volumes. AB - BACKGROUND AND PURPOSE: In hyperglycemic patients, who succumbed to septic shock, an increased rate of apoptosis of microglial cells and damaged neurons of the hippocampus were found. However, the influence of perioperative glucose levels on hippocampal brain structures has not yet been investigated. METHODS: As part of the ongoing BIOCOG project, a subgroup of N = 65 elderly nondemented patients were analyzed who underwent elective surgery of >=60 minutes. In these patients, at least one intraoperative blood glucose (BG) measurement was available from the medical charts. Intraoperative glucose maximum was determined in each patient. Preoperatively and at 3 months follow-up, structural neuroimaging was performed with T1-weighted magnetization prepared rapid gradient-echo sequence (MP-Rage) and a dedicated high-resolution hippocampus magnetic resonance imaging (MRI). The MRI scans were analyzed to assess pre- or postoperative volume changes of the hippocampus as a whole and hippocampal subfields. We also assessed changes of frontal lobe volume and cortical thickness. RESULTS: Overall, 173 intraoperative BG levels were obtained in 65 patients (median 2 per patient). A total of 18 patients showed intraoperative hyperglycemia (glucose maximum >=150 mg/dL). Controlling for age and diabetes status, no significant impact of intraoperative hyperglycemia was found on the pre-post volume change of the hippocampus as a whole, hippocampal subfields, frontal lobe, and frontal cortical thickness. CONCLUSIONS: This study found no effect of intraoperative hyperglycemia on postoperative brain structures and volumes including volumes of hippocampus and hippocampal subfields, frontal lobe, and frontal cortical thickness. Further studies investigating the impact of intraoperatively elevated glucose levels should consider a tighter or even continuous glycemic measurement and the determination of central microglial activation. PMID- 30468269 TI - Characterization of the chemical constituents in Hongjingtian injection by liquid chromatography quadrupole time-of-flight mass spectrometry. AB - Hongjingtian injection is made from Rhodiola wallichiana and used in the treatment of stable angina pectoris associated with coronary heart disease. In this study, the chemical constituents in Hongjingtian injection were comprehensively studied using liquid chromatography quadrupole time-of-flight mass spectrometry. A total of 49 compounds were identified or assumed, including 10 organic acids, nine phenylethanoids, 10 phenylpropanoids, two flavonoid glycosides, seven monoterpene glycosides, seven octylglycosides and four other types of compounds. The structures of seven compounds were confirmed by comparing their retention times, MS and UV spectra with the corresponding authentic standards. Amongst the 49 compounds, 35 were firstly found in R. wallichiana, while they have been reported in other species of the genus Rhodiola, including Rhodiola crenulata, Rhodiola sacra, Rhodiola rosea and Rhodiola kirilowii. The possible fragmentation pathways in the mass spectrometry of the major types of compounds are proposed and summarized. Our study demonstrates a rapid method for characterizing the chemical constituents present in the Hongjingtian injection, which could also be applied to the identification of chemical constituents in other TCM formulae containing R. wallichiana. PMID- 30468270 TI - Impact of nanoparticles on transcriptional regulation of catabolic genes of petroleum hydrocarbon-degrading bacteria in contaminated soil microcosms. AB - This study was conducted to determine what effects nanoparticles (NPs) like TiO2 , ZnO, and Ag may pose on natural attenuation processes of petroleum hydrocarbons in contaminated soils. The solid NPs used were identified using x-ray diffraction technique and their average size was certified as 18.2, 16.9, and 18.3 nm for Ag NPs, ZnO-NPs, and TiO2 -NPs, respectively. NPs in soil microcosms behave differently where it was dissolved as in case of Ag-NPs, partially dissolved as in ZnO-NPs or changed into other crystalline phase as in TiO2 -NPs. In this investigation, catabolic gene encoding catechol 2,3 dioxygenase (C23DO) was selected specifically as biomarker for monitoring hydrocarbon biodegradation potential by measuring its transcripts by RT-qPCR. TiO2 -NPs amended microcosms showed almost no change in C23DO expression profile or bacterial community which were dominated by Bacillus sp., Mycobacterium sp., Microbacterium sp., Clostridium sp., beside uncultured bacteria, including uncultured proteobacteria, Thauera sp. and Clostridia. XRD pattern suggested that TiO2 -NPs in microcosms were changed into other non-inhibitory crystalline phase, consequently, showing the maximum degradation profile for most low molecular weight oil fractions and partially for the high molecular weight ones. Increasing ZnO-NPs concentration in microcosms resulted in a reduction in the expression of C23DO with a concomitant slight deteriorative effect on bacterial populations ending up with elimination of Clostridium sp., Thauera sp., and uncultured proteobacteria. The oil degradation efficiency was reduced compared to TiO2 -NPs amended microcosms. In microcosms, Ag-NPs were not detected in the crystalline form but were available in the ionic form that inhibited most bacterial populations and resulted in a limited degradation profile of oil, specifically the low molecular weight fractions. Ag-NPs amended microcosms showed a significant reduction (80%) in C23DO gene expression and a detrimental effect on bacterial populations including key players like Mycobacterium sp., Microbacterium sp., and Thauera sp. involved in the biodegradation of petroleum hydrocarbons. PMID- 30468271 TI - Fine mapping of hydrophobic contacts reassesses the organisation of the first three dystrophin coiled-coil repeats. AB - Coiled-coil domain is a structural motif found in proteins crucial for achievement of central biological processes, such as cellular cohesion or neuro transmission. The coiled-coil fold consists of alpha-helices bundle that can be repeated to form larger filament. Hydrophobic residues, distributed following a regular seven-residues pattern, named heptad pattern, are commonly admitted to be essential for the formation and the stability of canonical coiled-coil repeats. Here we investigated the first three coiled-coil repeats (R1-3) of the central domain of dystrophin, a scaffolding protein in muscle cells whose deficiency leads to Duchenne and Becker Muscular Dystrophies. By an atomic description of the hydrophobic interactions, we highlighted (i) that coiled-coil filament conformational changes are associated to specific patterns of inter-helices hydrophobic contacts, (ii) that inter-repeat hydrophobic interactions determine the behaviour of linker regions including filament kinks, and (iii) that a non strict conservation of the heptad patterns is leading to a relative plasticity of the dystrophin coiled-coil repeats. These structural features and modulations of the coiled-coil fold could better explain the mechanical properties of the central domain of dystrophin. This contribution to the understanding of the structure-function relationship of dystrophin, and especially of the R1-3 fragment frequently used in the design of protein for gene therapies, should help in the improvement of the strategies for the cure of muscular dystrophies. This article is protected by copyright. All rights reserved. PMID- 30468272 TI - Reversible Carbene Insertion into a Ge-N Bond and New Insights into CO- and Carbene-Substitution Reactions Involving Amidinatogermylenes and Fischer Carbene Complexes. AB - The formation of the 5-membered-ring germylene complexes [M(CO)5{Ge(tBu2bzamC(OEt)Me)tBu}] (3M; M = Cr, W), which occurs readily at room temperature from the germylene Ge(tBu2bzam)tBu (1tBu) and the Fischer carbenes [M(CO)5{C(OEt)Me}] (2M; M = Cr, W), has been found to be reversible. Upon heating at 60 oC, complexes 3M undergo epimerization to a equilibrium mixture of 3M and 3'M. At that temperature, the chromium epimers (but not the tungsten ones) release CO to end in the mixed germylene-Fischer carbene complexes [Cr(CO)4{C(OEt)Me}{Ge(tBu2bzam)tBu}] (cis-4Cr and trans-4Cr). The latter decompose at 120 oC to [Cr(CO)5{Ge(tBu2bzam)tBu}] (6Cr). As the formation of cis 4Cr and trans-4Cr from 3M requires the presence of free 1tBu and 2M in the reacting solutions, the reactions of 1tBu with 2M to give 3M (and 3'M at 60 oC) should be reversible. This proposal has been proven by germylene-exchange crossover reactions in which free 1tBu and [M(CO)5{Ge(tBu2bzamC(OEt)Me)CH2SiMe3}] (5'M; M = Cr, W) were formed when complexes 3M were treated at room temperature with the germylene Ge(tBu2bzam)CH2SiMe3 (1tmsm). A clear differential behavior between NHCs and amidinatogermylenes (1tBu and 1tmsm) in their reactivity against group 6 metal Fischer carbene complexes is demonstrated. The higher electron donor capacity of amidinatogermylenes with respect to NHCs and the bias of the former to get involved in ring expansion processes are responsible for this differential behavior. PMID- 30468273 TI - Electrochemical Sensor Platforms Based on Nanostructured Metal Oxides, and Zeolite-Based Materials. AB - Electrochemical sensors have drawn significant attention over the last couple of decades because of their ability to improve detection of organic and inorganic analytes found in the field of biotechnology, environmental sciences, medicine, and food quality control. This personal account summarizes the state-of-art research carried out in the construction and evaluation of nanostructured metal oxides and zeolite based electrochemical sensors. Metal oxides and zeolite-based nanomaterials have many unique and extraordinary properties such as tunable redox activity, surface functionalization ability, optimum conductivity, large surface area, biocompatibility and so forth. In this personal account, the current advances in electrochemical sensor applications of metal oxides, zeolite-based nanomaterials, and their nanocomposites are described for the single and simultaneous determination of organic & inorganic contaminants present in water bodies, physiological bio-molecules present in human blood & urine samples, and organic contaminants present in food materials.Moreover, concluding section focuses discussion on the future developments and applications of these materials in various emerging technologies. PMID- 30468274 TI - Prognostic value of baroreflex sensitivity in heart failure. A 2018 reappraisal. PMID- 30468275 TI - Sex-dependent differences in ethanol inhibition of mouse lateral orbitofrontal cortex neurons. AB - Biological differences between males and females likely influence responses to alcohol and the propensity to engage in excessive drinking. In both humans and rodents, females escalate alcohol use and develop addiction-like behaviors faster than males, while males exhibit more severe withdrawal symptoms during abstinence. The mechanisms underlying these differences are not yet known but may reflect fundamental differences in the ethanol sensitivity of neurons in reward and control areas of the brain. To address this question, we recorded current evoked spiking of lateral orbitofrontal cortex (lOFC) neurons in male and female C57BL/6J mice following acute and chronic exposure to ethanol. Ethanol (11-66 mM) reduced firing of lOFC neurons but produced less inhibition in neurons from female mice. As previously reported for male mice, the glycine receptor blocker strychnine blocked ethanol inhibition of spiking of lOFC neurons from female mice and prevented the ethanol-induced increase in tonic current. Following chronic intermittent ethanol (CIE) exposure, current-evoked spiking of lOFC neurons was significantly enhanced with a greater effect observed in males. After CIE treatment, acute ethanol had no effect on spiking in neurons from male mice, while it produced a slight but significant decrease in firing in females. Finally, like male mice, the inhibitory effect of the glycine transport inhibitor sarcosine was blunted in CIE-exposed female mice. Together, these results suggest that while lOFC neurons in male and female mice are similarly affected by ethanol, there are significant differences in sensitivity that may contribute to differences in alcohol actions between males and females. PMID- 30468276 TI - Pulmonary artery wedge pressure respiratory variation is correlated with haemodynamic improvement with increased left ventricular assist system speed. PMID- 30468277 TI - Non-invasive ventilation: Essential requirements and clinical skills for successful practice. AB - Audits and case reviews of the acute delivery of non-invasive ventilation (NIV) have shown that the results achieved in real life often fall short of those achieved in research trials. Factors include inappropriate selection of patients for NIV and failure to apply NIV correctly. This highlights the need for proper training of all involved individuals. This article addresses the different skills needed in a team to provide an effective NIV service. Some detail is given in each of the key areas but it is not comprehensive and should stimulate further learning (reading, attendance on courses, e-learning, etc.), determined by the needs of the individual. PMID- 30468278 TI - Bufalin induces protective autophagy by Cbl-b regulating mTOR and ERK signaling pathways in gastric cancer cells. AB - Bufalin, a natural small-molecule compound derived from the traditional Chinese medicine Chan su, has shown promising anti-cancer effects against a broad variety of cancer cells through different mechanisms. It has been reported to induce autophagy in gastric cancer cells. However, the molecular mechanism involved is not fully elucidated. In the present study, we aimed to investigate the molecular mechanism by which bufalin induce autophagy in human gastric cancer cells. We found that bufalin induced apoptosis and autophagy in gastric cancer cells, and autophagy prevented human gastric cancer cells from undergoing apoptosis. Bufalin treatment changed the expression of autophagy-related proteins. Moreover, phosphorylated Akt, mTOR, and p70S6K were all significantly decreased, while phosphorylated ERK1/2 was increased by bufalin. Pretreatment of MGC803 cells with the ERK1/2-specific inhibitor PD98059 led to the down-regulation of LC3 II. Further study showed that Cbl-b positively regulated autophagy by suppressing mTOR and enhancing ERK1/2 activation. Therefore, our data provide evidence that bufalin induces autophagy in MGC803 cells via both Akt/mTOR/p70S6K and ERK signaling pathways, and Cbl-b-mediated suppression of mTOR and activation of ERK1/2 might play an important role. PMID- 30468279 TI - INCREASED OSMOLALITY ENHANCES THE TIGHT JUNCTION-MEDIATED BARRIER FUNCTION IN A CULTURED RENAL EPITHELIAL CELL LINE. AB - Osmotic alterations are associated with several human diseases, including diabetic nephropathy. We have previously shown that high glucose, which is a well known osmotic agent, induces significant disruption of the tight junction (TJ) mediated tubular barrier of the Madin-Darby canine kidney (MDCK) cell line. In this study, we investigated the effect of acute (24h) and chronic (72h) exposure to increased osmolality (with a 14.5 mM mannitol solution) on TJ-mediated barrier function in MDCK cells. The treatment with mannitol significantly increased the transepithelial electrical resistance (TEER) and accelerated the TEER recovery after Ca2+ switch assay in comparison with control monolayers. Immunofluorescence and Western blot analyses showed that mannitol treatment induced a significant increase in the tight junctional and cellular content of claudin-1 (a barrier forming claudin) as well as a significant decrease in claudin-2 (a pore-forming claudin) junctional and cellular contents. These data suggest that an increased osmolality induces enhancement of the TJ-mediated barrier of MDCK cells, and that, therefore, the negative effect of high glucose on the epithelial paracellular barrier cannot be attributed to its osmotic actions. In addition, a subtle increase in osmolality may have an impact on kidney function and renal related diseases. PMID- 30468280 TI - Radiofrequency spectral analysis of EBUS for peripheral pulmonary lesions. AB - BACKGROUND AND OBJECTIVE: We previously reported that histogram-based quantitative evaluation for endobronchial ultrasonography (EBUS) B-mode images could differentiate between benign and malignant lesions. However, these images were generated from reconstructed raw radiofrequency (RF) signals and had some limitations. Currently, there are no reports on raw RF signal data to quantitatively differentiate ultrasound information for peripheral pulmonary lesions. METHODS: We prospectively hypothesized that RF spectral analysis from EBUS images could reveal sonographic features of peripheral pulmonary diseases. RF data were imported into a frequency spectral analysis software programme, comparing four parameters: mean frequency (MHz); slope; mid-band fit (dB); and y intercept (dB), to differentiate between benign and malignant lesions. Furthermore, we compared subgroup analysis within benign and malignant lesions. RESULTS: RF data from EBUS images were obtained in 146 cases, of which, 106 lung cancers and 40 inflammatory diseases were present. Significant differences were observed for three parameters in benign and malignant lesions (mean frequency: P < 0.05, slope: P < 0.05, y-intercept: P < 0.01) with diagnostic accuracy of 61%, 57.5%, 63%, respectively. In subgroup analysis, the acute pneumonia group showed higher mean frequency, higher slope and lower y-intercept patterns compared to mycobacterial and fibrotic diseases (P < 0.05). In malignant lesions, small cell carcinoma showed higher mean frequency, higher slope and lower y-intercept pattern compared to other histopathological lung cancers (P < 0.01). CONCLUSION: RF analysis might be capable of demonstrating aspects of the lesion's pathological heterogeneity rather than precisely differentiating between benign and malignant lesions. PMID- 30468281 TI - Achiral Trisubstituted Thioureas as Secondary Ligands to Cu(I) Catalysts: Direct Catalytic Asymmetric Addition of alpha-Fluoronitriles to Imines. AB - Thioureas have emerged as proficient hydrogen-bonding catalysts over the last two decades, and are broadly utilized in asymmetric catalysis. Herein, we report that achiral trisubstituted thioureas function as beneficial secondary ligands to Cu(I) catalysts, allowing for a highly diastereo- and enantioselective addition of alpha-fluoronitriles to imines. The structure of the thiourea significantly affects the reaction outcome, and kinetic experiments indicate that the thioureas enhance the stereocontrol by binding to the Cu(I) complex. The reaction product was readily transformed into valuable beta-amino acid derivatives bearing a fluorinated tetrasubstituted stereogenic center. PMID- 30468282 TI - MicroRNA-1254 contributes to the controlling of pro-fibrogenic environment in LX 2 cells by modulating SMAD3 and wound repair: new insights in hepatic fibrosis. AB - Hepatic fibrosis and its end-stage cirrhosis have increased worldwide, and, despite all the efforts, no successful therapy is available. More recently, the heptapeptide angiotensin-(1-7) [ang-(1-7)] was reported to be able to modulate liver fibrosis and even steatosis; however, the molecular bases of these effects are not clear. In this study, we investigated the overexpression of the microRNA 1254 in the human hepatic stellate cell line LX-2, based on the effect of the heptapeptide in such cells, previously, demonstrated by our research group. In addition, this miRNA was chosen based on the identification of putative binding site of this small molecule in the mRNA sequences of different molecular connectors of the AKT/ PI3K pathway, which is modulated by the heptapeptide and connects to the control of several cellular mechanisms, including proliferation, survival, migration, and even liver fibrogenesis. The results revealed an innovative function of the miR-1254 in controlling SMAD3 and pro-fibrosing elements as well as the wound healing response in LX-2, attenuating the scaring repair of the injured tissue. The combined findings provide useful information for future studies on the controlling of hepatic fibrogenesis. PMID- 30468283 TI - Cardiovascular disease-related hospitalization and mortality among persons with von Willebrand disease: A nationwide register study in Sweden. AB - INTRODUCTION: It has been hypothesized that persons with von Willebrand disease (VWD) may be protected against arterial thrombosis despite having atherosclerosis. AIM: To calculate a nationwide estimate of the absolute and comparative burden of cardiovascular disease (CVD) hospitalization and mortality among persons with VWD using birthdate and sex-matched comparisons from the general population in Sweden. METHODS: Persons with VWD regardless of the type and severity, diagnosed by a medical doctor, who lived in Sweden for some time during the observation period 1987 through 2008 were included. For each participant with VWD, up to five randomly selected birthdate- and sex-matched persons from general population were selected as controls. RESULTS: A total of 2790 participants with VWD including 888 male and 1902 female subjects and 13 938 controls were included. Overall, the hazard of CVD-related hospitalization was 1.3-fold (95% CI: 1.1, 1.5) among participants with VWD after adjusting for sex, birthdate, diabetes and cancer. However, they had a 0.4-fold (95% CI: 0.3, 0.6) hazard of CVD-related mortality compared to general population sample. CONCLUSIONS: In this nationwide, long-term register study with individually matched controls, we have been able to show that persons with VWD have a higher hospitalization rate due to CVD events. However, the mortality rates appear lower than in the control population. The latter finding is consistent with previous studies and indicates a protective effect of the clotting factor deficiency inherited with VWD. PMID- 30468284 TI - A novel approach to immune tolerance induction in haemophilia A with factor VIII inhibitor. PMID- 30468285 TI - Diagnostic and Prognostic Role of Serum miR-20b, miR-17-3p, HOTAIR, and MALAT1 in Diabetic Retinopathy. AB - Noncoding RNAs are emerging biomarkers for many diseases including diabetic retinopathy (DR). This study aimed to measure the expression levels of serum miR 20b, miR-17-3p, HOTAIR, and MALAT1 in DR patients. A total of 80 patients diagnosed as type 2 diabetes (T2D) and 81 healthy subjects were recruited in this study. T2D patients were divided into three groups: nondiabetic retinopathy (NDR) group (30 patients), nonproliferative diabetic retinopathy (NPDR) group (30 patients), and proliferative diabetic retinopathy (PDR) group (20 patients). Quantitative real-time polymerase chain reaction (PCR) was used to assess the expression of serum miR-20b, miR-17-3p, HOTAIR, and MALAT1. We found a significant decrease in serum miR-20b and a significant increase in serum HOTAIR and MALAT1 in NDR patients compared to healthy subjects. Also, we revealed a significant decrease in serum miR-20b and miR-17-3p and a significant increase in serum HOTAIR and MALAT1 in each of NPDR and PDR groups when compared with healthy subjects. Furthermore, we reported a significant decrease in miR-20b and miR-17 3p and a significant increase in HOTAIR and MALAT1in DR as well as in PDR patients when compared with NDR patients. However, on comparing NPDR with NDR patients, no significant difference was observed regarding the expression levels of miR-20b and miR-17-3p, in contrast, significant elevation of serum HOTAIR and MALAT1 was found in NPDR. Moreover, we observed a significant decrease in serum miR-20b and miR-17-3p and a significant increase in serum HOTAIR and MALAT1 in PDR group relative to NPDR group. Receiver operating characteristic (ROC) curve was used for evaluating the diagnostic value of the examined serum noncoding RNAs as novel biochemical indicators detecting severity of DR. Our analyses suggested that the examined serum noncoding RNAs may discriminate DR (PDR and NPDR) from NDR. Furthermore, these noncoding RNAs (less importantly miR-17) can be used as promising novel biomarkers for prediction DR severity, distinguishing PDR from NPDR patients. We can conclude that serum miR-20b, miR-17-3p, HOTAIR, and MALAT1 may be used as noninvasive biomarkers for screening of DR and early diagnosis of PDR. (c) 2018 IUBMB Life, 1-11, 2018. PMID- 30468286 TI - Brief tools to measure obesity-related behaviours in children under 5 years of age: A systematic review. AB - INTRODUCTION: Valid and reliable tools for measuring obesity-related behaviours in young children that are brief and can be administered quickly and cost effectively in large-scale population studies are needed. The objectives of this systematic review were to describe brief tools that measure dietary intake, physical activity, sedentary behaviour, and sleep in young children. METHODS: A systematic review of studies published in English in six databases (CINAHL, Medline, Embase, PsycINFO, HaPI, and Cochrane) prior to April 2018 was undertaken using the PROSPERO protocol and PRISMA guidelines. Included studies were those reporting the psychometric properties of brief (<=15 items) tools that measure dietary, activity, or sleep-related behaviours, alone or in combination, in children birth to 4.9 years of age. RESULTS: The search identified 11 379 papers, 200 full-text articles were screened for eligibility, and 12 met the inclusion criteria. Three studies measured two behavioural domains, while most assessed a single behaviour (three diet, five physical activity, one sleep, and none sedentary behaviour). Only two (one diet, one sleep) focused on the under 2 age group. Few studies assessed reliability, and validity and findings were mixed. CONCLUSIONS: There is a need to develop brief tools to measure early life obesity related behaviours, particularly those assessing sedentary behaviour and sleep and tools that cover multiple domains. PMID- 30468288 TI - Catalyst-Free Enantiospecific Olefination with in-situ Generated Organocerium Species. AB - Described is the in-situ formation of triorganocerium reagents and their implications in catalyst-free Zweifel olefinations. These unique cerium species were generated through novel exchange reactions of organo-halides with n-Bu3Ce reagents. The adequate electronegativity of cerium allowed for compensating both disadvantages of usually functional group sensitive organolithium species and less reactive organomagnesium reagents. Exchange reactions were performed on aryl and alkenyl bromides, enabling enantiospecific transformations of chiral boron pinacol esters. Finally, these new organocerium species were engaged in selective 1,2-additions onto enolizable and sterically hindered ketones. PMID- 30468287 TI - Abscisic acid stimulates the release of insulin and of GLP-1 in the rat perfused pancreas and intestine. AB - AIMS: Previous results indicate that nanomolar concentrations of abscisic acid (ABA) stimulate insulin release from beta-pancreatic cells in vitro and that oral ABA at 50 mg/Kg increases plasma GLP-1 in the fasted rat. The aim of this study was to test the effect of ABA on the perfused rat pancreas and intestine, to verify the insulin- and incretin-releasing actions of ABA in controlled physiological models. MATERIALS AND METHODS: Rat pancreas and small intestine were perfused with solutions containing ABA at high-micromolar concentrations, or control secretagogues. Insulin and GLP-1 concentrations in the venous effluent were analysed by radioimmunoassay and ABA levels were determined by ELISA. RESULTS: High micromolar concentrations of ABA induced GLP-1 secretion from the proximal half of the small intestine and insulin secretion from pancreas. GLP-1 stimulated ABA secretion from pancreas in a biphasic manner. Notably, a positive correlation was found between the ABA area under the curve (AUC) and the insulin AUC upon GLP-1 administration. CONCLUSION: Our results indicate the existence of a cross talk between GLP-1 and ABA, whereby ABA stimulates GLP-1 secretion, and viceversa. Release of ABA could be considered as a new promising molecule in the strategy of T2D treatment and as a new endogenous hormone in the regulation of glycaemia. PMID- 30468289 TI - Thromboelastometry profiles after "in vitro" addition of a new plasma-derived factor V concentrate to whole blood from parahaemophilia patients. PMID- 30468290 TI - Ultrasound, Clinical, and Electrophysiological Findings in Persistent Carpal Tunnel Syndrome. AB - BACKGROUND AND PURPOSE: We present the clinical, electrophysiological, and nerve ultrasound findings in cases of persistent carpal tunnel syndrome (PCTS). METHODS: Eighteen PCTS patients underwent evaluation with the Boston Carpal Tunnel Syndrome Questionnaire (BCTSQ), electrophysiology, and nerve ultrasound with a mean of 3.5 months (SD +/- 1.4) after open surgery. RESULTS: PCTS patients showed a mean symptom severity scale score of 3.1 (SD +/- 1.1) and functional severity scale score of 3.2 (SD +/- 0.9) in BCTSQ. Nerve conduction studies revealed axonal affection of the median nerve in 13/18 patients, ultrasound showed disturbed echogenicity in all patients, a pathological wrist to forearm ratio in 16/18 patients, and cross-sectional area enlargement of the median nerve at the distal wrist crease in 12/18 patients. Ultrasound documented scar tissue formation (in 12/18 patients), incomplete release of retinaculum flexorum (in 4/18 patients), and neuroma of the median nerve (in 2/18 patients) as PCTS cause. CONCLUSION: Our data show significant functional disability, axonal nerve damage, and scar tissue formation as common PCTS causes. PMID- 30468291 TI - Templated-PISA: Driving Polymerization-Induced Self-Assembly towards the Fibre Morphology. AB - Dispersions of block-copolymer fibres in water have many potential applications and can be obtained by polymerization-induced self-assembly (PISA), but only in very restricted experimental conditions. In order to enlarge this experimental window, we introduced a supramolecular moiety, a hydrogen-bonded bis-urea sticker, in the macromolecular reversible addition-fragmentation chain transfer agent to drive the morphology of the nano-objects produced by RAFT-mediated PISA towards the fibre morphology. This novel concept is tested in the synthesis of a series of poly(N,N-dimethylacrylamide)-b-poly(2-methoxyethyl acrylate) (PDMAc-b PMEA) diblock copolymers prepared by dispersion polymerization in water. The results prove that the introduction of the templating bis-urea stickers into PISA greatly promotes the formation of fibres in a large experimental window. PMID- 30468292 TI - Heart failure with preserved ejection fraction in Asia: the far side of the moon? PMID- 30468293 TI - Shifts in the functional topography of frontal cortex-striatum connectivity in alcohol use disorder. AB - Frontostriatal circuits are centrally involved in the selection of behavioral programs and play a prominent role in alcohol use disorder (AUD) as well as other mental disorders. However, how frontal regions change their striatal connectivity to implement adaptive cognitive control is still not fully understood. Here, we developed an approach for functional magnetic resonance imaging (fMRI) connectivity analysis in which we change the focus from connectivity to individual voxels towards spatial information about the location of strongest functional connectivity. In resting state data of n = 66 participants with AUD and n = 40 healthy controls (HC) we used the approach to estimate frontostriatal connectivity gradients consistent with nonhuman primate tract-tracing studies, characterized for each frontal voxel the striatal peak connectivity location on this gradient (PeaCoG), and tested for group differences and associations with clinical variables. We identified a cluster in the right orbitofrontal cortex (rOFC) with a peak connectivity shift towards ventral striatal regions in AUD. Reduced variability of rOFC striatal peak connectivity in the AUD group suggests a "clamping" to the ventral striatum as the underlying effect. Within the AUD group striatal peak connectivity in the superior frontal gyrus was associated with self-efficacy to abstain from alcohol, in the medial frontal and dorsolateral prefrontal cortex with alcohol dependency, and in the right inferior frontal gyrus with the urge to consume alcohol. Our results demonstrate that the functional topography of frontostriatal circuits exhibits interindividual variability, which provides insight into frontostriatal network adaptations in AUD and potentially other mental disorders. PMID- 30468294 TI - Endothelial dysfunction and cellular repair in heart failure with preserved ejection fraction: response to a single maximal exercise bout. PMID- 30468295 TI - Touch imprint (TI) cytology of needle core biopsies (NCB) in pathology laboratories: A practice survey of participants in the College of American Pathologists (CAP) Non Gynecologic Cytopathology (NGC) Education Program. AB - BACKGROUND: Intra-procedural assessment of touch imprint (TI) cytology from needle core biopsies (NCB) is used to ensure sample adequacy and to provide immediate diagnosis in various settings. We aimed to survey laboratories for current practices on the use of cytology with NCB. METHODS: A voluntary supplemental questionnaire including questions on demographics, personnel involved, sites, accessioning, and reporting was sent with the College of American Pathologists (CAP) 2015 Non gynecologic Cytopathology Education Program to survey practices of cytologic assessment of NCB. RESULTS: Among 844 respondents, 403 (48%) performed cytologic assessment of NCB. Common body sites included lung (94%; 368/392), liver (87%; 340/ 392), and lymph nodes/spleen (77%; 303/392). Most of the time, a pathologist was present on-site 75% (295/393) for adequacy assessment which was usually verbally reported to the provider performing the procedure. Specimens were prepared by cytotechnologists (50%; 193 of 388) or pathologists (45%; 176 of 388) by touching the core to the slide (50%; 196 of 390) and rolling the core on the slide (45%; 177/390). Among the respondents, 19% said that cytotechnologists independently performed immediate assessment of TI of NCB. Most laboratories (69%; 264/384) evaluated air-dried slides with a modified Giemsa stain and rendered one TI/NCB combined report (87%, 334/385). CONCLUSIONS: This is the first survey performed specifically to determine the practice of adequacy assessment of TI of NCB. Cytotechnologists are generally not performing adequacy assessment of TI without pathologist oversight. A single report is usually issued which includes the adequacy assessment as a part of the final report. PMID- 30468296 TI - Prevalence of ROS1 fusion in Chinese patients with non-small cell lung cancer. AB - BACKGROUND: The study was conducted to investigate the clinicopathological features and prevalence of ROS1 gene fusion in Chinese patients with non-small cell lung cancer (NSCLC). METHODS: The presence of ROS1 fusion was assessed by quantitative real-time PCR. Associations between ROS1 fusion and clinical characteristics were analyzed. RESULTS: In total, 6066 patients with pathologically confirmed NSCLC and ROS1 fusion test results were enrolled. The average age was 60.89 +/- 10.60 years and fusion was detected in 157 (2.59%) patients. Fusion frequency was significantly correlated with age, gender, smoking status (all P < 0.001), pathology type (P = 0.017), and lymph node metastasis stage (P = 0.027). ROS1 fusion-positive patients were significantly younger (55.68 +/- 11.34 vs. negative 61.02 +/- 10.44 years; P < 0.01). Fusion frequency was higher in women (3.71% vs. men 1.81%), never-smokers (3.33% vs. smokers 1.21%), and patients with adenocarcinoma (2.77% vs. squamous lung cancer 0.93%) and at advanced node stages (1.31%, 1.40%, 2.07%, and 3.23% for N0, N1, N2, and N3, respectively). No significant correlation between ROS1 fusion status and pathological stage was found in subgroups classified by pathological, tumor, or metastasis stage (P > 0.05). Age, smoking status, and lymph node stage were statistically significantly correlated with ROS1 fusion frequency (all P < 0.05); gender and pathology type were not significantly correlated with ROS1 fusion status after adjusting for smoking status. CONCLUSION: An overall ROS1 fusion frequency of 2.59% was confirmed in this study. ROS1 fusion was more prevalent among younger patients, never-smokers, and those at advanced node stages. PMID- 30468297 TI - Plant Synthetic Biology - One Answer to Global Challenges. AB - In times of climate change, population growth and resource depletion, the future well-being of mankind will greatly depend on the ability to breed/engineer crop plants for high yield, low input and high quality. Based on the evaluation of historical yield increases, it seems that yield of major grain crops, such as rice or wheat, is plateauing (Grassini et al. 2013). Given these negative trends, food security and sustainable agriculture will only be achieved by coordinated international efforts, including the application of all technological and scientific advances made in plant breeding, molecular and synthetic biology. PMID- 30468298 TI - Different behaviour of DVL1, DVL2, DVL3 in astrocytoma malignancy grades and their association to TCF1 and LEF1 upregulation. AB - Key regulators of the Wnt signalling, DVL1, DVL2 and DVL3, in astrocytomas of different malignancy grades were investigated. Markers for DVL1, DVL2 and DVL3 were used to detect microsatellite instability (MSI) and gross deletions (LOH), while immunohistochemistry and immunoreactivity score were used to determine the signal strengths of the three DVL proteins and transcription factors of the pathway, TCF1 and LEF1. Our findings demonstrated that MSI at all three DVL loci was constantly found across tumour grades with the highest number in grade II (P = 0.008). Collectively, LOHs were more frequent in high-grade tumours than in low grade ones. LOHs of DVL3 gene were significantly associated with grade IV tumours (P = 0.007). The results on protein expressions indicated that high-grade tumours expressed less DVL1 protein as compared with low grade ones. A significant negative correlation was established between DVL1 expression and malignancy grades (P < 0.001). The expression of DVL2 protein was found similar across grades, while DVL3 expression significantly increased with malignancy grades (P < 0.001). The signal strengths of expressed DVL1 and DVL3 were negatively correlated (P = 0.002). However, TCF1 and LEF1 were both significantly upregulated and increasing with astrocytoma grades (P = 0.001). A positive correlation was established between DVL3 and both TCF1 (P = 0.020) and LEF1 (P = 0.006) suggesting their joint involvement in malignant progression. Our findings suggest that DVL1 and DVL2 may be involved during early stages of the disease, while DVL3 may have a role in later phases and together with TCF1 and LEF1 promotes the activation of Wnt signalling. PMID- 30468299 TI - The role of mindfulness in physical activity: a systematic review. AB - Despite continued public health campaigns to promote physical activity, a majority of the population is inactive. In recent years, mindfulness-based approaches have been used in health and lifestyle interventions for physical activity promotion. We conducted a systematic literature review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to investigate the evidence for the potential of mindfulness-based approaches for physical activity. We searched electronic databases for papers that met eligibility criteria and identified 40 studies for inclusion. Evidence from cross sectional studies (n = 20) indicated a positive relationship between dispositional mindfulness and physical activity, particularly with psychological factors related to physical activity. Five studies found that the mindfulness physical activity relationship was mediated by stress, psychological flexibility, negative affect and shame, satisfaction and state mindfulness. Evidence from mindfulness-based interventions (n = 20) suggested positive between-subjects effects on physical activity, but interventions varied in duration, session length, group size, delivery, content and follow-up. Mindfulness-based interventions were more likely to be successful if they were physical activity specific and targeted psychological factors related to physical activity. The body of research shows a need for more methodologically rigorous studies to establish the effect of mindfulness on physical activity and to identify potential mechanisms involved in the mindfulness-physical activity relationship reliably. PMID- 30468300 TI - Molecular processes in iron and zinc homeostasis and their modulation for biofortification in rice. AB - More than a billion people suffer from iron or zinc deficiencies globally. Rice (Oryza sativa L.) iron and zinc biofortification i.e., intrinsic iron and zinc enrichment of rice grains, is considered the most effective way to tackle these deficiencies. Rice iron biofortification by means of conventional breeding, however, proves difficult due to lack of sufficient genetic variation. Meanwhile, genetic engineering has led to significant increase in the iron concentration along with zinc concentration in rice grains. The design of impactful genetic engineering biofortification strategies relies upon vast scientific knowledge of precise functions of different genes involved in iron and zinc uptake, translocation and storage. In this review, we present an overview of molecular processes controlling iron and zinc homeostasis in rice. Besides, the genetic engineering approaches adopted so far to increase the iron and zinc concentrations in polished rice grains are discussed in detail, highlighting the limitations and/or success of individual strategies. Recent insight suggests that a few genetic engineering strategies are commonly utilized for elevating iron and zinc concentrations in different genetic backgrounds, and thus it is of great importance to accumulate scientific evidence for diverse genetic engineering strategies to expand the pool of options for biofortifying farmer-preferred cultivars. PMID- 30468301 TI - The long-term functional outcome in Mustard patients study: Another decade of follow-up. AB - OBJECTIVE: For over 20 years, we have followed a cohort of patients who underwent the Mustard procedure for d-transposition of the great arteries. The current study follows the same cohort from our last study in 2007 to reassess their functional capacity and quality of life. PARTICIPANTS: Of the original 45 patients, six patients have required cardiac transplant and 10 patients have died, including two of the transplanted patients. Twenty-five of the remaining patients agreed to participate in this current study. DESIGN: Patients underwent comparable testing to the previous studies when possible including exercise stress testing, echocardiography, MRI or CT evaluation of cardiac anatomy and function, Holter monitor, and quality of life questionnaire. RESULTS: Thirty-one percent of patients have experienced cardiac death either in the form of mortality or cardiac transplantation. The major cause of death was systemic right ventricular failure. Sixty-five percent have continuing abnormalities of rhythm. Exercise time and workload showed a statistically significant decrease from the original study (Time 1) to both 10-year (Time 2) and 20-year (Time 3) follow-up points. Right ventricular ejection fraction decreased significantly from the Time 1 to Time 2, and again to this current follow-up. Quality of life measures of energy level decreased significantly from the original study to both the Time 2 and Time 3. CONCLUSION: Cardiac mortality for Mustard patients remains high, and over time, systemic right ventricular ejection fraction, rhythm, exercise tolerance, and quality of life assessments show deterioration. There does not appear to be a single clear predictor of poor outcome. PMID- 30468302 TI - Cytomorphologic diagnosis of inguinal node metastasis of Sertoli cell tumour. PMID- 30468303 TI - Molecular and mechanical factors contributing to ductus arteriosus patency and closure. AB - Regulation of the ductus arteriosus, an essential fetal vessel connecting the pulmonary artery and aorta, is complex. Failure of this vessel to close after birth may result in a persistent left-to-right shunt through the patent ductus arteriosus, a condition associated with significant morbidities. Numerous factors contribute to the shift from fetal ductus patency to postnatal closure, requiring precise coordination of molecular cues with biomechanical forces and underlying genetic influences. Despite significant advances, questions remain regarding signaling dynamics and the natural time course of ductus closure, particularly in preterm neonates. This review highlights the contributions of early investigators and more recent clinician scientists to our understanding of the molecular and mechanical factors that mediate ductus patency and closure. PMID- 30468304 TI - Methionine329 in human serum albumin: a novel target for alkylation by sulfur mustard. AB - Exposure to the vesicant sulfur mustard (SM) may lead to erythema and blistering. Toxicity of SM is hypothesized to be due to the alkylation of DNA bases and nucleophilic amino acid side chains in proteins (adducts) by forming the hydroxyethylthioethyl (HETE) moiety. Despite of its prohibition by the chemical weapons convention, SM still represents a serious threat to military personnel and civilians. Therefore, development and improvement of forensic analytical methods for the verification of SM exposure is of high interest. Protein adducts have been shown to be highly suitable and beneficial biomarkers of poisoning. Herein we present methionine329 in human serum albumin (HSA) as a novel target of SM forming a HETE-methionyl sulfonium ion. The alkylated tetrapeptide LeuGlyMet329 (-HETE) Phe, LGM(-HETE) F, was detected after pepsin mediated proteolysis and subsequent analysis by microbore liquid chromatography electrospray ionization high-resolution tandem-mass spectrometry. Compound identity was confirmed by a synthetic reference. Proteolysis conditions for HSA were optimized towards maximum yield of LGM(-HETE) F and its limit of identification (32.3 nM SM in serum) was similar to those of the established HSA derived biomarkers HETE-CysPro and HETE-CysProPhe (15.6 nM SM in serum). Stability of the alkylated Met329 in vitro and in vivo was limited to 5 days making this modification a beneficial short-time biomarker. Furthermore, it was found that the HETE-methionyl sulfonium ion can transfer its HETE moiety to the side chain of cysteine and glutamic acid as well as to the N-terminus of peptides and proteins in vitro thus revealing novel insights into the molecular toxicity of SM. PMID- 30468305 TI - Exploiting serological data to understand the epidemiology of bluetongue virus serotypes circulating in Libya. AB - The epidemiological patterns of Bluetongue (BT) in North Africa and Mediterranean Basin (MB) dramatically changed by emergence of subsequent episodes of novel bluetongue virus (BTV) serotypes with highly pathogenic indexes and socio economic impacts. The objective of the study was to investigate the sero prevalence and serotype distribution of BTV in Libya. During 2015-2016, a total of 826 serum samples were collected from domestic ruminants in Libya. All sera were assayed by competitive enzyme-linked immunosorbent assays (c-ELISA). C-Elisa positive samples (43.3%; 173/400) were further analyzed by virus neutralization assay to identify BTV serotypes and determine the antibody titre of positive samples. An overall BTV sero-prevalence was 48.4% (95% CI: 45.0%-51.8%). Neutralizing antibodies were detected against the following BTV serotypes namely: BTV-1, BTV-2, BTV-3, BTV-4, BTV-9 and BTV-26. While BTV-1, BTV-2, BTV-4 and BTV-9 circulation was unsurprising as they have been responsible of the last year outbreaks in Northern African Countries, the detection of BTV-3 and BTV-26 was definitely new and concerning for the animal health of the countries facing the Mediterranean Basin. It is crucial that European and Northern African authorities collaborate in organizing common surveillance programmes to early detect novel strains or emerging serotypes in order to set up proper preventive measures, and, in case, develop specific vaccines and plan coordinated vaccination campaigns. PMID- 30468306 TI - A rapid method for estimation of the efficacy of potential antimicrobials in humans and animals by agar diffusion assay. AB - Drug resistance continues to challenge traditional antimicrobial drugs and limit their clinical utility. This requires us to continue our search for new drug candidates with novel mechanisms of action against infectious diseases. We now describe a simple agar diffusion assay, which can be used as a general method for the rapid detection of antimicrobial activity of drug candidates in animal or human blood plasma for the ultimate prediction of the efficacy of potential drugs prior to clinical trials. We present an example for a clinical candidate against Mycobacterium tuberculosis. PMID- 30468307 TI - Perspective: Appendage regeneration in amphibians and some reptiles derived from specific evolutionary histories. AB - Some hypotheses on the evolution of regeneration in amphibians and reptiles are presented. Amphibian regeneration is derived from metamorphosis present in sarcopterygian fish and amphibians of the Devonian-Carboniferous. The genetic ability to rebuild organs during metamorphosis was maintained in form of "regeneration" in urodele and anuran tadpoles. Amphibian regeneration may be a consequence of the transition from an aquatic to a terrestrial environment through the evolution of a developmental program for the tadpole stage and replacements of adult organs controlled by the endocrine and immune system. Following metamorphosis, the regeneration program for terrestrial anurans and amniotes was lost or modified, whereas the immune system involved in self integrity and microbial protection became in charge of regeneration that was replaced by scarring. Among amniotes only lizards regenerate an organ as large and complex as the tail. It is hypothesized that in Permian captorhinids and in Triassic lizards (eosuchians) a regenerative blastema evolved in relation to autotomy, a unique phenomenon present in these reptiles that enhanced survival against the larger predators of the Permian-Mesozoic. Appendage regeneration in amphibians and lizards occurs after the migration of activated mesenchymal and epidermal cells in the wounded areas to form soft and hyaluronate-rich blastemas. Autotomy and production of high hyaluronate levels allows high hydration and immunosuppression, favoring regeneration. It is suggested that a way for regenerative medicine to induce limb regeneration in humans is to develop medical procedures to recreate soft blastemas that can grow, a long and difficult process because it counteracts mammalian evolution toward scarring. PMID- 30468308 TI - Diverse preparation methods for small intestinal submucosa (SIS): decellularization, components and structure. AB - The native extracellular matrix (ECM) biomaterial derived from small intestinal submucosa (SIS) is widely applied in tissue engineering for tissue repair and regeneration. SIS ECM is obtained through physical and chemical methods to remove the intrinsic cells which would otherwise cause adverse immune reactions when the SIS ECM is implanted into the host body. Several research teams have reported diverse SIS decellularization methods. However, there was no consensus on the criteria to be used for the decellularization methods for SIS and further research on the mechanism action of SIS is needed for comprehensive detection of the biological composition. In this present study, we used three reported methods to prepare SIS and compared their effects on decellularization and the remaining biological components, microstructure and cytocompatibility. SIS prepared by the three kinds of decellularization methods all achieved the recommended criteria, had good biocompatibility and retained most active components. Nevertheless, regardless of which decellularization method was used, the microstructure and bioactive components of the prepared SIS were damaged in varying degrees. We recommend that researchers need to select a decellularization method that would be appropriate to use according to their research purposes. This article is protected by copyright. All rights reserved. PMID- 30468309 TI - Psychological and Genetic Predictors of Pain Tolerance. AB - Previous studies have shown associations between genetic polymorphisms and pain tolerance, but psychological evaluations are seldom measured. The objective of this study was to determine the independent effects of demographic, psychological and genetic predictors of cold noxious pain tolerance. Healthy subjects (n=89) completed the Pain Catastrophizing Scale (PCS) and Fear of Pain Questionnaire (FPQ-III), underwent genotyping for candidate single nucleotide polymorphisms (SNPs), and completed a cold-pressor test in a 1-2 degrees Celsius water bath for a maximum of three minutes. The primary outcome measure was pain tolerance, defined as the maximum duration of time subjects left their non-dominant hand in the cold-water bath. Cox proportional hazards regression indicated that female sex, Asian race, and increasing PCS and FPQ-III scores were associated with lower pain tolerance. No candidate SNP was significantly associated with pain tolerance. Future genetic studies should include demographic and psychological variables as confounders in experimental pain models. This article is protected by copyright. All rights reserved. PMID- 30468310 TI - Retraction. AB - "si-RNA-Mediated Knockdown of PDLIM5 Suppresses Gastric Cancer Cell Proliferation in Vitro" by Yanliang Li, Yongsheng Gao, Yue Xu, Xianjun Sun, Xilin Song, Heng Ma & Mingshan Yang.[1] The above article from Chemical Biology & Drug Design, published online on September 12, 2014 in Wiley Online Library (http://onlinelibrary.wiley.com), and in Volume 85, pp. 447-453, has been retracted by agreement between the journal Editor in Chief David Selwood, and John Wiley and Sons Ltd. The retraction has been agreed upon following the realisation that there are several serious errors with this paper with incorrect shRNA sequences being used. The paper has therefore been retracted. Reference [1] Y. Li, Y. Gao, Y. Xu, X. Sun, X. Song, H. Ma, M. Yang, Chem. Biol. Drug Des. 2015, 85, 447. PMID- 30468311 TI - Cell block cellularity: A comparison of two fixatives and their impact on cellularity. AB - BACKGROUND: Ancillary testing including immunohistochemistry and molecular diagnostics has become an increasingly important component for the evaluation of cytologic specimens. Ancillary testing is important not only for diagnosis but also for predictive and prognostic evaluation. While a number of substrates are appropriate for ancillary testing, cell block specimens are commonly utilized and the success of ancillary testing depends on cell-block cellularity. METHODS: Forty-six pairs of cases each fixed in both formalin and CytoLyt were each analyzed by two evaluators for overall cellularity. Linear regression was used to assess inter-rater reliability of cell counts for each method. Cellularity scores for each case were obtained by averaging the scores for each rater and cellularity was compared between the methods. RESULTS: Inter-rater agreement was very good for both methods. The coefficient of determination was 1.0 and 0.99 for the CytoLyt and formalin methods respectively. Cell blocks using the CytoLyt method have lower levels of cellularity than cell blocks performed by the formalin method. CONCLUSIONS: Cell blocks prepared using a formalin fixative yield significantly greater cellularity than those produced by the CytoLyt method. Formalin fixation appears to optimize cellularity of cell blocks useful for ancillary testing. PMID- 30468312 TI - Covalent immobilization of alkaline proteinase on amino-functionalized magnetic nanoparticles and application in soy protein hydrolysis. AB - Magnetic nanoparticles (MNPs) were synthesized and surface modified with (3 Aminopropyl)triethoxysilane (APTES). The alkaline proteinase (AP) was covalently immobilized on the APTES-modified MNPs through glutaraldehyde linkage. The resulting AP-loaded MNPs have an average size of 84 nm in aqueous solution, and a magnetization of 40 emu/g, endowing the immobilized enzyme with excellent magnetic responsively and dispersity. The maximum amount of AP and catalytic activity immobilized 1.0 mg MNPs was 120 MUg and 25.3 units, respectively. Immobilized AP showed maximum activity at pH 10.0 and 50 degrees C. Compared with free enzyme, the immobilized AP exhibited better storage stability. Moreover, immobilized AP can be reused ten times and still maintained about 50% of its initial activity. The degree of hydrolysis (DH) of soy protein hydrolysates for immobilized AP could reach 19.0%, which was closer to the value of free enzyme. The molecular weight (M.W.) analysis showed that the soy protein was hydrolyzed successfully into small peptides of two main fractions with an average M.W. of 742 Da and 2126 Da. This study indicated that the immobilized AP could be used to hydrolyze continuously soy protein for potential industry application. This article is protected by copyright. All rights reserved. PMID- 30468313 TI - Cervical cancer screening by molecular Pap-transformation of gynecologic cytology. AB - BACKGROUND: Cervical cancer is one of the common cancers in women accounting for 7.9% of all cancers. In India it is the second commonest cancer in women. The immortality of the cancer cell and the relatively long time frame from acquisition of infection to development of cervical cancer was established. As major advancements like LBC, HPV testing were introduced in the recent years, screening has taken a new avatar, the Molecular pap!! The objectives of this study were: To compare gynecologic cytology and abnormal results with respect to conventional and LBC. To study the role of HPV cotesting and ancillary tests performed, that is, HPV CISH, and p16ink4a by IHC. METHODS: About 71 924 Conventional and LBC samples were included from August 2009 to December 2017. Cases for HPV testing along the conventional smears were 1539. HPV can be tested from the same LBC vial as the sample remains stable at room temperature for 6 weeks. HPV DNA PCR was carried out in our laboratory for High and Low risk genotypes. Cytology findings were also correlated with histology. RESULTS: Detection rate of SILs in LBC samples were higher (2.20%). The commonest abnormality was LSIL in LBC and ASCUS in conventional smears. Commonest HR HPV and LR HPV detected was 1 61 856 and 61 142. CONCLUSION: LBC with HPV cotesting improves sensitivity and specificity and reduces ambiguous results; allows better compliance, as a negative result of both tests allows patients to get screening every 5 years, thereby increasing screening intervals, important in a resource limited situation. PMID- 30468314 TI - Spindle cell lipoma mimicking pleomorphic adenoma: A diagnostic challenge on cytology. AB - Spindle cell lipoma (SCL) is a benign neoplasm of mature adipose tissue mostly located in the neck, back, and shoulder region. It is composed of a variable admixture of adipocytes, benign spindle cells, and collagen fibres. While the histopathologic features of SCL are quite characteristic and well described, a cytologic diagnosis of SCL might be challenging. We present a case of a 36-year old female with a swelling in the left preauricular region since last 6 mo. On fine needle aspiration, a diagnosis of lipomatous pleomorphic adenoma (PA) was rendered because of the presence of benign spindle-shaped cells, adipocytes, and abundant myxoid material. However, on histopathologic examination, the diagnosis was SCL which was confirmed by immunohistochemistry. Preauricular region is a rare site of occurrence of SCL. An acquaintance with its varied cytomorphologic features and a knowledge of its unusual sites of occurrence is essential to prevent its misdiagnosis as other myxoid benign and malignant spindle cell lesions. PMID- 30468315 TI - Investigating the role of mechanics in lignocellulosic biomass degradation during hydrolysis. AB - Enzymes and mechanics play major roles in lignocellulosic biomass deconstruction in biorefineries by catalysing chemical cleavage or inducing physical breakdown of biomass, respectively. At industrially relevant substrate concentrations mechanical agitation is also a driving force for mass transfer as well as agglomeration of elongated biomass particles. On the contrary to the physically induced particle attrition, which typically facilitates feedstock handling, particle agglomeration tends to hinder mass transfer and in the worst case induces processing difficulties like pipe blockage. Understanding the complex interplay between mechanical agitation and enzymatic degradation during hydrolysis is therefore critical and was the aim of this study. Particle size analyses revealed that neither mechanical agitation alone nor enzymatic treatment without mechanical agitation had any noteworthy effect on flax fibre attrition. Similarly, successive treatment, where mechanical agitation was either preceded or proceeded by enzymatic hydrolysis, did not induce any substantial segmentation of flax fibres. Simultaneous enzymatic and mechanical treatment on the other hand was found to promote fast fibre shortening. Higher hydrolysis yields, however, were obtained from non-agitated samples after prolonged enzymatic treatment, indicating that mechanical agitation in the long run reduces activity of the cellulolytic enzymes. This article is protected by copyright. All rights reserved. PMID- 30468316 TI - Mediastinal seminoma presenting as a neck mass falsely diagnosed as anaplastic thyroid carcinoma: A case report. AB - Germ cell tumors can occur in the mediastinum. They account for about 20% of tumors at this location. The majority are located in the anterior mediastinum and usually occur in young adult males. Extension of mediastinal germ cell tumors into the neck with mass formation is a very rare and unusual event. Herein, we report a case of a 34 year old male who presented with a progressively enlarging neck mass. Fine Needle Aspiration (FNA) was performed as initial evaluation and showed cellular smears comprising atypical large cells with prominent irregular nucleoli and moderate amount of cytoplasm with lymphocytic infiltrate and some epithelioid granulomas in the background. The mass was misdiagnosed initially on the cytology smears as anaplastic thyroid carcinoma. The subsequent tissue core biopsy showed sheets and nests of atypical cells admixed with ill-defined granulomatous inflammation. By immunohistochemistry, the tumor cells were immunoreactive with SALL4, PLAP and OCT3/4, compatible with malignant germ cell tumor, seminomatous type. It is very rare for patients with primary mediastinal seminoma to present initially with a neck mass. Fine Needle Aspiration (FNA) of this "neck mass" can lead to misinterpretation of findings due to similarities in cytological features between malignant germ cell tumors and other undifferentiated malignant neoplasms and the diagnosis, therefore, can be very challenging. PMID- 30468317 TI - Bimolecular Nucleophilic Substitution Reactions: Predictive Models for Rate Constants and Molecular Reaction Pairs Analysis. AB - Here, we report the data visualization, analysis and modeling for a large set of 4830 SN 2 reactions the rate constant of which (logk) was measured at different experimental conditions (solvent, temperature). The reactions were encoded by one single molecular graph - Condensed Graph of Reactions, which allowed us to use conventional chemoinformatics techniques developed for individual molecules. Thus, Matched Reaction Pairs approach was suggested and used for the analyses of substituents effects on the substrates and nucleophiles reactivity. The data were visualized with the help of the Generative Topographic Mapping approach. Consensus Support Vector Regression (SVR) model for the rate constant was prepared. Unbiased estimation of the model's performance was made in cross validation on reactions measured on unique structural transformations. The model's performance in cross-validation (RMSE=0.61 logk units) and on the external test set (RMSE=0.80) is close to the noise in data. Performances of the local models obtained for selected subsets of reactions proceeding in particular solvents or with particular type of nucleophiles were similar to that of the model built on the entire set. Finally, four different definitions of model's applicability domains for reactions were examined. PMID- 30468318 TI - Combining chemical flocculation and bacterial co-culture of Cupriavidus taiwanensis and Ureibacillus thermosphaericus to detoxify a hardwood hemicelluloses hydrolysate and enable ABE fermentation leading to butanol. AB - Butanol, a fuel with better characteristics than ethanol, can be produced via Acetone-Butanol-Ethanol (ABE) fermentation using lignocellulosic biomass as a carbon source. However, many inhibitors present in the hydrolysate limit the yield of the fermentation process. In this work, a detoxification technology combining flocculation and biodetoxification within a bacterial co-culture composed of Ureibacillus thermosphaericus and Cupriavidus taiwanensis is presented for the first time. Co-culture based strategies to detoxify filtered and unfiltered hydrolysates have been investigated. The best results of detoxification were obtained for a two-step approach combining flocculation to biodetoxification. This sequential process led to a final phenolic compounds concentration of 1.4 g/L, a value close to the minimum inhibitory level observed for flocculated hydrolysate (1.1 g/L). The generated hydrolysate was then fermented with Clostridium acetobutylicum ATCC 824 for 120 h. A final butanol production of 8 g/L was obtained, although the detoxified hydrolysate was diluted to reach 0.3 g/L of phenolics to ensure non-inhibitory conditions. This article is protected by copyright. All rights reserved. PMID- 30468319 TI - Lobular breast carcinoma metastasis to skeletal muscle, two case reports diagnosed by ultrasound guided FNA with evaluation of the roles of interventional cytopathology. AB - Skeletal muscle metastasis from breast carcinoma is a relatively rare clinical entity. We report two cases of breast cancer metastatic to the skeletal muscle, diagnosed by ultrasound guided fine needle aspiration (US-FNA) biopsy done by interventional cytopathologists at an outpatient cytopathology center. Our two patients presented with lower anterior neck firmness and chest wall mass, respectively. Ultrasound evaluation of our first case demonstrated hypo-echoic thickened anterior strap muscles while in the second case there was significant distortion of the anatomy from previous surgeries. It was necessary to proceed with FNA biopsy even when their ultrasound findings were equivocal, to establish a definite rapid diagnosis. The immediate onsite evaluation findings were suggestive of malignancy in both cases with subsequent core biopsy confirming the diagnosis of metastatic breast carcinoma. In cytopathology, point-of-care (POC) ultrasound is used as an adjunct tool that offers visual guidance during FNA of nonpalpable masses and enables sampling of lesional "hot" spots to ensure specimen adequacy. Studies have demonstrated a reduction in FNA nondiagnostic rates with the use of ultrasound-guidance consequently reducing health care costs associated with nondiagnostic FNAs. US-FNA also provides adequate samples for cell block preparations. Metastatic lobular carcinoma of the breast has a wide range of clinical presentations and a high level of suspicion is advised. Cytopathologists-performed US-FNA is a proven, less-invasive, cost-effective tool that provides timely cytologic diagnosis. PMID- 30468320 TI - Cytomorphological features of high-grade intraepithelial neoplasia/carcinoma of the cervix following chemoradiotherapy. AB - BACKGROUND: Cervicovaginal cytology as a follow-up study in women with a history of a cervical carcinoma treated with chemo-radiotherapy (CRT) plays an important role; however, the cytomorphological characteristics for the diagnosis of high grade squamous intraepithelial lesions (H-SIL) in post-CRT patients have not been established. The aim of the study is to find the cytomorphological characteristics that support the diagnosis of H-SIL by conventional cytology in these patients. MATERIALS AND METHODS: This is a cross-sectional study from 2009 to 2015, which includes patients with a diagnosis of squamous cell carcinoma treated with CRT, who all have cervix cytology for follow-up and a later biopsy. RESULTS: We identified 82 cases, where the most frequent clinical stage was IIA1 to IIB with 26 cases (61.9%), the most common symptom was transvaginal bleeding (64.29%). The cytological characteristics that were statistically associated with the presence of a positive biopsy were the presence of a hemorrhagic background (45.2% vs. 12.5%, P = .007), high cellularity (45.2% vs. 15%, P < .001), disposition in groups/sheets (69% vs. 22.5%, P < .001), postradiotherapy changes at the background of the smear (73.8 vs. 50%, P < .001) and an increased nuclear/cytoplasmic ratio (100% vs. 22.5%, P < .001). CONCLUSIONS: In patients with CRT, the presence of specific features can help the diagnosis of H-SIL with excellent diagnostic performance. PMID- 30468321 TI - Role of fine needle aspiration cytology in the management of supraclavicular lymph node metastasis: Review of our experience. AB - INTRODUCTION: In the 19th century Virchow described that metastasis to left supraclavicular lymph nodes (SLN) could originate in neoplasms located under the diaphragm. In the same way, right SLN metastasis are usually thought to arise from thoracic neoplasms. Our aims are to review our experience with metastatic SLN diagnosed by fine-needle aspiration cytology (FNAC) and to discuss the location of the primary in these cases. METHODS: We have reviewed all lymph node FNACs diagnosed in a single tertiary hospital between 2010 and 2017 and we have included all cases of metastatic SLN. RESULTS: We have found 57 cases of SLN FNAC with a diagnosis of malignancy, 39 of which had no previous diagnosis (17 left, 20 right and 2 bilateral SLN). The most frequent diagnosis were adenocarcinoma, squamous cell carcinoma and small cell carcinoma. Right and bilateral SLN showed mainly lung metastasis. Left lesions were more widely distributed, with 11 originating in the lung, followed by the breast, gastroesophageal junction and prostate gland. In two cases, the primary origin was not identified. In SLN with metastasis of a known origin, the main source of the tumor was again the lung and only one case originated in the stomach (left SLN metastasis). CONCLUSIONS: The origin of SLN metastasis seems to be dependent on both the frequency of tumor types in each geographic area and tumor location. Left SLN are more frequently involved by infradiaphragmatic primary tumors, while right SLN are exclusively involved by supradiaphragmatic neoplasms. PMID- 30468322 TI - Yeasts and pseudoyeasts in genitourinary cytopathology. PMID- 30468323 TI - Anchorage-Dependent Cell Expansion in Fiber-Shaped Microcarrier Aggregates. AB - This paper describes a three-dimensional culture system for the expansion of anchorage-dependent cells using fiber-shaped microcarrier (MC; Cytodex3) aggregates, termed "MC fibers". The fiber encapsulates the cells, the MC aggregates, and collagen and is covered with a poly-l-lysine membrane. The thin structure of the fiber enables sufficient supply of O2 and nutrients to the cell. Using the MC fiber, we demonstrated the efficient expansion of C2C12 cells with high viability through serial passaging. Therefore, our culture system is useful for various applications where large-scale cell expansion is required, such as in pharmaceutical technologies, regenerative medicine, and cultured meat production. This article is protected by copyright. All rights reserved. PMID- 30468324 TI - A 10 year retrospective review of fine needle aspiration cytology of cystic lesions of the breast with emphasis on papillary cystic lesions. AB - BACKGROUND: Fine needle aspiration cytology (FNA) is a simple, safe, cost effective, and accurate method for diagnosis of cystic lesions of the breast. Our study aims to correlate FNA cytology of cystic lesions of the breast with the histologic diagnosis. METHODS: During a period of 10 years (2007-2017), 314 cases of breast cystic lesions were retrieved from a total 1073 cases of breast FNAs. Of these, 78 cases from 77 patients (mean age = 54.6, female: male = 76:1) with simultaneous FNA and core needle biopsy (CNB) and/or excision specimen were reviewed. The FNA cytology reports were correlated with the histology results of CNB (n = 72) and breast excision (n = 20). RESULTS: Overall, 73 of 78 (93.6%) FNA cases were concordant with CNB and/or excision results. Fifty-five benign FNAs were all concordant with histology and reported as benign (negative predictive value = 100%). The positive predictive value of FNA with a malignant diagnosis was 100%, 71.4% for a suspicious diagnosis, and 33.3% for atypical cytologic diagnosis. Two of six papillary lesions were discordant with the concurrent CNB, but the FNA results were concordant with the final histology on excision. CONCLUSIONS: FNA allows accurate diagnosis of benign cystic lesions. FNA also plays a prominent role in evaluating cystic papillary lesions of the breast and helps to prevent false negative results on the simultaneous CNB. It is essential that FNA and CNB diagnoses be used in combination to make the correct diagnosis and for clinical management. PMID- 30468325 TI - Evaluation of rumination time, subsequent yield, and milk trait changes dependent on the period of lactation and reproductive status of dairy cows. AB - The aim of this research was to determine rumination time (RT) and the subsequent milk yield, along with trait changes during lactation dependent on the reproductive status of dairy cows. 728 cows were selected for evaluation in regards to 1-150 days of milk production (DIM). According to their period of lactation and reproductive status, the cows were selected for the following groups: Inseminated (1-35 days after insemination, n=182), Open (45-90 days after calving, n=126), Fresh (1-44 days after calving, n=45); Not-pregnant (>35-60 days after inse- mination and not-pregnant, n=55); Pregnant (35-60 days after insemination and pregnant (n=320). The animals were milked with Lely Astronaut(r) A3 milking robots. The daily milk yield, rumination time, bodyweight, milk composition (fat, protein, lactose, somatic cell count and gynecological status date) were collected from the Lely T4C management program for analysis. We estimated the lowest productivity in the pregnant cows, where the average milk yield was 28.72 kg and the highest productivity in the fresh cow (p?0.001)(Table 1). The longest rumina- tion time was determined for the inseminated cows, statistically significantly higher at 9.92% (p?0.001) than in the non-pregnant cows, whose rumination time was the shortest. The statisti- cally reliably RT positively correlated with productivity (r=0.384, p?0.001) of the cows (from r=0.302 in the second lactation and r=0.471 in the first lactation to r=0.561 in multiparous cows; p0.001). Rumination time, according to groups of cows by milk yield, had a tendency to increase (2.14 times) from 202.0+/- 87.38 (in cows with a productivity of less than 10 kg milk) to 431.6+/-33.91 (in cows with a milk yield higher than 50 kg) by the linear regression equation: y = 38.02x + 232, R2 = 0.721 (p?0.001). The relation between the gynecological status and milk fat protein ratio of the cows was statistically significant (chi2=2.974, df= 8, p ?0.0001). The longest rumination time was determined for the inseminated cows (1 35 days after insemination), and the shortest for the not-pregnant cows (>35 - 60 days after insemination and not-pregnant). We can conclude that rumination time, subsequent yield, and milk trait change depends on the period of lactation and reproductive status of a dairy cow. PMID- 30468326 TI - Biological characteristics of a new antibacterial peptide and its antibacterial mechanisms against Gram-negative bacteria. AB - MDAP-2 is a new antibacterial peptide with a unique structure that was isolated from house- flies. However, its biological characteristics and antibacterial mechanisms against bacteria are still poorly understood. To study the biological characteristics, antibacterial activity, hemolytic activi- ty, cytotoxicity to mammalian cells, and the secondary structure of MDAP-2 were detected; the results showed that MDAP-2 displayed high antibacterial activity against all of the tested Gram-negative bacteria. MDAP-2 had lower hemolytic activity to rabbit red blood cells; only 3.4% hemolytic activity was observed at a concentration of 800MUg/ml. MDAP-2 also had lower cytotoxicity to mammalian cells; IC50 values for HEK-293 cells, VERO cells, and IPEC-J2 cells were greater than 1000 MUg/ml. The circular dichroism (CD) spectra showed that the peptide most- ly has alpha helical properties and some beta-fold structure in water and in membrane-like conditions. MDAP-2 is therefore a promising antibacterial agent against Gram negative bacteria. To deter- mine the antibacterial mechanism(s) of action, fluorescent probes, flow cytometry, and transmis- sion electron microscopy (TEM) were used to study the effects of MDAP-2 on membrane perme- ability, polarization ability, and integrity of Gram-negative bacteria. The results indicated that the peptide caused membrane depolarization, increased membrane permeability, and destroyed membrane integrity. In conclusion, MDAP-2 is a broad-spectrum, lower hemolytic activity, and lower cytotoxicity antibacterial peptide, which is mainly effective on Gram-negative bacteria. It exerts its antimicrobial effects by causing bacterial cytoplasm membrane depolarization, increas- ing cell membrane permeability and disturbing the membrane integrity of Gram-negative bacte- ria. MDAP-2 may offer a new strategy to for defense against Gram-negative bacteria. PMID- 30468327 TI - Sensitivity to antimicrobials of faecal Buttiauxella spp. from roe and red deer (Capreolus capreolus, Cervus elaphus)detected with MALDI-TOF mass spectrometry. AB - Wild ruminants are an interesting topic for research because only limited information exists regarding their microbiota. They could also be an environmental reservoir of undesirable bacteria for other animals or humans. In this study faeces of the 21 free-living animals was sampled (9 Cervus elaphus-red deer, adult females, 12 Capreolus capreolus-roe deer, young females). They were culled by selective-reductive shooting during the winter season of 2014/2015 in the Strzalowo Forest District-Piska Primeval Forest (53 degrees 36 min 43.56 sec N, 21 degrees 30 min 58.68 sec E) in Poland. Buttiauxella sp. is a psychrotolerant, facultatively anaerobic, Gram-negative rod anaerobic bacte- rial species belonging to the Phylum Proteobacteria, Class Gammaproteobacteria, Order Entero- bacteriales, Family Enterobacteriacae and to Genus Buttiauxella. Buttiauxella sp. has never previ- ously been reported in wild ruminants. In this study, identification, antimicrobial profile and sensitivity to enterocins of Buttiauxella strains were studied as a contribution to the microbiota of wild animals, but also to extend knowledge regarding the antimicrobial spectrum of enterocins. Five strains were identified using the MALDI-TOF identification system (evaluation score value was up to 2.224) and allotted to the genus Buttiauxella including the species Buttiauxella gaviniae, B. ferragutiae, B. agrestis. Strains were DNase negative, and they hydrolysed esculin; fermentation of L-arabinose, D-mannitol and D-mannose was positive. Dulcitol, inositol reaction, urea and indol were negative. Buttiauxella strains did not form biofilm. They were resistant to at least one of the 13 antibiotics tested. B. agrestis 2/109/1 was resistant to amdinocillin, clindamycin and pen- icillin. However, Buttiauxella strains were sensitive to the enterocins used (inhibition activity ranged from 100 to 25 600 AU/ml). PMID- 30468328 TI - A complete analysis of Relative Synonymous Codon Usage in HVRs1-4 region in adenovirus genome. AB - Recent outbreaks of adenovirus (FAdV) infections in poultry flocks have been determined in many countries in Europe, Asia and Australia connected with economic consequences, and loses in poultry production. To better understand the evolution and transmission of FAdV viruses, de- tailed codon usage analysis was performed for 137 recently obtained FAdV strains. A high effec- tive number of codons, and an indication the presence of low codon usage were determined. The presence of mutations, and their influence on codon usage was confirmed by a correlation be- tween nucleotide compositions at the 3rd codon positions, HVRs1 4, and ENCs. This presence indicate some influence of natural selection, and antigenic properties of examined FAdV strains. PMID- 30468329 TI - Concentration levels of cadmium and lead in the raw and processed meat of Helix pomatia snails. AB - This work reports on cadmium and lead contaminations in the edible snail Helix pomatia harvested in Poland. One hundred and 24 samples of Helix pomatia meat collected from seven provinces (voivodeships) of Poland were analyzed for their trace metal levels by graphite furnace atomic absorption spectrometry (GFAAS). The research was conducted in 2 stages. The 1st stage analyzed snail meat prior to any further technological treatment (raw meat). In the 2nd stage, the trace element levels were measured in meat subjected to technological treatment (processed meat). The trace element contents in raw meat samples ranged from 0.06 mg kg-1 to 0.22 mg kg-1 for Cd and from 0.06 mg kg-1 to 0.18 mg kg-1 for Pb. The analyses revealed an increase in the cad- mium content from 0.12 mg kg-1 to 0.18 mg kg-1 in thermally treated snail meat and no changes in lead concentration during the two-stage heat treatment. Regulation (EC) 1881/2006 does not specify the Cd and Pb residue limits in meat of terrestrial edible snails. The limits are set for in- vertebrate aquatic organisms meat (i.e. shellfish, mollusc, cephalopod) and range from 0.5 mg/kg to 1.5 mg/kg of tissue fresh weight for Pb and from 0.5 mg kg -1 to 1 mg kg-1 for Cd (EU Commis- sion 2006). The results demonstrate that the land snail Helix pomatia has a tendency to bioaccu- mulate trace elements, and the cooking process is likely to affect (increase) the Cd content in the snail meat. PMID- 30468330 TI - The influence of selenium and vitamin E supplementation on cytological assessment of red blood cell line of bone marrow in fallow deer kept in captivity. AB - Cytological evaluation of bone marrow smears stained by May-Grunwald Giemsa method was performed. The smears came from 20 fallow deer (Dama dama) 3 days old divided into 2 groups each consisting of 10 animals. The experimental group (E) received intramuscularly selenium and vitamin E at a dose of 3.0 ml (tocopherol acetate - 50 mg, sodium selenite - 0.5 mg, solvent - 1 ml) in the 3rd day of age. The control group (C) did not receive any supplementation or placebo. For hematological analyzes blood was collected three times: on 0, 15th and 25th day of the experiment. Serum concentration of selenium and vitamin E was determined using high perfor- mance liquid chromatography and glutathione peroxidase activity (GSH-Px) by kinetic method. On the 15th day after supplementation, a statistically significant increase in the percentage of erythroblastic cell line was observed in bone marrow smears. At that time, the increase in GSH-Px activity in the E group was also observed, reaching the value of 165.3 U/gHb, which was statisti- cally significant. The percentage of proerythroblasts (8.23% in group E and 5.02% in group C) differed significantly between groups at the 25th day after supplementation. This study revealed that supplementation of selenium and vitamin E resulted in an increase in the number of erythro- cytes to an average of 13.5 (? 1012/l) in the experimental group on 25th day with a significant increase in hemoglobin to 193 g/l in the experimental group. PMID- 30468331 TI - Detection of seroconversion to bovine herpesvirus 1 related alphaherpesvirus and bovine viral diarrhea virusin Polish free-living deer. AB - There are several infectious agents of domestic cattle that can also be present in free-living ruminant populations. These include bovine herpesvirus 1 (BoHV-1) and bovine viral diarrhea virus (BVDV) which are the causative agents of infectious bovine rhinotracheitis and bovine viral diarrhea, respectively. The study was conducted on serum samples from 59 red deer, 24 roe deer, and 3 fallow deer (86 in total), originating from two geographically separate areas of Poland. The samples were tested with commercially available ELISA tests for BoHV-1 and BVDV. The overall seroprevalence was 5.8% and 3.5%, respectively. All positive samples originated exclusively from red deer. Because of BoHV-1 ELISA cross reactivity with cervid herpesvirus 1 and 2 (CvHV-1 and -2) the nature of alphaherpesviruses infecting the sampled animals could not be assessed. PMID- 30468332 TI - Study on establishing normal ranges of chosen biochemical parameters of haemolymph of Cornu aspersum maxima and Cepaea nemoralis gastropods. AB - The aim of the study was to establish normal ranges for chosen biochemical parameters of haemolymph of snails (Gasropoda: Mollusca), in the light of the use of these animals as experi- mental models in various types of studies. The study was conducted on 100 specimens of Cornu aspersum maxima (CAM) and 100 specimens of Cepaea nemoralis (CN). The haemolymph col- lected from the animals was analysed using colorimetry to assay aspartate transaminase (AST) activity, alanine transaminase (ALT) activity, amylase activity and the concentrations of urea and triglycerides. In the further part of the study, the influence of administering doxycycline with feed on the change of AST and ALT activity in snail haemolymph has been studied. The normal values established for CAM are as follow: AST activity: 26-38 u/l, ALT activity: 0-11 u/l, amylase activity 9-16 u/l, concentration of urea: 3-6 mg/dl, concentration of triglycerides: 16-20 mg/dl. For CN, the following data have been obtained: AST activity: 30-80 u/l, ALT activity: 0-15 u/l, amylase activity 12-15 u/l, concentration of urea: 5-8 mg/dl, concentration of triglycerides: 18-24 mg/dl. It has been shown that doxycycline presents a high workload on the hepatopancreas of snails, which is reflected by a statistically significant (p ? 0.05) increase of AST and ALT activity in the haemolymph of the specimens which obtained doxycycline in feed, as compared to the groups with antibiotic-free feed. The haemolymph activity of both studied parameters increased together with study time and tetracycline administration time. PMID- 30468333 TI - Serological surveillance of avian influenza virus and canine distemper virus in captive Siberian Tigers in Northeastern China. AB - In order to understand infection of avian influenza A virus (AIV) and canine distemper virus (CDV) in the Siberian Tiger in Northeast China, 75 Siberian Tiger serum samples from three cap- tive facilities in northeastern China were collected. AIV and CDV antibody surveillance was test- ed by using hemagglutination inhibition and serum neutralization methods. The results showed that the seroprevalence of H5 AIV, H9 AIV and CDV was respectively 9.33% (7/75), 61.33% (46/75) and 16% (12/75). In the 1?years ?2 and > 5 year-old group, the seroprevalence of the H9 AIV was 24% and 80% (P ? 0.01), and the CDV seroprevalence was 6% and 36% (P ? 0.01), respectively. It was demonstrated that 3 (4%) out of 75 serum samples were AIV+CDV seropos- itive, with 2.67% (2/75) in H9+AIV and 1.33% (1/75) in H5+H9+AIV. To our knowledge, this is the first report of AIV and CDV seroprevalence in Siberian Tigers in China, which will provide base-line data for the control of AIV and CDV infection in Siberian Tigers in China. PMID- 30468334 TI - Screening for Mollicutes microorganisms in perinatal calf mortality cases in Polish dairy herds. AB - Perinatal calf mortality in dairy herds has been reported worldwide. The etiology of stillbirth is multifactorial, and can be caused by various species of bacteria and environmental factors. Among them some potential pathogens from the Mollicutes class such as Mycoplasma (M.) spp. and Ureaplasma (U.) diversum can be isolated from the bovine genital tract and other organs of the suspected cattle. The aim of this study was to evaluate if the bacteria belonging to the Molli- cutes class i.e. M. bovis, M. bovigenitalium, M. canadense, M. canis, M. arginini, M. bovirhinis, M. dispar, M. alkalescens and U. diversum could have an impact on perinatal calf mortality in selected Polish dairy farms. The material was: 121 stillborn calves (SB), 21 live born calves (C) and 131 cows (dams) from 30 Polish Holstein-Friesian herds. Samples were examined from all the SB calves' and six control euthanized calves' abomasal contents and lung samples collected during necropsy, and from the dams' serum and placenta. In dams the serological ELISA, and in calves and placenta samples molecular PCR/denaturing gradient gel electrophoresis, methods were used. Screening of dams' sera for antibodies to M. bovis (ELISA) showed seven dams positive for M. bovis, whereas none of the nine examined Mollicutes microorganisms were detected in the placenta and calves. PMID- 30468335 TI - Transthoracic lung and pleura ultrasonography as a diagnostic tool of pulmonary edema in dogs and cats. AB - Despite the consensus on the role of lung and pleura ultrasound in human medicine, veteri- nary medicine questions credibility of the pulmonary evaluation in ultrasound examination, based on the analysis of artifacts in animals with clinical signs of respiratory failure and possibility of pulmonary edema diagnosis with recognition of the degree of its severity. The study was conduct- ed on 47 animals (29 dogs and 18 cats) of different breeds, age and sex. In all of animals prior to the transthoracic lung and pleura ultrasound examination (TLPUS), all animals were subjected to a clinical examination and hematological blood test as well as chest radiography examination in three projections. Ultrasound imaging of the chest in each animal was performed at designated four defined segments. TLPUS in dogs and cats based on an analysis of artifacts allows recogni- tion of pulmonary edema, to the degree comparable to chest X-ray examination. The number of depicted B-lines artifacts is proportional to the degree of pulmonary edema. These results allow to reduce the number of radiographs and allow the shortening of the diagnostic process for pa- tients in life-threatening condition. PMID- 30468336 TI - Detection of rabbit haemorrhagic disease virus 2 (GI.2) in Poland. AB - In this paper we present the first cases of rabbit haemorrhagic disease virus 2 (RHDV2 - GI.2) in Poland. The virus was detected in liver samples of RHD suspected rabbits from Lodzkie and west Pomeranian voivodeships. In both cases, the typical clinical symptoms of the disease were observed despite the fact that the rabbits were previously vaccinated against RHD. In order to extend the analysis of the RHDV2 strain infecting the rabbits, the entire VP60 and NSP genes were amplified and sequenced. The results of rRT-PCR assay have shown that tested RHDV samples were positive for the presence of RHDV2. In the phylogenetic analysis of vp60gene the first Polish RHDV isolates (RED 2016 and VMS 2017) clustered together with the reference RHDV2, meaning they represent new evolutionary RHDV linkeages. The first Polish RHDV2 isolates showed about 97% nucleotide sequence identity with the reference RHDV2 strains and approximately 18% difference from classic RHDV and RHDVa variants. PMID- 30468337 TI - Immunoreactivity for calretininin interneurons of the hippocampal CA1 field and dentate gyrus in adult rats after administration of habanero peppers (Capsicum chinense Jacq.). AB - Calretinin (CR), a calcium-binding protein from EF-hand family, is localised in non-pyramidal GABA-ergic interneurons of the hippocampus. CR takes part in maintaining calcium binding homeostasis, which suggests its neuroprotective role. Hippocampal neurons contain membrane transient receptor potential vanilloid 1 (TRPV1) which binds to capsaicin (CAP) contained in habanero pepper fruits. Few in vivo studies have revealed the effect of CAP on interneurons containing CR. The aim of the present study was to investigate the CR immunoreac- tivity in interneurons of the hippocampal CA1 field and dentate gyrus (DG) in adult rats after intragastric admin- istration of the habanero pepper fruits. Wistar rats received a peanut oil - control group (C), and oil suspension of habanero pepper fruits at doses of 0.025 g dm/kg b.w. - group I and 0.08 g dm/kg b.w. - group II for 28 days. After euthanasia, the brains were collected and embedded in paraffin blocks using a routine histological tech- nique. Frontal hippocampal sections were immunohistochemically stained for CR by using a peroxidase-antiper- oxidase method. CR immunoreactive (CR-IR) interneurons were morphologically and morphometrically ana- lyzed under a light microscope. The results showed similar shapes and distribution of cells in both areas of the brain in group C and I of animals. However, CR-IR interneurons in the hippocampal CA1 field and in DG were occasionally observed in the group II of rats. The results of morphometric studies did not reveal statistically significant differences in the surface area and shape index of cells between examined brain regions from groups I and II compared to group C. Only in group II of rats, an increase in the digital immunostaining intensity of CR-IR interneurons was found in DG. Low number of CR IR interneurons in the hippocampal CA1 field and in the DG, under the influence of a large dose of habanero pepper fruits containing CAP, may be caused by the activation of TRPV1 receptors and the increase in Ca2+ ions in these cells. This phenomenon may ultimately lead to neuronal death and may disturb neuronal conduction. PMID- 30468338 TI - Histopathological changes and oxidative damage in hepatic tissue of rats experimentally infected with Babesia bigemina. AB - The present study was aimed to investigate oxidative stress, DNA damage, and histopatholog- ical alterations in hepatic tissues of splenectomized Wistar rats experimentally infected with Ba- besia bigemina. Rats were challenged with 5x106 infected erythrocytes. Babesia infection was con- firmed both with Giemsa's staining blood smears and nested-PCR amplified region of apical membrane antigen 1 (AMA-1) gene. Parasitemia reached approximately 10 % at day 5 post-in- fection. Livers of infected rats were enlarged and darker in color, became extremely brittle with marked congestion. Microscopic evaluation showed cytoplasmic clearing of hepatocytes and se- vere hydropic changes with significantly dilated sinusoids containing macrophages and also intra- sinosoidal parasitized erythrocytes. Severe infiltration of lymphoplasma cells was also present throughout the liver parenchyma. Furthermore, Kupffer cells were enlarged and, occasionally, containing Babesia-parasitized erythrocytes. The activity of Glutathione (GSH) and catalase (CAT), and total antioxidant capacity (TAC) were also significantly decreased (p ? 0.05) after infection of rats with B. bigemina. B. bigemina infection also induced a significant increase (p ? 0.05) in hepatic malondialdehyde (MDA) and nitric oxide-derived products (NOx) concentra- tions as well as amount of endogenous hepatocytes DNA damage. Hepatic damage was also re- flected through the measurement of lactic acid dehydrogenase (LDH) and protein carbonyl con- tent (PCO) in liver cells. These two indices of liver injury were also significantly elevated (p ? 0.5) during B. bigemina infection. Evaluation of correlation between assayed variables in infected rats revealed that MDA levels were positively correlated with PCO, NOx, LDH and DNA damage in the infected group and negatively correlated with GSH, CAT and TAC. There was also an inverse relationship between the antioxidant enzymes activities of GSH, CAT and TAC with PCO, NOx and DNA damage in infected rats. However, NOx showed positive correlation with PCO and DNA damage in infected rats. On the basis of the above results it can be concluded that the Ba- besia infection increases oxidative stress markers, protein carbonyl content and DNA damage and decreases antioxidant enzymes activities in the liver. These results suggest that B. bigemina infec- tion could alter the liver histopathology and causes DNA damage following oxidative stress in hepatic tissue. Further studies are needed to precisely define how hepatic tissue damage takes place in B. bigemina infection. PMID- 30468339 TI - Iron status in dogs with myxomatous mitral valve disease. AB - In humans, iron deficiency represents a relevant occurrence in heart failure (HF), with or without anaemia, and is associated with the worst outcome. Moreover, chronic kidney disease (CKD) is a well-known comorbidity of HF and is strongly associated with the risk of developing anaemia. The most common cause of HF in dogs is myxomatous mitral valve disease (MMVD). To the best of our knowledge, no studies have examined the iron status in dogs with HF, with and without CKD. The aim of this retrospective study was to evaluate the iron status in dogs affected by MMVD and how strong is the relation with HF. The retrospective study included 54 dogs with complete case records, echocardiography and laboratory analyses. Iron status was evaluated by measuring serum iron concentration (SIC), un- saturated iron binding capacity (UIBC), total iron binding capacity (TIBC), and percentage of saturation (%SAT). The prevalence of dogs showing low serum iron concentration (SIC) was 18% in the whole population, 33% in symptomatic patients, 100% in dogs with acute decompensated HF. No signif- icant differences in SIC, UIBC, TIBC and %SAT median values were found among dogs classi- fied in different ACVIM (American College of Veterinary Internal Medicine) classes, between symptomatic and non-symptomatic patients, and among IRIS (International Renal Interest Soci- ety) classes. Azotemic and non-azotemic patients presented a significant difference in SIC mean values (p=0.02). Generalised linear model (GLM) revealed that dogs with low SIC were at high- er risk of being included in a higher ACVIM class (OR=6.383, p-value=0.014). Log rank analysis showed shorter survival in dogs with low SIC (p=0.020), multivariate Cox analysis revealed that only HF symptoms can affect survival. PMID- 30468340 TI - Genotyping and pathogenic characterization of canine distemper virus based on mutations in the hemagglutinin gene in Chinese domestic dogs. AB - Canine distemper virus (CDV) infects wild and domestic Canidae worldwide. The hemag- glutinin (H) gene has the highest genetic variation in the genome of this virus. Thus, the H gene is commonly used for lineage identification and genetic analyses. In order to study the genetic characteristics and pathogenicity of CDV strains prevalent in China, 132 samples were collected from domestic dogs with suspected CDV infection, 58 samples were confirmed to be positive, and the H gene was successfully amplified from 15 samples. The epidemic strain was identified as type Asia-1 and the novel mutations, A51T, V58I, R179K and D262N, were detected in this strain. Isolated strains, BJ16B53, BJ16B14, and BJ17B8, were used for an animal infection experiment in raccoon dogs. BJ16B53 and BJ16B14 were found to cause clinical symptoms, death, and exten- sive lesions in various organs. These results are expected to facilitate the development of effective strategies to monitor and control CDV infection in China. PMID- 30468341 TI - Differences in the pharmacokinetics of flumequine after single and continuous oral administration in non-fasted broiler chickens. AB - The aim of this study was to determine the influence of feed on the pharmacokinetics of flumequine (FLU) administered to broiler chickens as follows: directly into the crop (10 mg/kg of BW) of fasted (group I/control) and non fasted chickens (group II), or administered continu- ously with drinking water (1 g/L for 72 h) and with unlimited access to feed (group III). Plasma concentration of FLU was determined by high-performance liquid chromatography with fluo- rescence detection. In group II, a significant decrease in the maximum concentration (Cmax = 2.13+/-0.7 MUg/mL) and the area under the concentration curve from zero to infinity (AUC0->infinity = 7.47+/-2.41 MUg.h/mL) was noted as compared to the control group (Cmax = 4.11+/-1.68 MUg/mL and AUC0->infinity = 18.17+/-6.85 MUg.h/mL, respectively). In group III, the decrease in AUC was signifi- cant only in the first 3 hours (AUC0->3 = 5.02+/-1.34 MUg.h/mL) as compared to the control group (AUC0->3 = 7.79+/-3.29 MUg.h/mL). The results indicate that feed reduced the bioavailability of FLU from the gastrointestinal tract by at least 50% after the administration of a single oral dose. However, continuous administration of FLU with drinking water could compensate for the feed-induced decrease in absorption after single oral dose. PMID- 30468342 TI - Detection of IL-1beta, IL-6 and TNF-alpha in Sprague-Dawely rats' atrophic thymus induced by lipopolysaccharide. AB - OBJECTIVE: This study aimed to investigate developmental changes of the thymus and intra- thymic IL-1beta, IL-6 and TNF-alpha expression in weaned Sprague Dawley rats induced by lipopolysac- charide. METHODS: Forty healthy weaned rats aged 26 days and weighing 83+/-4 g were randomly and equally divided into two groups. The lipopolysaccharide group was treated daily with a single injection of lipopolysaccharide for 10 consecutive days, and the saline group was treated with an equal volume of sterilized saline. On the 1st, 4th, 7th and 10th day, histological changes and distribu- tion of IL-1beta-, IL-6- and TNF-alpha positive cells were detected in the thymus by hematoxylin-eosin and immunohistochemistry staining, respectively. Subsequently, the expression levels of IL-1beta, IL-6 and TNF-alpha were evaluated in the thymus by the ELISA method. RESULTS: Thymus weight and index were significantly smaller in lipopolysaccharide treated rats than in saline-treated rats (p?0.05), but no substantial changes were found in the thymus microstructure after lipopolysaccharide induction. Moreover, a large number of IL-1beta-, IL-6- and TNF-alpha-positive cells were observed with brownish-yellow color and mainly distributed in the thy- mus parenchyma, both integrated optical density and average optical density increased signifi- cantly in lipopolysaccharide-treated rats than those in saline-treated rats. Compared with the saline group, most of the thymic homogenates had higher levels of IL-1beta, IL-6 and TNF-alpha in the lipopolysaccharide group on different days. CONCLUSION: These findings indicate that the thymus atrophied after lipopolysaccharide induction in weaned Sprague-Dawley rats, and excessive production of intrathymic IL-1beta, IL-6 and TNF-alpha was probably involved in the atrophic process. PMID- 30468343 TI - Genetic characterization of Infectious Bursal Disease Viruses isolated from the vaccinated broiler chicken flocks in Egypt during 2015-2016. AB - The present study was conducted to characterize the infectious bursal disease virus (IBDV) circulating in clinically diseased broiler chicken flocks with previous vaccination history during 2015-2016 in Egypt. IBDVs were isolated from 48 out of 63 of the investigated bursae from 10 flocks onto embryonated chicken eggs (ECEs) and verified by reverse transcriptase-poly- merase chain reaction (RT PCR). Histopathologically, bursae lesions revealed some lymphocytes depletion as well as the presence of vesicles in the lining epithelium. The hyper variable region (HVR) of VP2 and VP1 genes of the 10 isolates (1 isolate/flock) were partially sequenced and subjected to comparative alignment and phyologenetic analysis. Phylogenetically, IBDV isolates were clustered into two distinct genetic lineages: variants of classical virulent (cv) and very viru- lent (vv) IBDV strains based on VP1 and VP2 amino acid (aa) sequences. Alignment analysis of HVR-VP2 aa sequences has demonstrated that the vvIBDV isolates have the conserved residues of the vvIBDV pathotype (A222, I242, and I256), while, the cvIBDV isolates have the same aa sequences of the classical attenuated vaccine strain (D78). Expected single point mutation occurred at position 253 (H253N). All previously characterized isolates were re-subjected to molecular analysis with VP1 protein due to its correlation with virulence and pathogenicity of IBDVs. vvIBDV isolates have the conserved tripeptide (TDN), while, the cvIBDV isolates have aa substitutions at conserved tripeptide including NEG at 145-147 amino acid. The present study has demonstrated that variants of classical virulent and very virulent IBDV circulated among vaccinated flocks in Egypt during 2015-2016. PMID- 30468344 TI - Preovulatory progesterone secretion terminates the duration of reproductive behavior during heat in the bitch. AB - To evaluate the role of preovulatory progesterone on canine sexual behavior and the course of proestrus and estrus, seven bitches in spontaneous cycles were treated with aglepristone for temporary elimination of progesterone action. Aglepristone was administered at the dose 10 mg/kg b.m., two times 24 hours apart, beginning in early proestrus when progesterone concen- tration was ?0.5 ng/ml. Seven untreated bitches served as a control group. Reproductive sexual behavior (standing behavior, display vulva, tail deviation) was evaluated according to behavioral score. Cytologic, clinical and vaginoscopic examinations and progesterone measurements were used for the determination of proestrus and estrus and estimation of ovulation time. Although, a similar pattern and magnitude of sexual behavior were observed in both groups, the duration of a total reproductive behavior was significantly extended (28.71 +/- 2.06 vs 17.00 +/- 2.45, p ?0.05) in experimental group; similarly, the length of cytologic estrus (23.86 +/- 3.02 vs 11.14 +/- 2.41, p ?0.05) was prolonged in treated bitches. In contrast, ovulation rate, duration of proestrus did not differ between the groups (p >0.05). We conclude, that during the canine estrus cycle the preovulatory progesterone terminates the duration of reproductive behavior and cytologic estrus. PMID- 30468345 TI - The effect of obesity on the bone morphometry and histomorphometry in male and female Wistar rats. AB - The study was undertaken to determine the effect of continuation or changes of the diet on the morphometry and histomorphometry of bone in male and female Wistar rats with experimen- tally induced obesity by high energetic diet. Sixty four 90-day-old Wistar rats obtained from obese parents (16 male, 16 female) and control parents (16 male, 16 female) were used in this study. After 21 days of the baby period, rats were divided into four groups: obese rats fed with high energy feed (F/F), control rats fed with a standard diet (C/C), obese rats with changed diet from high energy diet to control diet (F/C) and control rats with changed diet from control diet to high energy diet (C/F). After 90 days of experimental feeding, the rats were sacrificed. Thereafter, body weight and the isolated humerus were measured and next, the histological stainings and counts were done. Our results revealed that change in the parent's diet from F to C in the female leads to increased bone growth length and reduction of body weight in female and male. Reverse diet changes (from C to F) lead to decreased bone length only in the female. Moreover, the con- tinuation by offspring of both sexes with a high-energy diet contributes to a reduction in osteo- cytes, reduction in bone marrow cavity and cortical expansion, but a change in nutrition from parents' standard diet to high-energy diet leads to increase in osteocytes dimensions. The contin- uation of feeding with F diet promotes the accumulation of adipocytes in the bone marrow in female and male, and correction of nutrition from F to standard diet leads to a reduction in their number in the bone marrow compared to groups continuing feeding with high-energy diet. PMID- 30468347 TI - Royal jelly protection on flunixin meglumine-induced spermiotoxicity and testicular degeneration in mice. AB - Current study was designed to investigate the protective effects of royal jelly on Flunixin me- glumine (FM)-induced spermiotoxicity related to sperm concentration, abnormal spermatozoa count and histopathological changes in mice testis. The subjects were divided into five groups according to FM and/or royal jelly intake: Control group; group 1, FM alone (25 mg/kg, im); group 2, combination of FM (25 mg/kg, im) and royal jelly (200 mg/kg, oral); group 3, FM alone (50 mg/kg, im); and group 4, combination of FM (50 mg/kg, im) and royal jelly (200 mg/kg, oral). The animals were fed once daily for 15 days and they were sacrificed last day. Epididymal sperm concentration and abnormal spermatozoa count were noted. Testicular histological findings were evaluated. On purpose, organization of each animal was graded according to Johnsen's scoring to assess the spermatogenesis relying on seminiferous tubule cross-section scores. Comparing to controls, FM administration caused a decrease in sperm concentration (p?0.05), an increase in total abnormal spermatozoa rates (p?0.05) and more degenerative changes in testes in mice. Royal jelly supplementation ameliorated both sperm concentration and abnormal spermato- zoa (p?0.05) comparing to the control group. In conclusion, we suggested that royal jelly might have protective effects in the FM-induced reductions in epididymal sperm concentration and in- crease in abnormal spermatozoa rate. PMID- 30468346 TI - CO2 concentration affects in vitro pig embryo developmental capacity. AB - Culture gas atmosphere is one of the most important factors affecting embryo development in vitro. The main objective of this study was to compare the effects of CO concentration on the subsequent pre-implantation developmental capacity of pig embryos in vitro, including embryos obtained via parthenogenesis, in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI). Pig embryos were developed in four different CO2 concentrations in air: 3%, 5%, 10%, or 15%. The cleavage rate of pig parthenogenetic, IVF, or ICSI embryos developed in CO2 concen- trations under 5% was the highest. There were no significant differences in the oocyte cleavage rate in ICSI embryos in CO2 concentrations under 3% and 5% (p>0.05). However, as CO2 levels increased (up to 15%) the blastocyst output on day 7, from parthenogenetic, IVF, and ICSI em- bryos, decreased to 0%. These findings demonstrate that CO2 positively affects the developmen- tal capacity of pig embryos. However, high or low CO2 levels do not significantly improve the developmental capacity of pig embryos. The best results were obtained for all of the pig embryos at a 5% CO2 concentration. PMID- 30468348 TI - Effect of bamboo vinegar powder on the expression of the immune-related genes MyD88 and CD14 in weaning piglets. AB - The aim was to explore the feasibility of using bamboo vinegar powder as an antibiotics substitute in weaning piglets. Forty-five healthy Duroc * Landrance * Yorshire piglets (weight 6.74 +/- 0.17 kg; age 31 days) were randomly divided into the control group (basic diet), ANT group (basic diet + 0.12% compound antibiotics), BV1 group (basic diet + 0.1% bamboo vinegar powder), BV5 group (basic diet + 0.5% bamboo vinegar powder) and BV10 group (basic diet + 1% bamboo vinegar powder). MyD88 and CD14 expression in immune tissues was examined using real-time PCR. MyD88 expression in the control group were significantly lower than that in other groups in all tissues (p?0.05), while CD14 expression showed the opposite trend. MyD88 expression was significantly higher in the BV10 group than in other groups in lung tissue (P?0.05), significantly higher in the ANT group than in the BV1 group in the kidneys (P?0.05), significantly higher in the BV10 group than in the BV1 group in the thymus (P?0.05), and signifi- cantly higher in the BV1 group than in the BV10 group in the lymphatic tissue (P?0.05). These differences between experimental groups were not observed for the CD14 gene (P>0.05). Thus, adding bamboo vinegar powder to the basic diet of weaning piglets had immune effects similar to antibiotics and the effect was dose-dependent. Moreover, the MyD88 and CD14 genes appear to play a role in these immune effects. PMID- 30468349 TI - Optimal expression and purification of sapelovirus A structural protein VP1, and its immunogenicity in mice. AB - Sapelovirus A (SV-A) is a positive-sense single-stranded RNA virus which is associated with acute diarrhea, pneumonia and reproductive disorders. The virus capsid is composed of four proteins, and the functions of the structural proteins are unclear. In this study, we expressed SV-A structural protein VP1 and studied its antigenicity and immunogenicity. SDS-PAGE analysis revealed that the target gene was expressed at high levels at 0.6 mM concentration of IPTG for 24 h. The mouse polyclonal antibody against SV-A VP1 protein was produced and reached a high antiserum titer (1: 2,048,000). Immunized mice sera with the recombinant SV A VP1 protein showed specific recognition of purified VP1 protein by western blot assay and could recognize native SV-A VP1 protein in PK-15 cells infected with SV A by indirect immunofluorescence assay. The successfully purified recombinant protein was able to preserve its antigenic determinants and the generated mouse anti-SV-A VP1 antibodies could recognize native SV-A, which may have the potential to be used to detect SV-A infection in pigs. PMID- 30468350 TI - The effect of oxygen concentration on arterial blood partial pressure of oxygen in dogs under general anesthesia. AB - Oxygen is used for medical treatment and general anesthesia. However, high concentrations of oxygen can have toxic effects on cells. In veterinary medicine, 100% oxygen is usually used during general anesthesia and it can be toxic to animals. However, there is little concern about its harmful effects in humans. The objective of this study was to demonstrate that using a high con- centration of oxygen increases the partial pressure of oxygen in arterial blood (PaO2) more so than a lower concentration, by comparing PaO2 at three different oxygen concentrations (100%, 60%, and 40%) in six dogs under general anesthesia for 3 hours. The mean PaO2 and standard error values at the 100%, 60%, and 40% oxygen concentrations were 535.8 +/- 24.01, 374 +/- 17.19, and 239 +/- 8.78 mmHg, respectively (p?0.05). These results show that 100% and 60% oxygen concentrations could increase oxidative stress. Further studies are needed to examine the oxygen concentration that causes toxicity. PMID- 30468351 TI - Perspectives on novel vaccine development. AB - Vaccination is a common routine for prevention and control of human and animal diseases by inducing antibody responses and cell-mediated immunity in the body. Through vaccinations, smallpox and some other diseases have been eradicated in the past few years. The use of a patho- gen itself or a subunit domain of a protein antigen as immunogens lays the basis for traditional vaccine development. But there are more and more newly emerged pathogens which have expe- rienced antigenic drift or shift under antibody selective pressures, rendering vaccine induced im- munity ineffective. In addition, vaccine development has been hampered due to problems includ- ing difficulties in isolation and culture of certain pathogens and the antibody-dependent enhancement of viral infection (ADE). How to induce strong antibody responses, especially neu- tralizing antibody responses, and robust cell-mediated immune responses is tricky. Here we re- view the progress in vaccine development from traditional vaccine design to reverse vaccinology and structural vaccinology and present with some helpful perspectives on developing novel vaccines. PMID- 30468352 TI - Reactive oxygen metabolites in alpha-herpesvirus-seropositive Mediterranean buffaloes (Bubalus bubalis): a preliminary study. AB - In the present study on Bubalus bubalis of the Campania Region (Italy) the serum levels of derivatives of reactive oxygen metabolites (d-ROMs), anti-ROM and oxidative stress index (Osi) were evaluated. These data were then related to the seropositive status of the animals against alpha-herpesviruses, precisely Bubaline herpesvirus 1 (BuHV-1) and Bovine herpesvirus 1 (BoHV-1). Clinically healthy Mediterranean buffaloes were selected for this study. The serum samples of these animals were taken, and d-ROMs, anti-ROM and Osi were measured using commercially available tests. The preliminary data demonstrated that animals seropositive to both BuHV-1 and BoHV-1 present more oxidative stress than seronegative animals, as revealed by a significant increase in d-ROMs. Our results provide, for the first time, insight into the reac- tive oxygen species (ROS) modulation induced by the herpesvirus in Bubalus bubalis. PMID- 30468353 TI - Iodine supplementation activates folliculogenesis in rabbit ovary. AB - The aim of this study was to assess the biological effect of the product Jodis Concentrate (JC) on the rabbit ovaries by evaluating the folliculogenesis and expression of oocyte-specific growth differentiation factor 9 (GDF9).The experiment was conducted with 30 female two month old New Zealand rabbits that were the F1 offspring born to mothers differently treated with Jodis concentrate. The control group (n=10), consisted of F1 offspring born to mothers without iodine treatment, and was not supple- mented with JC. The first experimental group (n=10), consisted of F1 offspring born to mothers treated with JC during pregnancy and the suckling period, and was supplemented with JC daily at a dose of 2 ml/L drinking. The second experimental group (n=10), consisted of F1 offspring born to mothers without iodine treatment, and was also supplemented daily with the same dose of JC - 2 ml/L drinking. All groups were fed with total mixed ration for growing rabbits. The trial lasted 48 days. The ovaries were weighed and prepared for histological examination. The GDF9 protein expression in the ovary was determined by immunohistochemical analysis. The addition of JC to the drinking water of female rabbits led to more active development of the ovarian follicles from primordial to tertiary stage in both experimental groups. More intensive GDF9 protein expression in the oocytes and cumulus cells of rabbits, supplemented with JC was observed. PMID- 30468354 TI - Comparative analysis of cat bone marrow and adipose tissue cell cultures. AB - Cell culture transplantation is very promising in the treatment of various diseases. Cells obtained from a number of sources have been analysed to provide a basis for further studies in the area of regenerative medicine. The objective of the study was to compare morphological and phenotypic changes in cat adipose tissue and bone marrow cell cultures from the first to fifth passages. Adipose tissue and bone marrow were used to obtain cell cultures (coming from 3 cats) using standard methods with own modification. Phenotype changes were monitored by CD-marker identification and CD pan-keratin. The cytogenetic analysis was performed on 50 metaphase plates of cell cultures from the first to fifth passage. Cytogenetic assays showed that the adipose tissue cell culture (ATCC) at all passages was more stable than the bone marrow cell culture (BMCC). PMID- 30468355 TI - Effects of a combined strength and conditioning training program on physical abilities in adolescent male basketball players. AB - BACKGROUND: The aim of this study was to evaluate the effects of an in-season strength and conditioning program on physical abilities in under-16 sub-elite basketball players. METHODS: Sixteen young male basketball players were assessed using countermovement jump (CMJ), squat jump (SJ), 10-meters sprint and Pro Agility test, before and after an 8-week in-season strength and conditioning program. Both the control group (BASK; n = 7) and the experimental group (SC; n = 9) were involved in regular basketball practice; additionally, the SC group performed 4 sessions per week of training intervention considering post-match days and prior days to next match. The training protocol consisted of three components: a stabilization block, a neuromuscular/strength block (i.e. circuit of mobility, plyometric, coordination, reaction, and stability exercises) and a power block (i.e. resisted movement training performed with VertiMax V6 platform). RESULTS: Substantial improvements in CMJ (likely; d=0.30-0.47) were found in both groups. Moreover, the SC group displayed substantial increase in SJ (likely; d=0.07-1.26) and also in 10 m-sprint (d=-0.13-1.34). The between-group analysis also revealed greater improvements for the SC group in 10-m sprint (d=1.37) and SJ (d=0.50). CONCLUSIONS: In-season regular basketball practice plus strength and conditioning training program can lead to a greater improvements on jumping and sprinting abilities in male young basketball players comparing to the regular basketball training. PMID- 30468356 TI - Does "Kinesio" taping improve on balance and functional performance in older adults: a pilot study. AB - BACKGROUND: The foot and ankle are important factors that provide balance and functional performance in older adults at risk of falling. It is important that proper posture of the foot via techniques such as taping and orthoses to increase contact with the ground. The purpose of this study was to investigate for a two week period and prolonged effects (fourteen days) of 'Kinesio' tape on the level of functional performance, balance, muscle strength of the lower extremities, pain, and functional independence when 'Kinesio' tape was applied to the foot and ankle of older adults. METHODS: Randomized trial. Forty-two older adults aged 65 years or more were selected randomly into one of two groups [('Kinesio' tape (n = 22) and control (n = 20)]. 'Kinesio' tape was used on the ankle and food of older adults for a two-week period. Participants were evaluated using the Visual Analog Scale, Berg Balance Scale, Timed Up and Go Test, Mini- Mental State Examination, 30-Second Sit to Stand test and Functional Independent Measurement instrument. RESULTS: A significant difference was found between baseline and following application in the TUG and the BBS scores (p = 0.001 and p < 0.0001, respectively) in the 'Kinesio' tape group. CONCLUSIONS: Our results show that Kinesio tape improves balance and functional performance and reduces the risk of falling among older adults. PMID- 30468357 TI - Active recovery strategy and lactate clearance in elite swimmers. AB - BACKGROUND: Swimming requires sustained high performance, with limited recovery between heats, recovery strategies are essential to performance but are often self-regulated and sub- optimal. Accordingly, we investigated a physiologically determined recovery protocol. METHODS: Fifteen (m=9, f=6) international junior age group swimmers participated in this study. The average age of the participants was 15.8 +/- 1.5 years. All participants completed a lactate elevation protocol (8 x 50 m sprints), followed by one of three recovery strategies, 1) velocity at lactate threshold (VLT), 2) coach prescribed protocol (COA) and 3) national governing body recommendations (NGB) and thereafter a 200-m time trial. RESULTS: [lac-]B was similar between trials at baseline (pooled data: 1.3 +/- 0.4 mmol.l-1, P>0.05) but increased following 8x50 m sprints (pooled data 9.5 +/- 3.5 mmol.l-1, P<0.05) and reduced in all conditions (mean reduction 6.4 +/- 1.7 mmol.l-1). [lac-]B remained elevated following NGB (5.6 +/- 0.8 mmol.l-1, P<0.05) compared with COA (2.3 +/- 1.7 mmol.l-1) and VLT (1.7 +/- 1.2 mmol.l-1) but was blunted during the 200-m time trial in VLT (6.4 +/- 1.7 mmol.l-1, P<0.05). Time trial performance was similar between trials; VLT (2.24 +/- 0.12 min), COA (2.23 +/- 0.14 min) and NGB (2.22 +/- 0.13 min, P>0.05). CONCLUSIONS: Despite similar performance, individually prescribed recovery strategy with a physiological basis will preserve repeated exercise performance performed on the same day. PMID- 30468358 TI - Preliminary results of a novel pure endoscopic procedure in the treatment of degenerative lumbar spinal disorders: double endoscopic technique. AB - BACKGROUND: With increased experience and the availability of new technical instrumentations, the surgical endoscopic indications for lumbar spinal pathologies have moved from simple prolapsed disk to canal stenosis. The available endoscopes come in two different sizes (10 mm and 6.3 mm in diameter); however, one is too bulky to use inside the spinal canal and the other is too small to achieve a fast bone decompression. METHODS: In order to overcome such problems, we developed and used a different surgical technique called: Double Endoscopic Technique. Using this approach, we operated and prospectively collected clinical information on 17 patients (Group A) suffering from a mixed (ligament-bone hypertrophy and prolapsed disk) single segmental lumbar canal stenosis. At a median of 13 months from surgery, all the patients in this group had a very good outcome with an improvement of the VAS and ODI. These clinical results were compared with those from another group of patients who had undergone surgery in the same Unit, but using standard MIS technique (Group B). Both groups were similar in terms of number, age, symptoms and stenosis location. In particular we compared the pre- and post-operative VAS and ODI values, the amount of postoperative pain killers used during the first week post-surgery, the length of in-hospital stay as well as the blood loss during surgery. RESULTS: Although our aim was only to present a novel surgical endoscopic technique, the results, with all the study limitations including small numbers and short follow-up, have shown that this procedure is safe and effective, yielding an outcome comparable to the standard MIS approach. Furthermore, it is less disruptive towards the involved anatomy, it gives less post-operative pain, it requires a smaller skin incision and the blood loss is negligible. CONCLUSIONS: Thus, this technique may guarantee a faster clinical recovery. PMID- 30468359 TI - Spinal meningioma surgery in the elderly: who benefits? AB - BACKGROUND: With increasing life expectancy and increasing demands on quality of life more spinal meningiomas will limit quality of life in elderly in the coming decades. We investigated whether elderly can improve neurologically and gain self dependence postoperatively. METHODS: Medical records of consecutive spinal meningioma patients from 2004 - 2015 were retrospectively analyzed. Age, gender, preoperative duration and quality of symptoms, pre- and postoperative McCormick score, Karnofsky Performace Status (KPS), American Society of Anesthesiologists Physical Status (ASA), modified Clinical Scoring System (mCSS) and tumor characteristics were included. Elderly were defined by >= 70 years. RESULTS: 129 patients were included, of which 44 >= 70 years. Younger patients were significantly better preoperatively in McCormick, KPS, ASA and mCSS within the first postoperative year. Both younger and elderly patients improved significantly postoperatively in McCormick, KPS and mCSS. Surgical complication rate was similar for younger and elderly patients (5.9 vs. 6.8%, resp.). Systemic complication rate was higher in elderly (0 vs. 6.8%, resp.). CONCLUSIONS: Surgery for spinal meningioma in elderly (KPS >= 40 and ASA <= 3) leads to a significant improvement of McCormick, KPS and mCSS postoperatively. This leads to a higher rate of self-dependency and thereby probably to an improvement of quality of life in elderly. However, special attention for systemic complications is necessary. PMID- 30468360 TI - The validity of the Acute Stroke Assessment using rapid Pseudo-continuous arterial spin labeling (ASAP-ASL) method for acute thrombectomy. AB - BACKGROUND: Recent clinical trials demonstrated the efficacy of thrombectomy for ischemic stroke against acute large vessel occlusion (LVO). To overcome the problem with excessive examination time for diagnosis of cerebral perfusion and/or the use of contrast agent to determine penumbra, we adopted a new magnetic resonance imaging technique named Acute Stroke Assessment using rapid Pseudo continuous arterial spin labeling (ASAP-ASL) method. METHODS: The study included healthy volunteers and clinical patients. The signal to noise ratio (SNR) and acquisition time were compared with various numbers of signal average (NSA) of rapid pseudo-continuous arterial spin labeling (pCASL) using the 10-mm thick slice width and narrow scan range focusing the level of basal ganglia by healthy volunteers. After applying clinically acceptable protocol for ASAP-ASL, we then checked image qualities and an accuracy of the method by comparing with the angiographical imaging obtained from the clinical patients regarding the degree of consistency. RESULTS: NSA were compared between two and fourteen, and 10 NSA was decided to be introduced for clinical use (1 minutes and 17 second) for obtaining clinically acceptable image, which was shorter than the time required for ordinary whole brain pCASL (approximately 5 minutes). In the clinical study, the occlusion site estimated by ASAP-ASL showed high correlation with that of digital subtraction angiography (kappa = 0.63-0.79). CONCLUSIONS: ASAP-ASL method requires approximately one minutes to obtain clinically relevant brain perfusion imaging which can successfully identify ischemic region in LVO patients. PMID- 30468361 TI - TiC14 promoted three component coupling reaction: an efficient method for the substituted tetrahydropyrilidene acetates. AB - The syntheses of substituted tetrahydropyrilidene acetates were accomplished by TiCl4 promoted carbon-carbon bond forming reaction of ethyl glyoxylate, 3,4 dihydro-2H-pyran and an appropriate carbon, oxygen or sulfur nucleophile. The reaction constitutes an efficient three component coupling process and the olefinic coupling product is dependent upon reaction temperature. PMID- 30468362 TI - All-in-One procedure: simultaneous percutaneous treatment of aortic and mitral valve disease in inoperable patient. PMID- 30468363 TI - Multidisciplinary biopsychosocial rehabilitation in chronic neck pain: a naturalistic prospective cohort study with intraindividual control of effects and 12-month follow-up. AB - BACKGROUND: In contrast to the large evidence of the effectiveness of multidisciplinary biopsychosocial rehabilitation (MBR) in chronic low back pain, little is known about the effects of MBR in chronic neck pain (CNP). AIM: To quantify short-term and 12-month effects of a 3-week CNP-specific MBR program. DESIGN: Naturalistic prospective observational cohort study with intraindividual control of effects. SETTING: Outpatient clinic at a tertiary physical medicine and rehabilitation centre. POPULATION: Consecutive patients with CNP (n=81) who participated in a CNP-specific MBR. METHODS: The intervention was a MBR outpatient clinic program. Primary Outcome was the North American Spine Society (NASS) questionnaire pain/function scale. Secondary outcomes included the NASS scale neurogenic symptoms, Short-Form 36 Health Survey (SF-36) and numerical rating scales (NRS) for maximum and average pain. Short-term changes of health were quantified using effect sizes (ES), which were corrected by the change during waiting time before MBR. RESULTS: At the end of treatment, the NASS pain/function scale showed significant improvement (p<.001) by a moderate corrected ES (ES=.59). Moderate significant improvements were also found for the NASS scale neurogenic symptoms (ES = .65), the SF- 36 scales bodily pain (ES = .56) and mental health (ES = .54), and the NRS maximum pain (ES = .59). Significant small corrected ES were found for the SF-36 scales physical functioning (ES = .32), physical role (ES = .41), vitality (ES = .42), social functioning (ES = .41), emotional role (ES = .41) and the NRS average pain (ES = .48). The improvement on the SF-36 scale general health was not significant (ES = .19). At the follow-up after 12 months, the NASS pain/function scale remained its moderate ES (ES = .52, p-value< .001). Also, the NASS scale neurogenic symptoms, the SF-36 scales bodily pain, general health, social functioning and mental health and both NRS pain scales showed significant benefits. CONCLUSIONS: This study showed that MBR may be effective in patients with CNP. Maintenance of moderate benefits in pain and function seems possible for at least 12 months. CLINICAL REHABILITATION IMPACT: The findings support the concept of CNP- specific MBR. PMID- 30468364 TI - Translation, cultural adaptation and validation of the cognistat for its use in Arabic speaking population with acquired brain injury. AB - BACKGROUND: The use of cognitive assessment tools is central to the detection of cognitive impairment in acquired brain injury patients. The Cognistat is a commonly used cognitive screening tool that can detect cognitive deficits among patients with neurological and psychiatric conditions. The Cognistat examines different major ability areas including level of language, construction, memory, calculation, reasoning, consciousness, orientation and attention. To date the Cognistat has not been translated/adapted for use in Arabic speaking countries. AIM: To provide normative data for the use of the Cognistat in Arabic-speaking populations with acquired brain injury. DESIGN: Cross-cultural validation study. SETTING: Inpatient TBI and stroke rehabilitation ward in a rehabilitation hospital. POPULATION: A total of 107 healthy Arabic speaking adults and 62 acquired brain injury patients were involved in the study. METHODS: After the completion of the cross-cultural adaptation process, psychometric properties of the adapted cognitive tool were evaluated. RESULTS: The Arabic Cognistat was found to have acceptable internal consistency, and the test-retest reliability showed high stability of scores over time. For concurrent validity, patients' performance on the Arabic Cognistat and the Mini-Mental State Examination were compared with excellent correlations overall. Significant differences between the performance of patients and the control group were found on all sub-tests. CONCLUSIONS: The Arabic Cognistat appears to be a valid and reliable cognitive screening tool. It is anticipated that the Arabic Cognistat will be widely used in the Arabic speaking countries, allowing for a very precise evaluation of cognitive deficits in acquired brain injury patients. CLINICAL REHABILITATION IMPACT: As part of the rehabilitation process, health care professionals are regularly required to test patients' cognitive abilities using appropriate measures. The findings of the study provide key solutions for the clinical assessment of Arabic populations: such cognitive tools could help improve the cognitive rehabilitation practice for the Arabic population by offering validated, reliable and culturally-adapted tests in the Arabic language. PMID- 30468365 TI - Are We Adhering To Paediatric DKA Guidelines? PMID- 30468366 TI - Tyranny of the pain score question after surgery PMID- 30468368 TI - La tyrannie de la question sur le score de douleur postoperatoire PMID- 30468369 TI - Could undertaking qualitative research serve to develop clinical empathy at undergraduate level? PMID- 30468370 TI - After the war is over: the role of General Sir Arthur Currie in the development of academic medicine in Canada AB - Summary: Canadian universities faced a challenge with the return of a large cohort of battle-hardened students and faculty from the First World War. General Sir Arthur Currie, considered one of the few successful generals of the war, returned to a welcome of silence in Canada. McGill University exploited the opportunity to recruit him as its president. Currie oversaw a campaign of building construction and faculty development at McGill that also had a significant effect on the rest of Canada. Through his fostering of the Montreal Neurological Institute and the recruitment of Dr. Wilder Penfield, Currie facilitated the development of multidisciplinary medicine, which integrates clinical care with research - an aspiration still held by specialty medicine in Canada today. PMID- 30468371 TI - My Father's Footsteps PMID- 30468372 TI - Correction: Reflections on recovery, rehabilitation and reintegration of injured service members and veterans from a bio-psychosocial-spiritual perspective PMID- 30468373 TI - Hidradenitis suppurativa: the "bright side" of autoinflammation and hidden diseases. PMID- 30468374 TI - Update on pathogenesis of hidradenitis suppurativa. AB - The exact pathogenesis of hidradenitis suppurativa (HS) is still unproven. In the last few years numerous studies hypothesized that the disease is triggered by genetic and environmental factors. Follicular occlusion seems to be central to its development followed by follicular rupture, and immune responses finally leading to the development of clinical HS lesions. Data to date suggest that there is immune dysregulation in both the cutaneous and systemic immune system in patients with HS, but relative contributions from the innate and adaptive immune systems have not been fully elucidated. Furthermore, it can be further assumed that endocrine disorders related to follicular diseases can be implicated in the pathophysiologic pathways of HS. This review focuses on the key role of the immune system and endocrine disorders in the pathogenesis of HS. PMID- 30468375 TI - Hidradenitis suppurativa and associated diseases. AB - Hidradenitis suppurativa is a chronic, inflammatory, recurrent, debilitating skin disease characterized by recurrent abscesses, draining sinuses, and scarring, affecting principally areas of body friction. Although the disease pathogenesis is not fully understood, recent advances suggest that hidradenitis suppurativa should be viewed as a systemic inflammatory disease. Moreover, recent studies have defined hidradenitis suppurativa as a systemic disease linked to several comorbidities. Metabolic disorders including obesity and metabolic syndrome are the most common associated conditions observed in patients with hidradenitis suppurativa. Autoimmune diseases, like inflammatory bowel diseases, autoinflammatory diseases, spondyloarthritis, some genetic keratin disorders and also the risk of skin tumor seems to occur more frequently in these patients. This disease can also have severe effects on self-esteem and quality of life and can be associated with psychiatric diseases. The link between hidradenitis suppurativa and systemic associations may be attributed to common genetic or environmental factors or shared inflammatory pathways. Due to these reasons it is mandatory that clinical intervention for hidradenitis suppurativa must include consideration and attention to these comorbidities and complications. In this article we have reviewed current available literature on diseases that can occur together with hidradenitis suppurativa. PMID- 30468376 TI - Multidisciplinary approach for hidradenitis suppurativa patients. AB - Hidradenitis suppurativa or acne inversa is an inflammatory, chronic disease of the hair follicles located in specific areas of the skin surface (axillae, submammary, inguinal and intergluteal folds, pubis, genitalia and buttocks). The diagnosis and the management of this disease are usually made by the dermatologist. However, the frequent association of hidradenitis suppurativa or acne inversa with important systemic comorbidities needs the cooperation with a number of specialists. In particular, the cooperation with rheumatologists, gastroenterologists, endocrinologists, microbiologists/infectivologists, psychologists/psychiatrics and plastic surgeons is often helpful or necessary. PMID- 30468377 TI - Role of the imaging techniques in the diagnosis and staging of hidradenitis suppurativa. AB - Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease mainly affecting the axillary, inguinal and anogenital regions, and characterized by the presence of nodules, abscesses and sinus tracts and scarring. Clinical examination alone may underestimate the disease extension and severity. Some non invasive skin imaging techniques such as ultrasound, magnetic resonance imaging, computed tomography, positron-emission tomography and dermoscopy, have been demonstrated to be useful in the diagnosis and management of HS. They may reveal some findings not appreciable at naked eye evaluation, suggesting the diagnosis in case of minimal/mild presentation or in non-active long-lasting cases and allowing a more accurate staging, treatment planning and monitoring of this debilitating disease. PMID- 30468378 TI - Understanding the surgical care needs and use of outpatient surgical care services among homeless patients at the Ottawa Hospital AB - Background: The use of outpatient health care services by homeless people is low compared to their high level of need; however, it is unclear whether this applies to surgical care. We sought to describe surgical care access among homeless patients in a Canadian tertiary care setting. Methods: We reviewed the medical records of adult (age > 18 yr) patients with no fixed address or a shelter address who presented to The Ottawa Hospital Emergency Department from Jan. 1, 2013, to Dec. 31, 2014, and required surgical referral. We analyzed the data using descriptive statistics. Results: A surgical referral was initiated in 129 emergency department visits for 97 patients (77 men [79%], mean age 46.7 yr). Most patients lived in shelters (77 [79%]) and had provincial health insurance (82 [84%]), but only 35 (36%) had a primary care physician. The mean number visits for any reason was 7.9 (standard deviation 13.7) (range 1-106). The majority of surgical referrals (83 [64.3%]) were for traumatic injuries, and the most frequently consulted service (52 [40.3%]) was orthopedic surgery. Just under half (48 [49%]) of referred patients attended at least 1 outpatient appointment, and only a third (33 [34%]) completed full follow-up. Conclusion: Homeless patients presenting to an emergency department and requiring surgical care were predominantly men living in shelters, most frequently seeking care for traumatic injuries. Current outpatient services may not meet the surgical care needs of these patients, as many do not access them. Alternative approaches to outpatient care must be considered, particularly among high-need services such as orthopedics, to support surgical care access among this population. PMID- 30468379 TI - Morphology Control of Porous Cellulose Particles by Tuning the Surface Tensions of Media at Drying. AB - We previously reported the preparation of cellulose particles by the solvent releasing method (SRM). The obtained cellulose particles had a porous structure filled with a surrounding medium. However, the structure was fragile and easily collapsed because of the capillary pressure as the medium evaporated, resulting in dense cellulose particles. To control the morphology of the cellulose particles in a dry state, we focused our study on the influence of surface tension of a surrounding medium on the structure of cellulose particles because the capillary pressure is proportional to the surface tension. Different media such as toluene, acetone, and pentane were investigated. The morphologies of the resulting cellulose particles were estimated by volume changes, specific surface areas, and compressive strengths. From these results, as the surface tension of the media filling the particles was lowered, the particle's specific surface area increased, resulting in the formation of softer particles. PMID- 30468380 TI - Molecular Simulations of Ion Effects on the Thermodynamics of RNA Folding. AB - How ions affect RNA folding thermodynamics and kinetics is an important but a vexing problem that remains unsolved. Experiments have shown that the free energy change, $?Delta G(c)$, of RNA upon folding varies with the salt concentration ($c$) as, $?Delta G(c) = k_c ?ln c+{?rm const}$, where the coefficient $k_c$ is proportional to the difference in the ion preferential coefficient, $?Delta ?Gamma$. We performed simulations of a coarse-grained model, by modeling electrostatic interactions implicitly and with explicit representation of ions, to elucidate the molecular underpinnings of the relationship between $?Delta G$ and $?Delta ?Gamma$. The simulations quantitatively reproduce the heat capacity for a pseudoknot, thus validating the model. We show that $?Delta G(c)$, calculated directly from $?Delta ?Gamma$, varies linearly with $?ln c$ ($c < 0.2$ M), for a hairpin and the PK, demonstrating a molecular link between the two quantities. Explicit ion simulations also show the linear dependence of $?Delta G(c)$ on $?ln c$ at all $c$ with $k_c = 2k_{?rm B} T$, except that $?Delta G(c)$ values are shifted by $?sim$2 kcal/mol higher than experiments. The discrepancy is due to an underestimation of $?Gamma$ for both the folded and unfolded states while giving accurate values for $?Delta ?Gamma$. The predictions for the salt dependence of $?Delta ?Gamma$ are amenable to test using single-molecule pulling experiments. The framework provided here can be used to obtain accurate thermodynamics for other RNA molecules as well. PMID- 30468381 TI - Dermal absorption of pesticide residues. AB - Current guidance for dermal exposure assessment of plant protection products typically uses in vitro skin penetration data for the active ingredient when applied as both the concentrated product and relevant spray dilutions thereof. However, typical re-entry scenarios involve potential skin exposure to a 'dried residue' of the spray dilution, from which the absorption of a pesticide may be quite different. The research reported in this paper has shown: [1] The method to assess the transfer of dried pesticide residues from a surface to the skin is reproducible for four active ingredients of diverse physicochemical properties, after their application in commercially relevant formulations. [2] Skin uptake and absorption of all four pesticides examined was significantly less from a dried residue than from a spray dilution; the difference, in general, was of the order of a factor of 2. [3] Decontamination experiments with one of the active ingredients tested (trinexapac-ethyl) showed that, post-exposure to a spray dilution, skin surface cleaning must be performed within 1 hour to significantly reduce potential systemic exposure (relative to continual contact for 24 hours); in contrast, after contact with a dried residue, the sooner decontamination was performed, the greater the decrease in exposure achieved, even when the time of contact was as long as 8 hours. PMID- 30468382 TI - Quantum Capacitance Based Amplified Graphene Phononics for Studying Neurodegenerative Diseases. AB - Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease, characterized by a rapid loss of upper and lower motor-neurons resulting in patient death from respiratory failure within 3-5 years of initial symptoms onset. Although at least 30 genes of major effect have been reported, the pathobiology of ALS is not well understood. Compounding this is the lack of a reliable laboratory test which can accurately diagnose this rapidly deteriorating disease. Herein, we report on graphene's phonon vibration-energies as a sensitive measure of the composite dipole moment of the components of the interfaced cerebrospinal fluid (CSF) to specifically identify patients with ALS disease. The second-order overtone of in-plane phonon vibration energy (2D) of graphene shifts by 3.2+/-0.5 cm-1 for all ALS patients studied in this work. Further, the amount of n-doping induced shift in phonon energy of graphene, interfaced with CSF, is specific to the investigated neurodegenerative disease (ALS, Multiple Sclerosis and Motor Neuron Disease). By removing a severe roadblock in disease detection, this technology can be applied to study diagnostic biomarkers for researchers developing therapeutics and clinicians initiating treatments for neurodegenerative diseases. PMID- 30468383 TI - Synthesis of Chiral Acyclic Nucleosides by Sharpless Asymmetric Dihydroxylation: Access to Cidofovir and Buciclovir. AB - An efficient method to construct chiral acyclic nucleosides via Sharpless asymmetric dihydroxylation of N-allylpyrimidines or N-alkenylpurines is reported. A range of chiral acyclic nucleosides with two adjacent hydroxyl groups present on the side chains could be produced in good yields (up to 97% yield) and excellent enantioselectivities (90-99% ee). The synthetic utility of the reaction was demonstrated by the catalytic asymmetric synthesis of (S)-Cidofovir and (R) Buciclover. PMID- 30468384 TI - Relative rates of hydrogen shift isomerizations depend strongly on multiple structure anharmonicity. AB - Hydroperoxyalkylperoxy species (OOQOOH) are important intermediates that are generated during the autoignition of transport fuels. A key reaction of hydroperoxyalkylperoxy radicals is a [1,5] hydrogen shift, for which kinetics data are experimentally unavailable. Here we study two typical OOQOOH reactions and compare their kinetics to one another and to a previous study to learn the effect of structural variations of the alkyl group on the competition between alternative [1,5] hydrogen shifts of hydroperoxyalkylperoxy species. We use electronic structure calculations to determine previously missing thermochemical data, and we use variational transition state theory (VTST) with multidimensional tunneling (MT), multiple structures, torsional potential anharmonicity, and high frequency anharmonicity to obtain more accurate rate constants than the ones that can computed by conventional single-structure harmonic transition state theory (TST) and than the empirically estimated rate constants that are currently used in combustion modeling. The calculated temperature range is 298-1500 K. The roles of various factors in determining the rates are elucidated, and we find an especially strong effect of multiple structure anharmonicity due to torsions. Thus, even though there is some cancellation between the anharmonicity of the reactant and the anharmonicity of the transition state, and even though the reactants are very similar in structure, differing only by a methyl group, the effect of multiple structure anharmonicity has a large effect on the relative rates - as large as a factor of 17 at room temperature and as large as a factor of 7 at 1500 K. This has broad implications for the estimation of reaction rates in many subfields of chemistry, including combustion chemistry and atmospheric chemistry, where rates of reaction of complex molecules are usually estimated without explicit consideration of this fundamental entropic effect. In addition, the pressure-dependence of the rate constants is modelled by system-specific quantum RRK theory. PMID- 30468385 TI - Graphene oxide quantum dot alters amyloidogenicity of hen egg white lysozyme via modulation of protein surface character. AB - A series of neurodegenerative disorders caused by intracellular or extracellular amyloid deposition including Alzheimer's disease, Parkinson's disease, Prion disease, etc. In order to prevent the progress of such amyloid-mediated disorders, various agents have been tested including nanoparticles. Among different nanomaterials, graphene oxide shows unique electrochemical properties which have potential applications in various biomedical fields. In our present investigation, we explored the effect of graphene oxide quantum dots (GOQD) in amyloid beta-fibrillation of hen egg white lysozyme (HEWL) under various conditions. Electron microscopy imaging showed that administration of GOQD inhibited HEWL amyloid beta-fibrillation via producing thin and small fragments of fibrils. Zeta potential measurement and 8-anilino-1-naphthalenesulfonic fluorescence study of lysozyme amyloid demonstrated a significant drop in surface hydrophobicity and an increase of surface charge of protein molecules. The reduced hydrophobic interaction and enhanced surface charge inhibit the hydrophobic assembly and colloidal stability of the protein. Circular dichroism and thioflavin-T fluorescence demonstrated that GOQD also interfered at secondary structure level and prevent amyloid beta-sheet formation and assembly of a protein by reducing the amount of amyloid beta-sheet formation. Further, cellular toxicity analysis with HaCaT and 3T3 cells showed reduced toxicity of amyloid samples prepared with GOQD. Therefore, GOQD might be used to be a potential amyloid-preventive agent in various neurodegenerative diseases. PMID- 30468386 TI - Design, synthesis and biological evaluation of 2-nitroimidazopyrazin-one/-es with antitubercular and antiparasitic activity. AB - Tuberculosis and parasitic diseases, such as giardiasis, amebiasis, leishmaniasis and trypanosomiasis, all urgently require improved treatment options. Recently, it has been shown that anti-tubercular bicyclic nitroimidazoles such as pretomanid and delamanid have potential as repurposed therapeutics for the treatment of visceral leishmaniasis. Here we show that pretomanid also possesses potent activity against Giardia lamblia and Entamoeba histolytica, thus expanding the therapeutic potential of nitroimidazo-oxazines. Synthetic analogs with the novel nitroimidazopyrazin-one/-e bicyclic nitroimidazole chemotype were designed, synthesized and structure activity relationships generated. Selected derivatives had potent antiparasitic and antitubercular activity whilst maintaining drug-like properties such as low cytotoxicity against mammalian cell lines (CC50 >100 MUM), good metabolic stability in human and mouse liver microsomes and high apparent permeability in a Caco-2 model of intestinal absorption. The kinetic solubility of the new bicyclic derivatives varied, and was found to be a key parameter for future optimization. Taken together, these results suggest promising subclasses of bicyclic nitroimidazoles containing different core architectures have potential for further development. PMID- 30468387 TI - Optical and Thermophoretic Control of Janus Nanopen Injection into Living Cells. AB - Devising strategies for the controlled injection of functional nanoparticles and reagents into living cells paves the way for novel applications in nano-surgery, sensing and drug delivery. Here, we demonstrate the light controlled guiding and injection of plasmonic Janus nanopens into living cells. The pens are made of a gold nanoparticle attached to a dielectric alumina shaft. Balancing optical and thermophoretic forces in an optical tweezer allows that single Janus nanopens are trapped and positioned on the surface of living cells. While the optical injection process involves strong heating of the plasmonic side, the temperature of the alumina stays significantly lower, thus allowing the functionalization with fluorescently labelled, single stranded DNA, and hence the spatially controlled injection of genetic material with an untethered nanocarrier. PMID- 30468388 TI - Adsorption characteristics of carboxymethylated lignin on rigid and soft surfaces probed by Quartz crystal microbalance. AB - Limited information is available on the interaction of anionically charged lignin and cationic particles, despite the promising use of anionic lignin as a coagulant and dispersant for suspension systems. The main objective of this study was to discover the fate of lignin on its interaction with rigid and soft surfaces. In this work, carboxymethylated lignin (CML) with two different charge densities were produced and their adsorption performance on gold and polydiallydimethyl ammonium chloride (PDADMAC)-coated gold surfaces was comprehensively studied. The viscoelastic properties of adsorbed CML on the gold surface was investigated by means of Quartz crystal microbalance with dissipation (QCM-D). A higher adsorbed amount and compact layer were observed for the adsorption of CML with a lower charge density of -1.16 meq/g (CML1). CML with a higher charge density (-2.92 meq/g), CML2, yielded a lower surface excess density of 2.31*10-6 mol/m2 and a higher occupied area per molecule (71.84 A2) at the interface of water and gold sensor. Below and at equilibrium, CML2 generated a bulkier adsorption layer than did CML1 on the gold sensor and on PDADMAC-coated sensor. Studies on the layer-by-layer (LBL) assembly of CML and PDADAMC revealed that CML1 adsorbed more greatly than CML2 on PDADMAC, and it generated a thicker but less viscoelastic layer. In this system, the greater loss to storage modulus (G"/G)'value was achieved for CML2, indicating its looser structure in the LBL system. Studies on the LBL assembly of carboxymethylated xylan/PDADMAC and CML/PDADMAC provided concrete evidence for the fate of 3-dimensional structure of CML on its adsorption performance. PMID- 30468389 TI - Rational Construction of Compact de Novo-Designed Biliverdin-Binding Proteins. AB - We report the rational construction of de novo-designed biliverdin-binding proteins by first principles of protein design, informed by energy minimization modeling in Rosetta. The self-assembling tetrahelical bundles bind biliverdin IXa (BV) cofactor autocatalytically in vitro, like photosensory proteins that bind BV (and related bilins or linear tetrapyrroles) despite lacking sequence and structural homology to the natural counterparts. Upon identification of a suitable site for ligation of the cofactor to the protein scaffold, stepwise placement of residues stabilized BV within the hydrophobic core. Rosetta modeling was used in the absence of a high-resolution structure to inform the structure function relationships of the cofactor binding pocket. Holoprotein formation stabilized BV, resulting in increased far-red BV fluorescence. Via removal of segments extraneous to cofactor stabilization or bundle stability, the initial 15 kDa de novo-designed fluorescence-activating protein was truncated without any change to its optical properties, down to a miniature 10 kDa "mini", in which the protein scaffold extends only a half-heptad repeat beyond the hypothetical position of the bilin D-ring. This work demonstrates how highly compact holoprotein fluorochromes can be rationally constructed using de novo protein design technology and natural cofactors. PMID- 30468390 TI - Impact of the Solid Interface on Proton Conductivity in Nafion Thin Films. AB - Proton conductivity of polyelectrolytes in the interfacial region with a solid is a key for the performance of polyelectrolyte-based fuel cells. The proton conductivity of Nafion thin films was examined as a function of the thickness along both directions, normal and parallel to the interface. Neutron reflectivity measurements revealed that a water-containing multilamellar structure was formed at the substrate interface. The presence of the interfacial layer, or the two dimensional proton-conductive pathway, suppressed and enhanced the out-of-plane and in-plane proton conductivity, respectively. The method of proton conductivity in the interfacial region differed from that in the bulk, namely the Grotthuss mechanism. Using laminated films, we conclude by showing that the proton conductivity in the Nafion thin film changes on the basis of the interface-to volume ratio. This knowledge will be helpful for the design of devices containing polyelectrolytes with solid materials. PMID- 30468391 TI - CO2 Reduction Catalysts on Gold Electrode Surfaces Influenced by Large Electric Fields. AB - Attaching molecular catalysts to metal and semiconductor electrodes is a promising approach to developing new catalytic electrodes with combined advantages of molecular and heterogeneous catalysts. However, the effect of the interfacial electric field on the stability, activity and selectivity of the catalysts are often poorly understood due to the complexity of interfaces. In this work, we examine the strength of the interfacial field at the binding site of CO2 reduction catalysts, including Re(S-2,2'-bipyridine)(CO)3Cl and Mn(S-2,2' bipyridine)(CO)3Br immobilized on Au electrodes. The vibrational spectra are probed by sum frequency generation spectroscopy (SFG), showing pronounced potential-dependent frequency shifts of the carbonyl stretching modes. Calculations of SFG spectra and Stark tuning rates based on density functional theory allow for direct interpretation of the configurations of the catalysts bound to the surfaces and the influence of the interfacial electric field. We find that electrocatalysts supported on Au electrodes have tilt angles of about 65-75?degrees, relative to the surface normal, with one of the carbonyl ligands in direct contact with the surface. Large interfacial electric fields of 10^8 10^9 V/m are determined through the analysis of experimental frequency shifts and theoretical Stark tuning rates of the symmetric CO stretching mode. These large electric fields thus significantly influence the CO2 binding site. PMID- 30468392 TI - Adjustment to acute or early HIV-1 infection diagnosis to prompt linkage to care and ART initiation: qualitative insights from coastal Kenya. AB - Diagnosing and treating patients with acute or early HIV-1 infection (AEHI) is an important strategy to prevent HIV-1 transmission. We used qualitative methods to understand factors that facilitate adjustment to AEHI diagnosis, prompt linkage to care and initiation of antiretroviral treatment (ART). Twenty-three AEHI patients (12 women, 11 men) included 18 participants identified at health facilities, and 5 participants identified in a sex worker cohort. Of these, 17 participants (9 women, 8 men) participated in qualitative interviews about their AEHI status 2 weeks after diagnosis. Thirteen participants (7 women, 6 men) returned for a second interview 12 weeks after diagnosis. Interviews explored participants' experiences at the time of and following their diagnosis, and examined perceptions about ART initiation and behavior change recommendations, including disclosure and partner notification. A grounded theory framework was used for analysis, eliciting three important needs that should be addressed for AEHI patients: 1) the need to better understand AEHI and accept one's status; 2) the need to develop healthy strategies and adjust to the reality of AEHI status; and 3) the need to protect self and others through ART initiation, adherence, safer sex, and disclosure. A preliminary conceptual framework to guide further intervention and research with AEHI populations is proposed. PMID- 30468393 TI - From telescope to binoculars. Dyadic outcome resulting from psychological counselling for infertile couples undergoing ART. AB - OBJECTIVE: This longitudinal study aims to evaluate the effect of psychological counselling on quality of life, marital satisfaction and need for parenthood in couples undergoing fertility treatments (ART). BACKGROUND: Recent guidelines on the ART suggest that psychological counselling should target both members of the infertile couple in order to improve their conjoint management of the infertility related stress. However, studies on the dyadic outcome of couples are scarce. METHODS: 262 patients were originally considered in the study and completed questionnaires on quality of life, need for parenthood and marital satisfaction, before treatment (T1) and at the day of intrauterine insemination/embryo transfer (T2). For the purposes of this study, 34 counselled couples were then matched to 34 non-counselled couples by propensity scores. The Common Fate Model (CFM) was used to examine dyadic changes. RESULTS: Couples receiving counselling had higher dyadic quality of life and lower dyadic stress due to the need for parenthood at T2 compared to non-counselled couples. No differences were found on marital satisfaction. CONCLUSION: The findings provide support for the effectiveness of counselling on interpersonal outcome. The CFM allows researchers to examine how the dyad as a whole responds to counselling, highlighting the change in the couple's relational dynamics. PMID- 30468394 TI - Validity and reliability of the Dundee difficult times of the day scale in Chinese children and adolescents with attention-deficit/hyperactivity disorder. AB - METHODS: A cross-sectional study enrolled 200 children and adolescents with attention-deficit/hyperactivity disorder visiting four Chinese tertiary care psychiatric clinics to assess the validity and reliability of the Dundee difficult times of the day scale (D-DTODS), using the Weiss functional impairment rating scale for parents form (WFIRS-P) and the Swanson, Nolan and Pelham, version IV 26-item teacher and parent rating scale (SNAP-IV-26). RESULTS: The calculated Cronbach's-alpha for the D-DTODS total score was 0.793. The calculated Spearman's correlation coefficients for D-DTODS versus WFRIS-P and Swanson, Nolan and Pelham, version IV 26-item teacher and parent rating scale (SNAP-IV-26) were 0.425 (p < 0.01) and 0.452 (p < 0.001), respectively. CONCLUSION: The D-DTODS was worth future test-retest confirmation regarding reliability and validity for assessing functional impairment associated with attention-deficit/hyperactivity disorder across different time periods of the day in Chinese children and adolescents. PMID- 30468395 TI - Pre-hospital risk assessment in suspected non-ST-elevation acute coronary syndrome: A prospective observational study. AB - BACKGROUND:: Pre-hospital risk stratification of non-ST-elevation acute coronary syndrome (NSTE-ACS) by the complete HEART score has not yet been assessed. We investigated whether pre-hospital risk stratification of patients with suspected NSTE-ACS using the HEART score is accurate in predicting major adverse cardiac events (MACE). METHODS:: This is a prospective observational study, including 700 patients with suspected NSTE-ACS. Risk stratification was performed by ambulance paramedics, using the HEART score; low risk was defined as HEART score ? 3. Primary endpoint was occurrence of MACE within 45 days after inclusion. Secondary endpoint was myocardial infarction or death. RESULTS:: A total of 172 patients (24.6%) were stratified as low risk and 528 patients (75.4%) as intermediate to high risk. Mean age was 53.9 years in the low risk group and 66.7 years in the intermediate to high risk group ( p<0.001), 50% were male in the low risk group versus 60% in the intermediate to high risk group ( p=0.026). MACE occurred in five patients in the low risk group (2.9%) and in 111 (21.0%) patients at intermediate or high risk ( p<0.001). There were no deaths in the low risk group and the occurrence of acute myocardial infarction in this group was 1.2%. In the high risk group six patients died (1.1%) and 76 patients had myocardial infarction (14.4%). CONCLUSIONS:: In suspected NSTE-ACS, pre-hospital risk stratification by ambulance paramedics, including troponin measurement, is accurate in differentiating between low and intermediate to high risk. Future studies should investigate whether transportation of low risk patients to a hospital can be avoided, and whether high risk patients benefit from immediate transfer to a hospital with early coronary angiography possibilities. PMID- 30468396 TI - Managing the risks of mood symptoms with LNG-IUS: a clinical perspective. AB - INTRODUCTION: Lack of awareness of reproductive hormone-related mood changes in the general population or limited acknowledgement of their existence by health care providers regularly contribute to fears or misconceptions about the link between hormonal contraception and potential mood changes. Recent media discussion linked the levonorgestrel intrauterine system (LNG-IUS 20 ug/d) to elevated cortisol levels and the possibility of panic attacks, anxiety, mood changes, sleep disturbance and restlessness. Efficacy of the LNG-IUS is based primarily on local effects but systemic effects, including a potential increase in mood symptoms, are a known risk and reflected in the product labelling for all LNG-IUS products. OBJECTIVE: There is a need to improve communication to the public and health care providers around potential risk of mood disorders in order to facilitate 'informed choice' amongst women considering an LNG-IUS as their contraceptive method and directly address the fears of women currently using an LNG-IUS. RESULTS: We propose a simple and brief, step-by-step process that can be embedded within current counselling that explores and clarifies the potential risk of developing mood symptoms prior to placement of LNG-IUS. It also addresses concerns from women using an LNG-IUS who either present with mood symptoms or are concerned about potential onset. CONCLUSION: Mood symptoms with use of LNG-IUS are uncommon; however, all women, including those who may experience an increased sensitivity to certain progestins, should be counselled appropriately to raise awareness of the potential risk within an informed discussion around effectiveness, benefits and possible adverse events. PMID- 30468397 TI - Use and costs of originator and biosimilar erythropoiesis-stimulating agents in the treatment of chemotherapy-induced anemia: real-world evidence from an Italian hospital. AB - The aim of this retrospective study is to evaluate adherence, switch and costs a year after the start of treatment with different erythropoietin-stimulating agents. There were 277 patients, 200 were originators (72.20%) and 77 (27.80%) were biosimilars. Adherence to treatment for originators is 0.84 +/- 0.22 versus 0.76 +/- 0.27 for biosimilars (p = 0.3241). Medication adherence was calculated as ratio between received daily dose to prescribed daily dose. The optimum value is 1, values less than 1 indicate loss of adherence. The cost of treatment per year is ?7365 per patient for the use of the originator drug versus ?2587 for biosimilars, with a difference of ?4777 per patient. PMID- 30468398 TI - Methylation profiles of IL33 and CCL26 in bronchial epithelial cells are associated with asthma. AB - AIM: This study aimed to characterize DNA methylation (DNA-me) in promoter region of IL33, IL1RL1 and CCL26 in asthma and their impacts on transcriptional activity in bronchial epithelial cells (BECs). PATIENTS & METHODS: We performed bis pyrosequencing, quantitative real-time PCR and sequencing in BECs from ten asthmatic and ten control individuals. RESULTS: We detected lower DNA-me levels of IL33 and CCL26 in asthmatic than control BECs. No correlation was found between methylation and expression levels. Interestingly, carriers of a mutative allele in a haplotype within the promoter of IL33 had a lower IL33 DNA-me level and CCL26 gene expression correlated with eosinophil count. CONCLUSION: These findings highlight the importance of investigating both epigenetic and genetic mechanisms in understanding the epithelial immune response in asthma. PMID- 30468399 TI - Insomnia Patients With Subjective Short Total Sleep Time Have a Boosted Response to Cognitive Behavioral Therapy for Insomnia Despite Residual Symptoms. AB - BACKGROUND: Two distinct insomnia disorder (ID) phenotypes have been proposed, distinguished on the basis of an objective total sleep time less or more than 6 hr. In particular, it has been recently reported that patients with objective short sleep duration have a blunted response to cognitive behavioral therapy for insomnia (CBT-I). The aim of this study was to investigate the differences of CBT I response in two groups of ID patients subdivided according to total sleep time. METHODS: Two hundred forty-six ID patients were subdivided into two groups, depending on their reported total sleep time (TST) assessed by sleep diaries. Patients with a TST greater than 6 hr were classified as "normal sleepers" (NS), while those with a total sleep time less than 6 hr were classified as "short sleepers" (SS). RESULTS: The delta between Insomnia Severity Index scores and sleep efficiency at the beginning as compared to the end of the treatment was significantly higher for SS in comparison to NS, even if they still exhibit more insomnia symptoms. No difference was found between groups in terms of remitters; however, more responders were observed in the SS group in comparison to the NS group. CONCLUSIONS: Our results demonstrate that ID patients with reported short total sleep time had a beneficial response to CBT-I of greater magnitude in comparison to NS. However, these patients may still experience the presence of residual insomnia symptoms after treatment. PMID- 30468400 TI - Negative cognitive styles as risk factors for the occurrence of PMS and PMDD. AB - BACKGROUND: The purpose of our study is to verify whether elements of cognitive vulnerability to affective disorders may enhance the occurrence of PMS/PMDD. METHODS: In total, 293 women with regular cycles took part in the study. The subjects were exposed to failure during the follicular phase or luteal phase, as appropriate, and the attributional style of failure, cognitive triad inventory (CTI) and presence of biased information processing were determined. The mood of the subjects before and after failure was measured, and the depressive mood was screened by CES-D. The occurrence of PMS/PMDD was assessed on the basis of PSST. RESULTS: The women suffering from PMS/PMDD differed from those without PMS in terms of the cognitive triad, the use of positive and negative adjectives when describing themselves and biased information processing. In the luteal cycle phase, considerably greater sadness and irritation were observed in women with PMS/PMDD after experiencing failure, but only in those from the group not taking oral contraceptives. CONCLUSIONS: Negative cognitive styles are an important factor in the development of PMS/PMDD. PMDD is similar to major depression regarding cognitive vulnerability. Only in the case of PMDD was biased information processing in the luteal cycle phase recorded. PMID- 30468401 TI - English Translation of M. Berard: Tumeur Embryonnaire Du Muscle Strie. [Embryonal Tumor of Striated Muscle]. Lyon Med 1894; 77: 52. AB - We have chosen to translate what we believe to be the first publication of a well documented case of a young patient with embryonal rhabdomyosarcoma. The author, M. Leon Berard, was a hospital fellow working in the department of M. Vincent at the Charite Hospital. The document was presented to La Societe des Sciences medicales de Lyon (The Society of Medical Sciences of Lyon, France), in July,1894. The translation follows below. PMID- 30468402 TI - UPD16 itself is not a cause of intrauterine growth restriction. AB - BACKGROUND: The clinical relevance of uniparental disomy (UPD16) for chromosome 16 is currently unclear. METHODS AND RESULT: We performed chromosome microarray analysis on two fetus and their placentas, fluorescence in situ hybridization (FISH) to exclude the hidden chr16 trisomy mosaicism in the fetuses, and clinical whole-exome sequencing to assess for homozygosity mutations of autosomal recessive diseases. RESULTS: Microarray analysis of two fetuses had UPD16. The membranous placenta of the case 1 had confined placental mosaicism (CPM) for trisomy 16. Clinical whole-exome sequencing on chromosome 16 revealed three potentially pathogenic single nucleotide polymorphisms (SNPs). Gap-polymerase chain reaction (PCR) and MLPA for a-thal deletions demonstrated that case 2 was homozygous for the -SEA deletion. CONCLUSIONS: The poor outcome in these fetuses may be attributed to other factors, the membranous placenta and the -SEA deletion, respectively. Fetal UPD16 itself might be not correlated with intrauterine growth restriction (IUGR) and thus is not the basic cause of IUGR. PMID- 30468403 TI - The future of protein biomarker research in type 2 diabetes mellitus. AB - INTRODUCTION: The onset of type 2 diabetes mellitus (T2DM) is strongly associated with obesity and subsequent perturbations in immuno-metabolic responses. To understand the complexity of these systemic changes and better monitor the health status of people at risk, validated clinical biomarkers are needed. Omics technologies are increasingly applied to measure the interplay of genes, proteins and metabolites in biological systems, which is imperative in understanding molecular mechanisms of disease and selecting the best possible molecular biomarkers for clinical use. Areas covered: This review describes the complex onset of T2DM, the contribution of obesity and adipose tissue inflammation to the T2DM disease mechanism, and the output of current biomarker strategies. A new biomarker approach is described that combines published and new self-generated data to merge multiple -omes (i.e. genome, proteome, metabolome etc.) toward understanding of mechanism of disease on the individual level and design multiparameter biomarker panels that drive significant impacts on personalized healthcare. Expert commentary: We here propose an approach to use cross-omics analyses to contextualize published biomarker data and better understand molecular mechanisms of health and disease. This will improve the current and future innovation gaps in translation of discovered putative biomarkers to clinically applicable biomarker tests. PMID- 30468404 TI - Patterns in the social representation of "hearing loss" across countries: how do demographic factors influence this representation? AB - This study aims to understand patterns in the social representation of hearing loss reported by adults across different countries and explore the impact of different demographic factors on response patterns. The study used a cross sectional survey design. Data were collected using a free association task and analysed using qualitative content analysis, cluster analysis and chi-square analysis. The study sample included 404 adults (18 years and over) in the general population from four countries (India, Iran, Portugal and UK). The cluster analysis included 380 responses out of 404 (94.06%) and resulted in five clusters. The clusters were named: (1) individual aspects; (2) aetiology; (3) the surrounding society; (4) limitations and (5) exposed. Various demographic factors (age, occupation type, education and country) showed an association with different clusters, although country of origin seemed to be associated with most clusters. The study results suggest that how hearing loss is represented in adults in general population varies and is mainly related to country of origin. These findings strengthen the argument about cross-cultural differences in perception of hearing loss, which calls for a need to make necessary accommodations while developing public health strategies about hearing loss. PMID- 30468405 TI - Manual Patient Transfers - Factors That Influence Decisions and Kinematic Strategies Employed by Nursing Aides. AB - While extensive literature has characterized factors that influence acceptable mass of 'boxes' during MMH tasks, little is known about these factors when moving 'people' in healthcare settings. This study examined factors that influence decisions/approaches employed during manual patient transfers. Sixteen nursing aides manually-transferred a standardized 'patient'; patient mass was adjusted (using a weight vest) to determine a maximum acceptable patient mass for this task (massmax). Grip strength was the only worker characteristic significantly associated with massmax (r = 0.48). Older worker age was associated with smaller peak trunk flexion (r=-0.58) and shoulder abduction (r=-0.59), and greater trunk axial twist (r = 0.52). Workers emphasized that patient characteristics (e.g. physical/cognitive status) influenced their decisions when performing transfers. These findings extend previous literature by suggesting that grip strength is a useful predictor of perceived work capacity, older workers adapt protective postural strategies during patient transfers, and worker-patient dynamics are crucial during this high-risk occupational task. Practitioner Summary:This study examined manual patient transfers performed by nursing aides. Worker grip strength (but not age or size) was associated with perceptions of maximum acceptable patient mass. Kinematic changes suggested more conservative strategies used by older workers. Workers emphasized that patient characteristics substantially influenced their decisions when performing transfer tasks. PMID- 30468406 TI - Anti TNF-alpha therapy in patients with relapsed and refractory Langerhans cell histiocytosis: a phase II study. AB - Tumor necrosis factor alpha (TNF-alpha) is produced in Langerhans cell histiocytosis (LCH) lesions and is elevated in plasma of patients with active LCH. It has been postulated that TNF-alpha may play a role in the pathophysiology of LCH. Etanercept, an anti-TNF-alpha antibody, has been used in TNF-modulated diseases such as rheumatoid arthritis (RA). We conducted a phase II study to determine the efficacy of etanercept for patients with refractory or relapsed LCH. Five LCH patients who had failed at least 2 prior treatments (range 2-9) received etanercept at a dose of 0.4 mg/kg twice weekly for up to a total of 24 doses. Disease response was assessed at 4 and 8 weeks. None of the five patients had improvement in their disease with etanercept treatment. Three progressed at week 4 and 1 progressed at week 8. One subject died after 3 weeks of treatment from disease progression. During the study, only one drug-related toxicity was noted which spontaneously resolved. The study was concluded early due to lack of response to etanercept and insufficient accrual rate. This data suggests that etanercept as given in this study may not be effective for relapsed or refractory LCH. However, the number of patients treated was not adequate enough to power this study and it is possible that a different dose and regimen of etanercept may be required to successfully treat this disease. PMID- 30468407 TI - Metabolic syndrome is associated worsened erectile function in patients undergoing TURP due to benign prostatic hyperplasia. AB - INTRODUCTION: Transurethral resection of the prostate (TURP) is the gold standard method for surgical treatment of benign prostatic hyperplasia (BPH). So, the complications of TURP is important, in which erectile dysfunction is the most important. The aim of the present study is to evaluate erectile dysfunction in patients undergoing TURP treatment for BPH and investigate the correlation between metabolic syndrome and erectile dysfunction. MATERIALS AND METHODS: This study included 120 patients who underwent surgery for BPH at Beylikduzu State Hospital and Okmeydani Training and Research Hospital. IIEF-5 form was administered to the patients before the surgery and six months after the surgery. The Student's t-test, Wilcoxon, and chi-square test were used in the statistical analysis. RESULTS: The patients were investigated by IIEF-5 scoring into three groups (severe, moderate, and non-ED (erectyl disfunction)-mild). The statistical analysis of IIEF-5 form administered to 120 patients who underwent surgery did not show any significant difference before surgery and six months after surgery (p > 0.05). Metabolic syndrome and erectile dysfunction correlation were examined, and a significant correlation was obtained between metabolic syndrome and severe erectile dysfunction (p < 0.05). CONCLUSIONS: IIEF-5 results administered before and after surgery showed no significant difference. The study showed that patients with metabolic syndrome have a higher probability of having erectile dysfunction after TURP compared to patients without metabolic syndrome. Moreover, post-surgery, patients with metabolic syndrome seemed to be affected negatively regarding erectile dysfunction compared to patients with no metabolic syndrome. PMID- 30468408 TI - Using Media Literacy Education for Adolescent Sexual Health Promotion in Middle School: Randomized Control Trial of Media Aware. AB - This study examined the short-term efficacy of Media Aware, a classroom-based media literacy education (MLE) program for improving adolescents' sexual health outcomes. In a randomized control trial, schools were randomly assigned to the intervention (N = 5 schools) or health promotion control (N = 4 schools) group. Students completed questionnaires at pretest (N = 880 students) and immediate posttest (N = 926 students). The Media Aware program had a significant favorable impact on adolescent outcomes related to sexual health, including increased self efficacy and intentions to use contraception, if they were to engage in sexual activity; enhanced positive attitudes, self-efficacy, and intentions to communicate about sexual health; decreased acceptance of dating violence and strict gender roles; and increased sexual health knowledge. Program effects were also found for media-related outcomes, including enhanced media deconstruction skills and increased media skepticism. Media deconstruction skills mediated the program's impact on students' intentions to communicate with a medical professional about sexual health issues. This study provides support for the use of MLE with adolescents to promote sexual health. PMID- 30468409 TI - Characterization of farnesyl diphosphate farnesyl transferase 1 (FDFT1) expression in cancer. AB - AIM: To help characterize the FDFT1 gene and protein expression in cancer. Cholesterol represents an important structural component of lipid rafts. These specializations can be involved in pathways stimulating cell growth, survival and other processes active in cancer. This cellular compartment can be expanded by acquisition of cholesterol from the circulation or by its synthesis in a metabolic pathway regulated by the FDFT1 enzyme. Given the critical role this might play in carcinogenesis and in the behavior of cancers, we have examined the level of this enzyme in various types of human cancer. Our demonstration of elevated levels of FDFT1 mRNA and protein in some tumors relative to surrounding normal tissue identifies this as a possible biomarker for disease development and progression, and as a potential new target for the treatment of cancer. PMID- 30468410 TI - Encore adulthood: Boomers on the edge of risk, renewal, and purpose. PMID- 30468411 TI - MTHFR polymorphisms as risk for male infertility in Pakistan and its comparison with socioeconomic status in the world. AB - AIM: 5,10-MTHFR-single nucleotide polymorphisms are important for normal functioning of the enzyme that plays a key role in DNA synthesis, folate metabolism and methylation reactions. Methodology & results: Male-infertility association of C665T and A1298C polymorphisms was explored, this topic is still debatable. Infertile men (232) and controls (114) were genotyped and statistically analyzed. Comparison of patients (6180) and controls (5744) of Caucasian populations was performed by meta-analysis. Pooled results showed A1298C minor allele and homozygous genotype to be of a significantly higher frequency in the low-income group. Increase in per capita income has shown an increasing trend in the minor allele frequency in various world populations, potentially due to dietry-folate compensation. CONCLUSION: A1298C seems more relevant marker than C665T for infertility association in Caucasian populations and may be addressed by improving dietary-folate. PMID- 30468412 TI - Responsiveness of a Persian version of Knee Injury and Osteoarthritis Outcome Score and Tegner activity scale in athletes with anterior cruciate ligament reconstruction following physiotherapy treatment. AB - PURPOSE: To evaluate the responsiveness and determine the minimal clinically important changes (MCICs), anchored by the patient response to a 7-point global rating scale, for Knee Injury and Osteoarthritis Outcome Score (KOOS), and Tegner activity scale in athletes undergoing physiotherapy treatment after anterior cruciate ligament reconstruction (ACL-R). METHODS: Fifty-four patients undergoing physiotherapy completed the Persian versions of KOOS and Tegner scales at weeks 6 and 10 post ACL-R. The 7-point global rating of change was also completed at week 10. Responsiveness was calculated via receiver operating characteristic curve and correlation analysis. RESULTS: Acceptable responsiveness was reached by the KOOS sports and recreation subscale (Sport/Rec) (area under the curve (AUC) = 0.72; Gamma = 0.37) and Tegner scale (AUC = 0.75; Gamma = 0.59). The MCIC scores of KOOS subscales and Tegner scale were reported. CONCLUSION: Our findings demonstrated that the KOOS Sport/Rec subscale and Tegner scale have adequate responsiveness between weeks 6 and 10 of physiotherapy. Therefore, these scales should be used to evaluate the effects of physiotherapy treatment and the changes in activity levels in this population. The MCIC scores of the KOOS and Tegner scale can be used to detect changes significant to the patient while avoiding limitations of other methods. PMID- 30468413 TI - Online communities as a new source of exploring patient dissatisfaction. AB - PURPOSE: The purpose of this paper is to analyse whether internet forums are an appropriate source for identification of causes of dissatisfaction of patients with non-medical aspects of healthcare services. DESIGN/METHODOLOGY/APPROACH: Based on the guidelines of netnography qualitative research the authors identify relevant posts or comments on selected online forums in which web users show their dissatisfaction with healthcare services. Five popular Slovenian forums representing different interest communities have been chosen and 42 forums' topics have been reviewed. FINDINGS: Online communities have an important role in exploring patient dissatisfaction. Through content analysis comments were coded into meaningful categories and subcategories. RESEARCH LIMITATIONS/IMPLICATIONS: Some comments were more explicit, while others have provided general and looser reasons for dissatisfaction, and in such cases coding and content analysis of comments was more difficult. PRACTICAL IMPLICATIONS: Contents expressed within online communities are helpful in designing improvement activities since they enable determination of concrete relevant measures aiming at eliminating and preventing the established causes of discontent, such as instituting new policies, introducing training programs, determining desired changes in culture. ORIGINALITY/VALUE: Usefulness of the netnography as a qualitative method of research is confirmed through confirmation that causes of dissatisfaction of Slovenian patients, which have been identified in the authors research are similar to those identified in previous research in the field of patient satisfaction conducted in Slovenia. Results constitute a new form of researching patient dissatisfaction and expose the specific causes of patient dissatisfaction with healthcare services in Slovenia. PMID- 30468414 TI - Examining the relationship between hospital ownership and population health efforts. AB - PURPOSE: The purpose of this paper is to investigate the relationship between ownership type and population health initiatives adopted by hospitals using the 2015 American Hospital Association data. DESIGN/METHODOLOGY/APPROACH: Hospitals of various sizes, ownership structures and geographic locations are represented in the survey. The outcome variables of interest include measures of hospital population health activities. FINDINGS: Findings indicate that nonprofit hospitals are most likely to express commitment to population health and participate in population health activities, with for-profit hospitals being least likely. Implications for policy and practice are discussed. RESEARCH LIMITATIONS/IMPLICATIONS: This study demonstrates that discrepancies in population health approaches exist across ownership status - particularly, nonprofit hospitals appear to be the most likely to be involved in population health efforts. PRACTICAL IMPLICATIONS: As we continue to push for population health management in the hospital setting, grappling with the definition and purpose of population health management will be essential. SOCIAL IMPLICATIONS: Overall, these results suggest that nonprofit hospitals are more likely to be implementing population health efforts than for-profit or government-owned hospitals. ORIGINALITY/VALUE: Although there are several studies on population health in hospitals, this study is the first to investigate the relationship between ownership type and population health initiatives adopted by hospitals. PMID- 30468415 TI - Costs will rather increase. AB - PURPOSE: The purpose of this paper was to study the unfolding of an urgent and extensive decommissioning program in Sweden, focusing on the public's reactions and their arguments when opposing the decommissioning activities. DESIGN/METHODOLOGY/APPROACH: The public's responses were studied through local media. Its content was surveyed and divided into actions and arguments. The arguments were further analyzed and categorized into inductively developed themes. FINDINGS: Protest activities, such as demonstrations, meetings and petitions, were not coordinated, but mostly carried out for withdrawals of unique services and services in remote areas. The public questioned the decision makers' information, calculations and competence, the adequacy of the consequence analyses and whether the decommissioning activities would lead to any real savings. Patient and public safety, the vulnerable in society, and effects on the local areas were important topics. Thus, it seems the decision makers did not fully succeed in communicating the demonstrable benefits or create clarity of the rationales for decommissioning the particular services. Furthermore, it seems the public has a more inclusive approach to health services and their value compared to decision makers that need to keep the budget. ORIGINALITY/VALUE: Decommissioning is an emerging field of research, and this study of the unfolding of an urgent and extensive decommissioning program contributes with evidence that may improve decommissioning policy and practice. The study illustrates that it may be possible to implement a decommissioning program despite public protest, but that the longer-term effects on the health system's legitimacy need to be studied. PMID- 30468416 TI - What initiatives do healthcare leaders agree are needed for healthcare system improvement? Results of a modified-Delphi study. AB - PURPOSE: The purpose of this paper is to identify five quality improvement initiatives for healthcare system leaders, produced by such leaders themselves, and to provide some guidance on how these could be implemented. DESIGN/METHODOLOGY/APPROACH: A multi-stage modified-Delphi process was used, blending the Delphi approach of iterative information collection, analysis and feedback, with the option for participants to revise their judgments. FINDINGS: The process reached consensus on five initiatives: change information privacy laws; overhaul professional training and work in the workplace; use co-design methods; contract for value and outcomes across health and social care; and use data from across the public and private sectors to improve equity for vulnerable populations and the sickest people. RESEARCH LIMITATIONS/IMPLICATIONS: Information could not be gathered from all participants at each stage of the modified-Delphi process, and the participants did not include patients and families, potentially limiting the scope and nature of input. PRACTICAL IMPLICATIONS: The practical implications are a set of findings based on what leaders would bring to a decision-making table in an ideal world if given broad scope and capacity to make policy and organisational changes to improve healthcare systems. ORIGINALITY/VALUE: This study adds to the literature a suite of recommendations for healthcare quality improvement, produced by a group of experienced healthcare system leaders from a range of contexts. PMID- 30468417 TI - Impact of organisational change for leaders in mental health. AB - PURPOSE: The purpose of this paper is to examine the impact of organisational and structural change on the evolution of quality and safety in health organisations, specifically in mental health services. DESIGN/METHODOLOGY/APPROACH: Data were gathered through semi-structured interviews. In total, 25 executive management team members in both public and private mental health services were interviewed and data were analysed using Burnard's framework. FINDINGS: Three overarching themes emerged: organisational characteristics, leadership and accountability; sustaining collaboration and engagement with stakeholders; and challenges to and facilitators of quality and safety. Taken together, the findings speak to the disruptive and disorienting impact of on-going organisational change and restructuring on leaders' ability to focus on, and advance, the quality and safety agenda. RESEARCH LIMITATIONS/IMPLICATIONS: Typical with qualitative research of this nature, the potentially limited generalisability of the findings must be acknowledged. PRACTICAL IMPLICATIONS: There is a need for strategies to implement change that are informed by evidence and theory and informed by decades of research on this topic, rather than introduced ad hoc. Change agents must pair effective change management and implementation science strategies to specific contexts, depending on what is being implemented and ensure appropriate evaluation of organisational change to bolster the evidence base around quality and safety and inform future decision-making. ORIGINALITY/VALUE: The study explores an identified gap in the literature on the impact of on-going organisational re-structuring and transformation on the evolution of quality and safety in mental health services. PMID- 30468419 TI - Scaling Up Evidence-Based Public Health Training. AB - Evidence-based public health (EBPH) is the process of integrating science-based interventions with community preferences. Training in EBPH improves the knowledge and skills of public health practitioners. To reach a wider audience, we conducted scale-up efforts including a train-the-trainer version of the EBPH course to build states' capacity to train additional staff. In this essay, we describe formats for course delivery and local adaptations to content, and we review success factors and barriers for state-based replication of the EBPH training course. Findings were based on our experiences and interviews. EBPH training was delivered in varied blended formats as well as in person and in distance courses, each with advantages and disadvantages. Adaptations were made to meet the needs of learners. Success factors included having committed and competent coordinators and trainers, organizational incentives, leadership support, funding, internal and external collaborators, the infrastructure to support training, and models to learn from. Barriers reported included insufficient staff or trainer capacity; time constraints for organizers, trainers, and participants; and lack of sustained funding. We hope our experience and findings will be a guide for states that are committed to building and sustaining capacity through continued EBPH training. Our lessons may also apply more generally to other workforce development training efforts. PMID- 30468420 TI - Promoting Healthy Environments In Afterschool Settings: The LiveWell Greenville Afterschool Initiative. AB - INTRODUCTION: LiveWell Greenville, a multi-organization community coalition, launched an initiative in 2011 to help afterschool programs promote environments that decrease the risk of obesity among children and adolescents. The objective of this study was to describe changes in nutrition and physical activity environments, policies, and practices among 37 afterschool programs after their participation in the LiveWell Greenville Afterschool Initiative. METHODS: The study used a nonexperimental, pre- and postsurvey design. The survey was based on the Nutrition and Physical Activity Self-Assessment for Child Care questionnaire and modified for afterschool settings. Items addressed sedentary time, physical activity time, availability of sugar-sweetened beverages, sweet and salty snack consumption, fruit consumption, staff behaviors, and policies that support nutrition and physical activity practices. The self-assessment survey was completed by an afterschool program supervisor at each site. The 9-month intervention consisted of program staff members' completing the pre-assessment and goal-setting worksheet, receiving technical support and training from LiveWell Greenville staff, attending networking meetings about nutrition and physical activity promotion strategies, and completing a postassessment. RESULTS: We found significant positive changes in afterschool environments in the type and frequency of snacks offered, duration of children's sedentary time, staff behaviors that supported healthy nutrition and physical activity practices, and education provided to staff, children, and parents. CONCLUSION: We found the LiveWell Greenville Afterschool Initiative, which involved self-assessment, goal setting and technical support, to be a successful strategy to change nutrition and physical activity environments in afterschool settings. PMID- 30468421 TI - Prevalence of Type 1 Diabetes Among People Aged 19 and Younger in the United States. PMID- 30468422 TI - Diabetes Treatment, Control, and Hospitalization Among Adults Aged 18 to 44 in Minnesota, 2013-2015. AB - INTRODUCTION: Of more than 300,000 adult Minnesotans who have received a diagnosis of diabetes, 16% are younger than 45 years; however, state diabetes surveillance data primarily describe older adults. National reports suggest adults younger than 45 years are less likely than older adults with diabetes to meet blood glucose (hemoglobin A1c [HbA1c]) goals. For this study on age-specific differences, we examined Minnesota data sets to determine if younger adults (ie, aged 18-44 y) are less likely to meet HbA1c goals and if hospitalization patterns differ from older adults (ie, aged 45-74 y) with diabetes. METHODS: We used Behavioral Risk Factor Surveillance System data to describe demographic characteristics and health behaviors of people with diabetes, clinical quality data to assess HbA1c levels, and hospital discharge data to assess reasons for hospitalization. RESULTS: Compared with older adults with diabetes, adults aged 18 to 44 were more likely to use tobacco and to have had depression; these younger adults were less likely to report having HbA1c levels checked in the last year. According to age-specific cutoffs, 40.5% of 18- to 44-year-olds met HbA1c goals versus 74.7% of people aged 45 to 64 and 84.4% of people aged 65 to 74. Hospitalization rates for diabetes as a primary cause were highest among 18- to 44-year-olds at 47 per 1,000 adults with diabetes, much higher than older ages. Hospitalization rates for mental health problems were higher among younger adults. CONCLUSION: Our analysis confirmed that 18- to 44-year-olds with diabetes have poorer HbA1c control than older adults with diabetes. These results underscore the importance of age-based public health surveillance of diabetes. Age-stratified surveillance can inform efforts to monitor clinical care quality and to design clinical/public health interventions. PMID- 30468423 TI - Effect of Media Use on Adolescent Body Weight. AB - INTRODUCTION: Adolescents spend a substantial amount of time consuming media, including watching television, playing video games, and using electronic devices to access the internet. We examined the relationship between prolonged media use on screen devices and its potential association with obesity through several mechanisms. METHODS: We used data from 659,288 eighth and eleventh grade students who participated in the 2015-2016 School Physical Activity and Nutrition (SPAN) survey in Texas to examine the associations between hours of media use per day and 3 behaviors related to obesity: timing of last food intake, unhealthy eating behavior, and sleep hours. Also, mediation analyses were conducted to examine the pathways between hours of media use and body mass index (BMI). RESULTS: Compared with adolescents who used media 2 hours or less per day, those who used media 6 hours or more had higher odds of nighttime eating (odds ratio [OR], 3.16; 95% confidence interval [CI], 1.76-5.66) and inadequate sleep (OR, 1.57; 95% CI, 1.05 2.36) and a higher coefficient for Unhealthy Eating Index score (3.87; 95% CI, 1.3-6.37). Mediation analysis demonstrated that for males sleep hours and timing of last food intake mediated the pathway between hours of media use and BMI. For females, unhealthy eating behavior mediated this pathway. CONCLUSION: Adolescents who used electronic media 6 or more hours at night had higher odds of unhealthy eating behavior and inadequate sleep hours than those with 2 hours' use or less. Attention to behaviors associated with adolescents' prolonged media use is needed to reduce risk of obesity. PMID- 30468424 TI - Bimanual palpation for staging of bladder cancer-clinical use and its predictors. AB - OBJECTIVE: To analyze the frequency of performing bimanual palpation (BP) during transurethral resection of the bladder tumor (TURBT) and to identify its predictors. MATERIAL AND METHODS: This retrospective analysis enrolled 568 consecutive patients, who underwent TURBT due to primary bladder cancer. There were thirty surgeons involved in the analysis, each performed a mean of 18.9 TURBTs (range 1-43). Univariate and multivariate logistic regression analyses were performed to identify factors predicting the BP use. This was a retrospective non-interventional study; the Ethical Board approval was waived according to institutional regulations. RESULTS: Two hundred and sixty-five patients (46.7%) underwent BP. BP was performed in 36.1% of Ta tumors, 49.1% of T1 tumors and 76.6% of >=T2 tumors (p<0.001); in 60.2% of tumors >3 cm and in 33.3% of tumors <3 cm (p<0.001). Female, and male doctors performed BP in 38.3%, and 48.8% of the cases, respectively (p=0.01). Senior residents performed BP more often than junior residents and certified junior and senior urologists (64.6% vs. 39.2% vs. 48.2% vs. 31.1%, respectively; p=0.03). In multivariate logistic regression analysis higher tumor stage, larger tumor size, as well as senior residents and male surgeons performing TURBT were independent predictors of BP. CONCLUSION: Though BP is recommended for each patient at the time of TURBT, it is performed only in the minority of patients undergoing TURBT, mainly those with advanced or larger tumors, operated by senior residents and male surgeons. PMID- 30468425 TI - Characteristics of the urethroplasty and our approach-Experience in patients with urethral stricture. AB - OBJECTIVE: Urethral stricture is a common pathology with different etiologic factors in different age groups and societies. In our research, patients who underwent urethroplasty because of urethral stricture were evaluated in terms of etiology, localization, surgical technique and demographic characteristics. MATERIAL AND METHODS: One hundred and sixty-three patients with a mean age of 53.43+/-16.5 years, operated between January 2008 and May 2016 because of urethral stricture were retrospectively included in the study. Diagnosis of the urethral stricture was established based on the complaints of the patient, results of urinalysis, urine culture, uroflowmetry, retrograde urethrography and/or voiding urethrography, and urethroscopy in case of need. Postoperative success for the patients was determined based on urinary flow rate and maximum flow rate of over 15 mL/sec were evaluated as success. RESULTS: Etiologic factors for urethral stricture included trauma in 40 (24.5%), urethral catheterization in 45 (27.6%), endoscopic procedure in 59 (36.2%), infection in 10 (6.2%), idiopathic etiologies in 9 (5.5%) out of 163 patients. Mean length of the stricture was 3.6+/-1.7 cm. While the indicated number of patients had buccal mucosa graft (n=73, 44.7%), penile skin flap (n=21, 12.8%), Heineke-Mikulicz repair (n=5, 3.0%), and end-to-end anastomosis (n=64, 39.1%). Mean follow-up period was 43.2+/-33.7 months. Buccal mucosa graft was applied as ventral (n=32, 43.8%), dorsal (n=22, 30.2%), and dorsolateral (n=14, 19.2%) onlay, and transventrally dorsal inlay (n=5, 6.8%) grafts. Average success rates were 83.5% (n=61/73) in buccal mucosa, 76.2% (n=16/21) in penile skin grafts; 85.9% (n=55/64) in end-to-end anastomosis and 80.0% (n=4/5) in Heineke-Mikulicz repair. CONCLUSION: Our assumption is that urethroplasty procedures have satisfactory long-term results, regardless of the location and size of the stenosis. According to our clinical experience, deciding on the most appropriate surgical technique by assessing each patient individually in experienced centers will increase success rates. PMID- 30468426 TI - Tourniquet and adrenaline use in hypospadias surgery: a survey on the current practice in Turkey. AB - OBJECTIVE: Aim of the study is to determine the hemostatic techniques among pediatric urologists in Turkey. MATERIAL AND METHODS: Questionnaire forms were sent to 459 pediatric urologist by e-mail. RESULTS: Ninety eight of 459 participants answered the questionnaire forms. Eighty-one (84.4%) of the participants were using tourniquet. The participants who didn't use tourniquet stated their justifications as follows: lack of need (n=10: 66.7%), development of edema, ischemia, delay of wound-graft healing and fistula risk (n=5: 33.3%). The indications of tourniquet use were stated as follows: penile (91.4%: n=74), distal (72.8%: n=59), penoscrotal (55.6%: n=45) hypospadias; fistula repair (33.3%: n=27), cripple hypospadias (33.3%: n=27), repair with flaps (30.9%: n=25), repair with grafts (27.2%: n=22), and isolated penile curvature (21%: n=17). Most commonly used tourniquet material (49.9%) was latex glove. Erection test was applied by 43.8% of participants. Scalp vein set was the most commonly (54.8%) used injector during erection test. Only 9.4% of participants were using adrenaline. Adrenaline dosages used at 1/100.000 dilution by 55.6%, lidocaine with 1/100.000 adrenaline by 44.4% of participants. CONCLUSION: Beside a few experimental ones there is a paucity of studies that can serve as a guideline for using these techniques in the literature. There is a necessity of realizing prospective, randomized studies with long-term follow up to evidence that postoperative complications could develop secondary to hemostatic techniques and also to facilitate safe use of these techniques. PMID- 30468427 TI - Prevalence and associated factors of urinary tract infections among diabetic patients in Arba Minch Hospital, Arba Minch province, South Ethiopia. AB - OBJECTIVE: Urinary tract infection (UTI) is a common and grave health problem in the world. In fact, patients with diabetes mellitus have an immense risk for developing UTI. The development of resistance among uropathogens to antibiotics is a major crisis which limits the use of drug of choice for the treatment of UTI. On this view point, the aim of the present study is to elucidate the prevalence of UTI, associated factors, causative agents and their antimicrobial susceptibility amongst diabetic patients attending Arba Minch Hospital, Arba Minch, Ethiopia. MATERIAL AND METHODS: A facility based cross-sectional study was carried out in diabetic patients visiting the Internal Medicine Unit of Arba Minch Hospital (AMH) during the study period (March to May 2016). Pre-tested structured questionnaire was used for collecting the data pertaining to socio demographic characteristics and possible risk factors. In order to quantify the uropathogens, midstream urine samples were collected in sterile leak proof culture bottles and streaked onto diverse bacteriological media. All the positive urine cultures showing significant bacteriuria as per the Kass count (>105 organisms/mL) were further subjected to biochemical tests. The antimicrobial susceptibility test was performed to determine the resistance/susceptibility pattern of isolated uropathogens. Data entry and analysis were done using Statistical Package for Social Services, version 20. RESULTS: In total, 239 diabetic patients were included in the study of which 60.2% (n=144) were females. A total of 81 (33.8%) diabetic patients had positive urine cultures. Sixty-eight (83.9%) female diabetic patients had significant bacteriuria (p=0.000). Fifty-two (64.1%) participants had drinking habit and 79 (97.5%) of respondents had higher glucose levels (>=126 mg/dL) (p=0.004 and p=0.003), respectively. According to the biochemical tests, in a total of 90 isolates from patients with significant bacteriuria, eight species of uropathogens such as Escherichia coli, Klebsiella sp., Proteus sp., Citrobacter spp., Staphylococcus aureus, Coagulase negative Staphylococcus (CNS), Enterococcus faecalis and yeast isolates were identified. The antibiogram evidenced that 79.6% (n=51) of Gram-negative bacteria were invariably resistant to amoxicillin and penicillin whereas 73.4% (n=47) and 65.6 % (n=42) of them were resistant to trimethoprim, erythromycin and chloramphenicol, respectively. Regarding the Gram-positive bacteria, high degree of resistance was exhibited towards penicillin and trimethoprim (100%, n=24) followed by amoxicillin (83.3%, n=20) and gentamicin (62.5%, n=15). Invariably, all the Gram-positive cocci and Gram-negative bacilli were susceptible (100%) to amikacin, doxycycline, ceftriaxone and nitrofurantoin. CONCLUSION: The prevalence of UTI is higher in diabetic patients. Results revealed that the predominant pathogens of UTI were Gram-negative bacilli (Enterobacteriaceae), particularly E. coli. Significant bacteriuria had an association with the consumption of alcohol, gender and glucose level. Based on the results of antimicrobial susceptibility tests, it might be inferred that the antibiotics such as amikacin, doxycycline, ceftriaxone and nitrofurantoin are the drugs of choice for the management of both Gram-negative and Gram-positive uropathogenic bacteria in the study area. PMID- 30468431 TI - Bendamustine and Rituximab Treatment, Chronic Lymphocytic Leukemia, Direct Antiglobulin Test, and false negative. PMID- 30468430 TI - A case of SF3B1 positive myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis. PMID- 30468429 TI - ASH1-catalyzed H3K36 methylation drives gene repression and marks H3K27me2/3 competent chromatin. AB - Methylation of histone H3 at lysine 36 (H3K36me), a widely-distributed chromatin mark, largely results from association of the lysine methyltransferase (KMT) SET 2 with RNA polymerase II (RNAPII), but most eukaryotes also have additional H3K36me KMTs that act independently of RNAPII. These include the orthologs of ASH1, which are conserved in animals, plants, and fungi but whose function and control are poorly understood. We found that Neurospora crassa has just two H3K36 KMTs, ASH1 and SET-2, and were able to explore the function and distribution of each enzyme independently. While H3K36me deposited by SET-2 marks active genes, inactive genes are modified by ASH1 and its activity is critical for their repression. ASH1-marked chromatin can be further modified by methylation of H3K27, and ASH1 catalytic activity modulates the accumulation of H3K27me2/3 both positively and negatively. These findings provide new insight into ASH1 function, H3K27me2/3 establishment, and repression in facultative heterochromatin. PMID- 30468432 TI - Wilm's tumor-1 (WT1) rs16754 polymorphism and clinical outcome in acute myeloid leukemia. PMID- 30468433 TI - Rare Presentation of Herpes Virus Lesions in a Case with Acute Pre-B Lymphoblastic Leukemia. PMID- 30468428 TI - Targets and genomic constraints of ectopic Dnmt3b expression. AB - DNA methylation plays an essential role in mammalian genomes and expression of the responsible enzymes is tightly controlled. Deregulation of the de novo DNA methyltransferase DNMT3B is frequently observed across cancer types, yet little is known about its ectopic genomic targets. Here, we used an inducible transgenic mouse model to delineate rules for abnormal DNMT3B targeting, as well as the constraints of its activity across different cell types. Our results explain the preferential susceptibility of certain CpG islands to aberrant methylation and point to transcriptional state and the associated chromatin landscape as the strongest predictors. Although DNA methylation and H3K27me3 are usually non overlapping at CpG islands, H3K27me3 can transiently co-occur with DNMT3B-induced DNA methylation. Our genome-wide data combined with ultra-deep locus-specific bisulfite sequencing suggest a distributive activity of ectopically expressed Dnmt3b that leads to discordant CpG island hypermethylation and provides new insights for interpreting the cancer methylome. PMID- 30468434 TI - A Successful Coronary Artery Bypass Operation with Intermittent Factor VIII Administration in a Hemophilia A Patient who Applied with Acute Myocardial Infarction: a rare and difficult case. PMID- 30468435 TI - Notes from the Field: Multiple Modes of Transmission During a Thanksgiving Day Norovirus Outbreak - Tennessee, 2017. PMID- 30468436 TI - Heterogeneous chemistry in the 3-D state: an original approach to generate bioactive, mechanically-competent bone scaffolds. AB - The present work investigates heterogeneous gas-solid reactions involved in the biomorphic transformation of natural wood into large 3-D hydroxyapatite (HA) scaffolds recapitulating physico-chemical, morphological and mechanical features typical of natural bone. In particular, we found that the use of a reactive CO2/H2O gas mixture, under supercritical conditions at high pressure, permits to control heterogeneous CaO-CO2 reactions throughout the whole bulk and to direct the nucleation-growth of CaCO3 at a relatively low temperature, thus obtaining a highly reactive 3-D precursor enabling the formation of a large biomorphic HA scaffold preserving fine nanostructure by a hydrothermal process. To the best of our knowledge, the application of heterogeneous chemical reactions in the 3-D state is an original way to generate large HA scaffolds maintaining bio-relevant ionic substitutions, with specific regard to Mg2+, Sr2+ and CO32- ions, conferring a superior ability to guide cell fate. We hypothesize that the original nanostructure of the final 3-D HA scaffold, not achievable by the classic sintering procedure, and the multi-scale hierarchical organization inherited by the original template, account for its high compression strength with damage-tolerant mechanical behaviour. The ability of the new scaffold to induce bone regeneration is attested by the overexpression of genes, early and late markers of the osteogenic differentiation pathway, and by the in vivo osteoinductivity. We hypothesize that the unique association of bioactive chemical composition, nanostructure and multi-scale hierarchy can synergistically act as instructing signals for cells to generate new bone tissue with organized 3 D architecture. These results point to its great applicative potential for the regeneration of large bone defects, which is a still unmet clinical need. PMID- 30468437 TI - Progress towards creating optically addressable molecular qubits. AB - The emerging field of quantum information science promises to transform a diverse range of scientific fields, ranging from computation to sensing and metrology. The interdisciplinary scientific community laid the groundwork for the next generation of quantum technologies through key advances in understanding the fundamental unit of quantum information science, the qubit. Electronic spin is a promising platform for qubits, demonstrating suitably long coherence times, optical initialization, and single spin addressability. Herein, we discuss recent accomplishments and future progress from our group targeted at imbuing transition metal complexes with the aforementioned properties, creating a pathway to fusing spatial precision with long coherence times. A strong emphasis of this feature article is progressing towards single spin measurements via a chemical approach for imbuing molecular qubits with an optically-induced spin polarization mechanism. PMID- 30468438 TI - Zeolites and zeolite-based materials in extraction and microextraction techniques. AB - Zeolites are ordered crystalline materials with a promising performance for a wide range of applications such as catalysis, petrochemistry, environmental remediation, and medicine, but have scarcely been evaluated in Analytical Chemistry. Their unique and fascinating properties such as their high surface area, high adsorption capacity and molecular selectivity, chemical and thermal stability, ion-exchange capacity, low cost extraction and synthesis, and their easy modification, which provides a wide range of zeolite-based materials, make zeolites potential sorbents for extraction procedures. Therefore, in this review, we provide an overview of the current status of zeolites and zeolite-based materials used in extraction and microextraction techniques with reference to recent applications and highlight some of the novel advances. PMID- 30468439 TI - Hemodynamic shear flow regulates biophysical characteristics and functions of circulating breast tumor cells reminiscent of brain metastasis. AB - Tumor cells disseminate to distant organs mainly through blood circulation, where they experience considerable levels of fluid shear flow. However, its influence on circulating tumor cells remains less understood. This study elucidates the effects of hemodynamic shear flow on biophysical properties and functions of breast circulating tumor cells with metastatic preference to brain. Only a small subpopulation of tumor cells are able to survive in shear flow with enhanced anti apoptosis ability. Compared to untreated cells, surviving tumor cells spread more on soft substrates that mimic brain tissue but less on stiff substrates. They exhibit much lower expression of F-actin and cell stiffness but generate significantly higher cellular contractility. In addition, hemodynamic shear flow upregulates the stemness genes and considerably changes the expression of the genes related to brain metastasis. The enhanced cell spreading on soft substrates, reduced stiffness, elevated cellular contractility, and upregulation of the stemness and brain metastasis genes in tumor cells after shear flow treatment may be related to breast cancer metastasis in soft brain tissues. Our findings thus provide the first piece of evidence that hemodynamic shear flow regulates biophysical properties and functions of circulating tumor cells that are associated with brain metastasis, suggesting that tumor cells surviving in blood shear flow may better reflect the characteristics of organ preference in metastasis. PMID- 30468440 TI - Dissipative phase transitions in systems with nonreciprocal effective interactions. AB - The reciprocity of effective interparticle forces can be violated in various open and nonequilibrium systems, in particular, in colloidal suspensions and complex (dusty) plasmas. Here, we obtain a criterion under which a nonreciprocal system can be strictly reduced to a pseudo-Hamiltonian system with a detailed dynamic equilibrium. In particular, the criterion is satisfied for catalytically active colloids interacting via nonreciprocal diffusiophoretic forces. However, in the general case, when this criterion is not satisfied, the steady state is determined by the interplay between dissipation and the energy source due to the nonreciprocity of interactions. The results indicate the realization of bistability and dissipative spinodal decomposition in a broad class of systems with nonreciprocal effective interactions. PMID- 30468441 TI - Mechano-responsive microcapsules with uniform thin shells. AB - Capsules often prolong the shelf-life of active ingredients, such as many types of drugs, food additives, or cosmetic substances, because they delay oxidation of these substances or prevent their reactions with molecules contained in the surrounding. If capsules are appropriately designed, they can offer an additional benefit: they allow close control over the timing and location of the release of active ingredients. To take advantage of these features, capsules must possess shells whose thickness and composition are well-defined. However, the shell thickness of capsules often varies considerably even within a single capsule, thereby hampering good control over the release kinetics of encapsulants. These variations can be reduced, and hence the degree of control over the release kinetics increased, if shells are made thin. Unfortunately, the controlled fabrication of mechanically stable microcapsules with well-defined sub-MUm thick shells is difficult. Here, we introduce a method to fabricate capsules with uniform semi-permeable shells with a thickness as low as 400 nm. This is achieved using water-oil-water double emulsions with 800 nm thick shells as templates to fabricate capsules with uniform 400 nm thin shells. These shells occupy less than 2% of the capsule volume, thereby minimizing their footprint. Despite their thin shells, these capsules are mechanically robust: they withstand pressures up to 1.3 MPa without deformation and remain intact if exposed to pressures up to 2.75 MPa. Moreover, while they are permeable towards water, they retain low molecular weight encapsulants even if dried and re-dispersed. The thin shells of the capsules open up new possibilities of their use to functionalize materials with at least one dimension that is small, such as coatings, where thick shells introduce defects, or as building blocks of new types of functional materials. PMID- 30468442 TI - Ab initio study of sodium diffusion and adsorption on boron-doped graphyne as promising anode material in sodium-ion batteries. AB - The electronic properties, adsorption energies and energy barrier of sodium ion diffusion in B-doped graphyne (BGY) are studied by density functional theory (DFT) method. If some carbon atoms in pristine graphyne (GY) are substituted by boron atoms (one substitution per unit cell in this work), BGY is obtained, and the band structure and density of state (DOS) plots indicate a transition from a semiconductive state for GY to a metallic state for BGY. The calculated adsorption energy shows an improvement in the trigonal-like pore (T site) and hexagonal ring (H site) adsorption of BGY compared to the corresponding analog sites in GY. The comparison of projected density of state (PDOS) plots before and after adsorption reveals charge transfer from sodium to nanosheets. Therefore, the interaction between adsorbed sodium atom and BGY/GY has ionic character and not covalent. This phenomenon is important for the reversible sodium adsorption in secondary batteries. Moreover, PDOS plots show that the electron transfer from sodium atom to host structure in BGY is more than in GY, which is in agreement with adsorption energies. According to diffusion energy barrier calculations, boron atoms in BGY structure provide low energy paths for sodium ions diffusion. We estimate a theoretical capacity of 751 mA h g-1 for the maximum sodium adsorption on BGY (without cluster formation). Therefore, BGY is a promising anode material for sodium ion batteries (SIBs). PMID- 30468443 TI - pH-Induced reorientation of cytochrome c on silica nanoparticles. AB - The orientation of cytochrome c molecules at the surface of silica nanoparticles was studied in a wide pH range by combining small-angle neutron scattering, adsorption measurements, and molecular dynamics simulations. The results indicate a reorientation of the ellipsoidal protein from head-on to side-on as the pH is increased. This is attributed to changes in the surface charge distribution of both the protein and the nanoparticles. PMID- 30468444 TI - Computer study of the solubilization of polymer chains in polyelectrolyte complex cores of polymeric nanoparticles in aqueous media. AB - The formation and structure of nanoparticles containing non-polar polymer chains solubilized in interpolyelectrolyte complex (IPC) cores and the partitioning of non-polar chains between bulk solvent and IPC cores were studied by coarse grained computer simulations. The choice of the model system was inspired by experimental results published by van der Burgh et al. (Langmuir, 2004, 20, 1073 1084). The dissipative particle dynamics (DPD) simulations reproduced the structure and basic features of co-assembled nanoparticles described by experimentalists well at the semi-quantitative coarse-grained level and revealed new properties of co-assembled particles. The simulated co-assemblies were used as reference systems for the solubilization studies. Their results show that non polar polymers (electrically neutral and compatible with core-forming chains) solubilize easily in IPC cores. They intermix with polyelectrolyte blocks in cores and do not hinder, but, on the contrary, they slightly promote the electrostatic co-assembly. PMID- 30468445 TI - Compound droplets derived from a cholesteric suspension of cellulose nanocrystals. AB - This study reports microfluidic generation of Janus droplets that consist of a liquid crystal component (a cholesteric aqueous suspension of cellulose nanocrystals, Ch-CNC) and a mineral oil (MO) component. The composition of the droplets was controlled by varying the relative flow rates of MO and Ch-CNC suspension. The shape of the Ch-CNC component of the droplets was changed from a truncated sphere to a hemisphere to a crescent moon. For these three Ch-CNC phase shapes, the Ch packing of the CNC pseudolayers was preserved, however the Ch pitch reduced, which was ascribed to the change in CNC orientation at the Ch CNC/MO interface from perpendicular to parallel. The shape of the compound droplets was tuned from a dumbbell to a sphere by reducing interfacial tension between the Ch-CNC suspension and MO phases. Photopolymerization of the monomer mixture introduced in the Ch-CNC phase of the droplets and the removal of the sacrificial MO phase enabled the generation of Ch microgels. The results of this work can be used for exploring new applications of Janus colloids and the fabrication of programmable active soft matter. PMID- 30468446 TI - High-throughput, non-equilibrium studies of single biomolecules using glass-made nanofluidic devices. AB - Single-molecule detection schemes offer powerful means to overcome static and dynamic heterogeneity inherent to complex samples. However, probing biomolecular interactions and reactions with high throughput and time resolution remains challenging, often requiring surface-immobilized entities. Here, we introduce glass-made nanofluidic devices for the high-throughput detection of freely diffusing single biomolecules by camera-based fluorescence microscopy. Nanochannels of 200 nm height and a width of several micrometers confine the movement of biomolecules. Using pressure-driven flow through an array of parallel nanochannels and by tracking the movement of fluorescently labelled DNA oligonucleotides, we observe conformational changes with high throughput. In a device geometry featuring a T-shaped junction of nanochannels, we drive steady state non-equilibrium conditions by continuously mixing reactants and triggering chemical reactions. We use the device to probe the conformational equilibrium of a DNA hairpin as well as to continuously observe DNA synthesis in real time. Our platform offers a straightforward and robust method for studying reaction kinetics at the single-molecule level. PMID- 30468447 TI - Platinum-mediated monohydration of SO2. AB - The monohydration of SO2 has been achieved in solution mediated by a platinum aquo complex. Benzamidate ligands play a key role along the process, acting as versatile proton shuttles. Finally, the platinum center allows the stabilization of benzimidic acid and a hydrogensulphite anion, the disfavored tautomers of benzamide and sulphonate, respectively. PMID- 30468448 TI - Non-volatile natural products in plant glandular trichomes: chemistry, biological activities and biosynthesis. AB - Covering: 1960s to end of August 2018Plant glandular trichomes (GTs) are adaptive structures that are well known as "phytochemical factories" due to their impressive capacity to biosynthesize and store large quantities of specialized natural products. The natural products in GTs are chemically diverse and mostly function as defense chemicals, therefore GTs are frequently regarded as "the first defense line" of plants against biotic and abiotic stresses. More importantly, many GT natural products are commercially desirable, thanks to their significant biological activities, thus attracting extensive interest in their biosynthesis. Consequently, it is well known that plant GTs are not only important reservoirs of biologically active natural products but are also a valuable bank of novel biosynthetic genes and enzymes. The non-volatile or oxygenated natural products in plant GTs, which need longer biosynthetic pathways and more energy from the plants, are of particular interest due to their more extensive biological activities and high commercial value. This review mainly focuses on these non-volatile natural products in plant GTs, including their chemistry, biological activities and biosynthesis. The methods employed for investigating natural products and their biosynthesis in plant GTs are also comprehensively discussed. PMID- 30468449 TI - Mitochondria-mediated disturbance of fatty acid metabolism in proximal tubule epithelial cells leads to renal interstitial fibrosis. AB - The article "Mitochondria-mediated disturbance of fatty acid metabolism in proximal tubule epithelial cells leads to renal interstitial fibrosis" by W. Shen, X.-X. Jiang, Y.-W. Li, Q. He, published in Eur Rev Med Pharmacol Sci 2018; 22 (3): 810-819 has been withdrawn. PMID- 30468450 TI - Osteoinductive effects of tantalum and titanium on bone mesenchymal stromal cells and bone formation in ovariectomized rats. AB - OBJECTIVE: Although Tantalum (Ta) exhibits better osteoinductivity in healthy subjects when compared with titanium (Ti), the relative effects in osteoporosis remain unknown. MATERIALS AND METHODS: In this study, bone mesenchymal stromal cells of ovariectomized rats (OVX-rBMSCs) were seeded on Ta and Ti substrates for in vitro evaluation of cell viability, reactive oxygen species (ROS) production, alkaline phosphatase (ALP) activity, extracellular mineralization osteogenic gene and protein expression involved in bone morphogenetic protein (BMP2)/small mothers against decapentaplegic homologs 1 (Smad1) pathway. For in vivo assessment, Ta and Ti implants were embedded in femur defects of ovariectomized rats, followed by sequential fluorochrome labeling and histological staining. RESULTS: Compared to Ti, the Ta substrates demonstrated higher viable cell percentages (96.5 +/- 0.26 vs. 88.17 +/- 2.23%), lower ROS levels (65% vs. Ti), and enhanced ALP activity and extracellular matrix calcification. Reverse Transcription-Polymerase Chain Reaction and Western blot assays validated the better osteoinductive effect of Ta regarding small mothers against decapentaplegic homologs 1 (Smad1), runt-related transcription factor 2, bone morphogenetic protein (BMP2), and ALP expression at both the mRNA (1.5-2-fold) and protein (1.2-1.8-fold) levels. BMP2/Smad1 signaling over-expression or knockdown yielded significantly enhanced or deteriorated OVX-rBMSC osteogenesis on the two surfaces. In addition, the Ta group revealed more new bone formation (1.3-1.5-fold vs. Ti) and slightly better bone-implant contact (31.82 +/- 4.07 vs. 25.2-3.84% at 8 weeks post-implantation, p = 0.052) without the contribution of specific surface structures. CONCLUSIONS: In comparison to Ti, Ta reveals better biocompatibility and osteoinductivity to OVX-rBMSCs, and the preferential Ta osteoinductivity may reflect its greater potential to trigger the BMP2/Smad1 cascade. Thus," in front of "Ta". Ta appears preferable to Ti as a bone-implant surface material under osteoporosis conditions. PMID- 30468451 TI - LncRNA-TCL6 promotes early abortion and inhibits placenta implantation via the EGFR pathway. AB - OBJECTIVE: The aim of this study was to investigate the role of long non-coding RNA (lncRNA) TCL6 in early abortion and to explore its underlying mechanism. PATIENTS AND METHODS: The expression levels of lncRNA-TCL6 and epidermal growth factor receptor (EGFR) in placental tissues of normal pregnancy, threatened abortion pregnancy, spontaneous abortion pregnancy, and induced abortion pregnancy were detected by quantitative Real-Time Polymerase Chain Reaction (qRT PCR), respectively. Trophoblast cells were transfected with siRNA to knock-down lncRNA-TCL6. Cell viability of trophoblast cells was detected by cell counting kit-8 (CCK-8) assay. The protein expression levels of EGFR, extracellular regulated protein kinases (ERK) and protein kinase B (AKT) in trophoblast cells after lncRNA-TCL6 knockdown were detected by Western blot. Rescue experiments were performed to investigate the relationship between EGFR and lncRNA-TCL6. RESULTS: The expression of lncRNA-TCL6 in placenta tissues of threatened abortion pregnancy was significantly higher than that of normal pregnancy. Meanwhile, the expression of lncRNA-TCL6 in placenta tissues of spontaneous abortion pregnancy was also markedly higher than induced abortion pregnancy. However, the expression of EGFR showed an opposite trend. After knockdown of lncRNA-TCL6 in trophoblast cells, the protein expression levels of EGFR, ERK, and AKT were significantly increased when compared with those of the control group. CCK-8 assay indicated that cell viability was remarkably increased after knockdown of lncRNA-TCL6, which could be reversed by EGFR knockdown. CONCLUSIONS: Compared with normal pregnancy, lncRNA-TCL6 was highly expressed in placental tissues of threatened abortion pregnancy. Moreover, the expression of lncRNA-TCL6 in placenta tissues of spontaneous abortion pregnancy was significantly higher than induced abortion pregnancy. Knockdown of lncRNA-TCL6 promoted the proliferation of trophoblast cells and inhibited the abortion via the EGFR signaling pathway. PMID- 30468452 TI - Association of serum inflammatory markers and diabetic retinopathy: a review of literature. AB - OBJECTIVE: Diabetic retinopathy is the leading cause of irreversible blindness in the western world, among the working-age people. Its exact pathogenesis, however, remains obscure. Systemic inflammation is regarded to play a significant role in diabetes by contributing, among others, to the development of diabetic retinopathy. This review focuses on the possible involvement of the systemic inflammatory markers in the pathogenesis of diabetic retinopathy. PATIENTS AND METHODS: We performed a systematic search of the literature of published papers until August 2017 using the PubMed search engine. RESULTS: We demonstrated that many systemic inflammatory markers contribute to the pathogenesis and progression of retinopathy, while we highlighted in several occasions their usefulness as a key tool in the monitoring of the disease progression and the treatment efficacy. CONCLUSIONS: To the best of our knowledge this is the first review in the literature that elaborates the possible association of serum inflammatory markers and diabetic retinopathy, a disease that may cause irreversible loss of vision. PMID- 30468453 TI - Interleukin-1beta exacerbates the catabolic effects of human nucleus pulposus cells through activation of the Nuclear Factor kappa B signaling pathway under hypoxic conditions. AB - OBJECTIVE: To determine the regulatory role of interleukin 1 beta (IL-1beta) in the Nuclear Factor kappa B (NF-kappaB) -mediated catabolic effects of the nucleus pulposus cells in human intervertebral disc degeneration under hypoxic conditions. PATIENTS AND METHODS: Human nucleus pulposus cells were cultured and exposed to IL-1beta under hypoxic or normoxic environments, with or without NF kappaB inhibition. The cell growth was determined using cell counting kit-8; gene and protein expressions were analyzed by Real-time polymerase chain reaction and Western blotting, respectively. RESULTS: Co-treatment with IL-1beta and hypoxia decreased cell viability in human nucleus pulposus cells. There was a positive effect of IL-1beta on human nucleus pulposus cells under hypoxia, which was through the up-regulation of matrix metalloproteinase-3 (MMP-3), MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and ADAMTS-5. IL-1beta-induced expressions of MMP-3, MMP-9, ADAMTS-4, and ADAMTS-5 under hypoxia were accompanied by increased activation of NF-kappaB. Inhibition of NF-kappaBp65 by small interfering RNA or specific inhibitor BAY11-7082 blocked IL-1beta-dependent gene upregulation of MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5 in a hypoxic environment. The gene expression of aggrecan was decreased by IL-1beta under hypoxic conditions, which was reversed by either BAY11-7082 or NF-kappaBp65 knockdown. CONCLUSIONS: IL-1beta and hypoxia synergetically contributed to the catabolic effects of the nucleus pulposus cells by upregulating the expression of MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5 through the activation of NF-kappaB signaling pathway, indicating that the NF-kappaB signaling pathway is a key mediator of intervertebral disc degeneration. PMID- 30468454 TI - Investigation for effects of iNOS on biological function of chondrocytes in rats with post-traumatic osteoarthritis. AB - OBJECTIVE: Inducible nitric oxide synthase (iNOS) is one rate-limiting enzyme in nitric oxide (NO) synthesis, and plays a role in mediating cell proliferation, apoptosis, and inflammation. Post-traumatic arthritis (PTA) is secondary after osteoarthritis (OA). This study thus established rat PTA model, on which the role of iNOS in PTA pathogenesis was investigated. MATERIALS AND METHODS: Chondrocytes and synovial fluids were collected for comparing NO content and iNOS activity. In vitro cultured PTA rat chondrocytes were tested for expression of iNOS, matrix metallopeptidase 13 (MMP-13), and alpha-1 chain of type II collagen (COL2A1) expression with or without Interleukin 1beta (IL-1beta) treatment. NO content and iNOS activity in the supernatant were measured, followed by flow cytometry for Ki 67 expression and apoptosis. IL-1beta treated cells were transfected with small interfere iNOS (si-iNOS), followed by expressional assay of iNOS, MMP-13 and Col2A1, activity assay of NO and iNOS, plus Ki-67 level and apoptosis. RESULTS: Compared to Sham group, PTA model rats had higher iNOS expression, NO content, and iNOS activity. IL-1beta treatment remarkably elevated iNOS and MMP-13 expression in chondrocytes, it decreased COL2A1 expression, increased NO content and iNOS activity, whilst suppressed cell proliferation to facilitate apoptosis. Silencing of iNOS expression decreased iNOS or MMP-13 expression, increased COL2A1 expression, suppressed NO or iNOS content, potentiated proliferation and decreased apoptosis. CONCLUSIONS: iNOS expression and NO content were elevated in PTA rat chondrocyte. iNOS and NO production can facilitate chondrocyte apoptosis and matrix degradation, and suppress chondrocyte proliferation, thus playing a role in PTA pathogenesis. PMID- 30468455 TI - Autologous oxygen release nano bionic scaffold composite miR-106a induced BMSCs enhances osteoblast conversion and promotes bone repair through regulating BMP-2. AB - OBJECTIVE: Suitable seed cells and selection of bioactive scaffold materials are the main research contents of bone tissue engineering. It was showed that autologous oxygen release nano bionic scaffold could promote the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). The role of microRNA-106a (miR-106a) in regulating BMSCs differentiation has not been reported. We intend to investigate the role of autologous oxygen release nano bionic scaffold composite miR-106a in inducing BMSCs constructing tissue engineering bone. MATERIALS AND METHODS: Rat BMSCs were isolated and transfected by using miR-106a scramble or miR-106a inhibitor. Healthy male Sprague-Dawly (SD) rats were randomly divided into three groups, including bone fracture group established as rat tibial fracture model, negative control group implanted by autologous oxygen release nano bionic scaffold composite miR-106a scramble BMSCs, and miR-106a inhibitor group implanted by autologous oxygen release nano bionic scaffold composite miR-106a inhibitor BMSCs. Callus growth was observed. Alkaline phosphatase (ALP) activity was detected. Bone morphogenetic protein 2 (BMP-2) expression was tested by Real-time PCR (RT-PCR) and Western blot assay. Collagen II production was determined by RT-PCR. RESULTS: Autologous oxygen release nano bionic scaffold composite BMSCs significantly increased local bone mineral density, promoted callus healing, facilitated ALP secretion, elevated collagen II expression, and up-regulated BMP-2 mRNA and protein levels compared with fracture group (p<0.05). Autologous oxygen release nano bionic scaffold composite miR-106a induced BMSCs exhibited more significant effect on bone repair (p<0.05). CONCLUSIONS: Autologous oxygen release nano bionic scaffold composite miR-106a induced BMSCs enhanced osteoblast conversion and promoted bone repair through regulating BMP-2. PMID- 30468456 TI - MOTS-c improves osteoporosis by promoting osteogenic differentiation of bone marrow mesenchymal stem cells via TGF-beta/Smad pathway. AB - OBJECTIVE: To explore whether MOTS-c could improve osteoporosis by promoting osteogenic differentiation of rat bone mesenchymal stem cells (BMSCs) via transforming growth factor-beta (TGF-beta)/Smad pathway. MATERIALS AND METHODS: Rat BMSCs were isolated and cultured, followed by osteogenic and lipid differentiation. CCK-8 (cell counting kit-8) assay was performed to detect the highest treatment dose of MOTS-c that did not affect cell proliferation. Expressions of osteogenesis-related genes (ALP, Bglap, and Runx2) were detected by qRT-PCR (quantitative Real-Time Polymerase Chain Reaction) and Western blot, respectively. Alizarin red staining and alkaline phosphatase (ALP) cytochemical staining were carried out to evaluate the effect of MOTS-c on BMSCs osteogenesis. TGF-beta/Smad pathway-related genes (TGF-beta1, TGF-beta2, and Smad7) in BMSCs treated with MOTS-c were detected. Finally, TGF-beta1 was knocked down to investigate the regulatory effect of MOTS-c on BMSCs osteogenesis. RESULTS: BMSCs exhibited an elongated morphology and was identified with a high purity by flow cytometry. After osteogenic differentiation, alizarin red staining and ALP staining were all positive. MOTS-c treatment could remarkably stimulate the formation of calcified nodules in BMSCs. Besides, TGF-beta/Smad pathway-related genes were significantly upregulated after BMSCs were treated with MOTS-c. Promoted osteogenesis by MOTS-c treatment was reversed by the TGF-beta1 knockdown. CONCLUSIONS: MOTS-c promotes cell differentiation of BMSCs to osteoblasts via TGF-beta/Smad pathway. PMID- 30468457 TI - Amplitude of Low Frequency Fluctuation (ALFF) study of the spontaneous brain activities of patients with phantom limb pain. AB - OBJECTIVE: Our objective was to use Amplitude of Low-Frequency Fluctuation (ALFF) method to investigate the changes in spontaneous brain activity in HM patients and their relationships with clinical features. PATIENTS AND METHODS: This study was set out to observe, using Functional magnetic resonance imaging (fMRI), the changes in spontaneous brain activity in patients with phantom limb pain (PLP). Eleven amputees with PLP closely matched in age, sex, and education in a right side lower limb were scanned using fMRI to measure the amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC) in the resting state of the brain (GPLP) before use of prosthetic. They were then scanned again after recovering from PLP (GPLPr) after use of artificial limbs. Eleven healthy volunteers (GC) were also scanned. RESULTS: When compared to GC, GPLP exhibited decreased ALFF in the left inferior parietal lobule, and GPLPr exhibited decreased ALFF in the left precuneus. When compared to GPLP, GC showed positive FC in the part regions of the limbic system structure. When compared to GC, the positive FC in GPLPr was significantly decreased in the midbrain. Finally, when compared to GPLPr, GPLP showed significantly decreased positive FC in the right precuneus and inferior parietal lobe. The central nervous system shows functional changes in the resting state of the brain in patients with PLP, which may indicate the presence of neurobiological changes. The recovery time of the changes may be longer than the pain symptoms of patients. CONCLUSIONS: The technique of fMRI of the resting network of the brain in patients with PLP may be able to be used to monitor clinical therapeutic effects. PMID- 30468458 TI - The impact of TRAIL on proliferation of secretory prostate cancer PC-3 cell and LMO2 gene expression. AB - OBJECTIVE: To determine the expressions of TRAIL protein and LMO2 gene in prostate cancer tissues with different differentiation degree and identify the influence of TRAIL on prostate cancer PC-3 cell proliferation. PATIENTS AND METHODS: Surgical specimens from a total of 30 prostate cancer patients with radical prostatectomy were collected. The subjects were divided into three groups according to the different degrees of differentiation. TRAIL positive rate was detected by immunohistochemistry (IHC). LMO2 expression was assessed by Real-time PCR and Western-blot. PC-3 cell proliferation was determined by CCK-8 assay. RESULTS: The positive rate of TRAIL protein was significantly higher in moderately differentiated group (80%) and well differentiated group (100%) compared with that in poorly differentiated group (54.55%), respectively (chi2 = 27.33, p < 0.05; chi2 = 40.12, p < 0.01). Streptavidin-peroxidase (SP) assay showed that TRAIL protein expression in well-differentiated group was significantly higher than that in moderately differentiated group and poorly differentiated group. qRT-PCR result demonstrated that LMO2 mRNA levels in moderately and well-differentiated group were significantly increased compared to that in poorly differentiated group (p < 0.001). Also, the proliferation rate of PC-3 cells in well-differentiated group was significantly higher than that in well-differentiated and moderately differentiated groups (p < 0.05). CONCLUSION: Our data indicated that the positive rate of TRAIL protein increased in a prostate cancer differentiation dependent manner. PMID- 30468459 TI - Circular RNA_LARP4 is lower expressed and serves as a potential biomarker of ovarian cancer prognosis. AB - OBJECTIVE: Circular RNAs (circRNAs) have been identified as important regulators in regulating cancer progression. The study aims to investigate the expression of circular RNA_LARP4 (circ LARP4) and clinical significance in ovarian cancer (OC). PATIENTS AND METHODS: The expression of circ LARP4 was detected in a total of 78 paired ovarian cancer tissue and adjacent normal tissue samples using quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) analyses. The chi-square test was used to assess the association between expression of circLARP4 and clinical-pathological parameters. Survival plot was evaluated using the Kaplan-Meier method. The multivariate Cox analysis model was used for tumor prognosis analysis. RESULTS: We identified that circLARP4 expression was significantly down-regulated in ovarian cancer tissues compared with corresponding controls. Furthermore, we found that circLARP4 expression was significantly associated with International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastases. Lower circLARP4 expression was associated with poor prognosis of OC patients. Moreover, multivariate Cox analysis showed that lower circLARP4 was an independent risk for OC prognosis. CONCLUSIONS: These results indicated that circLARP4 expression was lower and highlighted that circLARP4 was identified as a potential biomarker of ovarian cancer prognosis. PMID- 30468460 TI - Long non-coding RNA PVT1 functions as an oncogene in ovarian cancer via upregulating SOX2. AB - OBJECTIVE: The aim of this study was to identify the role of long non-coding RNA PVT1 (lnc-PVT1) in the progression of ovarian cancer. PATIENTS AND METHODS: The expression of lnc-PVT1 in ovarian cancer cells and 50 paired tissue samples were detected by quantitative Reverse Transcriptase-Polymerase Chain Reaction (qRT PCR). Moreover, cell proliferation assay and transwell assay were performed to identify the function of lnc-PVT1 in vitro. QRT-PCR and Western blot were utilized to explore the possible underlying mechanism. RESULTS: Compared with normal tissues, the expression of lnc-PVT1 T1 was remarkably upregulated in tumor tissues. Moreover, the proliferation and invasion of ovarian cancer were promoted after knockdown of lnc-PVT1 in vitro. Moreover, both the mRNA and protein levels of SOX2 were suppressed after knockdown of lnc-PVT1 in vitro. Besides, the expression of SOX2 in tumor tissues was positively correlated to lnc-PVT1. CONCLUSIONS: Lnc-PVT1 could enhance the invasion and proliferation of ovarian cancer cells through upregulating SOX2, which might serve as a new therapeutic target for the treatment of ovarian cancer. PMID- 30468461 TI - Effects of forkhead Box protein A1 on cell proliferation regulating and EMT of cervical carcinoma. AB - OBJECTIVE: Cervical cancer is a common tumor in gynecological malignancies. However, the patients are often in an advanced stage when diagnosed. It was found that forkhead box protein A1 (FOXA1) is abnormally expressed in various tumors, such as breast cancer, ovarian cancer, and is closely related to tumorigenesis. This study aimed to investigate the expression and the related roles of FOXA1 in cervical cancer. PATIENTS AND METHODS: Real Time-PCR (RT-PCR) and Western blot were used to analyze expression of FOXA1 in cervical cancer and adjacent tissue. The small-interfere RNA (siRNA) was adopted to down-regulate FOXA1 expression in HeLa cells. The effect of FOXA1 on apoptosis of HeLa cells was detected by using thiazolyl blue tetrazolium bromide (MTT) method. The apoptosis rate of HeLa cells was detected by using flow cytometry. The Western blot was selected to evaluate the epithelial mesenchymal transition (EMT) related protein, vimentin, E cadherin, and vascular endothelial growth factor (VEGF) changes. RESULTS: Compared with adjacent tissues, FOXA1 mRNA and protein expressions significantly increased in cervical cancer (p<0.05). SiRNA significantly reduced FOXA1 expression in Hela cells compared with the control group and siRNA-NC group, thus inhibiting tumor cell proliferation and enhancing cell apoptosis rate (p<0.05). E cadherin elevated, Vimentin decreased, and VEGF reduced after FOXA1 siRNA treatment. CONCLUSIONS: FOXA1 expression increased in cervical cancer. Inhibition of FOXA1 expression blocked the proliferation of cervical cancer, promoted tumor cell apoptosis, suppressed the occurrence of EMT and VEGF production, and can regulate cervical cancer metastasis. FOXA1 can be used as a new molecular biological target for cervical cancer diagnosis and treatment. PMID- 30468462 TI - MicroRNA-31 inhibits osteosarcoma cell proliferation, migration and invasion by targeting PIK3C2A. AB - OBJECTIVE: To elucidate the role of microRNA-31 (miR-31) in osteosarcoma and the molecular mechanism of miR-31 in the proliferation, migration, and invasion of osteosarcoma. PATIENTS AND METHODS: Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) was used to examine the expression of microRNA-31 in human osteosarcoma tissues. Pearson's chi-squared test was used to analyze the correlation between microRNA-31 and clinicopathological features. Proliferation, migration, invasion, and PI3K3C2A protein in treated osteosarcoma cells were detected by Cell Counting Kit-8 (CCK-8) assay, transwell assay without Matrigel, transwell assay with Matrigel, and Western blot analysis, respectively. RESULTS: qRT-PCR showed that miR-31 was down-regulated in osteosarcoma tissues compared with paired para-tumor bone tissues. The lower level of miR-31 was closely associated with high-grade osteosarcoma, metastasis, and poor overall survival. CCK-8 and transwell assay showed that miR-31 inhibited osteosarcoma cells proliferation, migration, and invasion. According to luciferase assay, miR-31 inhibits osteosarcoma cell proliferation, migration, and invasion through inhibiting PIK3C2A. Reversely, overexpression of PIK3C2A inhibited partial effect of miR-31 on proliferation, migration, and invasion in vitro. CONCLUSIONS: MiR-31 inhibits osteosarcoma cell proliferation, migration, and invasion by targeting PICK3C2A. MiR-31 can thus be used as a therapeutic target in osteosarcoma treatment. PMID- 30468463 TI - MiR-485-5p inhibits metastasis and proliferation of osteosarcoma by targeting CX3CL1. AB - OBJECTIVE: To investigate the potential effect of miR-485-5p on the development of osteosarcoma (OA) and its relevant mechanism. PATIENTS AND METHODS: The expression level of miR-485-5p was detected in OA tissues and cells (MG-63) comparing with corresponding adjacent normal tissues and normal human osteoblastic cell lines (Hfob1.19), respectively. Luciferase assay was performed to evaluate the interaction between miR-485-5p and CX3CL1, the effects of miR-485 5p on MG-63 cells were determined by subsequent experiments including cell proliferation, expression level of CX3CL1, detection of invasion and migration capacities. RESULTS: In our present research, miR-485-5p was down-regulated in OA tissues and we got the same result in OA cells. In order to obtain potential target of miR-485-5p, we checked it in three publicly available algorithms, TargetScan, miRDB and microRNA. We found that CX3CL1 is a direct target of miR 485-5p, and Luciferase assays confirmed our hypothesis. The results showed that decreased expression of CX3CL1 resulting from the up-regulation of miR-485-5p could decelerate cell proliferation, invasion and migration in OA cells. CONCLUSIONS: We showed the suppressor function of miR-485-5p in OA by targeting CX3CL1, indicating that miR-485-5p/CX3CL1 axis might be a potential therapeutic target for the treatment of OA. PMID- 30468464 TI - Role of miR-214-5p in the migration and invasion of pancreatic cancer cells. AB - OBJECTIVE: To analyze the role of miR-214-5p in proliferation and metastasis of pancreatic cancer (PC) cells, as well as its underlying mechanism. PATIENTS AND METHODS: 30 pairs of PC tissues and adjacent normal tissues were collected in our Department. The expression level of miR-214-5p was detected by quantitative Real time-polymerase chain reaction (qRT-PCR). Biological information analysis and luciferase report gene assay were used to verify potential target genes of miR 214-5p. Cell counting kit-8 (CCK-8) and transwell methods were applied to observe the interference of miR-214-5p on invasion and migration of PC cells. Western blot (WB) assay was applied to determine the expression changes of Jagged 1 (JAG1) and epithelial-mesenchymal transition (EMT)-related genes in PC cells. RESULTS: QRT-PCR results showed that the expression level of miR-214-5p is significantly down-regulated in PC tissues and cells. Bioinformatics software and luciferase report gene assay identified that JAG1 is a target gene of miR-214-5p. The negative correlation between protein expressions of miR-214-5p and JAG1 was assessed by Western Blot assay. Furthermore, miR-214-5p could suppress cell proliferation, invasion and migration, and it also blocked the EMT in PC cells in vitro. Meanwhile, JAG1 overexpression reversed the inhibitory effects of miR-214 5p on proliferation, invasion and migration of PC cells. CONCLUSIONS: Overexpressing miR-214-5p could significantly inhibit malignant behavior of PC cells through targeted regulation of JAG1. Thus, miR-214-5p might be a potential therapeutic target for treatment of PC. PMID- 30468465 TI - Down-regulation of LncRNA NR027113 inhibits cell proliferation and metastasis via PTEN/PI3K/AKT signaling pathway in hepatocellular carcinoma. AB - OBJECTIVE: Hepatocellular Carcinoma (HCC) is a worldwide common and malignant tumor. It is discovered in recent years that long non-coding RNAs (lncRNAs) participate in many biological processes of HCC. However, their specific role in HCC has not been entirely clarified yet. In this research, we aimed to explore biological functions, clinical significance and the underlying molecular mechanisms of lncRNA NR027113 in HCC. PATIENTS AND METHODS: qRT-PCR was performed to test the expression of NR027113 in HCC tissue samples and HCC cell lines. The association of NR027113 expression with overall survival, disease-free survival and clinicopathological factors was analyzed. MTT assays, Colony formation assay, flow cytometry and transwell invasion assays were performed to determine the effect of NR027113 in the regulation of biological behaviors of HCC cells. Western blot was performed to determine the activation of the PTEN/PI3K/AKT signaling pathway. RESULTS: In the present study, we proved that is significantly up-regulated in HCC tissues and cell lines. HCC patients with higher NR027113 expression were associated with significantly shorter overall survival and disease-free survival. NR027113 knockdown inhibited the proliferation and metastasis of HCC cells in vitro. In addition, NR027113 knock-down was found to inhibit the activity of the PI3K/Akt signaling pathway and restrain the EMT process. Furthermore, we found that PTEN silencing could reverse the inhibitory effect of NR027113 knockdown on Akt phosphorylation and HCC cells function. CONCLUSIONS: A brand new lncRNA NR027113 was found, which can promote the proliferation, invasion and metastasis of HCC via the PTEN/PI3K/AKT signaling pathway, and may be a potential therapeutic target in the future treatment of HCC. PMID- 30468466 TI - Role of miR-193a-5p in the proliferation and apoptosis of hepatocellular carcinoma. AB - OBJECTIVE: This study aims at exploring the regulatory effects of miR-193a-5p on hepatocellular carcinoma (HCC). It might provide new insight into the improvement of clinical treatment of HCC. PATIENTS AND METHODS: A total of 50 HCC patients who did not receive any tumor treatments were recruited, and 50 paired tumor tissues and adjacent non-tumor tissues were obtained. Quantitative Real Time Polymerase Chain Reaction (qRT-PCR) was performed to validate the expression and significance of miR-193a-5p in HCC tumor tissues, adjacent non-tumor tissues and cell lines. Binding-site of the target gene of miR-193a-5p was predicted by bioinformatics and further verified by Dual-Luciferase reporter gene assay and Western blotting (WB) assay. To investigate the potential role of miR-193a-5p in HCC development, cell counting kit-8 (CCK-8) assay was performed to study the proliferation and viability capacities. Flow cytometric analyses were adopted to test the cell cycle distribution and quantify the apoptotic cell proportion. RESULTS: MiR-193a-5p expression was specifically up-regulated in HCC tissues and cell lines compared with paired adjacent non-tumor tissues and normal liver cell lines (HL-7702) respectively. BMF was considered as a downstream gene of miR-193a 5p, which was further proofed in Dual-Luciferase reporter gene assay and Western blot assays. In vitro experiments showed that miR-193a-5p overexpression could accelerate the proliferation, facilitate the G1/S transition and suppress the apoptosis of HCC cells. However, BMF overexpression could reverse the effects of miR-193a-5p on the cellular functions of HCC cells. CONCLUSIONS: This finding suggested that miR-193a-5p is strongly up-regulated in HCC. MiR-193a-5p promoted the abnormal proliferation of HCC cells and limited their apoptosis by targeting the downstream gene BMF. Thus, the miR-193a-5p/BMF axis might be a novel regulatory pathway of apoptosis which could be potential therapeutic sites in HCC treatment. PMID- 30468467 TI - Overexpression of miR-215-3p sensitizes colorectal cancer to 5-fluorouracil induced apoptosis through regulating CXCR1. AB - OBJECTIVE: Chemo-resistance of colon cancer remains a major problem in therapy. The role of miR-215-3p in the chemo-sensitivity of colon cancer remains unidentified. PATIENTS AND METHODS: Here, we constructed a 5-Fluoracil (5-Fu) resistant HCT116 cell line (HCT116/5-Fu) and miR-215-3p expression levels were measured in 56 cases of colon cancer tissues and 23 cases of normal tissues by quantitative real-time polymerase chain reaction (qRT-PCR). The effects of miR 215-3p on colon cancer cell growth and apoptosis were investigated using cell counting kit-8 (CCK-8) and apoptosis assay, respectively. In addition, CXC chemokine receptor type1 (CXCR1) was identified as a target of miR-215-3p by using luciferase reporter assay. RESULTS: miR-215-3p was down-expressed in the 5 FU resistant cell compared to the parent cell. The level of miR-215-3p was correlated with the 5-Fu sensibility of colorectal cancer cell and the alteration of miR-215-3p affected the sensibility of colorectal cancer cells toward 5-Fu. Furthermore, miR-215-3p accelerated the apoptosis of colorectal cancer cell which was treated with 5-Fu. Mechanically, miR-215-3p regulated the level of endogenous CXCR1 in HCT116 cell and alternation of CXCR1 affected the 5-Fu sensibility mediated by miR-215-3p. Finally, overexpression of miR-215-3p restrained the growth of HCT116/5-Fu cells in the xenograft model. CONCLUSIONS: MiR-215-3p improved the 5-Fu sensibility via regulating the expression of CXCR1 in the colorectal cancer cell. PMID- 30468468 TI - MiR-136 triggers apoptosis in human gastric cancer cells by targeting AEG-1 and BCL2. AB - OBJECTIVE: Gastric cancer is the second most prevalent cancer across the globe and accounts for about 10% of new cancer cases. It is one among the leading causes of cancer-related deaths around the world. Recently, microRNAs have been identified as important therapeutic targets for the treatment of several cancers owing to their potential to target multiple genes and hinder several biological processes such as proliferation and apoptosis. In the current study, we investigated the potential of miR-136 as therapeutic target for gastric cancer. MATERIALS AND METHODS: Total RNA was isolated by RNeasy RNA isolation kit and cDNA was prepared byRevertAid cDNA synthesis kit. The transcript analysis was carried out by quantitative RT-PCR. The transfection of miR-136 mimics or plasmids was carried out by using the Lipofectamine 2000 reagent. Apoptosis was detected by DAPI and acridine orange/ethidium bromide (AO/EB) staining. Protein expression was examined by Western blotting. RESULTS: The results indicated that the expression of miR-136 is significantly downregulated in gastric cancer cells. Transfection and subsequent overexpression of miR-136 in gastric cancer cells significantly promoted apoptosis as evident from DAPI and OA staining. In silico analysis revealed AEG-1 and BCL2 to be the potential targets of miR-136. Therefore, the expression of AEG-1 and BCL2 was determined in untreated control, cisplatin treated control and miR-136 transfected AGS gastric cancer cells. The results revealed that overexpression of miR-136 expression causes significant downregulation of AEG-1 and BCL2 protein expression. CONCLUSIONS: Taken together, we conclude that miR-136 promotes apoptosis in gastric cancer cells by targeting AEG-1 and BCL2. Therefore, miR-136 may prove as a potential therapeutic target for the treatment of gastric cancer. PMID- 30468469 TI - Microbial community reshaped in gastric cancer. AB - Patients with gastric cancer harbor distinct microbiota in the stomach. It features with lowered biodiversity, discrete structure, and varied composition. Some bacteria from gastric microbiota are potentially carcinogenic as they are enriched or depleted in gastric cancer. Distinct profile of microbial community in gastric cancer is possibly resulted from altered caused by pathophysiological and environmental factors. H. pylori is a carcinogen colonizing the human stomach. Although persisting for decades, it rarely causes compositional alteration of microbiota. Secretion of acid decreases gradually during the carcinogenic process. Increased pH results in overgrowth of bacteria in gastric fluid. The abundance of a particular taxon, but not the profile of microbiota, is altered in proton pump inhibitor users. Compositions of microbiota vary substantially between individuals, which may account for differential cancer risk. It has been demonstrated that genetic variations contribute to inter individual variations in gut microbiota. However, their influence on the composition of gastric microbiota requires further exploration. Currently, it appears disrupted homeostasis and inter-individual variations of gastric microbiota are involved in cancer development. Clarifying factors responsible for these changes would reveal how microbiota induces carcinogenesis, benefiting the prevention of gastric cancer. PMID- 30468470 TI - MiR-874-3p is an independent prognostic factor and functions as an anti-oncomir in esophageal squamous cell carcinoma via targeting STAT3. AB - OBJECTIVE: Emerging evidence has suggested that dysregulation of miR-874-3p may be involved in tumor development and progression in various types of cancers. However, its expression and biological function in esophageal squamous cell carcinoma (ESCC) remains unclear. The aim of this study was to explore the roles of miR-874-3p in ESCC tumorigenesis and development. PATIENTS AND METHODS: Quantitative Real Time-PCR was used to detect the expression of related mRNAs and miRNA in both ESCC tissues and cells. Then, statistical analysis was performed to determine the associations of miR-874-3p expression with the clinical features and the prognosis of ESCC. Cells proliferation and metastasis were assessed by cell viability assay and transwell assay. Luciferase reporter assays and Western blot were performed to analyze the regulation of putative target of miR-874-3p. RESULTS: We found that the expressions of miR-874-3p in ESCC tissues and cell lines were much lower than that in normal control, respectively. Also, there is a statistically significance between miR-874-3p expression level and lymph nodes metastasis and clinical stage. Kaplan-Meier analysis showed that decreased miR 874-3p expression was associated with poor overall survival of patients. Multivariate Cox regression analysis showed that the expression of miR-874-3p was an independent prognostic factor for ESCC patients. After miR-874-3p mimics transfection, cell proliferation, migration, and invasion were significantly suppressed in the ESCC cells. Mechanistically, STAT3 was confirmed to be the downstream target of miR-874-3p in ESCC cells. CONCLUSIONS: We indicate that miR 874-3p could be a new therapeutic target and prognostic marker of ESCC. PMID- 30468471 TI - Suppression of long non-coding RNA UCA1 inhibits proliferation and invasion and induces apoptosis in human lung cancer cells. AB - OBJECTIVE: Lung cancer is one of the deadliest cancers responsible for significant mortality and morbidity across the globe. The unavailability of efficient treatments, lack of reliable biomarkers and potent therapeutic targets, limit the treatment of lung cancer. In this study, we explored the potential of long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) as the therapeutic target for lung cancer. MATERIALS AND METHODS: The expression analysis was carried out by quantitative Real Time-Polymerase Chain Reaction (qRT PCR). Cell viability was monitored by cell counting kit 8 (CCK-8) assay. The 4',6 diamidino-2-phenylindole (DAPI), annexin-V/Propidium iodide staining and comet assays were used to detect apoptosis. Boyden chamber and wound heal assays were used for cell to asses cell invasion and migration respectively. Protein expression was determined by immunoblotting. RESULTS: The expression of lncRNA UCA1 was determined by qRT-PCR in six different types of lung cancer cell lines. It was observed that lncRNA UCA1 was significantly (p < 0.05) upregulated in all the lung cancer cell lines. To investigate the role of lncRNA UCA1 in lung cancer, its expression was suppressed by transfection of the lung cancer NCI-H23 cells by si-UCA1. The results showed that suppression of lncRNA UCA1 significantly (p < 0.05) reduced the viability of NCI-H23 cancer cells via induction of the apoptosis. Furthermore, the lncRNA UCA1 suppression (p < 0.05) significantly inhibited the migration and invasion of the NCI-H23 lung cancer at least in part via inhibition of mitogen-activated protein kinase 1 (MAPK1). Additionally, the suppression of MAPK1 exhibited similar effects on the proliferation, migration, and invasion of the NCI-H23 cells as that of UCA1 silencing. Finally, the co-suppression of lncRNA UCA1 and MAPK1 exhibited synergistic effects on cell proliferation, migration, and invasion. CONCLUSIONS: We demonstrated that lncRNA UCA1 could be an important therapeutic target for curbing lung cancer. PMID- 30468472 TI - LncRNA GASL1 inhibits tumor growth of non-small cell lung cancer by inactivating TGF-beta pathway. AB - OBJECTIVE: Growth-Arrest Associated lncRNA 1 (GASL1) is a newly discovered lncRNA that plays a role as tumor suppressor gene in liver cancer, while its involvement in other malignancies is unknown. We aimed to investigate the involvement of GASL1 in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Tumor tissue and adjacent healthy tissues were collected from 98 patients with NSCLC, and blood samples were collected from both NSCLC patients and healthy controls to detect GASL1 expression. All patients were followed up for 5 years and the diagnostic and prognostic values of GASL1 for NSCLC were evaluated by ROC curve analysis and survival curve analysis, respectively. Correlations between serum levels of GASL1 and clinicopathological data of NSCLC patients were analyzed by Chi-square test. GASL1 overexpression and knockdown cancer cell lines were constructed and the effects on transforming growth factor beta1 (TGF-beta1) expression and cell proliferation were explored by Western blot and CCK-8 assay, respectively. RESULTS: We found that lncRNA GASL1 expression was significantly downregulated in tumor tissues than in adjacent healthy tissues. Serum level of GASL1 was also lower in cancer patients than in healthy controls. Serum GASL1 is a sensitive diagnostic biomarker for NSCLC, and low expression level of GASL1 indicated short postoperative survival time. Overexpression of GASL1 upregulated, while GASL1 knockdown downregulated TGF-beta1 expression. GASL1 overexpression inhibited, and GASL1 knockdown promoted cancer cell proliferation. CONCLUSIONS: We found that lncRNA GASL1 may inhibit tumor growth of NSCLC by downregulating TGF-beta1. PMID- 30468473 TI - Cisplatin induces apoptosis of A549 cells by downregulating peroxidase V. AB - OBJECTIVE: The purpose of the study was to investigate the role of peroxidase V (Prx V) in Cisplatin-induced apoptosis of A549 cells and its underlying mechanism. MATERIALS AND METHODS: MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was conducted to evaluate the regulatory effect of Cisplatin on the survival of A549 cells. ROS (Reactive Oxygen Species) level in A549 cells induced with 0, 2, 4, and 6 mol/L Cisplatin for 24 h was determined using immunofluorescence. Apoptosis of Cisplatin-induced A549 cells was determined by immunofluorescence and flow cytometry, respectively. Western blot was performed to detect protein levels of Prx V, Bcl-2 (B-cell lymphoma 2), BAD ,and caspase-3 in Cisplatin-induced A549 cells. RESULTS: Survival rate of A549 cells gradually decreased with the increased dose of Cisplatin. Immunofluorescence results elucidated that cellular ROS level in Cisplatin induced A549 cells increases in a dose-dependent manner. Both immunofluorescence and flow cytometry results revealed that the apoptotic rate of A549 cells increases with the elevation of Cisplatin dose. Besides, the apoptotic rate and ROS level of A549 cells were reduced by NAC pretreatment. Western blot results showed that the protein level of Prx V remarkably decreased in a dose-dependent manner, whereas Prx II expression did not change. With the treatment prolongation of 4 MUmol/L Cisplatin in A549 cells, Bcl-2 and caspase-3 were downregulated, while BAD upregulated. CONCLUSIONS: Cisplatin treatment induces the ROS production, increases the apoptotic rate and downregulates the Prx expression in A549 cells. PMID- 30468474 TI - A combination of mRNA expression profile and miRNA expression profile identifies detection biomarkers in different tumor stages of laryngeal squamous cell carcinoma. AB - OBJECTIVE: This study was conducted to investigate microRNA (miRNA) target regulations during the disease progression in laryngeal squamous cell carcinoma (LSCC) and identify biomarkers in different tumor stages. MATERIALS AND METHODS: The mRNA dataset GSE59102 and miRNA dataset GSE70289 were used in this study. After pretreatment, differentially expressed genes/miRNAs (DEGs/DEMs) in different tumor stages (beginning vs. margin, advanced vs. margin, and beginning vs. advanced) were selected on the basis of their limma package. Then, the enrichment analysis for these DEGs was conducted using ClueGO. Protein-protein interaction (PPI) network analysis was performed on the basis of the BioGRID database. After prediction of target genes of DEMs according to three validated miRNA databases, an integrated miRNA target network and its pathways were drawn using the multiMiR package. RESULTS: Numerous DEGs were identified in different tumor stages of LSCC (beginning vs. margin, advanced vs. margin, and beginning vs. advanced), and a set of 18 DEMs was identified. Cell cycle was the most significantly enriched pathway of the DEGs. Four hub nodes (MCM2, EGFR, CDK2, and CDK1) were highlighted in the PPI network. In the integrated miRNA target network, 2 miRNAs were predominant: hsa-miR-331-3p (2 predicted targets, E2F1 and TNFRSF10B) and has-miR-375 (1 predicted target, TNNI3). These genes were tied up with cell cycle or apoptosis pathway. CONCLUSIONS: Several genes and miRNAs might be used as markers for LSCC in different tumor stages (e.g., MCM2, EGFR, CDK1, CDK2, hsa-miR-331-3p, hsa-miR-375). They might function through the involvement of the cell cycle pathway. PMID- 30468475 TI - Upregulation of lncRNA LINC00473 promotes radioresistance of HNSCC cells through activating Wnt/beta-catenin signaling pathway. AB - OBJECTIVE: LncRNA LINC00473 was reported to be upregulated in human cancers. Whereas, the role of LINC00473 in head and neck squamous cell carcinoma (HNSCC) and radiotherapy remains elusive. PATIENTS AND METHODS: Gene array analysis was performed to detect lncRNA LINC00473. Then, the expression of LINC00473 in HNSCC 78 pairs of tissues and cell lines was measured by qRT-PCR assay. To explore the detailed functions of LINC00473 on cell proliferation, MTT and colony formation assays were conducted. We also investigated the influence of LINC00473 expression on radioresistance of HNSCC cells. Western blot assay was used to confirm the relationship between LINC00473 and Wnt/beta-catenin signaling pathway. Furthermore, the effects of x-ray treatment on LINC00473 expression and Wnt/beta catenin signaling pathway were detected by Western blot assay. RESULTS: LncRNA LINC00473 was upregulated in HNSCC tissues and cell lines. Functional assays showed that LINC00473 acted as oncogene to promote cell proliferation and inhibit apoptosis. In addition, downregulation of LINC00473 enhanced the sensitivity of radiotherapy for HNSCC cells. Furthermore, Western blot assays demonstrated that Wnt/beta-catenin signaling pathway was inhibited by LINC00473 knockdown. Notably, Western blot assay revealed that x-ray treatment suppressed the activity of Wnt/beta-catenin signaling pathway after LINC00473 knockdown. CONCLUSIONS: These data suggested that the upregulation of lncRNA LINC00473 promotes the radioresistance of HNSCC cells through activating Wnt/beta-catenin signaling pathway. PMID- 30468476 TI - CD151 promotes breast cancer metastasis by activating TGF-beta1/Smad signaling pathway. AB - OBJECTIVE: This study aimed to explore the expression characteristics of CD151 in breast cancer (BC) and to further study its role in the development of BC and potential regulatory mechanisms. PATIENTS AND METHODS: Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) was used to detect the level of CD151 in 82 pairs of BC tissues and adjacent normal ones, and the relationship between CD151 expression and BC pathological parameters and prognosis was analyzed. CD151 expression in BC cells was further validated using qRT-PCR. The CD151 knockdown model was constructed in BC cell lines including MCF-7 and SKBR3 using the small interference RNA. The cell counting kit-8 (CCK-8) and transwell assay were used to analyze the effect of CD151 on the biological function of BC cells, and finally Western blot was performed to explore its underlying mechanism. RESULTS: QRT-PCR analysis revealed that CD151 level in BC tissues was strikingly higher than that in normal ones, and the difference was statistically significant. Compared with patients with low CD151 level, patients with high CD151 level had worse tumor stage, lymph node metastasis, and distant metastases. The higher the incidence of metastasis, the lower the overall survival rate. Compared with the negative control group, the ability of cell proliferation or invasion and migration in the CD151 knockdown group was significantly reduced. In addition, Western blot results demonstrated that the levels of proteins in TGF-beta1/Smad pathway, including transforming growth factor-beta1 (TGF-beta1), p-Smad2, p Smad3, N-cad, Vimentin and MMP-9, were remarkably decreased in cells of si-CD151 group. CONCLUSIONS: The expression of CD151 in BC was significantly increased, which was found evidently associated with BC stage, lymph node or distant metastasis, and poor prognosis. Meanwhile, CD151 may promote the proliferation and invasion of BC by regulating TGF-beta1/Smad pathway. PMID- 30468477 TI - MiR-155 promotes the proliferation and migration of breast cancer cells via targeting SOCS1 and MMP16. AB - OBJECTIVE: The aim of this study was to investigate the effect of miR-155 on the proliferation and migration of breast cancer cells, and to explore the underlying mechanism. MATERIALS AND METHODS: The breast cancer cell line MDA-MB-231 was transfected with miR-155 mimics, inhibitor or negative control, respectively. The expression level of miR-155 was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Subsequently, the proliferation of MDA-MB-231 cells was detected by multi-cellular tumor spheroid (MTS) and colony formation assay. Cell migration was examined by transwell assay and scratch test. In addition, qRT-PCR was performed to analyze the expression of matrix metallopeptidase 16 (MMP16) after miR-155 mimics or inhibitor transfection in MDA-MB-231 cells. Meanwhile, Western blot was used to evaluate the protein expression levels of suppressor of cytokine signaling 1 (SOCS1) and MMP16 after miR-155 mimics or inhibitor transfection. RESULTS: QRT-PCR results showed that miR-155 mimics significantly increased the expression of miR-155 in MDA-MB-231 cells, whereas miR-155 inhibitor markedly decreased miR-155 expression (p < 0.05). Meanwhile, MTS and colony formation assay indicated that the proliferation of MDA-MB-231 cells was remarkably increased after miR-155 mimics transfection. However, miR-155 inhibitor transfection exhibited the opposite result in cell proliferation (p < 0.05). Moreover, miR-155 overexpression significantly increased the migration of MDA-MB-231 cells (p < 0.05). Western blot further confirmed that miR-155 overexpression down-regulated the expression level of target protein SOCS1 and upregulated the expression level of MMP16. CONCLUSIONS: We found that miR-155 significantly enhanced the proliferation and migration of MDA-MB-231 cells, which might serve as an oncogene in breast cancer. Therefore, it is preliminarily believed that miR-155 plays an important role in the proliferation and migration of breast cancer cells via down-regulating the expression of SOCS1 and up regulating the expression of MMP16. PMID- 30468478 TI - Oncoplastic conservative surgery for breast cancer: long-term outcomes of our first ten years experience. AB - OBJECTIVE: The main goal of oncoplastic breast surgery (OBS) is to optimize cosmetic outcomes and reduce patient morbidity, while still providing an oncologically-safe surgical outcome and extending the target population of conservative surgery. Although the growing number of reported experiences with oncoplastic surgery, few studies account for the long-term outcomes. PATIENTS AND METHODS: Between January 2000 and December 2010, 1024 consecutive oncoplastic surgeries were performed and prospectively included in a database. Demographic data, histological and oncological evaluation and surgical complications were recorded. The role of tumor and patients' characteristics on the development of local recurrence and metastases were assessed by multivariate analysis. RESULTS: Median follow up was 74.2 months. The average age of patients was 56.24. In 869 patients (84.9%) an invasive tumor and in 155 (15.1%) an in situ tumor (11% DCIS and 4% LIN) was found. The average size of the tumor was 24.5 mm. A positive margin presented in 67 (6.5%) patients. Forty patients (50%) underwent re excision and 39 (49.4%) underwent mastectomy. The overall breast conservation rate was 96.2%. Reported complications were: 17 wound infections (1.7%); 106 hematomas (10.4%); 94 lymphorrheas (9.2%), 48 partial wound dehiscence (4.7%). Local recurrences (LR) were observed in 49 patients (4.7%). The risk of local recurrence was significantly higher in the group of patients with lymphovascular invasion and with high grade (G) (p < 0.05). 52 (5.07%) distant metastases were reported and the related risk was significantly higher in the group of patients with lymphovascular invasion and with negative receptors (p < 0.05). CONCLUSIONS: Oncoplastic surgery provides an acceptable oncological long-term outcome and can be used to treat with conservative surgery also a selected population of patients who would had otherwise undergone mastectomy in the past. PMID- 30468479 TI - Molecular mechanism for P38 signaling pathway in autophagy of skin cancer cell line HS-1. AB - OBJECTIVE: Abnormal cell autophagy is correlated with aging, neurodegenerative disease, and skin cancer. The signal transduction pathway of autophagy in skin cancer is still unclear. This study aimed to investigate the role of P38 signal pathway-induced cell autophagy in skin cancer onset and potential clinical application value. MATERIALS AND METHODS: Skin cancer cell line HS-1 was used as the model for ultraviolet (UV) irritation. Western blot tested autophagy signal molecules P38 activation in skin cancer cell line HS-1. Cells were then treated with P38 pathway agonist and antagonist to test autophagy condition and P38 pathway activation. Correlation analysis was performed to investigate the correlation between P38 pathway and cell autophagy level. RESULTS: UV irradiation treated skin cancer cell line HS-1 led to cell autophagy and P38 activation. AICAR and SB203580 potentiated and inhibited UV-induced HS-1 cell autophagy, respectively. P38 signal pathway activation condition was positively correlated with autophagy level. CONCLUSIONS: UV irradiation can induce skin cancer cell autophagy via the P38 signal pathway, indicating that the regulation of the P38 signal pathway activation might be one potential strategy treating skin cancer. PMID- 30468480 TI - miR-497 promotes the progression of cutaneous squamous cell carcinoma through FAM114A2. AB - OBJECTIVE: To explore the possible role and mechanism of miR-497 in cutaneous squamous cell carcinoma. PATIENTS AND METHODS: Quantitative Real-time polymerase chain reaction (qRT-PCR) was used to detect miR-497 and FAM114A2 expression level in 38 cases of cutaneous squamous cell carcinoma (CSCC) and 22 normal skin tissues as well as in CSCC cell lines (A431, HSC-5) and normal cells (HaCaT). MiR 497 effects on cell proliferation and cell cycle were examined by CCK8 assays and flow cytometry. Dual luciferase reporter gene assay was performed to detect the regulating relationship between miR-497 and FAM114A2. In addition, the expression of FAM114A2 after overexpression or knockdown of miR-497 was detected by Western blot to evaluate whether miR-497 could regulate proliferation and cell cycle by regulating the expression of FAM114A2. RESULTS: MiR-497mRNA expression in CSCC tissues and cell lines was markedly lower than that in normal tissues and cells. Meanwhile, FAM114A2 mRNA and protein levels in CSCC tissues were markedly higher when compared to than that in normal tissues. miR-497 overexpression or knockdown could inhibit or promote the cell proliferation and cell cycle of A431, HSC-5. The dual luciferase reporter gene assay suggested that FAM114A2 might be a direct target gene of miR-497, and that FAM114A2 expression had a significant negative correlation with miR-497. Overexpression of miR-497 could inhibit FAM114A2 protein expression. Besides, FAM114A2 knockdown reversed the inhibitory effect of low expression of miR-497 on proliferation rate of A431 or HSC-5 cells. CONCLUSIONS: MiR-497 was lowly expressed in squamous cell carcinoma tissues and cells, which can participate in the regulation of cell proliferation through FAM114A2, thus promoting the progression of CSCC. PMID- 30468481 TI - Down-regulation of Treg by interference of enhances the killing effect of CIK on leukemia cell HL-60. AB - OBJECTIVE: Cytokine-induced killer cells (CIK) is a type of immune cell with antitumor activity induced by a variety of cytokines. Regulatory T cells (Treg) is a T cell subgroup featured as immunosuppressive function. Existing CIK cultivation system may inevitably induce Treg. Forkhead box protein 3 (Foxp3) is an essential transcription factor for Treg function. This study aimed to investigate the effects of CIK on the leukemia cell HL-60. MATERIALS AND METHODS: This work silenced Foxp3 expression on the basis of CIK induction, aiming to investigate its killing effect on HL-60 cells. Peripheral blood mononuclear cells were separated and differentiated to CIK in vitro. CD3+CD56+ and CD4+CD25+Foxp3+ Treg cells were detected by flow cytometry. CIK cells were co-cultured with HL-60 cells under the effector-target ratio at 20:1, 10:1, and 5:1, respectively. The killing activity of CIK on HL-60 cells was determined by CCK-8 assay. RESULTS: The ratio of CD3+, CD3+CD8+, and CD3+CD56+ cells gradually increased during CIK induction. Foxp3 interference significantly reduced Treg cell ratio on the 7th day (p < 0.05). Treg cell ratio was significantly lower in Foxp3 interference group at 1.62% +/- 0.07% compared with control (p < 0.05). The killing activity of CIK on HL-60 cells enhanced following the increase of effector-target ratio. Interference of Foxp3 significantly elevated the killing activity of CIK on HL-60 cells with effector-target ratio dependence (p < 0.05). CIK can effectively suppress HL-60 cell growth. Treg significantly inhibited the anti-tumor effect of CIK. CONCLUSIONS: Interference of Foxp3 expression significantly declined Treg level and attenuated its suppression impact on CIK, thus enhancing the killing effect of CIK on HL-60 cells. PMID- 30468482 TI - Long non-coding RNA LINC00899 as a novel serum biomarker for diagnosis and prognosis prediction of acute myeloid leukemia. AB - OBJECTIVE: Recently, several long non-coding RNAs (lncRNAs) have been implicated in acute myeloid leukemia (AML). However, the clinical significance of lncRNAs in AML patients still remains unclear. We aimed to evaluate the expression level of lncRNA LINC00899 (LINC00899) and its potential for diagnosis and prognosis in AML. PATIENTS AND METHODS: Expression levels of LINC00899 in bone marrow and serum obtained from AML patients and healthy controls were assessed by quantitative real-time PCR. Receiver operating characteristic (ROC) curves were used to evaluate the sensitivity and specificity of serum LINC00899. The association between serum LINC00899 expression and clinicopathological factors as well as the overall survival were analyzed. RESULTS: We found that the levels of serum LINC00899 were frequently upregulated in the bone marrow and serum of AML patients. Higher expression of serum LINC00899 was positively associated with FAB classification (p = 0.002) and cytogenetics (p = 0.005). Moreover, ROC curve analyses showed that serum LINC00899 could discriminate AML patients from healthy controls with the area under the curve (AUC) of 0.807 (95% CI, 0.7262- 0.8752). In addition, the serum LINC00899 expression level was significantly reduced when the patients achieved complete remission. Kaplan-Meier analysis showed that patients with high serum LINC00899 expression had a shorter overall survival compared with the low serum LINC00899 expression group (p = 0.0013). Finally, Cox proportional hazards analysis showed that high serum LINC00899 expression was an independent prognostic marker of poor outcome. CONCLUSIONS: We firstly found that serum LINC00899 might be a potential and useful noninvasive biomarker for the early clinical detection and prognosis of AML. PMID- 30468483 TI - MiR-10b regulates the proliferation and apoptosis of pediatric acute myeloid leukemia through targeting HOXD10. AB - OBJECTIVE: To investigate the role of miR-10b in the proliferation and apoptosis of acute myeloid leukemia (AML), and to explore the underlying mechanism. PATIENTS AND METHODS: The expression level of miR-10b in clinical AML cases and cell lines was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The interaction between miR-10b and homeobox D10 (HOXD10) was confirmed by qRT-PCR, Western blotting and Luciferase assay. The effect of miR 10b on biological functions of AML cell line (HL60) was analyzed in vitro. MTT (3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay and colony formation assay were used to detect the proliferation and colony formation ability of AML cells, respectively. Meanwhile, flow cytometry and TUNEL staining were applied to measure cell cycle and apoptosis of AML cells, respectively. RESULTS: miR-10b was significantly up-regulated in AML cases and cell lines. The potential target genes of miR-10b were analyzed by three public databases. Results showed that HOXD10 was a direct target of miR-10b. QRT-PCR, Western blotting and luciferase assay confirmed the regulatory effect of miR-10b on HOXD10. Overexpression of miR-10b accelerated the proliferation and colony formation ability of AML cells. Meanwhile, miR-10b overexpression decreased the percentage of AML cells in the G0/G1 phase when compared with S phase, and suppressed the apoptosis of AML cells. However, the addition of HOXD10 could reverse the effects of miR-10b. CONCLUSIONS: MiR-10b could regulate the proliferation, colony formation, cell cycle and apoptosis of AML cells through targeting HOXD10, indicating that miR-10b might be a potential therapeutic target for the treatment of AML. PMID- 30468484 TI - The correlation between the concentration of hepcidin in serum and the occurrence of insulin resistance and hyperandrogenemia in women with polycystic ovary syndrome. AB - OBJECTIVE: Scarce clinical and experimental studies suggest that hepcidin can be a protein participating in the development of metabolic disorders, while its synthesis and concentration in the circulation outside of the iron metabolism parameters can be influenced by hormones. The aim of the present study was to determine the correlation between the concentration of hepcidin in serum and the occurrence of insulin resistance and hyperandrogenemia in women with PCOS. PATIENTS AND METHODS: Five groups of women with PCOS were divided based on: correct body mass (17 without hyperandrogenemia and insulin resistance - G1; 17 with hyperandrogenemia and without insulin resistance - G2; 11 without hyperandrogenemia and with insulin resistance - G3; 10 with hyperandrogenemia and insulin resistance - G4), metabolic and hormonal parameters and selected markers of iron metabolism. RESULTS: Serum glucose levels were significantly higher in the group G3 than G1 and in the group G4 than G1 and G2. Serum insulin levels and HOMA-IR values were significantly higher in the groups G3 and G4 than G1 and G2. Serum androstenedione levels were significantly higher in the group G2 than G1 and G3 than G2. Serum transferrin levels were significantly lower in the group G1 than in the reaming study groups. CONCLUSIONS: It has been demonstrated that insulin resistance and hyperandrogenemia appear to be the factors decreasing the concentration of transferrin circulation, but not the remaining parameters of the iron metabolism in the studied women. No relationship between the concentration of hepcidin circulation and other studied parameters of the iron metabolism and the parameters of the carbohydrate metabolism was discovered. Androstenedione can stimulate hepcidin synthesis in women with PCOS with correct body mass. PMID- 30468485 TI - The effect of transcranial direct current stimulation combined with functional task training on motor recovery in stroke patients. AB - The field of neuromodulation encompasses a wide spectrum of interventional technologies that modify pathological activity within the nervous system to achieve a therapeutic effect. Therapy including transcranial direct current stimulation (tDCS) has all shown promising results across a range of neurological and neuropsychiatric disorders. This article reviews the state-of-the-art of neuromodulation for stroke and discusses the opportunities and challenges available for clinicians and researchers interested in advancing neuromodulation therapy. The annual worldwide incidence of stroke ranges from 27.5 to 63 individuals per 100,000. Stroke, a major cause of adult disability, has devastating effects on patients and their caregivers, which has a tremendous socioeconomic impact on families and healthcare systems around the world. There are only a few treatments available for the improvement of motor function in stroke patients. The majority of these treatments are based on functional motor learning (ML) strategies. Both the mechanisms underlying stroke recovery and the effectiveness of neurorehabilitation interventions still remain poorly understood for widespread implementation, although it strongly depends on the quality of rehabilitation service to reach maximal post-stroke recovery. PMID- 30468486 TI - Overexpression of TUG1 promotes neuronal death after cerebral infarction by regulating microRNA-9. AB - OBJECTIVE: This study aims at investigating whether TUG1 (Taurine Upregulated Gene 1) can regulate FOXO3 expression through competitive binding to microRNA-9, thus leading to increased neuronal death and promoting the occurrence and development of acute cerebral infarction. MATERIALS AND METHODS: TUG1 and FOXO3 expressions in cerebral cortical neurons of MCAO mice, control mice and primary neurons were detected by quantitative Real Time-Polymerase Chain Reaction (qRT PCR). The effects of TUG1 and FOXO3 on neuronal apoptosis were determined by TUNEL after cerebral infarction area was stained with TTC. The binding condition of microRNA-9, TUG1 and FOXO3 was verified by the Luciferase reporter gene assay. Western blot was performed to detect the protein expressions of B-cell lymphoma-2 (BCL-2) and BCL2-Associated X (BAX) after altering the TUG1 or FOXO3 expression in primary neurons. RESULTS: TUG1 and FOXO3 were overexpressed in cerebral cortical neurons of MCAO mice and primary neurons. The inhibition of TUG1 or FOXO3 resulted in less neuronal apoptosis. Luciferase reporter gene assay demonstrated that TUG1 regulates FOXO3 via TUG1/microRNA-9/FOXO3 regulatory network. Besides, TUG1 inhibited BCL-2 but promoted BAX expression in primary neurons. CONCLUSIONS: The overexpression of TUG1 can promote neuronal death after cerebral infarction in mice by competitive binding to microRNA-9 and promotion of FOXO3 expression. PMID- 30468487 TI - Subacute cerebellar ataxia as presenting symptom of systemic lupus erythematosus. AB - Neuropsychiatric manifestations are commonly observed in systemic lupus erythematosus (SLE) patients. In particular, neurological involvement is known to be more common in patients with positive anticardiolipin antibodies and lupus anticoagulants. Nevertheless, cerebellar ataxia has rarely been reported, especially as the first clinical manifestation of this systemic autoimmune disorder. Cerebral vascular infarction or ischemia, vasogenic oedema and antibody mediated cerebral vasculopathy or vasculitic process have been supposed as possible aetiologies of acute cerebellar ataxia related to SLE. We report the clinical and radiological features of a woman who developed a rapidly progressive cerebellar syndrome as first sign of SLE; no other cause explaining her cerebellar ataxia was found. The patient improved after high-dose steroids. The appearance of a cerebellar syndrome with unknown aetiology with associated features of possible systemic autoimmune dysfunction, should be taken into account in clinical practice for appropriate diagnostic workup in order to provide effective therapeutic options. PMID- 30468488 TI - Gut microbiota and aging. AB - The hypothesis of an important role of gut microbiota in maintaining physiological state into the gastrointestinal (GI) system is supported by qualitative and quantitative alteration of the intestinal flora in a number of physiological and pathological condition as shown in several studies. The evidence of the inflammatory state alteration, highlighted in neurodegenerative diseases such as Parkinson's and Alzheimer's strongly recalls the microbiota disturbance, highly suggesting a link between the gastrointestinal system and cognitive functions. Given this perspective, looking at the mutual influence between microbiota products, inflammation mediators and immune system, the modulation of gut microbiota may help to facilitate a physiological and non pathological aging process and, perhaps, to contrast the progression of degenerating mechanisms. Some studies have already characterized gut microbiota in elderly, with promising results. Future studies should be designed to better understand the correlation between the gut microbiota, the ageing process and degenerative diseases typical of the elderly. PMID- 30468489 TI - The roles of NF-kB in the development of lung injury after one-lung ventilation. AB - OBJECTIVE: To explore the roles of NF-kB in the development of lung injury after one-lung ventilation. MATERIALS AND METHODS: Eighteen Sprague-Dawley (SD) rats were randomly divided into 3 groups including control group, one-lung ventilation (OL) group and NF-kB inhibitor pyrrolidine dithiocarbamate (PDTC) group, with 6 rats in each group. Rats in OL and PDTC groups were used to establish one-lung ventilation model, and rats in PDTC group were subjected to intravenous injection of NF-kB specific inhibitor PDTC at 30 min before model construction. One-lung ventilation was performed for 3 h, and arterial blood gas analyzer was used for blood gas analysis. The hemodynamics and respiratory mechanics parameters were detected. The respiratory index (RI) and oxygenation index (OI) were calculated. The pathological changes of lung tissue were observed by HE staining. The levels of TNF-alpha, IL-1beta, IL-6, and IL-8 in lung tissue were detected by ELISA. The expression levels of p65, p-p65, p-IkappaBalpha and IkappaBalpha and the activity of NF-Kbeta in lung tissue were detected by Western Blot. RESULTS: Compared with OL group, HR, RI and W/D were significantly reduced and MAP and OI were significantly increased in PDTC group (p<0.05). Compared with OL group, alveolar fluid exudation, pulmonary interstitial thickening and inflammatory cell infiltration were significantly improved in PDTC group. The levels of TNF-alpha, IL-1beta, IL-6 and IL-8 in PDTC group were significantly lower than in OL group (p<0.05). The ratios of p-p65/p65 and p-IkappaBalpha/IkappaBalpha and the activity of NF-kB in OL group were significantly reduced than in PDTC group (p<0.05). CONCLUSIONS: NF-kB can promote lung injury after one-lung ventilation, and the inhibition of NF-kB may be a new way for the treatment of this disease. PMID- 30468490 TI - HOTAIR promotes inflammatory response after acute myocardium infarction by upregulating RAGE. AB - OBJECTIVE: The aim of this study was to explore the role of HOTAIR in inflammatory response after acute myocardium infarction (AMI) and to investigate its underlying mechanism. MATERIALS AND METHODS: The AMI model was first constructed in rats, and heart tissues were harvested. Expression levels of HOTAIR and receptor of advanced glycation end-products (RAGE) in rat heart were detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The protein expression level of pEKR in rat heart was detected by Western blot. The levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in rats were determined by enzyme-linked immunosorbent assay (ELISA). The hypoxia induced H9C2 cells were used to construct the MI model in vitro. Meanwhile, the expression levels of HOTAIR and RAGE in H9C2 cells were detected. The levels of TNF-alpha and IL-6 in the culture medium were determined by ELISA. Rescue experiments were conducted by co-transfecting pcDNA-HOTAIR and si-RAGE in H9C2 cells. Subsequently, the levels of pERK, TNF-alpha, and IL-6 were detected. RESULTS: The mRNA expression levels of HOTAIR and RAGE in the AMI group were significantly higher than those of the control group. Western blot showed remarkably higher protein levels of RAGE and pERK in AMI rats when compared with those of controls. Similarly, results of ELISA indicated that the levels of TNF alpha and IL-6 in AMI rats were significantly higher than those of controls. Meanwhile, overexpression of HOTAIR in H9C2 cells remarkably elevated the expression levels of HOTAIR and RAGE. In addition, upregulated pERK, TNF-alpha, and IL-6 were observed in H9C2 cells overexpressing HOTAIR, which could be reversed by RAGE knockdown. CONCLUSIONS: HOTAIR promotes inflammatory response after AMI by upregulating RAGE expression. PMID- 30468491 TI - Effects of miR-155 on hypertensive rats via regulating vascular mesangial hyperplasia. AB - OBJECTIVE: Vascular smooth muscle cell (VSMC) excessive proliferation is related to hypertension. The cell cycle inhibitory factor (p27) can arrest cell cycle, while its down-regulation is associated with hypertension. It is found that microRNA-155 (miR-155) plays a regulatory role in VSMC proliferation, while its relationship with hypertension is still unclear. Bioinformatics analysis reveals the targeted relationship between miR-155 and the 3'-UTR of p27 mRNA. This study aims to explore the role of miR-155 in regulating p27 expression, VSMC proliferation and apoptosis, and the pathogenesis of hypertension. MATERIALS AND METHODS: Dual luciferase reporter gene assay confirmed the relationship between miR-155 and p27. MiR-155, p27, alpha-smooth muscle actin (alpha-SMA), and Ki-67 expressions in the thoracic aorta media of rat hypertension model were detected. VSMCs were cultured in vitro and divided into five groups, including anti-miR-NC, anti-miR-155, pIRES2-blank, pIRES2-p27, and anti-miR-155 + pIRES2-p27 groups. Cell cycle was evaluated by using flow cytometry. Cell proliferation was detected with EdU staining. Hypertension rats were randomly divided into antagomir-155 and antagomir-control. Caudal artery systolic and diastolic pressures were measured. RESULTS: MiR-155 targeted suppressed p27 expression. MiR-155 and Ki-67 expressions significantly enhanced, while p27 and alpha-SMA levels reduced in the tunica media from hypertension rats compared with control. Down-regulation of miR 155 and/or up-regulation of p27significantly declined cell proliferation and arrested cell cycle in G1 phase. Antagomir-155 injection markedly decreased systolic and diastolic pressures, elevated p27 and alpha-SMA expressions in media, and reduced the thickness of tunica media. CONCLUSIONS: MiR-155 promoted VSMC proliferation by targeting p27. MiR-155 enhancement was related to hypertension. MiR-155 played a therapeutic effect on hypertension. PMID- 30468492 TI - LncRNA TUG1 promotes proliferation of vascular smooth muscle cell and atherosclerosis through regulating miRNA-21/PTEN axis. AB - OBJECTIVE: Atherosclerosis is a major risk factor for cardiovascular disease, but its mechanism of progression remained unclear. However, many long non-coding RNAs (lncRNAs) have recently been implicated in different processes for cardiovascular disease. In this study, we mainly focused on the role of lncRNA TUG1 in atherosclerosis. PATIENTS AND METHODS: qRT-PCR was used to detect the expression of lncRNA TUG1 in atherosclerosis patients and animal model. Moreover, the expression of TUG1 in vascular smooth muscle cell dysfunction model was also measured. Proliferation ability was tested by CCK-8 and cyclin D1 assay, through loss- and gain-of function approaches. Western-blot was used to measure the expression of PTEN, when TUG1 was in different levels. RESULTS: We found that the lncRNA TUG1 was highly expressed in serum samples from 38 patients with atherosclerosis, compared with 24 healthy volunteers. LncRNA TUG1 was dramatically upregulated in atherosclerotic plaques of ApoE-/- mice. We also found that the expression of TUG1 was upregulated in vascular smooth muscle cell injury model. Through loss- and gain-of function approaches, we showed that TUG1 promotes cell proliferation and induces apoptosis in vitro. What's more, TUG1 expression level was reversely correlated with PTEN expression in patients with atherosclerosis. LncRNA TUG1 could compete with PTEN for miR-21 binding. CONCLUSIONS: We found that lncRNA TUG1 was closely related to the progression of atherosclerosis, which could be a potential target for treating atherosclerosis. PMID- 30468493 TI - Correlation of QT dispersion with serum potassium or blood sodium levels post neonatal asphyxia. AB - OBJECTIVE: To investigate the correlation between the corrected QT dispersion (QTcd) and serum potassium/sodium levels in order to evaluate their significance for early diagnosis of neonatal asphyxia. PATIENTS AND METHODS: This study included 124 neonatal asphyxia patients. These patients were divided into mild and severe asphyxia groups based on their clinical features and diagnostic indexing. Sixty healthy infants were selected as controls. QTcd, and serum cardiac troponin T (cTNT), potassium and sodium levels in the three groups were compared, and the correlation between QTcd and serum potassium/sodium was analyzed by Spearman correlation tests. RESULTS: Both mild and severe groups developed significantly higher cTnT and QTcd (p < 0.05), but lower serum potassium and sodium compared with control group (p < 0.05). The severe group had significantly higher cTnT and QTcd (p < 0.05), but lower serum potassium and sodium when compared with mild group (p < 0.05). The serum potassium and sodium were both negatively correlated with QTcd (p < 0.05). CONCLUSIONS: Serum potassium and sodium can be used as indicators for neonatal asphyxia, which may markedly improve early diagnosis, prognosis and treatment efficacy.to the progression of atherosclerosis, which could be a potential target for treating atherosclerosis. PMID- 30468494 TI - Great saphenous vein reflux treatment in patients with femoral valve incompetence, the Excluded Saphenous Vein Technique (ESVT): a pilot study. AB - OBJECTIVE: To describe and evaluate feasibility and efficacy of a saphenous ablation technique performed in patients with varicose veins (VVs), great saphenous vein (GSV) incompetence, and proximal femoral valve incompetence: the Excluded Saphenous Vein Technique (ESVT). PATIENTS AND METHODS: Patients with primary great saphenous and proximal femoral valve incompetence underwent ESVT. This technique is composed of selective crossectomy, GSV ligation next to the thigh incompetent tributary vein, and saphenous vein sclerosing performed from the proximal zone. Demographic, clinical and instrumental data were collected. CEAP classification was used to describe VVs severity. The primary outcome was perioperative complications. Secondary outcomes were 30-days, 6-months and 1 years GSV occlusion rate, and VVs recurrence rate. RESULTS: During a ten months period, 104 patients were analyzed. Among these, 82 patients underwent ESVT (59 female, age 50 +/- 21 years), eighty C2 and two C5, according to CEAP classification. The average length of GSV treated was 23 +/- 9 cm. No intraoperative complications occurred. A 1-year follow-up analysis revealed no partial or complete saphenous recanalization, deep venous thrombosis, pulmonary embolism. No VVs recurrence was detected during the follow-up period among the entire population. CONCLUSIONS: ESVT seems to be a safe and effective treatment for primary saphenous reflux and proximal femoral valve incompetence. Further studies are needed to assess long-term results. PMID- 30468495 TI - Epigallocatechin gallate attenuates uric acid-induced injury in rat renal interstitial fibroblasts NRK-49F by up-regulation of miR-9. AB - OBJECTIVE: Hyperuricemia is a common symptom in chronic kidney disease (CKD) and uric acid (UA) was observed to be elevated in CKD. Epigallocatechin gallate (EGCG) was reported to have multiple protective functions in inflammatory process. In this study, we investigated the effects of EGCG in UA-treated NRK-49F cells. PATIENTS AND METHODS: NRK-49F cells induced by UA were treated with EGCG and/or transfected with microRNA-9 (miR-9) inhibitor or its negative control (NC). Cell viability and cell apoptosis were detected by Cell Counting Kit-8 (CCK 8) assay and flow cytometry, respectively. In addition, the expression of cell survival- and fibrosis-related factors was measured by qRT-PCR and Western blot, respectively. Concentrations of inflammatory cytokines were detected by enzyme linked immunosorbent assay (ELISA). RESULTS: Increasing cell viability (p < 0.01) and decreasing cell apoptosis (p < 0.01), cell fibrosis (p < 0.01) and inflammatory cytokines (p < 0.05) were observed by administration of EGCG in UA treated cells. In addition, miR-9 was significantly up-regulated by EGCG (p < 0.05 or p < 0.001). Furthermore, transfection with miR-9 inhibitor impaired the protective functions of EGCG in UA-treated NRK-49F cells (p < 0.05 or p < 0.01). EGCG significantly down-regulated expression of IkappaBalpha, p65, janus kinase (JAK) 2 and signal transducers and activator of transcription (STAT) 3 (all p < 0.05). CONCLUSIONS: EGCG attenuates UA-induced injury in NRK-49F cells by up regulation of miR-9 and might by inactivation of NF-kappaB and JAK-STAT signal pathways. PMID- 30468496 TI - Serum from patients with chronic obstructive pulmonary disease promotes proangiogenic behavior of the vascular endothelium. AB - OBJECTIVE: It has been documented that COPD is a risk factor for lung cancer. In COPD patients, changes in lung angiogenesis - a critical process in the development of lung cancer - have been poorly investigated. We aimed to determine whether serum from COPD patients could promote the proangiogenic capabilities of endothelial cells in vitro. PATIENTS AND METHODS: The research was carried out using sera from COPD patients and healthy volunteers, endothelial cells EA.hy926, and bronchial epithelial cells. The concentration of angiogenic molecules was quantified using ELISA tests. The proliferation and migration of EA.hy926 were tested using fluorescence-based methods. Tube formation was analyzed with a commercially available assay. RESULTS: Sera from COPD patients and conditioned media generated by epithelial cells exposed to these sera stimulate proliferation, but not migration, of EA.hy926. This coincided with increased tube formation in both experimental regimens. The sera from COPD patients contained increased levels of CCL2, CCL21, and HGF, whereas the conditioned media generated by epithelial cells treated with these sera exhibited increased levels of CCL2, CCL21, CXCL8, FGF, and sICAM-1. The concentration of angiogenic markers in the sera and conditioned media, and their effect on the behavior of the endothelium were independent of smoking status (COPD and controls), stage of obstruction, and disease group (COPD). CONCLUSIONS: The increased incidence of lung malignancy in COPD patients may be associated, at least to some extent, with the direct and indirect proangiogenic activity of their sera (via alterations in the secretome of epithelial cells). PMID- 30468497 TI - Use of balloon catheter dilation and steroid-eluting stent in light and severe rhinosinusitis of frontal sinus: a multicenter retrospective randomized study. AB - OBJECTIVE: Frontal sinus surgery has an increased rate of re-stenosis, if compared to other sinuses. It depends mainly on recurrent inflammation and abnormal scarring at the frontal recess and its reduction represents one of the keys to therapeutic success. Balloon catheter dilation (BCD) and implantable sinus stents/spacers represent strategies to improve sinus ventilation respecting the integrity of mucosa and reducing abnormal post-surgical scarring. The purpose of this study was to evaluate the effectiveness, safety and correct indication about the use of BCD and a non-absorbable stent (Relieva StratusTM MicroFlow spacer) in the management of chronic rhinosinusitis (CRS) of the frontal sinus. PATIENTS AND METHODS: In this multicentric retrospective study we included a population of 76 frontal sinuses with non-polypoid CRS. 41 frontal sinuses were treated with BCD alone and 35 frontal sinuses with BCD + Spacer. We analyzed both radiological (Lund-McKay CT scoring modified by Zinreich) and symptomatological results (SNOT-20 questionnaire) before surgery and after 12 months, dividing our population in two main groups: group "L" (light/mild frontal CRS) and group "S" (moderate/severe frontal CRS). RESULTS: Our results confirm a good safety and effectiveness of BCD in the management of frontal CRS and show a good safety but a not significative effectiveness of Relieva StratusTM MicroFlow spacer when added to BCD in the management of light and severe frontal chronic rhinosinusitis. CONCLUSIONS: BCD is an acclared option in the management of frontal CRS and in the near future, utilization of stents/spacers could become a new and effective weapon in the management of rhinosinusitis, both like an adjunct to standard therapies, and in patient populations where the use of systemic drugs is contraindicated. PMID- 30468498 TI - Curcumin inhibits the growth via Wnt/beta-catenin pathway in non-small-cell lung cancer cells. AB - OBJECTIVE: In recent decades, the death rate from lung cancer appears to be an increasing yearly trend, particularly for non-small-cell lung cancer (NSCLC). Curcumin is a yellow pigment found in turmeric rhizomes, reported to exhibit various anti-inflammatory, anti-angiogenic, anti-proliferative, and antioxidant properties. Many reports have suggested that curcumin could induce apoptosis in malignant cells, and therefore, has great potential in tumor treatment. However, little is known about the effect of curcumin on NSCLC or its associated mode of action. Therefore, in this study, we explored curcumin's effect on NSCLC and investigated its associated mechanism. MATERIALS AND METHODS: The non-small-cell lung cancer (NSCLC) cell line A549 was cultured and subjected to MTT and clonogenic survival assays to assess cell proliferation. Reactive oxygen species (ROS) levels were measured using a Fluostar Omega Spectrofluorimeter. Superoxide dismutase (SOD) and gamma-glutamyl cysteine synthetase (gamma-GCS) activity in A549 cells were both determined by a commercial determination kit. Expression levels of p-GSK3beta (Ser9), c-Myc, cyclin D1, beta-catenin alpha-tubulin, and proliferating cell nuclear antigen (PCNA) were analyzed by Western blot. RESULTS: Results of the MTT and clonogenic survival assay indicated that curcumin reduced A549 proliferation. ROS levels and SOD and gamma-GCS activities were detected. Curcumin decreased intracellular ROS levels and increased SOD and gamma-GCS activity. Meanwhile, the ROS inhibitor N-Acetylcysteine (NAC) reversed the decrease in ROS levels and the increase in SOD and gamma-GCS activity. These results indicate that oxidative stress is involved in the curcumin-induced reduction of A549 viability. Curcumin also strongly inhibited beta-catenin and p GSK3beta (Ser9) protein expression, as well as the expression of downstream cyclin D1 and c-Myc. Similarly, NAC reversed the inhibition of beta-catenin and p GSK3beta (Ser9) protein expression, as well as the expression of downstream cyclin D1 and c-Myc. CONCLUSIONS: We showed that curcumin inhibits NSCLC proliferation via the Wnt/beta-catenin pathway. PMID- 30468499 TI - Curcumin alleviates isoproterenol-induced cardiac hypertrophy and fibrosis through inhibition of autophagy and activation of mTOR. AB - OBJECTIVE: Curcumin has been reported to possess cardioprotective effects. However, the potential molecular mechanism of curcumin is still not clear. The aim of the present study was to investigate the role of curcumin in regulating autophagy and mammalian target of rapamycin (mTOR) signaling in isoproterenol induced cardiac hypertrophy and fibrosis in the rat. MATERIALS AND METHODS: Rats model of cardiac hypertrophy and fibrosis was induced by isoprenaline (5 mg/kg/day, subcutaneous injection), which were treated with or without curcumin (200 mg/kg/day, intragastric administration). Masson's trichrome staining was performed to investigate the effect of curcumin on fibrosis of cardiac hypertrophy rat. The expression of hypertrophic and fibrosis markers was determined by RT-qPCR. The protein expression of autophagic markers, mTOR, and phosphorylated-mTOR (p-mTOR) was performed by Western blotting. RESULTS: Isoprenaline treatment significantly up-regulated the mRNA expression of hypertrophic (ANP and MYH7) and fibrotic (procollagen I and III) markers in the hearts from rats. All of these markers were reversed by curcumin treatment in isoproterenol-treated rats. Histological analysis showed that curcumin attenuated the interstitial fibrosis of heart triggered by isoproterenol. Moreover, isoproterenol significantly reduced the mRNA levels of mTOR and the protein expression of p-mTOR. However, isoprenaline caused a significant induction of the mRNA levels of LC3 and Beclin-1 and the protein expression of LC3-II and Beclin 1, as well as LC3-II/I ratio. Curcumin abolished these isoprenaline-mediated changes in mTOR/autophagy signaling pathway. CONCLUSIONS: Our data demonstrated that curcumin targeted mTOR/autophagy axis could attenuate cardiac hypertrophy and fibrosis in a rat model. PMID- 30468500 TI - Vitamin D receptor regulates high-level glucose induced retinal ganglion cell damage through STAT3 pathway. AB - OBJECTIVE: To explore the protective role of Vitamin D Receptor (VDR) in retinal ganglion cells (RGCs) after high-level glucose induction, and to investigate its underlying mechanism. MATERIALS AND METHODS: Primary RGCs were isolated from 24 hour-old Sprague Dawley (SD) rats and cultured in 50 mmol/L glucose. The expression of VDR in RGCs induced by 50 mmol/L glucose at different time points was determined by Real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot, respectively. Subsequently, VDR siRNA was transfected into RGCs. Transfection efficiency was determined by qRT-PCR and Western blot, respectively. The protein expressions levels of VDR, signal transducer and activator of transcription 3 (STAT3) and p-STAT3 in RGCs after VDR knockdown were determined by Western blot. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) and cell counting kit-8 (CCK-8) assay were conducted to access the viability of RGCs after high-level glucose induction. Ki-67 staining was performed to detect the proliferation of RGCs. Meanwhile, the apoptosis of RGCs was evaluated by using Annexin-V FITC/PI and TUNEL (terminal dexynucleotidyl transferase(TdT)-mediated dUTP nick end labeling) assay, respectively. In addition, caspase-3 activity in RGCs was detected by relative commercial kit. RESULTS: After 4 days of high-level glucose induction, the viability of RGCs was remarkably decreased. VDR was highly expressed in RGCs during high-level glucose culture. The mRNA and protein expression levels of VDR were both significantly downregulated after the transfection of VDR siRNA in RGCs. Meanwhile, VDR knockdown in RGCs significantly increased the viability and proliferative ability of RGCs, whereas significantly decreased apoptotic rate and caspase-3 activity. In addition, the protein level of p-STAT3 in RGCs was remarkably downregulated after VDR knockdown. CONCLUSIONS: Inhibition of VDR exerts a protective role in high-level glucose induced RGCs damage by activating the STAT3 pathway. PMID- 30468501 TI - Melatonin protects methotrexate-induced testicular injury in rats. AB - OBJECTIVE: Melatonin possesses anti-inflammation and anti-oxidant potentials. However, whether NF-E2 related factor 2 (Nrf2) pathway and nuclear factor-kappaB (NF-kappaB) pathway are involved in the protective effect of melatonin are unknown. We aim to explore the regulatory effect of melatonin on methotrexate induced testicular injury. MATERIALS AND METHODS: Sprague Dawley (SD) rats were randomly assigned in sham group, methotrexate group and melatonin group, with 8 rats in each group. Testis tissues were collected 10 days after animal procedures. Pathological lesions and cell apoptosis in testis tissues were evaluated using HE (hematoxylin and eosin) staining and TUNEL assay, respectively. Oxidative stress in rat testis was accessed using relative commercial kits. Western blot was performed to detect protein expressions of relative genes in Nrf2 pathway and NF-kappaB pathway in rat testis tissues. RESULTS: Activities of SOD, GSH, CAT and T-AOC in testis homogenate in melatonin group were remarkably higher than those of methotrexate group (p < 0.05). On the contrary, levels of MDA, ROS and inflammatory factors (TNF-alpha, IL-1beta, IL-6 and KC-GRO) were markedly decreased after melatonin treatment. Besides, melatonin group showed alleviated pathological lesions and cell apoptosis in testis. Western blot results demonstrated that melatonin treatment upregulated expressions of Nrf2, GSR, GCLm, HO-1 and NQO-1 in testis. However, protein expressions of NF-kappaB, TNF-alpha, VCAM-1, ICAM-1 and MCP-1 were downregulated. CONCLUSIONS: Melatonin protects methotrexate-induced testicular damage in rats by improving antioxidant capacity and inhibiting inflammatory response via Nrf2 and NF-kappaB pathways. PMID- 30468502 TI - Effects of melatonin on expressions of beta-amyloid protein and S100beta in rats with senile dementia. AB - OBJECTIVE: To explore the effects of melatonin (MT) on expressions of beta amyloid protein (beta-AP) and S100beta in rats with senile dementia. MATERIALS AND METHODS: A total of 36 Sprague-Dawley rats were randomly divided into Sham group, Model group and MT group, with 12 rats in each group. Senile dementia models were established in each group except Sham group. After modeling, rats in Model group were given tail vein injection with 0.9% sodium chloride once per day. Rats in MT group were given tail vein injection with MT once per day. Materials were collected at 40 d after the intervention. Hematoxylin-Eosin (HE) staining was adopted to observe histomorphology of hippocampal area, Western blotting to detect expressions of beta-AP and S100beta protein, and quantitative polymerase chain reaction (qPCR) to detect expressions of beta-AP mRNA and S100beta mRNA. RESULTS: Histomorphology in hippocampal area of both Model group and MT group was changed compared with that in Sham group. Histomorphology data showed that the damage in the hippocampal area in MT group was improved compared with that in Model group. Western blotting detection showed that expressions of beta-AP and S100beta in Model group and MT group were significantly increased compared with those in Sham group (p<0.05). Expressions of beta-AP and S100beta protein in MT group were significantly decreased compared with those in Model group (p<0.05). Results of qPCR revealed that expressions of beta-AP mRNA and S100beta mRNA in Model group and MT group were also significantly increased compared with those in Sham group, and there were statistically significant differences (p<0.05). Expressions of beta-AP mRNA and S100beta mRNA in MT group were significantly decreased compared with those in Model group (p<0.05). CONCLUSIONS: MT can inhibit expressions of beta-AP and S100beta protein in the hippocampal area of model rats with senile dementia, which provides leads for the future treatment of senile dementia. PMID- 30468503 TI - Research on mechanism of PCS in damaging vascular endothelial cells and promoting formation of atherosclerosis via TLR4/TREM-1. AB - OBJECTIVE: The study aimed to explore the effects of p-cresyl sulfate (PCS) of damaging vascular endothelial cells and promoting the formation of atherosclerosis in mice. MATERIALS AND METHODS: The apolipoprotein E (ApoE)-/- mice were fed normally and with a high-fat diet; the ApoE-/- mice fed with high fat diet were divided into two groups and treated with blank control and PCS, respectively. The aortic arch in each group was taken and underwent the oil red O staining, and the serum PCS content in each group was detected. The basic components of plaque were observed, including foam cells, lipid deposition, and cholesterol crystal. Moreover, human umbilical vein endothelial cells were cultured and divided into control group, PCS treatment group (PCS), PCS treatment with TLR4 overexpression group (PCS+TLR4+), and PCS treatment with TLR4 knock-out group (PCS+TLR4-). The degree of endothelial cell damage was detected using a cluster of differentiation CD42b-/CD31+ endothelial microparticles (EMPs), and expressions of Toll-like receptor 4 (TLR4), triggering receptor expressed on myeloid cells-1 (TREM-1), phosphorylated-endothelial nitric oxide synthase (p eNOS), and tumor necrosis factor-alpha (TNF-alpha) in cells were detected via Polymerase Chain Reaction (PCR) and Western blotting. RESULTS: The serum PCS concentration in high-fat ApoE-/- mice was increased, and the aortic arch sections of ApoE-/- mice treated with PCS displayed the evident atherosclerotic plaques. Experimental results of human umbilical vein endothelial cells showed that the activity of human umbilical vein endothelial cells treated with PCS declined, the expression levels of TLR4, TREM-1, and TNF-alpha were increased, while that of p-eNOS was decreased. After the TLR4 knockout, the above effects of PCS were reversed. CONCLUSIONS: PCS damages vascular endothelial cells through TRL4/TREM-1, thereby accelerating the formation of atherosclerosis. PMID- 30468504 TI - CD31 induces inflammatory response by promoting hepatic inflammatory response and cell apoptosis. AB - OBJECTIVE: To investigate whether CD31 could regulate paracetamol-induced liver injury, thereby providing a new direction for the prevention and treatment of drug-induced hepatitis. MATERIALS AND METHODS: Wild-type (WT) mice were treated with acetaminophen (APAP) (250 mg/kg) or isodose of phosphate-buffered saline (PBS). 1, 3, 6 and 12 h after the treatment, the messenger RNA (mRNA) and protein expression level of CD31 in the liver of mice were determined by Real-time reverse transcription polymerase chain reaction (RT-PCR) and Western blotting, respectively. Once CD31 was confirmed to be involved in APAP-induced liver injury, the acute liver injury model in WT mice and CD31 gene deficient (CD31-/-) mice induced by APAP was established. Serum samples were collected at 8 and 24 h after APAP injection (250 mg/kg), and the activity of serum alanine aminotransferase (ALT) was measured. The liver tissues of mice were isolated and analyzed by hematoxylin and eosin (HE) staining. Meanwhile, mononuclear cells (MNCs) were isolated from the liver tissues of mice. The number of infiltrating macrophages and neutrophils was detected by flow cytometry, and the activation level of these cells was analyzed. The expression levels of proinflammatory cytokines in liver tissues, such as TNF-alpha, IL-1beta, keratinocyte chemoattractant (KC), MCP-1 and IL-6, were determined by RT-PCR. The expression levels of cytokines in serum were detected by enzyme-linked immunosorbent assay (ELISA). Moreover, the protein expression levels of JNK, Caspase-3, and cytochrome P450 2E1 (CYP2E1) in liver tissues were detected by Western blotting. RESULTS: After APAP treatment, we found that WT mice were more sensitive to APAP induced liver injury. The level of ALT in WT mice was significantly higher than that of CD31-/- mice, meanwhile, more necrotic or apoptotic cells were found in WT mice. Results also indicated that the expression levels of inflammatory cytokines, including KC, IL-1beta, MCP-1 and IL-6, were significantly higher in WT mice. Meanwhile, the number of infiltrating macrophages and neutrophils in the liver tissues of WT mice were much more than that of CD31-/- mice. CONCLUSIONS: APAP-treated CD31-/- mice exhibited less liver injury when compared with WT mice. We also confirmed that CD31 was greatly involved in APAP-induced inflammatory response by promoting hepatic inflammatory and cell apoptosis, which might provide a new strategy for the prevention and treatment of drug-induced hepatitis. PMID- 30468505 TI - The low protein diet affects the nonspecific inflammatory response of middle-aged and old mice through mTOR. AB - OBJECTIVE: To explore the effect of low protein diet on nonspecific inflammatory changes in mice during aging and related mechanisms. MATERIALS AND METHODS: Thirty-two 14-month-old female KM mice were randomly divided into 4 groups: control group, low protein group, high protein group, high protein + rapamycin group. Hematoxylin-eosin (HE) staining was performed to observe the pathological changes of the liver. Immunohistochemistry of liver sections was performed to detect the expression of CD68 protein. HE staining of colon sections was performed to observe intestinal lymphocyte infiltration. The percentage of spleen CD4+ T and CD8+ T cells was detected by flow cytometry. The mTOR expression in the liver was detected by Western blot and immunohistochemistry. RESULTS: Compared with the control group, HE staining of liver tissue sections in high protein group showed the cytoplasm of hepatocytes was loose and disordered, and the hepatic sinus was significantly expanded. Immunohistochemistry of the liver showed a significant increase in CD68 protein expression. Colorectal HE staining showed extensive lymphocyte infiltration. The number of CD4+ T and CD8+ T cells in spleen flow cytometry was significantly decreased (*p < 0.05). Western blot and immunohistochemistry detected a significant increase in mTOR expression in the liver (*p < 0.05, *p < 0.05). In the High Protein+Rapamycin group and Low protein group, the time-dependent changes were reduced, the numbers of CD4+ T cell and CD8+ T cell in the spleen were significantly increased (*p < 0.05) and the expression of mTOR was significantly reduced (*p < 0.05). CONCLUSIONS: Low protein diet is beneficial for delaying the non-specific inflammatory changes of liver and intestines in middle-aged and aged mice, and this effect may be achieved through down-regulation of mTOR. PMID- 30468506 TI - Hyaluronic acid for treatment of the radiation therapy side effects: a systematic review. AB - OBJECTIVE: The main limit of radiation therapy is the dose-dependent toxicity to healthy tissues. The 36% of patients exposed to radiotherapy for pelvic malignancies reporting gastrointestinal symptoms as incontinence, pain, mucus discharge, and bleeding (radiation proctopathy). In the cervix cancer, healthy tissues exposed to radiations easily develop inflammation of vaginal mucosa, bleeding and pain and to improve these symptoms, some medical devices were developed. One of the most interesting for its features is undoubtedly the hyaluronic acid. Considering the histological similarity between the vaginal and the rectal mucosa, the application of hyaluronic acid for the radiation proctopathy represents an interesting opportunity. MATERIALS AND METHODS: We performed a literature search of MEDLINE, EMBASE, PubMed, and Research Gate for studies published up to March 2018. The following combination of medical subject headings, terms and free text words were used: 'hyaluronic acid', 'hyaluronate', 'topical application' and 'radiation proctitis'. RESULTS: After the screening of titles and abstracts, and using the established criteria, 7 studies were selected for inclusion in the systematic review. CONCLUSIONS: The clinical use of hyaluronic acid for topical administration in patients with inflammatory conditions at the level of the vaginal and anal mucosa, following radio and chemo therapies, resulted an innovative approach to help patients in managing the AEs. Hyaluronic acid confirmed its totally safety profile and resulted effective in the inflammation decrease, improving the tissue health and the symptoms related. For all these reasons, we can easily promote the clinical application of hyaluronic acid on inflamed tissues though a substantial work is necessary to investigate more deeply the hyaluronic acid role on this context. PMID- 30468507 TI - Randomized, double blind placebo-controlled pilot study of the antihypertensive effects of Grana Padano D.O.P. cheese consumption in mild - moderate hypertensive subjects. AB - OBJECTIVE: Grana Padano, an Italian protected designation of origin (PDO) semi fat cheese, undergoes a long ripening period during which the proteolysis carried out by natural starter lactic acid bacteria releases peptides having sustained angiotensin-converting enzyme (ACE)-inhibitory activity. The length (generally 3 8 amino acid residues) and the sequence of these peptides are responsible for their ability to elicit ACE-inhibitory activity. The aim of this study has been the evaluation of the effect of a daily dietary supplement consisting in a small amount (30 g/day) of Grana Padano cheese, in terms of the lowering of the blood pressure (BP) of mild-moderate hypertensive subjects. PATIENTS AND METHODS: Thirty mild-moderate hypertensive patients, with BP values not on target (> 140 and/or > 90 mmHg) after at least 3 months of stable treatment were considered in this randomized, double-blind placebo-controlled cross-over study. All patients randomly received a dietary integration (30 g/day) of Grana Padano cheese or a placebo (made from flavored grated bread mixed with fats and salts in concentrations equal to those of the cheese). BP was evaluated at baseline and at the end of the active and placebo treatments (2 months each) by: - Office BP (OBP); - Automated Office BP (AOBP) using the BpTRU(r), an automated oscillometric device that provides the average of multiple (n=6) blood pressure measurements; - Ambulatory Blood Pressure (ABP) 24 hour monitoring. RESULTS: Dietary integration with Grana Padano cheese resulted in a significant decrease in Office, Automated Office and Ambulatory BP. The mean decrease (vs. placebo) for 24-hour ABP was -3.5 mmHg for systolic and -2.4 mmHg for diastolic BP (p = 0.0063 and p = 0.0065, respectively). CONCLUSIONS: Daily dietary integration with 30 g of Grana Padano DOP cheese effectively reduces BP and may help mild-to moderate hypertensive patients to reach a target BP. PMID- 30468508 TI - Recent advances in the management of allergy associated diseases in children. AB - The allergy symptoms could arise from variable organ systems and have fluctuating nature in severity as well as symptoms. Moreover, these symptoms could be related to multiple pathological states like common cold, chronic obstipation, diarrhea, etc. On the other hand, food allergy diagnosis that usually spread by IgE mediated inhalant also poses a great challenge in front of the scientific fraternity. So far, many advances in the field of allergy diagnosis, as well as therapeutics, have been made. These advances include skin prick testing (SPT), serum specific IgE (sIgE) level test, component resolved diagnosis (CRD) test, etc. The present review article would be focused on important pathological states associated with allergy observed commonly in children. Moreover, the latest developments about timely management and accurate diagnosis are also discussed. PMID- 30468509 TI - Probiotics, prebiotics and synbiotics for weight loss and metabolic syndrome in the microbiome era. AB - OBJECTIVE: Excessive body fat and the associated dysmetabolic consequences affect both developed and emerging countries. An altered gut microbiota composition is an important environmental cause of these conditions. Clinical trials targeting gut microbiome composition or functions with pro or prebiotics to promote a healthier profile are considered a promising tool for excessive body weight treatment and prevention of dysmetabolic complications. MATERIALS AND METHODS: We searched PubMed and Cochrane Library using combinations of probiotics/prebiotics and synbiotics with obesity/weight loss/metabolic syndrome as the search terms. Clinical studies and significant pre-clinical results showing molecular mechanisms supporting clinical results were also discussed. RESULTS: Several studies in humans and in animal models have elucidated biological mechanisms supporting the observed clinical efficacy of selected probiotic and prebiotic compounds for weight management. Efficacy appears to be species or strain specific. Fibers such as inulin or galactomannan promote independent and synergistic beneficial effects. CONCLUSIONS: Diet supplementation with synbiotics prepared using selected strains (such as Lactobacillus gasseri strains) showed to exert weight-reduction and anti-inflammatory activity in large independent studies. Their administration, together with galactomannan and/or inulin fibers, may increase weight management effects due to synergistic effect on short chain fatty acid production and microbiota 're-configuration'. PMID- 30468510 TI - Genome size-dependent pcna gene copy number in dinoflagellates and molecular evidence of retroposition as a major evolutionary mechanism. AB - Proliferating cell nuclear antigen (PCNA) plays critical roles in eukaryotic DNA replication and replication-associated processes. It is typically encoded by one or two gene copies (pcna) in eukaryotic genomes. Recently reported higher copy numbers of pcna in some dinoflagellates raised a question of how this gene has uniquely evolved in this phylum. Through real-time PCR quantification, we found a wide range of pcna copy number (2-287 copies) in 11 dinoflagellate species (n = 38), and a strong positive correlation between pcna copy number and genome size (log10 -log10 transformed). Intraspecific pcna diverged up to 21% and are dominated by nonsynonymous substitutions, indicating strong purifying selection pressure on and hence functional necessity of this gene. By surveying pcna copy numbers in eukaryotes, we observed a genome size threshold at 4 pg DNA, above which more than two pcna copies are found. To examine whether retrotransposition is a mechanism of pcna duplication, we measured the copy number of retroposed pcna, taking advantage of the 22-nt dinoflagellate-specific spliced leader (DinoSL) capping the 5' end of dinoflagellate nuclear-encoded mRNAs, which would exist in the upstream region of a retroposed gene copy. We found that retroposed pcna copy number increased with total pcna copy number and genome size. These results indicate co-evolution of dinoflagellate pcna copy number with genome size, and retroposition as a major mechanism of pcna duplication in dinoflagellates. Furthermore, we posit that the demand of faithful replication and maintenance of the large dinoflagellate genomes might have favored the preservation of the retroposed pcna as functional genes. PMID- 30468511 TI - Microextraction Sample Preparation Techniques in Forensic Analytical Toxicology. AB - Sample preparation is a critical step in forensic analytical toxicology. Different extraction techniques are employed with the goals of removing interferences from the biological samples, such as blood, tissues and hair, reducing matrix effects and concentrating the target analytes, among others. With the objective of developing faster and more ecological procedures, microextraction techniques have been expanding their applications in the recent years. This article reviews various microextraction methods, which include solid based microextraction, such as solid phase microextraction (SPME), microextraction by packed sorbent (MEPS), and Stir-bar sorptive extraction (SBSE), and liquid based microextraction, such as single drop/hollow fiber based liquid phase microextraction (LPME), dispersive liquid liquid microextraction (DLLME), as well as their applications to forensic toxicology analysis. Development trend in future microextraction sample preparation is discussed. PMID- 30468512 TI - New strategies for the management of decompensated cirrosis: long-term albumin administration for everyone? AB - Natural history of cirrhosis is characterized by the progression from a compensated to a decompensated state, which is defined by the development of several complications of the disease (1). Ascites is the most frequent complication of patients with decompensated cirrhosis, but other common complications include hepatic encephalopathy, GI bleeding, bacterial infections, kidney failure and hyponatremia. Decompensated cirrhosis is not only associated with poor outcome, with median survival of approximately 2 years, but also with impaired health-related quality of life and high economic burden due to frequent hospital admissions and use of health-care resources. Currently, management of decompensated cirrhosis is mainly based on symptomatic treatment of individual complications once they occur, rather than using a pathophysiological approach (2). This article is protected by copyright. All rights reserved. PMID- 30468513 TI - Synthesis of TiO2 (B) and High-temperature Stable Anatase TiO2 Nanowires by Hydrothermal Method and Investigation of Photocatalytic Activity. AB - In this study, TiO2 nanowires (TNWs) were synthesized through hydrothermal method and were characterized using X-Ray diffraction (XRD), transmission electron microscopy (TEM) and BET techniques. Monoclinic TiO2 (B) is the dominant phase of TNWs up to 600 degrees C which is completely transformed into a highly crystalline anatase phase at 800 degrees C. The photocatalytic activity of TNWs, prepared at various calcination temperatures, was investigated in the removal of Rhodamine B (RhB) as an organic model pollutant. The results indicated that the photocatalytic activity of TNWs, prepared at 800 degrees C calcination temperature (TNWs-800), was better than that of other samples and even TiO2 -P25 nanoparticles. This article is protected by copyright. All rights reserved. PMID- 30468514 TI - Effects of instantaneous and growth CO2 levels, and ABA on stomatal and mesophyll conductances. AB - C3 photosynthesis is often limited by CO2 diffusivity, or stomatal (gs ) and mesophyll (gm ) conductances. To characterize effects of stomatal closure induced by either high CO2 or abscisic acid (ABA) application on gm , we examined gs and gm in the wild type (Col-0) and ost1 and slac1-2 mutants of Arabidopsis thaliana grown at 390 or 780 MUmol mol-1 CO2 . Stomata of these mutants were reported to be insensitive to both high CO2 and ABA. When the ambient CO2 increased instantaneously, gm decreased in all these plants, while gs in ost1 and slac1-2 were unchanged. Therefore, the decrease in gm in response to high CO2 occurred irrespective of the responses of gs . gm was mainly determined by the instantaneous CO2 concentration during the measurement and not markedly by the CO2 concentration during the growth. Exogenous application of ABA to Col-0 caused the decrease in the intercellular CO2 concentration (Ci ). With the decrease in Ci , gm did not increase but decreased, indicating that the response of gm to CO2 and that to ABA are differently regulated and that ABA content in the leaves plays an important role in the regulation of gm . PMID- 30468515 TI - Sexual dysfunction and sex hormone abnormalities in patients with cirrhosis: Review of pathogenesis and management. AB - Healthy sexual function is important to maintain a good quality of life but is frequently impaired in patients with cirrhosis. The degree of sexual dysfunction appears to be linked with the degree of hepatic dysfunction. In men, sexual dysfunction can be related to the hyperestrogenism of portal hypertension and/or to decreased testosterone resulting from testicular dysfunction. In women, suppression of the hypothalamic-pituitary-gonadal axis appears to be a principal contributor, with no significant effect of portal hypertension. There is also a huge psychological barrier to breakthrough as there is a component of depression in many patients with cirrhosis. Sexual dysfunction is often underdiagnosed in the cirrhotic cohort. Management of sexual disorders in patients with cirrhosis can be challenging as they are often multifactorial. Multidisciplinary approach is the key in managing these patients. We review the current literature on the pathogenesis of sexual dysfunction in cirrhotic patients and propose a step-wise algorithm to better manage these patients. This article is protected by copyright. All rights reserved. PMID- 30468516 TI - 3D-printed Franz type diffusion cells. AB - OBJECTIVE: Franz cells are routinely used to measure in vitro skin permeation of actives and must be inert to the permeant under study. The aim of the present work was to develop and manufacture transparent Franz-type diffusion cells using 3D printing and test these using a range of model active compounds. The study also aims to identify the critical 3D printing parameters necessary for the process including object design, choice of printing resin, printout curing and post-curing settings and introduction of model coatings. METHODS: Transparent Franz cells were constructed using an online computer aided design program and reproduced with different stereolithography 3D printers. The two acrylate-based resins used for the fabrication process were a commercially available product and a polymer synthesised in-house. Comparative studies between glass and 3D printed Franz cells were conducted with selected model actives: terbinafine hydrochloride (TBF), niacinamide (NIA), diclofenac free acid (DFA) and n-methyl paraben (MPB). In preliminary studies, MPB showed the lowest recovery when exposed to the receptor compartment of 3D printed cells. Consequently, in vitro permeation studies were carried out using only MPB with polydimethylsiloxane (PDMS) membrane. RESULTS: A decrease in the amounts of selected compounds was observed for transparent 3D printed Franz cells compared to glass cells. MPB showed the lowest recovery (53.8 +/- 13.1%) when compared with NIA (74.9 +/- 4.0%), TBF (81.5 +/- 12.0%) and DFA (90.2 +/- 12.9%) after 72 h. Permeation studies conducted using 3D printed transparent cells with PDMS membrane also showed a decrease in MPB recovery of 51.4 +/- 3.7% for the commercial resin and 94.4 +/- 3.5% for the polymer synthesised in-house, when compared to glass cells. Although hydrophobic coatings were subsequently applied to the 3D printed cells the same reduction in MPB concentration was observed in the receptor solution. CONCLUSION: Transparent Franz cells were successfully prepared using 3D printing and were observed to be robust and leak-proof. There are few resins currently available for preparation of transparent materials and incompatibilities between the actives investigated and the 3D printed cells were evident. Hydrophobic coatings applied as barriers to the printed materials did not prevent these interactions. This article is protected by copyright. All rights reserved. PMID- 30468517 TI - 3D Organ Modeling with Open-Source Software. AB - To date, 3D organ modeling has not reached widespread clinical use, despite showing promise in medical literature. The majority of anatomic modeling that is presented in the literature is performed with proprietary software, presenting certain barriers to use such as price for usage rights. Open-source software not only circumvents this barrier, but also often provides greater customization offered by global communities. In this proof-of-concept experiment, a HeartMate II LVAD was "virtually fit" in a patient's left ventricle using only open-source software. Open-source programs provide a legitimate alternative to the proprietary software options. This article is protected by copyright. All rights reserved. PMID- 30468518 TI - Comparison of rheumatoid arthritis (RA) and osteoarthritis (OA) based on microarray profiles of human joint fibroblast-like synoviocytes. AB - The purpose of the present study was to investigate the underlying molecular mechanism of osteoarthritis (OA) and rheumatoid arthritis (RA) based on microarray profiles. Three human joint fibroblast-like synoviocytes (FLSs) microarray profiles including 26 OA samples, 33 RA samples, and 20 healthy control (HC) samples were downloaded from the GEO database. Differentially expressed genes (DEGs) between OA and HC (DEGsOA) and RA and HC (DEGsRA) were identified. Co-expressed and specific genes were analysed between DEGsOA and DEGsRA. Gene ontology, KEGG pathway enrichment, PPI network, and GSEA were performed to predict the function of DEGs. Two hundred seventy-six and 410 differential genes in DEGsOA and DEGsRA were observed. One hundred fifty coexpressed genes and 126 OA-specific genes (SELE, SERPINE1, and NFKBIA were the key genes) between DEGsOA and DEGsRA were enriched in the tumour necrosis factor (TNF) signalling pathway. However, 260 RA-specific genes of which the key genes were CCR5, CCR7, CXCR4, CCL5, and CCR4 were enriched in chemokine signalling pathway. Therefore, FLSs might exert an inflammatory effect by regulating TNF signalling pathway, targeting SELE, SERPINE1, and NFKBIA during the process of OA. Although TNF signalling pathway was also involved in the synovitis of RA, chemokine signalling pathway played the key role in RA FLSs mediating cell migration, invasion, and release of chemotaxis. In addition, CCR5, CCR7, CXCR4, CCL5, and CCR4 might be hub genes in RA. The different biomarkers and pathways identified in OA and RA may provide references for further study. SIGNIFICANCE OF THE STUDY: This study revealed the similar and different mechanisms of FLSs and different biomarkers that might with important regulatory effects on RA and OA. In OA, FLSs played an inflammatory role through TNF signalling pathway, targeting SELE, SERPINE1, and NFKBIA. Although TNF signalling pathway was also involved in the synovitis of RA, chemokine signalling pathway was a crucial pathway in mediating FLSs migration, invasion, and release of chemotaxis. CCR5, CCR7, CXCR4, CCL5, and CCR4 might be keys genes in RA. We expect that our results will bring more comprehensively understanding between RA and OA for researchers. PMID- 30468519 TI - Cai's Neiyi Prescription promotes apoptosis and inhibits inflammation in endometrial stromal cells with endometriosis through inhibiting USP10. AB - To observe the effect of Cai's Neiyi Prescription (CNYP) on the apoptosis and inflammation in endometrial stromal cells with endometriosis (EM) both in vivo and in vitro, EM model rats and endometrial stromal cells were treated with CNYP and the level of USP10, p-ERK1/2, ERK1/2, and apoptosis-related protein as well as the levels of proinflammatory factors were measured by Western blotting and ELISA, respectively. Rats with surgically induced EM showed increased USP10 expression and ERK/2 activation. Intragastric administration of CNYP granule significantly inhibited EM-induced ERK1/2 activation and expression of USP10 and Bcl-2, but increased the expression of Bax and Caspase-7 in EM-induced rats. CNYP granule administration also inhibited EM-induced inflammation in rats. Moreover, the ectopic endometrial stromal cells isolated from EM patients demonstrated decreased ERK1/2 activation and expression of USP10 and Bcl-2 and increased expression of Bax and Caspase-7 after cultured in DMEM containing CNYP-medicated rat serum, which were reversed by USP10 overexpression and were enhanced by USP10 siRNA. USP10 overexpression also inhibited while USP10 siRNA enhanced the CNYP induced inhibition of inflammation in ectopic endometrial stromal cells. Taken together, our results suggest that CNYP granule promotes apoptosis and inhibits inflammation in endometrial stromal cells with EM through inhibiting USP10. PMID- 30468520 TI - Low titer A plasma in three AB patients for therapeutic plasma exchange. AB - BACKGROUND: Currently, low titer A plasma is used on a routine basis in bleeding trauma patients of unknown AB type. Three AB non-bleeding apheresis patients are presented here who safely received a combination of AB and low titer A plasma during therapeutic plasma exchange (TPE). One control AB patient received AB plasma only. METHODS: Data was obtained retrospectively on number of procedures, volume replaced, total plasma, and A plasma volumes including hemolysis laboratory data. Average A plasma volume and % of A plasma out of total plasma volume used were calculated. RESULTS: Two female AB patients were treated for thrombotic thrombocytopenic purpura (TTP) with TPE and a third female AB patient was treated for microangiopathic hemolytic anemia. Patient 1 received a total of 12 procedures, 10/12 with AB+A plasma (average 916.3 +/-84.6 mL). Patient 2 received a total of 12 procedures, 4/12 with AB+A plasma (average 1210.5 +/-27.9 mL). Patient 3 received a total of six procedures, four out of six procedures with AB+A plasma (average 1009.8 +/-80.3 mL). Patient 4, control, received AB plasma only. Percent of A plasma volume exchanged ranged between 23.8% and 47.8%. Haptoglobin, LDH, hemoglobin, and total bilirubin were monitored and trends were comparable with the control patient. The patients had a negative follow up direct antiglobulin test, adequate platelet recovery and a favorable clinical outcome with treatments. CONCLUSIONS: TPE was effectively performed without evidence of increased hemolysis using up to 47.8% of low titer A plasma. This approach can reduce strains on limited supplies of AB plasma whereas providing a vital treatment alternative for AB patients undergoing TPE with plasma replacement. PMID- 30468521 TI - Perceived satisfaction with health services under National Health Insurance Scheme: Clients' perspectives. AB - The study aims to explore the perceived satisfaction of insured clients in financing health services through National Health Insurance in Ghana. A quantitative method was used to recruit 380 respondents, selected by multistage cluster sampling. Data were collected through the administration of questionnaires. More than half, 57.9%, of respondents were males, and the average age was 34 years. Most respondents, 74.3%, were insured. Overall, 53.12% of insured clients were dissatisfied with the services of providers. Factors, such as benefit package of insurance, willingness to pay higher premium, and perceived discrimination were significantly associated with poor satisfaction with health services. The current advocacy for and awareness about the use of health insurance as a prepayment plan should be prioritised in policy initiatives. The benefit package for the insurance should be increased in order to cover all disease conditions that afflict the Ghanaian population. PMID- 30468522 TI - Masseter muscle atrophy impairs bone quality of the mandibular condyle but not the alveolar process early after induction. AB - BACKGROUND: Masseter muscle function influences mandibular bone homeostasis. As previously reported, bone resorption markers increased in the mouse mandibular condyle two days after masseter paralysis induced with botulinum toxin type A (BoNTA), followed by local bone loss. OBJECTIVE: This study aimed to evaluate the bone quality of both the mandibular condyle and alveolar process in the mandible of adult mice during the early stage of a BoNTA-induced masseter muscle atrophy, using a combined 3D histomorphometrics and shape analysis approach. METHODS: Adult BALB/c mice were divided into an untreated control group and an experimental group; the latter received one single BoNTA injection in the right masseter (BoNTA-right) and saline in the left masseter (Saline-left). 3D bone microstructural changes in the mandibular condyle and alveolar process were determined with high-resolution microtomography. Additionally, landmark-based geometric morphometrics was implemented to assess external shape changes. RESULTS: After 2 weeks, masseter mass was significantly reduced (p-value < 0.001). When compared to Saline-left and untreated condyles, BoNTA-right condyles showed significant bone loss (p-value < 0.001) and shape changes. No significant bone loss was observed in the alveolar processes of any of the groups (p-value > 0.05). CONCLUSION: Condyle bone quality deteriorates at an early stage of BoNTA induced masseter muscle atrophy, and before the alveolar process is affected. Since the observed bone microstructural changes resemble those in human temporomandibular joint degenerative disorders, the clinical safety of BoNTA intervention in the masticatory apparatus remains to be clarified. This article is protected by copyright. All rights reserved. PMID- 30468524 TI - Research in Nursing & Health Author Guidelines. PMID- 30468523 TI - Absolute configuration and biological profile of pyrazoline enantiomers as MAO inhibitory activity. AB - A new racemic pyrazoline derivative was synthesized and resolved to its enantiomers using analytic and semipreparative high-pressure liquid chromatography. The absolute configuration of both fractions was established using vibrational circular dichroism. The in vitro monoamine oxidase (MAO) inhibitory profiles were evaluated for the racemate and both enantiomers separately for the two isoforms of the enzyme. The racemic compound and both enantiomers were found to inhibit hMAO-A selectively and competitively. In particular, the R enantiomer was detected as an exceptionally potent and a selective MAO-A inhibitor (Ki = 0.85 * 10-3 +/- 0.05 * 10-3 MUM and SI: 2.35 * 10-5 ), whereas S was determined as poorer compound than R in terms of Ki and SI (0.184 +/- 0.007 and 0.001). The selectivity of the enantiomers was explained by molecular modeling docking studies based on the PDB enzymatic models of MAO isoforms. PMID- 30468525 TI - Subwavelength Artificial Structures: Opening a New Era for Engineering Optics. AB - In the past centuries, the scale of engineering optics has evolved toward two opposite directions: one is represented by giant telescopes with apertures larger than tens of meters and the other is the rapidly developing micro/nano-optics and nanophotonics. At the nanoscale, subwavelength light-matter interaction is blended with classic and quantum effects in various functional materials such as noble metals, semiconductors, phase-change materials, and 2D materials, which provides unprecedented opportunities to upgrade the performance of classic optical devices and overcome the fundamental and engineering difficulties faced by traditional optical engineers. Here, the research motivations and recent advances in subwavelength artificial structures are summarized, with a particular emphasis on their practical applications in super-resolution and large-aperture imaging systems, as well as highly efficient and spectrally selective absorbers and emitters. The role of dispersion engineering and near-field coupling in the form of catenary optical fields is highlighted, which reveals a methodology to engineer the electromagnetic response of complex subwavelength structures. Challenges and tentative solutions are presented regarding multiscale design, optimization, fabrication, and system integration, with the hope of providing recipes to transform the theoretical and technological breakthroughs on subwavelength hierarchical structures to the next generation of engineering optics, namely Engineering Optics 2.0. PMID- 30468526 TI - Variable, but not free-weight, resistance back squat exercise potentiates jump performance following a comprehensive task-specific warm-up. AB - Studies examining acute, high-speed movement performance enhancement following intense muscular contractions (frequently called 'post-activation potentiation'; PAP) often impose a limited warm-up, compromizing external validity. In the present study the effects on countermovement vertical jump (CMJ) performance of back squat exercises performed with or without elastic bands during warm-up were compared. After familiarization, fifteen active men visited the laboratory on two occasions under randomized, counterbalanced experimental squat warm-up conditions: (1) free-weight resistance (FWR) and (2) variable resistance (VR). After completing a comprehensive task-specific warm-up, three maximal CMJs were performed followed by three back squat repetitions completed at 85% of 1-RM using either FWR or VR. Three CMJs were then performed 30 s, 4 min, 8 min and 12 min later. During CMJ trials, hip, knee and ankle joint kinematics, ground reaction force data and vastus medialis, vastus lateralis and gluteus maximus electromyograms (EMG) were recorded simultaneously using 3D motion analysis, force platform, and EMG techniques, respectively. No change in any variable occurred after FWR (p>0.05). Significant increases (p<0.05) were detected at all time points following VR in CMJ height (5.3-6.5%), peak power (4.4-5.9%), rate of force development (12.9-19.1%), peak concentric knee angular velocity (3.1-4.1%) and mean concentric vastus lateralis EMG activity (27.5-33.4%). The lack of effect of the free-weight conditioning contractions suggests that the comprehensive task-specific warm-up routine mitigated any further performance augmentation. However, the improved CMJ performance following the use of elastic bands is indicative that specific alterations in force-time properties of warm-up exercises may further improve performance. This article is protected by copyright. All rights reserved. PMID- 30468527 TI - Modeling Occupant Behavior of the Manual Control of Windows in Residential Buildings. AB - Window opening and closing is the most preferred behavior for occupants to control their indoor environment in homes. This study aims to identify driving forces for window opening and closing behavior in the home. The additional field survey was carried out for the cooling period after following the previous study. The state of windows and environmental variables for outdoor and indoor were continuously monitored in twenty-three sample homes over one year. The monitored data provide evidence that there is a statistically significant relationship between window opening behavior and outdoor temperature. The behavior of the occupant's manual control of windows can be described by seasonal effects, occupancy, and time of day. Indoor stimuli such as such as temperature, humidity, and CO2 , can better account for the window opening behavior than can outdoor stimuli. There are clear differences in driving variables between window opening and closing behavior. The closing behavior is better described when the outdoor and indoor variables are combined. Finally, multivariate logistic regression models were developed to predict typical patterns of window opening and closing as a function of indoor and outdoor variables. This article is protected by copyright. All rights reserved. PMID- 30468528 TI - A method to standardize the blood flow restriction pressure by an elastic cuff. AB - Blood flow restriction training using a practical (non-pneumatic) elastic-cuff has recently increased in popularity. However, a criticism of this method is that the pressure applied and the amount of blood flow restriction induced is unknown. The aim was to quantify blood flow following the application of an elastic-cuff and compare that to what is observed using a more traditional pressurized nylon cuff. Thirty-five young participants (16 men and 19 women) visited the laboratory once for testing. In a randomized order (one condition per arm), an elastic-cuff (5cm wide) was applied to one arm and blood flow was measured following the cuff being pulled to two distinct lengths; 10% and 20% of the resting length based on arm circumference. The other arm would follow a similar protocol but use a pressurized nylon-cuff (5cm wide) and be inflated to 40% and 80% of the individuals resting arterial occlusion pressure. There was a main effect of pressure for blood flow with it decreasing in a pressure dependent manner (High=0.509). The application of a pressure relative to the initial belt length, which is largely dependent upon arm circumference, appears to provide one method to standardize the practical blood flow restriction pressure for future research. This article is protected by copyright. All rights reserved. PMID- 30468529 TI - Accuracy of dermoscopy in distinguishing erythroplasia of Queyrat from common forms of chronic balanitis: results from a multicentric observational study. AB - BACKGROUND: Clinical differentiation of erythroplasia of Queyrat (EQ) and chronic forms of balanitis may be challenging, especially in early phases or in overlapping cases. Dermoscopy has been shown to be a useful supportive tool in facilitating the distinction between tumoral and inflammatory skin conditions, yet data on EQ and balanitis are scarce or sparse. OBJECTIVES: To systematically assess the dermoscopic features of both EQ and common forms of chronic balanitis and to investigate the accuracy of dermoscopy in distinguishing these conditions. METHODS: Subjects with EQ or chronic balanitis confirmed histologically or microbiologically (for infectious forms) were recruited. A representative dermoscopic image of a target lesion was retrospectively assessed for the presence of specific morphological findings. A correlation matrix was created using Spearman's rho. Proportions of dermoscopic variables scoring among different conditions were compared with the non-parametric Pearson's Chi Square test. RESULTS: A total of 81 lesions (14 EQ, 23 psoriasis, 31 Zoon plasma cell balanitis, and 13 candidal balanitis) from 81 patients were included in the study. Glomerular vessels (both clustered and diffusely distributed) were highly predictive for the diagnosis of EQ, while diffuse dotted vessels were strongly associated with psoriatic balanitis. Finally, Zoon plasma cell balanitis was characterized by orange structureless areas (focal or diffuse) and focused linear curved vessels, whereas cottage cheese-like structures (sparse white coating corresponding to Candida yeast colonies growth) showed a strong correlation with candidal balanitis. CONCLUSIONS: EQ and balanitis may display different dermoscopic patterns, thereby bearing the usefulness of dermoscopy as a supportive non-invasive tool for the recognition and differential diagnosis of such conditions. This article is protected by copyright. All rights reserved. PMID- 30468530 TI - "High dose" versus "medium dose" uva1 phototherapy in italian patients with severe atopic dermatitis. AB - BACKGROUND: the current evidences attest UVA1 phototherapy as effective in the treatment of severe atopic dermatitis (AD). Furthermore in this indication, "medium dose" is as effective as "high dose" regimen. To date, a randomized comparison study evaluating the effectiveness as well as safety of different UVA1 protocols in different skin types in the treatment of adult patients with severe AD is still lacking. OBJECTIVE: The aim of the present study was to compare the safety and the efficacy of medium and high dose UVA1 either in fair or in dark skin types. METHODS: Twenty-seven adult patients with severe AD were consecutively included in a randomized, controlled, open, two arms trial. Severity of AD was determined by means of SCORAD index and clinical improvement was also monitored. A total of 13/27 patients were treated with High Dose (130 J/cm2 ) UVA1 protocol while 14/27 patients received Medium Dose (60 J/cm2 ) UVA1 protocol. Phototherapy was performed 5 times weekly up to 3 weeks. Before and after UVA1 treatment each patient was evaluated for skin pigmentation through Melanin Index (MI) quantitative evaluation. RESULTS: Skin status improved in all patients resulting in a reduction of SCORAD index in all groups. Our results demonstrated that among patients with darker skin types and higher MI, High dose UVA1 was significantly more effective than Medium Dose (p < 0.0001) while within the groups with skin type II, no significant differences between high and medium dose protocols were observed. CONCLUSION: Our study, confirms previous observations that UVA1 phototherapy should be considered among the first approaches in the treatment of patients with severe generalized atopic dermatitis and also demonstrates that in darker skin types, high dose UVA1 phototherapy is more effective than medium dose in the treatment of adult patients with severe AD. This article is protected by copyright. All rights reserved. PMID- 30468531 TI - Diagnosis validation and clinical characterization of atopic dermatitis in Nurses' Health Study 2. AB - BACKGROUND: Epidemiologic studies of atopic dermatitis are often limited by case definitions that have not been validated. OBJECTIVE: In this study, we assessed the accuracy of self-report of atopic dermatitis in a large cohort of US female nurses, the Nurses' Health Study 2 (NHS2). We also provide clinical characteristics of atopic dermatitis in the cohort. METHODS: We sent an electronic questionnaire to NHS2 participants who previously reported ever having a diagnosis of atopic dermatitis. This questionnaire was designed to confirm cases of atopic dermatitis using previously validated algorithms with >85% specificity. We assessed the association of atopic dermatitis with asthma, comparing the results when different definitions of atopic dermatitis were applied. We also inquired about various aspects of participants' atopic dermatitis. RESULTS: Responses were received from 2,509 of 5,126 (49%) nurses who were sent the questionnaire, with an average age of 62. Most participants (1,996/2,509, 80%) reiterated their previously reported clinician diagnosis of atopic dermatitis. Application of the two diagnostic algorithms yielded confirmation of 1,538 and 1,293 prevalent cases, respectively. The association of atopic dermatitis with asthma was stronger when more stringent atopic dermatitis case definitions were applied. Participants generally reported mild disease (92% with <=10% maximal body surface area involved) and a high proportion (57%) reported adult-onset disease. CONCLUSIONS: Self-report of atopic dermatitis diagnosis has good reliability, and future analyses will be strengthened by our ability to conduct sensitivity analyses with refined confirmed atopic dermatitis subgroups. This article is protected by copyright. All rights reserved. PMID- 30468533 TI - Autochthonous and persistent cutaneous larva migrans in an infant successfully treated by topic albendazole ointment. PMID- 30468532 TI - A survey among dermatologists: Diagnostics of superficial fungal infections - what is used and what is needed to initiate therapy and assess efficacy? AB - BACKGROUND: Superficial fungal infections are common. It is important to confirm the clinical diagnosis by mycological laboratory methods before initiating systemic antifungal treatment, especially as antifungal sensitivity and in vitro susceptibility may differ between different genera and species. For many years the gold standard for diagnosis of superficial fungal infections has been direct fungal detection in the clinical specimen (microscopy) supplemented by culturing. Lately newer molecular based methods for fungal identification have been developed. OBJECTIVE: This study was initiated to focus on the current usage of mycological diagnostics for superficial fungal infections by dermatologists. It was designed to investigate if it was necessary to differentiate between initial diagnostic tests and those used at treatment follow-up in specific superficial fungal infections. METHODS: An online questionnaire was distributed among members of the EADV mycology Task Force and other dermatologists with a special interest in mycology and nail disease. RESULTS: The survey was distributed to 62 dermatologists of whom 38 (61%) completed the whole survey, 7 (11%) partially completed and 17 (27%) did not respond. Nearly all respondents (82-100%) said that ideally they would use the result of direct microscopy (or histology) combined with a genus / species directed treatment of onychomycosis, dermatophytosis, Candida- and Malassezia-related infections. The majority of the dermatologists used a combination of clinical assessment and direct microscopy for treatment assessment and the viability of the fungus was at this visit than when initiating the treatment. Molecular based methods were not available for all responders. CONCLUSION: The available diagnostic methods are heterogeneous and their usage differs between different practices as well as between countries. The survey confirmed that dermatologists find it important to make a mycological diagnosis, particularly prior to starting oral antifungal treatment in order to confirm the diagnose and target the therapy according to genus and species. This article is protected by copyright. All rights reserved. PMID- 30468534 TI - Single-operator Peroral Cholangioscope in Treating Difficult Biliary Stones: A Systematic Review and Meta-analysis. AB - OBJECTIVES: Current evidence supporting the utility of single-operator peroral cholangioscope (SOPOC) in the management of difficult bile duct stones is limited. We conducted the present systematic review and meta-analysis to evaluate the efficacy and safety of SOPOC in treating difficult bile duct stones. METHODS: We searched studies up to April 2018, using MEDLINE, EMBASE, the Cochrane Library, and Google Scholar. Quality assessment of the studies was completed with the Newcastle-Ottawa Scale. The main outcomes were complete stone clearance rate, single-session stone clearance rate, number of endoscopic sessions needed for stone clearance, and adverse events. We calculated the pooled estimates with random-effects models. Potential publication bias was assessed. RESULTS: Twenty four studies involving 2786 patients met the inclusion criteria. The pooled proportion of patients with complete stone clearance was 94.3% (95% confidence interval [95% CI]: 90.2%-97.5%). Single-session stone clearance was achieved in 71.1% (95% CI: 62.1%-79.5%) of the pooled patients. The pooled number of sessions needed for stone clearance was 1.26 (95% CI: 1.17-1.34). The pooled adverse event rate was 6.1% (95% CI: 3.8%-8.7%). Potential publication bias was detected but had no significant influence on the results. CONCLUSIONS: SOPOC is an effective and safe treatment for difficult bile duct stones when conventional methods have failed. More randomized controlled trials are warranted to confirm the results. This article is protected by copyright. All rights reserved. PMID- 30468535 TI - A Comparative Study of Onychomycosis and Traumatic Toenail Onychodystrophy Dermoscopic Patterns. AB - BACKGROUND: Onychomycosis (OM) and traumatic onychodystrophy (OD) are common causes of toenail changes. A clinical diagnosis is often impossible without mycology. Dermoscopy is helpful in this setting but yet under-explored. Prospective comparative studies between OM and OD onychoscopic findings have not been previously performed. OBJECTIVES: We sought to determine distinguishing dermoscopic presentations of OM and traumatic OD. METHODS: We performed a prospective, observational study including patients presenting with >=1 toenail onychodystrophy. All underwent onychoscopy, clinical and mycological examination. Based on these results, patients received a final diagnosis of OM or OD. Dermoscopic presentations of OM and OD patients were classified in patterns and compared. RESULTS: In all, 110 cases of OM and 82 of traumatic OD were compared. Statistical analyses revealed that the distal pulverized and the irregular spiked macular dermoscopic patterns were predictors of an OM diagnosis. The regular macular, the non-classifiable, the total and partial homogeneous background dermoscopic patterns, correlated with traumatic OD diagnosis. CONCLUSIONS: We demonstrated that OM and traumatic OD have distinctive onychoscopic presentations. Dermoscopy may be an important ancillary tool to guide their differential. This article is protected by copyright. All rights reserved. PMID- 30468536 TI - Onychoscopy of non-infectious nail abnormalities in patients after allogeneic haematopoietic stem cell transplantation. AB - Nail abnormalities after allogeneic haematopoietic stem cell transplantation procedure (alloHSCT) are often reported. Usually, they are related to chronic graft-versus-host disease (cGvHD). So far, only clinical manifestations of selected nail abnormalities have been described, without the presentation of dermoscopic images. In this article, we present morphologic and dermoscopic manifestations of potential non-infectious nail abnormalities in patients after alloHSCT procedure based on reviewed literature and our own experience with dermoscopic iconography. In majority of studies published till now, nail changes are not connected to severity of other cGvHD symptoms; however, e.g. the presence of pterygium inversum unguis may be an indicator of lung dysfunction. As nail changes may be an early sign of cGvHD and always present in association with other manifestations, routine clinical assessment should include nails examination. Knowledge of possible presentation of nail involvement after alloHSCT may be valuable for treating physician. PMID- 30468537 TI - Training and match volume and injury in adolescents playing multiple contact team sports: a prospective cohort study. AB - Training and competition loads have emerged as valuable injury risk factors but very few studies have explored injury outcomes in adolescent athletes. The aims of this study were to describe injuries and to explore the relationship between training and match load volumes and injury in adolescent athletes participating in multiple contact team sports. One hundred and three male youth rugby athletes aged 14 to 16 years from 8 rugby union teams were prospectively monitored during a season for weekly training and match volumes and injuries. The relationship between volume and injury was explored by comparing the weekly volume in the week prior to an injury vs. weeks without injury. There were 83 time-loss injuries in 58 athletes (62%). Overall injury incidence was 18.5 per 1000 player-hours. Mean weekly injury prevalence was 27% (95% CI 25-30). Average weekly volume was 5.4 (2.2) hours comprising 1.4 (1) match hours and 4 (2.6) training hours. Compared with weeks without injury, weeks prior to an injury had higher match volumes (110 [57] min vs 83 [59] min, p <0.001). Poisson regression demonstrated that match volume was a predictor of injury with an odds ratio of 1.41 (p=0.001). The contribution of match volumes to injury risk and the relatively high injury burden in these athletes may be profound. Very high match volumes are unlikely to be in the best interests of young athletes and could be avoided with a systematic approach to load management and athlete development. This article is protected by copyright. All rights reserved. PMID- 30468538 TI - Improving the performance of nadolol stereoisomers' preparative separation using Chiralpak IA by SMB chromatography. AB - The pseudobinary preparative separation of nadolol stereoisomers is performed by simulated moving bed chromatography (SMB). Using the Chiralpak IA adsorbent, a new 25:75:0.1 (v/v/v) methanol-acetonitrile-diethylamine solvent composition was selected to perform the experimental SMB separation and compare it with the previous results obtained using pure methanol. Using a 2 g L-1 total feed concentration of an equimolar mixture of the four stereoisomers of nadolol, the more retained component was fully recovered (100% purity and 100% recovery), with a system productivity of 0.77 g L-1 hour-1 and a solvent consumption of 9.62 L g 1 . Comparing these results with the ones previously reported using 100:0.1 methanol-diethylamine solvent composition, this work shows that the 25:75:0.1 methanol-acetonitrile-diethylamine is a better alternative for the preparative separation of nadolol stereoisomers by SMB chromatography. These results are confirmed by simulation of the SMB operation for higher feed concentrations, by comparing the performances of the two solvent compositions using the data obtained experimentally through the measurement of the adsorption equilibrium isotherms and the kinetic data obtained for both solvents. The new experimental and simulation results stress out that the performance of the preparative separation can be improved by a careful selection of the solvent composition. PMID- 30468539 TI - Spinal Injury Analysis for Typical Snowboarding Backward Falls. AB - Spinal injury (SPI) often causes death and disability in snow-sport accidents. SPIs often result from spinal compression and flexion, but the injury risks due to over flexion have not been studied. Back protectors are used to prevent SPIs but the testing standards do not evaluate the flexion-extension resistance. To investigate SPI risks and to better define back-protector specifications, this study quantified the flexion-extension range of motions (ROMs) of the thoracic lumbar spine during typical snowboarding backward falls. A human facet-multibody model, which was calibrated against spinal flexion-extension responses and validated against vehicle-pedestrian impact and snowboarding backward fall, was used to reproduce typical snowboarding backward falls considering various initial conditions (initial velocity, slope steepness, body posture, angle of approach, anthropometry and snow stiffness). The SPI risks were quantified by normalizing the numerical spinal flexion-extension ROMs against the corresponding ROM thresholds from literature. A high risk of SPI was found in most of the 324 accident scenarios. The thoracic segment T6-T7 had the highest injury risk and incidence. The thoracic spine was found more vulnerable than the lumbar spine. Larger anthropometries and higher initial velocities tended to increase SPI risks while bigger angles of approach helped to reduce the risks. SPIs can result from excessive spinal flexion-extension during snowboarding backward falls. Additional evaluation of back protector's flexion-extension resistance should be included in current testing standards. An ideal back protector should consider the vulnerable spinal segments, the snowboarder's skill level and anthropometry. This article is protected by copyright. All rights reserved. PMID- 30468540 TI - Sulfur Chemistry in Polymer and Materials Science. AB - Sulfur and its functional groups are major players in an area of exciting research taking place in modern polymer and materials science, both in academia and industry. In fact, manifold sulfur-based reactions that are both exceptionally versatile as well as tremendously useful have been implemented, and further utilized for the design and preparation of polymeric materials that lead to a plethora of applications ranging from medicine to optics and nanotechnology to separation science. Hence, within this review, an overview of strategies and developments used over the last 5 years to reinforce the importance of the sulfur functional group in modern polymer and materials science is presented. In particular, many important references in the primary literature of sulfur chemistry are referred to, including thiol-ene, thiol-yne, thiol-Michael addition, disulfide cross-linking, and thiol-disulfide exchange, among others, by explaining and illustrating the important principles. Last but not least, the grand aim to underpin the importance of sulfur in modern polymer and materials science is achieved by presenting selected examples in diverse fields and postulating the respective potential for real-world applications. PMID- 30468541 TI - A Bioinspired, Highly Transparent Surface with Dry-Style Antifogging, Antifrosting, Antifouling, and Moisture Self-Cleaning Properties. AB - Transparent coatings with antireflection, antifogging, antifrosting, antifouling, and moisture self-cleaning properties can dramatically improve the efficiency and convenience of optical elements and thus are highly desirable for practical applications. Here, it is demonstrated that a bionic nanocone surface (BNS) fabricated by a facile, low-cost process consisting of template-assisted prepolymer curing followed by surface modification can possess the multiple functions listed above. The polymer coating firmly adheres to a glass substrate due to bonding agents. After SiO2 nanoparticle deposition and low-surface-energy fluorosilane modification, the coating shows low microdroplet adhesion. As a result, the as-prepared BNS exhibits a high transmittance when exposed to fog and good clarity even when the temperature decreases to -20 degrees C in a humid environment. Dipping the BNS into exemplified graphite powder has almost no influence on the transparency, and the BNS can realize self-cleaning of moisture when the surface is covered with a thick layer of man-made contaminants. PMID- 30468542 TI - CONSTANS delays Arabidopsis flowering under short days. AB - Long days (LD) promote flowering of Arabidopsis thaliana compared to short days (SD) by activating the photoperiodic pathway. Here we show that growth under very SD (3 h) or darkness (on sucrose) also accelerates flowering on a biological scale, indicating that SD actively repress flowering compared to very-SD. CONSTANS (CO) repressed flowering under SD, and the early flowering of co under SD required FLOWERING LOCUS T (FT). FT was expressed at a basal level in the leaves under SD but these levels were not enhanced in co. This indicates that the action of CO in A. thaliana is not the mirror image of the action of its homologue in rice. In the apex, CO enhanced the expression of TERMINAL FLOWER 1 (TFL1) around the time when FT expression is important to promote flowering. Under SD, the tfl1 mutation was epistatic to co and in turn ft was epistatic to tfl1. These observations are consistent with the long-standing but not demonstrated model where CO can inhibit FT induction of flowering by affecting TFL1 expression. This article is protected by copyright. All rights reserved. PMID- 30468543 TI - Mitigating Chromatic Dispersion with Hybrid Optical Metasurfaces. AB - Metasurfaces control various properties of light via scattering across a large number of subwavelength-spaced nanostructures. Although metasurfaces appear to be ideal photonic platforms for realizing and designing miniaturized devices, their chromatic aberrations have hindered the large-scale deployment of this technology in numerous applications. Wavelength-dependent diffraction and resonant scattering effects usually limit their working operation wavelengths. In refractive optics, chromatic dispersion is a significant problem and is generally treated by cascading multiple lenses into achromatic doublets, triplets, and so on. Recently, broadband achromatic metalenses in the visible have been proposed to circumvent chromatic aberration but their throughput efficiency is still limited. Here, the dispersion of refractive components is corrected by leveraging the inherent dispersion of metasurfaces. Hybrid refractive-metasurface devices, with nondispersive refraction in the visible, are experimentally demonstrated. The dispersion of this hybrid component, characterized by using a Fourier plane imaging microscopy setup, is essentially achromatic over about 150 nm in the visible. Broadband focusing with composite plano-convex metasurface lenses is also proposed. These devices could find applications in numerous consumer optics, augmented reality components, and all applications including imaging for which monochromatic performance is not sufficient. PMID- 30468544 TI - Synthesis of Pure Silica MWW Zeolite in Fluoride Medium Using an Imidazolium Based Long Dication. AB - As the spacer length in 1,2-dimethylimidazolium-based dications increases beyond a point (6 methylene units), they fail in structure-direct the STW zeolite in any synthesis condition. They can instead produce, under fluoride concentrated conditions, either *BEA (for the 8-methylene SDA) or MWW (10-methylene). For any length of the dication, the default zeolite (MTW) is a dense zeolite with a unidimensional channel, while the zeolite demanding most specificity (STW, *BEA or MWW) is more porous, occluding a larger amount of dication. This work provides the first reported fluoride synthesis of pure silica MWW. Organic dications in this zeolite are charge balanced by combined "structural" silanolates, connectivity defects and occluded fluoride. Molecular mechanics calculations show a perfect fit of the 10-methylene dication in the intralayer pore system of MWW, while the dication is also able to stabilize the interlayer space without disturbing the H-bonding system holding the layers together in the as-made material. The 19F MAS NMR presents two distinct resonances at -71 and -83 ppm which, based on DFT calculations, we tentatively assign to fluoride occluded in [4662] and [415262] cages of the MWW structure, respectively. The same DFT study determines a different chemical shift of one methyl 13C NMR signal according to the imidazolium ring residing in the sinuosidal channels or in the large cup cavities, thus explaining an experimentally observed splitting of that resonance. PMID- 30468545 TI - Synthesis of u2-oxo-bridged iron(III)tetraphenylporphyrin-spacer-nitroxide dimers and their structural and dynamics characterization using EPR and MD simulations. AB - Iron(III)porphyrins have the propensity to form u2-oxo-dimers whose structure resembles two wheels on an axle. Whereas their crystal structure is known their solution structure and internal dynamics is not. In the present work, the structure and dynamics of such dimers was studied by means of electron paramagnetic resonance (EPR) spectroscopy and quantum chemistry based molecular dynamics (MD) simulations using the semiempirical tight-binding method (GFN-xTB). In order to enable EPR investigation on the dimers, a nitroxide was attached to each of the tertaphenylporphyrin core via a linear and a bent linker. The inter nitroxide distance distributions within the dimers were determined by cw-EPR and pulsed electron-electron double resonance (PELDOR of DEER) experiments and, with the help of MD, interpreted in terms of the rotation of the porphyrin planes with respect to each other around the Fe-O-Fe axis. It was found that such rotation is restricted to the four registers defined by the phenyl substituents. Within the registers, the rotation angle swings between 30 degrees and 60 degrees in the proximal and between 125 degrees and 145 degrees in the distal register. With EPR, all four angles were found to be equally populated, whereas the 30 degrees and 145 degrees angles are strongly favored on expense of the 60 degrees and 125 degrees angles in the MD simulation. In either case, the internal dynamics of these dimers does thus resemble the motion of a step motor. PMID- 30468546 TI - C3 and C6 Modification-specific OYE biotransformations of synthetic carvones and sequential BVMO chemoenzymatic synthesis of chiral caprolactones . AB - The scope for biocatalytic modification of non-native terpenone derivatives for speciality intermediates has hitherto been limited. Additionally, caprolactones are important feedstocks with diverse applications in the polymer industry and new non-native terpenone-derived biocatalytic caprolactone syntheses are of potential value for industrial biocatalytic materials applications. Biocatalytic reduction of synthetic analogues of R-(-)-carvone with additional substituents at C3 or C6, or both C3 and C6, using three types of OYEs (OYE2, PETNR and OYE3) shows significant impact of both regio-substitution and the substrate diastereomer. Bioreduction of (-)-carvone derivatives substituted with a Me and/or OH group at C6 is highly dependent on the substrate diastereomer. The products of bioreduction were efficiently biotransformed by Baeyer-Villiger monooxygenase (BVase), CHMO_Phi1, provides a biocatalytic entry to new trisubstituted chiral caprolactones with complete regioselectivity. This provides both new non-native polymerization feedstock chemicals, but also with enhanced efficiency and selectivity over native (+)-dihydrocarvone Baeyer-Villigerase expansion, Optimum enzymatic reactions were scaled up to 60-100 mg, demonstrating the utility for preparative biocatalytic synthesis of both new synthetic scaffold modified dihydrocarvones and efficient biocatalytic entry to new chiral caprolactones, which are potential single isomer-chiral polymer feedstocks. PMID- 30468547 TI - Discriminating Normal Regions within Cancerous Hen Ovarian Tissue Using Multivariate Hyperspectral Image Analysis. AB - RATIONALE: Identification of subregions under different pathological conditions on cancerous tissue is of great significance for understanding cancer progression and metastasis. Infrared matrix-assisted laser desorption electrospray ionization mass spectrometry (IR-MALDESI-MS) can be potentially used for the diagnostic purpose since it can monitor spatial distribution and abundance of metabolites and lipids in biological tissues. However, the large size and high dimensionality of hyperspectral data make analysis and interpretation challenging. To overcome these barriers, multivariate methods were applied to IR-MALDESI data for the first time, aiming at efficiently resolving mass spectral images, from which these results were then used to identify normal regions within cancerous tissue. METHODS: Molecular profiles of healthy and cancerous hen ovary tissues were generated by IR-MALDESI-MS. Principal Component Analysis (PCA) combined with color-coding built a single tissue image which summarizes the high-dimensional data features. Voxels with similar color indicated similar composition. PCA results from healthy tissue were further used to test each voxel in cancerous tissue to determine if it is healthy. Multivariate curve resolution-alternating least squares (MCR-ALS) was used to obtain major spatial features existing in ovary tissues, and group molecules with the same distribution patterns simultaneously. RESULTS: PCA as the predominating dimensionality reduction approach captured over 90% spectral variances by the first three PCs. The PCA images show the cancerous tissue is more chemically heterogeneous than healthy tissue, where at least 4 regions with different m/z profiles can be differentiated. PCA modeling assigns top regions of cancerous tissue as healthy like. MCR-ALS extracted 3 and 4 major compounds from healthy and cancerous tissue, respectively. Evaluating similarities of resolved spectra uncovered the chemical components that were distinct in some regions on cancerous tissue, serving as a supplement way to differentiate healthy and cancerous regions. CONCLUSIONS: Two unsupervised chemometric methods including PCA and MCR-ALS were applied for resolving and visualizing IR-MALDESI-MS data acquired from hen ovary tissues, improving the interpretation of mass spectrometry imaging results. Then possible normal regions were differentiated from cancerous tissue section. No prior knowledge is required using either chemometric method, so our approach is readily suitable for unstained tissue samples, which allows one to reveal the molecular events happening during disease progression. PMID- 30468548 TI - Local Adaptation, Genetic Divergence, and Experimental Selection in a Foundation Grass across the US Great Plains' Climate Gradient. AB - Many prior studies have uncovered evidence for local adaptation using reciprocal transplant experiments. However, these studies are rarely conducted for a long enough time to observe succession and competitive dynamics in a community context, limiting inferences for long-lived species. Furthermore, the genetic basis of local adaptation and genetic associations with climate has rarely been identified. Here we report on a long-term (6-yr) experiment conducted under natural conditions focused on Andropogon gerardii, the dominant grass of the North American Great Plains tallgrass ecosystem. We focus on this foundation grass that comprises 80% of tallgrass prairie biomass and is widely used in 20,000 km2 of restoration. Specifically, we asked 1) if ecotypes are locally adapted to regional climate in realistic ecological communities? 2) does adaptive genetic variation underpin divergent phenotypes across the climate gradient? 3) is there evidence of local adaptation if the plants are exposed to competition among ecotypes in mixed ecotype plots? Finally, 4) are local adaptation and genetic divergence related to climate? Reciprocal gardens were planted with 3 regional ecotypes (originating from dry, mesic, wet climate sources) of Andropogon gerardii across a precipitation gradient (500-1200 mm/yr) in the US Great Plains. We demonstrate local adaptation and differentiation of ecotypes in wet and dry environments. Surprisingly, the apparent generalist mesic ecotype performed comparably under all rainfall conditions. Ecotype performance was underpinned by differences in neutral diversity and candidate genes corroborating strong differences among ecotypes. Ecotype differentiation was related to climate, primarily rainfall. Without long-term studies, wrong conclusions would have been reached based on the first two years. Further, restoring prairies with climate-matched ecotypes is critical to future ecology, conservation and sustainability under climate change. This article is protected by copyright. All rights reserved. PMID- 30468549 TI - Highly sensitive and selective molecular probes for chromo-fluorogenic sensing of carbon monoxide in air, aqueous solution and cells. AB - Optical sensing offers a low-cost and effective means to sense carbon monoxide in air and in solution. This contribution reports the synthesis of a new series of vinyl complexes [Ru(CH=CHR)Cl(CO)(TBTD)(PPh3)2] (R = aryl, TBTD = 5-(3-thienyl) 2,1,3-benzothiadiazole) and shows them to be highly sensitive and selective probes for carbon monoxide in both solution and air. Depending on the vinyl substituent, chromogenic and fluorogenic responses signalled the presence of this invisible, odourless, tasteless and toxic gas. Adsorbing the complexes on silica produced colorimetric probes for the 'naked eye' detection of CO in the gas phase with a limit of detection as low as 8 ppm in some cases, while the release of the TBTD fluorophore allowed detection at much lower concentrations through the fluorescence response. Structural data were obtained by single crystal X-ray diffraction techniques, while the photophysical behaviour was explored computationally using TD-DFT experiments. The systems were also shown to be selective for CO over all other gases tested, including water vapour and common organic solvents. By introducing a poly(ethylene)glycol chain to the vinyl functionality, water compatibility was achieved and these non-cytotoxic complexes were employed in the sensing of CO in HeLa cells, offering a simple and rapid system for sensing this gasotransmitter in this challenging medium. PMID- 30468550 TI - Newborn screening for 3-hydroxy-3-methylglutaric aciduria using direct analysis in real-time mass spectrometry. AB - A novel method utilizing ambient thermal desorption ionization with a direct analysis in real-time source integrated with mass spectrometry (DART-MS) was established and applied to the rapid analysis of 3-hydroxy-3-methylglutaric (3 HMG) acid in the neonatal urine. Instrument parameter settings were optimized to obtain high sensitive and accurate determination of 3-HMG acid. The use of helium gas heated to temperature of 400 o C was observed to permit deprotonation, 3-HMG acid producing a abundant [M-H]- (m/z 161) in the negative ion mode. The calibration curve was determined to be linear over the range of 0.05-5 mg/L, with the correlation coefficient r = 0.9988 and the relative standard deviations (n=6) in the range of 1.5 to 11.8%. The limit of detection was 0.002 mg/L and the limit of quantitation was 0.007 mg/L. The recoveries ranged from 88.0% to 123.1%. Four urine samples from patients and four simulated urine samples were investigated. The results of DART-MS were in agreement with the values determined using established methods at the hospitals. The proposed method demonstrated significant potential in the application of the high-throughput screening in newborn screening. PMID- 30468551 TI - Genome-wide identification and expression analysis reveal the potential function of ERF (Ethylene responsive factor) gene family in response to Botrytis cinerea infection and ovule development in grapes (Vitis vinifera L.). AB - The prevention of Botrytis cinerea and the study of grape seedlessness are very important for grape industries. Finding correlated regulatory genes is an important approach towards understanding their molecular mechanisms. ERF (Ethylene Responsive Factor) transcription factors play critical roles in defense networks and the growth of plants. To date, no large-scale study of the ERF proteins associated with pathogen defense and ovule development has been performed in grape (Vitis vinifera L.). In the present study, we identified 113 ERF genes (VvERF) and named them based on their chromosome locations. The ERF genes could be divided into 11 groups based on a multiple sequence alignment and a phylogenetic comparison with homologs from Arabidopsis thaliana. Synteny analysis and Ka/Ks ratio calculation suggested that segmental and tandem duplications contributed to the expansion of the ERF gene family. The evolutionary relationships between the VvERF genes were investigated by exon intron structure characterization, and an analysis of the cis-acting regulatory elements in their promoters suggested potential regulation after stress or hormone treatments. Expression profiling after infection with the fungus, Botrytis cinerea, indicated that these genes function in responses to pathogen attack. In addition, the expression levels of most ERF genes were much higher during ovule development in seedless grapes suggesting a role in ovule abortion related to seedlessness. Taken together, these results indicate that VvERF proteins are involved in responses to Botrytis cinerea infection and in ovule development. This information may help guide strategies for improved grape production. This article is protected by copyright. All rights reserved. PMID- 30468552 TI - Diphosphoniodiphosphene formation by transition metal insertion into a triphosphenium zwitterion. AB - Treatment of two equivalents of the triphosphenium zwitterion L with sources of Ni(0) and Pd(0) form the mononuclear eta2-diphosphoniodiphosphene complexes Ni(L2) and Pd(L2). The reaction between L and [FeCp(CO)2]2 results in the binuclear mu- eta1:eta1 diphosphoniodiphosphene iron complex (L2)[Fe(CO)Cp]2 which features an alternative bonding motif of the diphosphoniodiphosphene unit. The formation of these species has been confirmed by spectroscopic methods and single crystal X-ray diffraction analysis, and their electronic structures have been elucidated using computational methods. PMID- 30468553 TI - "I actually just really need to stop work sometimes": Exploring fatigue-related barriers to employment among people with rheumatic diseases. AB - PURPOSE: Fatigue is a common symptom of many rheumatic diseases (RDs), but more research is needed to explore the experience of fatigue and its impact on employment among people with RDs. The aim of the present study was to investigate experiences of fatigue, its impact on employment and strategies that people with RD use to continue working. METHOD: Semi-structured in-depth interviews were conducted with five participants with a range of RDs living in New Zealand (three women, two men; aged 45-64 years). All participants were employed part time at the time of the interview. The transcripts were subjected to inductive thematic analysis, led by the first author, who had an RD. RESULTS: Four themes resulted from the analysis: (a) workplace management and coping strategies; (b) the function of positive workplace relationships; (c) barriers to understanding; and (d) collectively improving understanding. These themes act to explain how individuals with RDs in employment believe fatigue to have a bearing on their work, how they manage fatigue at work, how they believe coworkers and employers perceive and manage their fatigue, and what they believe could improve the understanding of fatigue in workplaces. CONCLUSIONS: Individuals with RDs in employment describe fatigue as playing a substantial role in their experiences at work. This research expands on previous literature addressing barriers to employment in those with RDs by specifically addressing the relevance of fatigue. It is imperative to provide information to employers, and guidelines for employees with an RD who are experiencing fatigue should outline appropriate strategies for success at work. PMID- 30468555 TI - The perspectives of physiotherapists on managing nonspecific low back pain following a training programme in cognitive functional therapy: A qualitative study. AB - BACKGROUND: It has long been acknowledged that nonspecific chronic low back pain (NSCLBP) is associated with a complex combination of biopsychosocial (BPS) factors, and recent guidelines advocate that the management of back pain should reflect this multidimensional complexity. Cognitive functional therapy (CFT) is a behaviourally oriented intervention that targets patients' individual BPS profiles. Although the efficacy of CFT has been demonstrated in primary care, little evidence exists about the training requirements of this approach. METHODS: Qualitative semistructured interviews were conducted with 10 physiotherapists working in primary care, who had undergone a formal training programme in CFT. A purposive sampling method was employed to seek the broadest perspectives. Thematic analysis was used to analyse the interview transcripts and capture the emergent themes. RESULTS: Five main themes emerged: (i) the learning challenge; (ii) self-reported changes in confidence; (iii) self-reported changes in communication practice; (iv) self-reported changes in attitudes and understanding; (v) the physiotherapists felt that CFT was more effective than their usual approach for NSCLBP but identified barriers to successful implementation, which included a lack of time and difficulties in engaging patients with strong biomedical beliefs. CONCLUSIONS: The study suggested that training in CFT has the capacity to produce self-reported changes in physiotherapists' attitudes, confidence and practice. The provision of such training has implications in terms of time and costs; however, this this may be warranted, given the physiotherapists' strong allegiance to the approach compared with their usual practice. PMID- 30468556 TI - Diverse roles of the E2/E3 hybrid enzyme UBE2O in the regulation of protein ubiquitination, cellular functions, and disease onset. AB - The ubiquitin-proteasome system is an important regulatory machinery involved in proteostasis and cellular signaling. Proteins are ubiquitinated via the concerted action of E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin ligases. Although most of the studies to date focus on the significance of E3 ubiquitin ligases in disease development and therapeutic treatment, recent discoveries suggest that E2 ubiquitin-conjugating enzymes might also be potential drug targets. The ubiquitin-conjugating enzyme E2 O (UBE2O), an E3-independent E2 (i.e. an E2/E3 hybrid enzyme), can directly mediate the ubiquitination of many substrates. These include 5'-AMP-activated protein kinase catalytic subunit alpha2 (AMPKalpha2), tumor suppressor ubiquitin carboxyl terminal hydrolase BAP1, mixed-lineage leukemia (MLL) protein, SMAD family member 6 (SMAD6), transcription factor c-Maf and aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL or BMAL1), and free ribosomal proteins, which are ubiquitinated in distinct ways, thereby associating UBE2O with a variety of biological functions. Furthermore, UBE2O is frequently amplified or mutated in multiple cancers, and its high expression is associated with low survival rate of gastric, lung, breast, and prostate cancer patients. However, the molecular mechanisms by which UBE2O contributes to tumor initiation and progression are not fully elucidated. This review focuses on emerging insights from genetics, biochemistry, and cell biology to explore the biological functions of UBE2O and its therapeutic potential. PMID- 30468557 TI - Suture is still the gold standard for closure of the skin incision at cesarean delivery. AB - There are now over 1,000 randomized controlled trials (RCTs) on the technical aspects of how to perform a cesarean delivery (CD) (McCurdy R. JayPee 2019). One important aspect of this most common of laparotomies is how to close the skin incision. About 20 RCTs have evaluated CD skin closure, comparing the options of sutures, staples, glue, and others, as well as different types of these options (e.g., different types of sutures or different types of staples). This article is protected by copyright. All rights reserved. PMID- 30468558 TI - Molecularly Imprinted Fluorescent Test Strip for Direct, Rapid, and Visual Dopamine Detection in Tiny Amount of Biofluid. AB - Paper-based assays for detection of physiologically important species are needed in medical theranostics owning to their superiorities in point of care testing, daily monitoring, and even visual readout by using chromogenic materials. In this work, a facile test strip is developed for visual detection of a neurotransmitter dopamine (DA) based on dual-emission fluorescent molecularly imprinted polymer nanoparticles (DE-MIPs). The DE-MIPs, featured with tailor-made DA affinity and good anti-interference, exhibit DA concentration-dependent fluorescent colors, due to the variable ratios of dual-emission fluorescence caused by DA binding and quenching. By facile coating DE-MIPs on a filter paper, the DA test strips are obtained. The resultant test strip, like the simplicity of a pH test paper, shows the potential for directly visual detection of DA levels just by dripping a tiny amount of biofluid sample on it. The test result of real serum samples demonstrates that the DA strip enables to visually and semiquantitatively detect DA within 3 min by using only 10 uL of serum samples and with a low detection limit ((100-150) * 10-9 m) by naked eye. This work thus offers a facile and efficient strategy for rapid, visual, and on-site detection of biofluids in clinic. PMID- 30468559 TI - Ablation of interferon regulatory factor 4 in T cells induces "memory" of transplant tolerance that is irreversible by immune checkpoint blockade. AB - Achieving transplant tolerance remains the ultimate goal in the field of organ transplantation. We demonstrated previously that ablation of the transcription factor interferon regulatory factor 4 (IRF4) in T cells induced heart transplant acceptance by driving allogeneic CD4+ T cell dysfunction. Herein, we showed that heart-transplanted mice with T cell-specific IRF4 deletion were tolerant to donor specific antigens and accepted the subsequently transplanted donor-type but not third-party skin allografts. Moreover, despite the rejection of the primary heart grafts in T cell-specific Irf4 knockout mice under immune checkpoint blockade, the establishment of donor-specific tolerance in these mice was unhindered. By tracking alloantigen-specific CD4+ T cells in vivo, we revealed that checkpoint blockade restored the expression levels of the majority of wild-type T cell expressed genes in Irf4-deficient T cells on day 6 post-heart grafting, indicating the initial reinvigoration of Irf4-deficeint T cells. Nevertheless, checkpoint blockade did not restore cell frequency, effector memory cell generation, and IFN-gamma/TNF-alpha production of Irf4-/- alloreactive T cells at day 30 post-heart grafting. Hence, targeting IRF4 represents a potential therapeutic strategy for driving intrinsic T cell dysfunction and achieving alloantigen-specific transplant tolerance. This article is protected by copyright. All rights reserved. PMID- 30468560 TI - Antimicrobial strategies for urinary catheters. AB - Over 75% of hospital-acquired or nosocomial urinary tract infections are initiated by urinary catheters, which are used during the treatment of 16% of hospitalized patients. Taking the United States as an example, the costs of catheter-associated urinary tract infections (CAUTI) are in excess of $451 million dollars/year. The biofilm formation by pathogenic microbes that protects pathogens from host immune defense and antimicrobial agents is the leading cause for CAUTI. Thus, tremendous efforts have been devoted to antimicrobial coating for urinary catheters in the past few decades, and it has been demonstrated to be one of the most direct and efficient strategies to reduce infections. In this article, we briefly summarize the current methods for preparation of antimicrobial coatings based on different stages in the biofilm formation, highlight recent progress in the urinary catheter coating material design and selection, discuss approaches to improving their long-term antimicrobial efficacy, biocompatibility, multidrug resistance and recurrent infections, and finally outline future requirements and prospects in antimicrobial coating material design. The scope of the works surveyed is confined to antimicrobial urinary catheters. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 00A: 000-000, 2018. PMID- 30468562 TI - Aberrant transcriptomes and DNA methylomes define pathways that drive pathogenesis and loss of brain laterality/asymmetry in schizophrenia and bipolar disorder. AB - Although the loss of brain laterality is one of the most consistent modalities in schizophrenia (SCZ) and bipolar disorder (BD), its molecular basis remains elusive. Our limited previous studies indicated that epigenetic modifications are key to the asymmetric transcriptomes of brain hemispheres. We used whole-genome expression microarrays to profile postmortem brain samples from subjects with SCZ, psychotic BD [BD[+]] or non-psychotic BD [BD(-)], or matched controls (10/group) and performed whole-genome DNA methylation (DNAM) profiling of the same samples (3-4/group) to identify pathways associated with SCZ or BD[+] and genes/sites susceptible to epigenetic regulation. qRT-PCR and quantitative DNAM analysis were employed to validate findings in larger sample sets (35/group). Gene Set Enrichment Analysis (GSEA) demonstrated that BMP signaling and astrocyte and cerebral cortex development are significantly (FDR q < 0.25) coordinately upregulated in both SCZ and BD[+], and glutamate signaling and TGFbeta signaling are significantly coordinately upregulated in SCZ. GSEA also indicated that collagens are downregulated in right versus left brain of controls, but not in SCZ or BD[+] patients. Ingenuity Pathway Analysis predicted that TGFB2 is an upstream regulator of these genes (p = .0012). While lateralized expression of TGFB2 in controls (p = .017) is associated with a corresponding change in DNAM (p <= .023), lateralized expression and DNAM of TGFB2 are absent in SCZ or BD. Loss of brain laterality in SCZ and BD corresponds to aberrant epigenetic regulation of TGFB2 and changes in TGFbeta signaling, indicating potential avenues for disease prevention/treatment. PMID- 30468561 TI - Homogeneous Metal Nitrate Hydroxide Nanoarrays Grown on Nickel Foam for Efficient Electrocatalytic Oxygen Evolution. AB - Developing facile routes for fabricating highly efficient oxygen evolution reaction (OER) electrocatalysts is in great demand but remains a great challenge. Herein, a novel molten salt decomposition method to prepare 3D metal nitrate hydroxide (MNH, M = Ni, Co, and Cu) nanoarrays homogenously grown on different conductive substrates, especially on nickel foam (NF) for OER applications, is reported. Compared with the as-prepared CoNH/NF and CuNH/NF, NiNH/NF presents a superior electrocatalytic OER activity and stability in an alkaline solution, with a very low overpotential of only 231 mV versus a reversible hydrogen electrode to deliver a geometrical catalytic current density of 50 mA cm-2 and a low Tafel slope of 81 mV dec-1 , outperforming most reported transition metal compound catalysts. Structural investigation after the OER process reveals the morphology integrity of the nanoarrays but the formation of metal oxyhydroxide (for NiNH and CoNH) or oxide (for CuNH) as the likely real active species. These metal nitrate hydroxide non-noble metal electrocatalysts can be prepared by an economical and simple method, with enhanced intrinsic activity and long-term stability and durability, which might be new candidates for energy conversion and storage applications. PMID- 30468563 TI - Repeat kidney transplant recipients with active rejection have elevated donor derived cell-free DNA. AB - In 2015, 13% of recipients of kidney transplants in the United States were repeat transplants for prior allograft failure (1). These repeat kidney transplant recipients (RKTR) have inferior graft survival and a higher risk of rejection to that of single kidney transplant recipients (SKTR) (1, 2). In spite of these risks, transplant patients benefit from a repeat transplant compared to dialysis support (3). The use of noninvasive biomarkers of allograft injury may optimize the care of RKTR. This article is protected by copyright. All rights reserved. PMID- 30468564 TI - Callers' perceptions of their contact with a rheumatology telephone helpline. AB - BACKGROUND: Telephone helplines are useful for improving patients' access to healthcare services and reducing the need for frequent face-to-face contact with healthcare professionals. Little is known about how people who phone a helpline perceive the encounter. OBJECTIVES: The aims of the present study were to describe the variation in how callers perceive their encounter with a rheumatology telephone helpline. METHODS: The study had a descriptive, qualitative design and used a phenomenographic approach, comprising 27 semi structured telephone interviews with callers to Rheuma Direct, a rheumatology telephone helpline with specially trained nurses. The callers comprised 22 women and five men, aged 22-89 years (mean 54 years). RESULTS: The callers phoned Rheuma Direct when they had problems obtaining answers to questions on the internet or from healthcare professionals. Three descriptive categories emerged: constructive dialogue, specialized competence and applicability. The callers perceived that it was a constructive dialogue when they were able to discuss their concerns with someone, received emotional support, felt reassured and were satisfied with the information provided. They perceived specialized competence when the nurses were experienced and skilful, the advice provided complemented previously received information and when they had more knowledge after the call. The callers perceived that Rheuma Direct had applicability because it was easy to access and they could make different choices before, during and after the telephone call. CONCLUSIONS: Callers to a rheumatology telephone helpline perceived it as a valuable complement to other sources of information, and felt that it could provide them with the tools to manage their disease better, as well as future contacts with healthcare professionals. PMID- 30468565 TI - Immune Cell and Cell Cluster Phenotyping, Quantitation, and Visualization Using In Silico Multiplexed Images and Tissue Cytometry. AB - Phenotyping immune cells and cell clusters in situ, including their activation state and function, can aid in interpretation of spatial relationships within the tissue microenvironment. Immune cell phenotypes require multiple biomarkers. However, conventional microscopy setups can only image up to four biomarkers at one time. In this report, we describe and give an example of a workflow to phenotype, quantitate, and visualize greater than four biomarkers in silico utilizing multiplexed fluorescence histology and the TissueFAXS quantitative imaging system with a conventional microscopy setup. Biomarkers were conjugated to Cy3 or Cy5. Multiplexed staining was performed on formalin-fixed paraffin embedded tissue sections. We imaged the slides, inactivated the dyes, and repeated the process until all biomarkers were stained. Phenotype profiles were built based on in silico combinations of the biomarkers. We used algorithms that aligned all images to create a composite image, isolated each cell in the image, and identified biomarker positive cells in the image. The in silico phenotypes were quantitated and displayed through flow cytometry-like histograms and dot scatterplots in addition to backgating into the tissue images. The advantage of our workflow is that it provides visual verification of cell isolation and identification as well as highlight characteristics of cells and cell clusters. (c) 2018 International Society for Advancement of Cytometry. PMID- 30468566 TI - Differences between the international guideline and national guidelines for the management of diabetic foot disease. AB - AIM: No studies have investigated if national guidelines to manage diabetic foot disease differ from international guidelines. This study aimed to compare guidelines of Western Pacific nations with the International Working Group on the Diabetic Foot (IWGDF) guidance documents. METHODS: The 77 recommendations in five chapters of the 2015 IWGDF guidance documents were used as the international gold standard reference. The IWGDF national representative(s) from 12 Western Pacific nations were invited to submit their nation's diabetic foot guideline(s). Four investigators rated information in the national guidelines as 'similar', 'partially similar', 'not similar', or 'different' when compared with IWGDF recommendations. National representative(s) reviewed findings. Disagreements in ratings were discussed until consensus agreement achieved. RESULTS: Eight of twelve nations (67%) responded: Australia, China, New Zealand, Taiwan, and Thailand provided national guidelines; Singapore provided the Association of Southeast Asian Nations guidelines; and Hong Kong and Philippines advised no formal national Diabetic Foot guidelines existed. The six national guidelines included were 39% similar/partially similar, 58% not similar and 2% different compared with the IWGDF recommendations. Within individual IWGDF chapters, the six national guidelines were similar/partially similar with 53% of recommendations for the IWGDF prevention chapter, 42% for wound healing, 40% for infection, 40% for peripheral artery disease and 20% for offloading. CONCLUSIONS: National diabetic foot disease guidelines from a large and diverse region of the world showed limited similarity to recommendations made in the peak international guidelines. The differences between the recommendations may contribute to differences in national diabetic foot disease outcomes and burdens. PMID- 30468567 TI - A Biodegradable Stent with Surface Functionalization of Combined-Therapy Drugs for Colorectal Cancer. AB - In-stent restenosis caused by tumor ingrowth is a major problem for patients undergoing stent placement because conventional stents often lack sustainable antitumor capabilities. The aim of this work is to develop a silk fibroin (SF) based nanofibrous membrane that is loaded with combined-therapy drugs by using electrospinning technologies, which is further coated on a polydioxanone (PDO) stent and used for the treatment of colorectal cancer (CRC). In order to improve treatment effectiveness, a combination of therapeutic drugs, i.e., curcumin (CUR) and 5-fluorouracil (5-FU), is dissolved into SF solution and then eletrospun onto the surface of the PDO stent. The morphology, secondary structure, and in vitro drug release profiles of the membranes are characterized. The antitumor efficacy is assessed in vitro and in vivo using a human CRC cell line and normal cells, and tumor-bearing nude mice. In vitro and in vivo studies on the nanofibrous memembrane-coating demonstrate improved antitumor effects for the CUR/5-FU dual drug system which can be attributed to cell cycle arrest in the S phase in association with induced apoptosis in tumor cells by blocking signal transducer and activator of transcription3 (Stat3) and nuclear factor kappa beta (NF-kB) signaling pathways, suggesting potential in the treatment of CRC in the future. PMID- 30468568 TI - Glioblastoma with primitive neuronal component: Cytologic findings in intraoperative squash preparations. PMID- 30468569 TI - Suitability of MMGBSA for the Selection of Correct Ligand Binding Modes from Docking Results. AB - The estimation of the correct binding mode and affinity of a ligand into a target protein using computational methods is challenging. However, docking can introduce poses from which the correct binding mode could be identified using other methods. Here, we analyzed the reliability of binding energy estimation using the molecular mechanics-generalized Born surface area (MMGBSA) method without and with energy minimization to identify the likely ligand binding modes within docking results. MMGBSA workflow (1) outperformed docking in recognizing the correct binding modes of androgen receptor ligands and (2) improved the correlation coefficient of computational and experimental results of rescored docking poses to phosphodiesterase 4B. Combined with stability and atomic distance analysis, MMGBSA helped to (3) identify the binding modes and sites of metabolism of cytochrome P450 2A6 substrates. The standard deviation of estimated binding energy within one simulation was lowered by minimization in all three example cases. Minimization improved the identification of the correct binding modes of androgen receptor ligands. Although only three case studies are shown, the results are analogous and indicate that these behaviors could be generalized. Such identified binding modes could be further used, for example, with free energy perturbation methods to understand binding energetics more accurately. This article is protected by copyright. All rights reserved. PMID- 30468570 TI - Does the urinary concentration of an inhaled beta 2 agonist always reflect the inhaled dose and method of administration? PMID- 30468571 TI - Circadian rhythms - daylight saving time, health, and body clocks. AB - Each year we are reminded of our body clocks with the change in "daylight saving times". At those times we are forcefully reminded of our bodily clocks and need to plan our daily schedules more carefully. In contrast, we like to deny our clocks becoming a 24/7 type, since we are "homo sapiens" (Latin - "wise man") as Carl Linnaeus, also known after his ennoblement as Carl von Linne, described us in his biological classification. This article is protected by copyright. All rights reserved. PMID- 30468572 TI - Influence of DOAC Stop on coagulation assays in samples from patients on rivaroxaban or apixaban. AB - INTRODUCTION: Direct oral anticoagulants (DOACs) require no laboratory monitoring, but they interfere with almost all clotting tests to a varying degree, depending on the DOAC, assay principles and reagents used. DOAC Stop (Haematex Research, Sydney, Australia) has recently been shown to adsorb DOACs from spiked and patient plasmas. The aim of our work was to investigate the DOAC Stop effect on a range of haemostasis assays on plasmas collected from patients on rivaroxaban or apixaban, to see whether it removes the effect of these drugs to enable more accurate interpretation of coagulation assays. METHODS: Samples from patients anticoagulated with either rivaroxaban, apixaban or no anticoagulant were tested for prothrombin time (PT), activated partial thromboplastin time (APTT), DOAC-specific anti-Xa assay, factor VIII (one-stage and chromogenic assay) and DRVVT (low and high phospholipid) before and after sample treatment with DOAC-Stop. RESULTS: DOAC Stop significantly removed the effects of rivaroxaban and apixaban on PT, APTT, anti-Xa activity, factor VIII (one-stage and chromogenic assays), and DRVVT (low and high phospholipid reagents), and reduced the number of false positive of lupus anticoagulant interpretations in patients on rivaroxaban. There was no effect on the results from patients that were not anticoagulated. CONCLUSION: This small study suggests that it is likely that DOAC Stop can be used in laboratories to screen for coagulopathy or lupus anticoagulants in samples containing rivaroxaban or apixaban. Care should be taken in the interpretation of results since complete reversal of the anti-Xa effect did not occur in every sample. PMID- 30468574 TI - Cumyl-PEGACLONE: A comparatively safe new synthetic cannabinoid receptor agonist entering the NPS market? PMID- 30468573 TI - Circulation and genetic diversity of Feline coronavirus type I and II from clinically healthy and FIP-suspected cats in China. AB - Feline infectious peritonitis (FIP) is a fatal infectious disease of wild and domestic cats, and the occurrence of FIP is frequently reported in China. To trace the evolution of type I and II feline coronavirus in China, 115 samples of ascetic fluid from FIP-suspected cats and 54 fecal samples from clinically healthy cats were collected from veterinary hospitals in China. The presence of FCoV in the samples was detected by RT-PCR targeting the 6b gene. The results revealed that a total of 126 (74.6%, 126/169) samples were positive for FCoV: 75.7% (87/115) of the FIP-suspected samples were positive for FCoV, and 72.2% (39/54) of the clinically healthy samples were positive for FCoV. Of the 126 FCoV positive samples, 95 partial S genes were successfully sequenced. The partial S gene-based genotyping indicated that type I FCoV and type II FCoV accounted for 95.8% (91/95) and 4.2% (4/95), respectively. The partial S gene-based phylogenetic analyses showed that the 91 type I FCoV strains exhibited genetic diversity; the four type II FCoV strains exhibited a close relationship with type II FCoV strains from Taiwan. Three type I FCoV strains, HLJ/HRB/2016/10, HLJ/HRB/2016/11 and HLJ/HRB/2016/13, formed one potential new clade in the nearly complete genome-based phylogenetic trees. Further analysis revealed that FCoV infection appeared to be significantly correlated with a multi-cat environment (p < 0.01) and with age (p < 0.01). The S gene of the three type I FCoV strains identified in China, BJ/2017/27, BJ/2018/22 and XM/2018/04, exhibited a six nucleotide deletion (C4035 AGCTC4040 ). Our data provide evidence that type I and type II FCoV strains co-circulate in the FIP-affected cats in China. Type I FCoV strains exhibited high prevalence and genetic diversity in both FIP-affected cats and clinically healthy cats, and a multi-cat environment and age (<6 months) were significantly associated with FCoV infection. PMID- 30468575 TI - Silver doping induced luminescence enhancement and red shift of gold nanoclusters with aggregation-induced emission. AB - Deep understanding on the luminescence property of aggregation-induced emission (AIE) featured metal nanoclusters (NCs) is highly desired. This paper reports a systematic study on enhancing the luminescence of AIE-featured Au NCs, which is achieved by Ag doping to engineer the size/structure and aggregation states of the Au(I)-thiolate motifs in the NC shell. Moreover, by prolonging reaction time, the luminescence of the as-synthesized AuAg NCs could be further tailored from orange to red, which is also due to the variation of the Au(I)-thiolate motifs of NCs. This study can facilitate the better understanding of this AIE-featured luminescent probe and the design of other synthetic routes for this rising family of functional materials. PMID- 30468576 TI - Internal Oriented Electric Fields as a Strategy for Selectively Modifying Photochemical Reactivity. AB - Time dependent density functional theory calculations have been performed on acetophenone derivatives to explore the pos-sibility of using charged functional groups as internal electric fields, the orientation of which can be altered to change photo-chemical behavior at will. Results demonstrate that non-conjugated charged groups can significantly alter, by up to -1.44 eV, the stabilities of excited states. Specifically, a non-conjugated negatively charged group in the para-position will destabilize the npi* and stabilize the pipi* transitions, while a positively charged group will do the opposite. These electrostatic effects can be tuned by moving these substituents into the meta and ortho positions. Through use of acids and bases, these charged groups can switched on or off with pH, allowing for selective alteration of the energy levels and photochemical reactivity. Solvent effects are shown to attenuate the electric field effect with increasing dielectric permittivity; however electrostatic effects are shown remain significant even in quite polar solvents. Using charged functional groups to deliver the position-dependent electrostatic (de)stabilization effects is therefore a potential route to improving the efficiency of desirable photo-chemical processes. PMID- 30468577 TI - Optimal temperature evaluation in molecular dynamics simulations with a large time step. AB - In molecular dynamics (MD) simulations, an accurate evaluation of temperature is essential for controlling temperature as well as pressure in the isothermal isobaric conditions. According to the Tolman's equipartition theorem, all motions of all particles should share a single temperature. However, conventional temperature estimation from kinetic energy does not include Hessian terms properly and thereby the equipartition theorem is not satisfied with a large time step. In this paper, we show how to evaluate temperature the most accurately without increasing computational cost. We define two kinds of kinetic energies, evaluated at full- and half-time steps that underestimate or overestimate temperature, respectively. A combination of these two kinetic energies provides an optimal instantaneous temperature up to the third order of the time step. The method is tested for a one-dimensional harmonic oscillator, pure water molecules, a Bovine pancreatic trypsin inhibitor (BPTI) protein in water molecules, and a hydrated 1,2-dispalmitoyl-sn-phosphatidylcholine (DPPC) lipid bilayer in water molecules. In all tests, the optimal temperature estimator fulfills the equipartition theorem better than existing methods and well reproduces the usual physical properties for time steps up to and including 5 fs. PMID- 30468578 TI - Defining an Optimal Metric for the Path Collective Variables. AB - Path Collective Variables (PCVs) are a set of path-like variables that have been successfully used to investigate complex chemical and biological processes and compute their associated free energy surfaces and kinetics. Their current implementation relies on general, but at times inefficient, metrics (such as RMSD or DRMSD) to evaluate the distance between the instantaneous conformational state during the simulation and the reference coordinates defining the path. In this work, we present a new algorithm to construct optimal PCVs metrics as linear combinations of different CVs weighted through a spectral gap optimization procedure. The method was tested first on a simple model, trialanine peptide in vacuo and then on a more complex path of an anticancer inhibitor binding to its pharmacological target. We also compared the results to those obtained with other path-based algorithms. We find that not only our proposed approach is able to automatically select relevant CVs for the PCVs metric, but also that the resulting PCVs allow to reconstruct the associated free energy very efficiently. What is more, at difference with other path-based methods, our algorithm is able to explore non-locally the reaction path space. PMID- 30468579 TI - Erroneous rates and false statistical confirmations from infrequent metadynamics and other equivalent violations of the hyperdynamics paradigm. AB - Recent combinations of hyperdynamics and adaptive biasing potentials or free energy based bias potentials introduce an implicit assumption: The bias potential need only be zero on the prominent free energy barriers of interest. Herein we demonstrate that this implicit assumption is flawed. Thus, hyperdynamics in collective variables is likely to fail unless there are no hidden barriers within the initial state. Moreoever, the one-sample Kolmogorov-Smirnov test used to declare "trust" in hyperdynamics is shown unable to classify this failure. In fact, non-zero bias potential on hidden barriers emerges as a contradiction of the hypothesis that a Poisson distributed set of hyperdynamics escape times is a correctly distributed set of escape times. We demonstrate failure in the alanine dipeptide benchmark and we present an apparent failure for a protein conformation change. The standards for "trustworthy" hyperdynamics in collective variables must be raised. PMID- 30468580 TI - Hydrogel Microelectrodes for the Rapid, Reliable, and Repeatable Characterization of Lipid Membranes. AB - Model lipid bilayer membranes provide approximations of natural cellular membranes that may be formed in the laboratory to study their mechanics and interactions with the surrounding environment. A new approach for their formation is proposed here based on the self-assembly of lipid monolayers at oil-water interfaces, creating a lipid-coated hydrogel-tipped electrode that produces a stable lipid membrane on the surface when introduced to a lipid-coated aqueous droplet. Membrane formation using the hydrogel microelectrode (HME) is tested for a variety of lipids and oils. The channel-forming peptide alamethicin is added to the membrane and its functionality is verified. Finally asymmetric membranes are created using varying lipid compositions and the capacity for repeated quantification of membrane structure is demonstrated. The proposed hydrogel microelectrodes are compatible with multiple oils and lipids, simple to use, and suitable for detecting the presence of both biomolecular transporters and dissolved lipid compositions within aqueous droplets. PMID- 30468581 TI - Ultra Sensitive Micro String Resonators for Solid State Thermomechanical Analysis of Small and Large Molecules. AB - Thermal analysis plays an important role in both industrial and fundamental research and is widely used to study thermal characteristics of a variety of materials. However, despite considerable effort using different techniques, research struggles to resolve the physico-chemical nature of many thermal transitions such as amorphous relaxations or structural changes in proteins. To overcome the limitations in sensitivity of conventional techniques and to gain new insight into the thermal and mechanical properties of small and large molecule samples, we have developed an instrumental analysis technique using resonating low stress silicon nitride microstrings. With a simple sample deposition method and post process data analysis, we are able to perform rapid thermal analysis of direct instrumental triplicate samples with only pico- to nanograms of material. Utilizing this method, we present the first measurement of amorphous alpha and beta relaxation, as well as liquid crystalline transitions and decomposition of small molecule samples deposited onto a micro string resonator. Furthermore, sensitive measurements of the glass transition of polymers and yet unresolved thermal responses of proteins below their apparent denaturation temperature, which seem to include the true solid state glass transition of pure protein, are reported. Where applicable, thermal events detected with the setup were in good agreement with conventional techniques such as differential scanning calorimetry and dynamic mechanical analysis. The sensitive detection of even subtle thermal transitions highlights further possibilities and applications of resonating microstrings in instrumental physico chemical analysis. PMID- 30468582 TI - Organic Polariton Lasing and the Weak to Strong Coupling Crossover. AB - Following experimental realizations of room temperature polariton lasing with organic molecules, we present a microscopic model that allows us to explore the crossover from weak to strong matter-light coupling. We consider a nonequilibrium Dicke-Holstein model, including both strong coupling to vibrational modes and strong matter-light coupling, providing the phase diagram of this model in the thermodynamic limit. We discuss the mechanism of polariton lasing, uncovering a process of self-tuning, and identify the relation and distinction between regular dye lasers and organic polariton lasers. PMID- 30468584 TI - Quantum Annealing and Thermalization: Insights from Integrability. AB - We solve a model that has basic features that are desired for quantum annealing computations: entanglement in the ground state, controllable annealing speed, ground state energy separated by a gap during the whole evolution, and a programmable computational problem that is encoded by parameters of the Ising part of the spin Hamiltonian. Our solution enables exact nonperturbative characterization of final nonadiabatic excitations, including a scaling of their number with the annealing rate and the system size. We prove that quantum correlations can accelerate computations and, at the end of the annealing protocol, lead to the perfect Gibbs distribution of all microstates. PMID- 30468585 TI - Magnetoresistance Scaling Reveals Symmetries of the Strongly Correlated Dynamics in BaFe_{2}(As_{1-x}P_{x})_{2}. AB - The phenomenon of T-linear resistivity commonly observed in a number of strange metals has been widely seen as evidence for the breakdown of the quasiparticle picture of metals. This study shows that a recently discovered H/T scaling relationship in the magnetoresistance of the strange metal BaFe_{2}(As_{1 x}P_{x})_{2} is independent of the relative orientations of current and magnetic field. Rather, its magnitude and form depend only on the orientation of the magnetic field with respect to a single crystallographic axis: the direction perpendicular to the magnetic iron layers. This finding suggests that the magnetotransport scaling does not originate from the conventional averaging or orbital velocity of quasiparticles as they traverse a Fermi surface, but rather from dissipation arising from two-dimensional correlations. PMID- 30468586 TI - Transverse Kerker Scattering for Angstrom Localization of Nanoparticles. AB - Angstrom precision localization of a single nanoantenna is a crucial step towards advanced nanometrology, medicine, and biophysics. Here, we show that single nanoantenna displacements down to few angstroms can be resolved with sub-angstrom precision using an all-optical method. We utilize the tranverse Kerker scattering scheme where a carefully structured light beam excites a combination of multipolar modes inside a dielectric nanoantenna, which then, upon interference, scatters directionally into the far field. We spectrally tune our scheme such that it is most sensitive to the change in directional scattering per nanoantenna displacement. Finally, we experimentally show that antenna displacement down to 3 A is resolvable with a localization precision of 0.6 A. PMID- 30468583 TI - Pseudospin Symmetry and Microscopic Origin of Shape Coexistence in the ^{78}Ni Region: A Hint from Lifetime Measurements. AB - Lifetime measurements of excited states of the light N=52 isotones ^{88}Kr, ^{86}Se, and ^{84}Ge have been performed, using the recoil distance Doppler shift method and VAMOS and AGATA spectrometers for particle identification and gamma spectroscopy, respectively. The reduced electric quadrupole transition probabilities B(E2;2^{+}->0^{+}) and B(E2;4^{+}->2^{+}) were obtained for the first time for the hard-to-reach ^{84}Ge. While the B(E2;2^{+}->0^{+}) values of ^{88}Kr, ^{86}Se saturate the maximum quadrupole collectivity offered by the natural valence (3s, 2d, 1g_{7/2}, 1h_{11/2}) space of an inert ^{78}Ni core, the value obtained for ^{84}Ge largely exceeds it, suggesting that shape coexistence phenomena, previously reported at N?49, extend beyond N=50. The onset of collectivity at Z=32 is understood as due to a pseudo-SU(3) organization of the proton single-particle sequence reflecting a clear manifestation of pseudospin symmetry. It is realized that the latter provides actually reliable guidance for understanding the observed proton and neutron single particle structure in the whole medium-mass region, from Ni to Sn, pointing towards the important role of the isovector-vector rho field in shell-structure evolution. PMID- 30468587 TI - Amorphous Silicon with Extremely Low Absorption: Beating Thermal Noise in Gravitational Astronomy. AB - Amorphous silicon has ideal properties for many applications in fundamental research and industry. However, the optical absorption is often unacceptably high, particularly for gravitational-wave detection. We report a novel ion-beam deposition method for fabricating amorphous silicon with unprecedentedly low unpaired electron-spin density and optical absorption, the spin limit on absorption being surpassed for the first time. At low unpaired electron density, the absorption is no longer correlated with electron spins, but with the electronic mobility gap. Compared to standard ion-beam deposition, the absorption at 1550 nm is lower by a factor of ~100. This breakthrough shows that amorphous silicon could be exploited as an extreme performance optical coating in near infrared applications, and it represents an important proof of concept for future gravitational-wave detectors. PMID- 30468588 TI - Majorana Kramers Pairs in Higher-Order Topological Insulators. AB - We propose a tune-free scheme to realize Kramers pairs of Majorana bound states in recently discovered higher-order topological insulators (HOTIs). We show that, by bringing two hinges of a HOTI into the proximity of an s-wave superconductor, the competition between local and crossed Andreev pairing leads to the formation of Majorana Kramers pairs, when the latter pairing dominates over the former. We demonstrate that such a topological superconductivity is stabilized by moderate electron-electron interactions. The proposed setup avoids the application of a magnetic field or local voltage gates, and requires weaker interactions compared with nonhelical nanowires. PMID- 30468589 TI - Quantifying Resources in General Resource Theory with Catalysts. AB - A question that is commonly asked in all areas of physics is how a certain property of a physical system can be used to achieve useful tasks and how to quantify the amount of such a property in a meaningful way. We answer this question by showing that, in a general resource-theoretic framework that allows the use of free states as catalysts, the amount of "resources" contained in a given state, in the asymptotic scenario, is equal to the regularized relative entropy of a resource of that state. While we need to place a few assumptions on our resource-theoretical framework, it is still sufficiently general, and its special cases include quantum resource theories of entanglement, coherence, asymmetry, athermality, nonuniformity, and purity. As a by-product, our result also implies that the amount of noise one has to inject locally to erase all the entanglement contained in an entangled state is equal to the regularized relative entropy of entanglement. PMID- 30468590 TI - Climbing the Rotational Ladder to Chirality. AB - Molecular chirality is conventionally understood as space-inversion-symmetry breaking in the equilibrium structure of molecules. Less well known is that achiral molecules can be made chiral through extreme rotational excitation. Here, we theoretically demonstrate a clear strategy for generating rotationally induced chirality: An optical centrifuge rotationally excites the phosphine molecule (PH_{3}) into chiral cluster states that correspond to clockwise (R enantiomer) or anticlockwise (L enantiomer) rotation about axes almost coinciding with single P?H bonds. The application of a strong dc electric field during the centrifuge pulse favors the production of one rotating enantiomeric form over the other, creating dynamically chiral molecules with permanently oriented rotational angular momentum. This essential step toward characterizing rotationally induced chirality promises a fresh perspective on chirality as a fundamental aspect of nature. PMID- 30468591 TI - Erratum: Cellular Uptake of Elastic Nanoparticles [Phys. Rev. Lett. 107, 098101 (2011)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.107.098101. PMID- 30468592 TI - Strong Effect of Hydrogen Order on Magnetic Kitaev Interactions in H_{3}LiIr_{2}O_{6}. AB - Very recently a quantum liquid was reported to form in H_{3}LiIr_{2}O_{6}, an iridate proposed to be a close realization of the Kitaev honeycomb model. To test this assertion we perform detailed quantum chemistry calculations to determine the magnetic interactions between Ir moments. We find that weakly bond dependent ferromagnetic Kitaev exchange dominates over other couplings, but still is substantially lower than in Na_{2}IrO_{3}. This reduction is caused by the peculiar position of the interlayer species: removing hydrogen cations next to a Ir_{2}O_{2} plaquette increases the Kitaev exchange by more than a factor of 3 on the corresponding Ir?Ir link. Consequently, any lack of hydrogen order will have a drastic effect on the magnetic interactions and strongly promote spin disordering. PMID- 30468593 TI - Postselection-Loophole-Free Bell Violation with Genuine Time-Bin Entanglement. AB - Entanglement is an invaluable resource for fundamental tests of physics and the implementation of quantum information protocols such as device-independent secure communications. In particular, time-bin entanglement is widely exploited to reach these purposes both in free space and optical fiber propagation, due to the robustness and simplicity of its implementation. However, all existing realizations of time-bin entanglement suffer from an intrinsic postselection loophole, which undermines their usefulness. Here, we report the first experimental violation of Bell's inequality with "genuine" time-bin entanglement, free of the postselection loophole. We introduced a novel function of the interferometers at the two measurement stations, that operate as fast synchronized optical switches. This scheme allowed us to obtain a postselection loophole-free Bell violation of more than 9 standard deviations. Since our scheme is fully implementable using standard fiber-based components and is compatible with modern integrated photonics, our results pave the way for the distribution of genuine time-bin entanglement over long distances. PMID- 30468594 TI - Observation of Nonreciprocal Wave Propagation in a Dynamic Phononic Lattice. AB - Acoustic waves in a linear time-invariant medium are generally reciprocal; however, reciprocity can break down in a time-variant system. In this Letter, we report on an experimental demonstration of nonreciprocity in a dynamic one dimensional phononic crystal, where the local elastic properties are dependent on time. The system consists of an array of repelling magnets, and the on-site elastic potentials of the constitutive elements are modulated by an array of electromagnets. The modulation in time breaks time-reversal symmetry and opens a directional band gap in the dispersion relation. As shown by experimental and numerical results, nonreciprocal mechanical systems like the one presented here offer opportunities to create phononic diodes that can serve for rectification applications. PMID- 30468595 TI - Hund-Enhanced Electronic Compressibility in FeSe and its Correlation with T_{c}. AB - We compute the compressibility of the conduction electrons in both bulk orthorhombic FeSe and monolayer FeSe on a SrTiO_{3} substrate, including dynamical electronic correlations within slave-spin mean-field + density functional theory. Results show a zone of enhancement of the electronic compressibility crossing the interaction-doping phase diagram of these compounds in accord with previous simulations on iron pnictides and in general with the phenomenology of Hund's metals. Interestingly, at ambient pressure FeSe is found slightly away from the zone with enhanced compressibility but moved right into it with hydrostatic pressure, while in monolayer FeSe the stronger enhancement region is realized on the electron-doped side. These findings correlate positively with the enhancement of superconductivity seen in experiments, and support the possibility that Hund's induced many-body correlations boost superconductive pairing when the system is at the frontier of the normal- to Hund's metal crossover. PMID- 30468596 TI - Interferometric Evanescent Wave Excitation of a Nanoantenna for Ultrasensitive Displacement and Phase Metrology. AB - We propose a method for ultrasensitive displacement and phase measurements based on a nanoantenna illuminated with interfering evanescent waves. We show that with a proper nanoantenna design, tiny displacements and relative phase variations can be converted into changes of the scattering direction in the Fourier space. These sensitive changes stem from the strong position dependence of the orientation of the purely imaginary Poynting vector produced in the interference pattern of evanescent waves. Using strongly confined evanescent standing waves, high sensitivity is demonstrated on the nanoantenna's zero-scattering direction, which varies linearly with displacement over a wide range. With weakly confined evanescent wave interference, even higher sensitivity to tiny displacement or phase changes can be reached near a particular location. The high sensitivity of the proposed method can form the basis for many metrology applications. Furthermore, this concept demonstrates the importance of the imaginary part of the Poynting vector, a property that is related to reactive power and is often ignored in photonics. PMID- 30468597 TI - Observation of Rydberg Blockade Induced by a Single Ion. AB - We study the long-range interaction of a single ion with a highly excited ultracold Rydberg atom and report on the direct observation of an ion-induced Rydberg excitation blockade mediated over tens of micrometer distances. Our hybrid ion-atom system is directly produced from an ultracold atomic ensemble via near-threshold photoionization of a single Rydberg excitation, employing a two photon scheme that is specifically suited for generating a very low-energy ion. The ion's motion is precisely controlled by small electric fields, which allows us to analyze the blockade mechanism for a range of principal quantum numbers. Finally, we explore the capability of the ion as a high-sensitivity, single-atom based electric field sensor. The observed ion-Rydberg-atom interaction is of current interest for entanglement generation or studies of ultracold chemistry in hybrid ion-atom systems. PMID- 30468598 TI - Melting Si: Beyond Density Functional Theory. AB - The melting point of silicon in the cubic diamond phase is calculated using the random phase approximation (RPA). The RPA includes exact exchange as well as an approximate treatment of local as well as nonlocal many body correlation effects of the electrons. We predict a melting temperature of about 1735 and 1640 K without and with core polarization effects, respectively. Both values are within 3% of the experimental melting temperature of 1687 K. In comparison, the commonly used gradient approximation to density functional theory predicts a melting point that is 200 K too low, and hybrid functionals overestimate the melting point by 150 K. We correlate the predicted melting point with the energy difference between cubic diamond and the beta-tin phase of silicon, establishing that this energy difference is an important benchmark for the development of approximate functionals. The current results demonstrate that the RPA can be used to predict accurate finite temperature properties and underlines the excellent predictive properties of the RPA for condensed matter. PMID- 30468599 TI - Asymmetric Metasurfaces with High-Q Resonances Governed by Bound States in the Continuum. AB - We reveal that metasurfaces created by seemingly different lattices of (dielectric or metallic) meta-atoms with broken in-plane symmetry can support sharp high-Q resonances arising from a distortion of symmetry-protected bound states in the continuum. We develop a rigorous theory of such asymmetric periodic structures and demonstrate a link between the bound states in the continuum and Fano resonances. Our results suggest the way for smart engineering of resonances in metasurfaces for many applications in nanophotonics and metaoptics. PMID- 30468601 TI - Droplet Crystal Ground States of a Dipolar Bose Gas. AB - We show that the ground state of a dipolar Bose gas in a cylindrically symmetric harmonic trap has a rich phase diagram, including droplet crystal states in which a set of droplets arrange into a lattice pattern that breaks the rotational symmetry. An analytic model for small droplet crystals is developed and used to obtain a zero temperature phase diagram that is numerically validated. We show that in certain regimes a coherent low-density halo surrounds the droplet crystal, giving rise to a novel phase with localized and extended features. PMID- 30468600 TI - Evidence for Coexisting Shapes through Lifetime Measurements in ^{98}Zr. AB - The lifetimes of the first excited 2^{+}, 4^{+}, and 6^{+} states in ^{98}Zr were measured with the recoil-distance Doppler shift method in an experiment performed at GANIL. Excited states in ^{98}Zr were populated using the fission reaction between a 6.2 MeV/u ^{238}U beam and a ^{9}Be target. The gamma rays were detected with the EXOGAM array in correlation with the fission fragments identified by mass and atomic number in the VAMOS++ spectrometer. Our result shows a very small B(E2;2_{1}^{+}->0_{1}^{+}) value in ^{98}Zr, thereby confirming the very sudden onset of collectivity at N=60. The experimental results are compared to large-scale Monte Carlo shell model and beyond-mean-field calculations. The present results indicate the coexistence of two additional deformed shapes in this nucleus along with the spherical ground state. PMID- 30468602 TI - Particle-Laden Pipe Flows at High Volume Fractions Show Transition Without Puffs. AB - Using ultrasound imaging velocimetry, we are able to present unique insight in transitional particle-laden flows. Together with a Moody diagram of time-averaged properties, we demonstrate that the laminar-turbulent transition behavior at high volume fractions is distinct from the single-phase case and cases with low volume fractions. For low volume fractions, a sharp transition is found with the presence of turbulent puffs, similar to the single-phase case. Seemingly, particles in this regime trigger subcritical transition. For high volume fractions a smooth transition is discovered without turbulent puffs in the transition regime. For this regime, particles cause a supercritical transition. PMID- 30468603 TI - Erratum: Optomagnonic Whispering Gallery Microresonators [Phys. Rev. Lett. 117, 123605 (2016)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.117.123605. PMID- 30468604 TI - Tracking Black Hole Kicks from Gravitational-Wave Observations. AB - Coalescing binary black holes emit anisotropic gravitational radiation. This causes a net emission of linear momentum that produces a gradual acceleration of the source. As a result, the final remnant black hole acquires a characteristic velocity known as recoil velocity or gravitational kick. The symmetries of gravitational wave emission are reflected in the interactions of the gravitational wave modes emitted by the binary. In this Letter, we make use of the rich information encoded in the higher-order modes of the gravitational wave emission to infer the component of the kick along the line of sight (or radial kick). We do this by performing parameter inference on simulated signals given by numerical relativity waveforms for nonspinning binaries using numerical relativity templates of aligned-spin (nonprecessing) binary black holes. We find that for suitable sources, namely those with mass ratio q>=2 and total mass M~100 M_{?}, and for modest radial kicks of 120 km/s, the 90% credible intervals of our posterior probability distributions can exclude a zero kick at a signal-to noise ratio of 15, using a single Advanced LIGO detector working at its early sensitivity. The measurement of a nonzero radial kick component would provide the first observational signature of net transport of linear momentum by gravitational waves away from their source. PMID- 30468605 TI - Fermions at Finite Density in 2+1 Dimensions with Sign-Optimized Manifolds. AB - We present Monte Carlo calculations of the thermodynamics of the (2+1) dimensional Thirring model at finite density. We bypass the sign problem by deforming the domain of integration of the path integral into complex space in such a way as to maximize the average sign within a parameterized family of manifolds. We present results for lattice sizes up to 10^{3} and we find that at high densities and/or temperatures the chiral condensate is abruptly reduced. PMID- 30468606 TI - Antiferromagnetism Emerging in a Ferromagnet with Gain. AB - We present a theoretical mapping to show that a ferromagnet with gain (loss) is equivalent to an antiferromagnet with an equal amount of loss (gain). Our findings indicate a novel first-order ferromagnet-antiferromagnet phase transition by tuning the gain-loss parameter. As an appealing application, we demonstrate the realization as well as the manipulation of the antiferromagnetic Skyrmion, a stable topological quasiparticle not yet observed experimentally, in a chiral ferromagnetic thin film with gain. We also consider ferromagnetic bilayers with balanced gain and loss and show that the antiferromagnetic Skyrmion can be found only in cases with a broken parity-time symmetry phase. Our results pave the way for investigating the emerging antiferromagnetic spintronics and parity-time symmetric magnonics in ferromagnets. PMID- 30468607 TI - Secure Quantum Key Distribution over 421 km of Optical Fiber. AB - We present a quantum key distribution system with a 2.5 GHz repetition rate using a three-state time-bin protocol combined with a one-decoy approach. Taking advantage of superconducting single-photon detectors optimized for quantum key distribution and ultralow-loss fiber, we can distribute secret keys at a maximum distance of 421 km and obtain secret key rates of 6.5 bps over 405 km. PMID- 30468608 TI - Casimir Effect in Yang-Mills Theory in D=2+1. AB - We study, for the first time, the Casimir effect in non-Abelian gauge theory using first-principles numerical simulations. Working in two spatial dimensions at zero temperature, we find that closely spaced perfect chromoelectric conductors attract each other with a small anomalous scaling dimension. At large separation between the conductors, the attraction is exponentially suppressed by a new massive quantity, the Casimir mass, which is surprisingly different from the lowest glueball mass. The apparent emergence of the new massive scale may be a result of the backreaction of the vacuum to the presence of the plates as sufficiently close chromoelectric conductors induce, in a space between them, a smooth crossover transition to a color deconfinement phase. PMID- 30468609 TI - Emittance Preservation in an Aberration-Free Active Plasma Lens. AB - Active plasma lensing is a compact technology for strong focusing of charged particle beams, which has gained considerable interest for use in novel accelerator schemes. While providing kT/m focusing gradients, active plasma lenses can have aberrations caused by a radially nonuniform plasma temperature profile, leading to degradation of the beam quality. We present the first direct measurement of this aberration, consistent with theory, and show that it can be fully suppressed by changing from a light gas species (helium) to a heavier gas species (argon). Based on this result, we demonstrate emittance preservation for an electron beam focused by an argon-filled active plasma lens. PMID- 30468610 TI - Duplication, Collapse, and Escape of Magnetic Skyrmions Revealed Using a Systematic Saddle Point Search Method. AB - Various transitions that a magnetic Skyrmion can undergo are found in calculations using a method for climbing up the energy surface and converging onto first order saddle points. In addition to collapse and escape through a boundary, the method identifies a transition where the Skyrmion divides and forms two Skyrmions. The activation energy for this duplication process can be similar to that of collapse and escape. A tilting of the external magnetic field for a certain time interval is found to induce the duplication process in a dynamical simulation. Such a process could turn out to be an important avenue for the creation of Skyrmions in future magnetic devices. PMID- 30468611 TI - Transport Peak in the Thermal Spectral Function of N=4 Supersymmetric Yang-Mills Plasma at Intermediate Coupling. AB - We study the structure of thermal spectral function of the stress-energy tensor in N=4 supersymmetric Yang-Mills theory at intermediate 't Hooft coupling and infinite number of colors. In gauge-string duality, this analysis reduces to the study of classical bulk supergravity with higher-derivative corrections, which correspond to (inverse) coupling corrections on the gauge theory side. We extrapolate the analysis of perturbative leading-order corrections to intermediate coupling by nonperturbatively solving the equations of motion of metric fluctuations dual to the stress-energy tensor at zero spatial momentum. We observe the emergence of a separation of scales in the analytic structure of the thermal correlator associated with two types of characteristic relaxation modes. As a consequence of this separation, the associated spectral function exhibits a narrow structure in the small frequency region which controls the dynamics of transport in the theory and may be described as a transport peak typically found in perturbative, weakly interacting thermal field theories. We compare our results with generic expectations drawn from perturbation theory, where such a structure emerges as a consequence of the existence of quasiparticles. PMID- 30468612 TI - Crack Front Interaction with Self-Emitted Acoustic Waves. AB - The interaction of a propagating crack in implanted silicon with self-emitted acoustic waves results in periodic patterns on fractured surfaces. Direct measurement of the acoustic emission ahead of the fracture front shows the emergence of dominant acoustic frequency related to the crack velocity. It is shown that the surface modifications are made of roughness modulations due to periodic deviations of the crack front. A physical mechanism explaining the pattern formation is proposed, well in agreement with the observed pattern wavelengths. PMID- 30468614 TI - Nonperturbative Analysis of the Electroweak Phase Transition in the Two Higgs Doublet Model. AB - We perform a nonperturbative study of the electroweak phase transition (EWPT) in the two Higgs doublet model (2HDM) by deriving a dimensionally reduced high temperature effective theory for the model, and matching to known results for the phase diagram of the effective theory. We find regions of the parameter space where the theory exhibits a first-order phase transition. In particular, our findings are consistent with previous perturbative results suggesting that the primary signature of a first-order EWPT in the 2HDM is m_{A_{0}}>m_{H_{0}}+m_{Z}. PMID- 30468617 TI - Band Alignment and the Built-in Potential of Solids. AB - The built-in potential is of central importance to the understanding of many interfacial phenomena because it determines the band alignment at the interface. Despite its importance, its exact sign and magnitude have generally been recognized as ill-defined quantities for more than half a century. Here, we provide a common energy reference of bulk matter which leads to an unambiguous definition of the built-in potential and innate (i.e., bulk) band alignment. Further, we find that the built-in potential is explicitly determined by the bulk properties of the constituent materials when the system is in electronic equilibrium, while the interface plays a role only in the absence of equilibrium. Our quantitative theory enables a unified description of a variety of important properties of interfaces, ranging from work functions to Schottky barriers in electronic devices. PMID- 30468616 TI - Reactivity of Hydrogen-Helium and Hydrogen-Nitrogen Mixtures at High Pressures. AB - Through a series of Raman spectroscopy studies, we investigate the behavior of hydrogen-helium and hydrogen-nitrogen mixtures at high pressure across a wide range of concentrations. We find that there is no evidence of chemical association or increased miscibility of hydrogen and helium in the solid state up to pressures of 250 GPa at 300 K. In contrast, we observe the formation of concentration-dependent N_{2}-H_{2} van der Waals solids, which react to form N-H bonded compounds above 50 GPa. Through this combined study, we can demonstrate that the recently reported chemical association of H_{2}-He can be attributed to significant N_{2} contamination and subsequent formation of N_{2}-H_{2} compounds. PMID- 30468618 TI - Disentanglement Cost of Quantum States. AB - We show that the minimal rate of noise needed to catalytically erase the entanglement in a bipartite quantum state is given by the regularized relative entropy of entanglement. This offers a solution to the central open question raised in [Groisman et al., Phys. Rev. A 72, 032317 (2005)PLRAAN1050 294710.1103/PhysRevA.72.032317] and complements their main result that the minimal rate of noise needed to erase all correlations is given by the quantum mutual information. We extend our discussion to the tripartite setting where we show that an asymptotic rate of noise given by the regularized relative entropy of recovery is sufficient to catalytically transform the state to a locally recoverable version of the state. PMID- 30468620 TI - Quantum Error Correction Decoheres Noise. AB - Typical studies of quantum error correction assume probabilistic Pauli noise, largely because it is relatively easy to analyze and simulate. Consequently, the effective logical noise due to physically realistic coherent errors is relatively unknown. Here, we prove that encoding a system in a stabilizer code and measuring error syndromes decoheres errors, that is, causes coherent errors to converge toward probabilistic Pauli errors, even when no recovery operations are applied. Two practical consequences are that the error rate in a logical circuit is well quantified by the average gate fidelity at the logical level and that essentially optimal recovery operators can be determined by independently optimizing the logical fidelity of the effective noise per syndrome. PMID- 30468619 TI - Unique Gap Structure and Symmetry of the Charge Density Wave in Single-Layer VSe_{2}. AB - Single layers of transition metal dichalcogenides (TMDCs) are excellent candidates for electronic applications beyond the graphene platform; many of them exhibit novel properties including charge density waves (CDWs) and magnetic ordering. CDWs in these single layers are generally a planar projection of the corresponding bulk CDWs because of the quasi-two-dimensional nature of TMDCs; a different CDW symmetry is unexpected. We report herein the successful creation of pristine single-layer VSe_{2}, which shows a (sqrt[7]*sqrt[3]) CDW in contrast to the (4*4) CDW for the layers in bulk VSe_{2}. Angle-resolved photoemission spectroscopy from the single layer shows a sizable (sqrt[7]*sqrt[3]) CDW gap of ~100 meV at the zone boundary, a 220 K CDW transition temperature twice the bulk value, and no ferromagnetic exchange splitting as predicted by theory. This robust CDW with an exotic broken symmetry as the ground state is explained via a first-principles analysis. The results illustrate a unique CDW phenomenon in the two-dimensional limit. PMID- 30468621 TI - Three-Dimensional Chiral Lattice Fermion in Floquet Systems. AB - We show that the Nielsen-Ninomiya no-go theorem still holds on a Floquet lattice: there is an equal number of right-handed and left-handed Weyl points in a three dimensional Floquet lattice. However, in the adiabatic limit, where the time evolution of the low-energy subspace is decoupled from the high-energy subspace, we show that the bulk dynamics in the low-energy subspace can be described by Floquet bands with extra left- or right-handed Weyl points, despite the no-go theorem. Assuming adiabatic evolution of two bands, we show that the difference of the number of right-handed and left-handed Weyl points equals twice the winding number of the adiabatic Floquet operator over the Brillouin zone. Based on these findings, we propose a realization of purely left- or right-handed Weyl particles on a 3D lattice using a Hamiltonian obtained through dimensional reduction of a four-dimensional quantum Hall system. We argue that the breakdown of the adiabatic approximation on the surface facilitates unusual closed orbits of wave packets in an applied magnetic field, which traverse alternatively through the low-energy and high-energy sector of the spectrum. PMID- 30468615 TI - Tuning the Coupling of an Individual Magnetic Impurity to a Superconductor: Quantum Phase Transition and Transport. AB - The exchange scattering at magnetic adsorbates on superconductors gives rise to Yu-Shiba-Rusinov (YSR) bound states. Depending on the strength of the exchange coupling, the magnetic moment perturbs the Cooper pair condensate only weakly, resulting in a free-spin ground state, or binds a quasiparticle in its vicinity, leading to a (partially) screened spin state. Here, we use the flexibility of Fe porphin (FeP) molecules adsorbed on a Pb(111) surface to reversibly and continuously tune between these distinct ground states. We find that the FeP moment is screened in the pristine adsorption state. Approaching the tip of a scanning tunneling microscope, we exert a sufficiently strong attractive force to tune the molecule through the quantum phase transition into the free-spin state. We ascertain and characterize the transition by investigating the transport processes as function of tip-molecule distance, exciting the YSR states by single electron tunneling as well as (multiple) Andreev reflections. PMID- 30468622 TI - Effect of prior chronic aerobic exercise on overload-induced skeletal muscle hypertrophy in mice. AB - This study aimed to examine how regular aerobic training can affect the muscle hypertrophy induced by overloading. Male C57BL/6J mice were randomly divided into three groups: rest group, low-intensity aerobic exercise group, and high intensity aerobic exercise group. Mice in the exercise groups were assigned to run at a speed of 10 m/min (low-intensity) or 25 m/min (high-intensity) for 30 min/day, five days/week, for four weeks. Then, the right hind leg gastrocnemius muscles were surgically removed to overload the plantaris and soleus muscles, while the left hind leg was subjected to a sham-operation. Both the plantaris and soleus muscles grew larger in the overloaded legs than those in the sham-operated legs. Muscle growth increased in the plantaris muscles in the low-intensity exercise group compared to that in the rest or high-intensity exercise groups at one and two weeks after overloading. This enhancement was not observed in the soleus muscles. Consistently, we observed changes in the expression of proteins involved in anabolic intracellular signaling, including Akt, mechanistic target of rapamycin (mTOR), and p70S6K, in the plantaris muscles. Our data showed for the first time that chronic low-intensity aerobic exercise precipitates overload induced muscle growth. PMID- 30468623 TI - Retrospective Self-reported Dietary Supplement Use by Australian Military Personnel during Deployment to Iraq and Afghanistan: Results from the Middle East Area of Operations Health Study. AB - The use of dietary supplements is popular among military personnel. There is a lack of understanding about the changes in use during deployment and specific factors associated with such changes. This study retrospectively examined the changes in the pattern of supplement use among Australian veterans during their deployment to Iraq (n = 8,848) and Afghanistan (n = 6,507) between 2001 and 2009 and identified work-related circumstances that were associated with these changes. The frequency of use of supplements at present and during deployment was assessed. Multiple logistic regression analysis was used to compare the use of supplements between different groups and between those with different deployment experiences. The study found that overall use of supplements was highest on deployment to Afghanistan (27.8%) compared to in Iraq (22.0%, p<0.001) or post deployment (current use 21.2%, p<0.001). Personnel who were younger or at the rank of non-commissioned officer were more likely to use dietary supplements. Men were more likely to use body-building supplements while women more often used weight-loss supplements. Those veterans who did not report using supplements regularly on deployment were far less likely to use them subsequently. Combat exposure, mixed duty cycles and working long hours during deployment were associated with higher supplement use. The findings confirmed that supplement use in the military reflects the unique demands and stressors of defence service. PMID- 30468624 TI - Corrigendum: Ameliorating effects of Sporidiobolus pararoseus extract on dyslipidemia in mice with high fat diet induced obesity. PMID- 30468625 TI - What's in a name? On fibroblast phenotype and nomenclature. AB - Fibroblasts have long been recognized as important stromal cells, playing key roles in synthesizing and maintaining the extracellular matrix, but historically were treated as a relatively uniform cell type. Studies in recent years have revealed a surprising level of heterogeneity of fibroblasts across tissues, and even within organs such as the skin and heart. This heterogeneity may have functional consequences, including during stress and disease. While the field has moved forward quickly to begin to address the scientific import of this heterogeneity, the descriptive language used for these cells has not kept pace, particularly when considering the phenotype changes that occur as fibroblasts convert to myofibroblasts in response to injury. We discuss here the nature and sources of the heterogeneity of fibroblasts, and review how our understanding of the complexity of the fibroblast to myofibroblast phenotype conversion has changed with increasing scrutiny. We propose that the time is opportune to re evaluate how we name and describe these cells, particularly as they transition to myofibroblasts through discrete stages. A standardized nomenclature is essential to address the confusion that currently exists in the literature as to the usage of terms like myofibroblast, and the description of fibroblast phenotype changes in disease. PMID- 30468626 TI - The effect of dominant first dorsal interosseous fatigue on the force production of a contralateral homologous and heterologous muscle. AB - Crossover and non-local muscle fatigue (NLMF) has generally focused on large muscle groups. It is unclear whether fatigue of a small muscle can result in NLMF of a larger muscle. The purpose of the present study was to examine the effect of small muscle (first dorsal interosseous; FDI) fatigue on the force and activation of contralateral homologous and larger heterologous muscles (biceps brachii, BB). Fifteen right-handed, male subjects performed three pre-test index finger abduction or elbow flexion maximum voluntary isometric contractions (MVICs) on the non-dominant side. Subsequently, they performed two 100s index finger abduction MVICs on the dominant side (experimental [fatigue] group) or rested for 5 minutes (control group). Afterwards, a single MVIC and a 12 repetition MVIC fatiguing protocol were completed with index finger abduction or elbow flexion on the non-dominant side. Force and electromyography (EMG) were measured from both sides. The force and EMG (median frequency:MDF) of non-exercised index finger abductors (IFA)/FDI and elbow flexors (EF)/BB significantly decreased after the fatiguing protocol. Compared with the control condition, the non-exercised IFA (12.5% and 5.7%) had significantly greater force and MDF fatigue indexes than the EF (5.2% and 1.7%). There were no significant force differences with the single MVIC test between conditions. The small muscle fatiguing protocol produced NLMF effects on both contralateral homologous and larger heterologous muscles, with the force decrements greater with the homologous muscle. PMID- 30468627 TI - Pediatric Central Nervous System Imaging of Nonaccidental Trauma: Beyond Subdural Hematomas. AB - Infants and children under 2 years of age are at greatest risk for devastating neurologic complications following nonaccidental trauma. While a subdural hematoma (SDH) is the most common finding and is often enough to raise suspicion for abuse, no single injury is pathognomonic for abusive head trauma (AHT). Rather, the combination of imaging and physical findings and the clinical presentation help confirm the diagnosis of AHT. Familiarity with the spectrum of findings and proper identification of the imaging abnormalities is important for the radiologist to facilitate treatment and removal of the patient from the abusive environment. Injury is usually a result of shaking, which includes hyperflexion, hyperextension, and rotational forces, and less commonly impact trauma or a combination of both. Key anatomic features unique to the infant's head, neck, and spine and associated biomechanical forces are responsible for entities such as hypoxic ischemic injury, bridging vein thrombosis, SDH, parenchymal lacerations, and spinal and retinal injuries. Although the association of subpial hemorrhage with AHT has not been investigated, it warrants attention in very young infants who endure accidental or inflicted trauma. A combination of CT of the head and MRI of the brain and cervical spine aids in the accurate diagnosis, appropriate management, and subsequent protection of these patients. (c)RSNA, 2018. PMID- 30468628 TI - New therapeutics based on emerging concepts in pulmonary fibrosis. AB - INTRODUCTION: Fibrosis is an irreversible pathological endpoint in many chronic diseases, including pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal condition characterized by (myo)fibroblast proliferation and transformation in the lung, expansion of the extracellular matrix, and extensive remodeling of the lung parenchyma. Recent evidence indicates that IPF prevalence and mortality rates are growing in the United States and elsewhere. Despite decades of research on the pathogenic mechanisms of pulmonary fibrosis, few therapeutics have succeeded in the clinic, and they have failed to improve IPF patient survival. Areas covered: Based on a literature search and our own results, we discuss the key cellular and molecular responses that contribute to (myo)fibroblast actions and pulmonary fibrosis pathogenesis; this includes signaling pathways in various cells that aberrantly and persistently activate (myo)fibroblasts in fibrotic lesions and promote scar tissue formation in the lung. Expert opinion: Lessons learned from recent failures and successes with new therapeutics point toward approaches that can target multiple pro-fibrotic processes in IPF. Advances in preclinical modeling and single-cell genomics will also accelerate novel discoveries for effective treatment of IPF. PMID- 30468629 TI - Transcatheter Aortic Valve Replacement: Alternative Access beyond the Femoral Arterial Approach. AB - Aortic stenosis is the most prevalent valvular cardiovascular disease affecting the population over the age of 65 years. Transcatheter aortic valve replacement (TAVR) was developed as a minimally invasive surgical intervention to treat aortic stenosis in patients at high risk for surgical complications. Although the most commonly used approach for placement of a transcatheter aortic valve is in retrograde fashion via a transfemoral approach, narrowed luminal diameters, extensive atherosclerotic disease, or significant tortuosity may limit use of this route. In these patients, alternative methods including subclavian, transaortic, and transapical approaches should be considered. An understanding of these access routes and their respective indications and contraindications allows the radiologist to provide additional preprocedure measurements and images to help guide placement of the valve. (c)RSNA, 2018. PMID- 30468631 TI - Comment on Jiang Y, Zhang J, Xi B, et al. [Degradation of toluene-2,4-diamine by persulphate. Environ Tech. 2015;36:1441-1447]. PMID- 30468630 TI - Calibration and validation of an activated sludge model for membrane bioreactor wastewater treatment plants. AB - A mathematical model to simulate the biological processes occurring in a membrane bioreactor (MBR) is presented. The model accounts for different MBR technical features by introducing specific permeability parameters for the applied membrane system. The model accounts for the heterotrophic storage process and the formation of soluble microbial products. The introduction of an inhibition coefficient influencing the anoxic kinetics enables the model to simulate the particular operating conditions of the plant, such as a high or low dissolved oxygen concentration in the denitrification tank. The model was applied at the MBR wastewater treatment plant of Vila Nova do Ceira (Portugal) which uses a classic pre-denitrification cycle. Data for calibration and validation were sampled at the same wastewater treatment plant. Calibration was achieved by varying the kinetic parameters of the model to match the simulation results to the experimental data. The values of the kinetic parameters were similar to those found in the literature. The validation was performed by two different methodologies to analyse the model response to diverse operating conditions, and to evaluate the resilience of the MBR. Calibration and validation results were evaluated with mean average error, root mean square error and fractional mean bias as performance indexes. In most cases, these indexes confirmed the high accuracy of the model. Overall, the results of the calibration and validation steps enriched the proposed model by providing an effective biological description of the processes characterizing the MBR. Thus, the model is a reliable tool for the management, and designing of MBR. PMID- 30468632 TI - Nigral injection of 6-hydroxydopamine induces changes in spatial arrangement of striatal neuron and glial cells. AB - In Parkinson's disease, nigral dopamine neurons are lost and the structure of the striatum is progressively degraded. These events lead to a substantial neuronal loss in the striatum, changing spatial pattern of the neurons and glial cells, and associated cellular connections. Therefore, the aim of this study was to develop a new insight into whether the Parkinson's disease causes a change in the spatial arrangement of the neurons and glial cells in the striatum. Nigral injection of 6-hydroxydopamine led to a significant reduction in the total number of the neurons, an increase in the number of striatal glial cells, and disruption in the spatial arrangement of glial and neuronal cells in the Parkinson's disease induced group, compared to the control group. The data support the idea that in Parkinson's disease, the function of the striatum is disturbed by both the loss of neurons and an increase in the number of glial cells, culminating in the disordered spatial distribution of these cells. PMID- 30468633 TI - Demethoxycurcumin ameliorates rotenone-induced toxicity in rats. AB - Rotenone, an environmental toxin, is used to induce neurodegeneration in both the cellular and animal model of Parkinson's disease. Demethoxycurcumin (DMC), derivative of curcumin has been reported to have antioxidant and anti inflammatory characteristics in in vitro and in vivo PD conditions. The present study was aimed to evaluate the efficacy of DMC in the management of neurodegeneration in PD. Male Wistar rats were radomized and divided into control, rotenone, DMC +rotenone and rotenone alone treated animals. Pre treatment with DMC one hour prior to the rotenone injection, attenuated the motor and non-motor deficits. Western blot analysis indicated that the administration of DMC to PD rats eased the protein expression of dopaminergic and apoptotic indices. These findings showed that DMC effects on ameliorating the PD symptoms induced by rotenone might be associated with the neuroprotective and antioxidant effects of this compound. PMID- 30468634 TI - Antiapoptotic role of Agaricus blazei extract in rodent model of Parkinson's disease. AB - Rotenone is a pesticide that has been shown to induce the pathological symptoms of Parkinson's disease (PD) in both cellular and animal models. In this study, we investigated the protective effect of Agaricus blazei extract on rotenone-induced dopaminergic degeneration and apoptosis in mice model. A. blazei extract blocked the rotenone-mediated diminution of dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT 2) expression and the downregulation of Bcl-2 and the upregulation of Bax, caspases-3, -6, -8 and caspase-9. Present data suggest that A. blazei extract plays a crucial role in regulation of proteins expression such as DAT and VMAT2 and pro-apoptotic and anti-apoptotic in Parkinsonism. In conclusion, the present study shows that A. blazei extract act as potential neuroprotective agent in the management of Parkinsonism. PMID- 30468635 TI - Fisetin protects against rotenone-induced neurotoxicity through signaling pathway. AB - The present study was designed to evaluate the protective effect of fisetin against rotenone induced toxicity in SH-SY5Y neuroblastoma cellular model of Parkinson's disease (PD). SH-SY5Y neuroblastoma cells were treated with fisetin (5uM) 2 hr prior to being treated with rotenone (100 nM). Following the exposure of SH-SY5Y cells to rotenone, there was marked decreased cell viability, increased oxidative stress, activation of caspase-3 and apoptosis (dual staining, expressions of pro-apoptotic and anti-apoptotic indices). However pretreatment with fisetin significantly and dose-dependently alleviated rotenone induced cytotoxicity and oxidative stress in SH-SY5Y cells. Moreover, fisetin attenuated rotenone induced toxicity by down-regulating Bax, caspases-3 protein expression and up-regulating protein expression of Bcl-2, p38/JNK-MAPK and PI3K, Akt, GSK 3beta pathways. Collectively, these results suggest that fisetin could prevent the rotenone-induced neurotoxicity via various signaling pathways. PMID- 30468636 TI - Three-dimensional printing as an educational tool in colorectal surgery. AB - 3D printing is a rapidly advancing technology which represents a significant technological achievement that could be useful in a variety of biomedical applications. In the field of surgery, 3D printing is envisioned as a significant step in the areas of surgical planning, education and training. The 3D printed models are considered as high quality and efficient educational tools. In this paper A randomized controlled trial was performed to compare the educational role of 3D printed models with that of the conventional MRI films in the training of surgical residents. Statistical analysis revealed that Resident surgeons who studied only the anal fistula printed models, (Group B) achieved a higher overall score in the fistula assessment test (87,2 (82,6-91,6)) compared to resident surgeons (Group A) who studied only MRI images (74,85 (66,8-73,5)). 3D printing technology can lead to improvement in preoperative planning accuracy, followed by efficient optimization of the treatment strategy. It is believed that 3D printing technology could be used in the case of various other surgical applications, thus representing a novel tool for surgical education. PMID- 30468637 TI - Diagnosis of TB: From conventional to modern molecular protocols. AB - Tuberculosis (TB) is an infectious disease caused by different strains of Mycobacterium tuberculosis complex. TB is a curable infection if diagnosed correctly and timely. Late diagnosis and improper treatment may lead to relapse or its escalation to MDR / XDR-TB. TB with HIV co-infection is difficult to diagnose by conventional set-up. Also, detection of child TB and extrapulmonary TB has its own set of problems and is not straightforward to diagnose. The increasing complexity of TB due to the advent of new circulating strains and invasion to the regions where it was non-existent or thought to be eradicated is putting a severe strain on the health management services and making it an unmanageable pandemic. This increasing complexity has led to the spurt in the development of TB diagnostics platforms. This review focuses on the new emerging technologies that have changed the diagnostics landscape. PMID- 30468638 TI - Beta2-adrenergic receptor variants in children and adolescents with bronchial asthma. AB - The region encoding the N-terminal of human beta2-adrenergic receptor gene (ADRB2) shows several polymorphisms. To this end, we studied change in susceptibility and/or response to therapy in 175 asthmatic children and adolescents by the two most common variants of the ADRB2 gene namely, rs1042713 (Gly16Arg) and rs1042714 (Gln27Glu). Although, the variants did not correlate with risk of development nor with the severity of the asthma, Gly16/Glu27 haplotype in homozygous individuals conferred protection against development of asthma and was associated with a lower frequency of dyspnea and sputum production. In contrast, the Arg16/Gln27 haplotype was associated with a better response to treatment. These findings show that the risk of development of asthma or response to treatment can be, respectively, deciphered by the detection of both rs1042713 and rs1042714 variants in ADRB2 gene. PMID- 30468639 TI - Characterization of embryonic cells obtained from multifetal reduction. AB - The multifetal reduction (MFR) procedure is usually reserved for high-order multiple pregnancies, and aspirated tissues are typically discarded. In this study, cells obtained from MFR tissue (termed multifetal reduction embryonic cells (MFR-ECs)), were characterized in vitro by genotypic and phenotypic analyses and tested in vivo by injection under the kidney capsule of nude mice. MFR-ECs were highly proliferative in culture and showed a normal karyotype by microarray CGH. Immunohistochemical analysis at day zero showed positive focal staining for desmin, S-100 protein, synaptophysin and chromogranin. Histology examination showed a mixture of cells from the three germ layers at different stages of differentiation. Markers of these stages included important developmental transcription factors, such as beta three-tubulin (ectoderm), paired box 6 (ectoderm) and alpha-smooth muscle actin (mesoderm). Quantitative polymerase chain reaction (qPCR) showed down-regulation of the mRNAs of cancer related genes such as TP53. In vivo transplantation in nude mice showed a typical hyaline cartilage plate and no teratoma formation. Thus, MFR-ECs represent a rich, unique source for studying stem cell development, embryogenesis and cell differentiation. PMID- 30468640 TI - Antimicrobial activity of Bacillus subtilis silver nanoparticles. AB - We tested the hypothesis that silver nanoparticles (BsAgNPs) made by Bacillus subtilis subsp. inaquosorum exhibit antibacterial and antifungal activities. The bacteria formed nanoparticles in UV-visible spectra with the peak around 430 nanometer detected by surface plasmon resonance and Lambdamax. The FTIR spectra, SEM and XRD revealed the involvement of interaction of biological moieties in the formation of crystalline cuboidal nanoparticles that were had an average size of 10-20 nm. The particles exerted dose dependent antibacterial and antifungal activities and high dose equivalent to standard antibiotics. Minimum inhibitory concentration, minimum bactericidal and fungicidal concentrations were in the range from 3.1-25 microgram/ml and 6.3-50 microgram/ml, respectively. BsAgNPs significantly inhibited the growth of multiple strains including multidrug resistant (MDR) bacteria. Moreover, the combination of BsAgNPs and antibiotics showed synergistic inhibition of MDR strains. These data show that BsAgNPs have a great potential in the treatment of MDR bacteria without or with standard antibiotics. PMID- 30468641 TI - Beta1-adrenergic receptor antibodies in children with dilated cardiomyopathy. AB - Autoantibodies to beta-1 adrenergic receptor have been reported in adult patients with dilated cardiomyopathy (DCM). Removal of these antibodies has a positive hemodynamic effect. Our aim was to investigate whether these antibodies are present in children with DCM and explore the potential hemodynamic benefit of immunoadsorption (IA). Seventeen children with DCM were tested for these antibodies. The etiology of DCM was genetic (n=5), myocarditis (n=4), DCM and congenital heart block (n=3), DCM associated to maternal lupus (n=1), DCM and Wolff Parkinson White Syndrome (n=1), and idiopathic (n=3). All patients evidenced ventricular dysfunction. Antibody testing was positive in 8 patients, 7 received IA. Three patients with high titers had a poor clinical outcome and needed transplantation. Two patients with low titers exhibited a full recovery of heart function. One patient with multiple myocarditis episodes was treated with immunoglobulin IgG and IA ; after 5 years this patient presented a LVEF of 40 percent. Beta-1 adrenergic receptors autoantibodies are present in children with DCM. Immunoadsorption therapy may help improve heart failure in this context. PMID- 30468642 TI - Curcumin prevents cigarette smoke extract induced cognitive impairment. AB - Curcumin is a major phytochemical constituent in Curcuma longa, an herbaceous perennial plant of Zingiberaceae family, which exhibits anti-oxidant, anti inflammatory and immunomodulatory properties. Here, we studied the therapeutic action of curcumin against CSE induced cognitive impairment in zebrafish. Montelukast (20 mg/kg), a cysteinyl-leukotriene receptor blocker was used as a reference drug. CSE exposure induced biochemical changes revealed that raise the brain acetylcholinesterase activity and lipid peroxidative products; and decrease the reduced glutathione levels in brain samples. Curcumin also protected against CSE induced neurocognitive impairment. These data suggest that curcumin can serve as a phytochemical constituent against CSE induced neurocognitive impairment. PMID- 30468643 TI - Role of flavonoid troxerutin on blood pressure, oxidative stress and regulation of lipid metabolism. AB - The objective of the present study was to investigate the effects of troxerutin (TX) on Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME) induced hypertension in male albino Wistar rats. L-NAME (40mg/kg body weight (bw)) administration caused a sustained increase in systolic blood pressure (SBP), levels of thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH), tissue lipids (liver and kidney) such as total cholesterol (TC), triglycerides (TG), free fatty acids (FFA), and significant decrease in the activities of enzymatic antioxidants, phospholipids (PL) and levels of non enzymatic antioxidants such as reduced glutathione (GSH), vitamin C and vitamin E. To assess the toxicity if any of TX treatment, hepatic and renal function markers were measured. TX supplementation throughout the experimental period significantly brings back all the above parameters. Among the three doses (25, 50, and 100 mg/kg) of TX, 100 mg/kg dosage exerts optimum protection against L Name induced hypertension. These results suggest that TX has enough potential to attenuate hypertension, oxidative stress and dyslipidemia in L-NAME induced hypertensive rats. PMID- 30468644 TI - Fibroblast activation protein in liver fibrosis. AB - Fibroblast activation protein (FAP) belongs to the dipeptidyl peptidase IV (DPP4; CD26) gene family. Other related genes in this family of enzyme include DPP4, 8 and 9. The FAP serine protease has the rare property of both dipeptidyl peptidase and endopeptidase activities capable of cleaving the post-proline bond at two or more residues from the N-terminus. FAP is involved in a variety of biological processes but its expression in healthy tissues is low. In contrast, FAP is significantly elevated in pathological conditions such as at sites of tissue remodelling and repair. Its differential pattern of expression in diseases supports the emerging concept for FAP as a potential disease biomarker as well as a useful therapeutic target for drug intervention. This review summarizes the current knowledge of FAP, particularly its diagnostic and pathological significance in liver fibrosis. PMID- 30468645 TI - Loss of balance in normal GPCR-mediated cell trafficking. AB - G protein-coupled receptors (GPCRs) form a most diverse family of integral membrane proteins that mediate homeostatic and pathological processes, most notably by orchestrating cell distribution throughout the body, their infiltration, and time of presence in inflamed tissues. Here we discuss loss-of orientation-effects in GPCR-mediated cell trafficking and migration and their impact on the phenotype of autoimmune diseases. In this context, we provide a systemic and integrative view of the contribution of abnormal GPCR expression as well as the levels of natural ligands and functional autoantibodies to the phenotype of autoimmune diseases. Currently, several studies propose that functional autoantibodies (including those targeting GPCRs) constitute an exclusively pathogenic or pathognomonic phenomenon. Here we reinforce the need of revising this point of view, and suggest that functional autoantibodies primary play a role in normal human physiology, while dysregulation of their functions causes autoimmune disease. Because patients with autoimmune diseases still suffer from severe morbidity and mortality rates, we consider expanding our knowledge on (patho)physiological roles of GPCR as a prerequisite for the development of novel specific therapeutic modalities. PMID- 30468646 TI - Graves' disease in clinical perspective. AB - Graves' disease (GD) is the most common cause for hyperthyroidism in iodine replete areas. The disease is caused by the appearance of stimulating TSH receptor autoantibodies (TRAb) leading to hyperthyroidism. Blocking and neutral TRAb have, however, also been described. TRAb can be measured either by competition assays, assays using a bridge technology or bioassays (for discriminating stimulating vs. blocking antibodies). Therapy of GD with antithyroid drugs belonging to the group of thionamides is the first-line treatment to be continued for 12 up to 18 months. In case of relapse, thyroid ablative therapy including radioiodine therapy or thyroidectomy, respectively, should be performed. Risk factors for relapse are a large thyroid volume, persistence of high TRAb serum titer, smoking, and others. Within this review, we will give insights into the pathogenesis of GD including the pathogenesis of Graves' ophthalmopathy. We also describe recent developments of TRAb measurement, which is used for the diagnosis of GD as well as for outcome prediction. Finally, we discuss therapy aspects as well as the important issue of GD and pregnancy. PMID- 30468647 TI - Functional autoantibody diseases: Basics and treatment related to cardiomyopathies. AB - In the 1970s, autoantibodies directed against G-protein-coupled receptors (GPCR, GPCR-AAB) were discovered. After receptor binding, GPCR-AAB trigger uncontrolled receptor mediated signal cascades, thus producing pathologies. Diseases associated with such functionally active autoantibody type (functional autoantibodies) can be called "functional autoantibody diseases". Here we focus exclusively on GPCR-AAB directed against the GPCR's extracellular loops. The GPCR's role in the pathogenesis and progression is accepted in idiopathic dilated cardiomyopathy and is increasingly considered in diseases such as Chagas' cardiomyopathy, peripartum cardiomyopathy, hypertension, diabetes mellitus and scleroderma and even dementia, complex regional pain syndrome and postural orthostatic tachycardia syndrome. We briefly summarize the mechanistic background of GPCR-AAB induced pathologies, mainly focused on autoantibodies targeting the beta1-adrenergic and muscarinic 2 receptors, due to their importance for cardiomyopathies. Furthermore, treatment strategies for "functional autoantibody diseases", such as for GPCR-AAB removal (therapeutic plasma exchange, immunoadsorption) and in vivo GPCR-AAB attack (intravenous IgG treatment, B-cell depletion, GPCR-AAB in vivo binding and neutralization) are critically reflected with respect to their patient benefits focused on but not exclusive to patients with dilated cardiomyopathy. PMID- 30468649 TI - What does "NO-Synthase" stand for ? AB - Mammalian NO-Synthases (NOSs) are the enzymatic sources of Nitric Oxide (NO degrees ), a paradigmatic gasotransmitter involved in many (patho)-physiological processes. The increasing number of available genomes led to the identification of hundreds of new NOS proteins throughout the kingdoms of life, calling for a global investigation of this family of proteins. These new NOSs are commonly believed to share the same structure, functioning and role as mammalian NOSs. The scope of this article is to highlight the singularity of these NOSs and to describe their complex structural and functional diversity. NOS appears as a unique enzymatic machinery that exhibits a complex Structure - Activity - Function relationship. Its sophisticated redox mechanism and enzymatic regulation, coupled to the vast biological chemistry of reactive nitrogen species, leads to a specific cross-talk between NOS catalysis and its biological environment that implies a complex evolution of NOS function. This paper addresses the relationship between structure, function and evolution of NOS proteins using three NOS model families and advocates for an integrative and interdisciplinary approach that combines modelling studies, structural characterization, and in vitro/in vivo functional investigations. PMID- 30468648 TI - Co-signaling receptors regulate T-cell plasticity and immune tolerance. AB - We took an experimental database mining analysis to determine the expression of 28 co-signaling receptors in 32 human tissues in physiological/pathological conditions. We made the following significant findings: 1) co-signaling receptors are differentially expressed in tissues; 2) heart, trachea, kidney, mammary gland and muscle express co-signaling receptors that mediate CD4+T cell functions such as priming, differentiation, effector, and memory; 3) urinary tumor, germ cell tumor, leukemia and chondrosarcoma express high levels of co-signaling receptors for T cell activation; 4) expression of inflammasome components are correlated with the expression of co-signaling receptors; 5) CD40, SLAM, CD80 are differentially expressed in leukocytes from patients with trauma, bacterial infections, polarized macrophages and in activated endothelial cells; 6) forward and reverse signaling of 50% co-inhibition receptors are upregulated in endothelial cells during inflammation; and 7) STAT1 deficiency in T cells upregulates MHC class II and co-stimulation receptors. Our results have provided novel insights into co-signaling receptors as physiological regulators and potentiate identification of new therapeutic targets for the treatment of sterile inflammatory disorders. PMID- 30468650 TI - Fungal lipids: biosynthesis and signalling during plant-pathogen interaction. AB - Lipids occur in fungi as major constituents of the membrane systems and minor component in the cell wall; they can store energy in the lipid bodies and, in some cases, they can act as intra-extracellular signals. Fungi contain a various set of lipids, including fatty acids, oxylipins, sphingolipids, phospholipids, glycolipids, and sterols. Current studies in lipids suggest their additional role in cell signalling; for instance, host-pathogen exchange lipid signals at the interface during their interaction. This review aims examining those fungal lipid classes involved in the pathogenic interaction with the host plants. The lipid signals may trigger host immune response as well as functioning as virulence factors altering the lipid homeostasis of the host cells. PMID- 30468651 TI - Fructose at the crossroads of the metabolic syndrome and obesity epidemics. AB - In this review, we highlight the specific metabolic effects of fructose consumption that are involved in the development of metabolic syndrome non alcoholic fatty liver disease and its association with obesity. The specifics effects of fructose on the liver are particularly germane to the development of a vicious cycle that starts with liver steatosis driving insulin resistance. These effects include 1) increased de novo lipogenesis, 2) increased liver fat, 3) dyslipidemia 4) increased uric acid production which feeds back on increased fructose metabolism and, 5) increased methylglyoxal and Maillard reaction that may affect adenosyl-monophosphate-dependent kinase Fructose increases cortisol activation especially in visceral fat. The hormones involved in satiety control are affected by fructose consumption. Fructose derived advance glycation end products may also induce a state of inflammation by engaging its receptor, RAGE. Directionality for the effect of fructose on metabolic syndrome is becoming clear: fructose drives hepatic fat, which in turn drives insulin resistance. There is an urgent need for more clinical and educational interventions to regulate/reduce fructose consumption in our population, especially in children and adolescents. PMID- 30468652 TI - Thyroid hormone binding motifs and iodination pattern of thyroglobulin. AB - A phylogenetically conserved 5-residue thyroid hormone (TH)- binding motif was originally found in a few TH plasma carriers and, more recently, in all known plasma and cell-associated proteins interacting with TH as well as in proteins involved in iodide uptake. Minor variations of the motif were found, depending on the particular class of those proteins. Since thyroglobulin (Tg) is the protein matrix for TH synthesis starting from iodination of a selected number of tyrosines (to form first monoiodotyrosine (MIT) and diiodotyrosine (DIT) and then T3 and T4), we hypothesized that by searching the presence of perfect or imperfect versions of that motif in two Tg species (human and murine) in which the iodinated tyrosines and pattern of iodotyrosine/iodothyronine formation are known, we could have found relevant explanations. Explanations, which are not furnished by the simple possession of tyrosine-iodination motifs and sequence of the iodination motif, concern why only some (but not other) tyrosine residues in one species are iodinated and why they have a particular iodination pattern. In this bioinformatics study, we provide such explanations. PMID- 30468653 TI - Voltammetry and monoamines determination: an old acquaintance revisited. AB - First steps in brain research progress were made during the early 19th century, whose swift progress was accompanied by the discovery of monoamines and their localization in the brain. Since the discovery of polarography in 1924, several variations of electrochemical techniques for in vitro and in vivo determination of monoamines have been developed, with the most prevalent being microdialysis and voltammetry. Voltammetry takes advantage of the chemical property of certain species to oxidize, videlicet to produce a current that can be measured and subsequently interpreted to concentration gradient. Voltammetric techniques require a three-electrode system and operate under the application of a potential at the working electrode, responsible to evoke the oxidation processes. Methodological variations include, among others, amperometry, cyclic voltammetry, differential pulse voltammetry, etc. In the present work we attempted to review the available knowledge on voltammetry, its uses and future endeavors since voltammetry is a promising method towards the investigation of brain and central nervous system physiology and pathophysiology. PMID- 30468654 TI - Dynamic transcriptional events mediated by estrogen receptor alpha. AB - 17beta-estradiol (E2), the main circulating estrogen hormone, is involved in a wide variety of physiological functions ranging from the development to the maintenance of many tissues and organs. The effects of E2 on cells are primarily conveyed by the transcription factors, estrogen receptor (ER) alpha and beta. The regulation of responsive genes by the well-defined ER alpha in response to E2 relies on complex and highly organized processes that dynamically integrate functions of many transcription regulators to induce spatiotemporal alterations in chromatin state and structure. Changes in gene expressions result in cell specific responses that include proliferation, differentiation and death. Deregulation of E2-ER alpha signaling contributes to the initiation and progression of target tissue malignancies. We aim here to provide a review of recent findings on dynamic transcriptional events mediated by E2-ER alpha with the anticipation that a better understanding of complex regulatory mechanisms underlying ER actions would be a critical basis for the development of effective prognostic tools for and therapeutic interventions against estrogen target tissue malignancies. PMID- 30468655 TI - Dysregulated circRNAs and ceRNA network in esophageal squamous cell carcinoma. AB - Accumulating evidence suggests that circular RNA (circRNA), once thought to be a transcriptional error, plays an important regulatory role in the tumor biological process. Some circRNAs regulate the protein-coding gene expression by competitive binding with microRNAs (miRNAs). However, functional roles of circRNA-mediated competitive endogenous RNAs (ceRNAs) in esophageal squamous cell carcinoma (ESCC) are rarely reported. To explore the biological functions of circRNAs in ESCC, we surveyed the integrating differential circRNA expression of ESCC and para-cancer tissues using microarray in three patients. Then, we screened out differentially expressed mRNAs obtained from 81 ESCC tissues and 11 normal tissues in The Cancer Genome Atlas (TCGA). Then, we constructed a hypothetical ceRNA network by integrating differential expression of circRNAs and mRNAs. Finally, 32 differentially expressed circRNAs and 98 differentially expressed mRNAs were linked by 64 miRNAs to build the ceRNA network in ESCC. We suggest that the identified ceRNA network can facilitate a better understanding of circRNA-related mechanisms in ESCC. PMID- 30468656 TI - Amelioration of prediabetes-induced changes of dendritic structural plasticity. AB - Accumulating evidence suggests that the diabetes-induced cognitive dysfunction can be alleviated when exposed to the enriched environment. However, the impact of the changes of the hippocampal plasticity on the cognitive decline and the possible effect of an enriched environment in prediabetes are still not clearly documented. To explore the effect of enriched environment for prediabetes-induced changes of dendritic structural plasticity in hippocampus pyramidal and cognitive deficits, the praxiology experiments for evaluating of anxiety, spatial learning and memory of prediabetic Wistar were performed, and then the dendritic spine density was assessed in the hippocampal CA1 pyramidal neuronal region. The prediabetic rats demonstrated a hyper-anxiety like behavior and significantly decreased spatial learning abilities and memory deficits. Exposing prediabetic rats to an enriched environment appeared to significantly mitigate the above changes in a time-dependent manner. The enriched environment also restored the density of the hippocampal dendritic spine which was significantly reduced in prediabetic rats. We found that the enriched environment was beneficial in overcoming the prediabetes-induced cognitive disorders and diminished dendritic plasticity of hippocampus pyramidal. PMID- 30468657 TI - Nobiletin sensitizes colorectal cancer cells to oxaliplatin by PI3K/Akt/MTOR pathway. AB - Oxaliplatin is one of the most common chemotherapy drugs for colorectal cancer (CRC), but its application is greatly limited owing to the drug resistance. Nobiletin is a natural flavonoid isolated from citrus peel and has many biological functions, including anti-inflammatory, antitumor and neuroprotective activities. However, little is known about the effect of nobiletin on the anti tumor activities of other chemotherapy drugs. In this study, we examined the effect of nobiletin on the efficacy of oxaliplatin in treatment of CRC by using two CRC cell lines. In vitro experiments indicated that nobiletin enhanced the inhibitory effect of oxaliplatin on the proliferation of CRC cells. Meanwhile, nobiletin promoted oxaliplatin-induced apoptosis of CRC cells, as demonstrated by the increased expression of pro-apoptotic proteins (Bax and cleaved-caspse3) and the down-regulation of anti-apoptotic protein Bcl-2. Mechanically, nobiletin sensitized CRC to oxaliplatin chemotherapy by down-regulating the PI3K/Akt/mTOR pathway. Taken together, our study has demonstrated that nobiletin could enhance the sensitivity of CRC to oxaliplatin chemotherapy, and provided a molecular basis for nobiletin's potential applications in the chemosensitization of CRC. PMID- 30468659 TI - Autism in the Gulf States: a regional overview. AB - In this review, we provide a Gulf region-centric view on autism with special focus on Qatar and Oman, including a review of seminal Qatari/Omani work from the literature. In addition, we offer a summary from the World Innovation Summit for Health and World Innovation Summit for Education autism reports as well as outline some of the main challenges, best practices and a path forward for the Gulf region from a healthcare perspective. Finally, we highlight the role of public outreach and awareness to lay the groundwork for enlightened policy for intervention and resource allocation to care for autistic individuals. PMID- 30468658 TI - Antioxidant therapies in attention deficit hyperactivity disorder. AB - Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder among children and adults. Impulsivity, inattention, and hyperactivity are hallmark of ADHD. While ADHD is not on the autism spectrum, they are related in several ways as they have some overlapping symptoms. The pathogenesis of ADHD has so far remained enigmatic, however, there is some evidence suggesting critical association among ADHD and the level of oxidative stress which trigger cell membrane damage, changes in inner structure and function of proteins, as well as structural damage to DNA which eventually culminate into development of ADHD. Although stimulants as well as some classes of non-stimulants are used to ameliorate symptom of ADHD, various adverse effects have been associated with such compounds. To date, treatment of ADHD is done with a combination of medications, behavior modifications, psycho-education, family therapy and life style changes. The American Academy of Pediatrics officially promote stimulant medications and/or behavior therapy as 'first line of therapy'. In addition to the presently therapeutic armamentarium, evidences are emerging on relevancy of natural products. There has been an interest on the therapeutic role of antioxidants in the treatment of ADHD. The present review aims to highlight the beneficiary role played by different antioxidants in mitigating the symptoms of ADHD. PMID- 30468660 TI - The effects of silver nanoparticles on RAW 264.7. Macrophages and human whole blood cell cultures. AB - Silver nanoparticles (AgNPs) are commonly found in consumer products due to their antimicrobial properties. This study evaluated the effects of AgNPs on the murine macrophage cell line RAW 264.7 and human whole blood cell cultures (WBCs). Effects of AgNPs on RAW cells were assessed in the presence or absence of lipopolysaccharide (LPS). Effects of AgNPs on WBCs were monitored under basal conditions and in the presence of either LPS or phytohaemmagglutinin (PHA). AgNPs were cytotoxic to WBCs at 250 MUg/ml. Under basal conditions, RAW cells >= 62.5. MUg/ml and WBCs > 25 MUg/ml AgNPs induced biomarkers associated with inflammation. Under LPS stimulated conditions, 250 MUg/ml AgNP inhibited biomarkers associated with inflammation for both cultures. Under basal conditions, and in the presence of 250 MUg/ml AgNP, WBCs produced acquired immune system cytokines IL-10 and IFNgamma. IL-10 synthesis by WBCs was partially inhibited by 250 MUg/ml AgNP in the presence of PHA. Proteome profiles of RAW cell supernatants show that AgNPs modulate biomarkers associated with inflammation. WBCs proteome analysis shows modulation of biomarkers associated with anti-inflammatory effects. PMID- 30468661 TI - Lactate as a signaling molecule: Journey from dead end product of glycolysis to tumor survival. AB - Global metabolism of cancers exhibits a peculiar phenotype that is lactate acidosis (high lactate with acidic pH) in tumor microenvironment. Why tumor microenvironment becomes so responsive towards lactate is still not clear. In this review we have discussed lactate generation and recycling either exogenously, directly or indirectly by cancer cells via some transporters. Tumor cells in hypoxia use glucose rapidly and produce lactate while cells which have profuse oxygen supply take up lactate and use it for energy production which is referred as lactate shuttling between tumor cells. Escaping immune evasion which is also an emerging hallmark of cancer cells has also been discussed in this review with respect of lactate acidosis. PMID- 30468662 TI - Role of microRNAs in the development of hepatocellular carcinoma and drug resistance. AB - Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide and has a relatively poor survival rate. Aside from liver transplantation, the most effective and leading curative measure for HCC is the chemotherapeutic agent sorafenib, which is a multikinase inhibitor used for treating late-stage HCC. However, the effects of sorafenib are short-lived because of rapid acquisition of multi-drug resistance (MDR) by tumor cells. MicroRNAs (miRNAs) have emerged as crucial regulatory molecules for almost every biochemical pathway in humans. The progression of HCC and acquired MDR are critically influenced by miRNAs through regulation of key genes in cell regulatory pathways. This review explores the involvement of miRNAs in the development of HCC and their role in key signaling pathways leading to MDR in HCC. PMID- 30468663 TI - State-of-the-art review on deep learning in medical imaging. AB - Deep learning (DL) is affecting each and every sphere of public and private lives and becoming a tool for daily use. The power of DL lies in the fact that it tries to imitate the activities of neurons in the neocortex of human brain where the thought process takes place. Therefore, like the brain, it tries to learn and recognize patterns in the form of digital images. This power is built on the depth of many layers of computing neurons backed by high power processors and graphics processing units (GPUs) easily available today. In the current scenario, we have provided detailed survey of various types of DL systems available today, and specifically, we have concentrated our efforts on current applications of DL in medical imaging. We have also focused our efforts on explaining the readers the rapid transition of technology from machine learning to DL and have tried our best in reasoning this paradigm shift. Further, a detailed analysis of complexities involved in this shift and possible benefits accrued by the users and developers. PMID- 30468664 TI - The mechanism of action of Lipiburn on fat metabolism. AB - Paeoniflorin (PF) is the active ingredient in Lipiburn, a fat loss supplement. PF is a component in Paeonia Lactiflora with multiple medicinal uses. Here, we studied the effect of Lipiburn on fat metabolism in differentiated 3T3-L1 adipocytes. Adipocytes exposed to Lipiburn exhibited significant increase in expression of beta-adrenergic receptors, HSL levels, and cAMP and exhibited increase in glycerol release. The data show that Lipiburn affects fat metabolism through the cAMP route by activating HSL which in turn breaks down triglycerides into glycerol and fatty acids. PMID- 30468665 TI - Cerebral ischemic stroke: cellular fate and therapeutic opportunities. AB - In cerebral tissues, due to continuous and high metabolic demand, energy is produced exclusively by mitochondrial oxidative phosphorylation (OXPHOS). Obstruction of blood flow leads to cerebral ischemia, hypoxia and decreased cellular ATP production. The reactive oxygen species (ROS) generated as by product of OXPHOS alter many intracellular signaling pathways and result in damaged cellular components. Under such hypoxic conditions, a key factor known as hypoxia inducible factor 1 (HIF1) is stabilized and activated and such activation induces expression of a defined set of target genes which are required for cell survival and angiogenesis. Reperfusion that follows such ischemia alters signaling pathways which are involved in cellular fate. Here, we will review the role of ROS, HIF-1 alpha and other signaling network in mitochondrial dysfunction and cell fate determination in ischemia-reperfusion models in the brain. We will also address both current and future therapeutic strategies for clinical significance that are being developed for treatment of cerebral ischemia. PMID- 30468666 TI - Polarity as a physiological modulator of cell function. AB - Cell polarity, the asymmetric distribution of proteins, organelles, and cytoskeleton, plays an important role in development, homeostasis, and disease. Understanding the mechanisms that govern cell polarity is critical for creating strategies to treat developmental defects, accelerate tissue regeneration, and hinder cancer progression. This review focuses on the role of cell polarity in a number of physiological processes, including asymmetric division, cell migration, immune response mediated by T lymphocytes, and cancer progression and metastasis, and highlights microfabrication techniques to systematically parse the role of microenvironmental cues in the regulation of cell polarity. PMID- 30468667 TI - Cytokine gene expression following RSV-A infection. AB - The present study determines the cytokine gene expression in chickens following RSV-A infection, using RT-qPCR. In susceptible chickens tumors progressed to fulminating metastatic tumors while it regressed in regressors chickens and some resistant non-responder chickens did not respond to RSV-A infection and thus did not develop tumors at all. The in vivo expression of pro-inflammatory cytokines, Th1 cytokines and Th2 cytokines was determined at the primary site of infection, as well as in different organs of progressor, regressor and non responder chicks at different time intervals. Our results indicated a significant upregulation of the pro-inflammatory cytokines, IL-6 and IL-8, in all the organs of progressor chicks, while they were significantly lower in regressor and non responder chicks. The expression of the Th1 cytokines IFN-gamma and TNF-alpha was low in all of the organs of the progressor group, except that in spleen. In contrast, regressor and non-responder groups showed high expression of IFN-gamma and TNF-alpha. Further, there was an early upregulation of the expression of the Th2 cytokine, IL-10, TGF-beta and GM-CSF, in all of the organs of progressors as compared to uninfected control. PMID- 30468668 TI - TGF-beta/TGF-beta RII/CLC-3 axis promotes cognitive disorders in diabetes. AB - Transforming growth factor beta (TGF-beta) and Chloride channel-3 (CLC-3) are critical for inflammatory response, cellular proliferation and apoptosis in hippocampus neurons. However, the relationship between CLC-3 and TGF-beta/TGF beta Receptor II (RII) pathway in diabetic encephalopathy (DE) is unknown. In this study, both diabetes rat model and diabetes cell model were employed to elucidate the mechanisms involved. The increased expressions of CLC-3 and TGF- beta RII with cognitive impairment were observed in diabetic rats. The most obvious reduction on the survival of HT22 cells was at 10 ng/ml or 15 ng/ml TGF- beta stimulation, while the expressions of CLC-3 and TGF-beta RII were significantly increased under high glucose condition. Moreover, the study showed that CLC-3 antagonists had no apparent effect on up-regulated TGF- beta RII, but TGF- beta 1 inhibitors could reduce the up-regulated CLC-3 under high glucose. Results from the present study indicated that CLC-3 and TGF- beta signals might be related to cognitive disorders. The CLC-3 might be modulated by TGF- beta /TGF beta RII signaling pathway during the development of DE. PMID- 30468669 TI - The regulatory role of coagulation factors in vascular function. AB - The coagulation takes place in the hemostasis system and is a is hallmarked by a complex interplay of reactions between coagulation proteins. In the presence of a vascular breach, the conversion of prothrombin to thrombin leads to the formation of insoluble fibrin fibers that will stop bleeding and limit blood loss. Hemostasis is known to be disturbed in many diseases leading to hemorrhages or thrombosis. Despite the role of coagulation in hemostasis, recent evidences suggested that coagulation factors are involved in other (patho)physiological processes in the vasculature not necessarily marked by overt clotting, such as atherosclerosis and hypertension. Many direct (through protease activated receptors) or indirect effects of several coagulation factors are now well described. This review is focusing on the role of coagulation factors in the (dys)regulation of vascular function. PMID- 30468670 TI - Role of platelet serotonin in innate immune cell recruitment. AB - Serotonin (5-Hydroxytryptamine, 5-HT) was discovered as a vasoconstrictor in 1937. Since its discovery, the involvement of serotonin in numerous physiological processes was described. It acts as an important neurotransmitter, regulates bowel movement, can be released as a tissue hormone and acts as a growth factor. Among the years, a link between serotonin and inflammation has been identified and further evidence suggests an important role of serotonergic components in immune responses. Peripheral serotonin is synthesized by the enzyme tryptophan hydroxylase (Tph), which exists in two different isoforms: Tph2 being responsible for serotonin synthesis in neurons and Tph1 for generation of serotonin in peripheral organs. After synthesis in intestinal enterochromaffin cells, serotonin is stored in platelets and released upon stimulation. Several immune cells express the serotonin transporter SERT and enzymes for serotonin metabolism (monoamine oxygenase, MAO). To be susceptible to changes in serotonin levels, serotonin receptors are required and almost all of the 15 receptor subtypes are represented on immune cells. In this review, we describe the distribution of serotonergic components in cells of the immune system and the impact of platelet derived serotonin on these cells. In particular, we aim to understand the effect of serotonin on immune cell recruitment to sites of inflammation. PMID- 30468671 TI - Morphometric analysis in ethnic neonates from multiple substance exposure. AB - In the United States, approximately 10% of newborn infants are exposed prenatally to alcohol and/or illicit substances. However, no studies have evaluated the compounding effects of multiple illicit substances exposure in utero as potential teratogen (s). The potential teratogenic effects of nicotine and illicit substances (e.g. cocaine, marijuana and heroin) have previously been studied but there has been no documentation of facial landmark dislocation (s). Our goal is to investigate whether morphometric analysis could differentiate facial landmark dislocations in neonates of African descent, when exposed to alcohol, nicotine and illicit substances, either singly or in combination. Craniofacial features from a cohort of 493 African-American neonates less than 48 hours of age were analyzed by Multivariate Hotelling's T2 analysis of 99 relevant facial landmark triangles. Morphometric analysis discriminated unique asymmetries in groups of certain illicit exposure(s). Neonates with multiple prenatal exposures had fewer facial landmark dislocation(s) compared to single exposures. Deviation from normal facial features has the potential to be used as a screening tool for prenatal exposure to some illicit substances. PMID- 30468672 TI - Role of microRNAs in the development of hepatocellular carcinoma and acquired drug resistance. AB - Hepatocellular Carcinoma (HCC) is a leading cause of cancer related death worldwide with a relatively poor survival rate. Aside from liver resection and subsequent transplant, the most effective and leading curative measure for HCC is the chemotherapeutic, sorafenib, a multi-kinase inhibitor used for treatment of late stage HCC. However, the effects of sorafenib are short lived due to the liver's rapid acquisition of Multi-Drug Resistance (MDR). MicroRNAs (miRNAs) have emerged as critical regulatory molecules for almost every biochemical pathway in an organism. The development and progression of HCC and acquired MDR are critically influenced by miRNAs through regulation of key genes in cell regulatory pathways. This review explores the involvement of miRNAs in development of HCC and their role in key signaling pathways for MDR in HCC. PMID- 30468673 TI - Generation of sRAGEhigh transgenic mice to study inflammaging. AB - The receptor for advanced glycation end products (RAGE) interacts with multiple ligands and transmits inflammatory signals from damage- and pathogen-associated molecular patterns (DAMPs and PAMPs) to cellular programs. RAGE shares ligands with another group of PRRs, i.e., Toll-like receptors. Such ligand-receptor promiscuity generates coordinated and complex signaling patterns that provide a basis for the development of multiple inflammaging diseases. Soluble RAGE (sRAGE) functions as a RAGE decoy that scavenges DAMP/PAMP ligands and dampens inflammatory signals. Epidemiological studies have shown that a lower level of circulating sRAGE is associated with metabolic syndromes including obesity, diabetes, hypertension, and subclinical brain disease. We hypothesize that an elevated level of circulating sRAGE serves to modulate systemic and low-grade chronical inflammation that often occurs in old age, and therefore minimizes the risk of inflammaing diseases. Consequently, a higher level of circulating sRAGE may improve the health-span of the organism. A newly generated transgenic mouse that has a higher level of circulating sRAGE and maintains normal expression levels of RAGE serves as a model to test this hypothesis. PMID- 30468674 TI - Modafinil and orexin system: interactions and medico-legal considerations. AB - Modafinil (Mo) is increasingly being used as an enhancement drug rather than for its therapeutic effects. The effects of this drug have been examined in attention deficit disorders, depression, mental fatigue, and in enhancing concentration. The drug possesses wakefulness-promoting properties which are mediated through the interaction of orexinergic system with the activated sympathetic nervous system. Mo exerts a synergistic effect on the orexin system, controls energy expenditure and strengthens the ability of the individual to exercise. Some view Mo as a drug that enhances sports performance, since it induces a prolonged wakefulness and decreasing the sense of fatigue. These characteristics being similar to conventional stimulants have allowed Mo to emerge as a novel stimulant requiring medico-legal considerations. However, more studies are needed to better understand the mid and long-term effects of the drug on user/abuser. PMID- 30468675 TI - Withaferin A attenuates ovalbumin induced airway inflammation. AB - The molecular mechanism of how airway inflammation develops is not fully understood. Withaferin A (WA) is a natural phytochemical isolated from the plant Withania somnifera. It is a well-investigated bioactive compound that possesses a variety of health-promoting effects, including anti-inflammatory and anti oxidative activities. In the present study, the effect of WA on ovalbumin (OVA) induced airway inflammation in mice was investigated. The results indicated that pre-treatment with WA inhibited OVA-induced lung injury and fibrosis progression in mice. Furthermore, WA significantly downregulated inflammatory cell infiltration into the bronchoalveolar lavage fluid and significantly reduced pro inflammatory cytokine expression in the lung tissue specimens. Additionally, WA significantly suppressed transforming growth factor-b1 expression in lung tissues. WA also caused the downregulation of collagen I, collagen III, alpha smooth muscle actin and tissue inhibitor of metalloproteinase-1, as well as SMADs and extracellular signal related kinase 1/2 inactivation. Notably, WA significantly reduced the activation of the NLRP3 inflammasome. The results indicate that WA may be an effective novel candidate for the treatment of airway inflammation. PMID- 30468676 TI - Astragaloside IV inhibits human colorectal cancer cell growth. AB - Colorectal cancer (CRC) is one of the most common malignancies worldwide. However, therapies against CRC have not been completely effective. Astragaloside IV (AS-IV) has shown anti-tumorigenic properties in certain cancers, but its role in CRC remains unclear. In this study, we investigated the therapeutic effect of AS-IV in CRC and explored its underlying mechanism. The results showed that AS-IV dose-dependently inhibited the proliferation of CRC cells and suppressed tumor growth in CRC xenograft mouse models. In addition, AS-IV promoted cell cycle arrest in the G0 phase, associated with increased expression of p21. Furthermore, flow cytometry demonstrated that AS-IV promoted apoptosis of CRC cells in a dose dependent manner. AS-IV induced caspase-dependent apoptosis, which involved the increased release of cytochrome c and Omi from the mitochondria into the cytoplasm and the up-regulation of Bax/Bcl-2 ratio, as well as the activation of PARP and caspase cascade (caspase-3 and -9). Taken together, our study has identified a novel function of AS-IV and provided a molecular basis for AS-IV's potential applications in the treatment of CRC and other cancers. PMID- 30468678 TI - Charge transport pathways in metal porphyrin as interplay between long and short range scattering processes. AB - We have investigated the ballistic transport for Mn, Fe-porphyrin molecules in contact with Au(111) electrodes by using density functional theory. We show that the information resulted from the projected density of electronic states does not provide a complete picture of the transport mechanism. Instead, we propose a methodology based on the concept of the orbital projected transmissions for selected groups of atoms. We have found that the transmission channels for occupied states can be assigned to short range scattering processes at gold molecule interface, while for the states above Fermi level the transmission takes place via long range scattering processes. The interplay between these two conduction mechanisms is responsible for the transport path in metal-porphyrin; our model is in qualitative agreement with the existing experimental data on transport pathway on single porphyrin molecules. PMID- 30468677 TI - Sarpogrelate attenuates pulmonary arterial hypertension via calcium/calcineurin axis. AB - Pulmonary arterial hypertension (PAH) is a syndrome caused by restricted blood flow in the pulmonary circulation, which results in a poor patient prognosis. The serotonin (5-HT), TRPC1 (Transient receptor potencial channel 1), TRPC6 (Transient receptor potencial channel 6), calcineurin A, and NFATc3 (an isoform of nuclear factor of activated T-cells family) are involved in cell proliferation and hypertrophy and the crosstalk between these molecules may play an essential role in the pathogenesis of pulmonary arterial hypertension. We hypothesized that 5-HT promotes PAH by affecting TRPC channels. We investigated the effects of sarpogrelate, a 5-HT2A receptor antagonist, on pulmonary arterial pressure, cardiac remodeling, pulmonary artery remodeling, and TRPC1, TRPC6, calcineurin A, and NFATc3 expression in pulmonary arteries from rats with PAH. The results showed that sarpogrelate reduced pulmonary arterial pressure, cardiac remodeling, pulmonary artery remodeling, and expression of TRPC1, TRPC6, calcineurin A, and NFATc3 in pulmonary arteries. In conclusion, Sarpogrelate reduced the severity of PAH in rat model and decreased the expression of TRPC1, TRPC6, calcineurin A, and NFATc3 in pulmonary arteries. PMID- 30468679 TI - A phase-change thin film-tuned photonic crystal device. AB - This paper reports a tunable photonic device that incorporates a thin layer of phase-change material, Ge2Sb2Te5 (GST), in a photonic crystal (PC) structure. The PC structure is based on a one-dimensional grating waveguide with a metal cladding. The metal-cladded PC structure supports a guided-mode resonance (GMR) that selectively absorbs light at a particular wavelength. Inserting the GST material into the gating waveguide makes it possible to control the GMR mode. Here, the GST-PC device was numerically designed and optimized to obtain significant tuning of the GMR mode around 1550 nm. The tuning phenomena were experimentally demonstrated by the heat-induced phase change between crystalline and amorphous phases of the GST thin film. A spectral shift of the resonant wavelength from 1440 to 1610 nm was achieved via the crystallization process. The phase tuning of GST exhibits good repeatability as demonstrated by switching between amorphous and crystalline phases of GST for multiple cycles. The GST-PC device represents a new approach for tuning optical resonances with potential applications including but not limited to integrated photonic circuits, optical communications, and high-performance optical filters. PMID- 30468680 TI - 68Ga-DOTA-TATE-a source of eye lens exposure for nuclear medicine department workers. AB - INTRODUCTION: Obtaining 68Ga-DOTA-TATE (a radioconjugate consisting of the somatostatin analogue tyrosine-3-octreotate (Tyr3-octreotate or TATE) labelled with the positron emission tomography tracer gallium 68Ga via the macrocyclic chelating agent dodecanetetraacetic acid (DOTA)) is a complex process and, as with any radiopharmaceutical whose basis is a short-lived radionuclide generator, it is based on a sequence of procedures beginning from the 68Ge/68Ga generator elution, labelling ligands with a radioisotope, dispensing doses of 68Ga-DOTA TATE for patients and finally injection of the preparation to patients. The complexity of this process may contribute to an increased exposure of eye lenses of the staff who perform the above-mentioned procedures, which is especially important at a time when the dose limit on the lens of the eye is being reduced from 150 to 20 mSv yr-1. OBJECTIVE: The work presents the exposure of eye lenses of the personnel of a nuclear medicine department who prepare and inject 68Ga DOTA-TATE. MATERIALS AND METHODS: Radiochemists and nurses were monitored by dosimetry measurements with thermoluminescent detectors (TLDs). RESULTS: The values of Hp(3)/A-normalised personal eye dose equivalent recorded in the group of radiochemists during the procedure of dispensing the doses of 68Ga-DOTA-TATE for patients exceeded the value of 274 MUSv/GBq. CONCLUSIONS: The estimated annual Hp(3) values may exceed 20 mSv, which is particularly important due to the fact that procedures using the 68Ga radioactivity are only a small part of the daily professional activity of the staff, resulting from the performance of other procedures that require the use of other radioisotopes. PMID- 30468681 TI - Coexistence of nanowire-like hex and (1 * 1) phases in the topmost layer of Au(100) surface. AB - Scanning tunneling microscopy and density functional theory calculations were used to study the structure of the Au(100) surface after ion bombardment. The results indicate a development of two phases: the quasi-hexagonal (hex) and the (1 * 1) on the surface. A decrease in the number of surface atoms caused by ion bombardment leads to the development of a coexistence of phases inside the surface layer. Our experimental data and theoretical results rule out a scenario that the unreconstructed (1 * 1) domains under study represent a subsurface atomic layer revealed by ion sputtering. The hex phase is anisotropic, with the quantized width in accord with (6n + 1) formula. In certain conditions, nanowire like structures consisting of seven atomic rows of alternating height are developed on the surface. PMID- 30468682 TI - SOI microdosimetry and modified MKM for evaluation of relative biological effectiveness for a passive proton therapy radiation field. AB - With more patients receiving external beam radiation therapy with protons, it becomes increasingly important to refine the clinical understanding of the relative biological effectiveness (RBE) for dose delivered during treatment. Treatment planning systems used in clinics typically implement a constant RBE of 1.1 for proton fields irrespective of their highly heterogeneous linear energy transfer (LET). Quality assurance tools that can measure beam characteristics and quantify or be indicative of biological outcomes become necessary in the transition towards more sophisticated RBE weighted treatment planning and for verification of the Monte Carlo and analytical based models they use. In this study the RBE for the CHO-K1 cell line in a passively delivered clinical proton spread out Bragg peak (SOBP) is determined both in vitro and using a silicon-on insulator (SOI) microdosimetry method paired with the modified microdosimetric kinetic model. The RBE along the central axis of a SOBP with 2 Gy delivered at the middle of the treatment field was found to vary between 1.11-1.98 and the RBE for 10% cell survival between 1.07-1.58 with a 250 kVp x-ray reference radiation and between 1.19-2.34 and 0.95-1.41, respectively, for a Co60 reference. Good agreement was found between RBE values calculated from the SOI-microdosimetry-MKM approach and in vitro. A strong correlation between proton lineal energy and RBE was observed particularly in the distal end and falloff of the SOBP. PMID- 30468683 TI - Plaque characterization using shear wave elastography-evaluation of differentiability and accuracy using a combined ex vivo and in vitro setup. AB - Ultrasound elastography has shown potential for improved plaque risk stratification. However, no clear consensus exists on what output metric to use, or what imaging parameters would render optimal plaque differentiation. For this reason we developed a combined ex vivo and in vitro setup, in which the ability to differentiate phantom plaques of varying stiffness was evaluated as a function of plaque geometry, push location, imaging plane, and analysed wave speed metric. The results indicate that group velocity or phase velocity ?1 kHz showed the highest ability to significantly differentiate plaques of different stiffness, successfully classifying a majority of the 24 analysed plaque geometries, respectively. The ability to differentiate plaques was also better in the longitudinal views than in the transverse view. Group velocity as well as phase velocities <1 kHz showed a systematic underestimation of plaque stiffness, stemming from the confined plaque geometries, however, despite this group velocity analysis showed lowest deviation in estimated plaque stiffness (0.1 m s 1 compared to 0.2 m s-1 for phase velocity analysis). SWE results were also invariant to SWE push location, albeit apparent differences in signal-to-noise ratio (SNR) and generated plaque particle velocity. With that, the study has reinforced the potential of SWE for successful plaque differentiation; however the results also highlight the importance of choosing optimal imaging settings and using an appropriate wave speed metric when attempting to differentiate different plaque groups. PMID- 30468684 TI - Accelerating multi-modal image registration using a supervoxel-based variational framework. AB - For the successful completion of medical interventional procedures, several concepts, such as daily positioning compensation, dose accumulation or delineation propagation, rely on establishing a spatial coherence between planning images and images acquired at different time instants over the course of the therapy. To meet this need, image-based motion estimation and compensation relies on fast, automatic, accurate and precise registration algorithms. However, image registration quickly becomes a challenging and computationally intensive task, especially when multiple imaging modalities are involved. In the current study, a novel framework is introduced to reduce the computational overhead of variational registration methods. The proposed framework selects representative voxels of the registration process, based on a supervoxel algorithm. Costly calculations are hereby restrained to a subset of voxels, leading to a less expensive spatial regularized interpolation process. The novel framework is tested in conjunction with the recently proposed EVolution multi-modal registration method. This results in an algorithm requiring a low number of input parameters, is easily parallelizable and provides an elastic voxel-wise deformation with a subvoxel accuracy. The performance of the proposed accelerated registration method is evaluated on cross-contrast abdominal T1/T2 MR-scans undergoing a known deformation and annotated CT-images of the lung. We also analyze the ability of the method to capture slow physiological drifts during MR guided high intensity focused ultrasound therapies and to perform multi-modal CT/MR registration in the abdomen. Results have shown that computation time can be reduced by 75% on the same hardware with no negative impact on the accuracy. PMID- 30468685 TI - Motion effects in proton treatments of hepatocellular carcinoma-4D robustly optimised pencil beam scanning plans versus double scattering plans. AB - Pencil beam scanning (PBS) proton therapy enables better dose conformality for complex anatomical geometries than passive proton scattering techniques, but is more susceptible to organ motion. This becomes an issue when treating moving tumours in the thorax or abdomen. Novel four-dimensional treatment planning approaches have been developed to increase the robustness of PBS plans against motion. However, their efficacy still needs to be examined by means of 4D dynamically accumulated dose (4DDD) analyses. This study investigates the potential use of 4D robust optimisation to maintain sufficient target coverage in the presence of organ motion, while sparing surrounding healthy tissue, for hepatocellular carcinoma (HCC). The liver is particularly suited to study motion interplay effects since the treatment region exhibits smaller density gradients and more homogeneous tissue than targets in the thorax, making it less prone to range errors. A facility-specific beam time model, developed and experimentally validated previously, was used for the clinical evaluation. 4DDD analyses of eleven target volumes did not show a significant improvement of the target coverage using 4D robust optimisation, but a reduction of the dose to close-by organs at risk. Interplay effects were averaged out for the applied fractionation scheme of 15 fractions. Contrary to PBS, passive double scattering (DS) plans yielded homogeneous 4DDD dose distributions in a single fraction. But, in some cases, they exceeded organ at risk dose limits, which were only satisfied in PBS. The average normal liver dose could be decreased by almost 6% compared to non robustly optimised PBS plans and by 16% compared to DS plans when implementing 4D robust optimisation. Except for some very small tumours with large motion amplitudes, 4D robustly optimised PBS plans were found to be clinically acceptable even without supplementary motion mitigation techniques. PMID- 30468686 TI - Trimetazidine Protects Against Atherosclerosis by Changing Energy Charge and Oxidative Stress. AB - BACKGROUND This study investigated the effect and the possible mechanism of trimetazidine in atherosclerosis. MATERIAL AND METHODS We established an atherosclerotic rat model by high-fat diet and vitamin D injection. Rats were separated into 3 different groups: control, atherosclerosis, and trimetazidine (n=10). The aortic artery was isolated and its morphological features were examined by hematoxylin and eosin (HE) staining. Serum low-density lipoprotein cholesterol (LDL-c), total cholesterol (TC), and triglycerides (TG) were analyzed using an automatic biochemical analyzer. Human aortic smooth muscle cells (HASMCs) were cultured and divided into 5 groups: no treatment, H2O2 treatment only, trimetazidine preincubation before H2O2 treatment, oxidized low-density lipoprotein (oxLDL) treatment only, and trimetazidine preincubation before oxLDL treatment. HASMCs proliferation was tested using the Cell Counting Kit-8. Reactive oxygen species (ROS) and malondialdehyde (MDA) levels, superoxide dismutase (SOD) activity of the aortic artery, and HASMCs were measured using commercially available kits. RESULTS HE staining assay showed that trimetazidine suppressed the progression of atherosclerosis and reduced foam cell formation in the aortic artery without affecting serum lipid levels. HASMCs proliferation assay revealed that trimetazidine alleviated the inhibitory effect of H2O2 on HASMCs proliferation and inhibited oxLDL-induced proliferation of HASMCs. Moreover, trimetazidine ameliorated ROS up-regulation elicited by H2O2 or oxLDL in HASMCs. Additionally, trimetazidine restored SOD activity and reduced MDA content of HASMCs. CONCLUSIONS Trimetazidine suppressed the progression of atherosclerosis by enhancing energy value, decreasing ROS level of aortic artery, modulating HASMCs proliferation, and reducing oxidative stress in HASMCs. PMID- 30468687 TI - Torque teno virus monitoring in transplantation: The quest for standardization. AB - We read with interest the recent article by Fernandez-Ruiz et al. detailing the power of early TTV monitoring after kidney transplantation at predicting events associated with excessive immune suppression (opportunistic infections and secondary cancers) (1). Despite transplantation of commensal flora possibly complicating kinetics interpretation (2), TTV is emerging as a promising marker to assess global functional immune competence, to predict post-transplant immune related adverse events, and eventually to customize immunosuppression. Table 1 summarizes what is currently known about TTV predictive cutoffs from the many single-center studies run to date in different transplantation settings (studies reporting only correlation analyses or only differences between medians/means were excluded). This article is protected by copyright. All rights reserved. PMID- 30468688 TI - Change in nuclear DNA content and pollen size with polyploidisation in the sweet potato (Ipomoea batatas, Convolvulaceae) complex. AB - Genome size evolution, and its relationships with pollen grain size, has been investigated in the sweet potato (Ipomoea batatas), an economically important crop, and closely related diploid and tetraploid species, assessing the nuclear DNA content of 22 accessions from five Ipomoea species, 10 sweet potato varieties and two outgroup taxa. Nuclear DNA amounts were determined by flow cytometry. Pollen grains have been studied at scanning and transmission electron microscopy. 2C DNA content of hexaploid I. batatas ranged over 3.12-3.29 pg, mean monoploid genome size being 0.539 pg (527 Mbp) much as for the related diploid accessions. In tetraploid species I. trifida and I. tabascana, 2C DNA content was respectively 2.07 and 2.03 pg. In the diploid species closely related to sweet potato e.g. I. *leucantha, I. tiliacea, I. trifida, I. triloba, 2C DNA content was 1.01-1.12 pg. However, two diploid outgroup species, I. setosa and I. purpurea, were clearly different from the other diploid species with 2C of 1.47 1.49 pg; they also have larger chromosomes. The I. batatas genome presents 60.0% of AT bases. DNA content and ploidy level were positively correlated within this complex. In I. batatas and the more closely related species I. trifida, genome size and ploidy levels were correlated with pollen size. Our results allow us proposing alternative or complementary hypotheses to the one currently proposed for the formation of hexaploid Ipomoea batatas. This article is protected by copyright. All rights reserved. PMID- 30468689 TI - Evidence of high 18F-Fluorodeoxyglucose uptake in the subcutaneous adipose tissue of the dorsocervical area in young adults. AB - NEW FINDINGS: What is the central question of this study?Some studies have performed biopsies of the subcutaneous adipose tissue (SAT) in the abdomen and they failed to find browning markers. Is abdomen the right place to take biopsies? What is the main finding and its importance?For first time, we observed that the glucose uptake in the SAT is higher in comparison to other SAT parts. ABSTRACT: Newborns have subcutaneous brown adipose tissue (BAT) in the dorsocervical area, and it is thought that these depots gradually disappear with age. Here, we study that young adults have high 18F-Flurodeoxyglucose (18 F-FDG) uptake in the subcutaneous adipose tissue (SAT) of the dorsocervical area. A total of 133 young adults (age 22 +/- 2 years; BMI: 25 +/- 5 kg/m2 ) were included in the present study. We performed a shivering threshold test for every participant. Later, we performed 2 hours of personalized cold exposure, just before performing a positron emission tomography/computed tomography scan. We show that 23 out of 133 participants had 18 F-FDG uptake in the dorsocervical area that achieved the criteria to be considered BAT mainly in women (96%, n = 22 out of 23). In the whole sample, the glucose uptake in the SAT of the dorsocervical area positively correlated with BAT volume and activity located in the supraclavicular area. We showed that the 18 F-FDG uptake of the SAT of the dorsocervical area in humans is different in comparison to other SAT area. Future studies are warranted to confirm the brown signature of this tissue. This article is protected by copyright. All rights reserved. PMID- 30468690 TI - The family impact of dental general anaesthesia in children: a meta-analysis. AB - BACKGROUND: The health and well-being of children are intimately linked to their parents' physical, emotional and social health, and social circumstances. AIM: To conduct a meta-analysis of studies that has used the Early Childhood Oral Health Impact Scale (ECOHIS) and Child Oral Health-Related Quality of Life (COHRQoL) instruments, to evaluate the family impact scale (FIS) changes following their children's dental treatment under general anaesthesia (DGA). METHODOLOGY: A systematic search was undertaken using the PRISMA guidelines. The inclusion criteria consisted of: patients below16 years of age, DGA, pre-and post-operative assessments, and the use of ECOHIS and COHRQoL. FIS changes were the primary outcome measure, where the mean difference (MD) was calculated. RESULTS: After initial search of 105 studies in the database, twenty-one articles were included in the analysis. A positive outcome in the FIS changes was identified in all studies. The combined MD for FIS using ECOHIS and COHRQoL were 1.52 [95% CI: 1.15 1.89; P< 0.00001; I2 =87%] and 1.10 [95% CI: 0.68-1.52; P< 0.00001; I2 =79%], respectively. CONCLUSIONS: DGA for children had a significant positive impact on parental emotions, activity and conflict. Following DGA there was significant improvement in the FIS, with large MD. This article is protected by copyright. All rights reserved. PMID- 30468691 TI - The magnitude of neuromuscular fatigue is not intensity-dependent when cycling above critical power but relates to aerobic and anaerobic capacities. AB - NEW FINDINGS: What is the central question of this study? Is the magnitude of neuromuscular fatigue dependent upon exercise intensity above critical power (CP) when W' (the curvature constant of the power-duration relationship) is depleted? What is the main finding and its importance? The magnitude of neuromuscular fatigue is the same following two bouts of supra-CP cycling (3 vs. 12 min) when controlling for W' depletion, but is larger for individuals of greater anaerobic capacity following the shorter, and smaller for individuals of greater aerobic capacity following the longer exercise. These findings provide new insight into the mechanisms underpinning exercise above CP. ABSTRACT: The aim of the present study was to test whether the development of neuromuscular fatigue within the severe intensity domain could be linked to the depletion of the curvature constant (W') of the power-duration relationship. Twelve recreationally active men completed tests to determine VO2peak , Critical Power (CP) and W', followed by two randomly assigned constant-load supra-CP trials set to fully deplete W' in 3 (P-3) and 12 min (P-12). Pre- to post-exercise changes in maximal voluntary contraction (MVC), potentiated quadriceps twitch force evoked by single (Qpot ) and paired high- (PS100) and low-frequency (PS10) stimulations and voluntary activation (VA) were determined. Cycling above CP reduced MVC (P-3: -20 +/- 10% vs. P-12: -15 +/- 7%), measures associated with peripheral fatigue (Qpot : -35 +/ 13% vs. -31 +/- 14%; PS10: -38 +/- 13% vs. -37 +/- 17%; PS100: -18 +/- 9% vs. 13 +/- 8% for P-3 and P-12, respectively) and VA (P-3: -12 +/- 3% vs. P-12: -13 +/- 3%) (P < 0.05), with no significant difference between trials (P > 0.05). Changes in MVC and evoked twitch forces were inversely correlated with CP and VO2peak following P-12, while W' was significantly correlated with changes in Qpot and PS10 following P-3 (P < 0.05). Therefore, the magnitude of neuromuscular fatigue does not depend on exercise intensity when W' is fully exhausted during severe intensity exercise, yet exploration of inter-individual variations suggests that mechanisms underpinning exercise tolerance within this domain differ between short- vs. long-duration exercise. This article is protected by copyright. All rights reserved. PMID- 30468692 TI - Light capture and pigment diversity in marine and freshwater cryptophytes. AB - Phenotypic traits associated with light capture and phylogenetic relationships were characterized in 34 strains of diversely pigmented marine and freshwater cryptophytes. Nuclear SSU and partial LSU rDNA sequence data from 33 of these strains plus an additional 66 strains produced a concatenated rooted maximum likelihood tree that classified the strains into 7 distinct clades. Molecular and phenotypic data together support: 1) the reclassification of Cryptomonas irregularis NIES 698 to the genus Rhodomonas, 2) revision of phycobiliprotein (PBP) diversity within the genus Hemiselmis to include cryptophyte phycocyanin (Cr-PC) 569, 3) the inclusion of previously unidentified strain CCMP 2293 into the genus Falcomonas, even though it contains cryptophyte phycoerythrin 545 (Cr PE 545), and 4) the inclusion of previously unidentified strain CCMP 3175, which contains Cr-PE 545, in a clade with PC-containing Chroomonas species. A discriminant analysis-based model of group membership correctly predicted 70.6% of the clades using three traits: PBP concentration per cell, the wavelength of PBP maximal absorption, and habitat. Non-PBP pigments (alloxanthin, chl-a, chl-c2 , alpha-carotene) did not contribute significantly to group classification, indicating the potential plasticity of these pigments and the evolutionary conservation of the PBPs. Pigment data showed evidence of trade-offs in investments in PBPs vs. chlorophylls (a +c2 ). This article is protected by copyright. All rights reserved. PMID- 30468693 TI - MRI Outperforms [18F]AV-1451 PET as a Longitudinal Biomarker in Progressive Supranuclear Palsy. AB - BACKGROUND: Elevated uptake of the [18 F]AV-1451 tau-PET ligand has been observed cross-sectionally in subjects with progressive supranuclear palsy (PSP). However, it is unknown how the ligand performs longitudinally in PSP. We aimed to determine how regional measures of change on [18 F]AV-1451 PET perform as longitudinal biomarkers of PSP compared with the more established biomarker of rate of midbrain atrophy. METHODS: Sixteen subjects with PSP underwent 2 serial [18 F]AV-1451 tau-PET scans and 3-Tesla MRI over 12 months and were age- and sex matched to 39 healthy controls with longitudinal [18 F]AV-1451 PET. Median [18 F]AV-1451 uptake was calculated for each scan for regions of interest across the brain and divided by uptake in cerebellar crus to create standard uptake value ratios. Midbrain volume on MRI was also calculated for each scan. Sample sizes required to power placebo-controlled treatment trials were calculated. RESULTS: Rate of midbrain atrophy was significantly increased in PSP compared with controls. [18 F]AV-1451 regional change measures were significantly increased in PSP compared with controls in the pallidum, precentral cortex, dentate nucleus of the cerebellum, and midbrain. Change over time in the PSP Rating Scale correlated with change in midbrain volume but did not correlate with change in the [18 F]AV 1451 measures. Smallest sample-size estimates were obtained with rate of midbrain atrophy, followed by the PSP Rating Scale, with both outperforming [18 F]AV-1451 measures. CONCLUSIONS: [18 F]AV-1451 tau-PET measures increase over time in subjects with PSP, but longitudinal [18 F]AV-1451 measures may not perform as well as rate of midbrain atrophy as biomarkers for PSP clinical trials. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 30468694 TI - Baseline predictors for progression 4 years after Parkinson's disease diagnosis in the De Novo Parkinson Cohort (DeNoPa). AB - OBJECTIVES: The objectives of this study were to investigate (1) the annual rate of progression of motor and cognitive symptoms and (2) baseline predictors of different modalities for this progression in early Parkinson's disease (PD) when compared with healthy controls. METHODS: A total of 135 de novo PD and 109 healthy controls (of the De Novo Parkinson cohort) were investigated at baseline and after 24 and 48 months. To delineate motor progression and cognitive decline, the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) and the Mini-Mental Status Examination (MMSE) were selected. Baseline variables used to predict progression included sociodemographic factors, comorbidities, motor/nonmotor symptoms, polysomnography, MRI, and laboratory biomarkers in serum and CSF. RESULTS: Symptoms worsened over 4 years in PD with an annual change of 1.8 points on the MDS-UPDRS III and 0.2 points on the MMSE. Baseline predictors of worse progression of motor symptoms in PD included male sex, orthostatic blood pressure drop, diagnosis of coronary artery disease, arterial hypertension, elevated serum uric acid, and CSF neurofilament light chain. Predictors of cognitive decline in PD included previous heavy alcohol abuse, current diagnoses of diabetes mellitus, arterial hypertension, elevated periodic limb movement index during sleep, decreased hippocampal volume by MRI, higher baseline levels of uric acid, C-reactive protein, high density lipoprotein (HDL) cholesterol, and glucose levels. CONCLUSION: Cardiovascular risk factors, deregulated blood glucose, uric acid metabolism, and inflammation were identified as risk markers for faster disease progression. Our panel of risk parameters needs validation during our continuing follow-up and also in independent patient cohorts. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 30468695 TI - GIS-Based Integration of Social Vulnerability and Level 3 Probabilistic Risk Assessment to Advance Emergency Preparedness, Planning, and Response for Severe Nuclear Power Plant Accidents. AB - In the nuclear power industry, Level 3 probabilistic risk assessment (PRA) is used to estimate damage to public health and the environment if a severe accident leads to large radiological release. Current Level 3 PRA does not have an explicit inclusion of social factors and, therefore, it is not possible to perform importance ranking of social factors for risk-informing emergency preparedness, planning, and response (EPPR). This article offers a methodology for adapting the concept of social vulnerability, commonly used in natural hazard research, in the context of a severe nuclear power plant accident. The methodology has four steps: (1) calculating a hazard-independent social vulnerability index for the local population; (2) developing a location-specific representation of the maximum radiological hazard estimated from current Level 3 PRA, in a geographic information system (GIS) environment; (3) developing a GIS based socio-technical risk map by combining the social vulnerability index and the location-specific radiological hazard; and (4) conducting a risk importance measure analysis to rank the criticality of social factors based on their contribution to the socio-technical risk. The methodology is applied using results from the 2012 Surry Power Station state-of-the-art reactor consequence analysis. A radiological hazard model is generated from MELCOR accident consequence code system, translated into a GIS environment, and combined with the Center for Disease Control social vulnerability index (SoVI). This research creates an opportunity to explicitly consider and rank the criticality of location-specific SoVI themes based on their influence on risk, providing input for EPPR. PMID- 30468696 TI - The spectrum of cutaneous adverse events during Encorafenib and Binimetinib treatment in BRAF mutant advanced melanoma. AB - BACKGROUND: BRAF inhibitor encorafenib alone and in combination with MEK inhibitor binimetinib improves survival in BRAF mutated melanoma patients. So far, the range of cutaneous adverse events has been characterized only for established BRAF inhibitors (vemurafenib, dabrafenib) and MEK inhibitors (trametinib, cobimetinib). OBJECTIVE: The aim of this study was to investigate cutaneous adverse events emerging in melanoma patients treated with encorafenib and binimetinib. METHODS: Patients treated with BRAF and MEK inhibitors in clinical trials at the University Hospital of Zurich were identified. Frequency and features of cutaneous adverse events as well as their management were assessed based on the prospectively collected clinical and histopathological data. The events emerging during encorafenib and/or binimetinib therapy were compared to other BRAF and MEK inhibitors at the institution and in the literature. RESULTS: The most frequent cutaneous adverse events observed in patients treated with encorafenib alone (n=24) were palmoplantar hyperkeratosis (54%), palmoplantar erythrodysesthesia (58%) and alopecia (46%). Drug-induced papulopustular eruptions prevailed in patients with binimetinib monotherapy (n=25). The most frequent cutaneous adverse events in patients treated with encorafenib/binimetinib (n=49) was palmoplantar hyperkeratosis (10%). CONCLUSION: Compared to data published for established BRAFi, encorafenib monotherapy showed less hyperproliferative cutaneous adverse events. In contrast, palmoplantar hyperkeratosis and palmoplantar erythrodysesthesia seem to occur more often. The combination encorafenib with binimetinib is well tolerated and induces few cutaneous adverse events. This article is protected by copyright. All rights reserved. PMID- 30468697 TI - Comparison between Cytospin and Liquid-Based Cytology in cerebro-spinal fluid diagnosis of neoplastic diseases. A single institution experience. AB - OBJECTIVE: The current tools available for detecting malignant neoplasms in the cerebrospinal fluid (CSF) are neurologic examination, followed by neuroimaging, cytology and molecular techniques. To highlight the role of cytology the diagnosis of metastatic tumors in cerebrospinal fluid (CSF) samples, we present our experience using cytospin and ThinPrep liquid-based cytology (LBC). METHODS: A retrospective analysis was conducted using the pathological records of 8,181 cytological specimens of CSF which were diagnosed over a 17-year period. Between 2000 and 2014, a total of 6,994 CSF samples were processed using cytospin method and 1,187 specimens were examined using ThinPrep method in the period between 2015 and 2017. RESULTS: The most frequent metastatic neoplasm of the first period was non Hodgkin lymphoma; in the second period the commonest malignancy found was brain tumor (Glioblastoma and Medulloblastoma). The samples processed by cytospin revealed cytolysis and hemorrhage, while the cases processed by ThinPrep had a clear background. Ten false-positive cases belonging to the suspicious category were processed by cytospin, while there was only one false positive case in the group processed by ThinPrep. The positive predictive value was 95% in cytospin and 100% in Thin Prep with comparable sensitivity, specificity, diagnostic accuracy and negative predictive values. CONCLUSIONS: CSF cytology is a reliable technique for identifying malignancy in CSF. ThinPrep technology can be applied with good results in terms of clear background, cell enrichment, better nuclear details and high cellularity per slide. This article is protected by copyright. All rights reserved. PMID- 30468698 TI - Optimization and validation of simultaneous analyses of ecgonine, cocaine and seven metabolites in human urine by gas chromatography-mass spectrometry using a one-step solid-phase extraction. AB - The presence of ecgonine in urine has been proposed as an appropriate marker of cocaine use. Only a few methods have been published for their determination along with cocaine and the rest of its metabolites. Due to their high polarity and consequent solubility in water, these have low recoveries, which is why it is necessary to increase the sensitivity, by the formation of hydrochloric salts or multiderivatization of the analytes or by performing two solid phase extractions (SPE), considerably increasing the time and cost of the analysis. This work describes a fast and fully validated procedure for the simultaneous detection and quantification of ecgonine, ecgonine-methyl-ester, benzoylecgonine, nor benzoylecgonine, m-hydroxybenzoylecgonine, cocaethylene, cocaine, norcocaine and norcocaethylene in human urine (500 MUL) using one SPE and simple derivatization. Separation and quantification were achieved by gas chromatography/electron ionization mass spectrometry (GC/EI-MS) in selected-ion monitoring mode. Quantification was performed by the addition of deuterated analogues as internal standards. Calibration curves were linear in the adopted ranges, with determination coefficients higher than 0.99. The lower limits of quantification ranged from 2.5 to 10 ng/mL. The intra- and inter-day precision, calculated in terms of relative standard deviation, were 1.2-14.9% and 1.8-17.9%, respectively. The accuracy, in terms of relative error, was within a +/-16.4% interval. Extraction efficiency ranged from 84 to 103%. Compared with existing methods, the herein described procedure is fast, since one SPE is required, and cost effective. In addition, this method provides a high recovery for ecgonine, resulting in a better alternative to the previously published methods. PMID- 30468699 TI - Application of a molecular networking approach for clinical and forensic toxicology exemplified in three cases involving 3-MeO-PCP, doxylamine, and chlormequat. AB - Untargeted toxicological screening is an analytical challenge, given the high number of molecules and metabolites to be detected and the constant appearance of new psychoactive substances (NPS). The combination of liquid chromatography with high-resolution tandem mass spectrometry (MS/MS) in a data-dependent acquisition mode generates a large volume of high quality spectral data. Commercial software for processing MS data acquired during untargeted screening experiments usually compare measured features (mass, retention time, and fragmentation spectra) against a predefined list of analytes. However, there is a lack of tools for visualizing and organizing MS data of unknown compounds. Here, we applied molecular networking to untargeted toxicological screening. This bioinformatic tool allows to explore and organize MS/MS data without prior knowledge of the sample's chemical composition. The organization of spectral data is based on spectral similarity. Hence, important information can be obtained even before the annotation step. The link established between molecules enables the propagation of structural information. We applied this approach to three clinical and forensic cases with various matrices: (i) blood and a syringe content in a forensic case of death by self-injection, (ii) hair segments in a case of drug facilitated assault, and (iii) urine and blood samples in a case of 3 methoxyphencyclidine intoxication. Data preprocessing with MZmine allows sample to-sample comparison and generation of multisample molecular networks. Our present study shows that molecular networking can be a useful complement to conventional approaches for untargeted screening interpretation e.g. for xenobiotics identification or NPS metabolism elucidation. PMID- 30468700 TI - Subnormothermic short-term cultivation improves the vascularization capacity of adipose tissue-derived microvascular fragments. AB - Adipose tissue-derived microvascular fragments (ad-MVF) are promising vascularization units for tissue engineering. In this study we analyzed the effects of normo- (37 degrees C) and subnormothermic (20 degrees C) short-term cultivation on their viability and network forming capacity. Ad-MVF from green fluorescent protein (GFP)+ and GFP- C57BL/6 mice were cultivated for 24 h at 37 degrees C or 20 degrees C. Freshly isolated, non-cultivated ad-MVF served as controls. Number, length, viability, proliferation and angiogenic activity of the ad-MVF were assessed by microscopic analysis and proteome profiling. GFP+ ad-MVF were seeded onto collagen-glycosaminoglycan matrices, which were implanted into dorsal skinfold chambers of GFP- mice to analyze their vascularization by means of intravital fluorescence microscopy, histology and immunohistochemistry. Depending on the temperature short-term cultivation of ad-MVF markedly changed their expression of multiple pro- and anti-angiogenic factors. Moreover, cultivation at 37 degrees C significantly increased the number of apoptotic cells within ad-MVF, while 20 degrees C preserved the viability of ad-MVF and even promoted the proliferation of endothelial and perivascular cells. Accordingly, ad-MVF cultivated at 20 degrees C also exhibited an enhanced in vivo vascularization capacity when compared to normothermically cultivated ad-MVF and non-cultivated controls. This was indicated by an accelerated network formation, an increased microvascular remodeling and a higher density of GFP+ microvessels within implanted matrices. Thus, if ad-MVF require short-term storage before in vivo application subnormothermic cultivation should be preferred to normothermic cultivation. PMID- 30468701 TI - Cytopathologic characteristics of HPV-related small cell carcinoma of the oropharynx. AB - BACKGROUND: Human papillomavirus (HPV)-related squamous cell carcinoma (SqCC) of the oropharynx is an epidemiologically and clinically distinct form of SqCC that is associated with an improved prognosis. However, HPV-related small cell carcinoma of the oropharynx is a rare and newly described variant that is associated with aggressive clinical behavior and poor outcomes. To date, fewer than 2 dozen reports of this entity exist in the literature, and there is no discussion of cytopathologic features. This article reports 6 cases and discusses the salient cytomorphologic findings, ancillary studies, and challenges when this entity is encountered. METHODS: Anatomic pathology archives were searched to identify patients with a diagnosis of HPV-related small cell carcinoma of the oropharynx. Medical records were reviewed to document the following: age, sex, smoking status, other relevant clinical history, primary location, treatment, and clinical outcome. Both p16 and high-risk HPV in situ hybridization (ISH) studies were positive in at least 1 specimen from each patient. The pathologic diagnoses, cytomorphologic characteristics, immunocytochemical stains, and HPV ISH studies were reviewed and recorded for all available cases. RESULTS: Six patients with 11 cytopathology specimens of HPV-related small cell carcinoma of the oropharynx were identified. The mean age was 61.3 years, and all patients died with widely metastatic disease (mean, 23 months; range, 12-48 months). Mixed small cell carcinoma and SqCC components were present in half of the cases. CONCLUSIONS: The identification of a small cell component can be reliably performed with cytology preparations and is crucial because this (and not the HPV status) determines the prognosis. PMID- 30468702 TI - Structure and Dynamics of Water at the Water-Air Interface Using First Principles Molecular Dynamics Simulations within Generalized Gradient Approximation. AB - First principles molecular dynamics simulations within the density functional theory framework have been used to predict the surface structure of water at various aqueous interfaces, whereas there is no clear consensus on the choice of appropriate simulation parameters, such as exchange-correlation functions and van der Waals corrections yet. Here, we report the systematic survey for the structure and dynamics of water at the water-air interface simulated with various combinations of the exchange-correlation functionals within the generalized gradient approximation and empirical dispersion corrections. Particularly, we focus on the structure and dynamics of the free O-D group of D2O, as well as the surface tension of water. Through the comparison of these quantities with the experimental and accurate force field calculation, we conclude that revPBE with van der Waals correction shows significantly better results for simulating various air-water interfacial properties than BLYP and PBE functionals. PMID- 30468703 TI - AMBER and CHARMM force fields inconsistently portray the microscopic details of phosphorylation. AB - Phosphorylation of serine, threonine, and tyrosine is one of the most frequently occurring and crucial post-translational modifications of proteins often associated with important structural and functional changes. We investigated the direct effect of phosphorylation on the intrinsic conformational preferences of amino acids as a potential trigger of larger structural events. We conducted a comparative study of force fields on terminally capped amino acids (dipeptides) as the simplest model for phosphorylation. Our bias-exchange metadynamics simulations revealed that all model dipeptides sampled a great heterogeneity of ensembles affected by introduction of mono- and dianionic phosphate groups. However, the detected changes in populations of backbone conformers and side chain rotamers did not reveal a strong discriminatory shift in preferences, as could be anticipated for the bulky, charged phosphate group. Furthermore, the AMBER and CHARMM force fields provided inconsistent populations of individual conformers as well as net structural trends upon phosphorylation. Detailed analysis of ensembles revealed competition between hydration and formation of internal hydrogen bonds involving amide hydrogens and the phosphate group. The observed difference in hydration free energy and potential for hydrogen bonding in individual force fields could be attributed to the different partial atomic charges used in each force field and, hence, the different parametrization strategies. Nevertheless, conformational propensities and net structural changes upon phosphorylation are difficult to extract from experimental measurements, and existing experimental data provide limited guidance for force field assessment and further development. PMID- 30468704 TI - Analysis of Lipid Order States and Domains in Lipid Bilayer Simulations. AB - We propose a general procedure to analyze lipid order states and domains in lipid bilayer simulations using surface areas and hydrophobic thicknesses of lipids. In our approach, the observable order states of individual lipids are inferred by a hidden Markov model analysis of their time series and by considering the deformation of a lipid at different packing environments. The assigned lipid order states are mapped onto the Voronoi tessellation of lipids, from which the ordered/disordered lipids are robustly clustered by the Getis-Ord local spatial autocorrelation statistics. The usefulness of this method is illustrated by its application to the quinary mixed bilayers consisting of cholesterol (Chol), 1,2 dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dimyristoyl-sn-glycero-3 phosphoethanolamin (DMPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), where any type of phospholipids does not show strong preference over the other types to be enriched in lipid domains. The independent order state analysis for each lipid type allows straightforward applications of our method to arbitrarily complex bilayer simulations. PMID- 30468705 TI - Hybrid Cascade-Type Molecular Dynamics with Markov State Model for Efficient Free Energy Calculations. AB - A protocol for calculating free energy landscape (FEL) is proposed based on a combination of two cascade-type molecular dynamics (MD) methods, parallel cascade selection MD (PaCS-MD) and outlier flooding method (OFLOOD), with a help of Markov state model (MSM). The former rapidly generate approximated transition paths directly connecting reactants with products, and the latter complementary resampled marginal conformational subspaces. Trajectories obtained by them give reliable microstates in MSM providing accurate FEL with low computational costs. As a demonstration, the present method was applied to a mini-protein (Chignolin and Trp-cage) in explicit water and successfully elucidated multiple folding paths on their free energy landscapes. Our method could be applicable to a wide variety of biological systems to estimate their free energy profiles. PMID- 30468706 TI - Colorimetric Detection of Carcinogenic Alkylating Fumigants on Nylon-6 Nanofibrous Membrane. Part I: Investigation of 4-( p-Nitrobenzyl) Pyridine as A "New" Sensing Agent with Ultra-High Sensitivity. AB - Alkylating fumigants are widely used in agricultural production for the control of soil-borne pests, but the acute toxicity and carcinogenicity of these chemicals pose a health threat to farm workers as well as residents. A nanofibrous membrane-based colorimetric sensor relying on the nucleophilic substitution reaction of 4-(p-nitrobenzyl) pyridine (NBP) is introduced for the convenient and portable detection of alkylating fumigants. Comparing with the traditional use of NBP in detecting alkylating agents, this sensor system achieves a ppb-level detection sensitivity toward alkylating fumigant gases without a high-temperature incubation or the addition of extra bases. The mechanisms of the detection reaction and the detection sensitivities of different fumigants were studied with computational methods, and the results comprehensively prove the proposed optimized detection mechanisms. The detection limit of methyl iodide, methyl bromide, and 1, 3-dichloropropene successfully reaches to the limiting exposure concentrations (PEL or REL) with a naked-eye detectable color difference within 5 min with a dynamic detection procedure. The designed sensing system is promising for a real-time monitoring of the air quality related to alkylating fumigants in the environment, especially in agricultural and industrial areas. PMID- 30468707 TI - The effects of SDS at subsolubilizing concentrations on the planar lipid bilayer permeability: Two kinds of current fluctuations. AB - Detergent effects on lipid bilayers of artificial and biological membranes at subsolubilizing concentrations are known to include the membrane permeabilization which manifests itself through both a flip-flop of detergent molecules from the outer monolayer to the inner monolayer and the membrane leakage of entrapped solutes. We have explored the current fluctuations occurring in planar BLM of asolectin in the presence of ionic detergent SDS at subsolubilizing concentration. Two groups of current fluctuations which the average duration differs by two orders of magnitude can be distinguished. We assume that these differences in the duration of current fluctuations are associated with a different number of SDS molecules in the walls of the putative toroidal hydrophilic pores. We associated short pulses with the formation of short-lived lipid hydrophilic pores. Impulses of greater duration (steps) were associated with the formation of hydrophilic pores, the walls of which contain detergent. Taking into account the characteristics of these pores, we estimated the pore energy, as well as the edge energy of these two kinds of pores. We believe that the flip-flop of SDS molecules in liposomes is provided by long-lived pores, and the contents of the liposome leakage occurs through all pores. PMID- 30468708 TI - Time of catheter removal in candidemia and mortality. AB - BACKGROUND: The impact of central venous catheter (CVC) removal on the outcome of patients with candidemia is controversial, with studies reporting discrepant results depending on the time of CVC removal (early or any time during the course of candidemia). OBJECTIVE: Evaluate the effect of time to CVC removal, early (within 48h from the diagnosis of candidemia) vs. removal at any time during the course of candidemia, on the 30-day mortality. METHODS: Retrospective cohort study of 285 patients with candidemia analyzing CVC removal within 48h (first analysis) or at any time (second analysis). RESULTS: A CVC was in place in 212 patients and was removed in 148 (69.8%), either early (88 patients, 41.5%) or late (60 patients, 28.3%). Overall, the median time to CVC removal was one day (range 1-28) but was six days (range 3-28) for those removed later. In the first analysis, APACHE II score (odds ratio [OR] 1.111, 95% confidence interval [95% CI] 1.066-1.158), removal at any time (OR 0.079, 95% CI 0.021-0.298) and Candida parapsilosis infection (OR 0.291, 95% CI 0.133-0.638) were predictors of 30-day mortality. Early removal was not significant. In the second analysis APACHE II score (OR 1.122, 95% CI 1.071-1.175) and C. parapsilosis infection (OR 0.247, 95% CI 0.103-0.590) retained significance. CONCLUSIONS: The impact of CVC removal is dependent on whether the optimal analysis strategy is deployed and should be taken into consideration in future analyses. PMID- 30468709 TI - CircZFR promotes hepatocellular carcinoma progression through regulating miR-3619 5p/CTNNB1 axis and activating Wnt/beta-catenin pathway. AB - Circular RNAs (circRNAs) have been discovered to exert essential roles in human cancers, including hepatocellular carcinoma. Although circZFR has been reported to facilitate the growth of papillary thyroid cancer, the role of circZFR in hepatocellular carcinoma (HCC) are largely unknown. In this study, bioinformatics analysis showed that circZFR was closely related with hepatocellular carcinoma. We then detect the expression of circZFR in HCC tissues using qRT-PCR. Furthermore, Kaplan-Meier method and log rank test revealed that high expression of circZFR was associated with the poor prognosis of patients with HCC. Subsequently, loss-of-function assay indicated that circZFR knockdown significantly suppressed cell proliferation and epithelial-mesenchymal transition (EMT) in HCC. In addition, microarray analysis was utilized to identify the differentially expressed mRNAs in response to circZFR knockdown. Moreover, Gene Ontology (GO) analysis further showed that circZFR might regulate Wnt/beta catenin signaling pathway. The results were further confirmed by luciferase reporter assay and western blot assays. Then bioinformatics tools predicted that cicrZFR enhanced the CTNNB1 expression via sponging miR-3619-5p. In summary, our findings indicated that circZFR may exert carcinogenic role in HCC through regulating miR-3619-5p/CTNNB1 axis and activating Wnt/beta-catenin pathway. These findings may provide a novel perspective for the treatment of hepatocellular carcinoma. PMID- 30468710 TI - Design and structural characterisation of monomeric water-soluble alpha-helix and beta-hairpin peptides: State-of-the-art. AB - Peptides are not only useful models for the structural understanding of protein folding and stability but also provide promising therapeutic avenues for the treatment of numerous diseases, and as biomaterials. The field has been very active over the last decades, but the complex conformational behaviour of peptides still poses challenges to the characterisation and rational design of defined structures. In this context, we aim to provide a comprehensive overview of linear water-soluble monomeric peptides able to form the two simplest structural motifs: alpha-helices and beta-hairpins. For both structures, we describe the geometry features, and the main contributions to stability: intrinsic propensities, position dependence of specific residues, particular capping motifs and side chain interactions. They should be considered to design alpha-helical or beta-hairpin peptides. Solvent influence on peptide stability and selected in silico design approaches are also discussed. Moreover, we provide guidelines for structural characterisation of alpha-helical and beta-hairpin forming peptides by NMR and circular dichroism. We also highlight recently reported designed peptides and current strategies developed to improve their stability, bioactivity and bioavailability. The information gathered herein may aid peptide design and characterisation of stable alpha-helical and beta-hairpin motifs in the search of biological constructs or improved peptide therapeutics. PMID- 30468711 TI - Ribosome biogenesis: An emerging druggable pathway for cancer therapeutics. AB - Ribosomes are nanomachines essential for protein production in all living cells. Ribosome synthesis increases in cancer cells to cope with a rise in protein synthesis and sustain unrestricted growth. This increase in ribosome biogenesis is reflected by severe morphological alterations of the nucleolus, the cell compartment where the initial steps of ribosome biogenesis take place. Ribosome biogenesis has recently emerged as an effective target in cancer therapy, and several compounds that inhibit ribosome production or function, killing preferentially cancer cells, have entered clinical trials. Recent research indicates that cells express heterogeneous populations of ribosomes and that the composition of ribosomes may play a key role in tumorigenesis, exposing novel therapeutic opportunities. Here, we review recent data demonstrating that ribosome biogenesis is a promising druggable pathway in cancer therapy, and discuss future research perspectives. PMID- 30468712 TI - BubR1 depletion delays apoptosis in the microtubule-depolymerized cells. AB - We investigated the role of a spindle assembly checkpoint protein, BubR1, in determining the mechanism of cell killing of an anti-microtubule agent CXI-benzo 84. CXI-benzo-84 dampened microtubule dynamics in live MCF-7 cells. The compound arrested MCF-7 cells in mitosis and induced apoptosis in these cells. Though CXI benzo-84 efficiently depolymerized microtubules in the BubR1-depleted MCF-7 cells, it did not arrest the BubR1-depleted cells at mitosis. Interestingly, apoptosis occurred in the BubR1-depleted MCF-7 cells in the absence of a mitotic block suggesting that the mitotic block is not a prerequisite for the induction of apoptosis by anti-microtubule agents. In the presence of CXI-Benzo-84, the level of apoptosis was initially found to be lesser in the BubR1-depleted MCF-7 cells than the control cells; however, the BubR1-depleted cells displayed a similar level of apoptosis as the control cells at 72 h of drug treatment. The depletion of BubR1 enhanced DNA damage in MCF-7 cells upon microtubule depolymerization. In addition, CXI-benzo-84 in combination with cisplatin induced more cell death in BubR1-depleted cells than the BubR1-expressing MCF-7 cells. The results indicated a possibility that the BubR1-compromised cancer patients can be treated with combination therapy. PMID- 30468713 TI - The cis-regulatory logic underlying abdominal Hox-mediated repression versus activation of regulatory elements in Drosophila. AB - During development diverse transcription factor inputs are integrated by cis regulatory modules (CRMs) to yield cell-specific gene expression. Defining how CRMs recruit the appropriate combinations of factors to either activate or repress gene expression remains a challenge. In this study, we compare and contrast the ability of two CRMs within the Drosophila embryo to recruit functional Hox transcription factor complexes. The DCRE CRM recruits Ultrabithorax (Ubx) and Abdominal-A (Abd-A) Hox complexes that include the Extradenticle (Exd) and Homothorax (Hth) transcription factors to repress the Distal-less leg selector gene, whereas the RhoA CRM selectively recruits Abd A/Exd/Hth complexes to activate rhomboid and stimulate Epidermal Growth Factor secretion in sensory cell precursors. By swapping binding sites between these elements, we found that the RhoA Exd/Hth/Hox site configuration that mediates Abd A specific activation can convey transcriptional repression by both Ubx and Abd-A when placed into the DCRE. We further show that the orientation and spacing of Hox sites relative to additional binding sites within the RhoA and DCRE is critical to mediate cell- and segment-specific output. These results indicate that the configuration of Exd, Hth, and Hox site within RhoA is neither Abd-A specific nor activation specific. Instead Hox specific output is largely dependent upon the presence of appropriately spaced and oriented binding sites for additional TF inputs. Taken together, these studies provide insight into the cis-regulatory logic used to generate cell-specific outputs via recruiting Hox transcription factor complexes. PMID- 30468714 TI - Changes of serum homocysteine levels during pregnancy and the establishment of reference intervals in pregnant Chinese women. AB - BACKGROUD: Reference intervals (RIs) of clinical laboratory indexes are important basis for interpretation of corresponding test results. While elevated homocysteine (HCY) level is a risk factor of some severe gestational diseases, HCY RIs for pregnant women have not been reported so far. The current use of HCY RIs established for general population in pregnant women may challenge clinicians' judgment. This study aims to investigate the changes of serum HCY levels during pregnancy and establish the RIs of serum HCY in healthy pregnant Chinese women to provide valuable data to clinicians and enable the provision of more appropriate therapy. METHODS: 354 healthy pregnant Chinese women were randomly selected and divided into three groups according to gestational age: 114 in first trimester (1-13 week), 120 in second trimester (14-27 week) and 120 in third trimester (>=28 week). 120 healthy non-pregnant Chinese women were randomly selected as the non-pregnant control group. Serum HCY levels were determined on automatic biochemical analyzer with enzymatic cycling method. The RIs of serum HCY for healthy pregnant women were established using a nonparametric method. RESULTS: the RIs of serum HCY for healthy pregnant women is 5.79-11.86 MUmol/L in first and second trimester (combined) and 6.13-16.75 MUmol/L in third trimester. Besides, the RIs of serum HCY for healthy non-pregnant women is 8.25-22.92 MUmol/L. CONCLUSIONS: Rigorously according to CLSI C28-A3 guidelines, the authoritative document of RIs establishment, the RIs of serum HCY for healthy pregnant Chinese women were established, which will provide a valuable reference for clinical work and laboratory researches. PMID- 30468715 TI - Noncoding RNA activated by DNA damage (NORAD): Biologic function and mechanisms in human cancers. AB - Noncoding RNA activated by DNA damage (NORAD) is a newly identified long non coding RNA (lncRNA) comprising one exon located on Chr20q11.23. NORAD is unique among lncRNAs because it is highly conserved, abundantly expressed, upregulated upon DNA damage, and maintains chromosomal stability in human cells. NORAD is dysregulated in different types of cancers and has been implicated in several processes correlated with carcinogenesis, such as cell proliferation, invasion, metastasis, and apoptosis. The mechanisms underlying the effects of NORAD are complex and involve multiple factors and signaling pathways. The biologic function and mechanisms of NORAD in human cancers are systematically reviewed here to provide new directions for future research. PMID- 30468716 TI - Quantitative LC-MS and MS/MS analysis of sialylated glycans modified by linkage specific alkylamidation. AB - Sialic acids (Sia) are involved in various biological and pathological processes, and are often found attached to non-reducing ends of glycans through either alpha2,3- or alpha2,6-linkages. To quantitatively analyze glycan structures with these linkage isoforms by liquid chromatography-mass spectrometry (LC-MS), we established a linkage-specific two-step alkylamidation method for N-glycans. Using this method, carboxyl groups of alpha2,3- and alpha2,6-linked Sia are derivatized with two kinds of alkylamines with different mass values in a linkage specific manner, allowing products to be easily distinguished. The reaction efficiencies for di-, tri-, and tetra-sialyl PA-N-glycans were >94%, with few by products. Mixtures of 2-aminopyridine (PA)-tagged N-glycans from human alpha1 acid glycoprotein were subjected to the method, and products were analyzed by LC MS and MS/MS, and simultaneously monitored with a fluorescence detector. The relative content of Siaalpha2-3Gal and Siaalpha2-6Gal was estimated from the integrated fluorescence intensity of each peak. Moreover, MS/MS data clearly indicated characteristic B-ion fragments of N-glycan branches, such as the sialyl Lex sequence, with Sia linkage-specific alkylamidation, suggesting that this method also provides useful information of branch sequences. We optimized the method with the aim of (1) enabling high-throughput analysis and (2) maximizing the analysis of glycans from various types of samples, including highly heterogeneous glycans. PMID- 30468717 TI - Simple and effective label free electrochemical immunosensor for Fig mosaic virus detection. AB - Here, the construction and characterization of the first immunosensor for highly sensitive and label free detection of Fig mosaic virus (FMV) is reported. The specific antibody against nucleocapsid of the virus was raised and immobilized at the surface of 11-mercaptoundecanoic acid (MUA) and 3-mercapto propionic acid (MPA) modified gold electrode, via carbodiimide coupling reaction. The immunosensor fabrication steps were characterized using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The electrochemical detection of FMV was conducted using differential pulse voltammetry in ferri/ferrocyanide solution as a redox probe. The proposed immunosensor exhibited high selectivity, good reproducibility and high sensitivity for FMV detection in a range from 0.1 nM to 1 MUM with a detection limit of 0.03 nM. Moreover, good results were obtained for determination of FMV in real samples, indicating the feasibility of the developed immunosensor for detection of fig mosaic disease, without the need for molecular (e.g. PCR) amplification. PMID- 30468718 TI - Elephant shark melanocortin receptors: novel interactions with MRAP1 and implication for the HPI axis. AB - The presence of Mrap1 and Mrap2 orthologs in the genome of the elephant shark (es), a cartilaginous fish, presented an opportunity to evaluate the potential interactions between these accessory proteins and melanocortin receptors of a cartilaginous fish. RT-PCR analysis indicated that Mrap1 mRNA was present in interrenal, brain, and pituitary tissue with mRNA for Mc2R, Mc3R, Mc4R, and Mc5r. Co-expression of esMrap1 cDNA with esMc2r cDNA or esMc5r cDNA in CHO cells increased sensitivity to stimulation with ACTH(1-24) 10 fold and 100 fold, respectfully, but had no effect on sensitivity to stimulation with DesAc-alphaMSH [i.e., ACTH(1-13)NH2] for either receptor, and had no effect on the ligand sensitivity of either esMc3r or esMc4r. Fluorescence image analysis indicated co localization of esMrap1/esMc2r, and esMrap1/esMc5r on the plasma membrane; however, cell surface ELISA analysis indicated that co-expression with esMrap1 had no effect, positive or negative, on the trafficking of either esMc2r or esMc5r to the plasma membrane. RT-PCR analysis also indicated that Mrap2 mRNA, as well as, mRNAs for Mc2r, Mc3r, Mc4r, and Mc5r could be detected in brain tissue, however no Mrap2 mRNA was detected in interrenal tissue. Co-expression of esMrap2 in CHO cells with, respectively, esMc2r, esMc4r, or esMc5r had no effect on ligand sensitivity. However, co-expression of esMrap2 with esMc3r did lower sensitivity to stimulation by DesAc-alphaMSH 10 fold. These observations are discussed in the context of the parallel evolution of melanocortin receptors and their accessory proteins, and the hypothalamus/pituitary/adrenal axis and the hypothalamus/pituitary/interrenal axis in bony vertebrates and cartilaginous fishes. PMID- 30468719 TI - Bruch's membrane allows unhindered passage of up to 2 MUm latex beads in an in vivo porcine model. AB - PURPOSE: It has been proposed that changes in the permeability of Bruch's membrane play a role in the pathogenesis of age-related macular degeneration (AMD). This paper investigates, in an in vivo porcine model, the migration of fluorescent latex beads across the Bruch's membrane after subretinal injection. METHODS: Forty-one healthy eyes of 33 three-month-old domestic pigs received a subretinal injection of 0.5, 1.0, 2.0, or 4.0 MUm fluorescent latex beads. Between three hours and five weeks after injection evaluations were performed with fundus photographs and histology. Fluorescent beads were identified in unstained histologic sections using the rhodamine filter with the light microscope. RESULTS: The fluorescent latex beads relocated from the subretinal space. Intact beads up to 2.0 MUm were found in the choroid, sclera, and extrascleral space. The smaller beads were also found inside choroidal and extrascleral blood vessels. In contrast, the larger beads of 4.0 MUm did not pass the Bruch's membrane. CONCLUSION: Subretinally implanted beads up to 2.0 MUm pass the Bruch's membrane intact and cross the blood-ocular barrier. The intact beads are found in the choroid, sclera and inside blood vessels. The results give reason to consider the role of subretinal clearance and passage of Bruch's membrane in the development of AMD. PMID- 30468720 TI - Incidence of uterine rupture in second trimester abortion with gemeprost alone compared to mifepristone and gemeprost. AB - OBJECTIVES: To compare uterine rupture rates in women having a medical abortion receiving gemeprost alone to those receiving mifepristone plus gemeprost. STUDY DESIGN: We reviewed the records of women undergoing medical abortion at 13 0/7-23 6/7weeks from January 2007 to December 2014 at a single center in Italy. Prior to January 2011, we used gemeprost 1mg vaginally every 3h up to a maximum of 5 doses. After January 2011, we added mifepristone 200 mg orally 24h prior to the same gemeprost protocol. The primary outcome of the study was the incidence of uterine rupture. We compared the outcome between women receiving gemeprost alone with the combination of gemeprost and mifepristone. RESULTS: One thousand and sixty-one (58.5%), and 753 (41.5%) women underwent medical abortion in the gemeprost alone and the gemeprost/mifepristone groups, respectively. Five (0.47%) uterine ruptures occurred in the gemeprost and four uterine ruptures occurred in the gemeprost/mifepristone groups, respectively (0.53%) (p=.89). All uterine ruptures occurred in women with prior cesarean delivery. CONCLUSIONS: We reported no difference in the incidence of uterine rupture between the gemeprost alone and gemeprost and mifepristone groups. IMPLICATIONS: Uterine rupture is a rare complication of second trimester medical abortion with gemeprost. Use of mifepristone prior to gemeprost does not affect this risk. PMID- 30468721 TI - Cell phone ownership and modern contraceptive use in Burkina Faso: implications for research and interventions using Mobile technology. AB - OBJECTIVES: With over 420 million unique cell phone subscribers in Sub-Saharan Africa, the opportunities to use personal cell phones for public health research and interventions are increasing. We assess the association between cell phone ownership and modern contraceptive use among women in Burkina Faso to understand the opportunity to track family planning indicators using cell phone surveys or provide family planning interventions remotely. STUDY DESIGN: We analyzed data from a cross-sectional, nationally representative population-based survey of women of reproductive age in Burkina Faso, the Performance Monitoring and Accountability 2020 (PMA2020) Round 4, which was conducted between November 2016 and January 2017. RESULTS: Among the 3215 female respondents aged 15 to 49years, 47% reported cell phone ownership. Overall, 22% of women reported current modern contraceptive use. Women who owned a cell phone were more likely to report modern contraceptive use than those who did not (29% versus 15%). Adjusted for covariates (age, wealth, education, area of residence and marital status), the odds of reporting modern contraceptive use were 68% higher among cell phone owners compared to non-owners (OR=1.68, 95% confidence interval 1.3-2.1). Method mix was substantially more diverse among those who owned cell phones, compared to their counterparts. CONCLUSIONS: The study shows cell phone ownership is significantly associated with modern contraceptive use in Burkina Faso, even after adjusting for women's sociodemographic characteristics. These results suggest that cell phone ownership selectivity and associated biases need to be addressed when planning family planning programs or conducting surveys using cell phones. IMPLICATIONS: Cell phones can be used for myriad family planning purposes, from confidential data collection to contraceptive promotion and knowledge dissemination, but ownership bias is significant. A cell phone-based intervention or population-based survey is unlikely to reach a critical mass of the population at highest risk for unintended pregnancy. PMID- 30468722 TI - A Retrospective Review of the Sepsis Definition after Publication of Sepsis-3. AB - PURPOSE: To determine if the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) was being utilized in defining sepsis in the clinical setting. BACKGROUND: Two and one-half years after the introduction of the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), clinicians continue to not be documenting Sequential Organ Failure Assessment (SOFA) scores. There continues to be variations in what standard is accepted by both commercial payers and CMS in diagnosing sepsis. METHODS: One hundred patients between February 2016 through March 2018 who were diagnosed with sepsis were retrospectively reviewed for the presence of criteria for the diagnosis of sepsis. Data points for SOFA criteria were analyzed. RESULTS: None of the septic patients were diagnosed utilizing Sequential Organ Failure Assessment (SOFA) scores. Many of the data points were found to not have been collected or measured to complete a SOFA score. CONCLUSIONS: Due to Sepsis-3 criteria not being accepted by Centers for Medicare and Medicaid (CMS) as well as the Infectious Disease Society of America along with it not being able to be operationalized for use in the clinical setting, it is recommended to continue utilizing SIRS criteria plus infection while Sepsis-3 continues to be evaluated. It will also allow for some time to study any effect it may have on patient outcomes. There is also a need for a uniform definition of sepsis. PMID- 30468723 TI - Cortical processing of irrelevant somatosensory information from the leg is altered by attention during early movement preparation. AB - The ability to actively suppress, or gate, irrelevant sensory information is needed for safe and efficient walking in sensory-rich environments. Both attention and the late phase of motor preparation alter somatosensory evoked potentials (SEPs) in healthy adults. The aim of this study was to examine the effect of attention on the processing of irrelevant somatosensory information during the early phase of preparation of plantarflexion movements. Young healthy individuals received tibial nerve stimulation while electroencephalography (EEG) recorded SEPs over the Cz electrode. Three conditions were tested in both legs: 1) Rest, 2) Attend To the stimulated limb, and 3) Attend Away from the stimulated limb. In conditions 2 and 3, vibration (80 Hz) was applied over the medial soleus muscle to cue voluntary plantarflexion movements of the stimulated (Attend To) or non-stimulated leg (Attend Away). Only SEPs delivered during early preparation were averaged for statistical analysis. Results demonstrated a main effect of condition for the N40 and N70 indicating that SEP amplitudes in the Attend To condition were smaller than rest (p <= 0.02). For the P50, no interaction effects or main effects were found (p >= 0.08). There was no main effect of leg for any component measured. The results indicate that gating of irrelevant sensory information during early preparation occurs in the leg when attention is directed within the same limb. If attention alters the somatosensory stimuli from a leg movement, then directing attention may affect safe community walking. PMID- 30468724 TI - Leptin and HPA Axis Activity in Diabetic Rats: Effects of adrenergic agonists. AB - Type I Diabetes (T1D) is associated with reduced leptin levels and increased stress axis activity marked by elevations in norepinephrine (NE) levels in the paraventricular nucleus (PVN) of the hypothalamus. We hypothesized that leptin suppresses stress axis activity in T1D through central and peripheral mechanisms. In the first experiment, adult male Sprague Dawley rats were implanted with a cannula in the PVN and randomly divided into a non-diabetic group treated with vehicle (n=6) and a diabetic group treated with streptozotocin (n=13). Food intake and water intake was measured for 14 days. On the last day, a subset of diabetic rats were treated with 500ug of leptin i.p. Rats were subjected to push pull perfusion of the PVN and hourly blood sampling for 5 hours. In the next experiment, diabetic rats were treated either with an alpha-2 adrenergic agonist, clonidine (CLON), or a beta adrenergic agonist isoproterenol (ISO), to reverse the effects of leptin. Rats were subjected to push pull perfusion and hourly blood sampling. In experiment 1, T1D increased food intake, water intake, NE release in the PVN and circulating CS levels. Leptin treatment decreased NE release modestly but produced a robust reduction in corticosterone (CS) levels. In experiment 2, CLON but not ISO was able to reverse the effect of leptin on NE levels in the PVN, however, both agonists were capable of blocking leptin's effects on circulating CS. These results suggest that in diabetic rats, the sensitivity of the hypothalamus to beta adrenergic agonists is altered, while the adrenals remain sensitive to both alpha and beta adrenergic agonists. PMID- 30468725 TI - Evaluation of cholinergic functions in patients with Japanese encephalitis and Herpes simplex encephalitis. AB - Cognitive and memory impairment are related to cholinergic dysfunction and are important complication of viral encephalitis, In view of paucity of studies on cholinergic dysfunction in encephalitis, this study has been undertaken. We report AChE and M2 receptor levels in HSE and Japanese encephalitis (JE) patients, and correlate these with cognitive functions and MRI findings. Patients with JE and HSE were evaluated for consciousness, neurological and MRI findings , plasma AChE and M2 receptor levels on admission and after one year Results: Twenty-nine patients with JE and 23 with HSE were included . Admission AChE levels in JE (48.32 +/- 5.36 nmol/min/ml) and HSE (41.92 +/- 5.12 nmol/min/ml) were significantly lower compared with controls (70.50 +/- 8.30 nmol/min/ml). M2 receptor levels were also low in JE (4.52 +/- 0.56 ng/ml) and HSE (4.35 +/- 0.57 ng/ml) compared with controls (7.95 +/- 0.41 ng/ml). In JE, AChE activity (r = 0.43, p = 0.02) and M2 receptor levels (r = 0.43, p = 0.02) correlated with caudate involvement, and AChE activity (r = 0.76, p = 0.03) with MMSE. In HSE, M2 receptor levels (r = 0.53, p = 0.03) correlated with MMSE. The levels of AChE and M2 receptors increased at one year compared to the baseline, which was greater in JE than in HSE. Both AChE and M2 receptors were reduced in JE and HSE and correlated with cognition at one year .Recovery of these biomarkers was more in JE than HSE. PMID- 30468726 TI - Dissociable neural mechanisms underlie value-driven and selection-driven attentional capture. AB - Stimuli associated with reward acquire the ability to automatically capture attention. It is also the case that, with sufficient training, former targets can acquire the ability to capture attention in the absence of extrinsic rewards. It remains unclear whether these two experience-dependent attentional biases share a common underlying mechanism. The present study examined the influence of selection history on attentional capture, and compared its neural correlates with those of value-driven attentional capture reported in Anderson et al. (2014a). Participants completed a four-day training in visual search for a specific colour target. In a subsequent test phase, they performed visual search for a shape defined target in which colour was task-irrelevant. Response times were slower when a former target-colour distractor was present than when it was absent, replicating attentional capture by unrewarded former targets. Neuroimaging results revealed preferential activation by a former target-colour distractor in sensory areas. A more right lateralised pattern of activation was observed, compared to attentional capture by reward cues. No distractor-evoked activity was found in the caudate tail. These results imply that attentional capture by selection history is primarily driven by plasticity in sensory areas, and that reward history and selection history influence attention via dissociable underlying mechanisms. PMID- 30468727 TI - Adjuvant chemotherapy improves survival in surgically resected stage IB squamous lung cancer. AB - BACKGROUND: At present, there is a significant lack of clinical data for patients with surgically resected stage I squamous lung cancer. The purpose of this study was to investigate the impact of postoperative chemotherapy in this specific population. METHODS: We retrospectively identified patients who had undergone complete squamous lung cancer resection at the Shanghai Chest Hospital between January 2008 and January 2014. RESULTS: A total of 596 patients (236 stage IA, 360 stage IB) were included in this study. Results demonstrated that adjuvant chemotherapy could provide longer overall survival for patients with p-stage IB disease (hazard ratio [HR] = 0.56, 95% confidence interval [CI]: 0.34-0.90, P = 0.017). Among p-stage IB patients, the adjuvant chemotherapy-treated cohort trended towards a benefit (HR = 0.69, 95% CI: 0.45-1.04) in recurrence-free survival, but failed to reach statistical significance (P = 0.076). After propensity score matching, the HRs of recurrence-free survival and overall survival were 0.58 (95% CI: 0.35-0.96, P = 0.033) and 0.49 (95% CI: 0.27-0.88, P = 0.017), respectively. With regards to patients with p-stage IA disease, neither overall survival (HR = 0.87, 95% CI: 0.34-2.27, P = 0.783) nor recurrence-free survival (HR = 0.79, 95% CI: 0.38-1.65, P = 0.534) was significantly different when compared between the patients receiving adjuvant chemotherapy and those who did not. Similar results were also achieved after propensity score matching. CONCLUSIONS: The data presented herein demonstrated that adjuvant chemotherapy might provide survival benefits for squamous lung cancer patients with p-stage IB disease. PMID- 30468728 TI - Minimally-invasive surgical aortic valve replacement through a right anterior thoracotomy: How I teach it. PMID- 30468729 TI - Interaction of Artepillin C with model membranes: Effects of pH and ionic strength. AB - Artepillin C is the major constituent of green propolis, one of the most consumed products in popular medicine owing to its therapeutic effects, including antitumor activity. Artepillin C differs from other cinnamic acid derivatives due to the presence of two prenylated groups in its structure, believed to enhance access to the cell membrane and resulting in pharmacological activity. The membrane outer leaflet of tumor cells is exposed to an acidic extracellular environment, which could modulate the protonation state of antitumor drugs and hence their interaction with the cell membrane. Herein, we investigated the interaction of Artepillin C with Langmuir monolayers and giant unilamellar vesicles (GUVs) of 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC) used as model membranes, in physiological and acidic environments. We observed that protonation of the carboxyl group of Artepillin C is essential for the interaction, with larger shifts induced in the surface pressure isotherms of DPPC monolayers in comparison with deprotonated Artepillin C. Also observed was a decrease in lipid packing inferred from the compressibility modulus and Brewster angle microscopy (BAM) images for monolayers on acidic subphases. Results with microscopy techniques on GUVs confirmed that. Artepillin C causes a curvature stress of the lipid bilayer only in its neutral state, causing the GUVs to burst. The stronger effects of neutral Artepillin C on both monolayers and GUVs were maintained when the ionic strength was increased. Taken together, the results indicate that Artepillin C may have preferential attachment to a more acidic environment which might be an important feature for its antitumor activity. PMID- 30468730 TI - Use of a gaming platform for balance training following a stroke: a randomized trial. AB - OBJECTIVE: To evaluate a personal computer (PC) gaming platform as a means of improving postural balance in stroke patients. PARTICIPANTS: A total of 54 stroke patients were enrolled and randomly divided into experimental and control groups. DESIGN: The experimental group underwent 12 weeks of rehabilitation involving playing PC games with the proposed gaming platform, whereas the control group played PC games with a computer mouse in the standing position. INTERVENTIONS: The experimental PC gaming platform allowed trunk movements in 3 directions, including lateral, downward, or upward reaching. MAIN OUTCOME MEASURES: Balance control was assessed before and after the intervention with the Midot Posture Scale Analyzer (a pressure platform), by measuring the center of pressure during quiet stance. The Berg Balance Scale, Fullerton Advanced Balance Scale, and timed up and go tests were used to evaluate functional balance. RESULTS: Analysis of covariance was used to assess how the PC games improve balance abilities. There were significant differences between the experimental and control groups in the results of sway kinematics and functional balance tests. The experimental group showed greater improvement than the control group. CONCLUSION: This new gaming platform with adaptive PC games could be a useful therapy to stroke rehabilitation in patients with postural imbalance. PMID- 30468731 TI - Knockdown of growth-arrest specific transcript 5 restores oxidized low-density lipoprotein-induced impaired autophagy flux via upregulating miR-26a in human endothelial cells. AB - Endothelial cells injury and autophagy dysfunction play vital roles in the development of atherosclerosis. Long noncoding RNAs (lncRNAs) have been identified to participate in the pathogenesis of atherosclerosis. However, it remains largely undefined whether lncRNA growth-arrest specific transcript 5 (GAS5) could influence ox-LDL-induced autophagy dysfunction in endothelial cells. The expression levels of GAS5 and miR-26a were detected in the plasma samples of patients with atherosclerosis and oxidized low-density lipoprotein (ox-LDL) treated human aortic endothelial cells (HAECs) by quantitative real-time PCR (qRT PCR). Luciferase reporter assay, RNA immunoprecipitation (RIP), and RNA pull down were performed to validate whether GAS5 could directly interact with miR-26a. The effects of ox-LDL, GAS5 or combined with miR-26a on apoptosis and autophagy were evaluated by flow cytometry analysis and western blot, respectively. Results showed that GAS5 expression was upregulated and miR-26a was downregulated in the plasma samples of patients with atherosclerosis and ox-LDL-treated HAECs. There was an interaction of reciprocal inhibition between GAS5 and miR-26a expressions in ox-LDL-treated HAECs. We further demonstrated that GAS5 directly bound to miR 26a in HAECs. Additionally, ox-LDL administration induced apoptosis and impaired autophagy flux in HAECs. Moreover, GAS5 knockdown inhibited cell apoptosis and activated autophagy flux, whereas inhibition of miR-26a reversed the effect of GAS5 in HAECs. These results revealed a novel regulatory mechanism for ox-LDL induced impaired autophagy flux in endothelial cells. PMID- 30468732 TI - Mahanine induces apoptosis, cell cycle arrest, inhibition of cell migration, invasion and PI3K/AKT/mTOR signalling pathway in glioma cells and inhibits tumor growth in vivo. AB - Gliomas are among the most frequent types of primary malignancies in the central nervous system. The main treatment for glioma includes surgical resection followed by a combination of radiotherapy and chemotherapy. Despite the availability of several treatments, the average survival for patients with glioma at advanced stages still remains 16 months only. Therefore, there is an urgent need to look for novel and more efficient drug candidates for the treatment of glioma. In the current study the anticancer activity of Mahanine was evaluated against a panel of glioma cells. The results revealed that Mahanine exerted significant anticancer effects on the glioma HS 683 cells with an IC50 of 7.5 MUM. However, the cytotoxic effects were less pronounced on the normal human astrocytes. Further the results showed that the anticancer effects were mainly due to induction of apoptosis and G2/M cell cycle arrest. Western blotting showed that Mahanine caused upregulation of Bax, cytochrome c, cleaved caspase 3 and 9 and cleaved PARP. However, the expression of cell cycle related proteins pCdc25c, Cdc25c, pCdc2, Cdc2 and cyclin B1 was significantly downregulated. The effect of Mahanine on the migration and invasion of HS 683 cells was also determined and results indicated that Mahanine inhibited the cell migration and invasion at IC50. Additionally, Mahanine-inhibited cell growth was simultaneous with suppression of p-PI3K, p-AKT and p-mTOR. Taken together these results indicate that Mahanine may prove to be an important lead molecule for the treatment of glioma and warrants further investigation. PMID- 30468733 TI - Comparison of bead array and glass nanoreactor multi-analyte platforms for the evaluation of CNS and peripheral inflammatory markers during HIV infection. AB - While human immunodeficiency virus (HIV) infection has become a treatable disease with the development of combination antiretroviral therapy (cART), chronic inflammation that affects the central nervous system and other organs is still common. Reliable methods are needed to study HIV-associated inflammatory biomarkers. In this study involving both plasma and cerebrospinal fluid (CSF), we compared multiplex bead array (MBA) to a relatively new technology based on microfluidics and glass nanoreactor (GNR) technology for the measurement of three commonly studied markers from HIV-infected individuals. We found that results correlated between the two platforms for MCP-1 in both fluids as well as for plasma TNFalpha (all p < .005). However, results between the two platforms did not correlate for CSF TNFalpha or fractalkine from plasma or CSF. A statistically significant decrease in CSF TNFalpha over time (p < .0001) was only detectable with the MBA platform, and TNFalpha on the MBA was the only CSF biomarker to correlate with CSF HIV RNA (rho = 0.71, p < .0001). Meanwhile, the GNR platform was superior in terms of intra-assay fractalkine (FKN) variability and the detection of a significant FKN decrease over time. Additionally, the only significant correlation between blood biomarkers and plasma HIV RNA was with FKN on the GNR platform (rho = 0.38, p = .015). Given the variability in results between platforms, more research is needed on methods to quantitate HIV associated inflammation. PMID- 30468734 TI - Non-invasive dynamic monitoring initiation and growth of pancreatic tumor in the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) transgenic mouse model. AB - The LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mouse is one of the most widely used transgenic models to evaluate tumor characteristics and to develop novel therapies for pancreatic ductal adenocarcinoma (PDAC). There is no report of the effective systemic evaluation of longitudinal KPC tumor imitation and growth. Therefore, we aimed to characterize the initiation and progression of pancreatic cancer in KPC mice using longitudinal multiparametric magnetic resonance imaging (MRI) approaches and overall survival. Ten KPC mice were used to develop spontaneous PDAC and monitored by MRI. Tumor growth was evaluated using weekly acquired MRI data. The relationship between diffusion-weighted MRI (DW-MRI) imaging biomarkers (apparent diffusion coefficient - ADC) and tumor fibrosis measurement by pathological methods was assessed by Pearson correlation coefficient. Six KPC mice developed spontaneously pancreatic tumors at the age of 20.0 +/- 2.9 weeks with a relatively short life span (6.8 +/- 1.8 weeks). The tumors could be detected by MRI with a minimum diameter of 3.88 +/- 1.18 mm (range, 2.18-5.20 mm), showing a rapid growth curve according to both the longest diameter (1.63 +/- 0.52 mm/week) and tumor volume (148.77 +/- 80.87 mm3)/week. Pathological results confirmed that the tumors display histopathological features of human pancreatic cancer. A strong correlation between ADC values and fibrosis measurements was observed (R = -0.825, P = .043). Our results show that the initiation and progression of pancreatic tumor in KPC mice can be evaluated by longitudinally non-invasive dynamic MRI approaches. The findings will be the fundamental KPC background data for developing novel therapeutic approaches, in particular for evaluation of response to novel treatments. PMID- 30468735 TI - Unravelling enhancement of antibody fragment stability - Role of format structure and cysteine modification. AB - Antibody-based diagnostics and therapeutics have huge commercial value. However, applications of antibodies are often limited by instability, particularly for recombinant antibody formats. This paper describes the conversion of a single chain variable fragment (scFv) antibody to a single-chain antibody fragment (scAb) with notably improved stability characteristics. This scAb retains antigen binding activity (i) at high temperature (up to 60 degrees C), (ii) in guanidine hydrochloride (GdnHCl, up to 1 M), and (iii) when stored at 37 degrees C for 6 months. However, limited improvement was observed when the original scFv was converted to a larger fragment antigen-binding (Fab) format. Certain Cys-to-Ala mutations in the third complementarity determining region of the antibody heavy chain (CDRH3) also led to stability improvements. Our findings indicate that the stability of an antibody derivative depends on its format and on the positions of cysteines in the CDRs. PMID- 30468736 TI - Improving TCR affinity on 293 T cells. AB - This study presents an efficient method to improve TCR affinity, comprising 1) CDR-directed saturation mutation of TCR cDNA, 2) transient TCR display on CD3 expressing HEK293T (CD3-293 T) cells by simple plasmid transfection, 3) staining with HLA-tetramers, and 4) multi-round sorting of cells with CD8-independent tetramer binding on a flow cytometer. Using these procedures, we successfully identified mutant TCRs with enhanced binding from an HLA-A*24:02-restricted, human telomerase reverse transcriptase (hTERT)-specific TCR. Two such clones, 2A7A and 2D162, harboring mutations in CDR1 and CDR2 of TCRbeta, respectively, were isolated with both showing sequential four amino acid substitutions. When expressed on CD3-293 T cells along with wild-type TCRalpha, the TCR molecules of these mutants as well as their combinatory mutation, bound to HLA-A24/hTERT tetramers more strongly than the wild-type TCRs, without binding to control tetramers. Besides, in order to facilitate a functional study of TCR, we established an artificial T cell line, designated as CD8I-J2, which expresses a human CD8 and IFN-gamma producing cassette by modifying Jurkat-derived J.RT3-T3.5 cells. CD8I-J2 cells expressing wild-type or affinity-enhanced hTERT-specific TCRs were analyzed for their recognition of serially diluted cognate peptide on HLA-A*24:02-transduced T2 cells. CD8I-J2 cells expressing each mutant TCR recognized the hTERT peptide at lower concentrations than wild-type TCR. The hierarchy of peptide recognition is concordant with tetramer binding on CD3-293 T cells and none of these mutant TCRs were cross-reactive with irrelevant peptides reported to be present on HLA-A*24:02 molecules as far as tested. These methods might thus be useful for obtaining high affinity mutants from other TCRs of interest. PMID- 30468737 TI - Molecular Mechanism of Spontaneous Nucleosome Unraveling. AB - Meters of DNA wrap around histone proteins to form nucleosomes and fit inside the micron-diameter nucleus. For the genetic information encoded in the DNA to become available for transcription, replication, and repair, the DNA-histone assembly must be disrupted. Experiment has indicated that the outer stretches of nucleosomal DNA "breathe" by spontaneously detaching from and reattaching to the histone core. Here, we report direct observation of spontaneous DNA breathing in atomistic molecular dynamics simulations, detailing a microscopic mechanism of the DNA breathing process. According to our simulations, the outer stretches of nucleosomal DNA detach in discrete steps involving 5 or 10 base pairs, with the detachment process being orchestrated by the motion of several conserved histone residues. The inner stretches of nucleosomal DNA are found to be more stably associated with the histone core by more abundant nonspecific DNA-protein contacts, providing a microscopic interpretation of nucleosome unraveling experiments. The CG content of nucleosomal DNA is found to anticorrelate with the extent of unwrapping, supporting the possibility that AT-rich segments may signal the start of transcription by forming less stable nucleosomes. PMID- 30468738 TI - Defecation initiates walking in the cricket Gryllus bimaculatus. AB - Feces provides information about the donor and potentially attracts both conspecifics and predators and also parasites. The excretory system must be coordinated with other behaviors in insects. We found that crickets started walking forward following defecation. Most intact crickets walked around the experimental arena, stopped at a particular site and raised their bodies up with a slight backward drift to defecate. After the feces dropped to the floor, a cricket started walking with a non-coordinated gait pattern away from the defecation site, and then changed to a tripod gait. To demonstrate that walking is a reflex response to defecation we analyzed the behavior of headless crickets and found that they also showed walking following defecation. In more than half of defecation events, headless crickets walked backwards before defecation. The posture adopted during defecation was similar to that of intact crickets, and forward walking after defecation was also observed. The frequency of forward walking after defecation in headless crickets was greater than in intact crickets. The gait pattern during forward walking was not coordinated and never transitioned to a tripod gait in headless crickets. In animals whose abdominal nerve cords were cut, in any position, pre- or post-defecation walking was not shown in either intact or headless crickets, although they defecated. These results indicated that the terminal abdominal ganglion receives information regarding hind gut condition. It also indicated that ascending signals from the terminal abdominal ganglion initiated leg movement through the neuronal circuits within the thoracic ganglia, and that descending signals from the brain must regulate the leg motor circuit to express the appropriate walking gait. PMID- 30468739 TI - Skin-Derived SPINK9 Kills Escherichia coli. AB - Antimicrobial peptides (AMP) play a critical role in the barrier function of human skin. They offer a fast response to invading microorganisms and hence protect from external microbial infection. Here we showed the isolation of the KLK5 inhibitor SPINK9 as a major antibacterial factor from healthy stratum corneum. Totally, six N-terminal SPINK9 variants were identified in the stratum corneum. Whereas all variants exhibited similar inhibition activities against KLK5, only three variants with either lysine or glutamine as their first N terminal residues were able to kill various Escherichia coli (E.coli) strains but not other bacteria or fungi. The killing activity also depended on the sequence essential for KLK5 inhibition. Ultrastructural electron microscopy analyses suggested that SPINK9 entered the cell and killed growing bacteria. A bacterial chaperone, named by a seventeen kilodalton protein (SKP), was identified as the major SPINK9 interacting partner in E.coli cells. The Skp-deleted mutant was more sensitive to SPINK9 than the wild-type control, suggesting that the bactericidal activity of SPINK9 should first overcome the resistance from the bacterial chaperone SKP. Thus, SPINK9 is a member of epidermal AMP for selective killing of E.coli, which may contribute to the innate barrier function of human skin. PMID- 30468740 TI - Dietary Pyrophosphate Modulates Calcification in a Mouse Model of Pseudoxanthoma Elasticum: Implication for Treatment of Patients. AB - Pseudoxanthoma elasticum (PXE) is a heritable disease caused by ABCC6 deficiency. Patients develop ectopic calcification in skin, eyes and vascular tissues. ABCC6, primarily found in liver and kidneys, mediates the cellular efflux of ATP, which is rapidly converted into pyrophosphate (PPi), a potent inhibitor of calcification. PXE patients and Abcc6-/- mice display reduced PPi levels in plasma and peripheral tissues. PXE is currently incurable, although some palliative treatments exist. In recent years, we have successfully developed therapeutic methodologies to compensate the PPi deficit in animal models and humans. Here, we inadvertently discovered that modulating dietary PPi can also be an effective approach to reducing calcification in Abcc6-/- mice. Our findings were prompted by a change in institutional rodent diet. The new chow was enriched in PPi, which increased plasma PPi, and significantly reduced mineralization in Abcc6-/- mice. We also found that dietary PPi is readily absorbed in humans. Our results suggest that the consumption of food naturally or artificially enriched in PPi represents a possible intervention to mitigate calcification progression in PXE, that dietary preferences of patients may explain PXE heterogeneous manifestations and that animal chow has the potential to influence data reproducibility. PMID- 30468741 TI - High-Fat Diet Exacerbates Dermatitis through up-regulation of TSLP. PMID- 30468742 TI - Activating Wnt/beta-catenin Signaling Pathway for Disease Therapy: Challenges and Opportunities. AB - Wnt/beta-catenin signaling pathway is essential for embryo development and adult tissue homeostasis and regeneration, abnormal regulation of the pathway is tightly associated with many disease types, suggesting that Wnt/beta-catenin signaling pathway is an attractive target for disease therapy. While the Wnt inhibitors have been extensively reviewed, small molecules activating Wnt/beta catenin signaling were rarely addressed. In this article, we firstly reviewed the diseases that were associated with disruption of Wnt/beta-catenin signaling pathway, including hair loss, pigmentary disorders, wound healing, bone diseases, neurodegenerative diseases and chronic obstructive pulmonary diseases, etc. We also comprehensively summarized small molecules that activated Wnt/beta-catenin signaling pathway in various models in vitro and in vivo. To evaluate the therapeutic potential of Wnt activation, we focused on the discovery strategies, phenotypic characterization, and target identification of the Wnt activators. Finally, we proposed the challenges and opportunities in development of Wnt activators for pharmacological agents in term of targeting safety and selectivity. PMID- 30468743 TI - Neurokinin-1 receptor-based bivalent drugs in pain management: The journey to nowhere? AB - Hybrid compounds (also known as chimeras, designed multiple ligands, bivalent compounds) are chemical units where two active components, usually possessing affinity and selectivity for distinct molecular targets, are combined as a single chemical entity. The rationale for using a chimeric approach is well documented as such novel drugs are characterized by their enhanced enzymatic stability and biological activity. This allows their use at lower concentrations, increasing their safety profile, particularly when considering undesirable side effects. In the group of synthetic bivalent compounds, drugs combining pharmacophores having affinities toward opioid and neurokinin-1 receptors have been extensively studied as potential analgesic drugs. Indeed, substance P is known as a major endogenous modulator of nociception both in the peripheral and central nervous systems. Hence, synthetic peptide fragments showing either agonism or antagonism at neurokinin 1 receptor were both assigned with analgesic properties. However, even though preclinical studies designated neurokinin-1 receptor antagonists as promising analgesics, early clinical studies revealed a lack of efficacy in human. Nevertheless, their molecular combination with enkephalin/endomorphin fragments has been considered as a valuable approach to design putatively promising ligands for the treatment of pain. This paper is aimed at summarizing a 20-year journey to the development of potent analgesic hybrid compounds involving an opioid pharmacophore and devoid of unwanted side effects. Additionally, the legitimacy of considering neurokinin-1 receptor ligands in the design of chimeric drugs is discussed. PMID- 30468744 TI - Non-invasive measurement of glucocorticoids: Advances and problems. AB - Glucocorticoids (GCs; i.e. cortisol/corticosterone) are a central component of the stress response and thus their measurement is frequently used to evaluate the impact of stressful situations. Their metabolites from faeces of various animal species are more and more taken as a non-invasive aid to assess GC release and thus adrenocortical activity. The current literature review includes an extensive collection (1327 papers) and evaluation (see also Supplementary Tables) of the literature on faecal cortisol/corticosterone metabolite (FCM) analysis published to date. It aims at giving reference for researchers interested in implementing FCM analysis into their study or seeking to improve such methods by providing background knowledge on GC metabolism and excretion, conveying insights into methodological issues and stating caveats of FCM analysis and by highlighting prerequisites for and some examples of a successful application of such methods. Collecting faecal samples and analysing FCMs may appear simple and straightforward, but researchers have to select and apply methods correctly. They also need to be aware of the many pitfalls and potentially confounding factors and, last but not least, have to carefully interpret results. Applied properly, measurement of FCMs is a powerful non-invasive tool in a variety of research areas, such as (stress) biology, ethology, ecology, animal conservation and welfare, but also biomedicine. PMID- 30468745 TI - A novel LRR-only protein mediates bacterial proliferation in hemolymph through regulating expression of antimicrobial peptides in mollusk Chlamys farreri. AB - Leucine-rich repeat (LRR)-only proteins are involved in innate immune responses through mediating protein-ligand or protein-protein interactions, yet the exact roles of most LRR-only proteins in invertebrates are not well documented. In the present study, a novel LRR-only protein (designated CfLRRop-7) was identified in Zhikong scallop Chlamys farreri. The full-length cDNA sequence of CfLRRop-7 was 1463 bp and contained an open reading frame of 1086 bp, which encoded a protein of 361 amino acids. Five LRR motifs with a conserved signature sequence LxxLxLxxNxL were identified in the predicted protein sequence. The expression of CfLRRop-7 was particularly high in hemocytes. The expression of CfLRRop-7 was relatively high in oocytes and embryos during the ontogenesis of scallops. CfLRRop-7 expression changed in hemocytes in response to stimulation with different microbes, including Vibrio splendidus, Staphylococcus aureus and Pichia pastoris. CfLRRop-7 recognized five kinds of ligands/agonists. CfLRRop-7 recombinant protein inhibited bacterial proliferation in hemolymph and induced lysozyme activity in serum. After knocking down CfLRRop-7, the mRNA expression of selected antimicrobial peptides was reduced. All these results indicated that CfLRRop-7 might be a potential pattern recognition receptor that recognizes various pathogen associated molecular patterns, and regulates antibacterial immunity in scallops. PMID- 30468746 TI - Tomatidine, a novel antiviral compound towards dengue virus. AB - Dengue is the most common arboviral disease worldwide with 96 million symptomatic cases annually. Despite its major impact on global human health and huge economic burden there is no antiviral drug available to treat the disease. The first tetravalent dengue virus vaccine was licensed in 2015 for individuals aged 9 to 45, however, most cases are reported in infants and young children. This, together with the limited efficacy of the vaccine to dengue virus (DENV) serotype 2, stresses the need to continue the search for compounds with antiviral activity to DENV. In this report, we describe tomatidine as a novel compound with potent antiviral properties towards all DENV serotypes and the related Zika virus. The strongest effect was observed for DENV-2 with an EC50 and EC90 value of 0.82 and 1.61 MUM, respectively, following infection of Huh7 cells at multiplicity of infection of 1. The selectivity index is 97.7. Time-of-drug-addition experiments revealed that tomatidine inhibits virus particle production when added pre, during and up to 12 h post-infection. Subsequent experiments show that tomatidine predominantly acts at a step after virus-cell binding and membrane fusion but prior to the secretion of progeny virions. Tomatidine was found to control the expression of the cellular protein activating transcription factor 4 (ATF4), yet, this protein is not solely responsible for the observed antiviral effect. Here, we propose tomatidine as a candidate for the treatment of dengue given its potent antiviral activity. PMID- 30468747 TI - A high-throughput inhibition assay to study MERS-CoV antibody interactions using image cytometry. AB - The emergence of new pathogens, such as Middle East respiratory syndrome coronavirus (MERS-CoV), poses serious challenges to global public health and highlights the urgent need for methods to rapidly identify and characterize potential therapeutic or prevention options, such as neutralizing antibodies. Spike (S) proteins are present on the surface of MERS-CoV virions and mediate viral entry. S is the primary target for MERS-CoV vaccine and antibody development, and it has become increasingly important to understand MERS-CoV antibody binding specificity and function. Commonly used serological methods like ELISA, biolayer interferometry, and flow cytometry are informative, but limited. Here, we demonstrate a high-throughput protein binding inhibition assay using image cytometry. The image cytometry-based high-throughput screening method was developed by selecting a cell type with high DPP4 expression and defining optimal seeding density and protein binding conditions. The ability of monoclonal antibodies to inhibit MERS-CoV S binding was then tested. Binding inhibition results were comparable with those described in previous literature for MERS-CoV spike monomer and showed similar patterns as neutralization results. The coefficient of variation (CV) of our cell-based assay was <10%. The proposed image cytometry method provides an efficient approach for characterizing potential therapeutic antibodies for combating MERS-CoV that compares favorably with current methods. The ability to rapidly determine direct antibody binding to host cells in a high-throughput manner can be applied to study other pathogen antibody interactions and thus can impact future research on viral pathogens. PMID- 30468748 TI - Synaptic topography - Converging connections and emerging function. AB - Brain circuits are fundamentally constituted of individual neurons that are interconnected with a vast array of synapses. In order to understand how brain function emerges from this complex synaptic network, immense efforts have been made to trace the synaptic topography, i.e. arrangement of synaptic connections, of the network. In addition to anatomically elaborating the synaptic layout at multiple levels across brain regions, recent studies have attempted to elucidate the fundamental wiring principles that underlie the neuronal activity manifested in the brain, establishing a link between anatomy and function. In this review, I will discuss recent discoveries on the topographical organization of synaptic connections at the cell-to-cell and subcellular levels in the cortex and hippocampus. Accumulating evidence leads us to acknowledge the highly structured, non-random synaptic connectivity that emerges together with sensory feature preferences of neurons and synchronous neuronal activity. PMID- 30468749 TI - pBuzz: A cryptic rolling-circle plasmid from a commensal Escherichia coli has two inversely oriented oriTs and is mobilised by a B/O plasmid. AB - Ampicillin, streptomycin and sulphamethoxazole resistant commensal E. coli 838-3B contains five plasmids that range in size from >90 kb to <2 kb. The resistance genes blaTEM (ampicillin), strA (streptomycin) and sul2 (sulphamethoxazole) transferred along with a B/O plasmid named p838B-R. However, three plasmids smaller than 7 kb were also found in transconjugants, suggesting that they could be mobilised by the B/O plasmid. The complete sequences of p838B-R and pBuzz, a small plasmid mobilised by p838B-R with 70% efficiency, were determined. p838B-R is 94,803 bp and contains an 8400 bp resistance island that includes the three antibiotic resistance genes. The p838B-R backbone contains a complete conjugative transfer region, including an oriT site upstream of nikAB that resembles the experimentally-defined oriT of R64. The 1982 bp pBuzz contains a rep gene and sites associated with replication that resemble those of pC194/pUB110 family rolling-circle plasmids. It also contains two, inversely oriented copies of an 84 bp sequence that differs from the oriT region in p838B-R at just 6 positions. These oriT-like sites likely explain the ability of pBuzz to co-transfer with the B/O plasmid using the NikB relaxase and NikA accessory protein encoded by p838B R, i.e. pBuzz utilises relaxase-in trans mobilisation. Several rolling-circle plasmids related to pBuzz were found in the GenBank non-redundant nucleotide database. They contain diverse potential oriTs, including sequences similar to known oriTs found in conjugative plasmids of I-complex (I1, B/O, K, Z and I2), L or M types. PMID- 30468750 TI - Comparison of freeze-thaw cycles for nucleic acid extraction and molecular detection of Cryptosporidium parvum and Toxoplasma gondii oocysts in environmental matrices. AB - Freeze-thaw DNA extraction methods and PCR primers were compared to optimize detection of Cryptosporidium parvum and Toxoplasma gondii oocysts in different matrices. Increasing FT cycles did not increase parasite DNA detection, and primers targeting the 18S ssrRNA gene yielded the most sensitive detection of C. parvum oocysts. PMID- 30468751 TI - Rapid detection of beta-lactamase production including carbapenemase by thin layer chromatography. AB - OBJECTIVES: To develop a rapid and simple method that can identify the presence of beta-lactamases in clinical isolates and samples, and determine their activity on different types of beta-lactam antibiotics, including carbapenems, within one hour. METHODS: In this study, we describe a thin layer chromatography-based method for rapid detection of beta-lactamases including carbapenemases. The method relies on the examination of changes in the migration rate of beta-lactams in chromatography, due to degradation by beta-lactamase enzymes. A total of 44 isolates, 29 carbapenemase-producers and 15 non-carbapenemase-producers, were screened by this method. RESULTS: The method has proven to be able to distinguish beta-lactamases as carbapenemase or non-carbapenemase producing strains with high sensitivity in one hour. CONCLUSIONS: The method developed, provides information about the production of beta-lactamases by bacteria and beta-lactam drugs inactivated by these enzymes, including carbapenems. This new method may play an important role in guiding antimicrobial treatment, especially in critically ill patients infected bacteria producing beta-lactamases. PMID- 30468752 TI - Perceiving perpendicular and parallel contours in the frontoparallel plane. AB - The perception of a pair of contours in a retinal image cannot be understood simply by adding up the perceptions of the individual contours, especially when they form a perpendicular junction, or are parallel to one another. It is the relationship among the contours that determines what is perceived. Note that it is hard to actually compare the perception of such configurations quantitatively. We managed to do this by testing the perception of such configurations in three psychophysical experiments in which the perception was characterized by measuring the orientation threshold of a single contour. This threshold was estimated by using a modified Method of Constant Stimuli based on the assumption that contours forming a configuration are perceived individually, and that they are integrated linearly. This assumption made the quantitative comparison of the perceived configurations possible. We found that changes of the estimated threshold depended on the type of the configuration, specifically thresholds estimated from a perpendicular junction were substantially lower than thresholds estimated from a single contour or from a non-perpendicular junction. The lowest thresholds were observed when the threshold was estimated from a pair of parallel contours. These results suggest that the visual system is sensitive to perpendicular junctions and parallel contours in a retinal image. PMID- 30468753 TI - Focusing on an illusion: accommodating to perceived depth? AB - Ocular accommodation potentially provides information about depth but there is little evidence that this information is used by the human visual system. We use the hollow-face illusion, an illusion of depth reversal, to investigate whether accommodation is linked to perceived depth. In Experiment 1 accommodation, like vergence, was in front of the physical surface of the mask when the mask was upright and people reported experiencing the illusion. Accommodation to the illusory face did not differ significantly from accommodation to the physically convex back surface of the same mask. Only accommodation to the inverted mask seen as hollow was significantly less and, like the physical surface, beyond the mid-plane of the mask. The effect on accommodation was the same for monocular as binocular viewing, showing that accommodation is not driven by binocular disparities through vergence, although voluntary vergence remains a possibility. In Experiment 2 a projected random dot pattern was used to flip perception between convex and concave in all presentation conditions. Accommodation was again in front of the physical surface when the illusion was experienced. Experiment 3 showed that projected dots are more effective in disambiguating the illusion as concave when they are sharp and provide a good accommodative stimulus than when they are objectively blurred. We interpret Experiments 1 and 2 as showing that accommodation is tied to perceived depth, directly or indirectly, even in a situation where multiple depth cues are available and feedback is not artificially open-looped. Experiment 3 is consistent with accommodation helping to disambiguate depth while not ruling out alternative explanations. PMID- 30468754 TI - Laparoscopic radical cystectomy with extracorporeal neobladder: our initial experience. AB - OBJECTIVES: To illustrate our technique to construct the Institute of Urology Peking University (IUPU) orthotopic ileal bladder and present our initial experience. METHODS: From August 2017 to April 2018, twelve patients with bladder cancer underwent radical cystectomy (RC), pelvic lymph node dissection (LND) and extracorporeal construction of an IUPU neobladder (IUPUB) by an experienced surgeon. We present the demographic, clinicopathologic, perioperative and follow up data. We also describe our step-by-step surgical technique for the IUPUB in this article. RESULTS: Laparoscopic RC (LRC) with an extracorporeal IUPUB was successfully accomplished in 11 patients, and one patient was converted to open radical cystectomy with an IUPUB. The median total operative time and median time spent suturing the pouch were 248 min and 23 min, respectively. The median estimated blood loss was 150 ml. The median time to recovery of bowel function (tolerance of a liquid diet) was 3.5 days. The urinary catheter was removed on postoperative day 21 in 10 patients. The ureteral stents and stoma catheter were removed on day 7 after cystography. At a median follow-up of 7.5 months, two patients had early complications (< 30 days), and no major complications (grade >= 3) occurred. The follow-up outcomes were satisfactory. The limitations included the small sample size and short-term outcomes. CONCLUSION: Our technique of constructing the IUPUB is feasible and safe. The operative time and early complication rates are acceptable. PMID- 30468755 TI - Advances in Echocardiography. PMID- 30468756 TI - Can we feel like being neither alert nor sleepy? The electroencephalographic signature of this subjective sub-state of wake state yields an accurate measure of objective sleepiness level. AB - Accurate measurement of objective level of sleepiness can have important implications for experimental and field studies of sleep deprived individuals. We proposed to accurately quantify changes in sleepiness level with single electroencephalographic (EEG) measures obtained from EEG spectra consisting of 16 spectral powers within the frequency interval from 1 to 16 Hz. The EEG signal was recorded every other hour from 19:00 of Friday to 19:00 of Sunday in 48 study participants. The differential spectra were calculated for the 1st minute with eyes closed as the differences between EEG spectra for pairs of distinct subjective sub-states (alert, neither alert nor sleepy, sleepy, and very sleepy sub-states scored on the Karolinska Sleepiness Scale as 3, 5, 7, and 9, respectively).The differential spectra were calculated for the sub-samples of those participants who succeeded and failed to succeed in completing all 25 EEG recording sessions (n = 25 and 23, respectively) and for the addition sample of 130 participants deprived from sleep for only one night. Single spectral EEG measures were then calculated by summation of 16 spectral powers weighted by a differential spectrum. The strongest correlation coefficients (0.981, 0.987, and 0.985) were attained between the time courses of subjective and objective measures when data on 130, 23 and 25 participants, respectively, were used for calculation of frequency waiting curve differentiating alert sub-sate either from sleepy sub-state or from neither alert nor sleepy sub-state. We recommended implementation of the proposed objective measure into experimental procedures requiring accurate estimation of objective sleepiness level. PMID- 30468757 TI - Suspected poisoning in beef cattle from ingestion of Prosopis nigra pods in north western Argentina. AB - The aim of this paper was to present the first report of Prosopis nigra poisoning of cattle in Argentina. Outbreaks occurred in five farms located in Salta and Santiago del Estero provinces. All animals were examined, euthanized and necropsied. Clinical signs included tongue protrusion, twitches and tremors of muscles of mastication, weight loss and lethargy. Severe atrophy of the masseter, buccinator and lingual muscles was observed, along with neuronal vacuolation in the nuclei of the trigeminal, facial, and hypoglossus nerves. These findings and the clinical signs are consistent with results obtained in animals, spontaneously and experimentally intoxicated with Prosopis juliflora in previous studies. Several species of this genus are native to Argentina. Farmers should be warned about the suspected toxicity by Prosopis nigra, since this species has wide geographical distribution in the country. PMID- 30468758 TI - Spontaneous outbreak of Astragalus pehuenches (Fabaceae) poisoning in cattle in Argentina. AB - This is the first report of a spontaneous outbreak of Astragalus pehuenches poisoning on a farm in Argentine Patagonia, where 63 out of 70 cattle died. The main clinical signs of affected animals were ataxia, balance loss and progressive emaciation. Purkinje cells presented vacuolation and marginalization of the nucleus. Astragalus pehuenches was detected in the paddock as well as in the ruminal content and fecal matter samples of the affected animals. Swainsonine concentrations in Astragalus specimens were found to be as high as 0.096%. PMID- 30468759 TI - Venom content and toxicity regeneration after venom gland depletion by electrostimulation in the scorpion Centruroides limpidus. AB - The scorpion venom is a cocktail of many components. Its composition can exhibit a level of plasticity in response to different behavioral and environmental factors, leading to intraspecific variation. The toxicity and specificity of scorpion venoms appear to be taxon-dependent, due to a co-evolutionary interaction with prey and predators, which shaped the composition at the molecular level. The venom regeneration by the venom glands is an asynchronous process, in which particular components are expressed at different stages and at different rates. According to this, it can be reasonably assumed that the regeneration of toxicity in the venom is also asynchronous. In this work, we studied the toxicity regeneration dynamics by the scorpion Centruroides limpidus after full venom depletion by electrical stimulation. For this, we evaluated the toxicity of venom samples extracted at different days post depletion, against insects (crickets) and mammals (humans, by assessing the venom activity on the human voltage-dependent Na+ channel Nav1.6). The regeneration of toxicity against humans lagged behind that against crickets (13 vs 10 days, respectively). Thirteen days after depletion the venom seems to be replenished. Our results show asynchrony in the regeneration of species-specific toxic activity in the venom of Centruroides limpidus. The understanding of the venom regeneration kinetics for the different scorpion species will help to design venom extraction protocols that could maximize the yield and quality of the collected venoms. PMID- 30468760 TI - Mathematical modeling in scheduling cancer treatment with combination of VEGF inhibitor and chemotherapy drugs. AB - The present paper considers a treatment of cancer with a combination of anti-VEGF (bevacizumab) and a chemotherapy drug (docetaxel). Since anti-VEGF reduces the perfusion of chemotherapy drugs, the question arises whether it is more effective to administer the two drugs at the same time, or non-overlapping, in order to reduce tumor volume more effectively. To address this question we develop a mathematical model and use it to simulate different schedules. We find that the treatment of cancer would be far more effective if the two drugs are given non overlappingly, with the chemotherapy drug at day 0 and anti-VEGF at day 7 in cycles of 21 days. PMID- 30468761 TI - The Pneumatic Retinopexy versus Vitrectomy for the Management of Primary Rhegmatogenous Retinal Detachment Outcomes Randomized Trial (PIVOT). AB - PURPOSE: The optimal surgical intervention to repair certain common configurations of uncomplicated rhegmatogenous retinal detachment (RRD) is unknown. The purpose of this trial was to compare outcomes of pneumatic retinopexy (PnR) versus pars plana vitrectomy (PPV) for the management of primary RRD. DESIGN: Prospective randomized controlled trial. PARTICIPANTS: Patients with RRD presenting with a single retinal break, or group of breaks within one clock hour, above the 8 and 4 o'clock meridians. METHODS: Patients were randomized to either the PnR or PPV intervention group. Macula-on and -off cases were assigned to intervention group by stratified randomization and treated within 24 and 72 hours respectively. MAIN OUTCOME MEASURES: The primary outcome was 1-year ETDRS visual acuity. Important secondary outcomes were subjective visual function (NEI VFQ-25), metamorphopsia score (M-CHARTSTM) and primary anatomical success. RESULTS: 176 patients were recruited between August 2012 and May 2016. ETDRS visual acuity following PnR exceeded PPV by 4.9 letters at 12 months (79.9+/-10.4 versus 75.0+/-15.2, P=0.024). Mean ETDRS visual acuity was also superior for the PnR group compared to PPV at 3 months (78.4+/-12.3 versus 68.5+/-17.8) and 6 months (79.2+/-11.1 versus 68.6+/-17.2). Composite NEI VFQ-25 scores were superior for PnR at 3 and 6 months. Vertical metamorphopsia scores were superior for the PnR group compared to PPV at 12 months (0.14+/-0.29 versus 0.28+/-0.42, P=0.026). Primary anatomical success at 12 months was achieved by 80.8% of patients undergoing PnR versus 93.2% undergoing PPV (P=0.045), with 98.7% and 98.6%, respectively achieving secondary anatomical success. 65% of phakic patients in the PPV arm underwent cataract surgery in the study eye before 12 months, versus 16% for PnR (P<0.001). CONCLUSIONS: PnR should be considered the first line treatment for RRD in patients fulfilling PIVOT recruitment criteria. PnR offers superior visual acuity, less vertical metamorphopsia and reduced morbidity when compared to PPV. PMID- 30468762 TI - Molecular fingerprint-derived similarity measures for toxicological read-across: Recommendations for optimal use. AB - Computational approaches are increasingly used to predict toxicity due, in part, to pressures to find alternatives to animal testing. Read-across is the "new paradigm" which aims to predict toxicity by identifying similar, data rich, source compounds. This assumes that similar molecules tend to exhibit similar activities i.e. molecular similarity is integral to read-across. Various of molecular fingerprints and similarity measures may be used to calculate molecular similarity. This study investigated the value and concordance of the Tanimoto similarity values calculated using six widely used fingerprints within six toxicological datasets. There was considerable variability in the similarity values calculated from the various molecular fingerprints for diverse compounds, although they were reasonably concordant for homologous series acting via a common mechanism. The results suggest generic fingerprint-derived similarities are likely to be optimally predictive for local datasets, i.e. following sub categorisation. Thus, for read-across, generic fingerprint-derived similarities are likely to be most predictive after chemicals are placed into categories (or groups), then similarity is calculated within those categories, rather than for a whole chemically diverse dataset. PMID- 30468763 TI - Role of the Klebsiella pneumoniae TolC porin in antibiotic efflux. AB - The major Gram-negative gated efflux channel TolC has been extensively characterized in Escherichia coli but there is minimal information about Klebsiella pneumoniae TolC. Using an arabinose-inducible plasmid-based expression system, we show that the K. pneumoniae TolC complements the efflux defect in an E. coli K-12 DeltatolC strain, restoring wild-type levels of resistance towards most antibiotics suggesting that it can interact with the E. coli AcrB efflux pump. We characterize the efflux properties of K. pneumoniae TolC using an orthogonal whole cell-based assay and quantify the extrusion of environment sensitive fluorescent probes and contrast the findings with the E. coli ortholog. PMID- 30468764 TI - Relic DNA does not obscure the microbial community of paddy soil microbial fuel cells. AB - Soil Microbial Fuel Cells (MFCs) are devices that can generate electricity by using the flooded soil's anode respiring microbial consortium. When the MFC starts to work, the microbial community in the anode vicinity rapidly changes. This shift in the microbial community results in many dead cells that may release their DNA (relic DNA) and obscure culture independent estimates of microbial community composition. Although relic DNA is expected to increase in MFCs, the effect of relic DNA has not been investigated in the soil MFCs system. In this study the effect of the MFCs on the soil microbial community composition within the soil profile and the influence of relic DNA were investigated. Microbial community analysis revealed that the MFCs deployment significantly influenced the community composition within the soil profile. The phylum Proteobacteria (34.4% vs 23.6%) and the class Deltaproteobacteria (16.8% vs 5.9%) significantly increased in the MFCs compared to the control, while the phylum Firmicutes (24.0% vs 28.7%) and the class Sphingobacteria (5.3% vs 7.0%) were more abundant in the control. Furthermore, the archaeal phyla Euryarchaeota (40.7% vs 52.3%) and Bathyarchaeota (10.1% vs 17.3%) were significantly lower in the MFCs, whereas the phylum Woesearchaeota (DHVEG6) (24.4% vs 19.4%) was slightly enhanced. Moreover, the results showed that relic DNA can affect the relative abundance of Geobacter and Candidatus Methanoperedens, however, it has no significant effects on the microbial community structure. These results indicate that MFCs can influence the soil microbial community profile, nevertheless the relic DNA generated has minimum effect on the culture independent estimates of microbial community composition. PMID- 30468765 TI - Development of a droplet digital PCR assay for sensitive detection of porcine circovirus 3. AB - Porcine circovirus 3 (PCV3), a newly emerged circovirus, is associated with porcine dermatitis and nephropathy syndrome, reproductive failure and multi systemic inflammation disease, and is widely distributed in pig populations worldwide. Therefore, developing specific diagnostic assays will be important for controlling this emerging pathogen. In this study, we developed a novel droplet digital PCR (ddPCR) assay targeting the PCV3 cap gene to improve the sensitivity of PCV3 detection. The established assay is highly specific to PCV3, and does not cross react with other important swine pathogens. The assay's detection limit was 1.68 +/- 0.29 copies of PCV3 DNA per reaction (n = 8), an approximately 10-fold greater sensitivity than that of our previously developed quantitative real-time PCR (qPCR) assay for the same virus. The ddPCR assay results were highly reproducible, with intra- and inter-assay coefficient of variation values of <9.0%. Of the 239 archived pig tissue and serum samples, 42 tested positive for PCV3 by the ddPCR assay. Among the 42 positive samples, 31 tested positive by the qPCR assay. Notably, PCV3 was detected in the serum samples collected from commercially imported healthy boars from the US, France and the UK during 2011 2017. The overall agreement between the two assays was 95.39% (228/239). Furthermore, the linear regression analysis showed that the ddPCR and the qPCR results were significantly correlated with an R2 value of 0.9945. Collectively, these results indicate that the ddPCR assay is a robust diagnostic tool for sensitive detection of PCV3, even in samples with low viral loads. PMID- 30468766 TI - Characterization and correlation of signal drift in diffusion weighted MRI. AB - Diffusion weighted MRI (DWMRI) and the myriad of analysis approaches (from tensors to spherical harmonics and brain tractography to body multi-compartment models) depend on accurate quantification of the apparent diffusion coefficient (ADC). Signal drift during imaging (e.g., due to b0 drift associated with heating) can cause systematic non-linearities that manifest as ADC changes if not corrected. Herein, we present a case study on two phantoms on one scanner. Different scan protocols exhibit different degrees of drift during similar scans and may be sensitive to the order of scans within an exam. Vos et al. recently reviewed the effects of signal drift in DWMRI acquisitions and proposed a temporal model for correction. We propose a novel spatial-temporal model to correct for higher order aspects of the signal drift and derive a statistically robust variant. We evaluate the Vos model and propose a method using two phantoms that mimic the ADC of the relevant brain tissue (0.36-2.2 * 10-3 mm2/s) on a single 3 T scanner. The phantoms are (1) a spherical isotropic sphere consisting of a single concentration of polyvinylpyrrolidone (PVP) and (2) an ice-water phantom with 13 vials of varying PVP concentrations. To characterize the impact of interspersed minimally weighted volumes ("b0's"), image volumes with b-value equal to 0.1 s/mm2 are interspersed every 8, 16, 32, 48, and 96 diffusion weighted volumes in different trials. Signal drift is found to have spatially varying effects that are not accounted for with temporal-only models. The novel model captures drift more accurately (i.e., reduces the overall change per-voxel over the course of a scan) and results in more consistent ADC metrics. PMID- 30468767 TI - Regulation of the stability and activity of CDC25A and CDC25B by protein phosphatase PP2A and 14-3-3 binding. AB - Cyclin-dependent kinase (CDK)-activating phosphatases, CDC25A and CDC25B, are labile proteins, and their levels vary in a cell cycle-dependent manner. Immediate-early response IER5 protein negatively regulates the cellular CDC25B levels, and stress-induced IER5 expression potentiates G2/M arrest. IER5 binds to protein phosphatase PP2A and regulates the PP2A substrate specificity. We show that IER5 binds to CDC25B and assists PP2A to convert CDC25B to hypophosphorylated forms. Hypophosphorylation at Ser323 results in the dissociation of CDC25B from 14-3-3 phospho-binding proteins. In IER5 expressing cells, CDC25B dissociated from 14-3-3 is unstable but slightly activated, because 14-3-3 inhibits CDC25B polyubiquitination and CDC25B binding to CDK1. The 14-3-3 binding to CDC25A also impedes CDC25A degradation and CDC25A-CDK2 interaction. We propose that 14-3-3 is an important regulator of CDC25A and CDC25B and that PP2A/IER5 controls the stability and activity of CDC25B through regulating the interaction of CDC25B and 14-3-3. PMID- 30468768 TI - An odorant receptor and glomerulus responding to farnesene in Helicoverpa assulta (Lepidoptera: Noctuidae). AB - Terpenoids emitted from herbivore-damaged plants were found to play an important role in regulating tritrophic interactions. How herbivores and their natural enemies perceive terpenoids has not been thoroughly elucidated to date. Using in vivo calcium imaging, we found in this study that farnesene activates one glomerulus in the antennal lobe of female Helicoverpa assulta. The response induced by a mixture of farnesene isomers is stronger than that elicited by E beta-farnesene alone. In the Xenopus oocyte expression system, HassOR23/ORco is narrowly tuned to farnesene isomers and compounds with similar structures. Finally, the behavioral studies showed that the farnesene isomers have an inhibitory effect on oviposition of female H. assulta, but have an attractive effect on host searching of Campoletis chlorideae, the key endoparasitoid of H. assulta larvae. These results demonstrate that farnesene isomers are encoded by a labeled-line mode in the olfactory system of female H. assulta, suggesting that farnesene as a chemical signal from plants has important behavioral relevance and evolutionary implications in the tritrophic context. PMID- 30468769 TI - Wolbachia infection may improve learning and memory capacity of Drosophila by altering host gene expression through microRNA. AB - Wolbachia are endosymbiotic bacteria present in a wide range of invertebrates. Although their dramatic effects on host reproductive biology have been well studied, little is known about the effects of Wolbachia on the learning and memory capacity (LMC) of hosts, despite their distribution in the host nervous system, including brain. In this study, we found that Wolbachia infection significantly enhanced LMC in both Drosophila melanogaster and D. simulans. Expression of LMC-related genes was significantly increased in the head of D. melanogaster infected with the wMel strain, and among these genes, crebA was up regulated the most. Knockdown of crebA in Wolbachia-infected flies significantly decreased LMC, while overexpression of crebA in Wolbachia-free flies significantly enhanced the LMC of flies. More importantly, a microRNA (miRNA), dme-miR-92b, was identified to be complementary to the 3'UTR of crebA. Wolbachia infection was correlated with reduced expression of dme-miR-92b in D. melanogaster, and dme-miR-92b negatively regulated crebA through binding to its 3'UTR region. Overexpression of dme-miR-92b in Wolbachia-infected flies by microinjection of agomirs caused a significant decrease in crebA expression and LMC, while inhibition of dme-miR-92b in Wolbachia-free flies by microinjection of antagomirs resulted in a significant increase in crebA expression and LMC. These results suggest that Wolbachia may improve LMC in Drosophila by altering host gene expression through a miRNA-target pathway. Our findings help better understand the host-endosymbiont interactions and, in particular, the impact of Wolbachia on cognitive processes in invertebrate hosts. PMID- 30468770 TI - Developmental expression patterns of protein kinase A catalytic subunits in zebrafish. AB - Protein kinase A (PKA), also known as cAMP dependent protein kinase, is an essential component of many signaling pathways, many of which regulate key developmental processes. Inactive PKA is a tetrameric holoenzyme, comprised of two catalytic (PRKAC), and two regulatory subunits. Upon cAMP binding, the catalytic subunits are released and thereby activated. There are multiple isoforms of PKA catalytic subunits, but their individual roles are not well understood. In order to begin studying their roles in zebrafish development, it is first necessary to identify the spatial and temporal expression profiles for each prkac subunit. Here we evaluate the expression profiles for the four zebrafish prkacs: prkacalphaa, alphab, betaa, and betab, at key developmental time points: 24, 48 and 72 h post fertilization. We show that zebrafish prkacs are expressed throughout the developing nervous system, each showing unique expression patterns. This body of work will inform future functional studies into the roles of PKA during development. PMID- 30468771 TI - Stimulus-induced gamma power predicts the amplitude of the subsequent visual evoked response. AB - The efficiency of neuronal information transfer in activated brain networks may affect behavioral performance. Gamma-band synchronization has been proposed to be a mechanism that facilitates neuronal processing of behaviorally relevant stimuli. In line with this, it has been shown that strong gamma-band activity in visual cortical areas leads to faster responses to a visual go cue. We investigated whether there are directly observable consequences of trial-by-trial fluctuations in non-invasively observed gamma-band activity on the neuronal response. Specifically, we hypothesized that the amplitude of the visual evoked response to a go cue can be predicted by gamma power in the visual system, in the window preceding the evoked response. Thirty-three human subjects (22 female) performed a visual speeded response task while their magnetoencephalogram (MEG) was recorded. The participants had to respond to a pattern reversal of a concentric moving grating. We estimated single trial stimulus-induced visual cortical gamma power, and correlated this with the estimated single trial amplitude of the most prominent event-related field (ERF) peak within the first 100 ms after the pattern reversal. In parieto-occipital cortical areas, the amplitude of the ERF correlated positively with gamma power, and correlated negatively with reaction times. No effects were observed for the alpha and beta frequency bands, despite clear stimulus onset induced modulation at those frequencies. These results support a mechanistic model, in which gamma-band synchronization enhances the neuronal gain to relevant visual input, thus leading to more efficient downstream processing and to faster responses. PMID- 30468772 TI - Pediatric continuity care intensivist: A randomized controlled trial. AB - INTRODUCTION: Long-stay critically ill patients in the Pediatric Intensive Care Unit (PICU) may be at risk for inconsistencies in treatment plan, delay in plan progression, and patient/family dissatisfaction with communication. This article describes the development and evaluation of an intervention designed to improve continuity and communication delivered by continuity PICU attendings. METHODS AND ANALYSIS: A randomized controlled trial of an intervention in one PICU that was randomized at the patient level. Eligible patients and their parents included those admitted to the PICU for longer than one week and were anticipated to remain for an additional 7 days. The intervention, a Continuity Care Intensivist (CCI), included early assignment of a continuity attending (separate from a regularly scheduled service attending), standardization of the continuity role to ensure consistent team and family contact and facilitate timely decision making, and enhancement of CCI communication skills. The outcomes evaluated were 1) patient PICU length of stay, ventilator-dependent days, and hospital acquired infections, 2) parental mood and satisfaction with PICU communication, and 3) intensivist perception of acceptability of intervention. Intention to treat analysis will be completed using multivariable linear regression to determine the impact of the intervention on outcomes. Lessons have been learned about the appropriate enrollment criteria for patients to allow for impact of continuity attending, frequent prognostic uncertainty in determining which patients will become longer stay in the PICU, and the difficulty of achieving timely initial contact of continuity attending with patients given the CCI's other commitments. PMID- 30468773 TI - Clinical immunology: A special issue on epigenetics. PMID- 30468774 TI - Mast cells as protectors of health. AB - Mast cells (MC), well known for their effector functions in Th2 skewed allergic and also autoimmune inflammation, become increasingly acknowledged for their role in protection of health. It is now clear that they are also key modulators of immune responses at interface organs like skin or gut. MC can prime tissues for adequate inflammatory responses and cooperate with dendritic cells in T cell activation. They also regulate harmful immune responses in trauma and help to successfully orchestrate pregnancy. This review focusses on the beneficial effects of mast cells on tissue homeostasis and elimination of toxins or venoms. MC can enhance pathogen clearance in many bacterial, viral, and parasite infections, e.g. by TLR2 triggered degranulation, secretion of antimicrobial cathelicidins, recruiting neutrophils or by providing extracellular DNA traps. The role of MC in tumors is more ambiguous, however, encouraging new findings show they can change the tumor microenvironment towards anti-tumor immunity when adequately triggered. Uterine tissue remodeling by alpha-chymase (MCP-5) is crucial for successful embryo implantation. MCP-4 and the tryptase MCP-6 emerge to be protective in CNS trauma by reducing inflammatory damage and excessive scar formation, thereby protecting axon growth. Last but not least, we see proteases like carboxypeptidase A released by FcepsilonRI activated MC detoxify an increasing number of venoms and endogenous toxins. A better understanding of the plasticity of MC will help to improve these advantageous effects, and hint on ways to cut down detrimental MC actions. PMID- 30468776 TI - Inter-laboratory variability in multiplexed pneumococcal antibody testing. AB - This pragmatic, updated assessment of variability among pneumococcal antibody assays suggests that variability may now be greater than previously reported, and potentially influential in clinical decision making. PMID- 30468775 TI - Chronic Rhinosinusitis in Elderly Patients is Associated with an Exaggerated Neutrophilic Pro-Inflammatory Response to Pathogenic Bacteria. AB - BACKGROUND: Potential effects of aging on chronic rhinosinusitis (CRS) pathophysiology have not been well defined, but may have important ramifications given a rapidly aging U.S. and world population. OBJECTIVE: The goal of the current study was to determine whether advanced age is associated with specific inflammatory CRS endotypes or immune signatures. METHODS: Seventeen mucus cytokines and inflammatory mediators were measured in 147 CRS patients. Hierarchical cluster analysis was used to identify and characterize inflammatory CRS endotypes as well as determine whether age was associated with specific immune signatures. RESULTS: A CRS endotype with a pro-inflammatory, neutrophilic immune signature was enriched with older patients. In the overall cohort, patients 60 years and older had elevated mucus levels of IL-1beta, IL-6, IL-8, and TNF-alpha when compared to their younger counterparts. Increases in pro inflammatory cytokines were associated with both tissue neutrophilia and symptomatic bacterial infection/colonization in aged patients. CONCLUSIONS: Aged CRS patients have a unique inflammatory signature that corresponds to a neutrophilic pro-inflammatory response. Neutrophil-driven inflammation in aged CRS patients may be less likely to respond to corticosteroids and may be closely linked with chronic microbial infection or colonization. PMID- 30468777 TI - REDUCED CONNECTIVITY BETWEEN MENTALIZING AND MIRROR SYSTEMS IN AUTISM SPECTRUM CONDITION. AB - The mentalizing system and mirror system are thought to play important roles in inferring the internal mental states of others - a process known as mentalizing. Autism spectrum condition (ASC) is associated with difficulties in mentalizing. The aim of this study was to determine whether the behavioural difficulties in mentalizing associated with ASC can be explained by changes in functional connectivity between the mentalizing and mirror system. We recruited 40 adult participants (20 with ASC and 20 typically-developing). Brain activity was monitored using functional magnetic resonance imaging while participants watched videos in which actors performed hand actions. The videos were shown in separate mentalizing and non-mentalizing blocks. During mentalizing blocks, participants were asked to indicate whether hand actions were clumsy or spiteful (i.e. to judge the intent of the action). During non-mentalizing blocks, participants indicated whether the actions were successful or unsuccessful (i.e. to judge the outcome of the action). Higher activity during the mentalizing blocks compared to non-mentalizing blocks was found in regions associated with the mentalizing system: the dorsal medial prefrontal cortex (dmPFC) and the temporo-parietal junction (TPJ), as well as in regions typically associated with the mirror system: the inferior frontal gyrus (IFG) and the inferior parietal lobe (IPL). Next, functional connectivity between regions was evaluated as a function of task. During mentalizing blocks, there was increased functional connectivity between the dmPFC and the mirror system in typically developing participants. In contrast, there was no increase in functional connectivity between these regions in ASC participants. Connectivity between the dmPFC and IFG was negatively correlated with autistic traits. The reduced connectivity in ASC participants was consistent with behavioural performance on the mentalizing task, which was also negatively correlated with the level of autistic traits. Together, these data emphasise the importance of functional connectivity between the mentalizing and mirror systems when inferring social intentions and show that reduced connectivity between these systems may explain some of the behavioural difficulties experienced by adults with ASC. PMID- 30468778 TI - Temporal expectations modulate face image repetition suppression of early stimulus evoked event-related potentials. AB - Repeated exposure to a stimulus leads to reduced responses of stimulus-selective sensory neurons, an effect known as repetition suppression or stimulus-specific adaptation. Several influential models have been proposed to explain repetition suppression within hierarchically-organised sensory systems, with each specifying different mechanisms underlying repetition effects. We manipulated temporal expectations within a face repetition experiment to test a critical prediction of the predictive coding model of repetition suppression: that repetition effects will be larger following stimuli that appear at expected times compared to stimuli that appear at unexpected times. We recorded event-related potentials from 18 participants and mapped the spatiotemporal progression of repetition effects using mass univariate analyses. We then assessed whether the magnitudes of observed face image repetition effects were influenced by temporal expectations. In each trial participants saw an adapter face, followed by a 500 ms or 1000 ms interstimulus interval (ISI), and then a test face, which was the same or a different face identity to the adapter. Participants' expectations for whether the test face would appear after a 500 ms ISI were cued by the sex of the adapter face. Our analyses revealed multiple repetition effects with distinct scalp topographies, extending until at least 800 ms from stimulus onset. An early (158-203 ms) repetition effect was larger for stimuli following surprising, rather than expected, 500 ms ISI durations, contrary to the model predictions of the predictive coding model of repetition suppression. During this time window temporal expectation effects were larger for alternating, compared to repeated, test stimuli. Statistically significant temporal expectation by stimulus repetition interactions were not found for later (230-609 ms) time windows. Our results provide further evidence that repetition suppression can reduce neural effects of expectation and surprise, indicating that there are multiple interactive mechanisms supporting sensory predictions within the visual hierarchy. PMID- 30468779 TI - Does the min-counting strategy for simple addition become automatized in educated adults? A behavioural and ERP study of the size congruency effect. AB - Recent studies have proposed that the sum-counting strategy for simple addition (i.e., count up of the summed value of the two operands one by one) used at early age becomes automatized in adults, challenging the long held view that skilled adults solve simple addition problems by fact retrieval. As arithmetic skill develops, however, the sum-counting strategy usually is replaced by a more advanced and efficient min-counting strategy (i.e., start counting at the value of the larger addend and count up by ones equal to the smaller or "min" addend). Thus, one would expect the min strategy, rather than the sum strategy, to become automatized if we assume automatic counting procedures exist. The present study sought evidence of the min-strategy in adults by investigating the size congruency effect (SCE) through behavioural and event related brain potential (ERP) experiments. The SCE is observed in number comparison tasks (e.g., identify the larger of two numbers), where RT is slower when the physical and numerical size of the numbers are incongruent compared to when they are congruent. The min counting strategy inherently requires a number comparison stage, because the min and max number must be determined before the counting begins. Experiment 1 tested 72 participants on addition and number comparison tasks. The results showed a robust behavioural SCE for number comparison but not for simple addition. Experiment 2 tested 20 participants with a large number of addition and number comparison problems and recorded ERP. The behavioural results replicated the findings of Experiment 1. The ERP results revealed brain signatures in line with previous studies and the current behavioural findings. No SCE indicated the absence of a number comparison stage for addition; thus, the present findings ruled out the possibility of a fast min-counting strategy, or more generally a min strategy, for adults' simple addition. PMID- 30468780 TI - Deletion of an intronic HIF-2alpha binding site suppresses hypoxia-induced WT1 expression. AB - Hypoxia-inducible factors (HIFs) play a key role in the adaptation to low oxygen by interacting with hypoxia response elements (HREs) in the genome. Cellular levels of the HIF-2alpha transcription factor subunit influence the histopathology and clinical outcome of neuroblastoma, a malignant childhood tumor of the sympathetic ganglia. Expression of the Wilms tumor gene, WT1, marks a group of high-risk neuroblastoma. Here, we identify WT1 as a downstream target of HIF-2alpha in Kelly neuroblastoma cells. In chromatin immunoprecipitation assays, HIF-2alpha bound to a HRE in intron 3 of the WT1 gene, but not to another predicted HIF binding site (HBS) in the first intron. The identified element conferred oxygen sensitivity to otherwise hypoxia-resistant WT1 and SV40 promoter constructs. Deletion of the HBS in the intronic HRE by genome editing abolished WT1 expression in hypoxic neuroblastoma cells. Physical interaction between the HRE and the WT1 promoter in normoxic and hypoxic Kelly cells was shown by chromosome conformation capture assays. These findings demonstrate that binding of HIF-2alpha to an oxygen-sensitive enhancer in intron 3 stimulates transcription of the WT1 gene in neuroblastoma cells by hypoxia-independent chromatin looping. This novel regulatory mechanism may have implications for the biology and prognosis of neuroblastoma. PMID- 30468781 TI - Maternal lipid profile differs by gestational diabetes physiologic subtype. AB - : Aim To characterize lipid profiles in women with different gestational diabetes mellitus (GDM) physiologic subtypes. METHODS: We measured seven lipid markers (total cholesterol, LDL, HDL, triglycerides, non-esterified fatty acids (NEFA), ApoA, ApoB) in fasting plasma collected in a prospective cohort of 805 pregnant women during second trimester. We estimated insulin sensitivity and secretion using oral glucose tolerance test-based validated indices. We categorized GDM physiologic subtypes by insulin sensitivity and secretion defects defined as values below the 25th percentile among women with normal glucose tolerance (NGT), as previously established. We compared lipid markers across NGT and GDM subtypes. We explored associations between lipid markers and newborns anthropometry in the overall group and stratified by glucose tolerance status. RESULTS: Among 805 women, 67 (8.3%) developed GDM. Women with GDM had higher body mass index (BMI; 29.3 vs. 26.6 kg/m2), while ethnicity (97.3% vs. 97.0% European ancestry) and age (28 vs. 29 years) were similar. In comparison to women with NGT, women with GDM characterized by a predominant insulin sensitivity defect had significantly higher triglycerides (2.20 vs. 1.82, P = 0.002), lower HDL (1.64 vs. 1.90, P = 0.01) and higher NEFA (0.34 vs. 0.24, P < 0.0001). GDM women with a predominant insulin secretion defect differed from women with NGT with respect to NEFA (0.32 vs. 0.24, P = 0.003) while other lipid markers were similar. These associations remained significant after adjusting for maternal age and BMI. Greater maternal levels of NEFA were associated with higher birth weight z-scores in women with an insulin secretion defect (BMI-adjusted r = 0.58, P = 0.01). We did not find significant associations between other lipid markers and newborn anthropometry in other groups. CONCLUSION: Women with GDM have distinct lipid profiles based on their GDM physiologic subtype which may not be apparent when investigating GDM as a single group. PMID- 30468782 TI - Metabolomics profiling of metformin-mediated metabolic reprogramming bypassing AMPKalpha. AB - BACKGROUND: Metformin is a first-line drug for treating type 2 diabetes and has gained considerable interest as a potential anticancer agent. Increasing evidence suggests that metformin antagonizes diabetes and tumors through disrupting metabolic homeostasis and altering energy state. However, whether AMP activated protein kinase (AMPK) contributes to such effects of metformin remains controversial. METHODS: We performed integrative metabolomics analyses to systematically examine the effects of metformin on metabolic pathways in Prkaa1 wild type (WT) and knock-out (KO) mouse embryonic fibroblast (MEF) cells as well as human cells based on gas chromatography-mass spectrometry and capillary electrophoresis-mass spectrometry (CE-MS). RESULTS: Metformin treatment induced metabolic reprogramming and reduced the energy state of both Prkaa1 WT and KO MEF cells, as evidenced by suppressed tricarboxylic acid (TCA) cycle, elevated lactate production as well as decreased NAD+/NADH ratio. Additionally, metabolic flux analysis also showed that metformin Ampkalpha-independently increased metabolic flux from glucose to lactate and decreased metabolic flux from acetyl CoA to TCA cycle as well as from pyruvate to malate. Moreover, metformin Ampkalpha-dependently upregulated P-Acc but Ampkalpha-independently inhibited the levels of P-mTor, PS6, Lc3, Atgl and P-Erk in MEF cells. Similarly, we demonstrated that a commonly used AMPK agonist 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) and fetal bovine serum (FBS) starvation, as a common model for energy stress, both led to Ampkalpha-independent metabolism alterations in MEF cells. Furthermore, these effects of metformin were also confirmed in human hepatocellular carcinoma (HCC) cells as well as in MCF10A shControl and shPRKAA1 cells. Importantly, we found that metformin could obviously inhibit colony conformation of HCC cells in an Ampkalpha-independent manner. CONCLUSIONS: Our data highlight a comprehensive view of metabolic reprogramming mediated by metformin as well as AICAR. These observations suggest that metformin could affect cellular metabolism largely bypassing Ampkalpha, and may provide a new insight for its clinical usage. PMID- 30468783 TI - Convenient synthesis of the immunogenic glycolipid BbGL1. AB - A simple and efficient method to synthesize the immunogenic glycolipid BbGL1 is introduced. Two simple steps were required to obtain the desired product in good yield. First, a highly efficient glycosylation of cholesterol using galactosyl trichloroacetimidate as a donor was performed to produce cholesteryl-beta-d galactoside. Finally, an efficient palmitoylation on the C6-OH of the galactose of the synthesized saponin using sym-collidine and acyl chloride under microwave heating that produced BbGL1 in good yield. The procedure is a convenient and cheaper alternative to the reported procedures allowing a rapid preparation of multiple analogs and conjugates. PMID- 30468784 TI - Association between ESR1 polymorphisms and second to fourth digit ratio in school aged children in the Hokkaido Study. AB - The ratio of the lengths of the 2nd and 4th digits (2D:4D) is considered an index of prenatal exposure to androgen. Indeed, androgen receptors have been linked to digit length, but estrogen receptors are rarely investigated in this context. Thus, we investigated the association between estrogen receptor 1 (ESR1) genetic polymorphisms and 2D:4D in school-aged children. The 2D:4D ratios were determined using Vernier calipers from photocopies of palms provided by 1800 children aged 7 years who were enrolled in an ongoing prospective cohort study in Hokkaido, Japan. The children were genotyped using cord blood collected at birth for single nucleotide polymorphisms in ESR1, specifically PvuII (T > C, dbSNP: rs2234693), XbaI (A > G, dbSNP: rs9340799), and rs2077647 (A > G). The association between ESR1 polymorphisms and 2D:4D was assessed by multiple linear regression adjusted for potential cofounding factors. Boys with the GG genotype at rs9340799 had a significantly lower 2D:4D in the right hand than boys with the AA/AG genotype ( 0.96% lower, 95% confidence interval: -1.68 to -0.24). However, this association was detected only in boys born to non-smoking mothers. No significant differences were found between rs9340799 polymorphisms and 2D:4D among girls. There was also no link between 2D:4D and polymorphisms at rs2234693 and rs2077647. These data suggest that rs9340799 polymorphisms in ESR1 may contribute to digit length and 2D:4D. PMID- 30468785 TI - Non-holostane aglycones of sea cucumber triterpene glycosides. Structure, biosynthesis, evolution. AB - Triterpene glycosides are known as characteristic metabolites of sea cucumbers (class Holothuroidea, phylum Echinodermata). The most of them have lanostane aglycones containing 18(20)-lactone, i.e. belongs to so-called holostane series. However non-holostane glycosides having no lactone (with the both normal and shortened side chains) or containing 18(16)-lactone function were also found in these invertebrates last a few decades. In addition, some very rare findings of the glycosides containing rearranged lanostane skeleton systems were reported. Probably, these natural products are formed in result of intramolecular aldol condensation of 1,6-diketo precursors as well as by Meinwald rearrangement of 1,2 epoxy precursor or pinacol-pinacolone rearrangement of fully substituted 1,2-diol precursor. Structures, biosynthesis and evolution of non-holostane aglycones of sea cucumber triterpene glycosides are discussed. Biological properties of the glycosides with hon-holostane aglycones are also discussed. PMID- 30468786 TI - Impact of neuroimmune activation induced by alcohol or drug abuse on adolescent brain development. AB - Evidence obtained in recent decades has demonstrated that the brain still matures in adolescence. Changes in neural connectivity occur in different regions, including cortical and subcortical structures, which undergo modifications in white and gray matter densities. These alterations concomitantly occur in some neurotransmitter systems and hormone secretion, which markedly influence the refinement of certain brain areas and neural circuits. The immaturity of the adolescent brain makes it more vulnerable to the effects of alcohol and drug abuse, whose use can trigger long-term behavioral dysfunction. This article reviews the action of alcohol and drug abuse (cannabis, cocaine, opioids, amphetamines, anabolic androgenic steroids) in the adolescent brain, and their impact on both cognition and behavioral dysfunction, including predisposition to drug abuse in later life. It also discusses recent evidence that indicates the role of the neuroimmune system response and neuroinflammation as mechanisms that participate in many actions of ethanol and drug abuse in adolescence, including the neurotoxicity and alterations in neurocircuitry that contribute to the dysfunctional behaviors associated with addiction. The new data suggest the therapeutic potential of anti-inflammatory targets to prevent the long-term consequences of drug abuse in adolescence. PMID- 30468788 TI - TOM7 silencing Exacerbates Focal Cerebral Ischemia Injury in Rat by Targeting PINK1/Beclin1-Mediated Autophagy. AB - Activated autophagy has been intensively observed in cerebrovascular diseases, including focal cerebral ischemia injury, but its molecular mechanisms remain unclear. TOM7, which is a component of the protein translocase of the outer mitochondrial membrane (TOM) complex, may modulate assembly of the TOM complex. However, an understanding of how TOM7 affects cerebral ischemia injury is limited. In this study, we demonstrate that the expression of TOM7 is up regulated after a photothrombotic cerebral ischemic model in rats, peaking at 3 days. In addition, TOM7 knockdown may aggravate cerebral ischemic injury and inhibit autophagy after ischemic stroke. Mechanically, TOM7 may regulate autophagy through the PINK1/Beclin1 pathway after cerebral ischemia injury. These results demonstrate that TOM7 silencing may aggravate cerebral ischemia injury through inhibiting PINK1/Beclin1 pathway- mediated autophagy. PMID- 30468787 TI - Interactions between whole-body heating and citalopram on body temperature, antidepressant-like behaviour, and neurochemistry in adolescent male rats. AB - Evidence suggests that affective disorders are associated with altered thermoregulation, and it has been hypothesized that therapeutic strategies targeting body-to-brain thermosensory systems may be effective for treating depression. Consistent with this hypothesis, a recent randomized, double blind, placebo-controlled clinical trial has suggested that infrared whole-body hyperthermia has therapeutic potential for the treatment of depression. Preclinical models may help uncover the mechanism(s) underlying the antidepressant-like effects of whole-body heating. We have previously shown that exposure to whole-body heating potentiates antidepressant-like behavioural responses following administration of a behaviourally subthreshold dose of the selective serotonin reuptake inhibitor citalopram, but the neurochemical and behavioural interactions between whole body heating and behaviourally effective doses of citalopram are not known. In these experiments, we examined the effects of whole-body heating, either with or without treatment of a suprathreshold dose of citalopram (20 mg/kg, s.c.), on body temperature, antidepressant-like behavioural responses in the forced swim test, and tissue concentrations of serotonin and its metabolite, 5-hydoxyindoleacetic acid (5-HIAA), in the prefrontal cortex of adolescent male Wistar rats. Although whole-body heating did not potentiate the behavioural effects of suprathreshold citalopram, citalopram was observed to increase body temperature and potentiate the effects of whole body heating on body temperature. Whole-body heating, by itself, decreased serotonin concentrations in the infralimbic cortex to a level similar to that observed following treatment with citalopram, suggesting that these treatments have convergent effects on a mesolimbocortical system innervating the medial prefrontal cortex, an effect that was correlated with effects of treatment on body temperature. PMID- 30468789 TI - Spontaneous recovery of conditioned eyeblink responses is associated with transiently decreased cerebellar theta activity in guinea pigs. AB - Behavioral studies have demonstrated that extinguished conditioned eyeblink responses (CR) can spontaneously recover after extinction. However, the neural mechanisms underlying this process are still unclear. We have shown that spontaneous cerebellar theta activity was predictive of subsequent CR extinction. Here, we sought to further evaluate the association between spontaneous recovery and cerebellar theta activity in behaving guinea pigs. It was found that trace conditioning training significantly diminished the degree of spontaneous recovery during extinction sessions as compared to delay training. Moreover, by recording local field potential in the cerebellum of guinea pigs undergoing an eyeblink conditioning extinction task, we found that spontaneous recovery of delay paradigm CRs was associated with transiently decreased CS-evoked theta activity in the cerebellum. These findings suggest that decreased CS-evoked cerebellar theta activity may contribute to the neural process that is important for the spontaneous recovery of extinguished motor memory. Future studies are needed to clarify the neural mechanism underlying changed cerebellar theta activity during altered behavioral contingencies. PMID- 30468790 TI - Stressful life events are associated with perinatal cigarette smoking. AB - Perinatal smoking, including smoking during pregnancy and postpartum smoking relapse, is a persistent public health problem. While childhood trauma has been linked to perinatal smoking, less is known about the association with more proximal stressful life events (SLEs). The objective of this study was to examine the association between SLEs that occurred during the year prior to childbirth with perinatal smoking. Using the Pregnancy Risk Assessment Monitoring System 2009-2011, perinatal smoking was assessed at three time points: (1) three months prior to pregnancy, (2) the last three months of pregnancy, and (3) two to six months postpartum. Survey respondents endorsed up to 13 SLEs (i.e., death of someone close). SLEs were analyzed individually, as well as using a cumulative score (range 0-13). Weighted analyses included unadjusted and adjusted logistic regression. Among those who smoked prior to pregnancy (n = 15,316), 48% (n = 7308) reported quitting smoking during pregnancy. Of those, 44% (n = 3126) reported postpartum smoking relapse. A total of 11 SLEs were associated with smoking during pregnancy and 2 SLEs were associated with postpartum smoking relapse. The odds of continued smoking during pregnancy was 12% higher for each SLE endorsed (adjusted odds ratio [aOR] = 1.12, 95% confidence interval [CI]: 1.09, 1.15) and this association was attenuated in relation to the odds of postpartum smoking relapse (aOR = 1.03, 95% CI: 0.99, 1.08). SLEs are associated with perinatal smoking. Additional research is needed to elucidate the mechanisms of action and to develop interventions specific to the needs of women who experience SLEs. PMID- 30468791 TI - Preventive impact of social participation on the onset of non-communicable diseases among middle-aged adults: A 10-wave hazards-model analysis in Japan. AB - Social participation (SP) is known to have a favorable impact on the health of older adults by reducing the risk of functional disability, psychological distress, cognitive impairment, and mortality. However, the preventive impact of SP on non-communicable diseases (NCDs) among middle-aged adults is largely understudied. Using the dataset from a population-based, 10-wave longitudinal survey that started with Japanese adults aged 50-59 years in 2005 (16,290 men and 17,248 women), we estimated Cox proportional hazards models to estimate the preventive impact of SP adjusted for baseline covariates. After controlling for baseline covariates, baseline participation in at least one of six types of SP prevented diabetes both for men (hazard rate [HR] = 0.86; 95% confidence interval [CI] = 0.77, 0.95) and women (HR = 0.75; 95% CI = 0.66, 0.85) and stroke both for men (HR = 0.83; 95% CI = 0.70, 0.99) and women (HR = 0.78; 95% CI = 0.64, 0.97). SP also had a preventive impact on hypertension only for women (HR = 0.91; 95% CI = 0.84, 0.99). SP did not prevent heart disease, hyperlipidemia, or cancer for either gender. We also found that SP tended to have a stronger preventive effect when it was conducted with other persons than done alone, highlighting personal interactions as a key aspect of SP for later health outcomes. Overall, the results showed that SP can prevent the onset of selected NCDs, suggesting that policy measures to encourage SP may be favorable for the health of middle-aged adults. PMID- 30468792 TI - Adherence to the 2015 Dietary Guidelines for Americans and mortality risk in a Mediterranean cohort: The SUN project. AB - The 2015-2020 Dietary Guidelines for Americans (DGA) was issued in early 2016. It remains untested if adherence to these guidelines could reduce mortality risk. Using a modified version of the 2015 Dietary Guidelines for American Index (2015 DGAI), we investigated if adherence to the new DGA is associated with mortality in a Spanish (the Seguimiento Universidad de Navarra, SUN) cohort. We assessed the habitual diet of 16,866 participants of this cohort recruited between 1999 and 2014 and calculated their adherence scores to the new DGA using the modified 2015 DGAI (0-21points). Mortality data was determined from the yearly National Death Index reports. After adjusting for demographic and lifestyle confounders, high adherence scores (fourth quartile) were found to be associated with reduced all-cause, cardiovascular and cancer mortality risk, hazard ratios (HR) (95% confidence intervals [CI]) 0.42 (0.25-0.70), 0.30 (0.10-0.90) and 0.46 (0.22 0.96), respectively, compared to low adherence scores (first quartile). A 2-point increase in the 2015 DGAI score was linearly inversely associated with all-cause mortality (HR [95% CI] 0.78 [0.67-0.92]). Main sources of variability in the adherence scores were whole-fat dairy products, red/orange vegetables, fresh fruits, red meat, and dark green vegetables. In conclusion, higher adherence to 2015-2020 Dietary Guidelines for Americans was inversely associated with total, cardiovascular and cancer mortality risk in a Spanish cohort. PMID- 30468793 TI - Maternal adverse childhood experiences, mental health, and child behaviour at age 3: The all our families community cohort study. AB - Links between adverse childhood experiences (ACEs) and threats to health and well being later in life are well established. The current study extends those findings into younger populations of pregnant women and their children; investigating how ACEs relates to maternal postpartum well-being, coping, and parenting, as well as child outcomes. Participants included 1994 mothers and children from the All Our Families community-based cohort in Alberta, Canada, followed from pregnancy (from 2008 to 2011) until child age 3 years. The sample is representative of the pregnant population in an urban Canadian centre. Mothers completed questionnaires on ACEs, postpartum mental health, as well as parenting morale, efficacy, coping, and personality. Child outcomes included internalizing and externalizing behavior, as well as temperament. Approximately 62% of participants experienced at least one ACE; 25% experienced 3 or more ACEs. The presence of 3 or more ACEs was associated with postpartum smoking, binge drinking, depressive and anxiety symptoms, lower optimism and higher neuroticism, and lower reported parenting morale. In children, 3 or more maternal ACEs was associated with higher levels of internalizing (e.g., anxiety) and externalizing difficulties (aggression and hyperactivity), as well as temperament (surgency and negative affectivity). Cumulative maternal ACEs are associated with postpartum mental health and parenting morale, as well as maladaptive coping strategies. The demonstrated downstream consequences of maternal ACEs for child outcomes suggests that early intervention strategies and community resources to improve life course outcomes for parents and children are critical for breaking intergenerational continuities of risk. PMID- 30468794 TI - Identifying opportunities to develop the science of implementation for community based non-communicable disease prevention: A review of implementation trials. AB - Implementation of interventions in community organisations such as schools, childcare centres, and sporting clubs are recommended to target a range of modifiable risks of non-communicable diseases. Poor implementation, however, is common and has contributed to the failure of non-communicable disease interventions globally. This study aimed to characterise experimental research regarding strategies to improve implementation of chronic disease prevention programs in community settings. The review used data collected in three comprehensive systematic reviews undertaken between August 2015 and July 2017. Randomised controlled trials, including cluster design, and non-randomised trials with a parallel control group were included. The data were extracted to describe trial characteristics, implementation strategies employed, implementation outcomes and study quality. Of the 40 implementation trials included in the study, unhealthy diet was the most common risk factor targeted (n = 20). The most commonly reported implementation strategies were educational meetings (n = 38, 95%), educational materials (n = 36, 90%) and educational outreach visits (n = 29, 73%). Few trials were conducted 'at-scale' (n = 8, 20%) or reported adverse effects (n = 5, 13%). The reporting of implementation related outcomes; intervention adoption (n = 13, 33%); appropriateness (n = 11, 28%); acceptability (n = 8, 20%); feasibility (n = 8, 20%); cost (n = 3, 8%); and sustainability (n = 2, 5%); was limited. For the majority of trials, risk of bias was high for blinding of study personnel/participants and outcome assessors. Testing of strategies to improve implementation of non-communicable disease prevention strategies in community settings, delivered 'at-scale', utilising implementation frameworks, including a comprehensive range of implementation outcomes should be priority areas for future research in implementation science. PMID- 30468795 TI - What are the potential preventive population-health effects of a tax on processed meat? A quantitative health impact assessment for Germany. AB - The International Agency for Research on Cancer considers processed meat to be carcinogenic. Further, processed meat is associated with diabetes, ischemic heart disease (IHD) and all-cause mortality. We aimed to assess health gains of four processed meat taxation scenarios in comparison to the reference and a minimum risk-exposure-scenario. To estimate the shift in processed meat intake following respective taxes, we calculated price elasticities for processed meat. DYNAMO-HIA was used to dynamically project policy-attributable differences in the prevalence of diseases and deaths. In projection year 10, an extra 9300 males and 4500 females would be alive under the lowest tax scenario (4% tax), compared to the reference scenario. Prevalent IHD, diabetes and colorectal cancer cases in males would be 8400, 9500 and 500 lower, respectively, and there would be 4600, 7800 and 300 less cases in females. Of the respective death and disease reduction that would be achieved under the minimum-risk-exposure-scenario, the lowest tax reaches 2.84% (colorectal cancer in males) to 6.02% (diabetes in females). Under the highest tax scenario (33.3% tax), an extra 76,700 males and 37,100 females would be alive, compared to the reference scenario. Prevalent IHD, diabetes and colorectal cancer cases would be 70,800, 77,900 and 4900 lower in males and 29,900, 48,900 and 2300 lower in females, which represents 27.84% (colorectal cancer in males) to 37.76% (diabetes in females) of the maximal preventable death and disease burden. Further research needs to examine to what extent these health benefits are outweighed by a simultaneous tax-induced decrease in fish intake. PMID- 30468796 TI - Neuroprotection by cannabidiol and hypothermia in a piglet model of newborn hypoxic-ischemic brain damage. AB - OBJECTIVE: Hypothermia, the gold standard after a hypoxic-ischemic insult, is not beneficial in all treated newborns. Cannabidiol is neuroprotective in animal models of newborn hypoxic-ischemic encephalopathy. This study compared the relative efficacies of cannabidiol and hypothermia in newborn hypoxic-ischemic piglets and assessed whether addition of cannabidiol augments hypothermic neuroprotection. METHODS: One day-old HI (carotid clamp and FiO2 10% for 20 min) piglets were randomized to vehicle or cannabidiol 1 mg/kg i.v. u.i.d. for three doses after being submitted to normothermia or 48 h-long hypothermia with a subsequent rewarming period of 6 h. Non-manipulated piglets (naive) served as controls. Hemodynamic or respiratory parameters as well as brain activity (aEEG amplitude) were monitored throughout the experiment. Following termination, brains were obtained for histological (TUNEL staining, apoptosis; immunohistochemistry for Iba-1, microglia), biochemical (protein carbonylation, oxidative stress; and TNFalpha concentration, neuroinflammation) or proton magnetic resonance spectroscopy (Lac/NAA: metabolic derangement; Glu/NAA: excitotoxicity). RESULTS: HI led to sustained depressed brain activity and increased microglial activation, which was significantly improved by cannabidiol alone or with hypothermia but not by hypothermia alone. Hypoxic-ischemic-induced increases in Lac/NAA, Glu/NAA, TNFalpha or apoptosis were not reversed by either hypothermia or cannabidiol alone, but combination of the therapies did. No treatment modified the effects of HI on oxidative stress or astroglial activation. Cannabidiol treatment was well tolerated. CONCLUSIONS: cannabidiol administration after hypoxia-ischemia in piglets offers some neuroprotective effects but the combination of cannabidiol and hypothermia shows some additive effect leading to more complete neuroprotection than cannabidiol or hypothermia alone. PMID- 30468797 TI - Lipopolysaccharide-induced depressive-like, anxiogenic-like and hyperalgesic behavior is attenuated by acute administration of alpha-(phenylselanyl) acetophenone in mice. AB - The lipopolysaccharide (LPS) is an endotoxin derived from gram-negative bacteria, which induces inflammation. The aims of this study were to evaluate the possible alpha-(phenylselanyl) acetophenone (PSAP) activity in reducing comorbid hyperalgesia, depressive-like and anxiogenic-like symptoms induced by LPS in mice. In additional, investigated physical chemical properties of PSAP through in silico analysis by ADMET predictor software. The LPS (100 MUg/kg, intraperitoneally) or saline were administered and after 4 h the treatment with PSAP (0.001-10 mg/kg, intragastric route [i.g.]) or FLX (10 mg/kg, i.g.) was performed, and after 30 min, the behavioral tests were carried out. LPS reduced the latency time for the first episode of immobility and increased the immobility time in the FST as well as decreased the grooming time in the splash test. PSAP reversed these alterations demonstrating an antidepressive-like effect. LPS also enhances the anxiogenic behavior in the elevated plus maze test (EPM). PSAP reversed these parameters, showing anxiolytic-like effect. LPS also decreased the latency time (s) on the hot plate and the treatment with PSAP at all doses significantly reversed the hyperalgesic effect of LPS. LPS increased the activation of p38MAPK and p-p65NF-kappaB pathways as well as the COX-2 levels in the cerebral cortex, which are indicative of an inflammatory response. Besides, it also reduced the levels of mBDNF, involved in neuroplasticity. Treatment with PSAP restored all these neurochemical alterations induced by LPS. The results demonstrated that PSAP presents antidepressive-like, anxiolytic-like and anti hyperalgesic effects related to reduction in neuroinflammation. PMID- 30468798 TI - The high efficacy of muscarinic M4 receptor in D1 medium spiny neurons reverses striatal hyperdopaminergia. AB - The opposing action of dopamine and acetylcholine has long been known to play an important role in basal ganglia physiology. However, the quantitative analysis of dopamine and acetylcholine signal interaction has been difficult to perform in the native context because the striatum comprises mainly two subtypes of medium sized spiny neurons (MSNs) on which these neuromodulators exert different actions. We used biosensor imaging in live brain slices of dorsomedial striatum to monitor changes in intracellular cAMP at the level of individual MSNs. We observed that the muscarinic agonist oxotremorine decreases cAMP selectively in the MSN subpopulation that also expresses D1 dopamine receptors, an action mediated by the M4 muscarinic receptor. This receptor has a high efficacy on cAMP signaling and can shut down the positive cAMP response induced by dopamine, at acetylcholine concentrations which are consistent with physiological levels. This supports our prediction based on theoretical modeling that acetylcholine could exert a tonic inhibition on striatal cAMP signaling, thus supporting the possibility that a pause in acetylcholine release is required for phasic dopamine to transduce a cAMP signal in D1 MSNs. In vivo experiments with acetylcholinesterase inhibitors donepezil and tacrine, as well as with the positive allosteric modulators of M4 receptor VU0152100 and VU0010010 show that this effect is sufficient to reverse the increased locomotor activity of DAT knockout mice. This suggests that M4 receptors could be a novel therapeutic target to treat hyperactivity disorders. PMID- 30468799 TI - Prognostic importance of mitochondrial markers in mucosal and cutaneous head and neck melanomas. AB - Mitochondrial dysfunction is caused by an imbalance in the fission and fusion processes, and it has been implicated in the pathogenesis of several human cancers. However, the role of mitochondrial markers in melanomas still remain poorly understood. In this study, the authors assessed the expression of three mitochondrial markers [antimitochondrial (AMT), fission protein 1 (FIS1) and mitofusin 2 (MFN2)] in a series of head and neck mucosal and cutaneous melanomas. Patients with cutaneous (n=56), and mucosal [oral - n=30 and sinonasal - n=26] melanomas of the head and neck region were enrolled in this study. Clinical and follow-up data were retrieved from medical records. The expression of three mitochondrial markers was assessed by the immunohistochemistry, then digitally quantified and correlated with clinicopathological data and outcome information. In the multivariate model, high mitochondrial content was identified as an independent prognostic value for disease-free survival (DFS) in cutaneous melanomas and overall survival (OS) in oral melanomas. FIS1 expression was significantly associated with lower OS rates in patients with oral melanomas, and strictly correlated with vascular invasion in mucosal melanomas. MFN2 was associated with high risk of distant metastasis in patients with cutaneous melanomas. In summary, the authors demonstrated that mitochondrial content, along with FIS1 and MFN2 expressions, are correlated with important clinicopathologic characteristics in patients with cutaneous and mucosal head and neck melanomas. PMID- 30468800 TI - A combination of GATA3 and SOX10 is useful for the diagnosis of metastatic triple negative breast Cancer. AB - In metastatic breast cancer (MBC), it can be difficult to establish the origin if the primary tumor is triple negative or if there is a loss of biomarker expression. SOX10 expression has been reported in primary triple negative breast cancer but is poorly studied in metastatic lesions. In this study, the diagnostic utility of a panel of SOX10, GATA3, and androgen receptor (AR) in MBC negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) was evaluated and compared to the expression of these markers in the matched primary breast cancer (PBC). In a series of 57 triple negative MBC, 82% were positive for GATA3, 58% for SOX10, and 25% for AR. Nearly all MBC (95%) were positive for either GATA3 or SOX10, with 46% dual positive and 5% of cases negative for both markers. Most GATA3 negative MBC cases were SOX10 positive (70%). AR expression was only seen in GATA3 positive MBC (25%), and was significantly more frequent in SOX10 negative MBC (48%) vs. SOX10 positive MBC (9%, P=.001). Concordance for GATA3, SOX10, and AR between the primary and metastasis was 89%, 88%, and 80% respectively. While GATA3 is a more sensitive lineage marker than SOX10 in MBC, SOX10 is a useful adjunct because it is positive in the majority of GATA3 negative breast metastases. Utilizing both GATA3 and SOX10 is recommended for confirming breast as the site of origin in metastases that lack ER, PR, and HER2 expression whereas the addition of AR is not helpful. PMID- 30468802 TI - The Iron Islands: Erythroblastic Islands and Iron Metabolism. AB - BACKGROUND: A healthy human can produce over 1 * 1015 blood cells throughout their life. This remarkable amount of biomass requires a concomitantly vast amount of iron to generate functional haemoglobin and functional erythrocytes. SCOPE OF THE REVIEW: Erythroblasts form multicellular clusters with macrophages in the foetal liver, bone marrow and spleen termed erythroblastic islands. How the central erythroblastic island macrophage co-ordinates the supply of iron to the developing erythroblasts will be a central focus of this review. MAJOR CONCLUSION: Despite being studied for over 60 years, the mechanisms by which the erythroblastic island niche serves to control erythroid cell iron metabolism are poorly resolved. GENERAL SIGNIFICANCE: Over 2 billion people suffer from some form of anaemia. Iron deficiency anaemia is the most prevalent form of anaemia. Therefore, understanding the processes by which iron is trafficked to, and metabolised in developing erythrocytes, is crucially important. PMID- 30468801 TI - HuC/D expression in small round cell tumors and neuroendocrine tumors: a useful tool for distinguishing neuroblastoma from childhood small round cell tumors. AB - The RNA-binding protein HuC/D displays a neuron-specific expression and is involved in neuronal differentiation and the maintenance of the nervous system. Here we investigated the diagnostic value of HuC/D in neuroblastomas. We evaluated 85 neuroblastic tumors: 81 neuroblastomas; three ganglioneuroblastomas, intermixed; one ganglioneuroma, maturing, and 101 other tumors consisting of 34 Ewing sarcomas, 14 nephroblastomas, 11 rhabdomyosarcomas, 15 pulmonary small cell carcinomas, 18 pancreatic neuroendocrine tumors, and nine pheochromocytomas. Immunohistochemistry for HuC/D, PHOX2B, and tyrosine hydroxylase was performed. The immunoreactivity for HuC/D was semi-quantified using the total score (TS, range: 0-8). HuC/D positivity was defined as a TS >=6. The TS of the neuroblastic tumors (mean TS, 7.94) was significantly higher than those of the other small round cell tumors and neuroendocrine tumors (P<.001) except for the pheochromocytomas (mean TS, 6.89; P=.074). HuC/D was positive in all 85 neuroblastic tumors, one (2.9%) Ewing sarcoma, one (6.7%) pulmonary small cell carcinoma, and eight (89%) pheochromocytomas. PHOX2B was positive in all of the neuroblastic tumors and pheochromocytomas. Tyrosine hydroxylase was positive in 80 (94%) neuroblastic tumors, one (9.1%) rhabdomyosarcoma, and all of the pheochromocytomas. Therefore, HuC/D serves as a highly sensitive diagnostic marker to distinguish neuroblastomas from other small round cell tumors. The combination of HuC/D and PHOX2B staining may be valuable for the diagnosis of neuroblastic tumors, especially in the assessment of small sections. HuC/D expression in tumors may be related to catecholamine production or a neural crest derived cell origin. PMID- 30468803 TI - Impact of increasing the proportion of healthier foods available on energy purchased in worksite cafeterias: A stepped wedge randomized controlled pilot trial. AB - Increasing the proportion of healthier foods available could encourage healthier consumption, but evidence to date is limited in scope and quality. The current study aimed to: (a) examine the feasibility and acceptability of intervening to change product availability in worksite cafeterias; and (b) estimate the impact on energy purchased of increasing the proportion of healthier (i.e. lower energy) cooked meals, snacks, cold drinks and sandwiches. Six English worksite cafeterias increased the proportion of healthier foods available, aiming to keep the total number of options constant, in a stepped wedge randomized controlled pilot trial conducted between January and May 2017. The intervention was generally successfully implemented and acceptable to clientele. Generalized linear mixed models showed a reduction of 6.9% (95%CI: -11.7%, -1.7%, p = 0.044) in energy (kcal) purchased from targeted food categories across all sites. However, impact varied across sites, with energy purchased from targeted categories significantly reduced in two sites (-10.7% (95%CI: -18.1% to -2.6%, p = 0.046); -18.4% (95%CI: 26.9% to -8.8%, p = 0.013)), while no significant differences were seen in the other four sites. Overall, increasing the proportion of healthier options available in worksite cafeterias seems a promising intervention to reduce energy purchased but contextual effects merit further study. PMID- 30468804 TI - Children's healthy and unhealthy beverage availability, purchase and consumption: A wearable camera study. AB - Children's sugar-sweetened beverages (SSBs) consumption presents significant risks for obesity, type 2 diabetes and dental health. But there is a lack of objective data on beverages in children's overall environments. This study aimed to determine the nature and extent of children's beverage availability, purchase and consumption, throughout their day, using wearable cameras for data collection. Data were sourced from 'Kids'Cam NZ', a study in which randomly selected New Zealand children (n = 168; 11-14y, mean 12.6y) wore cameras for four days (Thursday-Sunday), automatically taking a photo every 7s. Using content analysis, Thursday and Saturday images (n = 700,201) were systematically analysed. On average, 18.9 (95% CI 16.8, 21.4) drinks/day were available to the children (n = 158), of which 7.5 (95% CI 5.8, 9.7; 39.7%) were non-core drinks, including 6.4 (95% CI 5.0, 8.3; 33.9%) SSBs. At school and home, core drinks (water and unflavoured milk) were the most available. In all other locations in which children spent time (e.g., recreation venues and food retail outlets) non core drinks dominated, at rates 1.5-5 times that of core drinks availability. Almost all drinks (n = 17; 10.8%) the children purchased were non-core. On average, children (n = 111; 70.3%) consumed a drink 2.6 (95% CI 2.1, 3.1) times/day, including one (95% CI 0.7, 1.3) SSB. At school and home core drinks predominated. SSBs were available to most children in all locations in which they spent time, and dominated their drinks purchases and consumption. SSBs appear to be a typical feature of children's everyday environments, almost certainly making it difficult for children's beverage intakes to align with guidelines. The findings support calls for governments to urgently enact the SSB-related actions in the WHO Commission's Ending Childhood Obesity implementation plan and, in turn, improve child health. PMID- 30468805 TI - Food selectivity in a diverse sample of young children with and without intellectual disabilities. AB - Children with developmental concerns are more likely to be referred to feeding clinics for food selectivity than typically developing (TD) children. However, there is limited research on food selectivity in children with intellectual disabilities (ID). Fifty-nine TD children and 56 children with ID ages 3-8 years participated in the Children's Mealtime Study to compare food selectivity, conceptualized as food refusal and narrow food repertoire, among TD children and children with ID. Parents completed a 119-item food frequency questionnaire. Food refusal rate was calculated as the number of foods the child refused of those offered. Food repertoire, comprising the number of unique foods eaten, was determined from a 3-day food record. Compared to TD children, among children with ID the food refusal rate was significantly higher (28.5% vs. 15.7%) and mean food repertoire significantly narrower (20.7 vs. 24.2 unique foods) (p < 0.01). Approximately 10% of children with ID and approximately 4% of TD children reported eating no fruit on any of the three days of food intake recording, and approximately 10% of children with ID compared to approximately 2% of TD children reported no vegetable intake on any of the three days. In further analyses, we examined the two measures of food selectivity among children with both ID and probable autism spectrum disorder (ASD) (by the Autism Spectrum Rating Scale) compared to children with ID only and to TD children. Food selectivity appeared to be primarily attributable to those children who also had a probable diagnosis of ASD. These findings support the need for screening for food selectivity of children with ID, particularly those who also have ASD. Children who exhibit food selectivity should be referred for further evaluation and intervention. PMID- 30468806 TI - Effects of subcritical water extraction microenvironment on the structure and biological activities of polysaccharides from Lentinus edodes. AB - In the present study, we investigated the effects of subcritical water microenvironment on the structure and biological activities of polysaccharides from Lentinus edodes. The results showed that, under different SWE conditions (100-150 degrees C for 15 min, and 150 degrees C for 10-30 min), all the polysaccharides were heteropolysaccharides and consisted of glucose, mannose and galactose with different molar ratios. In addition, FT-IR results showed that all samples were typical beta-pyranose and protein-free polysaccharides. Moreover, Congo red staining and atomic force microscope (AFM) analyses showed that when the temperature was above 150 degrees C for 15 min, the triple-helix structure no longer existed. Furthermore, various polysaccharides had varying degrees of inhibitory effect on HepG2 cells and MCF-7 cells in vitro. These findings indicated that subcritical water microenvironment has an extremely important effect on the structure and bioactivities of polysaccharides. The polysaccharides may be extracted more effectively by changing the subcritical water microenvironment. PMID- 30468807 TI - Hard, medium-hard and extraordinarily soft wheat varieties: Comparison and relationship between various starch properties. AB - Starches from extraordinarily soft wheat (Ex-SW), medium-hard wheat (MHW) and hard wheat (HW) varieties were evaluated for various properties and their relationship with each other was established. Varieties showed wide variation in grain hardness index (GHI) that varied between 17 and 95. Starches were evaluated for physicochemical properties, granule size distribution, starch morphology, pasting and thermal properties. Starches from MHW showed the presence of the largest proportion of A-type granules and the smallest proportions of B-type and C-type granules whereas Ex-SW showed the greatest proportion of C-type granules. Starches from HW and MHW varieties showed lower swelling power (SP) and higher amylose content (AC) than that from Ex-SW varieties. Starches from HW varieties had greater crystallinity than starches from Ex-SW. Transition temperatures of starch gelatinization decreased with decrease in GHI. PMID- 30468808 TI - Tau folding and cytotoxicity of neuroblastoma cells in the presence of manganese oxide nanoparticles: Biophysical, molecular dynamics, cellular, and molecular studies. AB - Manganese oxide nanoparticles (Mn2O3 NPs) have been widely used in the medical and biological applications. However, few studies have been undertaken to investigate the cytotoxicity of Mn2O3 NPs against nervous system. This paper studied the toxicity of Mn2O3 NPs against tau protein and neuroblastoma cells (SH SY5Y). Circular dichroism (CD) spectroscopy, fluorescence spectroscopy, molecular docking, and molecular dynamic studies were used to study the conformational changes of protein. The cell-based experiments, such as viability, activation of caspases-3/9, apoptosis, and gene (Bax and Bcl-2) expression assays were performed in vitro. Spectroscopic methods and molecular dynamic studies revealed that Mn2O3 NPs can fold the structure of tau toward a more packed structure. The Mn2O3 NPs also decreased the cell viability in a dose-dependent manner. Indeed, activated caspase-3 and caspase-9, enhanced Bax/Bcl-2 ratio, and induced apoptosis were observed after exposure of SH-SY5Y to Mn2O3 NPs. In conclusion, tau folding and cytotoxicity against SH-SY5Y cells may be involved in adverse effects induced by Mn2O3 NPs. PMID- 30468809 TI - Construction of a Pichia pastoris strain efficiently secreting irisin and assessment of its bioactivity in HepG2 cells. AB - Irisin, a circulating myokine, has been shown to effectively ameliorate insulin resistance and type 2 diabetes mellitus by administration of the recombinant protein. Therefore, it is important to efficiently produce active irisin protein and further characterize its potential mechanism against hepatic insulin resistance. In this study, we obtained a multi-copy irisin-expressing P. pastoris strain through an optimized method, which is pH 5.5, 1.8% methanol for 96 h, for producing a high amount of recombinant irisin protein following a series of screening and optimization procedures. The higher-glycosylated irisin, which is supposed to be the active form was obtained by dialysis and ion-exchange chromatography purification method. Both of the laser scanning confocal microscope and the atomic force microscope not only detected the high effectiveness entering cells of FITC-irisin but also localized it on the membrane of HepG2 cells. Immunofluorescence staining further suggested that irisin could localize in the cytoplasm but not in the nucleus. We further showed that glycosylated irisin rescued palmitate-induced reduction in Glut2 expression and cell viability, inhibited the apoptosis, potentially by activating PI3K/AKT pathway. In summary, we developed an efficient irisin-expressing P. pastoris strain and optimal expression condition, visualized its distribution, demonstrated biological activity and potential mechanisms in hepatic cells. PMID- 30468810 TI - Molecular and biochemical characterization of All0580 as a methylglyoxal detoxifying glyoxalase II of Anabaena sp. PCC7120 that confers abiotic stress tolerance in E. coli. AB - Abiotic stresses enhance cellular reactive oxygen species (ROS) level which results in toxic methylglyoxal (MG) production. Glyoxalases catalyze the conversion of toxic MG into non-toxic lactic acid whose properties and function are still unknown in cyanobacteria. This is the first attempt to characterize All0580 from Anabaena sp. PCC7120 as GlyII using in silico and wet lab approaches. Data of functional complementation of E. coli GlyII mutant (DeltagloB), enzyme kinetics and ESI-MS analysis suggested that All0580 harbors distinctive GlyII activity. The catalytic efficiency of All0580 (3 * 106 M-1 s-1) is higher than Arabidopsis GlyII. AAS analysis revealed the presence of a binuclear Zn/Fe centre in All0580 active site. The qRT-PCR of the target gene revealed maximum up-regulation in salinity followed by drought, arsenic, heat, and UV-B stresses. BL21/pET-21a-all0580 showed 1.5 to 10 fold increased growth and up to 4 fold decreased intracellular MG level as compared to BL21/pET-21a cells under various abiotic stresses and MG. A 39% drop in ROS generation by BL21/pET-21a-all0580 under MG stress suggested its potential to manage MG toxicity. Above attributes suggest that the hypothetical protein All0580 is a novel GlyII of cyanobacteria which heterologously confers tolerance to multiple abiotic stresses in E. coli. PMID- 30468811 TI - Involvement of Nrf2 in myocardial ischemia and reperfusion injury. AB - The morbidity rate of myocardial ischemia and reperfusion has increased in modern society, and oxidative stress plays a critical role in the pathological process. Nuclear factor E2-associated factor 2 (Nrf2) is considered a pivotal regulator for maintaining the redox balance and is involved in the initiation of the transcriptional expression of downstream antioxidant enzymes. Moreover, Nrf2 also can be regulated in various ways. Nrf2/Keap1/ARE is one of the essential signaling pathways that can attenuate myocardial infarct size and preserve cardiac function after myocardial ischemia and reperfusion injury (MIRI). Nrf2 activation provides cardioprotection via the coordinated up-regulation of antioxidant, anti-inflammatory, and autophagy mechanisms. Numerous studies have shown that ischemic preconditioning and ischemic post-conditioning have a clear protective effect on MIRI, and the potential role of the Nrf2 signaling pathway in cardioprotection may be worth discussing. This review will summarize the current knowledge on the regulation of and involvement of Nrf2 in MIRI. PMID- 30468812 TI - Models to investigate intussusceptive angiogenesis: A special note on CRISPR/Cas9 based system in zebrafish. AB - Angiogenesis is a distinct process which follows sprouting angiogenesis (SA) and intussusceptive angiogenesis (IA) forming the basis for various physiological and pathological scenarios. Angiogenesis is a double edged sword exerting both desirable and discernible effects owing to the referred microenvironment. Therapeutic interventions to promote angiogenesis in regenerative medicine is essential to achieve functional syncytium of tissue constructs while, angiogenic inhibition is a key therapeutic target to suppress tumor growth. In the recent years, clustered regularly interspaced short palindromic repeats associated 9 (CRISPR-Cas9) based gene editing approaches have been gaining considerable attention in the field of biomedical research owing to its ease in tailoring targeted genome in living organisms. The Zebrafish model, with adequately high throughput fitness, is a likely option for genome editing and angiogenesis research. In this review, we focus on the implication of Zebrafish as a model to study IA and furthermore enumerate CRISPR/Cas9 based genome editing in Zebrafish as a candidate for modeling different types of angiogenesis and support its candidature as a model organism. PMID- 30468813 TI - Hydrophilic, hydrophobic, Janus and multilayer xanthan based cryogels. AB - Xanthan gum (XG) was applied for the creation of hydrophilic, hydrophobic and layered cryogels. Firstly, the correlation among synthesis parameters, such as solvent composition and polymer concentration (Cp) in the precursor gel and mold diameter (Phi), with physicochemical properties and morphological parameters of resulting hydrophilic XG cryogels was investigated. The addition of acetic acid to the precursor led to stiffer XG cryogels. The reduction of Cp and Phi promoted the increase in the cryogels surface area and porosity. Then, XG cryogels were silanized in order to produce hydrophobic cryogels, which presented sorption capacities for diesel, mineral and sunflower oils of 28 +/- 2 g/g, 16 +/- 2 g/g and 5.2 +/- 0.3 g/g, respectively. The hydrophobic XG cryogels were considerably more efficient to remove ethinyl estradiol, an estrogenic pollutant, from liquid media than the hydrophilic cryogels. Hydrophilic and hydrophobic XG cryogels presented similar capacity to remove bisphenol A, another estrogenic pollutant, from liquid media. A new family of alternated hydrophobic/hydrophilic "Janus" like and multilayered cryogels was created and applied in mixtures of diesel oil and water or oil/water emulsions. The "Janus" like and multilayered cryogels remained at the interface, where the hydrophobic and hydrophilic layers adsorbed oil and water selectively. PMID- 30468814 TI - Cuprizone-induced demyelination in the mouse hippocampus is alleviated by phytoestrogen genistein. AB - One of the major female sex hormones, estrogen, can influence a variety of mental states. Individuals with multiple sclerosis (MS) often suffer from mental health issues, which are correlated with the pathology of gray matter. In this study, we aimed to elucidate the validity of phytoestrogen genistein (GEN) for treating the gray matter lesions in MS using the mouse model of cuprizone (CPZ)-induced demyelination. First, we confirmed that 5-week 0.2% CPZ intoxication induced demyelination in the hippocampus, and that myelination was successfully recovered by GEN. Loss of mature oligodendrocytes following CPZ intoxication was counteracted by GEN. Neither CPZ nor GEN affected the densities of oligodendrocyte precursor cells and astrocytes. CPZ-induced activation and proliferation of microglia were not inhibited by GEN. Upregulation of gene expression of the pro-inflammatory cytokine, interleukin-1beta, in sorted microglia by CPZ was not inhibited by GEN either. However, the expression levels of genes related to phagocytosis, such as cluster of differentiation 68 and lysosomal-associated membrane protein 1, in sorted microglia were elevated by CPZ but lowered by GEN. Notably, physical contact of microglia with myelin was increased by CPZ but decreased by GEN. The expression levels of myelin-related genes, such as myelin basic protein and myelin oligodendrocyte glycoprotein, in the whole hippocampal tissue were decreased by CPZ but recovered by GEN. These results show that GEN may act on mature oligodendrocytes in the hippocampus by promoting their survival and myelin formation, and suggest the therapeutic potential of phytoestrogens for treating MS patients suffering from mental health issues. PMID- 30468815 TI - Video-based kinetic analysis of calcification in live osteogenic human embryonic stem cell cultures reveals the developmentally toxic effect of Snus tobacco extract. AB - Epidemiological studies suggest tobacco consumption as a probable environmental factor for a variety of congenital anomalies, including low bone mass and increased fracture risk. Despite intensive public health initiatives to publicize the detrimental effects of tobacco use during pregnancy, approximately 10-20% of women in the United States still consume tobacco during pregnancy, some opting for so-called harm-reduction tobacco. These include Snus, a type of orally consumed yet spit-free chewing tobacco, which is purported to expose users to fewer harmful chemicals. Concerns remain from a developmental health perspective since Snus has not reduced overall health risk to consumers and virtually nothing is known about whether skeletal problems from intrauterine exposure arise in the embryo. Utilizing a newly developed video-based calcification assay we determined that extracts from Snus tobacco hindered calcification of osteoblasts derived from pluripotent stem cells early on in their differentiation. Nicotine, a major component of tobacco products, had no measurable effect in the tested concentration range. However, through the extraction of video data, we determined that the tobacco-specific nitrosamine N'-nitrosonornicotine caused a reduction in calcification with similar kinetics as the complete Snus extract. From measurements of actual nitrosamine concentrations in Snus tobacco extract we furthermore conclude that N'-nitrosonornicotine has the potential to be a major trigger of developmental osteotoxicity caused by Snus tobacco. PMID- 30468816 TI - Prevention of acetaminophen-induced liver injury by alginate. AB - INTRODUCTION: Acetaminophen (APAP) intoxication is a major cause of acute liver failure. Alginate, an anionic polysaccharide, was previously shown as a macroporous scaffold, to reduce liver inflammation and sustain hepatic synthetic function, when implanted on liver remnant after extended partial hepatectomy. In the recent study we wanted to examine in a model of APAP intoxication the potential of a specially formulated alginate solution to prevent APAP toxicity. METHODS: Three alginate solutions from low (30-50 kDa, VLVG), medium (100 kDa, LVG54) and high (150 kDa, LVG150) molecular weights were examined. Mice were orally administered with the alginate solution before, with and after APAP administration and were compared to control mice which received vehicle only. All mice were euthanized 24 h after APAP administration. Liver enzyme, blood APAP, IL 6 and liver histology including Ki-67 proliferation, IgG necrosis and nitrotyrosine staining were studied. RESULTS: VLVG- treated mice presented low ALT levels while 20-40 fold increase was demonstrated in control mice. The effect of LVG solutions was marginal. Accordingly, liver histology was normal with no hepatocytes proliferation in the VLVG group while massive centrilobular necrosis, increased nitrotyrosine staining and high proliferation appeared in livers of control mice. APAP blood levels were comparable in the two groups. Treatment with VLVG was associated with prevention of increase of IL-6 serum levels. CONCLUSION: VLVG, a novel alginate solution, alleviated the liver toxicity and inhibited oncotic necrosis and related immune-mediated damage. VLVG may serve as a novel hepato-protector and prevent drug induced liver injury. PMID- 30468818 TI - Separate Production of Hydrogen and Methane from Cassava Wastewater with Added Cassava Residue under a Thermophilic Temperature in Relation to Digestibility. AB - In this research, the separate production of hydrogen (H2) and methane (CH4) from cassava wastewater with added cassava residue was investigated using a two-stage upflow anaerobic sludge blanket (UASB) system under thermophilic temperature (55 degrees C) in a continuous mode of operation and steady state condition. The two stage UASB system was operated under an optimum chemical oxygen demand (COD) loading rate of 10.29 kg/m3d (based on the total volume of both bioreactors) of the cassava wastewater with different concentrations of added cassava residue. The recycle ratio of the effluent from the second bioreactor to the feed flow rate was fixed at 1:1 (v/v). In addition, the solution pH in the first bioreactor was controlled at 5.5, while that in the second bioreactor was not controlled. Under the optimum cassava residue concentration of 1200 mg/L, the produced gas from the first bioreactor contained 43% H2, 55% carbon dioxide (CO2) and 2.70% CH4, while that from the second bioreactor contained 70.5% CH4, 28% CO2 and 1.5% H2. Apart from a high H2 and CH4 production performance (45.2 and 150% improvement, respectively, as compared to the system without added cassava residue) under the optimum cassava residue concentration (1200 mg/L) and the controlled COD loading rate (10.29 kg/m3d) of the cassava wastewater, the degradation performance of cellulose and hemicellulose were 41% and 22%, respectively, for the first bioreactor and 23% and 11%, respectively, for the second bioreactor. The digestibility of the cassava residue at thermophilic operation was higher than that at mesophilic temperature. PMID- 30468817 TI - Setting-up a fast and reliable cytokinin biosensor based on a plant histidine kinase receptor expressed in Saccharomyces cerevisiae. AB - Cytokinins (CK) have been extensively studied for their roles in plant development. Recently, they also appeared to ensure crucial functions in the pathogenicity of some bacterial and fungal plant pathogens. Thus, identifying cytokinin-producing pathogens is a prerequisite to gain a better understanding of their role in pathogenicity. Taking advantage of the cytokinin perception properties of Malus domestica CHASE Histidine Kinase receptor 2 (MdCHK2), we thereby developed a selective and highly sensitive yeast biosensor for the application of cytokinin detection in bacterial samples. The biosensor is based on the mutated sln1Delta Saccharomyces cerevisiae strain expressing MdCHK2. The biosensor does not require any extraction or purification steps of biological samples, enabling cytokinin analysis directly from crude bacterial supernatants. For the first time, the production of cytokinin was shown in the well-known plant pathogenic bacteria Erwinia amylovora and was also revealed in human pathogens Staphylococcus aureus and Streptococcus agalactiae. Importantly, this biosensor was shown to be an efficient tool for unraveling certain steps in cytokinin biosynthesis by micro-organisms since this it was successfully used to unveil the role of ygdH22, a LOG-like gene, that is probably involved in cytokinin biosynthesis pathway in Escherichia coli. Overall, we demonstrated that our biosensor displays several advantages including time- and cost-effectiveness by allowing a rapid and specific detection of cytokinins in bacterial supernatants These results also support its scalability to high-throughput formats. PMID- 30468819 TI - Stereoselective synthesis of a key chiral intermediate of (S)-Rivastigmine by AKR GDH recombinant whole cells. AB - Herein, three aldo/ketoreductases (AKRs) were obtained and used to prepare N- ethyl-methyl-carbamic acid-3-[(1S)-hydroxy-ethyl]-phenyl ester ((S)-NEMCA-HEPE), which is a key intermediate of (S)-Rivastigmine. To avoid the usage of extra cofactors, the recombinant whole-cells containing AKRs and glucose dehydrogenase (GDH) were constructed and applied in the reduction reaction. The excellent conversion of 83.3% and enantiomeric excess (e.e.p) of 99.9% for (S)-NEMCA-HEPE was obtained when the recombinant whole cell (iolS-GDH) was selected as a catalyst. Additional introduction of 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIm]BF4) in the whole cell-catalyzed reaction system, the reaction rates can be further enhanced, and the reaction conversion can be increased to 98.3% only in 1 h. The analysis of flow cytometry (FCM) and ultraviolet spectrum shows that [BMIm]BF4 can greatly enhance the whole cell catalyzed reaction activities by affecting the permeability of cell membrane. This study provided a low-cost and efficient process for preparation of (S)-NEMCA HEPE with high optical purity. PMID- 30468820 TI - Influence of the TNFSF4 rs1234315 polymorphism in the susceptibility to systemic lupus erythematosus and rheumatoid arthritis. AB - OBJECTIVES: The tumour necrosis factor superfamily 4 (TNFSF4) is a candidate gene for autoimmune diseases. We investigated the relationship of this gene with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in a Chinese Guangxi population. METHODS: A total of 294 patients with SLE, 210 with RA, and 282 healthy controls were genotyped for single nucleotide polymorphism (SNP) rs1234315 using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The potential functional effects of the SNP were predicted by in silico analysis. RESULTS: Statistically significant associations with SLE and RA were detected at rs1234315, both by allele analysis (odds ratio 1.47, 95% confidence interval 1.17-1.86, p = 0.001;odds ratio 1.49, 95% confidence interval 1.15-1.92, p = 0.002; respectively), and genotype analysis (p = 0.003 and p = 7.000*10-5, respectively). The Akaike's information criterion (AIC) values indicated that the recessive model may serve as the best-fit model for the SNP for SLE and RA. CONCLUSION: Our results provided support for TNFSF4 rsl234315 as a SLE and RA susceptibility locus in a Chinese Guangxi population. PMID- 30468821 TI - Structural characterization of potential endocrine disrupting activity of alternate plasticizers di-(2-ethylhexyl) adipate (DEHA), acetyl tributyl citrate (ATBC) and 2,2,4-trimethyl 1,3-pentanediol diisobutyrate (TPIB) with human sex hormone-binding globulin. AB - Plasticizers are chemical compounds used to increase the softness and fluidity of polymer materials. Phthalate compounds constitute the most common class of compounds used as plasticizers. However, phthalate plasticizers, especially the predominant di(2-ethylhexyl)phthalate, have been shown to have adverse effects on environment and human health. Hence, efforts have been made to use safer and environmentally friendly alternate non-phthalate plasticizers in industrial applications. The present study involves structural binding studies on endocrine disrupting potential of three high volume alternate plasticizer compounds, i.e., di-(2-ethylhexyl) adipate (DEHA), acetyl tributyl citrate (ATBC) and 2,2,4 trimethyl 1,3-pentanediol diisobutyrate (TPIB) with sex hormone binding globulin (SHBG). This study showed that DEHA, ATBC and TPIB bind in the ligand binding pocket of SHBG and the structural binding results suggested that the three alternate plasticizers may interfere in the steroid binding of SHBG and thus may cause dysfunction in sex steroid homeostasis. PMID- 30468822 TI - Trichloroethylene exposure in mid-pregnancy decreased fetal weight and increased placental markers of oxidative stress in rats. AB - Although epidemiology studies have associated maternal trichloroethylene (TCE) exposure with decreased birth weight and preterm birth, mechanistic explanations for these associations are currently lacking. We hypothesized that TCE targets the placenta with adverse consequences for pregnancy outcomes. Pregnant Wistar rats were exposed orally to vehicle or 480 mg TCE/kg body weight from gestational days (gd) 6-16, and tissues were collected on gd 16. Exposure to TCE significantly decreased average fetal weight without reducing maternal weight. In placenta, TCE significantly increased 8-hydroxy-deoxyguanosine, global 5 hydroxymethylcytosine, and mRNA expression of Tet3, which codes for an enzyme involved in 5-hydroxymethylcytosine formation. Furthermore, glutathione S transferase activity and immunohistochemical staining were increased in placentas of TCE-exposed rats. The present study provides the first evidence that TCE increases markers of oxidative stress in placenta in a fetal growth restriction rat model, providing new insight into the placenta as a potentially relevant target for TCE-induced adverse pregnancy outcomes. PMID- 30468823 TI - A feature extraction technique based on tunable Q-factor wavelet transform for brain signal classification. AB - BACKGROUND: Electroencephalogram (EEG) signals are important for brain health monitoring applications. Characteristics of EEG signals are complex, being non stationarity, aperiodic and nonlinear in nature. EEG signals are a combination of sustained oscillation and non-oscillation transients that are challenging to deal with using linear approaches. METHOD: This research proposes a new scheme based on a tunable Q-factor wavelet transform (TQWT) and a statistical approach to analyse various EEG recordings. Firstly, the proposed method decompose EEG signals into different sub-bands using the TQWT method, which is parameterized by its Q-factor and redundancy. This method depends on the resonance of a signal, instead of frequency or scaling as in the Fourier and wavelet transforms. Secondly, using a statistical feature extraction on the sub-bands to divide each sub-band into n windows, and then extract several statistical features from each window. Finally, the extracted features are forwarded to a bagging tree (BT), k nearest neighbor (k-NN), and support vector machine (SVM) as classifiers to evaluate the performance of the proposed feature extraction technique. RESULTS: The proposed method is tested on two different EEG databases: Bonn University database and Born University database. The experimental results demonstrate that the proposed feature extraction algorithm with thek-NN classifier produces the best performance compared with the other two classifiers. Comparison with existing methods: In order to further evaluate the performances, the proposed scheme is compared with the other existing methods in terms of accuracy. The results prove that the proposed TQWT based feature extraction method has great potential to extract discriminative information from brain signals. CONCLUSION: The outcomes of the proposed technique can assist doctors and other health experts to identify diversified EEG categories. PMID- 30468824 TI - Validation of a new data-driven automated algorithm for muscular activity detection in REM sleep behavior disorder. AB - BACKGROUND: Documentation of REM sleep without atonia is fundamental for REM sleep behavior disorder (RBD) diagnosis. The automated REM atonia index (RAI), Frandsen index (FRI) and Kempfner index (KEI) were proposed for this, but achieved moderate performances. NEW METHOD: Using sleep data from 27 healthy controls (C), 29 RBD patients and 36 patients with periodic limb movement disorder (PLMD), we developed and validated a new automated data-driven method for identifying movements in chin and tibialis electromyographic (EMG) signals. A probabilistic model of atonia from REM sleep of controls was defined and movements identified as EMG areas having low likelihood of being atonia. The percentages of movements and the median inter-movement distance during REM and non-REM (NREM) sleep were used for distinguishing C, RBD and PLMD by combining three optimized classifiers in a 5-fold cross-validation scheme. RESULTS: The proposed method achieved average overall validation accuracies of 70.8% and 61.9% when REM and NREM, and only REM features were used, respectively. After removing apnea and arousal-related movements, they were 64.2% and 59.8%, respectively. COMPARISON WITH EXISTING METHOD(S): The proposed method outperformed RAI, FRI and KEI in identifying RBD patients and in particular achieved higher accuracy and specificity for classifying RBD. CONCLUSIONS: The results show that i) the proposed method has higher performances than the previous ones in distinguishing C, RBD and PLMD patients, ii) removal of apnea and arousal-related movements is not required, and iii) RBD patients can be better identified when both REM and NREM muscular activities are considered. PMID- 30468825 TI - Open-source hardware designs for MRI of mice, rats, and marmosets: Integrated animal holders and radiofrequency coils. AB - BACKGROUND: Small-animal MRI is an important investigative tool for basic and preclinical research. High-resolution anatomical and functional studies of the brain require artifact-free images that are acquired with a highly sensitive radiofrequency (RF) coil. NEW METHOD: The animal holder plays an important role in mitigating image artifacts: motion artifacts are reduced by immobilizing the animal and geometric-distortion artifacts are reduced by accurately positioning the animal to improve static-field shimming. The RF coil, in turn, must provide high sensitivity over the whole brain and not physically interfere with the animal holder. To accomplish these tasks, the animal holder and RF coil should be designed in tandem. In this manuscript, animal holders and RF coils for mice, rats, and marmoset monkeys are described. Each animal holder includes components for anesthesia delivery and animal immobilization, as well as a compatible receive coil. RESULTS/COMPARISON WITH EXISTING METHOD(S): Animal holders were capable of accurate and reproducible positioning (for the marmoset, this was in the stereotactic plane), consequently reducing geometric distortion in echo planar images. Ear bars were designed in conjunction with receive-coil formers, thereby maximizing the sensitive region of coils, while concurrently reducing motion to less than a pixel over EPI time series. Motion and SNR were quantified to facilitate direct comparison to existing animal holders and RF coils. All computer-aided-design (CAD) files of animal holders and RF coils are provided to promote dissemination. CONCLUSIONS: The confluence of design between the animal holder and RF coil provides a pragmatic solution for routine imaging of small animals. PMID- 30468826 TI - Pharmacometric bridging approach for FDA approval and identification of Topiramate dosing regimen for pediatric patients 2 to 9 years of age with epilepsy. AB - This study was performed to identify an efficacious dosing regimen for FDA approval of topiramate for initial monotherapy in pediatric patients aged 2-9 years diagnosed with partial onset seizures and primary generalized tonic-clonic seizures using a pharmacometrics bridging approach. The approval of topiramate in monotherapy of epilepsy for adult and pediatric patients (10-15 years) was based on efficacy and safety data from clinical trials. Our analysis showed that exposure-response relationship was similar between adult and pediatric patients (6-15 years) treated with topiramate as monotherapy for epilepsy. Specific dosing in pediatric patients 2-9 years of age was derived and included in the label from simulations by matching predicted exposures in pediatric patients (2-9 years) to a range of exposures observed in adult and pediatric patients (6-9 years) in a previously conducted clinical trial. The analysis allowed for FDA approval of topiramate for initial monotherapy in pediatric patients (2-9 years). PMID- 30468827 TI - Particle Size Distribution Analysis of OTC Aerosol or Powder Drug Products with Potential for Inadvertent Inhalation Exposure to Consumers. AB - The potential for inadvertent inhalation of over-the-counter (OTC) aerosol/powder drug products for topical application requires understanding of the characteristic size distributions of the airborne particles or droplets generated when these products are used as per the directions on the product label. Particle/droplet size is an important factor in determining the depth of particle penetration into the respiratory system following inhalation. Because particles penetrating beyond the larynx into the lung may lead to adverse respiratory effects, OTC aerosol/powder drug product particle size distribution is important to characterize. In this study, laser diffraction was used to analyze the particle size distribution of thirty-two currently marketed OTC drug products as emitted after actuation or air dispersion from their final package. Among the products surveyed were sunscreens, antiperspirants, topical analgesics, skin protectants and acne products. The results may be useful to the FDA in its mission to protect as well as promote public health. PMID- 30468828 TI - The Potential of Exosomes from Cow Milk for Oral Delivery. AB - Many pharmaceuticals must be administered intravenously due to their poor oral bioavailability. In addition to issues associated with sterility and inconvenience, the cost of repeated infusion over a six-week course of therapy costs the healthcare system tens of billions of dollars per year. Attempts to improve oral bioavailability have traditionally focused on enhancing drug solubility and membrane permeability, and the use of synthetic nanoparticles has also been investigated. As an alternative strategy, some recent reports have clearly demonstrated that exosomes from cow milk are absorbed from the gastrointestinal tract in humans, and could potentially be used for oral delivery of drugs that are traditionally administered intravenously. Our previous work has shown that antibodies are present in exosome preparations, and the current work with milk exosomes suggests that absorption from the gastrointestinal tract occurs via the "neonatal" Fc receptor, FcRn. Furthermore, our results demonstrate that milk exosomes are absorbed from the gut as intact particles that can be modified with ligands to promote retention in target tissues. PMID- 30468829 TI - Improvement in the predicted partitioning of alcohol and polyethylene oxide groups between water and octanol (logP) in molecular dynamics simulations. AB - Molecular dynamics simulations can be applied to explore the complex liquid phase behaviour of lipid based formulations and the gastrointestinal tract lumen. In order for the results from these simulations to be of value, the manner in which molecules interact with both aqueous and oil phases present needs to be as correct as possible. An existing molecular dynamics forcefield, GROMOS 53a6, was demonstrated to poorly reproduce the partitioning of straight chain alcohol and short chain polyethylene glycol molecules between octanol and water phase (logP), with the molecules too hydrophobic. Forcefield parameters for Lennard-Jones interactions between CH2 and CH3 with water oxygen were adjusted to reproduce the experimental octanol logP, with all other Lennard-Jones and forcefield parameters left untouched. This parameter set, called 53a6DBW, was subsequently used to recalculate straight chain alcohol and short chain polyethylene glycol molecules, with significant improvement in the values obtained. Simulations of a non-ionic surfactant in water, octaethylene glycol monocaprylate, was also performed to observe the aggregation behaviour. 53a6DBW demonstrating significant improvements in water interactions with the PEG chains, well hydrating the PEG groups, and allowing the formation of micelles. Further improvements and evaluation of the improved parameter set is ongoing. PMID- 30468830 TI - Lyophilization Process Design and Development: A Single-Step Drying Approach. AB - High throughput lyophilization process was designed and developed for protein formulations using a single-step drying approach at a shelf temperature (Ts) of >= 40oC. Model proteins were evaluated at different protein concentrations in amorphous-only and amorphous-crystalline formulations. Single-step drying resulted in product temperature (Tp) above the collapse temperature (Tc) and a significant reduction (of at least 40%) in process time compared to the control cycle (wherein Tp 0.75, when averaged over 11 validation patients. Coronary artery segmentations were not successful with the atlas-based approach (mean DSC<0.3). STAPLE method with 10 matches (ST10) yielded highest DSC and lowest MDA for all high performing substructures (omitting coronary arteries). For ST10, >50% of all validation contours had centroid displacements<3.0mm, with largest shifts in coronary arteries. Atlas-generated contours had no statistical difference from ground truth for LADAmax, MHD, and LV-V5 (p>0.05). Qualitative contour grading showed that 8 substructures required minor modifications. CONCLUSION: The hybrid MR/CT atlas provided reliable segmentations of chambers, heart, and great vessels for patients undergoing non-contrast CT, suggesting potential widespread applicability for routine treatment planning. PMID- 30468850 TI - Ethanolic extract of Cordyceps cicadae exerts antitumor effect on human gastric cancer SGC-7901 cells by inducing apoptosis, cell cycle arrest and endoplasmic reticulum stress. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cordyceps cicadae (Miq.) Massee is a traditional Chinese medicine that has been used for approximately 1600 years in China. C. cicadae, a member of the Cordyceps genus, exerts a therapeutic effect on many diseases, such as cancer. OBJECTIVE: This study aimed to evaluate the antineoplasmic activity of C. cicadae and to identify its molecular mechanism of cell death. MATERIALS AND METHODS: The toxicity of the ethanolic extract of C. cicadae (EEC) against different cancer cell lines was determined through MTT assay. Human gastric cancer SGC-7901 cells were treated with EEC for 48 h. Cell morphology was examined by using an Olympus phase-contrast microscope. The cell apoptosis was quantified through Annexin V-FITC/PI staining. Cells were stained with PI and then subjected to flow cytometry for the investigation of cell cycle status. Cells were subjected to mitochondrial membrane potential (MMP) assay after incubation with JC-1 probes and to intracellular Ca2+ measurement through flow cytometry after incubation with Fluo-3 AM fluorescent probes. Western blot analysis was conducted to quantify the expression of proteins related to apoptosis, cell cycle and endoplasmic reticulum stress. High-performance liquid chromatography (HPLC) analysis was performed to analyse the biological activity components of EEC. RESULTS: EEC suppressed the proliferation of SGC-7901 cells and induced the development of abnormal morphological features in a dose dependent manner. Flow cytometry results indicated that EEC treatment caused cell apoptosis and arrested the cell cycle in the S phase. In addition, EEC treatment triggered MMP depolarization and Ca2+ overloading in the cytosol of SGC-7901 cells. Western blot analysis demonstrated that EEC increased Bax, AIF, caspase-8, caspase-6 and caspase-3 activities and decreased Bcl-2 activity. The release of cytochrome c from mitochondria was associated with mitochondrial dysfunction, which was caused by the activation of the cell surface receptor Fas and the cleavage of PARP. EEC-induced S phase arrest was associated with the up regulation of E2F1, cyclin A2, cyclin E and p53 expression levels and the down regulation of CDK2 expression. In addition, EEC increased the expression of endoplasmic reticulum stress-related proteins, such as calpain-1, caspase-12 and caspase-9. HPLC assay results suggested that EEC contained adenine, uridine, adenosine and N6-(2-Hydroxyethyl)-adenosine. CONCLUSION: EEC inhibited the proliferation of SGC-7901 cells by inducing caspase-dependent apoptosis, arresting the cell cycle in the S phase and increasing endoplasmic reticulum stress. This study revealed that C. cicadae is a potential natural source of anticancer drugs. PMID- 30468851 TI - Episcleral racemose hemangioma. AB - Racemose hemangioma is a rare, benign vascular malformation. In the episclera, it appears as dilated, tortuous blood vessels that pass from the fornix over the globe surface to the limbal area, without capillary architecture, and then loop backward into the fornix. Fluorescein angiogram reveals the vascular malformation with rapid flow and confirms the episcleral vessels to be large in caliber and with a curvilinear, twisted configuration. We report the case of a 22-year-old man with nonhemorrhagic, coincidental racemose hemangioma of the episclera. PMID- 30468852 TI - Role of type IV secretion system genes in virulence of rice bacterial brown stripe pathogen Acidovorax oryzae strain RS-2. AB - Type IV secretion system (T4SS) is a specialized nanomachine that is utilized for the pathogenicity of gram-negative bacteria. However, the role of T4SS genes in virulence of rice bacterial brown stripe pathogen Acidovorax oryzae (Ao) strain RS-2 is not clear, which contains T4SS gene cluster based on genome-wide analysis. Here we compared the virulence-related phenotypes between the wild-type strain RS-2 and nine T4SS mutants, which were constructed in this study. Results indicated that mutation of pilT, pilM, pilQ, or pilZ3 genes not only significantly reduced bacterial virulence, but also caused a reduction of 20.4 62.0% in biofilm formation and 37.7-47.7% reduction in motility, but had no effect on exopolysaccharide (EPS) production or extracellular enzymatic activities when compared to the wild type. The four T4SS genes had a differential effect on bacterial growth after 24 h post-incubation. The complemented strains of the four T4SS mutants restored similar virulence symptom as the wild type. In addition, no change was observed in bacterial virulence by mutation of the other five T4SS genes. Totally, these results demonstrated that T4SS played vital roles in bacterial virulence, motility and biofilm formation in plant pathogen Ao strain RS-2. PMID- 30468853 TI - Inhibition of alpha-hemolysin expression by resveratrol attenuates Staphylococcus aureus virulence. AB - Staphylococcus aureus is an important zoonotic pathogen that causes a variety of life-threatening diseases. The increasing emergence of drug resistance further complicates the treatment of S. aureus infections. The critical role of alpha hemolysin (Hla) in virulence renders this toxin an ideal target for the development of anti-infective agents for S. aureus. Here, We found that resveratrol, a natural compound widely found in fruits without antibacterial activity, could effectively inhibit Hla expression via down-regulating the transcription of hla, the gene that encodes Hla, and RNAIII, the effector molecule of the agr system. The addition of resveratrol to a co-culture system of S. aureus and A549 cells significantly alleviated bacteria-mediated cellular injury. Furthermore, treatment with resveratrol effectively protected mice from S. aureus pneumonia. Our results established resveratrol as an effective Hla inhibitor that reduces Hla expression without antimicrobial activity and can be further developed into novel therapeutics against S. aureus infections. PMID- 30468854 TI - Expression of B subunit of E. coli heat-labile enterotoxin in the progenies of transgenic tobacco bred by crossing nuclear- and chloroplast-transgenic lines. AB - The B subunit of Escherichia coli heat-labile toxin (LTB) is a model antigen that induces a strong immune response upon oral administration and enhances immune responses to conjugated and co-administered antigens. We previously examined high expression levels of LTB in plants by chloroplast and synthetic LTB gene expression and found substantially higher expression levels of LTB, compared to nuclear LTB expression in wild-type plants. The 2.5% LTB protein of total soluble protein that was observed by chloroplast transformation was approximately 250 fold greater expression than that of LTB via nuclear genome integration. In addition, the amount of LTB protein found in transgenic tobacco leaves using a synthetic LTB gene was 2.2% of the total soluble plant protein, which was approximately 200-fold higher than that in plants with native LTB gene expression. The purpose of our experiment was to increase LTB levels in plants by crossing chloroplast-transformed and synthetic LTB transgenic lines produced previously to express higher LTB levels. LTB protein levels in the F1 transgenic tobacco plants was significantly higher (3.3%), compared to the 2.2% of chloroplast-transformed line or 2.8% of synthetic LTB gene line. Our results suggest that LTB expression was successfully enhanced in the F1 hybrid generation of transgenic tobacco plants. PMID- 30468855 TI - The transient production of anti-TNF-alpha antibody Adalimumab and a comparison of its characterization to the biosimilar Cinorra. AB - Recombinant antibodies have emerged over the last few decades as the fastest growing class of therapeutic proteins for autoimmune diseases. Post-translation modifications of antibodies produced by human cell lines are highly consistent with those existing in natural human proteins and this is a major advantage of utilizing these cell lines. Cinorra is a biosimilar form of the antibody Adalimumab, which is an antagonist of TNF-alpha used for the treatment of autoimmune diseases. Adalimumab and Cinorra were produced by stable expression from CHO cells. The aim of this study was to select HEK cells as a host for producing Adalimumab to reveal whether the antibody produced by this human derived cell line has similar characterization to Cinorra. Adalimumab was transiently produced in HEK-293T cells, characterized and analyzed for its properties. Circular dichroism spectroscopy confirmed a strong structural similarity of the expressed antibody with Cinorra. Likewise its binding activity and kinetic affinity to TNF-alpha (EC50 = 416.5 ng/ml, KD = 3.89 E-10 M,) were highly similar to that of Cinorra (EC50 = 421.2 ng/ml and KD = 3.34 E-10 M,). Additionally there was near identical neutralization of TNF-alpha-mediated cellular cytotoxicity (IC50 of the expressed = 4.93 nM; IC50 of Cinorra = 4.5 nM). Results indicate that Adalimumab produced by HEK-293T cells possesses a similarly efficient function and biological activity to Cinorra. Consequently, human-derived host cells with human post-translational modifications might potentially provide a basis for the development of Adalimumab with pharmaceutical properties for research and therapeutic use. PMID- 30468856 TI - Nuclear hormone receptors: Ancient 9aaTAD and evolutionally gained NCoA activation pathways. AB - In higher metazoans, the nuclear hormone receptors activate transcription trough their specific adaptors, nuclear hormone receptor adaptors NCoA, which are absent in lower metazoans. The Nine amino acid TransActivation Domain, 9aaTAD, was reported for a large number of the transcription activators that recruit general mediators of transcription. In this study, we demonstrated that the 9aaTAD from NHR-49 receptor of nematode C.elegans activates transcription as a small peptide. We showed that the ancient 9aaTAD domains are conserved in the nuclear hormone receptors including human HNF4, RARa, VDR and PPARg. Also their small 9aaTAD peptides effectively activated transcription in absence of the NCoA adaptors. We also showed that adjacent H11 domains in ancient and modern hormone receptors have an inhibitory effect on their 9aaTAD function. PMID- 30468857 TI - SPR-Based study of affinity of cytochrome P450s / redox partners interactions modulated by steroidal substrates. AB - The goal of this work was to test the hypothesis that the affinity of protein protein interactions in the cytochrome P450-dependent monooxygenase system is modulated by the low-molecular-weight compounds (substrates or inhibitors). The surface plasmon resonance (SPR) based study was carried out using the recombinant protein preparations of three microsomal cytochromes P450 (CYP17A1, CYP21A2, and CYP2C19) and their redox partners: cytochrome b5 (CYB5A), NADPH - cytochrome P450 reductase (CPR), and also iron-sulfur protein adrenodoxin (Adx). As a result, we have revealed some specificity of the influence of the steroid substrates on the binding affinity of CYPs with their redox partners, namely: the lack of effect on CPR/CYPs and Adx/CYP complex formation, and a significant effect on interactions between CYB5A and steroidogenic CYPs. The equilibrium dissociation constant (Kd) value of the CYB5A/CYP17A1 complex decreased by 5 times in the presence of progesterone (P4), which was due to a 10 times increase in the association rate constant (kon). In this case, a twofold increase in the dissociation rate constant (koff) value of CYB5A/CYP17A1 complex formation was observed. It was also demonstrated that the affinity of CYB5A/CYP17A1 interaction increased in the presence of two other steroidal substrates 17alpha-hydroxyprogesterone and pregnenolone and that effect was comparable with P4. In contrast, only the twofold decrease in the affinity of CYB5A/CYP21A2 interaction in the presence of P4 was caused by a slight increase in the koff value (the kon value of the complex did not change). This indicates a different format of the steroidal substrates effects expressed in a change in the stability of the CYB5A/CYPs complexes. Thus, it was found that P4 modulated the both kinetic and equilibrium constants of CYB5A/CYP17A1 and CYB5/CYP21A2 complex formation and complexes, while not affecting the CYB5A/CYP2C19 interaction (2C19 is the cytochrome P450 isoenzyme possessing broad substrate specificity), thereby indicating a specific influence of steroidal substrates on interactions involving steroidogenic CYPs. Our results are consistent with current understanding of the role of CYB5A as a regulator of cytochrome P450 activity in P450-dependent monooxygenase system. PMID- 30468858 TI - What is the Impact of Surface Modifications and Particle Size on Commercial Titanium Dioxide Particle Samples? - A Review of In Vivo Pulmonary and Oral Toxicity Studies - Revised 11-6-2018. AB - There is an ongoing discussion on the influence of surface-modifications on the toxicity of commercial particulate materials and how alterations in physical chemical properties of surfaces impact toxicity. Titanium dioxide (TiO2) is a poorly soluble particulate material of significant socioeconomic importance that largely exists as surface-modified particle-types in commerce. The observed toxicological effects of TiO2 are primarily due to particle effects rather than substance chemistry, as such TiO2 is commonly considered to be a poorly soluble low toxicity (PSLT) particle. This review provides an overview of the effect of surface modifications on the inhalation and oral toxicity of commercial TiO2 particles with emphasis on in vivo studies with appropriate controls, and where both surface modified and untreated materials are present in the same study. Published literature findings involving pulmonary and oral exposures to surface modified TiO2 particles were reviewed and evaluated for quality and commercial relevance. Suitable publications involving animal studies were identified and summarized. Several studies have evaluated commercially-relevant surface-modified forms of titanium dioxide with appropriate data quality and with direct comparison to untreated counterparts. Hydrophilic inorganic surface modifications including silica, alumina/alumina hydroxide depositions have been evaluated along with common hydrophilic; and hydrophobic-organic surface treatments. The results for both pigmentary and nanoscale materials demonstrate similar behavior and indicate limited impact of particle size, surface chemistry, surface charge and surface wettability on observed pulmonary or oral toxicity. The low intrinsic toxicity of the TiO2 base particle and evaluated surface modifications may account for the observed outcomes. A few published studies have drawn different conclusions, however, these were either not conducted using commercial TiO2 samples (in addition to surface coatings), had several variables to investigate, or were carried out using mouse strains. The differences in experimental designs are described. The identified pulmonary and oral toxicity studies largely indicate that surface modifications and particle size alone have little or no impact on the lung toxicity of TiO2 particles following pulmonary exposures when all constituent materials are comprised of chemicals of low specific toxicity particles. In addition, based upon the results of 2 oral toxicity studies, one with surface treated TiO2 particles (OECD 408) and one without surface treated ((OECD 407) TiO2 particles, there appears to have been no adverse impact on toxicity with the surface-coated material, as both studies produced no adverse effects at the very high doses tested. PMID- 30468859 TI - Socioeconomic status and central adiposity as determinants of stress-related biological responses relevant to cardiovascular disease risk. AB - Stress-related processes have been implicated in the associations between lower socioeconomic status (SES), central adiposity, and cardiovascular disease risk. This study analysed the impact of SES and central adiposity on cardiovascular, inflammatory and neuroendocrine stress responses, and associations with cytomegalovirus (CMV) infection in a sample of 537 men and women aged 53-76 years (mean 62.89 years). SES was defined by grade of employment (higher, intermediate, and lower categories), and central adiposity was indexed by waist-hip ratio (WHR). Cardiovascular, inflammatory and cortisol responses were monitored during administration of a standardized mental stress testing protocol and salivary cortisol was measured repeatedly over the day. Lower SES was associated with raised systolic and diastolic blood pressure (BP), plasma interleukin (IL-6), fibrinogen, C-reactive protein, and salivary cortisol, and a large WHR accentuated SES differences in fibrinogen, C-reactive protein, and likelihood of CMV seropositivity, independently of general adiposity indexed by body mass index. During mental stress testing, return to resting levels (recovery) following behavioural challenge in systolic and diastolic BP and heart rate was impaired among lower SES participants, particularly those with large WHR. Lower SES participants had greater cortisol concentrations across the day, but this pattern did not vary with WHR. These findings extend the evidence relating lower SES to stress-related biological risk factors for cardiovascular disease, and indicate that central adiposity may augment these effects. PMID- 30468860 TI - Long-chain omega-3 polyunsaturated fatty acids and neuroinflammation - Efficacy may depend on dietary alpha-linolenic and linoleic acid background levels. PMID- 30468861 TI - Implantation of a completely right sided subcutaneous cardioverter-defibrillator in a patient with situs inversus dextrocardia. AB - Dextrocardia is a congenital anomaly where the heart is abnormally located in the right hemithorax. In these patients, the implementation of transvenous implantable cardioverter-defibrillator (TV-ICD) can be technically challenging and pose a higher risk of complications than the general population. We present the case of a male patient that was successfully submitted to right-sided implantation of subcutaneous ICD (S-ICD) as an alternative to transvenous ICD (TV ICD) for primary prevention of sudden cardiac death. This option is not only feasible but may potentially be ideal for these patients, as it circumvents challenges and potential complications of TV-ICD insertion. PMID- 30468862 TI - Translational research on chemical nerve agents. AB - This special issue will describe cutting-edge translational research on the development of safe and effective therapeutics for treating exposure to toxic chemical threat agents that target the nervous system. These studies are supported by the National Institutes of Health (NIH) Countermeasures Against Chemical Threats (CounterACT) program. Chemical threats include chemical warfare agents, pesticides and other toxic chemicals whose primary mode of action is targeted within the nervous system. Depending on the dose, the effects of these toxic chemicals can be lethal or cause serious morbidity including neuropathology and neurological deficits. Current topics in research on organophosphorus pesticides and chemical warfare agents include developing alternatives to currently approve acetylcholinesterase reactivators, control of seizures that are refractory to benzodiazepine drugs, and treatments for serious morbidity caused by non-lethal exposures. There is also an effort to understand the mechanisms of toxicity and treatments for other neuro-active agents such as tetramine and hydrogen sulfide. A robust translational research effort on nerve agents is essential for being better prepared with an effective medical response capability during chemical emergencies. PMID- 30468863 TI - High salt diet ameliorates functional, electrophysiological and histological characteristics of murine spontaneous autoimmune polyneuropathy. AB - BACKGROUND: It was previously reported that high salt dietary conditions can drive autoimmunity and worsen severity and symptoms of autoimmune diseases. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a common autoimmune condition of the peripheral nervous system which leads to progressive paralysis and sensory deficits due to a demyelination and secondary axonal loss of peripheral nerves. We used a previously described model with a knockout of CD86 in non-obese diabetic mice (CD86-/- NOD), which results in the spontaneous development of an autoimmune peripheral neuropathy similar to CIDP and investigated the influence of a high salt diet on functional impairment, electrophysiological parameters, demyelination and neuroinflammation in these mice. METHODS: At seven weeks of age, asymptomatic female CD86-/- NOD mice were randomly assigned to a normal or high salt diet containing 4% sodium chloride in food and 1% in water. The diet was continued for a total of 30 weeks. RESULTS: Mice on the high salt diet showed a delayed onset of clinical symptoms and an ameliorated disease course with a reduced decline of locomotor function. Furthermore, electrophysiological parameters of neuropathy and demyelination were attenuated in mice on the high salt diet, which was confirmed with histological analysis. Additionally, we observed a reduced immune cell infiltration of sciatic nerves in mice which had received the high salt diet. CONCLUSIONS: We demonstrate beneficial effects of high salt diet regarding disease progression, functional, electrophysiological and histological parameters in a transgenic mouse model of spontaneous autoimmune neuropathy. PMID- 30468864 TI - SIL1 deficiency causes degenerative changes of peripheral nerves and neuromuscular junctions in fish, mice and human. AB - BACKGROUND: Marinesco-Sjogren Syndrome (MSS) is a rare neuromuscular condition caused by recessive mutations in the SIL1 gene resulting in the absence of functional SIL1 protein, a co-chaperone for the major ER chaperone, BiP. As BiP is decisive for proper protein processing, loss of SIL1 results in the accumulation of misshaped proteins. This accumulation likely damages and destroys cells in vulnerable tissues, leading to congenital cataracts, cerebellar ataxia, vacuolar myopathy and other MSS phenotypes. Whether the peripheral nervous system (PNS) is affected in MSS has not been conclusively shown. METHODS: To study PNS vulnerability in MSS, intramuscular nerves fibres from MSS patients and from SIL1 deficient mice (woozy) as well as sciatic nerves and neuromuscular junctions (NMJ) from these mice have been investigated via transmission electron microscopic and immunofluorescence studies accompanied by transcript studies and unbiased proteomic profiling. In addition, PNS and NMJ integrity were analyzed via immunofluorescence studies in an MSS-zebrafish model which has been generated for that purpose. RESULTS: Electron microscopy revealed morphological changes indicative of impaired autophagy and mitochondrial maintenance in distal axons and in Schwann cells. Moreover, changes of the morphology of NMJs as well as of transcripts encoding proteins important for NMJ function were detected in woozy mice. These findings were in line with a grossly abnormal structure of NMJs in SIL1-deficient zebrafish embryos. Proteome profiling of sciatic nerve specimens from woozy mice revealed altered levels of proteins implicated in neuronal maintenance suggesting the activation of compensatory mechanisms. CONCLUSION: Taken together, our combined data expand the spectrum of tissues affected by SIL1 loss and suggest that impaired neuromuscular transmission might be part of MSS pathophysiology. PMID- 30468866 TI - Ontology-based Semantic Mapping of Chemical Toxicities. AB - This study was undertaken to evaluate the use of ontology-based semantic mapping (OS-Mapping) in chemical toxicity assessment. Nineteen chemical-species phenotypic profiles (CSPPs) were constructed by ontologically annotating the toxicity responses reported in more than seven hundred published studies of ten chemicals on six vertebrate species. The CSPPs were semantically compared against over 29 thousand publicly-available phenotypic profiles of genes, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, and diseases based on a cross species phenotype ontology. OS-Mapping could differentiate chemical toxicities among themselves, as well as within and across species. It also revealed cases of chemical by species interactions. Besides confirming similar MOAs (mechanisms of action) for a few chemicals, OS-Mapping also generated novel insights into the MOAs underlying some seemingly different, yet phenotypically similar, classes of chemicals. The nature of a unified cross-species phenotype ontology and its representation of diverse knowledge domains allowed construction of a complete phenotypic continuum for EE2_FHM (17alpha-ethynylestradiol_fathead minnow) across the biological levels of organization, which complemented a similar one derived from the Comparative Toxicogenomics Database but largely based on EE2-induced molecular phenotypes alone. Overall, we conclude that OS-Mapping offers a powerful approach to help bridge the gap between the molecular phenotypes of chemicals characterized by high throughput/traditional omics methods and their apical endpoints of greater regulatory relevance, which are typically phenotypes found at the higher levels of biological organization. OS-Mapping also enables comparative toxicity assessment among chemicals, both within and across species. Furthermore, semantic analysis of phenotypes can reveal additional novel MOAs for some of the well-known chemicals, and discover candidate MOAs for chemicals of less molecularly characterized. A full phenotypic continuum based on OS-Mapping will also be conducive to the future development of adverse outcome pathways. As phenomics data continues to grow in coverage and ontological annotation of literature becomes more automated, the power of OS-Mapping will be further enhanced. PMID- 30468865 TI - Inactivation of sphingosine-1-phosphate receptor 2 (S1PR2) decreases demyelination and enhances remyelination in animal models of multiple sclerosis. AB - Multiple sclerosis is an inflammatory disease of the central nervous system (CNS) in which multiple sites of blood-brain barrier (BBB) disruption, focal inflammation, demyelination and tissue destruction are the hallmarks. Here we show that sphingosine-1-phosphate receptor 2 (S1PR2) has a negative role in myelin repair as well as an important role in demyelination by modulating BBB permeability. In lysolecithin-induced demyelination of adult mouse spinal cord, S1PR2 inactivation by either the pharmacological inhibitor JTE-013 or S1PR2 gene knockout led to enhanced myelin repair as determined by higher numbers of differentiated oligodendrocytes and increased numbers of remyelinated axons at the lesion sites. S1PR2 inactivation in lysolecithin-induced demyelination of the optic chiasm, enhanced oligodendrogenesis and improved the behavioral outcome in an optokinetic reflex test. In order to see the effect of S1PR2 inactivation on demyelination, experimental autoimmune encephalitis (EAE) was induced by MOG peptide. S1PR2 inhibition or knockout decreased the extent of demyelinated areas as well as the clinical disability in this EAE model. Both toxin induced and EAE models showed decreased BBB leakage and reduced numbers of Iba1+ macrophages following S1PR2 inactivation. Our results suggest that S1PR2 activity impairs remyelination and also enhances BBB leakage and demyelination. The former effect could be mediated by Nogo-A, as antagonism of this factor enhances remyelination and S1PR2 can act as a Nogo-A receptor. PMID- 30468867 TI - Decabromodiphenyl ether exacerbates hyperglycemia in diet-induced obese mice. AB - Decabromodiphenyl ether (decaBDE) is a brominated flame retardant used in plastic and textile articles. It has become a ubiquitous environmental contaminant, however; the relationship between decaBDE and obesity remains to be elucidated. We aimed to clarify if oral decaBDE exposure can be a factor in obesity and its related metabolic dysfuctions. Male C57BL/6 J mice were fed a normal (ND, 9.0 kcal% fat) or high-fat (HFD, 62.2 kcal% fat) diet and treated with decaBDE (the equivalent of three doses of 0, 0.5 (L-DecaBDE), and 10 (H-DecaBDE) MUg/kg body weight/day) ad libitum in drinking water from 5 to 20 weeks of age. In HFD-fed mice, decaBDE exposure markedly increased both fasting blood glucose levels compared with vehicle exposure, which was more prominent in H-DecaBDE-exposed mice. DecaBDE exposure significantly reduced mRNA levels of glucose transporter 4 and thyroid hormone receptor alpha in skeletal muscle and mechanistic target of rapamycin complex 2 in brown adipose tissue compared with vehicle exposure under HFD-feeding. The tendency for hyperglycemia and the remarkable activation of insulin signaling pathway-related genes were observed in ND + DecaBDE mice compared to the ND + Vehicle mice. These results demonstrate that decaBDE can contribute to the enhancement of diet-induced hyperglycemia through disruption of glucose homeostasis. PMID- 30468868 TI - Model-informed pediatric development applied to bilastine: Analysis of the clinical PK data and confirmation of the dose selected for the target population. AB - Bilastine is a non-sedating second-generation H1 antihistamine approved for treatment of allergic rhinoconjunctivitis (AR) and urticaria (U) in adults at the oral (p.o.) dose of 20 mg once daily (OD). Optimal attributes can be anticipated for its clinical use in pediatrics due to its favorable safety and tolerability and age-independent PD profile. The aim of this work was to characterize bilastine PK in children through population modeling of data from a limited sampling confirmatory clinical trial in children with AR or U. The objective was also to ascertain whether the proposed dose (10 mg/day) in the target pediatric subset aged 2-<12 years matches the systemic exposure seen in adults at the 20 mg/day dose. A popPK model characterizing bilastine PK behavior in children aged from 4 to <12 years treated with 10 mg oral bilastine daily was successfully developed and qualified. No relationship was found between bilastine PK and age or weight; stopping rules pre-stablished to finalize the trial, i.e., model completeness and no dependence of exposure on decreasing age, were thus fulfilled. On a second step, the popPK model in children was linked to the PD model in adults assuming the same PD as described in adults and used to compare the PD outcome between both populations. Finally, an allometric scaling method and a physiological approximation were used to evaluate the suitability of the selected dose in the youngest children, showing that children from 2 years were deemed to belong to the same population as well. The achievement of comparable PK (i.e., within the range) to that observed in adults after the therapeutic dose of 20 mg, together with the achievement of similar PD and additional integrative analysis, served to confirm the validity of the 10 mg daily dose for the target pediatric subset (2 to <12 years). PMID- 30468869 TI - Extraction of levetiracetam for therapeutic drug monitoring by transdermal reverse iontophoresis. AB - Recently, transdermal reverse iontophoresis across the skin has been investigated as a novel technology for the purpose of diagnosis as well as therapeutic drug monitoring. Accordingly, the objective of this study was to investigate ex vivo and in vivo transdermal extraction of levetiracetam, an antiepileptic drug, across the pig ear skin by reverse iontophoresis. Reverse iontophoresis experiments were performed using three chambered diffusion cells. Extractions profiles were generated in phosphate buffers at different current intensities, pH and ionic strength as well donor drug concentrations. This was followed by ex vivo extraction in gels and in vivo extractions using New Zealand rabbits. Results indicate that levetiracetam was extracted at both anode and cathode. Flux values were unaffected by increase in current intensities (0.5 mA and 0.6 mA) but affected by pH and ionic strength. Neither in cathodal nor in anodal extraction, flux values did show a proportional relationship with the donor drug concentration. At low and medium concentration levels, flux values did not show any major change but the extraction flux at high donor concentration was much higher. In contrast, in vivo experiment with rabbits resulted in wide variation of fluxes with very high fluxes recorded at the cathodal end. Reasons attributed to this difference may include lower current intensity, and species variation. The most significant finding of this study is that measurable amounts of the levetiracetam were extracted at both the ends indicating its feasibility for non invasive drug monitoring. PMID- 30468870 TI - Nanofluidic microsystem for sustained intraocular delivery of therapeutics. AB - Globally, 145.2 million people suffer from moderate to severe vision impairment or blindness due to preventable or treatable causes. However, patient adherence to topical or intravitreal treatment is a leading cause of poor outcomes. To address this issue, we designed an intraocularly implantable device called the nanofluidic Vitreal System for Therapeutic Administration (nViSTA) for continuous and controlled drug release based on a nanochannel membrane that obviates the need for pumps or actuation. In vitro release analysis demonstrated that our device achieves sustained release of bimatoprost (BIM) and dexamethasone (DEX) at concentrations within clinically relevant therapeutic window. In this proof of concept study, we constructed an anatomically similar in silico human eye model to simulate DEX release from our implant and gain insight into intraocular pharmacokinetics profile. Overall, our drug-agnostic intraocular implant represents a potentially viable platform for long-term treatment of various chronic ophthalmologic diseases, including diabetic macular edema and uveitis. PMID- 30468871 TI - Small-scale culture of Plasmodium falciparum using MU-Slide Angiogenesis followed by automatic infection rate counting to assess drug effects. AB - It is very important to reduce the costs involved in malarial drug development by small-scale culture of Plasmodium falciparum, and automation of the assay system for drug efficacy against the parasites for high-throughput screening. In this study, we report that P. falciparum-infected erythrocytes can be stably cultured on MU-Slide Angiogenesis, which is used to investigate angiogenesis in tube formation assays, followed by automatic counting of the infection rate (parasitaemia). After 10 MUL of parasite-infected erythrocytes were added to the inner well of MU-Slide Angiogenesis to prevent a multilayer of erythrocytes, 30 MUL of silicon oil was overlaid on the culture medium to avoid evaporation of the medium, leading to stable small-scale parasite cultivation. The parasites were stained with a cell-permeant fluorescent nucleic acid stain (SYTO21) followed by cultivation. After taking bright field and fluorescent images using an inverted microscope, the infection rate could be calculated automatically by counting the number of erythrocytes and parasites using MetaMorph Offline software. The effect of anti-malarial drugs on parasite growth could be investigated on MU-Slide Angiogenesis, in which the parasite culture was added to the inner wells containing the drugs followed by their cultivation. Taken together, this method may be useful for image-based screening for anti-malarial drug candidates with automatic counting of parasite infection rates. PMID- 30468613 TI - Search for Resonant and Nonresonant Higgs Boson Pair Production in the bb[over ]tau^{+}tau^{-} Decay Channel in pp Collisions at sqrt[s]=13 TeV with the ATLAS Detector. AB - A search for resonant and nonresonant pair production of Higgs bosons in the bb[over -]tau^{+}tau^{-} final state is presented. The search uses 36.1 fb^{-1} of pp collision data with sqrt[s]=13 TeV recorded by the ATLAS experiment at the LHC in 2015 and 2016. Decays of the tau-lepton pairs with at least one tau lepton decaying to final states with hadrons and a neutrino are considered. No significant excess above the expected background is observed in the data. The cross-section times branching ratio for nonresonant Higgs boson pair production is constrained to be less than 30.9 fb, 12.7 times the standard model expectation, at 95% confidence level. The data are also analyzed to probe resonant Higgs boson pair production, constraining a model with an extended Higgs sector based on two doublets and a Randall-Sundrum bulk graviton model. Upper limits are placed on the resonant Higgs boson pair production cross-section times branching ratio, excluding resonances X in the mass range 305 GeV290 kJ, n = 3; low energy <200 kJ, n = 4; and intermediate 200 < 290 kJ, n = 3), and seven received captive bolt stunning, prior to exsanguination. In trial 2, following improvements to the efficiency of energy delivery, 20 cattle received DTS (200-360 kJ). Post treatment EEG was characterized by seizure-like activity and reductions in 95% spectral edge and median frequencies; with EEG suppression persisting for at least 80 s up to over 4 min post treatment application. Animals showed: Loss of posture, Loss of corneal responses; Loss of withdrawal response (pinprick); Eye staring, not following movement. The animals remained unresponsive to stimuli for up to 4 min post DTS, and behavioural expression of distress was not observed. Seventeen of the 30 animals showed indications of returning reflex responses after 100 s post treatment, suggesting that animals receiving lower energy applications may recover from the stun. PMID- 30468881 TI - Honoring Sydney Finegold, founding president of the Anaerobe Society of the Americas (1921-2018). PMID- 30468877 TI - Advancing nonclinical innovation and safety in pharmaceutical testing. AB - Nonclinical tests are considered crucial for understanding the safety of investigational medicines. However, the effective translation from nonclinical to human application is limited and must be improved. Drug development stakeholders are working to advance human-based in vitro and in silico methods that may be more predictive of human efficacy and safety in vivo because they enable scientists to model the direct interaction of drugs with human cells, tissues, and biological processes. Here, we recommend test-neutral regulations; increased funding for development and integration of human-based approaches; support for existing initiatives that advance human-based approaches; evaluation of new approaches using human data; establishment of guidelines for procuring human cells and tissues for research; and additional training and educational opportunities in human-based approaches. PMID- 30468883 TI - Zinc boosts EGCG's hIAPP amyloid Inhibition both in solution and membrane. AB - Amyloid aggregation of human islet amyloid polypeptide (hIAPP) is linked to insulin-producing islet cell death in type II diabetes. Previous studies have shown that zinc (Zn(II)) and insulin, co-secreted with hIAPP, have an inhibition effect on hIAPP aggregation. Lipid membranes have also been shown to significantly influence the aggregation kinetics of hIAPP. An increasing number of studies report the importance of developing small molecule inhibitors to suppress the hIAPP's aggregation and subsequent toxicity. The ability of epigallocatechin-gallate (EGCG) to inhibit aggregation of a variety of amyloid peptide/proteins initiated numerous studies as well as the development of derivative compounds to potentially treat amyloid diseases. In this study, a combination of Thioflavin-T fluorescence kinetics, transmission electron microscopy, isothermal titration calorimetery, circular dicrosim and nucelar magnetic resonance experiments were used to demonstrate a significant enhancement in EGCG's efficiency when complexed with Zn(II). We demonstrate that the Zn-EGCG complex is able to significantly suppress hIAPP's amyloid aggregation both in presence and absence of lipid membrane. Circular dichroism experiments indicate the formation and stabilization of a helical structure of hIAPP in presence of the EGCG:Zn(II) complex. Our results also reveal the ability of EGCG or EGCG:Zn(II) to efficiently suppress hIAPP's cellular toxicity. We believe that the reported results could be useful to develop strategies to trap hIAPP intermediates for further biophysical and structural studies, and also to devise approaches to abolish amyloid aggregation and cellular toxicity. PMID- 30468878 TI - Antibiotic Exposure and the Risk of Food Allergy: Evidence in the U.S. Medicaid Pediatric Population. AB - BACKGROUND: Food allergy is a significant public health concern in the United States, especially in the pediatric population. It places substantial clinical and economic burdens on the healthcare system. Exposure to antibiotics in early childhood is thought to increase the risk of subsequent food allergy. OBJECTIVE: The objective of the study was to examine the impact of exposure to antibiotics early in life on time to development of food allergy. METHODS: We conducted a population-based matched cohort study using Medicaid data from 28 states. Antibiotic non-users were matched 1:1 to antibiotic users on date of birth, sex, race, and state. A Cox proportional hazards regression model was used to evaluate the effect of antibiotic exposure on time to development of food allergy. Sensitivity analyses were performed to assess the robustness of study findings. RESULTS: We matched 500,647 antibiotic non-users to 500,647 antibiotic users in the Medicaid pediatric population. In the adjusted Cox proportional hazards regression analysis, antibiotic exposure was significantly associated with faster development of food allergy (HR: 1.40; 95% CI: 1.34-1.45). The magnitude and significance of the association between antibiotic exposure and food allergy did not change in the sensitivity analyses. A significant association between antibiotic exposure and faster development of food allergy was found in 17 of 28 states. CONCLUSION: Compared to antibiotic non-users, children with antibiotic prescription had an increased risk of food allergy. PMID- 30468884 TI - Membrane-mimetic systems for biophysical studies of the amyloid-beta peptide. AB - The interplay between the amyloid-beta (Abeta) peptide and cellular membranes have been proposed as an important mechanism for toxicity in Alzheimer's disease (AD). Membrane environments appear to influence Abeta aggregation and may stabilize intermediate Abeta oligomeric states that are considered to be neurotoxic. One important role for molecular biophysics within the field of Abeta studies is to characterize the structure and dynamics of the Abeta peptide in various states, as well as the kinetics of transfer between these states. Because biological cell membranes are very complex, simplified membrane models are needed to facilitate studies of Abeta and other amyloid proteins in lipid environments. In this review, we examine different membrane-mimetic systems available for molecular studies of Abeta. An introduction to each system is given, and examples of important findings are presented for each system. The benefits and drawbacks of each system are discussed from methodical and biological perspectives. PMID- 30468882 TI - Exploration of M(100)-2*1 (M=Si, Ge) surface termination through hydrogen passivation using ethane and ammonia-borane derivatives: A theoretical approach. AB - Termination process of Si(100)-2 * 1 as well as Ge(100)-2 * 1 reconstructed surfaces have been explored comprehensively through the dehydrogenation of ethane and ammonia-borane and their several analogues by employing density functional theory (DFT). From our study, it is evident that the termination of Si-surface via the dehydrogenation of aforementioned ethane and NH3BH3 derivatives is more feasible compared to Ge-surface. For ethane, the investigation shows that the substitution of non-participating hydrogens with +I group (electron donating) causes an enhancement in the kinetic and thermodynamic feasibility of the termination process, whereas the implementation of -I substituent (electron withdrawing) makes an adverse effect. While exploring the termination of Si- as well as Ge-surfaces through the dehydrogenation of NH3BH3 and its derivatives, it is noticed that from both the kinetic as well as thermodynamic perspectives, the termination processes are more feasible than that of ethane and its derivatives. We have further examined the detailed mechanism of each termination process by analyzing the geometrical parameters and NPA charges. From bonding evaluation, it is evident that the hydrogen abstraction from ethane by both the surfaces is symmetric in nature, where both the hydrogens show slightly positive charge. But for NH3BH3 the hydrogen abstraction process becomes asymmetric, where the boron associated hydrogen is abstracted as hydride by the electrophilic surface Si (Ge) and the hydrogen bonded with the N-centre is abstracted as proton by the nucleophilic surface Si (Ge). Overall, the present theoretical work reveals one of the efficient chemical processes for terminating Si as well as Ge(100)-2 * 1 reconstructed surfaces through the formation of non-polar SiH bonds. PMID- 30468885 TI - Obeticholic acid alleviate lipopolysaccharide-induced acute lung injury via its anti-inflammatory effects in mice. AB - Acute lung injury (ALI) is a common disease that may result in acute respiratory failure and death. However, there are still no effective treatments for ALI. Several studies have shown that farnesoid X receptor (FXR) has an anti inflammatory effect. We investigated the effects of obeticholic acid (OCA), an agonist of FXR, on Lipopolysaccharide (LPS)-induced ALI in mice. Sixty male mice were randomly divided into six groups, and orally administered with or without OCA once daily for 3 consecutive days before LPS (1.0 mg/kg). Animals were sacrificed at 0 h, 2 h or 6 h after LPS. As expected, OCA enhanced pulmonary FXR activity. OCA prevented LPS-induced ALI. Additional experiment showed that OCA alleviated LPS-induced up-regulation of pulmonary pro-inflammatory and chemokine genes. Moreover, OCA also repressed LPS-induced the release of TNF-alpha and KC in serum and bronchoalveolar lavage fluid. In contrast, OCA further up-regulated LPS-induced the expression of Il-10, an anti-inflammatory cytokine. Further study showed that OCA inhibited LPS-evoked NF-kappaB signaling in the lungs. OCA attenuated LPS-induced ERK1/2, JNK, p38 and Akt phosphorylation in the lungs. Overall, these results suggest that OCA prevent LPS-induced ALI may be through enhancing pulmonary FXR activity and then blockading several inflammatory signaling pathways. PMID- 30468880 TI - Isolation and characterization of bacteriophages active against methicillin resistant Staphylococcus pseudintermedius. AB - We aimed to isolate and characterize bacteriophages (phages) with preferential activity against methicillin-resistant Staphylococcus pseudintermedius (MRSP), a multidrug-resistant canine pathogen. Four phages were isolated from canine faeces using two MRSP strains as initial hosts. Phage host range was evaluated by the spot test on 17 MRSP, 43 methicillin-susceptible S. pseudintermedius (MSSP), and six other staphylococci isolated from dogs. Transmission electron microscopy was used for presumptive identification followed by whole genome sequencing (WGS). All phages lysed all MRSP isolates whereas only 16-28% of MSSP were lysed. Their lytic activity was limited to S. pseudintermedius and S. schleiferi. All phages had similar morphology and belonged to the Siphoviridae family. WGS indicated that the phages were 93.8-99.7% identical to each other, and exhibited the highest similarity (87%) to the temperate S. aureus phage 187. Confirmatory lytic activity tests showed that phages were able to produce clear plaques on lysogens, which was enabled by recombination of the lysogeny modules as shown by WGS of the phages after propagation and plaque formation. This study provides insight into the genetic diversity and biology of S. pseudintermedius temperate phages, which could be further developed for topical therapy of MRSP skin and wound infections. PMID- 30468886 TI - Interventions aimed at changing impulsive choice in rats: Effects of immediate and relatively long delay to reward training. AB - A relatively strong preference for smaller-sooner rewards (SSR) over larger-later rewards (LLR) is associated with a host of maladaptive behavioral patterns. As such, the clinical implications for increasing preference for LLR are profound. There is a growing body of literature that suggests extended exposure to delayed reward may increase preference for LLR in rats. However, questions remain about the underlying mechanism driving this effect and the extent to which extended exposure to immediate rewards may decrease LLR choice. In Experiment 1, we tested effects of a differential-reinforcement-of-low-rates schedule (DRL) to increase LLR choice using a pretest/posttest design with Wistar rats as subjects. We compared this group to a group of rats exposed to a differential-reinforcement-of high-rates schedule (DRH). The DRH intervention has never been employed in this research context, but explicitly programs an immediate response-reinforcement requirement. In Experiment 2, we tested effects of an intervention with a delay longer than those used in the delay discounting pretest and posttest. No previous research has tested effects of an intervention delay this long, relative to the delay discounting task. We compared this group to a group exposed to a delay that was part of the delay discounting pretest and posttest and to a group exposed to a traditional no-delay, fixed-ratio (FR) 2 control intervention. In both experiments, we found that exposure to delayed rewards in the intervention phase significantly increased LLR choice relative to pretest performance. These findings replicate and extend a growing body of literature showing that delay exposure increases preference for LLR. We also found significant decreases in LLR choice from pretest to posttest in the DRH and no-delay intervention groups in Experiments 1 and 2, respectively. This is the first report of such an effect and has implications for understanding and interpreting effects of delay exposure training in past and future research. Our results also suggested no relationship between improved temporal tracking of reward and increases in LLR choice as a result of delay exposure training. PMID- 30468887 TI - Understanding zebrafish aggressive behavior. AB - Aggression is a common agonistic behavior affecting social life and wellbeing of humans and animals. However, the underlying mechanisms of aggression remain poorly understood. For decades, studies of aggression have mostly focused on laboratory rodents. The growing importance of evolutionarily relevant, cross species disease modeling necessitates novel model organisms to study aggression and its pathobiology. The zebrafish (Danio rerio) is rapidly becoming a new experimental model organism in neurobehavioral research. Zebrafish demonstrate high genetic and physiological homology with mammals, fully sequenced genome, ease of husbandry and testing, and robust behavioral repertoire. As zebrafish present overt aggressive behaviors, here we focus on their behavioral models and discuss their utility in probing aggression neurobiology and its genetic, pharmacological and environmental modulation. We argue that zebrafish-based models represent an excellent translational tool to understand aggressive behaviors and related pathobiological brain mechanisms. PMID- 30468888 TI - Further observations on cardiac modulation of thoracic motoneuron discharges. AB - Previous analyses of recordings of alpha motoneuron discharges from branches of the intercostal and abdominal nerves in anesthetized cats under neuromuscular blockade demonstrated modulation with the cardiac cycle. This modulation was interpreted as evidence that thoracic somatosensory afferents, most likely muscle spindles, provide a signal to the CNS that could contribute to cardiac interoception. Here, two aspects of these observations have been extended. First, new measurements of thoracic and abdominal EMG activity in spontaneously breathing dogs show that a very similar modulation exists in these rather different circumstances. Second, further analysis of the cat recordings shows that cardiac modulation of the discharges of bulbospinal neurons that transmit the expiratory drive to thoracic motoneurons is weak and of an inappropriate time course to be a contributor to the effect seen in the motoneurons. PMID- 30468889 TI - Leukotriene-mediated sex dimorphism in murine asthma-like features during allergen sensitization. AB - The incidence and severity of asthma preponderate in women versus men. Leukotrienes (LTs) are lipid mediators involved in asthma pathogenesis, and sex disparities in LT biosynthesis and anti-LT pharmacology in inflammation have recently emerged. Here, we report on sex dimorphism in LT production during allergen sensitization and its correlation to lung function. While high plasma levels of IgE, as sensitization index, were elevated in both sexes, LT levels increased only in lungs of female ovalbumin-sensitized BALB/c mice. Sex-dependent elevated LT levels strictly correlated to an enhanced airway hyperreactivity, pulmonary inflammation and mast cell infiltration/activation in female mice. Importantly, this sex bias was coupled to superior therapeutic efficacy of different types of clinically used LT modifiers like zileuton, MK886 and montelukast in female animals. Our findings reveal sex-dependent LT production as a basic mechanism of sex dimorphism in allergic asthma, and suggest that women might benefit more from anti-LT asthma therapy. PMID- 30468890 TI - Comparative study of beta-thymosin in two scallop species Argopecten irradians and Chlamys farreri. AB - The beta-thymosin (Tbeta) proteins participate in numerous biological processes, such as cell proliferation and differentiation, anti-inflammatory and antimicrobial mechanism. To date, Tbeta proteins have been well studied in vertebrates, especially mammals. While limited Tbeta or Tbeta-like proteins have been reported in invertebrates. Moreover, rare information of Tbeta or Tbeta-like proteins is available in scallop species yet. In the present study, two Tbeta homologues, AiTbeta and CfTbeta, were identified and characterized from two scallop species bay scallop Argopecten irradians and Zhikong scallop Chlamys farreri. They were both 41 amino acid peptide and contained one THY domain, a highly conserved actin-binding motif and two conserved helix forming regions. Tissue distribution and expression profiles of their mRNA transcripts were roughly similar yet different in detail, while their recombinant proteins exhibited different immunomodulation activity on the downstream immune parameters. These results collectively indicated that the function of Tbeta family in scallop were functionally differentiated. PMID- 30468891 TI - Effects of dietary Bacillus subtilis and Shewanella algae in expression profile of immune-related genes from hemolymph of Litopenaeus vannamei challenged with Vibrio parahaemolyticus. AB - B. subtilis and S. algae effects in growth, survival and innate immunity were assessed on L. vannamei juveniles. During 60 days, shrimp were reared in three treatments: Bs, fed with 106 CFU of B. subtilis per gram of commercial feed, Sa, fed with 106 CFU of S. algae per gram of commercial feed and Control (without bacterial addition). Then, the animals were subjected to a V. parahaemolyticus challenge. For this purpose, four treatments were established: Control (shrimp not submitted to probiotic treatments), Vibrio (Vibrio challenged shrimp), Vibrio + Bs (Bs challenged shrimp) and Vibrio + Sa (Sa challenged shrimp). Shrimp hemolymph was sampled 45-days after rearing and 24 h post-challenge for quantification of prophenoloxidase (proPO), lipopolysaccharide and beta-1,3 glucan-binding protein (LGBP) and hemocyanin (HEM) transcripts by qPCR. Moreover, shrimp final weight and survival were also verified. B. subtilis administration enhanced shrimp growth and improved proPO, LGBP and HEM expression levels before and after challenge. After 60-days of feeding, Sa final weight was higher than the Control, whereas Vibrio + Sa cumulative mortality after 48 h of Vibrio challenge was lower than Vibrio group. These results could be correlated with the proPO and LGBP up regulation in Vibrio + Sa compared to Vibrio group, protecting L. vannamei from the bacterial infection. Together, these results suggest the probiotic potential of B. subtilis e S. algae in the modulation of immune-related genes as a tool to control V. parahaemolyticus infection inside shrimp. PMID- 30468892 TI - In vitro transcribed dsRNA limits viral hemorrhagic septicemia virus (VHSV)-IVb infection in a novel fathead minnow (Pimephales promelas) skin cell line. AB - The farming of baitfish, fish used by anglers to catch predatory fish species, is of economic and ecological importance in North America. Baitfish, including the fathead minnow (Pimephales promelas), are susceptible to infection from aquatic viruses, such as viral hemorrhagic septicemia virus (VHSV). VHSV infections can cause mass mortality events and have the potential to be spread to novel water bodies through baitfish as a vector. In this study, a novel skin cell line derived from fathead minnow (FHMskin) is described and its use as a tool to study innate antiviral immune responses and possible therapies is introduced. FHMskin grows optimally in 10% fetal bovine serum and at warmer temperatures, 25-30 degrees C. FHMskin is susceptible and permissive to VHSV-IVb infection, producing high viral titres of 7.35 * 107 TCID50/mL after only 2 days. FHMskin cells do not experience significant dsRNA-induced death after treatment with 50-500 ng/mL of in vitro transcribed dsRNA for 48 h and respond to dsRNA treatment by expressing high levels of three innate immune genes, viperin, ISG15, and Mx1. Pretreatment with dsRNA for 24 h significantly protected cells from VHSV-induced cell death, 500 ng/mL of dsRNA reduced cell death from 70% to less than 15% at a multiplicity of infection of 0.1. Thus, the novel cell line, FHMskin, represents a new method for producing high tires of VHSV-IVb in culture, and for studying dsRNA-induced innate antiviral responses, with future applications in dsRNA-based antiviral therapeutics. PMID- 30468893 TI - Administrations of autochthonous probiotics altered juvenile rainbow trout Oncorhynchus mykiss health status, growth performance and resistance to Lactococcus garvieae, an experimental infection. AB - The present study was tested how Oncorhynchus mykiss can respond to dietary supplementations of autochthonous probiotics, including Lactobacillus delbrukei subsp. bulgaricus and Lactobacillus acidophilus and Citrobacter farmeri by measuring different parameters. To address that, 300 fish weighing 19.08-32.9 g were fed by probiotics-enriched diets, containing 5 * 107 CFU g-1 for 60 days. Our results indicated that probiotics, especially L. acidophilus and L. bulgaricus are involved in enhancing the growth performance of this species as compared with the control group. Blood profile (Hemoglobin and Hematocrit) showed significant (P < 0.05) increases in probiotic fed groups compared with the control. Serum lysozyme and complement activities were higher in probiotic-fed fish while similar changes were not observed in the case of bactericidal activity and Nitroblue Tetrazolium (NBT) reduction. Better colonization of lactic acid bacteria in fish intestine was observed following L. acidophilus and L. bulgaricus administrations (P < 0.001). Digestive enzyme activities of intestine, including amylase, trypsin, lipase and alkaline phosphatase were elevated either significant or insignificant while protease activity did not act the same. All probiotic treatments led to mild or strong (P < 0.001) up-regulation of cytokine and growth gene expressions of intestine in comparison with the control group. Higher in vitro antagonist activities of L. acidophilus and L. bulgaricus against the Lactococcus garvieae were coincident with in vivo challenge test. The relative percentage of survival (RPS) was obtained 63.71 and 51.56 for L. bulgaricus and L. acidophilus, respectively, which were higher in those treated fish as compared to control fish. Our results may suggest that the probiotics, applied here, can promote growth performance by improving digestive enzyme activity, gut micro flora and growth gene expression. Up-regulation of immune regulatory proteins may increase the non-specific immune responses and bacterial resistance in this species as well. PMID- 30468894 TI - Reappraisal and suppression emotion-regulation tendencies differentially predict reward-responsivity and psychological well-being. AB - Individuals who suppress their emotions experience less positive emotions, worse relationships, and a reduced quality of life whereas those who tend to reappraise show an opposite pattern. Despite this divergent pattern, few have asked how the use of these emotion-regulation strategies relates to reward responsivity. We predicted that elevated suppression would be associated with blunted reward responsivity, whereas reappraisal would be associated with elevated reward responsivity. To test this hypothesis, participants completed a measure of individual differences in emotion-regulation strategies, measures of self reported reward responsivity, and then a reward time-estimation task (Kotani et al., 2003) while electroencephalography (EEG) was recorded. Results revealed that individual differences in cognitive reappraisal were unrelated to self-report measures of reward responsivity, whereas suppression was associated with blunted reward responsivity. At the neural level, reappraisal was associated with greater attention to the rewarding cues, as indexed by the P300 event-related potential (ERP) component, whereas suppression was related to blunted reward anticipation, as indexed by the stimulus-preceding negativity (SPN) ERP component. Suppression prospectively predicted worse psychological well-being 2.5 years later and blunted neural reward anticipation partially explained this association. Taken together with past research, these results suggest reappraisal tendencies may lead to better outcomes due, in part, to enhanced reward responsivity, whereas the negative consequences of suppression may be associated with blunted reward responsivity. PMID- 30468895 TI - Touch targeting C-tactile afferent fibers has a unique physiological pattern: A combined electrodermal and facial electromyography study. AB - Caress-like touch is thought to rely on C-tactile (CT) fiber signaling. Here, the arousing and emotional effects of CT-optimal touch were assessed via participants' skin conductance level (SCL), facial electromyography (EMG) responses and subjective ratings of pleasantness and intensity. Temporal facial EMG analysis was based on the conduction velocity of CT-fibers. 45 healthy participants received CT-optimal touch, control touch and visual control input during 2-minute trials. CT optimal touch was significantly more pleasant and intense than control touch. In the initial 700 ms of stimulation there was no difference in facial EMG responses to touch. Between 700 and 6300 ms there was a significant reduction of corrugator activity in response to CT optimal touch only, possibly reflecting the affective value of CT optimal touch. Based on the temporal dynamics of the reduced corrugator activity, we suggest that CT fibers are involved in mediating a reduction in corrugator activity. PMID- 30468896 TI - Neural response to reward and psychosocial risk factors independently predict antenatal depressive symptoms. AB - While psychosocial risk factors for peripartum depression are well-researched, studies on neural risk factors are scarce. Previous studies suggest a blunted neural response to reward may be a biomarker of depression and risk. In a sample of 86 pregnant women, the present study examined whether a reduced Reward Positivity (RewP), an event-related potential (ERP) elicited to feedback indicating monetary reward, relates to greater antenatal depressive symptoms. We also examined whether the RewP explains unique variance in antenatal depressive symptoms relative to other indices of risk, including annual income, history of a major depressive episodes, and score on a validated psychosocial risk measure, the Pregnancy Risk Questionnaire (PRQ). Zero-order correlations revealed that lower annual income, greater PRQ scores, and a blunted RewP were associated with greater antenatal depressive symptoms. The RewP and PRQ scores were identified as the best predictors of antenatal depressive symptoms in a stepwise regression, and together predicted 48 percent of the variance in antenatal depressive symptoms. PRQ scores accounted for 44% of the variance in antenatal depressive symptoms while the RewP accounted for 4% of additional incremental variance. This is the first study to combine self-report and neural activity to examine depressive symptoms in pregnant women. Future directions for research on perinatal depression are discussed. PMID- 30468897 TI - The presence of others reduces dyspnea and cortical neural processing of respiratory sensations. AB - Dyspnea is a threatening symptom frequently experienced by patients within social contexts such as in the presence of family members, health professionals, or other patients. However, the effects of social presence on perceived dyspnea remain unknown. Therefore, this study examined the effects of social presence on dyspnea perception and cortical neural processing of respiratory sensations using respiratory-related evoked potentials (RREPs) in the electroencephalogram while additionally investigating the impact of dyspnea-specific fear. Thirty-one healthy females underwent four experimental conditions while RREPs were induced by inspiratory occlusions: (1)observer present/no dyspnea, (2)observer present/dyspnea, (3)alone/no dyspnea, (4)alone/dyspnea. The observer presence reduced ratings of perceived dyspnea during dyspnea conditions either significantly or at trend level. Additionally, reduced amplitudes at trend level of RREP component P2 in conditions with an observer present were found. No associations with dyspnea-specific fear were found. Findings suggest that social presence might have beneficial effects for individuals experiencing dyspnea. PMID- 30468898 TI - Rose Bengal Incorporated to alpha-Cyclodextrin Microparticles for Photodynamic Therapy against the cariogenic microorganism Streptococcus mutans. AB - Rose Bengal@alpha-cyclodextrin (RB@alpha-CD) microparticles (uPs) were prepared and the RB inclusion in alpha-CD was experimentally demonstrated through infrared, UV-VIS absorption spectroscopy and cyclic voltammetry. The RB inclusion in alpha-CD was theoretically investigated using classical molecular mechanics calculations, the simulation results showing that RB can be included in both the narrow and wide apertures of the alpha-cyclodextrin ring with configurations exhibiting average binding energies of about 27 kcal mol-1. The prepared RB@alpha CD microparticles were characterized through Scanning Electron Microscopy (SEM) and it was demonstrated that they are highly efficient in the photodynamic therapy against a Streptococcus mutans (the main bacteria of cariogenic dental plaque) suspension, as a concentration of RB@alpha-CD uPs 10 times smaller than the usual concentration of pure RB is still capable to produce significant antibacterial activity. PMID- 30468899 TI - Pirfenidone-induced photosensitivity confirmed by pathological phototest. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an idiopathic interstitial progressive fibrotic lung disease and the most lethal of all interstitial lung diseases. Pirfenidone is a novel antifibrotic and anti-inflammatory agent which reduces decline in lung function and prolonges progression-free survival. It has a favourable benefit-risk profile and is generally well tolerated. However gastrointestinal events, photosensitivity reactions and rash are the most common adverse events. OBJECTIVE: We report a 71-year-old man with 1 week history of erythematous partially pruritic lesions on both sides of the neck and the back of the hands limited to sun exposed areas. He had been diagnosed with IPF and was being treated with pirfenidone (Esbriet) for 8 months. We suspected a photosensitivity reaction caused by pirfenidone. METHODS: A phototest and a punch biopsy were performed. RESULTS: The phototest had a pathological result. The minimal erythema dose was decreased, presenting with erythema and edema starting from 7 mJ/cm2 of UVB and an aberrant response to UVA starting from 2 J/cm2. Histopathological examination revealed spongiotic acute dermatitis with focal presence of necrotic keratinocytes. The patient was diagnosed with pirfenidone induced photosensitivity and treated with high potency topical steroid leading to the resolution of the lesions, without the need for discontinuation of the drug. CONCLUSION: To our Knowledge, this is the first pirfenidone-induced photosensitivity reported case confirmed by pathological phototest. Patient education and photoprotection advice are essential for prevention. PMID- 30468900 TI - Multiple aPDT sessions on periodontitis in rats treated with chemotherapy: Histomorphometrical, Immunohistochemical, Imunological and Microbiological Analyses. AB - BACKGROUND: The aim of this study was to evaluate the effect of multiple sessions of antimicrobial photodynamic therapy (aPDT) on the treatment of experimental periodontitis (EP) in rats treated with chemotherapy. METHODS: Chemotherapy using 5-fluorouracil (5-FU) consisted of intraperitoneal administration of 60 and 40 mg/kg of 5-FU. 120 rats were subjected to chemotherapy with 5-FU and divided into groups: PT (periodontal treatment); PT+1aPDT (PT and single aPDT session); PT+4aPDT(PT and 4 sessions of aPDT); 1aPDT (single aPDT session); 4aPDT(4 sessions of aPDT). EP was induced in the mandibular molars via ligature placement. The alveolar bone loss (ABL) area in the furcation region was analysed histometrically. Proliferating cell nuclear antigen (PCNA), tartrate-resistant acid phosphatase (TRAP), receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) and cleaved caspase-3 (CC3) were analysed by immunohistochemistry. Prostaglandin E2 was quantified using an ELISA, tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were assessed using a multiplex method. The prevalence of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella nigrescens, Prevotella intermedia and Fusobacterium nucleatum was assessed using PCR. The data were statistically analysed (P < 0.05). RESULTS: The PT+4aPDT group showed lower ABL than the PT or 1aPDT groups on day 7. Rats treated with aPDT showed a higher number of PCNA positive cells with reduced immunolabeling of RANKL. Significant reductions in Prevotella nigrescens were observed in the PT+4aPDT group and in Aggregatibacter actinomycetemcomitans for the 1aPDT and 4aPDT groups. CONCLUSION: Repeated sessions of aPDT as an adjunct or alternative therapy were effective at reducing ABL, regulating bone metabolism, and reducing Prevotella nigrescens and Aggregatibacter actinomycetemcomitans. PMID- 30468902 TI - Risk factors for postoperative severe morbidity after pheochromocytoma surgery: A single center retrospective analysis of 262 patients. AB - PURPOSE: Surgical resection is the primary treatment strategy for pheochromocytoma; however, it carries a high risk of morbidity and mortality. The risk factors for severe morbidity remain unclear and require further exploration. We aimed to identify the risk factors for severe morbidity after pheochromocytoma surgery in Chinese patients. METHODS: We retrospectively reviewed 262 patients who underwent unilateral laparoscopic or open pheochromocytoma surgery at our center between January 1, 2007 and December 31, 2016. Patient demographics, as well as extensive perioperative data were recorded. Adjusted odds ratios and 95% confidence intervals were determined by multivariate binary logistic regression. Cutoff values and the area under the curve for continuous risk factors were calculated through receiver operating characteristic curve analysis. A P < 0.05 was considered statistically significant. RESULTS: Of the 262 patients, 78 (29.8%) had severe morbidity. The independent risk factors for severe morbidity were female sex, lower body mass index, coronary heart disease, longer duration of surgery, and intraoperative hemodynamic instability, with odds ratios of 2.624 (P = 0.003), 0.780 (P < 0.001), 2.098, (P = 0.024), 1.005 (P = 0.031), and 2.920 (P = 0.005). The optimal cut off values for body mass index and duration of surgery were 24.25 kg/m2 and 203 min. CONCLUSIONS: Severe morbidity is common in patients after pheochromocytoma surgery. We identified five independent risk factors for severe morbidity: female sex, lower body mass index, coronary heart disease, longer duration of surgery, and intraoperative hemodynamic instability. Identification of these risk factors may help to improve perioperative strategy. PMID- 30468901 TI - Efficacy and safety of limb position on blood loss and range of motion after total knee arthroplasty without tourniquet: A randomized clinical trial. AB - BACKGROUND: The purpose of this study was to investigate the effect of postoperative limb position on blood loss and knee function after primary total knee arthroplasty without tourniquet. MATERIAL AND METHODS: One hundred patients were randomly assigned into 2 groups: Group A was given a knee flexion position at 60 degrees for 24 h after surgery but without the tourniquet use. Patients in group B was received the tourniquet use the same flexion position as the Group A. All patients received intravenous (IV) tranexamic acid (TXA) 15 mg/kg before skin incision and another 1 g of IV-TXA after 3 h. RESULTS: The total blood loss was similar in the 2 groups. Group A had significantly less hidden blood loss and drainage volume (P = 0.023, P < 0.001), and higher intraoperative blood loss than the Group B (P < 0.001). The visual analog scale and knee circumference in Group A were lower than the Group B on postoperative days 1, 3 and 5. The range of motion was also lowering in Group A than the Group B on postoperative days 1, 3, 5 and at the 1 month. No significant differences (P > 0.05) were observed between the 2 groups regarding maximum hemoglobin drop, transfusion rate, postoperative hospital stay, DVT and/or PE, and wound-related complications. CONCLUSION: Based on the current evidence, patients treated with postoperative limb positions without a tourniquet can effectively reduce hidden blood loss and drainage volume, as well as better early clinical benefits than those treated with a tourniquet. LEVEL OF EVIDENCE: Therapeutic Level I. PMID- 30468903 TI - A propensity score-matched comparison of laparoscopic distal versus total gastrectomy for middle-third advanced gastric cancer. AB - BACKGROUND: The optimal resection extent for middle-third advanced gastric cancer (AGC) still remains controversial. This study aimed to assess the long-term oncologic outcomes of laparoscopy-assisted distal gastrectomy (LADG) versus laparoscopy-assisted total gastrectomy (LATG) for middle-third AGC. METHODS: A retrospective cohort study was conducted using data from 464 patients who underwent LADG or LATG between September 2007 and March 2013. Propensity score matching (PSM) were used for reducing the confounding effects to compare the long term oncologic outcomes between two groups. Cox regression analysis was performed to clarify the prognostic factors. RESULTS: After PSM was performed, a well balanced cohort of 376 patients (188 LADG and 188 LATG) was further analyzed. Of interest, the LADG group had a significantly shorter operative time (244.6 +/- 28.0 vs. 259.1 +/- 30.1, P < 0.0001), less operative blood loss (142.9 +/- 50.9 vs. 157.8 +/- 54.1, P = 0.006), earlier day of first flatus (2.6 +/- 0.8 vs. 2.9 +/- 0.9, P = 0.014), fewer number of retrieved lymph nodes (36.5 +/- 7.9 vs. 41.4 +/- 9.8, P < 0.0001), and shorter postoperative hospital stay (9.7 +/- 1.3 vs. 10.7 +/- 1.4, P < 0.0001) than the LATG group. However, no significant differences were observed in days of eating liquid diet (P = 0.626) and days of eating soft diet (P = 0.353). The incidence of overall and severe postoperative complications (Clavien-Dindo grade >= IIIa) following the LADG group were significantly fewer than the LATG group (overall, 24.5% vs. 34.6%, P = 0.032; severe, 4.8% vs. 11.2%, P = 0.022). In addition, the LADG group had significantly more favorable overall survival (OS) and disease-free survival (DFS) rates than the LATG group (5-year OS rate, 55.6% vs. 41.8%, P = 0.002; 5-year DFS rate, 45.9% vs. 32.8%, P < 0.001). In multivariate analyses, resection extent was not an independent prognostic factor for OS and DFS. CONCLUSIONS: This PSM cohort analysis has indicated LADG with D2 lymphadenectomy appeared to be safe and reasonable option for patients with middle-third AGC in general. LADG could contribute to improved survival. PMID- 30468904 TI - Postoperative complications in elderly patients following pancreaticoduodenectomy lead to increased postoperative mortality and costs. A retrospective cohort study. AB - BACKGROUND: Complications frequently occur after pancreaticoduodenectomy. Patients undergoing pancreaticoduodenectomy tend to be older; age and postoperative complication may be associated. To clarify this association, we compared postoperative outcomes in patients undergoing pancreaticoduodenectomy based on age group. We aimed to determine whether we could identify an age cutoff where the incidence and cost of postoperative complications starts increasing and potentially outweigh the potential benefits of pancreaticoduodenectomy. MATERIALS AND METHODS: We built a retrospective cohort of consecutive patients undergoing pancreaticoduodenectomy at one institution from 2011 to 2017. Demographics, operative data and costs were obtained from hospital and administrative databases. A restricted cubic spline regression analysis was performed to graphically identify the age in which the comprehensive complication index (CCI) substantially increased. Cost analysis was undertaken from the perspective of a third-party payer. Differences in costs between age groups were tested using t test. RESULTS: Among 440 patients, the CCI became significantly higher at the age cutoff of 72 (median 21 in the older vs. 12 in the younger group, P = 0.014). Postoperative complications (74% vs. 64%, P = 0.038), and mortality (8% vs. 3%, P = 0.016) were also significantly higher in the older age group; mostly driven by pneumonia (11% vs. 6%, P = 0.097), myocardial infarction (12% vs. 4%, P < 0.002) and urinary tract infection (18% vs. 5%, P = 0.003). Median length of hospital stay was also longer for the older age group (10 vs. 8 days, P = 0.002). Total mean cost was significantly higher in the older age group ($38,225 CAD vs. $29,771 CAD). CONCLUSIONS: In our cohort of patients, after age 72, pancreaticoduodenectomy is associated with significantly more postoperative complications and deaths which translated in longer hospital stay and higher costs. This information may help patients and surgeons make informed decisions. PMID- 30468905 TI - Prognostic role of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in prostate cancer: A meta-analysis of results from multivariate analysis. AB - BACKGROUND: The prognostic role of neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) in patients with prostate cancer (PCa) remains inconsistent. Here we quantify the prognostic impact of these biomarkers and assess their consistency in PCa. MATERIALS AND METHODS: We systematically searched PubMed, Web of Science, and Embase for eligible studies embracing multivariate results. The Newcastle-Ottawa Scale were used to assess the study quality. Pooled hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated. RESULTS: A total of 7228 patients from 18 studies were included in the meta-analysis. Overall, elevated pretreatment NLR was associated with poor overall survival (OS, HR 1.58, 95% CI 1.41-1.78, P < 0.001), progression-free survival (PFS, HR 1.95, 95% CI 1.53-2.49, P < 0.001) and biochemical recurrence free survival (BRFS, HR 1.37, 95% CI 1.07-1.75, P = 0.011). And high pretreatment PLR was correlated with more inferior PFS (HR 1.62, 95% CI 1.20-2.19, P = 0.002), OS (HR 1.70, 95% CI 1.34-2.15, P < 0.001) and cancer-specific survival (CSS, HR 2.02, 95% CI 1.24-3.29, P = 0.005). Moreover, the subgroup analyses did not alter the direction of results for OS and PFS. CONCLUSION: Based on these findings, elevated NLR and PLR was associated with poor oncologic outcomes, and they can serve as prognostic factors in PCa patients. PMID- 30468906 TI - Modelling posttraumatic stress disorders in animals. AB - Animal models of posttraumatic stress disorder are useful tools to reveal the neurobiological basis of the vulnerability to traumatic events, and to develop new treatment strategies, as well as predicting treatment response contributing to personalized medicine approach. Different models have different construct, face and predictive validity and they model different symptoms of the disease. The most prevalent models are the single prolonged stress, electric foot-shock and predator odor. Freezing as 're-experiencing' in cluster B and startle as 'arousal' in cluster E according to DSM-5 are the most frequently studied parameters; however, several other symptoms related to mood, cognitive and social skills are part of the examinations. Beside behavioral characteristics, symptoms of exaggerated sympathetic activity and hypothalamic-pituitary-adrenocortical axis as well as signs of sleep disturbances are also warranted. Test battery rather than a single test is required to describe a model properly and the results should be interpreted in a comprehensive way, e.g. creating a z-score. Research is shifting to study larger populations and identifying the features of the resilient and vulnerable individuals, which cannot be easily done in humans. Incorporation of the "three hit theory" in animal models may lead to a better animal model of vulnerability and resilience. As women are twice as vulnerable as men, more emphasize should be taken to include female animals. Moreover, hypothesis free testing and big data analysis may help to identify an array of biomarkers instead of a single variable for identification of vulnerability and for the purpose of personalized medicine. PMID- 30468907 TI - The pivotal oncogenic role of Jab1/CSN5 and its therapeutic implications in human cancer. AB - Jab1/CSN5 is a conserved multifunctional protein involved in ubiquitin-mediated protein degradation. Deregulation of Jab1/CSN5 can exert dramatic effects on diverse cellular functions, including DNA repair, cell cycle control, apoptosis, angiogenesis, and signal transduction, all of which are critical for tumor development. Although increasing evidence has demonstrated that Jab1/CSN5 was overexpressed in a variety of human cancers and usually correlated with poor prognosis, little was known about the underlying regulatory principles that coordinated its function. In this review, we highlight recent advances of the oncogenic role of Jab1/CSN5 and its potential as a therapeutic target for anticancer intervention. PMID- 30468908 TI - Evaluation of miRNA-9 and miRNA-34a as potential biomarkers for diagnosis of breast cancer in Iranian women. AB - PURPOSE: MicroRNAs are involved in diverse biological processes and their dysregulation is a common event in various diseases including breast cancer. Breast cancer is a major threat to women's health. This study was designed to examine the expression levels of miR-9 and miR-34a in breast tumor tissue samples and plasma of breast cancer patients, compare their expression pattern between tissue samples and plasma samples of patients and analyze their relationship with tumor clinical features. Also, the potential of these miRNAs as diagnostic biomarkers for breast cancer was investigated. MATERIALS AND METHODS: The expression levels of miR-9, miR-34a and CDH1 were measured by real-time reverse transcription polymerase chain reaction and DeltaDeltact method. Data were analyzed using t-test and one-way ANOVA. The sensitivity and specificity of miRNAs were determined by receiver operating characteristic (ROC) curve. RESULTS AND DISCUSSION: The expression levels of miR-9 and miR-34a were significantly down-regulated in tumor tissues compared to healthy tissues (fold change = 0.26, p = 0.0051 for miR-9 and fold change = 0.55, p = 0.021 for miR-34a). While no significant difference was observed in the expression levels of miR-9 (p = 0.205) and miR-34a (p = 0.132) in plasma samples of patients compared to normal plasma. CDH1 expression in tumor tissue was not significantly different from normal tissue (p = 0.33). We found that expression level of miR-9 in patients with tumor size larger than 5 cm (p = 0.026) and expression level of miR-34a in patients with higher stage (lll & lV, p = 0.03) were significantly down-regulated. Also miR-34a expression level was positively correlated with patient's age (p = 0.03). CONCLUSION: According to the ROC curves, the area under the curve (AUC) of miR-9 in tissue was 0.71 (p = 0.009) with sensitivity 83.33% and specificity 70.37%. The AUC for miR-34a in tissue was 0.72 (p = 0.007) with sensitivity 72% and specificity 76%. Thus miR-9 and miR-34a have the capability for distinguishing tumor tissues from healthy tissues and the study of their expression levels in tissue may be used as a biomarker for the diagnosis of breast cancer patients from healthy women. PMID- 30468909 TI - High incidence of co-existing factors significantly modifying the phenotype in patients with Fabry disease. AB - Fabry disease results from deficiency of the lysosomal enzyme alpha-galactosidase A. The families of 11 index cases were screened by enzyme and molecular assays. Further clinical and laboratory investigations were carried out in all cases. Including 33 new patients, a total of 28 females (Age 25,82 +/- 12,1 Range 8-46) and 16 males (Age 24,56 +/- 15,04 Range 2-48) were investigated. Ten different disease-causing variants were found two of them being novel. One patient had co existing familial mediteranian fever, one had celiac disease and three had rheumatological disorders. Lipoprotein (a) levels were elevated in 17,6%, homocysteine in 22,2%, total and low density cholesterol in 12% and antithrombin 3 levels were elevated in 13,3%. One patient was found to be heterozygous for prothrombin p.G20210A disease-causing variant (5,8%) and two for factor V Leiden disease-causing variant (11,7%). Anticardiolipin IgM antibody was found to be positive in 11,7%. The patients with abnormal cranial imaging were also noticed to have additional risk factors for thrombosis. This study provides the largest data about Fabry patients from Turkey and implies that co-existing risk factors unrelated to Fabry Disease have significant association with the presence of clinical symptoms in females and might cause an early and severe clinical course in males. PMID- 30468910 TI - Generalizability and applicability of results obtained from populations of European descent regarding the effect direction and size of HDL-C level associated genetic variants to the Hungarian general and Roma populations. AB - OBJECTIVES: Large-scale association studies that mainly involve European populations identified many genetic loci related to high-density lipoprotein cholesterol (HDL-C) levels, one of the most important indicators of the risk for cardiovascular diseases. The question with intense speculation of whether the effect estimates obtained from European populations for different HDL-C level related SNPs are applicable to the Roma ethnicity, the largest minority group in Europe with a South Asian origin, was addressed in the present study. DESIGN: The associations between 21 SNPs (in the genes LIPC(G), CETP, GALNT2, HMGCP, ABCA1, KCTD10 and WWOX) and HDL-C levels were examined separately in adults of the Hungarian general (N = 1542) and Roma (N = 646) populations by linear regression. Individual effects (direction and size) of single SNPs on HDL-C levels were computed and compared between the study groups and with data published in the literature. RESULTS: Significant associations between SNPs and HDL-C levels were more frequently found in general subjects than in Roma subjects (11 SNPs in general vs. 4 SNPs in Roma). The CETP gene variants rs1532624, rs708272 and rs7499892 consistently showed significant associations with HDL-C levels across the study groups (p ? 0.05), indicating a possible causal variant(s) in this region. Although nominally significant differences in effect size were found for three SNPs (rs693 in gene APOB, rs9989419 in gene CETP, and rs2548861 in gene WWOX) by comparing the general and Roma populations, most of these SNPs did not have a significant effect on HDL-C levels. The beta coefficients for SNPs in the Roma population were found to be identical both in direction and magnitude to the effect obtained previously in large-scale studies on European populations. CONCLUSIONS: The effect of the vast majority of the SNPs on HDL-C levels could be replicated in the Hungarian general and Roma populations, which indicates that the effect size measurements obtained from the literature can be used for risk estimation for both populations. PMID- 30468911 TI - Molecular identification, phylogenomic characterization and expression patterns analysis of the LIM (LIN-11, Isl1 and MEC-3 domains) gene family in pear (Pyrus bretschneideri) reveal its potential role in lignin metabolism. AB - Lignin is the main component of stone cells, which are a key factor in determining pear quality. Therefore, modification of lignin biosynthesis has important implications for regulating stone cell formation. LIMs are involved in plant development, stress response and metabolism. However, there is still a lack of knowledge about the pear LIM family and lignin-related LIMs. To address this problem, we identified 14 LIMs from the pear genome and named them. Phylogenomic and feature domain analysis showed that they were divided into CRP- and DA&DAR LIM groups and five subclades. LIMs from the genomes of four rosids (Prunus mummer, Prunus persica, Fragaria vesca and Vitis vinifera) were also identified, and microsynteny analysis revealed the most orthologous gene pairs in the cross of pear/grape and pear/mei. The transcript levels of PbLIMs were significantly affected by SA, ABA and MeJA. Spatio-temporal expression analysis showed that PbLIMs of the deltaLIM2 subfamily were highly expressed in the flowers. Changes in the expression levels of PbWLIM1a and PbWLIM1b during fruit development was consistent with the changes in lignin content. Combining phylogenetic analyses, protein three-dimensional structure determination and sequence alignment analyses, these two genes were suggested as lignin-related PbLIMs. Subcellular localization results showed that PbWLIM1a and PbWLIM1b were located mainly in the chloroplast. This study lays the foundation for revealing the mechanism of LIM mediated lignin metabolism to regulate stone cell formation. PMID- 30468912 TI - Automatic Identification of Recent High Impact Clinical Articles in PubMed to Support Clinical Decision Making Using Time-agnostic Features. AB - OBJECTIVES: Finding recent clinical studies that warrant changes in clinical practice ("high impact" clinical studies) in a timely manner is very challenging. We investigated a machine learning approach to find recent studies with high clinical impact to support clinical decision making and literature surveillance. METHODS: To identify recent studies, we developed our classification model using time-agnostic features that are available as soon as an article is indexed in PubMed(r), such as journal impact factor, author count, and study sample size. Using a gold standard of 541 high impact treatment studies referenced in 11 disease management guidelines, we tested the following null hypotheses: 1) the high impact classifier with time-agnostic features (HI-TA) performs equivalently to PubMed's Best Match sort and a MeSH-based Naive Bayes classifier; and 2) HI-TA performs equivalently to the high impact classifier with both time-agnostic and time-sensitive features (HI-TS) enabled in a previous study. The primary outcome for both hypotheses was mean top 20 precision. RESULTS: The differences in mean top 20 precision between HI-TA and three baselines (PubMed's Best Match, a MeSH based Naive Bayes classifier, and HI-TS) were not statistically significant (12% vs. 3%, p=0.101; 12% vs. 11%, p=0.720; 12% vs. 25%, p=0.094, respectively). Recall of HI-TA was low (7%). CONCLUSION: HI-TA had equivalent performance to state-of-the-art approaches that depend on time-sensitive features. With the advantage of relying only on time-agnostic features, the proposed approach can be used as an adjunct to help clinicians identify recent high impact clinical studies to support clinical decision-making. However, low recall limits the use of HI-TA for literature surveillance. PMID- 30468913 TI - The influence on acoustic frequency characteristics of conductivity gradual varying tissue in magnetoacoustic tomography (MAT). AB - BACKGROUND: As a functional imaging technology, magneto acoustic tomography (MAT) has broad application prospect in early tumor diagnosis and image monitoring during treatment. METHOD: The influence on the acoustic field characteristics of the gradual change in conductivity was studied in magneto-acoustic tomography with current injection (MAT-CI) in this article. RESULT: Theoretical analysis showed that the value of electro-acoustic conversion ratio (E-ACR) was different in different source frequencies under the same conductivity gradual-varying boundary. CONCLUSION: The frequency characteristics of the acoustic pressure tend to shift towards the low frequency region. This conclusion provides a theoretical foundation for the MA signal detection and processing system optimization in the area of conductivity gradual-varying. PMID- 30468914 TI - Detection of the sul2-strA-strB gene cluster in an ice core from Dome Fuji Station, East Antarctica. AB - OBJECTIVES: Bacteria harboring antimicrobial-resistance genes (ARGs) have been isolated from various locations including ancient microbiomes, indicating that these genes predate the discovery of antibiotics. To gain further information regarding ARGs in the pre-antibiotic era, we examined ice samples derived from Dome Fuji Station, Eastern Antarctica. METHODS: DNA was extracted from firn or ice core samples (n=3; 1,200-1,400 ybp, 1,700-2,100 ybp, and 2,200-2,800 ybp, respectively) under sterile conditions, and whole genome amplification and PCR analyses were utilized to detect ARGs. RESULTS: We detected a 2,764 base-pair gene cluster containing the type II dihydropteroate synthase gene sul2 and the aminoglycoside phosphotransferase genes strA and strB in the 1,200-1,400 year-old Antarctic ice core (DF-63.5). The sul2-strA-strB gene cluster is frequently associated with RSF1010 plasmid and Tn5393 transposon; however, we did not detect these elements in the DF-63.5 sample. The gene cluster exhibited high levels of sequence identity to that harbored in present-day bacteria while there were sequence polymorphisms in strA. Furthermore, expression of this gene cluster in Escherichia coli resulted in reduced susceptibility to dihydrostreptomycin and sulfamethoxazole. CONCLUSIONS: The results of this study provide further evidence that certain ARGs existed in the pre-antibiotic era. Because the sul2 gene confers resistance to the synthetic compound sulfamethoxazole, our findings suggest that ARGs against synthetic antimicrobials emerged in bacteria during the pre-antibiotic era. PMID- 30468915 TI - KPC-PRODUCING KLEBSIELLA PNEUMONIAE GUT DECOLONIZATION AFTER CEFTAZIDIME/AVIBACTAM-BASED COMBINATION THERAPY: A RETROSPECTIVE OBSERVATIONAL STUDY. AB - OBJECTIVE: KPC-producing Klebsiella pneumoniae (KPC-Kp) gut colonization is a major risk factor for developing systemic infections. Ceftazidime/avibactam could have a role as decolonization therapy in special situations PATIENTS AND METHODS: retrospective, observational, multicenter study. We compared KPC-Kp gut decolonization rate of ceftazidime/avibactam-based therapy (Group A) and other antimicrobial regimens (Group B) in patients with a KPC-Kp infection. RESULTS: 11/12 (91.7%) patients of Group A achieved gut decolonization. None of the patients of Group B were decolonized. CONCLUSIONS: ceftazidime/avibactam-based therapy could be useful in KPC-Kp gut decolonization in high-risk patients. PMID- 30468916 TI - Proteomic analysis highlights the immune responses of the hepatopancreas against Hematodinium infection in Portunus trituberculatus. AB - The parasitic dinoflagellate Hematodinium is considered an important pathogen of economically important marine crustaceans and has been reported from many wild and cultured species. While limited studies have been conducted to reveal the host-parasite interaction in crustaceans, the underlying molecular mechanisms between Hematodinium and its crustacean hosts are scarcely known. We conducted a comprehensive study to investigate the proteomic responses to Hematodinium infection in the hepatopancreas of Portunus trituberculatus using an iTRAQ-based quantitative proteomic technology. A total of 905 identified proteins including 392 differentially expressed proteins (DEPs) were subjected to GO, COG and KEGG pathway enrichment analysis, with sixteen DEPs further validated by quantitative real-time PCR. Hematodinium parasites resulted in immune-suppressive and adverse effects on affected hosts, thorough inhibition of the important pattern recognition receptors (C-lectin, SR class B, and Toll)-mediated immune responses, regulation of the complement and coagulation pathway, dysregulation of important cell adhesion molecules and extracellular matrix, and imbalance of the cellular redox homeostasis in the hepatopancreas of affected crabs. Moreover, the lysosomes pathway was dysregulated seriously in the hepatopancreas of P. trituberculatus post Hematodinium challenge. The results provided evidences on how the Hematodinium parasite overcame the innate immunity of P. trituberculatus and caused pathological alteration in affected tissues BIOLOGICAL SIGNIFICANCE: The manuscript presented the first iTRAQ-based proteomic study of the host parasite interaction between an important marine crustacean and the parasitic dinoflagellate Hematodinium. The manuscript reported the key pathways and proteins involved in the host-parasite interactions. The major findings will contribute to the better understanding of the molecular mechanism of the particular host-parasite interaction, as wells as the pathogenic process in susceptible tissues of affected crustacean hosts. PMID- 30468917 TI - Collagen sequence analysis of fossil camels, Camelops and c.f. Paracamelus, from the Arctic and sub-Arctic of Plio-Pleistocene North America. AB - Proteomic analyses of ancient remains are increasing, with great potential to recover phylogenetic information on extinct animals beyond the reach of ancient DNA, but its limitations remain unclear. Here we carry out LC-MS/MS sequence analysis of a ~3.5 million year old specimen along with the younger Pleistocene remains of the Yukon giant camel (c.f. Paracamelus) and the western camel (Camelops hesternus) for comparison with complete sequences to both extant camels (Bactrian and Dromedary) and the alpaca. Although not complete (~75-80% sequence coverage), no amino acid sequence differences were confidently observed between the giant camels and the extant Dromedary, indicative of a closer relationship than that of the extant Bactrian lineage. However, multiple amino acid changes were observed for the western camel (Camelops) collagen sequence, placing it as a sister group to these members of Camelini tribe consistent recent ancient DNA analyses. Although this supports a role for the sequencing of ancient collagen in the understanding of vertebrate evolution, we also highlight the limitations in phylogenetic reconstructions based on partial sequence data retrieved from proteomic analyses, particularly, the impact of omitting even only a single peptide on the resulting tree topology. The presence of other non-collagenous proteins, such as biglycan and PEDF, indicates a further resource for phylogenetic information, but none more promising than the degraded camel albumin observed in the Plio-Pleistocene specimen. SIGNIFICANCE: As proteomics is becoming more frequently used in the study of ancient proteins, an emerging field known as 'palaeoproteomics' (or 'paleoproteomics'), understanding the limitations of the technique is essential. Here, through the study of the oldest undisputed collagen sequences obtained from proteomics, we confirm that some peptides following diagenetic modifications of tryptic sites are no longer matched with standard searches, but can be matched with Error Tolerant searches. We also demonstrate the ability to retrieve phylogenetic information consistent with that of ancient DNA methods, but that with the omission of only one or more key peptides, the inferred evolutionary relationships change. This is a significant finding for the field of palaeoproteomics implying a need for better understanding the particular composition of the partial sequences retrieved from proteomic analyses. PMID- 30468918 TI - Rapid, experience-related changes in the organization of children's semantic knowledge. AB - The organization of knowledge according to relations between concepts is crucially important for many cognitive processes, and its emergence during childhood is a key focus of cognitive development research. Prior evidence about the role of learning and experience in the development of knowledge organization primarily comes from studies investigating differences between preexisting, naturally occurring groups (e.g., children from rural vs. urban settings, children who own a pet vs. children who do not) and a handful of studies on the effects of researcher-developed educational interventions. However, we know little about whether knowledge organization can be relatively rapidly molded by shorter-term real-world learning experiences (e.g., on a timescale of days vs. years or months). The current study investigated whether naturalistic learning experiences can drive rapid measurable changes in knowledge organization in children by investigating the effects of a week-long zoo summer camp (compared with a control school-based camp) on the degree to which 4- to 9-year-old children's knowledge about animals was organized according to taxonomic relations. Although there were no differences in taxonomic organization between the zoo camp and the school-based camp at pretest, only children who participated in the zoo camp showed increases in taxonomic organization at posttest. Moreover, analyses of changes in taxonomic organization in zoo camp children suggested that these changes were primarily driven by improvements in the degree to which children differentiated between taxonomic categories. These findings provide novel evidence that naturalistic experiences can drive rapid changes in knowledge organization. PMID- 30468919 TI - Safety and Effectiveness of Vedolizumab in Patients with Steroid-Refractory GI Acute GvHD: A Retrospective Record Review. AB - Allogeneic hematopoietic cell transplantation can be curative in patients with hematological malignancies but carries a significant risk of graft-versus-host disease (GvHD). There are no standard treatments for steroid-refractory (SR) gastrointestinal (GI) acute GvHD (aGvHD). This multicenter, international, retrospective medical record review aimed to evaluate the off-label use of vedolizumab, a gut-selective immunomodulator, for treatment of SR GI aGvHD. Data from medical records of patients were collected, and criteria for extraction included: no more than 1 allogeneic hematopoietic cell transplantation and at least 1 dose of vedolizumab as treatment for SR GI aGvHD (stage I-IV GI aGvHD following >=1 previous treatment regimen containing >=1 mg/kg methylprednisolone or equivalent). Descriptive analyses of response rate, overall survival (OS), and serious adverse effects (SAEs) were performed. Twenty-nine patients were identified from 7 sites and had received 1-10 doses of IV vedolizumab 300 mg (median 3 doses) as treatment for SR GI aGvHD. The overall response rate at 6-10 weeks after vedolizumab initiation was 64% and OS at 6 months was 54%. There were 29 SAEs including 12 infections; 3 SAEs were considered possibly related to vedolizumab (2 of which were infections). Thirteen SAEs were fatal, 1 of which was possibly vedolizumab-related. There were 8 non-serious infections with confirmed GI origin and 1 serious (in 8 patients); there was no apparent pattern in the timing of these infections relative to the initiation of vedolizumab treatment. Further data on the efficacy and safety of vedolizumab in this setting are required from prospective trials. PMID- 30468920 TI - RNA-binding proteins RBM20 and PTBP1 regulate the alternative splicing of FHOD3. AB - Regulation of alternative splicing events is an essential step required for the expression of functional cytoskeleton and sarcomere proteins in cardiomyocytes. About 3% of idiopathic dilated cardiomyopathy cases present mutations in the RNA binding protein RBM20, a tissue specific regulator of alternative splicing. Transcripts expressed preferentially in skeletal and cardiac muscle, including TTN, CAMK2D, LDB3, LMO7, PDLIM3, RTN4, and RYR2, are RBM20-dependent splice variants. In the present study, we investigated the RBM20 involvement in post transcriptional regulation of splicing variants expressed by Formin homology 2 domain containing 3 (FHOD3) gene. FHOD3 is a sarcomeric protein highly expressed in the cardiac tissue and required for the assembly of the contractile apparatus. Recently, FHOD3 mutations have been found associated with heart diseases. We identified novel FHOD3 splicing variants differentially expressed in human tissues and provided evidences that FHOD3 transcripts are specific RBM20 and PTBP1 targets. Furthermore, we demonstrated that the expression of RBM20 and PTBP1 promoted the alternative shift, from inclusion to exclusion, of selected FHOD3 exons. These results indicate that RBM20 and PTBP1 play a role in the actin filament functional organization mediated by FHOD3 isoforms and suggest their possible involvement in heart diseases. PMID- 30468921 TI - A New Predictive Index for Survival in Symptomatic Spinal Metastases. AB - OBJECTIVE: Patients with spinal metastases have broad variability in morbidity, mortality, and survival. Existing prognostic scoring systems have limited predictive value. Our aim is, given recent advances in surgical and medical care for patients with cancer and spinal metastases, to develop a new survival index with superior prognostic value. METHODS: We completed a retrospective analysis on 77 patients who received surgery for metastatic tumors to the spine, of patient factors like pathological subtype, age, neurological examination, type of surgical procedure, Hauser Ambulation Index (HAI), and a novel scoring system for degree of tumor burden in several organ systems, among others. A survival index will be derived from the patient factors that, when measured pre-intervention, best predicted survival post-intervention. RESULTS: Although primary organ or pathological type was not predictive of survival for patients with metastatic disease in this population, the degree of Lung Tumor Burden (LTB), and pre operative Hauser Ambulation Index were predictive of survival. After a multivariable analysis of more than 20 different patient factors, the Jenkins Survival Index (JSI, a 0-21 scale) was constructed using a machine-learning system as the sum of the HAI (0-9 scale) and the LTB score (0-3 scale) multiplied by four [JSI=HAI+4*LTB], (Rho=-0.588, P<0.0001). The JSI had a positive predictive value of 92.0% compared to 54.1% and 56.9% for Tokuhashi and Tomita scales respectively. CONCLUSIONS: The JSI predicts in a meaningful way survival outcomes for patients symptomatic from spinal metastases, which will be of value to oncologists and other clinicians treating patients with metastatic disease. PMID- 30468922 TI - Large intradural tympano-jugular paragangliomas. A contribution on surgery and management. AB - OBJECTIVE: Large intradural growth of tympano-jugular paragangliomas (TJ-PGs) into the cerebellopontine angle is an infrequent condition that can determine an extensive involvement of vessels and brainstem, representing a surgical challenge. The current classifications lack in accuracy for defining large intradural TJ-PGs and assessing their operability. This study aims at retrospectively reappraising the management of our large intradural TJ-PGs surgical series, discussing operability criteria, treatment strategies and resection techniques. METHODS: Over a series of 63 class D TJ-PGs operated on between 1973 and 2008, patients with large intradural tumors were retrospectively reviewed. Surgical techniques and outcomes with long-term follow-up were analyzed. RESULTS: Seven patients presented large intradural tumors, ranging from 4 cm to 5.5 cm in diameter. These cases were treated either via petro-occipital trans-sigmoid approach in a single-stage resection (4 patients) or via petro occipital approach as a second-stage surgery after a previous infratemporal fossa approach on the extradural tumor (3 patients). Complete tumor resection was obtained in 5 cases through wide removal of the petro-occipital skull base and exposure of the dural root of the tumor which carries its main blood supply and allows preemptive hemostasis. No new postoperative cranial nerve losses were observed. The surgical procedure aborted in two cases because of cerebellar edema and carotid artery tear, respectively. CONCLUSIONS: Large intradural TJ-PGs can be effectively surgically managed with appropriate technique combined with relevant non-surgical strategies. Thus, operability criteria for these lesions can be extended. To share objective experience on large intradural TJ-PGs, a redefinition Di3 tumors is recalled. PMID- 30468923 TI - Use of hematocrit for short-term prognosis of traumatic brain injury patients post decompressive craniectomy. AB - OBJECTIVE: To discuss the effects of the hematocrit in traumatic brain injury patients post decompressive craniectomy. METHODS: Demographic data, inspection and treatment procedures, and 30-day prognosis were obtained for 158 head-injured patients who underwent unilateral decompressive craniectomy in our hospital between January 2013 and June 2018. Univariate and multivariate logistic regression was applied to analyze independent risk factors for 30-day outcome. The quantitative analysis of postoperative Hct, DeltaHct (postoperative Hct minus initial Hct) and their combination for the prognosis of TBI patients were displayed graphically using ROC curves. Multiple linear regression was used to explore factors influencing postoperative and DeltaHct. RESULTS: The short-term mortality was 29.7%. Univariate and multivariate logistic regression analysis showed that age (OR 1.064, p = 0.024), GCS score (OR 0.711, p=0.027), ISS score (OR 1.156, p = 0.047), midline shift in mm (OR 1.809, p <0.001), postoperative Hct (OR 0.743, p=0.001) and DeltaHct (OR 1.242, p =0.048) were independent risk factors for short-term death. In ROC curves, a combination of postoperative Hct and DeltaHct showed the highest sensitivity (77.5%) and highest specificity (89.4%). When using this combination to predict prognosis, we could achieve an accuracy of 94.5%. ISS score (beta=-0.172, p=0.022), initial Hct (beta=0.243, p =0.001), prinical hematoma location (beta=-2.628, p <0.001), hours of operation (beta=-0.884, p=0.048), and colloid quantity (beta=-0.002, p=0.001) were independent contributing factors for the DeltaHct, which was similar to the postoperative Hct. CONCLUSION: A combination of postoperative Hct and DeltaHct could better predict short-term survival of TBI patients. Developing an appropriate treatment strategy to increase postoperative Hct and reduce the change of the Hct, may be good to the short-term prognosis for TBI patients post DC. PMID- 30468924 TI - Pineal cyst related aqueductal stenosis as a cause of intractable headaches in non-hydrocephalic patients. AB - BACKGROUND: Pineal cysts (PCs) are histologically benign lesions of the pineal gland. Although the majority of PCs are asymptomatic, some cases are ambiguous and accompanied by non-specific symptoms of variable severity. We suggested that disabling headache in non-hydrocephalic patients with PCs is associated with cerebral aqueduct (CAq) stenosis. METHODS: A retrospective analysis was conducted in patients with PCs suffering from headache without secondary hydrocephalus who underwent surgical resection at Burdenko Neurosurgery Center between 1995 and 2016. All available medical records and radiographic images were retrospectively assessed in these patients. The comparison groups included 22 patients with non operated PCs and 25 healthy individuals. The specific MRI measures were selected to assess morphometry of the CAq and the degree of the stenosis. RESULTS: In Twenty-five patients (82%) we observed clinical improvement after surgery in a follow-up period. Among those with improvement, 10 (40%) experienced total relief and 15 (60%) - marked headache diminishment. In five patients headache remained persistent. The preoperative rostral CAq diameter appeared to be significantly more narrow (p = 0.0011045) and the preoperative rostral/caudal diameter ratio (Rd/Cd) was found to be lower (p = 0.004391) in patients who recovered from headache versus those who did not. CONCLUSION: The results indicate a statistically significant relationship between the changes in the CAq morphometrics and the clinical outcome in postoperative period. Surgical removal of symptomatic pineal cysts in patients without hydrocephalus can be considered as an effective treatment. However, a thorough preoperative examination and patient selection should be conducted in every case. PMID- 30468925 TI - Gamma knife radiosurgery for metastatic brain tumors from cancer of unknown primary. AB - OBJECTIVE: We retrospectively analyzed treatment efficacy and identified prognostic factors impacting tumor control and survival in patients with brain metastases from cancer of unknown primary (CUP) treated with gamma knife radiosurgery (GKRS). METHODS: We retrospectively reviewed the medical records of 87 patients with 520 tumors who underwent GKRS for brain metastases from CUP. RESULTS: Median overall survival time after initial GKRS was 6 months. The 6 month and 12-month overall survival rates were 79.3% and 14.9%, respectively. High age (p = 0.002), lower Karnofsky performance status score (p=0.026), extracranial metastases (p=0.013), and multiple brain metastases (p=0.007) were significantly correlated with shorter survival periods. The 6-month and 12-month neurological death rates were 25.3% and 32.2%, respectively. The 6-month and 12 month neurological deterioration rates were 24.1% and 27.6%, respectively. The 6 month and 12-month distant brain control failure rates were 21.8% and 24.1%, respectively. Median tumor volume was 1.7 cm3. The median marginal prescription dose was 18 Gy. The 6-month and 12-month tumor recurrence rates were 5.1% and 15.7%, respectively. Larger tumor volume (p<0.0001) and lower prescription dose (p=0.001) were significantly correlated with local tumor control failure. Seven patients had symptomatic radiation injury. The 6-month and 12-month GKRS-related complication rates were both 6.9%. CONCLUSIONS: The present findings suggest that GKRS is a relatively effective and safe treatment for control of tumor progression in patients with brain metastases from CUP. Overall and neurological survivals were short, but we recommend GKRS treatment to prevent early neurological dysfunction and death in patients with CUP. PMID- 30468926 TI - Clinical outcomes of atlantoaxial dislocation combined with high-riding vertebral artery using C-2 translaminar screws. AB - OBJECTIVE: Atlantoaxial stabilization procedure in high riding of vertebral artery (HRVA) cases is challenging. C-2 translaminar screws (TLS) are reportedly rigid and pose no risk to the VA. We would like to present the clinical outcomes of atlantoaxial dislocation(AAD) combined with HRVA using C-2 TLS. METHODS: Cases of AAD combined with HRVA surgically treated in our institution from 2007 to 2015 were retrospectively reviewed. The atlantodental interval (ADI) and clivus-axial angle (CAA) were measured. We utilized the Japanese Orthopedic Association (JOA) scale to evaluate neurologic status. RESULTS: Fifty-eight patients were enrolled: 15 with instability and 43 with dislocation, 13 of which were irreducible. The incidence of bilateral HRVA was 5.2%. C1-2 fixation was performed in 26 cases, ADI decreases from 9.9+/-3.7 to 1.0+/-1.7(P < 0.05). C0-2 fixation was performed in 32 cases, CAA increases from 125+/-13 degrees to 150+/-15 degrees (P < 0.05). The pre- and postoperative JOA scores of 56 patients with myelopathy were 11.9 +/- 2.8 and 14.6 +/- 2.4, respectively (P < 0.05). The fusion rate was 93.1% (54/58), while that at 4-months follow-up was 81% (47/58). 14 cases of re dislocation achieved final fusion, of them, three required an odontoidectomy. Four cases lacking bony fusion also required revision surgery. The re-dislocation rate was 31% (18/58) and the reoperation rate was 12.1% (7/58). CONCLUSIONS: The surgical results of C-2 TLS are unsatisfactory, with a high re-dislocation rate and reoperation rate in AAD cases, new treatment methods should be investigated to facilitate clinical outcomes, extending fixed segment should be considered. PMID- 30468927 TI - Comparison of Endovascular Embolization and Surgery in the Treatment of Spinal Intradural Dorsal Arteriovenous Fistulae. AB - OBJECTIVES: To compare the outcomes of endovascular embolization and surgery, and to investigate factors affecting clinical outcomes of spinal intradural dorsal arteriovenous fistulas (SIDAVFs). METHODS: The medical records of 26 patients who underwent endovascular embolization or surgery for SIDAVF between 2004 and 2014 were retrospectively reviewed. Recurrence rate and clinical outcome of each treatment modality were compared. Multivariate analysis was used to identify significant factors influencing clinical outcome using Aminoff and Logue (AL) score. RESULTS: Fourteen of 26 patients (56%) underwent endovascular embolization and eleven patients (44%) underwent surgery as the primary treatment. Embolization was applied as initial treatment in most cases. Surgery was adopted in patients with difficult superselection (n=5), multiple feeders (n=2) or easy surgical accessibility (n=4). Of 14 patients who underwent embolization as the primary treatment, 5 (36%) showed recurrence within an average of 29.6 (2-87) months. One patient with recurrent SIDAVF was treated with re-embolization and four patients underwent surgery. None of patients in surgical group showed any recurrence. Embolization as the primary treatment showed significantly higher recurrence than surgery (odds ratio=2.222, 95% confidence interval 1.369-3.608, p=0.046). Surgery demonstrated better clinical outcome than embolization (p=0.021). Final AL score was strongly affected by the preoperative AL score, micturition score, and recurrence (p=0.000, p=0.000, and p=0.011, respectively). CONCLUSIONS: Our study demonstrated that surgery had a low recurrence rate and superior clinical outcome. The multidisciplinary and ordered decision is crucial for the choice of treatment to ensure better outcome, especially in patients with the definite neurologic deficit at diagnosis. PMID- 30468928 TI - Thromboembolic Events With Enterprise Versus Pipeline: A Porcine In Vivo Experiment. PMID- 30468929 TI - Risk factors and Associated Complications with Symptomatic Venous Thromboembolism in Patients with Craniotomy for Meningioma. AB - OBJECTIVE: Patients undergoing surgical resection of meningioma are at increased risk for developing venous thromboembolism (VTE). The primary aim of this study was to assess the occurrence of VTE in patients who underwent surgery to remove their meningioma, and to determine the risk factors and associated complications with VTE. METHODS: The American College of Surgeons(ACS) National Surgical Quality Improvement Project (NSQIP) database from 2012-2015 was reviewed for patients who had undergone meningioma resection according to their primary Current Procedural Terminology codes and International Classification of Diseases, Ninth Revision. RESULTS: 5036 meningioma patients were included in this study. The rate of VTE in this cohort was 3.38%, with pulmonary embolism (PE) being 1.47%, and 2.42% for deep vein thrombosis (DVT). During the first 30 days following surgery, patients with VTE had a mortality rate of 5.88% compared to only 1.15% for patients without VTE. Multivariate binary logistic regression analysis determined 5 risk factors for VTE, including age >= 60 years, American Society of Anesthesiologists(ASA) classification of 3, operative time >=310 minutes, ventilator dependence and pre-operative transfusions. Univariate analysis revealed a number of occurrence complications significantly associated with VTE, including unplanned intubation, ventilator > 48 hours, stroke, sepsis, septic shock, pneumonia, urinary tract infection(UTI) and transfusions. CONCLUSIONS: Risk factors for VTE and associated complications were identified. Understanding these risk factors provides physicians with further insight in managing this subgroup of patients in a personalized fashion in the perioperative period to minimize the incidence and morbidity of VTE. PMID- 30468930 TI - Endoscopic endonasal vs. transorbital surgery for middle cranial fossa tumors: Comparison of clinical outcomes based on surgical corridors. AB - BACKGROUND: Based on our experience with the endoscopic endonasal approach (EEA) and transorbital approach (TOA) for middle cranial fossa tumors, we evaluated the efficacy and limitations of visualization and the clinical outcomes associated with the approaches depending on the surgical corridors. Additionally, we determined the optimal strategy for each approach. METHODS: Between September 2015 and May 2018, we retrospectively reviewed clinical outcomes in 21 patients who underwent minimally invasive endoscopic surgery for middle cranial fossa tumors involving the cavernous sinus. We classified the endoscopic approaches into 4 groups: endonasal quadrangular transcavernous (type I), endonasal infratemporal (type II), transclival medial-to-lateral (type III), and transorbital (type IV) routes. Displacement of the internal carotid artery, extent of tumor involvement, and the surgical corridor to the tumor direction were the primary determinants of the approach. RESULTS: The study enrolled 21 patients. Based on the classification of approaches, 6 patients underwent surgery via type I, 5 via type II, 1 via type III, 7 via type IV, and 2 via a combined approach. Among the 21 patients, gross total resection (GTR) was performed in 12 (57.1%), subtotal resection in 6, and partial resection in 3. Comparison of the type I (EEA) with the type 4 (TOA) route showed that the GTR rate with the EEA was 33.3% compared to 71.4% with the TOA (p=0.286). CONCLUSIONS: Endoscopic surgery can be considered an alternative with acceptable sequelae and reduced morbidity for the management of middle cranial fossa tumors. Surgeons should be aware of the strengths and weaknesses of each surgical corridor and select the optimal approach for each patient based on the tumor. PMID- 30468931 TI - Cyclical Hypersensitivity, Anaphylaxis and Related Hormonal Reaction. PMID- 30468932 TI - Title: Where does worsening asthma end and an asthma exacerbation begin? PMID- 30468933 TI - Sweet taste perception is greater in non-Hispanic black than in non-Hispanic white adults. AB - OBJECTIVE: Research suggests a difference in sweet taste perception between non Hispanic black (NHB) and non-Hispanic white (NHW) adults; however, limited research has examined sweet taste perception in relation to the dietary intake of sweet products. The aim of this study was to examine sweet taste perception and the consumption of sweet foods, beverages, and sugar in NHB and NHW adults, and to evaluate whether sweet taste perception is associated with dietary intake. METHODS: This cross-sectional study examined the association between race, sweet taste perception and sweet food, beverages, and sugar consumption in healthy, NHB and NHW adults. Seven day food records were analyzed in Nutrition Data System for Research software. Intensity of sweet taste perception was tested and the general labeled magnitude scale method was used to facilitate group comparisons. Independent t tests, Mann-Whitney tests, and Pearson correlations were used to assess associations. RESULTS: Participants were NHB (n = 98) and NHW (n = 90) adults, 41 +/- 1 y of age (mean +/- SEM) with energy intake of 2271 +/- 53 kcal. Body mass index was higher in NHBs than in NHWs (36 +/- 1 versus 32 +/- 1 kg/m2, P = 0.048), but no differences were observed in age, energy consumption, or total sugar intake. Sweet taste perception rating (median [interquartile range] NHB: 73.5 [63.9-83], NHW: 52.1 [46.4-57.7]; P = 0.001) and added sugar intake (NHB: 39.4 g/1000 kcal [36.3-42.4], NHW: 30 g/1000 kcal [26.7-33.4]; P < 0.001) were greater in NHB. Perceived sweet taste intensity was positively associated with consumption of servings of sweet products among NHBs (R2 = 0.057, P = 0.018) but not NHWs (R2 = -0.012, P = 0.314). CONCLUSIONS: NHBs have a higher intensity of sweet taste perception than NHWs. The positive association of sweet taste perception and sweet product consumption in NHBs suggests that a higher intensity of sweet taste perception may be associated with an increased proportion of energy consumption from added sugars. PMID- 30468934 TI - Body composition and bone mineral density in Huntington's disease. AB - OBJECTIVE: Understanding the body composition (BC) of patients with Huntington's disease (HD) could help to delay disease progression and improve treatment efficacy. The aim of this study was to assess BC parameters, including bone mineral density (BMD), and to find new biomarkers that can be early indicators for weight loss in patients with HD. METHODS: Twenty-one age- and sex-matched patients with HD and 29 healthy controls (CT) were enrolled. For each patient, body weight (BW), height, and body mass index (BMI) were evaluated. BC and BMD were measured by dual-energy x-ray absorptiometry. Subsamples were created according to sex and percent fat mass (FM) (obese and nonobese). All analyses were carried out using SPSS version 23. RESULTS: In all comparisons, BMD and T score were lower in the HD group, but were not correlated with lean body mass (LBM) or FM. In the HD group, LBM and truncal fat were mostly reduced, except in women with HD whose BC appeared to be less affected by the disease than men. Furthermore, LBM (r = 0.80) and truncal fat (r = 0.68) were better correlated with BW than BMI (r = 0.56). CONCLUSION: Complete BC assessment can be crucial for preventive interventions and prognosis definition in patients with HD. New biomarkers such as BMD, LBM, and truncal fat can be early indicators of weight loss in patients with HD. PMID- 30468935 TI - Plasma fatty acids: Biomarkers of dietary intake? AB - OBJECTIVE: To our knowledge, there is currently no consensus in the literature on the association between dietary fatty acids and circulating levels in plasma. The aim of this study was to assess the association of the intake of fatty acids with their relative plasma concentrations. METHODS: We conducted a study with 300 adults from the population-based health survey in Sao Paulo city (ISA-Capital 2008). We assessed demographic, lifestyle and anthropometric data, biochemical measurements, and two 24-h dietary recalls collected on non-consecutive days. Intake distribution was adjusted for intrapersonal variance to give usual dietary intake using the multiple source method (MSM). Percentage of fatty acids in plasma were analyzed by gas chromatography. The kappa statistic, Spearman's correlation, and multiple linear regression (adjusted for confounders) and ratio limits of agreement were employed to determine the relationship between plasma and dietary measurements. RESULTS: Low correlation and agreement were found between dietary and plasma fatty acids. Docosahexaenoic acid (beta = 0.25; P < 0.001) and saturated (beta = 0.19; P = 0.048) fatty acids exhibited an association for means of intake adjusted by the MSM and for confounding variables. A large mean difference, with a large variation of "ratio limits," were observed between the measurements. CONCLUSION: Plasma and dietary polyunsaturated and saturated fatty acids exhibited low correlation and agreement, as well as weak association between each other. No association between intake and plasma concentrations of monounsaturated fat was found. Plasma fatty acids are not good biomarkers of food intake. PMID- 30468936 TI - Efficacy of perioperative immunonutrition in esophageal cancer patients undergoing esophagectomy. AB - OBJECTIVE: Malnutrition is common in patients with esophageal cancer, resulting in increased postoperative complications and mortality. Although preoperative immunonutrition can significantly reduce the incidence of postoperative infectious complications, its effect in patietns with esophageal cancer undergoing esophagectomy remains unclear. The aim of this study was to investigate the effects of perioperative immunonutritional support on the postoperative course and long-term survival of this group of patients. METHODS: This prospective, randomized study enrolled 40 patients with thoracic esophageal carcinoma undergoing esophagectomy. The patients were divided into two groups and received either immunomodulating enteral nutrition (IMPACT group; IG) or standard enteral nutrition (Ensure group; EG) continuously for 7 d before and 7 d after surgery. Nutritional status, such as rapid turnover protein, postoperative intensive care unit (ICU) length of stay (LOS), postoperative hospital LOS, morbidity, and mortality were investigated prospectively. RESULTS: There were no significant differences in patient demographic characteristics between the two groups. Levels of retinol-binding protein, as a rapid-turnover protein, were significantly higher on postoperative day (POD) -1, 7, and 14 in the IG compared with the EG group (P = 0.009, P = 0.004, and P = 0.024, respectively). The incidence of postoperative infectious complications and changes to therapeutic antibiotics were significantly lower in the IG group than in the EG group (P = 0.048 and P = 0.012, respectively). There was no significant difference in postoperative ICU or postoperative hospital LOS between the two groups. The 5-y progression-free survival rates in the IG and EG groups were 75% and 64%, respectively (P = 0.188), and the overall survival rates were 68% and 55%, respectively (P = 0.187). CONCLUSIONS: Perioperative immunonutrition may improve early postoperative nutritional status and reduce postoperative infectious complications in patients with esophageal cancer undergoing esophagectomy. PMID- 30468937 TI - A comprehensive review of the current evidence for trabectedin in advanced myxoid liposarcoma. AB - Myxoid liposarcoma (MLS) is a rare mesenchymal tumor that constitutes 10-20% of all liposarcomas. MLS is a translocation-related sarcoma (TRS) related to the chromosomal translocation t(12:16) (q13:p11), producing the FUS-CHOP oncoprotein that constitutes one of the main targets of trabectedin in MLS patients. It is known to be chemosensitive namely to trabectedin in contrast to other soft tissue sarcomas. The efficacy of this agent in MLS have been demonstrated in different settings including treatment-naive and pre-treated patients with both locally advanced and metastatic disease. However, the benefits of trabectedin in MLS are shadowed by the limited activity of this drug in other subtypes of sarcomas that are enrolled within the same trials. This prompted us to screen the medical literature for clinical data that evaluates the efficacy and safety of trabectedin in MLS. In this review, we will summarize the available evidence for the applicability of trabectedin in MLS. PMID- 30468938 TI - Virome biogeography in the lower gastrointestinal tract of rhesus macaques with chronic diarrhea. AB - The composition of gastrointestinal tract viromes has been associated with multiple diseases. Our understanding of virus communities in the GI tract is still very limited due to challenges in sampling from different GI sites. Here we defined the GI viromes of 15 rhesus macaques with chronic diarrhea. Luminal content samples from terminal ileum, proximal and distal colon were collected at necropsy while samples from the rectum were collected antemortem using a fecal loop. The composition of and ecological parameters associated with the terminal ileum virome were distinct from the colon and rectum samples; these differences were driven by bacteriophages rather than eukaryotic viruses. The six contigs that were most discriminative of the viromes were distantly related to bacteriophages from three different families. Our analysis provides support for using fecal loop sampling of the rectum as a proxy of the colonic virome in humans. PMID- 30468939 TI - Species delimitation in the presence of strong incomplete lineage sorting and hybridization: Lessons from Ophioderma (Ophiuroidea: Echinodermata). AB - Accurate species delimitation is essential to properly assess biodiversity, but also for management and conservation purposes. Yet, it is not always trivial to accurately define species boundaries in closely related species due to incomplete lineage sorting. Additional difficulties may be caused by hybridization, now evidenced as a frequent phenomenon. The brittle star cryptic species complex Ophioderma longicauda encompasses six mitochondrial lineages, including broadcast spawners and internal brooders, yet the actual species boundaries are unknown. Here, we combined three methods to delimit species in the Ophioderma longicauda complex and to infer its divergence history: (i) unsupervised species discovery based on multilocus genotypes; (ii) divergence time estimation using the multi species coalescent; (iii) divergence scenario testing (including gene flow) using Approximate Bayesian Computation (ABC) methods. 30 sequence markers (transcriptome-based, mitochondrial or non-coding) for 89 O. longicauda and outgroup individuals were used. First, multivariate analyses revealed six genetic clusters, which globally corresponded to the mitochondrial lineages, yet with many exceptions, suggesting ancient hybridization events and challenging traditional mitochondrial barcoding approaches. Second, multi-species coalescent based analyses confirmed the occurrence of six species and provided divergence time estimates, but the sole use of this method failed to accurately delimit species, highlighting the power of multilocus genotype clustering to delimit recently diverged species. Finally, Approximate Bayesian Computation showed that the most likely scenario involves hybridization between brooders and broadcasters. Our study shows that despite strong incomplete lineage sorting and past hybridization, accurate species delimitation in Ophioderma was possible using a combination of complementary methods. We propose that these methods, especially multilocus genotype clustering, may be useful to resolve other complex speciation histories. PMID- 30468940 TI - Phylogeographic and diversification patterns of the white-nosed coati (Nasua narica): Evidence for south-to-north colonization of North America. AB - White-nosed coatis (Nasua narica) are widely distributed throughout North, Central, and South America, but the patterns of temporal and spatial diversification that have contributed to this distribution are unknown. In addition, the biogeographic history of procyonid species in the Americas remains contentious. Using sequences from three mitochondrial loci (Cytochrome b, NAHD5 and 16S rRNA; 2201 bp) and genotypes from 11 microsatellite loci, we analyzed genetic diversity to determine phylogeographic patterns, genetic structure, divergence times, and gene flow among Nasua narica populations throughout the majority of the species' range. We also estimated the ancestral geographic range of N. narica and other procyonid species. We found a high degree of genetic structure and divergence among populations that conform to five evolutionarily significant units. The most southerly distributed population (Panama) branched off much earlier (~3.8 million years ago) than the northern populations (<1.2 million years ago). Estimated gene flow among populations was low and mostly northwards and westwards. The phylogeographic patterns within N. narica are associated with geographic barriers and habitat shifts likely caused by Pliocene Pleistocene climate oscillations. Significantly, our findings suggest the dispersal of N. narica was south-to-north beginning in the Pliocene, not in the opposite direction during the Pleistocene as suggested by the fossil record, and that the most recent common ancestor for coati species was most likely distributed in South or Central America six million years ago. Our study implies the possibility that the diversification of Nasua species, and other extant procyonid lineages, may have occurred in South America. PMID- 30468941 TI - Phylogeny of the beetle supertribe Trechitae (Coleoptera: Carabidae): Unexpected clades, isolated lineages, and morphological convergence. AB - Using data from two nuclear ribosomal genes and four nuclear protein-coding genes, we infer a well-resolved phylogeny of major lineages of the carabid beetle supertribe Trechitae, based upon a sampling of 259 species. Patrobini is the sister group of Trechitae, but the genus Lissopogonus appears to be outside of the Patrobini + Trechitae clade. We find that four enigmatic trechite genera from the Southern Hemisphere, Bembidarenas, Argentinatachoides, Andinodontis, and Tasmanitachoides, form a clade that is the sister group of Trechini; we describe this clade as a new tribe, Bembidarenini. Bembidarenini + Trechini form the sister group of remaining trechites. Within Trechini, subtribe Trechodina is not monophyletic, as three trechodine genera from Australia (Trechobembix, Paratrechodes, Cyphotrechodes) are the sister group of subtribe Trechina. Trechini appears to have originated in the continents of the Southern Hemisphere, with almost all Northern Hemisphere lineages representing a single radiation within the subtribe Trechina. We present moderate evidence that the geographically and phylogenetically isolated genera Sinozolus (six species in the mountains of China), Chaltenia (one species in Argentina and Chile), and Phrypeus (one species in western North America) also form a clade, the tribe Sinozolini. The traditionally recognized tribe Bembidiini sens. lat., diagnosed by the presence of a subulate terminal palpomere, is shown to be polyphyletic; subulate palpomeres have arisen five times within Trechitae. Anillini is monophyletic, and the sister group of Tachyini + Pogonini + Bembidiini + Zolini + Sinozolini; within anillines, we confirm earlier results indicating the eyed New Zealand genus Nesamblyops as the sister to the rest. Sampled New World Pogonini are monophyletic, rendering the genus Pogonus non-monophyletic. Tachyina and Xystosomina are sister groups. Within Xystosomina, the New World members are monophyletic, and are sister to an Australia-New Zealand clade. The latter consists of the genus Philipis as well as taxa not previously recognized as xystosomines: Kiwitachys, the "Tachys" ectromioides group, and "Tachys" mulwalensis. Within Tachyina, the subgenus Elaphropus is not closely related to other subgenera previously placed in the genus Elaphropus; we move the other subgenera into the genus Tachyura. Tachyina with a bifoveate mentum do not form a clade; in fact, a bifoveate mentum is found in Xystosomina, Sinozolini, Trechini, Trechitae and its sister group, Patrobini. Extensive homoplasy in the morphological characters previously used as key indicators of relationship is supported by our results: in addition to multiple origins of subulate palpomeres and bifoveate menta, a concave protibial notch has arisen independently in Anillina, Xystosomina, and Tachyina. Phylogenetically and geographically isolated, species-poor lineages in Trechini, Bembidarenini, and Sinozolini may be relicts of more widespread faunas; many of these are found today on gravel or sand shores of creeks and rivers, which may be an ancestral habitat for portions of Trechitae. In addition to the description of Bembidarenini, we present a diagnosis of the newly delimited Sinozolini, and keys to the tribes of Trechitae. PMID- 30468942 TI - Improving innovative decision-making: Training-induced changes in fronto-parietal networks. AB - Innovative decision-making entails the balance of exploitative and explorative choices, and has been linked to the efficiency of executive functioning, including working-memory and attentional skills, associated with fronto-parietal networks. Based on the notion that such skills can be improved by cognitive training, we assessed whether a cognitive training enhancing basic executive skills might also improve the ability to manage the exploration-exploitation trade-off and its financial consequences, and whether any improvement in training related performance would be reflected in neurostructural changes within fronto parietal networks. Eighteen subjects participated in a baseline assessment, a training period and a follow-up measurement, while a matched group of 18 subjects did not undertake the training program. A subgroup of subjects underwent a multimodal MRI study to explore training-related changes in grey-matter volume and white-matter microstructure. After training, increased efficiency of innovative decision-making, related to the improvement of executive control skills, reflected neurostructural changes involving the right fronto-polar cortex and left superior longitudinal fasciculus. The quality of innovative decision making can be improved by ad-hoc cognitive training procedures focused on executive skills, promoting neurostructural changes in fronto-parietal networks. The manifold implications involve both managerial and rehabilitative settings concerned with the quality of choices in normal and pathological conditions, respectively. PMID- 30468943 TI - Photocytotoxic copper(II) complexes of N-salicylyl-l-tryptophan and phenanthroline bases. AB - Four ternary copper(II) complexes of N-salicylyl-l-Tryptophan (Sal-TrpH) and phenanthroline bases of general formula [Cu(Sal-Trp)(L)], where L is 1,10 phenanthroline (phen, 1), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 2), dipyrido[3,2-a:2',3'-c]phenazine (dppz, 3) and 2-(anthracen-1-yl)-1H-imidazo[4,5 f][1,10]phenanthroline (aip, 4), were synthesized and fully characterized. The complexes were evaluated for their affinity for biomolecules and photocytotoxic activities. Single crystal X-ray diffraction studies of complex 1 revealed that it has a square pyramidal CuN3O2 core with the phenolate oxygen of salicylaldehyde occupying the axial coordination site in the solid state. Complexes 1-4 displayed the Cu(II)-Cu(I) redox couples at ~-0.3 V vs. Ag/AgCl reference electrode in DMF-0.1 M [Bun4N](ClO4). A Cu(II)-based weak d-d band ~650 nm and a moderately strong ligand to metal charge transfer band at ~430 nm were observed in DMF-Tris-HCl buffer (pH 7.2) (1:4 v/v). The complexes are efficient binders to calf thymus DNA and model proteins such as bovine serum albumin and lysozyme. They cleave supercoiled plasmid DNA efficiently when exposed to 446 and 660 nm laser radiation. They are cytotoxic to HeLa (human cervical cancer) and MCF-7 (human breast cancer) cells showing significant enhancement of cytotoxicity upon photo-excitation with low energy visible light. The complexes are found to kill cancer cells through generation of reactive oxygen species (ROS) as confirmed by DCFDA (2',7'-dichlorofluorescin diacetate) assay. The apoptotic cell death induced by complex 4 was confirmed by Annexin V-Fluorescein isothiocyanate Propidium iodide assay. Confocal microscopic images using 4 showed its primary cytosolic localization in the HeLa and MCF-7 cells. PMID- 30468944 TI - Interaction of amylin species with transition metals and membranes. AB - Islet Amyloid Polypeptide (IAPP), also known as amylin, is a 37-amino-acid peptide hormone that is secreted by pancreatic islet beta-cells. Amylin is complementary to insulin in regulating and maintaining blood glucose levels in the human body. The misfolding and aggregation of amylin is primarily associated with type 2 diabetes mellitus, which is classified as an amyloid disease. Recently, the interactions between amylin and specific metal ions, e.g., copper(II), zinc(II), and iron(II), were found to impact its performance and aggregation processes. Therefore, the focus in this review will be on how the chemistry and structural properties of amylin are affected by these interactions. In addition, the impact of amylin and other amyloidogenic peptides interacting with metal ions on the cell membranes is discussed. In particular, recent studies on the interactions of amylin with copper, zinc, iron, nickel, gold, ruthenium, and vanadium are discussed. PMID- 30468945 TI - Beyond depression: The impact of executive functioning on quality of life in patients with temporal lobe epilepsy. AB - OBJECTIVE: Individuals with temporal lobe epilepsy (TLE) often experience diminished quality of life (QoL). Although comorbid depression is one of the most recognized predictors of poor QoL in TLE, impairments in verbal memory (VM) and executive functioning (EF), have also been identified as risk factors, independent of other biological and psychosocial factors. In this study, we examine the contribution of depression, VM, and EF to QoL in 52 well characterized medically-refractory TLE patients. METHODS: Quality of life was assessed with the Quality of Life in Epilepsy (QOLIE-31) questionnaire and depression symptomatology was evaluated with the Beck Depression Inventory-II (BDI-II). Tests of VM included the California Verbal Learning Test-Second Edition and the Wechsler Memory Scale-Third Edition, Logical Memory and Verbal Paired Associates subtests. Tests of EF included the D-KEFS Category Switching and Color Word Interference Tests, and the Trail Making Test. Using these measures, a principal component (PC) was derived for VM and for EF. Hierarchical multiple linear regression analysis was used to evaluate the unique contributions of BDI II Score, VM PC, and EF PC to the QOLIE-31 Total Score, while controlling for important clinical and demographic variables. Post-hoc analyses were also performed to examine the contribution of each variable to specific QOLIE subscales. RESULTS: Of the clinical variables, only number of antiepileptic drugs contributed to QOLIE scores. As expected, severity of depressive symptoms was the most significant predictor of QOLIE Total Score, explaining 43.4% of the variance in total QoL. The VM PC did not contribute to the QOLIE Total Score. Rather, our EF PC emerged as an important predictor of QoL, explaining an additional 5% of the variance, after controlling for clinical variables, depression severity, and VM performance. SIGNIFICANCE: These findings suggest that a combination of clinical, affective, and cognitive factors influence QoL in patients with TLE. Designing interventions with careful attention to depression and EF may be needed to optimize QoL in patients with refractory TLE and potentially other epilepsy syndromes. PMID- 30468946 TI - Efficient first principles simulation of electron scattering factors for transmission electron microscopy. AB - Electron microscopy is a powerful tool for studying the properties of materials down to their atomic structure. In many cases, the quantitative interpretation of images requires simulations based on atomistic structure models. These typically use the independent atom approximation that neglects bonding effects, which may, however, be measurable and of physical interest. Since all electrons and the nuclear cores contribute to the scattering potential, simulations that go beyond this approximation have relied on computationally highly demanding all-electron calculations. Here, we describe a new method to generate ab initio electrostatic potentials when describing the core electrons by projector functions. Combined with an interface to quantitative image simulations, this implementation enables an easy and fast means to model electron scattering. We compare simulated transmission electron microscopy images and diffraction patterns to experimental data, showing an accuracy equivalent to earlier all-electron calculations at a much lower computational cost. PMID- 30468947 TI - Assessment of the disaster medical response system through an investigation of a 43-vehicle mass collision on Jung-ang expressway. AB - PURPOSE: It was considered the challenges of the actual response and the potential for improvement, including the activities of the disaster response system, national emergency medical center, and the regional base hospital for the treatment of multiple traffic accident victims. The purpose of this study was to analyze the accident management system through real investigating the multiple collision over 10 vehicles with mass casualty events as a disaster situation. METHODS: This study was retrospective study to analyze the disaster event with multiple collision traffic accident on the expressway in Korea. We visited five medical centers for eight days since the accident occurred and interviewed the injured patients in this accident to examine the health status and medical records. After that, we visited the sixteen car-repair shops in four cities for real investigate about damaged vehicles. According to the arrangement of the accident situation for the accident vehicles through real-world investigation, we reproduced all parts of the accident scene, which were real-world investigated, by the accident situation sketch program. The collected data were summarized by Collision Deformation Classification (CDC) codes, and the medical records of the occupants were assessed using the Injury Severity Score (ISS). RESULTS: The cause of the accident was snow freezing of the road. The information about 72 injured patients on 31 damaged vehicles was collected by phone, visit, and actual accident investigation. Of the 72 patients who were examined, 4 were severely injured and 68 were mildly injured. The accident occurred in the order of Sedan 13 (41.9%), SUV 11 (35.5%), Truck 4 (12.9%), Van 2 (6.5%) and Bus 1 (3.2%). The median value of the age [lower quartile and upper quartile] was 43 [34.5-52] years old and the patients included 25 drivers, 11 passengers, 7 back seat passengers, and 29 bus passengers. CONCLUSION: The primary cause of this mass collision accident was road surface freezing, but the more serious secondary cause was a driver's inability to avoid the accident scene after the first collision. The severely injured occupants were occurred on the roads outside and inside the vehicle. In the event of a disaster, various teams from the police team, firefighting team, DMAT, EMS, road management team are gathered, and communication and command system between each team is important in order to identify and solve the disaster situation. To do this, it is important to develop manuals and prepare for training through repeated simulations. PMID- 30468948 TI - A meta-analysis of the crash risk of cannabis-positive drivers in culpability studies-Avoiding interpretational bias. AB - BACKGROUND: Culpability studies, a common study design in the cannabis crash risk literature, typically report odds-ratios (OR) indicating the raised risks of a culpable accident. This parameter is of unclear policy relevance, and is frequently misinterpreted as an estimate of the increased crash risk, a practice that introduces a substantial "interpretational bias". METHODS: A Bayesian statistical model for culpability study counts is developed to provide inference for both culpable and total crash risks, with a hierarchical effect specification to allow for meta-analysis across studies with potentially heterogeneous risk parameter values. The model is assessed in a bootstrap study and applied to data from 13 published culpability studies. RESULTS: The model outperforms the culpability OR in bootstrap analyses. Used on actual study data, the average increase in crash risk is estimated at 1.28 (1.16-1.40). The pooled increased risk of a culpable crash is estimated as 1.42 (95% credibility interval 1.11 1.75), which is similar to pooled estimates using traditional ORs (1.46, 95% CI: 1.24-1.72). The attributable risk fraction of cannabis impaired driving is estimated to lie below 2% for all but two of the included studies. CONCLUSIONS: Culpability ORs exaggerate risk increases and parameter uncertainty when misinterpreted as total crash ORs. The increased crash risk associated with THC positive drivers in culpability studies is low. PMID- 30468949 TI - Modeling and mitigating fatigue-related accident risk of taxi drivers. AB - Taxi drivers worldwide often have very long driving hours and experience frequent fatigue. These conditions are associated with a high prevalence of fatigue and accidents. However, the key factors that distinguish high/low fatigue-related accident risk (FRAR) taxi drivers are uncertain. By examining a series of potential factors related with fatigue or accident risk as discussed in previous research, the objective was to find out the most important factors that relate to taxi driver's FRAR, and to investigate the association of these factors and taxi driver's FRAR. Modeling methods were applied to questionnaire data collected from Beijing taxi drivers. A 269-sample dataset was analyzed to identify key factors related to FRAR and to fit FRAR prediction models. The model's performance on high-risk driver prediction was then tested using another independently collected 100-sample dataset. High-risk taxi drivers had significantly longer driving hours per working day, lower rest ratios, less driving experience, and were more confident about their fatigue resistance. The FRAR model with only four major measurable predictors achieved a sensitivity of 91.9% and a specificity of 94.6% on predicting labeled data. Adjusting drive-rest habits and self-evaluation pertaining to these predictors is good for high-risk drivers to mitigate their accident risk. It was concluded that taxi drivers' drive-rest habits, experience, and intention for fatigue driving are crucial, and to a large degree determine their FRAR, and the prediction model can satisfactorily identify high-risk taxi drivers. PMID- 30468950 TI - Do mindfulness interventions improve road safety? A systematic review. AB - Mindfulness has been identified as a potentially effective intervention for reducing road trauma. In this paper, we report on the results of a systematic review which examined the evidence regarding the relationship between mindfulness and road safety. The review was conducted following PRISMA guidelines (PROSPERO 2017: CRD42017075704). The primary outcomes measured were crash or near-crash rates and the secondary outcomes were driving violations (including speeding and texting while driving) and driving performance (i.e., errors in driving simulator, etc.). This review was registered with PROSPERO 2017: CRD42017075704. A systematic search of databases from the disciplines of public health, psychology and transport safety (Ovid Cochrane Library, Ovid PsycINFO, Ovid EMBASE, CINAHL PLUS, Ovid TRANSPORT and TRID: TRIS and ITRD database) was conducted on February 7th 2018. Seventeen studies (12 cross-sectional and 5 case control) published between 2011 and 2017 met the inclusion criteria. These all focused on the association between mindfulness or mind-wandering on road safety measures including driving performance (vehicle control, reaction time), compliance with speed zones and traffic signals, near-crash and crash rates, as well as propensity to engage in distracted driving behaviours. The results of the review suggest that mindfulness may be particularly useful for preventing distracted driving. However, a number of limitations in the existing research are noted. It is clear that more research is warranted to specifically investigate the effectiveness of mindfulness as an intervention for reducing road trauma. PMID- 30468951 TI - Elastic compression stockings one year after DVT diagnosis: Who might discontinue? AB - BACKGROUND: Elastic compression stockings (ECS) are uncomfortable to wear but may prevent post-thrombotic syndrome (PTS). The ability to predict PTS may help clinical decision making regarding the optimal duration of ECS after deep vein thrombosis (DVT). AIMS: Predefined endpoint analysis of the Octavia study that randomized patients who compliantly used ECS up to one year after DVT to continue or discontinue ECS treatment. Primary aim was to identify predictors of PTS. METHODS: Patient characteristics were collected and ultrasonography was performed to assess reflux, residual thrombosis and persistent thrombus load 12 months after DVT. Multivariable analyses were performed to identify factors related to PTS. RESULTS: Thrombus score >= 3, BMI >= 26, duration of symptoms before DVT diagnosis >= 8 days and a Villalta score of 2-4 points were statistically significant predictors of PTS. The predictive value for PTS for the assessed variables was not different between the 2 treatment groups. In the stop ECS group, 3.2% (95%CI 0.08-18) of patients without any predictors for PTS were diagnosed with mild PTS during follow-up, and none with severe PTS, for a sensitivity of 98% (95% CI 89-100), a specificity of 14% (95% CI 10-20), a positive predictive value of 20% (95% CI 19-22), and a negative predictive value of 97% (95% CI 81-100). CONCLUSION: We identified 4 predictors of PTS occurring in the 2nd year after DVT. Our findings may be used to decide on whether to continue ECS treatment for an additional year, after one year of compliant ECS use, keeping in mind that patients with none of the predictors will have the lowest PTS incidence. PMID- 30468952 TI - Rituximab treatment in seronegative autoimmune autonomic neuropathy and autoimmune autonomic ganglionopathy: Case-report and literature review. AB - BACKGROUND AND PURPOSE: Autoimmune autonomic ganglionopathy (AAG) is a rare disease with no well-established treatment. Until recently, AAG could be seropositive (50 to 60% of patients) or seronegative for ganglionic (alpha3-type) nicotinic acetylcholine receptor (Galpha3NAChR) antibodies. In early 2018, the two forms of the disease were distinguished, separating seropositive from seronegative ones, designating this latter form "seronegative autoimmune autonomic neuropathy" (SAAN). Most described treatments are plasma exchange (PE) and intravenous immunoglobulin (IVIG). However in some cases with no or small benefit, other immunomodulatory therapies, such as rituximab have been reported. We report the case of a 24-year-old female patient successfully treated for SAAN with rituximab and steroids after IVIG and PE failure. We also provide a review of case-reports reporting rituximab treatment for both SAAN and AAG. METHODS: To identify articles reporting SAAN and AAG treatment with rituximab, we searched the PubMed database using the terms "autoimmune autonomic ganglionopathy", "autoimmune autonomic neuropathy" or "seronegative autoimmune autonomic neuropathy" and "rituximab". RESULTS: Including our patient, nine cases have been described in the literature (4 SAAN and 5 AAG). Rituximab had a significant positive effect in 2 out of 4 SAAN and all 5 AAG cases, used alone or in association with other etiologic treatments. CONCLUSION: Our study suggests rituximab (alone or in association with other treatments) could provide efficacy in both SAAN and AAG when PE and/or IVIG are not effective enough. PMID- 30468953 TI - T cells in the post-ischemic brain: Troopers or paramedics? AB - The immune system is intricately involved in brain development and physiological neuronal function. The influence of the adaptive immune system on several brain diseases has been described in great detail. In ischemic stroke, numerous studies have particularly demonstrated a key role for T cells during the acute phase after the brain injury. Recently, a critical role for T cells has also become more evident for the chronic phase after stroke in modulating delayed neuronal (dys-) function and recovery. Here, T cells may also affect various non immunological pathways by interacting with brain-resident immune cells and modulating mechanisms such as neurogenesis and angiogenesis. This novel concept suggests T cells as potential therapeutic targets to modulate post-stroke regeneration. PMID- 30468954 TI - Elucidating the internal structure and dynamics of alpha-chitin by 2DPASS-MAS-NMR and spin-lattice relaxation measurements. AB - The structure and dynamics of the second most abundant biopolymer alpha-chitin were studied by high resolution solid state 13C cross-polarization magic angle spinning nuclear magnetic resonance (CP-MAS-NMR) spectral analysis, 13C relaxation measurements at eight chemically different carbon sites and chemical shift anisotropy measurement by two-dimensional phase-adjusted spinning sidebands (2DPASS) magic angle spinning (MAS) solid state NMR method.13C spin-lattice relaxation time was measured by high resolution Torchia CP method. Spin-lattice relaxation rate (1/T1) of side chain carbon nuclei were remarkably high, because those nuclei possess higher degree of motional freedom. Chemical shift anisotropy parameters of eight chemically different carbon nuclei were determined by 2DPASS MAS-NMR experiment. Large value of chemical shift anisotropy was observed for carbonyl group carbon (C7) nuclei, because of electrostatic effect, hydrogen bonding and molecular magnetic susceptibility. 13C relaxation mechanism is mainly governed by chemical shift anisotropy interaction, especially at high value of external magnetic field (11.74 T). Thus, the correlation time at different carbon sites were also calculated by using the spin-lattice relaxation times and chemical shift anisotropy values. The correlation time of side chain carbon (C8) was two orders of magnitude less than the carbonyl group carbon. These types of investigations would enlighten the correlation between the structure and dynamics of long polysaccharide chain compound. PMID- 30468955 TI - From a bat's perspective, protected riparian areas should be wider than defined by Brazilian laws. AB - Riparian areas around streams are those areas in which biological communites are directly influenced by the stream. The size of protected riparian areas and their conservation has become a controversial topic after changes implemented in the Brazilian Forest Code (BFC): a set of laws that regulates the size of Permanent Protection Areas (PPA). Here, we investigate the influence of distance from water bodies on bat-species and guild composition in a lowland Amazonian rainforest. Our hypotheses were that bat assemblages would change depending on the distance to the water body and that the abundance of herbivorous bats (frugivorous and nectarivorous) would be greater in areas close to water. Bats were captured with mist-nets in 24 riparian and 25 non-riparian plots within a trail grid in an old growth terra-firme forest, northeast of Manaus, Amazonas, Brazil. Each plot was sampled three times in a total of 7056 net-hours. We captured 1191 bats, comprising 51 species. We used model selection based on AIC (Akaike Information Criterion) to compare linear and piecewise regressions to estimate the ecological thresholds for different bat assemblages. Piecewise models with one breakpoint were more parsimonious than linear models for abundance data, and the species and guild composition of animalivorous and frugivorous bats. Animalivorous-bat abundance increased from the stream to about 181 m, and frugivorous-bat abundance decreased within 50 m of the stream. The patterns of guild abundance suggest that frugivorous bats may need greater access to streams than animalivorous bats. The most conservative model suggests that most of the variation in bat composition occurs close to the stream and extends to up 114 m from the banks. Therefore, the 30 m wide strip of riparian forest protected by Brazilian law would maintain a relatively small fraction of bat-species assemblages in Ducke Reserve, and is insufficient to represent most of the assemblage-composition variation within the riparian zone. The suggestion to reduce the width of the protected riparian zone from 30 to 15 m for streams smaller than 10 m wide, as is under discussion, would likely be prejudicial for bat assemblages. PMID- 30468956 TI - Improved landfill leachate quality using ozone, UV solar radiation, hydrogen peroxide, persulfate and adsorption processes. AB - Advanced oxidation processes based on ozonation, UV solar radiation, hydrogen peroxide, and persulfate were tested for the complete treatment of a specific landfill leachate. As a post-treatment of the advanced oxidation process, an additional adsorption process was carried out using a natural zeolite. Application of the UVsolar/O3/H2O2 process required 140 min of irradiation and the consumption of 0.67 g/L H2O2 to eliminate 56% and 17% of colour and chemical oxygen demand (COD), respectively. When adding persulfate to the system (UVsolar/O3/H2O2/S2O8-2), colour and COD were reduced by 29% and 77%, respectively, with a 0.2 g/L concentration of S2O8-2 requiring 250 min of irradiation time. In an experimental run with landfill leachate, adsorption post treatment with a natural zeolite resulted in 36%, 99%, and 18% total reductions in COD, ammonium, and chloride, respectively. In another experimental run, adsorption with a zeolite was used as a pre-treatment for the advanced oxidation process (UVsolar/O3/H2O2 and UVsolar/O3/H2O2/S2O8-2). The results were similar to those for adsorption post-treatment, with 30%, 90%, and 20% total reductions in COD, ammonium, and chloride, respectively. Despite improvements, some measured parameters of treated landfill leachate still exceeded Chilean regulations for water quality. Furthermore, Lactuca sativa seeds did not germinate after irrigation with 100% treated landfill leachate or dilutions above 3%. Finally, EC50 values were enhanced during treatment, going from 0.002% for raw landfill leachate to 1.179% after the adsorption process. PMID- 30468957 TI - Troubleshooting the problems arising from sustainable development. AB - Sustainable development as a concept of societal development encompasses some problems that need to be addressed carefully. They relate to overcoming the technical limits of individual systems, reducing environmental impact, social inclusion, green economic progress involving all stakeholders, limiting the impact of human activities, etc. Over the past few years, as a result of the increasingly pronounced climate change, more and more studies are addressing these problems and stress the importance of sustainable development. The key to sustainable development are, therefore, the solutions to the problems currently encountered by various stakeholders, that together contribute to the preservation of the environment for future generations. This is no longer based on the goodwill of individuals, but has become the responsibility of the entire generation. This article presents some examples of the solutions for the problems arising from sustainable development and is an overview of recent scientific achievements in the field of sustainable development that emerged from recent Sustainable Development of Energy, Water and Environment Systems (SDEWES) conferences. As such, it acts as an editorial paper for the virtual special issue of the Journal of Environmental Management, that is dedicated to the SDEWES2017 conference. PMID- 30468958 TI - Waste to energy potential in middle income countries of MENA region based on multi-scenario analysis for Kafr El-Sheikh Governorate, Egypt. AB - The environmental risks of traditional waste disposal methods, together with the resource and energy value of waste, had established the foundation for waste-to energy (WTE) technologies. WTE is rarely implemented in developing countries, mostly due to the lack of knowledge and experience under their specific local conditions. The present research investigates the feasibility of WTE strategies in middle income developing countries of the Middle East and North Africa (MENA) region. Multiple waste management scenarios, involving incineration and anaerobic digestion, were evaluated based on energy, economic, and environmental parameters. A multi-criteria assessment was conducted for the Governorate of Kafr El-Sheikh (Egypt); a 3.2-million rural-urban agro-industrial population with socio-economic and demographic features similar to those of the selected MENA countries. The actual waste generation rates and characteristics of Kafr El Sheikh were measured through a comprehensive field study. It was found that anaerobic digestion with recycling is the optimum strategy for Kafr El-Sheikh, with annual energy potential of 1170-kWh per ton of waste and net economic savings of 6.5 million USD. This optimum waste management scenario was extended to the selected MENA countries to investigate potential benefits of shifting to WTE-based waste management strategies. The total annual energy production was estimated to be 103,000-GWh, which translates to 17% of the total energy consumption. Moreover, greenhouse gas emissions were reduced by around 98,500-Gg CO2 annually, which represents around 6.5% of the total annual CO2 footprint generated by the selected countries. Furthermore, the overall economic benefits ranged between -12 and 200 million USD for the selected countries. PMID- 30468959 TI - Optimal investment in electric generating capacity under climate policy. AB - Mitigating climate change will require reduced use of fossil fuels to generate electricity. To do so while eschewing nuclear power, countries have turned to wind and solar energy. In this paper, load duration and screening curves are used to investigate the extent to which a jurisdiction should invest in intermittent (solar and wind) sources of energy, gas and nuclear power. The application is to the Alberta electricity grid because it is nearly 90 percent reliant on fossil fuels, particularly coal, and recent policy intends to eliminate coal generating capacity by 2030 and replace two-thirds of the lost capacity with renewables. Results suggest that solar and wind are unable to replace two-thirds of coal generation, and that larger than anticipated investments in natural gas capacity will be required. However, if Alberta is serious about reducing emissions, it will need to rely on nuclear energy; at high carbon prices, nuclear power could reduce CO2 emissions by some 95% compared to only 55% when relying totally on solar and wind. PMID- 30468960 TI - Human-mediated dispersal of terrestrial species between Antarctic biogeographic regions: A preliminary risk assessment. AB - The distribution of terrestrial biodiversity within Antarctica is complex, with 16 distinct biogeographic regions (Antarctic Conservation Biogeographic Regions) currently recognised within the Antarctic continent, Peninsula and Scotia Arc archipelagos of the Antarctic Treaty area. Much of this diversity is endemic not only to Antarctica as a whole, but to specific regions within it. Further complexity is added by inclusion of the biodiversity found on the islands located in the Southern Ocean north of the Treaty area. Within Antarctica, scientific, logistic and tourism activities may inadvertently move organisms over potentially long distances, far beyond natural dispersal ranges. Such translocation can disrupt natural species distribution patterns and biogeography through: (1) movement of spatially restricted indigenous species to other areas of Antarctica; (2) movement of distinct populations of more generally distributed species from one area of Antarctica to another, leading to genetic homogenisation and loss of assumed local patterns of adaptation; and (3) further dispersal of introduced non native species from one area of Antarctica to another. Species can be moved between regions in association with people and cargo, by ship, aircraft and overland travel. Movement of cargo and personnel by ship between stations located in different biogeographic regions is likely to present one of the greatest risks, particularly as coastal stations may experience similar climatic conditions, making establishment more likely. Recognising that reducing the risk of inter-regional transfer of species is a priority issue for the Antarctic Treaty Consultative Meeting, we make practical recommendations aimed at reducing this risk, including the implementation of appropriate biosecurity procedures. PMID- 30468961 TI - Inputs of rare earth elements in Brazilian agricultural soils via P-containing fertilizers and soil correctives. AB - The mineral exploration of rare earth elements (REEs) and their entry into the soil via fertilizers has generated concern about environmental impacts and human health risks. We evaluated 60 samples of limestone, gypsum and phosphate fertilizers marketed in Brazil in order to characterize their contents, signature and solubility of REEs. The fertilizers from igneous origin presented the largest accumulation of REEs. Accumulation of the light REEs Ce, La, Nd, Pr, Sm and Eu were larger than the heavy REEs (Y, Dy, Gd, Er, Yb, Ho, Tb and Lu). The solubility of fertilizers produced from sedimentary sources was greater than that of igneous sources. The mean annual REEs contribution of SSP and organo-mineral + phosphate rock (both of igneous origin) to soils was > 4000 t year-1, with highest additions for Ce, La, Nd and Y. Thus, phosphate fertilization and liming were considered to be significant sources of REEs and soils receiving continuously high doses of these inputs are likely to be enriched in REEs. Risk assessment studies are necessary to evaluate the impact of these REEs additions to soils on human health. PMID- 30468962 TI - Performance of aquatic weed - Waste Myriophyllum spicatum immobilized in alginate beads for the removal of Pb(II). AB - A new biosorbent - alginate encapsulated with Myriophyllum spicatum - MsA was investigated for lead ions removal. This biosorbent was characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), zeta potential, X ray Diffraction (XRD) and size distribution analysis. FT-IR analysis demonstrated that the lead ions sequestration mechanism included ion exchange and lead complexation with the carboxyl, carbonyl and hydroxyl groups in MsA. In order to better understand the mechanisms of the binding of Pb(II) on immobilized M. spicatum beads, 3 reaction and one diffusion based kinetic models were applied on kinetic data removal lead ions on three materials: M. spicatum, Ca-alginate and MsA. Myriophyllum spicatum encapsulated with alginate - MsA have higher adsorption capacity than M. spicatum. Among examined six isotherms Redlich Peterson and the Langmuir isotherm model exhibited the best fit to the experimental data, with capacities ranging from 230 to 268.7 mg/g. Among the various tested desorption agents, nitric acid has proven to be the best. The obtained results suggest that the immobilized M. spicatum biosorbent holds great potential for lead wastewater treatment applications. PMID- 30468963 TI - Sulphuric body odor under therapy with Brivaracetam. PMID- 30468964 TI - High prevalence of onchocerciasis-associated epilepsy in villages in Maridi County, Republic of South Sudan: A community-based survey. AB - PURPOSE: To determine the prevalence and incidence of epilepsy in an onchocerciasis endemic region of South Sudan. METHODS: In May 2018, a door-to door household survey was conducted in 8 study sites in an onchocerciasis endemic area in Maridi County. RESULTS: A total of 2511 households agreed to participate in the study, corresponding to 17,652 individuals. An epilepsy screening questionnaire identified 799 persons suspected to have epilepsy (4.5%); in 736 of the 766 persons (96.1%) seen by a clinical officer the diagnosis of epilepsy was confirmed. Adding 38 persons who were not seen but with a positive answer to a combination of screening questions, 774 persons (4.4%) had epilepsy. Epilepsy prevalence was highest in the 11-20 age group (10.5%); 66 persons with epilepsy (PWE) developed their first seizures in the year preceding the survey (annual incidence = 373.9/100.000). Neurocysticercosis cannot explain the high epilepsy prevalence since no pigs are kept in the area. Independent risk factors for epilepsy included male gender, belonging to a "permanent household" and a farming family, and living in a village bordering the Maridi River. Only 7209 (40.8%) of the population took ivermectin in 2017. CONCLUSION: A very high prevalence and incidence of epilepsy was observed in several villages in Maridi County located close to the Maridi River and the Maridi dam. Urgent action is needed to prevent children in Maridi County from developing OAE by strengthening the onchocerciasis elimination program. PMID- 30468965 TI - Repeat missing child reports in Wales. AB - BACKGROUND: There were approximately 306,000 reports of missing persons in the UK from 2012 to 2013, 64% involved children. Repeat missing incidents account for approximately 38% of reported missing incidences. Within their research Biehal et al. (2003) identified that 70% of missing children had voluntarily left their home and the majority of these were considered to have 'run away'. Research suggests that there is heavy demand on public services in responding to children that are regularly reported missing. OBJECTIVE: The purpose of this study was to explore data recorded in respect of children reported missing as a result of running away. The main objective of this study was to develop a set of risk factors to predict repeat missing incidences using a logistic regression method. PARTICIPANTS AND SETTING: This study explored the characteristics of 523 children who were reported missing to Gwent (Wales) Police as a result of running away. METHODS: Using data collected by the Gwent Missing Children's Team in Wales, over a one-year period, this study compared two groups of children: 275 (53%) who were reported missing once ('low risk') and 248 (47%) who were reported more than once ('high risk'). RESULTS: Results indicated that five significant risk factors identified by logistic regression could distinguish outcome in 73% of cases. The five risk factors were; looked after children, substance use, suspected sexual exploitation, known to Youth Offending Services and a history of abuse/neglect. CONCLUSIONS: These risk factors could potentially be used in Gwent to guide intervention strategies, with those children identified as 'high risk' of repeat missing incidents requiring more comprehensive intervention and support. PMID- 30468966 TI - Signs of attachment disorders and social functioning among early adolescents with a history of institutional care. AB - BACKGROUND: Institutional rearing is associated with increased risk for reactive attachment disorder (RAD) and disinhibited social engagement disorder (DSED). Disorders of attachment involve disturbances in children's primary caregiving relationships, and are likely to disturb multiple domains of social functioning. OBJECTIVE: To examine associations between signs of RAD and DSED and social functioning in early adolescence. PARTICIPANTS AND SETTING: Our participants were 110 children with a history of institutional rearing and 50 community comparison adolescents from the Bucharest Early Intervention Project, based in Bucharest, Romania. Participants were assessed at age 12 years (M age in years = 12.80, SD = 0.71). METHOD: Signs of RAD and DSED were obtained through caregiver report. Reports of social functioning were provided by caregivers and teachers. General and specific domains of social functioning were identified using bi-factor modeling. A general social functioning factor and four specific factors were revealed: peer conflict, caregiver views as victim, teacher views as victim, and social competence. RESULTS: Signs of RAD predicted poorer general social functioning (beta=-0.36, p < .01, 95% confidence interval [CI] [-.33, -.09]) and poorer social competence (beta=-0.38, p < .01, 95% CI[-0.05, -.01]) above and beyond time spent in institutional care and placement disruptions. Signs of DSED (beta=-0.38, p < .001, 95% CI[-0.49, -.16]) along with placement disruptions (beta=-0.22, p < .05, 95% CI[-.29, -.01]) predicted poorer general social functioning above and beyond time spent in institutional care. Signs of DSED predicted higher scores on caregiver views as victim (beta = 0.29, p < .05, 95% CI[0.02, 0.14]) and lower scores on social competence (beta=-0.29, p < .01, 95% CI[-.06, -.01]) above and beyond time spent in institutional care and placement disruptions. CONCLUSIONS: Attachment disorder signs in early adolescence are problematic for social functioning, although the manifestation of these social difficulties differs based on whether RAD or DSED signs are present. PMID- 30468967 TI - Attachment of iron oxide nanoparticles to carbon nanofibers studied by in-situ liquid phase transmission electron microscopy. AB - By using liquid phase transmission electron microscopy (LP-TEM), the dynamics of iron oxide nanoparticle (Fe-NP) attachment to carbon nanofibers (CNFs) and oxygen functionalized CNFs (CNF-Ox) were studied in-situ. The beam effect on the stability of the sample in various liquids was examined, and it was found that toluene provided the highest stability and resolution to image both CNF supports and Fe-NPs. Flowing particles dispersed in toluene through the liquid cell allowed direct monitoring of the attachment process at ambient temperature. Using CNF-Ox as a support led to a large extent and irreversible attachment of iron nanoparticle compared to a lower extent and reversible attachment of Fe-NPs to pristine CNF, indicating the influence of surface functionalization on colloidal particle attachment. The results were confirmed by lab-scale experiments as well as experiments performed with the electron beam switched off, verifying the notion that beam effects did not affect the attachment. This study revealed previously unknown phenomena in colloidal particle - support interactions and demonstrates the power of LP-TEM technique for studying such nanoscale processes. PMID- 30468968 TI - Automatic graph-based method for localization of cochlear implant electrode arrays in clinical CT with sub-voxel accuracy. AB - Cochlear implants (CIs) are neural prosthetics that provide a sense of sound to people who experience severe to profound hearing loss. Recent studies have demonstrated a correlation between hearing outcomes and intra-cochlear locations of CI electrodes. Our group has been conducting investigations on this correlation and has been developing an image-guided cochlear implant programming (IGCIP) system to program CI devices to improve hearing outcomes. One crucial step that has not been automated in IGCIP is the localization of CI electrodes in clinical CTs. Existing methods for CI electrode localization do not generalize well on large-scale datasets of clinical CTs implanted with different brands of CI arrays. In this paper, we propose a novel method for localizing different brands of CI electrodes in clinical CTs. We firstly generate the candidate electrode positions at sub-voxel resolution in a whole head CT by thresholding an up-sampled feature image and voxel-thinning the result. Then, we use a graph based path-finding algorithm to find a fixed-length path that consists of a subset of the candidates as the localization result. Validation on a large-scale dataset of clinical CTs shows that our proposed method outperforms the state-of art CI electrode localization methods and achieves a mean error of 0.12 mm when compared to expert manual localization results. This represents a crucial step in translating IGCIP from the laboratory to large-scale clinical use. PMID- 30468969 TI - Quality-based UnwRap of SUbdivided Large Arrays (URSULA) for high-resolution MRI data. AB - In Magnetic Resonance Imaging, mapping of the static magnetic field and the magnetic susceptibility is based on multidimensional phase measurements. Phase data are ambiguous and have to be unwrapped to their true range in order to exhibit a correct representation of underlying features. High-resolution imaging at ultra-high fields, where susceptibility and phase contrast are natural tools, can generate large datasets, which tend to dramatically increase computing time demands for spatial unwrapping algorithms. This article describes a novel method, URSULA, which introduces an artificial volume compartmentalisation that allows large-scale unwrapping problems to be broken down, making URSULA ideally suited for computational parallelisation. In the presented study, URSULA is illustrated with a quality-guided unwrapping approach. Validation is performed on numerical data and an application on a high-resolution measurement, at the clinical field strength of 3T is demonstrated. In conclusion, URSULA allows for a reduction of the problem size, a substantial speed-up and for handling large data sets without sacrificing the overall accuracy of the resulting phase information. PMID- 30468971 TI - Arguments supporting and opposing legalization of safe consumption sites in the U.S. AB - BACKGROUND: Safe consumption sites are spaces where people can legally use pre obtained drugs under medical supervision and are currently in operation in Canada, Australia and Western Europe. These sites are effective in reducing opioid overdose mortality and other harms associated with opioid use, such as HIV infection, and increasing drug treatment entry. Various U.S. communities are considering establishing safe consumption sites, however, only 29% of U.S. adults support their legalization. This purpose of this study is to assess what types of arguments resonate with the public in support of and opposition to legalizing safe consumption sites to combat the opioid epidemic. METHODS: A public opinion survey of U.S. adults in July-August 2017 (N = 1004) used a probability-based sample of respondents from a large, nationally representative online panel. The survey examined the public's perception of the strength of common arguments offered in support of and opposition to legalizing safe consumption sites. Arguments were identified through a detailed scan of news media coverage, public reports, and advocacy materials. RESULTS: The national sample of U.S. adults rated all arguments opposing legalization of safe consumption sites as stronger than any of the arguments supporting legalization. The most highly rated opposing arguments were that public funds were better spent on addiction treatment, and that sites were allowing illegal activity and encouraging people to use drugs. The highest rated arguments supporting legalization were that safe consumption sites were a better alternative than arresting people for using drugs, they would reduce HIV and hepatitis C by encouraging safe injection practices, and that they would lower emergency department admission and hospitalization costs. CONCLUSION: Legalization of this evidence-based harm reduction approach in U.S. communities will be difficult to advance without public education to confront persistent myths that safe consumption sites encourage drug use and do not facilitate treatment access. PMID- 30468970 TI - CATARACTS: Challenge on automatic tool annotation for cataRACT surgery. AB - Surgical tool detection is attracting increasing attention from the medical image analysis community. The goal generally is not to precisely locate tools in images, but rather to indicate which tools are being used by the surgeon at each instant. The main motivation for annotating tool usage is to design efficient solutions for surgical workflow analysis, with potential applications in report generation, surgical training and even real-time decision support. Most existing tool annotation algorithms focus on laparoscopic surgeries. However, with 19 million interventions per year, the most common surgical procedure in the world is cataract surgery. The CATARACTS challenge was organized in 2017 to evaluate tool annotation algorithms in the specific context of cataract surgery. It relies on more than nine hours of videos, from 50 cataract surgeries, in which the presence of 21 surgical tools was manually annotated by two experts. With 14 participating teams, this challenge can be considered a success. As might be expected, the submitted solutions are based on deep learning. This paper thoroughly evaluates these solutions: in particular, the quality of their annotations are compared to that of human interpretations. Next, lessons learnt from the differential analysis of these solutions are discussed. We expect that they will guide the design of efficient surgery monitoring tools in the near future. PMID- 30468972 TI - Short-term effects of very low dose cadmium feeding on copper, manganese and iron homeostasis: A gastropod perspective. AB - The available information on the interplay between low-dose cadmium intake and copper, manganese, and iron homeostasis in invertebrates is limited. We have currently studied the accumulation of these trace metals in the hepatopancreas of adult snails, Cantareus aspersus, following 14 and 28 days of exposure to low doses of dietary cadmium, up to 1 mg/kg dw (dry weight). The cadmium dose, but not the duration of exposure, had a significant effect on hepatopancreas copper deposition, the values being significantly elevated compared to controls. A significant peak in manganese levels at 14 days was found in snails administered the lowest cadmium dose. These increases occurred even in the absence of cadmium increase in the hepatopancreas. Our data suggest that low dose cadmium feeding can produce a transient disturbance in hepatopancreas copper and manganese homeostasis. Such responses may serve as early biomarkers of physiological changes occurring during the initial stages of cadmium intoxication. PMID- 30468973 TI - Chikungunya virus infection prevalence in Africa: a contemporaneous systematic review and meta-analysis. AB - OBJECTIVES: The (re)emergence of chikungunya virus (CHIKV) in Africa requires better knowledge on the epidemiology of CHIKV infection in the continent for efficient public health strategies. We aimed to describe the epidemiology of CHIKV infection in Africa, a neglected tropical disease (NTD). STUDY DESIGN: This was a systematic review with meta-analysis of studies reporting CHIKV infection prevalence. We searched Embase, PubMed, Africa Journal Online and Global Index Medicus to identify observational studies published from January 2000 to September 2017. METHODS: We used a random-effect model to pool the prevalence of CHIKV infections reported with their 95% confidence interval (CI). Heterogeneity was assessed via the Chi-squared test on Cochran's Q statistic. Review registration is in PROSPERO CRD42017080395. RESULTS: A total of 39 studies (37,881 participants; 18 countries) were included. No study was reported from Southern Africa. Thirty-two (82.0%), seven (18.0%) and no studies had low, moderate and high risk of bias, respectively. Outside outbreak periods, the pooled immunoglobulin M (IgM) and immunoglobulin G (IgG) seroprevalence was 9.7% (95% CI 3.0-19.6; 16 studies) and 16.4% (95% CI 9.1-25.2; 23 studies), respectively. The IgM seroprevalence was lower in Northern Africa, and there was no difference for IgG prevalence across regions in Africa. The IgM and IgG seroprevalences were not different between acute and non-acute febrile participants. The seroprevalence was not associated with GPS coordinates (latitude, longitude and altitude). CONCLUSIONS: Although considered a NTD, we find high prevalence of CHIKV infection in Africa. As such, chikungunya fever should deserve more attention from healthcare providers, researchers, policymakers and stakeholders from many sectors. PMID- 30468974 TI - Novel therapeutics in the treatment of hairy cell leukemia variant. PMID- 30468975 TI - Reduced prefrontal-temporal cortical activation during verbal fluency task in obsessive-compulsive disorder: A multi-channel near-infrared spectroscopy study. AB - Functional neuroimaging studies by near-infrared spectroscopy (NIRS) have focused on the role of the prefrontal cortex (PFC) in the pathophysiology of obsessive compulsive disorder (OCD). However, the reported areas in the PFC were inconsistent in OCD, and correlations between hemodynamic response and clinical symptoms have not been investigated. This study aimed to evaluate the hemodynamic response related to the verbal fluency task (VFT) and assess the relationship between activation and clinical status in OCD patients using a 52-channel NIRS with a wide coverage over the prefrontal and temporal cortices. Seventy patients with OCD and 70 age-, gender- and education level-matched healthy control subjects were examined by NIRS. The relative concentration changes of oxygenated hemoglobin ([oxy-Hb]) were measured. The Yale-Brown obsessive-compulsive scale (Y BOCS) was used to evaluate the severity of OCD symptoms. Compared to healthy controls group, OCD patients showed smaller [oxy-Hb] changes in most areas of the prefrontal and temporal cortex, including the bilateral orbitofrontal cortex (OFC), right dorsolateral prefrontal cortex (DLPFC), bilateral inferior prefrontal cortex (IPFC), bilateral frontopolar cortex (FPC), left superior temporal gyrus (STG), and bilateral middle temporal gyrus (MTG). Furthermore, the [oxy-Hb] changes in the right FPC were negatively correlated with the Y-BOCS obsessions score and Y-BOCS total score, and the [oxy-Hb] changes in the left OFC were negatively correlated with the Y-BOCS compulsions score. These results suggest that patients with OCD have reduced prefrontal-temporal cortex hemodynamic responses, and that the abnormalities of brain activation were associated with the severity of OCD symptoms. PMID- 30468976 TI - Supporting evidence for PCB pollution threatening global killer whale population. AB - A recent Science report predicted the global killer whale population to collapse due to PCB pollution. Here we present empirical evidence, which supports and extends the reports' statement. In 2016, a neonate male killer whale stranded on the German island of Sylt. Neonatal attributes indicated an age of at least 3 days. The stomach contained ~20 mL milk residue and no pathologies explaining the cause of death could be detected. Blubber samples presenting low lipid concentrations were analysed for persistent organic pollutants. Skin samples were collected for genotyping of the mitochondrial control region. The blubber PCB concentrations were very high [SPCBs, 225 mg/kg lipid weight (lw)], largely exceeding the PCB toxicity thresholds reported for the onset of immunosuppression [9 mg/kg lw ?PCB] and for severe reproductive impairment [41 mg/kg lw ?PCB] reported for marine mammals. Additionally, this individual showed equally high concentrations in p,p'-DDE [226 mg/kg lw], PBDEs [5 mg/kg lw] and liver mercury levels [1.1 MUg/g dry weight dw]. These results suggest a high placental transfer of pollutants from mother to foetus. Consequently, blubber and plasma PCB concentrations and calf mortality rates are both high in primiparous females. With such high pollutant levels, this neonate had poor prerequisites for survival. The neonate belonged to Ecotype I (generalist feeder) and carried the mitochondrial haplotype 35 present in about 16% of the North Atlantic killer whale from or close to the North Sea. The relevance of this data becomes apparent in the UK West Coast Community, the UK's only residentorca population, which is currently composed of only eight individuals (each four males and females) and no calves have been reported over the last 19 years.Despite worldwide regulations, PCBs persist in the environment and remain a severe concern for killer whale populations, placing calves at high risk due to the mother-offspring PCB-transfer resulting in a high toxicological burden of the neonates. PMID- 30468977 TI - Fate of four phthalate esters with presence of Karenia brevis: Uptake and biodegradation. AB - Phthalate esters (PAEs), one class of the most frequently detected endocrine disrupting chemicals (EDCs) in marine environment, have aroused wide public concerns because of their carcinogenicity, teratogenicity, and mutagenicity. However, the environmental fate of PAEs in the occurrence of harmful algal blooms remains unclear. In this research, four PAEs with different alkyl chains, i.e., dimethyl phthalate (DMP), diethyl phthalate (DEP), diallyl phthalate (DAP), and dipropyl phtalate (DPrP) were selected as models to investigate toxicity, uptake, and degradation of PAEs in seawater grown with K. brevis, one of the common harmful red tide species. The 96-h median effective concentration (96h-EC50) values followed the order of DMP (over 0.257 mmol L-1) > DEP (0.178 mmol L-1) > DAP (0.136 mmol L-1) > DPrP (0.095 mmol L-1), and the bio-concentration factors (BCFs) were positively correlated to the alkyl chain length. These results indicate that the toxicity of PAEs and their accumulation in K. brevis increased with increasing alkyl chains, due to the higher lipophicity of the longer chain PAEs. With growth of K. brevis for 96 h, the content of DMP, DEP, DAP, and DPrP decreased by 93.3%, 68.2%, 57.4% and 46.7%, respectively, mainly attributed to their biodegradation by K. brevis, accounting for 87.1%, 61%, 46%, 40% of their initial contents, respectively. It was noticed that abiotic degradation had little contribution to the total reduction of PAEs in the algal cultivation systems. Moreover, five metabolites were detected in the K. brevis when exposed to DEP including dimethyl phthalate (DMP), monoethyl phthalate (MEP), mono-methyl phthalate (MMP), phthalic acid (PA), and protocatechuic acid (PrA). While when exposed with to DPrP, one additional intermediate compound diethyl phthalate (DEP) was detected in the cells of K. brevis in addition to the five metabolites mentioned above. These results confirm that the main biodegradation pathways of DEP and DPrP by K. brevis included de-esterification, demethylation or transesterification. These findings will provide valuable evidences for predicting the environmental fate and assessing potential risk of PAEs in the occurrence of harmful algal blooms in marine environment. PMID- 30468978 TI - Impact of an immunosuppressive human pharmaceutical on the interaction of a bacterial parasite and its invertebrate host. AB - The interaction of pollutants and pathogens may result in altered and often enhanced effects of the chemical, the biotic stressor or both. These interaction effects cannot be reliably predicted from the toxicity of the chemical or the virulence of the pathogen alone. While standardized detection methods for immunotoxic effects of chemicals exist with regard to human health, employing host-resistance assays with vertebrates, such standardized test systems are completely lacking for invertebrate species and no guidance is available on how immunotoxic effects of a chemical in invertebrates could be definitively identified. In the present study, we investigated the impact of the immunosuppressive pharmaceutical cyclosporine A (CsA) on the invertebrate host pathogen system Daphnia magna - Pasteuria ramosa. CsA is a calcineurin-inhibitor in vertebrates and also known to have antibiotic as well as antifungal properties. Juvenile D. magna were exposed to CsA for 21 days with or without additional pathogen challenge during the first 72 h of exposure. Long-term survival of the host D. magna was synergistically impacted by co-exposure to the chemical and the pathogen, expressed e.g. in significantly enhanced hazard ratios. Additionally, enhanced virulence of the pathogen upon chemical co exposure was expressed in an increased proportion of infected hosts and an increased speed of Pasteuria-induced host sterilization. In contrast, effects on reproduction were additive in Pasteuria-challenged, but finally non-infected D. magna. The enhancing effects of CsA occurred at and below 3 MUg/L, which was in the absence of the pathogen the lowest concentration significantly impacting the standard toxicity endpoint 'reproduction' in D. magna. Hence, the present study provides evidence that a pharmaceutical intended to suppress the human immune system can also suppress disease resistance of an aquatic invertebrate organism at otherwise non-toxic concentrations. Plausible ways of direct interactions of CsA with the host's immune system are discussed, e.g. interference with phagocytosis or Toll-like receptors. Experimental verification of such a direct interference would be warranted to support the strong evidence for immunotoxic activity of CsA in invertebrates. While it remains open whether CsA concentrations in the environment are high enough to trigger adverse effects in environmental organisms, our findings highlight the need to consider immunotoxicity in an environmental risk assessment, and to develop suitable standardized methods for this purpose. PMID- 30468979 TI - Why wait for the verb? Turkish speaking children use case markers for incremental language comprehension. AB - During language comprehension we must rapidly determine the thematic roles of arguments (who did what to whom) in order to semantically integrate the players into a single event and predict upcoming structure. While some languages signal these relations mostly with reliable word order, others rely more on case markers. The present study explores whether Turkish-speaking children use case marking predictively during online language comprehension. Specifically, we use the visual-world paradigm to test whether 4-year-olds (and adults) can use a contrast between nominative and accusative case on the first noun to predict the referent of the second noun in verb-medial and verb-final spoken sentences. In verb-medial sentences, both children and adults used case to predict the upcoming noun, but children did so only after hearing the verb. In verb-final structures, however, both children and adults made predictive looks to the correct referent prior to the second noun (and the verb). Thus, Turkish-speaking preschoolers interpret case marking incrementally, independent of the verb, and use it to anticipate the upcoming argument. These findings are inconsistent with the hypothesis that the online interpretation of case marking depends on a late maturing neural circuit. The predictive use of case at four provides strong evidence that children's comprehension relies on broad, abstract mappings between syntax and semantics, which allow children to determine the event role of a case marked argument prior to identifying the verb. PMID- 30468980 TI - Cross-situational and ostensive word learning in children with and without autism spectrum disorder. AB - Numerous experimental studies have shown that infants and children can discover word meanings by using co-occurrences between labels and objects across individually ambiguous contexts-a phenomenon known as cross-situational learning. Like typically developing children, high-functioning school aged children with autism spectrum disorder (ASD) are capable of cross-situational learning. However, it is not yet clear whether cross-situational learning is similarly available to children with ASD who are younger and show a broader range of language and cognitive abilities. Using eye-tracking methodology, the current study provided the first evidence that preschool and early school-aged children with ASD can rely on cross-situational statistics to learn new words. In fact, children with ASD learned as well as typically developing children with similar vocabulary knowledge. In both groups, the children with the highest cross situational learning accuracy were those who showed the best familiar word processing skills. Surprisingly, children in both groups learned words equally well in the cross-situational task and an ostensive word-learning task, which presented only a single label-object pairing at a time. In combination, these results point to similarities in the word learning abilities available to typically developing children and children with ASD. PMID- 30468981 TI - Development of a web-based tool to evaluate competences of nursing students through the assessment of their clinical skills. AB - BACKGROUND: Assessing the clinical ability of nursing students continues to be a fundamental challenge within the nursing degree. Designing innovative teaching strategies while ensuring an educational experience that results in safe nursing practices is an additional challenge for all educators. OBJECTIVES: To design, develop and implement a tool to evaluate the clinical skills of nursing students. DESIGN: A two-phase study. In the second phase, a pre-experimental study was conducted. SETTINGS: Health Sciences Department of the University of Almeria, Spain. PARTICIPANTS: 250 Nursing students in the second year of their degree. METHODS: The study was divided into 2 phases: 1st) Web-based tool design and development and 2nd) Usability testing. In the second phase, a pre-experimental study was conducted both with an experimental group and a control group. RESULTS: In the first phase, a panel of 15 experts confirmed that the content and technical aspects of the tool were adequate (scores of 4-5/5). In the second phase, the participants of the experimental group showed higher final scores in the evaluated skills section, as well as shorter evaluation time and a greater number of observations and registered incidents than the participants in the control group. Finally, the students of the experimental group indicated a greater degree of satisfaction with the evaluation system used. CONCLUSIONS: The web-based tool designed is an effective strategy to evaluate clinical skills. It is important to have strategies and instruments that allow us to demonstrate the development and acquisition of the skills required for future nursing professionals. PMID- 30468982 TI - Sonographic and hysteroscopic endometrial examination in women treated with ulipristal acetate: Exploratory findings at a tertiary referral center. AB - OBJECTIVE: Ulipristal acetate (UPA) is a progesterone receptor modulator (PRM) agent that has shown benefits in women with symptomatic uterine fibroids. However, its effects on the endometrium are complex and not fully understood. We describe exploratory findings on macroscopic observation of the endometrium at transvaginal sonography (TVS) and hysteroscopy. The aim of the study is to characterize endometrial patterns commonly observed after UPA treatment. STUDY DESIGN: We performed a prospective longitudinal study at a tertiary referral center with 100 women with symptomatic uterine fibroids who received a 12-week treatment with UPA (5 mg/day). Patients underwent TVS before and after the treatment, and also a hysteroscopy examination was performed. Main outcome was to compare sonographic and hysteroscopic findings to histology after UPA treatment. RESULTS: Twenty one out of 100 (21%) women showed PAEC confirmed by histology after UPA treatment. Ultrasound findings were normal in most women after UPA treatment, but 18/100 (18%) showed an endometrial pattern suggestive of PRM effects (non-uniform, homogeneous endometrium with regular cystic areas). Endometrial thickness >=16 mm was detected in 6/100 patients (6%), and all of them also presented sonographic PRM pattern. No patient presented malignancy according to histology in this subgroup, and 100% of them had PAEC pattern at histology. Among total patient population showing PAEC at histology, only 33% of these were identified by hysteroscopy, while 57% were identified by TVS with the PRM suggestive pattern. Of note, visibility of endometrium was improved at TVS after UPA. CONCLUSION: Identification of increased endometrial thickness together with the categorized endometrial PRM pattern at TVS may be correlated to benign lesions and may not be a cause of concern. This study is exploratory and further research is necessary to support these conclusions. Nevertheless, TVS seems to be feasible to plan adequate follow-up protocols by avoiding unnecessary interventional procedures such as hysteroscopy. PMID- 30468983 TI - Diverting stoma-related complications following colorectal endometriosis surgery: a 163-patient cohort. AB - OBJECTIVE: Deep endometriosis may simultaneously infiltrate the vagina and the rectosigmoid, which associated resection may increase the risk of postoperative complications. Among these complications, rectovaginal fistula is one of the worst. To reduce the risk of rectovaginal fistula and related complications, surgeons may employ diverting stoma. The literature is rich in data concerning the usefulness of stoma in patients managed for low rectal cancer. However, extrapolation of these data to patients managed for rectal endometriosis is disputable. For this reason, there are no guidelines on the role of stoma in preventing rectovaginal fistula in patients managed for colorectal endometriosis. The objective of our study was to assess the risk of complications related to the use of stoma in patients managed for colorectal endometriosis. STUDY DESIGN: A retrospective comparative study has been performed using data prospectively recorded in the CIRENDO database. 163 consecutive women with colorectal endometriosis who had temporary stoma have been enrolled at the University Hospital of Rouen, from June 2009 to December 2016. The main outcome was stoma related complications rate using Clavien-Dindo classification. No women were lost to follow-up. RESULTS: Among the 163 women, 158 (96.9%) had a primary diverting stoma and 5 women (3.1%) with an immediate post-surgical bowel fistula had a secondary diverting stoma. Stoma involved the ileum in 28 women (17.2%) and the colon in 135 (82.8%). Surgical management of the rectosigmoid junction was rectal shaving in 2 women (1.2%), disc excision in 62 (38%), colorectal resection in 87 (53.4%), and combined rectal disc excision and sigmoid colon segmental resection in 12 (7.4%). Clavien Dindo I stoma-related complications occurred in 38 patients (23.3%) and were related to abnormal healing of stoma scar. Most Clavien-Dindo II complications were wound or urinary infections following stoma closure. Clavien Dindo III complications occurred in 14 patients (8.6%) and were related to leakage, hemoperitoneum, hernia of the abdominal wall, subcutaneous abscess and bowel obstruction syndrome. CONCLUSION: Specific complications may occur directly related to the use of stoma in the surgery of deep endometriosis of the rectosigmoid. The risk of these complications should be taken into account and full preoperative information should be provided to patients and their family. PMID- 30468984 TI - Pregnancy and post-partum muscle and cerebral oxygenation during intermittent exercise in gestational diabetes: A pilot study. AB - OBJECTIVE: This pilot, prospective, observational, cohort study aimed to examine, for the first time, the in vivo alterations in the oxygenation of the forearm skeletal muscles and the prefrontal lobes during intermittent exercise in women diagnosed with gestational diabetes mellitus (GDM), during and after pregnancy. STUDY DESIGN: Nine pregnant women, diagnosed with GDM, performed a 3-min intermittent handgrip exercise protocol (at 35% of Maximal Voluntary Contraction) during pregnancy (mean 27th gestational week) and following labor (mean 71 weeks). During the protocol, muscle and cerebral oxygenation were assessed with near-infrared spectroscopy. Resting vascular parameters [carotid intima-media thickness (cIMT) and hemodynamic parameters (using rheocardiography)], and hematological/biochemical parameters during pregnancy and after delivery have been compared. RESULTS: Although changes were observed in certain hematological parameters (p< 0.05), cIMT and hemodynamic parameters were not altered post partum. In addition, both muscle and cerebral oxygenation parameters during handgrip were not significantly altered post-partum. CONCLUSIONS: Despite significant changes in specific hematological parameters in women with GDM, impairments in muscle and cerebral oxygenation during exercise remained at one year after labor. These results indicate that alterations in vascular parameters and muscle/cerebral oxygenation associated with GDM do not entirely reverse post partum. Future studies are needed to examine which interventions will lead to improvements in microvascular parameters and prevent type 2 diabetes. PMID- 30468985 TI - Is episiotomy worthwile to prevent obstetric anal sphincter injury during operative vaginal delivery in nulliparous women? AB - OBJECTIVES: Episiotomy is a marker of Obstetric Anal Sphincter Injury (OASIS) condition, therefore, unmeasured factors could have biased the strength of the association between episiotomy and reduced OASIS during Operative Vaginal Delivery (OVD). The aim of this study was to compare the OASIS rate during OVD according to episiotomy practice. STUDY DESIGN: Retrospective cohort study of all nulliparous pregnant women attempting an OVD between 2014-2017. To avoid unmeasured bias, all maternal and delivery data were prospectively captured after the birth. The strong relationship between parity and episiotomy practice (indication bias) lead to analyze only nulliparous women. Association between mediolateral episiotomy and OASIS following OVD was performing by using multivariate logistic regression analysis including significant variable in univariate analysis and relevant factors known to be associated both with OASIS and/or OVD. RESULTS: Over the study period, 1709 (17.1%) women had an OVD, among them 40 (2.3%) had OASIS. In the 1342 (78.5%) nulliparous women, OASIS rate were 2% and 5.1% with and without episiotomy (p < 0.01). In multivariate analysis a lower incidence of OASIS with the use of episiotomy (OR 0.267 IC 0.132-0.541) were observed. The persistent occiput posterior position was associated with an increase risk of OASIS (OR 6.742 IC 2.376-19.124). Spatula/forceps, as compared to vacuum operative vaginal delivery increased the risk OASIS (OR 2.847 IC 1.311 7.168). Area under the curve of the model was 0.745. CONCLUSION: Episiotomy is a modifiable risk factors which can contribute to reduce the risk of OASIS in nulliparous women with operative vaginal delivery. This intervention should be included in a global management of the second stage of labor. PMID- 30468987 TI - Suppressing effect of CMPPE, a new positive allosteric modulator of the GABAB receptor, on alcohol self-administration and reinstatement of alcohol seeking in rats. AB - Positive allosteric modulators (PAMs) of the GABAB receptor constitute a class of pharmacological agents gaining increasing attention in the alcohol research field because of their ability to suppress several alcohol-related behaviors in rodents. CMPPE is a novel GABAB PAM, still limitedly characterized in vivo. It was therefore of interest to test its ability to affect operant, oral self administration of alcohol and cue-induced reinstatement of alcohol seeking in alcohol-preferring rats. To this end, female Sardinian alcohol-preferring (sP) rats were trained to lever-respond for alcohol (15% v/v) under the fixed ratio (FR) 5 (FR5) schedule of reinforcement. Once lever-responding had stabilized, rats were exposed to test sessions (under the FR5 [Experiment 1] and progressive ratio [PR; Experiment 2] schedules of reinforcement) preceded by treatment with CMPPE (0, 2.5, 5, and 10 mg/kg; intraperitoneally [i.p.]). In Experiment 3, once lever-responding had stabilized, rats underwent an extinction responding phase and then a single reinstatement session during which lever-responding was resumed by the non-contingent presentation of a complex of alcohol-associated cues; CMPPE (0, 2.5, 5, and 10 mg/kg; i.p.) was administered before the reinstatement session. Selectivity of CMPPE action was assessed by evaluating the effect of CMPPE (0, 2.5, 5, and 10 mg/kg; i.p.) on self-administration of a chocolate solution in male Wistar rats (Experiment 4). In Experiments 1 and 2, treatment with 5 and 10 mg/kg CMPPE reduced lever-responding and breakpoint for alcohol. In Experiment 3, treatment with 5 and 10 mg/kg CMPPE suppressed reinstatement of alcohol seeking. In Experiment 4, no dose of CMPPE affected lever-responding for the chocolate solution. These results extend to CMPPE the ability of all previously tested GABAB PAMs to affect alcohol-motivated behaviors in rodents and confirm that these effects are a shared feature of the entire class of GABAB PAMs. This conclusion is of relevance in view of the forthcoming transition of GABAB PAMs to clinical testing. PMID- 30468986 TI - The Korean Cohort for the Model Predicting a Suicide and Suicide-related Behavior: Study rationale, methodology, and baseline sample characteristics of a long-term, large-scale, multi-center, prospective, naturalistic, observational cohort study. AB - BACKGROUND: The Korean Cohort for the Model Predicting a Suicide and Suicide related Behavior (K-COMPASS) study is a prospective, naturalistic, observational cohort study, aiming to identify predictors of suicide attempt and suicide characteristics in the Korean suicidal population. The findings intend to contribute to a thorough understanding of suicidal phenomena and development of suicide prevention guidelines. The present cross-section study examines the study rationale, methodology, and baseline characteristics of the participants. METHODS: Participants were enrolled via the hospital and community gateways, establishing the hospital-based cohort (HC) and community-based cohort (CC), respectively. Baseline assessment was conducted on sociodemographic, clinical, diagnostic, and psychopathological aspects. The Columbia-Suicide Severity Rating Scale was used to investigate suicidality. RESULTS: A total of 800 suicidal people aged 15 years or older were enrolled from 8 university hospitals and 8 community mental health welfare centers (CMHWCs), among whom 480 (60%) were suicidal ideators and 320 (40%) were attempters. The ideators comprised 207 CC and 273 HC participants, whereas the attempters, 34 CC and 286 HC participants. Despite their lower severity in some measures, including suicidal ideation, compared with their HC counterparts, the CC participants within each group of ideators or attempters presented clinically significant psychopathology. Moreover, alcohol use problems and past suicide attempt were more likely to be found in CC participants. Only 11.1% to 21.6% of the participants in each of the four groups (defined by the cohorts and the ideators/attempters) were on any type of psychiatric treatment. CONCLUSIONS: Suicidal visitors to CMHWCs need to be as closely monitored as suicidal patients in university hospitals, especially considering their association with problem drinking and past suicide attempt. A cautious assumption is that the high suicide rate in Korea might be partly attributable to the low proportion of patients receiving psychiatric services. PMID- 30468989 TI - Impact of supports and partnership on family quality of life. AB - BACKGROUND: In recent decades, Family Quality of Life (FQOL) has emerged as a decisive construct, both to improve the living conditions of the families of people with disabilities and to assess the results on the services and supports that they receive. The aim of this research is to determine the perception of the families regarding their support needs, the quality of their partnerships with professionals, and their FQOL and then identify to what extent the supports of early childhood intervention centers have a positive impact on the families' FQOL while exploring whether the family-professional partnership has become a fundamental intervening factor of FQOL. METHOD: The participants were 202 families with children aged 0-6 with intellectual and developmental disabilities. We used the structural equation model to analyze the influence that the adequacy of the supports and the partnerships exerted on FQOL. RESULTS: The results indicate that the families have language and speech support needs for their children and information needs for themselves, and that they are mostly satisfied with their partnerships with the professionals and their FQOL. Our results also indicate that their degree of satisfaction with the support was a good predictor of FQOL and their ratings of partnership quality was a key factor interceding on this effect. CONCLUSIONS: This study provides professionals and public institutions with guidance when designing plans to improve early childhood intervention centers so the quality of life of these families and the progress of children with disabilities living in Spain become progressively stronger. PMID- 30468990 TI - Addressing adverse childhood experiences and health risk behaviors among low income, Black primary care patients: Testing feasibility of a motivation-based intervention. AB - OBJECTIVE: This pilot study tests the feasibility of implementing a two-session intervention that addresses adverse childhood experiences (ACEs), post-traumatic stress symptoms, and health risk behaviors (HRBs) among Black primary care patients. African Americans are disproportionately exposed to stressful and traumatic events and are at greater risk for PTSD than the general population. METHOD: A prospective cohort, experimental (pre-post) design with 2 post intervention assessments were used to evaluate the feasibility of a motivation based intervention for Black primary care patients with one or more ACEs. Indicators of feasibility implementation outcomes were assessed by participant adherence to treatment; suitability, satisfaction, and acceptability of the intervention; in addition to clinical outcomes of stress, HRBs, and behavioral health referral acceptance. RESULTS: Out of 40 intervention participants, 36 completed the intervention. Of the patients with one or more ACEs who participated in the intervention, 65% reported 4 or more ACEs and 58% had positive PTSD screens, and nearly two-thirds of those had at least one HRB. Satisfaction with the program was high, with 94% of participants endorsing "moderately" or "extremely" satisfied. The sample showed significant post intervention improvements in stress, alcohol use, risky sex, and nutrition habits. Although stress reduction continued through 2-month follow-up, unhealthy behaviors rebounded. Almost one-third of participants were connected to behavioral health services. CONCLUSIONS: Brief motivational treatment for ACEs is feasible in underserved primary care patients and could help individuals develop healthier ways of coping with stress and improve health. PMID- 30468988 TI - OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth. AB - Treatment of glioblastoma (GBM) remains a challenge using conventional chemotherapy, such as temozolomide (TMZ), and is often ineffective as a result of drug resistance. We have assessed a novel nitrone-based agent, OKN-007, and found it to be effective in decreasing tumor volumes and increasing survival in orthotopic GBM xenografts by decreasing cell proliferation and angiogenesis and increasing apoptosis. In this study, we assessed combining OKN-007 with TMZ in vivo in a human G55 GBM orthotopic xenograft model and in vitro in TMZ-resistant and TMZ-sensitive human GBM cell lines. For the in vivo studies, magnetic resonance imaging was used to assess tumor growth and vascular alterations. Percent animal survival was also determined. For the in vitro studies, cell growth, IC50 values, RNA-seq, RT-PCR, and ELISA were used to assess growth inhibition, possible mechanism-of actions (MOAs) associated with combined OKN-007 + TMZ versus TMZ alone, and gene and protein expression levels, respectively. Microarray analysis of OKN-007-treated rat F98 glioma tumors was also carried out to determine possible MOAs of OKN-007 in glioma-bearing animals either treated or not treated with OKN-007. OKN-007 seems to elicit its effect on GBM tumors via inhibition of tumorigenic TGF-beta1, which affects the extracellular matrix. When combined with TMZ, OKN-007 significantly increases percent survival, decreases tumor volumes, and normalizes tumor blood vasculature in vivo compared to untreated tumors and seems to affect TMZ-resistant GBM cells possibly via IDO-1, SUMO2, and PFN1 in vitro. Combined OKN-007 + TMZ may be a potentially potent treatment strategy for GBM patients. PMID- 30468991 TI - A precision medicine test predicts clinical response after idarubicin and cytarabine induction therapy in AML patients. AB - Complete remission (CR) after induction therapy is the first treatment goal in acute myeloid leukemia (AML) patients and has prognostic impact. Our purpose is to determine the correlation between the observed CR/CRi rate after idarubicin (IDA) and cytarabine (CYT) 3 + 7 induction and the leukemic chemosensitivity measured by an ex vivo test of drug activity. Bone marrow samples from adult patients with newly diagnosed AML were included in this study. Whole bone marrow samples were incubated for 48 h in well plates containing IDA, CYT, or their combination. Pharmacological response parameters were estimated using population pharmacodynamic models. Patients attaining a CR/CRi with up to two induction cycles of 3 + 7 were classified as responders and the remaining as resistant. A total of 123 patients fulfilled the inclusion criteria and were evaluable for correlation analyses. The strongest clinical predictors were the area under the curve of the concentration response curves of CYT and IDA. The overall accuracy achieved using MaxSpSe criteria to define positivity was 81%, predicting better responder (93%) than non-responder patients (60%). The ex vivo test provides better yet similar information than cytogenetics, but can be provided before treatment representing a valuable in-time addition. After validation in an external cohort, this novel ex vivo test could be useful to select AML patients for 3 + 7 regimen vs. alternative schedules. PMID- 30468992 TI - Periodontal mechanoreceptors and bruxism at low bite forces. AB - OBJECTIVE: In this study, we examined if 6-9 Hz jaw tremor, an indirect indicator of Periodontal Mechanoreceptor (PMR) activity, is different in bruxists compared to healthy participants during production of a low-level constant bite force. METHODS: Bite force and surface EMG from the masseter muscle were recorded simultaneously as participants (13 patients, 15 controls) held a force transducer between the upper and lower incisors very gently. RESULTS: Tremor in 6-9 Hz band for bruxists was greater on average compared to controls, but the difference was not significant, both for force recordings and EMG activity. CONCLUSIONS: The low effect sizes measured with the current protocol contrast highly with those of our previous study, where larger, dynamic bite forces were used, and where jaw tremor was markedly different in bruxists compared with controls. SIGNIFICANCE: We have now gained important insight into the conditions under which abnormal jaw tremor can be elicited in bruxism. From a scientific standpoint, this is critical for understanding the 'abnormality' of PMR feedback in bruxism. From a clinical perspective, our results represent progress towards the development of an optimal protocol in which jaw tremor can serve as a biological marker of bruxism. PMID- 30468993 TI - Gingival mesenchymal stem cells attenuate pro-inflammatory macrophages stimulated with oxidized low-density lipoprotein and modulate lipid metabolism. AB - OBJECTIVE: To examine the effects of gingival mesenchymal stem cells (GMSCs) on inflammatory macrophages upon oxidized low-density lipoprotein (ox-LDL) stimulation and evaluate therapeutic potential of GMSCs on mouse model of periodontitis associated with hyperlipidemia. METHODS: in vitro, GMSCs were co cultured with macrophages for 48 h in the absence or presence of M1 polarizing conditions and oxidized low-density lipoprotein in the transwell system. The supernatants were collected for ELISA. M1 and M2 markers of macrophages were analyzed by flow cytometry and PCR, and lipid accumulation was assessed by oil red O staining. in vivo, eighteen mice were divided into three groups (n = 6): Group A (periodontally healthy mice as control), Group B (periodontitis mice with hyperlipidemia), Group C (periodontitis mice with hyperlipidemia with the transplantation of GMSCs). The serum levels of cholesterol and inflammatory factors were measured by automatic analyzer. Bone regeneration was evaluated by Masson staining. RESULTS: When co-cultured with GMSCs, the M1 markers of Tumor Necrosis Factor (TNF) -alpha, Interleukin (IL) -6, Interleukin (IL) -1beta, CD86, and Human Leukocyte Antigen (HLA) -DR were significantly reduced. In contrast, M2 markers such as Interleukin(IL) -10 and CD206 were moderately increased. Similar results were obtained in the cell culture supernatants. In animal experiment, GMSCs suppressed the expression of sterol regulatory element binding transcription factor 1c (SREBP-1c) and elevated the levels of peroxisome proliferator-activated receptor alpha (PPARalpha) and peroxisome proliferator activator receptor- coactivator 1(PGC-1alpha) in the liver, attenuated cholesterol dysfunction via the downregulation of low-density lipoprotein (LDL) and total cholesterol (TC), and the upregulation of high-density lipoprotein (HDL), and decreased the levels of TNF-alpha and IL-6. Moreover, GMSC treatment improved bone regeneration. CONCLUSION: GMSCs inhibit the activation of M1 macrophages, regulate lipid metabolism and reduce inflammatory response, and promote bone regeneration in mouse model of periodontitis associated with hyperlipidemia. PMID- 30468994 TI - Immune response and evasion mechanisms in lip carcinogenesis: An immunohistochemical study. AB - OBJECTIVES: Programmed death ligand-1 (PD-L1) and human leukocyte antigen-G (HLA G) are considered immune checkpoint molecules that inhibit T-cell effectiveness, contributing to tumor immune escape. This study investigated PD-L1, HLA-G, CD8, and granzyme B (GrB) expression at different stages of lip carcinogenesis. DESIGN AND RESULTS: Forty cases of lip squamous cell carcinoma (LSCC), 55 actinic cheilitis (AC), and 10 healthy lip mucosa (HLM) were submitted to immunohistochemistry. Semiquantitative (PD-L1, HLA-G), and quantitative (CD8, GrB) analysis were performed. PD-L1 and HLA-G expression in neoplastic cells/keratinocytes and stroma/connective tissue was significantly higher in LSCC and AC, compared to HLM (p<0.05). PD-L1 was not associated with clinicopathological features of the lesions. HLA-G expression by malignant cells was significantly higher in LSCCs with distant metastasis (p = 0.041).CD8+ and GrB+ cell numbers progressively increased from HLMs to LSCC, with AC exhibiting intermediate numbers (p<0.01). Most LSCCs showed coexistence of PD-L1+ and CD8+ cells (72.5%). PD-L1 was directly correlated to CD8+ and GrB+ lymphocytic infiltration in LSCCs (p<0.05). Low cytotoxic immune response was associated with lymph node metastasis in LSCC (p<0.05). CONCLUSIONS: PD-L1 and HLA-G-mediated immune evasion mechanisms are likely to occur from early pre-malignant to advanced malignant stages of lip carcinogenesis, which might provide a rationale for therapeutic blockade of these pathways. PD-L1 expression in LSCCs was correlated with the cytotoxic markers, suggesting that PD-L1 may appear as an escape mechanism in response to an active antitumor response. PMID- 30468995 TI - Associations of gestational age with child health and neurodevelopment among twins: A nationwide Japanese population-based study. AB - BACKGROUND: The prevalence of multiple births has recently increased. However, the association between gestational age and long-term morbidity among twins remains unclear. AIMS: To examine the association of gestational age with child health and neurological development in early childhood among twins. STUDY DESIGN: Population-based longitudinal study. SUBJECTS: We included 947 children from 479 pairs of twins with information on gestational age. OUTCOME MEASURES: Hospitalization was used as an indicator of physical health, and responses to questions about age-appropriate behaviors were used as an indicator of neurobehavioral development. We conducted binomial log-linear regression analyses, controlling for both child and maternal variables in the model. We accounted for correlations within the pairs with generalized estimating equations. RESULTS: The early term group (i.e., 37 to 38 weeks of gestation) had a lower risk of poor child health and unfavorable neurodevelopment compared with the full term group (>=39 weeks of gestation) and preterm group (<37 weeks of gestation). Compared with the early term group, the adjusted risk ratios for hospitalization for all causes during the period from 7 to 18 months of age was 2.2 (95% confidence interval: 1.3-3.8) for very preterm children (<32 weeks of gestation), 1.1 (0.8-1.6) for moderately and late preterm children (32 to 36 weeks of gestation), and 1.8 (1.0-3.2) for full term children. CONCLUSION: We observed a U-shaped association of gestational age with child health and neurodevelopment. The early term group had the lowest risk of poor outcomes among twins. PMID- 30468996 TI - Generation of a human iPSC line, INMi002-A, carrying the most prevalent USH2A variant associated with Usher syndrome type 2. AB - We generated an induced pluripotent stem cell (iPSC) line using dermal fibroblasts from a patient with Usher syndrome type 2 (USH2). This individual was homozygous for the most prevalent variant reported in the USH2A gene, c.2299delG localized in exon 13. Reprogramming was performed using the non-integrative Sendai virus reprogramming method and the human OSKM transcription factor cocktail under feeder-free culture conditions. This iPSC line will be an invaluable tool for studying the pathophysiology of USH2 and for testing the efficacy of novel treatments. PMID- 30468998 TI - Initial cell maturity changes following transplantation in a hyaluronan-based hydrogel and impacts therapeutic success in the stroke-injured rodent brain. AB - Ischemic stroke results in a loss of neurons for which there are no available clinical strategies to stimulate regeneration. While preclinical studies have demonstrated that functional recovery can be obtained by transplanting an exogenous source of neural progenitors into the brain, it remains unknown at which stage of neuronal maturity cells will provide the most benefit. We investigated the role of neuronal maturity on cell survival, differentiation, and long-term sensorimotor recovery in stroke-injured rats using a population of human cortically-specified neuroepithelial progenitor cells (cNEPs) delivered in a biocompatible, bioresorbable hyaluronan/methylcellulose hydrogel. We demonstrate that transplantation of immature cNEPs result in the greatest tissue and functional repair, relative to transplantation of more mature neurons. The transplantation process itself resulted in the least cell death and phenotypic changes in the immature cNEPs, and the greatest acute cell death in the mature cells. The latter negatively impacted host tissue and negated any potential positive effects associated with cell maturity and the hydrogel vehicle, which itself showed some functional and tissue benefit. Moreover, we show that more mature cell populations are drastically altered during the transplantation process itself. The phenotype of the cells before and after transplantation had an enormous impact on their survival and the consequent tissue and behavioral response, emphasizing the importance of characterizing injected cells in transplantation studies more broadly. PMID- 30468997 TI - Analysis of the drivers of cost of management when patients with brain metastases are treated with upfront radiosurgery. AB - OBJECTIVES: We aimed to assess the driving factors for increased cost of brain metastasis management when using upfront stereotactic radiosurgery (SRS). PATIENT AND METHODS: 737 patients treated with upfront SRS without whole brain radiotherapy (WBRT). Patients were evaluated for use of craniotomy, length of hospital stay, need for rehabilitation or facility placement, and use of salvage SRS or salvage WBRT. Costs of care of these interventions were estimated based on 2013 Medicare reimbursements. Multiple linear regression was performed to determine factors that predicted for higher cost of treatment per month of life, as well as highest cumulative cost of care for brain metastasis. RESULTS: Mean cost of brain metastasis management per patient was $42,658, and $4673 per month of life. Upfront SRS represented the greatest contributor of total cost of brain metastasis management over a lifetime (49%), followed by use of any salvage SRS (21%), use of initial surgery (14%), use of salvage surgery (10%), hospitalization (3%) and cost of salvage WBRT (3%). Multiple linear regression identified brain metastasis velocity (BMV) (p < 0.001), use of cavity-directed SRS (<0.001), and CNS symptoms at time of presentation (p = 0.005) as factors that increased costs of care per month of survival. Use of salvage WBRT decreased per month cost of care in patients requiring salvage (p < 0.001). CONCLUSION: The cost of upfront SRS is the greatest contributor to cost of brain metastasis management when using upfront SRS. Higher BMV, progressive systemic disease and presence of symptoms are associated with increased cost of care. PMID- 30468999 TI - Silicate-based bioceramic scaffolds for dual-lineage regeneration of osteochondral defect. AB - Osteochondral defects are most commonly characterized by damages to both cartilage and bone tissues as a result of serious traumas or physical diseases; because these two tissues have their own unique biological properties, developing a single monophasic scaffold that can concurrently regenerate these two specific lineages becomes a challenge. To address this concern, a silicon-based bioceramic (SiCP) scaffold was fabricated. The efficiency and underlying mechanisms of SiCP for osteochondral defect regeneration were investigated. At 8 and 16 weeks post implantation in a rabbit model of osteochondral defect, gross morphology, histological, and micro-CT images showed that SiCP scaffolds distinctly promoted subchondral bone and cartilage regeneration when compared to calcium-phosphate based bioceramics (CP) scaffolds without silicon. In vitro, SiCP was also shown to promote bone marrow stem cells (BMSC) osteogenesis (ALP, RUNX2, OCN) and help maintain chondrocytes phenotype (Acan, Sox9, Col2a1), validated by qPCR, western blot, and RNA-sequencing (RNA-seq). Additionally, the descriptive analysis of RNA seq using Gene Ontology (GO) and KEGG pathway analysis revealed biological processes related to cartilage and bone development and extracellular matrices in chondrocytes, as well as related to early osteogenesis in BMSC, indicating that Si ions play an important role in the regeneration of both tissues. Conclusively, the development of silicon-based bioceramic scaffolds may be a promising approach for osteochondral defect regeneration due to their unique dual-lineage bioactivity. PMID- 30469000 TI - Risk assessment of toxicants on WHO TobReg priority list in mainstream cigarette smoke using human-smoked yields of Korean smokers. AB - Recently, the World Health Organization Study Group on Tobacco Product Regulation (WHO TobReg) announced a priority list of 38 toxicants among the more than 7000 chemicals found in cigarette smoke, building upon previous lists of toxicants in cigarette smoke. Here, we conducted a comprehensive study on the quantitative exposure and risk characterization of these priority toxicants in mainstream cigarette smoke listed by the WHO TobReg. The human-smoked toxicant yields estimated from spent cigarette butts of a total of 361 smokers using the part filter method (PFM) were applied to current exposure and risk estimation for the first time. The PFM can estimate human-smoked yields of toxicants using smokers' maximum mouth-level exposure. The human-smoked yield of each toxicant was converted to systemic uptake by considering bioavailability. Risk indicators including the incremental lifetime cancer risk (ILCR), cumulative ILCR, hazard quotient (HQ), hazard indices (HIs), and margin of exposure (MOE)-were estimated from the systemic uptake of toxicants combined with Korean exposure factors by gender and age group as well as for total smokers. It was demonstrated that cigarette smoking results in significant cancer and non-cancer health risks. A sensitivity analysis showed that the human-smoked toxicant yield is one of the most important contributors to risk level variations. Our risk estimation suggested that previous risk assessments might have ignored or underestimated the uncertainty of risk assessment. In conclusion, we assessed the risk level of the 38 toxicants on the priority list developed by the WHO TobReg and provided a Korean-specific priority list for the regulations on the emission of cigarette smoke. PMID- 30469001 TI - Photolysis of chloral hydrate in water with 254 nm ultraviolet: Kinetics, influencing factors, mechanisms, and products. AB - Chloral hydrate (CH) is a common disinfection by-product found in treated water, and its effective control is important to human health. This study evaluated the effects of some environmental factors (e.g., pH, CH dosage, typical ions) and operational variables (e.g., lamp power, irradiation time) on CH photolysis efficiency via low-pressure mercury lamp-induced ultraviolet (LPUV) at 254 nm. The results demonstrated that the photolysis rate increased significantly with increasing pH from 7.0 to 10.5 and lamp power from 6 to 12 W. Meanwhile, the presence of nitrate, iodide, or free chlorine facilitated CH photolysis, whereas the existence of natural organic matter hindered the process. Together, these factors may help explain varying CH photolysis in different types of waters: seawater > ultrapure water > tap water > lake water. In addition, the initial CH dosage also played an important role, with higher CH being degraded more slowly. Mechanistically, although no catalyst or oxidant was added, CH photolysis was to some extent inhibited by a hydroxyl radical quencher, tert-butyl alcohol, suggesting that indirect photolysis was also responsible for CH loss. In terms of reaction products, the CH photolysis yielded primarily chloride ions and carbon dioxide, thus supporting mineralization as the key pathway. The results may help better understand the control of CH in water using UV. PMID- 30469002 TI - Metabolism and spatial distribution of metalaxyl in tomato plants grown under hydroponic conditions. AB - Knowledge about translocation of plant protection products (PPP's) in plants is important to understand the uptake via the root system. Here we report the combination of analysis of tissue extracts by LC-HRMSn, autoradiography of 14C labeled compounds and MALDI-MSI, which combine qualitative and quantitative information of chemical composition and the spatial distribution of PPP's and their metabolites in situ. Therefore, the uptake of the phenylamide fungicide metalaxyl was studied in tomato plants (Solanum lycopersicum) using a hydroponic system. The plants have been cultivated in perlite until the two-leaf stage and were transferred into the hydroponic test system afterwards. The radioactive labeled fungicide was readily taken up by the roots during the normal water consumption and radioactivity was translocated uniformly to the aboveground part of the tomato plants, while only small proportion of the applied radioactivity were observed in the roots. The distribution of metalaxyl after the plant uptake experiment in the primary roots where analyzed by a transversal tissue section in the zone of maturation. Metalaxyl is mainly localized in root xylem and in cortex located at the epidermis. With LC-HRMSn and radiochemical analyses of stem and leaf, no parent compound was detectable. Four polar metabolites were the main identified components of the residue and could be visualized by MALDI-imaging mass spectrometry. With these results we could show, that the fungicide metalaxyl is taken up by the plant via the roots during the regular water consumption and transported to xylem. PMID- 30469003 TI - Application of ceramsite and activated alumina balls as recyclable bulking agents for sludge composting. AB - Composting is a major sludge-treatment method and bulking agents are very important in sludge composting. In this study, ceramsite and activated alumina balls were chosen as recyclable bulking agents for sludge composting. Variations in the temperature, pH, electrical conductivity, organic matter, dissolved organic carbon, moisture content, and heavy metals were detected during composting with different bulking-agent treatments as well as differences in the germination index values. The results showed that both bulking agents could ensure the maturity of the compost; further, ceramsite treatment resulted in the best water removal efficiency. According to the sequential extraction procedure, both ceramsite and activated alumina balls could stabilize Cd but they also increased the mobility of Zn. After comparing the effects of different particle sizes of ceramsite on composting, 20 mm was determined to be the most optimal value. Additionally, the recovery rates of ceramsite and activated alumina balls were 96.9% and 99.9%, respectively. PMID- 30469004 TI - Removal of natural organic matter and disinfection byproduct precursors from drinking water using photocatalytically regenerable nanoscale adsorbents. AB - Disinfection byproduct precursors (DBPs) were removed from raw surface water obtained from two Canadian drinking water treatment plants via adsorption to two regenerable linear engineered TiO2 nanomaterials (LENs). The temperature employed in the final heating step of the LEN synthesis procedure was varied to produce two distinct nanomaterials, NB 550 and NB 700. The LENs had similar dimensions but differed in terms of surface characteristics, surface area, and crystal structure. Unlike the commercial TiO2 nanoparticles, both LENs were easily removed from the treated water via settling or filtration. Although neither of the LENs were as effective for NOM adsorption as commercial nanoparticles, both were able to remove substantial amounts of DBP precursors. NB 550 reduced the trihalomethane (THM) formation potential of both water sources by up to 40% and their haloacetic acid (HAA) formation potential by approximately 50%. NB 700 reduced the THM formation potential of one water source by 25% and that of the other by 40%. HAA precursor removal by NB 700 ranged from 25% to 30%. The adsorption of DOC, UV254, THM precursors, and HAA precursors by commercial nanoparticles and the LENs fit a modified Freundlich adsorption isotherm model. When the LENs were regenerated via exposure to UVA light they experienced a gradual loss in adsorption capacity of up to 50% over five regeneration cycles. This loss occurred more quickly for the less photoactive of the two nanomaterials, and was affected by water source, suggesting that components of the water matrices may have interfered with regeneration. PMID- 30469005 TI - 4-Nonylphenol effects on rat testis and sertoli cells determined by spectrochemical techniques coupled with chemometric analysis. AB - Herein, vibrational spectroscopy has been applied for qualitative identification of biomolecular alterations that occur in cells and tissues following chemical treatment. Towards this end, we combined attenuated total reflection Fourier transform infrared (ATR-FTIR) and Raman spectroscopy to assess testicular toxicology after 4-nonylphenol (NP) exposure, an estrogenic endocrine disruptor affecting testicular function in rats and other species. Rats aged 21, 35 or 50 days received NP at intra-peritoneal doses of 0, 25, 50 or 100 mg/kg for 20 consecutive days. Primary Sertoli cells (SCs) were treated with NP at various concentrations (0, 2.5, 5, 10 or 20 MUM) for 12 h. Post-exposure, testicular cells, interstitial tissue and SCs were interrogated respectively using spectrochemical techniques coupled with multivariate analysis. Distinct biomolecular segregation between the NP-exposed samples vs. control were observed based on infrared (IR) spectral regions of 3200-2800 cm-1 and 1800-900 cm-1, and the Raman spectral region of 1800-900 cm-1. For in vivo experiments, the main wavenumbers responsible for segregation varied significantly among the three age classes. The main IR and Raman band differences between NP-exposed and control groups were observed for Amide (proteins), lipids and DNA/RNA. An interesting finding was that the peptide aggregation level, Amide ?-to-Amide II ratio, and phosphate-to-carbohydrate ratio were considerably reduced in ex vivo NP-exposed testicular cells or SCs in vitro. This study demonstrates that ATR-FTIR and Raman spectroscopy techniques can be applied towards analysing NP-induced testicular biomolecular alterations. PMID- 30469006 TI - Exposure to DBP induces the toxicity in early development and adverse effects on cardiac development in zebrafish (Danio rerio). AB - Dibutyl phthalate (DBP) is one of the most ubiquitous plasticizers used worldwide and has been frequently detected in soil, water, atmosphere, and other environmental media. DBP has become a ubiquitous environment contaminant and causes serious pollution. However, much attention has been paid to the toxicity of DBP, with only limited attention paid to its detrimental effects on the heart. In the present study, we investigated the toxicity of DBP in zebrafish embryo development, especially adverse effects on cardiac development. Embryos at 4-h post-fertilization (hpf) were exposed to different concentrations of DBP (0, 0.36, 1.8 and 3.6 MUM) until 72 hpf. Exposure to DBP resulted in morphological abnormalities in zebrafish embryos. Exposure to 1.8 MUM DBP significantly affected the growth, malformation rate, cardiac malformation rate and cardiac looping. Exposure to 3.6 MUM DBP significantly affected all endpoints. To preliminarily understand the underlying mechanisms of toxic effects of DBP on the embryo heart, we examined the expression of master cardiac transcription factors such as NKX2.5 and TBX5. The expression of this two transcription factors was significantly reduced with DBP treatment in a dose-dependent manner. Our results demonstrate that exposure to DBP resulted in zebrafish developmental toxicity, pericardial edema, cardiac structure deformities and function alteration, and changed the expression of master cardiac transcription factors such as NKX2.5 and TBX5. PMID- 30469007 TI - Transformation pathway and degradation mechanism of methylene blue through beta FeOOH@GO catalyzed photo-Fenton-like system. AB - To enhance the catalytic and separation properties of akaganeite nanoparticles, rice spike-like akaganeite impregnated graphene oxide (beta-FeOOH@GO) nanocomposite was fabricated through facile hydrolysis. The apparent first-order decolorization rate of methylene blue (MB) in beta-FeOOH@GO catalyzed photo Fenton-like system was 0.6322 min-1 about 3 folds that of prinstine beta-FeOOH nanoparticles. The degradation intermediates of MB adsorbed on the solid surface of beta-FeOOH@GO were comprehensively identified with time of flight-secondary ion mass spectroscopy (TOF-SIMS) for the first time. Newly identified sulfoxide intermediates, sulphone intermediates and desulfurization intermediates and N demethylaton or dedimethamine intermediates were reported for the first time. The proposed degradation pathway of MB predominantly proceeded with the rupture of phenothiazine rings oxided with OH, and singlet oxygen (1O2) radicals, which fully extending the reaction pathways proposed in previous work in literature. The enhanced catalytic activity of beta-FeOOH@GO was ascribed to the formation of heterojunctions confirmed by the presence of FeOC chemical bonds through X-ray photoelectron spectroscopy (XPS). The complete elimination of MB and its acute toxicity to Luminous bacteria showed that beta-FeOOH@GO would be served as a highly efficient Fenton-like catalyst for treatment of high concentration refractory organic contaminant. PMID- 30469008 TI - Assessment of the cytotoxicity, antioxidant activity and chemical composition of extracts from the cyanobacterium Fischerella major Gomont. AB - Cyanoprokaryotes (Cyanobacteria/Cyanophyta) are ancient photosynthetic prokaryotic organisms with cosmopolitan distribution. They are producers of a number of biologically active substances with antitumor and antifungal activity, vitamins, antibiotics, algaecides, insecticides, repellents, hormones, immunosuppressants and toxins. So far, the cyanobacterium Fischerella major Gomont has not been studied regarding its impact on the environment and human health. In this study, the cytotoxic, antioxidant and antitumor activities of four extracts prepared from Fischerella major were evaluated in vitro. In addition, the total phenolic content and the potential for production of cyanotoxins were also analyzed. The conducted GC/MS analysis identified 45 compounds with different chemical nature and biological activity. Presence of microcystins and saxitoxins was detected in all Fischerella major extracts. In vitro testing on cell cultures showed a significant concentration- and time dependent cytotoxic effect on all cell lines (HeLa, SK-Hep-1 and FL) treated at three exposure times (24, 48 and 72 h) with four extracts. A selective antitumor effect was not observed. This is the first study demonstrating biological activity of extracts from Fischerella major, which makes it an interesting subject for further research, including environmental risk assessments (as producer of cyanotoxins) or as a potential source of pharmaceuticals. PMID- 30469009 TI - Sensitivity to criticism and praise predicts schizotypy in the non-clinical population: The role of affect and perceived expressed emotion. AB - BACKGROUND: Schizotypy represents a cluster of personality traits consisting of magical beliefs, perceptual aberrations, disorganisation, and anhedonia. Schizotypy denotes a vulnerability for psychosis, one reason being psychosocial stress. High expressed emotion (EE), a rating of high criticism, hostility, and emotional over-involvement from a close relative, denotes psychosocial stress and vulnerability to psychosis, and is associated with schizotypy. This study aimed to decipher the relationship of schizotypy to perceived criticism and perceived praise in terms of affect and perceived EE. METHODS: Ninety-eight healthy participants listened to short audio-clips containing criticism, praise, and neutral comments from a stranger, and evaluated them in terms of the comments' arousal and personal relevance. Participants also answered self-report questionnaires of schizotypy, depression, mood, and perceived EE. Correlational analyses tested the relationship between schizotypy and the evaluations of criticism and praise. Mediation analyses then tested whether depression, positive mood, and perceived EE explained these relationships. RESULTS: Greater relevance of standard criticism correlated with higher positive schizotypy. This association was fully mediated by high depression and perceived irritability from a close relative. Lower relevance of standard praise correlated with higher cognitive disorganisation (another schizotypal trait). This relationship was partially mediated by low positive mood and high perceived intrusiveness from a close relative. CONCLUSION: Greater perceived criticism and lower perceived praise predict schizotypy in the healthy population. Affect and interpersonal sensitivity towards a close relative explain these relationships, such that depression increases perceived criticism, and positive mood increases perceived praise. Perceived EE defines the interpersonal nature of schizotypy. PMID- 30469010 TI - The problem of mephedrone in Europe: Causes and suggested solutions. PMID- 30469011 TI - Introduction of a new fetal examination protocol for on-field and clinical equine practice. AB - Prepartum fetal surveillance techniques have been widely used in both human and veterinary obstetrics, although these tests differ in their sensitivity for the assessment of fetal well-being. In equine reproduction, the 'gold standard' examination technique is the equine biophysical profile (EBP) described by Virginia Reef in 1995. Although this fetal assessment has many benefits, its accuracy, sensitivity and specificity have not been evaluated so far. In this study, 129 late-term pregnant mares were scanned twice in their last month of gestation using two different protocols (the EBP and a new, rapid examination protocol, REP) in order to determine the accuracy of these tests. The REP included the determination of fetal heart rate, fetal aortic diameter and the combined thickness of the uteroplacental unit. Twenty-seven fetuses proved to be compromised and 102 mares had healthy asymptomatic foals. Statistical analyses showed slight differences in test sensitivity (81.48% and 85.19%), specificity (83.3% and 87.25%) and accuracy (82.95% and 86.82%) for EBP and REP, respectively. Furthermore, a statistically significant interchangeability could be demonstrated between the two methods. It is concluded that, depending on the prevalence of the disease (here: compromised state), both methods are useful for the diagnosis of fetal abnormalities and make it possible to provide satisfactory care for broodmares and their fetuses. PMID- 30469012 TI - FMRP Interacts with C/D Box snoRNA in the Nucleus and Regulates Ribosomal RNA Methylation. AB - FMRP is an RNA-binding protein that is known to localize in the cytoplasm and in the nucleus. Here, we have identified an interaction of FMRP with a specific set of C/D box snoRNAs in the nucleus. C/D box snoRNAs guide 2'O methylations of ribosomal RNA (rRNA) on defined sites, and this modification regulates rRNA folding and assembly of ribosomes. 2'O methylation of rRNA is partial on several sites in human embryonic stem cells, which results in ribosomes with differential methylation patterns. FMRP-snoRNA interaction affects rRNA methylation on several of these sites, and in the absence of FMRP, differential methylation pattern of rRNA is significantly altered. We found that FMRP recognizes ribosomes carrying specific methylation patterns on rRNA and the recognition of methylation pattern by FMRP may potentially determine the translation status of its target mRNAs. Thus, FMRP integrates its function in the nucleus and in the cytoplasm. PMID- 30469013 TI - USP10 Is a Driver of Ubiquitinated Protein Aggregation and Aggresome Formation to Inhibit Apoptosis. AB - Accumulation of ubiquitinated proteins is cytotoxic, but cells inactivate these cytotoxicities by inducing aggresome formation. We found that ubiquitin-specific protease 10 (USP10) inhibits ubiquitinated protein-induced apoptosis by inducing aggresome formation. USP10 interacted with the ubiquitin receptor p62 and the interaction augmented p62-dependent ubiquitinated protein aggregation and aggresome formation, thereby cooperatively inhibiting apoptosis. We provide evidence that USP10/p62-induced protein aggregates inhibit proteasome activity, which increases the amount of ubiquitinated proteins and promotes aggresome formation. USP10 induced aggresomes containing alpha-synuclein, a pathogenic protein in Parkinson disease, in cultured cells. In Parkinson disease brains, USP10 was colocalized with alpha-synuclein in the disease-linked aggresome-like inclusion Lewy bodies, suggesting that USP10 inhibits alpha-synuclein-induced neurotoxicity by promoting Lewy body formation. Collectively, these findings suggest that USP10 is a critical factor to control protein aggregation, aggresome formation, and cytotoxicity in protein-aggregation-related diseases. PMID- 30469014 TI - Transcriptome Deconvolution of Heterogeneous Tumor Samples with Immune Infiltration. AB - Transcriptome deconvolution in cancer and other heterogeneous tissues remains challenging. Available methods lack the ability to estimate both component specific proportions and expression profiles for individual samples. We present DeMixT, a new tool to deconvolve high-dimensional data from mixtures of more than two components. DeMixT implements an iterated conditional mode algorithm and a novel gene-set-based component merging approach to improve accuracy. In a series of experimental validation studies and application to TCGA data, DeMixT showed high accuracy. Improved deconvolution is an important step toward linking tumor transcriptomic data with clinical outcomes. An R package, scripts, and data are available: https://github.com/wwylab/DeMixTallmaterials. PMID- 30469016 TI - Positive impact of DNA contamination minimization procedures taken within the laboratory. AB - DNA contamination incidents are one of the most frequent sources of error in forensic genetics and can have serious consequences. It is therefore essential to take measures to prevent these events and to monitor the real impact of contamination minimization procedures. In this study, we review and compare the number of contamination events detected on trace samples analyzed by the Forensic Genetic Unit (FGU) of the University Center of Legal Medicine in Switzerland before and after the implementation of new contamination minimization procedures. Interestingly, the number of contamination events by laboratory staff was significantly reduced by more than 70% after the implementation of the procedures. However, no significant change was observed for contamination events by police collaborators. This difference is likely to be explained by the differential impact of procedures taken in the laboratory and on crime scene. It suggests that the reduction observed for laboratory contamination incidents is due to the new procedures taken. In conclusion, our study highlights that taking appropriate measures is efficient and can reduce the number of contamination incidents. However, it is important that such contamination minimization procedures be implemented all along the chain of analysis of a stain (i.e. from crime scene to the laboratory). PMID- 30469015 TI - The effects of playing two consecutive matches in the shoulder rotational profiles of elite youth badminton players. AB - OBJECTIVE: The aim of the present study was to analyse the effects of playing two badminton matches on the same day on the shoulder profile (i.e., range of motion (ROM) and strength) of young badminton players. DESIGN: Cross-sectional study. SETTING: Indoor sports facility. PARTICIPANTS: Thirty-one elite junior badminton players (age 16.6 +/- 1.0 years, body mass 63.9 +/- 6.1 kg, height 174.8 +/- 6.1 cm), including 19 boys and 12 girls. MAIN OUTCOME MEASURES: Shoulder passive internal rotation (IR) and external rotation (ER) ROM as well as shoulder IR/ER maximal isometric strength were measured before and after a competition including two competitive matches. RESULTS: Significant decreases (p < 0.05) were found in the shoulder ROM (i.e., dominant and non-dominant ER ROMs as well as in the dominant and non-dominant total arc of motion [TAM]) in boys, while in girls, significant increases (p < 0.05) were found in the non-dominant ER absolute strength, with significant decreases were found in the non-dominant ER ROM and the non-dominant TAM. CONCLUSION: Playing two badminton matches on the same day led to gender-specific changes on the shoulder profile (i.e., ROM and strength) of young elite badminton players, with more impact on the shoulder profile of boys compared to girls. PMID- 30469017 TI - Large scale DNA identification: The ICMP experience. AB - The International Commission on Missing Persons (ICMP) is a treaty-based international organization with a global mandate to address the issue of missing persons. It works with governments, civil society organizations, and others, and utilizes data systems and technical assistance in forensic science. ICMP's initial work focused on the ~40,000 people missing in the Western Balkans from the conflicts of the 1990s. A "DNA-led" approach to large-scale DNA identification of the missing was developed, based on high-throughput autosomal STR testing of skeletal remains from mass graves and other sites, and the establishment of a regional database of DNA profiles from family members of the missing. Database pairwise and pedigree kinship searching is conducted using in house DNA matching software, the Identification Data Management System (iDMS), providing high-certainty DNA matches that are integrated in a multi-disciplinary identification process. Anthropological guidelines for sampling skeletal remains for DNA testing are based on tens of thousands of tests from a wide range of skeletal elements, allowing for prioritization based on DNA preservation. Large scale collection of family reference samples has been conducted, resulting in a database of more than 100,000 family reference DNA profiles across all projects and delivering family DNA match reports for more than 20,000 individuals. From the 1995 Srebrenica event, ICMP provided DNA matches for 6887 of the ~8000 missing from that event. In assistance to justice, ICMP has provided extensive evidence and expert testimony in multiple war crimes trials, including those conducted at the ICTY. This article provides an overview of ICMP's technical involvement over the last 17 years in areas of DNA testing and database matching, and training and capacity building projects with partners. It also touches on the development of massively parallel sequencing (MPS) strategies specifically tailored to missing persons applications. PMID- 30469018 TI - Clinical metric for differentiating intracranial hemangiopericytomas from meningiomas using diffusion weighted MRI. AB - PURPOSE: Intracranial Hemangiopericytomas (IHP) are dural based tumors that frequently recur/metastasize. Unfortunately, their imaging appearance overlaps significantly with more benign meningiomas. We evaluated the use of diffusion weighted imaging (DWI) to differentiate IHP from meningioma. METHODS: We compared MRI of IHP tumors (WHO Grades II/III) (n = 20) to meningioma (n = 48, WHO Grade I/II). FINDINGS: ADC values differed between IHP (1.05 * 10-3 mm2/s) and meningiomas (0.89 * 10-3 mm2/s) (p = 0.05). Normalized ADC ratios (nADC), differed between IHP and meningiomas (1.30 vs 1.07, p = 0.03). CONCLUSION: Importantly, a nADC cutoff of >1.3 was specific (96%) but not sensitive (35%) for identifying IHP. PMID- 30469019 TI - Modelling anaerobic, aerobic and partial nitritation-anammox granular sludge reactors - A review. AB - Wastewater treatment processes with granular sludge are compact and are becoming increasingly popular. Interest has been accompanied by the development of mathematical models. This contribution simultaneously reviews available models in the scientific literature for anaerobic, aerobic and partial nitritation-anammox granular sludge reactors because they comprise common phenomena (e.g. liquid, gas and granule transport) and thus pose similar challenges. Many of the publications were found to have no clearly defined goal. The importance of a goal is stressed because it determines the appropriate model complexity and helps other potential users to find a suitable model in the vast amount of literature. Secondly, a wide variety was found in the model features. This review explains the chosen modelling assumptions based on the different reactor types and goals wherever possible, but some assumptions appeared to be habitual within fields of research, without clear reason. We therefore suggest further research to more clearly define the range of operational conditions and goals for which certain simplifying assumptions can be made, e.g. when intragranule solute transport can be lumped in apparent kinetics and when biofilm models are needed, which explicitly calculate substrate concentration gradients inside granules. Furthermore, research is needed to better mechanistically understand detachment, removal of influent particulate matter and changes in the mixing behaviour inside anaerobic systems, before these phenomena can be adequately incorporated in models. Finally, it is suggested to perform full-scale model validation studies for aerobic and anammox reactors. A spreadsheet in the supplementary information provides an overview of the features in the 167 reviewed models. PMID- 30469020 TI - Occurrence and distribution of viruses and picoplankton in tropical freshwater bodies determined by flow cytometry. AB - This study aimed to examine the drivers in shaping the occurrence and distribution of total viruses and picoplankton in tropical freshwater ecosystems. Flow cytometry was used to quantify the concentrations of total viruses, picoheterotrophs, picophytoplankton, and picocyanobacteria. Three land use patterns (urban-, agriculture- and parkland-dominated) were evaluated using ArcGIS. Significant correlations were observed between water-borne microbial targets and water quality parameters (0.175 <= |r| <= 0.441), nutrients (0.250 <= r <= 0.570) and land use factors (0.200 <= |r| <= 0.460). In particular, the concentrations of total viruses and picoheterotrophic cells were higher in catchments whereas the abundances of picophytoplankton and picocyanobacteria were higher in reservoirs. Total viruses and picoplankton had higher concentrations in urban- and agriculture-dominated areas, probably due to anthropogenic inputs and agricultural inputs, respectively. Although surface water is a complex matrix influenced by niche-based (i.e., physicochemical properties, nutrients, land use impact etc.) and neutral-based factors (i.e., ecological drift, dispersal and species), land use patterns could help to elucidate the occurrence and distribution of the total microbial community at the macroscopic level. Meanwhile, inter-correlations among viruses, picoplankton and picoheterotrophs (0.715 <= r <= 0.990) also substantiates their mutual interactions in influencing the microbial community. Furthermore, the relationships between total microbial cells and bacterial and viral indicators were also investigated. Concentrations of total viruses, picoplankton and picoheterotrophs were positively correlated with bacterial indicators (0.427 <= r <= 0.590) and viral indicators (0.201 <= r <= 0.563). These results indicated that faecal and viral contamination could contribute to the numbers of total viruses and bacteria. PMID- 30469021 TI - AFISsys - An autonomous instrument for the preservation of brackish water samples for microbial metatranscriptome analysis. AB - Microbial communities are the main drivers of biogeochemical cycling of multiple elements sustaining life in the ocean. The rapidity of their response to stressors and abrupt environmental changes implies that even fast and infrequent events can affect local transformations of organic matter and nutrients. Modern molecular techniques now allow for monitoring of microbial activities and functions in the environment through the analysis of genes and expressed genes contained in natural microbial assemblages. However, messenger RNA turnover in cells can be as short as 30 seconds and stability varies greatly between transcripts. Sampling of in situ communities involves an inevitable delay between the collection of seawater and the extraction of its RNA, leaving the bacterial communities plenty of time to alter their gene expression. The characteristics of microbial RNA turnover make time-series very difficult because samples need to be processed immediately to limit alterations to the metatranscriptomes. To address these challenges we designed an autonomous in situ fixation multi-sampler (AFISsys) for the reliable sampling of microbial metatranscriptomes at frequent intervals, for refined temporal resolution. To advance the development of this instrument, we examined the minimal seawater volume necessary for adequate coverage of community gene expression, and the suitability of phenol/ethanol fixation for immediate and long-term preservation of transcripts from a microbial community. We then evaluated the field eligibility of the instrument itself, with two case studies in a brackish system. AFISsys is able to collect, fix, and store water samples independently at a predefined temporal resolution. Phenol/ethanol fixation can conserve metatranscriptomes directly in the environment for up to a week, for later analysis in the laboratory. Thus, the AFISsys constitutes an invaluable tool for the integration of molecular functional analyses in environmental monitoring in brackish waters and in aquatic environments in general. PMID- 30469022 TI - Tocilizumab in MOG-antibody spectrum disorder: a case report. AB - BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-related spectrum disorders (MOG-SD) are a heterogeneous group of inflammatory demyelinating diseases of the central nervous system, usually responsive to conventional immunosuppressive therapies. However, knowledge about treatment of non-responder patients is scarce. METHODS: We report on a 20-year-old MOG-SD patient who experienced clinical deterioration despite rituximab-induced B-cell depletion. RESULTS: Rescue therapy with tocilizumab (TCZ) prevented further relapses, with reduction of spinal-cord load on MRI, and a remarkable reduction of disability at the two-year follow-up. CONCLUSION: Our observations suggest that TCZ could induce clinico-radiologic improvements, which make it as an option for the treatment of MOG-SD. PMID- 30469023 TI - Sequential phases of RGC axonal and somatic injury in EAE mice examined using DTI and OCT. AB - BACKGROUND: Clinical imaging modalities including optical coherence tomography (OCT) and diffusion tensor imaging (DTI) are vital in Multiple Sclerosis (MS), but their relationships during the different phases of Retinal ganglion cell (RGC) degeneration are not clear. We hypothesize that initial injury in optic nerve causes axonal degeneration leading to RGC loss in retina, which can be characterized by a combination of DTI and OCT. Our objective was to examine the correlation between noninvasive and histological data to chronicle the degeneration profile of RGCs in the retina and optic nerve in a mouse model of MS. MATERIALS AND METHODS: Experimental Autoimmune Encephalomyelitis (EAE) was induced in 11 C57Bl/6 mice, with 8 mice reserved as controls. OCT and DTI was conducted 2-8 weeks after induction of EAE. The thickness of the retinal ganglion cell complex (GCC) was measured using OCT and compared to DTI indices measured in optic nerves. End-stage histology was used to quantify axon/myelin loss in the optic nerve and retinal thinning/RGC loss in the retina. RESULTS: Significant changes in DTI-derived Axial Diffusivity (AD, -17.2%) and Trace Diffusivity (TR, 18.3%) began after 2 weeks of EAE. Later significant reductions in Fractional Anisotropy (FA) and AD, with increases in Radial Diffusion (RD) were apparent after 4 and 8 weeks. OCT-derived measures of GCC thickness were reduced after 4 weeks, and reached significant reduction after 8 weeks. Among EAE mice, DTI (FA, AD and RD measures) and OCT measures were all significantly correlated after 4 and 8 weeks. Among histology measures, RGC density (-23%), RGC size (-27%), and the number of SMI31+ axons (-54%) were reduced significantly. DTI measures of FA and AD along with GCC thinning were the best independent predictors of axon loss. CONCLUSIONS: DTI and OCT measures are tightly correlated during the chronic phase of axonal degeneration (4-8 weeks) in EAE mice. After 8 weeks of EAE, both OCT and DTI measures are strong predictors of axon loss in the Optic Nerve. PMID- 30469024 TI - Novel alginate particles decorated with nickel for enhancing ciprofloxacin removal: Characterization and mechanism analysis. AB - The extensive occurrence of antibiotics (such as ciprofloxacin) in aqueous environment had raised severe concerns due to their impacts on humans and the ecosystem. In this study, a novel nickel alginate particles adsorbent had been successfully developed by combining an alginate matrix with nickel ion through immobilization and crosslinking technology and then was applied for the batch adsorption study of ciprofloxacin to evaluate its potential performance. The as prepared adsorbent exhibited excellent adsorption performance at the condition of the pH 7 and 328.15 K, and the results indicated that the maximum adsorption capacity was 135.18 mg g-1. The isotherm and kinetic studies were well fitted to the Langmuir and pseudo-second-order models, respectively. A thermodynamics analysis displayed that the ciprofloxacin adsorption process was endothermic, feasible and spontaneous. The as-prepared adsorbent before and after adsorption was characterized through SEM, EDX and XPS analyses, and the particle size of the as-prepared adsorbent was roughly 914 um. Hydrogen bond, the cation bonding bridge and n-pi electron-donor-acceptor interaction might be the driving force of the ciprofloxacin adsorption process. This study demonstrated that this as prepared adsorbent was a promising and efficient material for the ciprofloxacin adsorption from the aqueous solution. PMID- 30469025 TI - The human biomonitoring study in Serbia: Background levels for arsenic, cadmium, lead, thorium and uranium in the whole blood of adult Serbian population. AB - The purpose of this study was to establish reference values (RVs) for the occupationally- and environmentally-important toxic elements in the whole blood of adult Serbian population for the first time. Contaminated drinking water with arsenic, high share of smokers in the country, removing tetraethyl lead from the gasoline and war attack at the end of the twentieth century were some of the reasons to provide background information for arsenic (As), cadmium (Cd), lead (Pb), thorium (Th), and uranium (U) in the blood of the Serbian population. The whole blood samples were collected from the healthy respondents living in the Belgrade and surrounding areas of the capital (n = 305; w/m ratio = 154/151; mean age: 41 +/- 2). The concentrations of toxic metals were determined by inductively coupled plasma-mass spectrometry (ICP-MS). Reference values were estimated as the lower limit (LL) and upper limit (UL) of the 95% confidence interval (CI), together with the selected percentiles (P2.5-P97.5). The obtained geometric mean (GM) for As, Cd, Pb, Th, and U were: 0.50 ng/g, 0.32 ng/g, 20.94 ng/g, 0.30 ng/g, and 0.06 ng/g, respectively. The influences of age, sex and lifestyle on results were considered. Women have significantly higher levels of Cd and Th than men. The increased level of Th was observed in the aged group below 40 years, while smokers had significantly higher levels of Pb and double higher level of Cd in the blood than non-smokers (p < 0.05). In comparison with other population groups worldwide, the Serbian population had significantly higher levels of Th and U (up to 100 times higher). These findings could contribute to better understanding of the molecular basis for the development of various health hazards, including the increased incidence of cancer among the Serbian population which need be confirmed by clinical studies. PMID- 30469026 TI - Role of fluoride induced epigenetic alterations in the development of skeletal fluorosis. AB - Fluoride is an essential trace element required for proper bone and tooth development. Systemic high exposure to fluoride through environmental exposure (drinking water and food) may result in toxicity causing a disorder called fluorosis. In the present study, we investigated the alteration in DNA methylation profile with chronic exposure (30 days) to fluoride (8 mg/l) and its relevance in the development of fluorosis. Whole genome bisulfite sequencing (WGBS) was carried out in human osteosarcoma cells (HOS) exposed to fluoride. Whole genome bisulfite sequencing (WGBS) and functional annotation of differentially methylated genes indicate alterations in methylation status of genes involved in biological processes associated with bone development pathways. Combined analysis of promoter DNA hyper methylation, STRING: functional protein association networks and gene expression analysis revealed epigenetic alterations in BMP1, METAP2, MMP11 and BACH1 genes, which plays a role in the extracellular matrix disassembly, collagen catabolic/organization process, skeletal morphogenesis/development, ossification and osteoblast development. The present study shows that fluoride causes promoter DNA hypermethylation in BMP1, METAP2, MMP11 and BACH1 genes with subsequent down-regulation in their expression level (RNA level). The results implies that fluoride induced DNA hypermethylation of these genes may hamper extracellular matrix deposition, cartilage formation, angiogenesis, vascular system development and porosity of bone, thus promote skeletal fluorosis. PMID- 30469027 TI - Effect of the earthquake-tsunami (Chile, 2010) on toxic metal content in the Chilean abalone mollusc Concholepas concholepas. AB - Toxic metal content were measured in samples of mollusc Concholepas concholepas obtained from the Chilean coast. Samples were collected during two periods, one before and one after the earthquake-tsunami which occurred in the Maule Region, Chile, February 27th, 2010 as a result of an earthquake with a magnitude of 8.8. Quantification of toxic metals in samples of hepatopancreas and muscle tissue was performed using flame atomic absorption spectroscopy. The analytical methodology was validated with certified reference material. The content means measured in muscle tissue for January 2010 were Cu: 10.3; Cr: 0.7; Cd: < 0.1; Mn: 3.6 and Zn: 38.6 ug g-1 (dry weight). For October 2014, the means were Cu: 8; Cr: 2.4; Cd: < 0.1; Mn: 5.6 and Zn: 45.4 ug g-1 (dry weight). In hepatopancreas tissue, the content means were Cu: 14.8; Cr: 2.4; Cd: 246.2; Mn: 4.4 and Zn: 1552.9 ug g-1 (dry weight). For October 2014, the means were Cu: 53.7; Cr: 3.5; Cd: 118; Mn: 13.4 and Zn: 1352.3 ug g-1 (dry weight). Cd, Cr, Cu, Mn and Zn content in the samples of hepatopancreas were generally higher than those recorded in muscle tissue however they were not always statistically significant. Statistical analysis showed that Cu and Mn content in the post-tsunami period increased in the hepatopancreas tissue. The concentrations of Cd, Cr, Cu, Mn, and Zn measured in the muscular tissue (edible part) of the species Conchalepas concholepas, were lower than the maximum contents allowed by the current legislation (FAO/WHO, 2004; EU, 2001) and its consumption is not a risk to human health. PMID- 30469028 TI - Organic residues and biochar to immobilize potentially toxic elements in soil from a gold mine in the Amazon. AB - Waste from gold mining (Au) is a threat to the ecosystem and human health because it contains high levels of potentially toxic elements (PTEs). Organic waste and biochar can be used to recover contaminated soils from mining areas because they have the potential to immobilize PTEs and improve soil fertility, enabling revegetation. The objective of this study was to investigate the efficiency with which organic residues and biochar immobilize PTEs in a multicontaminated soil of a small-scale Au mine in the state of Para. The soil from a gold mining area was mixed with different proportions (v/v) of coffee ground residues (Bcoffee), Brazil nut tegument residues (BN), acai palm stone residues (A), and Brazil nuts biochar residues to determine which treatment is best for immobilizing PTEs. The treatments with the addition of BN and A resulted in low pH and high contents of organic matter (OM) and phosphor (P) The BN increased the available levels of Ba and reduced the available levels of Ni. The addition of coffee ground residues and biochar increased the uptake of Ba, Pb, and Ni in lettuce plants compared to treatments with BN and A. Plants grown with A showed higher dry matter yield and lower absorption and translocation of PTEs. Thus, the addition of BN and A residues in PTE phytostabilization programs in PTE-multicontaminated soils is a potential possibility. PMID- 30469029 TI - Adsorption characteristics of nitrite on natural filter medium: Kinetic, equilibrium, and site energy distribution studies. AB - Nitrite is one of the world's major contaminants in drinking water resources, and granular anthracite is often used as filter medium in water treatment. In this study, the adsorption characteristics of nitrite on granular anthracite under various temperatures were investigated through adsorption kinetic, isotherm models, and site energy distribution theory. The adsorption of nitrite on granular anthracite was an endothermic reaction, while intraparticle diffusion was not the only rate control step. The adsorption could be well described by using pseudo-second-order and Langmuir-Freundlich equations. The adsorption capacity was 402.51 mg NO2--N kg-1 at 298 K, which could be significantly improved to 1380.1 mg NO2--N kg-1 when the temperature reached 308 K. Furthermore, nitrite ions first occupied the high-energy adsorption sites and then diffused to the low-energy adsorption sites on granular anthracite. There were more sites, including high-energy sites and low-energy sites, for nitrite adsorption at 308 K. Besides, the thickness of the boundary layer increased with the adsorption capacity improved at a higher temperature, and nitrite ions were adsorbed mainly through chemical mechanisms. Moreover, the neutral pH was helpful for the adsorption. The presence of co-existing ions could limit the adsorption and the effect followed the order of PO43- > CO32- > SO42- > NO3- > Cl-. The saturated anthracite could be effectively regenerated by 0.2 mol L-1 HCl solution. Therefore, the granular anthracite used as filter medium also has a possible application as a nitrite scavenger at the same time. PMID- 30469031 TI - Lead removal from aqueous solution by means of integral natural clays honeycomb monoliths. AB - Different natural Moroccan clays were used as adsorbents for the removal of lead from aqueous solution. The study was performed not only employing the starting clays in the form of powder but also after their extrusion as honeycomb monoliths, this representing the major novelty of this work respect to the current state-of-art. The experiments were done in batch conditions with continuous stirring and using a recirculated flow, respectively. In addition to an exhaustive characterization of the clays by means of X-ray fluorescence, X-ray diffraction, thermogravimetric analysis, laser granulometry, N2 physisorption, infrared spectroscopy, SEM-EDS and evaluation of the cation exchange capacity, special attention was paid to the influence on the lead adsorption of variables such as adsorbent dosage, pH, contact time with the adsorbate and initial concentration of lead. Considering the cheap and abundant character of the raw materials, their easy processing (no additives were required for their extrusion) and the time and energy save due to no need for further modification through chemical/thermal activation, the obtained results (with retention over 90% for 30 ppm of lead) demonstrated the potential of the proposed design as low cost solution that may be competitive versus other technologies for water depollution, especially in developing regions. PMID- 30469030 TI - Selenium-binding protein 1 (SELENBP1) is a marker of mature adipocytes. AB - Selenium-binding protein 1 (SELENBP1) has recently been reported to catalyse the oxidation of methanethiol, an organosulfur compound produced by gut microbiota. Two of the reaction products of methanethiol oxidation, hydrogen peroxide and hydrogen sulphide, serve as signalling molecules for cell differentiation. Indeed, colonocyte differentiation has been found to be associated with SELENBP1 induction. Here, we show that SELENBP1 is induced when 3T3-L1 preadipocytes undergo terminal differentiation and maturation to adipocytes. SELENBP1 induction succeeded the up-regulation of known marker proteins of white adipocytes and the intracellular accumulation of lipids. Immunofluorescence microscopy revealed predominant cytoplasmic localisation of SELENBP1 in 3T3-L1 adipocytes, as demonstrated by co-staining with the key lipogenic enzyme, acetyl-CoA-carboxylase (ACC), located in cytosol. In differentiating 3T3-L1 cells, the mTOR inhibitor rapamycin and the pro-inflammatory cytokine tumour necrosis factor alpha (TNF alpha) likewise suppressed SELENBP1 induction, adipocyte differentiation and lipid accumulation. However, lipid accumulation per se is not linked to SELENBP1 induction, as hepatic SELENBP1 was down-regulated in high fructose-fed mice despite increased lipogenesis in the liver and development of non-alcoholic fatty liver disease (NAFLD). In conclusion, SELENBP1 is a marker of cell differentiation/maturation rather than being linked to lipogenesis/lipid accumulation. PMID- 30469032 TI - Co-site substitution by Mn supported on biomass-derived active carbon for enhancing magnesia desulfurization. AB - Oxidation of magnesium sulfite (MgSO3) is a crucial step for reclaiming the product in wet magnesia desulfurization processes. Here, for enhancing this reaction, a bimetallic catalyst was developed by loading CoOx and MnOx species on a biomass-derived active carbon (AC) support to minimize the costs and potential environmental risks during catalyst application. The substitution effect of Mn to Co sites was investigated, and a comparison of the catalyst with plain cobalt suggested that the ratio of Co/Mn must be greater than 3. A series of catalyst characterizations was performed to reveal the synergistic effect of Co and Mn in the bimetallic catalyst. The introduction of Mn species not only improved the dispersion of CoOx-MnOx mixed oxide but also generated abundant Co3+ species and surface-adsorbed oxygen, both of which acted as the main active sites for sulfite oxidation. Notably, in the bimetallic catalyst, the presence of Mn4+ species assisted regeneration of Co2+ to Co3+ species, further accelerating sulfite oxidation. Besides, the partial substitution of Co sites by Mn also suppressed the losing of Co species during reaction, favoring to decrease the environmental risk, as well as to save the cost of catalyst. PMID- 30469033 TI - Assessment of biodegradation of the anionic surfactant sodium lauryl ether sulphate used in two foaming agents for mechanized tunnelling excavation. AB - The anionic surfactant sodium lauryl ether sulphate (SLES) is the main component in most foaming agents used for mechanized tunneling excavation. The process produces huge amounts of soil debris that can have a potential impact on ecosystems. The lack of accurate information about SLES persistence in excavated soil has aroused increasing concern about how it is recycled. The objective of this study was to assess SLES biodegradability in two commercial foaming agents (P1 and P2). Microcosm experiments were performed with two different soils collected from a tunnel construction site and conditioned with P1 or P2 (85.0 or 83.0 mg kg -1 of SLES, respectively). At selected times soil samples were collected for assessing the SLES residual concentration using Pressured Liquid Extraction followed by methylene blue active substance analysis (MBAS). Simultaneously, soil microbial abundance (DAPI counts), viability (Live/Dead method), activity (dehydrogenase analysis) and phylogenetic structure (Fluorescent In Situ Hybridization) were evaluated. SLES halved faster in the silty-clay soil (6 d) than in the gravel in a clay-silty-sand matrix (8-9 days). At day 28 it was degraded in both soils. Its biodegradation was ascribed to the significant increase in Gamma-Proteobacteria. At this time, the spoil material can be considered as a by-product. PMID- 30469034 TI - Development of an algal treatment system for selenium removal: Effects of environmental factors and post-treatment processing of Se-laden algae. AB - In developing an algal treatment system, selenium (Se) removal efficiency by Chlorella vulgaris was evaluated under various conditions such as Se concentration, algal density, temperature and pH. A maximum removal efficiency plateau of ~90% was observed between 1000-3000 MUg Se/L while the tolerance of Se toxicity was found at 6000 MUg Se/L. C. vulgaris of 0.75 g DW/L showed the highest removal efficiency (84%), and volatilization was dominant below 1.37 g DW/L. Se volatilization was two times higher at 25 degrees C than at 20 degrees C in the first 24 h. Moreover, the highest removal efficiency (77%) was obtained at pH 8.0, compared to 66.5% at pH 6.5 and 40% at pH 10.0. To prevent ecotoxicity, Se laden algae were further burned to ashes or filtered out by Anodonta woodiana. After burning, biomass Se was reduced by 99%, with organo-Se entirely converted into inorganic Se, lowering Se bioavailability. A. woodiana removed 54% of Se in 24 h, leading to Se bioaccumulation in soft tissues, which may serve as dietary Se supplements for human health. Our results suggest the cleanup of Se-contaminated water from either agricultural runoff or industrial discharge could be achieved using an algal treatment system with minimum potential ecotoxicity. PMID- 30469035 TI - Effectiveness and mechanism of carbamide/fly ash cenosphere with bilayer spherical shell structure as explosion suppressant of coal dust. AB - This study aims to eliminate or suppress explosion accidents in powder preparation and storage systems of coal dust. The modified fly ash cenosphere (FAC) was used as an inner spherical shell carrier with carbamide impregnated. Carbamide/FAC composite suppressant with bilayer spherical shell was prepared by vacuum freeze-drying. The flame propagation and explosion performances of coal were tested, respectively. The results showed that the surface-loaded carbamide particles had a particle size of ~4 nm. With the increasing content of carbamide/FAC composite suppressant, the maximum flame length gradually decreased, and the explosion suppression effect was gradually improved. Nearly complete explosion suppression of coal could be achieved with an added amount of 40 wt% carbamide/FAC composite suppressant. The carbamide loaded in carbamide/FAC composite suppressant mainly acted in the 0-tau1 stage to weaken (dP/dt)max. FAC mainly but not solely acted on the stage of tau1-tau2 to decrease Pmax. Carbamide particles were highly efficient and responsive. The suppression mechanism of carbamide/FAC composite suppressant was proposed, which was micro-nano multiscale complementary effect and deceleration-depressurization coupling effect. PMID- 30469036 TI - An experimental and kinetic study of thermal decomposition of phenanthrene. AB - Polycyclic aromatic hydrocarbons (PAHs) have enormous potential hazards. It is necessary for China to propose more internationally stricter standards for PAHs, in order to improve the country's pollutant prevention and control policy system, and ultimately, provide institutional guarantees for implementing PAH emissions prevention and control. In this study, phenanthrene, a typical PAHs generated during municipal solid waste (MSW) to energy system, was applied as a model compound to study the thermal degradation mechanism during the combustion process. Combustion kinetics for the three major gaseous products, including hydrogen, methane, and carbon dioxide, were determined. Experimental results indicated that hydrogen was promoted compared to methane and carbon dioxide during the combustion of phenanthrene, especially in high oxygen concentrations. The apparent activation energy (Ea) of 8.299-11.51, 13.10-23.07, and 9.368-15.29 kJ/mol, pre-exponential factor (A) of 0.219-1.579, 5.034-10.12, and 6.553-15.51 s 1, and the reaction order (n) of 1.160-1.234, 1.059-1.305, and 1.636-1.774 were obtained for hydrogen, methane, and carbon dioxide, respectively. Research on combustion behavior of phenanthrene and reaction kinetics provides the theoretical basis for the high-temperature removal of PAHs as byproducts during the combustion of MSW in oxygen-rich atmosphere. PMID- 30469037 TI - A novel sulfate removal process by ettringite precipitation with aluminum recovery: Kinetics and a pilot-scale study. AB - A novel sulfate removal process via ettringite precipitation was developed by dissolving ettringite and recycling Al3+ under low pH condition. Effects of solid to liquid ratios, pH and temperature on ettringite dissolution, Al recovery and transformation of precipitates were investigated by batch experiments. The optimum condition for Al recovery is pH =3.0, suspended solid of 9.8 g/L and temperature below 303 K. Ettringite dissolution consists of two stages, (i) rapid but inconsistent dissolution with the fastest release of sulfate, followed by calcium, and then Al(OH)63-; (ii) slow dissolution of Al(OH)63- core and gypsum precipitation. Dissolution of Al(OH)63- core follows the first-order kinetics with activation energy of 41.18 kJ/mol, while gypsum re-precipitation follows the second-order kinetics with activation energy of 26.36 kJ/mol. Long-term results of pilot-scale systems for treatment of real flue gas desulfurization wastewater showed that the process achieved sulfate removal of 98.3%-99.5% and Al recovery above 98.4%, and converted 98.8% sulfate in ettringite to CaSO4, which resulted in 66.0% of sludge reduction and improved sludge dewaterability. Economic evaluation shows that the process with Al recovery reduces cost of ettringite precipitation by 35.1%, and is highly feasible and cost-effective for industrial application of high-sulfate content wastewater treatment. PMID- 30469038 TI - Catalytic oxidation at pilot-scale: Efficient degradation of volatile organic compounds in gas phase. AB - Volatile organic compounds (VOCs) are responsible for environmental problems and may affect human health. Several treatment technologies minimize VOCs emissions; among those, catalytic oxidation appears as a promising alternative. In this study, a pilot-scale catalytic reactor was developed and the influence of process parameters on toluene degradation were investigated. Inlet gases were heated by electrical resistances and the catalyst employed was a honeycomb shape commercial automotive catalyst (Umicore, model AFT). Toluene degradation higher than 99% was achieved for several conditions and temperature showed to be the most important process variable for it. For all concentrations, it was observed that when increasing temperature led to a decrease on the space time. At 800 ppmv, varying from 543 K to 633 K, the space time decreased from 0.121 s to 0.08 s, respectively. At 1600 ppmv for the same temperature range, space time was reduced from 0.098 s to 0.040 s, respectively. At 2400 ppmv, varying from 543 K to 633 K, space time decreased from 0.081 s to 0.048 s. The catalytic reactor developed proved to be efficient for VOCs treatment, showing a high potential of application at industrial emission sources. PMID- 30469039 TI - Anti-inflammatory activity of triazine derivatives: A systematic review. AB - Triazines are heterocyclic compounds with a variety of biological activities that have been increasingly studied in recent years due to their versatile structure (three isoforms) and the different derivatives that can be synthesized from them to ensure functional motifs. This systematic review provides the evidence in the literature of the in vitro and in vivo anti-inflammatory activity of triazine derivatives from 2008 to June 2018. Four bibliographical databases were consulted (PubMed, Web of Science, EMBASE and Scopus), and a total of 48 studies were included in this paper based on our eligibility criteria. Although 35.17% of evaluated triazines were demonstrated to be promising anti-inflammatory agents, further studies need to be conducted to explore their pharmacological profiles in the medical research of drug discovery to control the risk factors and pathophysiology of several chronic inflammation-based diseases. PMID- 30469040 TI - Synthesis of isatin based N1-alkylated 3-beta-C-glycoconjugated-oxopropylidene oxindoles as potent antiplasmodial agents. AB - In an attempt to develop new antimalarial drugs, we have synthesized a new class of N-alkylated 3-glycoconjugated-oxopropylidene oxindoles starting from substituted isatins and glucopyranosyl propanone via a well-known cross-aldol reaction followed by dehydration. The newly synthesized compounds were screened for their in vitro antiplasmodial activity, and among all the compounds 9g, 9f, 9b, 8d, 9d, 9c, and 9e displayed potent activity with the IC50 values in the range of 0.1-0.3 MUM against Chloroquine (CQ) sensitive Pf3D7 strain, while compounds 9d, 9b, 9e, 8c, 8f, 9c, and 9a have shown promising activity having IC50 values in 0.1-0.4 MUM range against CQ resistant PfK1 strain, which is even better than the standard drug chloroquine with IC50 value of 0.5 MUM. PMID- 30469041 TI - Diaryl hydroxylamines as pan or dual inhibitors of indoleamine 2,3-dioxygenase-1, indoleamine 2,3-dioxygenase-2 and tryptophan dioxygenase. AB - Tryptophan (Trp) catabolizing enzymes play an important and complex role in the development of cancer. Significant evidence implicates them in a range of inflammatory and immunosuppressive activities. Whereas inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) have been reported and analyzed in the clinic, fewer inhibitors have been described for tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase-2 (IDO2) which also have been implicated more recently in cancer, inflammation and immune control. Consequently the development of dual or pan inhibitors of these Trp catabolizing enzymes may represent a therapeutically important area of research. This is the first report to describe the development of dual and pan inhibitors of IDO1, TDO and IDO2. PMID- 30469042 TI - Pharmaceutical significance of azepane based motifs for drug discovery: A critical review. AB - Azepane-based compounds showed a variety of pharmacological properties, and its derivatives possess a high degree of structural diversity, and it is useful for the discovery of new therapeutic agents. The development of new less toxic, low cost and highly active azepane-containing analogs is a hot research topic in medicinal chemistry. Now, more than 20 azepane-based drugs have been approved by FDA, and widely used to treat various types of diseases. This review highlights the recent developments of azepane-based compounds in a wide range of therapeutic applications, such as anti-cancer, anti-tubercular, anti-Alzheimer's disease, and antimicrobial agents, as well as, histamine H3 receptor inhibitors, alpha glucosidase inhibitors, anticonvulsant drugs and other miscellaneous applications. We here briefly describe the structure-activity relationship (SAR) and molecular docking studies of potential bioactive compounds for future discovery of suitable drug candidates. It can serve as an inspiration for new ideas for design and development of less toxic and more powerful azepane-based drugs against numerous devastating diseases. PMID- 30469043 TI - Transient acute kidney injury after major abdominal surgery increases chronic kidney disease risk and 1-year mortality. AB - PURPOSE: We conducted a retrospective cohort study to determine incidences of transient and persistent acute kidney injury (AKI) after major abdominal surgery and their impacts on long-term outcome. MATERIALS AND METHODS: We enrolled 3751 patients undergoing major abdominal surgery. Postoperative AKI was classified as transient or persistent based on the return of serum creatinine to the non-AKI range within 7 days post-surgery. Primary outcome was mortality within 1 year. We used multivariable Cox proportional hazard regression analysis to assess independent associations between AKI type and mortality. RESULTS: Most patients with AKI were classified as transient (84%). Compared to patients without AKI, both patients with transient and persistent AKI demonstrated elevated 1-year mortality rates [adjusted hazard ratio (95% confidence interval): 2.01 (1.34 2.93); P = 0.001, and 6.20 (3.00-11.43); P < 0.001, respectively] and greater risk of chronic kidney disease progression at 1 year [adjusted odds ratio (95% confidence interval): 3.87 (2.12-7.08) and 23.70 (9.64-58.22), respectively; both P < 0.001]. CONCLUSIONS: Although most AKI cases after major abdominal surgery recover completely within 7 days, even these patients with transient AKI are at higher risk for 1-year mortality and chronic kidney disease progression compared to patients without AKI. PMID- 30469044 TI - Reliability of triggering inhibitory process is a better predictor of impulsivity than SSRT. AB - The ability to control behaviour is thought to rely at least partly on adequately suppressing impulsive responses to external stimuli. However, the evidence for a relationship between response inhibition ability and impulse control is weak and inconsistent. This study investigates the relationship between response inhibition and both self-report and behavioural measures of impulsivity as well as engagement in risky behaviours in a large community sample (N = 174) of healthy adolescents and young adults (15-35 years). Using a stop-signal paradigm with a number parity go task, we implemented a novel hierarchical Bayesian model of response inhibition that estimates stop-signal reaction time (SSRT) as a distribution and also accounts for failures to react to the stop-signal (i.e., "trigger failure"), and failure to react to the choice stimulus (i.e., "go failure" or omission errors). In line with previous studies, the model reduced estimates of SSRT by approximately 100 ms compared with traditional non parametric SSRT estimation techniques. We found significant relationships between behavioural and self-report measures of impulsivity and traditionally estimated SSRT, that did not hold for the model-based SSRT estimates. Instead, behavioural impulsivity measures were correlated with rate of trigger failure. The relationship between trigger failure and impulsivity suggests that the former may index a higher order inhibition process, whereas SSRT may index a more automatic inhibition process. We suggest that the existence of distinct response inhibition processes that may be associated with different levels of cognitive control. PMID- 30469045 TI - Comprehensive measurements of salivary pellicle thickness formed at different intraoral sites on Si wafers and bovine enamel. AB - The salivary pellicle is a thin acellular film formed on orally exposed surfaces by adsorption of macromolecules from the oral fluids and serves as a protective layer in the maintenance of oral health. Pellicle thickness measurements are a central tool helping to understand how exogenous manipulations may influence pellicle formation. This is of particular importance for the investigation of new preventive and therapeutic approaches. In the present study we determined the kinetics of the in situ pellicle thickness formation at different intraoral sites and investigated how pellicle formation occurs in different individuals. To address the kinetic aspect, the thickness of the in situ pellicle was determined after formation periods of 3 min, 30 min and 120 min. The thickness of the pellicle was either measured on silicon wafers by ellipsometry or on bovine enamel by transmission electron microscopy. We found a physiologically important rapid pellicle formation phase within the first minutes and a slow pellicle formation phase between 30 min and 120 min. Furthermore, our results identify significant inter-individual differences both for the pellicle thickness and for the formation kinetics, indicating the consideration of individual-specific differences of the pellicle layer as an important aspect for future studies. PMID- 30469046 TI - Multi-functional core-shell Fe3O4@Au nanoparticles for cancer diagnosis and therapy. AB - Multi-functional core-shell Fe3O4@Au nanoparticles (Fe3O4@Au-DOX-mPEG/PEG-FA NPs) conjugated with doxorubicin (DOX), methoxy poly(ethylene glycol) (mPEG), and folic acid-linked poly(ethylene glycol) (PEG-FA) were synthesized for cancer theranostic applications. In the developed NPs, the DOX was chemically conjugated at the surface of core-shell Fe3O4@Au NPs using L-cysteine methyl ester (LCME) as a linker by acid-sensitive hydrazone bond. The formation of Fe3O4@Au-DOX-mPEG/PEG FA NPs was confirmed by 1H-NMR analysis. The TEM image and DLS studies showed that the mean diameter of the prepared NPs was about 18 and 38 nm, respectively. Due to the existence of superparamagnetic Fe3O4, the Fe3O4@Au-DOX-mPEG/PEG-FA NPs presented the saturation magnetization (Ms) value of 23 emu/g. The developed NPs displayed the maximum amount of drug release in the acidic medium than that in the mild alkaline medium because of the presence of acid-sensitive hydrazone bond. Due to the presence of FA, the Fe3O4@Au-DOX-mPEG/PEG-FA NPs displayed the increased cellular uptake through a folate-receptor-mediated endocytosis, which results in the improved cytotoxic effect on the HeLa cells. Under the laser irradiation, the cytotoxicity of Fe3O4@Au-DOX-mPEG/PEG-FA NPs was found to be improved due to the photothermal effect of Au shell existing in the NPs. These results reveal that the Fe3O4@Au-DOX-mPEG/PEG-FA NPs could be a promising tumour targeted drug delivery system with the capabilities of combined MR/CT imaging, photothermal, and chemotherapy of tumours. PMID- 30469047 TI - A new catechol-functionalized polyamidoamine as an effective SPION stabilizer. AB - A synthetic strategy was established for decorating and stabilizing superparamagnetic iron oxide nanoparticles (SPIONs) with a zwitterionic linear polyamidoamine (PAA). The strategy was successfully tested with a PAA coded ISA23 previously found endowed with interesting biological properties, such as biocompatibility, degradability in aqueous media and stealth-like properties when injected in test animals. A post-synthetic functionalization with catechol bearing moieties of a preformed PAA was successfully carried out. ISA23 was obtained by polyaddition reactions of methyl-piperazine and 2,2 bis(acrylamidoacetic) acid. It was functionalized using nitrodopamine and 1-ethyl 3-(3-dimethylaminopropyl)carbodiimide as coupling agent, to randomly form amide bonds with 17% of ISA23 carboxylic groups (ISA23-ND). SPIONs were prepared by a thermal decomposition synthesis in 1-octadecene with oleic acid, and then transferred in water by two distinct ligand exchange procedures: i) the direct displacement of oleate molecules from SPION surface by ISA23 in a biphasic (n hexane/water) environment; ii) the two-step method involving an intermediate small molecule, tetramethylammonium hydroxide, used as a transient transfer agent, which was in turn exchanged with ISA23-ND in a second exchange step occurring in water. The two-step procedure provided a SPION@PAA nanocomposite more stable than that obtained by the one-step procedure in the presence of an applied external magnetic field. ATR-FTIR spectroscopy, zeta-potential and thermogravimetric analysis (TGA) showed the presence of the ISA23 on the SPION surface. In particular, TGA showed that the ISA23-ND amount on the NPs accounted for 26% of the overall nanocomposite mass. The nanocomposite size was determined by both TEM (21.1+/-2.9 nm) and DLS measurements (hydrodynamic size 100+/-28 nm). SPION@ISA23-ND were re-suspended after lyophilization reverting to their pristine dimensions. The SPION@ISA23-ND adsorption of BSA in water, considered as the first stage of phagocytosis, was very low, suggesting that ISA23 could impart stealthiness to SPION@ISA23-ND. 1H-NMR relaxivity measurements showed an r2 value of 158 s-1 mmol-1 L (vs 100 s-1 mmol-1L for Endorem(r)) at relevant clinical fields for magnetic resonance imaging (from 0.2 to 1.5 T). SPION@ISA23-ND was tested on HeLa cells and their internalization was visualized by reflectance microscopy. Finally, with the aim of prepare a new dual magneto-optical system, a synthetic procedure to decorate SPION@ISA23-ND with a fluorescent dye was devised, even though the emission intensity of the resultant conjugate was lower than expected, possibly due to luminescence quenching caused by the closeness of emitting moieties to the SPION surface. PMID- 30469048 TI - Paclitaxel-betulinic acid hybrid nanosuspensions for enhanced anti-breast cancer activity. AB - Paclitaxel-betulinic acid hybrid nanosuspensions (PTX-BA-NP) with increased anti breast cancer activity were developed. The resultant nanosuspensions (NP) had a mean particle size of 282.54 +/- 5.4 nm, a polydispersity index of approximately 0.242 +/- 0.02, a zeta potential of -19.7 +/- 0.19 mV and a redispersibility index of 103.3 +/- 0.01%. The cumulative dissolution percentage of PTX coarse powder and PTX-BA-NP dried powder at 60 min were 15.4% and 90.8%, respectively. MCF-7 cell-based testing showed that treatment with PTX-BA-NP led to more PTX-BA NP accumulation in the cytoplasm of breast cancer cells, less cell cycle arrest in the G2-M phase, more cell cycle arrest in the G0-G1 phase, more apoptosis induced cell death and stronger inhibition of cell migration than paclitaxel nanosuspensions (PTX-NP). Biodistribution studies showed that tumor accumulation levels at 12 h in the PTX-BA-NP group were approximately 2.67- and 2.33-fold higher than the levels in the Taxol(r) and PTX-NP groups, respectively. In vivo antitumor efficacy demonstrated that PTX-BA-NP exerted the strongest tumor inhibition among the four groups, with a tumor inhibition rate of 47.79 +/- 2.28%, followed by PTX-NP (35.05 +/- 5.55%), Taxol(r) (22.67 +/- 6.01%) and betulinic acid nanosuspension (BANP) (14.38 +/- 6.02%). These findings indicate that PTX-BA-NP holds great promise for breast cancer therapy. PMID- 30469049 TI - Study of engineered low-modulus Mg/PLLA composites as potential orthopaedic implants: An in vitro and in vivo study. AB - Low molecular weight poly-lactic acid (PLLA) is a polymer matrix of orthopaedic implants. The PLLA matrix incorporating bioactive magnesium ion (Mg2+) enhances bone regeneration. But the optimal ratio of Mg2+ to PLLA matrix has not been well reported and is worthy of study. We synthesized silane-coated Mg/PLLA composites containing 1%, 2%, 3%, 4% and 5% Mg micro-particles. The mechanical properties, in vitro cytocompatibility, cell viability and osteogenesis differentiation and in vivo performance of silane-coated Mg/PLLA composites were evaluated. These results showed that the bending and tensile strength of PLLA matrix was reduced by incorporation of Mg micro-particles. Mg/PLLA composites with higher Mg micro particles ratio showed higher Mg2+ leaching rate and pH value in immersion solutions. MC3T3-E1 pre-osteoblasts incubated with Mg/PLLA composites containing higher ratio of Mg micro-particles showed higher cytocompatibility, cell viability, osteogenesis differentiation and migration. In vitro cellular responses showed that MC3T3-E1 pre-osteoblasts had the highest cell viability at 50 ppm Mg2+. In vivo animal studies showed there was no change in serum Mg2+ concentration after implanting Mg/PLLA composites comparing with control and the implants of silane-coated Mg/PLLA composites accelerated bone formation. In summary, our study revealed the feasibility of silane-coated Mg/PLLA composites as orthopaedic implants. Silane-coated Mg/PLLA composites with Mg micro-particles ratio of 3% ~ 5% were optimal substitutes for bone regeneration. PMID- 30469050 TI - Characterization of neurocalcin delta membrane binding by biophysical methods. AB - Neurocalcin delta (NCALD) is a member of the neuronal calcium sensors protein family. In the retina, NCALD is expressed by ganglion and amacrine cells. NCALD is composed of 4 EF-hand motifs but only 3 of them may bind calcium. The binding of calcium induces a conformational change of the protein which leads to the extrusion of its N-terminal myristoyl group as well as some hydrophilic residues. This mechanism, named calcium-myristoyl switch, is presumably involved in its membrane binding. The parameters responsible for the interaction of NCALD with membranes are only partially known. The purpose of this study was thus to gather more information on the membrane binding behavior of NCALD using lipid monolayers, including the influence of the lipid composition, the calcium and the myristoyl group. NCALD was injected underneath different lipid monolayers and this model membrane allowed the determination of the binding parameters as maximum insertion pressure (MIP) and synergy. The values of MIP are larger when monolayers were composed of a saturated phospholipid with phosphoethanolamine polar head. This trend is confirmed by polarization modulation infrared reflection absorption spectroscopy measurements. Moreover, the observations by fluorescence microscopy show that NCALD preferentially interacts with phospholipids which are in the liquid-condensed physical state, as found in membrane microdomains. This observation could explain the changes of NCALD expression level in the brains of patients suffering from Alzheimer's disease because of the alteration of lipid composition in microdomains structures. PMID- 30469051 TI - Si-doping increases the adjuvant activity of hydroxyapatite nanorods. AB - Recombinant protein-based vaccines generally show limited immunogenicity and need adjuvants to achieve robust immune responses. Herein, to combine the excellent biocompatibility of hydroxyapatite (HA) and exciting adjuvant activity of silica, Si-doped HA nanorods with Si/P molar ratio from 0 to 0.65 were hydrothermally synthesized and evaluated as immunoadjuvants. Si-doping decreases the size and increases the BET surface area of the nanorods. Si-doping in HA nanorods increases the in vitro adjuvant activity, including CD11c+CD86+ expression and cytokine secretion of bone marrow derived dendritic cells (BMDCs). Moreover, Si doping in HA increases the ex vivo adjuvant activity as shown by the increase in both Th1 and Th2 cytokines secretion. Si-doped HA nanorods are promising as a new immunoadjuvant. PMID- 30469052 TI - Transcriptome analysis of mantle tissues reveals potential biomineralization related genes in Tectus pyramis Born. AB - The marine mollusk Tectus pyramis is a valuable shellfish primarily distributed in the tropical waters of the South China Sea, as well as in the Indo-Pacific Ocean and areas near the southern portion of the Japanese Peninsula. Despite major economic interest in this mollusk, limited genomic resources are available for this species, which has prevented studies of the molecular mechanism, such as biomineralization. Here, we report the first comprehensive transcript dataset of T. pyramis mantle tissue. From a total of 16,801,141 reads, 173,671 unique transcripts were assembled, which provides new genomic resources for the understanding of biomineralization in T. pyramis. The most abundant unique sequences of the top 30 most highly expressed genes were annotated as shematrin, while other highly expressed genes included glycine-rich protein and shematrin-1. Based on transcriptome annotation and Gene Ontology classification, 130 biomineralization-related genes were found including members of the BMP (bone morphogenetic proteins), calmodulin, perlucin, and shematrin families, as well as mantle genes, nacrein, and MSI60. The results of qPCR showed that 14 of 24 examined genes were highly expressed in the mantle. A phylogenetic tree of BMP, perlucin, shematrin proteins revealed conservation of their structure and functions and indicated that some members participated in biomineralization in T. pyramis. Taken together, the results presented herein will be useful in studies of molecular mechanisms and pathways of biomineralization in T. pyramis, as well as provide new insight into the mechanisms of biomineralization in gastropods. PMID- 30469053 TI - Association between gastric myoelectric activity disturbances and dyspeptic symptoms in gastrointestinal cancer patients. AB - PURPOSE: Dyspeptic symptoms present a severe problem in gastrointestinal (GI) cancer patients. The aim of the study was to analyze an association between gastric myoelectric activity changes and dyspeptic symptoms in gastrointestinal cancer patients. MATERIAL AND METHODS: The study included 80 patients (37 men and 43 women, mean age 61.2 +/- 7.8 years) diagnosed with GI tract malignancies: colon (group A), rectal (group B) and gastric cancers (group C). Gastric myoelectric activity in a preprandial and postprandial state was determined by means of a 4-channel electrogastrography. Autonomic nervous system was studied based on heart rate variability analysis. The results were compared with the data from healthy asymptomatic controls. RESULTS: In a fasted state, GI cancer patients presented with lesser percentages of normogastria time (A:44.23 vs. B:46.5 vs. C:47.10 vs. Control:78.2%) and average percentage slow wave coupling (ACSWC) (A:47.1 vs. B:50.8 vs. C:47.2 vs. Control:74.9%), and with higher values of dominant power (A:12.8 vs. B:11.7 vs. C:12.3 vs. Control:10.9) than the controls. Patients did not show an improvement in the percentage of normogastria time, dominant power, dominant frequency and ACSWC in response to food. The severity of dyspeptic symptoms correlated with the values of electrogastrography parameters. Patients showed lower values of heart rate variability parameters than the healthy controls, that indicate abnormal autonomic nervous system activity. CONCLUSION: GI cancers affect the gastric myoelectric activity, decreasing normogastria and slow wave coupling. These patients do not show adequate gastric motility response to food. Impaired gastric electric motility may result from cancer-induced autonomic disturbances. PMID- 30469054 TI - Decoding the antineoplastic efficacy of Aplysin targeting Bcl-2: A de novo perspective. AB - The B-cell lymphoma-2 (Bcl-2) family proteins have been attributed to be the key regulators in programmed cell death and apoptosis with a prominent role in human cancer. Understanding the fundamental principles of cell survival and death have been the main cornerstone in cancer drug discovery for identification of novel anticancer agents. In this context the Bcl-2 family of anti-and pro-apoptotic proteins provide an excellent opportunity for development of anticancer agents, as blocking the Bcl-2 or Bcl-XL functionally promotes apoptosis in tumor cells and also sensitize them to chemo- and radiotherapies. The present study reports the identification of novel Aplysin analogs as BCL-2 inhibitors from a sequential virtual screening approach using drug-like, ADMET, docking, pharmacophore filters and molecular dynamics simulation. We identified promising Aplysin analogs that have a potential to be Bcl-2 inhibitors just like the standard drug Obatoclax. One of the compound analog 11 was identified to be a promising inhibitor of Bcl-2 in the docking, pharmacophore and simulation based models.The molecular modeling information provided here can be vital in designing of the novel Bcl-2 inhibitors. PMID- 30469055 TI - Assessment of heat exposure in cities: Combining the dynamics of temperature and population. AB - Urban populations are typically subject to higher outdoor heat exposure than nearby rural areas due to the urban heat island (UHI) effect. Excessive Heat Events (EHEs) further amplify heat stress imposed on city dwellers. Heat exposure largely depends on the spatial and temporal distribution of temperature and population, however, few studies considered their concurrent variations. To better characterize exposure to heat in the context of long-term urban climatology and during excessive heat events, this study focuses on the dynamics of ambient temperature and population and proposes an open-data-based approach for spatiotemporal analysis of urban exposure to heat by using air temperature estimated from satellite observations and commute-adjusted diurnal population calculated primarily on the Census Transportation Planning Products. We use the metropolitan area of Chicago, U.S.A. as a case study to analyze the urban heat pattern changes during EHEs and their influence on population heat exposure diurnally. The intra-urban spatiotemporal analysis reveals that the population's exposure to heat changes fast as the nighttime temperature increases and the EHEs increase the spatial exposure impact due to the ubiquitous higher nocturnal temperature over the Chicago metropolitan area. "Hotspots" associated with a higher temperature and greater number of urban residents are identified in the heat exposure map. Meanwhile, the spatial extent of high ambient exposure areas varies diurnally. Our study contributes to a better understanding of the dynamic heat exposure patterns in urban areas. The approaches presented in this article can be used for informing heat mitigation as well as emergency response strategies at specific times and locations. PMID- 30469056 TI - Insecticide toxic effects and blood biochemical alterations in occupationally exposed individuals in Punjab, Pakistan. AB - Biomonitoring of people exposed to hazardous materials provides opportunities for early identification of several diseases, particularly in those individuals who are constantly exposed to pesticides, such as pesticide operators and workers in pesticide manufacturing industry. However, data on this hot topic are limited in Pakistan. In this study, insecticide toxic effects and biochemical alterations (i.e., damage in DNA and enzyme activity) were studied in blood samples of occupationally exposed individuals from Punjab, Pakistan. Eight out of twenty seven blood samples (29.6%) of the pesticide operators were found positive in five insecticides, with the maximum concentration found for chlorpyrifos-methyl (0.039 MUg/mL). Eleven out of twenty-seven blood samples (40.7%) of the pesticide industry workers were found positive in eight insecticides, with the maximum concentration found for endosulfan (0.051 MUg/mL). Comet tail length was 16.88 +/ 4.57 MUm in pesticide industry workers and 16.33 +/- 3.78 MUm in pesticide operators, which were significantly higher (P < 0.01) than that recorded in the control group (4.84 +/- 2.21 MUm). Values of serum cholinesterase (SChE) concentration were slightly lower (P > 0.05) in exposed individuals, whereas values of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) concentration were significantly higher (P < 0.01) in exposed individuals compared with control group. Exposure duration and total insecticide concentration in blood samples were positively associated with comet tail length, ALT activity, AST activity, and ALP activity, but negatively with SChE. DNA damage was higher in smokers vs. non-smokers. Also, a positive association was found between comet tail length and number of cigarettes per day. Overall, occupational exposure to insecticides can pose serious health risks to pesticide operators and workers in pesticide manufacturing industry, highlighting the necessity of personal protection in those groups for preventing exposure and resultant health disorders. PMID- 30469057 TI - A novel approach of combining isotopic and geochemical signatures to differentiate the sources of sediments and particulate nutrients from different land uses. AB - Determining the source of sediments and associated nutrients from terrestrial to aquatic environments is critical for managing the detrimental impacts of soil erosion and loss of nutrients from terrestrial into aquatic environment. However, tracing the source of particulate nutrients from different land uses has not been adequately carried out due to methodological difficulties in separating sources, particularly in the Great Barrier Reef (GBR) catchment. The objective of this study was to develop a method to differentiate the sources of particulate nutrients from soils collected from different land uses (combination of beef and dairy grazing, sugarcane, forest and banana) using both geochemical and isotopic signatures. In order to select a discriminative group of signatures, all soil samples collected from each of the land use areas were fractionated to <63 MUm size fraction and were analysed for both isotopic (delta13C, delta15N) and acid extractable geochemical properties (e.g. Zn, Pt and S). Considering the fact that the outcome of tracing models often depends on the type and robustness of the methods used, here we have employed a stable isotope mixing model (SIAR) to evaluate if the suite of selected elements could be used to estimate the relative contribution of different sources for a series of five virtually created sediment mixtures. For the five groups of virtual sediments, the SIAR model provided close estimates to the contribution values of sediment sources with the Mean Absolute Error (MAE) varying from 0.30 to 2.88%. Results from this study show for the first time that the combined use of isotopic and geochemical signatures enable the SIAR model to provide an accurate estimation of source apportionment where a variety of land uses needs to be investigated and shows promise as a valuable new sediment and particulate nutrient tracing tool. PMID- 30469058 TI - Spatiotemporal patterns of recent PM2.5 concentrations over typical urban agglomerations in China. AB - China experiences severe particulate matter pollution associated with rapid economic growth and accelerated urbanization. In this study, concentrations of PM2.5 (fine particulate matter with an aerodynamic diameter <= 2.5 MUm) throughout China, and specifically in nine typical urban agglomerations and one economic region, were statistically analyzed using high-resolution ground-based PM2.5 observations from June 2014 to May 2018. The spatial variation of PM2.5 was also explored via spatial autocorrelation analysis. High annual mean PM2.5 concentrations were predominantly concentrated in the Beijing-Tianjin-Hebei, Central Plain, Northern Slope of Tianshan Mountain, and Cheng-Yu urban agglomerations, as well as the Huaihai Economic Region. The proportion of air quality nationwide monitoring sites where annual average PM2.5 concentrations exceeded the Chinese Ambient Air Quality Standards (CAAQS) Grade II annual standard were 82.8%, 77.1%, and 70.8% in 2015, 2016, and 2017, respectively. Moreover, the frequency of PM2.5 concentrations meeting the CAAQS Grade I 24-h standard increased in five national-level urban agglomerations, and the average annual PM2.5 decreased from 2015 to 2017 with a reduction rate of over 20%. The southern Beijing-Tianjin-Hebei agglomeration and surrounding areas revealed the highest PM2.5 pollution in four seasons. Monthly mean PM2.5 typically exhibited a characteristic "U" shape. Diurnal mean PM2.5 concentrations were generally consistent with typical urban agglomerations, with maximum and minimum PM2.5 values occurring at approximately 08:00-12:00 and 15:00-17:00, respectively, except for the Northern Slope of Tianshan Mountain urban agglomeration (NSTM-UA) (14:00 and 08:00, respectively). A positive spatial autocorrelation of PM2.5 concentrations was observed in all urban agglomerations (except NSTM-UA); high high agglomeration centers of PM2.5 pollution were located far inland with a circular distribution, and low-low agglomeration centers formed at the periphery of the high-high agglomeration region. This study is key for understanding the difference in PM2.5 concentrations among urban agglomerations and region-oriented air pollution control strategies are highly suggested. PMID- 30469059 TI - Early childhood exposure to maternal smoking and Kawasaki Disease: A longitudinal survey in Japan. AB - Kawasaki disease is the leading cause of acquired childhood heart disease in most developed countries, but the etiology of the disease is unknown. An aberrant immune response to some environmental triggers may play a role and involuntary exposure to tobacco smoke can alter immune functions. We thus prospectively examined the association between early childhood exposure to maternal smoking and the incidence of Kawasaki disease. We used a large, nationwide population-based longitudinal survey ongoing since 2010 and restricted participants to a total of 38,444 children for whom information on maternal smoking was available. Maternal smoking status was ascertained at 6 months of age, and responses to questions about hospital admission for Kawasaki disease between the ages of 6 and 30 months were used as outcome. We conducted binomial log-linear regression analyses adjusting for children's, parental, and residential factors with children of non smoking mothers as our reference group. Maternal smoking increased the risk of admission, in particular for the period between 6 and 18 months of age, in a dose dependent manner. Compared with children of non-smoking mothers, the children of mothers who smoked had a risk ratio of 1.83 (95% confidence interval: 1.06, 3.35) for hospital admissions between 6 and 30 months of age and a risk ratio of 2.69 (95% confidence interval: 1.56, 4.64) for hospital admissions between 6 and 18 months of age. Early childhood exposure to maternal smoking may increase the risk of Kawasaki disease hospitalizations in childhood. PMID- 30469060 TI - Crucial sites and environmental variables for wintering migratory waterbird population distributions in the natural wetlands in East Dongting Lake, China. AB - Dongting Lake is the second largest freshwater lake in China and is one of the globally important wintering sites for migratory waterbirds in the East Asian Australasian Flyway. Crucial sites and environmental variables for wintering migratory waterbirds are of great concern in the Dongting Lake wetlands. In this research, based on annual (2003/2004-2016/2017) waterbird and habitat census data, we recognized the crucial sites for waterbirds during wintering seasons by comparing the difference of waterbird populations at the community, foraging guild and species levels in different natural wetlands within East Dongting Lake, and then identified the crucial environmental variables affecting waterbird distributions by analyzing the relationship between waterbird populations and the environmental variables, including vegetation area, mudflat area, water area with the depth of 0-20 cm, water area with the depth of 20-50 cm, water area with the depth of 50-100 cm, water area with the depth >100 cm, growth status of vegetation (Min, Mean and Max NDVI), and the human disturbance. Results indicated that five natural wetlands, i.e., Daxiaoxi, Chunfeng, Baihu lakes, Dingzi dyke and Tanjiaweizi, were recognized as the crucial wintering sites for migratory waterbirds in the East Dongting Lake. Among the ten selected environmental variables, water areas with the depth of 0-20 cm, 20-50 cm and >100 cm, human disturbance, Min and Mean NDVIs were identified as the crucial environmental variables overall. Waterbirds at different levels exhibited significant linear relationship with certain environmental variables, with the exception of Bean goose and Lesser White-fronted goose at the species level, which showed Gaussian distribution with changes in mean NDVI. The crucial environmental variables appeared to be foraging guild- and species-specific. These findings provide significant information for managers to understand the differences of wetlands and waterbird populations within East Dongting Lake, and to make more targeted conservation efforts. PMID- 30469061 TI - The effect of moisture on soil microbial properties and nitrogen cyclers in Mediterranean sweet orange orchards under organic and inorganic fertilization. AB - Water shortage and soil degradation are common environmental stressors encountered in the Mediterranean area. We evaluated how different soil moisture levels, dependent on distance from drip irrigation points, impact on the biological, chemical and physical properties of citrus soil under organic and inorganic fertilization. We measured soil physicochemical properties, basal soil respiration, soil microbial biomass carbon, soil microbial community structure (phospholipid fatty acid assay), bacterial load (16S rRNA gene abundance), enzymatic activities (urease, dehydrogenase, beta-glucosidase and acid phosphatase) and abundance of microbial nitrogen cyclers (quantitative PCR). A field experiment was established in an orange orchard (Citrus sinensis) in southeast Spain and eighteen soil samples were taken from each plot to compare the impacts of soil moisture: near (wet, w) or away (dry, d) from drip-irrigation points, in plots with inorganic fertilizers under intensive ploughing (PI) or organic fertilization (OA). The results showed that changes in microbial properties and soil microbial indexes were strongly associated with soil moisture content under both organic and inorganic fertilization, and with organic carbon content. Soil moisture influenced soil aggregation, basal soil respiration, phosphatase activity, bacterial and fungal load (PLFAs) and the abundances of bacterial N cycling genes, including nifH (nitrogen fixation) nirS/K and nosZ genes (denitrification) and amoA-B (bacterial nitrification). The potential for N fixation and denitrification, two microbial processes that are crucial for determining the amount of N in the soil, were improved by increased soil moisture in the proximity of the drip irrigation. Soil OC and total N, which are higher under organic fertilization than under inorganic fertilization, were also shown to be highly correlated with the abundance of the N cycling genes. By controlling irrigation doses and applying organic amendments, it may be possible to increase the microbial abundance and function in soil and support greater fertility of soils. PMID- 30469062 TI - Ambient PM2.5 and O3 and their combined effects on prevalence of presbyopia among the elderly: A cross-sectional study in six low- and middle-income countries. AB - BACKGROUND: Ambient air pollutant directly contacts with the eyes, however, the effect of ambient fine particulate matter (PM2.5) and ozone (O3) on vision impairment, such as presbyopia, has been kept largely unknown. METHODS: We surveyed a total of 36,620 participants aged 50 years and above in six low- and middle-income countries. Ambient annual concentrations of PM2.5 and O3 for the residential community were estimated using satellite data and chemical transport model. A mixed effects model was utilized to assess the effects of ambient PM2.5 and O3 on presbyopia, as well as their combined effects. RESULTS: A total of 13,841 presbyopia cases were identified among the participants with a prevalence rate of 41.17%. For both PM2.5 and O3, we found a J-shaped exposure-response relationship with the threshold being identified at 15 MUg/m3 for PM2.5 and 55 MUg/m3 for O3. The odds ratio (OR) of presbyopia was 1.15 (95% CI: 1.09, 1.21) for each 10 MUg/m3 increase in PM2.5 above 15 MUg/m3 and 1.37 (95% CI: 1.23, 1.54) for O3 above 55 MUg/m3 after adjusting for various potential confounding factors. There appeared to be a synergistic interaction between ambient PM2.5 and O3 on presbyopia in the additive model, the combined effect was significantly larger than the sum of their individual effects, with a synergistic index of 2.39. CONCLUSION: This study supports that exposures to ambient PM2.5 and O3 might be important risk factors of presbyopia among old adults, and simultaneously exposure to high level of the two pollutants could intensify their individual effects. PMID- 30469063 TI - Development of a novel solid phase microextraction calibration method for semi solid tissue sampling. AB - Accurate quantitative analysis using in vivo solid phase microextraction (SPME) for semi-solid tissue can be challenging due to the complexity of the sample matrix. In this paper, a comprehensive study was carried out on the extraction kinetics of SPME in the semi-solid sample, and subsequently proposed a new theoretical model to interpret the kinetic extraction process. Theoretically derived mathematical expressions well described the experimental desorption time profiles of the SPME process. Modelling experiments were also carried out to study the effect of sample tortuosity and binding matrix on the parameters affecting the extraction kinetics. Seven polyaromatic hydrocarbons (PAHs) and eight polychlorinated biphenyls (PCBs) in agarose gel and in real fish tissue were used for these experiments. The experimental data showed excellent agreement with theoretical prediction while providing excellent interpretation of the effect of tortuosity and binding matrix. Based on the theoretical model, an on fiber standard calibration method with fewer internal standards was developed. The newly developed calibration method was used to quantify PAHs and PCBs in agarose gel and fish tissue. By using the proposed calibration method, a large number of organic compounds can be quantified with fewer internal standards. Current study provides the theoretical foundation for in vivo SPME quantitative semi-solid tissue analysis in the future. PMID- 30469064 TI - Evaluation of changes in Microcystis aeruginosa growth and microcystin production by urea via transcriptomic surveys. AB - The freshwater cyanobacteria, Microcystis aeruginosa (M. aeruginosa), is well known to produce microcystins (MCs) and induce the formation of harmful algal blooms (HABs) in aquatic environments, but the effects that urea fertilizer has on cyanobacterial growth and toxin production from a molecular biology perspective remain poorly understood. We evaluated changes in the growth and toxicity of M. aeruginosa cultured under different conditions of nitrogen (N) starvation (NN), low nitrogen (LN), and high nitrogen (HN). Cell density and chlorophyll-a concentrations decreased in cyanobacteria exposed to N starvation and increased following the addition of urea, whereas MCs content increased to a peak and then decreased after urea addition. Transcriptomic analysis confirmed that most genes encoding MCs and genes involved in N metabolic pathways were upregulated under N starvation and LN conditions, whereas these genes were downregulated under HN conditions. Our results offer important insights into the exploring N in controlling the formation of HABs and toxin production based on both physiological and molecular response. PMID- 30469065 TI - Assessing stakeholders' risk perception to promote Nature Based Solutions as flood protection strategies: The case of the Glinscica river (Slovenia). AB - Evidences from flood risk management demonstrated that a deep understanding of the main physical phenomena to be addressed is often not enough but should be also integrated with stakeholders' knowledge and risk perception. Particularly, the effectiveness of flood risk management strategies is highly dependent on stakeholders' perception and attitudes, which play a critical role on how individuals and institutions act to mitigate risks. Furthermore, practitioners and policy-makers realized that grey infrastructures may not be the most suitable solution to reduce flood risk, and that a shift from grey solutions to Nature Based Solutions is required. Within this framework, the present work describes a methodology to enhance the Nature Based Solutions implementation by facilitating the generation, acquisition and diffusion of different stakeholders' risk perceptions. It is based on the combination of Problem Structuring Methods for the elicitation of stakeholders' risk perceptions through individual Fuzzy Cognitive Maps, and Ambiguity Analysis for the investigation of differences in risk perceptions and problem framing. The outputs of the Ambiguity Analysis, used during a participatory workshop, facilitated a dialogue aligning the divergences and promoting the social acceptance of Nature Based Solutions. These results of the implementation of this multi-step methodology in the Glinscica river basin (Slovenia) are discussed. PMID- 30469066 TI - A risk assessment of Europe's black truffle sector under predicted climate change. AB - The black truffle (Tuber melanosporum) is a highly revered culinary icon species that grows symbiotically with its host trees across several parts of southern Europe. Where harvested under natural or cultivated conditions, truffles can have a significant socioeconomic impact and may even form a key component of cultural identity. Although some aspects of truffle biology and ecology have been elucidated recently, the role of abiotic, environmental and climatic factors in the production and maturation of their fruitbodies is still largely unknown. Based on 36-year-long, continuous records of Mediterranean truffle yield, we demonstrate that decreased summer precipitation together with increased summer temperatures significantly reduce the fungus' subsequent winter harvest. Using state-of-the-art climate model projections, we predict that a significant decline of 78-100% in southern European truffle production is likely to occur between 2071 and 2100. The additional threats of forecasted heatwaves, forest fires, pest and disease outbreaks are discussed along with socioeconomic and ecological consequences of a warmer and dryer future climate. Our results emphasize the need for unravelling the direct and indirect effects of climate change on Europe's truffle sector and underline the importance of conservation initiatives at local to international scales. PMID- 30469067 TI - Untangling the water-food-energy-environment nexus for global change adaptation in a complex Himalayan water resource system. AB - Holistic water management approaches are essential under future climate and socio economic changes, especially while trying to achieve inter-disciplinary societal goals such as the Sustainable Development Goals (SDGs) of clean water, hunger eradication, clean energy and life on land. Assessing water resources within a water-food-energy-environment nexus approach enables the relationships between water-related sectors to be untangled while incorporating impacts of societal changes. We use a systems modelling approach to explore global change impacts on the nexus in the mid-21st century in a complex western Himalayan water resource system in India, considering a range of climate change and alternative socio economic development scenarios. Results show that future socio-economic changes will have a much stronger impact on the nexus compared to climate change. Hydropower generation and environmental protection represent the major opportunities and limitations for adaptation in the studied system and should, thereby, be the focus for actions and systemic transformations in pursue of the SDGs. The emergence of scenario-specific synergies and trade-offs between nexus component indicators demonstrates the benefits that water resource systems models can make to designing better responses to the complex nexus challenges associated with future global change. PMID- 30469068 TI - Dietary exposure of mussels to PVP/PEI coated Ag nanoparticles causes Ag accumulation in adults and abnormal embryo development in their offspring. AB - Toxicity of silver nanoparticles (Ag NPs) to aquatic organisms has been widely studied. However, the potential toxic effects of Ag NPs ingested through the food web, especially at environmentally relevant concentrations, as well as the potential effects on the offspring remain unknown. The aims of this work were to screen the cytotoxicity of Poly N-vinyl-2-pirrolidone/Polyethyleneimine (PVP/PEI) coated 5 nm Ag NPs in hemocytes exposed in vitro and to assess the effects of dietary exposure to Ag NPs on mussels growth, immune status, gonad condition, reproductive success and offspring embryo development. For this, mussels Mytilus galloprovincialis were fed daily with microalgae Isochrysis galbana previously exposed for 24 h to a dose close to environmentally relevant concentrations (1 MUg Ag/L Ag NPs) and to a high dose of 10 MUg Ag/L Ag NPs. After 24 h of in vitro exposure, Ag NPs were cytotoxic to mussel hemocytes starting at 1 mg Ag/L (LC50: 2.05 mg Ag/L). Microalgae significantly accumulated Ag after the exposure to both doses and mussels fed for 21 days with microalgae exposed to 10 MUg Ag/L Ag NPs significantly accumulated Ag in the digestive gland and gills. Sperm motility and fertilization success were not affected but exposed females released less eggs than non-exposed ones. The percentage of abnormal embryos was significantly higher than in control individuals after parental exposure to both doses. Overall, results indicate that Ag NPs taken up through the diet can significantly affect ecologically relevant endpoints such as reproduction success and embryo development in marine mussels. PMID- 30469069 TI - Bacterial community composition shaped by water chemistry and geographic distance in an anthropogenically disturbed river. AB - 'Core bacterial communities', bacterial species that are found consistently throughout a river continuum, have previously been identified. However, variations in core and non-core bacterial community structure, as well as the relationships between these communities and water chemistry or geographic distance have not been well studied. Here, we sampled in the entire course of the Le'an River, China, and explored the bacterial community composition at each site using Illumina high-throughput sequencing. The proportion of sequence reads assigned to the core community was ~95% in the upper and middle reaches, gradually decreasing below 90% in the lower reaches. Both the Chao1 richness index and the Shannon diversity index of the bacterial communities were significantly higher in the wet season than in the dry season, and both indices increased slightly from upstream to downstream. The variation in the non-core community was more aggregated from upstream to downstream in the wet season than in the dry season, while the aggregation of the core community was similar between the dry season and the wet season. The proportion of typical freshwater bacterial was significantly higher in the core community than in the non-core community. NO3--N was the subset of water chemistry parameters that best explained bacterial community dissimilarities, while 'river length' was the subset of geographic distance parameters that best explained bacterial community dissimilarities. Water chemistry parameters explained more of the variations in the bacterial communities than did geographic distance, especially in the dry season. However, the correlation between water chemistry and bacteria was primarily due to collective allochthonous input (mass effects), not because of any nutritious or toxic effects on bacterial growth competition (species sorting). The greater influence of the mass effects, as compared to species sorting, on bacterial community structure was due to the allochthonous input of bacteria from anthropogenic sources. PMID- 30469070 TI - Mixed-chemical exposure and predicted effects potential in wadeable southeastern USA streams. AB - Complex chemical mixtures have been widely reported in larger streams but relatively little work has been done to characterize them and assess their potential effects in headwater streams. In 2014, the United States Geological Survey (USGS) sampled 54 Piedmont streams over ten weeks and measured 475 unique organic compounds using five analytical methods. Maximum and median exposure conditions were evaluated in relation to watershed characteristics and for potential biological effects using multiple lines of evidence. Results demonstrate that mixed-contaminant exposures are ubiquitous and varied in sampled headwater streams. Approximately 56% (264) of the 475 compounds were detected at least once across all sites. Cumulative maximum concentrations ranged 1,922 162,346 ng L-1 per site. Chemical occurrence significantly correlated to urban land use but was not related to presence/absence of wastewater treatment facility discharges. Designed bioactive chemicals represent about 2/3rd of chemicals detected, notably pharmaceuticals and pesticides, qualitative evidence for possible adverse biological effects. Comparative Toxicogenomics Database chemical gene associations applied to maximum exposure conditions indicate >12,000 and 2,900 potential gene targets were predicted at least once across all sites for fish and invertebrates, respectively. Analysis of cumulative exposure-activity ratios provided additional evidence that, at a minimum, transient exposures with high probability of molecular effects to vertebrates were common. Finally, cumulative detections and concentrations correlated inversely with invertebrate metrics from in-stream surveys. The results demonstrate widespread instream exposure to extensive contaminant mixtures and compelling multiple lines of evidence for adverse effects on aquatic communities. PMID- 30469071 TI - Biomimicry of vascular plants as a means of saline soil remediation. AB - Soil salinization impacts millions of hectares of land around the world and threatens many soil ecosystem services. Impacts of soil salinization are long lasting and impact agriculture productivity, reduce plant diversity and cause increase soil erosion due a reduction or loss in surface vegetation. Generally, remediation of saline soil relies on soil washing methods and phytoremediation to translocate salts below the rooting depth of plants. However, standard methods can often be unsuccessful as leached salts are able to return to the rooting zone through subsequent capillary rise in the soil. Surface application of iron (III) ferrocyanide has been used to remediate salt contaminated soil as the ferrocyanide complex induces salts to efflorescence at the soil surface as water evaporates rather than crystallising within the soil matrix. However, surface application of iron (III) ferrocyanide tends to be less successful in clay textured soil and does not work well when subsequent reapplications of water are made for further salt removal. In this study we investigate a biomimetic approach to desalinate soil by mimicking the capillary transport mechanisms employed by vascular plants. Our approach uses evapotranspiration to translocate saline soil water above the soil surface where it is effloresced with ferrocyanides. After 30 days of treatment, the biomimetic approach used 2.1 pore volume equivalents of water and was able to reduce the concentration of salts from 8% (g.NaCl/g.soil) to 0.8% (g.NaCl/g.soil), resulting in a reduction of soil EC from 120 mS/cm to 14 mS/cm. Our findings indicate that the method, with further refinement and expansion to field based trials, could be an effective tool to desalinate soil and reduce global soil salinization. PMID- 30469072 TI - Spatial distribution and source apportionment of heavy metals in soil from a typical county-level city of Guangdong Province, China. AB - The contents of ten heavy metals (Cr, Hg, As, Pb, Ni, Cd, Ti, Cu, Zn and V) in 413 topsoil samples from Puning City, Guangdong Province, China were investigated. Obvious enrichment of Hg, As, Pb, Cd and Zn were presented, and the contents of Hg and As in 5.8% and 3.4% samples respectively were higher than the guideline values recommended by the Chinese Environmental Quality Standard for Soils. Chromium and V were presented no enrichment and no pollution. According to one-way analysis of variance, the mean contents of Hg, Pb, Cu and Zn in land for construction were significantly higher than farmland and natural vegetation, but the land use had no obvious effect on other heavy metals. Furthermore, the potential sources of ten heavy metals were identified and apportioned in combination with geostatistics, correlation analysis and positive matrix factorization model. The results were following as: a) Pb, Zn and Cu mainly origin from vehicle emission and atmosphere deposition, and the hotspots approximately distributed in the areas of intensive traffic and near main roads; b) Hg and Cd were derived to industrial activities related to pharmaceutical industries, the textile and dyeing industries and e-waste recycling industries, and high-value areas were mainly concentrated in the northeast of the urban area where the industrial parks have been distributed; c) Soil parent material (Jurassic shale) was the main source of Cr, Ni, V and Ti; d) As mainly came from agricultural inputs such as pesticides or herbicides, livestock and fertilizers. Meanwhile, the contributions of four sources were 33.08%, 24.04%, 27.11% and 15.77% of the total contribution, respectively. PMID- 30469073 TI - The epidemiology of sexual assault of older female nursing home residents, in Victoria Australia, between 2000 and 2015. AB - Sexual assault is the least acknowledged, detected, and reported type of assault against nursing home residents. Nursing home staff are responsible for reporting suspected allegations to the police, who will contact a clinical forensic examiner to conduct a forensic medical examination. This study examined the epidemiology of sexual assaults of older women (aged 65 years and older) residing in nursing homes in Victoria, Australia, between 2000 and 2015, whose alleged incidents were referred to a clinical forensic examiner for a forensic medical examination. A retrospective analysis of alleged sexual assaults reported to the Clinical Forensic Medicine Unit at the Victorian Institute of Forensic Medicine between 1 January 2000 and 31 December 2015 was conducted. The study identified 28 forensic medical examinations performed for alleged sexual assault. The alleged victims frequently had cognitive impairments; injuries were infrequent; and alleged victims were cooperative. The forensic medical examiner responded within 72 h of reporting; and frequently noted limitations to physical examinations of the alleged victim. The actual number of sexual assaults during this period may be masked by under-reporting and, lack of identification by nursing home staff. There are many unresolved issues including: incidence, levels of reporting, nature of investigations, responses required to assist the victim, and the interventions needed to prevent sexual assault. Better data is vital. This data should be standardized, validated, reliable, and gathered prospectively across Australia and internationally. PMID- 30469074 TI - Biomolecular charges influence the response of surface plasmon resonance biosensors through electronic and ionic mechanisms. AB - Surface plasmon resonance (SPR) biosensors have become an important label-free optical biomolecular sensing technology and a "gold standard" for retrieving information on the kinetics of biomolecular interactions. Even though biomolecules typically contain an abundance of easily ionizable chemical groups, there is a gap in understanding of whether (and how) the electrostatic charge of a biomolecular system influences the SPR biosensor response. In this work we show that negative static charge present in a biomolecular layer on the surface of an SPR sensor results in significant SPR spectral shifts, and we identify two major mechanisms responsible for such shifts: 1) the formation of an electrical double layer (ionic mechanism), and 2) changes in the electron density at the surface of a metal (electronic mechanism). We show that under low ionic strength conditions, the electronic mechanism is dominant and the SPR wavelength shift is linearly proportional to the surface concentration of biomolecular charges. At high ionic strength conditions, both electric and ionic mechanisms contribute to the SPR wavelength shift. Using the electronic mechanism, we estimated the pKa of surface bound carboxylic groups and the relative concentration of the carboxyl-terminated alkanethiols in a binary self-assembled monolayer of alkanethiols. The reported sensitivity of SPR to surface charge is especially important in the context of biomolecular sensing. Moreover, it provides an avenue for the application of SPR sensors for fast, label-free determination of the net charge of a biomolecular coating, which is of interest in material science, surface chemistry, electrochemistry, and other fields. PMID- 30469076 TI - Simple, low-cost, sensitive and label-free aptasensor for the detection of cardiac troponin I based on a gold nanoparticles modified titanium foil. AB - This research demonstrated the electrochemical modification of low-cost titanium (Ti) metal substrate with gold nanoparticles (AuNPs) for the aptamer-based detection of cardiac troponin I (cTnI). AuNPs were deposited onto Ti sheets by the potential-step deposition method with high density and homogeneity as well as good crystallinity. It was then applied as a transducer to immobilize a thiol functionalized DNA aptamer via the self-assembled monolayer mechanism for the specific binding of cTnI. This was verified through electrochemical and morphological analyses. The aptasensor could detect cTnI in a linear range of 1 1100 pM with a detection limit of ca. 0.18 pM. The aptasensor showed high sensitivity and specificity to cTnI over other interfering compounds with good recoveries in the diluted human serum samples. PMID- 30469075 TI - A versatile loop-mediated isothermal amplification microchip platform for Streptococcus pneumoniae and Mycoplasma pneumoniae testing at the point of care. AB - Community-acquired pneumonia (CAP) is the leading cause of mortality in children under five years of age, globally. Given that Streptococcus pneumoniae (S. pneumoniae) and Mycoplasma pneumoniae (M. pneumoniae) are the most common pathogens associated with CAP requiring hospital admission, a simple, low cost, highly sensitive method is in great need for immediate and early diagnosis of CAP. Herein, we report a versatile microfluidic chip platform integrated with loop-mediated isothermal amplification (LAMP) for simultaneous S. pneumoniae and M. pneumoniae testing at the point of care. The platform includes a polymer/paper microfluidic chip and a portable device. On-chip magnetic particle-based nucleic acid extraction is used for concentration of pathogens' genomic DNA and is followed by LAMP. The portable device has the function of heating the microfluidic chip, and photographing and transmitting the result to a smartphone. Complete extraction of the DNA using the microfluidic chip took ~15 min versus >1.5 h with a phenol-chloroform method. The analytical sensitivity of the assay was determined to be 20 fg by testing serial dilutions of target DNA ranging from 2 ng to 2 fg per reaction. We evaluated the clinical sensitivity and specificity of the IPuchip assay using 63 randomly selected oropharyngeal swabs and bronchoalveolar lavage fluid specimens from children. For comparison, these specimens were also tested against real-time PCR assay (M. pneumoniae), conventional PCR assay (S. pneumoniae), and culture tests (S. pneumoniae). These results yielded positive and negative predictive values for M. pneumoniae testing with the IPuchip platform of 96.9% and 100%, respectively. Compared with S. pneumoniae IPuchip, the clinical sensitivity of S. pneumoniae PCR and culture tests was 60% and 40%, respectively, while clinical specificity of the two tests was 100%. This versatile IPuchip platform has great potential for point of care testing of different kinds of pathogens, especially for developing nations. PMID- 30469077 TI - Recent progress on cell-based biosensors for analysis of food safety and quality control. AB - Food quality and safety has become a subject of major concern for authorities and professionals in the food supply chain. Rapid methods, particularly biosensors, have exceptional specificity and sensitivity, rapid response times, low cost, relatively compact size, and are user friendly to operate. Cell-based biosensors are portable, and provide the biological activity of the analyte suitable for an initial screening of food. In this overview, the utilization of cell-based biosensors for food safety and quality analyses, such as detecting toxins, foodborne pathogens, allergens, and evaluating toxicity and function are summarized. Our results will promote the future development of cell-based biosensors in the food field. PMID- 30469078 TI - Nectin-3 is a new biomarker that mediates the upregulation of MMP2 and MMP9 in ovarian cancer cells. AB - Nectin-3 is a cell adhesion molecule that functions in tight junctions. Recent reports have implicated nectin-3 in pancreatic adenocarcinoma and lung adenocarcinoma. However, there has been little exploration of the expression, cellular invasion and migration of nectin-3 in ovarian cancer (OC). We evaluated the distribution of cells that were positive for nectin-3 using immunohistochemistry in specimens of human OC and correlated these results with overall survival (OS). The nectin-3 expression was significantly increased accompanied by a degree of malignancy in ovarian tumors; moreover, the expression of matrix metallopeptidases (MMP) 2 and 9 was upregulated. In addition, an increased level of nectin-3 was related to a poorer OS. In summary, we have demonstrated that cellular migration and invasion via nectin-3 mediate the upregulation of MMP2 and MMP9 in OC cells. Nectin-3 may be a new biomarker for OC diagnosis. PMID- 30469079 TI - Beta-caryophyllene alleviates diet-induced neurobehavioral changes in rats: The role of CB2 and PPAR-gamma receptors. AB - BACKGROUND AND PURPOSE: Insulin resistance (IR) and obesity predispose diseases such as diabetes, cardiovascular and neurodegenerative disorders. Beta caryophyllene (BCP), a natural sesquiterpene, exerts neuroprotective, anxiolytic and antidepressant effects via its selective agonism to cannabinoid receptor 2 (CB2R). BCP was shown to have an anti-diabetic effect, however, the implication of CB2R is yet to be elucidated. A link between CB2R agonism and PPAR-gamma activation has been discussed, but the exact mechanism is not well-defined. This study was designed to examine the role of BCP in improving diet-induced metabolic (insulin resistance), neurobehavioral (anxiety, depression and memory deficit), and neurochemical (oxidative, inflammatory and neurotrophic factor) alterations in the prefrontal cortex of obese rats' brain. The involvement of CB2R and/or PPAR-gamma dependent activity was also investigated. EXPERIMENTAL APPROACH: Male Wistar rats were fed a high fat/fructose diet (HFFD) for 12 weeks to induce IR and obesity. Rats were treated with BCP for the last 4 weeks. Either CB2R antagonist AM630 or PPAR-gamma antagonist BADGE was administered before BCP treatment to study the mechanism of BCP actions. KEY RESULTS: Beta-caryophyllene alleviated HFFD-induced IR, oxidative-stress, neuroinflammation and behavioral changes. The anxiolytic, anti-oxidant and anti-inflammatory effects of BCP were mediated by both PPAR-gamma and CB2R. The effects of BCP on glycemic parameters seem to be CB2R-dependent with the non-significant role of PPAR-gamma. Furthermore, BCP-evoked antidepressant and memory improvement are likely mediated only via CB2R, mainly by upregulation of PGC-1alpha and BDNF. CONCLUSION: This study suggests the potential effect of BCP in treating HFFD-induced metabolic and neurobehavioral alterations. BCP seems to activate PPAR-gamma in a ligand independent manner, via upregulation and activation of PGC-1alpha. The BCP activation of PPAR--gamma seems to be CB2R-dependent. PMID- 30469080 TI - Macrocyclic lactones from seafood Amphioctopus neglectus: Newly described natural leads to attenuate angiotensin-II induced cardiac hypertrophy. AB - Amphioctopus neglectus (Family: Octopodidae) is recognised as culinary delicacy in many cultures and a common sea food item on the Mediterranean and Asian coasts. Bioassay-directed fractionation of ethyl acetate/methanol extract of A. neglectus ensued in the characterisation of four previously undescribed macrocyclic lactones (1-4). These compounds exhibited potential radical scavenging capacities (IC50 0.95-1.73 mM) along with anti-hypertensive activities (IC50 1.12-2.34 mM) against angiotensin converting enzyme (ACE). The optimum binding affinity of compound 2 (-9.84 kcal mol-1) bearing furo[1,4,8]trioxacyclohexadecine-12,19-dione moiety with ACE, along with its permissible hydrophobic-hydrophilic balance, manifested towards its greater anti hypertensive activity compared to other analogues. The compound 2, with lesser values of the inhibitory constant (Ki = 1.0 mM) towards ACE, was found to bind more effectively to the enzyme in a non-competitive manner, and could describe the greater inhibitory ramifications than those displayed by other compounds (Ki >1.1 mM). The ex-vivo studies revealed that compound 2 imparted protective effects against angiotensin-II induced cardiac hypertrophy at 25 MUg mL-1 on H9C2 cell lines, wherein about 34 percent decrease in cell area with increase in viability could be attributed to anti-hypertrophic effects of the compound administrated. These results confirmed that the protective effect of the isolated macrocyclic lactones is mediated by enhancement of anti-oxidant defense systems, which subsequently attenuates the hypertensive related disorders. PMID- 30469081 TI - Differential expression of entorhinal cortex and hippocampal subfields alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D aspartate (NMDA) receptors enhanced learning and memory of rats following administration of Centella asiatica. AB - Centella asiatica (CA) is a widely used traditional herb, notably for its cognitive enhancing effect and potential to increase synaptogenesis. The alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and N methyl-D-aspartate receptors (NMDARs) mediate fast excitatory neurotransmission with key roles in long-term potentiation which is believed to be the cellular mechanism of learning and memory. Improved learning and memory can be an indication to the surface expression level of these receptors. Our previous study demonstrated that administration of CA extract improved learning and memory and enhanced expression of AMPAR GluA1 subunit while exerting no significant effects on GABAA receptors of the hippocampus in rats. Hence, to further elucidate the effects of CA, this study investigated the effects of CA extract in recognition memory and spatial memory, and its effects on AMPAR GluA1 and GluA2 subunit and NMDAR GluN2 A and GluN2B subunit expression in the entorhinal cortex (EC) and hippocampal subfields CA1 and CA3. The animals were administered with saline, 100 mg/kg, 300 mg/kg, and 600 mg/kg of CA extract through oral gavage for 14 days, followed by behavioural analysis through Open Field Test (OFT), Novel Object Recognition Task (NORT), and Morris Water Maze (MWM) and lastly morphological and immunohistochemical analysis of the surface expression of AMPAR and NMDAR subunits were performed. The results showed that 14 days of administration of 600 mg/kg of CA extract significantly improved memory assessed through NORT while 300 mg/kg of CA extract significantly improved memory of the animals assessed through MWM. Immunohistochemical analysis revealed differential modulation effects on the expressions of receptor subunits across CA1, CA3 and EC. The CA extract at the highest dose (600 mg/kg) significantly enhanced the expression of AMPAR subunit GluA1 and GluA2 in CA1, CA3 and EC, and NMDAR subunit GluN2B in CA1 and CA3 compared to control. At 300 mg/kg, CA significantly increased expression of AMPAR GluA1 in CA1 and EC, and GluA2 in CA1, CA3 and EC while 100 mg/kg of CA significantly increased expression of only AMPAR subunit GluA2 in CA3 and EC. Expression of NMDAR subunit GluN2 A was significantly reduced in the CA3 (at 100, 300, and 600 mg/kg) while no significant changes of subunit expression was observed in CA1 and EC compared to control. The results suggest that the enhanced learning and memory observed in animals administered with CA was mainly mediated through increased expression of AMPAR GluA1 and GluA2 subunits and differential expression of NMDAR GluN2 A and GluN2B subunits in the hippocampal subfields and EC. With these findings, the study revealed a new aspect of cognitive enhancing effect of CA and its therapeutic potentials through modulating receptor subunit expression. PMID- 30469082 TI - Nanoemulsions improve the efficacy of turmeric in palmitate- and high fat diet induced cellular and animal models. AB - Turmeric is a well-known functional food exhibiting multiple biological activities in health and disease. However, low aqueous solubility and poor bioavailability limit its therapeutic potential. Herein, we investigated the utility of nanoemulsions as a carrier to improve the efficacy of turmeric. Compared with turmeric extract (TE), 5% TE-loaded nanoemulsion (TE-NE), which contains 20-fold lower curcumin content than TE, achieved similar inhibition of palmitate-induced lipotoxicity in HepG2 cells. Exposure of HepG2 cells to 5% TE NE also suppressed the palmitate-induced accumulation of lipid vacuoles and reactive oxygen species comparably with TE, and was accompanied by decreased levels of sterol regulatory element-binding protein (SREBP)-1, peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2), cleaved caspase-3, and poly (ADP-ribose) polymerase (PARP). Consistent with these effects in HepG2 cells, oral administration of 5% TE-NE to mice fed a high fat diet (HFD) markedly suppressed lipid accumulation in liver, leading to a significant reduction in body weight and adipose tissue weight, equivalent to the effects observed with TE. Compared with TE, 5% TE-NE also equivalently inhibited the levels of SREBP-1, PPAR-gamma2, cleaved caspase-3, and PARP in the liver of mice fed a HFD. Furthermore, TE and 5% TE-NE significantly improved serum lipid profiles in a similar manner. These observations indicate that nanoemulsions can improve the efficacy of turmeric, thereby eliciting more potent biological efficacy against palmitate- and high fat diet (HFD)-induced cellular damage. PMID- 30469083 TI - Low neuroticism and cognitive performance are differently associated to overweight and obesity: A cross-sectional and longitudinal UK Biobank study. AB - BACKGROUND: A growing body of research has linked personality traits to cognitive performance. This relationship might play a role in the predisposition toward obesity. Neuroticism and executive function seem to be particularly involved, and reduced executive function has been proposed to underlie the association of neuroticism with sedentary behaviors and fatty food consumption. Despite the link between neuroticism, cognitive functions and obesity has been largely reported, conflicting evidence exists. Moreover, information regarding other cognitive domains, and studies on overweight individuals, are still scarce. METHODS: We examined cross-sectional associations of neuroticism and cognitive function with overweight and obesity in a sample of 170 310 individuals from the UK Biobank cohort, adjusted for sociodemographic and life-style factors. Measures on fluid intelligence (FI) (reasoning ability), trail making test (TMT) (executive function), numeric memory test and pairs matching (PM) task (short-term memory) were extracted from the database. Correlations between neuroticism and cognitive performance were explored. Moreover, we investigated whether neuroticism and executive function could predict BMI variability over time. RESULTS: Reduced FI and short-term memory were associated with overweight and obesity, while reduced executive function was associated with obesity but not with overweight. Low neuroticism was associated with being overweight rather than lean or obese independently of gender and life-style. Furthermore, baseline neuroticism scores could predict BMI variations over 5-10 years follow-up, and high neuroticism correlated with lower cognitive performance. CONCLUSIONS: Lower cognitive performance is associated with both overweight and obesity, except for executive function, which was only related to obesity. Neuroticism correlated with performance on most of the cognitive domains tested, supporting the link between personality and cognition. Our findings also support the role of neuroticism in leading to greater weight variability over time, rather than to overweight/obesity itself. PMID- 30469084 TI - Assay validation of hair androgens across the menstrual cycle. AB - INTRODUCTION: Saliva is a common noninvasive biofluid for measuring stress and sex hormones, yet one pressing limitation is that salivary hormones fluctuate momentarily, daily, and (for girls) across the menstrual cycle. Hair steroid assays are thought to provide a cumulative index which collapses across hormonal variability, potentially eliminating the confound of daily and menstrual cyclicity and thereby reflecting individual differences in average hormone levels. Here we seek to validate a hair bioassay methodology and test whether hair androgens accurately measure long-term, stable androgen levels in emerging adult women across two menstrual cycles. METHODS: Hair samples were collected at the end of each menstrual cycle for two cycles, and saliva samples were collected in the morning once per week across two menstrual cycles (N = 11 women). Hair samples were segmented by 1 cm for the first 4 cm to reflect the hormone levels of the past four serial months. Hair samples were assayed using commercially available enzyme-immuno-assays for testosterone and DHEA. RESULTS: Hair androgen concentrations were significantly correlated with averaged saliva hormone levels (DHEA: r = .75, p < .05; Testosterone: r = .67, p < .05). With respect to hair hormone stability, there were significant correlations for almost all the pairs of two 1 cm hair segments collected in two months that corresponded to the same time period. Hair androgens in one segment were significantly correlated with those in next segment. Regarding salivary androgen stability, the intra-class correlation across the weekly saliva samples indicated that for DHEA 59% of the total variance was within person and 41% was between person; and for testosterone 91% of the total variance was between person, and only 9% within person. DISCUSSION: Results suggest that a one-time measure of hair provides a valid and reliable estimate of average steroid levels across two months. Moreover, whereas saliva measures of androgen levels capture week-to-week fluctuations in steroids, hair samples provide information on individual differences in average exposure to steroids, across long periods of time, such as months. Results are encouraging that hair DHEA and testosterone reflects the cumulative hormonal concentration and can be used as a stable hormonal index. Results also indicate that it is feasible to collect the first 3-4 centimeters of hair for studies of stable hormone levels. PMID- 30469085 TI - Hippocampal volume modulates salivary oxytocin level increases after intranasal oxytocin administration. AB - Adverse childhood experiences have been shown to affect sensitivity to intranasal oxytocin administration, but the neural mechanisms underlying this altered sensitivity are unclear. The aim of the current study was to examine whether hippocampal abnormalities underlie the effects of adversity on the response to oxytocin administration. In a sample of healthy women (N = 54, age M = 19.63), we examined 1) the association between hippocampal volume and experiences of emotional maltreatment and 2) whether hippocampal volume reductions influence the effect of intranasal oxytocin administration on salivary oxytocin levels. There was no association between hippocampal volume and experiences of emotional maltreatment in the current study. However, we found that larger hippocampal volume was related to a stronger increase in salivary oxytocin level after intranasal oxytocin administration. The hippocampus may be a neural substrate underlying individual differences in sensitivity to oxytocin administration. PMID- 30469086 TI - Virtually stressed? A refined virtual reality adaptation of the Trier Social Stress Test (TSST) induces robust endocrine responses. AB - In recent years, virtual reality (VR) technology has found its way into nearly all fields of psychology. Previous studies indicated that virtual reality adaptations of the TSST are less potent in stimulating HPA-axis responses, with lower salivary cortisol responses recorded as compared to the in-vivo TSST. (TSST IV). In the present experiment we tested the stress-induction potential of a refined version of the TSST-VR using a fully orthogonal experimental design in which ninety-three healthy males were either assigned to the TSST condition or a corresponding control condition in a real or virtual environment. We found a significant increase of endocrine, autonomic and self-reported stress markers in both stress conditions. Notably, we found a robust rise in salivary cortisol to the TSST-VR comparable to that observed in the TSST-IV. Despite subtle differences in response between virtual and in vivo settings, we conclude that VR adaptations of in-vivo stressors have the potential to induce real physiological and subjective reactions. PMID- 30469087 TI - Foot massage evokes oxytocin release and activation of orbitofrontal cortex and superior temporal sulcus. AB - Massage may be an important method for increasing endogenous oxytocin concentrations and of potential therapeutic benefit in disorders with social dysfunction such as autism where basal oxytocin levels are typically reduced. Here we investigated oxytocin release and associated neural responses using functional near infrared spectroscopy (fNIRS) during hand- or machine administered massage. 40 adult male subjects received 10 min of light foot massage either by hand or machine in a counterbalanced order and then rated pleasure, intensity, arousal and how much they would pay for the massage. Blood samples were taken before and after each massage condition to determine plasma oxytocin concentrations. Neural responses from medial and lateral orbitofrontal cortex, superior temporal sulcus and somatosensory cortex were measured (fNIRS oxy-Hb) together with skin conductance responses (SCR), ratings of the massage experience, autistic traits and sensitivity to social touch. Results showed subjects gave higher ratings of pleasure, but not intensity or arousal, after hand- compared with machine-administered massage and there were no differential effects on SCR. Subjects were also willing to pay more for the hand massage. Plasma oxytocin increased after both massage by hand or machine, but more potently after massage by hand. Both basal oxytocin concentrations and increases evoked by hand-, but not machine-administered massage, were negatively associated with trait autism and attitudes towards social touch, but massage by hand-evoked changes were significant in higher as well as lower trait individuals. Increased neural responses to hand vs. machine-administered massage were found in posterior superior temporal sulcus and medial/lateral orbitofrontal cortex but not somatosensory cortex. Orbitofrontal cortex and superior temporal cortex activation during hand massage was associated with the amount of money subjects were willing to pay and between orbitofrontal cortex activation and autism scores. Thus, hand-administered massage can potently increase oxytocin release and activity in brain regions involved in social cognition and reward but not sensory aspects of affective touch. Massage by hand induced changes in both oxytocin concentrations and neural circuits involved in processing social affective trust may have therapeutic potential in the context of autism. PMID- 30469088 TI - Short- and long-term alterations of FKBP5-GR and specific microRNAs in the prefrontal cortex and hippocampus of male rats induced by adolescent stress contribute to depression susceptibility. AB - Maladaptation of the hypothalamic-pituitary-adrenal (HPA) axis is involved in susceptibility to depression. Glucocorticoid receptors (GRs) and the co-chaperone protein, FK506 binding protein 51 (FKBP5), play crucial roles in dysfunction of the HPA axis. Further, certain microRNAs (miRNAs), such as miR-124a and miR-18a, which could reduce GR protein expression, contribute to affective disorders, while miR-511 as a regulator of FKBP5 is involved in an increased risk of depression. However, the short-term and persistent impacts of adolescent stress on miR-124a, miR-18a, and miR-511 expressions in the brain are unknown. Using depression models of chronic unpredictable mild stress (CUMS) or dexamethasone administration of adolescent rats, the authors of the present study probed the depressive-like behaviors, GR and FKBP5 expressions, and miR-124a, miR-18a, and miR-511 expressions in the prefrontal cortex and hippocampus. The GR antagonist RU486 was used as intervention. The results revealed that both CUMS and dexamethasone administration in the adolescent period resulted in anhedonia, altered locomotor behaviors, anxiety, and cognitive impairment. A remarkable decrease in GR expression, and increase in FKBP5, miR-124a, and miR-18a expressions were detected in the prefrontal cortex and hippocampus of adolescent rats. Furthermore, the similar long-term changes on behaviors and expressions of GR, FKBP5 and GR-related microRNAs were found in the adult rats following CUMS and dexamethasone treatment in adolescence. However, reduced miR-511 expression was observed only in the prefrontal cortex of adult rats exposed to adolescent CUMS or dexamethasone administration. These data suggested that the downregulation of GR, upregulation of FKBP5, miR-124a, and miR-18a in the prefrontal cortex and hippocampus, and downregulation of miR-511 in the prefrontal cortex were relevant to depressive-like behaviors. PMID- 30469089 TI - Randomized controlled trial of cognitive behavioural therapy for depressive and anxiety symptoms in Chinese women with breast cancer. AB - Depressive and anxiety symptoms are frequently observed in breast cancer survivors. To date, few randomized controlled trials have been conducted on the efficacy of cognitive behavioural therapy (CBT) for depressive and anxiety symptoms in Chinese population. This study aims to verify the efficacy of CBT in Chinese breast cancer survivors. Women (n = 392) with breast cancer were randomly assigned to 3 groups: CBT (n = 98), self-care management (SCM, n = 98), and usual care (UC, n = 196) using the proportion 1:1:2. Women in the CBT and SCM groups received a series of nine sessions for 12 weeks, while women in the UC group received their usual medical care only. Depressive and anxiety symptoms were assessed using the Hamilton Depression Rating Scale (HAMD) and the Hamilton Anxiety Scale (HAMA) score at baseline, 2, 4, 8, 12, 16, and 24 weeks. A significant intergroup difference was found in the HAMD and HAMA scores. Women in the CBT group showed significantly less depressive and anxiety symptoms compared with women in the SCM and UC groups over time. In conclusion, this study supports the efficacy of CBT for depressive and anxiety symptoms in Chinese breast cancer survivors. PMID- 30469090 TI - Visual impairments in tobacco use disorder. AB - Prior studies found small effects of chronic smoking on spatial and color vision, but they were inconclusive. This study tries to: (1) replicate and extend these previous findings, and (2) rule in that this relationship is pronounced by tobacco addiction. Data were recorded in 71 healthy controls (M = 33.5 years; SD = 5.4 years) and 63 individuals with tobacco addiction (M = 34.7 years; SD = 4.8 years). Visual processing was assessed in the forms of contrast sensitivity for linear sine-wave gratings (spatial frequencies ranging between 0.2 and 16 cycles per degree) and color discrimination (using the Ellipse and Trivector subtests). The groups were matched for age, gender and level of education. The group with heavy smokers had reduced sensitivity for all spatial frequencies (p < .001), and impairments in color discrimination for both Trivector (all p-values < .001 for Protan, Deutan and Tritan) and Ellipse (all p-values < .001). This study consistently replicates and extended previous findings, and showed that visual processing can be strongly associated with tobacco addiction. These results indicate that excessive use of cigarettes, or chronic exposure to their compounds, affects visual discrimination, supporting the existence of overall deficits in visual processing in tobacco addiction. PMID- 30469091 TI - Frequency of nonsuicidal self-injury is associated with impulsive decision-making during criticism. AB - Research indicates that nonsuicidal self-injury (NSSI) is associated with impulsive traits, but not impulsive behavior on laboratory tasks, even in the context of negative mood. However, previous studies may not have induced forms of negative affect most relevant to NSSI. For example, evidence implicates both self criticism and feeling criticized by others in NSSI engagement. We conducted two studies examining whether negative mood related to criticism increases impulsive decision-making among individuals with NSSI histories, using a gambling task embedded with auditory critical comments; participants imagined loved ones saying these comments to them. Study 1 evaluated community adults with (n = 33) and without (n = 31) NSSI histories. Despite no group differences in task performance, we found an association between past-year NSSI frequency and more impulsive choices during criticism. This was confirmed in Study 2 using a separate sample of adults (n = 69) with more frequent and recent NSSI. In regression models including self-criticism and depressive symptoms, only task performance (i.e., decision-making while receiving critical feedback) predicted NSSI frequency across multiple measurement periods. These studies suggest that more frequent and recent NSSI is associated with neurocognitive impulsivity, specifically in negative emotional contexts involving actual or imagined criticism in close relationships. PMID- 30469092 TI - Facets of identity disturbance reported by patients with borderline personality disorder and personality-disordered comparison subjects over 20 years of prospective follow-up. AB - This study had two objectives. The first was to determine the levels of identity disturbance reported by 290 patients with borderline personality disorder (BPD) and 72 personality-disordered comparison subjects over 20 years of prospective follow-up. The second aim was to describe the levels of identity disturbance reported by 152 ever recovered vs. 138 never recovered borderline patients over 20 years of prospective follow-up. Participants were followed and re-assessed every two years for a total of 20 years of follow-up. Borderline patients reported levels of these states that were more than three times higher than personality-disordered comparison subjects, with both groups demonstrating significant declines in these states over time. For three of these inner states ("I feel like I am worthless," "I feel like a complete failure," and "I feel like I am evil"), recovered borderline patients had lower baseline scores and significantly different patterns of decline than non-recovered patients. For the fourth state, "I feel like I am a bad person," recovered patients had lower scores over time, but the groups declined at the same rate. These results suggest that borderline patients report experiencing inner states related to having a negative identity less often over time. Additionally, recovery status is significantly associated with decreased time experiencing these states. PMID- 30469093 TI - Inter-muscular adipose tissue is associated with adipose tissue inflammation and poorer functional performance in central adiposity. AB - BACKGROUND: The presence of concomitant sarcopenia and obesity in sarcopenic obesity (SO) confers worse functional, morbidity and mortality outcomes compared to either alone. Excess adiposity and central redistribution of fats are associated with systemic inflammation and ectopic tissue fat infiltration in forms of Intermuscular adipose tissue (IMAT). Our study examines the profile of IMAT across a spectrum of body compositions and associations with physical performance and inflammatory biomarkers including Monocyte Chemoattractant Protein-1 (MCP-1), a novel biomarker of adipose tissue inflammation. METHODS: 187 community dwelling elderly participants were recruited and classified into 4 subgroups: normal, obese, sarcopenia and SO, using validated criteria for sarcopenia and waist circumference to define central obesity. We performed magnetic resonance imaging of mid-thigh sections to segment IMAT and muscle. Participants were assessed for muscle strength, physical performance and blood inflammatory biomarkers of interleukin-6, C-Reactive Protein and MCP-1. We examined correlation of IMAT(ratio) with muscle function measures and blood biomarkers. Multiple regression analyses were used to examine the association of body composition types and IMAT(ratio) with muscle function. RESULTS: IMAT(ratio) was highest in SO and obese groups. Overall, higher IMAT(ratio) is significantly associated with raised MCP-1, lower gait speed and muscle strength. SO had lowest scores in Short Physical Performance Battery (SPPB), gait speed, hand-grip and knee extension strength. IMAT(ratio) is independently associated with SPPB and handgrip strength, whilst SO is independently associated with muscle strength. CONCLUSION: Our results suggest the possible role of IMAT as a candidate imaging biomarker for adipose tissue inflammation and associated poorer functional outcomes in SO. PMID- 30469094 TI - Gray matter volumetric study of major depression and suicidal behavior. AB - Structural brain deficits are linked to risk for suicidal behavior. However, there is disagreement about the nature of these deficits, probably due to the heterogeneity of suicidal behavior in terms of the suicidal act's lethality. We hypothesized that individuals with major depressive disorder (MDD) and history of more lethal suicide attempts would have lower gray matter volume (GMV) of the prefrontal regions and insula compared with MDD lower-lethality attempters and MDD non-attempters. We collected structural MRI scans on 91 individuals with MDD; 11 with history of higher-lethality suicide attempts, 14 with lower-lethality attempts, and 66 were non-attempters. Differences in GMV between these three groups were examined using both regions-of-interest (ROI) and brain-wide voxel based morphometry (VBM) analyses. Both ROI and VBM analyses showed that higher lethality suicide attempters have greater GMV of the prefrontal cortical regions and insula, compared with the other two groups. Although this contrasts with our hypothesis, the observed larger prefrontal cortex GMV in higher-lethality suicide attempters may underlie the set of attributes observed previously in this suicidal subgroup, including enhanced suicide attempt planning, greater response inhibition, and delayed reward capabilities. Future studies should further examine the role of these brain regions in relation to suicidal intent and planning. PMID- 30469095 TI - Effects of acute treatments with the serotonin 2A antagonist M100907 alone or in combination with the serotonin 2C agonist WAY163909 on methamphetamine self administration in rhesus monkeys. AB - BACKGROUND: Serotonin 5-HT2A receptor antagonists and 5-HT2C receptor agonists have been proposed as important candidates for the development of pharmacotherapies for psychostimulant abuse, with evidence suggesting that those receptors may act together to control behavior. However, the role of 5-HT2A receptors on the reinforcing effects of psychostimulant drugs has not been fully elucidated. METHODS: In the present study, we investigated the effects of the selective 5HT2A receptor antagonist M100907 alone or in combination with the selective 5HT2C agonist WAY 163909 on intravenous methamphetamine self administration in rhesus macaques (N = 3). Methamphetamine self-administration (0.01-0.03 mg/kg/inf) was evaluated under a fixed-ratio 20-schedule of reinforcement, and acute pretreatments were conducted 1 h (M100907) or 45 min (WAY 163,909) prior to the beginning of self-administration sessions at the EDMax dose of methamphetamine once stability criteria were met. RESULTS: Pretreatment with M100907 (0.03-0.3 mg/kg, i.m.) dose-dependently attenuated methamphetamine self-administration, with the highest dose significantly decreasing response rates compared to vehicle. Combined administration of ineffective doses of M100907 and WAY 163,909 had no effects on methamphetamine self-administration. CONCLUSIONS: Our study indicates that acute selective 5-HT2A receptor blockade decreases peak methamphetamine intake in nonhuman primates. Combination approaches with sub-threshold doses of 5-HT2A receptor antagonists and 5-HT2C receptor agonists, on the other hand, do not seem to be effective in decreasing methamphetamine reinforcement. Further studies are needed in order to investigate the effects of chronic treatments with M100 on complete METH SA dose-response curves. PMID- 30469096 TI - Lamotrigine attenuates the motivation to self-administer ketamine and prevents cue- and prime-induced reinstatement of ketamine-seeking behavior in rats. AB - BACKGROUND: Lamotrigine is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. A case report has demonstrated that a ketamine addict experienced a significant reduction in craving and ketamine use after taking lamotrigine. The present study determined whether lamotrigine can reduce the motivation for ketamine and prevent the relapse to ketamine seeking behavior in rats. METHODS: Male Sprague-Dawley rats were trained to respond for intravenous ketamine (0.5 mg/kg/infusion) self-administration or food pellets. The effects of lamotrigine on the motivation for ketamine or food were assessed using breakpoint test under a progressive ratio (PR) paradigm. Furthermore, the effects of lamotrigine on reinstatement of ketamine-seeking and food-seeking behaviors were examined after extinction. RESULTS: Lamotrigine significantly decreased the breakpoint for ketamine and prevented cue- and ketamine priming induced reinstatement of ketamine seeking behavior. However, lamotrigine did not affect the breakpoint for food reinforcement, cue-induced reinstatement of food seeking behavior, or spontaneous locomotor activity. CONCLUSIONS: Our data reveal that lamotrigine is capable of attenuating the reinforcing efficacy of ketamine and reducing ketamine craving and relapse risk, which lays the foundation for conducting clinical trials in patients with ketamine use disorder. PMID- 30469097 TI - Alcohol use disorders associated with an increased risk of mesenteric ischemia: A nationwide cohort study. AB - BACKGROUND: To evaluate the relationship of patients with a history of alcohol use disorders (AUD) and its diagnostic categories with risk of subsequent mesenteric ischemia in Taiwan. METHODS: A nationwide population-based cohort study was conducted using data from the Taiwan's National Health Insurance Research Database. We identified 73,583 patients hospitalized for AUD between 2001 and 2010, and matched each case with four comparison patients based on age, gender, Charlson comorbidity index, and the index date. Cox proportional hazard models were used to evaluate the risk of mesenteric ischemia between the AUD and non-AUD cohorts. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated. RESULTS: Patients with AUD exhibited a significantly increased risk of developing mesenteric ischemia (HR = 2.25; 95% CI 1.92-2.64) compared with those with non-AUD after adjustment for patient sociodemographic, coexisting comorbid conditions, and hospital characteristics. Furthermore, a 2.29- and 2.17 fold higher risk of mesenteric ischemia was observed in patients with alcohol abuse/dependence (HR = 2.29; 95% CI 1.94-2.71) and alcoholic psychosis (HR = 2.17; 95% CI 1.72-2.73), respectively, than in non-AUD comparisons after covariate adjustment. CONCLUSIONS: This study confirmed that the risk of mesenteric ischemia was significantly higher among patients with different diagnostic categories of AUD, particularly for those with alcohol abuse/dependence. PMID- 30469098 TI - Effects of voluntary memberships and volunteering on alcohol and tobacco use across the life course: Findings from the German Socio-Economic Panel. AB - BACKGROUND: It is unclear whether specific components of individual social capital promote or protect against substance use and whether such effects vary across the life course. In this study, we investigated the effects of voluntary memberships and volunteering on alcohol and tobacco consumption in age comparison. METHODS: Preregistration is accessible at https://osf.io/qhkrn/. We used data from the German Socio-Economic Panel (1984-2015), where alcohol consumption was assessed in 2006, 2008, and 2010 and smoking was assessed at least biennially since 1998. We divided participants into three age groups (14 29, 40-50, and 65-75 years of age at baseline). To disentangle intraindividual change over time and interindividual differences (potential selection effects), we employed multilevel analysis. RESULTS: At the within level, voluntary memberships at one occasion predicted higher alcohol consumption a year later in middle-aged and older adults, but memberships had no significant longitudinal effects on smoking. Several positive effects of volunteering on alcohol and tobacco use one year later were found in males. No significant differences in the longitudinal effects between age groups or between nonpolitical and political volunteering emerged. At the between level, voluntary memberships and volunteering were usually associated with more alcohol consumption at low and moderate levels but with less smoking. DISCUSSION: Over time, voluntary memberships and volunteering in Germany appear to promote, rather than to protect against, alcohol and tobacco use. On average, more engaged individuals drink more (at moderate levels) and smoke less, which may be due to selection effects. PMID- 30469099 TI - A parent-oriented alcohol prevention program "Effekt" had no impact on adolescents' alcohol use: Findings from a cluster-randomized controlled trial in Estonia. AB - AIM: To evaluate the effectiveness of a universal parent-oriented alcohol prevention program ("Effekt") in Estonia. The main objective of the program was to delay and reduce adolescents' alcohol consumption by maintaining parental restrictive attitudes towards adolescents' alcohol use over time. METHODS: A matched-pair cluster randomized controlled trial with a three-year assessment period (baseline (T1), 18-months (T2) and 30-months (T3) follow-ups) was undertaken in 2012-2015 among 985 fifth grade adolescents and 790 parents in sixty-six schools (34 intervention, 32 control). The primary outcome measure was adolescents' alcohol use initiation. Secondary outcome measures were lifetime drunkenness and alcohol use in the past year. Intermediate outcomes were restrictive parental attitudes towards adolescents' alcohol use reported by parents and perceived restrictive parental attitudes and parental alcohol supply reported by adolescents. RESULTS: There were no significant differences in adolescents' alcohol use initiation, lifetime drunkenness, alcohol use in the past year, parental alcohol supply, and adolescent's perception of parental restrictive attitudes between intervention and control school participants at T2 and T3. There were significant differences in parental attitudes - the odds of having restrictive attitudes were 2.05 (95% confidence interval (CI) = 1.32-3.17) times higher at T2 and 1.92 (95% CI = 1.31-2.83) times higher at T3 in the intervention group than in the control group. CONCLUSIONS: The Estonian version of the "Effekt" program had a positive effect on parental attitudes, but it did not succeed in delaying or reducing adolescents' alcohol consumption. PMID- 30469100 TI - Influence of comorbid drug use disorder on receipt of evidence-based treatment for alcohol use disorder among VA patients with alcohol use disorder and Hepatitis C and/or HIV. AB - BACKGROUND: Alcohol use is risky for patients with hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV) infection, but alcohol use disorder (AUD) treatment is underutilized in these populations. Comorbid drug use disorders (DUD) are common, but their influence on AUD treatment receipt is understudied. We evaluated the association between DUD and AUD treatment receipt in two national samples of patients with AUD, those with HIV and those with HCV, in the U.S. Veterans Health Administration. METHODS: Samples included patients with AUD and HCV and/or HIV among positive alcohol screens (AUDIT-C>=5) documented 10/01/09-5/30/13 in the national electronic health record. Poisson regression models estimated incidence rate ratios for receiving specialty treatment (stop codes) and pharmacotherapy (filled prescription for naltrexone, disulfiram, acamprosate, or topiramate) within 365 days of positive alcohol screening for patients with DUD versus those without. Models were clustered on patient and adjusted for potential confounders. RESULTS: Among 22,039 patients with HCV/AUD, 45.2% (N = 9,964) had DUD, which was associated with receiving specialty treatment [adjusted incidence rate ratio: 1.89 (95% confidence interval 1.82 1.96)] and pharmacotherapy [aIRR: 1.50 (1.37-1.65)]. Among 1,834 patients with HIV/AUD, 56.9% (N = 1,043) had DUD, which was associated with receiving specialty treatment [aIRR: 1.94 (1.68-2.24)], but not pharmacotherapy. CONCLUSIONS: Rates of AUD treatment receipt among patients with AUD and HCV and/or HIV were low overall, but likelihood of treatment receipt was generally higher among those with comorbid DUD. Future research should investigate mechanisms underlying these associations, such as enhanced readiness for treatment or differential provider prescribing or referral practices. PMID- 30469101 TI - Electronic decision support for treatment of hospitalized smokers: A qualitative analysis of physicians' knowledge, attitudes, and practices. AB - BACKGROUND: We recently demonstrated the ability of a suite of tools embedded in an electronic medical record (EMR) to improve tobacco cessation treatment for adult smokers admitted to the hospital. A randomized controlled trial conducted by our group demonstrated the ability of an EMR-embedded tobacco use disorder treatment tool, the Electronic Support Tool and Orders for the Prevention of Smoking (E-STOPS), to increase the identification and treatment of smokers, but its uptake varied among 126 physicians randomized to the intervention arm. The purpose of this study was to identify facilitators and barriers to using E-STOPS. METHODS: Semi-structured individual interviews from a purposive sample of 12 hospitalist attending physicians and nine internal medicine residents who were randomized to the E-STOPS intervention were analyzed thematically. RESULTS: Three themes shaped E-STOPS use: the inpatient environment, prescriber attitudes and beliefs, and information needs. Overall, participants were pleased with E-STOPS, but had specific suggestions for improvements regarding the timing of the intervention, suppression logic, and additional decision support and training. A few had concerns about the clinical appropriateness of beginning treatment for tobacco dependence during a hospitalization and the proper role of the inpatient team in that treatment. CONCLUSIONS: Tobacco dependence treatment for hospitalized smokers and facilitated by the EMR is generally acceptable to hospitalists and resident physicians. Improvements in provider training and feedback as well as the timing and content of the electronic tools may increase their utilization by inpatient physicians. PMID- 30469102 TI - Reduction in methamphetamine consumption trends from 2015 to 2018 detected by wastewater-based epidemiology in Dalian, China. AB - BACKGROUND: Wastewater-based epidemiology (WBE) has become a useful tool in long term or short-term continuous monitoring of illicit drugs consumption over the world. METHODS: We investigated the trend of methamphetamine (METH) use between 2015 and 2018 through WBE in Dalian, a typical Chinese city. Samples were collected in 11 municipal wastewater treatment plants (WWTPs). An analytical method, solid-phase extraction combined with trifluoroacetic anhydride derivatization prior to gas chromatography-mass spectrometry (GC-MS) analysis was applied to detect METH concentrations. RESULTS: During the sampling period, the METH concentrations increased slowly from 315 +/- 243 ng/L in 2015 to 523 +/- 549 ng/L in 2016, followed by a significant decrease with the concentrations 188 +/- 187 ng/L in 2017 and 54.6 +/- 42.9 ng/L in 2018. Ammonium nitrogen (NH4-N) was applied to estimate population size. The average coefficient of variation for population in 11 WWTPs was 35.3 +/- 8.9%, reflecting the dynamic variations of population effectively. For METH consumption, there was a gradual increase from 2015 (231 mg/day/1000 people) to 2016 (414 mg/day/1000 people) and a significant linear decrease to 2017 (206 mg/day/1000 people) and 2018 (53.9 mg/day/1000 people). The prevalence of METH increased from 2015 (0.78%) to 2016 (1.06%), then decreased to 2017 (0.55%) and 2018 (0.17%), showed similar trends with the consumption. CONCLUSIONS: The obvious reduction trends of METH consumption via WBE over the period in Dalian provides objective evidence for declined METH consumption in local population. The reduction is probably due to the severe crack-down of illicit drugs by the government. PMID- 30469103 TI - Visual feedback gait re-training in overweight children can reduce excessive tibial acceleration during walking and running: An experimental intervention study. AB - BACKGROUND: Being overweight may increase the risk for developing stress fracture, as overweight adults and children were reported to have greater pressure peaks and rates under the heel during walking when compared with their normal-weight counterparts. Biofeedback gait retraining was shown to reduce ground impact magnitude in adults but not yet in children. RESEARCH QUESTION: The study examined whether overweight children have greater tibia peak positive acceleration (PPA) at ground impact during fast walking and running compared to healthy weight children, and whether visual feedback gait retraining program can be used to reduce PPA in overweight children. METHODS: Twenty five overweight and 12 healthy weight children participated in the study. Overweight children were randomly assigned into either feedback group or control no-feedback group of 8 sessions training program over 2-weeks. Tibia PPA at ground impact output from a wearable inertial sensor attached to the tibia was the feedback displayed on a monitor placed in front of the treadmill during walking and running. RESULTS: Compared to healthy weight children, overweight participants showed significant greater PPA values in running (p < 0.05), but not in fast walking. Feedback group significantly reduced PPA by 16% (p < 0.01), and these changes persisted at the 1 month follow-up. SIGNIFICANCE: Tibia PPA may be used in evaluating overweight children as a risk assessment to potential injuries due to high ground impact during running. Gait retraining using real-time feedback of tibia PPA may be useful in rehabilitation programs to reduce ground impact in overweight children. PMID- 30469104 TI - Influence of accuracy constraints on bimanual coordination and gait performance in children with unilateral spastic cerebral palsy. AB - BACKGROUND: Children with unilateral spastic cerebral palsy (USCP) have both upper and lower extremities movement impairments of their more affected side. Many daily activities require whole body movement control. However, most studies for children with USCP only evaluated either upper or lower extremity impairments. RESEARCH QUESTION: The present study aimed to assess the effects of accuracy constraints on walking and bimanual coordination for children with USCP during a whole body task. METHODS: Ten children with USCP (age: 7-12 years; GMFCS levels: I - II) and ten age-matched typically-developed children (TDC) participated in the study. They were asked to walk and carry a water bottle with and without a cap using a tray at a preferred speed while 3-D kinematic analyses were performed. The two tasks of carrying a water bottle with and without a cap were each performed 5 trials with randomized order between participants. RESULTS: TDC significantly decreased their walking speed, stride length, height differences between the two hands (symmetric bimanual coordination), vertical hand movement, and elbow joint excursion under higher accuracy constraints with no water bottle cap. Children with USCP showed significantly decreased walking speed, vertical hand movement, and elbow joint excursion under higher accuracy constraints. Children with USCP also significantly decreased walking deviation of line of progression. SIGNIFICANCE: It is exciting to see that children with USCP GMFCS levels I and II were able to maintain their bimanual coordination and modify their gait performance under higher accuracy constraints. Therefore, future treatments or assessments could consider manipulating accuracy constraints even during complex whole body tasks for children with USCP. PMID- 30469105 TI - Compensatory strategy for ankle dorsiflexion muscle weakness during gait in patients with drop-foot. AB - BACKGROUND: Pathological movement patterns are characterized by abnormal kinematics, kinetics and muscle activations that alter the distribution of muscle forces during walking. AIM: The objective of this study was to identify what compensatory strategy is evident in muscle force distribution in patients with drop-foot, in response to weakness in the dorsiflexor muscles. METHODS: A sample of 10 patients with drop-foot were evaluated by a computerized gait analysis system and compared to a group of 10 healthy subjects. Muscle-actuated simulations of normal and drop-foot walking were performed using OpenSim software. A musculoskeletal model with 43 muscles acting on one lower extremity was used in order to perform the simulations. In order to evaluate the difference between muscle force curves in the healthy and the drop-foot populations, an integrals of each muscle curve were computed. RESULTS: The group of patients with drop-foot exhibited an increased force integral for all muscle groups, except for the ankle evertors. The highest increases were observed for hip adductors (112%), hip extensors (88%), knee and hip flexors (83% and 50%, respectively) and for the plantarflexor (47%). These results were mainly influenced by the following muscles: flexor digitorum and hallucius, tibialis posterior and semitendinosus. The force integral for these muscles increased by more than 200% in the drop-foot group as compared to the control group. In addition, significant changes (>100%) were noted for the posterior thigh muscle group (semitendinosus, biceps femoris long and short head), which are responsible for bending the knee joint and straightening the hip joint. CONCLUSIONS: It was proved that the loss in muscle force in individual muscle groups of the ankle joint are compensated for by the increased force and activity in other muscles acting on this joint and another muscles in neighbouring joints. The results may have important implications for physiotherapy treatments. PMID- 30469106 TI - Effects of arm swing on spatiotemporal characteristics of gait in unilateral transhumeral amputees. AB - BACKGROUND: Gait is an autonomic process consisting of coordinated movements of the upper extremities, lower extremities, trunk and pelvis. However, researches regarding effects of upper extremity problems on gait parameters are limited. RESEARCH QUESTION: The aim of this study was to investigate the effects of arm swing on spatiotemporal characteristics of gait in individuals with unilateral transhumeral amputations. METHODS: A total of 25 unilateral transhumeral amputees and 25 healthy subjects were included. Information on the demographic features of individuals, amputations, and prosthetic devices were recorded. Spatiotemporal characteristics of gait were obtained using the GAITRite electronic walkway, and the arm swing was evaluated with the two video-cameras and analyzed using the Dartfish Pro Suite 7 software. RESULTS: The groups were similar regarding their age, height and weight. Mean duration from the amputation was 14.91 +/- 10.90 years, and the mean weight of the prostheses was 1.44 +/- 0.39 kg. Amputees had a less ambulatory arm swing on their amputated sides compared to their intact arms and healthy individuals. When the amputee group was compared to the healthy individuals, their step and stride lengths were shorter and their foot progression angle was higher, their gait velocity and cadence were lower than the healthy group. SIGNIFICANCE: The reduction of arm swing on the amputated side in unilateral transhumeral amputees is thought to be due to (1) use of the contralateral side in functional activities, (2) restriction of shoulder joint movement of socket boundaries and (3) fixed mechanical elbow joint. It has been thought that a decrease in the arm swing during walking may lead to a decrease in step length, stride length, and gait velocity. PMID- 30469107 TI - Are tibial angles measured with inertial sensors useful surrogates for frontal plane projection angles measured using 2-dimensional video analysis during single leg squat tasks? A reliability and agreement study in elite football (soccer) players. AB - During single leg squats (SLS), tibial angle (TA) quantification using inertial measurement units (IMU) may offer a practical alternative to frontal plane projection angle (FPPA) measurement using 2-dimensional (2D) video analysis. This study determined: (i) the reliability of IMUs and 2D video analysis for TA measurement, and 2D video analysis for FPPA measurement; (ii) the agreement between IMU TA and both 2D video TA and FPPA measurements during single leg squats in elite footballers. 18 players were tested on consecutive days. Absolute TA (ATA) and relative TA (RTA) were measured with IMUs. ATA and FPPA were measured concurrently using 2D video analysis. Within-session reliability for all measurements varied across days (intraclass correlation coefficient (ICC) range = 0.27-0.83, standard error of measurement (SEM) range = 2.12-6.23 degrees , minimal detectable change (MDC) range = 5.87-17.26 degrees ). Between-sessions, ATA reliability was good for both systems (ICCs = 0.70-0.74, SEMs = 1.64-7.53 degrees , MDCs = 4.55-7.01 degrees ), while IMU RTA and 2D FPPA reliability ranged from poor to good (ICCs = 0.39-0.72, SEMs = 2.60-5.99 degrees , MDCs = 7.20-16.61 degrees ). All limits of agreement exceeded a 5 degrees acceptability threshold. Both systems were reliable for between-session ATA, although agreement was poor. IMU RTA and 2D video FPPA reliability was variable. For SLS assessment, IMU derived TAs are not useful surrogates for 2D video FPPA measures in this population. PMID- 30469109 TI - Design of Experiments in metabolomics-related studies: An overview. AB - Nowadays, Design of Experiments (DoE) approach is a very popular methodology of planning and conducting experiments, where the effect of each tested factor on the studied responses is systematically examined and documented. The results obtained in such manner represent the design space more precisely than in the case of One-Variable-At-Time (OVAT) approach, leading to reliable and comprehensive results, while saving time and resources. Despite such a large increase of interest in this approach recently, its implementation in metabolomics research seems to be limited. Therefore, in this short overview, apart from summarizing some basic concepts of DoE, we wanted to provide a guideline for those who are about to plan metabolomics-related experiments. This overview is divided into four sections. In addition to the first section, which will introduce the history and basics of DoE, second part will provide concise description of the most popular experimental designs. Furthermore, third section will describe examples of DoE application in metabolomics and related studies. We will conclude with fourth section, providing you briefly with opportunities and trends in metabolomics research utilizing experimental design. PMID- 30469108 TI - Liquid chromatography-tandem mass spectrometry of recombinant human extracellular superoxide dismutase (rhSOD3) in mouse plasma and its application to pharmacokinetic study. AB - The antioxidant enzyme human extracellular superoxide dismutase (SOD3) is a promising biopharmaceutical candidate for the treatment of various diseases. To support the early development of SOD3 as a biopharmaceutical, a simple, sensitive, and rapid liquid chromatography tandem mass spectrometry procedure was developed and validated for the determination of SOD3 levels in the plasma of ICR mice. After purification with Ni-NTA magnetic beads and digestion with trypsin, SOD3 signature peptides and internal standard signature peptide (ISP) were separated via high performance liquid chromatography using a Zorbax C18 column (2.1 * 50 mm, 3.5 MUm) and a mobile phase consisting of 10 mM ammonium formate, 0.1% formic acid, and acetonitrile. The analyte and ISP were detected via a tandem mass spectrometer in electrospray ionization and multiple reaction monitoring modes to select both the signature peptide for SOD3 at m/z 669 to 969 and the ISP at m/z 655 to 941 in the positive ion mode. The calibration curves were linear (r > 0.99) between 5 and 1000 MUg/mL with a lower limit of quantification of 5 MUg/mL. The relative standard deviation ranged from 3.08 to 8.84% while the relative error ranged from -0.13 to -9.56%. This method was successfully applied to a preclinical pharmacokinetic study of SOD3 in male ICR mice. PMID- 30469110 TI - Development of molecularly imprinted electrochemical sensor with reduced graphene oxide and titanium dioxide enhanced performance for the detection of toltrazuril in chicken muscle and egg. AB - A molecularly imprinted electrochemical sensor for toltrazuril (TZR) detection based on molecularly imprinted polymers (MIPs) immobilized on reduced graphene oxide (rGO) and titanium dioxide (TiO2) modified platinum (Pt) electrode surface was fabricated for the first time. The synergistic fast electron transfer ability, large electroactive surface area and high catalytic activity from rGO and TiO2 contribute to amplify the electrochemical signal and consequently improve the sensitivity of the sensor. The cyclic voltammetry (CV), differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS) tests were used to evaluate the performance of the electrochemical sensor. The results showed that the electrochemical sensor possessed high sensitivity, good selectivity and anti-interference ability toward TZR. By using the DPV, the electrochemical sensor displayed a wide linear concentration range from 0.43 to 42.54 MUg/L, with a limit of detection of 0.21 MUg/L (S/N = 3). Moreover, the recoveries and relative standard deviations (RSD) were 85.0%-97.0% and 3.5%-6.4% at three concentration levels, respectively, implying that the established sensor is promising for the accurate detection of TZR at trace levels in chicken muscle and egg samples. PMID- 30469111 TI - Comprehensive metabolic profile of phenolic acids and flavonoids in Glechomae Herba using ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry with diagnostic ion filtering strategy. AB - Glechomae Herba (GH), a traditional Chinese medicine, is commonly used for the treatment of urolithiasis and cholelithiasis based on its diuretic and cholagogic actions. However, relatively few studies have been conducted to describe this medicine's metabolites. Therefore, an ultra-high-performance liquid chromatography coupled to quadrupole time of flight tandem mass spectrometry (UHPLC-QTOF-MS/MS) analysis with diagnostic product ions and neutral loss filtering strategy was established for the metabolic profiling profile of GH. First, an analytical method was established to detect the compounds in GH extracts and complex rat biosamples, including urine, bile, plasma and feces, after oral administration of GH extracts based on the holistic fingerprint approach utilizing UHPLC-QTOF-MS/MS. Second, the exogenously sourced ions were filtered out by the MarkerView software incorporated in Microsoft Office. Third, the diagnostic product ions and neutral loss filtering strategy were developed for the rapid identification of the metabolites. Finally, a total of 91 constituents, including 13 prototype compounds and 78 metabolites, were unambiguously or reasonably identified in rat biosamples. The metabolites were mainly eliminated by urine (82 metabolites) and bile (19 metabolites), and notably few metabolites were eliminated through feces (4 metabolites). Glucuronidation, methylation and sulfation were the primary metabolic pathways of phenolic acids and flavonoids. The primarily urine and bile elimination of metabolites may be related to the anti-urolithiasis and anti-cholelithiasis effects of GH. This work demonstrated the feasibility of an integrated strategy for the rapid identification of the metabolites after oral administration of GH extracts provided essential data for exploring the bioactive ingredients of GH in the treatment of urolithiasis and cholelithiasis. PMID- 30469112 TI - Spontaneous water adsorption-desorption oscillations in mesoporous thin films. AB - Understanding fluid transport and phase changes in nanopore structures is of great interest to many application fields, from energy conversion to water harvesting. This work discusses the spontaneous oscillations of the water saturation of mesoporous thin films, in the zone adjacent to a sessile water drop, at ambient conditions. The wetting-front dynamics onto the film is described by considering three coexisting phenomena: infiltration from the water drop, condensation from air vapor, and evaporation to the ambient. It was found that the oscillations follow spontaneous condensation-evaporation imbalances, which are governed by the hysteretic character of the adsorption-desorption behavior of the mesoporous material. The outcomes of this work provide insights on the complex interplay between water and nanopore structures, which has practical implications for the handling of humid microenvironments in lab-on-a chip technology, as well as for many processes that take part of the cycle of water in nature. PMID- 30469113 TI - Assembly of surface-defect single-crystalline strontium titanate nanocubes acting as molecular bricks onto surface-defect single-crystalline titanium dioxide (B) nanorods for efficient visible-light-driven photocatalytic performance. AB - Ti3+ self-doped single-crystalline SrTiO3-x nanocubes acting as molecular bricks are successfully assembled onto Ti3+ self-doping single-crystalline TiO2-x(B) nanorods through an effortless two-step hydrothermal process coupled with an in situ solid-state chemical reduction method. SrTiO3-x nanocubes act as molecular bricks, which are uniformly assembled onto the surface of TiO2-x(B) nanorods due to lattice matching. The band gap of the resultant SrTiO3-x/TiO2-x(B) sample is ~2.97 eV, which exhibits excellent photocatalytic performance for the reduction of Cr(VI) and hydrogen production under visible light. The apparent rate constant k value for the photocatalytic reaction of SrTiO3-x/TiO2-x(B) for Cr(VI) reduction is ~8 times higher than that of white TiO2(B). The photocatalytic hydrogen production rate for SrTiO3-x/TiO2-x(B) is ~160.2 MUmol g-1 h-1, which is ~5 times higher than that of white TiO2(B). The enhanced photocatalytic activity can be considered to be caused by a synergetic effect of heterojunction formation and the introduction of Ti3+ self-doping, which can not only facilitate the separation of photogenerated charge carriers between TiO2-x(B) and SrTiO3-x, but also broaden the photoresponse from the UV to visible-light region. PMID- 30469114 TI - Rheological properties of fresh and reconstituted milk protein concentrates under standard and processing conditions. AB - As the processability of fresh and reconstituted milk protein concentrates crucially depends on their rheological properties, a considerable amount of studies focuses on this topic. By means of a direct comparison, we are the first to clearly show that distinct rheological differences can exist between fresh and reconstituted milk protein concentrates under standard and processing conditions. We show that reconstituted milk protein concentrates made from commercial milk protein powders exhibit higher viscosities than fresh ones. Furthermore, we found that during intense shearing, the reconstituted milk protein concentrates undergo a loss of structure, which manifests itself in a significant viscosity decrease. The inverse effect can be observed for fresh milk protein concentrates. Besides these differences, the reconstituted milk protein concentrates exhibit gel-like properties above a certain protein content. We attribute these observations to protein-protein interactions in the milk protein powder, which are induced by manufacturing and/or storing conditions. Our results demonstrate that rheological properties of fresh and reconstituted milk protein concentrates are quantitatively not invariably interchangeable. Thus, the purpose of this article is to emphasize the necessity for researchers and engineers to take into account the rheological particularities of different milk protein concentrates prior to usage. PMID- 30469116 TI - Biomass waste-derived nitrogen-rich hierarchical porous carbon offering superior capacitive behavior in an environmentally friendly aqueous MgSO4 electrolyte. AB - Nitrogen-doped porous carbons have been extensively investigated to improve the specific capacitance in aqueous electrolytes by increasing the specific surface area and nitrogen content and by optimizing the pore structure. However, research on the effect of electrolyte cations on the specific capacitance of these materials is rare, especially for neutral electrolytes. Herein, a nitrogen-rich hierarchically porous carbon (NRHPC) with a high nitrogen content of 12.3 atm% is successfully prepared by pyrolyzing a mixture of bagasse, K2CO3 and urea in a mass ratio of 2:1:4. It is found that NRHPC shows superior electrochemical performance in MgSO4 than in Li2SO4 electrolyte, with specific capacitances of 315.0, 274.4, and 188.1 F g-1 at 1.0, 10.0, and 100 A g-1, respectively. Furthermore, it is found that the capacitance enhancement is closely related to the nitrogen content of the porous carbon materials. Theoretical calculation reveals that the Mg2+ ions have higher affinity towards the N atoms than Li+, producing higher charge storage capability via interaction between the Mg2+ and N atoms. When the 1.0 M MgSO4 is used as electrolyte, a symmetric capacitor based on the nitrogen-rich hierarchically porous carbon shows a high energy density of 39.5 Wh kg-1 at a power density of 0.9 kW kg-1. Moreover, this as-assembled device displays superior long-term cycling stability, with a capacitance retention of >96.2% after 10,000 cycles at 10.0 A g-1. PMID- 30469115 TI - Preferential adsorption of selenium oxyanions onto {1 1 0} and {0 1 2} nano hematite facets. AB - As the commercial use of nano metal oxides, including iron oxides, becomes more prevalent, there is a need to understand functionality as it relates to the inherent properties of the nanomaterial. Many applications of nanomaterials rely on adsorption, ranging from catalysis to aqueous remediation. In this paper, adsorption of selenium (Se), an aqueous contaminant, is used as a model sorbate to elucidate the relationships of structure, property, and (adsorptive) function of nano-hematite (nalpha-Fe2O3). As such, six nalpha-Fe2O3 particles were synthesized controlling for size, shape and surface area without capping agents. Sorbent characteristics of the six particles were then assessed for their impact on selenite (HSeO3-) and selenate (SeO42-) adsorption capacity and mechanism. Mechanism was assessed using in-situ attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy and extended X-ray absorption fine edge spectroscopy (EXAFS). Regression analyses were then performed to determine which characteristics best describe adsorption capacity and binding mechanisms of Se on nalpha-Fe2O3. The results demonstrate that crystal surface structure, specifically presence of the {0 1 2} facet promotes adsorption of Se and the presence of {0 1 2} facets promotes SeO42- sorption to a greater extent than HSeO3-. The data further indicates that {1 1 0} facets bind HSeO3- with binuclear complexes while {0 1 2} facets bind HSeO3- via mononuclear inner-sphere complexes. Specific nalpha-Fe2O3 facets also likely direct the ratio of inner to outer-sphere complexes in SeO42- adsorption. PMID- 30469117 TI - Manganese oxide doping carbon aerogels prepared with MnO2 coordinated by N, N - dimethylmethanamide for supercapacitors. AB - Carbon aerogels with excellent conductive characteristics and high specific capacitance have attracted more and more interests for next-generation energy storage applications. Three-dimensional interconnected Mn2O3/carbon aerogel supercapacitor electrodes are prepared by a novel doping method using MnO2 coordinated by N, N-dimethylmethanamide (DMF). The coordinative MnO2 (DMF/MnO2) plays a key role in the sol-gel process of resorcinol and formaldehyde. The doped carbon aerogels exhibits a high specific surface area of 859 m2 g-1 and a good pore-size distribution of 10-15 nm. All of the doped carbon aerogels exhibit higher specific capacitance than pure carbon aerogels, and the highest specific capacitance (170 F g-1), at current density of 1.0 A g-1, is obtained in Mn-CA-5% when 5 mol% DMF/MnO2 is added to the precursor solution. The specific capacitance is as high as 100 F g-1, at current density of 10.0 A g-1, and 97% of initial capacitance is retained over 1000 cycles at a current density of 5.0 A g-1. The doped carbon aerogels exhibits a high coulombic efficiency (up to 99.8%) and a good rate capability. The corresponding result is due to the novel doping method of DMF/MnO2 addition. PMID- 30469118 TI - Voltage-controlled ion transport and selectivity in a conical nanopore functionalized with pH-tunable polyelectrolyte brushes. AB - Chemically functionalized bioinspired nanopores are widely adopted to control the ionic transport for various purposes. A detailed understanding of the underlying mechanisms is not only desirable but also necessary for device design and experimental data interpretation. Here, the conductance and the ion selectivity of a conical nanopore surface modified by a polyelectrolyte (PE) layer are studied through adjusting the pH, the bulk salt concentration, and the level of the applied potential bias. Possible mechanisms are proposed and discussed in detail. We show that the conductance is sensitive to the variation in the solution pH. The ion selectivity of the nanopore is influenced significantly by both the solution pH and the level of the applied potential bias. In particular, a cation-selective nanopore might become anion-selective through raising the applied potential bias. The ion transport behavior can be tuned easily by adjusting the level of pH, salt concentration, and applied potential bias, thereby providing useful information for the design of nanopore-based sensing devices. PMID- 30469119 TI - Intermolecular and surface forces at solid/oil/water/gas interfaces in petroleum production. AB - Many challenging issues are encountered along the petroleum production such as the wettability alteration of reservoir solids due to deposition of petroleum materials, stabilization/destabilization of water-in-oil and oil-in-water emulsions and treatment of tailings water. All these problems are essentially driven by the fundamental intermolecular and surface forces among the different components (i.e., water, oil, solid and gas) in the surrounding complex fluid media, and comprehensive understanding of the interactions among these components will pave the way to the development of advanced materials and technologies for improved petroleum production processes. In this work, we have reviewed the quantitative force measurement methods in different petroleum systems by using nanomechanical techniques including surface forces apparatus (SFA) and atomic force microscope (AFM). Interaction forces between petroleum components (e.g., asphaltenes) and mineral solids in both organic solvents and aqueous solutions are reviewed and correlated to the wettability change of the reservoir solids. The recent key progress in quantifying the surface forces of water-in-oil and oil in-water emulsion drops using AFM drop probe techniques are discussed. The interaction forces of polymer flocculants and colloidal particles are correlated to the performance of tailings water treatment. The current knowledge gap and future perspectives are also presented. PMID- 30469120 TI - Improved photoelectrochemical properties of tungsten oxide by modification with plasmonic gold nanoparticles for the non-enzymatic sensing of ethanol. AB - Herein, vertically aligned plate-like tungsten trioxide (VAP-WO3) sensitized with gold nanoparticles (AuNPs) is reported for the non-enzymatic photoelectrochemical (PEC) sensing of ethanol in liquors. For the fabrication of the novel ethanol sensor, AuNPs were electrodeposited onto fluorine-doped tin oxide (FTO), and, subsequently, VAP-WO3 was hydrothermally grown on the AuNPs/FTO surface. Owing to the localized surface plasmon resonance, as well as the good conductivity of the AuNPs, the efficiency of the light absorption and the photoelectron-hole separation of VAP-WO3 were much improved, resulting in a significant enhancement in the VAP-WO3/AuNPs/FTO photocurrent. Interestingly, ethanol functioned as a sacrificial agent, leading to further amplification of the PEC signal on the VAP WO3/AuNPs/FTO electrode. Inspired by this phenomenon, a sensitive and non enzymatic PEC platform was constructed for monitoring ethanol in the range of 1.0 1000 MUM with a detection limit of 0.5 MUM, which is comparable with those obtained by the enzymatic ethanol sensors. In addition, the non-enzymatic ethanol PEC sensor has an acceptable anti-interference ability, excellent stability, and good reproducibility. Finally, the as-fabricated PEC sensor was successfully applied to determine the concentration of ethanol in liquors. Thus, this study paves the way to improved PEC performance of WO3/FTO-based electrodes and provides a promising signal-on PEC platform for ethanol determination in food. PMID- 30469121 TI - A high-resolution study of in situ surface-enhanced Raman scattering nanotag behavior in biological systems. AB - The colloidal stability of surface-enhanced Raman scattering (SERS) nanotags (Raman reporter-conjugated plasmonic nanoparticles) significantly affects the accuracy and reproducibility of SERS measurements, particularly in biological systems. Limited understanding of SERS nanotag stability may partly hamper the translation of SERS nanotags from the laboratory to their use in the clinic. In this contribution, we utilized differential centrifugal sedimentation (DCS), a reliable and straightforward technique to comprehensively analyze the colloidal stability of SERS nanotags in biological systems. Compared with other particle characterization techniques, DCS has been shown to have a unique advantage for high-resolution and high-throughput polydisperse particle characterization. DCS data revealed that the universal aggregation prevention practice of coating SERS nanotags with silica or bovine serum albumin layers did not sufficiently stabilize them in common measurement environments (e.g., 1 * PBS). Combined DCS and SERS measurements established a strong correlation between the degrees of nanotag aggregation and signal intensities, further reinforcing the necessity of characterizing SERS nanotag stability for every condition in which they are used. We also found that increasing the protein thickness by the inclusion of extra protein components in the detection environments and antibody functionalization can improve the stability of SERS nanotags. We believe that this study can provide guidelines on appropriate measurement techniques and particle design considerations to assess and improve SERS nanotag stability in complex biological systems. PMID- 30469122 TI - Determining the surface dilational rheology of surfactant and protein films with a droplet waveform generator. AB - Understanding rheological properties of surfactant and protein films plays a crucial role in a variety of industrial and research areas, such as food processing, cosmetics, and pharmacology. To determine the surface dilational modulus using drop shape analysis, one needs to measure the dynamic surface tension in response to a sinusoidal oscillation of the surface area of the droplet. Despite many applications of drop shape analysis in studying interfacial rheology, oscillation of the droplet surface area is usually controlled in an indirect manner. Existing methods are only capable of controlling volume oscillations of the droplet rather than its surface area. We have developed an arbitrary waveform generator (AWG) to directly oscillate the surface area of a millimeter-sized droplet in a predefined sinusoidal waveform. Here, we demonstrated the capacity of this AWG, in conjunction with constrained drop surfactometry (CDS), in studying the surface dilational rheology of adsorbed surfactant and protein films. It is found that the surface dilational modulus determined for a dilute surfactant (C12DMPO) and two protein solutions (bovine serum albumin and beta-casein) revealed their adsorption mechanisms. Our methods hold promise in studying the interfacial rheology of various thin-film materials, biomembranes, foams, and emulsions. PMID- 30469123 TI - Electrophysiology of obsessive compulsive disorder: A systematic review of the electroencephalographic literature. AB - Obsessive-compulsive disorder (OCD) is a chronic disease that causes significant decline in the quality of life of those affected. Due to our limited understanding of the underlying pathophysiology of OCD, successful treatment remains elusive. Although many have studied the pathophysiology of OCD through electroencephalography (EEG), limited attempts have been made to synthesize and interpret their findings. To bridge this gap, we conducted a comprehensive literature review using Medline/PubMed and considered the 65 most relevant studies published before June 2018. The findings are categorised into quantitative EEG, sleep related EEG and event related potentials (ERPs). Increased frontal asymmetry, frontal slowing and an enhancement in the ERP known as error related negativity (ERN) were consistent findings in OCD. However, sleep EEG and other ERP (P3 and N2) findings were inconsistent. Additionally, we analysed the usefulness of ERN as a potential candidate endophenotype. We hypothesize that dysfunctional frontal circuitry and overactive performance monitoring are the major underlying impairments in OCD. Additionally, we conceptualized that defective fronto-striato-thalamic circuitry causing poor cerebral functional connectivity gives rise to the OCD behavioural manifestations. Finally, we have discussed transcranial magnetic stimulation and EEG (TMS-EEG) applications in future research to further our knowledge of the underlying pathophysiology of OCD. PMID- 30469124 TI - Physiotherapist perceptions of optimal sitting and standing posture. AB - BACKGROUND: Assessment of, and advice about, spinal posture is common when people with spinal pain present to physiotherapists. Most descriptions regarding optimal spinal posture have been qualitative in nature. OBJECTIVES: To determine the beliefs of physiotherapists regarding optimal sitting and standing posture. DESIGN: Online survey. METHOD: 544 Greek physiotherapists selected an optimal sitting (choice of seven) and standing (choice of five) posture, while providing justification for their choice. RESULTS: Education regarding optimal sitting and standing posture was considered "considerably" or "very" important by 93.9% of participants. Three different sitting postures, and two different standing postures, were selected as the optimal posture by 97.5% and 98.2% of physiotherapists respectively. While this reflects a lack of complete consensus on optimal posture, the most commonly selected postures were all some variation of upright lordotic sitting, in contrast slouched spinal curves (sitting) or forward head posture (sitting and standing) almost never being selected as optimal. Interestingly, participants used similar arguments (e.g. natural curves, muscle activation) to justify their selection regardless of the spinal configuration of each selected posture. CONCLUSIONS: These results reinforce previous data suggesting that upright lordotic sitting postures are considered optimal, despite a lack of strong evidence that any specific posture is linked to better health outcomes. While postural re-education may play a role in the management of spinal pain for some patients, awareness of such widespread and stereotypical beliefs regarding optimal posture may be useful in clinical assessment and management. PMID- 30469125 TI - Plastic Pirates sample litter at rivers in Germany - Riverside litter and litter sources estimated by schoolchildren. AB - Rivers are an important source of marine anthropogenic litter, but the particular origins of riverine litter itself have not been well established. Here we used a citizen science approach where schoolchildren examined litter at riversides and identified possible sources at over 250 sampling spots along large and small rivers in Germany, during autumn 2016 and spring 2017. Litter densities have an overall median of 0.14, interquartile range 0-0.57 items m-2 and an overall average (+/-standard deviation) of 0.54 +/- 1.20 litter items m-2. Litter quantities differed only little by sampling year. The principal litter types found were plastics and cigarette butts (31% and 20%, respectively), followed by glass, paper, and metal items, indicating recreational visitors as the principal litter source. At many sites (85%), accumulations of litter, consisting principally of cigarettes and food packaging, have been found. At almost all sampling sites (89%), litter potentially hazardous to human health has been observed, including broken glass, sharp metal objects, used personal hygiene articles and items containing chemicals. In the search for litter sources, the schoolchildren identified mainly people who use the rivers as recreational areas (in contrast to residents living in the vicinity, illegal dumping, or the river itself depositing litter from upstream sources). These results indicate the urgent need for better education and policy measures in order to protect riparian environments and reduce input of riverine litter to the marine environment. PMID- 30469126 TI - Assessing the exposure-response relationship of sleep disturbance and vibration in field and laboratory settings. AB - Exposure to nocturnal freight train vibrations may impact sleep, but exposure response relationships are lacking. The European project CargoVibes evaluated sleep disturbance both in the field and in the laboratory and provides unique data, as measures of response and exposure metrics are comparable. This paper therefore provides data on exposure-response relationships of vibration and sleep disturbance and compares the relationships evaluated in the laboratory and the field. Two field studies (one in Poland and one in the Netherlands) with 233 valid respondents in total, and three laboratory studies in Sweden with a total of 59 subjects over 350 person-nights were performed. The odds ratios (OR) of sleep disturbance were analyzed in relation to nighttime vibration exposure by ordinal logit regression, adjusting for moderating factors common for the studies. Outcome specific fractions were calculated for eleven sleep outcomes and supported comparability between the field and laboratory settings. Vibration exposure was significantly associated with sleep disturbance, OR = 3.51 (95% confidence interval 2.6-4.73) denoting a three and a half times increase in the odds of sleep disturbance with one unit increased 8 h nighttime log10 Root Mean Square vibration. The results suggest no significant difference between field and laboratory settings OR = 1.37 (0.59-3.19). However, odds of sleep disturbance were higher in the Netherlands as compared to Sweden, indicating unexplained differences between study populations or countries, possibly related to cultural and contextual differences and uncertainties in exposure assessments. Future studies should be carefully designed to record explanatory factors in the field and enhance ecological validity in the laboratory. Nevertheless, the presented combined data set provides a first set of exposure response relationships for vibration-induced sleep disturbance, which are useful when considering public health outcomes among exposed populations. PMID- 30469127 TI - Physico-chemical characterization and in vitro inflammatory and oxidative potency of atmospheric particles collected in Dakar city's (Senegal). AB - Exposure to atmospheric pollutants has been recognized as a major risk factor of respiratory and cardiovascular diseases. Fine particles (PM2.5) and a coarser fraction (PM>2.5) sampled at an urban site in Dakar (HLM), characterized by high road traffic emissions, were compared with particles sampled at a rural area, Toubab Dialaw located about 40 km from Dakar. The physicochemical characteristics of samples revealed that PMs differ for their physical (surface area) and chemical properties (in terms of CHN, metals, ions, paraffins, VOCs and PAHs) that were 65-75% higher in urban samples. Moreover the fine PMs contain higher amounts of anthropogenic related pollutants than the PM>2.5 one. These differences are sustained by the ratios reported for the analysed PAHs which suggest as predominant primary emission sources vehicle exhausts at urban site and biomass combustion at the rural site. The inflammatory response and the oxidative damages were evaluated in BEAS-2B cells by the quantification of 4 selected inflammatory cytokines (TNF-alpha, IL-1beta, IL-6, IL-8) and of total carbonylated proteins and the oxidative DNA adduct 8-OHdG after 8 or 24 h exposure. In accordance with the different sources and different physical and chemical properties, the inflammatory response and the oxidative damages were found higher in bronchial cells exposed to urban PMs. These data confirm the importance, also for West African countries, to evaluate the correlation between PM physico-chemical properties and potential biological impacts. PMID- 30469128 TI - Combining versatility with cost-effectiveness: Determination of both free and bound sialic acids, N-acetylneuraminic and N-glycolylneuraminic in unprocessed bovine milk. PMID- 30469129 TI - Ionization study and simultaneous determination of avermectins and milbemycines in fish tissue by LC-ESI-MS/MS. AB - In this study, the simultaneous determination of avermectins (emamectin, eprinomectin, abamectin, doramectin and ivermectin) and milbemycines (moxidectin) in fish tissue with LC-ESI-MS/MS, was studied. Optimum chromatographic separation of target analytes was achieved using a Waters Acquity UPLC BEH C18 (100 mm * 2.1 mm, 1.7 mm) analytical column, operated at 40 degrees C and the composition of the mobile phase used was (A): ACN-MeOH (0.1% HCOOH) (1:1) and (B): 1 mM HCOONH4 (0.1% HCOOH). Various mobile phases were tested and the effect of the mobile phase composition on the analytes ionization was thoroughly examined in an extensive ionization study, aiming to increase the analytes' sensitivity. Deuterated ivermectin (IVR-d2) was used as an internal standard (IS). Avermectin's and milbemycine's extraction from the fish matrix was conducted with acidified ACN (0.1% HCOOH), followed by QuEChERS methodology. The method developed herein was validated according to the European Legislation requirements (Commission Decision 657/2002/EC) and recoveries ranged from 86 to 106% for all target analytes, with relative standard deviations < 20%. LODs ranged from 0.07 MUg/kg (emamectin) to 1.3 MUg/kg (doramectin), indicating the excellent sensitivity of the method. The developed methodology was successfully applied to fish samples obtained from aquaculture. PMID- 30469130 TI - Different effects of fenofibrate on cardiometabolic risk factors in young women with and without hyperprolactinemia. AB - BACKGROUND: Elevated prolactin levels are associated with increased cardiometabolic risk. No previous study has compared the effect of hypolipidemic therapy on plasma levels of lipids and other cardiometabolic risk factors in patients with and without hyperprolactinemia. METHODS: The study included three age-, weight-, blood pressure- and lipid-matched groups of premenopausal women: 18 women with untreated hyperprolactinemia, 19 women with bromocriptine-treated hyperprolactinemia and 20 drug-naive women with normal prolactin levels. Because of concomitant atherogenic dyslipidemia, all patients were treated with fenofibrate (200 mg daily) for 12 weeks. Plasma lipids, glucose homeostasis markers, as well as plasma levels of uric acid, high-sensitivity C-reactive protein (hsCRP), homocysteine and fibrinogen were assessed at baseline and at the end of hypolipidemic treatment. RESULTS: Unlike similar baseline lipid levels, plasma concentrations of the remaining investigated cardiometabolic risk factors were higher in women with elevated prolactin levels than in patients with normal prolactin levels. The impact of fenofibrate on total cholesterol, LDL cholesterol, HDL cholesterol and triglyceride levels, as well as on uric acid, hsCRP, homocysteine, and fibrinogen was less pronounced in women with untreated hyperprolactinemia than in women with bromocriptine-treated hyperprolactinemia and drug-naive women with normal prolactin levels. CONCLUSIONS: The results of our study indicate that cardiometabolic effects of fenofibrate depend on plasma prolactin levels. PMID- 30469131 TI - Controlled mercerization of bacterial cellulose provides tunability of modulus and ductility over two orders of magnitude. AB - Effects of mercerization process on plant-based cellulose is well studied in the literature whereas the effects of mercerization on mechanical properties of bacterial cellulose is not investigated. In this work bacterial cellulose (BC) was mercerized in NaOH solution with different molar concentrations of 0, 1.50, 1.75, 2.00, 2.13, 2.25, 5.00, 7.00 and 10.00 M. The BC samples shrunk substantially with increasing NaOH concentration. At the same concentration, NaOH treatment resulted in significantly larger shrinkage than KOH treatment. Mercerization of BC samples in 7 M NaOH resulted in an order of magnitude increase in elongation from 5.4 +/- 1.6% to 50.8 +/- 5.7% along with about 30 fold reduction in Young's modulus. Mercerized samples in 4 M NaOH had maximum toughness among all groups at a value of 64.0 +/- 15.8 MJ m-3. Changes in BC crystalline structure from cellulose I to cellulose II were characterized and confirmed semiquantitatively by using X-ray diffraction (XRD) and Raman spectroscopy. Results of this work demonstrated mercerization as a method to tune the mechanical properties of BC precisely. Mercerized BC as a biocompatible material with tunable mechanical properties shows potential to be utilized in tissue engineering and regenerative medicine in the future. PMID- 30469132 TI - Simultaneous quantification of simeprevir sodium: A hepatitis C protease inhibitor in binary and ternary mixtures with sofosbuvir and/or ledipasvir utilizing direct and H-point standard addition strategies. AB - Simeprevir sodium (SMV); a novel hepatitis C inhibitor, quells hepatitis C viral replication by binding to and repressing the protease, hepatitis C infection (HCV) NS3/4A. In this way, it is known as a prompt acting antiviral agent. Calibration curves of SMV were built in various solvents; ethanol, methanol, acetonitrile, chloroform and dichloromethane. It is obeyed up to 60.0 MUg/mL; in all solvents at two maximum wavelengths (280 and 327 nm). Several investigations show that, SMV might be present in a mixture of Sofosbuvir (SOF) and/or Ledipasvir (LDP). So far as that is concerned, H-point standard addition strategy (HPSAS) is made to identify it in binary or ternary mixtures. Recovery studies are in the prevalent range (93.0-107.0%) with relative standard deviation <1.5%. A correlation between the developed techniques is carried out and it demonstrates that these strategies are effectively applied for the simultaneous analysis of SMV, SOF and LDP in several synthetic samples and pharmaceutics. Statistical treatment of the acquired data is carried out against a newly published HPLC technique using F- and t-treatments. PMID- 30469133 TI - Internal standard metabolites for obtaining absolute quantitative information on the components of bloodstains by standardization of samples. AB - Analysis of the components of bloodstains found at crime scenes can provide important information for solving the crime. However, components of blood and bloodstains vary with volume and various other unpredictable factors. Therefore, it is necessary to specify the volume of the initial liquid blood droplet and standardize the analysis. In this study, internal standard metabolites that remained constant in a certain amount of bloodstain, long after deposition of the stain, were identified. Liquid chromatography-electrospray ionization-tandem mass spectrometry of the metabolites extracted from the bloodstain samples at various time points (0, 7, 14, 21, and 28 days) was performed. The coefficient of variation (CV) of the obtained molecular features was calculated for each criterion: time point, subject, and all data (time and subject, triplicate of each). Five molecular features with average CVs of less than or equal to 5% were selected as candidates. Partial least squares discriminant analysis and principal component analysis showed that the effect on the candidates was very low over time. The fold-change value of abundances was confirmed according to time. Stigmasterol exhibited the most stable pattern; l-methionine remained stable until day 14 and after day 21. This study was the first attempt to identify internal standard metabolites that were maintained at a constant level in a bloodstain for a sufficiently long time. Analysis of internal standard metabolites in bloodstains will facilitate determination of the initial blood volume from which the bloodstain was made. Moreover, this method will provide an approach for standardization of bloodstains to obtain absolute quantitative information of bloodstain components at crime scenes. PMID- 30469134 TI - Enhanced butyric acid production using mixed biomass of brown algae and rice straw by Clostridium tyrobutyricum ATCC25755. AB - A brown alga Saccharina japonica and rice straw are attractive feedstock for microbial butyric acid production. However, inefficient fermentation of mannitol (a dominant component in S. japonica) and toxicity of inhibitors in lignocellulosic hydrolysate are limitations. This study demonstrated that mixed biomass with S. japonica and rice straw was effective in butyric acid production over those restrictions. Mannitol was consumed only when acetic acid was present. Notably, acetic acid was not produced but consumed along with mannitol. By mixing S. japonica and rice straw to take advantage of glucose and acetic acid in rice straw, Clostridium tyrobutyricum effectively consumed mannitol by utilizing acetic acid in hydrolysate and acetic acid derived from glucose with the enhanced butyric acid production. Furthermore, cell growth was restored owing to the decreased inhibitor concentration. The results demonstrate the potential of butyric acid production from mixed biomass of macroalgae/lignocellulose overcoming the drawbacks of single biomass. PMID- 30469135 TI - Effects of individual and combined zinc oxide nanoparticle, norfloxacin, and sulfamethazine contamination on sludge anaerobic digestion. AB - This work investigated the individual and combined effects of zinc oxide, norfloxacin, and sulfamethazine on sludge anaerobic digestion-associated methane production, protein and carbohydrate metabolism, and microbial diversity. Norfloxacin and sulfamethazine (500 mg/kg) did not inhibit methane production, but inhibited its production rate. Zinc oxide nanoparticles with antibiotics inhibited hydrolysis, fermentation, and methanogenesis over varying digestion periods. Complex pollution had a greater impact on methane production than zinc oxide alone, with acute, synergistic toxicity to methanogenesis over short periods. Complex pollution also had varying effects on bacterial and archaeal communities during digestion. These results aid understanding of the toxicity of emerging contaminants in sludge digestion, with the potential to improve pollution removal and reduce associated risks. PMID- 30469136 TI - Rapid reformation of larger aerobic granular sludge in an internal-circulation membrane bioreactor after long-term operation: Effect of short-time aeration. AB - The investigation aimed at revealing the influence of an external disturbance on the rapid reformation of larger aerobic granular sludge (AGS) in an internal circulation membrane bioreactor (IC-MBR) after long-term operation. The used IC MBR was continuously operated well for more than one year, in which, the biomass was still in the state of AGS with a balanced average size at around 200 MUm and an even size distribution. By providing short-time aeration to the biomass within this bioreactor, the characteristics of biomass were totally changed in a very short time, including the surface hydrophilicity, physic-chemical properties, and the structure of microbial community, which created suitable conditions for the growth of filamentous bacteria (Saccharibacteria). Such a variation was very beneficial to the reformation of larger AGS, which resulted in the average size of AGS increased to nearly 400 MUm with a compact structure and clear edge in no more than one month. PMID- 30469137 TI - Biomethane from Short Rotation Forestry and Microalgal Open Ponds: System Modeling and Life Cycle Assessment. AB - Gasification of Short Rotation Forestry (SRF) poplar wood chips and anaerobic digestion of the microalga Chlorella vulgaris have been analyzed as alternative supply chains for the production of biomethane. Life Cycle Assessment (LCA) was performed from the biomass cultivation to the upgrading stages. Process simulation of gasification and upgrading was carried out, environmental impacts of the entire supply chains have been estimated and discussed. The highest CO2 removal has been reached by absorption on monoethanolamine. Electricity requirements heavily affect the SRF chain, while productions of carbon dioxide and fertilizers are the main sources of impact of the microalgae cultivation. The recycle of non-absorbed fertilizers, as well as integration of microalgae digestion in wastewater plants, are recommended. Capture and re-injection of the CO2 lost during the upgrading stages would result, simultaneously, in an 8.53% reduction of the atmospheric emission, and in a minor demand to promote algal growth. PMID- 30469138 TI - Long-term evaluation of methane production in a bio-electrochemical anaerobic digestion reactor according to the organic loading rate. AB - In this study, the effects of differing organic loading rates (OLRs) on methane production were evaluated via long-term operation of a bio-electrochemical anaerobic digestion (BEAD) reactor and an anaerobic digestion (AD) reactor. In the AD reactor, the maximum OLR was 4 kg/m3.d whereas the electro-active microbial community in bulk and on the biofilm of the BEAD reactor produced methane even at 10 kg/m3.d. The BEAD reactor rapidly removed volatile fatty acids (VFAs) and reduced H+ to H2 at high OLRs, thereby preventing VFA accumulation and pH decrease. After the steady state was achieved, both the AD and BEAD reactors exhibited similar organic matter removal and methane production at a low OLR. Thus, a BEAD reactor can stably produce methane under conditions of high OLR and severe OLR fluctuation and can even shorten the stabilization period over the long term. PMID- 30469139 TI - Response of nitritation performance and microbial community structure in sequencing biofilm batch reactors filled with different zeolite and alkalinity ratio. AB - Ammonium (NH4+-N) adsorption capacity of zeolite varies from place to place, a unique attempt to use different zeolite as adsorbent media in sequencing biofilm batch reactor (SBBR) for maintaining appropriate free ammonia (FA) range to achieve partial nitritation. SBR filled with synthetic zeolite (SSBBR) and natural zeolite (NSBBR) were applied to evaluate the NH4+-N adsorption capacity impacts on nitrogen transformation and microbial characteristics. Significant differences in nitrite production rate (NPR) were both observed in two reactors during 4 different alkalinity ratios. The highest NPR in SSBBR and NSBBR were both obtained when the alkalinity ratio was 5:1 with the values of 1.11 and 0.90 kg N/(m3.d), respectively. According to Haldane model with inhibition by FA, the kinetics of the reaction were analyzed. High-throughput sequencing analysis results further presented that SSBBR had higher relative abundance average of nitrosobacteria in genus level, which was in favor of better partial nitritation. PMID- 30469140 TI - On-board saline black water treatment by bioaugmentation original marine bacteria with Pseudoalteromonas sp. SCSE709-6 and the associated microbial community. AB - To reduce fresh water load on ships, seawater can be used for toilet flushing on board. And saline black water was treated on-site by bioaugmentation original marine bacteria with Pseudoalteromonas sp. SCSE709-6 (P. sp. SCSE709-6) to prevent marine pollution. In the batch experiments, P. sp. SCSE709-6 was effective in nutrient removal, which was not closely related to the amount of inoculation. In the on-board continuous experiments, the systems inoculated with P. sp. SCSE709-6 possessed excellent TP removal ability (removal rate: 80.93% for T3 and 88.39% for T4). The inoculum of P. sp. SCSE709-6 changed the microbial community structure and increased the similarity of microbial communities. P. sp. SCSE709-6 had a significant influence on the performance and microbial community of the systems. This study strongly proposes that the P. sp. SCSE709-6 is a promising alternative in saline black water treatment, which has great significance to the practice of on-board seawater flushing toilet. PMID- 30469141 TI - Approaches to identify extracellular receptor-ligand interactions. AB - Thousands of secreted factors and plasma membrane-associated cell surface receptors are categorised into families that vary widely in their structures and functions. They often participate in extracellular binding events, but due to their unique physicochemical properties, their interactions are challenging to study. As lists of extracellular proteins become more complete and accurate, new methodologies are being developed to systematically identify how these proteins interact. Two main approaches have been used: direct binding between recombinant soluble receptor ectodomains and cell-based assays. Recent advances in chemoproteomic reagents, cDNA overexpression, and cell-based genetic approaches promote the identification of extracellular protein-protein interactions within the context of an intact plasma membrane in living cells and opens up the discovery of cell surface recognition events that were previously intractable. PMID- 30469142 TI - Protective effect of leptin-mediated caveolin-1 expression on neurons after spinal cord injury. AB - Spinal cord injury (SCI) causes long-term disability and has no effective clinical treatment. After SCI, extracellular adenosine triphosphate (ATP) leads to an influx of extracellular Ca2+, and this Ca2+ overload causes neuronal toxicosis and apoptosis. The biological functions of leptin have been widely investigated in the central nervous system. In this study, we discovered that the administration of leptin could improve locomotor recovery following SCI. The aim of this study was to determine the neuroprotective mechanism of leptin in vivo and in vitro. The neuronal apoptosis and Ca2+ imaging signal induced by ATP were suppressed by leptin, due to elevated caveolin-1 expression. In vivo two-photon observations revealed that leptin reduced the neuronal Ca2+ imaging signal in the exposed spinal cords of live Thy1-YFP mice. In conclusion, leptin promotes locomotor functional recovery and suppresses neuronal impairment after SCI, suggesting that leptin has a promising clinical therapeutic value for treatment of SCI. PMID- 30469144 TI - Synthesis and biological evaluation of N-glucosyl indole derivatives as sodium dependent glucose co-transporter 2 inhibitors. AB - Sodium-dependent glucose co-transporter 2 (SGLT2) inhibition has been demonstrated to efficiently control hyperglycemia via an insulin secretion independent pathway. The unique mode of action eliminates the risk of hypoglycemia and makes SGLT2 inhibitors an attractive option for the treatment of type 2 diabetes. In a continuation of our previous studies on SGLT2 inhibitors bearing different sugar moieties, sixteen new N-glucosyl indole derivatives were designed, synthesized, and evaluated for their inhibitory activity against hSGLT2. Of these sixteen, acethydrazide-containing N-glucosyl indole 9d was found to be the most potent SGLT2 inhibitor, and caused a significant elevation in urine glucose excretion in rats at 50 mg/kg, relative to the vehicle control. PMID- 30469143 TI - Dorsal-approach open reduction for irreducible dislocation of the hallux interphalangeal joint: A case series. AB - INTRODUCTION: The common treatment for hallux interphalangeal joint dislocation is closed reduction, but some cannot be reduced by interposition of the sesamoid or the plantar plate in the interphalangeal joint, and such cases need open reduction. PRESENTATION OF CASE: In case 1, the patient was a 17-year-old boy who was injured when a motorcycle fell on his right hallux. X-ray revealed Miki type 2 IP joint dislocation. Because closed reduction failed, open reduction via the dorsal approach to the hallux IP joint was performed. In case 2, the patient was a 17-year-old boy who was hit by a car whilst walking. X-ray revealed Miki type 2 dorsal dislocation of the hallux IP joint. After closed reduction, X-ray and CT revealed that the IP joint dislocation changed from Miki type 2 to type 1. Open reduction was performed through the dorsal approach. DISCUSSION: Fifteen cases of Miki type 2 changed to type 1 after closed reduction, and type 1 dislocation is often overlooked, leading to some chronic cases. X-rays should be performed after repositioning, specifically in lateral and oblique views. CONCLUSION: We experienced two cases of irreducible dislocation of the hallux IP joint. One of our cases was reclassified from Miki type 2 to type 1, but we did not overlook the failed closed reduction, as we performed CT. Hence, we recommend additional lateral-view X-rays and/or CT imaging. PMID- 30469145 TI - Synthesis and biological evaluation of new quinoline derivatives as antileishmanial and antitrypanosomal agents. AB - As a part of our project aimed at developing new safe chemotherapeutic agents against tropical diseases, a series of aryl derivatives of 2- and 3 aminoquinoline, some of them new compounds, was designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible for American trypanosomiasis (Chagas' disease), and Leishmania mexicana, the etiological agent of Leishmaniasis. Some of them showed a remarkable activity as parasite growth inhibitors. Fluorine-containing derivatives 11b and 11c were more than twice more potent than geneticin against intracellular promastigote form of Leishmania mexicana exhibiting both IC50 values of 41.9 MUM. The IC50 values corresponding to fluorine and chlorine derivatives 11b-d were in the same order than benznidazole against epimastigote form. These drugs are interesting examples of effective antiparasitic agents with outstanding potential not only as lead drugs but also to be used for further in vivo studies. In addition, the obtained compounds showed no toxicity in Vero cells, which makes them good candidates to control tropical diseases. Regarding the probable mode of action, assayed quinoline derivatives interacted with hemin, inhibiting its degradation and generating oxidative stress that is not counteracted by the antioxidant defense system of the parasite. PMID- 30469146 TI - A Study of Siberia's Medicinal Plants Used in Homeopathy. AB - BACKGROUND: A current priority of national health care in Russia is to expand the range of drug substances, based on naturally occurring compounds, to use for treating socially significant diseases, such as cancer and cardiovascular diseases. OBJECTIVE: The main objective of our study was to compile a contemporary list of Siberia's 'homeopathic plants', describing for each plant the corresponding therapeutic indications or main symptoms of disease. METHODS: The textbook, Global Resources of Homeopathic Medicinal Raw Materials, was used to scrutinize the 709 species that are allowed for use in Russia, designating each of the 709 as either indigenous or non-indigenous to the region of Siberia. A homeopathic repertory, containing description of more than 1,800 single component homeopathic medicines, was used to identify Siberia's medicinal plants used in homeopathy, along with the medical indications of each. RESULTS: The medicinal plants of Siberia used in homeopathy comprise 137 species of flowering plants, gymnosperms and sporophytes, belonging to 52 families. The most represented are the Compositae, Rosaceae, and Lamiaceae families. CONCLUSION: The inventory of Siberian plants has allowed us to identify the plants of this region used in homeopathy and will help to inform research on additional species with the potential for introduction into homeopathic practice. PMID- 30469147 TI - Baicalin Induces Apoptotic Death of Human Chondrosarcoma Cells through Mitochondrial Dysfunction and Downregulation of the PI3K/Akt/mTOR Pathway. AB - The aim of the present study was to investigate the cytotoxic and antitumour effects of baicalin in human chondrosarcoma both in vivo and in vitro. We examined the effects of baicalin on the growth and apoptosis of human chondrosarcoma cells. Baicalin inhibited the growth of SW1353 and CH2879 cells in a dose- and time-dependent manner, but did not inhibit the growth of normal chondrocytes. Baicalin reduced tumour growth and induced apoptotic death in SW1353-transplanted nude mice without reducing their body weight. Further studies showed that baicalin reduced the mitochondrial membrane potential, upregulated the expression of Bax and cytoplasmic cytochrome c, downregulated the expression of Bcl-2 and mitochondrial cytochromes, and activated caspase-3 and caspase-9. Baicalin inhibited the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway by decreasing the expression of phosphorylated phosphoinositide 3-kinase, phosphorylated protein kinase B, and phosphorylated mammalian target of rapamycin both in vivo and in vitro. Moreover, the mice that received SC79 and baicalin exhibited a greater tumour size compared with the mice that received baicalin. The mice that received LY294002 and baicalin showed a smaller tumour size compared with the mice that received baicalin. In the in vitro study, SC79 and LY294002 affected the baicalin-induced cytotoxic effects on chondrosarcoma cells in the same manner. Our data suggest baicalin has therapeutic efficacy in human chondrosarcoma through the induction of apoptosis and inhibition of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway. Baicalin can be considered a potential therapeutic agent for treating chondrosarcomas. PMID- 30469148 TI - A tricky case of pancreatic arteriovenous malformation: the role of endoscopic ultrasound in the diagnosis of this rare condition. PMID- 30469149 TI - Percutaneous endoscopic necrosectomy using a fully covered self-expandable metal stent in severe necrotizing pancreatitis. PMID- 30469150 TI - Gastrointestinal hemorrhage caused by the direct invasion of a hepatocellular carcinoma successfully treated with polyglycolic acid sheet shielding. PMID- 30469151 TI - Langerhans cell histiocytosis: a rare case of large-bowel inflammatory lesions. PMID- 30469152 TI - Endoscopic ultrasound-guided hepaticogastrostomy combined with antegrade stenting using a double bare covered metal stent. PMID- 30469153 TI - Cervical esophageal adenocarcinoma arising from heterotopic gastric mucosa, treated with endoscopic submucosal dissection. PMID- 30469154 TI - Novel metallic stent designed for endoscopic bilateral stent-in-stent placement in patients with hilar malignant biliary obstruction. PMID- 30469155 TI - Computer-assisted diagnosis of early esophageal squamous cell carcinoma using narrow-band imaging magnifying endoscopy. AB - BACKGROUND: We developed a computer-assisted diagnosis model to evaluate the feasibility of automated classification of intrapapillary capillary loops (IPCLs) to improve the detection of esophageal squamous cell carcinoma (ESCC). METHODS: We recruited patients who underwent magnifying endoscopy with narrow-band imaging for evaluation of a suspicious esophageal condition. Case images were evaluated to establish a gold standard IPCL classification according to the endoscopic diagnosis and histological findings. A double-labeling fully convolutional network (FCN) was developed for image segmentation. Diagnostic performance of the model was compared with that of endoscopists grouped according to years of experience (senior > 15 years; mid level 10 - 15 years; junior 5 - 10 years). RESULTS: Of the 1383 lesions in the study, the mean accuracies of IPCL classification were 92.0 %, 82.0 %, and 73.3 %, for the senior, mid level, and junior groups, respectively. The mean diagnostic accuracy of the model was 89.2 % and 93.0 % at the lesion and pixel levels, respectively. The interobserver agreement between the model and the gold standard was substantial (kappa value, 0.719). The accuracy of the model for inflammatory lesions (92.5 %) was superior to that of the mid level (88.1 %) and junior (86.3 %) groups (P < 0.001). For malignant lesions, the accuracy of the model (B1, 87.6 %; B2, 93.9 %) was significantly higher than that of the mid level (B1, 79.1 %; B2, 90.0 %) and junior (B1, 69.2 %; B2, 79.3 %) groups (P < 0.001). CONCLUSIONS: Double-labeling FCN automated IPCL recognition was feasible and could facilitate early detection of ESCC. PMID- 30469156 TI - [Techniques for the Reconstruction of the Posterior Eyelid Lamella]. AB - The reconstruction of the posterior lamella is basically very important for a successful and permanent eyelid reconstruction. Generally, there are no fixed rules for the technique selection. The type of care is rather determined by the individual patient's situation and the surgeon's preference. The main objective in the reconstruction of the lateral canthus is the durable fixation of the eyelids, for example, with a Tenzel flap, a periosteal flap or eccentric Hughes or Cutler-Beard procedure. In the case of central defects of the eyelid, it is important to pay attention to a regular lid margin and stable support. For the Cutler-Beard procedure, the Hughes flap or various free transplants of the rear lamella are very well suited. The medial canthus is the hardest to reconstruct; often done with a sliding graft of the lid. It is important never to combine two free transplants. Therefore, free posterior lamella grafts are combined with skin muscle lobes. These lobes ensure a sufficient vascular supply of the posterior lamella grafts. PMID- 30469157 TI - Biomarkers in Non-Complicated Pregnancy: Insights About Serum Myeloperoxidase and Ultrasensitive C-Reactive Protein. AB - INTRODUCTION: Pregnancy is characterized by increased innate immune response, with low-grade systemic inflammation. The specific role of MPO during normal pregnancy remains not well understood. Therefore, the aim of this study was to evaluate plasma levels of MPO, hs-CRP, total leukocyte, absolute neutrophil and monocyte counts, in all trimesters of normal human pregnancy compared with non pregnant controls. In addition, possible fluctuations of MPO according to different inflammatory conditions in the normal gestation were studied. MATERIALS AND METHODS: Case-control study (n=84) developed with 63 normal pregnant women and 21 healthy non-pregnant women. Total leukocyte, absolute neutrophils and absolute monocytes count, hs-CRP and MPO were measured in non-pregnant women and normal human pregnancy. They were evaluated according to the 3 trimesters of pregnancy and systemic low grade inflammatory status, which was identified through increased hs-CRP levels. RESULTS: MPO levels in the normal pregnant women were not elevated in every 3 trimesters of pregnancy (P=0.456) or in systemic inflammation (P=0.446). The hs-CRP levels, total leukocyte, absolute neutrophil and monocyte counts are present in higher concentrations in normal pregnant women in relation to non-pregnant women. CONCLUSIONS: The MPO did not show fluctuations in plasma levels during the 3 trimesters of gestation or in relation to different inflammation conditions. Considering MPO and hs-CRP levels are changed in high cardiovascular risk conditions and MPO levels (unlike hs-CRP) didn't increase during non complicated pregnancy, MPO could be a better biomarker than hs-CRP to monitor these patients. PMID- 30469158 TI - Advanced Adrenocortical Carcinoma - What to do when First-Line Therapy Fails? AB - Adrenocortical carcinoma is a rare endocrine malignant disease with a generally unfavorable but heterogeneous prognosis. Although even in advanced stages a subset of patients experiences long-term disease stabilisation, effective systemic treatment options are limited. Mitotane is the only approved drug and the combination of etoposide, doxorubicin and cisplatin (plus mitotane) is currently considered as treatment standard for advanced adrenocortical carcinoma based on the results of a large randomized phase III trial. However, progression free survival is often limited and further treatment options are frequently needed. Here we summarize the current knowledge about second and third-line therapeutic modalities (local and systemic) in advanced disease. Following the recent ESE-ENSAT guidelines local therapies play an important role for these patients. Regarding systemic therapies the best data are available for gemcitabine+capecitabine or streptozotocin (both with or without mitotane). Furthermore, we introduce our own approach to patients with advanced adrenocortical carcinoma based on our experience as a large multidisciplinary clinic dedicated to the care of patients with this orphan disease. PMID- 30469159 TI - [Management of Postoperative Prolonged Air Leak]. AB - Prolonged air leak is one of the most common postoperative complications in thoracic surgery. For elective partial lung resections, postoperative air leak lasting longer than 5 - 7 days is arbitrarily defined as prolonged. There are several predictive factors for the development of prolonged air leak that can be subdivided as either preoperative, such as obstructive pulmonary disease, or intraoperative risk factors, such as pleural adhesions or fused fissures. The treatment of postoperative prolonged air leak is performed on an individual basis for each patient and may vary considerably. Four major treatment options can be varied in sequence and use: intensified conservative therapy, installation of sclerosing agents or autologous blood, endoscopic procedures and surgical revision. Prevention, detection and treatment of postoperative prolonged air leak are common aspects of thoracic surgery with high clinical relevance. In contrast to standardised procedures in risk identification and diagnostic work-up, the treatment of prolonged air leak is performed on an individual basis and requires a great deal of surgical expertise. For effective targeted therapy, it seems advisable to agree on a specific standardised therapy sequence within a clinic. PMID- 30469160 TI - Is Intraoperative Fluoroscopy Necessary for Central Venous Port System Placement in Children? AB - INTRODUCTION: Central venous port (CVP) placement is traditionally performed under fluoroscopy guidance. However, efforts for radiation dose reduction in children have allowed the introduction of ultrasound guidance (USG) and anatomic landmarks as an alternative technique for CVP placement. The aim of this study is to determine whether intraoperative fluoroscopy (IF) is required to confirm the correct position of the catheter tip in children. PATIENTS AND METHODS: A prospective, single-center study was performed between July and December 2017. Standard venous access site was the right internal jugular vein under USG. Estimated catheter length (ECL) was measured using anatomic landmarks. Ideal catheter length (ICL) was measured after placement under fluoroscopy guidance in the same patient. Age, sex, radiation dose, and complications were also analyzed. A t-test for paired samples and intraclass correlation coefficient were performed to analyze results. RESULTS: A total of 30 consecutive patients aged 7 +/- 2 years underwent CVP placement. The mean ECL was 17.1 +/- 1.8 cm, while the mean ICL was 17.7 +/- 1.8 cm. The mean difference between measurements was 0.28 cm (95% confidence interval [CI], -0.29 to 0.86; p = 0.324). Intraclass correlation coefficient analysis showed an agreement of 0.95 (95% CI, 0.91-0.98) between measurements. Mean radiation exposure during the procedure was 1.060.78 mGym2 during 0.34 +/- 0.6 minutes. There were no complications registered during CVP placement. CONCLUSION: The correlation between IF and USG and anatomically guided catheter tip placement is optimal. These results suggest that fluoroscopy and the radiation exposure it entails can be safely avoided in selected children. PMID- 30469161 TI - Pneumonia after Repair of Esophageal Atresia-Incidence and Main Risk Factors. AB - INTRODUCTION: Esophageal atresia (EA) is associated with significant respiratory mortality. We aimed to assess incidence and predictive factors of EA associated pneumonia during the first 5 years of life. MATERIALS AND METHODS: Institutional ethical consent was obtained. Hospital records of patients with EA from 2002 to 2017 were reviewed. Episodes of pneumonia that were diagnosed in university or regional hospitals were included. For instance, respiratory infections other than pneumonia, anastomotic complications, aortopexy, fundoplication, major EA associated diseases, types of EA, and EA anastomosis dilatations were tested as potential risk factors for pneumonia. RESULTS: A total of 104 patients (56 males; type A 7, B 3, C 83, D 3, E 6, F 2) was included. Thirty-five (34%) patients had 94 episodes of pneumonia corresponding to median 2 (IQR [interquartile range]: 1-4) and 609 episodes per thousand patient years. Majority of pneumonias occurred before the age of 3 years. The cause of pneumonias could be identified as RS (respiratory syncytial) virus in 15(16%) and aspiration in seven (7.4%) episodes. In univariate analysis, pneumonia was predicted by occurrence and number of nonpneumonia respiratory infections, anastomotic reoperations, fundoplication, and number of EA anastomosis dilatations. In multivariate logistic regression analysis, significant risk factors for pneumonia were occurrence of nonpneumonia respiratory infections and number of anastomotic dilatations. CONCLUSION: Episodes of pneumonia occurred in one-third of patients with EA. After the final repair, the incidence of pneumonia was highest during the first 3 years of life. Patients with other acute respiratory infections and high number of dilatations were at the greatest risk. PMID- 30469162 TI - Ephrin-B1, -B2, and -B4 Expression is Decreased in Developing Diaphragms and Lungs of Fetal Rats with Nitrofen-Induced Congenital Diaphragmatic Hernia. AB - INTRODUCTION: Congenital diaphragmatic hernia (CDH) is assumed to originate from a malformation of the amuscular mesenchymal component of the primordial diaphragm. Mutations in ephrin-B1, a membrane protein that is expressed by mesenchymal cells, have been found in newborn infants with CDH and associated pulmonary hypoplasia (PH), highlighting its important role during diaphragmatic and airway development. Ephrin-B1, -B2, and -B4 are expressed in fetal rat lungs and have been identified as key players during lung branching morphogenesis. We hypothesized that diaphragmatic and pulmonary expression of ephrin-B1, -B2, and B4 is decreased in the nitrofen-induced CDH model. MATERIALS AND METHODS: Time mated rats received nitrofen or vehicle on day 9 (D9). Fetal diaphragms (n = 72) and lungs (n = 72) were harvested on D13, D15, and D18, and divided into control and nitrofen-exposed specimens. Ephrin-B1, -B2, and -B4 gene expression was analyzed by quantitative real-time polymerase chain reaction. Immunofluorescence double staining for ephrin-B1, -B2, and -B4 was combined with mesenchymal and epithelial markers (Gata-4/Fgf-10 and calcitonin gene-related peptide) to evaluate protein expression/localization. RESULTS: Ephrin-B1, -B2, and -B4 gene expression was significantly reduced in pleuroperitoneal folds/primordial lungs (D13), developing diaphragms/lungs (D15), and fully muscularized diaphragms/differentiated lungs (D18) of nitrofen-exposed fetuses compared with controls. Confocal laser scanning microscopy demonstrated markedly diminished ephrin-B1 immunofluorescence in diaphragmatic and pulmonary mesenchyme of nitrofen-exposed fetuses on D13, D15, and D18 compared with controls, whereas ephrin-B2 and -B4 expression was mainly decreased in distal airway epithelium. CONCLUSION: Decreased ephrin-B1, -B2, and -B4 expression may disrupt diaphragmatic development and lung branching morphogenesis by interfering with epithelial-mesenchymal interactions, thus causing diaphragmatic defects and PH. PMID- 30469163 TI - Re: Impact of the four-hour National Emergency Access Target on 30 day mortality, access block and chronic emergency department overcrowding in Australian emergency departments. PMID- 30469164 TI - The Sydney Triage to Admission Risk Tool (START2) using machine learning techniques to support disposition decision-making. AB - OBJECTIVE: To further develop and refine an Emergency Department (ED) in-patient admission prediction model using machine learning techniques. METHODS: This was a retrospective analysis of state-wide ED data from New South Wales, Australia. Six classification algorithms (Bayesian networks, decision trees, logistic regression, naive Bayes, neural networks and nearest neighbour) and five feature selection techniques (none, manual, correlation-based, information gain and wrapper) were examined. Presenting problem was categorised using broad (n = 20) and specific (n = 100) representations. Models were evaluated based on Area Under the Curve (AUC) and accuracy. The results were compared with the Sydney Triage to Admission Risk Tool (START), which uses logistic regression and six manually selected features. RESULTS: Sixty admission prediction models were trained and validated using data from 1 721 294 patients. Under the broad representation of presenting problem, the nearest neighbour algorithm with manual feature selection had the best AUC of 0.8206 (95% CI +/-0.0006), while the decision tree with no feature selection had the best accuracy of 74.83% (95% CI +/-0.065). Under the specific representation, almost all models improved; the nearest neighbour with information gain feature selection had the best AUC of 0.8267 (95% CI +/-0.0006), while the decision tree with wrapper or no feature selection had the best accuracy of 75.24% (95% CI +/-0.064). Eleven of the machine learning models had slightly better AUC than the START model. CONCLUSION: Machine learning methods demonstrate similar performance to logistic regression for ED disposition prediction models using basic triage information. This should be investigated further, especially for larger data sets with more complex clinical information. PMID- 30469165 TI - Impact of emergency department occupancy on waiting times, rates of admission and representation, and length of stay when hospitalised: A data linkage study. AB - OBJECTIVES: To assess the association between ED occupancy and relevant outcomes including ED waiting times, rates of admission and representation and length of stay when hospitalised. METHODS: Retrospective study of all ED presentations by New South Wales (NSW), Australia, residents to 15 NSW public, principal referral or paediatric specialist hospitals between 1 January to 31 December 2015 (N = 935 282). ED data were linked longitudinally (to ED data) and cross-sectionally to hospital admissions data. An ED-system measure of occupancy was assigned to each ED record. The study outcomes were ED waiting time, admission to hospital, 28 day representation, and length of stay (LOS) when admitted. Outcomes were analysed using univariate analyses and multivariable general linear and binary logistic regression models. RESULTS: Increased ED occupancy was associated with increased ED waiting times, particularly at low-baseline occupancy (e.g. rate ratio = 2.22, 95% confidence interval [CI] [2.10-2.35], for non-urgent triaged patients). However, results were conditional on triage category, such that estimated effects were smaller or not significant in emergency and resuscitation triaged patients (e.g. rate ratio = 1.59, 95% CI [1.52-1.65], for emergency patients). ED occupancy only showed small or no associations with admission to hospital, 28 day representation and LOS when admitted. CONCLUSIONS: Higher ED occupancy was associated with increased waiting times conditional on triage category and baseline occupancy. Collectively, the results show that NSW principal referral EDs are robust, and are currently capable of handling variation in occupancy by prioritising treatment for the most urgent patients. PMID- 30469166 TI - An accurate and reproducible method for simultaneous determination of four flavonoids in EtOAc extracts from Sophora flavescens Ait. in rat plasma based on UHPLC Q-Exactive Mass spectrometry: application to a pharmacokinetics study. AB - In previous studies, it was revealed that ethyl acetate (EtOAc) extracts from Sophora flavescens Ait. improved glucose tolerance, reduced hyperglycemia, and restored insulin levels to treat diabetes. The aim of this study was to develop an accurate and sensitive UHPLC-MS method for simultaneous determination of flavonoids in EtOAc extracts of Kushen in rat plasma. Ethyl acetate-acetonitrile (2:1) was selected as the solvent to extract the four flavonoids from rat plasma. A BEH C18 column (2.1 mm*100 mm, 1.7 MUm) with a C18 guard cartridge was chosen as the separation plant using a gradient elution with acetonitrile (solvent A) and 0.1% formic acid (solvent B) in water. For all four analytes, the method showed good linearity (r2 > 0.991) in 1-500 ng/mL. The inter- and intra-day accuracy ranged from -13.78-7.19%, and the precision (RSD) was less than 8.75%. Recoveries of all four flavonoids ranged from 85.9 to 101.3%. According to the results of multi-target pharmacokinetic studies, we find that four active flavonoids in EtOAc extracts from Kushen have similar absorption kinetics but have very different metabolic kinetics and double peak phenomenon was observed in the concentration-time curve of norkurarinone which is different from previous study. In conclusion, the detection and multi-target pharmacokinetic studies of active flavonoids after oral administration of EtOAc extracts from Kushen by an efficient, sensitive and selective UHPLC-MS method were established successfully, and the results may provide a foundation for future studies of Kushen. PMID- 30469167 TI - Synthesis and Properties of Metal Oxide Aerogels via Ambient Pressure Drying. AB - Metal oxide aerogels such as zirconia (ZrO2), titania (TiO2), and alumina (Al2O3) aerogels are very interesting nanoporous materials applicable as thermal insulators, catalysts, sensors, and so on. To obtain the aerogels, the first key step is a sol-gel process to prepare the gel followed by either supercritical drying, ambient pressure drying, or freeze-drying. Although the expensive and energy-intensive supercritical drying method restricts the commercialization of the aerogels, ambient pressure drying has shown great potential as an alternative and very simple method for aerogel synthesis. The sol-gel method and preparation parameters such as hydrolysis water, the silylating agent concentration, and the thermal treatment temperature have a profound impact on the textural and structural properties of the aerogels. Therefore, in this review, we study the synthesis and the influence of these parameters on the properties of metal oxide aerogels via ambient pressure drying. PMID- 30469168 TI - Development of a Connector for Carbon Fiber Screened Cables with Conductive Springs. AB - Research is in progress to lighten cables for vessels by replacing shield layers with carbon fiber materials. Since there has been no actual case where carbon fiber is used as a shield material for cables, it is necessary, first of all, to secure the safety of this new material by examining the physical property, connecting modes of cable connectors and the contact resistance of carbon fiber. Carbon fiber has a difficulty in maintaining its shape thus special property is required when used for connections and an easy break-down due to characteristic binding post-tensioning force. So, a new type of screened cable connector needs to be developed, which overcomes carbon fiber's easy breaking or cutting and also minimizes contact resistance in connections. In this study, a conductive spring applied and gland-type cable connector was designed and manufactured, followed by applicability evaluation through measurement of contact resistance of the cable. As for aluminum alloy connectors, the total weight was reduced as much as 60% in comparison with brass connectors, and the contact resistance was as high as that of non-connected solid cables. This study sheds light on new design technology for new connectors in cables typically used in heavy transportations. PMID- 30469169 TI - A Study on Shielding Effects for Electromagnetic Waves of the Sheet Heating Elements. AB - Exposure of human bodies to the electromagnetic waves emitted in various ways in our daily lives has become a growing concern. The extremely low frequency (ELF) electromagnetic waves generated from ordinary products and electric power facilities are closely related to our daily lives. Nevertheless, there has been no clear solution suggested to shield the ELF electromagnetic waves from electronic products used by the general public. This study investigated the electromagneticwave shielding effects when exposed to ELF-emitting heating products. We (i) installed an actual surface heater on the floor of the classroom, (ii) measured the electromagnetic wave exposure at different settings (shielding/non-shielding/isolation distance), (iii) compared the measured results with the applicable international standards, and (iv) suggested a solution to shield electromagnetic waves and underscored the importance of isolation distance. PMID- 30469171 TI - Improvement in Resistance Switching of SiC-Based Nonvolatile Memory by Solution Deposited HfOx Thin Film. AB - In this study, we implemented a resistance change memory (ReRAM) device using a SiC layer with excellent physical properties. We fabricated devices composed of Ti/SiC/Pt and Ti/HfOx/SiC/Pt structures and investigated their memory characteristics. The Ti/SiC/Pt ReRAM devices exhibited stable bipolar resistive switching characteristics but had a relatively small memory window, whereas the Ti/HfOx/SiC/Pt ReRAM devices had a large memory window and low operating voltage. In addition, the Ti/HfOx/SiC/Pt ReRAM devices exhibited stable endurance characteristics over 500 cycles and excellent retention characteristics at room temperature and high temperatures for 1*104 s. Further, the Ti/HfOx/SiC/Pt ReRAM devices exhibited multi-level conduction states by modulating the reset stop voltage, and each resistance level had excellent endurance characteristics. The average transmittance of the HfOx/SiC bilayer in visible light was 87%. Such a high value indicates that the HfOx/SiC bilayer fabricated by the stacking method is expected to be a suitable material for highly reliable nonvolatile memory and transparent electronic devices, even in harsh environments. PMID- 30469170 TI - Development of a New Electrochemical Atomic Force Microscopy Tool for Obtaining Surface Morphology Through Electrochemical Reaction. AB - Electrochemical atomic force microscopy is a complex electrochemical analysis method that has been applied in many fields. Electrochemical atomic force microscopy consists of an electrochemical cell, electrochemical analysis system, and atomic force microscopy. To simultaneously analyze the electrochemical system and the atomic force microscopy, an electrochemical cell with a suitable structure is needed. We developed the electrochemical atomic force microscopy analysis system using a self-developed electrochemical cell. To confirm the in situ analytical ability of the developed electrochemical atomic force microscopy analysis system, we observed the electrochemical corrosion process of copper with respect to changes in pH of a sulfuric acid solution. The operation of the electrochemical atomic force microscopy tool was verified by experiments on the electrochemical corrosion of copper, and the factors affecting the corrosion process were examined. It was confirmed that electrochemical atomic force microscopy can perform electrochemical analysis and atomic force microscopy image analysis at the same time. PMID- 30469172 TI - Improvement of Electrical Conductivity and Chemical Durability in Fe2O3 Doped V2O5-B2O3-P2O5 Glasses. AB - In this study, we verified the relationship among the electrical conductivity, chemical durability, and structure of conductive vanadate glass in which Fe2+ Fe3+ and V4+-V5+ systems simultaneously coexist. We prepared samples of iron vanadium borophosphate glass with various compositions given by 78V2O5-15P2O5 7B2O3-xFe2O3 (1, 5, 7.5 and 10 mol%) and analyzed the electrical conductivity, chemical durability, FTIR spectra, thermal properties, density, and molar volume. The results indicated that the addition of Fe2O3 improved the electrical conductivity, chemical durability, and thermal properties. The following conclusions could be drawn: Fe2+-O-P bonds or Fe3+-O-P bonds were generated in the glass structure, and Fe3+ and Fe2+ ions were located at tetrahedral and octahedral sites. Furthermore, V?O bonds were expected to be replaced with Fe-O-V and P-O-V bonds, which are stronger than double bonds, so that the complete glass structure was strong. The structural reinforcement of the glasses was additionally confirmed based on thermal and chemical properties and electrical conductivity. PMID- 30469173 TI - Sintering Behavior of Copper Nanoparticle Ink by Laser in Air. AB - This paper presents a sintering technique using a laser in air which can provide heat for a few hundred milliseconds. In this study, a laser having a wavelength of 532 nm and a maximum-power output of 5 W was used. The effects of irradiated laser power at 104-282 W/cm2 and sintering time of 50-330 milliseconds applied on spin-coated copper nanoparticle ink were investigated. The residual organic agent, oxidation, and specific resistance of the laser-sintered copper nanoparticle ink were characterized, and the sintering behavior was analyzed. For application, laser-sintered copper nanoparticle ink was confirmed to offer acceptable performance as a source and drain electrode in a thin-film transistor. PMID- 30469174 TI - Surface Characterizations of Railway Electrical Wires Coated with Anti-Icing Mixtures of Ethylene Glycol or Glycerol with Tap Water. AB - Icing of railway contact wires in the cold climates of the USA, Canada, China, Japan, and South Korea can cause significant problems and delays in the operation schedules of electric-powered trains and subway cars. As anti-icing methods, manual de-icing, contact-wire thermal running, resistive-wire-heating de-icing, and chemical de-icing have all been explored and tested. Among them, environmentally friendly chemical de-icing based on the same concept as that of automobileengine antifreezer can be practically effective for application to contact wires at railcar depots. In the present study, the railway contact wires are coated with anti-icing mixtures of ethylene glycol/tap water and glycerol/tap water at various ratios (v/v %) as well as with tap water alone, at temperatures of -30 and -40 degrees C in a deep freezer. The morphological change on the wire surfaces is observed under optical microscopy. The surface-contact angles are measured to examine the surface difference between uncoated and coated railway contact-wire fragments. Conclusively, the fragments coated with 40/60 and 60/40 (v/v %) ratios of ethylene glycol or glycerol with tap water, as compared with the uncoated fragments, are shown to have been effectively de-iced. The surface characterizations data thus indicate that mixtures of glycerol or ethylene glycol with tap water can be practical de-icing agents for application to railway contact wires. PMID- 30469175 TI - Electrical and Magnetic Properties of Barium Hexaferrite Modified Barium Zirconium Titanate Lead-Free Ceramics. AB - The (BaZr0.07Ti0.93O3)/x(BaFe12O19); (BZT/xBF) (x = 0, 0.1, 0.5 and 1 mol%) ceramics have been prepared via a solid state reaction process. Effects of BF content on the physical, microstructural, magnetic and electrical properties have been systematically investigated. High density sintered specimens (5.65-5.74 g/cm3) are obtained for all compositions. SEM micrographs show a decrease of grain size value when BF is added. Examination of the dielectric spectra show that the two phase-transition temperatures as observed for pure BZT, merges into a single phase-transition temperature for the added-samples. The addition of BF also improves the magnetic behavior (M-H hysteresis loops) of BZT ceramic and resultes in slight changes in ferroelectric properties. The maximum of remanent magnetization (Mr) of 7.19 emu/g is obtained for the 1 mol% sample. PMID- 30469176 TI - Study on the Characteristics of Metal-Coated Carbon Fiber and 0.6/1 kV Lightweight Cable. AB - In this study, 0.6/1 kV lightweight cable was manufactured using metal-coated carbon fiber (MCF) instead of metal, for utilization in low voltage cable shield screen. It was investigated the properties of MCF such as a fusing current, coating and so on. The epoxy and urethane sizing treatments were found to be effective in bundling, flexibility and fluff reduction. Braid MCF cables with 6,000 strands (6 K), 16 spindles, and braid density of 90% or more was adopted. By replacing the screen with MCF, the weight of the cable was reduced by approximately 62%. The fusing current of MCF was 7.4 A, but showed to be approximately 17 times lower than the cooper wire. The MCF cable braided with 6 K has a value of shield effectiveness about 50 dB and 60 dB from the frequency of 100 K to 100 MHz in accordance with IEC standard. In the cable connection, spring was added to the contact surface to reduce the resistance and fiber brittleness. PMID- 30469177 TI - Flexible Energy Harvester Based on Poly(vinylidene fluoride) Composite Films. AB - In these days, we are facing emerging energy crisis due to depletion of fossil fuels. Therefore, renewable energy which is based on wind energy, mechanical force energy, microwave energy and vibrations energy have attracted a lot of attentions. Piezoelectric energy harvesting is one of the promising renewable energy sources. As the use portable electronic devices increases, the need for portable renewable energy sources further increases. Especially, piezoelectric materials can be the best selection due to their robust properties. In this research, piezoelectric composites were prepared and investigated for piezoelectric energy harvesting applications. In this study, two types of flexible energy harvesters, 0.36BS-0.64PT-PVDF composite and PVDF film, were prepared and analyzed. Due to its high Curie temperature and low lead content, BS PT is expected to be a substitute for PZT in the near future. The composite materials based on the PVDF and 0.36BS-0.64PT film showed higher open circuit voltage (0.73 V) than PVDF film (0.49 V). Also, the stored voltage of 0.36BS 0.64PT-PVDF composite film was 330 nJ which is 5.68 times higher than 58 nJ for PVDF films. By introducing the piezoelectric BS-PT ceramics, 0.36BS-0.64PT-PVDF composite film shows the enhanced performance such as open circuit voltage, energy and dielectric constant compared with those of PVDF materials. It seems that 0.36BS-0.64PT-PVDF composite film is more suitable for flexible energy device. PMID- 30469178 TI - Nano-Programmable Logics Based on Double-Layer Anti-Facing Memristors. AB - The memristor, as theorized by Chua in 1971 (L. Chua, IEEE Trans. Circuit Theory 18, 507 (1971)), is a two-terminal device whose resistance state is based on the history of charge flow brought about as a result of the voltage applied across its terminals. High-density regular fabrics for nanoscale memristors, such as crossbar arrays, are emerging architectures for system-on-chip (SoC) implementation, which provide both simplified structure and improved performance (W. H. Yu, et al., IEEE Trans. VLSI 20, 1012 (2012)). The advantage of using memristors as the switching devices within crossbar arrays is their nanoscale switching capability, which specifically changes their resistance state between high and low. In this paper, we propose a new nano-programmable logic array (PLA) device in the form of an on anti-facing double-layer memristor array. The PLA is composed of an AND plane and an OR plane merged onto the same layer. The AND and OR planes are stacked vertically such that each layer forms a crossbar architecture; thus, a cross section reveals two anti-facing memristors with 5 layers: the bottom metal layer, a memristive layer, the intermediate metal layer, an anti-facing memristive layer, and the top metal layer. The intermediate metal layer provides its output at the AND plane which is the input of the OR plane, and as such, the input and output nodes of the two logic functions are shared. Thus, the proposed architecture reduces the propagation delay of the AND plane by 70% by sharing the OR plane input wires. Additionally, the anti-facing architecture makes it easy to determine appropriate values for the pull-up and pull-down registers of the PLA. PMID- 30469179 TI - Effects of the Process Parameters on the Properties of Sputter-Deposited Tin Oxide Thin Films. AB - This study examined the effects of the oxygen partial pressure on the properties of tin oxide (SnOx) thin films deposited by radio frequency magnetron sputtering using a SnO target. The properties of the samples were characterized by Hall Effect measurements, dynamic-secondary ion mass spectrometry, X-ray photoelectron spectroscopy (XPS), X-ray diffraction, and atomic force microscopy. All the samples exhibited dominant Sn2+ XPS peaks, indicating that SnO with p-type conductivity was the main composition regardless of the oxygen partial pressure. The samples deposited with an oxygen partial pressure of 12% showed the best p type characteristics, which included a maximum hole mobility of 1.94 cm2/Vs, carrier concentration of 3.83*1017/cm3, Sn2+ peak area percentage of 91.34%, Sn4+ peak area percentage of 2.35%, and Sn0 peak area percentage of 6.31%. As the oxygen partial pressure was increased to more than 12%, the Sn2+ peak area percentage decreased while the Sn4+ peak area percentage increased. This was attributed to the reduction of the SnO phase and the growth of the SnO2 phase in the samples due to the incorporation of more oxygen. These results are expected to contribute to the development of p-type SnO-based TFTs with good performance. PMID- 30469180 TI - Design of Piezoelectric Actuator for Braille Module by Finite Element Method. AB - Piezoelectric actuators, exhibiting large displacement and torque, are attractive for use in a broad range of actuator applications. One of the important applications is a tactile device, e.g., refreshable Braille display. Piezoelectric actuation in the Braille module requires large torque and large displacement for the tactile sensing of the human finger. In this study, we design piezoelectric actuators for the tactile interface including a Braille cell by finite element method (FEM) simulations. FEM simulations allow us to capture the entire device physics and solve the coupled piezoelectricity/solid mechanics problem. We investigated the effect of the structure, geometric variation, and physical properties of the materials used on the displacement and torque force. The studied structure includes a trilayer bimorph consisting of piezoelectric and supporting layers, and a multilayer with multiple bimorphs. The simulation result provides a useful guide toward piezoelectric actuators of tactile function. PMID- 30469181 TI - Fabrication of Pressure-Sensitive Multiwalled Carbon Nanotubes-Poly(methyl methacrylate) Nanocomposites for Pressure-Sensing Applications. AB - In this study, we fabricated novel, pressure-sensitive nanocomposites through two different methods. These materials were thoroughly evaluated and compared with one another. Multiwalled carbon nanotubes (MWCNTs) were added to thermoplastic polyurethane (TPU) by melt mixing and to Poly(methyl methacrylate) (PMMA) beads of different sizes to make the first type of sample. A solution mixing method was used to coat PMMA beads of different sizes with MWCNTs, and then the TPU polymer was added to make another nanocomposite. The effects of different PMMA bead sizes on the pressure-sensing properties of both nanocomposites were studied by applying different external loads. PMMA beads were used to increase the internal volume and achieve a segregated electro-conductive network structure, leading to an early percolation threshold. Scanning electron and Raman microscopy were used to study the morphology of the nanocomposites. The electrical and thermal conductivities of the nanocomposites were also investigated under different applied loads, and the two methods were compared. The electrical responses of the nanocomposites under different applied pressures demonstrated a linear decrease in the electrical resistivity with increasing applied external load, thereby confirming that these novel nanocomposites are suitable for use as pressure sensing materials; they also show repeatability in their electrical response when an external load was applied repeatedly. These materials represent ideal candidates for use in pressure-sensitive devices. PMID- 30469182 TI - Structure Analysis and Ferroelectric Response of Bi0.5Na0.5TiO3 Nanopowder Synthesized by Sol-Gel Method. AB - In this work, bismuth sodium titanate, Bi0.5+/-xNa0.5+/-yTiO3 (BNT, x, y = -0.05 0.08) nanopowders were produced using the low-temperature sol-gel technique. The effects of deficient and excess amounts of Bi and Na on BNT structure were systemically examined through X-ray powder diffraction (XRD), energy dispersive analysis (EDS) and scanning electron microscope (SEM). The optimized composition of the BNT nanopowder was pelletized and sintered at different temperatures (950 degrees C-1150 degrees C). Highly dense ceramics possessing pure perovskite phase was observed for the sample sintered at an optimum sintering temperature (1100 degrees C). The ferroelectric properties were found to increase with an increase in sintering temperature up to 1100 degrees C and then decrease. This study justifies that Bi and Na non-stoichiometry (proper excess), processing and sintering temperatures play important role in the successful synthesis of BNT ceramics. PMID- 30469183 TI - Role of Hydrophilic APTES-PP Separator in Enhancing the Electrochemical Performance of Ni-Rich Cathode for Li-Ion Battery. AB - Polypropylene (PP) separators essentially have poor compatibility with normal liquid electrolytes, including EC/DEC, due to the low surface energies of their hydrophobic surfaces. Therefore, they have a poor ability to retain electrolyte solutions within the separators because of low absorption capacity for the liquid electrolytes, which could directly damage the AC impedance and C-rate performance of LIBs. This study aims to improve the hydrophilicity and adhesion properties using (3-aminopropyl)triethoxysilane (APTES) coating on hydrophobic PP separators. Their surfaces were treated with a thin and stable silane layer, using APTES with -NH2 of the hydrophilic group. Hydrophilic PP separator surfaces with pore structures were fabricated by a facile solution-immersion method. The contact angle of the APTES-PP separator decreased from 102+/-2.5 degrees to 60+/ 1.5 degrees . The electrochemical measurement results indicate that the cell using the modified PP separator showed a better initial discharge capacity of 165.79 mAh g-1 during the first cycle, at a current density of 0.1 C, as compared with the initial discharge capacity (141.61 mAh g-1) of the cell with a bare PP separator. The performances of all cells with coated PP separators were improved with regard to interfacial resistance, discharge capacity and C-rate capacity, compared to the uncoated PP separator. PMID- 30469184 TI - Novel Core-Shell-Type Design of Na0.5[Li0.5(Ni0.8Co0.1Mn0.1)1-x(Ni0.5 Co0.1Mn0.4)x]O2 Cathode Material for Sodium-Ion Batteries. AB - High-nickel cathode materials possess several disadvantages such as poor cycle performance and thermal instability resulting from the side reaction with the electrolyte that occurs during cycling. In order to improve the cycle performance and thermal stability of the Na0.5[Li0.5(Ni0.8Co0.1Mn0.1)]O2 (core), we synthesized the core-shell structure of Na0.5[Li0.5(Ni0.8Co0.1Mn0.1)1 x(Ni0.5Co0.1Mn0.4)x]O2. The results of energy-dispersive X-ray spectroscopy (EDS) line analysis showed that the core of the high-nickel NCM precursor and the shell of the low-nickel NCM precursor were successfully synthesized as two phases. The core-shell cathode material shows a small capacity loss after 30 cycles (capacity retention=60.78%) compared with the core cathode material (capacity retention = 48.57%). The results of differential scanning calorimetry (DSC) show that the 4.6 V charged core-shell cathode material has a large exothermic peak at 297.4 degrees C, and the low reaction releases 246.1 J.g-1 of heat. The core-shell cathode material shows improved electrochemical performance and is a thermally stable material for use as a cathode material for sodium-ion batteries. PMID- 30469185 TI - Magnetic Moment of Melted YBaCuO Superconducting Bulk. AB - YBaCuO superconductor with variations in the BaZrO3 content was fabricated via thermal diffusion, to study the changes in its electrical properties and superconducting behavior. While the critical temperature of the YBaCuO superconductor did not predominately depend on the BaZrO3 content, the addition of BaZrO3 formed a pinning center for the magnetic BaZrO3, which effected a change in the electromagnetic properties of the YBaCuO superconductor. This result indicates that magnetization is proportional to the number of magnetic flux lines passing through the superconductor. PMID- 30469186 TI - Improvement of On/Off Current Ratio of Amorphous In-Ga-Zn-O Thin-Film Transistor with Off-Planed Source/Drain Electrodes. AB - In this study, we fabricated amorphous In-Ga-Zn-O thin-film transistors (TFTs) with a new structure, in which the source/drain (S/D) electrode is located on different planes. This structure made it possible to use materials with different work functions, in this case indium-tin-oxide (ITO) and titanium (Ti), as the source and drain electrodes to control the overall work function of the TFT. Among the fabricated TFTs, we measured the electrical properties by setting up the Ti (PhiTi?3.4 eV) and ITO (PhiITO?4.7 eV) electrodes as the source and drain, respectively. The off-planed S/D a-IGZO TFT showed excellent electrical characteristics: a threshold voltage of -0.33 V, a subthreshold swing of 219.9 mV/dec, field-effect-mobility of 18.1 cm2/V sec, and an Ion/Ioff ratio of 2.3*108. Additionally, the threshold voltage shift was the smallest in both the positive and negative biastemperature stress tests, respectively. As a result, the a-IGZO TFT with an off-planed S/D electrode is shown to be a promising structure capable of improving the electrical performance and reliability. PMID- 30469187 TI - Optimal Co(OH)2 Nanowire Contents in Graphene Nanosheet Electrode on Its Electrochemical Performance of Supercapacitor. AB - Graphene/Co(OH)2 nanowire composite films were successfully synthesized using a simple three-step treatment, and the effect of the Co(OH)2 nanowire content on the electrochemical properties of the composite films was studied in this study. One-dimensional Co(OH)2 nanowires were homogeneously embedded and dispersed between the prepared graphene papers, forming a layered graphene/Co(OH)2 nanowire hybrid structure. These composite films exhibited better electrochemical properties than the previously reported graphene composites with carbon spheres such as graphene/CNT composites. These graphene composites were fabricated using the same method we used in this study but without the addition of Co(OH)2 nanowires. The addition of a small amount of Co(OH)2 to reduced graphene oxide (rGO) (RGO:Co(OH)2=5:1) yielded thick paper-like rGO/Co(OH)2 sandwiches, which showed an excellent specific capacitance of 1032.57 Fg-1 at a scan rate of 5 mVs 1. These results indicate the potential of these composites for the development of highly capacitive energy storage devices for practical applications. PMID- 30469188 TI - Electrically Conductive Adhesives and the Shingled Array Cell for High Density Modules. AB - The shingled array of solar cells has the advantages of a larger active area and smaller current density than conventional solar cells. Because the power loss is mainly driven by the decrease in current density, this new method has the benefit of increasing module power with the same installed area as used in other methods. As the electrically conductive adhesive (ECA), CA3556HF was chosen and characterized by analysis of reflectance and sheet resistance. These analyzed data show consistent and relevant results for the cell efficiency of separated and serially connected cells fabricated by means of the shingled array method. We successfully demonstrated the increase of the high density module (HDM) power by 5.1% for a 30 cm*30 cm area and the fill factor also increased by 2% compared with conventional modules. PMID- 30469189 TI - New Observation Structural Change from O3 to P2 Type by Changing Sodium Contents for Na-Ion Batteries. AB - Stable Na+-ion-storage cathodes with adequate reversible capacities are increasingly needed for the application of Na-ion batteries in large-scale, low cost electric storage systems. Ion-storage oxides have been classified into P2- and O3-type phases based on their sodium content. There have been few studies on the structural stability and electrochemical properties of such oxides. Here, we report the synthesis of a sodium-ion battery (SIB) cathode material Nax[Ni0.8Co0.1Mn0.1]O2 (x = 0.67, 1) using a hydroxide co-precipitation method. The effects of different sodium contents on the structural and electrochemical properties of this cathode material were studied. The results indicated better electrochemical performance of the P2-type materials compared to the O3-type in terms of high discharge capacity and good cycling performance. The P2 Na0.67[Ni0.8Co0.1Mn0.1]O2 cathode exhibited a good charge storage capacity of 108.74 mAhg-1, with a capacity retention of over 67% after 50 voltage cycles (between 2.0 and 4.5 V) at 0.1 C. The developed material may potentially be used as a cathode in sodium-ion batteries. PMID- 30469190 TI - Double GaAs/Si Heterojunction Layers in Si Solar Cells Fabricated by Electron Beam Evaporation. AB - We investigated silicon solar cells with double gallium arsenide heterojunctions. Both p-type and n-type GaAs were deposited on the back and front side of the Si pn junction using an electron beam evaporator under a high vacuum condition to fabricate ppnn cells, respectively. The ppnn cell with a micro-textured Si surface showed enhanced quantum efficiency by about 10% in the shorter wavelength region and by about 1% in the longer wavelength region compared to ppnn cell with nanotextured Si surface. Moreover, the average minority carrier lifetime was increased by 1 MUs and conversion efficiency was increased by 0.74% for the micro ppnn cell despite its high series resistance. Morphological analysis showed that GaAs thin-film on Si surface was As-rich in the as-deposition case. It became distorted at higher annealing temperatures, leading to formation of cracks. Moreover, annealing of the deposited GaAs on a nano-textured Si surface at 100 degrees C for 30 min resulted in formation of GaAs nanodots in an amorphous GaAs matrix. PMID- 30469192 TI - Numerical Investigation for Scale-Up of an Electron Cyclotron Resonance Plasma for Fluorine-Doped Tin Oxide Thin Film Production. AB - A low-temperature process is required to deposit fluorine doped tin oxide (FTO) as a transparent conductive oxide on polyethylene terephthalate (PET) substrate, as the latter is polymeric and has a low melting point. An electron cyclotron resonance (ECR) plasma system is the best way to deposit metal oxide with high transparency and electrical conductivity at temperatures below 100 degrees C. Characteristics of an ECR plasma include its high ionization energy and electron density; however, its use is limited in large-scale deposition. In order to overcome this limitation, a large-scale ECR plasma system with a dual microwave generator was designed by numerical investigation of a laboratory-scale ECR plasma system. FTO films prepared in the laboratory-scale and large-scale systems were compared. The change in electrical resistivity and optical transmittance with deposition pressure in the large-scale ECR plasma system with dual linear microwave generator is similar to that observed in the laboratory-scale ECR plasma system. The velocity distribution of active species near the substrate in the large-scale ECR plasma system showed a very similar pattern to that in the laboratory-scale ECR plasma system over a range of 1.5*10-2 to 0.8*10-2 m/s. The electrical resistivity and optical transmittance of FTO films deposited by a large-scale ECR plasma system using a dual microwave generator had respective values of 4.3*10-3 ~ 9.18*10-3 Omega .cm and 86.5~88.2%. PMID- 30469191 TI - Polypropylene/Silica Aerogel Composite Incorporating a Conformal Coating of Methyltrimethoxysilane-Based Aerogel. AB - Silica aerogels possess low thermal conductivity but have a brittle nature, while their polymers tend to exhibit enhanced mechanical properties. In this study, we introduce a new approach to overcoming this brittle property of silica aerogels. Polypropylene/silica aerogel composites were prepared by thermally induced phase separation followed by a supercritical CO2 drying method. Silica aerogel was formed onto a polypropylene scaffold using a two-step sol-gel process with methyltrimethoxysilane as the silica precursor. Enhancement of the mechanical properties of the polypropylene/silica aerogel composite compared with a pristine methyltrimethoxysilane-based silica aerogel was observed. The effects of the latter on the microstructure and physical properties of the polypropylene/silica aerogel (hereafter referred to as the polymer matrix aerogel) composite were investigated. Compared with the polypropylene monolith, the polymer matrix aerogel composite demonstrated enhanced surface-chemical and microporous structural properties such as higher hydrophobicity (135 degrees ), pore volume (0.18 cm3/g), average pore diameter (12.55 nm), and specific surface area (57.2 m2/g). This novel approach of incorporating methyltrimethoxysilane-based silica aerogel onto polypropylene when synthesizing the polymer matrix aerogel composite shows great potential as a durable superhydrophobic and corrosion resistant thermal insulating material. PMID- 30469193 TI - Water Resistances of Ag2O-, BaO-, and CuO-Doped V2O5-P2O5-TeO2 Glass Sealants. AB - V2O5-P2O5-TeO2, a low-temperature vanadate-based glass sealant, was doped with metal oxides (MO = Ag2O, BaO, or CuO), which generate Ag, Ba, and Cu ions, respectively, to strengthen the glass structure and improve its water resistance. These ions reduce the number of nonbridging oxygen atoms in the glass structure by forming V-O-M or P-O-M crosslinks in the V2O5-P2O5 glass system. Structural analysis using Fourier-transform infrared spectroscopy indicated that the numbers of P-O-P, V?O, and V-O-V bonds decreased with increasing metal oxide content. Thermal property analyses revealed that the glass transition temperatures increased by approximately 2-30 degrees C and that the coefficients of thermal expansion only varied within approximately +/-10*10-7 K-1 among all the glass samples. The contact angles were measured to quantify the wetting properties of the doped glasses. The contact angle increased from 11 to 36 degrees with increasing metal oxide content at 410 degrees C. As an indication of the water resistances of the doped glasses, the dissolution rates of the 9 mol% Ag2O-doped and pure glasses were 0.078 and 0.523 g cm-2, respectively. PMID- 30469194 TI - Highly Efficient Organic Light-Emitting Diodes Based on Naphthoanthracene Derivatives Containing Different Arylamines. AB - Herein, we designed and synthesized emitting materials based on naphthoanthracene with the different arylamino-substituents. Organic Light Emitting-Diodes (OLEDs) devices using these materials were fabricated in the following sequence; ITO/N,N' diphenyl-N,N'-(2-napthyl)-(1,1'-phenyl)-4,4'- diamine (NPB) (500 A)/Emitters (400 A)/Alumium quinolate (Alq3) (150 A)/lithium quinolate (Liq) (20 A)/Al (1000 A). All devices showed efficient emissions. In particular, a device using 4-((5,5 dimethyl-9-phenyl-5H-naphtho[3,2,1-de]anthracen-3-yl)(phenyl)amino)benzonitrile as an emitter exhibited the luminous efficiency, power efficiency, and external quantum efficiency of 9.15 cd/A, 6.36 lm/W, 2.72% at 20 mA/cm2, respectively, with the Commission Internationale d'Enclairage (CIE) coordinates of (0.30, 0.62) at 6.0 V. PMID- 30469195 TI - Effect of NaF Removal on the Upconversion Phosphor NaYF4:Yb3+, Tm3. AB - To improve the light conversion efficiency of the upconversion phosphor NaYF4:Yb3+, Tm3+ for use in solar cells, its phosphor surface was treated by removing the NaF phase from the surface of the NaYF4 host crystals. The surface of the phosphor was treated by a simple procedure consisting of washing, filtering, and drying. It is confirmed that the NaF compound is efficiently eliminated from the surface of NaYF4-based phosphors by this surface treatment. The experimental results strongly suggest that the removal of NaF from the surface of the NaYF4:Yb3+, Tm3+ phosphor reduces surface defects and enhances the photoluminescence characteristics of upconversion phosphors. PMID- 30469196 TI - High Sensitivity Polarimetric Optical Fiber Pressure Sensor Based on Tapered Polarization-Maintaining and Fiber Bragg Grating. AB - In this paper, we propose a high sensitivity polarimetric optical fiber pressure sensor (OFPS) using a polarization-diversity loop composed of a polarization beam splitter, polarization controllers, and a sensor head. The sensor head consists of 8-cm-long tapered panda-type polarization-maintaining fiber (PMF) and a fiber Bragg grating (FBG) directly spliced with PMF, and the sensor head is located inside a pressure chamber. A pressure-induced birefringence change due to the photoelastic effect can be greatly enhanced at the tapered section of PMF, thereby increasing the pressure sensitivity of the sensor head. The tapered PMF was fabricated using a fusion splicer, and the tapered length and center waist diameter of the tapered PMF segment were ~350 and ~56.82 MUm, respectively. At the polarization-diversity loop, PMF is used as a birefringent element to create an interference spectrum due to polarization interference. A pressure-induced birefringence change of PMF results in a wavelength shift of the interference spectrum. Because the PMF birefringence also has a cross sensitivity to temperature, the FBG is utilized for the compensation of the temperature effect on it. The resonance wavelength of the FBG is sensitive to ambient temperature changes but insensitive to changes in pressure. This spectral response of the FBG can be used to compensate additional ambient temperature changes occurred at the sensor head. The pressure sensitivity of our sensor was measured as approximately -27.70 nm/MPa, and an adjusted R2 value representing the sensor linearity was measured as ~0.9903 in a measurement range of 0-0.5 MPa. Our fabricated sensor exhibits the highest pressure sensitivity among previously reported polarimetric OFPS. PMID- 30469197 TI - AC Conductivity and Dielectric Properties of (1-x)(0.94Bi0.5Na0.5TiO3-0.06BaTiO3) xTa Lead Free Ceramics. AB - Piezoelectric ceramics such as Pb(Zr,Ti)O3 (PZT) are currently used by electronic devices because of their superb properties. Lead-based ceramics has caused a lot of environmental problems due to their toxicity. So, lead-free ceramics have been studied as an alternative method due to the toxicity of lead-based ceramics. Lead free energy harvesting application (Bi0.5N0.5)TiO3-BaTiO3 (BNT-BT), is famous for its excellent piezoelectric and electrical properties. The substitution of BNT-BT and Ta5+ also is very effective in improving the relative dielectric permittivity and electrical properties. Because of the device performance depends on the relative dielectric permittivity, temperature and frequency of ceramic are very important condition. In this study, the electrical and relative dielectric permittivity of substitution of BNT-BT with Ta will be analyzed and AC conductivity depending on temperature and frequency will be shown. Also, it will calculate and analyze activation energy in different ranges of frequency. PMID- 30469198 TI - Tribological and Electrical Properties of Chromium-Doped Carbon Films Fabricated by Unbalanced Magnetron Sputtering for Medical Stents. AB - Chromium-doped carbon (Cr:C) films were fabricated by using unbalanced magnetron sputtering with chromium (Cr) and graphite (C) targets. We investigated the structural, tribological, and electrical properties of the Cr:C films fabricated with various target power densities. The surface of all the Cr:C films was smooth and uniform, and the cross section showed a more compact and clear columnar structure as the target power density increased. The root mean square surface roughness increased and the contact angle on the film surface increased with the increase in target power density. Furthermore, the hardness and elastic modulus of the Cr:C films showed improvements, while the resistivity decreased with the increase in target power density. These results are associated with the ion bombardment and resputtering owing to the effects of the applied target power density. PMID- 30469199 TI - Optimization of a Solution-Processed Quantum-Dot Light-Emitting-Diode with an Inverted Structure. AB - Colloidal quantum-dot based light-emitting diodes (QD-LEDs) are attractive for use in display devices because of the remarkable electrical and optical characteristics of colloidal quantum dots. An inverted structure may be one method to achieve the necessary multilayer device structures in QD-LEDs. In this study, each layer of an inverted-structure QD-LED was optimized. The effect of the solvent on the hole transfer layer was investigated, along with the effect of the concentration of the electron transfer layer, the effect of the co-solvent on the hole transfer layer, and the effect of the concentration and solvent of quantum dot layer. The quantum dots and ZnO NPs were synthesized as the emitting layer and carrier transporting layer using a solution-mediated process. The inverted QD-LED device showed a luminance of 3,762 cd/m2, current efficiency of 1.86 cd/A, and EQE of 1.18%. PMID- 30469200 TI - Improved pH Sensitivity and Reliability for Extended Gate Field-Effect Transistor Sensors Using High-k Sensing Membranes. AB - In this study, we fabricated extended-gate (EG) field-effect transistor (FET) pH sensors with dualgate (DG) structures, using a range of dielectric sensing membranes (SiO2, Si3N4, HfO2 and Ta2O5) to vary their sensitivity. The fabricated EGFETs consisted of a silicon-on-insulator (SOI)-based metal-oxide semiconductor field-effect transistor (MOSFET) transducer and an EG sensor. We amplified the sensitivity of the device far beyond the Nernst limit (59 mV/pH), which is the theoretical maximum of conventional ion-selective FET (ISFET) sensing, by applying capacitive coupling. Among the evaluated dielectric sensing membranes, we obtained the highest sensitivity (478 mV/pH), low hysteresis (100.2 mV) and drift rate (24.6 mV/h) from the pH sensor with a Ta2O5 membrane. Hence, we expect DG FET configurations using Ta2O5 films as EG sensing membranes to be useful for high performance biosensor applications, as they satisfy the requirements for sensitivity, stability and reliability. PMID- 30469201 TI - Study of Annealing Influence on Basic Properties of Indium Tin Oxide Nanorod Films Deposited Using Glancing Angle Ion-Assisted Electron Beam Evaporation. AB - Indium tin oxide (ITO) nanorod films were deposited onto glass slides and Si wafers using ionassisted electron beam evaporation with a glancing angle deposition technique. The annealing influence on the basic properties of the as deposited ITO nanorod films was studied in the range of 100-500 degrees C for two hours in air. The crystallinity of the ITO nanorod films was enhanced with the increasing annealing temperature, and the average transmission of the as deposited ITO nanorod films in the visible range was 90%. This value did not change significantly after the annealing process. The optical bandgap of the as deposited ITO nanorod films was 3.94 eV and increased slightly after annealing. The sheet resistance of the as-deposited ITO nanorod films was 12.9 Omega/ and increased to 57.8 Omega/ at an annealing temperature of 500 degrees C. The as deposited ITO nanorod films showed nanorod structures with average diameters of 79 nm, which changed slightly with the annealing temperature. The root mean square roughness of the as-deposited ITO nanorod films was 7.9 nm and changed slightly with annealing. The as-deposited ITO nanorod films had an average contact angle of 110.9 degrees , which decreased to 64.2 degrees at an annealing temperature of 500 degrees C. The experimental results showed that varying the annealing temperature influenced the structural, electrical and wettability properties of the ITO nanorod films while the optical properties and surface morphology were almost unaffected. PMID- 30469202 TI - Low-Temperature Process for Direct Formation of MoS2 Thin Films on Soda-Lime Glass Substrates. AB - To obtain molybdenum disulfide (MoS2) patterns without any mechanical problems caused by the transfer process, direct current (DC) sputtering and rapid thermal processing (RTP) were used to form MoS2 instead of the conventional chemical vapor deposition (CVD) process. To form MoS2 on a soda-lime glass substrate at temperatures below 600 degrees C, MoS2 films were deposited at various DC sputtering powers and annealed at various temperatures from 400 degrees C to 550 degrees C. From the scanning electron microscope (SEM) and atomic force microscope (AFM) results, the surface morphologies of the MoS2 films can be observed, depending on the sputtering power and the film thickness. The Raman spectrum results showed that the E12g and A1g mode peaks appeared at approximately 372 cm-1 and 400 cm-1, respectively, and the MoS2 surface was crystallized in the in-plane direction. The X-ray photoelectron spectroscopy (XPS) results showed noticeable S 2p (2p3/2, 2p1/2) peaks and Mo 3d (3d5/2, 3d3/2) peaks at stable binding energies after RTP at temperatures below 600 degrees C. The high mobilities and carrier densities of all the MoS2 films can be investigated from the Hall measurements. PMID- 30469203 TI - Photovoltaic Properties and Series Resistance of p-Type Si/Intrinsic Si/n-Type Nanocrystalline FeSi2 Heterojunctions Created by Utilizing Facing-Targets Direct Current Sputtering. AB - p-Type Si/intrinsic Si/n-type nanocrystalline iron disilicide heterojunctions were created by utilizing facing targets direct-current sputtering at the pressure of 1.33*10-1 Pa that investigated the photovoltaic properties. They exhibited a large leakage current and a small energy conversion efficiency of 0.62%. From using the method of Nicollian and Brews, the series resistance (Rs) values at zero bias voltage were 7.40 Omega at 2 MHz and 7.57 Omega at 50 kHz, respectively, which were in agreement with that estimated by the means of Norde. From applying the method of Hill-Coleman, the interface state density (nss) values were 3.15*1015 cm-2 eV-1 at 50 kHz and 8.93*1013 cm-2 eV-1 at 2 MHz. The obtained results revealed the presence of Rs and nss at the junction interface, which should be the potential cause of spoiled photovoltaic performance in the heterojunctions. PMID- 30469204 TI - Breakdown Voltage of a Floating Metal Ring Using Mo Metal. AB - Silicon Carbide (SiC)-based devices have been proposed to replace conventional silicon-based devices based on their physical properties and have become an active research topic. Several studies have reported a high breakdown voltage in SiC-powered devices in the implanted limited field ring structure. However, the problems of ion-implanted edge termination in field-limited rings appear to be associated with the ion implantation process, such as damage to the grid and leakage current increases due to ion implantation. In this paper, SiC Schottky Barrier Diode (SBD) Floating Metal Ring (FMR) edge-termination structures are produced regardless of whether we are using ion implantation and proceed with the breakdown voltage comparison. The experimental method for producing an SiC SBD after FMR structural design through a simulation was performed with a comparative analysis of the breakdown voltage with No-FMR and FMR. We measured the breakdown voltage of the fabricated No-FMR and FMR, and the results confirmed that FMR SiC SBD was approximately 35% higher than the breakdown voltage No-FMR. It was confirmed that the breakdown voltage increased due to the balancing effect of the electric field structure of FMR. PMID- 30469205 TI - Highly Transparent Conducting Indium Tin Oxide Thin Films Prepared by Radio Frequency Magnetron Sputtering and Thermal Annealing. AB - High-quality ITO (indium tin oxide) films were grown by radio frequency (RF) magnetron sputtering and post thermal annealing. Both the thermal annealing temperature and the atmosphere significantly influenced the optical and electrical properties of ITO films. The as-grown 110-nm-thick ITO film showed an optical transmittance of 34.2% at a wavelength of 550 nm and electrical resistivity of 9.2*10-4 Omegacm. Notably, the ITO films annealed at 850 degrees C for 1 min in nitrogen ambient led to a significantly improved optical transmittance (97.3%) and the low electrical resistivity of 1.3*10-4 Omegacm, while those annealed in air or oxygen ambient produced poorer electrical properties despite their good optical transmittance owing to the presence of oxygen. The high quality of the ITO film annealed in nitrogen could be attributed to the combined effects of effective suppression of oxygen incorporation into films (thus maintaining oxygen vacancies in the ITO film), enhanced Sn doping, and improved the crystallinity with larger grain size. PMID- 30469206 TI - Thermal and Optical Performance of Glass Cloth Reinforced Organic-Inorganic Hybrid Polymer Composite Film. AB - Recently there has been considerable interest in flexible display as the next generation display. The flexible plastic has been recommended as a strong candidate for substrate, but these plastic substrates have many problems to provide the comparable properties of dimensional stability, thermal stability, and solvent resistance to glass in order to apply conventional thin film transistor technology to flexible display. Then in this study, a glass cloth reinforced polymer (GCRP) composite was prepared. To improve the thermal property, glass cloth with an excellent coefficient of thermal expansion (CTE) for reinforcement and organic-inorganic hybrid nanomaterial with polyhedral oligomeric silsesquioxane (POSS) material having excellent heat resistance were introduced to ensure the excellent properties like transmittance, haze, yellow index, thermal stability and chemical resistance. The optical property of GCRP composite was measured by using a spectrophotometer and the CTE of GCRP composite was observed by thermomechanical analysis (TMA). PMID- 30469207 TI - Improved Electrical Performance of SiO2-Doped Indium Zinc Oxide Thin-Film Transistor. AB - In this study, we investigated the effect of oxygen content on the stability and the role of silicon in amorphous SiO2-doped indium-zinc-oxide thin film transistor. The SiO2-doped IZO (SIZO) thinfilms were deposited at room temperature by radio-frequency magnetron co-sputtering. To optimize stability and electrical performance, we changed the amount of oxygen by changing oxygen gas ratio in reactive sputtering (11%, 12%, and 13%) and used SiO2 target to deposit SIZO active layer. By adjusting the parameters of SIZO thin-film transistor (TFT) preparation, we found that the best performance was obtained when the oxygen ratio of a-SIZO films was 11%. The optimized a-SIZO TFT exhibited an on/off current ratio (Ion/Ioff) of 2.1*107, saturation mobility (MUsat) of 53.6 cm2/V . s, threshold voltage (Vth) of -7.3 V, and subthreshold swing (S.S.) of 1.7 V/decade. Compared to a-IZO films, the a-SIZO film showed better stability and electrical performance because it had fewer oxygen vacancies and defects. PMID- 30469208 TI - Fabrication of an Aluminum-Based Thermoelectric Module Substrate via Anodization and Nickel Plating. AB - In this study, a thermoelectric module substrate was fabricated by subjecting an aluminum plate to a surface treatment process. To achieve this, the aluminum based substrate was carried out to electrolytic etching, anodization, and Ni plating. The anodization of aluminum created an oxide film, which served as an insulation layer, while the Ni plating formed a conductive circuit layer. The substrate fabricated in this study exhibited excellent insulation performance, demonstrating its potential for future use in thermoelectric module substrates. Its adhesion properties were verified using a cross-cut adhesion test; microstructures of the surface and cross-section revealed the successful formation of the oxide film and Ni circuit layers on the aluminum base. From the results of these, it is clearly confirmed that the anodized aluminum substrate developed in this study provides suitable insulating performances and bonding nature with Ni electrode. PMID- 30469209 TI - Electron Beam Irradiated Al Doped ZnO Thin Films as Efficient Tunnel Recombination Junction for Hydrogenated Amorphous Silicon/Cu(In,Ga)Se2 Tandem Solar Cells. AB - A tunnel recombination junction (TRJ) layer for hydrogenated amorphous silicon (a Si:H)/ Cu(In,Ga)Se2 (CIGS) tandem solar cells is investigated. An Al-doped zinc oxide (AZO) thin film is applied to the TRJ, and the influence of electron beam (e-beam) irradiation on defects along the TRJ is investigated. The AZO thin films are prepared using radio frequency (RF) sputtering and the e-beam is irradiated at 200 W RF power and 2 keV DC power for 5 min. In the e-beam irradiated AZO thin film, the number of oxygen vacancies and Zn interstitials increases, which in turn strengthens the effect of defect-enhanced tunnel recombination. PMID- 30469210 TI - Development of Refractive-Index-Matched MTO/Ag/MTO Multilayer Film on Poly(ethylene terephthalate) Substrate. AB - In this study, we fabricate a transparent conductive multilayer film consisting of an Ag layer sandwiched between manganese-doped SnO2 layers (MTO/Ag/MTO) with a refractive index-matching layer (IML) on a poly(ethylene terephthalate) (PET) substrate. SiO2 (n = 1.5 @ 550 nm) and MTO (n = 2.7 @ 550 nm) are selected as the low and high-refractive-index materials. In order to evaluate the reflectance (DeltaR550 nm) and color difference (Deltab*) properties relate to the electrode pattern visibility of transparent conducting oxide (TCO) films, we systematically investigate the influence of the SiO2/MTO IMLs on the MTO (40 nm)/Ag (13 nm)/MTO (40 nm) TCO film. We find that the optical transmittance of all fabricated films are above 85% at a wavelength of 550 nm. The thickness of the IMLs exhibiting optimum characteristics is SiO2 (70, 80, 90 nm)/MTO (10 nm). In addition, the DeltaR550 nm and Deltab* of the optimized films are 2.5, 2.1, and 1.6%, and 1.4, 1.1, and 0.7, respectively. PMID- 30469211 TI - Performance Enhancement of GaN-Based Light-Emitting Diodes with Magnesium Nitride Inter-Layers. AB - High quality GaN epilayers were obtained by using a magnesium nitride (MgxNy) inter-layer. X-ray photoelectron spectroscopy (XPS) reveals Mg 2p core-level spectra from the MgxNy inter-layers. The roughness of the MgxNy layers increased with the growth time, though a prolonged processing time resulted in a decrease in the roughness. A high-resolution X-ray diffraction omega-scan rocking curve was used to reveal that the screw dislocation density (TDD) of GaN with an MgxNy inter-layer was reduced and the crystalline quality of the GaN epitaxial layer was enhanced. Furthermore, the luminous efficiency of an LED with the MgxNy layers was increased by 20% relative to a reference LED. PMID- 30469212 TI - Facile and Scalable Preparation of a MoS2/Carbon Nanotube Nanocomposite Anode for High-Performance Lithium-Ion Batteries: Effects of Carbon Nanotube Content. AB - To investigate the effects of carbon nanotube content on the electrochemical performance in MoS2/CNT nanocomposite, a simple high-energy mechanical milling method was employed to prepare nanocomposites from MoS2 and CNT. Prepared with a one-step, 24-h ball-milling method, the MoS2/CNT nanocomposite showed improved performance in terms of specific capacity after 70 cycles when compared to pure MoS2. In addition, upon studying the effects of the weight ratio between MoS2 and the CNTs at (1:2), (1:1), and (2:1), we found the MoS2/CNT-(1:2) showed the highest specific capacity (~765 mAh g-1) after 70 cycles and the best rate capability due to increased conductivity. Overall, the results suggested that the addition of conductive CNTs in MoS2 not only improves the cycling stability, but also leads to an increase in the specific capacity of MoS2/CNTs, which suggests our MoS2/CNT nanocomposite as a new and promising anode material for lithium-ion batteries (LIBs). PMID- 30469213 TI - Pressure and Temperature Dependence of Field-Induced Oscillation in Two-Terminal Device Based on Vanadium Dioxide Thin Film. AB - In this paper, we investigated the pressure and temperature dependence of the frequency and amplitude of the field-induced oscillation created in a two terminal device based on a vanadium dioxide (VO2) thin film. First, a simple oscillation circuit was constructed using a VO2-based two-terminal device, a standard resistor, and a DC power supply. Then, the frequency and amplitude variation of the field-induced oscillation was observed for pressure changes applied to the VO2 device in a pressure chamber. This variation of the oscillation characteristics was also examined for ambient temperature changes applied to the VO2 device using a plate heater. When the chamber pressure increased from 0 to 5 MPa with a step of 1 MPa at 25 degrees C, the oscillation frequency increased from ~592 to ~739 kHz, and the oscillation amplitude decreased from ~12.60 to ~11.40 V. Similarly, when the heater temperature increased from 25 to 50 degrees C (step: 5 degrees C) without applied pressure, the oscillation frequency increased from ~592 to ~819 kHz, and the oscillation amplitude decreased from ~12.60 to ~7.16 V. Owing to linear pressure and temperature responses of the VO2 oscillation, the pressure and temperature sensitivities of the oscillation frequency and amplitude could be obtained as four different constant coefficients from the measurement results. These coefficients can be directly utilized for simultaneously measuring pressure and temperature variation applied to the VO2 device, which can be beneficially applied to localized temperature and pressure sensing at a very small area less than 1 mm2. PMID- 30469214 TI - Conducting Super-Hydrophobic Thin Film for Electric Heating Applications. AB - Frost presents a serious problem for the human environment, resulting in such phenomena as downed power lines, damaged crops and stalled aircraft. In addition, frost and ice accumulation significantly decrease the performance of ships, wind turbines, and HVAC systems with high failure risk. Super-hydrophobic (SH) surface can be an appropriate solution for frost problems, due to its anti-icing properties that can prevent ice nucleation on the surface. In addition, in the case of conducting SH surface using carbon nanotubes (CNTs) as a filler, it can form an excellent heating unit, owing to the resistive heating effect. The purpose of this study is to produce a large-area conducting SH film that can prevent ice nucleus and remove ice formation rapidly. High aspect ratio carbon nanotubes (CNTs) as a conducting filler and adhesive polymer resin as a binder were used to form coating layer. In addition, silica particles (~7 nm) were used to stabilize nano-size roughness of the SH surface. Wet and dry etching processes were used on the substrate to improve wettability and to produce organic functional groups. To evaluate the de-icing effect, the fabricated SH surface was rapidly heated to 150 degrees C by applying voltage. PMID- 30469215 TI - Alkaline Hydrothermal Synthesis, Characterization, and Photocatalytic Activity of TiO2 Nanostructures: The Effect of Initial TiO2 Phase. AB - One-dimensional (1D) titanate nanostructures were synthesized by hydrothermal route, using commercially available TiO2 (P25) and anatase powders as precursor materials and strong NaOH solution as catalyzer. The prepared titanates were calcined, followed by protonation to produce TiO2 nanostructures having enhanced photocatalytic and photovoltaic properties. The synthesized TiO2 1D nanostructures were characterized using field-emission scanning electron microscope, high-resolution electron microscope, X-ray diffraction analysis, and UV-Vis photospectroscopy to understand the effect of initial TiO2 phase on morphological and crystallographic features, and bandgap. Methylene blue degradation test was applied to evaluate the photoactivity of the products obtained after different stages of the process. The findings indicate that 1D TiO2 nanostructures form by different mechanisms from dissolved aggregates during hydrothermal process, depending on the crystal structure of the initial precursor used. Photocatalytic test results reveal that protonated titanates have considerable adsorption capability, while photocatalytic degradation depends on TiO2 transformation. PMID- 30469216 TI - Mitigation of Volume Expansion of Silica Anodes by Porous Titanium Dioxide Coating for Lithium-Ion Batteries. AB - Silica (SiO2) is one of the most promising anode materials for LIBs due to its high theoretical capacity. However, the huge volume change of silica during the lithiation/delithiation processes is a disadvantage that results in poor electrochemical performance. In this study, the volume change of silica was effectively mitigated by coating the SiO2 anode with porous TiO2. The porous TiO2 has a large amount of internal space that can mitigate the volume expansion of SiO2. To verify the ratio of the volume change, the crosssection of the electrodes was analyzed by scanning electron microscopy (SEM). The ratio of the volume change decreased from 293.5% to 140.7% upon application of the TiO2 coating. Fourier transform infrared analysis suggested that the Ti-O-Si bond helped mitigate the volume expansion. Furthermore, the decrease in the volumetric expansion resulted in good electrochemical performance with increased charge capacity and stable cycle performance. The TiO2 coated SiO2 anode displayed a capacity of 72.33 mA h g-1 at a current density of 98 mA g-1 for up to 50 cycles, which was higher than that of the pristine SiO2 anode (42.29 mA h g-1). The TiO2 coated anode materials are applicable for rechargeable lithium-ion batteries. PMID- 30469217 TI - Effect of Surface Modifications and Their Reaction Conditions on Multi-Walled Carbon Nanotubes for Thermal Conductive Composite Material. AB - Thermally conductive composite materials were fabricated using Al2O3 and surface modified MWCNTs on an ETDS matrix. The MWCNT surfaces were modified using a solution containing H2O2 and H2SO4/HNO3 and examined at various reaction times. After surface modification, the ratios of the functional groups introduced were compared. The changes in MWCNT morphology and thermal conductivity were also investigated for various reaction times. It was observed from the results that the MWCNTs exposed to 1 h acid treatment had the highest thermal conductivity without any decrease in their length. Based on the optimum oxidization of MWCNTs, further surface modification was performed using APTES, a silane coupling agent, using two different reactions. After the reaction, large particle aggregations were observed on the amine-terminated MWCNTs, which reacted with a mixture of EtOH and DI water. These agglomerates did not re-disperse after long-time sonication. However, the silanol-terminated MWCNTs were easily dispersed in EtOH via sonication, and their composite materials had outstanding thermal conductivities. Moreover, more amount of MWCNTs were processable using the same Al2O3 and ETDS concentrations, which also led to enhanced thermal conductivities compared to the other surface modification methods. PMID- 30469218 TI - Thermoelectric Properties of Cu-Doped Bi2Te2.7Se0.3 Fabricated by Hot Pressing. AB - Owing to the energy and environmental issues, energy recovery technologies attract an increasing interest. Thermoelectric power generation is a recycling technology, which directly converts heat energy into electric energy by reusing waste heat. In this study, n-type Bi2Te2.7Se0.3 thermoelectric materials doped with Cu were fabricated by hot pressing. The Bi-Te system has excellent thermoelectric properties in the middle- and low-temperature ranges; when a certain amount of Cu dopant is added, the thermoelectric properties are improved. The thermoelectric properties of the samples doped with Cu were compared with those of the intrinsic Bi-Te-based sample without Cu doping. In addition, the effects of the Cu concentration on the thermoelectric-material structures were investigated. PMID- 30469219 TI - Spring-Based Active Shock Absorber Systems with Piezoelectric Energy Harvesters. AB - In this research, energy harvesters with different types of spring-based shock absorbers were invested for the active shock absorber applications. Two different types of spring-based shock absorbers were prepared for the comparison, coil type spring-based shock absorbers and specially designed slice type spring-based shock absorbers. Shock absorbers have been widely employed to protect the complicated main system by cancelling the applied mechanical forces from outsides. Therefore, in the classical points of view, shock absorber can be prepared by the elastic materials to store and release the applied mechanical energy with sequentially in the form of elastic energy, thermal energy, and sound energy. However, in recently, there are strong demands to replace this classical shock absorber to the energy harvesters, which can collect the wasted energy in the form of electrical energy. Therefore, in this research, alternative two different types of spring-based advanced shock absorber will be presented and discussed. To combine with the spring-based shock absorber, multilayered piezoelectric energy harvesters were attached to collect the applied mechanical energy. PMID- 30469220 TI - 60 mA Bidirectional Current Gating in Vanadium-Dioxide-Based Planar Device Using CO2 Laser. AB - Here we show 60 mA bidirectional current gating in a two-terminal planar device based on a highly resistive vanadium dioxide (VO2) thin film by harnessing photothermally induced phase transition occurred in VO2 when irradiating the VO2 film with a CO2 laser oscillating at 10.6 MUm. The VO2 thin film was grown by a pulsed laser deposition method, and the two-terminal planar device was fabricated using the VO2 film isolated with sub-millimeter dimensions. The bidirectional current gating between 0 and 60 mA was accomplished by irradiating the VO2-based device with repetitive pulses of the CO2 laser. In terms of laser modulation parameters such as the pulse width and repetition rate, their effect on the transient responses of laser-gated currents was also investigated. With a minimum energy per pulse of ~766 mJ, a stable bidirectional current gating of up to 60 mA could be successfully implemented for the repetition rates of 0.5-3.0 Hz in a VO2 device biased at ~5.4 V, showing a switching contrast between off- and on-state currents of ~11089. This maximum onstate current (60 mA) and switching contrast are the highest values among previous gating results attained in VO2 devices with a CO2 laser. PMID- 30469221 TI - Performance of Perovskite Solar Cell Using Compact Layer by Sputter Deposition. AB - A uniform compact layer is essential for obtaining high-efficiency perovskite solar cells (PSCs). This is because direct contact between the FTO glass substrate and the perovskite layer should be blocked to suppress electron recombination and to collect electrons. In the present study, PSCs were fabricated using sputtered TiO2 compact layers prepared at different deposition times. The structure, morphology, and electrical properties of the sputter deposited TiO2 compact layer were compared to those of a spin coated TiO2 film. The TiO2 compact layer prepared by the sputtering process was very smooth and inhibited electron recombination at the FTO interface, resulting in a higher open circuit voltage and a higher short circuit current density. A photoelectric conversion efficiency of 13.37% was obtained using the TiO2 compact layer deposited for 30 min. PMID- 30469222 TI - Spinning of Photocatalytic Fiber as Splittable Segmented-Pie Bi-Component Fibers for Antibacterial Textiles. AB - The increase of public concern regarding hygienic living environments has accelerated research on anti-microbial modifications for many commodity and technical textile products. This study attempted to produce a durable self cleaning and antibacterial textile material with a relatively low production cost using inorganic photocatalytic nanoparticles embedded in the textile fibers. The spinning of segmented-pie bi-component fibers was conducted using compositions of polyethylene and nylon 6 with 1.0% of TiO2 as photocatalytic particulate filler. A lab-scale double-extrusion fiber spinning system was used to spin the filament fibers with differing winding speeds of 300 m/min, 500 m/m, and 700 m/m. The extruded round fibers were split into minuscule pie-shaped filaments, which significantly increased their photocatalytic surface areas. The compositions and morphologies of the split filaments and the TiO2 particles in the filaments were characterized by optical microscopic images. Scanning electron microscopic images were used to investigate particles secured on the filament surfaces. The antibacterial effects of the fibers were assessed using a modified method based on the standard method, AATCC100: Assessment of Antibacterial Finishes on Textile Materials, by adding a visible light source above the test samples. The filament samples were tested with the two test organisms of Staphylococcus aureus and Klebsiella pneumoniae. The numbers of bacteria present were determined, and the percent reduction for the specimens with fibers embedded with TiO2 and that with fibers without TiO2 were calculated. The segmented-pie bi-component fiber with 1.0% TiO2 showed enhanced bioactivity against both species of tested bacteria. PMID- 30469223 TI - Synthesis of Sulfonation Poly(N-propylsulfonicacid isatin biphenylene) for Polymer Electrolyte Membrane Fuel Cell Containing SiO2 Nanocomposite Membrane. AB - Polymer containing isatin was synthesized by super acid-catalyzed carbon-carbon coupling reaction. Propylsulfonic acid was grafted on isatin unit by substitution reaction with potassium salt of 3-bromo-1-propanesulfonic acid. The sulfonic acid composition was regulated at 25~80 mol% of propylsulfonic acid in order to achieve expected ion exchange capacity of maximum 2.0 meq/g. The copolymers were of high molecular weight (inherent viscosity, etainh = 1.2 dL/g) to afford a tough membrane by solution casting. Composite membranes were prepared by sulfonated polymer and SiO2 nanoparticles (20 nm, 4~10% wt). All these composite membranes were casted from the solution of sulfonated polymer in dimethylsulfoxide (DMSO) to afford 25 MUm. The structural properties of the synthesized polymers were investigated by 1H NMR spectroscopy. The membranes were studied by ion exchange capacity (IEC), water uptake, dimensional stability and proton conductivity assessment by comparing with Nafion(r). As increasing the IEC values, the small hydrophobic components induced high proton conductivities and proton diffusion coefficients. These kinds of membranes without ether linkages showed low water swelling as well. PMID- 30469224 TI - Diode Parameters of Heterojunctions Comprising p-Type Ultrananocrystalline Diamond Films and n-Type Si Substrates. AB - In the current research, heterojunctions comprising p-type ultrananocrystalline diamond/hydrogenated amorphous carbon composite (UNCD/a-C:H) films and n-type Si substrates were formed via pulsed laser deposition. To extract their junction parameters via thermionic emission (TE) theory and Norde model, the measurement of dark current density-voltage curves was carried out under various temperatures ranging from 300 to 60 K. Through TE theory, the ideality factor values at 300 K and 60 K were 2.70 and 8.66, respectively. This justified that a heavy recombination process occurs at the junction interface in addition to another tunneling process at 300 K. The tunneling process is predominant at low temperatures. The barrier height values were 0.78 eV and 0.18 eV at 300 K and 60 K, respectively. The values for series resistance (Rs) calculated via Norde model at 300 K and 60 K were 275.24 Omega and 78.66 kOmega, respectively. The increment of Rs at low temperatures was likely due to the decrease of carrier concentration in the B-doped UNCD/a-C:H films when temperature was decreased. PMID- 30469225 TI - Low Energy Effect of Electron Beam Irradiation on Si Solar Cells. AB - We investigated the change in the cell efficiency resulting from electron beam accelerated irradiation to understand the possibility of using silicon solar cells with nano-surfaces for satellites. The Si solar cells were made of 6" micro textured p-type Si wafers. The Si solar cells were fabricated using a standard cell fabrication process, including POCl3 diffusion, anti-reflection coating layer deposition, and metal contact and co-firing heat treatment. After manufacturing the cell, we irradiated the cell with a low-energy electron beam to determine its effect. We analyzed the changes in the cell resulting from the irradiation with the electron beam by evaluating the photo-reflectance, transmission electron microscopy, electroluminescence and current-voltage curve. PMID- 30469226 TI - Effects of Y2O3 Additive on Mechanical and Thermal Properties of Cordierite Mullite Ceramics. AB - Cordierite is an alumina-magnesia-silica compound widely used as a thermal shock resistant material due to its high thermal shock resistance, low coefficient of thermal expansion (CTE), low dielectric constant, and good electrical insulation. However, its narrow sintering temperature range and low mechanical strength hinder its application in ceramic heaters. Although mullite shows excellent thermal and chemical stability, heat resistance, and mechanical strength, it has the disadvantages of high sintering temperatures (1600-1700 degrees C) and poor thermal shock resistance. In this study, a composite phase was prepared by mixing cordierite and mullite to expand the narrow sintering temperature range of cordierite and adjust its CTE to be similar to that of Si. Furthermore, Y2O3 was added to reduce the sintering temperature and to increase the mechanical strength. Therefore, the composite showed the highest density of 2.5 g/cm3 at 1380 degrees C when the ratio of mullite to cordierite was 20 wt%. When 11 wt% Y2O3 was added to this composition, the highest density was 2.8 g/cm3 for a sintering temperature of 1320 degrees C, and the mechanical strength was relatively good as 180 MPa of 3-points bending strength was comparatively good. The CTE was 2.6*10-6.K-1, which was similar to that of Si. PMID- 30469227 TI - A Stretchable Graphene Thin-Film Sensor for Detecting All of Lateral and Vertical Strains. AB - In this work, we propose a stretchable graphene film sensor that can detect all of lateral and vertical strain with unique architecture in single sensor element since most approaches so far are only available for detecting either lateral or vertical strain, but not both. The sensor is fabricated with percolative networks of graphene nanoplatelet using spray-coating method for constructing strain sensing channel and electrode simultaneously. The sensor exhibits a high stretchability of 150% with a gauge factor of 8.56 (0-100%) and 19.8 (100-150%) in the two regimes, for lateral strain. The sensor also presents a high sensitivity ((DeltaR/R0)/DeltaP of -0.026 kPa-1) for vertically applied pressure in the range of 100-20,000 Pa, belonging to general human pressure perception range. Based on the sensing properties demonstrated, the proposed graphene sensor is a promising candidate for sensor that can detect both lateral and vertical strains in single sensor element. PMID- 30469228 TI - Brazing Characteristics and Bonding Strength of Pure Titanium Joints Brazed with Low-Melting Temperature Zi-17Ti-22Ni Filler Metal. AB - The brazing characteristics and bonding strengths of pure titanium joints are evaluated for joints brazed with Zr-17Ti-22Ni filler. Vacuum brazing was conducted at temperatures between the melting temperatures of the filler metals and the beta-transition temperature of pure titanium at 3 MPa of pressure for 5 min. Fracturing of the pure titanium joint brazed at 1,093 K occurred before yielding during the tensile tests owing to the presence of a serious segregation region containing harder and more brittle [Ti, Zr]2Ni intermetallic compounds. In contrast, in pure titanium joints brazed at and above 1,113 K, fracturing occurred at the base metal. The yield strengths of the samples brazed at 1,113 K 1,133 K were estimated to be in the range of 320-350 MPa and the ultimate tensile strengths likewise ranged from 350 to 380 MPa. The strength of pure titanium brazed at 1,153 K decreased rapidly. The results of this study show that the optimum temperature to ensure good performance after the brazing of pure titanium with Zr-17Ti-22Ni as a filler metal ranges from 1,113 K to 1,133 K. PMID- 30469229 TI - Fabrication of Blue Organic Light-Emitting Diodes Based on Indeno Phenanthrene/Triphenylene Amine Derivatives. AB - Among the three primary colors, blue-emitting materials are limited by the wide energy band gap. In this study, we designed and synthesized emitting materials based on indeno-phenanthrene/ triphenylene derivatives. Organic light emitting diodes (OLEDs) using these materials were fabricated in the following sequence; ITO/N,N'-diphenyl-N,N'-(2-napthyl)-(1,1'-phenyl)-4,4'-diamine (NPB) (500 A)/Blue materials (30 nm)/4,7-diphenyl-1,10-phenanthroline (BPhen) (30 nm)/lithium quinolate (Liq) (20 A)/Al (1000 A). All the devices showed efficient blue emission. Particularly, a device using 10,10-dimethyl-N,N-diphenyl-10H-indeno[1,2 b]triphenylen-12-amine as an emitter exhibited luminous efficiency, power efficiency, and external quantum efficiency of 3.62 cd/A, 1.83 lm/W, 2.82% at 20 mA/cm2, respectively, with Commission Internationale d'Enclairage (CIE) coordinates of (0.16, 0.15) at 6.0 V. PMID- 30469230 TI - Polarization-Controlled Switching of Dual-Wavelength Lines with Orthogonal Polarization in Erbium-Doped Fiber Ring Laser. AB - By incorporating an inline switching filter, which is comprised of a polarization diversified loop (PDL), two fiber Bragg gratings (FBGs) with different resonances, and three quarter-wave plates (QWPs), we propose a dual-wavelength switchable erbium-doped fiber (EDF) ring laser that can select and switch between two lasing lines with orthogonal polarization. The proposed laser is composed of EDF, a 980 nm laser diode, a wavelength-division-multiplexing coupler, a rotatable linear polarizer, an optical isolator, a 3 dB optical coupler, and the inline switching filter. At a special combination of the orientation angles of the three QWPs, the inline filter can offer a different transmittance according to input polarization, e.g., reflection spectra of one and the other of the two FBGs for linear horizontally and vertically polarized input light, respectively. At this special combination of the QWPs, one of two different resonances of the two FBGs can be selected by varying laser cavity polarization through the adjustment of the orientation angle of the rotatable linear polarizer. Consequently, switching operation between two laser lines with orthogonal polarization at the two FBG resonance wavelengths could be obtained by properly controlling cavity polarization. The polarization extinction ratio of each lasing line was measured as more than 19.9 dB. PMID- 30469231 TI - Synthesis and Characterization of Co-Mn (O)OH Nanosheets Assembled Structure Covered of Reduced Graphene Oxide Hybrid Structures by Hydrothermal Method. AB - In this study, we prepared cobalt-manganese (oxy) hydroxide nanosheets assembled structure covered of reduced graphene oxide hybrid structure (Co-Mn (O)OH NAS@rGO HS) via reduction and hydroxylation of Mn1.5Co1.5[Co(CN)6]2@graphene oxide (GO). Obtained precursors were optimized at 15 mg GO, and these are hybrid structures in which nanocubes 200-400 nm in size were fully covered by multi-layered GO. The functional group (-COOH, -OH, C-O-C) of GO was removed through reduction by L ascorbic acid. We obtained MnCOOH, Co(OH)2, and Co-Mn LDH synthesized by hydroxylation of Mn1.5Co1.5[Co(CN)6]2@GO via ion exchange between the CN group and OH-. The hybrid nanostructure between transition-metal oxide/hydroxide and reduced graphene oxide could be used in various fields, including lithium ion batteries, supercapacitors, and electrocatalyst for water splitting. PMID- 30469232 TI - Fabrication and Analysis of Perovskite Solar Cells (PSCs) by Using Phosphor and TiO2 Photoelectrode. AB - In this work, to explore the influence of phosphor additives on the conversion efficiency of perovskite solar cells (PSC), we introduce a Y3Al5O12:Ce3+ (YAG:Ce3+) phosphor layer. The YAG:Ce3+ nanophosphor acts as a light down converting material to absorb high energy photons and emit lower energy photons that match well with the absorption of the perovskite layer, yielding more excited photo-generated electron-hole pairs. Therefore, the incident solar light can be harvested more effectively. We used 8 mg/ml of TiO2 mixed with YAG:Ce3+ in the PSCs and realized a light-to-electric energy conversion efficiency of 13.34%, a short circuit current density of 21.23 mA/cm2, an open circuit voltage of 0.97 V, and a FF of 55.96%. Higher efficiencies were achieved for PSCs with phosphor mixed TiO2 than for cells with pure TiO2 nanoparticles. The samples were characterized by XRD, SEM, UV-vis, PL, and IV-curves. Photoelectrode DSSC with light-to-electric energy conversion efficiency was achieved under a simulated solar light irradiation of 100 mW/cm2 (AM 1.5). PMID- 30469233 TI - Laser-Regulated 60 mA Current Switching in VO2-Based Two-Terminal Device Using 976 nm Laser Diode. AB - By incorporating a high-power 976 nm laser diode (LD), we demonstrated laser regulated current switching in a two-terminal planar device based on a vanadium dioxide (VO2) thin film. The VO2 thin film was grown by pulsed laser deposition method and etched to sub-millimeter dimension for the fabrication of a two terminal device. The reversible current switching was implemented by controlling the on/off state of the LD, which illuminates the VO2-based device. The transient responses of the device currents were analyzed when the device was excited with laser pulses of various repetition rates of up to 5.0 Hz with a pulse width fixed as 75 ms. A switching contrast between off- and on-state currents was calculated as ~9530, and average rising and falling times were measured as ~31 and ~21 ms, respectively. PMID- 30469234 TI - Samarium-Doped Indium-Tin-Oxide Electrode for Organic Light-Emitting Devices. AB - Here in, properties of samarium-doped indium-tin-oxide (ITO:Sm) films deposited by DC-magnetron sputtering, and organic light-emitting devices (OLEDs) using an ITO:Sm film as an anode were investigated. The electrical resistivity of the ITO:Sm films increased with Sm doping. The work function of each ITO:Sm film (5.2 5.7 eV) was higher than that of an ITO film (4.8 eV). The crystal structure of the ITO:Sm films was In2O3-type when the doping ratio of Sm in the film was up to 5 at.%, and the structure was amorphous in more strongly samarium-doped films. The properties of the OLEDs were varied by the doping ratio of samarium in the ITO:Sm electrodes. The OLEDs with the ITO:Sm electrode exhibited higher efficiency than that of an ITO-based control device at the same current density. PMID- 30469235 TI - A Flexible Graphene-Polydimethylsiloxane Nanocomposite Force Sensor with Linear Response Across a Wide Pressure Detection Range. AB - As a flexible force sensor operating in the pressure range covering the entire general human pressure detection range, we developed a piezoresistive nanocomposite using graphene flakes as the conducting filler with polydimethylsiloxane (PDMS) as the polymer matrix. The homogeneous dispersion of graphene flakes allows their uniform distribution in the PDMS matrix with a low percolation threshold owing to their geometrically high aspect ratio, thus resulting in a linear piezoresistive response across a wide pressure detection range (100 Pa-1,020 kPa), when static forces are externally applied. Furthermore, the sensor shows sensitive piezoresistive responses to dynamically applied forces. Based on the characteristics demonstrated and described in this study, graphene- PDMS nanocomposites can be considered promising materials for flexible force sensors capable of describing human pressure perception ability. PMID- 30469236 TI - Performance of Cu(In, Ga)Se2 Solar Cells on Zinc Sulfide Buffer Layers for Various Power Values of an Intense Pulsed Light System. AB - The effect of using an Intense Pulse Light system has been studied on zinc sulfide thin films and Cu(In, Ga)Se2 solar cells. The deposition of thin films on the zinc sulfide buffer layer is carried out on the glass and Cu(In, Ga)Se2 using the chemical bath deposition process. These zinc sulfide thin films were then subjected to treatment at different irradiation light intensities from 500 W to 2000 W, and then the effects on the layer were compared to a thermal annealed layer. The morphology and optical transmittance of the zinc sulfide layer were analyzed by field emission scanning electron microscopy and ultraviolet-visible spectrophotometry, respectively. This methodology was also applied to fabricate and investigate the efficiency, short-circuit current density, and external quantum efficiencies of the solar cells. This analysis shows that the treatments significantly change the properties of the zinc sulfide buffer layer and performance of the Cu(In, Ga)Se2 thin film solar cells. PMID- 30469237 TI - Effect of Annealing Temperature on Morphology and Electrical Property of Hydrothermally-Grown ZnO Nanorods/p-Si Heterojunction Diodes. AB - In this study, ZnO nanorods (NRs) were synthesized using the hydrothermal method, and the effects of annealing temperature (150 degrees C-600 degrees C) on morphology, crystallinity, defects states of the NRs, and electrical property of the n-type ZnO NRs/p-type Si heterojunction diodes were investigated. No appreciable changes in the morphology and crystal structure of the ZnO NRs were observed with increasing annealing temperature up to 450 degrees C. As the temperature increased to 600 degrees C, the average length and diameter of the NRs decreased due to the partial melting and sintering in the NRs. From the X-ray photoelectron spectroscopy (XPS) results, the concentration of internal oxygen vacancies decreased with increasing annealing temperature to 450 degrees C due to thermal diffusion of oxygen vacancies to the surface. The electrical conductivity of the NRs increased to 450 degrees C, which was attributed to the increased crystallinity and low defects concentration (oxygen vacancy) in the NRs. Conversely, the electrical conductivity degraded at 600 degrees C due to the decreased effective contact area. PMID- 30469238 TI - Intermetallic Growth Mechanism and Mechanical Properties of Post-Annealed SAC305 Solder Joints on Cu-Based Electrode Interfaces. AB - Intrinsic Cu- and Ni-added Cu electrodes were prepared to study Sn-3Ag-0.5Cu lead free solder joints. Our work focused on three categories: (1) formation and role of intermetallic compounds, (2) structural and compositional change of intermetallic compounds due to thermal aging effects, and (3) mechanical bonding strength of solder joints. A series of SEM, EDX, and bonding test analyses were performed on two electrode types to study joint morphologies, the types of intermetallic compounds formed, and bonding strengths, respectively. As a result, after heat treatments at 150 degrees C for 10 h, 100 h, and 300 h, Cu6Sn5 and (Ni, Cu)3Sn4 were obtained at the interfaces of the intrinsic Cu electrode and the Ni-added Cu electrode, respectively. In the Ni-added Cu electrode samples, the growth rate of the intermetallic compounds was reduced, but the mechanical bonding strength had a higher value compared to that of the intrinsic Cu electrode. The bonding characteristics under different heat treatment conditions are also discussed. PMID- 30469239 TI - Fabrication of Water Soluble Polymer Capsules for Protecting Mineral Admixtures in Groundwater for Emergency Recovery of Sinkhole. AB - Polyethylene glycol (PEG) based water-soluble polymer composites were fabricated for mineral admixture encapsulants to be used in underground sinkhole restoration. Linear low-density polyethylene (LLDPE) and talc were added to the composites to increase their mechanical strengths and heat resistances. PEG/LLDPE/Talc composites were manufactured via melt mixing using a twin extruder. Blending PEG and LLDPE increased the mechanical properties and heat resistances of the composite, but decreased the water solubility. Talc was added to the composite to increase mechanical properties and heat resistance. The addition of talc increased the water solubilities of PEG-based composites. The highest tensile strength and impact strength were 2.89 MPa and 2.86, respectively, the increase rate being 9.63-fold relative to that of pristine PEG. PMID- 30469241 TI - Characteristics of Vanadium Oxide Thin Films Fabricated by Unbalanced Magnetron Sputtering for Smart Window Application. AB - Vanadium oxide (VOx) thin films were deposited by an unbalanced magnetron (UBM) sputtering system with a vanadium metal target and O2 reaction gas, and thermally treated at various annealing temperatures. In this work, the structural, electrical, and optical properties of the fabricated VOx films with various annealing temperatures were experimentally investigated. The UBM sputter grown VOx thin films exhibited amorphous structure, and had a very weak peak of V2O5 (002) owing to very thin films. However, the crystallite size of VOx films increased with increasing annealing temperature. The surface roughness of VOx films and average transmittance decreased with increasing annealing temperature. The resistivity of VOx films also decreased with increasing annealing temperature, while the electrical properties of films improved. PMID- 30469240 TI - Analysis of Optical Plasma Monitoring in Plasma-Enhanced Atomic Layer Deposition Process of Al2O3. AB - A noninvasive, optical plasma monitoring method in plasma-enhanced atomic layer deposition (PEALD) process for nanoscale water vapor barrier film is presented. Any equipment malfunction, as well as a deviation in the condition of individual components can easily jeopardize the process result. Al2O3 deposition process was employed in this research as a test vehicle, and high-speed optical plasma monitoring was demonstrated. It is shown that optical plasma monitoring is useful for not only measuring plasma pulses in real time, but also for the detection of any variation in plasma condition which enables inferring plasma dynamics for advanced process control in nanoscale thin film deposition process. PMID- 30469242 TI - Study on 3.3 kV Super Junction Field Stop Insulated Gate Bipolar Transistor According to Design and Process Parameters. AB - In this paper, we analyzed the electrical characteristics of 3.3 kV super junction FS IGBT as next generation power device by structural design. The device parameters were extracted by design and process simulation. Especially, to obtain optimal breakdown voltage, we researched the breakdown characteristic. To begin with, we confirmed that the breakdown voltage was decreased as trench depth was increased. And we analyzed the breakdown voltage according to p-pillar dose. As a result of experiment, we confirmed that the breakdown voltage was increased as p pillar dose was increased. To obtain over 3.3 kV, the dose of p-pillar was 5*1013 cm-2, the resistivity of epi layer was 140 Omega.cm. We will extract design and process parameters considering on state voltage drop. PMID- 30469243 TI - Effect of O2 Flow Rate on Properties of Mn-SnO2/Ag/Mn-SnO2 Multilayer Film. AB - Multilayer films with Mn-SnO2 (MTO)/Ag/Mn-SnO2 (MTO) hybrid structure were prepared on a flexible polyethylene terephthalate (PET) substrate using a DC/RF sputtering system at room temperature. The optical, electrical, and structural properties of the thus-synthesized multilayer films were systematically investigated as a function of the O2/(Ar+O2) flow rate. The transmittance of the MTO/Ag/MTO multilayer films at 550 nm increased gradually from 83.1% to 87.9% and the sheet resistance (Rs) of the multilayer films increased from 6.3 to 9.8 Omega/sq upon increasing the O2/(Ar+O2) flow rate. The highest figure of merit (phiTC) of MTO/Ag/MTO multilayer film was 45.7*10-3 Omega-1 at an O2/(Ar+O2) flow rate of 2.8%. X-ray photoelectron spectra of multilayer films obtained with different O2/(Ar+O2) flow rates showed no noticeable variation. PMID- 30469244 TI - Dispersion Optimization of Alumina Slurry with Variation of the Dispersant. AB - Plate-type alumina ceramics are widely applied as the major components in display and semiconductor manufacturing equipment. These materials are mainly produced by a filter casting method. There have been few studies on the dispersion of these slurries. Therefore, various commercial dispersants were compared and evaluated here in an effort to optimize the slurry dispersion, which affects the homogeneity characteristics in the field of alumina manufacturing. In order to optimize the slurry dispersion, three types of water-based dispersants were selected through preliminary experiments and the viscosity, frequency sweep, particle size distribution, and sedimentation height were compared under optimum conditions after optimizing the amounts of these dispersants. The amount of dispersant in each case was optimized for the 5468CF, BYK-194, and BYK-012 dispersants, after which the frequency sweep, particle size distribution, and sedimentation height were compared according to the type of dispersant. The viscosity, frequency sweep and sedimentation height were thus measured, and it was confirmed that BYK-012, 5468CF and BYK-194 all had excellent dispersibility, in that order. As a result, it could be confirmed that the condition under which BYK-012 was added, at 0.9 wt%, led to the best dispersibility. In addition, microstructural changes of sintered body samples according to the type of dispersant used were observed. These observations indicated that the microstructure of BYK-012 at 0.9 wt% with excellent dispersibility led to suppressed grain growth with a finer pore size. PMID- 30469245 TI - Electrical Properties of the Carbon-Nanotube Composites Film Under Extreme Temperature Condition. AB - Carbon nanotube (CNT) composites have been widely investigated for electric heating applications (such as water heater, de-icing unit, and patternable micro heaters) owing to their rapid heating, flexibility and light-weight properties. For practical use of CNT composite as heating element applications, the change of resistance with varying temperature must be interpreted. In this study, electric heating behavior of CNT/Nylon 6 composite film (10 wt%) and CNT/Polydimethylsiloxane (PDMS) composite film (10 wt%) were evaluated by measuring the change in normalized resistance under extreme temperature from -50 degrees C to 100 degrees C. While CNT/PDMS composite film showed 25% normalized resistance change from -50 degrees C to 100 degrees C, in the case of CNT/Nylon 6 composite film, only 10% normalized resistance change was shown. The difference of resistance change is attributed to the difference of the polymer's coefficient of thermal expansion (CTE), which is a crucial factor to consider in the design of CNT composites as a heater or heating sensor. CNT/Nylon 6 composite film is appropriate for flexible heating unit and de-icing application, due to the lower degree of resistance change than that of CNT/PDMS composite film. In addition, a thermal cycling test was conducted to determine the thermal stability and repeatability of CNT composites. PMID- 30469246 TI - Effect of the Active Channel Thickness Variation in Amorphous In-Zn-Sn-O Thin Film Transistor. AB - Ternary oxide thin films in the In2O3-ZnO-SnO2 system were studied for potential applications in oxide semiconductor thin film transistors (TFTs). An amorphous In Zn-Sn-O (a-IZTO) active channel layer was deposited by RF magnetron sputtering at room temperature on an n++ Si substrate. Films from a sintered ceramic target with a nominal chemical composition of In:Zn:Sn = 40:50:10 at.% were prepared with thicknesses ranging from 15 nm to 150 nm, which was followed by annealing at 350 degrees C for 30 minutes in air. Subsequently, a bilayer Cu/Ti metal contact was deposited as the source/drain electrodes on the top surface through a shadow mask using an e-beam evaporator. The thickness of the active channel layer greatly influenced the characteristics of the oxide thin film transistors. The best transistor characteristics were observed from the test device with a channel thickness of 30 nm and a high on/off current ratio of approximately 108, high field effect mobility of 25 cm2/Vs, low threshold voltage of -0.1 V, and very small subthreshold swing of 0.14 V/dec. PMID- 30469247 TI - Production of Cu@SiO2 Core-Shell Nanoparticles with Antibacterial Properties. AB - Antimicrobial agents based on organic materials have limited use owing to their low heat resistance and short lifetimes. Therefore, various studies on antibacterial agents that are based on inorganic material systems are increasingly being performed to supplement them. In this study, Cu@SiO2 core shells are fabricated using Cu cores and SiO2 shells, and are known to have antimicrobial effects. The core-shell was coated with SiO2 using the sol-gel method. Experiments were conducted using X-ray diffraction and the shaking flask method (KS J 4206) to evaluate the characteristics of the core-shell. In the case of X-ray diffraction, both the Cu core and the core-shell fabricated using the sol-gel process were characterized. Escherichia coli and Staphylococcus aureus were evaluated using the KS J 4206 method for their antibacterial properties. Through this study, it is confirmed that a Cu@SiO2 core-shell can be fabricated via the sol-gel method, and that Cu with a core-shell structure has antibacterial effects. PMID- 30469248 TI - Finite-Difference Time-Domain Simulation of Fractal-Like Microlens Arrays for High Outcoupling Efficiency of Organic Light-Emitting Diodes. AB - The outcoupling efficiencies (OCEs) of organic light-emitting diodes (OLEDs) were studied for a fractal-like two-dimensional structure consisting of three layers of semicircular microlens on a glass substrate using a finite-difference time domain (FDTD) method. The OCE with only one semicircular microlens layer was 29.5%, 1.75 times larger than that of the basic OLED. Additional layers with smaller diameters on the first layer did not improve the OCE. The OCE remained constant or slightly decreased with the increase of the number of layers. Two possible origins of this result were suggested; first, the possibility that the escaped light enters the nearby microlens becomes higher with the introduction of an additional protruded layer; second, the Mie scattering effect becomes important with the decrease of the diameter of the semicircular microlens from 20 MUm to 0.8 MUm. An additional FDTD simulation was performed for the OLED with only one microlens array as a function of the diameter. The OCE decreased approximately monotonously with the decrease of the diameter from 20 MUm to 0.2 MUm. In particular, the OCE became lower than that of the basic OLED when the diameter decreased from 0.5 MUm to 0.2 MUm. This is consistent with the observation that smaller fractal-like structures on the large microlens array did not further enhance the OCE. PMID- 30469249 TI - Influence of the Sintering Temperature of Al-Doped Higher Manganese Silicide for Improved Thermoelectric Properties. AB - Higher manganese silicide is generally used in thermoelectric devices between 700 K and 900 K. MnSi1.73Al0.005 samples were fabricated by two continuous solid state reactions followed by hot pressing because the electrical conductivity of all the samples is strongly dependent on Al doping, showing superior thermoelectric performance to the as-synthesized higher manganese silicide. The solid-state-reaction was performed at 1173 K for 6 hours. The effects of the sintering temperature were examined by sintering at three different temperatures: 1273 K, 1323 K and 1373 K. For the surface, microstructural, and electrical properties, scanning electron microscopy, X-ray diffraction, and a series of electric conductivity, Seebeck coefficient, and thermal conductivity analyses were conducted, respectively. As a result, the optimal process temperature for Al doped higher manganese silicide using a hot-press technique was determined. PMID- 30469250 TI - Microstructural and Mechanical Characteristics of A356 Alloys as a Function of Mn Content and Cast Thickness. AB - In this study, the changes in the microstructural characteristics and mechanical properties of A356 alloys as a function of Mn content and cast thickness were evaluated using structural analysis and tensile tests. Five different A356+x%Mn alloys were prepared by casting in molds of different thicknesses followed by solid solution treatment at 813 K for 195 min and aging treatment at 423 K for 120 min. It was confirmed that the secondary dendrite arm spacing (SDAS) increased with increasing thickness of the cast sample, whilst, for a given thickness, the addition of small amounts of Mn resulted in a decrease of the SDAS. Mn contents of 0.05-0.15% resulted in ~7-9% improvements in the spheroid ratio of the primary Si particles compared to that of the commercial A356 alloy. Further, the spheroid ratio of the primary Si particles obtained in the thin cast samples were higher than that obtained in the thick cast samples. In particular, the addition of small amounts of Mn was also effective in suppressing the formation of the needle-like beta Al-Fe-Si intermetallic compound. The yield and tensile strengths of the thinner cast samples were higher than those of the thicker cast samples. Finally, Mn contents of 0.05-0.15% resulted in enhanced yield and tensile strengths, but Mn content >=0.1% resulted in decreased elongation. PMID- 30469251 TI - Up-Conversion Photoluminescence of Sol-Gel Derived CaY2O4 Powders Under 980 nm Excitation. AB - Up-conversion is an anti-stokes process that can convert near-infrared light into visible light. Besides the requirement of high optical conversion efficiency, the thermochemical stability of the host materials is critical for in practical applications, and a stable oxide host material is optimal. CaY2O4 follows the same ordered structure of CaFe2O4, which is composed of an (R2O4)2- (R = rare earth metal) framework of double octahedral moieties with rare earth ions residing within the framework. CaY2O4 is a promising host material due to its favorable characteristics such as high chemical and thermal stability, low-phonon energy, and environment friendliness. Rare earth ion (Er3+ and Yb3+)-doped nano crystalline phosphors were prepared by a sol-gel process. The synthesized sample was characterized by X-ray diffraction analysis and the crystallite size was confirmed by Scherrer's formula and transmission electron microscopy. The surface morphology of the powders was determined by scanning electron microscopy. X-ray diffraction patterns confirmed their pure orthorhombic structure after annealing at 1,200 degrees C and the morphology of particles was found to be a nearly spherical shape with a diameter of the order of ~100 nm. Photoluminescence properties of the powders were measured by exciting the samples with a 980 nm diode laser at room temperature. Under the 980-nm laser excitation, the green and red up-conversion emissions were observed at around 520- 540 nm, 540-570 nm and 640-680 nm, which, are attributed to the transitions of 2H11/2 ->4I15/2, 4S3/2 >4I15/2 and 4F9/2 ->4I15/2 of Er3+ ions, respectively. The up-conversion intensity as a function of laser power shows that the up-conversion mechanism corresponding to green and red emissions occurs via a two-photon process. PMID- 30469252 TI - Effect of Fluoride Ions on Wet Etching of Copper/ Molybdenum in Hydrogen Peroxide Solution. AB - Copper metallization is a key issue for high performance thin film transistor technology. Hydrogen peroxide-based copper etchants are widely used in copper metallization. Recently, a hydrogen peroxide-based copper etchant for a copper/molybdenum double layer was investigated for its versatile use in both amorphous silicon TFTs and in metal-oxide TFTs. However, little is known about the etching mechanism for molybdenum and copper in a hydrogen peroxide solution containing fluorine ions. In this paper, it is shown that the amount of fluorine ions in the hydrogen peroxide-based copper etchant plays an important role in controlling the galvanic reaction between the copper and the molybdenum. A new mechanism of molybdenum dissolution in the presence of fluoride ions in 1.5 M hydrogen peroxide solution is suggested. The concentration of the fluoride ions is also important in eliminating the residue of molybdenum after wet patterning. PMID- 30469253 TI - The Optimal Design of Field Ring for Reliability and Realization of 3.3 kV Insulated-Gate Bipolar Transistor Power Semiconductor. AB - This research was about field ring for 3.3 kV planar gate power IGBT. Therefore, we designed optimal field ring for 3.3 kV power IGBT and we analyzed the electrical characteristics of 3.3 kV planar gate power IGBT according to parameters of field ring. Based on this background, we obtained 3.3 kV high breakdown voltage and 2.9 V on state voltage drop for 3.3 kV planar gate power IGBT. To obtain high breakdown voltage, we confirm that the counts of field ring were 23. And we obtained optimal parameters. The gap distance between field rings to field ring was 13 MUm and the width of field ring was 5 MUm. This design technology will be adapt field stop IGBT and super junction IGBT. Thyristor device for power conversion switch will be replaced to super high voltage power IGBT. PMID- 30469255 TI - Improved Device Performance of Solution-Processed Single-Wall Carbon Nanotube Transistors by a Patterning Technique Using a Selective Surface Treatment. AB - During the fabrication processes for single-wall carbon nanotube thin-film transistors (SWCNT-TFTs), the impurities of organic residues such as photoresist and developer can be induced, which affects the charge transport. As a result, solution-processed SWCNT-TFTs exhibit poor and non-uniform device performance regardless of the intrinsic electrical characteristics. Here, we demonstrate a patterning technique using a selective surface treatment with solution-processed hydrophobic fluorocarbon copolymer in SWCNT-TFTs. By using the difference of wettability in a selective area, a channel region in SWCNT-TFTs can be patterned without the conventional photolithography and etching process. Furthermore, the optimized surface treatment results in denser random networks of SWCNTs in the channel patterned by such technique, compared to the dropcasted SWCNT. The statistical results of the key device metrics such as mobility and threshold voltage extracted from 30 SWCNT-TFTs conclusively prove the improved device performance of SWCNT-TFTs fabricated by such pattering technique. We believe that this work can provide a promising route to stimulate the process innovation of fabrication for high performance solution-processed electronics based on SWCNT random networks. PMID- 30469254 TI - High Temperature Deformation Characteristics of Al-Zn-Mg Alloy Modified with CaO Added Mg. AB - Hot torsion tests were performed on an Al-Zn-Mg alloy modified with CaO-added Mg to investigate the effects of the Mg additive on the high temperature deformation characteristics. Effective stress- strain curves and processing maps were established from the experimental results under a range of deformation conditions. The fracture strain of the CaO-added Al-Zn-Mg alloy was higher than that of the Al-Zn-Mg alloy. The CaO-added Al-Zn-Mg alloy did not show an instability region in the processing map but the commercial Al-Zn-Mg alloy exhibited adiabatic shear bands at low temperatures and at a high strain rate. The results shown in this study were attributed to the reduction of the second phase by the addition of CaO-added Mg. PMID- 30469256 TI - Surface Enrichment of Mg and Ca in Cu-Mg Alloy Containing a Trace Amount of Ca and Its Effects on Oxidation Resistance. AB - In this study, the surface segregation of Mg and Ca in Cu-Mg alloys containing a trace amount of Ca under an oxidative atmosphere and its effects on oxidation resistance were examined. The use of a Mg+Mg2Ca master alloy as an alloying element for Mg rendered significant surface protection during melting and casting. During solid-state oxidation, the oxidation resistance was increased by the addition of Mg. Ca containing alloys with the same Mg exhibited a relatively higher oxidation resistance. From the phase diagram with the oxygen partial pressure as a function of the Mg content, the Ca containing alloy led to the formation of CaO as the primary oxide. The improved oxidation resistance of Ca containing alloys can be attributed to a mixed surface layer of CaO and MgO. PMID- 30469257 TI - Fabrication of a Bi2Te3-Based Thermoelectric Module Using Tin Electroplating and Thermocompression Bonding. AB - A method for directly bonding thermoelectric elements onto copper electrodes without applying a solder paste was developed in this study. A tin coating of thickness approximately 50 MUm was deposited via electroplating onto the surface of a Bi2Te3-based thermoelectric element, which had a nickel diffusion barrier layer. The resulting structure was subsequently subjected to direct thermocompression bonding at 250 degrees C on a hotplate for 3 min at a pressure of 1.1 kPa. Scanning electron microscopy imaging confirmed that a strong and uniform bond was formed at the copper electrode-thermoelectric element interface, and the melted or solidified tin layer remained defect-free. The thermoelectric module fabricated using tin plating had an average bonding strength similar to that fabricated using soldering. PMID- 30469258 TI - Porous TiO2 Nanotube Arrays for Drug Loading and Their Elution Sensing. AB - Porous TiO2 nanotube arrays have been attracting much attention as optical sensing layers and surface layers of dental implants because they are stable in acid and biocompatible. To use them as the optical sensing layers, TiO2 nanotube arrays with various structures were fabricated and obtained an optimized microstructure at 50 V, 50 min and 0.5 wt% of NH4F, 7.4 vol% deionized water in ethylene glycol. TiO2 nanotube arrays which had diameters of ~73.54 nm and lengths of ~3.39 MUm showed the best sensing performance. A Ti implant was also anodized at 60 V for 4 hr in an ethylene glycol electrolyte and TiO2 nanotube arrays showed the pore diameter of 156.01 nm and the thickness of 6.87 MUm. Recombinant human bone morphogenetic protein-2 (rhBMP-2), isobutylphenyl propionic acid, and sodium alendronate were loaded into the TiO2 nanotube arrays on the surface of the Ti implant. For elution of these drugs, optical thickness changes of 2.4 nm, 3.5 nm and 3.1 nm were respectively observed for about 2.2 hr, 3.6 hr and 3.1 hr. The TiO2 nanotube arrays were useful for drug loading and their elution interferometric sensing. PMID- 30469259 TI - Wet Etching Method for Electroless Ni-P Plating of Bi-Te Thermoelectric Element. AB - In this study, a method for electroless Ni-P plating with excellent adhesion via chemical wet etching to fabricate Bi-Te thermoelectric modules is proposed. The electroless Ni-P plating formed through the proposed method showed excellent adherence without peeling, even under heat treatment of 200 degrees C for 24 h. Wet etching and electroless Ni-P plating was performed on a Bi-Te thermoelectric module, which showed the excellent bond strength of approximately 10 MPa. The surface roughness of the Bi-Te thermoelectric element was increased significantly by the wet etching process, which secured the adherence of the Ni-P plating by anchoring to this induced surface roughness. PMID- 30469260 TI - Development of Amorphous SIZO/Ag/Amorphous SIZO Multilayer for High-Performance Transparent Conducting Electrode by Controlling Ag Layer Thickness. AB - A multilayered transparent conductive film of amorphous SiInZnO/Ag/amorphous SiInZnO (SIZO/Ag/SIZO) was fabricated and characterized. The electrical and optical properties of the multilayers changed with changes in the Ag film thickness. The electrodes with the optimized thickness showed an excellent average transmittance (Tav) of 94.04% and a high figure of merit (FOM) of 38.1*10 3 Omega-1. As the Ag layer thickness increased over 9 nm, the FOM and sheet resistance decreased. This result could be attributed to the decrease in Tav due to light absorption and reflection from the thick Ag layer. PMID- 30469261 TI - Low-Voltage Operating Single-Wall Carbon Nanotube Thin-Film Transistors Using High Work Function Contacts on Flexible Substrates. AB - There have been constant attempts as regards high-performance thin-film transistors (TFTs) by improving the charge injection between the source/drain electrode (S/D) and the channel. In this paper, we investigate the effect of the electric contact on the device performance of single-wall carbon nanotube (SWCNT) TFTs employing the suitable work function material. In order to realize the electric contacts for the dominant hole injection between the S/D and the SWCNT active channel, a high work function material of molybdenum trioxide (MoOx) fabricated by an optimized process are utilized. The contact resistance is extracted by plotting the width-normalized resistance of SWCNTTFT with Pd and MoOx contacts as a function of channel length. We also demonstrate low-voltage operating SWCNT TFTs on flexible polyimide substrates with the reduced electric contacts. Without a buffer film which has been widely used to improve the device performance of TFT on a flexible substrate, high-performance low-voltage operating SWCNT-TFTs were achieved. PMID- 30469262 TI - Effects of Heat-Treatment on Photoluminescence Spectra and Photocatalytic Properties of Solution-Combusted ZnO Nanopowders. AB - ZnO nanopowders were prepared by a solution combustion method (SCM). The SCM ZnO nanopowders were heat-treated at 200, 400, 500, or 700 degrees C for 30 min in air and the photoluminescence (PL) of the nanopowders was evaluated. Two strong PL emission peaks are generally recognized as the unique PL signature of ZnO, one is from the band-edge emission and the other corresponds to green emission. The green emission is derived from crystalline defects, and is a critical obstacle for the electrooptical applications of ZnO. Surprisingly, the PL spectra of the SCM ZnO powders showed a single sharp peak near 390 nm. Furthermore, the intensity of this blue emission doubled when the synthesized ZnO powder was heat treated at 400 degrees C. The green emission appeared for the sample treated at 500 degrees C, and was the highest for that treated at 700 degrees C. To comfirm the photocatalytic activity of the ZnO powder heat-treated at 400 degrees C, the removal of Ag ions from a used photofilm developer was evaluated, with complete removal within 10 min. The removal of the Ag ions by the ZnO powder heat-treated at 400 degrees C was more than two orders of magnitude faster than that achieved with the SCM ZnO powder. The relation between PL and photocatalytic activity was explained in terms of recombination of the photogenerated electrons. These results might be very useful for highly efficient photocatalyst applications. PMID- 30469263 TI - Photoluminescence and Electrical Properties of ZnO Nanopowders Prepared by a Solution Combustion Method for Optoelectronic Device Application. AB - Nano-sized powders of ZnO phosphor were prepared by a solution combustion method (SCM). The ZnO powder prepared using Zn(OH)2 and glycine as the oxidant and fuel, respectively, (fuel/oxidant = 0.8), show good powder characteristics such as an average grain size of 30 nm and specific surface area of 120 m2/g. Single-phase ZnO powders were obtained regardless of the fuel/ oxidant ratio. The photoluminescence spectra of the obtained ZnO powders show a single sharp peak near 390 nm corresponding to a deep blue color. This was confirmed by cathodoluminescence measurement and CIE color coordinate values. The PL spectra, powder characteristics and electrical properties show very good consistency. Furthermore, the electron carrier concentration of the ZnO nanopowders prepared by SCM is more than 3 orders of magnitude higher than that of the purest ZnO single crystal, which is commercially available. These powders could be potentially applied as blue phosphors of displays such as A.C. powder electroluminescent devices and plasma display panels. PMID- 30469264 TI - Evaluation of the Hot Workability of Commercially Pure Ti Using Hot Torsion Tests. AB - Optimum processing conditions were obtained by evaluating the hot working behavior of commercially pure Ti using hot torsion tests. Hot torsion tests were conducted at temperatures ranging from 800 degrees C-1000 degrees C and strain rates ranging from 0.1-10 s-1. The flow curves show that the peak stress increases as the temperature decreases and the strain rate increases. The optimum processing conditions were derived by comparing the processing and activation energy maps. The microstructure was characterized based on various regions of the processing map. The activation energy for plastic deformation was obtained using the constitutive equation. The activation energy differs depending on the constituent phases. PMID- 30469265 TI - Energy Harvesting Through Wasted Thermal Energy by Light Grid Sources. AB - In this study, emitted light energy and the recycling of thermal energy from the arrays of a light emitting diode system were investigated. A light grid system is composed of the array of high power LED chips, thermoelement and heat sink. High power LED source has an advantage of high luminous efficiency, which combined with wasted thermal energy. Thermal energy loss can be regarded wasted energy. However, this wasting thermal energy can be effectively converted to the electrical energy from thermoelement and heat sink of a light grid system. By introducing the light grid system, the optical energy and thermal energy can be more effectively managed. In particular, we have intensively studied energy conversion efficiency of light grid system and energy harvesting characteristic through thermal energy. PMID- 30469266 TI - H2S Gas Sensor Based on Ru-MoO3 Nanoflake Thick Film. AB - In this study, H2S-sensing characteristics of the spincoated ruthenium loaded molybdenum trioxide nanoflake (Ru-MoO3 NFs) thick films with 0-1.00 wt% Ru concentrations have been studied. The morphologies, cross section and elemental compositions of sensing films were characterized by SEM and EDS line-scan analyses. The influence of Ru concentration on H2S response of the thick film sensor was studied at the operating temperatures ranging from 200 to 350 degrees C. It was found that 0.5 wt% RuMoO3 film exhibited an enhanced response of ~30 to 10 ppm H2S, which was more than one order of magnitude higher than that of unloaded one. Plausible mechanisms responsible for the enhanced H2S response by sensing films of Ru-MoO3 NFs were discussed on the basis of the catalytic spill over effects and enhanced specific surface area provided by Ru nanoparticles. PMID- 30469267 TI - Development of Chemically Signal Amplified Nano-Biosensor Mediated by Poly-L Lysine. AB - Amyloid beta (Abeta) is considered to be one of a potential biomarker to monitor Alzheimer's Disease (AD) not only for diagnostic purposes but for early detection. Here we describe a novel nano-biosensor for Abeta mediated by poly-L lysine (PLL) which was used for the amplification of detection signal for Abeta. The indirect enzyme-linked immunosorbent assay (ELISA) method was modified using PLL for the amplification of the Abeta detection signal. A commercially available ELISA plate was modified by PLL using chemical agent and the amplified amino groups were activated by a chemical agent for the detection of Abeta. The detection was carried out by the traditional immunochemistry using primary antibody and fluorescence molecules conjugated secondary antibody. In the result, the fluorescence intensity was increased by the increasing treated Abeta amount, and the sensitivity was approximately 2 times higher in the concentration of 2 ng/mL Abeta treatment, and approximately 4 times higher in the concentration of 200 ng/mL Abeta treatment compare with that of indirect ELISA detection method. We suggest our novel signal amplification method for the Abeta early detection. PMID- 30469268 TI - Transparent and Conducting Oxide Films: SiO2-Doped ZnO. AB - (SiO2)x(ZnO)100-x films with x = 2, 3, 4, and 5 wt.% were deposited on slide glass substrates at room temperature by the conventional Rf magnetron sputtering method. Their resistivities were investigated as a function of SiO2 content. The lowest resistivity of 4.5*10-3 Omega.. cm was obtained for the (SiO2)x(ZnO)100-x film with x = 2 wt.%. This film showed an excellent average transmittance of 85% in the visible range with a wide band gap over 3.4 eV and a high refractive index of 2.1. In addition, the electrical conductivity of the films was improved by annealing at a temperature films decrease range from 100 degrees C to 400 degrees C in vacuum. The resistivities of (SiO2)x(ZnO)100-x with increasing annealing temperature. In particular, SZO film with x = 2 wt.% shows a minimum resistivity of ~10-3 Omega.cm after the heat treatment for 30 min at 300 degrees C in vacuum. Thus, we suggest that (SiO2)x(ZnO)100-x films being sufficiently transparent and having a high conductivity, are suitable for application as transparent and conductive oxide films. PMID- 30469269 TI - Analysis of Electrical and Nano-Mechanical Properties of Cu-Fe Thin Foil Using Dynamic Nanoindentation. AB - A Cu-Fe thin foil for high-performance leadframe semiconductor packaging was prepared by powder metallurgy and mechanical rolling, and its nano-mechanical and electrical properties were analyzed. The phases in the final Cu-Fe thin foil were Cu (Fm-3m), Fe (Im-3m), and Cu0.8Fe0.2 (Fm-3m). The nano-hardness, stiffness, and fatigue limit values of the Cu-Fe thin foil based on the Oliver and Alekhin models were 2.3 GPa, 158.1 MPa, and 0.17, respectively, while its surface resistivity was 6.953 Omega/sq. PMID- 30469270 TI - Improvement of the Electrical Properties of a Cu(In,Ga)Se2 Solar Cell Based on a ZnS Buffer Layer from Radio Frequency Magnetron Sputtering. AB - We fabricated zinc sulfide (ZnS) buffer layers with a great band gap and small light loss at a short wavelength, and then applied them to copper indium gallium sulphur-selenide (CIGS) thin film solar cells. A CIGS evaporation system was used for fabrication of the CIGS thin films, and a thickness monitor was used to check the evaporation rate at each source. The evaporation rate and deposition time were adjusted to change the composition ratio of the thin films. Also, CIGS thin films were deposited by changing the temperature of the substrates from room temperature (RT) to 150 degrees C, 250 degrees C, and 350 degrees C during ZnS deposition, and among them, the optimal substrate temperature was selected to measure the light conversion efficiency of ZnS-deposited CIGS thin film solar cells. The grown ZnS thin films were analyzed for crystallinity and composition by using X-ray diffraction, and by using a scanning electron microscope, the cross section and surface shape of the thin films were examined. When we applied the ZnS thin film that was fabricated at a temperature of 150 degrees C with a thickness of 50 nm as a buffer layer for the CIGS solar cells, we obtained a light conversion efficiency of 14.48% without an antireflection layer. PMID- 30469271 TI - Functional Coating to Improve the Anti-Pollution Characteristics for the Cover Glass of Photovoltaic Module. AB - A functional coating designed to prevent pollution was investigated on the surfaces of cover glass substrates for a photovoltaic (PV) module to improve the cover glass's anti-pollution characteristics. To identify the characteristics that can prevent pollution as well as the change in the contact angle of the thin film on the cover glass surface, three field-applicable coating methods were applied, and the coatings were annealed in two different annealing steps using a furnace. Step 1 refers to the annealing treatment of the coated films at 200 degrees C while step 2 refers to the second annealing treatment at 200, 300, and 400 degrees C. The anti-pollution characteristics, contact angle, transmittance, hardness, and adhesion were measured, and the results were analyzed. It was confirmed that the contact angle and the anti-pollution characteristics were better when the coated substrate was annealed twice at 200 degrees C than when it was annealed only once. PMID- 30469272 TI - Low-Temperature Sintering of Garnet-Type Li7La3Zr2O12 Solid Electrolyte with Li3BO3 Additive Prepared by Polymeric Complex Method. AB - In this study, a Li3BO3 (LBO) compound is synthesized via the heat-treatment of polymeric precursors containing Li and B in air at 700 degrees C for 5 h to use as a sintering additive for the densification of Li7La3Zr2O12 (LLZ) solid electrolyte. The synthesized LBO powder is suitable for promoting the densification, cubic phase stability, and ionic conductivity of LLZ. X-ray diffraction analysis indicated that monophasic cubic LLZ could be obtained by the addition of LBO in sintering, changing to cubic LLZ phase from LZ impurities detected in raw LLZ. The sintered LLZ-12 wt% LBO showed that the densification of the LLZ with LBO occurred by a coupling effect including the particle rearrangement of LLZ in the melted LBO phase and grain growth of LLZ particles. The density of the LLZ-12 wt% LBO composite sintered at 1100 degrees C for 8 h was 3.72 g/cm3 (86% of theoretical density); the composite showed the high Li-ion conductivity of 1.18*10-4 S.cm-1 at 28 degrees C. PMID- 30469273 TI - High-Efficiency Cu(In,Ga)Se2 Thin Film Solar Cells Using ZnS and CdS Buffer Layers. AB - Most of the existing copper indium gallium diselenide (CIGS) thin film solar cells are based on a cadmium sulfide (CdS) buffer layer fabricated using a chemical bath deposition (CBD) process. However, due to environmental pollution caused by material toxicity and the unique wet process's incompatibility with the vacuum process, many studies are now being actively carried out on nontoxic buffer layers. In this study, to replace CdS buffer layers, zinc sulfide (ZnS) buffer layers with a big band gap and a low optical loss at a short wavelength were fabricated using a magnetron sputtering system. For comparative analysis, this study also fabricated CdS buffer layers using the CBD process. Then, the conversion efficiency of CIGS thin film solar cells deposited with ZnS and CdS thin film as buffer layers was measured. The light conversion efficiency of ZnS buffer layer-based CIGS was measured at 14.44%, while that of the CdS buffer layer-based CIGS was measured at 15.71%. Given that both are higher than the minimum conversion efficiency required for commercialization (10%), ZnS buffer layer-based solar cells could have a competitive edge over the existing CdS buffer layer-based solar cells. PMID- 30469274 TI - Effect of Ca on Phase Stability and Oxidation Resistance of Al3Mg2 at Elevated Temperature. AB - In this study, effect of Ca on phase stability and oxidation of Al3Mg2 at elevated temperature was investigated. From thermogravimetric analysis (TGA) at 420 degrees C, rapid weight gains in the initial stage and incubation were observed for Al3Mg2 and Ca-added Al3Mg2. After incubation for some time, Al3Mg2 sample exhibited the second weight growth, while Ca added sample exhibited continuous incubation during the testing time. The phase diagrams calculated by Factsage 7.1 revealed that Ca exists as Laves_C36 in Al3Mg2 and also forms Ca3MgAl4O10, following formation of MgO and MgAl2O4-spinel as primary and secondary oxides, respectively, on the surface during oxidation at 420 degrees C. PMID- 30469275 TI - Preparation of beta-Phase Poly(vinylidene fluoride) Films on Aluminum Substrate with the Addition of Hydrated Metal Salts. AB - Poly(vinylidene fluoride) (PVDF) is one of the most studied polymers that exhibits piezoelectric and ferroelectric properties. PVDF crystallizes into four different forms, namely alpha, beta, gamma, and delta phases. Generally, the nonpolar alpha phase, as a replacement for the polar beta phase with the most superior ferroelectric and piezoelectric properties, is formed from the precursor melt and solution. Here, we report a method for the preparation of beta-phase dominant PVDF thin films by doping PVDF solution with a metal hydrated salt, such as Co(NO3)2.6H2O, without any stretching procedure. The crystal structure of the film was analyzed using X-ray diffraction ?-2? scanning and Fourier transform infrared spectroscopy. The morphology of the film was observed using a field emission-scanning electron microscope. To determine the frequency dependence of dielectric properties, an LCR meter was used in the range of 50 Hz to 1 MHz. The crystalline phase and morphology of the electrostatic spray-deposited PVDF films depended on the chemical additive. Our results show that the addition of a metal hydrated salt can induce an in situ poling effect, consequently facilitating the preferred dipole orientation in the electrostatically sprayed PVDF films. PMID- 30469276 TI - Effects of Melting Conditions on Cerium Oxidation State and Catalytic Properties of CeO2-P2O5 Glass Systems. AB - As with any solvent, stabilizing a multivalent element at a given oxidation state in glass depends on the thermodynamic conditions. The effects of temperature on the oxidation-reduction equilibrium have been previously noted with higher temperatures being more conducive to reduced states. Herein, 30CeO2-70P2O5 binary system glasses were prepared. The melting temperature and time dependency on Ce4+ and Ce3+ ion concentrations were studied using X-ray photoelectron spectroscopy. Different melting conditions were investigated at temperatures ranging from 1300 degrees C to 1500 degrees C for 60 min, and at 1400 degrees C for durations ranging from 30 min to 90 min. The changes in the catalytic properties of the glasses as a function of Ce4+ and Ce3+ ion concentrations were confirmed based on the changes in the decomposition starting temperatures using thermogravimetric analysis. The main changes in the oxidation states according to melting conditions were discussed in terms of the catalytic properties of CeO2-P2O5 glass systems. PMID- 30469277 TI - Electrophysical Characteristics of Y Based Superconducting Composite. AB - The research in this paper was conduced with the purpose of developing a electrophoretic deposition process technology, and finding out an optimization method for fabrication of YBCO superconductor thick film tapes by using superconducting YBCO powder, and applying the electrophoresis technique. Through the development of an electrodeposition process, this study tried to determine an optimization method to improve the density and orientation of powder particles and a way to obtain a uniform surface to overcome cracking and porosity problems possibly occurring in the drying and heat-treatment processes. In this study, the electrophoretic deposition technique, which is to align and maintain particles toward the backside of the C axis of Ag substrates in a tape form, through excitation of powder particles with AC electric current, and then to perform deposition under a condition, was applied to the electrophoretic deposition process. PMID- 30469278 TI - Electrical Properties of YBaCuO Ceramic Oxides Using Electrodeposit. AB - In this paper, an alternating voltage of 60 Hz and (25-120) V/cm was proposed to be applied for subsidiary source deposition, so that the fabricated thin film showed uniform surface morphology with less voids and cracks, and Tc, zero of 90 K and a critical current density of 3,320 A/cm2. Compared to the superconducting thin film fabricated by a single constant electric field, the film fabricated by the subsidiary alternating electric field showed an improvement in the critical current density from (2,250 to 2,319) A/cm2, showing that the latter is superior to the former. In particular, it is noteworthy that it was performed by the subsidiary electric field with the condition of commercial frequency and low electric field, rather than high voltage and frequency, of over 300 V and 150 Hz, respectively. PMID- 30469279 TI - Numerical Analysis on Piezoelectrically Driven Jet Dispensing Mechanism for Nanoliter Droplet of High Viscosity Liquid. AB - Various research on a dispenser head applied with the technology of piezoelectric ceramics which has high response, force generation and resolution have been actively conducted. A piezoelectric dispenser head for functional high viscous liquid generates micro droplets utilizing a different mechanism with conventional valves. This mechanism makes it difficult to calculate the pressure build-up and flow quantity. Because of this difficulty, proper displacement of a tappet cannot be selected and the displacement of the piezoelectric ceramic is being used with excessive amplification. To address these issues, a piezo dispenser head has been modeled to numerically analyze this mechanism. The mechanism has been simulated to calculate the pressure build-up and flow quantity. In addition, the load on the tappet was calculated, and the appropriate displacement of the tappet was confirmed. In this study, we have succeeded in numerically analyzing the mechanism of the piezoelectric dispenser head and we confirmed that the displacement of the appropriate tappet is about 200 MUm; at this time the load on the tappet is about 3.7 N and the droplet volume is about 19.89 nL. PMID- 30469280 TI - Contaminants in bald eagles of the upper Midwestern U.S.: A framework for prioritizing future research based on in-vitro bioassays. AB - Several organic contaminants (OCs) have been detected in bald eagle (Haliaeetus leucocephalus) nestling (eaglet) plasma in the upper Midwestern United States. Despite frequent and relatively high concentrations of OCs in eaglets, little is understood about potential biological effects associated with exposure. We screened an existing database of OC concentrations in eaglet plasma collected from the Midwestern United States against bioactivity information from the ToxCast database. ToxCast bioactivity information consists of concentrations expected to elicit responses across a range of biological space (e.g. cellular, developmental, etc.) obtained from a series of high throughput assays. We calculated exposure-activity ratios (EAR) by calculating the ratio of plasma concentrations to concentrations available in ToxCast. Bioactivity data were not available for all detected OCs. Therefore, our analysis provides estimates of potential bioactivity for 19 of the detected OCs in eaglet plasma. Perfluorooctanesulfonic acid (PFOS) EAR values were consistently the highest among all study areas. Maximum EAR values were >=1 for PFOS, perfluorononanoic acid, and bisphenol A in 99.7, 0.53 and 0.26% of samples, indicating that some plasma concentrations were greater than what may be expected to elicit biological responses. About 125 gene targets, indicative of specific biological pathways, were identified as potentially being affected. Inhibition of several CYP genes, involved in xenobiotic metabolism, were most consistently identified. Other identified biological responses have potential implications for motor coordination, cardiac functions, behavior, and blood circulation. However, it is unclear what these results mean for bald eagles, given that ToxCast data are generated using mammalian-based endpoints. Despite uncertainties and limitations, this method of screening environmental data can be useful for informing future monitoring or research focused on understanding the occurrence and effects of OCs in bald eagles and other similarly-positioned trophic species. PMID- 30469281 TI - Should oral exposure in Hypoaspis aculeifer tests be considered in order to keep them in Tier I test battery for ecological risk assessment of PPPs? AB - The laboratory reproduction test with the predatory mite Hypoaspis aculeifer is currently a mandatory test in the new EU data requirements for prospective environmental risk assessment of Plant Protection Products (PPPs). However, the low sensitivity often shown by this mite towards PPPs, when compared to other invertebrates (namely Folsomia candida and Eisenia fetida), makes the test with this species not very useful in the lower tier test battery. However, the current test protocol only considers exposure to contaminants via contaminated soil, disregarding exposure via contaminated food and does not take into account the fact that H. aculeifer is a predatory species. Therefore, through this protocol, the toxicity of contaminants to soil mites might be underestimated and, thus, an adaptation of the test performance, by including exposure via contaminated food, may be necessary. With this aim, two reproduction tests with H. aculeifer were performed using copper chloride as model substance, artificial soil as test substrate and cheese mites as food. The OECD guideline was followed but, while in one test cheese mites from normal laboratory breeding cultures (clean prey mites) were provided, in the other test, cheese mites previously exposed to copper (Cu pre-exposed prey mites) were provided. Predatory mites were affected at lower concentrations in tests using Cu pre-exposed prey compared to test with clean prey (NOEC = 1225 and 1508 mg kg-1 and EC10 = 1204 and 1903 mg kg-1 using Cu pre exposed and clean prey, respectively). However, this higher sensitivity was not detected by EC50 values (EC50 = 2634 and 2814 mg kg-1 using Cu pre-exposed and clean prey, respectively). Further tests are needed in order to (i) investigate the relevance of oral exposure to different PPPs, (ii) optimize the contamination of prey mites according to the chemical properties of each substance and (iii) substantiate a proposal to adapt the standard protocol. PMID- 30469282 TI - Chemical characteristics of airborne particles in Xi'an, inland China during dust storm episodes: Implications for heterogeneous formation of ammonium nitrate and enhancement of N-deposition. AB - To identify the sources and heterogeneous reactions of sulfate and nitrate with dust in the atmosphere, airborne particles in Xi'an, inland China during the spring of 2017 were collected and measured for chemical compositions, along with a laboratory simulation of the heterogeneous formation of ammonium nitrate on the dust surface. Our results showed that concentrations of Ca2+, Na+ and Cl- in the TSP samples were enhanced in the dust events, with the values of 41.8, 5.4 and 4.0 MUg m-3, respectively, while NO3- (7.1 MUg m-3) and NH4+ (2.4 MUg m-3) remarkably decreased, compared to those in the non-dust periods. During the dust events, NH4+ correlated only with NO3- (R2 = 0.52) and abundantly occurred in the coarse mode (>2.1 MUm), in contrast to that in the non-dust periods, which well correlated with sulfate and nitrate and enriched in the fine mode (<2.1 MUm). SO42- in Xi'an during the dust events existed mostly as gypsum (CaSO4.2H2O) and mirabilite (Na2SO4.10H2O) and dominated in the coarse mode, suggesting that they were directly transported from the upwind Gobi Desert region. Our laboratory simulation results showed that during the long-range transport hygroscopic salts in the Gobi dust such as mirabilite can absorb water vapor and form a liquid phase on the particle surface, then gaseous NH3 and HNO3 partition into the aqueous phase and form NH4NO3, resulting in the strong correlation of NH4+ with NO3- and their accumulation on dust particles. The dry deposition flux of total inorganic nitrogen (NH4+ + NO3-) in Xi'an during the dust events was 0.97 mg-N m 2 d-1 and 37% higher than that in the non-dust periods. Such a significant enhanced N-deposition is ascribed to the heterogeneous formation of NH4NO3 on the dust particle surface, which has been ignored and should be included in future model simulations. PMID- 30469283 TI - Emerging contaminants and nutrients in a saline aquifer of a complex environment. AB - The quality and availability of water has become a pressing issue worldwide, being particularly important in semi-arid regions, where climate change has aggravated the problem. The use of anthropogenic chemicals, classified as emerging pollutants, adds to the problem representing a treat, since they are not regulated and have a potential impact on human and environmental health. This pressing problem has not been studied widely in complex environments like the one we present here. Distribution and seasonal variability of fecal sterols, alkylphenols, pesticides (emerging pollutants) and nutrients were determined in 35 wells used for agriculture and human consumption in the Valley of Maneadero, located in the semi-arid region of Baja California, Mexico. The presence of the tested pollutants in the saline aquifer was heterogeneous, showing important differences in concentration and distribution. Wells destined for household use showed the highest variability. In these wells, anthropogenic fecal sterols were detected and, alkylphenols, such as octyphenol and nonylphenol had maximum concentrations (2.7 ng/mL). In agriculture and urban wells, we identified DDT and organochlorine pesticides, as well as myclobutanil, which is considered a modern pesticide. Nitrates were identified in concentrations above international standards, mainly during the dry season, in both the agricultural and urban areas. As emerging pollutants represent a negative effect on environmental and human health, this is the first paper showing the importance of measuring this type of pollutant in agricultural/semi-urban areas, especially in aquifers that have been overexploited and communities that have relied on the use of septic tanks for decades. PMID- 30469284 TI - Extreme enrichment of arsenic and rare earth elements in acid mine drainage: Case study of Wisniowka mining area (south-central Poland). AB - The Wisniowka rock strip mining area (south-central Poland) with quartzite quarries, acid water bodies and tailings piles is one of the most unique acid mine drainage (AMD) sites throughout the world. This is due to the occurrence of enormous amounts of pyrite unknown in sedimentary formations worldwide. Of the two mineralization zones, one that is the most abundant in arsenical pyrite occurs in the lowermost Upper Cambrian formation of the Podwisniowka quarry. The As-rich pyritiferous clastic rocks are exposed as a result of deep quartzite extraction during 2013-2014. In addition, the clayey-silty shale interbeds are enriched in rare earth element (REE) minerals. The mining operation left an acidic lake with a pH of about 2.4-2.6 and increased contents of sulfates, metal(loid)s and REE. The Podwisniowka pyrite-rich waste material was stacked up in many places of the mining area giving rise to strongly acidic spills that jeopardized the neighboring environment. One of these unexplored tailings piles was a source of extremely sulfate- and metal(loid)-rich pools with unusual enrichments in As (up to 1548 mg L-1) and REE (up to 24.84 mg L-1). These distinctly exceeded those previously reported in the Wisniowka area. A broad scope of geochemical, mineralogical and petrographic methods was used to document these specific textural and mineralogical properties of pyrite facilitating its rapid oxidation. The pyrite oxidation products reacted with REE-bearing minerals releasing these elements into acid water bodies. Statistical methods were employed to connect the obtained tailings pool hydrogeochemical data with those derived from this and the previous studies of the Podwisniowka and Wisniowka Duza acid pit lakes. In contrast to metal(loid) profiles, the characteristic shale normalized REE concentration patterns turned out to be more suitable for solving different AMD issues including provenance of mine waste material in the tailings pile examined. PMID- 30469285 TI - Differential patterns of nitrogen and delta15N in soil and foliar along two urbanized rivers in a subtropical coastal city of southern China. AB - Urbanization usually pollutes the environment leading to alterations in key biogeochemical cycles. Therefore, understanding its effects on forest nitrogen (N) saturation is becoming increasingly important for addressing N pollution challenges in urban ecosystems. In this study, we compared soil (N availability, net N mineralization, net nitrification, and delta15N) and foliar (N concentrations and delta15N) variables in upstream, midstream and downstream forest stands of Bailongjiang River (BJR; more urbanized) and Wulongjiang River (WJR; less urbanized), the two branches of the Minjiang River Estuary. Total soil N, ammonium, nitrate, net N mineralization and nitrification rates, as well as soil delta15N were significantly higher in BJR compared with WJR forest stands. While no substantial difference in foliar N concentrations was noted between rivers, foliar delta15N was on average more than 2.5 times higher in BJR than WJR forest stands. Across the study area, foliar delta15N was positively related to soil delta15N, which also had positive linear relationships with soil nitrate concentrations, net N mineralization and net nitrification rates. Moreover, all variables except foliar delta15N and ammonium concentrations showed decreasing patterns in the order: upstream > midstream > downstream along the BJR forest stands. Soil ammonium and foliar values (N concentrations and delta15N) revealed clear patterns along the WJR, with the former increasing and the latter decreasing from the upstream to downstream forest stands. Our findings indicate an increase in urbanization-induced N inputs from the WJR to BJR and that forest stands along the BJR especially at the upstream have higher N availability and are shifting rapidly towards N saturation state. These results emphasize the need for effective N pollution control in urban environments through sustainable urban planning. PMID- 30469286 TI - Maternal exposure to short-to medium-term outdoor air pollution and obstetric and neonatal outcomes: A systematic review. AB - BACKGROUND: Little is known about the impacts of maternal exposure to acute episodes of outdoor air pollution, such as that resulting from wildfires, on obstetric and neonatal outcomes. This systematic review aims to synthesise the existing literature exploring the relationship between maternal exposure to short to medium-term changes in outdoor air quality and obstetric and neonatal outcomes. METHODS: A systematic search of peer-reviewed articles using PubMed, Cochrane Library, EMBASE, ScienceDirect, Web of Science, ProQuest, GreenFILE and Scopus was conducted in January 2018 using selected search terms. Quality of included studies were assessed using the Newcastle Ottawa Scale. RESULTS: Eleven studies were included; eight assessed the impact of maternal exposure to air pollution exacerbation events, such as wildfires, oil well fires and volcanic eruptions, and three assessed the impact of improvement events, such as the 2018 Beijing Olympics and closure of industrial activities, on obstetric and neonatal outcomes. Studies were highly heterogenous in methodology. Six studies found a significant association between acute changes in air quality and markers of fetal growth restriction, while two did not. Three studies found an adverse association between acute changes in air quality and markers of gestational maturity, and one did not. CONCLUSION: Overall, there is some evidence that maternal exposure to acute changes in air quality of short-to medium-term duration increases the risk of fetal growth restriction and preterm birth. The relationship for other adverse obstetric or neonatal outcomes is less clear. PMID- 30469287 TI - Transcriptomic analysis of short-term 17alpha-ethynylestradiol exposure in two Californian sentinel fish species sardine (Sardinops sagax) and mackerel (Scomber japonicus). AB - Endocrine disrupting chemicals (EDCs) are substances which disrupt normal functioning of the endocrine system by interfering with hormone regulated physiological pathways. Aquatic environments provide the ultimate reservoir for many EDCs as they enter rivers and the ocean via effluent discharges and accumulate in sediments. One EDC widely dispersed in municipal wastewater effluent discharges is 17alpha-ethynylestradiol (EE2), which is one of the most widely prescribed medicines. EE2 is a bio-active estrogen employed in the majority of oral contraceptive pill formulations. As evidence of the health risks posed by EDCs mount, there is an urgent need to improve diagnostic tools for monitoring the effects of pollutants. As the cost of high throughput sequencing (HTS) diminishes, transcriptional profiling of an organism in response to EDC perturbation presents a cost-effective way of screening a wide range of endocrine responses. Coastal pelagic filter feeding fish species analyzed using HTS provide an excellent tool for EDC risk assessment in the marine environment. Unfortunately, there are limited genome sequence data and annotation for many of these species including Pacific sardine (Sardinops sagax) and chub mackerel (Scomber japonicus), which limits the utility of molecular tools such as HTS to interrogate the effects of endocrine disruption. In this study, we carried out RNA sequencing (RNAseq) of liver RNA harvested from wild sardine and mackerel exposed for 5 h under laboratory conditions to a concentration of 12.5 pM EE2 in the tank water. We developed an analytical framework for transcriptomic analyses of species with limited genomic information. EE2 exposure altered expression patterns of key genes involved in important metabolic and physiological processes. The systems approach presented here provides a powerful tool for obtaining a comprehensive picture of endocrine disruption in aquatic organisms. PMID- 30469288 TI - Enhanced and selective adsorption of Hg2+ to a trace level using trithiocyanuric acid-functionalized corn bract. AB - A novel trithiocyanuric acid-modified corn bract (TCA-CCB) was prepared, and its removal properties for Hg2+ were investigated. TCA-CCB showed a remarkable absorbability for Hg2+ in mixed ion solutions. Adsorption kinetics experiments indicated that the removal of Hg2+ on TCA-CCB was quick, with a removal rate of 99.07% within 5 min. In addition, the removal rate of Hg2+ exceeded 98% over all pH conditions. The adsorption process can be best described by pseudo-second order kinetic and Hill isotherm models. The saturated adsorption capacity of TCA CCB for Hg2+ was 390 mg/g. The TCA-CCB could efficiently adsorb Hg2+ from the simulated wastewater and reduce the Hg2+ concentration from 10 ppm to 12.35 ppb, which was lower than the greatest allowable value of 50 ppb and satisfied the emission standards required by the Chinese government. Moreover, the removal rate of Hg2+ was beyond 99% after three cycles. The results of the zeta potential and X-ray photoelectron spectroscopy (XPS) implied that the chelation and ion exchange between amino/thiol groups and Hg2+ played a significant role in the improvement of the adsorption properties. The corn bract modified by trithiocyanuric acid exhibits apparent advantages in the removal of Hg2+ from ppm to ppb due to its high selectivity, adsorption capacity and stability. PMID- 30469289 TI - Neurotoxicity of nonylphenol exposure on Caenorhabditis elegans induced by reactive oxidative species and disturbance synthesis of serotonin. AB - The present study was performed to evaluate the neurobehavioural deficit induced by nonylphenol (NP), a well-known xenobiotic chemical. The neurotoxic mechanism from oxidative stress and serotonin-related progress was also investigated. Caenorhabditis elegans was exposed at different levels of NP ranging from 0 to 200 MUg L-1 for 10 days. The results revealed that from a relatively low concentration (i.e., 10 MUg L-1), significant effects including decreased head thrashes, body bends and forging behaviour could be observed, along with impaired learning and memory behaviour plasticity. The level of reactive oxygen species (ROS) in head was significantly elevated with the increase of NP concentrations from 10 to 200 MUg L-1. Through antioxidant experiment, the oxidative damage caused by NP restored to some extent. At a NP concentration of 200 MUg L-1, the significant increased expression of stress-related genes, including sod-1, sod-3, ctl-2, ctl-3 and cyp-35A2 gene, was observed from integrated gene expression profiles. In addition, in comparison with wild-type N2 worms, the ROS accumulation was increased significantly with the mutation of sod-3. Tryptophan hydroxylase (TPH) in ADF and NSM neurons sharply decreased at the concentrations of 10-200 MUg L-1. The transcription of TPH synthesis-related genes and serotonin related genes were both suppressed, including tph-1, cat-1, cat-4, ser-1, and mod 5. Overall, these results indicated that NP could induce neurotoxicity on Caenorhabditis elegans through excessive induction of ROS and disturbance synthesis of serotonin. The conducted research opened up new avenues for more effective exploration of neurotoxicity caused by NP. PMID- 30469290 TI - Assessment of the sources and inflow processes of microplastics in the river environments of Japan. AB - The numerical and mass concentrations of microplastics collected at 36 sites on the surfaces of 29 Japanese rivers were mapped and compared with four basin characteristics (basin area, population density, and urban and agricultural ratios) and six water quality parameters (pH, biochemical oxygen demand (BOD), suspended solids (SS), dissolved oxygen (DO), total nitrogen (T-N), and total phosphorus (T-P)) in each river basin. Microplastics were found in 31 of the 36 sites, indicating that some plastics fragment into small pieces before reaching the ocean. The microplastic concentrations are significantly correlated with urbanisation and population density, indicating that the microplastic concentrations in the river depend on human activities in the river basin. Furthermore, we found a significant relationship between the numerical and mass concentrations and BOD, which is an environmental indicator of river pollution. This result demonstrates that microplastic pollution in river environments has progressed more in polluted rivers with poor water quality than in rivers with good water quality, leading to the conclusion that the sources and inflow processes of microplastics in river environments are similar to those of other pollutants. Our findings can help identify potential sources (i.e., point and non point sources) of fragmented microplastics to improve waste management in Japan and model the transport fluxes of fragmented microplastics in Japanese rivers using water quality parameters and basin characteristics. PMID- 30469291 TI - Is residential ambient air limonene associated with asthma? Findings from the Canadian Health Measures Survey. AB - Asthma is a common chronic disease. Exposure to limonene is commonplace because it may be used in the manufacture of personal care products and household cleaners. We investigated the influence of limonene on asthma in a population based sample of approximately 3000 Canadians. During the Canada Health Measures Survey, carried out between 2012 and 2013, participants were asked if they wheezed or had a diagnosis of asthma, and underwent spirometry and measurement of the fraction of exhaled nitric oxide (FeNO). These variables were tested for an association with limonene concentrations measured in their household air samples, using linear regression analysis A 100% increase in air limonene concentration was associated with an approximate 17% adjusted relative increase wheezing with an odds ratio of 1.17 (95%CI 1.16, 1.18). The percent change in FeNO for a 100% increase in limonene was twice as large for children, 2.89% (95% CI 1.88, 4.43) compared to adults, 1.44% (95%CI 1.16, 1.79). Among boys, the odds ratio was 1.50 (95%CI 1.48, 1.52) between a 100% increase in limonene and a diagnosis of asthma. This study provides evidence that household exposure to limonene may increase the prevalence of asthma in the general population. PMID- 30469292 TI - Comparing and modeling sedimentary profiles of elemental carbon and polycyclic aromatic hydrocarbons between early- and newly-urbanized areas in Shanghai. AB - Rapid urbanization created unique urban environment with a characteristic of dramatic modification of land cover, consequently causing profound perturbations in the transport and fate of pollutants in urban ecosystem. Taking a hyper urbanization city (Shanghai) as an example to reveal the influence of urbanization development on pollutant footprint, this study reconstructed and compared historical evolutions of elemental carbon (EC) and polycyclic aromatic hydrocarbons (PAHs) based on two lake sediment cores (DSL: Dianshan Lake; LXL: Luxun Lake) from early- and newly-urbanized areas, respectively. Historical fluxes of EC and total PAH (Sigma16PAHs) showed similar and sharply fluctuant increases occurring after the 1950s in the DSL core later than the LXL core after the 1900s. In modern times (after 2000), the mean fluxes of EC and Sigma16PAHs in the LXL core were 2.68- and 1.38-fold greater than those in the DSL core, respectively, indicating the stronger influence from more intensive human activities and longer industrial history in early urbanized area. Based on the significant correlations among socioeconomic factors with EC and Sigma16PAH fluxes, the extended STIRPAT (stochastic impacts by regression on population, affluence and technology) models were successfully constructed, revealing that significance of these driving factors were in the order of population > the proportion of heavy industry > coal consumption > gross domestic product (GDP) per capita > vehicle amount. In general, the obvious discrepancy in historical stage and intensity of sedimentary EC and PAH accumulations implied that some newly fast-developing cities still have a chance to adjust urban development strategy to avoid more serious pollution. PMID- 30469293 TI - Responses of forest ecosystems in Europe to decreasing nitrogen deposition. AB - Average nitrogen (N) deposition across Europe has declined since the 1990s. This resulted in decreased N inputs to forest ecosystems especially in Central and Western Europe where deposition levels are highest. While the impact of atmospheric N deposition on forests has been receiving much attention for decades, ecosystem responses to the decline in N inputs received less attention. Here, we review observational studies reporting on trends in a number of indicators: soil acidification and eutrophication, understory vegetation, tree nutrition (foliar element concentrations) as well as tree vitality and growth in response to decreasing N deposition across Europe. Ecosystem responses varied with limited decrease in soil solution nitrate concentrations and potentially also foliar N concentrations. There was no large-scale response in understory vegetation, tree growth, or vitality. Experimental studies support the observation of a more distinct reaction of soil solution and foliar element concentrations to changes in N supply compared to the three other parameters. According to the most likely scenarios, further decrease of N deposition will be limited. We hypothesize that this expected decline will not cause major responses of the parameters analysed in this study. Instead, future changes might be more strongly controlled by the development of N pools accumulated within forest soils, affected by climate change and forest management. PMID- 30469294 TI - Letter to the Editor Regarding "De Novo Spinal Dural Arteriovenous Fistula in Patient with Lipomyelomeningocele: Case Report". PMID- 30469295 TI - Demographics of Aneurysmal Subarachnoid Hemorrhage. PMID- 30469296 TI - In Reply to "Demographics of Aneurysmal Subarachnoid Hemorrhage". PMID- 30469297 TI - Expanding Indications for Minipterional Craniotomy-Parasellar Meningiomas. PMID- 30469298 TI - In Reply to "Expanding Indications for Minipterional Craniotomy-Parasellar Meningiomas". PMID- 30469299 TI - Letter to the Editor Regarding "The Results of Neuroendoscopic Surgery in Patients with Posttraumatic and Posthemorrhagic Hydrocephalus". PMID- 30469300 TI - In Reply to the Letter to the Editor Regarding "The Results of Neuroendoscopic Surgery on Patients with Posttraumatic and Posthemorrhagic Hydrocephalus". PMID- 30469301 TI - Intraparenchymal Brain Hemorrhage: "Birdlime" Effect Usefulness. PMID- 30469302 TI - In Reply to "Intraparenchymal Brain Hemorrhage: "Birdlime" Effect Usefulness". PMID- 30469303 TI - Holistic Approach for Optimizing Patient's Care. PMID- 30469304 TI - Predictors of Outcome in Spontaneous Intracerebral Hemorrhage-Role of Oxidative Stress Biomarkers. PMID- 30469305 TI - In Reply to "Predictors of Outcome in Spontaneous Intracerebral Hemorrhage-Role of Oxidative Stress Biomarkers". PMID- 30469306 TI - Letter to the Editor Regarding "Comparison of the Effectiveness of Radiotherapy with Photons and Particles for Chordoma After Surgery: A Meta-Analysis". PMID- 30469307 TI - Hypothesis on the Origin of Dance: Mirror Neuron System and Imitation from Movement Disorders. PMID- 30469308 TI - In Reply to "Hypothesis on the Origin of Dance: Mirror Neuron System and Imitation From Movement Disorders". PMID- 30469309 TI - Second Response to Second Criticism Concerning Our Article Entitled "Aneurysm Clip Compression Technique in the Surgery of Aneurysms with Hard/Calcified Neck". PMID- 30469310 TI - In Reply to 'Second Response to Second Criticism Concerning Our Article Entitled "Aneurysm Clip Compression Technique in the Surgery of Aneurysms with Hard/Calcified Neck"'. PMID- 30469311 TI - Mismatched Expectations. PMID- 30469312 TI - Size Fractionation of Fluorescent Graphene Quantum Dots Using a Cross-Flow Membrane Filtration System. AB - Graphene quantum dots (GQDs) have received great attention as optical agents because of their low toxicity, stable photoluminescence (PL) in moderate pH solutions, and size-dependent optical properties. Although many synthetic routes have been proposed for producing GQD solutions, the broad size distribution in GQD solutions limits its use as an efficient optical agent. Here, we present a straightforward method for size fractionation of GQDs dispersed in water using a cross-flow filtration system and a track-etched membrane with cylindrical uniform nanopores. The GQD aqueous suspension, which primarily contained blue-emitting GQDs (B-GQDs) and green-emitting GQDs (G-GQDs), was introduced to the membrane in tangential flow and was fractionated with a constant permeate flow of about 800 L m-2 h-1 bar-1. After filtration, we observed a clear blue PL spectrum from the permeate side, which can be attributed to selective permeation of relatively small B-GQDs. The process provided a separation factor (B-GQDs/G-GQDs) of 0.74. In the cross-flow filtration system, size-dependent permeation through cylindrical nanochannels was confirmed by simulation. Our results demonstrate a feasible method facilitating size fractionation of two-dimensional nanostructures using a cross-flow membrane filtration system. Since membrane filtration is simple, cost-effective, and scalable, our approach can be applied to prepare a large amount of size-controlled GQDs required for high performance opto electronics and bio-imaging applications. PMID- 30469313 TI - A Simple and Convenient Synthesis of Unlabeled and 13C-Labeled 3-(3 Hydroxyphenyl)-3-Hydroxypropionic Acid and Its Quantification in Human Urine Samples. AB - An improved method to synthesize the highly abundant and biomedically important urinary metabolite 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA) is reported. The modified protocol is based on an indium-mediated sonochemical Reformatsky reaction. The synthesis is a simple two-step route as opposed to a complex four-step route previously reported in the literature that requires specialized equipment, flammable materials, and high-pressure reaction vessels. The described procedure also provides an expedient route to prepare a 13C isotopically labeled HPHPA that can be used as a standard for quantitative LC-MS analysis. This report also illustrates how the synthesized metabolite standard was used to detect and accurately quantify its presence in human urine samples using both NMR and LC-MS techniques. PMID- 30469314 TI - Relationship of Gallbladder Diseases with Sociodemographic Characteristics, Lifestyle, and Chronic Diseases in Northeastern China. AB - BACKGROUND: Gallbladder diseases are common in Jilin, China. However, there have been few previous studies on this disease. Our study used the chronic disease database in Jilin Province to study the factors correlated with gallbladder diseases. METHODS: A total of 21,435 people were selected from the Jilin Province adult chronic disease survey conducted in 2012. Multistage stratified random cluster sampling was used in this cross-sectional study. Multiple logistic regression analysis was used to explore the independent associations of different factors with gallbladder diseases. RESULTS: There were 1876 people with gallbladder diseases, and the prevalence of the diseases was 8.8% (males 4.4%, females 12.8%). Multivariate logistic regression analysis showed that female (prevalence odds ratio (POR) = 3.13, 95% confidence intervals (CIs): 2.76-3.55), older people (30-45 years (POR = 2.79, 95% CIs: 2.06-3.77), 45-60 years (POR = 4.26, 95% CIs: 3.17-5.73), 60-79 years (POR = 4.72, 95% CIs: 3.48-6.41)), people living in rural areas (POR = 1.65, 95% CIs: 1.49-1.82), smoking (current smoker (POR = 1.15, 95% CIs: 1.01-1.31), former smoker (POR = 1.37, 95% CIs: 1.13 1.66)), high frequency of eating seafood (POR = 0.77, 95% CIs: 0.63-0.93), and high frequency of eating soy products (POR = 0.50, 95% CIs: 0.44-0.58) were associated with gallbladder diseases. CONCLUSIONS: We found that there were some factors associated with gallbladder disease, and there needs to be further studies to confirm these associations. PMID- 30469315 TI - Expression of Selenoprotein Genes and Association with Selenium Status in Colorectal Adenoma and Colorectal Cancer. AB - Dietary selenium (Se) intake is essential for synthesizing selenoproteins that are important in countering oxidative and inflammatory processes linked to colorectal carcinogenesis. However, there is limited knowledge on the selenoprotein expression in colorectal adenoma (CRA) and colorectal cancer (CRC) patients, or the interaction with Se status levels. We studied the expression of seventeen Se pathway genes (including fifteen of the twenty-five human selenoproteins) in RNA extracted from disease-normal colorectal tissue pairs, in the discovery phase of sixty-two CRA/CRC patients from Ireland and a validation cohort of a hundred and five CRC patients from the Czech Republic. Differences in transcript levels between the disease and paired control mucosa were assessed by the Mann-Whitney U-test. GPX2 and TXNRD3 showed a higher expression and GPX3, SELENOP, SELENOS, and SEPHS2 exhibited a lower expression in the disease tissue from adenomas and both cancer groups (p-values from 0.023 to <0.001). In the Czech cohort, up-regulation of GPX1, SELENOH, and SOD2 and down-regulation of SELENBP1, SELENON, and SELENOK (p-values 0.036 to <0.001) was also observed. We further examined the correlation of gene expression with serum Se status (assessed by Se and selenoprotein P, SELENOP) in the Irish patients. While there were no significant correlations with both Se status markers, SELENOF, SELENOK, and TXNRD1 tumor tissue expression positively correlated with Se, while TXNRD2 and TXNRD3 negatively correlated with SELENOP. In an analysis restricted to the larger Czech CRC patient cohort, Cox regression showed no major association of transcript levels with patient survival, except for an association of higher SELENOF gene expression with both a lower disease-free and overall survival. Several selenoproteins were differentially expressed in the disease tissue compared to the normal tissue of both CRA and CRC patients. Altered selenoprotein expression may serve as a marker of functional Se status and colorectal adenoma to cancer progression. PMID- 30469316 TI - Anti-inflammatory and Neuroprotective Effects of Fungal Immunomodulatory Protein Involving Microglial Inhibition. AB - Microglia polarization of classical activation state is crucial to the induction of neuroinflammation, and has been implicated in the pathogenesis of numerous neurodegenerative diseases. Fungal immunomodulatory proteins are emerging health promoting natural substances with multiple pharmacological activities, including immunomodulation. Herein, we investigated the anti-inflammatory and neuroprotective potential of fungal immunomodulatory protein extracted from Ganoderma microsporum (GMI) in an in vitro rodent model of primary cultures. Using primary neuron/glia cultures consisting of neurons, astrocytes, and microglia, a GMI showed an alleviating effect on lipopolysaccharide (LPS)/interferon-gamma (IFN-gamma)-induced inflammatory mediator production and neuronal cell death. The events of neuroprotection caused by GMI were accompanied by the suppression of Nitric Oxide (NO), Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin-1beta (IL-1beta), and Prostaglandin E2 (PGE2) production, along with the inhibition of microglia activation. Mechanistic studies showed that the suppression of microglia pro-inflammatory polarization by GMI was accompanied by the resolution of oxidative stress, the preservation of protein tyrosine phosphatase and serine/threonine phosphatase activity, and the reduction of NF kappaB, AP-1, cyclic AMP response element-binding protein (CREB), along with signal transducers and activators of transcription (Stat1) transcriptional activities and associated upstream activators. These findings suggest that GMI may have considerable potential towards the treatment of neuroinflammation mediated neurodegenerative diseases. PMID- 30469317 TI - Legume Cytosolic and Plastid Acetyl-Coenzyme-A Carboxylase Genes Differ by Evolutionary Patterns and Selection Pressure Schemes Acting before and after Whole-Genome Duplications. AB - Acetyl-coenzyme A carboxylase (ACCase, E.C.6.4.1.2) catalyzes acetyl-coenzyme A carboxylation to malonyl coenzyme A. Plants possess two distinct ACCases differing by cellular compartment and function. Plastid ACCase contributes to de novo fatty acid synthesis, whereas cytosolic enzyme to the synthesis of very long chain fatty acids, phytoalexins, flavonoids, and anthocyanins. The narrow leafed lupin (Lupinus angustifolius L.) represents legumes, a plant family which evolved by whole-genome duplications (WGDs). The study aimed on the contribution of these WGDs to the multiplication of ACCase genes and their further evolutionary patterns. The molecular approach involved bacterial artificial chromosome (BAC) library screening, fluorescent in situ hybridization, linkage mapping, and BAC sequencing. In silico analysis encompassed sequence annotation, comparative mapping, selection pressure calculation, phylogenetic inference, and gene expression profiling. Among sequenced legumes, the highest number of ACCase genes was identified in lupin and soybean. The most abundant plastid ACCase subunit genes were accB. ACCase genes in legumes evolved by WGDs, evidenced by shared synteny and Bayesian phylogenetic inference. Transcriptional activity of almost all copies was confirmed. Gene duplicates were conserved by strong purifying selection, however, positive selection occurred in Arachis (accB2) and Lupinus (accC) lineages, putatively predating the WGD event(s). Early duplicated accA and accB genes underwent transcriptional sub-functionalization. PMID- 30469318 TI - Evaluation of Object Surface Edge Profiles Detected with a 2-D Laser Scanning Sensor. AB - Canopy edge profile detection is a critical component of plant recognition in variable-rate spray control systems. The accuracy of a high-speed 270 degrees radial laser sensor was evaluated in detecting the surface edge profiles of six complex-shaped objects. These objects were toy balls with a pink smooth surface, light brown rectangular cardboard boxes, black and red texture surfaced basketballs, white smooth cylinders, and two different sized artificial plants. Evaluations included reconstructed three-dimensional (3-D) images for the object surfaces with the data acquired from the laser sensor at four different detection heights (0.25, 0.50, 0.75, and 1.00 m) above each object, five sensor travel speeds (1.6, 2.4, 3.2, 4.0, and 4.8 km h-1), and 8 to 15 horizontal distances to the sensor ranging from 0 to 3.5 m. Edge profiles of the six objects detected with the laser sensor were compared with images taken with a digital camera. The edge similarity score (ESS) was significantly affected by the horizontal distances of the objects, and the influence became weaker when the objects were placed closer to each other. The detection heights and travel speeds also influenced the ESS slightly. The overall average ESS ranged from 0.38 to 0.95 for all the objects under all the test conditions, thereby providing baseline information for the integration of the laser sensor into future development of greenhouse variable-rate spray systems to improve pesticide, irrigation, and nutrition application efficiencies through watering booms. PMID- 30469319 TI - Concise Synthesis of (+)-beta- and gamma-Apopicropodophyllins, and Dehydrodesoxypodophyllotoxin. AB - Herein, we present an expeditous synthesis of bioactive aryldihydronaphthalene lignans (+)-beta- and gamma-apopicropodophyllins, and arylnaphthalene lignan dehydrodesoxypodophyllotoxin. The key reaction is regiocontrolled oxidations of stereodivergent aryltetralin lactones, which were easily accessed from a nickel catalyzed reductive cascade approach developed in our group. PMID- 30469320 TI - Current Status of the Sm14/GLA-SE Schistosomiasis Vaccine: Overcoming Barriers and Paradigms towards the First Anti-Parasitic Human(itarian) Vaccine. AB - Schistosomiasis, a disease historically associated with poverty, lack of sanitation and social inequality, is a chronic, debilitating parasitic infection, affecting hundreds of millions of people in endemic countries. Although chemotherapy is capable of reducing morbidity in humans, rapid re-infection demonstrates that the impact of drug treatment on transmission control or disease elimination is marginal. In addition, despite more than two decades of well executed control activities based on large-scale chemotherapy, the disease is expanding in many areas including Brazil. The development of the Sm14/GLA-SE schistosomiasis vaccine is an emblematic, open knowledge innovation that has successfully completed phase I and phase IIa clinical trials, with Phase II/III trials underway in the African continent, to be followed by further trials in Brazil. The discovery and experimental phases of the development of this vaccine gathered a robust collection of data that strongly supports the ongoing clinical phase. This paper reviews the development of the Sm14 vaccine, formulated with glucopyranosyl lipid A (GLA-SE), from the initial experimental developments to clinical trials including the current status of phase II studies. PMID- 30469321 TI - Pseudoginsengenin DQ Exhibits Therapeutic Effects in Cisplatin-Induced Acute Kidney Injury via Sirt1/NF-kappaB and Caspase Signaling Pathway without Compromising Its Antitumor Activity in Mice. AB - In this study, the protective effects of pseudoginsengenin DQ (PDQ) on cisplatin (CDDP)-induced nephrotoxicity were assessed, with a primary investigation into the mechanisms involved. Our results showed that pretreatment with PDQ remarkably restored levels of blood urea nitrogen (BUN) and creatinine (CRE), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta). Meanwhile, PDQ decreased the CDDP-induced overexpression of heme oxygenase 1 (HO 1), cytochrome P450 E1 (CYP2E1), TNF-alpha, nuclear factor-kappa B (NF-kappaB), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) in renal tissues. Hoechst 33258 and TdT-mediated dUTP nick-end labeling (TUNEL) staining showed that CDDP-induced renal tubular cell apoptosis was apparently inhibited by PDQ. Western blotting showed that PDQ reversed the CDDP-induced (1) downregulation of Sirtuin-1 (Sirt-1), nuclear-related factor 2 (Nrf2), and Bcl-2, and (2) upregulation of NF-kappaB, Nox-4, Bax, caspase-9, and caspase-3. In addition, PDQ enhanced the antitumor activity of cisplatin in Lewis lung cancer xenograft tumor model mice. In conclusion, we found that PDQ exerted a renal protective effect against CDDP-induced acute nephrotoxicity via Sirt1/NF-kappaB and the caspase signaling pathway without compromising the antitumor activity of CDDP, which provides a new potential strategy for the clinical treatment of cancer and presents a new medicinal application of PDQ. PMID- 30469322 TI - Coptisine Suppresses Mast Cell Degranulation and Ovalbumin-Induced Allergic Rhinitis. AB - Coptisine is one of the main components of isoquinoline alkaloids in the coptidis rhizome. The effect of coptisine on allergic rhinitis has not been investigated. In this study, we report the effects and mechanisms of coptisine using monoclonal anti-2,4,6-dinitrophenyl-immunoglobulin (Ig) E/human serum albumin (DNP-IgE/HSA) stimulated rat basophilic leukemia cells (RBL-2H3 cells) in vitro and an ovalbumin (OVA)-induced allergic rhinitis (AR) in mice. The results showed that coptisine markedly decreased the levels of beta-hexosaminidase, histamine, interleukin (IL)-4, and tumor necrosis factor (TNF)-alpha. Coptisine also prevented morphological changes, such as restoring an elongated shape, inhibiting granule release on toluidine blue staining, and reorganizing inhibited filamentous actins (F-actin). Additionally, coptisine blocked the phosphorylation of phosphoinositide3-kinase (PI3K)/Akt (as known as protein kinase B(PKB)) in RBL 2H3 cell. Furthermore, the results showed that coptisine suppressed OVA-induced allergic rhinitis symptoms, such as nasal rubbing and OVA-specific IgE, and histamine, IL-4 and TNF-alpha levels in the serum of AR mice. These data suggested that coptisine should have inhibitory effects on the inflammatory responses of mast cells, and may be beneficial for the development of coptisine as a potential anti-allergic drug. PMID- 30469323 TI - DOPS Adjuvant Confers Enhanced Protection against Malaria for VLP-TRAP Based Vaccines. AB - Vaccination remains the most effective and essential prophylactic tool against infectious diseases. Enormous efforts have been made to develop effective vaccines against malaria but successes remain so far limited. Novel adjuvants may offer a significant advantage in the development of malaria vaccines, in particular if combined with inherently immunogenic platforms, such as virus-like particles (VLP). Dioleoyl phosphatidylserine (DOPS), which is expressed on the outer surface of apoptotic cells, represents a novel adjuvant candidate that may confer significant advantage over existing adjuvants, such as alum. In the current study we assessed the potential of DOPS to serve as an adjuvant in the development of a vaccine against malaria either alone or combined with VLP using Plasmodium falciparum thrombospondin-related adhesive protein (TRAP) as a target antigen. TRAP was chemically coupled to VLPs derived from the cucumber mosaic virus fused to a universal T cell epitope of tetanus toxin (CuMVtt). Mice were immunized with TRAP alone or formulated in alum or DOPS and compared to TRAP coupled to CuMVtt formulated in PBS or DOPS. Induced immune responses, in particular T cell responses, were assessed as the major protective effector cell population induced by TRAP. The protective capacity of the various formulations was assessed using a transgenic Plasmodium berghei expressing PfTRAP. All vaccine formulations using adjuvants and/or VLP increased humoral and T cell immunogenicity for PfTRAP compared to the antigen alone. Display on VLPs, in particular if formulated with DOPS, induced the strongest and most protective immune response. Thus, the combination of VLP with DOPS may harness properties of both immunogenic components and optimally enhance induction of protective immune responses. PMID- 30469324 TI - Viral Proteins U41 and U70 of Human Herpesvirus 6A Are Dispensable for Telomere Integration. AB - Human herpesvirus-6A and -6B (HHV-6A and -6B) are two closely related betaherpesviruses that infect humans. Upon primary infection they establish a life-long infection termed latency, where the virus genome is integrated into the telomeres of latently infected cells. Intriguingly, HHV-6A/B can integrate into germ cells, leading to individuals with inherited chromosomally-integrated HHV-6 (iciHHV-6), who have the HHV-6 genome in every cell. It is known that telomeric repeats flanking the virus genome are essential for integration; however, the protein factors mediating integration remain enigmatic. We have previously shown that the putative viral integrase U94 is not essential for telomere integration; thus, we set out to assess the contribution of potential viral recombination proteins U41 and U70 towards integration. We could show that U70 enhances dsDNA break repair via a homology-directed mechanism using a reporter cell line. We then engineered cells to produce shRNAs targeting both U41 and U70 to inhibit their expression during infection. Using these cells in our HHV-6A in vitro integration assay, we could show that U41/U70 were dispensable for telomere integration. Furthermore, additional inhibition of the cellular recombinase Rad51 suggested that it was also not essential, indicating that other cellular and/or viral factors must mediate telomere integration. PMID- 30469325 TI - Salmonella enterica Serovar Typhimurium and Escherichia coli Survival in Estuarine Bank Sediments. AB - Estuarine bank sediments have the potential to support the survival and growth of fecal indicator organisms, including Escherichia coli. However, survival of fecal pathogens in estuarine sediments is not well researched and therefore remains a significant knowledge gap regarding public health risks in estuaries. In this study, simultaneous survival of Escherichia coli and a fecal pathogen, Salmonella enterica serovar Typhimurium, was studied for 21 days in estuarine bank sediment microcosms. Observed growth patterns for both organisms were comparable under four simulated scenarios; for continuous-desiccation, extended-desiccation, periodic-inundation, and continuous-inundation systems, logarithmic decay coefficients were 1.54/day, 1.51/day, 0.14/day, and 0.20/day, respectively, for E. coli, and 1.72/day, 1.64/day, 0.21/day, and 0.24/day for S. Typhimurium. Re wetting of continuous-desiccated systems resulted in potential re-growth, suggesting survival under moisture-limited conditions. Key findings from this study include: (i) Bank sediments can potentially support human pathogens (S. Typhimurium), (ii) inundation levels influence the survival of fecal bacteria in estuarine bank sediments, and (iii) comparable survival rates of S. Typhimurium and E. coli implies the latter could be a reliable fecal indicator in urban estuaries. The results from this study will help select suitable monitoring and management strategies for safer recreational activities in urban estuaries. PMID- 30469327 TI - Effect of Pretreatment with the NADPH Oxidase Inhibitor Apocynin on the Therapeutic Efficacy of Human Placenta-Derived Mesenchymal Stem Cells in Intracerebral Hemorrhage. AB - Several studies have demonstrated the beneficial effect of mesenchymal stem cells (MSCs) on intracerebral hemorrhage (ICH). Enhancement of the therapeutic efficacy of MSCs in ICH is necessary, considering the diseases high association with mortality and morbidity. Various preconditioning methods to enhance the beneficial properties of MSCs have been introduced. We suggested apocynin, a well known nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, as a novel preconditioning regimen to enhance the therapeutic efficacy of MSCs in ICH. Rat ICH models were made using bacterial collagenase. 24 h after ICH induction, the rats were randomly divided into apocynin-preconditioned MSC-treated (Apo MSC), naive MSC-treated and control groups. Hematoma volume, brain edema, and degenerating neuron count were compared at 48 h after the ICH induction. The expression of tight junction proteins (occludin, zona occludens [ZO]-1) were also compared. Hematoma size, hemispheric enlargement and degenerating neuron count were significantly lower in the Apo-MSC group than in the naive MSC group (p = 0.004, 0.013 and 0.043, respectively), while the expression of occludin was higher (p = 0.024). Apocynin treatment enhances the therapeutic efficacy of MSCs in ICH in the acute stage, through the improvement of the beneficial properties of MSCs, such as neuroprotection and the reinforcement of endovascular integrity of cerebral vasculature. PMID- 30469328 TI - A Tellurium Oxide Microcavity Resonator Sensor Integrated On-Chip with a Silicon Waveguide. AB - We report on thermal and evanescent field sensing from a tellurium oxide optical microcavity resonator on a silicon photonics platform. The on-chip resonator structure is fabricated using silicon-photonics-compatible processing steps and consists of a silicon-on-insulator waveguide next to a circular trench that is coated in a tellurium oxide film. We characterize the device's sensitivity by both changing the temperature and coating water over the chip and measuring the corresponding shift in the cavity resonance wavelength for different tellurium oxide film thicknesses. We obtain a thermal sensitivity of up to 47 pm/ degrees C and a limit of detection of 2.2 * 10-3 RIU for a device with an evanescent field sensitivity of 10.6 nm/RIU. These results demonstrate a promising approach to integrating tellurium oxide and other novel microcavity materials into silicon microphotonic circuits for new sensing applications. PMID- 30469329 TI - Biological Roles of Ornithine Aminotransferase (OAT) in Plant Stress Tolerance: Present Progress and Future Perspectives. AB - Plant tolerance to biotic and abiotic stresses is complicated by interactions between different stresses. Maintaining crop yield under abiotic stresses is the most daunting challenge for breeding resilient crop varieties. In response to environmental stresses, plants produce several metabolites, such as proline (Pro), polyamines (PAs), asparagine, serine, carbohydrates including glucose and fructose, and pools of antioxidant reactive oxygen species. Among these metabolites, Pro has long been known to accumulate in cells and to be closely related to drought, salt, and pathogen resistance. Pyrroline-5-carboxylate (P5C) is a common intermediate of Pro synthesis and metabolism that is produced by ornithine aminotransferase (OAT), an enzyme that functions in an alternative Pro metabolic pathway in the mitochondria under stress conditions. OAT is highly conserved and, to date, has been found in all prokaryotic and eukaryotic organisms. In addition, ornithine (Orn) and arginine (Arg) are both precursors of PAs, which confer plant resistance to drought and salt stresses. OAT is localized in the cytosol in prokaryotes and fungi, while OAT is localized in the mitochondria in higher plants. We have comprehensively reviewed the research on Orn, Arg, and Pro metabolism in plants, as all these compounds allow plants to tolerate different kinds of stresses. PMID- 30469326 TI - Beneficial Effects of Resveratrol Administration-Focus on Potential Biochemical Mechanisms in Cardiovascular Conditions. AB - Resveratrol (RV) is a natural non-flavonoid polyphenol and phytoalexin produced by a number of plants such as peanuts, grapes, red wine and berries. Numerous in vitro studies have shown promising results of resveratrol usage as antioxidant, antiplatelet or anti-inflammatory agent. Beneficial effects of resveratrol activity probably result from its ability to purify the body from ROS (reactive oxygen species), inhibition of COX (cyclooxygenase) and activation of many anti inflammatory pathways. Administration of the polyphenol has a potential to slow down the development of CVD (cardiovascular disease) by influencing on certain risk factors such as development of diabetes or atherosclerosis. Resveratrol induced an increase in Sirtuin-1 level, which by disrupting the TLR4/NF kappaB/STAT signal cascade (toll-like receptor 4/nuclear factor kappa-light-chain enhancer of activated B cells/signal transducer and activator of transcription) reduces production of cytokines in activated microglia. Resveratrol caused an attenuation of macrophage/mast cell-derived pro-inflammatory factors such as PAF (platelet-activating factor), TNF-alpha (tumour necrosis factor-alpha and histamine. Endothelial and anti-oxidative effect of resveratrol may contribute to better outcomes in stroke management. By increasing BDNF (brain-derived neurotrophic factor) serum concentration and inducing NOS-3 (nitric oxide synthase-3) activity resveratrol may have possible therapeutical effects on cognitive impairments and dementias especially in those characterized by defective cerebrovascular blood flow. PMID- 30469330 TI - In Vitro Evaluation of Sulforaphane and a Natural Analog as Potent Inducers of 5 Fluorouracil Anticancer Activity. AB - Isothiocyanates (R-NCS) are sulphur-containing phytochemicals. The main source are plants of the Brassicaceae family. The best known plant-derived isothiocyanate is sulforaphane that has exhibited anticancer activity in both in vivo and in vitro studies. Recent attempts to expand their use in cancer therapy involve combining them with standard chemotherapeutics in order to increase their therapeutic efficacy. The aim of this paper is to determine the impact of sulforaphane and its natural analog alyssin on the anticancer activity of the well-known anticancer drug 5-fluorouracil. The type of drug-drug interactions was determined in prostate and colon cancer cell lines. Confocal microscopy, western blot and flow cytometry methods were employed to determine the mechanism of cytotoxic and cytostatic action of the combinations. The study revealed that additive or synergistic interactions were observed between 5-fluorouracil and both isothiocyanates, which enhanced the anticancer activity of 5-fluorouracil, particularly in colon cancer cell lines. An increased cytostatic effect was observed in case of alyssin while for sulforaphane the synergistic interaction with 5-fluorouracil involved an intensification of apoptotic cell death. PMID- 30469331 TI - Selective Inhibition of Human AKR1B10 by n-Humulone, Adhumulone and Cohumulone Isolated from Humulus lupulus Extract. AB - Hop-derived compounds have been subjected to numerous biomedical studies investigating their impact on a wide range of pathologies. Isomerised bitter acids (isoadhumulone, isocohumulone and isohumulone) from hops, used in the brewing process of beer, are known to inhibit members of the aldo-keto-reductase superfamily. Aldo-keto-reductase 1B10 (AKR1B10) is upregulated in various types of cancer and has been reported to promote carcinogenesis. Inhibition of AKR1B10 appears to be an attractive means to specifically treat RAS-dependent malignancies. However, the closely related reductases AKR1A1 and AKR1B1, which fulfil important roles in the detoxification of endogenous and xenobiotic carbonyl compounds oftentimes crossreact with inhibitors designed to target AKR1B10. Accordingly, there is an ongoing search for selective AKR1B10 inhibitors that do not interact with endogeneous AKR1A1 and AKR1B1-driven detoxification systems. In this study, unisomerised alpha-acids (adhumulone, cohumulone and n humulone) were separated and tested for their inhibitory potential on AKR1A1, AKR1B1 and AKR1B10. Also AKR1B10-mediated farnesal reduction was effectively inhibited by alpha-acid congeners with Ki-values ranging from 16.79 +/- 1.33 uM (adhumulone) to 3.94 +/- 0.33 uM (n-humulone). Overall, alpha-acids showed a strong inhibition with selectivity (115-137 fold) for AKR1B10. The results presented herein characterise hop-derived alpha-acids as a promising basis for the development of novel and selective AKR1B10-inhibitors. PMID- 30469332 TI - Evolution and Expression Characteristics of Receptor-Like Cytoplasmic Protein Kinases in Maize, Rice and Arabidopsis. AB - Receptor-like cytoplasmic protein kinases (RLCKs) are involved in various activities in plant growth and development. We have totally identified 162, 160, and 402 RLCK genes in maize, rice, and Arabidopsis genomes, respectively. Phylogenetic analyses divided 724 RLCK genes into 15 subfamilies and similar structural patterns of kinase activity sites and functional sites were observed within the subfamilies. Furthermore, the structural patterns of intron/exon in the same subfamilies were similar, implicating their close evolutionary relationship. Chromosome distribution indicated that segmental duplication of RLCK genes might be a major mechanism contributing to the expansion of the RLCK superfamilies in maize, rice, and Arabidopsis, respectively. The analysis of the synteny relationship and gene structure indicated that the evolution of most RLCKs in maize were prior to rice and Arabidopsis. Most of the ratio of Ka/Ks is inferior to one, suggesting that RLCK genes have experienced the negative selection in maize, rice and Arabidopsis. Duplication time revealed that the maize was the earliest emergence among these three species. The expression profiles showed that there are some specifically expressed RLCK genes in maize root, leaf, ear, and tassel. These specific expression genes may participate in the developmental regulation of these maize tissues. Our results will be useful in providing new insights into evolution of RLCKs and revealing the regulatory network of maize, rice, and Arabidopsis development. PMID- 30469334 TI - Solution Conformation of Heparin Tetrasaccharide. DFT Analysis of Structure and Spin-Spin Coupling Constants. AB - Density functional theory (DFT) has provided detailed information on the molecular structure and spin-spin coupling constants of heparin tetrasaccharide (GlcNS,6S-IdoA2S-GlcNS,6S-IdoA2S-OMe) representing the predominant heparin repeating-sequence. The fully optimised molecular structures of two tetrasaccharide conformations (differing from each other in the conformational form of the sulphated iduronic acid residue-one 1C4 and the other 2S0) were obtained using the B3LYP/6-311+G(d,p) level of theory and applying explicit water molecules to simulate the presence of a solvent. The theoretical data provided insight into variations of the bond lengths, bond angles and torsion angles, formations of intra- and intermolecular hydrogen bonds and ionic interactions. Optimised molecular structures indicated the formation of a complex hydrogen bond network, including interresidue and intraresidue bonds. The ionic interactions strongly influence the first hydration shell and, together with hydrogen bonds, play an important role in shaping the 3D tetrasaccharide structure. DFT-derived indirect three-bond proton-proton coupling constants (3JH-C-C-H) showed that the best agreement with experiment was obtained with a weighted average of 67:33 (1C4:2S0) of the IdoA2S forms. Detailed analysis of Fermi-contact contributions to 3JH-C-C-H showed that important contributions arise from the oxygen lone pairs of neighbouring oxygen atoms. The analysis also showed that the magnitude of diamagnetic spin-orbit contributions are sufficiently large to determine the magnitude of some proton-proton coupling constants. The data highlight the need to use appropriate quantum-chemical calculations for a detailed understanding of the solution properties of heparin oligosaccharides. PMID- 30469333 TI - Lipoprotein Subclass Profile after Progressive Energy Deficits Induced by Calorie Restriction or Exercise. AB - Weight loss, induced by chronic energy deficit, improves the blood lipid profile. However, the effects of an acute negative energy balance and the comparative efficacy of diet and exercise are not well-established. We determined the effects of progressive, acute energy deficits (20% or 40% of daily energy requirements) induced by a single day of calorie restriction (n = 19) or aerobic exercise (n = 13) in healthy subjects (age: 26 +/- 9 years; body mass index (BMI): 21.8 +/- 2.9 kg/m2). Fasting plasma concentrations of very low-, intermediate-, low-, and high density lipoprotein (VLDL, LDL, IDL, and HDL, respectively) particles and their subclasses were determined using nuclear magnetic resonance. Total plasma triglyceride and VLDL-triglyceride concentrations decreased after calorie restriction and exercise (all p <= 0.025); the pattern of change was linear with an increasing energy deficit (all p < 0.03), with no evidence of plateauing. The number of circulating large and medium VLDL particles decreased after diet and exercise (all p < 0.015), with no change in small VLDL particles. The concentrations of IDL, LDL, and HDL particles, their relative distributions, and the particle sizes were not altered. Our data indicate that an acute negative energy balance induced by calorie restriction and aerobic exercise reduces triglyceride concentrations in a dose-dependent manner, by decreasing circulating large and medium VLDL particles. PMID- 30469335 TI - Validation of Finite Element Model by Smart Aggregate-Based Stress Monitoring. AB - Concrete compressive strength is an important parameter of material properties for assessing seismic performance of reinforced concrete (RC) structures, which has a certain level of uncertainty due to its inherent variability. In this paper, the method of concrete strength validation of finite element model using smart aggregate (SA)-based stress monitoring is proposed. The FE model was established using Open System for Earthquake Engineering Simulation (OpenSEES) platform. The concrete strengths obtained from the material test, peak stress of SA, and estimated concrete strength based on SA stress were employed in FE models. The lateral displacement monitored by Liner variable differential transformer and vertical axial load monitored by load cell in the experiment are applied in the model. By comparing the global response (i.e., lateral reaction force and hysteretic loop), local response (i.e., concrete stress, rebar strain, and cross-section moment) and corresponding root-mean-square error obtained from experiment and numerical analysis, the capabilities of validation of FE model using SA-based stress monitoring method were demonstrated. PMID- 30469336 TI - Editorial for the Special Issue on 3D Printed Microfluidic Devices. AB - Three-dimensional (3D) printing has revolutionized the microfabrication prototyping workflow over the past few years. [...]. PMID- 30469337 TI - Recurrent Kawasaki Disease: A Case Report of Three Separate Episodes at >4-Year Intervals. AB - Kawasaki disease (KD) is a self-limited systemic vasculitis, most often occurring in children 1-5 years old. It has a 2% recurrence rate and is associated with coronary aneurysms (CA), which can develop within two weeks of onset. A 25% increased risk is noted in patients who are recalcitrant to treatment. We describe a patient with recurrence of KD three times, approximately four years apart. A 10-year-old female with two previous episodes of KD, at 11 months and five years of age), in which she met five out of five criteria for KD and had no coronary involvement, presented with 15 days of fever, conjunctivitis and mucocutaneous changes. Infectious work-up was negative, and she was diagnosed with incomplete KD meeting three out of five criteria. An echocardiogram (ECHO) on day 12 revealed dilation of the right coronary artery (RCA) and left coronary artery (LCA). Treatment with intravenous immunoglobulin (IVIG) and high-dose aspirin was started at an outside hospital. After transfer, serial ECHOs showed evolving coronary aneurysms, left anterior descending (LAD) z-score + 8.2 and RCA z-score + 4.0. She received 10 mg/kg infliximab (day 18) and began clopidogrel. A cardiac MRI (day 20) demonstrated progression of the LAD aneurysm, with a z-score + 13, and warfarin was started. To our knowledge, this is the first report of recurrent KD occurring three times at ~5 year intervals. PMID- 30469338 TI - A Cysteine-Reactive Small Photo-Crosslinker Possessing Caged-Fluorescence Properties: Binding-Site Determination of a Combinatorially-Selected Peptide by Fluorescence Imaging/Tandem Mass Spectrometry. AB - To determine the binding-site of a combinatorially-selected peptide possessing a fluoroprobe, a novel cysteine reactive small photo-crosslinker that can be excited by a conventional long-wavelength ultraviolet handlamp (365 nm) was synthesized via Suzuki coupling with three steps. The crosslinker is rationally designed, not only as a bioisostere of the fluoroprobe, but as a caged fluorophore, and the photo-crosslinked target protein became fluorescent with a large Stokes-shift. By introducing the crosslinker to a designated sulfhydryl (SH) group of a combinatorially-selected peptide, the protein-binding site of the targeted peptide was deduced by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)/fluorescence imaging followed by matrix-assisted laser desorption ionization-time of flight tandem mass spectrometry (MALDI-TOF-MS/MS) analysis. PMID- 30469341 TI - Effects of Compressive Stockings and Standard Stockings in Skin Temperature and Pressure Pain Threshold in Runners with Functional Ankle Equinus Condition. AB - OBJECTIVE: To assess clinical differences in the Achilles tendons of runners with ankle equinus wearing either compressive or standard stockings. DESIGN: Case control study. METHODS: In this study, we conducted clinical examinations of 98 sportsmen (runners) with equinus, before and after 30 min of running on a treadmill; 49 runners wore compressive stockings and 49 wore standard stockings. Clinical assessments of the runners' Achilles tendons were based on the pressure pain threshold (PPT) and skin temperature analysis. RESULTS: Achilles tendon evaluations identified significant differences in skin temperature modification and PPT between the compressive and standard stocking groups. CONCLUSIONS: Based on our findings, we propose that higher skin temperatures are associated with lower pressure pain thresholds in the Achilles tendons of runners with ankle equinus. PMID- 30469342 TI - Eliminating Neglected Tropical Diseases in Urban Areas: A Review of Challenges, Strategies and Research Directions for Successful Mass Drug Administration. AB - Since 1950, the global urban population grew from 746 million to almost 4 billion and is expected to reach 6.4 billion by mid-century. Almost 90% of this increase will take place in Asia and Africa and disproportionately in urban slums. In this context, concerns about the amplification of several neglected tropical diseases (NTDs) are warranted and efforts towards achieving effective mass drug administration (MDA) coverage become even more important. This narrative review considers the published literature on MDA implementation for specific NTDs and in country experiences under the ENVISION and END in Africa projects to surface features of urban settings that challenge delivery strategies known to work in rural areas. Discussed under the thematics of governance, population heterogeneity, mobility and community trust in MDA, these features include weak public health infrastructure and programs, challenges related to engaging diverse and dynamic populations and the limited accessibility of certain urban settings such as slums. Although the core components of MDA programs for NTDs in urban settings are similar to those in rural areas, their delivery may need adjustment. Effective coverage of MDA in diverse urban populations can be supported by tailored approaches informed by mapping studies, research that identifies context specific methods to increase MDA coverage and rigorous monitoring and evaluation. PMID- 30469340 TI - Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport. AB - Nuclear transport receptors of the karyopherin superfamily of proteins transport macromolecules from one compartment to the other and are critical for both cell physiology and pathophysiology. The nuclear transport machinery is tightly regulated and essential to a number of key cellular processes since the spatiotemporally expression of many proteins and the nuclear transporters themselves is crucial for cellular activities. Dysregulation of the nuclear transport machinery results in localization shifts of specific cargo proteins and associates with the pathogenesis of disease states such as cancer, inflammation, viral illness and neurodegenerative diseases. Therefore, inhibition of the nuclear transport system has future potential for therapeutic intervention and could contribute to the elucidation of disease mechanisms. In this review, we recapitulate clue findings in the pathophysiological significance of nuclear transport processes and describe the development of nuclear transport inhibitors. Finally, clinical implications and results of the first clinical trials are discussed for the most promising nuclear transport inhibitors. PMID- 30469343 TI - Synthesis and Biological Evaluation of Phaeosphaeride A Derivatives as Antitumor Agents. AB - New derivatives of phaeosphaeride A (PPA) were synthesized and characterized. Anti-tumor activity studies were carried out on the HCT-116, PC3, MCF-7, A549, K562, NCI-N929, Jurkat, THP-1, RPMI8228 tumor cell lines, and on the HEF cell line. All of the compounds synthesized were found to have better efficacy than PPA towards the tumor cell lines mentioned. Compound 6 was potent against six cancer cell lines, HCT-116, PC-3, K562, NCI-H929, Jurkat, and RPMI8226, showing a 47, 13.5, 16, 4, 1.5, and 7-fold increase in anticancer activity comparative to those of etoposide, respectively. Compound 1 possessed selectivity toward the NCI H929 cell line (IC50 = 1.35 +/- 0.69 MUM), while product 7 was selective against three cancer cell lines, HCT-116, MCF-7, and NCI-H929, each having IC50 values of 1.65 MUM, 1.80 MUM and 2.00 MUM, respectively. PMID- 30469344 TI - A Review on Electroporation-Based Intracellular Delivery. AB - Intracellular delivery is a critical step in biological discoveries and has been widely utilized in biomedical research. A variety of molecular tools have been developed for cell-based gene therapies, including FDA approved CAR-T immunotherapy, iPSC, cell reprogramming and gene editing. Despite the inspiring results of these applications, intracellular delivery of foreign molecules including nucleic acids and proteins remains challenging. Efficient yet non invasive delivery of biomolecules in a high-throughput manner has thus long fascinates the scientific community. As one of the most popular non-viral technologies for cell transfection, electroporation has gone through enormous development with the assist of nanotechnology and microfabrication. Emergence of miniatured electroporation system brought up many merits over the weakness of traditional electroporation system, including precise dose control and high cell viability. These new generation of electroporation systems are of considerable importance to expand the biological applications of intracellular delivery, bypassing the potential safety issue of viral vectors. In this review, we will go over the recent progresses in the electroporation-based intracellular delivery and several potential applications of cutting-edge research on the miniatured electroporation, including gene therapy, cellular reprogramming and intracellular probe. PMID- 30469339 TI - Copper-Fructose Interactions: A Novel Mechanism in the Pathogenesis of NAFLD. AB - Compelling epidemiologic data support the critical role of dietary fructose in the epidemic of obesity, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). The metabolic effects of fructose on the development of metabolic syndrome and NAFLD are not completely understood. High fructose intake impairs copper status, and copper-fructose interactions have been well documented in rats. Altered copper-fructose metabolism leads to exacerbated experimental metabolic syndrome and NAFLD. A growing body of evidence has demonstrated that copper levels are low in NAFLD patients. Moreover, hepatic and serum copper levels are inversely correlated with the severity of NAFLD. Thus, high fructose consumption and low copper availability are considered two important risk factors in NAFLD. However, the causal effect of copper-fructose interactions as well as the effects of fructose intake on copper status remain to be evaluated in humans. The aim of this review is to summarize the role of copper-fructose interactions in the pathogenesis of the metabolic syndrome and discuss the potential underlying mechanisms. This review will shed light on the role of copper homeostasis and high fructose intake and point to copper-fructose interactions as novel mechanisms in the fructose induced NAFLD. PMID- 30469345 TI - Water Regime Evolution of Large Seasonal Lakes: Indicators for Characterization and an Application in Poyang Lake, China. AB - Impacted by ongoing climate change and anthropogenic activities, large seasonal lakes experience water regime evolution, which raises challenges for the management of water resources and environment. The water regime evolution refers to the spatial and temporal alterations in the hydrological features of lakes. Characterizing the lake water regime and its alteration may help policymakers design effective adaption strategies. Therefore, total 47 hydrological indicators were proposed, considering intra-annual fluctuations, flood and drought features, and rate and frequency of water level variations. Combined with Mann-Kendall algorithm and Sen's slope, the indicators were applied in Poyang Lake, a typically large seasonal lake in China, as a case study. The results revealed temporal and spatial variations in different hydrological indicators. The most dramatic alteration was the water level decline in October and November over the entire study phase, especially over the past 30 years. This was an urgent environmental problem that Poyang Lake faced, partially caused by the increased hydraulic gradient between southern and northern lake. It could trigger the drought occurring earlier, prolong the drought duration, and impair the wetland ecosystem. Environmental water requirements of both Poyang Lake and Yangtze River were suggested for regional sustainable development. The application in Poyang Lake showed the practicability and reliability of the indicators, which are applicable in international seasonal lakes. The series of indicators can be used in whole or in part, determined by the ecohydrological characters of a specific lake and the research objectives. PMID- 30469346 TI - Gallbladder Stone Disease Is Associated with an Increased Risk of Migraines. AB - Background: Several pathophysiological mechanisms are shared in both gallbladder stone disease (GSD) and migraines. We assessed the migraine risk for patients diagnosed with GSD. Methods: We identified 20,427 patients who were diagnosed with GSD between 2000 and 2011 from Taiwan's National Health Insurance Research Database (NHIRD) as the study cohort. We randomly selected 81,706 controls from the non-GSD population with frequency matching by age and index year for the control cohort. All patient cases were followed until the end of 2011 to measure the incidence of migraines. Results: The cumulative incidence of migraines was greater in patients with GSD than in those without GSD (log-rank test: p < 0.001). The risk of migraine (3.89 vs. 2.30 per 10,000 person-years, adjusted hazard ratio (aHR) = 1.56, 95% confidence interval (CI) = 1.41-1.73) was greater for the GSD cohort than that for the non-GSD cohort. The risk of migraine increased with the time of follow-up after a diagnosis of GSD. The risk of migraine contributed by GSD was greater for all age groups. The risk of migraine for GSD patients with depression (aHR = 2.89, 95% CI = 2.21-3.77), anxiety (aHR = 2.07, 95% CI = 1.58-2.70), and coronary artery disease (CAD) (aHR = 2.05, 95% CI = 1.69-2.48) tended to be greater than that for GSD patients without depression (aHR = 1.54, 95% CI = 1.39-1.72), anxiety (aHR = 1.62, 95% CI = 1.46-1.81), and CAD (aHR = 1.65, 95% CI = 1.47-1.85), respectively. Compared with the patients without GSD, the risk of developing migraines was greater in those GSD patients either with (aHR = 1.39, 95% CI = 1.19-1.63) or without (aHR = 1.67, 95% CI = 1.48-1.88) cholecystectomy. Compared with the GSD patients that have not had a cholecystectomy, the risk of developing migraines was lower in the GSD patients that had a cholecystectomy (aHR = 0.83, 95% CI = 0.69-0.99). Conclusions: GSD is associated with an increased risk of migraines in the Taiwanese population, but the risk diminishes after a cholecystectomy. Furthermore, in the development of migraines, GSD is synergic with some migraine-associated comorbidities, such as CAD, depression, and anxiety. Further study is necessary to clarify whether GSD is a causal risk factor for migraine. PMID- 30469347 TI - Metabolic Changes of Amino Acids and Flavonoids in Tea Plants in Response to Inorganic Phosphate Limitation. AB - The qualities of tea (Camellia sinensis) are not clearly understood in terms of integrated leading molecular regulatory network mechanisms behind inorganic phosphate (Pi) limitation. Thus, the present work aims to elucidate transcription factor-dependent responses of quality-related metabolites and the expression of genes to phosphate (P) starvation. The tea plant organs were subjected to metabolomics analysis by GC*GC-TOF/MS and UPLC-Q-TOF/MS along with transcription factors and 13 metabolic genes by qRT-PCR. We found P starvation upregulated SPX2 and the change response of Pi is highly dependent on young shoots. This led to increased change in abundance of carbohydrates (fructose and glucose), amino acids in leaves (threonine and methionine), and root (phenylalanine, alanine, tryptophan, and tyrosine). Flavonoids and their glycosides accumulated in leaves and root exposed to P limitation was consistent with the upregulated expression of anthocyanidin reductase (EC 1.3.1.77), leucoanthocyanidin dioxygenase (EC 1.4.11.19) and glycosyltransferases (UGT78D1, UGT78D2 and UGT57L12). Despite the similar kinetics and high correlation response of Pi and SPX2 in young shoots, predominating theanine and other amino acids (serine, threonine, glutamate, valine, methionine, phenylalanine) and catechin (EGC, EGCG and CG) content displayed opposite changes in response to Pi limitation between Fengqing and Longjing-43 tea cultivars. PMID- 30469348 TI - The Association between Children's and Parents' Co-TV Viewing and Their Total Screen Time in Six European Countries: Cross-Sectional Data from the Feel4diabetes-Study. AB - In many European children, high levels of screen time can be found, which is associated with several adverse health outcomes. Therefore, there is a need for identifying effective intervention strategies that reduce screen time in children. A factor that may contribute to excessive screen time in children may be "co-TV viewing" (i.e., the time that parents and children spend on watching TV together), as parents often recognize the importance of limiting children's (individual) screen time, but often encourage TV viewing as a family because of its perceived benefits (e.g., educational purposes). The primary aim of this study was to investigate the (sex-specific) association between co-TV viewing and both children's and parents' screen time, and these associations were investigated across and within six European countries. In total, 10,969 parents (Meanage = 40.7 +/- 5.3 years, MeanBMI = 24.4 +/- 4.6) of primary school children (Meanage = 8.2 +/- 1.0 years, 49.0% boys, MeanBMI = 17.3 +/- 2.8) completed a questionnaire assessing co-TV viewing and screen time. Multilevel regression analyses were conducted. Across countries, positive associations were found between co-TV viewing and both children's (beta = 11.85, SE = 3.69, p < 0.001) and parents' screen time (beta = 14.47, SE = 4.43, p = 0.001). Similar associations were found in most (but not all) countries. The results suggest that targeting co-TV viewing might be a promising intervention strategy because of its potential to limit screen time of both children and parents. PMID- 30469350 TI - Biotherapeutics: Challenges and Opportunities for Predictive Toxicology of Monoclonal Antibodies. AB - Biotherapeutics are a rapidly growing portion of the total pharmaceutical market accounting for almost one-half of recent new drug approvals. A major portion of these approvals each year are monoclonal antibodies (mAbs). During development, non-clinical pharmacology and toxicology testing of mAbs differs from that done with chemical entities since these biotherapeutics are derived from a biological source and therefore the animal models must share the same epitopes (targets) as humans to elicit a pharmacological response. Mechanisms of toxicity of mAbs are both pharmacological and non-pharmacological in nature; however, standard in silico predictive toxicological methods used in research and development of chemical entities currently do not apply to these biotherapeutics. Challenges and potential opportunities exist for new methodologies to provide a more predictive program to assess and monitor potential adverse drug reactions of mAbs for specific patients before and during clinical trials and after market approval. PMID- 30469349 TI - Static Range of Motion of the First Metatarsal in the Sagittal and Frontal Planes. AB - The first metatarsal and medial cuneiform form an important functional unit in the foot, called "first ray". The first ray normal range of motion (ROM) is difficult to quantify due to the number of joints that are involved. Several methods have previously been proposed. Controversy exists related to normal movement of the first ray frontal plane accompanying that in the sagittal plane. The objective of this study was to investigate the ROM of the first ray in the sagittal and frontal planes in normal feet. Anterior-posterior radiographs were done of the feet of 40 healthy participants with the first ray in a neutral position, maximally dorsiflexed and maximally plantarflexed. They were digitalized and the distance between the tibial malleolus and the intersesamoid crest in the three positions mentioned was measured. The rotation of the first ray in these three positions was measured. A polynomic function that fits a curve describing the movement observed in the first ray was obtained using the least squares method. ROM of the first ray in the sagittal plane was 6.47 (SD 2.59) mm of dorsiflexion and 6.12 (SD 2.55) mm of plantarflexion. ROM in the frontal plane was 2.69 (SD 4.03) degrees of inversion during the dorsiflexion and 2.97 (SD 2.72) degrees during the plantarflexion. A second-degree equation was obtained, which represents the movement of the first ray. Passive dorsiflexion and plantarflexion of the first ray were accompanied by movements in the frontal plane: 0.45 degrees of movement were produced in the frontal plane for each millimeter of displacement in the sagittal plane. These findings might be useful for the future design of instruments for clinically quantifying first ray mobility. PMID- 30469351 TI - A Bayesian Density Model Based Radio Signal Fingerprinting Positioning Method for Enhanced Usability. AB - Indoor navigation and location-based services increasingly show promising marketing prospects. Indoor positioning based on Wi-Fi radio signal has been studied for more than a decade because Wi-Fi, a signal of opportunity without extra cost, is extensively deployed for internet connections. Bayesian fingerprinting positioning, a classical Wi-Fi-based indoor positioning method, consists of two phases: radio map learning and position inference. Thus far, the application of Bayesian fingerprinting positioning is limited due to its poor usability; radio map learning requires an adequate number of received signal strength indication (RSSI) observables at each reference point, long-term fieldwork, and high development and maintenance costs. In this paper, based on a statistical analysis of actual RSSI observables, a Weibull-Bayesian density model is proposed to represent the probability density of Wi-Fi RSSI observables. The Weibull model, which is parameterized with three parameters that can be calculated with fewer samples, can calculate the probability density with a higher accuracy than the traditional histogram method. Furthermore, the parameterized Weibull model can simplify the radio map by storing only three parameters that can restore the whole probability density, i.e., it is not necessary to store the probability distribution based on traditionally separated RSSI bins. Bayesian positioning inference is performed in the positioning phase using probability density rather than the traditional probability distribution of predefined RSSI bins. The proposed method was implemented on an Android smartphone, and the performance was evaluated in different indoor environments. Results revealed that the proposed method enhanced the usability of Wi-Fi Bayesian fingerprinting positioning by requiring fewer RSSI observables and improved the positioning accuracy by 19-32% in different building environments compared with the classic histogram-based method, even when more samples were used. PMID- 30469352 TI - Functional Biological Activity of Sorafenib as a Tumor-Treating Field Sensitizer for Glioblastoma Therapy. AB - Glioblastoma, the most common primary brain tumor in adults, is an incurable malignancy with poor short-term survival and is typically treated with radiotherapy along with temozolomide. While the development of tumor-treating fields (TTFields), electric fields with alternating low and intermediate intensity has facilitated glioblastoma treatment, clinical outcomes of TTFields are reportedly inconsistent. However, combinatorial administration of chemotherapy with TTFields has proven effective for glioblastoma patients. Sorafenib, an anti-proliferative and apoptogenic agent, is used as first-line treatment for glioblastoma. This study aimed to investigate the effect of sorafenib on TTFields-induced anti-tumor and anti-angiogenesis responses in glioblastoma cells in vitro and in vivo. Sorafenib sensitized glioblastoma cells to TTFields, as evident from significantly decreased post-TTFields cell viability (p < 0.05), and combinatorial treatment with sorafenib and TTFields accelerated apoptosis via reactive oxygen species (ROS) generation, as evident from Poly (ADP ribose) polymerase (PARP) cleavage. Furthermore, use of sorafenib plus TTFields increased autophagy, as evident from LC3 upregulation and autophagic vacuole formation. Cell cycle markers accumulated, and cells underwent a G2/M arrest, with an increased G0/G1 cell ratio. In addition, the combinatorial treatment significantly inhibited tumor cell motility and invasiveness, and angiogenesis. Our results suggest that combination therapy with sorafenib and TTFields is slightly better than each individual therapy and could potentially be used to treat glioblastoma in clinic, which requires further studies. PMID- 30469354 TI - Degradation of the Nonsteroidal Anti-Inflammatory Drug Piroxicam by Iron Activated Persulfate: The Role of Water Matrix and Ultrasound Synergy. AB - This work examined the oxidation of Piroxicam (PIR), a representative nonsteroidal anti-inflammatory drug using iron activated persulfate. The effect of persulfate dosing was vital for the efficiency of the process. The addition of 20 mg/L sodium persulfate (SPS) eliminated 500 MUg/L of PIR in less than 20 min at natural pH. PIR decomposition followed pseudo-first-order kinetics, and the observed kinetic constant increased by 2.1 times when the initial concentration of PIR decreased from 2000 to 250 MUg/L. Acidic pH favored the PIR destruction, while both sulfate and hydroxyl radicals are involved in PIR destruction at natural pH. The effect of inorganic ions like bicarbonate and chlorides was almost insignificant on PIR removal. The presence of humic acid reduced PIR removal from 100% to 67% after 20 min of treatment with 2 mg/L Fe2+ and 20 mg/L SPS. The experiment that was performed with bottled water showed similar efficiency with ultrapure water, while in the case of secondary effluent, PIR removal decreased by 26% after 30 min of treatment. The Fe2+/SPS/ultrasound hybrid process showed a low degree of synergy (18.3%). The ecotoxicity of aqueous solution using the Vibrio fischeri as an indicator was reduced during the treatment, although with a different trend from the removal of PIR, possibly due to byproducts derived from the oxidation of secondary effluent and PIR. PMID- 30469355 TI - Hierarchical Clustering of DNA k-mer Counts in RNAseq Fastq Files Identifies Sample Heterogeneities. AB - We apply hierarchical clustering (HC) of DNA k-mer counts on multiple Fastq files. The tree structures produced by HC may reflect experimental groups and thereby indicate experimental effects, but clustering of preparation groups indicates the presence of batch effects. Hence, HC of DNA k-mer counts may serve as a diagnostic device. In order to provide a simple applicable tool we implemented sequential analysis of Fastq reads with low memory usage in an R package (seqTools) available on Bioconductor. The approach is validated by analysis of Fastq file batches containing RNAseq data. Analysis of three Fastq batches downloaded from ArrayExpress indicated experimental effects. Analysis of RNAseq data from two cell types (dermal fibroblasts and Jurkat cells) sequenced in our facility indicate presence of batch effects. The observed batch effects were also present in reads mapped to the human genome and also in reads filtered for high quality (Phred > 30). We propose, that hierarchical clustering of DNA k mer counts provides an unspecific diagnostic tool for RNAseq experiments. Further exploration is required once samples are identified as outliers in HC derived trees. PMID- 30469353 TI - Parental Education Attainment and Educational Upward Mobility; Role of Race and Gender. AB - Background. The Minorities' Diminished Return theory suggests that education attainment and other socioeconomic resources have smaller effects on the health and well-being of African Americans and other racial and ethnic minorities compared to Whites. Racial and ethnic differences in the processes involved with educational upward mobility may contribute to the diminished returns of education attainment for African Americans compared to Whites. Aim: This study compared African Americans and non-Hispanic Whites for the effect of parental education attainment on educational upward mobility and explored gender differences in these effects. Methods. The National Survey of American Life (NSAL 2003) is a nationally representative survey of American adults. Participants included 891 non-Hispanic White and 3570 African American adults. Gender, race/ethnicity, age, highest parental education attainment, and respondents' educational attainment were measured. Data were analyzed using linear regression models. Results. Overall, higher parental education attainment was associated with higher educational upward mobility (b = 0.34, p < 0.001), however, this boosting effect was significantly smaller for African Americans compared to Whites (b = -0.13, p = 0.003). Our further analysis showed that race by parental education attainment can be found for females (b = -0.14, p = 0.013) but not males (p > 0.05). Conclusion. African American females are at a disadvantage compared to White females regarding the effect of parental education attainment on their educational upward mobility, a phenomenon which could not be observed when comparing African American and White males. These results advocate for taking intersectionality frameworks to study the effects of race, gender, and class in the US. PMID- 30469356 TI - mRNA Expression and Activity of Nucleoside Transporters in Human Hepatoma HepaRG Cells. AB - The HepaRG cell line is a highly differentiated human hepatoma cell line, displaying the expression of various drug transporters. However, functional expression of nucleoside transporters remains poorly characterized in HepaRG cells, although these transporters play a key role in hepatic uptake of antiviral and anticancer drugs. The present study was, therefore, designed to characterize the expression, activity and regulation of equilibrative (ENT) and concentrative (CNT) nucleoside transporter isoforms in differentiated HepaRG cells. These cells were found to exhibit a profile of nucleoside transporter mRNAs similar to that found in human hepatocytes, i.e., notable expression of ENT1, ENT2 and CNT1, with very low or no expression of CNT2 and CNT3. ENT1 activity was, next, demonstrated to be the main uridine transport activity present in HepaRG cells, like in cultured human hepatocytes. Various physiological factors, such as protein kinase C (PKC) activation or treatment by inflammatory cytokines or hepatocyte growth factor (HGF), were additionally found to regulate expression of ENT1, ENT2 and CNT1; PKC activation and HGF notably concomitantly induced mRNA expression and activity of ENT1 in HepaRG cells. Overall, these data suggest that HepaRG cells may be useful for analyzing cellular pharmacokinetics of nucleoside-like drugs in human hepatic cells, especially of those handled by ENT1. PMID- 30469357 TI - Platycodin D Suppresses Type 2 Porcine Reproductive and Respiratory Syndrome Virus In Primary and Established Cell Lines. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is a continuous threat to the pork industry as it continues to cause significant economic loss worldwide. Currently, vaccination strategies provide very limited protection against PRRSV transmission. Consequently, there is an urgent need to develop new antiviral strategies. Platycodin D (PD) is one of the major bioactive triterpenoid saponins derived from Platycodon grandiflorum, a traditional Chinese medicine used as an expectorant for pulmonary diseases and a remedy for respiratory disorders. Here, we demonstrate that PD exhibits potent activity against PRRSV infection in Marc-145 cells and primary porcine alveolar macrophages. PD exhibited broad-spectrum inhibitory activities in vitro against high pathogenic type 2 PRRSV GD-HD strain and GD-XH strain as well as classical CH-1a and VR2332 strains. PD at concentrations ranging 1-4 MUM significantly inhibited PRRSV RNA synthesis, viral protein expression and progeny virus production in a dose-dependent manner. EC50 values of PD against four tested PRRSV strains infection in Marc-145 cells ranged from 0.74 to 1.76 MUM. Mechanistically, PD inhibited PRRSV replication by directly interacting with virions therefore affecting multiple stages of the virus life cycle, including viral entry and progeny virus release. In addition, PD decreased PRRSV- and LPS induced cytokine (IFN-alpha, IFN-beta, IL-1alpha, IL-6, IL-8 and TNF-alpha) production in PAMs. Altogether, our findings suggested that PD is a potent inhibitor of PPRSV infection in vitro. However, further in vivo studies are necessary to confirm PD as a potential novel and effective PPRSV inhibitor in swine. PMID- 30469358 TI - Interactions Between Spermine-Derivatized Tentacle Porphyrins and The Human Telomeric DNA G-Quadruplex. AB - G-rich DNA sequences have the potential to fold into non-canonical G-Quadruplex (GQ) structures implicated in aging and human diseases, notably cancers. Because stabilization of GQs at telomeres and oncogene promoters may prevent cancer, there is an interest in developing small molecules that selectively target GQs. Herein, we investigate the interactions of meso-tetrakis-(4 carboxysperminephenyl)porphyrin (TCPPSpm4) and its Zn(II) derivative (ZnTCPPSpm4) with human telomeric DNA (Tel22) via UV-Vis, circular dichroism (CD), and fluorescence spectroscopies, resonance light scattering (RLS), and fluorescence resonance energy transfer (FRET) assays. UV-Vis titrations reveal binding constants of 4.7 * 106 and 1.4 * 107 M-1 and binding stoichiometry of 2-4:1 and 10-12:1 for TCPPSpm4 and ZnTCPPSpm4, respectively. High stoichiometry is supported by the Job plot data, CD titrations, and RLS data. FRET melting indicates that TCPPSpm4 stabilizes Tel22 by 36 +/- 2 degrees C at 7.5 eq., and that ZnTCPPSpm4 stabilizes Tel22 by 33 +/- 2 degrees C at ~20 eq.; at least 8 eq. of ZnTCPPSpm4 are required to achieve significant stabilization of Tel22, in agreement with its high binding stoichiometry. FRET competition studies show that both porphyrins are mildly selective for human telomeric GQ vs duplex DNA. Spectroscopic studies, combined, point to end-stacking and porphyrin self association as major binding modes. This work advances our understanding of ligand interactions with GQ DNA. PMID- 30469359 TI - Phase Transformation, Twinning, and Detwinning of NiTi Shape-Memory Alloy Subject to a Shock Wave Based on Molecular-Dynamics Simulation. AB - Martensitic transformation, reverse martensitic transformation, twinning, and detwinning of equiatomic nickel-titanium shape-memory alloy (NiTi SMA) under the action of a shock wave are studied using a molecular-dynamics simulation. In the loading process of a shock wave, B2 austenite is transformed into B19' martensite, whereas in the unloading process of the shock wave, B19' martensite is transformed into B2 austenite. With repeated loading and unloading of the shock wave, martensitic transformation occurs along with twinning, but reverse martensitic transformation appears along with detwinning. The mechanisms for the twinning and detwinning of NiTi SMA subjected to a shock wave are revealed in order to lay the theoretical foundation to investigate the shape-memory effect and superelasticity. PMID- 30469360 TI - Virulence of Marburg Virus Angola Compared to Mt. Elgon (Musoke) in Macaques: A Pooled Survival Analysis. AB - Angola variant (MARV/Ang) has replaced Mt. Elgon variant Musoke isolate (MARV/MtE Mus) as the consensus standard variant for Marburg virus research and is regarded as causing a more aggressive phenotype of disease in animal models; however, there is a dearth of published evidence supporting the higher virulence of MARV/Ang. In this retrospective study, we used data pooled from eight separate studies in nonhuman primates experimentally exposed with either 1000 pfu intramuscular (IM) MARV/Ang or MARV/MtE-Mus between 2012 and 2017 at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID). Multivariable Cox proportional hazards regression was used to evaluate the association of variant type with time to death, the development of anorexia, rash, viremia, and 10 select clinical laboratory values. A total of 47 cynomolgus monkeys were included, of which 18 were exposed to MARV/Ang in three separate studies and 29 to MARV/MtE-Mus in five studies. Following universally fatal Marburg virus exposure, compared to MARV/MtE-Mus, MARV/Ang was associated with an increased risk of death (HR = 22.10; 95% CI: 7.08, 68.93), rash (HR = 5.87; 95% CI: 2.76, 12.51) and loss of appetite (HR = 35.10; 95% CI: 7.60, 162.18). Our data demonstrate an increased virulence of MARV/Ang compared to MARV/MtE-Mus variant in the 1000 pfu IM cynomolgus macaque model. PMID- 30469361 TI - Decellularized Human Umbilical Artery Used as Nerve Conduit. AB - Treatment of injuries to peripheral nerves after a segmental defect is one of the most challenging surgical problems. Despite advancements in microsurgical techniques, complete recovery of nerve function after repair has not been achieved. The purpose of this study was to evaluate the use of the decellularized human umbilical artery (hUA) as nerve guidance conduit. A segmental peripheral nerve injury was created in 24 Sprague-Dawley rats. The animals were organized into two experimental groups with different forms of repair: decellularized hUA (n = 12), and autologous nerve graft (n = 12). Sciatic faction index and gastrocnemius muscle values were calculated for functional recovery evaluation. Nerve morphometry was used to analyze nerve regeneration. Results showed that decellularized hUAs after implantation were rich in nerve fibers and characterized by improved Sciatic Functional index (SFI) values. Decellularized hUA may support elongation and bridging of the 10 mm nerve gap. PMID- 30469362 TI - Hydroxide Conduction Enhancement of Chitosan Membranes by Functionalized MXene. AB - In this study, imidazolium brushes tethered by -NH2-containing ligands were grafted onto the surface of a 2D material, MXene, using precipitation polymerization followed by quaternization. Functionalized MXene was embedded into chitosan matrix to prepare a hybrid alkaline anion exchange membrane. Due to high interfacial compatibility, functionalized MXene was homogeneously dispersed in chitosan matrix, generating continuous ion conduction channels and then greatly enhancing OH- conduction property (up to 172%). The ability and mechanism of OH- conduction in the membrane were elaborated based on systematic tests. The mechanical-thermal stability and swelling resistance of the membrane were evidently augmented. Therefore, it is a promising anion exchange membrane for alkaline fuel cell application. PMID- 30469364 TI - Accumulation of As, Cd, and Pb in Sixteen Wheat Cultivars Grown in Contaminated Soils and Associated Health Risk Assessment. AB - This study investigated the accumulation of As, Cd, and Pb in 16 wheat cultivars and the associated health risks for the inhabitants of Jiyuan, China. The results indicated that the concentrations of As, Cd, and Pb decreased in the order of root > leaf > stem > grain. The concentrations of As, Cd, and Pb in wheat grains varied from 0.13 for Pingan8 to 0.34 mg kg-1 for Zhengmai7698, 0.10 for Luomai26 to 0.25 mg kg-1 for Zhengmai7698, and 0.12 for Zhoumai207 to 0.42 mg kg-1 for Zhengmai379, respectively. There were significant differences in the bioaccumulation factors of As, Cd, and Pb among the 16 wheat cultivars. Cd was more readily accumulated to higher levels than As and Pb in wheat. The Target Hazard Quotients (THQs) of Cd and Pb in the grains from 16 wheat cultivars were below 1, while As THQ exceeded 1. The lowest detrimental human health effects via wheat consumption were found in cultivar AY58 among the 16 wheat cultivars, with total THQs (TTHQs) of 1.82 for children and 1.60 for adults, suggesting that children absorb more heavy metals than adults and they are more vulnerable to the adverse effects of these metals. PMID- 30469363 TI - Understanding the Determinants of BnAb Induction in Acute HCV Infection. AB - Despite recent advances in curative therapy, hepatitis C virus (HCV) still remains a global threat. In order to achieve global elimination, a prophylactic vaccine should be considered high priority. Previous immunogens used to induce broad neutralising antibodies (BnAbs) have been met with limited success. To improve immunogen design, factors associated with the early development of BnAbs in natural infection must first be understood. In this study, 43 subjects identified with acute HCV were analysed longitudinally using a panel of heterogeneous HCV pseudoparticles (HCVpp), to understand the emergence of BnAbs. Compared to those infected with a single genotype, early BnAb development was associated with subjects co-infected with at least 2 HCV subtypes during acute infection. In those that were mono-infected, BnAbs were seen to emerge with increasing viral persistence. If subjects acquired a secondary infection, nAb breadth was seen to boost upon viral re-exposure. Importantly, this data highlights the potential for multivalent and prime-boost vaccine strategies to induce BnAbs against HCV in humans. However, the data also indicate that the infecting genotype may influence the development of BnAbs. Therefore, the choice of antigen will need to be carefully considered in future vaccine trials. PMID- 30469365 TI - Evaluation of Bone Sialoprotein Coating of Three-Dimensional Printed Calcium Phosphate Scaffolds in a Calvarial Defect Model in Mice. AB - The bioactive coating of calcium phosphate cement (CPC) is a promising approach to enhance the bone-healing properties of bone substitutes. The purpose of this study was to evaluate whether coating CPCs with bone sialoprotein (BSP) results in increased bone formation. Forty-five female C57BL/6NRj mice with an average age of six weeks were divided into three groups. Either a BSP-coated or an uncoated three-dimensional plotted scaffold was implanted into a drilled 2.7-mm diameter calvarial defect, or the defect was left empty (control group; no CPC). Histological analyses revealed that BSP-coated scaffolds were better integrated into the local bone stock eight weeks after implantation. Bone volume/total volume (BV/TV) ratios and bone thickness at the bone-implant contact were analyzed via micro computed tomography (uCT) after eight weeks. BSP-coated scaffolds and uncoated CPC scaffolds increased bone thickness in comparison to the control (CPC + BSP: 691.1 +/- 253.5 um, CPC: 603.1 +/- 164.4 um, no CPC: 261.7 +/- 37.8 um, p < 0.01). Accordingly, BV/TV was enhanced in both scaffold groups (CPC + BSP: 1.3 +/- 0.5%, CPC: 0.9 +/- 0.5%, no CPC: 0.2 +/- 0.3%, p < 0.01). The BSP coating showed a tendency towards an increased bone thickness (p = 0.18) and BV/TV (p = 0.18) in comparison to uncoated CPC scaffolds. However, a significant increase in bone formation through BSP coating was not found. PMID- 30469366 TI - Assessing the Aflatoxin B1 Adsorption Capacity between Biosorbents Using an In Vitro Multicompartmental Model Simulating the Dynamic Conditions in the Gastrointestinal Tract of Poultry. AB - Experiments were carried out to evaluate the effectiveness of three different biosorbents (banana peel, Pyracantha leaves, and Aloe powder) in removing aflatoxin B1 (AFB1). A noncommercial mycotoxin binder (zeolite) was used as a reference material. A laboratory model that simulated the in vivo conditions of the poultry gastrointestinal tract was utilized to prove the removal efficiency of the biosorbents when added to AFB1-contaminated diet (100 ug/kg). The concentration of AFB1 was determined using antibody-based immunoaffinity column and spectrofluorometry methodologies. Z potential (zeta), point of zero charge (pHpzc), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), Fourier transform infrared spectroscopy with attenuated total reflection (FTIR ATR), and UV-Vis diffuse reflectance spectroscopy (DRS) techniques were used to further characterize the biosorbents. The addition of the biosorbents (1.5%, w/w) to the diet significantly reduced the bioavailability of AFB1 in the intestinal section. The highest aflatoxin adsorption values were 69% and 70% using Aloe powder and zeolite, respectively. A moderate biosorption uptake of 46% was achieved using Pyracantha leaves. The biomaterial with the lowest removal capacity was banana peel (28%). In conclusion, Aloe powder could be used as an alternative to conventional systems for AFB1 removal. PMID- 30469367 TI - Enhancing the Production of the Fungal Pigment Aurofusarin in Fusarium graminearum. AB - There is an increasing demand for products from natural sources, which includes a growing market for naturally-produced colorants. Filamentous fungi produce a vast number of chemically diverse pigments and are therefore explored as an easily accessible source. In this study we examine the positive regulatory effect of the transcription factor AurR1 on the aurofusarin gene cluster in Fusarium graminearum. Proteomic analyses showed that overexpression of AurR1 resulted in a significant increase of five of the eleven proteins belonging to the aurofusarin biosynthetic pathway. Further, the production of aurofusarin was increased more than threefold in the overexpression mutant compared to the wild type, reaching levels of 270 mg/L. In addition to biosynthesis of aurofusarin, several yet undescribed putative naphthoquinone/anthraquinone analogue compounds were observed in the overexpression mutant. Our results suggest that it is possible to enhance the aurofusarin production through genetic engineering. PMID- 30469368 TI - Comparison of CO2 Vertical Profiles in the Lower Troposphere between 1.6 um Differential Absorption Lidar and Aircraft Measurements Over Tsukuba. AB - A 1.6 MUm differential absorption Lidar (DIAL) system for measurement of vertical CO2 mixing ratio profiles has been developed. A comparison of CO2 vertical profiles measured by the DIAL system and an aircraft in situ sensor in January 2014 over the National Institute for Environmental Studies (NIES) in Tsukuba, Japan, is presented. The DIAL measurement was obtained at an altitude range of between 1.56 and 3.60 km with a vertical resolution of 236 m (below 3 km) and 590 m (above 3 km) at an average error of 1.93 ppm. An in situ sensor for cavity ring down spectroscopy of CO2 was installed in an aircraft. CO2 mixing ratio measured by DIAL and the aircraft sensor ranged from 398.73 to 401.36 ppm and from 399.08 to 401.83 ppm, respectively, with an average difference of -0.94 +/- 1.91 ppm below 3 km and -0.70 +/- 1.98 ppm above 3 km between the two measurements. PMID- 30469369 TI - Tear Film Amphiphilic and Anti-Inflammatory Lipids in Bovine Pink Eye. AB - Background: Tear film fluid serves as a dynamic barrier that both lubricates the eye and protects against allergens and infectious agents. However, a detailed analysis of a bacteria-induced immune response on the tear film lipidome has not been undertaken. Methods: We undertook a high-resolution mass spectrometry lipidomics analysis of endogenous anti-inflammatory and structural tear film lipids in bovine pink eye. Results: Bovine pink eye resulted in dramatic elevations in tear fluid levels of the anti-inflammatory lipids resolvin E2, cyclic phosphatidic acid 16:0, and cyclic phosphatidic acid 18:0. In addition, there were elevated levels of the structural lipids (O-acyl)-omega-hydroxy-fatty acids, cholesterol sulfate, ethanolamine plasmalogens, and sphingomyelins. Lipid peroxidation also was augmented in pink eye as evidenced by the hydroperoxy derivatives of ethanolamine plasmalogens. Conclusions: Ocular infections with Moraxella bovis result in the induction of a number of endogenous anti inflammatory lipids and augmentation of the levels of structural glycerophospholipids and sphingolipids. Increased levels of hydroperoxy glycerophospholipids also indicate that this bacterial infection results in lipid peroxidation. PMID- 30469371 TI - Off-Set and Focus Effects on Grade 5 Titanium to 6061 Aluminum Alloy Fiber Laser Weld. AB - Joining dissimilar metal alloys together has become a major issue in the welding industry since the rapid development of innovative and performing multi-materials products. In case, titanium and Aluminum alloys can be laser-welded using a placement of the laser beam aside the weld centerline, which is called off-set. The fused zone is deep and narrow and the reaction between titanium and Aluminum is limited to a thin interlayer, which improves mechanical properties. In this paper, the effect of focus and off-set distance of the laser beam on the weldability of grade 5 titanium to 6061 Aluminum alloy dissimilar butt weld are presented. The interlayer thickness was correlated to the process parameters and tensile behavior of the weld. The map of deformation showed different deformations of the two weld sides. The data coming from the metallurgical and mechanical characterization of the weld were analyzed to figure out the best off set and focus combination in the range studied. PMID- 30469370 TI - Ultrasound Imaging for the Cutaneous Nerves of the Extremities and Relevant Entrapment Syndromes: From Anatomy to Clinical Implications. AB - Cutaneous nerve entrapment plays an important role in neuropathic pain syndrome. Due to the advancement of ultrasound technology, the cutaneous nerves can be visualized by high-resolution ultrasound. As the cutaneous nerves course superficially in the subcutaneous layer, they are vulnerable to entrapment or collateral damage in traumatic insults. Scanning of the cutaneous nerves is challenging due to fewer anatomic landmarks for referencing. Therefore, the aim of the present article is to summarize the anatomy of the limb cutaneous nerves, to elaborate the scanning techniques, and also to discuss the clinical implications of pertinent entrapment syndromes of the medial brachial cutaneous nerve, intercostobrachial cutaneous nerve, medial antebrachial cutaneous nerve, lateral antebrachial cutaneous nerve, posterior antebrachial cutaneous nerve, superficial branch of the radial nerve, dorsal cutaneous branch of the ulnar nerve, palmar cutaneous branch of the median nerve, anterior femoral cutaneous nerve, posterior femoral cutaneous nerve, lateral femoral cutaneous nerve, sural nerve, and saphenous nerve. PMID- 30469372 TI - An Efficient Synthesis of Acenaphtho[1,2-b]indole Derivatives via Domino Reaction. AB - A concise and efficient synthesis of acenaphtho[1,2-b]indole derivatives via the domino reactions of enaminones with acenaphthoquinone catalyzed by l-proline has been developed. This protocol has the advantages of good yields, operational convenience and high regioselectivity. PMID- 30469374 TI - Near-Net Forming Complex Shaped Zr-Based Bulk Metallic Glasses by High Pressure Die Casting. AB - Forming complex geometries using the casting process is a big challenge for bulk metallic glasses (BMGs), because of a lack of time of the window for shaping under the required high cooling rate. In this work, we open an approach named the "entire process vacuum high pressure die casting" (EPV-HPDC), which delivers the ability to fill die with molten metal in milliseconds, and create solidification under high pressure. Based on this process, various Zr-based BMGs were prepared by using industrial grade raw material. The results indicate that the EPV-HPDC process is feasible to produce a glassy structure for most Zr-based BMGs, with a size of 3 mm * 10 mm and with a high strength. In addition, it has been found that EPV-HPDC process allows complex industrial BMG parts, some of which are hard to be formed by any other metal processes, to be net shaped precisely. The BMG components prepared by the EVP-HPDC process possess the advantages of dimensional accuracy, efficiency, and cost compared with the ones formed by other methods. The EVP-HPDC process paves the way for the large-scale application of BMGs. PMID- 30469373 TI - Using Pupillometry to Assess the Atypical Pupillary Light Reflex and LC-NE System in ASD. AB - With recent advances in technology, there has been growing interest in use of eye tracking and pupillometry to assess the visual pathway in autism spectrum disorder (ASD). Within emerging literature, an atypical pupillary light reflex (PLR) has been documented, holding potential for use as a clinical screening biomarker for ASD. This review outlines dominant theories of neuropathology associated with ASD and integrates underlying neuroscience associated with the atypical PLR through a reciprocal model of brainstem involvement and cortical underconnectivity. This review draws from animal models of ASD demonstrating disruption of cranial motor nuclei and brain imaging studies examining arousal and the influence of the locus coeruleus norepinephrine (LC-NE) system on the pupillary response. Pupillometry methods are explained in relation to existing data examining the PLR in ASD and pupillary parameters of constriction latency and tonic pupil diameter as key parameters for investigation. This focused review provides preliminary data toward future work developing pupillometry metrics and offers direction for studies aimed at rigorous study replication using pupillometry with the ASD population. Experimental conditions and testing protocol for capturing pupil parameters with this clinical population are discussed to promote clinical research and translational application. PMID- 30469375 TI - Reactive Oxygen Species and the Redox-Regulatory Network in Cold Stress Acclimation. AB - Cold temperatures restrict plant growth, geographical extension of plant species, and agricultural practices. This review deals with cold stress above freezing temperatures often defined as chilling stress. It focuses on the redox regulatory network of the cell under cold temperature conditions. Reactive oxygen species (ROS) function as the final electron sink in this network which consists of redox input elements, transmitters, targets, and sensors. Following an introduction to the critical network components which include nicotinamide adenine dinucleotide phosphate (NADPH)-dependent thioredoxin reductases, thioredoxins, and peroxiredoxins, typical laboratory experiments for cold stress investigations will be described. Short term transcriptome and metabolome analyses allow for dissecting the early responses of network components and complement the vast data sets dealing with changes in the antioxidant system and ROS. This review gives examples of how such information may be integrated to advance our knowledge on the response and function of the redox regulatory network in cold stress acclimation. It will be exemplarily shown that targeting the redox network might be beneficial and supportive to improve cold stress acclimation and plant yield in cold climate. PMID- 30469377 TI - Characterization of Sicilian Honeys Pollen Profiles Using a Commercial E-Tongue and Melissopalynological Analysis for Rapid Screening: A Pilot Study. AB - Honey is usually classified as "unifloral" or "multifloral", depending on whether a dominating pollen grain, originating from only one particular plant, or no dominant pollen type in the sample is found. Unifloral honeys are usually more expensive and appreciated than multifloral honeys, which highlights the importance of honey authenticity. Melissopalynological analysis is used to identify the botanical origin of honey, counting down the number of pollens grains of a honey sample, and calculating the respective percentages of the nectariferous pollens. In addition, sensory properties are also very important for honey characterization, and electronic senses emerged as useful tools for honey authentication. In this work, a comparison of the results obtained from melissopalynological analysis with those provided by a potentiometric electronic tongue is given, resulting in a 100% match between the two techniques. PMID- 30469376 TI - Neuroprotective Activity of Some Marine Fungal Metabolites in the 6 Hydroxydopamin- and Paraquat-Induced Parkinson's Disease Models. AB - A new melatonin analogue 6-hydroxy-N-acetyl-beta-oxotryptamine (1) was isolated from the marine-derived fungus Penicillium sp. KMM 4672. It is the second case of melatonin-related compounds isolation from microfilamentous fungi. The neuroprotective activities of this metabolite, as well as 3-methylorsellinic acid (2) and 8-methoxy-3,5-dimethylisochroman-6-ol (3) from Penicillium sp. KMM 4672, candidusin A (4) and 4"-dehydroxycandidusin A (5) from Aspergillus sp. KMM 4676, and diketopiperazine mactanamide (6) from Aspergillus flocculosus, were investigated in the 6-hydroxydopamine (6-OHDA)- and paraquat (PQ)-induced Parkinson's disease (PD) cell models. All of them protected Neuro2a cells against the damaging influence of 6-OHDA to varying degrees. This effect may be realized via a reactive oxygen species (ROS) scavenging pathway. The new melatonin analogue more effectively protected Neuro2A cells against the 6-OHDA-induced neuronal death, in comparison with melatonin, as well as against the PQ-induced neurotoxicity. Dehydroxylation at C-3" and C-4" significantly increased free radical scavenging and neuroprotective activity of candidusin-related p-terphenyl polyketides in both the 6-OHDA- and PQ-induced PD models. PMID- 30469380 TI - Evaluation of Strategies for the Development of Efficient Code for Raspberry Pi Devices. AB - The Internet of Things (IoT) is faced with challenges that require green solutions and energy-efficient paradigms. Architectures (such as ARM) have evolved significantly in recent years, with improvements to processor efficiency, essential for always-on devices, as a focal point. However, as far as software is concerned, few approaches analyse the advantages of writing efficient code when programming IoT devices. Therefore, this proposal aims to improve source code optimization to achieve better execution times. In addition, the importance of various techniques for writing efficient code for Raspberry Pi devices is analysed, with the objective of increasing execution speed. A complete set of tests have been developed exclusively for analysing and measuring the improvements achieved when applying each of these techniques. This will raise awareness of the significant impact the recommended techniques can have. PMID- 30469381 TI - The Question of a Role for Statins in Age-Related Macular Degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of irreversible central vision loss in patients over the age of 65 years in industrialized countries. Epidemiologic studies suggest that high dietary fat intake is a risk factor for the development and progression of both vascular and retinal disease. These, and other associations, suggest a hypothesis linking elevated cholesterol and AMD progression. It follows, therefore, that cholesterol-lowering medications, such as statins, may influence the onset and progression of AMD. However, the findings have been inconclusive as to whether statins play a role in AMD. Due to the significant public health implications of a potential inhibitory effect of statins on the onset and progression of AMD, it is important to continually evaluate emerging findings germane to this question. PMID- 30469379 TI - Peripheral Blood Mononuclear Cell Metabolism Acutely Adapted to Postprandial Transition and Mainly Reflected Metabolic Adipose Tissue Adaptations to a High Fat Diet in Minipigs. AB - Although peripheral blood mononuclear cells (PBMCs) are widely used as a valuable tool able to provide biomarkers of health and diseases, little is known about PBMC functional (biochemistry-based) metabolism, particularly following short term nutritional challenges. In the present study, the metabolic capacity of minipig PBMCs to respond to nutritional challenges was explored at the biochemical and molecular levels. The changes observed in enzyme activities following a control test meal revealed that PBMC metabolism is highly reactive to the arrival of nutrients and hormones in the circulation. The consumption, for the first time, of a high fat-high sucrose (HFHS) meal delayed or sharply reduced most of the observed postprandial metabolic features. In a second experiment, minipigs were subjected to two-month HFHS feeding. The time-course follow-up of metabolic changes in PBMCs showed that most of the adaptations to the new diet took place during the first week. By comparing metabolic (biochemical and molecular) PMBC profiles to those of the liver, skeletal muscle, and adipose tissue, we concluded that although PBMCs conserved common features with all of them, their response to the HFHS diet was closely related to that of the adipose tissue. As a whole, our results show that PBMC metabolism, particularly during short-term (postprandial) challenges, could be used to evaluate the whole-body metabolic status of an individual. This could be particularly interesting for early diagnosis of metabolic disease installation, when fasting clinical analyses fail to diagnose the path towards the pathology. PMID- 30469378 TI - Scaffold Structural Microenvironmental Cues to Guide Tissue Regeneration in Bone Tissue Applications. AB - In the process of bone regeneration, new bone formation is largely affected by physico-chemical cues in the surrounding microenvironment. Tissue cells reside in a complex scaffold physiological microenvironment. The scaffold should provide certain circumstance full of structural cues to enhance multipotent mesenchymal stem cell (MSC) differentiation, osteoblast growth, extracellular matrix (ECM) deposition, and subsequent new bone formation. This article reviewed advances in fabrication technology that enable the creation of biomaterials with well-defined pore structure and surface topography, which can be sensed by host tissue cells (esp., stem cells) and subsequently determine cell fates during differentiation. Three important cues, including scaffold pore structure (i.e., porosity and pore size), grain size, and surface topography were studied. These findings improve our understanding of how the mechanism scaffold microenvironmental cues guide bone tissue regeneration. PMID- 30469382 TI - Molecular and Cellular Functions of the Warsaw Breakage Syndrome DNA Helicase DDX11. AB - DDX11/ChlR1 (Chl1 in yeast) is a DNA helicase involved in sister chromatid cohesion and in DNA repair pathways. The protein belongs to the family of the iron-sulphur cluster containing DNA helicases, whose deficiencies have been linked to a number of diseases affecting genome stability. Mutations of human DDX11 are indeed associated with the rare genetic disorder named Warsaw breakage syndrome, showing both chromosomal breakages and chromatid cohesion defects. Moreover, growing evidence of a potential role in oncogenesis further emphasizes the clinical relevance of DDX11. Here, we illustrate the biochemical and structural features of DDX11 and how it cooperates with multiple protein partners in the cell, acting at the interface of DNA replication/repair/recombination and sister chromatid cohesion to preserve genome stability. PMID- 30469384 TI - Synergistic Effects of Weightlessness, Isoproterenol, and Radiation on DNA Damage Response and Cytokine Production in Immune Cells. AB - The implementation of rotating-wall vessels (RWVs) for studying the effect of lack of gravity has attracted attention, especially in the fields of stem cells, tissue regeneration, and cancer research. Immune cells incubated in RWVs exhibit several features of immunosuppression including impaired leukocyte proliferation, cytokine responses, and antibody production. Interestingly, stress hormones influence cellular immune pathways affected by microgravity, such as cell proliferation, apoptosis, DNA repair, and T cell activation. These pathways are crucial defense mechanisms that protect the cell from toxins, pathogens, and radiation. Despite the importance of the adrenergic receptor in regulating the immune system, the effect of microgravity on the adrenergic system has been poorly studied. Thus, we elected to investigate the synergistic effects of isoproterenol (a sympathomimetic drug), radiation, and microgravity in nonstimulated immune cells. Peripheral blood mononuclear cells were treated with the sympathomimetic drug isoproterenol, exposed to 0.8 or 2 Gy gamma-radiation, and incubated in RWVs. Mixed model regression analyses showed significant synergistic effects on the expression of the beta2-adrenergic receptor gene (ADRB2). Radiation alone increased ADRB2 expression, and cells incubated in microgravity had more DNA strand breaks than cells incubated in normal gravity. We observed radiation-induced cytokine production only in microgravity. Prior treatment with isoproterenol clearly prevents most of the microgravity-mediated effects. RWVs may be a useful tool to provide insight into novel regulatory pathways, providing benefit not only to astronauts but also to patients suffering from immune disorders or undergoing radiotherapy. PMID- 30469386 TI - TiO2-Based Hybrid Nanocomposites Modified by Phosphonate Molecules as Selective PAH Adsorbents. AB - A robust sol-gel process was developed for the synthesis of surface functionalized titania nanocrystallites bearing unsaturated groups starting from molecular heteroleptic single-source precursors. Molecules and nanomaterials were thoroughly characterized by multinuclear liquid and solid-state nuclear magnetic resonance (NMR), infra-red (FT-IR, DRIFT) spectroscopies. Nitrogen adsorption desorption (BET), thermogravimetric (TG) and elemental analyses demonstrated the reliability and the fine tuning of the surface functionalization in terms of ratio TiO2:ligand. The as-prepared materials were used as nano-adsorbents to remove mixture of 16 polycyclic aromatic hydrocarbon (PAHs) from aqueous solutions. Adsorption kinetic experiments were carried out for 24 h in solutions of one PAH [benzo(a)pyrene, 220 ppb] and of a mixture of sixteen ones [220 ppb for each PAH]. Most kinetic data best fitted the pseudo-second order model. However, in PAHs mixture, a competition process took place during the first hours leading to a remarkable high selectivity between light and heavy PAHs. This selectivity could be fine-tuned depending on the nature of the unsaturated group of the phosphonate framework and on the nanomaterial textures. PMID- 30469383 TI - The Relationship between Body Composition and a Gluten Free Diet in Children with Celiac Disease. AB - The primary and proven therapy, in cases of celiac disease (CD), is a rigorous gluten-free diet (GFD). However, there are reports of its negative effects in the form of nutritional deficiencies, obesity, and adverse changes in body composition. The study aimed to assess the impact of a GFD on the body composition of children with CD. In a case-controlled study (n = 41; mean age 10.81 y; SD = 3.96) children with CD, in various stages of treatment, underwent medical assessment. The control group consisted of healthy children and adolescents, strictly matched for gender and age in a 1:1 case-control manner. More than half of the examined children (n = 26) followed a GFD. CD children had significantly higher mean values of the fat free mass (FFM% = 80.68 vs. 76.66, p = 0.015), and total body water (TBW% = 65.22 vs. 60.47, p = 0.012), and lower mean values of the fat mass (FM% = 19.32 vs. 23.34, p = 0.015). Children who were on a GFD presented slightly higher, but not statistically significant, mean values of FM and FFM, than children who did not follow dietary recommendations (FM [kg] = 7.48 vs. 5.24, p = 0.064; FM% = 20.81 vs. 16.73, p = 0.087; FFM [kg] = 28.19 vs. 22.62, p = 0.110). After minimum one year of a GFD, CD children showed significantly higher values of FFM [kg] (p = 0.001), muscle mass (MM) [kg] (p < 0.001), TBW [L] (p < 0.001) and body cell mass (BCM) [kg] (p < 0.001). Furthermore, CD children who were on a GFD presented a significantly higher increase in weight (p = 0.034) and body mass index (BMI) (p = 0.021). The children adhering to a GFD demonstrate a tendency towards higher indices of selected body composition components. PMID- 30469385 TI - Increased Risk of Ulcerative Colitis in Patients with Periodontal Disease: A Nationwide Population-Based Cohort Study. AB - Both periodontal disease (PD) and inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are important diseases of the alimentary tract. Microbiome and immune-mediated inflammatory processes play important roles in these diseases. An association between PD and IBD may exist. This study investigated the risk of IBD in patients with PD. This study used data from the National Health Insurance Research Database of Taiwan from 1996 to 2013. A total of 27,041 patients with PD were enrolled as a study group, and 108,149 patients without PD were selected as the control group after matching by gender, age, insured region, urbanization, and income with a 1:4 ratio. Cox proportional hazards regression was used to calculate the risk of IBD. Of the 135,190 participants enrolled in this study, 5392 (4%) with newly diagnosed IBD were identified. The overall incidence of subsequent IBD was similar in both groups (3.8% vs. 4%, adjusted hazard ratio (aHR) = 1.01, 95% confidence interval (CI): 0.94-1.08). However, an increased risk of UC in the PD group was found after adjusting confounding factors (aHR: 1.56, 95% CI: 1.13-2.15; p < 0.05). This study demonstrated that patients with PD had approximately one-half higher risk of subsequent UC. Further studies are warranted to elucidate the relationship between PD and UC. PMID- 30469387 TI - Spin Polarization Properties of Pentagonal PdSe2 Induced by 3D Transition-Metal Doping: First-Principles Calculations. AB - The electronic structure and spin polarization properties of pentagonal structure PdSe2 doped with transition metal atoms are studied through first- principles calculations. The theoretical investigations show that the band gap of the PdSe2 monolayer decreases after introducing Cr, Mn, Fe and Co dopants. The projected densities of states show that p-d orbital couplings between the transition metal atoms and PdSe2 generate new spin nondegenerate states near the Fermi level which make the system spin polarized. The calculated magnetic moments, spin density distributions and charge transfer of the systems suggest that the spin polarization in Cr-doped PdSe2 will be the biggest. Our work shows that the properties of PdSe2 can be modified by doping transition metal atoms, which provides opportunity for the applications of PdSe2 in electronics and spintronics. PMID- 30469388 TI - The Antidepressant-Like Effect of Lactate in an Animal Model of Menopausal Depression. AB - BACKGROUND: This study aimed to investigate the antidepressant-like effect of lactate and elucidate its mechanisms in ovariectomized rats with repeated stress. METHODS: Two experiments were conducted on female rats in which all groups, except normal, were ovariectomized and underwent immobilization for 14 days. Lactate was administered orally (100, 250, and 500 mg/kg) for 14 consecutive days, and the rats' cutaneous body temperature was measured during the same period. Depression-like behavior in rats was assessed by the tail suspension test (TST) and forced swimming test (FST). Furthermore, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were conducted to evaluate the changes that occurred in the neurotransmitter levels and activity. RESULTS: The lactate 100 and 250 groups had reduced time spent immobile in TST and FST and decreased peripheral body temperature. In ELISA tests, the lactate 250 group expressed elevated levels of serotonin and dopamine in many brain areas. Tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), and protein kinase C (PKC) immunoreactive cells showed increased density and cell counts in lactate administered groups. CONCLUSION: Results indicated that lactate has an antidepressant effect that is achieved by activation of PKC and upregulation of TH and TPH expression, which eventually leads to enhanced serotonin and dopamine levels in the menopausal rat's brain. PMID- 30469389 TI - Gramicidin Lateral Distribution in Phospholipid Membranes: Fluorescence Phasor Plots and Statistical Mechanical Model. AB - When using small mole fraction increments to study gramicidins in phospholipid membranes, we found that the phasor dots of intrinsic fluorescence of gramicidin D and gramicidin A in dimyristoyl-sn-glycero-3-phosphocholine (DMPC) unilamellar and multilamellar vesicles exhibit a biphasic change with peptide content at 0.143 gramicidin mole fraction. To understand this phenomenon, we developed a statistical mechanical model of gramicidin/DMPC mixtures. Our model assumes a sludge-like mixture of fluid phase and aggregates of rigid clusters. In the fluid phase, gramicidin monomers are randomly distributed. A rigid cluster is formed by a gramicidin dimer and DMPC molecules that are condensed to the dimer, following particular stoichiometries (critical gramicidin mole fractions, Xcr including 0.143). Rigid clusters form aggregates in which gramicidin dimers are regularly distributed, in some cases, even to superlattices. At Xcr, the size of cluster aggregates and regular distributions reach a local maximum. Before a similar model was developed for cholesterol/DMPC mixtures (Sugar and Chong (2012) J. Am. Chem. Soc. 134, 1164-1171) and here the similarities and differences are discussed between these two models. PMID- 30469390 TI - Insect Transcription Factors: A Landscape of Their Structures and Biological Functions in Drosophila and beyond. AB - Transcription factors (TFs) play essential roles in the transcriptional regulation of functional genes, and are involved in diverse physiological processes in living organisms. The fruit fly Drosophila melanogaster, a simple and easily manipulated organismal model, has been extensively applied to study the biological functions of TFs and their related transcriptional regulation mechanisms. It is noteworthy that with the development of genetic tools such as CRISPR/Cas9 and the next-generation genome sequencing techniques in recent years, identification and dissection the complex genetic regulatory networks of TFs have also made great progress in other insects beyond Drosophila. However, unfortunately, there is no comprehensive review that systematically summarizes the structures and biological functions of TFs in both model and non-model insects. Here, we spend extensive effort in collecting vast related studies, and attempt to provide an impartial overview of the progress of the structure and biological functions of current documented TFs in insects, as well as the classical and emerging research methods for studying their regulatory functions. Consequently, considering the importance of versatile TFs in orchestrating diverse insect physiological processes, this review will assist a growing number of entomologists to interrogate this understudied field, and to propel the progress of their contributions to pest control and even human health. PMID- 30469391 TI - Design and Evaluation of Europium Containing Mesoporous Bioactive Glass Nanospheres: Doxorubicin Release Kinetics and Inhibitory Effect on Osteosarcoma MG 63 Cells. AB - Functional ions and drug factors play a vital role in stimulating bone tissue regeneration as we understand it. In this work, europium-containing mesoporous bioactive glass nanospheres (Eu/MBGs), composed of 60% SiO2-(36-x)%CaO-x%Eu2O3 4%P2O5 (x = 0, 0.5, 1, 2 mol%), were prepared by a facile sol-gel process. The results indicate that Eu ions play an important role to influence the microstructure of MBGs, in which a suitable concentration of Eu (1 mol%) increases their surface area (502 m2/g) as well as their pore volume (0.34 cm3/g). Proper doping of Eu ions in MBGs can observably induce apatite mineralization and improve the doxorubicin (DOX) release behavior. Furthermore, DOX-loaded Eu/MBGs could maintain a long-term inhibitory effect on the viability of osteosarcoma MG 63 cells. This work has demonstrated that it is possible to develop functional Eu/MBGs by combining excellent apatite-mineralization ability, controllable drug (DOX) release and antitumor functions for the therapy of bone tissue regeneration. PMID- 30469393 TI - Quercetin Enhances the Thioredoxin Production of Nasal Epithelial Cells In Vitro and In Vivo. AB - Background: Thioredoxin (TRX) acts as both a scavenger of reactive oxygen species (ROS) and an immuno-modulator. Although quercetin has been shown to favorably modify allergic rhinitis (AR) symptoms, its influence on TRX production is not well defined. The present study was designed to examine whether quercetin could favorably modify AR symptoms via the TRX production of nasal epithelial cells in vitro and in vivo. Methods: Human nasal epithelial cells (HNEpCs) were stimulated with H2O2 in the presence of quercetin. TRX levels in 24-h culture supernatants were examined with ELISA. BALB/c male mice were intraperitoneally sensitized to ovalbumin (OVA) and intranasally challenged with OVA every other day, beginning seven days after the final sensitization. The mice were orally administered quercetin once a day for five consecutive days, beginning seven days after the final sensitization. Nasal symptoms were assessed by counting the number of sneezes and nasal rubbing behaviors during a 10-min period immediately after the challenge. TRX levels in nasal lavage fluids obtained 6 h after the challenge were examined by ELISA. Results: Treatment with 1.0 nM quercetin increased H2O2 induced TRX levels. The oral administration of 20.0 mg/kg of quercetin significantly inhibited nasal symptoms after the challenge. The same dose of quercetin significantly increased TRX levels in nasal lavage fluids. Conclusions: Quercetin's ability to increase TRX production may account, at least in part, for its clinical efficacy toward AR. PMID- 30469394 TI - Designing a Robust Kelvin Probe Setup Optimized for Long-Term Surface Photovoltage Acquisition. AB - We introduce a robust low-budget Kelvin probe design that is optimized for the long-term acquisition of surface photovoltage (SPV) data, especially developed for highly resistive systems, which exhibit-in contrast to conventional semiconductors-very slow photoinduced charge relaxation processes in the range of hours and days. The device provides convenient optical access to the sample, as well as high mechanical and electrical stability due to off-resonance operation, showing a noise band as narrow as 1 mV. Furthermore, the acquisition of temperature-dependent SPV transients necessary for SPV-based deep-level transient spectroscopy becomes easily possible. The performance of the instrument is demonstrated by recording long-term SPV transients of the ultra-slowly relaxing model oxide strontium titanate (SrTiO 3 ) over 20 h. PMID- 30469395 TI - Optical Properties of Graphene/MoS2 Heterostructure: First Principles Calculations. AB - The electronic structure and the optical properties of Graphene/MoS2 heterostructure (GM) are studied based on density functional theory. Compared with single-layer graphene, the bandgap will be opened; however, the bandgap will be reduced significantly when compared with single-layer MoS2. Redshifts of the absorption coefficient, refractive index, and the reflectance appear in the GM system; however, blueshift is found for the energy loss spectrum. Electronic structure and optical properties of single-layer graphene and MoS2 are changed after they are combined to form the heterostructure, which broadens the extensive developments of two-dimensional materials. PMID- 30469396 TI - Accuracy Assessment of Semi-Automatic Measuring Techniques Applied to Displacement Control in Self-Balanced Pile Capacity Testing Appliance. AB - Static load tests of foundation piles are the basic method for the designing or verification of adopted design solutions which concern the foundation of a building structure. Preparation of a typical test station using the so-called inverted beam method is very expensive and labor-intensive. The settlement values of the loaded pile are usually recorded using accurate dial gauges. These gauges are attached to a reference beam located in close proximity to the pile under test, which may cause systematic errors (difficult to detect) caused by the displacement of the adopted reference beam. The application of geodetic methods makes it possible to maintain an independent, external reference system, and to verify the readouts from dial gauges. The article presents an innovative instrumentation for a self-balanced stand for the static load test made from a closed-end, double steel pipe. Instead of typical, precise geometric leveling, the semi-automatic measuring techniques were used: motorized total station measurement and terrestrial laser scanning controlled by a computer. The processing of the acquired data made it possible to determine the vertical displacements of both parts of the examined pile and compare displacements with the results from the dial gauges. On the basis of the excess of the collected observations, it was possible to assess the accuracy, which confirmed the usefulness of measuring techniques under study. PMID- 30469392 TI - Bidirectional Association between Nonalcoholic Fatty Liver Disease and Gallstone Disease: A Cohort Study. AB - Nonalcoholic fatty liver disease (NAFLD) and gallstone disease (GD) are often found to coexist but the sequential relationship of NAFLD and GD to each other remains controversial. We prospectively evaluated the bidirectional relationship of NAFLD with GD. A cohort study was performed on Korean adults who underwent a health checkup and were followed annually or biennially for a mean of 6.0 years. Fatty liver and gallstones were diagnosed by ultrasound. NAFLD was defined as hepatic steatosis on ultrasonography in the absence of excessive alcohol use or other identifiable causes. The NAFLD severity was determined by non-invasive fibrosis markers. Among 283,446 participants without either gallstones or cholecystectomy at baseline, 6440 participants developed gallstones. Among 219,641 participants without NAFLD at baseline, 49,301 participants developed NAFLD. The multivariable-adjusted hazard ratio (95% confidence interval) for incident gallstone comparing the NAFLD group vs. the non-NAFLD group was 1.26 (1.17-1.35). Increased non-invasive fibrosis markers of NAFLD were positively associated with an increased incidence of gallstones in a graded and dose responsive manner (p-trend < 0.01). The multivariable-adjusted hazard ratios (95% confidence intervals) for incident NAFLD comparing gallstone and cholecystectomy to no GD were 1.14 (1.07-1.22) and 1.17 (1.03-1.33), respectively. This large scale cohort study of young and middle-aged individuals demonstrated a bidirectional association between NAFLD and GD. NAFLD and its severity were independently associated with an increased incidence of gallstones, while GD and cholecystectomy were also associated with incident NAFLD. Our findings indicate that the conditions may affect each other, requiring further studies to elucidate the potential mechanisms underlying this association. PMID- 30469397 TI - Oxysterols from a Marine Sponge Inflatella sp. and Their Action in 6 Hydroxydopamine-Induced Cell Model of Parkinson's Disease. AB - Four new oxysterols 1-4 along with previously known oxygenated sterols 5-14 were isolated from the sponge Inflatella sp., collected from the Sea of Okhotsk. Structures of 1-4 were elucidated by the detailed NMR spectroscopic and mass spectrometric analyses as well as by comparison of the corresponding experimental data with those reported in literature. The influence of compounds 1-14 on the viability of neuronal Neuro2a cells treated by 6-hydroxydopamine and reactive oxygen species (ROS) formation in these cells was investigated. PMID- 30469398 TI - Time-Lapse Helical X-ray Computed Tomography (CT) Study of Tensile Fatigue Damage Formation in Composites for Wind Turbine Blades. AB - Understanding the fatigue damage mechanisms in composite materials is of great importance in the wind turbine industry because of the very large number of loading cycles rotor blades undergo during their service life. In this paper, the fatigue damage mechanisms of a non-crimp unidirectional (UD) glass fibre reinforced polymer (GFRP) used in wind turbine blades are characterised by time lapse ex-situ helical X-ray computed tomography (CT) at different stages through its fatigue life. Our observations validate the hypothesis that off-axis cracking in secondary oriented fibre bundles, the so-called backing bundles, are directly related to fibre fractures in the UD bundles. Using helical X-ray CT we are able to follow the fatigue damage evolution in the composite over a length of 20 mm in the UD fibre direction using a voxel size of (2.75 um)3. A staining approach was used to enhance the detectability of the narrow off-axis matrix and interface cracks, partly closed fibre fractures and thin longitudinal splits. Instead of being evenly distributed, fibre fractures in the UD bundles nucleate and propagate locally where backing bundles cross-over, or where stitching threads cross-over. In addition, UD fibre fractures can also be initiated by the presence of extensive debonding and longitudinal splitting, which were found to develop from debonding of the stitching threads near surface. The splits lower the lateral constraint of the originally closely packed UD fibres, which could potentially make the composite susceptible to compressive loads as well as the environment in service. The results here indicate that further research into the better design of the positioning of stitching threads, and backing fibre cross over regions is required, as well as new approaches to control the positions of UD fibres. PMID- 30469399 TI - Metformin Inhibits Migration and Invasion by Suppressing ROS Production and COX2 Expression in MDA-MB-231 Breast Cancer Cells. AB - BACKGROUND: Several mechanisms of action have been proposed to explain the apparent antineoplastic functions of metformin, many of which are observed at high concentrations that may not be reflective of achievable tissue concentrations. We propose that metformin at low concentrations functions to inhibit ROS production and inflammatory signaling in breast cancer, thereby reducing metastasis. METHODS: Using the highly invasive MDA-MB-231 breast carcinoma model, we ascertained the impact of metformin on cell viability by DNA content analysis and fluorescent dye exclusion. Migration and invasion assays were performed using a modified Boyden chamber assay and metastasis was ascertained using the chorioallantoic membrane (CAM) assay. PGE2 production was measured by Enzyme-Linked Immunosorbent Assay (ELISA). COX2 and ICAM1 levels were determined by flow cytometry immunoassay. RESULTS: Metformin acutely decreased cell viability and caused G2 cell cycle arrest only at high concentrations (10 mM). At 100 uM, however, metformin reduced ICAM1 and COX2 expression, as well as reduced PGE2 production and endogenous mitochondrial ROS production while failing to significantly impact cell viability. Consequently, metformin inhibited migration, invasion in vitro and PGE2-dependent metastasis in CAM assays. CONCLUSION: At pharmacologically achievable concentrations, metformin does not drastically impact cell viability, but inhibits inflammatory signaling and metastatic progression in breast cancer cells. PMID- 30469400 TI - Long-Term Effects of Spironolactone on Kidney Function and Hyperkalemia Associated Hospitalization in Patients with Chronic Kidney Disease. AB - BACKGROUND: Spironolactone, a non-selective mineralocorticoid receptor antagonist, can protect against cardiac fibrosis and left ventricular dysfunction, and improve endothelial dysfunction and proteinuria. However, the safety and effects of spironolactone on patient-centered cardiovascular and renal endpoints remain unclear. METHODS: We identified predialysis stage 3-4 chronic kidney disease (CKD) patients between 2000 and 2013 from the Longitudinal Health Insurance Database 2005 (LHID 2005). The outcomes of interest were end-stage renal disease (ESRD), major adverse cardiovascular events (MACE), hospitalization for heart failure (HHF), hyperkalemia-associated hospitalization (HKAH), all cause mortality and cardiovascular mortality. The Fine and Gray sub-distribution hazards approach was adopted to adjust for the competing risk of death. RESULTS: After the propensity score matching, 693 patients with stage 3-4 CKD were spironolactone users and 1386 were nonusers. During the follow-up period, spironolactone users had a lower incidence rate for ESRD than spironolactone non users (39.2 vs. 53.69 per 1000 person-years) and a higher incidence rate for HKAH (54.79 vs. 18.57 per 1000 person-years). The adjusted hazard ratios for ESRD of spironolactone users versus non-users were 0.66 (95% CI, 0.51-0.84; p value < 0.001) and 3.17 (95% CI, 2.41-4.17; p value < 0.001) for HKAH. A dose-response relationship was found between spironolactone use and risk of ESRD and HKAH. There were no statistical differences in MACE, HHF, all-cause mortality and cardiovascular mortality between spironolactone users and non-users. CONCLUSION: Spironolactone represented a promising treatment option to retard CKD progression to ESRD amongst stage 3-4 CKD patients, but strategic treatments to prevent hyperkalemia should be enforced. PMID- 30469401 TI - Experimental Combined Immunotherapy of Tumours with Major Histocompatibility Complex Class I Downregulation. AB - Combined immunotherapy constitutes a novel, advanced strategy in cancer treatment. In this study, we investigated immunotherapy in the mouse TC-1/A9 model of human papillomavirus type 16 (HPV16)-associated tumors characterized by major histocompatibility complex class I (MHC-I) downregulation. We found that the induction of a significant anti-tumor response required a combination of DNA vaccination with the administration of an adjuvant, either the synthetic oligodeoxynucleotide ODN1826, carrying immunostimulatory CpG motifs, or alpha galactosylceramide (alpha-GalCer). The most profound anti-tumor effect was achieved when these adjuvants were applied in a mix with a one-week delay relative to DNA immunization. Combined immunotherapy induced tumor infiltration with various subsets of immune cells contributing to tumor regression, of which cluster of differentiation (CD) 8+ T cells were the predominant subpopulation. In contrast, the numbers of tumor-associated macrophages (TAMs) were not markedly increased after immunotherapy but in vivo and in vitro results showed that they could be repolarized to an anti-tumor M1 phenotype. A blockade of T cell immunoglobulin and mucin-domain containing-3 (Tim-3) immune checkpoint had a negligible effect on anti-tumor immunity and TAMs repolarization. Our results demonstrate a benefit of combined immunotherapy comprising the activation of both adaptive and innate immunity in the treatment of tumors with reduced MHC-I expression. PMID- 30469403 TI - Early, Subclinical Hematological Changes Associated with Occupational Exposure to High Levels of Nitrous Oxide. AB - This study was undertaken to determine whether exposure of operating room personnel to inhalation anesthetics, nitrous oxide, isoflurane, and sevoflurane was associated with any hematological changes. This historical cohort study was performed in 2018 at a large public hospital in Shiraz, where 52 operating room personnel and 52 administrative staff were investigated. The blood sample was taken from all individuals for Complete Blood Count. Furthermore, demographic information was collected through questionnaires. Mean atmospheric concentrations of nitrous oxide, isoflurane, and sevoflurane, to which subjects were exposed, were 850.92, 2.40, and 0.18 ppm, respectively. The hematological parameters were within the normal range in both groups. However, the mean values of hemoglobin, hematocrit, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and red blood cell count in the exposed group were significantly lower than the control group. No significant differences were noted between the two groups as far as other hematological factors were concerned. These findings provide circumstantial evidence to further substantiate the notion that occupational exposure to inhalation anesthetics, under the exposure scenario explained in this study, is associated with subtle, subclinical, prepathologic hematological changes. Long-term consequence and ramifications of these effects require further investigation. The range of exposure levels to anesthetic gases in operating rooms. PMID- 30469402 TI - Beneficial Effects of Marine Algae-Derived Carbohydrates for Skin Health. AB - Marine algae are considered to be an abundant sources of bioactive compounds with cosmeceutical potential. Recently, a great deal of interest has focused on the health-promoting effects of marine bioactive compounds. Carbohydrates are the major and abundant constituent of marine algae and have been utilized in cosmetic formulations, as moisturizing and thickening agents for example. In addition, marine carbohydrates have been suggested as promising bioactive biomaterials for their various properties beneficial to skin, including antioxidant, anti melanogenic and skin anti-aging properties. Therefore, marine algae carbohydrates have potential skin health benefits for value-added cosmeceutical applications. The present review focuses on the various biological capacities and potential skin health benefits of bioactive marine carbohydrates. PMID- 30469404 TI - Gaussian Process Based Bayesian Inference System for Intelligent Surface Measurement. AB - This paper presents a Gaussian process based Bayesian inference system for the realization of intelligent surface measurement on multi-sensor instruments. The system considers the surface measurement as a time series data collection process, and the Gaussian process is used as mathematical foundation to establish an inferring plausible model to aid the measurement process via multi-feature classification and multi-dataset regression. Multi-feature classification extracts and classifies the geometric features of the measured surfaces at different scales to design an appropriate composite covariance kernel and corresponding initial sampling strategy. Multi-dataset regression takes the designed covariance kernel as input to fuse the multi-sensor measured datasets with Gaussian process model, which is further used to adaptively refine the initial sampling strategy by taking the credibility of the fused model as the critical sampling criteria. Hence, intelligent sampling can be realized with consecutive learning process with full Bayesian treatment. The statistical nature of the Gaussian process model combined with various powerful covariance kernel functions offer the system great flexibility for different kinds of complex surfaces. PMID- 30469405 TI - An Integrated Machine Learning Algorithm for Separating the Long-Term Deflection Data of Prestressed Concrete Bridges. AB - Deflection is one of the key indexes for the safety evaluation of bridge structures. In reality, due to the changing operational and environmental conditions, the deflection signals measured by structural health monitoring systems are greatly affected. These ambient changes in the system often cover subtle changes in the vibration signals caused by damage to the system. The deflection signals of prestressed concrete (PC) bridges are regarded as the superposition of different effects, including concrete shrinkage, creep, prestress loss, material deterioration, temperature effects, and live load effects. According to multiscale analysis theory of the long-term deflection signal, in this paper, an integrated machine learning algorithm that combines a Butterworth filter, ensemble empirical mode decomposition (EEMD), principle component analysis (PCA), and fast independent component analysis (FastICA) is proposed for separating the individual deflection components from a measured single channel deflection signal. The proposed algorithm consists of four stages: (1) the live load effect, which is a high-frequency signal, is separated from the raw signal by a Butterworth filter; (2) the EEMD algorithm is used to extract the intrinsic mode function (IMF) components; (3) these IMFs are utilized as input in the PCA model and some uncorrelated and dominant basis components are extracted; and (4) FastICA is applied to derive the independent deflection component. The simulated results show that each individual deflection component can be successfully separated when the noise level is under 10%. Verified by a practical application, the algorithm is feasible for extracting the structural deflection (including concrete shrinkage, creep, and prestress loss) only caused by structural damage or material deterioration. PMID- 30469406 TI - Non-Structural Protein NSm of Tomato Spotted Wilt Virus Is an Avirulence Factor Recognized by Resistance Genes of Tobacco and Tomato via Different Elicitor Active Sites. AB - Tomato spotted wilt virus (TSWV) is one of the most destructive viral pathogens of plants. Recently, a single dominant gene conferring complete resistance to TSWV (RTSW) was identified in Nicotina alata and introgressed into cultivated tobacco (N. tabacum). However, whether the TSWV carries an avirulence (Avr) factor directed against RTSW remains obscure. In the present study, we identified the non-structural protein (NSm), the movement protein of TSWV, which is an RTSW specific Avr factor, by using two different transient expression systems. Using amino acid (aa) substitution mutants, we demonstrated the ability to induce RTSW mediated hypersensitive response (HR) of NSm is independent of its movement function. Moreover, key substitutions (C118Y and T120N), a 21-aa viral effector epitope, and different truncated versions of NSm, which are responsible for the recognition of the Sw-5b resistance gene of tomato, were tested for their ability to trigger HR to TSWV in tobacco. Together, our results demonstrated that RTSW mediated resistance is triggered by NSm in the same way as by Sw-5b, however, via different elicitor active sites. Finally, an Avr gene-based diagnostic approach was established and used to determine the presence and effectiveness of resistance genes in tobacco. PMID- 30469407 TI - Accelerated Bioprocess Development of Endopolygalacturonase-Production with Saccharomyces cerevisiae Using Multivariate Prediction in a 48 Mini-Bioreactor Automated Platform. AB - Mini-bioreactor systems enabling automatized operation of numerous parallel cultivations are a promising alternative to accelerate and optimize bioprocess development allowing for sophisticated cultivation experiments in high throughput. These include fed-batch and continuous cultivations with multiple options of process control and sample analysis which deliver valuable screening tools for industrial production. However, the model-based methods needed to operate these robotic facilities efficiently considering the complexity of biological processes are missing. We present an automated experiment facility that integrates online data handling, visualization and treatment using multivariate analysis approaches to design and operate dynamical experimental campaigns in up to 48 mini-bioreactors (8-12 mL) in parallel. In this study, the characterization of Saccharomyces cerevisiae AH22 secreting recombinant endopolygalacturonase is performed, running and comparing 16 experimental conditions in triplicate. Data-driven multivariate methods were developed to allow for fast, automated decision making as well as online predictive data analysis regarding endopolygalacturonase production. Using dynamic process information, a cultivation with abnormal behavior could be detected by principal component analysis as well as two clusters of similarly behaving cultivations, later classified according to the feeding rate. By decision tree analysis, cultivation conditions leading to an optimal recombinant product formation could be identified automatically. The developed method is easily adaptable to different strains and cultivation strategies, and suitable for automatized process development reducing the experimental times and costs. PMID- 30469408 TI - Ordinary Optical Fiber Sensor for Ultra-High Temperature Measurement Based on Infrared Radiation. AB - An ordinary optical fiber ultra-high temperature sensor based on infrared radiation with the advantages of simple structure and compact is presented. The sensing system consists of a detection fiber and a common transmission fiber. The detector fiber is formed by annealing a piece of ordinary fiber at high temperature twice, which changes the properties of the fiber and breaks the temperature limit of ordinary fiber. The transmission fiber is a bending insensitive optical fiber. A static calibration system was set up to determine the performance of the sensor and three heating experiments were carried out. The temperature response sensitivities were 0.010 dBm/K, 0.009 dBm/K and 0.010 dBm/K, respectively, which indicate that the sensor has good repeatability. The sensor can withstand a high temperature of 1823 K for 58 h with an error of less than 1%. The main reason why the developed ordinary optical fiber sensor can work steadily for a long time at high temperature is the formation of beta cristobalite, which is stable at high-temperature. PMID- 30469409 TI - Optimal Routing for Time-Driven EH-WSN under Regular Energy Sources. AB - The recent provision of energy-harvesting capabilities to wireless sensor networks (WSN) has entailed the redefinition of design objectives. Specifically, the traditional goal of maximizing network lifetime has been replaced by optimizing network performance, namely delay and throughput. The present paper contributes to this reformulation by considering the routing problem for the class of time-driven energy-harvesting WSN (EH-WSN) under regular or quasi periodic energy sources. In particular, this paper shows that the minimum hop count (MHC) criterion maximizes the average duty cycle that can be sustained by nodes in this type of scenarios. This is a primary objective in EH-WSN, since large duty cycles lead to enhanced performance. Based on a previous result, a general expression is first obtained that gives mathematical form to the relationship between duty cycle and traffic load for any node in a time-driven EH WSN fed by a regular energy source. This expression reveals that the duty cycle achievable by a node decreases as its traffic load increases. Then, it is shown that MHC minimizes the average traffic load over the network, and thus it maximizes the average duty cycle of nodes. This result is numerically validated via simulation by comparison with other well-known routing strategies. Accordingly, this paper suggests assigning top priority to the MHC criterion in the development of routing protocols for time-driven EH-WSN under regular energy sources. PMID- 30469410 TI - Coping with Reactive Oxygen Species to Ensure Genome Stability in Escherichia coli. AB - The facultative aerobic bacterium Escherichia coli adjusts its cell cycle to environmental conditions. Because of its lifestyle, the bacterium has to balance the use of oxygen with the potential lethal effects of its poisonous derivatives. Oxidative damages perpetrated by molecules such as hydrogen peroxide and superoxide anions directly incapacitate metabolic activities relying on enzymes co-factored with iron and flavins. Consequently, growth is inhibited when the bacterium faces substantial reactive oxygen insults coming from environmental or cellular sources. Although hydrogen peroxide and superoxide anions do not oxidize DNA directly, these molecules feed directly or indirectly the generation of the highly reactive hydroxyl radical that damages the bacterial chromosome. Oxidized bases are normally excised and the single strand gap repaired by the base excision repair pathway (BER). This process is especially problematic in E. coli because replication forks do not sense the presence of damages or a stalled fork ahead of them. As consequence, single-strand breaks are turned into double-strand breaks (DSB) through replication. Since E. coli tolerates the presence of DSBs poorly, BER can become toxic during oxidative stress. Here we review the repair strategies that E. coli adopts to preserve genome integrity during oxidative stress and their relation to cell cycle control of DNA replication. PMID- 30469411 TI - Improvement of Quality Properties and Shelf Life Stability of New Formulated Muffins Based on Black Rice. AB - Effects of partial (50%) and total replacement of wheat flour with black rice flour on the phytochemical, physico-chemical, sensorial, and textural properties of muffins were studied. Partial or total replacement of wheat flour with black rice flour in muffins improved their nutritional and antioxidative properties with a positive effect on microbiological and color stability during the storage period in accelerated conditions. The low gluten muffins had an anthocyanin content of 27.54 +/- 2.22 mg cyanidin-3-glucoside (C3G)/100 g dry weight (DW), whereas the gluten free muffins had 46.11 +/- 3.91 mg C3G/100 g DW, with significant antioxidant values. Retention of 60% and 64% for anthocyanins and 72% and 80% for antioxidant activity after baking was found. The fracturability and hardness scores increased with the addition of black rice flour, whereas firmness and chewiness increased for gluten free muffins. The confocal analysis revealed a tendency of glucidic components to aggregate, with gathers of small bunches of black rice starch granules comprising anthocyanin. The results allowed designing two new value added bakery products, low and free gluten muffins, with significant high amounts of bioactive compounds, suggesting the functional potential of black rice flour. PMID- 30469413 TI - Indoor Air Quality and Potential Health Risk Impacts of Exposure to Antibiotic Resistant Bacteria in an Office Rooms in Southern Poland. AB - The aims of this article are to characterize: the quantity of culturable bacterial aerosol (QCBA) and the quality of culturable bacterial aerosol (QlCBA) in an office building in Southern Poland during the spring. The average concentration of culturable bacterial aerosol (CCBA) in this building ranged from 424 CFU m-3 to 821 CFU m-3, below Polish proposals for threshold limit values. Size distributions were unimodal, with a peak of particle bacterial aerodynamic diameters less than 3.3 MUm, increasing potentially adverse health effects due to their inhalation. The spring office exposure dose (SPED) of bacterial aerosol was estimated. The highest value of SPED was in April (218 CFU kg-1), whereas the lowest was in June (113 CFU kg-1). Analysis was undertaken to determine the antibiotic resistance of isolated strains and their ability to form biofilms, which may facilitate the spread of antibiotic resistance genes. In the course of the study, it was found that Staphylococcus xylosus had the greatest ability to form biofilms, while the strains with the highest antibiotic resistance were Micrococcus luteus D and Macrococcus equipercicus. Given that mainly antibiotic sensitive bacteria from bioaerosol were isolated, which transfers resistance genes to their plasmids, this shows the need for increased monitoring of indoor air quality in workplaces. PMID- 30469414 TI - Effects of Internal Partitions on Flow Field and Air Contaminant Distribution under Different Ventilation Modes. AB - Based on frequently used internal partitions in offices, the effects of pollutant source characteristics and an internal partition on airflow and contaminant distribution under different ventilation modes are studied in this paper. The indoor flow field measurement is implemented in a 1:1 single environmental chamber under different ventilation patterns, and then the numerical model is established. The numerical method is verified and analyzed by comparing the measured and simulated results. According to the verification results, the numerical simulation is introduced to study the influence of different supply and return air mixes and pollutant source distributions on the flow field and diffusion performance with an internal partition. The indoor flow field and concentration distribution under different conditions are compared, and the discharge efficiency under different working conditions is analyzed. The results indicate that internal partitions have a greater influence on the down-supply up return ventilation mode than the floor-supply up-return and top-supply down return ventilation mode. Furthermore, if the room is zoned, the effect of source position is larger under the down-supply up-return ventilation mode than under the other two modes. PMID- 30469412 TI - A Randomized, Placebo-Controlled, Pilot Clinical Trial to Evaluate the Effect of Supplementation with Prebiotic Synergy 1 on Iron Homeostasis in Children and Adolescents with Celiac Disease Treated with a Gluten-Free Diet. AB - Iron deficiency anemia (IDA) occurs in 15-46% of patients with celiac disease (CD), and in some cases, it may be its only manifestation. Studies in animal models have shown that prebiotics, including inulin, may help to increase intestinal absorption of iron. The aim of this study was to evaluate the effect of a prebiotic, oligofructose-enriched inulin (Synergy 1), on iron homeostasis in non-anemic children and adolescents with celiac disease (CD) in association with a gluten-free diet (GFD). Thirty-four CD patients (4-18 years old) were randomized into two groups receiving Synergy 1 (10 g/day) or a placebo (maltodextrin) for three months. Before and after intervention, blood samples were collected from all patients for assessment of blood morphology, biochemical parameters and serum hepcidin concentration. We found that serum hepcidin concentration after the intervention was significantly decreased by 60.9% (p = 0.046) in the Synergy 1 group, whereas no significant difference was observed in the placebo group. No differences in morphological and biochemical blood parameters (including ferritin, hemoglobin and C-reactive protein (CRP)) were observed after intervention in either group. Given that hepcidin decrease may improve intestinal iron absorption, these results warrant further investigation in a larger cohort and especially in patients with IDA. PMID- 30469415 TI - Point-of-Care Compatibility of Ultra-Sensitive Detection Techniques for the Cardiac Biomarker Troponin I-Challenges and Potential Value. AB - Cardiac biomarkers are frequently measured to provide guidance on the well-being of a patient in relation to cardiac health with many assays having been developed and widely utilised in clinical assessment. Effectively treating and managing cardiovascular disease (CVD) relies on swiftly responding to signs of cardiac symptoms, thus providing a basis for enhanced patient management and an overall better health outcome. Ultra-sensitive cardiac biomarker detection techniques play a pivotal role in improving the diagnostic capacity of an assay and thus enabling a better-informed decision. However, currently, the typical approach taken within healthcare depends on centralised laboratories performing analysis of cardiac biomarkers, thus restricting the roll-out of rapid diagnostics. Point of-care testing (POCT) involves conducting the diagnostic test in the presence of the patient, with a short turnaround time, requiring small sample volumes without compromising the sensitivity of the assay. This technology is ideal for combatting CVD, thus the formulation of ultra-sensitive assays and the design of biosensors will be critically evaluated, focusing on the feasibility of these techniques for point-of-care (POC) integration. Moreover, there are several key factors, which in combination, contribute to the development of ultra-sensitive techniques, namely the incorporation of nanomaterials for sensitivity enhancement and manipulation of labelling methods. This review will explore the latest developments in cardiac biomarker detection, primarily focusing on the detection of cardiac troponin I (cTnI). Highly sensitive detection of cTnI is of paramount importance regarding the rapid rule-in/rule-out of acute myocardial infarction (AMI). Thus the challenges encountered during cTnI measurements are outlined in detail to assist in demonstrating the drawbacks of current commercial assays and the obstructions to standardisation. Furthermore, the added benefits of introducing multi-biomarker panels are reviewed, several key biomarkers are evaluated and the analytical benefits provided by multimarkers-based methods are highlighted. PMID- 30469416 TI - Fucosyl-Agalactosyl IgG1 Induces Cholangiocarcinoma Metastasis and Early Recurrence by Activating Tumor-Associated Macrophage. AB - Concern over roles of serum IgG agalactosylation in chronic inflammatory diseases has been mounting for years but less touched in cancers. The present study addressed the underlying role of agalactosylated IgG beyond tumorigenesis. Liquid chromatography-tandem mass spectrometry was leveraged for the analysis of IgG1 and IgG2 N-glycomes. We found that a high percentage of serum fucosyl-agalactosyl IgG1 (IgG1-G0F) in patients with cholangiocarcinoma was associated with poor tumor differentiation and tumor metastasis. Results from Kaplan-Meier analyses and a stepwise Cox regression analysis showed that patients with serum IgG1-G0F >=40% were highly correlated with poor recurrence-free survivals and overall survivals. Interestingly, patients with cholangiocarcinoma whose serum IgG1-G0F >=40% had more CD163+ tumor-associated macrophages in cancerous tissues than adjacent non-cancerous counterparts. In vitro assays revealed that agalactosylated IgG upregulated tumor-associated macrophage markers CD163 and CD204 in human U-937 cells and peripheral macrophages. Moreover, a positive and a negative feedback loop of transforming growth factor-beta1 and interferon-gamma, respectively, on IgG agalactosylation was identified using hybridoma cells and verified in sera of the patients. In conclusion, agalactosylated IgG activates tumor-associated macrophages, thereby promoting tumor metastasis and recurrence of cholangiocarcinoma. PMID- 30469418 TI - Enhancement of Localization Systems in NLOS Urban Scenario with Multipath Ray Tracing Fingerprints and Machine Learning. AB - A hybrid technique is proposed to enhance the localization performance of a time difference of arrival (TDOA) deployed in non-line-of-sight (NLOS) suburban scenario. The idea was to use Machine Learning framework on the dataset, produced by the ray tracing simulation, and the Channel Impulse Response estimation from the real signal received by each sensor. Conventional localization techniques mitigate errors trying to avoid NLOS measurements in processing emitter position, while the proposed method uses the multipath fingerprint information produced by ray tracing (RT) simulation together with calibration emitters to refine a Machine Learning engine, which gives an extra layer of information to improve the emitter position estimation. The ray-tracing fingerprints perform the target localization embedding all the reflection and diffraction in the propagation scenario. A validation campaign was performed and showed the feasibility of the proposed method, provided that the buildings can be appropriately included in the scenario description. PMID- 30469417 TI - ZIKV Demonstrates Minimal Pathologic Effects and Mosquito Infectivity in Viremic Cynomolgus Macaques. AB - To evaluate the effects of ZIKV infection on non-human primates (NHPs), as well as to investigate whether these NHPs develop sufficient viremia to infect the major urban vector mosquito, Aedes aegypti, four cynomolgus macaques (Macaca fascicularis) were subcutaneously infected with 5.0 log10 focus-forming units (FFU) of DNA clone-derived ZIKV strain FSS13025 (Asian lineage, Cambodia, 2010). Following infection, the animals were sampled (blood, urine, tears, and saliva), underwent daily health monitoring, and were exposed to Ae. aegypti at specified time points. All four animals developed viremia, which peaked 3-4 days post infection at a maximum value of 6.9 log10 genome copies/mL. No virus was detected in urine, tears, or saliva. Infection by ZIKV caused minimal overt disease: serum biochemistry and CBC values largely fell within the normal ranges, and cytokine elevations were minimal. Strikingly, the minimally colonized population of Ae. aegypti exposed to viremic animals demonstrated a maximum infection rate of 26% during peak viremia, with two of the four macaques failing to infect a single mosquito at any time point. These data indicate that cynomolgus macaques may be an effective model for ZIKV infection of humans and highlights the relative refractoriness of Ae. aegypti for ZIKV infection at the levels of viremia observed. PMID- 30469419 TI - International Journal of Molecular Science 2018 Best Paper Award. AB - The Editors of the International Journal of Molecular Sciences have established the Best Paper Award to recognize the most outstanding articles published in the areas of molecular biology, molecular physics, and chemistry that have been published in the International Journal of Molecular Sciences. [...]. PMID- 30469421 TI - Comparison of Cohesive Models in EDEM and LIGGGHTS for Simulating Powder Compaction. AB - The purpose of this work was to analyse the compaction of a cohesive material using different Discrete Element Method (DEM) simulators to determine the equivalent contact models and to identify how some simulation parameters affect the compaction results (maximum force and compact appearance) and computational costs. For this purpose, three cohesion contact models were tested: linear cohesion in EDEM, and simplified Johnson-Kendall-Roberts (SJKR) and modified SJKR (SJKR2) in LIGGGHTS. The influence of the particle size distribution (PSD) on the results was also investigated. Further assessments were performed on the effect of (1) selecting different timesteps, (2) using distinct conversion tolerances to export the three-dimensional models to standard triangle language (STL) files, and (3) moving the punch with different speeds. Consequently, we determined that a timestep equal to a 10% Rayleigh timestep, a conversion tolerance of 0.01 mm, and a punch speed of 0.1 m/s is adequate for simulating the compaction process using the materials and the contact models in this work. The results showed that the maximum force was influenced by the PSD due to the rearrangement of the particles. The PSD was also related to the computational cost because of the number of simulated particles and their sizes. Finally, an equivalence was found between the linear cohesion and SJKR2 contact models. PMID- 30469420 TI - Trace Element Provision in Parenteral Nutrition in Children: One Size Does Not Fit All. AB - Routine administration of trace elements is recognised as a standard of care in children requiring parenteral nutrition. However, there is a lack of global consensus regarding trace elements provision and dosing in pediatric parenteral nutrition. This review provides an overview of available evidence regarding trace elements supply and posology in parenteral nutrition in neonates and children. Trace elements provision in children should be tailored to the weight and clinical condition of the child with emphasis on those at risk of toxicity or deficiency. Based on current evidence, there is a need to review the formulation of commercial solutions that contain multiple-trace elements and to enable individual trace elements additives to be available for specific indications. Literature supports the removal of chromium provision whereas manganese and molybdenum supplementation are debated. Preterm neonates may have higher parenteral requirements in iodine, selenium and copper than previously recommended. There is growing support for the routine provision of iron in long term parenteral nutrition. Further studies on trace elements contamination of parenteral nutrition solutions are needed for a range of trace elements. PMID- 30469423 TI - Prenatal Programming of Neuroendocrine System Development by Lipopolysaccharide: Long-Term Effects. AB - Various stress factors during critical periods of fetal development modulate the epigenetic mechanisms controlling specific genes, which can affect the structure and function of physiological systems. Maternal immune stress by bacterial infection simulated by lipopolysaccharide (LPS) in an experiment is considered to be a powerful programming factor of fetal development. Studies of the molecular mechanisms controlling the formation and functioning of physiological systems are in the pilot stage. LPSs are the most potent natural inflammation factors. LPS induced increases in fetal levels of pro- and anti-inflammatory cytokines can affect brain development and have long-term effects on behavior and neuroendocrine functions. The degradation of serotonergic neurons induced by LPS in the fetus is attributed to the increased levels of interleukin (IL)-6 and tumor necrosis factor (TNFalpha) as well as to anxiety and depression in children. Dopamine deficiency causes dysthymia, learning disability, and Parkinson's disease. According to our data, an LPS-induced increase in the levels of IL-6, leukemia inhibitory factor (LIF), and monocyte chemotactic protein (MCP 1) in maternal and fetal rats during early pregnancy disturbs the development and functioning of gonadotropin-releasing hormone production and reproductive systems. It is important to note the high responsiveness of epigenetic developmental mechanisms to many regulatory factors, which offers opportunities to correct the defects. PMID- 30469424 TI - The Effectiveness of Home Services in Taiwan: A People-Centered Approach. AB - Among available home and community-based services in Taiwan, there should be a focus on providing people with people-centered, value-based services. This study aims to follow up the people-centered health outcomes of care recipients and to examine the factors associated with to feedback for policy and practice in long term care. A total of 9889 persons from the long-term care dataset were followed up for two years (T0-T4). The Cox Proportional Hazard Regression analyses to analyze mortality and the mixed effect models for health outcomes were used. Three classes among the care recipients were identified. Health profiles (HR = 1.46 and 2.56 for FI and FD compared with RI, p < 0.001), subsidy gap (HR = 1.01), and living status (HR = 0.88 for those living with spouse only) had a significant impact on mortality. The overall dropout rate was 52.3% at two years, and the health profiles at baseline significantly influenced the health outcome's change. The health heterogeneity matters and influences subsequent outcomes. To reach the goal of the HCBS, regular and exact monitoring of care recipients is crucial, while feedback regarding health outcomes and a greater focus on providing person-centered and responsive services in the community are also required. PMID- 30469422 TI - Network Pharmacology to Unveil the Biological Basis of Health-Strengthening Herbal Medicine in Cancer Treatment. AB - Health-strengthening (Fu-Zheng) herbs is a representative type of traditional Chinese medicine (TCM) widely used for cancer treatment in China, which is in contrast to pathogen eliminating (Qu-Xie) herbs. However, the commonness in the biological basis of health-strengthening herbs remains to be holistically elucidated. In this study, an innovative high-throughput research strategy integrating computational and experimental methods of network pharmacology was proposed, and 22 health-strengthening herbs were selected for the investigation. Additionally, 25 pathogen-eliminating herbs were included for comparison. First, based on network-based, large-scale target prediction, we analyzed the target profiles of 1446 TCM compounds. Next, the actions of 166 compounds on 420 antitumor or immune-related genes were measured using a unique high-throughput screening strategy by high-throughput sequencing, referred to as HTS2. Furthermore, the structural information and the antitumor activity of the compounds in health-strengthening and pathogen-eliminating herbs were compared. Using network pharmacology analysis, we discovered that: (1) Functionally, the predicted targets of compounds from health strengthening herbs were enriched in both immune-related and antitumor pathways, similar to those of pathogen eliminating herbs. As a case study, galloylpaeoniflorin, a compound in a health strengthening herb Radix Paeoniae Alba (Bai Shao), was found to exert antitumor effects both in vivo and in vitro. Yet the inhibitory effects of the compounds from pathogen eliminating herbs on tumor cells proliferation as a whole were significantly stronger than those in health-strengthening herbs (p < 0.001). Moreover, the percentage of assay compounds in health-strengthening herbs with the predicted targets enriched in the immune-related pathways (e.g., natural killer cell mediated cytotoxicity and antigen processing and presentation) were significantly higher than that in pathogen-eliminating herbs (p < 0.05). This finding was supported by the immune-enhancing effects of a group of compounds from health-strengthening herbs indicated by differentially expressed genes in the HTS2 results. (2) Compounds in the same herb may exhibit the same or distinguished mechanisms in cancer treatment, which was demonstrated as the compounds influence pathway gene expressions in the same or opposite directions. For example, acetyl ursolic acid and specnuezhenide in a health-strengthening herb Fructus Ligustri lucidi (Nv Zhen Zi) both upregulated gene expressions in T cell receptor signaling pathway. Together, this study suggested greater potentials in tumor immune microenvironment regulation and tumor prevention than in direct killing tumor cells of health-strengthening herbs generally, and provided a systematic strategy for unveiling the commonness in the biological basis of health-strengthening herbs in cancer treatment. PMID- 30469425 TI - Methodological Challenges in the Economic Evaluation of Occupational Health and Safety Programmes. AB - An emerging issue in occupational health and safety (OHS) is that interventions increasingly have to demonstrate that they offer sufficient value for money. To this end, the last decennia have seen more and more economic evaluation methods being employed in this field. However, several recent publications have indicated that many of the published studies suffer from important shortcomings. This paper aims to highlight difficulties in assessing the value of OHS by use of current economic evaluation methods. First, a summary framework presents an overview of the costs and benefits relevant for OHS interventions. Next, three elements from this framework are selected that are at the same time crucial to OHS value, but also challenging to measure and monetise: Effects on worker productivity, 'intangible' benefits, such as reputation effects, and the influence of the broader legal-fiscal context in which an intervention takes place. The following sections then discuss the following research questions for each of these elements: Why is it difficult to exclude these factors from OHS economic evaluations? Why do they pose a challenge to the quality of economic evaluations in OHS? How can they be included, and what are the known advantages and disadvantages of the methods to measure these factors? Future work should investigate (and standardise) better methods to include these elements. PMID- 30469426 TI - Lack of LTbetaR Increases Susceptibility of IPEC-J2 Cells to Porcine Epidemic Diarrhea Virus. AB - The essential requirement of the lymphotoxin beta receptor (LTbetaR) in the development and maintenance of peripheral lymphoid organs is well recognized. Evidence shows that LTbetaR is involved in various cellular processes; however, whether it plays a role in maintaining the cellular function of intestinal porcine enterocytes (IPEC-J2), specifically during porcine epidemic diarrhea virus (PEDV) infection, remains unknown. In this study, we generated LTbetaR null IPEC-J2 cells using CRISPR/Cas9 to examine the importance of LTbetaR in cell proliferation, apoptosis, and the response to PEDV infection. Our results showed that the lack of LTbetaR leads to significantly decreased cell proliferation, potentially due to S phase arrest in LTbetaR-/- IPEC-J2 cells. Label-free digital holographic microscopy was used to record the three-dimensional morphology of both cell types for up to 72 hours and revealed significantly increased numbers of LTbetaR-/- cells undergoing apoptosis. Furthermore, we found that PEDV infected LTbetaR-/- null IPEC-J2 cells exhibited significant suppression of nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB) target genes (interleukin (IL)-6 and IL-8) and mucosal barrier integrity-related genes (vascular cell adhesion molecule 1 (VCAM1) and IL-22), which may explain why LTbetaR-/- cells are more susceptible to PEDV infection. Collectively, our data not only demonstrate the key role of LTbetaR in intestinal porcine enterocytes, but also provide data for the improved understanding of the cellular response to PEDV infection. PMID- 30469427 TI - Uric Acid and Xanthine Levels in Pregnancy Complicated by Gestational Diabetes Mellitus-The Effect on Adverse Pregnancy Outcomes. AB - Uric acid (UA) levels are associated with many diseases including those related to lifestyle. The aim of this study was to evaluate the influence of clinical and anthropometric parameters on UA and xanthine (X) levels during pregnancy and postpartum in women with physiological pregnancy and pregnancy complicated by gestational diabetes mellitus (GDM), and to evaluate their impact on adverse perinatal outcomes. A total of 143 participants were included. Analyte levels were determined by HPLC with ultraviolet detection (HPLC-UV). Several single nucleotide polymorphisms (SNPs) in UA transporters were genotyped using commercial assays. UA levels were higher within GDM women with pre-gestational obesity, those in high-risk groups, and those who required insulin during pregnancy. X levels were higher in the GDM group during pregnancy and also postpartum. Positive correlations between UA and X levels with body mass index (BMI) and glycemia levels were found. Gestational age at delivery was negatively correlated with UA and X levels postpartum. Postpartum X levels were significantly higher in women who underwent caesarean sections. Our data support a possible link between increased UA levels and a high-risk GDM subtype. UA levels were higher among women whose glucose tolerance was severely disturbed. Mid-gestational UA and X levels were not linked to adverse perinatal outcomes. PMID- 30469428 TI - An Example of a Novel Efficient Plant Extraction Technique: Electromagnetic Induction Heating. AB - A simple and easy to handle extraction procedure based on the use of electromagnetic induction heating is described. To assess the potential, scopes, and limitations of this novel process, extraction and subsequent HPLC quantification of emodin from an hydroalcoholic extract of rhizome of Rheum palmatum (Chinese rhubarb) was selected as the reference experiment. Maceration at room temperature and by heating, ultrasound-assisted, and microwave-assisted extractions were also carried out for comparison. Results obtained with electromagnetic induction heating showed that this methodology performed largely better both in terms of time process and extraction yields. PMID- 30469429 TI - Prophylactic Transcatheter Arterial Embolization Helps Intraoperative Hemorrhagic Control for REMOVING Invasive Placenta. AB - OBJECTIVES: The purpose of this article is to investigate the estimated blood loss in pregnant women undergoing cesarean section and placental extirpation to treat abnormal placentation and compare the outcomes of those who underwent prophylactic transcatheter arterial embolization (TAE) with those who did not. METHODS: A retrospective study was conducted on 17 pregnant women diagnosed with abnormal placentation in 2001-2018 in a single tertiary center. The patients were diagnosed by surgical finding, ultrasound, or magnetic resonance imaging (MRI). These patients were divided into two groups: a prophylactic TAE group (11 patients) and a control group (6 patients). In the former group, prophylactic TAE of the bilateral uterine artery (UA) and/or internal iliac artery (IIA) was performed immediately after delivery of the infant. The placenta was removed in both groups. The primary outcomes were estimated blood loss (EBL), units of packed red blood cell (pRBC) transfusion, operative time, whether hysterectomy was performed, whether the patient was transferred to the intensive care unit (ICU), and hospitalization days. The secondary outcome was maternal complications. RESULTS: Patients who received prophylactic TAE had significantly reduced intraoperative blood loss (990.9 +/- 701.7 mL vs. 3448.3 +/- 1767.4 mL, p = 0.018). Units of pRBC transfusion, operative time, hysterectomy, transfer to the ICU, and postoperative hospitalization days were not significantly different between the two groups. Thirteen patients (9 in the TAE group and 4 in the control group) received a blood transfusion during the operation. Three patients underwent a hysterectomy (1 in the TAE group and 2 in the control group). Five patients were transferred to the ICU (3 in the TAE group and 2 in the control group) for maternal complications or monitoring. In the prophylactic TAE group, 3 patients (27%) had a subsequent pregnancy within the next 5 years. CONCLUSIONS: Prophylactic TAE was safe and effective for reducing intraoperative hemorrhage from removing an invasive placenta in patients with abnormal placentation. PMID- 30469431 TI - Veterinary Public Health Activities and Management of the Livestock Sector during Earthquakes and Snowstorms in the Abruzzo Region-Italy, January 2017. AB - In 2017 the Abruzzo region, located in central Italy, was struck by a sequence of four moderately powerful seismic events (5.0 magnitude on Richter scale), in addition to heavy snowfall that caused a state of emergency affecting the resident population and farm animals. A total of 282 stables were reported to have collapsed or been damaged and several animals (224 cows, 4025 ewes, 40,725 chickens, 22 horses and 3092 pigs) were killed. The Istituto Zooprofilattico of Abruzzo and Molise "G. Caporale" (IZSAM)-National Reference Center for Veterinary Urban Hygiene and Non-Epidemic Emergencies (IUVENE), played a crucial role in planning, coordinating and controlling veterinary activities during these catastrophic events. Operational and information tools were used to manage the needs of the communities involved, as well as to prioritize the veterinary interventions, record information, provide real-time data access, and produce reporting maps and Geographic Information System (GIS) layers. These events have highlighted how the integration of veterinary services into disaster management efforts can play an important role in protecting the health and welfare of animals, whilst also restoring economic activity and community life. PMID- 30469432 TI - Characterization of Arginine Catabolism by Lactic Acid Bacteria Isolated from Kimchi. AB - Kimchi fermentation depends on diverse lactic acid bacteria, which convert raw materials into numerous metabolites that contribute to the taste of food. Amino acids and saccharides are important primary metabolites. Arginine is nearly exhausted during kimchi fermentation, whereas the concentrations of other amino acids are reported not to increase or decrease dramatically. These phenomena could imply that arginine is an important nutritional component among the amino acids during kimchi fermentation. In this study, we investigated the arginine catabolism pathway of seven lactic acid bacteria isolated from kimchi and evaluated the products of arginine catabolism (citrulline and ornithine) associated with the bacteria. The arginine content dramatically decreased in cultures of Lactobacillus brevis and Weissella confusa from 300 MUg/mL of arginine to 0.14 +/- 0.19 and 1.3 +/- 0.01 MUg/mL, respectively, after 6 h of cultivation. Citrulline and ornithine production by L. brevis and W. confusa showed a pattern that was consistent with arginine catabolism. Interestingly, Pediococcus pentosaceus, Lactobacillus plantarum, Leuconostoc mesenteroides, and Leuconostoc lactis did not show increased citrulline levels after arginine was added. The ornithine contents were higher in all bacteria except for L. lactis after adding arginine to the culture. These results were consistent with the absence of the arginine deiminase gene among the lactic acid bacteria. Arginine consumption and ornithine production were monitored and compared with lactic acid bacteria by metagenomics analysis, which showed that the increment of ornithine production correlated positively with lactic acid bacteria growth. PMID- 30469430 TI - The Role of Long Noncoding RNAs in Diabetic Alzheimer's Disease. AB - Long noncoding RNAs (lncRNAs) are involved in diverse physiological and pathological processes by modulating gene expression. They have been found to be dysregulated in the brain and cerebrospinal fluid of patients with neurodegenerative diseases, and are considered promising therapeutic targets for treatment. Among the various neurodegenerative diseases, diabetic Alzheimer's disease (AD) has been recently emerging as an important issue due to several unexpected reports suggesting that metabolic issues in the brain, such as insulin resistance and glucose dysregulation, could be important risk factors for AD. To facilitate understanding of the role of lncRNAs in this field, here we review recent studies on lncRNAs in AD and diabetes, and summarize them with different categories associated with the pathogenesis of the diseases including neurogenesis, synaptic dysfunction, amyloid beta accumulation, neuroinflammation, insulin resistance, and glucose dysregulation. It is essential to understand the role of lncRNAs in the pathogenesis of diabetic AD from various perspectives for therapeutic utilization of lncRNAs in the near future. PMID- 30469434 TI - Stackelberg Dynamic Game-Based Resource Allocation in Threat Defense for Internet of Things. AB - With the rapid development of the Internet of Things, there are a series of security problems faced by the IoT devices. As the IoT devices are generally devices with limited resources, how to effectively allocate the restricted resources facing the security problems is the key issue at present. In this paper, we study the resource allocation problem in threat defense for the resource-constrained IoT system, and propose a Stackelberg dynamic game model to get the optimal allocated resources for both the defender and attackers. The proposed Stackelberg dynamic game model is composed by one defender and many attackers. Given the objective functions of the defender and attackers, we analyze both the open-loop Nash equilibrium and feedback Nash equilibrium for the defender and attackers. Then both the defender and attackers can control their available resources based on the Nash equilibrium solutions of the dynamic game. Numerical simulation results show that correctness and effeteness of the proposed model. PMID- 30469433 TI - Lung Protection Strategies during Cardiopulmonary Bypass Affect the Composition of Blood Electrolytes and Metabolites-A Randomized Controlled Trial. AB - Cardiac surgery with cardiopulmonary bypass (CPB) causes an acute lung ischemia reperfusion injury, which can develop to pulmonary dysfunction postoperatively. This sub-study of the Pulmonary Protection Trial aimed to elucidate changes in arterial blood gas analyses, inflammatory protein interleukin-6, and metabolites of 90 chronic obstructive pulmonary disease patients following two lung protective regimens of pulmonary artery perfusion with either hypothermic histidine-tryptophan-ketoglutarate (HTK) solution or normothermic oxygenated blood during CPB, compared to the standard CPB with no pulmonary perfusion. Blood was collected at six time points before, during, and up to 20 h post-CPB. Blood gas analysis, enzyme-linked immunosorbent assay, and nuclear magnetic resonance spectroscopy were used, and multivariate and univariate statistical analyses were performed. All patients had decreased gas exchange, augmented inflammation, and metabolite alteration during and after CPB. While no difference was observed between patients receiving oxygenated blood and standard CPB, patients receiving HTK solution had an excess of metabolites involved in energy production and detoxification of reactive oxygen species. Also, patients receiving HTK suffered a transient isotonic hyponatremia that resolved within 20 h post-CPB. Additional studies are needed to further elucidate how to diminish lung ischemia-reperfusion injury during CPB, and thereby, reduce the risk of developing severe postoperative pulmonary dysfunction. PMID- 30469435 TI - Hepcidin Therapeutics. AB - Hepcidin is a key hormonal regulator of systemic iron homeostasis and its expression is induced by iron or inflammatory stimuli. Genetic defects in iron signaling to hepcidin lead to "hepcidinopathies" ranging from hereditary hemochromatosis to iron-refractory iron deficiency anemia, which are disorders caused by hepcidin deficiency or excess, respectively. Moreover, dysregulation of hepcidin is a pathogenic cofactor in iron-loading anemias with ineffective erythropoiesis and in anemia of inflammation. Experiments with preclinical animal models provided evidence that restoration of appropriate hepcidin levels can be used for the treatment of these conditions. This fueled the rapidly growing field of hepcidin therapeutics. Several hepcidin agonists and antagonists, as well as inducers and inhibitors of hepcidin expression have been identified to date. Some of them were further developed and are currently being evaluated in clinical trials. This review summarizes the state of the art. PMID- 30469436 TI - Prevalence of Diabetes Mellitus among Roma Populations-A Systematic Review. AB - BACKGROUND: The aim of this study was to estimate the prevalence of diabetes mellitus in the Roma population and compare it to the prevalence in the Caucasian population. METHODS: Using the words "Roma", "Gypsies", "Romani", and "traveler" in combination with "diabetes, "metabolic syndrome", "cardiovascular disease" and "health status" we searched the MEDLINE, Pubmed and Scopus databases for articles in English that focused on the prevalence of diabetes mellitus among Roma populations published until December 2017. RESULTS: Five studies met the inclusion criteria. The results of four of them suggested a higher prevalence of diabetes among Romani compared to Caucasians but none of them reached the standards regarding representative samples and number of cases for a conclusive result. CONCLUSION: Although some of the existing studies suggest a substantial prevalence of diabetes among Roma populations and even a higher risk of developing diabetes for Roma persons compared to Caucasians, the number of published literature on this topic remains very low and insufficient in design and number of participants to draw any conclusions. PMID- 30469437 TI - Influence of Disease Duration on Circulating Levels of miRNAs in Children and Adolescents with New Onset Type 1 Diabetes. AB - Circulating microRNAs (miRNAs) have been implicated in several pathologies including type 1 diabetes. In the present study, we aimed to identify circulating miRNAs affected by disease duration in children with recent onset type 1 diabetes. Forty children and adolescents from the Danish Remission Phase Cohort were followed with blood samples drawn at 1, 3, 6, 12, and 60 months after diagnosis. Pancreatic autoantibodies were measured at each visit. Cytokines were measured only the first year. miRNA expression profiling was performed by RT qPCR. The effect of disease duration was analyzed by mixed models for repeated measurements adjusted for sex and age. Eight miRNAs (hsa-miR-10b-5p, hsa-miR-17 5p, hsa-miR-30e-5p, hsa-miR-93-5p, hsa-miR-99a-5p, hsa-miR-125b-5p, hsa-miR-423 3p, and hsa-miR-497-5p) were found to significantly change in expression (adjusted p-value < 0.05) with disease progression. Three pancreatic autoantibodies, ICA, IA-2A, and GAD65A, and four cytokines, IL-4, IL-10, IL-21, and IL-22, were associated with the miRNAs at different time points. Pathway analysis revealed associations with various immune-mediated signaling pathways. Eight miRNAs that were involved in immunological pathways changed expression levels during the first five years after diagnosis and were associated with variations in cytokine and pancreatic antibodies, suggesting a possible effect on the immunological processes in the early phase of the disease. PMID- 30469438 TI - Wireless Communication Technologies for Safe Cooperative Cyber Physical Systems. AB - Cooperative Cyber-Physical Systems (Co-CPSs) can be enabled using wireless communication technologies, which in principle should address reliability and safety challenges. Safety for Co-CPS enabled by wireless communication technologies is a crucial aspect and requires new dedicated design approaches. In this paper, we provide an overview of five Co-CPS use cases, as introduced in our SafeCOP EU project, and analyze their safety design requirements. Next, we provide a comprehensive analysis of the main existing wireless communication technologies giving details about the protocols developed within particular standardization bodies. We also investigate to what extent they address the non functional requirements in terms of safety, security and real time, in the different application domains of each use case. Finally, we discuss general recommendations about the use of different wireless communication technologies showing their potentials in the selected real-world use cases. The discussion is provided under consideration in the 5G standardization process within 3GPP, whose current efforts are inline to current gaps in wireless communications protocols for Co-CPSs including many future use cases. PMID- 30469439 TI - Long-Term Exposure to Air Pollutants and Cancer Mortality: A Meta-Analysis of Cohort Studies. AB - The aim of this study was to examine the relationship between main air pollutants and all cancer mortality by performing a meta-analysis. We searched PubMed, EMBASE (a biomedical and pharmacological bibliographic database of published literature produced by Elsevier), and the reference lists of other reviews until April 2018. A random-effects model was employed to analyze the meta-estimates of each pollutant. A total of 30 cohort studies were included in the final analysis. Overall risk estimates of cancer mortality for 10 ug/m3 per increase of particulate matter (PM)2.5, PM10, and NO2 were 1.17 (95% confidence interval (CI): 1.11-1.24), 1.09 (95% CI: 1.04-1.14), and 1.06 (95% CI: 1.02-1.10), respectively. With respect to the type of cancer, significant hazardous influences of PM2.5 were noticed for lung cancer mortality and non-lung cancer mortality including liver cancer, colorectal cancer, bladder cancer, and kidney cancer, respectively, while PM10 had harmful effects on mortality from lung cancer, pancreas cancer, and larynx cancer. Our meta-analysis of cohort studies indicates that exposure to the main air pollutants is associated with increased mortality from all cancers. PMID- 30469440 TI - Molecular Processes Connecting DNA Methylation Patterns with DNA Methyltransferases and Histone Modifications in Mammalian Genomes. AB - DNA methylation is an essential part of the epigenome chromatin modification network, which also comprises several covalent histone protein post-translational modifications. All these modifications are highly interconnected, because the writers and erasers of one mark, DNA methyltransferases (DNMTs) and ten eleven translocation enzymes (TETs) in the case of DNA methylation, are directly or indirectly targeted and regulated by other marks. Here, we have collected information about the genomic distribution and variability of DNA methylation in human and mouse DNA in different genomic elements. After summarizing the impact of DNA methylation on genome evolution including CpG depletion, we describe the connection of DNA methylation with several important histone post-translational modifications, including methylation of H3K4, H3K9, H3K27, and H3K36, but also with nucleosome remodeling. Moreover, we present the mechanistic features of mammalian DNA methyltransferases and their associated factors that mediate the crosstalk between DNA methylation and chromatin modifications. Finally, we describe recent advances regarding the methylation of non-CpG sites, methylation of adenine residues in human cells and methylation of mitochondrial DNA. At several places, we highlight controversial findings or open questions demanding future experimental work. PMID- 30469441 TI - Sensitive and Reproducible Gold SERS Sensor Based on Interference Lithography and Electrophoretic Deposition. AB - Surface-enhanced Raman spectroscopy (SERS) is a promising analytical tool due to its label-free detection ability and superior sensitivity, which enable the detection of single molecules. Since its sensitivity is highly dependent on localized surface plasmon resonance, various methods have been applied for electric field-enhanced metal nanostructures. Despite the intensive research on practical applications of SERS, fabricating a sensitive and reproducible SERS sensor using a simple and low-cost process remains a challenge. Here, we report a simple strategy to produce a large-scale gold nanoparticle array based on laser interference lithography and the electrophoretic deposition of gold nanoparticles, generated through a pulsed laser ablation in liquid process. The fabricated gold nanoparticle array produced a sensitive, reproducible SERS signal, which allowed Rhodamine 6G to be detected at a concentration as low as 10 8 M, with an enhancement factor of 1.25 * 105. This advantageous fabrication strategy is expected to enable practical SERS applications. PMID- 30469442 TI - An Improved Multi-Relaxation Time Lattice Boltzmann Method for the Non-Newtonian Influence of the Yielding Fluid Flow in Cement-3D Printing. AB - The multi-relaxation time lattice Boltzmann method (MRT-LBM) has an excellent performance in dealing with the complex flow in many different areas. According to the specific behavior of the fluids, it also has some shortcomings when applied to some special flow like as the non-Newtonian flow. In Cement-3D printing, the fluids always exhibit according to the yielding behavior. When using the standard MRT-LBM, the simulation maybe divergent. In order to solve the problem, this work presents an improved MRT-LBM considering the non-Newtonian effect as a special forcing term to ensure the stable and accurate simulation. Finally, the Poiseuille flow was used to validate the feasibility of the proposed method. PMID- 30469443 TI - Frequency Offset Tolerant Synchronization Signal Design in NB-IoT. AB - Timing detection is the first step and very important in wireless communication systems. Timing detection performance is usually affected by the frequency offset. Therefore, it is a challenge to design the synchronization signal in massive narrowband Internet of Things (NB-IoT) scenarios where the frequency offset is usually large due to the low cost requirement. In this paper, we firstly proposed a new general synchronization signal structure with a couple of sequences which are conjugated to remove the potential timing error that arises from large frequency offset. Then, we analyze the suitable sequence for our proposed synchronization signal structure and discuss a Zadoff-Chu (ZC) sequence with root 1 as an example. Finally, the simulation results demonstrate that our proposed synchronization signal can work well when the frequency offset is large. It means that our proposed synchronization signal design is very suitable for the massive NB-IoT. PMID- 30469444 TI - Fast Tracks and Roadblocks for Zika Vaccines. AB - In early 2014, a relatively obscure virus, the Zika virus, made headlines worldwide following an increase in the number of congenital malformations. Since then, research on Zika virus, treatment and vaccines have progressed swiftly with various drugs being repurposed and vaccines heading into clinical trials. Nonetheless, the need for a vaccine is crucial in order to eradicate this re emerging arthropod-borne virus which remained silent since its first discovery in 1947. In this review, we focused on how the inconspicuous virus managed to spread, the key immunological factors required for a vaccine and the various vaccine platforms that are currently being studied. PMID- 30469445 TI - Improving the Error of Time Differences of Arrival on Partial Discharges Measurement in Gas-Insulated Switchgear. AB - Partial Discharge (PD) detection based on Ultra-High-Frequency (UHF) measurements in Gas-Insulated Switchgear (GIS) is often used for fault location based on extraction of Time Differences of Arrival (TDoA), and the core technique is to obtain the precise time difference of each UHF signal. Usually, TDoA extraction algorithms can be categorized as cross-correlation function method (CCF), minimum energy method (ME), and threshold value method (TV) are not qualified to analyze the time difference with high accuracy and efficiency, especially the complicated UHF PD signals in the field. In this paper, multiple tests were carried out based on the real GIS UHF signals. Three typical algorithms (CCF, ME, and TV) were used to extract and calculate the TDoA of UHF signals. Afterwards, depending on the disassembly of equipment, the accuracy and effective range of the algorithms are analyzed by means of error and variance. To minimize the error and the variance, an average method with the combination (CA) and portfolio of traditional algorithms is proposed and verified in different situations. The results demonstrate that the improved algorithm could increase the accuracy of time difference extraction, less than 4.0%. PMID- 30469446 TI - HSP70 Inhibitor Suppresses IGF-I-Stimulated Migration of Osteoblasts through p44/p42 MAP Kinase. AB - Heat shock protein 70 (HSP70) is a ubiquitously expressed molecular chaperone in a variety of cells including osteoblasts. We previously showed that insulin-like growth factor-I (IGF-I) elicits migration of osteoblast-like MC3T3-E1 cells through the activation of phosphatidylinositol 3-kinase/Akt and p44/p42 mitogen activated protein (MAP) kinase. In the present study, we investigated the effects of HSP70 inhibitors on the IGF-I-elicited migration of these cells and the mechanism involved. The IGF-I-stimulated osteoblast migration evaluated by a wound-healing assay and by a transwell cell migration was significantly reduced by VER-155008 and YM-08, which are both HSP70 inhibitors. VER-155008 markedly suppressed the IGF-I-induced phosphorylation of p44/p42 MAP kinase without affecting that of Akt. In conclusion, our results strongly suggest that the HSP70 inhibitor reduces the IGF-I-elicited migration of osteoblasts via the p44/p42 MAP kinase. PMID- 30469447 TI - The Effect of Edible Chitosan Coatings Incorporated with Thymus capitatus Essential Oil on the Shelf-Life of Strawberry (Fragaria x ananassa) during Cold Storage. AB - The strawberry is a fruit appreciated in the food industry for its high content of bioactive compounds. However, it is considered a highly perishable fruit, generally attacked by pests of phytopathogenic origin, which decreases its shelf life. Normally, to diminish the losses caused by pathogenic microbes, coatings of polysaccharides in combination with natural products like essential oils are applied. In this work, we describe the effect of edible coatings from chitosan (CT) incorporating Thymus capitatus essential oil (TCEO), applied to strawberries stored under refrigeration conditions (5 +/- 0.5 degrees C). Different concentrations of TCEO were applied to chitosan coatings, with different effects on the physical and microbiological properties of the strawberries. All the products had greater acceptance and quality than the controls, being more effective those with essential oil incorporation. It is noteworthy that all the essential oil treatments lead to an increase in the shelf-life of strawberries of up to 15 days. Scanning electron microscopy (SEM) analysis of the microstructure showed a decrease in compactness with TCEO introduction, but without compromising food preservation after 15 days. In addition, treated strawberries delayed the loss of physicochemical and antioxidant properties, due to protection against the microbial development of aerobic mesophylls, molds, and yeasts. PMID- 30469448 TI - A 40-MHz Ultrasound Transducer with an Angled Aperture for Guiding Percutaneous Revascularization of Chronic Total Occlusion: A Feasibility Study. AB - Complete blockage of a coronary artery, called chronic total occlusion (CTO), frequently occurs due to atherosclerosis. To reopen the obstructed blood vessels with a stent, guidewire crossing is performed with the help of angiography that can provide the location of CTO lesions and the image of guidewire tip. Since angiography is incapable of imaging inside a CTO lesion, the surgeons are blind during guidewire crossing. For this reason, the success rate of guidewire crossing relies upon the proficiency of the surgeon, which is considerably reduced from 69.0% to 32.5% if extensive calcification, not penetrated by a guidewire, exists in CTO lesions. In this paper, a recently developed 40-MHz forward-looking intravascular ultrasound (FL-IVUS) transducer to visualize calcification within CTO lesions is reported. This transducer consists of a single element angled aperture and a guidewire passage. The aperture is spherically deformed to have a focal length of 3 mm in order to improve spatial resolution of FL-IVUS images. The angle between the beam direction and the axis of rotation is designed to be 30 degrees to effectively visualize calcification within a CTO lesion as well as the blood vessel wall. The experimental results demonstrated that the developed FL-IVUS transducer facilitates visualization of calcification within CTO lesions and makes it possible to help the surgeon make decisions about whether to push the guidewire in order to cross the lesion or to change the surgical procedure. PMID- 30469449 TI - Impact of Out-of-Pocket Cost on Herpes Zoster Vaccine Uptake: An Observational Study in a Medicare Managed Care Population. AB - Herpes zoster (HZ) vaccination is approved for adults aged 50+ for the prevention of HZ, but it is underutilized. The objective of this study was to evaluate the association between out-of-pocket cost and HZ vaccine utilization. Adults aged 65 or older enrolled for at least 12 months in Medicare Advantage/Part D (MAPD) and Medicare Part D only (PDP) plans from 1 January 2007 to 30 June 2014 were selected. Abandonment was defined as a reversed claim for HZ vaccine with no other paid claim within 90 days. Out-of-pocket costs used were actual amounts recorded in the claim. Overall, the HZ vaccine abandonment rate was 7.3%. Mean out-of-pocket costs were higher for individuals who abandoned versus those who did not ($88 (+/-$55) versus $80 (+/- $49)). Logistic regression indicated individuals with out-of-pocket costs of $80-$90 were 21% more likely (OR = 1.21, 1.16-1.27 95% CI), and those with out-of-pocket costs >$90 were 90% more likely (OR = 1.90, 1.85-1.96 95% CI) to abandon than those with out-of-pocket costs <$80. The models also suggested that socioeconomic, racial, and ethnic disparities in vaccine abandonment existed. Different vaccine targeting efforts and pharmacy benefit design strategies may be needed to increase use, improve adherence, and minimize disparities. PMID- 30469450 TI - Disability Adjusted Life Years (DALYs) in Terms of Years of Life Lost (YLL) Due to Premature Adult Mortalities and Postneonatal Infant Mortalities Attributed to PM2.5 and PM10 Exposures in Kuwait. AB - Ambient air pollution in terms of fine and coarse particulate matter (PM2.5 and PM10) has been shown to increase adult and infant mortalities. Most studies have estimated the risk of mortalities through attributable proportions and number of excess cases with no reference to the time lost due to premature mortalities. Disability adjusted life years (DALYs) are necessary to measure the health impact of Ambient particulate matter (PM) over time. In this study, we used life-tables for three years (2014-2016) to estimate the years of life lost (YLL), a main component of DALYs, for adult mortalities (age 30+ years) and postneonatal infant mortalities (age 28+ days-1 year) associated with PM2.5 exposure and PM10 exposure, respectively. The annual average of PM2.5 and PM10 concentrations were recorded as 87.9 MUg/m3 and 167.5 MUg/m3, which are 8 times greater than the World Health Organization (WHO) air quality guidelines of 10 MUg/m3 and 20 MUg/m3, respectively. Results indicated a total of 252.18 (95% CI: 170.69-322.92) YLL for all ages with an increase of 27,474.61 (95% CI: 18,483.02-35,370.58) YLL over 10 years. The expected life remaining (ELR) calculations showed that 30- and 65-year-old persons would gain 2.34 years and 1.93 years, respectively if the current PM2.5 exposure levels were reduced to the WHO interim targets (IT-1 = 35 MUg/m3). Newborns and 1-year old children may live 79.81 and 78.94 years, respectively with an increase in average life expectancy of 2.65 years if the WHO PM10 interim targets were met (IT-1 = 70 MUg/m3). Sensitivity analyses for YLL were carried out for the years 2015, 2025, and 2045 and showed that the years of life would increase significantly for age groups between 30 and 85. Life expectancy, especially for the elderly (>=60 years), would increase at higher rates if PM2.5 levels were reduced further. This study can be helpful for the assessment of poor air quality represented by PM2.5 and PM10 exposures in causing premature adult mortalities and postneonatal infant mortalities in developing countries with high ambient air pollution. Information in this article adds insights to the sustainable development goals (SDG 3.9.1 and 11.6.2) related to the reduction of mortality rates attributed to ambient air levels of coarse and fine particulate matter. PMID- 30469451 TI - 8-Oxo-9-Dihydromakomakine Isolated from Aristotelia chilensis Induces Vasodilation in Rat Aorta: Role of the Extracellular Calcium Influx. AB - 8-Oxo-9-dihydromakomakine is a tetracyclic indole alkaloid extracted from leaves of the Chilean tree Aristotelia chilensis. The present study investigated the effects of this alkaloid on vascular response in tissues isolated from aortic segments obtained from normotensive rats. Our results showed that 8-oxo-9 dihydromakomakine induced a dose-dependent relaxation of aortic rings pre contracted with phenylephrine (PE; 10-6 M). The vasorelaxation induced by 8-oxo-9 dihydromakomakine in rat aortic rings is independent of endothelium. The pre incubation of aortic rings with 8-oxo-9-dehydromakomakine (10-4 M) significantly reduced the contractile response to KCl (p < 0.001) more than PE (p < 0.05). The highest dose of 8-oxo-9-dehydromakomakine (10-4 M) drastically reduced the contraction to KCl (6.10-2 M), but after that, PE (10-6 M) caused contraction (p < 0.05) in the same aortic rings. The addition of 8-oxo-9-dihydromakomakine (10-5 M) decreased the contractile response to tetraethylammonium (a voltage-dependent potassium channels blocker; TEA; 5 * 10-3 M; p < 0.01) and BaCl2 (a non-selective inward rectifier potassium channel blocker; 5 * 10-3 M; p < 0.001) in rat aorta. 8-oxo-9-dihydromakomakine (10-5 M) decreased the contractile response to PE in rat aorta in the presence or absence of ouabain (an inhibitor of Na,K-ATPase; 10 3 M; p < 0.05). These results could indicate that 8-oxo-9-dihydromakomakine partially reduces plasma membrane depolarization-induced contraction. In aortic rings depolarized by PE, 8-oxo-9-dihydromakomakine inhibited the contraction induced by the influx of extracellular Ca2+ in a Ca2+ free solution (p < 0.01). 8 oxo-9-dihydromakomakine reduced the contractile response to agonists of voltage dependent calcium channels type L (Bay K6844; 10-8 M; p < 0.01), likely decreasing the influx of extracellular Ca2+ through the voltage-dependent calcium channels. This study provides the first qualitative analysis indicating that traditional folk medicine Aristotelia chilensis may be protective in the treatment of cardiovascular pathologies. PMID- 30469452 TI - Medium-Chain Triglycerides Attenuate Liver Injury in Lipopolysaccharide Challenged Pigs by Inhibiting Necroptotic and Inflammatory Signaling Pathways. AB - This study was conducted to investigate whether medium-chain triglycerides (MCTs) attenuated lipopolysaccharide (LPS)-induced liver injury by down-regulating necroptotic and inflammatory signaling pathways. A total of 24 pigs were randomly allotted to four treatments in a 2 * 2 factorial design including diet (0 and 4% MCTs) and immunological challenge (saline and LPS). After three weeks of feeding with or without 4% MCTs, pigs were challenged with saline or LPS. MCTs led to a significant increase in eicosapentaenoic acid, docosahexaenoic acid and total (n 3) polyunsaturated fatty acid concentrations. MCTs attenuated LPS-induced liver injury as indicated by an improvement in liver histomorphology and ultrastructural morphology of hepatocytes, a reduction in serum alanine aminotransferase and alkaline phosphatase activities as well as an increase in claudin-1 protein expression. In addition, MCTs also reduced serum tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta and IL-6 concentrations, liver TNF-alpha and IL-1beta mRNA expression and protein concentrations and enhanced liver heat shock protein 70 protein expression in LPS-challenged pigs. Moreover, MCTs decreased mRNA expression of receptor-interacting serine/threonine-protein kinase (RIP) 3, mixed-lineage kinase domain-like protein (MLKL) and phosphoglycerate mutase 5 and inhibited MLKL phosphorylation in the liver. Finally, MCTs decreased liver mRNA expression of toll-like receptor (TLR) 4, nucleotide-binding oligomerization domain protein (NOD) 1 and multiple downstream signaling molecules. MCTs also suppressed LPS-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation and increased extracellular signal-related kinase 1/2 phosphorylation in the liver. These results indicated that MCTs are capable of attenuating LPS-induced liver damage by suppressing hepatic necroptotic (RIP1/RIP3/MLKL) and inflammatory (TLR4/NOD1/p38 MAPK) signaling pathways. PMID- 30469453 TI - Correntropy Based Divided Difference Filtering for the Positioning of Ships. AB - In this paper, robust first and second-order divided difference filtering algorithms based on correntropy are proposed, which not only retain the advantages of divided difference filters, but also exhibit robustness in the presence of non-Gaussian noises, especially when the measurements are contaminated by heavy-tailed noises. The proposed filters are then applied to the problem of ship positioning. In order to improve the accuracy and reliability of ship positioning, the positioning method combines the Dead Reckoning (DR) algorithm and the Global Positioning System (GPS). Experimental results of an illustrative example show the superior performance of the new algorithms when applied to ship positioning. PMID- 30469454 TI - Upper Normal Serum Creatinine Concentrations as a Predictor for Chronic Kidney Disease: Analysis of 14 Years' Korean Genome and Epidemiology Study (KoGES). AB - Both serum creatinine (sCr) and estimated glomerular filtration rate (eGFR) have been used to assess kidney function in public health check-ups. However, when the sCr is within the normal levels but the eGFR is <60 mL/min/1.73 m2, a dilemma arises, as the patients might progress to chronic kidney disease (CKD) after several years. We aimed to evaluate the association between normal sCr and the risk of incident CKD in the general population. For this, 9445 subjects from the Korean Genome and Epidemiology Study, with normal sCr and eGFR of >60 mL/min/1.73 m2 were analyzed. The subjects were classified into quartiles based on sCr levels. The primary outcome was the development of eGFR <60 mL/min/1.73 m2 on two consecutive measures. During a mean follow-up of 8.4 +/- 4.3 years, 779 (8.2%) subjects developed eGFR <60 mL/min/1.73 m2. The incidence of the development of eGFR <60 mL/min/1.73 m2 was higher in the higher quartiles than in the lowest quartile. In multivariable Cox analysis, the highest quartile was associated with an increased risk for the development of eGFR <60 mL/min/1.73 m2 (hazard ratio (HR), 4.71; 95% confidence interval (CI), 3.29-6.74 in females; HR, 12.77; 95% CI, 7.69-21.23 in males). In the receiver operating characteristic curve analysis, adding sCr to the traditional risk factors for CKD improved the accuracy of predicting the development of eGFR <60 mL/min/1.73 m2 (area under the curve, 0.83 vs. 0.80 in females and 0.85 vs. 0.78 in males), and the cutoff value of sCr was 0.75 mg/dL and 0.78 mg/dL in females and males. Cautious interpretation is necessary when sCr is within the normal range, considering that the upper normal range of sCr has a higher risk of CKD development. PMID- 30469455 TI - A Handheld Real-Time Photoacoustic Imaging System for Animal Neurological Disease Models: From Simulation to Realization. AB - This article provides a guide to design and build a handheld, real-time photoacoustic (PA) imaging system from simulation to realization for animal neurological disease models. A pulsed laser and array-based ultrasound (US) platform were utilized to develop the system for evaluating vascular functions in rats with focal ischemia or subcutaneous tumors. To optimize the laser light delivery, finite element (FE)-based simulation models were developed to provide information regarding light propagation and PA wave generation in soft tissues. Besides, simulations were also conducted to evaluate the ideal imaging resolution of the US system. As a result, a PA C-scan image of a designed phantom in 1% Lipofundin was reconstructed with depth information. Performance of the handheld PA system was tested in an animal ischemia model, which revealed that cerebral blood volume (CBV) changes at the cortical surface could be monitored immediately after ischemia induction. Another experiment on subcutaneous tumors showed the anomalous distribution of the total hemoglobin concentration (HbT) and oxygen saturation (SO2), while 3D and maximum intensity projection (MIP) PA images of the subcutaneous tumors are also presented in this article. Overall, this system shows promise for monitoring disease progression in vascular functional impairments. PMID- 30469456 TI - Jatrorrhizine Hydrochloride Suppresses RANKL-Induced Osteoclastogenesis and Protects against Wear Particle-Induced Osteolysis. AB - Wear particle-induced aseptic prosthetic loosening is a major complication associated with total joint arthroplasty (TJA). A growing body of evidence suggests that receptor activator of nuclear factor kappa-B ligand (RANKL) stimulated osteoclastogenesis and bone resorption are responsible for peri implant loosening. Thus, agents which attenuate excessive osteoclast differentiation and function have been considered to offer therapeutic potential for prolonging the life of TJA implants. Jatrorrhizine hydrochloride (JH), a major protoberberine alkaloid isolated from the traditional Chinese herb Coptis chinensis, has been reported to have antimicrobial, antitumor, and antihypercholesterolemic and neuroprotective activities. However, its effects on osteoclast biology remain unknown. Here, we found that JH inhibited RANKL-induced osteoclast formation and bone resorption in vitro and exerted protection against titanium (Ti) particle-induced osteolysis in vivo. Biochemical analysis demonstrated that JH suppressed RANKL-induced activation of MAPKs (p38 and ERK) which down-regulated the production of NFATc1 and NFATc1-regulated osteoclastic marker genes, such as TRAP, CTR and CTSK. Collectively, our findings suggest that JH may be a promising anti-osteoclastogenesis agent for treating periprosthetic osteolysis or other osteoclast-related osteolytic diseases. PMID- 30469458 TI - Step-Double-Zone-JTE for SiC Devices with Increased Tolerance to JTE Dose and Surface Charges. AB - In this paper, an edge termination structure, referred to as step-double-zone junction termination extension (Step-DZ-JTE), is proposed. Step-DZ-JTE further improves the distribution of the electric field (EF) by its own step shape. Step DZ-JTE and other termination structures are investigated for comparison using numerical simulations. Step-DZ-JTE greatly reduces the sensitivity of breakdown voltage (BV) and surface charges (SC). For a 30-MUm thick epi-layer, the optimized Step-DZ-JTE shows 90% of the theoretical BV with a wide tolerance of 12.2 * 1012 cm-2 to the JTE dose and 85% of the theoretical BV with an improved tolerance of 3.7 * 1012 cm-2 to the positive SC are obtained. Furthermore, when combined with the field plate technique, the performance of the Step-DZ-JTE is further improved. PMID- 30469459 TI - Cod Residual Protein Prevented Blood Pressure Increase in Zucker fa/fa Rats, Possibly by Inhibiting Activities of Angiotensin-Converting Enzyme and Renin. AB - Hypertension is the leading risk factor for cardiovascular disease, and prevention of high blood pressure through diet and lifestyle should be a preferred approach. High intake of fish is associated with lower blood pressure, possibly mediated through the proteins since peptides with angiotensin-converting enzyme (ACE) inhibiting capacities have been identified in fish skin, backbone, and fillet. The effects of cod meals made from residual materials and fillet on blood pressure were investigated in obese Zucker fa/fa rats which spontaneously develop high blood pressure. Rats were fed diets containing water-soluble (stickwater) or water-insoluble (presscake) fractions of protein-rich meals from cod residual materials (head, gut, backbone with muscle residuals, skin, trimmings) or fillet. Rats were fed diets containing 25% of total protein from cod meal and 75% of protein from casein, or casein as the sole protein source (control group) for four weeks. Results show that a diet containing residual presscake meal with high gut content prevented blood pressure increase, and this cod residual meal also showed the strongest in vitro inhibitions of ACE and renin activities. In conclusion, a diet containing water-insoluble proteins (presscake meal) with high gut content prevented increase in blood pressure in obese Zucker fa/fa rats. PMID- 30469457 TI - Liquid Crystals: A Novel Approach for Cancer Detection and Treatment. AB - Liquid crystals are defined as the fourth state of matter forming between solid and liquid states. Earlier the applications of liquid crystals were confined to electronic instruments, but recent research findings suggest multiple applications of liquid crystals in biology and medicine. Here, the purpose of this review article is to discuss the potential biological impacts of liquid crystals in the diagnosis and prognosis of cancer along with the risk assessment. In this review, we also discussed the recent advances of liquid crystals in cancer biomarker detection and treatment in multiple cell line models. Cases reviewed here will demonstrate that cancer diagnostics based on the multidisciplinary technology and intriguingly utilization of liquid crystals may become an alternative to regular cancer detection methodologies. Additionally, we discussed the formidable challenges and problems in applying liquid crystal technologies. Solving these problems will require great effort and the way forward is through the multidisciplinary collaboration of physicists, biologists, chemists, material-scientists, clinicians, and engineers. The triumphant outcome of these liquid crystals and their applications in cancer research would be convenient testing for the detection of cancer and may result in treating the cancer patients non-invasively. PMID- 30469460 TI - Counter Anion Effect on the Photophysical Properties of Emissive Indolizine Cyanine Dyes in Solution and Solid State. AB - Near-infrared emissive materials with tunable Stokes shifts and solid-state emissions are needed for several active research areas and applications. To aid in addressing this need, a series of indolizine-cyanine compounds varying only the anions based on size, dipole, and hydrophilicity were prepared. The effect of the non-covalently bound anions on the absorption and emission properties of identical pi-system indolizine-cyanine compounds were measured in solution and as thin films. Interestingly, the anion choice has a significant influence on the Stokes shift and molar absorptivities of the dyes in solution. In the solid state, the anion choice was found to have an effect on the formation of aggregate states with higher energy absorptions than the parent monomer compound. The dyes were found to be emissive in the NIR region, with emissions peaking at near 900 nm for specific solvent and anion selections. PMID- 30469461 TI - Improvement of Detection Sensitivity of Microbubbles as Sensors to Detect Ambient Pressure. AB - Microbubbles are considered a promising tool for noninvasive estimation of local blood pressure. It is reported that the subharmonic scattering amplitude of microbubbles decreases by 9 to 12 dB when immersed in the media under an ambient pressure variation from 0 to 180 mmHg. However, the pressure sensitivity still needs to be improved to satisfy clinical diagnostic requirements. Here, we investigated the effects of acoustic parameters on the pressure sensitivity of microbubbles through measuring the acoustic attenuation and scattering properties of commercially available SonoVue microbubbles. Our results showed that the first harmonic, subharmonic, and ultraharmonic amplitudes of microbubbles were reduced by 6.6 dB, 10.9 dB, and 9.3 dB at 0.225 mechanical index (MI), 4.6 dB, 19.8 dB, and 12.3 dB at 0.25 MI, and 18.5 dB, 17.6 dB, and 12.6 dB at 0.3 MI, respectively, when the ambient pressure increased from 0 to 180 mmHg. Our finding revealed that a moderate MI (0.25-0.4) exciting microbubbles could significantly improve their sensitivities to detect ambient pressure. PMID- 30469462 TI - Validity and Repeatability of Single-Sensor Loadsol Insoles during Landing. AB - Clinically feasible methods for quantifying landing kinetics could help identify patients at risk for secondary anterior cruciate ligament injuries. The purpose of this study was to evaluate the validity and between-day repeatability of the loadsol insole during a single-hop and bilateral stop-jump. Thirty healthy recreational athletes completed seven single-hops and seven stop-jumps while simultaneous loadsol (100 Hz) and force plate (1920 Hz) measurements were recorded. Peak impact force, loading rate, and impulse were computed for the dominant limb, and limb symmetry was calculated between limbs for each measure. All outcomes were compared between the loadsol and force plate using intraclass correlation coefficients (ICC) and Bland-Altman plots. Fifteen participants completed a second day of testing to assess between-day repeatability of the loadsol. Finally, an additional 14 participants completed the first day of testing only to assess the validity of the newest generation loadsol, which sampled at 200 Hz. At 100 Hz, validity ICC results were moderate to excellent (0.686-0.982), and repeatability ICC results were moderate to excellent (0.616 0.928). The 200 Hz loadsol demonstrated improved validity ICC (0.765-0.987). Bland-Altman plots revealed that the loadsol underestimated load measures. However, this bias was not observed for symmetry outcomes. The loadsol device is a valid and repeatable tool for evaluating kinetics during landing. PMID- 30469463 TI - Gut Microbiota-Dependent Trimethylamine N-Oxide Pathway Associated with Cardiovascular Risk in Children with Early-Stage Chronic Kidney Disease. AB - Despite cardiovascular disease (CVD) being the leading cause of morbidity and mortality in chronic kidney disease (CKD), less attention has been paid to subclinical CVD in children and adolescents with early CKD stages. Gut microbiota and their metabolite, trimethylamine N-oxide (TMAO), have been linked to CVD. Ambulatory blood-pressure monitoring (ABPM) and arterial-stiffness assessment allow for early detection of subclinical CVD. We therefore investigated whether gut microbial composition and TMAO metabolic pathway are correlated with blood pressure (BP) load and vascular abnormalities in children with early-stage CKD. We enrolled 86 children with G1-G3 CKD stages. Approximately two-thirds of CKD children had BP abnormalities on ABPM. Children with CKD stage G2-G3 had a higher uric acid level (6.6 vs. 4.8 mg/dL, p < 0.05) and pulse-wave velocity (4.1 vs. 3.8 m/s, p < 0.05), but lower TMAO urinary level (209 vs. 344 ng/mg creatinine, p < 0.05) than those with stage G1. Urinary TMAO level was correlated with the abundances of genera Bifidobacterium (r = 0.307, p = 0.004) and Lactobacillus (r = 0.428, p < 0.001). CKD children with abnormal ABPM profile had a lower abundance of the Prevotella genus than those with normal ABPM (p < 0.05). Our results highlight the link between gut microbiota, microbial metabolite TMAO, BP load, and arterial-stiffness indices in children with early-stage CKD. Early assessments of these surrogate markers should aid in decreasing cardiovascular risk in childhood CKD. PMID- 30469464 TI - Investigation of Camphor Effects on Fusarium graminearum and F. culmorum at Different Molecular Levels. AB - Fusarium graminearum and F. culmorum are phytopathogens, which cause destructive diseases in cereals. Epidemics of these phytopathogens are caused by mycotoxin contamination and the reduction of crop quality. In this study, the alteration due to in vitro camphor treatment on F. culmorum 9F and F. graminearum H11 isolates was investigated in terms of epigenetic, cellular, and transcription levels. Camphor with different concentrations (0.2, 0.4, 0.8, 1, 2, and 4 ug/uL) was applied to potato dextrose agar (PDA) growth media. The minimum inhibitory concentration (MIC) and the half maximal inhibitory concentration (IC50) were calculated as 2 and 1 ug/uL, respectively. hog1, mst20, CAT, POD, mgv1, stuA, and tri5 genes, which are related to various cellular processes and pathogenesis, were examined by qPCR assay. qPCR analysis showed that camphor treatment leads to the downregulation of tri5 expression but the upregulation of the remaining genes. Apoptosis and oxidative stress were confirmed via acridine orange/ethidium bromide (AO/EB) and dichlorofluorescin diacetate (DCF-DA) staining, respectively. Moreover, coupled restriction enzyme digestion-random amplification (CRED-RA) assay, used for DNA methylation analysis, was carried out to evaluate epigenetic alterations. The decrease in genomic template stability (GTS) values, which resulted due to the alterations in random amplified polymorphic DNA (RAPD) profiles caused by camphor treatment, were detected as 97.60% in F. culmorum 9F and 66.27% in F. graminearum H-11. The outer and inner methylated cytosine profiles are determined by CRED-RA assay as type I-IV epigenetic alterations. The outcomes indicated that camphor could lead to alterations at several molecular levels of F. graminearum and F. culmorum. PMID- 30469465 TI - AuNPs-Based Thermoresponsive Nanoreactor as an Efficient Catalyst for the Reduction of 4-Nitrophenol. AB - A new AuNPs-based thermosensitive nanoreactor (SiO2@PMBA@Au@PNIPAM) was designed and prepared by stabilizing AuNPs in the layer of poly(N,N' methylenebisacrylamide) (PMBA) and subsequent wrapping with the temperature sensitive poly(N-isopropylacrylamide) (PNIPAM) layer. The new nanoreactor exhibited high dispersibility and stability in aqueous solution and effectively prevented the aggregation of AuNPs caused by the phase transformation of PNIPAM. The XPS and ATR-FTIR results indicated that AuNPs could be well stabilized by PMBA due to the electron transfer between the N atoms of amide groups in the PMBA and Au atoms of AuNPs. The catalytic activity and thermoresponsive property of the new nanoreactor were invested by the reduction of the environmental pollutant, 4-nitrophenol (4-NP), with NaBH4 as a reductant. It exhibited a higher catalytic activity at 20 degrees C and 30 degrees C (below LCST of PNIPAM), but an inhibited catalytic activity at 40 degrees C (above LCST of PNIPAM). The PNIPAM layer played a switching role in controlling the catalytic rate by altering the reaction temperature. In addition, this nanoreactor showed an easily recyclable property due to the existence of a silica core and also preserved a rather high catalytic efficiency after 16 times of recycling. PMID- 30469466 TI - Defective T-Cell Apoptosis and T-Regulatory Cell Dysfunction in Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is a chronic, progressive, systemic autoimmune disease that mostly affects small and large synovial joints. At the molecular level, RA is characterized by a profoundly defective innate and adaptive immune response that results in a chronic state of inflammation. Two of the most significant alterations in T-lymphocyte (T-cell) dysfunction in RA is the perpetual activation of T-cells that result in an abnormal proliferation state which also stimulate the proliferation of fibroblasts within the joint synovial tissue. This event results in what we have termed "apoptosis resistance", which we believe is the leading cause of aberrant cell survival in RA. Finding therapies that will induce apoptosis under these conditions is one of the current goals of drug discovery. Over the past several years, a number of T-cell subsets have been identified. One of these T-cell subsets are the T-regulatory (Treg) cells. Under normal conditions Treg cells dictate the state of immune tolerance. However, in RA, the function of Treg cells become compromised resulting in Treg cell dysfunction. It has now been shown that several of the drugs employed in the medical therapy of RA can partially restore Treg cell function, which has also been associated with amelioration of the clinical symptoms of RA. PMID- 30469467 TI - Augmentation of 5-Aminolevulinic Acid Treatment of Glioblastoma by Adding Ciprofloxacin, Deferiprone, 5-Fluorouracil and Febuxostat: The CAALA Regimen. AB - The CAALA (Complex Augmentation of ALA) regimen was developed with the goal of redressing some of the weaknesses of 5-aminolevulinic acid (5-ALA) use in glioblastoma treatment as it now stands. 5-ALA is approved for use prior to glioblastoma surgery to better demarcate tumor from brain tissue. 5-ALA is also used in intraoperative photodynamic treatment of glioblastoma by virtue of uptake of 5-ALA and its preferential conversion to protoporphyrin IX in glioblastoma cells. Protoporphyrin IX becomes cytotoxic after exposure to 410 nm or 635 nm light. CAALA uses four currently-marketed drugs-the antibiotic ciprofloxacin, the iron chelator deferiprone, the antimetabolite 5-FU, and the xanthine oxidase inhibitor febuxostat-that all have evidence of ability to both increase 5-ALA mediated intraoperative glioblastoma demarcation and photodynamic cytotoxicity of in situ glioblastoma cells. Data from testing the full CAALA on living minipigs xenotransplanted with human glioblastoma cells will determine safety and potential for benefit in advancing CAALA to a clinical trial. PMID- 30469468 TI - Effect of Selective Laser Melting Process Parameters on the Quality of Al Alloy Parts: Powder Characterization, Density, Surface Roughness, and Dimensional Accuracy. AB - Additive manufacturing (AM) of high-strength Al alloys promises to enhance the performance of critical components related to various aerospace and automotive applications. The key advantage of AM is its ability to generate lightweight, robust, and complex shapes. However, the characteristics of the as-built parts may represent an obstacle to the satisfaction of the parts' quality requirements. The current study investigates the influence of selective laser melting (SLM) process parameters on the quality of parts fabricated from different Al alloys. A design of experiment (DOE) was used to analyze relative density, porosity, surface roughness, and dimensional accuracy according to the interaction effect between the SLM process parameters. The results show a range of energy densities and SLM process parameters for AlSi10Mg and Al6061 alloys needed to achieve "optimum" values for each performance characteristic. A process map was developed for each material by combining the optimized range of SLM process parameters for each characteristic to ensure good quality of the as-built parts. This study is also aimed at reducing the amount of post-processing needed according to the optimal processing window detected. PMID- 30469469 TI - Effects of the Carbon Fiber-Carbon Microcoil Hybrid Formation on the Effectiveness of Electromagnetic Wave Shielding on Carbon Fibers-Based Fabrics. AB - Carbon fiber-carbon microcoil (CF-CMC) hybrids were formed on carbon fiber (CF) based fabric. The morphologies of CF-based fabrics and CF-CMC hybridized fabrics were investigated. The electrical conductivities of the CF-CMC hybridized fabrics were examined and compared with those of native CF-based fabrics. Furthermore, the electromagnetic wave shielding effectiveness (SE) of the CF-CMC hybridized fabrics was investigated across operating frequencies in the 8.0-12.0 GHz range, and the results were compared with those for native CF-based fabrics. For the CF based nonwoven fabrics, the SE values were improved by the CF-CMC hybridization reaction, although the electrical conductivities of the nonwoven fabric were reduced by the CF-CMC hybrid formation. For the CF-based woven fabrics, the SE values were improved by more than twofold throughout the entire range of frequencies, owing to the CF-CMC hybrid formation. This dramatic improvement was partly ascribed to the enhanced electrical conductivity, particularly in the transverse direction to the individual CFs. Owing to the increased thickness of the woven or nonwoven fabrics after the CF-CMC hybrid formation and the intrinsic characteristics of CMCs, the absorption mechanism for the SE was determined for the main factor that contributed to the improvement of the SE values. PMID- 30469470 TI - Hsp60 in Skeletal Muscle Fiber Biogenesis and Homeostasis: From Physical Exercise to Skeletal Muscle Pathology. AB - Hsp60 is a molecular chaperone classically described as a mitochondrial protein with multiple roles in health and disease, participating to the maintenance of protein homeostasis. It is well known that skeletal muscle is a complex tissue, rich in proteins, that is, subjected to continuous rearrangements, and this homeostasis is affected by many different types of stimuli and stresses. The regular exercise induces specific histological and biochemical adaptations in skeletal muscle fibers, such as hypertrophy and an increase of mitochondria activity and oxidative capacity. The current literature is lacking in information regarding Hsp60 involvement in skeletal muscle fiber biogenesis and regeneration during exercise, and in disease conditions. Here, we briefly discuss the functions of Hsp60 in skeletal muscle fibers during exercise, inflammation, and ageing. Moreover, the potential usage of Hsp60 as a marker for disease and the evaluation of novel treatment options is also discussed. However, some questions remain open, and further studies are needed to better understand Hsp60 involvement in skeletal muscle homeostasis during exercise and in pathological condition. PMID- 30469471 TI - Localized Deformation and Fracture Behaviors in InP Single Crystals by Indentation. AB - The indentation-induced deformation mechanisms in InP(100) single crystals were investigated by using nanoindentation and cross-sectional transmission electron microscopy (XTEM) techniques. The results indicated that there were multiple "pop in" events randomly distributed in the loading curves, which were conceived to arise primarily from the dislocation nucleation and propagation activities. An energetic estimation on the number of nanoindentation-induced dislocations associated with pop-in effects is discussed. Furthermore, the fracture patterns were performed by Vickers indentation. The fracture toughness and the fracture energy of InP(100) single crystals were calculated to be around 1.2 MPa.m1/2 and 14.1 J/m2, respectively. PMID- 30469472 TI - Comparison of a Novel Ultrasonic Scaler Tip vs. Conventional Design on a Titanium Surface. AB - The aim of this in vitro study was to evaluate the alterations of a titanium surface after treatment with two different types of ultrasonic tips: conventional steel versus an innovative copper alloy silver-plated one. Twenty smooth-surface, grade IV unalloyed titanium discs were divided into two groups. The discs were ultrasonically instrumented and the scaler was connected with a loading machine. The surface morphology was examined using scanning electron microscopy (SEM) and fractal analysis of lacunarity was calculated to highlight the alteration of the surface using the two different tips. The SEM analysis showed different degrees of surface roughness between the two types of scaler tips. Moreover, these observations demonstrated that the new tip showed fewer irregularities on the disc's surface than the conventional steel tip. The statistical and fractal analysis showed a statistically significant difference between the two groups. Surface alterations of titanium induced by the conventional ultrasonic tips were much greater than those made by copper alloy silver plated tips. The presented results suggest that the use of this new ultrasonic tip may reduce the alterations on the implant surface during its use in dental practice. PMID- 30469473 TI - The Transcriptional Repressor BS69 is a Conserved Target of the E1A Proteins from Several Human Adenovirus Species. AB - Early region 1A (E1A) is the first viral protein produced upon human adenovirus (HAdV) infection. This multifunctional protein transcriptionally activates other HAdV early genes and reprograms gene expression in host cells to support productive infection. E1A functions by interacting with key cellular regulatory proteins through short linear motifs (SLiMs). In this study, the molecular determinants of interaction between E1A and BS69, a cellular repressor that negatively regulates E1A transactivation, were systematically defined by mutagenesis experiments. We found that a minimal sequence comprised of MPNLVPEV, which contains a conserved PXLXP motif and spans residues 112-119 in HAdV-C5 E1A, was necessary and sufficient in binding to the myeloid, Nervy, and DEAF-1 (MYND) domain of BS69. Our study also identified residues P113 and L115 as critical for this interaction. Furthermore, the HAdV-C5 and -A12 E1A proteins from species C and A bound BS69, but those of HAdV-B3, -E4, -D9, -F40, and -G52 from species B, E, D, F, and G, respectively, did not. In addition, BS69 functioned as a repressor of E1A-mediated transactivation, but only for HAdV-C5 and HAdV-A12 E1A. Thus, the PXLXP motif present in a subset of HAdV E1A proteins confers interaction with BS69, which serves as a negative regulator of E1A mediated transcriptional activation. PMID- 30469474 TI - Pax3 Gene Regulated Melanin Synthesis by Tyrosinase Pathway in Pteria penguin. AB - The paired-box 3 (Pax3) is a transcription factor and it plays an important part in melanin synthesis. In this study, a new Pax3 gene was identified from Pteria penguin (Roding, 1798) (P. penguin) by RACE-PCR (rapid-amplification of cDNA ends polymerase chain reaction) and its effect on melanin synthesis was deliberated by RNA interference (RNAi). The cDNA of PpPax3 was 2250 bp long, containing an open reading fragment of 1365 bp encoding 455 amino acids. Amino acid alignment and phylogenetic tree showed PpPax3 shared the highest (69.2%) identity with Pax3 of Mizuhopecten yessoensis. Tissue expression profile showed that PpPax3 had the highest expression in mantle, a nacre-formation related tissue. The PpPax3 silencing significantly inhibited the expression of PpPax3, PpMitf, PpTyr and PpCdk2, genes involved in Tyr-mediated melanin synthesis, but had no effect on PpCreb2 and an increase effect on PpBcl2. Furthermore, the PpPax3 knockdown obviously decreased the tyrosinase activity, the total content of eumelanin and the proportion of PDCA (pyrrole-2,3-dicarboxylic acid) in eumelanin, consistent with influence of tyrosinase (Tyr) knockdown. These data indicated that PpPax3 played an important regulating role in melanin synthesis by Tyr pathway in P. penguin. PMID- 30469476 TI - An Optimized Colorimetric Readout Method for Lateral Flow Immunoassays. AB - Despite its broad penetration of various markets, the quantitative lateral flow immunoassay (LFIA) suffers from sensitivity issues in some cases. To solve this problem, an optimized colorimetric readout method for LFIA quantification is proposed in this study. An assay reader device utilizing a color camera and an analysis method using a Bayer filtered image were developed. Spectrometric measurements of the assay test line were performed to determine the color channel that contains the test line information and effectively minimizes noise. The change in the intensity ratio with increasing concentration of the target substance in the sample was largest in the green channel. The linear range of the output curve ranged from 0 to 10 ng/mL, and the detection limit was 2 ng/mL. The suggested instrumentation and analysis methods are expected to effectively resolve the low-sensitivity problems of the former LFIA systems and to offer other prospective functionalities for LFIA quantification. PMID- 30469475 TI - Variation of the Bacterial Community in the Rhizoplane Iron Plaque of the Wetland Plant Typha latifolia. AB - The survival of wetland plants in iron, sulfur and heavy metals-rich mine tailing ponds has been commonly attributed to the iron plaque (IP) on the root surface that acts as a protective barrier. However, the contribution of bacteria potentially regulates the iron-sulfur cycle and heavy metal exclusion at the root surface has not been studied in depth, particularly from a microbial ecology perspective. In this study, a pot experiment using Typha latifolia, a typical wetland plant, in non-polluted soil (NP) and tailing soil (T) was conducted. Samples from four zones, comprising non-rhizosphere soil (NR), rhizosphere soil (R) and internal (I) and external (E) layers of iron plaque, were collected from the NP and T and analyzed by 16S rRNA sequencing. Simpson index of the genus level showed greater diversities of bacterial community in the NP and its I zone is the most important part of the rhizosphere. PICRUSt predicted that the I zones in both NP and T harbored most of the functional genes. Specifically, functional genes related to sulfur relay and metabolism occurred more in the I zone in the T, whereas those related to iron acquisition and carbon and nitrogen circulation occurred more in the I zone in the NP. Analysis of dominant bacterial communities at genus level showed highest abundance of heavy metal resistant genus Burkholderia in the E zones in both soils, indicating that heavy metal resistance of Typha latifolia driven by Burkholderia mainly occurred at the external layer of IP. Moreover, many bacterial genera, such as Acidithiobacillus, Ferritrophicum, Thiomonas, Metallibacterium and Sideroxydans, involved in iron and sulfur metabolisms were found in the T and most showed higher abundance in the I zone than in the other zones. This work, as the first endeavor to separate the iron plaque into external and internal layers and investigate the variations of the bacterial communities therein, can provide an insight for further understanding the survival strategy of wetland plants, e.g., Typha latifolia, in extreme environment. PMID- 30469477 TI - Association of Inadequately Low Left Ventricular Mass with Enhanced Myocardial Contractility in Severe Degenerative Aortic Stenosis. AB - BACKGROUND: Left ventricular hypertrophy (LVH), traditionally considered an adaptive mechanism that is aimed at the maintenance of LV systolic function, is absent in 10%-35% of patients with severe aortic stenosis (AS). Our aim was to estimate the clinical and hemodynamic characteristics in patients with severe AS and absent LVH, or inadequately low LV mass (i-lowLVM) relative to an individual hemodynamic load. METHODS: We retrospectively analyzed in-hospital records of 100 patients with pure severe degenerative AS, preserved LV systolic function and without relevant coexistent diseases, except for well-controlled hypertension or diabetes. RESULTS: Clinical characteristics were similar in patients with and without LVH, as well as those with and without i-lowLVM, except for slightly lower GFR at i-lowLVM. When compared to their counterparts, subjects without LVH or with i-lowLVM had smaller LV cavities, decreased LV wall thicknesses and higher EF. There were no significant differences in stenosis severity and indices of afterload (valvulo-arterial impedance and circumferential end-systolic LV wall stress), according to the presence or absence of either LVH or i-lowLVM. However, LV fractional shortening at the midwall level was elevated only in patients with i-lowLVM, but not in those without LVH, compared to the remainder (15.8 +/- 3.3 vs. 12.9 +/- 3.2%, p < 0.001 for those with and without i-lowLVM, respectively; 13.7 +/- 3.7 vs. 13.8 +/- 3.6% for LVH presence and absence, p = 0.9). CONCLUSIONS: Inadequately low LVM relative to the individual hemodynamic load could potentially reflect a different mode of the LV response to severe AS, associated with enhanced load-independent LV systolic performance, i.e., better LV contractility. If confirmed in a large series of patients, our small preliminary study may add to the possible mechanisms of a previously reported counterintuitive tendency of a lower, not higher, risk of adverse outcome in patients with low LV mass despite severe AS. Prospective studies are warranted, in order to determine a potential utility of LVM inadequacy in the risk stratification of patients with AS. PMID- 30469478 TI - Inflammation-Accelerated Senescence and the Cardiovascular System: Mechanisms and Perspectives. AB - Low-grade chronic inflammation is a common denominator in atherogenesis and related diseases. Solid evidence supports the occurrence of an impairment in the innate and adaptive immune system with senescence, favoring the development of acute and chronic age-related diseases. Cardiovascular (CV) diseases (CVD), in particular, are a leading cause of death even at older ages. Inflammation associated mechanisms that contribute to CVD development include dysregulated redox and metabolic pathways, genetic modifications, and infections/dysbiosis. In this review, we will recapitulate the determinants and consequences of the immune system dysfunction at older age, with particular focus on the CV system. We will examine the currently available and potential future strategies to counteract accelerated CV aging, i.e., nutraceuticals, probiotics, caloric restriction, physical activity, smoking and alcohol cessation, control of low-grade inflammation sources, senolytic and senescence-modulating drugs, and DNA targeting drugs. PMID- 30469479 TI - Anatomic Association of the Proximal Fingernail Matrix to the Extensor Pollicis Longus Tendon: A Morphological and Histological Study. AB - BACKGROUND: Extensor tendon disorders may cause severe functional impairments, and there is a lack of knowledge about their anatomic associations with the proximal fingernail matrix. OBJECTIVE: To delineate the association between the distal extensor pollicis longus tendon (EPLT) insertion and the limit of the fingernail matrix in the thumb. METHODS: The limit of the fingernail matrix and the distal bony insertion of the EPLT were identified in five thumbs from fresh frozen human cadavers. An additional five thumbs were fixed and the longitudinal thumb sections were histologically analyzed. RESULTS: The terminal limit of the matrix and fingernail was dorsal and overlapped to the EPL tendon, which was located between the fingernail matrix and the phalanx, and extended dorsally to the distal section of the terminal phalanx in all ten thumb bodies. CONCLUSION: The fingernail matrix is not directly inserted into the periosteum of the dorsal section of the base to the distal phalanx, because this anatomic relationship is separated by the deep fibers of the EPLT. PMID- 30469480 TI - Release of Graphene and Carbon Nanotubes from Biodegradable Poly(Lactic Acid) Films during Degradation and Combustion: Risk Associated with the End-of-Life of Nanocomposite Food Packaging Materials. AB - Nanoparticles of graphene and carbon nanotubes are attractive materials for the improvement of mechanical and barrier properties and for the functionality of biodegradable polymers for packaging applications. However, the increase of the manufacture and consumption increases the probability of exposure of humans and the environment to such nanomaterials; this brings up questions about the risks of nanomaterials, since they can be toxic. For a risk assessment, it is crucial to know whether airborne nanoparticles of graphene and carbon nanotubes can be released from nanocomposites into the environment at their end-life, or whether they remain embedded in the matrix. In this work, the release of graphene and carbon nanotubes from the poly(lactic) acid nanocomposite films were studied for the scenarios of: (i) biodegradation of the matrix polymer at the disposal of wastes; and (ii) combustion and fire of nanocomposite wastes. Thermogravimetric analysis in air atmosphere, transmission electron microscopy (TEM), atomic force microscopy (AFM) and scanning electron microscope (SEM) were used to verify the release of nanoparticles from nanocomposite films. The three factors model was applied for the quantitative and qualitative risk assessment of the release of graphene and carbon nanotubes from nanocomposite wastes for these scenarios. Safety concern is discussed in respect to the existing regulations for nanowaste stream. PMID- 30469481 TI - A Miniaturized Amperometric Hydrogen Sulfide Sensor Applicable for Bad Breath Monitoring. AB - Bad breath or halitosis affects a majority of the population from time to time, causing personal discomfort and social embarrassment. Here, we report on a miniaturized, microelectromechanical systems (MEMS)-based, amperometric hydrogen sulfide (H2S) sensor that potentially allows bad breath quantification through a small handheld device. The sensor is designed to detect H2S gas in the order of parts-per-billion (ppb) and has a measured sensitivity of 0.65 nA/ppb with a response time of 21 s. The sensor was found to be selective to NO and NH3 gases, which are normally present in the oral breath of adults. The ppb-level detection capability of the integrated sensor, combined with its relatively fast response and high sensitivity to H2S, makes the sensor potentially applicable for oral breath monitoring. PMID- 30469482 TI - Applications of Functional Near-Infrared Spectroscopy (fNIRS) Neuroimaging in Exercise-Cognition Science: A Systematic, Methodology-Focused Review. AB - For cognitive processes to function well, it is essential that the brain is optimally supplied with oxygen and blood. In recent years, evidence has emerged suggesting that cerebral oxygenation and hemodynamics can be modified with physical activity. To better understand the relationship between cerebral oxygenation/hemodynamics, physical activity, and cognition, the application of state-of-the art neuroimaging tools is essential. Functional near-infrared spectroscopy (fNIRS) is such a neuroimaging tool especially suitable to investigate the effects of physical activity/exercises on cerebral oxygenation and hemodynamics due to its capability to quantify changes in the concentration of oxygenated hemoglobin (oxyHb) and deoxygenated hemoglobin (deoxyHb) non invasively in the human brain. However, currently there is no clear standardized procedure regarding the application, data processing, and data analysis of fNIRS, and there is a large heterogeneity regarding how fNIRS is applied in the field of exercise-cognition science. Therefore, this review aims to summarize the current methodological knowledge about fNIRS application in studies measuring the cortical hemodynamic responses during cognitive testing (i) prior and after different physical activities interventions, and (ii) in cross-sectional studies accounting for the physical fitness level of their participants. Based on the review of the methodology of 35 as relevant considered publications, we outline recommendations for future fNIRS studies in the field of exercise-cognition science. PMID- 30469483 TI - Theoretical Study of Hydrogen on LaFeO3 (010) Surface Adsorption and Subsurface Diffusion. AB - Based on density functional theory, this paper studies the adsorption and the subsurface occupation by H on LaFeO3 (010) surface and their corresponding transition states. As shown from the results, the best storage positions of hydrogen are on the O top position of the LaFeO3 (010) surface and the interstice near the oxygen of the subsurface. In addition, the position of surface Fe atom can also store hydrogen, but H atom prefers to adsorb on O atom first. Whether the H atom is adsorbed on O or Fe atom, it is easy diffuse to the nearby more stable O atom. However, the diffusion between the Fe atoms is difficult to occur. The main diffusion path of the H atom from the surface to the subsurface is the process of inward layer by layer around the O atom. With the fracture of the old H-O bond and the formation of the new H-O bond, the H is around O atom to constantly repeat the process of a hopping-rotational diffusion. H diffuses through the nearest neighbor position, which is more favorable than the direct diffusion. PMID- 30469484 TI - Evidence for Right-Sided Horses Being More Optimistic than Left-Sided Horses. AB - An individual's positive or negative perspective when judging an ambiguous stimulus (cognitive bias) can be helpful when assessing animal welfare. Emotionality, as expressed in approach or withdrawal behaviour, is linked to brain asymmetry. The predisposition to process information in the left or right brain hemisphere is displayed in motor laterality. The quality of the information being processed is indicated by the sensory laterality. Consequently, it would be quicker and more repeatable to use motor or sensory laterality to evaluate cognitive bias than to perform the conventional judgment bias test. Therefore, the relationship between cognitive bias and motor or sensory laterality was tested. The horses (n = 17) were trained in a discrimination task involving a box that was placed in either a "positive" or "negative" location. To test for cognitive bias, the box was then placed in the middle, between the trained positive and negative location, in an ambiguous location, and the latency to approach the box was evaluated. Results indicated that horses that were more likely to use the right forelimb when moving off from a standing position were more likely to approach the ambiguous box with a shorter latency (generalized linear mixed model, p < 0.01), and therefore displayed a positive cognitive bias (optimistic). PMID- 30469485 TI - Redescriptions, Lectotype Designations, New Synonyms and New Geographic Records for the "Tiger" Species of Mycotretus Lacordaire, 1842 (Coleoptera: Erotylidae: Tritomini). AB - The Neotropical Mycotretus Lacordaire, 1842 is one of the largest and most widespread genera of the Erotylidae, encompassing more than 200 described species. Among the species with a similar body coloration, there is a "group" of six valid species-called here the "tiger" Mycotretus-that possess several pronotal and elytral black spots, as follows: M. tigrinus (Olivier, 1792); M. multimaculatus Taschenberg, 1870; M. centralis Arrow, 1909; M. tigrinoides Mader, 1942; M. tigripennis Mader, 1942; and M. prioteloides Mader, 1942. Different from any other Mycotretus with spots, the spots of the "tiger" Mycotretus are numerous and are not bilaterally symmetrical in pattern. Here, new geographical records, diagnoses and redescriptions are provided for M. tigrinus, M. centralis, M. tigrinoides, M. tigripennis and M. prioteloides, including the first descriptions of their male and female terminalia. Lectotypes are designated for M. multimaculatus, M. centralis, and M. leopardus. Mycotretus multimaculatus and M. tigrinus pardalis Crotch, 1876 are proposed as new junior synonyms of M. tigrinus. Additionally, the authorship of the name M. leopardus is attributed to Crotch, 1876, because he was the first author to provide a description for that taxon, and the synonymy of M. leopardus and M. conspersus (Germar, 1824) with M. tigrinus (Olivier, 1792) is confirmed. PMID- 30469486 TI - Calorie Restriction Mimetics: Upstream-Type Compounds for Modulating Glucose Metabolism. AB - Calorie restriction (CR) can prolong the human lifespan, but enforcing long-term CR is difficult. Therefore, a compound that reproduces the effect of CR without CR is needed. In this review, we summarize the current knowledge on compounds with CR mimetic (CRM) effects. More than 10 compounds have been listed as CRMs, some of which are conventionally categorized as upstream-type CRMs showing glycolytic inhibition, while the others are categorized as downstream-type CRMs that regulate or genetically modulate intracellular signaling proteins. Among these, we focus on upstream-type CRMs and propose their classification as compounds with energy metabolism inhibition effects, particularly glucose metabolism modulation effects. The upstream-type CRMs reviewed include chitosan, acarbose, sodium-glucose cotransporter 2 inhibitors, and hexose analogs such as 2 deoxy-d-glucose, d-glucosamine, and d-allulose, which show antiaging and longevity effects. Finally, we discuss the molecular definition of upstream-type CRMs. PMID- 30469487 TI - Impact of Physical Activity and Sleep Duration on Depressive Symptoms in Hypertensive Patients: Results from a Nationally Representative Korean Sample. AB - Depressive symptoms among individuals with hypertension may increase the risk of cardio-cerebrovascular disease, disease burden, and mortality. However, few studies have examined the relationships among physical activity, sleep duration, and depressive symptoms. Thus, this cross-sectional study examined the associations of physical activity and sleep duration with depressive symptoms in individuals with hypertension. We analyzed data collected as part of the 2014 Korea National Health and Nutrition Examination Survey, which included 846 patients with hypertension aged 19 or older. The prevalence rate of depressive symptoms was around 11.2%. A logistic regression analysis showed that moderate to vigorous physical activity (odds ratio (OR) = 4.42; 95% confidence interval (CI) = 2.19-8.89) and short (OR = 2.18; 95% CI = 1.11-4.28) and long sleep duration (OR = 4.09; 95% CI = 1.83-9.13) increased the risk of depressive symptoms after adjusting for confounding factors. Additionally, older age and low educational levels were associated with depressive symptoms. Our findings highlight that physical activity and sleep duration should be key components of lifestyle modification among hypertensive patients with depressive symptoms. Further investigation might benefit from validating these findings using a longitudinal design and examining the mediating effects of physical activity and/or sleep duration on the relationship between individual characteristics and depressive symptoms. PMID- 30469488 TI - Loss of Myeloid-Specific TGF-beta Signaling Decreases CTHRC1 to Downregulate bFGF and the Development of H1993-Induced Osteolytic Bone Lesions. AB - The role of myeloid cell-specific TGF-beta signaling in non-small-cell lung cancer (NSCLC)-induced osteolytic bone lesion development is unknown. We used a genetically engineered mouse model, Tgfbr2LysMCre knockout (KO), which has a loss of TGF-beta signaling specifically in myeloid lineage cells, and we found that the area of H1993 cell-induced osteolytic bone lesions was decreased in Tgfbr2LysMCre KO mice, relative to the area in control littermates. The bone lesion areas were correlated with tumor cell proliferation, angiogenesis, and osteoclastogenesis in the microenvironment. The smaller bone lesion area was partially rescued by bFGF, which was expressed by osteoblasts. Interestingly, bFGF was able to rescue the osteoclastogenesis, but not the tumor cell proliferation or angiogenesis. We then focused on identifying osteoclast factors that regulate bFGF expression in osteoblasts. We found that the expression and secretion of CTHRC1 was downregulated in osteoclasts from Tgfbr2LysMCre KO mice; CTHRC1 was able to promote bFGF expression in osteoblasts, possibly through the Wnt/beta-catenin pathway. Functionally, bFGF stimulated osteoclastogenesis and inhibited osteoblastogenesis, but had no effect on H1993 cell proliferation. On the other hand, CTHRC1 promoted osteoblastogenesis and H1993 cell proliferation. Together, our data show that myeloid-specific TGF-beta signaling promoted osteolytic bone lesion development and bFGF expression in osteoblasts; that osteoclast-secreted CTHRC1 stimulated bFGF expression in osteoblasts in a paracrine manner; and that CTHRC1 and bFGF had different cell-specific functions that contributed to bone lesion development. PMID- 30469489 TI - Fish, Fish Oils and Cardioprotection: Promise or Fish Tale? AB - Fish and commercially available fish oil preparations are rich sources of long chain omega-3 polyunsaturated fatty acids. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the most important fatty acids in fish oil. Following dietary intake, these fatty acids get incorporated into the cell membrane phospholipids throughout the body, especially in the heart and brain. They play an important role in early brain development during infancy, and have also been shown to be of benefit in dementia, depression, and other neuropsychiatric disorders. Early epidemiologic studies show an inverse relationship between fish consumption and the risk of coronary heart disease. This led to the identification of the cardioprotective role of these marine derived fatty acids. Many experimental studies and some clinical trials have documented the benefits of fish oil supplementation in decreasing the incidence and progression of atherosclerosis, myocardial infarction, heart failure, arrhythmias, and stroke. Possible mechanisms include reduction in triglycerides, alteration in membrane fluidity, modulation of cardiac ion channels, and anti inflammatory, anti-thrombotic, and anti-arrhythmic effects. Fish oil supplements are generally safe, and the risk of toxicity with methylmercury, an environmental toxin found in fish, is minimal. Current guidelines recommend the consumption of either one to two servings of oily fish per week or daily fish oil supplements (around 1 g of omega-3 polyunsaturated fatty acids per day) in adults. However, recent large-scale studies have failed to demonstrate any benefit of fish oil supplements on cardiovascular outcomes and mortality. Here, we review the different trials that evaluated the role of fish oil in cardiovascular diseases. PMID- 30469490 TI - Prevalence of Childhood Overweight and Obesity in Liverpool between 2006 and 2012: Evidence of Widening Socioeconomic Inequalities. AB - The primary aim of this study was to describe the prevalence of childhood overweight and obesity in Liverpool between 2006 and 2012. A secondary aim was to examine the extent to which socioeconomic inequalities relating to childhood overweight and obesity in Liverpool changed during this six-year period. A sample of 50,125 children was created using data from the National Child Measurement Program (NCMP) in Liverpool. The prevalence of overweight and obesity was calculated for Reception and Year 6 aged children in Liverpool for each time period by gender and compared against published averages for England. Logistic regression analyses examined the likelihood of children in Liverpool being classified as overweight and obese based on deprivation level for each time period. Analyses were conducted separately for Reception and Year 6 aged children and were adjusted for gender. The prevalence of overweight and obesity among Reception and Year 6 aged children in Liverpool increased between 2006 and 2012. During the same period, socioeconomic disparities in overweight and obesity prevalence between children living in the most deprived communities in Liverpool and those living in less deprived communities in Liverpool, widened. This study evidences rising rates of overweight and obesity among Liverpool children and widening socioeconomic health inequalities within Liverpool, England's most deprived city between 2006 and 2012. PMID- 30469491 TI - Imaging and Molecular Mechanisms of Alzheimer's Disease: A Review. AB - Alzheimer's disease is the most common form of dementia and is a significant burden for affected patients, carers, and health systems. Great advances have been made in understanding its pathophysiology, to a point that we are moving from a purely clinical diagnosis to a biological one based on the use of biomarkers. Among those, imaging biomarkers are invaluable in Alzheimer's, as they provide an in vivo window to the pathological processes occurring in Alzheimer's brain. While some imaging techniques are still under evaluation in the research setting, some have reached widespread clinical use. In this review, we provide an overview of the most commonly used imaging biomarkers in Alzheimer's disease, from molecular PET imaging to structural MRI, emphasising the concept that multimodal imaging would likely prove to be the optimal tool in the future of Alzheimer's research and clinical practice. PMID- 30469492 TI - Field and Laboratory Studies on the Ecology, Reproduction, and Adult Diapause of the Asian Comma Butterfly, Polygonia c-aureum L. (Lepidoptera: Nymphalidae). AB - Adult diapause and reproduction of a nymphalid butterfly, Polygonia c-aureum L., were investigated in field and laboratory examinations. Laboratory studies showed that old virgin male butterflies of non-diapausing generations had heavy accessory glands and simplex, which were suppressed in diapausing generations. The number of eupyrene sperm bundles in the duplex increased with adult age, whereas testis size decreased with age. Field examinations indicated that reproductive development of both sexes of diapausing generations in autumn was suppressed, and developed in spring. We attempted to estimate the physiological age of wild-caught males, as adult male age can be estimated from the testis size. We also attempted to determine whether or not wild male butterflies had mated from the development of the accessory glands and simplex, as well as the number of eupyrene sperm bundles in the duplex, by comparing unmated males with mated males. Field examinations suggest that almost all females in a population of non-diapausing generations mated and showed a tendency toward polyandry, while in the diapausing generation, in spring, monoandry rather than polyandry predominated. This suggests a different mating strategy between non-diapausing and diapausing generations. PMID- 30469493 TI - Laser Displacement Sensors for Wind Tunnel Model Position Measurements. AB - Wind tunnel measurements of two-dimensional wing sections, or airfoils, are the building block of aerodynamic predictions for many aerodynamic applications. In these experiments, the forces and pitching moment on the airfoil are measured as a function of the orientation of the airfoil relative to the incoming airflow. Small changes in this angle (called the angle of attack, or alpha ) can create significant changes in the forces and moments, so accurately measuring the angle of attack is critical in these experiments. This work describes the implementation of laser displacement sensors in a wind tunnel; the sensors measured the distance between the wind tunnel walls and the airfoil, which was then used to calculate the model position. The uncertainty in the measured laser distances, based on the sensor resolution and temperature drift, is comparable to the uncertainty in traditional linear encoder measurements. Distances from multiple sensors showed small, but statistically significant, amounts of model deflection and rotation that would otherwise not have been detected, allowing for an improved angle of attack measurement. PMID- 30469494 TI - Mouse Cardiac Pde1C Is a Direct Transcriptional Target of Pparalpha. AB - Phosphodiesterase 1C (PDE1C) is expressed in mammalian heart and regulates cardiac functions by controlling levels of second messenger cyclic AMP and cyclic GMP (cAMP and cGMP, respectively). However, molecular mechanisms of cardiac Pde1c regulation are currently unknown. In this study, we demonstrate that treatment of wild type mice and H9c2 myoblasts with Wy-14,643, a potent ligand of nuclear receptor peroxisome-proliferator activated receptor alpha (PPARalpha), leads to elevated cardiac Pde1C mRNA and cardiac PDE1C protein, which correlate with reduced levels of cAMP. Furthermore, using mice lacking either Pparalpha or cardiomyocyte-specific Med1, the major subunit of Mediator complex, we show that Wy-14,643-mediated Pde1C induction fails to occur in the absence of Pparalpha and Med1 in the heart. Finally, using chromatin immunoprecipitation assays we demonstrate that PPARalpha binds to the upstream Pde1C promoter sequence on two sites, one of which is a palindrome sequence (agcTAGGttatcttaacctagc) that shows a robust binding. Based on these observations, we conclude that cardiac Pde1C is a direct transcriptional target of PPARalpha and that Med1 may be required for the PPARalpha mediated transcriptional activation of cardiac Pde1C. PMID- 30469495 TI - The Benefits of Closed-Loop Transcranial Alternating Current Stimulation on Subjective Sleep Quality. AB - BACKGROUND: Poor sleep quality is a common complaint, affecting over one third of people in the United States. While sleep quality is thought to be related to slow wave sleep (SWS), there has been little investigation to address whether modulating slow-wave oscillations (SWOs) that characterize SWS could impact sleep quality. Here we examined whether closed-loop transcranial alternating current stimulation (CL-tACS) applied during sleep impacts sleep quality and efficiency. METHODS: CL-tACS was used in 21 participants delivered at the same frequency and in phase with endogenous SWOs during sleep. Sleep quality was assessed in the morning following either verum or sham control stimulation during sleep, with order counterbalanced within participants. RESULTS: Higher sleep quality and efficiency were found after verum stimulation nights compared to control. The largest effects on sleep quality were found immediately following an adaptation night in the laboratory for which sleep quality was reduced. CONCLUSIONS: Applying CL-tACS at the same frequency and phase as endogenous SWOs may offer a novel method to improve subjective sleep quality after a night with poor quality sleep. CL-tACS might be helpful for increasing sleep quality and efficiency in otherwise healthy people, and in patients with clinical disorders that involve sleep deficits. PMID- 30469496 TI - Parawixin2 Protects Hippocampal Cells in Experimental Temporal Lobe Epilepsy. AB - Epilepsy is considered as one of the major disabling neuropathologies. Almost one third of adult patients with temporal lobe epilepsy (TLE) do not respond to current antiepileptic drugs (AEDs). Additionally, most AEDs do not have neuroprotective effects against the inherent neurodegenerative process underlying the hippocampal sclerosis on TLE. Dysfunctions in the GABAergic neurotransmission may contribute not only to the onset of epileptic activity but also constitute an important system for therapeutic approaches. Therefore, molecules that enhance GABA inhibitory effects could open novel avenues for the understanding of epileptic plasticity and for drug development. Parawixin2, a compound isolated from Parawixia bistriata spider venom, inhibits both GABA and glycine uptake and has an anticonvulsant effect against a wide range of chemoconvulsants. The neuroprotective potential of Parawixin2 was analyzed in a model of TLE induced by a long-lasting Status Epilepticus (SE), and its efficiency was compared to well known neuroprotective drugs, such as riluzole and nipecotic acid. Neuroprotection was assessed through histological markers for cell density (Nissl), astrocytic reactivity (GFAP) and cell death labeling (TUNEL), which were performed 24 h and 72 h after SE. Parawixin2 treatment resulted in neuroprotective effects in a dose dependent manner at 24 h and 72 h after SE, as well as reduced reactive astrocytes and apoptotic cell death. Based on these findings, Parawixin2 has a great potential to be used as a tool for neuroscience research and as a probe to the development of novel GABAergic neuroprotective agents. PMID- 30469498 TI - Construction of Z-Scheme g-C3N4/CNT/Bi2Fe4O9 Composites with Improved Simulated Sunlight Photocatalytic Activity for the Dye Degradation. AB - In this work, ternary all-solid-state Z-scheme g-C3N4/carbon nanotubes/Bi2Fe4O9 (g-C3N4/CNT/BFO) composites with enhanced photocatalytic activity were prepared by a hydrothermal method. The morphology observation shows that ternary heterojunctions are formed in the g-C3N4/CNT/BFO composites. The photocatalytic activity of the samples for the degradation of acid orange 7 was investigated under simulated sunlight irradiation. It was found that the ternary composites exhibit remarkable enhanced photocatalytic activity when compared with bare BFO and g-C3N4/BFO composites. The effect of the CNT content on the photocatalytic performance of the ternary composites was investigated. The photocatalytic mechanism of g-C3N4/CNT/BFO was proposed according to the photoelectrochemical measurement, photoluminescence, active species trapping experiment and energy band potential analysis. The results reveal that the introduction of CNT as an excellent solid electron mediator into the ternary composites can effectively accelerate the electron migration between BFO and g-C3N4. This charge transfer process results in highly-efficient separation of photogenerated charges, thus leading to greatly enhanced photocatalytic activity of g-C3N4/CNT/BFO composites. Furthermore, the g-C3N4/CNT/BFO composites also exhibit highly-efficient photo Fenton-like catalysis property. PMID- 30469497 TI - ISG15 Promotes ERK1 ISGylation, CD8+ T Cell Activation and Suppresses Ovarian Cancer Progression. AB - Increased number of tumor-infiltrating CD8+ lymphocytes is associated with improved survival in patients with advanced stage high grade serous ovarian cancer (HGSOC) but the underlying molecular mechanism has not been thoroughly explored. Using transcriptome profiling of microdissected HGSOC tissue with high and low CD8+ lymphocyte count and subsequent validation studies, we demonstrated that significantly increased ISG15 (Interferon-stimulated gene 15) expression in HGSOC was associated with high CD8+ lymphocyte count and with the improvement in median overall survival in both univariate and multivariate analyses. Further functional studies showed that endogenous and exogenous ISG15 suppressed ovarian cancer progression through ISGylation of ERK in HGSOC, and activation of NK cells and CD8+ T lymphocytes. These data suggest that the development of treatment strategies based on up-regulating ISG15 in ovarian cancer cells or increased circulating ISG15 in ovarian cancer patients is warranted. PMID- 30469499 TI - Lectins at Interfaces-An Atomic Force Microscopy and Multi-Parameter-Surface Plasmon Resonance Study. AB - Lectins are a diverse class of carbohydrate binding proteins with pivotal roles in cell communication and signaling in many (patho)physiologic processes in the human body, making them promising targets in drug development, for instance, in cancer or infectious diseases. Other applications of lectins employ their ability to recognize specific glycan epitopes in biosensors and glycan microarrays. While a lot of research has focused on lectin interaction with specific carbohydrates, the interaction potential of lectins with different types of surfaces has not been addressed extensively. Here, we screen the interaction of two specific plant lectins, Concanavalin A and Ulex Europaeus Agglutinin-I with different nanoscopic thin films. As a control, the same experiments were performed with Bovine Serum Albumin, a widely used marker for non-specific protein adsorption. In order to test the preferred type of interaction during adsorption, hydrophobic, hydrophilic and charged polymer films were explored, such as polystyrene, cellulose, N,-N,-N-trimethylchitosan chloride and gold, and characterized in terms of wettability, surface free energy, zeta potential and morphology. Atomic force microscopy images of surfaces after protein adsorption correlated very well with the observed mass of adsorbed protein. Surface plasmon resonance spectroscopy studies revealed low adsorbed amounts and slow kinetics for all of the investigated proteins for hydrophilic surfaces, making those resistant to non specific interactions. As a consequence, they may serve as favorable supports for biosensors, since the use of blocking agents is not necessary. PMID- 30469500 TI - A New Measure for Assessing the Intensity of Addiction Memory in Illicit Drug Users: The Addiction Memory Intensity Scale. AB - Disrupting the process of memory reconsolidation could be a promising treatment for addiction. However, its application may be constrained by the intensity of addiction memory. This study aimed to develop and initially validate a new measure, the Addiction Memory Intensity Scale (AMIS), for assessing the intensity of addiction memory in illicit drug users. Two studies were conducted in China for item analysis (n = 345) and initial validation (n = 1550) of the AMIS. The nine-item AMIS was found to have two factors (labelled Visual Clarity and Other Sensory Intensity), which accounted for 64.11% of the total variance. The two factor structure provided a reasonable fit for sample data and was invariant across groups of different genders and different primary drugs of use. Significant correlations were found between scores on the AMIS and the measures of craving. The AMIS and its factors showed good internal consistency (Cronbach's alpha: 0.72-0.89) and test-retest reliability (r: 0.72-0.80). These results suggest that the AMIS, which demonstrates an advantage as it is brief and easy to administer, is a reliable and valid tool for measuring the intensity of addiction memory in illicit drug users, and has the potential to be useful in future clinical research. PMID- 30469501 TI - MicroRNAs as Regulators of Insulin Signaling: Research Updates and Potential Therapeutic Perspectives in Type 2 Diabetes. AB - The insulin signaling pathway is composed of a large number of molecules that positively or negatively modulate insulin specific signal transduction following its binding to the cognate receptor. Given the importance of the final effects of insulin signal transduction, it is conceivable that many regulators are needed in order to tightly control the metabolic or proliferative functional outputs. MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively modulate gene expression through their specific binding within the 3'UTR sequence of messenger RNA (mRNA), thus causing mRNA decoy or translational inhibition. In the last decade, miRNAs have been addressed as pivotal cellular rheostats which control many fundamental signaling pathways, including insulin signal transduction. Several studies demonstrated that multiple alterations of miRNAs expression or function are relevant for the development of insulin resistance in type 2 diabetes (T2D); such alterations have been highlighted in multiple insulin target organs including liver, muscles, and adipose tissue. Indirectly, miRNAs have been identified as modulators of inflammation-derived insulin resistance, by controlling/tuning the activity of innate immune cells in insulin target tissues. Here, we review main findings on miRNA functions as modulators of insulin signaling in physiologic- or in T2D insulin resistance- status. Additionally, we report the latest hypotheses of prospective therapies involving miRNAs as potential targets for future drugs in T2D. PMID- 30469502 TI - The Association between Low Body Weight and Scoliosis among Korean Elementary School Students. AB - Background: The prevalence of scoliosis in Korean elementary school students is increasing, leading to various physical and psychological problems. This study aimed to investigate the association between low body weight and scoliosis among Korean elementary school students. Methods: This was a cross-sectional analysis. Participants were 1062 elementary school students in the metropolitan areas of Korea. Participants were evaluated for scoliosis based on body composition, including weight and height, and with spine structure analysis equipment. Scoliosis diagnosis was defined as having a Cobb's angle greater than 10 degrees . Results: Participants were divided into Normal Weight (NW), Underweight (UW), and Severely Underweight (SUW) groups. Results show that the UW and SUW groups had significantly higher risks of developing scoliosis (odds ratio (OR): 1.43, 95% CI (confidence interval): 1.07-1.90; OR: 1.45, 95% CI: 1.02-2.05) compared to the NW group; after controlling for age and gender, the OR were 1.44 (95% CI: 1.08-1.92) and 1.46 (95% CI: 1.01-2.09), respectively. Conclusions: Low weight and the risk of developing scoliosis are very closely associated. Maintenance of appropriate and normal weight in Korean elementary school students appears to be a very effective method for preventing and reducing the risk of scoliosis. PMID- 30469503 TI - Investigation of the Effects of Polymer Dispersants on Dispersion of GO Nanosheets in Cement Composites and Relative Microstructures/Performances. AB - This study focused on the uniform distribution of graphene oxide (GO) nanosheets in cement composites and their effect on microstructure and performance. For this, three polymer dispersants with different level of polar groups (weak, mild, and strong) poly(acrylamide-methacrylic acid) (PAM), poly(acrylonitrile hydroxyethyl acrylate) (PAH), and poly(allylamine-acrylamide) (PAA) were used to form intercalation composites with GO nanosheets. The results indicated that GO nanosheets can exist as individual 1-2, 2-5, and 3-8 layers in GO/PAA, GO/PAH, and GO/PAM intercalation composites, respectively. The few-layered (1-2 layers) GO can be uniformly distributed in cement composites and promote the formation of regular-shaped crystals and a compact microstructure. The compressive strengths of the blank, control, GO/PAM, GO/PAH, and GO/PAA cement composites were 55.72, 78.31, 89.75, 116.82, and 128.32 MPa, respectively. Their increase ratios relative to the blank sample were 40.54%, 61.07%, 109.66%, and 130.29%, respectively. Their corresponding flexural strengths were 7.53, 10.85, 12.35, 15.97, and 17.68 MPa, respectively, which correspond to improvements of 44.09%, 64.01%, 112.09%, and 134.79%. PMID- 30469504 TI - 2D- and 3D-Based Intestinal Stem Cell Cultures for Personalized Medicine. AB - Colorectal cancer (CRC) is one of the most common cancers that have high occurrence and death in both males and females. As various factors have been found to contribute to CRC development, personalized therapies are critical for efficient treatment. To achieve this purpose, the establishment of patient derived tumor models is critical for diagnosis and drug test. The establishment of three-dimensional (3D) organoid cultures and two-dimensional (2D) monolayer cultures of patient-derived epithelial tissues is a breakthrough for expanding living materials for later use. This review provides an overview of the different types of 2D- and 3D-based intestinal stem cell cultures, their potential benefits, and the drawbacks in personalized medicine in treatment of the intestinal disorders. PMID- 30469505 TI - Molecular Characterization, Expression and Functional Analysis of Chicken STING. AB - Innate immunity is an essential line of defense against pathogen invasion which is gained at birth, and the mechanism involved is mainly to identify pathogen associated molecular patterns through pattern recognition receptors. STING (stimulator of interferon genes) is a signal junction molecule that hosts the perception of viral nucleic acids and produces type I interferon response, which plays a crucial role in innate immunity. However, relatively few studies have investigated the molecular characterization, tissue distribution, and potential function of STING in chickens. In this study, we cloned the full-length cDNA of chicken STING that is composed of 1341 bp. Sequence analyses revealed that STING contains a 1140-bp open-reading frame that probably encodes a 379-amino acid protein. Multiple sequence alignments showed that the similarity of the chicken STING gene to other birds is higher than that of mammals. Real-time polymerase chain reaction (PCR) assays revealed that STING is highly expressed in the spleen, thymus and bursa of fabricious in chickens. Furthermore, we observed that STING expression was significantly upregulated both in vitro and in vivo following infection with Newcastle disease virus (NDV). STING expression was also significantly upregulated in chicken embryo fibroblasts upon stimulation with poly(I:C) or poly(dA:dT). Taken together, these findings suggest that STING plays an important role in antiviral signaling pathways in chickens. PMID- 30469506 TI - Cold Plasma as an Innovative Construction Method of Voltammetric Biosensor Based on Laccase. AB - Development of new, faster methods of biosensor construction is a huge challenge for current science and industry. In this work, biosensor construction was carried out using a new soft plasma polymerization (SPP) method in which a bio recognition layer of laccase enzyme was polymerized and bonded to a glassy carbon electrode (GCE) substrate under atmospheric pressure with a corona discharge jet. Laccase belongs to the oxidoreductase enzyme group with four copper atoms in its active center. Application of the corona SPP plasma method allows reduction of the time needed for biosensor construction from several hours to minutes. The presented work includes optimization of the laccase bio-recognition layer deposition time, structural studies of the deposited laccase layer, as well as study of the fabricated biosensor applicability for the determination of Rutin in real pharmaceutical samples. This method produces a biosensor with two linear ranges from 0.3 MUmol/dm3 to 0.5 MUmol/dm3 and from 0.8 MUmol/dm3 to 16 MUmol/dm3 of Rutin concentration. Results shown in this work indicate that application of the one-step, corona SPP method enables biosensor construction with comparable analytical parameters to biosensors fabricated by conventional, multi-step, wet methods. PMID- 30469507 TI - Orthosteric and/or Allosteric Binding of alpha-Conotoxins to Nicotinic Acetylcholine Receptors and Their Models. AB - alpha-Conotoxins from Conus snails are capable of distinguishing muscle and neuronal nicotinic acetylcholine receptors (nAChRs). alpha-Conotoxin RgIA and alphaO-conotoxin GeXIVA, blocking neuronal alpha9alpha10 nAChR, are potential analgesics. Typically, alpha-conotoxins bind to the orthosteric sites for agonists/competitive antagonists, but alphaO-conotoxin GeXIVA was proposed to attach allosterically, judging by electrophysiological experiments on alpha9alpha10 nAChR. We decided to verify this conclusion by radioligand analysis in competition with alpha-bungarotoxin (alphaBgt) on the ligand-binding domain of the nAChR alpha9 subunit (alpha9 LBD), where, from the X-ray analysis, alphaBgt binds at the orthosteric site. A competition with alphaBgt was registered for GeXIVA and RgIA, IC50 values being in the micromolar range. However, high nonspecific binding of conotoxins (detected with their radioiodinated derivatives) to His6-resin attaching alpha9 LBD did not allow us to accurately measure IC50s. However, IC50s were measured for binding to Aplysia californica AChBP: the RgIA globular isomer, known to be active against alpha9alpha10 nAChR, was more efficient than the ribbon one, whereas all three GeXIVA isomers had similar potencies at low uM. Thus, radioligand analysis indicated that both conotoxins can attach to the orthosteric sites in these nAChR models, which should be taken into account in the design of analgesics on the basis of these conotoxins. PMID- 30469508 TI - Enhanced Accuracy of CMOS Smart Temperature Sensors by Nonlinear Curvature Correction. AB - In this paper, we demonstrate an improvement in the accuracy of a low-cost smart temperature sensor, by measurement of the nonlinear curvature correction at multiple temperature references. The sensors were positioned inside a climate chamber and connected outside to a micro-controller via a network cable. The chamber temperature was increased systematically over a wide range from -20 degrees C to 55 degrees C. A set of calibration curves was produced from the best fitting second-order polynomial curves for the offset in temperature between the sensor and reference. An improvement in accuracy of +/-0.15 degrees C is with respect to the mentioned temperature range, compared to the significantly higher value reported of +/-0.5 degrees C by the manufacturer for similar conditions. In summary, we demonstrate a significant improvement in the calibration of a low-cost, smart sensor frequently used in research and academic projects over a useful range of temperatures. PMID- 30469509 TI - Matriptase-Induced Phosphorylation of MET is Significantly Associated with Poor Prognosis in Invasive Bladder Cancer; an Immunohistochemical Analysis. AB - Hepatocyte growth factor (HGF) plays an important role in cancer progression via phosphorylation of MET (c-met proto-oncogene product, receptor of HGF). HGF zymogen (pro-HGF) must be processed for activation by HGF activators including matriptase, which is a type II transmembrane serine protease and the most efficient activator. The enzymatic activity is tightly regulated by HGF activator inhibitors (HAIs). Dysregulated pro-HGF activation (with upregulated MET phosphorylation) is reported to promote cancer progression in various cancers. We retrospectively analyzed the expression of matriptase, phosphorylated-MET (phospho-MET) and HAI-1 in tumor specimens obtained from patients with invasive bladder cancer by immunohistochemistry. High expression of phospho-MET and increased expression of matriptase were significantly associated with poor prognosis, and high matriptase/low HAI-1 expression showed poorer prognosis. Furthermore, high expression of matriptase tended to correlate with phosphorylation of MET. Increased expression of matriptase may induce the ligand dependent activation of MET, which leads to poor prognosis in patients with invasive bladder cancer. PMID- 30469510 TI - Conformal and Disposable Antenna-Based Sensor for Non-Invasive Sweat Monitoring. AB - This paper presents a feasibility study for a non-wearable, conformal, low cost, and disposable antenna-based sensor for non-invasive hydration monitoring using sweat. It is composed of a patch antenna implemented on a cellulose filter paper substrate and operating in the range 2-4 GHz. The paper substrate can absorb liquids, such as sweat on the skin, through two slots incorporated within the antenna structure. Thus, the substrate dielectric properties are altered according to the properties of the absorbed liquid. Changes in reflection-based measurements are used to analyze salt solutions and artificial sweat, specifically the amount of sampled solution and the sodium chloride (NaCl) concentration. Using the shift in resonant frequency and magnitude of the reflection coefficient, NaCl concentrations in the range of 8.5-200 mmol/L, representing different hydration states, are detected. The measurements demonstrate the feasibility of using microwave based measurements for hydration monitoring using sweat. PMID- 30469511 TI - Aberrant Epigenetic Regulation in Head and Neck Cancer Due to Distinct EZH2 Overexpression and DNA Hypermethylation. AB - Enhancer of Zeste homologue 2 (EZH2) overexpression is associated with tumor proliferation, metastasis, and poor prognosis. Targeting and inhibition of EZH2 is a potentially effective therapeutic strategy for head and neck squamous cell carcinoma (HNSCC). We analyzed EZH2 mRNA expression in a well-characterized dataset of 230 (110 original and 120 validation cohorts) human head and neck cancer samples. This study aimed to investigate the effects of inhibiting EZH2, either via RNA interference or via pharmacotherapy, on HNSCC growth. EZH2 upregulation was significantly correlated with recurrence (p < 0.001) and the methylation index of tumor suppressor genes (p < 0.05). DNMT3A was significantly upregulated upon EZH2 upregulation (p = 0.043). Univariate analysis revealed that EZH2 upregulation was associated with poor disease-free survival (log-rank test, p < 0.001). In multivariate analysis, EZH2 upregulation was evaluated as a significant independent prognostic factor of disease-free survival (hazard ratio: 2.085, 95% confidence interval: 1.390-3.127; p < 0.001). Cells treated with RNA interference and DZNep, an EZH2 inhibitor, showed the most dramatic changes in expression, accompanied with a reduction in the growth and survival of FaDu cells. These findings suggest that EZH2 upregulation is correlated with tumor aggressiveness and adverse patient outcomes in HNSCC. Evaluation of EZH2 expression might help predict the prognosis of HNSCC patients. PMID- 30469512 TI - Prediction of Signal Peptides in Proteins from Malaria Parasites. AB - Signal peptides are N-terminal presequences responsible for targeting proteins to the endomembrane system, and subsequent subcellular or extracellular compartments, and consequently condition their proper function. The significance of signal peptides stimulates development of new computational methods for their detection. These methods employ learning systems trained on datasets comprising signal peptides from different types of proteins and taxonomic groups. As a result, the accuracy of predictions are high in the case of signal peptides that are well-represented in databases, but might be low in other, atypical cases. Such atypical signal peptides are present in proteins found in apicomplexan parasites, causative agents of malaria and toxoplasmosis. Apicomplexan proteins have a unique amino acid composition due to their AT-biased genomes. Therefore, we designed a new, more flexible and universal probabilistic model for recognition of atypical eukaryotic signal peptides. Our approach called signalHsmm includes knowledge about the structure of signal peptides and physicochemical properties of amino acids. It is able to recognize signal peptides from the malaria parasites and related species more accurately than popular programs. Moreover, it is still universal enough to provide prediction of other signal peptides on par with the best preforming predictors. PMID- 30469513 TI - Determining k-Value with Regard to Freeze-Thaw Resistance of Concretes Containing GGBS. AB - The European concrete standard EN 206 introduces the k-value concept as one of the three methods allowing the use of granulated blast furnace slag in the design of the freeze-thaw-resistant concrete mix. It is assumed that the freeze-thaw durability of the concrete, whose composition (w/c ratio) has been corrected by adopting a certain k-value, is the same as the freeze-thaw resistance of the reference concrete made with the cement containing no addition (CEM I). This article presents the results of freeze-thaw resistance analysis (modified with the ASTM C666A standard Class XF3) of 24 series of concretes made with a binder containing varied amounts of slag, with a w/b ratio ranging from 0.25 to 0.55. The aim of the study was to estimate the k-value as a parameter defined by the w/b ratio and the slag content in the binder. In this approach, the k-value is determined by trial and error in such a way that the deformation of the concrete specimens containing the slag corresponds to the deformation of the reference concrete. As shown by the analysis, the k-value decreases with increasing slag content in the binder. PMID- 30469514 TI - Actin Bundles in The Pollen Tube. AB - The angiosperm pollen tube delivers two sperm cells into the embryo sac through a unique growth strategy, named tip growth, to accomplish fertilization. A great deal of experiments have demonstrated that actin bundles play a pivotal role in pollen tube tip growth. There are two distinct actin bundle populations in pollen tubes: the long, rather thick actin bundles in the shank and the short, highly dynamic bundles near the apex. With the development of imaging techniques over the last decade, great breakthroughs have been made in understanding the function of actin bundles in pollen tubes, especially short subapical actin bundles. Here, we tried to draw an overall picture of the architecture, functions and underlying regulation mechanism of actin bundles in plant pollen tubes. PMID- 30469515 TI - Rheological and Curing Behavior of Acrylate-Based Suspensions for the DLP 3D Printing of Complex Zirconia Parts. AB - The present study demonstrates the possibility of fabricating zirconia parts with a complex shape and internal architecture using a low-cost stereolithography based technique. One of the critical steps in ceramics stereolithography is the preparation of a photo-curable slurry with properties that fulfill specific requirements, such as having a low viscosity, high solids loading and appropriate curing characteristics. Slurries with different acrylic monomers and ceramic fillers were studied concerning their rheological and curing behavior. New formulations based on mono- and tri-functional acrylic monomers revealed the following excellent rheological properties: The viscosity of the mono-/tri acrylate-based slurry with 75 wt.% of zirconia was 1.6 Pa.s at 30 s-1. Zirconia stabilized with 3 mol.% yttria was found to be more favorable than zirconia with 8 mol.% yttria for slurry preparation, because of its lower surface area and higher tapped density. It was shown that the cure depth of the suspensions was suitable for printing objects with a 50 um layer thickness, good interlayers connection and surface finishing. PMID- 30469516 TI - Fucoidan Extracted from the New Zealand Undaria pinnatifida-Physicochemical Comparison against Five Other Fucoidans: Unique Low Molecular Weight Fraction Bioactivity in Breast Cancer Cell Lines. AB - Fucoidan, the complex fucose-containing sulphated polysaccharide varies considerably in structure, composition, and bioactivity, depending on the source, species, seasonality, and extraction method. In this study, we examined five fucoidans extracted from the same seaweed species Undaria pinnatifida but from different geological locations, and compared them to the laboratory-grade fucoidan from Sigma (S). The five products differed in molecular composition. The amount of over 2 kDa low molecular weight fraction (LMWF) of the New Zealand crude fucoidan (S1) was larger than that of S, and this fraction was unique, compared to the other four fucoidans. The difference of molecular compositions between S and S1 explained our previous observation that S1 exhibited different anticancer profile in some cancer cell lines, compared with S. Since we observed this unique LMWF, we compared the cytotoxic effects of a LMWF and a high molecular weight fucoidan (HMWF) in two breast cancer cell lines-MCF-7 and MDA-MB 231. Results indicated that the molecular weight is a critical factor in determining the anti-cancer potential of fucoidan, from the New Zealand U. pinnatifida, as the LMWF exhibited a dose-dependent inhibition on the proliferation of breast cancer cells, significantly better than the HMWF, in both cell lines. A time-dependent inhibition was only observed in the MCF-7. Induction of caspase-dependent apoptosis was observed in the MDA-MB-231 cells, through the intrinsic apoptosis pathway alone, or with the extrinsic pathway. LMWF stimulated a dose-dependent NOS activation in the MDA-MB-231 cells. In conclusion, the fucoidan extracted from the New Zealand U. pinnatifida contains a unique LMWF, which could effectively inhibit the growth of breast cancer cell lines. Therefore, the LMWF from New Zealand U. pinnatifida could be used as a supplement cancer treatment. PMID- 30469517 TI - Implementation of a Competency-Based, Interdisciplinary Pediatric Palliative Care Curriculum Using Content and Format Preferred by Pediatric Residents. AB - Palliative care competencies at the pediatric resident training level expand learned knowledge into behavior. The objective of this study was to investigate mode of palliative care education delivery preferred by pediatric residents and to report on participatory approach to resident palliative care curriculum design. A one-hour monthly palliative care curriculum was designed and implemented in a participatory manner with 20 pediatric residents at a free standing Midwestern children's hospital. Outcome measures included pediatric residents' personal attitude and perceived training environment receptivity before and after implementation of a palliative care competency-based curriculum. An 18-item survey utilizing Social Cognitive Theory Constructs was administered at baseline and after palliative care curriculum implementation (2017-2018 curricular year). Pediatric residents prioritized real case discussions in group format (16/20) over other learning formats. Topics of highest interest at baseline were: discussing prognosis and delivering bad news (weighted average 12.9), pain control (12.3), goals of care to include code status (11.1), and integrative therapies (10.7). Summary of ordinal responses revealed improvement in self-assessment of personal attitude toward palliative care and training environment receptivity to palliative care domains after year-long curriculum implementation. Curricular approach which is attentive to pediatric residents' preferred learning format and self-assessment of their behaviors within their care setting environment may be beneficial in competency-based primary palliative training. PMID- 30469518 TI - The Impact of miRNA in Colorectal Cancer Progression and Its Liver Metastases. AB - Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high incidence and mortality rate. An essential challenge in colorectal cancer management is to identify new prognostic factors that could better estimate the evolution and treatment responses of this disease. Considering their role in cancer development, progression and metastasis, miRNAs have become an important class of molecules suitable for cancer biomarkers discovery. We performed a systematic search of studies investigating the role of miRNAs in colorectal progression and liver metastasis published until October 2018. In this review, we present up-to-date information regarding the specific microRNAs involved in CRC development, considering their roles in alteration of Wnt/betacatenin, EGFR, TGFbeta and TP53 signaling pathways. We also emphasize the role of miRNAs in controlling the epithelial-mesenchymal transition of CRC cells, a process responsible for liver metastasis in a circulating tumor cell-dependent manner. Furthermore, we discuss the role of miRNAs transported by CRC-derived exosomes in mediating liver metastases, by preparing the secondary pre-metastatic niche and in inducing liver carcinogenesis in a Dicer-dependent manner. PMID- 30469519 TI - Nitrogen Removal by Sulfur-Based Carriers in a Membrane Bioreactor (MBR). AB - Sulfur-based carriers were examined to enhance the nitrogen removal efficiency in a mixed anoxic-anaerobic-membrane bioreactor system, in which sulfur from the carrier acts as an electron donor for the conversion of nitrate to nitrogen gas through the autotrophic denitrification process. A total nitrogen removal efficiency of 63% was observed in the system with carriers, which showed an increase in the removal efficiency of around 20%, compared to the system without carriers. The results also indicated that the carriers had no adverse effect on biological treatment for the organic matter and total phosphorus. The removal efficiencies for chemical oxygen demand (COD) and total phosphorus (TP) were 98% and 37% in both systems, respectively. The generation of sulfate ions was a major disadvantage of using sulfur-based carriers, and resulted in pH drop. The ratio of sulfate in the effluent to nitrate removed in the system ranged from 0.86 to 1.97 mgSO42-/mgNO3--N, which was lower than the theoretical value and could be regarded as due to the occurrence of simultaneous heterotrophic and autotrophic denitrification. PMID- 30469520 TI - Biological Relevance of Extra Virgin Olive Oil Polyphenols Metabolites. AB - Extra virgin olive oil (EVOO) polyphenols beneficial effects have widely been debated throughout the last three decades, with greater attention to hydroxytyrosol and tyrosol, which are by far the most studied. The main concern about the evaluation of EVOO phenols activities in vitro and in vivo is that the absorption and metabolism of these compounds once ingested lead to the production of different metabolites in the human body. EVOO phenols in the ingested forms are less concentrated in human tissues than their glucuronide, sulfate and methyl metabolites; on the other hand, metabolites may undergo deconjugation before entering the cells and thus act as free forms or may be reformed inside the cells so acting as conjugated forms. In most in vitro studies the presence of methyl/sulfate/glucuronide functional groups does not seem to inhibit biological activity. Parent compounds and metabolites have been shown to reach tissue concentrations useful to exert beneficial effects others than antioxidant and scavenging properties, by modulating intracellular signaling and improving cellular response to oxidative stress and pro-inflammatory stimuli. This review aims to give an overview on the reported evidence of the positive effects exerted by the main EVOO polyphenols metabolites in comparison with the parent compounds. PMID- 30469521 TI - Monitoring Candida parapsilosis and Staphylococcus epidermidis Biofilms by a Combination of Scanning Electron Microscopy and Raman Spectroscopy. AB - The biofilm-forming microbial species Candida parapsilosis and Staphylococcus epidermidis have been recently linked to serious infections associated with implanted medical devices. We studied microbial biofilms by high resolution scanning electron microscopy (SEM), which allowed us to visualize the biofilm structure, including the distribution of cells inside the extracellular matrix and the areas of surface adhesion. We compared classical SEM (chemically fixed samples) with cryogenic SEM, which employs physical sample preparation based on plunging the sample into various liquid cryogens, as well as high-pressure freezing (HPF). For imaging the biofilm interior, we applied the freeze-fracture technique. In this study, we show that the different means of sample preparation have a fundamental influence on the observed biofilm structure. We complemented the SEM observations with Raman spectroscopic analysis, which allowed us to assess the time-dependent chemical composition changes of the biofilm in vivo. We identified the individual spectral peaks of the biomolecules present in the biofilm and we employed principal component analysis (PCA) to follow the temporal development of the chemical composition. PMID- 30469522 TI - Noradrenaline Sensitivity Is Severely Impaired in Immortalized Adipose-Derived Mesenchymal Stem Cell Line. AB - Primary adipose tissue-derived multipotent stem/stromal cells (adMSCs) demonstrate unusual signaling regulatory mechanisms, i.e., increased of sensitivity to catecholamines in response to noradrenaline. This phenomenon is called "heterologous sensitization", and was previously found only in embryonic cells. Since further elucidation of the molecular mechanisms that are responsible for such sensitization in primary adMSCs was difficult due to the high heterogeneity in adrenergic receptor expression, we employed immortalized adipose derived mesenchymal stem cell lines (hTERT-MSCs). Using flow cytometry and immunofluorescence microscopy, we demonstrated that the proportion of cells expressing adrenergic receptor isoforms does not differ significantly in hTERT MSCs cells compared to the primary adMSCs culture. However, using analysis of Ca2+-mobilization in single cells, we found that these cells did not demonstrate the sensitization seen in primary adMSCs. Consistently, these cells did not activate cAMP synthesis in response to noradrenaline. These data indicate that immortalized adipose-derived mesenchymal stem cell lines demonstrated impaired ability to respond to noradrenaline compared to primary adMSCs. These data draw attention to the usage of immortalized cells for MSCs-based regenerative medicine, especially in the field of pharmacology. PMID- 30469523 TI - Effect of Accommodating Elastic Bands on Mechanical Power Output during Back Squats. AB - The aim of this study was to investigate whether accommodating elastic bands with barbell back squats (BSQ) increase muscular force during the deceleration subphase. Ten healthy men (mean +/- standard deviation: Age: 23 +/- 2 years; height: 170.5 +/- 3.7 cm; mass: 66.7 +/- 5.4 kg; and BSQ one repetition maximum (RM): 105 +/- 23.1 kg; BSQ 1RM/body mass: 1.6 +/- 0.3) were recruited for this study. The subjects performed band-resisted parallel BSQ (accommodating elastic bands each sides of barbell) with five band conditions in random order. The duration of the deceleration subphase, mean mechanical power, and the force and velocity during the acceleration and deceleration subphases were calculated. BSQ with elastic bands elicited greater mechanical power output, velocity, and force during the deceleration subphase, in contrast to that elicited with traditional free weight (p < 0.05). BSQ with elastic bands also elicited greater mechanical power output and velocity during the acceleration subphase. However, the force output during the acceleration subphase using an elastic band was lesser than that using a traditional free weight (p < 0.05). This study suggests that BSQ with elastic band elicit greater power output during the acceleration and deceleration subphases. PMID- 30469524 TI - The Role of Zwitterionic Materials in the Fight against Proteins and Bacteria. AB - Zwitterionization of biomaterials has been heightened to a potent tool to develop biocompatible materials that are able to inhibit bacterial and non-specific proteins adhesion. This constitutes a major progress in the biomedical field. This manuscript overviews the main functionalization strategies that have been reported up to date to design and develop these advanced biomaterials. On this regard, the recent research efforts that were dedicated to provide their surface of zwitterionic nature are summarized by classifying biomaterials in two main groups. First, we centre on biomaterials in clinical use, concretely bioceramics, and metallic implants. Finally, we revise emerging nanostructured biomaterials, which are receiving growing attention due to their multifunctionality and versatility mainly in the local drug delivery and bone tissue regeneration scenarios. PMID- 30469525 TI - Identifying the Incidence of Exercise Dependence Attitudes, Levels of Body Perception, and Preferences for Use of Fitness Technology Monitoring. AB - Background: The study was focused on identifying the relationship between the incidence of exercise dependence attitudes, the level of body perception, and preferences for use of fitness technology monitoring. Methods: We investigated 241 students from physical education and sports specializations. We used a questionnaire structured in 5 parts: personal information (age, gender, weight, height, and institutional membership), Exercise Dependence Scale-R (EDS-21), the Compulsive Exercise Test (CET), Body perception questionnaire, and Fitness Monitoring Technology. Results: Application of EDS-21 revealed 8.3% with dependence and CET with 13.4%. Body mass index (BMI) in combination with self image body: 18 (7.4%) of subjects over-estimated themselves, 18 (7.4%) of subjects underestimated themselves, 38.6% of the subjects were satisfied with their appearance, 17% were very satisfied and none were dissatisfied. A total of 36.1% thought they had the correct weight and 8.7% thought of losing weight. The most preferred monitoring technologies were the treadmill and the smartphone's fitness applications. A total of 11.6% of the subjects always used technologies, and 17% of subjects never did so. Conclusions: In order to identify the level of incidence of exercise dependence, body perception, and preference and frequency of use of monitoring technology, it is necessary to expand the level of knowledge about health and physical activities. The approach would diminish medical incidences of addiction, improve proactive behaviors, and correct prohealth. PMID- 30469526 TI - Therapy and Management of Pneumocystis jirovecii Infection. AB - The rates of Pneumocystis pneumonia (PcP) are increasing in the HIV-negative susceptible population. Guidance for the prophylaxis and treatment of PcP in HIV, haematology, and solid-organ transplant (SOT) recipients is available, although for many other populations (e.g., auto-immune disorders) there remains an urgent need for recommendations. The main drug for both prophylaxis and treatment of PcP is trimethoprim/sulfamethoxazole, but resistance to this therapy is emerging, placing further emphasis on the need to make a mycological diagnosis using molecular based methods. Outbreaks in SOT recipients, particularly renal transplants, are increasingly described, and likely caused by human-to-human spread, highlighting the need for efficient infection control policies and sensitive diagnostic assays. Widespread prophylaxis is the best measure to gain control of outbreak situations. This review will summarize diagnostic options, cover prophylactic and therapeutic management in the main at risk populations, while also covering aspects of managing resistant disease, outbreak situations, and paediatric PcP. PMID- 30469527 TI - Adaptive Dynamic Programming-Based Multi-Sensor Scheduling for Collaborative Target Tracking in Energy Harvesting Wireless Sensor Networks. AB - Collaborative target tracking is one of the most important applications of wireless sensor networks (WSNs), in which the network must rely on sensor scheduling to balance the tracking accuracy and energy consumption, due to the limited network resources for sensing, communication, and computation. With the recent development of energy acquisition technologies, the building of WSNs based on energy harvesting has become possible to overcome the limitation of battery energy in WSNs, where theoretically the lifetime of the network could be extended to infinite. However, energy-harvesting WSNs pose new technical challenges for collaborative target tracking on how to schedule sensors over the infinite horizon under the restriction on limited sensor energy harvesting capabilities. In this paper, we propose a novel adaptive dynamic programming (ADP)-based multi sensor scheduling algorithm (ADP-MSS) for collaborative target tracking for energy-harvesting WSNs. ADP-MSS can schedule multiple sensors for each time step over an infinite horizon to achieve high tracking accuracy, based on the extended Kalman filter (EKF) for target state prediction and estimation. Theoretical analysis shows the optimality of ADP-MSS, and simulation results demonstrate its superior tracking accuracy compared with an ADP-based single-sensor scheduling scheme and a simulated-annealing based multi-sensor scheduling scheme. PMID- 30469528 TI - Regulation of Protein Structural Changes by Incorporation of a Small-Molecule Linker. AB - Proteins have the potential to serve as nanomachines with well-controlled structural movements, and artificial control of their conformational changes is highly desirable for successful applications exploiting their dynamic structural characteristics. Here, we demonstrate an experimental approach for regulating the degree of conformational change in proteins by incorporating a small-molecule linker into a well-known photosensitive protein, photoactive yellow protein (PYP), which is sensitized by blue light and undergoes a photo-induced N-terminal protrusion coupled with chromophore-isomerization-triggered conformational changes. Specifically, we introduced thiol groups into specific sites of PYP through site-directed mutagenesis and then covalently conjugated a small-molecule linker into these sites, with the expectation that the linker is likely to constrain the structural changes associated with the attached positions. To investigate the structural dynamics of PYP incorporated with the small-molecule linker (SML-PYP), we employed the combination of small-angle X-ray scattering (SAXS), transient absorption (TA) spectroscopy and experiment-restrained rigid body molecular dynamics (MD) simulation. Our results show that SML-PYP exhibits much reduced structural changes during photo-induced signaling as compared to wild-type PYP. This demonstrates that incorporating an external molecular linker can limit photo-induced structural dynamics of the protein and may be used as a strategy for fine control of protein structural dynamics in nanomachines. PMID- 30469529 TI - Recruitment of 53BP1 Proteins for DNA Repair and Persistence of Repair Clusters Differ for Cell Types as Detected by Single Molecule Localization Microscopy. AB - DNA double stranded breaks (DSBs) are the most serious type of lesions introduced into chromatin by ionizing radiation. During DSB repair, cells recruit different proteins to the damaged sites in a manner dependent on local chromatin structure, DSB location in the nucleus, and the repair pathway entered. 53BP1 is one of the important players participating in repair pathway decision of the cell. Although many molecular biology details have been investigated, the architecture of 53BP1 repair foci and its development during the post-irradiation time, especially the period of protein recruitment, remains to be elucidated. Super-resolution light microscopy is a powerful new tool to approach such studies in 3D-conserved cell nuclei. Recently, we demonstrated the applicability of single molecule localization microscopy (SMLM) as one of these highly resolving methods for analyses of dynamic repair protein distribution and repair focus internal nano architecture in intact cell nuclei. In the present study, we focused our investigation on 53BP1 foci in differently radio-resistant cell types, moderately radio-resistant neonatal human dermal fibroblasts (NHDF) and highly radio resistant U87 glioblastoma cells, exposed to high-LET 15N-ion radiation. At given time points up to 24 h post irradiation with doses of 1.3 Gy and 4.0 Gy, the coordinates and spatial distribution of fluorescently tagged 53BP1 molecules was quantitatively evaluated at the resolution of 10-20 nm. Clusters of these tags were determined as sub-units of repair foci according to SMLM parameters. The formation and relaxation of such clusters was studied. The higher dose generated sufficient numbers of DNA breaks to compare the post-irradiation dynamics of 53BP1 during DSB processing for the cell types studied. A perpendicular (90 degrees ) irradiation scheme was used with the 4.0 Gy dose to achieve better separation of a relatively high number of particle tracks typically crossing each nucleus. For analyses along ion-tracks, the dose was reduced to 1.3 Gy and applied in combination with a sharp angle irradiation (10 degrees relative to the cell plane). The results reveal a higher ratio of 53BP1 proteins recruited into SMLM defined clusters in fibroblasts as compared to U87 cells. Moreover, the speed of foci and thus cluster formation and relaxation also differed for the cell types. In both NHDF and U87 cells, a certain number of the detected and functionally relevant clusters remained persistent even 24 h post irradiation; however, the number of these clusters again varied for the cell types. Altogether, our findings indicate that repair cluster formation as determined by SMLM and the relaxation (i.e., the remaining 53BP1 tags no longer fulfill the cluster definition) is cell type dependent and may be functionally explained and correlated to cell specific radio-sensitivity. The present study demonstrates that SMLM is a highly appropriate method for investigations of spatiotemporal protein organization in cell nuclei and how it influences the cell decision for a particular repair pathway at a given DSB site. PMID- 30469530 TI - mTOR Activation in Liver Tumors Is Associated with Metabolic Syndrome and Non Alcoholic Steatohepatitis in Both Mouse Models and Humans. AB - Non-alcoholic steatohepatitis (NASH) can cause liver fibrosis and cirrhosis, with final progression to hepatocellular carcinoma (HCC) in some cases. Various factors have been suggested to be involved in the development of NASH. Considering the many possible contributing factors, we postulated that mechanisms of progression from NASH to HCC could differ depending on the risk factors. In the present study, we applied two mouse models of NASH-HCC and performed histopathological and proteome analyses of mouse liver tumors. Furthermore, to compare the mechanisms of NASH-HCC progression in mice and humans, we investigated HCCs in humans with a background of metabolic syndrome and NASH, as well as HCCs associated with hepatitis virus infection by immunohistochemistry. It was demonstrated that upstream regulators associated with the mammalian target of rapamycin (mTOR) pathway were altered in liver tumors of mice with metabolic syndrome characteristics (TSOD mice) using proteome analysis. Immunohistochemical analysis showed that mTOR was characteristically phosphorylated in liver tumors of TSOD mice and HCCs from metabolic syndrome cases in humans. These results indicated that the mTOR pathway is characteristically activated in liver tumors with metabolic syndrome and NASH, unlike liver tumors with other etiologies. PMID- 30469531 TI - Valorization of Brewers' Spent Grain for the Production of Lipids by Oleaginous Yeast. AB - Brewers' spent grain (BSG) accounts for 85% of the total amount of by-products generated by the brewing industries. BSG is a lignocellulosic biomass that is rich in proteins, lipids, minerals, and vitamins. In the present study, BSG was subjected to pretreatment by two different methods (microwave assisted alkaline pretreatment and organosolv) and was evaluated for the liberation of glucose and xylose during enzymatic saccharification trials. The highest amount of glucose (46.45 +/- 1.43 g/L) and xylose (25.15 +/- 1.36 g/L) were observed after enzymatic saccharification of the organosolv pretreated BSG. The glucose and xylose yield for the microwave assisted alkaline pretreated BSG were 34.86 +/- 1.27 g/L and 16.54 +/- 2.1 g/L, respectively. The hydrolysates from the organosolv pretreated BSG were used as substrate for the cultivation of the oleaginous yeast Rhodosporidium toruloides, aiming to produce microbial lipids. The yeast synthesized as high as 18.44 +/- 0.96 g/L of cell dry weight and 10.41 +/- 0.34 g/L lipids (lipid content of 56.45 +/- 0.76%) when cultivated on BSG hydrolysate with a C/N ratio of 500. The cell dry weight, total lipid concentration and lipid content were higher compared to the results obtained when grown on synthetic media containing glucose, xylose or mixture of glucose and xylose. To the best of our knowledge, this is the first report using hydrolysates of organosolv pretreated BSG for the growth and lipid production of oleaginous yeast in literature. The lipid profile of this oleaginous yeast showed similar fatty acid contents to vegetable oils, which can result in good biodiesel properties of the produced biodiesel. PMID- 30469532 TI - Residual Tensile Strength of the Multi-Impacted Scarf-Repaired Glass Fiber Reinforced Polymer (GFRP) Composites. AB - The effect of multiple/repeated impacts on a repaired composite was investigated using a low-velocity impact test. The composite samples were fabricated through a vacuum resin infusion method (VARI) and repaired by a scarf repair technique. Later, a repeated low-velocity impact test was performed on the original and repaired composites samples. Performance of the multi-impacted repaired and original samples was evaluated and compared by measuring maximum contact force, maximum displacement, maximum time duration, absorbed energy and damage area. Photographs of the post-impacted samples were taken to observe the multi-impact damage progression through visual inspection. The results showed that each repeated impact subjected the samples to more damage. Tensile tests revealed that the scarf repair restored 81.23% strength. It was also observed that the sample obtained the highest damage dent in the low-velocity impact test that failed early during a tensile test and carried the lowest ultimate load. PMID- 30469533 TI - Reduced Risks of Both Ischemic and Hemorrhagic Strokes in Nurses: A Population Based Cohort Study in Taiwan. AB - BACKGROUND: Nurses are typically required to address patient emergencies, and they experience high stress levels in their work, which may expose them to a higher risk of stroke. This cohort study compared the risk of stroke between nurses and the general population. METHODS: We used the Taiwan National Health Insurance database to conduct our retrospective cohort study, and we identified 83,641 individuals in the nurse group and 334,564 individuals in the control group. For the nurse group and the control group, we used the chi-square test in addition to applying Student's t-test, in order to compare the distribution differences for the continuous variables. We estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) for ischemic stroke and hemorrhagic stroke through univariate and multivariate Cox proportional-hazards regression models, with stratification according to age, sex, and comorbidity. RESULTS: The nurse group had a lower risk of ischemic stroke and hemorrhagic stroke in the crude model (HR = 0.66, 95% CI = 0.58-0.75; HR = 0.58, 95% CI = 0.47-0.72). After adjusting the prevalent variables, the nurse group still had a lower risk of stroke (HR = 0.68, 95% CI = 0.60-0.77; HR = 0.59, 95% CI = 0.48-0.73). CONCLUSION: The risks of both stroke types were lower in the nurse group than in the control. For stroke prevention, more frequent physical examinations are needed in order to enhance the health and well-being of people, including the nurses. PMID- 30469534 TI - Fouling Mitigation and Wastewater Treatment Enhancement through the Application of an Electro Moving Bed Membrane Bioreactor (eMB-MBR). AB - High operational cost due to membrane fouling propensity remains a major drawback for the widespread application of membrane bioreactor (MBR) technology. As a result, studies on membrane fouling mitigation through the application of integrated processes have been widely explored. In this work, the combined application of electrochemical processes and moving bed biofilm reactor (MBBR) technology within an MBR at laboratory scale was performed by applying an intermittent voltage of 3 V/cm to a reactor filled with 30% carriers. The treatment efficiency of the electro moving bed membrane bioreactor (eMB-MBR) technology in terms of ammonium nitrogen (NH4-N) and orthophosphate (PO4-P) removal significantly improved from 49.8% and 76.7% in the moving bed membrane bioreactor (MB-MBR) control system to 55% and 98.7% in the eMB-MBR, respectively. Additionally, concentrations of known fouling precursors and membrane fouling rate were noticeably lower in the eMB-MBR system as compared to the control system. Hence, this study successfully demonstrated an innovative and effective technology (i.e., eMB-MBR) to improve MBR performance in terms of both conventional contaminant removal and fouling mitigation. PMID- 30469535 TI - Effect of Polypropylene Fibre Addition on Properties of Geopolymers Made by 3D Printing for Digital Construction. AB - This paper investigates the effect of polypropylene (PP) fibres on the fresh and hardened properties of 3D-printed fibre-reinforced geopolymer mortars. Different percentages of PP fibres ranging between 0.25% and 1.00% by volume were added to an optimised geopolymer mixture. All samples showed reasonable workability and extrudability. In addition, shape-retention ability in the fresh state was investigated as a major requirement for 3D-printing. The compressive strength of the printed specimens was tested in the hardened state in three loading directions, viz. longitudinal, perpendicular, and lateral. The flexural strength of samples was also tested in the longitudinal and lateral directions. In addition, the interlayer bond strength was investigated. Fibre addition seems to influence compressive strengths positively only when the loading is perpendicular to the interface plane. This is due to the preferential fibre alignment parallel to the direction of extrusion. The addition of fibre significantly enhanced the flexural performance of the printed samples. The use of fibre dosages of 0.75 and 1.00 vol % caused deflection-hardening behaviour of the 3D-printed geopolymers and, hence, a significantly higher fracture energy in comparison to specimens without fibre or with lower fibre content. However, an increase in the fibre volume caused some minor reduction in interlayer bond strength. With respect to properties in the fresh state, higher fibre volumes caused better shape-retention ability in the printed samples. The results indicate the possibility of printing fibre-reinforced geopolymers which meet all the necessary properties in both the fresh and hardened states. PMID- 30469536 TI - Selenium, Selenoproteins, and Female Reproduction: A Review. AB - Selenium (Se) is an essential micronutrient that has several important functions in animal and human health. The biological functions of Se are carried out by selenoproteins (encoded by twenty-five genes in human and twenty-four in mice), which are reportedly present in all three domains of life. As a component of selenoproteins, Se has structural and enzymatic functions; in the latter context it is best recognized for its catalytic and antioxidant activities. In this review, we highlight the biological functions of Se and selenoproteins followed by an elaborated review of the relationship between Se and female reproductive function. Data pertaining to Se status and female fertility and reproduction are sparse, with most such studies focusing on the role of Se in pregnancy. Only recently has some light been shed on its potential role in ovarian physiology. The exact underlying molecular and biochemical mechanisms through which Se or selenoproteins modulate female reproduction are largely unknown; their role in human pregnancy and related complications is not yet sufficiently understood. Properly powered, randomized, controlled trials (intervention vs. control) in populations of relatively low Se status will be essential to clarify their role. In the meantime, studies elucidating the potential effect of Se supplementation and selenoproteins (i.e., GPX1, SELENOP, and SELENOS) in ovarian function and overall female reproductive efficiency would be of great value. PMID- 30469537 TI - Model of a Light Extinction Sensor for Assessing Wear Particle Distribution in a Lubricated Oil System. AB - Light extinction based optical wear particle counters (OPCs) have been widely used in the industry for oil condition monitoring for several years, and while experiments have tested the benefits and drawbacks of the measurement principle, limited research has been conducted regarding a theoretical approach to evaluate opportunities and limitations of the measurement scheme. In this paper, we present a method for theoretically modelling the output of an OPC based on the light extinction principle in the regime of geometrical optics, with a special focus on the influence of sensor optical design, particle concentration and measurement noise. Moreover, we show that, if only signal amplitude is considered, an algorithm for evaluating sensor output can cause an erroneous assessment of particle contamination level. PMID- 30469538 TI - Discovery of Non-Peptidic Compounds against Chagas Disease Applying Pharmacophore Guided Molecular Modelling Approaches. AB - Chagas disease is one of the primary causes of heart diseases accounting to 50,000 lives annually and is listed as the neglected tropical disease. Because the currently available therapies have greater toxic effects with higher resistance, there is a dire need to develop new drugs to combat the disease. In this pursuit, the 3D QSAR ligand-pharmacophore (pharm 1) and receptor-based pharmacophore (pharm 2) search was initiated to retrieve the candidate compounds from universal natural compounds database. The validated models were allowed to map the universal natural compounds database. The obtained lead candidates were subjected to molecular docking against cysteine protease (PDB code: 1ME3) employing -Cdocker available on the discovery studio. Subsequently, two Hits have satisfied the selection criteria and were escalated to molecular dynamics simulation and binding free energy calculations. These Hits have demonstrated higher dock scores, displayed interactions with the key residues portraying an ideal binding mode complemented by mapping to all the features of pharm 1 and pharm 2. Additionally, they have rendered stable root mean square deviation (RMSD) and potential energy profiles illuminating their potentiality as the prospective antichagastic agents. The study further demonstrates the mechanism of inhibition by tetrad residues compromising of Gly23 and Asn70 holding the ligand at each ends and the residues Gly65 and Gly160 clamping the Hits at the center. The notable feature is that the Hits lie in close proximity with the residues Glu66 and Leu67, accommodating within the S1, S2 and S3 subsites. Considering these findings, the study suggests that the Hits may be regarded as effective therapeutics against Chagas disease. PMID- 30469539 TI - Dual-Band Unidirectional Reflectionless Propagation in Metamaterial Based on Two Circular-Hole Resonators. AB - Dual-band unidirectional reflectionless propagation at two exceptional points is investigated in metamaterial, which is composed of only two gold resonators with circular holes, by simply manipulating the angle of incident wave and distance between two resonators. Furthermore, the dual-band unidirectional reflectionless propagation can be realized in the wide ranges of incident angle from 0 ? to 50 ? and distance from 255 nm to 355 nm between two resonators. In addition, our scheme is insensitive to polarization of incident wave due to the circular-hole structure of the resonators. PMID- 30469540 TI - Liver-Derived Exosomes and Their Implications in Liver Pathobiology. AB - The liver has a wide range of physiological functions in the body, and its health is maintained by complex cross-talk among hepatic cells, including parenchymal hepatocytes and nonparenchymal cells. Exosomes, which are one method of cellular communication, are endosomal-derived small vesicles that are released by donor cells and delivered to the target cells at both short and long distances. Because exosomes carry a variety of cargoes, including proteins, mRNAs, microRNAs and other noncoding RNAs originating from donor cells, exosomes convey cellular information that enables them to potentially serve as biomarkers and therapeutics in liver diseases. Hepatocytes release exosomes to neighboring hepatocytes or nonparenchymal cells to regulate liver regeneration and repair. Nonparenchymal cells, including hepatic stellate cells, liver sinusoidal endothelial cells, and cholangiocytes, also secrete exosomes to regulate liver remodeling upon liver injury. Exosomes that are released from liver cancer cells create a favorable microenvironment for cancer growth and progression. In this review, we summarize and discuss the current findings and understanding of exosome-mediated intercellular communication in the liver, with a particular focus on the function of exosomes in both health and disease. Based on the current findings, we suggest the potential applications of exosomes as biomarkers and therapeutics for liver diseases. PMID- 30469541 TI - Urinary 8-Hydroxy-2'-deoxyguanosine (8-OHdG) Concentrations and Menstrual Cycle Characteristics in Female University Students. AB - Higher concentrations of oxidative stress biomarkers are found in women with polycystic ovary syndrome (PCOS) and endometriosis, conditions linked to irregular menstrual cycles and menstrual pain. The aim of the present study was to test whether women with higher oxidative stress are more likely to show irregular menstrual cycles and severe menstrual pain compared with women with lower oxidative stress. A cross-sectional study was conducted targeting female university students with a mean (SD) age of 20.5 (1.8) years (n = 188). Participants completed a questionnaire on reproductive characteristics and anthropometry and kept a menstrual cycle diary for 5 consecutive months. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), cotinine, and creatinine concentrations were measured once during the study period. The mean (SD) value of the urinary 8 OHdG concentration was 4.7 (2.0) MUg/g of creatinine. A total of 1021 menstrual cycles were recorded. The participants were categorized as either having regular (68%) or irregular (18%) cycles or oligomenorrhea (13%) or polymenorrhea (1%). The urinary 8-OHdG concentration did not significantly differ across menstrual cycle regularity or pain categories. Even after adjusting for age, body mass index (BMI), and urinary cotinine concentrations, having irregular cycles or more severe menstrual pain was not associated with urinary 8-OHdG concentration. PMID- 30469542 TI - Distribution of Glycerophospholipids in the Adult Human Lens. AB - In humans, the age of fibre cells differs across the ocular lens, ranging from those formed before birth in the core of the lens to those formed just prior to death in the outer cortex. The distribution of glycerophospholipids in the adult human lens should reflect this range; however, limited data currently exists to confirm this hypothesis. Accordingly, this study aimed to determine the distribution of glycerophospholipids in adult human lens using mass spectrometry imaging. To achieve this, 20-um thick slices of two human lenses, aged 51 and 67 were analysed by matrix-assisted laser desorption ionisation imaging mass spectrometry. The data clearly indicate that intact glycerophospholipids such as phosphatidylethanolamine, phosphatidylserine, and phosphatidic acid are mainly present in the outer cortex region, corresponding to the youngest fibre cells, while lyso-phosphatidylethanolamine, likely produced by the degradation of phosphatidylethanolamine, is present in the nucleus (older fibre cells). This study adds further evidence to the relationship between fibre cell age and glycerophospholipid composition. PMID- 30469543 TI - Taxifolin Resensitizes Multidrug Resistance Cancer Cells via Uncompetitive Inhibition of P-Glycoprotein Function. AB - P-glycoprotein (P-gp) effluxes lots of chemotherapeutic agents and leads to multidrug resistance (MDR) in cancer treatments. The development of P-gp inhibitors from natural products provide a potential strategy for the beneficial clinical outcomes. This study aimed to evaluate the effects of the natural flavonoid taxifolin, luteolin, (-)-gallocatechin, and (-)-catechin on human P-gp activity. The kinetic interactions and underlying mechanisms of taxifolin mediated transporter inhibition were further investigated. The transporter inhibition ability was evaluated in human P-gp stable expression cells (ABCB1/Flp InTM-293) by calcein-AM uptake assays. The kinetics study for P-gp inhibition was evaluated by doxorubicin and rhodamine123 efflux assays. The MDR reversal ability of taxifolin were performed by SRB assays to detect the cell viability in sensitive cancer cell line (HeLaS3), and resistant cancer cell line (KB-vin). Cell cycle analysis and ABCB1 real-time RT-PCR were used for mechanical exploration. The results demonstrated that taxifolin decreased ABCB1 expression in a concentration-dependent manner. The function of P-gp was inhibited by taxifolin through uncompetitive inhibition of rhodamine 123 and doxorubicin efflux. The combination of taxifolin significantly resensitized MDR cancer cells to chemotherapeutic agents. These results suggested that taxifolin may be considered as a potential P-gp modulator for synergistic treatment of MDR cancers. PMID- 30469544 TI - Qualitative Identification of the Static Pull-In and Fundamental Frequency of One Electrode MEMS Resonators. AB - This paper attempts to qualitatively identify the static pull-in position, pull in voltage, and fundamental frequency of one-electrode microresonators from a physical perspective. During theoretical derivation, a generalized one-degree-of freedom (1-DOF) model in nondimensional form derived using the differential quadrature method (DQM) is first introduced and then transformed for frequency normalization. Based on the deduced formulas, the upper and lower bounds of the static pull-in position and pull-in voltage are both deduced through mathematical proof. To distinguish the monotonic and nonmonotonic behavior of the fundamental frequency versus direct current (DC) voltage, a critical condition decided only by cubic stiffness is then determined. For the first time, two extreme static positions, as well as the corresponding fundamental frequencies and DC voltages to identify different frequency behaviors are derived, and their variations versus cubic stiffness are then discussed and verified. During the simulation process, a high-order DQM and COMSOL 2D model are both applied for numerical analyses. Guided by nondimensional results, typical behaviors with specific physical parameters are examined in detail. Results demonstrate that the curve tendencies between all the qualitative results and quantitative numerical simulations in dimensional form agree well with each other, implying the possibility of using 1-DOF model to qualitatively discuss physical parameters effects on the system statics and dynamics. PMID- 30469545 TI - Measurement and Calibration of Plant-Height from Fixed-Wing UAV Images. AB - Continuing population growth will result in increasing global demand for food and fiber for the foreseeable future. During the growing season, variability in the height of crops provides important information on plant health, growth, and response to environmental effects. This paper indicates the feasibility of using structure from motion (SfM) on images collected from 120 m above ground level (AGL) with a fixed-wing unmanned aerial vehicle (UAV) to estimate sorghum plant height with reasonable accuracy on a relatively large farm field. Correlations between UAV-based estimates and ground truth were strong on all dates (R2 > 0.80) but are clearly better on some dates than others. Furthermore, a new method for improving UAV-based plant height estimates with multi-level ground control points (GCPs) was found to lower the root mean square error (RMSE) by about 20%. These results indicate that GCP-based height calibration has a potential for future application where accuracy is particularly important. Lastly, the image blur appeared to have a significant impact on the accuracy of plant height estimation. A strong correlation (R2 = 0.85) was observed between image quality and plant height RMSE and the influence of wind was a challenge in obtaining high-quality plant height data. A strong relationship (R2 = 0.99) existed between wind speed and image blurriness. PMID- 30469546 TI - Nile Tilapia Derived Antimicrobial Peptide TP4 Exerts Antineoplastic Activity Through Microtubule Disruption. AB - Some antimicrobial peptides (AMPs) exhibit anti-cancer activity, acting on cancer cells either by causing membrane lysis or via intracellular effects. While intracellular penetration of AMPs has been shown to cause cancer cell death, the mechanisms of toxicity remain largely unknown. Here we show that a tilapia derived AMP, Tilapia piscidin (TP) 4, penetrates intracellularly and targets the microtubule network. A pull-down assay identified alpha-Tubulin as a major interaction partner for TP4, and molecular docking analysis suggested that Phe1, Ile16, and Arg23 on TP4 are required for the interaction. TP4 treatment in A549 cells was found to disrupt the microtubule network in cells, and mutation of the essential TP4 residues prevented microtubule depolymerization in vitro. Importantly, the TP4 mutants also showed decreased cytotoxicity in A549 cells, suggesting that microtubule disruption is a major mechanistic component of TP4 mediated death in lung carcinoma cells. PMID- 30469547 TI - Sodium Phenylbutyrate Ameliorates Inflammatory Response Induced by Staphylococcus aureus Lipoteichoic Acid via Suppressing TLR2/NF-kappaB/NLRP3 Pathways in MAC-T Cells. AB - This study aimed to investigate the anti-inflammatory properties of sodium phenylbutyrate (SPB) against Staphylococcus aureus (S. aureus) lipoteichoic acid (LTA)-stimulated bovine mammary alveolar (MAC-T) cells. Quantitative PCR was performed to examine the effect of SPB on inflammatory cytokines and host defense peptide (HDP) gene expression. Western blot wanalysis was used to detect the effect of SPB on the TLR2/NF-kappaB/NLRP3 signaling pathway. The results showed that SPB significantly suppressed the expression of TNF-alpha, IL-1beta, IL-6; meanwhile, the markedly decreased expression of LTA-stimulated TLR2, NLRP3, ASC, caspase-1, and IL-1beta, and the inhibited IkBalpha and p65 phosphorylation were also observed. However, increased TAP and Bac5 expression in LTA-stimulated MAC-T cells was further detected. In summary, these results suggest that SPB ameliorates the inflammatory response induced by S. aureus LTA via suppressing the TLR2/NF-kappaB/NLRP3 signaling pathway, which indicates that SPB may be a potential agent for the treatment of bovine mastitis. PMID- 30469548 TI - Performance Consistency of AlSi10Mg Alloy Manufactured by Simulating Multi Laser Beam Selective Laser Melting (SLM): Microstructures and Mechanical Properties. AB - Multi-laser beam selective laser melting (SLM) technology based on a powder bed has been used to manufacture AlSi10Mg samples. The AlSi10Mg alloy was used as research material to systematically study the performance consistency of both the laser overlap areas and the isolated areas of the multi-laser beam SLM manufactured parts. The microstructures and mechanical properties of all isolated and overlap processing areas were compared under optimized process parameters. It was discovered that there is a raised platform at the junction of the overlap areas and the isolated areas of the multi-laser SLM samples. The roughness is significantly reduced after two scans. However, the surface roughness of the samples is highest after four scans. As the number of laser scans increases, the relative density of the overlap areas of the samples improves, and there is no significant change in hardness. The tensile properties of the tensile samples are poor when the overlap area width is 0, 0.1, or 0.2 mm. When the widths of the overlap areas are equal to or greater than 0.3 mm, there is no significant difference in the tensile strength between the overlap and the isolated areas. PMID- 30469549 TI - The Interaction of miR-378i-Skp2 Regulates Cell Senescence in Diabetic Nephropathy. AB - Diabetic nephropathy (DN) is the major cause of end stage renal disease. Proximal tubular epithelial cell (PTEC) injury occurs early in diabetic kidney, and it is correlated with consequent renal failure. Cellular senescence participates in the pathophysiology of DN, but its role remains unclear. We conducted a cross disciplinary study, including human, in vivo, and in vitro studies, to explore the novel molecular mechanisms of PTEC senescence in DN. We found that HG induced cell senescence in PTECs, supported by enhanced beta-galactosidase staining, p53 and p27 expression, and reduced cyclin E levels. Transcriptome analysis of PTECs from a type 2 diabetic patient and a normal individual using next generation sequencing (NGS) and systematic bioinformatics analyses indicated that miR-378i and its downstream target S-phase kinase protein 2 (Skp2) contribute to HG induced senescence in PTECs. High glucose (HG) elevated miR-378i expression in PTECs, and miR-378i transfection reduced Skp2 expression. Urinary miR-378i levels were elevated in both db/db mice and type 2 diabetic patients, whereas decreased Skp2 levels were shown in proximal tubule of db/db mice and human DN. Moreover, urinary miR-378i levels were positively correlated with urinary senescence associated secretory phenotype cytokines and renal function in in vivo and human study. This study demonstrates that the interaction between miR-378i and Skp2 regulates PTEC senescence of DN. miR-378i has the potential to predict renal injury in DN. These findings suggest future applications in both therapy and in predicting renal dysfunction of DN. PMID- 30469550 TI - Target illusion by shifting a distance. AB - A novel homogeneous illusion device with arbitrary polygonal cross section that acts as either invisible cloak or shifting medium has been proposed and designed based on coordinate transformation method. The material parameters of the device are derived and the effectiveness is verified by full-wave simulation. Results show that whether the illusion device acts as invisible cloak or shifting medium depends on a value of shifting distance which is about 2a (ais circum-radius of the outer polygon).When the shifting distance is larger than 2a, the illusion device acts as an invisible cloak, and otherwise it acts as shifting medium. The stealth effect of all kinds of illusion devices are investigated, including identical-size mapped polygonal devices or non-identical size mapped polygonal devices. The results show that the device is a novel interactive cloak and is different from pre-proposed cloaks. The shifting properties of the device are validated by two examples, including moving the target object virtually and generating illusionary image of a line source. The material parameters of the device are homogeneous, which makes it more practicable in reality. It is hoped that our works may open an avenue for designing novel invisible cloaks, and are helpful for speeding up the potential applications of the illusion devices, such as aircraft or military equipment stealth, target objects camouflage or protection. PMID- 30469551 TI - Generation of random on-off modulation pulses by optically injecting a gain switched Fabry-Perot semiconductor laser with a dual-mode injection for random modulation pulsed lidar applications. AB - We study the generation of random on-off modulation pulses by optically injecting a gain-switched Fabry-Perot semiconductor laser with a dual-mode injection for random-modulation pulsed lidar applications. In the dual-mode injection scheme proposed, the first master laser (ML1) injecting on a resonant sidemode of the gain-switched slave laser (SL) randomly locks such injected sidemode and suppresses the output pulses in the center mode through gain-competition. The second master laser (ML2) injecting on the center mode then stabilizes and enhances the output pulses to have equal amplitudes suitable for digital threshold detection and time-correlated single photon counting. Under different injection conditions, we identify dynamical states including unlocked, stable locking, bistable, and instability. By operating the laser in the bistable states randomly switching between the unlocked and stable locking states, we successfully generate random on-off modulation pulses without employing any digital circuits or external modulators. We analyze the signal-to-noise ratio (SNR) and detection probability of the proposed scheme to show its feasibility in random-modulation pulsed lidar applications. Moreover, we study its anti interference capability by adding interference from additional channels with similar modulated pulses. We show that, with injection strengths of 0.418 and 0.038 from the ML1 and ML2 and a correlation length Tc = 90 us, a detection probability of 1 can be readily achieved even under the interference from more than 49 additional channels. PMID- 30469552 TI - Z2 topological edge state in honeycomb lattice of coupled resonant optical waveguides with a flat band. AB - Two-dimensional (2D) coupled resonant optical waveguide (CROW), exhibiting topological edge states, provides an efficient platform for designing integrated topological photonic devices. In this paper, we propose an experimentally feasible design of 2D honeycomb CROW photonic structure. The characteristic optical system possesses two-fold and three-fold Dirac points at different positions in the Brillouin zone. The effective gauge fields implemented by the intrinsic pseudo-spin-orbit interaction open up topologically nontrivial bandgaps through the Dirac points. Spatial lattice geometries allow destructive wave interference, leading to a dispersionless, near-flat energy band in the vicinity of the three-fold Dirac point in the telecommunication frequency regime. This nontrivial structure with a near-flat band yields topologically protected edge states. These characteristics underpin the fundamental importance as well as the potential applications in various optical devices. Based on the honeycomb CROW lattice, we design the shape-independent topological cavity and the beam splitter, which demonstrate the relevance for a wide range of photonic applications. PMID- 30469553 TI - Highly sensitive and selective CO sensor using a 2.33 MUm diode laser and wavelength modulation spectroscopy. AB - A ppm-level CO sensor based on a 2f wavelength modulation spectroscopy (2f-WMS) technique was developed for the application of SF6 decomposition analysis in an electric power system. A detailed investigation of the optimum target line selection was carried out to avoid spectral interference from high purity SF6 in a wide wavelength range. A diode laser emitting at 2.33 MUm and a 14.5-m multipass gas cell (MGC) was employed to target the R(6) line of the CO first overtone band and increase the optical path, respectively, thus resulting in a minimum detection sensitivity of 1 ppm. A Levenberg-Marquardt nonlinear least squares fit algorithm makes full use of the information from all data points of the 2f spectrum and as a result, a measurement precision of ~40 ppb was achieved with a data update rate of 0.6 s. The sensor performance was also evaluated in terms of the gas flow rate, stability, and linearity. The results showed that the best operating condition with a precision of 6 ppb can be achieved by increasing the gas flow rate to the value that matches the optimum averaging time of 48 s. PMID- 30469554 TI - Efficient image reconstruction of high-density molecules with augmented Lagrangian method in super-resolution microscopy. AB - High-density molecules localization algorithm is crucial to obtain sufficient temporal resolution in super-resolution fluorescence microscopy, particularly in view of the challenges associated with live-cell imaging. In this work, an algorithm based on augmented Lagrangian method (ALM) is proposed for reconstructing high-density molecules. The problem is firstly converted to an equivalent optimization problem with constraints using variable splitting, and then the alternating minimization method is applied to implement it straightforwardly. We also take advantage of quasi-Newton method to tackle the sub-problems for acceleration, and total variation regularization to reduce noise. Numerical results on both simulated and real data demonstrate that the algorithm can achieve using fewer frames of raw images to reconstruct high resolution image with favorable performance in terms of detection rate and image quality. PMID- 30469555 TI - Optimisation of ultrafast laser assisted etching in fused silica. AB - Ultrafast laser assisted etching (ULAE) in fused silica is an attractive technology for fabricating three-dimensional micro-components. ULAE is a two-step process whereby ultrafast laser inscription (ULI) is first used to modify the substrate material and chemical etching is then used to remove the laser modified material. In this paper, we present a detailed investigation into how the ULI parameters affect the etching rate of laser modified channels and planar surfaces written in fused silica. Recently, potassium hydroxide (KOH) has shown potential to outperform the more commonly used hydrofluoric acid (HF) as a highly selective etchant for ULAE. Here we perform a detailed comparison of HF and KOH etching after laser inscription with a wide range of ultrafast laser irradiation parameters. Etching with KOH is found to be significantly more selective, removing the laser modified material up to 955 times faster than pristine material, compared with up to 66 when using HF. Maximum etching rates for the two etchants were comparable at 320 MUm/hour and 363 MUm/hour for HF and KOH respectively. We further demonstrate that highly selective, isotropic etching of non-planar surfaces can be achieved by controlling the polarization state of the laser dynamically during laser inscription. PMID- 30469556 TI - Multi-stage generation of extreme ultraviolet dispersive waves by tapering gas filled hollow-core anti-resonant fibers. AB - In this work, we numerically investigate an experimentally feasible design of a tapered Ne-filled hollow-core anti-resonant fiber and we report multi-stage generation of dispersive waves (DWs) in the range 90-120 nm, well into the extreme ultraviolet (UV) region. The simulations assume a 800 nm pump pulse with 30 fs 10 uJ pulse energy, launched into a 9 bar Ne-filled fiber with a 34 um initial core diameter that is then tapered to a 10 um core diameter. The simulations were performed using a new model that provides a realistic description of both loss and dispersion of the resonant and anti-resonant spectral bands of the fiber, and also importantly includes the material loss of silica in the UV. We show that by first generating solitons that emit DWs in the far-UV region in the pre-taper section, optimization of the following taper structure can allow re-collision with the solitons and further up-conversion of the far-UV DWs to the extreme-UV with energies up to 190 nJ in the 90-120 nm range. This process provides a new way to generate light in the extreme-UV spectral range using relatively low gas pressure. PMID- 30469557 TI - Multifunctional waveguide interferometer sensor: simultaneous detection of refraction and absorption with size-exclusion function. AB - A waveguide Young interferometer is presented with simultaneous detection of complex refractive index of a liquid sample. The real part of the refractive index change (refraction) is detected by tracing phase shifts of the interferogram generated by a sensing and reference waveguide. The imaginary part of the refractive index (absorption) is determined by the attenuation of the transmitted signal at certain wavelength. Furthermore, nano-filters are fabricated atop the sensing waveguide, which enables size-exclusion filtering of species to the evanescent field. It shows capability of distinguishing small and large particles from 100 nm to 500 nm in diameter, which is further confirmed by fluorescent excitation experiments. The present sensor could find broad application in optical characterization of complex turbid media with regard to their complex refractive index. PMID- 30469558 TI - Measurement uncertainties in PSICAM and reflective tube absorption meters. AB - The nature and magnitude of measurement uncertainties (precision and accuracy) associated with two approaches for measuring absorption by turbid waters (b(532 nm) ranging from 0.20 m-1 to 22.89 m-1) are investigated here: (a) point source integrating cavity absorption meters (PSICAM), and (b) reflective tube absorption meters (AC-9 and AC-s - both WET Labs Inc., USA). Absolute measurement precision at 440 nm was quantified using standard deviations of triplicate measurements for the PSICAM and de-trended, bin averaged time series for the AC-9/s, giving comparable levels (< 0.006 m-1) for both instruments. Using data collected from a wide range of UK coastal waters, PSICAM accuracy was assessed by comparing both total non-water absorption and absorption by coloured dissolved organic material (CDOM) measured on discrete samples by two independent PSICAMs. AC-9/s performance was tested by comparing total non-water absorption measured in situ by an AC-9 and an AC-s mounted on the same frame. Results showed that the PSICAM outperforms AC-9/s instruments with regards to accuracy, with average spread in the PSICAM total absorption data of 0.006 m-1 (RMSE) compared to 0.028 m-1 for the AC-9/s devices. Despite application of a state of the art scattering correction method, the AC-9/s instruments still tend to overestimate absorption compared to PSICAM data by on average 0.014 m-1 RMSE (AC-s) and 0.043 m-1 RMSE (AC-9). This remaining discrepancy can be largely attributed to residual limitations in the correction of AC-9/s data for scattering effects and limitations in the quality of AC-9/s calibration measurements. PMID- 30469559 TI - Broadband MoS2-based absorber investigated by a generalized interference theory. AB - In this paper, a broadband absorber utilizing monolayer molybdenum disulfide (MoS2) is proposed, and a generalized interference theory (GIT) is derived to investigate this absorber. Using the hybrid Lorentz-Drude and Gaussian model of monolayer MoS2 and the dyadic Green's functions, the propagation properties of monolayer MoS2 are first investigated. Then, a sandwich-like MoS2-based absorber design is proposed in the visible regime. The sandwich-like structure is mounted on a fully reflective gold mirror, which forms a Fabry-Perot resonator to strengthen light-matter interactions and enhance the absorption. To numerically calculate the absorption performance of this absorber, the GIT is next derived from interference theory. The numerical results indicate that an absorption >= 90% is obtained for a range of wavelengths (lambda) from 389 to 517 nm, and this absorber can operate well, even with an angle of incidence up to 60 degrees , which also verifies the prediction of the MoS2-based absorber mainly operating at lambda < 700 nm. Afterward, the operating mechanism of the proposed design is determined using the theory of destructive interference. Finally, the proposed design and derived GIT are validated by a simulation using commercial electromagnetic software. The derived GIT drives the numerical investigation of the multilayer structure with various polarization types and angles of incidence of the waves, and the MoS2-based absorber can be used in several applications such as photoelectric storage and photoelectric detection. PMID- 30469560 TI - Thin-film lithium niobate-on-insulator waveguides fabricated on silicon wafer by room-temperature bonding method with silicon nanoadhesive layer. AB - Lithium niobate-on-insulator (LNOI) waveguides fabricated on a silicon wafer using a room-temperature bonding method have potential application as Si-based high-density photonic integrated circuits. A surface-activated bonding method using a Si nanoadhesive layer was found to produce a strong bond between LN and SiO2/Si at room temperature, which is sufficient to withstand both the wafer thinning (LN thickness <5 MUm) and surface micromachining processes used to form the strongly confined waveguides. In addition, the bond quality and optical propagation characteristics of the resulting LNOI waveguides were investigated, and the applicability of this bonding method to low-loss LNOI waveguide fabrication is discussed. The propagation loss for the ridged waveguide was approximately 2 dB/cm at a wavelength of 1550 nm, which was sufficiently low for the device application. The results of the present study will be of significant use in the development of fabrication techniques for waveguides with any bonded materials using this room-temperature bonding method, and not only LN core/SiO2 cladding waveguides. PMID- 30469561 TI - Using convex optimization of autocorrelation with constrained support and windowing for improved phase retrieval accuracy. AB - In imaging modalities recording diffraction data, such as the imaging of viruses at X-ray free electron laser facilities, the original image can be reconstructed assuming known phases. When phases are unknown, oversampling and a constraint on the support region in the original object can be used to solve a non-convex optimization problem using iterative alternating-projection methods. Such schemes are ill-suited for finding the optimum solution for sparse data, since the recorded pattern does not correspond exactly to the original wave function. Different iteration starting points can give rise to different solutions. We construct a convex optimization problem, where the only local optimum is also the global optimum. This is achieved using a modified support constraint and a maximum-likelihood treatment of the recorded data as a sample from the underlying wave function. This relaxed problem is solved in order to provide a new set of most probable "healed" signal intensities, without sparseness and missing data. For these new intensities, it should be possible to satisfy the support constraint and intensity constraint exactly, without conflicts between them. By making both constraints satisfiable, traditional phase retrieval with superior results is made possible. On simulated data, we demonstrate the benefits of our approach visually, and quantify the improvement in terms of the crystallographic R factor for the recovered scalar amplitudes relative to true simulations from .405 to .097, as well as the mean-squared error in the reconstructed image from .233 to .139. We also compare our approach, with regards to theory and simulation results, to other approaches for healing as well as noise-tolerant phase retrieval. These tests indicate that the COACS pre-processing allows for best-in class results. PMID- 30469562 TI - Polarization dependent laser damage growth of optical coatings at sub-picosecond regime. AB - We report the influence of polarization on the damage mechanism of oxide thin films submitted to multiple pulses in the sub-picosecond regime. We have exposed single layer coatings of oxide materials and multilayer stacks (mirrors) to multiple laser pulses at 1030nm, 500fs, and the events on the tested sample sites were recorded in situ with high resolution microscopy. For multiple shots while keeping the fluence below the single shot threshold, damage on the film begins to form and for some of the samples the damage growth follows polarization dependent patterns. This damage growth was investigated and our results match with the assumption that the existence of nano-defects contributes to the early stage of the formation of damage, in which the energy absorption in a defect site causes local nanoablation at a laser fluence under the intrinsic ablation threshold and nanovoid formation. Based on the simulation of the interference of the scattered wave by the nanovoid with the incident wave, we obtain good correlation between simulated and observed damage growth behavior. This process leads to the formation of specific damage morphology that is strongly dependent on the polarization of the incident wave. PMID- 30469563 TI - Fast optimization of coded apertures in X-ray computed tomography. AB - Coded aperture X-ray computed tomography (CAXCT) is a novel X-ray imaging system capable of reconstructing high quality images from a reduced set of measurements. Coded apertures are placed in front of the X-ray source in CAXCT so as to obtain patterned projections onto a detector array. Then, compressive sensing (CS) reconstruction algorithms are used to reconstruct the linear attenuation coefficients. The coded aperture is an important factor that influences the point spread function (PSF), which in turn determines the capability to sample the linear attenuation coefficients of the object. A coded aperture optimization approach was recently proposed based on the coherence of the system matrix; however, this algorithm is memory intensive and it is not able to optimize the coded apertures for large image sizes required in many applications. This paper introduces a significantly more efficient approach for coded aperture optimization that reduces the memory requirements and the execution time by orders of magnitude. The features are defined as the inner product of the vectors representing the geometric paths of the X-rays with the sparse basis representation of the object; therefore, the algorithm aims to find a subset of features that minimizes the information loss compared to the complete set of projections. This subset corresponds to the unblocking elements in the optimized coded apertures. The proposed approach solves the memory and runtime limitations of the previously proposed algorithm and provides a significant gain in the reconstruction image quality compared to that attained by random coded apertures in both simulated datasets and real datasets. PMID- 30469564 TI - Stable radio frequency dissemination via a 1007 km fiber link based on a high performance phase lock loop. AB - In this paper, we propose an active-compensation stable radio frequency (RF) transmission scheme based on a high-performance phase lock loop (PLL). In our PLL, a new structure for phase-detection is designed with only one standard RF signal to obtain a simple structure with no interference from other signals. In addition, different optical wavelengths carrying the same RF signal are utilized in the two directions to suppress Rayleigh scattering. The low phase noise homemade bi-directional erbium doped fiber amplifier (EDFA) module is used to reduce signal-to-noise ratio (SNR) deterioration. Hence, the transmission distance is greatly improved. The effects of polarization mode dispersion and phase noise produced by the EDFA on the transmission distance are discussed. Ultimately, a stable RF signal with 2.4 GHz transmitted over a 1007 km fiber link is obtained. The experimental results demonstrate that frequency instabilities of 1.2*10- 13 at 1s and 5.1*10- 16 at 20000s. Therefore, the system can be used for atomic clocks comparisons and provides frequency standard for time transfer systems over a long-haul fiber. PMID- 30469565 TI - Universal fine-structure eraser for quantum dots. AB - We analyze the degree of entanglement measurable from a quantum dot via the biexciton-exciton cascade as a function of the exciton fine-structure splitting and the detection time resolution. We show that the time-energy uncertainty relation provides means to measure a high entanglement even in presence of a finite fine-structure splitting when a detection system with high temporal resolution is employed. Still, in many applications it would be beneficial if the fine-structure splitting could be compensated to zero. To solve this problem, we propose an all-optical approach with rotating waveplates to erase this fine structure splitting completely which should allow obtaining a high degree of entanglement with near-unity efficiency. Our optical approach is possible with current technology and is also compatible with any quantum dot showing fine structure splitting. This bears the advantage that for example the fine-structure splitting of quantum dots in nanowires and micropillars can be directly compensated without the need for further sample processing. PMID- 30469566 TI - Nanosecond-pulsed RT-operating at ~4 MUm Fe:ZnSe laser pumped inside the cavity of a LD side-pumped Er:YLF laser. AB - Characteristics of an Fe:ZnSe laser with a new pump scheme were presented. An Fe:ZnSe crystal was placed inside the cavity of the Er:YLF laser pumped by a bar of laser diodes (LD) emitting at 975 nm. The high power 2.66 MUm wave ~50 ns pulses were generated inside the cavity due to passive Q-switching of the Er:YLF laser by an Fe:ZnSe saturated absorber. These pulses pumped the Fe:ZnSe laser. As a result, the pulses with an energy of ~2 MUJ at a wavelength around 4 MUm and time duration of about 50 ns were generated. The laser operated in periodic pulsed pump regime at room temperature with a repetition rate up to 200 Hz. The Q switching pulse repetition rate during the pump pulse ran up to 2.5 kHz. PMID- 30469567 TI - On-demand routing, modulation level and spectrum allocation (OD-RMSA) for multicast service aggregation in elastic optical networks. AB - The light-tree based multicast service aggregation (LT-MSA) scheme provides a cost-efficient method to accommodate a large number of finer-grained multicast services in optical networks. However, when multiple multicast services that do not have exactly the same requesters are aggregated together, some fiber links will be allocated with redundant spectrum. This shortcoming causes high spectrum consumption and narrow application range. In elastic optical networks (EONs), leveraging node architecture that supports both optical multicasting and bandwidth-variable spectrum selection, we consider on-demand routing, modulation level and spectrum allocation (OD-RMSA) for the LT-MSA scheme. It improves resource utilization by allocating spectrum on each link according to the desired multicast services of downstream destination users of this link. We also define the maximum aggregating group (MAG) to eliminate node adjacent redundancy on each link. An Integer Linear Programing (ILP) model and a heuristic approach are developed to realize the OD-RMSA strategy. Simulations show that the OD-RMSA strategy can eliminate spectrum redundancy and greatly reduces transceiver consumption than the light-tree scheme. Moreover, it can also greatly reduce spectrum consumption than the conventional consistent routing, modulation level and spectrum allocation (C-RMSA) strategy. PMID- 30469568 TI - Photonics meets topology. AB - The topological phases in materials have been studied in recent decades for their unique boundary states and transport properties. Photonic systems with band structures embrace the topological phases closely, where they not only provide platforms to testify the topological band theory, but also shed light on designing novel optical devices. In this review, we present exciting developments, supported by brief descriptions of prominent milestones of topological phases in photonic systems in recent years. These studies may sustain further developments of optical devices and offer novel methods for light manipulations. PMID- 30469569 TI - Mode density multiplication of an optical frequency comb by N2 with phase modulation. AB - We introduce a simple scheme for mode-density multiplication of an optical frequency comb (OFC) by a factor of square of an arbitrary integer N using phase modulation. This scheme is employed to multiply the mode density of an erbium doped fiber laser OFC (repetition rate of 66.87 MHz) by factors of 42, 82, and 3 . 42 using an electro-optic phase modulator. The OFC multiplied by 42 is applied to direct-comb spectroscopy of methane with a spectral resolution of 4.18 MHz. PMID- 30469570 TI - Single-photodiode 112-Gbit/s 16-QAM transmission over 960-km SSMF enabled by Kramers-Kronig detection and sparse I/Q Volterra filter. AB - We have experimentally demonstrated a single-photodiode 112-Gbit/s 16-QAM transmission over 960-km standard single mode fiber with Kramers-Kronig (KK) detection and a sparse I/Q Volterra filter (VF). KK detection is used to mitigate the signal to signal beating interference. A novel I/Q VF based on dual-input real-valued Volterra series is proposed to overcome the constraints of non-linear distortions. Two conventional single-input real-valued VFs are employed as a contrast to prove the necessity of I/Q hybrid structure in I/Q VF when the system suffers from severe I/Q imbalance and crosstalk. The proposed I/Q VF brings nearly two order magnitude improvement in BER performance compared with the conventional linear equalizer for back to back case and doubles the transmission distance from 480 km to 960 km at the hard-decision forward error correction threshold of 3.8 * 10-3. To reduce the complexity of full I/Q VF, a simple l1 regularization-based least mean square (LMS) algorithm is employed to identify the significant kernels and construct a sparse I/Q VF. Compared with full I/Q VF, the sparse I/Q VF reduces up to 58% complexity at 960 km while having the similar BER performance. PMID- 30469571 TI - Concurrent polarization IR analysis to determine the 3D angles and the order parameter for molecular orientation imaging. AB - A non-tomographic analysis method is proposed to determine the 3D angles and the order parameter of molecular orientation using polarization-dependent infrared (IR) spectroscopy. Conventional polarization-based imaging approaches provide only 2D-projected orientational information of single vibrational modes. The newly proposed method concurrently analyses polarization angle-dependent absorptance of two non-parallel transition dipole moments. The relative phase angle and the maximum-to-minimum ratios observed from the two polarization profiles are used to calculate the 3D angles of the mean molecular orientation and the order parameter of the orientational distribution. Usage of those relative observables as intermediate input parameters makes the analysis results robust against variations in concentration, thickness, absorption peak, and absorption cross-section, which can occur in typical imaging conditions. This analysis is based on a single-step, non-iterative calculation that does not require any analytical model function of an orientational distribution function. This concurrent polarization analysis method is demonstrated using two simulation data examples, followed by associated error propagation analysis and discussion on the effect of absorption strength. Application of this robust spectral analysis method to polarization IR microscopy will provide a full molecular orientation image without tilting that tomographies require. PMID- 30469572 TI - All-optical characterization of the two-dimensional waveform and the Gouy phase of an infrared pulse based on plasma fluorescence of gas. AB - The characterization of the temporal waveform of few-cycle laser pulses is an indispensable part in strong-field physics and attosecond science. Recently, a simple waveform-characterization technique called TIPTOE (tunneling ionization with a perturbation for the time-domain observation of an electric field) has been demonstrated for measuring linearly polarized few-cycle pulses. We theoretically and experimentally show that TIPTOE can be extended to resolve more characteristics of an optical waveform: the two-dimensional polarization and the Gouy phase. Based on the plasma fluorescence of a gaseous medium, we achieve all optical and spatially resolved measurements of the waveform of an infrared pulse. This detection method enables the remote characterization of a waveform without the need to place an apparatus near the focal point of the laser beam. The proposed approach represents a simple and powerful method for conducting waveform diagnostics on few-cycle laser sources. PMID- 30469573 TI - Designing double freeform surfaces for collimated beam shaping with optimal mass transportation and linear assignment problems. AB - We propose a method for designing refractive optical elements for collimated beam shaping in the geometrical optics approximation. In this method, the problem of finding a ray mapping is formulated as a linear assignment problem, which is a discrete version of the corresponding mass transportation problem. A method for reconstructing optical surfaces from a computed discrete ray mapping is proposed. The method is suitable for designing continuous piecewise-smooth optical surfaces. The design of refractive optical elements transforming beams with circular cross-section to variously shaped (rectangular, triangular, and cross shaped) beams with plane wavefront is discussed. The presented numerical simulation results confirm high efficiency of the designed optical elements. PMID- 30469574 TI - Surface-enhanced Raman scattering using nanoporous gold on suspended silicon nitride waveguides. AB - A hybrid integration of nanoporous gold with silicon nitride waveguide has been realized for surface-enhanced Raman spectroscopy (SERS) at 633-nm wavelength. The SERS signal is excited through 580-nm-thick T-shape suspended waveguides and collected through an objective lens. Raman spectra for different mesa width at either transverse electric (TE) or transverse magnetic (TM) mode are measured and compared. The localized surface plasmon resonance of the nanoporous gold can result in a waveguide and polarization-dependent SERS enhancement. The presented miniaturized SERS chips can work from visible to near-infrared wavelength and a wide application prospect could be expected. PMID- 30469575 TI - Electrical generation of terahertz blackbody radiation from graphene. AB - Recent experimental work on the application of graphene for novel illumination motivated us to present a theoretical study of the blackbody radiation emission from a freely suspended graphene driven by a dc electric field. Strong terahertz (THz) emission, with intensity up to mW/cm2, can be generated with increasing electric field strength due to the heating of electrons in graphene. We show that the intensity of the THz emission generated electrically from graphene depends rather sensitively on the lattice temperature in relatively weak electric fields, whereas it is less sensitive to the lattice temperature in relative strong electric fields. Our study highlights the practical application of graphene as intense THz source where the radiation is generated electrically. PMID- 30469576 TI - Real-time multi-channel SPR sensing based on DMD-enabled angular interrogation. AB - This paper reports a digital micro-mirror device (DMD)-enabled real-time multi channel biosensing system based on angular interrogation surface plasmon resonance (SPR). In the experiments, angular scanning is achieved by a DMD that facilitates SPR measurements using a single-point photodetector. In the four channel measurement setup, real-time monitoring of bovine serum albumin (BSA) and anti-BSA binding interactions is performed at various concentration levels. The experimental results have verified that the system has a resolution of 3.54 * 10 6 RIU (refractive index unit); and a detection limit of 9 ng/mL. The new DMD based SPR interrogation system presents a new design route for practical solid state SPR biosensing with a user-selectable range of interrogation, enhanced signal-to-noise ratio, and fast data throughput. PMID- 30469577 TI - Near-field probing the magnetic field vector of visible light with a silicon nanoparticle probe and nanopolarimetry. AB - Magnetic light-matter interaction plays a crucial role in nanophysics, such as in photonic topological insulators and metamaterials. Recent advances in all dielectric nanophotonics especially demand vectorial mapping of magnetic light at visible wavelengths. Here, we report that a novel functional nanoprobe decorated with a silicon nanoparticle predominantly senses both the vertical and lateral magnetic field, that is, the magnetic field vector, complementary to a metal nanoparticle probe detecting the local electric field vector. As a proof-of principle experiment, we demonstrate the mapping of magnetic field vectors in a transverse electric (TE) evanescent standing wave by this probe in a scanning near-field optical microscope (SNOM) with nanopolarimetry. It is for the first time that the full magnetic field vector of visible light, whose frequency exceeds 550 THz, can be directly detected with deep subwavelength resolution. Such functional probe and nanopolarimetry may pave the way toward complete vectorial near-field characterization over the whole visible band for nano-optics and subwavelength optics. PMID- 30469578 TI - Watt-level Tm:LiYF4 channel waveguide laser produced by diamond saw dicing. AB - Low-loss surface channel waveguides with a cross-section of 30 * 30 MUm2 are produced by diamond saw dicing of 6.2 at.% Tm3+, 3.5 at.% Gd3+:LiYF4 films grown by liquid phase epitaxy (LPE) on (001)-oriented bulk undoped LiYF4 substrates. Pumped by a Ti:Sapphire laser at 783 nm, a continuous-wave Tm:LiYF4 waveguide laser generated 1.30 W at 1880 nm (for pi-polarization) with a slope efficiency of 80% with respect to the absorbed pump power. The laser threshold was at 80 mW. The waveguide morphology was studied revealing low roughness (3 +/- 2 MUm) as expressed by the propagation losses of <0.3 dB/cm. A combination of LPE and diamond saw dicing is a promising technology for multi-watt single-mode channel waveguide lasers and amplifiers. PMID- 30469579 TI - Rounding noise effects' reduction for estimated movement of speckle patterns. AB - The problem of resolution enhancement for speckle patterns analysis-based movement estimation is considered. In our previous publications we showed that this movement represents the corresponding tilt vibrations of the illuminated object and can be measured as a relative spatial shift between time adjacent images of the speckle pattern. In this paper we show how to overcome the resolution limitation obtained when using an optical sensor available in an optical mouse and which measures the Cartesian coordinates of the shift as an integer number of pixels. To overcome such a resolution limitation, it is proposed here to use simultaneous measurements from the same illuminated spot by a few cameras (sensors) each having imaging lenses with different amounts of defocusing. The amount of defocusing defines the proportion ratio between actual changes in the tilt plane and measured shift between speckle images. To utilize the diversity of such ratios we apply a beam-forming signal processing approach that makes it possible to achieve different design criteria and improve the measurement accuracy, respectively. The validity and properties of the proposed solution are demonstrated by a few examples of in-vivo touchless measurements of human heart beat sounds. PMID- 30469580 TI - High-birefringence direct UV-written waveguides for use as heralded single-photon sources at telecommunication wavelengths. AB - Direct UV-written waveguides are fabricated in silica-on-silicon with birefringence of (4.9 +/- 0.2) * 10-4, much greater than previously reported in this platform. We show that these waveguides are suitable for the generation of heralded single photons at telecommunication wavelengths by spontaneous four-wave mixing. A pulsed pump field at 1060 nm generates pairs of photons in highly detuned, spectrally uncorrelated modes near 1550 nm and 800 nm. Waveguide-to fiber coupling efficiencies of 78-91 % are achieved for all fields. Waveguide birefringence is controlled through dopant concentration of GeCl4 and BCl3 using the flame hydrolysis deposition process. The technology provides a route towards the scalability of silica-on-silicon integrated components for photonic quantum experiments. PMID- 30469581 TI - Scaling the repetition rate of thulium-doped ultrafast soliton fiber lasers to the GHz regime. AB - GHz high repetition rate compact sources with femtosecond pulse durations and stable performance can enable a wide range of applications. In this paper, several high repetition rate ultrafast thulium fiber lasers with repetition rates varying between 532 MHz to 1.25 GHz are demonstrated with femtosecond pulse durations down to 426 fs. An approach of maintaining comparable pulse energies while scaling the repetition rates allows high-quality femtosecond mode-locking performance with low noise performance in thulium soliton lasers for the first time. PMID- 30469582 TI - Diode-pumped 915-nm Pr:YLF laser passively mode-locked with a SESAM. AB - A diode-pumped, passively mode-locked laser emitting at 915 nm with a praseodymium-doped yttrium lithium fluoride (Pr:YLF) crystal was demonstrated for the first time, to the best of our knowledge. Utilizing two polarization-combined blue pumping laser diodes (LDs) and a semiconductor saturable absorber mirror (SESAM), stable continuous-wave (CW) mode-locking operations were achieved with a maximum average output power of 408 mW and a slope efficiency of 10.8%. Laser pulse durations of 15 ps were obtained with a spectral full width at half maximum (FWHM) of 0.15 nm and a repetition rate of 1.53 GHz. PMID- 30469583 TI - Design of random and sparse metalens with matrix pencil method. AB - We propose a matrix pencil method for designing one- or two- dimensional (1D or 2D) metalenses with randomly distributed meta-atoms. In contrast to the standard random synthesis algorithm that only randomizes the position of the meta-atoms, the proposed method designs both the position and phase of each meta-atom rigorously. Several all-dielectric random metalenses, in both 1D and 2D operating at 220 GHz, are presented by using our proposed algorithm. Minimum reduction of focusing efficiency can be achieved with respect to a standard metalens with periodically arranged meta-atoms. In contrast to previously reported random metalenses, our random metalenses achieve much higher efficiency, while staying polarization-independent. This synthesis method will pave a way for future random metasurface-based device designs, which could have more degrees of freedom to information multiplexing. PMID- 30469584 TI - Enhancing the detectivity of an upconversion single-photon detector by spatial filtering of upconverted parametric fluorescence. AB - Due to advantages of low dark-count rate, reduced dead-time, and room-temperature operation, single-photon upconversion detectors for the telecom band are gaining strong interest as an alternative to other single-photon counters. In this work, we investigate the spatial and spectral distribution of upconverted spontaneous parametric downconversion (USPDC) noise, which is the typical dominant noise source in short-wavelength-pumped single-photon upconversion detectors for 1.5 um - 1.6 um. Our upconversion detector relies on a bulk periodically poled lithium niobate (PPLN) crystal and a 1064 nm intracavity pump system that spectrally translates the signal to the visible (~630 nm) where efficient, uncooled, and low dark-count Si based single-photon detectors operate. Experimental results show that the spectral and spatial distribution of the USPDC noise has a relatively broadband and radially modulated pattern that depends on the PPLN temperature, which is in good agreement with our numerical simulations. We also demonstrate that for narrow-linewidth 1575 nm signal photons, the dark-count rate can be significantly reduced by (1) using a phase-matched signal angle that corresponds to an upconverted output angle where the USPDC noise is at a "local minimum" and (2) applying a spatial filter (instead of an ultra-narrow bandpass filter) at the output. This simple spatial filtering technique resulted in a 14 dB dark-count rate reduction. Due to a corresponding decrease in the interaction length of the signal with the pump, the upconversion efficiency also decreased, but only with a 2.2 dB penalty. PMID- 30469585 TI - kW-class fiber-coupled diode laser source based on dense spectral multiplexing of an ultra-narrow channel spacing. AB - A dense spectral multiplexing structure based on the reflective volume Bragg gratings is introduced to realize the diode laser multiplexing with an ultra narrow channel spacing of 1.5 nm. With the combination of polarization multiplexing and coarse spectral multiplexing, a diode laser source producing 2045 W power from an output fiber with a core diameter of 105 um and NA of 0.2 is achieved at an injection current of 10 A. The electro-optical and optical-optical efficiency of the laser source is 42% and 76%, respectively. Experimental results demonstrate the ability of dense spectral multiplexing based on VBG to realize high output power and brightness. PMID- 30469586 TI - Improved correction for non-photochemical quenching of in situ chlorophyll fluorescence based on a synchronous irradiance profile. AB - In situ chlorophyll fluorometers have been used to quantify the distribution of chlorophyll concentration in natural waters for decades. However, chlorophyll fluorescence is depressed during daylight hours due to non-photochemical quenching (NPQ). Corrections attempted to date have provided improvement but still remain unsatisfactory, often over-estimating the expected value. In this study, we examine the relationship between NPQ and instantaneous Photosynthetically Active Radiation (iPAR) using field data from BGC-Argo floats equipped with Chlorophyll-a fluorometers and radiometers. This analysis leads to an improved NPQ correction that incorporates both iPAR and mixed layer depth (MLD) and is validated against data collected at sunrise or sunset. The optimal NPQ light threshold is found to be iPAR = 15 MUmol quanta m-2 s-1, and the proposed methods based on such a light threshold correct the NPQ effect more accurately than others, except in "shallow-mixing" waters (NPQ light threshold depth deeper than MLD). For these waters, an empirical-relationship-based method is proposed for improvement of NPQ correction using an iPAR profile. It is therefore recommended that, for optimal NPQ corrections, profiling floats measuring chlorophyll fluorescence in daytime be equipped with iPAR radiometers. PMID- 30469587 TI - Detecting the ocean surface from the raw data of the MABEL photon-counting lidar. AB - With much smaller footprints (approximately a few tens of meters), the data of a laser altimeter are promising for obtaining the sea level near offshore areas, where radar altimeters with larger footprints cannot operate. However, the current ocean surface detection methods for a photon-counting lidar cannot effectively eliminate the noise photons when measuring the sea surface, thereby introducing a ranging bias. In this paper, a new ocean surface detection method is derived based on the JONSWAP (Joint North Sea Wave Project) wave spectrum and LM (Levenberg-Marquardt) nonlinear least-squares fitting. Using the data photons that are captured by the NASA MABEL (Multiple Altimeter Beam Experimental Lidar) photon-counting lidar, the new method is tested and compared to the MABEL standard result. The new method achieved better profile detection of sea surfaces and successfully discarded the noise photons in a sub-layer below the sea surface from the MABEL standard result. By reconstructing the "accumulated waveform", we found that the noise photons in the sub-layer produce small tails after the main waveform, which introduces an overestimated ranging bias of 9 cm. This difference of 9 cm is similar to the sea level bias of 10 cm that was obtained from the ICESat/GLAS laser altimeter data and the TOPEX/Poseidon radar altimeter data in an earlier study, which limited the use of laser altimeter data. According to the analysis in this paper, we can partially interpret what occurred for the ICESat/GLAS waveform tails when ICESat was measuring sea surfaces. The newly derived method can protect the MABEL and incoming ICESat-2 data photons from noise photon interference and ranging bias when measuring the sea surface. PMID- 30469588 TI - Snapshot quantitative phase microscopy with a printed film. AB - This paper proposes a low-cost snapshot quantitative phase imaging approach. The setup is simple and adds only a printed film to a conventional microscope. The phase of a sample is regarded as an additional aberration of the optical imaging system. And the image captured through a phase object is modeled as the distorted version of a projected pattern. An optimization algorithm is utilized to recover the phase information via distortion estimation. We demonstrate our method on various samples such as a micro-lens array, IMR90 cells and the dynamic evaporation process of a water drop, and our approach has a capability of real time phase imaging for highly dynamic phenomenon using a traditional microscope. PMID- 30469589 TI - Spectral shaping of an OPCPA preamplifier for a sub-20-fs multi-PW laser. AB - We developed an OPCPA preamplifier with an actively shaped output spectrum to obtain a sub-20-fs-duration pulse for a 4-PW laser. The active spectral shaping was facilitated by controlling the temporal profile of a pump pulse in the OPCPA preamplifier. By optimizing the output spectrum of the OPCPA to compensate for the gain-depletion effect in the 4-PW laser, a final laser pulse with a broad spectrum of 101-nm in width (FWHM), resulting in a short pulse duration of 17 fs, was achieved. PMID- 30469590 TI - Improved color uniformity in white light-emitting diodes using newly developed phosphors. AB - We report novel white light-emitting diode (WLED) devices that improve emission color uniformity. The WLEDs consist of a violet chip and a mixed-phosphor layer of three phosphors previously developed by us. It is found that each phosphor does not reabsorb the luminescence from the other phosphors; consequently, the emission color of the WLEDs does not get affected by the mounted quantity of phosphors and/or the variation in chip emission wavelength. Furthermore, an encapsulated WLED with a hemispherical dome-shaped mixed-phosphor layer enables an area to be irradiated with uniform color, producing an excellent color rendering index and improved luminous flux because of the reduced inelastic scattering loss in the phosphor layer. PMID- 30469591 TI - Frequency domain transformation optics for diffusive photon density waves' cloaking. AB - We make use of transformation optics technique to realize cloaking operation in the light diffusive regime, for spherical objects. The cloak requires spatially heterogeneous anisotropic diffusivity, as well as spatially varying speed of light and absorption. Analytic calculations of Photon's fluence confirm minor role of absorption in reduction of far-field scattering, and a monopole fluence field converging to a constant in the static regime in the invisibility region. The latter is in contrast to acoustic and electromagnetic cloaks, for which the field vanishes inside the core. These results are finally discussed in the context of mass diffusion, where cloaking can be achieved with a heterogeneous anisotropic diffusivity. PMID- 30469592 TI - Multiple OAM vortex beams generation using 1-bit metasurface. AB - In this paper, a novel method to generate multiple orbital angular momentum (OAM) vortex beams is proposed using a 1-bit metasurface. Through carefully adjusting the phase shift of each element, mirror-symmetrical OAM vortex beams are generated in targeted directions by a 1-bit metasurface under plane-wave illumination. Moreover, the topological charges of the generated vortex beams are opposite. Based on this phenomenon, dual-beam, four-beam, and full-space OAM vortex waves are respectively studied and generated by conducting full-wave simulations. Finally, a prototype of the proposed metasurface is fabricated and measured in an anechoic chamber. The measurement results show that multiple OAM vortex beams are successfully generated and detected, verifying the effectiveness of the proposed method. PMID- 30469593 TI - Aberration fields of off-axis astronomical telescopes induced by rotational misalignments. AB - Due to the absence of rotational symmetry, off-axis astronomical telescopes with off-set pupil become subject to rotational misalignments. Rotational misalignments of large off-axis mirrors with reference to their geometric center can greatly degrade the imaging quality. This paper presents an in-depth discussion on the net aberration fields of off-axis astronomical telescopes induced by rotational misalignments. Aberration function of off-axis telescopes with rotational misalignments is derived based on the framework of nodal aberration theory. Expressions of several important aberrations are obtained under some approximations. Then the specific field characteristics of these aberrations are presented and explicated. Meanwhile, we demonstrate that rotational misalignments can be converted to a kind of surface decenters; on the other hand, the effects of rotational misalignments have their special features which are different from the effects of general surface decenters. Besides, some other insightful discussions are further presented. This work is also applicable to the rotational misalignments of the off-axis segments of primary mirror in segmented mirror astronomical telescopes. PMID- 30469594 TI - Polarization-independent metasurface lens employing the Pancharatnam-Berry phase. AB - Metasurface optical elements, optical phased arrays constructed from a dense arrangement of nanoscale antennas, are promising candidates for the next generation of flat optical components. Metasurfaces that rely on the Pancharatnam Berry phase facilitate complete and efficient wavefront control. However, their operation typically requires control over the polarization state of the incident light to achieve a desired optical function. Here, we circumvent this inherent sensitivity to the incident polarization by multiplexing two metasurfaces that were designed to achieve the same optical function with incident light of opposite helicity. We analyze the optical performance of different multiplexing approaches, and demonstrate a subwavelength random interleaved polarization independent metasurface lens operating in the visible spectrum, providing a diffraction-limited spot size for the shared-aperture. PMID- 30469595 TI - Ultrasensitive optical sensing in aqueous solution based on microfiber modal interferometer. AB - In this paper, an ultrahigh sensitivity sensing in aqueous solution for microfiber modal interferometer (MMI) is realized. The group refractive index (RI) difference between HE11 and HE12 mode will come down to 0 at a certain wavelength, resulting in ultrahigh sensitivity near this wavelength. MMI with different diameters have their individual ultrasensitive wavelength band, which indicates the broad range of optional probing wavelength and more liberal diameter condition on fiber fabrication. In the experimentation, infrared absorption band in water around 1360-1600nm is easy to keep away by adjusting the microfiber diameter. As a result, an ultrahigh sensitivity of 14.95 pm/ppm is realized for sodium nitrate at 1320nm, whose equivalent sensitivity is about 1.26 * 105-nm/RIU for RI, which is much higher than most of the existing naked sensors with magnitude of 102-104nm/RIU. PMID- 30469596 TI - Real time g(2) monitoring with 100 kHz sampling rate. AB - We introduce a technique to determine photon correlations of optical light fields in real time. The method is based on ultrafast phase-randomized homodyne detection and allows us to follow the temporal evolution of the second-order correlation function g(2)(0) of a light field. We demonstrate the capabilities of our approach by applying it to a laser diode operated in the threshold region. In particular, we are able to monitor the emission dynamics of the diode switching back and forth between lasing and spontaneous emission with a g(2)(0)-sampling rate of 100 kHz. PMID- 30469597 TI - Off-axis virtual-image display and camera by holographic mirror and blur compensation. AB - We propose off-axis virtual-image display and camera systems, which integrate a vertically-standing holographic off-axis mirror, blur-compensation optical systems, and digital imaging devices. In the system, the holographic mirror is used for an off-axis reflector, which realizes an upright and thin screen for virtual-image formation. By combining it with a display unit, an off-axis virtual image display is realized, where the virtual image can be seen behind the upright holographic mirror. Simultaneously, by combining it with a camera unit, an off axis camera is implemented, which realizes frontal shooting of objects by a camera placed at an off-axis position. Since both the off-axis display and the camera can be implemented by a single holographic mirror, it can be applied to a two-way visual-telecommunication system with a thin screen, which implements eye contact and the observer--image distance. A problem with the proposed system is image blur, which is caused by the chromatic dispersion of the holographic mirror. To solve this, we designed optical blur-compensation systems using a diffractive optical element and a diffuser or a lens. Experimental results verify the concept of the proposed systems with clarifying the effect of designed blur compensation methods. PMID- 30469598 TI - Resolution enhancement in laser scanning microscopy with deconvolution switching laser modes (D-SLAM). AB - Laser scanning microscopy is limited in lateral resolution by the diffraction of light. Superresolution methods have been developed since the 90s to overcome this limitation. However superresolution is generally achieved at the expense of a greater complexity (high power lasers, very long acquisition times, specific fluorophores) and limitations on the observable samples. In this paper we propose a method to improve the resolution of confocal microscopy by combining different laser modes and deconvolution. Two images of the same field are acquired with the confocal microscope using different laser modes and used as inputs to a deconvolution algorithm. The two laser modes have different Point Spread Functions and thus provide complementary information leading to an image with enhanced resolution compared to using a single confocal image as input to the same deconvolution algorithm. By changing the laser modes to Bessel-Gauss beams we were able to further improve the efficiency of the deconvolution algorithm and obtain images with a residual Point Spread Function having a width of 0.14 lambda (72 nm at a wavelength of 532 nm). This method only requires a laser scanning microscope and is not dependent on certain specific properties of fluorescent proteins. The proposed method requires only a few add-ons to classical confocal or two-photon microscopes and can easily be retrofitted into an existing commercial laser scanning microscope. PMID- 30469599 TI - Quantitative traceable temperature measurement using novel thermal imaging camera. AB - Conventional thermal imaging cameras, based on focal-plane array (FPA) sensors, exhibit inherent problems: such as stray radiation, cross-talk and the calibration uncertainty of ensuring each pixel behaves as if it were an identical temperature sensor. Radiation thermometers can largely overcome these issues, comprising of only a single detector element that can be optimised and calibrated. Although the latter approach can provide excellent accuracy for single-point temperature measurement, it does not provide a temperature image of the target object. In this work, we present a micromechanical systems (MEMS) mirror and silicon (Si) avalanche photodiode (APD) based single-pixel camera, capable of producing quantitative thermal images at an operating wavelength of 1 um. This work utilises a custom designed f-theta wide-angle lens and MEMS mirror, to scan +/- 30 degrees in both x- and y-dimensions, without signal loss due to vignetting at any point in the field of view (FOV). Our single-pixel camera is shown to perform well, with 3 degrees C size-of-source effect (SSE) related temperature error and can measure below 700 degrees C whilst achieving +/- 0.5 degrees C noise related measurement uncertainty. Our measurements were calibrated and traceable to the International Temperature Scale of 1990 (ITS-90). The combination of low SSE and absence of vignetting enables quantitative temperature measurements over a spatial field with measurement uncertainty at levels lower than would be possible with FPA based thermal imaging cameras. PMID- 30469600 TI - Processing-based approach for resolving the sample optic axis in endoscopic polarization-sensitive optical coherence tomography. AB - Fiber-based polarization-sensitive optical coherence tomography (PS-OCT) that utilizes a rotationally-scanning catheter has a variety of potential biomedical applications in luminal organ systems due to its ability to provide intrinsic contrast for birefringent tissue. Incorporating the optic axis (OA) of the tissue greatly enhances this potential by also permitting information about the orientation of the tissue to be extracted; however, measurement distortion that occurs has up to this point made it impossible to obtain accurate sample OA measurements. In this paper we present a straightforward calibration technique that allows the sample OA to be recovered. This technique requires no hardware modifications making it generally applicable, and as a result has tremendous potential in improving the utility of endoscopic PS-OCT image data. PMID- 30469601 TI - Video-rate centimeter-range optical coherence tomography based on dual optical frequency combs by electro-optic modulators. AB - Imaging speed and range are two important parameters for optical coherence tomography (OCT). A conventional video-rate centimeter-range OCT requires an optical source with hundreds of kHz repetition rate and needs the support of broadband detectors and electronics (>1 GHz). In this paper, a type of video-rate centimeter-range OCT system is proposed and demonstrated based on dual optical frequency combs by leveraging electro-optic modulators. The repetition rate difference between dual combs, i.e. the A-scan rate of dual-comb OCT, can be adjusted within 0~6 MHz. By down-converting the interference signal from optical domain to radio-frequency domain through dual comb beating, the down-converted bandwidth of the interference signal is less than 22.5 MHz which is at least two orders of magnitude lower than that in conventional OCT systems. A LabVIEW program is developed for video-rate operation, and the centimeter imaging depth is proved by using 10 pieces of 1-mm thick glass stacked as the sample. The effective beating bandwidth between two optical comb sources is 7 nm corresponding to ~108 comb lines, and the axial resolution of the dual-comb OCT is 158 um. Dual optical frequency combs provide a promising solution to relax the detection bandwidth requirement in fast long-range OCT systems. PMID- 30469602 TI - Insulator string leakage current-monitoring sensor based on fiber Bragg grating. AB - A novel insulator string leakage current-monitoring sensor based on a fiber Bragg grating (FBG), cantilever beam, and spiral coil is demonstrated. The spiral coil is used to convert the leakage current into the force exerted on the cantilever structure, which is obtained by measuring the strain of the FBG. Experimental results show that the linear regression correlation coefficient is 0.99964. In addition, although the leakage current measurement is not sufficiently accurate, the 50-Hz component measurement is accurate. The sensor is suitable for use as an insulator string flashover warning and has promising prospects for future grid security protection applications. PMID- 30469603 TI - Real-time monitoring and gradient feedback enable accurate trimming of ion implanted silicon photonic devices. AB - Fabrication errors pose significant challenges on silicon photonics, promoting post-fabrication trimming technologies to ensure device performance. Conventional approaches involve multiple trimming and characterization steps, impacting overall fabrication complexity. Here we demonstrate a highly accurate trimming method combining laser annealing of germanium implanted silicon waveguide and real-time monitoring of device performance. Direct feedback of the trimming process is facilitated by a differential spectroscopic technique based on photomodulation. The resonant wavelength trimming accuracy is better than 0.15 nm for ring resonators with 20-um radius. We also realize operating point trimming of Mach-Zehnder interferometers with germanium implanted arms. A phase shift of 1.2pi is achieved by annealing a 7-MUm implanted segment. PMID- 30469604 TI - Investigation of the error self-compensation effect associated with direct broad band monitoring of coating production. AB - Computational manufacturing experiments are used to detect the types of optical coatings that are showing the presence of a strong error self-compensation effect in the coating production with direct broad band monitoring. It is shown that predictions made on the basis of these experiments coincide with the predictions of the previously developed rigorous mathematical approach to the investigation of the error self-compensation effect. PMID- 30469605 TI - Moire-free fingerprint sensors based on multilayer oxide-metal-oxide electrodes. AB - The display quality of touchscreen devices with on-screen fingerprint sensors is reduced by moire patterns, interference phenomena caused by an overlap between the pixel pattern of the display, and the electrode pattern of the fingerprint sensor. A promising strategy for resolving this issue is to reduce the visibility of the moire pattern, by including a filling layer with a transmittance similar to that of the electrodes, between the different patterns. We propose a moire free fingerprint sensor that uses an oxide-metal-oxide (IZO/Ag/IZO) multilayer as a highly transparent electrode. To verify the moire reduction effect, we conducted a two-dimensional spectral analysis to calculate the spatial frequencies of the superimposed image of the display and the sensor patterns, and demonstrated experimentally that the proposed electrode greatly reduces the undesirable moire phenomenon. PMID- 30469606 TI - Improving modulation bandwidth of c-plane GaN-based light-emitting diodes by an ultra-thin quantum wells design. AB - The GaN-based light emitting diodes (LEDs) have a great potential for visible light communication (VLC) due to their ubiquitous application in general lighting, but the modulation bandwidth of conventional c-plane LEDs is limited by carrier recombination rate in InGaN quantum wells (QWs) due to the polarization field-induced quantum confined Stark effect (QCSE). Furthermore, the high modulation bandwidth on c-plane sapphire substrates can only be achieved at high current densities. Here, blue LEDs with ultra-thin InGaN QWs (1nm) and GaN barriers (3nm) are grown on c-plane sapphire substrate to suppress QCSE and extend the cut-off frequency from 214 MHz for conventional LEDs to 536 MHz at a current density of 2.5 kA/cm2, which is comparable to devices grown on semi-polar substrates. PMID- 30469607 TI - Metallic mesh devices-based terahertz parallel-plate resonators: characteristics and applications. AB - The capability to design, fabricate, and optimize metamaterials based on various structures and material platforms has been crucial for the rapid development of modern terahertz (THz) technology. While the detailed structures of artificial unit cells within a metamaterial is certainly worth investigating, there has been increasing demand to integrate novel metamaterials with a traditional functional photonic device to form a hybrid device, whose performance is so significantly improved as to be promising for real-world applications. In this study, we proposed, for the first time, a THz parallel-plate resonator based on metallic mesh devices (MMDs) for chemical sensing applications. We studied the influences of various structural parameters through simulations, fabricated MMD-based resonator devices, and fully characterized the device performance through THz spectroscopy experiments. Furthermore, we experimentally demonstrated that our device can detect a doxycycline hydrochloride aqueous solution whose concentrations is as low as 1 mg L-1 through resonance frequency shifts, evidencing the device sensitivity capable of delicate chemical sensing tasks. Our work presents a practical and low cost architecture for chemical sensing using THz radiation, which opens new avenues for numerous useful THz devices based on metamaterials. PMID- 30469608 TI - Dispersion control for temporal contrast optimization. AB - We investigate the temporal contrast of the Light Wave Synthesizer 20 (LWS-20): a powerful, few-cycle source based on the optical parametric synthesizer principle. Saturation effects in the RF amplifier driving the acousto-optic programmable dispersive filter (AOPDF) were found to degrade the coherent contrast for non monotonic group delay corrections. We subsequently present a new dispersion scheme and design a novel transmission grism-based stretcher optimized for LWS 20. The resulting temporal contrast of the amplified, compressed output pulses is improved by 2-4 orders of magnitude compared to the former design. PMID- 30469609 TI - Proof of concept for ultrahigh resolution photonic spectral processor. AB - We propose a novel photonic spectral processor which overcomes current 0.8GHz spectral resolution limitation. The new spectral processor uses a Fabry Perot interferometer array located before the dispersive element of the system, thus significantly improving the spectral separation resolution, which is now limited by the Fabry Perot interferometers' full width at half maximum rather than the dispersive element's spectral resolution. A proof of concept experiment was performed utilizing two Fabry-Perot interferometers and a diffractive optical grating with a spectral resolution of 6.45GHz, achieving high spectral resolution of 577MHz. Further improvement of the experimental setup can result in resolution of about 50MHz. PMID- 30469610 TI - Single-particle photothermal imaging via inverted excitation through high-Q all glass toroidal microresonators. AB - Whispering-gallery mode (WGM) microresonators have recently been employed as platforms for label-free single-molecule and single-particle detection, imaging, and spectroscopy. However, innovations in device geometry and integration are needed to make WGM microresonators more versatile for biological and chemical applications. Particularly, thick device substrates, originating from wafer-scale fabrication processing, prevent convenient optical interrogation. In this work, we fabricate all-glass toroidal microresonators on a coverslip thickness (~170 MUm) substrate, enabling excitation delivery through the sample, simplifying optical integration. Further, we demonstrate the application of this new geometry for single-particle photothermal imaging. Finally, we discover and develop simulations to explain a non-trivial astigmatism in the point spread function (PSF) arising from the curvature of the resonator. PMID- 30469611 TI - Electricity mediated plasmonic tip engineering on single Ag nanowire for SERS. AB - An electricity-mediated plasmonic engineering was applied on a single Ag nanowire to engineer its tip for surface-enhanced Raman scattering (SERS). Under this constant photoelectric field treatment, a significant sharpening of the tip and reduction of the surface fluctuation was observed for the Ag nanowire tip via in situ atomic force microscopy. A significant SERS signal enhancement was thus obtained after the tip engineering. The relevant dynamic mechanisms of the tip engineering, including the light-induced plasmonic phase transition and electrostatic force driven flow on the Ag nanowire tip are discussed in detail. It is expected that this type of tip engineering will greatly enhance the signal of single metal nanowire SERS probes and provide new insights into fabrication technologies for metal nanostructures. PMID- 30469612 TI - Efficient volumetric method of moments for modeling plasmonic thin-film solar cells with periodic structures. AB - Metallic nanoparticles (NPs) support localized surface plasmon resonances (LSPRs), which enable to concentrate sunlight at the active layer of solar cells. However, full-wave modeling of the plasmonic solar cells faces great challenges in terms of huge computational workload and bad matrix condition. It is tremendously difficult to accurately and efficiently simulate near-field multiple scattering effects from plasmonic NPs embedded into solar cells. In this work, a preconditioned volume integral equation (VIE) is proposed to model plasmonic organic solar cells (OSCs). The diagonal block preconditioner is applied to different material domains of the device structure. As a result, better convergence and higher computing efficiency are achieved. Moreover, the calculation is further accelerated by two-dimensional periodic Green's functions. Using the proposed method, the dependences of optical absorption on the wavelengths and incident angles are investigated. Angular responses of the plasmonic OSCs show the super-Lambertian absorption on the plasmon resonance but near-Lambertian absorption off the plasmon resonance. The volumetric method of moments and explored physical understanding are of great help to investigate the optical responses of OSCs. PMID- 30469613 TI - Polarimetric image recovery in turbid media employing circularly polarized light. AB - Circular polarization memory is a well-known phenomenon indicating that the circular polarization light can persist better its polarization property during propagating through turbid media compared with the linear polarization light. Therefore, in principle, using circularly polarized light can probably improve the quality of image recovery in dense turbid media than using the linearly polarized light. In this paper, we propose a new polarimetric image recovery method in dense turbid media with the illumination light of circular polarization, and we realize the image recovery combining the circular polarization information and linearly polarization information. The real-world experiment results demonstrate that the proposed method is more effective than previous methods, including the traditional polarimetric image recovery method by Schechner's [Appl. Opt.42, 511 (2003)] based on linear polarization. PMID- 30469614 TI - Novel on chip rotation detection based on the acousto-optic effect in surface acoustic wave gyroscopes. AB - An Acousto-Optic Gyroscope (AOG) consisting of a photonic integrated device embedded into two inherently matched piezoelectric surface acoustic wave (SAW) resonators sharing the same acoustic cavity is presented. This constitutes the first demonstration of a micromachined strain-based optomechanical gyroscope that uses the effective index of the optical waveguide due to the acousto-optic effect rather than conventional displacement sensing. The theoretical analysis comparing various photonic phase sensing techniques is presented and verified experimentally for the cases based on a Mach-Zehnder interferometer, as well as a racetrack resonator. This first prototype integrates acoustic and photonic components on the same lithium niobate on insulator (LNOI) substrate and constitutes the first proof of concept demonstration of the AOG. This approach enables the development of a new class of micromachined gyroscopes that combines the advantages of both conventional microscale vibrating gyroscopes and optical gyroscopes. PMID- 30469615 TI - Foveated imaging for near-eye displays. AB - The angular resolution of current near-eye display devices is still far below human-eye acuity. How to achieve retina-level resolution while keeping wide field of-view (FOV) remains a great challenge. In this work, we demonstrate a multi resolution foveated display with two display panels and an optical combiner. The first display panel provides a wide FOV but relatively low resolution for the surrounding region, while the second one offers an ultra-high resolution for the central fovea region, by an optical minifying system which enhances the effective resolution by 5 *. In addition, a switchable Pancharatnam-Berry phase deflector is employed to shift the high-resolution region. The proposed design effectively reduces the pixelation and screen-door effect in near-eye displays. PMID- 30469616 TI - Fourier rainbow holography. AB - We present Fourier rainbow holographic imaging approach. It involves standard laser holographic recording and novel horizontal parallax only holographic display. In the display, the rainbow effect is introduced in an illumination module by high-frequency diffraction grating and white light LED source. The display is addressed by Fourier rainbow digital hologram (FRDH) encoding defocused object field with removed spatial frequency components in one direction by hologram slitting and without spherical phase factor. Theoretically and experimentally it is shown that the method extends the viewing zone of the classical viewing window display in vertical and longitudinal directions, thus the comfort of observation is improved. It is also numerically and experimentally validated that the numerical slitting applied within FRDH generation improves reconstruction depth of the display, here up to 400 mm. PMID- 30469617 TI - Dynamic characteristics of stimulated Raman scattering in high power fiber amplifiers in the presence of mode instabilities. AB - Impact of mode instability on dynamic characteristics of stimulated Raman scattering in high power fiber amplifiers has been studied for the first time, which reveals another characterization of mode instability from the aspect of optical spectrum. It shows that, after the onset of mode instability, the measured light spectrums, especially the Raman light spectrums, are different from those without mode instability, which become burr-like. As mode instability evolves into different stages, the intensity of stimulated Raman scattering effects as laser power increasing also behaves differently. During the transition region, the stimulated Raman scattering effect becomes stronger as the lasing power increases until the mode instability evolves into chaotic regions, where the stimulated Raman scattering effect weakens. The effect of stimulated Raman scattering on mode instability has also been studied. Due to that the stimulated Raman scattering effect is weak and that the fraction of Raman light is only a few percent, the stimulated-Raman-scattering-induced mode instability has not been observed in the experiment, and the observed mode instability is induced by ytterbium ion gain of signal laser. It also revealed that the stimulated Raman scattering has negligible influence on the mode instability induced by ytterbium ion gain. PMID- 30469618 TI - New model of the fiber coupling efficiency of a partially coherent Gaussian beam in an ocean to fiber link. AB - The fiber coupling efficiency between the turbulent ocean to fiber of a partially coherent Gaussian beam propagating through the weak to strong anisotropic oceanic turbulence is studied. We derive the expression of new model of the fiber coupling efficiency for the partially coherent Gaussian beam. The numerical analyses reveal that larger inner scale and anisotropic factor, weaker oceanic turbulence strength, and smaller temperature-salinity contribution ratio will lead to a higher coupling efficiency; a longer wavelength, an suitable aperture diameter of the coupling lens, an optimum focal length and beam size, and a higher coherent degree will improve the fiber coupling efficiency. Our fiber coupling efficiency is higher than the previous fiber coupling efficiency. PMID- 30469619 TI - Experimental demonstration of 50 Gb/s (2 * 25 Gb/s) TDM/WDM PON over 64-way power split using O-band up/down transmission over 20 km with dynamic bandwidth allocation and SDN control. AB - For the accommodation of mobile, business, and residential service in the same optical distribution network, we experimentally demonstrate 50 Gb/s (25 Gb/s * 2 wavelengths) wireless and wired service converged optical access network with 64 way power split over 20 km of single mode fiber in 1300 nm band. Applying simple Reed-Solomon based forward-error-correction and a cost-effective avalanche photodiode receiver without using an optical amplifier realize the 64-way power split. Accommodating dynamic bandwidth allocation and open interface control with OpenDaylight (ODL) controller via network configuration protocol (NETCONF) interface are demonstrated. Furthermore, error-free packet transmission of 50 Gb/s with low latency and guaranteed bandwidth are successfully demonstrated. PMID- 30469620 TI - Passive Q-switching induced by few-layer MoTe2 in an Yb:YCOB microchip laser. AB - We report on passive Q-switching action induced by a few-layer MoTe2 saturable absorber in an Yb:YCa4O(BO3)3 (Yb:YCOB) microchip laser. With a sapphire-based few-layer MoTe2 incorporated into the 4 mm long plane-parallel resonator of the Yb:YCOB microchip laser, efficient stable passively Q-switched operation was achieved under output couplings of 40%-70%, producing, at an incident pump power of 5.0 W, an average output power of 1.58 W at a repetition rate of 704 kHz with a slope efficiency of 36%; the pulse energy and peak power were respectively 2.25 MUJ and 40.8 W, while the shortest pulse duration obtained was 52 ns. PMID- 30469621 TI - Spatial integration and differentiation of optical beams in a slab waveguide by a dielectric ridge supporting high-Q resonances. AB - We show that a very simple structure consisting of a single subwavelength dielectric ridge on the surface of a slab waveguide enables spatial integration and differentiation of the profile of optical beams propagating in the waveguide. The integration and differentiation operations are performed in reflection and in transmission, respectively, at oblique incidence of the beam impinging on the ridge. The implementation of these operations is associated with the resonant excitation of a cross-polarized eigenmode of the ridge. We demonstrate that the quality factor of the resonances strongly varies along the dispersion curves and allows one to achieve the required tradeoff between the integration (or differentiation) quality and the amplitude of the resulting beam. The presented rigorous numerical simulation results confirm high-quality integration and differentiation. The proposed integrated structure may find application in ultrafast all-optical analog computing and signal processing systems. PMID- 30469622 TI - Lyman-beta narrowband coatings with strong Lyman-alpha rejection. AB - Novel narrowband multilayer coatings efficient at a wavelength as short as 100 mn are presented, which pushes shortwards the existing limit of reported narrowband multilayers. Such limit had been established at ~120 nm, close to the MgF2 cutoff wavelength. The new multilayers combine layers of Al, LiF, and SiC, in an Al/LiF/SiC/LiF multilayer design (four layers, starting with the innermost layer). Among these materials, Al and LiF are deposited by evaporation and SiC by ion-beam-sputtering. In addition to a high, narrow peak close to H Lyman beta (102.6 nm), these multilayers simultaneously provide a very small reflectance at H Lyman alpha (121.6 nm). This combined performance is demanded in space instrumentation for astrophysics and solar physics observations among others, where imaging the sky at the important diagnostic spectral line of Lyman beta line requires rejecting the frequently much more intense background at Lyman alpha line. Such is the case for solar corona observations at Lyman beta, which is masked by the strong Lyman alpha line. The multilayer peak is placed close to another important diagnostic tool: the OVI doublet at 103.2 and 103.8 nm. The target of small reflectance at 121.6 nm was seen to be the most critical. The best strategy in multilayer preparation was to prepare it with such minimum reflectance at slightly shorter wavelengths so that the coating evolved to shift it longwards over time. Multilayers kept a remarkable 102.6 nm/121.6 nm reflectance ratio over time in spite of some performance degradation. Hence, a multilayer coating aged of 4 years kept a reflectance of 43% at 102.6 nm and 0.2% at 121.6 nm. PMID- 30469623 TI - Multi-band plasmonic color filters for visible-to-near-infrared image sensors. AB - We propose a plasmonic color filter consisting of a single aperture surrounded by concentric periodic corrugations for simultaneous imaging of a spectral range from the visible to the near-infrared. The incident light coupled with surface plasmons propagates through the sub-wavelength aperture as beaming light. The beaming light transmission is able to suppress the spatial color cross-talk between the pixels in an image sensor. We analyzed the transmission characteristics of a plasmonic color filter with periodic corrugations in a silver thin film by using the finite-difference time-domain algorithm. We demonstrated a multi-band transmission wavelength selectivity, of about 100 nm, for the spectral bandwidth ranging from visible to near-infrared. The simultaneous discrimination of visible and near-infrared light with a high color purity by the plasmonic color filter achieves both improved image recognition and smaller system-size compared with conventional systems, which is particularly important for applications such as vehicle-mounted cameras, security, and biological tissue engineering. PMID- 30469624 TI - Ultrashort pulse synthesis for energy concentration control in nanostructures. AB - A waveform synthesis technique is introduced and applied to the femtosecond pulse excitation of plasmonic nanoantennas for temporal and spatial energy concentration control. The waveform synthesis process is based on phase and polarization shaping and an understanding of the electromagnetic response of the nanostructure. Linear and radial nano-dipole arrays are analyzed before the log periodic toothed nanoantenna is investigated as a nanostructure capable of combining the benefits of the nano-dipole arrays. The consistent superiority of the log-periodic toothed nanoantenna is established by comparing its electromagnetic response to that of the radial nano-dipole array using a variety of synthesized excitation waveforms. PMID- 30469625 TI - Loss-induced transparency in optomechanics. AB - We study optomechanically induced transparency (OMIT) in a compound system consisting of coupled optical resonators and a mechanical mode, focusing on the unconventional role of loss. We find that optical transparency can emerge at the otherwise strongly absorptive regime in the OMIT spectrum, by using an external nanotip to enhance the optical loss. In particular, loss-induced revival of optical transparency and the associated slow-to-fast light switch can be identified in the vicinity of an exceptional point. These results open up a counterintuitive way to engineer micro-mechanical devices with tunable losses for e.g., coherent optical switch and communications. PMID- 30469626 TI - Holographic optical trapping Raman micro-spectroscopy for non-invasive measurement and manipulation of live cells. AB - We present a new approach for combining holographic optical tweezers with confocal Raman spectroscopy. Multiple laser foci, generated using a liquid crystal spatial light modulator, are individually used for both optical trapping and excitation of spontaneous Raman spectroscopy from trapped objects. Raman scattering from each laser focus is spatially filtered using reflective apertures on a digital micro-mirror device, which can be reconfigured with flexible patterns at video rate. We discuss operation of the instrument, and performance and viability considerations for biological measurements. We then demonstrate the capability of the instrument for fast, flexible, and interactive manipulation with molecular measurement of interacting live cell systems. PMID- 30469627 TI - Compressive spectral imaging system based on liquid crystal tunable filter. AB - Liquid crystal tunable filters (LCTF) are extensively used in hyperspectral imaging systems to successively acquire different spectral components of scenes by adjusting the center wavelength of the filter. However, the spectral and spatial resolutions of the imager are limited by the bandwidth of LCTF, and the pitch dimension of the detector, respectively. This paper applies compressive sensing principles to improve both of the spatial and spectral resolutions of the LCTF-based hyperspectral imaging system. An accurate transmission model of the LCTF is used to represent its bandpass filtering effects on the spectra. In addition, a random coded aperture placed behind the LCTF is used to modulate the spectral images in the spatial domain. Then, the three-dimensional encoded spectral images are projected onto a two-dimensional detector. Benefiting from the spectral-dependent transmission property of the LCTF, information of the entire spectrum is collected by a few snapshots using different center wavelengths of the LCTF. Super-resolution hyperspectral images can be reconstructed from a small set of compressive measurements by solving a convex optimization problem. Simulations and experiments show that the proposed method can effectively improve the spectral and spatial resolutions of traditional LCTF based spectral imager without changing the structures of the LCTF and detector. Finally, a multi-channel spectral coding method is proposed to further increase the compression capacity of the system. PMID- 30469628 TI - Output characteristics of two-circle coaxial optical fiber bundle with regard to three-dimensional tip clearance. AB - A two-circle coaxial optical fiber bundle is a type of optical sensor which has been widely used in non-contact radial displacement measurement applications. This paper has focused on output characteristics of a two-circle coaxial optical fiber bundle used as a measurement unit in a probe designed to measure a three dimensional tip clearance. First, a model that could calculate intensity point-by point on each receiving fiber with a simplified algorithm of overlap area was established, an aperture angle compensation algorithm was then proposed to improve the performance of the model. In order to test the reliability of the model, an experiment was done with different three-dimensional displacement of the reflector. Comparison between experimental and simulation results indicates the model built in this article could better describe how three-dimensional displacement of reflector affects the output of the bundle than previous studies. PMID- 30469629 TI - Gate tunable surface plasmon resonance enhanced graphene/Ag nanoparticles polymethyl methacrylate/graphene/p-GaN heterostructure light-emitting diodes. AB - By combining the surface plasmon enhancement technique with gating effect, a tunable blue lighting emitting diode (LED) based on graphene/Ag nanoparticles (NPs)-polymethyl methacrylate (PMMA)/graphene/p-GaN heterostructure has been achieved. The surface plasmon enhancement is introduced through spin-coating Ag nanoparticles on graphene/p-GaN heterostructure while the gating effect is demonstrated through a graphene/PMMA/graphene sandwich structure, where the top graphene layer acts as the gate electrode. Compared with initial graphene/p-GaN heterostructure LEDs, the electroluminescence (EL) emission intensity of Ag NPs/graphene/p-GaN heterostructure LEDs has been largely enhanced, attributing to the surface plasmon resonance (SPR) of Ag nanoparticles. The EL emission intensity of graphene/Ag NPs-PMMA/graphene/p-GaN heterostructure LEDs can further be gate-tunable effectively through exerting a static voltage between the sandwich structure, which tunes the Fermi level of graphene contacting with p GaN. These results indicate that through sophisticated design, graphene/Ag NPs PMMA/graphene/p-GaN heterostructure LEDs can be a potential candidate for many essential electronic and optoelectronic applications. PMID- 30469630 TI - Arbitrarily shaped thermal cloaks with non-uniform profiles in homogeneous media configurations. AB - We propose a novel class of "complete" arbitrary thermal cloaks through rotatory linear maps. Different from the conventionally circular and arbitrary shape cloaks, as well as the unconventionally non-continuous shape cloaks, the proposed cloaking performances are observed in non-uniformly structural devices. Four schemes are demonstrated with homogeneous media configurations, and expected cloaking behaviors are exhibited in the internal regions. Further investigations reveal that the proposed devices perform robustness on the thermal profiles. The findings may also open up a novel avenue to generally achieve novel behaviors in the fields of optics, electromagnetics, and so forth. PMID- 30469631 TI - Virtual cavity in distributed Bragg reflectors. AB - We show theoretically and experimentally that distributed Bragg reflector (DBR) supports a surface electromagnetic wave exhibiting evanescent decay in the air and oscillatory decay in the DBR. The wave exists in TM polarization only. The field extension in the air may reach several wavelengths of light. Once gain medium is introduced into the DBR a novel class of diode lasers, semiconductor optical amplifiers, light-emitting diodes, etc. can be developed allowing a new type of in-plane or near-field light outcoupling. To improve the wavelength stability of the laser diode, a resonant cavity structure can be coupled to the DBR, allowing a coupled state of the cavity mode and the near-field mode. A GaAlAs-based epitaxial structure of a vertical-cavity surface-emitting laser (VCSEL) having an antiwaveguiding cavity and multiple GaInAs quantum wells as an active region was grown and processed as an in-plane Fabry-Perot resonator with cleaved facets. Windows in the top stripe contact were made to facilitate monitoring of the optical modes. Three types of the optical modes were observed in electroluminescence (EL) studies under high current densities > 1 kA/cm2. Mode A with the longest wavelength is a VCSEL-like mode emitting normal to the surface. Mode B has a shorter wavelength, emitting light at two symmetric lobes tilted with respect to the normal to the surface in the direction parallel to the stripe. Mode C has the shortest wavelength and shifts with a temperature at a rate 0.06 nm/K. Polarization studies reveal predominantly TE emission for modes A and B and purely TM for mode C in agreement with the theory. Spectral position, thermal shift and polarization of mode C confirm it to be a coupled state of the cavity mode and near-field DBR surface-trapped mode. PMID- 30469632 TI - Diaphragm-based optical fiber sensor array for multipoint acoustic detection. AB - Multipoint acoustic sensing system plays an important role in industrial applications. Here, a diaphragm based optical fiber sensor array is proposed, in which each sensor tip is made of 10-layer graphene diaphragm and optical fiber pigtail, with the compact size of about 2.5 mm in diameter. In particular, coherent phase detection is adopted to improve detection signal-to-noise ratio (SNR) and eliminate the demodulation dependence on structural parameters of sensor tips, and thus to achieve the multiplexing ability. Through time division multiplex (TDM), a multiplexing capacity up to 248 in theory can be realized, which is the first time to theoretically demonstrate large-scale acoustic sensor array for diaphragm based fiber sensor by phase detection, to the best of our knowledge. A prototype of 2 *2 sensor array is built to demonstrate the acoustic sensing performance. The field test results show excellent acoustic sensitivity of higher than -136 dB re 1 rad/MUPa within the frequency range of 300 Hz~15 kHz, as well as the MDP of only 75 MUPa/Hz1/2. Besides, good temperature stability and wide directivity are demonstrated. The proposed sensor array is promising in sound source localization, where the positioning accuracy of 3.55 cm is successfully realized. PMID- 30469633 TI - Liquid-crystal-loaded chiral metasurfaces for reconfigurable multiband spin selective light absorption. AB - Light absorption plays a key role in numerous photonic devices. In this work, we theoretically demonstrate that multiband circularly polarized light can be spin selectively absorbed with a single-layered metasurface. The difference of absorption efficiency between left- and right-handed circularly polarized light can reach 40%. This giant chiroptical effect originates from different plasmonic resonances induced by the incident circularly polarized light with opposite spin states. Furthermore, by integrating the metasurface with nematic liquid crystals, the spin-selective absorption and the chirality can be dynamically reconfigured via applying a bias voltage. The advantageous features of being multiband absorptive, backplane-free and reconfigurable make our proposed liquid-crystal loaded chiral metasurfaces potentially useful for various photonic applications. PMID- 30469634 TI - Trilayer hybrid structures for highly efficient THz modulation. AB - We demonstrate a novel technique to achieve a highly efficient terahertz (THz) modulation based on hybrid structures of organic layers (fullerene derivative [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) and 6,13 bis(triisopropylsilylethynyl) pentacene (TIPS-pentacene) fabricated on both sides of a silicon (Si) substrate. The organic layer generating an optically induced electron (or hole) transfer is deposited on the back (or front) side of the Si substrate. The spatial charge separation improved owing to the transferred photo excited electrons or holes at both interfaces of PCBM/Si and TIPS-pentacene/Si, enables a highly efficient THz wave modulation. The photoexcitation on the hole transfer organic layer (TIPS-pentacene/Si) further improves the modulation efficiency, as the diffusion of electrons through the Si substrate is faster than that of photo-excited holes. PMID- 30469635 TI - Investigation of scan errors in the three-element Risley prism pair. AB - In this paper, the error analysis model for the three-element Risley-prism scan system (TRSS) is established, and categories of error sources are redefined. The impact of each error on the pointing accuracy is graphically presented with analytical and numerical results. The analysis method can be implemented to any Risley-prism beam scan system. For thin prisms, an error compensation algorithm for the TRSS is developed to accomplish high-accuracy beam scanning, which can be referred to the error calibration of the TRSS. PMID- 30469636 TI - Design and fabrication of multiplexed volume Bragg gratings as angle amplifiers in high power beam scanning system. AB - In this study, the realization of multiplexed volume Bragg gratings (VBGs) working as angle amplifiers in high power beam scanning system is theoretically and experimentally investigated. The design of the multiplexed VBG for the working wavelength of 1064 nm is described. We propose a cascaded multiplexed VBGs scheme that consists of 12 grating channels. Three 4-channel multiplexed VBGs were fabricated inside photo-thermo-refractive (PTR) glasses by multiple exposures and subsequent heat treatment. The test results show that this angle amplifier can achieve discrete angle deflection ranging from -45 degrees to + 45 degrees . The relative diffraction efficiency of all the grating channels is more than 80% and is almost polarization independent. PMID- 30469637 TI - Design method of nonsymmetric imaging systems consisting of multiple flat phase elements. AB - Imaging systems consisting of flat phase elements can realize the same functions and applications of conventional geometric optical systems, as well as the ones using aspherical or freeform optics, but can achieve more compactness, lighter weight and easier-alignment. In addition, it is easy to integrate multiple phase elements into a single flat element. Here we propose a novel design method and realize the design of off-axis nonsymmetric imaging systems consisting of multiple flat phase elements. Compared with other traditional design methods of phase elements, the whole design process starts from an initial system using simple true geometric planes. The phase profiles or functions are generated point by-point directly based on the given system specifications and configuration. In comparison with other direct or point-by-point design methods of flat phase elements, the rays of multiple fields and pupil positions are employed in the design framework. Closed-form phase functions of multiple flat elements are designed quickly and effectively by connecting and integrating the real three dimensional space and the phase function space. This method can be taken as a fast phase retrieval method to some degree. To demonstrate the feasibility of the proposed design method, we present a high-performance compact system as design example. The design method and framework depicted in this paper can be applied in many areas, such as virtual reality (VR) and augmented reality (AR), miniature cameras, high-performance telescopy, microscopy, and illumination design. PMID- 30469638 TI - White powder identification using broadband coherent light in the molecular fingerprint region. AB - We show that a variety of white powder samples, including painkillers, amino acids, stimulants and sugars are readily discriminated by diffuse reflectance infrared spectroscopy involving no preparation of the sample and no physical contact with it. Eleven powders were investigated by illuminating each sample with broadband coherent light in the 8-9-um band from an OPGaP femtosecond optical parametric oscillator. The spectra of the scattered light were obtained using Fourier-transform spectroscopy. Similarities between different spectra were quantified using Pearson's correlation coefficient, confirming that spectral features in the 8-9-um wavelength region were sufficient to discriminate between all eleven powders evaluated in the study, offering a route to simple and automated non-contact chemical detection. PMID- 30469639 TI - Wide-field anti-aliased quantitative differential phase contrast microscopy. AB - Differential phase contrast (DPC) microscopy is a popular methodology to recover quantitative phase information of thin transparent samples under multi-axis asymmetric illumination patterns. Based on spatially partially coherent illuminations, DPC provides high-quality, speckle-free 3D reconstructions with lateral resolution up to twice the coherent diffraction limit, under the precondition that the pixel size of the imaging sensor is small enough to prevent spatial aliasing/undersampling. However, microscope cameras are in general designed to have a large pixel size so that the intensity information transmitted by the optical system cannot be adequately sampled or digitized. On the other hand, using an image sensor with a smaller pixel size or adding a magnification camera adapter to the camera can resolve the undersampling at the expense of a reduced field of view (FOV). To solve this tradeoff, we introduce a new variation of quantitative DPC approach, termed anti-aliased DPC (AADPC), which uses several aliased intensity images under asymmetric illuminations to recover wide-field aliasing-free phase images. Besides, phase transfer functions under different illumination patterns in DPC are analyzed to design an illumination scheme with better phase transfer characteristics. AADPC starts from an initial phase estimate obtained by a DPC-like deconvolution based on the system's weak phase transfer function under discrete half-annular illumination. Then the obtained initial phase map is further refined by the iterative de-multiplexing algorithm to overcome pixel-aliasing and improve the imaging resolution. The data redundancy requirement as well as the optimal illumination scheme of AADPC are analyzed and discussed based on several simulations, suggesting that the spatial undersampling can be mitigated through the iterative algorithm that uses only 4 images, yielding a nearly 4-fold increase in the space-bandwidth product (SBP) compared to the conventional DPC approach. We experimentally verify that AADPC can achieve a half-pitch imaging resolution of 345 nm, corresponding to 1.88* of the theoretical Nyquist-Shannon sampling resolution limit imposed by the sensor pixel size. The high-speed, high-throughput quantitative phase imaging capabilities of AADPC are also demonstrated by imaging HeLa cells mitosis in vitro, achieving a full-pitch lateral resolution of 665 nm across a wide FOV of 1.77mm2 at 25 fps. PMID- 30469640 TI - Plasma dispersion effect based super-resolved imaging in silicon. AB - We present here a new method for shaping a pulsed IR (lambda = 1550nm) laser beam in silicon. The shaping is based on the plasma dispersion effect (PDE). The shaping is done by a second pulsed pump laser beam at 532nm (in either a Gaussian mode or a donut mode) which simultaneously and collinearly illuminates the silicon's surface with the IR beam. Following the PDE, and in proportion to its spatial intensity distribution, the 532nm laser beam shapes the point spread function (PSF) by controlling the lateral transmission of the IR probe beam. The use of this probe in a laser scanning microscope allows imaging and a wide range of contactless electrical measurements in silicon integrated circuits (IC) being under operation. We propose this shaping method to overcome the diffraction resolution limit in silicon microscopy on and deep under the silicon surface. PMID- 30469641 TI - Convex blazed grating of high diffraction efficiency fabricated by swing ion-beam etching method. AB - A swing ion-beam etching method to fabricate convex blazed gratings used in shortwave infrared hyperspectral imaging spectrometers is presented. This method solves the consistency problem of blaze angles by swing etching through the meridian direction of the gratings. The mathematical relationship of the curvature, aperture, and diffraction efficiency of convex gratings is studied to demonstrate the limitation of conventional translational lithography and the necessity of swing etching. A geometric model is built to analyze the influence of swinging speed and beam slit width on groove evolution. Convex gratings with a 45.5 gr/mm groove density, 67 mm aperture, 156.88 mm radius of curvature, and 2.2 degrees blaze angle have been fabricated and measured where the peak and average diffraction efficiency in the shortwave infrared band reach 90% and 70%, respectively. Experimental results validate that high-efficiency convex gratings of small blaze angle and high groove consistency can be produced by swing etching, which satisfy the requirements for high spectral resolution and miniaturization of imaging spectrometers. PMID- 30469642 TI - Distributed acoustic sensor based on a two-mode fiber. AB - A distributed optical fiber dynamic strain sensor also known as a distributed acoustic sensor (DAS) based on two-mode fiber is demonstrated. By using phi-OTDR interrogation technique, the backscattered light from higher order modes can be used to fully quantify vibrations along the sensing fiber. In addition, by combining the results obtained from different modes, 2.52dB improvement in noise floor is achieved. These results confirm that few-mode fibers can be used for DAS applications. PMID- 30469643 TI - Comprehensive characterization of a general composite waveplate by spectroscopic Mueller matrix polarimetry. AB - Composite waveplates (CWs) consisting of multiple single waveplates are basic polarization elements and widely used to manipulate the polarized light in optical systems, and their performances affect the final accuracy and precision significantly. This research proposes a method for the comprehensive characterization of an arbitrary CW based on spectroscopic Mueller matrix polarimetry. An analytical model is established to describe a general CW by extending Jones' equivalent theorem with Mueller matrix calculus. In this model, an arbitrary CW is optically equivalent to a cascaded system consisting of a linear retarder with slight diattenuation followed by an optical rotator, and its polarization properties are completely described by four polarization parameters, including the retardance, the fast axis azimuth, the rotation angle, and the diattenuation angle. Analytical relations between the polarization properties, the structure, and the Mueller matrix of the CW are then derived from the established model. By the proposed method, the polarization parameters of an arbitrary CW can be comprehensively characterized over an ultra-wide spectral range via only one measurement. Moreover, the actual structure of the CW, including the thicknesses and fast axis azimuths of the single waveplates, as well as the axis alignment errors, can be completely reconstructed from the polarization spectra. Experiments performed with a house-developed broadband Mueller matrix polarimeter on three typical CWs including a compound zero-order waveplate, an achromatic waveplate and a specially designed biplate have demonstrated the capability of the proposed method. PMID- 30469644 TI - Molecular gases for pulse compression in hollow core fibers. AB - We introduce hydrofluorocarbon molecules as an alternative medium to noble gases with low ionization potential like krypton or xenon to compress ultrashort pulses of relatively low energy in a conventional hollow core fiber with subsequent dispersion compensation. Spectral broadening of pulses from two different laser systems exceeded those achieved with argon and krypton. Initially 40 fs, 800 nm, 120 MUJ pulses were compressed to few optical cycles duration. With the same approach a compression factor of more than 10 was demonstrated for an ytterbium based laser (1030 nm, 170 fs, 200 MUJ) leading to 15.6 fs. PMID- 30469645 TI - Integrated digital holographic microscopy based on surface plasmon resonance. AB - We propose a novel digital holographic microscopy (DHM) by integrating surface plasmon holographic microscopy (SPHM) with reflection DHM based on the angular and polarization multiplexing techniques. Taking advantages of the high sensitivity of surface plasmon resonance (SPR) and the high reflectivity of gold film, the tiny variations of specimen's refractive index (RI) can be measured by using SPHM, and meanwhile, the thickness changes of the specimen can be determined by means of reflection DHM. We experimentally monitor the volatilization process of an alcohol-water mixture droplet to verify the validity of the integrated DHM. The proposed microscopy is very promising in the objective coupling SPR microscopy for multi-information measurements of diverse specimens with low-contrast RI distributions (biomolecules, nanofluids, etc.) in a dynamic and nondestructive way. PMID- 30469646 TI - 8-channel WDM silicon photonics transceiver with SOA and semiconductor mode locked laser. AB - We demonstrate an integrated 8 by 14 Gbps dense wavelength division multiplexed silicon photonics transceiver that makes use of an external mode-locked laser as a light source and a single semiconductor optical amplifier for post-modulation signal amplification. Remaining components necessary for modulation, filtering and (de-)multiplexing are monolithically integrated in a single chip. In all system experiments, all eight channels are jointly operated with independent data streams in order to include impairments arising out of nonlinear effects inside the SOA while benchmarking the system performance. The transmitter, measured with a commercial reference receiver, supports on-off keying data transmission with an uncorrected BER ranging between 1e-5 and 5e-7 for all channels in back-to-back configuration and between 8e-4 and 1e-5 after 10 km transmission (both PRBS 231 1). The three best channels of the full link consisting in the silicon photonics transmitter operated with the silicon photonics receiver in back-to-back configuration maintain a BER better than the targeted 5e-5. Based on link budget modeling, we expect this target to be reached for all 8 channels pending improvement of the receiver offset compensation loop. PMID- 30469647 TI - Gain-assisted ultra-high-Q spoof plasmonic resonator for the sensing of polar liquids. AB - By directly incorporating a sub-wavelength amplifier chip into the spoof plasmonic resonator, the quality (Q) factor of the original passive resonator has been significantly increased by several orders of magnitude. The spoof plasmonic resonator is composed of a corrugated ring with a slit whose optimized offset angle phi is 45 degrees , aiming to achieve a better Q-factor. By tuning the bias voltage applied to the amplifier chip that is placed across the slit, the Q factor has been increased from 9.8 to 21000 for the quadrupole mode when a plastic pipe filled with polar liquids is placed upon the resonator. Experiments at the microwave frequencies verify that the amplifier chip could greatly compensate the loss introduced by the polar liquids under investigation, resulting in an ultra-high-Q sensor for the detection of polar liquids. PMID- 30469648 TI - Near-field ptychographic microscope for quantitative phase imaging. AB - Quantitative phase imaging (QPI) is the name given to a set of microscopy techniques that map out variations in optical path lengths across a sample. These maps are a useful source of contrast for transparent samples such as biological cells, and because they are quantitative they can be used to measure refractive index and thickness variations. Here we detail the setup and operation of a new form of QPI microscope based on near-field ptychography. We test our system using a range of phase objects, and analyse the phase images it produces. Our results show that accurate, high quality images can be obtained from a ptychographical dataset containing as few as four near-field diffraction patterns. We also assess how our system copes with optically thick samples and samples with a wide range of spatial frequencies - two areas where conventional and Fourier ptychography struggle. PMID- 30469649 TI - 3D printing of resin composites doped with upconversion nanoparticles for anti counterfeiting and temperature detection. AB - Rapid prototyping (RP) techniques allow the construction of complex and sophisticated physical models based on personal needs, and the applications of the produced objects can be greatly extended by functionalizing the raw materials (e.g., resins) with components showing electrical, optical and magnetic properties. Here, we demonstrate a simple method for the realization of a three dimensional architecture through 3D printing of organic resin doped with inorganic upconversion (UC) nanoparticles by using stereolithography technique. In our process, the wet-chemistry derived NaYF4: RE (RE: rare earth) nanoparticles with red, green and blue UC emission were incorporated into a resin matrix. We printed out pre-designed 3D structures with high precision and examined the UC emission properties. In a proof-of-concept experiment, we demonstrate that the 3D printed objects have reliable optical anti-counterfeiting based on high concealment in daylight and multi-color UC emission excited by a near-infrared laser at 980 nm. We also show that the 3D part with UC emission can be used for ratiometric temperature sensing from 303.15 K to 463.15 K, making it possible to map the temperature distribution for studying the thermal diffusion process in complex objects. PMID- 30469650 TI - Efficiency improvement of up-conversion process of plasmonic-enhanced Er-doped NaYF4 nanoparticles under IR excitation. AB - The up-conversion process is extensively studied because of its wide variety of applications such as bioimaging, energy harvesting, and optical sensors. However, the optical conversion efficiency is still relatively low and needs to be improved. Therefore, this paper introduces a detailed study of improving the up conversion emission efficiency through adding plasmonic metallic nanostructures to the up-conversion optical centers. Our idea is to couple the optical plasmonic resonance with the visible emission of the optical centers under IR excitation. The optical centers are erbium ions hosted by fluoride low-phonon environment. Our calculations consider most possible transitions that can occur between the optical centers; tri-valent erbium ions, through Judd-Ofelt analysis. In addition, the effect of changing some parametric values is discussed, such as irradiance, and multi-phonon relaxations, to show their optimum values which correspond to best quantum yield efficiency. By increasing the diameter of added gold nanoparticles (Au NPs), the probability of occupation has been increased, and consequently, both the luminescence and up-conversion efficiency have been increased. PMID- 30469651 TI - Feature issue introduction: Topological Photonics and Materials. AB - Photonic crystals have become a very common and powerful concept in optics since its introduction in the 1980s by Eli Yablonovitch and Sajeev John. It is in fact a concept borrowed from condensed matter physics. The discussion of photonic bands and bandgaps allows us to manipulate light on an optical chip, along a photonic crystal fiber and even in the quantum optics regime. Now, we are witnessing another round of concept translation again from condensed matter physics to optics about topology. Describing photonic bands by using their topology in the reciprocal space gives us a new tool to understand wave propagation and to design optical components. Topology is also an important aspect in light-matter interaction in the field of metamaterials and 2D materials. PMID- 30469652 TI - In situ measurement of seawater salinity with an optical refractometer based on total internal reflection method. AB - An optical refractive index sensor used for underway seawater salinity monitoring is proposed. Due to the empirical relation to salinity, refractive index measurement provides an alternative solution to obtain salinity of seawater. We developed a compact refractive index sensor based on total internal reflection (TIR) method. Through the repeatability and stability experiment and temperature correction, the performance of the sensor has been demonstrated experimentally. To evaluate the applicability of the sensor under real turbid sea conditions, field performance of the TIR sensor has been tested on an oceanographic cruise in the eastern of Yangtze Estuary in July 2017. The underway monitoring results show good correlation with the results provided by commercial CTD profiler. PMID- 30469653 TI - Global motion compensation for compressing holographic videos. AB - Large high-resolution digital holographic displays may become feasible in the near future, and they will need considerable amounts of data. Handling this bandwidth is particularly challenging for dynamic content operating at video rates. Conventional motion compensation algorithms from classical video coders are ineffective on holograms because, in contrast to natural imagery, each pixel contains partial information from the whole scene. We propose an accurate motion compensation model predicting how hologram content changes with respect to 3D rigid-body motion that arises in natural scenes. Using diffraction theory, we derive tractable closed form expressions for transforming 2D complex-valued holographic video frames. Our experiments use computer generated hologram videos with known ground truth motion. We integrated the proposed motion compensation model into the HEVC codec. We report Bjontegaard delta-PSNR ratio gains of 8 dB over standard HEVC. PMID- 30469654 TI - Single shot, large area metal sintering with micrometer level resolution. AB - - This paper presents the optics design for a microscale Selective Laser Sintering (MU-SLS) system that aims to allow large areas of nanoparticles to be sintered simultaneously while still maintaining micrometer scale feature resolutions in order to improve the throughput of the microscale additive manufacturing process. The optics design is shown to be able to sinter a 2.3 mm by 1.3 mm area of metal nanoparticles that have been spread into a ~400 nm thick layer with a feature resolution of ~3 MUm in a single shot. The optical resolution of this system is shown to be ~1.2 MUm indicating that only about 2-3 pixels are needed to form a good sintered part. In addition, using the optical design presented in this paper, it is estimated that the MU-SLS system should be able to achieve a volumetric throughput of ~63 mm3/hr, making this process one of the highest throughput processes available today for the microscale additive manufacturing of three-dimensional metal structures. PMID- 30469655 TI - Truncated triangular diffraction lattices and orbital-angular-momentum detection of vortex SU(2) geometric modes. AB - We report, for the first time to the best of our knowledge, a truncated diffraction with a triangular aperture of the SU(2) geometric modes and propose a method to detect the complicated orbital angular momentum (OAM) of an SU(2) wave packet. As a special vortex beam, a nonplanar SU(2) mode carrying special intensity and OAM distributions brings exotic patterns in a truncated diffraction lattice. A meshy structure is unveiled therein by adjusting the illuminated aperture in the vicinity of the partial OAM regions, which can be elaborately used to evaluate the partial topological charge and OAM of an SU(2) wave-packet by counting the dark holes in the mesh. Moreover, through controlling the size and position of the aperture at the center region, the truncated triangular lattice can be close to the classical spot-array lattice for measuring the center OAM. These effects being fully validated by theoretical simulations greatly extend the versatility of topological structures detecting special beams. PMID- 30469656 TI - Polarization-independent and angle-insensitive broadband absorber with a target patterned graphene layer in the terahertz regime. AB - We propose a broadband tunable metamaterial absorber with near-unity absorption in the terahertz regime based on a target-patterned graphene sheet. Due to gradient diameter modulation of the graphene sheet and circular symmetry of the unit cell, broadband and polarization-independent properties are achieved in the absorber. A full-wave numerical simulation is performed, and the results show that the absorber's bandwidth of 90% terahertz absorption reaches 1.57 THz with a central frequency of 1.83 THz under normal incidence. At oblique incidence, the broadband absorption of the absorber remains more than 75% over a wide incidence angles up to 60 degrees for the transverse electric (TE) mode and 75 degrees for the transverse magnetic (TM) mode. Furthermore, tunable property is implemented and the peak absorption of the absorber can be tuned from 19% to near 100% by changing the Fermi energy of the graphene sheet from 0 to 0.9 eV via electrostatic doping. The absorber is scalable to the infrared and visible frequencies, which could be used as tunable sensors, filters and photovoltaic devices. PMID- 30469657 TI - Reconfigurable phase-change meta-absorbers with on-demand quality factor control. AB - Perfect absorber type devices are well-suited to many applications, such as solar cells, spatial light modulators, bio-sensors, and highly-sensitive photo detectors. In such applications, a method for the design and fabrication of devices in a simple and efficient way, while at the same time maintaining design control over the key performance characteristics of resonant frequency, reflection coefficient at resonance and quality factor, would be particularly advantageous. In this work we develop such a method, based on eigenmode analysis and critical coupling theory, and apply it to the design of reconfigurable phase change metasurface absorber devices. To validate the method, the design and fabrication of a family of absorbers was carried out with a range of 'on-demand' quality factors, all operating at the same resonant frequency and able to be fabricated simply and simultaneously on the same chip. Furthermore, by switching the phase-change layer between its amorphous and crystalline states, we show that our devices can provide an active or reconfigurable functionality. PMID- 30469658 TI - Adiabatic four-wave mixing frequency conversion. AB - We introduce the concept of adiabatic four-wave mixing (AFMW) frequency conversion in cubic nonlinear media through an analogy to dynamics in quantum two level systems. Rapid adiabatic passage in four-wave mixing enables coherent near 100% photon number down-conversion or up-conversion over a bandwidth much larger than ordinary phase-matching bandwidths, overcoming the normal efficiency bandwidth trade-off. We develop numerical methods to simulate AFWM pulse propagation in silicon photonics and fiber platforms as examples. First, we show that with a longitudinally varying silicon waveguide structure, a bandwidth of 70 nm centered at 1820 nm can be generated with 90% photon number conversion. Second, we predict the broadband generation of nanojoule energy, 4.2-5.2 MUm mid infrared light in a short, linearly tapered fluoride step-index fiber. We expect the AFWM concept to be broadly applicable to cubic nonlinear platforms, for applications as diverse as bright ultrafast light pulse generation, sensing, and conversion between telecommunications bands. PMID- 30469659 TI - High performance ultra-compact SOI waveguide crossing. AB - Waveguide crossing is an important integrated photonic component that will be routinely used for high-density and large-scale photonic integrated circuits, such as optical switches and routers. Several techniques have been reported in achieving high performance waveguide crossings on a silicon-on-insulator photonic platform, i.e., low-loss and low-crosstalk waveguide crossings based on multimode interference, bi-layer tapering, optical transformation, metamaterials, and subwavelength gratings. Until recently, not much attention has been given to the reduction of the footprint of waveguide crossings. Here we experimentally demonstrate an ultra-compact waveguide crossing on silicon photonic platform with a footprint only ~1 * 1 MUm2. Our simulations show that it has a low insertion loss (< 0.175 dB) and low crosstalk (< -37dB) across the whole C-band, while the fabricated one has an insertion loss < 0.28 dB and crosstalk around -30 dB for the C-band. PMID- 30469660 TI - Paraxial design of four-component zoom lens with fixed position of optical center composed of members with variable focal length. AB - The paper presents paraxial analysis of special types of zoom lenses, which are composed of four members with variable focal length. The position of optical center of these systems is required to be fixed for a given value of focal length (i.e., the position of the optical center does not depend on object distance for given value of focal length of the zoom). The formulas that enable the calculation of the optical powers of individual members of such a zoom lens are derived from--and the practical application of the derived formulas is demonstrated with--an example. Such optical systems represent a completely new family of zoom optical systems with applications in measuring systems in photogrammetry, computer vision, triangulation sensors, fringe projection techniques, surveying, machine vision, and so forth. PMID- 30469661 TI - Terahertz polarization-maintaining subwavelength filters. AB - Terahertz (THz) polarization-maintaining waveguides, which have been considered fundamental elements in polarization-sensitive THz systems, are promising platforms in developing functional THz devices. Here, we propose a THz grating based on a subwavelength rectangular polymer waveguide, which filters two polarization states simultaneously. The proposed gratings are characterized and discussed using numerical simulations. We observe two transmission dips with over a 20.9 dB extinction ratio (ER) and around a 21.1 GHz full-width half-maximum (FWHM), where the reflective frequencies of the two polarization waves and the separation between them can be harnessed with appropriate structure designs. Furthermore, we demonstrate that the grating can operate as a polarization maintaining narrow bandpass filter (ER>12.3 dB and FWHM<1.7 GHz) by introducing a pi-phase shift. This work has the potential to open a new avenue for steering polarized THz radiation using the waveguide-based filters, which could be integrated in THz polarization-sensitive imaging, sensing, and wireless communication systems. PMID- 30469662 TI - Ultra-compact multi-channel all-optical switches with improved switching dynamic characteristics. AB - We propose and demonstrate four-channel all-optical switches based on silicon photonic crystal (PhC) nanobeam cavities, with an area of only 31 MUm2 per channel. For these switches, signal extraction and rejection functions have been successfully demonstrated while the signal speed is limited to 2.5 Gb/s due to the slow switching recovery process in silicon. In order to improve the signal speed, first, a blue-detuned filtering method is employed to suppress the slow switching recovery tails of the output signal light based on passive resonant devices. The suppressing mechanism relies on the extraction of the large blue chirped component in the fast rising edge, while suppressing the red-chirped component in the slow switching recovery tail. A detailed theoretical model is established to analyze the improvement mechanism of the switching dynamic characteristics in the silicon PhC nanobeam cavity. Moreover, the simulated and experimental results have both shown that the switching recovery time of the output signal light is greatly reduced from 500 ps to 50 ps. Thus, the processing of 10-Gb/s optical signals has been experimentally demonstrated with the help of the blue-detuned filtering method. PMID- 30469663 TI - High signal-to-noise ratio ultra-compact lab-on-a-chip microflow cytometer enabled by silicon optical antennas. AB - We experimentally demonstrate an all-silicon nanoantenna-based micro-optofluidic cytometer showing a combination of high signal-to-noise ratio (SNR) > 14 dB and ultra-compact size. Thanks to the ultra-high directivity of the antennas (>150), which enables a state-of-the-art sub-micron resolution, we are able to avoid the use of the bulky devices typically employed to collimate light on chip (such as lenses or fibers). The nm-scale antenna cross section allows a dramatic reduction of the optical system footprint, from the mm-scale of previous approaches to a few um2, yielding a notable reduction in the fabrication costs. This scheme paves the way to ultra-compact lab-on-a-chip devices that may enable new applications with potential impact on all branches of biological and health science. PMID- 30469664 TI - Insulator to metal transition induced by surface plasmon polaritons in VO2/Au thin films. AB - We report on a new mechanism capable of inducing the insulator-metal transition (IMT) in VO2 via surface plasmon polaritons (SPP). Our theoretical model predicts that for a bilayer Au-VO2 sample an enhanced electromagnetic energy density at the Au-VO2 interface will occur at 1064nm laser wavelength when SPPs are excited in the Au layer. This effect can assist the IMT in the VO2 layer and at the same time, the SPP absorption can be used to detect it. Changes in the optical properties of the VO2 thin layer in such structure can be observed in the reflected light in Kretschmann configuration, via a shift in the nadir location due to light absorption at resonance. This optical mechanism occurs at 2mW threshold transition energies and fully saturates at 5mW. PMID- 30469665 TI - Low loss Ge-on-Si waveguides operating in the 8-14 um atmospheric transmission window. AB - Germanium-on-silicon waveguides were modeled, fabricated and characterized at wavelengths ranging from 7.5 to 11 um. Measured waveguide losses are below 5 dB/cm for both TE and TM polarization and reach values of ~ 1 dB/cm for >= 10 um wavelengths for the TE polarization. This work demonstrates experimentally for the first time that Ge-on-Si is a viable waveguide platform for sensing in the molecular fingerprint spectral region. Detailed modeling and analysis is presented to identify the various loss contributions, showing that with practical techniques losses below 1 dB/cm could be achieved across the full measurement range. PMID- 30469666 TI - Optimized sensing of sparse and small targets using lens-free holographic microscopy. AB - Lens-free holographic microscopy offers sub-micron resolution over an ultra-large field-of-view >20 mm2, making it suitable for bio-sensing applications that require the detection of small targets at low concentrations. Various pixel super resolution techniques have been shown to enhance resolution and boost signal-to noise ratio (SNR) by combining multiple partially-redundant low-resolution frames. However, it has been unclear which technique performs best for small target sensing. Here, we quantitatively compare SNR and resolution in experiments using no regularization, cardinal-neighbor regularization, and a novel implementation of sparsity-promoting regularization that uses analytically calculated gradients from Bayer-pattern image sensors. We find that sparsity promoting regularization enhances the SNR by ~8 dB compared to the other methods when imaging micron-scale beads with surface coverages up to ~4%. PMID- 30469667 TI - Metasurface-based broadband orbital angular momentum generator in millimeter wave region. AB - Orbital angular momentum (OAM) is an intrinsic property that all electromagnetic waves can carry. Interesting properties of OAM beams have enabled many novel applications. But broadband OAM generator has rarely been investigated, especially in the millimeter wave frequency band. In this work, a broadband OAM generator applying a metallic reflective metasurface operating from 59 to 70 GHz is designed, simulated, fabricated and measured. Both simulation and experiment results demonstrate that broadband millimeter wave OAM beams with good quality can be reliably launched by the designed metasurface. The proposed broadband OAM generator alleviates malfunctions caused by dispersion and provides new possibilities of multiplexing for millimeter wave communication applications. PMID- 30469668 TI - Generalized inverse matrix-exterior penalty function (GIM-EPF) algorithm for data processing of multi-wavelength pyrometer (MWP). AB - The unknown emissivity of materials is a huge obstacle in multi-wavelength pyrometry (MWP). It leads to a set of ill-posed equations that cannot be directly inverted to obtain the true temperature from a set of multi-wavelength measurements. Constraint optimization algorithms such as the gradient projection (GP) and internal penalty function (IPF) algorithms provide solutions without any emissivity model assumptions but require a narrow fixed emissivity range and an appropriate initial emissivity input value, otherwise, accuracy and computational efficiency are greatly affected. Here, we propose a generalized inverse matrix exterior penalty function (GIM-EPF) algorithm to realize an efficient and accurate inversion without limiting the emissivity range in advance. First, a set of emissivities is obtained by the generalized inverse matrix method; these emissivities are used as initial values in the exterior penalty function iteration algorithm, from which temperature and spectral emissivity are obtained. Simulation results show that the GIM-EPF algorithm provides results superior to IPF, especially in computational efficiency. The proposed GIM-EPF method is 8 times faster than the IPF method with a 0.56% relative error at the 1800 K true temperature. The GIM-EPF method also allows near real-time diagnosis of rocket exhaust flame temperature. Rocket nozzle temperature experiment results show that the temperatures derived by the GIM-EPF algorithm agree well with the theoretical design temperature and the IPF inversion temperature. PMID- 30469669 TI - Frequency diffraction management through arbitrary engineering of photonic band structures. AB - It is of fundamental interest to control light diffraction in discrete optical systems. However, photon hopping in discrete systems is dominated by the nearest neighbor coupling, limiting the realization of nonlocal diffraction phenomena. Here, we generalize the discrete diffraction from spatial to the frequency domain using optical phase modulators. By inducing long-rang couplings in the frequency lattice through periodic modulation signals, we find the lattice band structure can be artificially engineered, giving rise to the realization of arbitrary frequency diffraction. Particularly, we create linear, bilinear and semicircular band structures using sawtooth, triangular and semicircular modulation waveforms and realize the directional, bidirectional, omnidirectional frequency diffraction as well as the spectral "superlens". We also revisit frequency discrete Talbot effect and generalize the allowed incident period to arbitrary integers through band structure engineering. Moreover, as the frequency transition also carries a wave vector mismatch, an effective electric field will emerge, through which we can realize frequency Bloch oscillations that manifest the effects of arbitrary spectral routing and self-imaging. The study paves a promising way towards versatile spectrum management for both optical communications and signal processing. PMID- 30469670 TI - Integrated tilt angle sensing for large displacement scanning MEMS mirrors. AB - Fourier transform spectrometers (FTS) based on piston-scanning MEMS mirrors have clear advantages of small size and low cost. However, the performance of this type of MEMS FTS is seriously limited by the difficulty of precisely controlling the tilt angle of the MEMS mirror plate during its piston scanning. This paper reports an integrated tilt angle sensing method, which is achieved via a mixed signal integrated optoelectronic position sensor (iOE-PS) that is bonded directly on the back of an electrothermally-actuated MEMS mirror. The iOE-PS integrates a laser diode, a band-gap reference, a quadrant photo-detector (QPDs), and the QPDs' readout circuits all on a single chip. The iOE-PS has been fabricated in a 180 nm CMOS process. Experimental results show that the iOE-PS has a linear response when the MEMS mirror plate moves vertically between 1.31 mm to 1.50 mm over the iOE-PS chip; the tilt angle can be measured up to at least 5 degrees with a resolution of 0.0067 degrees . The iOE-PS can greatly reduce the size and complexity of MEMS mirrors-enabled systems with integrated closed-loop control capability. PMID- 30469671 TI - Simultaneous LIBS signal and plasma density measurement for quantitative insight into signal instability at elevated pressure. AB - Laser-induced breakdown spectroscopy (LIBS) evaluates the emission spectra of ions, radicals, and atoms generated from the breakdown of molecules by the incident laser; however, the LIBS signal is unstable at elevated pressures. To understand the cause of the signal instability, we perform simultaneous time resolved measurements of the electron density and LIBS emission signal for nitrogen (568 nm) and hydrogen (656 nm) at high pressure (up to 11 bars). From correlations between the LIBS signal and electron number density, we find that the uncontrollable generation of excess electrons at high pressure causes high instability in the high-pressure LIBS signal. A possible method using ultrafast lasers is proposed to circumvent the uncontrolled electron generation and improve signal stability at high pressure. PMID- 30469672 TI - Few-mode fiber true time delay lines for distributed radiofrequency signal processing. AB - We report, for the first time to our knowledge, distributed radiofrequency signal processing built upon true time delay operation on a step-index few-mode fiber. Two 3-sample configurations with different time delay properties are implemented over the same 60-meter 4-LP-mode fiber link. The inscription of a long period grating at a specific fiber position converts part of the LP01 mode into the LP02, permitting sample time delay engineering. Delay line performance is experimentally demonstrated when applied to radiofrequency signal filtering, example of fiber-distributed processing functionality exhibiting one order or magnitude gain in terms of compactness. PMID- 30469673 TI - 20 GHz actively mode-locked thulium fiber laser. AB - A high repetition-rate actively mode-locked thulium fiber laser is demonstrated where an electro-optic lithium niobate phase modulator is used to synchronize the longitudinal modes in the cavity. The repetition rate of the actively mode-locked laser is tunable from 14.6 MHz to 19 GHz, where the 19 GHz pulses exhibit a super mode suppression ratio of 46 dB. Furthermore, the output pulse width could be manipulated through finely controlling the detuning frequency or repetition rate. We have also experimentally observed rational harmonic mode-locking in the laser and obtained 14 GHz and 21 GHz repetition rate pulses using a 7 GHz modulating signal. To the best of our knowledge, we have improved the repetition-rate of actively mode-locked thulium fiber laser by more than one order of magnitude. Such a high repetition source can be readily synchronized to a master clock, which makes it very suitable for high speed optical data processing, communication and remote sensing. PMID- 30469674 TI - Microparticle discrimination using laser feedback interferometry. AB - In this work, we present a method to discriminate between different microparticle sizes in mixed flowing media based on laser feedback interferometry, which could ultimately form the basis for a small, low-cost, real-time microembolus detector. We experimentally evaluated the performance of the system using microparticle phantoms, and the system achieved approximately 45% positive predictive value and better than 98% negative predictive value in the detection and classification of abnormally large particles. PMID- 30469675 TI - 100-kHz, dual-beam OPA delivering high-quality, 5-cycle angular-dispersion compensated mid-infrared idler pulses at 3.1 um. AB - We demonstrate a dual-beam infrared optical parametric source featuring a noncollinear KTA booster amplifier and straightforward angular dispersion compensation of the idler beam. Through careful beam and pulse characterization, and high-harmonic generation in a crystalline solid, we show that the corrected idler beam is diffraction-limited, astigmatism-free, and compressible to its transform-limited, 5-cycle pulse duration. Pumped by only 40-uJ pulses at 1.03 um, the parametric source delivers 7.8-uJ, 38-fs, 1.53-um and 2.3-uJ, 53-fs, CEP stable, 3.1-um pulses at a repetition rate of 100 kHz. The scheme provides a promising route to scale the pulse energy and average power beyond PPLN- or KTA based collinear OPA architectures. PMID- 30469676 TI - Video-rate terahertz digital holographic imaging system. AB - Terahertz (THz) imaging has been demonstrated in numerous applications from medical to non-destructive evaluation (NDE), but current systems require expensive components, provide slow frame-rates and low resolutions. THz holography offers a potentially low-cost, high-performance alternative. Here we demonstrate the first full video-rate THz digital holography system at 2.52 THz (118.8 um) using low-cost optical components. 2D digital reconstructions of samples are performed at frame-rates of 50 Hz - an order of magnitude higher than previous systems, whilst imaging of samples concealed in common packaging types demonstrates suitability for NDE applications. A lateral resolution of 250 um was determined using a 1951 USAF target. PMID- 30469677 TI - High-Q integrated photonic microresonators on 3C-SiC-on-insulator (SiCOI) platform. AB - We report a high-quality 3C-silicon carbide (SiC)-on-insulator (SiCOI) integrated photonic material platform formed by wafer bonding of crystalline 3C-SiC to a silicon oxide (SiO2)-on-silicon (Si) substrate. This material platform enables to develop integrated photonic devices in SiC without the need for undercutting the Si substrate, in contrast to the structures formed on conventional 3C-SiC-on-Si platforms. In addition, we show a unique process in the SiCOI platform for minimizing the effect of lattice mismatch during the growth of SiC on Si through polishing after bonding. This results in a high-quality SiCOI platform that enables record high Qs of 142,000 in 40 um radius SiC microring resonators. The resulting SiCOI platform has a great potential for a wide range of applications in integrated optics, including nonlinear optical devices, quantum optical devices, and high-power optical devices. PMID- 30469678 TI - Range dependence of an optical pulse position modulation link in the presence of background noise. AB - We analyze the information efficiency of a deep-space optical communication link with background noise, employing the pulse position modulation (PPM) format and a direct-detection receiver based on Geiger-mode photon counting. The efficiency, quantified using Shannon mutual information, is optimized with respect to the PPM order under the constraint of a given average signal power in simple and complete decoding scenarios. We show that the use of complete decoding, which retrieves information from all combinations of detector photocounts occurring within one PPM frame, allows one to achieve information efficiency scaling as the inverse of the square of the distance, i.e. proportional to the received signal power. This represents a qualitative enhancement compared to simple decoding, which treats multiple photocounts within a single PPM frame as erasures and leads to inverse quartic scaling with the distance. We provide easily computable formulas for the link performance in the limit of diminishing signal power. PMID- 30469679 TI - Displaceable and focus-tunable electrowetting optofluidic lens. AB - A conventional optofluidic lens usually has one liquid-liquid (L-L) interface, which can be deformed to achieve variable focal length. Such a single lens cannot be used alone to realize optical zooming because its back focal distance keeps changing. Here, we report a novel displaceable and focus-tunable electrowetting optofluidic lens. In comparison with the conventional optofluidic lens, our new lens has a different working principle and it can function as an optical zoom lens. The L-L interface can be displaced by a voltage. The object distance and image distance can be adjusted by shifting the L-L interface position to achieve the desired magnification, yet the lens can refocus the image by reshaping the L L interface with another voltage. Under such condition, only one lens is adequate to realize the zooming functionality. To prove the concept, we fabricate an optofluidic lens whose largest displaceable distance is ~8.3 mm and the zooming ratio is ~1.31 *. The proposed optofluidic lens greatly simplifies the zoom lens system. Widespread application of such an adaptive zoom lens is foreseeable. PMID- 30469680 TI - Active bidirectional electrically-controlled terahertz device based on dimethyl sulfoxide-doped PEDOT:PSS. AB - A high-efficiency active bidirectional electrically-controlled terahertz device based on DMSO-doped PEDOT:PSS with low-power photoexcitation is investigated. Under low-power optical excitation of 30 mW (0.5 W/cm2) and under bias voltages ranging from -0.6 V to 0.5 V, spectrally broadband modulation of THz transmission over a range from -54% to 60% is obtained over the frequency range from 0.2 to 2.6 THz in a MEH-PPV/PEDOT:PSS:DMSO/Si/PEDOT:PSS:DMSO hybrid structure. By considering the combined carrier density characteristics of the proposed device, it is found that the large-scale amplitude modulation can be ascribed to the electrically-controlled carrier density in the silicon layer with the assistance of the p-n junction that consists of the DMSO-doped PEDOT:PSS and silicon. Bidirectional modulation has a larger modulation range and is easier to use in communications applications when compared with unidirectional modulation. These results show great potential for application to the design of active broadband terahertz devices. PMID- 30469681 TI - Broadband snapshot complete imaging polarimeter based on dual Sagnac-grating interferometers. AB - A broadband snapshot complete imaging polarimeter (BSCIP), covering 400-700 nm, is presented. The device, which is based on two cascade Sagnac-grating interferometers, offers significant advantages over previous implementations. Specifically, with no moving parts, electrically controllable or micro polarization elements, the broadband full polarization images of a scene can be acquired in a single frame. The operation principle of the system is explained by using the Mueller calculus. Optical efficiency and interference visibility are calculated. Finally, the device's validity is demonstrated by Stokes parameters measurement and polarimetric imaging test experiments. PMID- 30469682 TI - High-speed ptychographic imaging based on multiple-beam illumination. AB - Ptychography is a lensless phase imaging technique that obtains an image by scanning a specimen at several points with respect to a localized illumination beam. For larger specimens, it takes a longer time to complete scanning and hence higher stability is required in the setup which is often not guaranteed. An alternative technique is proposed here that reduces the sequential scanning time for such applications. A pinhole array is used to generate multiple tiny spatially separated beams to scan an object simultaneously at various points. The resulting diffraction patterns are recorded and processed in the Fresnel regime to obtain the images. Unlike other ptychographic methods using multiple beams, the proposed method does not require the use of a multimode ptychography algorithm or autocorrelation filtering of the diffraction patterns. The effectiveness of the method is studied through simulations and experiments. In contrast to conventional single-beam ptychography, the proposed method has the ability to achieve a larger field of view while leaving the number of scanned positions unchanged. PMID- 30469683 TI - Depth reconstruction with coaxial multi-wavelength aperture telecentric optical system. AB - An optical system to measure depth information is proposed here. The proposed optical system has double coaxial multi-wavelength apertures, which makes it possible to simultaneously take an orthogonal projection image and a perspective projection image with these two images separated by wavelengths. The three dimensional physical position of an object can be derived with the ratio of the radial distances of these separated images with the centers located on the optical axis. Validation of the system by a ray-tracing simulation and an experiment shows that the proposed optical system can be used for depth reconstruction. PMID- 30469684 TI - Line of sight calibration for the laser ranging interferometer on-board the GRACE Follow-On mission: on-ground experimental validation. AB - The laser ranging interferometer (LRI) on board of the GRACE follow-on spacecraft, launched in May 2018, is the first laser interferometer to perform an inter-satellite range measurement. It is designed for ranging noise levels of 80 nm Hz-1/2 for frequencies above 20 mHz, i.e., about a ten-fold improvement with respect to the GRACE follow-on main microwave ranging instrument. One of the most critical steps during the commissioning phase of the instrument is the so-called initial line of sight calibration procedure (or initial acquisition). This process is required to quantify large uncertainties with respect to laser beam pointing angles and laser frequency, which must be known to establish the interferometer link. It is a nine hour scan of five degrees of freedom, which all need to match simultaneously at least once. Here we report on laboratory tests to further validate the calibration procedure using a mock-up LRI and a set-up, the so-called laser link simulator, that creates conditions similar to those with ~220 km distance between the SC. The experiments presented here made use of LRI like hardware and software and were carried out recreating critical conditions such as received laser powers on the pico-Watt level and their dependence on the SC misalignments, flat-top beams as receiving beams and Doppler frequency shifts. Several configurations were tested, including a full line of sight calibration with angular scans in both mock-up SC and frequency scan in one of the lasers. Results are well in agreement with the expectations and confirm, well before the LRI commissioning phase, the robustness of the procedure under realistic conditions, which had not yet been fully tested experimentally. PMID- 30469685 TI - Collective compensation of an inter-chip intensity discrepancy for a 4ch QPSK FE SOCDM system with Si-based ODFT and electrical DFT. AB - An intensity-sloped optical code with an optical chip-pulse stream generated by Si-based ODFT suffers from crosstalk and signal-to-noise (SNR) degradation. To mitigate these problems related to code-orthogonality reduction, we propose a simple intensity-discrepancy-compensation scheme that involves adjusting the chip level intensity in the digital-domain. We numerically show a 0.1 dB SNR improvement for 40 Gb/s quadrature phase-shift keying (QPSK) Fourier-encoded synchronized optical code division multiplexing (FE-SOCDM) signal when multiplexing 1 dB/chip intensity-sloped optical codes. A proof-of-principle experiment achieves a 0.3 dB received power improvement using intensity discrepancy compensation for two optical code multiplexing signals with 1.5 dB/chip. PMID- 30469686 TI - Proof-of-principle demonstration of parametric down-conversion source-based quantum key distribution over 40 dB channel loss. AB - Quantum key distribution (QKD) offers information-theoretic security verified by quantum mechanics to share keys between legitimate users. Most of the existing QKD systems employ active decoy states based on weak coherent sources (WCS). Meanwhile, parametric down-conversion (PDC) sources are seldom used due to several of their shortcomings. In the present work, to show the superiority of PDC sources, we have accomplished a proof-of-principle demonstration of a PDC source-based QKD with over 40 dB based on the one-way BB84 protocol. In this QKD system, a novel passive decoy-state scheme-secure to coherent attacks-is proposed, using several built-in decoy states for parameter estimation. This not only avoids intensity modulating errors, but also diminishes all possible information leakage from the intensity modulating process. The experimental results show a significantly enhanced performance compared with existing PDC source-based QKD systems. In addition, it exhibits some superiority even over active decoy-state QKD systems based on WCS. PMID- 30469687 TI - 120 Gbaud PAM-4 transmission over 80-km SSMF using optical band interleaving and Kramers-Kronig detection. AB - We demonstrate generation and detection of 120-Gbaud PAM-4 signals using an I/Q modulator based on optical band interleaving (OBI) technique. The spectral components of target PAM signals are split and pre-processed before being sent to two digital-to-analog convertors (sub-DACs) whose outputs are imprinted to an optical carrier by an optical I/Q modulator forming a carrier-suppressed tandem single side-band (SSB) signal. The PAM signals can be recovered after photo detection provided that an optical beating tone is added at the edge of the signal spectrum along with the modulator output. The proposed method requires only half of the Nyquist bandwidth of the target PAM signal for the transmitter and has the advantage of a simple implementation. Using Kramers-Kronig (K-K) detection, a 120 Gbaud PAM-4 transmission over 80-km standard single mode fiber (SSMF) is successfully demonstrated. The proposed scheme entails a simple implementation and a much lower bandwidth requirement at the transmitter compared with conventional all-electronic high baud rate signal generation schemes. PMID- 30469688 TI - Deterministic coupling of quantum emitters in WSe2 monolayers to plasmonic nanocavities. AB - We discuss coupling of site-selectively induced quantum emitters in exfoliated monolayers of WSe2 to plasmonic nanostructures. Gold nanorods of 20 nm-240 nm size, which are arranged in pitches of a few micrometers on a dielectric surface, act as seeds for the formation of quantum emitters in the atomically thin materials. We observe characteristic narrow-band emission signals from the monolayers, which correspond well with the positions of the metallic nanopillars with and without thin dielectric coating. Single photon emission from the emitters is confirmed by autocorrelation measurements, yielding g2(tau = 0) values as low as 0.17. Moreover, we observe a strong co-polarization of our single photon emitters with the frequency matched plasmonic resonances, as a consequence of light-matter coupling. Our work represents a significant step towards the scalable implementation of coupled quantum emitter-resonator systems for highly integrated quantum photonic and plasmonic applications. PMID- 30469689 TI - Liquid crystal-based tunable photodetector operating in the telecom C-band. AB - Liquid crystal (LC) microcells monolithically integrated on the surface of InGaAs based photodiodes (PDs) are demonstrated. These LC microcells acting as tunable Fabry-Perot filters exhibit a wavelength tunability of more than 100 nm around 1550 nm with less than 10V applied voltage. Using a tunable laser operating in the S and C bands, photocurrent measurements are performed. On a 70 nm tuning range covered with a driving voltage lower than 7V, the average sensitivity for the PD is 0.4 A/W and the spectral linewidth of the LC filter remains constant, showing a FWHM of 1.5 nm. Finally, the emission spectrum from an Er-doped fiber is acquired by using this tunable PD as a micro-spectrometer. PMID- 30469690 TI - Plasmonic resonance of distorted graphene nano-ribbon analyzed by boundary element method. AB - Surface plasmon resonances (SPRs) of graphene nano-ribbons (GNRs) have great application potentials in sensing, wave-front control and wave absorbing. However, as a flexible material, graphene is often observed with corrugations in the fabrication and transfer processes. Here the scattering properties of a distorted GNR with a bending ridge are studied by the boundary element method (BEM). It is found that, compared with the flat GNRs, the resonant wavelengths are red-shifted, and the resonant intensity of the 1st order mode is decreased, while that of the higher order modes are increased dramatically for the distorted GNRs. Particularly, due to the appearance of the ridge, both odd modes and even modes are able to be stimulated under tilted incidence. In addition, as the ridge increases, the resonances corresponding to various order modes change in different ways. Applying the spring oscillator theoretical model, these results are explained by the blocking effect of the ridge on the motions of electrons. This work is anticipated to help to understand the physical mechanisms of plasmonic resonances of curved GNRs and distorted structures. PMID- 30469691 TI - Twisted partially coherent array sources and their transmission in anisotropic turbulence. AB - A new class of twisted Schell-model array correlated sources are introduced based on Mercer's expansion. It turns out that such sources can be expressed as superposition of fully coherent Laguerre-Gaussian modes, and the twistable condition is established. Furthermore, on the basis of a stretched coordinate system and a quadratic approximation, analytical expressions for the mutual coherence function of an anisotropic non-Kolmogorov turbulence and the cross spectral density of a twisted Gaussian Schell-model array beam are rigorously derived. Due to the presence of the twist phase, the beam spot and the degree of coherence rotate as they propagate, but their rotation centers are different. It is shown that the anisotropy of turbulence causes an anisotropic beam spreading in the horizontal and vertical directions. However, impressing a twist phase on source beams can significantly inhibit this effect. For an anticipated atmospheric channel condition, a comprehensive selection of initial optical signal parameters, receiver aperture size and receiver capability, etc., is necessary. Our work is helpful for exploring new forms of twistable sources, and promotes guidance on optimization of partial coherent beam applications. PMID- 30469692 TI - Distributed polarization analysis with binary polarization rotators for the accurate measurement of distance-resolved birefringence along a single-mode fiber. AB - We describe a first distributed polarization analysis (DPA) system using binary polarization rotators in an optical frequency domain reflectormeter (OFDR) capable of measuring the variations of polarization states along a single-mode fiber (SMF). We demonstrate using such a DPA system to accurately measure the distance-resolved birefringence with 12 fiber loops of different radii with different birefringence values along a length of SMF and obtain a bending-induced birefringence coefficient (BBC) of 6.601 * 10-10 m2, agreeing well with the theoretically estimated value of 5.334 * 10-10 m2. To further verify the measurement accuracy, we obtain the birefringence values of the 12 fiber loops of different radii one at a time using a non-distributed polarization analysis system with an accuracy traceable to a birefringence standard made with a quartz crystal, and obtain a BBC value of 6.490 * 10-10 m2, agreeing well with our distributed measurement with a relative error of only 1.68%. In addition, we measure the residual birefringence of the SMF with both distributed and non distributed polarization analysis systems and obtain similar results with a relative error of only 0.59%. Our experiments not only validate the performances of our DPA system, but also the first to use DPA to experimentally obtain the accurate birefringence values along the SMF and verify the theory of bending induced birefringence. Our work further proves that such an OFDR-based DPA system is a practical tool for optical component characterization, nondestructive optical material inspection, and distributed fiber optic transversal stress sensing. PMID- 30469693 TI - Robust 700 MHz mode-locked Yb:fiber laser with a biased nonlinear amplifying loop mirror. AB - We demonstrate a self-starting 700 MHz repetition rate Yb:fiber laser incorporated with a phase biased nonlinear amplifying loop mirror as an artificial saturable absorber. The laser delivers a maximum power of 150 mW and a pulse width of 215 fs at a pump power of 710 mW. The integration of relative intensity noise (RIN) between 10 Hz and 10 MHz results in a minimum integrated RIN of 0.015%. The phase noise of the fundamental repetition rate was also characterized at different net-cavity dispersion. Although the laser is made of nonpolarization maintaining fiber, the mode locking sustains over two weeks in open air, showing its environmental stability. PMID- 30469694 TI - Synthetic imaging through wavy water surface with centroid evolution. AB - Imaging through a wavy water surface is a challenging task, as the wavy water surface introduces anisoplanatism effects difficult to model and track. A typical recovery method is usually involving multiple-stage processing on a pre-acquired image sequence. A new progressive restoration scheme is demonstrated, it can run simultaneously with image acquisition and mitigate both distortion and blur progressively. This method extends the anisotropic evolution in lucky region fusion with a novel progressive optical flow based de-warping scheme, centroid evolution. A comparison has been made with other state-of-art techniques, the proposed method can create comparable results, even with much less frames acquired. Experiments with real through-water scenes have also proved the effectiveness of the method. PMID- 30469695 TI - Determination of the thermally induced focal shift of processing optics for ultrafast lasers with average powers of up to 525 W. AB - The continuous increase of the average laser power of ultrafast lasers is a challenge with respect to the thermal load of the processing optics. The power which is absorbed in an optical element leads to a temperature increase, temperature gradients, changing refractive index and shape, and finally causes distortions of the transmitted beam. In a first-order approximation this results in a change of the focal position, which may lead to an uncon-trolled change of the laser machining process. The present study reports on investigations on the focal shift induced in thin plano-convex lenses by a high-power ultra-short pulsed laser with an average laser power of up to 525 W. The focal shift was determined for lenses made of different materials (N-BK7, fused silica) and with different coatings (un-coated, broadband coating, specific wavelength coating). PMID- 30469696 TI - High resolution photon time-tagging lidar for atmospheric point cloud generation. AB - The application of time-correlated single photon counting hardware and techniques to atmospheric lidar is presented. The results establish the viability of adapting photon time-tagging techniques to atmospheric lidar systems, facilitating high-range resolution (millimeter-level precision) and dynamic system observing capabilities that address the variety of atmospheric scatterers often present in atmospheric lidar profiles. The technique is demonstrated through measurements made by a high repetition rate, low pulse energy, elastic scattering, photon counting lidar. Detection probabilities with a non-zero system dead-time are derived and tested using acquired data. Atmospheric point cloud generation and the statistical implications on data retrievals utilizing this approach are presented. The results show an ability to preserve backscattered intensities while generating photon detections at picosecond resolution from a variety atmospheric scatterers. PMID- 30469697 TI - Intensity-dependent two-electron emission dynamics in nonsequential double ionization by counter-rotating two-color circularly polarized laser fields. AB - Nonsequential double ionization of helium in counter-rotating two-color circularly polarized laser fields is investigated with a three-dimensional classical ensemble model. At moderate intensity, the momentum distribution of the two electrons shows a maximum in the middle of each side of the triangle of the negative vector potential. At high intensity, the momentum distribution exhibits a double-triangle structure, which is attributed to the different values of the laser intensity where the two electrons are released after recollision. At low intensity, the momentum distribution shows a shift deviating from the middle of the side of the triangle of the negative vector potential. This is because the first electrons are emitted within a narrow time window after the field maximum. In addition, at low intensity, double-recollision events and NSDI originating from doubly excited states induced by recollision are prevalent. PMID- 30469698 TI - Temperature sensor with enhanced sensitivity based on silicon Mach-Zehnder interferometer with waveguide group index engineering. AB - We propose a highly-sensitive temperature sensor employing a Mach-Zehnder interferometer (MZI) based on silicon-on-insulator (SOI) platform. The waveguide widths in the two MZI arms are tailored to have different temperature sensitivities but nearly the same group refractive indices. A temperature sensor with an enhanced sensitivity of larger than 438pm/ degrees C is experimentally demonstrated, which is over seven times larger than that of conventional silicon optical temperature sensor (about 60pm/ degrees C for quasi-TM mode). Moreover, the sensor is easy to fabricate, only by a single mask, and no need of any polymer cladding, which makes it more robust, and can be used in lab-on-chip systems as a temperature monitor. PMID- 30469699 TI - Artifact-free, penetration-adjustable elliptical-mirror-based TIRF microscopy. AB - Evanescent field distribution in the focal region of the elliptical-mirror-based total-internal-reflection fluorescence (e-TIRF) microscopy is analyzed based on vectorial diffraction theory. The simulation demonstrates that the intensity of an evanescent field generated by elliptical mirror decreases exponentially with the penetration depth, and the polarization characteristic of the evanescent wave in various directions is given. We build up an e-TIRF microscope utilizing a focused hollow-cone illumination with all-direction and large range of incidence. The experiment shows the artifact effect can be well suppressed by using the azimuthal-direction illumination method. In addition, the penetration depth of the evanescent field can be controlled by adjusting the sizes of the aperture and obstruction with a large range. PMID- 30469700 TI - Simulation of 2um single clad thulium-doped silica fiber amplifiers by characterization of the 3F4 - 3H6 transition. AB - We report measurements of absorption, gain, and the lifetime of the transition 3H6 - 3F4 for three commercially available thulium-doped single clad silica fibers. These measurements are used in a steady-state simulation of thulium-doped fiber amplifiers (TDFAs). Comparison of simulation and experimental results yield good agreement for a single stage TDFA at 1952 nm and a tandem TDFA at 1910 nm. PMID- 30469701 TI - Multi-wavelength multi-angle reflection tomography. AB - We have developed a reflection tomographic microscope in which the sample is reconstructed from different holograms recorded under various angles and wavelengths of incidence. We present an iterative inversion algorithm based on a rigorous modeling of the wave-sample interaction that processes all the data simultaneously to estimate the sample permittivity distribution. We show that using several wavelengths permits a significant improvement of the reconstruction, especially along the optical axis. PMID- 30469702 TI - Broadband transmission Raman measurements using a field-widened spatial heterodyne Raman spectrometer with mosaic grating structure. AB - A field-widened spatial heterodyne Raman spectrometer with a mosaic grating structure is developed for the simultaneous sensitivity enhancement and broadband transmission Raman measurements. We optimize the etendue to maximize the signals collected from the samples by using field-widening prisms and employ two mosaic gratings to achieve broadband operation, covering 5638 cm-1 with 2.865 cm-1 spectral resolution. The signal-to-noise ratios are improved by a factor of more than 11 and show a good stability and fair repeatability. We investigate the effects of the sample thickness and outer layer depth and observe liquids, solids, mixed targets, and anti-Stokes shifts. The instrument exhibits good performance for wide-field, high-resolution broadband transmission Raman measurements. PMID- 30469703 TI - On-the-fly estimation of a microscopy point spread function. AB - A proper estimation of realistic point-spread function (PSF) in optical microscopy can significantly improve the deconvolution performance and assist the microscope calibration process. In this work, by exemplifying 3D wide-field fluorescence microscopy, we propose an approach for estimating the spherically aberrated PSF of a microscope, directly from the observed samples. The PSF, expressed as a linear combination of 4 basis functions, is obtained directly from the acquired image by minimizing a novel criterion, which is derived from the noise statistics in the microscope. We demonstrate the effectiveness of the PSF approximation model and of our estimation method using both simulations and real experiments that were carried out on quantum dots. The principle of our PSF estimation approach is sufficiently flexible to be generalized non-spherical aberrations and other microscope modalities. PMID- 30469704 TI - Pixelated phosphors for high-resolution and high-contrast white light sources. AB - Porous phosphor microstructures are studied for their potential as light converter in laser-based, high-resolution lighting systems. Phosphor particles are filled into pre-patterned silicon molds and coated by an atomic layer deposition with a thin layer of Al2O3 for mechanical stability. Pixel sizes of 2 mm by 2 mm down to 25 um by 25 um are fabricated. The structures show a significant drop in luminance between the illuminated and the non-illuminated, adjacent pixel. The high thermal conductivity of the silicon allows an efficient cooling of the structures. Having removed the backside silicon, an active air flow cooling of the porous phosphor structure is possible. PMID- 30469705 TI - Wavelength-division multiplexing Si photonic crystal beam steering device for high-throughput parallel sensing. AB - We proposed and demonstrated a wavelength-division multiplexing (WDM) optical beam-steering device consisting of a thermally controlled doubly periodic Si two dimensional bulk photonic crystal waveguide and coupled microring multiplexers. Beam forming and steering while maintaining a sharp profile is much easier in this device than with optical phased arrays which need the fine phase control. By dividing the range of beam-steering angles into different wavelength channels, it is possible to cover a wide range of angles, even when each angle is small. In this study, we fabricated a device with four wavelength channels, each of which showed beam steering of 4 degrees -5 degrees as a result of heating, resulting in a total of 16 degrees . Two-dimensional steering is also achieved by loading a collimator lens and selecting one waveguide from those arrayed. We evaluated 112 resolution points with four wavelengths and 448 points in total by switching four waveguides. If this WDM concept is introduced into light detection and ranging and the number of wavelengths is increased, it will be possible to increase the sensing throughput, which is usually constrained by the round-trip time of light, by simultaneous parallel operation. PMID- 30469706 TI - Nonlinear optical effects during femtosecond superradiant emission generation in semiconductor laser structures. AB - This paper presents theoretical and experimental studies of ultrabright internal second harmonic during femtosecond superradiant emission generation in multiple sections GaAs/AlGaAs laser structures at room temperature. Experimentally measured conversion efficiencies are by 1-2 orders of magnitude greater than expected. To explain this fact, a model based on one-dimensional nonlinear Maxwell curl equations without taking into consideration the slowly-varying envelope approximation has been developed. It has been demonstrated that strong transient periodic modulation of e-h density and refraction index dramatically affects the process of superradiance in semiconductor media and can explain the ultrastrong internal second harmonic generation. PMID- 30469707 TI - Illumination separation of non-Lambertian scenes from a single hyperspectral image. AB - In this paper, we propose a general framework to estimate the spectrum of the illumination from global specular information in a single hyperspectral image. By utilizing the specular independent subspace, we iteratively separate the reflectance components and shape a weight scheme in order to find specular contaminated pixels. After that, the illumination can be directly estimated by factorizing the weighted specular-contaminated pixels. The proposed method enables a direct and effective decomposition of the illumination and reflectance components from a single hyperspectral image. We demonstrate the robustness and accuracy of our method on simulation and real experiments. Moreover, we capture a hyperspectral image dataset with ground-truth illumination to quantitative compare the performance. PMID- 30469708 TI - Efficient laser operations of unprocessed thin plate of Nd:YPO4 crystal. AB - The laser properties of Nd:YPO4 crystal were demonstrated for the first time. For a 1.2 at.% doped Nd:YPO4 crystal, the absorption cross-section at 803 nm, stimulated emission cross-section at 1063 nm, and fluorescence lifetime was measured to be 8.1 * 10-20 cm2, 1.6 * 10-19 cm2, 156 MUs, respectively. With an as-grown 0.6 mm thin slice which was unpolished and uncoated, efficient diode pumped continue-wave (CW) laser operations were realized at 1.06 and 1.3 MUm wavebands. The 1063 nm output power reached 2.16 W when the absorbed pump power was 4.07 W, corresponding to an optical-to-optical efficiency of 53%, and a slope efficiency of 56.4%. The 1.3 MUm laser output exhibited the simultaneous operations of dual-wavelengths, i.e. 1338 and 1347 nm. The maximum output power was 800 mW at an absorbed pump power of 3.08 W, giving an optical-to-optical efficiency of 26% and a slope efficiency of 28.2%. PMID- 30469709 TI - Experimental demonstration of a flexible DOE loop with wideband speckle suppression for laser pico-projectors. AB - The compact and straightforward construction of a pico-projector using an original method for speckle suppression via a simple 1D diffractive optical element (DOE) structure on a loop of flexible film with tracked motion is demonstrated. The 1D-DOE structure is based on binary pseudorandom sequences. The method requires very little energy and space and can decrease speckle noise to levels below the detection sensitivity of the human eye. Large speckle suppression coefficients and low speckle contrasts are obtained for blue, green, and red lasers. Speckle suppression efficiency will be further significantly improved by optimization of the DOE structure and film material. PMID- 30469710 TI - High-Q antisymmetric multimode nanobeam photonic crystal cavities in silicon waveguides. AB - Antisymmetric multimode nanobeam photonic crystal cavities (AM-NPCs) are proposed and demonstrated in this paper. Due to transverse symmetry-breaking of the antisymmetric multimode periodic waveguide, anti-crossing of the fundamental mode and 1st-order mode is realized and confirmed by band structure calculation. Two mode filtering and reflection-free cavity filters based on this characteristic are demonstrated. Experimental results on silicon-on-insulator platform shows that broadband (> 100 nm) reflection suppression (< -10 dB) and high-Q (7 * 104) AM-NPCs can be achieved using existed design methodology and fabrication facility. We also explain resonance splitting of the measured transmission spectra and find resonance-enhanced mode-conversion phenomena in the AM-NPCs. PMID- 30469711 TI - Near-infrared acetylene sensor system using off-axis integrated-cavity output spectroscopy and two measurement schemes. AB - For highly sensitive and accurate acetylene (C2H2) detection, a near-infrared (NIR) off-axis integrated-cavity output spectroscopy (OA-ICOS) sensor system based on an ultra-compact cage-based absorption cell was proposed. The absorption cell with dimensions of 10 cm * 8 cm * 6 cm realized a dense-pattern and an easily-aligned stable optical system. The OA-ICOS sensor system employed a 6cm long optical cavity that was formed by two mirrors with a reflectivity of 99.35% and provided an effective absorption path length of ~9.28 m. The performance of the C2H2 sensor system based on two measurement schemes, i.e. laser direct absorption spectroscopy (LDAS) and wavelength modulation spectroscopy (WMS) is reported. A NIR distributed feedback (DFB) laser was employed for targeting a C2H2 absorption line at 6523.88 cm-1. An Allan deviation analysis yielded a detection sensitivity of 760 parts-per-billion in volume (ppbv) for an averaging time of 304 s using the LDAS-based OA-ICOS. A detection sensitivity of 85 ppbv for an averaging time of 250 s was obtained using the WMS-based OA-ICOS, which was further improved by a factor of ~9 compared to the result obtained with the LDAS method. The proposed sensor system has the advantages of reduced size and cost with acceptable detection sensitivity, which is suitable for applications in trace gas sensing in harsh environments and weight-limited balloon-embedded observations. PMID- 30469712 TI - Fully-correlated multi-mode pumping for low-noise dual-frequency VECSELs. AB - We report a fully-correlated multi-mode pumping architecture optimized for dramatic noise reduction of a class-A dual-frequency Vertical External Cavity Surface Emitting Laser (VECSEL). Thanks to amplitude division of a laser diode, the two orthogonally polarized modes emitted by the VECSEL oscillating at 852 nm are separately pumped by two beams exhibiting fully in-phase correlated intensity noises. This is shown to lead to very strong and in-phase correlations between the two lasing modes intensities. As a result, the phase noise power spectral density of the RF beat note generated by the two modes undergoes a drastic reduction of about 10 to 20 dB throughout the whole frequency range from 10 kHz to 20 MHz and falls below the detection floor above a few MHz. A good agreement is found with a model which uses the framework of rate equations coupled by cross saturation. The remaining phase noise is attributed to thermal effects and additional technical noises and lies mainly within the bandwidth of a phase locked-loop. PMID- 30469713 TI - Ultra-broadband terahertz absorption using bi-metasurfaces based multiplexed resonances. AB - In this paper, we demonstrate an ultra-broadband terahertz (THz) bi-metasurfaces absorber composed of two stacking metasurfaces backed by a metallic ground plane. The bottom metasurface consists of four multiplexed cross resonators with different geometries on a thin parylene layer, achieving a bandwidth of 3.80 THz with the absorption higher than 50% at high frequency. Meanwhile, the top metasurface, including two multiplexed cross resonators with different sizes on a relatively thicker parylene layer, provides a low frequency absorption band with an additional Salisbury screen absorption peak that connects the two absorption bands of the two metasurfaces, therefore enabling an ultra-broadband absorption. The experimental absorption spectrum of the bi-metasurfaces shows a bandwidth of 4.46 THz while the absorption exceeding 50% and a full width at half maxima (FWHM) of 97.7%. The ultra-broadband absorber will be a promising candidate for THz broadband detection. PMID- 30469714 TI - Ultra-broadband linear polarization converter based on anisotropic metasurface. AB - Through the manipulation of co-polarized reflection and cross-polarized reflection from a periodic array of metal-dielectric-metal resonators, a plethora of unprecedented metamaterial devices have been successfully demonstrated, such as perfect absorber and polarization converter. Recently, some broadband absorbers based on anisotropic resonators have been reported, which are actually poor absorbers when the cross-polarized reflection is considered. Here, we demonstrate that an ultra-wideband and high-efficiency reflective cross polarization convertor can be achieved by breaking the symmetry of the resonator unit of a perfect absorber. Simulation results show that the polarization conversion ratio of the proposed metasurface is above 90% in the frequency range from 6.67 to 17.1 GHz and the relative bandwidth reaches 87.7%. The experimental results are in good agreement with the simulation results. The method paves a new way for the design of broadband polarization convertor, which can also be extended to the terahertz band. PMID- 30469715 TI - Efficient and broadband subwavelength grating coupler for 3.7 MUm mid-infrared silicon photonics integration. AB - A grating coupler is an essential building block for compact and flexible photonics integration. In order to meet the increasing demand of mid-infrared (MIR) integrated photonics for sensitive chemical/gas sensing, we report a silicon-on-insulator (SOI) based MIR subwavelength grating coupler (SWGC) operating in the 3.7 MUm wavelength range. We provide the design guidelines of a uniform and apodized SWGC, followed by numerical simulations for design verification. We experimentally demonstrate both types of SWGC. The apodized SWGC enables high coupling efficiency of -6.477 dB/facet with 3 dB bandwidth of 199 nm, whereas the uniform SWGC shows larger 3dB bandwidth of 263.5 nm but slightly lower coupling efficiency of -7.371 dB/facet. PMID- 30469716 TI - Reconfigurable three-dimensional mode (de)multiplexer/switch via triple-silicon ITO-waveguide directional coupler. AB - A reconfigurable mode (de)multiplexer/switch (RMDS) is a pivotal component for the mode routing in mode-division multiplexing (MDM) networks. Here, we propose a three-dimensional (3D) RMDS via a triple-waveguide directional coupler, consisting of a lower doped silicon waveguide, a central plasmonic horizontal slot waveguide with indium-tin-oxide (ITO) and an upper doped polycrystalline silicon waveguide. The enhanced light-matter-interactions can be achieved via the central plasmonic metal-oxide-semiconductor (MOS) mode. The multiplexing states of the proposed 3D-RMDS can be switched by adjusting the applied voltage bias on the ITO layer. The simulation results reveal that a 3D quasi-TM0 and quasi-TM1 RMDS is with a compact length of 8.429 MUm, the mode crosstalk of -20.3 dB (-9.2 dB) and the insertion loss of 0.06 dB (1.47dB) at the wavelength of 1550 nm for the "OFF" ("ON") state, respectively. The proposed 3D-RMDS can be applied in future 3D on-chip MDM networks to achieve a flexible mode-routing and further enhance the transmission capacity. PMID- 30469717 TI - Hybrid long-range hyperbolic phonon polariton waveguide using hexagonal boron nitride for mid-infrared subwavelength confinement. AB - Long propagation waveguides are critical for any photonic-on-chip applications. There has been an extensive investigation in using plasmon polaritons for near infrared and optical networks, however, for mid- to long-wave IR applications phonon polaritons are required given that plasmonic polaritonic effects are negligible. In recent years, extensive research has been conducted on hexagonal boron nitride (h-BN), which has shown h-BN to have naturally occurring subwavelength, volumetrically confined hyperbolic phonon polaritons (HPhPs). This work presents numerical results for both long- and short-range phononic volumetric polariton modes in a slab of h-BN. A hybrid long-range phononic waveguide consisting of two identical dielectric cylinder wires symmetrically placed on each side of the h-BN slab is coupled to the long-range HPhP mode. Based on analytical coupled-mode theory and computational finite element analysis, we have investigated the modal characteristics of the hybrid long-range phonon polaritonic waveguide. Due to the strong coupling between the high index cylindrical-waveguide mode and the HPhPs in the h-BN thin film, subwavelength confinement can be achieved (modal area ranging from 10-2lambdao2 to 10 1lambdao2) while enabling long propagation distances (7lambda0-370lambda0). PMID- 30469718 TI - Second harmonic generation in metal-LiNbO3-metal and LiNbO3 hybrid-plasmonic waveguides. AB - Nanoplasmonic waveguides based on lithium niobate (LN) are shown to provide the light-matter interaction required for next-generation developments in nonlinear frequency-conversion nanostructures. Here, we numerically investigate second harmonic generation of a 1550 nm, 100 fs pulse in metal-LN-metal (MLNM) nanoplasmonic and LN hybrid-plasmonic (LNHP) waveguides. In comparison to a photonic LN waveguide, a 2.1 um-long LNHP waveguide exhibits a conversion efficiency improvement of 11 times, whereas a 20 um-long MLNM nanoplasmonic waveguide is shown to have a conversion efficiency of 1.1 * 10-4. The MLNM nanoplasmonic and LNHP waveguides have the potential to operate as sources of optical radiation for on-chip photonic systems. PMID- 30469719 TI - Multicascade-linked synthetic wavelength digital holography using an optical-comb referenced frequency synthesizer. AB - Digital holography (DH) is a promising method for non-contact surface topography because the reconstructed phase image can visualize the nanometer unevenness in a sample. However, the axial range of this method is limited to the range of the optical wavelength due to the phase wrapping ambiguity. Although the use of two different wavelengths of light and the resulting synthetic wavelength, i.e., synthetic wavelength DH, can expand the axial range up to several hundreds of millimeters, its axial precision does not reach sub-micrometer. In this article, we constructed a tunable external cavity laser diode phase-locked to an optical frequency comb, namely, an optical-comb-referenced frequency synthesizer, enabling us to generate multiple synthetic wavelengths within the range of 32 um to 1.20 m. A multiple cascade link of the phase images among an optical wavelength ( = 1.520 um) and 5 different synthetic wavelengths ( = 32.39 um, 99.98 um, 400.0 um, 1003 um, and 4021 um) enables the shape measurement of a reflective millimeter-sized stepped surface with the axial resolution of 34 nm. The axial dynamic range, defined as the ratio of the axial range ( = 2.0 mm) to the axial resolution ( = 34 nm), achieves 5.9 * 105, which is larger than that of previous synthetic wavelength DH. Such a wide axial dynamic range capability will further expand the application field of DH for large objects with meter dimensions. PMID- 30469720 TI - Effect of surface recombination in high performance white-light CH3NH3PbI3 single crystal photodetectors. AB - Methylammonium lead iodide (CH3NH3PbI3), with the organic-inorganic hybrid perovskite (OIHP) structure, has gained tremendous research interest due to its excellent photo-electron conversion ability in the application of photovoltaics. Despite its solution processed polycrystalline thin film form in solar cells, the single crystalline counterpart may offer some incredibly novel optoelectronic functionalities. In this work, a sizable (>5 mm) and high quality CH3NH3PbI3 single crystal has been synthesized by the inverse temperature crystallization method, and a white-light photodetector of the structure glass/ITO/Ga/ CH3NH3PbI3/Au was fabricated. Overbroad photo-excitation intensities ranging from 0.1 mW/cm2 to 100 mW/cm2 using a sun-light simulator, the on-off ratio is tunable in a wide-range from 65 to 2250 at zero bias voltage. The responsivity (R) and detectivity (D*) are 36.2 mA/W and 2.68*1011 Jones respectively at a weak white light intensity such as 0.1 mW/cm2. Both the photodetective parameters decrease with the increase of the illumination intensity. Based on impedance spectra obtained at working condition and light intensity dependent Jsc measurements, the surface trap-assist recombination may play a dominating role. The corresponding lifetime (tausurf) and resistance (Rsurf_trap) exhibit fast decays at higher illumination intensities. This fundamental study may pave the way for exploring the contribution of the surface trap-assist recombination in the CH3NH3PbI3 single crystal based photodetector. We believe it is applicable for integration in micro-photonics for sensitive and weak white-light photo-detection. PMID- 30469721 TI - Integration of stimulated Raman gain and stimulated Raman losses detection modes in a single nonlinear microscope. AB - This work addresses some key challenges in the fields of bio and nanophotonics by stimulated Raman microscopy. We present the design and the implementation of a femtosecond stimulated Raman scattering microscope, equipped with three femtosecond laser sources, which allows the coexistence of stimulated Raman gain (SRG) and stimulate Raman losses (SRL) detection modes in a single microscopy setup and to generate images of the same region in succession, without adding or removing components. In order to demonstrate the switching between the two detection modes, SRL and SRG images of polystyrene beads are acquired and the images quality are evaluated and compared. PMID- 30469722 TI - Lensing and waveguiding in birefringent double-twist cylinders demonstrated using FDTD simulations. AB - We demonstrate that birefringent profiles of double-twist cylinders, found in some chiral nematic systems such as blue phases, can perform as polarization selective microlenses and waveguides in the regime of negative birefringence. Specifically, we solve Maxwell's equation using the finite-difference time-domain (FDTD) method, to simulate light propagation through double-twist cylinder birefringent structures. We show that, in case of negative material birefringence, azimuthally polarized beams experience lensing which can further be extended to waveguiding in double-twist cylinders. Lensing and waveguiding efficiency are shown to be strongly dependent on the ratio between the width of the double-twist cylinder profile and the beam width. We further characterize waveguiding in terms of losses, which are investigated in case of straight as well as curved double-twist cylinders. More generally, this work is a contribution to the design and development of (soft) birefringent profiles for optical and photonic applications. PMID- 30469723 TI - Design of rare-earth-doped microbottle lasers. AB - Coupling strength in taper-coupled microbottle resonators can be tuned by offsetting the taper along the resonator profile, similar to controlling the air gap in microsphere excitation, and hence, achieve desired coupling characteristics for a specific mode. Such flexibility makes microbottles attractive and adaptable laser cavities. In this paper, lasing characteristics of Yb3+-doped microbottle laser (MBL) coupled to tapered fiber are theoretically investigated. It is demonstrated that desired lasing characteristics for a particular mode are achievable by controlling the taper-resonator coupling, intrinsic quality factor (Q) and dopant concentration. Although, high Q whispering gallery cavities provide high internal powers, which is favorable especially for low gain materials, they lack high output powers. Hence, care should be taken in designing MBLs to attain the highest possible output power. Here, we address such issues, and optimized the required resonator parameters (for both pump and signal) for a low threshold pump power, high efficiency and desired lasing wavelength. PMID- 30469724 TI - High-power blue superluminescent diode for high CRI lighting and high-speed visible light communication. AB - We demonstrated a high-power (474 mW) blue superluminescent diode (SLD) on c plane GaN-substrate for speckle-free solid-state lighting (SSL), and high-speed visible light communication (VLC) link. The device, emitting at 442 nm, showed a large spectral bandwidth of 6.5 nm at an optical power of 105 mW. By integrating a YAG-phosphor-plate to the SLD, a CRI of 85.1 and CCT of 3392 K were measured, thus suitable for solid-state lighting. The SLD shows a relatively large 3-dB modulation bandwidth of >400 MHz, while a record high data rate of 1.45 Gigabit per-second (Gbps) link has been achieved below forward-error correction (FEC) limit under non-return-to-zero on-off keying (NRZ-OOK) modulation scheme. Our results suggest that SLD is a promising alternative for simultaneous speckle-free white lighting and Gbps data communication dual functionalities. PMID- 30469725 TI - Near-field nanoprobing using Si tip-Au nanoparticle photoinduced force microscopy with 120:1 signal-to-noise ratio, sub-6-nm resolution. AB - We propose using a Si tip-Au nanoparticle (NP) combination system in photoinduced force microscopy (PiFM) to fundamentally improve its accuracy in the nanoscale characterization of light-matter interaction. Compared to conventional PiFM with Au-coated tips, such Si tip and Au NP combination enables superior photo-induced force detection while overcoming the tip-induced anisotropy by Au-coating. We map the near-field distribution of Au NPs in different arrangements achieving 120 signal-to-noise ratio and sub-6-nm resolution, even surpassing the tip-curvature limitation; we also map the azimuthally polarized beam profile showing an excellent symmetry. The proposed approach is essential to the promising single molecule spectroscopy. PMID- 30469726 TI - Broadband terahertz pulse generation driven by an ultrafast thin-disk laser oscillator. AB - We demonstrate broadband THz generation driven by an ultrafast thin-disk laser (TDL) oscillator. By optical rectification of 50-fs pulses at 61 MHz repetition rate in a collinear geometry in crystalline GaP, THz radiation with a central frequency at around 3.4 THz and a spectrum extending from below 1 THz to nearly 7 THz are generated. We realized a spectroscopic characterization of a GaP crystal and a benchmark measurement of the water-vapor absorption spectrum in the THz range. Sub-50-GHz resolution is achieved within a 5 THz bandwidth. Our experiments show the potential of ultrafast TDL oscillators for driving MHz repetition-rate broadband THz systems. PMID- 30469727 TI - Generation of propagation-invariant and intensity-controlled dark hollow beams by a refractive beam shaping system. AB - Dark hollow beams (DHBs) have great potential in the applications of optical manipulation, and the generation of DHBs is still a challenging and rewarding issue. In this paper, we present a beam shaping system for generating DHBs. The proposed system is composed of a freeform lens array and a non-classical zoom system which has a constant focal length but various image locations. The DHBs with a well-controlled intensity profile generated by the proposed system is not sensitive to the change of the intensity distribution of the incident beam, which allows flexible choices of light sources. Moreover, the annular pattern produced by the DHB remains unchanged when the image plane is moved a long distance of 17mm, and the energy efficiency of the beam shaping system is greater than 90% when Fresnel loss is considered. The proposed beam shaping system endows the generated DHBs with new properties and may have great potential in the field of optical tweezers and atom guides. PMID- 30469728 TI - Broadband lower-IF RF receiver based on microwave photonic mixer and Kramers Kronig detection. AB - A broadband lower- intermediate-frequency (IF) radio frequency (RF) receiver with low cost and complexity based on a microwave photonic mixer and Kramers-Kronig (KK) detection is proposed and experimentally demonstrated. The feasibility of the proposed RF receiver is verified by comparing the error vector magnitude (EVM) performance of a down-converted IF signal with and without KK detection. EVM is measured as a function of IF carrier frequency, input local oscillator (LO) power, input RF power, and the coupling ratio between RF and LO paths. With KK detection, EVM can be improved by more than 9.5% when the IF carrier frequency is close to half of the signal bandwidth. This implies that a lower IF frequency can be down-converted with good EVM and that a low-speed photodetector and a low sampling rate analog to digital converter can be used for wideband RF signal reception. PMID- 30469729 TI - Femtosecond laser pulse generation with self-similar amplification of picosecond laser pulses. AB - Compressing picosecond laser pulses to the femtosecond level is an attractive shortcut for obtaining femtosecond laser pulses. However, dechirped pulses generated by nonlinear compression with self-phase modulation (SPM) show obvious pedestals, which are induced by nonlinear chirp accumulation in spectral broadening process and cannot be easily suppressed. Here, we report systematic numerical simulations and experimental studies on self-similar amplification of picosecond pulses in a short gain fiber for obtaining ~100-fs laser pulses with nearly transform-limited (TL) temporal quality. It is demonstrated that self similar amplification with picosecond seed pulses is only sensitive to pulse duration and pulse energy. Based on this optimization guideline, we built a compact self-similar amplification fiber system with a picosecond fiber laser as the seed source. This system outputs 66-fs pulses with 6.1-W average power at a repetition rate of 30 MHz. Due to the linear chirp produced in self-similar evolution process, compressed pulses show nearly TL temporal quality. It promises an efficient way of obtaining high-quality femtosecond laser pulses from a picosecond laser source. PMID- 30469730 TI - Feedback control for microring weight banks. AB - Microring weight banks present novel opportunities for reconfigurable, high performance analog signal processing in photonics. Controlling microring filter response is a challenge due to fabrication variations and thermal sensitivity. Prior work showed continuous weight control of multiple wavelength-division multiplexed signals in a bank of microrings based on calibration and feedforward control. Other prior work has shown resonance locking based on feedback control by monitoring photoabsorption-induced changes in resistance across in-ring photoconductive heaters. In this work, we demonstrate continuous, multi-channel control of a microring weight bank with an effective 5.1 bits of accuracy on 2Gbps signals. Unlike resonance locking, the approach relies on an estimate of filter transmission versus photo-induced resistance changes. We introduce an estimate still capable of providing 4.2 bits of accuracy without any direct transmission measurements. Furthermore, we present a detailed characterization of this response for different values of carrier wavelength offset and power. Feedback weight control renders tractable the weight control problem in reconfigurable analog photonic networks. PMID- 30469731 TI - Spatio-spectral metrology at focus of ultrashort lasers: a phase-retrieval approach. AB - The complete characterization of an ultrashort laser beam ultimately requires the determination of its spatio-temporal electric field E(x, y, t), or its spatio spectral counterpart E(x, y, omega). We describe a new measurement technique called INSIGHT, which determines E(x, y, omega), up to an unknown spatially homogeneous spectral phase. Combining this information with a temporal measurement at a single point of the beam then enables the determination of the spatio-temporal field E(x, y, t). This technique is based on the combination of spatially-resolved Fourier-transform spectroscopy with an alternate-projection phase-retrieval algorithm. It can be applied to any reproducible laser source with a repetition rate higher than about 0.1 Hz, relies on a very simple device, does not require any reference beam, and circumvents the difficulty associated with the manipulation of large beam diameters by working in the vicinity of the beam focus. We demonstrate INSIGHT on a 100 TW-25 fs laser, and use the measurement results to introduce new representations for the analysis of spatio temporal/spectral couplings of ultrashort lasers. PMID- 30469732 TI - 7 to 8 um emission from Sm3+ doped selenide fibers. AB - We report on the observation of the long wave-infrared (LWIR) emission centered at 7.3 um of Sm3+ doped chalcogenide fibers. The chemical composition of the selenide glass host matrix (Ga5Ge20Sb10Se65) enables the drawing of 500 ppm and 1000 ppm Sm3+ doped fibers. By means of conventional glass elaboration methods, these Sm3+ doped fibered materials exhibit a significant emission band from 6.5 to 8.5 um with a maximum emission around 7.3 um whether they are excited at 1.45 um or at 2.05 um. Absorption spectra, Judd-Ofelt analysis, NIR, MWIR and LWIR luminescence spectra are presented and discussed. PMID- 30469733 TI - Deep learning approach for Fourier ptychography microscopy. AB - Convolutional neural networks (CNNs) have gained tremendous success in solving complex inverse problems. The aim of this work is to develop a novel CNN framework to reconstruct video sequences of dynamic live cells captured using a computational microscopy technique, Fourier ptychographic microscopy (FPM). The unique feature of the FPM is its capability to reconstruct images with both wide field-of-view (FOV) and high resolution, i.e. a large space-bandwidth-product (SBP), by taking a series of low resolution intensity images. For live cell imaging, a single FPM frame contains thousands of cell samples with different morphological features. Our idea is to fully exploit the statistical information provided by these large spatial ensembles so as to make predictions in a sequential measurement, without using any additional temporal dataset. Specifically, we show that it is possible to reconstruct high-SBP dynamic cell videos by a CNN trained only on the first FPM dataset captured at the beginning of a time-series experiment. Our CNN approach reconstructs a 12800*10800 pixel phase image using only ~25 seconds, a 50* speedup compared to the model-based FPM algorithm. In addition, the CNN further reduces the required number of images in each time frame by ~ 6*. Overall, this significantly improves the imaging throughput by reducing both the acquisition and computational times. The proposed CNN is based on the conditional generative adversarial network (cGAN) framework. We further propose a mixed loss function that combines the standard image domain loss and a weighted Fourier domain loss, which leads to improved reconstruction of the high frequency information. Additionally, we also exploit transfer learning so that our pre-trained CNN can be further optimized to image other cell types. Our technique demonstrates a promising deep learning approach to continuously monitor large live-cell populations over an extended time and gather useful spatial and temporal information with sub-cellular resolution. PMID- 30469734 TI - High repetition rate gain-switched Ho-doped fiber laser at 2.103 MUm pumped by h shaped mode-locked Tm-doped fiber laser at 1.985 MUm. AB - We present a MHz level high repetition rate gain-switched Ho-doped fiber laser at 2.103 MUm using a h-shaped mode-locked Tm-doped fiber laser as the pump, for the first time. A NPR mode-locked Tm-doped ring cavity was designed as the seed, which could generate h-shaped pulses at 1.985 MUm with a fundamental repetition rate of 1.435 MHz. It had a pump-dependent ns scale pulse duration with an almost unchanged peak amplitude. Then its output power and pulse energy were significantly scaled to 3.92W and 2.71 MUJ, respectively based on a one-stage Tm doped fiber based amplifier. After that, the amplified pulses were fed to a linear cavity Ho-doped fiber laser formed by a HR FBG and a perpendicularly cleaved fiber end, resulting in stable gain-switched pulses at 2.103 MUm with a repetition rate of 1.435 MHz, which marks the record of gain-switched fiber lasers in this spectral region. At this repetition rate, the maximum output power of 1.13 W and pulse energy of 0.79 MUJ were achieved at a high slope efficiency of 75.4% with respect to its absorbed pump power, giving the shortest pulse duration of 10.8 ns. The results indicated that the h-shaped pulses were an alternative choice for high repetition rate gain-switching in an all-fiber configuration. PMID- 30469735 TI - Complete plenoptic imaging using a single detector. AB - Multi-dimensional imaging is a powerful technique for many applications, such as biological analysis, remote sensing, and object recognition. Most existing multi dimensional imaging systems rely on scanning or camera array, which make the system bulky and unstable. To some extent, these problems can be mitigated by employing compressed sensing algorithms. However, they are computationally expensive and highly rely on the ill-posed assumption that the information is sparse in a given domain. Here, we propose a snapshot spectral-volumetric imaging (SSVI) system by introducing the paradigm of light-field imaging into Fourier transform imaging spectroscopy. We demonstrate that SSVI can reconstruct a complete plenoptic function, P(x,y,z,theta,phi,lambda,t), of the incoming light rays using a single detector. Compared with other multidimensional imagers, SSVI features prominent advantages in compactness, robustness, and low cost. PMID- 30469736 TI - Vector solitons in nonparity-time-symmetric complex potentials. AB - The existence and stability of vector solitons in non-parity-time (PT)-symmetric complex potentials are investigated. We study the vector soliton family, in which the propagation constants of the two components are different. It is found that vector solitons can be stable below and above the phase transition of the non-PT symmetric complex potentials. Below the phase transition, vector solitons are stable in the low power region. Above the phase transition, there are two continuous stable intervals in the existence region. The profiles of two components of these vector solitons show the asymmetry and we also study the transverse power flow in the two components of these vector solitons in the non PT-symmetric complex potentials. PMID- 30469737 TI - Design of discretely depth-varying holographic grating for image guide based see through and near-to-eye displays. AB - For the see-through and near-to-eye displays, light throughput and uniformity of luminance over the field of view are improved by employing an optical image guide with discretely depth-varying surface relief holographic gratings. In the design process, a newly developed mathematical model, in conjunction with rigorous coupled wave analysis of diffraction efficiency, eliminates massive and time consuming iteration of non-sequential ray tracing but rapidly identifies the depth-varying structure and optimum optical performance. The depth-varying grating based approach achieved a 1.37x improvement in light throughput compared to the conventional depth un-varying design, 315 cd/m2/lm, along with improved uniformity over the field of view of 35 (H) x 20 (V) degrees with an eye box size of 17 (H) x 14 (V) mm. PMID- 30469738 TI - Investigation of a novel SMS fiber based planar multimode waveguide and its sensing performance. AB - A novel, MMI-based all-fiber structure, which consists of two single-mode fibers and a multimode fiber polished on both sides, is described. The light propagation characteristics of this fiber structure, as well as its superior sensing performance, are analyzed theoretically by using the beam propagation method (BPM). This fiber structure demonstrates a significant spectral response to changes of the surrounding refractive index (RI), and the measured results exhibit good agreement with the predicted data. The measured average RI sensitivity is as high as 151.29 nm/RIU over an RI range from 1.3450 to 1.4050, when the polished depth is 30 um on both sides of the multimode fiber. This fiber structure can be an advantageous platform for various applications, especially for a lab-on-fiber type sensing application. PMID- 30469739 TI - Overcoming repetition rate limitations in liquid crystal laser systems. AB - Liquid crystal lasers have advantageous features, including continuous wavelength tuning at low cost. Although many potential applications have been highlighted, use of these lasers is not widespread, partially due to performance limitations. This paper presents a method of overcoming repetition rate limitations. A rapidly spinning stage is used to allow operation of a LC laser at 10 kHz: two orders of magnitude greater than possible with a static cell. Average power outputs of up to 3.5 mW are achieved along with an improvement in emission stability. Lastly, a mechanical wavelength-switching method is demonstrated. The spinning cell approach will enable research into the use of liquid crystal lasers in fluorescence imaging and display applications. PMID- 30469740 TI - Accelerated and high-quality Fourier ptychographic method using a double truncated Wirtinger criteria. AB - Fourier ptychographic microscopy (FPM) is a recently developed computational microscopy technique for wide-field-of-view and super-resolution complex imaging. Wirtinger-flow-based methods can effectively suppress noise and reduce data acquisition time, but they are time-consuming during the phase reconstruction. In this paper, we present a Wirtinger-flow-based reconstruction method for FPM, which combines the Poisson maximum likelihood objective function, improved truncated Wirtinger criteria, and improved adaptive momentum method. Both the simulation and experimental results demonstrate that the proposed method runs faster and the reconstruction quality is similar to or better than other state-of the-art Wirtinger-flow-based methods. PMID- 30469741 TI - New reconstruction method for few-view grating-based phase-contrast imaging via dictionary learning. AB - Grating-based phase-contrast is a hot topic in recent years owing to its excellent imaging contrast capability on soft tissues. Although it is compatible with conventional X-ray tubes and applicable in many fields, long scanning time, and high radiation dose obstruct its wider use in clinical and medical fields, especially for computed tomography applications. In this study, we solve this challenge by reducing the projection views and compensating the loss of reconstruction quality through dual-dictionary learning algorithm. The algorithm is implemented in two steps. First, estimated high-quality absorption images are obtained from the first dual-quality dictionary learning, which uses the correspondence between high-quality images and low-quality ones reconstructed from highly under-sampled data. Then, the second absorption-phase dual-modality dictionary learning is adopted to yield both estimated phase and absorption images, resulting in complementary information for both modality images. Afterwards the absorption and phase images are gradually improved in iterative reconstructions. By using SSIM RMSE measurements and visual assessment for enlarged regions of interest, our proposed method can improve the resolution of these two modality images and recover smaller structures, as compared to conventional methods. PMID- 30469742 TI - A robust probabilistic shaping PON based on symbol-level labeling and rhombus shaped modulation. AB - A probabilistic shaping passive optical network (PON) based on symbol-level labeling and rhombus-shaped modulation is proposed in this paper, which indicates optical access network can be deployed in a flexible and robust way with reasonable costs. Energy efficiency is also achieved significantly. An experiment that demonstrates probabilistic shaping PON data transmission over 25 km standard single-mode fiber (SSMF) with CAP (carrier-less amplitude and phase) modulation is successfully conducted. Results show that the received optical power has improved by 2 dB at the threshold of 1*10-3 BER compared with the conventional 16 CAP, which suggests the superiority of our proposed scheme in next generation PON. PMID- 30469743 TI - Investigation of the antiphase dynamics of the orthogonally polarized passively Q switched Nd:YLF laser. AB - The antiphase dynamics of Q-switched orthogonally polarized emissions have been thoroughly investigated. A Nd:YLF crystal with the anisotropic thermal lensing effect is used as the gain medium for achieving dual polarized laser. By using the Cr4+:YAG saturable absorber, the passively Q-switched output shows intriguing switching dynamics, where the number of pulses for both polarized components within one switching period is directly determined by the power ratio between the orthogonally polarized emissions. Experimental results reveal that the pulse energies of every single pulse for both orthogonally polarized states are equal with the maximum value of 223 MUJ. The pulse durations for pi- and sigma polarization are measured to be 15 ns and 11 ns and the corresponding peak power levels are up to 15.0 kW and 20.3 kW, respectively. PMID- 30469744 TI - Room temperature continuous-wave nanolaser diode utilized by ultrahigh-Q few-cell photonic crystal nanocavities. AB - Few-cell point-defect photonic crystal (PhC) nanocavities (such as LX and H1 type cavities), have several unique characteristics including an ultra-small mode volume (Vm), a small device footprint advantageous for dense integration, and a large mode spacing advantageous for high spontaneous-emission coupling coefficient (beta), which are promising for energy-efficient densely-integratable on-chip laser light sources enhanced by the cavity QED effect. To achieve this goal, a high quality factor (Q) is essential, but conventional few-cell point defect cavities do not have a sufficiently high Q. Here we adopt a series of modified designs of LX cavities with a buried heterostructure (BH) multi-quantum well (MQW) active region that can achieve a high Q while maintaining their original advantages and fabricate current-injection laser devices. We have successfully observed continuous-wave (CW) lasing in InP-based L1, L2, L3 and L5 PhC nanocavities at 23 degrees C with a DC current injection lower than 10 MUA and a bias voltage lower than 0.9 V. The active volume is ultra-small while maintaining a sufficiently high confinement factor, which is as low as ~10-15 cm3 for a single-cell (L1) nanocavity. This is the first room-temperature current injection CW lasing from any types of few-cell point-defect PhC nanocavities (LX or H1 types). Our report marks an important step towards realizing a nanolaser diode with a high cavity-QED effect, which is promising for use with on-chip densely integrated laser sources in photonic networks-on-chip combined with CMOS processors. PMID- 30469745 TI - Construction of traceable absolute distances network for multilateration with a femtosecond pulse laser. AB - The traceable absolute distances network with multiple global targets for multilateration is developed with a femtosecond pulse laser. It is aiming to enhance the ability and flexibility of the coordinate measurement, especially to monitor the positions of distributed stations in real time for some critical industrial environments. Here, multi-target absolute distances are determined by the temporal coherence method simultaneously with the pulse-to-pulse interferometer. Besides, the performance of the proposed system is evaluated in detail by comparing with a conventional interferometer. The experimental results indicate that the accuracy of distances measurement could all reach the sub micron level and could be traceable to the length standard. Furthermore, a simple scheme of multilateration is presented based on the developed network. The coordinate of the initial point of multiple beams is measured by cooperation with a laser tracker. The results of coordinate measurement show that these methods have the potential for further industrial applications. PMID- 30469746 TI - Demonstration of an erbium-doped fiber with annular doping for low gain compression in cladding-pumped amplifiers. AB - We present the design and characterization of a cladding-pumped amplifier with erbium doping located in an annular region near the core. This erbium-doped fiber is proposed to reduce gain saturation, leading to smaller gain compression when compared to uniform core doping. Through numerical simulations, we first compare the performance of three fibers with different erbium doping profiles in the core or the cladding. When the doped fibers are operated at the optimum length, results show that the smaller overlap of the signal mode field with the annular erbium doping region leads to higher gain and lower saturation of the amplifier. A single-core erbium-doped fiber with an annular doping and a D-shaped cladding was fabricated. Measurements demonstrate less than 4 dB of gain compression over the C-band for input power ranging from -40 dBm to 3 dBm. Small gain compression EDFAs are of interest for applications that require input channel reconfiguration. Higher gain and saturation output power are also key issues in cladding-pumped multi-core amplifiers. PMID- 30469747 TI - Design of a high-performance in-coupling grating using differential evolution algorithm for waveguide display. AB - Illuminance nonuniformity caused by natural vignetting can seriously affect the display quality of large-field-of-view (FOV) waveguide displays. In this paper, an optimization method based on the differential evolution algorithm is proposed for in-coupling grating design to improve coupling efficiency and compensate for natural vignetting. The in-coupling grating parameters are optimized to achieve efficiency distributions in which efficiency increases continuously with incidence angle, realizing uniform illuminance over a large FOV of 45 degrees . The angular uniformity reaches 0.89. Additionally, average diffraction efficiency reaches 89.13% for transverse-electric polarization at 532 nm and 76% in the wavelength region between 450 and 700 nm. PMID- 30469748 TI - Imaging through scattering media using speckle pattern classification based support vector regression. AB - Imaging through scattering media is a common practice in many applications of biomedical imaging. Object image would deteriorate into unrecognizable speckle pattern when scattering media is presented. Many methods have been investigated to reconstruct the object image when only speckle pattern is available. In this paper, we demonstrate a method of single-shot imaging through scattering media. This method is based on classification and support vector regression of the measured speckle pattern. We prove the possibility of speckle pattern classification and related formulas are presented. The specified and limited imaging capability without speckle pattern classification is demonstrated. Our proposed approach, that is, speckle pattern classification based support vector regression method, makes up the deficiency. Experimental results show that, with our approach, speckle patterns could be utilized for classification when object images are unavailable, and object images can be reconstructed with high fidelity. The proposed approach for imaging through scattering media is expected to be applicable to various sensing schemes. PMID- 30469749 TI - Pulse control in a wide frequency range for a quasi-continuous wave diode-pumped cesium atom vapor laser by a pump modulation in the spectral domain. AB - Diode-pumped alkali-atom laser (DPAL) has attracted intense attention due to its inherently high quantum efficiency, a good beam quality, and a high potential in the power scaling. However, most of DPAL research has been confined to the continuous wave and only a few pulsed operations have been attempted with limited performances. Here, we proposed and experimentally demonstrated a new scheme using a fast mode-hopping in the pump laser diode (LD), which enabled the quasi continuous-wave (QCW) pulse modulation in a cesium (Cs) DPAL to control both the pulse width and the repetition rate. The pump wavelength was efficiently modulated in a fast cycle within discrete spectral ranges provided by the mode hopping in the pump LD. The spectral range was successfully adjusted to include the resonant D2 absorption line of Cs atom to result in an effective gain modulation. Using this proposed scheme, we successfully achieved Cs-DPAL QCW modulation, whose pulse width was varied from tens of microseconds to a few milliseconds and the repetition rate was also variable in a wide frequency range from 10 Hz to 7.0 kHz. Detailed pump modulation method and the corresponding laser characteristics are discussed. The proposed method can be readily applied to pulse modulation of other types of alkali vapor lasers overcoming the previous limitations of DPAL to further expand applications in various light-matter interactions. PMID- 30469750 TI - Transient vibration imaging with time-resolved synthetic holographic confocal microscopy. AB - We introduce a new modality for dynamic phase imaging in confocal microscopy based on synthetic optical holography. By temporal demultiplexing of the detector signal into a series of holograms, we record time-resolved phase images directly in the time domain at a bandwidth as determined by the photo detector and digitizer. We demonstrate our method by optical imaging of transient vibrations in an atomic force microscope cantilever with 100 ns time resolution, and observe the dynamic deformation of the cantilever surface after excitation with broadband mechanical pulses. Temporal Fourier transform of a single data set acquired in 4.2 minutes yields frequency and mode profile of all excited out-of-plane vibration modes with sub-picometer vertical sensitivity and sub-micrometer lateral resolution. Our method has the potential for transient and spectroscopic vibration imaging of micromechanical systems at nano-and picosecond scale time resolution. PMID- 30469751 TI - Gaussian kernel-aided deep neural network equalizer utilized in underwater PAM8 visible light communication system. AB - In this paper, we demonstrate a novel Gaussian kernel-aided deep neural network (GK-DNN) equalizer that can effectively compensate for the high nonlinear distortion of underwater PAM8 visible light communication (VLC) channels. The application of a Gaussian kernel can reduce the necessary training iterations to 47.06%, enabling it to outperform the traditional DNN equalizer. At the same time, a novel design strategy with respect to the structure of the GK-DNN equalizer is proposed, which can effectively save computing resources and reduce the data volume of the necessary training data set. By using the GK-DNN equalizer, a 1.5 Gbps PAM8 VLC system over 1.2-m underwater transmission is successfully demonstrated. PMID- 30469752 TI - Inverse design of compact multimode cavity couplers. AB - Efficient coupling between on-chip sources and cavities plays a key role in silicon photonics. However, despite the importance of this basic functionality, there are few systematic design tools to simultaneously control coupling between multiple modes in a compact resonator and a single waveguide. Here, we propose a large-scale adjoint optimization approach to produce wavelength-scale waveguide cavity couplers operating over tunable and broad frequency bands. We numerically demonstrate couplers discovered by this method that can achieve critical, or nearly critical, coupling between multi-ring cavities and a single waveguide at up to six widely separated wavelengths spanning the 560-1500 nm range of interest for on-chip nonlinear optical devices. PMID- 30469753 TI - Special-purpose computer HORN-8 for phase-type electro-holography. AB - Electro-holography is a promising display technology that can reconstruct a photorealistic three-dimensional (3D) movie; however, it is yet to be realized practically owing to the need for enormous calculation power. A special-purpose computer for electro-holography, namely HORN, has been studied for over 20 years as a means to solve this problem. The latest version of HORN, HORN-8, was developed using field programmable gate array (FPGA) technology. Initially, a circuit for amplitude-type electro-holography was implemented in HORN-8; however, implementation of phase-type electro-holography has remained an issue. In this paper, the development of new version of HORN-8 and its cluster system, which achieved a real-time reconstruction of a 3D movie with point clouds comprised of 32,000 points for phase-type electro-holography, was reported. PMID- 30469754 TI - Gaussian mixture model for coarse-grained modeling from XFEL. AB - We explore the advantage of Gaussian mixture model (GMM) for interpretation of single particle diffraction patterns from X-ray free electron laser (XFEL) experiments. GMM approximates a biomolecular shape by the superposition of Gaussian distributions. As the Fourier transformation of GMM can be quickly performed, we can efficiently simulate XFEL diffraction patterns from approximated structure models. We report that the resolution that GMM can accurately reproduce is proportional to the cubic root of the number of Gaussians used in the modeling. This behavior can be attributed to the correspondence between the number of adjustable parameters in GMM and the amount of sampling points in diffraction space. Furthermore, GMMs can successfully be used to perform angular assignment and to detect conformational variation. These results demonstrate that GMMs serve as useful coarse-grained models for hybrid approach in XFEL single particle experiments. PMID- 30469755 TI - High-power OPCPA generating 1.7 cycle pulses at 2.5 um. AB - We present a high-power mid-infrared (mid-IR) optical parametric chirped-pulse amplifier (OPCPA) generating 14.4 fs pulses centered at 2.5 um with an average power of 12.6 W and a repetition rate of 100 kHz. The short pulses are obtained without nonlinear pulse compression. This is in contrast to most few-cycle systems operating in the mid-IR. In our case, the ultrashort pulse duration is enabled by a careful design of the gain profile of each amplification stage as well as a precise control of the signal dispersion throughout the system. A pulse shaper is used in the seed beam to adjust the spectral phase at the output of the OPCPA system. This approach allows for a clean temporal profile leading to a high peak power of 6.3 GW. PMID- 30469756 TI - Decoherence of fiber supercontinuum light source for speckle-free imaging. AB - Speckle-free imaging is attractive in laser-illuminated imaging systems. The evolutionary process of supercontinuum decoherence in extra-large mode area step index multimode fiber is analyzed to provide high-quality broadband light source for speckle-free imaging. It is found that spectral bandwidth, number of spatial transverse modes, and decoherence among different modes all greatly contribute to speckle reduction. The combination of supercontinuum and extra-large mode area step-index multimode fiber can considerably increase the efficiency of decoherence process for speckle-free imaging. This work may enrich the research of speckle-free imaging and also provide guidance on speckle-free imaging using fiber-optics based light source. PMID- 30469757 TI - Implementation of nondiffracting Bessel beam sources in FDTD for scattering by complex particles. AB - In this paper, the nondiffracting Bessel beam sources are implemented in finite difference time-domain (FDTD) method. The high-order scattered-field algorithm of the FDTD (SF-FDTD (2, 4)) method is employed to investigate the scattering of particles illuminated by Bessel beams. In the SF-FDTD (2, 4) method, the scattered fields of the whole region are calculated directly by time stepping and the incident fields are obtained by the vector expressions of the diffraction free Bessel beam. Some numerical results are included to illustrate the validity and capability of the proposed method. This study is expected to provide a new efficient method to investigate the interactions between nondiffracting beams and complex particles. PMID- 30469758 TI - Improvement of the focusing ability by double deformable mirrors for 10-PW-level Ti: sapphire chirped pulse amplification laser system. AB - Double deformable mirrors (DMs) with different actuator densities are cascaded to optimize the wavefront aberrations to improve the focus intensity of the Shanghai super-intense ultrafast laser facility (SULF), which plans to generate 10 PW laser pulse. The beam aberrations near the focal spot are corrected from 0.556 um to 0.112 um in RMS by a 300-mm DM with a large stroke installed after the compressor. After then, it is further optimized to 0.041 um using a 130-mm DM with a high spatial resolution working after the main amplifier. The corrected beam is focused to 2.75 * 2.87 um2 at the full width at half maximum (FWHM) with an f/2.5 off-axis parabolic mirror (OAP), which contains approximately 27.69% energy. A peak intensity of 2 * 1022 W/cm2 is achieved at the output of 5.4 PW, and it could exceed 1023 W/cm2 in the SULF 10 PW laser facility using an f/1.8 OAP. PMID- 30469759 TI - Optical downlink propagation from space-to-earth: aperture-averaged power fluctuations, temporal covariance and power spectrum. AB - In this work, we consider optical downlink from space-based laser sources and develop a consistent quantitative analysis of the collected power fluctuations by finite receiving apertures, and both the corresponding temporal covariance and power spectral density (PSD). Here we assume weak to moderate scintillation conditions where lognormal statistics are valid. We derive both exact solutions and highly accurate engineering easy to implement approximations for the downlink aperture-averaging factor, and both the corresponding aperture-averaged signal temporal covariance and PSD. Additionally, highly accurate elementary analytic scaling relations are derived for the corresponding aperture-averaged characteristic correlation time and scintillation bandwidth, which are in good agreement with available experimental observations. Finally closed form expressions for the so-called quasi-frequency that is central to the determination of level crossing rates and duration of fades and surges in a propagation channel are derived. Wherever possible, we endeavor to derive "user friendly" accurate engineering approximations for the various statistical quantities of interest. PMID- 30469760 TI - Automatic method to monitor floating macroalgae blooms based on multilayer perceptron: case study of Yellow Sea using GOCI images. AB - Timely and accurate information about floating macroalgae blooms (MAB), including their distribution, movement, and duration, is crucial in order for local government and residents to grasp the whole picture, and then plan effectively to restrain economic damage. Plenty of threshold-based index methods have been developed to detect surface algae pixels in various ocean color data with different manners; however, these methods cannot be used for every satellite sensor because of the spectral band configuration. Also, these traditional methods generally require other reliable indicators, and even visual inspection, in order to achieve an acceptable mapping of MAB that appears under diverse environmental conditions (cloud, aerosol, and sun glint). To overcome these drawbacks, a machine learning algorithm named Multi-Layer Perceptron (MLP) was used in this paper to establish a novel automatic method to monitor MAB continuously in the Yellow Sea, using Geostationary Ocean Color Imager (GOCI) imagery. The method consists of two MLP models, which consider both spectral and spatial features of Rayleigh-corrected reflectance (Rrc) maps. Accuracy assessment and performance comparison showed that the proposed method has the capability to provide prediction maps of MAB with high accuracy (F1-score approaching 90% or more), and with more robustness than the traditional methods. Most importantly, the model is practically adaptable for other ocean color instruments. This allows customized models to be built and used for monitoring MAB in any regional areas. With the development of machine learning models, long term mapping of MAB in global ocean is conducive to promoting the associated studies. PMID- 30469761 TI - Partially coherent fractional vortex beam. AB - We introduce a new kind of partially coherent vortex (PCV) beam with fractional topological charge named partially coherent fractional vortex (PCFV) beam and derive the propagation formula for such beam passing through a stigmatic ABCD optical system with the help of the convolution method. We calculate numerically the propagation properties of a PCFV beam focused by a thin lens, and we find that the PCFV beam exhibits unique propagation properties. The opening gap of the intensity pattern and the rotation of the beam spot disappear gradually and the cross-spectral density (CSD) distribution becomes more symmetric and more recognizable with the decrease of the spatial coherence width, being qualitatively different from those of the PCV beam with integral topological charge. Furthermore, we carry out experimental generation of a PCFV beam with controllable spatial coherence, and measure its focusing properties. Our experimental results are consistent with the theoretical predictions. PMID- 30469762 TI - PSF model for diffractive optical elements with improved imaging performance in dual-waveband infrared systems. AB - Single-layer diffractive optical elements (SLDOEs) have advantages in terms of configuration, fabrication, range of angles and cost; however, the diffraction efficiency decreases sharply with wavelength deviating from the design wavelength, especially for dual-waveband imaging, causing apparent image blur. We propose a point spread function (PSF) model affected by the diffraction efficiency, which is called PSFDOE, and a method of restoring the blurred image to improve imaging performance in dual-waveband infrared systems with an SLDOE. Then, a design example of cooled MWIR and LWIR is presented. Furthermore, imaging simulations with different grades noises and restorations are conducted. Results reveal that the PSFDOE model can significantly improve the image blur caused by the decreased diffraction efficiency. PMID- 30469764 TI - Full-color video and still imaging using two flat lenses. AB - At least two lenses are required in imaging systems to adjust focus and magnification and to match the acceptance properties of the image sensor. Here, we demonstrate the tandem use of two millimeter-scale planar diffractive lenses for video and still imaging over the full visible spectrum. First we designed, fabricated, and characterized individual lenses with focal length of 25mm and NA = 0.05. Then, we assembled the lenses with a conventional color CMOS image sensor to demonstrate imaging. Illumination conditions as varied as ambient sunlight, halogen lamp and LED lamps are used. Due to the ease of fabrication of diffractive lenses compared to metalenses, this demonstration will enable future generations of low-cost, lightweight, broadband cameras. PMID- 30469763 TI - Reference-free polarization-sensitive quantitative phase imaging using single point optical phase conjugation. AB - We propose and experimentally demonstrate a method of polarization-sensitive quantitative phase imaging using two photodetectors and a digital micromirror device. Instead of recording wide-field interference patterns, finding the modulation patterns maximizing focused intensities in terms of the polarization states enables polarization-dependent quantitative phase imaging without the need for a reference beam and an image sensor. The feasibility of the present method is experimentally validated by reconstructing Jones matrices of several samples including a polystyrene microsphere, a maize starch granule, and a mouse retinal nerve fiber layer. Since the present method is simple and sufficiently general, we expect that it may offer solutions for quantitative phase imaging of birefringent materials. PMID- 30469765 TI - 5-beam grating interferometry for extended phase gradient sensing. AB - A novel, single-shot, low-cost, multidirectional lateral shear interferometer for extended range wave front phase gradient sensing has been developed. It exploits the Fresnel diffraction field, which is formed by the five lowest diffraction orders of a simple binary amplitude checker grating. The Fresnel intensity pattern encodes information on four directional partial derivatives of the wave front under test. It has been theoretically, numerically, and experimentally shown that for larger gradient phase objects or shear amounts only the diagonal derivative information is easily accessible. The horizontal and vertical direction gradient maps are strongly amplitude modulated. Therefore, their demodulation becomes a challenging task. The same feature has been found in widely used quadriwave interferometer, which was developed at ONERA, France. The results of analytical and numerical studies and experimental works, including fringe pattern processing and phase demodulation, are presented. PMID- 30469766 TI - Long-term measurement of high Q optical resonators based on optical vector network analysis with Pound Drever Hall technique. AB - An optical vector network analysis (OVNA) based on double sidebands (DSB) modulation and the Pound Drever Hall (PDH) technique is proposed and demonstrated. The frequency responses measurement of the high Q optical device with high stability are achieved by transmitting the DSB modulation signals through the device. The high stability can be realized by using the PDH feedback loop. Compared with the conventional DSB-based OVNA, the proposed scheme with only one step measurement avoids the complex post-processing. Moreover, the long term measurement with high stability can also be realized. A proof-of-concept experiment is carried out, which achieves the magnitude and phase responses of the Fabry-Perot interferometer, and there is no frequency response shift even though the test time is up to 90 minutes. The proposed method is simple and stable, which can be potentially applied in characterization and fabrication of high Q optical devices. PMID- 30469767 TI - Optically controlled tunable ultra-narrow linewidth fiber laser with Rayleigh backscattering and saturable absorption ring. AB - We propose an optically controlled tunable ultra-narrow linewidth fiber laser assisted with the mode selection induced by a saturable absorption interference ring and linewidth narrowing of fiber Rayleigh backscattering (RBS). The interference ring serves as an artificial narrow-band filter, which conduces to the laser operating at a single-frequency state. To realize narrower linewidths, additional single-mode fiber is utilized to accumulate a weak RBS feedback. On basis of inherent wavelength universality of this linewidth-narrowing mechanism, an all-optical technique is employed to enable linear and stable tunability of the laser. Cooperating with a micro-fiber Bragg grating covered by graphene, the lasing wavelength is tuned precisely and reversibly with a sensitivity of 12.4 pm/mW and a linear fitting R2 over 0.997 by changing the power of a controlling beam. During a stability test with the controlling pump power fixed, the long term free-running power fluctuation is less than 0.5%. The Output laser linewidth is compressed to be ~200 Hz, which is also confirmed by the descending frequency noise spectrum. PMID- 30469768 TI - Highly stable, 15 W, few-cycle, 65 mrad CEP-noise mid-IR OPCPA for statistical physics. AB - We demonstrate a 100 kHz optical parametric chirped-pulse amplifier delivering under 4-cycle (38 fs) pulses at ~3.2 um with an average power of 15.2 W with a pulse-to-pulse energy stability <0.7% rms and a single-shot CEP noise of 65 mrad RMS over 8h. This source is continuously monitored, by using a fast 100 kHz data acquisition device, and presents an extreme stability, in the short and long terms. PMID- 30469769 TI - Wavelength-locked continuous-wave and Q-switched Ho:CaF2 laser at 2100.5 nm. AB - In this paper, we demonstrated a linewidth-narrowed continuous-wave (CW) and acousto-optical Q-switched Ho:CaF2 laser for the first time. With a volume Bragg grating, a maximum CW output power of 6.94 W at 2100.5 nm, and slope efficiency of 57.9%, an FWHM linewidth of 0.31 nm was obtained. When absorbed pump power was 13.2 W, the maximum average output powers of 6.08 W, 5.9 W, and 5.71 W were achieved in a Q-switched Ho:CaF2 laser under pulse repetition frequencies of 10 kHz, 5 kHz, and 3 kHz, corresponding to the slope efficiencies of 51.2%, 49.6%, and 48.5%, respectively. The minimum pulse width of 54 ns was achieved at pulse repetition frequency of 3 kHz. PMID- 30469770 TI - Direct generation of vortex beams from a double-end polarized pumped Yb:KYW laser. AB - Double-end polarized pumping scheme combined with off-axis pumping technique has been first introduced to generate vortex beams in a z-type cavity. By employing double-end pumping, two different transverse modes can be excited simultaneously. The phase delay between these two modes can be finely tuned by manipulating the cavity structure. Direct emission of a chirality controllable Laguerre Gaussian LG01 vortex beam with slope efficiency of more than 40% has been realized by a double-end polarized pumped Yb:KYW laser. Other modes, such as dual-LG01 mode, cross-shaped mode, and LG10 mode, have also been demonstrated from our laser setup. PMID- 30469771 TI - Photonic band engineering in absorbing media for spectrally selective optoelectronic films. AB - Spectrally selective materials are of great interest for optoelectronic devices in which wavelength-selectivity of the photoactive material is necessary for applications such as multi-junction solar cells, narrow-band photodetectors, transparent photovoltaics, and tailored emission sources. Achieving controlled transparency or opacity within multiple wavelength bands in the absorption, reflection, and transmission spectra are difficult to achieve in traditional semiconductors that typically absorb at all energies above their electronic band gap and is generally realized by the use of external bandpass filters. Here, we propose an alternate method for achieving spectral selectivity in optoelectronic thin films: the use of photonic band engineering within the absorbing region of a semiconductor in which resonant photonic bands are strongly coupled to the external reflectivity and transmission spectra. As a first step, we use optical simulations to systematically study the effect of material absorption on the properties of the photonic bands in a photonic crystal slab structure. We find that adding a weak loss to the materials model does not appreciably change the frequencies of the photonic bands but does reduce the quality factor of the associated photonic modes. Critically, the radiating photonic bands induce strong Fano resonance features in the transmission and reflection spectra, even in the presence of material absorption, due to coupling between the bands and external electromagnetic plane waves. These resonances can be tuned by adjusting the photonic crystal structural properties to induce spectral selectivity in the absorbing region of semiconductors. Lastly, we demonstrate this tuning method experimentally by fabricating a proof-of-principle photonic structure consisting of a self-assembled polystyrene bead monolayer infiltrated with PbS CQDs that displays both near-infrared absorption enhancement and visible transparency enhancement over a homogeneous control film, qualitatively matching predictions and showing promise for optoelectronic applications. PMID- 30469772 TI - Self-healing high-dimensional quantum key distribution using hybrid spin-orbit Bessel states. AB - Using spatial modes for quantum key distribution (QKD) has become highly topical due to their infinite dimensionality, promising high information capacity per photon. However, spatial distortions reduce the feasible secret key rates and compromise the security of a quantum channel. In an extreme form such a distortion might be a physical obstacle, impeding line-of-sight for free-space channels. Here, by controlling the radial degree of freedom of a photon's spatial mode, we are able to demonstrate hybrid high-dimensional QKD through obstacles with self-reconstructing single photons. We construct high-dimensional mutually unbiased bases using spin-orbit hybrid states that are radially modulated with a non-diffracting Bessel-Gaussian (BG) profile, and show secure transmission through partially obstructed quantum links. Using a prepare-measure protocol we report higher quantum state self-reconstruction and information retention for the non-diffracting BG modes as compared to Laguerre-Gaussian modes, obtaining a quantum bit error rate (QBER) that is up to 3* lower. This work highlights the importance of controlling the radial mode of single photons in quantum information processing and communication as well as the advantages of QKD with hybrid states. PMID- 30469773 TI - Auto-alignment of X-ray focusing mirrors with speckle-based at-wavelength metrology. AB - Significant improvements have been made in the fabrication of diffraction-limited X-ray optics used to pursue an aberration-free wavefront. Alignment of these optics plays a crucial role in the resultant beam quality. Here, we present a simple and fast alignment method based on imaging X-ray near-field speckle patterns, with experimental demonstration using a pair of Kirkpatrick-Baez mirrors. The proposed technique has the potential to be an alternative to conventional methods. It loosens the stringent demand for high-resolution scanning stages compared to conventional knife-edge scan and, hence, can be applied to nano-focusing optics. The flexibility and straightforward implementation of the method allow it to be applied to a wide range of experiments at synchrotron facilities and laboratory-based sources. PMID- 30469774 TI - Mixing of polarization states in zincblende nonlinear optical crystals. AB - We describe second-order nonlinear optical mixing in non-birefringent, zincblende structure materials that can be quasi-phasematched. Lack of birefringence and quasi-phasematching together allow efficient nonlinear mixing between diverse polarization states. We derive six coupled-wave equations that describe nonlinear optical mixing between the two orthogonal polarizations of the three frequencies in the second-order nonlinear interaction. The interactions of the additional polarization states can lead to apparent reduction in conversion efficiencies in optical parametric oscillators and amplifiers. PMID- 30469775 TI - On-chip optical trapping of extracellular vesicles using box-shaped composite SiO2-Si3N4 waveguides. AB - The application of on-chip optical trapping and Raman spectroscopy using a dual waveguide trap has so far been limited to relatively big synthetic and biological particles (e.g., polystyrene beads and blood cells). Here, from simulations, we present the capabilities of dual-waveguide traps built from composite SiO2-Si3N4 waveguides for optical trapping of extracellular vesicles (EVs). EVs, tiny cell derived particles of size in the range 30-1000 nm, strongly attract attention as potential biomarkers for cancer. EVs are hard to trap, because of their smallness and low index contract w.r.t. water. This poses a challenge for on-chip trapping. From finite-difference time-domain simulations we obtain the narrow beam emitted from the waveguide facet into water, for lambda = 785 nm. For a pair of such beams, in a counter-propagating geometry and for facet separations of 5, 10 and 15 um, we derive the inter-facet optical field, which has a characteristic interference pattern with hot spots for trapping, and calculate the optical force exerted on EVs of size in the range 50-1000 nm, as a function of EV position. We use two refractive index models for the EV optical properties. Integration of the force curves leads to the trapping potentials, which are well-shaped in the transverse and oscillatory in the longitudinal direction. By applying Ashkin's criterion, the conditions for stable trapping are established, the central result of this work. Very small EVs can be stably trapped with the traps by applying a power also suitable for Raman spectroscopy, down to a smallest EV diameter of 115 nm. We thus argue that this dual-waveguide trap is a promising lab-on-a-chip device with clinical relevance for diagnosis of cancer. PMID- 30469776 TI - Vivid structural colors from long-range ordered and carbon-integrated colloidal photonic crystals. AB - A facile strategy to prepare high-quality colloidal photonic crystals (PCs) with good visibility is proposed. Based on a high refractive-index material (zinc sulfide), highly monodispersed colloidal particles are successfully produced and assembled into long-range ordered crystalline colloidal arrays. The carbon-based materials are in situ incorporated with the long-range ordered colloidal PCs, which endows PCs with the combined characteristics to simultaneously achieve an intense photonic stop band and excellent control of incoherent light scattering. Owing to these merits, the obtained ZnS colloidal PCs have demonstrated strong brightness with the maximum reflectivity of 98%. Moreover, the coloration, saturation, and viewing angle are all improved. This study provides a straightforward and cost-effective strategy to create structural colors with high quality visibility, which is expected to facilitate future applications of colloidal PCs. PMID- 30469777 TI - Mid-infrared cavity resonator integrated grating filters. AB - Cavity Resonator Grating Filters (CRIGFs) working in the Mid-Infrared are reported, with narrow-band resonant reflectivity peaks around 2200 cm-1 (4.6 um). They are fabricated in the GaAs/AlGaAs material system that can potentially cover the whole [1-12] um spectral range. TE-polarized peak reflectivity is 30% with a 4 cm-1 full width at half maximum. PMID- 30469778 TI - Change of blue light hazard and circadian effect of LED backlight displayer with color temperature and age. AB - In order to provide a theoretical reference for the personalized design and color temperature adjustment of LED backlight displayer, the spectral distribution of the LED backlight displayer at different color temperatures (1200-6500K) was measured. According to the transmittance of human eye at different ages (1-100 years old), the effective spectral distribution of the LED backlight displayer on the retina of the human eye at different ages was calculated. Based on the fitting of the response function of the human eye, the correlation studies on the changes of the blue light hazard factor, the proportion of blue light in the range of wavelength 400-500 nm, the circadian rhythm factor, and the proportion of blue light in the range of wavelength 446-477 nm with color temperature and age were conducted respectively. The results showed that the blue light hazard and circadian rhythm increased with the increase of the color temperature while decreased with the increase of age. For one-year-old infants, when the color temperature increased from 1200K to 6500K, the blue light hazard factor and circadian rhythm factor of the effective spectrum of the retina increased by 12.2 and 9.5 times respectively. For a 6500K LED backlight displayer, when the age increased from 1-year-old to 100 years old, the corresponding value of the two factors decreased by 0.2 and 0.3 times respectively. The proportion of blue light in the range of wavelength 400-500 nm can be used to approximately replace the blue light hazard factor to demonstrate the degree of blue light hazard. This conclusion can provide a certain theoretical reference for the personalized design and use of LED backlight displayer from the perspective of blue light hazard and circadian rhythm. PMID- 30469779 TI - Impact of windscreen scatter on laser eye dazzle. AB - This study investigates the extent to which a windscreen affects the severity of laser eye dazzle (disability glare produced by a laser) experienced by a human observer. Windscreen scatter measurements were taken for a range of windscreens in a variety of conditions, showing that windscreen scatter is similar in magnitude to scatter from the human eye. Human subject experiments verified that obscuration angles caused by laser eye dazzle could be increased by the presence of a windscreen when comparing a dirty automobile windscreen to an eye-only condition with a 532-nm laser exposure. However, a light aircraft windscreen with lower scatter did not exhibit increased obscuration angles at 532 nm, and neither windscreen exhibited an increase at 635 nm. A theoretical analysis of laser eye dazzle, using measured windscreen scatter functions, has provided insight into the delicate interplay between scatter, transmission and the angular extent of dazzle. A model based on this analysis has been shown to be a useful tool to predict the impact of windscreens on laser eye dazzle, with the goal of informing future updates to the authors' laser eye dazzle safety framework. PMID- 30469780 TI - Broadband integrated beam splitter using spatial adiabatic passage. AB - Light routing and manipulation are important aspects of integrated optics. They essentially rely on beam splitters which are at the heart of interferometric setups and active routing. The most common implementations of beam splitters suffer either from strong dispersive response (directional couplers) or tight fabrication tolerances (multimode interference couplers). In this paper we fabricate a robust and simple broadband integrated beam splitter based on lithium niobate with a splitting ratio achromatic over more than 130 nm. Our architecture is based on spatial adiabatic passage, a technique originally used to transfer entirely an optical beam from a waveguide to another one that has been shown to be remarkably robust against fabrication imperfections and wavelength dispersion. Our device shows a splitting ratio of 0.52+/-0.03 and 0.48+/-0.03 from 1500 nm up to 1630 nm. Furthermore, we show that suitable design enables the splitting in output beams with relative phase 0 or pi. Thanks to their independence to material dispersion, these devices represent simple, elementary components to create achromatic and versatile photonic circuits. PMID- 30469781 TI - Wavefront aberration correction for integral imaging with the pre-filtering function array. AB - In integral imaging, the quality of a reconstructed image degrades with increasing viewing angle due to the wavefront aberrations introduced by the lens array. A wavefront aberration correction method is proposed to enhance the image quality with a pre-filtering function array (PFA). To derive the PFA for an integral imaging display, the wavefront aberration characteristic of the lens array is analyzed and the intensity distribution of the reconstructed image is calculated based on the wave optics theory. The minimum mean square error method is applied to manipulate the elemental image array (EIA) with a PFA. The validity of the proposed method is confirmed through simulations as well as optical experiments. A 45-degree viewing angle integral imaging display with enhanced image quality is achieved. PMID- 30469782 TI - Optical see-through holographic near-eye-display with eyebox steering and depth of field control. AB - We propose an optical see-through holographic near-eye-display that can control the depth of field of individual virtual three-dimensional image and replicate the eyebox with dynamic steering. For optical see-through capability and eyebox duplication, a holographic optical element is used as an optical combiner where it functions as multiplexed tilted concave mirrors forming multiple copies of the eyebox. For depth of field control and eyebox steering, computer generated holograms of three-dimensional objects are synthesized with different ranges of angular spectrum. In optical experiment, it has been confirmed that the proposed system can present always-focused images with large depth of field and three dimensional images at different distances with shallow depth of field at the same time without any time-multiplexing. PMID- 30469783 TI - Mechanisms of perfect absorption in nano-composite systems. AB - Recently, it was noted that losses in plasmonics can also enable several useful optical functionalities. One class of structures that can maximize absorption are metal insulator metal systems. Here, we study 3-layer systems with a nano composite metal layer as top layer. These systems can absorb almost 100% of light at visible frequencies, even though they contain only dielectrics and highly reflecting metals. We elucidate the underlying physical phenomenon that leads to this extraordinary high and broadband absorption. A comprehensive study of the particle material and shape, mirror material and dielectric spacer thickness is provided to identify their influence on the overall absorption. Thus, we can provide detailed design guidelines for realizing optical functionalities that require near-perfect absorption over specific wavelength bands. Our results reveal the strong role of lossy Fabry-Perot interference within these systems despite their thickness being well below half a wavelength. PMID- 30469784 TI - Chiral plasmonic nanocrescents: large-area fabrication and optical properties. AB - Large-area arrays of substrate-supported plasmonic gold crescents are fabricated by using the new colloidal lithography technique, which is based on an in situ deposited silica resistance layer. The method provides the means to control the particles' asymmetry just by changing the mutual deposition angle of gold and silica. Asymmetric crescent structures exhibit a pronounced circular dichroism in near-infrared region, with the chiral asymmetry factor reaching 0.2. According to the simulation, the optical chirality enhancement reaches between one and two orders of magnitude and is localized near the crescents' tips. PMID- 30469785 TI - Diffraction-limited near-spherical focal spot with controllable arbitrary polarization using single objective lens. AB - We report a time-reversal method based on the Richards-Wolf vectorial diffraction theory to generate a diffraction-limited near-spherical focal spot with arbitrary three-dimensional state of polarization using single objective lens. Three orthogonal dipole antennae are positioned above a flat mirror at a prescribed distance and an aplanatic objective lens is utilized to collect all the radiation fields emitted by the dipole antennae. The optical field in the pupil plane is calculated in a time-reversal manner and the vectorial Debye integral is used to verify the spatial intensity and polarization distributions in the focal region. The ability to confine the optical power within a subwavelength near-spherical volume with controllable three-dimensional polarization with single objective lens may be exploited in high-resolution imaging, high-density data storage, laser direct writing, lithography, spin-directional coupling, anisotropic particle trapping and manipulation. PMID- 30469786 TI - Upper and lower bounds to the information rate transferred through the Pol-Mux channel. AB - Pol-Mux transmission is a well established technique that enhances spectral efficiency by simultaneously transmitting over horizontal and vertical polarizations of the electrical field. However, cross-coupling of the two polarizations impairs transmission. Under the assumption that the cross-coupling matrix is a Markov process with free-running state, we propose upper and lower bounds to the information rate that can be transferred through the channel. Simulation results show that the two bounds are tight for values of the cross coupling power of practical interest and modulation formats up to 16-QAM (quadrature amplitude modulation). PMID- 30469787 TI - Enhanced fault characterization by using a conventional OTDR and DSP techniques. AB - To plan a rapid response and minimize operational costs, passive optical network operators require to automatically detect and identify faults that may occur in the optical distribution network. In this work, we present DSP-Enhanced OTDR, a novel methodology for remote fault analysis based on conventional optical time domain reflectometry complemented with reference traces and DSP-based techniques. We first obtain the optimal decision thresholds to detect deviations in the noisy OTDR measurement. In order to quantify and characterize the fault, the detection stage is followed by one of estimation where its return loss and insertion loss are determined. We experimentally demonstrate that this approach allows to detect and characterize faults with an accuracy higher than that found in conventional OTDR trace analysis. In our experiments, we achieved detection sensitivities higher than 0.2 dB in a 1:16 split-ratio PON, and higher than 1 dB in a 1:64 split-ratio PON, achieving estimation errors that can be as low as 0.01 dB. We also verified how the optical network terminal's reflectivity can improve the detection capabilities. PMID- 30469788 TI - Parity-time symmetry in periodically curved optical waveguides. AB - The coupling strength between two parity-time (PT) symmetric resonators determines whether the PT phase is broken or not. Here we investigate the scenario that two optical waveguides are spatially curved so that they switch periodically between unbroken and broken PT phases. We show that the existence of locally broken PT phase does not necessarily render a broken phase to waves propagating inside. Criteria are proposed to characterize the collective dynamics of wave near the Brillouin zone (BZ) edge, toward the cases of a totally broken phase, a partially broken phase, or a totally unbroken phase. We also discuss the characteristics of two special kinds of exceptional points (EPs) at the BZ edge, and show that their field patterns are displaced by half a period with each other. Full-wave numerical simulation proves our analysis. Potential applications especially these associated with EPs are discussed. This study helps us to understand how the locally PT-symmetric related eigenstate influences the globally collective dynamics of wave in spatially periodic configuration. PMID- 30469789 TI - Unidirectional light emission in PT-symmetric microring lasers. AB - The synergetic use of gain and loss in parity-time symmetric coupled resonators has been shown to lead to single-mode lasing operation. However, at the corresponding resonance frequency, an ideal ring resonator tends to support two degenerate eigenmodes, traveling along the cavity in opposite directions. Here, we show a unidirectional single-moded parity-time symmetric laser by incorporating active S-bend structures with opposite chirality in the respective ring resonators. Such chiral elements break the rotation symmetry of the ring cavities by providing an asymmetric coupling between the clockwise (CW) and the counterclockwise (CCW) traveling modes, hence creating a new type of exceptional point. This property, consequently, leads to the suppression of one of the counter-propagating modes. In this paper, we first measure the extinction ratio between the CW and CCW modes in a single ring resonator in the presence of an S bend waveguide. We then experimentally investigate the unidirectional emission in PT-symmetric systems below and above the exceptional point. Finally, unidirectional emission will be shown in systems of two S-bend ring resonators coupled through a link structure. PMID- 30469790 TI - Extended-image-based correction of aberrations using a deformable mirror with hysteresis. AB - With a view to the next generation of large space telescopes, we investigate guide-star-free, image-based aberration correction using a unimorph deformable mirror in a plane conjugate to the primary mirror. We designed and built a high resolution imaging testbed to evaluate control algorithms. In this paper we use an algorithm based on the heuristic hill climbing technique and compare the correction in three different domains, namely the voltage domain, the domain of the Zernike modes, and the domain of the singular modes of the deformable mirror. Through our systematic experimental study, we found that successive control in two domains effectively counteracts uncompensated hysteresis of the deformable mirror. PMID- 30469791 TI - Light-sheet based two-dimensional Scheimpflug lidar system for profile measurements. AB - This work presents a novel concept for 2D Scheimpflug lidar. A light-sheet based 2D Scheimpflug lidar system is developed and realized for surface profile measurements. The theory of a geometrical relationship underlying the system is developed, and the possibility of 3D profile measurements for a plastic bowl, a rhombic carton box and a manikin are presented. The sizes of reconstructed images are consistent with respective physical objects with small (~mm) errors at close range. Experimental results show that the 2D Scheimpflug lidar system performs well for 3D surface profiling and has great potential for close-range applications in other fields. PMID- 30469792 TI - Ultra-long (290 km) remote interrogation sensor network based on a random distributed feedback fiber laser. AB - In this work, an interferometric sensor has been interrogated 290 km away from the monitoring station, reaching the longest distance in fiber optic sensing up to date. This has been attained by employing a double-pumped random distributed feedback fiber laser as the light source for a fiber optic low-coherence interferometry scheme. Additionally, the capability of the system to achieve coherence multiplexing for ultra-long range measurements (up to 270 km) has been proved, without presenting crosstalk between the sensors. The use of coherence multiplexing together with a random distributed feedback fiber laser addresses two of the main limitations of long-range sensing setups: their limited multiplexing capability and the need to reach the maximum monitoring distance. PMID- 30469793 TI - Experimental demonstration of a directionally-unbiased linear-optical multiport. AB - All existing optical quantum walk approaches are based on the use of beamsplitters and multiple paths to explore the multitude of unitary transformations of quantum amplitudes in a Hilbert space. The beamsplitter is naturally a directionally biased device: the photon cannot travel in the reverse direction. This causes rapid increases in the optical hardware resources required for complex quantum walk applications, since the number of options for the walking particle grows with each step. Here we present the experimental demonstration of a directionally-unbiased linear-optical multiport, which allows reversibility of the photon direction. An amplitude-controllable probability distribution matrix for a unitary three-edge vertex is reconstructed with only linear-optical devices. Such directionally-unbiased multiports allow direct execution of quantum walks over a multitude of complex graphs and in tensor networks. This approach would enable simulation of complex Hamiltonians of physical systems and quantum walk applications in a more efficient and compact setup, substantially reducing the required hardware resources. PMID- 30469794 TI - Completeness condition for unambiguous profile reconstruction by sub-aperture stitching. AB - We describe the conditions required for a set of displaced sub-aperture measurements to contain sufficient information to reconstruct the stitched mirror profile removing all additive systematic errors of the measuring instrument, independent of the reference surface and of the guidance error of the linear stage used for the translation. We show that even-spaced stitching must be avoided and that the pitch error of the linear stage or the curvature of the reference must be measured, to avoid periodic errors and curvature errors in the reconstructed profile. We show that once these uncertainties are solved, the 1D profile can be reconstructed free of any additive systematic error. The theory is supported by computer simulations and by experimental results using two different instruments. PMID- 30469795 TI - Single-channel 10.2 Tbit/s (2.56 Tbaud) optical Nyquist pulse transmission over 300 km. AB - We describe a single-channel 10.2 Tbit/s online transmission using non-coherent ultrashort optical Nyquist pulses. A 10.2 Tbit/s signal was generated at a symbol rate of as fast as 2.56 Tbaud with a polarization-multiplexed DQPSK format. We developed a new ultrafast optical sampler for Nyquist OTDM demultiplexing with a nonlinear optical loop mirror, an RZ-CW conversion technique to improve the SNR, and an active stabilization technique providing stable long-term demultiplexing operation. With precise higher-order dispersion compensation up to fourth order, a 10.2 Tbit/s signal was transmitted over 300 km for the first time as a real time demonstration with a spectral efficiency of 2.5 bit/s/Hz. We also report a 10.2 Tbit/s transmission over 225 km with a spectral efficiency of 3.7 bit/s/Hz, which we realized by reducing the roll-off factor to zero. PMID- 30469796 TI - Real-time particle pollution sensing using machine learning. AB - Particle pollution is a global health challenge that is linked to around three million premature deaths per year. There is therefore great interest in the development of sensors capable of precisely quantifying both the number and type of particles. Here, we demonstrate an approach that leverages machine learning in order to identify particulates directly from their scattering patterns. We show the capability for producing a 2D sample map of spherical particles present on a coverslip, and also demonstrate real-time identification of a range of particles including those from diesel combustion. PMID- 30469797 TI - Investigation of different configurations and operation regimes of fiber pulse generators based on nonlinear spectral re-shaping. AB - In this work, we investigate the operation of linear fiber pulse generator circuits, based on self-phase modulation-induced spectral broadening and offset alternating spectral filtering. The influence of fiber chromatic dispersion and other parameters of the circuit for stable pulse generation and the characteristics of generated pulses are described by numerical calculations and confirmed by experiments. Self-starting pulse generation is demonstrated experimentally, and conditions allowing the achievement of self-starting are discussed. PMID- 30469798 TI - Field-programmable photonic arrays. AB - We propose a new programmable integrated photonic device, the Field Programmable Photonic Array, which follows a similar rationale as that of Field Programmable Gate Arrays and Field Programmable Analog Arrays in electronics. This high-level concept, basic photonic building blocks, design principles, and technology and physical implementation are discussed. Experimental evidence of its feasibility is also provided. PMID- 30469799 TI - Self-adaptive terahertz spectroscopy from atmospheric vapor based on Hilbert Huang transform. AB - Absorption lines of atmospheric vapor commonly appear in terahertz (THz) spectra measured in a humid air environment. However, these effects are generally undesirable because they may mask critical spectroscopic information. Here, a self-adaptive method is demonstrated for effectively identifying and eliminating atmospheric vapor noise from THz spectra of an all-fiber THz system with the Hilbert-Huang transform. The THz signal was decomposed into eight components in different time scales called the intrinsic mode functions and the interference of atmospheric vapor was accurately isolated. A series of experiments confirmed the effectiveness and strong self-adaptiveness of the proposed system in vapor noise elimination. PMID- 30469800 TI - Optimal third-harmonic generation in an optical microcavity with chi(2) and chi(3) nonlinearities. AB - Third-harmonic generation can be realized via both chi(3) and cascaded chi(2) nonlinear processes in a triply-resonant microcavity. It is still unknown how these processes interfere with each other and the optimization of the conversion efficiency still remains as a question. In this work, the interplay between the direct third-harmonic generation and the cascaded process combining of the second harmonic generation and the sum-frequency generation are investigated. It is found that the interference effect between these two processes can be used to improve the conversion efficiency. By optimizing the cavity resonance and the external coupling conditions, the saturation of the nonlinear conversion is mitigated and the third-harmonic conversion efficiency is increased. A design rule is provided for achieving efficient third-harmonic generation in an optical microcavity, which can be generalized further to the high-order harmonic generations. PMID- 30469801 TI - Wavelength-multiplexed digital holography for quantitative phase measurement using quantum dot film. AB - We propose an enhanced quantitative three-dimensional measurement system using wavelength-multiplexed digital holography. To simplify the configuration, a dual peak quantum dot wavelength converter, combined with a blue LED, is adapted as a single low-coherence light source. Rather than a conventional dual-wavelength method, which records and reconstruct the object wave for each wavelength, the proposed system can capture the holograms of two wavelengths simultaneously with fewer acquisitions, simple setup, and low noise. To verify the system's performance, the measurements of the step height sample are presented. PMID- 30469802 TI - Counterfactual entanglement swapping enables high-efficiency entanglement distribution. AB - We propose an alternative entanglement swapping scheme based on the principle of the counterfactual quantum communication, which demonstrates nonlocal entanglement swapping can be achieved by the operations of a third party. During the whole process, it is not needed to transmit any physical particles among the participants. Furthermore, all the entangled particles are not destroyed in the counterfactual entanglement swapping process, which means we can obtain two pairs of nonlocal entanglement at the same time, thus achieve high-efficiency entanglement distribution. The numerical analysis about the performance of the presented scheme shows that this counterfactual protocol can be implemented with high success probability and fidelity in the ideal asymptotic limit. The scheme may be meaningful for large-scale quantum communication network and quantum repeater. PMID- 30469803 TI - Integrated light-sheet illumination using metallic slit microlenses. AB - Light sheet microscopy (LSM) - also known as selective plane illumination microscopy (SPIM) - enables high-speed, volumetric imaging by illuminating a two dimensional cross-section of a specimen. Typically, this light sheet is created by table-top optics, which limits the ability to miniaturize the overall SPIM system. Replacing this table-top illumination system with miniature, integrated devices would reduce the cost and footprint of SPIM systems. One important element for a miniature SPIM system is a flat, easily manufactured lens that can form a light sheet. Here we investigate planar metallic lenses as the beam shaping element of an integrated SPIM illuminator. Based on finite difference time domain (FDTD) simulations, we find that diffraction from a single slit can create planar illumination with a higher light throughput than zone plate or plasmonic lenses. Metallic slit microlenses also show broadband operation across the entire visible range and are nearly polarization insensitive. Furthermore, compared to meta-lenses based on sub-wavelength-scale diffractive elements, metallic slit lenses have micron-scale features compatible with low-cost photolithographic manufacturing. These features allow us to create inexpensive integrated devices that generate light-sheet illumination comparable to tabletop microscopy systems. Further miniaturization of this type of integrated SPIM illuminators will open new avenues for flat, implantable photonic devices for in vivo biological imaging. PMID- 30469804 TI - Optical thermometry based on cooperation of temperature-induced shift of charge transfer band edge and thermal coupling. AB - A novel optical thermometry is put forward, based on the cooperation of temperature-induced red shift of the charge transfer band (CTB) edge of the vanadates and thermal population of the thermally coupled energy levels (TCELs). Particularly, temperature-dependent CTB of Sm3+ (Er3+) doped LuVO4 was investigated from 300 to 480 K. Then, under the excitation of 360 nm at which the excitation efficiency enhances with temperature due to the temperature induced red shift of the CTB edge, temperature-dependent emissions of the TCELs of Sm3+ and Er3+ were investigated. The results indicate that the emission from the upper level in the TCELs exhibits a dramatic increase, along with the increase of temperature. High relative sensitivity of 4304/T2 was obtained, which is remarkably superior to the previous reported sensors, using the temperature dependent fluorescence intensity ratio of TCELs. This suggests that the proposed strategy is a promising candidate for highly sensitive optical thermometry. PMID- 30469805 TI - Quantitative subsurface imaging in strongly scattering media. AB - We present a method to obtain quantitatively accurate images of small obstacles or inhomogeneities situated near the surface of a strongly scattering medium. The method uses time-resolved measurements of backscattered light to form the images. Using the asymptotic solution of the radiative transfer equation for this problem, we determine that the key information content in measurements is modeled by a diffusion approximation that is valid for small source-detector distances, and shallow penetration depths. We simplify this model further by linearizing the effect of the inhomogeneities about the known background optical properties using the Born approximation. The resulting model is used in a two-stage imaging algorithm. First, the spatial location of the inhomogeneities are determined using a modification of the multiple signal classification (MUSIC) method. Using those results, we then determine the quantitative values of the inhomogeneities through a least-squares approximation. We find that this two-stage method is most effective for reconstructing a sequence of one-dimensional images along the penetration depth corresponding to null source-detector separations rather than simultaneously using measurements over several source-detector distances. This method is limited to penetration depths and distances between boundary measurements on the order of the scattering mean-free path. PMID- 30469806 TI - Frequency-demultiplication OEO for stable millimeter-wave signal generation utilizing phase-locked frequency-quadrupling. AB - A novel scheme for the generation and stabilization of the millimeter-wave (mmW) signal employing a frequency-demultiplication optoelectronic oscillator (FD-OEO) has been theoretically analyzed and experimentally demonstrated. The FD-OEO can keep sustaining without optical first-order sidebands, which would help to simplify the photonic-assisted frequency multiplication process and provide a wide frequency compensation range for the mmW system simultaneously. The stability of the generated 40-GHz mmW signal reaches 1.38 * 10-12 at the average time of 100s. Besides, the measured single-sideband phase noise of the generated mmW signal exhibits as low as -103 dBc/Hz at 10-kHz offset frequency, maintaining a spurious level of -97 dBc. PMID- 30469807 TI - Helical pitch-dependent electro-optics of optically high transparent nano-phase separated liquid crystals. AB - Feeble light leakage in a dark state of conventional optically isotropic liquid crystal (OILC) device has a strong impact on the contrast ratio of a liquid crystal (LC) device. In order to overcome such intrinsic problem, we proposed an OILC in which the LC directors inside droplets are twisted by introducing chirality. The light leakage is effectively suppressed by matching the refractive indices between LC and polymer matrix; consequently, we achieved a high contrast ratio, 1:1401. Interestingly, the on-state transmittance is enhanced by ~49% compared to conventional OILC. The response time was also improved and the hysteresis was suppressed to be negligible. The improved electro-optic performances of the proposed OILC device would give diverse applications in upcoming flexible display and various photonic devices. PMID- 30469808 TI - Design and simulation of a snapshot multi-focal interferometric microscope. AB - Realizing both high temporal and spatial resolution across a large volume is a key challenge for 3D fluorescent imaging. Towards achieving this objective, we introduce an interferometric multifocus microscopy (iMFM) system, a combination of multifocus microscopy (MFM) with two opposing objective lenses. We show that the proposed iMFM is capable of simultaneously producing multiple focal plane interferometry that provides axial super-resolution and hence isotropic 3D resolution with a single exposure. We design and simulate the iMFM microscope by employing two special diffractive optical elements. The point spread function of this new iMFM microscope is simulated and the image formation model is given. For reconstruction, we use the Richardson-Lucy deconvolution algorithm with total variation regularization for 3D extended object recovery, and a maximum likelihood estimator (MLE) for single molecule tracking. A method for determining an initial axial position of the molecule is also proposed to improve the convergence of the MLE. We demonstrate both theoretically and numerically that isotropic 3D nanoscopic localization accuracy is achievable with an axial imaging range of 2um when tracking a fluorescent molecule in three dimensions and that the diffraction limited axial resolution can be improved by 3-4 times in the single shot wide-field 3D extended object recovery. We believe that iMFM will be a useful tool in 3D dynamic event imaging that requires both high temporal and spatial resolution. PMID- 30469809 TI - Bright and vivid plasmonic color filters having dual resonance modes with proper orthogonality. AB - The mode orthogonality fundamentally influences the scattering spectra of multi resonance systems, such as plasmonic color filters. We show that planar arrays of silver nanostructures with dual localized surface plasmon resonances and the right mode orthogonality can function as transmissive RGB color filters with peak transmittances higher than 70%, and color gamut areas larger than 90% of the sRGB space. These are the brightest and most saturated of all designs proposed thus far. We present the Pareto frontier from designs with more than 80% peak transmittance, to designs that achieve a color gamut larger than 120% of the sRGB space. PMID- 30469810 TI - High-Q inverted silica microtoroid resonators monolithically integrated into a silicon photonics platform. AB - We report on the monolithic integration of a new class of reflown silica microtoroid resonators with silicon nanowaveguides fabricated on top of the silica film. Connectivity with other silicon photonics devices is enabled by inversion of the toroid geometry, defined by etching a circular opening rather than a disk in an undercut silica membrane. Intrinsic quality factors of up to 2 million are achieved and several avenues of process improvement are identified that can help attain the higher quality factors (> 108) that are possible in reflown microtoroids. Moreover, due to the microtoroid being formed by standard microfabrication and post-processing by local laser induced heating, these devices are in principle compatible with monolithic co-fabrication with other electro-optic components. PMID- 30469811 TI - Optical modeling of wide-bandgap perovskite and perovskite/silicon tandem solar cells using complex refractive indices for arbitrary-bandgap perovskite absorbers. AB - Wide-bandgap perovskites are attractive top-cell materials for tandem photovoltaic applications. Comprehensive optical modeling is essential to minimize the optical losses of state-of-the-art perovskite/perovskite, perovskite/CIGS, and perovskite/silicon tandems. Such models require accurate optical constants of wide-bandgap perovskites. Here, we report optical constants determined with ellipsometry and spectrophotometry for two new wide-bandgap, cesium-formamidinium-based perovskites. We validate the optical constants by comparing simulated quantum efficiency and reflectance spectra with measured cell results for semi-transparent single-junction perovskite cells and find less than 0.3 mA/cm2 error in the short-circuit current densities. Such simulations further reveal that reflection and parasitic absorption in the front ITO layer and electron contact are responsible for the biggest optical losses. We also show that the complex refractive index of methylammonium lead triiodide, the most common perovskite absorber for solar cells, can be used to generate approximate optical constants for an arbitrary wide-bandgap perovskite by translating the data along the wavelength axis. Finally, these optical constants are used to map the short-circuit current density of a textured two-terminal perovskite/silicon tandem solar cell as a function of the perovskite thickness and bandgap, providing a guide to nearly 20 mA/cm2 matched current density with any perovskite bandgap between 1.56 and 1.68 eV. PMID- 30469812 TI - Multiplexed ultrafast fiber laser emitting multi-state solitons. AB - Ultrafast fiber lasers have been serving as an ideal playground for spreading the extensive industrial applications and exploring the optics nonlinear dynamics. Here, we report a bidirectional fiber laser scheme for validating the possibility of a multiplexed laser system, which is passively mode-locked by the nonlinear polarization rotation (NPR) technique. In particular, the proposed fiber laser consists of one main cavity and two counter-propagating branches with different dispersion distributions. Thus, different formation mechanisms are introduced into the lasing oscillator. Consequently, stable conventional solitons (CSs) and dissipative solitons (DSs) are respectively formed in the clockwise (CW) and counterclockwise (CCW) directions of the same lasing oscillator. Moreover, attributing to the strong birefringence filtering effect, the wavelength selection mechanism is induced. Through the proper management of intra-cavity birefringence, wideband wavelength tuning and switchable multi-wavelength operations are experimentally observed. The central wavelength of CS can be continuously tuned from 1560 nm to 1602 nm. Additionally, the evolution process of different multi-wavelength operations is also elucidated. Benefiting from this multiplexed laser scheme, bidirectional lasing oscillation, multi-state soliton emission, wavelength tuning and multi-wavelength operations are synchronously realized in a single laser cavity. To the best of our knowledge, it is the first time for such a multiplexed fiber laser has been reported. The results provide information for multifunctional ultrafast fiber laser system, which is potentially set for telecommunications, fiber sensing and optics signal processing, etc. PMID- 30469813 TI - Mean irradiance profile of a Gaussian beam under random jitter. AB - The mean irradiance profile has been widely applied in performance analysis and atmospheric channel research for free space optical communication; however, the modeling method and a closed-form expression of the mean irradiance profile under random jitter have rarely been discussed. To the best of our knowledge, this work presents a modeling method and a closed-form expression for a mean irradiance profile under random jitter through the ensemble average principle for the first time. We find that, with an increase in random jitter variance, the mean irradiance profile varied from an approximately Gaussian profile to a flat-topped profile to a hollow profile. These findings were verified using multilayer random phase screen simulations. The model of the mean irradiance profile under random jitter developed in this study will improve the accuracy of performance analysis and atmospheric channel research. PMID- 30469814 TI - Cost-effective near-perfect absorber at visible frequency based on homogenous meta-surface nickel with two-dimension cylinder array. AB - To date, near-perfect light absorbers at visible frequency are still severely impeded by the complicated architecture design and time-consuming costly fabrication procedures. In this work, we design and fabricate a new cost effective near-perfect absorber at visible frequency based on homogenous meta surface nickel (Ni) with a two-dimension cylinder array. The simulated and measured average absorption at normal incidence are beyond 94% and 92% over the entire visible wavelength band from 400 nm to 700 nm, respectively. Additionally, the absorbance property was well retained, and the absorptivity still remained beyond 70% when the incident angles vary from 0 degrees to 60 degrees . Our theoretically and experimentally results indicate that the broadband wide-angular absorption can be ascribed to the Rayleigh-Wood anomaly combined with slot modes induced by excited surface plasmon polaritons. Moreover, the low-cost double-beam interference lithography followed by soft nano-imprinting and electroforming technology, which are directly compatible with the cost-effective and high volume manufacturing requirements, are employed to fabricate the proposed absorber. The proposed approach is simple and inexpensive and the obtained ultrathin homogenous meta-surface nickel absorber can be rolled or folded on the surface of various optoelectronics, such as solar system and radiation thermal devices. PMID- 30469815 TI - Analysis of super-resolution via 3D structured illumination intensity correlation microscopy. AB - Intensity correlation microscopy (ICM), which is prominently known through antibunching microscopy or super-resolution optical fluctuation imaging (SOFI), provides super-resolution through a correlation analysis of antibunching of independent quantum emitters or temporal fluctuations of blinking fluorophores. For correlation order m the PSF in the signal is effectively taken to the mth power, and is thus directly shrunk by the factor m. Combined with deconvolution, a close to linear resolution improvement of factor m can be obtained. Yet, analysis of high correlation orders is challenging, which limits the achievable resolutions. Here we propose to use three dimensional structured illumination along with mth-order correlation analysis to obtain an enhanced scaling of up to m + m = 2m. Including the stokes shift or plasmonic sub-wavelength illumination enhancements beyond 2m can be achieved. Hence, resolutions far below the diffraction limit in full 3D imaging and with already low correlation orders, can potentially be achieved. Since ICM operates in the linear regime our approach may be particularly promising for enhancing the resolution in biological imaging at low illumination levels. PMID- 30469816 TI - Photon-induced carrier recombination in the nonlayered-structured hybrid organic inorganic perovskite nano-sheets. AB - The hybrid organic-inorganic perovskites (HOIPs) have attracted much attention recently due to their preeminent efficiency in solar cells. According to the difference on the crystalline structure, the HOIPs could be classified into layered and non-layered perovskites. Very recently, it has been realized that the non-layered HOIPs with common-vertex structure possess even better opto electrical performance. Yet the carrier recombination mechanism in perovskite remains not very clear, and a clear understanding of this mechanism is essential to pinpoint the working mechanism of photovoltaic and electroluminescent materials. Here we report the optical studies on the hybrid perovskite crystalline nano-sheet of CH3NH3PbBr3 with common-vertex structure. It is shown that the non-layered perovskite crystalline nanosheets possess the exciton binding energy about two orders of magnitude smaller than that of the layered perovskite and the colloidal nanoplates, which is beneficial for the designing of the high-efficiency photovoltaic devices. By measuring the temperature-dependent photoluminescence (PL) spectra, the excitation-power-variant PL spectra, and the time-resolved PL spectra, we identify that both the free-carrier and the localized exciton recombination channels may coexist in the crystallites. Further, for the thin crystallite (~60 nm), the free-carrier recombination channel dominates; whereas when the thickness increases beyond 200 nm, the localized exciton recombination channel plays the major role. We suggest these results are helpful to improve further the photovoltaic and electroluminescent performances of perovskite devices. PMID- 30469817 TI - Optical spectrometer based on continuously-chirped guided mode resonance filter. AB - In this work we introduce a tunable GMR filter based on continuously period chirped (DeltaP = 130 nm) gratings using a Ta2O5 waveguide layer with graded thickness (DeltaT = 36 nm). The structure of the gradient-period grating is defined using a modified Lloyd's mirror interferometer with a convex mirror, and Ta2O5 film used for the gradient is deposited using masked e-beam evaporation. The as-realized chirped GMR filter provides sharp transmission dips at resonant wavelengths with a filter bandwidth of approximately 4.2 nm and 0.78 nm when respectively applied to TE and TM polarized light under normal incidence. Gradually sweeping the chirped GMR filter makes it possible to monotonically sweep through resonant wavelengths from 500 to 700 nm, while maintaining stable filter bandwidth and transmission intensity. The optical spectrum of the incoming light can then be loyally reconstructed accordingly. We successfully demonstrate the spectrum reconstruction of a white light emitting diode and a dual-peak laser beam using the proposed chirped GMR filter as a dispersive device. PMID- 30469818 TI - Anamorphic fractional Fourier transforms graded index lens designed using transformation optics. AB - An anamorphic fractional Fourier transform (AFrFT) lens based on graded index (GRIN) materials and designed with the help of transformation optics is proposed. Cross sections of the new lens are mapped from those of a standard quadratic GRIN lens via gradually varied conformal transformations. This lens can afford complicated anamorphic patterns in the fractional Fourier domain for any fractional order, possibly leading to many new applications. Three samples are shown, which offer higher distinguishability in the fractional Fourier domain, a more precisely recognized matched filter, and stronger security of the AFrFT based optical encryption. With metamaterials development, including three dimensional printing technologies, GRIN media fabrication has become more convenient; thus, the proposed lens may have vast application prospects in signal processing. The design also demonstrates the ability and flexibility of the transformation optics in exploring new Fourier optics devices. PMID- 30469819 TI - High-performance composite Ag-Ni mesh based flexible transparent conductive film as multifunctional devices. AB - Conventional fabrication methods for realization of metal mesh (MM) based transparent conductive film (TCF) are not economic and environmentally friendly. By combination of the scrape and selective electroplating techniques, a vacuum sputtering/evaporation-free process is explored for fabrication of high performance MM based TCF. The fabricated TCF exhibits ultra-low sheet electrical resistance (Rs = 0.07 Omega sq-1) at average transmittance of 83% in visible region. The sample cannot only exhibit high heating temperatures (140 degrees C) at low input voltage (1.5 V) with fast and stable thermal response but provide high electromagnetic interference shielding efficiency (EMI SE) more than 43 dB in X-band. The processing chain provides a robust, powerful and scalable platform, which may open up a new avenue for realizing multifunctional TCF in diverse applications. PMID- 30469820 TI - Single-line-extracted pure rotational Raman lidar to measure atmospheric temperature and aerosol profiles. AB - We have built a pure rotational Raman (PRR) lidar system that effectively detects two isolated N2 molecule PRR line signals and elastic backscatter signals. This system enables all-day temperature profiles to be accurately obtained without calibration, according to the simple two-parameter functional relationship between the temperature and ratio of the two PRR line signals. Based on the derived temperature profiles, the aerosol backscatter and extinction profiles can be further determined strictly from one measured PRR line signal and elastic backscatter signal without additional assumptions. The two aerosol parameters and resultant lidar ratio provide strict standards for the lidar measurements of aerosol. PMID- 30469821 TI - Demonstration of longitudinally polarized optical needles. AB - Longitudinally polarized optical needles are beams that exhibit ultra-long depth of field, subwavelength transverse confinement, and polarization oriented along the longitudinal direction. Although several techniques have been proposed to generate such needles, their scarce experimental observations have been indirect and incomplete. Here, we demonstrate the creation and full three-dimensional verification of a longitudinally polarized optical needle. This needle is produced by generating a radially polarized Bessel-Gauss beam at the focus of a high numerical aperture microscope objective. Using three-dimensional spatial mapping of second-harmonic generation from a single vertically aligned GaAs nanowire, we directly verify such a longitudinally polarized optical needle's properties, which are formed at the focus. The needle exhibits a dominant polarization, which is oriented along the longitudinal direction, an ultra-long depth of field (30 lambda), and high spatial homogeneity. These are in agreement with corresponding focal field calculations that use vector diffraction theory. Our findings open new opportunities for manipulation and utilization of longitudinally polarized optical needles. PMID- 30469822 TI - Multi-parallax views synthesis for three-dimensional light-field display using unsupervised CNN. AB - Multi-view applications have been used in a wide range, especially Three Dimensional (3D) display. Since capturing dense multiple views for 3D light-field display is still a difficult work, view synthesis becomes an accessible way. Convolutional neural networks (CNN) has been used to synthesize new views of the scene. However, training targets are sometimes difficult to obtain, and it views are very difficult to synthesize at arbitrary positions. Here, an unsupervised network of Multi-Parallax View Net (MPVN) is proposed, which can synthesize multi parallax views for 3D light-field display. Existing parallax views are re projected to the target position to build input towers. The network is operated on these towers, and outputs a color tower and a selection tower. These two towers yield the final output image by per-pixel weight summing. MPVN adopts end to-end unsupervised training to minimize prediction errors at existing positions. It can predict virtual views at any parallax position between existing views in a high quality. Experimental results demonstrate the validation of our proposed network, and SSIM of synthetic views are mostly over 0.95. We believe that this method can effectively provide enough views for 3D light-field display in the future work. PMID- 30469823 TI - Optimal illumination pattern for transport-of-intensity quantitative phase microscopy. AB - The transport-of-intensity equation (TIE) is a well-established non interferometric phase retrieval approach, which enables quantitative phase imaging (QPI) of transparent sample simply by measuring the intensities at multiple axially displaced planes. Nevertheless, it still suffers from two fundamentally limitations. First, it is quite susceptible to low-frequency errors (such as "cloudy" artifacts), which results from the poor contrast of the phase transfer function (PTF) near the zero frequency. Second, the reconstructed phase tends to blur under spatially low-coherent illumination, especially when the defocus distance is beyond the near Fresnel region. Recent studies have shown that the shape of the illumination aperture has a significant impact on the resolution and phase reconstruction quality, and by simply replacing the conventional circular illumination aperture with an annular one, these two limitations can be addressed, or at least significantly alleviated. However, the annular aperture was previously empirically designed based on intuitive criteria related to the shape of PTF, which does not guarantee optimality. In this work, we optimize the illumination pattern to maximize TIE's performance based on a combined quantitative criterion for evaluating the "goodness" of an aperture. In order to make the size of the solution search space tractable, we restrict our attention to binary-coded axis-symmetric illumination patterns only, which are easier to implement and can generate isotropic TIE PTFs. We test the obtained optimal illumination by imaging both a phase resolution target and HeLa cells based on a small-pitch LED array, suggesting superior performance over other suboptimal patterns in terms of both signal-to-noise ratio (SNR) and spatial resolution. PMID- 30469824 TI - Random laser based method for direct measurement of scattering properties. AB - Optical sensing is a very important method for investigating different kinds of samples. Recently, we proposed a new kind of optical sensor based on random lasing [ Sci. Rep.6, 35225 (2016)], that couples the advantages of stimulated emission in detecting small variations on scattering properties of a sensed material, to the needs of no alteration of the sample under investigation. Here, we present a method to achieve a quantitative measurement of the scattering properties of a material. The results on samples of calibrated microspheres show a dependence of the peak intensity of the emission spectrum on the transport mean free path of the light within the sample, whatever the dimension (down to ~100 nm of particle diameter) and the concentration of scatterers dispersed in the sensed material. A direct and fast measurement of the scattering properties is obtained by calibration with a well-known and inexpensive reference medium. PMID- 30469825 TI - Magnetic field sensor based on a dual-frequency optoelectronic oscillator using cascaded magnetostrictive alloy-fiber Bragg grating-Fabry Perot and fiber Bragg grating-Fabry Perot filters. AB - A magnetic field sensor using a dual-frequency optoelectronic oscillator (OEO) incorporating cascaded magnetostrictive alloy-fiber Bragg grating-Fabry Perot (MA FBG-FP) and FBG-FP filters is proposed and demonstrated. In the OEO resonant cavity, two microwave signals are generated, whose oscillation frequencies are determined by the FBG-FP filter and MA-FBG-FP filter filters with two ultra narrow notches and two laser sources. Due to the characteristics of MA and FBG, the two generated microwave signals show different magnetic field and temperature sensitivities. By monitoring the variations of two oscillating frequencies and the beat signal using a digital signal processor, the simultaneous measurement for the magnetic field and temperature can be realized. The proposed sensor has the advantages of high-speed and high-resolution measurement, which make it very attractive for practical magnetic field sensing applications. The sensitivities of the proposed OEO sensor for magnetic field and temperature are experimentally measured to be as high as -38.4MHz/Oe and -1.23 or -2.45 GHz/ degrees C corresponding to the MA-FBG-FP filter and FBG-FP filter, respectively. PMID- 30469826 TI - Mitigating pattern dependent nonlinearity in SiP IQ-modulators via iterative learning control predistortion. AB - Silicon based Mach Zehnder modulators, unlike lithium niobate, suffer from nonlinear pattern-dependent behavior beyond simple intersymbol interference. We experimentally demonstrate a novel predistortion method based on the iterative learning control (ILC) technique to address this issue using quasi-real-time adaptation with hardware-in-the-loop. We compare bit error rate performance to that of linear solutions at several M-QAM modulation levels and baud rates. We demonstrate 256QAM at 20 Gbaud which linear compensation alone cannot achieve. For 40 Gbaud 128QAM, we improve power sensitivity by 4.4 dB. We combine optical compensation with ILC to improve power sensitivity by ~ 5 dB for 60 Gbaud 32QAM. PMID- 30469827 TI - Highly sensitive all-optical control of light in WS2 coated microfiber knot resonator. AB - All-optical light-control-light functionality is realized in a layered tungsten disulfide (WS2) nanosheet coated microfiber knot resonator (MKR) structure. Mainly due to the photon generated excitons induced refractive index variation in WS2 nanosheets, a large variation in the transmitted power (?T) can be observed under external violet/red laser excitation. The ?T variation rates can reach up to ~0.4 dB/mW under violet pump light excitation whereas the state of the art light-control-light structures usually has a variation rate of less than 0.25 dB/mW. In terms of the response time, the averaged rise/fall time is ~0.12/0.1 s. The demonstrated structure has the advantages of easy fabrication, low cost and high sensitivity, therefore, it might be a promising candidate for building future all-fiber-optics based functional devices and all-optical circuitry. PMID- 30469828 TI - Photonics based microwave dynamic 3D reconstruction of moving targets. AB - In this paper, a photonics based microwave dynamic 3D reconstruction of moving targets is proposed for the first time. The system is based on optical arbitrary waveform generation and photonics assisted 3D imaging processing. An X-band system is established experimentally. A 3D reconstruction of two pairs of cross placement rotary balls is demonstrated to prove the effectiveness of the proposed system. Experimental results show that the proposed system can provide information on the stereoscopic physical structure of the targets dynamically, being favorable to identification and surveillance of the complex targets. PMID- 30469829 TI - Quantitative comparison of plasmon resonances and field enhancements of near field optical antennae using FDTD simulations. AB - Plasmon resonances and electric field enhancements of several near-field optical antennae with plasmonic nanostructures engineered at their apices were quantitatively compared using finite difference time domain simulations. Although many probe designs have been tested experimentally, a systematic comparison of field enhancements has not been possible, due to differences in instrument configuration, reporter mechanism, excitation energy, and plasmonic materials used. For plasmonic nanostructures attached to a non-plasmonic support (e.g., a nanoparticle functionalized AFM tip), we find that the complex refractive index of the support material is critical in controlling the overall plasmonic behavior of the antenna. Supports with strong absorption at optical energies (Pt, W) dampen plasmon resonances and lead to lower enhancements, while those with low absorption (SiO2, Si3N4, Si) boost enhancement by increasing the extinction cross section of the apex nanostructure. Using a set of physically realistic constraints, probes were optimized for peak plasmonic enhancement at common near field optical wavelengths (633-647 nm) and those with focused ion-beam milled grooves near the apex were found to give the largest local field enhancements (~30x). Compared to unstructured metal cones, grooved probes gave a 300% improvement in field strength, which can boost tip-enhanced Raman spectroscopy (TERS) signals by 1-2 orders of magnitude. Moreover, grooved probe resonances can be easily tuned over visible and near-infrared energies by varying the plasmonic metal (Ag or Au) and groove location. Overall, this work shows that probes with strong localized surface plasmon resonances at their apices can be engineered to provide large field enhancements and boost signals in near-field optical experiments. PMID- 30469830 TI - Localized plasmon resonances for black phosphorus bowtie nanoantennas at terahertz frequencies. AB - In this work, a periodic bowtie structure based on black phosphorus (BP) is theoretically proposed and characterized. It is demonstrated that localized surface plasmons can be excited in the BP nanoantennas at terahertz (THz) frequencies. Numerical investigations, using the numerical method finite difference time-domain (FDTD), have been utilized to analyze the the dimensions' impact on absorption spectra. Furthermore, the electric field distribution is plotted and discussed to explain the resonance wavelength tuning by different geometrical sizes of the structure. Results reveal that the optimized BP bow-tie structure can be allowed for the realization of two-dimensional nanophotonics at terahertz frequencies. PMID- 30469831 TI - Mechanical effect of photonic spin-orbit interaction for a metallic nanohelix. AB - Upon illumination by a circularly polarized plane wave, a nanohelix converts part of the incoming optical spin angular momentum into optical orbital angular momentum. Here, by combining partial wave analysis with band structure and eigenmode calculations, we studied the optical torque and light extinction for a gold nanohelix. It is found that spin-orbital angular momentum conversion is a necessary condition for inducing recoil optical torque, but not for light extinction. In other words, a particle can have a large light extinction cross section but not a strong torque, or vice versa. Our calculation also shows that broad frequency band negative optical torque can also exist in a nanohelix, which possesses screw-axis symmetry. PMID- 30469832 TI - Loss-tolerant quantum dense metrology with SU(1,1) interferometer. AB - Heisenberg uncertainty relation in quantum mechanics sets the limit on the measurement precision of non-commuting observables in one system, which prevents us from measuring them accurately at the same time. However, quantum entanglement between two systems allows us to infer through Einstein-Podolsky-Rosen correlations two conjugate observables with precision better than what is allowed by Heisenberg uncertainty relation. With the help of the newly developed SU(1,) interferometer, we implement a scheme to jointly measure information encoded in multiple non-commuting observables of an optical field with a signal-to-noise ratio improvement of about 20% over the classical limit on all measured quantities simultaneously. This scheme can be generalized to the joint measurement of information in arbitrary number of non-commuting observables. PMID- 30469833 TI - Enhancement of luminous efficacy for LED lamps by introducing polyacrylonitrile electrospinning nanofiber film. AB - Polyacrylonitrile electrospinning nanofiber film was introduced into a light emitting diode (LED) lamp to exploit the strong reflective and scattering effects. The light extraction mechanism was studied systematically for three different electrospinning types in three different types of LED lamps. For the all-electrospinning types, the luminous efficacy increased for the white LED, outwards remote phosphor layer, and inwards remote phosphor layer lamps by 10.98, 16.97, and 18.35%, respectively, compared with the reference lamp. Lamps with stronger backscatter had larger luminous efficacy enhancements. The reflector electrospinning type helped redirect lights with large emission angles. The substrate-electrospinning type was beneficial for recycling the total interior reflection lights and increasing the yellow to blue ratio. Additionally, the all electrospinning white LED lamps remains 97.89% luminous flux after a 96-hour aging process. Electrospinning fiber films are favorable luminous efficacy enhancers for the future generation of LED lamps. PMID- 30469834 TI - Femtosecond polarization-structured optical field meets an anisotropic nonlinear medium. AB - Filamentation, as a universal femtosecond phenomenon that could occur in various nonlinear systems, has aroused extensive interest, owing to its underlying physics, complexity and applicability. It is always anticipated to realize the controllable and designable filamentation. For this aim, the crucial problem is how to actively break the symmetry of light-matter nonlinear interaction. A kind of extensively used approaches is based on the controllable spatial structure of optical fields involving phase, amplitude and polarization. Here we present an idea to control the optical field collapse by introducing optical anisotropy of matter as an additional degree of freedom, associated with polarization structure. Our theoretical prediction and experimental results reveal that the synergy of optical anisotropy and polarization structure is indeed a very effective means for controlling the optical field collapse, which has the robust feature against random noise. PMID- 30469835 TI - Intense water-window soft x-ray emission by spectral control using dual laser pulses. AB - We demonstrate intense emission in the water-window soft x-ray spectral region by controlling the spectral behavior through changing the balance between emissivity and self-absorption in an expanding plasma. The number of photons obtained from a dual laser irradiated target with a 150-ps pre-pulse was maximized at 3.8 * 1014 photons/sr in lambda = 2.34 - 4.38 nm at a pulse separation time of 7 - 10 ns. Enhancement of the number of photons is attributed to efficient coupling with the main laser pulse while maintaining a tiny source size. PMID- 30469836 TI - Design and fabrication of prototype piezoelectric adjustable X-ray mirrors. AB - Lynx, a next generation X-ray observatory concept currently under study, requires lightweight, high spatial resolution X-ray mirrors. Here we detail the development and fabrication of one of the candidate technologies for Lynx, piezoelectric adjustable X-ray optics. These X-ray mirrors are thin glass shell mirrors with Cr/Ir X-ray reflective coatings on the mirror side and piezoelectric thin film actuators on the actuator side. Magnetron sputtering was used to deposit metal electrodes and metal-oxide piezoelectric layers. The piezoelectric (Pb0.995(Zr0.52Ti0.48)0.99Nb0.01O3) was divided into 112 independent piezoelectric actuators, with 100% yield achieved. We discuss the fabrication procedure, residual thermal stresses and tuning of the Cr/Ir coating stress for the purposes of stress balancing. PMID- 30469837 TI - Magnetic-enhanced modulation transfer spectroscopy and laser locking for 87Rb repump transition. AB - Locking of a laser frequency to an atomic or molecular resonance line is a key technique in applications of laser spectroscopy and atomic metrology. Modulation transfer spectroscopy (MTS) provides an accurate and stable laser locking method which has been widely used. Normally, the frequency of the MTS signal would drift due to Zeeman shift of the atomic levels and rigorous shielding of stray magnetic field around the vapor cell is required for the accuracy and stability of laser locking. Here on the contrary, by applying a transverse bias magnetic field, we report for the first time observation of a magnetic-enhanced MTS signal on the transition of 87Rb D2-line Fg = 1-> Fe = 0 (close to the repump transition of Fg = 1-> Fe = 2), with signal to noise ratio larger than 100:1. The error signal is immune to the external magnetic fluctuation. Compared to the ordinary MTS scheme, it provides a robust and accurate laser locking approach with more stable long term performance. This technique can be conveniently applied in areas of laser frequency stabilization, laser manipulation of atoms and precision measurement. PMID- 30469838 TI - Super-resolution technique for high-resolution multichannel Fourier transform spectrometer. AB - We propose a super-resolution technique for multichannel Fourier transform spectrometers, which is advantageous for feeble-light spectroscopy. The spectral resolution of an area sensor is limited by the number of lateral pixels. Our method fills the signals with vertical pixels, which is practically equivalent to increasing the number of lateral pixels. When applying our proposed technique, the resolution of an Ar-lamp spectrum, which is obtained by using an area sensor with 659 lateral pixels, becomes comparable to that of an area sensor with 1,626 lateral pixels. The spectral resolution is improved at least twice. Thus, using our method, a spectrometer with an area sensor can overcome the Nyquist frequency limitations. PMID- 30469839 TI - Design method for assembly-insensitive freeform reflective optical systems. AB - The sensitivity of an optical system to assembly errors can greatly affect the actual image quality. The system design must be changed if its tolerance for assembly errors is too tight. In this paper, we present an automated design method for initial systems of freeform reflective optical systems that are insensitive to assembly errors. By this method, an assembly-insensitive initial system comprised of surfaces with different types (sphere, aspheric, freeform) can be obtained directly without human interaction. To illustrate the design process, an assembly-insensitive off-axis optical system that has two freeform surfaces and one spherical surface is designed, which shows the effectiveness of the proposed method. PMID- 30469840 TI - Linear assignment problem in the design of freeform refractive optical elements generating prescribed irradiance distributions. AB - We consider the problem of calculating the eikonal function defined on a certain curved surface from the condition of generating a prescribed irradiance distribution on a target surface. We show that the calculation of the "ray mapping" corresponding to the eikonal function is reduced to the solution of a linear assignment problem (LAP). We propose an iterative algorithm for calculating a refractive optical surface from the condition of generating a prescribed near-field irradiance distribution in a non-paraxial case. The algorithm is based on sequential calculation of eikonal functions defined on curved surfaces using the LAP-based approach. The proposed algorithm is applied to the calculation of refractive optical elements generating uniform irradiance distributions in a rectangular region and in a region in the form of the letters "IPSI" in the case of a circular incident beam. The presented ray-tracing simulations of the designed optical elements demonstrate high efficiency of the proposed iterative algorithm. PMID- 30469841 TI - User-centric quality of experience optimized resource allocation algorithm in VLC network with multi-color LED. AB - Visible light communication (VLC) can provide indoor illumination while achieving high network throughput. In order to mitigate the performance degradation caused by inter-cell interference (ICI) and support multiple users, this paper utilizes the white LED synthesized by multi-color light sources as indoor illumination and signal transmissions. Compared with ordinary LEDs, multi-color LEDs not only has excellent color rendering index, but also realize multi-channel parallel transmission, which greatly improves the transmission speed of VLC. Meanwhile, we propose a user-centric (UC) quality of experience (QoE) optimization scheduling scheme for the VLC down-link system. In contrast to the traditional network centric (NC) design, the UC scheme is based on the user-centric dynamic construction and adjustment of the network model. Furthermore, in order to further analyze the performances of the illuminations and signal transmissions of the VLC system with multi-color LED, we consider the system model under two scenarios of 3-color and 4-color synthetic white LEDs. For these two different LED composition and optimization problems, we design a new greedy algorithm to allocate optical bandwidth, and dynamically searched for the optimal access point user equipment (AP-UE) link based on optimization of the UEs' QoE values. In order to analyze the robustness of the algorithm, we further consider the influences of UEs on the transmission performance under different UEs' spatial distributions, e.g., uniform and Poisson distributions. The simulation results illustrate that the proposed scheme guarantees the UEs' QoE while offering illumination quality. Meanwhile, compared to ordinary LEDs and the traditional network-centric (NC) design, our proposed scheme can schedules more UEs. PMID- 30469842 TI - Spontaneous pump depolarization in ultralong cavity Raman fiber laser amplifiers. AB - We present an experimental demonstration of polarization-independent performance in a forward and backward-pumped 2nd-order ultralong cavity Raman laser amplifiers with highly polarized pumps. Our findings show that the depolarization of the Stokes component due to gain saturation leads to polarization-insensitive performance in terms of output gain and relative intensity noise in the signal. These results pave the way for the use of individual highly polarized low-RIN semiconductor laser diodes in Raman-amplified optical communications. PMID- 30469843 TI - Turbo-coded 16-ary OAM shift keying FSO communication system combining the CNN based adaptive demodulator. AB - In this paper, a novel turbo-coded 16-ary orbital angular momentum - shift keying free space optical (OAM-SK-FSO) communication system combining a convolutional neural network (CNN) based adaptive demodulator under strong atmospheric turbulence is proposed for the first time. The feasibility of the scheme is verified by transmitting a 256-grayscale two-dimensional digital image. The bit error ratio (BER) performance of the system is investigated and the effect of different factors such as turbulence strength, propagation distance, code rate, length of random interleaver and length of bit interleaver is also taken into account. An advanced encoder/decoder structure and mapping scheme are applied to diminish the influence of CNN misclassification and reduce the BER effectively. With the optimal encoder/decoder structure and CNN model settings, the BER varies from 0 to 4.89*10-4 when the propagation distance increases from 200m to 1000m for a given turbulence strength Cn2 equals 5*10-14m-2/3. For a determined propagation distance equals 400m, the BER ranges from 0 to 4.01*10-4 when Cn2increases from 1*10-15m-2/3 to 4*10-13m-2/3. Our numerical simulations demonstrate that the proposed system can provide better BER performance under strong atmospheric turbulence and conditions when the classification ability of CNN is limited. PMID- 30469844 TI - Control of thermal radiation in metal hole array structures formed by anisotropic anodic etching of Al. AB - An efficient preparation process for Al hole array structures emitting wavelength selective thermal radiation that is based on the anisotropic anodic etching of Al was demonstrated. The formation of an ordered hole array was achieved by a masking process prior to the anodic etching. The present process allows the preparation of large samples because the masking of the Al foil has a high throughput owing to the simple printing process using a flexible stamp. The thermal radiation properties of the Al hole array could be controlled by adjusting the depth and aperture size of the holes. PMID- 30469845 TI - Design and analysis of high-speed optical access networks in the O-band with DSP free ONUs and low-bandwidth optics. AB - In this paper, we demonstrate and investigate high-speed passive optical networks (PON) in the O-band without using any digital signal processing (DSP) at the ONU side, meanwhile still adopting cost-effective low-bandwidth optics. We show that with commercial 10G-class optics including DML and PIN-TIA, 50Gb/s PAM4 PON with a power budget up to 29dB is achieved under the HD-FEC BER limit. We present the detailed design procedure of the DSP including the downlink Nyquist pulse shaping and pre-equalization and uplink post-equalization, and conduct a comprehensive study on this system including DSP complexity, DAC/ADC sampling rate requirement and tolerance to the response diversity of ONU receivers. We conclude that, 1) 55 and 35 taps are sufficient for downlink and uplink digital filters to approach the BER floor; 2) the minimum required DAC and ADC sampling rate are respectively 33.75GS/s and 32GS/s to achieve the optimal performance; and 3) with 1dB sensitivity penalty at the HD-FEC BER limit, the allowable response diversity of ONU receivers can be from -2.2dB/10GHz to 1.8dB/10GHz. Furthermore, we explore and demonstrate the suitable data rate based on on-off keying and duobinary modulation formats in this system and present corresponding results. PMID- 30469846 TI - Effective, angle-independent radiative cooler based on one-dimensional photonic crystal. AB - A simple and low-cost radiative cooler based on one-dimensional photonic crystal is proposed in this work, which has an average emissivity of 96% within the atmospheric transparency window (8-13MUm). The ultra-broadband emissivity property is realized by constructing the strongly overlapped optical resonances with a tandem structure composed of two lossy materials while an additional lossless material is adopted as the top layer to reduce the Fresnel reflection of the whole structure. The maximum cooling power density of the fabricated radiative cooler can reach 113.0W/m2 at night. When integrated with an excellent solar reflector that can reflect 97% incident solar power, it theoretically has the maximum cooling power of 83.0 W/m2 in the case of solar irradiance up to 1000 W/m2 at noon. PMID- 30469847 TI - Rectangular Hermite non-uniformly correlated beams and its propagation properties. AB - We introduce a new class of non-uniformly correlated beams that are called rectangular Hermite non-uniformly correlated (RHNUC) beams, which possess rectangular symmetry in their degree of coherence. It is shown that, in free space and in turbulence, these beams possess self-focusing properties and that the position of the focus can be adjusted in 3-D space by manipulating the correlation properties of the source. Furthermore, it is demonstrated that, by choosing different mode orders and correlation lengths along two transverse directions, one creates astigmatic beams that can be designed to have a high and near-constant intensity over an extended propagation range. PMID- 30469848 TI - Wavelength multiplexing of four-wave mixing based fiber temperature sensor with oil-filled photonic crystal fiber. AB - A fiber temperature sensor based on four-wave mixing (FWM) with an oil-filled photonic crystal fiber (PCF) is proposed in this study, and a multipoint measurement based on the wavelength multiplexing of such sensors is constructed for the first time. The sensing performance and signal spectral characteristics of the temperature sensor are theoretically and experimentally studied. The maximum temperature sensitivity of the signal light of 0.207 nm/ degrees C is achieved using a FWM sensing fiber with a length of 10 cm. The signal wavelength response to excitation power is also explored in this experiment. Results showed that the temperature sensor is relatively insensitive to the fluctuation of power change. The wavelength multiplexing of a FWM-based PCF temperature sensor also presents the possibility of multiplexing measurement and multipoint sensing, and high multiplexed capability is theoretically predicted to be obtainable with optimized sensitivity and splicing loss. PMID- 30469849 TI - Demonstration of terahertz ferroelectric metasurface using a simple and scalable fabrication method. AB - We report on experimental implementation of a ferroelectric metasurface using an x-cut KTiOPO4 (KTP) crystal for efficient manipulation of terahertz (THz) radiation. Based on the multipolar resonances that are accommodated in KTP micro blocks in a square array, the metasurface is fabricated by precision diamond blade dicing. Adjusting the size of the KTP micro-blocks to tailor the relative spectral positions of the anisotropic multipolar resonances, we demonstrate a subwavelength-thin THz polarizer that functions as a transparent film in the y direction and a magnetic mirror in the z-direction with a transmission contrast of 13 dB near 0.37 THz (820 um). The ferroelectric-based all-dielectric metasurface will provide a versatile platform to engineer the THz waves in the far field and could potentially be combined with THz generation in the same material. PMID- 30469850 TI - Asymptotic analysis of V-BLAST MIMO for coherent optical wireless communications in Gamma-Gamma turbulence. AB - This paper investigates the asymptotic BER performance of coherent optical wireless communication systems in Gamma-Gamma turbulence when applying the V BLAST MIMO scheme. A new method is proposed to quantify the performance of the system and mathematical solutions for asymptotic BER performance are derived. Counterintuitive results are shown since the diversity gain of the V-BLAST MIMO system is equal to the number of the receivers. As a consequence, it is shown that when applying the V-BLAST MIMO scheme, the symbol rate per transmission can be equal to the number of transmitters with some cost to diversity gain. This means that we can simultaneously exploit the spatial multiplexing and diversity properties of the MIMO system to achieve a higher data rate than existing schemes in a channel that displays severe turbulence and moderate attenuation. PMID- 30469851 TI - Counterpropagating path-entangled photon pair sources based on simultaneous spontaneous parametric down-conversion processes of nonlinear photonic crystal. AB - Ultra-bright source of entangled photons is an essential component in optical quantum information processing. Here we propose a counterpropagating path entangled photon pair sources using a quasi-periodic modulated lithium niobate crystal. The nonlinear crystal designed by a dual-grid method, simultaneously phase-matched two spontaneous parametric down-conversion processes. Signal and idler modes have opposite propagation directions in the two spontaneous parametric down-conversion processes, which is the key to generating path entangled photon pairs. Compared to copropagating entangled sources, the counterpropagating path-entangled sources result in a much narrower spectrum. The quantum state of the path-entanglement source is not only suited for quantum coding, but also to allow the implementation of complex quantum algorithms on a photonic chip. PMID- 30469852 TI - Demonstration of long-term thermally stable silicon-organic hybrid modulators at 85 degrees C. AB - We report on the first demonstration of long-term thermally stable silicon organic hybrid (SOH) modulators in accordance with Telcordia standards for high temperature storage. The devices rely on an organic electro-optic sidechain polymer with a high glass transition temperature of 172 degrees C. In our high temperature storage experiments at 85 degrees C, we find that the electro-optic activity converges to a constant long-term stable level after an initial decay. If we consider a burn-in time of 300 h, the pi-voltage of the modulators increases on average by less than 15% if we store the devices for an additional 2400 h. The performance of the devices is demonstrated by generating high-quality 40 Gbit/s OOK signals both after the burn-in period and after extended high temperature storage. PMID- 30469853 TI - High-density gas capillary nozzles manufactured by hybrid 3D laser machining technique from fused silica. AB - In this report, an efficient hybrid laser technique, nanosecond laser rear-side processing and femtosecond laser-assisted selective etching (FLSE) for the manufacturing of high-density gas capillary targets, is demonstrated. Cylindrical capillary nozzles for laser betatron X-ray sources were numerically simulated, manufactured from fused silica by 3D laser inscription and characterized using interferometry and gas density reconstruction. The dependence of gas concentration profiles on the wall roughness of cylindrical channels is presented. PMID- 30469854 TI - Nonlinear frequency division multiplexing with b-modulation: shifting the energy barrier. AB - The recently proposed b-modulation method for nonlinear Fourier transform-based fiber-optic transmission offers explicit control over the duration of the generated pulses and therewith solves a longstanding practical problem. The currently used b-modulation however suffers from a fundamental energy barrier. There is a limit to the energy of the pulses, in normalized units, that can be generated. In this paper, we discuss how the energy barrier can be shifted by proper design of the carrier waveform and the modulation alphabet. In an experiment, it is found that the improved b-modulator achieves both a higher Q factor and a further reach than a comparable conventional b-modulator. Furthermore, it performs significantly better than conventional approaches that modulate the reflection coefficient. PMID- 30469855 TI - Form determination of optical surfaces by measuring the spatial coherence function using shearing interferometry. AB - We present a new method for the form measurement of optical surfaces using the spatial coherence function, which enables a shearing interferometer in combination with an LED multispot illumination to function as a measurement device. A new evaluation approach connects the measured data with the surface form by inverse raytracing. First measurement results with the inverse evaluation procedures are shown. We present the whole measurement in combination with the evaluation procedure. In addition, the convergence and stability of the implemented optimization task is investigated. PMID- 30469856 TI - Automated logic synthesis for electro-optic logic-based integrated optical computing. AB - Integrated optical computing attracts increasing interest recently as Moore's law approaches the physical limitation. Among all the approaches of integrated optical computing, directed logic that takes the full advantage of integrated photonics and electronics has received lots of investigation since its first introduction in 2007. Meanwhile, as integrated photonics matures, it has become critical to develop automated methods for synthesizing optical devices for large scale optical designs. In this paper, we propose a general electro-optic (EO) logic in a higher level to explore its potential in integrated computing. Compared to the directed logic, the EO logic leads to a briefer design with shorter optical paths and fewer components. Then a comprehensive gate library based on EO logic is summarized. At last, an And-Inverter Graphs (AIGs) based automated logic synthesis algorithm is described as an example to implement the EO logic, which offers an instruction for the design automation of high-speed integrated optical computing circuits. PMID- 30469857 TI - Photonic generation of binary and quaternary phase-coded microwave signals by utilizing a dual-polarization dual-parallel Mach-Zehnder modulator. AB - A photonic method to generate binary and quaternary phase-coded microwave signals using a dual-polarization dual-parallel Mach-Zehnder modulator (DP-DPMZM) is proposed and experimentally demonstrated. The upper DPMZM driven by a radio frequency (RF) signal acts as an optical wavelength shifter, while the lower DPMZM is used to generate a binary phase shift key (BPSK) or quadrature phase shift key (QPSK) signal. By combining the wavelength-shifted optical sideband and phase-modulated optical carrier, both binary and quaternary phase-coded microwave signals can be generated. Such signals with the carrier frequency of 10 GHz and 15 GHz are demonstrated. The pulse compression performance is also investigated. PMID- 30469858 TI - Photonics-enabled balanced Hartley architecture for broadband image-reject microwave mixing. AB - Conventional image-reject mixing based on Hartley and Weaver architectures cannot deal with the mixing spurs generated by the nonlinearity of the mixer, leading to a fundamental restriction on the instantaneous bandwidth and frequency tuning range. This paper proposes and demonstrates a new architecture for broadband image-reject mixing enabled uniquely by photonics. The RF signal and the electrical LO signal are converted into the optical domain and are then launched into the signal and LO ports of a 90-degree optical hybrid, respectively. The optical hybrid coupler introduces 0, pi, pi/2 and 3pi/2 phase shifts to the input signals, so a new dimension for additional balanced detection is enabled, which can dramatically remove the undesirable mixing spurs and the common-mode noises. As a result, the proposed architecture suppresses the downconverted image and the nonlinear mixing spurs simultaneously, enabling a truly wideband microwave frequency mixer. A theoretical and experimental investigation is performed. More than 60-dB image rejection and mixing spur suppression is achieved over a 40-GHz working frequency range. PMID- 30469859 TI - Brillouin characterization of slimmed polymer optical fibers for strain sensing with extremely wide dynamic range. AB - To date, most distributed Brillouin sensors for structural health monitoring have employed glass optical fibers as sensing fibers, but they are inherently fragile and cannot withstand strains of >3%. This means that the maximal detectable strain of glass-fiber-based Brillouin sensors was ~3%, which is far from being sufficient for monitoring the possible distortion caused by big earthquakes. To extend this strain dynamic range, polymer optical fibers (POFs) have been used as sensing fibers. As POFs can generally withstand even ~100% strain, at first, Brillouin scattering in POFs was expected to be useful in measuring such large strain. However, the maximal detectable strain using Brillouin scattering in POFs was found to be merely ~5%, because of a Brillouin-frequency-shift hopping phenomenon accompanied by a slimming effect peculiar to polymer materials. This conventional record of the strain dynamic range (5%) was still far from being sufficient. Here, we have thought of an idea that the strain dynamic range can be further extended by employing a POF with its whole length slimmed in advance and by avoiding the Brillouin-frequency-shift hopping. The experimental results reveal that, by applying 3.0% strain to a slimmed POF beforehand, we can achieve a >25% strain dynamic range, which is >5 times the conventional value and will greatly extend the application fields of fiber-optic Brillouin sensing. PMID- 30469860 TI - Graphene aperture-based metalens for dynamic focusing of terahertz waves. AB - We theoretically study a tunable reflective focusing lens, based on graphene metasurface, which consists of rectangle aperture array. Dynamic control of either the focal intensity or focal length for terahertz circular polarized waves can be achieved by uniformly tuning the graphene Fermi energy. We demonstrate the graphene apertures with the same geometry; however, spatially varying orientations can only control the focal intensity. To change the focal length, the spatially varying aperture lengths are also required. A comparative study between the metalenses, which generate only geometric or both gradient and geometric phase changes, has shown that the apertures' spatially varying length distribution is the key factor for determining the modulation level, rather than the focal length's modulation range. This kind of metalens provides tunable, high efficiency, broadband, and wide-angle off-axis focusing, thereby offering great application potential in lightweight and integrated terahertz devices. PMID- 30469861 TI - Giant impact of self-photothermal on light-induced ultrafast insulator-to-metal transition in VO2 nanofilms at terahertz frequency. AB - Ultrafast detection and switching of light are key processes in high-speed optoelectronic devices. However, the performances of VO2-based optoelectronics are strongly degraded by photothermal. The mechanism of the latter is still unclear. Here, by using femtosecond-laser (fs-laser) driven kinetic terahertz wave absorption, we quantitatively separate slow photothermal response and ultrafast photodoping response (e.g. light-induced insulator-to-metal transition) from second- to picosecond-timescales, and discover the competing interplay between them. With self-photothermal (mainly determined by fs-laser pulse repetition rate and pump fluence), the ultrafast transition time was degraded by 190% from 50 ps to 95 ps, the ultrafast transition threshold was decreased to 82% from 11mJ/cm2 to 9mJ/cm2, while the amplitudes of the two photoresponse are competing. Percolation theory, along with the macroscopic conductivity response, is used to explain the competing interplay. Our findings are relevant for designing and optimizing VO2-based ultrafast optoelectronic devices. PMID- 30469862 TI - Testing the transmitted wavefront of large aperture and long-focal-length lens with computer-generated hologram. AB - A method for testing the transmitted wavefront of large aperture and long-focal length lens with a multizone computer-generated hologram (CGH) is proposed. The multizone CGH has 5 zones: one main zone for the null testing of long-focal length lens and four auxiliary zones for the pre-alignment of measured lens. Both 1st order wavefront and 0th order wavefront of CGH are measured, and 0th order wavefront is used to calibrate the substrate error. To verify this test approach, a 450mm * 450mm multizone CGH is designed and fabricated for testing the spatial filter lens. Experiments and error analysis are carried out. The results show that the desired precision can be reached with use of CGH. PMID- 30469863 TI - In-fiber Mach-Zehnder interferometer with piecewise interference spectrum based on hole-assisted dual-core fiber for refractive index sensing: erratum. AB - This erratum is presented to correct Fig. 3 in [Opt. Express26(15), 19091 (2018)]. PMID- 30469864 TI - Approach for recognizing and tracking beacon in inter-satellite optical communication based on optical flow method. AB - In inter-satellite laser communication systems, accurate positioning of the beacon is essential for establishing a steady laser communication link. For inter satellite optical communication, the main factor affecting the acquisition and tracking of the beacon is the background noise, such as stellar background light. In this study, we considered the effect of the background noise on a beacon in inter-satellite optical communication and proposed a new recognition algorithm for the beacon, which uses the optical flow vector obtained from the image data. We verified the feasibility of this method by performing simulation analysis and experiments. Both simulation and experiments showed that the new algorithm could accurately obtain the position of the centroid of the beacon under the effect of the background light. Furthermore, considering the identification probability of a light spot through the background light, the locating accuracy of the new algorithm was higher than that of the conventional gray centroid algorithm. Therefore, this new approach would be beneficial for the design of satellite-to ground optical communication systems. PMID- 30469865 TI - Photonic temporal-mode multiplexing by quantum frequency conversion in a dichroic finesse cavity. AB - Photonic temporal modes (TMs) form a field-orthogonal basis set representing a continuous-variable degree of freedom that is in principle infinite dimensional, and create a promising resource for quantum information science and technology. The ideal quantum pulse gate (QPG) is a device that multiplexes and demultiplexes temporally orthogonal optical pulses that have the same carrier frequency, spatial mode, and polarization. The QPG is the chief enabling technology for usage of orthogonal temporal modes as a basis for high-dimensional quantum information storage and processing. The greatest hurdle for QPG implementation using nonlinear-optical, parametric processes with time-varying pump or control fields is the limitation on achievable temporal mode selectivity, defined as perfect TM discrimination combined with unity efficiency. We propose the use of pulsed nonlinear frequency conversion in an optical cavity having greatly different finesses for different frequencies to implement a nearly perfectly TM selective QPG in a low-loss integrated-optics platform. PMID- 30469866 TI - Diffuse scattering due to stochastic disturbances of 1D-gratings on the example of line edge roughness. AB - Diffuse scattering of optical one-dimensional gratings becomes increasingly critical as it constrains the performance, e.g., of grating spectrometers. In particular, stochastic disturbances of the ideal grating structure provoke straylight. In this paper, the straylight spectrum of stochastically disturbed gratings is examined. First, a 1D-method is presented that allows to calculate 2D diffuse scattering of arbitrarily polarized light originating from stochastic disturbances of the grating geometry on the basis of standard optical simulation tools. Within the scope of this method an enormous reduction of computational effort is achieved compared to the full 2D-simulation approach, i.e., the computation time can be reduced by several orders of magnitude. Hence, the method also allows to address even large period gratings that are not possible to calculate within a full 2D-approach. In analogy to scattering theories for surface roughness the method relies on typical characteristics of straylight originating from small disturbances, that the angle resolved scattering (ARS) can be separated into a product of the power spectral density describing the 2D stochastic process and additional factors depending on the undisturbed 1D grating structure. In a second part, an analytical model within Fourier optics utilizing thin element approximation (TEA) describing the wide angle scattering of lamellar gratings disturbed by line edge roughness (LER) for TE-polarized light is derived and verified by applying the 1D-simulation method. For shallow gratings, we find an excellent agreement between simulation and TEA over the whole transmission half space. In addition, this model allows a descriptive understanding of the underlying physical effects and, accordingly, the influence of relevant parameters (grating geometry, refractive indices, illumination) onto the scattering spectra is discussed. Further, it is shown that LER-scattering can be described within a modified Rayleigh-Rice-ARS usually found within the frame of surface roughness. PMID- 30469867 TI - Optically addressed modulator for tunable spatial polarization control. AB - We present an optically addressed non-pixelated spatial light modulator. The system is based on reversible photoalignment of a LC cell using a red light sensitive novel azobenzene photoalignment layer. It is an electrode-free device that manipulates the liquid crystal orientation and consequently the polarization via light without artifacts caused by electrodes. The capability to miniaturize the spatial light modulator allows the integration into a microscope objective. This includes a miniaturized 200 channel optical addressing system based on a VCSEL array and hybrid refractive-diffractive beam shapers. As an application example, the utilization as a microscope objective integrated analog phase contrast modulator is shown. PMID- 30469868 TI - High optical feedback tolerance of InAs/GaAs quantum dot lasers on germanium. AB - This work experimentally investigates the optical feedback sensitivity of InAs/GaAs quantum dot (Qdot) lasers epitaxially grown on Ge substrate. In comparison with a Qdot laser on GaAs substrate with identical epilayer and cavity structures, the Ge-based laser is found to exhibit lower sensitivity to the optical feedback, although it has a higher epitaxial defect density. Theoretical analysis proves that the high defect density strongly increases the damping factor while slightly reduces the linewidth broadening factor, which lead to high tolerance to the optical feedback. This work suggests the high potential of Qdot lasers on Ge for isolator-free operation in photonic integrated circuits. PMID- 30469869 TI - Efficient and tunable spectral compression using frequency-domain nonlinear optics. AB - A key requirement in the field of ultrafast vibrational spectroscopy is to efficiently generate intense tunable narrowband picosecond laser pulses synchronized to a broadband femtosecond laser source. Current nonlinear methods for picosecond pulse generation suffer from complexities in both experimental implementation and pulse frequency tunability. We present here a straightforward method for spectral bandwidth compression that produces frequency tunable picosecond pulses with efficient power conversion. Broadband femtosecond laser pulses are compressed to narrowband picosecond pulses using frequency domain sum frequency generation of spatially chirped pulses, achieving spectral bandwidths of <20 cm-1 and power conversion efficiency of ~18%. The experimental design of the bandwidth compressor is presented and its application to stimulated Raman spectroscopy is demonstrated. PMID- 30469870 TI - Direct laser writing of barriers with controllable permeability in porous glass. AB - Barriers were produced in porous glass through its local bulk density modification by direct femtosecond writing accompanied by SO2-laser surface thermal densification, to make functional microfluidic elements separated by such physical barriers with different controlled permeability. The separation of multi component solutions into individual components with different molecule sizes (molecular separation) was performed in this first integrated microfluidic device fabricated in porous glass. Its application in the environmental gas-phase analysis was demonstrated. PMID- 30469871 TI - One-step generation of hybrid micro-optics with high-frequency diffractive structures on infrared materials by ultra-precision side milling. AB - Hybrid micro-optics of infrared (IR) materials are of great advantage in realizing the function integration and minimization of advanced IR optical systems. However, due to the hard-and-brittle nature of IR materials, it is still challenging for both non-mechanical and mechanical technologies to achieve one step generation of hybrid infrared micro-optics with high form accuracy. In the present study, a flexible method, namely ultra-precision side milling (UPSM), is first introduced to achieve one-step generation of infrared hybrid micro-optics in ductile mode, and the corresponding reflective diffraction characteristics are analyzed. In UPSM, the reflective/refractive primary surface of the hybrid micro optics is formed via the removal of workpiece material, and the high-frequent secondary diffractive micro/nanostructures are simultaneously generated by the tool residual marks of cutting trajectories. With the consideration of the changing curvature of the primary surface, the optimal toolpath generation strategy is introduced to acquire the desired shapes of the secondary micro/nanostructures, and the selecting criteria of the machining parameters is discussed to avoid the brittle fractures of IR materials. In practice, two types of hybrid micro-optic components, namely hybrid micro-aspheric arrays and sinusoid grid surface with high-frequent secondary unidirectional phase gratings, are successfully fabricated on single-crystal silicon to validate the proposed method. The method adopted in this study is very promising for the deterministic fabrication of hybrid micro-optics on infrared materials. PMID- 30469872 TI - Orbital angular momentum vector modes (de)multiplexer based on multimode micro ring. AB - Orbital angular momentum (OAM) multiplexing has emerged as an important method to increase the communication capacities in future optical information technologies. In this work, we demonstrate a silicon integrated OAM (de)multiplexer with a very simple structure. By simply tapping the evanescent wave of two different whispering gallery modes rotating inside a multimodal micro-ring resonator, four in-plane waveguide modes are converted to four free-space vector OAM beams with high mode purity. We further demonstrate chip-to-chip OAM multiplexing transmission using a pair of silicon devices, which shows low-level mode crosstalk and favorable link performance. PMID- 30469873 TI - Optical tweezers as a mathematically driven spatio-temporal potential generator. AB - The ability to create and manipulate spatio-temporal potentials is essential in the diverse fields of science and technology. Here, we introduce an optical feedback trap system based on high precision position detection and ultrafast feedback control of a Brownian particle in the optical tweezers to generate spatio-temporal virtual potentials of the desired shape in a controlled manner. As an application, we study the nonequilibrium fluctuation dynamics of the particle in a time-varying virtual harmonic potential and validate the Crooks fluctuation theorem in the highly nonequilibrium condition. PMID- 30469874 TI - Delta-sigma-modulated IFoF transmission system assisted by a correlative-level encoding technique. AB - A delta-sigma-modulated intermediate-frequency-over-fiber (IFoF) transmission system assisted by a correlative-level coding technique is proposed and experimentally demonstrated. Unlike conventional delta-sigma IFoF systems with multiple output levels to achieve higher signal quality or larger capacity, a correlative-level encoder is exploited as a second modulator preceded by the delta-sigma modulator. The encoder compresses the bandwidth of the delta-sigma modulated signal by creating a correlation between adjacent signal symbols. As a result, the sampling frequency of the delta-sigma modulator in the proposed system can be increased beyond the transmission bandwidth of the IFoF system, considerably improving the in-band signal quality and the transmission capacity over the conventional multi-level approach. This is because the quantization noise from the delta-sigma modulation in the proposed scheme is more aggressively pushed away from the signal bandwidth with the high sampling frequency. According to experimental results, the proposed link provides at least a 40% larger transmission capacity for similar in-band signal quality or 2.1% better average EVM performance for the same capacity than the conventional four-level pulse amplitude-modulation delta-sigma IFoF systems. PMID- 30469875 TI - Interplay between optical pumping and Rydberg EIT in magnetic fields. AB - We perform Zeeman spectroscopy on a Rydberg electromagnetically induced transparency (EIT) system in a room-temperature Cs vapor cell, in magnetic fields up to 50 Gauss. The magnetic interactions of the |6S1/2 Fg = 4> ground, |6P3/2 Fe = 5> intermediate, and |33S1/2> Rydberg states that form the ladder-type EIT system are in the linear Zeeman, quadratic Zeeman, and the Paschen-Back regimes, respectively. We explain the dependence of Rydberg EIT spectra on the magnetic field and polarization. The asymmetry of the EIT spectra, which is caused by the quadratic Zeeman effect of the intermediate state, becomes paramount in magnetic fields >=40 Gauss. We investigate the interplay between Rydberg EIT, which reduces photon scattering, and optical pumping, which relies on photon scattering. We employ a quantum Monte Carlo wave-function approach to quantitatively model the spectra and their asymmetry behavior. Simulated spectra are in good agreement with the experimental data. PMID- 30469876 TI - Impact of fiber parameters on EDFA and/or Raman amplified high-spectral efficiency coherent WDM transmissions. AB - The impact of fiber properties is investigated for coherent systems employing polarization-division multiplexed high-level quadrature amplitude modulation, wavelength-division multiplexing, and erbium-doped fiber amplifier and/or distributed Raman amplification. This is done by comparing the performances of fiber links of various attenuation coefficients and effective areas via experimentally verified analytical methods. Results show that the excess noise, which originates at amplifiers compensating for the losses of filters and switches located between fiber spans, can weaken or even diminish the performance enhancement brought about by lowering the fiber attenuation coefficient, especially if distributed Raman amplification is employed. This leads to the difference in the link performance assessment between our analytical results and some previously published figures of merit (FOM). On the other hand, increasing the fiber effective area results in the same amount of performance improvement regardless of the amplification scheme or the excess noise, which agrees with the FOMs. Since the larger effective area causes poorer pumping efficiency for systems employing distributed Raman amplification, a tradeoff between high performance and low power consumption needs to be determined for such systems. PMID- 30469877 TI - Photothermal properties of plasmonic nanoshell-blended nanofluid for direct solar thermal absorption. AB - The excitation of localized surface plasmon at the metal nanoparticles can significantly enhance the absorption of solar energy. However, the absorption peak is sharp at the resonant frequency. To achieve a broadband absorption, the blended nanofluid formed by SiO2/Ag nanoshells of different core size and shell thickness is employed. The blended nanofluid has a good solar absorption property, whose extinction spectrum matches the solar spectrum well. The transient temperature response of the nanofluid is simulated. It is found that the photothermal performance of the solar thermal collector is related to the geometric parameters and operation conditions of the solar collector, and the optical and thermophysical properties of nanofluid. As the flow velocity increases, the outlet temperature is gradually reduced. But, the collector efficiency is increased since less heat is lost to the environment via convection as nanofluid flows fast in the channel. In order to obtain a large outlet temperature at high velocity, it can be considered to elongate the channel length. Due to the strong extinction properties of the blended nanofluid, the required volume fraction can be significantly reduced, only 1/10 of that of Ag nanofluid for an equal temperature increases. PMID- 30469878 TI - Polarimetric precision of micropolarizer grid-based camera in the presence of additive and Poisson shot noise. AB - Polarimetric cameras based on micropolarizer grids make it possible to design division of focal plane (DoFP) polarimeters. However, the polarimetric estimation precision reached by these devices depends on their realization quality, which is estimated by calibration. We derive the theoretical expressions of the estimation variance of such polarimetric parameters as an angle of linear polarization and degree of linear polarization as a function of the calibrated micropolarizer characteristics. These values can be compared with the variances that would be obtained with ideal micropolarizers in order to quantitatively assess the effect of manufacturing defects on polarimetric performance. These results are validated by experimental measurements on a real-world camera. PMID- 30469879 TI - High sensitivity active flat optics optical phased array receiver with a two dimensional aperture. AB - Optical phased arrays (OPAs) on integrated photonic platforms provide a low-cost chip-scale solution for many applications. Despite the numerous demonstrations of OPA transmitters, the realization of a functional OPA receiver presents a challenge due to the low received signal level in the presence of noise and interference that necessitates high sensitivity of the receiver. In this paper, an integrated receiver system is presented that is capable of on-chip adaptive manipulation and processing of the captured waveform. The receiver includes an optoelectronic mixer that down-converts optical signals to radio frequencies while maintaining their phase and amplitude information. The optoelectronic mixer also provides conversion gain that enhances the system sensitivity and its robustness to noise and interference. Using this system, the first OPA receiver with a two-dimensional aperture of 8-by-8 receiving elements is demonstrated which can selectively receive light from 64 different angles. The OPA receiver can form reception beams with a beamwidth of 0.75 degrees over an 8 degrees grating-lobe-free field of view. PMID- 30469880 TI - Integrated optical frequency domain reflectometry device for characterization of complex integrated devices. AB - Because of the demand for advanced measurement systems in the field of modern photonic integrated circuits, optical frequency domain reflectometry (OFDR) is a robust technique for characterizing design-to-fabrication deviations. In this paper we report an OFDR device where the interferometric part is monolithically integrated along with the device under test. We discuss the advantages in terms of compactness and performance, and the importance of the incorporated dispersion de-embedding mechanism. Experimental validation is carried out by interrogating an arrayed waveguide grating on a silicon nitride platform. The results establish the proposed device as a first step in the quest for a universal test structure for integrated devices. PMID- 30469881 TI - Patterned illumination single molecule localization microscopy (piSMLM): user defined blinking regions of interest. AB - Single molecule localization microscopy (SMLM) has been established as an important super-resolution technique for studying subcellular structures with a resolution down to a lateral scale of 10 nm. Usually samples are illuminated with a Gaussian shaped beam and consequently insufficient irradiance on the periphery of the illuminated region leads to artifacts in the reconstructed image which degrades image quality. We present a newly developed patterned illumination SMLM (piSMLM) to overcome the problem of uneven illumination by computer-generated holography. By utilizing a phase-only spatial light modulator (SLM) in combination with a modified Gerchberg-Saxton algorithm, a user-defined pattern with homogeneous and nearly speckle-free illumination is obtained. Our experimental results show that irradiance 1 to 5 kW/cm2 was achieved by using a laser with an output power of 200 mW in a region of 2000 um2 to 500 um2, respectively. Higher irradiance of up to 20 kW/cm2 can be reached by simply reducing the size of the region of interest (ROI). To demonstrate the application of the piSMLM, nuclear structures were imaged based on fluctuation binding activated localization microscopy (fBALM). The super-resolution fBALM images revealed nuclear structures at a nanometer scale. PMID- 30469882 TI - Tunable single-mode lasing in a single semiconductor microrod. AB - Developing micro/nanoscale wire lasers with single-mode operation and lasing wavelength modulation is essential for realizing their practical applications such as optical communication and saturated spectroscopy. We demonstrated, to the best of our knowledge, the first tunable single-mode microrod laser without complicated micro/nano-manipulation and without additional environmental requirement. In this letter, we realized the wavelength modulation in a single semiconductor microrod simply and directly by changing the axial location of the active region, owing that the active region position plays a key role in determining the lasing mode of microrod lasers. Based on this feature, we proposed a pair of asymmetrical distributed Bragg reflectors (DBRs) with specific spectral selectivity to be induced in a GaN microrod to realize tunable single mode lasing in a single semiconductor microrod. By using this method, lasing wavelength can be modulated from 369.5 to 375.7 nm flexibly and repeatedly in a 45 MUm GaN microrod with the change of the excitation source position. This approach demonstrates a big application potential in numerous fields consisting of optical telecommunication and environmental monitoring. PMID- 30469883 TI - Electron acceleration driven by sub-cycle and single-cycle focused optical pulse with radially polarized electromagnetic field. AB - The space-time properties of the expressions of sub-cycle and single-cycle focused optical pulses with radially polarized electromagnetic field based on the Sink-Source model are studied. The self-induced blue shift of the center frequency of spectrum in the center of the pulse field is found to have an important impact on the electrons acceleration. When the electrons approach to the center of pulse, the electrons will obtain a large kinetic energy gain in a short time. The effect of radiation-reaction force can't be ignored if the net kinetic energy gain of electrons is more than GeVs. The electrons will deviate from the original acceleration channel and the gain of kinetic energy that electrons may gain will be greatly reduced if the radiation-reaction effect is considered. In contrast to the few-cycle laser pulse accelerating electrons, the gain of kinetic energy obtained by electrons is a few times higher and the corresponding peak optical power is one order of magnitude lower in the case of the sub-cycle laser pulses accelerating electrons. The maximal kinetic energy gain of electrons is robust against the variation of the incident angles. PMID- 30469884 TI - Photonic lantern broadband orbital angular momentum mode multiplexer. AB - Optical vortex beams that carry orbital angular momentum (OAM), also known as OAM modes, have attracted considerable interest in recent years as they can comprise an additional degree of freedom for a variety of advanced classical and quantum optical applications. While canonical methods of OAM mode generation are effective, a method that can simultaneously generate and multiplex OAM modes with low loss and over broad spectral range is still in great demand. Here, via novel design of an optical fiber device referred to as a photonic lantern, where the radial mode index ("m") is neglected, for the first time we demonstrate the simultaneous generation and multiplexing of OAM modes with low loss and over the broadest spectral range to date (550 nm). We further confirm the potential of this approach to preserve the quality of studied OAM modes by fusion splicing the end-facet of the fabricated device to a delivery ring-core fiber (RCF). PMID- 30469885 TI - Pyrochlore lattice, self-assembly and photonic band gap optimizations. AB - Non-spherical colloidal building blocks introduce new design principles for self assembly, making it possible to realize optical structures that could not be assembled previously. With this added complexity, the phase space expands enormously so that computer simulation becomes a valuable tool to design and assemble structures with useful optical properties. We recently demonstrated that tetrahedral clusters and spheres, interacting through a DNA-mediated short-range attractive interaction, self-assemble into a superlattice of interpenetrating diamond and pyrochlore sublattices, but only if the clusters consist of partially overlapping spheres. Here we show how the domain of crystallization can be extended by implementing a longer range potential and consider how the resultant structures affect the photonic band gaps of the underlying pyrochlore sublattice. We show that with the proper design, using clusters of overlapping spheres lead to larger photonic band gaps that open up at lower optical contrast. PMID- 30469886 TI - Propagation of partially coherent four-petal elliptic Gaussian vortex beams in atmospheric turbulence. AB - The beam spreading and evolution behavior of the intensity profile and coherent vortices of partially coherent, four-petal elliptic Gaussian vortex beams propagating in atmospheric turbulence are studied. The analytical expressions for cross-spectral density function, as well as root mean square (rms) beam width, are derived based on the extended Huygens-Fresnel principle. Results showed that, unlike the partially coherent four-petal Gaussian vortex beams, the partially coherent four-petal elliptic Gaussian vortex beam could change its petal number into six. The dependencies of occurrence, appearance, and transition speed from four- to six-petal profile on the topological charge, the beam order, and the ellipticity factor are illustrated. The far field behaviors of partially coherent four-petal elliptic Gaussian vortex beams propagating in atmospheric turbulence and are compared in free space. Beams with larger topological charge, smaller beam order, and larger ellipticity factor were found to be less influenced by atmospheric turbulence. Further, the ellipticity factor can be used as an additional degree of freedom in controlling the conservation distance of coherence vortices' topological charge. PMID- 30469887 TI - Polarization-insensitive silicon nitride Mach-Zehnder lattice wavelength demultiplexers for CWDM in the O-band. AB - Polarization-insensitive silicon nitride (SiN) 4-channel wavelength (de)multiplexers based on Mach-Zehnder interferometer lattice filters for coarse wavelength division multiplexing (CWDM) in the O-band are demonstrated in a SiN on-silicon photonic platform. For the best-performing device, the insertion loss was < 2.8 dB, the inter-channel crosstalk was < -11.5 dB for a polarization scrambled input, and the passband shift between the orthogonal polarizations was < 1.5 nm. Across the 200mm wafer, the die-averaged insertion loss and maximum crosstalk were 3.1 dB and -10.6 dB, respectively. The higher-than-expected crosstalk was due to dimensional variations. This work shows the potential of SiN photonic circuits for CWDM without polarization diversity. PMID- 30469888 TI - Broadband negative-refractive index terahertz metamaterial with optically tunable equivalent-energy level. AB - An optically tunable terahertz negative-refractive index metamaterial (NIM) is proposed. The NIMs are composed of two aluminum rings and two photosensitive ring shaped silicon apertures coaxially coated on the both sides of Teflon substrate. The NIMS are also designed to realize wide incident angle, polarization insensitivity, and tunability. Similar to the real atom, the unit cell of NIMs is equivalent to the Teflon nucleus surrounded by top and bottom resonator electrons, which indicates that the equivalent-energy level of NIMs can be dynamically controlled by the resonator electrons, once the scale of substrate nucleus is fixed. Using the LC-circuit model, the dynamic control of the equivalent-energy level of NIMs is studied in detail. Simulation results indicate that the transmission of NIMs is tuned from lowpass to highpass when the conductivity of silicon is increased, and the corresponding phase at lower frequency can be continually tuned. Correspondingly, the negative refractive index of NIMs represents dynamically tunable property, and the tunable negative refraction is simulated by classical wedge prism model. Besides, the phase flow indicates that the direction of phase velocity of NIMs is negative for the single negative index. PMID- 30469889 TI - Electro-optic deflection in a lithium niobate quasi-single mode waveguide with microstructured electrodes. AB - We propose an electro-optic mode deflection device based on an annealed proton exchange (APE) waveguide in lithium niobate, associated with isosceles-triangle shaped array electrodes and a horn-shaped input waveguide. The input waveguide is tapered down to ensure that the output of the device has a good beam quality, i.e., a quasi-single mode in this case. This new device allows beam deflection at a relative low voltage and large deflection angle. At an APE-waveguide width of 80 MUm, mode deflections of 0.265 and 0.240 MUm/V are obtained for 1064 and 980 nm, respectively. This beam deflection device can be applied in high-speed optical switch, and beam smoothing of a high-power laser, etc. PMID- 30469890 TI - High-sensitivity gas pressure sensor based on hollow-core photonic bandgap fiber Mach-Zehnder interferometer. AB - We propose and experimentally demonstrate a highly sensitive gas pressure sensor based on a near-balanced Mach-Zehnder interferometer (MZI) and constructed by hollow-core photonic bandgap fiber (HC-PBF) in this paper. The MZI is simply constructed by fusion splicing two HC-PBFs, which are of slightly different lengths, between two 3-dB couplers. The two output ends of each coupler are approximately equal in length, to ensure that the optical path variations of the MZI only result from the differences in the lengths between the two HC-PBFs. To apply the MZI for gas pressure sensing, a femtosecond laser is employed to drill a micro-channel in one of the two HC-PBF arms. The experiment result shows that the proposed MZI based gas pressure sensor achieves an ultrahigh sensitivity, up to 2.39 nm/kPa, which is two orders of magnitude higher than that of the previously reported MZI-based gas pressure sensors. Additionally, the effects resulting from the absolute length and relative length of the two HC-PBFs on gas pressure sensing performance are also investigated experimentally and theoretically, respectively. The ultra-high sensitivity and ease of fabrication make this device suitable for gas pressure sensing in the field of industrial and environmental safety monitoring. PMID- 30469891 TI - Definition of a measurement scale of graininess from reflectance and visual measurements. AB - Effect pigments in coatings produce eye-catching colour and texture effects and are widely used in automotive, cosmetics, coatings, inks, flooring, textile or decoration. One of these texture effects is graininess, which is the perceived texture exhibited when the effect coating is observed under diffuse illumination. To date there is not a standard procedure to measure graininess from reflectance measurements. The objective of this work is to propose a methodology for traceable graininess measurements, similarly as it was proposed for colour in 1931. In this article, the relevant reflectance-based quantities are clearly defined, and a formal relation with data from visual experiments is given. This methodology would allow a measurement scale of graininess and a difference formula to be agreed once conclusive visual data become available. PMID- 30469892 TI - Enhancement of phase retrieval capability in ptychography by using strongly scattering property of the probe-generating device. AB - In common ptychographic coherent diffractive imaging (PCDI) systems, the probe generating devices typically exhibit strong scattering, which is not fully used. Here, we report the reasonableness of using the diffraction pattern of the probe generating device as the frequency-domain information of the scanning probe located in the sample plane, and we propose a method introducing this frequency domain information into an iterative process to improve the imaging quality of PCDI. The new method was demonstrated using both a visible laser source and a synchrotron radiation X-ray source; the proposed method significantly improved the imaging quality in both demonstrations. PMID- 30469893 TI - Wavelength-time coding for multispectral 3D imaging using single-photon LiDAR. AB - Single-photon multispectral light detection and ranging (LiDAR) approaches have emerged as a route to color reconstruction and enhanced target identification in photon-starved imaging scenarios. In this paper, we present a three-dimensional imaging system based on a time-of-flight approach which is capable of simultaneous multispectral measurements using only one single-photon detector. Unlike other techniques, this approach does not require a wavelength router in the receiver channel. By observing multiple wavelengths at each spatial location, or per pixel (four discrete visible wavelengths are used in this work), we can obtain a single waveform with wavelength-to-time mapped peaks. The time-mapped peaks are created by the known chromatic group delay dispersion in the laser source's optical fiber, resulting in temporal separations between these peaks being in the region of 200 to 1000 ps, in this case. A multispectral single waveform algorithm was proposed to fit these multiple peaked LiDAR waveforms, and then reconstruct the color (spectral response) and depth profiles for the entire image. To the best of our knowledge, this is the first dedicated computational method operating in the photon-starved regime capable of discriminating multiple peaks associated with different wavelengths in a single pixel waveform and reconstructing spectral responses and depth. PMID- 30469894 TI - Machine learning guided rapid focusing with sensor-less aberration corrections. AB - Non-invasive, real-time imaging and deep focus into tissue are in high demand in biomedical research. However, the aberration that is introduced by the refractive index inhomogeneity of biological tissue hinders the way forward. A rapid focusing with sensor-less aberration corrections, based on machine learning, is demonstrated in this paper. The proposed method applies the Convolutional Neural Network (CNN), which can rapidly calculate the low-order aberrations from the point spread function images with Zernike modes after training. The results show that approximately 90 percent correction accuracy can be achieved. The average mean square error of each Zernike coefficient in 200 repetitions is 0.06. Furthermore, the aberration induced by 1-mm-thick phantom samples and 300-um thick mouse brain slices can be efficiently compensated through loading a compensation phase on an adaptive element placed at the back-pupil plane. The phase reconstruction requires less than 0.2 s. Therefore, this method offers great potential for in vivo real-time imaging in biological science. PMID- 30469895 TI - True versus effective Kerr nonlinear response in optical filamentation. AB - The optical Kerr effect, and the nonlinear polarization in general, represents an important light-matter interaction governing many regimes encountered in the nonlinear optics. We reason that in the context of optical filamentation one should distinguish the third-order Kerr effect occurring at relatively low light intensities from the effective Kerr nonlinearity relevant to higher intensity. While many properties of filaments can be captured well with a third-order nonlinear polarization model with a nonlinear index chosen somewhat higher than the true nonlinear index operative at low intensities, our comparative simulations indicate that some filamentation aspects carry significant signatures from the higher-order nonlinearity. PMID- 30469896 TI - Heterodyne confocal microscopy using symmetrical shifted-focus phase filters. AB - We propose a heterodyne confocal microscopy technique that uses the symmetry properties of conjugate phase-pupil filters to shift the axial intensity-response curves of two confocal systems symmetrically with respect to the geometric focal plane. A monotonic position-measuring curve is obtained by subtracting the output signals of the two confocal systems collected synchronously, while eliminating the influence of environmental noise. The system's three-dimensional tomographic ability can be improved by optimizing the pupil filter. Theoretical analyses and experiments indicate that the proposed method improves the axial and transverse resolutions of differential confocal microscopy and simplifies system installation and integration. PMID- 30469897 TI - 11.4 W long-wave infrared source based on ZnGeP2 optical parametric amplifier. AB - In this paper we present a high power long-wave infrared ZnGeP2 (ZGP) optical parametric amplifier (OPA) pumped by a 2097-nm Q-switched Ho:YAG laser with pulse repetition frequency of 20 kHz. When the incident Ho pump power was 116.0 W, the maximum average output power of 11.4 W at 8.3 MUm was achieved in the ZGP OPA. The optical conversion efficiency from Ho to long-wave infrared was about 9.8%. The ZGP OPA produced 30.4 ns long-wave infrared laser pulse. The beam quality factor (M2) of ZGP OPA was measured to be about 2.9 at the maximum average output power. PMID- 30469898 TI - Sideways adiabaticity: beyond ray optics for slowly varying metasurfaces. AB - Optical metasurfaces (subwavelength-patterned surfaces typically described by variable effective surface impedances) are typically modeled by an approximation akin to ray optics: the reflection or transmission of an incident wave at each point of the surface is computed as if the surface were "locally uniform," and then the total field is obtained by summing all of these local scattered fields via a Huygens principle. (Similar approximations are found in scalar diffraction theory and in ray optics for curved surfaces.) In this paper, we develop a precise theory of such approximations for variable-impedance surfaces. Not only do we obtain a type of adiabatic theorem showing that the "zeroth-order" locally uniform approximation converges in the limit as the surface varies more and more slowly, including a way to quantify the rate of convergence, but we also obtain an infinite series of higher-order corrections. These corrections, which can be computed to any desired order by performing integral operations on the surface fields, allow rapidly varying surfaces to be modeled with arbitrary accuracy, and also allow one to validate designs based on the zeroth-order approximation (which is often surprisingly accurate) without resorting to expensive brute-force Maxwell solvers. We show that our formulation works arbitrarily close to the surface, and can even compute coupling to guided modes, whereas in the far-field limit our zeroth-order result simplifies to an expression similar to what has been used by other authors. PMID- 30469899 TI - Spatial resolution improvement for an optical transition radiation monitor by asymmetric light collection. AB - The applicability of optical transition radiation (OTR) for measurements of micron sized transverse electron beam profiles is limited not only by the optical system resolution which has a fundamental limit imposed by the uncertainty principle. In the case of OTR generation, a single electron crossing the boundary between vacuum and screen cannot be considered as a single emitting point with isotropic angular distribution. On the contrary, the radiation is emitted from an area with a transverse range that is defined by the radial extension of the electron's Lorentz contracted Coulomb field and is typically estimated as gammalambda (with gamma the Lorentz factor and lambda the wavelength of observation). The OTR angular distribution has a characteristic "funnel" shape. As a result the one-dimensional image of a single electron measured with an ideal thin lens has a double lobe shape, and the resolution of any OTR based imaging system is determined by this double lobe function which is also known as OTR Point Spread Function (PSF). As a consequence, the reconstruction of micron sized electron beam profiles is hampered not only due to the fundamental diffraction limit, but also due to the PSF lobe shape. In this paper we present two approaches to improve the spatial resolution of an OTR monitor based on asymmetric light collection using a traditional optical system which allows blocking of one of the lobes. With such a scheme, an OTR PSF can be achieved that is comparable to the one of an ideal point source (Airy distribution). PMID- 30469900 TI - Excitation of higher-order modes in optofluidic photonic crystal fiber. AB - Higher-order modes up to LP33 are controllably excited in water-filled kagome- and bandgap-style hollow-core photonic crystal fibers (HC-PCF). A spatial light modulator is used to create amplitude and phase distributions that closely match those of the fiber modes, resulting in typical launch efficiencies of 10-20% into the liquid-filled core. Modes, excited across the visible wavelength range, closely resemble those observed in air-filled kagome HC-PCF and match numerical simulations. Mode indices are obtained by launching plane-waves at specific angles onto the fiber input-face and comparing the resulting intensity pattern to that of a particular mode. These results provide a framework for spatially resolved sensing in HC-PCF microreactors and fiber-based optical manipulation. PMID- 30469901 TI - Coupling between multimode fibers and slab waveguides. AB - In guided-wave optics, using gratings to couple between single mode waveguides and single mode fibers and vice versa is well-established. In contrast, the coupling between multimode waveguides is more complex and a much less understood topic, even though multimode coupling is essential for the excitation of guided modes from spatially incoherent sources or for the extraction of spatially incoherent radiation from a guided-wave platform. Here, we present the design for a grating that couples multiple modes of a 2D slab waveguide into a multimode fiber and vice versa and discuss the corresponding challenges. We highlight the importance of matching mode numbers and scattering angles and show that the coupling efficiency can readily drop to low values. We present a rudimentary design that illustrates the key issues by demonstrating the coupling from a multimode fiber into a waveguide slab and back into another fiber, which achieves a total efficiency of -34 dB. By modeling the same geometry, we achieve good agreement, which allows us to explain the physics of the coupler and to suggest improvements. Future options are discussed to improve the coupling elements with a better directivity in order to achieve a maximal coupling efficiency. Our findings can be exploited for improving the multimode light injection into and out of integrated guided-wave optical systems. PMID- 30469902 TI - Array of plasmonic Vivaldi antennas coupled to silicon waveguides for wireless networks through on-chip optical technology - WiNOT. AB - Optical technology applied to on-chip wireless communication is particularly promising to overcome the performance limitations of the state-of-the-art networks on-chip. A key enabling component for such applications is the plasmonic antenna coupled to conventional silicon waveguides, which can guarantee full compatibility with standard optical circuitry. In this paper, we propose an antenna array configuration based on tilted plasmonic Vivaldi antennas coupled to a silicon waveguide. The details of the single antenna and of the array design are reported. The radiation characteristics of the array are suitable for on-chip point-to-point communication, i.e. in-plane maximum gain of 14.70 dB for an array with five antennas. The array exploits a travelling wave feeding scheme and, therefore, is compact in size (about 3.5 um * 8.7 um ). PMID- 30469903 TI - Relationship between the effective attenuation coefficient of spaceborne lidar signal and the IOPs of seawater. AB - Multiple scattering is an inevitable effect in spaceborne oceanic lidar because of the large footprint size and the high optical density of seawater. The effective attenuation coefficient klidar in the oceanic lidar equation, which indicates the influence of the multiple scattering effect on the formation of lidar returns, is an important parameter in the retrieval of inherent optical properties (IOPs) of seawater. In this paper, the relationships between klidar of the spaceborne lidar signal and the IOPs of seawater are investigated by solving the radiative transfer equation with an improved semianalytic Monte Carlo model. Apart from the geometric loss factors, klidar is found to decrease exponentially with the increase of depth in homogeneous waters. klidar is given as an exponential function of depth and IOPs of seawater. The mean percentage errors between klidar calculated by the exponential function and the simulated ones in three typical stratified waters are within 0.5%, proving the effectiveness and applicability of this klidar-IOPs function. The results in this paper can help researchers have a better understanding of the multiple scattering effect of spaceborne lidar and improve the retrieval accuracy of the IOPs and the chlorophyll concentration of case 1 water from spaceborne lidar measurements. PMID- 30469904 TI - CMOS-compatible multi-band plasmonic TE-pass polarizer. AB - A CMOS-compatible plasmonic TE-pass polarizer capable of working in the O, E, S, C, L, and U bands is numerically analyzed. The device is based on an integrated hybrid plasmonic waveguide (HPW) with a segmented metal design. The segmented metal will avoid the propagation of the TM mode, confined in the slot of the HPW, while the TE fundamental mode will pass. The TE mode is not affected by the metal segmentation since it is confined in the core of the HPW. The concept of the segmented metal can be exploited in a plasmonic circuit with HPWs as the connecting waveguides between parts of the circuit and in a silicon photonics circuit with strip or slab waveguides connecting the different parts of the circuit. Using 3D FDTD simulations, it is shown that for a length of 5.5 MUm the polarization extinction ratios are better than 20 dB and the insertion losses are less than 1.7 dB over all the optical communication bands. PMID- 30469905 TI - Impact of SOA-induced pattern effect on the filter requirements in vestigial sideband direct detected PAM4 transmission. AB - In an optical filter based VSB-DD transmission system, semiconductor optical amplifier (SOA) is a promising option to enhance system optical power margin. While, in practical system, the low input saturation power makes the SOA amplified signal susceptible to the pattern effect, which causes a considerable spectral broadening, thereby influencing the design of VSB filter. In this paper, the relationship between SOA-induced pattern effect and the requirements of the VSB filter is systematically investigated. Firstly, qualitative analysis is given and upper sideband (USB) is proved better than lower sideband (LSB) owing to the suppression of SOA-induced pattern effect. Then, 56Gbps IM/DD PAM4 transmission is experimentally conducted. With respective optimal filter configuration, performance of USB signal is superior to LSB signal in all cases. Results show that USB signal has 1dB sensitivity superiority to LSB signal for 56Gb/s PAM4 after 40km transmission. And in 80km case, only by using USB signal, can HD-FEC limit (3.8 * 10-3) be achieved. Also, we study requirements on other filter parameters, including redundant bandwidth and filter steepness. PMID- 30469906 TI - Collision induced magnetic resonance in Cesium atoms. AB - The radiofrequency-optical double magnetic resonance in cesium atoms filled in a vapor cell is investigated experimentally. One resonant signal involving spin exchange collisions is observed in the MZ type magnetic resonance spectrum. We solve Liouville equations describing the dynamics of the system and analyze the role of the spin-exchange collisions in the atomic population distributions under resonant conditions. The theoretical calculations agree very well with the experimental results. In contrast with the normal magnetic resonance, the collision induced magnetic resonance exhibits the interesting saturation effect: both the signal amplitude and the signal linewidth are nearly constant when the laser intensity is above a moderate threshold value, which can be useful for precision measurements of the geomagnetic field. PMID- 30469907 TI - Optical properties of molecular nanocrystals consisting of J-aggregates of anionic and cationic cyanine dyes. AB - We report results of experimental studies of the photoabsorption, photoluminescent and photoelectric properties of a new type of multilayer molecular nanocrystals, consisting of highly ordered J-aggregates of one anionic and two cationic J-aggregates of cyanine dyes. In contrast to conventional J aggregated dyes the multichromic nanocrystals synthesized in this work, are capable of efficient light absorption in three excitonic bands of the visible and near-IR spectral ranges. The spectral peak positions in the absorption bands can be controlled by appropriately selecting a set of dyes a molecular crystal is made of. Our investigations of the photoelectric properties of multichromic crystals have shown that each of them can potentially be used as a photosensitive layer of a photocell with photoconductivity in three peaks of excitonic absorption. The synthesized nanocrystals are attractive for the creation of thin film organic photodetectors with a large photosensitive area and varied photoabsorption spectra, excitonic waveguides and for some other applications in organic and hybrid photonics and optoelectronics. PMID- 30469908 TI - Single-laser, polarization-controlled optical sampling system. AB - Optical sampling systems traditionally require either one mode-locked laser with an external delay line or two mode-locked lasers with a controllable repetition rate difference. In this paper we present a novel polarization-multiplexed laser architecture combining the benefits of both approaches. The laser emits two mode locked pulse trains sharing only one gain section without any external delay line. The colliding pulses in the laser have orthogonal polarization as well as opposite propagation directions to reduce coupling effects. With this, the two pulse trains can be freely phase controlled to conduct pump-probe measurements. To further analyze the timing stability of the system, we conducted a two-photon absorption experiment, leading to a timing accuracy of 30 fs. Based on the novel laser architecture, we call this new approach single-laser polarization controlled optical sampling, or SLAPCOPS. PMID- 30469909 TI - Dual-polarized highly sensitive plasmonic sensor in the visible to near-IR spectrum. AB - We propose and numerically characterize the optical characteristics of a novel photonic crystal fiber (PCF) based surface plasmon resonance (SPR) sensor in the visible to near infrared (500-2000 nm) region for refractive index (RI) sensing. The finite element method (FEM) is used to design and study the influence of different geometric parameters on the sensing performance of the sensor. The chemically stable plasmonic material gold (Au) is used to produce excitation between the core and plasmonic mode. On a pure silica (SiO2) substrate, a rectangular structured core is used to facilitate the coupling strength between the core and the surface plasmon polariton (SPP) mode and thus improves the sensing performance. By tuning the geometric parameters, simulation results show a maximum wavelength sensitivity of 58000 nm/RIU (Refractive Index Unit) for the x polarization and 62000 nm/RIU for the y polarization for analyte refractive indices ranging from 1.33 to 1.43. Moreover, we characterize the amplitude sensitivity of the sensor that shows a maximum sensitivity of 1415 RIU-1 and 1293 RIU-1 for the x and y polarizations, respectively. To our knowledge, this is the highest sensitivity for an SPR in published literature, and facilitates future development of sensors for accurate and precise analyte measurement. The sensor also attains a maximum figure of merit (FOM) of 1140 and fine RI resolution of 1.6 * 10-6. Owing to strong coupling strength, high sensitivity, high FOM and improved sensing resolution, the proposed sensor is suited for real-time, inexpensive and accurate detection of biomedical and biological analytes, biomolecules, and organic chemicals. PMID- 30469910 TI - Design of an on-chip Fourier transform spectrometer using waveguide directional couplers and NEMS. AB - A novel concept of on-chip Fourier transform spectrometer is proposed. It consists of semiconductor waveguide directional couplers and NEMS actuators. The optical path difference can be tuned by controlling the NEMS actuators to couple or decouple the directional couplers. With 9 stages of directional couplers, we demonstrate numerically that the spectral resolution can reach up to 4 nm in 1.5 MUm to 1.8 MUm wavelength range. Further enhancement can be achieved by increasing the number of integrated NEMS driven directional couplers. This design meets the requirement of small size, weight and power and may be useful in future on-chip spectroscopic sensors. PMID- 30469911 TI - Few cycle pulse laser ablation study of single layer TiO2 thin films using time resolved surface microscopy. AB - The few cycle optical pulse induced strong field laser solid interaction is a rich area of fundamental and applied research that spans from the study of extreme non-linearities in solids and next generation ultra-broad band high damage threshold optics design and fabrication to peta-Hertz optoelectronics of the future. Our understanding of the extremely non-pertubative phenomena of few cycle pulse (FCP) laser damage and ablation of bulk solids and thin films is still limited. In this work, we present a systematic study of the dynamics of the FCP laser ablation process of single layer TiO2 thin films from 1 ps to 10 ns after a single 9 fs pulse with nominal wavelength of 760 nm interacts with the surface using time-resolved surface microscopy (TRSM) technique. It is observed that FCP ablation craters for certain films exhibit markedly different features when compared to those created by 50 - 150 fs pulses with similar fluences. TRSM measurements also reveal that FCP ablation dynamics strongly depend on the thickness-dependent E-field distribution inside the films (nominally lambda/2 vs lambda/4), in which the dynamics of free carrier generation due to strong field ionization may play an important role as well. A one-dimensional finite difference time-domain (FDTD) simulation that takes into account strong field ionization and free carrier absorption is used in conjunction with the TRSM measurements to estimate the excited free carrier density prior to ablation. We also propose a mechanism for the differences in ablation craters between the films based on the FDTD simulation results. PMID- 30469912 TI - Giant enhancement of the effective Raman susceptibility in metasurfaces made of silicon photonic crystal nanocavities. AB - We demonstrate that stimulated Raman amplification can be enhanced by more than four orders of magnitude in a silicon metasurface consisting of a periodic distribution of specially engineered photonic crystal (PhC) cavities in a silicon PhC slab waveguide. In particular, by designing the PhC cavities so as they possess two optical modes separated by the Raman frequency of silicon, one can achieve large optical field enhancement at both the pump and Stokes frequencies. As a consequence, the effective Raman susceptibility of the nonlinear metasurface, calculated using a novel homogenization technique, is significantly larger than the intrinsic Raman susceptibility of silicon. Implications to technological applications of our theoretical study are discussed, too. PMID- 30469913 TI - Simultaneously nearly zero forward and nearly zero backward scattering objects. AB - With theoretical analyses and numerical calculations, we show that a passive scatterer at the sub-wavelength scale can simultaneously exhibit both nearly zero forward scattering (NZFS) and nearly zero backward scattering (NZBS). It is related to the interference of dipolar quadrupole modes of different origin, leading to coexistence of Kerker's first and second conditions at the same time. For optical frequencies, we propose two different sets of composited materials in multi-layered nano-structures, i.e., CdTe/Si/TiO2 and TiO2/Au/Si, for the experimental realization. PMID- 30469914 TI - Hybrid Tamm-surface plasmon polaritons mode for detection of mercury adsorption on 1D photonic crystal/gold nanostructures by total internal reflection ellipsometry. AB - Spectroscopic ellipsometry was used for the generation and study of the hybrid TPP-SPP mode as a sensor probe for the real-time formation of amalgam structures on the surface of a plasmon active gold layer. The Au/Hg amalgam formation features and the mercury atoms' penetration into the gold layer were determined by means of the experimental TIRE data and a regression analysis of a multi-layer model containing the index-profile amalgam layer. The hybrid TPP-SPP mode behavior of the coupled excitations provided more information about the mercury atoms' penetration into the gold layer than the single TPP and SPP resonances did. The present study demonstrated the possibility of using the hybrid TPP-SPP mode to design advanced optical gas sensor technologies. PMID- 30469915 TI - Accuracy improvement of quantitative analysis in spatially resolved fiber-optic laser-induced breakdown spectroscopy. AB - Fiber-optic laser-induced breakdown spectroscopy (FO-LIBS) has been employed in many applications because of the flexibility of optical fiber cable. However, the inhomogeneous elemental distribution of plasmas can cause a self-absorption effect and, hence, significantly hinder the determination of FO-LIBS. Here, to solve this flaw, we took iron (Fe), magnesium (Mg), and zinc (Zn) elements in aluminum alloy as examples to investigate the self-absorption reduction and accuracy improvement using spatially resolved FO-LIBS. Spatially resolved FO-LIBS means the spectra were collected at different positions along the direction parallel to the surface of the sample rather than at the center of the plasma. With this method, the self-absorption effect could be improved by selecting different acquisition positions along the X-axis. The root mean square error of cross-validations (RMSECV) for Fe, Mg, and Zn were reduced from 0.388, 0.348, and 0.097 wt. % to 0.172, 0.224, and 0.024 wt. %, respectively. Generally, spatial resolution is an effective method of self-absorption reduction and accuracy improvement in FO-LIBS. PMID- 30469916 TI - Simultaneous acquisition of complex transmittance and birefringence with two counter-rotating, circularly polarized THz pulses. AB - Here we demonstrate simultaneous measurements of the complex transmittance and birefringence using left- and right-handed circularly polarized terahertz (THz) pulses. We change the polarization of the THz pulses periodically by modulating the polarization of the pump pulses directed onto a ZnTe (111) crystal, and we convert linear to circular polarization using a broadband THz quarter-wave retarder. By integrating the alternating-emission system with the polarization sensitive terahertz time-domain spectrometer, we are able to obtain the electric field vector of the transmitted terahertz pulses for both the left- and right handed circular polarizations. Utilizing this technique, we are able to measure simultaneously the frequency-dependent complex refractive indices (real and imaginary parts) and the orientations of the slow and fast axes of birefringent materials, a quartz disc and a barium borate crystal, in a single temporal sweep. PMID- 30469917 TI - Optimizing illumination for full field imaging at high brilliance hard X-ray synchrotron sources. AB - A new technique is presented to overcome beam size limitation in full field imaging at high brilliance synchrotron sources using specially designed refractive X-ray optics. These optics defocus the incoming beam in vertical direction and reshape the intensity distribution from a Gaussian to a more desirable top-hat-shaped profile at the same time. With these optics X-ray full field imaging of extended objects becomes possible without having to stack several scans or applying a cone beam geometry in order to image the entire specimen. For in situ experiments in general and for diffraction limited sources in particular this gain in field of view and the optimization of the intensity distribution is going to be very beneficial. PMID- 30469918 TI - Decay channels of gap plasmons in STM tunnel junctions. AB - We study the decay of gap plasmons localized between a scanning tunneling microscope tip and metal substrate, excited by inelastic tunneling electrons. The overall excited energy from the tunneling electrons is divided into two categories in the form of resistive dissipation and electromagnetic radiation, which together can further be separated into four diffierent channels, including SPP channel on the tip, SPP channel on the substrate, air mode channel and direct quenching channel. In this work, we study the enhancement factor, i.e. Purcell factor, of the STM tunnel junctions, which are mediated by the nearby metallic structures. We find that the gap plasmon mode is most likely to couple to the SPP channel on the tip, rather than the SPP channel on the substrate or the air mode. The direct quenching in the apex of tip also takes a considerable portion especially in high frequency region, the enhancement factor of direct quenching in the tip is much higher than the direct quenching in the substrate. We adopt four tips with diffierent apex radii, i.e., 1 nm, 5 nm, 10 nm, 20 nm. When the apex size is small, the frequency dependent enhancement factor from the SPPs contribution has a pronounced peak at 1.55 eV, however, as the radius increases, the peak of enhancement factor in the high frequency region appears, the 1.55 eV peak becomes less dominated. This phenomenon can be attributed to the change of tip shape, in the form of mode coupling. Our results also show a relationship between the direct quenching in the substrate and in the tip. With the larger radius of apex, the ratio of these two part of energy approaches 1, which indicate that the energy distribution of direct quenching is sensitive to the shape of the tip-substrate gap. PMID- 30469919 TI - Spreading a water droplet through filter paper on the metal substrate for surface enhanced laser-induced breakdown spectroscopy. AB - To improve the quantitative analysis accuracy of an aqueous solution using surface-enhanced laser-induced breakdown spectroscopy (SENLIBS), the filter paper was used as a transmission medium by placing it onto the surface of a metallic substrate to make the microdroplet spreading more uniform in a fixed region of the substrate surface. The trace elements (Cu, Pb, Cd, and Cr) in an aqueous solution were detected successfully using this method. The results showed that the sample preparation repeatability of SENLIBS was noticeably improved with the aid of filter paper. Moreover, the limit of detection (LoD) values was similar to those without filter paper. Furthermore, the R2 values were improved from 0.6192~0.9321 to 0.9481~0.9766, the RMSECV values were decreased from 0.53~1.95 MUg/mL to 0.33~1.06 MUg/mL, and the average relative error (ARE) values were decreased from 8.96~22.31% to 4.28~14.37% with the aid of filter paper. This demonstrated that the use of filter paper could improve the quantitative analysis accuracy of SENLIBS by increasing the sample preparation repeatability. PMID- 30469920 TI - Terahertz-wave generation devices using electro-optic polymer slab waveguides and cyclo-olefin polymer clads. AB - We fabricated terahertz (THz) wave generation devices using electro-optic (EO) polymer slab waveguides and cyclo-olefin polymer (COP) clads with very small absorption loss of the THz waves based on a novel device fabrication procedure involving bonding of the poled EO polymer layer to the COP substrates. We demonstrated THz wave generation from the EO polymer slab devices using a 1.55 um band femtosecond fiber laser and evaluated the THz wave generation properties of the devices. Our results will lead to the development of compact, highly efficient, and ultrabroadband THz devices using EO polymers. PMID- 30469921 TI - Tunable-frequency three-dimensional structured illumination microscopy with reduced data-acquisition. AB - The performance of a tunable three-dimensional (3D) structured illumination microscope (SIM) system and its ability to provide simultaneously super resolution (SR) and optical-sectioning (OS) capabilities are investigated. Numerical results show that the performance of our 3D-SIM system is comparable with the one provided by a three-wave interference SIM, while requiring 40% fewer images for the reconstruction and providing frequency tunability in a cost effective implementation. The performance of the system has been validated experimentally with images from test samples, which were also imaged with a commercial SIM based on incoherent-grid projection for comparison. Restored images from data acquired from an axially-thin fluorescent layer show a 1.6* improvement in OS capability compared to the commercial instrument while results from a fluorescent tilted USAF target show the OS and SR capabilities achieved by our system. PMID- 30469922 TI - Confocal microscopy with a radially polarized focused beam. AB - Rigorous vectorial focusing theory is used to study the imaging of small adjacent particles with a confocal laser scanning system. We consider radially polarized illumination with an optimized amplitude distribution and an annular lens to obtain a narrower distribution of the longitudinal component of the field in focus. A polarization convertor at the detector side is added to transform radial polarization to linear polarization in order to make the signal detectable with a single mode fiber. PMID- 30469923 TI - Optical refractometry using lensless holography and autofocusing. AB - Conventional optical refractometry methods are often limited by a narrow measurement range, complex hardware, or relatively high cost. Here, we present a novel refractometry method to measure the bulk refractive index (RI) of materials (including solids and liquids) using lensless holographic on-chip imaging and autofocusing, which is simple, cost-effective, and has a large RI measurement range. As a proof of concept, two compact prototypes were built to measure the RIs of solid materials and liquids, respectively, and they were tested by measuring the RIs of a ZnSe plate and a microscopy immersion oil. Experimental results show that our devices have an average accuracy of ~3 * 10-4 RI unit (RIU) with an estimated precision of ~3 * 10-3 RIU for solids; and an average accuracy of ~1 * 10-4 RIU with an estimated precision of ~3 * 10-4 RIU for liquids. We believe that this cost-effective and portable RI measurement platform holds promise to be used in laboratory and industrial settings. PMID- 30469924 TI - Robust in-fiber spatial interferometer using multicore fiber for vibration detection. AB - We report the demonstration of a novel in-fiber spatially integrated Michelson interferometer based on weakly coupled multicore fiber (MCF) for vibration sensing. The compact interferometer is constructed by using two separate cores of the MCF, where the fiber end is cleaved in order to generate strong Fresnel reflection, and independent light coupling between the cores of MCF and the single mode fibers (SMFs) is enabled by the fan-in coupler. Vibration gives rise to differential strain variation between cores which results in the modification of phase difference of the interferometer. A narrow linewidth laser is employed, in order to interrogate the phase change induced reflection power variation. Vibration event can be identified and the vibration frequency can be retrieved by processing the measured reflection power with fast Fourier transform (FFT). Broad vibration frequency response range up to 12 kHz (limited by the cut-off frequency of the voltage driver of the vibration source) has been achieved. Performance of the sensor has been shown to be independent of the selection of different core pairs, where the MCF is wound to a piezoelectric transducer (PZT). The proposed in-fiber integrated spatial interferometer does not require any special processing of the fiber (e.g., tapering, splicing, and so forth). The unique sensor structure provides some extraordinary merits, including ultra-compact size, high mechanical strength, high sensitivity and temperature insensitivity. PMID- 30469925 TI - Plasmo-thermomechanical radiation detector with on-chip optical readout. AB - Plasmonic structures have long proved their capabilities to concentrate and manipulate light in micro- and nano-scales that facilitate strong light-matter interactions. Besides electromagnetic properties, ultra-small plasmonic structures may lead to novel applications based on their mechanical properties. Here we report efficient coupling between optical absorption and mechanical deformation in nanoscales through plasmonically enhanced fishbone nanowires. Using tailorable absorbers, free-space radiation energy is converted into heat to thermally actuate the suspended nanowires whose deformation is sensed by the evanescent fields from a waveguide. The demonstration at 660 nm wavelength with above 30% absorption shows the potential of the device to detect nW/?Hz power in an uncooled environment. PMID- 30469926 TI - High-efficiency hybrid amorphous silicon grating couplers for sub-micron-sized lithium niobate waveguides. AB - We demonstrate hybrid amorphous silicon uniform grating couplers for efficient coupling between the standard single-mode fiber and sub-micron lithium niobate waveguides. The grating couplers exhibit coupling efficiency of -3.06 dB and 1-dB bandwidth of 55 nm. The amorphous silicon grating couplers can also provide a universal building block applicable to other photonic platforms such as silicon nitride waveguides, whose moderate refractive index values prevent high efficiency grating couplers to be fabricated in the native waveguide. PMID- 30469927 TI - Scaffolds in a shell-a new approach combining one-photon and two-photon polymerization. AB - We report on a laser system combining one-photon and two-photon polymerization for precise and fast fabrication of macroscopic three-dimensional structures featuring microscale and nanoscale characteristics. This single-stage process significantly reduces the production time as demonstrated by scaffolds in a shell application. Porous scaffolds with different pore sizes are surrounded by a ring so that cells can be seeded directly to the scaffolds kept in a shell and do not spread over the whole substrate expecting a saving of cell suspension, faster growth on the scaffolds, and a more controllable environment. Compared to a two photon polymerization process, the ring is fabricated about 500 times faster using one-photon polymerization. The presented hybrid process qualifies for further applications illustrated by a fluidic system. PMID- 30469928 TI - Femtosecond laser induced selective etching in fused silica: optimization of the inscription conditions with a high-repetition-rate laser source. AB - Femtosecond laser induced selective etching (FLISE) of dielectric materials is a promising technique for fabricating various microfluidic devices. Here we experimentally studied the dependence of the selective etching speed in fused silica glass on laser pulse energy, repetition rate, and inscription speed using a 1030 nm femtosecond laser. The evolution of micromorphology of the laser inscribed lines was revealed with optical microscopy, scanning electron microscopy, as well as anisotropic diffraction of the optical gratings formed by these inscribed lines. A single pulse energy threshold is required to initiate the FLISE. Further, a laser repetition rate window between an upper threshold and a lower threshold was observed, which were limited by the thermal-induced disruption of the nanogratings and by the disconnection of successive pulses modified spots respectively. The synergetic influences of the above factors were evaluated by the exposure laser energy density, which shows a common threshold for different inscription conditions and demonstrates itself to be an excellent criterion for choosing appropriate parameters in FLISE. The formation of continuous nanogratings is confirmed to be the major mechanism of FLISE in fused silica. Our observations not only help one to understand the micro mechanism in FLISE of fused silica, but also are of great use for fabricating large-scale microfluidic circuits. PMID- 30469929 TI - All-fiber high-order mode laser using a metal-clad transverse mode filter. AB - We propose and demonstrate an all-fiber laser with LP11 mode output. A transverse mode filter is designed and fabricated to suppress the fundamental mode and enable the fiber laser to oscillate in the second-order (LP11) transverse mode. The mechanism is to introduce relatively low ohmic loss for the TE01 mode and much higher ohmic losses for other modes through the loss of evanescent waves in the metal clad. The fiber laser operates at the center wavelength of 1053.9 nm with a narrow 3 dB linewidth of 0.019 nm. Four states of cylindrical vector mode with high modal purity are obtained through adjusting the intra-cavity polarization controller. This approach has great potentiality and scalability of realizing single high-order mode fiber laser, from which a wide range of applications could benefit. PMID- 30469930 TI - Femtosecond laser filament-assisted AgI-type pyrotechnic nucleant-induced water condensation in cloud chamber. AB - AgI-type pyrotechnics are widely used in the field of weather modification, as a kind of artificial ice nuclei. However, their precipitation yield remains an intensively studied area. In this paper, we present a study of AgI-type pyrotechnic nucleant-induced water condensation promoted by femtosecond laser filaments in a cloud chamber. It is found that when 50-ml sample was irradiated by the laser filaments, the particles condensed on the glass slide are more soluble and slightly larger (5-15 MUm). The irradiation of the laser filament on the nucleant rarely induces the generation of particles of sizes larger than 1 MUm; however, it increases the decay time of particles from 13 to 18 min by the creation of numerous small particles. The amount of snow on the cold bottom plate increases by 4.2-13.1% in 2 h, compared to that without the irradiation of the laser filament. These results are associated with the production of high concentration HNO3 by the laser filament. The concentration of HNO3 in the melt water increases by more than ten times when the sample was irradiated by the laser filaments. PMID- 30469931 TI - Tapping underwater wireless optical communication in pure water and natural Dead Sea ultra-high-salinity water by diffraction grating. AB - Although underwater wireless optical communication (UWOC) receives much interest lately, security issues associated with it get little attention. In this paper, we show how a message communicated using UWOC can be eavesdropped without a sender's or addressee's awareness, by employing a diffraction grating. We also analyze the propagation of multiple diffracted Gaussian beams in water, and show for the first time that UWOC is feasible even in natural ultra-salty water taken from the Dead-Sea. We evaluate how far from the addressee the message could be eavesdropped, and discuss different possibilities of tapping the channel - one from the air and one underwater. PMID- 30469932 TI - High-resolution distributed polarization crosstalk measurement for polarization maintaining fiber with considerable dispersion. AB - We present a high-resolution polarization crosstalk measurement method for polarization maintaining fiber (PMF) with considerable dispersion. The birefringence dispersion of the PMF severely degrades the spatial resolution of the distributed polarization crosstalk measurement. Conventional dispersion compensation methods are effective for modest birefringence dispersion coefficients (for instance, of 0.0014 ps/nm/km). We present an iterative matched filter (IMF) method to cope with the case of considerable birefringence dispersion. We measured the distributed polarization crosstalk of a PMF coil with a birefringence dispersion coefficient of 0.235 ps/nm/km. By applying the IMF method, we obtained a spatial resolution of 0.09 m at any position of the PMF (a maximum of 12.36 m without dispersion compensation). PMID- 30469933 TI - Distributed Brillouin optical fiber temperature and strain sensing at a high temperature up to 1000 degrees C by using an annealed gold-coated fiber. AB - In this study, the distributed temperature and strain sensing with an annealed single mode gold-coated optical fiber over a wide temperature range up to 1000 degrees C is demonstrated by using the differential pulse pair (DPP) Brillouin optical time domain analysis (BOTDA). Owing to the protection provided by the gold coating, the fiber can withstand high temperature environments and maintain a high strength, which enables the gold-coated fiber acting as a repeatable high temperature sensor. After annealing twice to remove the internal stress, the temperature coefficient of the gold-coated fiber is stable and consistent with a nonlinear function. Owing to the residual stress accumulated during the cooling process of coating and the low yield strength of gold, a pre-pulling test is essential to measure the strain of a gold-coated fiber. An equal axial force model is used to recalculate the strain distribution induced by the large temperature difference within the furnace. The high-temperature strain coefficient of an annealed gold-coated fiber decreases with temperature, i.e. from ~0.046 MHz/MUepsilon at 100 degrees C to ~0.022 MHz/MUepsilon at 1000 degrees C, mainly due to the increase in Young's modulus of silica with temperature. To the best of our knowledge, this is the first time that an annealed gold-coated fiber has been applied for distributed high-temperature strain sensing, which demonstrates the potential applications for strain monitoring in complex, high-temperature devices such as jet engines or turbines. PMID- 30469934 TI - Submillisecond-response polymer network liquid crystals for mid-infrared applications. AB - We formulated a high birefringence, large dielectric anisotropy, UV stable, and low absorption loss nematic liquid crystal mixture, named UCF-15, for mid-wave infrared (MWIR) applications. To achieve fast response time, we fabricated a polymer network liquid crystal (PNLC) using UCF-15 as host. At 40 degrees C operating temperature, our PNLC shows 2pi phase change at lambda = 4 MUm, submillisecond response time, and over 98% transmittance in the 3.8 to 5.1 MUm region. Potential applications of this PNLC phase modulator for high speed laser beam steering, adaptive optics, and optical tweezer are foreseeable. PMID- 30469935 TI - High efficiency terahertz generation in a multi-stage system. AB - We describe a robust system for laser-driven narrowband terahertz generation with high conversion efficiency in periodically poled Lithium Niobate (PPLN). In the multi-stage terahertz generation system, the pump pulse is recycled after each PPLN stage for further terahertz generation. By out-coupling the terahertz radiation generated in each stage, extra absorption is circumvented and effective interaction length is increased. The separation of the terahertz and optical pulses at each stage is accomplished by an appropriately designed out-coupler. To evaluate the proposed architecture, the governing 2-D coupled wave equations in a cylindrically symmetric geometry are numerically solved using the finite difference method. Compared to the 1-D calculation which cannot capture the self focusing and diffraction effects, our 2-D numerical method captures the effects of difference frequency generation, self-phase modulation, self-focusing, beam diffraction, dispersion and terahertz absorption. We found that the terahertz generation efficiency can be greatly enhanced by compensating the dispersion of the pump pulse after each stage. With a two-stage system, we predict the generation of a 17.6 mJ terahertz pulse with total conversion efficiency etatotal = 1.6% at 0.3 THz using a 1.1 J pump laser with a two-lines spectrum centered at 1 MUm. The generation efficiency of each stage is above 0.8% with the out coupling efficiencies above 93.0%. PMID- 30469936 TI - A local Fourier slice equation. AB - We present a local Fourier slice equation that enables local and sparse projection of a signal. Our result exploits that a slice in frequency space is an iso-parameter set in spherical coordinates. The projection of suitable wavelets defined separably in these coordinates can therefore be computed analytically, yielding a sequence of wavelets closed under projection. Our local Fourier slice equation then realizes projection as reconstruction with "sliced" wavelets with computational costs that scale linearly in the complexity of the projected signal. We numerically evaluate the performance of our local Fourier slice equation for synthetic test data and tomographic reconstruction, demonstrating that locality and sparsity can significantly reduce computation times and memory requirements. PMID- 30469937 TI - Experimental demonstration of DFB lasers with active distributed reflector. AB - We experimentally demonstrated DFB lasers containing an active distributed reflector that has the same waveguide core as the active section. Although without current injection, the distributed reflector will be optically pumped to near transparency by the laser itself, and therefore can provide relatively high reflection to the laser. The laser, fabricated with processing steps similar to standard DFB lasers, has achieved 10-mA threshold current, 0.38-mW/mA slope efficiency, above 55-dB side mode suppression ratio, and 24-GHz modulation bandwidth at 60-mA current injection. 28-Gb/s transmission over 10-km single-mode fibers with a power penalty of less-than 0.5 dB has been demonstrated as well. PMID- 30469938 TI - Performance improvement of NOMA visible light communication system by adjusting superposition constellation: a convex optimization approach. AB - Non-orthogonal multiple access (NOMA) can increase the overall spectral efficiency of visible light communication (VLC) system. In this paper, we proposed a novel scheme to improve the bit error rate (BER) performance of a two user NOMA VLC system by adjusting superposition constellation. The corresponding closed-form BER expressions are derived. Convex optimization is used to find the optimal parameters of the adjusted superposition constellation, where the overall BER is minimized. The BER performances are evaluated by theoretical analysis, Monte-Carlo (MC) simulation and experiment. The results illustrate that 8.9-dB and 8.1-dB signal-to-noise ratios (SNRs) are reduced to achieve BER of 10-3 for the two users, whose power allocation coefficients are 0.6 and 0.4, respectively. PMID- 30469939 TI - Optical frequency combs from high-order sideband generation. AB - We report on the generation of frequency combs from the recently-discovered phenomenon of high-order sideband generation (HSG). A near-band gap continuous wave (cw) laser with frequency fNIR was transmitted through an epitaxial layer containing GaAs/AlGaAs quantum wells that were driven by quasi-cw in-plane electric fields FTHz between 4 and 50 kV/cm oscillating at frequencies fTHz between 240 and 640 GHz. Frequency combs with teeth at fsideband = fNIR + nfTHz (n even) were produced, with maximum reported n > 120, corresponding to a maximum comb span > 80 THz. Comb spectra with the identical product fTHz * FTHz were found to have similar spans and shapes in most cases, as expected from the picture of HSG as a scattering-limited electron-hole recollision phenomenon. The HSG combs were used to measure the frequency and linewidth of our THz source as a demonstration of potential applications. PMID- 30469940 TI - Sub-wavelength tight-focusing of terahertz waves by polarization-independent high numerical-aperture dielectric metalens. AB - A focusing device is one of the key elements for terahertz applications, including homeland security, medicine, industrial inspection, and other fields. Sub-wavelength tight-focusing of terahertz waves is attractive for microscopy and spectroscopy. Flat optical lenses based on metasurfaces have shown potential in diffraction-limit focusing and advantages of ultrathin thickness and lightweight for large-aperture optics. However previously reported THz metalenses suffered from either polarization-dependency or small numerical aperture (NA), which greatly limits their focusing performance. In this paper, to achieve high-NA and polarization-free operation, we proposed a polarization-independent dielectric metasurface with a sub-wavelength period of 0.4lambda. A planar terahertz lens based on such metasurface was designed for a wavelength of lambda = 118.8 MUm with a focal length of 100lambda, a radius of 300lambda, and a high NA of 0.95, which was fabricated with a silicon-on-insulator wafer. The experimental results demonstrate a tight focal spot with sub-wavelength full widths at half-maxima of 0.45lambda and 0.61lambda in the x and y directions, respectively, on the focal plane. In the x direction, the size of 0.45lambda is even smaller than the diffraction limit 0.526lambda (0.5lambda/NA). Such a metalens is favorable for sub-wavelength tight-focusing terahertz waves with different polarizations, due to its polarization independence. The metalens has potential applications in THz imaging, spectroscopy, information processing, and communications, among others. PMID- 30469941 TI - Simultaneous control of polarization and amplitude over broad bandwidth using multi-layered anisotropic metasurfaces. AB - In this paper, the broadband transmissive modulation of polarization and amplitude is demonstrated with high efficiency and tunability using multi-layered aluminum metasurfaces. Broadband and nondispersive optical rotation in the optical frequency region is realized by using Fabry-Perot-like cavity and phase compensation. Simultaneously, the transmission amplitude can be independently controlled by adjusting the twist angle of the anisotropic metasurfaces. The proposed polarization-amplitude modulators are numerically demonstrated to achieve large tunability with an amplitude modulation depth of 0.95 and maximum rotation angle of 180 degrees . PMID- 30469942 TI - Loop-based subtraction of a single photon from a traveling beam of light. AB - Manipulating light by adding and subtracting individual photons is a powerful approach with a principal drawback: the operations are fundamentally probabilistic and the probability is often small. This limits not only the fundamental scalability but also the number of operations that can be applied in realistic experimental settings. We propose and analyze a loop-based technique which can significantly increase the probability of success while preserving the quality of the photon subtraction. We show the improvement both in single mode preparation and manipulation of non-Gaussian states with negative Wigner functions and in two-mode entanglement distillation protocol with Gaussian states of light. PMID- 30469943 TI - Contactless THz-based bulk semiconductor mobility measurements using two-photon excitation. AB - We perform contactless bulk mobility measurements for ZnSe, ZnTe, GaP, CdS, and GaSe in an optical pump THz probe experiment. As opposed to above-gap excitation or contact methods, two-photon absorption excites the entire sample thickness producing measurable signals with 1013 carriers/cm3 and higher density. For ZnTe and GaSe samples, the measured mobility using two-photon excitation is higher than that measured with one-photon excitation. PMID- 30469944 TI - Removal of surface-normal spot beam from on-chip 2D beam pattern projecting lasers. AB - Static arbitrary two-dimensional beam patterns have been demonstrated using on chip size "integrable spatial-phase-modulating surface-emitting lasers," which use the band edge mode of a two-dimensional photonic crystal as an in-plane resonator, while the spatial phase of the lightwaves of the band edge mode are simultaneously modulated in a holographic manner by a local positional shift of holes from their lattice points. Meanwhile, the beam patterns include a spot beam in the surface-normal direction (0th-order beam), which corresponds to components of vertical diffraction of the band edge modes without spatial phase modulation. A promising method, used to remove the 0th-order beam, uses a structure that prohibits the vertical diffraction of band edge modes. For this purpose, we set the period of the virtual photonic crystal structure from the conventional Gamma2 band edge to the MU1 band edge, where vertical diffraction is prohibited. Moreover, the additional spatial phase modulation that cancels the in-plane component of the wavevectors of the lightwaves of the band edge modes at the MU1 band edge are also imposed to output the beam patterns vertically. As a result, we successfully demonstrated two-dimensional beam patterns without a spot beam in the surface-normal direction. PMID- 30469945 TI - Raman-converted high-energy double-scale pulses at 1270 nm in P2O5-doped silica fiber. AB - This work presents implementation of a new approach to single-cascade Raman conversion of laser pulses from the spectral range around 1.1 um into the 1.3-um wavelength region. The proposed conversion technique relies on double-scale pico femtosecond pulses for synchronous pumping of an external cavity made of phosphosilicate fiber with high-precision adjustment of pulse repetition rate to the inter-mode frequency of the external cavity. This enabled generation of double-scale pulses centered at 1270 nm featuring a record energy of 63 nJ and the pulse envelope duration of 88-180 ps with the sub-pulse duration of 200 fs. The fraction of the radiation that was converted into the 1270 nm range amounted to 47 percent of the total Raman-converted radiation power. The generated results offer promising possibilities for new spectral ranges to be developed in the field of high-energy pulsed sources with unique double-scale temporal structure. PMID- 30469946 TI - Compact high-performance adiabatic 3-dB coupler enabled by subwavelength grating slot in the silicon-on-insulator platform. AB - We demonstrate a compact high-performance adiabatic 3-dB coupler for the silicon on-insulator platform. The refractive index of the gap region between two coupling waveguides is effectively increased using subwavelength grating, which leads to high-performance operation and a compact design footprint, with a mode evolution length of only 25 um and an entire device length of 65 um. The designed adiabatic 3-dB coupler has been fabricated using electron beam lithography and the feature size used in our design is CMOS compatible. The fabricated device is characterized in the wavelength range from 1500 nm to 1600 nm, with a measured power splitting ratio better than 3 +/- 0.27 dB and an average insertion loss of 0.20 dB. PMID- 30469947 TI - Microcavities with suspended subwavelength structured mirrors. AB - We investigate the optical properties of microcavities with suspended subwavelength structured mirrors, such as high-contrast gratings or two dimensional photonic crystals slabs, and focus in particular on the regime in which the microcavity free-spectral range is larger than the width of a Fano resonance of the highly reflecting structured mirror. In this unusual regime, the transmission spectrum of the microcavity essentially consists in a single mode, whose linewidth can be significantly narrower than both the Fano resonance linewidth and the linewidth of an equally short cavity without structured mirror. This generic interference effect-occuring in any Fabry-Perot resonator with a strongly wavelength-dependent mirror-can be exploited for realizing small modevolume and high quality factor microcavities and, if high mechanical quality suspended structured thin films are used, for optomechanics and optical sensing applications. PMID- 30469948 TI - Ownership protection of holograms using quick-response encoded plenoptic watermark. AB - In actual applications of three-dimensional (3D) holographic display, the holograms need to be effectively stored and transmitted through the network. Thereby, there is an urgent demand for protecting the ownership of holograms against piracy and malicious manipulation. This paper realizes an ownership protection for holograms by embedding the watermark into the optimized cellular automata (OCA) domains. This work has the advantages of simultaneously improving the imperceptibility by selecting the "best" rule and OCA domains for watermark embedding and increasing robustness via the property of the multiple memory of the plenoptic image. We present experimental results of the visual quality of watermarked holograms and the robustness of 3D watermark to verify the performance of the proposed watermarking method. Experimental results confirm the imperceptibility and robustness of the proposed method. PMID- 30469949 TI - Spectrum collapse, narrow linewidth, and Bogatov effect in diode lasers locked to high-Q optical microresonators. AB - We present a novel method allowing high-power single-frequency emission with sub kHz linewidth from a compact multi-frequency diode laser locked to high-Q optical microresonator. Using high-Q MgF2microresonator and multi-frequency diode laser operating at 1535 nm with the output power of 100 mW and an emission spectrum consisting of approximately 50 lines with MHz linewidth, we observed a spectrum collapse to a single line or several lines with a sub-kHz linewidth and output power power of 50 mW. The Bogatov effect predicted more than 30 years ago was observed and studied in the spectrum of the locked laser. For analysis of the considered effect, original theoretical model taking into account self-injection locking effect, mode competition and Bogatov asymmetric mode interaction was developed and numerical modeling was performed. All numerical results are in a good agreement with our experimental data. Accurate analytical estimations for the parameters critical for the considered effect were obtained. The proposed method may be applied for different types of diode lasers operating in different spectral ranges. PMID- 30469950 TI - Waveform reconstruction with a Cs based free-induction-decay magnetometer. AB - We demonstrate an optically pumped magnetometer (OPM) operated in a free induction-decay (FID) configuration that is capable of tracking oscillating magnetic signals in the presence of a 50 MUT static field. Excellent waveform reconstruction is demonstrated for low frequency modulations with respect to the Nyquist limited bandwidth. A 100 pT oscillation was successfully reconstructed using signal averaging, and an optimum sensitivity of 3.9 pT/Hz was measured from the spectrum of the residuals relative to the sinusoidal fit. The impact of the pump-probe repetition rate and spin depolarization on the frequency response of the sensor is investigated in detail using miniaturized vapor cell technology, with the (-3 dB) bandwidths residing beyond the Nyquist limit in each case. We also discuss technical limitations associated with the magnetometer when exposed to oscillating fields of sufficiently high amplitude or frequency. This is discussed in the context of potential distortions arising in the reproduced signals, induced by frequency modulation (FM) and aliasing artefacts. PMID- 30469951 TI - Optimizing the linearity in high-speed photodiodes. AB - Analog photonic links require high-fidelity, high-speed optical-to-electrical conversion for applications such as radio-over-fiber, synchronization at kilometer-scale facilities, and low-noise electronic signal generation. Photodetector nonlinearity is a particularly vexing problem, causing signal distortion and excess noise, especially in systems utilizing ultrashort optical pulses. Here we show that photodetectors designed for high power handling and high linearity can perform optical-to-electrical conversion of ultrashort optical pulses with unprecedented linearity over a large photocurrent range. We also corroborate and expand upon the physical understanding of how the broadband, complex impedance of the circuit following the photodiode modifies the linearity in some cases quite significantly. By externally manipulating the circuit impedance, we extend the detector's linear range to higher photocurrents, with over 50 dB rejection of amplitude-to-phase conversion for photocurrents up to 40 mA. This represents a 1000-fold improvement over state-of-the-art photodiodes and significantly extends the attainable microwave power by a factor of four. As such, we eliminate the long-standing requirement in ultrashort pulse detection of precise tuning of the photodiode's operating parameters to coincide with a nonlinearity minimum. These results should also apply more generally to reduce nonlinear distortion in a range of other microwave photonics applications. PMID- 30469952 TI - Ge photodetector monolithically integrated with amorphous Si waveguide on wafer bonded Ge-on-insulator substrate. AB - We present a proof-of-concept demonstration of a Ge/a-Si hybrid photonic integrated circuit platform utilizing a high-quality Ge-on-insulator (GeOI) wafer fabricated by wafer bonding technology. Amorphous Si (a-Si) formed by PECVD is found to be a promising alternative to conventional Si passive waveguides on a SiO2 BOX. Taking advantage of the high crystal quality of the Ge active layer and the easy fabrication of an a-Si waveguide, a low-dark-current Ge waveguide PIN photodetector monolithically integrated with an a-Si passive waveguide is successfully demonstrated on a GeOI wafer. PMID- 30469953 TI - Retrievals of phytoplankton community structures from in situ fluorescence measurements by HS-6P. AB - Phytoplankton community is an important organism indicator of monitoring water quality, and accurately estimating its composition and biomass is crucial for understanding marine ecosystems and biogeochemical processes. Identifying phytoplankton species remains a challenging task in the field of oceanography. Phytoplankton fluorescence is an important biological property of phytoplankton, whose fluorescence emissions are closely related to its community. However, the existing estimation approaches for phytoplankton communities by fluorescence are inaccurate and complex. In the present study, a new, simple method was developed for determining the Chlorophytes, Chrysophytes, Cryptophytes, Diatoms, Dinoflagellates, and Prymnesiophytes based on the fluorescence emission spectra measured from the HOBI Labs Hydroscat-6P (HS-6P) in the Bohai Sea, Yellow Sea, and East China Sea. This study used single bands, band ratios, and band combinations of the fluorescence signals to test their correlations with the six dominant algal species. The optimal band forms were confirmed, i.e., X1 (i.e., fl(700), which means the fluorescence emission signal at 700 nm band) for Chlorophytes, Cryptophytes, Dinoflagellates, and Prymnesiophytes (R = 0.947, 0.862, 0.911, and 0.918, respectively) and X7 (i.e., [fl(700) + fl(550)]/[fl(550)/fl(700)], where fl(550) denotes the fluorescence emission signal at 550 nm band) for Chrysophytes and Diatoms (R = 0.893 and 0.963, respectively). These established models here show good performances, yielding low estimation errors (i.e., root mean square errors of 0.16, 0.02, 0.06, 0.36, 0.18, and 0.03 for Chlorophytes, Chrysophytes, Cryptophytes, Diatoms, Dinoflagellates, and Prymnesiophytes, respectively) between in situ and modeled phytoplankton communities. Meanwhile, the spatial distributions of phytoplankton communities observed from both in situ and fluorescence-derived results agreed well. These excellent outputs indicate that the proposed method is to a large extent feasible and robust for estimating those dominant algal species in marine waters. In addition, we have applied this method to three vertical sections, and the retrieved vertical spatial distributions by this method can fill the gap of the common optical remote sensing approach, which usually only detects the sea surface information. Overall, our findings indicate that the proposed method by the fluorescence emission spectra is a potentially promising way to estimate phytoplankton communities, in particular enlarging the profiling information. PMID- 30469954 TI - Low-cost, readily available 3D microscopy imaging system with variable focus spinner. AB - A large open aperture in an optical system can capture high-resolution images but yields a shallow depth of field. To overcome this issue, we investigated a low cost, readily available method for retrofitting microscopy imaging systems to achieve 3D focus scanning in this study. Specifically, a procedure for fabricating variable focus spinners with dissimilar plates was introduced, and a sequence of 12 images was captured in different focal planes. The image scale and phase were corrected, and the in-focus pixels were abstracted by employing the Laplacian operator. Finally, an all-in-focus sharp image was generated, and a depth map was obtained. PMID- 30469955 TI - Bragg grating cavities embedded into nano-photonic waveguides for Purcell enhanced quantum dot emission. AB - In the present work, we demonstrate the fabrication and optical properties of Bragg grating cavities that are directly integrated into ridge waveguides along with the Purcell enhanced emission from integrated quantum dots. Measured Q factors up to 4600 are observed in combination with resonances of the fundamental mode within a +/- 0.11 nm range along the full fabricated chip. The measured Purcell enhancement up to a factor of 3.5 +/- 0.5 shows the potential utility for state-of-the-art on-chip quantum optical experiments as realized in off-chip implementations. Our measurements are fully supported via FDTD simulations giving a theoretical Purcell enhancement up to a factor of 20 with a highly directional betadir-factor of 70 %. The straightforward upscaling and robust design of the investigated Bragg grating cavity in combination with a substantial Purcell enhancement represents a major step towards large scale on-chip quantum photonic circuits. PMID- 30469956 TI - Multi-layer silicon nitride-on-silicon polarization-independent grating couplers. AB - A polarization-independent grating coupler is proposed and demonstrated in a 3 layer silicon nitride-on-silicon photonic platform. Polarization independent coupling was made possible by the supermodes and added degrees of geometric freedom unique to the 3-layer photonic platform. The grating was designed via optimization algorithms, and the simulated peak coupling efficiency was -2.1 dB with a 1 dB polarization dependent loss (PDL) bandwidth of 69 nm. The fabricated grating couplers had a peak coupling efficiency of -4.8 dB with 1 dB PDL bandwidth of over 100 nm. PMID- 30469957 TI - Nanofocusing in SOI-based hybrid plasmonic metal slot waveguides. AB - Through a process of efficient dielectric to metallic waveguide mode conversion, we calculate a >400-fold field intensity enhancement in a silicon photonics compatible nanofocusing device. A metallic slot waveguide sits on top of the silicon slab waveguide with nanofocusing being achieved by tapering the slot width gradually. We evaluate the conversion between the numerous photonic modes of the planar silicon waveguide slab and the most confined plasmonic mode of a 20 x 50 nm2 slot in the metallic film. With an efficiency of ~80%, this system enables remarkably effective nanofocusing, although the small amount of inter mode coupling shows that this structure is not quite adiabatic. In order to couple photonic and plasmonic modes efficiently, in-plane focusing is required, simulated here by curved input grating couplers. The nanofocusing device shows how to efficiently bridge the photonic micro-regime and the plasmonic nano-regime whilst maintaining compatibility with the silicon photonics platform. PMID- 30469958 TI - Diffraction limited mid-infrared reflectance microspectroscopy with a supercontinuum laser. AB - Chemical mapping was demonstrated with a mid-infrared (MIR) microspectroscopy setup based on a supercontinuum source (SC) emitting in the spectral range from 1.55 to 4.5 um and a MEMS-based Fabry-Perot filter spectrometer. Diffraction limited spatial resolution in reflection geometry was achieved. A multilayer film consisting of different polymers and mixtures thereof was measured and results were compared to those gained with a conventional FTIR microscope equipped with a thermal MIR source. Results show that compared to thermal sources, the application of the SC source results in higher signal-to-noise ratios together with better spatial resolution and faster scanning. Furthermore, diffraction limited imaging of red blood cells was demonstrated for the first time in the MIR spectral region in reflection mode. The distinctive characteristics of the MIR spectral region in conjunction with the high brightness, spatial coherence and broadband nature of supercontinuum radiation show the potential for improving infrared microscopy significantly. PMID- 30469959 TI - Ultrasensitive specific terahertz sensor based on tunable plasmon induced transparency of a graphene micro-ribbon array structure. AB - We proposed an ultrasensitive specific terahertz sensor consisting of two sets of graphene micro-ribbon with different widths. The interference between the plasmon resonances of the wide and narrow graphene micro-ribbons gives rise to the plasmon induced transparency (PIT) effect and enables ultrasensitive sensing in terahertz region. The performances of the PIT sensor have been analyzed in detail considering the thickness and refractive index sensing applications using full wave electromagnetic simulations. Taking advantage of the electrical tunability of graphene's Fermi level, we demonstrated the specific sensing of benzoic acid with detection limit smaller than 6.35 ug/cm2. The combination of specific identification and enhanced sensitivity of the PIT sensor opens exciting prospects for bio/chemical molecules sensing in the terahertz region. PMID- 30469960 TI - Fabrication of 4 * 1 signal combiner for high-power lasers using hydrofluoric acid. AB - We report a new method to fabricate a 4 * 1 signal combiner that comprises an output fiber port and a tapered fused bundle (TFB) with four input fiber ports. The TFB is etched in a solution of hydrofluoric acid and spliced with an output fiber of core diameter 105 MUm and cladding diameter 125 MUm. Each cladding of the four input optical fiber is etched to approximately 72.5 MUm. The etched TFB was fabricated by tapering after forming a bundle of four etched optical fibers. Subsequently, the 4 * 1 signal combiner is fabricated by fusion splicing between the fabricated TFB and output optical fiber with a numerical aperture of 0.15. The efficiency of each port of the fabricated 4 * 1 signal combiner is in the range of 93.3-98.3%. When an optical power of approximately 624.5 W was input to the signal combiner, the maximum output was ~612 W and the efficiency was ~98%. The beam quality factor, M 2is measured to be approximately 14.6, which is calculated as the beam parameter product (BPP) of 5.02 mm.mrad. PMID- 30469961 TI - Polarization-switchable holograms based on efficient, broadband multifunctional metasurfaces in the visible regime. AB - Gradient metasurfaces provide a novel approach to the phase manipulation of incident electromagnetic waves. Thus, they have the potential to create compact, light-weight optical solutions. An attractive feature of metasurfaces is the ability to integrate multiple optical functionalities into a single surface design. Here we demonstrate a high-efficiency (up to ~60%), reflective meta hologram for visible light by using an ultra-thin (~lambda/4 thick) gap surface plasmon-based metasurface. By precisely sampling the predesigned image phase and amplitude to the unit cells of our device, polarization-controlled dual images are reconstructed with a high polarization extinction ratio and high fidelity. The proposed technique expands the range of possibilities for high-quality hologram generation by using ultra-thin nanophotonic devices and paves the way for variousholography-related applications across the visible band. PMID- 30469962 TI - Circuit QED: single-step realization of a multiqubit controlled phase gate with one microwave photonic qubit simultaneously controlling n - 1 microwave photonic qubits. AB - We present a novel method to realize a multi-target-qubit controlled phase gate with one microwave photonic qubit simultaneously controlling n - 1 target microwave photonic qubits. This gate is implemented with n microwave cavities coupled to a superconducting flux qutrit. Each cavity hosts a microwave photonic qubit, whose two logic states are represented by the vacuum state and the single photon state of a single cavity mode, respectively. During the gate operation, the qutrit remains in the ground state and thus decoherence from the qutrit is greatly suppressed. This proposal requires only a single-step operation and thus the gate implementation is quite simple. The gate operation time is independent of the number of the qubits. In addition, this proposal does not need applying classical pulse or any measurement. Numerical simulations demonstrate that high fidelity realization of a controlled phase gate with one microwave photonic qubit simultaneously controlling two target microwave photonic qubits is feasible with current circuit QED technology. The proposal is quite general and can be applied to implement the proposed gate in a wide range of physical systems, such as multiple microwave or optical cavities coupled to a natural or artificial Lambda type three-level atom. PMID- 30469963 TI - Super multi-view near-eye display to solve vergence-accommodation conflict. AB - A super multi-view (SMV) technique is applied to near-eye displays to solve the vergence-accommodation conflict that causes visual fatigue. The proposed SMV near eye display employs a high-speed spatial light modulator (SLM), a two-dimensional (2D) light source array, and an imaging optics for each eye. The imaging optics produces a virtual image of the SLM and real images of the light sources to generate a 2D array of viewpoints. The SMV images are generated using a time multiplexing technique: the multiple light sources sequentially emit light while the SLM synchronously displays corresponding parallax images. A monocular experimental system was constructed using a ferroelectric liquid crystal display and an LED array. A full-parallax SMV image generation with 21 viewpoints was demonstrated and a comparison of full-parallax and horizontal parallax SMV images provided. PMID- 30469964 TI - Ultrafast laser writing quill effect in low loss waveguide fabrication regime. AB - The quill effect is a laser writing phenomenon in which different fabrication effects occur, depending upon the direction of laser translation. It has not yet, to our knowledge, been studied in the low-loss-waveguide (LLW) writing regime, probably due to its very weak visibility under conventional transmission microscope in that regime. In this report, with the help of adaptive third harmonic generation microscopy, we reveal the quill effect in the LLW writing regime and show its influences on the properties of laser-written photonic integrated components, in terms of polarization-related properties in fused silica and beam-splitting ratios of three-waveguide-coupler in borosilicate glass. PMID- 30469965 TI - In situ noncontact measurement system and two-step compensation strategy for ultra-precision diamond machining. AB - Ultra-precision diamond machining is a promising technique for non-rotationally symmetrical surfaces with sub-micrometer form accuracy. The measurement and compensation processes in the fabrication process must be conducted carefully to achieve high form accuracy. However, significant challenges remain to improve the measurement accuracy and machining efficiency. Because of the remounting process, the off-machine measurements would reduce the efficiency. On the other hand, contact-type measurements can cause physical damage to some soft materials. To overcome these problems, a noncontact on-machine measurement (OMM) system is developed using two optical probes, and a two-step compensation strategy is proposed to generate a modified tool path. To verify the accuracy of the proposed measurement system, OMMs were performed on a spherical mirror using this system and were later compared with off-machine measurements. To evaluate the compensation strategy, an off-axis paraboloid mirror was diamond-machined and compensated using the proposed method. The results show that the OMM system and compensation strategy are effective for improving the form accuracy while simultaneously enhancing the machining efficiency. PMID- 30469966 TI - Broadband c-Si metasurfaces with polarization control at visible wavelengths: applications to 3D stereoscopic holography. AB - Visual arts and entertainment related industries are continuously looking at promising innovative technologies to improve users' experience with state-of-the art visualization platforms. This requires further developments on pixel resolution and device miniaturization which can be achieved, for instance, with high contrast materials, such as crystalline silicon (c-Si). Here, a new broadband stereoscopic hologram metasurface is introduced, where independent phase control is achieved for two orthogonal polarizations in the visible spectrum. The holograms are fabricated with a birefringent metasurface consisting of elliptical c-Si nanoposts on Sapphire substrate. Two holograms are combined on the same metasurface (one for each polarization) where each is encoded with four phase levels. The theoretical bandwidth is 110 nm with a signal to noise ratio (SNR) >15 dB. The stereoscopic view is obtained with a pair of cross-polarized filters in front of the observers' eyes. The measured transmission and diffraction efficiencies are about 70% and 15%, respectively, at 532 nm (the design wavelength). The metasurfaces are also investigated at 444.9 nm and 635 nm to experimentally assess their bandwidth performance. The stereoscopic effect is surprisingly good at 444.9 nm (and less so at 635 nm) with transmission and diffraction efficiencies around 70% and 18%, respectively. PMID- 30469967 TI - Fluorescence fiber optic temperature sensor based on fused upconversion luminescent nanoparticles. AB - A new type of fluorescence fiber optic temperature sensor based on the detection of fluorescence intensity ratio (FIR) is proposed. Benefited from the temperature dependent characteristic of upconversion luminescence (UCL), it can be applied in fiber optic temperature sensors. Rare earth doped upconversion nanoparticles (UCNPs) NaYF4:Er3+,Yb3+ are embedded in a multi-mode quartz fiber through the technology of fiber fusion as the sensing unit of temperature sensors. A 980 nm laser is used to stimulate UCL in a temperature range from 40 degrees C to 100 degrees C. Experimental validation and spectral analysis are carried out to confirm the rationality of sensors' design. Results show that FIR changes with the temperature in Boltzmann distribution law. The sensitivity of the temperature sensors can reach the value between 0.0087 and 0.0144 K-1. PMID- 30469968 TI - Deep learning optical-sectioning method. AB - Current optical-sectioning methods require complex optical system or considerable computation time to improve imaging quality. Here we propose a deep learning based method for optical sectioning of wide-field images. This method only needs one pair of contrast images for training to facilitate reconstruction of an optically sectioned image. The removal effect of background information and resolution that is achievable with our technique is similar to traditional optical-sectioning methods, but offers lower noise levels and a higher imaging depth. Moreover, reconstruction speed can be optimized to 14 Hz. This cost effective and convenient method enables high-throughput optical sectioning techniques to be developed. PMID- 30469969 TI - Generation of mechanical squeezing and entanglement via mechanical modulations. AB - We discuss the generation of strong stationary mechanical squeezing and entanglement in the modulated two-and three-mode optomechanics. Following the reservoir engineering scheme, the beam-splitter and parametric optomechanical interactions can be simultaneously achieved through appropriately choosing the modulation frequency on mechanical motion, which is essential to strong squeezing and entanglement. In the two-mode modulated optomechanics, squeezing is tunable by the relative ratio of parametric and beam-splitter couplings, and also robust to thermal noise due to the simultaneously optically induced cooling process. In the three-mode modulated optomechanics, strong EPR-type entanglement is also attainable, which can surpass the 3dB limit of nondegenerate parametric interaction. However, the ideal entanglement is impossible since only one of mechanical Bogoliubov modes is cooled by the cavity mode, which also makes the entanglement fragile to the mechanical noise. PMID- 30469970 TI - Single-transverse-mode broadband InAs quantum dot superluminescent light emitting diodes by parity-time symmetry. AB - Parity-time (PT) symmetry breaking in counterintuitive gain/loss coupled waveguide designs is numerically and theoretically investigated. The PT symmetry mode selection conditions are determined theoretically. Single-transverse-mode broadband InAs quantum dot (QD) superluminescent light emitting diodes (SLEDs) are fabricated and characterized; the PT symmetric broad-area SLEDs contain laterally coupled gain and loss PT- symmetric waveguides. Single-transverse-mode operation is achieved by parity-time symmetry breaking. The broadband SLEDs exhibit a uniform Gaussian-like emission spectrum with the 3-dB bandwidth of 110 nm. Far-field characteristics of the coupled waveguide SLEDs exhibit a single lobe far-field pattern when the gain and loss waveguides are biased at the injection current of 600 mA and 60 mA, respectively. PMID- 30469971 TI - Group geometric calibration and rectification for circular multi-camera imaging system. AB - Calibration on multi-camera imaging system in circular arrangement is a challenge task, because the preliminary shared feature points are absent among opposite viewpoints in the calibration procedure. In this paper, we propose a scheme of group geometric calibration and ideal rectification for circular multi-camera imaging system. In this scheme, a three-dimensional (3D) calibration object with new patterns is firstly designed to extract the extrinsic parameters. After that, the ideal camera projection matrix is estimated based on these parameters. Finally, we extend our scheme from static to dynamic scenario. In the experiments, our method has a superior performance over state-of-the-art calibration methods. Furthermore, we verify our scheme by application of 3D modeling and improvements can also be found. These results demonstrate that our method performance on such imaging system is applicable for future interactive visual applications. PMID- 30469972 TI - Efficient terahertz generation in highly nonlinear organic crystal HMB-TMS. AB - We report on generation of strong and broadband terahertz (THz) pulses via collinearly phase-matched optical rectification of near-infrared femtosecond pulses in the organic nonlinear optical HMB-TMS (2-(4-hydroxy-3-methoxystyryl)-3 methylbenzo[d]thiazol-3-ium 2,4,6-trimethylbenzenesulfonate) single crystals which exhibit optimal molecular orientation and large macroscopic optical nonlinearity for efficient THz wave generation. Single-cycle THz pulses with a peak electric field strength of 0.66 MV/cm and a bandwidth from 0.1 to 5.4 THz are achieved from an HMB-TMS crystal with only a 2-mm clear aperture pumped by 1350 nm pulses at moderate fluences. The generated THz energy is about 1 uJ and the corresponding pump-to-THz energy conversion efficiency reaches 0.23%. PMID- 30469973 TI - Network selection method based on MADM and VH-based multi-user access scheme for indoor VLC hybrid networks. AB - Recently, the visible light communication (VLC) based on LEDs has attracted much attention. In this paper, in order to realize multi-user wireless communication for VLC-based indoor hybrid networks, a network selection method based on Multi Attribute Decision Making (MADM) is proposed, which effectively combines the subjective preference of the user with the objective performance of each network. And then, a VH-based (virtual handover) multi-user access scheme is proposed, which considers different MAC and channel information. Wherein, a concept of backoff lock is presented to control the access request of the user to different channels; a concept of VH is also put forward to reduce access delay, and improve access success ratio. When VH is triggered, the user can use the backoff lock to lock the current access request and send access request to other networks. The expressions of collision probability, access delay, and access success ratio are given. Analytical and simulation results show that the proposed network selection method can effectively meet the users' requirement, and the evaluation value obtained by our method is also in accordance with the objective network performance, and that the VH-based multi-user access scheme can reduce the collision probability and the access delay, and increase the access success ratio for VLC-based hybrid networks. PMID- 30469974 TI - Amplification of flat laser pulse train. AB - We present modeling and measurements of flattop amplification of a laser pulse train in a diode pumped Nd:YLF system. We establish a theoretical model, accounting for the transverse Gaussian shape of an amplified laser beam, in order to explain remaining slopes in the pulse train energy. The influence of the transverse Gaussian shape on the train's flatness has been experimentally verified. Based on the model we are able to increase the total amplification of a long train of infrared seed beam in the drive laser system at the Fermilab Accelerator Science and Technology facility. The single-pass amplifier improvements resulted in a gain of ~7 with flat output pulse train for up to 1000 seed pulses. PMID- 30469975 TI - Fs-laser-written erbium-doped double tungstate waveguide laser. AB - We report on the first erbium (Er3+) doped double tungstate waveguide laser. As a gain material, we studied a monoclinic Er3+:KLu(WO4)2 crystal. A depressed-index buried channel waveguide formed by a 60 um-diameter circular cladding was fabricated by 3D femtosecond direct laser writing. The waveguide was characterized by confocal laser microscopy, u-Raman and u-luminescence mapping, confirming that the crystallinity of the core is preserved. The waveguide laser, diode pumped at 981 nm, generated 8.9 mW at 1533.6 nm with a slope efficiency of 20.9% in the continuous-wave regime. The laser polarization was linear (E || Nm). The laser threshold was at 93 mW of absorbed pump power. PMID- 30469976 TI - Butterfly neural equalizer applied to optical communication systems with two dimensional digital modulation. AB - This article aims to present, analyze and evaluate a new equalizer architecture, inspired by the butterfly equalizer used in optical communication, based on Artificial Neural Networks (ANN) of the Multi-Layer Perceptron (MLP) type for nonlinear systems with two-dimensional modulation named the Butterfly Neural Equalizer (NE-Butterfly). The NE-Butterfly is intended to equalize any channel that has real or complex taps, whether linear or nonlinear. Simulation results are presented for different types of nonlinear fiber optic channels with complex and real taps, also containing inter symbolic interference and additive noise. The results are compared with other neural equalizers in the literature with the objective of validating the performance of the NE-Butterfly, which stands out as having the overall best performance against the ones it was compared to. PMID- 30469977 TI - Extreme terahertz electric-field enhancement in high-Q photonic crystal slab cavity with nanoholes. AB - A one-dimensional photonic-crystal (PC) cavity with nanoholes is proposed for extreme enhancement of terahertz (THz) electric fields using the electromagnetic (EM) boundary conditions. Both slot (for the perpendicular component of the electric displacement field) and anti-slot (for the parallel component of the electric field) effects contribute to the considerable field enhancement. The EM energy density can be enhanced by a factor of (epsilonh/epsilonl)2 in the high refractive-index material, where epsilonh and epsilonl are the permittivities of the high- and low-refractive-index materials, respectively. Correspondingly, the mode volume can be reduced by a factor of 288, compared with a conventional THz PC cavity, and is three orders of magnitude smaller than the diffraction limitation. Further, the proposed THz cavity design also supports modes with high quality factors (Q) > 104, which induces strong Purcell enhancement by a factor exceeding 106. Our THz cavity design is feasible and attractive for experimental demonstrations, because the semiconductor layer in which the EM is maximized can naturally be filled with quantum-engineered active materials. Thus, the proposed design can possibly be used to develop room-temperature coherent THz radiation sources. PMID- 30469978 TI - Significantly enhanced infrared absorption of graphene photodetector under surface-plasmonic coupling and polariton interference. AB - Here, we present a graphene-based long-wavelength infrared photodetector, for enhancing the infrared absorption of which the design consists of magnetic- and electric-plasmon resonators of metasurface to excite the graphene surface plasmonic polaritons (SPPs). Through tuning the graphene Fermi energy to achieve the distinct resonances in a matching frequency, peak graphene absorbance exceeding 67.2% is confirmed, even when a lossy dielectric is used, and the field angle of view is up to 90 degrees . If the graphene is of a different carrier mobility, then the absorption frequency is lockable, and the device always can keep the system absorbance close to 100 percent. The significantly enhanced graphene absorbance, up to ~29-fold that of a suspended graphene (general 2.3%), is attributed to the surface-plasmonic coupling between the magnetic and the electric resonances, as well as Fabry-Perot interference of the coherent SPPs. The plasmonic cavity-mode model and equivalent-circuit method developed in this study will also be useful in guiding other optoelectronic device design. PMID- 30469979 TI - Surface enhanced perfect absorption in metamaterials with periodic dielectric nanostrips on silver film. AB - Integrated dielectric metamaterials with plasmonic structures can cause drastic optical resonances and strengthen the capacity of light absorption. Here, we describe the optical properties of silicon nanoarrays on a thin silver film for extreme light confinement at subwavelength nanoscales. We attain the nearly total absorption in silicon nanostrips, which support magnetic quadruple Mie-type resonances in the visible regions. The Mie resonant field of the dielectric nanostrip engages the screening response of the silver film, resulting in plasmon resonance configuration and thus achieving perfect light absorption in the dielectric nanostrip. Moreover, we can attain similar results in other nanostructures, such as silicon cylinder and rhombus column arrays. Because it can sustain hybridized plasmon modes and magnetic modes, the combined system will benefit the application of solar energy accumulation. PMID- 30469980 TI - Autonomous illumination control for localization microscopy. AB - Super-resolution fluorescence microscopy improves spatial resolution, but this comes at a loss of image throughput and presents unique challenges in identifying optimal acquisition parameters. Microscope automation routines can offset these drawbacks, but thus far have required user inputs that presume a priori knowledge about the sample. Here, we develop a flexible illumination control system for localization microscopy comprised of two interacting components that require no sample-specific inputs: a self-tuning controller and a deep learning-based molecule density estimator that is accurate over an extended range of densities. This system obviates the need to fine-tune parameters and enables robust, autonomous illumination control for localization microscopy. PMID- 30469981 TI - 4 * 128-Gb/s PDM-DMT signal transmission over 1440-km SSMF with high phase noise tolerance. AB - In this paper, we propose an intensity modulation and coherent detection scheme with high phase noise tolerance for polarization division multiplexing (PDM) discrete multi-tone (DMT) signal transmission by employing Kramers-Kronig (KK) detection and digital carrier regeneration (DCR). At the transmitter side, DMT signal is modulated by a Mach-Zehnder modulator (MZM) setting bias around the null point and transmitted with the suppressed optical carrier. At the receiver side, a directly modulated lasers (DMLs) locating at the edge of DMT signal is used as the local oscillator (LO) for coherent detection. For signal recovery, KK detection is first used to reduce the signal to signal beating noise. Digital optical carrier is then regenerated by the DCR scheme and the DMT signal could be recovered by enveloping detection with the regenerated digital carrier, which can achieve high laser line-width tolerance and mitigate the residual phase noise caused by KK detection. To verify the effectiveness of the proposed scheme, we compare the KK and DCR based receiver digital signal processing (DSP) with conventional receiver DSP by using both DMLs with larger linewidth (~10 MHz) or external cavity lasers (ECLs) with smaller linewidth (less than 100 kHz) as optical carrier and LO. The results show that KK and DCR can mutually improve the system performance with ECLs as optical carrier and LO. Moreover, it is shown that the signal using DMLs cannot be recovered without the DCR method due to the high laser line-width of DML. Finally, we successfully demonstrate 4 * 128-Gb/s KK and DCR based PDM-DMT signal transmission over 1440-km SSMF by employing DMLs as optical carrier and LO. PMID- 30469982 TI - Light scattering control in transmission and reflection with neural networks. AB - Scattering often limits the controlled delivery of light in applications such as biomedical imaging, optogenetics, optical trapping, and fiber-optic communication or imaging. Such scattering can be controlled by appropriately shaping the light wavefront entering the material. Here, we develop a machine-learning approach for light control. Using pairs of binary intensity patterns and intensity measurements we train neural networks (NNs) to provide the wavefront corrections necessary to shape the beam after the scatterer. Additionally, we demonstrate that NNs can be used to find a functional relationship between transmitted and reflected speckle patterns. Establishing the validity of this relationship, we focus and scan in transmission through opaque media using reflected light. Our approach shows the versatility of NNs for light shaping, for efficiently and flexibly correcting for scattering, and in particular the feasibility of transmission control based on reflected light. PMID- 30469983 TI - Reconfiguring structured light beams using nonlinear metasurfaces. AB - Ultra-compact, low-loss, fast, and reconfigurable optical components, enabling manipulation of light by light, could open numerous opportunities for controlling light on the nanoscale. Nanostructured all-dielectric metasurfaces have been shown to enable extensive control of amplitude and phase of light in the linear optical regime. Among other functionalities, they offer unique opportunities for shaping the wave front of light to introduce the orbital angular momentum (OAM) to a beam. Such structured light beams bring a new degree of freedom for applications ranging from spectroscopy and micromanipulation to classical and quantum optical communications. To date, reconfigurability or tuning of the optical properties of all-dielectric metasurfaces have been achieved mechanically, thermally, electrically or optically, using phase-change or nonlinear optical materials. However, a majority of demonstrated tuning approaches are either slow or require high optical powers. Arsenic trisulfide (As2S3) chalcogenide glass offering ultra-fast and large chi(3)nonlinearity as well as a low two-photon absorption coefficient in the near and mid-wave infrared spectral range, could provide a new platform for the realization of fast and relatively low intensity reconfigurable metasurfaces. Here, we design and experimentally demonstrate an As2S3 chalcogenide glass based metasurface that enables reshaping of a conventional Hermite-Gaussian beam with no OAM into an OAM beam at low intensity levels, while preserves the original beam's amplitude and phase characteristics at high intensity levels. The proposed metasurface could find applications for a new generation of optical communication systems and optical signal processing. PMID- 30469984 TI - Dynamically tunable multi-lobe laser generation via multifocal curved beam. AB - Beams with curved properties, represented by Airy beam, have already shown potential applications in various fields. Here we propose a simple method to achieve a multifocal curved beam (MCB). The scheme is based on the ability of microspheres to control the distribution of the light field. Combined with the caustic effect, the dynamic control of the beam curvature and the foci can be realized. The simulation results confirm the mechanism behind this phenomenon. Furthermore, MCB is applied experimentally into the end-pumped microchip laser. This work has verified the theory of MCB and achieved a dynamically tunable multi lobe laser, which has a wide application prospect. PMID- 30469985 TI - Structural coloration with hourglass-shaped vertical silicon nanopillar arrays. AB - We demonstrate that arrays of hourglass-shaped nanopillars patterned into crystalline silicon substrates exhibit vibrant, highly controllable reflective structural coloration. Unlike structures with uniform sidewall profiles, the hourglass profile defines two separate regions on the pillar: a head and a body. The head acts as a suspended Mie resonator and is responsible for resonant reflectance, while the body acts to suppress broadband reflections from the surface. The combination of these effects gives rise to vibrant colors. The size of the nanopillars can be tuned to provide a variety of additive colors, including the RGB primaries. Experimental results are shown for nanopillar arrays fabricated using nanoimprint lithography and plasma etching. A finite difference time domain (FDTD) model is validated against these results and is used to elucidate the electromagnetic response of the nanopillars. Furthermore, a COMSOL model is used to investigate the angle dependence of the reflectance. In view of display applications, a genetic algorithm is used to optimize the nanopillar geometries for RGB color reflective pixels, showing that nearly all of the sRGB color space and most of the Adobe RGB color space can be covered with this technique. PMID- 30469986 TI - Multi-dimensional QAM equivalent constellation using coherently coupled orbital angular momentum (OAM) modes in optical communication. AB - In this work, a 1550 nm fiber-to-free-space optical communication link is successfully demonstrated employing the superposition of two coherently coupled orbital angular momentum (CCOAM) states. Information is encoded onto both the amplitude and phase of the CCOAM beams and is mapped to a three-dimensional (3D) constellation space using quadrature amplitude modulation (QAM) equivalent architecture. The 3D QAM constellation is based on a higher-order Poincare sphere equivalent for OAM states, and multiple spherical constellations are demonstrated for 64- and 128-QAM, providing a 6X and 7X increase in spectral efficiency by fully exploiting the available 3D space. The experimental results are presented showing a bit error rate (BER) below the forward error correction (FEC) limit. Multiple experimental parameters which could contribute to constellation distortions are also discussed. PMID- 30469987 TI - Enhanced flatness of 20 GHz channel spacing multiwavelength Brillouin-Raman fiber laser with sub-millimeter air gap. AB - We discover the technique of controlling the flatness in signal amplitude of a multiwavelength Brillouin-Raman fiber laser by employing an air-gap outside of the cavity. The structure that is adjustable within sub-millimeter length behaves as flexible optical feedback that provides modifiable portions of multiple Fresnel reflectivities. This is the main benchmark that allows the efficient management of gain competition between self-lasing modes and Brillouin Stokes waves that is vital for self-flattening initiation. When setting the Brillouin pump wavelength at 1529 nm and the air-gap distance to 0.4 mm, 296 Stokes lines are produced with a channel spacing of 0.158 nm. The lasing bandwidth is 46.60 nm that covers from 1529.16 to 1575.76 nm wavelength. In this case at Raman power of 950 mW, the intense Brillouin pump power of 2 dBm saturates the cascaded higher orders lasing lines. As a result, the overall peak power discrepancy is maintained at just 1.8 dB where an average optical-signal-to-noise ratio of 20 dB is realized. To date, this is the widest bandwidth with the flattest spectrum attained in multiwavelength fiber lasers that incorporate a single Raman pump unit. PMID- 30469988 TI - Three-dimensional double helical DNA structure directly revealed from its X-ray fiber diffraction pattern by iterative phase retrieval. AB - Coherent diffraction imaging (CDI) allows the retrieval of an isolated object's structure, such as a macromolecule, from its diffraction pattern. CDI requires the fulfillment of two conditions: the imaging radiation must be coherent and the object must be isolated. We discuss that it is possible to directly retrieve the molecular structure from its diffraction pattern, which was acquired neither with coherent radiation nor from an individual molecule. This is provided that the molecule exhibits periodicity in one direction, as in the case of fiber diffraction. We demonstrate that, when we apply iterative phase retrieval methods to a fiber diffraction pattern, the repeating unit; that is, the molecule structure, can directly be reconstructed without any prior modeling. For example, we recover the the DNA double helix's structure in three-dimensions from its two dimensional X-ray fiber diffraction pattern, Photograph (Photo) 51, which was acquired in Raymond Gosling and Rosalind Franklin's famous experiment at a resolution of 3.4 A. PMID- 30469989 TI - Random laser model for Nd3+-doped powders and its application to stimulated emission cross-section calculations. AB - A new theoretical approach for random lasing of Nd3+doped powders is presented. The model's singularity lies in the fact that it proposes a probability distribution of the stimulated photon paths lengths in the sample, as well as a population inversion shared by different photon paths. The model's predictions satisfactorily compare with the results of laser threshold and absolute input/output energy slope of a real Random Laser. The main novel issue is that the best fit to the experimental results requires considering a high level of shared population inversion among different paths. The model simulation of local and spatially integrated Random Laser emissions, as well as their time evolution, is in accordance with the experimental behavior. These results also provide a new method of measuring the stimulated emission cross-section in this kind of random laser materials. PMID- 30469990 TI - Spectrally interleaved topologies using geometric phase metasurfaces. AB - Metasurfaces facilitate the interleaving of multiple topologies in an ultra-thin photonic system. Here, we report on the spectral interleaving of topological states of light using a geometric phase metasurface. We realize that a dielectric spectrally interleaved metasurface generates multiple interleaved vortex beams at different wavelengths. By harnessing the space-variant polarization manipulations that are enabled by the geometric phase mechanism, a vectorial vortex array is implemented. The presented interleaved topologies concept can greatly enhance the functionality of advanced microscopy and communication systems. PMID- 30469991 TI - Time-resolved high-harmonic spectroscopy of ultrafast photoisomerization dynamics. AB - We report the first time-resolved high-harmonic spectroscopy (TR-HHS) study of a chemical bond rearrangement. We investigate the transient change of the high harmonic signal from 1,3-cyclohexadiene (CHD), which undergoes ring-opening and isomerizes to 1,3,5-hexatriene (HT) upon photoexcitation. We associated the harmonic yield variation with the changes in the molecule's electronic state and vibrational frequencies, which are caused by isomerization. This showed us that the electronic excited state of CHD created through two-photon absorption of 3.1 eV photons relaxes almost completely within 100 fs to the electronic ground state of CHD with vibrational excitation. Subsequently, the molecule isomerizes to HT (i.e., ring-opening occurs, around 400 fs after the excitation). The present results demonstrate that TR-HHS, which can track both electronic and nuclear dynamics, is a powerful tool for studying ultrafast photochemical reactions. PMID- 30469992 TI - Approach for identifying optically shallow pixels when processing ocean-color imagery. AB - Ocean-color remote sensing is routinely used to derive marine geophysical parameters from sensor-observed spectral water-leaving radiances. However, in clear geometrically shallow regions, traditional ocean-color algorithms can be confounded by light reflected from the seafloor. Such regions are typically referred to as "optically shallow". When performing spatiotemporal analyses of ocean color datasets, optically shallow features such as submerged sand banks and coral reefs can lead to unexpected regional biases. Most contemporary approaches mask or flag suspected optically shallow pixels based on ancillary bathymetric data. However, the extent to which seafloor reflectance contaminates the water leaving radiance is dependent on bathymetry, water clarity and seafloor albedo. In this paper, an approach for flagging optically shallow pixels has been developed that considers all three of these variables. In the method, the optical depth of the water column at 547 nm, zeta(547), is predicted from bathymetric data and estimated water-column optical properties. If zeta(547) is less then the pre-defined threshold, a pixel is flagged as potentially optically shallow. Radiative transfer modeling was used to identify a conservative threshold value of zeta(547) = 20 for a bright sand seafloor. In addition, pixels in waters shallower than 5 m are also flagged. We also examined how varying bathymetric datasets may affect the optically shallow flag using MODIS data. It is anticipated that the optically shallow flag will benefit end-users when quality controlling derived ocean color products. Further, the flag may prove useful as a mechanism for switching between optically deep and shallow algorithms during ocean color processing. PMID- 30469993 TI - Suppression of parasitic interference in a fiber-tip Fabry-Perot interferometer for high-pressure measurements. AB - We demonstrate a novel design and fabrication process for fiber-tip Fabry-Perot interferometric (FTFPI) pressure sensors which eliminates fringe envelopes in the reflection spectrum. The outer facet reflectivity and thickness of the FTFPI silica diaphragm were reduced through orthogonal rough-polishing of the fiber end facet. A silica FTFPI sample with a diaphragm thickness of ~10.7 MUm was produced and tested under hydraulic pressures ranging from 0 to 30 MPa. The proposed sensor achieved a pressure sensitivity of -284 pm/MPa at 1555 nm and could be a valuable new tool for high pressure measurements. PMID- 30469994 TI - Single-shot aperture-scanning Fourier ptychography. AB - Aperture-scanning Fourier ptychography [Opt. Express22, 13586 (2014)] is a promising non-interferometric wavefront measurement technique. It eliminates the thin-sample requirement in typical Fourier ptychography employing angle-varying illumination. However, as aperture-scanning Fourier ptychography is based on step by-step scanning, it requires long data acquisition time and a high-stability optical system. In this paper, we propose a single-shot aperture-scanning Fourier ptychography method. In our method, multiple low-resolution images are collected in a single shot by inserting a Dammann grating at a certain distance before the aperture, and the images are subsequently converted to a high-resolution complex wavefront. Compared with scanning-based aperture-scanning Fourier ptychography, the total acquisition time of the proposed method is dramatically reduced. The feasibility of our proposed method is demonstrated by proof-of-concept experiments. PMID- 30469995 TI - Ultranarrow-band metagrating absorbers for sensing and modulation. AB - Nanostructured plasmonic metamaterials are an excellent platform for narrowband optical absorption, which has wide applications in sensing, filtering, modulation, and emission tailoring. However, achieving a subnanometer absorption bandwidth for optical sensing and dynamical control of light is still challenging. Here, we propose an asymmetric metagrating structure and make use of the propagating surface plasmonic mode that has a small dissipation rate, to achieve perfect optical absorption with a bandwidth of 0.28 nm near the wavelength of 1.55 MUm. Our proposed structure can be used in solution environments as a chemical or biological sensor in the visible spectral range just by changing the structural parameters. The sensor possesses a sensitivity of 440 nm/RIU and figure of merit of 1333.33 RIU-1. In addition, by combining an organic electro-optic material with this metagrating, our device can be reconfigurable with a dynamic range of 15.52 dB. Therefore, our proposed metagrating platform not only works as an ultranarrow-band absorber, but also can be employed for optical sensing and dynamic control of light. PMID- 30469996 TI - High tolerance against chirp induced distortions in PAM4-based digital mobile fronthaul by sample bits interleaving. AB - Directly modulated lasers (DMLs) and electro-absorption modulated lasers (EMLs) are key transmitter options in future short-haul networks. However, both of them suffer from frequency chirp, which incurs nonlinear distortions, especially to high order modulation signals. In this paper, we investigate their application in PAM4-based digital mobile fronthaul and propose a scheme to remarkably improve the fidelity of radio signal. We first give a detailed study of the BER distribution of DML/EML based PAM4 signals and find that the BER of the second bit is much higher than that of the first bit in both systems. Accordingly, we propose to adopt sample bit interleaving to reduce the radio signal distortions caused by sample bit errors. Experimental results of 56Gbps I/Q data transmission reveal that, in a DML-based transmission system, the proposed scheme respectively leads to up to 8dB and 13dB EVM reduction to accommodate 33 * 100MHz 1024QAM OFDM signals and 64QAM OFDM signals in 10km and 20km cases. As well as in an EML-based transmission system, 14dB EVM reduction is achieved in 10km to finally accommodate 33 * 100MHz 256QAM OFDM signal. PMID- 30469997 TI - 4 * 4 MIMO architecture supporting IFoF-based analog indoor distributed antenna system for 5G mobile communications. AB - We demonstrate the analog indoor distributed antenna system (DAS) for 5G mobile communications that supports 4 * 4 multiple-input multiple-output (MIMO) configuration. For this, we exploit a pair of intermediate frequency over fiber (IFoF)-based analog optical links, transporting 32 frequency allocation (FA) 5G mobile signals (effectively ~4 GHz bandwidth). The analog optical link manifests its high fidelity in the measured characteristics: small gain variation (< +/- 1 dB for the entire transmission bandwidth), low noise (<-136 dBm/Hz), and large dynamic range (spurious free dynamic range of >106 dB?Hz2/3), subsequently providing superior error vector magnitude (EVM) performance (~2%) for a wide range of ambient temperatures (-20 ~60 degrees C). Consequently, the IFoF-based 4 * 4 MIMO supporting analog indoor DAS is capable of providing record high peak throughput of 5.3 Gb/s for millimeter wave based 5G mobile communication system. PMID- 30469998 TI - Metasurface of deflection prism phases for generating non-diffracting optical vortex lattices. AB - A functional metasurface of both transparent medium slices and multiple deflection prisms is proposed, where phase retardations for generating non diffracting vortex lattices are integrated and encoded as rotation angles of nano apertures. Under plane-wave illumination, the transmitted waves from the thin flat metasurface act analogously as multiple beams, each with a designed propagating direction and pre-scribed phase shift, that generate an optical lattice within their overlapping region of space. By altering the design parameters of the metasurface, lattice type and size can be controlled. Both numerical simulations and experiments were conducted, verifying the possibility of the proposed method and the non-diffracting properties of the generated vortex lattices. PMID- 30469999 TI - Limiting efficiency of indoor silicon photovoltaic devices. AB - Energy harvesting from ambient light can be used to power wireless sensors and other standalone electronic devices. The intensity of light used for illumination is 300-3000x lower than sunlight and the spectrum of artificial light is normally narrowly concentrated in the visible range. As a result, the optimal design of photovoltaic devices for energy harvesting from ambient light differs from conventional solar cells. We calculate the maximum efficiency for Si photovoltaic devices operating under conditions expected indoors as a function of the cell thickness, taking into account the relevant properties of Si. The optimum thickness for devices operating under 250 lux illumination produced by white LED's is 1.8 um and the efficiency is 29.0%, whereas for direct sunlight, the optimum thickness is much larger at 109 um, while the maximum efficiency is almost the same (29.7%). The relative efficiency increases logarithmically with light intensity at 8.5% per decade. PMID- 30470000 TI - Azimuthal modulation of electromagnetically induced transparency using structured light. AB - Recently a scheme has been proposed for detection of the structured light by measuring the transmission of a vortex beam through a cloud of cold rubidium atoms with energy levels of the Lambda-type configuration [N. Radwell et al., Phys. Rev. Lett.114, 123603 (2015) ]. This enables observation of regions of spatially dependent electromagnetically induced transparency (EIT). Here we suggest another scenario for detection of the structured light by measuring the absorption profile of a weak nonvortex probe beam in a highly resonant five-level combined tripod and Lambda (CTL) atom-light coupling setup. We demonstrate that due to the closed-loop structure of CTL scheme, the absorption of the probe beam depends on the azimuthal angle and orbital angular momentum (OAM) of the control vortex beams. This feature is missing in simple Lambda or tripod schemes, as there is no loop in such atom-light couplings. One can identify different regions of spatially structured transparency through measuring the absorption of probe field under different configurations of structured control light. PMID- 30470001 TI - Performance of mode diversity reception of a polarization-division-multiplexed signal for free-space optical communication under atmospheric turbulence. AB - We investigated the performance of mode diversity reception of a polarization division-multiplexed (PDM) signal with few-mode-fiber (FMF) coupling for high speed free-space optical communications under atmospheric turbulence. Optical propagation through eigenmodes of a FMF yields coupling between different linearly polarized (LP) modes in orthogonal polarizations, which causes power imbalance and loss of the orthogonality of multiplexed signals within each individual LP mode. Due to this phenomenon, the architecture of mode diversity combining affects the receiver performance. We numerically simulated the power fluctuation coupled to each LP mode after atmospheric propagation and FMF propagation in the condition of an optical downlink from a low-Earth-orbital satellite to the ground. We found that full receiver-side multiple-input multiple output (Rx-MIMO) architecture in three-mode diversity reception improved the performance by 5 dB compared with selection combining (SC) of signals decoded individually in LP modes, and that it mitigated the required transmitted power by 6 dB compared with reception with single mode fiber (SMF) coupling. We also experimentally confirmed in three-mode diversity reception of a 128 Gb/s PDM quadrature phase-shift keying with a diffuser plate as a turbulence emulator, that full Rx-MIMO with adaptive filters could work under severe fading and that it outperformed SC. PMID- 30470002 TI - Probing bianisotropic biomolecules via a surface plasmon resonance sensor. AB - The transfer matrix method is developed to probe bianisotropic biomolecules via a Kretschmann configuration surface plasmon resonance (SPR) sensor. This method employs wave vectors and 4 * 4 transfer matrices derived by using anisotropic and magnetoelectric coupling constitutive relations. The transfer matrices relate four eigenstates and trace four transverse field components through the multilayer to account for cross-polarization coupling due to the chirality of the biomolecule layer. The validity of the method is confirmed by means of numerical results. It is shown that cross-polarized reflection waves are enhanced around the SPR angle, as the water solution and bianisotropic biomolecules to be detected are placed in contact with the graphene layer of the sensor. The effects of optical activity and bianisotropy on the SPR sensor are investigated. This work enriches the transfer matrix theory for SPR sensors to detect the chirality parameter of bianisotropic chiral material, and may lead to a better design of SPR sensors against the chirality parameter variation. PMID- 30470003 TI - Removing the dichroism and retardance artifacts in a collinear backscattering Mueller matrix imaging system. AB - In this paper we report a method for removing artifacts caused by the beam splitter in a collinear backscattering Mueller matrix (CBMM) imaging system. As an essential optical component in a collinear back reflection optical path, a 45epsilon6,rho8,delta10 beam splitter has to be used to separate the incident and the reflection beam. Since the beam splitter induces parasitic dichroism and retardance artifacts in both the illumination and detection optical paths, it leads to artifacts in the experimental results of Muller matrix measurements. We examined the influence of the beam splitter to the measured Mueller matrices in detail and reduced those artifacts in the CBMM system by precisely reconstructing the instrument matrix with a numerical calculation method. By measuring three standard samples we can calculate multiple systematic errors and the polarization characteristics of beam splitter in the CBMM system simultaneously. After the calibration, the maximum error in the Mueller matrix elements can be reduced to less than 0.02. PMID- 30470004 TI - All-polarization-maintaining dual-wavelength mode-locked fiber laser based on Sagnac loop filter. AB - We demonstrate an all polarization-maintaining (PM) fiber based dual-wavelength mode-locked Er-fiber laser. A nonlinear amplifying loop mirror (NALM) with an intracavity nonreciprocal phase shifter is used for self-started mode-locking. A short segment of PM fiber is angle-spliced to the NALM, functioning as a PM Sagnac loop filter, thus enabling dual-wavelength mode-locking. The wavelength separation is solely determined by the angle-spliced PM fiber length. Stable dual wavelength mode-locking operation is switchable between 1570/1581 nm and 1581/1594 nm. The two-color pulse trains oscillating in the same cavity have an inherent offset repetition rate of ~1 kHz owing to cavity dispersion, allowing future high precision dual-comb applications with a simple and robust configuration. PMID- 30470005 TI - Pulse length variation causing spectral distortions in OPO-based hyperspectral coherent Raman scattering microscopy. AB - Picosecond optical parametric oscillators (OPOs) with broad wavelength tunability are frequently used as light sources in hyperspectral coherent Raman scattering (CRS) microscopy. We investigate how changes in the pulse length during OPO wavelength tuning of the pump beam affect hyperspectral CRS imaging. We find that significant distortions of the resulting CRS spectra occur if the OPO is operated without monitoring pulse length variations. By utilizing a custom-written MATLAB based control program to counteract changes in pulse length, normalized and reproducible data sets can be acquired. We demonstrate this by comparing hyperspectral data obtained from pure substances, as well as relevant biological specimens. PMID- 30470006 TI - Automated precision alignment of optical components for hydroxide catalysis bonding. AB - We describe an interferometric system that can measure the alignment and separation of a polished face of a optical component and an adjacent polished surface. Accuracies achieved are ~ 1MUrad for the relative angles in two orthogonal directions and ~ 30MUm in separation. We describe the use of this readout system to automate the process of hydroxide catalysis bonding of a fused silica component to a fused-silica baseplate. The complete alignment and bonding sequence was typically achieved in a timescale of a few minutes, followed by an initial cure of 10 minutes. A series of bonds were performed using two fluids - a simple sodium hydroxide solution and a sodium hydroxide solution with some sodium silicate solution added. In each case we achieved final bonded component angular alignment within 10 MUrad and position in the critical direction within 4 MUm of the planned targets. The small movements of the component during the initial bonding and curing phases were monitored. The bonds made using the sodium silicate mixture achieved their final bonded alignment over a period of ~ 15 hours. Bonds using the simple sodium hydroxide solution achieved their final alignment in a much shorter time of a few minutes. The automated system promises to speed the manufacture of precision-aligned assemblies using hydroxide catalysis bonding by more than an order of magnitude over the more manual approach used to build the optical interferometer at the heart of the recent ESA LISA Pathfinder technology demonstrator mission. This novel approach will be key to the time-efficient and low-risk manufacture of the complex optical systems needed for the forthcoming ESA spaceborne gravitational waves observatory mission, provisionally named LISA. PMID- 30470007 TI - Spectral imaging based on 2D diffraction patterns and a regularization model. AB - We present a variational approach to reconstruct a multispectral image from an array of diffraction patterns captured in one monochromatic image. The mathematical model relies on the superposition of wavelength dependent calibration diffraction patterns and a spectral regularization with second order differences. The necessary preprocessing steps which influence the mathematical setting are discussed in detail. For computing a minimizer of our model we propose an active set method with model specific modifications. We validate our approach by experimental results for spectra within the range of 400 nm to 700 nm. PMID- 30470008 TI - Multi-vibration detection by probe pulses with ergodic SOPs in a POTDR system. AB - Polarization optical time domain reflectometers (POTDR) can detect vibration of fiber via the change of the state of polarization (SOP) of the Rayleigh backscattered light. For traditional POTDR systems, one key problem is the high misdiagnosis rate when multiple vibrations are simultaneously applied on the sensing fiber due to the random birefringence along the fiber. To solve this problem, we propose in this paper a novel implementation of the POTDR using probe pulses with ergodic SOPs. A series of vibration spectra along the fiber are obtained by sweeping the SOP of the probe pulse. The sum of these vibration spectra, which should be immune to the birefringence of the sensing fiber, is used to analyze the vibration information. Numerical simulation and experiments are carried out to analyze the performance of the proposed system when the input SOPs are traversed with uniform distribution and random distribution. Results show that the misdiagnosis rate of detecting multi-vibration with different frequencies is greatly reduced. In addition, detection of more-than-two vibrations with the same frequency based on POTDR is successfully performed for the first time to the best of our knowledge. PMID- 30470009 TI - Transparent and broadband absorption-diffusion-integrated low-scattering metamaterial by standing-up lattice. AB - In this paper, a transparent absorption-diffusion-integrated metamaterial (ADMM) based on standing-up lattice structure is proposed which takes full advantage of electromagnetic absorption and destructive interference simultaneously for the suppression of broadband backward scattering within a wide angular domain, especially for the lower-frequency scattering. The proposed ADMM is constituted by two kinds of rhombic and squared ITO lattices arranged in a pseudorandom distribution and then backed with ITO film. Calculation, simulation, and experimental measurement show that the proposed ADMM can achieve low scattering with normalized reflection less than 0.1 in the frequency band of 6.1-21.0GHz. In addition, owing to the standing-up lattice structure, the averaged optical transmittance of our ADMM reaches the optimal value of around 82.1% in the visible wavelength range of 380-780nm, promising an excellent optical transparency. The proposed comprehensive scheme provides an effective way to achieve broadband scattering suppression and high compatibility with optical transparency, enabling a wide range of applications in the window glass of stealth armament, electromagnetic compatibility facility and photovoltaic solar device. PMID- 30470010 TI - Solving thermal issues in tensile-strained Ge microdisks. AB - We propose to use Ge-dielectric-metal stacking to allow one to address both thermal management with the metal as an efficient heat sink and tensile strain engineering with the buried dielectric as a stressor layer. This scheme is particularly useful for the development of Ge-based optical sources. We demonstrate experimentally the relevance of this approach by comparing the optical response of tensile-strained Ge microdisks with an Al heat sink or an oxide pedestal. Photoluminescence indicates a much reduced temperature rise in the microdisk (16 K with Al pedestal against 200 K with SiO2 pedestal under a 9 mW continuous wave optical pumping). An excellent agreement is found with finite element modeling of the temperature rise. This original stacking combining metal and dielectrics is promising for integrated photonics where thermal management is an issue. PMID- 30470011 TI - Orthogonal polarization switchable lasing based on axial polarization pulling of SBS in polarization-maintaining fiber. AB - The axial polarization pulling, due to stimulated Brillouin scattering (SBS) in linear polarization maintaining fibers (PMFs), is proposed, simulated by vectored SBS equations, and demonstrated experimentally. The simulation shows that the SBS pulling is always towards one of principal axes of PMF, depending on the pump light projection of the input state of polarization (SOP) on the polarization vector of PMFs. Based on this principle, an SBS fiber laser with 20 m PMF is configured. Further, we observe that the SOP of lasing light switches between two orthogonal SOPs, as the pump light changes its SOP between two half spheres of the Poincare sphere. Moreover, the orthogonal polarization switching (OPS) scenarios relating to different powers and SOPs of pump light are studied. We analyze and experimentally demonstrate the lasing conditions for the fully polarized OPS state, where only one of the principal polarization modes resonates, as well as the depolarization state, where two principal polarization modes resonate simultaneously. PMID- 30470012 TI - Superior techniques for eliminating ring artifacts in X-ray micro-tomography. AB - Synchrotron-based X-ray micro-tomography systems often suffer severe ring artifacts in reconstructed images. In sinograms the artifacts appear as straight lines or stripe artifacts. These artifacts are caused by the irregular response of a detecting system giving rise to a variety of observed types of stripes: full stripes, partial stripes, fluctuating stripes, and unresponsive stripes. The use of pre-processing techniques such as distortion correction or phase retrieval blurs and enlarges these stripes. It is impossible for a single approach to remove all types of stripe artifacts. Here, we propose three techniques for tackling all of them. The proposed techniques are easy to implement; do not generate extra stripe artifacts and void-center artifacts; and give superior quality on challenging data sets and in comparison with other techniques. Implementations in Python and a challenging data set are available for download. PMID- 30470013 TI - Depth from defocus measurement method based on liquid crystal lens. AB - This paper describes a depth from defocus (DFD) method to recover the depth of scene from two images taken by a liquid crystal (LC) lens imaging system. The system is composed of a camera module and an LC lens. The system's focal length is electrically adjusted by the voltages that are applied on the LC lens. We use two images that are taken at maximum positive and negative, respectively, and the LC lens's optical power, to obtain the depth information via DFD. The principle is described and the experimental results are successfully obtained. The method is simple in that it needs not to involve any mechanical lens movements in the imaging system. PMID- 30470014 TI - Quantum frequency conversion for multiplexed entangled states generated from micro-ring silicon chip. AB - Silicon-on-chip photonic circuits are among some very promising platforms for generating nonclassical photonic quantum state, because of its low loss, small footprint, and compatibility with complementary metal-oxide-semiconductor (CMOS) and telecommunications techniques. Dense wavelength division multiplexing (DWDM) is a leading technique for enhancing the transmission capacity of both classical and quantum communications. To bridge the frequency gap between silicon-chip and other quantum systems, such as quantum memories, a quantum interface is indispensable. Here, we demonstrate a quantum interface for multiplexed energy time entanglement states, which are generated on a silicon micro-ring cavity that is based on frequency up-conversion. By switching the pump wavelength, energy time entanglement from any channel can be selected at will after being up converted. The high visibilities of two-photon interference over three channels after frequency up-conversion clearly prove that the entanglement is fully preserved during the quantum frequency conversion (QFC) process. Our work provides new perspectives regarding channel capacity enhancement in quantum communications and for quantum resources being transferred between two different quantum systems. PMID- 30470015 TI - Single-shot nanosecond-resolution multiframe passive imaging by multiplexed structured image capture. AB - The Multiplexed Structured Image Capture (MUSIC) technique is used to demonstrate single-shot multiframe passive imaging, with a nanosecond difference between the resulting images. This technique uses modulation of light from a scene before imaging, in order to encode the target's temporal evolution into spatial frequency shifts, each of which corresponds to a unique time and results in individual and distinct snapshots. The resulting images correspond to different effective imaging gate times, because of the optical path delays. Computer processing of the multiplexed single-shot image recovers the nanosecond resolution evolution. The MUSIC technique is used to demonstrate imaging of a laser-induced plasma. Simultaneous single-shot measurements of electron numbers by coherent microwave scattering were obtained and showed good agreement with MUSIC characterization. The MUSIC technique demonstrates spatial modulation of images used for passive imaging. This allows multiple frames to be stacked into a single image. This method could also pave the way for real-time imaging and characterization of ultrafast processes and visualization, as well as general tracking of fast objects. PMID- 30470016 TI - Cost-effective 400-Gbps micro-intradyne coherent receiver using optical butt coupling and FPCB wirings. AB - We present a cost-effective and bandwidth-enhanced 64-Gbaud micro-intradyne coherent receiver based on hybrid integration of InP waveguide-photodetector (WG PD) and silica planar lightwave circuit (PLC). InP waveguide-photodetector (WG PD) arrays are simply chip-to-chip bonded and optically butt-coupled to a silica based dual-polarization optical hybrid chip. Multiple flexible printed circuit boards are adapted for electrical RF and DC wirings, which provide low-cost integration and good RF performance of the receiver. A 3-dB bandwidth of the fabricated coherent receiver is extended to ~36 GHz by optimization of bondwire inductance between the WG-PD array and the transimpedance amplifier (TIA), even when commercial TIAs with a typical bandwidth of ~29 GHz are used. Through optimization of the silica hybrid integrated coherent receiver, 64-Gbaud DP-16QAM signal transmission over 1050-km standard single-mode fiber is successfully demonstrated below a bit error rate of 2 * 10-3. This is the threshold for a soft decision-based forward error correction, at the optical signal to noise ratio of 23.8 dB. PMID- 30470017 TI - Carrier-envelope offset frequency stabilization of a thin-disk laser oscillator operating in the strongly self-phase modulation broadened regime. AB - We demonstrate the carrier-envelope offset (CEO) frequency stabilization of a Kerr lens mode-locked Yb:Lu2O3 thin-disk laser oscillator operating in the strongly self-phase modulation (SPM) broadened regime. This novel approach allows overcoming the intrinsic gain bandwidth limit and is suited to support frequency combs from sub-100-fs pulse trains with very high output power. In this work, strong intra-oscillator SPM in the Kerr medium enables the optical spectrum of the oscillating pulse to exceed the bandwidth of the gain material Yb:Lu2O3 by a factor of two. This results in the direct generation of 50-fs pulses without the need for external pulse compression. The oscillator delivers an average power of 4.4 W at a repetition rate of 61 MHz. We investigated the cavity dynamics in this regime by characterizing the transfer function of the laser output power for pump power modulation, both in continuous-wave and mode-locked operations. The cavity dynamics in mode-locked operation limit the CEO modulation bandwidth to ~10 kHz. This value is sufficient to achieve a tight phase-lock of the CEO beat via active feedback to the pump current and yields a residual in-loop integrated CEO phase noise of 197 mrad integrated from 1 Hz to 1 MHz. PMID- 30470018 TI - 2.7 MUm dual-wavelength laser performance of LD end-pumped Er:YAP crystal. AB - We demonstrate a laser diode (LD) end-pumped Er:YAP laser with dual-wavelength outputs of 2710 and 2728 nm. The maximum average powers of 739 and 738 mW are achieved in the continuous wave (CW) and pulse modes, which corresponds to optical-to-optical efficiencies of 10.1% and 12.3%, and the slope efficiencies of 12.1% and 13.8%, respectively. In addition, a comparison of laser performance on differently sized crystals indicates that the 1 * 1 * 5 mm3 Er:YAP crystal has a best cooling efficiency. This helps to decrease the thermal lensing effect, which contributes to improving laser efficiency and beam quality. PMID- 30470019 TI - In situ real-time beam monitoring with dielectric meta-holograms. AB - A novel approach for performing in situ and real-time beam monitoring, based on dielectric meta-hologram, is proposed and demonstrated. The ultrathin dielectric meta-hologram projects a portion of the beam power onto a screen to provide a visual indicator of the spatial intensity distribution of a Gaussian laser beam, as well as its waist position along the optical axis. Specifically, we demonstrate simple monitoring of the spot size, astigmatism, lateral position, and position along the optical axis of the beam. Good agreement is found with both theory and conventional knife-edge beam profiler measurements. This in situ beam monitoring approach could provide a highly useful tool for numerous optical applications. PMID- 30470020 TI - Particle swarm optimization of nanoantenna-based infrared detectors. AB - The multi-resonant response of three-steps tapered dipole nano-antennas, coupled to a resistive and fast micro-bolometer, is investigated for the efficient sensing in the infrared band. The proposed devices are designed to operate at 10.6 MUm, regime where the complex refractive index of metals becomes important, in contrast to the visible counterpart, and where a full parametric analysis is performed. By using a particle swarm algorithm (PSO) the geometry was adjusted to match the impedance between the nanoantenna and the micro-bolometer, reducing the return losses by a factor of 650%. This technique is compared to standards matching techniques based on transmission lines, showing better accuracy. Tapered dipoles therefore open the route towards an efficient energy transfer between load elements and resonant nanoantennas. PMID- 30470021 TI - Measurement of ultrafast combustion process of premixed ethylene/oxygen flames in narrow channel with digital holographic interferometry. AB - The premixed ethylene and oxygen flame that is burning in a narrow channel is investigated with digital holographic interferometry (DHI). Combustion in either a narrow tube or channel is quite different. This is caused by the significant effects of the boundary layer. The flame's acceleration rate will be enhanced as the tube diameter decreases. Usually, flame and shock wave propagation, which occurs during the premixed ethylene/oxygen flame combustion in the measurement area, is less than few milliseconds, so that general camera can rarely capture this fast event. This paper demonstrates that, by introducing the high-speed camera to DHI, the propagation of weak compression wave, flame, and shock wave generated in the narrow channel is successfully measured with a temporal resolution of 10 MUs. The ultrafast processes of the flame front changing, as well as the shock wave coupling and separating, are clearly shown from the reconstructed phase distributions of the recorded holograms; corresponding density variations are simultaneously calculated. The results could provide references for the micro-scale propulsion and power devices design and use, and this proposed configuration can also easily adapt to other kinds of ultrafast processes in fluids. PMID- 30470022 TI - High-resolution additive light field near-eye display by switchable Pancharatnam Berry phase lenses: errata. AB - We correct a typo in the system parameter. The size of monocular eyebox is corrected to be 16mm (W) by 16mm (H). PMID- 30470023 TI - Study of W/HfO2 grating selective thermal emitters for thermophotovoltaic applications. AB - This paper explores the performance potential of gratings based on tungsten/hafnia (W/HfO2) stacks for thermophotovoltaic thermal emitters via numerical simulations. Structures consisting of a W grating over a HfO2 spacer layer and a W substrate are analyzed over a range of geometries. For shallow gratings (W grating thickness much smaller than the grating pitch), an emittance of 99.9% can be achieved for transverse magnetic (TM) polarization, but the transverse electric (TE) performance is appreciably lower. For deep gratings (W grating thickness on the order of the grating pitch), peak emittances of 97.8% and 99.7% for TE and TM polarizations, respectively, are achieved. We find that both surface plasmon polaritons and magnetic polaritons play a crucial role in shaping the emittance for TM radiation. On the other hand, cavity resonances are responsible for the almost perfect emittance in the case of TE polarization. These results suggest that by introducing an HfO2 layer it is possible to reach high emittance for operating temperatures that match the absorption characteristics of GaSb and InGaAs photovoltaic cells. PMID- 30470024 TI - Field stitching approach for the wave optical modeling of black silicon structures. AB - The interest in black silicon structures as an anti-reflective interface at the front side of silicon solar cells increased strongly with the rise of diamond wire sawing. The application of optical modeling in order to predict optimal structure parameters could be highly valuable. However, due to the random nature of the structure as well as dimensions in the range of the wavelengths of interest, optical modeling is still a challenge. Within this work, the stitching method of rigorously calculated fields is extended and applied to a black silicon structure. A Fourier transform is used to determine the angular intensity distribution in the far field. In combination with the OPTOS formalism, this allows modeling of silicon substrates with black silicon front side and shows a reasonably good agreement with optical measurement results. Implementing the investigated structure into a solar cell configuration reveals not only a low reflectance but also a very good light trapping performance close to that of a Lambertian scatterer. PMID- 30470025 TI - Roles of polarization effects in InGaN/GaN solar cells and comparison of p-i-n and n-i-p structures. AB - The p-i-n and n-i-p InGaN/GaN solar cells (SCs) with Ga-face and N-face under different Indium composition were investigated and compared. From the charge distribution analysis, it can be deduced that if p-i-n was converted to n-i-p and the polarity of the SC was reversed simultaneously, or vice versa, the role of polarization effect (i.e. whether hinder or facilitate the photon-generated carriers transport) for the two SC structures would be resembling, though they had difference in degrees. The SC performance, energy band diagram at zero bias condition, recombination rate distribution and carrier concentration distribution of these SCs were analyzed, which suggested that although the polarization effect could facilitate the carrier transport both in p-i-n N-face SC and n-i-p Ga-face SC, the p-i-n N-face SC was apt to have better performance more or less if the barrier induced by band-offset at the hetero-interface would not block the carrier transport dominantly, e.g. when Indium content was less than or equal to 0.3. Besides, the high Indium content would result in the high band-offset barrier, and the barrier would affect the carrier transport in two ways, one was to hamper the carrier transport directly, and the other was to influence the electric field in i-region indirectly. PMID- 30470026 TI - Theoretical comparison of the excitation efficiency of waveguide and surface plasmon modes between quantum-mechanical and electromagnetic optical models of organic light-emitting diodes. AB - We theoretically compare the excitation efficiency of waveguide and surface plasmon modes between quantum-mechanical and classical electromagnetic optical models of organic light-emitting diodes (OLEDs). A sophisticated optical model combining the two approaches is required to obtain an accurate calculation result and a comprehensive understanding of the micro-cavity effect in OLEDs. In the quantum-mechanical approach based on the Fermi's golden rule, the mode expansion method is used to calculate the excitation efficiency. In the classical electromagnetic approach, the spectral power density calculated by the point dipole model is fitted by the summation of the Lorentzian line shape functions, which provide the excitation probability of each waveguide and surface plasmon modes. The mode coupling efficiencies on the basis of the two approaches are calculated in a bottom-emitting OLED when the position of a dipole emitter is varied. By comparing the calculation results, we confirm the equivalence of two approaches and obtain the better optical interpretation to the calculated excitation efficiency of waveguide and surface plasmon modes. The ratio of mode excitation efficiencies calculated by two approaches agrees well with each other except the contribution of the near-field absorption component. PMID- 30470027 TI - Photodarkening-resistance improvement of Yb3+/Al3+ co-doped silica fibers fabricated via sol-gel method. AB - Yb3+/Al3+ co-doped silica fibers (YDFs) with almost identical core glass compositions were prepared using the sol-gel and modified chemical vapor deposition (MCVD) methods. The photodarkening (PD) and laser performance before and after the PD process were tested under 974 nm pumping. The doping homogeneity of Yb3+ ions and clusters of Yb3+ ions in preform slices of these two fibers were investigated via optical absorption spectroscopy, photoluminescence emission spectra, electron probe microanalysis (EPMA), and low-temperature (4 K) electron paramagnetic resonance (EPR). It is known that the PD resistance of YDFs prepared via the sol-gel method is significantly better than that of YDFs prepared via MCVD under the same test conditions. EPMA mapping reveals that the doping homogeneity of Yb3+ ions in the sol-gel fiber core glass is better than that in the MCVD fiber. The low-temperature (4 K) EPR and cooperative luminescence spectra of Yb3+ ions indicate that the clustering degree of Yb3+ ions in the sol gel fiber is lower than that in the MCVD fiber. In the absorption and emission spectra, small amounts of Yb2+ ions are observed in the preform slice from the sol-gel method. A model of the color-center generation in the PD process was proposed to explain the mechanism of PD resistance improvement for the YDFs fabricated via the sol-gel method. PMID- 30470028 TI - Wave optic modeling of semi-transparent textured curved surfaces. AB - Lightwave propagation through a multilayer structure of patterned semi transparent curved surfaces is a fundamental issue for various display applications from practical industrial problems such as moire pattern strain in touch panel displays to fundamental research issues in layered tensor displays and layered complex modulation holographic displays. In this paper, a wave optic modeling of multiple layers of patterned semi-transparent curved surfaces is presented. The proposed wave optic modeling is based on the algorithmic framework used in the field of polygon computer-generated holograms, a framework which can additionally devise the characteristic transmittance function of textured curved surfaces. To present an industrial application, the proposed modeling method is used to numerically simulate the visual perception of the moire patterns observed in the layered structures of transparent phase-only patterned curved surfaces and their diverse variations with a change in observation angle. PMID- 30470029 TI - Flat metasurfaces to collimate electromagnetic waves with high efficiency. AB - Directional beaming of electromagnetic waves passing through a subwavelength aperture has attracted considerable interests in photonics, but the traditional approach of utilizing gratings to directionally couple surface waves (SWs) to a desired far-field direction faces the low-efficiency issue owing to high-order diffractions. Here we experimentally demonstrate that directional beaming of light can be realized with very high efficiencies, in which two specifically designed metasurfaces (MTSs) are placed at two sides of the aperture to serve as SW to propagating-wave meta-couplers. Different from the grating couplers, the well-designed phase-gradient meta-couplers can freely select the desired diffraction orders by suppressing the undesired diffraction orders. We design and fabricate MTSs with different phase gradients, and perform both far-field and near-field measurements to verify the predicted high-efficiency on/off-axis directional beaming effects. Experimental results are in good agreement with full wave simulations and theoretical analyses. PMID- 30470030 TI - Accurate three dimensional body scanning system based on structured light. AB - Three dimensional (3D) body scanning has been of great interest to many fields, yet it is still a challenge to generate accurate human body models in a convenient manner. In this paper, we present an accurate 3D body scanning system based on structured light technology. A four-step phase shifting combined with Gray-code method is applied to match pixels in camera and projector planes. The calculation of 3D point coordinates are also derived. The main contribution of this paper is twofold. First, an improved registration algorithm is proposed to align point clouds reconstructed from different views. Second, we propose a graph optimization algorithm to further minimize registration errors. Experimental results demonstrate that our system can produce accurate 3D body models conveniently. PMID- 30470031 TI - Experimental investigation on multiple breakdown in water induced by focused nanosecond laser. AB - Multiple breakdowns in liquids still remains obscure for its complex, non equilibrium and transient dynamic process. We introduced three methods, namely, plasma imaging, light-scattering technique, and acoustic detection, to measure the multiple breakdown in water induced by focused nanosecond laser pulses simultaneously. Our results showed that linear dependence existed among the cavitation-bubble lifetime, the far-field peak pressure of the initial shock wave, and the corresponding plasma volume. Such a relationship can be used to evaluate the ideal size and energy of each bubble during multiple breakdown. The major bubble lifetime was hardly affected by the inevitable coalescence of cavitation bubbles, thereby confirming the availability of light-scattering technique on the estimation of bubble size during multiple breakdown. Whereas, the strength of collapse-shock-wave and the subsequent rebound of bubbles was strongly influenced, i.e., the occurrence of multiple breakdown suppressed the cavitation-bubble energy being converted into collapse-shock-wave energy but enhanced conversion into rebound-bubble energy. This study is a valuable contribution to research on the rapid mixing of microfluidics, damage control of microsurgery, and photoacoustic applications. PMID- 30470032 TI - Spatial multiplexing and autofocus in holographic contouring for inspection of micro-parts. AB - We present a method for fast geometrical inspection of micro deep drawing parts. It is based on single-shot two-wavelength contouring digital holographic microscopy (DHM). Within the capturing process, spatial multiplexing is utilized in order to record the two required holograms in a single-shot. For fast evaluation, determining the locations where the object is in focus and stitching all focus object's areas together is achieved digitally without the need for any external intervention using an autofocus algorithm. Thus, the limited depth of focus of the microscope objective is improved. The autofocus algorithm is based on minimizing the total variation (TV) of phase difference residuals of the two wavelength measurements. In contrast to standard DHM, an object side telecentric microscope objective is used for overcoming the image scaling distortions caused by a conventional microscope objective. The method is used to reconstruct the 3D geometrical shape of a cold drawing micro cup. Experimental results verify the improvement of DHM's depth of focus. PMID- 30470033 TI - Polarization patterns under different sky conditions and a navigation method based on the symmetry of the AOP map of skylight. AB - The polarization states of a skylight can be used for navigation by a lot of insects as well as by human beings. However, the polarization patterns of skylight are greatly influenced by the atmospheric conditions. This paper studied the polarization patterns of skylight under different sky conditions by polarized imaging measurements, in which the AOT (Aerosol Optical Thickness) and clouds were taken into account. The results showed that both the aerosol and cloud disturbed the polarization patterns of the skylight, but the patterns of AOP (Angle of Polarization) showed great robustness. The symmetry of the AOP images was found to be quite steady under most of the sky conditions. We proposed a navigation method by finding out the solar meridian according to the symmetry of an AOP map. The results showed that the solar meridian can be identified accurately under different situations. The calculation errors slightly fluctuated along with the aerosol and cloud. PMID- 30470034 TI - Using a passively stable attosecond beamline for relative photoemission time delays at high XUV photon energies. AB - We present and demonstrate an experimental scheme that enables overlap-free reconstruction of attosecond beating by interference of two-photon transitions (RABBITT) measurements at high extreme-ultraviolet (XUV) photon energies. A compact passively-stabilized attosecond beamline employing a multilayer (ML) mirror allows us to obtain XUV pulses consisting of only two odd high-harmonic orders from an attosecond pulse train (APT). We compare our new technique to existing schemes that are used to perform RABBITT measurements and discuss how our scheme resolves the limitations imposed by spectral complexity of the harmonic comb at high photon energies. We further demonstrate first applications of our scheme for rare gases and gas mixtures, and show that this scheme can be extended to gas-molecule mixtures. PMID- 30470035 TI - Laser frequency stabilization and spectroscopy at 2051 nm using a compact CO2 filled Kagome hollow core fiber gas-cell system. AB - We describe a compact, all fiber, frequency stabilized diode laser system at 2051 nm using CO2 gas-filled Kagome Hollow Core Fiber (HCF), capable of tuning continuously over four transitions in 12C16O2: R(24), R(26), R(28), and R(30). This laser system has been designed for use in future space-based atmospheric monitoring using differential absorption lidar (DIAL). The fully spliced Kagome HCF gas cell is filled to 2 kPa CO2 partial pressure and we compare the observed CO2 lineshape features with those calculated using HITRAN, to quantify the properties of the CO2-filled fiber cell. In this first demonstration of Kagome HCF used in a fully sealed gas cell configuration for spectroscopy at 2 um, we characterize the frequency stability of the locked system by beat frequency comparison against a reference laser. Results are presented for the laser locked to the center of the 12C16O2 R(30) transition, with frequency stability of ~40 kHz or better at 1 s, and a frequency reproducibility at the 0.4-MHz level over a period of > 1 month. For DIAL applications, we also demonstrate two methods of stabilizing the laser frequency ~3 GHz from this line. Furthermore, no pressure degradation was observed during the ~15-month period in which frequency stability measurements were acquired. PMID- 30470036 TI - Improved angular color uniformity and hydrothermal reliability of phosphor converted white light-emitting diodes by using phosphor sedimentation. AB - We investigated the effect of phosphor deposition methods on the correlated color temperature (CCT), luminous flux and thermal characteristics of packaged white light-emitting diodes (WLEDs) for use in mobile display products. For both the samples, the CCT decreased with increasing viewing angle. Phosphor sedimentation samples displayed much better angular color uniformity than phosphor dispersion samples. The phosphor sedimentation sample had higher luminous flux and luminous efficacy at 20 mA than the phosphor dispersion sample. The phosphor sedimentation sample displayed much better high-temperature/humidity (85 degrees C/85%) reliability and lower package temperatures compared with the phosphor dispersion sample. PMID- 30470037 TI - Mode partition noise mitigation for VCSEL-MMF links by using wavefront shaping technique. AB - In this paper, we propose a new method to mitigate the mode partition noise (MPN) in VCSEL-MMF based links by using wavefront shaping technique. The noise characteristic of the VCSEL-MMF links is theoretically studied and the impacts of coupling coefficients between VCSEL and MMF on the MPN and the system performance are investigated via simulation and experiment. The simulation results show that for 25-Gb/s OOK signal after 300-m MMF transmission, five orders of magnitude improvement of BER can be observed and the standard deviation of the received signal, which is the characterization of the MPN, is reduced for about an order when wavefront shaping is applied. With the help of wavefront shaping, we show that the DSP complexity has been profoundly reduced in order to achieve reliable 56-Gb/s and 112-Gb/s PAM-4 transmission by simulation. We perform experiment for 25-Gb/s OOK signal transmission over 300-m OM3 MMF with the launching optical power of -4 dBm to the fiber. About 1-dB power penalty improvement has been achieved at 7% FEC threshold after 300-m MMF transmission and the noise in the eye diagram is mitigated. The results of our simulation and experiment show the effectiveness of wavefront shaping to mitigate the MPN, therefore reduce the DSP complexity and improve transmission performance for the VCSEL and MMF based high speed short reach optical interconnects. PMID- 30470038 TI - Athermal echelle grating filter in silicon-on-insulator using a temperature synchronized input. AB - Athermal design of integrated photonic devices can reduce the need for active temperature stabilization and consequently the energy required to operate photonic integrated circuits. For silicon photonic filters such as AWGs which employ wire or ridge waveguides, temperature insensitivity can be achieved using cladding materials with negative thermo-optic coefficients. On the other hand, in echelle grating filters the inteference takes place in the slab free-propagation region, and therefore the modal overlap with the cladding is small, rendering this method ineffective. In this work we present an approach to design an athermal echelle grating filter exploiting a temperature-synchronized Mach Zehnder interferometer as input. This reduces the spectral shift over a temperature range of 20 K to less than +/-45 pm compared to the 1.6 nm shift for the same echelle grating with a conventional waveguide input. Furthermore, the proposed design relies exclusively on a standard fabrication process for silicon on-insulator photonic devices and exhibits a good tolerance to fabrication uncertainties. PMID- 30470039 TI - Diagnosis of nasopharyngeal carcinoma from serum samples using hyperspectral imaging combined with a chemometric method. AB - Diagnosing nasopharyngeal carcinoma (NPC) is a significant challenge because of the highly complex process. We proposed an approach to diagnose NPC serum using a combination of hyperspectral imaging and weight-based principal component analysis. Samples were prepared by pressing boric acid into pellets for use as the sera substrate. The sera, collected from 100 healthy volunteers and 60 NPC patients, was dripped onto the surface of the substrate for hyperspectral imaging. The characteristic spectral bands were selected based on the variable weight obtained from a support vector machine (SVM) model, using principal component analysis (PCA) to reduce the dimension in the extracted bands. Obtained results show that the accuracy rate, sensitivity, and specificity between the NPC sera and the sera of the healthy controls reached extremely high levels of 99.15%, 98.79%, and 99.36%, respectively. For the model's consistency evaluation, we found that the Kappa and area under the curve (AUC) of the receiver operating characteristic (ROC) curve were 0.99 and 0.98, respectively. These results suggest that the developed approach could serve as a noninvasive diagnostic and screening tool for highly accurate and consistent detection of NPC. Hence, a combination of hyperspectral imaging (HSI) and a weighted principal component analysis (WPCA)-SVM model represents a powerful and promising tool for NPC diagnosis. PMID- 30470040 TI - Strain dependence of photoluminescence and circular dichroism in transition metal dichalcogenides: a k . p analysis. AB - Within a two-band k . p method we analyze different types of strain for the K valley optical characteristics of a freestanding monolayer MoS2, MoSe2, WS2 and WSe2. We predict that circular polarization selectivity for energies above the direct transition onset deteriorates/improves by tensile/compressive strain. Wide range of available strained-sample photoluminescence data can be reasonably reproduced by this simple bandstructure combined with accounting for excitons at a variational level. According to this model strain impacts optoelectronic properties through its hydrostatic component, whereas the shear strain only causes a rigid wavevector shift of the valley. Furthermore, under the stress loading of flexible substrates the presence of Poisson's effect or the lack of it are examined individually for the reported measurements. PMID- 30470041 TI - Acousto-optic modulation detection method in an all-optical K-Rb hybrid atomic magnetometer using uniform design method. AB - An acousto-optic modulation (AOM) detection method is demonstrated to detect the atomic Larmor precession frequency in an all-optical K-Rb atomic magnetometer operated in Spin-Exchange Relaxation Free (SERF) regime. Magnetic field sensitivity of 14 fT/Hz1/2 was achieved by employing the uniform design (UD) [Acta Math Appl Sin.3, 363 (1980)] and subsequently optimizing the AOM modulation conditions. Results were compared to those of Faraday and the balanced polarimetry method in the same magnetometer. The AOM detection method has several advantages, such as small volume, no extra magnetic shielding for the modulator, high measurement signal-to-noise ratio and stability. It has a good prospect for compact and multi-channel atomic magnetometers. PMID- 30470042 TI - Do EnChroma glasses improve color vision for colorblind subjects? AB - The commercialization of EnChroma glasses has generated great expectations for people to be able to see new colors or even correct color vision deficiency (CVD). We evaluate the effectiveness of these glasses using two complementary strategies for the first time. The first consists of using the three classical types of tests - recognition, arrangement and discrimination - with and without glasses, with a high number of individuals. In the second, we use the spectral transmittance of the glasses to simulate the appearance of stimuli in a set of scenes for normal observers and observers with CVD. The results show that the glasses introduce a variation of the perceived color, but neither improve results in the diagnosis tests nor allow the observers with CVD to have a more normal color vision. PMID- 30470043 TI - Proposal of novel structure for wide wavelength tuning in distributed Bragg reflector laser diode with single grating mirror. AB - We report a novel structure that is capable of wide wavelength tuning in the distributed Bragg reflector laser diode (DBR-LD) with a single grating mirror. This device's DBR section has two tuning elements, plasma, and heater tunings, which are implemented simultaneously on the top of a single waveguide by using an in-between dielectric layer. For the proposed structure, a three-dimensional thermal simulation was conducted. The results showed that the temperature profile within the waveguide is highly affected by the position of heater metal and thermal conductivity of the p-cladding layer. As a result, it is important to use a uniform temperature region in the DBR section for a wide tuning range and stable single-mode operation. For a 550-MUm long DBR-LD with a 250-MUm long DBR section, a tuning range of 26 nm (i.e., 7 nm for plasma tuning and 19 nm for heater tuning); an SMSR of more than 45 dB; and a peak power variation of less than +/- 2.5 dB were obtained. From the comparisons of two DBR-LDs with only one tuning element, we confirmed that using the dielectric layer is a very effective way of achieving a wide tuning under the independent tuning operation. PMID- 30470044 TI - SOON: self-optimizing optical networks with machine learning. AB - As optical networks undergo rapid development, the trade-offs among higher network service capability, and increasing operating expense (OPEX) about operations, administration and maintenance (OAM) become telecom operators' key obstacles. Intelligent and automatic OAM is considered to effectively satisfy service requirements, while dampening OPEX growth. In particular, machine learning (ML) has been investigated as a possible method of replacing human image recognition, nature language processing, automatic drive, and so forth. This is because of its essential feature extraction ability. ML application in optical networks was studied in a preliminary way recently. In ML-enabled optical networks, huge data storage and powerful computing resources are required to handle computer-intensive tasks performed in order to analyze features from big data sets. Integration of these two key resources into existing optical network architectures, in order to improve network performance, is an emerging challenge for ML-enabled optical networks. This article proposes a novel optical network architecture, which is based on software-defined networking (SDN), which is also named self-optimizing optical networks (SOON). First, we comb through intelligence development of optical networks, and introduce SOON as an OAM oriented optical network architecture. Second, we demonstrate four typical applications within SOON, including tidal traffic prediction, alarm prediction, anomaly action detection, and routing and wavelength assignment. Finally, we discuss some open issues. PMID- 30470045 TI - Generation of Bessel beam sources in FDTD. AB - In this paper, a straightforward approach is presented to generate Bessel beam sources in three-dimensional finite-difference time-domain (FDTD) method. Based on the angular spectrum representation (ASR), the incident Bessel beam is described as a superposition of plane waves whose wavevectors covering a conical surface. This decomposition of Bessel beam is then approximated by a finite collection of plane waves, which are injected into FDTD simulation domain using the total-field/scattered-field (TF/ST) method. The present method's correctness and accuracy are verified by comparing the reconstructed field in FDTD with the original field. Far-field scattered diagrams of a dielectric sphere and a spheroid particle illuminated by a zero-order or a higher-order Bessel beam are calculated using FDTD. The results are compared with those calculated using the generalized Lorenz-Mie theory (GLMT) and surface integral equation method (SIEM). Very good agreements have been achieved, which partially indicate the correctness of our method. Internal and near-surface field distributions for a two-layer hemisphere particle, which are illuminated by Bessel beams, are also displayed to show the potentials of this approach in solving scattering problems of complex particles. This approach can also be applied to generate other structured beam sources in FDTD, which provides an access to solve structured beam scattering by complex particles using FDTD. PMID- 30470046 TI - Mechanical modulation of terahertz wave via buckled carbon nanotube sheets. AB - Manipulation of terahertz (THz) wave plays an important role in THz imaging, communication, and detection. The difficulty in manipulating the THz wave includes single function, untunable, and inconvenient integration. Here, we present a mechanically tunable THz polarizer by using stretchable buckled carbon nanotube sheets on natural rubber substrate (BCNTS/rubber). The transmittance and degree of polarization of THz wave can be modulated by stretching the BCNTS/rubber. The experiments showed that the degree of polarization increased from 17% to 97%, and the modulation depth reached 365% in the range of 0.2-1.2 THz, as the BCNTS/rubber was stretched from 0% to 150% strain. These changes can be also used for high strain sensing up to 150% strain, with a maximum sensitivity of 2.5 M/S. A spatial modulation of THz imaging was also realized by stretching and rotating BCNTS/rubber. The theoretical analysis and numerical modeling further confirm the BCNTS/rubber changes from weak anisotropic to highly anisotropic structure, which play key roles in THz wave modulation. This approach for active THz wave manipulation can be widely used in polarization imaging, wearable material for security, and highly sensitive strain sensing. PMID- 30470047 TI - In situobservation of dynamic pitch jumps of in-planar cholesteric liquid crystal layers based on wavelength-swept laser. AB - We report in situ observation of dynamic pitch jumps in cholesteric liquid crystal (CLC) layers that depend on the applied electric field. A high-speed and wide bandwidth wavelength-swept laser is used as an optical broadband source to measure the dynamic pitch jumps. We could not observe the dynamic pitch jump in the quasi-static pitch variation. Instead, we carry out two driving methods, a normal driving and an overdriving method, in order to measure the dynamic pitch jump in the CLC cell. For the case of normal driving, it has been confirmed that the reflection band from the measurement region is discontinuously shifted by movement of the defect wall. The reflection band was compressed and recovered before the band moved, but the dynamic pitch jump of the helix could not be observed. For the case of overdriving, however, it was possible to observe the unwinding of the helix during the dynamic pitch jump. The entire dynamic pitch jump process in the CLC cell could be observed by measuring the transmission spectra from the CLC cell by varying the applied electric field. We confirm that the entire reaction time with the overdriving method was about 800 ms, which was shorter than with the normal driving method. This study contributes to the development of fast in-plane switching research and the development of new CLC devices. PMID- 30470048 TI - Ultra-highly sensitive gas pressure sensor based on dual side-hole fiber interferometers with Vernier effect. AB - We have presented and demonstrated a fiber optic gas pressure sensor with ultra high sensitivity based on Vernier effect. The sensor is composed of two integrated parallel Mach-Zehnder interferometers (MZIs) which are fabricated by fusion splicing a short section of dual side-hole fiber (DSHF) in between two short pieces of multimode fibers (MMFs). Femtosecond laser is applied for cutting off part of the MMF and drilling openings on one air hole of the DSHF to achieve magnified gas pressure measurement by Vernier effect. Experimental results show that the gas pressure sensitivity can be enhanced to about -60 nm/MPa in the range of 0-0.8 MPa. In addition, the structure possesses a low temperature cross sensitivity of about 0.55 KPa/ degrees C. This presented sensor has practically value in gas pressure detection, environmental monitoring and other industrial applications. PMID- 30470049 TI - High positional freedom SOI subwavelength grating coupler (SWG) for 300 mm foundry fabrication. AB - We present an apodized, single etch-step, subwavelength grating (SWG) high positional freedom (HPF) grating coupler based on the 220 nm silicon-on-insulator (SOI) with 2MUm BOX substrate. The grating coupler was designed for 1550 nm light with transverse electric (TE) polarization. It has a measured maximum coupling efficiency of -7.49 dB (17.8%) and a -1 dB/-3 dB bandwidth of ~14 nm/29.5 nm respectively. It was fabricated in a 300mm state of the art CMOS foundry. This work presents an SOI-based grating coupler with the highest-to the best of our knowledge- -1 dB single mode fiber lateral alignment of 21.4 MUm * 10.1 MUm. PMID- 30470050 TI - Distributed multi-parameter sensing utilizing Brillouin frequency shifts contributed by multiple acoustic modes in SSMF. AB - A multi-parameter optical-fiber sensor, which is based on multiple acoustic modes in stimulated Brillouin scattering (SBS) effect, for distributed measurement of temperature and strain utilizing standard single-mode fiber (SSMF) is proposed and experimentally demonstrated. By manipulating doping level and refractive index profile of the fiber, the properties of Brillouin gain spectrum (BGS) related to the guided optical and acoustic modes are analyzed. The simulated results indicate that multiple acoustic modes can be excited in single-mode fiber (SMF) and the BGS is composed of multiple peaks corresponding to multiple acoustic modes. Moreover, the temperature and strain sensitivities of different acoustic modes are unequal and the capability of discriminative measurement between temperature and strain can be proved. Simultaneously, the mode field diameter, the dispersion parameter, and the cutoff wavelength are calculated and the results show that parts of SSMF can be used for multi-parameter measurement. However, the accuracy of measurement is varied with the fiber structure parameters. Consequently, in experimental section, two different SSMFs are put into test and both have multiple-peak BGSs although the BGSs show a great difference to each other. The discrimination of temperature and strain is successfully demonstrated by analyzing the coefficients of the Brillouin frequency shifts introduced by different acoustic modes. In the fiber which has a better measurement result, the sensitivities of the fundamental acoustic mode are 1.19 MHz/ degrees C and 62.28 kHz/MUepsilon with an accuracy of 0.98 degrees C and 19.6 MUepsilon in 20 km sensing range. PMID- 30470051 TI - Two-photon lensless micro-endoscopy with in-situ wavefront correction. AB - Multi-core fiber-bundle endoscopes provide a minimally-invasive solution for deep tissue imaging and opto-genetic stimulation, at depths beyond the reach of conventional microscopes. Recently, wavefront-shaping has enabled lensless bundle based micro-endoscopy by correcting the wavefront distortions induced by core-to core inhomogeneities. However, current wavefront-shaping solutions require access to the fiber distal end for determining the bend-sensitive wavefront-correction. Here, we show that it is possible to determine the wavefront correction in-situ, without any distal access. Exploiting the nonlinearity of two-photon excited fluorescence, we adaptively determine the wavefront correction in-situ using only proximal detection of epi-detected fluorescence. We experimentally demonstrate diffraction-limited, three-dimensional, two-photon lensless microendoscopy with commercially-available ordered- and disordered multi-core fiber bundles. PMID- 30470052 TI - Ultrafast switching of optical singularity eigenstates with compact integrable liquid crystal structures. AB - By using the strong nonlinear effect and ultrafast electronic response of cholesteric liquid crystals (CLC), ultrafast all optical switching between polarization vortex and phase vortex is realized in a system combining CLC and q plate. The experimental result shows that switching with high modulation depth can be accomplished in less than 1 picosecond. Furthermore, CLC and q-plates will enable compact integrated devices with sub-mm thicknesses. PMID- 30470053 TI - Periodically poled ridge waveguides in KTP for second harmonic generation in the UV regime. AB - Waveguide circuits play a key role in modern integrated optics and provide an appealing approach to scalability in quantum optics. We report on periodically poled ridge waveguides in z-cut potassium titanyl phosphate (KTiOPO4 or KTP), a material that has recently received growing interest due to its unique dispersion properties. Ridges were defined in surface-near rubidium-exchanged KTP by use of a precise diamond-blade dicing saw. We fabricated single-mode ridge waveguides at around 800 nm which exhibit widths of 1.9-3.2 MUm and facilitated type-II second harmonic generation from 792 nm to 396 nm with high efficiency of 6.6 %/W.cm2. Temperature dependence of the second harmonic process was found to be 53 pm/K. The low temperature dependence and high nonlinear conversion efficiency make our waveguides ideally suited for future operations in classical nonlinear integrated optics and integrated quantum networking applications. PMID- 30470054 TI - Tunable slow and fast light in parity-time-symmetric optomechanical systems with phonon pump. AB - We study the response of parity-time (PT)-symmetric optomechanical systems with tunable gain and loss to the weak probe field in the presence of a strong control field and a coherent phonon pump. We show that the probe transmission can exceed unity at low control power due to the optical gain of the cavity and it can be further enhanced or suppressed by tuning the amplitude and phase of the phonon pump. Furthermore, the phase dispersion of the transmitted probe field is modified by controlling the applied fields, which allows one to tune the group delay of the probe field. Based on this optomechianical system, we can realize a tunable switch between slow and fast light effect by adjusting the gain-to-loss ratio, power of the control field as well as the amplitude and phase of the phonon pump. Our work provides a platform to control the light propagation in a more flexible way. PMID- 30470055 TI - Stable ultra-broadband gain spectrum with wide-angle non-collinear optical parametric amplification. AB - Comparing with the non-collinear optical parametric amplification (NOPA), the gain bandwidth could be significantly enhanced by the wide-angle NOPA (WNOPA), i.e., with a divergent signal (WNOPA-S) or pump (WNOPA-P). In a uniaxial crystal, the spectral symmetry/asymmetry of WNOPA is introduced. In WNOPA-S, the ultra broadband gain spectrum can be obtained in two phase-matching directions at both sides of the pump, however, the output is heavily angularly dispersed. In WNOPA P, although the gain bandwidth enhancement is only achieved in one phase-matching direction, i.e., on the opposite side of the crystal axis, it is free of angular dispersion. The stabilities of the gain spectrum in NOPA and in WNOPA-P are experimentally compared and theoretically analyzed. Compared with NOPA, WNOPA-P supports an even broader and more stable gain spectrum, and compared with WNOPA S, WNOPA-P is angular-dispersion-free. The conversation efficiency of WNOPA-P is the same as NOPA. We suppose WNOPA-P is ideally suitable for the amplification of stable ultra-broadband few-cycle pulse lasers. PMID- 30470056 TI - Photothermal spectroscopy of CO2 in an intracavity mode-locked fiber laser configuration. AB - A novel configuration of a photothermal gas sensor is demonstrated. Photothermal induced gas refractive index (RI) modulation is probed by a simple, mode-locked (ML) ring cavity fiber laser, operating in the 1.55 um wavelength region. The measured gas sample is placed in an open-path section of the ML laser and the RI variations directly translate to its optical path-length change, which is easily detectable as pulse repetition frequency deviations. Wavelength modulation spectroscopy (WMS) technique was used along with a custom-built FM demodulator simplifying the signal retrieval and acquisition. Normalized noise equivalent coefficient calculated for the sensor was 1 x 10-5 cm-1 W Hz-1/2. PMID- 30470057 TI - Single photon polarization conversion via scattering by a pair of atoms. AB - The single photon scattering in one-dimensional waveguide coupled to two separated atoms is investigated. The first atom is considered as a Lambda system and the second one is taken as V -type configuration. The analytical expressions of the single photon scattering spectra are obtained. The calculated results show that the polarization conversion of single photon can be realized by controlling the distance between the two atoms due to the interference effects. The conversion efficiency can reach unit in the ideal case. Furthermore, the polarization conversion of the single photon also depends on the initial state of the Lambda system. The influences of dissipations on the single photon polarization conversion are also shown. PMID- 30470058 TI - Performance enhancement of free-space optical communications under atmospheric turbulence using modes diversity coherent receipt. AB - This paper numerically and experimentally investigates the performance of free space optical receiver using modes diversity coherent receipt under moderate-to strong turbulence. By utilizing a three-mode photonic lantern with digital maximum ratio combining, a 40 Gbps QPSK optical signal is received. The turbulence strength is measured by the ratio of beam diameter to atmospheric coherence length, D/r0. The larger the D/r0, the stronger the turbulence is, and vice versa. Compared with conventional single mode fiber based receipt, the required transmitted power can reduce by 4.6 dB and 4 dB at 10% interruption probability under turbulence strength D/r0 = 8 and 16. The required transmitted power at bit error ratio of 2.2 * 10-2 can relax by 4.2 dB and 5 dB under turbulence strength D/r0 = 8 and 16. PMID- 30470059 TI - Broadband zero backward scattering by all-dielectric core-shell nanoparticles. AB - Efficiently controlling the direction of optical radiation at nanoscale dimensions is essential for various nanophotonics applications. All-dielectric nanoparticles can be used to engineer the direction of scattered light via overlapping of electric and magnetic resonance modes. Herein, we propose all dielectric core-shell SiO2-Ge-SiO2 nanoparticles that can simultaneously achieve broadband zero backward scattering and enhanced forward scattering. Introducing higher-order electric and magnetic resonance modes satisfies the generalized first Kerker condition for breaking through the dipole approximation. Zero backward scattering occurs near the electric and magnetic resonant regions, this directional scattering is therefore efficient. Adjusting the nanoparticles' geometric parameters can shift the spectral position of the broadband zero backward scattering to the visible and near-infrared regions. The wavelength width of the zero backward scattering could be enlarged as high as 142 and 63 nm in the visible and near-infrared region. Due to these unique optical features the proposed core-shell nanoparticles are promising candidates for the design of high performance nanoantennas, low-loss metamaterials, and photovoltaic devices. PMID- 30470060 TI - Fluorescence spectrum photo-bleaching analysis for distinguishing microorganisms (bacteria and fungi) from other particles in air. AB - A new device with a 405 nm blue laser diode is developed for collecting samples in air and detecting their spectra variation. The multi-sample particles which are pure microorganisms can be distinguished from interferents in the air by photo-bleaching phenomenon. Six types of microorganisms and twelve types of interferents from the air, which exhibit laser-induced fluorescence, are used to evaluate the performance of the analysis approach, and their fluorescence emission spectra are presented. The results show that when microorganisms are illuminated by the laser, the fluorescence spectra will change significantly within several minutes, including both the wavelength of the main peak and fluorescence intensity. Our work provides a potential approach to distinguish microorganisms from other particles by the changes. PMID- 30470061 TI - Experimental realization of path-polarization hybrid high-dimensional pure state. AB - High-dimensional entanglement offers promising perspectives in quantum information science. However, how to generate high-quality high-dimensional entanglement and control it efficiently is still a challenge. Here, we experimentally demonstrate a polarization-path hybrid high-dimensional entangled two-photon source with extremely high quality. Based on stable interferometers, we measured fidelities exceeding 0.99 for both three-dimensional and four dimensional maximal entanglement. The experimental setup can also be used to prepare arbitrary high-dimensional pure state and can be efficiently extended to even higher dimensional systems. Our new source will shed new light on high dimensional quantum information processes. PMID- 30470062 TI - Fabrication of hexagonal compound eye microlens array using DMD-based lithography with dose modulation. AB - In this study, a method is proposed for the rapid fabrication of a hexagonal compound eye microlens array (HCE-MLA) using maskless lithography technique based on digital micromirror device (DMD), in which a hexahedron array is lithographed, and subsequently, a microlens structure is lithographed layer by layer upon the hexahedron. Owing to the high filling rate of the hexagon and the aspheric surface of the paraboloid profile of the microlens, after the distribution of the required exposure dose of HCE-MLA was calculated based on dose modulation, a series of circular pattern with different radius could be obtained by equal-arc mean slicing strategy that can adapt to the variable curvature of the target contour and improve its reconstruction precision. Then, after a hexagonal photoresist island was fabricated on the substrate, and the dose accumulated over multiple exposures, the required exposure dose profiles were reconstructed on the hexagonal photoresist island. Finally, a high-quality HCE-MLA with a smooth surface was fabricated via thermal reflow. The fabrication of the designed HCE MLA using this method was demonstrated in experiments. The results indicate that the actual profile of HCE-MLA shows good agreement with the design profile and that simultaneously increasing the number of the slicing layers can improve the quality of the profile. The research indicated that this method is feasible and convenient for the fabrication of high-quality HCE-MLA. PMID- 30470063 TI - Technique for generating periodic structured light beams using birefringent elements. AB - We put forward a simple, scalable and robust technique for generating periodically structured light beams with intensity patterns, e.g. of the form cos2n(kxx) cos2m(kyy), where kx and ky are real numbers that can be tailored and n and m are integers. The technique combines the use of Gaussian beams with curved wavefronts, birefringent crystals (Savart plates) and linear polarizers. Applications range from photolithography to fabrication of micro-lens array and fiber Bragg gratings, 3D printing and tailoring of optical lattices for trapping atoms and molecules. PMID- 30470064 TI - Lasing threshold of the bound states in the continuum in the plasmonic lattices. AB - Distributed feedback plasmonic laser based on the periodic array of holes in the silver half-space and covered with gain medium is considered. Square, hexagonal and several rectangular lattices are studied. It is demonstrated that the bound states in the continuum provide substantially lower threshold than radiating modes. Moreover, it is shown that while the hole size increases the lasing threshold of some modes decreases. Among the studied types of lattices, lasing in the hexagonal lattice requires the lowest material gain of only 18 cm-1. Our results pave the way to the development of the efficient low-threshold distributed feedback plasmonic lasers. PMID- 30470065 TI - Zak phase and topological plasmonic Tamm states in one-dimensional plasmonic crystals. AB - The Zak phase and topological plasmonic Tamm states in plasmonic crystals based on periodic metal-insulator-metal waveguides are systematically investigated. We reveal that robust topological interfacial states against structural defects exist when the Zak phase between two adjoining plasmonic lattices are different in a common band gap. A kind of efficient admittance-based transfer matrix method is proposed to calculate and optimize the configuration with inverse symmetry. The topologically protected states are favorable for the spatial confinement and enhancement of electromagnetic fields, which open a new avenue for topological photonic applications. PMID- 30470066 TI - .Maximizing the spectral efficiency of Stokes vector receiver with optical field recovery. AB - Stokes vector receivers (SVR) bridge the 4-D (i.e. dual-polarization complex signals) coherent detection and the conventional intensity-only 1-D direct detection (DD). By multi-dimensional polarization modulation in Stokes space, SVR maximizes the electrical spectral efficiency (ESE) of DD receivers by recovering at most 3-D signals. However, most 3-D schemes lack the capability of optical field recovery, an essential requirement for digital post-compensation of fiber dispersion that elongates the achievable distance. We propose a 3-D Stokes-space field modulation to enable 3-D signal field recovery, verified by a 3-D 32-Gbaud per dimension probabilistic-constellation-shaped 64-QAM transmission over 260-km fiber at C-band. This sets an ESE record of 16.5 (net ESE of 13.9) bit/s/Hz for DD receivers. PMID- 30470067 TI - Registration-based multi-orientation tomography. AB - We propose a combination of an experimental approach and a reconstruction technique that leads to reduction of artefacts in X-ray computer tomography of strongly attenuating objects. Through fully automatic data alignment, data generated in multiple experiments with varying object orientations are combined. Simulations and experiments show that the solutions computed using algebraic methods based on multiple acquisitions can achieve a dramatic improvement in the reconstruction quality, even when each acquisition generates a reduced number of projections. The approach does not require any advanced setup components making it ideal for laboratory-based X-ray tomography. PMID- 30470068 TI - Classification accuracy improvement of laser-induced breakdown spectroscopy based on histogram of oriented gradients features of spectral images. AB - To improve the classification accuracy of laser-induced breakdown spectroscopy (LIBS), image histogram of oriented gradients (HOG) features method (IHFM) for materials analysis was proposed in this work. 24 rice (Oryza sativa L.) samples were carried out to verify the proposed method. The results showed that the classification accuracy of rice samples by the full-spectra intensities method (FSIM) and IHFM were 60.25% and 81.00% respectively. The classification accuracy was obviously improved by 20.75%. Universality test results showed that this method also achieved good results in the plastics, steel, rock and minerals classification. This study provides an effective method to improve the classification performance of LIBS. PMID- 30470069 TI - Continuous-discontinuous Galerkin time domain (CDGTD) method with generalized dispersive material (GDM) model for computational photonics. AB - The discontinuous Galerkin time domain (DGTD) method and its recent flavor, the continuous-discontinuous Galerkin time domain (CDGTD) method, have been extensively applied to simulations in the radio frequency (RF) and microwave (MW) regimes due to their inherent ability to efficiently model multiscale problems. We propose to extend the CDGTD method to nanophotonics while exploiting its advantages which have already been established in the RF and MW regimes, such as domain decomposition, non-conformal meshing, high-order elements, and hp refinement. However, at optical frequencies many materials are highly dispersive, so the modeling of nanophotonic devices requires accurate handling of different dielectric functions, including those of plasmonic elements, dielectrics, and tunable materials. In this paper, we propose a CDGTD method that incorporates a generalized dispersive material (GDM) model which is an efficient way to implement a wide range of optical dispersion models with a universal analytic function. Physics-based dispersion models, such as the Drude, Debye, Lorentz, and critical points as well as more complicated behavior founded on ab-initio principles can all be obtained as special cases of the universal GDM approach. The accuracy and convergence of this GDM-incorporated CDGTD are verified by numerical examples. The CDGTD method, equipped with the GDM model, paves the way to the efficient design and optimization of large scale photonic devices with a diverse range of optical dispersive materials. PMID- 30470070 TI - Comparative study of equivalent circuit models for photoconductive antennas. AB - Comparison of equivalent circuit models (ECM) for photoconductive antennas (PCA) represents a challenge due to the multiphysics phenomena involved during PCA operation and the absence of a standardized validation methodology. In this work, currently reported ECMs are compared using a unique set of simulation parameters and validation indicators (THz waveform, optical power saturation, and ECM voltages consistency). The ECM simulations are contrasted with measured THz pulses of an H-shaped 20MUm gap PCA at different optical powers (20mW to 220mW). In addition, an alternative two-element ECM that accounts for both space-charge and radiation screening effects is presented and validated using the proposed methodology. The model shows an accurately reproduced THz pulse using a reduced number of circuital elements, which represents an advantage for PCA modeling. PMID- 30470071 TI - Integrated silicon photonic device design by attractor selection mechanism based on artificial neural networks: optical coupler and asymmetric light transmitter. AB - Recently, different nanophotonic computational design methods based on optimization algorithms have been proposed which revolutionized the conventional design techniques of photonic integrated devices. The intelligently designed photonic devices have small footprints and high operating performance along with their fabrication feasibility. In this study, we introduce a new approach based on attractor selection algorithm to design photonic integrated devices. In order to demonstrate the potential of the proposed approach, we designed two structures: an optical coupler and an asymmetric light transmitter. The designed photonic devices operate at telecom wavelengths and have compact dimensions. The designed optical coupler has a footprint of only 4 * 2 MUm2 and coupling efficiency of 87.5% at a design wavelength of 1550 nm with spatial beam width compression ratio of 10:1. Moreover, the designed optical coupler operates at a wide bandwidth of 6.45% where the transmission efficiency is above 80%. In addition, the designed asymmetric light transmitter with a size of 2 * 2 MUm2 has the forward and backward transmission efficiencies of 88.1% and 8.6%, respectively. The bandwidth of 3.47% was calculated for the designed asymmetric light transmitter where the forward transmission efficiency is higher than 80% and the backward efficiency transmission is under 10%. In order to evaluate the operating performance of the designed photonic devices, coupling losses are analyzed. The presented results show that the attractor selection algorithm, which is based on artificial neural networks, can bring a conceptual breakthrough for the design of efficient integrated nanophotonic devices. PMID- 30470072 TI - High-time-resolved 64-channel single-flux quantum-based address encoder integrated with a multi-pixel superconducting nanowire single-photon detector. AB - We propose and demonstrate a 64-channel event-driven encoder based on single-flux quantum (SFQ) circuits for application to a multi-pixel superconducting nanowire single-photon detector (SSPD) system. Multi-pixel SSPD systems were developed to improve maximum count rates and realize ultra-sensitive imaging systems. An intelligent signal processor is required, which we designed based on SFQ circuits. We were able to obtain an address based on the reserve timing information for the photon detection that occurs in the SSPD, as well as read the time-tagged address information for the SSPDs through the SFQ encoder. The overall observed FWHM jitter was 56.5 ps. PMID- 30470073 TI - Improved single-illumination estimation accuracy via redefining the illuminant invariant descriptor and the grey pixels. AB - A grey pixel detection method, based on the illuminant-invariant descriptor in three logarithmic color channels, was proposed and proved effective for illuminant estimation [25]. In this work, an incremental improvement measure, based on Yang's work, is proposed by redefining the illuminant-invariant descriptor and the grey pixels. In order to improve the accuracy, appropriate parameters of grey pixels ratio and filter size are statistically analyzed and selected on different data sets. Experimental results show that the improved method is not only effective compared with classical statistics-based methods, but also outperforms many learning-based methods. PMID- 30470074 TI - Directional scattering and multipolar contributions to optical forces on silicon nanoparticles in focused laser beams. AB - Nanoparticles made of high index dielectric materials have seen a surge of interest and have been proposed for various applications, such as metalenses, light harvesting and directional scattering. With the advent of fabrication techniques enabling colloidal suspensions, the prospects of optical manipulation of such nanoparticles becomes paramount. High index nanoparticles support electric and magnetic multipolar responses in the visible regime and interference between such modes can give rise to highly directional scattering, in particular a cancellation of back-scattered radiation at the first Kerker condition. Here we present a study of the optical forces on silicon nanoparticles in the visible and near infrared calculated using the transfer matrix method. The zero backscattering Kerker condition is investigated as an avenue to reduce radiation pressure in an optical trap. We find that while asymmetric scattering does reduce the radiation pressure, the main determining factor of trap stability is the increased particle response near the geometric resonances. The trap stability for non-spherical silicon nanoparticles is also investigated and we find that ellipsoidal deformation of spheres enables trapping of slightly larger particles. PMID- 30470075 TI - Step-modulated decay cavity ring-down detection for double resonance spectroscopy. AB - A method of measuring double resonant two-photon signal and background from a single cavity ring-down decay is introduced. This is achieved by modulating the double resonance loss via one of the light sources exciting the transition. The noise performance of the method is characterized theoretically and experimentally. The addition of a new parameter to the fitting function introduces a minor noise increase due to parameter correlation. However, the concurrent recording of the background can extend the stable measurement time. Alternatively, the method allows a faster measurement speed, while still recording the background, which is often advantageous in double resonance measurements. Finally, the method is insensitive to changes in the cavity decay rate at short timescales and can lead to improved performance if they have significant contribution to the final noise level compared to the detector noise. PMID- 30470076 TI - Improving the phase sensitivity of an SU(1,1) interferometer with photon-added squeezed vacuum light. AB - We study the phase sensitivity of an SU(1,1) interferometer from two aspects, i.e., the phase estimation determined by the error propagation formula and that by the quantum Cramer-Rao bound (QCRB). The results show that the phase sensitivity by using the intensity detection reaches the sub-shot-noise limit with a coherent state and an m-photon-added squeezed vacuum state (m-PA-SVS) as inputs. The phase sensitivity gradually approaches the Heisenberg limit for increasing m, and the ultimate phase precision improves with the increase of m. In addition, the QCRB can be saturated by the intensity detection with inputting the m-PA-SVS. PMID- 30470077 TI - 3D-printed lambda/4 phase plate for broadband microwave applications. AB - An efficient design for a quarter-wave (lambda/4) retardation plate (QWP) operating at microwave frequencies has been designed and manufactured using dual head fused deposition modelling (FDM) 3D printing. Exploiting a bespoke composite material feedstock filament with high dielectric permittivity epsilonr = 10.8, the resulting 3D-printed QWP comprising alternative layers of high and low permittivity had a high artificial double refraction of Deltaepsilon = 2.9. The QWP provided broadband conversion of linear to circular polarization and phase modulation of an incident plane electromagnetic wave at 12-18 GHz, and demonstrated the potential for optical devices via additive manufacture for use in the microwave frequency range. PMID- 30470078 TI - Optical emission from ultrafast laser filament-produced air plasmas in the multiple filament regime. AB - We perform optical emission spectroscopy of ultrafast laser filament-produced air plasmas in the multiple filament regime at driving wavelengths of 400 nm and 800 nm. The spatiotemporal structure of the emission from the plasmas are observed and the emission spectra are used to estimate plasma temperature and density for a range of laser parameters. Plasma temperatures are determined from the molecular nitrogen fluorescence, while the electron densities are estimated from Stark broadening of the oxygen-I 777.19-nm line. Electron temperatures are determined to be in the range of 5000-5200 K and they do not vary significantly along the length of the filament, nor are they sensitive to incident laser energy or wavelength. Electron densities are on order of 1016 cm-3 and show a greater variation with axial position, laser energy, and laser wavelength. We discuss mechanisms responsible for spatial localization of emitting species within the filament. Optical emission spectroscopy offers a simple, non-perturbing method to measure filament properties, that allows the information on the associated molecular transitions and excitation/ionization mechanisms to be extracted. PMID- 30470079 TI - Reconstruction of reference error in high overlapping density subaperture stitching interferometry. AB - The vibration modulated stitching interferometry acquires many subaperture phases timely forming the high overlapping density subapertures for asphere phase stitching. The large number of overlapping subapertures had been proven effective in suppressing the reference error. In this research, we propose a pixel-by-pixel reference calibration method by using the averaged difference between the stitched phase and compensated phase within the overlapping subapertures. The measurement for both tested optics and calibration of the reference optics are accomplished in a single phase stitching process. The requirement for a high quality reference optics or dedicated reference calibration procedure for subaperture stitching interferometry is therefore significantly eliminated. Both the simulation and experimental results shows the feasibility of the proposed method for high frequency reference error and most of the form error in the third order Zernike aberrations. PMID- 30470080 TI - Subsurface plankton layers observed from airborne lidar in Sanya Bay, South China Sea. AB - In recent years, airborne lidar has been used in a wide range of oceanic applications, including detection of bathymetry, bubbles, internal waves, and schools of fish. However, it has not yet been extensively applied in Chinese seas. For example, there have been no studies to detect subsurface plankton layers in the South China Sea (SCS) by airborne lidar. In this study, we investigated this technology's applicability for identifying subsurface plankton layers in Sanya Bay, SCS. Three airborne lidar flight experiments were carried out in March 2018 and in September 2017. Shipboard synchronous measurements were carried out in March 2018 to validate the lidar measurements. The method that is presented here can be used to detect a subsurface plankton layer, which is characterized by depth, thickness, and intensity. Compared with chlorophyll-a profile synchronously measured by shipborne fluorometer, there was a consistent relationship. The subsurface plankton layer depth error was less than 0.7 m. Next, the spatial distribution and seasonal variation of lidar measured subsurface plankton layers in Sanya Bay, SCS, was analyzed. The results showed that airborne lidar can potentially detect subsurface plankton layer within 50 meters deep in relatively clear water. This will enhance our understanding of biogeochemical processes in these optically complex aquatic systems. PMID- 30470081 TI - Highly sensitive gas refractometers based on optical microfiber modal interferometers operating at dispersion turning point. AB - In most fiber-optic gas sensing applications where the interested refractive index (RI) is ~1.0, the sensitivities are greatly constrained by the large mismatch between the effective RI of the guided mode and the RI of the surrounding gaseous medium. This fundamental challenge necessitates the development of a promising fiber-optic sensing mechanism with the outstanding RI sensitivity to achieve reliable remote gas sensors. In this work, we report a highly sensitive gas refractometer based on a tapered optical microfiber modal interferometer working at the dispersion turning point (DTP). First, we theoretically analyze the essential conditions to achieve the DTP, the spectral characteristics, and the sensing performance at the DTP. Results show that nonadiabatic tapered optical microfibers with diameters of 1.8-2.4 um possess the DTPs in the near-infrared range and the RI sensitivities can be improved significantly around the DTPs. Second, we experimentally verify the ultrahigh RI sensitivity around the DTP using a nonadiabatic tapered optical microfiber with a waist diameter of ~2 MUm. The experimental observations match well with the simulation results and our proposed gas refractometer provides an exceptional sensitivity as high as -69984.3 +/- 2363.3 nm/RIU. PMID- 30470082 TI - Connecting two Gaussian cluster states by quantum entanglement swapping. AB - Cluster state is an important resource for one-way quantum computation and quantum network. In this paper, we present a scheme for connecting two Gaussian cluster states by entanglement swapping, which can be used to connect two local quantum networks composed by cluster states. The connection schemes between different types of four-mode cluster states are analyzed and we show that the structure of the output states after entanglement swapping may be not the same as that of the input states. The entanglement of the obtained new cluster states are presented when suitable feedforward schemes are applied in the entanglement swapping process. By using optimal gains in the classical channel and inseparability criteria, the requirement of squeezing parameters for obtaining entanglement of output states are reduced. The presented scheme provides a concrete reference for constructing quantum networks with cluster states. PMID- 30470083 TI - Three-step random phase retrieval approach based on difference map normalization and diamond diagonal vector normalization. AB - To overcome the phase shift error in phase shifting interferometry, a three-step random phase retrieval approach based on difference map normalization and diamond diagonal vector normalization (DN&DDVN) is proposed. It does not need pre filtering for the interferograms and can obtain relatively accurate phase distribution with a simple process and less computational time. This simulation and experiment verify the correctness and feasibility of DN&DDVN. PMID- 30470084 TI - Coherent perfect absorption and asymmetric interferometric light-light control in graphene with resonant dielectric nanostructures. AB - Engineering light absorption in graphene has been the focus of intensive research in the past few years. In this paper, we show numerically that coherent perfect absorption can be realized in monolayer graphene in the near infrared range by harnessing resonances of dielectric nanostructures. The asymmetry of the structure results in different optical responses for light illuminated from the top side and the substrate side and enables asymmetric interferometric light light control. The absorbed and scattered light exhibit interesting nonlinear behavior, allowing switching a strong optical signal output with a weak light. This work may stimulate potential applications including new types of sensors, coherent photodetectors and all-optical logical devices. PMID- 30470085 TI - Realization of mid-infrared broadband absorption in monolayer graphene based on strong coupling between graphene nanoribbons and metal tapered grooves. AB - In this paper, we theoretically propose an effective broadband absorption architecture in mid-infrared region based on strong coupling between the plasmonic resonance of graphene nanoribbons and the waveguide mode of a metal tapered groove. The special architecture facilitates two new hybrid modes splitting with very strong energy distribution on graphene ribbon, which results in the broadband absorption effect. To well explain these numerical results, an analytical dispersion relation of waveguide mode is obtained based on the classical LC circuit model. The fluctuating range of absorption passband is investigated by adjusting the filled medium inside of the grooves. Leveraging the concept and method, a broadband flat-top (bandwidth ~2.5 um) absorption with absorption rate over 60% is demonstrated. Such a design not only enhances the intrinsic weak plasmons resonance in mid-infrared spectral region, but also reduces the absorption fluctuations caused by coupling, which are the key features for developing next-generation mid-infrared broadband optical devices. PMID- 30470086 TI - Reflow soldering method with gradient energy band generated by optical system. AB - Laser reflow soldering is an important technology in electronic components processing. In this paper, we presented a simple but efficient method to achieve reflow soldering process with gradient energy band created by just two parallel mirrors. The detailed influence of the variety of optical parameters on the soldering process has been analyzed by using the finite element method. And the modulation of the optical parameters on reflow soldering parameters also has been demonstrated. In our experiment, one HR mirror and one-mirror with transmissivity of 10% have been used to create a gradient energy band with an incident laser power of 50W. In summary, both the simulations and the experiments show that the typical reflow soldering profile has been acquired by the optical system. The high quality joints on both the front and rear surface of the capacitor can be acquired by just one surface radiation of the optical system. PMID- 30470087 TI - Enhanced energy gain in a dielectric laser accelerator using a tilted pulse front laser. AB - Using an 800 nm, 45 fs pulse-front-tilted laser we demonstrate a record 315 keV energy gain in a dual grating dielectric laser accelerator (DLA) and average accelerating gradients of 560 MV/m over 0.5 mm. These results open a new regime in DLA characterized by significant evolution of the beam distribution in the longitudinal phase space, corresponding to > 1/4 of a synchrotron oscillation. By tilting the laser wavefront we control the resonant velocity of the DLA and observe a net energy gain, indicating that a tapered optical phase could be used to achieve very high energy gain. PMID- 30470088 TI - Performance of spectral amplitude coded multiple pulse position modulation with non-uniform energy slots and fading. AB - Multiple-pulse position modulation (MPPM) is an advanced modulation method for optical wireless communication (OWC), which could provide better performance when channel information is not available. We consider the evaluation of a symbol error rate (SER) expression for MPPM applied within OWC. In the proposed model, MPPM is realized by spectral-amplitude coding (SAC) with non-uniform spectral slot energies. The derived fading channel SER expression is applicable for an arbitrary fading distribution, which may be due to either atmospheric turbulence or transceiver pointing error. A detailed theoretical analysis of the SER is provided and the resulting SER expression is verified by simulation. PMID- 30470089 TI - Modeling optical memory effects with phase screens. AB - During the last decade, optical memory effects have been explored extensively for various applications. In this letter we propose phase screen models to facilitate the analysis and the simulation of wave propagation through optical media that exhibits memory effects. We show that the classical optical memory effect, which implies tilt wave correlations of the input and the scattered fields, can be readily modeled by a single random phase screen. For the recently discovered generalized optical memory effect, which implies the existence of shift wave correlations in addition to the tilt correlation, we propose an appropriate generalized random phase screen model. PMID- 30470091 TI - Micro-lens aperture array for enhanced thin-film imaging using luminescent concentrators. AB - We present a 300 MUm thick optical Soller collimator realized by X-ray lithography on a PMMA wafer which, when paired with luminescent concentrator films, forms the first complete prototype of a short-distance, flexible, scalable imaging system that is less than 1 mm thick. We describe two ways of increasing the light-gathering ability of the collimator by using hexagonal aperture cells and embedded micro-lenses, evaluate a new micro-lens aperture array (MLAA) for proof of concept, and analyze the optical imaging properties of flexible MLAAs when realized as thin films. PMID- 30470090 TI - Transflective spin-orbital angular momentum conversion device by three dimensional multilayer liquid crystalline materials. AB - In this paper, a liquid crystal device for generating transflected optical vortices with high efficiency based on Pancharatnam-Berry phase is devised and demonstrated experimentally. In the experiment, both photo-alignment material and polymer-alignment material are used for assembling three-dimensional distributed liquid crystal polymer and cholesteric liquid crystal. Through the interaction between the incident light and the device, both transmitted light and reflected light get spin-orbital angular momentum conversion. Moreover, the amount of transmitted and reflected beams can be modulated by the input polarization. In our proposal, the device is dual functional, low-cost and simple in manufacturing process. PMID- 30470092 TI - Multi-level sorting of nanoparticles on multi-step optical waveguide splitter. AB - We propose an optofluidic sorting method for nanoparticles with different size by using optical waveguide splitter, and moreover, multiple cascaded splitters with different threshold could act as multi-level sorting unit. For a directional coupler (DC) with a specific wavelength excitation, the power splitting ratio is related to the coupling length and the gap between parallel waveguides. The power splitting ratio further determines the trapping force and potential wells distribution of both output ports. Most importantly, the potential well distribution is dependent on the particle size. For larger particles, the potential wells of both waveguides are inclined to merge, which makes it easier to be attracted and transfers to the adjacent waveguide with deeper potential well. The critical size of sorting is corresponding to the case when the barrier between wells just disappears, or the second derivative of the potential distribution is exactly zero. Moreover, since the sorting threshold of nanoparticles is related to coupling length and gap, multiple cascaded splitters with length or gap gradually varied could act as a multi-level sorting unit. A four-level sorting unit with a critical particle size of 600nm, 700nm, and 800nm are demonstrated. By considering the Brownian motion of particles and using particle-tracking method, the random distribution of nanoparticles on parallel waveguides in the sorting process is statistically presented, which agreed well with its corresponding potential wells distribution analysis. This sorting method based on multi-step optical waveguide splitter offers a number of advantages including single wavelength excitation, low loss, low power performance and ease of fabrication. This design can realize the high-throughput and large-scale nanoparticle automatic sorting in integrated photonic circuits, which have great potential for a large scale lab-on-a-chip system. PMID- 30470093 TI - Quantum plasmonic sensing using single photons. AB - Reducing the noise below the shot-noise limit in sensing devices is one of the key promises of quantum technologies. Here, we study quantum plasmonic sensing based on an attenuated total reflection configuration with single photons as input. Our sensor is the Kretschmann configuration with a gold film, and a blood protein in an aqueous solution with different concentrations serves as an analyte. The estimation of the refractive index is performed using heralded single photons. We also determine the estimation error from a statistical analysis over a number of repetitions of identical and independent experiments. We show that the errors of our plasmonic sensor with single photons are below the shot-noise limit even in the presence of various experimental imperfections. Our results demonstrate a practical application of quantum plasmonic sensing is possible given certain improvements are made to the setup investigated, and pave the way for a future generation of quantum plasmonic applications based on similar techniques. PMID- 30470094 TI - Morphology of single picosecond pulse subsurface laser-induced modifications of sapphire and subsequent selective etching. AB - The effect of 1030nm single picosecond pulsed laser-induced modification of the bulk of crystalline sapphire using a combined process of laser amorphization and selective wet chemical etching is studied. Pulse durations of more than 1 picosecond are not commonly used for this subsurface process. We examine the effect of 7 picosecond pulses on the morphology of the unetched, as well as etched, single pulse modifications, showing the variation of shape and size when varying the pulse energy and the depth of processing. In addition, a qualitative analysis of the material transformation after irradiation is provided as well as an analysis of cracking phenomena. Finally, a calculated laser intensity profile inside sapphire, using the Point Spread Function (PSF), is compared to the shape of the modifications. This comparison is employed to calculate the intensity threshold leading to amorphization, which equals 2.5?1014 +/- 0.4?1014 W/cm2. PMID- 30470095 TI - General quantum broadcast and multi-cast communications based on entanglement. AB - Broadcast and multi-cast communications are two important applications in quantum information science. Such applications guarantee the implementation of quantum information theory. In this paper, we propose two general schemes for the quantum broadcast and multi-cast communications to ensure that the central party (sender) can broadcast arbitrary single-qubit state to multiple receivers synchronously. Moreover, it is guaranteed that the information among the multiple receivers is different to satisfy the requirement in multi-cast communications. In particular, the proposed schemes indicate the probabilities, of which the multiple receivers obtain the quantum states successfully, could reach 1. We expect this works will shed some light for the prospective research on multi-party quantum communications and quantum cryptography. PMID- 30470096 TI - Anomalous vibration suppression in a weak-value-emulated heterodyne roll interferometer. AB - We experimentally validate the vibration suppression capabilities of a weak-value like protocol. The phase-sensitive heterodyne technique exhibits advantageous characteristics of a weak measurement including anomalous amplification in sensitivity and technical noise suppression. It does not, however, leverage the entanglement between the system and meter to amplify the signal of interest, as is typical in a weak measurement. In this formalism, we demonstrate an amplification in sensitivity to the roll angle of over 700 times. High precision roll experiments anchor numerical simulations to show that the interferometer outperforms standard interferometry by a factor of 500 in terms of peak-to-peak noise amplitude. During the measurement of a rolling stage, technical noise - primarily in the form of vibrations - is substantially attenuated. This is the first demonstration of vibration suppression capabilities that are inherent to the light from a metrology instrument instead of achieved via mechanical damping. The emulation presented in this work also identifies an avenue to achieve anomalous amplification outside of the standard weak measurement protocol. PMID- 30470097 TI - Run-time reconfigurable adaptive LDPC coding for optical channels. AB - In this paper, we proposed a class of large-girth QC-LDPC codes designed to maximize the girth property with code rates ranging from 0.5 to 0.8, which leads to well-structured parity-check matrix and generator matrix. Instead of implementing several FEC encoder and decoder engines in hardware, we design an efficient unified FPGA-based architecture enabling run-time reconfigurable capability. Apart from four principle LDPC codes being incorporated into a unified design, shortening is adopted to bridge the rate gap between principle codes. With our proposed unified LDPC engine, the signal-to-noise ratio (SNR) limits of -1 dB to 2.2 dB have been demonstrated at BER of 10-12 in additive white Gaussian noise (AWGN) channel by FPGA emulation. It is desirable for the application to both free-space optical (FSO) and fiber optics communications. Large code rate range is preferred to deal with various channel impairments. To further verify the proposed unified code engine for FSO applications, we tested the scheme through a spatial light modulator (SLM)-based FSO channel emulator. We showed that in medium atmospheric turbulence regime, a post-FEC BER below 10-8 can be achieved without any interleaver and adaptive optics. PMID- 30470098 TI - High-speed multi-pass tunable diode laser absorption spectrometer based on frequency-modulation spectroscopy. AB - We report a multi-pass tunable diode laser absorption spectrometer based on the frequency-modulation spectroscopy (FMS) technique. It has the advantage of high scan speed and is immune to the etalon effect. A multi-pass Herriott-type cell was used in the spectrometer to increase the effective optical length to 17.5 m and compact the physical dimensions of the spectrometer to 60*30*30 cm3. Noise due to low-frequency fluctuation of the laser power and the 1/f noise in the rapid detection are sufficiently reduced by FMS. Interference fringes are effectively suppressed when the modulation frequency equals to integer or half integer times of their free spectral range (FSR). An absorption line of C2H2 around 1.51 um was recorded with the spectrometer to demonstrate its capabilities. The response frequency of the spectrometer is up to 100 kHz (10 us) thanks to the high modulation frequency of FMS. The detection sensitivity of the spectrometer is about 240 ppb (3sigma) at 100 kHz measurement repetition rate. The amplitude of the absorption signal is highly linear to the C2H2 concentration in the range of 300 ppb -100 ppm. Based on the Allan variation, the detection limit was determined to be 18 ppb with a detection time of 166 s. PMID- 30470099 TI - Spectral pre-modulation of training examples enhances the spatial resolution of the phase extraction neural network (PhENN). AB - The phase extraction neural network (PhENN) [Optica 4, 1117 (2017)] is a computational architecture, based on deep machine learning, for lens-less quantitative phase retrieval from raw intensity data. PhENN is a deep convolutional neural network trained through examples consisting of pairs of true phase objects and their corresponding intensity diffraction patterns; thereafter, given a test raw intensity pattern, PhENN is capable of reconstructing the original phase object robustly, in many cases even for objects outside the database where the training examples were drawn from. Here, we show that the spatial frequency content of the training examples is an important factor limiting PhENN's spatial frequency response. For example, if the training database is relatively sparse in high spatial frequencies, as most natural scenes are, PhENN's ability to resolve fine spatial features in test patterns will be correspondingly limited. To combat this issue, we propose "flattening" the power spectral density of the training examples before presenting them to PhENN. For phase objects following the statistics of natural scenes, we demonstrate experimentally that the spectral pre-modulation method enhances the spatial resolution of PhENN by a factor of 2. PMID- 30470100 TI - Tunable terahertz guided-mode resonance filter with a variable grating period. AB - A variable grating period made of quartz has been applied to fabricate a tunable guided mode resonance (TGMR) filter with transverse-electric (TE) and -magnetic (TM) modes in the terahertz (THz) region. We prepared three TGMR filters with grating periods of 5.0, 3.3, and 1.7 MUm/mm over the length of the filter. For the 5.0 MUm/mm, the resolution of resonance frequency shift of the TE0,1, TE1.1, and TM0,1 was 3.6, 4.0, and 3.4 GHz/mm, respectively. With a metal slit spacing of 2 mm located in front of the TGMR filter, the movable range of the TGMR was 24 mm, and the resonance frequency could be shifted up to 87, 96, and 82 GHz, where the center frequencies of each resonance were 0.402, 0.579, and 0.460 THz, for the TE0,1, TE1.1, and TM0,1, respectively. Furthermore, because the TGMR and guided mode resonance (GMR) filters are placed independently in the THz beam path, both tunable and fixed resonances can be obtained at the same time in the spectrum. PMID- 30470101 TI - Implementation of plasmonic band structure to understand polariton hybridization within metamaterials. AB - Gap surface plasmons (GSPs) serve a diverse range of plasmonic applications, including energy harvesting, communications, molecular sensing, and optical detection. GSPs may be realized where tightly spaced plasmonic structures exhibit strong spatial overlap between the evanescent fields. We demonstrate that within similar, nested geometries that the near-fields of the GSPs within the individual nanostructures are hybridized. This creates two or more distinct resonances exhibiting near-field distributions extended over adjacent spatial regions. In contrast, dissimilar, nested structures exhibit two distinct resonances with nominally uncoupled near-fields, resulting in two or more individual antenna resonance modes. We deploy plasmonic band structure calculations to provide insight into the type and degree of hybridization within these systems, comparing the individual components. This understanding can be used in the optimized design of polaritonic metamaterial structures for desired applications. PMID- 30470102 TI - Statistical analysis of dynamic light scattering data: revisiting and beyond the Schatzel formulas. AB - We revisited the classical Schatzel formulas (K. Schatzel, Quantum Optics2, 2871990) of the variance and covariance matrix associated to the normalized auto correlation function in a Dynamic Light Scattering experiment when the sample is characterized by a single exponential decay function. Although thoroughly discussed by Schatzel who also outlined a correcting procedure, such formulas do not include explicitly the effects of triangular averaging that arise when the sampling time Deltat is comparable or larger than the correlation time tauc. If these effects are not taken into account, such formulas might be highly inaccurate. In this work we have solved this problem and worked out two exact analytical expressions that generalize the Schatzel formulas for any value of the ratio Deltat/tauc. By the use of extensive computer simulations we tested the correctness of the new formulas and showed that the variance formula can be exploited also in the case of fairly broad bell-shaped polydisperse samples (polydispersities up to ~ 50 - 100%) and in connection with single exponential decay cross-correlation functions, provided that the average count rate is computed as the geometrical mean of the average count rates of the two channels. Finally, when tested on calibrated polystyrene particles, the new variance formula is able to reproduce quite accurately the error bars obtained by averaging the experimental data. PMID- 30470103 TI - Nonlinear propagation effects in high harmonic generation in reflection and transmission from gallium arsenide. AB - High harmonic spectroscopy in solids is emerging as a new tool to investigate ultrafast electron dynamics in the presence of strong optical fields. However, the observed high harmonic spectra do not usually reflect the microscopic origin of high harmonic generation (HHG) because of nonlinear and/or linear propagation effects. Here, we systematically investigate the HHG in reflection and transmission from gallium arsenide exposed to intense mid-infrared optical pulses. In transmission geometry, we find that the properties of high harmonics are drastically changed by nonlinear effects during the propagation of even tens of micrometers. Especially, the nonlinear absorption and/or nonlinearly induced ellipticity of the drive pulses as well as a cascade nonlinear mixing significantly alter the high harmonic signals in the case of the transmission geometry, making an extraction of the microscopic electron dynamics of gallium arsenide difficult. On the contrary, in reflection geometry, we obtain HHG spectra that are free from propagation effects, opening a general approach for high harmonic spectroscopy. PMID- 30470104 TI - Non-local orientation filtered imaging with incoherent light source. AB - A non-local spatial filtered imaging experiment using an orientation filter has been performed with spatially incoherent thermal light, which is based on Abbe Porter imaging system. A two-dimensional periodic grid object and an orientation filter are placed in two correlated light beams, namely a test beam and a reference beam, generated by splitting the thermal light beam via a beam splitter. The filtering process has been produced by manipulating the orientation of a slit aperture, which is in the back focal plane of the biconvex imaging lens in the reference beam. The detected object is placed in the test beam, whose modulated images have been achieved through optical field intensity correlation measurement between the two correlated beams. The experimental results are in good agreement with theoretical analysis. The research results here show considerable possibilities to distributively manipulate the image of an object with spatially incoherent light source, which could find potential applications in the remote imaging technology in the fields of geological survey and spectral analysis. PMID- 30470105 TI - Surface enhanced resonant Raman scattering in hybrid MoSe2@Au nanostructures. AB - We report on the surface enhanced resonant Raman scattering (SERRS) in hybrid MoSe2@Au plasmonic-excitonic nanostructures, focusing on the situation where the localized surface plasmon resonance of Au nanodisks is finely tuned to the exciton absorption of monolayer MoSe2. Using a resonant excitation, we investigate the SERRS in MoSe2@Au and the resonant Raman scattering (RRS) in a MoSe2@SiO2 reference. Both optical responses are compared to the non-resonant Raman scattering signal, thus providing an estimate of the relative contributions from the localized surface plasmons and the confined excitons to the Raman scattering enhancement. We determine a SERRS/RRS enhancement factor exceeding one order of magnitude. Furthermore, using numerical simulations, we explore the optical near-field properties of the hybrid MoSe2@Au nanostructure and investigate the SERRS efficiency dependence on the nanodisk surface morphology and on the excitation wavelength. We demonstrate that a photothermal effect, due to the resonant plasmonic pumping of electron-hole pairs into the MoSe2 layer, and the surface roughness of the metallic nanostructures are the main limiting factors of the SERRS efficiency. PMID- 30470106 TI - Compact reservoir computing with a photonic integrated circuit. AB - Photonic reservoir computing is a new paradigm for performing high-speed prediction and classification tasks in an efficient manner. The major challenge for the miniaturization of photonic reservoir computing is the need for the use of photonic integrated circuits. Herein, we experimentally demonstrate reservoir computing using a photonic integrated circuit with a semiconductor laser and a short external cavity. We propose a method to increase the number of virtual nodes in delayed feedback using short node intervals and outputs from multiple delay times. We perform time-series prediction and nonlinear channel equalization tasks using reservoir computing with the photonic integrated circuit. We show that the photonic integrated circuit with optical feedback outperforms the photonic integrated circuit without optical feedback for prediction tasks. To enhance the memory effect we feed past input signals in the current input data and demonstrate successful performance in an n-step-ahead prediction task. PMID- 30470107 TI - Bandwidth and size limits of achromatic printed-circuit metasurfaces. AB - Metasurfaces can implement a wide variety of wave-manipulation functions with sub wavelength layers. They are typically created from resonant elements, thus their refraction properties depend strongly on frequency. The resulting chromatic aberration is undesirable for most applications, motivating recent efforts in the development of achromatic metasurfaces. However, it remains unclear whether there are any physical limits on the achievable operating bandwidth of achromatic metasurfaces. Here we address this question, considering a common microwave metasurface geometry based on three metallic layers, separated by dielectric substrates. Since each of these metallic layers is modeled as an impedance, we apply Foster's reactance theorem to determine the bandwidth over which they are physically realizable using passive, causal and lossless structures. We derive limits for the bandwidth and total size of the metasurface, showing that there is a trade-off between these two parameters. A higher angle of refraction, corresponding to a larger numerical aperture for a lens, further limits the realizable bandwidth. We consider both Huygens' and Omega-bianisotropic metasurface types, and show that the limit is more severe for bianisotropic metasurfaces, making them less suitable for broadband achromatic designs. PMID- 30470108 TI - Reconfigurable metasurface for multiple functions: magnitude, polarization and phase modulation. AB - A novel reconfigurable metasurface for multiple functions is designed and investigated. The lattice of the metasurface is proposed to realize integrated absorption and polarization rotation and named as polarization conversion absorber (PCA). Then, lattices are arranged together to realize a certain function. Due to the independence of each lattice, the metasurface can present different performance based on different arrangement principle. Magnitude, polarization and phase modulation can be presented by manually arranging metasurface with 6 * 6 lattices. Both simulations and measurements prove that the proposed method provides a simple, flexible and effective strategy for multifunctional metasurface design. PMID- 30470109 TI - Millijoule femtosecond pulses at 1937 nm from a diode-pumped ring cavity Tm:YAP regenerative amplifier. AB - We present an infrared source operating at 1937 nm center wavelength capable of generating 1.35 mJ pulse energies with 1 kHz repetition rate and 2 GW peak power based on a diode-pumped Tm:YAP regenerative amplifier. The obtained pulses after 45 round trips have been compressed down to 360 fs. Using only a small portion (15 MUJ) of the output of the system we managed to generate a white light continuum in a 3 mm YAG window that exhibits the viability of the system as a suitable candidate for a pumping source of a mid-infrared optical parametric amplifier. PMID- 30470110 TI - Two-photon interferences on a silica-on-silicon chip with telecom-band photon pairs generated in a fiber. AB - We report two-photon interferences on a silica-on-silicon chip of Mach-Zehnder interferometer using telecommunication-band correlated photon pairs. The photon pairs were generated by spontaneous four-waving mixing process in a dispersion shifted fiber. The integrated chip, which was fabricated by standard silica-on silicon planar lightwave circuit technology, contained a Mach-Zehnder interferometer with a thermo-optic phase shifter. The insertion loss of the interferometer was less than 1 dB. We demonstrated two-photon interferences with both degenerate- and non-degenerate-frequency photon pairs on the Mach-Zehnder interferometer chip. A high fringe visibility was achieved in the interference with nondegenerate-frequency photons. Properties of quantum interference were demonstrated in the interference with degenerate-frequency photon pairs, which is an important way to manipulate the quantum state. These results show great potential of silica-on-silicon photonic chips in applications for the fiber-chip scheme in quantum networks. PMID- 30470111 TI - Ultrafast Zn(Cd,Mg)O:Ga nanoscintillators with luminescence tunable by band gap modulation. AB - Photo-induced synthesis was used for preparation of powder Zn(Cd,Mg)O:Ga scintillating nanocrystals featuring properties of solid solutions. Only ZnO phase was identified without any phase separation up to 10% of Cd after optimization of the preparation. Radioluminescence spectra show the exciton related emission in UV spectral range with significant blue (ZnMgO:Ga) or red (ZnCdO:Ga) shifts. The emission wavelength is tunable by the Cd/Mg content. Defect-related emission is completely suppressed after treatment in reducing atmosphere. Photoluminescence and cathodoluminescence decays show extremely fast component. Subnanosecond decay together with band gap modulation make Zn(Cd,Mg)O:Ga good candidate for practical applications like X-ray induced photodynamic therapy (PDTX) or those requiring superfast timing. PMID- 30470112 TI - Cool white light emission from Dy3+ activated alkaline alumino silicate phosphors. AB - A series of single phase white light emitting CaSrAl2SiO7:Dy3+ phosphors were prepared by traditional high temperature solid state reaction method. Structural characterization was done by X-ray diffraction, field emission scanning electron microscopy and energy dispersive spectroscopy analyses. Optical characterization was performed from photoluminescence and thermoluminescence studies. When excited at 350 nm, CaSrAl2SiO7:Dy3+ phosphors showed two intense emission bands in the blue region (480 nm and 493 nm) corresponding to 4F9/2 -> 6H15/2 transition and one in yellow region (576 nm) corresponding to 4F9/2 -> 6H13/2 transition. The Commission Internationale de I'Eclairage diagram was drawn for entire series. It confirmed that by manipulating Dy3+ content the luminescence color of CaSrAl2SiO7:Dy3+ phosphors were tuned from blue to white region. Computation of correlated color temperature suggested that present phosphor was cool in appearance hence CaSrAl2SiO7:Dy3+ phosphor can serve as a white light emitting phosphor and may be useful in outdoor illumination. A detailed study on thermoluminescence of ultraviolet exposed samples was done and possible mechanism of thermoluminescence was discussed. TL emission spectrum was also measured. PMID- 30470113 TI - Efficient directional coupling from multilayer-graphene-based long-range SPP waveguide to metal-based hybrid SPP waveguide in mid-infrared range. AB - Graphene-based and metal-based surface plasmon polariton (SPP) waveguides have attracted intense research interest because they can be used as basic components to propagate electromagnetic (EM) waves in future optical integrated systems. We propose a directional coupler, which can couple EM energy from a multilayer graphene-based cylindrical long-range SPP waveguide to a metal-based cylindrical hybrid SPP waveguide in the mid-infrared range. This coupler exhibits relatively low coupling length, high coupling efficiency, low insertion loss, and high extinction ratio after adjustment of the wave vector mismatch of the two waveguides. Moreover, this coupler is tolerant to practical fabrication errors like misalignment of graphene layres, and can effectively work in the range of Fermi energy Ef > 0.6 eV when the mobility of graphene varies from 10000 to 800 cm2/Vs. Hence, the coupler offers potential applications in signal routing and information exchange between graphene-based and metal-based SPP waveguides in photonic integrated circuits. PMID- 30470114 TI - Design of thin-film photonic crystals with complete photonic bandgap. AB - We theoretically investigate the optical characteristics of a thin-film photonic crystal structure with a complete photonic bandgap for both polarization of the transverse electric and transverse magnetic modes for any in-plane direction. The structure consists of three-layer stacked two-dimensional photonic crystal slabs, and the thickness of the structure is less than a few wavelengths. We show that a wide complete photonic bandgap can be obtained in the asymmetrically stacked photonic crystal structure. In addition, we designed a waveguide with a broad bandwidth of 100 nm and a nanocavity with a quality factor of 3.7 * 107 in the structures. PMID- 30470115 TI - Control on helical filaments by twisted beams in a nonlinear CS2 medium. AB - Curved filament with large bent angle and controllable propagation behavior has always been great expectation and challenge due to its novelty and complexity. The unique properties of curved filaments make it possible to achieve many applications in micro-fabrication, spectroscopy and meteorology. Here we realize experimentally and theoretically control on helical filaments induced by twisted beams in CS2. The results show that helical filaments exhibit a robust pattern and high rotation rate. Specific intensity pattern of the twisted beam confines the filaments in fixed relative position and the azimuthal energy flux drives the rotating of the filamentation pattern. In addition, we demonstrated that the global orbital angular momentum (OAM) of twisted beams is still conservative to be zero, but local OAMs exhibit distinct variation during nonlinear propagation. Our idea has its significance which realizes the construction of helical filaments with flexibility and controllability and then facilitates to push the development of related researches. PMID- 30470116 TI - Informationally symmetrical Bell state preparation and measurement. AB - Bell state measurement (BSM) plays crucial roles in photonic quantum information processing. The standard linear optical BSM is based on Hong-Ou-Mandel interference where two photons meet and interfere at a beamsplitter (BS). However, a generalized two-photon interference is not based on photon-photon interaction, but interference between two-photon probability amplitudes. Therefore, it might be possible to implement BSM without interfering photons at a BS. Here, we investigate a linear optical BSM scheme which does not require two photon overlapping at a BS. By unleashing the two photon coexistence condition, it can be symmetrically divided into two parties. The symmetrically dividable property suggests an informationally symmetrical BSM between remote parties without a third party. We also present that our BSM scheme can be used for Bell state preparation between remote parties without a third party. Since our BSM scheme can be easily extended to multiple photons, it can be useful for various quantum communication applications. PMID- 30470117 TI - High-accuracy sinewave-scanned direct absorption spectroscopy. AB - A novel method with high accuracy and easy implementation was proposed based on the sinewave-scanned direct absorption spectroscopy (DAS) in this paper. A fitting routine in the time domain was developed to simultaneously deduce the baseline and more importantly, absorbance through the explicit baseline expression offered by the sinewave scan. This method effectively solves the difficulties of baseline determination and provides more accurate wavelength calibration compared with conventional DAS. The accuracy and performance with narrow scans and high frequency were experimentally verified using CO transition at 4300.699 cm-1, from which the inferred line strength agrees well with HITRAN 2016. Meanwhile, a more accurate N2 collisional broadening was provided and the speed-dependent collisional broadening coefficient of this transition was reported for the first time. PMID- 30470118 TI - Controllable radiation properties of a driven exciton-biexciton quantum dot couples to a graphene sheet. AB - We investigate the radiation properties of a driven exciton-biexciton structure quantum dot placed close to a graphene sheet. The study of the Purcell factor then demonstrates the tunability of light-matter coupling, which in turn provides the possibility to control the steady-state populations. As the result, dipole transitions can be selectively enhanced and asymmetry in the resonance fluorescence can be observed. Meanwhile, both quadratures can exhibit two-mode squeezing at the Rabi sideband frequencies. A further study shows that although the increase in the environment temperature has a destructive influence on the population imbalance, squeezing occurs even at room temperature. Due to the flexibility in controlling the resonance fluorescence spectrum and producing two mode squeezed states, our proposal would have potential applications in quantum information and other quantum research fields. PMID- 30470119 TI - Reference image based phase unwrapping framework for a structured light system. AB - A novel real-time full-field phase unwrapping framework is proposed for the one projector and one-camera structured light system. In this framework, only four patterns (including three fringe patterns and a binary speckle pattern) are required to measure the absolute 3D shape of the targets. We use the structured light system to capture four images of a nearly planar target (e.g. wall), of which the speckle image is taken as the reference image, and the corresponding absolute phase map is computed and stored, before measuring. So each pixel in the reference image can be mapped to an absolute phase value. In this way, if we can create the correspondences between the current and the reference speckle images in the process of measurement by using a matching algorithm, we can directly map the absolute values for the pixels of the current image. The mapped absolute phases can be used to determine the period of the relative phases. The experimental results verified the effectiveness and efficiency of the proposed framework. On a consumer-grade GPU (Nvidia GTX1060), our method can run at 187 fps. PMID- 30470120 TI - Regeneration of ischemic tissue and improvement of blood supply using stem cells up-to-date knowledge and potential use in no-option critical limb ischemia. AB - INTRODUCTION: Cardiovascular disorders and their complications are the leading causes of death all over the world. The number of patients with critical limb ischemia and in risk of amputation is increasing together with increased incidence of cardiovascular diseases. In comparison with comparable population, the prognosis of patients after limb amputation is much worse. In case with no possible revascularisation, stem cell therapy offers a possible option for limb salvage. METHODS: We collected relevant informations from published and accessible studies available on internet database Pubmed in period of 2007-2017. The key words stem cell and critical limb ischemia were used. CONCLUSION: Available informations show promising results in the use of stem cells in the treatment of no-option limb ischemia. Multicenter randomized clinical trials and unified recommendations and guidelines are needed to accept this method as available option for treatment. This article is presenting a short rewiev of circumstancies and conditions of this evolving method of treatment. Key words: stem cell - limb ischemia. PMID- 30470121 TI - Strategies preventing deep sternal wound infection in cardiac surgery review. AB - Deep sternal wound infection is a feared complication of cardiac surgery due to the negative impact on mortality, morbidity and long-term survival. Its incidence has remained more or less unchanged over the last three decades despite the significant increase in patients' morbidity and complexity of cardiac surgery. The review summaries strategies to reduce the incidence of deep sternal wound reflecting general surgical site infection prevention and specificities of surgery performed through the median sternotomy. Furthermore, contemporary evidence-based recommendations for prevention of this complication are highlighted in the review. Key words: sternal infection - prevention - cardiac surgery. PMID- 30470122 TI - Bipolar radiofrequency-induced thermotherapy of haemorrhoids: a 10-year experience. AB - INTRODUCTION: Bipolar radiofrequency-induced thermotherapy of advanced stage haemorrhoid disease has been used successfully at the Atlas Hospital in Zlin for ten years. The aim of this study was to evaluate long-term outcomes of the method. METHOD: RFITTH is bipolar radiofrequency-induced thermotherapy of haemorrhoidal diseases. High frequency electric current causes thermal coagulation of tissue. The procedure results in the elimination or significant reduction of prolapse and bleeding of hemorrhoids. RESULTS: 228 RFITTH procedures were performed in 217 patients at the Department of Surgery at the Atlas Hospital from 9/2007 to 1/2017. The group consisted of 134 men and 94 women, the average age was 51 years. 107 operations were performed in stage III and 121 in stage IV. Complications of the procedure involved postoperative fissure occurring in 20 patients (8.7 %). Thrombotic haemorrhoid developed in 6 patients (2.6 %), hyperspasm of the sphincters in 9 patients (3.9 %). Prolapse of the rectal mucosa was diagnosed in 4 patients (1.7 %). The disease recurred in 9 patients and 10 reoperations were performed (3.9 %). CONCLUSION: The method is a safe miniinvasive therapeutic option for advanced stage haemorrhoidal disease. Key words: RFITTH - haemorrhoidal disease - radiofrequency coagulation. PMID- 30470123 TI - Celiac axis compression syndrome - diagnostic and surgical treatment. AB - INTRODUCTION: Celiac axis compression syndrome is one of the causes of chronic abdominal ischemia. The authors describe their experience with the surgical treatment of Dunbar syndrome in 12 patients. The purpose of the authors was a retrospective analysis of the surgical treatment of celiac axis compression syndrome. METHOD: Between 2007 and 2016, we treated 12 patients for the celiac axis compressive syndrome. Each patient has performed abdominal sonography, CT angiography, or angiography. The method of choice in these patients was surgical treatment. In 4 patients we resected median arcuate ligament and nerve fibers of celiac axis. In 8 patients we had to resect the stenotic or occluded celiac axis. We reconstructed the blood supply to the celiac axis by the aorto-celiac bypass, using prothetic or venous grafting or patch plastic of celiac axis stenosis. RESULTS: There were no significant complications and deaths in the post - operative period. In one patient signs of chronic abdominal ischemia postoperatively persist. CONCLUSION: Surgery is the method of choice of celiac axis compression syndrome. Indications for surgical reconstruction are symptomatic patients with arterial stenosis over 50%. Proper diagnosis and early surgical treatment are essential for treating chronic visceral ischemia and reducing surgical complications. Key words: celiac axis compression syndrome - chronic abdominal ischemia - resection of ligamentum median arcuate. PMID- 30470124 TI - Asynchronous tumour quadruplicity: rectosigmoid adenocarcinoma, renal cell carcinoma, prostate adenocarcinoma and neuroendocrine small-cell lung cancer - a case report. AB - INTRODUCTION: Multiple tumors belong to rare cancers. Almost all malignancies may occur in combination, the most common combination being gastrointestinal cancer with respiratory or urogenital tract cancer and with breast cancer in females. CASE REPORT: In 1999, a 66-year-old patient was diagnosed with a rectosigmoid tumor histologically proven as adenocarcinoma. Rectosigmoid resection was performed, followed by adjuvant radiotherapy and the Mayo Clinic FU/FA chemotherapy regimen. Radical nephrectomy was performed in January 2005 due to right kidney tumor, histologically detected as clear cell carcinoma. In February 2006, the patient underwent bilateral pelvic lymphadenectomy for biopsy-verified adenocarcinoma of the prostate with PSA 20.8 ng/ml. Radical prostatectomy was performed in April 2006. Histology demonstrated moderately differentiated adenocarcinoma in both prostatic lobes classified as Gleason score 4 (1+3), without invasion into the capsule or seminal vesicles infiltration. In June 2016, a native X-ray of the lungs revealed a subpleural small dense node in the right upper pulmonary field. PET/CT of the trunk was also performed showing liver metastasis and pulmonary deposits, including enlargement of the mediastinal nodules. In October 2016, liver biopsy was taken and the serum level of neuron specific enolase (NSE: 93 ng/ml) was measured. Histology demonstrated neuroendocrine carcinoma of the small cell type. In November 2016, palliative chemotherapy with carboplatin and etoposide administered once a month was initiated. After 4 chemotherapy cycles, no deposits on the liver were detected by sonography. A native X-ray image of the lungs still showed a 15mm deposit, but NSE levels returned to normal. In March 2017, treatment continued with palliative radiotherapy of the right lung, mediastinal lymphatic nodes and prophylactic radiotherapy of the skull was planned as a next step. In August 2017, the patient died due to renal function failure and deterioration of the general condition. CONCLUSION: The patient worked in uranium mines and underwent radio-chemotherapy after the first malignancy - rectosigmoid tumor. Genetic examination was not performed. The patient died of therapeutic complications of the last malignancy. Our case report does not confirm findings described so far - a shortening interval between malignancies - but confirms their increasing aggressiveness. Key words: quadruplicity - rectosigmoid adenocarcinoma - renal-cell carcinoma - prostate adenocarcinoma - neuroendocrine small-cell lung cancer. PMID- 30470125 TI - Fasciitis necrotisans - duplicitas casuum. AB - Necrotizing fasciitis is a dangerous bacterial infectious disease that is not commonplace in Czech society. On the other hand, neither is it so rare that the majority of surgeons should not come across it occasionally. In the early stages, pathological changes in fascia, subcutaneous tissue and even skin may run an inconspicuous course. However, this can rapidly deteriorate into shock and sepsis which may lead to multi-organ failure and an imminent life-threatening condition. The fatality rate of necrotizing fasciitis among high-risk groups (e.g. diabetics, patients who are immuno-compromised, obese and/or elderly, malnourished, or with a history of drug use), is particularly steep, reaching as high as 73%. Treatment for this condition consists of early, radical surgical intervention in conjunction with targeted antibiotherapy. Complex resuscitative and intensive care, including rehabilitation, are standard components of post surgical management. Use of hyperbaric oxygen therapy, if such an opportunity exists, is also recommended. Interdisciplinary collaboration is a vital prerequisite for successful treatment. This article describes two case-studies of necrotizing fasciitis that occurred in men of similar age during a three-year period. Both patients presented with very similar and complicated disease courses, and both were successfully treated by the same interdisciplinary team comprised of clinicians from various specialized departments. Key words: necrotizing fasciitis - radical necrectomy - antibiotherapy - hyperbaric oxygen therapy - complex resuscitative and intensive care. PMID- 30470126 TI - Clear-cell sarcoma of tendons and aponeuroses in the right genitofemoral line - a case report. AB - INTRODUCTION: Our case report presents a rare occurrence of clear cell sarcoma in the genitofemoral line region that has not been described to date. CASE REPORT: A 57-year-old male patient with clear-cell sarcoma of tendons and aponeuroses is presented. The patient underwent a radical operation and adjuvant radiotherapy. CONCLUSION: The patient is still alive, in a good health condition, without local recurrence or generalised disease. Key words: clear-cell sarcoma of tendons and aponeuroses - genitofemoral line. PMID- 30470127 TI - Isolation of a new natural kingiside aglucone derivative and other anti inflammatory constituents from Syringa reticulata. AB - A new secoiridoid, (1R,5S,8S,9R)-1-methyl-kingiside aglucone (1), along with nine known compounds (2-10), were isolated from the ethanol extract of the stem bark of Syringa reticulata (Bl.) Hara. The structure of compound 1 was elucidated using HR-ESI-MS, 1D and 2D NMR spectroscopy. Compounds 1-10 were evaluated for their inhibitory activity against NO, TNF-alpha and IL-6 production. Compounds 1, 3, 5 and 7-10 significantly inhibited the levels of NO, TNF-alpha and IL-6 in LPS induced RAW264.7 cells from concentrations of 3 to 30 MUM. PMID- 30470128 TI - Anti-inflammatory effects of mulberry (Morus alba L.) root bark and its active compounds. AB - Mulberry (Morus alba L.) root bark (MRB) was extracted using methanol and the extracts were subjected to tests of anti-inflammatory effects. The ethyl acetate fraction demonstrated the best anti-inflammatory effects. Purified compounds, sanggenon B, albanol B and sanggenon D, showed inhibitory effects on NO production in LPS-stimulated RAW264.7 cells and albanol B demonstrated the best anti-inflammatory effects. Regarding the underlying molecular mechanisms, further investigations showed that treatments with Albanol B reduced production of pro inflammatory cytokines and decreased expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). These results would contribute to development of novel anti-inflammatory drugs from MRB. PMID- 30470129 TI - Efficient preparation of rare Sagittatoside A from epimedin A, by recyclable aqueous organic two-phase enzymatic hydrolysis. AB - The rare secondary flavonol glycoside Sagittatoside A has much better in vivo bioactivities than epimedin A in Epimedii Folium. However, its current preparation methods are of low efficiency, with byproducts generated. The aim of this study was to establish a novel catalysis system for effective and convenient preparation of Sagittatoside A from epimedin A based on recyclable and integrated aqueous organic two-phase enzymatic hydrolysis. The system was consisted of propyl acetate and HAc-NaAc buffer (pH4.5) containing beta-dextranase/epimedin A, and the hydrolysis was performed at 60 degrees C for 1 h. Consequently, epimedin A was completely hydrolyzed to sagittatoside A, and 95.02% of the product was transferred into the organic phase. Moreover, 90% of its initial activity was retained after seven cycles of hydrolysis. Additionally, the procedure was simpler than conventional enzymatic hydrolysis. Collectively, the newly proposed strategy is an efficient and promising approach for the preparation of sagittatoside A in industrial application. PMID- 30470130 TI - Potential beneficial and/or adverse effects of Capsicum annuum L. (cv. Fiesta) at two stage of ripening in CD-1 mice. AB - Aim of the present study was to evaluate the potential beneficial and/or adverse effects of Capsicum annuum L. (cv. Fiesta) extracts at two stage of ripening (immature and mature), and at two dosages (low and high) by evaluation of biochemical profile and oxidative status in CD-1 mice. The extracts were daily administered to mice by oral gavage for 20 days. At the end of the trial, the animals were euthanatized and blood was collected. Evidence of liver damage (increase of AST, ALT and bilirubin) in the group receiving the higher dosage of immature peppers extract were observed. Even if no adverse effects were seen at the lower doses, also no signs of beneficial effects in term of health status, biochemical profile and oxidative status were detected. These results are in contrast with in vitro findings and raise doubts about the possible use of Capsicum annuum L. (cv. Fiesta) as a nutritional supplement. PMID- 30470131 TI - Inhibitory effects of schisantherin F from Schisandra propinqua subsp. sinensis on human melanoma A375 cells through ROS-induced mitochondrial dysfunction and mitochondria-mediated apoptosis. AB - Schisandra propinqua subsp. sinensis is a traditional medicinal plant used in Chinese folk medicine. Melanoma is the most dangerous form of skin cancer. To discover bioactive phytochemicals for preventing human melanoma, we have investigated the inhibitory effects of schisantherin F in Schisandra propinqua subsp. sinensis on human melanoma A375 cells and relevant mechanisms. The results showed that schisantherin F can inhibit A375 cells through inducing apoptosis. Further investigations have demonstrated schisantherin F attenuated the overproduction of ROS, depolarization of MMP, and mPTP opening. Meanwhile, schisantherin F inhibited the activity of Caspase-3 and up-stream Caspase-9, down regulated Bcl-2 and up-regulated Bax. These findings propose the inhibitory mechanisms of schisantherin F in A375 cells include induction of mitochondrial dysfunction and mitochondria-mediated apoptosis. PMID- 30470132 TI - Isolation and characterization of novel antibacterial compound from an untapped plant, Stereospermum fimbriatum. AB - Stereospermum fimbriatum or locally known as "Chicha" is traditionally used for itchy skin, earache, stomachache and postpartum treatments. This study was designed to evaluate the antimicrobial potential of S. fimbriatum's stem bark against 11 pathogens and isolate its bioactive compound. Successive soxhlet extraction was conducted using n-hexane, dichloromethane (DCM) and methanol. Disc diffusion, minimum inhibitory and bactericidal concentration (MIC & MBC) assays were done to examine the antimicrobial activity. Bioassay-guided isolation was conducted on S. fimbriatum's extract. The DCM extract of stem bark (DS) was the most potent extract followed by n-hexane extract of the stem bark (NS). A novel compound was isolated and coded as C1 which demonstrated potent antibacterial effects with the MIC values as low as 3.13 ug/mL to 6.25 ug/mL, against S. epidermidis, MRSA and S. aureus. Thus, S. fimbriatum could be a potential source of antimicrobial agents for the treatment of skin infections, specifically, MRSA. PMID- 30470133 TI - Improvement of stilbenoid production by 2-hydroxypropyl-beta-cyclodextrin in white mulberry (Morus alba L.) callus cultures. AB - Mulberroside A, oxyresveratrol and resveratrol, commonly found in Morus alba L., are potent anti-aging phytostilbenes. In this study, the effect of the addition of 2-hydroxypropyl-beta-cyclodextrin on the levels of phytostilbenes in M. alba callus cultures was investigated. Commercial cyclodextrin was used in the hydrolytic and culture processes of the M. alba callus cultures. The hydrolytic study indicated that 2-hydroxypropyl-beta-cyclodextrin acted as a retardant for stilbenoid hydrolysis. It reduced mulberroside A deglycosylation and stabilised oxyresveratrol. The elicitation result showed that extracellular oxyresveratrol was increased by adding 2-hydroxypropyl-beta-cyclodextrin to the culture media of both free and immobilised M. alba callus (>730-fold and >169-fold, respectively) compared with those of the control. However, the intracellular mulberroside A levels in the treatment groups did not increase compared with those of the control. The results show that the addition of 2-hydroxypropyl-beta-cyclodextrin significantly changed the patterns and levels of the stilbenoids in M. alba callus cultures. PMID- 30470134 TI - Isolation and structure determination of a new indene derivative from endophytic fungus Aspergillus flavipes Y-62. AB - As part of the search for naturally derived secondary metabolites, a novel indene derivative, compound 1, together with nine known metabolites (2-10) have been purified from an ethyl acetate extract of the plant-associated fungus Aspergillus flavipes Y-62, isolated from Suaeda glauca (Bunge) Bunge which was collected along Zhoushan coast, Zhejiang province, East China. The structure of the new compound 1 was elucidated by extensive use of spectroscopic techniques like 1D, 2D NMR, and HR-TOF-MS, while the known metabolites were established based on both spectral methods as well as by comparison with the previous literature. Compound 1 exhibited antimicrobial activities against the gram-negative pathogen Pseudomonas aeruginosa and Klebsiella pneumoniae with equal MIC values of 32 ug/ml. PMID- 30470135 TI - New trans-beta-bergamotene derivatives in the root and the flower essential oils of Cyanthillium cinereum (L.) H. Rob. from Cote d'Ivoire. AB - Root and flower essential oils of Cyanthillium cinereum (L.) H. Rob. (Synonym Vernonia cinerea (L.) Less.) (Asteraceae) collected in Southern Cote d'Ivoire was investigated using a combination of chromatographic and spectroscopic techniques. The root oil composition was dominated by trans-beta-bergamotene (20.7%), beta elemene (19.0%), cyperene (10.6%), germacrene A (7.1%) and beta-pinene (3.8%), whereas gamma-humulene (31.0%), (E)-beta-caryophyllene (17.0%), trans-beta bergamotene (7.7%), beta-pinene (7.5%) and (E)-beta-farnesene (6.0%) were the major components of flower oil. Two new compounds bearing the trans-beta bergamotene framework were identified: trans-beta-bergamotenone and (E)-trans beta-bergamotenol. PMID- 30470137 TI - The age of ambergris. AB - Ambergris, which is a coprolith originating from the sperm whale, has been found only rarely, but for centuries, as jetsam on beaches all over the world. There are no reliable data indicating how long such samples may have remained at sea, with unsubstantiated accounts suggesting maybe decades. Here, we obtained over forty jetsam samples, many collected on known dates, from mostly known beach locations across the globe. Such an inventory of verified jetsam ambergris is unprecedented. Each sample was characterised by analytical methods such as gas chromatography-mass spectrometry (GC-MS). We then determined the radiocarbon ages of some of the samples by well-described accelerator-MS techniques. Surprisingly, some samples of jetsam have remained in the environment for about a thousand years. PMID- 30470136 TI - A new tetracyclic saponin from Astragalus glycyphyllos L. and its neuroprotective and hMAO-B inhibiting activity. AB - A new tetracyclic saponin, 17(R),20(R)-3beta,6alpha,16beta-trihydroxycycloartanyl 23-carboxylic acid 16-lactone 3-O-beta-D-glucopyranoside (1) together with one known flavonoid, camelliaside A (2) were isolated from the aerial parts of Astragalus glycyphyllos L. Their structures were determined by chemical, HRESIMS and NMR methods. On 6-hydroxydopamine in vitro model on isolated rat brain synaptosomes, compounds 1-2 had statistically significant neuroprotective activity similar to that of Silibinin, tested at 100 MUM. Saponin 1 possessed the most prominent neuroprotective and antioxidant effects in this in vitro model. On human recombinant monoamine oxidase type B enzyme compound 1 displayed strong inhibiting activity, compared to Selegiline (1 MUM). It could be concluded that the new epoxycycloartane saponin 1 could be a promising leading structure in respect of neurodegenerative diseases. PMID- 30470138 TI - A new phenolic compound from Phedimus middendorffianus with antiproliferative activity. AB - A new phenolic compound (1) and together with 12 known compounds-eight flavonoids (2 ~ 9), two phenolic compounds (10 and 11) and two benzoic acid (12 and 13)-were isolated from Phedimus middendorffianus (Maxim.). The structures of all compound were determined on the basis of spectroscopic (MS and NMR) analyses. Compounds 4, 5, 7 and 11 ~ 13 were showed anti-proliferative activities against MCF-7 than PC 3 cell line. Also compound 12 and 13 showed the significant cytotoxic activities against two cancer cell lines, PC-3 and MCF-7. PMID- 30470139 TI - Organic pollution in PGI and non-PGI lemons and related soils from Italy and Turkey. AB - In this work 67 organic contaminants in Protected Geographical Indication (PGI) and non-PGI Interdonato Lemon pulps, peels, leave and related soils were evaluated by GC/MS-MS. It is possible to highlight that in Italian pulps and peels the residues were under LODs (0.10-10.30 ng.g-1), whereas the leaves showed piperonyl butoxide in 33% of samples (11.76 +/- 1.24 ng.g-1) and cypermethrins in 33% of samples (Cypermethrin I, 6.12 +/- 0.35 ng.g-1; Cypermethrin II, 8.67 +/- 0.48 ng.g-1; Cypermethrin III, 8.90 +/- 1.52 ng.g-1; Cypermethrin IV, 12.25 +/- 2.46 ng.g-1). Turkish samples were mainly contaminated by piperonyl butoxide: it was revealed in the 33% of pulps (3.35 +/- 1.03 ng.g-1), in 100% of peels (23.46 +/- 17.69 ng.g-1) and in 100% of leaves (1302.44 +/- 527.40 ng.g-1). In both soils a different contamination was detected. This study confirms that the European brand (PGI) of Interdonato Lemon Messina is a valuable instrument for the consumer protection. PMID- 30470140 TI - Short-term delayed recall of auditory verbal learning test provides equivalent value to long-term delayed recall in predicting MCI clinical outcomes: A longitudinal follow-up study. AB - This study was conducted to compare predictive power of Auditory verbal learning test (AVLT) recall measures for Alzheimer's disease (AD) conversion and normal cognition (NC) reversion from mild cognitive impairment (MCI). A total of 262 amnestic MCI patients were followed up longitudinally, who were then classified into different groups based on clinical outcomes. Demographic information and AVLT recall scores at baseline were compared among these groups. Receiver operating characteristic (ROC) curves were constructed to evaluate differentiating value of AVLT recall measures for MCI outcomes. Binary stepwise logistic regression analysis was performed to identify predictive AVLT measures. After average 30.8 +/- 11.6 months follow-up, 89 patients converted to AD and 88 participants reverted to NC. At baseline, AD converters scored significantly lower in AVLT than nonconverters, while NC reverters performed much better than nonreverters (p < .01). AVLT-SR and AVLT-LR had larger areas under curve than AVLT-IR and AVLT-REC in distinguishing patients who progressed to AD or not (p < .05). Both AVLT-SR and AVLT-LR were significant predictors of MCI-to-AD conversion and MCI-to-NC reversion. Among AVLT recall measures, AVLT-SR and AVLT LR provided the best and equivalent values in predicting MCI outcomes. Patients with lower AVLT-SR and AVLT-LR scores are more likely to develop AD. Consequently, AVLR-SR is a valuable and time-saving memory measure that deserves further application in memory clinical practice. PMID- 30470141 TI - Inhibitory potential of Hydroxychavicol on Ehrlich ascites carcinoma model and in silico interaction on cancer targets. AB - Hydroxychavicol (HC), a major phenolic derivative isolated from the leaves of Piper betle L. is well known for its antibacterial, antifungal and antimutagenic properties. The present study evaluated the in vivo antitumor activity of HC against Ehrlich Ascites Carcinoma (EAC) cells in Swiss albino mice and in silico interaction of HC with the receptors involved in the cancer. Hydroxychavicol (200 and 400 mg/kg bw) was orally administered for 21 consecutive days and was effective in inhibiting the tumor growth in ascitic mouse model. HC consistently reduced the tumor volume, viable cell count, lipid peroxidation and elevated the life span of HC treated mice. Besides the hematological profiles, SGOT and SGPT levels reverted back to normal and oxidative stress markers GSH, SOD and CAT also increased in HC treated groups. In silico docking analysis revealed that HC possessed potent antagonist activity against all the cancer targets demonstrating its inhibitory activity. PMID- 30470142 TI - Gypensapogenin H from hydrolyzate of total Gynostemma pentaphyllum saponins induces apoptosis in human breast carcinoma cells. AB - Gypensapogenin H (Gyp H) is a novel dammarane-type triterpene, isolated from hydrolyzate of total saponins from Gynostemma pentaphyllum. Our previous work demonstrated that Gyp H exhibited potent growth inhibitory effects on tumor cells. It significantly inhibited the growth of human breast cancer cells (MDA-MB 231), while having low toxicity to normal human breast epithelial cells, MCF-10a. Further mechanistic study demonstrated that Gyp H decreased survival, inhibited proliferation, migration, induced apoptosis and led to cell cycle arrest. For the MDA-MB-231 cell lines, Gyp H increased expression of P21, Bax and cytochrome c, induced PARP cleavage and activated caspases. Gyp H also reduced expression of CDK2/4, CyclinD1, E2F1 and Bcl2, which associated with the cell cycle arrest. Thus, our finding may be useful for understanding the mechanism of action of Gyp H on breast cancer cells and suggest that Gyp H would be a leading agent for the treatment of breast cancer. PMID- 30470143 TI - Sleep in cluster headache revisited: Results from a controlled actigraphic study. AB - BACKGROUND AND AIM: Cluster headache attacks exhibit a nocturnal predilection, but little is known of long-term sleep and circadian rhythm. The aim was to compare actigraphy measures, firstly in episodic cluster headache patients in bout and in remission and, secondly, to compare each disease phase with controls. METHODS: Episodic cluster headache patients (ICHD III-beta), from the Danish Headache Center and healthy, age- and sex-matched controls participated. Sleep and activity were measured using actigraphy continuously for 2 weeks, along with sleep diaries and, for patients, also attack registration. RESULTS: Patients in bout (n = 17, 2.3 attacks/day) spent more time in bed (8.4 vs. 7.7 hours, p = 0.021) and slept more (7.2 vs. 6.6 hours, p = 0.036) than controls (n = 15). In remission (n = 11), there were no differences compared with controls. Neither were there differences between patients in the two disease phases. In five patients, attacks/awakenings occurred at the same hour several nights in a row. CONCLUSION: Actigraphy offers the possibility of a continuous and long study period in a natural (non-hospital) environment. The study indicates that sleep does not differ between the bout and remission phase of episodic cluster headache. The repeated attacks/awakenings substantiate that circadian or homeostatic mechanisms are involved in the pathophysiology. The protocol was made available at ClinicalTrials.gov (NCT02853487). PMID- 30470144 TI - Comparison of chemical composition and antioxidant activities of two Winter savory subspecies (Satureja montana subsp. variegata and Satureja montana subsp. montana) cultivated in Northern Italy. AB - The Satureja L. genus belongs to the Lamiaceae family and comprises about 30 species commonly known as savory. Savory is represented by aromatic plants which are used as spice, tea and food additive. In this study, we explored the differences in essential oil composition and antioxidant activity between two subspecies occurring in Italy, namely S. montana subsp. variegata and subsp. montana. Essential oils were analyzed by gas chromatography/mass spectrometry and the major volatile constituents were carvacrol (22.5%), p-cymene (17.6%), thymol (17,4%) in the subsp. variegata, and carvacrol (61.9%), p-cymene (9,9%) and gamma terpinene (8.2%) in the subsp. montana. The main chemical difference was the carvacrol:thymol ratio, with the latter much higher in the subsp. montana (above 300) compared with the subsp. variegata. The antioxidant activity was determined by using DPPH, ABTS and FRAP and essential oils displayed noteworthy radical scavenging effects against the ABTS radical (IC50 of 30.02-34.5 ug/ml). PMID- 30470145 TI - A pair of humulane sesquiterpenoid enantiomers from Syringa pinnatifolia. AB - Two humulane-type sesquiterpenoids, namely (+)-alashanoid I (1a) and (-) alashanoid I (1b), were isolated as a pair of enantiomers from the peeled stems of Syringa pinnatifolia. Their structures were elucidated by extensive spectroscopic data (1 D and 2 D NMR, UV, and IR), and the absolute configurations were resolved by X-ray diffraction and experimental and calculated ECD data analysis. PMID- 30470146 TI - Patient preferences for attributes of topical anti-psoriatic medicines. AB - Background Patient preferences should be considered when prescribing topical treatments to drive up adherence and improve clinical outcomes. Objetive The aim of this work was to identify the most important attributes of topical medicines for psoriasis treatment in the patients' view, and explore the sociodemographic and clinical determinants of these preferences. Methods A questionnaire for the evaluation of the relevancy given to specific attributes of topical medicines used for psoriasis treatment was developed (PSO-TOPAP) and was applied to a total of seventy-nine patients, members of the Portuguese Association of Psoriasis (PSOPortugal) or outpatients of a dermatology unit of a central hospital. Results Overall, attributes belonging to the formulation and application domains were greatly valued over attributes related with the container. Only a small number of patient preferences was influenced by age, gender, duration of the disease and age at first diagnosis. Limitations Our findings need to be verified in larger and more diverse patient samples, before generalization can be made. Conclusion The insight obtained in this work can provide guidance to pharmaceutical drug product design and has also potential to improve patient care through the acknowledgement of patient preferences in clinical practice. PMID- 30470147 TI - Two placebo-controlled crossover studies in healthy subjects to evaluate gastric acid neutralization by an alginate-antacid formulation (Gaviscon Double Action). AB - OBJECTIVE: To investigate the intragastric acid neutralization activity of a combined alginate-antacid formulation. SIGNIFICANCE: Published studies have investigated the reflux-suppressing alginate component of Gaviscon Double Action (Gaviscon DA; RB, UK) but intragastric acid neutralization activity of the antacid component has not been evaluated in vivo. METHODS: Intragastric pH monitoring, using a custom-made 10-electrode catheter, was evaluated in a 2-part exploratory study in healthy subjects; Part I (n = 6) tested suitability of the catheter using antacid tablets (Rennie; Bayer, Germany); Part II (n = 12) evaluated gastric acid neutralization activity of Gaviscon DA liquid (20 ml) versus placebo in fasted subjects using a randomized, open-label, crossover design. The primary endpoint was the percentage of time that intragastric pH >=4 was measured during 30 minutes post-treatment. A confirmatory study of identical design was subsequently conducted (n = 20). RESULTS: Monitoring pH using the multi-electrode catheter was a viable approach, directly detecting changes in intragastric pH following a single dose of antacid tablets. In the exploratory study the percentage of time that pH >=4 during 30 minutes post-treatment was 46.8% with Gaviscon DA liquid versus 4.7% with placebo (p = 0.0004). These findings were supported by the confirmatory study, where pH >=4 was recorded 50.8% of the time with Gaviscon DA versus 3.5% with placebo (p = 0.0051). In this study Gaviscon DA was safe and well tolerated. CONCLUSIONS: These studies demonstrate the effective acid neutralizing capacity of Gaviscon DA versus placebo in healthy, fasted subjects. This adds to the evidence base for the combination of alginates and antacids. [Eudra CT 2014-003158-15; 2016-000539-42]. PMID- 30470148 TI - Cancer epigenetics and the potential of epigenetic drugs for treating solid tumors. AB - INTRODUCTION: Epigenetic modification without DNA sequence mutation plays an important role in cancer development. Some small molecular inhibitors targeting key epigenetic molecules have been approved by the Food and Drug Administration to treat hematological malignancies. However, the anticancer effects of these drugs on solid tumors are not satisfactory, and the mechanisms of action remain largely unknown. Areas covered: The review summarizes the latest research on cancer epigenetics and discusses the potentials and limitations of using epigenetic drugs to treat solid tumors. An analysis of possible reasons for epigenetic drug treatment failure in solid tumors in some clinical trials is discussed along with prospects for future development. Expert commentary: Next generation small molecule inhibitors will target novel epigenetic regulators with high cancer specificity. Combined modalities exploiting epigenetic drugs with chemo-/radiotherapy, molecular-targeting drugs and immunotherapy will be able to effectively treat solid tumors in the near future. PMID- 30470149 TI - Identification and characterization of a novel gene-encoded antioxidant peptide obtained from amphibian skin secretions. AB - Amphibian skin is known to secrete gene-encoded antioxidant peptides of small molecular weight, which play important roles in host defense. However, recognition of such peptides is still in its infancy. Here, we discovered a novel gene-encoded antioxidant peptide (named OM-GF17) from skin secretions of amphibian species, Odorrana margaretae. Produced by the post-translational processing of a 61-residue prepropeptide, the amino acid sequence of OM-GF17 was 'GFFKWHPRCGEEHSMWT', with a molecular mass of 2135.7 Da. Functional analysis revealed that OM-GF17 scavenged ABTS+, DPPH, NO and decreased iron oxidation. Our results also implied that five amino acid residues, including Cys, Pro, Met, Trp, and Phe, be related to the antioxidant activity of OM-GF17. Furthermore, OM-GF17 did not exhibit direct microbe-killing activity. This novel gene-encoded antioxidant peptide could help in the development of new antioxidant agents and increase our understanding of the biological functions of amphibian skin. PMID- 30470150 TI - Nanocapsules embedded in microparticles for enhanced oral bioavailability and efficacy of Lopinavir as an anti-AIDS drug. AB - Lopinavir (LPV), an efficient drug for HIV infection treatment, was incorporated into biodegradable PLGA nanocapsules (NCs) embedded in microparticles (MCPs) using the spray-drying technique in an attempt to bypass the P-gp efflux and protect the drug from CYP3A pre-systemic metabolism without ritonavir (RTV). SEM observations confirmed the formation of NCs and their entrapment in the MCPs. LPV loaded NCs and free LPV were released from the MCPs at pH of 7.4 as evidenced by in vitro release studies. Results obtained from rat studies showed a 2-fold higher bioavailability of LPV following oral administration of the optimal formulation than Kaletra(r), the marketed drug, showing that when properly entrapped, LPV can be effectively protected from CYP degradation in the gut as well as from the liver following systemic absorption. It was also shown that serum derived from rats following LPV oral administration in two formulations and Kaletra(r) significantly decreased the multiplication of HIV-1 in cultured SupT1 cells. Furthermore, the LPV formulations markedly restricted the titer of infectious HIV-1 production compared to Kaletra(r) confirming the improved antiviral activity of LPV delivered in the rat blood circulation by the nanocapsules embedded in microparticle formulations. PMID- 30470151 TI - The Use of Videoconferencing for Qualitative Interviewing: Opportunities, Challenges, and Considerations. PMID- 30470152 TI - Family caregivers' involvement in decision-making processes regarding admission of persons with dementia to nursing homes. AB - The current Western health policy of ageing in place relies on a triad collaboration among patients, healthcare service providers and family caregivers. Such collaborations presuppose involvement in a vague juridical landscape. This article explores family caregivers' experiences with involvement in and influence on nursing home decision-making processes for persons with dementia. The data consist of 12 in-depth interviews with family caregivers. Using positioning theory, we demonstrate how family caregivers strive to balance their assumed duty to care for the person with their needs to care for themselves. Their involvement (or non-involvement) in the complex decision-making process is demonstrated through the following seven positions: (1) self-condemning determiner, (2) dominant, (3) proponent, (4) saluting, (5) pending, (6) prisoner, and (7) stooge. Furthermore, we discuss why expedient positions are more available for some individuals and the consequences of family caregivers' various positions on the healthcare policy aims of collaboration and equal healthcare services. PMID- 30470153 TI - A translational case study of empowerment into practice: A realist evaluation of a member-led dementia empowerment service. AB - Involving people with dementia in decision-making is widely accepted as a means of empowering them to lead more independent lives and have more meaningful roles in shaping their care. However, there is a need to conduct rigorous evaluations of empowerment-driven services and policies in order to develop a deeper understanding about how to optimise successful implementation. This paper presents the results of an evaluation of Dementia Northern Ireland, an organisation initiated and led by people with dementia. We used a realist evaluation approach that comprised interviews with 15 people with dementia, three staff and two board members, ethnographic observations, along with documentary analysis to identify 'what works, for whom, under what circumstances'. The analysis used realist logic to build up context-mechanism-outcome configurations. The Dementia Northern Ireland service model of empowerment revolved around the formation and maintenance of social groups of people with dementia. Facilitators, recruited and selected by people with dementia, supported six groups, consisting of one to four members with mild to moderate cognitive impairment. Facilitators helped expand empowerment groups, facilitate decision-making, awareness raising and consultation opportunities with group members. The 'Empowerment Groups' appeared to lead to the development of a shared social identity and a sense of collective strength as indicated by interview and observational data demonstrating an activist mentality among group members to challenge the stigma surrounding dementia. Group members also reported improved quality of life. Widespread implementation of the empowerment model has the potential to lead to reduced stigma and greater social inclusion, increased involvement of people with dementia as active co-producers of policy and service development, better services and support. This case study of Dementia Northern Ireland illustrates that there are boundaries and challenges to empowerment in terms of requiring additional support from staff without dementia. However, despite these challenges, empowerment-driven organisations can and should be committed to involving members in lead roles and key decision-making. PMID- 30470155 TI - Medical Teacher in Ten Minutes. PMID- 30470154 TI - The effectiveness of a couple-based intervention for mild Alzheimer's disease patients and their spousal caregivers in Korea. AB - BACKGROUND AND OBJECTIVES: We evaluated the effectiveness of a Korean version of the Couples Life Story Approach (CLSA-K), a structured life-review program originally developed in the U.S. to help older adults with dementia and their spousal caregivers engage with each other and improve their quality of life. Research design and methods: Fifty mild Alzheimer's disease patients and their spouses were recruited and 37 couples completed the five-week CLSA-K program. Data on psychosocial outcomes-i.e., depressive symptoms, talkativeness, mutuality (for both caregivers and care recipients) and burden (for caregivers)-were collected one week prior to (Time 1) and one week after the intervention (Time 2). Using repeated measures generalized linear models, we examined the differences in the amounts and patterns of the changes in outcomes according to age, gender, and the care-recipients' level of cognitive impairment. RESULTS: Some participants benefited from the CLSA-K program, while others did not. For caregivers, mental health, and marital quality remained stable, while caregiver burden increased among those with spouses who had moderate levels of cognitive impairment. For care-recipients, younger and male participants showed increased talkativeness. Discussion and implications: CLSA-K appears to be promising for specific subgroups of participants in Korea. Multi-component or other approaches may be more beneficial for other couples. Cultural differences as well as social positions may play a role in the acceptability and efficacy of the couple-based intervention. PMID- 30470156 TI - Top-rated AMEE MedEdPublish Papers - May 2018. PMID- 30470157 TI - Community Pharmacy Response in the Aftermath of Natural Disasters: Time-Sensitive Opportunity for Research and Evaluation. AB - One year ago, Hurricane Maria passed over the archipelago of Puerto Rico, leaving widespread disruption of nearly all human services, including the health care sector. In the aftermath of the hurricane, limited access to medical care and prescription medications presented a serious challenge to maintaining control of preexisting chronic diseases. Many patients did not have access to refrigeration for heat-sensitive medications. Significant dietary changes due to the limited availability of shelf-stable foods further exacerbated chronic conditions such as heart failure and diabetes. The role of community pharmacists following a natural disaster has previously been documented, and may include the triage of evacuees, assessment of immunization needs, and provision of prescription medications under a collaborative practice agreement. However, our experience in Puerto Rico demonstrated a variety of barriers limited pharmacists' ability to adequately respond to the magnitude of this disaster. These included medication shortages, extended loss of power, and limited telecommunications for contacting prescribers, disaster relief agencies, and third-party payers. Ultimately, the lack of preexisting emergency protocols made overcoming such barriers difficult. As the first and sometimes only accessible health care provider to many patients following a natural disaster, we must build a solid evidence base and better understanding of the individual, interpersonal, and environmental factors that contribute to the community pharmacist response. To date, however, a paucity of data exists on both the pharmacist and patient factors, which may contribute to an effective immediate response to patient needs at the community pharmacy following a natural disaster. Future research must focus on these multi-level factors to better inform public policy and effective disaster planning. Ultimately, such research and planning will lead to increased resiliency in our primary health care systems in the face of future disasters. PMID- 30470158 TI - Computational Study of Conformational Changes in Human 3-hydroxy-3-methylglutaryl Coenzyme Reductase Induced by Substrate Binding. AB - The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is mainly involved in the regulation of cholesterol biosynthesis. HMGR catalyses the reduction of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonate at the expense of two NADPH molecules in a two-step reversible reaction. In the present study, we constructed a model of human HMGR (hHMGR) to explore the conformational changes of HMGR in complex with HMG-CoA and NADPH. In addition, we analysed the complete sequence of the Flap domain using molecular dynamics (MD) simulations and principal component analysis (PCA). The simulations revealed that the Flap domain plays an important role in catalytic site activation and substrate binding. The apo form of hHMGR remained in an open state, while a substrate induced closure of the Flap domain was observed for holo hHMGR. Our study also demonstrated that the phosphorylation of Ser872 induces significant conformational changes in the Flap domain that lead to a complete closure of the active site, suggesting three principal conformations for the first stage of hHMGR catalysis. Our results were consistent with previous proposed models for the catalytic mechanism of hHMGR. PMID- 30470159 TI - Relationships Between Flow, Mental Toughness, and Subjective Performance Perception in Various Triathletes. AB - This study examined the relationship between mental toughness (MT), subjectively perceived performance, and dispositional flow in a sample of 114 high-performing ironmen and standard distance triathletes ( Mage = 28.81 years, SD = 3.45) recruited from triathlon clubs. Participants completed the Mental Toughness Questionnaire, Dispositional Flow Scale, and self-rated subjectively perceived performance. Pearson's correlations between these measures revealed a significant, positive relationship between global MT and subjective performance ratings ( r = .62, p < .01) and between global MT and all Dispositional Flow subscales ( r = .67-.81, p < .05). Linear regression analyses found that MT subscales accounted for 64% of the variance in dispositional flow. Subjective performance ratings did not add significantly to the regression model. Overall, these findings suggest that MT may contribute positively to ironman competitors' and triathletes' exertion of the cognitive and emotional control necessary to experience flow and perform better. We discuss these results in the context of ironman and triathlon competitions. PMID- 30470160 TI - Fathers' presence in the birth room - Implications for professional practice in the Caribbean. AB - : Aims or Objectives: This study explored the perspectives of Obstetricians and Registered Nurses/Midwives on the presence of expectant fathers in the birth room to better understand the implications for professional practice. METHODS: A qualitative research design was used to explore challenges that affect perceptions and attitudes of Obstetricians and Registered Nurses/Midwives on the research issue. Data were collected using five focus group and five key informant interviews. Data were analyzed using Van Manen's (2007) interpretative phenomenological approach. RESULTS: Four themes emerged (i) perception of the Obstetrician/Registered Nurse/Midwife, (ii) demands on the practitioner, (iii) and support for staff and (iv) potential challenges for practice. Participants held positive views about having expectant fathers' present in the birth room with advantages and disadvantages for practice. With the current staff shortage, expectant fathers' could assume a central role in monitoring and reporting changes in the status of the woman in labour. Depending on the nature of the birth experience, there was a view among respondents that this could have negative implications for the expectant father, as well as, increase the demands on the clinical practitioner. Communication emerged as an essential skill, especially in emergency setting as poor communication could be a source of contention to exacerbate negative perceptions of staff by expectant fathers. CONCLUSIONS: The presence of expectant fathers in the delivery room could have a positive impact on the birth experience for mothers, fathers and health professionals in the Caribbean. Prospective fathers' involvement in birth could support the role of the health professionals, especially in contexts where there are staff shortages. Communication skills are an essential element of quality care and enhancing positive perceptions of health personnel, especially in critical emergency situations. However, depending on the context, it could place additional demands on the health team especially in emergencies. PMID- 30470161 TI - Study of interaction between citrate-coated silver nanoparticles and gamma globulin using spectroscopic method. AB - Studies on the interactions between nanomaterials and biomacromolecules have attracted great attention since it is helpful for the development of functional nanomaterials. Here, the citrate-coated silver nanoparticles (AgNPs) with a diameter of 25.4 +/- 2.0 nm were synthesized by a "seed grow" method. The synthesized AgNPs were characterized by UV-vis absorption spectroscopy, high resolution transmission electron microscopy (TEM), X-ray diffraction (XRD) measurement, EDX analysis as well as Zeta potential measurements. The results indicate that the AgNPs possess uniform size and good monodispersity. The interaction of the synthesized AgNPs with gamma globulin (?-globulin) has been studied by UV-vis absorption spectroscopy, fluorescence spectroscopy, fluorescence lifetime measurement, synchronous fluorescence spectroscopy, three dimensional (3D) fluorescence spectroscopy and circular dichroism (CD) spectroscopy. The results indicate that AgNPs can bind to ?-globulin with high affinity and quench the intrinsic fluorescence of ?-globulin. AgNPs form complex with ?-globulin molecules and the fluorescence quenching is in a static mechanism. The apparent association constant calculated from UV-vis spectra study (Kapp =1.43 * 106 M-1) matches well with the result of fluorescence spectra study (Kb =1.47 * 106 M-1). The calculated thermodynamic parameters (?H, ?S and ?G) suggest that van der Waals interactions and hydrogen bonds play great role in the binding of ?-globulin to AgNPs. Synchronous fluorescence, 3D fluorescence and CD spectroscopy studies show that the synthesized AgNPs can induce slight conformational changes in ?-globulin. PMID- 30470162 TI - Future Technology on the Flight deck: Assessing the use of touchscreens in vibration environments. AB - Use of touchscreens in the flight deck has been steadily increasing, however their usability may be severely impacted when turbulent conditions arise. Most previous research focusses on using touchscreens in static conditions, therefore this study assessed touchscreen use whilst undergoing turbulent representative motion, generated using a 6-axis motion simulator. Touchscreens were tested in centre, side and overhead positions, to investigate how turbulence affected: (1) error rate, movement times and accuracy, (2) arm fatigue and discomfort. Two touchscreen technologies were compared: a 15" infra-red and a 17.3" projected capacitive touchscreen with force sensing capability. The potential of the force sensing capability to minimise unintentional interactions was also investigated. Twenty-six participants undertook multi-direction tapping (ISO 9241; ISO, 2010) and gesture tasks, under four vibration conditions (control, light chop, light turbulence and moderate turbulence). Error rate, movement time and workload increased and usability decreased significantly, with screen position and increasing turbulence level. PMID- 30470163 TI - Preparation of Gelatin Hydrogel Sponges Incorporating Bioactive Glasses Capable for the Controlled Release of Fibroblast Growth Factor-2. AB - Gelatin hydrogel sponges incorporating bioactive glasses (Gel-BG) were fabricated. We evaluated the characteristics of Gel-BG as scaffolds from the perspective of their mechanical properties and the formation of hydroxyapatite by the incorporation of bioactive glasses (BG). In addition, the Gel-BG degradation and the profile of fibroblast growth factor-2 (FGF-2) release from the Gel-BG were examined. Every Gel-BG showed an interconnected pore structure with the pore size range of 180-200 um. The compression modulus of sponges incorporating BG increased. The time profiles of degradation for the 72-h crosslinked gelatin hydrogel sponges incorporating 10 wt% BG (Gel-BG(10)) and 50 wt% BG (Gel-BG(50)) were analogous to that of the 24-h crosslinked gelatin hydrogel sponge without BG (Gel-BG(0)). In measuring the release of FGF-2 from Gel-BG, the Gel-BG(10) and Gel-BG(50) showed almost analogous 100% cumulative release within 28 days in vivo. Additionally, a bioactivity evaluation showed that the presence of gelatin does not affect the in vitro bioactivity of Gel-BG. These sponges showed mechanical and chemical functionality as scaffolds, featuring both the controlled release of FGF-2 and the induction of hydroxyapatite crystallization. PMID- 30470164 TI - Acid-base and electrolyte disturbances in patients with diabetes mellitus. PMID- 30470165 TI - Healthcare market segmentation and data mining: A systematic review. AB - Providing insight into healthcare consumers' behaviors and attitudes is critical information in an environment where healthcare delivery is moving rapidly towards patient-centered care that is premised upon individuals becoming more active participants in managing their health. A systematic review of the literature concerning healthcare market segmentation and data mining identified several areas for future health marketing research. Common themes included: (a) reliance on survey data, (b) clustering methods, (c) limited classification modeling after clustering, and (d) detailed analysis of clusters by demographic data. Opportunities exist to expand health-marketing research to leverage patient level data with advanced data mining methods. PMID- 30470166 TI - Dribbling speed along curved paths predicts attacking performance in match realistic one vs. one soccer games. AB - This study assessed whether a new, closed-skill dribbling or sprinting task could predict attacking performance in soccer. Twenty-five male players were recruited from the Londrina Junior Team Football Academy in Brazil and asked to either dribble the ball or sprint through five custom circuits that varied in average curvature (0-1.37 radians.m-1). These measures were then validated using a realistic one vs. one competition in which each player acted as attacker or defender in turn (N = 1330 bouts). Sprinting (ICC = 0.96) and dribbling (ICC = 0.97) performances were highly repeatable for individual players. Average dribbling speed decreased non-linearly with increasing circuit curvature (F = 239.5; P < 0.001) from 5.19 +/- 0.11 ms-1 on the straightest path to 2.13 +/- 0.03 ms-1 on the curviest. Overall, dribbling but not sprinting performance predicted attacking success in the one vs. one competition, explaining more than 50% of the variation in attacking success alone (rp = 0.70; P < 0.001). In conclusion, our new closed-skill dribbling assessment is a valid and reliable protocol to predict a soccer player's success in attacking performance in one vs. one situation, and can be used to identify talented players. PMID- 30470167 TI - Spontaneous Regression of Atypical Teratoid Rhabdoid Tumor Without Therapy in a Patient With Uncommon Regional Inactivation of SMARCB1 ( hSNF5/INI1). AB - Atypical teratoid/rhabdoid tumor (ATRT) is a high-grade central nervous system tumor, with poor prognosis despite intensive multimodal therapy. Loss of nuclear immunostaining for INI1 due to inactivation of the hSNF5/INI1 tumor suppressor gene is pathognomonic of ATRT. We present a patient with congenital ATRT, who had spontaneous tumor regression without therapy, and is disease-free 4 years later. Tumor histopathology showed rhabdoid cells characteristic of ATRT, but immunohistochemistry revealed heterogeneous loss of nuclear INI1 staining. The populations of INI1-intact and INI1-deficient cells were separated by laser microdissection, for molecular analysis with DNA sequencing and fluorescence in situ hybridization. The INI1-negative cells were found to harbor a heterozygous deletion and truncating mutation of the hSNF5/INI1 locus, while the INI1-intact cells had 2 copies of the wild-type INI1 gene. To our knowledge, this is the first report of spontaneous regression of ATRT, with molecular heterogeneity for SMARCB1 inactivation, with no radiographic signs of recurrence at 4 years after diagnosis. PMID- 30470168 TI - Improvement of the CRISPR-Cpf1 system with ribozyme-processed crRNA. AB - The recently discovered clustered regularly interspaced short palindromic repeats (CRISPR)-Cpf1 system expands the genome editing toolbox. This system exhibits several distinct features compared to the widely used CRISPR-Cas9 system, but has reduced gene editing efficiency. To optimize the CRISPR-Cpf1 (Cas12a) system, we report the inclusion of self-cleaving ribozymes that facilitate processing of the crRNA transcript to produce the precise guide molecule. Insertion of the 3' terminal HDV ribozyme boosted the gene editing activity of the CRISPR-Cpf1 system ranging from 1.1 to 5.2 fold. We also demonstrate that this design can enhance CRISPR-based gene activation. We thus generated an improved CRISPR-Cpf1 system for more efficient gene editing and gene regulation. PMID- 30470169 TI - Maternal health-still a long way to go. PMID- 30470171 TI - Non-invasive vagus nerve stimulation for treatment of cluster headache: early UK clinical experience. AB - BACKGROUND: Evidence supports the use of non-invasive vagus nerve stimulation (nVNS; gammaCore(r)) as a promising therapeutic option for patients with cluster headache (CH). We conducted this audit of real-world data from patients with CH, the majority of whom were treatment refractory, to explore early UK clinical experience with nVNS used acutely, preventively, or both. METHODS: We retrospectively analysed data from 30 patients with CH (29 chronic, 1 episodic) who submitted individual funding requests for nVNS to the National Health Service. All patients had responded to adjunctive nVNS therapy during an evaluation period (typical duration, 3-6 months). Data collected from patient interviews, treatment diaries, and physician notes were summarised with descriptive statistics. Paired t tests were used to examine statistical significance. RESULTS: The mean (SD) CH attack frequency decreased from 26.6 (17.1) attacks/wk. before initiation of nVNS therapy to 9.5 (11.0) attacks/wk. (P < 0.01) afterward. Mean (SD) attack duration decreased from 51.9 (36.7) minutes to 29.4 (28.5) minutes (P < 0.01), and mean (SD) attack severity (rated on a 10 point scale) decreased from 7.8 (2.3) to 6.0 (2.6) (P < 0.01). Use of abortive treatments also decreased. Favourable changes in the use of preventive medication were also observed. No serious device-related adverse events were reported. CONCLUSIONS: Significant decreases in attack frequency, severity, and duration were observed in these patients with CH who did not respond to or were intolerant of multiple preventive and/or acute treatments. These real-world findings complement evidence from clinical trials demonstrating the efficacy and safety of nVNS in CH. PMID- 30470172 TI - Impact of Glossina pallidipes salivary gland hypertrophy virus (GpSGHV) on a heterologous tsetse fly host, Glossina fuscipes fuscipes. AB - BACKGROUND: Tsetse flies (Diptera: Glossinidae) are the vectors of African trypanosomosis, the causal agent of sleeping sickness in humans and nagana in animals. Glossina fuscipes fuscipes is one of the most important tsetse vectors of sleeping sickness, particularly in Central Africa. Due to the development of resistance of the trypanosomes to the commonly used trypanocidal drugs and the lack of effective vaccines, vector control approaches remain the most effective strategies for sustainable management of those diseases. The Sterile Insect Technique (SIT) is an effective, environment-friendly method for the management of tsetse flies in the context of area-wide integrated pest management programs (AW-IPM). This technique relies on the mass-production of the target insect, its sterilization with ionizing radiation and the release of sterile males in the target area where they will mate with wild females and induce sterility in the native population. It has been shown that Glossina pallidipes salivary gland hypertrophy virus (GpSGHV) infection causes a decrease in fecundity and fertility hampering the maintenance of colonies of the tsetse fly G. pallidipes. This virus has also been detected in different species of tsetse files. In this study, we evaluated the impact of GpSGHV on the performance of a colony of the heterologous host G. f. fuscipes, including the flies' productivity, mortality, survival, flight propensity and mating ability and insemination rates. RESULTS: Even though GpSGHV infection did not induce SGH symptoms, it significantly reduced all examined parameters, except adult flight propensity and insemination rate. CONCLUSION: These results emphasize the important role of GpSGHV management strategy in the maintenance of G. f. fuscipes colonies and the urgent need to implement measures to avoid virus infection, to ensure the optimal mass production of this tsetse species for use in AW-IPM programs with an SIT component. PMID- 30470173 TI - Propofol inhibited autophagy through Ca2+/CaMKKbeta/AMPK/mTOR pathway in OGD/R induced neuron injury. AB - BACKGROUND: The neuroprotective role of propofol (PPF) in cerebral ischemia reperfusion (I/R) has recently been highlighted. This study aimed to explore whether the neuroprotective mechanisms of PPF were linked to its regulation of Ca2+/CaMKKbeta (calmodulin-dependent protein kinase kinase beta)/AMPK (AMP activated protein kinase)/mTOR (mammalian target of rapamycin)/autophagy pathway. METHODS: Cultured primary rat cerebral cortical neurons were treated with oxygen glucose deprivation and re-oxygenation (OGD/R) to mimic cerebral I/R injury in vitro. RESULTS: Compared with the control neurons, OGD/R exposure successfully induced neuronal I/R injury. Furthermore, OGD/R exposure notably caused autophagy induction, reflected by augmented LC3-II/LC3-I ratio and Beclin 1 expression, decreased p62 expression, and increased LC3 puncta formation. Moreover, OGD/R exposure induced elevation of intracellular Ca2+ concentration ([Ca2+]i). However, PPF treatment significantly antagonized OGD/R-triggered cell injury, autophagy induction, and [Ca2+]i elevation. Further investigation revealed that both autophagy induction by rapamycin and [Ca2+]i elevation by the Ca2+ ionophore ionomycin significantly reversed the PPF-mediated amelioration of OGD/R-triggered cell injury. Importantly, ionomycin also significantly abrogated the PPF-mediated suppression of autophagy and CaMKKbeta/AMPK/mTOR signaling in OGD/R-exposed neurons. Additionally, activation of CaMKKbeta/AMPK/mTOR signaling abrogated the PPF-mediated autophagy suppression. CONCLUSION: Our findings demonstrate that PPF antagonized OGD/R-triggered neuronal injury, which might be mediated, at least in part, via inhibition of autophagy through Ca2+/CaMKKbeta/AMPK/mTOR pathway. PMID- 30470170 TI - The role of advanced glycation end-products in the development of coronary artery disease in patients with and without diabetes mellitus: a review. AB - BACKGROUND: Traditional risk factors are insufficient to explain all cases of coronary artery disease (CAD) in patients with diabetes mellitus (DM). Advanced glycation end-products (AGEs) and their receptors may play important roles in the development and progression of CAD. BODY: Hyperglycemia is the hallmark feature of DM. An increase in the incidence of both micro-and macrovascular complications of diabetes has been observed with increased duration of hyperglycemia. This association persists even after glycemic control has been achieved, suggesting an innate mechanism of "metabolic memory." AGEs are glycated proteins that may serve as mediators of metabolic memory due to their increased production in the setting of hyperglycemia and generally slow turnover. Elevated AGE levels can lead to abnormal cross linking of extracellular and intracellular proteins disrupting their normal structure and function. Furthermore, activation of AGE receptors can induce complex signaling pathways leading to increased inflammation, oxidative stress, enhanced calcium deposition, and increased vascular smooth muscle apoptosis, contributing to the development of atherosclerosis. Through these mechanisms, AGEs may be important mediators of the development of CAD. However, clinical studies regarding the role of AGEs and their receptors in advancing CAD are limited, with contradictory results. CONCLUSION: AGEs and their receptors may be useful biomarkers for the presence and severity of CAD. Further studies are needed to evaluate the utility of circulating and tissue AGE levels in identifying asymptomatic patients at risk for CAD or to identify patients who may benefit from invasive intervention. PMID- 30470174 TI - Genome-scale analysis of syngas fermenting acetogenic bacteria reveals the translational regulation for its autotrophic growth. AB - BACKGROUND: Acetogenic bacteria constitute promising biocatalysts for the conversion of CO2/H2 or synthesis gas (H2/CO/CO2) into biofuels and value-added biochemicals. These microorganisms are naturally capable of autotrophic growth via unique acetogenesis metabolism. Despite their biosynthetic potential for commercial applications, a systemic understanding of the transcriptional and translational regulation of the acetogenesis metabolism remains unclear. RESULTS: By integrating genome-scale transcriptomic and translatomic data, we explored the regulatory logic of the acetogenesis to convert CO2 into biomass and metabolites in Eubacterium limosum. The results indicate that majority of genes associated with autotrophic growth including the Wood-Ljungdahl pathway, the reduction of electron carriers, the energy conservation system, and gluconeogenesis were transcriptionally upregulated. The translation efficiency of genes in cellular respiration and electron bifurcation was also highly enhanced. In contrast, the transcriptionally abundant genes involved in the carbonyl branch of the Wood Ljungdahl pathway, as well as the ion-translocating complex and ATP synthase complex in the energy conservation system, showed decreased translation efficiency. The translation efficiencies of genes were regulated by 5'UTR secondary structure under the autotrophic growth condition. CONCLUSIONS: The results illustrated that the acetogenic bacteria reallocate protein synthesis, focusing more on the translation of genes for the generation of reduced electron carriers via electron bifurcation, rather than on those for carbon metabolism under autotrophic growth. PMID- 30470175 TI - Metarhizium anisopliae infection reduces Trypanosoma congolense reproduction in Glossina fuscipes fuscipes and its ability to acquire or transmit the parasite. AB - BACKGROUND: Tsetse fly-borne trypanosomiasis remains a significant problem in Africa despite years of interventions and research. The need for new strategies to control and possibly eliminate trypanosomiasis cannot be over-emphasized. Entomopathogenic fungi (EPF) infect their hosts through the cuticle and proliferate within the body of the host causing death in about 3-14 days depending on the concentration. During the infection process, EPF can reduce blood feeding abilities in hematophagous arthropods such as mosquitoes, tsetse flies and ticks, which may subsequently impact the development and transmission of parasites. Here, we report on the effects of infection of tsetse fly (Glossina fuscipes fuscipes) by the EPF, Metarhizium anisopliae ICIPE 30 wild-type strain (WT) and green fluorescent protein-transformed strain (GZP-1) on the ability of the flies to harbor and transmit the parasite, Trypanosoma congolense. RESULTS: Teneral flies were fed T. congolense-infected blood for 2 h and then infected using velvet carpet fabric impregnated with conidia covered inside a cylindrical plastic tube for 12 h. Control flies were fed with T. congolense-infected blood but not exposed to the fungal treatment via the carpet fabric inside a cylindrical plastic tube. Insects were dissected at 2, 3, 5 and 7 days post fungal exposure and the density of parasites quantified. Parasite load decreased from 8.7 * 107 at day 2 to between 8.3 * 104 and 1.3 * 105 T. congolense ml- 1 at day 3 post-fungal exposure in fungus-treated (WT and GZP-1) fly groups. When T. congolense-infected flies were exposed to either fungal strain, they did not transmit the parasite to mice whereas control treatment flies remained capable of parasite transmission. Furthermore, M. anisopliae-inoculated flies which fed on T. congolense-infected mice were not able to acquire the parasites at 4 days post fungal exposure while parasite acquisition was observed in the control treatment during the same period. CONCLUSIONS: Infection of the vector G. f. fuscipes by the entomopathogenic fungus M. anisopliae negatively affected the multiplication of the parasite T. congolense in the fly and reduced the vectorial capacity to acquire or transmit the parasite. PMID- 30470177 TI - Prevalence of symbionts and trypanosome infections in tsetse flies of two villages of the "Faro and Deo" division of the Adamawa region of Cameroon. AB - BACKGROUND: Tsetse flies are vectors of human and animal African trypanosomiasis. In spite of many decades of chemotherapy and vector control, the disease has not been eradicated. Other methods like the transformation of tsetse fly symbionts to render the fly refractory to trypanosome infection are being evaluated. The aim of the present study was to evaluate the association between trypanosome infections and the presence of symbionts in these tsetse species. Tsetse flies were trapped in two villages of the "Faro and Deo" Division of the Adamawa region of Cameroon. In the field, tsetse fly species were identified and their infection by trypanosomes was checked by microscopy. In the laboratory, DNA was extracted from their midguts and the presence of symbionts (Sodalis glossinidius and Wolbachia sp.) and trypanosomes was checked by PCR. Symbionts/trypanosomes association tests were performed. RESULTS: Three tsetse fly species including Glossina tachinoides (90.1%), Glossina morsitans submorsitans (9.4%) and Glossina fuscipes fuscipes (0.5%) were caught. In all the population we obtained an occurrence rate of 37.2% for Sodalis glossinidius and 67.6% for Wolbachia irrespective to tsetse flies species. S. glossinidius and Wolbachia sp. occurrence rates were respectively 37 and 68% for G. tachinoides and 28.6 and 59.5% for G. m. submorsitans. Between Golde Bourle and Mayo Dagoum significant differences were observed in the prevalence of symbionts. Prevalence of trypanosomes were 34.8% for Glossina tachinoides and 40.5% for Glossina morsitans submorsitans. In G. tachinoides, the trypanosome infection rates were 11, 2.6 and 13.7%, respectively, for T. brucei s.l., T. congolense forest type and T. congolense savannah type. In G. m. submorsitans, these infection rates were 16.7, 9.5 and, 2.4% respectively, for T. brucei s.l., T. congolense forest type and T. congolense savannah type. CONCLUSIONS: The rate of tsetse fly infection by trypanosomes was low compared to those obtained in HAT foci of south Cameroon, and this rate was not statistically linked to the rate of symbiont occurrence. This study allowed to show for the first time the presence of Wolbachia sp. in the tsetse fly sub-species Glossina morsitans submorsitans and Glossina tachinoides. PMID- 30470176 TI - What can a weevil teach a fly, and reciprocally? Interaction of host immune systems with endosymbionts in Glossina and Sitophilus. AB - The tsetse fly (Glossina genus) is the main vector of African trypanosomes, which are protozoan parasites that cause human and animal African trypanosomiases in Sub-Saharan Africa. In the frame of the IAEA/FAO program 'Enhancing Vector Refractoriness to Trypanosome Infection', in addition to the tsetse, the cereal weevil Sitophilus has been introduced as a comparative system with regards to immune interactions with endosymbionts. The cereal weevil is an agricultural pest that destroys a significant proportion of cereal stocks worldwide. Tsetse flies are associated with three symbiotic bacteria, the multifunctional obligate Wigglesworthia glossinidia, the facultative commensal Sodalis glossinidius and the parasitic Wolbachia. Cereal weevils house an obligatory nutritional symbiosis with the bacterium Sodalis pierantonius, and occasionally Wolbachia. Studying insect host-symbiont interactions is highly relevant both for understanding the evolution of symbiosis and for envisioning novel pest control strategies. In both insects, the long co-evolution between host and endosymbiont has led to a stringent integration of the host-bacteria partnership. These associations were facilitated by the development of specialized host traits, including symbiont housing cells called bacteriocytes and specific immune features that enable both tolerance and control of the bacteria. In this review, we compare the tsetse and weevil model systems and compile the latest research findings regarding their biological and ecological similarities, how the immune system controls endosymbiont load and location, and how host-symbiont interactions impact developmental features including cuticle synthesis and immune system maturation. We focus mainly on the interactions between the obligate symbionts and their host's immune systems, a central theme in both model systems. Finally, we highlight how parallel studies on cereal weevils and tsetse flies led to mutual discoveries and stimulated research on each model, creating a pivotal example of scientific improvement through comparison between relatively distant models. PMID- 30470178 TI - Analysis of the gut-specific microbiome from field-captured tsetse flies, and its potential relevance to host trypanosome vector competence. AB - BACKGROUND: The tsetse fly (Glossina sp.) midgut is colonized by maternally transmitted and environmentally acquired bacteria. Additionally, the midgut serves as a niche in which pathogenic African trypanosomes reside within infected flies. Tsetse's bacterial microbiota impacts many aspects of the fly's physiology. However, little is known about the structure of tsetse's midgut associated bacterial communities as they relate to geographically distinct fly habitats in east Africa and their contributions to parasite infection outcomes. We utilized culture dependent and independent methods to characterize the taxonomic structure and density of bacterial communities that reside within the midgut of tsetse flies collected at geographically distinct locations in Kenya and Uganda. RESULTS: Using culture dependent methods, we isolated 34 strains of bacteria from four different tsetse species (G. pallidipes, G. brevipalpis, G. fuscipes and G. fuscipleuris) captured at three distinct locations in Kenya. To increase the depth of this study, we deep sequenced midguts from individual uninfected and trypanosome infected G. pallidipes captured at two distinct locations in Kenya and one in Uganda. We found that tsetse's obligate endosymbiont, Wigglesworthia, was the most abundant bacterium present in the midgut of G. pallidipes, and the density of this bacterium remained largely consistent regardless of whether or not its tsetse host was infected with trypanosomes. These fly populations also housed the commensal symbiont Sodalis, which was found at significantly higher densities in trypanosome infected compared to uninfected flies. Finally, midguts of field-captured G. pallidipes were colonized with distinct, low density communities of environmentally acquired microbes that differed in taxonomic structure depending on parasite infection status and the geographic location from which the flies were collected. CONCLUSIONS: The results of this study will enhance our understanding of the tripartite relationship between tsetse, its microbiota and trypanosome vector competence. This information may be useful for developing novel disease control strategies or enhancing the efficacy of those already in use. PMID- 30470180 TI - Special issue on enhancing vector refractoriness to trypanosome infection foreword. PMID- 30470179 TI - Combining paratransgenesis with SIT: impact of ionizing radiation on the DNA copy number of Sodalis glossinidius in tsetse flies. AB - BACKGROUND: Tsetse flies (Diptera: Glossinidae) are the cyclical vectors of the causative agents of African Trypanosomosis, which has been identified as a neglected tropical disease in both humans and animals in many regions of sub Saharan Africa. The sterile insect technique (SIT) has shown to be a powerful method to manage tsetse fly populations when used in the frame of an area-wide integrated pest management (AW-IPM) program. To date, the release of sterile males to manage tsetse fly populations has only been implemented in areas to reduce transmission of animal African Trypanosomosis (AAT). The implementation of the SIT in areas with Human African Trypanosomosis (HAT) would require additional measures to eliminate the potential risk associated with the release of sterile males that require blood meals to survive and hence, might contribute to disease transmission. Paratransgenesis offers the potential to develop tsetse flies that are refractory to trypanosome infection by modifying their associated bacteria (Sodalis glossinidius) here after referred to as Sodalis. Here we assessed the feasibility of combining the paratransgenesis approach with SIT by analyzing the impact of ionizing radiation on the copy number of Sodalis and the vectorial capacity of sterilized tsetse males. RESULTS: Adult Glossina morsitans morsitans that emerged from puparia irradiated on day 22 post larviposition did not show a significant decline in Sodalis copy number as compared with non-irradiated flies. Conversely, the Sodalis copy number was significantly reduced in adults that emerged from puparia irradiated on day 29 post larviposition and in adults irradiated on day 7 post emergence. Moreover, irradiating 22-day old puparia reduced the copy number of Wolbachia and Wigglesworthia in emerged adults as compared with non-irradiated controls, but the radiation treatment had no significant impact on the vectorial competence of the flies. CONCLUSION: Although the radiation treatment significantly reduced the copy number of some tsetse fly symbionts, the copy number of Sodalis recovered with time in flies irradiated as 22-day old puparia. This recovery offers the opportunity to combine a paratransgenesis approach - using modified Sodalis to produce males refractory to trypanosome infection - with the release of sterile males to minimize the risk of disease transmission, especially in HAT endemic areas. Moreover, irradiation did not increase the vector competence of the flies for trypanosomes. PMID- 30470181 TI - Towards improving tsetse fly paratransgenesis: stable colonization of Glossina morsitans morsitans with genetically modified Sodalis. AB - BACKGROUND: Tsetse flies (Glossina sp.) refractory to trypanosome infection are currently being explored as potential tools to contribute in the control of human and animal African trypanosomiasis. One approach to disrupt trypanosome transmission by the tsetse fly vector involves the use of paratransgenesis, a technique that aims to reduce vector competence of disease vectors via genetic modification of their microbiota. An important prerequisite for developing paratransgenic tsetse flies is the stable repopulation of tsetse flies and their progeny with its genetically modified Sodalis symbiont without interfering with host fitness. RESULTS: In this study, we assessed by qPCR analysis the ability of a chromosomally GFP-tagged Sodalis (recSodalis) strain to efficiently colonize various tsetse tissues and its transmission to the next generation of offspring using different introduction approaches. When introduced in the adult stage of the fly via thoracic microinjection, recSodalis is maintained at high densities for at least 21 days. However, no vertical transmission to the offspring was observed. Oral administration of recSodalis did not lead to the colonization of either adult flies or their offspring. Finally, introduction of recSodalis via microinjection of third-instar larvae resulted in stably colonized adult tsetse flies. Moreover, the subsequent generations of offspring were also efficiently colonized with recSodalis. We show that proper colonization of the female reproductive tissues by recSodalis is an important determinant for vertical transmission. CONCLUSIONS: Intralarval microinjection of recSodalis proves to be essential to achieve optimal colonization of flies with genetically modified Sodalis and its subsequent dissemination into the following generations of progeny. This study provides the proof-of-concept that Sodalis can be used to drive expression of exogenous transgenes in Glossina morsitans morsitans colonies representing a valuable contribution to the development of a paratransgenic tsetse fly based control strategy. PMID- 30470182 TI - Enhancing vector refractoriness to trypanosome infection: achievements, challenges and perspectives. AB - With the absence of effective prophylactic vaccines and drugs against African trypanosomosis, control of this group of zoonotic neglected tropical diseases depends the control of the tsetse fly vector. When applied in an area-wide insect pest management approach, the sterile insect technique (SIT) is effective in eliminating single tsetse species from isolated populations. The need to enhance the effectiveness of SIT led to the concept of investigating tsetse-trypanosome interactions by a consortium of researchers in a five-year (2013-2018) Coordinated Research Project (CRP) organized by the Joint Division of FAO/IAEA. The goal of this CRP was to elucidate tsetse-symbiome-pathogen molecular interactions to improve SIT and SIT-compatible interventions for trypanosomoses control by enhancing vector refractoriness. This would allow extension of SIT into areas with potential disease transmission. This paper highlights the CRP's major achievements and discusses the science-based perspectives for successful mitigation or eradication of African trypanosomosis. PMID- 30470184 TI - Sodalis glossinidius presence in wild tsetse is only associated with presence of trypanosomes in complex interactions with other tsetse-specific factors. AB - BACKGROUND: Susceptibility of tsetse flies (Glossina spp.) to trypanosomes of both humans and animals has been associated with the presence of the endosymbiont Sodalis glossinidius. However, intrinsic biological characteristics of the flies and environmental factors can influence the presence of both S. glossinidius and the parasites. It thus remains unclear whether it is the S. glossinidius or other attributes of the flies that explains the apparent association. The objective of this study was to test whether the presence of Trypanosoma vivax, T. congolense and T. brucei are related to the presence of S. glossinidius in tsetse flies when other factors are accounted for: geographic location, species of Glossina, sex or age of the host flies. RESULTS: Flies (n = 1090) were trapped from four sites in the Shimba Hills and Nguruman regions in Kenya. Sex and species of tsetse (G. austeni, G. brevipalpis, G. longipennis and G. pallidipes) were determined based on external morphological characters and age was estimated by a wing fray score method. The presence of trypanosomes and S. glossinidius was detected using PCR targeting the internal transcribed spacer region 1 and the haemolysin gene, respectively. Sequencing was used to confirm species identification. Generalised Linear Models (GLMs) and Multiple Correspondence Analysis (MCA) were applied to investigate multivariable associations. The overall prevalence of trypanosomes was 42.1%, but GLMs revealed complex patterns of associations: the presence of S. glossinidius was associated with trypanosome presence but only in interactions with other factors and only in some species of trypanosomes. The strongest association was found for T. congolense, and no association was found for T. vivax. The MCA also suggested only a weak association between the presence of trypanosomes and S. glossinidius. Trypanosome-positive status showed strong associations with sex and age while S. glossinidius-positive status showed a strong association with geographic location and species of fly. CONCLUSIONS: We suggest that previous conclusions about the presence of endosymbionts increasing probability of trypanosome presence in tsetse flies may have been confounded by other factors, such as community composition of the tsetse flies and the specific trypanosomes found in different regions. PMID- 30470183 TI - Blood feeding tsetse flies as hosts and vectors of mammals-pre-adapted African Trypanosoma: current and expected research directions. AB - Research on the zoo-anthropophilic blood feeding tsetse flies' biology conducted, by different teams, in laboratory settings and at the level of the ecosystems- where also co-perpetuate African Trypanosoma- has allowed to unveil and characterize key features of tsetse flies' bacterial symbionts on which rely both (a) the perpetuation of the tsetse fly populations and (b) the completion of the developmental program of the African Trypanosoma. Transcriptomic analyses have already provided much information on tsetse fly genes as well as on genes of the fly symbiotic partners Sodalis glossinidius and Wigglesworthia, which account for the successful onset or not of the African Trypanosoma developmental program. In parallel, identification of the non- symbiotic bacterial communities hosted in the tsetse fly gut has recently been initiated: are briefly introduced those bacteria genera and species common to tsetse flies collected from distinct ecosystems, that could be further studied as potential biologicals preventing the onset of the African Trypanosoma developmental program. Finally, future work will need to concentrate on how to render tsetse flies refractory, and the best means to disseminate them in the field in order to establish an overall refractory fly population. PMID- 30470185 TI - High-sensitivity detection of cryptic Wolbachia in the African tsetse fly (Glossina spp.). AB - BACKGROUND: In African tsetse flies Glossina, spp. detection of bacterial symbionts such as Wolbachia is challenging since their prevalence and distribution are patchy, and natural symbiont titers can range at levels far below detection limit of standard molecular techniques. Reliable estimation of symbiont infection frequency, especially with regard to interrelations between symbionts and their potential impact on host biology, is of pivotal interest in the context of future applications for the control and eradication of Glossina vectored African trypanosomosis. The presence or absence of symbionts is routinely screened with endpoint polymerase chain reaction (PCR), which has numerous advantages, but reaches its limits, when detecting infections at natural low titer. To not only determine presence of native tsetse symbionts but also to localize them to specific host tissues, fluorescence in situ hybridization (FISH) can be applied. However, classic FISH assays may not detect low-titer infections due to limitations in sensitivity. RESULTS: We have compared classic endpoint PCR with high-sensitivity blot-PCR. We demonstrate that the latter technique allows for clear detection of low-titer Wolbachia in the morsitans and palpalis groups while classic endpoint PCR does not. In order to localize Wolbachia in situ in high and low-titer Glossina species, we applied high-end Stellaris(r) rRNA-FISH. We show that with this high sensitivity method, even low amounts of Wolbachia can be traced in specific tissues. Furthermore, we highlight that more tissues and organs than previously recorded are infested with Wolbachia in subspecies of the morsitans and palpalis groups. CONCLUSIONS: Our results demonstrate that overall symbiont infection frequencies as well as the presence in specific host tissues may be underestimated when using low-sensitivity methods. To better understand the complex interrelation of tsetse flies and their native symbionts plus the pathogenic trypanosomes, it is important to consider application of a broader range of high-sensitivity detection tools. PMID- 30470188 TI - Effect of antibiotic treatment and gamma-irradiation on cuticular hydrocarbon profiles and mate choice in tsetse flies (Glossina m. morsitans). AB - BACKGROUND: Symbiotic microbes represent a driving force of evolutionary innovation by conferring novel ecological traits to their hosts. Many insects are associated with microbial symbionts that contribute to their host's nutrition, digestion, detoxification, reproduction, immune homeostasis, and defense. In addition, recent studies suggest a microbial involvement in chemical communication and mating behavior, which can ultimately impact reproductive isolation and, hence, speciation. Here we investigated whether a disruption of the microbiota through antibiotic treatment or irradiation affects cuticular hydrocarbon profiles, and possibly mate choice behavior in the tsetse fly, Glossina morsitans morsitans. Four independent experiments that differentially knock down the multiple bacterial symbionts of tsetse flies were conducted by subjecting tsetse flies to ampicillin, tetracycline, or gamma-irradiation and analyzing their cuticular hydrocarbon profiles in comparison to untreated controls by gas chromatography - mass spectrometry. In two of the antibiotic experiments, flies were mass-reared, while individual rearing was done for the third experiment to avoid possible chemical cross-contamination between individual flies. RESULTS: All three antibiotic experiments yielded significant effects of antibiotic treatment (particularly tetracycline) on cuticular hydrocarbon profiles in both female and male G. m. morsitans, while irradiation itself had no effect on the CHC profiles. Importantly, tetracycline treatment reduced relative amounts of 15,19,23-trimethyl-heptatriacontane, a known compound of the female contact sex pheromone, in two of the three experiments, suggesting a possible implication of microbiota disturbance on mate choice decisions. Concordantly, both female and male flies preferred non-treated over tetracycline treated flies in direct choice assays. CONCLUSIONS: While we cannot exclude the possibility that antibiotic treatment had a directly detrimental effect on fly vigor as we are unable to recolonize antibiotic treated flies with individual symbiont taxa, our results are consistent with an effect of the microbiota, particularly the obligate nutritional endosymbiont Wigglesworthia, on CHC profiles and mate choice behavior. These findings highlight the importance of considering host-microbiota interactions when studying chemical communication and mate choice in insects. PMID- 30470187 TI - Prevalence of trypanosomes, salivary gland hypertrophy virus and Wolbachia in wild populations of tsetse flies from West Africa. AB - BACKGROUND: Tsetse flies are vectors of African trypanosomes, protozoan parasites that cause sleeping sickness (or human African trypanosomosis) in humans and nagana (or animal African trypanosomosis) in livestock. In addition to trypanosomes, four symbiotic bacteria Wigglesworthia glossinidia, Sodalis glossinidius, Wolbachia, Spiroplasma and one pathogen, the salivary gland hypertrophy virus (SGHV), have been reported in different tsetse species. We evaluated the prevalence and coinfection dynamics between Wolbachia, trypanosomes, and SGHV in four tsetse species (Glossina palpalis gambiensis, G. tachinoides, G. morsitans submorsitans, and G. medicorum) that were collected between 2008 and 2015 from 46 geographical locations in West Africa, i.e. Burkina Faso, Mali, Ghana, Guinea, and Senegal. RESULTS: The results indicated an overall low prevalence of SGHV and Wolbachia and a high prevalence of trypanosomes in the sampled wild tsetse populations. The prevalence of all three infections varied among tsetse species and sample origin. The highest trypanosome prevalence was found in Glossina tachinoides (61.1%) from Ghana and in Glossina palpalis gambiensis (43.7%) from Senegal. The trypanosome prevalence in the four species from Burkina Faso was lower, i.e. 39.6% in Glossina medicorum, 18.08%; in Glossina morsitans submorsitans, 16.8%; in Glossina tachinoides and 10.5% in Glossina palpalis gambiensis. The trypanosome prevalence in Glossina palpalis gambiensis was lowest in Mali (6.9%) and Guinea (2.2%). The prevalence of SGHV and Wolbachia was very low irrespective of location or tsetse species with an average of 1.7% for SGHV and 1.0% for Wolbachia. In some cases, mixed infections with different trypanosome species were detected. The highest prevalence of coinfection was Trypanosoma vivax and other Trypanosoma species (9.5%) followed by coinfection of T. congolense with other trypanosomes (7.5%). The prevalence of coinfection of T. vivax and T. congolense was (1.0%) and no mixed infection of trypanosomes, SGHV and Wolbachia was detected. CONCLUSION: The results indicated a high rate of trypanosome infection in tsetse wild populations in West African countries but lower infection rate of both Wolbachia and SGHV. Double or triple mixed trypanosome infections were found. In addition, mixed trypanosome and SGHV infections existed however no mixed infections of trypanosome and/or SGHV with Wolbachia were found. PMID- 30470189 TI - Low recovery of bacterial community after an extreme salinization-desalinization cycle. AB - BACKGROUND: Understanding the recovery of bacterial communities after extreme environmental disturbances offers key opportunities to investigate ecosystem resilience. However, it is not yet clear whether bacterial communities can rebound to their pre-disturbance levels. To shed light on this issue, we tracked the responses of bacterial communities during an extreme salinization desalinization cycle. RESULTS: Our results showed that salinization-up process induced an ecological succession, shifting from a community dominated by Betaproteobacteria to Gammaproteobacteria. Within the desalinization-down process, taxon-specific recovery trajectories varied profoundly, with only Gammaproteobacteria returning to their initial levels, of which Alphaproteobacteria was the most prominent member. The alpha-diversity indices gradually increased at oligosaline environment (0.030/00 to 30/00) and subsequently decreased profoundly at hypersaline condition (100/00 to 900/00). However, the indices did not return to pre-disturbance level along the previous trajectory observed during the desalinization. Approximately half of the original OTUs were not detected during desalinization, suggesting that the seed bank may be damaged by the hypersaline environment. Moreover, Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) implied that the osmosensors' capacity of bacterial communities was also impaired by the hypersaline condition. CONCLUSIONS: These results suggested that the bacterial communities showed a low recovery after the extreme salinization-desalinization cycle. PMID- 30470186 TI - Coevolution of hytrosaviruses and host immune responses. AB - BACKGROUND: Hytrosaviruses (SGHVs; Hytrosaviridae family) are double-stranded DNA (dsDNA) viruses that cause salivary gland hypertrophy (SGH) syndrome in flies. Two structurally and functionally distinct SGHVs are recognized; Glossina pallidipes SGHV (GpSGHV) and Musca domestica SGHV (MdSGHV), that infect the hematophagous tsetse fly and the filth-feeding housefly, respectively. Genome sizes and gene contents of GpSGHV (~ 190 kb; 160-174 genes) and MdSGHV (~ 124 kb; 108 genes) may reflect an evolution with the SGHV-hosts resulting in differences in pathobiology. Whereas GpSGHV can switch from asymptomatic to symptomatic infections in response to certain unknown cues, MdSGHV solely infects symptomatically. Overt SGH characterizes the symptomatic infections of SGHVs, but whereas MdSGHV induces both nuclear and cellular hypertrophy (enlarged non replicative cells), GpSGHV induces cellular hyperplasia (enlarged replicative cells). Compared to GpSGHV's specificity to Glossina species, MdSGHV infects other sympatric muscids. The MdSGHV-induced total shutdown of oogenesis inhibits its vertical transmission, while the GpSGHV's asymptomatic and symptomatic infections promote vertical and horizontal transmission, respectively. This paper reviews the coevolution of the SGHVs and their hosts (housefly and tsetse fly) based on phylogenetic relatedness of immune gene orthologs/paralogs and compares this with other virus-insect models. RESULTS: Whereas MdSGHV is not vertically transmitted, GpSGHV is both vertically and horizontally transmitted, and the balance between the two transmission modes may significantly influence the pathogenesis of tsetse virus. The presence and absence of bacterial symbionts (Wigglesworthia and Sodalis) in tsetse and Wolbachia in the housefly, respectively, potentially contributes to the development of SGH symptoms. Unlike MdSGHV, GpSGHV contains not only host-derived proteins, but also appears to have evolutionarily recruited cellular genes from ancestral host(s) into its genome, which, although may be nonessential for viral replication, potentially contribute to the evasion of host's immune responses. Whereas MdSGHV has evolved strategies to counteract both the housefly's RNAi and apoptotic responses, the housefly has expanded its repertoire of immune effector, modulator and melanization genes compared to the tsetse fly. CONCLUSIONS: The ecologies and life-histories of the housefly and tsetse fly may significantly influence coevolution of MdSGHV and GpSGHV with their hosts. Although there are still many unanswered questions regarding the pathogenesis of SGHVs, and the extent to which microbiota influence expression of overt SGH symptoms, SGHVs are attractive 'explorers' to elucidate the immune responses of their hosts, and the transmission modes of other large DNA viruses. PMID- 30470190 TI - Nuclear and Wolbachia-based multimarker approach for the rapid and accurate identification of tsetse species. AB - BACKGROUND: Tsetse flies (Diptera: Glossinidae) are solely responsible for the transmission of African trypanosomes, causative agents of sleeping sickness in humans and nagana in livestock. Due to the lack of efficient vaccines and the emergence of drug resistance, vector control approaches such as the sterile insect technique (SIT), remain the most effective way to control disease. SIT is a species-specific approach and therefore requires accurate identification of natural pest populations at the species level. However, the presence of morphologically similar species (species complexes and sub-species) in tsetse flies challenges the successful implementation of SIT-based population control. RESULTS: In this study, we evaluate different molecular tools that can be applied for the delimitation of different Glossina species using tsetse samples derived from laboratory colonies, natural populations and museum specimens. The use of mitochondrial markers, nuclear markers (including internal transcribed spacer 1 (ITS1) and different microsatellites), and bacterial symbiotic markers (Wolbachia infection status) in combination with relatively inexpensive techniques such as PCR, agarose gel electrophoresis, and to some extent sequencing provided a rapid, cost effective, and accurate identification of several tsetse species. CONCLUSIONS: The effectiveness of SIT benefits from the fine resolution of species limits in nature. The present study supports the quick identification of large samples using simple and cost effective universalized protocols, which can be easily applied by countries/laboratories with limited resources and expertise. PMID- 30470191 TI - Hytrosavirus genetic diversity and eco-regional spread in Glossina species. AB - BACKGROUND: The management of the tsetse species Glossina pallidipes (Diptera; Glossinidae) in Africa by the sterile insect technique (SIT) has been hindered by infections of G. pallidipes production colonies with Glossina pallidipes salivary gland hypertrophy virus (GpSGHV; Hytrosaviridae family). This virus can significantly decrease productivity of the G. pallidipes colonies. Here, we used three highly diverged genes and two variable number tandem repeat regions (VNTRs) of the GpSGHV genome to identify the viral haplotypes in seven Glossina species obtained from 29 African locations and determine their phylogenetic relatedness. RESULTS: GpSGHV was detected in all analysed Glossina species using PCR. The highest GpSGHV prevalence was found in G. pallidipes colonized at FAO/IAEA Insect Pest Control Laboratory (IPCL) that originated from Uganda (100%) and Tanzania (88%), and a lower prevalence in G. morsitans morsitans from Tanzania (58%) and Zimbabwe (20%). Whereas GpSGHV was detected in 25-40% of G. fuscipes fuscipes in eastern Uganda, the virus was not detected in specimens of neighboring western Kenya. Most of the identified 15 haplotypes were restricted to specific Glossina species in distinct locations. Seven haplotypes were found exclusively in G. pallidipes. The reference haplotype H1 (GpSGHV-Uga; Ugandan strain) was the most widely distributed, but was not found in G. swynnertoni GpSGHV. The 15 haplotypes clustered into three distinct phylogenetic clades, the largest contained seven haplotypes, which were detected in six Glossina species. The G. pallidipes infecting haplotypes H10, H11 and H12 (from Kenya) clustered with H7 (from Ethiopia), which presumably corresponds to the recently sequenced GpSGHV-Eth (Ethiopian) strain. These four haplotypes diverged the most from the reference H1 (GpSGHV-Uga). Haplotypes H1, H5 and H14 formed three main genealogy hubs, potentially representing the ancestors of the 15 haplotypes. CONCLUSION: These data identify G. pallidipes as a significant driver for the generation and diversity of GpSGHV variants. This information may provide control guidance when new tsetse colonies are established and hence, for improved management of the virus in tsetse rearing facilities that maintain multiple Glossina species. PMID- 30470192 TI - Bacterial diversity obtained by culturable approaches in the gut of Glossina pallidipes population from a non sleeping sickness focus in Tanzania: preliminary results. AB - BACKGROUND: Glossina pallidipes is a haematophagous insect that serves as a cyclic transmitter of trypanosomes causing African Trypanosomiasis (AT). To fully assess the role of G. pallidipes in the epidemiology of AT, especially the human form of the disease (HAT), it is essential to know the microbial diversity inhabiting the gut of natural fly populations. This study aimed to examine the diversity of G. pallidipes fly gut bacteria by culture-dependent approaches. RESULTS: 113 bacterial isolates were obtained from aerobic and anaerobic microorganisms originating from the gut of G. pallidipes. 16S rDNA of each isolate was PCR amplified and sequenced. The overall majority of identified bacteria belonged in descending order to the Firmicutes (86.6%), Actinobacteria (7.6%), Proteobacteria (5.5%)and Bacteroidetes (0.3%). Diversity of Firmicutes was found higher when enrichments and isolation were performed under anaerobic conditions than aerobic ones. Experiments conducted in the absence of oxygen (anaerobiosis) led to the isolation of bacteria pertaining to four phyla (83% Firmicutes, 15% Actinobacteria, 1% Proteobacteria and 0.5% Bacteroidetes, whereas those conducted in the presence of oxygen (aerobiosis) led to the isolation of bacteria affiliated to two phyla only (90% Firmicutes and 10% Proteobacteria). Phylogenetic analyses placed these isolates into 11 genera namely Bacillus, Acinetobacter, Mesorhizobium, Paracoccus, Microbacterium, Micrococcus, Arthrobacter, Corynobacterium, Curtobacterium, Vagococcus and Dietzia spp.which are known to be either facultative anaerobes, aerobes, or even microaerobes. CONCLUSION: This study shows that G. pallidipes fly gut is an environmental reservoir for a vast number of bacterial species, which are likely to be important for ecological microbial well being of the fly and possibly on differing vectorial competence and refractoriness against AT epidemiology. PMID- 30470193 TI - Witches' broom resistant genotype CCN51 shows greater diversity of symbiont bacteria in its phylloplane than susceptible genotype catongo. AB - BACKGROUND: Theobroma cacao L. (cacao) is a perennial tropical tree, endemic to rainforests of the Amazon Basin. Large populations of bacteria live on leaf surfaces and these phylloplane microorganisms can have important effects on plant health. In recent years, the advent of high-throughput sequencing techniques has greatly facilitated studies of the phylloplane microbiome. In this study, we characterized the bacterial microbiome of the phylloplane of the catongo genotype (susceptible to witch's broom) and CCN51 (resistant). Bacterial microbiome was determined by sequencing the V3-V4 region of the bacterial 16S rRNA gene. RESULTS: After the pre-processing, a total of 1.7 million reads were considered. In total, 106 genera of bacteria were characterized. Proteobacteria was the predominant phylum in both genotypes. The exclusive genera of Catongo showed activity in the protection against UV radiation and in the transport of substrates. CCN51 presented genus that act in the biological control and inhibition in several taxonomic groups. Genotype CCN51 presented greater diversity of microorganisms in comparison to the Catongo genotype and the total community was different between both. Scanning electron microscopy analysis of leaves revealed that on the phylloplane, many bacterial occur in large aggregates in several regions of the surface and isolated nearby to the stomata. CONCLUSIONS: We describe for the first time the phylloplane bacterial communities of T. cacao. The Genotype CCN51, resistant to the witch's broom, has a greater diversity of bacterial microbioma in comparison to Catongo and a greater amount of exclusive microorganisms in the phylloplane with antagonistic action against phytopathogens. PMID- 30470194 TI - Drought stress has transgenerational effects on seeds and seedlings in winter oilseed rape (Brassica napus L.). AB - BACKGROUND: Drought stress has a negative effect on both seed yield and seed quality in Brassica napus (oilseed rape, canola). Here we show that while drought impairs the maternal plant performance, it also increases the vigour of progeny of stressed maternal plants. We investigated the transgenerational influence of abiotic stress by detailed analysis of yield, seed quality, and seedling performance on a growth-related and metabolic level. Seeds of eight diverse winter oilseed rape genotypes were generated under well-watered and drought stress conditions under controlled-environment conditions in large plant containers. RESULTS: We found a decrease in seed quality in seeds derived from mother plants that were exposed to drought stress. At the same time, the seeds that developed under stress conditions showed higher seedling vigour compared to non-stressed controls.This effect on seed quality and seedling vigour was found to be independent of maternal plant yield performance. CONCLUSIONS: Drought stress has a positive transgenerational effect on seedling vigour. Three potential causes for stress-induced improvement of seedling vigour are discussed: (1) Heterotic effects caused by a tendency towards a higher outcrossing rate in response to stress; (2) an altered reservoir of seed storage metabolites to which the seedling resorts during early growth, and (3) inter-generational stress memory, formed by stress-induced changes in the epigenome of the seedling. PMID- 30470195 TI - RNA interference-based antiviral immune response against the salivary gland hypertrophy virus in Glossina pallidipes. AB - BACKGROUND: Glossina pallidipes salivary gland hypertrophy virus (GpSGHV; Hytrosaviridae) is a non-occluded dsDNA virus that specifically infects the adult stages of the hematophagous tsetse flies (Glossina species, Diptera: Glossinidae). GpSGHV infections are usually asymptomatic, but unknown factors can result to a switch to acute symptomatic infection, which is characterized by the salivary gland hypertrophy (SGH) syndrome associated with decreased fecundity that can ultimately lead to a colony collapse. It is uncertain how GpSGHV is maintained amongst Glossina spp. populations but RNA interference (RNAi) machinery, a conserved antiviral defense in insects, is hypothesized to be amongst the host's mechanisms to maintain the GpSGHV in asymptomatic (persistent or latent) infection state. Here, we investigated the involvement of RNAi during GpSGHV infections by comparing the expression of three key RNAi machinery genes, Dicer (DCR), Argonaute (AGO) and Drosha, in artificially virus injected, asymptomatic and symptomatic infected G. pallidipes flies compared to PBS injected (controls) individuals. We further assessed the impact of AGO2 knockdown on virus infection by RT-qPCR quantification of four selected GpSGHV genes, i.e. odv-e66, dnapol, maltodextrin glycosyltransferase (a tegument gene) and SGHV091 (a capsid gene). RESULTS: We show that in response to hemocoelic injections of GpSGHV into G. pallidipes flies, increased virus replication was accompanied by significant upregulation of the expression of three RNAi key genes; AGO1, AGO2 and DCR2, and a moderate increase in the expression of Drosha post injection compared to the PBS-injected controls. Furthermore, compared to asymptomatically infected individuals, symptomatic flies showed significant downregulation of AGO1, AGO2 and Drosha, but a moderate increase in the expression of DCR2. Compared to the controls, knockdown of AGO2 did not have a significant impact on virus infection in the flies as evidenced by unaltered transcript levels of the selected GpSGHV genes. CONCLUSION: The upregulation of the expression of the RNAi genes implicate involvement of this machinery in controlling GpSGHV infections and the establishment of symptomatic GpSGHV infections in Glossina. These findings provide a strategic foundation to understand GpSGHV infections and to control latent (asymptomatic) infections in Glossina spp. and thereby control SGHVs in insect production facilities. PMID- 30470196 TI - Different laboratory populations similar bacterial profile? The case of Glossina palpalis gambiensis. AB - BACKGROUND: Microbiota plays an important role in the biology, ecology and evolution of insects including tsetse flies. The bacterial profile of 3 Glossina palpalis gambiensis laboratory colonies was examined using 16S rRNA gene amplicon sequencing to evaluate the dynamics of the bacterial diversity within and between each G. p. gambiensis colony. RESULTS: The three G. p. gambiensis laboratory colonies displayed similar bacterial diversity indices and OTU distribution. Larval guts displayed a higher diversity when compared with the gastrointestinal tract of adults while no statistically significant differences were observed between testes and ovaries. Wigglesworthia and Sodalis were the most dominant taxa. In more detail, the gastrointestinal tract of adults was more enriched by Wigglesworthia while Sodalis were prominent in gonads. Interestingly, in larval guts a balanced co-existence between Wigglesworthia and Sodalis was observed. Sequences assigned to Wolbachia, Propionibacterium, and Providencia were also detected but to a much lesser degree. Clustering analysis indicated that the bacterial profile in G. p. gambiensis exhibits tissue tropism, hence distinguishing the gut bacterial profile from that present in reproductive organs. CONCLUSIONS: Our results indicated that age, gender and the origin of the laboratory colonies did not significantly influence the formation of the bacterial profile, once these populations were kept under the same rearing conditions. Within the laboratory populations a tissue tropism was observed between the gut and gonadal bacterial profile. PMID- 30470197 TI - Diversity and phylogenetic relationships of Glossina populations in Nigeria and the Cameroonian border region. AB - BACKGROUND: Tsetse flies are vectors of trypanosomes, parasites that cause devastating disease in humans and livestock. In the course of vector control programmes it is necessary to know about the Glossina species present in the study area, the population dynamics and the genetic exchange between tsetse fly populations. RESULTS: To achieve an overview of the tsetse fly diversity in Nigeria and at the Nigeria-Cameroon border, tsetse flies were trapped and collected between February and March 2014 and December 2016. Species diversity was determined morphologically and by analysis of Cytochrome C Oxidase SU1 (COI) gene sequences. Internal transcribed spacer-1 (ITS-1) sequences were compared to analyse variations within populations. The most dominant species were G. m. submorsitans, G. tachinoides and G. p. palpalis. In Yankari Game Reserve and Kainji Lake National Park, G. submorsitans and G. tachinoides were most frequent, whereas in Old Oyo National Park and Ijah Gwari G. p. palpalis was the dominant species. Interestingly, four unidentified species were recorded during the survey, for which no information on COI or ITS-1 sequences exists. G. p. palpalis populations showed a segregation in two clusters along the Cameroon-Nigerian border. CONCLUSIONS: The improved understanding of the tsetse populations in Nigeria will support decisions on the scale in which vector control is likely to be more effective. In order to understand in more detail how isolated these populations are, it is recommended that further studies on gene flow be carried out using other markers, including microsatellites. PMID- 30470198 TI - Symbiotic microbes affect the expression of male reproductive genes in Glossina m. morsitans. AB - BACKGROUND: Tsetse flies (Diptera, Glossinidae) display unique reproductive biology traits. Females reproduce through adenotrophic viviparity, nourishing the growing larva into their modified uterus until parturition. Males transfer their sperm and seminal fluid, produced by both testes and male accessory glands, in a spermatophore capsule transiently formed within the female reproductive tract upon mating. Both sexes are obligate blood feeders and have evolved tight relationships with endosymbionts, already shown to provide essential nutrients lacking in their diet. However, the partnership between tsetse and its symbionts has so far been investigated, at the molecular, genomic and metabolomics level, only in females, whereas the roles of microbiota in male reproduction are still unexplored. RESULTS: Here we begin unravelling the impact of microbiota on Glossina m. morsitans (G. morsitans) male reproductive biology by generating transcriptomes from the reproductive tissues of males deprived of their endosymbionts (aposymbiotic) via maternal antibiotic treatment and dietary supplementation. We then compared the transcriptional profiles of genes expressed in the male reproductive tract of normal and these aposymbiotic flies. We showed that microbiota removal impacts several male reproductive genes by depressing the activity of genes in the male accessory glands (MAGs), including sequences encoding seminal fluid proteins, and increasing expression of genes in the testes. In the MAGs, in particular, the expression of genes related to mating, immunity and seminal fluid components' synthesis is reduced. In the testes, the absence of symbionts activates genes involved in the metabolic apparatus at the basis of male reproduction, including sperm production, motility and function. CONCLUSIONS: Our findings mirrored the complementary roles male accessory glands and testes play in supporting male reproduction and open new avenues for disentangling the interplay between male insects and endosymbionts. From an applied perspective, unravelling the metabolic and functional relationships between tsetse symbionts and male reproductive physiology will provide fundamental information useful to understanding the biology underlying improved male reproductive success in tsetse. This information is of particular importance in the context of tsetse population control via Sterile Insect Technique (SIT) and its impact on trypanosomiasis transmission. PMID- 30470199 TI - Gene expression in reproductive organs of tsetse females - initial data in an approach to reduce fecundity. AB - BACKGROUND: Tsetse flies are vectors of African trypanosomes, and their vectorial capacity results in a major public health emergency and vast economic losses in sub-Saharan Africa. Given the limited ability of trypanosome prevention and eradication, tsetse vectors remain major targets of control efforts. Larvae of all three instars are developed in mothers' uteri, nourished through milk, and 'larviposited' shortly before pupation. The past few years have witnessed the emergence of approaches based on knockdown of genes involved in milk production, resulting in a significant reduction of fecundity. RESULTS: In order to identify further genes applicable in the control of tsetse flies, we determined the expression of protein-coding genes in ovaries and uteri from both virgin and heavily pregnant Glossina morsitans morsitans females. Comparison of expression profiles allowed us to identify candidate genes with increased expression in pregnant individuals. Lists with the highest increases include genes involved in oocyte and embryonic development, or nourishment. Maximum ovarian fold change does not exceed 700, while the highest uterine fold change reaches to more than 4000. Relatively high fold changes of two neuropeptide receptors (for corazonin and myosuppressin) propose the corresponding genes alternative targets. CONCLUSIONS: Given the higher fold changes in the uterus, targeting gene expression in this tissue may result in a more evident reduction of fecundity. However, ovaries should not be neglected, as manifested by several genes with top fold changes involved in early developmental stages. Apart from focusing on the highest fold changes, neuropeptide receptors with moderate increases in expression should be also verified as targets, given their roles in mediating the tissue control. However, this data needs to be considered initial, and the potential of these genes in affecting female fecundity needs to be verified experimentally. PMID- 30470201 TI - A randomized controlled trial to evaluate the effectiveness of a staff training program to implement consumer directed care on resident quality of life in residential aged care. AB - BACKGROUND: Residential Aged Care Facilities (RACFs) are moving towards a Consumer Directed Care (CDC) model of care. There are limited examples of CDC in ageing research, and no evaluation of a comprehensive CDC intervention in residential care was located. This study will implement and evaluate a staff training program, Resident at the Center of Care (RCC), designed to facilitate and drive CDC in residential care. METHODS: The study will adopt a cluster randomized controlled design with 39 facilities randomly allocated to one of three conditions: delivery of the RCC program plus additional organizational support, delivery of the program without additional support, and care as usual. A total of 834 staff (22 in each facility, half senior, half general staff) as well as 744 residents (20 in each facility) will be recruited to participate in the study. The RCC program comprises five sessions spread over nine weeks: Session 1 clarifies CDC principles; Sessions 2 to 5 focus on skills to build and maintain working relationships with residents, as well as identifying organizational barriers and facilitators regarding the implementation of CDC. The primary outcome measure is resident quality of life. Secondary outcome measures are resident measures of choice and control, the working relationship between resident and staff; staff reports of transformational leadership, job satisfaction, intention to quit, experience of CDC, work role stress, organizational climate, and organizational readiness for change. All measures will be completed at four time points: pre-intervention, 3-months, 6-months, and 12-month follow-up. Primary analyses will be conducted on an intention to treat basis. Outcomes for the three conditions will be compared with multilevel linear regression modelling. DISCUSSION: The RCC program is designed to improve the knowledge and skills of staff and encourage transformational leadership and organizational change that supports implementation of CDC. The overarching goal is to improve the quality of life and care of older people living in residential care. TRIAL REGISTRATION: ACTRN12618000779279; Registered 9 May 2018 with the Australian and New Zealand Clinical Trials Registry (ANZCTR; http://www.anzctr.org.au/ ). PMID- 30470200 TI - Factors influencing the quality of life of pregnant women: a systematic review. AB - BACKGROUND: Pregnancy is a period of transition with important physical and emotional changes. Even in uncomplicated pregnancies, these changes can affect the quality of life (QOL) of pregnant women, affecting both maternal and infant health. The objectives of this study were to describe the quality of life during uncomplicated pregnancy and to assess its associated socio-demographic, physical and psychological factors in developed countries. METHODS: A systematic review was performed according to the PRISMA guidelines. Searches were made in PubMed, EMBASE and BDSP (Public Health Database). Two independent reviewers extracted the data. Countries with a human development index over 0.7 were selected. The quality of the articles was evaluated on the basis of the STROBE criteria. RESULTS: In total, thirty-seven articles were included. While the physical component of QOL decreased throughout pregnancy, the mental component was stable and even showed an improvement during pregnancy. Main factors associated with better QOL were mean maternal age, primiparity, early gestational age, the absence of social and economic problems, having family and friends, doing physical exercise, feeling happiness at being pregnant and being optimistic. Main factors associated with poorer QOL were medically assisted reproduction, complications before or during pregnancy, obesity, nausea and vomiting, epigastralgia, back pain, smoking during the months prior to conception, a history of alcohol dependence, sleep difficulties, stress, anxiety, depression during pregnancy and sexual or domestic violence. CONCLUSIONS: Health-related quality of life refers to the subjective assessment of patients regarding the physical, mental and social dimensions of well-being. Improving the quality of life of pregnant women requires better identification of their difficulties and guidance which offers assistance whenever possible. PMID- 30470202 TI - Safety and fertility outcomes after the conservative treatment of endometrioid borderline ovarian tumours. AB - BACKGROUND: Because of the rarity of endometrioid borderline ovarian tumours (EBOTs), there is a paucity of data concerning the natural history and prognosis of this condition. Thus, the objective of our study was to establish the feasibility of fertility preservation in young women with EBOTs, as well as their oncological and reproductive outcomes. METHODS: Consecutive patients with EBOTs, treated at a tertiary referral centre during a span of 22 years, were retrospectively analysed. Recurrence-free interval, as well as its association with the type of surgery and with other clinical and pathological features, was assessed using the Kaplan-Meier and Cox proportional hazards methods. RESULTS: Of the 59 patients studied, the median follow-up time was 30 months (range, 6-177 months). Nine (15.3%) patients developed 13 recurrences 6-137 months after the initial surgeries, including three patients (5.1%; n = 3/59) who developed six invasive recurrences 8, 18 and 68 months after their initial surgeries. Conservative surgery showed a tendency towards a high recurrence rate (17.2% versus 13.3%); however, this difference was not significant (p = 0.45). The 5 year recurrence-free survival rate was significantly higher in the oophorectomy group than in the cystectomy group (p = 0.001). Cox regression analysis showed that none of the variables assessed were associated with an increased hazard ratio for recurrence, except for a younger age at diagnosis (p = 0.021). Of 20 patients who attempted to conceive, three pregnancies among two patients (10.0%) resulted in two live births. CONCLUSIONS: Conservative surgery with unilateral adnexectomy can be proposed for young women with EBOTs with fertility desire; however, the reproductive result is not satisfactory. In addition, careful evaluations of the endometria should be offered during the initial surgery and follow-up period. TRIAL REGISTRATION: Retrospectively registered. PMID- 30470203 TI - Miscarriages in families with an offspring that have classic congenital adrenal hyperplasia and 21-hydroxylase deficiency. AB - BACKGROUND: The most common form of congenital adrenal hyperplasia is 21 hydroxylase deficiency (CAH). Both men and women with classic CAH have lower fertility rates than the general population, and an increased rate of miscarriages has been reported in affected women. There are no data on the incidence rate of miscarriages in families with an offspring that have classic CAH. METHODS: We studied families with a history of classic CAH. The families came from different parts of Germany and attended the annual meeting of the German CAH support group for parents and patients which was held in Hamburg in September 2014. The data was collected anonymously by a paper-based questionnaire which was completed by the families at home. The families also accepted the responsibility to address this question to their siblings. In all, the data of 50 families with at least one child with classic CAH, and the data of 164 parental siblings were available for evaluation. Miscarriage rates were calculated in relation to the reported pregnancies. RESULTS: Twenty-two miscarriages were reported from 19 families. At least one miscarriage occurred in 38% of the families, three families experienced two miscarriages and 16 families had one miscarriage each. The mean miscarriage rate was 15.8%. The heterozygous mothers had a total of 90 siblings (41 m, 49 f), while 74 siblings (33 m, 41 f) were reported from the heterozygous fathers. The miscarriage rate was 10.1% in the families of the mothers' siblings, and 11.4% in the families of the fathers' siblings. The genotype was known in all parents that have an offspring with classic CAH, but not defined in 82% of the maternal siblings, and in 86% of the paternal siblings. No child with classic CAH has been diagnosed in any of the sibling's families to date. CONCLUSION: Our data show that the miscarriage rate in German families with a child with classic CAH is not elevated. PMID- 30470204 TI - Diaphragmatic parameters by ultrasonography for predicting weaning outcomes. AB - BACKGROUND: Diaphragmatic dysfunction remains the main cause of weaning difficulty or failure. Ultrasonographic measurement of diaphragmatic function can be used to predict the outcomes of weaning from mechanical ventilation. Our primary objective was to investigate the performance of various sonographic parameters of diaphragmatic function for predicting the success of weaning from mechanical ventilation. METHODS: We prospectively enrolled 68 adult patients requiring mechanical ventilation who were admitted to the intensive care unit from June 2013 to November 2013. The diaphragmatic inspiratory excursion, time to peak inspiratory amplitude of the diaphragm (TPIAdia), diaphragmatic thickness (DT), DT difference (DTD), and diaphragm thickening fraction (TFdi) were determined by bedside ultrasonography performed at the end of a spontaneous breathing trial. A receiver operating characteristic curve was used for analysis. RESULTS: In total, 62 patients were analyzed. The mean TPIAdia was significantly higher in the weaning success group (right, 1.27 +/- 0.38 s; left, 1.14 +/- 0.37 s) than in the weaning failure group (right, 0.97 +/- 0.43 s; left, 0.85 +/- 0.39 s) (P < 0.05). The sensitivity, specificity, positive predictive value, and negative predictive value of a TPIAdia of > 0.8 s in predicting weaning success were 92, 46, 89, and 56%, respectively. The diaphragmatic inspiratory excursion, DTD, and TFdi were associated with reintubation within 48 h. The P values were 0.047, 0.021, and 0.028, and the areas under the receiver operating characteristic curve were 0.716, 0.805, and 0.784, respectively. CONCLUSION: Among diaphragmatic parameters, TPIAdia exhibits good performance in predicting the success of weaning from mechanical ventilation. This study demonstrated a trend toward successful use of TPIAdia rather than diaphragmatic inspiratory excursion as a predictor of weaning from mechanical ventilation. PMID- 30470205 TI - Effect of physical interventions on physical performance and physical activity in older patients during hospitalization: a systematic review. AB - BACKGROUND: To counteract decline in physical performance and physical activity in older patients during hospitalization, multiple physical interventions were developed. However, it is unknown whether these are effective in this particular population. This systematic review aimed to identify the effect of physical interventions on physical performance and physical activity in older patients during hospitalization. METHODS: The systematic search included PubMed, EMBASE, Cinahl, the Trials database of The Cochrane Library and SPORTdiscus from inception to 22 November 2017. Studies were included if the mean age of the patient cohort was 65 years and older and the effect of physical interventions on physical performance or physical activity was evaluated during hospitalization. RESULTS: Fifteen randomized controlled trials met the inclusion criteria. Overall, the effect of physical interventions on physical performance was inconsistent. Patient tailored interventions, i.e. continuously adapted to the capabilities of the patient were not found to be superior over interventions that were not. Physical activity as outcome measure was not addressed. Reporting of intensity of the interventions and adherence were frequently lacking. CONCLUSIONS: Evidence for the effect of physical interventions on physical performance in older patients during hospitalization was found uncertain. Further research on the efficacy of the intervention is needed, comparing types of intervention with detailed reporting of frequency, intensity and duration. PMID- 30470207 TI - Factors associated with high-risk HPV infection and cervical cancer screening methods among rural Uyghur women aged > 30 years in Xinjiang. AB - BACKGROUND: Cervical cancer is the most common genital malignant tumor in women worldwide. However, the reliability of different detection methods may vary according to populations and epidemics. This study analyzed factors relevant to high-risk human papillomavirus (hrHPV) infection among rural Uyghur women aged > 30 years and evaluated the value of different screening methods for cervical precancerous lesions. METHODS: From July 2015 to May 2016, 225 rural Uyghur women aged > 30 years were recruited from local health clinics throughout Pishan, Xinjiang, China. HrHPV DNA testing, colposcopy, biopsy of cervical precancerous lesions, and surveys were conducted. The results of different screening methods were compared, and factors associated with hrHPV infection were analyzed. RESULTS: The rates of hrHPV infection and cervical epithelial lesions were 9.3 and 1.8%, respectively. The area under the ROC curve was 0.538 (95% CI: 0.292, 0.784; P = 0.753) for the HPV test and 0.995 (95% CI: 0.988, 1.003; P < 0.001) for colposcopy. Factors associated with HPV infection included widowhood (OR = 13.601 (2.170, 85.263), P = 0.005) and >= 3 sexual partners in the past 5 years (OR = 16.808 (4.148, 68.101), P < 0.001). . CONCLUSIONS: Among rural Uyghur women aged > 30 years, the main factors for HPV infection include marriage and frequent sexual intercourse. Colposcopy has a higher screening value for cervical epithelial lesions than hrHPV testing. PMID- 30470206 TI - Decisional conflict of physicians during the decision-making process for a simulated advanced-stage cancer patient: an international longitudinal study with German and Belgian physicians. AB - BACKGROUND: Decision making with advanced cancer patients is often associated with decisional conflict regarding treatment outcomes. This longitudinal multicenter study investigated German physicians' course of decisional conflict during the decision-making process for a Simulated advanced-stage cancer Patient (SP). Results were compared to a matched sample of Belgian physicians. METHODS: German physicians' (n = 30) decisional conflict was assessed with the Decisional Conflict Scale (DCS) at baseline (t1) and after the four steps of a decision making process: after reviewing the SP chart (t2), after viewing an assessment video interview with the SP (t3), after reviewing the team recommendations (t4), and after conducting the patient-physician decision-making interview (t5). The results were compared to those of a Belgian matched sample (n = 30). RESULTS: Decisional conflict of German physicians decreased during the Decision-Making process (M = 53.5, SD = 11.6 at t2 to M = 37.8, SD = 9.6 at t5, p < 0.001). This was similar to the pattern in the Belgian sample (M = 53.5, SD = 12.5 at t2 to M = 34.1, SD = 10.9 at t5, p < 0.001). There was no significant difference between the two groups for Decisional conflict end scores (p = 0.171). At the end of the Decision-making process, in both groups, still 43.3% of the physicians among each group (n = 13) reported a high Decisional Conflict (DCS > 37.5). CONCLUSIONS: Physicians' decisional conflict decreases during the decision-making process for an advanced cancer SP, though it remains at a high level. Culture, language and different health care systems have no influence on this process. The results emphasize the influence of psychosocial factors. We conclude that this issue should be considered more intensively in future research and in clinical care. PMID- 30470208 TI - Prevalence, patterns, and predictors of diarrhea: a spatial-temporal comprehensive evaluation in India. AB - BACKGROUND: Spatial analysis has been vital in mapping the spread of diseases and assisting in policy making. Targeting diarrhea transmission hotspots is one of the potential strategies for reducing diarrhea cases. This study aimed to examine the spatial-temporal variations and to identify the modifiable determinants of diarrhea while controlling for the spatial dependence in the data. METHODS: An ecological study on diarrhea data from DLHS-3 and NFHS- 4 in India. Moran's I and LISA were used to detect the spatial clustering of diarrhea cases and to test for clustering in the data. Spatial regression was used to identify the modifiable factors associated with the prevalence of diarrhea. The study comprised of the prevalence of diarrhea among the children below the age of five years (U-5 s) across different states in India. The determinants of diarrhea were obtained using spatial lag models. The software used were GeoDa 1.6.6 and QGIS 2.0. RESULTS: The presence of spatial autocorrelation in DLHS-3 and NFHS-4 (Moron's I = 0.577 and 0.369 respectively) enforces the usage of geographical properties while modeling the diarrhea data. The geographic clustering of high-prevalence districts was observed in the state of UP consistently. The spatial pattern of the percentage of children with diarrhea was persistently associated with the household with a sanitation facility (%) (p = 0.023 and p = 0.011). Compared to the diarrhea cases in the period 2007-2008, no much reduction was observed in the period 2015-2016. The prevalence of diarrhea and percentage of household with sanitation were ranging between 0.1-33.8% and 1.3-96.1% in the period 2007-2008 and 0.6-29.1% and 10.4-92.0% in the period 2015-2016 respectively. The least and highest prevalence of diarrhea being consistently from Assam and UP respectively. CONCLUSION: Despite improvements in controlling spread of diarrheal disease, the burden remains high. Focus on widespread diarrheal disease control strategy by addressing the social determinants of health like basic sanitation is crucial to reduce the burden of diarrhea among U-5 s in India. The identification of hotspots will aid in the planning of control strategies for goal setting in the targeted regions. PMID- 30470209 TI - Implementation of a co-designed physical activity program for older adults: positive impact when delivered at scale. AB - BACKGROUND: Despite known health benefits of physical activity (PA), older adults remain among the least physically active age group globally with 30-60% not meeting guidelines. In Canada, 87% do not meet recommended guidelines. To influence population health, interventions that are effective in small trials must be disseminated at scale. Despite evidence for efficacy, few PA interventions are scaled up to reach the wider community. In 2015, British Columbia (BC) Ministry of Health released a PA strategy where older adults were identified as a priority. In partnership with the Ministry, the Active Aging Research Team co-created a health promotion program called Choose to Move (CTM). CTM will be implemented in three phases at increasingly greater scale across BC. The objective of this study is to evaluate the effectiveness of CTM during Phase I (pilot) and Phase II (initial scale up) on PA, mobility, and social connectedness among older adults in BC, Canada. METHODS: We used a type 2 hybrid effectiveness-implementation study design, and herein focus on effectiveness. The implementation evaluation will be published as a companion paper elsewhere. Two community delivery partner organizations delivered 56 CTM programs in 26 large and small urban locations across BC. Outcome measurement occurred at 0 (baseline), 3 (mid-intervention) and 6 (post-intervention) months. We collected survey data from all participants (n = 458; province-wide) and also conducted a subset evaluation (n = 209). RESULTS: PA increased significantly during the active intervention phase (baseline-3 months) in younger (60-74 yrs.; + 1.6 days/week; p < 0.001) and older (>=75 yrs.; + 1.0 days/week; p < 0.001) participants. The increase was sustained at 6 months in younger participants only, who remained significantly more active than at baseline (+ 1.4 days/week; p < 0.001). Social exclusion indicators declined significantly in the younger group. Mobility and strength improved significantly at 3 months in the younger group, and in both groups at 6 months. CONCLUSIONS: CTM adopted central tenets of implementation science that consider the complicated systems where interventions are delivered to improve public health. In this iteration of CTM we demonstrate that a partner-based health promotion intervention can be effectively implemented across settings to enhance PA, mobility and social connectedness in older adults. PMID- 30470210 TI - Intraoperative relaxed muscle positioning technique results in a tertiary Center for Thyroid Orbitopathy Related Strabismus. AB - BACKGROUND: Previous techniques resulted with low rates of successful fusion after the surgeries and high necessity of additional surgeries in the treatment of thyroid orbitopathy related strabismus. In this study, reviewing the results of our patients who had surgical correction with relaxed muscle positioning technique due to thyroid orbitopathy related strabismus to evaluate the effectiveness of the surgery was aimed. METHODS: The medical records of 8 patients who had surgical correction with intraoperative relaxed muscle positioning (IRMP) technique were studied retrospectively. The extent of strabismus was determined with prism cover test both at near and distance. The extent of recession was determined by marking the natural place of the released tendon during the primary position. The muscle then sutured to the globe at this precise point. RESULTS: Seven eyes (87.5%) of 8 patients had orthophoria after the surgery and they reported no diplopia in primary and reading gaze. The mean age of the patients was 51 +/- 8.8 years. The mean follow-up time was 32.7 +/- 18.5 months. Three patients had inferior rectus recession (IRR), 3 had bilateral medial rectus recession (MRR), 1 had only right MRR and 1 had combined MRR with IRR during the surgical correction of the strabismus. The mean amount of recession for IR was 7.5 +/- 1.34 mm and it was 6.75 +/- 0.95 mm for the MR muscles. The mean prism diopter before the surgery was 37.8 +/- 23.3 and it was 0 after surgery except only one of the patients who had > 60 prism diopter (PD) left esotropia (ET) before surgery and had 30 PD left ET after surgery (3.3 +/- 9.4). CONCLUSION: IRMP technique is a unique option for the surgical correction of thyroid orbitopathy related strabismus. By showing a dramatic increase in the quality of life of the patients, our surgical results are promising despite limited number of patients. PMID- 30470211 TI - 10-year follow-up of congenital cytomegalovirus infection complicated with severe neurological findings in infancy: a case report. AB - BACKGROUND: Congenital cytomegalovirus (cCMV) infection leads to sensorineural hearing loss (SNHL) and neurodevelopmental delays. However, the long-term outcomes of cCMV infection with severe neurological manifestations in infancy remain unclear. CASE PRESENTATION: The patient was a one-month-old girl visited owing to abnormalities in neonatal hearing screening. Central nervous system involvement including intracranial calcification and extensive white matter abnormalities was identified. Right SNHL (50 dB) was detected by auditory brain response (ABR) testing. The cause of her hearing loss was determined to be cCMV infection by polymerase chain reaction (PCR) using a dried blood spot. At 1.5 months of age, the patient was treated with intravenous ganciclovir (GCV) for 5 weeks followed by oral valganciclovir (VGCV) for an additional 6 weeks. Cytomegalovirus (CMV) loads in her urine continued to be detected until she was 10 years old. Fortunately, during this time, her right hearing loss did not deteriorate, and her left hearing remained normal. Furthermore, the extensive abnormal areas of white matter observed at 1 month of age mostly disappeared by the time the patient was 9 years old. Her neurodevelopmental score was normal, and motor milestones were not delayed as of 10 years of age. CONCLUSIONS: Here, we report the 10-year follow-up of a patient with cCMV who showed normal neurodevelopment, no progression of hearing loss, and ameliorating magnetic resonance imaging (MRI) findings, despite having various complications and severe neurological findings during infancy. PMID- 30470212 TI - Insulin metabolism markers are predictors of subclinical atherosclerosis among overweight and obese children and adolescents. AB - BACKGROUND: To investigate the association between markers of insulin metabolism and carotid intima-media thickness(cIMT) among overweight and obese children and adolescents. METHODS: A total of 378 children and adolescents aged from 6 to 13 years, with WHO body mass index Z-Scores >=2 were enrolled in this study. We measured fasting serum insulin and glucose, conducted a homeostatic model assessment of insulin resistance(HOMA-IR), and calculated the quantitative insulin sensitivity check index(QUICKI). Carotid intima-media thickness was measured in the common carotid artery with high-resolution ultrasonography. RESULTS: The study participants consisted of 198 boys and 180 girls with a mean(+/-SD) age of 9.3 +/- 1.7 years, 18.3% being pre-pubertal. In boys, after controlling for confounders, a one-SD increase in fasting insulin and HOMA-IR were associated with 0.351 mm(P < 0.001) and 0.350 mm(P < 0.001) increases in cIMT, respectively. However, a one-SD increase in QUICKI was associated with a - 0.305 mm(P = 0.001) decrease in cIMT. When categorizing into tertiles, a one-SD increase in fasting insulin and HOMA-IR were associated with 87 and 81% increases in the odds of higher categories of cIMT(both P < 0.05). However, a one-SD increase in QUICKI was associated with 37% lower odds of higher categories of cIMT(P = 0.022). No significant associations were found among girls. CONCLUSION: This study demonstrated that insulin resistance and sensitivity markers were independent predictors of cIMT in overweight and obese boys, but not in girls, highlighting the importance of chronically elevated insulin levels for predisposing these boys to alterations in their vascular structure. PMID- 30470213 TI - Pirfenidone improves survival in IPF: results from a real-life study. AB - BACKGROUND: Pirfenidone is an antifibrotic compound approved for the treatment of idiopathic pulmonary fibrosis (IPF). We present our real-world experience in terms of Pirfenidone's effect on mortality and adverse events profile outside the restrictions of a clinical trial. METHODS: This is a retrospective observational intention to treat study of 82 consecutive IPF patients (UHH cohort). RESULTS: We observed a high 3-years survival rate of 73% without excluding patients who discontinued treatment for different reasons. The survival was compared to the survival of an IPF cohort from a tertiary referral center (RBH cohort). After exclusion of severe cases (DLco< 30%), in unadjusted analysis, the survival in the UHH cohort was better than in the RBH cohort (HR:0.32, 95% CI: 0.19-0.53, p < 0.0001). After adjustment for age, gender and FVC, the survival remained higher in the UHH cohort (HR:0.28, 95% CI: 0.16-0.48, p < 0.0001). We observed a similar safety profile compared to previously published data and a lower rate of drug discontinuation due to photosensitivity reactions. CONCLUSION: Pirfenidone provides a survival benefit in a real-life IPF cohort compared to previously used medications. Counselling patients and proactively managing possible adverse effects can reduce the necessity to discontinue pirfenidone. PMID- 30470214 TI - Effective coverage as a new approach to health system performance assessment: a scoping review. AB - BACKGROUND: Delivering interventions is the main task of health systems whose accurate measurement is an essential input into tracking performance. Recently, the concept of effective coverage was introduced by World Health Organization to incorporate into health system performance assessment. The aim of present scoping review was mapping the key elements and steps of effective coverage assessment in practical efforts including kinds of interventions, criteria for selecting them and the need, use and quality estimation approaches and strategies of each intervention. METHODS: We conducted a scoping review of health system/program assessments which assessed effective coverage till May 2017. Seven databases were systematically searched with no time and language restriction through applying combined keyword of "effective coverage". RESULTS: Eighteen studies contributed findings on monitoring effective coverage of health interventions and they all were included in the review. Only 4 contributed findings on health system and the others were related to specific intervention(s) assessment. The interventions monitored by effective coverage were mainly in child health, prenatal and antenatal care and delivery, and chronic conditions areas. Potential impact on the burden of disease, leading causes of mortality and morbidity, and high occurrence and prevalence rate were among the main intervention selection criteria. Availability of data was the critical prerequisite, especially, in all of the studies applied ex post approach in estimating effective coverage. Estimation based on a norm, self- reporting from surveys and biomarkers were the main strategies and methods of need, utilization and quality measurement, respectively. CONCLUSIONS: More studies are needed to contribute to the ongoing improvement in the development of effective coverage concept and increasing practical efforts, especially through defining prospective approaches and strategies into estimation of composite measures based on the effective coverage framework. Also, further attention needs to be paid to quality measures of effective coverage in a manner that better conceptualizes and measures the connection between coverage rates and interventions' effectiveness. At the administrative system level, more innovation is needed to develop data systems in order to enhance capacity of routine health service information. PMID- 30470215 TI - Problematic social networking site usage and substance use by young adolescents. AB - BACKGROUND: Substance use and abuse by young adolescents has become a serious issue for public health services, and several socio-environmental factors can influence how vulnerable a young adolescent may be to their appeal. The present study was devised to examine whether substance use in early adolescence is associated with problematic social networking site usage (PSNSU). METHODS: In the academic year 2013-2014, secondary schools in Padua (north-eastern Italy) were involved in a survey called "Pinocchio". A sample of 1325 pupils attending years 6 to 8 (i.e. aged from 11 to 13 years) completed self-administered questionnaires, in which PSNSU was measured by applying the DSM-IV criteria of dependence to identify any social network addiction disorder and its fallout on daily life. Multivariate analysis (ordered logistic regression) was performed to assess an adjusted association between young adolescents' substance use and PSNSU. RESULTS: The percentage of pupils classified as problematic social networking site users rose with age (from 14.6% in year 6 to 24.3% in year 7, and 37.2% in year 8), and it was higher in girls (27.1%) than in boys (23.6%). In a fully-adjusted model, PSNSU conferred a higher likelihood of being substance users (OR 2.93 95% CI 1.77-4.85). CONCLUSION: This study identified an association between PSNSU and the likelihood of substance use (smoking, alcohol and energy drink consumption), providing further evidence of the need to pay more attention to PSNSU in early adolescence. PMID- 30470216 TI - The usefulness of pleural fluid presepsin, C-reactive protein, and procalcitonin in distinguishing different causes of pleural effusions. AB - BACKGROUND: We aimed to determine the presepsin concentration in pleural fluid from patients with pleural effusions of different aetiologies and to compare its diagnostic value with that of pleural fluid C-reactive protein (CRP) and procalcitonin (PCT). METHODS: We enrolled 132 patients with pleural effusion who underwent diagnostic evaluation, and we classified them into six categories: empyema, parapneumonic effusion, tuberculous effusion, malignant effusion, paramalignant effusion, and transudate effusion. Additionally, all pleural effusions were categorised as infectious or non-infectious effusions. RESULTS: Receiver operating characteristic analysis was used to evaluate diagnostic performance. When diagnosing empyema, the marker with the highest sensitivity was pleural fluid presepsin (cut-off: 754 pg/mL; sensitivity: 90.9%, specificity: 74.4%) and that with the highest specificity was pleural fluid CRP (cut-off: 4.91 mg/dL; sensitivity: 63.6%, specificity: 89.3%). Pleural fluid PCT tended to be lower in patients with empyema than in those with parapneumonic effusion, but this was not useful for the diagnosis of empyema. When diagnosing infectious pleural effusion, a combination of pleural fluid CRP (cut-off: 2.59 mg/dL) and presepsin (cut-off: 680 pg/mL) produced the highest diagnostic accuracy (83.3%). CONCLUSIONS: Pleural fluid presepsin was found at high levels in patients with empyema and parapneumonic effusion. This pattern closely resembles the previously reported pattern of pleural fluid CRP. Some combinations of pleural fluid inflammatory markers may be more clinically useful than these markers in isolation. PMID- 30470217 TI - Disseminated learning from clinician-scientists: a multiple case study in physiotherapeutic care. AB - BACKGROUND: Clinician-Scientists are considered to be important for continuous improvement of patient care, because they are ideally positioned to bridge the gap between scientific research and clinical care. However, limited empirical evidence is available about how they connect these two realms. So far research has mainly focused on their direct role in bridging the gap. This study investigates an additional mechanism; that is whether clinician-scientists also connect science and care indirectly through disseminated learning. During this type of learning, clinical colleagues learn by working with clinician-scientists. METHODS: Disseminated learning was studied in five physiotherapeutic care settings in the Netherlands with clinician-scientists (N = 5) and their clinical colleagues (N = 14). Semi-structured interviews were conducted between March and May of 2016. Interviews were transcribed verbatim and analyzed using thematic analysis. RESULTS: Clinicians and clinician-scientists in all settings reported clinicians learning informally. They learned by being informed about (evidence for) new tests and treatments, through increased understanding of the research process and research results, and through awareness of an academic reflective approach to care. Learning took place primarily through knowledge sharing, and to a lesser extent through role modeling or joint implementation. Interpersonal and organizational conditions, such as overlapping clinical expertise and organizational policy and culture, seemed to facilitate or hinder learning. CONCLUSIONS: This study highlights disseminated learning as a mechanism of how clinician-scientists may connect science and care. Furthermore, it provides insight into how disseminated learning may take place and the conditions that may facilitate or restrict learning. PMID- 30470218 TI - Patient, study thyself. AB - The past 15 years have seen the emergence of a new paradigm in medical research, namely of people living with medical conditions (whether patients, parents, or caregivers) using digital tools to conduct N-of-1 trials and scientifically grounded research on themselves, whilst using the Internet to form communities of like-minded individuals willing to self-experiment. Prominent examples can be found in amyotrophic lateral sclerosis/motor neurone disease (the 'lithium study' on PatientsLikeMe), Parkinson's disease ('digital patient' Sara Riggare), and diabetes (the 'open artificial pancreas' of the #WeAreNotWaiting movement). Through transparency, data sharing, open source code, and publication in the peer reviewed scientific literature, such activities conform to expected scientific conventions. However, other conventions, such as ethical oversight, regulation, professionalization, and the ability to translate this new form of relatively biased data into generalizable decisions, remain challenged. While critics worry such participant-led research merely muddies the waters of high-quality medical research and exposes patients to new harms, the potential is there to enroll millions of active minds in unravelling the wicked problems of complex medical disorders that degrade the human health span. PMID- 30470219 TI - Sexual motivations during the menopausal transition among Iranian women: a qualitative inquiry. AB - BACKGROUND: Women's sexuality may be adversely affected during the menopausal transition. This exploratory qualitative study was conducted to explore how women assign meaning to and process sexual motivation during the menopausal transition. METHODS: We purposefully approached 22 married women ages 44-59 (52.81 +/- 3.6 years) in urban health care centers and workplaces in Tabriz city, located in northwest Iran. Individual face-to-face interviews were performed at a place and time convenient to the women. All interviews were audio recorded and then transcribed to create verbatim written accounts. Inspiring Graneheim and Lundman approach, we employed conventional content analysis to derive coding categories directly from our row data. FINDINGS: Four main themes emerged from data analysis: "Diminished sexual capacity" (effect of menopause, Illnesses associated with mid-life, desire discrepancy); "intimate coupling" (lack of physical and/or emotional intimacy, couple communication and romance); "sociocultural scripts" (sexual script, parental responsibilities); and "sense of youthfulness" (having an active and happy life, maintaining physically attractiveness). CONCLUSION: The qualitative findings suggest that providing sexual health education and counseling, to encourage critical discussions regarding current sociocultural scripts and to create an environment that would enable men and women alike to adopt a healthy and happy lifestyle for eliminating barriers and preserving and enhancing motivational factors associated with sexuality. PMID- 30470220 TI - Obesity education for front-line healthcare providers. AB - BACKGROUND: To assess the effect of an interprofessional educational activity on professional skills, attitudes, and perceived challenges toward obesity management among front-line healthcare providers. METHODS: A one-day interprofessional obesity education activity was organized for healthcare providers across various disciplines. All participants were invited to complete an anonymous survey pre- and post-event, and at six-month post-event. The survey was created based on a comprehensive list of perceived skills, professional attitudes and challenges toward obesity intervention compiled from existing literature. RESULTS: Sixty-seven healthcare providers completed the survey pre- and post-event. Participants reported increases in professional skills such as their ability to assess weight (p = 0.04), to address weight management issues (p < 0.001), to teach/motivate patients toward physical activity (p < 0.001) and healthy eating practices (p = 0.001), to use behavior modification techniques (p < 0.001), and to deal with family issues (p < 0.001). Professional attitudes: practitioners felt more educated/competent in obesity management (P < 0.001), learned where to refer patients (p < 0.001), were more comfortable in discussing obesity in managing obesity (p < 0.001), were less likely to avoid the topic (p = 0.004) and felt less frustrated with the low success rate (p = 0.030). Enhancement in professional attitudes remained 6 months after the event. Improvements were mainly associated with male gender, younger age, fewer years of professional practice and healthcare professionals other than physicians. No statistically significant changes in perceived challenges were found after the educational event. CONCLUSION: Results of this study showed that this interprofessional learning activity contributed to the improvement of professional skills and attitudes of front-line healthcare providers caring for those who are obese or at risk for obesity. The positive results of this interprofessional learning activity aligns with the training needs identified by healthcare practitioners in previous studies, and suggest that this design and content could be used to guide future educational programming in the care of obese people. PMID- 30470221 TI - Validity and reproducibility of a tool for assessing clinical competencies in physical therapy students. AB - BACKGROUND: The evaluation of competencies in the clinical field is essential for health professionals, as it allows the acquisition of these competencies to be tracked. The objective of this study was to create and evaluate the validity and reliability of a tool for measuring clinical competencies in physical therapy (PT) students to assess the quality of their performance in a professional context. METHODS: A descriptive study was designed. The Measurement Tool for Clinical Competencies in PT (MTCCP) was developed based on the evaluation of 39 experts: 15 clinicians and 24 instructors. The content validity was evaluated using the Content Validity Index (CVI). Three professors were invited to apply the tool to 10 students. Cronbach's alpha, exploratory factor analysis, and the intraclass correlation coefficient were used to determine the reliability and validity of the scale. RESULTS: The CVI was positive-higher than 0.8. Principal component analysis confirmed the construct validity of the tool for two main factors: clinical reasoning (first factor) and professional behavior (second factor). With regard to reliability, the MTCCP achieved an internal congruence of 0.982. The inter-evaluator reproducibility for clinical reasoning, professional behavior, and the total MTCCP score was almost perfect; the ICCs were 0.984, 0.930, and 0.983, respectively. CONCLUSIONS: The MTCCP is a valid and reliable instrument for assessing the performance of PT students in hospital settings and can be used to determine what skills students feel less confident using and what additional training/learning opportunities could be provided. Further research is needed to determine whether the MTCCP has similar validity and reproducibility in other Spanish-speaking national and international PT programs. PMID- 30470222 TI - Development, validity and reliability of the Italian version of the Copenhagen neck functional disability scale. AB - BACKGROUND: Valid and reliable patient-reported outcome measures support health professionals in evaluating the results of clinical research and practice. The Copenhagen Neck Functional Disability Scale (CNFDS) has shown promising measurement properties to measure disability in patients with neck pain, but an Italian version of this questionnaire is not available. The objective of this study was to cross-culturally adapt the CNFDS into Italian (CNFDS-I), and to assess its validity and reliability in patients with neck pain. METHODS: The CNFDS-I was developed according to well-established guidelines for cross-cultural adaptation of patient-reported outcome measures. A cross-sectional clinimetric study was conducted to evaluate its validity and reliability. Patients with chronic neck pain (pain > 3 months) participated in this study. The following measurement properties (defined by the COSMIN initiative) were assessed: structural validity (exploratory factor analysis), internal consistency (Cronbach's alpha), construct validity [by testing hypotheses on expected correlations with the Neck Disability Index (NDI), the Neck Bournemouth Questionnaire (NBQ), and pain Visual Analogue Scale (VAS)]. Test-retest reliability [Intraclass Correlation Coefficient for agreement (ICCagreement)], and measurement error [Smallest Detectable Change (SDC)] were also assessed in 50 clinically stable patients. Floor/ceiling effects and acceptability were calculated. RESULTS: One-hundred and sixty-two patients (mean age = 47.9 +/- 14.5 years, 70% female) were included. The CNFDS-I exhibited sufficient unidimensionality (one factor explained 83% of the variability) and internal consistency (alpha = 0.83). Construct validity was sufficient as all correlations with the other questionnaires were as expected (r = 0.846 with NDI, r = 0.708 with NBQ, r = 0.570 with VAS). Test-retest reliability was excellent (ICCagreement = 0.99, 95% CI from 0.995 to 0.999), while measurement error was equal to 8.31 scale points (27% scale range). No floor/ceiling effects were detected. The average time for filling the questionnaire was two minutes. CONCLUSIONS: The CNFDS-I proved to be a valid and reliable outcome measure to assess disability in patients with chronic neck pain. Head-to-head comparison studies on the CNFDS-I measurement properties against other disability measures for neck pain (e.g. NDI and NBQ) are required to determine the relative merits of these different measures. PMID- 30470223 TI - A mixed-methods exploration of cognitive dispositions to respond and clinical reasoning errors with multiple choice questions. AB - BACKGROUND: Cognitive dispositions to respond (i.e., cognitive biases and heuristics) are well-established clinical reasoning phenomena. While thought by many to be error-prone, some scholars contest that these cognitive dispositions to respond are pragmatic solutions for reasoning through clinical complexity that are associated with errors largely due to hindsight bias and flawed experimental design. The purpose of this study was to prospectively identify cognitive dispositions to respond occurring during clinical reasoning to determine whether they are actually associated with increased odds of an incorrect answer (i.e., error). METHODS: Using the cognitive disposition to respond framework, this mixed methods study applied a constant comparative qualitative thematic analysis to transcripts of think alouds performed during completion of clinical-vignette multiple-choice questions. The number and type of cognitive dispositions to respond associated with both correct and incorrect answers were identified. Participants included medical students, residents, and attending physicians recruited using maximum variation strategies. Data were analyzed using generalized estimating equations binary logistic model for repeated, within subjects measures. RESULTS: Among 14 participants, there were 3 cognitive disposition to respond categories - Cognitive Bias, Flaws in Conceptual Understanding, and Other Vulnerabilities - with 13 themes identified from the think aloud transcripts. The odds of error increased to a statistically significant degree with a greater per-item number of distinct Cognitive Bias themes (OR = 1.729, 95% CI [1.226, 2.437], p = 0.002) and Other Vulnerabilities themes (OR = 2.014, 95% CI [1.280, 2.941], p < 0.001), but not with Flaws in Conceptual Understanding themes (OR = 1.617, 95% CI [0.961, 2.720], p = 0.070). CONCLUSION: This study supports the theoretical understanding of cognitive dispositions to respond as phenomena associated with errors in a new prospective manner. With further research, these findings may inform teaching, learning, and assessment of clinical reasoning toward a reduction in patient harm due to clinical reasoning errors. PMID- 30470224 TI - Tensile testing of the mechanical behavior of the human periodontal ligament. AB - BACKGROUND: The periodontal ligament (PDL) plays a key role in alveolar bone remodeling and resorption during tooth movements. The prediction of tooth mobility under functional dental loads requires a deep understanding of the mechanical behavior of the PDL, which is a critical issue in dental biomechanics. This study was aimed to examine the mechanical behavior of the PDL of the maxillary central and lateral incisors from human. The experimental results can contribute to developing an accurate constitutive model of the human PDL in orthodontics. METHODS: The samples of human incisors were cut into three slices. Uniaxial tensile tests were conducted under different loading rates. The transverse sections (cervical, middle and apex) normal to the longitudinal axis of the root of the tooth were used in the uniaxial tensile tests. Based on a bilinear simplification of the stress-strain relations, the elastic modulus of the PDL was calculated. The values of the elastic modulus in different regions were compared to explore the factors that influence the mechanical behavior of the periodontal ligament. RESULTS: The obtained stress-strain curves of the human PDL were characterized by a bilinear model with two moduli (E1 and E2) for quantifying the elastic behavior of the PDL from the central and lateral incisors. Statistically significant differences of the elastic modulus were observed in the cases of 1, 3, and 5 N loading levels for the different teeth (central and lateral incisors). The results showed that the mechanical property of the human incisors' PDLs is dependent on the location of PDL (ANOVA, P = 0.022, P < 0.05). The elastic moduli at the middle planes were greater than at the cervical and apical planes. However, at the cervical, middle, and apical planes, the elastic moduli of the mesial and distal site were not significantly different (ANOVA, P = 0.804, P > 0.05). CONCLUSIONS: The values of elastic modulus were determined in the range between 0.607 and 4.274 MPa under loads ranging from 1 to 5 N. The elastic behavior of the PDL is influenced by the loading rate, tooth type, root level, and individual variation. PMID- 30470225 TI - Is sleep position associated with glenohumeral shoulder pain and rotator cuff tendinopathy: a cross-sectional study. AB - BACKGROUND: Glenohumeral pain and rotator cuff tendinopathy (RCT) are common musculoskeletal complaints with high prevalence among working populations. The primary proposed pathophysiologic mechanisms are sub-acromial RC tendon impingement and reduced tendon blood flow. Some sleep postures may increase subacromial pressure, potentially contributing to these postulated mechanisms. This study uses a large population of workers to investigate whether there is an association between preferred sleeping position and prevalence of: (1) shoulder pain, and (2) rotator cuff tendinopathy. METHODS: A cross-sectional analysis was performed on baseline data from a multicenter prospective cohort study. Participants were 761 workers who were evaluated by questionnaire using a body diagram to determine the presence of glenohumeral pain within 30 days prior to enrollment. The questionnaire also assessed primary and secondary preferred sleep position(s) using 6 labeled diagrams. All workers underwent a structured physical examination to determine whether RCT was present. For this study, the case definition of RCT was glenohumeral pain plus at least one of a positive supraspinatus test, painful arc and/or Neer's test. Prevalence of glenohumeral pain and RCT were individually calculated for the primary and secondary sleep postures and odds ratios were calculated. RESULTS: Age, sex, Framingham cardiovascular risk score and BMI had significant associations with glenohumeral pain. For rotator cuff tendinopathy, increasing age, Framingham risk score and Hand Activity Level (HAL) showed significant associations. The sleep position anticipated to have the highest risk of glenohumeral pain and RCT was paradoxically associated with a decreased prevalence of glenohumeral pain and also trended toward being protective for RCT. Multivariable logistic regression showed no further significant associations. CONCLUSION: This cross-sectional study unexpectedly found a reduced association between one sleep posture and glenohumeral pain. This cross-sectional study may be potentially confounded, by participants who are prone to glenohumeral pain and RCT may have learned to avoid sleeping in the predisposing position. Longitudinal studies are needed to further evaluate a possible association between glenohumeral pain or RCT and sleep posture as a potential risk factor. PMID- 30470227 TI - The long noncoding RNA LINC00312 induces lung adenocarcinoma migration and vasculogenic mimicry through directly binding YBX1. AB - Vasculogenic mimicry (VM) gives rise to tumor neovascularization that is critical for tumor growth and metastasis. Long non-coding RNAs (lncRNAs) have been implicated in diverse and fundamental biological processes. LINC00312 is associated with lung adenocarcinoma. In this study, we found that LINC00312 induced migration, invasion and VM of lung cancer cells by direct binding to the transcription factor Y-Box Binding Protein 1 (YBX1). Moreover, we demonstrated that YBX1 is associated with different fragments within 0-2410 nt 5'region of LINC00312. In addition, LINC00312 is associated with VM in 124 lung adenocarcinoma clinical specimens. The results suggest that LINC00312 is a promising therapeutic and diagnostic target for lung adenocarcinoma. PMID- 30470226 TI - Relative survival following hemi-and total hip arthroplasty for hip fractures in Sweden. AB - BACKGROUND: Hip fractures are a common problem in the ageing population. Hip arthroplasty is the common treatment option for displaced intracapsular neck of femur fractures. Even though hip replacements are successful in restoring mobility, reducing pain and diminishing loss of health-related quality of life, the potential impact of a hip fracture on life expectancy as well as the postoperative mortality need consideration. The purpose of this study was to describe the mid-term relative survival rate for a cohort of Swedish patients whom underwent total- or hemiarthroplasty surgery following hip fracture. We also explored whether the survival rate is prosthesis-type specific and influenced by comorbidities, sex, socioeconomic and surgical factors. METHODS: Using prospectively collected information of the Swedish Hip Arthroplasty Register linked database we identified 43,891 patients operated between 2005 and 2012. Patient- and surgery-specific data in combination with socio-economic data were available for this analysis. We studied relative survival rate and used multivariable modelling with Cox Proportional Hazards Model in Transformed Time. RESULTS: Compared to the Swedish general population the baseline excess hazard was very high in the first half year after the operation, thereafter the excess hazard decreased but remained non-negligible through the 8 years' follow-up period. The mortality rate of males was higher compared to women. Higher Elixhauser comorbidity index (ECI) was associated with worsening survival. However, patients who had ECI = 0 had higher mortality than patients with ECI =1 the first 420 days post fracture. Patients with a hemiarthroplasty had a worse survival than patients with a total hip arthroplasty. Of the hospital types considered university hospitals had lower survival rate. Younger patients had a greater loss of expected life span than patients who suffer hip fracture in their more advanced ages. CONCLUSIONS: Swedish hip fracture patients who undergo arthroplasty surgery had a high excess hazard of dying in the first half year following surgery, and this excess hazard never subsided to negligible levels at least up to 8 years after surgery. Interestingly having no prior record of illnesses worsened the initial mortality. Men living alone had the highest long term excess mortality. PMID- 30470229 TI - Comparison of statin plus ezetimibe with double-dose statin on lipid profiles and inflammation markers. AB - BACKGROUND: Achievement of low-density lipoprotein cholesterol (LDL-C) goal is the most important for the patients with atherosclerotic cardiovascular diseases (ASCVD) who received lipid-lowering therapy. It is unclear that whether combination of ezetimibe with statin is superior to double-dose of statin regarding both of the lipid-lowering efficacy and improvement of inflammation in Chinese patients with ASCVD. Therefore, this study was performed to compare the effects of these two regimes on lipid profiles and inflammation markers. METHODS: In this randomized control study, ninety eight patients with ASCVD, who were naive to statins or other lipid-lowering agents, were enrolled into the study, and randomly assigned into two groups, A40 group (atorvastatin 40 mg/d, n = 50), A20E10 group (atorvastatin 20 mg/d combined with ezetimibe 10 mg/d, n = 48).The patients were followed up at week 4 and week 12 after treatment. The lipid profiles and oxidative low-density lipoprotein cholesterol (ox-LDL) were measured at the end of study. RESULTS: There were no differences in clinical characteristics including lipid, ox-LDL and hypersensitive C reactive protein (Hs CRP) among groups at baseline. However, the average level of LDL-C was lower in group A20E10 than that in group A40 significantly (1.59 +/- 0.44 mmol/L vs 1.99 +/- 0.56 mmol/L, p = 0.001) during follow-up at week 12 after treatment. Importantly, the higher rate of achievement of LDL-C goal was attained at group of combination statin with ezetimibe (79.2% in group A20E10 vs 50.0% in group A40, p = 0.016). The difference of the level of ox-LDL between both the groups after 12 weeks treatment had not statistical significance (3.63 +/- 1.13 U/L in group A20E10 vs 4.14 +/- 1.32 U/L in group A40, p = 0.077).Similarly, the level of Hs-CRP between both the groups after treatment was not significantly different (p > 0.05). CONCLUSIONS: In this randomized study, the data showed that a combination of moderate statin and ezetimibe achieved more reduction of LDL-C compared to the double-dose statin but similar impact on inflammation markers. PMID- 30470228 TI - Microbial virulence, molecular epidemiology and pathogenic factors of fluoroquinolone-resistant Haemophilus influenzae infections in Guangzhou, China. AB - BACKGROUND: Fluoroquinolone-resistant Haemophilus influenzae (FRHI) has been reported worldwide but remain unclear in China. METHODS: A total of 402 H. influenzae isolates collected from 2016 to 2017 were included. Antimicrobial susceptibility on 10 antibiotics was performed, and minimum inhibitory concentration of ciprofloxacin- and nalidixic acid-resistant strains were further determined by E-test strips, with risk factors also evaluated. Strains with resistance or reduced susceptibility to ciprofloxacin were subjected to sequencing of the quinolone resistance-determining regions (QRDR) and plasmid mediated quinolone resistance genes by sequencing, with multi-locus sequence typing. RESULTS: 2.2% of H. influenzae strains were non-susceptible (7/402, 1.7%) or susceptible (2/402, 0.5%) to ciprofloxacin but NAL-resistant by E-test, and multidrug resistance was more common in fluoroquinolones non-susceptible H. influenzae group (p = 0.000). Infection risk factors included invasive procedure (p = 0.011), catching cold/previous contact with someone who had a cold (p = 0.019), fluoroquinolones use during previous 3 months (p = 0.003). With none of mutations obtained in gyrB, parE and other plasmid-mediated quinolone resistance genes, 7 and 4 strains were found for Ser-84-Leu substitutions in gyrA and one amino acid substitution in the QRDR of gyrA linked with one amino acid substitution in the QRDR of parC, respectively. In addition, five sequence types (ST) were identified, with ST1719 firstly found. CONCLUSIONS: For the first time, this study has reported the incidence, risk factors, molecular determinants on fluoroquinolones resistance and ST of FRHI strains in mainland China, representing the first evidence of mutation of gyrA and parC in China and the new ST1719 worldwide. PMID- 30470230 TI - The so far farthest reaches of the double jelly roll capsid protein fold. AB - BACKGROUND: During the last two decades, structural biology analyses have shown that viruses infecting hosts far apart in evolution share similar architectural features, prompting a new virus classification based on structural lineages. Until recently, only a few prokaryotic viruses had been described for one of the lineages, whose main characteristic is a capsid protein with a perpendicular double jelly roll. MAIN BODY: Metagenomics analyses are showing that the variety of prokaryotic viruses encoding double jelly roll capsid proteins is much larger than previously thought. The newly discovered viruses have novel genome organisations with interesting implications for virus structure, function and evolution. There are also indications of their having a significant ecological impact. CONCLUSION: Viruses with double jelly roll capsid proteins that infect prokaryotic hosts form a large part of the virosphere that had so far gone unnoticed. Their discovery by metagenomics is only a first step towards many more exciting findings. Work needs to be invested in isolating these viruses and their hosts, characterizing the structure and function of the proteins their genomes encode, and eventually access the wealth of biological information they may hold. PMID- 30470231 TI - M2 macrophages promote myofibroblast differentiation of LR-MSCs and are associated with pulmonary fibrogenesis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by the histopathological pattern of usual interstitial pneumonia and is associated with a high mortality rate. Recently, lung resident mesenchymal stem cells (LR-MSCs) have been identified as an important contributor to myofibroblast activation in pulmonary fibrosis. Macrophages are also believed to play a critical role in pulmonary fibrosis. However, the underlying connections between LR-MSCs and macrophages in the pathogenesis of pulmonary fibrosis are still elusive. METHODS: In this study, we investigated the interaction between LR MSCs and macrophages using a bleomycin-induced mouse pulmonary fibrosis model and a coculture system. RESULTS: Here, we show that blocking pulmonary macrophage infiltration attenuated bleomycin-induced pulmonary fibrosis. In addition, as determined by flow cytometry, we discovered that the recruited macrophages in fibrotic lungs of bleomycin-treated mice were mainly M2 macrophages. In particular, we found that M2, rather than M1 macrophages, promoted myofibroblast differentiation of LR-MSCs. Moreover, we demonstrated that suppression of the Wnt/beta-catenin signaling pathway could attenuate myofibroblast differentiation of LR-MSCs induced by M2 macrophages and bleomycin-induced pulmonary fibrosis. Tissue samples from IPF patients confirmed the infiltration of M2 macrophages and activation of Wnt/beta-catenin signaling pathway. CONCLUSION: In summary, this study furthered our understanding of the pulmonary fibrosis pathogenesis and highlighted M2 macrophages as a critical target for treating pulmonary fibrosis. PMID- 30470232 TI - Effects of fatty and lean fish intake on stroke risk: a meta-analysis of prospective cohort studies. AB - BACKGROUND: Fish intake has been postulated to reduce the risk of stroke. However, whether the beneficial effect of fish are mainly linked to fat content, as a source of omega-3 polyunsaturated fatty acids, remains unclear. We conducted a meta-analysis to compare the effect of fatty and lean fish intake on stroke risk. METHODS: We performed a literature search on four database (PubMed, Embase, Scopus, and Cochrane Library) through February 1, 2018 to identify prospective studies of fatty and lean fish in relation to stroke risk. A random-effects model was used to calculate the summary estimates. RESULTS: We identified five prospective studies, including 7 comparisons for fatty fish intake and 5 comparisons for lean fish intake. Compared with the highest category of intake with lowest category, the summary relative risk was 0.88 [95% confidence interval (CI), 0.74-1.04] for fatty fish intake and 0.81 (95% CI, 0.67-0.99) for lean fish intake. No heterogeneity across studies and publication bias were observed. CONCLUSION: Our findings demonstrated that fatty and lean fish intake has beneficial effects on stroke risk, especially lean fish intake. Additional prospective studies are necessary to confirm these observations. PMID- 30470233 TI - On the unraveling of 'revitalization of local health traditions' in India: an ethnographic inquiry. AB - BACKGROUND: India has recently renewed emphasis on non-allopathic systems of medicine as a means to address the health needs of its populace. Earlier in 2002, its national health policy had sought to 'revitalize' community-based health knowledge and practices - jointly christened 'local health traditions'. Yet policy texts remain silent on the actual means by which 'revitalization of local health traditions' should take place. Our research sought to understand the policy lessons of and for revitalization of local health traditions in the three Southern Indian states through an ethnographic inquiry in 2014-2016. METHODS: Our inquiry included a narrative synthesis of policy texts tracing the history of governance processes and mechanisms pertaining to traditional medicine, including local health traditions, linking this to the activities of non-governmental organizations (NGOs) and networks involved in "revitalization". Through in-depth interviews, observations and case studies, we sought to understand the life worlds of local health tradition practitioners and what revitalization meant to them. Our method revealed that beyond a purely academic inquiry, we needed an (inter)action that would give greater voice to these perspectives and views leading to hosting an interactive dialogue among practitioners, NGO representatives, academics, and government officials. RESULTS: Our ethnographic inquiry unraveled the problematic of a litotic approach to local health traditions as those which are non- institutionalized, non-certified, non documented; assuming the state to be the only source of power and legitimacy. Revitalization discussions were restricted (and often misled) by such an approach. Local health practitioners and others directed us to interesting possibilities of revitalization either through participatory modes of documentation of traditional health knowledge, strengthening existing collective forums for formal social recognition, and building pedagogical institutions that promote experiential learning. CONCLUSION: Were we not enabled by ethnography as a method that changes its shape apace with emerging findings, we would have not been able to comprehensively answer our questions. This is critical because not only was this already a marginalized area of inquiry, but with any other method we risked reinforcing inequities by imposing epistemological and other hierarchies on our participants- whom we would argue were partners - in arriving at our conclusions. PMID- 30470234 TI - High neopterin and IP-10 levels in cerebrospinal fluid are associated with neurotoxic tryptophan metabolites in acute central nervous system infections. AB - BACKGROUND: The host response to intruders in the central nervous system (CNS) may be beneficial but could also be harmful and responsible for neurologic symptoms and sequelae in CNS infections. This immune response induces the activation of the kynurenine pathway (KP) with the production of neuroactive metabolites. Herein, we explored cytokine and KP responses in cerebrospinal fluid (CSF) and serum in patients with encephalitis, aseptic, and bacterial meningitis. METHODS: Cytokines were measured in CSF and serum by multiplex assay in adult patients with encephalitis of infectious, autoimmune or unknown etiology (n = 10), aseptic meningitis (ASM, n = 25), acute bacterial meningitis (ABM, n = 6), and disease control patients with similar symptoms but without pleocytosis in CSF (n = 42). Liquid chromatography-tandem mass spectrometry (LC-MS/ MS) was used to measure KP metabolites in CSF and serum. RESULTS: A characteristic pattern of increasing cytokine levels and KP metabolites was found in CSF from encephalitis to ASM, with the highest levels in ABM. In ASM and ABM, most inflammatory mediators, including IL-6, IL-8, and IFN-inducible protein-10 (IP-10), showed markedly elevated levels in CSF compared with serum, indicating production within the CNS. In contrast to most mediators, the highest level of IP-10 was found in the ASM group, suggesting a potential role for IP-10 in aseptic/viral meningitis. Neopterin and IP-10 were associated with marked changes in KP metabolites in CSF with increasing kynurenine/tryptophan ratio reflecting indoleamine 2,3 dioxygenase activity. Neopterin, a marker of IFN-gamma activity, was associated with an unfavorable balance between neuroprotective and neurotoxic tryptophan metabolites. CONCLUSION: We show that parenchymal and meningeal inflammations in CNS share a characteristic cytokine profile with a general immune response in the CSF with limited influence from the systemic circulation. IFN-gamma activity, assessed by neopterin and IP-10 levels, may play a role in the activation of the KP pathway in these patients, potentially mediating neurotoxic effects. PMID- 30470236 TI - Healthy bi-regional connection: The EU-LAC Health initiative has promoted equitable and collaborative health research and innovation. AB - The European Union and Latin America and the Caribbean regions have enjoyed privileged relations since the first bi-regional Summit of Heads of State and Government, held in Rio de Janeiro, Brazil, in 1999, and the lunching of a Strategic Partnership. Health research stands as one of the major areas of research and development expenditure in both regions and has also been the focus of roughly 30% of all bilateral cooperation agreements and programmes.EU-LAC Health, a project funded by the European Union from 2011 to 2017, had the main objective to develop a consensus roadmap to enhance and coordinate the bi regional collaboration between the European Union member states and Latin America and Caribbean countries in health research. From April 2013, EU-LAC Health has also supported the Working Group on Health created and designated by decision makers at the highest political level to implement a bi-regional Join Initiative on Research and Innovation.This article collects and summarises the context, methodology (series of workshops, surveys and iterative deskwork by multiple bi regional stakeholders) of this project, as well as the main outputs of (1) definition of a strategic roadmap, containing a scientific research agenda, to guide policy-makers in equitable and collaborative health research and innovation; (2) launching of the Joint Initiative on Health Research and Innovation, with the vision of being the reference body on the bi-regional health research and innovation collaboration; and (3) funding of 13 bi-regional health research and innovation projects.EU-LAC Health represents a successful example of bi-regional collaboration and the emerging networks and expertise gathered during the lifetime of the project have the potential to tackle common health challenges affecting the quality of life of citizens from the two regions and beyond. The project has also paved the way for more specific bi-regional initiatives such as a new initiative for bi-regional collaboration in personalised medicine that is being arranged by the partnership. Furthermore, it can inspire future initiatives for bi-regional research collaboration on other fields. PMID- 30470235 TI - Effects of physiological aging factor on bone tissue engineering repair based on fetal BMSCs. AB - BACKGROUND: At present, many laboratories and hospitals all over the world are attempting and exploring the clinical transformation of this tissue engineered bone graft (TEBG) strategy. Many successful cases of bone tissue engineering (BTE) repair were based on young individuals. But there are little studies about the effectiveness of TEBG strategy in physiological aged individuals. METHODS: In this research, we studied whether aging factor has influence on the skull repair effect of Fetal-TEBG, at the level of the large animal models. We used the fetal bone marrow stromal cells (Fetal-BMSCs) as the seed cells, combining the decalcified bone matrix (DBM) scaffolds, to repair the skull defects of the aged goats and the young goats. The repair effects on both aged goat and young goat were compared by Micro-CT and histology examination. RESULTS: The skull defects of the young goats could be repaired better than that of the aged goats after 6 months by Fetal-TEBG; In the aged goats, although not completely repaired, the defects repaired by Fetal-TEBG was better than that repaired by the Control DBM scaffold. CONCLUSIONS: Aging factor has impact on the bone repair effect of Fetal TEBG; and the BTE strategy is still efficacious even in the aged individuals. The improvement of the aged state may promote the repair effect of the BTE in the aged individuals. PMID- 30470237 TI - Ukrainian health care system and its chances for successful transition from Soviet legacies. AB - BACKGROUND: Ukraine, one of the largest states formed on the rubble of the Soviet Union, is widely perceived as a country that has lost its opportunities. Being devastated by corruption, it shows incapable to modernize and enter the economic path of sustainable growth. Similarly in the health care system no deeper reform efforts have been taken in the entire post-soviet period, leaving the system in bonds of ineffective solutions taken out of the Soviet era. MAIN BODY: The recent geopolitical and economic crisis seem to favor the introduction of radical solutions that might lead to a rapid change in the organizational paradigm of the economic system, as well as in health care in Ukraine. In this paper we aim to highlight the key features of the ongoing health reform in Ukraine, identify basic challenges for it, and assess rationality and feasibility of the reform. We found that the projected scope and schedule of changes in the Ukrainian health system give promising prognosis regarding its final effect. CONCLUSIONS: The final success of health reform in Ukraine is dependent on a number of factors, including the financial foundation arising of economic stability of the country, balance assurance between public and private spending for health and ability to eliminate the long-lasting practices, particularly when they are connected with activities of lobbying groups occupying particular positions in the health system. A consequence of actions taken by the political decision-makers in the longer perspective are also to highly determine the reform's chances for success. PMID- 30470238 TI - Questionnaire results of user experiences with wearable exoskeletons and their preferences for sensory feedback. AB - BACKGROUND: Wearable exoskeletons can be a powerful tool for the facilitation of ambulation of complete Spinal Cord Injury (SCI) subjects, which has several psychological and physical advantages. However, exoskeleton control is difficult for this group of users and requires a long period of training. People with SCI not only lack the motor control, but also miss the sensory information from below the level of the lesion, which is for example very important in their perception of body posture and makes balancing with an exoskeleton difficult. It is hypothesized that through sensory substitution part of the missing sensory information can be provided and might thereby improve the control of an exoskeleton. However, it is not known which information would be most important to receive while using an exoskeleton and how this feedback should be provided. METHODS: To investigate the preferences of users of an exoskeleton, a questionnaire was filled out by 10 SCI subjects who underwent a training program with a commercial exoskeleton (ReWalk). The questionnaire consisted of questions about the use of the exoskeleton to identify which information is missing and which instructions from the therapists were needed to be able to control the exoskeleton. The second part of the questionnaire focused on the possibilities of sensory feedback and preferences for stimulation methods (auditory, vibrotactile or visual) and feedback timing (discrete or continuous) were investigated. Furthermore, six options for feedback parameters (step initiation, continuous and discrete gait phases, foot position and mediolateral and anteroposterior weight shift) were proposed and the respondents were asked to indicate their preferences. RESULTS: Three feedback parameters (feedback about mediolateral and anteroposterior weight shift and feedback about step initiation) were considered as possibly helpful by the respondents. Furthermore, there were slight preferences for the use of vibrotactile (over auditory and visual) and discrete (over continuous) feedback. CONCLUSIONS: The answers of the respondents on the optimal feedback parameters were rather variable and therefore it is recommended to let the users choose their preferred feedback system during a training session with several feedback options. However, there are slight preferences for the use of vibrotactile stimulation provided in a discrete way. PMID- 30470239 TI - Preconception counselling for low health literate women: an exploration of determinants in the Netherlands. AB - BACKGROUND: Women from lower socioeconomic groups tend to be at greater risk of adverse perinatal outcomes, but are less likely to participate in preconception counselling compared to higher socioeconomic groups. This could be partly because of their limited skills to assess, understand and use health related information in ways that promote and maintain good health (health literacy skills). In this study we explored determinants of participation in preconception counselling among women with low health literacy in The Netherlands. METHODS: Potential determinants of participation in preconception counselling were derived from the literature, and mapped onto a theoretical framework, which was tested for perceived relevance and completeness in an expert review (n = 20). The framework was used to prepare face-to-face interviews with women with low health literacy and a wish to conceive (n = 139). In the interviews we explored preconception counselling awareness, knowledge, considerations, subjective norms, self efficacy, attitude, and intention. Linear regression analyses were used to test associations with intention to participate in preconception counselling. RESULTS: Most women (75%) were unaware of the concept of preconception counselling and the provision of counselling, even if they lived in areas where written invitations had been disseminated. Common considerations for participation were: preparation for pregnancy; perceived lack of information; and problems in a previous pregnancy. Considerations not to participate were mostly related to perceived sufficient knowledge and perceived low risk of perinatal problems. Respondents generally had a positive attitude towards participation in preconception counselling for themselves, and 41% reported that they would participate in preconception counselling. CONCLUSION: Women with low health literacy were generally unaware of the concept and provision of preconception counselling, but seemed to be interested in participation. Further research should investigate how to effectively reach and inform this group about preconception counselling. This knowledge is essential for evidence-based development of interventions to increase the accessibility and understanding of preconception counselling. PMID- 30470240 TI - Anti-inflammatory and anti-oxidant mechanisms of an MMP-8 inhibitor in lipoteichoic acid-stimulated rat primary astrocytes: involvement of NF-kappaB, Nrf2, and PPAR-gamma signaling pathways. AB - BACKGROUND: Recent evidence suggests that reactive astrocytes play an important role in neuroinflammation and neurodegenerative diseases. Thus, controlling astrocyte reactivity has been suggested as a promising strategy for treating neurodegenerative diseases. In the present study, we investigated whether a matrix metalloproteinase (MMP)-8 inhibitor, M8I, could control neuroinflammation in lipoteichoic acid (LTA)-stimulated rat primary astrocytes. METHODS: The effects of M8I on the expression of inducible nitric oxide synthase, cytokines, and MMPs were examined in LTA-stimulated rat primary astrocytes by ELISA, RT-PCR, and Western blot analysis. The effects of M8I on reactive oxygen species (ROS) generation and phase II antioxidant enzyme expression were examined by the DCF-DA assay, RT-PCR, and Western blot analysis. The detailed molecular mechanisms underlying the anti-inflammatory and antioxidant effects of M8I were analyzed by the electrophoretic mobility shift assay, the reporter gene assay, Western blot, and RT-PCR analysis. RESULTS: Treatment with LTA, a major cell wall component of Gram-positive bacteria, led to astrocyte activation and induced the expression of inflammatory molecules such as iNOS, COX-2, and pro-inflammatory cytokines. In addition, LTA induced the expression of MMPs such as MMP-1, MMP-3, MMP-8, MMP-9, and MMP-13 in rat primary astrocytes. Based on previous reports showing that MMP 8 plays a role as a proinflammatory mediator in microglia, we investigated whether MMP-8 is also involved in inflammatory reactions of reactive astrocytes. We found that treatment of astrocytes with M8I significantly inhibited LTA induced expression of iNOS, TNF-alpha, IL-1beta, IL-6, and TLR-2. In addition, M8I inhibited LTA-induced NF-kappaB, MAP kinase, and Akt activities, while it increased the anti-inflammatory PPAR-gamma activities. Moreover, M8I showed antioxidant effects by suppressing ROS production in LTA- or H2O2-stimulated astrocytes. Interestingly, M8I increased the expression of phase II antioxidant enzymes such as hemeoxygenase-1, NQO1, catalase, and MnSOD by modulating the Nrf2/ARE signaling pathway. CONCLUSIONS: The data collectively suggest the therapeutic potential of an MMP-8 inhibitor in neuroinflammatory disorders that are associated with astrocyte reactivity. PMID- 30470241 TI - Feasibility study of dual parametric 2D histogram analysis of breast lesions with dynamic contrast-enhanced and diffusion-weighted MRI. AB - BACKGROUND: This study aimed to investigate the diagnostic value of a dual parametric 2D histogram classification method for breast lesions. METHODS: This study included 116 patients with 72 malignant and 44 benign breast lesions who underwent CAIPIRINHA-Dixon-TWIST-VIBE dynamic contrast-enhanced (CDT-VIBE DCE) and readout-segmented diffusion-weighted magnetic resonance examination. The volume of interest (VOI), which encompassed the entire lesion, was segmented from the last phase of DCE images. For each VOI, a 1D histogram analysis (mean, median, 10th percentile, 90th percentile, kurtosis and skewness) was performed on apparent diffusion coefficient (ADC) and volume transfer constant (Ktrans) maps; a 2D histogram image (Ktrans-ADC) was generated from the pixelwise aligned maps, and its kurtosis and skewness were calculated. Each parameter was correlated with pathological results using the Mann-Whitney test and receiver operating characteristic curve analysis. RESULTS: For the Ktrans histogram, the area under the curve (AUC) of the mean, median, 90th percentile and kurtosis had statistically diagnostic values (mean: 0.760; median: 0.661; 90th percentile: 0.781; and kurtosis: 0.620). For the ADC histogram, the AUC of the mean, median, 10th percentile, skewness and kurtosis had statistically diagnostic values (mean: 0.661; median: 0.677; 10th percentile: 0.656; skewness: 0.664; and kurtosis: 0.620). For the 2D Ktrans-ADC histogram, the skewness and kurtosis had statistically higher diagnostic values (skewness: 0.831, kurtosis: 0.828) than those of the 1D histogram (all P < 0.05). CONCLUSIONS: The dual-parametric 2D histogram analysis revealed better diagnostic accuracy for breast lesions than single parametric histogram analysis of either Ktrans or ADC maps. PMID- 30470242 TI - Expression of Concern to: Does ovary need D-chiro-inositol? PMID- 30470243 TI - The safety and efficacy of on-site paramedic and allied health treatment interventions targeting the reduction of emergency department visits by long-term care patients: systematic review protocol. AB - BACKGROUND: Older adults are more likely to access the emergency department, which suffers from overcrowding and congestion, for conditions that could potentially be treated in other settings. Older adults living in long-term care centers have access to healthcare resources in their residence, and several programs have been created with the intent of treating medical conditions on site. The aim of this study is to identify and systematically review programs and interventions at long-term care centers that aim to treat patients on-site, avoiding unscheduled transportation to the emergency department. METHODS: We will follow the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We will perform a comprehensive search of Embase, MEDLINE, CINAHL, ClinicalTrials.gov , PROSPERO, and the Cochrane Central Registry of Controlled Trials using a broad search strategy. Two independent reviewers will assess titles and abstracts against inclusion criteria, and we will further evaluate relevant full-text articles for inclusion. We will assess the risk of bias using the Newcastle-Ottawa scale for included non-randomized studies and the Cochrane Risk of Bias tool for randomized trials. We will present a narrative synthesis of results and complete a meta-analysis only if enough homogeneity is found. We will create funnel plots to evaluate possible reporting bias and use The Grading of Recommendations Assessment Development and Evaluation (GRADE) methodology to assess the confidence in cumulative evidence. DISCUSSION: As pressure on the healthcare system continues to rise, many areas are looking for alternative models of care. Several programs have been put in place in long-term care centers that seek to avoid transportation to the emergency department by providing enhanced care on-site. These programs are quite variable, and, to date, there is no standardized program or model of care. SYSTEMATIC REVIEW REGISTRATION: PROSPERO ( CRD42018091636 ). PMID- 30470244 TI - Surgical repair of partial anomalous pulmonary venous return with intact atrial septum in a 65-year-old woman: a case report. AB - BACKGROUND: Partial anomalous pulmonary venous return is a rare congenital cardiac anomaly that usually involves the right pulmonary vein and an atrial septal defect. Isolated partial anomalous pulmonary venous return with an intact atrial septum is even rarer, and this condition is usually treated surgically in younger patients. We describe isolated partial anomalous pulmonary venous return in a 65-year-old woman who was treated by caval division with pericardial patch baffling through a surgically created atrial septal defect and reconstruction of the superior vena cava using a prosthetic graft. CASE PRESENTATION: A 65-year-old Asian woman who presented with exertional dyspnea was diagnosed with isolated partial anomalous pulmonary venous return. The surgical indications and strategy were controversial because of the rarity of this pathology. She had an indication for surgery because she was symptomatic and had a high ratio of pulmonary to systemic blood flow. We considered that surgical procedures should avoid postoperative stenosis of a reconstructed flow tract, sinus node dysfunction, and thrombogenesis. We created a caval division with pericardial patch baffling through a surgically created atrial septal defect and reconstructed the superior vena cava using a prosthetic graft for the isolated partial anomalous pulmonary venous return. She has since remained free of exertional dyspnea, arrhythmia, and thrombotic complications. This surgical strategy is safe and effective for treating isolated partial anomalous pulmonary venous return in older symptomatic adults. CONCLUSIONS: The long-term outcome of surgical repair of partial anomalous pulmonary venous return with an intact atrial septum in our patient, a symptomatic 65-year-old woman, was excellent. PMID- 30470245 TI - Rare case of low-grade extranodal NK/T-cell lymphoma, nasal type, arising in the setting of chronic rhinosinusitis and harboring a novel N-terminal KIT mutation. AB - BACKGROUND: Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT), is a rare aggressive subtype of non-Hodgkin lymphoma characterized by angioinvasion, angiodestruction, necrosis and strong association with Epstein-Barr virus (EBV). ENKTCL-NT occurs worldwide and is more prevalent in Asian and the Native American populations of Mexico, Central and South America. It represents approximately 10% of all peripheral T-cell lymphomas worldwide. The aim of this report is to present a rare case of ENKTCL-NT with an unusually indolent clinical course and low-grade histopathologic features. CASE PRESENTATION: A 71-year-old Asian woman with a long-standing history of seasonal rhinosinusitis presented with persistent nasal congestion, cough, and fever unresponsive to antihistamines and antibiotics. Histopathological evaluation of a polypoid nasal mass revealed an atypical infiltrate with predominantly small lymphoid cells that were CD2+, surface CD3-, cytoplasmic CD3+, CD5(dim)+, CD7(dim)+, cytotoxic markers (granzyme B and perforin)+, EBER+ and CD56-. The Ki-67 proliferative index was very low (< 1%). T-cell receptor gamma gene rearrangement studies were positive for a monoclonal rearrangement, and sequencing studies identified a novel KIT mutation (p. K167 M, c. 500 A > T). A diagnosis of low-grade ENKTCL-NT was rendered. CONCLUSIONS: Our case of ENKTCL-NT is unusual due to (1) an indolent clinical course (2) low-grade histopathologic features including a low proliferative index (3) lack of CD56 expression and (4) a novel KIT mutation. This case raises awareness of the existence of a subset of cases of ENKTCL-NT that can potentially be misdiagnosed as a reactive process, particularly in patients with recurrent chronic rhinosinusitis. PMID- 30470246 TI - The bird's-eye view on chromosome evolution. AB - The study of the evolution of chromosomal number and structure has long been of interest to evolutionary biologists. However, this research has been hindered by the lack of chromosome-level genome assemblies for multiple species across phylogenetic lineages. Three recent studies from same research group have demonstrated the power of bioinformatic approaches in producing chromosome level genome assemblies and reconstructing the karyotypic history of birds. PMID- 30470247 TI - Internet-based interventions for adults with hearing loss, tinnitus and vestibular disorders: a protocol for a systematic review. AB - BACKGROUND: Internet-based interventions are emerging as an alternative way of delivering accessible healthcare for various conditions including hearing and balance disorders. A comprehensive review regarding the evidence-base of Internet based interventions for auditory-related conditions is required to determine the existing evidence of their efficacy and effectiveness. The objective of the current protocol is to provide the methodology for a systematic review regarding the effects of Internet-based interventions for adults with hearing loss, tinnitus and vestibular disorders. METHOD: This protocol was developed according to the Preferred Reporting Items for Systematic reviews and Meta-analyses for Protocols (PRISMA-P) 2015 guidelines. Electronic database searches will include EBSCOhost, PubMed and Cochrane Central Register performed by two researchers. This will be complemented by searching other resources such as the reference lists for included studies to identify studies meeting the eligibility for inclusion with regard to study designs, participants, interventions, comparators and outcomes. The Cochrane risk of bias tool (RoB 2) for randomised trials will be used for the bias assessments in the included studies. Criteria for conducting meta-analyses were defined. DISCUSSION: The result of this systematic review will be of value to establish the effects of Internet-based interventions for hearing loss, tinnitus and vestibular disorders. This will be of importance to guide future planning of auditory intervention research and clinical services by healthcare providers, researchers, consumers and stakeholders. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018094801. PMID- 30470248 TI - Early life immunity in the era of systems biology: understanding development and disease. AB - Systems immunology has the potential to offer invaluable insights into the development of the immune system. Two recent studies offer an in-depth view of both the dynamics of immune system development and the heritability of the levels of key immune modulators at birth. PMID- 30470250 TI - miR-181b/Notch2 overcome chemoresistance by regulating cancer stem cell-like properties in NSCLC. AB - BACKGROUND: Lung cancer stem cells have the ability to self-renew and are resistant to conventional chemotherapy. MicroRNAs (miRNAs) regulate and control the expression and function of many target genes; therefore, miRNA disorders are involved in the pathogenesis of human diseases, such as cancer. However, the effects of miRNA dysregulation on tumour stemness and drug resistance have not been fully elucidated. miR-181b has been reported to be a tumour suppressor miRNA and is associated with drug-resistant non-small cell lung cancer. METHODS: Cancer stem cell (CSC)-like properties were tested by a cell proliferation assay and flow cytometry; miR-181b expression was measured by real-time PCR; and Notch2 and related proteins were detected by Western blotting and immunohistochemistry. A mouse xenograft model was also established. RESULTS: In this study, we found that ectopic miR-181b expression suppressed cancer stem cell properties and enhanced sensitivity to cisplatin (DDP) treatment by directly targeting Notch2. miR-181b could inactivate the Notch2/Hes1 signalling pathway. In addition, tumours from nude mice treated with miR-181b were significantly smaller than tumours from mice treated with control agomir. Decreased miR-181b expression and increased Notch2 expression were observed to have a significant relationship with overall survival (OS) and CSC-like properties in non-small cell lung cancer (NSCLC) patients. CONCLUSIONS: This study elucidates an important role of miR-181b in the regulation of CSC-like properties, suggesting a potential therapeutic target for overcoming drug resistance in NSCLC. PMID- 30470251 TI - Association between dementia and mortality in the elderly patients undergoing hip fracture surgery: a meta-analysis. AB - OBJECTIVE: This study was designed to verify the association between dementia and mortality in the elderly undergoing hip fracture surgery, and assessed the mortality of patients with dementia after hip fracture surgery. MATERIAL AND METHODS: PubMed, Embase, and Web of Science were searched until April, 2018 without language restrictions. Two reviewers selected related studies, assessed study quality, and extracted data independently. Risk ratios (RRs) with 95% confidence intervals (CI) were derived using random-effects model throughout all analyses. The endpoints included 30-day, 6-month, 1-year, and more than 1-year mortality. This meta-analysis was performed following PRISMA statement and carried out by using stata14.0 software. RESULTS: Dementia significantly increased postoperative mortality of patients suffered from hip fracture in 30 day [RR = 1.57, 95% CI (1.29, 1.90), P<0.00], 6-month [RR = 1.97, 95% CI (1.47, 2.63), P<0.00], 1-year [RR = 1.77, 95% CI (1.54, 2.04), P<0.00], and more than 1 year follow up [RR = 1.60, 95% CI (1.30, 1.96), P<0.00] respectively. The mortality of dementia patients after hip fracture surgery in 30-day [ES = 12%, 95% CI (8%, 15%)], 6-month [ES = 32%, 95% CI (17%, 48%)], 1-year [ES = 39%, 95% CI (35%, 43%)], and more than 1-year follow up [ES = 45%, 95% CI (32%, 58%)]. CONCLUSIONS: Our meta-analysis demonstrated that the mortality of patients with dementia suffered from hip fracture surgery is 12%, 32%, 39%, and 45%, and dementia increased 1.57, 1.97, 1.77, and 1.60-fold mortality in patients undergoing hip fracture surgery in 30-day, 6-month, 1-year, and more than 1-year follow up respectively. PMID- 30470249 TI - A urine-based DNA methylation assay, ProCUrE, to identify clinically significant prostate cancer. AB - BACKGROUND: Prevention of unnecessary biopsies and overtreatment of indolent disease remains a challenge in the management of prostate cancer. Novel non invasive tests that can identify clinically significant (intermediate-risk and high-risk) diseases are needed to improve risk stratification and monitoring of prostate cancer patients. Here, we investigated a panel of six DNA methylation biomarkers in urine samples collected post-digital rectal exam from patients undergoing prostate biopsy, for their utility to guide decision making for diagnostic biopsy and early detection of aggressive prostate cancer. RESULTS: We recruited 408 patients in risk categories ranging from benign to low-, intermediate-, and high-risk prostate cancer from three international cohorts. Patients were separated into 2/3 training and 1/3 validation cohorts. Methylation biomarkers were analyzed in post-digital rectal exam urinary sediment DNA by quantitative MethyLight assay and investigated for their association with any or aggressive prostate cancers. We developed a Prostate Cancer Urinary Epigenetic (ProCUrE) assay based on an optimal two-gene (HOXD3 and GSTP1) LASSO model, derived from methylation values in the training cohort, and assessed ProCUrE's diagnostic and prognostic ability for prostate cancer in both the training and validation cohorts. ProCUrE demonstrated improved prostate cancer diagnosis and identification of patients with clinically significant disease in both the training and validation cohorts. Using three different risk stratification criteria (Gleason score, D'Amico criteria, and CAPRA score), we found that the positive predictive value for ProCUrE was higher (59.4-78%) than prostate specific antigen (PSA) (38.2-72.1%) for all risk category comparisons. ProCUrE also demonstrated additive value to PSA in identifying GS >= 7 PCa compared to PSA alone (DeLong's test p = 0.039), as well as additive value to the PCPT risk calculator for identifying any PCa and GS >= 7 PCa (DeLong's test p = 0.011 and 0.022, respectively). CONCLUSIONS: ProCUrE is a promising non-invasive urinary methylation assay for the early detection and prognostication of prostate cancer. ProCUrE has the potential to supplement PSA testing to identify patients with clinically significant prostate cancer. PMID- 30470252 TI - A systematic review of the cost and cost-effectiveness studies of immune checkpoint inhibitors. AB - BACKGROUND: Escalating healthcare costs are necessitating the practice of value based oncology. It is crucial to critically evaluate the economic impact of influential but expensive therapies such as immune checkpoint inhibitors (ICIs). To date, no systematic assessment of the cost-effectiveness (CE) of ICIs has been performed. METHODS: PRISMA-guided systematic searches of the PubMed database were conducted. Studies of head/neck (n = 3), lung (n = 5), genitourinary (n = 4), and melanoma (n = 8) malignancies treated with ICIs were evaluated. The reference willingness-to-pay (WTP) threshold was $100,000/QALY. RESULTS: Nivolumab was not cost-effective over chemotherapy for recurrent/metastatic head/neck cancers (HNCs). For non-small cell lung cancer (NSCLC), nivolumab was not cost-effective for a general cohort, but increased PD-L1 cutoffs resulted in CE. Pembrolizumab was cost-effective for both previously treated and newly-diagnosed metastatic NSCLC. For genitourinary cancers (GUCs, renal cell and bladder cancers), nivolumab and pembrolizumab were not cost-effective options. Regarding metastatic/unresected melanoma, ipilimumab monotherapy is less cost-effective than nivolumab, nivolumab/ipilimumab, and pembrolizumab. The addition of ipilimumab to nivolumab monotherapy was not adequately cost-effective. Pembrolizumab or nivolumab monotherapy offered comparable CE profiles. CONCLUSIONS: With limited data and from the reference WTP, nivolumab was not cost effective for HNCs. Pembrolizumab was cost-effective for NSCLC; although not the case for nivolumab, applying PD-L1 cutoffs resulted in adequate CE. Most data for nivolumab and pembrolizumab in GUCs did not point towards adequate CE. Contrary to ipilimumab, either nivolumab or pembrolizumab is cost-effective for melanoma. Despite these conclusions, it cannot be overstated that careful patient selection is critical for CE. Future publication of CE investigations and clinical trials (along with longer follow-up of existing data) could substantially alter conclusions from this analysis. PMID- 30470253 TI - Long-term results and PSA kinetics after robotic SBRT for prostate cancer: multicenter retrospective study in Korea (Korean radiation oncology group study 15-01). AB - BACKGROUND: To evaluate the treatment outcome and prostate-specific antigen (PSA) change after stereotactic body radiotherapy (SBRT) for localized prostate cancer. METHODS: Patients with localized prostate cancer treated with SBRT at three academic hospitals were enrolled. Treatment was delivered using Cyberknife with dose range from 35 to 37.5 Gy in 5 fractions. Biochemical failure (BCF) was assessed with Phoenix definition and toxicities were scored with Radiation Therapy Oncology Group (RTOG) toxicity criteria. The PSA kinetics were analyzed in patients who received no androgen deprivation therapy (ADT) and showed no recurrence. RESULTS: Of the total 88 patients, 14 patients (15.9%) received ADT. After median follow-up of 63.8 months, the 5-year BCF free survival (BCFFS) was 94.7%. Two patients experienced late grade >= 3 GI toxicities (2.2%). The median nadir PSA was 0.12 ng/mL (range, 0.00-2.62 ng/mL) and the median time to nadir was 44.8 months (range, 0.40-85.7 months). Patients who reached nadir before 24 months showed poorer BCFFS than the others. The rate of PSA decline was maximum in the first year after treatment and gradually decreased with time. The pattern of PSA change was significantly different according to the risk groups (p = 0.011) with the slope of - 0.139, - 0.161 and - 0.253 ng/mL/month in low-, intermediate- and high-risk groups, respectively. CONCLUSION: SBRT for localized prostate cancer showed favorable efficacy with minimal toxicities. The time to PSA nadir was significantly associated with treatment outcome. PSA revealed rapid initial decline and slower decrease with longer follow-up and the patterns of PSA changes were different according to the risk groups. PMID- 30470254 TI - Effectiveness of Multi-Criteria Optimization-based Trade-Off exploration in combination with RapidPlan for head & neck radiotherapy planning. AB - BACKGROUND: A new strategy is introduced combining the use of Multi-Criteria Optimization-based Trade-Off Exploration (TO) and RapidPlanTM (RP) for the selection of optimisation parameters that improve the trade-off between sparing of organs at risk (OAR) and target coverage for head and neck radiotherapy planning. Using both approaches simultaneously; three different workflows were proposed for the optimisation process of volumetric-modulated arc therapy (VMAT) plans. The generated plans were compared to the clinical plans and the plans that resulted using RP and TO individually. METHODS: Twenty clinical VMAT plans previously administered were selected. Five additional plans were created for each patient: a clinical plan further optimised with TO (Clin+TO); two plans generated by in-house built RP models, RP_1 with the model built with VMAT clinical plans and RP_TO with the model built with VMAT plans optimised by TO. Finally, these last two plans were additionally optimised with TO for the creation of the plans RP_1 + TO and RP_TO+ respectively. The TO management was standardised to maximise the sparing of the parotid glands without compromising a clinically acceptable PTV coverage. Resulting plans were inter-compared based on dose-volume parameters for OAR and PTVs, target homogeneity, conformity, and plans complexity and deliverability. RESULTS: The plans optimised using TO in combination with RP showed significantly improved OAR sparing while maintaining comparable target dose coverage to the clinical plans. The largest OAR sparing compared to the clinical plans was achieved by the RP_TO+ plans, which reported a mean parotid dose average of 15.0 +/- 4.6 Gy vs 22.9 +/- 5.5 Gy (left) and 17.1 +/- 5.0 Gy vs 24.8 +/- 5.8 Gy (right). However, at the same time, RP_TO+ showed a slight dose reduction for the 99% volume of the nodal PTV and an increase for the 95% (when comparing to the clinical plans 76.0 +/- 1.2 vs 77.4 +/- 0.6 and 80.9 +/- 0.9 vs 79.7 +/- 0.4) but remained within clinical acceptance. Plans optimised with RP and TO combined, showed an increase in complexity but were proven to be deliverable. CONCLUSION: The use of TO combined with RP during the optimisation of VMAT plans enhanced plan quality the most. For the RP_TO+ plans, acceptance of a slight deterioration in nodal PTV allowed the largest reduction in OAR dose to be achieved. PMID- 30470256 TI - Evaluation of a maternity waiting home and community education program in two districts of Malawi. AB - BACKGROUND: The implementation of Maternity Waiting Homes (MWHs) is a strategy to bring vulnerable women close to a health facility towards the end of their pregnancies. To date, while MWHs are a popular strategy, there is limited evidence on the role that MWHs play in reaching women most in need. This paper contributes to this topic by examining whether two program-supported MWHs in Malawi are reaching women in need and if there are changes in women reached over time. METHODS: Two rounds of exit interviews (2015 and 2017) were conducted with women within 3 months of delivery and included both MWH users and non-MWH users. These exit interviews included questions on sociodemographic factors, obstetric risk factors and use of health services. Bivariate statistics were used to compare MWH users and non-MWH users at baseline and endline and over time. Multivariable logistic regression was used to determine what factors were associated with MWH use, and Poisson regression was used to study factors associated with HIV knowledge. Descriptive data from discharge surveys were used to examine satisfaction with the MWH structure and environment over time. RESULTS: Primiparous women were more likely to use a MWH compared to women of parity 2 (p < 0.05). Women who were told they were at risk of a complication were more likely to use a MWH compared to those who were not told they were at risk (p < 0.05). There were also significant findings for wealth and time to a facility, with poorer women and those who lived further from a facility being more likely to use a MWH. Attendance at a community event was associated with greater knowledge of HIV (p < 0.05). CONCLUSIONS: MWHs have a role to play in efforts to improve maternal health and reduce maternal mortality. Education provided within the MWHs and through community outreach can improve knowledge of important health topics. Malawi and other low and middle income countries must ensure that health facilities affiliated with the MWHs offer high quality services. PMID- 30470257 TI - Evaluation of the diagnostic performance of the simple method of computed tomography in the assessment of patients with shoulder instability: a prospective cohort study. AB - BACKGROUND: Physical examinations may reveal the instability of a glenohumeral joint but cannot diagnose the bony Bankart lesions. Soft tissue Bankart lesion cannot be visualized on traditional radiogram. Magnetic resonance images have high cost and availability issues. The purpose of the study was to access the diagnostic performance of the Computed Tomography (CT) in the assessment of patients with shoulder instability and to diagnose the Bankart and bony Bankart lesions. METHODS: A total of 145 patients with shoulder instability were included in the study. Patients were subjected to clinical examination tests, traditional radiography, and CT. Two orthopedic surgeons, two engineers (trained in musculoskeletal imaging), and two physiotherapists have analyzed the radiological images, CT scans, and the clinical examination tests respectively. The Chi-square test or one-way ANOVA/ Dunnett Multiple comparisons test was performed at 99% of confidence level. RESULTS: Sensitivity (0.972 +/- 0.18 vs. 1, p = 0.11) and accuracy (0.942 +/- 0.17 vs. 1, p < 0.0001, q = 3.88) for the clinical examination tests combining the traditional radiological images were same to CT. However, the clinical examination tests combining the traditional radiological images had more inconclusive results (5 vs. 1), false-positive results (6 vs. 5), and false negative results (4 vs. 1) than CT. The area that detects the Bankart and bony Bankart lesions at least one time for CT was higher than that of the clinical examination tests combining the traditional radiological images. CONCLUSION: CT should be considered for evaluation in patients with shoulder instability and suspected Bankart and bony Bankart lesions. TRIAL REGISTRATION: Researchregistry3990 dated 15 December 2014 ( www.researchregistry.com ). PMID- 30470255 TI - A modified clinicopathological tumor staging system for survival prediction of patients with penile cancer. AB - BACKGROUND: The 8th American Joint Committee on Cancer tumor-node-metastasis (AJCC-TNM) staging system is based on a few retrospective single-center studies. We aimed to test the prognostic validity of the staging system and to determine whether a modified clinicopathological tumor staging system that includes lymphovascular embolization could increase the accuracy of prognostic prediction for patients with stage T2-3 penile cancer. METHODS: A training cohort of 411 patients who were treated at 2 centers in China and Brazil between 2000 and 2015 were staged according to the 8th AJCC-TNM staging system. The internal validation was analyzed by bootstrap-corrected C-indexes (resampled 1000 times). Data from 436 patients who were treated at 15 centers over four continents were used for external validation. RESULTS: A survivorship overlap was observed between T2 and T3 patients (P = 0.587) classified according to the 8th AJCC-TNM staging system. Lymphovascular embolization was a significant prognostic factor for metastasis and survival (all P < 0.001). Based on the multivariate analysis, only lymphovascular embolization showed a significant influence on cancer-specific survival (CSS) (hazard ratio = 1.587, 95% confidence interval = 1.253-2.011; P = 0.001). T2 and T3 patients with lymphovascular embolization showed significantly shorter CSS than did those without lymphovascular embolization (P < 0.001). Therefore, a modified clinicopathological staging system was proposed, with the T2 and T3 categories of the 8th AJCC-TNM staging system being subdivided into two new categories as follows: t2 tumors invade the corpus spongiosum and/or corpora cavernosa and/or urethra without lymphovascular invasion, and t3 tumors invade the corpus spongiosum and/or corpora cavernosa and/or urethra with lymphovascular invasion. The modified staging system involving lymphovascular embolization showed improved prognostic stratification with significant differences in CSS among all categories (all P < 0.005) and exhibited higher accuracy in predicting patient prognoses than did the 8th AJCC-TNM staging system (C-index, 0.739 vs. 0.696). These results were confirmed in the external validation cohort. CONCLUSIONS: T2-3 penile cancers are heterogeneous, and a modified clinicopathological staging system that incorporates lymphovascular embolization may better predict the prognosis of patients with penile cancer than does the 8th AJCC-TNM staging system. Trial registration This study was retrospectively registered on Chinese Clinical Trail Registry: ChiCTR16008041 (2016-03-02). http://www.chictr.org.cn. PMID- 30470258 TI - Endothelial damage, vascular bagging and remodeling of the microvascular bed in human microangiopathy with deep white matter lesions. AB - White matter lesions (WMLs) are a common manifestation of small vessel disease (SVD) in the elderly population. They are associated with an enhanced risk of developing gait abnormalities, poor executive function, dementia, and stroke with high mortality. Hypoperfusion and the resulting endothelial damage are thought to contribute to the development of WMLs. The focus of the present study was the analysis of the microvascular bed in SVD patients with deep WMLs (DWMLs) by using double- and triple-label immunohistochemistry and immunofluorescence. Simultaneous visualization of collagen IV (COLL4)-positive membranes and the endothelial glycocalyx in thick sections allowed us to identify endothelial recession in different types of string vessels, and two new forms of small vessel/capillary pathology, which we called vascular bagging and ghost string vessels. Vascular bags were pouches and tubes that were attached to vessel walls and were formed by multiple layers of COLL4-positive membranes. Vascular bagging was most severe in the DWMLs of cases with pure SVD (no additional vascular brain injury, VBI). Quantification of vascular bagging, string vessels, and the density/size of CD68-positive cells further showed widespread pathological changes in the frontoparietal and/or temporal white matter in SVD, including pure SVD and SVD with VBI, as well as a significant effect of the covariate age. Plasma protein leakage into vascular bags and the white matter parenchyma pointed to endothelial damage and basement membrane permeability. Hypertrophic IBA1 positive microglial cells and CD68-positive macrophages were found in white matter areas covered with networks of ghost vessels in SVD, suggesting phagocytosis of remnants of string vessels. However, the overall vessel density was not altered in our SVD cohort, which might result from continuous replacement of vessels. Our findings support the view that SVD is a progressive and generalized disease process, in which endothelial damage and vascular bagging drive remodeling of the microvasculature. PMID- 30470260 TI - Peripheral blood biomarkers correlate with outcomes in advanced non-small cell lung Cancer patients treated with anti-PD-1 antibodies. AB - BACKGROUND: Anti-programmed cell death 1 (PD-1) antibodies have demonstrated improved overall survival (OS) and progression-free survival (PFS) in a subset of patients with metastatic or locally advanced non-small cell lung cancer (NSCLC). To date, no blood biomarkers have been identified in NSCLC to predict clinical outcomes of treatment with anti-PD-1 antibodies. PATIENT AND METHODS: We performed an analysis of retrospectively registered data of 157 patients with advanced NSCLC treated with anti-PD-1 antibodies at Mayo Clinic in Florida and Rochester. White blood cell count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), ANC to ALC (ANC: ALC) ratio, absolute eosinophil count, absolute monocyte count (AMC), platelet counts, and myeloid to lymphoid (M:L) ratio at baseline and throughout treatment were assessed. Kaplan-Meier method and Cox proportional hazards model were performed. RESULTS: We treated 146 patients with nivolumab and 11 with pembrolizumab between January 1, 2015 and April 15, 2017. At median follow-up of 20 months, median OS and PFS were 6.0 and 2.6 months, respectively. Higher baseline ANC, AMC, ANC: ALC ratio and M: L ratio correlated with worse clinical outcomes in patients who underwent anti-PD-1 treatment. A baseline ANC: ALC ratio of 5.9 or higher had a significantly increased risk of death (hazard ratio [HR] =1.94; 95% confidence interval [CI], 1.24-3.03; P = 0.004) and disease progression (HR, 1.65; 95% CI, 1.17-2.34; P = 0.005) compared with patients with lower ratio. Similarly, a baseline M: L ratio of 11.3 or higher had significantly increased risk of death (HR, 2.5; 95% CI, 1.54-4.05; P < 0.001), even after a multivariate analysis (HR, 2.31; P = 0.002), compared to those with lower ratio. CONCLUSIONS: Increased baseline ANC: ALC ratio and M: L ratio before initiation of anti-PD1 antibodies were associated with poor PFS and OS in advanced NSCLC patients. The potential predictive value of these readily available biomarkers might help with risk stratification and treatment strategies. These findings warrant further investigation in a larger, prospective study. PMID- 30470259 TI - AMBIsome Therapy Induction OptimisatioN (AMBITION): High Dose AmBisome for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: Study Protocol for a Phase 3 Randomised Controlled Non-Inferiority Trial. AB - BACKGROUND: Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen). METHODS: An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10% and 90% power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged >= 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance. DISCUSSION: A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment. TRIAL REGISTRATION: ISRCTN, ISRCTN72509687 . Registered on 13 July 2017. PMID- 30470261 TI - CircSLC3A2 functions as an oncogenic factor in hepatocellular carcinoma by sponging miR-490-3p and regulating PPM1F expression. AB - BACKGROUND: Non-coding RNAs (ncRNAs) have been reported to participate in tumor progression by regulating gene expression. Previous studies showed that protein phosphatase Mg2+/Mn2+ dependent 1F (PPM1F) acts a dual role in cancer growth and metastasis. But, the underlying mechanisms by which ncRNAs regulate PPM1F expression in hepatocellular carcinoma (HCC) are poorly understood. METHODS: The association between PPM1F or miR-490-3p expression and clinicopathological features and prognosis in patients with HCC was analyzed by TCGA RNA-sequencing data. CircSLC3A2 was identified to bind with miR-490-3p by bioinformatic analysis, and the binding sites between miR-490-3p and PPM1F or circSLC3A2 were confirmed by dual luciferase report and RNA immunoprecipitation (RIP) assays. The localization and clinical significance of miR-490-3p and circSLC3A2 in patients with HCC were investigated by fluorescence in situ hybridization (FISH). MTT, Agar, and Transwell assays were conducted to evaluate the effects of miR-490-3p or circSLC3A2 on cell proliferation and invasive potential. RESULTS: The expression of PPM1F or miR-490-3p was associated with poor survival and tumor recurrence, and acted as an independent prognostic factor in patients with HCC. Re-expression of miR-490-3p inhibited HCC cell proliferation and invasion by targeting PPM1F, but its inhibitor reversed these effects. Moreover, circSLC3A2, predominantly localized in the cytoplasm, exhibited an oncogenic role by sponging miR-490-3p and regulating PPM1F expression, and harbored a positive correlation with poor survival in patients with HCC. CONCLUSION: CircSLC3A2 acts as an oncogenic factor in HCC by sponging miR-490-3p and regulating PPM1F expression. PMID- 30470262 TI - EIF4A3-induced circular RNA MMP9 (circMMP9) acts as a sponge of miR-124 and promotes glioblastoma multiforme cell tumorigenesis. AB - BACKGROUND: Circular RNAs (circRNAs) have been found to play critical roles in the development and progression of various cancers. However, little is known about the effects of the circular RNA network on glioblastoma multiforme (GBM). METHODS: A microarray was used to screen circRNA expression in GBM. Quantitative real-time PCR was used to detect the expression of circMMP9. GBM cells were transfected with a circMMP9 overexpression vector or siRNA, and cell proliferation, migration and invasion, as well as tumorigenesis in nude mice, were assessed to examine the effect of circMMP9 in GBM. Biotin-coupled miRNA capture, fluorescence in situ hybridization and luciferase reporter assays were conducted to confirm the relationship between circMMP9 and miR-124. RESULTS: In this study, we screened differentially expressed circRNAs and identified circMMP9 in GBM. We found that circMMP9 acted as an oncogene, was upregulated in GBM and promoted the proliferation, migration and invasion abilities of GBM cells. Next, we verified that circMMP9 served as a sponge that directly targeted miR-124; circMMP9 accelerated GBM cell proliferation, migration and invasion by targeting miR-124. Furthermore, we found that cyclin-dependent kinase 4 (CDK4) and aurora kinase A (AURKA) were involved in circMMP9/miR-124 axis-induced GBM tumorigenesis. Finally, we found that eukaryotic initiation factor 4A3 (eIF4A3), which binds to the MMP9 mRNA transcript, induced circMMP9 cyclization and increased circMMP9 expression in GBM. CONCLUSIONS: Our findings indicate that eIF4A3-induced circMMP9 is an important underlying mechanism in GBM cell proliferation, invasion and metastasis through modulation of the miR-124 signaling pathway, which could provide pivotal potential therapeutic targets for the treatment of GBM. PMID- 30470265 TI - Foreword. PMID- 30470264 TI - Clinical evaluation of a dedicated next generation sequencing panel for routine glioma diagnostics. AB - Since 2013 next-generation sequencing (NGS) targeting genes mutated in diffuse gliomas is part of routine diagnostics in our institute. In the present report, we evaluate the use of this custom tailored NGS platform on 434 samples. The NGS panel assesses mutations in ATRX, CIC, EGFR, FUBP1, NOTCH1, PTEN; H3F3A, IDH1/2, PIK3CA, and BRAF, amplifications in EGFR or MDM2 and copy number alterations (CNA) of chromosome 1p, 7, 10 and 19q. TERT promoter mutations were assessed separately when indicated. Of the 433 samples of individual tumors with NGS data available, 176 cases were diagnosed as grade 2 or 3 glioma (40.6) and in 201 patients a glioblastoma (46.4%). Of the remaining 56 patients, 22 had inconclusive histology. In 378 cases (87.1%) a diagnosis solely based on glioma targeted NGS could be established and resulted in a different diagnosis in ~ 1/4 of the cases. In 17 out of 22 cases without a conclusive histological diagnosis NGS resulted in a molecular diagnosis.The current study on a large cohort of patients confirms the diagnostic strength of the platform we developed, with a clear separation of glioma subgroups with different outcomes. It demonstrates the diagnostic value and the efficiency of glioma-targeted NGS for routine glioma diagnostics allowing with a single assay a glioma diagnosis in the large majority of cases. It allows in one run the molecular assessments required for the WHO classification of diffuse gliomas, including the recent recommendations to assess copy number alterations of chromosome 7 and 10, and of the TERT promoter region in IDHwt lower grade glioma. PMID- 30470267 TI - Robotic gastrointestinal surgery. PMID- 30470263 TI - Tonic ATP-mediated growth suppression in peripheral nerve glia requires arrestin PP2 and is evaded in NF1. AB - Normal Schwann cells (SCs) are quiescent in adult nerves, when ATP is released from the nerve in an activity dependent manner. We find that suppressing nerve activity in adult nerves causes SC to enter the cell cycle. In vitro, ATP activates the SC G-protein coupled receptor (GPCR) P2Y2. Downstream of P2Y2, beta arrestin-mediated signaling results in PP2-mediated de-phosphorylation of AKT, and PP2 activity is required for SC growth suppression. NF1 deficient SC show reduced growth suppression by ATP, and are resistant to the effects of beta arrestin-mediated signaling, including PP2-mediated de-phosphorylation of AKT. In patients with the disorder Neurofibromatosis type 1, NF1 mutant SCs proliferate and form SC tumors called neurofibromas. Elevating ATP levels in vivo reduced neurofibroma cell proliferation. Thus, the low proliferation characteristic of differentiated adult peripheral nerve may require ongoing, nerve activity dependent, ATP. Additionally, we identify a mechanism through which NF1 SCs may evade growth suppression in nerve tumors. PMID- 30470268 TI - Imaging Considerations in Pregnancy. AB - Pregnancy is a complex physiologic state with hormonal, hemodynamic, hematologic, and immunologic changes at both global and cellular levels affecting brain, heart, pituitary, thyroid, and kidney. There are many situations in which imaging can aid in diagnosis and subsequent treatment of neurologic conditions during pregnancy. PMID- 30470269 TI - Lower Extremity Weakness and Numbness in the Postpartum Period: A Case-Based Review. AB - This article reviews the common lower extremity postpartum neuropathies, including their incidence, risk factors, clinical features, and treatment. In addition, the rarer complications from neuraxial anesthesia are also discussed. PMID- 30470270 TI - Management of Myasthenia Gravis in Pregnancy. AB - Myasthenia gravis is an autoimmune disorder characterized by fluctuating weakness of extraocular and proximal limb muscles. It occurs in 1 in 5000 in the overall population and is 2 times more common in women than men. The onset in women is most common in the third decade, and risk of severe exacerbation occurs most frequently in the year after presentation. The disease does not have an impact on fertility and overlap with pregnancy is expected. This article provides a description of the disease process and its impact on the expecting mother, fetus, and newborn. Management options in pregnancy and lactation are discussed. PMID- 30470271 TI - Connective Tissue Disorders in Pregnancy. AB - Connective tissue disorders are now understood to include autoimmune and genetic diseases affecting organs, blood vessels, and surrounding fascia. Many of these diseases predominantly affect women in childbearing years and are associated with neurologic complications. Pregnancy can affect disease activity (such as flares of systemic lupus erythematosus), and the diseases can affect pregnancy outcome (such as increased risk of preterm labor). We review the neurologic complications and changes with pregnancy for systemic lupus erythematosus, Sjogren syndrome, idiopathic inflammatory myopathy, and Marfan syndrome. PMID- 30470272 TI - Stroke in Pregnancy: An Update. AB - Pregnancy confers a substantially increased risk of stroke in women. The period of highest risk of stroke is the peripartum/postpartum phase, coinciding with the highest risk for hypertensive disorders of pregnancy and peak gestational hypercoagulability. Hemorrhagic stroke is the most common type of obstetric stroke. Hypertensive disorders of pregnancy are important contributors to obstetric stroke and predispose women to premature cardiovascular disease. The rate of stroke associated with hypertensive disorders of pregnancy has increased in the United States. Other conditions associated with obstetric stroke include posterior reversible encephalopathy, reversible cerebral vasoconstriction syndrome, and cerebral venous sinus thrombosis. PMID- 30470273 TI - Management of Demyelinating Disorders in Pregnancy. AB - Multiple sclerosis (MS) and neuromyelitis optica (NMO) are chronic inflammatory demyelinating disorders of the central nervous system that often affect women during childbearing years. Therefore, issues of conception, pregnancy, and delivery are of significant importance to patients and treating physicians. The current review provides updated information regarding the effects of pregnancy on MS and NMO, as well as the available safety data on immunomodulatory MS therapies for pregnant and lactating women. Management issues of women with MS and NMO during conception, gestation, and the postpartum period also are addressed. PMID- 30470274 TI - Headache in Pregnancy and the Puerperium. AB - Migraine is the most common cause of headache during pregnancy. Pregnancy increases risk for many causes of headache, including pathologic vascular processes. Headache associated with neurologic signs or symptoms or that is progressive and refractory to treatment; acute in onset; and severe, postural, or different from typical headaches should be evaluated. Work-up should include cerebral and cerebrovascular imaging and monitoring for hypertension. Acetaminophen is first-line symptomatic treatment during pregnancy, and evidence supports triptans rather than butalbital combination analgesics as second-line treatment. Propranolol is preferred preventive treatment, and amitriptyline and verapamil may be considered. Treatment of migraine during lactation is less restrictive than during pregnancy. PMID- 30470275 TI - Epilepsy in Pregnancy. AB - Epilepsy is a prevalent, chronic, and serious neurologic disease affecting many women of childbearing age. Specific concerns, including contraception, fertility, teratogenic risk of antiepileptic drugs, delivery, and breastfeeding, are addressed in this article. Evidence-based counseling and management strategies are provided to help clinicians and women with epilepsy through the different stages of pregnancy. PMID- 30470276 TI - Pituitary Disorders in Pregnancy. AB - Pregnancy is associated with alterations in pituitary hormonal function and enlargement of the pituitary gland. Pituitary dysfunction diagnosis can be challenging during pregnancy due to known alterations in hormonal status. Pituitary disorders are relatively common; with advancements in medical care, more women with pituitary disorders are becoming pregnant. Management includes optimization of hormonal function and close monitoring for signs of tumor progression during pregnancy. Tumor-directed medical therapy is generally discontinued during pregnancy but can be reinitiated if there is evidence of tumor growth. Most women do not show aggressive tumor growth during pregnancy and can be managed conservatively until delivery. PMID- 30470278 TI - Introduction to Neurology of Pregnancy. PMID- 30470277 TI - Neuro-Ophthalmic Disorders in Pregnancy. AB - The physiologic changes that accompany pregnancy can have important implications for neuro-ophthalmic disease. This article discusses pregnancy-related considerations for meningioma, pituitary disorders, demyelinating disease, myasthenia gravis, thyroid eye disease, idiopathic intracranial hypertension, cerebral venous sinus thrombosis, stroke, migraine, and cranial neuropathies. The article also details the potential neuro-ophthalmic complications of preeclampsia and eclampsia and reviews the use of common diagnostic studies during pregnancy. PMID- 30470279 TI - Tokyo Guidelines for the Diagnosis of Acute Cholecystitis. PMID- 30470280 TI - Evaluating the Diagnostic Accuracy and Management Protocols: In Reply to Strasberg. PMID- 30470281 TI - Reconstruction after Abdominoperineal Resection. PMID- 30470283 TI - A Question of Simpson's Paradox. PMID- 30470282 TI - Perineal Reconstruction Remains Challenging: In Reply to Boccara and colleagues. PMID- 30470284 TI - Database Differences and Limitations: In reply to McLean. PMID- 30470285 TI - December 2018 Featured Articles, Volume 227. PMID- 30470286 TI - Correction. PMID- 30470287 TI - Correction. PMID- 30470288 TI - Adult Stem Cells for Regenerative Therapy. AB - Cell therapy has been identified as an effective method to regenerate damaged tissue. Adult stem cells, also known as somatic stem cells or resident stem cells, are a rare population of undifferentiated cells, located within a differentiated organ, in a specialized structure, called a niche, which maintains the microenvironments that regulate the growth and development of adult stem cells. The adult stem cells are self-renewing, clonogenic, and multipotent in nature, and their main role is to maintain the tissue homeostasis. They can be activated to proliferate and differentiate into the required type of cells, upon the loss of cells or injury to the tissue. Adult stem cells have been identified in many tissues including blood, intestine, skin, muscle, brain, and heart. Extensive preclinical and clinical studies have demonstrated the structural and functional regeneration capabilities of these adult stem cells, such as bone marrow-derived mononuclear cells, hematopoietic stem cells, mesenchymal stromal/stem cells, resident adult stem cells, induced pluripotent stem cells, and umbilical cord stem cells. In this review, we focus on the human therapies, utilizing adult stem cells for their regenerative capabilities in the treatment of cardiac, brain, pancreatic, and eye disorders. PMID- 30470289 TI - Effects of Estrogens on Central Nervous System Neurotransmission: Implications for Sex Differences in Mental Disorders. AB - Nearly one of every five US individuals aged 12 years old or older lives with certain types of mental disorders. Men are more likely to use various types of substances, while women tend to be more susceptible to mood disorders, addiction, and eating disorders, all of which are risks associated with suicidal attempts. Fundamental sex differences exist in multiple aspects of the functions and activities of neurotransmitter-mediated neural circuits in the central nervous system (CNS). Dysregulation of these neural circuits leads to various types of mental disorders. The potential mechanisms of sex differences in the CNS neural circuitry regulating mood, reward, and motivation are only beginning to be understood, although they have been largely attributed to the effects of sex hormones on CNS neurotransmission pathways. Understanding this topic is important for developing prevention and treatment of mental disorders that should be tailored differently for men and women. Studies using animal models have provided important insights into pathogenesis, mechanisms, and new therapeutic approaches of human diseases, but some concerns remain to be addressed. The purpose of this chapter is to integrate human and animal studies involving the effects of the sex hormones, estrogens, on CNS neurotransmission, reward processing, and associated mental disorders. We provide an overview of existing evidence for the physiological, behavioral, cellular, and molecular actions of estrogens in the context of controlling neurotransmission in the CNS circuits regulating mood, reward, and motivation and discuss related pathology that leads to mental disorders. PMID- 30470290 TI - Hair Follicle-Associated Pluripotent(HAP) Stem Cells. AB - The hair follicle has been known, since 1990, to contain stem cells located in the bulge area. In 2003, we reported a new type of stem cell in the hair follicle that expresses the brain stem-cell marker nestin. We have termed these cells as hair-follicle-associated pluripotent (HAP) stem cells. HAP stem cells can differentiate into neuronal and glial cells, beating cardiac-muscle cells, and other cell types in culture. HAP stem cells can be used for nerve and spinal-cord repair such that locomotor activity is recovered. A major function in situ of the HAP stem cells is for growth of the hair follicle sensory nerve. HAP stem cells have critical advantages over embryonic stem cells and induced pluripotent stem (IPS) cells for regenerative medicine in that they are highly accessible, require no genetic manipulation, are nontumorigenic, and do not present ethical issues. PMID- 30470291 TI - Fluorescent Proteins as Sensors for Cellular Behavior in Mice. AB - Imaging of cancer cells in mice expressing fluorescent proteins has allowed the real-time tracing of cancer growth and metastasis and determination of efficacy of candidate antitumor and antimetastatic agents, especially in mouse orthotopic models. The use of fluorescent proteins to differentially label cancer cells in the nucleus and cytoplasm can visualize the nuclear-cytoplasmic dynamics of cancer cells in vivo, including mitosis, apoptosis, cell-cycle position, and differential behavior of nucleus and cytoplasm that occurs during cancer cell deformation, migration, and extravasation. Recent applications of the technology described here include linking fluorescent proteins with cell cycle-specific proteins such that the cells change color from red to green as they transit from G1 to S phases. Any in vivo process can be imaged using fluorescent proteins, allowing molecular biology to advance from in vitro studies to studying molecular processes in the living animal. PMID- 30470292 TI - Arrestins: Introducing Signaling Bias Into Multifunctional Proteins. AB - Arrestins were discovered as proteins that bind active phosphorylated G protein coupled receptors (GPCRs) and block their interactions with G proteins, i.e., for their role in homologous desensitization of GPCRs. Mammals express only four arrestin subtypes, two of which are largely restricted to the retina. Two nonvisual arrestins are ubiquitous and interact with hundreds of different GPCRs and dozens of other binding partners. Changes of just a few residues on the receptor-binding surface were shown to dramatically affect GPCR preference of inherently promiscuous nonvisual arrestins. Mutations on the cytosol-facing side of arrestins modulate their interactions with individual downstream signaling molecules. Thus, it appears feasible to construct arrestin mutants specifically linking particular GPCRs with signaling pathways of choice or mutants that sever the links between selected GPCRs and unwanted pathways. Signaling-biased "designer arrestins" have the potential to become valuable molecular tools for research and therapy. PMID- 30470295 TI - Evaluation of Surrogate End Points for Progression to ESKD: Necessary and Challenging. PMID- 30470294 TI - Preface. PMID- 30470293 TI - Analysis of Biased Agonism. AB - Agonists and most natural ligands bind to receptors in their inactive state and quickly induce an active receptor conformation that initiates cell signaling. The active receptor state initiates signaling because of its structural complementariness with coupling proteins that activate signaling pathways, such as G proteins and G protein-coupled receptor kinases. Agonist bias refers to the propensity of an agonist to direct receptor signaling through one pathway relative to another. Thus, if the agonist exhibits much higher affinity for active state 1 compared to active state 2, it will cause a robust activation of receptor coupling protein 1 but not 2, and ultimately, a preferential stimulation of signaling pathway 1. Biased agonists are potentially more selective therapeutic agents because there are numerous cases where the therapeutic and adverse effects of an agonist are mediated by distinct pathways involving G proteins and beta-arrestin. Given the mechanism for agonist bias, the most straightforward approach for quantifying bias involves the estimation of agonist affinity for the inactive receptor state and the active receptor states involved in signaling through different pathways. The approach provides quantitative estimates of the sensitivities of different signaling pathways, enabling one to determine to what extent the observed selectivity is caused by agonist or system bias. In addition, the approach is a powerful adjunct to in silico docking studies and can be applied to in vivo assays, structure-activity relationships, and the analysis of published agonist concentration-response curves. PMID- 30470296 TI - Long-term Adverse Outcomes of Urolithiasis. PMID- 30470297 TI - Urate-Lowering Therapy for Preventing Kidney Disease Progression: Are We There Yet? PMID- 30470298 TI - A Simple Case of Hyponatremia? PMID- 30470299 TI - Improving Oncology Clinical Trial Participation and Experience. AB - Cancer patients are underrepresented in clinical trial populations because of protocol-, physician-, and patient-related barriers. We engaged focus groups of patients who had participated in breast and ovarian cancer trials to identify concerns regarding their experiences. The lessons learnt are applicable to improving patient experience during future trials. PMID- 30470300 TI - Exons of Leukemia Suppressor Genes: Creative Assembly Required. AB - Alternative splicing (AS) has many important roles in the pathogenesis of leukemia. Recent papers suggest that one of its key aspects is exclusion of 3' terminal exons in favor of premature termination using intronic polyadenylation signals. This process generates leukemia suppressor isoforms with truncated C termini and acting in loss-of-function or dominant-negative manners. PMID- 30470301 TI - Regulators of Asymmetric Cell Division in Breast Cancer. AB - The aggressive triple-negative breast cancer (TNBC) pathological group poses significant challenges for both diagnosis and treatment because high levels of cellular heterogeneity are one of its hallmarks. In a recent issue of Cell Reports, Granit et al. shed light into how regulation of asymmetric cell division contributes to heterogeneity in TNBC, and identify key control factors. With the help of technological advances, deeper understanding of these processes will lead to new cancer therapeutics. PMID- 30470302 TI - The Multiple Layers of the Tumor Environment. AB - The notion of tumor microenvironment (TME) has been brought to the forefront of recent scientific literature on cancer. However, there is no consensus on how to define and spatially delineate the TME. We propose that the time is ripe to go beyond an all-encompassing list of the components of the TME, and to construct a multilayered view of cancer. We distinguish six layers of environmental interactions with the tumor and show that they are associated with distinct mechanisms, and ultimately with distinct therapeutic approaches. PMID- 30470304 TI - Maximizing the Utility of Cancer Transcriptomic Data. AB - Transcriptomic profiling has been applied to large numbers of cancer samples, by large-scale consortia, including The Cancer Genome Atlas, International Cancer Genome Consortium, and Cancer Cell Line Encyclopedia. Advances in mining cancer transcriptomic data enable us to understand the endless complexity of the cancer transcriptome and thereby to discover new biomarkers and therapeutic targets. In this paper, we review computational resources for deep mining of transcriptomic data to identify, quantify, and determine the functional effects and clinical utility of transcriptomic events, including noncoding RNAs, post-transcriptional regulation, exogenous RNAs, and transcribed genetic variants. These approaches can be applied to other complex diseases, thereby greatly leveraging the impact of this work. PMID- 30470303 TI - The MYC Enhancer-ome: Long-Range Transcriptional Regulation of MYC in Cancer. AB - MYC is one of the most important oncogenes in cancer. Indeed, MYC is upregulated in 50-60% of all tumors. MYC overexpression can be achieved through a variety of mechanisms, including gene duplications, chromosomal translocations, or somatic mutations leading to increased MYC stability. However, recent studies have identified numerous tissue-specific noncoding enhancers of MYC that play major roles in cancer, highlighting long-range transcriptional regulation of MYC as a critical novel mechanism leading to MYC hyperactivation and as a potential target for new therapeutic strategies in the near future. Here we summarize the regions and mechanisms involved in the long-range transcriptional regulation of MYC, underscoring the relevance of MYC enhancers both in normal physiological development and in MYC-driven cancer initiation and progression. PMID- 30470305 TI - Microvascular Mural Cells in Cancer. AB - Microvascular mural cells (MMCs) are important regulators of tumor vessel properties, such as endothelial cell differentiation and vessel permeability, and are recognized as modulators of tumor angiogenesis and growth. Emerging experimental studies suggest impact of MMCs on additional aspects of tumor biology, exerted by functionally distinct subsets. These have been shown to control metastasis both in primary tumors and in the premetastatic niche. Other studies link marker-defined MMCs to tumor immune surveillance and drug sensitivity. In parallel, recent efforts to profile MMCs in clinical samples are confirming the existence of clinically relevant marker-defined MMC subsets which show marker- and tumor-type- specific associations with prognosis and response to treatment. Collectively, findings encourage to continued analyses of MMC subsets as candidate biomarkers and drug targets. PMID- 30470306 TI - Cancer Cachexia: More Than Skeletal Muscle Wasting. AB - Cancer cachexia is a multifactorial condition characterized by body weight loss that negatively affects quality of life and survival of patients with cancer. Despite the clinical relevance, there is currently no defined standard of care to effectively counteract cancer-associated progressive tissue wasting. Skeletal muscle atrophy represents the main manifestation of cancer cachexia. However, cancer cachexia is increasingly seen as a systemic phenomenon affecting and/or influenced by various organs. Here, we describe recent developments elucidating the roles of different tissues as well as tissue crosstalk in this wasting syndrome, including potential links to other cancer-associated morbidities. A more comprehensive understanding of cancer cachexia etiology and heterogeneity may enable the development of intervention strategies to prevent or reverse this devastating condition. PMID- 30470307 TI - Elevation of tumor necrosis factor alpha levels is associated with restless legs symptoms in clinically depressed patients. AB - BACKGROUND: Restless legs syndrome is a sensorimotor disorder associated with several mental illnesses particularly depression. METHODS: A cross-sectional study of primary care patients. The prevalence of restless legs symptoms was studied in 706 patients with depressive symptoms and 426 controls without a psychiatric diagnosis by using a structured questionnaire. The depressive symptoms were evaluated with the BDI and the psychiatric diagnosis was confirmed by means of a diagnostic interview (M.I.N.I.). The subjects with elevated depressive symptoms were divided into two groups subjects with depressive symptoms with and without clinical depression. RESULTS: The prevalence of restless legs symptoms was 24.8% in the controls, 50.0% in the patients with clinical depression and 42.4% in the patients with depressive symptoms. CRP value was significantly higher (p = .003) in the clinically depressed patients than in the other groups. There was a higher concentration of TNF-alpha in the subjects with restless legs symptoms (7.4 ng/l +/- 3.2) compared with the subjects without symptoms (6.7 ng/l +/- 2.3)(p < .001). There was a significant difference in the TNF-alpha levels between the subjects with and without restless legs symptoms in the depression group (p < .001) and among the patients with depressive symptoms but no a depression diagnosis (p = .022). In these groups, restless legs symptoms were associated with elevated levels of TNF-alpha. CONCLUSIONS: TNF-alpha level was associated with restless legs symptoms only among subjects with depressive symptoms whether they had clinical depression or not. We suggest that TNF-alpha could be an underlying factor between restless legs symptoms and comorbidities. PMID- 30470308 TI - Elevated allostatic load in individuals presenting at psychiatric emergency services. AB - OBJECTIVE: Individuals requiring psychiatric emergency services are often highly distressed and intoxicated. To provide an objective and comprehensive measure of their stress-related physiological dysregulations, we indexed allostatic load with 14 biomarkers collected within 24 h of patients' admission to the largest psychiatric hospital in the Canadian province of Quebec. METHODS: This study (N = 278) combines data for emergency patients (n = 76; 65.8% women; M age = 44.97, SE = 1.6) and hospital workers who served as sex- and age-matched controls (n = 202; 70.8% women; M age = 40.10, SE = 0.83). Sex-specific allostatic load indices summarized neuroendocrine (cortisol), immune (tumor necrosis factor-alpha, interleukin-6, c-reactive protein), metabolic (insulin, glycosylated hemoglobin, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, body mass index), and cardiovascular (heart rate, systolic and diastolic blood pressure) functioning. Well-validated questionnaires assessed substance (ab)use. RESULTS: Individuals presenting at psychiatric emergency showed elevated allostatic load, drug abuse, and tobacco use compared to controls. Elevated allostatic load in emergency patients was driven by elevated cortisol, interleukin-6, systolic blood pressure, and heart rate; however, allostatic load was not explained by substance (ab)use or demographic variables. Sub-group analyses revealed that emergency patients primarily diagnosed with bipolar, depressive, or anxiety disorders showed higher allostatic load than those diagnosed with personality disorder(s). CONCLUSIONS: This study demonstrates that individuals presenting at psychiatric emergency services show physiological dysregulations associated with chronic stress. Future research should explore the clinical utility of allostatic load in predicting comorbidities among psychiatric patients. PMID- 30470309 TI - The Intentional Non-Adherence Scale (INAS): Initial development and validation. AB - OBJECTIVE: Adherence continues to be a major challenge in healthcare but there is still limited understanding of all the factors which can influence adherence behaviour. The present study was designed to identify a range of factors associated with intentional non-adherence and to see if they could be formed into a psychometrically sound scale. METHODS: Patients in three different clinical groups (Hypertension (N = 175); Oncology (N = 115); Gout (N = 196)) were given the new scale together with an adherence self-report and/or biomarker measure. Other, more established measures of factors known to be associated with adherence (BMQ, PAM, BIPQ), were also completed by patients for comparative and validation purposes. Exploratory Factor Analysis (EFA) was conducted to examine the factor structure of the new scale, and other statistical analyses were used for testing the psychometric properties of the new scale. RESULTS: EFA revealed two factors, which were labelled "Resisting illness" and "Testing treatment". Both scales were found to have good psychometric properties and explained unique variance in adherence in all three clinical groups. CONCLUSION: This new scale shows promise in describing and explaining some relatively novel factors underlying treatment non-adherence. Further work in different patient groups and clinical contexts is needed to confirm the factor structure and predictive value of these scales. PMID- 30470310 TI - Autonomic reactivity in blood-injection-injury and snake phobia. AB - OBJECTIVE: This research aimed to study the salivary flow and other autonomic reactions -heart rate (HR) and skin conductance response (SCR)- in blood injection-injury (BII) phobia and snake phobia participants, under the assumption that exposure to blood-related pictures in BII phobia will provoke an increase in parasympathetic activity that, in turn, will lead to a greater saliva production than other affective contents. METHODS: We selected 18 BII phobia and 14 snake phobia participants along with 22 non-phobia individuals. All participants were exposed to 3 blocks of pictures (12 pictures per block) depicting either mutilations, snakes or neutral, household objects. Saliva samples were taken in the 2-min interval before and after each block. RESULTS: In comparison to other contents, blood-related pictures provoked an increase in salivary flow in BII phobia participants, as well as an increase in the number of SCRs. In the snake phobia group, snake pictures provoked HR acceleration, but the SCRs they elicited did not differ from the SCRs provoked by the blood-related pictures. CONCLUSION: BII phobia individuals react to their phobic object with a series of physiological changes resulting from a sympathetic-parasympathetic co-activation. This is in contrast with other specific phobias (e.g., small animal phobias) that usually show a sympathetically mediated, defensive reactivity when exposed to their disorder-relevant stimuli. These data support the use of therapeutic interventions in BII phobia that may differ in some respect from those used in other specific phobias. PMID- 30470311 TI - Blended group-based psychoeducation for somatoform disorders. PMID- 30470312 TI - Predicting physical and mental health symptoms: Additive and interactive effects of difficulty identifying feelings, neuroticism and extraversion. AB - OBJECTIVE: Alexithymia, neuroticism, and extraversion have been described as relevant predictors of mental and physical health conditions, but their putative interactive effects remain poorly understood and their prospective effects are not well studied. The present study has investigated the differential contributions of distinct personality traits in predicting mental and somatic health symptoms in cross-sectional and longitudinal analyses. METHODS: Additive and interactive effects of neuroticism and extraversion (NEO-FFI), the TAS-20 total score (20-Item Toronto Alexithymia Scale) and its factors (Difficulty Identifying Feelings (DIF), Difficulty Describing Feelings (DDF) and External Oriented Thinking (EOT)) have been investigated on depressive symptoms, the number of chronic diseases, somatic and mental subjective health complaints. Analyses have been based on data from the population-based "Study of Health in Pomerania" (SHIP) in cross-sectional (N = 1704) and longitudinal (N = 1244) analyses. RESULTS: In cross-sectional and longitudinal analyses, additive associations of the TAS-20 total score and neuroticism on somatic and mental health complaints have been observed. The effects of the TAS-20 total score have been mainly carried by DIF. Further, in interaction effetcs extraversion has attenuated the negative impact of neuroticism, whereas DIF has augmented it. CONCLUSION: The present study is the first demonstrating longitudinal effects of alexithymia, particularly DIF, neuroticism, and extraversion in predicting mental and somatic health symptoms. Associations between DIF, neuroticism, and extraversion have been additive and interactive. Hence, subjects high in neuroticism and DIF but low in extraversion have reported most health symptoms and thus might be in need for prevention strategies. Treatments chould be adapted to the associated combination of the personality characteristics. PMID- 30470313 TI - Prospective study of provided smoking cessation care in an inpatient psychiatric setting. AB - OBJECTIVE: People with mental health difficulties (MHD) are more likely to smoke and to have smoking-related diseases, yet little research has investigated the provision of smoking cessation care in psychiatric inpatient settings. This study aimed to evaluate current levels of cessation care provided, and 3-month quit rates, in one such setting in Ireland. METHODS: From January to October 2016, inpatients across all 8 adult wards of St Patrick's University Hospital were recruited to participate in a baseline face-to-face survey (N = 246), assessing demographic information, smoking history and quit attempts, motivation to quit, nicotine dependence, attitudes towards cessation advice and actual care received. For baseline current smokers (n = 84) who consented, casenotes were also audited for documentation of smoking status and cessation care (n = 77/84) while quit rates were assessed at three months (n = 72/84), including a carbon monoxide test for those who reported quitting. RESULTS: Current smoking prevalence was 34% (n = 84/246). At baseline 75% of smokers wanted to quit and 48% reported they would like cessation advice while in hospital. Few reported receiving cessation advice from any healthcare professional in the past year (13%), while just 6% had smoking cessation care clearly documented in their casenotes. The 3-month quit rate was 17%, with a 100% pass rate for those completing an objective CO validation test. CONCLUSION: Despite a high current smoking prevalence among psychiatric inpatients, and similar motivation and quit rates to other populations, current cessation care rates are low. Smoking cessation care needs to be prioritised in psychiatric settings. PMID- 30470314 TI - The impact of non-motor symptoms on the health-related quality of life in patients with functional movement disorders. AB - OBJECTIVE: Pain, fatigue, cognitive complaints and psychiatric comorbidities are common in patients with functional movement disorder and may significantly affect their quality of life. The aim of the study was to assess the impact of motor and non-motor symptoms on health-related quality of life in patients with functional movement disorder. METHODS: Sixty-one patients with clinically established functional movement disorder and 61 matched healthy controls completed standardized questionnaires for depression, anxiety, cognitive complaints, fatigue, pain, sleepiness, apathy and health-related quality of life. Motor disorder severity was assessed using The Simplified Functional Movement Disorders Rating Scale. Personality traits were assessed using the 44-Item Big Five Inventory. RESULTS: Compared to controls, patients reported significantly lower health-related quality of life and higher levels of all assessed non-motor symptoms except for apathy. No difference was found in personality traits. In both groups, health-related quality of life scores negatively correlated with depression, anxiety, pain, cognitive complaints, apathy, and neuroticism. No correlation was found between health-related quality of life and motor symptom severity in patients with functional movement disorder. Multiple regression analysis of the predictors of health-related quality of life showed significant impact of trait anxiety and cognitive complaints scores. CONCLUSIONS: Multiple non-motor symptoms but not motor symptom severity correlated with impaired health related quality of life in patients with functional movement disorder. Impaired health-related quality of life was predicted by anxiety and cognitive complaints. Our results highlight the importance of assessing and treating both motor and non motor symptoms in patients with functional movement disorder. PMID- 30470315 TI - Clusters of premenstrual symptoms in women with PMDD: Appearance, stability and association with impairment. AB - Although premenstrual dysphoric disorder (PMDD) is assumed to be a homogenous diagnostic entity, it is hallmarked by highly diverse clinical symptoms. In this study, we investigate symptom clusters in women prospectively diagnosed with severe premenstrual syndrome (PMS) or PMDD using factor analysis; analyze the stability of the structures of different symptom patterns and their association with impairment at work, in recreation, and in relationships. A total of 174 prospective symptom diaries were analyzed with principal axis factoring revealing six clusters named affective dysphoria, somatic dysphoria, irritability, breast/body sensitivity, pain, and eating behavior. Cronbach's alpha was good for all clusters (0.83 to 0.91) with the exception of the cluster pain (0.69). Clusters of symptoms appeared to be stable between two consecutive menstrual cycles (except of pain and eating behavior) and between two cycles with a waiting period of eight weeks in between. Multiple regression analyses showed different associations of the clusters with impairment. Somatic dysphoria was the cluster most strongly associated with impairment. The results indicate that in severe PMS/PMDD, different symptom patterns should be considered. As the risk of impairment differs between symptom clusters, individual treatment options should be considered and further investigated in research and treatment. PMID- 30470316 TI - Type D personality affects health-related quality of life in patients with lone atrial fibrillation by increasing symptoms related to sympathetic activation. AB - BACKGROUND: Health-related quality of life (HRQoL) is impaired in patients with atrial fibrillation (AF), and even more so in patients with a Distressed personality type (Type D). It is unknown whether this extends to patients with 'lone AF'. Since chronic stress is associated with increased arousal, it might affect recurrences and thus HRQoL. The current study examined the influence of Type D on the trajectory of disease-specific and generic HRQoL, compared it with HRQoL in the general population, and assessed the mediating role of arousal symptoms (e.g., tachycardia, sweating). METHODS: 159 patients with 'lone AF' (age: 61.6+/-0.8, 63% men, 3.3+/-5.0 years since diagnosis) filled out a survey on personality (Type D: DS14), quality of life (SF-36, AFQoL) and symptoms (ATSSS) of AF at inclusion, and 6, 12, and 18 months later. Linear mixed modeling was used. RESULTS: Generic HRQoL was reduced as compared to the general population, and all HRQoL scales remained stable across time. Type D personality was a significant predictor of worse disease-specific (estimate= -17.1 ; 95%CI: 23.9 - -10.2; p<.001), and generic HRQoL (estimatePCS=-5.5; 95%CI:-9.3 - -1.8; p=.004; estimateMCS=-14.8; 95%CI:-18.9- -10.6; p<.001), with arousal symptoms accounting for substantial change in the Type D estimate, suggesting partially shared variance between Type D and arousal symptoms in predicting HRQoL. CONCLUSION: HRQoL was stable across time, and systematically poorer in distressed 'lone AF' patients. Arousal symptoms partly explained the relation between Type D and HRQoL. Chronic distress may affect AF patients' HRQoL through sympathetic activation and accompanying complaints. PMID- 30470317 TI - The emotional burden of chronic skin disease dominates physical factors among women, adversely affecting quality of life and sexual function. AB - BACKGROUND: Both physical and emotional effects are linked with the natural history of chronic skin diseases (CSD). Skin lesions can be confined to covered areas or involve emotionally charged regions (genitalia/exposed areas). OBJECTIVE: To investigate the contribution of the physical effects of CSD and their emotional burden in adversely affecting the quality of life (QOL) and sexual function. METHODS: Two groups were included: A group of women suffering from CSD and a control group. All participants answered the 19-item Female Sexual Function Index (FSFI) questionnaire. Women suffering from CSD answered the 10 item Dermatology Life Quality Index (DLQI) questionnaire; this group was divided into various subgroups according to the type of disease and regional involvement. RESULTS: Neither the DLQI score (P = .06) nor the FSFI scores were significantly affected by the type of disease. The DLQI score was significantly higher in the subgroups with involvement of genitalia or exposed areas (P: < 0.001and 0.01, respectively). Moreover, genital involvement was associated with pervasive and significantly lower FSFI scores, and the arousal, satisfaction, and total scores were significantly lower among women with the involvement of exposed areas. The DLQI score was significantly negatively correlated with the FSFI scores. CONCLUSION: The emotional burden of CSD should not be overlooked as it dominates the physical effects of disease by adversely affecting QOL and sexual function among women. It is necessary to provide this information to dermatologists and patients, especially in light of effective cognitive-behavior therapy that can be undertaken to ameliorate the emotional stresses. PMID- 30470318 TI - Death anxiety and its association with hypochondriasis and medically unexplained symptoms: A systematic review. AB - OBJECTIVE: To systematically review of the available literature to (1) examine the association between death anxiety and hypochondriasis and (2) examine the association between death anxiety and medically unexplained symptoms (MUS). METHODS: A systematic literature search was conducted in Embase, PsycINFO, Pubmed and Ovid databases and reference lists of selected articles. Articles were included when the research population concerned people with hypochondriasis and/or MUS in who death anxiety was assessed by a validated research method. Two independent reviewers verified that the studies met the inclusion criteria, assessed the quality of the studies and extracted relevant characteristics and data. The data were descriptively analysed. RESULTS: Of the 1087 references identified in the search, six studies on the association between death anxiety and hypochondriasis and three studies on the association between death anxiety and MUS met inclusion criteria. All studies found a positive association of death anxiety with hypochondriasis and/or MUS. The design of all studies was cross sectional and the overall quality of the studies was low. The influence of age or sex on these associations was not analysed in any of the studies. Given the diversity in setting, population, study design, and methods used, a meta-analysis was not possible. CONCLUSION: All studies found a positive association of death anxiety with hypochondriasis and/or MUS. Acknowledging that death anxiety may play a prominent role in hypochondriasis/MUS populations, future research should address (potentially modifiable) determinants of death anxiety in these populations. PMID- 30470319 TI - Identifying and predicting distinct distress trajectories following a breast cancer diagnosis - from treatment into early survival. AB - OBJECTIVE: Most longitudinal studies on distress in breast cancer (BC) patients reported a continuous decrease after diagnosis, however masking individual variations in patterns of adjustment. We sought to identify distinct trajectories of distress during primary treatment into survivorship and to identify variables that are determinants of which patient follows which type of adjustment trajectory. METHODS: Psychological distress was measured at four significant time points (after surgery/biopsy, at treatment completion, two and six months thereafter) among 181 newly diagnosed BC patients. A latent growth mixture modeling approach was used to identify distinct distress trajectories. RESULTS: Four distress trajectories were identified: a 'resilient' pattern (73.1%), a 'high-remitting' (7.7%) trajectory, a 'delayed' increase in distress (7.9%), and a constantly high 'chronic' distress (11.3%) pattern. High perceived burden from physical symptoms at treatment completion encompassed a higher chance for the 'high-remitting' and 'chronic' distress trajectory. High self-efficacy at baseline increased chances for the 'high-remitting' pattern. Neither type of treatment, demographic or medical characteristics, nor baseline distress reliably predicted distress trajectories. CONCLUSION: The majority of BC patients adjust well through a demanding treatment period. High patient-perceived burden from physical symptoms, and high coping self-efficacy is suggesting a transient, self limiting distress trajectory, while patients experiencing constant 'chronic' distress, and those developing distress following treatment completion only cannot be identified by a single, initial assessment. Only systematic tracking with repeated measurement extending into survivorship can eliminate this problem. Interventions should aim at reducing the impact of symptom burden on women's every-day life and on strengthening coping-self efficacy. PMID- 30470320 TI - Cumulative effect of depressed mood and obesity on type II diabetes incidence: Findings from the MONICA/KORA cohort study. AB - BACKGROUND: Obesity and depression both individually contribute to the risk of Type II Diabetes (T2DM). The extent to which obesity can be set-off by depression is unknown. METHODS: In a sample of 9340 participants followed for 15.4 years (79,372 person-years) from the prospective MONICA/KORA population-based cohort conducted in Southern Germany, we investigated the impact of obesity, defined as Body Mass Index (BMI) >= 30, and depression on the incidence of T2DM using Cox Proportional Hazards Regression. RESULTS: The relative risk of T2DM was over 6 fold higher among obese participants in comparison to normal weight participants (HR 6.05; 95% CI 4.82 to 7.59; p < .0001). Nonetheless, among participants with obesity, comorbidity of depression was associated with an additional 2 fold risk T2DM (HR 8.05, 95% CI 5.90-10.98; p < .0001). This finding corresponded to an increase in the 15.4-year absolute risk of T2DM from 15.9 cases per 1000 person years (py) in participants with obesity but not depression, to 21.4 cases per 1000 py for participants with obesity and depression. Further analysis of joint effects and Relative Excess Risk due to Interaction disclosed that depressed mood is associated with significantly higher risk of T2DM in participants with obesity, and to a lesser extent in overweight participants, however an association was not found in normal weight participants. CONCLUSIONS: The present investigation discloses that despite the overreaching importance of obesity as a risk factor for T2DM, there is room for depressed mood to add measurable risk prediction. PMID- 30470321 TI - Public stigma towards individuals with somatic symptom disorders - Survey results from Germany. AB - OBJECTIVE: The study aims to investigate (1) the magnitude of public stigma towards individuals with somatic symptom disorder (SSD), (2) differences in public stigma between SSD and depression, and (3) predictors of social distance towards individuals with SSD. METHODS: Analyses are based on a national telephone survey in Germany (N = 1004). Two vignettes with symptoms of SSD were used. Vignettes differed regarding main type of symptom (pain vs. fatigue) and existence of an earlier somatic disease (yes vs. no). Stigma was measured by stereotypes, negative emotional reactions, and desire for social distance. RESULTS: There were no significant differences in public stigma regarding type of symptom and existence of an earlier somatic disease. Two of three components of public stigma under study (stereotypes and desire for social distance) showed higher values in case of depression compared to SSD (both vignettes pooled). Age and negative emotional reactions were positively associated with desire for social distance in case of both SSD vignettes, whereas associations with stereotypes and experience (own affliction and contact to persons afflicted) were inconsistent. Education was not associated with social distance towards people with SSD. CONCLUSIONS: Results indicated public stigma towards people affected by SSD in Germany. Compared with depression, SSD stigma was lower in most components. Magnitude of SSD stigma was similar, irrespective of main type of symptom (pain vs. fatigue) and existence of an earlier somatic disease (yes vs. no). Reducing SSD stigma could help to improve illness behaviour and prevent chronification. PMID- 30470322 TI - Defense mechanisms in cancer patients: a systematic review. AB - The importance of defense mechanisms in cancer progression and adaptation have been largely observed. However, few studies referred to the generally accepted hierarchical organization of defenses and used validated measurements for defensive assessment. In this systematic review, we investigated the whole hierarchy of defense mechanisms and how they associate with various psychological aspects in cancer patients. A literature search was conducted using electronic databases. Among 1570 records published from 1990 to date, only 15 articles met inclusion criteria. Findings related to cancer patients' defensive functioning and its relations with other physical and psychological variables were extracted. A general consistency emerges on the role of defense mechanisms in cancer progression and recovery. Following the hierarchical organization of defenses, higher physical and emotional functioning emerged as being associated with High adaptive defenses, while Mental Inhibition defenses, in particular repression, promote psychosomatic symptoms, passive decisional preferences and worse physical and emotional health. Disavowal defenses foster lower anxiety and higher emotional functioning by denying anxiety about death. Image distortion defenses, including both Minor and Major image-distorting defenses, were more frequent in cancer patients than in control groups and finally, Action defenses predicted sleep disturbance and lower survival probability. The early detection of maladaptive defensive functioning may foster appropriate psychotherapeutic intervention and prevent worsening of the illness. Further investigations are required to replicate these findings and highlight associations between defense mechanisms and various aspects of mental functioning in cancer patients. PMID- 30470323 TI - No moderating impact of a medically unexplained etiology on the relationship between psychological profile and chronic pain. AB - OBJECTIVES: The objective of the present study was to test the moderating impact of an unknown pain etiology on the relationship between psychological factors and chronic pain intensity and disability. METHODS: N = 471 chronic pain sufferers presented to an online Cognitive Behavioral Therapy randomized control trial, known as the Pain Course. Participants' etiology was classified as medically unexplained or medically explained via interview and self-reported data. Standardized psychological measures at baseline were used in a non-hierarchical cluster analysis, which allocated chronic pain participants into mutually exclusive groups. RESULTS: Four distinct clusters were identified: Psychologically healthy, mild psychological distress, high psychological distress, and average. The profile with high psychological distress experienced the greatest pain intensity (mean: 6.44 (SD = 1.66)) and disability (mean: 17.53 (SD: 3.65)). This relationship was not moderated by preceding pain etiology being medically explained or unexplained (chi2 (3) = 0.45, p = 0.93 and chi2 (3) = 7.07, p = 0.07 respectively). CONCLUSION: These findings indicate that an unknown pain etiology has little role in altering the relationship between psychological factors and pain disability in individuals experiencing chronic pain. This suggests that the psychological association with pain disability and intensity experienced by people with medically unexplained symptoms is similar to people with medically explained symptoms. PMID- 30470324 TI - Asthma and other allergic diseases in relation to suicidal behavior among South Korean adolescents. AB - OBJECTIVES: Adolescent asthma can be the cause of social and psychological problems. We investigated the association between asthma with other allergic diseases and suicidal risk behavior among South Korean adolescents using nationally representative data. METHODS: Web-based self-report data from the Korean Youth Risk Behavior Web-Based Survey were used in this study (N = 237,022). Complex sample logistic regression was used to define the relationship between suicidal behavior and asthma (n = 7177), with other allergic diseases [asthma with allergic rhinitis (AR) or asthma with atopic dermatitis (AD) (n = 9720), asthma with AD and AR (n = 4971)]. RESULTS: Participants with asthma and other allergies showed a higher prevalence of substance use, greater sexual experience, greater perceived stress, poorer perceived health, more severe depression, more suicidal ideation, and more suicide attempts than those without allergy. Depression, suicidal ideation, and suicide attempts increased trend in the following order: no asthma, asthma only, asthma with one other allergy (asthma with AD or asthma with AR), and asthma with AD and AR. After adjusting for multiple confounders, the odds ratio for suicidal ideation with asthma and AD and AR was 1.13 [95% confidence interval (CI), 1.06-1.19] and that for suicide attempts was 1.31 (95% CI, 1.20-1.43). CONCLUSIONS: Adolescent asthma and other allergies were associated with suicidal behavior. PMID- 30470325 TI - Latest Advances in Wide Awake Hand Surgery. AB - Injection of tumescent local anesthesia should no longer be painful. WALANT anesthesia, strong sutures, a slightly bulky repair, intraoperative testing of active movement, and judicious venting of the A2 and A4 pulleys improve results in flexor tendon repair. WALANT K wire finger fracture reduction permits intraoperative testing of K wire stability with active movement to facilitate early protected movement at 3 to 5 days after surgery. WALANT can decrease costs and garbage production while increasing accessibility and affordability. Several surgeons have found no infection difference when the K wires are inserted with full operating room sterility versus field sterility. PMID- 30470326 TI - The Current and Possible Future Role of Wide-Awake Local Anesthesia No Tourniquet Hand Surgery in Military Health Care Delivery. AB - Wide-awake hand surgery is versatile and can be performed in a variety of settings for various pathologies. The benefits associated with wide-awake local anesthesia no tourniquet hand surgery can be extremely beneficial in the military health care system. Military medicine focuses on supporting soldiers in areas of combat, providing humanitarian care to local nationals, and to delivering health care to active duty soldiers and veterans in the domestic setting. The ability to perform hand surgery without general or sedating anesthesia conserves limited anesthetic resources and allows patients to maintain situational awareness perioperatively. PMID- 30470327 TI - The Canadian Model for Instituting Wide-Awake Hand Surgery in Our Hospitals. AB - Clinic-based hand surgery performed under local anesthetic has been steadily increasingly performed in Canada for 50 years. The drive for its development stems from the Canadian health care system's finite funding structure and resources. Benefits have extended far beyond cost and garbage reduction. It has resulted in greatly improving patient care by increasing comfort and safety with the elimination of sedation, the tourniquet, night surgery, and by improving access to care. This article details the rationale and development of clinic based hand surgery from a Canadian perspective and provides tips and strategies for other centers looking to implement a similar clinic. PMID- 30470328 TI - Impact of Wide-Awake Local Anesthesia No Tourniquet on Departmental Settings, Cost, Patient and Surgeon Satisfaction, and Beyond. AB - This article reviews the impact of wide-awake hand surgery without tourniquet on departmental settings and savings on patients' medical cost, and efficiency of fellowship training and practice of junior hand surgeons in 3 units in 3 countries. The medical cost of the commonly performed procedures is decreased remarkably with this approach in the 3 units. Hand surgery fellowship training and practice of junior surgeons are benefited from this approach in 2 units in Turkey and Switzerland. Overall, this approach improves the surgeons' and patients' quality of life and its application is expanding to almost all procedures of hand surgery. PMID- 30470329 TI - Wide Awake Secondary Tendon Reconstruction. AB - The wide awake anesthesia technique is a useful tool in secondary tendon reconstruction. With active participation of the patient, the tendon repair can be adjusted appropriately to prevent repairs that are too tight or too loose. Areas of tendon scarring or triggering can be identified and released. Other advantages of active participation include reduction of gapping, ensuring adequate strength of repair, and avoiding tendon imbalances. Last, it allows intraoperative patient education and may therefore increase patient satisfaction. This article discusses how the technique can be applied to tenolysis, 2-stage tendon reconstruction, and tendon transfer. PMID- 30470330 TI - Practice in Wide-Awake Hand Surgery: Differences Between United Kingdom and Cyprus. AB - The implementation of the wide-awake local anesthetic no tourniquet (WALANT) approach to surgical procedures in Cyprus has led to significant cost savings. In the United Kingdom, the implementation of WALANT has led to shorter waiting times for hand surgical procedures, cost savings for the National Health Service, and high patient satisfaction rates. In both countries, patient education is a prerequisite for WALANT surgery. It increases the satisfaction rate among patients and enhances the patient-surgeon relationship. Patients need to know they can participate actively in a procedure, because a patient moving the hand during a procedure can improve the outcome. PMID- 30470331 TI - Wide Awake Hand Surgery Under Local Anesthesia No Tourniquet in South America. AB - The authors report the introduction and development of wide awake hand surgery under local anesthesia no tourniquet (WALANT) in South America, specifically in Brazil, where thousands of cases have already been performed with this technique. This was largely stimulated by Dr Lalonde's first visit to Brazil in 2012. The authors began with smaller procedures such as trigger fingers and carpal tunnels, which were easily implemented. There has been an increase in the number of more complex procedures, such as flexor tenolysis or tendon transfers, in which patient cooperation can help improve results. PMID- 30470332 TI - Lessons Learned in the Authors' First Years of Wide-Awake Hand Surgery at the W Hospital in Korea. AB - Wide-awake local anesthesia no tourniquet (WALANT) is a promising development for surgeons and patients through improved operation outcomes in hand and wrist surgery. The authors have mostly used WALANT for flexor and extensor tendon repair, tenolysis, and tendon transfer. Its application at W Hospital in korea has bolstered surgeon confidence in tendon repair integrity, gliding ability, and transfer tension via direct observation and patient feedback. The authors do not use WALANT in complicated tenolysis or in secondary surgeries in previous severe injury situations. The procedure has proven similarly unsuitable in incomplete or complete digit replantation. PMID- 30470333 TI - Wide Awake Tendon Transfers in Leprosy Patients in India. AB - Dr Akbar Khan began using the wide awake local anesthesia no tourniquet (WALANT) technique for leprosy tendon transfers in the summer of 2015 at the Damien Foundation Hospital in Nellore, India. This article summarizes his first 18 months of experience and describes 5 of his operations. He found that WALANT provides effective anesthesia with good visibility for leprosy tendon transfers. WALANT permits economically disadvantaged leprosy patients to afford the surgery. All of the leprosy patients who have undergone WALANT tendon transfers in this series would like the same technique for their next tendon transfers. PMID- 30470334 TI - Wide-Awake Hand Surgery in Two Centers in China: Experience in Nantong and Tianjin with 12,000 patients. AB - This article summarizes the application of local anesthesia no tourniquet in 2 hand surgery centers in China, Nantong and Tianjin, where more than 12,000 patients were operated on with the new approach. This approach achieves excellent anesthetic and vasoconstrictive effects. In Nantong, surgeons performed fracture fixation, soft tissue tumor excision, and flap transfer in the hand with this approach. In Tianjin, surgeons applied it to cases of hand trauma emergency surgery. The authors' experience shows that this approach to hand surgery is safe, economical, and patient friendly, with no increase in infection rate. PMID- 30470335 TI - Wide-Awake Wrist and Small Joints Arthroscopy of the Hand. AB - The minimally invasive nature of wrist and small joint arthroscopy renders it particularly suitable for the application of the wide-awake local anesthesia no tourniquet (WALANT) technique. The application of WALANT wrist and small joint arthroscopy has given surgeons the ability to visualize both static and dynamic movements of a joint, to show the pathology and discuss with the patient, and to visualize a patient's repaired structures. This reinforces confidence in surgeons and encourages patients to comply with postoperative rehabilitation. PMID- 30470336 TI - Wide Awake Surgery as an Opportunity to Enhance Clinical Research. AB - Wide Awake surgery under Local Anesthesia with No Tourniquet (WALANT) has revolutionized clinical hand surgery, improving clinical outcomes and reducing postoperative pain and morbidity. It can also be used to deepen scientific knowledge, because the unsedated patient, with sensation intact and without the adverse effects of tourniquet neurapraxia or paralysis, can follow commands and actively move the limb after tendon and nerve surgery. These movements can be correlated with fingertip force, tendon tension, nerve conduction and amplitude, and muscle sarcomere length measurements to develop new insights into the effectiveness of many different tendon and nerve procedures in the hand. PMID- 30470337 TI - Extending Applications of Local Anesthesia Without Tourniquet to Flap Harvest and Transfer in the Hand. AB - The authors' experience demonstrates that wide-awake flap surgery in the hand is safe. The authors used this approach in 4 commonly used flaps in the hand in 27 patients: the extended Segmuller flap, the homo-digital reverse digital artery flap, the dorsal metacarpal artery perforator flap, and the Atasoy advancement flap. Wide-awake flap surgery works very well and safely achieved excellent anesthetic and vasoconstrictive effects in the authors' cases. The authors found that vasoconstriction caused by epinephrine mainly affects the capillaries and does not affect digital arteries and their major branches in the hand. PMID- 30470338 TI - How the Wide Awake Tourniquet-Free Approach Is Changing Hand Surgery in Most Countries of the World. PMID- 30470339 TI - Local Anesthesia Without Tourniquet in Hand and Forearm Surgery: My Story of Using and Promoting it. PMID- 30470340 TI - [Update 2018-2020 of French ccAFU guidelines - Editorial]. PMID- 30470342 TI - Obesogens: accounting for environmental factors in obesity. PMID- 30470341 TI - Research digest: genetics in cardiometabolic disease. PMID- 30470343 TI - Editorial overview: Embroidering the canvas of life. PMID- 30470344 TI - Foreward. PMID- 30470346 TI - Extremity compartment syndrome. PMID- 30470347 TI - Invited commentary. PMID- 30470348 TI - Invited commentary. PMID- 30470349 TI - Invited commentary. PMID- 30470350 TI - Invited commentary. PMID- 30470351 TI - Invited commentary. PMID- 30470352 TI - Invited commentary. PMID- 30470353 TI - Invited commentary. PMID- 30470354 TI - Vascular science: A glimpse into the future. PMID- 30470355 TI - Invited commentary. PMID- 30470356 TI - Invited commentary. PMID- 30470357 TI - Invited commentary. PMID- 30470358 TI - Invited commentary. PMID- 30470359 TI - Invited commentary. PMID- 30470360 TI - Invited commentary. PMID- 30470361 TI - Invited commentary. PMID- 30470362 TI - Invited commentary. PMID- 30470364 TI - Correction. PMID- 30470365 TI - Challenges and opportunities of electronic publishing. PMID- 30470363 TI - Resolvin D1 decreases abdominal aortic aneurysm formation by inhibiting NETosis in a mouse model. AB - OBJECTIVE: Resolvins have been shown to attenuate inflammation, whereas NETosis, the process of neutrophils releasing neutrophil extracellular traps (NETs), produces increased inflammation. It is hypothesized that treatment of animals with resolvin D1 (RvD1) would reduce abdominal aortic aneurysm (AAA) formation by inhibiting NETosis. METHODS: Wild-type 8- to 12-week-old C57BL/6 male mice (n = 47) and apolipoprotein E-deficient (ApoE-/-) mice (n = 20) were used in two models to demonstrate the effects of RvD1 on AAA growth. In the topical elastase AAA model, wild-type mice were divided into three groups: a deactivated elastase control group, in which sham surgery was performed using deactivated elastase and mice were intravenously injected with phosphate-buffered saline (PBS) once a day until harvest; an elastase group, in which active elastase was used to induce AAA and mice were injected with PBS daily until harvest; and an RvD1-treated group, in which AAA was induced and mice were injected with RvD1 daily until harvest. In the angiotensin II (Ang II)-induced AAA model, ApoE-/- mice were fed a high-fat diet and implanted with osmotic infusion pumps containing Ang II (1000 ng/kg/min). The Ang II model was divided into two groups: an Ang II control group, in which Ang II was delivered and mice were injected with PBS daily until harvest; and an RvD1-treated group, in which Ang II was delivered and mice were injected with RvD1 daily until harvest. On postoperative day 3, day 14, or day 28, aortic and blood samples were collected for Western blot, histology, cytokine array, enzyme-linked immunosorbent assay, and gelatin zymography after aortic diameter measurement. RESULTS: The day 14 RvD1-treated group demonstrated 42% reduced AAA diameter compared with the elastase group (P < .001). On postoperative day 3, the RvD1-treated group showed decreased levels of NETosis markers citrullinated histone H3 (P = .04) and neutrophil elastase (P = .002) compared with the elastase group. Among important cytokines involved in AAA formation, interleukin (IL) 1beta was downregulated (P = .02) whereas IL-10, a protective cytokine, was upregulated (P = .01) in the RvD1-treated group. Active matrix metalloproteinase 2 also decreased in the RvD1-treated group (P = .03). The RvD1-treated group in the Ang II AAA model, a second model, demonstrated reduced AAA diameter compared with the Ang II control group on day 28 (P < .046). The RvD1-treated group showed decreased levels of citrullinated histone H3 on day 3 (P = .002). Cytokines interferon gamma, IL-1beta, C-X-C motif chemokine ligand 10, monocyte chemotactic protein 1, and regulated on activation, normal T cell expressed and secreted (RANTES) were all decreased on day 28 (P < .05). CONCLUSIONS: RvD1-mediated inhibition of NETosis may represent a future medical treatment for the attenuation of AAA growth. PMID- 30470366 TI - Invited commentary. PMID- 30470367 TI - Invited commentary. PMID- 30470368 TI - Invited commentary. PMID- 30470369 TI - Major adverse limb events and major adverse cardiac events after contemporary lower extremity bypass and infrainguinal endovascular intervention in patients with claudication. AB - OBJECTIVE: Major adverse limb events (MALEs) and major adverse cardiovascular events (MACEs) at 30 days provide standardized metrics for comparison and have been adopted by the Society for Vascular Surgery's objective performance goals for critical limb ischemia. However, MALEs and MACEs have not been widely adopted within the claudication population, and the comparative outcomes after lower extremity bypass (LEB) and infrainguinal endovascular intervention (IEI) remain unclear. The purpose of this study was to compare MALEs and MACEs after LEB and IEI in a contemporary national cohort and to determine predictors of MALEs and MACEs after revascularization for claudication. METHODS: A national data set of LEB and IEI performed for claudication was obtained using National Surgical Quality Improvement Program vascular targeted Participant Use Data Files from 2011 to 2014. Patients were stratified by LEB vs IEI and compared by appropriate univariate analysis. The primary outcomes were MALE (defined as untreated loss of patency, reintervention on the index arterial segment, or amputation of the index limb) and MACE (defined as stroke, myocardial infarction, or death). Multivariable logistic regression was used to identify predictors of MALEs and MACEs. RESULTS: A total of 3925 infrainguinal revascularization procedures (2155 LEB and 1770 IEI) were performed for claudication. There was no difference in 30 day MALEs between LEB and IEI (4.0% vs 3.2%; P = .17). On multivariable logistic regression, predictors of 30-day MALEs included tibial revascularization (odds ratio [OR], 2.2; P < .0001) and prior LEB on the same arterial segment (OR, 1.8; P = .004). LEB had significantly higher 30-day MACEs (2.0% vs 1.0%; P = .01) but similar mortality (0.5% vs 0.4%; P = .6). Predictors of MACEs included LEB vs IEI (OR, 2.1; P = .01), chronic obstructive pulmonary disease (OR, 2.2; P = .01), dialysis dependence (OR, 4.4; P = .003), and diabetes (OR, 1.9; P = .02). CONCLUSIONS: In this large national cohort, LEB and IEI for claudication are associated with similar 30-day MALEs. Tibial revascularization and revascularization after prior failed bypass predict MALEs in claudicants and should therefore be undertaken with caution. LEB was associated with more 30-day MACEs but comparable 30-day mortality compared with IEI. Patients with end-stage renal disease, chronic obstructive pulmonary disease, and diabetes are at high risk for MACEs. The risk of 30-day MACEs after LEB should be weighed against the longer term outcomes of LEB vs IEI and conservative management, particularly in these higher risk patients. This analysis helps define contemporary 30-day outcomes after infrainguinal revascularization performed for claudication and serves as a baseline with which the short-term outcomes of future treatments can be compared. PMID- 30470370 TI - Outcomes of lower extremity bypass surgery in patients with renal transplants. AB - OBJECTIVE: Outcomes of infrainguinal bypass surgery (IBS) in patients with renal transplants are largely undescribed. This study evaluated perioperative and long term outcomes of IBS using autogenous and prosthetic conduits in a large population-based cohort of renal transplantation patients. METHODS: A retrospective review of all renal transplantation patients who underwent IBS between January 2007 and December 2011 in the United States Renal Data System was performed. Univariable, Kaplan-Meier, multivariable logistic, and Cox regression analyses were employed to evaluate 30-day postoperative (graft failure, limb loss, conduit infection, and death) and long-term (primary patency, primary assisted patency, secondary patency, limb salvage, and mortality) outcomes. RESULTS: There were 1048 IBSs performed (autogenous, 68%; prosthetic, 32%), predominantly for critical limb ischemia (70%). Of these, 480 (46%) were femoral popliteal, 330 (31%) were femoral-tibial, and 238 (23%) were popliteal-tibial bypasses. Comparing autogenous vs prosthetic conduits, primary patency was 33% vs 28% (P = .22), primary assisted patency was 38% vs 31% (P = .13), secondary patency was 48% vs 53% (P = .67), limb salvage was 53% vs 63% (P = .73), and patient survival was 47% vs 51% (P = .88), all at 5 years. Risk-adjusted analyses demonstrated higher primary assisted patency (adjusted hazard ratio [aHR], 1.33; 95% confidence interval [CI], 1.06-1.66; P = .012), secondary patency (aHR, 1.33; 95% CI, 1.02-1.74; P = .034), and limb salvage (aHR, 1.35; 95% CI, 1.02-1.80; P = .037) for autogenous compared with prosthetic bypasses. There was no difference in mortality of patients who received autogenous vs prosthetic conduits. CONCLUSIONS: We have presented postoperative and long-term outcomes of IBS in renal transplantation patients. Autogenous bypasses outperform prosthetics with regard to primary assisted patency, secondary patency, and limb salvage. Given the modest survival advantage conferred by renal transplantation, maximum efforts should be made to create bypasses with autogenous conduits when it is feasible. These results should inform the patient's and surgeon's expectations in planning of IBS for these patients. PMID- 30470371 TI - Invited commentary. PMID- 30470372 TI - Spontaneous complete resolution of mycotic superior mesenteric artery pseudoaneurysm. PMID- 30470373 TI - A systematic review and meta-analysis of early outcomes after endovascular versus open repair of thoracoabdominal aortic aneurysms. AB - OBJECTIVE: The objective of this study was to compare the early results of endovascular vs open thoracoabdominal aortic aneurysm (TAAA) repair. METHODS: MEDLINE and Embase were searched for studies from January 2006 to March 2018 that compared endovascular vs open repair of TAAA using branched or fenestrated endografts. Data were subjected to a meta-analysis using a random-effects model. The outcomes of interest included early mortality, spinal cord injury, renal failure requiring dialysis, stroke, and hospital length of stay. RESULTS: Eight comparative studies met inclusion criteria. There were two retrospective propensity-matched studies, two unadjusted single-center retrospective studies, and four unadjusted national population-based studies. Mortality in the matched studies was equivalent in both groups. Pooled analysis of all unmatched observational studies revealed a survival benefit for endovascular over open repair (relative risk [RR], 0.63; 95% confidence interval [CI],0.45-0.87); P < .01, I2 = 47%). Endovascular repair was also associated with lower incidence of spinal cord injury (RR, 0.65; 95% CI, 0.42-1.01; P = .05; I2 = 28%). For unmatched studies, pooled RR of renal failure requiring dialysis significantly favored endovascular repair (RR, 0.44; 95% CI, 0.23-0.85; P = .01; I2 = 0%), although in the adjusted cohort, risk of dialysis was not different (RR, 1.00; 95% CI, 0.06-15.65; P = 1.00). Postoperative stroke rate was reported in three unadjusted studies and was not different between groups (RR, 0.81; 95% CI, 0.28 2.40; P = .71; I2 = 77%). Hospital length of stay was reported in four studies and was shorter in the endovascular group (mean difference, -4.4 days; 95% CI, 6.6 to -1.7; P < .01; I2 = 73%). CONCLUSIONS: There are few reports comparing endovascular vs open repair of TAAAs. Short-term outcomes may be improved in patients undergoing endovascular treatment of TAAA on the basis of a limited number of studies with high risk of bias. These findings highlight the need for larger comparative studies with standardization of reporting. PMID- 30470375 TI - Turning a negative into a positive. PMID- 30470374 TI - Accessing your Quality Payment Program feedback reports. PMID- 30470376 TI - Trends in PDA treatment: is less really more? PMID- 30470377 TI - A difficult decision, illuminated. PMID- 30470378 TI - Lean use of antibiotics in fragile neonates as well as children in the community: we can do better. PMID- 30470379 TI - 50 Years Ago in The Journal of Pediatrics: Survival of Children with Neuroblastoma Treated with Combination Chemotherapy. PMID- 30470380 TI - 50 Years Ago in The Journal of Pediatrics: The Treatment of Prolonged Seizure Activity with Intravenous Diazepam. PMID- 30470381 TI - Sleep and obesity. PMID- 30470382 TI - Long-Term Parathyroid Hormone 1-34 Replacement Therapy in Children with Hypoparathyroidism. AB - OBJECTIVE: To determine whether multiple daily injections of parathyroid hormone (PTH) 1-34 are safe and effective as long-term therapy for children with hypoparathyroidism. STUDY DESIGN: Linear growth, bone accrual, renal function, and mineral homeostasis were studied in a long-term observational study of PTH 1 34 injection therapy in 14 children. METHODS: Subjects were 14 children with hypoparathyroidism attributable to autoimmune polyglandular syndrome type 1 (N = 5, ages 7-12 years) or calcium receptor mutation (N = 9, ages 7-16 years). Mean daily PTH 1-34 dose was 0.75 +/- 0.15 ug/kg/day. Treatment duration was 6.9 +/- 3.1 years (range 1.5-10 years). Patients were evaluated semiannually at the National Institutes of Health Clinical Center. RESULTS: Mean height velocity and lumbar spine, whole body, and femoral neck bone accretion velocities were normal throughout the study. In the first 2 years, distal one-third radius bone accrual velocity was reduced compared with normal children (P < .003). Serum alkaline phosphatase correlated with PTH 1-34 dose (P < .006) and remained normal (235.3 +/- 104.8 [SD] U/L, N: 51-332 U/L). Mean serum and 24-hour urine calcium levels were 2.05 +/- 0.11 mmol/L (N: 2.05-2.5 mmol/L) and 6.93 +/- 1.3 mmol/24 hour (N: 1.25-7.5 mmol/24 hour), respectively-with fewer high urine calcium levels vs baseline during calcitriol and calcium treatment (P < .001). Nephrocalcinosis progressed in 5 of 12 subjects who had repeated renal imaging although renal function remained normal. CONCLUSIONS: Twice-daily or thrice-daily subcutaneous PTH 1-34 injections provided safe and effective replacement therapy for up to 10 years in children with hypoparathyroidism because of autoimmune polyglandular syndrome type 1 or calcium receptor mutation. PMID- 30470383 TI - Validity Evidence for the General Pediatrics Board Certification Examinations: A Practice Analysis. PMID- 30470384 TI - Corrections. PMID- 30470386 TI - Foreward. PMID- 30470385 TI - Corrections. PMID- 30470388 TI - Abdominal Wall Hernia. PMID- 30470389 TI - Geospatial distribution of periodontists and US adults with severe periodontitis. AB - BACKGROUND: In this study, the authors report on the geospatial distributions of periodontists and adults with severe periodontitis in the United States. METHODS: The authors used geospatial analysis to describe the distribution of periodontists and adults, periodontists vis-a-vis estimated density of adults with severe periodontitis, and their ratios to adults with severe periodontitis. The authors identified locations of 5,415 practicing periodontists through the 2014 National Provider Identifier Registry, linked them with the weighted census number of adults, and estimated the number of adults within a series of circular distance zones. RESULTS: Approximately 60% of adults 30 through 79 years lived within 5 miles of a periodontist, 73% within 10 miles, 85% within 20 miles, and 97% within 50 miles. Proximity to a periodontist varied widely. In urban areas, 95% of adults resided within 10 miles of a periodontist and 100% within 20 miles. Only 24% of adults in rural areas lived within 10 miles of a periodontist. Most periodontists (96.1%) practiced in urban areas, clustering along the eastern and western coasts and in the Midwest, 3.1% in urban clusters elsewhere, and 0.8% in rural areas. Ratios of fewer than 8,000 adults with periodontitis to 1 or more periodontists within 10 miles were clustered mostly in the Northeast, central East Coast, Florida, West Coast, Arizona, and Midwest. CONCLUSIONS: In this study, the authors identified wide variations in geographic proximity to a practicing periodontist for adults with severe periodontitis. PRACTICAL IMPLICATIONS: Dental practitioners may provide preventive care and counseling for periodontitis and referrals for specialty care. Geographic proximity to specialized periodontal care may vary widely by locality. PMID- 30470390 TI - Excessive gingival display treated with 2-piece segmental Le Fort I osteotomy: A case report. AB - BACKGROUND: The demand for orthognathic surgery has increased worldwide. Women with jaw deformity tend to have a worse quality of life than men owing to the deformity's negative effects on body image, low self-esteem, lack of self confidence, and dissatisfaction with life. Therefore, they wish for more reliable treatment options. CASE DESCRIPTION: A woman aged 25 years and 9 months sought treatment for a convex profile and excessive gingival display caused by a skeletal Class II jaw-base relationship. Gingival exposure was up to 6.5 millimeters at full smile. She chose orthognathic surgery, and the authors performed a 2-piece segmental Le Fort I osteotomy and bilateral sagittal split ramus osteotomy. After active orthodontic treatment, the protrusive profile was improved, and an acceptable occlusion and an attractive smile were achieved. PRACTICAL IMPLICATIONS: It is hoped that 2-piece segmental Le Fort I osteotomy becomes a common treatment option for patients with protrusive profiles and excessive gingival displays. PMID- 30470391 TI - Similar anxiety levels and postoperative pain, trismus, and swelling between acupuncture and sham acupuncture in patients undergoing third-molar surgical extraction. PMID- 30470392 TI - Very serious limitations in systematic review summarizing how minimally invasive techniques compare with defective restoration replacement render it not useful for making clinical decisions. PMID- 30470393 TI - The Biology and Clinical Features of Cutaneous Polyomaviruses. AB - Human polyomaviruses are double-stand DNA viruses with a conserved genomic structure, yet they present with diverse tissue tropisms and disease presentations. Merkel cell polyomavirus, trichodysplasia spinulosa polyomavirus, human polyomavirus 6 and 7, and Malawi polyomavirus are shed from the skin, and Merkel cell polyomavirus, trichodysplasia spinulosa polyomavirus, human polyomavirus 6 and 7 have been linked to specific skin diseases. We present an update on the genomic and clinical features of these cutaneous polyomaviruses. PMID- 30470394 TI - Editing a medical journal: Decisions, dilemmas and dreams .... PMID- 30470395 TI - IHRS President's page. PMID- 30470396 TI - Epidemiology and Molecular Epidemiology. AB - Incidence, prevalence, and survival for diffuse low-grade gliomas and diffuse anaplastic gliomas (including grade II and grade III astrocytomas and oligodendrogliomas) varies by histologic type, age at diagnosis, sex, and race/ethnicity. Significant progress has been made in identifying potential risk factors for glioma, although more research is warranted. The strongest risk factors that have been identified thus far include allergies/atopic disease, ionizing radiation, and heritable genetic factors. Further analysis of large, multicenter epidemiologic studies, and well-annotated "omic" datasets, can potentially lead to further understanding of the relationship between gene and environment in the process of brain tumor development. PMID- 30470397 TI - Chemotherapy Treatment and Trials in Low-Grade Gliomas. AB - There is currently no universally accepted standard of care treatment for low grade gliomas, a molecularly heterogeneous group of tumors with similarly heterogeneous clinical outcomes. Risk stratification by clinical and molecular features is useful to help determine which patients benefit the most from adjuvant treatment. The addition of combination chemotherapy with procarbazine, lomustine, and vincristine confers survival advantage, as likely does temozolomide, but radiochemotherapy may not be appropriate for all patients owing to its toxicity profile. We review the approach to treatment in patients with low grade gliomas with an emphasis on the clinical trials focusing on adjuvant chemotherapy in this population. PMID- 30470398 TI - Low-Grade Glioma Radiotherapy Treatment and Trials. AB - Low-grade gliomas represent an important class of primary brain tumors. They account for approximately 20% of primary brain tumors and typically present in the fourth decade of life. Standard management gliomas involves observation, surgery, chemotherapy, and/or radiotherapy. Treatment decisions are based on many factors including prognostic molecular markers, potential benefits of increased progression-free survival, and potential long-term treatment complications. Recent studies have improved our understanding regarding therapeutic interventions. This review provides an overview of low-grade glioma and discusses the roles of radiation therapy. We discuss advances in techniques and recent and ongoing radiation therapy-related clinical trials for low-grade gliomas. PMID- 30470399 TI - Higher-Order Surgical Questions for Diffuse Low-Grade Gliomas: Supramaximal Resection, Neuroplasticity, and Screening. AB - Diffuse low-grade glioma (DLGG) is a brain neoplasm that migrates within the connectome and that becomes malignant if left untreated. Early and maximal safe surgical resection by means of awake mapping enables a significant improvement of survival and quality of life. Supramaximal functional-based resection seems to prevent DLGG malignant transformation. Neuroplasticity is helpful to remove DLGG in eloquent areas. When radical excision cannot be achieved due to invasion of critical neural networks, cerebral remapping over time may lead to a reoperation with an optimized resection. To discover and treat DLGG earlier, a screening in the general population should be considered. PMID- 30470400 TI - How to Build a Neurosurgical Oncology Practice Specializing in Gliomas. AB - For the neurosurgical oncologist, a specialty practice in gliomas represents an intersection of tailored surgical approaches, emerging intraoperative technologies, expanding surgical trial portfolios, and new paradigms in glioma biology. Assembling these disparate pieces into a cohesive career trajectory is a difficult task but ultimately enables the subspecialist to navigate all domains relevant to improving glioma patient outcomes. Within the larger clinical and basic science community, thoughtful integration and intensive collaborations are essential mechanisms when building a multidisciplinary glioma program. PMID- 30470402 TI - Alterations in the Brain Microenvironment in Diffusely Infiltrating Low-Grade Glioma. AB - Glioma cells diffusely infiltrate the surrounding brain tissue where they intermingle with nonneoplastic brain cells, including astrocytes, microglia, oligodendrocytes and neurons. The infiltrative margins of glioma represent the structural and functional interface between neoplastic and nonneoplastic brain tissue that underlies neurologic alterations associated with glioma, including epilepsy and neurologic deficits. Technological advancements in molecular analysis, including single cell sequencing, now allow us to assess alterations in specific cell types in the brain tumor microenvironment, which can enhance the development of novel therapies that target glioma growth and glioma-induced neurologic symptoms. PMID- 30470401 TI - Molecular Pathogenesis of Low-Grade Glioma. AB - Advances in genome sequencing have elucidated the genetics of low-grade glioma. Available evidence indicates a neomorphic mutation in isocitrate dehydrogenase (IDH) initiates gliomagenesis. Mutant IDH produces the oncometabolite 2 hydroxyglutarate, which inhibits enzymes that demethylate genomic DNA and histones. Recent findings by the authors and others suggest the ensuing hypermethylation alters chromatin conformation and the transcription factor landscape in brain progenitor cells, leading to a block in differentiation and tumor initiation. Work in preclinical models has identified selective metabolic and molecular vulnerabilities of low-grade glioma. These new concepts will trigger a wave of innovative clinical trials in the near future. PMID- 30470403 TI - Clinical Presentation, Natural History, and Prognosis of Diffuse Low-Grade Gliomas. AB - Diffuse low-grade gliomas (DLGGs) are primary brain tumors characterized by slow growth but extensive infiltration into the surrounding brain. Patients are typically 30 to 40 years at disease onset and present with focal or focal to bilateral tonic-clonic seizures. The tumor will transform into a malignant glioma and eventually lead to death, but after varying lengths of time. The specific features of DLGG impose a major challenge to decide optimal treatment strategies and timing of treatment, while maintaining patients' quality of life. We discuss the clinical challenges at disease onset with regard to the natural history and long-term prognosis. PMID- 30470404 TI - Diffuse Low-Grade Glioma-Related Epilepsy. AB - The World Health Organization classifies diffuse low-grade gliomas (DLGGs) are highly epileptogenic primary brain tumors; epileptic seizures occur in more than 90% of cases. Epileptic seizures and drug resistance progress during the course of DLGGs. The glioma-related epileptogenic mechanisms are multifactorial; epileptogenic foci lie within the infiltrated peritumoral neocortex. A short seizure duration before surgery and a large extent of resection are the main predictors of postoperative seizure control in DLGGs. A supratotal resection of a DLGG can improve postoperative seizure control. Epileptic seizure at diagnosis positively affects DLGGs malignant transformation and overall survival. PMID- 30470405 TI - Mapping in Low-Grade Glioma Surgery: Low- and High-Frequency Stimulation. AB - Surgery for lower grade glioma requires the use of brain mapping techniques to identify functional boundaries, which represent the limit of the resection. Two stimulation paradigms are currently available and their use should be tailored to the clinical context to extend tumor removal and decrease the odds of postoperative permanent deficits. PMID- 30470406 TI - Surgical Adjuncts to Increase the Extent of Resection: Intraoperative MRI, Fluorescence, and Raman Histology. AB - In low-grade glioma surgery, depicting tumor margins is challenging. 7 - Bowden 2018 - Sodium Fluorescein Facilitates Guided Sampling of Diagnostic Tumor Tissue.pdf Several tools have emerged to assist surgical decision-making. Intraoperative MRI, albeit expensive and time-consuming, can provide useful information during surgery. Fluorescence-guidance with 5-aminolevulinic acid (5 ALA) helps provide real-time information during surgery regardless of brain shift, assists in finding anaplastic foci in low-grade tumors, and enables diagnosis of malignant tissue. Raman histology has potential for detecting viable tumor in biopsied tissue and for identifying tumor infiltration in vivo. This article analyzes and discusses these surgical adjuncts. PMID- 30470407 TI - Beyond Language: Mapping Cognition and Emotion. AB - The use of intraoperative cognitive mapping and monitoring during awake surgery is not new, but this surgical approach has undergone important changes in recent years, especially in the context of low-grade glioma surgery. This rapid development is related to the growing awareness from neurosurgeons that sustaining quality of life in patients with a long-survival expectancy implies assessment and preservation of a range of important functions during surgery, beyond "overt" functions, such as language or motricity. Here we describe the different behavioral paradigms typically used, and how they are selected and modulated to identify and spare critical brain-wide cognitive systems. PMID- 30470408 TI - Evidence for Improving Outcome Through Extent of Resection. AB - Surgical resection plays a central role in the management of gliomas however many tumors are within areas resulting in sensorimotor and cognitive consequences. This article reviews the evidence in support of extent of resection to improve survival, symptom management, and time to malignant transformation in low-grade gliomas. The authors summarize the evolving literature regarding the role of maximal safe resection in light of WHO subclassification of low-grade gliomas. Long lasting neurological deficits following glioma resection may hinder both survival and quality of life. New insights into glioma related central nervous system plasticity impact both surgical planning and timing of interventions. PMID- 30470409 TI - Extent of Resection Versus Molecular Classification: What Matters When? AB - For malignant gliomas, the survival benefit of new combination therapies after surgical resection is measured in weeks to months. In contrast, optimizing treatment for low-grade gliomas can potentially provide additional years of life. The relatively indolent but not benign clinical course provides the opportunity for clinicians and scientists to focus not only on the duration of survival, but also to maximize quality of life. Ideal management of low-grade gliomas among the most important yet paradoxically most neglected subjects in neuro-oncology. This article examines the molecular underpinnings of these tumors and evaluates the role of extensive surgery in maximizing outcomes. PMID- 30470410 TI - Low-Grade Glioma: Epidemiology, Pathophysiology, Clinical Features, and Treatment. PMID- 30470411 TI - Analysis of chromosome 12p over-representation and clinicopathological features in mediastinal teratomas. AB - Teratomas show diverse biologic behaviour and prognosis as well as variable histological features. Importantly, post-pubertal testicular teratomas composed of mature components have a potential for malignant behaviour, in contrast to ovarian dermoid cysts and pre-pubertal testicular teratomas which are considered almost always benign. On the other hand, the biological behaviour and histogenesis of extragonadal teratomas are still not fully elucidated. In this study of mediastinal mature teratoma (MT), we investigated clinicopathological features and chromosome 12 short arm (12p) status which constitutes a major genetic aberration in the germ cell tumours (GCT) and is indicative of malignant potential. A total of 123 cases of primary mediastinal MT were included, and clinical data were retrieved regarding demographic information, adjuvant treatment, post-operative clinical course, and level of serum tumour markers. Histopathological features were evaluated in 123 cases and 12p status was studied by FISH in 25 cases. Female predilection was identified in the post-pubertal group (38 males vs 77 females), and paediatric teratoma cases had longer follow up (mean 62.2 months vs 26.5 months). All patients had excellent prognosis with no tumour-associated death, regardless of age and sex. None of the MT cases had cytological atypia and all 21 cases finally evaluated by fluorescence in situ hybridisation were negative for 12p over-representation. Our results support the benign nature of mediastinal MT and suggest the possibility that it may share a common histogenesis with pre-pubertal type GCTs. PMID- 30470412 TI - Radiologist performance in the detection of lung cancer using CT. AB - AIM: To measure the level of radiologists' performance in lung cancer detection, and to explore radiologists' performance in cancer specialised and non specialised centres. MATERIALS AND METHODS: Thirty radiologists read 60 chest computed tomography (CT) examinations. Thirty cases had surgically or biopsy proven lung cancer and 30 were cancer-free cases. The cancer cases were validated by four expert radiologists who located the malignant lung nodules. Reader performance was evaluated by calculating sensitivity, location sensitivity, specificity, and area under the receiver operating characteristic (ROC) curve (AUC). In addition, sensitivity at fixed specificity (0.794) was computed from each reader's estimated ROC curve. RESULTS: The radiologists had a mean sensitivity of 0.749, sensitivity at fixed specificity of 0.744, location sensitivity of 0.666, specificity of 0.81 and AUC of 0.846. Radiologists in the specialised and non-specialised cancer centres had the following (specialised, non-specialised) pairs of values: sensitivity=(0.80, 0.719); sensitivity for fixed 0.794 specificity=(0.752, 0.740); location sensitivity=(0.712, 0.637); specificity=(0.794, 0.82) and AUC=(0.846, 0.846). CONCLUSION: The efficacy of radiologists was comparable to other studies. Furthermore, AUC outcomes were similar for specialised and non-specialised cancer centre radiologists, suggesting they have similar discriminatory ability and that the higher sensitivity and lower specificity for specialised-centre radiologists can be attributed to them being less conservative in interpreting case images. PMID- 30470413 TI - Acute-Onset Vertical Nystagmus and Limb Tremors in Chronic Renal Failure. PMID- 30470414 TI - Should I test more babies? Solutions for transparent data peeking. AB - Research with infants is often slow and time-consuming, so infant researchers face great pressure to use the available participants in an efficient way. One strategy that researchers sometimes use to optimize efficiency is data peeking (or "optional stopping"), that is, doing a preliminary analysis (whether a formal significance test or informal eyeballing) of collected data. Data peeking helps researchers decide whether to abandon or tweak a study, decide that a sample is complete, or decide to continue adding data points. Unfortunately, data peeking can have negative consequences such as increased rates of false positives (wrongly concluding that an effect is present when it is not). We argue that, with simple corrections, the benefits of data peeking can be harnessed to use participants more efficiently. We review two corrections that can be transparently reported: one can be applied at the beginning of a study to lay out a plan for data peeking, and a second can be applied after data collection has already started. These corrections are easy to implement in the current framework of infancy research. The use of these corrections, together with transparent reporting, can increase the replicability of infant research. PMID- 30470415 TI - Rehabilitation in the Department of Veterans Affairs Polytrauma System of Care: Historical Perspectives. AB - The purpose of this article is to inform the reader of the historical aspects of the Polytrauma System of Care, understand the solutions that were implemented in addressing the continuum of care needs for service members and veterans, and provide an understanding of ongoing research efforts that will inform future solutions to strategically identified future care needs. PMID- 30470416 TI - Rehabilitation of Burn Injuries: An Update. AB - A major burn is a severe injury with a global impact. Our system of medical evacuation has led to the survival of many severely injured service members. Burn rehabilitation is a complex and dynamic process and will not be linear. Recovery requires a comprehensive, interdisciplinary team-based approach, individually designed to maximize function, minimize disability, promote self-acceptance, and facilitate survivor and family reintegration into the community. PMID- 30470417 TI - Department of Veterans Affairs Polytrauma Rehabilitation Centers: Inpatient Rehabilitation Management of Combat-Related Polytrauma. AB - Traumatic brain injury (TBI) is one of the signature injuries of Operation Iraqi Freedom and Operation Enduring Freedom. To ensure that rehabilitation care needs of veterans and active duty servicemembers with TBI and polytrauma injuries were met, the Department of Veterans Affairs (VA) established the Polytrauma System of Care (PSC) in 2005. The 5 VA Polytrauma Rehabilitation Centers provide tertiary, acute inpatient rehabilitation for the PSC. Interdisciplinary treatment teams of multiple rehabilitation disciplines provide the complex, patient-centered care to achieve maximum benefit. After discharge, veterans and servicemembers with TBI and polytrauma receive lifelong support and care through the PSC. PMID- 30470418 TI - Neurobehavioral Management of the Polytrauma Veteran. AB - Since the inception of the Afghanistan and Iraq wars, an increasing number of veterans have sought treatment from the Department of Veterans Affairs for combat related injuries. Many veterans experience postconcussive symptoms, traumatic stress, chronic pain, sensory deficits, and/or headaches. The goal of this article was to highlight some of the challenges treatment providers may face, while providing rehabilitation specialists with important evaluation and treatment considerations in working with this population to maximize outcomes for these veterans. PMID- 30470419 TI - Rehabilitation Assessment and Management of Neurosensory Deficits After Traumatic Brain Injury in the Polytrauma Veteran. AB - Neurosensory deficits after traumatic brain injury can frequently lead to disability; therefore, diagnosis and treatment are important. Posttraumatic headaches typically resemble migraines and are managed similarly, but adjuvant physical therapy may be beneficial. Sleep-related issues are treated pharmacologically based on the specific sleep-related complaint. Fatigue is difficult to treat; cognitive behavioral therapy and aquatic therapy can be beneficial. Additionally, methylphenidate and modafinil have been used. Peripheral and central vestibular dysfunction causes dizziness and balance dysfunction, and the mainstay of treatment is vestibular physical therapy. Visual dysfunction incorporates numerous different diagnoses, which are frequently treated with specific rehabilitation programs. PMID- 30470420 TI - Vision Rehabilitation After Traumatic Brain Injury. AB - Visual dysfunctions and symptoms are commonly experienced after even mild traumatic brain injury (TBI) despite excellent visual acuity. All individuals who have experienced a TBI/concussion should be screened for vision symptoms and visual dysfunction. A TBI-specific eye examination is necessary to identify the visual sequelae of TBI and address any vision/ocular issues that may be contributing to other post-TBI complaints. A vision rehabilitation plan that includes vision therapy can improve visual dysfunction secondary to TBI. Combining office-based and home-based vision therapy training will maximize visual potential and functional results. PMID- 30470421 TI - Rehabilitation of Cognitive Dysfunction Following Traumatic Brain Injury. AB - This article outlines key principles and considerations in the rehabilitation of cognitive challenges following mild, moderate, and severe traumatic brain injuries, with a focus on the needs of the service member and veteran population. The authors highlight specific evidence-based strategies and interventions and provide functional examples to support implementation. By emphasizing the array of tools and resources that have been designed to address cognitive challenges in the service member and veteran population, they focus on optimizing cognition to support successful community reintegration and the resumption of a full and meaningful life. PMID- 30470422 TI - Department of Veterans Affairs Polytrauma Telerehabilitation: Twenty-First Century Care. AB - The use of telehealth for the management of the polytrauma patient provides a unique opportunity to leverage technology to enhance care for a complex patient cohort, to assist in clinical care, and to enhance support for community reintegration for veteran patients. Telehealth connects experts to patients in remote or underserved areas, thereby decreasing a health care disparity. This is especially important when the rehabilitation team is multidisciplinary. The future of telerehabilitation is unknown and implementing virtual care into rehabilitation providers' standard practice will be impeded until state licensure and payment issues are resolved. PMID- 30470423 TI - Assistive Technology in Polytrauma Rehabilitation. AB - Assistive technology (AT) is a service or device that provides individuals with polytrauma injuries the chance to engage in their daily activities. AT specialists use the Human Activity Assistive Technology frame of reference to guide their evaluation, treatment, selection, and training process as it also takes into account the context in which AT devices would be used. AT devices include augmentative and alternative communication, electronic cognitive devices, wheeled mobility, electronic aides to daily living, adaptive computer access, and adaptive sports. Within all of these areas of AT, other considerations include accessing the devices, mounting the devices, and integrating the technology when possible. PMID- 30470424 TI - Integrative Medicine and Health Coaching in Polytrauma Rehabilitation. AB - Veterans Health Administration (VHA) has embarked on a journey of cultural transformation focused on creating a personalized and patient-driven experience with health care service. In addition to training thousands of providers in the principles of whole health and expanding availability of complementary medicine, VHA also pursues developing the evidence for such care. The Polytrauma Integrative Medicine Pilot explored the feasibility of implementing health coaching in polytrauma care. The qualitative and quantitative data collected on 547 participants in the pilot shows high satisfaction with the health coaching services received and statistically significant positive changes in domains of life satisfaction and well-being. PMID- 30470425 TI - Reintegrating Veterans with Polytrauma into the Community and Workplace. AB - This article addresses employment as a critical part of community reintegration for polytrauma patients. Interdisciplinary polytrauma teams can work to effectively identify and eliminate known barriers to employment for veterans and offer continued support and guidance. This article discusses key themes pertinent to vocational reentry for service members/veterans, identifies evidenced-based employment models, highlights the essential role of everyday technology in meeting support needs, and describes 2 exemplar polytrauma models: the Louis Stokes Cleveland Veteran Affairs Medical Center in Cleveland, Ohio, and the Service member Transitional Advanced Rehabilitation (STAR) program at the Hunter Holmes McGuire Veterans Affairs Medical Center in Richmond, Virginia. PMID- 30470426 TI - Adaptive Sports in the Rehabilitation of the Disabled Veterans. AB - Sports are ingrained in our society and are part of being a human. Through the Armed Forces, military personnel and veterans are trained and adapt to the learned behavior of perseverance, comradery, and teamwork, putting them in an ideal situation for using adaptive sports as a rehabilitation modality. Integrating sports into this unique population of disabled individuals helps to produce productive members of society. This article outlines the challenges and benefits of adaptive sports for veterans. PMID- 30470427 TI - Evolution of Care for the Veterans and Active Duty Service Members with Disorders of Consciousness. AB - The Veteran Health Administration Polytrauma Rehabilitation Center Emerging Consciousness Program (ECP) has served veterans and service members with disorders of consciousness (DOC) over the past 10 years. The ECP has evolved to meet the unique needs of this patient population, including updating admission criteria to follow evidence-based guidelines for the management of DOC, expanding the use of treatment modalities, and monitoring longitudinal outcomes. The authors review current assessment tools, medical management, and interventions and describe the current state of the ECP and how the evolution of the ECP has enhanced the care of veterans and service members with DOC. PMID- 30470428 TI - A Model of Care for Community Reintegration: The Polytrauma Transitional Rehabilitation Program. AB - The Department of Veterans Affairs Polytrauma Transitional Rehabilitation Program was established to extend the rehabilitation of veterans and active duty service members past the acute phase and reintegrate them into the community. Effective community reintegration is best achieved with a diverse interdisciplinary team that treats patients' physical, cognitive, and psychological deficits in a collaborative approach. Barriers, such as lack of accurate awareness of functional limitations and premorbid psychosocial stressors, can limit the recovery process. Recovery from polytrauma injuries is often a lifelong process, with the goal of maximizing functional independence and quality of life. PMID- 30470429 TI - Comprehensive Care for Persons with Spinal Cord Injury. AB - Spinal cord injury results in multiple secondary comorbidities, which vary based on injury severity and other characteristics. Persons with spinal cord injury are at lifelong risk for many complications, most of which are at least partially preventable with proper medical care. The Veterans Health Administration Spinal Cord Injury and Disorders (SCI&D) System of Care offers these evaluations to all persons in their registries. Annual evaluations are performed at any of the 24 SCI&D Veterans Administration Centers nationwide. This allows veterans to receive the care from an interdisciplinary team that specializes in the care of veterans with spinal cord injury. PMID- 30470430 TI - Upper Extremity Amputation and Prosthetics Care Across the Active Duty Military and Veteran Populations. AB - The hand and arm are exceptionally dexterous, exquisitely sensitive, and proficient in performing tasks and functions. Given the invaluable functions of the upper extremity in daily life, replacement of a missing limb through prosthetic substitution is challenging. Prosthetic and rehabilitation needs of injured Service members from recent military conflicts have brought upper extremity amputation to the forefront, which has led to an increase in attention and resource allocation. This article provides an overview of the care of the upper extremity amputee including surgical considerations, prosthetic design and fitting, and preprosthetic and post-prosthetic rehabilitation considerations. PMID- 30470432 TI - A Heritage to Remember. PMID- 30470431 TI - Lower Limb Amputation Care Across the Active Duty Military and Veteran Populations. AB - Traumatic amputation can result from injuries sustained both within and outside the military setting. Individuals with trauma-related amputations have unique needs and require specialized management with an interdisciplinary team approach and care coordination across the continuum of care to facilitate optimal outcomes. Management considerations include issues with the amputation itself, issues related to injury of other body parts, and the management of longer-term secondary conditions. Some of these issues are more prevalent and of greater severity in the early recovery period, whereas others develop later and have the potential for progressive worsening over time. PMID- 30470433 TI - Preface. PMID- 30470434 TI - Comparative analysis of expression of microbial sensing molecules in mucosal tissues with periodontal disease. AB - Host-derived pattern recognition receptors (PRRs) are necessary for effective innate immune engagement of pathogens that express microbial-associated molecular patterns (MAMP) ligands for these PRRs. This study used a nonhuman primate model to evaluate the expression of these sensing molecules in gingival tissues. Macaca mulatta aged 12-24 with a healthy periodontium (n = 13) or periodontitis (n = 11) provided gingival tissues for assessment of naturally-occurring periodontitis. An additional group of animals (12-23 years; n = 18) was subjected to a 5 month longitudinal study examining the initiation and progression of periodontitis, RNA was isolated and microarray analysis conducted for gene expression of the sensing PRRs. The results demonstrated increased expression of various PRRs in naturally occurring established periodontitis. Selected PRRs also correlated with both bleeding on probing (BOP) and pocket depth (PD) in the animals. The longitudinal model demonstrated multiple TLRs, as well as selected other PRRs that were significantly increased by 2 weeks during initiation of the lesion. While gene expression levels of various PRRs correlated with BOP and PD at baseline and resolution of disease, few correlated with these clinical parameters during initiation and progression of the lesion. These findings suggest that the levels of various PRRs are affected in established periodontitis lesions, and that PRR expression increased most dramatically during the initiation of the disease process, presumably in response to the juxtaposed microbial challenge to the tissues and goal of reestablishing homeostasis. PMID- 30470435 TI - Medical and Scientific Publishing in the 21st Century: A Search for Equipoise. PMID- 30470436 TI - alpha-galactosidase A deficiency promotes von Willebrand factor secretion in models of Fabry disease. AB - Fabry disease results from loss of activity of the lysosomal enzyme alpha galactosidase A (GLA), leading to the accumulation of globoseries glycosphingolipids in vascular endothelial cells. Thrombosis and stroke are life threatening complications of Fabry disease; however, the mechanism of the vasculopathy remains unclear. We explored the relationship between GLA deficiency and endothelial cell von Willebrand factor (VWF) secretion in in vivo and in vitro models of Fabry disease. Plasma VWF was significantly higher at two months and increased with age in Gla-null compared to wild-type mice. Disruption of GLA in a human endothelial cell line by siRNA and CRISPR/Cas9 resulted in a 3-fold and 5-fold increase in VWF secretion, respectively. The increase in VWF levels was associated with decreased endothelial nitric oxide synthase (eNOS) activity in both in vitro models. Pharmacological approaches that increase nitric oxide bioavailability or decrease reactive oxygen species completely normalized the elevated VWF secretion in GLA deficient cells. In contrast, the abnormality was not readily reversed by recombinant human GLA or by inhibition of glycosphingolipid synthesis with eliglustat. These results suggest that GLA deficiency promotes VWF secretion through eNOS dysregulation, which may contribute to the vasculopathy of Fabry disease. PMID- 30470438 TI - Relationship between long non-coding RNAs and Alzheimer's disease: a systematic review. AB - Alzheimer disease (AD), is a typical progressive and destructive neurodegenerative disease. It is the leading cause of senile dementia that is mainly represented as neurocognitive symptoms, including progressive memory impairment, cognitive disorder, personality change and language barrier, etc. The pathogeny and nosogenesis of AD have not been clearly explained. AD is characterized by extracellular senile plaques (SP) formed by beta amyloid (Abeta) deposition and neurofibrillary tangles in neuronal cells formed by hyperphosphorylation of tau, as well as the deficiency of neuronal with gliosis. However, the complete spectrum of regulating factors in molecular level that affect the pathogenesis of AD is unclear. Long non-coding RNAs (lncRNAs) are involved in numerous neurodegenerative diseases, such as Parkinson's disease (PD) and AD. It is increasingly recognized that lncRNAs is tightly related to the pathogenesis and prevention and cure of AD. In the review, we highlighted the roles of lncRNAs in AD pathways and discussed increasing interest in targeting and regulating lncRNAs for the therapeutics of AD. PMID- 30470437 TI - Deceased-donor acute kidney injury is not associated with kidney allograft failure. AB - Deceased-donor acute kidney injury (AKI) is associated with organ discard and delayed graft function, but data on longer-term allograft survival are limited. We performed a multicenter study to determine associations between donor AKI (from none to severe based on AKI Network stages) and all-cause graft failure, adjusting for donor, transplant, and recipient factors. We examined whether any of the following factors modified the relationship between donor AKI and graft survival: kidney donor profile index, cold ischemia time, donation after cardiac death, expanded-criteria donation, kidney machine perfusion, donor-recipient gender combinations, or delayed graft function. We also evaluated the association between donor AKI and a 3-year composite outcome of all-cause graft failure or estimated glomerular filtration rate <= 20 mL/min/1.73 m2 in a subcohort of 30% of recipients. Among 2,430 kidneys transplanted from 1,298 deceased donors, 585 (24%) were from donors with AKI. Over a median follow-up of 4.0 years, there were no significant differences in graft survival by donor AKI stage. We found no evidence that pre-specified variables modified the effect of donor AKI on graft survival. In the subcohort, donor AKI was not associated with the 3-year composite outcome. Donor AKI was not associated with graft failure in this well phenotyped cohort. Given the organ shortage, the transplant community should consider measures to increase utilization of kidneys from deceased donors with AKI. PMID- 30470439 TI - Cornelia de Lange syndrome: Ventricular size and function in six children without congenital heart defects. PMID- 30470440 TI - Atypical presentation of Reed syndrome. PMID- 30470441 TI - Erythematous nodule in a child. PMID- 30470442 TI - Prenatal diagnosis of congenital heart diseases in a tertiary hospital in two years. PMID- 30470443 TI - Acute thrombosis of the azygos vein and severe post-thrombotic syndrome of superior vena cava. PMID- 30470444 TI - Vertebral hemangiomatosis as atipic cause of acute myelopathy. PMID- 30470445 TI - Xanthomas and xantelasmas in primary biliary cholangitis. PMID- 30470446 TI - Accuracy of focused cardiac ultrasound performed by a non cardiologist resident. PMID- 30470447 TI - Hemicorporal paresthesias in a parvovirus infection. PMID- 30470448 TI - Self-reported physical activity in community-dwelling adults with diabetes and its association with diabetes complications. AB - AIMS: To describe the physical activity levels of an Australian community-based adult population with diabetes, and investigate the interaction between diabetes complications and physical activity. METHODS: Anthropometric, demographic, biochemical and self-reported physical activity measures (IPAQ) were performed. Associations and multiple regression analyses were undertaken between physical activity, known risk factors for diabetes complications, and history of cardiovascular disease (CVD), neuropathy and foot ulceration obtained from medical records. RESULTS: 240 participants were recruited (96% type 2 diabetes; age 68.7 +/- 10.5 y; 58% men; diabetes duration 14.3 +/- 11.4 y). Sixty seven percent of participants reported undertaking moderate or vigorous intensity exercise to recommended levels, and 29% reported no moderate-vigorous exercise. In addition to being associated with known demographic and biochemical risk factors and other complications, diabetes complications were also associated with different physical activity behaviours. Individuals with a history of CVD were more likely to participate in moderate-vigorous exercise and meet exercise guidelines, individuals with neuropathy undertook less walking and moderate intensity exercise, and those with a history of foot ulceration sat more and participated less in vigorous exercise. CONCLUSIONS: In Australian adults, the presence of diabetes complications may influence physical activity participation, and associate with characteristic physical activity approaches. PMID- 30470449 TI - [Anesthesia for surgical repair of the pentatology of Cantrell: case report]. AB - Pentalogy of Cantrell is a congenital anomaly associated with defects in the abdominal wall, sternum, diaphragm, and diaphragmatic pericardium formation, in addition to the development of cardiac abnormalities. It is a rare disease with an estimated incidence of one case for every 65,000 births, being more common in males (60% of cases). It has a reserved prognosis with mortality around 63%, and a maximum of 9 months survival after surgery. There are few case reports addressing the pentalogy of Cantrell, which is justified by the rarity of this pathology. In this report our objective was to describe a surgical case of a female patient and make some anesthetic considerations about this rare congenital malformation. PMID- 30470450 TI - Complex congenital heart disease with absent pulmonary arteries. PMID- 30470451 TI - A 2018 overview of diuretic resistance in heart failure. AB - Heart failure is a disease with high direct and indirect costs. Current treatment includes drugs that alter disease progression and drugs that to improve symptoms. Loop diuretics are the cornerstone of congestion relief for acute management, as well as for chronic stabilization. In heart failure patients, maximal diuretic response is reduced by many individual factors. Diuretic resistance is defined as failure to achieve effective congestion relief despite appropriate or escalating diuretic doses. Its causes include impaired delivery of the diuretic to its luminal site of action, neurohormonal activation, tubular compensatory adaptation and drug interactions. Several strategies can be employed to aid decongestion of patients with impaired diuretic response. These include salt restriction, a higher effective single dose or higher dose frequency of loop diuretics, continuous infusion of diuretics and/or sequential nephron blockade through a synergistic combination of two or more diuretics from different classes. Ultrafiltration has also been found to be another effective and safe therapeutic option and should be considered in patients with refractory diuretic resistance. Overall, there is a lack of high-quality clinical data to guide the choice of treatment strategy and therapy should be tailored on a case-by-case basis. PMID- 30470452 TI - Improving affinity of boronate capillary monolithic column for microextraction of glycoproteins with hydrophilic macromonomer. AB - A novel boronate affinity monolithic capillary was prepared by in-situ polymerization and successfully applied to microextraction (PMME) of glycoproteins. Using functional monomer 3-(acrylamido)phenylboronic acid (AAPBA) and hydrophilic macromonomer oligo (ethylene glycol) methyl ether methacrylate (OEG), crosslinking monomer ethylene glycol dimethacrylate (EDMA) and binary porogens of n-propanol and 1,4-butanediol, poly(AAPBA-co-OEG-co-EDMA) monolith was made with uniform structure and good column permeability. Systematic optimization of preparation conditions were performed, including AAPBA content, the molar ratio of AAPBA to OEG, crosslinking monomer content, n-propanol content in binary porogens. The optimized OEG boronic monolithic column was characterized with infrared absorption spectroscopy, field emission scanning electron microscopy and N2 adsorption experiment. In this study, extraction performance was tested by PMME of horseradish peroxidase (HRP) and ovalbumin (OVA). Compared with the corresponding OEG-free boronate monolith, the recovery of HRP and OVA was significantly improved to 97.51% and 93.97% (RSDs < 5.0%), respectively, which increased by 30.0%. Moreover, the newly developed monolith was further applied for extraction of HRP and OVA from the egg white samples with the recovery of 96.10% and 92.24% (RSDs < 7.5%), respectively. The results suggested that the introduction of hydrophilic macromonomer into boronic material is an effective method to improve the affinity of boronate affinity chromatography to glycoproteins. PMID- 30470453 TI - Ionic liquid-functionalized silica aerogel as coating for solid-phase microextraction. AB - To improve the extraction performance and mechanical property, a bipyridyl ionic liquid-hybridized silica aerogel was synthesized, and explored as the solid-phase microextraction (SPME) coating. Due to the embedding of the bipyridyl ionic liquid in silica aerogel via the covalent bond, the hybridized material not only provided the three-dimensional and porous structure of the aerogel, and it also possessed good extraction performance of the ionic liquid. Based on the pi-pi interaction between the aerogel and polycyclic aromatic hydrocarbons (PAHs), PAHs were selected as model analytes. The main parameters including extraction time, extraction temperature, ionic strength, stirring rate and desorption time were investigated and optimized, through coupling the SPME fiber with gas chromatography. Under the optimized conditions, the analysis method was established. The linear ranges of 0.015-20 and 0.03-30 MUg L-1 and the correlation coefficients of 0.9981-0.9998 were obtained. The limits of detection and the limits of quantification were 0.005-0.01 MUg L-1 and 0.015-0.03 MUg L-1, respectively. The method was applied to the detection of PAHs in aqueous solutions of cigarette gas and residual cigarette ash. All targets were detected and it could be known that there were more PAHs in cigarette gas than that in cigarette ash. PMID- 30470455 TI - Non-sulfated cholecystokinin-8 reduces meal size and prolongs the intermeal interval in male Sprague Dawley rats. AB - The current study measured seven feeding responses by non-sulfated cholecystokinin-8 (NS CCK-8) in freely fed adult male Sprague Dawley rats. The peptide (0, 0.5, 1, 3, 5 and 10 nmol/kg) was given intraperitoneally (ip) prior to the onset of the dark cycle, and first meal size (MS), second meal size, intermeal interval (IMI) length, satiety ratio (SR = IMI/MS), latency to first meal, duration of first meal, number of meals and 24-hour food intake were measured. We found that NS CCK-8 (0.5 and 1.0 nmol/kg) reduced MS, prolonged IMI length and increased SR during the dark cycle. Furthermore, the specific CCK-B receptor antagonist L365, 260 (1 mg/kg, ip) attenuated these responses. These results support a possible role for NS CCK-8 in regulating food intake. PMID- 30470454 TI - Gas chromatography-mass spectrometry with spiral large-volume injection for determination of fluoridated phosphonates produced by fluoride-mediated regeneration of nerve agent adduct in human serum. AB - A sensitive method for determination of fluoridated phosphonates produced by fluoride-mediated regeneration of nerve agent adduct in human serum was developed using gas chromatography-mass spectrometry (GCMS) with large-volume injection. The GC injection was administered using stomach-type spiral injector (LVI, AiSTI SCIENCE) enabling introduction of only target compounds from 50 MUL ethyl acetate extract after purging the solvent. For GCMS analysis of sarin (GB), 670 times higher sensitivity, based on limit of detection (LOD, S/N = 3, on extracted ion chromatogram (EIC) at m/z 99), was achieved using this injection (50 MUL) compared to that achieved using 1 MUL split injection (ratio 20:1). Ethyl (EtGB), isopropyl (GB), n-propyl (nPrGB), isobutyl (iBuGB), pinacolyl (GD), cyclohexyl (GF) methylphosphonofluoridates, and O-ethyl N, N-dimethylphosphoramidofluoridate (GAF) were detected with low LOD (15-75 pg/mL) and sharp peak shapes (high practical plate number (defined as 5.54 x (tR/Wh)2, where tR is the retention time and Wh is the bandwidth at half-height): 1100000-2400000) in GCMS using a polar separation column, electron ionization, and quadruple mass analyzer. During the analysis of fluoridated phosphonate-spiked ethyl acetate extract of solid phase extraction (SPE, Bond Elut NEXUS) from fluoride-mediated regeneration of blank human plasma, LOD (on EIC at m/z 99 except for GAF (m/z 126)) were 25-140 pg/mL with sharp peak shapes. The reaction recoveries in fluoride-mediated regeneration of plasma, which was inhibited by GB, GD, GA, GF, VX, and Russian VX (10 ng/mL), were 49-114% except for GD (10%). The concentration levels of 0.3-1 ng/mL of nerve agents in plasma could be determined. PMID- 30470456 TI - E-cigarette palatability in smokers as a function of flavorings, nicotine content and propylthiouracil (PROP) taster phenotype. AB - BACKGROUND: The popularity of E-cigarettes is due in part to their flavorings. The purpose of this study was to determine the effect on smokers' sensory perceptions and liking of various e-cigarette flavorings, and the degree to which those perceptions are influenced by nicotine level, sex, and PROP bitter taster phenotype. METHODS: We recruited 132 non-treatment-seeking, daily cigarette smokers. In repeated trials in one laboratory session participants vaped the Joyetech eGo-C e-cigarette with each of the following flavorings (in random order): unflavored, tobacco, cherry, chocolate, and menthol. Participants vaped the e-juice first without nicotine and then with high nicotine (18 mg/ml), and provided sensory (bitterness/sourness, irritation, sweetness) and liking ratings. Perceived intensity of 6-n-propylthiouracil (PROP) was used to classify the participants as non-tasters (n = 28), medium-tasters (n = 74), or supertasters (n = 28). Mixed-effects linear models and generalized estimating equations were used to evaluate ratings as a function of flavor interacting with nicotine content, sex and taster phenotype, adjusting for age, race/ethnicity, menthol use, and nicotine dependence. RESULTS: Regardless of nicotine level, cherry (beta = 1.76, p < .001) and chocolate (beta = 0.69, p < .001) were rated as sweeter, but were not better liked, than unflavored e-juice. Menthol elicited the highest liking rating, especially for women (beta = 12.23, p < .05) and supertasters (beta = 20.52, p < .05). Regardless of flavor, high nicotine was rated as more irritating (OR = 1.43, 95% CI = 1.02-2.01) than the no-nicotine e-juice. Irritation (beta = 13.65, p < .001), bitterness/sourness (beta = -11.38, p < .001), and sweetness (beta = 4.79, p < .001) were associated with liking. CONCLUSION: Menthol may enhance e-cigarette palatability for some smokers, which may increase e-cigarette utility in smoking cessation. PMID- 30470457 TI - [Analysis of the effect of a program of cognitive stimulation in elderly people with normal aging in primary care: Randomized clinical trial]. AB - OBJECTIVE: To provide evidence of the effectiveness of a community health intervention, that includes a cognitive stimulation program, to prevent the deterioration of cognitive abilities in our population of elderly people with normal cognition that are living in the community. DESIGN: Randomized clinical trial (CONSORT group norms) LOCATION: San Jose Norte-Centro Health Center and La Caridad Foundation (Zaragoza, Spain). PARTICIPANTS: 201 people aged 65 or older, with a MEC score of at least 28 points, which were randomized between the Intervention group (101) and the Control group (100). INTERVENTION: The intervention was applied in 10 sessions of 45minutes, one per week. It used materials designed by one of the authors, which addressed the following areas: memory, orientation, language, praxis, gnosis, calculation, perception, logical reasoning, attention-concentration and programming. MAIN MEASUREMENTS: The main outcome variables were MEC, Set-Test, Barthel and Lawton-Brody. RESULTS: Increases of the main result variables over their baseline level were analized. For MEC variable, the Intervention group obtained, on average, 1.58 points more than the Control group in the evaluation performed immediately after the intervention. After 6months, the improvement was 1.51 points and after a year, it was of 2.04 points. All these differences were statistically significant. For Set Test, Barthel and Lawton-Brody variables, no statistically significant differences were observed between Intervention group and Control group. CONCLUSIONS: Cognitive stimulation with our program is effective to maintain or improve cognitive performance, measured with the variable MEC, our population of elderly people with normal cognition that are living in the community. There is no evidence that this improvement is transferred to the activities of daily life measured with Barthel and Lawton-Brody variables. PMID- 30470458 TI - Alcohol-related seizures may be associated with more severe depression, alcohol dependence syndrome, and more pronounced alcohol-related problems. AB - Severe alcohol abuse and related medical and social functioning risks, as well as clinically significant depression, are common in patients who are admitted to hospital with alcohol-related seizures (ARS) and significantly affect the quality of life of the patient. Compared with studies involving patients with alcohol dependence, no large-scale studies with the aim of finding the prevalence and severity of depression and its most commonly affected aspects for patients with ARS have been carried out in Latvia yet. The habits and frequency of alcohol use in correlation to depression and its severity are also not known. One hundred ten patients were included in the study - 60 patients with ARS and 50 patients with alcohol use disorder (AUD) - without ARS. The research population consists mainly of working-age adults; however, most patients with ARS have significantly impaired daily activity and social life. Compared with patients who only have alcohol dependence, a more common problem in patients with ARS is having an alcohol dependence level that requires additional clinical examinations and consultations by a narcologist using the Alcohol Use Disorder Identification Test (AUDIT) scale, and this level is more often related to depression particularly characterized by pronounced suicidal thoughts (exhibited by almost 1 out of every 4 patients). According to the Hamilton Depression Rating Scale (HAM-D), depression has affected 81.7% of patients with ARS and 96% of patients with AUD. Seizures negatively affect patients' physical and emotional well-being in over 80% of cases; moreover, it is common for most patients to feel depressed after the seizures. Over half of the patients with ARS scored 20-40 points according to the AUDIT scale, indicating serious alcohol abuse disorder. Our research data can help bring awareness of the need to more carefully evaluate patients with ARS for an early detection of alcohol abuse disorder and depression with a risk of self harm and unintentional harm to others as well as to decrease the burden on social care and healthcare. This article is part of the Special Issue "Individualized Epilepsy Management: Medicines, Surgery and Beyond". PMID- 30470459 TI - 5-year oncological outcomes of targeted axillary sampling in pT1-2N1 breast cancer. AB - BACKGROUND: axillary lymph nodes dissection (ALND) has been a standard treatment in breast cancer with positive sentinel LNs. However, various short- and long term postoperative morbidities have been reported after conventional ALND. To define the concept of targeted axillary sampling (AS) and to assess its oncological feasibility for breast cancer. We compared the oncological outcomes in the axillary area between conventional ALND and targeted AS with or without radiotherapy. METHODS: One hundred and twenty-nine female patients with cT1-2N1 breast cancer underwent breast and axillary surgery. We defined the concept of targeted AS in clinical and pathological terms, and the oncological outcomes were compared between ALND and AS, and between AS with and without radiotherapy. RESULTS: There were no significant differences in oncological outcomes in the axilla between conventional ALND and AS, or between AS with radiotherapy and AS alone. CONCLUSIONS: The 5-year oncological outcomes of targeted AS were not inferior to those of conventional ALND, regardless of whether radiotherapy was added. PMID- 30470460 TI - Long-term prognosis after surgery for infective endocarditis: Distinction between predictors of early and late survival. AB - OBJECTIVES: Cardiac surgery is a life-saving procedure in patients diagnosed with infective endocarditis (IE). There are several validated risk scores developed to predict early-mortality; nevertheless, long-term survival has been less investigated. The aim of the present study is to analyze the impact of IE specific risk factors for early and long-term mortality. METHODS: An observational retrospective study was conducted that included all patients who underwent surgery for IE from 2002 to 2016. Median follow-up time after surgery was 53.2 months (IQI 26.2-106.8 months). In-hospital mortality was analyzed using multiple logistic regression. Long-term survival was analyzed after one, two and five years. Cox proportional hazards regression was employed to identify risk factors related to long-term mortality. RESULTS: Of the 180 patients underwent cardiac surgery, 133 were discharged alive (in-hospital mortality was 26.11%). 6 variables were identified as independent factors associated with in-hospital mortality, most of them closely related to the severity of IE: age, multivalvular involvement, critical preoperative status, preoperative mechanical ventilation, abscess and thrombocytopenia. Long-term survival in patients discharged alive was 89.1%, 87.4% and 77.6% after one, two and five years. Long-term mortality was independent of specific IE factors and 86.51% of deaths were not related to cardiovascular or infectious diseases. CONCLUSION: Despite the high perioperative mortality rate after surgical treatment for active IE, long-term survival after hospital discharge was acceptable, regardless of the severity of the endocarditis episode. Although in-hospital survival depended mainly on several IE factors, long-term survival was not related to the severity of endocarditis baseline affection. PMID- 30470462 TI - Echocardiography in myocardial perfusion and mechanics analysis after acute myocardial infarction - Old dog, new tricks. PMID- 30470461 TI - Vitamin D binding protein, but not vitamin D or vitamin D-related peptides, is associated with septic shock mortality. AB - BACKGROUND: The aim of this study was to assess the prognostic value of vitamin D, vitamin D binding protein (VDBP) and vitamin D-related peptides in septic shock patients in relation to hospital mortality. METHODS: This is a single center, prospective, observational study that included all consecutive patients meeting criteria for septic shock who were admitted to the ICU. VDBP, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, cathelicidin and beta-defensin levels were determined in blood samples obtained on admission to the ICU. RESULTS: Seventy five patients were studied. The best area under the curve (AUC) for prediction of in-hospital mortality was for VDBP (0.78), with a negative predictive value of 85.45% for the optimal cut-off point. VDBP was also the only variable that had a statistically significant association with a higher risk of in-hospital mortality, regardless of other assessed variables and pre-determined confounders: adjusted odds ratio of 5.20 (95% confidence interval: 1.21-22.36). When restricted to patients with vitamin D insufficiency (n=54), the AUC was 0.77, and the adjusted OR 12.22 (95% CI: 1.46-102.14; p=0.021) for in-hospital mortality. CONCLUSIONS: VDBP levels showed a statistically significant association with in hospital mortality, supporting the clinical utility of VDBP as a good prognostic marker in septic shock patients. Vitamin D and vitamin D-related peptides are not associated with in-hospital mortality. These results should be confirmed in a multicentre study with a larger sample size. PMID- 30470463 TI - You may stay forever young: An editorial regarding management of heart disease in pregnancy. PMID- 30470464 TI - Preparation of ionic liquids/montmorillonite composites and its application for diclofenac sodium removal. AB - Ionic liquid (IL) is an environment friendly organic solvent, which has a relatively low vapor pressure. This work focuses on adsorption of montmorillonite (Mt) to IL as well as removal of diclofenac sodium (DS), an anionic contaminant in water, by IL-modified Mt. The experiment shows absorption of DS increased by increasing IL dosage in modifying Mt. As a result, to modified Mt. with a concentration of IL of 200% cationic exchange capacity (CEC), its static absorption of modified Mt. to DS is 310 mmol/kg, with a rapid rate (reaching balance in 5 min). In dynamic column experiment, absorption of DS reaches balance after 24 h, which absorption amount is 2490 mmol/kg. It can be inferred that modification of IL change surface charge of Mt. and renders intercalation of DS into Mt. interlayers, thus increasing adsorption capacity to DS. These features could further expand the application of ILs and enable IL-modified Mt. to be used as inexpensive sorbents for the removal of chromate and other oxyanions from water. PMID- 30470465 TI - Postoperative Recovery After General and Regional Anesthesia in Patients Undergoing Day Surgery: A Mixed Methods Study. AB - PURPOSE: To investigate differences and describe experiences of postoperative recovery after day surgery between patients undergoing general anesthesia (GA) versus regional anesthesia (RA). DESIGN: A mixed methods design. METHODS: Day surgery patients (N = 401) were included. Postoperative recovery was assessed daily for 14 days using the Swedish Web Version of the Quality of Recovery questionnaire included in a mobile application. In addition, qualitative interviews were completed with 20 day surgery patients. Quantitative and qualitative data were first analyzed separately and then merged. FINDINGS: There were significant differences in Swedish Web Version of the Quality of Recovery between GA and RA on days 1 to 13 (P < .05). These findings could not be confirmed in the qualitative findings, except for psychological issues as well as tiredness and fatigue. Unexpected issues contributed to a greater extent to the theme not feeling well. Pain in the surgical wound was overall the biggest problem. CONCLUSIONS: There seems to be a poorer recovery after GA compared with RA. Tiredness or fatigue is present also after minor surgery in RA. Unexpected issues affect recovery negatively, and therefore should be addressed by health care. PMID- 30470466 TI - The Effect of Foot Massage on Postoperative Pain and Anxiety Levels in Laparoscopic Cholecystectomy Surgery: A Randomized Controlled Experimental Study. AB - PURPOSE: This study determined the effect of foot massage on postoperative pain and anxiety levels in patients undergoing laparoscopic cholecystectomy surgery. DESIGN: A randomized controlled trial. METHODS: This study was conducted in a general surgery clinic of a university hospital between May 2016 and March 2018. The research sample consisted of 167 patients (85 in the experimental group and 82 in the control group) who met the research inclusion criteria. FINDINGS: The pain intensity of patients in the experimental group was less than in the control group at 30, 60, 90, and 120 minutes after intervention (P < .05). A significant reduction was determined in the need for analgesics for the patients in the experimental group compared with the control group (P < .05). A significant positive relationship was found between pain intensity and state anxiety levels in patients of the experimental group. CONCLUSIONS: Foot massage decreased postoperative pain and anxiety levels in patients undergoing laparoscopic cholecystectomy surgery. PMID- 30470467 TI - The fitting accuracy of pre-bend reconstruction plates and their impact on the temporomandibular joint. AB - BACKGROUND: Various causes for bone defects of the lower jaw have been described. As a result, patients often suffer from compromised aesthetics and a loss of, or reduction in, important physiological functions, such as swallowing, breathing, and speaking. A change in the shape of the lower jaw can impair the natural occlusion and leads to an atypical or modified position of the temporomandibular joint. Titanium reconstruction plates are the standard approach to jaw reconstruction, and are used for temporary bridging of a jaw defect or fixation of a bone graft. Conventionally these plates are intraoperatively adjusted to the mandible by the surgeon. Computer-aided manufacturing, computer-aided design, and rapid prototyping have gained increasing importance in the field of medicine, as they allow the production of individual models of the lower jaw, with the possibility of preoperatively bending the reconstruction plates. In this retrospective study, the accuracy of pre-bent titanium plates and their effect on the temporomandibular joint situation in comparison with intraoperatively curved plates will be discussed. MATERIALS AND METHODS: Patients who attended our department for lower jaw reconstruction between March 2013 and February 2015 were included in this retrospective study. Within that time 20 patients were treated with pre-bent reconstruction plates (group 1). 20 comparable patients were selected with reconstruction and conventional intraoperative bending (group 2). To evaluate the accuracy of the plates and the condylar position, postoperative cone beam computed tomograms and computed tomograms were used to assess the bone plate distance at 12 defined points and four angles in axial reconstruction. The results were compared, statistically evaluated, and discussed. RESULTS: Regarding the maximum bone-plate distances and the sum of distances, there was a significant difference between the accuracy of the pre-bent and the conventionally bent reconstruction plates (p = 0.022, p = 0.048). Regarding the condylar position, there was no significant difference between both methods (p = 0.867). CONCLUSION: The results of this study show that a better fitting accuracy can be achieved using pre-bent plates. Preparation of the plates proves to be advantageous and meaningful, especially in complex bone defects and deformations of the lower jaw. Nevertheless, concerning the position of the temporomandibular joint, no significant difference could be ascertained between the shown methods, contradicting several studies. PMID- 30470468 TI - Contribution of cone-beam computed tomography in the decision of surgical management for bone lesions of the maxillofacial region. AB - The aim of this study was to evaluate the contribution of cone-beam computed tomography (CBCT) in the decision of surgical management for bone lesions of the maxillofacial region. It is a retrospective cross-sectional observational study that includes a sample of panoramic radiography (PR) and CBCT from patients with some type of bone lesion in the maxillofacial region. PR and CBCT images were evaluated by three previously assessed examiners, specialists in oral and maxillofacial surgery. Each image was evaluated randomly, and a surgical procedure was suggested, initially in PR and then in CBCT. The obtained results were submitted to the McNemar test to evaluate the frequencies of changes in the surgical management between the first and the second evaluation in PR and CBCT, and intra-examiner and inter-examiner agreements were analyzed by the Cohen's kappa test. The level of significance was set at 5% (p < 0.05). Intra-examiner agreement increases when CBCT is used. Inter-examiner agreement was low, independently of the evaluated exam, which shows that the choice of treatment plan is examiner-dependent and not exam-dependent. CBCT increases the certainty of the professional in the evaluation of the bone lesions of the maxillofacial region; however, it does not change the indication of the treatment type. PMID- 30470469 TI - Plasma metabolites in first episode psychoses. PMID- 30470471 TI - Use of short acting reversible contraception in adolescents: The pill, patch, ring and emergency contraception. AB - Long acting reversible contraception (LARC) is the recommend form of birth control for adolescents by both the American Academy of Pediatrics and the American Congress of Obstetrics and Gynecology, but the majority of adolescents continue to use short acting reversible contraception (SARC) such as the oral contraceptive pill, vaginal ring, and transdermal patch. For this reason, it is important for medical providers to be familiar with how to prescribe and manage SARC in adolescents, paying particular attention to which patients are eligible to use them, which benefits the methods have outside of contraception, what side effects to be aware of, and special considerations for adolescents. Many adolescents will choose not to use any form of hormonal contraception-thus having a knowledge about and comfort with use of emergency contraception is of equal importance. PMID- 30470470 TI - Occupational risk for personnel working in veterinary clinics through exposure to vectors of rickettsial pathogens. AB - Workers at veterinary clinics are exposed to zoonotic pathogens, which, though infrequently, can lead to serious consequences. The aim of the present study was to estimate the seroprevalence for rickettsial pathogens in veterinary clinic personnel in Ciudad Juarez, Chihuahua, Mexico. Voluntary participants included 106 veterinarians, 19 pet groomers, 36 veterinary assistants and 6 administrative workers who supplied blood samples taken by venipuncture. Detection of Rickettsia rickettsii, Ehrlichia spp. and Anaplasma phagocytophilum was conducted by indirect immunofluorescence assay (IFA) and polymerase chain reaction (PCR) techniques. To determine risk factors for the seroprevalence, the study considered social, demographic and occupational variables as well as the clinical signs and symptoms of the participants. Logistic regression procedures were performed, and the odds ratio (OR) was calculated with confidence intervals corresponding to a probability of 95%. The results indicate that 54% of the participants had a positive seroreaction to at least one of the pathogens evaluated and 2% were positive to all. The coexposure was as follows: 3% to R. rickettsii and A. phagocytophilum, 9% to Ehrlichia spp. and A. phagocytophilum, and 2% to Ehrlichia spp. and R. rickettsii. It was established that grooming posed the highest risk for R. rickettsii exposure. The implementation of appropriate management practices for zoonotic diseases is recommended to avoid health problems that may be life threatening to personnel in veterinary clinics. PMID- 30470472 TI - Reply: Perioperative use of cefazolin without preliminary skin testing in patients with reported penicillin allergy. PMID- 30470473 TI - Pleural dissemination of cholangiocarcinoma caused by percutaneous transhepatic biliary drainage during the management of resectable cholangiocarcinoma. AB - BACKGROUND: Only 3 case reports have addressed pleural dissemination in association with percutaneous transhepatic biliary drainage. The aim of this study was to investigate recurrence after resection of cholangiocarcinoma after percutaneous transhepatic biliary drainage and to clarify the incidence of and the factors responsible for pleural dissemination. METHODS: Between 2001 and 2015, we reviewed retrospectively all consecutive patients who underwent resection for perihilar or distal cholangiocarcinoma after percutaneous transhepatic biliary drainage for recurrence, including pleural dissemination. RESULTS: During the study period, all consecutive patients underwent resection of cholangiocarcinoma after management with percutaneous transhepatic biliary drainage. Of these, 100 patients (32.1%) underwent left-sided percutaneous transhepatic biliary drainage alone, and 212 (67.9%) underwent right-sided percutaneous transhepatic biliary drainage with or without left-sided percutaneous transhepatic biliary drainage. Pleural dissemination, which developed exclusively on the right side of the thoracic cavity after resection, was found in 12 patients (3.8%); these patients underwent right-sided percutaneous transhepatic biliary drainage; computed tomography demonstrated that the percutaneous transhepatic biliary drainage catheter passed through the thoracic cavity in all 12 patients. The diagnosis of pleural dissemination was made at a median of 381 days (range, 44 to 2,944 days) after operation. Survival was poor, with a median survival time of 516 days. Statistically, right-sided percutaneous transhepatic biliary drainage was identified as a risk factor for pleural dissemination. CONCLUSION: Pleural dissemination after right-sided percutaneous transhepatic biliary drainage is likely a procedure-related iatrogenic complication because of the "special route" by which the percutaneous transhepatic biliary drainage catheter must be passed through the right thoracic cavity. PMID- 30470474 TI - Tracheal synechia visualized in flexible fibrobronchoscopy in induction of anesthesia for thoracic surgery. PMID- 30470475 TI - Interest and challenges of pharmacoepidemiology for the study of drugs used in diabetes. AB - In the field of diabetes, pharmacoepidemiologic (PE) studies are numerous and represent an essential tool to assess the real life effects of diabetes drugs. However, the specificity of the study of drugs used in diabetes, characterized by a high frequency of switches, interruptions and add-on, must be kept in mind by pharmacoepidemiologists in order to perform well-conducted studies and avoid several biases. In this article, the authors discussed the specific interest of PE studies in the field of diabetes, provide a brief overview of biases that can affect those studies, and suggest pragmatic solutions for more correct results and appropriate interpretation. PMID- 30470476 TI - The systematic case-referent method. AB - The systematic case-referent method is a special case-referent design originally developed for pharmacoepidemiologic research purposes. It consists in the systematic collection of series of incident cases of various disorders and the assembling of a general reference pool, from which "controls" are secondarily selected to be matched to specific cases. Both series are collected independently from each other and with no a priori hypothesis to be investigated. The reference pool can be either general or limited to a subpopulation, representative of the source population of the cases. Based on clinical recruitment of cases and referents, the design allows a very high specificity of diagnosis and documentation of clinical variables. All cases and referents are systematically documented on all treatments received before the incidence of the cases or before identification of referents. This documentation is done preferentially using objective sources assembled independently (linkage to claims data, medical records, pharmacy records, prescription records, hospital discharge letters). It can be completed with patients' interviews using standardised research tools, in particular for over-the-counter drug use and self-medication, and for the documentation of adherence to treatment and specific time-windows of exposure. Likewise, all cases and all referents are systematically documented on a series of risk factors, which are common to most epidemiological studies and are not hypothesis-dependent. Whenever the documentation of a confounding factor specific to the disease at hand is necessary, additional questionnaires can be applied to all or a sample of patients. The method has been successfully implemented for the pharmacoepidemiologic study of myocardial infarction, stroke, lupus, multiple sclerosis, rheumatoid arthritis, Guillain Barre syndrome, idiopathic thrombocytopenic purpura, type 1 diabetes mellitus, suicide attempts, breast cancer, and other disorders, for the analysis of the risk or preventing action of NSAIDs, statins, antiplatelet agents, anticoagulants, insulins, vaccines and other drugs. PMID- 30470477 TI - Clinical added value of drugs: An empirical survey of French transparency committee opinions. AB - OBJECTIVES: To identify criteria used by French health authorities to assess the clinical added value (ASMR) of drugs seeking reimbursement. METHODS: We conducted a systematic review of the opinions of the transparency committee (TC) of the French national authority for health (HAS) between March, 2014 and October, 2016 in ten therapeutic areas. TC opinions content was coded and analysed using descriptive statistics and logistic models. RESULTS: The database comprised 160 opinion texts, which included ASMR assessments using a 5 level scale (1=highest ASMR 5=no ASMR). Main elements that were linked with ASMR 1,2,3,4 as compared to ASMR 5 were appraisal of the medical need, population size (<5000 patients), and clinical relevance of the evaluated results. The factors associated with ASMR 4 as compared to ASMR 1-3 were the safety profile and clinical relevance of the results. However, the factors associated with ASMR level varied according to the therapeutic area considered. CONCLUSIONS: The assessment of the drug ASMR conducted by the French transparency commission of the HAS appears to be at least in part determined by criteria (medical need, population size) which reflect the burden of the disease but not reflect the ASMR of the medicine assessed. Other criteria used for the assessment of ASMR are not clearly defined and depend on the therapeutic domain. The lack of sufficient clarity and consistency in assessment of ASMR complicate the decision making process for drug development. Moreover, this situation can be a barrier for a harmonized process of ASMR assessment at European level. PMID- 30470478 TI - Developing a systematic search strategy related to people with disability: A brief report testing the utility of proposed disability search terms in a search about opioid use. AB - BACKGROUND: The varied use of the term "disability" in the scientific literature makes it challenging to conduct systematic reviews of health issues among people with disability. Utilizing general disability search terms has been suggested as an efficient way to ensure a broad capture of the literature related to disability. OBJECTIVES: This study evaluates the utility of general disability terms versus condition-specific terms, in the context of systematically searching for articles related to disability and other conditions or issues, in this case, opioid use. METHODS: Systematic searches were conducted using three databases. An initial search of articles mentioning opioids and disability was conducted employing the general search terms recommended by Walsh et al.1 The results were then compared to 16 condition-specific searches. The proportion of unique articles from each condition-specific search that overlapped with the general search was assessed. RESULTS: There was very little overlap between the articles captured using condition-specific search terms and the articles captured utilizing the general search terms. The highest amount of overlap was for spinal muscular atrophy at 33.3%, with the overall median proportion of overlap being 13.4% (mean = 15.7%; SD = 11.7%). CONCLUSIONS: With a systematic search for articles about disability associated with opioid use as an example, condition specific search terms capture a large proportion of articles not identified using general disability search terms. Disability researchers should be aware of pitfalls using general terminology and the importance of using disability specific search terms. PMID- 30470479 TI - Critical role of platelets in the production of thymus and activation-regulated chemokine in children: A case series study. PMID- 30470480 TI - Only in the darkness can you see the stars: Severe alcoholic hepatitis and higher grades of acute-on-chronic liver failure. PMID- 30470481 TI - Reply to: "Over-gap PCR amplification to identify presence of replication competent HBV DNA from integrated HBV DNA: An updated occult HBV infection definition". PMID- 30470482 TI - Response to critique of article "Calibration of Safecast dose rate measurements". PMID- 30470483 TI - Comments regarding "Calibration of Safecast dose rate measurements" by Cervone and Hultquist. PMID- 30470484 TI - Impact of amoxicillin and oral amoxicillin-clavulanic acid defined daily doses on consumption indicators. AB - OBJECTIVE: To measure the impact of the differences between recommended daily average maintenance doses and defined daily doses on antimicrobial consumption indicators (amoxicillin+amoxicillin-clavulanic acid). MATERIAL AND METHODS: We calculated the impact of the antibacterial agent switch or de-escalation and reviewed the consumption indicators of our French hospital with defined daily doses (DDD) of 3g. We also applied these DDDs to French and European community setting indicators in private practice. RESULTS: We observed a modification in trend consumption indicators over a 10-year period: indicator stability for our hospital (-0.32% versus +5.45%), decrease for French community indicators (-9.9% versus +6.7%). The recalculated 2015 data for European community indicators showed France as the 9th largest European consumer (versus 4th position before). CONCLUSION: DDDs must be modified to have appropriate indicators to evaluate antimicrobial stewardship programs and to penalize prescriptions favoring the emergence of resistant pathogens. PMID- 30470485 TI - Dissecting the Genetics of Osteoporosis using Systems Approaches. AB - Osteoporosis is a condition characterized by low bone mineral density (BMD) and an increased risk of fracture. Traits contributing to osteoporotic fracture are highly heritable, indicating that a comprehensive understanding of bone requires a thorough understanding of the genetic basis of bone traits. Towards this goal, genome-wide association studies (GWASs) have identified over 500 loci associated with bone traits. However, few of the responsible genes have been identified, and little is known of how these genes work together to influence systems-level bone function. In this review, we describe how systems genetics approaches can be used to fill these knowledge gaps. PMID- 30470486 TI - Solving the Polyploid Mystery in Health and Disease. AB - Polyploidy (the more than doubling of a cell's genome) frequently arises during organogenesis, tissue repair, and age-associated diseases. Despite its prevalence, major gaps exist in how polyploid cells emerge and affect tissue function. Studies have begun to elucidate the signals required for polyploid cell growth as well as the advantages and disadvantages of polyploidy in health and disease. This review highlights the recent advances on the role and regulation of polyploidy in Drosophila and vertebrate models. The newly discovered versatility of polyploid cells has the potential to provide alternative strategies to promote tissue growth and repair, while limiting disease and dysfunction. PMID- 30470488 TI - Central retinal thickness assessment in a real life setting after cataract surgery in diabetic patients. AB - PURPOSE: To assess in a real life setting the progression of central retinal thickness (CRT) during the first month after surgery in diabetic patients without previous diabetic macular edema (DME) and to identify potential risk factors for DME leading to increased postoperative follow-up. METHODS: We conducted a prospective study of diabetic patients without history of DME who underwent uncomplicated cataract surgery. Best-corrected visual acuity (BCVA) and SD-OCT were performed 7 days and 1 month after surgery. We assumed absence of preoperative DME when there was no edema of SD-OCT at D7. Our primary endpoint was the central retinal thickness (CRT) variation between 7 days and 1 month after cataract surgery in patients without previous history of DME. RESULTS: We included 55 eyes of 42 patients. BCVA was 0.57+/-0.72 logMar (20/80) prior to surgery and increased significantly to 0.11+/-0.17 (20/25) at one month (P=0.001) post-surgery. The mean baseline CRT was 209+/-35MUm and 229+/-69MUm (P=0.06) one month after surgery. Four eyes (7.4%) developed macular edema at one month. We found no linear correlation between HbA1C and CRT. DISCUSSION/CONCLUSION: We found no link between a high level of HbA1C and postoperative increase in CRT. We found that cataract surgery in diabetic patients without previous DME has no negative impact on CRT, and visual outcomes are good. We suggest that in diabetic patients without complete visual recovery at 1-month post-cataract surgery, OCT examination should be performed in order to detect an early stage of DME. PMID- 30470487 TI - [Evaluation of intravitreal injection practice patterns in Cotonou]. AB - INTRODUCTION: Intravitreal injections of medication are designed to obtain a high concentration in the posterior segment. We conducted a retrospective study of our practice of intravitreal injections to assess safety of the technique and short- and medium-term tolerability, and to analyze indications and the complications. PATIENTS AND METHODS: This analytic retrospective study focused on consecutive patients treated with intravitreal injections for the period of January 2015 to June 2016 in the "Lumiere" ohthalmology clinic in Cotonou, with incidents or accidents during the injection procedure as a measure of safety. Included were all patients undergoing one or more intravitreal injections regardless of the type of product injected, who had undergone a complete ophthalmologic work-up prior to injection and who had been followed at one week (W1) and 1 month (M1) after treatment. RESULTS: During the study period, we safely performed 124 intravitreal injections on 49 patients. The indications were diabetic macular edema in 53.06% and macular edema due to vein occlusions in 26.53%. The main complication observed was ocular hypertension in 60%, mainly related to triamcinolone injection. In 51.02%, the drug used was Ranibizumab, followed by Bevacizumab in 28.54% and Triamcinolone in 20.40%. DISCUSSION: The main goal of intravitreal injection is to achieve instantly effective concentrations in the center of the globe. Intravitreal injection is a safe, feasible practice in our context. The male predominance observed in our series is explained by the low socio-economic status of women in our context as well as the economically difficult accessibility of important drugs such as anti-VEGF. Significant improvements in D7 and D30 visual acuity in our patients highlights the beneficial effects of the presence of the active molecule in the vitreous cavity for these indications. CONCLUSION: Intravitreal injection is a common practice in our context, which is being performed safely. The indications are many, and ocular hypertension is a significant complication. The difficulties in terms of supply and preservation of the main drugs used (anti-VEGF) remains to be resolved. PMID- 30470489 TI - Combined hamartoma of the retina and retinal pigment epithelium with intense pigmentation of the inner retinal layers. PMID- 30470490 TI - Synthesis and biological evaluation of clovamide analogues with catechol functionality as potent Parkinson's disease agents in vitro and in vivo. PMID- 30470491 TI - Discovery of novel pyruvate dehydrogenase kinases inhibitors by screening of an in-house small molecule library for anti-lung cancer therapeutics. AB - Pyruvate dehydrogenase kinases (PDKs) are widely over-expressed in various human solid cancers, making them attractive therapeutic targets for cancer treatment. Herein, we report the identification of structurally novel PDKs inhibitors by screening of an in-house small molecule library. Biochemical assay indicated that the identified compounds 1-4 inhibited PDK1 activity with EC50 values of 0.50, 1.99, 4.64, and 0.42 uM, respectively. The ITC analysis suggested that the identified compounds 1-4 were pan-isoform PDK inhibitors, which bound to and inhibited the four PDK isoforms. Moreover, 1-4 dose-dependently reduced pyruvate dehydrogenase complex phosphorylation in NCI-H1975 cell. Molecular docking suggested that the most potent compound 4 docked well in the ATP binding pocket of the four PDK isoforms, forming direct hydrogen bond interactions with the conserved amino acids Thr and Asp in ATP binding pocket of PDKs. The cell viability assay demonstrated that 4 potently blocked NCI-H1975 cell proliferation (IC50 = 3.32 uM), but had little effect on human normal lung cell MRC-5 even with the tested concentration up to 40 uM. All the data demonstrated that 4 was a promising lead for the development of structurally novel PDKs inhibitor for the cancer treatment. PMID- 30470492 TI - Resorcinol alkyl glucosides as potent tyrosinase inhibitors. AB - Resorcinol alkyl glucosides 7-12 were developed as novel tyrosinase inhibitors based on the structure of rhododendrin. These were synthesized from 2,4 dibenzyloxybenzaldehyde using either the Wittig or the Horner-Wadsworth-Emmons reaction with Koenigs-Knorr glycosylation as key steps. The tyrosinase inhibitory activity of 7-12 increased with the length of the alkyl spacer between resorcinol and glucose. The 50% inhibitory concentration (IC50) of tetradecyl derivative 12 was 0.39 MUM, making it the most potent of the compounds synthesized. The IC50 of 8 (3.62 MUM) with a propyl spacer was ca 10 times that of 7 (35.9 MUM) with an ethyl spacer. This significant activity difference suggests that an interaction between resorcinol alkyl glucoside and tyrosinase may increase remarkably if the length of the alkyl spacer exceeds C3. PMID- 30470493 TI - Corrigendum to "Eupatilin inhibits angiogenesis-mediated human hepatocellular metastasis by reducing MMP-2 and VEGF signaling" [Bioorg. Med. Chem. Lett. 28(19) (2018) 3150-3154]. PMID- 30470494 TI - On the origin of the 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate scaffold's unique group II selectivity for the mGlu receptors. AB - Analogs based on the 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate scaffold showed high potency and selectivity as both group II mGlu receptors orthosteric agonists and antagonists. This scaffold was initially designed to mimic the fully extended glutamate backbone conformation that was hypothesized to be the active conformation for the group II mGlu receptors. With the availability of crystal structures of l-Glu-bound amino terminal domain proteins from multiple mGlu receptor subtypes spanning all three subgroups, a new steric hindrance hypothesis was proposed to account for the scaffold's unique group II selectivity that explores the subtle distance differences between the alpha-carbon of l-Glu and the center of the tyrosine phenyl ring from the bottom lobe (e.g. Y216 of mGlu2). PMID- 30470495 TI - A carbapenem-based fluorescence assay for the screening of metallo-beta-lactamase inhibitors. AB - Reported herein is a fluorescence assay for the rapid screening of metallo-beta lactamase (MBL) inhibitors. This assay employs a fluorogenic carbapenem CPC-1 as substrate and is compatible with all MBLs, including B1, B2 and B3 subclass MBLs. The efficiency of this assay was demonstrated by the rapid inhibition screening of a number of molecules against B2 MBL CphA and 2,3-dimercaprol was identified as a potent CphA inhibitor. PMID- 30470496 TI - Antibiotic-Induced Dysbiosis of Gut Microbiota Impairs Corneal Nerve Regeneration by Affecting CCR2-Negative Macrophage Distribution. AB - Although antibiotics are useful, they can also bring negative effects. We found that antibiotic-treated mice exhibit an alteration in the gene expression profile of corneal tissues and a decrease in corneal nerve density. During corneal wound healing, antibiotic treatment was found to impair corneal nerve regeneration, an effect that could be largely reversed by reconstitution of the gut microbiota via fecal transplant. Furthermore, CCR2- corneal macrophages were found to participate in the repair of damaged corneal nerves, and a decrease in CCR2- corneal macrophages in antibiotic-treated mice, which could be reversed by fecal transplant, was observed. Adoptive transfer of CCR2- corneal macrophages promoted corneal nerve regeneration in antibiotic-treated mice. The application of probiotics after administration of antibiotics also restored the proportion of CCR2- corneal macrophages and increased the regeneration of corneal nerve fibers after epithelial abrasion. These results suggest that dysbiosis of the gut microbiota induced by antibiotic treatment impairs corneal nerve regeneration by affecting CCR2- macrophage distribution in the cornea. This study also indicates the potential of probiotics as a therapeutic strategy for promoting the regeneration of damaged corneal nerve fibers when the gut microbiota is in dysbiosis. PMID- 30470497 TI - Pharmacology of medications used for ovarian stimulation. AB - Medications to stimulate the ovaries may be used to induce ovulation in patients with anovulatory infertility or to hyperstimulate the ovaries in a controlled fashion in ovulatory patients as part of assisted reproductive treatments (ART). The pharmacology of all current major medications used to stimulate ovarian function is reviewed in this article, including letrozole, clomiphene citrate, gonadotropins, and pulsatile gonadotropin releasing hormone (GnRH). Novel potential compounds and adjuvant treatment approaches are also discussed, such as kisspeptin agonists and androgens. PMID- 30470498 TI - Crazy'App: A web survey on representations and attitudes toward mental disorders using video testimonies. AB - : In the international context of efforts to combat the stigmatization of people with mental health problems, representations and attitudes about these illnesses have not to date been widely investigated in France. However, new technologies offer an unprecedented opportunity to collect such information on a large scale and to deploy more efficient action against stigma. OBJECTIVES: The Crazy'App survey was designed as an instrument for studying potentially stigmatizing representations and attitudes towards mental disorders. It asks respondents to react, rather than to standard diagnostic labels or case vignettes, to video testimonies by people with different mental disorders talking about their experiences. METHODS: The web survey was made available on smartphone or computer and advertised on various media and during a French exhibition about mental disorders, mental health and well-being ("Mental Desordre", Cite des sciences, Paris, 2016). It consisted of short (<2min) video testimonials by four people presenting respectively anorexia, bipolar disorder, obsessive-compulsive disorder and addiction to alcohol. Each testimony was immediately followed by series of questions to which participants were to respond using visual analog scales. The questionnaires investigated different domains, such as the causes of each of these mental disorders, the possible treatments and the respondent's personal attitudes in hypothetical situations (e.g. working with the person seen in the video). After having completed the survey, respondents were offered an opportunity to compare their own responses to those of the other respondents, and watch expert psychiatrists interviews delivering clinical and scientific knowledge and sharing their own attitudes. RESULTS: The respondents (n=2600) were young, mostly women, educated and concerned about the subject. They exhibited good knowledge of the disorders. They reported a multi-causal view of the etiologies, where psychological causes were rated higher than neurobiological causes (although less so for respondents reporting having had a mental disorder themselves), while other types of causes (environmental, spiritual, and nutritional) received much lower ratings. Respondents also expressed high potential social proximity, but this result varied according to the type of disorder, in particular, the social distance and the perception of dangerousness were greater for addiction and bipolar disorder. CONCLUSIONS: Crazy'App operationalizes emerging strategies in the efforts to combat stigma, implementing what is known as a "contact based intervention" in English-speaking countries. While it does not erase the differences in attitudes observed from one pathology to another, this type of survey-intervention based on video testimonies could help to reduce the desire for social distancing from people with mental disorders, even in a particularly sensitized and informed population. Multimedia technologies are an efficient way to offer rich, potentially interactive content better able to embody people and their actual experiences than clinical descriptions or even life narratives. However the use of videos could put the focus on the individual characteristics (physical, gestural, verbal, nonverbal...), and this should be cautiously taken into account according to the anti-stigma objectives. Connected technologies also make it possible to enhance the more classic de-stigmatization actions focused on the deconstruction of preconceived ideas, making the action more participatory, while simultaneously assessing their efficacy. By mediating contact with individuals and behaviors perceived as deviant, the aim would be to develop psycho-social skills and concrete abilities for action in the general population, to include people with mental disorders in the community. PMID- 30470499 TI - [Child psychiatry interventions in patients with 22q11 deletion syndrome: From treatment to prevention]. AB - 22q11.2DS is one of the more frequent genetic syndromes associated to psychiatric symptoms. It has been associated to an increased risk to develop schizophrenia in adolescence or early adulthood. However, psychiatric symptoms appear early on, and should be recognized as soon as possible by child psychiatrists in order to improve the present well-being of children and their family, and to prevent further risks of developing severe and chronic psychiatric diseases later on. In this paper, we present a review of the recent literature concerning the 22q11.2DS syndrome focused on the risk factors that may be associated to an increased risk of psychotic transition. We advocate for the development of systematic specialized child psychiatry consultations for these patients, included in networks with geneticists, adult psychiatrists, and family associations, in order to improve their psychiatric prognosis and to support the development of translational research. PMID- 30470500 TI - Psychometric properties of the French Version of the Social Responsiveness Scale in autism spectrum disorder with or without attention deficit hyperactivity disorder. AB - OBJECTIVES: The Social Responsiveness Scale (SRS) is an instrument that is commonly used to screen for Autism Spectrum Disorder (ASD). Attention Deficit Hyperactive Disorder (ADHD) frequently occurs with ASD and both disorders share some phenotypic similarities. In the present study, we aimed to determine the psychometric properties of the French version of the Social Responsiveness Scale (SRS) and its 5 subscales (social awareness, social cognition, social communication, social motivation, and autistic mannerisms) to discriminate between children with ADHD and those with ASD (differential diagnosis) and children with ADHD from those with a dual diagnosis of ADHD and ASD (comorbid diagnosis). METHOD: SRS total scores and the 5 subscores of the SRS were compared between 4 groups of children: ADHD (n=32), ASD+ADHD (n=30), ASD (n=31) and typical neurodevelopment (TD; n=30) children. The discriminant validity was estimated using the Area Under the ROC Curves (AUC). RESULTS: SRS Social cognition (AUC=0.73) and Autistic mannerisms (AUC=0.70) subscores were the most discriminating for differential diagnosis of ASD and ADHD. SRS total scores (AUC=0.70), and Social communication (AUC=0.66) and Autistic mannerisms (AUC=0.75) subscores were the most discriminating for comorbid diagnosis of ASD among ADHD children. CONCLUSION: The SRS autistic mannerisms subscore was found to be clinically relevant for both differential diagnosis of ASD and ADHD and comorbid diagnoses of ASD among ADHD children but with a modest discriminant power. PMID- 30470501 TI - [Changes in the number of suicide attempts in the NPC region since the start of VigilanS: First estimates]. AB - BACKGROUND: The implementation of a surveillance program after a suicide attempt (SA) is a very innovative step in the evolution of our system of care. It was interesting to know if we observe a decline in suicide attempts in the region, in particular of recurrences of SA. METHOD: We measured the evolution of the number of suicide attempts before and after implantation of VigilanS, using two types of analysis: a first from the national medical information systems in Medicine Surgery-Obstetrics (PMSI-MCO) and a second from the collection of the ER stays for SA in the hospitals involved in the VigilanS program. RESULTS: In 2014 (year before start of VigilanS), a total of 10 119 ER stays for SA was observed (5626 women and4463 men); in 2017, the total was 9.230 stays for SA (5047 women and 3 839 men), representing a decrease of 13.5%. The reduction was balanced between men (-14%) and women (-10%). Based on the figures of PMSI, we see an acceleration of the reduction of stay for SA in the Nord-Pas-de-Calais after 2014 (-16% instead of -6%), instead of the two Picardy departments the most comparable which show a degradation of the phenomenon (+13%), and opposed to the Department of the Oise which shows a stable maintenance of the current decline (-12%). CONCLUSION: These two indicators are imperfect, but evolution over three years since the implementation of VigilanS goes in the same direction. We find a uncoupling of a hospital stay in connection with a SA. The intensity of this decline seems correlated to the penetrance of the program. PMID- 30470503 TI - Exclusive MRI-targeted biopsy: not so fast. PMID- 30470502 TI - Use of prostate systematic and targeted biopsy on the basis of multiparametric MRI in biopsy-naive patients (MRI-FIRST): a prospective, multicentre, paired diagnostic study. AB - BACKGROUND: Whether multiparametric MRI improves the detection of clinically significant prostate cancer and avoids the need for systematic biopsy in biopsy naive patients remains controversial. We aimed to investigate whether using this approach before biopsy would improve detection of clinically significant prostate cancer in biopsy-naive patients. METHODS: In this prospective, multicentre, paired diagnostic study, done at 16 centres in France, we enrolled patients aged 18-75 years with prostate-specific antigen concentrations of 20 ng/mL or less, and with stage T2c or lower prostate cancer. Eligible patients had been referred for prostate multiparametric MRI before a first set of prostate biopsies, with a planned interval of less than 3 months between MRI and biopsies. An operator masked to multiparametric MRI results did a systematic biopsy by obtaining 12 systematic cores and up to two cores targeting hypoechoic lesions. In the same patient, another operator targeted up to two lesions seen on MRI with a Likert score of 3 or higher (three cores per lesion) using targeted biopsy based on multiparametric MRI findings. Patients with negative multiparametric MRI (Likert score <=2) had systematic biopsy only. The primary outcome was the detection of clinically significant prostate cancer of International Society of Urological Pathology grade group 2 or higher (csPCa-A), analysed in all patients who received both systematic and targeted biopsies and whose results from both were available for pathological central review, including patients who had protocol deviations. This study is registered with ClinicalTrials.gov, number NCT02485379, and is closed to new participants. FINDINGS: Between July 15, 2015, and Aug 11, 2016, we enrolled 275 patients. 24 (9%) were excluded from the analysis. 53 (21%) of 251 analysed patients had negative (Likert <=2) multiparametric MRI. csPCa-A was detected in 94 (37%) of 251 patients. 13 (14%) of these 94 patients were diagnosed by systematic biopsy only, 19 (20%) by targeted biopsy only, and 62 (66%) by both techniques. Detection of csPCa-A by systematic biopsy (29.9%, 95% CI 24.3-36.0) and targeted biopsy (32.3%, 26.5-38.4) did not differ significantly (p=0.38). csPCa-A would have been missed in 5.2% (95% CI 2.8-8.7) of patients had systematic biopsy not been done, and in 7.6% (4.6-11.6) of patients had targeted biopsy not been done. Four grade 3 post-biopsy adverse events were reported (3 cases of prostatitis, and 1 case of urinary retention with haematuria). INTERPRETATION: There was no difference between systematic biopsy and targeted biopsy in the detection of ISUP grade group 2 or higher prostate cancer; however, this detection was improved by combining both techniques and both techniques showed substantial added value. Thus, obtaining a multiparametric MRI before biopsy in biopsy-naive patients can improve the detection of clinically significant prostate cancer but does not seem to avoid the need for systematic biopsy. FUNDING: French National Cancer Institute. PMID- 30470504 TI - Effect of contrast agent dosage on longitudinal relaxation time, signal and apparent tumor volume in glioblastoma at 9.4T. AB - INTRODUCTION: Glioblastoma multiforme is the most frequent innate brain tumor and still yields an unfavorable prognosis of 15 months of survival after diagnosis. Animal models play an important role in the investigation of therapeutic strategies of brain tumors. Thereby, MRI is substantial to individual follow-up examination for therapeutic response. Contrast agent dosage at 1.5 and 3T MRI has been thoroughly tested, while there is hardly any data for 9.4T. Therefore, the aim of this study was to find the optimal contrast agent dosage at 9.4T for examination of T1 relaxation time and apparent tumor volume in an animal model. MATERIAL AND METHODS: Six animals with a U-87 glioblastoma were part of this study. Scans were performed on a 9.4T MRI. The MRI protocol contained a standard T1w sequence, which was employed for tumor volumetry and signal intensity measurement after single, double and triple contrast agent dosage injections and a T2w sequence for volumetry of tumor and edema. From a T1 map, T1 relaxation times and tumor area were measured. Histologic tumor size measurements were also performed for two animals. RESULTS: The mean apparent tumor volume in T1w MRI increased significantly with each additional contrast agent injection, mainly due to the increase of the hyperintense tumor rim. Volumetry based on T2w MRI resulted in a higher tumor volume than in T1w volumetry, whereas the tumor volume in T1w MRI approached the volume in T2w MRI with increasing contrast agent dosage. Histology revealed an apparent tumor volume that corresponded to the volume of the hypointense center in T1w MRI. In contrast, T1 time decrease and T1w signal increase occurred mainly in the tumor rim. CONCLUSION: Increasing the contrast agent dosage led to an increase in apparent tumor volume. High-dose T1 MRI, however, overestimated the tumor volume that was determined by histology. Thereby, it can be concluded that standard contrast agent dosage is sufficient to visualize the core tumor volume in T1w MRI. Measurement of tumor volume after increasing contrast agent dosage depicts tumor core and edema, which can be due to diffusion or accumulation or both. Tumor core and edema, however, can be visualized by T2w MRI without need of additional contrast agent. PMID- 30470505 TI - Response to letter to the editor: Fluid volume, fluid balance and patient outcome in severe sepsis and septic shock: A systematic review. PMID- 30470506 TI - Some questions about fluid balance for patients with severe sepsis and septic shock. PMID- 30470507 TI - The Ataxia telangiectasia-mutated and Rad3-related protein kinase regulates cellular hydrogen sulfide concentrations. AB - The ataxia telangiectasia-mutated and Rad3-related (ATR) serine/threonine kinase plays a central role in the repair of replication-associated DNA damage, the maintenance of S and G2/M-phase genomic stability, and the promotion of faithful mitotic chromosomal segregation. A number of stimuli activate ATR, including persistent single-stranded DNA at stalled replication folks, R loop formation, hypoxia, ultraviolet light, and oxidative stress, leading to ATR-mediated protein phosphorylation. Recently, hydrogen sulfide (H2S), an endogenous gasotransmitter, has been found to regulate multiple cellular processes through complex redox reactions under similar cell stress environments. Three enzymes synthesize H2S: cystathionine-beta-synthase, cystathionine gamma-lyase, and 3-mercaptopyruvate sulfurtransferase. Since H2S can under some conditions cause DNA damage, we hypothesized that ATR activity may regulate cellular H2S concentrations and H2S syntheszing enzymes. Here we show that human colorectal cancer cells carrying biallelic knock-in hypomorphic ATR mutations have lower cellular H2S concentrations than do syngeneic ATR wild-type cells, and all three H2S synthesizing enzymes show lower protein expression in the ATR hypomorphic mutant cells. Additionally, ATR serine 428 phosphorylation is altered by H2S donor and H2S synthesis enzyme inhibition, while the oxidative-stress induced phosphorylation of the ATR-regulated protein CHK1 on serine 345 is increased by H2S synthesis enzyme inhibition. Lastly, inhibition of H2S production potentiated oxidative stress-induced double-stranded DNA breaks in the ATR hypomorphic mutant compared to ATR wild-type cells. Our findings demonstrate that the ATR kinase regulates and is regulated by H2S. PMID- 30470508 TI - Loss of the p12 subunit of DNA polymerase delta leads to a defect in HR and sensitization to PARP inhibitors. AB - Human DNA polymerase delta is normally present in unstressed, non-dividing cells as a heterotetramer (Pol delta4). Its smallest subunit, p12, is transiently degraded in response to UV damage, as well as during the entry into S-phase, resulting in the conversion of Pol delta4 to a trimer (Pol delta3). In order to further understand the specific cellular roles of these two forms of Pol delta, the gene (POLD4) encoding p12 was disrupted by CRISPR/Cas9 to produce p12 knockout (p12KO) cells. Thus, Pol delta4 is absent in p12KO cells, leaving Pol delta3 as the sole source of Pol delta activity. GFP reporter assays revealed that the p12KO cells exhibited a defect in homologous recombination (HR) repair, indicating that Pol delta4, but not Pol delta3, is required for HR. Expression of Flag-tagged p12 in p12KO cells to restore Pol delta4 alleviated the HR defect. These results establish a specific requirement for Pol delta4 in HR repair. This leads to the prediction that p12KO cells should be more sensitive to chemotherapeutic agents, and should exhibit synthetic lethal killing by PARP inhibitors. These predictions were confirmed by clonogenic cell survival assays of p12KO cells treated with cisplatin and mitomycin C, and with the PARP inhibitors Olaparib, Talazoparib, Rucaparib, and Niraparib. The sensitivity to PARP inhibitors in H1299-p12KO cells was alleviated by expression of Flag-p12. These findings have clinical significance, as the expression levels of p12 could be a predictive biomarker of tumor response to PARP inhibitors. In addition, small cell lung cancers (SCLC) are known to exhibit a defect in p12 expression. Analysis of several SCLC cell lines showed that they exhibit hypersensitivity to PARP inhibitors, providing evidence that loss of p12 expression could represent a novel molecular basis for HR deficiency. PMID- 30470509 TI - The DNA damage response is developmentally regulated in the African trypanosome. AB - Genomes are affected by a wide range of damage, which has resulted in the evolution of a number of widely conserved DNA repair pathways. Most of these repair reactions have been described in the African trypanosome Trypanosoma brucei, which is a genetically tractable eukaryotic microbe and important human and animal parasite, but little work has considered how the DNA damage response operates throughout the T. brucei life cycle. Using quantitative PCR we have assessed damage induction and repair in both the nuclear and mitochondrial genomes of the parasite. We show differing kinetics of repair for three forms of DNA damage, and dramatic differences in repair between replicative life cycle forms found in the testse fly midgut and the mammal. We find that mammal infective T. brucei cells repair oxidative and crosslink-induced DNA damage more efficiently than tsetse-infective cells and, moreover, very distinct patterns of induction and repair of DNA alkylating damage in the two life cycle forms. We also reveal robust repair of DNA lesions in the highly unusual T. brucei mitochondrial genome (the kinetoplast). By examining mutants we show that nuclear alkylation damage is repaired by the concerted action of two repair pathways, and that Rad51 acts in kinetoplast repair. Finally, we correlate repair with cell cycle arrest and cell growth, revealing that induced DNA damage has strikingly differing effects on the two life cycle stages, with distinct timing of alkylation-induced cell cycle arrest and higher levels of damage induced death in mammal-infective cells. Our data reveal that T. brucei regulates the DNA damage response during its life cycle, a capacity that may be shared by many microbial pathogens that exist in variant environments during growth and transmission. PMID- 30470510 TI - A sweeping highlight of the literature examining social status, eating behavior, and obesity. PMID- 30470511 TI - Novel non-angiogenic role for mesenchymal stem cell-derived vascular endothelial growth factor on keratinocytes during wound healing. AB - With chronic wounds remaining a substantial healthcare issue, new therapies are sought to improve patient outcomes. Various studies have explored the benefits of promoting angiogenesis in wounds by targeting proangiogenic factors such as Vascular Endothelial Growth Factor (VEGF) family members to improve wound healing. Along similar lines, Mesenchymal Stem Cell (MSC) secretions, usually containing VEGF, have been used to improve angiogenesis in wound healing via a paracrine mechanism. Recent evidence for keratinocyte VEGF receptor expression, as well as proliferative and chemotactic responses by keratinocytes to exogenous VEGFA in vitro implies distinct non-angiogenic actions for VEGF during wound healing. In this review, we discuss the expression of VEGF family members and their receptors in keratinocytes in relation to the potential for wound healing treatments. We also explore recent findings of MSC secreted paracrine wound healing activity on keratinocytes. We report here the concept of keratinocyte wound healing responses driven by MSC-derived VEGF that is supported in the literature, providing a new mechanism for cell-free therapy of chronic wounds. PMID- 30470512 TI - Potential roles of IL-1 subfamily members in glycolysis in disease. AB - The interleukin-(IL)-1 subfamily consists of IL-1alpha, IL-1beta, IL-1 receptor antagonist IL-1Ra and IL-33. These cytokines are the main members of the IL-1 family and have been widely recognized as having significant roles in pro inflammatory and immunomodulatory actions. Mounting evidence has revealed that these cytokines also play key roles in the regulation of glycolysis, which is an important metabolic pathway in most organisms that provides energy. Dysregulation of glycolysis is associated with various diseases, including type 2 diabetes, rheumatoid arthritis (RA) and cancer. We reviewed studies addressing the important roles of IL-1 subfamily cytokines, with particular focus on their ability to regulate glycolysis in disease states. In this review, we summarize the potential roles of IL-1 subfamily members in glycolysis in disease states and address the underlying mechanisms. Furthermore, we discuss the potential of these cytokines as therapeutic targets in clinical applications to provide insight into possible therapeutic strategies for treatment, especially for cancers. PMID- 30470513 TI - Triage Performance in Emergency Medicine: A Systematic Review. AB - STUDY OBJECTIVE: Rapid growth in emergency department (ED) triage literature has been accompanied by diversity in study design, methodology, and outcome assessment. We aim to synthesize existing ED triage literature by using a framework that enables performance comparisons and benchmarking across triage systems, with respect to clinical outcomes and reliability. METHODS: PubMed, EMBASE, Scopus, and Web of Science were systematically searched for studies of adult ED triage systems through 2016. Studies evaluating triage systems with evidence of widespread adoption (Australian Triage Scale, Canadian Triage and Acuity Scale, Emergency Severity Index, Manchester Triage Scale, and South African Triage Scale) were cataloged and compared for performance in identifying patients at risk for mortality, critical illness and hospitalization, and interrater reliability. This study was performed and reported in adherence to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: A total of 6,160 publications were identified, with 182 meeting eligibility criteria and 50 with sufficient data for inclusion in comparative analysis. The Canadian Triage and Acuity Scale (32 studies), Emergency Severity Index (43), and Manchester Triage Scale (38) were the most frequently studied triage scales, and all demonstrated similar performance. Most studies (6 of 8) reported high sensitivity (>90%) of triage scales for identifying patients with ED mortality as high acuity at triage. However, sensitivity was low (<80%) for identification of patients who had critical illness outcomes and those who died within days of the ED visit or during the index hospitalization. Sensitivity varied by critical illness and was lower for severe sepsis (36% to 74%), pulmonary embolism (54%), and non-ST-segment elevation myocardial infarction (44% to 85%) compared with ST-segment elevation myocardial infarction (56% to 92%) and general outcomes of ICU admission (58% to 100%) and lifesaving intervention (77% to 98%). Some proportion of hospitalized patients (3% to 45%) were triaged to low acuity (level 4 to 5) in all studies. Reliability measures (kappa) were variable across evaluations, with only a minority (11 of 42) reporting kappa above 0.8. CONCLUSION: We found that a substantial proportion of ED patients who die postencounter or are critically ill are not designated as high acuity at triage. Opportunity to improve interrater reliability and triage performance in identifying patients at risk of adverse outcome exists. PMID- 30470514 TI - Emergency Department Crowding Is Associated With Delayed Antibiotics for Sepsis. AB - STUDY OBJECTIVE: Barriers to early antibiotic administration for sepsis remain poorly understood. We investigated the association between emergency department (ED) crowding and door-to-antibiotic time in ED sepsis. METHODS: We conducted a retrospective cohort study of ED sepsis patients presenting to 2 community hospitals, a regional referral hospital, and a tertiary teaching hospital. The primary exposure was ED occupancy rate, defined as the ratio of registered ED patients to licensed ED beds. We defined ED overcrowding as an ED occupancy rate greater than or equal to 1. We used multivariable regression to measure the adjusted association between ED crowding and door-to-antibiotic time (elapsed time from ED arrival to first antibiotic initiation). Using Markov multistate models, we also investigated the association between ED crowding and pre antibiotic care processes. RESULTS: Among 3,572 eligible sepsis patients, 70% arrived when the ED occupancy rate was greater than or equal to 0.5 and 14% arrived to an overcrowded ED. Median door-to-antibiotic time was 158 minutes (interquartile range 109 to 216 minutes). When the ED was overcrowded, 46% of patients received antibiotics within 3 hours of ED arrival compared with 63% when it was not (difference 14.4%; 95% confidence interval 9.7% to 19.2%). After adjustment, each 10% increase in ED occupancy rate was associated with a 4.0 minute increase (95% confidence interval 2.8 to 5.2 minutes) in door-to antibiotic time and a decrease in the odds of antibiotic initiation within 3 hours (odds ratio 0.90; 95% confidence interval 0.88 to 0.93). Increasing ED crowding was associated with slower initial patient assessment but not further delays after the initial assessment. CONCLUSION: ED crowding was associated with increased sepsis antibiotic delay. Hospitals must devise strategies to optimize sepsis antibiotic administration during periods of ED crowding. PMID- 30470515 TI - Changes in Reimbursement to Emergency Physicians After Medicaid Expansion Under the Patient Protection and Affordable Care Act. AB - STUDY OBJECTIVE: We examine the effect of Medicaid expansion on reimbursement for emergency physicians' professional services. METHODS: We conducted a retrospective study using data from a national emergency medicine group in a sample of 50 emergency departments (EDs) from July 1, 2012, to June 30, 2015. We categorized facilities in 14 states into full-expansion (23), partial-expansion (17), and nonexpansion (10) categories based on pre-expansion Medicaid eligibility criteria for all adults. We used a difference-in-differences design to assess the effect of Medicaid expansion on provider reimbursement per visit. Secondary outcomes included reimbursement per relative value unit and relative value units per visit, both overall and by payer type, controlling for age, sex, billing codes, and health system relationship. RESULTS: We studied greater than 6.7 million ED visits during July 2012 to December 2015, 3.0 million pre expansion and 3.7 million postexpansion. After adjusting for covariates, reimbursement per visit increased 6.3% (95% confidence interval 1.4% to 11.1%) in full-expansion relative to nonexpansion states and did not change significantly in partial-expansion versus nonexpansion states. Reimbursement per visit for commercial insurance increased 17.1% (95% confidence interval 9.9% to 24.2%) in full-expansion versus nonexpansion states. Reimbursement for self-pay visits increased 9.7% (95% confidence interval 3.7% to 15.7%) in full-expansion versus nonexpansion states. Changes in payments were driven by higher reimbursement per relative value unit; relative value units per visit declined slightly in full expansion compared with nonexpansion states. CONCLUSION: In this sample, full Medicaid expansion increased payments for emergency physicians' professional services compared with reimbursement in nonexpansion states. Higher reimbursement was driven primarily by lower proportions of uninsured patients and increased reimbursement per visit for both commercially insured and self-pay patients in states with full Medicaid expansion. PMID- 30470516 TI - Can S100B Serum Biomarker Testing Reduce Head Computed Tomography Scanning in Children With Mild Traumatic Brain Injury? PMID- 30470517 TI - Postdischarge Unplanned Care Events Among Commercially Insured Patients With an Observation Stay Versus Short Inpatient Admission. AB - STUDY OBJECTIVE: Observation stays are composing an increasing proportion of unscheduled hospitalizations in the United States, with unclear consequences for the quality of care. This study used a nationally representative data set of commercially insured patients hospitalized from the emergency department (ED) to compare 30-day postdischarge unplanned care events after an observation stay versus a short inpatient admission. METHODS: This was a retrospective analysis of ED hospitalizations using the 2015 Truven MarketScan Commercial Claims and Encounters data set. Adult observation stays and short inpatient hospitalizations of 2 days or less were identified and followed for 30 days from hospital discharge to identify unplanned care events, defined as a subsequent inpatient admission, observation stay, or return ED visit. A propensity score analysis was used to compare rates of unplanned events after each type of index hospitalization. RESULTS: Among the propensity-weighted cohorts, patients with an index observation stay were 28% more likely to experience any unplanned care event within 30 days of discharge compared with those with a short inpatient admission (20.4% versus 15.9%; risk ratio 1.28; 95% confidence interval [CI] 1.21 to 1.34). Specifically, patients in the observation stay group had substantially higher rates of postdischarge observation stays (4.8% versus 1.9%; odds ratio 2.60; 95% CI 2.15 to 3.16) and ED revisits with discharge (11.1% versus 8.8%; odds ratio 1.26; 95% CI 1.21 to 1.44) compared with those in the inpatient group, but were less likely to be readmitted as inpatients (6.4% versus 7.2%; odds ratio 0.90; 95% CI 0.83 to 0.96). CONCLUSION: Commercially insured patients with an observation stay from the ED have a higher risk of postdischarge acute care events compared with similar patients with a short inpatient admission. Additional research is necessary to determine the extent to which quality of care, including care transitions, may differ between these 2 groups. PMID- 30470518 TI - Evaporation-induced self-assembly synthesis of nanostructured alumina-based mixed metal oxides with tailored porosity. AB - The one-pot synthesis of nanostructured ternary mixed oxides is challenging due to the heterogeneous nature of the hydrolysis and condensation processes of all metal oxide precursors. In addition, the solvents and additives used can affect these processes too. Herein, we report the effect of different solvents (ethanol, 1- and 2-propanol, or butanol) and additives (citric acid or 1,3,5 triisopropylbenzene) used on the formation of binary and ternary alumina-based oxides, NiO-Al2O3, NiO-TiO2-Al2O3, and NiO-ZrO2-Al2O3 in the presence of triblock copolymer Pluronic P123 used as a soft template. For comparison, this study includes also mesoporous Al2O3 prepared at the same conditions. It is shown that the kinetics of hydrolysis and condensation processes of metal alkoxides, and consequently, the properties of the resulting alumina-based mixed metal oxides are controllable by varying the solvents used. The use of propanol instead of ethanol affords mixed metal oxides with improved degree of mesostructure uniformity as evidenced by narrower pore size distributions. This finding is attributed to the smaller exchange of propanol with propoxide groups in Al(OPri)3, Ti(OPri)4, and Zr(OPrn)4 which results in an enhanced stability of the formed mesophase. Furthermore, the addition of citric acid leads to smaller pore sizes without significant changes in the textural properties of metal oxides, while addition of 1,3,5-triisopropylbenzene affords oxides with enlarged pores. The mixed metal oxides studied feature large specific surface areas (310-460 m2.g 1), large pore volumes (0.5-0.75 cm3.g-1), and uniform mesopores with widths ranging from 5 to 18 nm. Solid-state kinetic studies performed by thermal analysis using both isoconversional and model fitting methods reveal the complexity of the mesophase formation. The thermal decomposition of condensed oxoalkoxide species into metal oxides is mainly diffusion-controlled and affected by the type of solvent used too. This study shows that there are tremendous opportunities in tailoring porous structures of mixed metal oxides prepared via evaporation induced self-assembly (EISA) by selecting proper solvents and additives, and thermal treatment. PMID- 30470519 TI - Insulin use for type 2 diabetes: the challenges of predicting trends and modelling care. PMID- 30470520 TI - Estimation of global insulin use for type 2 diabetes, 2018-30: a microsimulation analysis. AB - BACKGROUND: The amount of insulin needed to effectively treat type 2 diabetes worldwide is unknown. It also remains unclear how alternative treatment algorithms would affect insulin use and disability-adjusted life-years (DALYs) averted by insulin use, given that current access to insulin (availability and affordability) in many areas is low. The aim of this study was to compare alternative projections for and consequences of insulin use worldwide under varying treatment algorithms and degrees of insulin access. METHODS: We developed a microsimulation of type 2 diabetes burden from 2018 to 2030 across 221 countries using data from the International Diabetes Federation for prevalence projections and from 14 cohort studies representing more than 60% of the global type 2 diabetes population for HbA1c, treatment, and bodyweight data. We estimated the number of people with type 2 diabetes expected to use insulin, international units (IU) required, and DALYs averted per year under alternative treatment algorithms targeting HbA1c from 6.5% to 8%, lower microvascular risk, or higher HbA1c for those aged 75 years and older. FINDINGS: The number of people with type 2 diabetes worldwide was estimated to increase from 405.6 million (95% CI 315.3 million-533.7 million) in 2018 to 510.8 million (395.9 million-674.3 million) in 2030. On this basis, insulin use is estimated to increase from 516.1 million 1000 IU vials (95% CI 409.0 million-658.6 million) per year in 2018 to 633.7 million (500.5 million-806.7 million) per year in 2030. Without improved insulin access, 7.4% (95% CI 5.8-9.4) of people with type 2 diabetes in 2030 would use insulin, increasing to 15.5% (12.0-20.3) if insulin were widely accessible and prescribed to achieve an HbA1c of 7% (53 mmol/mol) or lower. If HbA1c of 7% or lower was universally achieved, insulin would avert 331 101 DALYs per year by 2030 (95% CI 256 601-437 053). DALYs averted would increase by 14.9% with access to newer oral antihyperglycaemic drugs. DALYs averted would increase by 44.2% if an HbA1c of 8% (64 mmol/mol) were used as a target among people aged 75 years and older because of reduced hypoglycaemia. INTERPRETATION: The insulin required to treat type 2 diabetes is expected to increase by more than 20% from 2018 to 2030. More DALYs might be averted if HbA1c targets are higher for older adults. FUNDING: The Leona M and Harry B Helmsley Charitable Trust. PMID- 30470521 TI - Functional and socioprofessional outcome of surgery for Volkmann's contracture. AB - OBJECTIVES: Volkmann's ischemic contracture is rare and surgical treatment remains a challenge. The goal of treatment is to obtain permanent recovery of joint range of motion and strength. The goal of this study was to evaluate the functional and socioprofessional outcome of surgical treatment of Volkmann's ischemic contracture. METHODS: This retrospective study was performed in two centers with one surgeon. Seven patients were included; mean age 23.6 years old. The Quick-Dash score, Patient Rated Wrist Questionnaire (PRWE) scores were obtained. Grip strength was compared to the contralateral side. Satisfaction was evaluated by the question: would you have surgery again? The surgical technique included 7 muscle slide procedures. RESULTS: Wrist and finger range of motion was good at least 6.1years in all cases according to the system by Buck-Gramcko. Grip strength on the operated side was 72.3% of the contralateral side. The mean PRWE was 14.64/100, mean QUICK-DASH score was 7.9/100. Patients returned to their professional activities in all cases. Patients who were questioned were all satisfied with surgery. CONCLUSIONS: Once the contracture is established in Volkmann's contracture Page-Scaglieti-Gosset muscle slide procedure can be used with good results allowing a return to socioprofessional activities. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 30470522 TI - Preoperative planning of tibial tubercle medialisation according to the trochlear groove angle. AB - The tibial tubercle-trochlear groove distance (TT-TG) was first described four decades ago. Since then, a considerable body of research has become available on the pathophysiology of chronic patellar instability, whose diagnosis and treatment remain challenging. Tibial tubercle medialisation can correct an abnormal TT-TG. Preoperative planning based on the TT-TG and trochlear angle may avoid both under-correction inducing persistent instability and overcorrection responsible for pain. Preoperative planning should be patient-specific. With appropriate preoperative planning, compensation for moderate trochlear dysplasia can be achieved without any additional procedure. PMID- 30470523 TI - Corrigendum to "Evolutionary history and biogeography of Mandragora L. (Solanaceae)" [Molecular Phylogenetics and Evolution 129 (2018) 85-95]. PMID- 30470524 TI - Corrigendum to "Phylogenetic evaluation of Amynthas earthworms from South China reveals the initial ancestral state of spermathecae" [ Molecular Phylogenetics and Evolution Volume 115, October 2017, Pages 106-114]. PMID- 30470525 TI - Corrigendum to "Towards a higher-level Ensifera phylogeny inferred from mitogenome sequences" [Molecular Phylogenetics and Evolution 108 (2017) 22-33]. PMID- 30470526 TI - Barriers to hand hygiene practices among health care workers in sub-Saharan African countries: A narrative review. AB - BACKGROUND: Hand hygiene (HH) is the primary measure in the prevention of health care-associated infections; however, from published studies, compliance of health care workers (HCWs) to HH guidelines is low. There is currently no review on HH compliance rates in developing countries, specifically sub-Saharan Africa (SSA), or the barriers to compliance. We therefore, through a narrative review, sought to identify the compliance with and the barriers to HH in SSA. METHODS: From 3 databases, we performed a search of peer-reviewed studies from SSA, conducted among HCWs, published in the English language between 2005 and 2017. Only studies that reported HH compliance and/or barriers were included. RESULTS: A total of 278 articles were identified, and the final sample of 27 articles was analyzed in full length. Overall, the HH compliance rate was estimated to be 21.1%, and doctors had better compliance irrespective of the type of patient contact. The main barriers identified were heavy workload, infrastructural deficit (eg, lack of water, soap, hand sanitizers, and blocked/leaking sinks), and poorly positioned facilities. CONCLUSIONS: HH compliance is poor among SSA HCWs. There is a need for more reports of HH compliance in SSA, and emphasis needs to be placed on surgical wards in which surgical site infections-the most common form of health care-associated infections in SSA-are most likely to occur. Barriers identified in this review are consistent with the findings of studies conducted elsewhere; however, it appears that heavy workload, infrastructural deficit, and poorly positioned facilities are more likely in developing countries. PMID- 30470527 TI - Role of transfusions in the development of hospital-acquired urinary tract related bloodstream infection among United States Veterans. AB - BACKGROUND: Urinary tract-related bloodstream infection (BSI) is associated with substantial morbidity, mortality, and financial costs. We examined the role of red blood cell (RBC) transfusions on developing this condition among US Veterans. METHODS: We conducted a matched case-control study among adult inpatients admitted to 4 Veterans Affairs hospitals. Cases were patients with a positive urine culture result obtained 48 hours or longer after admission and a blood culture obtained within 14 days of the urine culture, which grew the same organism. Controls included patients with a positive urine culture result who were at risk for but did not develop BSI (control group 1) and patients without a positive urine culture result who were present in the facility at the time of case diagnosis (control group 2). RESULTS: Compared with the findings in control group 1, receipt of RBCs was not significantly associated with urinary tract related BSI (odds ratio, 1.03; 95% confidence interval, 1.00-1.07; P = .07). However, we found increased odds of urinary tract-related BSI compared with the results in patients without infection (control group 2) (odds ratio, 1.11; 95% confidence interval, 1.06-1.17; P < .001). CONCLUSIONS: Given the heightened risk of urinary tract-related BSI associated with receiving a greater number of RBC transfusions, adhering to recommendations to transfuse the minimum amount of blood products necessary may minimize the risk of this infection among Veterans. PMID- 30470528 TI - [Extrapolation of data to inform system-level decisions of the Federal Joint Committee]. AB - The evaluation procedures of the Federal Joint Committee (G-BA) often raise the question of whether and under what conditions findings can be transferred to other areas of application or interventions. Additional information is required in each case to test transferability. On the basis of selected examples from the decision-making practice of the G-BA, the complex weighing processes are outlined and the need for transparent illustration of the reasons for decisions is pointed out. The criteria, which in any case must be examined, cannot be described conclusively. Depending on the concrete question - method, pharmaceutical - further criteria may be relevant. A systematic approach still has to be developed so that the complex weighing processes could be simplified by transfer assumptions with sufficient certainty. PMID- 30470529 TI - Systematic review analysis of robotic and transanal approaches in TME surgery- A systematic review of the current literature in regard to challenges in rectal cancer surgery. AB - Several patients' and pathological characteristics in rectal surgery can significantly complicate surgical loco regional tumor clearance. The main factors are obesity, short tumor distance from anal verge, bulky tumors, and narrow pelvis, which have been shown to be associated to poor surgical results in open and laparoscopic approaches. Minimally invasive surgery has the potential to reduce perioperative morbidity with equivalent short- and long-term oncological outcomes compared to conventional open approach. Achilles' heel of laparoscopic approaches is conversion to open surgery. High risk for conversion is evident for patients with bulky and low tumors as well as male gender and narrow pelvis. Hence, patient's characteristics represent challenges in rectal cancer surgery especially in minimally invasive approaches. The available surgical techniques increased remarkably with recently developed and implemented improvements of minimally invasive rectal cancer surgery. The controversial discussions about sense and purpose of these novel approaches are still ongoing in the literature. Herein, we evaluate, if latest technical advances like transanal approach or robotic assisted surgery have the potential to overcome known challenges and pitfalls in rectal cancer surgery in demanding surgical cases and highlight the role of current minimally invasive approaches in rectal cancer surgery. PMID- 30470531 TI - Ileocolic intussusception in adults. PMID- 30470530 TI - A personal technical experience and results of a modified end-to-side technique of pancreatojejunostomy: A 350 patients retrospective cohort study. AB - BACKGROUND: In pancreatoduodenectomy,the treatment of pancreatic stump is a critical step, pancreaticoduodenectasis and hemorrhage are the two most common complications, which are closely related to the operation of pancreaticojejunostomy and because leaks from this incur major morbidity and mortality. We describe the special technical experience of a modified end-to-side pancreatojejunostomy(mPJ): surgical methods which combine jejunal decompression tube with pancreatic duct jejunal parachute monolayer suture,and report on the outcome of the consecutive 350 patients. METHOD: From December 2009 to December 2016, 350 pancreatic resections were performed by a single surgeon which are consecutive. Data were retrieved from a prospectively collected Institutional database, and used for the present retrospective evaluation. Post-operative pancreatic fistulas (POPF) were stratified with the Fistula Risk Score (FRS), based on the 2005-International Study Group of Pancreatic Fistula classification (ISGPFc) and on the subsequent 2016-revised version (ISGPSc). RESULTS: ISGPFc POPF occurred in 67/350 (19.14%): grade A in 48/350 (13.71%), grade B in 16/350 (4.57%) and grade C in 3/350 (0.86%). On the ISGPSc, POPF rate averaged 5.43%: grade B in 16/350 (4.57%) and grade C in 3/350 (0.86%). POPF rate associated with high FRS was 22.6%/9.7% (ISGPFc/ISGPSc). With low and intermediate FRS, POPFs were 5.3%/1.3% (ISGPFc/ISGPSc) and 25.7%/6.9% (ISGPFc/ISGPSc) respectively. Re operation rate was 0.86%. In-hospital mortality rate was 0.86% and specific mortality rate for POPF was 0.86%. CONCLUSIONS: The mPJ technique is associated with a POPF rate which was less than expected, especially for "difficult" pancreas with high FRS (soft gland texture and small duct). A larger prospective series is needed in addition to comparative studies with other techniques for robust assessment. PMID- 30470532 TI - Moving across the static magnetic field of a 1.5 T MRI scanner: Analysing compliance with Directive 2013/35/EU. AB - Does the exposure of magnetic resonance imaging personnel to static magnetic fields fully comply with Directive 2013/35/EU? Despite the obligation to satisfy this question, a general answer cannot be provided, nor are final satisfying good practices methods for exposure assessment currently available. In order to contribute to fix this problem, three different 1.5 T scanners are analysed and - by a new theoretical insight - a positive answer is provided. PMID- 30470533 TI - Outcomes of arthroscopic rotator cuff repair with muscle advancement for massive rotator cuff tears. AB - BACKGROUND: We performed arthroscopic rotator cuff repair (ARCR) combined with miniopen supraspinatus and infraspinatus muscle advancement for massive rotator cuff tears (RCTs) to decrease tension at the repair site with the goal of reduction of the failure rate. We evaluated the clinical outcomes and failure rate after this procedure. METHODS: This study included 47 patients diagnosed with chronic massive RCTs between October 2010 and March 2015. Of these patients, 21 underwent transosseous equivalent (TOE) ARCR only (control group), and 26 underwent TOE ARCR with muscle advancement (study group). We evaluated shoulder clinical outcomes at preoperative and postoperative assessments and also measured muscle strength and the acromiohumeral interval (AHI) at the same time in both groups. Failure rates were calculated in both groups by evaluating the cuff integrity with postoperative magnetic resonance imaging. RESULTS: Although there was statistically significant improvement for the mean clinical scores in the both groups, there were no significant differences between the 2 groups. The postoperative abduction muscle strength and AHI were significantly higher in the study group (46.3 +/- 20.6 N and 9.4 +/- 2.9 mm; P = .04) than in the control group (34.6 +/- 20.0 N and 7.7 +/- 3.0 mm; P = .04). The failure rates were significantly lower in the study group than in the control group (23.1% and 52.4%; P = .03). CONCLUSION: The TOE ARCR with muscle advancement can achieve significantly better abduction muscle strength, wider AHI, and lower failure rates for massive RCTs than the normal TOE ARCR. PMID- 30470534 TI - Redox signaling and unfolded protein response coordinate cell fate decisions under ER stress. AB - Endoplasmic reticulum (ER) is a dynamic organelle orchestrating the folding and post-translational maturation of almost all membrane proteins and most secreted proteins. These proteins synthesized in the ER, need to form disulfide bridge to acquire specific three-dimensional structures for function. The formation of disulfide bridge is mediated via protein disulfide isomerase (PDI) family and other oxidoreductases, which contribute to reactive oxygen species (ROS) generation and consumption in the ER. Therefore, redox regulation of ER is delicate and sensitive to perturbation. Deregulation in ER homeostasis, usually called ER stress, can provoke unfolded protein response (UPR) pathways with an aim to initially restore homeostasis by activating genes involved in protein folding and antioxidative machinery. Over time, however, activated UPR involves a variety of cellular signaling pathways which determine the state and fate of cell in large part (like autophagy, apoptosis, ferroptosis, inflammation, senescence, stemness, and cell cycle, etc.). This review will describe the regulation of UPR from the redox perspective in controlling the cell survival or death, emphasizing the redox modifications of UPR sensors/transducers in the ER. PMID- 30470535 TI - Fetal midline anomalies: Diagnosis and counselling part 2: Septal anomalies. PMID- 30470536 TI - TRPM7 reflected in Cryo-EMirror. AB - TRPM7 is an atypical type of ion channel because its pore-forming moiety is covalently linked to a protein kinase domain. The channel-kinase TRPM7 controls a wide range of biological processes such as mineral homeostasis, immune responses, cell motility, proliferation and differentiation. Earlier this year, Duan J & co workers [1] published three TRPM7 structures resolved by cryo-electron microscopy (cryo-EM). This study tremendously advances our mechanistic understanding of TRPM7 channel function and forms the basis for informed structure-function assessment of this extraordinary protein. PMID- 30470537 TI - Unifocalization revision: Patches, patches and more patches.... PMID- 30470538 TI - First survive the crash: When to bail on the unbalanced atrioventricular valve. PMID- 30470539 TI - Just say NO? Does nitric oxide improve myocardial protection during cardiac surgery? PMID- 30470540 TI - Neoadjuvant or adjuvant chemotherapy for non-small-cell lung cancer: Does the timing matter? PMID- 30470541 TI - The first 5 years: Building a minimally invasive valve program. PMID- 30470542 TI - Valve choice in dialysis-dependent patients: A question of patient durability. PMID- 30470543 TI - The effect of adjuvant chemotherapy in resectable cholangiocarcinoma: A meta analysis and systematic review. AB - BACKGROUND: The benefit of adjuvant chemotherapy for resectable cholangiocarcinoma remains unclear due to the lack of randomized control studies. This study aimed to investigate the possible benefit of postoperative adjuvant chemotherapy for resectable cholangiocarcinoma. DATA SOURCES: Relevant research articles published before 1st March 2018 in PubMed, Embase and the Cochrane library databases were retrieved. Published data were extracted and analyzed by RevMan 5.3, and the results were presented as hazard ratios (HRs) [95% confidence intervals (CI)] and forest plots. RESULTS: One prospective and eighteen retrospective studies were included, with a total number of 11,458 patients, 4696 of whom received postoperative chemotherapy. There was a significant improvement of the overall survival (OS) for patients who underwent operation + adjuvant chemotherapy compared to those who underwent operation alone (HR = 0.61; P < 0.001). Subgroup analyses show that the postoperative chemotherapy group compared with operation alone group are indicated as follows: hilar cholangiocarcinoma group (HR = 0.60; P < 0.001), intrahepatic cholangiocarcinoma group (HR = 0.60; P < 0.001), R1 resection group (HR = 0.71; P = 0.04), LN-positive diagnosis group (HR = 0.58; P < 0.001), gemcitabine-based chemotherapy group (HR = 0.42, P < 0.001), distal cholangiocarcinoma group (HR = 0.48; P = 0.17), R0 resection group (HR = 0.69; P = 0.43), and 5-flurouracil-based chemotherapy group (HR = 0.90, P = 0.66), respectively. CONCLUSIONS: Postoperative adjuvant chemotherapy can improve the OS in intrahepatic and hilar cholangiocarcinoma patients. However, distal cholangiocarcinoma patients gain no benefit from postoperative adjuvant chemotherapy. Prospective randomized trials are warranted in order to define the standard chemotherapy regimen. PMID- 30470544 TI - Re: van Dijk et al: Half-dose photodynamic therapy versus high-density subthreshold micropulse laser treatment in patients with chronic central serous chorioretinopathy: The PLACE trial (Ophthalmology. 2018;125:1547-1555.). PMID- 30470545 TI - Reply. PMID- 30470546 TI - Contemporary epidemiology of systemic sclerosis: A population-based cohort study in the United Kingdom. AB - OBJECTIVE: To estimate the contemporary epidemiology of systemic sclerosis (SSc) in the UK and to explore the validity of using The Health Improvement Network (THIN) primary care database to study SSc. METHODS: 4,520,299 individuals (2000 2012) aged 1-99 years were followed to identify potential incident cases of SSc; potential prevalent cases were identified at start of follow-up. Patient profiles, including free-text comments, were manually reviewed to verify cases of SSc, and case validation was undertaken for a sample (n = 100) using questionnaires to primary care physicians. Incidence, prevalence and mortality rates were calculated. RESULTS: Following manual review, we identified 1321 cases of SSc (689 incident and 632 prevalent) over a mean follow-up of 7.6 years; mean age at diagnosis 59.1 years. Using information from 91/100 valid questionnaires returned, the positive predictive value of SSc diagnoses in THIN following manual review was 94%. Incidence rates of SSc per 100,000 person-years (95% CI) were 2.02 (1.87-2.17) overall, [3.36 (3.09-3.64) in females, 0.61 (0.49-0.74) in males], ranging from 1.53 (1.11-2.06) to 2.56 (1.78-3.56) across calendar years. Prevalence of SSc per 100,000 (95% CI) increased from 17.13 (14.97-19.51) to 25.38 (23.68-27.16) over the study period, and was higher in females. Using Poisson regression, the adjusted mortality rate ratio was 2.82 (95% CI: 2.55 3.13) among SSc cases versus the general population. CONCLUSIONS: THIN enables precise and valid estimates of SSc occurrence to be determined. The observed increase in SSc prevalence has not been driven by increasing incidence. PMID- 30470547 TI - Applications of Immunomodulatory Immune Synergies to Adjuvant Discovery and Vaccine Development. AB - Pathogens comprise a diverse set of immunostimulatory molecules that activate the innate immune system during infection. The immune system recognizes distinct combinations of pathogenic molecules leading to multiple immune activation events that cooperate to produce enhanced immune responses, known as 'immune synergies'. Effective immune synergies are essential for the clearance of pathogens, thus inspiring novel adjuvant design to improve vaccines. We highlight current vaccine adjuvants and the importance of immune synergies to adjuvant and vaccine design. The focus is on new technologies used to study and apply immune synergies to adjuvant and vaccine development. Finally, we discuss how recent findings can be applied to the future design and characterization of synergistic adjuvants and vaccines. PMID- 30470548 TI - Zinc-Based Biomaterials for Regeneration and Therapy. AB - Zinc has been described as the 'calcium of the twenty-first century'. Zinc-based degradable biomaterials have recently emerged thanks to their intrinsic physiological relevance, biocompatibility, biodegradability, and pro-regeneration properties. Zinc-based biomaterials mainly include: metallic zinc alloys, zinc ceramic nanomaterials, and zinc metal-organic frameworks (MOFs). Metallic zinc implants degrade at a desirable rate, matching the healing pace of local tissues, and stimulating remodeling and formation of new tissues. Zinc ceramic nanomaterials are also beneficial for tissue engineering and therapy thanks to their nanostructures and antibacterial properties. MOFs have large surface areas and are easily functionalized, making them ideal for drug delivery and cancer therapy. This review highlights recent developments in zinc-based biomaterials, discusses obstacles to overcome, and pinpoints directions for future research. PMID- 30470549 TI - Pulmonary Hemorrhage Following Percutaneous Computed Tomography-Guided Lung Biopsy: Retrospective Review of Risk Factors, Including Aspirin Usage. AB - BACKGROUND: To evaluate the significance of aspirin, as well as, other potential confounding risk factors, on the incidence and volume of pulmonary hemorrhage in patients undergoing percutaneous computed tomography-guided lung biopsy. METHODS: This retrospective study was approved by the institutional review board. Between September 2013 and December 2014, 252 patients taking aspirin underwent transthoracic computed tomography-guided lung biopsy. Patient, technical, and lesion-related risk factors were evaluated. Univariate analysis was performed with a Student's t test, chi-square test, or Fisher's exact test, as appropriate followed by multivariate logistic regression. RESULTS: Of 252 patients, 49 (19.4%) continued or stopped aspirin <=4 days prior to biopsy and 203 (80.6%) patients stopped aspirin >=5 days prior to biopsy. Pulmonary hemorrhage occurred in 174 cases (69.0%). The median volume of hemorrhage was 3.74 cm3 (range, 0 163.5 cm3). Multivariate analysis revealed that lesion size (P < 0.0001) and lesion depth (P < 0.0001) were independent risk factors for the incidence of pulmonary hemorrhage, while lesion size (P = 0.0035), transgression of intraparenchymal vessels (P < 0.0001), and lesion depth (P = 0.0047) were independent risk factors for severity of hemorrhage. Aspirin stopped <=4 days from a percutaneous lung biopsy was not associated with pulmonary hemorrhage. CONCLUSION: Aspirin taken concurrently or stopped within 4 days of transthoracic lung biopsy is not an independent risk factor for pulmonary hemorrhage. The incidence of hemorrhage following lung biopsy is associated with lesion size and depth, while the severity of hemorrhage is associated with lesion size, depth, as well as traversal of intraparenchymal vessels. PMID- 30470550 TI - Patient-centered surgical prehabilitation. PMID- 30470551 TI - Surgical procedural map scoring for decision-making in laparoscopic cholecystectomy. AB - INTRODUCTION: The objective of this study was to determine whether decision-based procedural mapping demonstrates differences in attendings versus residents. METHODS: Attendings and residents were interviewed about operative decision making in laparoscopic cholecystectomy (LC) using a cognitive task analysis framework. Interviews were converted into procedural maps. Operative steps, patient factors, and surgeon factors noted by attendings and residents were compared. Two scoring methods were used to compare map structures of attendings versus residents. RESULTS: Six attendings and six residents were interviewed. There were no significant differences in the number of patient or surgeon factors identified. Attendings had significantly more operative steps (29.67 +/- 1.9 vs. 23.3 +/- 1.9, p = 0.04) and crosslinks (3.2 +/- 0.5 vs. 1 +/- 0.4, p = 0.005) in their maps and a higher total score (90.2 +/- 8.4 vs. 63.2 +/- 3.8, p = 0.015) than residents. CONCLUSION: LC procedural map scoring for attendings and residents demonstrated significant differences in structural complexity and may provide a useful framework for assessing decision making. PMID- 30470553 TI - Long-term treatment with linaclotide of intestinal pseudo-obstruction secondary to Ehlers-Danlos syndrome. PMID- 30470552 TI - Single versus double experimental bile duct ligation model for inducing bacterial translocation. AB - BACKGROUND: Double common bile duct ligation plus section in rats is used as a model for bacterial translocation, a phenomenon that has been correlated with the degree of liver damage. This study analyzes whether a simpler variant of the technique is also a valid model to study bacterial translocation. METHODS: Fifty six male Sprague Dawley rats underwent one of three surgical interventions: a) proximal double ligation and section of the common bile duct; b) proximal simple ligation of the bile duct; and c) sham operation. Bacterial translocation was measured by cultures of mesenteric lymph nodes, blood, spleen and liver. Stool culture and histological analysis of liver damage were also performed. RESULTS: The incidence of bacterial translocation in SBL and DBDL groups was 23,5% and 25% respectively. Mortality was similar between ligation groups (11.2% versus 10%). Liver cirrhosis developed in the group of double ligation and section (100% of the animals at 4 weeks), while portal hypertension appeared starting at week 3. None of the animals submitted to simple ligation developed liver cirrhosis. CONCLUSIONS: Simple bile duct ligation is associated with a similar incidence of bacterial translocation as double ligation, but without cirrhosis or portal hypertension. PMID- 30470554 TI - The evolving scenario of HBV infection and disease: A never-ending story. PMID- 30470555 TI - Contrasting patterns in habitat selection and recruitment of temperate reef fishes among natural and artificial reefs. AB - Artificial reefs, a common management tool for stock enhancement of recreational fisheries and marine habitat restoration, have been deployed all over the world. However, little is known about the attractiveness of artificial compared to natural reefs to reef fishes. Here we investigated the habitat preferences of three reef fish species: Trachinops caudimaculatus, Vincentia conspersa and Trinorfoklia clarkei through the observation of recruitment patterns to three study habitats: Reef Ball reefs, custom-designed artificial reefs, and natural reefs in Port Phillip Bay, Victoria, Australia. Additionally, we examined habitat preferences of new recruits of T. caudimaculatus and V. conspersa using laboratory-based habitat choice experiments. In general, T. caudimaculatus recruitment was at least twice as high on natural reefs compared to both artificial reefs, whereas V. conspersa recruitment was almost three times greater on Reef Ball reefs compared to the other two habitats. T. clarkei recruited in equal numbers across all habitats. However, in the laboratory experiments T. caudimaculatus recruits selected the Reef Ball reef almost three times as often as the other two habitats, while V. conspersa exhibited no habitat preference. Little is known about the growth, condition, survival or reproduction of individuals that occupy artificial reefs. In areas where habitat is not limiting, the higher preference or equal attractiveness of some artificial habitats may negatively influence fish populations, if larvae are redirected to poorer quality artificial reef habitat, that lead to lower fitness advantages. PMID- 30470556 TI - Impact of a Monthly Compliance Review on Interventional Radiology Adverse Event Reporting. AB - PURPOSE: Our aims were to analyze the change in interventional radiology physician major adverse event (AE) reporting after initiation of a monthly morbidity and mortality (M&M) conference compliance review and to describe the association of procedure class and potentially preventable errors with major AE occurrence. METHODS: In late 2010, to motivate timely reporting, we instituted a structured monthly M&M conference review confirming whether each complication warranted institutional AE reporting and whether timely reporting had occurred. In this study, we retrospectively analyzed the M&M conference minutes over the subsequent 5 years. Logistic regression was used to model the change of AE reporting over time as well as the association of procedure class with the risk of an AE. Each AE was classified as to whether it seemed potentially preventable. RESULTS: There were 46,660 patient encounters, 1,160 (2.5%) major and minor complications, and 462 (1.0%) reportable AEs. From 2011 to 2015, the percentage of reportable AEs reported increased from 67% to 98%. The number of months from initiation of the M&M conference review was a significant predictor of the likelihood of AE reporting (odds ratio 1.06, 95% confidence interval 1.04, 1.08, P < .0001). Procedure class was strongly associated with the risk of a reportable AE (P < .0001). At least 111 (24%) reportable AEs were potentially preventable. CONCLUSIONS: Increasing AE reporting occurred after initiation of a monthly M&M conference compliance review. The incidence of reportable AEs was strongly associated with procedure class, and a significant percentage of these events were potentially preventable. PMID- 30470557 TI - Heterogeneity and complexity in bronchiectasis: A pending challenge. PMID- 30470558 TI - Accidental Breakage of an Aspiration Needle During EBUS-TBNA. PMID- 30470559 TI - The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology. AB - Volumetric reductions in the hippocampus and medial prefrontal cortex (mPFC) are among the most well-documented neural abnormalities in major depressive disorder (MDD). Hippocampal and mPFC structural reductions have been specifically tied to MDD illness progression markers, including greater number of major depressive episodes (MDEs), longer illness duration, and nonremission/treatment resistance. Chronic stress plays a critical role in the development of hippocampal and mPFC deficits, with some studies suggesting that these deficits occur irrespective of MDE occurrence. However, preclinical and human research also points to other stress-mediated neurotoxic processes, including enhanced inflammation and neurotransmitter disturbances, which may require the presence of an MDE and contribute to further brain structural decline as the illness advances. Specifically, hypothalamic-pituitary-adrenal axis dysfunction, enhanced inflammation and oxidative stress, and neurotransmitter abnormalities (e.g., serotonin, glutamate, gamma-aminobutyric acid) likely interact to facilitate illness progression in MDD. Congruent with stress sensitization models of MDD, with each consecutive MDE it may take lower levels of stress to trigger these neurotoxic pathways, leading to more pronounced brain volumetric reductions. Given that stress and MDD have overlapping and distinct influences on neurobiological pathways implicated in hippocampal and mPFC structural decline, further work is needed to clarify which precise mechanisms ultimately contribute to MDD development and maintenance. PMID- 30470560 TI - New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process? PMID- 30470562 TI - Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder. AB - Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. The deficiency of this enzyme represents an encephalomyopathic form of mtDNA depletion syndromes. We describe the fatal clinical course of a female patient with a pathogenic mutation in SUCLG1 (c.626C > A, p.Ala209Glu) heterozygous at the genomic DNA level, but homozygous at the transcriptional level. The patient exhibited early-onset neurometabolic abnormality culminating in severe brain atrophy and dystonia leading to death by the age of 3.5 years. Urine and plasma metabolite profiling was consistent with SUCL deficiency which was confirmed by enzyme analysis and lack of mitochondrial substrate-level phosphorylation (mSLP) in skin fibroblasts. Oxygen consumption- but not extracellular acidification rates were altered only when using glutamine as a substrate, and this was associated with mild mtDNA depletion and no changes in ETC activities. Immunoblot analysis revealed no detectable levels of SUCLG1, while SUCLA2 and SUCLG2 protein expressions were largely reduced. Confocal imaging of triple immunocytochemistry of skin fibroblasts showed that SUCLG2 co localized only partially with the mitochondrial network which otherwise exhibited an increase in fragmentation compared to control cells. Our results outline the catastrophic consequences of the mutated SUCLG1 leading to strongly reduced SUCL activity, mSLP impairment, mislocalization of SUCLG2, morphological alterations in mitochondria and clinically to a severe neurometabolic disease, but in the absence of changes in mtDNA levels or respiratory complex activities. PMID- 30470563 TI - Potential Impact of Initial Clinical Data on Adjustment of Pediatric Readmission Rates. AB - OBJECTIVE: Comparison of readmission rates requires adjustment for case-mix (ie, differences in patient populations), but previously only claims data were available for this purpose. We examined whether incorporation of relatively readily available clinical data improves prediction of pediatric readmissions and thus might enhance case-mix adjustment. METHODS: We examined 30-day readmissions using claims and electronic health record data for patients <=18 years and 29 days of age who were admitted to 3 children's hospitals from February 2011 to February 2014. Using the Pediatric All-Condition Readmission Measure and starting with a model including age, gender, chronic conditions, and primary diagnosis, we examined whether the addition of initial vital sign and laboratory data improved model performance. We employed machine learning to evaluate the same variables, using the L2-regularized logistic regression with cost-sensitive learning and convolutional neural network. RESULTS: Controlling for the core model variables, low red blood cell count and mean corpuscular hemoglobin concentration and high red cell distribution width were associated with greater readmission risk, as were certain interactions between laboratory and chronic condition variables. However, the C-statistic (0.722 vs 0.713) and McFadden's pseudo R2 (0.085 vs 0.076) for this and the core model were similar, suggesting minimal improvement in performance. In machine learning analyses, the F-measure (harmonic mean of sensitivity and positive predictive value) was similar for the best-performing model (containing all variables) and core model (0.250 vs 0.243). CONCLUSIONS: Readily available clinical variables do not meaningfully improve the prediction of pediatric readmissions and would be unlikely to enhance case-mix adjustment unless their distributions varied widely across hospitals. PMID- 30470564 TI - Systematic review of case reports of oropharyngeal dysphagia following the use of antipsychotics. AB - OBJECTIVE: The purpose of this systematic review was to examine the effect of antipsychotic medication on dysphagia based on clinical case reports. PATIENTS AND METHODS: Literature searches were performed using the electronic databases PubMed and Embase. In PubMed, we used the MeSH terms "antipsychotic agents" OR "tranquilizing agents" combined with "deglutition disorders" OR "deglutition". In Embase, we used the Emtree terms "neuroleptic agents" combined with "swallowing" OR "dysphagia". Two reviewers assessed the eligibility of each case independently. RESULTS: A total of 1043 abstracts were retrieved, of which 36 cases met the inclusion criteria; 14 cases were related to typical antipsychotics and 22 to atypical antipsychotics. Dysphagia occurred together with extrapyramidal symptoms in half of the cases and was the only prominent symptom in the other half. The most common strategy against dysphagia was changing to another antipsychotic (n=13, 36.1%). CONCLUSIONS: The data from this review indicate that antipsychotics can increase the prevalence of dysphagia. PMID- 30470565 TI - Clinical hepatocyte transplantation. AB - A severe shortage of suitable allografts is a long-standing and worldwide problem for patients who are waiting for organ transplantation. Hepatocyte transplantation has been proposed as an alternative therapeutic approach for liver disease patients to address this urgent and unmet medical need. The cell replacement approach does not replace orthotopic liver transplantation (OLT), but rather it complements OLT especially for patients who do not require whole liver replacement, such as those with congenital metabolic disorders. This review article summarizes the current knowledge and limitations of clinical hepatocyte transplantation and aims to advance our understanding toward the goal of developing novel cell replacement therapies for patients who are on the OLT waiting list. PMID- 30470566 TI - Bowel perforation after pneumatic dilatation: Management with fully covered self expandable metallic stent. PMID- 30470567 TI - Bilateral pyoderma gangrenosum associated with ulcerative colitis and restorative proctocolectomy. PMID- 30470561 TI - Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process? PMID- 30470568 TI - Evaluation of the analgesic effects of duloxetine in burn patients: An open-label randomized controlled trial. AB - OBJECTIVES: To evaluate efficacy of addition of duloxetine to usual analgesic regimens in management of burn pain. METHODS: In a 3-week open label randomized controlled trial, burn patients were assigned to the intervention (duloxetine 60mg/day+usual analgesic regimens) or control group (usual analgesic regimens: morphine+/-acetaminophen+/-gabapentin). Intensity and quality of background pain and severity of procedural pain were evaluated using neuropathic pain scale (NPS) and visual analog scale (VAS), respectively. The primary outcome measure was "intensity" item of the NPS (evaluating intensity of the background pain). RESULTS: Forty six patients (age: 35.5+/-6.3 years, TBSA: 36.7+/-15%) (23 per group) completed the study. At baseline, scores of the "intensity" item were 9.13+/-1.42 and 9.13+/-1.86 (P=1) in the intervention and control group, respectively. Comparison of difference in mean changes from baseline to the end of the study showed that addition of duloxetine only significantly reduced the scores of the "intensity" {1.74 (95% CI: 0.61 to 2.86); P=0.003}, and "hot" {1.39 (95% CI: 0.166 to 2.614) P=0.02} items and score of the VAS {2.13 (95% CI: 1.476 to 2.784) P<0.001}. The most reported adverse effects were nausea and insomnia in the both groups. CONCLUSION: Addition of duloxetine may increase efficacy of the other analgesics in reduction of the burn pain. PMID- 30470569 TI - Impact of direct-acting antiviral drugs for chronic hepatitis C on mood: Preliminary results from a longitudinal study. PMID- 30470570 TI - CircRNA has_circ_0006427 suppresses the progression of lung adenocarcinoma by regulating miR-6783-3p/DKK1 axis and inactivating Wnt/beta-catenin signaling pathway. AB - Recently, circular RNAs (circRNAs) are identified as a novel class of noncoding RNAs playing important roles in human malignant tumors. However, the regulatory function of circRNA in lung adenocarcinoma (LUAD) is still largely unknown. Present study aimed to explore the role of circ_0006427 in LUAD progression. Firstly, the downregulation of circ_0006427 in LUAD tissues and cell lines was revealed by microarray analysis and qRT-PCR analysis. And we also confirmed the circ_0006427 as a prognostic target in LUAD patients. Functionally, overexpression of circ_0006427 effectively suppressed cell proliferation, migration and invasion. Mechanistically, circ_0006427 was found to be predominantly located in the cytoplasm of LUCA cell, and was further revealed to positively regulate DKK1 in LUAD by sponging miR-6783-3p. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis and western blot analysis revealed that circ_0006427 inactivated Wnt/beta-catenin signaling pathway by upregulating DKK1. At last, rescue assays proved the function of circ_0006427/miR 6783-3p/DKK1 axis in LUAD progression. In conclusion, our study revealed that circ_0006427 suppressed lung adenocarcinoma progression through regulating miR 6783-3p/DKK1 axis. PMID- 30470571 TI - The role of conventional antibodies targeting the CD4 binding site and CD4 induced epitopes in the control of HIV-1 CRF01_AE viruses. AB - HIV-1 CRF01_AE viruses are highly prevalent in Southeast Asia. However, vulnerability sites in Env of CRF01_AE viruses have not been investigated sufficiently. We examined the sensitivity of CRF01_AE viruses from Japan and Vietnam, together with subtype B viruses from Japan, to neutralization and Fc mediated signaling. Neutralization coverage of broadly neutralizing antibodies (bnAbs), 2G12 and b12, was significantly low against CRF01_AE viruses, compared with subtype B viruses. In contrast, the conventional antibody targeting the CD4 binding site (CD4bs), 49G2, showed better neutralization and Fc-mediated signaling activities against CRF01_AE viruses than subtype B viruses. Fc-mediated signaling activity of anti-CD4 induced (CD4i) antibody, 4E9C, was also detected against CRF01_AE viruses more than subtype B viruses. These results suggest that conventional antibodies against CD4bs and CD4i may play an important role in the control of CRF01_AE viruses. PMID- 30470572 TI - Interleukin-6 derived from cutaneous deficiency of stearoyl-CoA desaturase- 1 may mediate metabolic organ crosstalk among skin, adipose tissue and liver. AB - Stearoyl-CoA desaturase 1 (SCD1), a lipogenic enzyme that adds a double bond at the delta 9 position of stearate (C18: 0) and palmitate (C16: 0), has been proven to be important in the development of obesity. Mice with skin-specific deficiency of SCD1 (SKO) display increased whole-body energy expenditure, which is protective against adiposity from a high-fat diet because it improves glucose clearance, insulin sensitivity, and hepatic steatosis. Of note, these mice also display elevated levels of the "pro-inflammatory" plasma interleukin-6 (IL-6). In whole skin of SKO mice, IL-6 mRNA levels are increased, and protein expression is evident in hair follicle cells and in keratinocytes. Recently, the well-known role of IL-6 in causing white adipose tissue lipolysis has been linked to indirectly activating the gluconeogenic enzyme pyruvate carboxylase 1 in the liver, thereby increasing hepatic glucose production. In this study, we suggest that skin-derived IL-6 leads to white adipose tissue lipolysis, which contributes to the lean phenotype of SKO mice without the incidence of meta-inflammation that is associated with IL-6 signaling. PMID- 30470573 TI - Self-healing and injectable hybrid hydrogel for bone regeneration of femoral head necrosis and defect. AB - BACKGROUND: HA modified by bisphosphonate (BP) (HA-BP) was synthesized by chemical reaction and possessed promising properties such as self-healing, injection ability, and strong adhesion. The main aim of this study was to confirm its role in promoting osteogenic differentiation in vitro and bone regeneration in vivo. METHODS: The cell biocompatibility of this material was determined using the CCK-8 assay. Alkaline phosphatase (ALP), osteocalcin (OT), vascular endothelial growth factor (VEGF), and collagen I were assessed by quantitative real-time polymerase chain reaction (Q-PCR) in the treated group. The number and density of calcium nodules and ALP were evaluated by Alizarin Red staining and ALP staining. We have successfully developed an animal model simulating osteonecrosis of the femoral head (ONFH). Utilizing this animal model, the impact of HA-BP/CaP on bone formation was assessed. The amount of bone regeneration at 1 and 2 months after HA-BP/CaP injection was estimated by micro-computed tomography (micro-CT) analysis and H&E, collagen I, and periostin staining. RESULTS: The number of cells gradually increased in the experimental group over time and was close to that of the blank control group. ALP, collagen I, and VEGF expression was significantly higher in the experimental group than in the blank group (VEGF, ALP, both **p < 0.01; collagen I, ***p<0.001). In addition, the number and density of calcium nodules and ALP was clearly greater in the material group than in the control group. The quantification analysis showed that the mineral contents of regenerated bone at 1 and 2 months after HA-BP/CaP injection were significantly greater than those in the control group, according to micro-CT evaluation (**p<0.01). The amount of organic components in the HA-BP/CaP group was greater than that in the control group after decalcification and H&E staining. In addition, collagen I and periostin staining further confirmed the results of H&E staining. CONCLUSION: This material can boost proliferation and osteogenic differentiation of MC3T3-E1 cells in vitro. It can intensely accelerate bone regeneration in vivo, which is a promising strategy for tissue engineering. PMID- 30470574 TI - Impact of Atrial Fibrillation on Falls in Older Patients: Which is a Problem, Existence or Persistence? AB - OBJECTIVES: Several studies have suggested a possible relationship between atrial fibrillation (AF) and falls. However, whether the relationship depends on AF types is unclear. We investigated the relationship between sustaining AF and falls. DESIGN: Single hospital-based cohort study with a follow-up of falls within 3 years after baseline. SETTING AND PARTICIPANTS: A total of 14,056 patients from our cohort between February 2010 and March 2016. MEASURES: Incidence of falls within 3 years by baseline cardiac rhythm was measured, and we investigated the effects of AF types on incidence of falls. RESULTS: The study population was divided into younger (<75 years old; n = 11,808) and older (>=75 years old; n = 2248) groups, and then divided into 3 groups according to the baseline cardiac rhythm: sinus rhythm (SR), paroxysmal AF (PAF), and persistent AF (PeAF). There were more male patients in the PeAF group; these patients had more comorbidities both in the younger and older groups. The cumulative incidence rates of falls at 1 year in patients with SR, PAF, and PeAF were similar in the younger group (0.4%, 0.4%, and 0.6%, respectively; P = .496), whereas those were significantly different in the older group (2.3%, 2.7%, and 5.0%, respectively; P = .024). In multivariate analysis, both PAF [hazard ratio (HR) 1.179; 95% confidence interval (CI) 0.553-2.511, reference SR] and PeAF (HR 1.502; 95% CI 0.635-3.556) were not associated with falls in the younger group. In the older group, PeAF was independently associated with incidence of falls (HR 2.257; 95% CI 1.262-4.037), but PAF was not (HR 1.317; 95% CI 0.673-2.574). CONCLUSIONS/IMPLICATIONS: PeAF, not PAF, was associated independently with falls in older patients, suggesting the possible effect of irregular beats on physical frailty in the older population. PMID- 30470575 TI - Association Between End-of-Life Conversations in Nursing Homes and End-of-Life Care Outcomes: A Systematic Review and Meta-analysis. AB - OBJECTIVE: Less aggressive end-of-life (EOL) care has been observed when health care professionals discuss approaching EOL and preferences about life-sustaining treatments with nursing home (NH) residents or their families. We performed a comprehensive systematic review to evaluate the association between health care professionals-residents and health care professionals-family EOL conversations and EOL care outcomes. DESIGN: Systematic review with meta-analysis. SETTING AND PARTICIPANTS: Seven databases were searched in December 2017 to find studies that focused on health care professionals-residents (without oncologic disease) and health care professionals-family EOL conversations and aimed to explore the impact of EOL conversations on resident's or family's EOL care outcomes. MEASURES: Random effects meta-analyses with subsequent quality sensitivity analysis and meta-regression were performed to assess the effects of EOL conversations on the decision to limit or withdraw life-sustaining treatments. A funnel plot and Eagger test were used to assess publication bias. RESULTS: 16 studies were included in the qualitative and 7 in the quantitative synthesis. Health care professionals-family EOL conversations were positively associated with the family's decision to limit or withdraw life-sustaining treatments (odds ratio = 2.23, 95% confidence interval: 1.58-3.14). The overall effect of health care professionals-family EOL conversations on the family's decision to limit or withdraw life-sustaining treatments remained stable in the quality sensitivity analysis. In the meta-regression, family members with a higher level of education were less influenced by EOL conversations with health care professionals when making decisions about limiting or withdrawing life-sustaining treatments. No publication bias was detected (P = .4483). CONCLUSIONS/IMPLICATIONS: This systematic review shows that EOL conversations promote palliative care. Structured conversations aimed at exploring NH resident preferences about EOL treatment should become routine. NH administrators should offer health care professionals regular training on EOL conversations, and resident-centered care that involves residents and their families in a shared decision-making process at EOL needs to be promoted. PMID- 30470576 TI - Frailty as a Predictor of Emergency Department Utilization among Community Dwelling Older People: A Systematic Review and Meta-Analysis. PMID- 30470577 TI - Vitamin D Deficiency Is Associated With an Increased Likelihood of Incident Depression in Community-Dwelling Older Adults. AB - OBJECTIVE: To examine the prospective relationship between vitamin D status and incident depression in a large cohort of nondepressed community-dwelling older people. DESIGN: Longitudinal study examining the relationship between vitamin D levels at baseline (wave 1) and incident depression at 2 and 4 years (waves 2 and 3), embedded within the Irish Longitudinal Study on Aging. Participants with depression at wave 1 were excluded. Logistic regression models reporting odds ratios were used to analyze the longitudinal association of vitamin D categories with incident depression. Analysis was weighted for attrition. SETTING AND PARTICIPANTS: Almost 4000 community-dwelling people aged >=50 years. MEASURES: A score >=9 on the Center for Epidemiologic Studies Depression Scale-8 at wave 2 or 3 was indicative of incident depression. Vitamin D analysis was performed using liquid chromatography-tandem mass spectrometry and deficiency, insufficiency, and sufficiency were defined as <30, 30-50, and >50 nmol/L, respectively. RESULTS: The incident depression group (400/3965) had a higher likelihood of baseline vitamin D deficiency (proportional estimation 19.4) [95% confidence interval (CI) 15.1-24.7] vs [12.4 (95% CI 11.1-14.0); Z = 3.93; P < .001]. Logistic regression models demonstrated that participants with vitamin D deficiency had a significantly higher likelihood of incident depression (odds ratio 1.75, 95% CI 1.24-2.46; t = 3.21; P = .001). This finding remained robust after controlling for relevant covariates including physical activity, chronic disease burden, cardiovascular disease and antidepressant use. CONCLUSIONS/IMPLICATIONS: This study demonstrates that vitamin D deficiency is associated with a significant increase in the likelihood of developing depression in later life. These findings are important, given the high prevalence of vitamin D deficiency among older people, the fact that supplementation has a low risk of toxicity or side effects, as well as the significant adverse effect depression can have on functional status and longevity in later life. PMID- 30470578 TI - Reply to psychiatric disorders' paradoxical protective effect on cardiovascular procedures and mortality. PMID- 30470579 TI - Clopidogrel Versus Aspirin for the Treatment of Acute Coronary Syndrome After a 12-Month Dual Antiplatelet Therapy: A Cost-effectiveness Analysis From China Payer's Perspective. AB - PURPOSE: Monotherapy with either aspirin or clopidogrel is recommended for long term use after discontinuation of dual-antiplatelet therapy (DAPT) for acute coronary syndrome (ACS) management after percutaneous coronary intervention (PCI). The present study is to evaluate the cost-effectiveness of clopidogrel versus aspirin after 12-month DAPT for patients with ACS who underwent PCI in China. METHODS: A 2-part model was developed to estimate the cost-effectiveness of clopidogrel compared with aspirin. The short-term part was a decision tree that included health states such as myocardial infarction (MI), stroke, MI and stroke, cardiovascular death, and death from other causes with a treatment horizon of 1 year (base case), 2 years or 3 years after 12-month DAPT. Major bleeding was included. The long-term (lifetime) part was a Markov model that included different health states such as MI, after MI, stroke, after stroke, and death. Drug acquisition cost and other direct medical costs were based on pricing records, literature, and expert panels. Clinical outcomes and utilities were based on literature. The model output included incremental cost-effectiveness ratio of quality-adjusted life-years (QALYs) and total costs per patient. Both 1 way sensitivity analysis and probabilistic sensitivity analysis (PSA) were conducted. FINDINGS: In the base-case scenario, the total costs of the treatment with clopidogrel and aspirin were Y12,590 ($1849/?1590) and Y10,642 ($1563/?1344), respectively; the total QALYs of the 2 patient populations were 9.7341 and 9.6894, respectively. The incremental cost-effectiveness ratio of Y43,593 ($6402/?5515) per QALY gained was lower than 3 times of gross domestic product (GDP) per capita in China (Y161,940, $23,786/?20,449). Both 1-way sensitivity analysis and PSA confirmed the robustness of the results. PSA results indicated that clopidogrel was cost effective versus aspirin in 80.5% of the simulations, considering >3 times the GDP per capita as the threshold. Results in other scenarios (clopidogrel or aspirin for 2 or 3 years after 12-month DAPT) also indicated that clopidogrel was more cost effective than aspirin for patients with ACS after 12-month DAPT. IMPLICATIONS: Compared with aspirin monotherapy, clopidogrel monotherapy for 1 year after 12-month DAPT was cost effective for patients with ACS who underwent PCI in China. Furthermore, when the duration of clopidogrel the monotherapy extended up to 3 years, clopidogrel was still cost effective compared with aspirin. The study was limited by lack of high-quality efficacy data among the Chinese population. PMID- 30470580 TI - Effectiveness of Delayed-release Dimethyl Fumarate on Clinical and Patient Reported Outcomes in Patients With Relapsing Multiple Sclerosis Switching From Glatiramer Acetate: RESPOND, a Prospective Observational Study. AB - PURPOSE: The goal of this study was to evaluate clinical outcomes and patient reported outcomes (PROs) over 12 months in patients with relapsing multiple sclerosis (RMS) who switched from glatiramer acetate (GA) to delayed-release dimethyl fumarate (DMF) 240 mg BID after suboptimal response to GA in real-world clinical practice. METHODS: The RESPOND (Effectiveness of DMF and Its Impact on PROs in Suboptimal GA Responders With RMS) study was a Phase IV, prospective, multicenter, open-label, single-arm, 12-month observational trial. The study was conducted in the United States at 63 sites between August 2013 and February 2016. Patients diagnosed with RMS who experienced a suboptimal response to GA (defined as perceived suboptimal efficacy, intolerance, or poor adherence to GA) were eligible for enrollment. DMF treatment was initiated within 60 days of enrollment. The primary objective was to estimate the annualized relapse rate (ARR) at 12 months based on data collected from medical records and compare it with the 12 months before DMF initiation. Secondary objectives of the study included assessing the change in PRO scores from baseline to 12 months; PROs were recorded before and at 6 and 12 months after DMF initiation. FINDINGS: Of the 318 patients included in the analysis population, 247 (78%) completed treatment. Mean (SD) time on GA treatment before switching to DMF was 51.3 months (49.1 months). The ARR (95% CI) reported for the 12 months before DMF initiation was 0.49 (0.42 0.57) compared with 0.11 (0.07-0.17) at 12 months after DMF initiation, representing a 78% reduction in ARR (P < 0.0001). Statistically significant improvements from baseline were observed for multiple PROs, including the 36-item Short Form Health Survey physical and mental component summaries (P = 0.0201 and P = 0.0014, respectively), the 5-item Modified Fatigue Impact Scale (P = 0.0002), the 14-item Treatment Satisfaction Questionnaire for Medication (P < 0.0001), and the 7-item Beck Depression Inventory (P = 0.0117). IMPLICATIONS: DMF may be an effective treatment option in patients with RMS who experience a suboptimal response to GA. The results should be interpreted with caution due to the observational nature of the study and the lack of a control group. Other limitations of the study include a potential bias due to regression to the mean and lack of randomization. ClinicalTrials.gov identifier: NCT01903291. PMID- 30470581 TI - Early disease progression and treatment discontinuation in patients with advanced ovarian cancer receiving immune checkpoint blockade. AB - OBJECTIVE: Delayed responses observed with immune checkpoint blockade (ICB) present a challenge for patients with peritoneal malignancies, who risk early symptomatic disease progression requiring treatment discontinuation. While efforts are ongoing to define the biomarkers of response, it is equally important to identify patients at risk for early discontinuation. We sought to investigate the timing of disease progression in epithelial ovarian cancer (EOC) patients treated with ICB and to identify pre-treatment clinical parameters associated with early discontinuation. METHODS: Retrospective analysis was performed on EOC patients treated with ICB at MSKCC from January 2013 to May 2017. Cutoffs for early and very early discontinuation due to disease progression were defined at 12 and 8 weeks, respectively. Univariate and multivariate logistic regression models were built based on pre-treatment clinical variables. RESULTS: Of 108 identified patients, 89 were included in the analysis. Forty-six (51.7%) patients discontinued therapy early, 30 of which (33.7%) discontinued therapy very early. Eight patients (9.0%) died within 12 weeks of ICB initiation from disease progression. In multivariate analyses, bulky peritoneal disease (p = 0.009, OR: 4.94) and liver parenchymal metastases (p = 0.001, OR: 8.08) were associated with early discontinuation. Liver parenchymal metastases (p = 0.001, OR 6.64), and high neutrophil-to-lymphocyte ratio (p = 0.021, OR: 3.54), were associated with very early discontinuation. CONCLUSIONS: Over 50% of EOC patients suffer disease progression requiring early discontinuation of ICB. Pre-treatment prognostic clinical characteristics may identify patients at highest risk for early discontinuation due to disease progression and warrant caution in using these agents in late line patients with advanced disease. PMID- 30470582 TI - Relationship Between Cortical Excitation and Inhibition and Task-Induced Activation and Deactivation: A Combined Magnetic Resonance Spectroscopy and Functional Magnetic Resonance Imaging Study at 7T in First-Episode Psychosis. AB - BACKGROUND: Schizophrenia is thought to be a disorder of brain dysconnectivity. An imbalance between cortical excitation/inhibition is also implicated, but the link between these abnormalities remains unclear. The present study used magnetic resonance spectroscopy and functional magnetic resonance imaging at 7T to investigate how measurements of glutamate and gamma-aminobutyric acid (GABA) relate to the blood oxygen level-dependent (BOLD) response during a cognitive task, and how these relationships are altered in schizophrenia. METHODS: Usable functional magnetic resonance imaging data from 17 first-episode psychosis (FEP) patients (4 women, 13 men) and 21 matched healthy control subjects (HCs) (5 women, 16 men) were acquired during a Stroop task. Within- and between-group comparisons of the BOLD response were performed. Neurometabolite levels were measured in the dorsal anterior cingulate cortex. Two multiple regressions investigated how glutamate, glutamine, and GABA related to the BOLD response in HCs and FEP patients separately. A third investigated between-group differences in the relationships between the BOLD response and each of these neurometabolites. RESULTS: Compared with HCs, FEP patients showed an increased BOLD response within regions of the executive and default mode networks. In FEP patients, the relationship between anterior cingulate cortex glutamate levels and the BOLD response in regions of the posterior default mode network was opposite to that of HCs. In FEP patients but not HCs, anterior cingulate cortex GABA levels correlated with the local BOLD response and with the Stroop reaction time. CONCLUSION: These results suggest a mechanism whereby alterations in the relationship between cortical glutamate/GABA and BOLD response is disrupting the dynamic of major neural networks, possibly affecting cognition. PMID- 30470583 TI - The Neurobiology of Personal Control During Reward Learning and Its Relationship to Mood. AB - BACKGROUND: The majority of reward learning neuroimaging studies have not focused on the motivational aspects of behavior, such as the inherent value placed on choice itself. The experience and affective value of personal control may have particular relevance for psychiatric disorders, including depression. METHODS: We adapted a functional magnetic resonance imaging reward task that probed the value placed on exerting control over one's decisions, termed choice value, in 122 healthy participants. We examined activation associated with choice value; personally chosen versus passively received rewards; and reinforcement learning metrics, such as prediction error. Relationships were tested between measures of motivational orientation (categorized as autonomy, control, and impersonal) and subclinical depressive symptoms. RESULTS: Anticipating personal choice activated left insula, cingulate, right inferior frontal cortex, and ventral striatum (pfamilywise error-corrected < .05). Ventral striatal activations to choice were diminished in participants with subclinical depressive symptoms. Personally chosen rewards were associated with greater activation of the insula and inferior frontal gyrus, cingulate cortex, hippocampus, thalamus, and substantia nigra compared with rewards that were passively received. In participants who felt they had little control over their own behavior (impersonal orientation), prediction error signals in nucleus accumbens were stronger during passive trials. CONCLUSIONS: Previous findings regarding personal choice have been verified and advanced through the use of both reinforcement learning models and correlations with psychopathology. Personal choice has an impact on the extended reward network, potentially allowing these clinically important areas to be addressed in ways more relevant to personality styles, self-esteem, and symptoms such as motivational anhedonia. PMID- 30470584 TI - Infections related to healthcare in patients hospitalized in a Urology service: resistance patterns and adequacy of empirical antibiotic treatment as a prognostic factor. AB - OBJECTIVES: To evaluate the suitability of empirical antibiotic therapy in HAIs and the antibiotic resistance patterns of the responsible microorganisms, as well as the incidence of mortality and risk factors involved. METHOD: A prospective observational study was carried out on patients of both sexes older than 16years, admitted by any urological process during a period of 4years. The incidence and characteristics of HAIs, as well as the causative organism and its resistance, the initial empirical antibiotic therapy and its modification, if required, and mortality rates are analysed. RESULTS: Out of 6,546 patients, 6.3% suffered HAIs, 70.5% corresponding to urinary tract infection and 22.1% to infection of the surgical wound. E.coli, Enterococcus spp., Klebsiella spp. y P.aeruginosa were the most frequently implicated (25.1%, 17.5%, 13.5% and 12.3%, respectively). E.coli and Klebsiella spp. were producers of extended-spectrum beta-lactamases (ESBL) in 24.7% and 47.8%, respectively. 4.3% of Klebsiella and 33.3% of Pseudomonas were carbapenems-resistant. The overall resistance to quinolones was approximately 50%. The most commonly used antibiotics for empirical therapy were cephalosporins of 3rd and 4th generation (33.6%) and carbapenems (28.2%). An overall rate of adequacy of empirical antibiotic therapy of 82.9% was obtained. The mortality rate in patients with HAIs was 2.2%, compared with 0.3% in patients without infection. In a multivariate analysis, the variables associated with the highest mortality risk were the isolation of ESBL-producing enterobacteria and the inadequate empirical antibiotic treatment. CONCLUSIONS: The selection of empirical antibiotic therapy was quite accurate. An increase in HAIs by multiresistant microorganisms, such as ESBL Enterobacteria or multiresistant P.aeruginosa is being observed. The mortality risk increases with inadequate initial empirical antibiotic therapy or when the responsible microorganism is an ESBL enterobacteria. PMID- 30470586 TI - Postoperative pain and cosmetic results of minilaparoscopic nephrectomy compared to the conventional technique. AB - INTRODUCTION: In recent years urology has been focussing on less invasive forms of laparoscopy with less impact on the abdominal wall. The minilaparoscopy (ML) is promising in this regard. Our objective is to compare the results of a series of patients who underwent minilaparoscopic nephrectomy with another series who underwent conventional laparoscopy (CL). MATERIAL AND METHODS: We chose 8 nephrectomies performed by mini-laparoscopy in a single hospital (NmL group) from a total of 110 patients included in multiple centres and compared them retrospectively with a contemporary series of 16 patients who underwent CL (NL group). From 1 to 3 3mm and 5mm trocars were used for the NmL and the NL, respectively, one 10mm trocar in the pararectal edge of a Pfannenstiel incision and another 11mm paraumbilical trocar for the optics. Age, BMI, ASA, complications, analgesic requirements in the postoperative period and cosmetic satisfaction were recorded using the Patient Scar Assessment Questionnaire (PSAQ), one month after the intervention. RESULTS: Both groups were comparable and there were no differences in terms of surgery time, number of ports used, hospital stay or intra-and postoperative complications. In only one patient from the NmL group, a 3mm trocar had to be replaced by a 5mm trocar and one patient in the NL group was converted to hand-assisted surgery due to severe adherences. The patients in the NmL group had less postoperative pain on the VAS (+/-0 vs. 4+/ 25, P=.05) and were more satisfied with their appearance on the PSAQ (8.5+/-1.4 vs. 16.6+/-3.1, P=.05) compared to the NL group. CONCLUSIONS: The results obtained with the ML instrument were similar to those obtained by CL, but with the advantages of less postoperative pain and better cosmetic results. PMID- 30470585 TI - Cognitive function assessment in elderly patients with overactive bladder treated with transdermal oxybutynin. AB - INTRODUCTION AND OBJECTIVES: Older patients with overactive bladder under antimuscarinic treatment are especially susceptible to cognitive impairment. The aim was to assess short term changes in cognitive function in elderly patients with overactive bladder treated with transdermal oxybutynin. MATERIALS AND METHODS: Observational, retrospective, multicentre study in patients with overactive bladder aged 65-80 years undergoing treatment with transdermal oxybutynin. Before and after one month of treatment, cognitive function using the Memory Alteration Test and Clock-Drawing Test, changes in symptoms with validated questionnaires, patient perception of treatment response using Treatment Benefit Scale and treatment adherence with the modified Morisky-Green test, were assessed. RESULTS: From 85 eligible patients, 70 completed the assessment (mean age: 71.4+/-4.5; BMI: 28.7+/-3.1kg/m2). No cognitive impairment was observed after one month with transdermal oxybutynin: Memory Alteration Test (+1 point; 95%CI: 0.0-1.5), Clock-Drawing Test (0 points; 95%CI: 0.0-0.0). A statistically significant improvement (P<.001) was observed in all urinary storage symptoms, except stress urinary incontinence. There was an improvement in the Bladder Control Self-Assessment Questionnaire (symptom score: -2.27; 95%CI: -2.8, -1.7; P<.001; bother score: -2.73; 95%CI: -3.3, -2.1; P<.001). 70% of patients reported either a stable or improved bladder condition according to the Patient Perception of Bladder Condition questionnaire. 72.8% of patients reported that their urinary problems had improved or greatly improved with an 84.3% treatment adherence. CONCLUSIONS: No cognitive impairment was observed in elderly patients after one month of treatment with transdermal oxybutynin; urinary urgency symptoms improved and there was adequate treatment adherence. PMID- 30470587 TI - MiR-708-5p is inversely associated with EWS/FLI1 Ewing sarcoma but does not represent a prognostic predictor. AB - BACKGROUND: Overall survival of Ewing sarcoma (EWS) remains poor and less than 30% of patients with metastatic or recurrent disease survive despite current treatments. Thus, there is a constant search for new biomarkers for diagnosis, prognosis and prediction of therapy. Numerous studies have reported the abnormal expression of miR-708-5p in tumors of different origins. However, its role in EWS remains unclear. PROCEDURE: qRT-PCR was performed in nineteen consecutive EWS samples and twelve non-tumor bone samples from age-matched controls. Functional assays were performed in SK-ES-1 cells transfected with miR-708 lentiviral-based vectors and results analyzed in terms of clonogenicity, migration, invasion and western blot. RESULTS: We show that miR-708-5p is downregulated in EWS tissues though no associations with any prognostic features such as HUVOS grade, event or survival were found in our cohort. Nonetheless, expression levels of this micro RNA were inversely associated with the presence of the EWS/FLI1 translocation. When miR-708-5p was transfected into the SK-ES-1 cell line, it did not affect migration or clonogenicity, but promoted a significant increase on the invasive potential of cells endorsed with high expression of MMP2. CONCLUSIONS: Taken together, our results suggest that despite downregulated in EWS samples, this miRNA might represent a secondary genetic alteration derived from the pleiotropic cellular effects of the abnormal EWS/FLI1 transcription factor that does not affect tumor growth but instead, is related with the promotion of tumor invasion, not being suitable for future therapeutic intervention. PMID- 30470588 TI - Genome-wide isoform-level analysis reveals tumor-specific isoforms for lung adenocarcinoma diagnosis and prognosis. AB - Last decades have witnessed the great progress in exploration of tumor transcriptome. However, most researches were restricted in gene-level expression. mRNA isoforms, especially tumor-specific isoforms have not been fully explored in tumor. Here, by analyzing RNA-seq data derived from hundreds of samples in TCGA projects, we comprehensively characterized the expression variations of mRNA isoforms in adenocarcinoma of lung (LUAD), which is one of leading causes of cancer-related death. Our analysis found that a variety of mRNA isoforms showed differential expression in LUAD tumor samples. Some of them even showed distinct variations compared to their host genes. Further analysis of functional enrichment revealed that up- and down-regulated mRNA isoforms took part in different types of biological process. In addition, we also identified hundreds of isoforms that expressed exclusively in LUAD tumor samples. Furthermore, the expression level of several isoforms, such as uc001kuk.3 and uc003yls.2, could separate tumor patients by overall survival periods. Our study provided new candidates for the diagnosis and prognosis of lung cancer. PMID- 30470589 TI - Leveraging calcium imaging to illuminate circuit dysfunction in addiction. AB - Alcohol and drug use can dysregulate neural circuit function to produce a wide range of neuropsychiatric disorders, including addiction. To understand the neural circuit computations that mediate behavior, and how substances of abuse may transform them, we must first be able to observe the activity of circuits. While many techniques have been utilized to measure activity in specific brain regions, these regions are made up of heterogeneous sub-populations, and assessing activity from neuronal populations of interest has been an ongoing challenge. To fully understand how neural circuits mediate addiction-related behavior, we must be able to reveal the cellular granularity within brain regions and circuits by overlaying functional information with the genetic and anatomical identity of the cells involved. The development of genetically encoded calcium indicators, which can be targeted to populations of interest, allows for in vivo visualization of calcium dynamics, a proxy for neuronal activity, thus providing an avenue for real-time assessment of activity in genetically and anatomically defined populations during behavior. Here, we highlight recent advances in calcium imaging technology, compare the current technology with other state-of the-art approaches for in vivo monitoring of neural activity, and discuss the strengths, limitations, and practical concerns for observing neural circuit activity in preclinical addiction models. PMID- 30470590 TI - Establishing Validity and Cross-Context Equivalence of Measures and Indicators. AB - Quantitative research depends on using measures to collect data that are valid (ie, reflect well the phenomena of interest) and perform equivalently across contexts. Demonstrating validity and cross-context equivalence requires specifically designed studies, but many such studies have problems that have limited their usefulness. This article explains validity and cross-context equivalence of measures (and important related concepts) and clarifies how to establish them. Validation is the process of determining whether a measure or indicator is suitable for providing useful analytical measurement for a given purpose and context. Cross-context equivalence means that a measure performs comparably across contexts. Four types of equivalence are construct, item, measurement, and scalar. Establishing validity and cross-context equivalence requires representing mathematically the errors (ie, imprecision, undependability, and inaccuracy) of a measure and using appropriate statistical methods to quantify these errors. Studies aiming to provide evidence about the validity of a measure need to clarify the purpose and context for use of that measure. Choose one of the two conceptual systems for validation; obtain data to establish the extent to which the measure is well constructed, reliable, and accurate; and use analytic methods beyond simple correlations to provide a basis for making reasoned judgment about whether the measure provides useful analytic measurement for the particular purpose(s) and context. Establishing accuracy of a measure requires having available other measures known to be accurate as comparators; in the case that no other measure understood to be more accurate is available, then the study will be able to establish agreement rather than validity. PMID- 30470591 TI - 5-Fluorouracil-related Cardiotoxicity; Findings From Five Randomized Studies of 5 Fluorouracil-based Regimens in Metastatic Colorectal Cancer. AB - BACKGROUND: 5-Fluorouracil (5-FU) represents the backbone of systemic therapy regimens of colorectal cancer. The current study aims at evaluating the patterns and predictors of cardiac adverse events associated with various 5-FU-based systemic therapy regimens among patients with metastatic colorectal cancer. MATERIALS AND METHODS: This pooled analysis includes de-identified patient-level datasets from 5 randomized studies (NCT00272051, NCT00305188, NCT00115765, NCT00364013, and NCT00384176). In order to evaluate factors predicting the development of all cardiac toxicities, arrhythmias, and ischemic events, univariate logistic regression analysis was conducted. Subsequently, factors with P < .05 in univariate analysis were included in multivariate logistic regression analysis. RESULTS: A total of 3223 patients were included in the pooled analysis. A total of 255 (7.9%) patients developed some form of a cardiac toxicity, among which 153 (4.7%) patients developed some form of arrhythmia and 62 (1.9%) patients developed an ischemic event. Within multivariate logistic regression analysis for factors predicting cardiac toxicities, only bevacizumab-containing regimens (P = .002) and panitumumab-containing regimens (P < .001) were predictive for the occurrence of cardiac toxicity. Similarly, within multivariate logistic regression analysis for factors predicting cardiac arrhythmias, only panitumumab-based regimens were predictive of the occurrence of arrhythmias (P < .001). Likewise, within multivariate logistic regression analysis for factors predicting cardiac ischemia, only bevacizumab-containing regimens were predictive of ischemic events (P = .004). CONCLUSIONS: Bevacizumab- and panitumumab containing regimens seem to be associated with a higher risk of cardiac toxicities compared with other 5-FU-based regimens. Bevacizumab-containing regimens seem to increase the risk of 5-FU-related ischemic events, whereas panitumumab-containing regimens seem to increase the risk of arrhythmias. PMID- 30470592 TI - Improving the quality of life of care home residents with dementia: Cost effectiveness of an optimized intervention for residents with clinically significant agitation in dementia. AB - INTRODUCTION: To examine whether an optimized intervention is a more cost effective option than treatment as usual (TAU) for improving agitation and quality of life in nursing home residents with clinically significant agitation and dementia. METHODS: A cost-effectiveness analysis within a cluster-randomized factorial study in 69 care homes with 549 residents was conducted. Each cluster was randomized to receive either the Well-being and Health for people with Dementia (WHELD) intervention or TAU for nine months. Health and social care costs, agitation, and quality of life outcomes were evaluated. RESULTS: Improvements in agitation and quality of life were evident in residents allocated to the WHELD intervention group. The additional cost of the WHELD intervention was offset by the higher health and social care costs incurred by TAU group residents (mean difference, L2103; 95% confidence interval, -13 to 4219). DISCUSSION: The WHELD intervention has clinical and economic benefits when used in residents with clinically significant agitation. PMID- 30470593 TI - How Much Loading Does Water Resistance Voice Therapy Impose on the Vocal Folds? An Experimental Human Study. AB - OBJECTIVES: Water resistance voice therapy applies phonation into water through a tube. This study investigates how strenuous this therapy can be for the vocal folds in terms of impact stress (IS). It further examines whether it is possible to estimate the IS using the contact quotient (CQ) and maximum derivative from an electroglottogram (EGG). STUDY DESIGN: Experimental study. METHODS: A male participant sustained a rounded back vowel [u:] or [o:] at a comfortable speaking pitch and loudness, and phonated into a silicone "Lax Vox" tube submerged 2 cm in water. High-speed videolaryngoscopy was performed with a rigid scope. Oral air pressure (Poral) was registered in a mouthpiece through which an endoscope was inserted into the larynx. An EGG was recorded. RESULTS: The CQEGG from the EGG and the closed quotient from the glottal width (CQarea) increased, while the maximum glottal amplitude and absolute value of derivative minimum (dmin) and also the derivative maximum from the EGG decreased for phonation into water. Normalized amplitude quotient from the glottal width variation also decreased but the change was not significant. CONCLUSIONS: Based on the glottal area findings, water resistance therapy does not seem to increase vocal fold loading (in terms of increased IS) even if the increase of CQarea, and CQEGG suggest so. CQEGG may qualitatively correspond to that of area, but the reliability of CQ (from the glottal area or the EGG) and the maximum derivative from the EGG as estimates of IS in semiocclusion exercises warrant further studies. PMID- 30470594 TI - Prevalence, Characterization, and Impact of Voice Disorders in Fado Singers. AB - INTRODUCTION: Fado is a genre of urban folk music from Portugal characterized by some particularities. Some indictions in the study point this population of singers to be at higher risk of developing voice disorders. AIM: This study aims to provide estimates of the prevalence of voice disorders in Fado singers, and to characterize the professional practice and the impact of voice disorders on their careers. METHODS: This is a cross sectional study based on a self-administered questionnaire split into six parts and 55 questions. RESULTS: A gender-balanced sample of 111 singers was achieved. Most of them recorded at least once. Winter and spring were found to be the most difficult seasons in which to sing. The overall prevalence of self-reported voice disorders was 39.6%, significantly higher in females. Almost all sought clinical guidance. Vocal fold nodules, functional dysphonia, and vocal fold polyp were the most common diagnoses. Vocal fatigue and hoarseness were the main symptoms reported. Nearly half of the singers had to cancel shows due to voice disorders. CONCLUSION: Fado singers reveal both a relative high prevalence of voice disorders and related concerns, even though some discrepancies were found regarding other apparently similar singer populations. These results lead support the need for further investigation regarding the risk or protective factors influencing voice disorders. PMID- 30470595 TI - Characterizing vulnerable brain areas and circuits in mouse models of autism: Towards understanding pathogenesis and new therapeutic approaches. AB - Recent human genetics studies have identified many genetic variants that may be responsible for autism spectrum disorder (ASD). ASD mouse models with genetic modifications mimicking these rare genetic variants have provided invaluable mechanistic insights into the disruption of various biological processes and brain areas/circuitry affected in ASD patients. In this review, we begin by reviewing several mouse models for ASD-associated copy number variations (CNVs) to illustrate how they have been employed to establish causal links between their behavioral phenotypes and the affected genes. We then focus on studies using one of the principal behavioral abnormalities associated with ASD, social behavior, to identify the molecular and circuit-level deficits involved. Finally, we end by discussing other mouse models designed to probe how the disruption of specific biological processes such as autophagy and neurogenesis may contribute to ASD pathogenesis. By achieving a greater understanding of the pathophysiology and pathogenic mechanisms involved in ASD and related disorders, novel therapeutic strategies may be devised for ASD patients in the near future. PMID- 30470596 TI - Corrigendum to 'Design, synthesis and in vitro study of densely functionalized oxindoles as potent alpha-glucosidase inhibitors' [Bioorg. Med. Chem. 26(18) (2018) 4996-5005]. PMID- 30470597 TI - Small molecules inhibit ex vivo tumor growth in bone. AB - Bone is a common site of metastasis for breast, prostate, lung, kidney and other cancers. Bone metastases are incurable, and substantially reduce patient quality of life. To date, there exists no small-molecule therapeutic agent that can reduce tumor burden in bone. This is partly attributed to the lack of suitable in vitro assays that are good models of tumor growth in bone. Here, we take advantage of a novel ex vivo model of bone colonization to report a series of pyrrolopyrazolone small molecules that inhibit cancer cell invasion and ex vivo tumor growth in bone at single-digit micromolar concentration. We find that the compounds modulated the expression levels of genes associated with bone-forming osteoblasts, bone-destroying osteoclasts, cancer cell viability and metastasis. Our compounds provide chemical tools to uncover novel targets and pathways associated with bone metastasis, as well as for the development of compounds to prevent and reverse bone tumor growth in vivo. PMID- 30470598 TI - Discovery of novel 2,5-dihydroxyterephthalamide derivatives as multifunctional agents for the treatment of Alzheimer's disease. AB - A series of 2,5-dihydroxyterephthalamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives exhibited good multifunctional activities. Among them, compound 9d showed the best inhibitory activity against both RatAChE and EeAChE (IC50 = 0.56 MUM and 5.12 MUM, respectively). Moreover, 9d exhibited excellent inhibitory effects on self induced Abeta1-42 aggregation (IC50 = 3.05 MUM) and Cu2+-induced Abeta1-42 aggregation (71.7% at 25.0 MUM), and displayed significant disaggregation ability to self- and Cu2+-induced Abeta1-42 aggregation fibrils (75.2% and 77.2% at 25.0 MUM, respectively). Furthermore, 9d also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activities and appropriate BBB permeability. These multifunctional properties highlight 9d as promising candidate for further studies directed to the development of novel drugs against AD. PMID- 30470599 TI - Using ultrasound to guide fluid management in children. PMID- 30470600 TI - Comparison of SIRS, qSOFA, and NEWS for the early identification of sepsis in the Emergency Department. AB - OBJECTIVES: The increasing use of sepsis screening in the Emergency Department (ED) and the Sepsis-3 recommendation to use the quick Sepsis-related Organ Failure Assessment (qSOFA) necessitates validation. We compared Systemic Inflammatory Response Syndrome (SIRS), qSOFA, and the National Early Warning Score (NEWS) for the identification of severe sepsis and septic shock (SS/SS) during ED triage. METHODS: This was a retrospective analysis from an urban, tertiary-care academic center that included 130,595 adult visits to the ED, excluding dispositions lacking adequate clinical evaluation (n = 14,861, 11.4%). The SS/SS group (n = 930) was selected using discharge diagnoses and chart review. We measured sensitivity, specificity, and area under the receiver operating characteristic (AUROC) for the detection of sepsis endpoints. RESULTS: NEWS was most accurate for triage detection of SS/SS (AUROC = 0.91, 0.88, 0.81), septic shock (AUROC = 0.93, 0.88, 0.84), and sepsis-related mortality (AUROC = 0.95, 0.89, 0.87) for NEWS, SIRS, and qSOFA, respectively (p < 0.01 for NEWS versus SIRS and qSOFA). For the detection of SS/SS (95% CI), sensitivities were 84.2% (81.5-86.5%), 86.1% (83.6-88.2%), and 28.5% (25.6-31.7%) and specificities were 85.0% (84.8-85.3%), 79.1% (78.9-79.3%), and 98.9% (98.8-99.0%) for NEWS >= 4, SIRS >= 2, and qSOFA >= 2, respectively. CONCLUSIONS: NEWS was the most accurate scoring system for the detection of all sepsis endpoints. Furthermore, NEWS was more specific with similar sensitivity relative to SIRS, improves with disease severity, and is immediately available as it does not require laboratories. However, scoring NEWS is more involved and may be better suited for automated computation. QSOFA had the lowest sensitivity and is a poor tool for ED sepsis screening. PMID- 30470601 TI - Central nervous system toxicity due to mefenamic acid. AB - Mefenamic acid is a fenamate nonsteroidal anti-inflammatory (NSAI) drug, which is used for several years for pain management. However, it has been rarely reported that, mefenamic acid can induce central nervous system toxicity both in toxic doses and therapeutic usage. We report a case of a 27-year-old female who presented to the emergency department (ED) with altered mental status and vomiting. On admission to the ED, she was lethargic and disoriented. Her vital signs were normal and her physical examination was completely normal except dysarthric speech. The etiology of altered mental status was investigated with electrolyte levels, cranial computed tomography, cranial magnetic resonance imaging and EEG, however the results were normal. Her blood gas analysis revealed a deep metabolic acidosis with a pH of 7.14. Neither etiologic agent nor drug use history was provided at the presentation; she had only osteogenesis imperfecta since several years and she had been using various NSAI drugs. However, her relatives later stated that, she took mefenamic acid for her pains since two weeks. After her admission to intensive care unit, her neurologic state was improved gradually after plasmapheresis and she was discharged healthy. Although mefenamic acid has been considered as one of the safe NSAI drugs, its effects due to central nervous system toxicity should be cautiously handled. PMID- 30470602 TI - Right iliac bone pathological fracture mimicking acute appendicitis. AB - Simple bone cyst (SBC) also known as unicameral bone cyst is a benign, radiolucent bone lesion that is seen commonly in childhood. These lesions are usually found incidentally although pain and swelling can be seen. The most common complication is a pathological fracture, and this is often the cause of presentation. Here, we present a 22-year-old male with right lower quadrant pain due to SBC related pathological fracture of right iliac bone which is mimicking acute appendicitis. PMID- 30470603 TI - Markers of cardiogenic shock predict persistent acute kidney injury after out of hospital cardiac arrest. AB - OBJECTIVE: Ischemia and reperfusion injury (IRI) in cardiac arrest patients after return to spontaneous circulation causes dysfunctions in multiple organs. Kidney injury is generally transient but in some patients persists and contributes both to mortality and increased resource utilisation. Ongoing shock may compound renal injury from IRI, resulting in persistent dysfunction. We tested whether cardiac dysfunction was associated with the development of persistent acute kidney injury (PAKI) in the first 72 h after cardiac arrest. METHODS: We performed an observational retrospective study from January 2013 to April 2017. We included consecutive patients treated after out-of-hospital cardiac arrest at a single academic medical center with renal function measured and immediately and for 48 h post arrest. We also recorded each patient's pre arrest baseline creatinine, demographic and clinical characteristics. Our primary outcome of interest was PAKI, defined as acute kidney injury (AKI) on at least 2 measurements 24 h apart. We compared demographics and outcomes between patients with PAKI and those without, and used logistic regression to identify independent predictors of PAKI. RESULTS: Of 98 consecutive patients, we excluded 24 for missing data. AKI was present in 75% of subjects on arrival. PAKI developed in 35% of patients. PAKI patients had a longer hospital length of stay (median 21 vs 11 days) and lower hospital survival (47% vs 71%). Serum lactate levels, dosage of adrenaline during resuscitation and days of dobutamine infusion strongly predicted PAKI. CONCLUSIONS: Among patient who survive cardiac arrest, acute AKI is common and PAKI occurs in more than one third. PAKI is associated both with survival and with length of stay at the hospital. High doses of adrenaline, high serial serum lactate levels, and dose of dobutamine predict PAKI. Evaluation of the trajectory of renal function over the first few days after resuscitation can provide prognostic information about patient recovery. PMID- 30470604 TI - Combined cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as a treatment for recurrent epithelial ovarian cancer-National Cancer Institute experience. AB - BACKGROUND: Complete cytoreduction has been associated with survival benefit in the treatment of recurrent epithelial ovarian cancer (EOC). In this study, the aim is to investigate the role of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of recurrent EOC. PATIENTS AND METHODS: This is a descriptive (case series) study including 9 patients with recurrent EOC treated by CRS and HIPEC. They were treated and followed up between December 2011 and December 2017. The study was performed at The National Cancer Institute (NCI) - Cairo University (CU). RESULTS: Postoperative death occurred in 2 cases, while recurrence occurred in one case. Six cases had smooth postoperative course and free follow-up. Median follow-up period was 39 months, ranging from 29 to 47 months. Median overall survival was 42 months while median disease-free survival was not reached. CONCLUSIONS: Treatment of recurrent EOC by CRS and HIPEC appears to be promising. However, this line of treatment requires further evaluations and larger studies for better assessment of the potential survival benefits and possible complications. PMID- 30470605 TI - Neuroendocrine tumors of the lung: A five-year retrospective experience of Egyptian NCI (2010-2014). AB - BACKGROUND: The spectrum of lung neuroendocrine tumors (NETs) encompasses low grade typical carcinoid (TC), intermediate grade atypical carcionid (AC) and high grade, both large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC), with extreme differences in management and survival. OBJECTIVE: To study clinicopathologic and prognostic factors affecting survival of lung NETs. PATIENTS AND METHODS: This is a retrospective study evaluating 35 patients with primary lung NETs treated at National Cancer Institute of Egypt (NCI-E) between January 2010 and December 2014. Pathological diagnosis depended on definite morphology and positivity to at least one of the neuroendocrine markers by immunohistochemistry. RESULTS: The mean age of the patients was 53 +/- 11.2 years with male predominance. Performance status (PS) I was encountered in 48.6%. SCLC was the prevalent histology in 68.6%, followed by LCNEC & TC in 20 & 11.4%, respectively. Curative surgery was employed in 100 & 57% of TC & LCNEC patients, respectively. Stage IV was anticipated in 87.5 & 43% of SCLC & LCNEC, respectively. For the entire cohort, the median event-free survival (EFS) and overall survival (OS) were 8.0 and 13.7 months, respectively, whereas the 3-year EFS and OS were 17.8 & 20%, respectively. SCLC patients showed significantly the worst OS compared to other NETs (p = 0.001). Patients who presented with stage IV and PS > I demonstrated significantly shorter OS than those with locoregional and PS I (p = 0.00001 &p = 0.002, respectively). CONCLUSIONS: SCLC subtype, stage IV and initial PS > I are poor prognostic factors for lung NETs associated with shorter survival. This conclusion needs to be confirmed by larger studies. PMID- 30470606 TI - Real-Time Standard View Classification in Transthoracic Echocardiography Using Convolutional Neural Networks. AB - Transthoracic echocardiography examinations are usually performed according to a protocol comprising different probe postures providing standard views of the heart. These are used as a basis when assessing cardiac function, and it is essential that the morphophysiological representations are correct. Clinical analysis is often initialized with the current view, and automatic classification can thus be useful in improving today's workflow. In this article, convolutional neural networks (CNNs) are used to create classification models predicting up to seven different cardiac views. Data sets of 2-D ultrasound acquired from studies totaling more than 500 patients and 7000 videos were included. State-of-the-art accuracies of 98.3% +/- 0.6% and 98.9% +/- 0.6% on single frames and sequences, respectively, and real-time performance with 4.4 +/- 0.3 ms per frame were achieved. Further, it was found that CNNs have the potential for use in automatic multiplanar reformatting and orientation guidance. Using 3-D data to train models applicable for 2-D classification, we achieved a median deviation of 4 degrees +/- 3 degrees from the optimal orientations. PMID- 30470607 TI - Individuality rooted in the brain's development. PMID- 30470608 TI - Rewiring public understanding of neurological disorders. PMID- 30470609 TI - Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis. AB - Treatment of the neuronal ceroid lipofuscinoses, also known as Batten disease, is at the start of a new era because of diagnostic and therapeutic advances relevant to this group of inherited neurodegenerative and life-limiting disorders that affect children. Diagnosis has improved with the use of comprehensive DNA-based tests that simultaneously screen for many genes. The identification of disease causing mutations in 13 genes provides a basis for understanding the molecular mechanisms underlying neuronal ceroid lipofuscinoses, and for the development of targeted therapies. These targeted therapies include enzyme replacement therapies, gene therapies targeting the brain and the eye, cell therapies, and pharmacological drugs that could modulate defective molecular pathways. Such therapeutic developments have the potential to enable earlier diagnosis and better targeted therapeutic management. The first approved treatment is an intracerebroventricularly administered enzyme for neuronal ceroid lipofuscinosis type 2 disease that delays symptom progression. Efforts are underway to make similar progress for other forms of the disorder. PMID- 30470610 TI - Adolescent Infertility: A Case Report. PMID- 30470611 TI - Association between precystectomy epithelial tumor marker response to neoadjuvant chemotherapy and oncological outcomes in urothelial bladder cancer. AB - INTRODUCTION AND OBJECTIVES: We previously reported that elevated precystectomy serum levels of epithelial tumor markers predict worse oncological outcome in patients with invasive bladder cancer (BC). Herein, we evaluated the effect of neoadjuvant chemotherapy (NAC) on elevated tumor marker levels and their association with oncological outcomes. METHODS: Under IRB approval, serum levels of Carbohydrate Antigen 125 (CA-125), Carbohydrate Antigen 19-9 (CA 19-9) and Carcinoembryonic Antigen (CEA) were prospectively measured in 480 patients with invasive BC from August 2011 through December 2016. In the subgroup undergoing NAC, markers were measured prior to the first and after the last cycle of chemotherapy (prior to cystectomy). RESULTS: Three hundred and thirty-seven patients were eligible for the study, with a median age was 71 years (range 34 93) and 81% (272) male. Elevated precystectomy level of any tumor markers (31% of patients) was independently associated with worse recurrence-free survival (hazard ratio [HR] = 2.81; P < 0.001) and overall survival (HR = 3.97; P < 0.001). One hundred and twenty-five (37%) patients underwent NAC, of whom 59 had a complete tumor marker profile and 30 (51%) had an elevated pre-NAC tumor marker. Following completion of chemotherapy, 10/30 (33%) patients normalized their tumor markers, while 20/30 (67%) had one or more persistently elevated markers. There was no difference in clinical or pathological stage between groups (P = 0.54 and P = 0.09, respectively). Further analysis showed a significantly lower rate and longer median time to recurrence/progression in the responder group (50% in responders vs. 90% in nonresponders at a median time of 22 vs. 4.8 months, respectively; P = 0.015). There was also significant difference in mortality rates and median overall survival between the study groups (30% in responders vs. 70% in nonresponders at a median time of 27.3 vs. 11.6 months respectively; P = 0.037). Two of the three patients that died in the normalized tumor marker group had tumor marker relapse at recurrence prior to their death. CONCLUSIONS: To our knowledge, this is the first study showing tumor marker response to NAC. Patients with persistently elevated markers following NAC have a very poor prognosis following cystectomy, which may help identifying chemotherapy resistant tumors. A larger, controlled study with longer follow up is needed to determine their role in predicting survival. PMID- 30470612 TI - Evaluation of the antifibrotic potency by knocking down SPARC, CCR2 and SMAD3. AB - BACKGROUND: The genes of SPARC, CCR2, and SMAD3 are implicated in orchestrating inflammatory response that leads to fibrosis in scleroderma and other fibrotic disorders. The aim of the studies is to evaluate synergistic anti-fibrotic potency of the siRNAs of these genes. METHODS: The efficacy of the siRNA combination was evaluated in bleomycin-induced mouse fibrosis. The pathological changes of skin and lungs of the mice were assessed by hematoxylin and eosin and Masson's trichrome stains. The expression of inflammation and fibrosis associated genes and proteins in the tissues were assessed by real-time RT-PCR, RNA sequencing, Western blots and ELISA. Non-crosslinked fibrillar collagen was measured by the Sircol colorimetric assay. FINDINGS: The applications of the combined siRNAs in bleomycin-induced mice achieved favorable anti-inflammatory and anti-fibrotic effects. Activation of fibroblasts was suppressed in parallel with inhibition of inflammation evidenced by reduced inflammatory cells and proinflammatory cytokines in the BALF and/or the tissues by the treatment. Aberrant expression of the genes normally expressed in fibroblasts, monocytes/ macrophage, endothelial and epithelial cells were significantly restrained after the treatment. In addition, transcriptome profiles indicated that some bleomycin induced alterations of multiple biological pathways were recovered to varying degrees by the treatment. INTERPRETATION: The application of the combined siRNAs of SPARC, CCR2, and SMAD3 genes ameliorated inflammation and fibrosis in bleomycin-induced mice. It systemically reinstated multiple biopathways, probably through controlling on different cell types including fibroblasts, monocytes/macrophages, endothelial cells and others. The multi-target-combined therapeutic approach examined herein may represent a novel and effective therapy for fibrosis. PMID- 30470613 TI - Proteolytic cleavage of amyloid precursor protein by ADAM10 mediates proliferation and migration in breast cancer. AB - BACKGROUND: Amyloid precursor protein (APP), best known for its association with Alzheimer disease, has recently been implicated in breast cancer progression. However, the precise mechanism involved remains unclear. Here, we investigated the role of APP proteolytic cleavage in breast cancer functions. METHODS: The presence of APP proteolytic cleavage products was examined in breast cancer cell lines. The functional roles of APP in breast cancer were studied in vitro and tumor xenograft model using siRNA. The effects of full length APP and the alpha secretase cleaved ectodomain fragment, soluble APPalpha (sAPPalpha) were further investigated for their overexpression in breast cancers. The alpha-secretase involved was identified. The alpha-secretase expression together with APP was examined in clinical breast cancers. RESULTS: We showed that APP underwent proteolytic cleavage in breast cancer cells to generate sAPPalpha. The sAPPalpha and full length protein mediated breast cancer migration and proliferation, but in different functional extent. This proteolytic cleavage was mediated by ADAM10. Downregulation of APP and ADAM10 brought about similar functional effects. Overexpression of sAPPalpha reversed the effects of ADAM10 downregulation. Interestingly, in patients with non-luminal breast cancers, APP and ADAM10 expression correlated with each other and their co-expression was associated with the worst outcome. CONCLUSIONS: These results demonstrated the contributory role of APP cleavage on its oncogenic roles in breast cancer. ADAM10 was the key alpha secretase. APP and ADAM10 co-expression was associated with worse survival in non luminal breast cancers. Targeting of APP or its processing by ADAM10 might be a promising treatment option in these cancers. PMID- 30470614 TI - Association between preoperative Vasostatin-1 and pathological features of aggressiveness in localized nonfunctioning pancreatic neuroendocrine tumors (NF PanNET). AB - BACKGROUND: A reliable and accessible biomarker for nonfunctioning pancreatic neuroendocrine tumors (NF-PanNET) is currently unavailable. Chromogranin A (CgA) represents the best-described neuroendocrine biomarker, but its accuracy is low. Vasostatin-1 (VS-1), a fragment derived from the cleavage of CgA, was recently investigated and found to be more accurate as tumor biomarker in a cohort of patients affected by mainly metastatic small intestinal NET. METHODS: Patients submitted to surgery for sporadic localized NF-PanNET at San Raffaele Hospital were included. Preoperative plasma samples were prospectively collected. Circulating levels of total-CgA and VS-1 were retrospectively investigated by sandwich Enzyme-Linked ImmunoSorbent Assays. RESULTS: Overall, 50 patients were included. VS-1 value (P=0.0001) was the only preoperatively retrievable factor independently associated with NF-PanNET size. No significant correlation between CgA and tumor diameter was found (P = 0.057). A VS-1 value of 0.39 nM was identified as the optimal VS-1 cut-off accurately associated with NF-PanNET larger than 4 cm. Patients with VS-1 > 0.39 nM had a significantly higher frequency of microvascular invasion (P = 0.005) and nodal metastasis (P = 0.027). Median VS-1 plasma level was significantly higher in the presence of microvascular invasion (P = 0.001) and nodal metastasis (P = 0.012). PPI assumption significantly increased total-CgA levels, but not those of VS-1 (P = 0.111). CONCLUSIONS: In localized, non-metastatic NF-PanNET, VS-1 is strongly associated to tumor dimension and its plasma levels are significantly higher in the presence of microvascular invasion and nodal metastases; moreover, VS-1 value is not affected by the PPI use. PMID- 30470615 TI - Neighborhood socioeconomic status and adherence to dietary recommendations among Finnish adults: A retrospective follow-up study. AB - Neighborhood socioeconomic status (SES) is associated with dietary habits among the residents, but few studies have examined this association separately among long-term residents and movers. We calculated cumulative neighborhood SES score weighted by residential time in each address over 6 years for non-movers (n = 7704) and movers (n = 8818) using national grid database. Increase in average neighborhood SES was associated with higher adherence to dietary recommendations in both groups. Among the movers, an upward trajectory from low to high neighborhood SES was also associated with better adherence. Our findings suggest high SES areas might offer healthier food environments than low SES areas. PMID- 30470616 TI - The burden of not-weighted factors in nursing workload: Can Nursing Activities Score be more suitable than TISS 28 and NEMS? PMID- 30470617 TI - MSH2 Expression and Resistance to Cisplatin in Muscle-invasive Bladder Cancer: A Mix of Progress and Challenges. PMID- 30470619 TI - Fish Consumption and Stroke Risk: A Meta-Analysis of Prospective Cohort Studies. AB - BACKGROUND: Inconsistent results of the association between fish consumption and stroke risk have been indicated in previous epidemiological studies. Therefore, we performed a meta-analysis of prospective cohort studies to estimate the impact of fish consumption on stroke risk. METHODS: The PubMed and EMBASE databases were searched through a computer search. Prospective cohort studies satisfying predetermined inclusion criterion were included. Random-effect model was adopted in this meta-analysis. Analysis of subgroup, sensitivity, publication bias, dose response, power, and quality of evidence was also conducted. RESULTS: Thirty one publications including 33 independent prospective cohort studies were identified in this meta-analysis. In the primary analysis of the highest versus lowest categories of fish consumption, pooled results indicated that a significant trend toward an inverse association between fish intake and stroke risk (HR = .90, 95% confidence interval [CI] .85-.96). Further subgroup analyses indicated an inverse association was more pronounced in the group of hemorrhagic stroke (HR=.88, 95% CI .80-.96), female (HR =.83, 95% CI .75-.92), and Asia-Pacific (HR = .87, 95% CI .80-.95). Both the funnel plot and Egger tests suggested no evidence of publication bias. Dose-response analysis showed a linear relationship between fish intake and stroke and the risk of stroke decreased by 2%-12% with increasing intake of fish up to 100-700 g/week. According to the NutriGrade scoring system, the level of metaevidence quality was moderate. CONCLUSIONS: Based on current evidence from prospective cohort studies, we concluded that fish consumption was associated with a decreased risk of stroke. PMID- 30470618 TI - Retrospective evaluation of children with immune thrombocytopenic purpura and factors contributing to chronicity. AB - OBJECTIVE: Immune thrombocytopenic purpura (ITP) is the most common cause of acquired thrombocytopenia children. The aim of this retrospective study is to describe presenting features and clinical characteristics of ITP and evaluate clinical course, treatment modalities, and complications and determine the effects of preceding infection history, age, gender, treatment modality, and admission platelet count on chronicity. METHOD: Two hundred and eleven patients who were diagnosed ITP and followed-up in Department of Pediatric Hematology, Ankara Children Hematology Oncology Education and Research Hospital between January 2008 and September 2012 were included. Age of the patients, gender, date of admission, date of diagnosis, complaint in the application, previous infection and laboratory tests were recorded. RESULTS: Mean age of the patients on diagnosis was 5.4 +/- 4.1 years. The female/male ratio was 1.03. The clinical courses were determined as acute or chronic in 72% and 28% of patients respectively. Mean age at diagnosis was significantly higher in chronic ITP (p < 0.01). Chronic course was significantly higher in female patients (p < 0.05). The most frequent complaint was bruises on the skin (68%). The most common physical examination findings were petechiae, purpura and ecchymosis (89%). Patients with a history of past infection (53.6%) and who had serologically positive infection (15.6%) frequently had acute course (p < 0.01). The most common serologically positive infection was Rubella. The mean platelet count was significantly higher in chronic ITP (p < 0.01). In the initial treatment of patients admitted in the acute phase, megadose methylprednisolone (MDMP) was used in 31% of patients, intravenous immune globulin (IVIG) in 55% of patients and anti-D in 2% of patients while 12% did not receive any treatment. There were no significant differences between the recurrence rate and treatment modality (p > 0.05). CONCLUSION: In our study, in females and in patients without any history of past infection, platelet count >20 * 109/L and initial diagnosis age > 10 years were found to increase the probability of chronic disease, which is compatible with the literature. PMID- 30470620 TI - Systemic infection with Candida Albicans in breast tumor bearing mice: Cytokines dysregulation and induction of regulatory T cells. AB - OBJECTIVE: The effect of candidemia on immunologic parameters in breast tumor bearing patients is not well studied. Here, we hypothesised that candidemia in the tumor background may change the outcome of immunologic parameters and tumor condition. METHOD: Mice were divided into four groups, including normal, tumor, Candida infected (only Candidiasis) and tumor/Candidiasis groups. Tumor changes were recorded daily after tumor transplantation and induction of candidemia. Splenocytes of mice were harvested, cultured, and stimulated with PHA; afterwards, IL-4, IL-10, IFN-gamma, TNF-alpha and TGF-beta cytokines were assessed using ELISA kits. We also evaluated the population of CD4+CD25+Foxp3+ regulatory T cells in the tumor infiltrated and splenocytes. RESULTS: The results showed that infection with C. albicans decreased the IFN-gamma/IL-4 ratio in tumor/candidiasis and candidiasis groups versus their non-infected controls. IL 10, TGF-beta and TNF-alpha levels increased in the candidiasis group. In addition, Candidemia led to an increase in the Treg population in tumor microenvironment and splenocytes of experimental groups compared with non infected controls. Finally, candidemia increased tumor growth of tumor/Candidiasis group compared with the tumor group. CONCLUSION: It seems that systemic infection with C. albicans could not only induce regulatory T cells but also result in dysregulation of cytokine network and thereby facilitate tumor growth. PMID- 30470621 TI - Deep neck infection in patients with and without human immunodeficiency virus: a comparison of clinical features, complications, and outcomes. AB - We retrospectively studied the clinical features, complications, and outcomes of deep neck infections in 31 adult patients with the human immunodeficiency virus (HIV) (HIV group) and 192 patients without (non-HIV group). In the HIV group, the cause was more likely to be odontogenic (21 (68%) compared with 90 (47%); odds ratio (OR) 2.38; 95% CI 1.06 to 5.32). In both groups, the parapharyngeal, submandibular, and masticator spaces, were those most often involved. However, in the HIV group, Ludwig's angina was common, and was the main cause of airway obstruction. Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa were most often isolated in the HIV group. Upper airway obstruction tended to be more common in the HIV group (5/31 compared with 13/192). These patients also had a higher risk of other complications (sepsis, mediastinitis, jugular vein thrombosis, and pneumonia) (6/31 compared with 12/192; OR 3.60; 95% CI 1.24 to 10.45), a higher mortality rate (3/31 compared with 2/192), and longer hospital stay (19days compared with 16 days). Factors associated with an increased risk of complications in this group were an age of 55 years or over and a CD4 count of less than 350 cells/mm3. Deep neck infections in these patients are more severe. Dental health care, appropriate empirical antibiotics, early detection, and management of the airway and complications, may improve outcomes. PMID- 30470622 TI - Mitchell-Hoole-Kanatas (MHK) questionnaire: the first to measure patient-reported outcomes relating to problems with intimacy after diagnosis and treatment of head and neck cancer. AB - Patient-reported outcomes are increasingly used by clinical teams as indicators of quality when assessing treatment after a diagnosis of head and neck cancer. About a third of patients report reduced sexual interest or enjoyment after such treatment but, despite that, there is no questionnaire about intimacy that has been developed specifically for them. The aim of this study was to develop such a questionnaire, to gain an indication of the relative incidence of individual items, and to compare characteristics such as age, stage, treatment, time since treatment for an established head and neck cancer, and a health-related quality of life (QoL) measure (European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30 with the Head and Neck 35 module). The development of the new instrument was based on an exploratory observational study that included quantitative and qualitative methods. The qualitative element was achieved by the generation of items - from published studies, the comments of patients and carers, and a cross-sectional survey of patients with head and neck cancer who were alive and free of disease. The quantitative element comprised analysis of exploratory and confirmatory factors, internal reliability assessment (Cronbach's alpha), and a correlation analysis. Forty-two patients were included in the focus groups, and 101 patients participated in the cross-sectional survey (both male and female, in a relationship and single, age range 30-70 years for the focus group, and 62-117 in the cross-sectional survey). All treatments were included. We found that the ability to enjoy a sex life had been adversely affected in about half the sample and that this had significantly changed from before their cancer in a third. The qualitative part of the study resulted in 22 items that covered a range of domains from dry mouth and thick saliva to loss of sensation (lips, fingertips), restricted head/neck movement, fatigue, and pain. The exploratory analysis covered four domains (physical, sensation, movement, and communication) from 12 of 22 items. Cronbach's alphas ranged from 0.62 to 0.84, and the correlation analysis indicated "good fit" statistics for these domains. In terms of the EORTC QoL Questionnnaire - Head and Neck 35, the four MHK domains showed good levels of association with anticipated domains. Head and neck cancer and its associated treatments significantly adversely affect intimacy and sexuality in half the population sampled. The MHK tool may be used to identify specific issues related to intimacy in patients with a history of diagnosis and treatment of head and neck cancer. Further work is essential to identify its precise role and to help develop specific interventions. PMID- 30470623 TI - Risk Reduction and Survival Benefit of Risk-Reducing Salpingo-oophorectomy in Hereditary Breast Cancer: Meta-analysis and Systematic Review. AB - BACKGROUND: Objections have been raised to performing risk-reducing salpingo oophorectomy (RRSO) to reduce disease incidence and mortality of women with BRCA mutations. We aimed to examine the relationship between RRSO and breast cancer (BC) risk and mortality with a meta-analysis. MATERIALS AND METHODS: We conducted a comprehensive literature search using the PubMed and Embase databases for literature published from these databases' creation to September 2017. Hazard ratio (HR) estimates were identified directly from the original articles. Pooled results were calculated on the basis of nonoverlapping studies by fixed-effect meta-analysis. RESULTS: RRSO was associated with a significant reduction in the incidence of BC in women with BRCA1/2 mutations who had no history of BC (HR = 0.58; 95% confidence interval [CI], 0.37 to 0.78). Even in women with a history of BC, RRSO could reduce the risk of recurrence (HR = 0.50; 95% CI, 0.31 to 0.69). We further found that publication year was a critical interaction factor from a corresponding subgroup analyses in BC risk (Pheterogeneity = .024). In addition, we found that RRSO could improve the survival of women with BC (HR = 0.33; 95% CI, 0.28 to 0.38). CONCLUSION: Summary estimates presented here indicate that RRSO was closely related to the reduced risk of BC caused by BRCA mutations, but publication year was a critical interaction factor and it should be noted that more recent studies have failed to find a significant reduction in BC risk associated with RRSO. PMID- 30470624 TI - Fibroepithelial Breast Lesion: When Sequencing Can Help to Make a Clinical Decision. A Case Report. PMID- 30470625 TI - Recommendations of the International Society of Intraoperative Neurophysiology for intraoperative somatosensory evoked potentials. AB - Intraoperative somatosensory evoked potentials (SEPs) provide dorsal somatosensory system functional and localizing information, and complement motor evoked potentials. Correct application and interpretation require in-depth knowledge of relevant anatomy, electrophysiology, and techniques. It is advisable to facilitate cortical SEPs with total intravenous propofol-opioid or similarly favorable anesthesia. Moreover, SEP optimization is recommended to enhance surgical feedback speed and accuracy by maximizing signal-to-noise ratio (SNR); it consists of selecting highest-SNR peripheral and cortical derivations while omitting low-SNR channels. Confounding factors causing non-surgical SEP reduction should be excluded before issuing a warning. It is advisable to facilitate their identification with peripheral SEP controls and cortical SEP systemic controls whenever possible. Warning criteria should adjust for baseline drift and reproducibility. The recommended adaptive warning criterion is visually obvious amplitude reduction from recent pre-change values and clearly exceeding trial-to trial variability, particularly when abrupt and focal. Acquisition and interpretation should be done by qualified technical and professional level personnel. Indications for SEP monitoring include intracranial, posterior fossa, and spinal neurosurgery, as well as orthopedic spine, cerebrovascular, and descending aortic surgery. Indications for SEP mapping include sensorimotor cortex and dorsal column midline identification. Future advances could modify current recommendations. PMID- 30470626 TI - Centriole Biogenesis: Symmetry Breaking and Site Selection. AB - Centrioles must duplicate as cells progress through the cell cycle but it is unclear how the site of duplication is selected. A recent computational study demonstrates that two separate but interacting feedback mechanisms (autocatalytic activation and substrate depletion) are capable of selecting a single site for centriole biogenesis. PMID- 30470627 TI - Artificial intelligence and medical imaging 2018: French Radiology Community white paper. AB - The rapid development of information technology and data processing capabilities has led to the creation of new tools known as artificial intelligence (AI). Medical applications of AI are emerging, and the French radiology community felt it was therefore timely to issue a position paper on AI as part of its role as a leader in the development of digital projects. Essential information about the application of AI to radiology includes a description of the available algorithms with a glossary; a review of the issues raised by healthcare data, notably those pertaining to imaging (imaging data and co-variables, metadata); a look at research and innovation; an overview of current and future applications; a discussion of AI education; and a scrutiny of ethical issues. In addition to the principles set forth at the Asilomar Conference on Beneficial AI, the French radiology community has developed ten principles aimed at governing the use and development of AI tools in a manner that will create a concerted approach centered on benefits to patients, while also ensuring good integration within clinical workflows. High-quality care in radiology and opportunities for managing large datasets are two avenues relevant to the development of a precision, personalized, and participative radiology practice characterized by improved predictive and preventive capabilities. PMID- 30470628 TI - Non-viral, Tumor-free Induction of Transient Cell Reprogramming in Mouse Skeletal Muscle to Enhance Tissue Regeneration. AB - Overexpression of Oct3/4, Klf4, Sox2, and c-Myc (OKSM) transcription factors can de-differentiate adult cells in vivo. While sustained OKSM expression triggers tumorigenesis through uncontrolled proliferation of toti- and pluripotent cells, transient reprogramming induces pluripotency-like features and proliferation only temporarily, without teratomas. We sought to transiently reprogram cells within mouse skeletal muscle with a localized injection of plasmid DNA encoding OKSM (pOKSM), and we hypothesized that the generation of proliferative intermediates would enhance tissue regeneration after injury. Intramuscular pOKSM administration rapidly upregulated pluripotency (Nanog, Ecat1, and Rex1) and early myogenesis genes (Pax3) in the healthy gastrocnemius of various strains. Mononucleated cells expressing such markers appeared in clusters among myofibers, proliferated only transiently, and did not lead to dysplasia or tumorigenesis for at least 120 days. Nanog was also upregulated in the gastrocnemius when pOKSM was administered 7 days after surgically sectioning its medial head. Enhanced tissue regeneration after reprogramming was manifested by the accelerated appearance of centronucleated myofibers and reduced fibrosis. These results suggest that transient in vivo reprogramming could develop into a novel strategy toward the acceleration of tissue regeneration after injury, based on the induction of transiently proliferative, pluripotent-like cells in situ. Further research to achieve clinically meaningful functional regeneration is warranted. PMID- 30470629 TI - Long-Term Effects of In Vivo Genome Editing in the Mouse Retina Using Campylobacter jejuni Cas9 Expressed via Adeno-Associated Virus. AB - Genome editing with CRISPR systems provides an unprecedented opportunity to modulate cellular responses in pathological conditions by inactivating undruggable targets, such as transcription factors. Previously, we demonstrated that the smallest Cas9 ortholog characterized to date, from Campylobacter jejuni (CjCas9) targeted to Hif1a and delivered in an adeno-associated virus (AAV) vector, effectively suppressed pathological choroidal neovascularization in the mouse retina. Before implementation of CjCas9 as an in vivo therapeutic modality, it is essential to investigate the long-term effects of target gene disruption via AAV-mediated delivery of CjCas9 in vivo. In this study, histologic and electroretinographic analyses demonstrated that CjCas9 targeted to Hif1a did not induce any definite toxicity in the retina, although the target gene was mutated with a frequency ranging from 45% to 79% in retinal or retinal pigment epithelial cells. Importantly, at 14 months after injection, no indels were detected at potential off-target sites identified using Digenome-seq and Cas-OFFinder, suggesting that long-term expression of CjCas9 does not aggravate off-target effects. Taken together, our results show that intravitreal injection of AAV encoding CjCas9 targeted to Hif1a effectively induced and maintained mutations in retinal tissues for more than 1 year and did not affect retinal histologic integrity or functions. PMID- 30470630 TI - Gynecologic Organ Involvement During Radical Cystectomy for Bladder Cancer: Is It Time to Routinely Spare the Ovaries? AB - PURPOSE: To determine a subset of women who could undergo ovary-sparing radical cystectomy (OSRC) for bladder cancer without compromising oncologic safety. PATIENTS AND METHODS: A retrospective review was performed of 164 consecutive women who underwent cystectomy at a single tertiary-care center from 1997 to 2018. Clinicopathologic and preoperative radiographic data were reviewed. Univariable and multivariable logistic regression models adjusting for pathologic stage, lymphovascular invasion (LVI), and carcinomain-situ were performed to evaluate the risk of ovarian and reproductive organ (RO) involvement. RESULTS: A total of 123 women with a median age of 71 years underwent radical cystectomy (RC) with removal of ROs for primary bladder cancer. Nineteen women (15%) had RO involvement by bladder cancer, and 5 of them (4%) were specifically found to have ovarian involvement. Patients with ovarian involvement of bladder cancer had more locally advanced disease (P = .01), LVI (P = .003) and positive margins (P = .003). On multivariable logistic regression, >= pT3 (odds ratio = 10.2; 95% confidence interval, 2.0-51.6; P = .005) and LVI (odds ratio = 3.9; 95% confidence interval, 1.1-14.2; P = .037) were associated with increased risk of RO involvement. Among 15 patients excluded for having a nonbladder primary malignancy, a third had RO involvement, and 2 (13%) had ovarian metastases. No women in our cohort had a primary ovarian malignancy detected at the time of RC. CONCLUSION: Women with ovarian involvement by malignancy at the time of RC either had locally advanced disease with LVI or a non-bladder primary malignancy. The risk of incompletely resecting the primary malignancy would be rare if OSRC was performed on women with organ-confined (<=T2) urothelial carcinoma. PMID- 30470631 TI - Reliability analysis of road networks in disaster waste management. AB - The condition of road networks which connect disaster affected areas and final disposal sites has a critical role in the management of disaster waste. In this paper, we present a two-stage framework to estimate the overall reliability and failure modes of a disaster waste management system considering the reliability of each route involved in the road network. In the first stage, first order reliability method and Ditlevsen bounds are applied to estimate system reliability. In the second stage, an event tree approach is implemented to analyse the failure modes of the system. The methodology is demonstrated with an artificial case study considering three different scales of disasters. The results obtained from the case study can provide information to decision makers regarding the priority of the routes in the system and the most likely failure mode. PMID- 30470632 TI - Assessing the generation, recycling and disposal practices of electronic/electrical-waste (E-Waste) from major cities in Pakistan. AB - Rapid increase in the quantity of electronic/electrical-waste (e-waste) has become an emerging issue throughout the world. To avoid higher expenditures on safe disposal and recycling, large quantities of e-waste are being exported from developed to developing countries like Pakistan. Emerging issue of e-waste in Pakistan demands its effective management strategy for the country. However, it cannot be achieved until assessment of e-waste quantification and disposal is carried out. The main objective of this study was to quantify the e-waste inventory and it's processing from major cities of Pakistan to evaluate its generation (domestic/import) and recycling practices. This study comprises the information of only those e-waste items (desktop computers, laptops/notebooks, computer monitors and liquid-crystal display units) which form the major portion of e-waste imported to Pakistan. Survey based data collected from three major cities/areas have been extrapolated to develop an e-waste generation inventory for the country. The study reveals that approximately 50 kt of e-waste is being imported as scrap in addition to its local generation of about 38 kt per year. During field visits and data collection surveys, it has been observed that the processing of e-waste in the country is being carried out in crude manner without safety gears. Findings of our study strongly recommend dire need for urgent and effective monitoring as well as control of informal e-waste management in Pakistan. PMID- 30470633 TI - Surgical deroofing in the treatment of patients with auricular pseudocyst. AB - OBJECTIVE: An auricular pseudocyst is a fluid filled cavity, characterized by a lack of epithelium, in the intra-cartilaginous space. Clinically, it presents as a painless lump on the upper anterior surface of the ear. Various treatment methods have been discussed in the literature, including aspiration, incision and drainage, or steroid injection. However, these approaches are associated with a high rate of recurrence and results are often esthetically unsatisfactory; therefore, a need for improved treatment approaches remains. METHODS: From March, 2015, to June, 2017, 15 patients with auricular pseudocyst were treated with surgical deroofing followed by local contour pressure dressing with a simple bolster. In addition, the structure of the auricular pseudocyst was assessed at a microscopic level. RESULTS: Patients were followed up for a mean period of 12 months, during which time there were no reports of postoperative complications or recurrence. The results were cosmetically excellent in all patients and no cartilage deformity was seen. Considering the composition of pseudocysts seen on microscopic evaluation, deroofing to remove the anterior leaflet and removal of debris from the posterior leaflet is an appropriate treatment modality. CONCLUSION: This reliable and simple approach may be recommended as first line treatment for auricular pseudocysts to avoid recurrence and complications associated with other treatment modalities, such as cartilage deformity, skin depigmentation, and scarring. PMID- 30470634 TI - Cardiac metastasis in a living patient with oral cancer. AB - Cardiac metastasis from head and neck cancers are very rare. Metastases to heart are mostly diagnosed at autopsy, and seldom found while patients are alive. Patients with cardiac metastasis do not present with specific symptoms in the early stages, and diagnosis is often delayed until the disease has advanced significantly. Here, we report a 66-year-old lady who was diagnosed with cardiac metastasis 10 months after surgical resection of oral cancer. She died one month following the discovery of cardiac metastasis. Cardiac metastasis should be considered when unexplained and progressive decline of general health is observed, even in the absence of abnormalities on the electrocardiogram. Early diagnosis may be made by analyzing the chronological changes in the cardiac accumulation of fluorodeoxyglucose during positron emission tomography-computed tomography scan. PMID- 30470635 TI - Should tobacco interventions be different in men and women? PMID- 30470636 TI - Recommendations by the Spanish Society of Rheumatology on Osteoporosis. AB - OBJECTIVE: To update the recommendations on osteoporosis (OP) of the Spanish Society of Rheumatology (SER) based on the best possible evidence. METHODS: A panel of nine expert rheumatologists in OP was created, previously selected by the SER through an open call. The phases of the work were: identification of the key areas for updating the previous consensus, analysis and synthesis of the scientific evidence (using the SIGN levels of evidence) and formulation of recommendations based on this evidence and consensus techniques. RESULTS: This revision of the recommendations implies an update in the diagnostic evaluation and treatment of OP. It proposes some criteria to consider the high risk of fracture and some indications to start treatment. The recommendations also address issues related to the safety of treatments and the management of special situations such as inflammatory diseases and treatment with glucocorticoids. CONCLUSIONS: We present an update of SER recommendations on OP. PMID- 30470637 TI - Efficacy of a new topical formulation containing selamectin plus sarolaner against three common tick species infesting cats in the United States. AB - The efficacy of a single topical application of a combination product containing selamectin and sarolaner (selamectin/sarolaner; Revolution(r) Plus/Stronghold(r) Plus) was evaluated in seven laboratory studies against Ixodes scapularis (three studies), Dermacentor variabilis (two studies), or Amblyomma maculatum (two studies). In each study, cats were randomly allocated to treatment groups based on pre-treatment host-suitability tick counts. On Days -2, 5, 12, 19, 26 and 33, the cats were infested with unfed adult ticks. On Day 0, cats were treated with either a placebo (vehicle control) or with the spot-on solution at the minimum dose of 6.0 mg selamectin and 1.0 mg sarolaner/kg bodyweight. In one study with I. scapularis and one with D. variabilis an additional group of cats was treated with selamectin alone (Revolution(r), Zoetis) at 6.0 mg/kg bodyweight. Tick counts were conducted after treatment and after each weekly re-infestation and efficacy determined relative to placebo-treated animals. There were no treatment related adverse reactions in any of the studies. Geometric mean live tick counts were significantly (P < 0.05) lower in the selamectin/sarolaner-treated groups compared to the geometric mean tick counts in the placebo-treated groups at all time-points in all studies. For all species, a single topical administration of the selamectin/sarolaner combination resulted in>90% efficacy against existing infestations based on geometric means. Efficacy against weekly re-infestations was >90% based on geometric means for at least 5 weeks for I. scapularis and D. variabilis, and for at least 4 weeks against A. maculatum. Selamectin alone had no efficacy against I. scapularis, where counts on selamectin-treated cats were not significantly different from placebo at all time points (P > 0.05), and for D. variabilis, counts were not significantly different from placebo at 2, 3 and 5 weeks after treatment (P > 0.05) and efficacy was never greater than 85%. Thus, the activity of the sarolaner against three common tick species found on cats in the US is complementary to the existing broad-spectrum parasite control of selamectin. The inclusion of sarolaner with selamectin in a combination product (Revolution(r) Plus/Stronghold(r) Plus) provides for the treatment of existing tick infestations and gives at least one month of control against re-infestation following a single topical application. PMID- 30470638 TI - Efficacy and safety of a new topical formulation of selamectin plus sarolaner in the treatment and control of natural infections of Ancylostoma tubaeforme and Toxocara cati in cats presented as veterinary patients in the United States. AB - A new topical formulation of selamectin plus sarolaner (Revolution(r) Plus/Stronghold(r) Plus, Zoetis) was evaluated in the treatment and control of naturally occurring infections of Ancylostoma tubaeforme and Toxocara cati in cats presented as veterinary patients in the United States. Three thousand three hundred three (3303) cats were screened in 25 veterinary practices in 15 states and 153 hookworm-positive cats (A. tubaeforme and/or A. braziliense), mainly from Alabama, Mississippi, Texas, and Hawaii, were identified; 135 cats met all the criteria for enrollment and were included on study. The cats were randomly assigned to treatment with Revolution(r) (at the label dosage, to provide a minimum dosage of 6 mg/kg selamectin) or selamectin plus sarolaner (at a dosage of 6-12 mg/kg plus 1-2 mg/kg, respectively). Treatments were administered at the time of enrollment and repeated 30 days later. Fecal samples were collected for differential fecal egg count prior to the first treatment (Day 0), prior to the second treatment (Day 30), and approximately 30 days later (Day 60). Efficacy was based on the percentage reductions in geometric mean fecal egg count for A. tubaeforme on Day 30 and Day 60 compared with Day 0. Where cats were co-infected with T. cati, efficacy against this species was also evaluated. Efficacy data were evaluated for A. tubaeforme for 40 cats on both Day 30 and Day 60 for the group treated with the selamectin/sarolaner combination and reductions in geometric mean fecal egg counts of 99.4% and 99.7% were demonstrated for Day 30 and Day 60, respectively. For the group treated with selamectin alone, 44 and 40 cats were evaluated and percent reductions for Day 30 and Day 60 were 99.5% and 99.9%, respectively. For T. cati, 14 cats were evaluated in the selamectin/sarolaner-treated group for Day 30 and for Day 60, and the reduction in geometric mean fecal egg count was 100% for both days. There were 11 and 9 cats evaluated for Day 30 and Day 60, respectively, for the selamectin-treated group and the reduction was again 100% for both days. The geometric mean fecal egg counts post-treatment were significantly lower than pre-treatment for both A. tubaeforme and T. cati, for both treatments, and for both periods of interest (P < 0.0001). No serious adverse events related to treatment with either product occurred during the study. Thus, both selamectin alone and the combination product of selamectin/sarolaner were safe and effective when administered on a monthly basis for the treatment and control of natural infections of A. tubaeforme and T. cati. The addition of sarolaner to the formulation did not interfere with the efficacy of selamectin against these nematodes. PMID- 30470639 TI - Vaccine-driven serotype-rearrangement is seen with latency in clinical isolates: Comparison of carried and clinical pneumococcal isolates from the same time period in Hungary. AB - Young children - the main asymptomatic carriers of pneumococcus - are often the source of pneumococcal infections. PCV13 replaced PCV7 in 2010 in Hungary and it became a mandatory vaccine in 2014. In this work we surveyed the effect of vaccination in three groups: in healthy children under 7 years; in children of the same age but infected with pneumococcus (P1); in older patients (P2) who were very likely not vaccinated. Nasal swabs were taken from 522 healthy children to screen pneumococcal carriage between March 2015 and May 2016. In the same time period, 146 clinical isolates were collected, mainly from mucosal infections. Serotypes, antibiotic susceptibility and clonality of the isolates was determined and compared. The carriage rate was 39.1%. Regarding carriage, the serotype distribution showed the total disappearance of serotypes 3 and 6A compared to former Hungarian studies. The prevalence of PCV13 serotypes was only 5.8% represented by three serotypes (19F, 19A, 9V). Of note, serotype 19A (a very resistant and invasive type) also decreased significantly. In the patient groups, PCV13 prevalence was higher: 17.5% (P1) and 32.6% (P2). Although serotype 3 was present in P1 (7.9%), the leading serotype was 23B (22.2%), a non-vaccine type (NVT). P2 showed the most diverse serotype distribution, but serotype 3 was predominant here (15.7%). Pneumococcal isolates from the patients were more resistant towards the tested antibiotics compared to those from carriers. PCV13 seems to be highly successful in reducing the prevalence of vaccine serotypes. The serotype-rearrangement can be seen also among clinical isolates, albeit somewhat later in time. Fortunately, the replacing serotypes are less invasive and less resistant, but, most worrisome, serotype 19F can be found again with increased frequency among carriage isolates and mucosal infections. Further surveillance is needed to carefully monitor such successful, antibiotic resistant "refugees". PMID- 30470640 TI - The immunopotentiator CVC1302 enhances immune efficacy and protective ability of foot-and-mouth disease virus vaccine in pigs. AB - The immunological enhancement characteristics of the immunopotentiator CVC1302 were evaluated for foot-and-mouth disease virus (FMDV) inactivated vaccine in pigs. Eight-week-old piglets were vaccinated with the foot-and-mouth disease (FMD) vaccine alone (FMD-vaccine group) or with the addition of CVC1302 (FMD CVC1302 group), and the serum liquid phase blocking ELISA (LPB-ELISA) antibody titers, IgG1 and IgG2 levels, and the levels of four cytokines secreted by peripheral blood lymphocytes were measured at 28 days post vaccination (dpv). In the FMD-CVC1302 group, the LPB-ELISA antibody titers, IgG1, and IgG2 titers, and IL-2, IL-4, IL-6, and IFN-gamma levels at 28 dpv were significantly higher than those in the FMD-vaccine group. The FMD-CVC1302 group had long-lasting antibody titers (>7.8 log2), lasting for at least 6 months. In addition, piglets were vaccinated with or without addition of CVC1302 to the FMD vaccine at three different doses (1, 1/3, and 1/9 of the standard vaccine dose) and the serum LPB ELISA antibody and serum neutralizing (SN) antibody titers were detected at 28 dpv. Then all pigs were challenged with virulent FMDV for PD50 value, and the levels of FMDV-specific RNA copies for the two full-dose groups at 3 and 10 days post challenge (dpc) were measured. The LPB-ELISA and SN antibody titers for the three doses in the FMD-CVC1302 groups were significantly higher than those in the FMD-vaccine groups at the same doses (p < 0.05). Post-virus challenge, the FMDV specific RNA copy number in the FMD-CVC1302 group was lower than that in the FMD vaccine group at 3 and 10 dpc. The PD50 value was 15.85 for the FMD-CVC1302 group, which was obviously higher than that for the FMD-vaccine group (10.96), and in the 1/9-dose of FMD-vaccine group only 3/5 pigs were protected. These results indicate that CVC1302 can enhance the immune efficacy and protective ability of the FMD vaccine in pigs. PMID- 30470641 TI - Mandatory policies for influenza vaccination: Views of managers and healthcare workers in England. AB - INTRODUCTION: Mandatory policies have the potential to increase uptake of influenza ('flu') vaccination among healthcare workers (HCWs), but concerns have been expressed about their acceptability and effectiveness. We explored views on three mandatory policies (declination forms, face masks or reduced patient contact, and mandatory vaccination) among both HCWs and flu vaccination programme managers in the National Health Service (NHS) in England. METHOD: A mixed method approach was employed. An online cross-sectional survey was conducted with staff responsible for implementing influenza campaigns in NHS trusts (healthcare organisations) in England (n = 72 trusts). The survey measured perceived effectiveness of the three mandatory policies and perceived support for them among HCWs. Qualitative interviews were conducted in four trusts, with influenza campaign managers (n = 24) and with HCWs who had the opportunity to receive the influenza vaccination (n = 32). Interviews explored respondents' views of the three strategies and were analysed thematically using QSR NVivo 11 All data were collected shortly after the 2016/2017 influenza season. RESULTS: In the survey, views varied on the effectiveness of the three policies and none of the interventions were thought to be strongly supported by HCWs, with particularly low levels of support perceived for mandatory vaccination and for face masks or reduced patient contact. The qualitative interviews revealed substantial concerns around the practicability and enforceability of mandatory policies and the potential discriminatory effect on HCWs who made a principled decision or had medical reasons for exemption. Additional doubts were also expressed regarding the effectiveness of face masks and their potential to worry patients, and the ethics of compelling staff to accept medical intervention. DISCUSSION: Mandatory vaccination and face masks would not be strongly supported if introduced in the UK. If declination forms are adopted, they should be used in a constructive intelligence-gathering manner which avoids stigmatising HCWs. PMID- 30470642 TI - Tree-based scan statistic - Application in manufacturing-related safety signal detection. AB - BACKGROUND AND OBJECTIVES: Over the last decades, medicinal regulations have been put into place and have considerably improved manufacturing practices. Nevertheless, safety issues may still arise. Using the simulation described in this manuscript, our aim is to develop adequate detection methods for manufacturing-related safety signals, especially in the context of biological products. METHODS: Pharmaceutical companies record the entire batch genealogies, from seed batches over intermediates to final product (FP) batches. We constructed a hierarchical tree based on this genealogy information and linked it to the spontaneous safety data available for the FP batch numbers. The tree-based scan statistic (TBSS) was used on simulated data as a proof of concept to locate the source that may have subsequently generated an excess of specific adverse events (AEs) within the manufacturing steps, and to evaluate the method's adjustment for multiple testing. All calculations were performed with a customized program in SAS v9.2. RESULTS: The TBSS generated a close to expected number of false positive signals, demonstrating that it adjusted for multiple testing. Overall, the method detected 71% of the simulated signals at the correct production step when a 6-fold increase in reports with AEs of interest (AEOI) was applied, and 31% when a 2-fold increase was applied. The relatively low detection performance may be attributed to the higher granularity associated with the lower levels of the hierarchy, leading to a lack of power and the stringent definition criteria that were applied for a true positive result. CONCLUSION: As a data mining method for manufacturing-related safety signal detection, the TBSS may provide advantages over other disproportionality analyses (using batch information) but may benefit from complementary methods (not relaying on batch information). While the method warrants further refinement, it may improve safety signal detection and contribute to improvements in the quality of manufacturing processes. PMID- 30470643 TI - Nurses' recognition and response to clinical deterioration in the cardiac catheterisation laboratory. AB - BACKGROUND: Patients presenting to the cardiac catheter laboratory for treatment of unstable acute coronary syndromes (ACS) experience a mismatch in myocardial oxygen supply and demand, causing vital sign abnormalities prior to neurological, cardiac and respiratory deterioration. Delays in detecting clinical deterioration and escalating care increases risk of adverse events, unplanned intensive care (ICU) admission, cardiac arrest, and in-hospital mortality. OBJECTIVES: The objective of the study was to explore how nurses in the cardiac catheter laboratory (CCL) recognise and respond to clinical deterioration in patients with unstable ACS undergoing primary percutaneous coronary intervention (PCI). METHODS: A prospective exploratory descriptive design was used with 30 participants completing 10 written clinical scenarios. Participants scored their level of concern for each physiological cue and then then ranked their preferred immediate response based on the deterioration identified. RESULTS: Hypotension and the presence of pain were the physiological cues of highest concern. The most common responses to clinical deterioration were to increase vital sign assessment to 5-minutely intervals, administer pain relief or provide reassurance. Despite the presence of clinical deterioration fulfilling organisational escalation of care criteria, calling cardiac arrest or rapid response team (RRT) were not commonly selected responses. CONCLUSION: Nurses most commonly use hypotension and the presence of pain to recognise clinical deterioration in patients presenting to the CCL with an unstable ACS. Once clinical deterioration is identified, interventional cardiac nurses delay the escalation of care to the RRT or cardiac arrest team, preferring to implement local nurse initiated interventions. PMID- 30470644 TI - Prevalence of pressure injury in adults presenting to the emergency department by ambulance. AB - INTRODUCTION: Pressure injuries are harmful, painful, and potentially preventable. Although hospital-acquired pressure injury prevalence is decreasing, it is unclear if some pressure injuries develop before hospital admission. The objective of this study was to investigate the prevalence of pressure injury in adults on arrival by ambulance to the emergency department (ED). METHODS: An observational, cross-sectional descriptive study design was used. Participants (n = 212) were recruited from the EDs of two Australian tertiary hospitals. Full skin inspection and pressure injury risk assessment, using Braden and Waterlow scores, were undertaken within 1 h of presentation. RESULTS: Pressure injuries were identified in 11 of 212 participants, giving a prevalence of 5.2% at presentation. Nearly all were admitted to hospital, giving a prevalence of 7.8% at this entry point. Participants with pressure injury and those at high risk of injury were found to have spent longer in the ambulance and within the ED. During ambulance transport and in the first hour of presentation to the ED, it was rare that pressure-relieving interventions were implemented, even for those with an identified pressure injury and those at high risk. CONCLUSIONS: The results indicate that early pressure injury surveillance and risk assessment are merited at the point of presentation to the ED, so that prevention and treatment can be implemented at the earliest possible opportunity. Although it is more challenging to manage pressure injuries within the ambulance and ED, the use of pressure relieving devices should be considered for those at greatest risk. Further research is recommended. PMID- 30470645 TI - Cryobiopsy with endobronchial ultrasonography using a guide sheath for peripheral pulmonary lesions and DNA analysis by next generation sequencing and rapid on site evaluation. AB - BACKGROUND: The purpose of this study was to evaluate the diagnostic accuracy of Cryo with endobronchial ultrasonography using a guide sheath (EBUS-GS) for peripheral pulmonary lesions (PPLs) to assess the volume of specimen, determine DNA sequencing analysis, and evaluate the utility of rapid on-site evaluation (ROSE). METHODS: Out of 30 patients assessed for eligibility, 23 were enrolled in this prospective study. The histological diagnostic yield of Cryo was evaluated and the volume was compared to that of trans-bronchial biopsy (TBB). DNA analysis of Cryo was performed using next generation sequencing (NGS). ROSE was compared with the final diagnosis. RESULTS: The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy rate was 85%, 100%, 100%, 50%, 87% for Cryo and 80%, 100%, 100%, 42.9%, 82.6% for TBB, respectively. The mean volume was 0.078 cm3 for Cryo and 0.003 cm3 for TBB (p < 0.0001). All Cryo specimens provided sufficient quantity and quality of DNA for analysis by NGS. ROSE had a high sensitivity (70%), specificity (100%), PPV (100%), and diagnostic accuracy (73.9%). There were no clinically serious adverse events except mild bleeding in 4 cases. CONCLUSIONS: Cryo with EBUS-GS for PPLs is a safe and potentially useful diagnostic strategy. It has a high diagnostic yield, and provides significantly larger specimens than TBB. It also provides high quantity and quality of DNA for NGS and high concordance rate between ROSE and the final diagnosis. PMID- 30470646 TI - Low-dose Desmopressin Orally Disintegrating Tablet: Suggested Clinically Meaningful Benefit in Patients with Nocturia Due to Nocturnal Polyuria. AB - BACKGROUND: Clinical benefit has not been evaluated much in patients with nocturia. OBJECTIVE: To assess the clinical benefit of desmopressin orally disintegrating tablet (ODT) in women (25MUg) and men (50MUg) with nocturia due to nocturnal polyuria (NP). DESIGN, SETTING, AND PATIENTS: Patients with NP from two randomised, placebo-controlled trials in men (CS41) and women (CS40) with two or more nocturnal voids per night were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Change from baseline in nocturnal voids, 33% and 50% responder status (average reduction of <=33% and <=50%, respectively, in the mean number of nocturnal voids vs baseline), and percentage of nights with at most one void or no voids (ie, complete response) during 3-mo treatment period were assessed for clinical benefit. Two-sided test (5% significance level) was used for all endpoints. RESULTS AND LIMITATIONS: Demographics and baseline characteristics of patients in CS41 (N=230) and CS40 (N=232) were similar. A greater reduction in the mean number of nocturnal voids was seen with desmopressin ODT in men (treatment difference [TD]: -0.37 voids) compared with women (TD: -0.29 voids). For 33% and 50% responder status, TD with ODT versus placebo were 21% and 12%, respectively, in men, and 12% and 17%, respectively, in women. For the number of nights with at most one void, TDs were 11% and 13% (p<0.009 for both) for men and women, respectively. For complete response, TD was significant in men (TD: 9%, p<0.001). Limitations inherent in this analysis were evident as the data for cotreatments (baseline) and quality of life were not collected. CONCLUSIONS: A stronger treatment effect with desmopressin ODT versus placebo and the magnitude of differences are indicative of clinical benefit in patients with NP. PATIENT SUMMARY: We looked at the clinical benefit of desmopressin ODT in patients with nocturnal polyuria. We conclude that clinical benefit was observed with desmopressin ODT in these patients. PMID- 30470647 TI - Risk Stratification Tools and Prognostic Models in Non-muscle-invasive Bladder Cancer: A Critical Assessment from the European Association of Urology Non-muscle invasive Bladder Cancer Guidelines Panel. AB - CONTEXT: This review focuses on the most widely used risk stratification and prediction tools for non-muscle-invasive bladder cancer (NMIBC). OBJECTIVE: To assess the clinical use and relevance of risk stratification and prediction tools to enhance clinical decision making and counselling of patients with NMIBC. EVIDENCE ACQUISITION: The most frequent, currently used risk stratification tools and prognostic models for NMIBC patients were identified by the members of the European Association of Urology (EAU) Guidelines Panel on NMIBC. EVIDENCE SYNTHESIS: The 2006 European Organization for Research and Treatment of Cancer (EORTC) risk tables are the most widely used and validated tools for risk stratification and prognosis prediction in NMIBC patients. The EAU risk categories constitute a simple alternative to the EORTC risk tables and can be used for comparable risk stratification. In the subgroup of NMIBC patients treated with a short maintenance schedule of bacillus Calmette-Guerin (BCG), the Club Urologico Espanol de Tratamiento Oncologico (CUETO) scoring model is more accurate than the EORTC risk tables. Both the EORTC risk tables and the CUETO scoring model overestimate the recurrence and progression risks in patients treated according to current guidelines. The new concept of conditional recurrence and progression estimates is very promising during follow-up but should be validated. CONCLUSIONS: Risk stratification and prognostic models enable outcome comparisons and standardisation of treatment and follow-up. At present, none of the available risk stratification and prognostic models reflects current standards of treatment. The EORTC risk tables and CUETO scoring model should be updated with previously unavailable data and recalculated. PATIENT SUMMARY: Non-muscle-invasive bladder cancer is a heterogeneous disease. A risk based therapeutic approach is recommended. We present available risk stratification and prediction tools and the degree of their validation with the aim to increase their use in everyday clinical practice. PMID- 30470648 TI - Physiologic pituitary hyperplasia causing visual disturbance during adolescence. AB - We report for the first time two cases of physiologic pituitary hyperplasia causing visual disturbance during adolescence. Case 1. A 15-year-old boy visited our department with a pituitary mass lesion on magnetic resonance imaging (MRI) associated with headache and transient bitemporal hemianopsia repeating. A visual field defect became apparent on the bitemporal upper side, and the area of the visual field defect enlarged to hemianopsia. The visual defect usually occurred in relation to exercise and continued for approximately 10 min. MRI showed the mass effect of pituitary hyperplasia to the optic chiasm. At six months later after the initial onset of the symptom, the visual field defect disappeared. Case 2. A 14-year-old girl came to our emergency department with a pituitary mass lesion on MRI associated with acute headache and visual disturbance occurring during exercise. MRI revealed the possibility of pituitary hyperplasia compressing the optic chiasm; however, her clinical course showed pituitary apoplexy. We conducted emergency transsphenoidal surgery to decompress her optic chiasm. The operative findings and histological examinations revealed a normal pituitary gland. Her visual disturbance immediately recovered after the surgery. Physiologic pituitary hyperplasia during adolescence can cause visual disturbance. Surgery should be carefully conducted, given the possibility of physiologic pituitary hyperplasia with visual symptoms. PMID- 30470649 TI - Interplays of estrogen receptor alpha gene rs2234693 with post-traumatic stress disorder influence serum glucose and lipids profiles in Chinese adolescents. AB - Both post-traumatic stress disorder (PTSD) and estrogen receptor alpha (ESR1) gene rs2234693 were reported to influence serum glucose and lipids profiles. However, their interactions on serum glucose and lipids profiles have not been reported. A total of 708 Chinese Han high school students were recruited at 6th months after the 2008 Wenchuan Earthquake. Serum concentrations of fasting blood glucose (FBG), fasting blood insulin (FBI), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were detected. Body mass index (BMI) and homeostatic model assessment of insulin resistance (HOMA-IR) were calculated. PTSD was assessed by the PTSD Checklist Civilian Version (PCL-C). Variants of ESR1 rs2234693 was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analyses and verified by DNA sequencing. The male subjects with PTSD had a trend of higher FBG (p = 0.077) and significantly higher FBI and HOMA-IR than male controls. The PTSD subjects had significantly higher levels of FBG, FBI, HOMA-IR and HDL-C than the controls only in the male C allele carriers irrespective of adjustment for age and BMI. In the male controls group, the C allele carriers had significantly lower HDL-C than the TT homozygotes regardless of adjustment for age and BMI. In female PTSD group, the C allele carriers had significantly higher TC/HDL-C and LDL-C/HDL-C than the TT homozygotes after adjustment for age and BMI. These results suggest the interplays of ESR1 rs2234693 with PTSD influence serum glucose and lipids profiles with a gender dependent manner. PMID- 30470650 TI - A novel technique for stabilization of high-grade spondylolisthesis with transvertebral fusion without reduction. AB - Surgical treatment of high-grade spondylolisthesis and spondyloptosis is recommended in symptomatic patients, yet there exists much debate regarding the optimal surgical approach and the need for reduction. Similar to the Bohlman technique in that fixation is achieved across two vertebral endplates, we discuss a novel technique with the advantage of using bilateral threaded pedicle screws of large diameter and length instead of a single fibula allograft. Patients underwent posterior instrumented fusion without spondylolisthesis reduction using a novel technique placing pedicle screws with a transvertebral trajectory through the two end plates involved in the spondylolisthesis. Following screw placement, patients underwent decompression +/- discectomy. Screws were connected to adjacent pedicle screws either in the upper adjacent vertebrae (i.e. L5) or the more rostral adjacent vertebrae (i.e. L4) if spinal alignment or instability necessitate including additional levels of fixation. Three patients were reviewed with ages of 67, 62, 58 years, operative times of 377-790 min, estimated blood loss 400-1050 cc, and follow-up times of 478-1082 days. There were no CSF leaks, intragenic neurologic deficits post-operatively, implant failures, revisions, or other systemic events. Two patients achieve radiographic fusion assessed by CT. At the time of final follow up, all patients were satisfied and essentially pain free. This one-stage technique offers the ability to manage local malalignment with a technique that inherently minimizes risk. The minimal complications and favorable outcomes make this technique an effective, efficient and safe procedure. Additional studies will focus on long term outcomes and should include larger patient samples. PMID- 30470651 TI - Acute necrotizing encephalopathy and a carnitine palmitoyltransferase 2 variant in an adult. AB - A 54-year-old Japanese man had a fever of over 40 degrees C for 7 days and developed unconsciousness, seizure and respiratory arrest. T2-weighted imaging magnetic resonance imaging revealed high-intensity signals on bilateral thalamus and it gradually extended to the brain white matter. Moreover, the lesion progressed to the spinal gray matter. The patient was diagnosed with acute necrotizing encephalopathy. CPT2 variants have been reported to be associated with acute necrotizing encephalopathy particularly in children and spinal cord lesions are extremely rare. We report a case of ANE in an adult with a CPT2 variant who developed spinal cord lesions. PMID- 30470652 TI - Reconstructing patient-specific cerebral aneurysm vasculature for in vitro investigations and treatment efficacy assessments. AB - Perianeurysmal hemodynamics play a vital role in the initiation, growth and rupture of intracranial aneurysms. In vitro investigations of aneurysmal hemodynamics are helpful to visualize and measure blood flow, and aiding surgical planning approaches. Improving in vitro model creation can improve the feasibility and accuracy of hemodynamic investigations and surgical planning, improving clinical value. In this study, in vitro models were created from three dimensional rotational angiography (3DRA) of six patients harboring intracranial aneurysms using a multi-step process involving 3D printing, index of refraction matching and silicone casting that renders the models transparent for flow visualization. Each model was treated with the same commercially-available, patient-specific, endovascular devices (coils and/or stents). All models were scanned by synchrotron X-ray microtomography to obtain high-resolution imaging of the vessel lumen, aneurysmal sac and endovascular devices. Dimensional accuracy was compared by quantifying the differences between the microtomographic reconstructions of the fabricated phantoms and the original 3DRA obtained during patient treatment. True-scale in vitro flow phantoms were successfully created for all six patients. Optical transparency was verified by using an index of refraction matched working fluid that replicated the mechanical behavior of blood. Synchrotron imaging of vessel lumen, aneurysmal sac and endovascular devices was successfully obtained, and dimensional errors were found to be O(100 MUm). The creation of dimensionally-accurate, optically-transparent flow phantoms of patient-specific intracranial aneurysms is feasible using 3D printing technology. Such models may enable in vitro investigations of aneurysmal hemodynamics to aid in treatment planning and outcome prediction to devise optimal patient-specific neurointerventional strategies. PMID- 30470653 TI - Pseudomeningocele and percutaneous intrathecal lead placement complication for spinal cord stimulator. AB - The incidence of symptomatic percutaneous intrathecal subarachnoid lead placement for spinal cord stimulator is almost an unheard of complication in the literature. We present the first case of a spinal cord stimulator implant with a complication of symptomatic intrathecal subarachnoid lead placement with a pseudomeningocele. This complication was found with myelogram and addressed by replacement with a new spinal cord stimulator implant with paddle leads instead of percutaneous leads and obliterating the pseudomeningocele tract. Technique for epidural lead placement is discussed. This case illustrates a spinal cord stimulator implant complication of intrathecal percutaneous lead placement with pseudomeningocele and its recognition and treatment involving replacement of the system while minimizing risk of postoperative cerebrospinal fluid leakage. Intraoperative neuromonitoring and interrogation of the spinal cord stimulator system during implantation are effective tools for accurate epidural lead placement. PMID- 30470654 TI - Secondary sacral tethered cord syndrome after treatment of secondary cervical syringomyelia. AB - A female patient operated at the age of 11 on a pilocytic astrocytoma in the posterior fossa, was re-operated for a recurrence 9 years later. A Torkildsen drain was placed in the 4th ventricle and she remained asymptomatic for 15 years before presenting again with acute hydrocephalus, tonsillar herniation, and a massive cervicothoracic syrinx. The symptoms retreated following craniocervical untethering and decompression. Two weeks later, however, she suffered from debilitating radiculopathy provoked by tethering of the cauda equina. Again, symptoms retreated completely after microsurgical intervention. This combination of a secondary Chiari-like malformation with cervical syringomyelia and tethering of the cauda equina in a single patient as a delayed complication of posterior fossa surgery has not been reported before. Diagnosis and treatment of lower tethered cord syndrome may be obscured and delayed in complex clinical situations. In particular, awareness to symptoms that are not related to syringomyelia is important in patients with a known syrinx and a history of posterior fossa surgery. PMID- 30470655 TI - Transcranial color-coded sonography findings of patients with reversible cerebral vasoconstriction syndromes. AB - Reversible cerebral vasoconstriction syndromes (RCVS) have been well recognized recently as one cause of cerebrovascular disease, but the time course of vessel vasoconstriction remains uncertain. We report herein 2 cases with RCVS in which we clarified temporal changes in vessel vasoconstriction in detail using transcranial color-coded sonography (TCCS). The first case involved a 27-year-old woman who developed intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) after severe headache. TCCS showed peak systolic velocity (PSV) in the left middle cerebral artery (MCA) peaked at 212 cm/s on day 6 and gradually decreased, whereas PSV of the left posterior cerebral artery (PCA) and left anterior cerebral artery (ACA) re-elevated to 190 cm/s on day 15. The second case involved a 53-year-old woman who developed cerebral infarction in the PCA territory 9 days after severe headache. TCCS study showed PSV elevation in the right MCA. Although TCCS seemed to normalize 7 days after admission, PSV of the left PCA, left ACA, and left MCA re-elevated at day 17. Both cases showed bimodal PSV peaks, with the posterior circulation peak preceded by the anterior circulation peak. These findings may be important in clarifying the mechanisms underlying vasoconstriction in patients with RCVS. PMID- 30470656 TI - The virtual reality of Parkinson's disease freezing of gait: A systematic review. AB - INTRODUCTION: Freezing of gait is an episodic inability to move the feet forward despite the intention to walk. It is a common cause of falls and subsequent morbidity and mortality in Parkinson's disease. Virtual reality paradigms provide an opportunity to safely evaluate freezing of gait, in order to better understand the underlying pathophysiology. This article focuses on the methodology, threshold used to define freezing of gait, results, limitations of studies using virtual reality paradigms, and proposes future directions of research. Summarizing these articles improves our understanding of freezing of gait in Parkinson's disease, and critical evaluation provides an opportunity for future studies to improve upon these efforts. METHODS: We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines, of studies using VR paradigms to elucidate the underlying pathophysiology of PD-FOG. RESULTS: This review initially identified 57 articles, but after exclusion of duplicates, abstracts, and studies not focused on the underlying pathophysiology of this disorder, 12 peer-reviewed articles using virtual reality paradigms to evaluate freezing of gait in Parkinson's disease were found. CONCLUSION: Virtual reality paradigms are able to reproduce freezing of gait. Studies using MRI compatible virtual reality to evaluate freezing of gait found dysfunctional connectivity between cortical and subcortical structures during episodes. However, several important limitations of these studies should caution our interpretation of these results. Future studies which improve the design and methodology are needed to ultimately identify the cause and subsequent treatments for freezing of gait in Parkinson's disease. PMID- 30470657 TI - Combined action observation and motor imagery influences hand movement amplitude in Parkinson's disease. PMID- 30470658 TI - Pharmacological treatment of apathy in Lewy body disorders: A systematic review. AB - INTRODUCTION: There are no approved treatments for apathy, a frequent and incapacitating symptom in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We reviewed the literature on the pharmacological treatment of apathy in PD and DLB to inform practice and future research. METHOD: We searched PubMed and PsycINFO using the terms "apathy", "treatment", and "Parkinson" or "Lewy body (bodies)." The results were filtered for "clinical trials" and "case reports." We included articles if apathy was measured as an outcome measure, before and after treatment. References of included articles were also reviewed. RESULTS: The PD search identified 19 articles: 13 randomized control trials (RCTs), 4 open-label studies, 1 case series, and 1 case report. Apathy was the primary outcome in 11 out of 19 studies. A decrease in apathy ratings was seen in 14 of the 19 studies. Of these 14 studies, 9 investigated medications with some dopaminergic effect. Three investigated acetylcholinesterase inhibitors (AChEIs) and found benefit in improving apathy. The DLB search identified 4 articles: 1 RCT, 2 open-label studies, and 1 case series. All 4 studies demonstrated decreased apathy and investigated AChEIs. CONCLUSIONS: We identified 23 studies that assessed the pharmacological treatment of apathy. In PD, agents with dopaminergic activity were the most studied and appeared to have the most benefit. AChEIs also appeared to have benefit in both PD and DLB but were less studied. Future studies of apathy treatment would benefit from larger samples and standardized assessments of apathy to define study populations and endpoints. PMID- 30470659 TI - Pulmonary and muscle profile in pneumosepsis: A temporal analysis of inflammatory markers. AB - In sepsis, greater understanding of the inflammatory mechanism involved would provide insights into the condition and into its extension to the muscular apparatus in critically ill patients. Therefore, this study evaluates the inflammatory profile of pneumosepsis induced by Klebsiella pneumoniae (K.p.) in lungs and skeletal muscles during the first 72 h. Male BALB/c mice were divided into 4 groups, submitted to intratracheal inoculation of K.p. at a concentration of 2 * 108 (PS) or PBS, and assessed after 24 (PS24), 48 (PS48) and 72 (PS72) hours. The Maximum Physical Capacity Test (MPCT) was performed before and after induction. Pulmonary inflammation was assessed by total cell number, nitric oxide levels (NOx), IL-1beta and TNF-alpha levels in bronchoalveolar lavage fluid (BALF); inflammation and muscle trophism were evaluated by the levels of TNF alpha, IL-6, TGF-beta and BDNF by ELISA and NF-kappaB by western blotting in muscle tissue. Cells and colony forming units (CFU) were also analyzed in blood samples. The PS groups showed an increase in total cells in the BALF (p < 0.05), as well in the number of granulocytes in the blood (p < 0.05) and a decrease in performance in the MPCT (p < 0.05). NOx levels showed significant increase in PS72, when compared to Control group (p = 0.03). The PS24 showed a significant increase lung in TNF-alpha levels (p < 0.001) and in CFU (p = 0.013). We observed an increase in muscular IL-6 and nuclear NF-kappaB levels in PS24 group, when compared to PS48 and Control groups (p < 0.05). Nevertheless, mild signs of injury in the skeletal muscle tissue does not support the idea of an early muscular injury in this experimental model, suggesting that the low performance of the animals during the MPCT may be related to lung inflammation. PMID- 30470660 TI - Relationship between interleukin-17A and isolated coronary ectasia. AB - The aim of this study was to evaluate serum interleukin (IL)-17A levels in patients with coronary artery ectasia (CAE), the relationship between IL and 17A and CAE, and to determine the relationship between the severity of coronary ectasia and the level of IL-17A. In total, 41 patients (19 female and 22 male) with ischemic symptoms whose non-invasive cardiac tests were positive for myocardial ischemia, and in whom coronary artery ectasia were detected after coronary angiography, and 45 patients (32 female and 13 male) with normal coronary arteries were included in this study. Echocardiographic assessments were performed. Serum IL-17A levels of all patients were evaluated using an enzyme linked immunosorbent assay. IL-17A levels of the group with isolated coronary artery ectasia were significantly higher compared with the control group (4.86 +/ 3.24 and 1.37 +/- 1.56 ng/ml, respectively; p < 0.001). There was no correlation between the levels of IL-17A and the extension of the CAE, but IL-17A levels were high in both groups. CAE patients have significantly increased levels of IL-17A, fibrinogen, and RDW compared to patients with normal coronary arteries. It was demonstrated that increased levels of IL-17A were associated with ectasia formation in CAE patients. PMID- 30470661 TI - Sulfatase 2 mediates, partially, the expression of endothelin-1 and the additive effect of Ang II-induced endothelin-1 expression by CXCL8 in vascular smooth muscle cells from spontaneously hypertensive rats. AB - The extracellular sulfatases (Sulfs), sulfatase 1 (Sulf1) and sulfatase 2 (Sulf2), have an important role in cell signaling by modulating the 6-O-sulfation of heparan sulfate proteoglycans (HSPGs) on the cell surface. Gene expression and enzyme activity of Sulfs are elevated in hypertensive vascular smooth muscle cells (VSMCs) compared to those in normotensive VSMCs. CXC-chemokine ligand (CXCL) 8 has a pathogenic role in the development and progression of hypertension. In this study, we investigated the effect of Sulfs on the expression of CXCL8-induced endothelin (ET)-1, a hypertensive mediator, in VSMCs from spontaneously hypertensive rats (SHR). Expression of ET-1 and elevation of angiotensin (Ang) II-induced ET-1 expression by CXCL8 were reduced in Sulf2 small interfering RNA (siRNA)-transfected SHR VSMCs. But, downregulation of Sulf1 did not affect the expression of CXCL8-induced ET-1 and additive effect of CXCL8 on Ang II-induced ET-1 expression in SHR VSMCs. CXCL8-induced ET-1 expression and the additive effect of CXCL8 on Ang II-induced ET-1 expression were dependent on the Ang II type 1 receptor (AT1 R) pathway, not the Ang II type 2 receptor (AT2 R) pathway. In addition, downregulation of Sulf2 reduced the expression of CXCL8 induced AT1 R and abrogated the additive effect of CXCL8 on Ang II-induced AT1 R expression in SHR VSMCs. Sulf2 mediated, partially, the expression of ET-1 and the additive expression of Ang II-induced ET-1 mRNA by CXCL8 via the AT1 R pathway in SHR VSMCs. These findings suggest that Sulf2 is an up-regulatory factor in the additive action of CXCL8 via the AT1 R pathway on Ang II-induced ET 1 expression in VSMCs under hypertension environment. PMID- 30470662 TI - Efficacy of cariprazine across symptom domains in patients with acute exacerbation of schizophrenia: Pooled analyses from 3 phase II/III studies. AB - Schizophrenia affects various symptom domains, including positive and negative symptoms, mood, and cognition. Cariprazine, a dopamine D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, with preferential binding to D3 receptors, is approved for the treatment of adult patients with schizophrenia (US, Europe) and mania associated with bipolar I disorder (US). For these investigations, data were pooled from 3 positive, 6-week, double-blind, placebo-controlled, phase II/III trials of cariprazine in patients with acute exacerbation of schizophrenia (NCT00694707, NCT01104766, NCT01104779); 2 trials were fixed-dose and 1 trial was flexible-dose. Post hoc analyses evaluated mean change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) derived symptom factors (positive symptoms, negative symptoms, disorganized thought, uncontrolled hostility/excitement, anxiety/depression) and PANSS single items for cariprazine (1.5-9.0 mg/d) versus placebo. P values were not adjusted for multiple comparisons. At week 6, statistically significant differences versus placebo were seen for cariprazine on all 5 PANSS factors (P < 0.01 all). Effects sizes ranged from 0.21 (anxiety/depression) to 0.47 (disorganized thought). Dose response analysis from the fixed-dose studies found significant differences for all cariprazine doses (1.5, 3.0, 4.5, and 6.0 mg/d) versus placebo in PANSS total score, and in negative symptom and disorganized thought factor scores (P < 0.001). Differences between cariprazine and placebo were also statistically significant on 26 of 30 PANSS single items (P < 0.05). In these post hoc analyses, cariprazine was effective versus placebo in improving all 5 PANSS factor domains, suggesting that it may have broad-spectrum efficacy in patients with acute schizophrenia. PMID- 30470663 TI - Urinary incontinence as a cause of depression and sexual dysfunction: Questionnaire-based study. AB - INTRODUCTION: Urinary incontinence is a severe and common health problem. In this study, we aimed to assess severity of sexual dysfunction and depression in patients with urinary incontinence. MATERIALS AND METHODS: The study has been conducted between 2015 and 2017. Age, body mass index, accompanying health problems, Over Active Bladder (OAB) symptom score, Type of urinary incontinence, Beck Depression Scale were assessed for all patients. International Index of Erectile Function-5 (IIEF-5) was used for male patients in order to assess sexual dysfunction. Index of Female Sexual Function (IFSF) and Female Sexual Distress Scale (FSDS) were used in female patients in order to assess sexual dysfunction. RESULTS: 33 patients have been included in the study (Male-12: Urge-10/Stress 1/Mixed-1/Female-21: Urge-10/Stress-6/Mixed-5). Mean age of all patients was 47.9 (Male-49.3/Female-47.2). Mean Body Mass Index for all patients was 23.2 (Male 25.9/Female-21.8). Mean OAB score was 24.3 for all patients (Male-27.5: Urge 28.6/Stress-17/Mixed-27/Female-22.5: Urge-24.2/Stress:21.3/Mixed-20.6). Mean Beck Depression Result for all patients was 20.9 (Male-18.5: Urge-20.2/Stress-9/Mixt 11/Female-22.4: Urge-19.1/Stress-20.3/Mixed-31.6). Mean IIEF-5 score for male patients was 39.5 (Urge-41.4/Stress-55/Mixed-5). Mean IFSF score for female patients was 19.9 (Urge-17.9/Stress-21.3/Mixed-22.4) and mean FSDS score for female patients was 22.1 (Urge-22.3/Stress-23.1/Mixed-20.8). DISCUSSION: Most of the patients that have been included in the study were diagnosed as urge incontinence. When assessing the OAB scores, they were higher in urge incontinence group. Beck depression results showed higher scores in female patients and it was higher in urge group of male patients and mixt group of female patients. Sexual dysfunction rates were found to be higher for both genders. PMID- 30470664 TI - Iron deficiency and anemia in patients with inherited bleeding disorders. AB - Patients with inherited bleeding disorders are predisposed to acute and chronic blood loss, which places them at high risk of iron deficiency anemia (IDA). The clinical effects of iron deficiency (ID) and IDA in the general population are significant and include low energy, reduced cardiovascular health, impaired cognition and reduced health-related quality of life. However, the incidence and impact of ID and IDA in patients with bleeding disorders is largely unknown. Here we review our approach to the diagnosis and management of iron deficiency in patients with inherited bleeding disorders. Given their risk of future iron losses, we propose more aggressive iron supplementation and higher target ferritin values in patients with ID and ongoing bleeding. PMID- 30470665 TI - Brazilian Association of Hematology, Hemotherapy and Cell Therapy update. PMID- 30470666 TI - Exercise during pregnancy has a preventative effect on excessive maternal weight gain and gestational diabetes. A randomized controlled trial. AB - BACKGROUND: Excessive gestational weight gain is associated with several adverse events and pathologies during pregnancy. OBJECTIVE: The purpose of this study was to examine the effects of an exercise program throughout pregnancy on maternal weight gain and prevalence of gestational diabetes. METHOD: A randomized controlled trial was designed that included an exercise intervention group (EG) and standard care control group (CG). The exercise intervention included moderate aerobic exercise performed three days per week (50-55minutes per session) for 8 10 weeks to 38-39 weeks gestation. RESULTS: 594 pregnant women were assessed for eligibility and 456 were included (EG n=234; CG n=222). The results showed a higher percentage of pregnant women gained excessive weight in the CG than in the EG (30.2% vs 20.5% respectively; odds ratio, 0.597; 95% confidence interval, 0.389-0.916; p=0.018). Similarly, the prevalence of gestational diabetes was significantly higher in the CG than the EG (6.8% vs 2.6% respectively; odds ratio, 0.363; 95% confidence interval, 0.138-0.953; p=0.033). CONCLUSION: The results of this trial indicate that exercise throughout pregnancy can reduce the risk of excessive maternal weight gain and gestational diabetes. PMID- 30470667 TI - Reliability of two functional clinical tests to evaluate trunk and lumbopelvic neuromuscular control and proprioception in a healthy population. AB - OBJECTIVES: The need to accurately assess trunk and lumbopelvic proprioception and neuromuscular control is widely accepted. However, based on current literature, there is a lack of reliable clinical tests to evaluate these aspects in clinical practice. The objective of this study is to investigate intra- and inter-tester reliability of the lateral step down test and the lumbopelvic position-reposition test in a healthy population. METHODS: Protocol and scoring methods were developed for the lateral step down test and lumbopelvic position reposition test, used to assess trunk and lumbopelvic neuromuscular control and proprioception respectively. Each test was performed once by thirty participants and video analysis for test scoring was performed. Three items on the lateral step down test were scored to evaluate neuromuscular control and, four items on the lumbopelvic position-reposition test were scored to evaluate proprioception. Aggregate scores for each test were calculated based on the separate item scores. Intraclass correlation coefficients and linear weighted kappa coefficients were determined for intra- and inter-tester reliability. RESULTS: Based on the aggregate score, excellent intra- and inter-tester reliability (ICC (2,1)=0.73 0.88) was found for both tests. Moderate/almost perfect intra-and inter-tester agreement (K=0.62-0.91) was found for the separate items of the lateral step down test and fair/substantial agreement (K=0.25-0.76) for the items of the lumbopelvic position-reposition test. CONCLUSION: Current testing protocol and scoring method for the lateral step down test is reliable. Adjustments for the scoring method of the lumbopelvic position-reposition test are warranted to improve reliability. PMID- 30470668 TI - Conjugated estrogens in the endometrium during the estrous cycle in pigs. AB - Estrogen metabolism results in the formation of inactive estrogen sulphates and glucuronides. Despite the lack of receptor binding, circulating conjugated estrogens might serve as a reservoir for the active form through the involvement of specific cleaving enzymes. In order to elucidate the potential role that estrogen conjugates play in the regulation of the estrous cycle, we determined the concentration of progesterone, estrogen and estrogen conjugates in serum and endometrial homogenates of cycling gilts. In addition, we determined the mRNA expression changes of enzymes (UDP glucuronosyltransferase (UGT), beta glucuronidase (GUSB), sulphotransferases (SULT) and steroid sulphatase (STS)) and transporters (multidrug resistance-associated protein (MRP), organic anion transporting polypeptide (OATPs)) involved in the estrogen metabolism in the endometrium across the estrous cycle. GUSB displayed highest expression at estrous (day 0), decreasing expression during metestrus (day 3 and 6), minimal expression on day 10 and 12, and increasing expression towards proestrus (day 18), suggesting either a stimulation by estrogens or a negative impact of progesterone. The mRNA expression of the influx-transporter OATP1A2 significantly increased from day 0 to 6 and decreased again by day 10, while the efflux transporters (MRP1, MRP2, and MDR1) displayed minimal expression at day 3 and 6. The mRNA expression of the UDP-glucuronsyltransferases followed a similar pattern, with minimal expression found at day 6. The analyses of the concentration of local and circulating steroid hormones points towards an interaction of the analyzed transporters and enzymes with steroid hormones, thereby possibly regulating the reservoir of active steroids contributing to the endometrial function. PMID- 30470670 TI - The addiction paradox. PMID- 30470669 TI - Haptic interaction for needle insertion training in medical applications: The state-of-the-art. AB - Computer-based simulation for medical procedures training has been gaining relevance, as well the use of haptic devices for developing fine motor skills in such simulations. The purpose of this paper is to present a review of the state of-the-art in virtual needle insertion training simulation based on haptic interaction. A systematic review method was applied to gather documentation that enables a rigorous audit of the process stages and results. We established a classification system based on certain characteristics of the studies analyzed, including: main procedures and target body regions in medical applications; ways to generate haptic feedback; devices; types of environment; and user validation. In addition, the review aimed to identify challenges and trends in the field, indicating research opportunities. Results showed the predominance of Virtual Reality and commercial haptic devices in simulations. Since most studies are based on subjective tests, finding ways to objectively evaluate haptic interaction perception represents a promising research field. We also found that devices and ways to generate haptic feedback and to represent tissue and needle behavior pose limitations and challenges for computer simulation. Finally, the realism provided is a constant concern in the validation process, which brings another problem: defining and performing suitable user tests. PMID- 30470671 TI - A stitch in time saves nine: Untreated perinatal depression hurts future generations. PMID- 30470672 TI - The plastic surgeon as employee: Survey of the American Society of Plastic Surgeons. PMID- 30470673 TI - Microvascular anastomosis with fish-mouth suturing and adhesive sealants. PMID- 30470674 TI - Use of innovative negative pressure therapy for cartilage exposure in microtia reconstruction. PMID- 30470675 TI - Perioperative intralesional injection of fibrin glue for extirpation of oral haemangioma: A technical note. PMID- 30470676 TI - An Empathy-Driven, Conversational Artificial Intelligence Agent (Wysa) for Digital Mental Well-Being: Real-World Data Evaluation Mixed-Methods Study. AB - BACKGROUND: A World Health Organization 2017 report stated that major depression affects almost 5% of the human population. Major depression is associated with impaired psychosocial functioning and reduced quality of life. Challenges such as shortage of mental health personnel, long waiting times, perceived stigma, and lower government spends pose barriers to the alleviation of mental health problems. Face-to-face psychotherapy alone provides only point-in-time support and cannot scale quickly enough to address this growing global public health challenge. Artificial intelligence (AI)-enabled, empathetic, and evidence-driven conversational mobile app technologies could play an active role in filling this gap by increasing adoption and enabling reach. Although such a technology can help manage these barriers, they should never replace time with a health care professional for more severe mental health problems. However, app technologies could act as a supplementary or intermediate support system. Mobile mental well being apps need to uphold privacy and foster both short- and long-term positive outcomes. OBJECTIVE: This study aimed to present a preliminary real-world data evaluation of the effectiveness and engagement levels of an AI-enabled, empathetic, text-based conversational mobile mental well-being app, Wysa, on users with self-reported symptoms of depression. METHODS: In the study, a group of anonymous global users were observed who voluntarily installed the Wysa app, engaged in text-based messaging, and self-reported symptoms of depression using the Patient Health Questionnaire-9. On the basis of the extent of app usage on and between 2 consecutive screening time points, 2 distinct groups of users (high users and low users) emerged. The study used mixed-methods approach to evaluate the impact and engagement levels among these users. The quantitative analysis measured the app impact by comparing the average improvement in symptoms of depression between high and low users. The qualitative analysis measured the app engagement and experience by analyzing in-app user feedback and evaluated the performance of a machine learning classifier to detect user objections during conversations. RESULTS: The average mood improvement (ie, difference in pre- and post-self-reported depression scores) between the groups (ie, high vs low users; n=108 and n=21, respectively) revealed that the high users group had significantly higher average improvement (mean 5.84 [SD 6.66]) compared with the low users group (mean 3.52 [SD 6.15]); Mann-Whitney P=.03 and with a moderate effect size of 0.63. Moreover, 67.7% of user-provided feedback responses found the app experience helpful and encouraging. CONCLUSIONS: The real-world data evaluation findings on the effectiveness and engagement levels of Wysa app on users with self-reported symptoms of depression show promise. However, further work is required to validate these initial findings in much larger samples and across longer periods. PMID- 30470677 TI - Providing a Smart Healthy Diet for the Low-Income Population: Qualitative Study on the Usage and Perception of a Designed Cooking App. AB - BACKGROUND: Health behaviors among low-income groups have become a major issue in the context of increasing social inequalities. The low-income population is less likely to be receptive to nutritional recommendations, but providing cooking advice could be more effective. In this domain, taking advantage of digital devices can be a bonus with its own challenges. OBJECTIVE: The aim of this study was to develop and deploy NutCracker, a social network-based cooking app for low income population, including cooking tips and nutritional advices, aiming at creating small online communities. We further determined the usefulness, perceptions, barriers, and motivators to use NutCracker. METHODS: The smartphone app, designed jointly with beneficiaries of the social emergency services, was implemented in a disadvantaged neighborhood of Magny, (Paris region, France). Once the app became available, 28 subjects, living in the neighborhood, tested the app for a 6-month period. Logs to the app and usages were collected by the software. In total, 12 in-depth, semistructured interviews were conducted among the users and the social workers to analyze their uses and perceptions of the app relative to their interest in cooking, cooking skills, socioeconomic constraints, and social integration. These interviews were compared with 21 supplementary interviews conducted among low-income individuals in the general population. RESULTS: NutCracker was developed as a social network-based app, and it includes cooking tips, nutritional advice, and Web-based quizzes. We identified barriers to uses (especially technical barriers, lack of knowledge in the field of new technologies and written comprehension, and search for real contacts) and motivators (in particular, good social integration, previous use of social networks, and help of children as intermediaries). Cooking skills were both a barrier and a lever. CONCLUSIONS: Targeting the low-income groups through a cooking app to promote healthier behaviors offers many advantages but has not been fully explored. However, the barriers in low-income milieu remain high, especially among the less socially integrated strata. Lessons from this intervention allow us to identify barriers and possible levers to improve nutrition promotion and awareness in deprived areas, especially in the time of social crisis. PMID- 30470678 TI - Evidence-Based Evaluation of eHealth Interventions: Systematic Literature Review. AB - BACKGROUND: Until now, the use of technology in health care was driven mostly by the assumptions about the benefits of electronic health (eHealth) rather than its evidence. It is noticeable that the magnitude of evidence of effectiveness and efficiency of eHealth is not proportionate to the number of interventions that are regularly conducted. Reliable evidence generated through comprehensive evaluation of eHealth interventions may accelerate the growth of eHealth for long term successful implementation and help to experience eHealth benefits in an enhanced way. OBJECTIVE: This study aimed to understand how the evidence of effectiveness and efficiency of eHealth can be generated through evaluation. Hence, we aim to discern (1) how evaluation is conducted in distinct eHealth intervention phases, (2) the aspects of effectiveness and efficiency that are typically evaluated during eHealth interventions, and (3) how eHealth interventions are evaluated in practice. METHODS: A systematic literature review was conducted to explore the evaluation methods for eHealth interventions. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were followed. We searched Google Scholar and Scopus for the published papers that addressed the evaluation of eHealth or described an eHealth intervention study. A qualitative analysis of the selected papers was conducted in several steps. RESULTS: We intended to see how the process of evaluation unfolds in distinct phases of an eHealth intervention. We revealed that in practice and in several conceptual papers, evaluation is performed at the end of the intervention. There are some studies that discuss the importance of conducting evaluation throughout the intervention; however, in practice, we found no case study that followed this. For our second research question, we discovered aspects of efficiency and effectiveness that are proposed to be assessed during interventions. The aspects that were recurrent in the conceptual papers include clinical, human and social, organizational, technological, cost, ethical and legal, and transferability. However, the case studies reviewed only evaluate the clinical and human and social aspects. At the end of the paper, we discussed a novel approach to look into the evaluation. Our intention was to stir up a discussion around this approach with the hope that it might be able to gather evidence in a comprehensive and credible way. CONCLUSIONS: The importance of evidence in eHealth has not been discussed as rigorously as have the diverse evaluation approaches and evaluation frameworks. Further research directed toward evidence-based evaluation can not only improve the quality of intervention studies but also facilitate successful long-term implementation of eHealth in general. We conclude that the development of more robust and comprehensive evaluation of eHealth studies or an improved validation of evaluation methods could ease the transferability of results among similar studies. Thus, the resources can be used for supplementary research in eHealth. PMID- 30470679 TI - Simulation Modeling for Psychiatric Service Planning: Protocol for a Mixed Methods Study. AB - BACKGROUND: Mental health service managers must take into account multiple factors when making decisions about the best way to deliver care to clients across increasingly larger service areas. This task is made more difficult by the lack of evidence and tools historically available to inform these decisions. In recent decades, the increasing availability of epidemiological and service use data for mental illness has solved the problem of evidence, but there still exists a challenge to make these data easily accessible and understandable for managers. OBJECTIVE: This study aims to develop a simulation modeling tool to allow managers to explore various service configurations in virtual reality, enabling predictions to be made about the cost and quality of care. METHODS: This is a longitudinal, mixed-methods case study, comprising overlapping intervention and evaluation phases. In partnership with senior managers of a mental health program, the researchers will develop a series of simulation models in Arena to address key strategic issues facing the service. Thematic and content analyses of semistructured interviews, meeting observations, and document analysis will be used to evaluate the process of model implementation and the outcomes for both researchers and managers. The study is being conducted in Australia. RESULTS: Data collection has been ongoing since late 2013. To date, 3 prototype simulation models have been developed and presented to senior managers, and 18 evaluation interviews have been conducted. The project is expected to conclude in late 2018. CONCLUSIONS: Findings of this study have the potential to shape decision making in mental health service delivery, by providing key examples of how to integrate patient data using simulation modeling. In addition, the results will provide key insights into how researchers and consultants can effectively implement simulation modeling in real-world health care organizations. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/11119. PMID- 30470680 TI - Glucose Control, Disease Burden, and Educational Gaps in People With Type 1 Diabetes: Exploratory Study of an Integrated Mobile Diabetes App. AB - BACKGROUND: Self-monitoring and self-management, crucial for optimal glucose control in type 1 diabetes, requires many disease-related decisions per day and imposes a substantial disease burden on people with diabetes. Innovative technologies that integrate relevant measurements may offer solutions that support self-management, decrease disease burden, and benefit diabetes control. OBJECTIVE: The objective of our study was to evaluate a prototype integrated mobile phone diabetes app in people with type 1 diabetes. METHODS: In this exploratory study, we developed an app that contained cloud-stored log functions for glucose, carbohydrates (including a library), insulin, planned exercise, and mood, combined with a bolus calculator and communication functions. Adults with diabetes tested the app for 6 weeks. We assessed the feasibility of app use, user experiences, perceived disease burden (through questionnaires), insulin dose and basal to bolus ratio, mean glucose level, hemoglobin A1c, and number of hypoglycemic events. RESULTS: A total of 19 participants completed the study, resulting in 5782 data entries. The most frequently used feature was logging blood glucose, insulin, and carbohydrates. Mean diabetes-related emotional problems (measured with the Problem Areas in Diabetes scale) scores decreased from 14.4 (SD 10.0) to 12.2 (SD 10.3; P=.04), and glucose control improved, with hemoglobin A1c decreasing from 7.9% (mean 62.3, SD 8 mmol/mol) to 7.6% (mean 59.8, SD 7 mmol/mol; P=.047). The incidence of hypoglycemic events did not change. Participants were generally positive about the app, rating it as "refreshing," and as providing structure by reinforcing insulin-dosing principles. The app revealed substantial knowledge gaps. Logged data enabled additional detailed analyses. CONCLUSIONS: An integrated mobile diabetes app has the potential to improve diabetes self-management and provide tailored educational support, which may decrease disease burden and benefit diabetes control. PMID- 30470682 TI - 60 seconds on . . . rainbow badges. PMID- 30470681 TI - Real-World Technology Use Among People With Mental Illnesses: Qualitative Study. AB - BACKGROUND: There is growing interest in using technology-based tools to support mental health recovery. Yet, despite evidence suggesting widespread access to technology among people with mental illnesses, interest in using technology to support mental health, and effectiveness of technology-based tools developed by researchers, such tools have not been widely adopted within mental health settings. Little is currently known about how mental health consumers are using technology to address mental health needs in real-world settings outside of controlled research studies. OBJECTIVE: This qualitative study examined current practices and orientations toward technology among consumers in 3 mental health settings in the United States. METHODS: Ethnographic observations and semistructured interviews were conducted. Observations focused on if and how technology was salient within the setting and documented relevant behaviors, interactions, and dialogue in fieldnotes. Ethnographic data informed the development of a semistructured interview that inquired into technology use and interest among consumers (n=15) in a community mental health setting. Fieldnotes and interview transcripts were reviewed and coded by multiple researchers. Key concepts and patterns identified were refined by the research team to develop the main findings. RESULTS: Ownership of technology, although common, was not ubiquitous and was varied across the sites. Participants had varying levels of awareness regarding the key capabilities of modern technologies. Participants used technology for many purposes, but there was limited evidence of technology use to support mental health. Technology-based tools specific to mental health were not routinely used, although some participants found widely available mobile apps to be helpful in recovery. CONCLUSIONS: Qualitative findings suggest that many, but not all, clients will be interested in using technology to support mental health needs. The variability in type and quality of technology owned by participants suggests the need to design for a range of functionality in the development of mental health tools. Findings also suggest thinking broadly about using existing platforms and widely available tools to support consumers in mental health recovery. PMID- 30470683 TI - Rare and striking complication of Henoch-Schonlein purpura. PMID- 30470684 TI - Can a ketogenic diet be safely used to improve glycaemic control in a child with type 1 diabetes? PMID- 30470685 TI - Language in 2-year-old children born preterm and term: a cohort study. AB - PURPOSE: Language skills are critical. Children born very preterm are vulnerable to language problems, but further work is needed to determine characteristics and specific predictors of language problems in this population. We aimed to compare language outcomes between 2-year-old children born <30 weeks and their term-born peers; and to explore risk factors for language difficulties in this cohort. DESIGN: Language at 2 years was examined in 134 children born <30 weeks and 133 children born at term using the Bayley Scales of Infant and Toddler Development - 3rd Edition (Bayley-3) and the Communication and Symbolic Behaviour Scale: Developmental Profile (Infant Toddler Checklist) (CSBS:DP). Outcomes were compared between groups. Factors hypothesised to predict language outcome were examined in the preterm group: gestational age at birth, birth weight z-score, sex, hearing loss, multilingualism, maternal education, brain abnormality on MRI, medical risk and oromotor concerns at 12 months. RESULTS: Children born <30 weeks performed more poorly on the CSBS:DP (particularly the social and symbolic composites) and the language scale of the Bayley-3 at 2 years than term-born peers. Lower gestational age at birth, male sex, hearing loss and multilingualism predicted poorer language scores. CONCLUSIONS: Despite improvements in medical management, children born very preterm exhibit language delays at 2 years of age, with specific deficits in social communication and symbolic skills. Significant predictors of poorer language outcomes were similar to those in the general population (male sex, hearing loss, multilingualism), suggesting that further work is needed to establish which specific factors place preterm-born children at heightened risk. PMID- 30470686 TI - Patterns of moderate and severe injury in children after the introduction of major trauma networks. AB - OBJECTIVE: To describe the demographics, mechanisms, presentation, injury patterns and outcomes for children with traumatic injuries. SETTING: Data collected from the UK's Trauma and Audit Research Network. DESIGN AND PATIENTS: The demographics, mechanisms of injury and outcomes were described for children with moderate and severe injuries admitted to the Major Trauma Network in England between 2012 and 2017. RESULTS: Data regarding 9851 children were collected. Most (69%) were male. The median age was 6.4 (SD 5.2) years, but infants aged 0.1 year (36.5 days) were the most frequently injured of all ages (0-15 years); 447 (36.0%) of injuries in infants aged <1 year were from suspected child abuse. Most injuries occurred in the home, from falls <2 m, after school hours, at weekends and during the summer. The majority of injuries were of moderate severity (median Injury Severity Score 9.0, SD 8.7). The limbs and pelvis, followed by the head, were the most frequently and most severely injured body parts. Ninety-two per cent were discharged home and 72.8% made a 'good recovery' according to the Glasgow Outcome Scale. 3.1% of children died, their median age was 7.0 years (SD 5.8), but infants were the most commonly fatally injured group. CONCLUSIONS: A common age of injury and mortality was infants aged <1 year. Accident prevention strategies need to focus on the prevention of non-accidental injuries in infants. Trauma services need to be organised to accommodate peak presentation times, which are after school, weekends and the summer. PMID- 30470687 TI - Approach to syncope in the emergency department. AB - Syncope is a common reason for ED attendance and it presents a major management challenge with regard to the appropriate workup and disposition. Nearly 50% of patients are admitted, and for many this is unnecessary; clinical decision rules have not proven to decrease unnecessary admissions. The European Society of Cardiology has recently developed guidance for managing syncope in the ED. This article highlights the key steps in evaluating syncope in the ED, factors involved in determining risk of a cardiac cause, and considerations for admission, observation or discharge. PMID- 30470688 TI - Comparison of the use of lung ultrasound and chest radiography in the diagnosis of rib fractures: a systematic review. AB - INTRODUCTION: It is well-recognised that the detection of rib fractures is unreliable using chest radiograph. The aim of this systematic review was to investigate whether the use of lung ultrasound is superior in accuracy to chest radiography, in the diagnosis of rib fractures following blunt chest wall trauma. METHODS: The search filter was used for international online electronic databases including MEDLINE, EMBASE, Cochrane and ScienceDirect, with no imposed time or language limitations. Grey literature was searched. Two review authors completed study selection, data extraction and data synthesis/analysis process. Quality assessment using the Quality Assessment of Diagnostic Accuracy Studies Tool (QUADAS-2) was completed. RESULTS: 13 studies were included. Overall, study results demonstrated that the use of lung ultrasound in the diagnosis of rib fractures in blunt chest wall trauma patients appears superior compared with chest radiograph. All studies were small, single centre and considered to be at risk of bias on quality assessment. Meta-analysis was not possible due to high levels of heterogeneity, lack of appropriate reference standard and poor study quality. DISCUSSION: The results demonstrate that lung ultrasound may be superior to chest radiography, but the low quality of the studies means that no definitive statement can be made. PMID- 30470689 TI - Chaperoning junior faculty: Institutional support and guidance can relieve challenges for early-career group leaders and improve academic performance. PMID- 30470690 TI - Initial Report of Second-Line FOLFIRI in Combination with Ramucirumab in Advanced Gastroesophageal Adenocarcinomas: A Multi-Institutional Retrospective Analysis. AB - BACKGROUND: The randomized phase III RAINBOW trial established paclitaxel (pac) plus ramucirumab (ram) as a global standard for second-line (2L) therapy in advanced gastric and gastroesophageal junction adenocarcinoma, together gastroesophageal adenocarcinoma (GEA). Patients (pts) receiving first-line (1L) FOLFOX often develop neuropathy that renders continued neurotoxic agents in the 2L setting unappealing and other regimens more desirable. As such, FOLFIRI-ram has become an option for patients with 2L GEA. FOLFIRI-ramucirumab (ram) has demonstrated safety and activity in 2L colorectal cancer, but efficacy/safety data in GEA are lacking. SUBJECTS, MATERIALS, AND METHODS: Patients with GEA treated with 2L FOLFIRI-ram between August 2014 and April 2018 were identified. Clinicopathologic data including oxaliplatin neurotoxicity rates/grades (G), 2L treatment response, progression-free survival (PFS), overall survival (OS), safety, and molecular features were abstracted from three U.S. academic institutions. Kaplan-Meier survival analysis was used to generate PFS/OS; the likelihood ratio test was used to determine statistical significance. RESULTS: We identified 29 pts who received 2L FOLFIRI-ram. All pts received 1L platinum + fluoropyrimidine, and 23 of 29 (79%) had post-1L neuropathy; 12 (41%) had G1, and 11 (38%) had G2. Patients were evenly split between esophagus/gastroesophageal junction (12; 41%) and gastric cancer (17; 59%). Among evaluable pts (26/29), the overall response rate was 23% (all partial response) with a disease control rate of 79%. Median PFS was 6.0 months and median OS was 13.4 months among all evaluable pts. Six- and 12-month OS were 90% (n = 18/20) and 41% (n = 7/17). There were no new safety signals. CONCLUSION: We provide the first data suggesting FOLFIRI-ram is a safe, non-neurotoxic regimen comparing favorably with the combination of pac + ram used in the seminal RAINBOW trial. IMPLICATIONS FOR PRACTICE: Results of this study provide initial support for the safety and efficacy of second-line (2L) FOLFIRI-ramucirumab (ram) after progression on first line platinum/fluoropyrimidine in patients with gastroesophageal adenocarcinoma (GEA). The overall response, progression-free survival, overall survival, and toxicity profile compare favorably with paclitaxel (pac) + ram and highlight the importance of the ongoing phase II RAMIRIS trial examining FOLFIRI-ram versus pac + ram in 2L GEA (NCT03081143). FOLFIRI-ram may warrant consideration for inclusion as an alternate regimen in consensus guidelines for GEA. PMID- 30470691 TI - Concomitant Medications and Risk of Chemotherapy-Induced Peripheral Neuropathy. AB - BACKGROUND: Peripheral neuropathy is the dose-limiting toxicity of many oncology drugs, including paclitaxel. There is large interindividual variability in the neuropathy, and several risk factors have been proposed; however, many have not been replicated. Here we present a comprehensive study aimed at identifying treatment and physiopathology-related paclitaxel-induced neuropathy risk factors in a large cohort of well-characterized patients. PATIENTS AND METHODS: Analyses included 503 patients with breast or ovarian cancer who received paclitaxel treatment. Paclitaxel dose modifications caused by the neuropathy were extracted from medical records and patients self-reported neuropathy symptoms were collected. Multivariate logistic regression analyses were performed to identify concomitant medications and comorbidities associated with paclitaxel-induced neuropathy. RESULTS: Older patients had higher neuropathy: for each increase of 1 year of age, the risk of dose modifications and grade 3 neuropathy increased 4% and 5%, respectively. Cardiovascular drugs increased the risk of paclitaxel dose reductions (odds ratio [OR], 2.51; p = .006), with a stronger association for beta-adrenergic antagonists. The total number of concomitant medications also showed an association with dose modifications (OR, 1.25; p = .012 for each concomitant drug increase). A dose modification predictive model that included the new identified factors gave an area under the curve of 0.74 (p = 1.07 * 10 10). Preexisting nerve compression syndromes seemed to increase neuropathy risk. CONCLUSION: Baseline characteristics of the patients, including age and concomitant medications, could be used to identify individuals at high risk of neuropathy, personalizing chemotherapy treatment and reducing the risk of severe neuropathy. IMPLICATIONS FOR PRACTICE: Peripheral neuropathy is a common adverse effect of many cancer drugs, including chemotherapeutics, targeted therapies, and immune checkpoint inhibitors. About 40% of survivors of cancer have functional deficits caused by this toxicity, some of them irreversible. Currently, there are no effective treatments to prevent or treat this neuropathy. This study, performed in a large cohort of well-characterized patients homogenously treated with paclitaxel, identified concomitant medications, comorbidities, and demographic factors associated with peripheral neuropathy. These factors could serve to identify patients at high risk of severe neuropathy for whom alternative non-neurotoxic alternatives may be considered. PMID- 30470692 TI - Prognosis of Young Survivors of Gastric Cancer in China and the U.S.: Determining Long-Term Outcomes Based on Conditional Survival. AB - BACKGROUND: Young survivors of gastric cancer (GC) have better prognoses than elderly patients, yet their disease-specific survival (DSS) has received little attention. PATIENTS AND METHODS: Data on young patients (aged <=40 years) with GC undergoing resections at three Chinese institutions (n = 542) and from the SEER database (n = 533) were retrospectively analyzed. Three-year conditional disease specific survival (CS3) was assessed. The effects of well-known prognostic factors over time were analyzed by time-dependent Cox regression. RESULTS: Overall, young Chinese patients with GC had a better 5-year DSS than U.S. patients (62.8% vs. 54.1%; p < .05). The disease-specific mortality likelihood of the entire cohort was not constant over time, with most deaths occurring during the first 3 years after surgery but peaking at 1 and 2 years in China and the U.S., respectively. Based on 5-year survivorship, the CS3 rates of both groups were similar (90.9% [U.S.] vs. 91.5% [China]; p > .05). Cox regression showed that for Chinese patients, site, size, T stage, and N stage were independent prognostic factors at baseline (p < .05). For U.S. patients, grade, T stage. and N stage significantly affected DSS at baseline (p < .05). In both groups, only T stage continuously affected DSS within 3 years after gastrectomy. However, for both groups, the initial well-known prognostic factors lost prognostic significance after 5 years of survival (all p > .05). Although the 5-year DSS rates of young Chinese patients with T3 and T4a disease were significantly better than those of young U.S. patients, in each T stage, the CS3 of both regions trended toward consistency over time. CONCLUSION: For young patients with GC, the factors that predict survival at baseline vary over time. Although the initial 5 year DSS is heterogeneous, insight into conditional survival will help clinicians evaluate the long-term prognoses of survivors while ignoring population differences. IMPLICATIONS FOR PRACTICE: With the increasing number of young survivors of gastric cancer (GC), it is essential for clinicians to understand the dynamic prognosis of these patients. Based on large data sets from China and the U.S., this study found that the prognostic factors that predict survival for young patients with GC at baseline vary over time. Although the initial 5-year disease-specific survival is heterogeneous, insight into conditional survival will help clinicians evaluate the long-term prognoses of survivors while ignoring population differences. This knowledge may be more effective in helping young patients with GC to manage future uncertainties, especially when they need to make important life plans. PMID- 30470693 TI - Surgeon who endangered patients' lives at abortion clinic is struck off. PMID- 30470694 TI - GPs are being "emotionally blackmailed" to prescribe outside competency, conference hears. PMID- 30470695 TI - GP leader calls for "long term cure" for general practice. PMID- 30470697 TI - Thrombectomy can be considered up to 24 hours after onset of stroke, says NICE. PMID- 30470696 TI - The immune system profoundly restricts intratumor genetic heterogeneity. AB - Tumors develop under the selective pressure of the immune system. However, it remains critical to establish how the immune system affects the clonal heterogeneity of tumors that often display cell-to-cell variation in genetic alterations and antigenic expression. To address these questions, we introduced a multicolor barcoding strategy to study the growth of a MYC-driven B cell lymphoma harboring a large degree of intratumor genetic diversity. Using intravital imaging, we visualized that lymphoma subclones grow as patches of sessile cells in the bone marrow, creating a spatially compartmentalized architecture for tumor diversity. Using multicolor barcoding and whole-exome sequencing, we demonstrated that immune responses strongly restrict intratumor genomic diversity and favor clonal dominance, a process mediated by the selective elimination of more immunogenic cells and amplified by epitope spreading. Anti-PD-1 treatment also narrowed intratumor diversity. Our results provide direct evidence that immune pressure shapes the level of intratumor genetic heterogeneity and have important implications for the design of therapeutic strategies. PMID- 30470698 TI - Evaluating effects of recent changes in NHS resource allocation policy on inequalities in amenable mortality in England, 2007-2014: time-series analysis. AB - BACKGROUND: Health investment in England post-2010 has increased at lower rates than previously, with proportionally less being allocated to deprived areas. This study seeks to explore the impact of this on inequalities in amenable mortality between local areas. METHODS: We undertook a time-series analysis across 324 lower-tier local authorities in England, evaluating the impact of changes in funding allocations to health commissioners from 2007 to 2014 on spatial inequalities in age-standardised under-75 mortality rates for conditions amenable to healthcare for men and women, adjusting for trends in household income, unemployment and time-trends. RESULTS: More deprived areas received proportionally more funding between 2007 and 2014, though the reorganisation of commissioning in 2012 stalled this. Funding increases to more deprived local areas accounted for a statistically significant reduction in inequalities in male amenable mortality between local areas of 13 deaths per 100 000 (95% CI 2.5 to 25.9). Funding changes were associated with a reduction in inequalities in female amenable mortality of 7.0 per 100,000, though this finding did not reach significance (p=0.09). CONCLUSION: Current National Health Service (NHS) resource allocation policy in England appears to be contributing to a convergence in health outcomes between affluent and deprived areas. However, careful surveillance is needed to evaluate whether diminished allocations to more deprived areas in recent years and reduced NHS investment as a whole is impacting adversely on inequalities between groups. PMID- 30470699 TI - Prospective impact of individual, family and community youth assets on adolescent suicide ideation. AB - BACKGROUND: Studies have found that youth assets have a protective influence on many risk behaviours. However, the relationship between youth assets and adolescent suicide ideation is poorly understood. The purpose of this study was to determine if youth assets were prospectively associated with suicide ideation. METHODS: Four waves of data were collected from 1111 youth and their parents living in randomly sampled census tracts that were stratified by income and race/ethnicity using census data. Computer-assisted, in-person data collection methods were used to measure assets at the individual (6 assets), family (4 assets) and community (6 assets) levels. Generalised linear mixed models were used to prospectively assess the relationship between the number of individual level, family-level and community-level assets and suicide ideation, while controlling for known confounders. RESULTS: About half of the sample was female (53%). Participants were racially/ethnically diverse (white (41%), Hispanic (29%) and black (24%)). Eleven of the 16 assets were associated with reduced odds of suicide ideation. In addition, there was a graded relationship between the number of assets at each level (individual, family and community) and the odds of suicide ideation. For example, compared with youth with 0-2 family assets, those with 3 (OR 0.61; 95% CI 0.42 to 0.90) or 4 (OR 0.32; 95% CI 0.21 to 0.51) family assets had lower odds of suicide ideation. CONCLUSIONS: This prospective analysis showed a protective relationship between youth assets and suicide ideation, with the greatest protection among youth with the most assets. Interventions designed to build youth assets may be a useful strategy for reducing adolescent suicide ideation. PMID- 30470700 TI - Employment trajectories in midlife and cognitive performance in later life: longitudinal study of older American men and women. AB - BACKGROUND: Although being employed during midlife is positively associated with cognitive function in later life, little is known with respect to cumulative trajectories or durations of time spent in different kinds of work. METHODS: We investigated the relationships between employment trajectory from ages 31 years to 50 years and cognitive skills at ages 50-78 years among 2521 adults in the US Panel Study of Income Dynamics from 1968 to 2016. Sequence analysis was used to identify prototypical employment trajectories, capturing employment status and high versus lower job skill level at each year of age from 31 years to 50 years. Adjusted and weighted logistic regression was used to estimate relationships between employment trajectory and performance on each of four cognitive tests representing numerical reasoning, verbal reasoning, health literacy and financial literacy. Dose-response relationships between the duration of high-skill employment and cognitive skills were examined. RESULTS: Seven prototypical employment trajectories were identified, the most common being consistently lower skill employment (44%; 1105/2521). Consistently high-skill and fluctuating skill trajectories were associated with high numerical reasoning scores (OR=1.54, 95% CI 0.99 to 2.40; OR=2.52, 95% CI 1.39 to 4.58, respectively), compared with consistently lower skill employment. There was a dose-response relationship between duration of high-skill employment and numerical reasoning (OR=1.17; 95% CI 1.06 to 1.28), plateauing after approximately 4 years of high-skill employment. CONCLUSIONS: Sequence analysis of exposure trajectories is a novel method for life course epidemiology that accounts for exposure timing, duration and ordering. Our results using this method indicate that the duration may be more important than the timing of high-skill midlife employment for later-life numerical reasoning skills. PMID- 30470701 TI - Palliative care in a tertiary neonatal intensive care unit: a 10-year review. AB - OBJECTIVES: When active treatment is no longer in the best interests of the patient, redirection of care to palliation is an important transition. We review, within a tertiary neonatal intensive care unit (NICU), the journey leading to the decision to redirect care, the means of symptom control and the provision of psychosocial supports. METHODS: A retrospective review of all 166 deaths of NICU affiliated patients during a 10- year epoch. Medical notes were reviewed, and the provision and type of, or barriers to, effective palliative care was defined. RESULTS: Extreme prematurity accounted for 71/145 (49%) of deaths with relatively high proportions of Maori 17/71 (25%) and Pacific Islanders 9/71 (13%). Almost all eligible infants received some form of palliation. Transition from curative to palliative care was refused by the family in a single case. Median time from decision to redirect care until first recorded action was 80 min, and median time from action until death was 60 min. The majority of infants received some form of comfort cares, (128/166) most commonly morphine (94/128, 73%). Three infants had documented seizure activity or respiratory distress but did not receive any pharmacological intervention. Psychosocial supports were offered in 98/145 (67%) of cases, but only 71/145 (49%) of families were formally offered an opportunity to discuss the infant's clinical course after their death. CONCLUSIONS: Clinical documentation of care plans was often incomplete, potentially leading to inconsistent delivery of care, increased risk of symptom breakthrough and/or inadequate psychosocial supports for family. Formal individualised palliative care plans are under development to standardise documentation and improve therapeutic and psychosocial interventions available to the infant and their family. PMID- 30470702 TI - Soma-germ line interactions and a role for muscle in the regulation of C. elegans sperm motility. AB - The development of highly differentiated sperm cells specialized for navigating to and fusing with an oocyte is critical for sexual reproduction. As a major part of differentiation, sperm undergo extensive post-meiotic maturation en route to the oocyte. This is regulated largely by soma-derived cues. In C. elegans, this process is called sperm activation, and it transforms immotile spermatids into migratory, fertilization-competent cells. Here we show that the negative regulator of sperm activation, SWM-1, is produced in an unexpected cell type: body wall muscle. SWM-1 is secreted into the body cavity and enters the gonad; there, it is present with its likely target, TRY-5, a spermiogenesis activator. We show that in addition to SWM-1, the somatic gonad and body fluid can exchange other factors, suggesting that soma-germ line transfer could affect other reproductive processes. Additionally, we show that SWM-1 may have a separate role in the sperm migratory environment, to which it is contributed by both males and hermaphrodites. These findings reveal that late stages in gamete differentiation can be regulated at the whole-organism level by broadly secreted factors. PMID- 30470703 TI - Conserved regulatory state expression controlled by divergent developmental gene regulatory networks in echinoids. AB - Evolution of the animal body plan is driven by changes in developmental gene regulatory networks (GRNs), but how networks change to control novel developmental phenotypes remains in most cases unresolved. Here we address GRN evolution by comparing the endomesoderm GRN in two echinoid sea urchins, Strongylocentrotus purpuratus and Eucidaris tribuloides, with at least 268 million years of independent evolution. We first analyzed the expression of twelve transcription factors and signaling molecules of the S. purpuratus GRN in E. tribuloides embryos, showing that orthologous regulatory genes are expressed in corresponding endomesodermal cell fates in the two species. However, perturbation of regulatory genes revealed that important regulatory circuits of the S. purpuratus GRN are significantly different in E. tribuloides Thus for instance mesodermal Delta/Notch signaling controls exclusion of alternative cell fates in E. tribuloides but controls mesoderm induction and activation of a positive feedback circuit in S. purpuratus These results indicate that the architecture of the sea urchin endomesoderm GRN evolved by extensive gain and loss of regulatory interactions between a conserved set of regulatory factors that control endomesodermal cell fate specification. PMID- 30470704 TI - The zinc finger transcription factor Gli3 is a regulator of precerebellar neuronal migration. AB - Hindbrain precerebellar neurons arise from progenitor pools at the dorsal edge of the embryonic hindbrain, the caudal rhombic lip. These neurons follow distinct migratory routes to establish nuclei that provide climbing or mossy fiber inputs to the cerebellum. Gli3, a zinc transcription factor in the Sonic hedgehog signaling pathway, is an important regulator of dorsal brain development. We demonstrate that in Gli3 null mutant mice disrupted neuronal migratory streams lead to a disorganization of precerebellar nuclei. Precerebellar progenitors are properly established in Gli3 null embryos and using conditional gene inactivation, we provide evidence that Gli3 does not play a cell-autonomous role in migrating precerebellar neurons. Thus, Gli3 likely regulates the development of other hindbrain structures, such as non-precerebellar nuclei or cranial ganglia and their respective projections, which may in turn influence precerebellar migration. While the organization of non-precerebellar hindbrain nuclei appears to be largely unaffected in absence of Gli3, trigeminal ganglia and their central descending tracts are disrupted. We show that rostrally migrating precerebellar neurons are normally in close contact with these tracts, but are detached in Gli3 null embryos. PMID- 30470705 TI - MicroRNA let-7 and miR-278 regulate insect metamorphosis and oogenesis via targeting juvenile hormone early response gene Kruppel-homolog 1. AB - Kruppel-homolog 1 (Kr-h1), a zinc finger transcription factor, transduces juvenile hormone (JH) signaling in inhibiting larval metamorphosis and promoting adult reproduction. While the transcriptional regulation of Kr-h1 has been extensively studied, little is known about its regulation at the post transcriptional level. By using the migratory locust, Locusta migratoria as a model system, we report here that microRNA let-7 and miR-278 bound to Kr-h1 coding sequence and downregulated its expression. Application of let-7 and miR 278 agomiRs significantly reduced the level of Kr-h1 transcripts, resulting in partially precocious metamorphosis in nymphs as well as markedly decreased yolk protein precursors, arrested ovarian development and blocked oocyte maturation in adults. Moreover, the expression of let-7 and miR-278 was repressed by JH, constituting a regulatory loop of JH signaling. This study thus discovers a previously unknown mechanism by which JH suppresses the expression of let-7 and miR-278, which, together with JH induction on Kr-h1 transcription, prevents the precocious metamorphosis of nymphs and stimulates the reproduction of adult females. The results advance our understanding in the coordination of JH and miRNA regulation in insect development. PMID- 30470706 TI - Government urged to clarify plan to protect drug supply in event of "no deal" Brexit. PMID- 30470707 TI - Intensive antihypertensive treatment and serious adverse events in older people. AB - Review of: Sink KM, et al Syncope, hypotension and falls in the treatment of hypertension: results from the randomized clinical systolic blood pressure intervention trial. J Am Ger Soc 2018;66:679-86. PMID- 30470708 TI - Omega-3 fatty acid supplements do not improve symptoms of dry eye disease. AB - Review of: The Dry Eye Assessment and Management Study Research Group. N-3 fatty acid supplementation for the treatment of dry eye disease. NEJM 2018;378:1681-90. PMID- 30470709 TI - Written information on medicines for patients: learning from the PIL. PMID- 30470710 TI - Case of drug-induced interstitial lung disease secondary to adalimumab. AB - In conjunction with BMJ Case Reports, DTB will feature occasional drug-related cases that are likely to be of interest to readers. These will include cases that involve recently marketed drugs for which there is limited knowledge of adverse effects and cases that highlight unusual reactions to drugs that have been marketed for several years. PMID- 30470711 TI - Single event visualization of unconventional secretion of FGF2. AB - FGF2 is exported from cells by an unconventional secretory mechanism. Here, we directly visualized individual FGF2 membrane translocation events at the plasma membrane using live cell TIRF microscopy. This process was dependent on both PI(4,5)P2-mediated recruitment of FGF2 at the inner leaflet and heparan sulfates capturing FGF2 at the outer plasma membrane leaflet. By simultaneous imaging of both FGF2 membrane recruitment and the appearance of FGF2 at the cell surface, we revealed the kinetics of FGF2 membrane translocation in living cells with an average duration of ~200 ms. Furthermore, we directly demonstrated FGF2 oligomers at the inner leaflet of living cells with a FGF2 dimer being the most prominent species. We propose this dimer to represent a key intermediate in the formation of higher FGF2 oligomers that form membrane pores and put forward a kinetic model explaining the mechanism by which membrane-inserted FGF2 oligomers serve as dynamic translocation intermediates during unconventional secretion of FGF2. PMID- 30470712 TI - Deep learning for retinopathy of prematurity screening. PMID- 30470713 TI - Corneal neurotisation by great auricular nerve transfer and scleral-corneal tunnel incisions for neurotrophic keratopathy. AB - BACKGROUND/AIMS: Medical management of neurotrophickeratopathy is challenging and costly. Supra-orbital nerve transfer to thecornea has proven effective for management of keratopathy, but yieldsconsiderable donor site morbidity. Herein, a novel technique for reinnervationof the anaesthetic cornea is presented and early results characterised. METHODS: Sensory fibres of the ipsilateral greatauricular nerve were directed via an interposition graft to the anteriorcorneal stroma using scleral-corneal tunnel incisions in two patients withgrade III neurotrophic keratopathy. RESULTS: Improvements in visual acuity, cornealpachymetry, corneal esthesiometry, and corneal neurotisation as assessed by invivo confocal microscopy were observed within nine months of surgery in bothpatients. CONCLUSION: Corneal neurotisation by interposition grafttransfer of great auricular nerve fibres via scleral-corneal tunnel incisionsappears effective in the management of neurotrophic keratopathy. PMID- 30470714 TI - Foveal microstructure and visual outcomes of myopic macular hole surgery with or without the inverted internal limiting membrane flap technique. AB - PURPOSE: The aim of this study was to determine the effect of the inverted internal limiting membrane (ILM) flap technique on the macular hole (MH) closure and foveal microstructure recovery of patients with highly myopic MH. METHODS: Pars plana vitrectomy and gas tamponade with the inverted ILM flap technique (19 eyes) or with the ILM peeling technique (21 eyes) were performed in patients with highly myopic MH with or without retinal detachment. The rate of MH closure and retinal reattachment, the reconstructive anatomical change of the foveal microstructure and the best-corrected visual acuities (BCVA) of the two groups were compared. RESULTS: The anatomic closure rate was statistically significantly higher in the inverted group (100%) than in the peeling group (66.7%; p=0.009). All eyes with MH retinal detachment had successful retinal reattachment in these two groups. However, the rate of the external limiting membrane (ELM) and ellipsoid zone (EZ) (p=0.020), as well as gliosis (p=0.049) in macular area, detected by OCT, was significantly greater in the inverted group than in the peeling group. The postoperative BCVA was significantly better in the eyes with ELM, EZ (p=0.031) and gliosis (p=0.008), but without hyperreflective foci (p=0.001). CONCLUSIONS: These findings demonstrate that the inverted ILM flap technique has better efficacy than the ILM peeling technique for patients with myopic MH in closure rate, foveal microstructure and postoperative BCVA. PMID- 30470715 TI - Evaluation of a deep learning image assessment system for detecting severe retinopathy of prematurity. AB - BACKGROUND: Prior work has demonstrated the near-perfect accuracy of a deep learning retinal image analysis system for diagnosing plus disease in retinopathy of prematurity (ROP). Here we assess the screening potential of this scoring system by determining its ability to detect all components of ROP diagnosis. METHODS: Clinical examination and fundus photography were performed at seven participating centres. A deep learning system was trained to detect plus disease, generating a quantitative assessment of retinal vascular abnormality (the i-ROP plus score) on a 1-9 scale. Overall ROP disease category was established using a consensus reference standard diagnosis combining clinical and image-based diagnosis. Experts then ranked ordered a second data set of 100 posterior images according to overall ROP severity. RESULTS: 4861 examinations from 870 infants were analysed. 155 examinations (3%) had a reference standard diagnosis of type 1 ROP. The i-ROP deep learning (DL) vascular severity score had an area under the receiver operating curve of 0.960 for detecting type 1 ROP. Establishing a threshold i-ROP DL score of 3 conferred 94% sensitivity, 79% specificity, 13% positive predictive value and 99.7% negative predictive value for type 1 ROP. There was strong correlation between expert rank ordering of overall ROP severity and the i-ROP DL vascular severity score (Spearman correlation coefficient=0.93; p<0.0001). CONCLUSION: The i-ROP DL system accurately identifies diagnostic categories and overall disease severity in an automated fashion, after being trained only on posterior pole vascular morphology. These data provide proof of concept that a deep learning screening platform could improve objectivity of ROP diagnosis and accessibility of screening. PMID- 30470716 TI - A bilobal model of Ca2+-dependent inactivation to probe the physiology of L-type Ca2+ channels. AB - L-type calcium channels (LTCCs) are critical elements of normal cardiac function, playing a major role in orchestrating cardiac electrical activity and initiating downstream signaling processes. LTCCs thus use feedback mechanisms to precisely control calcium (Ca2+) entry into cells. Of these, Ca2+-dependent inactivation (CDI) is significant because it shapes cardiac action potential duration and is essential for normal cardiac rhythm. This important form of regulation is mediated by a resident Ca2+ sensor, calmodulin (CaM), which is comprised of two lobes that are each capable of responding to spatially distinct Ca2+ sources. Disruption of CaM-mediated CDI leads to severe forms of long-QT syndrome (LQTS) and life-threatening arrhythmias. Thus, a model capable of capturing the nuances of CaM-mediated CDI would facilitate increased understanding of cardiac (patho)physiology. However, one critical barrier to achieving a detailed kinetic model of CDI has been the lack of quantitative data characterizing CDI as a function of Ca2+ This data deficit stems from the experimental challenge of uncoupling the effect of channel gating on Ca2+ entry. To overcome this obstacle, we use photo-uncaging of Ca2+ to deliver a measurable Ca2+ input to CaM/LTCCs, while simultaneously recording CDI. Moreover, we use engineered CaMs with Ca2+ binding restricted to a single lobe, to isolate the kinetic response of each lobe. These high-resolution measurements enable us to build mathematical models for each lobe of CaM, which we use as building blocks for a full-scale bilobal model of CDI. Finally, we use this model to probe the pathogenesis of LQTS associated with mutations in CaM (calmodulinopathies). Each of these models accurately recapitulates the kinetics and steady-state properties of CDI in both physiological and pathological states, thus offering powerful new insights into the mechanistic alterations underlying cardiac arrhythmias. PMID- 30470717 TI - Visualization of expanding fusion pores in secretory cells. PMID- 30470718 TI - Deciphering cancer fibroblasts. AB - In this issue of JEM, Raz et al. (https://doi.org/10.1084/jem.20180818) identify a subset of bone marrow-derived cells that uniquely promotes breast cancer angiogenesis and tumor growth. The existence of functional heterogeneity among stromal populations motivates further fundamental and therapeutic inquiries. PMID- 30470719 TI - Bone marrow-derived fibroblasts are a functionally distinct stromal cell population in breast cancer. AB - Cancer-associated fibroblasts (CAFs) are highly prominent in breast tumors, but their functional heterogeneity and origin are still largely unresolved. We report that bone marrow (BM)-derived mesenchymal stromal cells (MSCs) are recruited to primary breast tumors and to lung metastases and differentiate to a distinct subpopulation of CAFs. We show that BM-derived CAFs are functionally important for tumor growth and enhance angiogenesis via up-regulation of Clusterin. Using newly generated transgenic mice and adoptive BM transplantations, we demonstrate that BM-derived fibroblasts are a substantial source of CAFs in the tumor microenvironment. Unlike resident CAFs, BM-derived CAFs do not express PDGFRalpha, and their recruitment resulted in a decrease in the percentage of PDGFRalpha-expressing CAFs. Strikingly, decrease in PDGFRalpha in breast cancer patients was associated with worse prognosis, suggesting that BM-derived CAFs may have deleterious effects on survival. Therefore, PDGFRalpha expression distinguishes two functionally unique CAF populations in breast tumors and metastases and may have important implications for patient stratification and precision therapeutics. PMID- 30470721 TI - More is not always better: hyperglutamylation leads to neurodegeneration. PMID- 30470720 TI - Correction: Epidermal gammadelta T cells originate from yolk sac hematopoiesis and clonally self-renew in the adult. PMID- 30470722 TI - Separated and Sick: An Immigrant Child's Traumatic Experience of Illness and Recovery. PMID- 30470723 TI - Diagnosis of Attenuated Mucopolysaccharidosis VI: Clinical, Biochemical, and Genetic Pitfalls. AB - Mucopolysaccharidosis type VI (MPS VI) is a clinically heterogeneous lysosomal disease, which can be divided into 2 main categories on the basis of age of onset and severity of symptoms. The diagnosis of the attenuated form is often delayed given subtle facial features rather than the typical coarse facial features of the classic form. Here, we discuss the difficulties in establishing the diagnosis of MPS VI on the basis of the report of 4 individuals. The most common signs and symptoms in our series were bone abnormalities and hip pain as initial manifestations and cardiac changes detected after follow-up studies. On the basis of our cohort and others worldwide, awareness of attenuated forms of MPS VI should be increased particularly among general practitioners, pediatricians, rheumatologists, orthopedists, ophthalmologists, and cardiologists. Moreover, these health care providers should be aware of the technical aspects involved in the molecular and biochemical diagnosis process so that they are aware how diagnostic errors may occur. PMID- 30470724 TI - Biology and bias: do we have the will to improve cardiovascular disease outcomes for women? PMID- 30470725 TI - Sex differences in quality indicator attainment for myocardial infarction: a nationwide cohort study. AB - AIM: To investigate sex differences in acute myocardial infarction (AMI) guideline-indicated care as defined by the European Society of Cardiology (ESC) Acute Cardiovascular Care Association (ACCA) quality indicators. METHODS: Nationwide cohort study comprising 691 290 AMI hospitalisations in England and Wales (n=233 hospitals) from the Myocardial Ischaemia National Audit Project between 1 January 2003 and 30 June 2013. RESULTS: There were 34.5% (n=238 489) women (median age 76.7 (IQR 66.3-84.0) years; 33.9% (n=80 884) ST-elevation myocardial infarction (STEMI)) and 65.5% (n=452 801) men (median age 67.1 (IQR 56.9-77.2) years; 42.5% (n=192 229) STEMI). Women less frequently received 13 of the 16 quality indicators compared with men, including timely reperfusion therapy for STEMI (76.8% vs 78.9%; p<0.001), timely coronary angiography for non-STEMI (24.2% vs 36.7%; p<0.001), dual antiplatelet therapy (75.4% vs 78.7%) and secondary prevention therapies (87.2% vs 89.6% for statins, 82.5% vs 85.6% for ACE inhibitor/angiotensin receptor blockers and 62.6% vs 67.6% for beta-blockers; all p<0.001). Median 30-day Global Registry of Acute Coronary Events risk score adjusted mortality was higher for women than men (median: 5.2% (IQR 1.8%-13.1%) vs 2.3% (IQR 0.8%-7.1%), p<0.001). An estimated 8243 (95% CI 8111 to 8375) deaths among women could have been prevented over the study period if their quality indicator attainment had been equal to that attained by men. CONCLUSION: According to the ESC ACCA AMI quality indicators, women in England and Wales less frequently received guideline-indicated care and had significantly higher mortality than men. Greater attention to the delivery of recommended AMI treatments for women has the potential to reduce the sex-AMI mortality gap. PMID- 30470726 TI - A proteasomal partner goes missing in Angelman syndrome. AB - Loss-of-function mutations in the UBE3A ubiquitin ligase are associated with Angelman syndrome (AS), a severe neurologic disorder. A new study defines the role of mutations in an N-terminal "AZUL" domain as mediating direct binding to a proteasomal subunit and shows that this interaction is correlated with the ability of UBE3A to promote Wnt/beta-catenin signaling. These results provide new insights into a central biomolecule in AS and suggest that defects in Wnt/beta catenin signaling may underlie some AS phenotypes. PMID- 30470727 TI - Correction: Importin beta2 mediates the spatio-temporal regulation of anillin through a noncanonical nuclear localization signal. PMID- 30470728 TI - Withdrawal: Glucose regulates MafA transcription factor abundance and insulin gene expression by inhibiting AMP-activated protein kinase in pancreatic beta cells. PMID- 30470729 TI - Correction: Transcription factor-7-like 2 (TCF7L2) gene acts downstream of the Lkb1/Stk11 kinase to control mTOR signaling, beta cell growth, and insulin secretion. PMID- 30470730 TI - Migration into the bladder of a ventriculoperitoneal shunt with calculus formation: a remediable condition. PMID- 30470731 TI - Twelve commandments of radiology: guidance on the use of imaging in clinical practice. PMID- 30470732 TI - Intraoperative Blood Transfusion and Postoperative Morbidity Following Liver Resection. AB - BACKGROUND Blood transfusion is common during liver resection (LR). The objective of the present study was to investigate the effects of intraoperative transfusion of different blood components on post-LR morbidity. MATERIAL AND METHODS We included 610 patients undergoing LR and grouped them according to intraoperative transfusion of different blood components: packed red blood cells only (PRBC, n=81); frozen fresh plasma, platelets, and cryoprecipitate (FPC, n=38); transfusion only with PRBC + FPC transfusion (n=244); and no blood transfusion (n=247). Propensity score matching (PSM) analysis was used to mitigate selection bias in comparisons. RESULTS The overall blood transfusion rate was 59.5%. In comparison with the no blood transfusion group, PRBC-only and PRBC + FPC transfusion were more common in patients with lower preoperative hemoglobin, worse liver function, larger tumor size, and undergoing a major LR, and thus were associated with increased postoperative morbidity. In contrast, FPC-only transfusion was more frequent in patients with a liver function of Child-Pugh B and lower preoperative albumin vs. the no blood transfusion group. In the propensity model, transfusion of PRBC (PRBC-only and PRBC+FPC) and FPC (FPC-only and FPC+PRBC) were significantly associated with increased postoperative complications vs. the no blood transfusion group (OR and 95% CI, 1.9 [1.2-2.7], p=0.002; OR and 95% CI, 1.6 [1.0-2.4], p=0.029). In contrast, intraoperative PRBC only or FPC-only transfusion showed no significant adverse effects on postoperative morbidity. CONCLUSIONS Allogenic transfusion of PRBC and FPC blood components was associated with increased postoperative morbidity after liver surgery. Different blood components should be used only when absolutely necessary. PMID- 30470733 TI - Radiologic Findings in Polyarticular Amyloid Arthropathy and Myopathy in Multiple Myeloma: A Case Report. AB - BACKGROUND Amyloid arthropathy and myopathy are complications of amyloidosis that can be associated with non-specific imaging findings, which may be challenging to interpret. The report is of a case of polyarticular amyloid arthropathy and myopathy in a 56-year-old man with multiple myeloma and includes a description of the radiographic, computed tomography (CT), and magnetic resonance imaging (MRI) findings. CASE REPORT A 56-year-old man with multiple myeloma presented with chronic polyarticular pain and swelling. Soft tissue thickening of the wrist and knee were found on MRI to be of intermediate T1 weighted imaging (T1WI) and low to intermediate T2 weighted imaging (T2WI) signal intensity. Denervation muscle edema seen in the thenar muscles on the MRI of the right wrist were associated with carpal tunnel syndrome secondary to amyloid deposition. Soft tissue lesions in the periarticular regions of both hip joints were contiguous with subchondral bone lesions. Diffusely scattered myeloma lesions were shown as hyperintense on short tau inversion recovery (STIR) MRI imaging throughout the appendicular and axial skeleton, with vertebral compression fractures. Bilateral iliopsoas involvement with hypertrophy and abnormal surrounding fat reticulated signal intensity was consistent with amyloid myopathy. The patient had a pathological fracture of the right femoral neck and underwent surgical fixation. Histology of the right femoral head confirmed amyloid deposits. CONCLUSIONS Because the clinical presentation and imaging findings of musculoskeletal amyloidosis can be nonspecific, they can result in delay in diagnosis and treatment. Early radiologic identification of polyarticular amyloid arthropathy and myopathy should prompt confirmatory biopsy to confirm the diagnosis. PMID- 30470734 TI - Evidence for genetic contribution to the increased risk of type 2 diabetes in schizophrenia. AB - The epidemiologic link between schizophrenia (SCZ) and type 2 diabetes (T2D) remains poorly understood. Here, we investigate the presence and extent of a shared genetic background between SCZ and T2D using genome-wide approaches. We performed a genome-wide association study (GWAS) and polygenic risk score analysis in a Greek sample collection (GOMAP) comprising three patient groups: SCZ only (n = 924), T2D only (n = 822), comorbid SCZ and T2D (n = 505); samples from two separate Greek cohorts were used as population-based controls (n = 1,125). We used genome-wide summary statistics from two large-scale GWAS of SCZ and T2D from the PGC and DIAGRAM consortia, respectively, to perform genetic overlap analyses, including a regional colocalisation test. We show for the first time that patients with comorbid SCZ and T2D have a higher genetic predisposition to both disorders compared to controls. We identify five genomic regions with evidence of colocalising SCZ and T2D signals, three of which contain known loci for both diseases. We also observe a significant excess of shared association signals between SCZ and T2D at nine out of ten investigated p value thresholds. Finally, we identify 29 genes associated with both T2D and SCZ, several of which have been implicated in biological processes relevant to these disorders. Together our results demonstrate that the observed comorbidity between SCZ and T2D is at least in part due to shared genetic mechanisms. PMID- 30470735 TI - Magnetic seizure therapy reduces suicidal ideation and produces neuroplasticity in treatment-resistant depression. AB - Therapeutic seizures may work for treatment-resistant depression (TRD) by producing neuroplasticity. We evaluated whether magnetic seizure therapy (MST) produces changes in suicidal ideation and neuroplasticity as indexed through transcranial magnetic stimulation and electroencephalography (TMS-EEG) of the dorsolateral prefrontal cortex (DLPFC). Twenty-three patients with TRD were treated with MST. Changes in suicidal ideation was assessed through the Scale for Suicidal Ideation (SSI). Before and after the treatment course, neuroplasticity in excitatory and inhibitory circuits was assessed with TMS-EEG measures of cortical-evoked activity (CEA) and long-interval cortical inhibition (LICI) from the left DLPFC, and the left motor cortex as a control condition. As in our previous report, the relationship between TMS-EEG measures and suicidal ideation was examined with the SSI. Results show that 44.4% of patients experienced resolution of suicidal ideation. Based on DLPFC assessment, MST produced significant CEA increase over the frontal central electrodes (cluster p < 0.05), but did not change LICI on a group level. MST also reduced the SSI scores (p < 0.005) and the amount of reduction correlated with the decrease in LICI over the right frontal central electrodes (cluster p < 0.05; rho = 0.73 for Cz). LICI change identified patients who were resolved of suicidal ideation with 90% sensitivity and 88% specificity (AUC = 0.9, p = 0.004). There was no significant finding with motor cortex assessment. Overall, MST produced significant rates of resolution of suicidal ideation. MST also produced neuroplasticity in the frontal cortex, likely through long-term potentiation (LTP)-like mechanisms. The largest reduction in suicidal ideation was demonstrated in patients showing concomitant decreases in cortical inhibition-a mechanism linked to enhanced LTP-like plasticity. These findings provide insights into the mechanisms through which patients experience resolution of suicidal ideation following seizure treatments in depression. PMID- 30470736 TI - Author Correction: WWOX controls hepatic HIF1alpha to suppress hepatocyte proliferation and neoplasia. AB - Since the publication of their article, the authors reported that duplication had mistakenly occurred in Fig 3A and D - H&E panels. PMID- 30470737 TI - Energy landscape underlying spontaneous insertion and folding of an alpha-helical transmembrane protein into a bilayer. AB - Membrane protein folding mechanisms and rates are notoriously hard to determine. A recent force spectroscopy study of the folding of an alpha-helical membrane protein, GlpG, showed that the folded state has a very high kinetic stability and a relatively low thermodynamic stability. Here, we simulate the spontaneous insertion and folding of GlpG into a bilayer. An energy landscape analysis of the simulations suggests that GlpG folds via sequential insertion of helical hairpins. The rate-limiting step involves simultaneous insertion and folding of the final helical hairpin. The striking features of GlpG's experimentally measured landscape can therefore be explained by a partially inserted metastable state, which leads us to a reinterpretation of the rates measured by force spectroscopy. Our results are consistent with the helical hairpin hypothesis but call into question the two-stage model of membrane protein folding as a general description of folding mechanisms in the presence of bilayers. PMID- 30470738 TI - Author Correction: Mechanically tunable conductive interpenetrating network hydrogels that mimic the elastic moduli of biological tissue. AB - The original version of this Article contained an error in the second sentence of the 'Materials' section of the Methods, which incorrectly read 'PEDOT:PSS synthesized by Orgacon (739324 Aldrich, MDL MFCD07371079) was purchased as a surfactant-free aqueous dispersion with 1.1 wt% solid content.' The correct version replaces this sentence with 'PEDOT:PSS Orgacon ICP 1050 was provided by Agfa as a surfactant-free aqueous dispersion with 1.1 wt% solid content.' This has been corrected in both the PDF and HTML versions of the Article. PMID- 30470739 TI - Topoisomerase 3beta interacts with RNAi machinery to promote heterochromatin formation and transcriptional silencing in Drosophila. AB - Topoisomerases solve topological problems during DNA metabolism, but whether they participate in RNA metabolism remains unclear. Top3beta represents a family of topoisomerases carrying activities for both DNA and RNA. Here we show that in Drosophila, Top3beta interacts biochemically and genetically with the RNAi induced silencing complex (RISC) containing AGO2, p68 RNA helicase, and FMRP. Top3beta and RISC mutants are similarly defective in heterochromatin formation and transcriptional silencing by position-effect variegation assay. Moreover, both Top3beta and AGO2 mutants exhibit reduced levels of heterochromatin protein HP1 in heterochromatin. Furthermore, expression of several genes and transposable elements in heterochromatin is increased in the Top3beta mutant. Notably, Top3beta mutants defective in either RNA binding or catalytic activity are deficient in promoting HP1 recruitment and silencing of transposable elements. Our data suggest that Top3beta may act as an RNA topoisomerase in siRNA-guided heterochromatin formation and transcriptional silencing. PMID- 30470740 TI - Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap. AB - Activation of the Hippo pathway effector Yap underlies many liver cancers, however no germline or somatic mutations have been identified. Autophagy maintains essential metabolic functions of the liver, and autophagy-deficient murine models develop benign adenomas and hepatomegaly, which have been attributed to activation of the p62/Sqstm1-Nrf2 axis. Here, we show that Yap is an autophagy substrate and mediator of tissue remodeling and hepatocarcinogenesis independent of the p62/Sqstm1-Nrf2 axis. Hepatocyte-specific deletion of Atg7 promotes liver size, fibrosis, progenitor cell expansion, and hepatocarcinogenesis, which is rescued by concurrent deletion of Yap. Our results shed new light on mechanisms of Yap degradation and the sequence of events that follow disruption of autophagy, which is impaired in chronic liver disease. PMID- 30470741 TI - Systematic review of the effectiveness of community-based self-management interventions among primary care COPD patients. AB - COPD self-management reduces hospital admissions and improves health-related quality of life (HRQoL). However, whilst most patients are managed in primary care, the majority of self-management trials have recruited participants with more severe disease from secondary care. We report the findings of a systematic review of the effectiveness of community-based self-management interventions in primary care patients with COPD. We systematically searched eleven electronic databases and identified 12 eligible randomised controlled trials with seven included in meta-analyses for HRQoL, anxiety and depression. We report no difference in HRQoL at final follow-up (St George's Respiratory Questionnaire total score -0.29; 95%CI -2.09, 1.51; I2 0%), nor any difference in anxiety or depression. In conclusion, supported self-management interventions delivered in the community to patients from primary care do not appear to be effective. Further research is recommended to identify effective self-management interventions suitable for primary care populations, particularly those with milder disease. PMID- 30470742 TI - Studies into the mechanism of measles-associated immune suppression during a measles outbreak in the Netherlands. AB - Measles causes a transient immune suppression, leading to increased susceptibility to opportunistic infections. In experimentally infected non-human primates (NHPs) measles virus (MV) infects and depletes pre-existing memory lymphocytes, causing immune amnesia. A measles outbreak in the Dutch Orthodox Protestant community provided a unique opportunity to study the pathogenesis of measles immune suppression in unvaccinated children. In peripheral blood mononuclear cells (PBMC) of prodromal measles patients, we detected MV-infected memory CD4+ and CD8+ T cells and naive and memory B cells at similar levels as those observed in NHPs. In paired PBMC collected before and after measles we found reduced frequencies of circulating memory B cells and increased frequencies of regulatory T cells and transitional B cells after measles. These data support our immune amnesia hypothesis and offer an explanation for the previously observed long-term effects of measles on host resistance. This study emphasises the importance of maintaining high measles vaccination coverage. PMID- 30470743 TI - Deep learning for universal linear embeddings of nonlinear dynamics. AB - Identifying coordinate transformations that make strongly nonlinear dynamics approximately linear has the potential to enable nonlinear prediction, estimation, and control using linear theory. The Koopman operator is a leading data-driven embedding, and its eigenfunctions provide intrinsic coordinates that globally linearize the dynamics. However, identifying and representing these eigenfunctions has proven challenging. This work leverages deep learning to discover representations of Koopman eigenfunctions from data. Our network is parsimonious and interpretable by construction, embedding the dynamics on a low dimensional manifold. We identify nonlinear coordinates on which the dynamics are globally linear using a modified auto-encoder. We also generalize Koopman representations to include a ubiquitous class of systems with continuous spectra. Our framework parametrizes the continuous frequency using an auxiliary network, enabling a compact and efficient embedding, while connecting our models to decades of asymptotics. Thus, we benefit from the power of deep learning, while retaining the physical interpretability of Koopman embeddings. PMID- 30470745 TI - Quantum-enhanced sensing using non-classical spin states of a highly magnetic atom. AB - Coherent superposition states of a mesoscopic quantum object play a major role in our understanding of the quantum to classical boundary, as well as in quantum enhanced metrology and computing. However, their practical realization and manipulation remains challenging, requiring a high degree of control of the system and its coupling to the environment. Here, we use dysprosium atoms-the most magnetic element in its ground state-to realize coherent superpositions between electronic spin states of opposite orientation, with a mesoscopic spin size J = 8. We drive coherent spin states to quantum superpositions using non linear light-spin interactions, observing a series of collapses and revivals of quantum coherence. These states feature highly non-classical behavior, with a sensitivity to magnetic fields enhanced by a factor 13.9(1.1) compared to coherent spin states-close to the Heisenberg limit 2J = 16-and an intrinsic fragility to environmental noise. PMID- 30470744 TI - Orchestration of protein acetylation as a toggle for cellular defense and virus replication. AB - Emerging evidence highlights protein acetylation, a prevalent lysine posttranslational modification, as a regulatory mechanism and promising therapeutic target in human viral infections. However, how infections dynamically alter global cellular acetylation or whether viral proteins are acetylated remains virtually unexplored. Here, we establish acetylation as a highly regulated molecular toggle of protein function integral to the herpesvirus human cytomegalovirus (HCMV) replication. We offer temporal resolution of cellular and viral acetylations. By interrogating dynamic protein acetylation with both protein abundance and subcellular localization, we discover finely tuned spatial acetylations across infection time. We determine that lamin acetylation at the nuclear periphery protects against virus production by inhibiting capsid nuclear egress. Further studies within infectious viral particles identify numerous acetylations, including on the viral transcriptional activator pUL26, which we show represses virus production. Altogether, this study provides specific insights into functions of cellular and viral protein acetylations and a valuable resource of dynamic acetylation events. PMID- 30470746 TI - High throughput in situ metagenomic measurement of bacterial replication at ultra low sequencing coverage. AB - We developed Growth Rate InDex (GRiD) for estimating in situ growth rates of ultra-low coverage (>0.2*) and de novo-assembled metagenomes. Applying GRiD to human and environmental metagenomic datasets to demonstrate its versatility, we uncovered new associations with previously uncharacterized bacteria whose growth rates were associated with several disease characteristics or environmental interactions. In addition, with GRiD-MG (metagenomic), a high-throughput implementation of GRiD, we estimated growth dynamics of 1756 bacteria species from a healthy skin metagenomic dataset and identified a new Staphylococcus Corynebacterium antagonism likely mediated by antimicrobial production in the skin. GRiD-MG significantly increases the ability to extract growth rate inferences from complex metagenomic data with minimal input from the user. PMID- 30470747 TI - Accelerating water dissociation kinetics by isolating cobalt atoms into ruthenium lattice. AB - Designing highly active and robust platinum-free catalysts for hydrogen evolution reaction is of vital importance for clean energy applications yet challenging. Here we report highly active and stable cobalt-substituted ruthenium nanosheets for hydrogen evolution, in which cobalt atoms are isolated in ruthenium lattice as revealed by aberration-corrected high-resolution transmission electron microscopy and X-ray absorption fine structure measurement. Impressively, the cobalt-substituted ruthenium nanosheets only need an extremely low overpotential of 13 mV to achieve a current density of 10 mA cm-2 in 1 M KOH media and an ultralow Tafel slope of 29 mV dec-1, which exhibit top-level catalytic activity among all reported platinum-free electrocatalysts. The theoretical calculations reveal that the energy barrier of water dissociation can greatly reduce after single cobalt atom substitution, leading to its superior hydrogen evolution performance. This study provides a new insight into the development of highly efficient platinum-free hydrogen evolution catalysts. PMID- 30470748 TI - Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis. AB - Oncogenic KRAS is the key driver of pancreatic ductal adenocarcinoma (PDAC). We previously described a role for KRAS in PDAC tumor maintenance through rewiring of cellular metabolism to support proliferation. Understanding the details of this metabolic reprogramming in human PDAC may provide novel therapeutic opportunities. Here we show that the dependence on oncogenic KRAS correlates with specific metabolic profiles that involve maintenance of nucleotide pools as key mediators of KRAS-dependence. KRAS promotes these effects by activating a MAPK dependent signaling pathway leading to MYC upregulation and transcription of the non-oxidative pentose phosphate pathway (PPP) gene RPIA, which results in nucleotide biosynthesis. The use of MEK inhibitors recapitulates the KRAS dependence pattern and the expected metabolic changes. Antagonizing the PPP or pyrimidine biosynthesis inhibits the growth of KRAS-resistant cells. Together, these data reveal differential metabolic rewiring between KRAS-resistant and sensitive cells, and demonstrate that targeting nucleotide metabolism can overcome resistance to KRAS/MEK inhibition. PMID- 30470749 TI - In situ monitoring of molecular aggregation using circular dichroism. AB - The aggregation of molecules plays an important role in determining their function. Electron microscopy and other methods can only characterize the variation of microstructure, but are not capable of monitoring conformational changes. These techniques are also complicated, expensive and time-consuming. Here, we demonstrate a simple method to monitor in-situ and in real-time the conformational change of (R)-1,1'-binaphthyl-based polymers during the aggregation process using circular dichroism. Based on results from molecular dynamics simulations and experimental circular dichroism measurements, polymers with "open" binaphthyl rings are found to show stronger aggregation-annihilated circular dichroism effects, with more negative torsion angles between the two naphthalene rings. In contrast, the polymers with "locked" rings show a more restrained aggregation-annihilated circular dichroism effect, with only a slight change of torsion angle. This work provides an approach to monitor molecular aggregation in a simple, accurate, and efficient way. PMID- 30470750 TI - Entropy production rate is maximized in non-contractile actomyosin. AB - The actin cytoskeleton is an active semi-flexible polymer network whose non equilibrium properties coordinate both stable and contractile behaviors to maintain or change cell shape. While myosin motors drive the actin cytoskeleton out-of-equilibrium, the role of myosin-driven active stresses in the accumulation and dissipation of mechanical energy is unclear. To investigate this, we synthesize an actomyosin material in vitro whose active stress content can tune the network from stable to contractile. Each increment in activity determines a characteristic spectrum of actin filament fluctuations which is used to calculate the total mechanical work and the production of entropy in the material. We find that the balance of work and entropy does not increase monotonically and the entropy production rate is maximized in the non-contractile, stable state of actomyosin. Our study provides evidence that the origins of entropy production and activity-dependent dissipation relate to disorder in the molecular interactions between actin and myosin. PMID- 30470751 TI - Clinical predictors of long-term survival in newly diagnosed transplant eligible multiple myeloma - an IMWG Research Project. AB - PURPOSE: multiple myeloma is considered an incurable hematologic cancer but a subset of patients can achieve long-term remissions and survival. The present study examines the clinical features of long-term survival as it correlates to depth of disease response. PATIENTS & METHODS: this was a multi-institutional, international, retrospective analysis of high-dose melphalan-autologous stem cell transplant (HDM-ASCT) eligible MM patients included in clinical trials. Clinical variable and survival data were collected from 7291 MM patients from Czech Republic, France, Germany, Italy, Korea, Spain, the Nordic Myeloma Study Group and the United States. Kaplan-Meier curves were used to assess progression-free survival (PFS) and overall survival (OS). Relative survival (RS) and statistical cure fractions (CF) were computed for all patients with available data. RESULTS: achieving CR at 1 year was associated with superior PFS (median PFS 3.3 years vs. 2.6 years, p < 0.0001) as well as OS (median OS 8.5 years vs. 6.3 years, p < 0.0001). Clinical variables at diagnosis associated with 5-year survival and 10 year survival were compared with those associated with 2-year death. In multivariate analysis, age over 65 years (OR 1.87, p = 0.002), IgA Isotype (OR 1.53, p = 0.004), low albumin < 3.5 g/dL (OR = 1.36, p = 0.023), elevated beta 2 microglobulin >= 3.5 mg/dL (OR 1.86, p < 0.001), serum creatinine levels >= 2 mg/dL (OR 1.77, p = 0.005), hemoglobin levels < 10 g/dL (OR 1.55, p = 0.003), and platelet count < 150k/MUL (OR 2.26, p < 0.001) appeared to be negatively associated with 10-year survival. The relative survival for the cohort was ~0.9, and the statistical cure fraction was 14.3%. CONCLUSIONS: these data identify CR as an important predictor of long-term survival for HDM-ASCT eligible MM patients. They also identify clinical variables reflective of higher disease burden as poor prognostic markers for long-term survival. PMID- 30470752 TI - Pulsed axial epitaxy of colloidal quantum dots in nanowires enables facet selective passivation. AB - Epitaxially stacking colloidal quantum dots in nanowires offers a route to selective passivation of defective facets while simultaneously enabling charge transfer to molecular adsorbates - features that must be combined to achieve high efficiency photocatalysts. This requires dynamical switching of precursors to grow, alternatingly, the quantum dots and nanowires - something not readily implemented in conventional flask-based solution chemistry. Here we report pulsed axial epitaxy, a growth mode that enables the stacking of multiple CdS quantum dots in ZnS nanowires. The approach relies on the energy difference of incorporating these semiconductor atoms into the host catalyst, which determines the nucleation sequence at the catalyst-nanowire interface. This flexible synthetic strategy allows precise modulation of quantum dot size, number, spacing, and crystal phase. The facet-selective passivation of quantum dots in nanowires opens a pathway to photocatalyst engineering: we report photocatalysts that exhibit an order-of-magnitude higher photocatalytic hydrogen evolution rates than do plain CdS quantum dots. PMID- 30470754 TI - Comparative expression profiling reveals widespread coordinated evolution of gene expression across eukaryotes. AB - Comparative studies of gene expression across species have revealed many important insights, but have also been limited by the number of species represented. Here we develop an approach to identify orthologs between highly diverged transcriptome assemblies, and apply this to 657 RNA-seq gene expression profiles from 309 diverse unicellular eukaryotes. We analyzed the resulting data for coevolutionary patterns, and identify several hundred protein complexes and pathways whose expression levels have evolved in a coordinated fashion across the trillions of generations separating these species, including many gene sets with little or no within-species co-expression across environmental or genetic perturbations. We also detect examples of adaptive evolution, for example of tRNA ligase levels to match genome-wide codon usage. In sum, we find that comparative studies from extremely diverse organisms can reveal new insights into the evolution of gene expression, including coordinated evolution of some of the most conserved protein complexes in eukaryotes. PMID- 30470755 TI - Normal faulting and viscous buckling in the Tibetan Plateau induced by a weak lower crust. AB - Flow of weak lower crust has been invoked to reconcile observed topographic gradients, uniform elevations, slow seismic velocity, and high conductivity measured in the Tibetan Plateau, with viscosity estimates of 1016-1021 Pa.s. Here we investigate the dynamic response resulting from a range of lower crust viscosities in a 3-D lithospheric-scale geodynamic simulation of the India Eurasia collision zone to determine bounds of physically viable lower crustal strengths. We show that thickening of the plateau is accommodated through viscous buckling of the upper crust in response to lower crustal flow for a lower crustal viscosity on the order of 1020 Pa.s. This generates two east-west trending bands of surface subsidence and dilatation consistent with observed normal faulting and estimates of vertical velocity. These results suggest viscous buckling of the upper crust, induced by lower crustal flow from gravitational pressure gradients due to high topography, is responsible for the observed extension in Tibet. PMID- 30470753 TI - The fluid membrane determines mechanics of erythrocyte extracellular vesicles and is softened in hereditary spherocytosis. AB - Extracellular vesicles (EVs) are widely studied regarding their role in cell-to cell communication and disease, as well as for applications as biomarkers or drug delivery vehicles. EVs contain membrane and intraluminal proteins, affecting their structure and thereby likely their functioning. Here, we use atomic force microscopy for mechanical characterization of erythrocyte, or red blood cell (RBC), EVs from healthy individuals and from patients with hereditary spherocytosis (HS) due to ankyrin deficiency. While these EVs are packed with proteins, their response to indentation resembles that of fluid liposomes lacking proteins. The bending modulus of RBC EVs of healthy donors is ~15 kbT, similar to the RBC membrane. Surprisingly, whereas RBCs become more rigid in HS, patient EVs have a significantly (~40%) lower bending modulus than donor EVs. These results shed light on the mechanism and effects of EV budding and might explain the reported increase in vesiculation of RBCs in HS patients. PMID- 30470756 TI - Mediated nuclear import and export of TAZ and the underlying molecular requirements. AB - Nucleocytoplasmic distribution of Yap/TAZ is regulated by the Hippo pathway and the cytoskeleton. While interactions with cytosolic and nuclear "retention factors" (14-3-3 and TEAD) are known to control their localization, fundamental aspects of Yap/TAZ shuttling remain undefined. It is unclear if translocation occurs only by passive diffusion or via mediated transport, and neither the potential nuclear localization and efflux signals (NLS, NES) nor their putative regulation have been identified. Here we show that TAZ cycling is a mediated process and identify the underlying NLS and NES. The C-terminal NLS, representing a new class of import motifs, is necessary and sufficient for efficient nuclear uptake via a RAN-independent mechanism. RhoA activity directly stimulates this import. The NES lies within the TEAD-binding domain and can be masked by TEAD, thereby preventing efflux. Thus, we describe a RhoA-regulated NLS, a TEAD regulated NES and propose an improved model of nucleocytoplasmic TAZ shuttling beyond "retention". PMID- 30470757 TI - Cobalt-catalyzed difluoroalkylation of tertiary aryl ketones for facile synthesis of quaternary alkyl difluorides. AB - The selective incorporation of gem-difluoroalkyl groups into biologically active molecules has long been used as an efficient strategy for drug design and discovery. However, the catalytic C(sp3)-CF2 bond-forming cross-coupling reaction for selective incorporation of difluoromethylene group into diverse alkyl chains, especially more sterically demanding secondary and tertiary functionalized alkanes, still remains as a major challenge. Herein, we describe a cobalt catalyzed difluoroalkylation of tertiary aryl ketones for facile synthesis of quaternary alkyl difluorides, which exhibited high efficiency, broad scope and mild conditions. The synthetic utility of this method is demonstrated by late stage difluoroalkylation of donepezil, a well-known acetylcholinesterase inhibitor used to treat the Alzheimer's disease. Preliminary mechanistic investigations indicate that a difluoroalkyl radical is involved in a Co(I)/Co(III) catalytic cycle. This cobalt-catalyzed fluoroalkylation thus offers insights into an efficient way for the synthesis of fluoroalkylated bioactive molecules for drug discovery. PMID- 30470758 TI - Inflammasome activation negatively regulates MyD88-IRF7 type I IFN signaling and anti-malaria immunity. AB - The inflammasome plays a critical role in inflammation and immune responses against pathogens. However, whether or how inflammasome activation regulates type I interferon (IFN-I) signaling in the context of malaria infection remain unknown. Here we show mice deficient in inflammasome sensors AIM2, NLRP3 or adaptor Caspase-1 produce high levels of IFN-I cytokines and are resistant to lethal Plasmodium yoelii YM infection. Inactivation of inflammasome signaling reduces interleukin (IL)-1beta production, but increases IFN-I production. Mechanistically, we show inflammsome activation enhances IL-1beta-mediated MyD88 TRAF3-IRF3 signaling and SOCS1 upregulation. However, SOCS1 inhibits MyD88-IRF7 mediated-IFN-I signaling and cytokine production in plasmacytoid dendritic cells. By contrast, ablation of inflammsome components reduces SOCS1 induction, and relieves its inhibition on MyD88-IRF7-dependent-IFN-I signaling, leading to high levels of IFN-alpha/beta production and host survival. Our study identifies a previously unrecognized role of inflammasome activation in the negative regulation of IFN-I signaling pathways and provides potential targets for developing effective malaria vaccines. PMID- 30470760 TI - AutoFoci, an automated high-throughput foci detection approach for analyzing low dose DNA double-strand break repair. AB - Double-strand breaks (DSBs) are the most lethal DNA damages induced by ionising radiation (IR) and their efficient repair is crucial to limit genomic instability. The cellular DSB response after low IR doses is of particular interest but its examination requires the analysis of high cell numbers. Here, we present an automated DSB quantification method based on the analysis of gammaH2AX and 53BP1 foci as markers for DSBs. We establish a combination of object properties, combined in the object evaluation parameter (OEP), which correlates with manual object classification. Strikingly, OEP histograms show a bi-modal distribution with two maxima and a minimum in between, which correlates with the manually determined transition between background signals and foci. We used algorithms to detect the minimum, thus separating foci from background signals and automatically assessing DSB levels. To demonstrate the validity of this method, we analyzed over 600.000 cells to verify results of previous studies showing that DSBs induced by low doses are less efficiently repaired compared with DSBs induced by higher doses. Thus, the automated foci counting method, called AutoFoci, provides a valuable tool for high-throughput image analysis of thousands of cells which will prove useful for many biological screening approaches. PMID- 30470761 TI - Density resistance evaluation of maize varieties through new "Density-Yield Model" and quantification of varietal response to gradual planting density pressure. AB - Increasing planting density is the main method and key management to enhance the grain yield. Preventing lodging and premature senescence in high planting density, and screening and enhancing the density-tolerance of maize variety is the main goal of agronomy. Differential response of maize hybrids to high plant density greatly affect the dry matter accumulation and its allocation to maize kernel, depending upon various traits responsible for crowding stress tolerance, of which ear characteristics are pivotal. Density resistance as a quality appraisal of certain variety permits the construction of a simple and accurate method to determine this value, useful for plant breeding. Therefore, we created a new quantitative method, which tested several maize varieties planted populary in China (e.g. Zhengdan 958, Xianyu 335, and Denghai 661) to quantify their response to crowding stress through model. We established 13 planting densities (ranging 1.67-16.67 plants m-2) by adopting fixed line spacing (80 * 40 cm) and then gradually increasing row spacing from 1 m to increasing planting density. A conventional standard plot was also established for verification and evaluation of the plant morphologic characteristics, ear traits, and the yield of maize at various standard densities during 5-year study period. By studying the density yield relationship, a quantitative model was constructed to identify the density resistance of maize. Grain yield of maize varieties under varying planting densities were simulated, and models of population yield and yield per plant that fitted the data well with high biological significance were produced. From the models, the optimal density of the popular main maize varieties planted in China and the morphological characteristics of each variety at that density were identified. The density-resistance of each variety was referred to as the ear sensitivity classification. With the highest yield at the optimal density, the plant height of each variety reached 98% to that of tallest plant. The ear/plant ratio was about 0.45, and the ratio between the stem diameter and the largest stem diameter was 0.65-0.80. During the harvest period, the ratio between average single-plant yield and the highest single-plant yield was 0.40-0.50. By gradually increasing planting density, the density resistance of the maize and the changes in yield with density were quantified. Present study provides a convenient tool for the effective selection of varieties by plant breeders through this method and model will help to rapidly identify the density resistance for a new variety and accurate confirmation to optimal planting density, it could be optimized to enable practical production at reasonable planting densities. PMID- 30470759 TI - Understanding structure-activity relationships in linear polymer photocatalysts for hydrogen evolution. AB - Conjugated polymers have sparked much interest as photocatalysts for hydrogen production. However, beyond basic considerations such as spectral absorption, the factors that dictate their photocatalytic activity are poorly understood. Here we investigate a series of linear conjugated polymers with external quantum efficiencies for hydrogen production between 0.4 and 11.6%. We monitor the generation of the photoactive species from femtoseconds to seconds after light absorption using transient spectroscopy and correlate their yield with the measured photocatalytic activity. Experiments coupled with modeling suggest that the localization of water around the polymer chain due to the incorporation of sulfone groups into an otherwise hydrophobic backbone is crucial for charge generation. Calculations of solution redox potentials and charge transfer free energies demonstrate that electron transfer from the sacrificial donor becomes thermodynamically favored as a result of the more polar local environment, leading to the production of long-lived electrons in these amphiphilic polymers. PMID- 30470762 TI - RNAm5Cfinder: A Web-server for Predicting RNA 5-methylcytosine (m5C) Sites Based on Random Forest. AB - 5-methylcytosine (m5C) is a common nucleobase modification, and recent investigations have indicated its prevalence in cellular RNAs including mRNA, tRNA and rRNA. With the rapid accumulation of m5C sites data, it becomes not only feasible but also important to build an accurate model to predict m5C sites in silico. For this purpose, here, we developed a web-server named RNAm5Cfinder based on RNA sequence features and machine learning method to predict RNA m5C sites in eight tissue/cell types from mouse and human. We confirmed the accuracy and usefulness of RNAm5Cfinder by independent tests, and the results show that the comprehensive and cell-specific predictors could pinpoint the generic or tissue-specific m5C sites with the Area Under Curve (AUC) no less than 0.77 and 0.87, respectively. RNAm5Cfinder web-server is freely available at http://www.rnanut.net/rnam5cfinder . PMID- 30470764 TI - Associations between sleep parameters, non-communicable diseases, HIV status and medications in older, rural South Africans. AB - As part of the Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa (HAALSI), we investigated sleep habits and their interactions with HIV or non-communicable diseases (NCDs) in 5059 participants (median age: 61, interquartile range: 52-71, 54% females). Self-reported sleep duration was 8.2 +/- 1.6h, and bed and rise times were 20:48 +/- 1:15 and 05:31 +/- 1:05 respectively. Ratings of insufficient sleep were associated with older age, lack of formal education, unemployment, and obesity (p < 0.05). Ratings of restless sleep were associated with being older, female, having more education, being unemployed, and single. Hypertension was associated with shorter self reported sleep duration, poor sleep quality, restless sleep, and periods of stopping breathing during the night (p < 0.05). HIV positive individuals not on antiretroviral treatment (ART) reported more nocturnal awakenings than those on ART (p = 0.029) and HIV negative individuals (p = 0.024), suggesting a negative net effect of untreated infection, but not of ART, on sleep quality. In this cohort, shorter, poor-quality sleep was associated with hypertension, but average self-reported sleep duration was longer than reported in other regions globally. It remains to be determined whether this is particular to this cohort, South Africa in general, or low- to middle-income countries undergoing transition. PMID- 30470763 TI - Cytokine and Chemokine Concentrations as Biomarkers of Feline Mycobacteriosis. AB - Mycobacteriosis is an emerging zoonotic disease of domestic cats and timely, accurate diagnosis is currently challenging. To identify differential cytokine/chemokine concentrations in serum/plasma of cats, which could be diagnostic biomarkers of infection we analysed plasma/serum from 116 mycobacteria infected cats, 16 healthy controls and six cats hospitalised for unrelated reasons was analysed using the Milliplex MAP Feline Cytokine Magnetic Bead multiplex assay. Three cytokines; sFAS, IL-13 and IL-4 were reduced while seven; GM-CSF, IL-2, PDGF-BB, IL-8, KC, RANTES and TNF-alpha were elevated in mycobacteria-infected cats compared to healthy controls. However, IL-8 and KC concentrations were not significantly different from cats hospitalised for other reasons. Elevations in TNF-alpha and PDGF-BB may have potential to identify M. bovis and M. microti infected cats specifically while GM-CSF, IL-2 and FLT3L were increased in MTBC infected cats. This study demonstrates potential use of feline tuberculosis as a spontaneously occurring model of this significant human disease. Cytokine profiling has clear diagnostic potential for mycobacteriosis of cats and could be used discriminate tuberculous from non-tuberculous disease to rapidly inform on zoonotic risk. Future work should focus on the in-field utility of these findings to establish diagnostic sensitivity and specificity of these markers. PMID- 30470765 TI - Cryo-EM reveals ligand induced allostery underlying InsP3R channel gating. AB - Inositol-1,4,5-trisphosphate receptors (InsP3Rs) are cation channels that mobilize Ca2+ from intracellular stores in response to a wide range of cellular stimuli. The paradigm of InsP3R activation is the coupled interplay between binding of InsP3 and Ca2+ that switches the ion conduction pathway between closed and open states to enable the passage of Ca2+ through the channel. However, the molecular mechanism of how the receptor senses and decodes ligand-binding signals into gating motion remains unknown. Here, we present the electron cryo-microscopy structure of InsP3R1 from rat cerebellum determined to 4.1 A resolution in the presence of activating concentrations of Ca2+ and adenophostin A (AdA), a structural mimetic of InsP3 and the most potent known agonist of the channel. Comparison with the 3.9 A-resolution structure of InsP3R1 in the Apo-state, also reported herein, reveals the binding arrangement of AdA in the tetrameric channel assembly and striking ligand-induced conformational rearrangements within cytoplasmic domains coupled to the dilation of a hydrophobic constriction at the gate. Together, our results provide critical insights into the mechanistic principles by which ligand-binding allosterically gates InsP3R channel. PMID- 30470766 TI - Adolescent conditioning affects rate of adult fear, safety and reward learning during discriminative conditioning. AB - Fear and reward memories formed in adulthood are influenced by prior experiences. Experiences that occur during sensitive periods, such as adolescence, can have an especially high impact on later learning. Fear and reward memories form when aversive or appetitive events co-occur with initially neutral stimuli, that then gain negative or positive emotional load. Fear and reward seeking behaviours are influenced by safety cues, signalling the non-occurrence of a threat. It is unclear how adolescent fear or reward pre-conditioning influences later dynamics of these conditioned emotions, and conditioned safety. In this study, we presented male rats with adolescent fear or reward pre-conditioning, followed by discriminative conditioning in adulthood. In this discriminative task, rats are simultaneously conditioned to reward, fear and safety cues. We show that adolescent reward pre-conditioning did not affect the rate of adult reward conditioning, but instead accelerated adult safety conditioning. Adolescent fear pre-conditioning accelerated adult fear and reward seeking behaviours but delayed adult safety expression. Together, our results suggest that the dynamics of safety conditioning can be influenced by adolescent priming of different valences. Taking adolescent experiences into consideration can have implications on how we approach therapy options for later learned fear disorders where safety learning is compromised. PMID- 30470768 TI - Compassion and mercy are not helpful in resolving intractable family-physician conflicts on end-of-life care. AB - "Compassion and mercy" are important values for humanizing medicine. There are limits, however, in their ability to help resolve disputes between physicians and families regarding appropriate end-of-life care. The recent cases of Charlie Gard and Alfie Evans in England highlight the issue. The English courts resolve such conflicts by an independent assessment of a court. The American judicial system does not share the centralized system of the English courts. In the United States Federal structure some 50 state legislatures and 50 state court systems go their separate ways. The result is differing, frequently conflicting, standards. We explore possible ways to avoid court involvement in the American context for resolving such disputes within the patient-physician relationship. PMID- 30470767 TI - Proof of concept study of mass cytometry in septic shock patients reveals novel immune alterations. AB - Innovative single cell technologies such as mass cytometry (CyTOF) widen possibilities to deeply improve characterisation of immune alterations mechanisms in human diseases. So far, CyTOF has not been used in sepsis - a condition characterized by complex immune disorders. Here, we evaluated feasibility of CyTOF analysis in patients with septic shock. We designed a mass cytometry panel of 25 extracellular markers to study mononuclear cells from 5 septic shock patients and 5 healthy donors. We explored single-cell data with global and specific unsupervised approaches such as heatmaps, SPADE and viSNE. We first validated relevance of our CyTOF results by highlighting established immune hallmarks of sepsis, such as decreased monocyte HLA-DR expression and increased expressions of PD1 and PD-L1 on CD4 T cells and monocytes. We then showed that CyTOF analysis reveals novel aspects of sepsis-induced immune alterations, e.g. B cell shift towards plasma cell differentiation and uniform response of several monocyte markers defining an immune signature in septic patients. This proof of concept study demonstrates CyTOF suitability to analyse immune features of septic patients. Mass cytometry could thus represent a powerful tool to identify novel pathophysiological mechanisms and therapeutic targets for immunotherapy in septic shock patients. PMID- 30470769 TI - Enhancement in surface mobility and quantum transport of Bi2-xSbxTe3-ySey topological insulator by controlling the crystal growth conditions. AB - Despite numerous studies on three-dimensional topological insulators (3D TIs), the controlled growth of high quality (bulk-insulating and high mobility) TIs remains a challenging subject. This study investigates the role of growth methods on the synthesis of single crystal stoichiometric BiSbTeSe2 (BSTS). Three types of BSTS samples are prepared using three different methods, namely melting growth (MG), Bridgman growth (BG) and two-step melting-Bridgman growth (MBG). Our results show that the crystal quality of the BSTS depend strongly on the growth method. Crystal structure and composition analyses suggest a better homogeneity and highly-ordered crystal structure in BSTS grown by MBG method. This correlates well to sample electrical transport properties, where a substantial improvement in surface mobility is observed in MBG BSTS devices. The enhancement in crystal quality and mobility allow the observation of well-developed quantum Hall effect at low magnetic field. PMID- 30470770 TI - Diversity and predictive metabolic pathways of the prokaryotic microbial community along a groundwater salinity gradient of the Pearl River Delta, China. AB - Almost half of the groundwater in the Pearl River Delta (PRD) contains salt water originally derived from paleo-seawater due to the Holocene transgression, which then generates intense physicochemical gradients in the mixing zone between freshwater and saltwater. Although some studies have been conducted on the hydrological and geochemical characteristics of groundwater in the PRD to monitor the intrusion of seawater, little attention has been paid to the microbial community of this particular region. In this study, we implemented a high throughput sequencing analysis to characterize the microbial communities along a salinity gradient in the PRD aquifer, China. Our results indicated that the microbial community composition varied significantly depending on the salinity of the aquifer. The presence of abundant anaerobic microorganisms of the genera Desulfovibrio and Methanococcus in certain saltwater samples may be responsible for the gas generation of H2S and CH4 in the stratum. In saline water samples (TDS > 10 g/L), the linear discriminant analysis effect size (LEfSe) analysis found two biomarkers that usually live in marine environments, and the aquifers of the PRD still contained large quantity of saltwater, indicating that the impact of the paleo-seawater has lasted to this day. The predictive metagenomic analysis revealed that the metabolic pathways present in the groundwater samples studied, included the degradation of pesticides and refractory organics (dichlorodiphenyltrichloroethane (DDT), atrazine and polycyclic aromatic hydrocarbons), matter cycling (methane, nitrogen and sulfur), and inorganic ion and mineral metabolites. This study can help enhance our understanding of the composition of the microbial assemblages and its implications as an environmental indicator in an aquifer affected by saltwater intrusion. PMID- 30470772 TI - Abrogation of transforming growth factor-beta-induced tissue fibrosis in mice with a global genetic deletion of Nox4. AB - Excessive connective tissue deposition in skin and various internal organs is characteristic of systemic sclerosis (SSc). The profibrotic growth factor TGF beta plays a crucial role in SSc pathogenesis. The expression of NADPH oxidase 4 (NOX4), a critical mediator of oxidative stress, is potently stimulated by TGF beta. Here, we evaluated the effect of NOX4 on the development of TGF-beta induced tissue fibrosis. C57BL6/J control mice and Nox4 knockout mice were implanted subcutaneously with osmotic pumps containing either saline or 2.5 ug TGF-beta1. After 28 days, skin and lung samples were isolated for histopathologic analysis, measurement of hydroxyproline content and gene expression analysis. Histopathology of skin and lungs from normal C57BL6/J mice treated with TGF-beta1 showed profound dermal fibrosis and peribronchial and diffuse interstitial lung fibrosis. In contrast, TGF-beta-treated Nox4 knockout mice showed normal skin and lung histology. Hydroxyproline levels in TGF-beta-treated C57BL6/J mice skin and lungs demonstrated significant increases, however, hydroxyproline content of TGF beta-treated Nox4 knockout mice tissues was not changed. Expression of various profibrotic and fibrosis-associated genes was upregulated in skin and lungs of TGF-beta1-treated C57BL6/J mice but was not significantly changed in TGF-beta1 treated Nox4 knockout mice. The induction of skin and lung tissue fibrosis by TGF beta1 parenteral administration in mice was abrogated by the genetic deletion of Nox4 confirming that NOX4 is an essential mediator of the profibrotic effects of TGF-beta. These results suggest Nox4 inhibition as a potential therapeutic target for SSc and other fibroproliferative disorders. PMID- 30470771 TI - On the use of abiotic sialic acids to attenuate cell inflammation. AB - Sialic acid (Sia) residues on cell surface are critical for myriad cellular events such as immunity and inflammation. We herein reported the use of abiotic Sia to raise the thresholds of inflammatory cell responses. Identified from a panel of structurally diversified Sia analogs via a cell inflammation assay, Sia 2, with N-butyryl moiety at C-5, markedly lowered LPS-stimulated NF-kappaB activity in macrophages. Further analysis shows that Sia-2 attenuates phosphorylation of IkappaB and Erk1/2/p38/JNK, critical for NF-kappaB signaling and MAPK signaling, and lowers gene transcription of proinflammatory interleukin 6. These results support the use of abiotic Sia as promising agents to modulate cell surface Sia-pertinent cell signaling. PMID- 30470773 TI - Author Correction: Pan-cancer subtyping in a 2D-map shows substructures that are driven by specific combinations of molecular characteristics. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30470774 TI - Antimicrobial Compounds Effective against Candidatus Liberibacter asiaticus Discovered via Graft-based Assay in Citrus. AB - Huanglongbing (HLB), the most destructive citrus disease, is caused by three species of phloem-limited Candidatus Liberibacter. Chemical control is a critical short-term strategy against Candidatus Liberibacter asiaticus (Las). Currently, application of antibiotics in agricultural practices is limited due to public concerns regarding emergence of antibiotic-resistant bacteria and potential side effects in humans. The present study screened 39 antimicrobials (non-antibiotics) for effectiveness against Las using an optimized graft-based screening system. Results of principal component, hierarchical clustering and membership function analyses demonstrated that 39 antimicrobials were clustered into three groups: "effective" (Group I), "partly effective" (Group II), and "ineffective" (Group III). Despite different modes of action, 8 antimicrobials (aluminum hydroxide, D,L-buthionine sulfoximine, nicotine, surfactin from Bacillus subtilis, SilverDYNE, colloidal silver, EBI-601, and EBI-602), were all as highly effective at eliminating or suppressing Las, showing both the lowest Las infection rates and titers in treated scions and inoculated rootstock. The ineffective group, which included 21 antimicrobials, did not eliminate or suppress Las, resulting in plants with increased titers of Candidatus Liberibacter. The other 10 antimicrobials partly eliminated/suppressed Las in treated and graft-inoculated plants. These effective antimicrobials are potential candidates for HLB control either via rescuing infected citrus germplasms or restricted field application. PMID- 30470775 TI - Host-specific signatures of the cell wall changes induced by the plant parasitic nematode, Meloidogyne incognita. AB - Root-knot nematodes (Meloidogyne spp.) are an important group of plant parasitic nematodes that induce within host plant roots unique feeding site structures, termed giant cells, which supply nutrient flow to the nematode. A comparative in situ analysis of cell wall polysaccharides in the giant cells of three host species (Arabidopsis, maize and aduki bean) infected with Meloidogyne incognita has been carried out. Features common to giant cell walls of all three species include the presence of high-esterified pectic homogalacturonan, xyloglucan and pectic arabinan. The species-specific presence of xylan and mixed-linkage glucan (MLG) epitopes in giant cell walls of maize reflected that host's taxonomic group. The LM5 galactan and LM21 mannan epitopes were not detected in the giant cell walls of aduki bean but were detected in Arabidopsis and maize giant cell walls. The LM2 arabinogalactan-protein epitope was notable for its apparent global variations in root cell walls as a response to infection across the three host species. Additionally, a set of Arabidopsis cell wall mutants were used to determine any impacts of altered cell wall structures on M. incognita infection. Disruption of the arabinogalactan-protein 8 gene had the greatest impact and resulted in an increased infection rate. PMID- 30470776 TI - Prevalence and Prognosis of Coexisting Frailty and Cognitive Impairment in Patients on Continuous Ambulatory Peritoneal Dialysis. AB - The aim of this study was to investigate the prevalence of coexisting frailty and cognitive impairment and its association with clinical outcomes in patients on continuous ambulatory peritoneal dialysis (CAPD). Patients on CAPD started to enroll from 2014 to 2016 and ended follow-up by 2017. Frailty was assessed by clinical frailty scale (CFS), and cognitive function was assessed by Montreal Cognitive Assessment (MoCA). Totally 784 CAPD patients were recruited, with median duration of PD 30.7 (8.9~54.3) months. The mean age was 48.8 +/- 14.6 years, 320 (40.8%) patients were female and 130 (16.6%) had diabetic nephropathy. Patients with cognitive impairment were more than those with frailty (55.5% vs. 27.6%). Coexisting frailty and cognitive impairment was present in 23.9% patients. Pathway analysis showed that CFS score was negatively associated with MoCA score (beta = -0.69, P < 0.001). Coexisting frailty and cognitive impairment was associated with decreased patient survival rate (Log-rank = 84.33, P < 0.001) and increased peritonitis rate (0.22 vs. 0.11, 0.15 and 0.12 episodes per patient year, respectively; all P < 0.001). It was concluded that there was a relatively high prevalence of coexisting frailty and cognitive impairment among patients on CAPD. Frailty was positively associated with cognitive impairment. Coexisting frailty and cognitive impairment increased the risk of adverse outcomes. PMID- 30470777 TI - The presence of extracellular microRNAs in the media of cultured Drosophila cells. AB - While regulatory RNA pathways, such as RNAi, have commonly been described at an intracellular level, studies investigating extracellular RNA species in insects are lacking. In the present study, we demonstrate the presence of extracellular microRNAs (miRNAs) in the cell-free conditioned media of two Drosophila cell lines. More specifically, by means of quantitative real-time PCR (qRT-PCR), we analysed the presence of twelve miRNAs in extracellular vesicles (EVs) and in extracellular Argonaute-1 containing immunoprecipitates, obtained from the cell free conditioned media of S2 and Cl.8 cell cultures. Next-generation RNA sequencing data confirmed our qRT-PCR results and provided evidence for selective miRNA secretion in EVs. To our knowledge, this is the first time that miRNAs have been identified in the extracellular medium of cultured cells derived from insects, the most speciose group of animals. PMID- 30470778 TI - Complementary medicine use in the Australian population: Results of a nationally representative cross-sectional survey. AB - In order to describe the prevalence and characteristics of complementary medicine (CM) practice and product use by Australians, we conducted a cross-sectional online survey with Australian adults aged 18 and over. Rates of consultation with CM practitioners, and use of CM products and practices were assessed. The sample (n = 2,019) was broadly representative of the Australian population. Prevalence of any CM use was 63.1%, with 36% consulting a CM practitioner and 52.8% using any CM product or practice. Bodywork therapists were the most commonly consulted CM practitioners (massage therapists 20.7%, chiropractors 12.6%, yoga teachers 8.9%) and homeopaths were the least commonly consulted (3.4%). Almost half of respondents (47.8%) used vitamin/mineral supplements, while relaxation techniques/meditation were the most common practice (15.8%). CM users were more likely to be female, have a chronic disease diagnosis, no private health insurance, a higher education level, and not be looking for work. Prevalence of CM use in Australia has remained consistently high, demonstrating that CM is an established part of contemporary health management practices within the general population. It is critical that health policy makers and health care providers acknowledge CM in their attempts to ensure optimal public health and patient outcomes. PMID- 30470779 TI - Feature Ranking in Predictive Models for Hospital-Acquired Acute Kidney Injury. AB - Acute Kidney Injury (AKI) is a common complication encountered among hospitalized patients, imposing significantly increased cost, morbidity, and mortality. Early prediction of AKI has profound clinical implications because currently no treatment exists for AKI once it develops. Feature selection (FS) is an essential process for building accurate and interpretable prediction models, but to our best knowledge no study has investigated the robustness and applicability of such selection process for AKI. In this study, we compared eight widely-applied FS methods for AKI prediction using nine-years of electronic medical records (EMR) and examined heterogeneity in feature rankings produced by the methods. FS methods were compared in terms of stability with respect to data sampling variation, similarity between selection results, and AKI prediction performance. Prediction accuracy did not intrinsically guarantee the feature ranking stability. Across different FS methods, the prediction performance did not change significantly, while the importance rankings of features were quite different. A positive correlation was observed between the complexity of suitable FS method and sample size. This study provides several practical implications, including recognizing the importance of feature stability as it is desirable for model reproducibility, identifying important AKI risk factors for further investigation, and facilitating early prediction of AKI. PMID- 30470780 TI - Cyclic undecapeptide Cyclosporin A mediated inhibition of amyloid synthesis: Implications in alleviation of amyloid induced neurotoxicity. AB - Amyloids are highly organized fibril aggregates arise from inappropriately folded form of the protein or polypeptide precursors under both physiological as well as simulated ambience. Amyloid synthesis is a multistep process that involves formation of several metastable intermediates. Among various intermediate species, the as-formed soluble oligomers are extremely toxic to the neuronal cells. In the present study, we evaluated cyclosporine A (CsA), an undecapeptide, for its potential to prevent aggregation of model protein ovalbumin (OVA). In an attempt to elucidate involved operative mechanism, the preliminary studies delineate that CsA affects both primary nucleation as well as other secondary pathways involved in OVA fibrillation process. By its specific interaction with amyloid intermediates, the cyclic peptide CsA seems to regulate the lag phase of the fibrillation process in concentration dependent manner. The present study further suggests that exposure to CsA during lag phase ensues in reversal of OVA fibrillation process. On the contrary, mature OVA fibril remained impervious to the CsA treatment. The cyclic undecapeptide CsA was also found to successfully alleviate amyloid induced toxicity in neuroblastoma cells. PMID- 30470781 TI - Publisher Correction: Multiple biomarker responses (serum biochemistry, oxidative stress, genotoxicity and histopathology) in Channa punctatus exposed to heavy metal loaded waste water. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30470783 TI - Major intensification of Atlantic overturning circulation at the onset of Paleogene greenhouse warmth. AB - During the Late Cretaceous and early Cenozoic the Earth experienced prolonged climatic cooling most likely caused by decreasing volcanic activity and atmospheric CO2 levels. However, the causes and mechanisms of subsequent major global warming culminating in the late Paleocene to Eocene greenhouse climate remain enigmatic. We present deep and intermediate water Nd-isotope records from the North and South Atlantic to decipher the control of the opening Atlantic Ocean on ocean circulation and its linkages to the evolution of global climate. The marked convergence of Nd-isotope signatures 59 million years ago indicates a major intensification of deep-water exchange between the North and South Atlantic, which coincided with the turning point of deep-water temperatures towards early Paleogene warming. We propose that this intensification of Atlantic overturning circulation in concert with increased atmospheric CO2 from continental rifting marked a climatic tipping point contributing to a more efficient distribution of heat over the planet. PMID- 30470782 TI - Whole genome amplification of cell-free DNA enables detection of circulating tumor DNA mutations from fingerstick capillary blood. AB - The ability to measure mutations in plasma cell-free DNA (cfDNA) has the potential to revolutionize cancer surveillance and treatment by enabling longitudinal monitoring not possible with solid tumor biopsies. However, obtaining sufficient quantities of cfDNA remains a challenge for assay development and clinical translation; consequently, large volumes of venous blood are typically required. Here, we test proof-of-concept for using smaller volumes via fingerstick collection. Matched venous and fingerstick blood were obtained from seven patients with metastatic breast cancer. Fingerstick blood was separated at point-of-care using a novel paper-based concept to isolate plasma centrifuge-free. Patient cfDNA was then analyzed with or without a new method for whole genome amplification via rolling-circle amplification (WG-RCA). We identified somatic mutations by targeted sequencing and compared the concordance of mutation detection from venous and amplified capillary samples by droplet digital PCR. Patient mutations were detected with 100% concordance after WG-RCA, although in some samples, allele frequencies showed greater variation likely due to differential amplification or primer inaccessibility. These pilot findings provide physiological evidence that circulating tumor DNA is accessible by fingerstick and sustains presence/absence of mutation detection after whole genome amplification. Further refinement may enable simpler and less-invasive methods for longitudinal or theranostic surveillance of metastatic cancer. PMID- 30470785 TI - Genetic constraints of population expansion of the Carpathian lynx at the western edge of its native distribution range in Central Europe. AB - Even though populations of many large carnivores are expanding throughout Europe, the Eurasian lynx population in the Western Carpathians seems unable to spread beyond the western boundaries of its current distributional range. Many factors, both extrinsic and intrinsic, can influence the potential for range expansion: landscape fragmentation, natal philopatry, low natural fecundity and high mortality, and low and sex-biased dispersal rates. In this study we used non invasive genetic sampling to determine population size fluctuation, sub structuring and social organisation of the peripheral lynx population at the Czech-Slovak border. Even though the population size has been relatively stable over the period studied (2010-2016), the individual inbreeding coefficients of residents at the end of the study were much higher than those of founders at the beginning of the study. While non-resident individuals (predominantly males) occurred regularly in the study population, only resident individuals with well established home ranges participated in breeding and produced offspring. Almost half the offspring detected in the study (predominantly females) settled in or near the natal area. Subsequent incestuous mating resulted in production of inbred individuals, reduction of effective population size of the population, and sub-structuring of the population through formation of two distinct family lineages. Our study illustrates how social constraints, such as territoriality, breeding of residents and natal philopatry of females, lead to incestuous mating in small-sized populations, especially at the periphery of their distribution. This threat should be taken into account in planning of conservation and population recovery of species with similar social structure. PMID- 30470786 TI - Diagnosis and management of urinary extravasation after high-grade renal trauma. AB - Renal trauma research has historically focused on parenchymal injuries and the risk of bleeding. However, much less is known about the diagnosis and optimal management of urinary extravasation, which complicates ~30% of high-grade renal injuries. Immediate or delayed ureteral stenting is the most common procedure used to treat collecting system injuries when intervention is needed. However, the lack of evidence-based guidelines leaves the diagnosis and management of urinary extravasation largely dependent upon physicians' experience, initial and follow-up imaging protocols, and the definitions used for grading the injuries. The knowledge gaps in the management of urinary extravasation that need to be addressed include the timing of excretory-phase CT imaging, patterns of clinically significant urinary extravasation, predictors of complications when urinary extravasation occurs, protocols for obtaining and interpreting follow-up imaging, and the role of ureteral stenting and other interventions in management. To improve the management of urinary extravasation after high-grade renal trauma, large, multi-institutional prospective trails assessing different diagnostic and therapeutic protocols are needed. PMID- 30470784 TI - Changes of Percent Body Fat as a Useful Surrogate for Risk of Declined Renal Function. AB - The association between anthropometric indices with chronic kidney disease (CKD) was examined previously. However, the effect of body fat on renal function was not determined clearly. Our aim was to investigate the association of percent body fat (PBF) and renal function in adult population from health examination in Tri-Service General Hospital (2010-2016). 35087 participants aged 20 years and older were enrolled in the study. PBF was measured by bioelectrical impedance analysis (BIA). Estimation of renal function was performed by Taiwanese MDRD equation. Optimal cut-off values of PBF was accessed by a receiver-operator characteristic (ROC) curve analysis. Multivariate regression models were used in the relationship among changes of PBF, renal function, and future CKD. In terms of baseline PBF for CKD, optimal cut-off values of PBF in males and females were 21.55 and 40.75. The changes of PBF were more closely associated with renal function decline than waist circumference (WC) with beta values of -0.173 (95% CI: -0.233, -0.112) and -0.077 (95% CI: -0.104, -0.049), respectively. After stratified by gender, this relationship remained significant in male population with beta values of -0.276 (95% CI: -0.371, -0.181) and -0.159 (95% CI: -0.207, 0.112), respectively. Female subjects with increased baseline PBF over cut-off values had increased risk for predicting the future CKD with odd ratios (ORs) of 2.298 (95% CI: 1.006-5.252). Body fat had detrimental impact on renal function and development of CKD in adult population. Measurement of PBF for surveillance of renal function impairment was warranted. PMID- 30470787 TI - Current insights into the mechanisms and management of infection stones. AB - Infection stones are complex aggregates of crystals amalgamated in an organic matrix that are strictly associated with urinary tract infections. The management of patients who form infection stones is challenging owing to the complexity of the calculi and high recurrence rates. The formation of infection stones is a multifactorial process that can be driven by urine chemistry, the urine microenvironment, the presence of modulator substances in urine, associations with bacteria, and the development of biofilms. Despite decades of investigation, the mechanisms of infection stone formation are still poorly understood. A mechanistic understanding of the formation and growth of infection stones - including the role of organics in the stone matrix, microorganisms, and biofilms in stone formation and their effect on stone characteristics - and the medical implications of these insights might be crucial for the development of improved treatments. Tools and approaches used in various disciplines (for example, engineering, chemistry, mineralogy, and microbiology) can be applied to further understand the microorganism-mineral interactions that lead to infection stone formation. Thus, the use of integrated multidisciplinary approaches is imperative to improve the diagnosis, prevention, and treatment of infection stones. PMID- 30470788 TI - Galiellalactone inhibits the STAT3/AR signaling axis and suppresses Enzalutamide resistant Prostate Cancer. AB - Most prostate cancer patients will progress to a castration-resistant state (CRPC) after androgen ablation therapy and despite the development of new potent anti-androgens, like enzalutamide (ENZ), which prolong survival in CRPC, ENZ resistance (ENZR) rapidly occurs. Re-activation of the androgen receptor (AR) is a major mechanism of resistance. Interrogating our in vivo derived ENZR model, we discovered that transcription factor STAT3 not only displayed increased nuclear localization but also bound to and facilitated AR activity. We observed increased STAT3 S727 phosphorylation in ENZR cells, which has been previously reported to facilitate AR binding. Strikingly, ENZR cells were more sensitive to inhibition with STAT3 DNA-binding inhibitor galiellalactone (GPA500) compared to CRPC cells. Treatment with GPA500 suppressed AR activity and significantly reduced expression of Cyclin D1, thus reducing cell cycle progression into S phase and hindering cell proliferation. In vivo, GPA500 reduced tumor volume and serum PSA in ENZR xenografts. Lastly, the combination of ENZ and GPA500 was additive in the inhibition of AR activity and proliferation in LNCaP and CRPC cells, providing rationale for combination therapy. Overall, these results suggest that STAT3 inhibition is a rational therapeutic approach for ENZR prostate cancer, and could be valuable in CRPC in combination with ENZ. PMID- 30470789 TI - Development a stacking pad design for enhancing the sensitivity of lateral flow immunoassay. AB - Lateral flow immunoassays (LFIAs) have wide application in point-of-care testing, particularly in resource-poor settings. To achieve signal amplification in a gold nanoparticle-based lateral flow assay without an additional procedure or the need for complex fabrication, a new and simple method was developed for using a "stacking pad" configuration that adds an additional membrane between the conjugation pad and test pad to the conventional AuNP-based LFIA format. This design helps to accumulate the antibody and antigen on the stacking pad, hence extending the antigen/antibody binding interactions to enhance the test's detection sensitivity. With the enhanced lateral flow assay, as low as 1 ng/mL of Protein A and 15.5 ng/mL of C-reactive protein can be visualized with the naked eye. We also successfully applied the stacking pad system in the analysis of C reactive protein in human serum and synovial fluid samples. These results suggest that this stacking pad LFIA can provide sensitive and on-site prognosis for detection in synovial fluid and serum samples in resource-limited settings. PMID- 30470790 TI - Publisher Correction: Computational repositioning and preclinical validation of mifepristone for human vestibular schwannoma. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30470791 TI - Introduction of a leguminous shrub to a rubber plantation changed the soil carbon and nitrogen fractions and ameliorated soil environments. AB - The conversion of monoculture rubber (Hevea brasiliensis) plantations into rubber based agroforestry systems has become a common trend in forestry management in the past few decades. Rubber-Flemingia macrophylla (a leguminous shrub) systems are popular in southwestern China's Xishuangbanna region. The biogeochemical cycles of soil carbon and nitrogen in forests are mainly affected by their fractions. This study investigated the effect of introducing Flemingia macrophylla to rubber plantations of different ages on soil carbon and nitrogen fractions. The experimental treatments included R1 (young rubber plantation), RF1 (young rubber-Flemingia macrophylla system), R2 (mature rubber plantation) and RF2 (mature rubber-Flemingia macrophylla system). The results showed that the introduction of Flemingia macrophylla to rubber plantations of different ages significantly changed soil carbon and nitrogen fractions, improved soil labile organic carbon and nitrogen contents, and ameliorated soil environments. The average soil microbial biomass organic carbon, nitrogen and nitrate-nitrogen in the 0-10 cm soil layer during the experimental period was 38.9%, 55.5%, and 214.7% higher in RF1 than R1, respectively, and 22.1%, 22.2%, and 652.2% higher in RF2 than R2, respectively. Therefore, Flemingia macrophylla can be used as an alternative interplanted tree species within rubber plantations in similar environments of southeastern Asia. PMID- 30470792 TI - The utility of urinary CD80 as a diagnostic marker in patients with renal diseases. AB - CD80, which regulates T cell activation, may provide a differential diagnostic marker between minimal change disease (MCD) and other renal diseases, including focal segmental glomerular sclerosis (FSGS). However, recent reports show contrasting results. Therefore, we evaluated the utility of urinary CD80 as a diagnostic biomarker. We collected 65 urine samples from 55 patients with MCD (n = 31), FSGS (n = 4), inherited nephrotic syndrome (n = 4), Alport syndrome (n = 5) and other glomerular diseases (n = 11), and control samples (n = 30). We measured urinary CD80 levels by ELISA. Urinary CD80 (ng/gCr) (median, interquartile range) levels were significantly higher in patients with MCD in relapse (91.5, 31.1-356.0), FSGS (376.2, 62.7-1916.0), and inherited nephrotic syndrome (220.1, 62.9-865.3), than in patients with MCD in remission (29.5, 21.7 52.8) (p < 0.05). Elevation of urinary CD80 was observed, even in patients with inherited nephrotic syndrome unrelated to T cell activation. Additionally, urinary CD80 was positively correlated with urinary protein levels. Our results suggest that urinary CD80 is unreliable as a differential diagnostic marker between MCD in relapse and FSGS or inherited kidney diseases. Increased urinary CD80 excretion was present in all patients with active kidney disease. PMID- 30470793 TI - A review of the pathways of human exposure to poly- and perfluoroalkyl substances (PFASs) and present understanding of health effects. AB - Here, we review present understanding of sources and trends in human exposure to poly- and perfluoroalkyl substances (PFASs) and epidemiologic evidence for impacts on cancer, immune function, metabolic outcomes, and neurodevelopment. More than 4000 PFASs have been manufactured by humans and hundreds have been detected in environmental samples. Direct exposures due to use in products can be quickly phased out by shifts in chemical production but exposures driven by PFAS accumulation in the ocean and marine food chains and contamination of groundwater persist over long timescales. Serum concentrations of legacy PFASs in humans are declining globally but total exposures to newer PFASs and precursor compounds have not been well characterized. Human exposures to legacy PFASs from seafood and drinking water are stable or increasing in many regions, suggesting observed declines reflect phase-outs in legacy PFAS use in consumer products. Many regions globally are continuing to discover PFAS contaminated sites from aqueous film forming foam (AFFF) use, particularly next to airports and military bases. Exposures from food packaging and indoor environments are uncertain due to a rapidly changing chemical landscape where legacy PFASs have been replaced by diverse precursors and custom molecules that are difficult to detect. Multiple studies find significant associations between PFAS exposure and adverse immune outcomes in children. Dyslipidemia is the strongest metabolic outcome associated with PFAS exposure. Evidence for cancer is limited to manufacturing locations with extremely high exposures and insufficient data are available to characterize impacts of PFAS exposures on neurodevelopment. Preliminary evidence suggests significant health effects associated with exposures to emerging PFASs. Lessons learned from legacy PFASs indicate that limited data should not be used as a justification to delay risk mitigation actions for replacement PFASs. PMID- 30470794 TI - Growth Differentiation Factor 11 treatment leads to neuronal and vascular improvements in the hippocampus of aged mice. AB - Aging is the biggest risk factor for several neurodegenerative diseases. Parabiosis experiments have established that old mouse brains are improved by exposure to young mouse blood. Previously, our lab showed that delivery of Growth Differentiation Factor 11 (GDF11) to the bloodstream increases the number of neural stem cells and positively affects vasculature in the subventricular zone of old mice. Our new study demonstrates that GDF11 enhances hippocampal neurogenesis, improves vasculature and increases markers of neuronal activity and plasticity in the hippocampus and cortex of old mice. Our experiments also demonstrate that systemically delivered GDF11, rather than crossing the blood brain barrier, exerts at least some of its effects by acting on brain endothelial cells. Thus, by targeting the cerebral vasculature, GDF11 has a very different mechanism from that of previously studied circulating factors acting to improve central nervous system (CNS) function without entering the CNS. PMID- 30470795 TI - Impact of elevated anti-apoptotic MCL-1 and BCL-2 on the development and treatment of MLL-AF9 AML in mice. AB - Many acute myeloid leukaemias (AMLs) express high levels of BCL-2 and MCL-1, especially after therapy. To test the impact of these anti-apoptotic proteins on AML development and treatment, we used haemopoietic reconstitution to generate MLL-AF9 AMLs expressing BCL-2 or Mcl-1 transgenes. AMLs with elevated BCL-2 or MCL-1 had a higher proportion of mature myeloid cells but, like conventional MLL AF9 AMLs, were readily transplantable. Short-term cell lines established from multiple primary AMLs of each genotype were tested in vitro for susceptibility to chemotherapeutics currently used for treating AML (daunorubicin, etoposide, cytarabine); the proteasome inhibitor bortezomib; CDK7/9 inhibitors; and BH3 mimetics, which bind and inhibit pro-survival proteins. The BH3 mimetics tested, alone and in combination with the other drugs, were: ABT-737 which, like its clinical counterpart navitoclax, targets BCL-2, BCL-XL and BCL-W; BCL-2-specific ABT-199 (venetoclax); BCL-XL-specific A-1331852; and S63845, a new MCL-1-specific BH3 mimetic. As single agents, daunorubicin and bortezomib had the greatest efficacy. Elevated MCL-1 or BCL-2 reduced sensitivity to daunorubicin but, surprisingly, not to bortezomib. MCL-1 markedly enhanced resistance to ABT-737 and ABT-199 but not S63845, and BCL-2 increased resistance to S63845 but not to ABT-737 or ABT-199. Notable synergies were achieved by combining BH3 mimetics with daunorubicin: S63845 increased the sensitivity of both MCL-1 and BCL-2 overexpressing MLL-AF9 AMLs, and ABT-737 aided in killing those overexpressing BCL-2. Synergy between daunorubicin and ABT-199 was also apparent in vivo, although not curative. Impressive synergistic responses were achieved for human MLL-fusion AML cell lines treated with daunorubicin plus either ABT-737, ABT-199 or S63845, and with ABT-199 plus S63845, with or without daunorubicin. Our data suggest that AML patients may benefit from combining conventional cytotoxic drugs with BH3 mimetics targeting BCL-2 or MCL-1 or, if tolerated, both these agents. PMID- 30470796 TI - Death and fire-the concept of necroinflammation. PMID- 30470797 TI - Author Correction: An Autogenously Regulated Expression System for Gene Therapeutic Ocular Applications. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30470799 TI - Novel upregulation of amyloid-beta precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5'-untranslated region: Implications in Alzheimer's disease. AB - In addition to the devastating symptoms of dementia, Alzheimer's disease (AD) is characterized by accumulation of the processing products of the amyloid-beta (Abeta) peptide precursor protein (APP). APP's non-pathogenic functions include regulating intracellular iron (Fe) homeostasis. MicroRNAs are small (~ 20 nucleotides) RNA species that instill specificity to the RNA-induced silencing complex (RISC). In most cases, RISC inhibits mRNA translation through the 3' untranslated region (UTR) sequence. By contrast, we report a novel activity of miR-346: specifically, that it targets the APP mRNA 5'-UTR to upregulate APP translation and Abeta production. This upregulation is reduced but not eliminated by knockdown of argonaute 2. The target site for miR-346 overlaps with active sites for an iron-responsive element (IRE) and an interleukin-1 (IL-1) acute box element. IREs interact with iron response protein1 (IRP1), an iron-dependent translational repressor. In primary human brain cultures, miR-346 activity required chelation of Fe. In addition, miR-346 levels are altered in late-Braak stage AD. Thus, miR-346 plays a role in upregulation of APP in the CNS and participates in maintaining APP regulation of Fe, which is disrupted in late stages of AD. Further work will be necessary to integrate other metals, and IL-1 into the Fe-miR-346 activity network. We, thus, propose a "FeAR" (Fe, APP, RNA) nexus in the APP 5'-UTR that includes an overlapping miR-346-binding site and the APP IRE. When a "healthy FeAR" exists, activities of miR-346 and IRP/Fe interact to maintain APP homeostasis. Disruption of an element that targets the FeAR nexus would lead to pathogenic disruption of APP translation and protein production. PMID- 30470798 TI - Modeling Diabetic Corneal Neuropathy in a 3D In Vitro Cornea System. AB - Diabetes mellitus is a disease caused by innate or acquired insulin deficiency, resulting in altered glucose metabolism and high blood glucose levels. Chronic hyperglycemia is linked to development of several ocular pathologies affecting the anterior segment, including diabetic corneal neuropathy and keratopathy, neovascular glaucoma, edema, and cataracts leading to significant visual defects. Due to increasing disease prevalence, related medical care costs, and visual impairment resulting from diabetes, a need has arisen to devise alternative systems to study molecular mechanisms involved in disease onset and progression. In our current study, we applied a novel 3D in vitro model of the human cornea comprising of epithelial, stromal, and neuronal components cultured in silk scaffolds to study the pathological effects of hyperglycemia on development of diabetic corneal neuropathy. Specifically, exposure to sustained levels of high glucose, ranging from 35 mM to 45 mM, were applied to determine concentration dependent effects on nerve morphology, length and density of axons, and expression of metabolic enzymes involved in glucose metabolism. By comparing these metrics to in vivo studies, we have developed a functional 3D in vitro model for diabetic corneal neuropathy as a means to investigate corneal pathophysiology resulting from prolonged exposure to hyperglycemia. PMID- 30470800 TI - Characterisation and use of a functional Gadd45g bacterial artificial chromosome. AB - Bacterial artificial chromosomes (BACs) offer a means of manipulating gene expression and tagging gene products in the mammalian genome without the need to alter endogenous gene structure and risk deleterious phenotypic consequences. However, for a BAC clone to be useful for such purposes it must be shown to contain all the regulatory elements required for normal gene expression and allow phenotypic rescue in the absence of an endogenous gene. Here, we report identification of a functional BAC containing Gadd45g, a gene implicated in DNA repair, DNA demethylation and testis determination in mice and exhibiting a broad pattern of embryonic expression. Mouse fetuses lacking the endogenous Gadd45g gene undergo normal testis development in the presence of the Gadd45g BAC transgene. Moreover, a survey of embryonic Gadd45g expression from the BAC reveals that all reported sites of expression are maintained. This functional BAC can now be used for subsequent manipulation of the Gadd45g gene with the confidence that regulatory elements required for embryonic expression, including testis determination, are present. We describe the generation and characterisation of a Gadd45g-mCherry fluorescent reporter exhibiting strong expression in developing gonads and neural tissue, recapitulating endogenous gene expression, as evidence of this. PMID- 30470802 TI - High prevalence of erectile dysfunction in men with psoriasis: evidence from a systematic review and meta-analysis. AB - Psoriasis is a common skin disease with the global prevalence of about 2%. Mounting evidence has emerged indicating that there was an association between psoriasis and increased susceptibility to erectile dysfunction (ED). We aimed to assess whether psoriasis was a risk factor for ED through a comprehensive literature review and meta-analysis. The MEDLINE (PubMed), EMBASE, and the Cochrane Library were systematically searched for all studies investigating the erectile function in psoriatic patients. The association between psoriasis and risk of ED was summarized using the odds ratios (OR) with a 95% confidence interval (CI). The protocol for this meta-analysis is available from PROSPERO (CRD42018093025). Overall, 1829449 participants (the mean age ranged from 44 years to 56.3 years) were included from 8 studies (6 cross-sectional, 1 cohort, and 1 case-control study); 39490 of whom were patients with psoriasis, with the mean disease duration from 6 months to 19.9 years. The methodological quality of the 8 included studies was considered to be either moderate or high quality. Synthesis results from the included studies revealed that psoriasis was significantly associated with an increased risk of ED in psoriatic patients (OR = 1.62, 95%CI: 1.37-1.91, P < 0.001; heterogeneity: I2 = 62.6%, P = 0.009). The results were consistent after multivariable adjustment (6 studies; combined OR = 1.5, 95%CI: 1.31-1.72, P < 0.001; heterogeneity: I2 = 53.5%, P = 0.056). Evidence from this meta-analysis indicates that patients with psoriasis have a significantly elevated risk of ED. PMID- 30470801 TI - Association of C-type lectin 18 levels with extrahepatic manifestations in chronic HCV infection. AB - Mixed cryobulinemia (MC) is the most common chronic hepatitis C virus (HCV) associated extrahepatic manifestation. C-type lectin 18 (CLEC18) is a novel secretory lectin that is abundantly expressed in hepatocytes and peripheral blood cells (PBCs). We investigated the associations between CLEC18 expression during HCV infection and the presence of extrahepatic manifestations. A total of 41 rheumatic patients with HCV infection (including 28 patients with MC syndrome), 45 rheumatic patients without infection, and 14 healthy subjects were enrolled. The CLEC18 levels in PBCs and serum were determined by using flow cytometry and enzyme-linked immunosorbent assay, respectively. Significantly higher CLEC18 levels were observed in patients with HCV infection (P < 0.001) and were positively correlated with HCV viral loads (gamma = 0.56, P < 0.05). Among patients with HCV infection, significantly increased CLEC18 levels were observed in patients with MC syndrome, particularly in those with type II MC (P < 0.05). CLEC18 levels were associated with cryoglobulin and C4 levels (P < 0.05). CLEC18 was significantly associated with HCV infection, particularly in those with HCV associated MC. CLEC18 levels were also positively correlated with MC disease activity, suggesting its involvement in MC pathogenesis. CLEC18 may be a novel indicator of HCV infection and a potential therapeutic target in rheumatic patients. PMID- 30470803 TI - The effect of a very low calorie diet on subjective depressive symptoms and anxiety: meta-analysis and systematic review. AB - There are conflicting findings regarding the effect very low calorie diets (VLCDs) have on self-reported depressive symptoms and anxiety levels. Some studies have reported decreased subjective depressive symptoms and anxiety post diet, whereas other studies have not. Further complicating matters, the protocol for VLCDs vary substantially across studies, which could account for the mixed findings. The primary goal of this meta-analysis and systematic review was to determine the effect VLCDs have on subjective depressive symptoms and anxiety pre to post-diet. In addition, potential moderators (the presence/absence of behavioral therapy, duration of diet, inclusion/exclusion of low intensity exercise, and amount of weight lost) were examined to assess the effect of procedural deviations across VLCD studies on depressive symptoms and anxiety. A random-effects model was used for the meta-analysis and included nine studies with 16 independent samples. To further explain the results, study rigor was examined in the systematic review, which included 11 studies with 20 independent samples. Depressive symptoms significantly decreased pre- to post-diet when behavioral therapy was implemented during the diet, the duration of the diet was relatively long (8-16 weeks), low intensity exercise was included, and the dieters lost 14.1 kg or more post-diet. However, no difference in depressive symptoms were observed pre- to post-diet when behavioral therapy was not included, the diet was shorter (1-7 weeks), no exercise was implemented and dieters lost <14 kg of weight post-diet. There was no change in anxiety pre- to post-diet. Health care providers involved in supervising VLCDs should consider using a VLCD of at least 8 weeks that includes behavioral therapy and low intensity exercise in order to enhance the potential benefits of VLCDs on depressive symptoms. More research is required to examine the effect of VLCDs on anxiety. PMID- 30470804 TI - Effect of intermittent compared to continuous energy restriction on weight loss and weight maintenance after 12 months in healthy overweight or obese adults. AB - BACKGROUND AND OBJECTIVE: Intermittent energy restriction (IER) is an alternative to continuous energy restriction (CER) for weight loss. There are few long-term trials comparing efficacy of these methods. The objective was to compare the effects of CER to two forms of IER; a week-on-week-off energy restriction and a 5:2 program, during which participants restricted their energy intake severely for 2 days and ate as usual for 5 days, on weight loss, body composition, blood lipids, and glucose. SUBJECTS AND METHODS: A one-year randomized parallel trial was conducted at the University of South Australia, Adelaide, Australia. Participants were 332 overweight and obese adults, ages 18-72 years, who were randomized to 1 of 3 groups: CER (4200 kJ/day for women and 5040 kJ/day for men), week-on-week-off energy restriction (alternating between the same energy restriction as the continuous group for one week and one week of habitual diet), or 5:2 (2100 kJ/day on modified fast days each week for women and 2520 kJ/day for men, the 2 days of energy restriction could be consecutive or non-consecutive). Primary outcome was weight loss, and secondary outcomes were changes in body composition, blood lipids, and glucose. RESULTS: For the 146 individuals who completed the study (124 female, 22 male, mean BMI 33 kg/m2) mean weight loss, and body fat loss at 12 months was similar in the three intervention groups, -6.6 kg for CER, -5.1 kg for the week-on, week-off and -5.0 kg for 5:2 (p = 0.2 time by diet). Discontinuation rates were not different (p = 0.4). HDL-cholesterol rose (7%) and triglycerides decreased (13%) at 12 months with no differences between groups. No changes were seen for fasting glucose or LDL-cholesterol. DISCUSSION AND CONCLUSION: The two forms of IER were not statistically different for weight loss, body composition, and cardiometabolic risk factors compared to CER. PMID- 30470805 TI - Data visualisation to support obesity policy: case studies of data tools for planning and transport policy in the UK. AB - Data visualisation is becoming an established way to drive discovery and develop theory and hypotheses among researchers. Data visualisations can also serve as tools for knowledge translation with policy makers, who are increasingly using data and evidence to inform and implement policy. For obesity policy, data visualisation tools can help policy makers and other professionals understand the socio-spatial distribution of risk factors and quantify social and environmental conditions that are recognised upstream determinants of diet, activity and obesity. The demand for and use of data visualisation tools can be driven by an identified policy need, which can be met by researchers and data scientists. Alternatively, researchers are developing and testing data visualisations, which may be subsequently adapted for, and adopted by policy users.Two recently released interactive data visualisation tools in the UK illustrate these points. The Propensity to Cycle Tool (PCT) was developed with funding from the UK government to inform the investment of cycling infrastructure in England. The Food environment assessment tool (Feat) evolved as a translational output from a programme of epidemiological research. This article uses PCT and Feat as case studies, drawing parallels and contrasts between them. We discuss these two tools from policy context and scientific underpinnings, to product launch and evaluation. We review challenges inherent in the development and dissemination of data tools for policy, including the need for technical expertise, feedback integration, long-term sustainability, and provision of training and user support. Finally, we attempt to derive learning points that may help overcome challenges associated with the creation, dissemination and sustaining of data tools for policy. We contend that, despite a number of challenges, data tools provide a novel gateway between researchers and a range of stakeholders, who are seeking ways of accessing and using evidence to inform obesity programs and policies. PMID- 30470806 TI - Long-term mortality in obese subjects undergoing malabsorptive surgery (biliopancreatic diversion and biliointestinal bypass) versus medical treatment. AB - BACKGROUND AND AIM: Aim of this study was to analyze long-term mortality in obese patients receiving malabsorptive bariatric surgery (BS)[biliopancreatic diversion (BPD) and biliointestinal bypass (BIBP)] in comparison to medical treatment of obesity. PATIENTS AND METHODS: Medical records of 1877 obese patients [body mass index (BMI) > 35 kg/m2, aged 18-65 years, undergoing BS (n = 472, 111 with diabetes) or non-surgical medical treatment (n = 1405, 385 with diabetes), during the period 1999-2008 (visit 1)] were collected; non-surgical patients were matched for age, sex, BMI, and blood pressure, and life status and causes of death were ascertained through December 2016. Survival was compared across surgery patients and non-surgical patients using Kaplan-Meier plots and Cox regression analyses. RESULTS: Observation period was 12.1 +/- 3.41 years (mean +/ SD). Compared to non-surgical patients, BS patients had reduced all-cause mortality (34/472 (7.2%) vs 181/1,405 (12.9%) patients, chi2 = 11.25, p = 0.001; HR = 0.64, 95% C.I. 0.43-0.93, p = 0.019). Cardiovascular and cancer causes of death were significantly less frequent in surgery vs no-surgery (HR = 0.26, 95% C.I. 0.09-0.72, p = 0.003; HR = 0.21, 95% C.I. 0.09-0.45, p < 0.001, respectively). CONCLUSION: Patients who have undergone BPD and BIBP have lower long-term all-cause, cardiovascular-caused and cancer-caused mortality compared to non-surgical medical weight-loss treatment patients. Malabsorptive bariatric surgery significantly reduces long-term mortality in severely obese patients. PMID- 30470807 TI - Weight change in relation to mortality in middle-aged and elderly Chinese: the Singapore Chinese Health Study. AB - OBJECTIVES: To examine the association between weight change and mortality in middle-aged and elderly Chinese. METHODS: We used data from the Singapore Chinese Health Study among 36 338 participants aged 45 to 74 years at recruitment (1993 1998). Weight change was computed as the difference between weights at baseline and the follow-up 1 (1999-2004) surveys and classified as moderate-to-large weight loss (>=10%), small weight loss (5.1-9.9%), stable weight (+/-5%), small weight gain (5.1-9.9%) and moderate-to-large weight gain (>=10%). The participants were free of cancer and cardiovascular disease (CVD) at the follow up 1 survey and were followed for mortality through linkage with the Singapore Birth and Death Registry. RESULTS: Until 31 December 2016, a total of 7551 deaths were identified during 517 128 person-years of follow-up (mean follow-up: 14.2 years). Compared to those with stable weight, significantly increased risk of all cause mortality was found for participants with moderate-to-large weight loss (hazard ratio [HR]: 1.39; 95% CI: 1.30, 1.49), small loss (1.14; 1.06, 1.22), and moderate-to-large gain (1.13; 1.05, 1.22). Moderate-to-large weight loss was significantly associated with increased risk of mortality from CVD (including both ischemic heart disease and stroke) and respiratory disease, while moderate to-large weight gain was significantly associated with CVD mortality. Associations were generally consistent in stratified analyses by sex, age groups (<60 and >=60 years old), smoking status (never, former and current smoking), and baseline body mass index (<23 and >=23 kg/m2), although significant effect modifications were found for certain strata. CONCLUSIONS: Our findings showed that both moderate-to-large weight gain and loss conferred excess risk for all cause and CVD mortality in middle-aged and elderly Chinese, with slightly higher risk for weight loss than weight gain. However, it remains to be examined in clinical trials whether maintaining stable body weight should be proposed to reduce mortality risk in middle-aged and elderly populations. PMID- 30470808 TI - Ensuring the care for our youngest graduates with medically complex conditions. PMID- 30470809 TI - Differences in plasma fibrin clot composition in patients with thrombotic antiphospholipid syndrome compared with venous thromboembolism. AB - The prothrombotic fibrin clot phenotype has been reported in patients with thrombotic antiphospholipid syndrome (APS) and venous thromboembolism (VTE). Protein composition of plasma fibrin clots in APS has not been studied. We evaluated 23 patients with thrombotic APS, 19 with VTE alone, and 20 well-matched controls. A proteomic analysis of fibrin clots generated from citrated plasma was based on liquid chromatography-mass spectrometry. Plasma levels of thrombospondin 1 (TSP1), apolipoprotein(a), A-I, and B-100, complement components (C)3a, C5b-C9, histidine-rich glycoprotein (HRG), and prothrombin were evaluated using immunoenzymatic tests. In plasma fibrin clots of APS patients, compared with VTE subjects and controls, we identified decreased amounts of (pro)thrombin, antithrombin-III, apolipoprotein A-I, and HRG with no differences in plasma levels of antithrombin, prothrombin, along with lower plasma HRG and apolipoprotein A-I. In APS patients, plasma HRG positively correlated with amounts of clot-bound HRG, while apolipoprotein A-I was inversely associated with clot-bound levels of this protein. The most predominant proteins within the clots of APS patients were bone marrow proteoglycan, C5-C9, immunoglobulins, apolipoprotein B-100, platelet-derived proteins, and TSP1. Our study is the first to demonstrate differences in the protein composition of fibrin clots generated from plasma of thrombotic APS patients versus those with VTE alone. PMID- 30470810 TI - A structural-chemical explanation of fungal laccase activity. AB - Fungal laccases (EC 1.10.3.2) are multi-copper oxidases that oxidize a wide variety of substrates. Despite extensive studies, the molecular basis for their diverse activity is unclear. Notably, there is no current way to rationally predict the activity of a laccase toward a given substrate. Such knowledge would greatly facilitate the rational design of new laccases for technological purposes. We report a study of three datasets of experimental Km values and activities for Trametes versicolor and Cerrena unicolor laccase, using a range of protein modeling techniques. We identify diverse binding modes of the various substrates and confirm an important role of Asp-206 and His-458 (T. versicolor laccase numbering) in guiding substrate recognition. Importantly, we demonstrate that experimental Km values correlate with binding affinities computed by MMGBSA. This confirms the common assumption that the protein-substrate affinity is a major contributor to observed Km. From quantitative structure-activity relations (QSAR) we identify physicochemical properties that correlate with observed Km and activities. In particular, the ionization potential, shape, and binding affinity of the substrate largely determine the enzyme's Km for the particular substrate. Our results suggest that Km is not just a binding constant but also contains features of the enzymatic activity. In addition, we identify QSAR models with only a few descriptors showing that phenolic substrates employ optimal hydrophobic packing to reach the T1 site, but then require additional electronic properties to engage in the subsequent electron transfer. Our results advance our ability to model laccase activity and lend promise to future rational optimization of laccases toward phenolic substrates. PMID- 30470811 TI - Dorsal-zone-specific reduction of sensory neuron density in the olfactory epithelium following long-term exercise or caloric restriction. AB - Exercise (Ex) and caloric restriction (CR) reduce oxidative stress and improve organ function. For instance, voluntary Ex or CR is known to reduce age-related cochlear damage in male C57BL/6J mice. However, the effect of Ex and CR on the olfactory system is unknown. In this study, we confirmed the positive effect of Ex and CR on age-related cochlear damage, but found that Ex and CR affected negatively cell dynamics in the olfactory epithelium (OE) by reducing the number of mature olfactory sensory neurons (OSNs) and increasing the number of proliferative basal cells and apoptotic OSNs in the dorsal zone of the olfactory epithelium (OE), which contains neurons expressing NADPH quinone oxido-reductase 1 (NQO1). In addition, these interventions resulted in lower odor-induced c-fos expression in areas of the olfactory bulb receiving projections from dorsal-zone OSNs than in areas receiving ventral-zone projections. Further, we observed substantial oxidative stress in NQO1-positive cells and apoptotic OSNs in the dorsal zone in Ex and CR animals. These results suggest that, in contrast to their positive effects in other organs, Ex and CR facilitate oxidative stress and negatively impact structure and function in dorsal-zone OSNs, probably in association with NQO1 bioactivation. PMID- 30470813 TI - Reduce your speed. PMID- 30470812 TI - New insights into mitral heart valve prolapse after chordae rupture through fluid structure interaction computational modeling. AB - Mitral valve (MV) dynamics depends on a force balance across the mitral leaflets, the chordae tendineae, the mitral annulus, the papillary muscles and the adjacent ventricular wall. Chordae rupture disrupts the link between the MV and the left ventricle (LV), causing mitral regurgitation (MR), the most common valvular disease. In this study, a fluid-structure interaction (FSI) modeling framework is implemented to investigate the impact of chordae rupture on the left heart (LH) dynamics and severity of MR. A control and seven chordae rupture LH models were developed to simulate a pathological process in which minimal chordae rupture precedes more extensive chordae rupture. Different non-eccentric and eccentric regurgitant jets were identified during systole. Cardiac efficiency was evaluated by the ratio of external stroke work. MV structural results showed that basal/strut chordae were the major load-bearing chordae. An increased number of ruptured chordae resulted in reduced basal/strut tension, but increased marginal/intermediate load. Chordae rupture in a specific scallop did not necessarily involve an increase in the stress of the entire prolapsed leaflet. This work represents a further step towards patient-specific modeling of pathological LH dynamics, and has the potential to improve our understanding of the biomechanical mechanisms and treatment of primary MR. PMID- 30470814 TI - Investigating the Neurological Correlates of Workplace Deviance Using a Rodent Model of Extinction. AB - Employee deviance and time theft is an expensive and pervasive workplace problem. Research indicates that a primary reason employees engage in deviant behaviour is the perception of injustice often associated with psychological contract breach (i.e., broken promises). This study used a rodent model to mimic said experience of broken promises and then examined the subsequent neurophysiological changes that lead to the display of deviant behaviours. Specifically, we generated a psychological contract using a 3 choice serial reaction task, then broke the promise, and finally examined deviant behaviours and neurological correlates. After the broken promise, rats had elevated levels of corticosterone and testosterone, engaged in riskier behaviour, and were more aggressive. The most prominent changes in gene expression were associated with serotonin and stress, and were found in the nucleus accumbens. This study highlights the value of pre clinical models in the investigation of the theoretical tenants of industrial and organizational psychology. PMID- 30470815 TI - Ectopic pregnancy incidence in the Republic of Korea in 2009-2015: A population based cross-sectional study. AB - We estimated the incidence of ectopic pregnancy (EP) and the success rate of expectant management of EP in South Korea. We analyzed data from 2009 to 2015 using the Health Insurance Review and Assessment Service National Inpatient Sample (HIRA-NIS) database. EP was identified by diagnostic codes, and strict EP was identified by both diagnostic codes and treatment codes. From 2009 to 2015, 369,701 cases of EP, abortion, or delivery were extracted from a total of 4,476,495 women. Of the total pregnancies, 8,556 cases were EPs. The incidence of EP was 34.1 +/- 0.7 per 1,000 pregnancies and the incidence of strict EP was 17.3 +/- 0.3 per 1,000 pregnancies. Among women aged 25-44 years, age was associated with a higher incidence of EP (odds ratio [OR]: 1.13; 95% confidence interval [CI]: 1.06, 1.19; P < 0.01). The incidence rates of EP (OR: 0.99; 95% CI: 0.97, 1.01; P = 0.51) did not significantly differ by year. The incidence of EP in Korea was 17.3 +/- 0.3 per 1,000 pregnancies, and almost did not change over 7 years. About 50% of EPs were treated without surgery or methotrexate. This study provides an important reference for the treatment of EP. PMID- 30470818 TI - Turning foes to friends: targeting cancer-associated fibroblasts. AB - Current paradigms of cancer-centric therapeutics are usually not sufficient to eradicate the malignancy, as the cancer stroma may prompt tumour relapse and therapeutic resistance. Among all the stromal cells that populate the tumour microenvironment, cancer-associated fibroblasts (CAFs) are the most abundant and are critically involved in cancer progression. CAFs regulate the biology of tumour cells and other stromal cells via cell-cell contact, releasing numerous regulatory factors and synthesizing and remodelling the extracellular matrix, and thus these cells affect cancer initiation and development. The recent characterization of CAFs based on specific cell surface markers not only deepens our insight into their phenotypic heterogeneity and functional diversity but also brings CAF-targeting therapies for cancer treatment onto the agenda. In this Review, we discuss the current knowledge of biological hallmarks, cellular origins, phenotypical plasticity and functional heterogeneity of CAFs and underscore their contribution to cancer progression. Moreover, we highlight relevant translational advances and potential therapeutic strategies that target CAFs for cancer treatment. PMID- 30470816 TI - Effect of a Repeated Sprint Ability test on the muscle contractile properties in elite futsal players. AB - The aim of this study was to evaluate the effect of a repeated sprint ability (RSA) test on the contractile properties of the muscles in elite futsal players. A total of 20 elite players completed the RSA test (7 * 30 m), and the contractile response from the rectus femoris (RF) and biceps femoris (BF) of both legs were analysed pre and post through tensiomyography. There was a significant increment in 30-m times from the third sprint onwards (p < 0.05). The percent decrement in sprint ability (RSADEC) with respect to the first sprint was significantly higher in the last sprint. The players did not show evidence of lateral asymmetry in any of the muscle groups analysed after the RSA test (p > 0.05). Following the RSA test there was a significant reduction in the delay time (Td) in RF, a significant decrement in half-relaxation time (Tr) in the RF, and a significant reduction in sustain time (Ts) in the RF and BF of both legs. The maximum radial displacement of the muscle belly (Dm) increased (1.6 mm; effect size = 0.75; p < 0.05) in the RF after the RSA test, indicating reduced muscle stiffness and the ability to generate strength rapidly. The decrement in performance during the RSA test was significantly correlated with changes in contraction time (Tc) in RF and BF, Td in BF, and Dm in RF (p < 0.05). The RSA test generated alterations in the contractile properties of the RF and BF in elite players. However, futsal players did not present asymmetries in any muscular parameters. The baseline contractile muscle parameters could be an important factor related to performance of players during repeated high-intensity actions. PMID- 30470817 TI - Epigenetic Heterogeneity in Human Colorectal Tumors Reveals Preferential Conservation And Evidence of Immune Surveillance. AB - Genomic intratumoral heterogeneity (ITH) is common in cancers, but the extent of phenotypic ITH is uncertain because most subclonal mutations are passengers. Since tumor phenotypes are largely driven by epigenetics, methylomic analyses can provide insights into phenotypic ITH. Following this principle, we determined the extent of epigenetic ITH in 16 human colorectal tumors by comparing the methylomes from spatially separated regions in each tumor. Methylomes from opposite tumor sides were similar (Pearson correlation >0.95) with little evidence of ITH or stepwise selection during growth, suggesting that the epigenome of a sampled tumor largely reflects that of its founder cell. Epigenetic conservation was functional, with higher conservation at promoters and expressed genes compared to non-coding regions. Despite epigenomic conservation, RNA expression varied between individual tumor glands, indicating continued adaption during growth. Because many promoters and enhancers were unmethylated, continued adaptation may be due to phenotypic plasticity. Gene enrichment analyses identified that interferon signaling and antigen-processing and presenting pathways were strongly conserved during tumor growth, suggesting a mechanism for immune evasion. In summary, our findings suggest that epigenomes are preferentially conserved during tumor growth and that early tumor cells are poised for rapid growth, phenotypic adaptation, and immune evasion. PMID- 30470819 TI - Efficient and irreversible antibody-cysteine bioconjugation using carbonylacrylic reagents. AB - There is considerable interest in the development of chemical methods for the precise, site-selective modification of antibodies for therapeutic applications. In this protocol, we describe a strategy for the irreversible and selective modification of cysteine residues on antibodies, using functionalized carbonylacrylic reagents. This protocol is based on a thiol-Michael-type addition of native or engineered cysteine residues to carbonylacrylic reagents equipped with functional compounds such as cytotoxic drugs. This approach is a robust alternative to the conventional maleimide technique; the reaction is irreversible and uses synthetically accessible reagents. Complete conversion to the conjugates, with improved quality and homogeneity, is often achieved using a minimal excess (typically between 5 and 10 equiv.) of the carbonylacrylic reagent. Potential applications of this method cover a broad scope of cysteine tagged antibodies in various formats (full-length IgGs, nanobodies) for the site selective incorporation of cytotoxic drugs without loss of antigen-binding affinity. Both the synthesis of the carbonylacrylic reagent armed with a synthetic molecule of interest and the subsequent preparation of the chemically defined, homogeneous antibody conjugate can be achieved within 48 h and can be easily performed by nonspecialists. Importantly, the conjugates formed are stable in human plasma. The use of liquid chromatography-mass spectrometry (LC-MS) analysis is recommended for monitoring the progression of the bioconjugation reactions on protein and antibody substrates with accurate resolution. PMID- 30470820 TI - Generation of human antral and fundic gastric organoids from pluripotent stem cells. AB - The human stomach contains two primary domains: the corpus, which contains the fundic epithelium, and the antrum. Each of these domains has distinct cell types and functions, and therefore each presents with unique disease pathologies. Here, we detail two protocols to differentiate human pluripotent stem cells (hPSCs) into human gastric organoids (hGOs) that recapitulate both domains. Both protocols begin with the differentiation of hPSCs into definitive endoderm (DE) using activin A, followed by the generation of free-floating 3D posterior foregut spheroids using FGF4, Wnt pathway agonist CHIR99021 (CHIR), BMP pathway antagonist Noggin, and retinoic acid. Embedding spheroids in Matrigel and continuing 3D growth in epidermal growth factor (EGF)-containing medium for 4 weeks results in antral hGOs (hAGOs). To obtain fundic hGOs (hFGOs), spheroids are additionally treated with CHIR and FGF10. Induced differentiation of acid secreting parietal cells in hFGOs requires temporal treatment of BMP4 and the MEK inhibitor PD0325901 for 48 h on protocol day 30. In total, it takes ~34 d to generate hGOs from hPSCs. To date, this is the only approach that generates functional human differentiated gastric cells de novo from hPSCs. PMID- 30470821 TI - L-Proline functionalized magnetic nanoparticles: A novel magnetically reusable nanocatalyst for one-pot synthesis of 2,4,6-triarylpyridines. AB - In this work, an efficient method for the immobilization of L-proline on magnetic nanoparticles was offered and evaluated as a recoverable magnetic nanocatalyst for synthesis of 2,4,6-triarylpyridines through one-pot three-component reaction of acetophenone, aryl aldehydes and ammonium acetate. This article is the first report of the catalytic application of L-proline functionalized magnetic nanoparticles in organic reactions as a magnetic nanocatalyst. This novel magnetic nanocatalyst proved to be effective and provided the products in high to excellent yield under solvent-free conditions. The structure of obtained nanoparticles was characterized by Fourier transform infrared spectrophotometry (FT-IR), field-emission scanning electron microscopy (FE-SEM), thermogravimetric analysis (TGA) and energy-dispersive X-ray spectroscopy (EDX). TGA result revealed that it is stable up to 200 degrees C for using as a catalyst in organic reactions. FE-SEM image of the synthesized nanocatalyst showed that it has nearly core-shell spherical shape and uniform size distribution with an average size about 80 nm. Moreover, the catalyst could be easily recovered by facile separation by magnetic forces and recycled for several times without significant loss of its catalytic activity. The benefits of this study are simplicity, nontoxicity, low cost, simple workup, and an environmentally benign nature. PMID- 30470822 TI - Large observational bias on discharge in the Indus River since 1970s. AB - The discharge of one of the world's largest river - Indus River was reported to be increasing that was not supported by the Karakoram (KK) glacier expansion. A major hydrometric bias was ignored, which seemed similar to the montage that the Himalayan glaciers would disappear. This study proposed a framework for quantifying the bias resulting from inaccurate data affecting hydrologic studies on the Indus. We constructed a statistical model by converting the rating curves of rivers into air temperature (T) - discharge (Q) curves from an adjacent catchment in China where flow measurement was carried out using a standard method. We found that most flow data for the Indus were much greater than the error limits of T-Q curves estimated by daily data, a greater bias occurred in recent decades when discharge increased, the higher the flow was, the larger the bias was. The estimated mean annual and maximum monthly bias was 22.5% and 210%, respectively. These biases indicated that discharge increase in the Indus probably resulted from the large errors of hydrometrics without a scientific basis. We suggested a montage bias was needed in the hydrologic science of KK's rivers that may strongly affect water resource management. PMID- 30470823 TI - Indian Hedgehog links obesity to development of hepatocellular carcinoma. AB - Obesity increases the risk of hepatocellular carcinoma (HCC), but precise identification and characterization of druggable oncogenic pathways that contribute to the progression of NAFLD to HCC, and hence to the increased incidence and aggressiveness of HCC in obese individuals is lacking. In this regard, we demonstrate that the Indian Hedgehog (Ihh) signaling pathway is upregulated in the fatty livers of mice consuming a high fat diet, and furthermore sustained in HCC tumors specifically within the context of a NAFLD microenvironment. Using a diet-induced mouse model of HCC wherein only obese mice develop HCC, targeted ablation of hepatocyte-secreted Ihh results in a decreased tumor burden and lower grade tumors. Ihh activation regulates the transdifferentiation of ciliated stellate cells and proliferation of Epcam+ ductal cells to promote fibrosis. Mechanistically, increased expression of hitherto uncharacterized effectors of Hh pathway, namely Myc and Tgf-beta2 is critical to the observed physiology. This pro-tumorigenic response is driven by increased expression of Wnt5a to effect a poorly-differentiated and invasive tumor phenotype. Wnt5a secreted from activated stellate cells act on Ror2 expressing hepatocytes. We further demonstrate that Wnt5a expression is also elevated in poorly-differentiated HCC cells, suggesting that these ligands are also able to function in an autocrine positive feedback manner to sustain poorly differentiated tumors. Taken together, our study provides a mechanistic understanding for how Ihh signaling promotes HCC tumorigenesis specifically in obese mice. We propose that therapeutic targeting of the Hh pathway offers benefit for patients with dietary / NAFLD-driven steatotic HCC. PMID- 30470824 TI - The risk variant rs884225 within EGFR impairs miR-103a-3p's anti-tumourigenic function in non-small cell lung cancer. AB - Epidermal growth factor receptor (EGFR) status is the major determinant of non small cell lung cancer (NSCLC) therapy selection. Studies have hinted that EGFR antibodies or tyrosine kinase inhibitors were beneficial in patients with EGFR mutation-negative but EGFR-overexpressing of NSCLC. However, the mechanisms underlying EGFR amplification and overexpression in NSCLC remain largely unknown. Here, we report that rs884225, a single nucleotide polymorphism in the EGFR 3' terminal untranslated region, was significantly associated with EGFR expression level and contributed to NSCLC susceptibility. Mechanistically, the rs884225 C allele enhanced EGFR expression by altering the miR-103a-3p binding site, thus impairing miR-103a-3p's anti-tumourigenic function. As a tumour suppressor gene, miR-103a-3p expression correlated with overall and recurrence-free survival in NSCLC patients. Furthermore, miR-103a-3p inhibited growth and metastasis via effects on the KRAS pathway and epithelial-to-mesenchymal transition in EGFR wild type NSCLC cell lines, respectively, which substantially reduced EGFR expression and activity. Thus, rs884225 may be a biomarker for NSCLC susceptibility, and miR 103a-3p may be a potential therapeutic target in NSCLC. PMID- 30470826 TI - Understanding the intrinsic radioactivity energy spectrum from 176Lu in LYSO/LSO scintillation crystals. AB - Lutetium oxyorthosilicate (LSO) or lutetium yttrium oxyorthosilicate (LYSO) are the scintillator materials most widely used today in PET detectors due to their convenient physical properties for the detection of 511 keV annihilation photons. Natural lutetium contains 2.6% of 176Lu which decays beta to excited states of 176Hf producing a constant background signal. Although previous works have studied the background activity from LSO/LYSO, the shape of the spectrum, resulting from beta-particle and gamma radiation self-detection, has not been fully explained. The present work examines the contribution of the different beta particle and gamma-ray interactions to provide a fuller comprehension of this background spectrum and to explain the differences observed when using crystals of different sizes. To this purpose we have shifted the continuous beta-particle energy spectrum of 176Lu from zero to the corresponding energy value for all combinations of the isomeric transitions of 176Hf (gamma-rays/internal conversion). The area of each shifted beta-spectrum was normalized to reflect the probability of occurrence. To account for the probability of the gamma-rays escaping from the crystal, Monte Carlo simulations using PENELOPE were performed in which point-like sources of monoenergetic photons were generated, inside LYSO square base prisms (all 1 cm thick) of different sizes: 1.0 cm to 5.74 cm. The analytic distributions were convolved using a varying Gaussian function to account for the measured energy resolution. The calculated spectra were compared to those obtained experimentally using monolithic crystals of the same dimensions coupled to SiPM arrays. Our results are in very good agreement with the experiment, and even explain the differences observed due to crystal size. This work may prove useful to calibrate and assess detector performance, and to measure energy resolution at different energy values. PMID- 30470825 TI - Synthesis of polyvinyl alcohol (PVA) infiltrated MWCNTs buckypaper for strain sensing application. AB - Buckypaper (BP)/polymer composites are viewed as a viable option to improve the strain transfer across the buckypaper strain sensor by means of providing better interfacial bonding between the polymer and carbon nanotubes (CNTs). Multiwall carbon nanotubes (MWCNTs) BP/polyvinyl alcohol (PVA) composites were fabricated by a sequence of vacuum filtration and polymer intercalation technique. The optimized conditions for achieving a uniform and stable dispersion of MWCNTs were found to be using ethanol as a dispersion medium, 54 MUm ultrasonic amplitude and 40 min sonication time. FTIR analysis and SEM spectra further confirmed the introduction of oxygenated groups (-COOH) on the surface of MWCNTs BP and the complete infiltration of PVA into the porous MWCNTs network. At MWCNTs content of 65 wt. %, the tensile strength, Young's modulus and elongation-at-break of PVA infiltrated MWCNTs BP achieved a maximum value of 156.28 MPa, 4.02 GPa and 5.85%, improved by 189%, 443% and 166% respectively, as compared to the MWCNTs BP. Electrical characterization performed using both two-point probe method and Hall effect measurement showed that BP/PVA composites exhibited reduced electrical conductivity. From the electromechanical characterization, the BP/PVA composites showed improved sensitivity with a gauge factor of about 1.89-2.92. The cyclic uniaxial tensile test validated the high reproducibility and hysteresis-free operation of 65-BP/PVA composite under 3 loading-unloading cycles. Characterization results confirmed that the flexible BP/PVA composite (65 wt. %) with improved mechanical and electromechanical properties is suitable for strain sensing applications in structural health monitoring and wearable technology, as an alternative choice to the fragile nature of conventional metallic strain sensors. PMID- 30470827 TI - Optical Characteristics of ZnS Passivated CdSe/CdS Quantum Dots for High Photostability and Lasing. AB - Nanocrystal quantum dots (QDs) have great potential for optoelectronic applications such as light emitting diodes and lasers due to their superior optical properties. The core-shell CdSe/CdS QDs can suppress Auger recombination effectively and enhance the emission efficiency. However, it will lead to poor photostability due to the small conduction band offset between CdSe core and CdS shell. For effective electron confinement, a thin shell of wide band gap ZnS semiconductor was grown on the CdSe/CdS core-shell QDs. The influence of ZnS shell has been investigated by comprehensive spectroscopic characterization. It is demonstrated that the CdSe/CdS/ZnS QDs show high photostable and temperature insensitive emission. Moreover, room temperature lasing based on CdSe/CdS/ZnS QDs coated on a fiber was achieved. The lasing action can maintain under higher temperature up to 312.6 K. The experimental result is important for high performance optoelectronic device application based on colloidal QDs. PMID- 30470830 TI - Scaling-up phase selection. PMID- 30470829 TI - Cooperation among cancer cells: applying game theory to cancer. AB - Cell cooperation promotes many of the hallmarks of cancer via the secretion of diffusible factors that can affect cancer cells or stromal cells in the tumour microenvironment. This cooperation cannot be explained simply as the collective action of cells for the benefit of the tumour because non-cooperative subclones can constantly invade and free-ride on the diffusible factors produced by the cooperative cells. A full understanding of cooperation among the cells of a tumour requires methods and concepts from evolutionary game theory, which has been used successfully in other areas of biology to understand similar problems but has been underutilized in cancer research. Game theory can provide insights into the stability of cooperation among cells in a tumour and into the design of potentially evolution-proof therapies that disrupt this cooperation. PMID- 30470828 TI - CKD-506, a novel HDAC6-selective inhibitor, improves renal outcomes and survival in a mouse model of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic multisystemic autoimmune disease with an unknown etiology. Recently, it has been elucidated that dysregulated histone deacetylase (HDAC) activity is related to the pathogenesis of inflammatory and autoimmune diseases. Broad-spectrum HDAC inhibitors are effective for the treatment of allergy, cancer, and autoimmune diseases, but they have several adverse side effects. Thus, the purpose of this study was to evaluate the effects of a novel HDAC 6-specific inhibitor, CKD-506, in a murine SLE model. CKD-506 significantly improved survival rate and significantly decreased the incidence of severe proteinuria, blood urea nitrogen, kidney inflammation, and glomerular infiltration of IgG and C3. In addition, CKD 506 reduced the proportions of CD138+ plasma cells, CD4-CD8- T cells, and CD25+ cells and the Th1/Th2 ratio in the spleen. CKD-506 significantly reduced inflammatory cytokines such as IL-10, IL-15, IL-17, TNF-alpha, and IFN-inducible protein (IP 10) and significantly increased TGF-beta in serum. CKD-506 also significantly reduced IFN-gamma, IL-1beta, IL-4, IL-6, IP-10, MCP-1, and CCL4 levels in kidney. CKD-506 decreased the production of various pro-inflammatory cytokines and chemokines in the serum and kidneys, resulting in inhibition of cell migration and suppression of lupus nephritis without adverse effects. PMID- 30470831 TI - Control by cell size. PMID- 30470832 TI - Learning from the big picture. PMID- 30470833 TI - The materials science imperative in meeting the Sustainable Development Goals. PMID- 30470834 TI - Unrealistic techno-optimism is holding back progress on resource efficiency. PMID- 30470835 TI - Be part of the chain. PMID- 30470836 TI - Combination treatment of acute myeloid leukemia cells with DNMT and HDAC inhibitors: predominant synergistic gene downregulation associated with gene body demethylation. AB - DNA methyltransferase inhibitors (DNMTi) approved for older AML patients are clinically tested in combination with histone deacetylase inhibitors (HDACi). The mechanism of action of these drugs is still under debate. In colon cancer cells, 5-aza-2'-deoxycytidine (DAC) can downregulate oncogenes and metabolic genes by reversing gene body DNA methylation, thus implicating gene body methylation as a novel drug target. We asked whether DAC-induced gene body demethylation in AML cells is also associated with gene repression, and whether the latter is enhanced by HDACi.Transcriptome analyses revealed that a combined treatment with DAC and the HDACi panobinostat or valproic acid affected significantly more transcripts than the sum of the genes regulated by either treatment alone, demonstrating a quantitative synergistic effect on genome-wide expression in U937 cells. This effect was particularly striking for downregulated genes. Integrative methylome and transcriptome analyses showed that a massive downregulation of genes, including oncogenes (e.g., MYC) and epigenetic modifiers (e.g., KDM2B, SUV39H1) often overexpressed in cancer, was associated predominantly with gene body DNA demethylation and changes in acH3K9/27. These findings have implications for the mechanism of action of combined epigenetic treatments, and for a better understanding of responses in trials where this approach is clinically tested. PMID- 30470837 TI - MMSET I acts as an oncoprotein and regulates GLO1 expression in t(4;14) multiple myeloma cells. AB - Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. T(4;14) MM overexpresses multiple myeloma SET domain-containing protein (MMSET). MMSET has three major isoforms: the full-length form MMSET II and the short isoforms REIIBP and MMSET I. Here we show that the short isoform MMSET I is an oncoprotein that promoted cell survival and tumorigenesis in vitro and in vivo. Gene expression array analysis indicated that MMSET I increased glyoxalase I (GLO1) expression. Chromatin immunoprecipitation (ChIP) coupled with qPCR indicated that MMSET I bound upstream of the GLO1 transcription start site. Ectopic overexpression of MMSET I or its mutants showed MMSET I depended on its C terminus to regulate GLO1 expression. GLO1 knockdown (KD) induced apoptosis and reduced colony formation. MMSET I or GLO1 KD reduced the levels of anti-apoptosis factors such as MCL1 and BCL2. Ectopic overexpression of GLO1 resulted in the significant rescue of KMS11 cells from MMSET I KD-induced apoptosis and glycolysis inhibition. This suggested that GLO1 may be of functional importance target downstream of MMSET I. Cumulatively, our study suggests that MMSET I is an oncoprotein and potential therapeutic target for t(4;14) MM. PMID- 30470838 TI - JAK2V617F but not CALR mutations confer increased molecular responses to interferon-alpha via JAK1/STAT1 activation. AB - Pegylated interferon-alpha (peg-IFNa) treatment induces molecular responses (MR) in patients with myeloproliferative neoplasms (MPNs), including partial MR (PMR) in 30-40% of patients. Here, we compared the efficacy of IFNa treatment in JAK2V617F- vs. calreticulin (CALR)-mutated cells and investigated the mechanisms of differential response. Retrospective analysis of MPN patients treated with peg IFNa demonstrated that patients harboring the JAK2V617F mutation were more likely to achieve PMR than those with mutated CALR (p = 0.004), while there was no significant difference in hematological response. In vitro experiments confirmed an upregulation of IFN-stimulated genes in JAK2V617F-positive 32D cells as well as patient samples (peripheral blood mononuclear cells and CD34+ hematopoietic stem cells) compared to their CALR-mutated counterparts, and higher IFNa doses were needed to achieve the same IFNa response in CALR- as in JAK2V617F-mutant 32D cells. Additionally, Janus-activated kinase-1 (JAK1) and signal transducers and activators of transcription 1 (STAT1) showed constitutive phosphorylation in JAK2V617F-mutated but not CALR-mutated cells, indicating priming towards an IFNa response. Moreover, IFN-induced growth arrest was counteracted by selective JAK1 inhibition but enhanced by JAK2 inhibition. In conclusion, our data suggest that, clinically, higher doses of IFNa are needed in CALR-mutated vs. JAK2V617F positive patients and we suggest a model of JAK2V617F-JAK1/STAT1 crosstalk leading to a priming of JAK2V617F-positive cells to IFNa resulting in differential sensitivity. PMID- 30470839 TI - Predator odor increases avoidance and glutamatergic synaptic transmission in the prelimbic cortex via corticotropin-releasing factor receptor 1 signaling. AB - Acute exposure to a salient stressor, such as in post-traumatic stress disorder, can have lasting impacts upon an individual and society. To study stress in rodents, some naturalistic methods have included acute exposure to a predator odor, such as the synthetic fox odor 2,4,5, trimethyl-3-thiazoline (TMT). These experiments explore the stress-related behaviors and cortical activity induced by TMT exposure in adult male C57BL/6J mice and the influence of the stress neuropeptide corticotropin-releasing factor (CRF) on these responses. Compared to H2O and a novel odorant, vanilla, mice exposed to TMT in the home cage showed increased avoidance and defensive burying indicative of evident stress responses. Consistent with stress-induced activation of the medial prefrontal cortex (mPFC), we found that the prelimbic (PL) and infralimbic (IL) subregions of the mPFC had elevated c-Fos immunolabeling after TMT and vanilla compared to H2O. Slice physiology recordings were performed in layers 2/3 and 5 of the PL and IL, following TMT, vanilla, or H2O exposure. In TMT mice, but not vanilla or H2O mice, PL layers 2/3 showed heightened spontaneous excitatory post-synaptic currents and synaptic drive, suggesting TMT enhanced excitatory transmission. Synaptic drive in PL was increased in both TMT and H2O mice following bath application of 300 nM CRF, but only H2O mice increased excitatory currents with 100 nM CRF, suggesting dose-effect curve shifts in TMT mice. Further, systemic pretreatment with the CRF-R1 antagonist CP154526 and bath application with the CRF-R1 antagonist NBI27914 reduced excitatory transmission in TMT mice, but not H2O mice. CP154526 also reduced stress-reactive behaviors induced by TMT. Taken together, these findings suggest that exposure to TMT leads to CRF-R1 driven changes in behavior and changes in synaptic function in layer 2/3 neurons in the PL, which are consistent with previous findings that CRF-R1 in the mPFC plays an important role in predator odor-related behaviors. PMID- 30470840 TI - Measuring novel antecedents of mental illness: the Questionnaire of Unpredictability in Childhood. AB - Increasing evidence indicates that, in addition to poverty, maternal depression, and other well-established factors, unpredictability of maternal and environmental signals early in life influences trajectories of brain development, determining risk for subsequent mental illness. However, whereas most risk factors for later vulnerability to mental illness are readily measured using existing, clinically available tools, there are no similar measures for assessing early-life unpredictability. Here we validate the Questionnaire of Unpredictability in Childhood (QUIC) and examine its associations with mental health in the context of other indicators of childhood adversity (e.g., traumatic life events, socioeconomic status, and parenting quality). The QUIC was initially validated through administration to a cohort of adult females (N = 116) and then further refined in two additional independent cohorts (male Veterans, N = 95, and male and female adolescents, N = 175). The QUIC demonstrated excellent internal (alpha = 0.89) and test-retest reliability (r = 92). Scores on the QUIC were positively correlated with other prospective indicators of exposures to unpredictable maternal inputs in infancy and childhood (unpredictable maternal mood and sensory signals), and accuracy of recall also was confirmed with prospective data. Importantly, the QUIC predicted symptoms of anxiety, depression, and anhedonia in the three study cohorts, and these effects persisted after adjusting for other previously established risk factors. The QUIC, a reliable and valid self-report assessment of exposure to unpredictability in the social, emotional, and physical domains during early life, is a brief, comprehensive, and promising instrument for predicting risk for mental illness. PMID- 30470842 TI - Downregulation of miR-152 contributes to DNMT1-mediated silencing of SOCS3/SHP-1 in non-Hodgkin lymphoma. AB - Understanding the molecular mechanisms for the development of non-Hodgkin lymphoma (NHL) will improve our ability to cure the patients. qRT-PCR was applied for the examination of the efficiency of shRNA for DNMT1, the expression of suppressor genes, miRNA-152. The MTT analysis, cell cycle analysis, clonal formation, and apoptotic analysis were used to examine the functions of DNMT1 and miR-152 in lymphoma cells. Methylation-specific polymerase chain reaction (MSP) was used to examine the methylation of tumor suppressor genes. The dual luciferase assay and western blot were used to validate if DNMT1 is the target of miR-152. For the in vivo experiments, the lymphoma cells were injected into the nude mice for quantification of the tumor growth after transfection of miR-152 mimics. Knockdown of DNMT1 by shRNA (sh-DNMT1) in OCI-Ly10 and Granta-159 cells significantly upregulated the expression of tumor suppressor genes (SOCS3, BCL2L10, p16, p14, and SHP-1) via decreasing their methylation level. At the cellular level, we found sh-DNMT1 inhibited the proliferation, clonal formation and cell cycle progression and induced the cell apoptosis of lymphoma cells. Furthermore, we found miR-152 can downregulates the expression of DNMT1 via directly targeting the gene. Overexpression of miR-152 also increased the expression of tumor suppressor genes SOCS3 and SHP-1. And miR-152 also can inhibit the cell proliferation and induce the cell apoptosis. Moreover, we found overexpression of miR-152 significantly repressed the tumor growth with decreased DNMT1 expression and increased expression of tumor suppressor genes in vivo. Our study demonstrates that miR-152 can inhibit lymphoma growth via suppressing DNMT1 mediated silencing of SOCS3 and SHP-1. These data demonstrate a new mechanism for the development of NHL and this may provide a new therapeutic target for NHL. PMID- 30470841 TI - Concurrent live imaging of DNA double-strand break repair and cell-cycle progression by CRISPR/Cas9-mediated knock-in of a tricistronic vector. AB - Cell-cycle progression can be arrested by ionizing radiation-induced DNA double strand breaks (DSBs). Although DSBs are patched by DSB repair systems, which comprise proteins such as p53-binding protein 1 (53BP1), the relationship between DSB repair progression and cell-cycle status in living cells is unclear. The probe FUCCI (fluorescent ubiquitination-based cell-cycle indicator) was previously developed for visualizing cell-cycle status. Here, we established novel live-imaging probes based on custom-designed plasmids designated "Focicles" harboring a tricistronic compartment encoding distinct fluorescent proteins ligated to the murine 53BP1 foci-forming region (FFR) and two cell-cycle indicators that are known components of FUCCI (hCdt1 and hGmnn). We used CRISPR/Cas9-mediated genome editing to obtain Focicle knock-in cell lines in NIH3T3 cells, which were subject to X-ray irradiation that induced comparable numbers of Focicle and endogenous-53BP1 foci. In addition, the Focicle probes enabled the kinetic analysis of both DSB repair and cell-cycle arrest/progression after irradiation, demonstrating that the Focicle knock-in cells progressed to cell division after DNA damage elimination. These newly developed probes can help to gain a better understanding of the dynamics of DSB repair and cell-cycle control to in turn guide cancer treatment development and cancer-risk assessments. PMID- 30470843 TI - Uptake of microplastics and related health effects: a critical discussion of Deng et al., Scientific reports 7:46687, 2017. PMID- 30470844 TI - Small-scale Variation of Testate Amoeba Assemblages: the Effect of Site Heterogeneity and Empty Shell Inclusion. AB - Studies on testate amoeba species distribution at small scales (i.e., single peatland sites) are rare and mostly focus on bogs or mineral-poor Sphagnum fens, leaving spatial patterns within mineral-rich fens completely unexplored. In this study, two mineral-rich fen sites of contrasting groundwater chemistry and moss layer composition were selected for the analysis of testate amoeba compositional variance within a single site. At each study site, samples from 20 randomly chosen moss-dominated plots were collected with several environmental variables being measured at each sampling spot. We also distinguished between empty shells and living individuals to evaluate the effect of empty shell inclusion on recorded species distribution. At the heterogeneous-rich Sphagnum-fen, a clear composition turnover in testate amoebae between Sphagnum-dominated and brown moss dominated samples was closely related to water pH, temperature and redox potential. We also found notable species composition variance within the homogeneous calcareous fen, yet it was not as high as for the former site and the likely drivers of community assembly remained unidentified. The exclusion of empty shells provided more accurate data on species distribution as well as their relationship with some environmental variables, particularly moisture. Small scale variability in species composition of communities seems to be a worthwhile aspect in testate amoeba research and should be considered in future sampling strategies along with a possible empty shell bias for more precise understanding of testate amoeba ecology and paleoecology. PMID- 30470845 TI - A fatal case of Fournier's gangrene during neoadjuvant radiotherapy for rectal cancer. AB - PURPOSE: To report the development of an ultimately fatal occurrence of Fournier's gangrene in a rectal cancer patient undergoing neoadjuvant radiotherapy without chemotherapy. METHODS: A 53-year-old male patient with G2 cT3 cN1a cM0 stage IIIB adenocarcinoma of the lower rectum and several comorbidities including ulcerative colitis was treated with 56 Gy to the primary tumor in 28 fractions because he declined the recommended simultaneous chemotherapy. He was also enrolled in the ketogenic diet arm of our KETOCOMP study, so that prospective measurements of blood parameters, quality of life, and body composition were made. RESULTS: The patient died 6 days after completion of radiotherapy due to septic shock associated with Fournier's gangrene reaching from the right buttock into the gluteal muscles and descending into the scrotum. In retrospect, there were several signs probably indicating the development of the gangrene: (i) a decline in bioelectrical phase angle; (ii) an accelerated weight and fat-free mass loss starting in the third week of radiotherapy; (iii) an increase in C-reactive protein (CRP) and concurrent drop in high-density lipoprotein (HDL) cholesterol and insulin-like growth factor(IGF)-1 concentrations; and (iv) the occurrence of a sharp pain in the perianal region reported in the fifth week of radiotherapy. Notably, his self-reported quality of life score was the same at the end of as before radiotherapy. CONCLUSIONS: This case highlights the occurrence of Fournier's gangrene as an extremely rare but life-threatening complication during neoadjuvant radiotherapy for rectal cancer which should be refreshed in the awareness of radiation oncologists and radiologists. PMID- 30470846 TI - Biliary duct stenosis after image-guided high-dose-rate interstitial brachytherapy of central and hilar liver tumors : A systematic analysis of 102 cases. AB - OBJECTIVE: Image-guided high-dose-rate interstitial brachytherapy (iBT) with iridium-192 is an effective treatment option for patients with liver malignancies. Little is known about long-term radiation effects on the bile duct system when central hepatic structures are exposed to iBT. This retrospective analysis investigates the occurrence of posthepatic cholestasis (PHC) and associated complications in patients undergoing iBT. MATERIALS AND METHODS: We identified patients who underwent iBT of hepatic malignancies and had point doses of >=1 Gy to central bile duct structures. Patients with known bile duct-related diseases or prior bile duct manipulation were excluded. RESULTS: 102 patients were retrospectively included. Twenty-two patients (22%) developed morphologic PHC after a median of 17 (3-54) months; 18 of them were treated using percutaneous transhepatic cholangiopancreatography drainage or endoscopic retrograde cholangiopancreatography. The median point dose was 24.8 (4.4-80) Gy in patients with PHC versus 14.2 (1.8-61.7) Gy in those without PHC (p = 0.028). A dose of 20.8 Gy (biological effective dose, BED3/10 = 165/64.1 Gy) was identified to be the optimal cutoff dose (p = 0.028; 59% sensitivity, 24% specificity). Abscess/cholangitis was more common in patients with PHC compared to those without (4 of 22 vs. 2 of 80; p = 0.029). Median survival did not differ between patients with and without PHC (43 vs. 36 months; p = 0.571). CONCLUSION: iBT of liver malignancies located near the hilum can cause PHC when the central bile ducts are exposed to high point doses. Given the long latency and absence of impact of iBT-induced PHC on median survival, the rate of cholestasis and complications seen in our patients appears to be acceptable. PMID- 30470847 TI - Automated CT Perfusion Imaging Versus Non-contrast CT for Ischemic Core Assessment in Large Vessel Occlusion. AB - PURPOSE: There is increasing use of automated computed tomography perfusion (CTP) to aid thrombectomy decision in emergent large vessel occlusion. It is important to understand the performance of these software packages in predicting ischemic core and tissue-at-risk in the real-world setting. The aim of this study was to evaluate whether ischemic core on non-contrast CT (NCCT) and automated CTP correspond and predict infarct extent after thrombectomy for ischemic stroke. METHODS: Consecutive patients with acute anterior circulation large vessel occlusion undergoing successful thrombectomy (TICI 2b/3) were studied. All patients had baseline CT, CTP with RAPID post-processing software (RAPID-CTP), and post-thrombectomy 24 h CT. Ischemic cores were assessed by two blinded raters independently using the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) on each modality. The interrater agreement for ASPECTS, and correlation between baseline CT-ASPECTS, RAPID-CTP-ASPECTS, and 24h CT-ASPECTS were calculated. RESULTS: A total of 86 patients with a mean age of 70.3 years (SD 16.5) were studied. The median baseline CT-ASPECTS was 9.5 (interquartile range, IQR 8-10), median RAPID-CTP-ASPECTS was 9 (IQR 8-10), and mean RAPID-CTP-ischemic core volume was 14.4 ml (SD 27.9 ml). The mean mismatch volume (difference of Tmax > 6s and cerebral blood flow (CBF) < 30%) was 128.6 ml (SD 126.0 ml). There was substantial correlation between baseline and 24h CT-ASPECTS (rs: 0.62; p < 0.001), but poor correlation between RAPID-CTP-ASPECTS and RAPID-CTP ischemic core volume with 24h NCCT-ASPECTS (rs: 0.21; p = 0.06 and -0.16; p = 0.15 respectively). The positive predictive value of any established infarct for baseline CT-ASPECTS was 81%, while that of RAPID-CTP-ASPECTS was 64%. CONCLUSION: In this series of successfully revascularized patients, ischemic core as estimated by RAPID-CTP-ASPECTS did not correlate with the baseline CT and tended to depict a larger infarct core than the infarct extent as assessed by 24h CT ASPECTS. PMID- 30470848 TI - Imaging Spectrum of TIPIC Syndrome : Validation of a new Entity with Vessel Wall Imaging. AB - PURPOSE: Acute neck pain can have non-vascular and vascular causes. Some patients present with distinct vascular and perivascular changes on imaging at the site of tenderness. This study aimed to evaluate the imaging findings of transient perivascular inflammation of the carotid artery (TIPIC) syndrome with an emphasis on vessel wall imaging using 3-Tesla (3-T) high-resolution (HR) magnetic resonance imaging (MRI). METHODS: Clinical data along with diagnostic and follow up imaging of patients presenting to these hospitals with acute neck pain/tenderness and at least 1 imaging study using color Doppler ultrasound (CDU) and/or MRI including vessel wall imaging from September 2013 through September 2017 were retrospectively evaluated. A total of 15 patients with no other underlying cause of pain, findings meeting the imaging criteria for TIPIC syndrome and clinical recovery (spontaneous or with treatment) were included in the study. RESULTS: The mean patient age was 43.2 years. With CDU and precontrast MRI, perivascular inflammation (PVI) of the involved artery segment was evident in all patients. Contrast enhancement of the adventitia and PVI were noted on postcontrast HR vessel wall MRI in all patients. Of the patients five had co existing plaques at the site of tenderness. Follow-up imaging demonstrated pronounced regression or complete resolution of the findings. CONCLUSION: Imaging is useful for the establishment of TIPIC syndrome diagnosis and to rule out other conditions. The use of CDU is usually sufficient for diagnosis and follow-up but in clinically doubtful and complicated cases, vessel wall imaging with HR-MRI is very valuable. Thorough knowledge of this entity among radiologists enables a prompt diagnosis, which accelerates the clinical management. PMID- 30470849 TI - Correction to: Recognition of evolving medial patellofemoral anatomy provides insight for reconstruction. AB - Unfortunately, the middle name of author was incorrectly published as Jorge A. Chahla instead of Jorge Chahla in the original article. PMID- 30470850 TI - Reconstruction of chronic proximal hamstring avulsion injuries using ipsilateral distal hamstring tendons results in good clinical outcomes and patient satisfaction. AB - PURPOSE: To report outcomes following proximal hamstring reconstruction employing an ipsilateral distal hamstring tendon autograft, in patients with chronic proximal ruptures. METHODS: Six patients presenting with a chronic proximal hamstring avulsion and a medial time from injury of 11.0 months (range 7-18), confirmed via magnetic resonance imaging, underwent proximal hamstring repair using a free graft harvested from the ipsilateral distal hamstrings. Patients were evaluated at 6, 12 and 24 months post-surgery, via the Perth Hamstring Assessment Tool, the Short Form Health Survey, the Lower Extremity Functional Scale, a Patient Satisfaction Questionnaire, the Active Knee Extension and 6 min walk tests, the single and triple hop tests for distance, and isokinetic knee extensor and flexor strength. Knee strength was assessed at 180 degrees and 240 degrees /s (total work, peak and average torque), and both mean absolute scores and limb symmetry indices (LSIs) comparing the operated and non-operated limbs were presented. RESULTS: Patients demonstrated good clinical improvement throughout the post-operative timeline in all subjective and objective outcomes. Mean knee extensor LSIs had recovered by 12 and 24 months. At 24 months post surgery, while mean LSIs for knee flexor peak and average torque were at (or above) 90%, a significant difference still existed between the operated and non operated limbs in knee flexor total work. At 24 months, five patients (83%) were satisfied with the results of the surgery, as well as their ability to return to recreational and sporting activities. There were two adverse events including an early deep vein thrombosis and a secondary surgery to remove a loosened staple. CONCLUSIONS: While isokinetic hamstring strength had not fully recovered by 24 months, this surgical technique demonstrated a high level of patient satisfaction and return to function, in patients with chronic proximal hamstring ruptures. As the clinical relevance, this surgical technique provides a viable option with good post-operative outcomes for patients with chronic proximal hamstring tears that cannot be approximated back to the ischium. LEVEL OF EVIDENCE: IV. PMID- 30470851 TI - Underhang of the tibial component increases tibial bone resorption after total knee arthroplasty. AB - PURPOSE: One of the causes of aseptic loosening is marked tibial bone resorption (TR) at the tibial bone-component interface after total knee arthroplasty (TKA). It was hypothesized that insufficient coverage of the tibial component and improper cementing technique would cause increased TR after cemented TKA. METHODS: One hundred thirty-four primary TKAs in 107 patients with varus osteoarthritis were included in this study. The relationships between the TRs at 2 years after TKA and the tibial component underhang (TUH), the thickness of the cement mantle around the keel, and clinical parameters were evaluated. RESULTS: The widths of TRs on anteroposterior radiographs were significantly larger on the medial side than on the lateral side (p = 0.001), whereas the difference between the anterior and posterior sides on lateral radiographs was relatively small. Multiple regression analyses showed that medial TR was positively related to medial TUH (p = 0.006), and lateral TR was positively related to a thicker distal cement mantle (p = 0.027). On the lateral view, stepwise selection indicated that postoperative knee flexion angle was the most significant risk factor (p = 0.005) for anterior TR, and posterior TUH was the strongest predictor (p = 0.001) of posterior TR. CONCLUSIONS: To avert postoperative progressive TR, surgeons should perfectly fit a suitably sized tibial component to the medial edge of the tibia. Also, care should be taken to avoid an excessive cement mantle at the distal portion of the keel during TKA. LEVEL OF EVIDENCE: IV. PMID- 30470852 TI - Transcription factor Ptf1a in development, diseases and reprogramming. AB - The transcription factor Ptf1a is a crucial helix-loop-helix (bHLH) protein selectively expressed in the pancreas, retina, spinal cord, brain, and enteric nervous system. Ptf1a is preferably assembled into a transcription trimeric complex PTF1 with an E protein and Rbpj (or Rbpjl). In pancreatic development, Ptf1a is indispensable in controlling the expansion of multipotent progenitor cells as well as the specification and maintenance of the acinar cells. In neural tissues, Ptf1a is transiently expressed in the post-mitotic cells and specifies the inhibitory neuronal cell fates, mostly mediated by downstream genes such as Tfap2a/b and Prdm13. Mutations in the coding and non-coding regulatory sequences resulting in Ptf1a gain- or loss-of-function are associated with genetic diseases such as pancreatic and cerebellar agenesis in the rodent and human. Surprisingly, Ptf1a alone is sufficient to reprogram mouse or human fibroblasts into tripotential neural stem cells. Its pleiotropic functions in many biological processes remain to be deciphered in the future. PMID- 30470853 TI - Polymyxin B hemoperfusion in endotoxemic septic shock patients without extreme endotoxemia: a post hoc analysis of the EUPHRATES trial. AB - PURPOSE: The EUPHRATES trial examined the impact of polymyxin B hemoperfusion (PMX) on mortality in patients with septic shock and endotoxemia, defined as EAA >= 0.60. No difference was found in 28-day all-cause mortality. However, the trial showed that in some patients with septic shock the burden of endotoxin activity was extreme (EAA >= 0.9). In a post hoc analysis, we evaluated the impact of PMX use in patients with septic shock and endotoxin activity measured between 0.6-0.89. METHODS: Post-hoc analysis of the EUPHRATES trial for the 194 patients with EAA >= 0.6-0.89 who completed two treatments (PMX or sham). The primary end point was mortality at 28 days adjusted for APACHE II score and baseline mean arterial pressure (MAP). Additional end points included changes in MAP, cumulative vasopressor index (CVI), median EAA reduction, ventilator-free days (VFD), dialysis-free days (DFD) and hospital length of stay. Subpopulations analyzed were site and type of infection and those with norepinephrine dose > 0.1 mcg/kg/min at baseline. RESULTS: At 28 days, 23 patients of 88 (26.1%) in the PMX group died versus 39 of 106 (36.8%) in the sham group [risk difference 10.7%, OR 0.52, 95% CI (0.27, 0.99), P = 0.047]. When unadjusted for baseline variables, P = 0.11. The 28-day survival time in the PMX group was longer than for the sham group [HR 0.56 (95% CI 0.33, 0.95) P = 0.03]. PMX treatment compared with sham showed greater change in MAP [median (IQR) 8 mmHg (- 0.5, 19.5) vs. 4 mmHg (- 4.0, 11) P = 0.04] and VFD [median (IQR) 20 days (0.5, 23.5) vs. 6 days (0, 20), P = 0.004]. There were no significant differences in other end points. There was a significant difference in mortality in PMX-treated patients with no bacterial growth on culture [PMX, 6/30 (20%) vs. sham, 13/31 (41.9%), P = 0.005]. The median EAA change in the population was - 12.9% (range: increase 49.2%-reduction 86.3%). The mortality in the above median EAA change group was PMX: 6/38 (15.7%) vs. sham 15/49 (30.6%), P = 0.08. CONCLUSIONS: These hypothesis-generating results, based on an exploratory post hoc analysis of the EUPHRATES trial, suggest measurable responses in patients with septic shock and an EAA >= 0.6 to 0.89 on changes in mean arterial pressure, ventilator-free days and mortality. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01046669. Funding Spectral Medical Incorporated. PMID- 30470855 TI - A systematic review of non-invasive modalities used to identify women with anal incontinence symptoms after childbirth. AB - INTRODUCTION AND HYPOTHESIS: Anal incontinence following childbirth is prevalent and has a significant impact upon quality of life (QoL). Currently, there is no standard assessment for women after childbirth to identify these symptoms. This systematic review aimed to identify non-invasive modalities used to identify women with anal incontinence following childbirth and assess response and reporting rates of anal incontinence for these modalities. METHODS: Ovid Medline, Allied and Complementary Medicine Database (AMED), Cumulative Index of Nursing and Allied Health Literature (CINAHL), Cochrane Collaboration, EMBASE and Web of Science databases were searched for studies using non-invasive modalities published from January 1966 to May 2018 to identify women with anal incontinence following childbirth. Study data including type of modality, response rates and reported prevalence of anal incontinence were extracted and critically appraised. RESULTS: One hundred and nine studies were included from 1602 screened articles. Three types of non-invasive modalities were identified: validated questionnaires/symptom scales (n = 36 studies using 15 different instruments), non-validated questionnaires (n = 50 studies) and patient interviews (n = 23 studies). Mean response rates were 92% up to 6 weeks after childbirth. Non personalised assessment modalities (validated and non-validated questionnaires) were associated with reporting of higher rates of anal incontinence compared with patient interview at all periods of follow-up after childbirth, which was statistically significant between 6 weeks and 1 year after childbirth (p < 0.05). CONCLUSIONS: This systematic review confirms that questionnaires can be used effectively after childbirth to identify women with anal incontinence. Given the methodological limitations associated with non-validated questionnaires, assessing all women following childbirth for pelvic-floor symptomatology, including anal incontinence, using validated questionnaires should be considered. PMID- 30470856 TI - Promotion of microtubule acetylation plays an important role in degranulation of antigen-activated mast cells. AB - OBJECTIVE: The aim of this study was to investigate whether microtubule acetylation is triggered by antigen stimulation and how it affects mast cell degranulation. METHODS: The RBL-2H3 cell line was used as a model for mast cells. Acetylation of alpha-tubulin was analyzed by Western blotting. Intracellular distribution of alpha-tubulin and acetylated alpha-tubulin was observed by immunostaining. Degranulation was monitored by measuring the activity of beta hexosaminidase secreted into cell supernatants. Tukey-Kramer test was used to compare differences between groups. RESULTS: Microtubule acetylation proceeds globally in mast cell cytoplasm after antigen stimulation in addition to accelerated formation of microtubule-organizing centers. Pretreatment with 5Z-7 oxozeaenol (5 umol/l), an inhibitor of TGF-beta-activated kinase 1, which is a key activator of alpha-tubulin acetyltransferase 1, did not affect the distribution and acetylation of microtubules in resting cells; however, it significantly suppressed antigen-evoked microtubule acetylation and their reorganization, and subsequent degranulation (95.0 +/- 1.2% inhibition, n = 3, P < 0.01). CONCLUSIONS: These results provided new insight into the post translational modifications of microtubule to regulate mast cell degranulation. PMID- 30470857 TI - An association study in PTPN22 suggests that is a risk factor to Takayasu's arteritis. AB - OBJECTIVES: Takayasu's arteritis (TA) represents a rare autoimmune disease (AD) characterized by systemic vasculitis that primarily affects large arteries, especially the aorta and the aortic arch and its main branches. Genetic components in TA are largely unknown. PTPN22 is a susceptibility loci for different ADs; however, the role of different PTPN22 single-nucleotide polymorphisms (SNPs) in the susceptibility to TA is not clear. METHODS: We evaluated the PTPN22 R620W (C1858T), R263Q (G788A), and - 123G/C SNPs in a group of patients with TA and in healthy individuals from Mexico. Our study included 111 patients with TA and 314 healthy individuals. Genotyping was performed with the 5' exonuclease (TaqMan(r)) assay. RESULTS: Our data showed that the PTPN22 R620W polymorphism is a risk factor for TA (CC vs. CT: OR 4.3, p = 0.002, and C vs. T: OR 4.1, p = 0.003); however, the PTPN22 R263Q and - 1123G/C polymorphisms are not associated with this AD. In addition, the PTPN22 CGT haplotype, which carries the minor allele of the PTPN22 C1858T variant, was also associated with TA susceptibility. CONCLUSION: This is the first report documenting an association between PTPN22 R620W and TA. PMID- 30470858 TI - QTL mapping of insect resistance components of Solanum galapagense. AB - KEY MESSAGE: QTLs for insect resistance parameters, trichome type IV development, and more than 200 non-volatile metabolites, including 76 acyl sugars, all co locate at the end of Chromosome 2 of Solanum galapagense. Host plant resistance is gaining importance as more and more insecticides are being banned due to environmental concerns. In tomato, resistance towards insects is found in wild relatives and has been attributed to the presence of glandular trichomes and their specific phytochemical composition. In this paper, we describe the results from a large-scale QTL mapping of data from whitefly resistance tests, trichome phenotyping and a comprehensive metabolomics analysis in a recombinant inbred line population derived from a cross between the cultivated Solanum lycopersicum and the wild relative S. galapagense, which is resistant to a range of pest insects. One major QTL (Wf-1) was found to govern the resistance against two different whitefly species. This QTL co-localizes with QTLs for the presence of trichomes type IV and V, as well as all 76 acyl sugars detected and about 150 other non-volatile phytochemicals, including methyl esters of the flavonols myricetin and quercetin. Based on these results, we hypothesize that Wf-1 is regulating the formation of glandular trichome type IV on the leaf epidermis, enabling the production and accumulation of bioactive metabolites in this type of trichomes. PMID- 30470860 TI - Altered fecal microbiota composition in the Flinders sensitive line rat model of depression. AB - RATIONALE: The gut microbiota is increasingly recognized as a potential mediator of psychiatric diseases. Depressed patients have been shown to have a different microbiota composition compared with healthy controls, and several lines of research now aim to restore this dysbiosis. To develop novel treatments, preclinical models may provide novel mechanistic insights. OBJECTIVE AND METHODS: We characterized the gut microbiota of male adult Flinders sensitive line (FSL) rats, an animal model of depression, and their controls, Flinders resistant line (FRL) rats using 16S rRNA amplicon sequencing. Moreover, we performed fecal microbiota transplantation (using saline or pooled FRL/FSL feces) to study if the potential strain-specific differences could be transferred from one strain to the other, and if these differences were reflected in their depressive-like behavior in the forced swim test. RESULTS: FSL rats tended to have lower bacterial richness and altered relative abundances of several bacterial phyla, families, and species, including higher Proteobacteria and lower Elusimicrobia and Saccharibacteria. There was a clear separation between FRL and FSL rat strains, but no effect of treatment, i.e., the bacterial composition of FSL rats receiving FRL feces was still more similar to FSL and not FRL rats. Similarly, the transplantation did not reverse behavioral differences in the forced swim test, although FSL feces significantly increased immobility compared with saline. CONCLUSIONS: Our study showed that the gut microbiota composition of the depressive-like rats markedly differed from their controls, which may be of value for future microbiota-targeted work in this and similar animal models. PMID- 30470859 TI - Adult-onset hypothyroidism increases ethanol consumption. AB - RATIONALE: Only in Europe it can be estimated that more than 20 million of people would be affected by hypothyroidism in some moment of their life. Given that ethanol consumption is so frequent, it would be reasonable to ask what the consequences of ethanol consumption in those individuals affected by hypothyroidism are. OBJECTIVES: To study the interaction between hypothyroidism and ethanol consumption. METHODS: We study ethanol consumption in a rat model of methyl-mercaptoimidazole-induced-adult-onset hypothyroidism and thyroid T4/T3 hormone supplementation. Also, we studied the effects of ethanol on motor activity, memory, and anxiety. RESULTS: We found that hypothyroidism increased the voluntary ethanol consumption and that this was enhanced by thyroid hormone supplementation. Hypothyroidism was associated with motor hyperactivity which was prevented either by T4/T3 supplementation or ethanol. The relationship between hypothyroidism, ethanol, and anxiety was more complex. In an anxiogenic context, hypothyroidism and T4/T3 supplementation would increase immobility, an anxiety like behavior, while in a less anxiogenic context would decrease rearing, a behavior related to anxiety. Regarding memory, acute ethanol administration did not alter episodic-like memory in hypothyroid rats. Gene expression of enzymes involved in the metabolism of ethanol, i.e., Adh1 and Aldh2, were altered by hypothyroidism and T4/T3 supplementation. CONCLUSIONS: Our results suggest that hypothyroid patients would need personalized attention in terms of ethanol consumption. In addition, they point that it would be useful to embrace the thyroid axis in the study of ethanol addiction, including as a possible therapeutic target for the treatment of alcoholism and its comorbid disorders. PMID- 30470861 TI - Sound check, stage design and screen plot - how to increase the comparability of fear conditioning and fear extinction experiments. AB - In the recent decade, fear conditioning has evolved as a standard procedure for testing cognitive abilities such as memory acquisition, consolidation, recall, reconsolidation, and extinction, preferentially in genetically modified mice. The reasons for the popularity of this powerful approach are its ease to perform, the short duration of training and testing, and its well-described neural basis. So why to bother about flaws in standardization of test procedures and analytical routines? Simplicity does not preclude the existence of fallacies. A short survey of the literature revealed an indifferent use of acoustic stimuli in terms of quality (i.e., white noise vs. sine wave), duration, and intensity. The same applies to the shock procedures. In the present article, I will provide evidence for the importance of qualitative and quantitative parameters of conditioned and unconditioned stimuli for the experimental outcome. Moreover, I will challenge frequently applied interpretations of short-term vs. long-term extinction and spontaneous recovery. On the basis of these concerns, I suggest a guideline for standardization of fear conditioning experiments in mice to improve the comparability of the experimental data. PMID- 30470862 TI - Role of dopamine D2-like receptors and their modulation by adenosine receptor stimulation in the reinstatement of methamphetamine seeking. AB - RATIONALE AND OBJECTIVE: Previous work has demonstrated that dopamine and adenosine receptors are involved in drug-seeking behaviors, yet the pharmacological interactions between these receptors in methamphetamine (MA) seeking are not well characterized. The present studies examined the role of the dopamine D2-like receptors in MA seeking and identified the interactive effects of adenosine receptor stimulation. METHODS: Adult male Sprague-Dawley rats were trained to lever press for MA in daily 2-h self-administration sessions on a fixed-ratio 1 schedule for 10 consecutive days. After 1 day of abstinence, lever pressing was extinguished in six daily extinction sessions. Treatments were administered systemically prior to a 2-h reinstatement test session. RESULTS: An increase in MA seeking was observed following the administration of the dopamine D2-like agonist, quinpirole, or the D3 receptor agonist, 7-OH-DPAT. Stimulation of D2 or D4 receptors was ineffective at inducing MA seeking. Quinpirole-induced MA seeking was inhibited by D3 receptor antagonism (SB-77011A or PG01037), an adenosine A1 agonist, CPA, and an adenosine A2A agonist, CGS 21680. MA seeking induced by a MA priming injection or D3 receptor stimulation was inhibited by a pretreatment with the adenosine A1 agonist, CPA, but not the adenosine A2A agonist, CGS 21680. CONCLUSIONS: These results demonstrate the sufficiency of dopamine D3 receptors to reinstate MA seeking that is inhibited when combined with adenosine A1 receptor stimulation. PMID- 30470863 TI - Technical feasibility of semiautomatic three-dimensional threshold-based cardiac computed tomography quantification of left ventricular mass. AB - BACKGROUND: Semiautomatic three-dimensional (3-D) threshold-based cardiac computed tomography (CT) quantification has not been attempted for left ventricular mass. OBJECTIVE: To evaluate the technical feasibility of semiautomatic 3-D threshold-based cardiac CT quantification of left ventricular mass in patients with various degrees of left ventricular hypertrophy. MATERIALS AND METHODS: In 99 patients, cardiac CT was utilized to quantify ventricular volume and mass by using a semiautomatic 3-D threshold-based method. Left ventricular mass values were compared between the end-systole and the end diastole. Volumetric parameters were compared among three left ventricular hypertrophy groups (definite, borderline, none). The reproducibility was assessed. The t-test, one-way analysis of variance and Pearson correlation were used. RESULTS: There were no technical failures. The left ventricular mass between the two sessions exhibited a small mean difference of 2.3+/-1.1% (mean+/ standard deviation). The indexed mass values were significantly higher at the end systole than at the end-diastole (71.4+/-42.9 g/m2 vs. 65.9+/-43.3 g/m2, P<0.001), with significant correlation (R=0.99, P<0.001). The definite group (83.5+/-41.3 g/m2) showed statistically significantly higher indexed mass values than the borderline and none groups (64.7+/-26.9 and 55.6+/-23.9 g/m2, respectively; P<0.03), while demonstrating no statistically significant difference between the latter two groups (P>0.05). Left ventricular volume-mass and mass-volume ratios could be calculated in all three groups. CONCLUSION: CT quantification of left ventricular mass using semiautomatic 3-D threshold-based segmentation is feasible with high reproducibility and the mass values and its ratios with ventricular volumes may be used in patients with various degrees of left ventricular hypertrophy. PMID- 30470864 TI - Presence of Intra-helical Salt-Bridge in Loop E Half-Helix Can Influence the Transport Properties of AQP1 and GlpF Channels: Molecular Dynamics Simulations of In Silico Mutants. AB - Major intrinsic protein (MIP) superfamily contains water-transporting AQP1 and glycerol-specific GlpF belonging to two major phylogenetic groups, namely aquaporins (AQPs) and aquaglyceroporins (AQGPs). MIP channels have six transmembrane helices (TM1 to TM6) and two half-helices (LB and LE). LE region contributes two residues to the aromatic/arginine (Ar/R) selectivity filter (SF) within the MIP channel. Bioinformatics analyses have shown that all AQGPs have an intra-helical salt-bridge (IHSB) in LE half-helix and all AQGPs and majority of AQPs have helix destabilizing Gly and/or Pro in the same region. In this paper, we mutated in silico the acidic and basic residues in GlpF to Ser and introduced salt-bridge interaction in AQP1 LE half-helix by substituting Ser residues at the equivalent positions with acidic and basic residues. We investigated the influence of IHSB in LE half-helix on the transport properties of GlpF and AQP1 mutant channels using molecular dynamics simulations. With IHSB abolished in LE half-helix, the GlpF mutant exhibited a significantly reduced water transport. In contrast, the introduction of IHSB in the two AQP1 mutants has increased water transport. Absence of salt-bridge in LE half-helix alters the SF geometry and results in a higher energy barrier for the solutes in the Ar/R selectivity filter. Presence/absence of IHSB in LE half-helix influences the channel transport properties and it is evident especially for the AQGPs. By modulating its helical flexibility, LE half-helix can perhaps play a regulatory role in transport either on its own or in conjunction with other extracellular regions. PMID- 30470865 TI - Adjacent segment degeneration after fusion spinal surgery-a systematic review. AB - PURPOSE: Adjacent segment degeneration (ASDeg) and disease (ASDis) have become major concerns after fusion surgery. However, there is no definitive data or knowledge about the incidence or risk factors. The review discusses the incidence and risk factors and prevention of ASDeg and ASDis in the relevant literature. METHODS: We performed a systematic review of meta-analyses, randomized control trials, and cohort studies published in English to provide evidence-based information about ASDeg and ASDis. RESULTS: According to a meta-analysis, the pooled incidence of ASDeg after lumbar and cervical fusion surgery was 26.6% and 32.8%, respectively. Approximately 1/4-1/3 of ASDeg progressed to ASDis. Risk factors after cervical fusion surgery were young age, pre-existing disc degeneration, short fusion segment, high T1 slope, disruption of adjacent soft tissue, and plate placement close to the adjacent disc. The risk factors of ASDeg and ASDis after lumbar fusion surgery were age, genetic factors, high body mass index, pre-existing adjacent segment degeneration, laminectomy at the adjacent level of fusion, excessive distraction of the fusion level, insufficient lumbar lordosis, multilevel fixation, floating fusion, coronal wedging of L5-S disc, pelvic tilt, and osteoporosis. Motion-preserving surgeries seem to have less risk of ASDeg and ASDis than conventional fusion surgery both in the lumbar and cervical spine. CONCLUSIONS: The existent literature points out variables involved in ASDeg and ASDis. High evidence-level studies should provide more relevant data to guide strategies for avoiding ASDeg and ASDis. PMID- 30470866 TI - Effects of vitamin E incorporation in polyethylene on oxidative degradation, wear rates, immune response, and infections in total joint arthroplasty: a review of the current literature. AB - Highly cross-linked ultrahigh molecular weight polyethylene (UHMWPE) was introduced to decrease wear debris and osteolysis. During cross-linking, free radicals are formed, making highly cross-linked polyethylene vulnerable to oxidative degradation. In order to reduce this process, anti-oxidant vitamin E can be incorporated in polyethylene. This review provides an overview of the effects of vitamin E incorporation on major complications in total joint arthroplasty: material failure due to oxidative degradation, wear debris and subsequent periprosthetic osteolysis, and prosthetic joint infections. Secondly, this review summarizes the first clinical results of total hip and knee arthroplasties with vitamin E incorporated highly cross-linked polyethylene. Based on in vitro studies, incorporation of vitamin E in polyethylene provides good oxidative protection and preserves low wear rates. Incorporation of vitamin E may have the beneficial effect of reduced inflammatory response to its wear particles. Some microorganisms showed reduced adherence to vitamin E-incorporated UHMWPE; however, clinical relevance is doubtful. Short-term clinical studies of total hip and knee arthroplasties with vitamin E-incorporated highly cross-linked UHMWPE reported good clinical results and wear rates similar to highly cross linked UHMWPE without vitamin E. PMID- 30470867 TI - Living kidney donation from people at risk of nephrolithiasis, with a focus on the genetic forms. AB - Deciding whether to accept a donor with nephrolithiasis is a multifaceted task because of the challenge of finding enough suitable donors while at the same time ensuring the safety of both donors and recipients. Until not long ago, donors with a history of renal stones or with stones emerging during screening on imaging were not considered ideal, but recent guidelines have adopted less stringent criteria for potential donors at risk of stones. This review goes through the problems that need to be approached to arrive at a wise clinical decision, balancing the safety of donors and recipients with the need to expand the organ pool. The risk of declining renal function and worsening stone formation is examined. Documents (consensus statements, guidelines, etc.) on this issue released by the most important medical societies and organizations are discussed and compared. Specific problems of living kidney donation associated with certain systemic (chronic hypercalcemia due to CYP24A1 gene mutations, primary hyperoxaluria, APRT deficiency) and renal (medullary sponge kidney, cystinuria, distal renal tubular acidosis, Dent's disease, Bartter syndrome, familial hypomagnesemia with hypercalciuria and nephrocalcinosis) Mendelian disorders that cause nephrolithiasis are also addressed. PMID- 30470868 TI - The prevalence rate of periodontal pathogens and its association with oral squamous cell carcinoma. AB - Mounting evidence suggests a causal relationship between specific bacterial infections or microbial compositions and the development of certain malignant neoplasms. In this study, we performed research through 16S rRNA amplicon sequencing, qPCR and fluorescence in situ hybridization to certify the relationship between periodontal pathogens and oral squamous cell carcinoma (OSCC). Subgingival plaque, cancer and paracancerous tissues from 6 patients with OSCC were selected for mapping bacterial profiles by 16S rRNA amplicon sequencing. The research showed that periodontal pathogens were enriched in cancer and paracancerous tissues, while the bacterial profiles were similar between the cancer tissues and subgingival plaque. Furthermore, the relative abundance of Porphyromonas gingivalis, Fusobacterium nucleatum and Streptococcus sanguinis was detected in 61 cancer tissues, paracancerous tissues and subgingival plaque samples and in 30 normal tissues by qPCR. The results revealed that P. gingivalis and F. nucleatum existed at higher levels in cancer tissue than in normal tissues and were correlated with subgingival plaques. P. gingivalis was detected using a special oligonucleotide probe in 60.7% of OSCC tissues, 32.8% of paracancerous tissues and 13.3% of normal tissues. Relevance analysis showed that P. gingivalis infection was positively associated with late clinical staging, low differentiation and lymph node metastasis in patients with OSCC, which was accompanied by deeper periodontal pockets, severe clinical attachment loss and loss of teeth. This study revealed that there might be a close relationship between oral microorganisms, particularly periodontal pathogens, and OSCC, which might enrich the pathogenesis of oral squamous carcinoma. PMID- 30470869 TI - Recent achievements and perspectives for large-scale recombinant production of antimicrobial peptides. AB - Antibiotic resistance poses a growing threat to global public health. It is urgent to develop new alternative antibiotics. Antimicrobial peptide (AMP) is a diverse class of natural-occurring molecules that constitute immune systems of living organisms. More than 2500 AMPs have been identified and isolated from natural sources. Compared to conventional antibiotics, AMPs exhibit antimicrobial activities against a broad spectrum of microorganisms including bacteria, fungi, and even viruses. More importantly, the unique antimicrobial mechanisms of AMPs make it difficult for microorganisms to develop resistance. Therefore, it is very promising to develop AMPs as high-value antimicrobial candidates. This mini review provides an update of recent progresses in recombinant production of AMPs after fusion of AMP with carrier proteins and their scale-up. Key factors including selection of expression host and fusion tags are firstly introduced, followed by subsequent discussions on purification of fusion proteins and recovery of antimicrobial peptides. The scale production of AMPs is also explored. PMID- 30470870 TI - [Questionnaire for the assessment of the voice self-concept in a neurological practice : Applicability for the identification of patients with high consultation needs]. AB - INTRODUCTION: Hoarseness occurs as a symptom of a multitude of neurological diseases. The importance people attribute to their voice differs greatly and it seems advisable to take this into account during consultation. The Questionnaire for the assessment of the voice self-concept (FESS) is able to measure this importance. The aim of this study was to determine the applicability of the FESS in a neurological and psychiatric medical practice. MATERIAL AND METHODS: A total of 556 patients of a neurological and psychiatic medical practice completed the FESS and the severity of hoarseness was measured objectively by means of the Acoustic Voice Quality Index (AVQI). Another 75 patients only completed the questionnaire. The value distribution of the questionnaire, the correlation with age and gender, the voice quality as well as the daily strain on the voice were investigated. RESULTS: The value distribution ranges of all three scales of the FESS are completely utilized. Floor and ceiling effects do not play a relevant role. Gender and age do not seem to be of significance. The influence of the measurable voice quality is minor. In contrast a correlation between voice self concept and the daily voice strain was detected. DISCUSSION: The FESS has the potential to be an interesting instrument for the measurement of the subjective importance of a patient's voice. Here reference values are generated, against which individual results can be correlated. The AVQI provides an inexpensive fast instrument for the objective measurement of hoarseness in a neurological and psychiatric medical practice. PMID- 30470871 TI - [Urachal cancer - current concepts of a rare cancer (German version)]. AB - Urachal cancer is a rare but aggressive disease. In addition to the non-glandular tumors, non-cystic urachal adenocarcinomas are nowadays distinguished from the primary cystic variant. (Immunohistochemical) markers are only of minor differential diagnostic value and, therefore, the diagnosis is primarily established in a multidisciplinary approach. The non-cystic variant accounts for the majority of cases (83%), is more common in men (63%), shows a median age at diagnosis of 51 years and has a 5-year survival rate of about 50%. In organ confined disease, usually a partial cystectomy of the tumor in the bladder dome, including the median umbilical ligament and umbilicus, is performed. In advanced stages, systemic therapy is needed while 5-fuorouracil (5-FU) containing regimes have been shown to be more effective. Due to the rarity of the tumor, targeted therapy approaches based on a biological rationale are becoming increasingly relevant. As molecular data are still sparse, we compiled and analyzed the largest urachal cancer cohort to date. In 31% of the cases, MAPK-/PI3K signaling pathway alterations were detected (especially in K-/NRAS) with implications for anti-EGFR therapy approaches. Further potentially therapeutic alterations were detected in FGFR1, MET, PDGFRA, and erbB2/HER2. Additionally, PD-L1 tumor cell expression (clone: 22C3) was demonstrated in 16% of cases, therefore making anti PD-1/PD-L1 immuno-oncological approaches worth considering despite the absence of mismatch repair deficiency (MMR-d) and/or high microsatellite instability (MSI h). Finally, urachal adenocarcinomas seem to be a distinct entity on the molecular level with closer resemblance to colorectal adenocarcinomas than to urothelial carcinomas. PMID- 30470872 TI - The effect of diet on BPH, LUTS and ED. AB - OBJECTIVE: Benign prostatic hyperplasia (BPH) and erectile dysfunction (ED) are common conditions that increase in the aging population. Several environmental factors have been linked to the development and progression of BPH and ED. Several studies have shown potential direct and indirect influences of several micronutrients and macronutrients on the risk of developing these conditions. We reviewed the available published literature of the effect of diet on BPH and ED. METHODS: A comprehensive search was performed to identify studies that evaluated how diet affected males with BPH and ED. Searches were run on July 5th, 2018 in the following databases: Ovid MEDLINE(r); Ovid EMBASE; and The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL). There were no language restrictions, publication date restrictions, or article type restrictions on the search strategy. RESULTS: We retrieved a total of 1670 results across all databases. After removing any duplicated results, 2 independent reviewers screened a total of 1325 citations. A total of 35 articles were selected for inclusion in this review. Diet is an important factor affecting the risk of development of BPH and ED. Several studies have shown the effect of dietary interventions for BPH and ED. DISCUSSION: A better understanding diet and its relative effects on the development, treatment and prevention of these diseases are an important area of further research for the given aging male population. PMID- 30470873 TI - Does an increase in energy return and/or longitudinal bending stiffness shoe features reduce the energetic cost of running? AB - PURPOSE: This study focused on the effects of shoe energy return and shoe longitudinal bending stiffness on the energetic cost and biomechanics of running. METHODS: The energetic cost of running and biomechanical variables altering running economy (ground contact times, stride frequency, vertical and leg stiffness, ground reaction force impulses, alignment between the resultant ground reaction force and the leg) were measured for nineteen male recreational runners. Participants ran overground under their ventilatory anaerobic threshold (10.8 +/- 1.1 km h-1 on average) using four shoe prototypes with features combining low or high magnitudes of energy return and longitudinal bending stiffness. RESULTS: Neither the energy return, nor the longitudinal bending stiffness, or the interaction of these shoe features altered the energetic cost of running. High energy return shoes induced significant increased ground contact time from 274.5 +/- 18.3 to 277.1 +/- 18.7 ms, and significant decreased stride frequency from 1.34 +/- 0.05 to 1.33 +/- 0.05 Hz. High bending stiffness shoes induced significant increased ground contact time from 273.8 +/- 18.2 to 277.9 +/- 18.7 ms, significant increased vertical stiffness from 23.2 +/- 3.4 to 23.8 +/- 3.0 kN m-1, and significant decreased net vertical impulse from 245.4 +/- 17.2 to 241.7 +/- 17.5 BW ms. CONCLUSIONS: Increased energy return and longitudinal bending stiffness induced subtle changes in the running biomechanics, but did not induce any decrease in the energetic cost of running. PMID- 30470874 TI - Cladribine in the remission induction of adult acute myeloid leukemia: where do we stand? AB - The combination of cytarabine and an anthracycline has been the standard of care for the induction of remission in acute myeloid leukemia (AML). The response to treatment and survival of adult patients with AML are still variable and depend on multiple factors. Therefore, there have been many efforts to improve the response to treatment and survival rates by either increasing the cytarabine dose or adding a third agent to the standard induction chemotherapy regimen. Unfortunately, attempts to improve response and survival have been mostly unsuccessful. Recent clinical trials and retrospective studies explored the addition of cladribine to standard induction chemotherapy for AML. Some of these studies showed higher rates of complete remission, and one showed improved survival. In this review, we will discuss the antileukemic properties of cladribine and summarize the recent clinical data regarding its incorporation into the induction therapy for adult AML. PMID- 30470875 TI - Navigating the treatment landscape in multiple myeloma: which combinations to use and when? AB - Multiple myeloma is one of the most common hematological malignancies, affecting mainly elderly patients. The treatment landscape for the management of this disease has evolved significantly over the past 15 years, and a vast array of therapeutics is now available, including immunomodulatory drugs, proteasome inhibitors, histone deacetylase inhibitors, and monoclonal antibodies. As a result, deciding which drugs to use and when, and whether these should be used in a particular order or combination, can be challenging. Although combination regimens are often associated with deeper responses and better long-term outcomes than monotherapy, and are becoming the standard of care, they may result in significant incremental toxicity; hence, a sequential approach may be more appropriate for some patients. In particular, treatment choices can vary depending on whether the patient has newly diagnosed multiple myeloma, is eligible for transplant, has relapsed and/or refractory multiple myeloma, or is considered to have high-risk disease. In this review, we discuss factors to be taken into account when making treatment decisions in each of these settings. We also briefly discuss possible therapeutic strategies involving agents that may become available in the future. PMID- 30470877 TI - The pterygopalatine fossa: morphometric CT study with clinical implications. AB - PURPOSE: The pterygopalatine fossa is a deep viscerocranial space containing the maxillary artery and nerve, the pterygopalatine ganglion, and the nerve of the pterygoid canal (vidian nerve). The endoscopic approach to this area relies on adequate preoperative imaging, such as computed tomography (CT). The aim was to determine the morphometric characteristics of the pterygopalatine fossa and its communications, including several previously unpublished measurements. METHODS: 100 CT scans (56 male and 44 female patients) were analyzed. The axial, coronal, and sagittal slices, together with the three-dimensional reconstructions, were used in the study. RESULTS: The central diameter and the length of the foramen rotundum, the vertical diameter and the length of the pterygoid (vidian) canal, and the diameter of the sphenopalatine foramen were significantly larger in men. The central diameters of the foramen rotundum and the vidian canal were significantly smaller than their anterior and posterior transverse diameters. The vidian canal length of 12.1 mm indicates the presence of the type 3 VC with a sensitivity of 83% and a specificity of 85%. CONCLUSION: Several new descriptions of the pterygopalatine fossa are presented here (such as the angle between the sphenopalatine foramen and the vidian canal, a new aspect in the understanding of the FR, and the distance between the posterior wall of the maxillary sinus to the vidian canal and the foramen rotundum), which might prove useful in the comprehension of the anatomy of the pterygopalatine fossa. PMID- 30470876 TI - Anti-VEGF treatment for choroidal neovascularization complicating pattern dystrophy-like deposit associated with pseudoxanthoma elasticum. AB - PURPOSE: To evaluate the efficacy of intravitreal anti-VEGF injections in choroidal neovascularization (CNV) related to pattern dystrophy-like deposit in pseudoxanthoma elasticum (PXE). METHODS: One-year prospective, interventional study. Nine eyes were recruited in the ophthalmology departments of San Raffaele University and University of Barcelona. Each patient underwent best corrected visual acuity (BCVA) measurement on ETDRS chart, slit-lamp biomicroscopy, fluorescein angiography (FA), indocyanine green angiography (ICGA), and optical coherence tomography (OCT). The protocol included a first anti-VEGF injection, followed by monthly evaluations with re-treatments based on new funduscopic hemorrhages, fluid on OCT or leakage on FA and/or ICGA. Primary outcome measures were the mean BCVA changes. Secondary outcomes included central macular thickness (CMT) variations and the number of injections needed. RESULTS: At month 12, mean BCVA significantly improved from 20/45 to 20/35 Snellen equivalent, with 3 eyes gaining at least 3 ETDRS lines. Mean CMT decreased from 297 +/- 22 to 262 +/- 13 MUm, after 5.5 +/- 4.0 injections. No leakage was observed at the end of follow up. CONCLUSIONS: Intravitreal anti-VEGF injections represent an effective treatment for CNV related to pattern dystrophy-like deposit in PXE, with an improvement of BCVA and CMT. Mean injection number is in line with other studies performed in CNV secondary to angioid streaks. PMID- 30470878 TI - Three-dimensional growth of tibial shaft ossification in the human fetus: a digital-image and statistical analysis. AB - PURPOSES: Tibial shaft ossification in terms of its size and growth may be criticalin describing both the fetal stage and maturity, and in identifying innate disorders. The present study was executed to quantitatively assess ossification of the tibial shaft, taking its morphometric linear, planar and volumetric parameters into account. MATERIALS AND METHODS: With the use of methods of CT, digital-image analysis and statistics, the evolutionof tibial shaft ossification in 47 spontaneously aborted human fetuses at the age of 17-30 weeks was studied. RESULTS: Without any male-female and right-left morphometric differences, the best fit growth dynamics fortibial shaft ossification was modelled by the following functions: y = 5.312 + 0.034 * (age)2 +/- 0.001 (R2 = 0.89) for its length, y = - 2.855 + 0.307 * age +/- 0.009 (R2 = 0.96) for its proximal transverse diameter, y = - 0.758 + 0.153 * age +/- 0.005 (R2 = 0.88) for its middle transverse diameter, y = - 1.844 + 0.272 * age +/- 0.09 (R2 = 0.90) for its distal transverse diameter, y = - 40.263 + 0.258 * (age)2 +/- 0.007 (R2 = 0.94) for its projection surface area, and y = - 287.996 + 1.186 * (age)2 +/- 0.037 (R2 = 0.92) for its volume. The femoral-to-tibial ossification length ratio was 1.15 +/- 0.1. CONCLUSIONS: The size of tibial shaft ossification displays neither sex nor laterality differences. Tibial shaft ossification follows quadratic functions with respect to its length, projection surface area and volume, and linear functions with respect to its proximal, middle and distal transverse diameters. The obtained morphometric data of tibial shaft ossification are considered normative age-specific references of relevance in both the estimation of fetal ages and the ultrasound diagnostics of congenital defects. PMID- 30470879 TI - Percutaneous albumin/doxycycline injection versus open surgery for aneurysmal bone cysts in the mobile spine. AB - PURPOSE: This study aimed to validate the safety and effectiveness of percutaneous doxycycline/albumin injection for spinal aneurysmal bone cysts (ABCs) as an alternative to open surgery. METHODS: From January 2000 to December 2016, 25 patients who had no/minor neurological deficits (modified Frankel scale D or E) and acceptable local stability (spinal instability neoplastic score < 12) were included in the study, of whom 14 were treated with percutaneous doxycycline/albumin injection (injection group) and 11 were treated with open surgery (surgery group). The demographic and clinical information of the injection and surgery groups were recorded and compared. RESULTS: In the injection group, lesion size was significantly reduced in all 14 patients, all patients showed complete neurological recovery, and 13 patients had complete relief of neck pain; their mean visual analogue scale (VAS) decreased from 3.4 to 0.5. No complication or recurrence was observed during the mean 30.7-month follow up (range, 24-50 months). In the surgery group, 9 patients had complete neurological recovery and 2 patients had residual slight paresthesia; their mean VAS decreased from 3.4 to 0.5. Two had local recurrence during their follow-up at 66.5 months (range, 50-96 months). Compared with the surgery group, the injection group showed no significant difference in the rate of recurrence (P = 0.14) and complication (P = 0.36). CONCLUSIONS: Percutaneous doxycycline/albumin injection for spinal ABCs can be safely and effectively performed in well-selected cases. It could serve as an alternative treatment, especially for spinal ABCs lesions with acceptable local stability and in patients without severe neurological deficits. These slides can be retrieved under Electronic Supplementary Material. PMID- 30470880 TI - Association between erythrocyte fatty acids in de novo lipogenesis pathway and DXA-derived body fat and trunk fat distribution in Chinese adults: a prospective study. AB - PURPOSE: Higher levels of fatty acids (FAs) in the de novo lipogenesis (DNL) pathway might be associated with higher levels of fat mass (FM), while limited evidence is available from the general population. We aimed to examine the associations between DNL-FAs and body fat and fat distribution in a general population of Chinese adults. METHODS: This community-based prospective cohort study included 3,075 participants (68% women) aged 40-75 years in urban Guangzhou, China. We measured erythrocyte DNL-FAs composition (including C16:0, C16:1n-7, C18:0, and C18:1n-9) at baseline and %FM over the total body (TB), trunk, limbs, android (A) and gynoid (G) regions after 3.2 years and 6.3 years of follow-up, respectively. RESULTS: Generally, higher proportions of individual erythrocyte DNL-FAs and their combined index were positively associated with adipose indices in the multivariable cross-sectional and longitudinal analyses. The cross-sectional percentage mean differences in quartile 4 (vs. 1) of the DNL index were 3.43% (TB), 4.56% (trunk), and 2.67% (A/G ratio) (all P trends < 0.01). The corresponding values in longitudinal changes of adipose indices were 1.40% (TB), 1.78% (trunk), and 1.32% (A) (all P trends < 0.05). The above associations tended to be more pronounced in the trunk and android area than the limbs and gynoid area. CONCLUSIONS: Erythrocyte DNL-FAs may contribute to an increase in total body fat in Chinese adults, particularly FM distributed in trunk and abdominal regions. PMID- 30470881 TI - What drives changes in institutionalised mental health care? A qualitative study of the perspectives of professional experts. AB - BACKGROUND: Since 1990, the provision of mental healthcare has changed substantially across Western Europe. There are fewer psychiatric hospital beds and more places in forensic psychiatric hospitals and residential facilities. However, little research has investigated the drivers behind these changes. This study explored qualitatively the perspectives of mental health professional experts on what has driven the changes in Western Europe. METHODS: In-depth interviews were conducted with twenty-four mental health experts in England, Germany and Italy, who as professionals had personal experiences of the changes in their country. Interviewees were asked about drivers of changes in institutionalised mental health care from 1990 to 2010. The accounts were subjected to a thematic analysis. RESULTS: Four broad themes were revealed: the overall philosophy of de-institutionalisation, with the aim to overcome old fashioned asylum style care; finances, with a pressure to limit expenditure and an interest of provider organisations to increase income; limitations of community mental health care in which most severely ill patients may be neglected; and emphasis on risk containment so that patients posing a risk may be cared for in institutions. Whilst all themes were mentioned in all three countries, there were also differences in emphasis and detail. CONCLUSIONS: Distinct factors appear to have influenced changes in mental health care. Their precise influence may vary from country to country, and they have to be considered in the context of each country. The drivers may be influenced by professional groups to some extent, but also depend on the overall interest and attitudes in the society at large. PMID- 30470882 TI - Quality of life, recovery and decision-making: a mixed methods study of mental health recovery in social care. AB - PURPOSE: Mental health care is a complex system that includes social care organisations providing support for people with continuing needs. The relationship over time between decisional conflict, social support, quality of life and recovery outcomes across two time periods for people experiencing mental health problems in receipt of social care was investigated. METHODS: This is a mixed methods study comprised of a quantitative survey at two time points using measures of decisional conflict, social support, recovery and quality of life in a random sample (n = 122) using social care services in Wales, UK. In addition, 16 qualitative case studies were developed from data collected from individuals, a supportive other and a care worker (n = 41) to investigate trajectories of care. Survey responses were statistically analysed using SPSS and case study data were thematically analysed. RESULTS: Participants reported increasing decisional conflict and decreasing social support, recovery and quality of life over the two time points. Linear regression indicated that higher recovery scores predict better quality of life ratings and as ratings for social support decline this is associated with lower quality of life. Correlational analysis indicated that lower decisional conflict is associated with higher quality of life. Thematic analysis indicated that 'connectedness and recovery' is a product of 'navigating the system of care' and the experience of 'choice and involvement' achieved by individuals seeking help. CONCLUSIONS: These results indicate that quality of life for people experiencing mental health difficulties is positively associated with social support and recovery and negatively associated with decisional delay. PMID- 30470883 TI - Importance of endomyocardial biopsy in distinguishing between cardiac sarcoidosis and giant cell myocarditis : Need to distinguish between sarcoidosis and giant cell myocarditis. PMID- 30470884 TI - Association between exposure to macrolides and the development of infantile hypertrophic pyloric stenosis: a systematic review and meta-analysis. AB - Macrolides are bacteriostatic antibiotics with a broad spectrum of activity against Gram-positive bacteria. The aim of this study was to systematically review and meta-analyze the association between infantile hypertrophic pyloric stenosis (IHPS) and macrolides. Nine databases were searched systematically for studies with information on the association between macrolides and IHPS. We combined findings using random effects models. Our study revealed 18 articles investigating the association between macrolides and IHPS. There was a significant association between the development of IHPS and erythromycin (2.38, 1.06-5.39). The association was strong when erythromycin was used during the first 2 weeks of life (8.14, 4.29-15.45). During breastfeeding, use of macrolides showed no significant association with IHPS in infants (0.96, 0.61-1.53). IHPS was not associated with erythromycin (1.11, 0.9-1.36) or macrolides use during pregnancy (1.15, 0.98-1.36).Conclusions: There is an association between erythromycin use during infancy and developing IHPS in infants. However, no significant association was found between macrolides use during pregnancy or breastfeeding. Additional large studies are needed to further evaluate potential association with macrolide use. What is known? * Erythromycin intake in the first 2 weeks of life is associated with an increased risk of pyloric stenosis. What is New? * There is currently no evidence of significant association between macrolides use during pregnancy or breastfeeding and pyloric stenosis. PMID- 30470885 TI - Reply to: "Nasal injury and comfort with jet versus bubble continuous positive airway pressure delivery systems in preterm infants with respiratory distress". PMID- 30470886 TI - Spatiotemporal characteristics of fibroblasts-dependent cancer cell invasion. AB - PURPOSE: Cancer cells can invade the surrounding stroma with the aid of fibroblasts (fibroblasts-dependent invasion). The aim of this study was to explore the spatiotemporal characteristics of fibroblast-dependent invasion of cancer cells. METHODS: We performed an in vitro three-dimensional collagen invasion assay using Fluorescent Ubiquitination-based Cell Cycle indicator (Fucci)-labeled A431 carcinoma cells co-cultured with fibroblasts. We used time lapse imaging to analyze the total cell number, frequencies of small cancer cell nests and S/G2/M phase of A431 cells in the invasion area. We compared the frequencies of small cancer cell nests and geminin (+) cancer cells within fibroblast-rich areas and fibroblast-poor areas in surgically resected human invasive squamous cell carcinoma tissue. RESULTS: The total invasion number of A431 cells was significantly higher when cultured with fibroblasts than without. The formation of small cancer cell nests was observed within the invasion area only in the presence of fibroblasts. The frequency of S/G2/M phase cells was significantly higher in A431 cells when cultured with fibroblasts than without. Immunohistochemical analysis of surgically resected human invasive squamous cell carcinoma tissue revealed that the frequencies of small cancer cell nests and geminin-positive cancer cells were significantly higher in fibroblast-rich areas compared to those in fibroblast-poor areas within the same tumor region. CONCLUSION: Our current study clearly showed that fibroblast-dependent cancer cell invasion was characterized by the progression in cell cycle and formation of small cancer cell nests. PMID- 30470887 TI - Huge multiple spinal extradural meningeal cysts in infancy. AB - BACKGROUND: Multiple spinal extradural meningeal cysts (SEMCs) are rare lesions. SEMCs communicate with the subarachnoid space through multiple dural defects and expand into the extradural space with progressive spinal cord compression. CASE PRESENTATION: We report a 5-month-old boy with hydronephrosis involving nine huge SEMCs that were distributed from the T1-L5 levels. Eight SEMCs, except for one small noncommunicating cyst, were exposed through laminoplastic laminotomy at the T10-L5 and T3-5 levels. Five transdural communications with dural defects were packed with a piece of autologous muscle and fibrin glue. Tenting sutures to lift up the dura to the vertebral arch were added to minimize the extradural dead space. Postoperatively, cord compression was relieved and hydronephrosis improved. CONCLUSION: In conclusion, packing of all dural defects and dural tenting sutures at a one-staged operation is useful in the surgical management of huge and multiple SEMCs in infancy. PMID- 30470888 TI - Does body growth impair immune function in a large herbivore? AB - According to the principle of allocation, trade-offs are inevitable when resources allocated to one biological function are no longer available for other functions. Growth, and to a lesser extent, immunity are energetically costly functions that may compete with allocation to reproductive success and survival. However, whether high allocation to growth impairs immune system development during the growing period or immune system performance during adulthood is currently unknown in wild mammals. Using three roe deer (Capreolus capreolus) populations experiencing contrasting environmental conditions, we tested for potential costs of growth on immune phenotype over both the short-term (during growth), and the long-term (during adulthood) over the course of an individuals' life. We investigated potential costs on a set of 12 immune traits that reflect both innate and adaptive responses, and compared them between sexes and populations. Although fast growth tended to be associated with low levels of some humoral traits (globulins) during the growing period and some cellular immune traits (i.e. eosinophil and neutrophil counts) during adulthood, evidence for a trade-off between growth and other immune components was limited. Unexpectedly, no detectable growth costs on immunity were found in females from the population experiencing the least favourable environment. We discuss our findings in the light of the complex interplay between resource allocation strategies among reproduction, maintenance and immunity, in relation to local environmental conditions experienced by roe deer. PMID- 30470889 TI - Accounting for intraspecific diversity when examining relationships between non native species and functional diversity. AB - Quantifying changes in functional diversity, the facet of biodiversity accounting for the biological features of organisms, has been advocated as one of the most integrative ways to unravel how communities are affected by human-induced perturbations. The present study assessed how functional diversity patterns varied among communities that differed in the degree to which non-native species dominated the community in temperate lake fish communities and whether accounting for intraspecific functional variability could provide a better understanding of the variation of functional diversity across communities. Four functional diversity indices were computed for 18 temperate lake fish communities along a gradient of non-native fish dominance using morphological functional traits assessed for each life-stage within each species. First, we showed that intraspecific variability in functional traits was high and comparable to interspecific variability. Second, we found that non-native fish were functionally distinct from native fish. Finally, we demonstrated that there was a significant relationship between functional diversity and the degree to which non native fish currently dominated the community and that this association could be better detected when accounting for intraspecific functional variability. These findings highlighted the importance of incorporating intraspecific variability to better quantify the variation of functional diversity patterns in communities facing human-induced perturbations. PMID- 30470890 TI - Keeping us all whole: Acknowledging the agency of African American breast cancer survivors and their systems of social support. AB - While all cancer patients face a bewildering array of treatments, side effects, and emotions, several researchers have shown that African American women with breast cancer experience greater stress and burdens because of unmet supportive needs associated with psychological distress, financial distress, and lower physical/functional well-being. Social support has been shown to improve health outcomes for African American breast cancer patients. The purpose of this paper is to understand the meaning of social support among African American women diagnosed with breast cancer. A total of 47 African American women with breast cancer participated in the in-depth qualitative interviews. Key findings indicate that social support was received in the context of the stability of the extended family network. Moreover, social support was received in the context of distributing the social support received among many members in their personal networks and that social support was only received on patient's own terms. The findings of this paper provide an understanding to the inter-relational and cultural meanings of receiving support by diverse cancer patients. In addition, the findings of this paper have implications for health care professionals working with African American breast cancer patients in understanding how social support can be received. PMID- 30470891 TI - The requirements of hospital-based spiritual care for cancer patients. AB - PURPOSE: This paper aimed to discover the requirements of hospital-based spiritual care for cancer patients. METHODS: This study was a descriptive qualitative-exploratory research, in which 25 participants were selected through purposive sampling and had semi-structured interviews. RESULT: The data analysis revealed 3 themes and 8 sub-themes including fundamental requirements (changes in the attitudes and behaviors of the healthcare team), structural requirements (inter-professional collaborations, a reference system), and functional requirements (religious-spiritual, pastoral, psycho-spiritual, and supportive spiritual care). In this study, the received topics have been related to the spiritual care which can help improve patient care. CONCLUSION: The results were added to the repertoire of knowledge about the spiritual needs of cancer patients. The results indicated that it is essential to get acquainted with the spiritual care requirements in the hospital and enforce them through inter professional collaboration. Accordingly, the spiritual care program should be designed, implemented, and evaluated. PMID- 30470893 TI - Radial glia fibers translate Fgf8 morphogenetic signals to generate a thalamic nuclear complex protomap in the mantle layer. AB - Thalamic neurons are distributed between different nuclear groups of the thalamic multinuclear complex; they develop topologically ordered specific projections that convey information on voluntary motor programs and sensory modalities to functional areas in the cerebral cortex. Since thalamic neurons present a homogeneous morphology, their functional specificity is derived from their afferent and efferent connectivity. Adequate development of thalamic afferent and efferent connections depends on guide signals that bind receptors in nuclear neuropils and axonal growth cones, respectively. These are finally regulated by regionalization processes in the thalamic neurons, codifying topological information. In this work, we studied the role of Fgf8 morphogenetic signaling in establishing the molecular thalamic protomap, which was revealed by Igsf21, Pde10a and Btbd3 gene expression in the thalamic mantle layer. Fgf8 signaling activity was evidenced by pERK expression in radial glia cells and fibers, which may represent a scaffold that translates neuroepithelial positional information to the mantle layer. In this work, we describe the fact that Fgf8-hypomorphic mice did not express pERK in radial glia cells and fibers and presented disorganized thalamic regionalization, increasing neuronal death in the ventro lateral thalamus and strong disruption of thalamocortical projections. In conclusion, Fgf8 encodes the positional information required for thalamic nuclear regionalization and the development of thalamocortical projections. PMID- 30470892 TI - Effectiveness of myofascial release after breast cancer surgery in women undergoing conservative surgery and radiotherapy: a randomized controlled trial. AB - PURPOSE: The scars derived from the treatment of breast cancer lead to adverse effects such as fibrosis or retractions of the connective tissue. Myofascial release (MR) seeks to reduce restrictions of the fascial system. Therefore, the aim of this study was to analyze the clinical impact of MR treatment on women survivors of breast cancer. METHODS: We enrolled 24 women with breast cancer, 13 received myofascial release treatment (MR) and 11, a placebo manual lymphatic drainage treatment (PMLD). Both interventions were administered over a period of 4 weeks. The outcomes studied were pain, shoulder range of motion (ROM), functionality, quality of life (QoL), and depression, immediately after treatment and 1 month later. RESULTS: After 4 weeks of treatment, only the participants who received MR experienced a significant decrease in pain intensity in the short and midterm (p < 0.05). This therapy also achieved a general improvement in ROM (p < 0.05), except for internal rotation, that persisted 1 month after treatment. Regarding functionality, both therapies achieved the level of significance (p < 0.05), but only MRG sustained the improvement in the midterm. General QoL, assessed with FACT-B, and its physical well-being dimension were significantly improved after MR implementation (p < 0.05), while the emotional dimension and the breast cancer subscale improved only with PMLD (p < 0.05). CONCLUSIONS: In conclusion, an MR-based treatment shows physical benefits (i.e., overall shoulder movement, functionality, and perceived pain) in women after breast cancer surgery. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov NCT03182881. PMID- 30470894 TI - Hippocampal LTP modulation and glutamatergic receptors following vestibular loss. AB - Vestibular dysfunction strongly impairs hippocampus-dependent spatial memory performance and place cell function. However, the hippocampal encoding of vestibular information at the synaptic level, remains sparsely explored and controversial. We investigated changes in in vivo long-term potentiation (LTP) and NMDA glutamate receptor (NMDAr) density and distribution after bilateral vestibular lesions (BVL) in adult rats. At day 30 (D30) post-BVL, the LTP of the population spike recorded in the dentate gyrus (DG) was higher in BVL rats, for the entire 3 h of LTP recording, while no difference was observed in the fEPSP slope. However, there was an increase in EPSP-spike (E-S) potentiation in lesioned rats. NMDArs were upregulated at D7 and D30 predominantly within the DG and CA1. At D30, we observed a higher NMDAr density in the left hippocampus. NMDArs were overexpressed on both neurons and non-neuronal cells, suggesting a decrease of the entorhinal glutamatergic inputs to the hippocampus following BVL. The EPSP-spike (E-S) potentiation increase was consistent with the dorsal hippocampus NMDAr upregulation. Such an increase could reflect a non-specific enhancement of synaptic efficacy, leading to a disruption of memory encoding, and therefore might underlie the memory deficits previously reported in rats and humans following vestibular loss. PMID- 30470895 TI - Mapping multiple principles of parietal-frontal cortical organization using functional connectivity. AB - Resting state functional connectivity has been promoted as a promising tool for creating cortical maps that show remarkable similarity to those established by invasive histological methods. While this tool has been largely used to identify and map cortical areas, its true potential in the context of studying connectional architecture and in conducting comparative neuroscience has remained unexplored. Here, we employ widely used resting state connectivity and data driven clustering methods to extend this approach for the study of the organizational principles of the macaque parietal-frontal system. We show multiple, overlapping principles of organization, including a dissociation between dorsomedial and dorsolateral pathways and separate parietal-premotor and parietal-frontal pathways. These results demonstrate the suitability of this approach for understanding the complex organizational principles of the brain and for large-scale comparative neuroscience. PMID- 30470896 TI - Postoperative thoracic and low back pain following endovascular aortic repair associated with stenting location. AB - BACKGROUND: We have noted that patients frequently complain of thoracic or low back pain after undergoing an endovascular aortic repair, which we speculated was caused by the indwelling stent. METHODS: We investigated the patients who underwent an elective thoracic or abdominal endovascular aortic repair (TEVAR or EVAR) and noted the location of stent, and postoperative pain. The incidence of either thoracic or low back pain at individual vertebra levels was determined, after which we fitted the sigmoidal function to the discrete data to obtain a cut off line. The study patients were then divided into 2 groups using the cut-off line to compare the incidence of pain. RESULTS: We analyzed 96 patients (68 TEVAR, 28 EVAR). The incidence of thoracic pain was significantly higher in TEVAR as compared to EVAR (26.5% vs. 3.6%, P = 0.01), while that of low back pain was significantly higher in EVAR (35.7% vs. 16.2%, P = 0.04). With the cut-off line for thoracic pain set at the 12th thoracic vertebra, the incidence of thoracic pain was significantly higher in patients with the upper end of the stent above the cut-off as compared to at a lower point (26.5% vs. 3.6%, P = 0.01). As for low back pain, the cut-off line was set at the 9th thoracic vertebra, and the incidence of that pain was significantly higher in patients with the lower end of the stent below that line (30.9% vs. 0.0%, P < 0.01). CONCLUSION: Thoracic and low back pain after an endovascular aortic repair procedure were associated with stenting site. PMID- 30470897 TI - Secondary rise in blood pressure and leg swelling after central arteriovenous anastomosis. PMID- 30470898 TI - A hypothesis about the origin of carotenoid lipid droplets in the green algae Dunaliella and Haematococcus. AB - MAIN CONCLUSION: Hypercarotenogenesis in green algae evolved by mutation of PSY that increased its transcription at high light, disintegration of the eyespot in Dunaliella and acquisition of the capacity to export carotenoids from chloroplasts in Haematococcus. Carotenoids (Car) are lipid-soluble pigments synthesized in plants, algae, bacteria and fungi. Car have strong antioxidative properties and as such are utilized to reduce the danger of different diseases in humans. Two green microalgae are utilized as rich natural sources for Car: Dunaliella salina/bardawil accumulates 10% (w/w) beta-carotene (betaC), which is also pro-vitamin A, and Haematococcus pluvialis accumulates 4% (w/w) astaxanthin (Ast), the strongest antioxidant among Car. D. bardawil accumulates betaC in plastoglobules within the chloroplast, whereas H. pluvialis deposits Ast in cytoplasmic lipid droplets (CLD). In this review we compare the hypercarotenogenic responses (HCR) in Dunaliella and in Haematococcus and try to outline hypothetical evolutionary pathways for its origin. We propose that a mutation in phytoene synthetase that increased its transcription level in response to high light stress had a pivotal role in the evolution of the HCR. Proteomic analyses indicated that in D. bardawil/salina the HCR evolved from dissociation and amplification of eyespot lipid globules. The more robust HCR in algae that accumulate carotenoids in CLD, such as H. pluvialis, required also acquisition of the capacity to export betaC out of the chloroplast and its enzymatic conversion into Ast. PMID- 30470899 TI - Engineering modular diterpene biosynthetic pathways in Physcomitrella patens. AB - MAIN CONCLUSION: Modular assembly and heterologous expression in the moss Physcomitrella patens of pairs of diterpene synthases results in accumulation of modern land plant diterpenoids. Physcomitrella patens is a representative of the ancient bryophyte plant lineage with a genome size of 511 Mb, dominant haploid life cycle and limited chemical and metabolic complexity. For these plants, exceptional capacity for genome editing through homologous recombination is met with recently demonstrated in vivo assembly of multiple heterologous DNA fragments. These traits earlier made P. patens an attractive choice as a biotechnological chassis for photosynthesis-driven production of recombinant peptides. The lack of diterpene gibberellic acid phytohormones in P. patens combined with the recent targeted disruption of the single bifunctional diterpene synthase yielded lines devoid of endogenous diterpenoid metabolites and well suited for engineering of terpenoid production. Here, we mimicked the modular nature of diterpene biosynthetic pathways found in modern land plants by developing a flexible pipeline to install three combinations of class II and class I diterpene synthases in P. patens to access industrially relevant diterpene biomaterials. In addition to a well-established neutral locus for targeted integration, we also explored loci created by a class of Long Terminal Repeat Retrotransposon present at moderate number in the genome of P. patens. Assembly of the pathways and production of the enzymes from the neutral locus led to accumulation of diterpenes matching the reported activities in the angiosperm sources. In contrast, insights gained with the retrotransposon loci indicate their suitability for targeting, but reveal potentially inherent complications which may require adaptation of the experimental design. PMID- 30470900 TI - Non-crystallographic symmetry in proteins: Jahn-Teller-like and Butterfly-like effects? AB - Partial symmetry, i.e., the presence of more than one molecule in the asymmetric unit of a crystal, is a relatively rare phenomenon in small-molecule crystallography, but is quite common in protein crystallography, where it is typically known as non-crystallographic symmetry (NCS). Several papers in literature propose molecular determinants such as crystal contacts, thermal factors, or TLS parameters as an explanation for the phenomenon of intrinsic asymmetry among molecules that are in principle equivalent. Nevertheless, are all of the above determinants the cause or are they rather the effect? In the general frame of the NCS often observed in crystals of biomolecules, this paper deals with nickel(II)-substituted human carbonic anhydrase(II) (hCAII) and its SAD structure determination at the nickel edge. The structure revealed two non equivalent molecules in the asymmetric unit, the presence of a secondary nickel binding site at the N-terminus of both molecules (which had never been found before in the nickel-substituted enzyme) and two different coordination geometries of the active site nickel (hexa-coordinated in one molecule and mainly penta-coordinated in the other). The above-mentioned standard molecular crystallographic determinants of this asymmetry are analyzed and presented in detail for this particular case. From these considerations, we speculate on the existence of a fundamental, although yet unknown, common cause for the partial symmetry that is so often encountered in X-ray structures of biomolecules. PMID- 30470901 TI - Comparative survey of secretory structures and floral anatomy of Cohniella cepula and Cohniella jonesiana (Orchidaceae: Oncidiinae). New evidences of nectaries and osmophores in the genus. AB - The morpho-anatomical structure of nectaries, osmophores, and elaiophores, and the anatomical and micromorphological features of floral pieces of Cohniella cepula Hoffmans. and Cohniella jonesiana Rchb.f. were comparatively analyzed. In both species, bracteal and sepal nectaries are structured, i.e., they present a secretory epidermis, secretory parenchyma, and vascular bundles. Nectar secretion is released through stomata. The anatomical and micromorphological traits are similar in both nectaries, which can be detected only if the nectar drops are secreted. Considering the location of these nectaries, the secreted nectar would not be a reward to pollinators. Osmophores are located at the base of both callus and laterals lobes, and consist of a layer of secretory epidermis composed of quadrangular cells and papillae. Elaiophores are found on the callus of the labellum and are of the epithelial type. The anatomical features of floral pieces are similar in both species. The anatomical analysis of sepals and petals showed a few differences, which could be of potential taxonomic value. Our results contribute valuable and novel information for the knowledge of these species and the genus, which will be useful in future taxonomic evaluations. PMID- 30470902 TI - Amyotrophic lateral sclerosis associated with statins. A disproportionality analysis of the WHO Program for International Drug Monitoring database (VigiBase). PMID- 30470903 TI - The Aalborg Bolt-Connected Drain (ABCD) study: a prospective comparison of tunnelled and bolt-connected external ventricular drains. AB - BACKGROUND: Acutely increased intracranial pressure (ICP) is frequently managed by external ventricular drainage (EVD). This procedure is life-saving but marred by a high incidence of complications. It has recently been indicated that bolt connected external ventricular drainage (BC-EVD) compared to the standard technique of tunnelled EVD (T-EVD) may result in less complications. AIM: To prospectively sample and compare two cohorts by consecutive allocation to either BC-EVD or T-EVD from the introduction of the BC-EVD technique in our department and 12 months onward. METHODS: Patients undergoing ventriculostomy between the 1st of March 2017 and the 28th of February 2018 were considered for inclusion. The neurosurgeon on-call sovereignly set the indication and decided on EVD type (BC-EVD or T-EVD), consequently resulting in two cohorts as 3/7 senior neurosurgeons on call were open to the use of BC-EVD, while 4/7 were reluctant to use this technique. Data was continuously collected using patient records, including results of cerebrospinal fluid (CSF) culturing and available CT/MRI scans. Recorded complications included CSF leakage, accidental discontinuation, placement-related intracranial haemorrhage, malfunction, migration, infection and revision. RESULTS: Forty-nine EVDs (32 T-EVDs/17 BC-EVDs) were included; 19/32 (59.4%) T-EVDs and 3/17 (17.6%) BC-EVDs were found to have complications (p = 0.007). The relative risk of complications when using T-EVD was 3.4 times that of BC-EVD. CONCLUSION: Ventriculostomy by BC-EVD compared to T-EVD reduces incidence and risk of complications and should be the first choice in EVD placement. That said, T-EVD has a role in paediatric patients and for intraoperatively and occipitally placed EVDs. PMID- 30470904 TI - Hearing preservation after removal of small vestibular schwannomas: the role of ABR neuromonitoring. PMID- 30470906 TI - Dorsal transosseous reduction and locking plate fixation for articular depressed middle phalangeal base fracture. AB - PURPOSE: An articular depressed fragment at the base of the middle phalanx can be an obstacle to congruent reduction and stable fixation. This study assessed the outcomes of a transosseous reduction technique combined with locking plate fixation for the treatment of articular depressed middle phalangeal base fracture. METHODS: Between 2015 and 2017, seven patients (eight fingers) with intraarticular comminuted middle phalangeal base fracture were included in this study. Mean follow-up was 19 months (range 12-30 months). All patients showed depression of the articular fragment on sagittal computed tomography (CT) scan and were treated with a transosseous reduction technique and dorsal locking plate fixation. Radiographic evaluation was performed to ensure restoration of a concentric articular surface postoperatively. Total active range of motion (TAM) of the finger, grip strength, and the quick Disabilities of the Arm, Shoulder and Hand (quick DASH) score were evaluated at the last follow-up. Complications were also assessed. RESULTS: All fractures obtained bony union with a concentric joint. There was no significant loss of reduction during the follow-up period. The mean active proximal interphalangeal (PIP) joint and distal interphalangeal joint motion arcs at follow-up were 89 degrees and 61 degrees , respectively. Mean TAM of the affected finger and mean grip strength were 94% (range 80-100%) and 94% (range 86-100%) of the contralateral side, respectively. Mean quick DASH score was 2.3 (range 0-9.1). All patients returned to work. No surgery-related complications occurred. CONCLUSIONS: This technique provides satisfactory restoration of articular congruence and enables the early joint mobilization of articular depression-type fractures of the base of the middle phalanx. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic, level IV. PMID- 30470905 TI - Human serum albumin templated MnO2 nanosheets are oxidase mimics for colorimetric determination of hydrogen peroxide and for enzymatic determination of glucose. AB - This paper reports on a colorimetric assay for H2O2 and glucose. It is based on the use of human serum albumin-templated MnO2 nanosheets that possess oxidase like activity. They are capable of oxidizing 3,3',5,5'-tetramethylbenzidine (TMB) with oxygen to give a blue product (oxTMB) with an absorbance maximum at 652 nm. When H2O2 is introduced, the MnO2 nanosheets are reduced to Mn(II) ions, and this inhibits the formation of oxTMB. Based on these findings, a colorimetric assay was established for H2O2 that has a 0.56 MUM detection limit. If glucose is oxidized by glucose oxidase under formation of H2O2, the nanosheets can be used to quantify H2O2 and thereby to sense glucose. Response is linear in the 0.5 MUM to 50 MUM glucose concentration range, and the detection limit is 0.32 MUM. The method was applied to the determination of glucose in spiked serum samples and gave satisficatory results. Graphical abstract Human serum albumin (HSA) is used as a template for the synthesis of MnO2 nanosheet. These possess oxidase mimicking activity. H2O2 can reduce the nanosheets. The effect is exploited in colorimetric assays for H2O2 and glucose using tetramethylbenzidine (TMB) as a chromogenic substrate. PMID- 30470907 TI - Potential of in situ SSF laccase produced from Ganoderma lucidum RCK 2011 in biobleaching of paper pulp. AB - Production of laccase from Ganoderma lucidum RCK 2011 under solid-state fermentation (SSF) conditions was optimized using response surface methodology, resulting in an approximate eightfold increase compared to that in the unoptimized media. Further, the enzyme produced under SSF as whole fermented substrate (in situ SSF laccase) was found to be more stable than the in vitro enzyme (harvested by downstreaming processing of fermented wheat bran). Interestingly, the biobleaching potentials of both in situ and in vitro SSF laccases were comparable, saving 25% chlorine dioxide for achieving similar pulp brightness as obtained in the pulp treated chemically. The reduction in the demand of chlorine dioxide in the pulp bleaching sequence subsequently decreased the levels of adsorbable organic halogen (AOX) in the resulting effluents of the process by 20% compared to the effluents obtained from chemical bleaching sequence. Therefore, direct application of in situ SSF laccase in pulp biobleaching will be environmentally friendly as well as economical and viable for implementation in paper mills. PMID- 30470908 TI - Acetone, butanol, and ethanol production from the green seaweed Enteromorpha intestinalis via the separate hydrolysis and fermentation. AB - Acetone, butanol, and ethanol (ABE) were produced following the separate hydrolysis and fermentation (SHF) method using polysaccharides from the green macroalgae Enteromorpha intestinalis as biomass. We focused on the optimization of enzymatic saccharification as pretreatments for the fermentation of E. intestinalis. Pretreatment was carried out with 10% (w/v) seaweed slurry and 270 mM H2SO4 at 121 degrees C for 60 min. Monosaccharides (mainly glucose) were obtained from enzymatic hydrolysis with a 16-U/mL mixture of Celluclast 1.5 L and Viscozyme L at 45 degrees C for 36 h. ABE fermentation with 10% (w/v) E. intestinalis hydrolysate was performed using the anaerobic bacteria Clostridium acetobutylicum with either uncontrolled pH, pH controlled at 6.0, or pH controlled initially at 6.0 and then 4.5 after 4 days, which produced ABE contents of 5.6 g/L with an ABE yield (YABE) of 0.24 g/g, 4.8 g/L with an YABE of 0.2 g/g, and 8.5 g/L with an YABE of 0.36 g/g, respectively. PMID- 30470909 TI - Emerging techniques for cell disruption and extraction of valuable bio-molecules of microalgae Nannochloropsis sp. AB - Microalgae of Nannochloropsis sp. present valuable source of bio-molecules (pigments, lipids, proteins) that have nutritional potential for the prevention and treatment of human diseases. Moreover, some species of Nannochloropsis are the promising sources of biofuels and excellent candidates for the replacement of classical biofuel crops. This review describes and compares the efficiency of different conventional and novel techniques that can be used for cell disruption and recovery of bio-molecules from Nannochloropsis sp. Classification of different extraction techniques includes chemical, enzymatic, mechanical and other physical methods. The detailed analysis of extraction efficiency assisted by pressure and temperature (subcritical and supercritical fluids, hydrothermal liquefaction), ultrasound, microwaves, and pulsed electric energy (pulsed electric fields and high voltage electrical discharges) is presented. The general discussion includes comparison between techniques, their effectiveness for cell disruption and selectivity of bio-molecules extraction from Nannochloropsis sp. The cost-effectiveness, benefits and limitations of different techniques are also analyzed. PMID- 30470910 TI - Effect of doxycycline on chronic intermittent hypoxia-induced atrial remodeling in rats. AB - BACKGROUND: Atrial remodeling in the form of fibrosis is considered the basis in the development of atrial fibrillation (AF). The aim of this study was to investigate the effects of doxycycline on atrial remodeling induced by chronic intermittent hypoxia (CIH) and the mechanisms underlying such changes. METHODS: A total of 45 Sprague-Dawley rats were randomized into three groups: control group, CIH group, CIH with doxycycline treatment (CIH-D) group. A rat model of atrial remodeling was established by CIH and Masson staining was used to evaluate the extent of atrial fibrosis. We studied the expression levels of microRNA-1 (miR 1), microRNA-21 (miR-21), microRNA-29b (miR-29b), microRNA-30 (miR-30), microRNA 133a (miR-133a), microRNA-328 (miR-328), transforming growth factor-beta1 (TGF beta1), and connective tissue growth factor (CTGF). Atrial effective refractory period and AF inducibility were examined via isolated heart models of cardiac electrophysiology. RESULTS: Compared with the control rats, CIH rats showed higher atrial interstitial collagen deposition, increased AF inducibility, and increased miR-1, miR-21, miR-133a, miR-328, TGF-beta1, and CTGF levels. Treatment with doxycycline significantly attenuated CIH-induced atrial fibrosis, improved AF inducibility, and reduced miR-1, miR-21, miR-133a, miR-328, TGF-beta1, and CTGF. CONCLUSION: CIH induced significant atrial remodeling, which was attenuated by doxycycline in our rat model. These changes can be explained by the alterations initiated in the miR-133a/TGF-beta1/CTGF pathway by doxycycline. PMID- 30470911 TI - Clinical characteristics and prognosis of cardiac tamponade patients: 5-year experience at a tertiary center. AB - BACKGROUND: Cardiac tamponade (CT) is characterized by compression of the cardiac chambers due to pericardial fluid accumulation. The etiology and prognosis may vary in different regions, and thus patient series from various regions can be useful for exploring the etiological and prognostic disparities. The aim of this study was to determine the clinical characteristics of patients with imminent CT, to evaluate the diagnostic performance of biochemical, microbiologic, and pathologic laboratory analysis, and to ascertain the prognosis of CT patients. METHODS: We enrolled all patients with imminent CT who underwent percutaneous pericardiocentesis between July 2012 and December 2017 in this retrospective study. The patients were classified into three etiology groups: (a) malignancy (MRCT); (b) iatrogenic/mechanical complication of myocardial infarction (IMCT); and (c) other causes (OCT). Clinical information, laboratory findings, and survival data were recorded. RESULTS: In total, 186 pericardiocentesis procedures were performed on 153 consecutive patients with CT. The median follow-up was 137 days (range: 1-1937). The MRCT group had the highest mortality rate (79%) in 12 months, while the OCT group had the lowest rate (27%). We determined that increased age, higher serum urea levels, and malignancy-related CT were independent predictors of mortality. The mortality rates of the MRCT and IMCT groups were similar, with both of them being significantly higher than the rate of the OCT group. In all, 15 patients were diagnosed with a new malignancy via pericardial fluid cytology. CONCLUSION: Patients in the MRCT and IMCT groups had a poor prognosis. The presence of malignancy was found to be the most powerful predictor of mortality in CT patients. PMID- 30470912 TI - Non-alcoholic fatty liver disease in the first trimester and subsequent development of gestational diabetes mellitus. AB - AIMS/HYPOTHESIS: Although there is substantial evidence that non-alcoholic fatty liver disease (NAFLD) is associated with impaired glucose homeostasis, the clinical significance of NAFLD in pregnant women has not been well determined. This study investigates the relationship between NAFLD in the first trimester and the subsequent development of gestational diabetes mellitus (GDM). METHODS: A multicentre, prospective cohort study was conducted in which singleton pregnant Korean women were assessed for NAFLD at 10-14 weeks using liver ultrasound, fatty liver index (FLI) and hepatic steatosis index (HSI). Maternal plasma adiponectin and selenoprotein P concentrations were measured. Participants were screened for GDM using the two-step approach at 24-28 weeks. RESULTS: Six hundred and eight women were included in the final analysis. The prevalence of NAFLD was 18.4% (112/608) and 5.9% (36/608) developed GDM. Participants who developed GDM had a higher prevalence of radiological steatosis (55.6% vs 16.1%; p < 0.001) and higher FLI (40.0 vs 10.7; p < 0.001) and HSI (35.5 vs 29.0; p < 0.001). The risk of developing GDM was significantly increased in participants with NAFLD and was positively correlated with the severity of steatosis. This relationship between NAFLD and GDM remained significant after adjustment for metabolic risk factors, including measures of insulin resistance. Maternal plasma adiponectin and selenoprotein P levels were also correlated with both NAFLD severity and the risk of developing GDM. CONCLUSIONS/INTERPRETATION: NAFLD in early pregnancy is an independent risk factor for GDM. Adiponectin may be a useful biomarker for predicting GDM in pregnant women. PMID- 30470913 TI - [Erratum to: Management of the difficult airway : Overview of the current guidelines]. PMID- 30470914 TI - Construction of H2O2-responsive asymmetric 2D nanofluidic channels with graphene and peroxidase-mimetic V2O5 nanowires. AB - The flexible two-dimensional (2D) nanosheet structure, high specific surface, and unique electrical properties make graphene an emerging nano-building block for molecule-responsive nanochannels. Herein, we report a novel graphene and V2O5 nanowire-based porous asymmetric membrane, which shows excellent catalytic performance and sensitive and quick response for H2O2. Poly(diallyldimethylammonium chloride)-functionalized graphene nanosheets were made into restacked lamellar film with porous structure and high anion selectivity. V2O5 nanowire, a kind of enzyme-mimetic nanomaterial, was mounted on one side of the graphene membrane through a sequential vacuum filtration method. The V2O5 nanowires on the membrane have high catalytic activities for H2O2 reduction, with the Michealis-Menten constant (KM) of 1.74 mM, better than various reported peroxidase-based nanocomposites and peroxidase mimics. This composite membrane showed quick response to H2O2 within 5 s, with good reproducibility and high operational stability. The responsive linear range was from 10 MUM to 1 mM, with the detection limit of 9.5 MUM. This fabrication of 2D layered nanomaterials and enzyme mimics could be extended for developing novel smart molecule-responsive devices. Graphical abstract ?. PMID- 30470915 TI - Asymmetrical flow field-flow fractionation for improved characterization of human plasma lipoproteins. AB - High- and low-density lipoproteins (HDL and LDL) are attractive targets for biomarker discovery. However, ultracentrifugation (UC), the current methodology of choice for isolating HDL and LDL, is tedious, requires large sample volume, results in sample loss, and does not readily provide information on particle size. In this work, human plasma HDL and LDL are separated and collected using semi-preparative asymmetrical flow field-flow fractionation (SP-AF4) and UC. The SP-AF4 and UC separation conditions, sample throughput, and liquid chromatography/mass spectrometry (LC/MS) lipidomic results are compared. Over 600 MUg of total proteins is recovered in a single SP-AF4 run, and Western blot results confirm apoA1 pure and apoB100 pure fractions, consistent with HDL and LDL, respectively. The SP-AF4 separation requires ~ 60 min per sample, thus providing a marked improvement over UC which can span hours to days. Lipidome analysis of SP-AF4-prepared HDL and LDL fractions is compared to UC-prepared HDL and LDL samples. Over 270 lipids in positive MS mode and over 140 lipids in negative MS mode are identified by both sample preparation techniques with over 98% overlap between the lipidome. Additionally, lipoprotein size distributions are determined using analytical scale AF4 coupled with multiangle light scattering (MALS) and dynamic light scattering (DLS) detectors. These developments position SP-AF4 as a sample preparation method of choice for lipoprotein biomarker characterization and identification. Graphical abstract ?. PMID- 30470916 TI - Direct quantitation and characterization of fatty acids in salmon tissue by condensed phase membrane introduction mass spectrometry (CP-MIMS) using a modified donor phase. AB - Existing mass spectrometric methods for the analysis of fatty acids often require derivatization, chromatographic separations, and/or extensive sample preparation. Direct mass spectrometry strategies can avoid these requirements, but may also suffer from poor quantitation and/or lack of sensitivity. Condensed phase membrane introduction mass spectrometry (CP-MIMS) provides direct quantitative measurements of analytes in complex samples with little or no sample preparation. CP-MIMS uses a semipermeable membrane to transfer neutral, hydrophobic compounds from real-world samples to a mass spectrometer. The results presented utilize aqueous/organic sample solvent (donor) mixtures to allow for the sensitive (pptr) detection of a range of fatty acids. The relative sensitivity across a homologous series of fatty acids is observed to change, favoring short- or long-chain fatty acids, depending on the amount of miscible co-solvent added to the donor phase. Further, lithium acetate added online via the acceptor phase was used in tandem mass spectrometry experiments to determine the location of double bonds in polyunsaturated fatty acids (PUFAs). The method was applied to direct measurements and structural determinations for selected PUFAs in salmon tissue samples. Standard addition was employed to quantify the amount of PUFAs in a variety of salmon samples, yielding 0.27-0.42 and 0.40-0.84 w/w % for eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively, for Sockeye and Chinook salmon, in good agreement with the literature. This work presents, to our knowledge, the first use of CP-MIMS for the direct analysis of fatty acids in oily foodstuff samples. Graphical abstract ?. PMID- 30470917 TI - Assessment of spatial learning and memory in the Barnes maze task in rodents methodological consideration. AB - Among the methods valuable for assessing spatial learning and memory impairments in rodents, the Barnes maze (BM) task deserves special attention. It is based on the assumption that the animal placed into the aversive environment should learn and remember the location of an escape box located below the surface of the platform. Different phases of the task allow to measure spatial learning, memory retrieval, and cognitive flexibility. Herein, we summarize current knowledge about the BM procedure, its variations and critical parameters measured in the task. We highlight confounding factors which should be taken into account when conducting BM task, discussing briefly its advantages and disadvantages. We then propose an extended version of the BM protocol which allows to measure different aspects of spatial learning and memory in rodents. We believe that this review will help to standardize the BM methodology across the laboratories and eventually make the results comparable. PMID- 30470918 TI - Lack of thiazide diuretic inhibition of agonist constriction of mouse mesenteric arterioles ex vivo. AB - The chronic reduction of arterial blood pressure by thiazide diuretics (TZD) in hypertensive patients is mediated through an extra-renal mechanism. It is widely held that this extra-renal mechanism is a direct TZD inhibition of vasoconstriction. This study tested whether the TZD, hydrochlorothiazide (HCTZ), inhibited agonist constriction of mesenteric arterioles ex vivo. Mice deficient in the kidney distal convoluted tubule Na+/Cl- cotransporter (NCC), i.e., the target of thiazide inhibition-mediated diuresis, and wild type (WT), were subjected to Na+-restricted diet. Mesenteric arterioles from NCC knockout and WT mice were then isolated, placed under constant pressure, and the inhibitory effects of HCTZ (100 MUM) on phenylephrine constriction determined. HCTZ did not inhibit phenylephrine constriction of arterioles from NCC knockout and wild type (WT) mice subjected to Na+-restricted diet. This study suggests that future investigations to identify the extra-renal site of chronic TZD treatment should (1) focus on indirect inhibition of vascular constriction and (2) be determined under clinically relevant conditions. These conditions include chronic TZD at relevant concentrations in hypertensive animals. PMID- 30470919 TI - Cucurbitacin B induces mitochondrial-mediated apoptosis pathway in cholangiocarcinoma cells via suppressing focal adhesion kinase signaling. AB - Low efficacy and high resistance rate associated with existing chemotherapeutic drugs enforce a requirement for novel therapeutic strategies for extremely aggressive cholangiocarcinoma (CCA). In the present study, the apoptosis-inducing activity of cucurbitacin B, a compound derived from plants of Cucurbitaceae family, against KKU-100 CCA cells and the underlying mechanism mediating its effect were investigated. The results showed that cucurbitacin B significantly decreased CCA cells viability by induction of apoptosis. Increased apoptotic cell death following cucurbitacin B treatment was correlated with caspase-9 and caspase-3 activations, Bax upregulation, increased cytochrome c, apoptosis inducing factor release, and decreased Bcl-2 and Bcl-XL levels, suggesting activation of the mitochondrial-mediated apoptosis pathway. Further molecular analyses revealed that cucurbitacin B inhibited focal adhesion kinase (FAK), which is an important regulator of the apoptosis process, and its downstream pathway, PI3K/Akt. Knockdown of FAK expression by small interfering RNA appeared to induce CCA cell apoptosis which was accompanied with elevated level of cytochrome c and cleaved caspase-9, and decreased level of Bcl-2, phospho-PI3K, and phospho-Akt. Taken together, cucurbitacin B induces an intrinsic mitochondrial apoptosis pathway in CCA cells partly through suppression of FAK mediated oncogenic signaling. This compound should be considered as a candidate agent for CCA treatment. PMID- 30470920 TI - Bark and latex harvesting short-term impact on native tree species reproduction. AB - The bark and the latex of plants constitute non-timber forest products (NTFPs) of medicinal and economic value that are widely harvested throughout the world. Bark and latex harvesting impacts on plant reproduction are controversial in the literature. Some species are negatively impacted, some do not show any response, and others may exhibit higher flower and fruit production after harvesting. In areas of rainforests and cerrado (tropical savanna) in northeastern Brazil, local people intensely remove the bark of Himatanthus drasticus (for latex collection) and Stryphnodendron rotundifolium for medicinal purposes. We aimed to investigate the short-term impact of harvesting upon reproductive effort of tree species, using those species as models. We assumed that bark harvesting negatively interferes in the reproductive capacity of plant species. Individuals of both species were harvested 2 months before blooming (treated) and the production of reproductive structures, physical characteristics of fruits and seeds, and the pre-emergent reproductive success were compared between treated and control (intact) individuals. All parameters of H. drasticus declined after bark removal, except pollen and ovule production. The only reproductive parameters of S. rotundifolium that were negatively affected were pollen and ovule production, and the pre-emergent reproductive success was higher in treatment individuals. We discuss the differences found between the species regarding responses to harvesting. Our results show that harvesting have short-term effects upon reproduction and may impair gene flow by affecting pollination and seed dispersal of tree species. PMID- 30470921 TI - ? PMID- 30470922 TI - Fabrication of 6-gingerol, doxorubicin and alginate hydroxyapatite into a bio compatible formulation: enhanced anti-proliferative effect on breast and liver cancer cells. AB - Ample attention has been devoted to the construction of anti-cancer drug delivery systems with increased stability, and controlled and targeted delivery, minimizing toxic effects. In this study we have designed a magnetically attractive hydroxyapatite (m-HAP) based alginate polymer bound nanocarrier to perform targeted, controlled and pH sensitive drug release of 6-gingerol, doxorubicin, and their combination, preferably at low pH environments (pH 5.3). They have exhibited higher encapsulation efficiency which is in the range of 97.4 98.9% for both 6-gingerol and doxorubicin molecules whereas the co-loading has accounted for a value of 81.87 +/- 0.32%. Cell proliferation assays, fluorescence imaging and flow cytometric analysis, demonstrated the remarkable time and dose responsive anti-proliferative effect of drug loaded nanoparticles on MCF-7 cells and HEpG2 cells compared with their neat counter parts. Also, these systems have exhibited significantly reduced toxic effects on non-targeted, non-cancerous cells in contrast to the excellent ability to selectively kill cancerous cells. This study has suggested that this HAP based system is a versatile carrier capable of loading various drug molecules, ultimately producing a profound anti proliferative effect. PMID- 30470923 TI - Photothermal/pH Dual-Responsive Drug Delivery System of Amino-Terminated HBP Modified rGO and the Chemo-Photothermal Therapy on Tumor Cells. AB - In this paper, a simple method to prepare hydrophilic reduced graphene oxide (rGO) was proposed via reducing GO by amino-terminated hyperbranched polymer (NHBP), the as-prepared NrGO could present excellent dispersibility, near infrared (NIR) light absorbance, photothermal conversion ability and stability. Then, the doxorubicin hydrochloride (DOX) was conjugated with NrGO to prepare the drug-loading system, and a pH/photothermal dual-responsive drug delivery behavior was characterized. At acidic environment or under NIR laser irradiation, the drug release rate could be improved, which is beneficial to control release anti-tumor drug in tumor tissues. What is more, the in vitro cell experiments revealed that NrGO was well biocompatible, and in the tumor inhibition part, comparing to the control group without any treatment, DOX@NrGO gained efficient chemo-photothermal synergetic therapy, the inhibition rate of which was much higher than single chemotherapy of released DOX. Therefore, the as-prepared DOX@NrGO obtained great potential application in tumor therapy and an excellent candidate in other biomed applications. PMID- 30470924 TI - Postpartum contraceptive counseling for first-time adolescent mothers: a randomized controlled trial. AB - PURPOSE: Rapid repeat pregnancy is common among adolescent mothers and is associated with increased risks of adverse perinatal and maternal outcomes. Increasing contraceptive uptake among postpartum adolescents may decrease these outcomes through pregnancy prevention. This randomized controlled trial of 100 postpartum adolescent women assessed the effect of a standardized immediate postpartum contraceptive counseling intervention emphasizing healthy birth spacing and the use of long-acting reversible contraceptives (LARC). METHODS: After a baseline survey about reproductive health and pregnancy intentions, all subjects received routine postpartum contraceptive counseling. The intervention group also received the standardized counseling intervention. All participants had access to immediate postpartum contraceptive implant initiation or to intrauterine device (IUD) insertion at postpartum follow-up. Contraceptive use and repeat pregnancy were assessed quarterly for 12 months. Differences in repeat pregnancy, as well as contraceptive initiation, continuation, and satisfaction were analyzed. RESULTS: There was no difference in repeat pregnancy or contraceptive initiation, continuation or satisfaction between the study groups. However, regardless of group assignment, all subjects who desired the contraceptive implant used the method, compared to 15% of subjects who desired the IUD (p < 0.001). Three pregnancies occurred among subjects who desired the IUD versus none amongst subjects who desired the implant (p = 0.10). CONCLUSIONS: This standardized postpartum contraceptive counseling intervention did not affect teens' repeat pregnancies or contraceptive use. However, immediate postpartum availability of the contraceptive implant was associated with increased utilization of this method when compared to the IUD. Future postpartum contraceptive efforts should investigate procedures to improve teens' access to postpartum contraception. CLINICALTRIALS. GOV IDENTIFIER: NCT01814930. PMID- 30470925 TI - Neutropenia and Thrombocytopenia Induced by Proton Pump Inhibitors: A Case Report. AB - An 85-year-old man was admitted to our hospital because of dysphagia, and was diagnosed with benign stricture of the esophagus. He was hospitalized repeatedly for balloon dilations. Pantoprazole sodium (80 mg, twice daily, intravenously) was administered each time when he was in hospital, while esomeprazole (20 mg/day, orally) was administered intermittently when he was at home. Reductions in both white blood cells and platelets were noticed about 4 months after proton pump inhibitors were introduced. Bone marrow suppression induced by proton pump inhibitors was diagnosed as proven by bone marrow biopsy. White blood cell, neutrophil, and platelet counts went back to the normal range after proton pump inhibitors were stopped. The present case shows a rare bi-cytopenia associated with proton pump inhibitors and suggests the importance of awareness of hematological adverse events during proton pump inhibitor therapy. PMID- 30470926 TI - Behavioural and physiological responses to low- and high-intensity locomotion in Chinese shrimp Fenneropenaeus chinensis. AB - We explored stroke behaviour, energy sources, and their related metabolic enzymes during multi-intensity swimming and tail-flipping at low- and high-intensity modes in Chinese shrimp Fenneropenaeus chinensis. In swimming, shrimp were encouraged to swim at velocities of 3, 6, 9 cm s-1 for 200 min (low-intensity), and at 12, 15, 18 cm s-1 until fatigue (high-intensity). In tail-flipping, shrimp were encouraged to tail-flip by tapping cephalothorax at frequencies of 0.020, 0.040, 0.063 Hz (one tap every 50, 25, 16 s) for 5 min (low-intensity), and at 0.083, 0,100, 0.125 Hz (one tap every 12, 10, 8 s) until no response (high intensity). Results showed that shrimp increased stroke rates of pleopods and uropods to elevate swimming and tail-flipping ability. For low-intensity locomotion, glycogen was burned in aerobic pathway due to low pleopods beat frequency in swimming; however, glycogen was anaerobically burned due to high uropods beat amplitude in tail-flipping. Anaerobic metabolism occurred in high intensity locomotion in either swimming or tail-flipping. Critical contents of muscle lactate causing locomotion fatigue might be around threefold of rest condition. Shrimp reduced locomotive time to avoid glycogen exhaustion and lactate accumulation during high-intensity locomotion. These findings highlight our understanding of physiological mechanisms of locomotion activities in shrimp. PMID- 30470927 TI - Berberine chloride mediates its antileishmanial activity by inhibiting Leishmania mitochondria. AB - Berberine chloride, a plant-derived isoquinoline alkaloid, has been demonstrated to have leishmanicidal activity, which is mediated by generation of a redox imbalance and depolarization of the mitochondrial membrane, resulting in a caspase-independent apoptotic-like cell death. However, its impact on mitochondrial function remains to be delineated and is the focus of this study. In UR6 promastigotes, berberine chloride demonstrated a dose-dependent increase in generation of reactive oxygen species and mitochondrial superoxide, depolarization of the mitochondrial membrane potential, a dose-dependent inhibition of mitochondrial complexes I-III and II-III, along with a substantial depletion of ATP, collectively suggesting inhibition of parasite mitochondria. Accordingly, the oxidative stress induced by berberine chloride resulting in an apoptotic-like cell death in Leishmania can be exploited as a potent chemotherapeutic strategy, mitochondria being a prime contributor. PMID- 30470928 TI - An integrated approach towards the development of novel antifungal agents containing thiadiazole: synthesis and a combined similarity search, homology modelling, molecular dynamics and molecular docking study. AB - BACKGROUND: This study aims to synthesise and characterise novel compounds containing 2-amino-1,3,4-thiadiazole and their acyl derivatives and to investigate antifungal activities. Similarity search, molecular dynamics and molecular docking were also studied to find out a potential target and enlighten the inhibition mechanism. RESULTS: As a first step, 2-amino-1,3,4-thiadiazole derivatives (compounds 3 and 4) were synthesised with high yields (81 and 84%). The target compounds (6a-n and 7a-n) were then synthesised with moderate to high yields (56-87%) by reacting 3 and 4 with various acyl chloride derivatives (5a n). The synthesized compounds were characterized using the IR, 1H-NMR, 13C-NMR, Mass, X-ray (compound 7n) and elemental analysis techniques. Later, the in vitro antifungal activities of the synthesised compounds were determined. The inhibition zones exhibited by the compounds against the tested fungi, their minimum fungicidal activities, minimum inhibitory concentration and the lethal dose values (LD50) were determined. The compounds exhibited moderate to high levels of activity against all tested pathogens. Finally, in silico modelling was used to enlighten inhibition mechanism using ligand and structure-based methods. As an initial step, similarity search was carried out and the resulting proteins that belong to Homo sapiens were used as reference in sequence similarity search to find the corresponding amino acid sequences in target organisms. Homology modelling was used to construct the protein structure. The stabilised protein structure obtained from molecular dynamics simulation was used in molecular docking. CONCLUSION: The overall results presented here might be a good starting point for the identification of novel and more active compounds as antifungal agents. PMID- 30470929 TI - Magnetoviscous Property and Hyperthermia Effect of Amorphous Nanoparticle Aqueous Ferrofluids. AB - Magnetic Fe-B, Fe-Ni-B, and Co-B nanoparticles were successfully synthesized and introduced to water to prepare aqueous ferrofluids. The Fe-B, Fe-Ni-B, and Co-B particles are homogeneous amorphous nanoparticles with an average particle size 15 nm. The shape of the amorphous nanoparticles is regular. The Fe-B, Fe-Ni-B, and Co-B amorphous nanoparticles are superparamagnetic. Moreover, the saturation magnetizations of Fe-B and Fe-Ni-B amorphous nanoparticles are 75 emu/g and 51 emu/g. These are approximately 2.8 and 1.9-fold larger than Co-B nanoparticles, respectively. The viscosity of the amorphous ferrofluids has a strong response to external magnetic field. The yield stress increases with increasing magnetic field. The hyperthermia research of amorphous ferrofluids was firstly investigated. The experimental results indicate that the heating temperature of Fe-B ferrofluid and Fe-Ni-B ferrofluid could increase to 42 degrees C in 750 s and 960 s, respectively, when the output current is 300 A. The temperature could reach 61.6 degrees C for a Fe-B ferrofluid. The heating efficiencies of the amorphous ferrofluids demonstrate that the Fe-B ferrofluid and Fe-Ni-B ferrofluid may have great potential for biomedical applications. PMID- 30470930 TI - Two-Dimensional CeO2/RGO Composite-Modified Separator for Lithium/Sulfur Batteries. AB - In this work, a modified separator coated with a functional layer of reduced graphene oxide (RGO) anchored by cerium oxide (CeO2) nanoparticles was developed. The superior conductivity of RGO and chemical immobilization of high-ordered sulfur-related species (mainly Li2Sn 4 <= n <= 8) of CeO2 yielded batteries with enhanced characteristics. A remarkable original capacity of 1136 mAh g-1 was obtained at 0.1 C with capacity retention ratio of 75.7% after 100 charge/discharge cycles. Overall, these data indicate that the separator with CeO2/RGO composite is promising to suppress the shuttling of polysulfides for better utilization of the active material. PMID- 30470931 TI - Sustained low efficiency dialysis should not be interrupted for performing transpulmonary thermodilution measurements. AB - BACKGROUND: Treatment of multiple organ failure frequently requires enhanced hemodynamic monitoring. When renal replacement is indicated, it remains unclear whether transpulmonary thermodilution (TPTD) measurements are influenced by renal replacement therapy (RRT) and whether RRT should be paused for TPTD measurements. Our aim was therefore to investigate the effect of pausing RRT on TPTD results in two dialysis catheter locations. MATERIALS AND METHODS: In total, 62 TPTD measurements in 24 patients (APACHE: 32 +/- 7 [mean +/- standard deviation (SD)]) were performed using the PiCCOTM system (Pulsion, Germany). Patients were treated with sustained low efficiency dialysis (SLED; GeniusTM system, Fresenius, Germany) as RRT. Measurements were taken during ongoing hemodialysis (HD, HDO), during paused HD (HDP) and immediately after termination of HD and blood restitution (HDT). Dialysis catheters were placed either in the superior vena cava (SVC, 19 times) or in the inferior vena cava (IVC, 5 times). Statistical analysis was performed to assess the effects of the measurement setting, SLED (blood flow rate) and the catheter location, on cardiac index (CI), global end diastolic volume index (GEDVI) and extravascular lung water index (EVLWI) as measured by TPTD. Multilevel models were used for the analysis due to the triplicate measurements and due to 12 out of 19 SVC and 2 out of 5 IVC patients having more than one TPTD measured. RESULTS: CI and GEDVI were significantly higher at time point HDP compared to both HDO and HDT. In contrast, values for EVLWI were lower at HDP when compared to HDO and HDT. These findings were independent of the site of dialysis catheter insertion and blood flow rate. CONCLUSIONS: PiCCOTM measurements assessed at paused SLED significantly deviate from ongoing and terminated SLED. Therefore, the dialysis system should not be paused for measurements. TPTD measurements in patients with PiCCO monitoring seem sufficiently reliable during ongoing SLED as well as after its termination. An effect of dialysis catheter location (SVC vs IVC) and blood flow rate on PiCCOTM measurements could not be shown. PMID- 30470932 TI - Fully automated real-time PCR for EGFR testing in non-small cell lung carcinoma. AB - Molecular testing for mutations in the EGFR gene is commonplace for patients with non-small cell lung cancer (NSCLC). These patients are often very sick and management decisions need to be made urgently. In many cases, the results of molecular testing are needed the same day, in order to start targeted therapy and allow maximum benefit for patients. The IdyllaTM EGFR Mutation Test offers rapid results within three hours of requesting. This study aimed to assess the concordance of IdyllaTM EGFR Mutation Test results with current standard tests. Forty formalin-fixed, paraffin-embedded NSCLC tumour cases (20 EGFR mutant and EGFR 20 wild type) were analysed by the IdyllaTM EGFR Mutation Test (CE-IVD) and compared with PCR and NGS methodologies. The overall concordance between IdyllaTM and standard testing was 92.5% (95% CI 80.14% to 97.42%) and the specificity of IdyllaTM was 100% (95% CI 83.89% to 100%). The sensitivity was affected by loss of tumour content in tissue blocks in a small number of NGS cases; however, comparing IdyllaTM with PCR alone, there was 100% concordance (95% CI 89.85% to 100%). The IdyllaTM EGFR Mutation Test shows comparative accuracy to routine PCR testing for the most common EGFR mutations in NSCLC. The IdyllaTM also offers significantly reduced turn-around times compared with existing modalities and therefore the platform would be a useful addition to many molecular diagnostics units. PMID- 30470933 TI - Precision immunoprofiling by image analysis and artificial intelligence. AB - Clinical success of immunotherapy is driving the need for new prognostic and predictive assays to inform patient selection and stratification. This requirement can be met by a combination of computational pathology and artificial intelligence. Here, we critically assess computational approaches supporting the development of a standardized methodology in the assessment of immune-oncology biomarkers, such as PD-L1 and immune cell infiltrates. We examine immunoprofiling through spatial analysis of tumor-immune cell interactions and multiplexing technologies as a predictor of patient response to cancer treatment. Further, we discuss how integrated bioinformatics can enable the amalgamation of complex morphological phenotypes with the multiomics datasets that drive precision medicine. We provide an outline to machine learning (ML) and artificial intelligence tools and illustrate fields of application in immune-oncology, such as pattern-recognition in large and complex datasets and deep learning approaches for survival analysis. Synergies of surgical pathology and computational analyses are expected to improve patient stratification in immuno-oncology. We propose that future clinical demands will be best met by (1) dedicated research at the interface of pathology and bioinformatics, supported by professional societies, and (2) the integration of data sciences and digital image analysis in the professional education of pathologists. PMID- 30470934 TI - Adoptive cellular therapies: the current landscape. AB - For many cancer types, the immune system plays an essential role in their development and growth. Based on these rather novel insights, immunotherapeutic strategies have been developed. In the past decade, immune checkpoint blockade has demonstrated a major breakthrough in cancer treatment and has currently been approved for the treatment of multiple tumor types. Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) or gene-modified T cells expressing novel T cell receptors (TCR) or chimeric antigen receptors (CAR) is another strategy to modify the immune system to recognize tumor cells and thus carry out an anti-tumor effector function. These treatments have shown promising results in various tumor types, and multiple clinical trials are being conducted worldwide to further optimize this treatment modality. Most successful results were obtained in hematological malignancies with the use of CD19-directed CAR T cell therapy and already led to the commercial approval by the FDA. This review provides an overview of the developments in ACT, the associated toxicity, and the future potential of ACT in cancer treatment. PMID- 30470935 TI - [New developments in cardiac implantable electronic devices]. PMID- 30470936 TI - Hospitalization rates and resource utilization of schizophrenic patients switched from oral antipsychotics to aripiprazole-depot in Germany. AB - OBJECTIVE: Examine cost-driving factors of schizophrenia in Germany for patients prior- and post-switch from an oral antipsychotic therapy to aripiprazole-depot and perform a budget impact analysis (BIA) referring to the context of German health care. METHODS: A single-armed, retrospective, non-interventional pre-post comparison study with 132 patients to compare the total psychiatric hospitalization rates and the associated costs of both, the treatment with oral antipsychotics and aripiprazole-depot. The BIA was performed to compare both treatment periods with respect to health-related costs. A subsequent univariate sensitivity analysis examined the robustness of the results. RESULTS: After switching the treatment to aripiprazole-depot, the total psychiatric hospitalization rates for the 6-month treatment period were significantly (p < 0.001) lower (14%) compared to the hospitalization rates when treated with oral antipsychotics (55.1%). 18.2% of the patients reported to be employed, with 29.2% having work incapacities. The mean number of schizophrenia episodes was 2.58 episodes per patient during the oral-antipsychotic treatment compared to 0.41 episodes per patient during the aripiprazole-depot phase (p < 0.001). The treatment with aripiprazole-depot also significantly reduced the mean number of hospitalizations per patient (0.63 to 0.16, p < 0.001) and the mean number of hospitalized days (27.39 to 5.56, p < 0.001) compared to the oral antipsychotic treatment. Additionally a significant reduction of the mean stay in day-clinics and psychiatric institute ambulances (PIAs) was observed (46.13 days to 7.29 days, p < 0.01). Treatment of a patient suffering from schizophrenia with oral antipsychotics produced costs of 9935.38? (direct costs: 9498.36 ?), while aripiprazole-depot generated costs of 4557.56? (direct costs: 4449.83 ?) per patient for a one-year observation period. This resulted in total costs of 6,517,606,265.43? for the oral antipsychotic treatment and 2,989,756,603.05? for aripiprazole-depot treatment from the perspective of the German health care system. The results remained robust during sensitivity analysis, with aripiprazole-depot being the more cost-effective strategy. CONCLUSIONS: The results suggest that aripiprazole-depot treatment for schizophrenia patients has major potential in terms of cost savings for the German statutory health insurance. PMID- 30470937 TI - Depressive symptom prevalence after intracerebral hemorrhage: a multi-center study. AB - INTRODUCTION: Depressive symptoms in patients with intracerebral hemorrhage (ICH) are common and are associated with worse outcomes. It is not well described how often depressive symptoms are ascertained and treated in large unselected cohorts of patients, and whether depressive symptoms would be a potential target for improving outcomes. METHODS: Data were electronically retrieved from a multi center EHR repository in Chicago, IL, from 2006 to 2012 ("multicenter cohort"). In the multicenter cohort, we retrieved diagnostic codes and medication data from four university health systems across Chicago. In the single center cohort, we prospectively screened for depressive symptoms (NIH Patient Reported Outcomes Measurement Information System, PROMIS, T Score >= 60), at one, three and twelve months after ICH onset. It should be noted that not all depressive symptoms are optimally characterized through diagnostic codes. RESULTS: Diagnostic codes for depressive symptoms up to three months after ICH onset were recorded in 132 of 3422 (3.8%) of the multicenter cohort; fewer than 10% of patients received a typical medication to treat depressive symptoms, and < 2% one month later. In the single-center cohort, PROMIS assessments were indicative of depressive symptoms in 26 of 116 (22.4%), and depressive symptoms were more likely to be found with screening (OR 7.20, 95% CI 4.5-11.5, P < 0.0001). Results were similar up to 12 months after ICH. CONCLUSIONS: Depressive symptoms in patients with ICH are more common than medication treatment or a coded diagnosis in a multi-center cohort, and are a potential opportunity for additional treatment to improve outcomes. There are currently no AHA/ASA treatment guidelines for depression screening of patients with ICH. PMID- 30470938 TI - Ethylene glycol elimination in amine loop for more efficient gas conditioning. AB - The gas sweetening unit of phase 2 and 3 in South Pars Gas Field (Asalouyeh, Iran) was first simulated to investigate the effect of mono ethylene glycol (MEG) in the amine loop. MEG is commonly injected into the system to avoid hydrate formation while a few amounts of MEG is usually transferred to amine gas sweetening plant. This paper aims to address the points where MEG has negative effects on gas sweetening process and what the practical ways to reduce its effect are. The results showed that in the presence of 25% of MEG in amine loop, H2S absorption from the sour gas was increased from 1.09 to 3.78 ppm. Also, the reboiler temperature of the regenerator (from 129 to 135 degrees C), amine degradation and required steam and consequently corrosion (1.10 to 17.20 mpy) were increased. The energy consumption and the amount of amine make-up increase with increasing MEG loading in amine loop. In addition, due to increasing benzene, toluene, ethylbenzene and xylene (BTEX) and heavy hydrocarbon solubility in amine solution, foaming problems were observed. Furthermore, side effects of MEG presence in sulfur recovery unit (SRU) such as more transferring BTEX to SRU and catalyst deactivation were also investigated. The use of total and/or partial fresh MDEA, install insulation and coating on the area with the high potential of corrosion, optimization of operational parameters and reduction of MEG from the source were carried out to solve the problem. The simulated results were in good agreement with industrial findings. From the simulation, it was found that the problem issued by MEG has less effect when MEG concentration in lean amine loop was kept less than 15% (as such observed in the industrial plant). Furthermore, the allowable limit, source and effects of each contaminant in amine gas sweetening were illustrated. PMID- 30470939 TI - Initial hospitalization with rigorous bed rest followed by bracing and rehabilitation as an option of conservative treatment for osteoporotic vertebral fractures in elderly patients: a pilot one arm safety and feasibility study. AB - : We assessed the safety and feasibility of a unified conservative treatment protocol for osteoporotic vertebral fractures in the elderly patients with a 24 week follow-up. Our results showed that initial hospitalization with rigorous bed rest followed by a rehabilitation program using a Jewett brace was safe and feasible in managing patients. PURPOSE: The purpose of this study was to prove the safety and feasibility of a unified conservative treatment protocol, which included initial hospitalization with rigorous bed rest followed by a rehabilitation program with Jewett brace for osteoporotic vertebral fractures (OVFs) in the elderly patients with a 24-week follow-up. METHODS: Between April 2012 and Mach 2015, one hundred fifty-four patients met the eligibility for this study. Radiological findings at the 3-week, 6~8-week, 24-week assessment were evaluated. Among these, 11 patients underwent early surgery within the first 2 weeks after admission and 19 patients lost follow-up. Therefore, 124 patients were assessed at the final follow-up visit. RESULTS: The average vertebral instability in all the present series was 4.9 +/- 4.8 degrees at 3-week, 2.9 +/- 3.5 degrees at 6~8-week, and 1.8 +/- 3.0 degrees at 24-week follow-up visit. Delayed union was observed in 16 patients on the 24-week follow-up visit. Therefore, the present conservative treatment protocol resulted in bony union in 98 out of 124 patients (79.0%, per protocol set analysis) and 98 out of 154 patients including drop-out (63.6%, intention-to-treat analysis). There was no severe adverse event related to initial bed rest. The vertebral instability at 3 week assessment was significantly higher in the delayed union group when compared with that in the union group. Univariate analyses followed by multivariate logistic regression analysis revealed that T2-weighted image of confined high intensity on MRI and having more than 5 degrees of vertebral instability on dynamic X-ray at 3-week assessment are the independent risk factors for delayed union of conservative treatment in the present series. CONCLUSIONS: Our results showed that initial hospitalization with rigorous bed rest followed by a rehabilitation program using a Jewett brace was safe and feasible. Therefore, the present conservative treatment protocol can be one of the acceptable treatment options in managing OVF patients. PMID- 30470940 TI - Soluble intercellular adhesion molecule-1 is a prognostic marker in colorectal carcinoma. AB - PURPOSE: Serological tumor markers are routinely used to monitor tumor onset and progression. In colorectal carcinoma (CRC), the carcinoembryonic antigen (CEA) is roughly elevated in 50% of patients at initial diagnosis. Soluble ICAM-1 (sICAM 1) is elevated in different cancers. The aim of this study was to evaluate the prognostic relevance of sICAM-1 combined with CEA in patients with CRC. METHODS: In blood samples of 297 CRC patients, sICAM-1 was determined by ELISA and CEA by microparticle enzyme immunoassay the day before oncologic resection. Separation in patients with sICAM-1high and sICAM-1low was performed by minimum p value approach; separation in CEA normal and elevated was performed according to the established diagnostic cutoff. Clinical data were obtained from the prospective collected data from the Erlangen Registry for Colorectal Carcinomas. RESULTS: Cancer-related 5-year survival rate of patients with sICAM-1low (< 290 ng/ml, n = 208) was significantly increased (83.4%) as compared to that of patients with sICAM-1high (>= 290 ng/ml, n = 89) (66.2%; p < 0.001). Patients with normal CEA concentrations (n = 199; 90.8%) showed a significantly (p < 0.001) improved cancer-related 5-year survival rate compared to patients with elevated CEA concentrations (n = 98; 52.1%). Moreover, high sICAM-1 was an independent risk factor (hazard ratio 1.6) in multivariate analysis. Of note, increased sICAM-1 levels, either within normal or within elevated CEA, allowed to identify high risk subgroups, both for overall (p < 0.001) and cancer-related survival (p < 0.001). CONCLUSION: Application of a novel risk score combining CEA/sICAM-1 serum concentrations allows the identification of high-risk groups for poor survival in CRC patients. PMID- 30470942 TI - Effects of elastomer roller stimulation of facial skin on autonomic nervous activity. PMID- 30470941 TI - Laparoscopic surgery may decrease the risk of clinical anastomotic leakage and a nomogram to predict anastomotic leakage after anterior resection for rectal cancer. AB - INTRODUCTION: Anastomotic leakage is still one of the most dreaded complications after anterior resection for rectal cancer. This study aimed to identify risk factors for anastomotic leakage and to create a nomogram for precise prediction of anastomotic leakage after anterior resection for rectal cancer. METHODS: Two thousand six hundred eighteen consecutive patients who underwent anterior resection for rectal cancer with primary anastomosis, with or without diverting stoma, were retrospectively analyzed as a training dataset. Univariate and multivariable Cox regression analyses were used to determine independent risk factors associated with anastomotic leakage. A nomogram was constructed to predict anastomotic leakage. Data containing 611 patients were prospectively collected as a test dataset. The performance of the nomogram was evaluated by using a bootstrapped-concordance index and calibration plots. RESULTS: The rate of clinical anastomotic leakage was 9.3% in the training dataset. Multivariate analysis identifies the following variables as independent risk factors for anastomotic leakage: gender (male) (odds ratio (OR) = 2.286), distance of tumor to anal verge (OR = 0.791), tumor size (OR = 1.175), operating time (OR = 1.009), diabetes mellitus (OR = 1.704), laparoscopic surgery (OR = 0.445), anastomotic bleeding (OR = 13.46), and diverting stoma (OR = 0.386). We created a nomogram with high discriminative ability (concordance index, 0.722). The area under the curve value, which evaluated the predictive performance of external validation, was 0.723. CONCLUSIONS: A protective diverting stoma and laparoscopic surgery significantly decrease the risk of anastomotic leakage. Our nomogram was a useful tool for precise prediction of anastomotic leakage after anterior resection for rectal cancer. PMID- 30470943 TI - Functional neuroimaging of the central autonomic network: recent developments and clinical implications. AB - PURPOSE: The central autonomic network (CAN) is an intricate system of brainstem, subcortical, and cortical structures that play key roles in the function of the autonomic nervous system. Prior to the advent of functional neuroimaging, in vivo studies of the human CAN were limited. The purpose of this review is to highlight the contribution of functional neuroimaging, specifically functional magnetic resonance imaging (fMRI), to the study of the CAN, and to discuss recent advances in this area. Additionally, we aim to emphasize exciting areas for future research. METHODS: We reviewed the existing literature in functional neuroimaging of the CAN. Here, we focus on fMRI research conducted in healthy human subjects, as well as research that has been done in disease states, to understand CAN function. To minimize confounding, papers examining CAN function in the context of cognition, emotion, pain, and affective disorders were excluded. RESULTS: fMRI has led to significant advances in the understanding of human CAN function. The CAN is composed of widespread brainstem and forebrain structures that are intricately connected and play key roles in reflexive and modulatory control of autonomic function. CONCLUSIONS: fMRI technology has contributed extensively to current knowledge of CAN function. It holds promise to serve as a biomarker in disease states. With ongoing advancements in fMRI technology, there is great opportunity and need for future research involving the CAN. PMID- 30470944 TI - Computational investigation of ultrastructural behavior of bone using a cohesive finite element approach. AB - Bone ultrastructure at sub-lamellar length scale is a key structural unit in bone that bridges nano- and microscale hierarchies of the tissue. Despite its influence on bulk response of bone, the mechanical behavior of bone at ultrastructural level remains poorly understood. To fill this gap, in this study, a two-dimensional cohesive finite element model of bone at sub-lamellar level was proposed and analyzed under tensile and compressive loading conditions. In the model, ultrastructural bone was considered as a composite of mineralized collagen fibrils (MCFs) embedded in an extrafibrillar matrix (EFM) that is comprised of hydroxyapatite (HA) polycrystals bounded via thin organic interfaces of non collagenous proteins (NCPs). The simulation results indicated that in compression, EFM dictated the pre-yield deformation of the model, then damage was initiated via relative sliding of HA polycrystals along the organic interfaces, and finally shear bands were formed followed by delamination between MCF and EFM and local buckling of MCF. In tension, EFM carried the most of load in pre-yield deformation, and then an array of opening-mode nano-cracks began to form within EFM after yielding, thus gradually transferring the load to MCF until failure, which acted as crack bridging filament. The failure modes, stress-strain curves, and in situ mineral strain of ultrastructural bone predicted by the model were in good agreement with the experimental observations reported in the literature, thus suggesting that this model can provide new insights into sub-microscale mechanical behavior of bone. PMID- 30470945 TI - Performance, feed utilization, and hepatic metabolic response of weaned juvenile Atlantic bluefin tuna (Thunnus thynnus L.): effects of dietary lipid level and source. AB - Two trials were performed using extruded diets as on-growing feeds for weaned Atlantic bluefin tuna (Thunnus thynnus; ABT) to establish adequate dietary levels of both lipid and omega-3 long-chain polyunsaturated fatty acids (LC-PUFAs), and impacts on lipid metabolism via liver gene expression. In trial A, ABT were fed with either a commercial feed (Magokoro(r); MGK) as a reference diet or two experimental feeds differing in lipid levels (15 or 20%) using krill oil (KO) as the single lipid source in order to estimate suitable lipid content. Fish fed MGK displayed the highest growth, followed by 15KO, and therefore a dietary lipid content of 15% was considered preferable to 20% at this stage. In trial B, fish were fed MGK, 15KO, or a feed containing 15% lipid with a blend of KO and rapeseed oil (RO) (1:1, v/v; 15KORO). Fish fed 15KO and 15KORO showed no difference in weight gain, specific growth rate, and fork length. Increasing dietary lipid level or including vegetable oil, RO, in the feeds did not increase liver lipid content. Liver fatty acid compositions largely reflected dietary profiles confirming very limited endogenous LC-PUFA biosynthesis. Liver of ABT fed 15KO and 20KO displayed the highest contents of docosahexaenoic acid (DHA). The hepatic expression of genes encoding enzymes and transcription factors involved in lipid and fatty acid metabolism, as well as genes encoding antioxidant enzymes, showed that many of these genes were regulated by dietary lipid and LC-PUFA content. Results suggested that ABT juveniles can be on-grown on inert dry feeds that support good fish growth and the accumulation of DHA. PMID- 30470946 TI - Rationale, Design, and Baseline Characteristics of the Prospective Japan Acute Myocardial Infarction Registry (JAMIR). AB - BACKGROUND: Antiplatelet therapy is a cornerstone of treatment following acute myocardial infarction (AMI). Recently, prasugrel, a new and potent antiplatelet agent, has been introduced in clinical practice. To date, however, real-world in hospital and follow-up data in Japanese patients with AMI remain limited. OBJECTIVES: To examine ischemic and bleeding events in Japanese patients with AMI and the association between these events and antiplatelet therapy. METHODS: The Japan AMI Registry (JAMIR) is a multicenter, nationwide, prospective registry enrolling patients with AMI from 50 institutions. The inclusion criterion is spontaneous onset of AMI diagnosed based on either the universal definition or Monitoring Trends and Determinants in Cardiovascular disease (MONICA) criteria. The major exclusion criteria are hospital admission >= 24 h after onset, no return of spontaneous circulation on admission following out-of-hospital cardiopulmonary arrest, and AMI as a complication of percutaneous coronary intervention or coronary artery bypass grafting. The primary end point of the study is the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Major safety end points include major bleeding based on Thrombolysis in Myocardial Infarction (TIMI) criteria and type 3 or type 5 bleeding based on Bleeding Academic Research Consortium (BARC) criteria. Between December 2015 and May 2017, a total of 3411 patients (mean age 68.1 +/- 13.2 years, 23.4% female) were enrolled in the study. Patients will be followed for 1 year. CONCLUSIONS: JAMIR will provide important information regarding contemporary practice patterns in the management of Japanese patients with AMI, their demographic and clinical characteristics, in-hospital and post-discharge outcomes, and how they are related to antiplatelet therapy. PMID- 30470947 TI - Use of isotope hydrology in groundwater conceptualization for modeling flow and contaminant transport at northwestern Sinai, Egypt. AB - The study area extends along northwestern Sinai coastal plain, which is considered an integral part of the Mediterranean Sea. It depends mainly on the groundwater resource for different type of human activities such as agricultural and drinking. Many programs and policies should be implemented in this area to concurrently improve the sustainability of groundwater use and manage the risks of its degradation. Leakage from some factories in Bir El-Abd might be a contamination source that would threaten groundwater. In this paper, an attempt was made using an integrated approach of the hydrogeological setting and the conjugation of the hydrogeochemical data with the stable isotope hydrology for representation of the conceptual model of the study area. Those tools give more insights on the characterization of the groundwater system with all relevant boundaries and main recharge sources of the aquifer; which is considered to be the key components of a groundwater modeling. A particular focus is placed on modeling a hypothetical accident for contaminant transport in the groundwater system, using both lead and chromium as a typical contaminant component. Further predication of the concentration of those elements has been estimated, and the safety distances of their plume have been determined. This study would be helpful in dealing with water management issues related to contaminant hydrogeology. As well, it introduces some finding for reducing the environmental risk form the industrial development at the study area. PMID- 30470948 TI - Application of Toxigenic Alternaria oxytropis to Soybeans and its Effect on Swainsonine Detection in Different Environments. AB - Alternaria oxytropis is an endophytic fungus of locoweeds that synthesizes swainsonine toxin. In this work, we evaluated the effect of A. oxytropis on soybean seedlings and quantified swainsonine in different culture conditions. Soybean (Glycine max) seeds were co-cultured with A. oxytropis (at different concentrations of mycelial suspensions) in agar media and soil culture, and swainsonine was assayed using LC-MS/MS. The results showed evidence that A. oxytropis infected soybean seedlings produced detectable swainsonine in agar culture while the toxin was undetectable or below the detection limit (0.006% of swainsonine dry weight) in soil media even at higher concentrations of the fungus. These results suggest that swainsonine detection is highly dependent on culture conditions and that soybeans co-cultured with A. oxytropis in soil could potentially be used to limit toxin production. PMID- 30470949 TI - Accurate and Sensitive Analytical Strategy for the Determination of Antimony: Hydrogen Assisted T-Shaped Slotted Quartz Tube-Atom Trap-Flame Atomic Absorption Spectrometry. AB - Antimony is known to have some adverse health effects on human health. Flame atomic absorption spectrometry (FAAS) is a widely used instrumental for the determination of antimony and other metals. However, it lacks the sensitivity to determine these metals at trace levels. This study was aimed at overcoming this setback by using hydrogen assisted T-shaped slotted quartz tube technique to preconcentrate and determine antimony by FAAS. All the system parameters were optimized to enhance the detection power of the system. Under the optimum experimental conditions, the limits of detection and quantification were found to be 0.75 and 2.49 ug L-1, respectively with R2 value of 0.9999. Accuracy of the developed method was validated by experimental results agreeing to the certified value of a standard reference material. Recovery studies were also carried out to determine the method's applicability to tap and mineral water samples, and the results obtained were appreciable. PMID- 30470950 TI - The role of Frankia inoculation in casuarina plantations in China. AB - Casuarina trees are planted along the coast from Hainan province in South China to the Zhoushan Islands of Zhejiang province in Southeastern China. Three key species, Casuarina equisetifolia, Casuarina cunninghamiana and Casuarina glauca, are used as windbreaks, in agroforestry systems, and for the production of timber and fuel wood. Frankia have been studied in China since 1984. Today, Frankia research fields are very wide, and cover morphology, physiology and genetic diversity, and the application of inocula for specific purposes on poor quality sites. In this paper, we review the role of Frankia inoculations in nurseries and casuarina plantations in China and discuss the benefits of inoculation. PMID- 30470951 TI - Circadian clock genes' overexpression in Drosophila alters diet impact on lifespan. AB - Diet restriction is one of the most accurately confirmed interventions which extend lifespan. Genes coding circadian core clock elements are known to be the key controllers of cell metabolism especially in aging aspect. The molecular mechanisms standing behind the phenomenon of diet-restriction-mediated life extension are connected to circadian clock either. Here we investigate the effects of protein-rich and low-protein diets on lifespan observed in fruit flies overexpressing core clock genes (cry, per, Clk, cyc and tim). The majority of core clock genes being upregulated in peripheral tissues (muscles and fat body) on protein-rich diet significantly decrease the lifespan of male fruit flies from 5 to 61%. Nevertheless, positive increments of median lifespan were observed in both sexes, males overexpressing cry in fat body lived 20% longer on poor diet. Overexpression of per also on poor medium resulted in life extension in female fruit flies. Diet restriction reduces mortality caused by overexpression of core clock genes. Cox-regression model revealed that diet restriction seriously decreases mortality risks of flies which overexpress core clock genes. The hazard ratios are lower for flies overexpressing clock genes in fat body relatively to muscle-specific overexpression. The present work suggests a phenomenological view of how two peripheral circadian oscillators modify effects of rich and poor diets on lifespan and hazard ratios. PMID- 30470952 TI - Association between parental body mass index and autism spectrum disorder: a systematic review and meta-analysis. AB - Studies have examined the association between parental body mass index (BMI) and autism spectrum disorder (ASD) in offspring, with inconsistent results, especially regarding maternal obesity, overweight and underweight. Cochrane Library, EMBASE, PubMed and PsycINFO databases were searched up to March 2018 for relevant observational studies with no language restriction. Our literature search identified 13 eligible studies for meta-analysis (involving 943,293 children and 30,337 cases). For maternal BMI (13 studies), both maternal obesity [OR 1.41 (95% CI 1.19-1.67)] and maternal overweight [OR 1.16 (95% CI 1.05-1.27)] were significantly associated with ASD, while maternal underweight was not associated with ASD [OR 1.08 (95% CI 0.98-1.20)]. For paternal BMI (three studies), no association was found (paternal obesity: OR 1.28, 95% CI 0.94-1.74; overweight: OR 1.07, 95% CI 0.99-1.15; underweight: OR 1.12, 95% CI 0.87-1.44). Pooled estimates were robust in sensitivity analysis and subgroup analyses. Publication bias may exist for studies assessing maternal BMI and ASD risk, but the filled estimates were not altered. Relative to normal weight, maternal obesity and overweight were significantly associated with increased ASD risk, while maternal underweight was not associated with ASD. Although no association between paternal BMI and ASD was found, current evidence is limited (three studies). Future studies are warranted to address more confounding factors and to identify potential mediators of the association, but pre-pregnancy weight control is suggested. PMID- 30470953 TI - NAFLD Induction Delays Postoperative Liver Regeneration of ALPPS in Rats. AB - BACKGROUND: Associating liver partition and portal vein ligation (ALPPS) is a promising two-step hepatectomy that is beneficial for accumulative regeneration of the future liver remnant (FLR) and avoids postoperative liver failure. AIMS: Our study aimed to evaluate whether nonalcoholic fatty liver disease affected the liver regeneration induced by ALPPS. METHODS: Sprague-Dawley rats fed a high-fat diet were used to construct the NAFLD model. ALPPS were performed, and blood and future liver remnant samples were collected at postoperative days 1 (POD1), POD3, and POD7. RESULTS: The hepatic regeneration rate (HRR) of ALPPS was higher than that of portal vein ligation (PVL) at POD3 and POD7 (p < 0.05), and the number of Ki-67-positive hepatocytes (POD3) and CD68-positive Kupffer cells (POD7) per visual field was higher in the ALPPS group than in the PVL group (p < 0.05). The serum TNF-alpha, hepatocyte growth factor protein, and the serum IL-6 level were higher in the ALPPS group than in the PVL group at POD3 and POD7. Compared with those of the standard laboratory diet (SLD)-fed rats, the rats with NAFLD exhibited a decrease in the HRR, Ki-67-positive hepatocytes, and CD68-positive Kupffer cells in the FLR. The number of CD68-positive Kupffer cells was lower in rats with NAFLD than that in SLD-fed rats; noteworthily, the serum level of IL-6 and TNF-alpha changed dramatically after surgeries. CONCLUSIONS: NAFLD induction delayed liver regeneration induced by the ALPPS procedure, which might be associated with hepatocyte proliferation and the number of Kupffer cells. PMID- 30470954 TI - Intranasal curcumin protects against LPS-induced airway remodeling by modulating toll-like receptor-4 (TLR-4) and matrixmetalloproteinase-9 (MMP-9) expression via affecting MAP kinases in mouse model. AB - OBJECTIVE: Bacterial infections can exacerbate asthmatic inflammation depending on lipopolysaccharide (LPS) composition, the outermost component of cell wall, its exposure timings as well as host's immune status. In present study, Balb/c mice were exposed to antigen (ovalbumin) and LPS simultaneously to establish an asthmatic model. Curcumin (diferuloylmethane), well known for its anti inflammatory potential, was administered through intranasal route 1 h before LPS and OVA (ovalbumin) exposure to evaluate its efficacy against airway structural changes. METHODS: Inflammatory cell infiltration in lungs was measured by flow cytometry and further eosinophils were especially measured by immunofluorescence detection of major basic protein (MBP) as marker of eosinophilc granule protein. We also measured reactive oxygen species (ROS) in BALF by spectrofluorometry. MMP 9 activity was evaluated by gelatin zymography and mRNA expressions of MMP-9, TIMP-1, TGF-beta1, IL-13, Collagen-1 and TLR-4 were measured in lungs. Protein expression of MAP kinases (P-ERK, P-JNK, P-p38), TLR-4, Cox-2, Lox-5 and Eotaxin was measured by western blotting. Hydroxyproline level and masson's trichrome staining were used to evaluate collagen deposition in lung. RESULTS: Exposure to LPS (0.1 ug) exacerbates airway inflammation and induces structural changes in lungs by enhanced ROS production, collagen deposition, expression of genes involved in airway remodeling and activation of MAP kinases pathway enzymes. Intranasal curcumin pretreatment had significantly suppressed inflammatory mediators and airway remodeling proteins. CONCLUSION: Our results strongly suggest that intranasal curcumin effectively protects LPS-induced airway inflammation and structural changes by modulating genes involved in airway remodeling in safer way; hence, it can be considered as supplementary alternative towards asthma treatments. PMID- 30470955 TI - Flash visual evoked potentials (FVEP) in various stimulation conditions. AB - AIM: To compare flash visual evoked potentials (FVEP) elicited using a Ganzfeld bowl (G), Mini Ganzfeld (MG) and Flash Goggles (GG) with eyes open and closed. PATIENTS AND METHOD: The study group comprised 17 volunteers with mean age of 30 years; all of them were examined with the Roland Consult electrophysiological diagnostic system. Active electrodes were placed at O1 and O2. With the G and MG stimulators, the flash generated by white-light-emitting diodes (LEDs) presented standard flash of 3 cd s m-2. The GG used red LED flash of 3 cd s m-2. Stimulus frequency of 1.0 Hz, low-pass filter of 1.0 Hz and high-pass filters of 100 Hz (G); 50 Hz (MG); 30 Hz (GG) were used. P2 amplitude and latency were compared by the means of the Wilcoxon matched-pairs signed-rank test. RESULTS: After right eye stimulation (from O1; n = 17), the mean amplitudes of P2, elicited with the G, MG and GG, were 13, 7 and 10 uV, respectively. The respective latencies were 129, 114 and 110 ms. Hence, the difference between the results obtained with these stimulators was statistically significant (p < 0.05). The mean P2 amplitudes, acquired by the means of the G, MG and GG, were 13 uV, 7 uV and 10 uV for open eyes, and 11 uV, 8 uV and 8 uV for closed eyes. The respective latencies were 129, 114 and 110 ms for eyes open, and 127, 125 and 121 ms for eyes closed. These results of the MG (latency only) and GG (latency and amplitude) stimulation differed significantly (p < 0.05). CONCLUSION: The amplitudes and latencies of the FVEP P2 elicited with different stimulators are not suitable for comparison. Closing the eye during the examination had a significant effect on the components of FVEP waveform elicited with the Flash Goggle and on the latency of P2 elicited with the MG. PMID- 30470956 TI - Correlation between macular structure and function in patients with age-related macular degeneration treated with intravitreal ranibizumab: 12-month-results. AB - PURPOSE: To determine the significance of the correlation between optical coherence tomographic (OCT) findings and focal macular electroretinograms (fmERG) at 12 months after beginning intravitreal injections of ranibizumab (IVR) in eyes with age-related macular degeneration (AMD). STUDY DESIGN: Prospective, clinical study. METHOD: We studied 28 eyes of 28 patients with AMD treated with IVR at monthly intervals for the initial three months. Additional IVR was given according to a pro re nata (PRN) regimen. OCT and fmERGs were performed preoperatively and at 3 and 12 months postoperatively. The fmERGs were elicited by a 15 degrees white stimulus spot centered on the fovea. The thickness of the inner, middle, and outer layers of the retina and also of the serous retinal detachment (SRD) and pigment epithelial detachment (PED) in the horizontal and vertical meridians at 1.2 mm from the fovea (parafoveal) were measured in the OCT images. RESULTS: The b-wave amplitude at 12 months was significantly correlated with the thicknesses of the outer retinal layer, SRD, and PED (P=0.001-0.02). Multiple regression analyses showed that the outer retinal layer thickness was an independent determinant (P= 0.0001). The changes in the b-wave amplitude between the baseline and 12 months were significantly correlated with the changes in the SRD thickness (P=0.006). The changes in the b-wave amplitude during the PRN period were significantly correlated with the changes in the PED thickness (P=0.02). CONCLUSIONS: At 12 months after beginning treatment, the reduction in the SRD thickness affects macular function recovery. As recurrences of the PED can occur during the PRN period, control of the PED is necessary to obtain good macular function for the long term. PMID- 30470957 TI - Effect of RAB31 silencing on osteosarcoma cell proliferation and migration through the Hedgehog signaling pathway. AB - Osteosarcoma (OS) is a prevalent cancer that plagues people worldwide. Identifying prognostic markers would be useful in treating human OS. In this study, we aimed to explore the functions of Ras-related protein Rab-31 (RAB31) in OS-cell proliferation, migration, and invasion as well as its roles in the Hedgehog signaling pathway for better understanding of the mechanism. To assess the detailed regulatory mechanism of RAB31 silencing on OS, both RT-qPCR and Western blot analysis were employed to evaluate the expressions of RAB31 as well as the Hedgehog signaling pathway-related genes. Besides, we also investigated the effects of silenced RAB31 both in vitro and in vivo. First, we found that in OS tissues, both mRNA and protein expressions of RAB31 and PCNA had a significant increase. Second, the Hedgehog signaling pathway was detected to play an integral role in OS progression. Finally, after transfection of RAB31-siRNA to reduce the expression of RAB31, the Hedgehog signaling pathway was suppressed, along with cell proliferation, invasion, and migration. Therefore, we conclude that RAB31 plays an important role in OS development and its silencing delays the OS progression via suppression of the Hedgehog signaling pathway. PMID- 30470958 TI - Self-esteem following maxillofacial and orthopedic injuries: preliminary observations in sub-Saharan Africans. AB - BACKGROUND: The face is a vital component of one's personality and body image while extremities are important in function (mobility, routine daily activities). Recovery and rehabilitation from acquired maxillofacial and orthopedic traumas are psychological in nature. METHODS: This was a prospective study of recruited subjects in a Nigerian University teaching hospital. A total of 160 participants (80 with maxillofacial injuries and 80 with orthopedic injuries) had repeated review assessments within 1 week of arrival in the hospital (time 1), 4-8 weeks after initial contact (time 2), and 10-12 weeks thereafter (time 3), using Rosenberg's Self-Esteem Questionnaire. RESULTS: Thirty-three (41.3%) participants in the maxillofacial injured and 12 (15.0%) in the orthopedic injured subjects scored between 0 and 14 at time 1. At time 2, 39 (51.3%) subjects in the maxillofacial fracture group and 20 (29.0%) in the orthopedic injured group scored between 0 and 14, while at time 3, 7 (9.2%) in the maxillofacial fracture group and 1 (1.5%) in the orthopedic injured group scored between 0 and 14. There was a statistical significant difference between the two groups when compared at times 1, 2, and 3 with p < 0.001, p = 0.006, and p = 0.041 respectively. Subjects with maxillofacial fracture consistently had lower self-esteem compared to subjects with orthopedic injured for times 1, 2, and 3. CONCLUSIONS: Self-esteem may be reduced following maxillofacial injuries; therefore, measures should be taken by surgeons to minimize the risk of facial scarring by careful handling of tissues. Also, management of these injuries should integrate multidisciplinary care that will address psychological needs of patients. TRIAL REGISTRATION: Not applicable. PMID- 30470959 TI - Donor functionalized quinoline based organic sensitizers for dye sensitized solar cell (DSSC) applications: DFT and TD-DFT investigations. AB - The influence of different donor groups in quinoline based novel sensitizers for dye sensitized solar cell (DSSC) applications is analyzed by using density functional theory (DFT) and time dependent density functional theory (TD-DFT). Quinoline and donor functionalized quinoline based novel organic sensitizers have been designed with different pi-spacers for DSSC applications. The ground state molecular structure of novel organic sensitizers is fully optimized by DFT calculation in both gas and chloroform phases. Electronic absorption characteristics are predicted by the TD-DFT calculation in both gas and chloroform phases. The polarizable continuum model is used for solvent phase optimization. The net electron transfer from the donor to acceptor is calculated from natural bond orbital (NBO) analysis. The injection energy and dye regeneration energy values are also calculated. Different donor groups are substituted in quinoline, and these substituted quinoline donors are used as the donor group. Cyanovinyl and thiophene groups act as pi-spacers and cyanoacrylic acid acts as an acceptor. DFT and TD-DFT studies of the quinoline and donor functionalized quinoline sensitizers show that the coumarin based and N hexyltetrahydroquinoline donors are more efficient for DSSC application. PMID- 30470960 TI - Chromosomal abnormalities in couples with recurrent spontaneous miscarriage: a 21 year retrospective study, a report of a novel insertion, and a literature review. AB - PURPOSE: The aim of this study is to evaluate the frequency and nature of chromosomal abnormalities in Moroccan couples with recurrent spontaneous miscarriage (RSM). In addition, the data were compared with those reported elsewhere in order to give a global estimation of chromosomal abnormalities frequencies. METHODS: The study was performed for all couples with RSM who were referred to the cytogenetic department, Pasteur Institute of Morocco, from different hospitals in Morocco between 1996 and 2016. Cytogenetic analysis was performed according to the standard method. RESULTS: Among 627 couples with RSM, the chromosomal abnormalities were identified in 11.00% of couples, with chromosomal inversions in 4.30%, reciprocal translocations in 2.71%, Robertsonian translocations in 1.43%, and deletion, isochromosome, and insertion in 0.15% each. The insertion identified [46,XX,ins(6)(p24q21q27)] is new, and is the fourth reported in association with RSM. The mosaic karyotypes were observed in 0.64%, polymorphic variants were identified in 1.27%, and numerical aneuploidy was observed in 0.15%. In regrouping our results with those in 27 other studies already published in 21 different countries, we obtained the frequency of chromosomal abnormalities in couple with RSM to be 5.16% (991/19197 couples). The reciprocal translocation was the most frequent with 2.50%, followed by Robertsonian translocation 0.83% and inversions 0.77%. The other types of chromosomal abnormalities were present with 0.98% in the world. CONCLUSION: This data showed that the frequency of chromosomal abnormalities in Moroccan couples with RSM is 11.00%, and in regrouping our results with other studies, the frequency changes to 5.16%. PMID- 30470961 TI - Effect of intra-ovarian injection of mesenchymal stem cells in aged mares. AB - PURPOSE: This study aims to determine if intra-ovarian injection of bone marrow derived mesenchymal stem cells (MSCs) improves or restores ovarian function in aged females. METHODS: Prospective randomized study of eight aged mares and six young mares receiving intra-ovarian injection of MSCs or vehicle. Main outcome measures were antral follicle count and serum anti-Mullerian hormone (AMH) (aged and young mares), and for aged mares, oocyte meiotic and developmental competence; gross and histological ovarian assessment; evaluation of presence of chimerism in recovered granulosa cells and in ovarian tissue samples; and gene expression in ovarian tissue as assessed by RNA sequencing. RESULTS: Injection of MSCs was not associated with significant changes in follicle number, oocyte recovery rate on follicle aspiration, oocyte maturation rate, or blastocyst rate after ICSI in aged mares, or in changes in follicle number in young mares. There were no significant changes in peripheral AMH concentrations, indicating a lack of effect on growing follicles. MSC donor DNA was not recovered in granulosa cells or in ovarian tissue, indicating lack of persistence of injected MSC. RNA sequencing revealed significant differences in gene expression between MSC- and vehicle-injected ovaries. CONCLUSIONS: Intra-ovarian injection of bone marrow derived MSCs altered gene expression but did not improve ovarian function in aged mares. PMID- 30470962 TI - Brief Behavioral Intervention for Disruptive Behavior in a Child with a Hypothalamic Hamartoma: A Case Report. AB - Most children with hypothalamic hamartoma (HH) manifest symptoms of epilepsy and associated cognitive deficits and behavioral difficulties as well as central precocious puberty (CPP). However, there is little to no research examining behavioral difficulties in children with HH without epilepsy, nor is there research examining treatments to address the behavioral difficulties of patients with HH without epilepsy. In the current case report, the authors implemented a validated parent management training program [the Brief Behavioral Intervention (BBI)], to treat symptoms of ADHD and disruptive behavior in a 6-year-old female patient with HH and CPP. The family participated in six BBI sessions over a period of 8 weeks. Parent behavioral ratings suggested significant reductions of symptoms of ADHD and disruptive behaviors to the normal range. The current case report demonstrates the effectiveness of the BBI program in the treatment of behavioral difficulties in a patient with HH and CPP. Further, the present study explores behavioral manifestations rarely explored in patients with HH without epilepsy. PMID- 30470963 TI - Multiple-step chromosomal integration of divided segments from a large DNA fragment via CRISPR/Cas9 in Escherichia coli. AB - Although CRISPR/Cas9-mediated gene editing technology has developed vastly in Escherichia coli, the chromosomal integration of large DNA fragment is still challenging compared with gene deletion and small fragment integration. Moreover, to guarantee sufficient Cas9-induced double-strand breaks, it is usually necessary to design several gRNAs to select the appropriate one. Accordingly, we established a practical daily routine in the laboratory work, involving multiple step chromosomal integration of the divided segments from a large DNA fragment. First, we introduced and optimized the protospacers from Streptococcus pyogenes in E. coli W3110. Next, the appropriate fragment size for each round of integration was optimized to be within 3-4 kb. Taking advantage of the optimized protospacer/gRNA pairs, a DNA fragment with a total size of 15.4 kb, containing several key genes for uridine biosynthesis, was integrated into W3110 chromosome, which produced 5.6 g/L uridine in shake flask fermentation. Using this strategy, DNA fragments of virtually any length can be integrated into a suitable genomic site, and two gRNAs can be alternatively used, avoiding the tedious construction of gRNA-expressing plasmids. This study thus presents a useful strategy for large DNA fragment integration into the E. coli chromosome, which can be easily adapted for use in other bacteria. PMID- 30470965 TI - Differential methylation pattern in patients with coronary artery disease: pilot study. AB - Epidemiological studies have revealed that coronary artery disease (CAD) is highly heritable. However, genetic studies have not been able to fully elucidate its etiology. Accumulating evidences suggest that epigenetic alterations like DNA methylation may provide an alternative and additional explanation of its pathophysiology. DNA methylation regulates hypomethylation and hypermethylation of various genes which are involved in the development of CAD. Our aim was to identify differentially methylated regions (DMRs) in genome of CAD patients by using the microarray chip having a coverage of > 4,50,000 CpG sites (Illumina's Infinium HumanMethylation450 BeadChip). In this pilot study, an epigenome-wide analysis of DNA methylation from whole blood was performed in six angiographically positive male cases, who were age and gender matched with six angiographically negative controls. All subjects were non-smokers, non-diabetic, non-alcoholic, with no previous history of cardiac ailment. Illumina's GenomeStudio (v 2011.1) software was used to identify DMRs and pathway analysis, gene ontology was carried out using DAVID (Database for Annotation, Visualisation and Integrated Discovery). 429 DMRs were found to be significant of which 222 were hypomethylated and 207 were hypermethylated. Antigen processing and presentation was identified to be the most significant biological function with a statistical significance of p = 4.35 * 10- 5. HLA-DRB1, HLA-DQA1, HLA-DQB1 along with non-classical HLA molecules HLA-G, HLA-C are responsible for triggering the inflammatory pathway which have been identified in our study. To the best of our knowledge, this is the first study to identify a panel of DMRs using a high coverage microarray chip in India. PMID- 30470964 TI - Dynamic modelling on the confined crystallization of mono-sized cubic particles under mechanical vibration. AB - The dynamic crystallization of cubic granular particles under three-dimensional mechanical vibration is numerically investigated by the discrete element method. The effects of operational conditions (vibration, container shape and system size) and particle properties (gravity and friction) on the formation of crystals and defects are discussed. The results show that the formation and growth of clusters with face-to-face aligned cubic particles can be easily realized under vibrations. Especially, a single crystal with both translational and orientational ordering can be reproduced in a rectangular container under appropriate vibrations. It is also found that the gravitational effect is beneficial for the ordering of a packing; the ordering of frictional particles can be improved significantly with an enlarged gravitational acceleration. The flat walls of a rectangular container facilitate the formation of orderly layered structures. The curved walls of a cylindrical container contribute to the formation of ring-like structures, whereas they also cause distortions and defects in the packing centers. Finally, it is shown that the crystallization of inelastic particles is basically accomplished by the pursuit of a better mechanical stability of the system, with decreasing kinetic and potential energies. PMID- 30470966 TI - Presence of Toxoplasma gondii infection in brain as a potential cause of risky behavior: a report of 102 autopsy cases. AB - Toxoplasmosis was linked to impairment in brain function, encompassing a wide range of behavioral and neuropsychiatric changes. Currently, the precise localization of Toxoplasma gondii in the human brain is limited and the parasite DNA was not found in population-based screening of autopsy cases. The aim of proposed study was to identify the presence of parasite DNA within the brain and its association with risky behavior and alcohol consumption in postmortem examination. Preliminarily, 102 cases with certain circumstances of death at time of forensic autopsy was included. Due to high risk of bias, the females were excluded from the analysis and final study group consists 97 cases divided into three groups: risky behavior, inconclusively risky behavior, and control group. The obtained tissue samples for Nested PCR covered four regions of the brain: symmetric left/right and anterior/posterior horns of lateral ventricles comprising lining ependyma and hippocampus. The second type of material comprised blood evaluated for antibodies prevalence using ELISA and alcohol concentration using HS-GC-FID. Analysis demonstrated 16.5% prevalence concerning the parasite DNA presence in examined brain tissue samples without specific distribution and association with age at death or days after death until an autopsy was performed. Results have shown correlation between occurrence of risky behavior leading to death and higher proportions of positive parasite DNA presence within the brain. Correlation was not observed between parasite DNA presence and excessive alcohol consumption. Conducted screening demonstrated correlation between parasite DNA presence in the brain with risky behavior and provided new information on possible effects of latent toxoplasmosis. PMID- 30470967 TI - Direct oral anticoagulants in the early phase of non valvular atrial fibrillation related acute ischemic stroke: focus on real life studies. AB - Strong evidence for the use of direct oral anticoagulants (DOACs) in the early phase of non valvular atrial fibrillation (NVAF)-related acute ischemic stroke (AIS) is lacking, because this kind of patients were excluded from phase III randomized clinical trials (RCT) and ad hoc RCTs are ongoing. In the latest years a lot of real life studies on this topic have been published. The aim of our review was to focus on these. We reviewed the PubMed databases searching articles reporting on DOACs starting time within 2 weeks from AIS onset. We selected fifteen studies, eight with retrospective, six with prospective observational and one with a prospective, open-label, single arm design. Overall, 2920 patients (47.8% females) were included. In twelve studies median or mean age of patients was over 75 years. Mean or median NIHSS ad hospital admission was <= 12 in all studies. About one-third of patients (32.4%) received urgent reperfusion by systemic thrombolysis or mechanical thrombectomy. About one-fifth of patients (22.8%) had large infarct size. Median starting time of DOACs was reported in thirteen studies and it ranged from 2 to 8 days. About one-half of patients (45.9%) received a low dose of DOACs. In studies reporting on median or mean CHA2DS2-VASC score, it was >= 3 in all. In studies reporting on median or mean HAS-BLED score, it was >= 2 in all. Ninety-day follow-up was available for nine studies, overall including about 2200 patients. Incidence of 90-day TIA/stroke recurrence, symptomatic haemorrhagic transformation or intracranial bleeding and all cause mortality was 2.25%, 0.90% and 1.5%, respectively. The real life evidence suggests that early starting of DOACs in patients with NVAF-related AIS is safe and associated with low recurrence risk and all-cause mortality. PMID- 30470968 TI - From solution to surface to filament: actin flux into branched networks. AB - The actin cytoskeleton comprises a set of filament networks that perform essential functions in eukaryotic cells. The idea that actin filaments incorporate monomers directly from solution forms both the "textbook picture" of filament elongation and a conventional starting point for quantitative modeling of cellular actin dynamics. Recent work, however, reveals that filaments created by two major regulators, the formins and the Arp2/3 complex, incorporate monomers delivered by nearby proteins. Specifically, actin enters Arp2/3-generated networks via binding sites on nucleation-promoting factors clustered on membrane surfaces. Here, we describe three functions of this surface-associated actin monomer pool: (1) regulating network density via product inhibition of the Arp2/3 complex, (2) accelerating filament elongation as a distributive polymerase, and (3) converting profilin-actin into a substrate for the Arp2/3 complex. These linked functions control the architecture of branched networks and explain how capping protein enhances their growth. PMID- 30470969 TI - Predicting change in quality of life from age 79 to 90 in the Lothian Birth Cohort 1921. AB - PURPOSE: Quality of life (QoL) decreases in very old age, and is strongly related to health outcomes and mortality. Understanding the predictors of QoL and change in QoL amongst the oldest old may suggest potential targets for intervention. This study investigated change in QoL from age 79 to 90 years in a group of older adults in Scotland, and identified potential predictors of that change. METHOD: Participants were members of the Lothian Birth Cohort 1921 who attended clinic visits at age 79 (n = 554) and 90 (n = 129). Measures at both time points included QoL (WHOQOL-BREF: four domains and two single items), anxiety and depression, objective health, functional ability, self-rated health, loneliness, and personality. RESULTS: Mean QoL declined from age 79 to 90. Participants returning at 90 had scored significantly higher at 79 on most QoL measures, and exhibited better objective health and functional ability, and lower anxiety and depression than non-returners. Hierarchical multiple regression models accounted for 20.3-56.3% of the variance in QoL at age 90. Baseline QoL was the strongest predictor of domain scores (20.3-35.6% variance explained), suggesting that individual differences in QoL judgements remain largely stable. Additional predictors varied by the QoL domain and included self-rated health, loneliness, and functional and mood decline between age 79 and 90 years. CONCLUSIONS: This study has identified potential targets for interventions to improve QoL in the oldest old. Further research should address causal pathways between QoL and functional and mood decline, perceived health and loneliness. PMID- 30470970 TI - Association between medication adherence and quality of life of patients with diabetes and hypertension attending primary care clinics: a cross-sectional survey. AB - PURPOSE: To evaluate the association between medication adherence and quality of life (QoL) of patients with diabetes and/or hypertension attending primary care clinics. METHODS: In this cross-sectional study, patients with at least one long term condition (hypertension or diabetes mellitus) meeting the eligibility criteria were recruited from five primary care clinics in Saudi Arabia. Arabic version of Morisky Medication Adherence Scale (MMAS-8) and the World Health Organization Quality of Life-BREF (WHOQOL-BREF) tool were used to assess medication adherence and QoL, respectively. Patients' sociodemographic, medical and medication data were collected using a structured, pilot-tested data collection form. RESULTS: Three hundred patients with a mean (+/- SD) age of 56.79 (12.8) years participated in the study. Fifty-eight had hypertension only, 96 had diabetes (Type 1 or 2), and 146 had both hypertension and diabetes. After adjusting for socioeconomic characteristics, multiple linear regression analysis found that adherent patients had significantly higher mean overall perception of QoL and health scores by 14.6 (P = 0.001) and 17.2 (P = 0.001) points, respectively, compared to non-adherent patients. In addition, irrespective of the type of long-term condition, adherence status was found to be an independent predictor of all QoL domains. CONCLUSION: There is an association between medication adherence and QoL among patients with diabetes and/or hypertension attending primary care clinics. Medication adherence should be assessed and emphasised during routine clinical consultations in primary care in order to achieve the desired clinical outcomes and overall well-being of patients. PMID- 30470971 TI - Left atrial functional response after a marathon in healthy amateur volunteers. AB - Middle-aged marathon runners have an increased risk of developing atrial fibrillation (AF). A previous study described that repetitive marathon running was associated with left atrial (LA) dysfunction. However, whether this change is common in marathon runners and which runners are at risk of LA dysfunction remain unknown. The purpose of this study was to determine which factors could predict LA dysfunction. We prospectively examined 12 healthy amateur volunteers (9 males, 31 +/- 8 years old) who participated in a full marathon. All echocardiographic measurements and speckle-tracking echocardiography were performed before and after the marathon. The endpoint was defined as reduced LA reservoir strain 1 day after the marathon (non-responder group). Seven participants were in the non responder group. Age (35 +/- 9 vs. 26 +/- 2 years, p = 0.020), augmentation index (76 +/- 12 vs. 55 +/- 8, p = 0.002), and diastolic blood pressures (83 +/- 11 vs. 70 +/- 7 mmHg, p = 0.021) in the non-responder group were significantly higher compared with the responder group. In multivariate linear regression analysis, only the augmentation index was an independent predictor of reduced LA reservoir function after the marathon (beta = - 0.646, p = 0.023). The augmentation index was a predictive marker for reduction in LA reservoir function after a marathon in healthy amateur volunteers. PMID- 30470972 TI - New Horizons in the Treatment of Metastatic Pancreatic Cancer: A Review of the Key Biology Features and the Most Recent Advances to Treat Metastatic Pancreatic Cancer. AB - Only a limited number of therapeutic strategies are available for patients diagnosed with pancreatic adenocarcinoma, and disease recurrence and mortality are consequently high. For metastatic disease, two combinations are approved in the first line setting: a triplet with 5-fluoruracil, irinotecan, and oxaliplatin, and the combination of gemcitabine and nab-paclitaxel. In patients who have progressed on gemcitabine, a new nanoliposomal formulation of irinotecan has recently been approved. While these treatments have demonstrated some efficacy, there has been little increase in survival rates for metastatic pancreatic cancer patients. Consequently, there is an urgent need for research and development of new treatments. As there is now a deeper understanding of pancreatic cancer biology, new drugs targeting altered pathways are under research, including agents that target TGF-beta, IGF, or NOTCH. Furthermore, taking into account the role of the tumor stroma in this disease, some stroma targeting drugs are being developed, including PEGPH20, a pegylated recombinant human hyaluronidase. In the immunotherapy field, although checkpoint inhibitors have failed to demonstrate benefit as monotherapies, combinations with other drugs are being investigated, with promising preliminary results. Other strategies under research are targeting tumor metabolism or DNA repair deficiency. PMID- 30470973 TI - Supported Catalysts for Continuous Flow Synthesis. AB - Flow chemistry and heterogenous catalysis hold incredible potential from a sustainability point of view and from a green perspective. In fact, if heterogenous catalysts are required by the chemical industry for their efficiency, on the other hand, heterogenous flow catalysis would allow performing greener and more efficient chemistry at an industrial level. In the context of sustainable flow chemistry, in this chapter we report and discuss selected examples recently published in the specialized literature on the use of supported organic and organometallic catalysts for continuous flow synthesis. The use in chemo- and stereoselective synthesis, as well as versatility and robustness of the newly developed supported catalysts are discussed. PMID- 30470974 TI - Targeting tyrosine kinases for treatment of ocular tumors. AB - Uveal melanoma is the most common intraocular primary malignant tumor in adults, and retinoblastoma is the one in children. Current mainstay treatment options include chemotherapy using conventional drugs and enucleation, the total removal of the eyeball. Targeted therapies based on profound understanding of molecular mechanisms of ocular tumors may increase the possibility of preserving the eyeball and the vision. Tyrosine kinases, which modulate signaling pathways regarding various cellular functions including proliferation, differentiation, and attachment, are one of the attractive targets for targeted therapies against uveal melanoma and retinoblastoma. In this review, the roles of both types of tyrosine kinases, receptor tyrosine kinases and non-receptor tyrosine kinases, were summarized in relation with ocular tumors. Although the conventional treatment options for uveal melanoma and retinoblastoma are radiotherapy and chemotherapy, respectively, specific tyrosine kinase inhibitors will enhance our armamentarium against them by controlling cancer-associated signaling pathways related to tyrosine kinases. This review can be a stepping stone for widening treatment options and realizing targeted therapies against uveal melanoma and retinoblastoma. PMID- 30470975 TI - Correction to: Efficacy and safety of fulvestrant in postmenopausal patients with hormone receptor-positive advanced breast cancer: a systematic literature review and meta-analysis. AB - In the original publication of the article, the authors' affiliation was published incorrectly. The corrected affiliation is given in this correction. The author also found few corrections in the article which are given below. PMID- 30470976 TI - MDM2, MDM2-C, and mutant p53 expression influence breast cancer survival in a multiethnic population. AB - PURPOSE: The purpose of the study was to examine the association between expression of mutant p53 (mtp53), full-length MDM2 (MDM2), and MDM2 isoform C (MDM2-C) and survival in multiethnic breast cancer patients. METHODS: A total of 787 invasive breast tumors included in a clinically annotated multiethnic population-based tissue microarray (TMA) were screened utilizing commercially available antibodies to p53 and MDM2, and a newly developed monoclonal antibody recognizing MDM2-C. RESULTS: Mutant p53 (mtp53) was more common in younger (< 50 years) breast cancer patients. Among the 787 cases included in the study, mtp53, MDM2, and MDM2-C expression were not significantly associated with risk of overall or breast cancer-specific mortality. However when associations within individual racial/ethnic groups (White, Japanese, and Native Hawaiian) were examined, expression of MDM2-C was found to be associated with lower risk of breast cancer-specific mortality exclusively for White patients HR 0.32, 95% CI 0.15-0.69 and mtp53 expression was associated with higher overall mortality in Japanese patients (HR 1.63, 95% CI 1.02-2.59). Also, Japanese patients positive for the joint expression of MDM2-C and mtp53 had a greater than twofold risk of overall mortality (HR 2.15, 95% CI 1.04-4.48); and White patients with positive MDM2-C and wild-type p53 expression (HR 0.28, 95% CI 0.08-0.96) were at lower risk of mortality when compared to patients with negative MDM2-C and wild-type p53 expression in their respective racial/ethnic group. CONCLUSION: Racial/ethnic differences in expression profiles of mtp53, MDM2, and MDM2-C and associations with breast cancer-specific and overall mortality. MDM2-C may have a positive or negative role in breast tumorigenesis depending on mtp53 expression. PMID- 30470977 TI - Glutamate dehydrogenase (GLUD1) expression in breast cancer. AB - BACKGROUND: Dysregulated cellular metabolism is one of the hallmarks of cancer with some tumours utilising the glutamine metabolism pathway for their sustained proliferation and survival. Glutamate dehydrogenase (GLUD1) is a key enzyme in glutaminolysis converting glutamate to alpha-ketoglutarate for entry into the TCA cycle. Breast cancer (BC) comprises a heterogeneous group of tumours in terms of molecular biology and clinical behaviour, and we have previously shown that altered glutamine metabolism varies substantially among the different molecular subtypes. We hypothesise that the prognostic value of GLUD1 expression will differ between the BC molecular subtypes and may act as a potential therapeutic target for BC tumours. METHODS: GLUD1 was assessed at the DNA, mRNA (n = 1980) and protein (n = 1300) levels in large, well-characterised cohorts and correlated with clinicopathological parameters, molecular subtypes, patient outcome, and treatments. RESULTS: There was a correlation between GLUD1 mRNA and GLUD1 protein expression which were highly expressed in low grade luminal/ER + BC (p < 0.01). GLUD1 mRNA and protein was associated with good patient outcome but not in any specific molecular subtypes. However, high GLUD1 protein expression was associated with a better outcome in triple negative (TN) patients treated with chemotherapy (p = 0.03). High GLUD1 mRNA was associated with the glutamine transporter, SLC1A5, and leucine transporter, SLC7A8 as well as mTOR (p < 0.0001). CONCLUSION: We provide comprehensive data indicating GLUD1 plays an important role in luminal/ER + BC. GLUD1 expression predicts a better patient outcome and we show that it has the potential for predicting response to chemotherapy in TNBC patients. PMID- 30470978 TI - The Effects of the Nurse Navigation Program in Promoting Colorectal Cancer Screening Behaviors: a Randomized Controlled Trial. AB - Although screening programs are known and recommended for the early detection of colorectal cancer (CRC), the screening rates for the fecal occult blood test (FOBT) and colonoscopy are very low among adult individuals. Navigation programs, also known as individualized counseling, have recently begun to be used for increasing screening rates. The purpose of this study was to compare the efficacy of the Nurse Navigation Program versus usual care on CRC screening participation and movement in stage of adoption for CRC screening and to examine perceived benefits of and barriers to CRC screening. This study was designed in line with a pre- and posttest two-group methodology. A total of 110 participants (55 nurse navigated and 55 non-navigated patients) were studied. Data were collected using the following three tools: a sociodemographic information form, the Harvard Colorectal Cancer Risk Assessment Tool, and Instruments to Measure Colorectal Cancer Screening Benefits and Barriers. Following the Nurse Navigation Program, the FOBT (82 and 84%, respectively) and colonoscopy completion rates (15 and 22%, respectively) were significantly higher in the nurse-navigated group than in the non-navigated group at 3 and 6 months follow-up. Following the program, the benefit perceptions of the nurse-navigated group about CRC screening were improved, and their barrier perceptions were reduced. The results showed that the Nurse Navigation Program had significant effects on CRC screening behavior and health-related beliefs concerning CRC screening. Further assessment of the Nurse Navigation Program in different groups should be performed to observe its effects. PMID- 30470979 TI - Comparison of decision-making in neonatal care between China and Japan. AB - BACKGROUND: Various differences between China and Japan in approaches to medical treatment have been noted, but a few studies have examined differences in medical decision-making, especially in neonatal care. The aim of this study was to clarify these differences by means of a questionnaire. METHODS: The subjects were physicians on the staff of NICUs in China and Japan. The study questionnaire consisted of three parts dealing with the general characteristics of the participants, questions about treatment strategies for hypothetical, critically ill infants, and general questions about the treatment of foreign patients. The Likert scale was used to assess the treatment strategies and the results were analyzed statistically. Subgroup analysis by age, sex, and medical and NICU experience was also performed. RESULTS: The proportion of respondents in the Chinese and Japanese groups was 26/26 (100%) and 26/31 (84%), respectively. There was a significant difference between the Chinese and Japanese groups for 8 of 75 questions; Chinese physicians chose the positive treatment or examination options for these eight questions unlike their Japanese counterparts. The responses of the younger, less experienced physicians in both countries were more similar to each other, and more positive than those of their older, more experienced colleagues. CONCLUSION: Chinese physicians showed a more positive attitude toward examination and treatment, whereas Japanese physicians showed a more cautious attitude. PMID- 30470980 TI - Approach to Molecular Diagnosis of Chronic Granulomatous Disease (CGD): an Experience from a Large Cohort of 90 Indian Patients. AB - BACKGROUND: Chronic granulomatous disease (CGD) is characterized by mutation in any one of the five genes coding NADPH oxidase components that leads to functional abnormality preventing the killing of phagocytosed microbes by affecting the progression of a respiratory burst. CGD patients have an increased susceptibility to infections by opportunistic and pathogenic organisms. Though initial diagnosis of CGD using a nitroblue tetrazolium (NBT) test or dihydrorhodamine (DHR) test is relatively easy, molecular diagnosis is challenging due to involvement of multiple genes, presence of pseudogenes, large deletions, and GC-rich regions, among other factors. The strategies for molecular diagnosis vary depending on the affected gene and the mutation pattern prevalent in the target population. There is a paucity of molecular data related to CGD for Indian population. METHOD: This report includes data for a large cohort of CGD patients (n = 90) from India, describing the diagnostic approach, mutation spectrum, and novel mutations identified. We have used mosaicism in mothers and the expression pattern of different NADPH components by flow cytometry as a screening tool to identify the underlying affected gene. The techniques like Sanger sequencing, next-generation sequencing (NGS), and Genescan analysis were used for further molecular analysis. RESULT: Of the total molecularly characterized patients (n = 90), 56% of the patients had a mutation in the NCF1 gene, 30% had mutation in the CYBB gene, and 7% each had mutation in the CYBA and NCF2 genes. Among the patients with NCF1 gene mutation, 82% of the patients had 2 bp deletion (DelGT) mutations in the NCF1 gene. In our cohort, 41 different mutations including 9 novel mutations in the CYBB gene and 2 novel mutations each in the NCF2, CYBA, and NCF1 genes were identified. CONCLUSION: Substantial number of the patients lack NCF1 gene on both the alleles. This is often missed by advanced molecular techniques like Sanger sequencing and NGS due to the presence of pseudogenes and requires a simple Genescan method for confirmation. Thus, the diagnostic approach may depend on the prevalence of affected genes in respective population. This study identifies potential gene targets with the help of flow cytometric analysis of NADPH oxidase components to design an algorithm for diagnosis of CGD in India. In Indian population, the Genescan method should be preferred as the primary molecular test to rule out NCF1 gene mutations prior to Sanger sequencing and NGS. PMID- 30470981 TI - Successful Bone Marrow Transplantation for XMEN: Hemorrhagic Risk Uncovered. PMID- 30470982 TI - Transplantation of Hematopoietic Stem Cells for Primary Immunodeficiencies in Brazil: Challenges in Treating Rare Diseases in Developing Countries. AB - The results of hematopoietic stem cell transplant (HSCT) for primary immunodeficiency diseases (PID) have been improving over time. Unfortunately, developing countries do not experience the same results. This first report of Brazilian experience of HSCT for PID describes the development and results in the field. We included data from transplants in 221 patients, performed at 11 centers which participated in the Brazilian collaborative group, from July 1990 to December 2015. The majority of transplants were concentrated in one center (n = 123). The median age at HSCT was 22 months, and the most common diseases were severe combined immunodeficiency (SCID) (n = 67) and Wiskott-Aldrich syndrome (WAS) (n = 67). Only 15 patients received unconditioned transplants. Cumulative incidence of GVHD grades II to IV was 23%, and GVHD grades III to IV was 10%. The 5-year overall survival was 71.6%. WAS patients had better survival compared to other diseases. Most deaths (n = 53) occurred in the first year after transplantation mainly due to infection (55%) and GVHD (13%). Although transplant for PID patients in Brazil has evolved since its beginning, we still face some challenges like delayed diagnosis and referral, severe infections before transplant, a limited number of transplant centers with expertise, and resources for more advanced techniques. Measures like newborn screening for SCID may hasten the diagnosis and ameliorate patients' conditions at the moment of transplant. PMID- 30470983 TI - Nrf2 deficiency in aged mice exacerbates cellular senescence promoting cerebrovascular inflammation. AB - Aging-induced pro-inflammatory phenotypic alterations of the cerebral vasculature critically contribute to the pathogenesis of vascular cognitive impairment. Cellular senescence is a fundamental aging process that promotes inflammation; however, its role in cerebrovascular aging remains unexplored. The present study was undertaken to test the hypothesis that advanced aging promotes cellular senescence in the cerebral vasculature. We found that in cerebral arteries of 24 month-old mice, expression of molecular markers of senescence (p16INK4a, p21) is upregulated as compared to that in young controls. Induction of senescence programs in cerebral arteries is associated by an upregulation of a wide range of inflammatory cytokines and chemokines, which are known to contribute to the senescence-associated secretory phenotype (SASP) in vascular cells. Age-related cerebrovascular senescence and inflammation are associated with neuroinflammation, as shown by the molecular footprint of microglia activation in the hippocampus. Genetic depletion of the pro-survival/anti-aging transcriptional regulator Nrf2 exacerbated age-related induction of senescence markers and inflammatory SASP factors and resulted in a heightened inflammatory status of the hippocampus. In conclusion, our studies provide evidence that aging and Nrf2 dysfunction promote cellular senescence in cerebral vessels, which may potentially cause or exacerbate age-related pathology. PMID- 30470984 TI - The impact of duration on the recurrence of rhegmatogenous retinal detachment: optimal cutoff value. AB - PURPOSE: To assess the impact of symptom duration on the recurrence of rhegmatogenous retinal detachment (RRD) and to determine the threshold symptom duration for recurrence. PATIENT AND METHODS: In this non-comparative, observational case series, a retrospective evaluation was made of the records of patients with RRD at baseline and during the postoperative follow-up period, in respect of postoperative anatomic outcome, prognostic factors for recurrent retinal detachment and the cutoff value of symptom duration. RESULTS: Recurrent retinal detachment was detected in 33 (17.8%) of 185 patients following primary retinal detachment surgery. The surgery type in phakic patients and preoperative symptom duration had a significantly high odds ratio for evidence of surgical failure. According to the ROC analysis, the threshold preoperative symptom duration was 20.5 days. CONCLUSION: Our results showed that early reattachment surgery is necessary to lower the risk of retinal redetachment. The threshold at which RRD recurrence significantly increases is 20.5 days. PMID- 30470985 TI - Dexamethasone implant as an adjuvant therapy to ranibizumab loading dose in persistent diabetic macular edema. AB - PURPOSE: This study evaluates the effectiveness of a single-dose dexamethasone implant (DI) as an auxiliary therapy to continued intravitreal ranibizumab (IVR) treatment in patients with persistent diabetic macular edema (DME). METHODS: Twenty-five pseudophakic eyes of 25 patients with DME who underwent a single injection of DI as an adjuvant therapy following an IVR loading dose were examined retrospectively. All patients were treatment naive and had a poor response to a loading dose of three consecutive monthly IVR injections. IVR treatments were continued pro re nata after the DI. The main outcome measures were changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT) at 1, 3, 6 and 8 months post-DI treatment. RESULTS: After the IVR loading dose, the mean BCVA and CMT were 0.9 +/- 0.6 LogMAR and 478.2 +/- 107.8 um, respectively. One month after the DI, the mean BCVA and CMT had improved to 0.6 +/- 0.4 LogMAR (p = 0.005) and 313.8 +/- 62.7 um (p < 0.001), respectively. This improvement was maintained with mean 0.8 +/- 0.8 IVR injections throughout the follow-up period. The final mean BCVA and CMT were 0.5 +/- 0.5 LogMAR and 298.4 +/- 71.5 um. Subgroup analyses revealed that different DME types did not have any effect on CMT or BCVA improvement (p = 0.188, p = 0.136; respectively). CONCLUSION: Adding DI results in rapid anatomical and visual improvement in patients who respond poorly to an IVR loading dose. Improvements may be maintained with additional IVR in follow-up. PMID- 30470986 TI - The effect of combined phacotrabeculectomy, trabeculectomy and phacoemulsification on the corneal endothelium in the early stage: a preliminary study. AB - PURPOSE: We aimed to investigate the effect of combined phacotrabeculectomy, trabeculectomy and phacoemulsification on the corneal endothelium in the early stage. MATERIALS AND METHODS: In this prospective and non-randomized study, three groups were identified each consisting of 20 eyes (Group I phacotrabeculectomy, group II trabeculectomy, group III phacoemulsification). In the pre- and postop month 1, corneal endothelial cell density (CECD), coefficient of variation (CV) (polymegathism) and hexagonality (Hex) (pleomorphism) were measured by means of a non-contact specular microscope (Nidek CEM-530, NIDEK Co., Ltd. Japan). RESULTS: The postop CECD in each of the three groups showed a significant decrease when compared with the preop period (6.1% in the phacotrabeculectomy group, 4.9% in the trabeculectomy group and 7.4% in the phacoemulsification group). The amount of decrease in the preop and postop CECD values showed no significant difference among these three groups. The postop CV value in each of the three groups showed a significant increase when compared with the preop period. The postop Hex value in each of the three groups showed no significant change when compared with the preop period. CONCLUSION: In our study, we observed that performing a combined phacotrabeculectomy on patients with glaucoma and cataract association in the same session did not do more harm to the corneal endothelium than other surgical methods. For this reason, this method can be applied safely to a patient population that is likely to develop corneal decompensation. PMID- 30470987 TI - Assessment of Schlemm's canal in acute primary angle closure: an anterior segment optical coherence tomography study. AB - PURPOSE: To image and quantitatively evaluate the Schlemm's canal (SC) dimensions in the eyes with acute primary angle closure (APAC) with anterior segment optical coherence tomography (AS-OCT), and compare it with the SC measurements taken after the control of intraocular pressure (IOP) and in the normal age-matched controls. MATERIALS AND METHODS: Seventeen eyes of 14 patients with the newly diagnosed APAC and 59 age-matched normal subjects underwent AS-OCT to image SC. SC cross-sectional area, SC meridional and coronal diameters were measured in the temporal and nasal regions at 3 and 9 o'clock position. After laser iridotomy and control of the IOP, all SC parameters were measured again at a week later, in APAC eyes. Intrasession intraobserver reliability of the SC measurements was assessed with intraclass correlation coefficient. RESULTS: Mean SC-SCA (10,600 +/ 2691 um2), SC meridional (682 +/- 125 um) and coronal diameters (21.2 +/- 8.2 um) showed a significant increase in the APAC eyes at presentation, when compared to the SC parameters measured at a week later (6499 +/- 1754 um2, 450 +/- 169 um and 15.75 +/- 8.6 um, p = < 0.0001, < 0.0001 and 0.01, respectively) and in the normal controls (7192 +/- 1022 um2, 499.2 +/- 179.8 um, 15.43 +/- 4.35 um, p = 0.02, < 0.0001, 0.01, respectively). There was no difference in the measured SC parameters between the normal controls and APAC eyes, when the parameters were measured at a week, after resolution of the acute attack (all p > 0.05). CONCLUSION: A significant expansion of SC was observed in the APAC eyes at presentation, when compared to the normal controls and after the acute attack resolved. SC parameters may provide a useful research tool for evaluating morphological changes in the SC in APAC eyes, during an acute attack. PMID- 30470988 TI - Homophone Advantage in Sentence Acceptability Judgment: An Experiment with Japanese Kanji Words and Articulatory Suppression Technique. AB - The purpose of this study was to examine the role and nature of phonology in silent reading of Japanese sentences. An experiment was conducted using a Japanese sentence acceptability judgment task. One important finding was that participants more rapidly rejected homophonic sentences in which one two-kanji compound word was replaced by its homophone word than non-homophonic sentences. In the latter, the word was replaced by a non-homophone spelling control; that is, we observed a homophone advantage. Participants were able to identify the correct word easily through foil's homophonic mate. This indicated that activated phonology played a role in the Japanese sentence acceptability judgment task and it contributed to the error detection/recovery process. Another important finding was that the homophone facilitation effect remained under articulatory suppression. It confirmed that phonology was activated at an early stage as abstract, non-articulatory phonology. PMID- 30470990 TI - Defective levels of both circulating dendritic cells and T-regulatory cells correlate with risk of recurrence in cutaneous melanoma. AB - BACKGROUND: Immune markers in the peripheral blood of melanoma patients provide useful information for clinical management although there is poor consensus on circulating cells which could putatively reflect the disease activity and play a prognostic role. Here, we investigated both dendritic cells (DCs) and T regulatory cells (Tregs). METHODS: The number of DC subsets as myeloid (m) and plasmacytoid was measured by flowcytometry in 113 melanoma patients in different clinical stages and correlated with the disease activity to evaluate the recurrence free survival (RFS) calculated as difference between baseline and post surgical values in relation to the criteria for the melanoma staging, as primary tumor removal, sentinel lymph node biopsy and completion of lymph node dissection. RESULTS: Circulating mDC levels were significantly lower in metastatic melanoma than in other stages and inversely correlated to Treg values while both populations were similarly expressed in inactive disease at stage I III. Furthermore, the levels of these cells after melanoma removal were apparently related to the disease activity since their persistent defect reflected high risk of recurrence and reduced the RFS. CONCLUSIONS: This work highlighted the role of immune cell measurement for the management of melanoma activity and the identification of patients at potential risk of recurrence based on the mDC ratio. PMID- 30470991 TI - SEOM clinical practice guideline: management and prevention of febrile neutropenia in adults with solid tumors (2018). AB - Febrile neutropenia (FN) is a common dose-limiting toxicity of chemotherapy, with a profound impact on the evolution of patients with cancer, due to the potential development of serious complications, mortality, delays, and decrease in treatment intensity. This article seeks to present an updated clinical guideline, with recommendations regarding the diagnosis, prevention, and treatment of febrile neutropenia in adults with solid tumors. The aspects covered include how to properly approach the risk of microbial resistances, epidemiological aspects, considerations about the initial empirical approach adapted to the risk, special situations, and prevention of complications. A decision-making algorithm is included for use in the emergency department based on a new, validated tool, the Clinical Index of Stable Febrile Neutropenia, which can be used in patients with solid tumors who appear stable in the initial phase of neutropenic infections, and can help detect those at high risk for complications in whom early discharge must be avoided. PMID- 30470992 TI - Active surveillance as a successful management strategy for patients with clinical stage I germ cell testicular cancer. AB - BACKGROUND: Cancer-specific survival for patients with clinical stage I (CSI) germ cell testicular cancer (GCTC) is outstanding after inguinal orchidectomy regardless the treatment utilized. This study evaluated whether active surveillance (AS) of such patients yielded similar health outcomes to other therapeutic strategies such as adjuvant chemotherapy, radiotherapy or primary retroperitoneal lymphadenectomy as described in the literature. PATIENTS AND METHODS: Patients with CSI GCTC were screened between January 2012 and December 2016. Patients had previously undergone inguinal orchidectomy as the primary treatment and chosen AS as their preferred management strategy after receiving information about all available strategies. RESULTS: Out of 91 patients screened, 82 patients selected AS as their preferred management strategy. Relapse rate in the overall population was 20% (95% CI 12-30) and median time to relapse was 11.5 months (range 1.0-35.0). In patients with seminomatous tumors, relapse rate decreased to 13% and median time to relapse was 13 months; whereas in patients with non-seminomatous tumors, relapse rate was 33% (IA) or 29% (IB) and median time to relapse was 12 months in stage IA and 4.5 months in stage IB patients. All relapses were rescued with three or four cycles of chemotherapy and two also required a retroperitoneal lymphadenectomy. All patients are currently alive and free of disease. CONCLUSIONS: The clinical outcomes of patients with CSI GCTC managed by AS in this series were excellent. This strategy limited the administration of active treatments specifically to the minority of patients who relapsed without compromising performance. PMID- 30470993 TI - The dual effect of morphine on tumor development. AB - Morphine is a classic opioid drug used for reducing pain and is commonly prescribed as an effective drug to control cancer pain. Morphine has a direct role in the central nervous system to relieve pain, but because of its peripheral functions, morphine also has some side effects, such as nausea, constipation, and addiction (Gupta et al. in Sci World J 2015:10, 2015). In addition to its analgesic effect, the role of morphine in tumor development is an important question that has been investigated for many years with conflicting results. Numerous studies suggest that morphine has a role in both promoting and inhibiting tumor growth. In this extensive review, we attempt to comprehensively understand the effects of morphine and summarize both its positive and negative influences on various aspects of tumors, including tumor growth, angiogenesis, metastasis, inflammation, and immunomodulation. PMID- 30470994 TI - Impact of systemic inflammation biomarkers on the survival outcomes of cervical cancer patients. AB - BACKGROUND: Inflammatory biomarkers have recently attracted attention as valuable prognosticators and predictors of survival outcomes in many cancers. We describe a new pre-treatment biomarker, expressed as the eosinophil-lymphocytes ratio (ELR) and validate other biomarkers such as the level of circulating eosinophils, neutrophil-lymphocytes ratio (NLR), platelet-lymphocytes ratio (PLR) and systemic immune-inflammatory index (SII) as prognostic factors in cervical cancer (CC) patients. METHODS: A retrospective cohort of 151 consecutive patients diagnosed with CC and treated according to the European guidelines with radiotherapy and/or chemotherapy and/or surgery in our institution from 2009 to 2016 were evaluated. Patients were categorized into two different groups based on the optimal cut-off for each biomarker, according to the receiver operating characteristic (ROC) curves. Impact of blood biomarkers on overall survival (OS), cancer-specific survival (CCS) and progression-free survival (PFS) were examined. RESULTS: Higher values of ELR, eosinophils and age >= 50 years were associated with better OS in univariate Cox analysis, while high NLR, PLR, SII, neutrophils >= 7.0, Bulky tumor and FIGO stage III-IV at diagnosis were prognosticators of worse survival outcomes. In multivariate analysis, the only factors independently impacting OS were ELR >= 0.07 (HR = 0.49, p = 0.048) and FIGO stage III-IV (HR = 2.5, p = 0.018). High PLR and SII were associated with shorter PFR. CONCLUSIONS: Increased values of ELR and eosinophils portend better OS in CC. To our best knowledge, this is the first report describing eosinophils-related biomarker as an independent prognostic factor in CC. PMID- 30470995 TI - SICE national survey: current state on the adoption of laparoscopic approach to the treatment of colorectal disease in Italy. AB - The real diffusion of laparoscopy for the treatment of colorectal diseases in Italy is largely unknown. The main purpose of the present study is to investigate among surgeons dedicated to minimally invasive surgery, the volume of laparoscopic colorectal procedures, the type of operation performed in comparison to traditional approach, the indication for surgery (benign and malignant) and to evaluate the different types of technologies used. A structured questionnaire was developed in collaboration with an international market research institute and the survey was published online; invitation to participate to the survey was issued among the members of the Italian Society of Endoscopic Surgery (SICE). 211 surgeons working in 57 surgical departments in Italy fulfilled and answered the online survey. A total of 6357 colorectal procedures were recorded during the year 2015 of which 4104 (64.1%) were performed using a minimally invasive approach. Colon and rectal cancer were the most common indications for laparoscopic approach (83.1%). Left colectomy was the operation most commonly performed (41.8%), while rectal resection accounted for 23.5% of the cases. Overall conversion rate was 5.9% (242/4104). Full HD standard technology was available and routinely used in all the responders' centers. The proportion of colorectal resections that are carried out laparoscopically in dedicated centers has now reached valuable levels with a low conversion rate. PMID- 30470996 TI - Endovascular stroke treatment's impact on malignant type of edema (ESTIMATE). AB - BACKGROUND AND PURPOSE: In patients with acute ischemic stroke and large vessel occlusion, the prognosis has improved tremendously since the implementation of endovascular thrombectomy (EVT). The effect of EVT on the incidence of malignant middle cerebral artery infarctions (MMI) has not been studied before. METHODS: ESTIMATE, a multicenter retrospective study, evaluates data of ischemic stroke patients with occlusion in the anterior circulation in the years of 2007-2015 comparing three treatment options (no therapy; IV-TPA; IV-TPA plus EVT or EVT only). Primary endpoint of the study was the incidence of MMI on follow-up imaging and mortality rates. Secondary endpoints were functional outcome, further clinical and imaging data. Logistic and Cox-regression models with a propensity score weighting approach were applied to evaluate differences between treatment groups. RESULTS: In 2161 patients over 9 years, EVT reduced the MMI rates significantly: patients without acute stroke treatment had increased odds for MMI of 1.57 [95% confidence interval (CI) 1.49-1.65]. In contrast, after treatment with IV-TPA, only we observed an OR of 0.88 (95% CI 0.83-0.94, p < 0.001), and after EVT an OR of 0.80 (95% CI 0.76-0.85, p < 0.001). This was more pronounced in larger pretreatment infarctions (ASPECTS < 5, p < 0.01). IV-TPA also lowers the MMI rates but not to the same extent. EVT-treated patients had increased survival rates (p < 0.05) and the best functional outcome at discharge. CONCLUSIONS: The findings of this study illustrate that occurrence of MMI and mortality rates was significantly reduced in patients treated with EVT. PMID- 30470997 TI - Jean Baptiste Octave Landry (1866-1940). PMID- 30470998 TI - The identification of a transthyretin variant p.D38G in a Chinese family with early-onset leptomeningeal amyloidosis. AB - Familial amyloid polyneuropathies (FAPs) are life-threatening, autosomal dominant diseases resulting, in most instances, from transthyretin gene (TTR) variants. A small number of TTR variants lead to leptomeningeal amyloidosis (LA), which is a rare FAP subtype with late-onset central nervous system (CNS) impairment symptoms. Previous studies suggest that LA's CNS selectivity was due to complete endoplasmic reticulum-associated degradation of highly destabilized mutants in peripheral tissues. LA's later age at onset (AAO) was due to lower choroid plexus secretory efficacy. This study reports on a family with LA, including six symptomatic and three presymptomatic members. The LA diagnosis was confirmed by leptomeningeal enhancement on contrast MRI, elevated cerebrospinal fluid protein levels, and positive Congo red staining. The predominant symptoms included headaches, dizziness, vomiting, hallucinations, and cognitive impairments which associated with obstructive hydrocephalus. The TTR p.D38G variant with the lowest secretory efficacy was identified as the genetic cause by whole exome sequencing. The family had a statistically significantly earlier mean AAO of 31.3 +/- 7.4 (p = 0.001). These uncommon phenotypes indicate unknown factors influencing the progress of CNS impairment via TTR mutants. Medical imaging examinations suggest the potential early diagnosis value of contrast MRI and the importance of ependyma involvement in LA. LA genetic and clinical data were reviewed and summarized. These findings expand the FAPs' phenotypic spectrum and are valuable in FAP diagnosis, treatment, and further research. PMID- 30470999 TI - Utility of transthoracic impedance and novel algorithm for sleep apnea screening in pacemaker patient. AB - BACKGROUND: Pacing patients was revealed with a high prevalence of sleep disorder, but mostly undiagnosed. The pacemaker with transthoracic impedance sensor and novel algorithm could identify sleep apnea (SA) event. This study aimed to evaluate accuracy of pacemaker in sleep apnea diagnosis. METHODS: This is a prospective study which enrolled patients implanted with pacemakers integrated with transthoracic impedance sensor and SA-identified algorithm (AP Scan). All patients underwent a polysomnography (PSG). The apnea and hypopnea index (AHI) of the PSG (PSG-AHI) and the respiratory disturbance index (RDI) of the pacemaker (PM-RDI) were recorded on the same night. The correlation between two methods was evaluated by the kappa coefficient, receiver operating characteristic (ROC) curves, and Bland and Altman statistics. RESULTS: Sixty-four patients were enrolled, who had never been diagnosed with SAS or underwent PSG exam. After PSG examination, 76.4% patients were diagnosed as combining with SA (20% severe, 18.2% moderate, and 38.2% mild). RDI calculated by PM has a strong positive correlation with PSG-AHI (r = 0.76, p < 0.001, 95% CI 0.61-0.85). The optimal cutoff value of PM-RDI for advanced SAS (PSG-AHI >= 15) diagnosis was 26, with AUC of 0.89 (95% CI 0.77 to 0.96, p < 0.001). The best cutoff value for severe SA (PSG-AHI >= 30) identification was 41, with a sensitivity of 81.6%, a specificity of 88.6%. CONCLUSIONS: Pacemaker patients present a high prevalence of undiagnosed SA. Detection of SA by pacemaker is feasible and accurate in SA screening and monitoring. PMID- 30471000 TI - Next-generation glycogen storage diseases. PMID- 30471001 TI - Differentiation-Dependent Effects of a New Recombinant Manganese Superoxide Dismutase on Human SK-N-BE Neuron-Like Cells. AB - We have recently isolated a new isoform of recombinant manganese superoxide dismutase (rMnSOD) which provides a potent antitumor activity and strongly counteracts the occurrence of oxidative stress and tissue inflammation. This isoform, in addition to the enzymatic action common to all SODs, also shows special functional and structural properties, essentially due to the presence of a first leader peptide that allows the protein to enter easily into cells. Among endogenous antioxidants, SOD constitutes the first line of natural defence against pathological effects induced by an excess of free radicals. Here, we firstly describe the effects of our rMnSOD administration on the proliferant and malignant undifferentiated human neuroblastoma SK-N-BE cell line. Moreover, we also test the effects of rMnSOD in the all trans retinoic-differentiated SK-N-BE neuron-like cells, a quiescent "not malignant" model. While rMnSOD showed an antitumor activity on proliferating cells, a poor sensitivity to rMnSOD overload in retinoid-differentiated neuron-like cells was observed. However, in the latter case, in presence of experimental-induced oxidative stress, overcharge of rMnSOD enhanced the oxidant effects, through an increase of H2O2 due to low activity of both catalase and glutathione peroxidase. In conclusion, our data show that rMnSOD treatment exerts differential effects, which depend upon both cell differentiation and redox balance, addressing attention to the potential use of the recombinant enzyme on differentiated neurons. These facts ultimately pave the way for further preclinical studies aimed at evaluation of rMnSOD effects in models of neurodegenerative diseases. PMID- 30471003 TI - Omadacycline: First Global Approval. AB - Paratek Pharmaceuticals are developing omadacycline (NUZYRATM), a first-in-class orally active aminomethylcycline antibacterial, as a treatment for various bacterial infections. The drug, which is available in intravenous and oral formulations, has a broad spectrum of antibacterial activity and was recently approved in the USA as a treatment for the treatment of community acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) in adults. This article summarizes the milestones in the development of omadacycline leading to this first global approval for the treatment of CABP and ABSSSI. PMID- 30471002 TI - Tapentadol Prolonged Release: A Review in Pain Management. AB - Tapentadol prolonged release (tapentadol PR) [Palexia(r) SR in EU] is a long acting tablet formulation of the strong central analgesic tapentadol, which acts as both a MU-opioid receptor (MOR) agonist and a noradrenaline reuptake inhibitor. Tapentadol PR is approved for chronic pain in various countries, with its EU indication (severe chronic pain manageable only with opioid analgesics) being the focus here. Well-designed trials and clinical practice data support tapentadol PR use in this setting. Short term, tapentadol PR was an effective and generally well tolerated analgesic for moderate to severe pain of varying aetiologies, including neuropathic pain. It provided analgesia at least as good as that of conventional strong opioids and appeared more favourable in terms of gastrointestinal tolerability, likely due to less potent MOR binding. Severe back pain with a neuropathic component responded well to moderate-dose tapentadol PR in some patients, while for others, an increase to the maximum recommended tapentadol PR dosage provided analgesia at least as good as that of moderate-dose tapentadol PR plus pregabalin and appeared to have some CNS tolerability benefits. Data also support the use of tapentadol PR in opioid rotation, including when conventional opioids are intolerable. Longer-term data in musculoskeletal pain conditions indicate continued benefit over up to 2 years' treatment with tapentadol PR with no evidence of tolerance. Thus, tapentadol PR is a useful option for the management of severe chronic pain. PMID- 30471004 TI - Endocrine and metabolic adverse effects of immune checkpoint inhibitors: an overview (what endocrinologists should know). AB - Immune checkpoint inhibitors (ICIs) are novel anticancer agents, recently introduced with the aim of boosting the immune response against tumors. ICIs are monoclonal autoantibodies that specifically target inhibitory receptors on T cells: cytotoxic T lymphocyte antigen 4 (CTLA4), programmed death 1 (PD-1) and its ligand (PD-1L). ICIs also generate peculiar dysimmune toxicities, called immune-related adverse events (irAEs), that can potentially affect any tissue, and some may be life-threatening if not promptly recognized. The endocrine and metabolic side effects of ICIs are reviewed here, with a particular focus on their clinical presentation and management. They are among the most frequent toxicities (around 10%) and include hypophysitis, thyroid disorders, adrenalitis, and diabetes mellitus. Treatment is based on the replacement of specific hormone deficits, accompanied by immunosuppression (with corticosteroids or other drugs), depending on irAEs grade, often without the need of ICI withdrawal, except in more severe forms. Prompt recognition of endocrine and metabolic irAEs and adequate treatment allow the patients to continue a therapy they are benefiting from. Endocrinologists, as an integral part of the multidisciplinary oncologic team, need to be familiar with the unique toxicity profile of these anticancer agents. Practical recommendations for their management are proposed. PMID- 30471005 TI - The repeatable battery for the assessment of the neuropsychological status (RBANS): a diagnostic validity study in Greek elderly. AB - OBJECTIVE: There is a broad need for a rapid and efficient neurocognitive battery to detect cognitive decline and differentiate MCI (mild cognitive impairment) and mild dementia from cognitively intact elders. The purpose of this study is to create a version of the repeatable battery for the assessment of neuropsychological status (RBANS) for the Greek population. METHOD: One hundred and sixty-three (163) adults, including healthy controls (HC), MCI and patients with mild dementia, irrespective etiology, were recruited from the day centers of Greek Alzheimer Association after having followed the diagnostic procedure set by the DSM V. The three groups of our sample were matched for age, gender, and education. RESULTS: The Greek RBANS had satisfactory internal reliability, as it yielded the satisfactory coefficient of 0.914. According to the criterion validity, the sensitivity of the RBANS Total score to discriminate controls from patients with mild dementia was 0.94, whereas the specificity was 0.97. In addition, RBANS was also able to discriminate HC from MCI population (sensitivity = 0.87, specificity = 0.81) and MCI from patients with mild dementia (sensitivity = 0.91, specificity = 0.97). CONCLUSIONS: The current data suggest that the Greek version of RBANS is both a valid and reliable psychometric tool, as well as sensitive for detecting cognitive impairment in MCI and early dementia, irrespective etiology. Therefore, taken into account that it revealed coherence in discriminating HC from clinical population, it should be utilized as a neuropsychological screening battery in Greek elders in clinical practice, and also in research protocols. PMID- 30471006 TI - A simplified classification of proximal femoral fractures improves accuracy, confidence, and inter-reader agreement of hip fracture classification by radiology residents. AB - PURPOSE: To demonstrate the effect of teaching a simplified treatment-based classification of proximal femoral fractures on the accuracy, confidence, and inter-reader agreement of radiology residents. The authors hypothesize that these measures will improve after viewing an educational presentation. MATERIALS AND METHODS: Three radiology residents independently classified 100 operative proximal femoral fractures, both before and after viewing a 45-min educational video describing the simplified classification scheme, with a washout period of at least 12 weeks between sessions. Based on the gold standard established by consensus of two radiologists and an orthopedic trauma surgeon utilizing intraoperative fluoroscopic imaging, operative reports, and pre-procedural imaging, accuracy of classification was calculated for each reader before and after viewing the educational video. Reader confidence was recorded on a 0-10 scale, and inter-reader agreement was calculated with Fleiss's kappa. McNemar's test was used to compare accuracy, a paired t test was used to compare confidence, and the Z-test was used to compare kappa values after bootstrapping to determine the standard error of the mean. RESULTS: The study cohort included 60/100 females, with a mean age of 76.6 years. The pooled classification accuracy was initially 65%, which improved to 80% in the second reading session after viewing the educational video (p < 0.0001). Confidence improved from 6.9 initially to 8.6 (p < 0.0001). Inter-reader agreement improved from a kappa of 0.45 (moderate agreement) to 0.74 (substantial agreement) (p < 0.0001). CONCLUSIONS: A simplified treatment-based classification of proximal femoral fractures is easily taught to radiology residents and resulted in increased accuracy, increased inter-reader agreement, and increased reader confidence. PMID- 30471007 TI - Arsenite biotransformation and bioaccumulation by Klebsiella pneumoniae strain SSSW7 possessing arsenite oxidase (aioA) gene. AB - Arsenite oxidizing Klebsiella pneumoniae strain SSSW7 isolated from shipyard waste Goa, India showed a minimum inhibitory concentration of 21 mM in mineral salts medium. The strain possessed a small supercoiled plasmid and PCR amplification of arsenite oxidase gene (aioA) was observed on plasmid as well as chromosomal DNA. It was confirmed that arsenite oxidase enzyme was a periplasmic protein with a 47% increase in arsenite oxidase activity at 1 mM sodium arsenite. Scanning electron microscopy coupled with electron dispersive X-ray spectroscopic (SEM-EDS) analysis of 15 mM arsenite exposed cells revealed long chains of cells with no surface adsorption of arsenic. Transmission electron microscopy combined with electron dispersive X-ray spectroscopic (TEM-EDS) analysis demonstrated plasma membrane disruption, cytoplasmic condensation and periplasmic accumulation of arsenic. The bacterial strain oxidized 10 mM of highly toxic arsenite to less toxic arsenate after 24 h of incubation. Fourier transformed infrared (FTIR) spectroscopy confirmed the interaction of arsenite with functional groups present on the bacterial cell surface. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of 5 mM arsenite exposed cells demonstrated over-expression of 87 kDa and 14 kDa proteins of two subunits aioA and aioB of heterodimer arsenite oxidase enzyme as compared to control cells. Therefore, this bacterial strain might be employed as a potential candidate for bioremediation of arsenite contaminated environmental sites. PMID- 30471008 TI - A generalised dynamic model of leaf-level C3 photosynthesis combining light and dark reactions with stomatal behaviour. AB - Global food demand is rising, impelling us to develop strategies for improving the efficiency of photosynthesis. Classical photosynthesis models based on steady state assumptions are inherently unsuitable for assessing biochemical and stomatal responses to rapid variations in environmental drivers. To identify strategies to increase photosynthetic efficiency, we need models that account for the timing of CO2 assimilation responses to dynamic environmental stimuli. Herein, I present a dynamic process-based photosynthetic model for C3 leaves. The model incorporates both light and dark reactions, coupled with a hydro-mechanical model of stomatal behaviour. The model achieved a stable and realistic rate of light-saturated CO2 assimilation and stomatal conductance. Additionally, it replicated complete typical assimilatory response curves (stepwise change in CO2 and light intensity at different oxygen levels) featuring both short lag times and full photosynthetic acclimation. The model also successfully replicated transient responses to changes in light intensity (light flecks), CO2 concentration, and atmospheric oxygen concentration. This dynamic model is suitable for detailed ecophysiological studies and has potential for superseding the long-dominant steady-state approach to photosynthesis modelling. The model runs as a stand-alone workbook in Microsoft(r) Excel(r) and is freely available to download along with a video tutorial. PMID- 30471010 TI - Effects of Clavulanic Acid Treatment on Reinstatement to Methamphetamine, Glial Glutamate Transporters, and mGluR 2/3 Expression in P Rats Exposed to Ethanol. AB - Evidence demonstrated that the glutamatergic system is implicated in mediating relapse to several drugs of abuse, including methamphetamine (METH). Glutamate homeostasis is maintained by a number of glutamate transporters, such as glutamate transporter type 1 (GLT-1), cystine/glutamate transporter (xCT), and glutamate aspartate transporter (GLAST). In addition, group II metabotropic glutamate receptors (mGluR2/3) were found to be implicated in relapse-seeking behavior. Ample evidence showed that beta-lactam antibiotics are effective in upregulating GLT-1 and xCT expression, thus improving glutamate homeostasis and attenuating relapse to drugs of abuse. In this study, we investigated the reinstatement of METH using conditioned place preference (CPP) in male alcohol preferring (P) rats exposed to home-cage free choice ethanol drinking. Here, we tested the effect of clavulanic acid (CA), a beta-lactam, on the reinstatement of METH-seeking and ethanol drinking. In addition, we examined the expression of GLT 1, xCT, and GLAST as well as metabotropic glutamate receptor (mGluR2/3) in the nucleus accumbens (NAc) shell, NAc core, and dorsomedial prefrontal cortex (dmPFC). A priming i.p. injection of METH reinstated preference in METH-paired chamber following extinction. Chronic exposure to ethanol decreased the expression of GLT-1 and xCT in the NAc shell, but not in the NAc core or dmPFC. CA treatment blocked the reinstatement of METH-seeking, decreased ethanol intake, and restored the expression of GLT-1 and xCT in the NAc shell. In addition, the expression of mGluR2/3 was increased by CA treatment in the NAc shell and dmPFC. These findings suggest that these glutamate transporters and mGluR2/3 might be potential therapeutic targets for the attenuation of reinstatement to METH seeking. PMID- 30471009 TI - Mild Hypothermia Prevents NO-Induced Cytotoxicity in Human Neuroblastoma Cells Via Induction of COX-2. AB - The cold-inducible protein RBM3 mediates hypothermic neuroprotection against nitric oxide (NO)-induced cell death. Meanwhile, it is well-known that cyclooxygenase-2 (COX-2) is upregulated by RBM3 in several types of cells; however, it is still unclear whether COX-2 contributes to the neuroprotective effects of mild hypothermia/RBM3 against NO-induced cell death. Using human SH SY5Y neuroblastoma cells, it was revealed that NO remarkably downregulates the expression of COX-2 at both mRNA and protein levels. When COX-2 was silenced using siRNA technique, cells became more sensitive to NO-induced cell death. Conversely, the overexpression of COX-2 significantly prevented NO-induced cell death in SH-SY5Y cells, indicating a pro-survival role of COX-2. Upon mild hypothermia pre-treatment, COX-2 was notably induced at both mRNA and protein levels; however, COX-2 silencing abrogated hypothermia-related neuroprotection against NO-induced cell death. Furthermore, it was revealed that either silencing or overexpression of RBM3 had no effects on the expression of COX-2 in SH-SY5Y cells. These findings suggest that mild hypothermia could protect neuroblastoma cells against NO-induced cell death by inducing COX-2 in a RBM3-independent manner. PMID- 30471011 TI - The relationship between urotensin II and insulin resistance in women with gestational diabetes mellitus. AB - AIM: Urotensin II (UII), a pluripotent vasoactive peptide, plays a crucial role in development of insulin resistance. Gestational diabetes mellitus (GDM) is a metabolic disorder associated with insulin resistance. The aims of the current study were to compare UII levels in women with or without GDM and to investigate the relationship between UII and insulin resistance in women with GDM. METHODS: A total of 84 women were recruited in this case-control study (42 women with GDM and 42 age- and body mass index (BMI)-matched pregnant women without GDM as controls). GDM was diagnosed by a 2-h 75-g oral glucose tolerance test over a period of 24-28 gestational weeks. Circulating UII levels were assessed via the ELISA method. The metabolic parameters of the recruited women were also determined. RESULTS: The circulating levels of UII in women with GDM were higher than in controls (11.56 +/- 4.13 vs. 7.62 +/- 3.45 ng/ml, P < 0.001). UII showed a positive correlation with insulin resistance marker (HOMA-IR), fasting blood glucose, and BMI. Moreover, according to the results of multiple linear regression analyses, UII was independently related to HOMA-IR. Additionally, the binary logistic analysis revealed that the women with the highest tertile of UII levels showed increased risk for GDM by comparison with those women with the lowest tertile of UII levels. CONCLUSION: Elevated UII levels are associated with insulin resistance in women with GDM. PMID- 30471012 TI - Efficacy and Safety of Brodalumab in Patients with Moderate-to-Severe Plaque Psoriasis and Skin of Color: Results from the Pooled AMAGINE-2/-3 Randomized Trials. AB - BACKGROUND: Data on treatment outcomes in patients with psoriasis who have skin of color are limited. Brodalumab has shown efficacy in patients with moderate-to severe plaque psoriasis. OBJECTIVE: Our objective was to evaluate the efficacy, safety, and health-related quality of life associated with brodalumab in patients with skin of color participating in two phase III, multicenter, randomized, double-blind, placebo- and active comparator-controlled studies (AMAGINE-2/-3). METHODS: Patients were self-categorized into racial subgroups (black, Asian, or white) or the non-mutually exclusive ethnic subgroup Hispanic/Latino. Patients were randomized to receive brodalumab 210 mg every 2 weeks (Q2W) or ustekinumab (45 mg in patients weighing <= 100 kg and 90 mg in patients weighing > 100 kg) for 52 weeks. Skin clearance was monitored using the Psoriasis Area and Severity Index (PASI) and Static Physician's Global Assessment (sPGA). Treatment-emergent adverse events (TEAEs) were summarized by treatment and racial and ethnic subgroup. Health-related quality of life was assessed using the Dermatology Life Quality Index (DLQI). RESULTS: During the 12-week induction phase, 613 patients received ustekinumab (black, n = 20; Asian, n = 24; white, n = 551; Hispanic/Latino, n = 68) and 1236 patients received brodalumab 210 mg Q2W (black, n = 36; Asian, n = 39; white, n = 1116; Hispanic/Latino, n = 132). At week 52, a total of 590 patients received continuous ustekinumab (black, n = 19; Asian, n = 23; white, n = 532; Hispanic/Latino, n = 64) and 339 patients were re-randomized to continue receiving brodalumab 210 mg Q2W (black, n = 10; Asian, n = 7; white, n = 308; Hispanic/Latino, n = 40). Among patients who received brodalumab 210 mg Q2W, skin clearance response rates were similar across racial and ethnic subgroups at week 12 and week 52; rates of 75%, 90%, and 100% improvement in PASI from baseline were also higher, as was sPGA score <= 1, than in patients who received ustekinumab across all racial and ethnic subgroups. Rates of TEAEs and >= 5-point improvement in DLQI score were similar across racial and ethnic subgroups. CONCLUSIONS: Brodalumab 210 mg Q2W is well tolerated and efficacious across diverse racial and ethnic subgroups in patients with psoriasis, including black, Asian, white, and Hispanic/Latino patients. TRIAL REGISTRY: ClinicalTrials.gov identifier NCT01708603 (AMAGINE-2); NCT01708629 (AMAGINE-3). PMID- 30471013 TI - Synthesis of (E)-2-amino-N'-benzylidenehexahydroquinoline-3-carbohydrazide. AB - A one-pot, multi-component protocol for the synthesis of a new class of functionalized quinoline carbohydrazide derivatives via reaction of various anilines, dimedone, aromatic aldehydes, and cyanoacetohydrazide is described. The reactions are completed in the presence of catalytic amount of piperidine, respectively, in melt conditions and then in ethanol/water (1:1) as green solvent at 80 degrees C. Mild conditions, green medium, short reaction times, simple workup and purification process with no chromatographic technique, and good yields are the main advantages of this method. PMID- 30471014 TI - Is Malaysia's banded langur, Presbytis femoralis femoralis, actually Presbytis neglectus neglectus? Taxonomic revision with new insights on the radiation history of the Presbytis species group in Southeast Asia. AB - The disjunct distribution of Presbytis femoralis subspecies across Sumatra (P. f. percura), southern (P. f. femoralis) and northern (P. f. robinsoni) Peninsular Malaysia marks the unique vicariance events in the Sunda Shelf. However, the taxonomic positions and evolutionary history of P. f. femoralis are unresolved after decades of research. To elucidate this evolutionary history, we analyzed 501 base pairs of the mitochondrial HVSI gene from 25 individuals representing Malaysia's banded langur, with the addition of 29 sequences of Asian Presbytis from Genbank. Our results revealed closer affinity of P. f. femoralis to P. m. mitrata and P. m. sumatrana while maintaining the monophyletic state of P. f. femoralis as compared to P. f. robinsoni. Two central theses were inferred from the results; (1) P. f. femoralis does not belong in the same species classification as P. f. robinsoni, and (2) P. f. femoralis is the basal lineage of the Presbytis in Peninsular Malaysia. Proving the first hypothesis through genetic analysis, we reassigned P. f. femoralis of Malaysia to Presbytis neglectus (Schlegel's banded langur) (Schlegel in Revue Methodique, Museum d'Histoire Naturelle des Pays-Bas 7:1, 1876) following the International Code of Zoological Nomenclature (article 23.3). The ancestors of P. neglectus are hypothesized to have reached southern Peninsular Malaysia during the Pleistocene and survived in refugium along the western coast. Consequently, they radiated upward, forming P. f. robinsoni and P. siamensis resulting in the highly allopatric distribution in Peninsular Malaysia. This study has successfully resolved the taxonomic position of P. neglectus in Peninsular Malaysia while providing an alternative biogeographic theory for the Asian Presbytis. PMID- 30471015 TI - Assessing Disease Activity in Psoriatic Arthritis: A Literature Review. AB - Psoriatic arthritis (PsA) is a multifaceted disease, with a high impact on patients' psychological and physical well-being. There is increasing recognition that assessment of both clinical aspects of disease and patient identified concerns, such as fatigue, work disability, and treatment satisfaction need to be addressed. Only then can we fully understand disease burden and make well informed treatment decisions aimed at improving patients' lives. In recent years, there has been much progress in the development of unidimensional and composite measures of disease activity, as well as questionnaires capturing the patient's perspective in psoriatic disease. Despite these advances, there remains disagreement amongst clinicians as to which instruments should be used. As a consequence, they are yet to receive widespread implementation in routine clinical practice. This review aims to summarize currently available clinical and patient-derived assessment tools, which will provide clinicians with a practical and informative resource. PMID- 30471016 TI - Cyclosporine Metabolites' Metabolic Ratios May Be Markers of Cardiovascular Disease in Kidney Transplant Recipients Treated with Cyclosporine A-Based Immunosuppression Regimens. AB - Cardiovascular disease (CVD) remains one of the primary causes of death after kidney transplantation (KTX). Cyclosporine (CsA) metabolites may play a role in CVD. Metabolic ratio (MR) may be considered a measure of intra-individual differences of CsA metabolism. The study was aimed at analysis of associations of CVD with indices of CsA metabolism: MRs and dose-adjusted CsA concentrations (C/D and C/D/kg). The study was performed in the Department of Immunology, Transplant Medicine, and Internal Diseases of the Medical University of Warsaw and involved 102 KTX recipients. Whole blood concentrations of cyclosporine A, AM1, AM9, AM4N, demethylcarboxylated (dMC-CsA), dihydroxylated (DiH-CsA), trihydroxylated (TriH CsA) cyclosporine metabolites were determined by liquid chromatography coupled with tandem mass spectrometry. Lower AM9/CsA were observed in diabetics. Patients with coronary disease and/or myocardial infarction had lower dMC-CsA/CsA and higher AM4N/CsA. Supraventricular arrhythmia (SVA) was associated with higher AM1/CsA and AM4N/CsA. Hypertriglyceridemia (hTG) was associated with lower AM9/CsA, higher C/D and C/D/kg. Decrease of AM9/CsA and AM4N and higher D/C were associated with overweight/obesity. Systolic blood pressure (BP) positively correlated with dMC-CsA/CsA and negatively with C/D/kg. Diastolic BP correlated positively with AM1/CsA, dMC-CsA/CsA, DiH-CsA/CsA and TriH-CsA/CsA. We have demonstrated the association of coronary disease/myocardial infarction, SVA, hTG, overweight/obesity and elevated arterial BP with higher MRs of AM1, AM4N, dMC CsA, DiH-CsA and TriH-CsA, and lower MRs of AM9, which may indicate deleterious and favourable effects of individual CsA metabolites on cardiovascular system and suggest engagement of specific enzymatic pathways. PMID- 30471017 TI - Italian census on neurosciences: the ICoNe2 study. AB - BACKGROUND: The growing impact of the emergency neurology of trauma centers and of mechanical thrombectomy for the treatment of acute ischemic stroke is revolutionizing the domain of eurosciences. METHODS: A census focused on the demographic distribution of the three main cohorts of neurosciences (neurologists, neuroradiologists, and neurosurgeons) was conducted in Italy between December 2015 and February 2017, and results were compared to the estimated retirement rates and loss for other reasons. RESULTS: The total number of neurosciences specialists active in Italy was 4394 at the end of the period of the survey. The estimated retirement rates and losses seem not be supplied by the physicians in training in the same period. CONCLUSIONS: A proper redistribution of the resources and the modification of the training programs seem to be mandatory to maintain acceptable standards of care for the Italian neurosciences during the next decade. PMID- 30471018 TI - The antiquity of hydrocephalus: the first full palaeo-neuropathological description. AB - The Pathology Museum of the University of Florence houses a rich collection of anatomical specimens and over a hundred waxworks portraying pathological conditions occurring in the nineteenth century, when the museum was established. Clinical and autopsy findings of these cases can still be retrieved from the original museum catalogue, offering a rare opportunity for retrospective palaeo pathological diagnostics. We present a historical case of severe hydrocephalus backed by modern-day anthropological, radiological and molecular analyses conducted on the skeleton of an 18-month-old male infant deceased in 1831. Luigi Calamai (1796-1851), a wax craftsman of La Specola workshop in Florence, was commissioned to create a life-sized wax model of the child's head, neck and upper thorax. This artwork allows us to appreciate the cranial and facial alterations determined by 30 lb of cerebrospinal fluid (CSF) accumulated within the cerebral ventricular system. Based on the autopsy report, gross malformations of the neural tube, tumours and haemorrhage could be excluded. A molecular approach proved helpful in confirming sex. We present this case as the so-far most compelling case of hydrocephalus in palaeo-pathological research. PMID- 30471019 TI - Angelo Mosso (1846-1910). Brain's rule in physiognomic. A new face of pathological diagnosis. PMID- 30471020 TI - A case report of Fisher syndrome with the detection of anti-GM3 and anti-GD1b IgG antibodies. PMID- 30471021 TI - Comment on "Drinking Strategies: Planned Drinking Versus Drinking to Thirst". PMID- 30471022 TI - Simple Way to Detect Trp to Tb3+ Resonance Energy Transfer in Calcium-Binding Peptides Using Excitation Spectrum. AB - The sensitized phosphorescence of Tb3+ is often used for the assessment of the ion binding to various chelating agents or natural Ca2+-binding proteins. The detailed structure of the Tb3+ excitation spectrum gives a special advantage for analysis; any extra absorption peak can be easily detected which provides simple and direct evidence that resonance energy transfer occurs. By employing the Tb3+ phosphorescence, we characterized the Ca2+-binding sites of two related peptides self-processing module of the FrpC protein produced by bacterium Neisseria meningitidis and the shorter peptide derived from FrpC. Here we show that while the increase of direct Tb3+ excitation at 243 nm generally corresponds to Tb3+ association with various binding sites, the excitation enhancement in the 250-300 nm band signifies Tb3+-binding in the close proximity of aromatic residues. We demonstrate that the presence of resonance energy transfer could be easily detected by inspecting Tb3+ excitation spectra. Additionally, we show that the high level of specificity of Tb3+ steady state detection on the spectral level could be reached at very low Tb3+ concentrations by taking advantage of its narrow phosphorescence emission maximum at 545 nm and subtracting the averaged autofluorescence intensities outside this peak, namely at 525 and 565 nm. PMID- 30471023 TI - Overviews of Biomimetic Medical Materials. AB - This chapter describes the overviews of biomimetic medical materials which covers innovation and significance of terminology, diverse fabrication methods, and technologies ranges from nanotechnology to 3D printing to develop biomimetic materials for medical applications. It also depicts specific fundamental characteristics required for a material to be a model biomimetic material for particular medical application. It basically outlines current statuses of biomimetic medical materials used for tissue engineering and regenerative medicine, drug/protein delivery, bioimaging, biosensing, and 3D bioprinting technology. It also illustrates the effect of functionalization of a material through chemical and biological approaches towards different applications. Not only, the key properties and potential applications of the biomimetic materials, but it also explains the protection and utilization of intellectual property associated with biomedical materials. PMID- 30471024 TI - Protein Cage Nanoparticles as Delivery Nanoplatforms. AB - Protein cage nanoparticles are made of biomaterials, proteins, and have well defined cage-like architectures designed and built by nature. They are composed of multiple copies of one or a small number of chemically identical subunits having a highly uniform nano-size and symmetric structure. Protein cage nanoparticles have genetic and chemical plasticity amenable to simultaneously introducing multiple cell-specific targeting ligands, diagnostic agents, and their corresponding therapeutic agents at desired sites depending on its purpose. A wide range of protein cage nanoparticles, such as ferritin, lumazine synthase, encapsulin, and virus-like particles, has been extensively explored and utilized in biomedical fields as effective delivery nanoplatforms of diagnostics and/or therapeutics. Highly biocompatible and plastic protein cage nanoparticles may provide a new paradigm for developing simple, but versatile in vivo delivery systems. PMID- 30471025 TI - Cell Membrane Coated Nanoparticles: An Emerging Biomimetic Nanoplatform for Targeted Bioimaging and Therapy. AB - Biomimetic nanoplatform being a recent and emerging strategy plays an important role in a wide variety of applications. The different types of membranes used for coating include membranes from red blood cells, platelets, leucocytes, neutrophils, cancer cells, stem cells, etc. The as obtained membrane vesicles are fused onto the core nanoparticles through extrusion, sonication, electroporation. Biomimetic nanoparticles attain special functions which include ligand recognition and targeting, long blood circulation, immune escaping, tumor targeting depending on the core-shell interactions. The membrane coated nanoparticles indeed mimic the source cells and improves the therapeutic efficacy of drugs other cargos through specific delivery and enhanced accumulation in the tumor. PMID- 30471026 TI - Graphene-Based Nanomaterials and Their Applications in Biosensors. AB - Recently graphene has been drawing tremendous attention mainly due to its potential contributions to applications in biology, information technology and energy. Among these applications graphene-based biosensors have been particularly progressed caused in part by development of diverse derivatives of graphene such as graphene oxides (GOs) and graphene quantum dots (GQDs). In this chapter preparation and functionalization of the graphene and GOQs are described together with their optoelectronic properties. Recent progresses in graphene and GQD-based biosensors are also highlighted with emphasis on immunoassay which utilizes unique interaction between antigen and antibody, and oligonucleotide assay which utilizes hybridization process. Since electrical and optical features are the most prominent characteristics of graphene-based nanomaterials, biosensor systems will be focused on electrochemical and fluorescence-based detection scheme. PMID- 30471027 TI - Graphene-Functionalized Biomimetic Scaffolds for Tissue Regeneration. AB - Graphene is a two-dimensional atomic layer of graphite, where carbon atoms are assembled in a honeycombed lattice structure. Recently, graphene family nanomaterials, including pristine graphene, graphene oxide and reduced graphene oxide, have increasingly attracted a great deal of interest from researchers in a variety of science, engineering and industrial fields because of their unique structural and functional features. In particular, extensive studies have been actively conducted in the biomedical and related fields, including multidisciplinary and emerging areas, as their stimulating effects on cell behaviors have been becoming an increasing concern. Herein, we are attempting to summarize some of recent findings in the fields of tissue regeneration concerning the graphene family nanomaterial-functionalized biomimetic scaffolds, and to provide the promising perspectives for the possible applications of graphene family nanomaterial. PMID- 30471029 TI - Biomimetic Scaffolds for Bone Tissue Engineering. AB - The use of biomimetic scaffolds for bone tissue engineering has been studied for a long time. Biomimetic scaffolds can assist and accelerate bone regeneration that is similar to that of authentic tissue, which represents the environment of cells in a living organism. Currently, numerous biomaterials have been reported for use as a biomimetic scaffold. This review focuses on the design of biomimetic scaffolds, kinds of biomaterials and methods used to fabricate biomimetic scaffolds, growth factors used with biomimetic scaffold for bone regeneration, mobilization of biological agents into biomimetic scaffolds, and studies on (pre)clinical bone regeneration from biomimetic scaffolds. Then, future prospects for biomimetic scaffolds are discussed. PMID- 30471028 TI - Influence of Biomimetic Materials on Cell Migration. AB - In recent tissue engineering applications, the advance of biomaterials has focused on the devising of biomimetic materials that are directing new tissue formation and capable of causing specific cellular responses. These advances can be controlled by modifying the devising parameters of the materials. The biomimetic materials potentially mimic many roles of ECM in tissues. For the homogeneous distribution and biocompatibility of scaffolds by cell migration with biomimetic materials, cell migration is studied because it has a important role in physiological phenomenon and in pathologies; cancer metastasis, immune response or embryonic development. This review discusses the migration of cells with biomimetic materials for tissue engineering. It is also summarized that the recent advances of cell migration with biomimetic materials in 2-D and 3-D for tissue engineering. PMID- 30471030 TI - Recent Progress in Vascular Tissue-Engineered Blood Vessels. AB - Cardiovascular disease is the number one cause of death in the U.S and results in the loss of approximately one million lives and more than 400 billion U.S. dollars for treatments every year. Recently, tissue engineered blood vessels have been studied and developed as promising replacements for treatment with autologous veins. Here, we summarize the cell sources and methods to make tissue engineered blood vessels (TEBVs), the recent progress in TEBV related research, and also the recent progress in TEBV related clinical studies. PMID- 30471031 TI - Microenvironmental Regulation of Stem Cell Behavior Through Biochemical and Biophysical Stimulation. AB - Stem cells proliferate by undergoing self-renewal and differentiate into multiple cell lineages in response to biochemical and biophysical stimuli. Various biochemical cues such as growth factors, nucleic acids, chemical reagents, and small molecules have been used to induce stem cell differentiation or reprogramming or to maintain their pluripotency. Moreover, biophysical cues such as matrix stiffness, substrate topography, and external stress and strain play a major role in modulating stem cell behavior. In this chapter, we have summarized microenvironmental regulation of stem cell behavior through biochemical and biophysical stimulation. PMID- 30471032 TI - Decellularized Tissue Matrix for Stem Cell and Tissue Engineering. AB - Decellularization is a technique to remove cellular components from native tissues, which could reduce immune reactions to the scaffolds. Decellularized matrices are valuable for tissue engineering, as they preserve tissue-specific structural, mechanical, and biochemical microenvironments, while promoting cellular engraftment and functions in the matrix. So far, various tissues have been decellularized by combinations of mechanical, chemical, and enzymatic processes and utilized in preparing bioscaffolds to provide tissue-specific environments for various cell types, including primary cells, progenitor cells, and stem cells. In addition, decellularized matrices could be manipulated into several formats according to the final application, such as tissue-engineering scaffolds, artificial organs, cell culture matrices, and transplantation carriers. In this chapter, we describe various types of decellularized tissue matrices and their extensive use in regenerative medicine, including reconstruction of artificial organs and regeneration of damaged tissues. PMID- 30471033 TI - Biomaterials for Stem Cell Therapy for Cardiac Disease. AB - Myocardial Infarction (MI) in cardiac disease is the result of heart muscle losses due to a wide range of factors. Cardiac muscle failure is a crucial condition that provokes life-threatening outcomes. Heretofore, regeneration therapies in MI have used stem-cell-based therapy instantly after a myocardial injury to prevent the disease process and tissue malfunction. Despite the therapeutic utility of stem-cell-based regenerative therapy, barriers to successful treatment have been addressed. In this chapter, we illustrate a variety of emerging biomaterial strategies for enhancing the function of therapeutic stem cells, such as cell surface modification to synthetically endowing stem cells with new characteristics and hydrogels with its biological and mechanical properties. These investments offer a potential accompaniment to traditional stem-cell-based therapies for enhancing the efficacy of stem cell therapy to design properly activating cardiac tissues. PMID- 30471034 TI - Immunomodulation of Biomaterials by Controlling Macrophage Polarization. AB - Macrophages are key players in innate immune responses to foreign substances. They participate in the phagocytosis of biomaterial-derived particles, angiogenesis, recruitment of fibroblasts, and formation of granulation tissues. Most macrophage functions are achieved through the release of various cytokines and chemokines; the release profile of cytokines is dependent on the phenotype of macrophages, namely proinflammatory M1 or antiinflammatory M2. M1 and M2 macrophages coexist during an inflammatory phase, and the M1/M2 ratio is considered to be an important factor for wound-healing or tissue regeneration. This ratio depends on the chemical and physical properties of biomaterials. To obtain a favorable foreign body reaction to biomaterials, the phenotypes of the macrophages can be modulated by cytokines, antibodies, small chemicals, and microRNAs. Geometrical surface fabrication of biomaterials can also be used for modulating the phenotype of macrophages. PMID- 30471035 TI - Artificial Methods for T Cell Activation: Critical Tools in T Cell Biology and T Cell Immunotherapy. AB - Antigen-specific immunity conferred by T lymphocytes is a result of complex molecular interactions at the immunological synapse. A variety of biomimetic approaches have been devised to artificially induce T cell activation either to study the T cell biology or to expand and prime the therapeutic T cell populations. Here we first briefly review the molecular and cellular, structural and phenotypical bases that are involved in T cell activation. The artificial methods for T cell activation are then discussed in two grand categories, the soluble (3D) and the surface-anchored (2D) platforms with their design parameters. With the growing number of successful adoptive T cell therapies, the spurring demands for effective and safe T cell expansion as well as precise control over resulting T cell functions and phenotypes warrant the extensions of engineering parameters in the development of novel methodologies for T cell activation. PMID- 30471036 TI - Regulatory T Cell-Mediated Tissue Repair. AB - Regulatory T-cells (Treg cells) are a specific group of T-cells that maintain immune homeostasis by counteracting the immune responses of conventional T-cells. So far, the therapeutic applications of Treg cells have focused on the treatment of autoimmune diseases, as depletion of Treg cells or Treg-related genes is known to cause autoimmune defects. However, Treg cells can be a potential solution for tissue repair as they can terminate the pro-inflammatory phase and initiate the anti-inflammatory or regenerative phase at the tissue injury site. This review summarizes the known characteristics of Treg cells and lists examples of their therapeutic applications. The use of Treg cells in the treatment of myocardial infarctions, skeletal muscle injuries, and ischemia injuries has revealed their potential as a promising tissue repair method. We have also discussed the limitations and scope of Treg cells in tissue repair. PMID- 30471037 TI - ROS-Responsive Biomaterial Design for Medical Applications. AB - Stimuli-responsive biomaterials undergo significant alterations in material structure and property in response to changes of local environmental factors (e.g. pH, temperature, enzyme activation, and water absorption). In particular, reactive oxygen species (ROS) is considered as a major stimulus because over production of ROS involves most types of major pathogenesis. The application of ROS-responsive biomaterials requires suitable material designs to program user defined changes of their structure and property in response to a sudden change in the local ROS level. This chapter summarizes the progress in designing and applying major types of ROS-responsive biomaterials within the past 10 years. PMID- 30471038 TI - Fibrin-Based Biomaterial Applications in Tissue Engineering and Regenerative Medicine. AB - The fibrin matrix is fundamentally formed by the polymerization of fibrinogen and thrombin in blood plasma. It is a natural biopolymeric material to widely investigate for various tissue regenerations due to good biocompatibility, rapid biodegradability, and easy fabrication. In particular, the conjugated bioactive molecules with fibrinogen can promote tissue morphogenesis or maturation after cell adhesion on the matrices, migration, proliferation, or differentiation. Using these physiological properties with cell-material interactions, the fibrin matrices have been utilized in tissue engineering applications such as skin tissue, cardiovascular tissue, musculoskeletal tissue, or nerve tissue in preclinical and clinical situations. This chapter demonstrates the fibrin material and its tissue engineering applications as the therapeutic strategies. PMID- 30471039 TI - Fabrication of Electrochemical-Based Bioelectronic Device and Biosensor Composed of Biomaterial-Nanomaterial Hybrid. AB - The field of bioelectronics has paved the way for the development of biochips, biomedical devices, biosensors and biocomputation devices. Various biosensors and biomedical devices have been developed to commercialize laboratory products and transform them into industry products in the clinical, pharmaceutical, environmental fields. Recently, the electrochemical bioelectronic devices that mimicked the functionality of living organisms in nature were applied to the use of bioelectronics device and biosensors. In particular, the electrochemical-based bioelectronic devices and biosensors composed of biomolecule-nanoparticle hybrids have been proposed to generate new functionality as alternatives to silicon-based electronic computation devices, such as information storage, process, computations and detection. In this chapter, we described the recent progress of bioelectronic devices and biosensors based on biomaterial-nanomaterial hybrid. PMID- 30471040 TI - Biomimetic Self-Assembling Peptide Hydrogels for Tissue Engineering Applications. AB - Tissue engineering is an appealing research field that involves the replacement and repair of damaged cells and tissues. Scientists and researchers are facing a great challenge to design and develop suitable scaffold materials with biological activities for the applications in tissue regeneration. Among a variety of natural and synthetic materials, biomimetic self-assembling peptides hold great promises as building blocks for fabricating hydrogel scaffolds with three dimensional (3D) network structures, which could mimic the natural extracellular matrix (ECM). Furthermore, functionalized self-assembling peptides are easily obtained by introducing multiple bioactive peptide motifs derived from naturally occurring proteins. Over the past two decades, many kinds of biomimetic self assembling peptides have been designed and developed, and these formed peptide hydrogel scaffolds show great potential applications in tissue engineering, such as angiogenesis, bone, cartilage, and nerve regeneration. In this chapter, we have endeavored to do a comprehensive review of biomimetic self-assembling peptides that form nanofiber hydrogel scaffolds. In particular, recent advances of biomimetic self-assembling peptide hydrogel for tissue engineering applications are also highlighted. PMID- 30471041 TI - Bioartificial Esophagus: Where Are We Now? AB - The current treatments for esophageal diseases, such as carcinomas, trauma or congenital malformations, require surgical intervention and esophageal reconstruction using redundant parts of the gastrointestinal tract. However, the use of gastrointestinal segments can cause various surgical morbidities and mortality because additional abdominal surgery may be required at the expense of other anatomic structures. Therefore, tissue engineering using various biomaterial or cell sources has emerged as an alternative strategy of biomimicking the native esophageal tissue that could be implanted as an artificial graft. Although tissue engineering techniques have promise as an effective regenerative strategy, no functional solution currently exists for esophageal reconstruction. Here, we present a review of the progress made in the field of regenerative medicine for esophageal reconstruction from bench to bedside. PMID- 30471042 TI - ECM Based Bioink for Tissue Mimetic 3D Bioprinting. AB - To create tissue replacements with qualities similar to human tissues, and for ease of tissue loss repair, novel 3D printing fabrication methods have recently been introduced and popularized in the field of tissue engineering and regenerative medicine as an alternative to the scaffold fabrication methods. 3D printing may provide the fabricate process to better mimic the internal microstructure and external appearance. Printable bioink should be developed for stable 3D structure stratification. Advanced bioinks for 3D printing are rationally designed materials intended to improve the functionality of printed tissue scaffolds. The search for an appropriate bioink capable of providing a suitable microenvironment to support cellular activities is ongoing. The extracellular matrix (ECM) provides instructive cues for cell attachment, proliferation, differentiation, and ultimately tissue regeneration. The use of ECM-based biomaterials in regenerative medicine is therefore, rapidly expanding. In this respect, the decellularized ECM biomaterials have gained popularity as an excellent source of bioink, given its capability to inherit the intrinsic cues from a native ECM. In this chapter, we describe the current status of ECM-based biomaterials, the emerging trends in ECM bioink development, and bioink requirements that could enable proper selection of the bioink to fabricate an engineered tissue/organ. In particular, rheological properties of bioprinting materials are significant for printing resolution and shape fidelity. We propose a general method of measuring non-Newtonian rheological properties based on rotational rheometers in oscillatory mode. In addition, the mathematical modeling incorporating the power law model is discussed. These approaches can be easily used to optimize printing parameters and verify the bioink printability because a variety of dECM-based bioinks possess shear-thinning properties. PMID- 30471043 TI - 3D Bioprinting for Artificial Pancreas Organ. AB - Type 1 diabetes mellitus (T1DM) results from an autoimmune destruction of insulin producing beta cells in the islet of the endocrine pancreas. Although islet transplantation has been regarded as an ideal strategy for T1D, transplanted islets are rejected from host immune system. To immunologically protect them, islet encapsulation technology with biocompatible materials is emerged as an immuno-barrier. However, this technology has been limited for clinical trial such as hypoxia in the central core of islet bead, impurity of islet bead and retrievability from the body. Recently, 3D bioprinting has been emerged as an alternative approach to make the artificial pancreas. It can be used to position live cells in a desired location with real scale of human organ. Furthermore, constructing a vascularization of the artificial pancreas is actualized with 3D bioprinting. Therefore, it is possible to create real pancreas-mimic artificial organ for clinical application. In conclusion, 3D bioprinting can become a new leader in the development of the artificial pancreas to overcome the existed islet. PMID- 30471044 TI - Current Status of Development and Intellectual Properties of Biomimetic Medical Materials. AB - Biomimetic medical materials are the biomaterials which mimic the important characteristic features of natural material/tissue structures or architectures and are mainly used in biomedical field for their applications in tissue regeneration, medical devices, biosensors and drug delivery. It is one of the leading research topics which have the ability to replace the existing biomaterials and medical devices and to development new biomaterials. The innovation and development in this research area are growing quickly because of the state-of-the-art techniques like nanobiotechnology, biosensors, tissue engineering and regenerative medicine, and 3D (bio)printing. These techniques can mimic the biomacromolecules, peptide sequences, morphology, chemical and physical structures more precisely than other currently available methods. The importance of hydrogels and its composites as examples among many other biomaterials are increasing vastly because of their recent advancements in its biological, chemical and physical cues which are biomimetic to native tissues. Furthermore, an enhancement in the 3D bioprinting technology where live cells are printed along with biomaterials demonstrates the capabilities of this technology to innovate novel tissue engineering products in micro- to macro-technology. The recent trends of development and intellectual properties related to biomimetic medical materials along with their perspectives and area of scope are discussed by focusing on 3D bioprinting in this chapter. PMID- 30471045 TI - Incidence of incisional hernias following single-incision versus traditional laparoscopic surgery: a meta-analysis. AB - PURPOSE: To compare, using a meta-analysis of randomized controlled trials, the risk of incisional hernia in patients undergoing single-incision laparoscopic surgery to those undergoing traditional laparoscopic surgery. METHODS: MEDLINE and EMBASE databases were searched. Randomized controlled trials comparing single incision laparoscopic surgery to traditional laparoscopic surgery and which reported incisional hernias over a minimum 6-month follow-up period were eligible. Risk of bias was assessed as outlined in the Cochrane Handbook. Pooled odds ratios were calculated using RevMan. RESULTS: Of 309 identified studies, 22 were included in this meta-analysis. Pooled results showed higher odds of incisional hernia following single-incision laparoscopic surgery relative to traditional laparoscopic surgery (odds ratio 2.83, 95% CI 1.34-5.98, p = 0.006, I2 = 0%). There was no difference in the odds of incisional hernias requiring surgical repair (p = 0.10). Subgroup analysis found no difference in the odds of incisional hernias based on procedure type (p = 0.69) or method of follow-up (p = 0.85). The quality of evidence was determined to be moderate. CONCLUSION: Single incision laparoscopic surgery is associated with a threefold increase in the odds of incisional hernia compared with traditional laparoscopic surgery. PMID- 30471046 TI - Diagnostic Algorithms for Cardiovascular Death in Administrative Claims Databases: A Systematic Review. AB - INTRODUCTION: Valid algorithms for identification of cardiovascular (CV) deaths allow researchers to reliably assess the CV safety of medications, which is of importance to regulatory science, patient safety, and public health. OBJECTIVE: The aim was to conduct a systematic review of algorithms to identify CV death in administrative health plan claims databases. METHODS: We searched MEDLINE, EMBASE, and Cochrane Library for English-language studies published between January 1, 2012 and October 17, 2017. We examined references in systematic reviews to identify earlier studies. Selection included any observational study using electronic health care data to evaluate the sensitivity, specificity, positive predictive value (PPV), or negative predictive value (NPV) of algorithms for CV death (sudden cardiac death [SCD], myocardial infarction [MI]-related death, or stroke-related death) among adults aged >= 18 years in the United States. Data were extracted by two independent reviewers, with disagreements resolved through further discussion and consensus. The Quality Assessment of Diagnostic Accuracy Studies-2 instrument was used to assess the risk of bias. RESULTS: Five studies (n = 4 on SCD, n = 1 on MI- and stroke-related death) were included after a review of 2053 citations. All studies reported algorithm PPVs, with incomplete reporting on other accuracy parameters. One study was at low risk of bias, three studies were at moderate risk of bias, and one study was at unclear risk of bias. Two studies identified community-occurring SCD: one identified events using International Classification of Disease, Ninth Revision (ICD-9) codes on death certificates and other criteria from medical claims (PPV = 86.8%) and the other identified events resulting in hospital presentation using first-listed ICD-9 codes on emergency department or inpatient medical claims (PPV = 92.3%). Two studies used death certificates alone to identify SCD (PPV = 27% and 32%, respectively). One study used medical claims to identify CV death (PPV = 36.4%), coronary heart disease mortality (PPV = 28.3%), and stroke mortality (PPV = 34.5%). CONCLUSION: Two existing algorithms based on medical claims diagnoses with or without death certificates can accurately identify SCD to support pharmacoepidemiologic studies. Developing valid algorithms identifying MI- and stroke-related death should be a research priority. PROSPERO 2017 CRD42017078745. PMID- 30471047 TI - Long agonal period deteriorates cardiac death donor lung function in a rat EVLP model. AB - PURPOSE: We investigated the impact of the duration of agonal period on donor lung function after reperfusion in an ex vivo rat lung perfusion model. METHODS: Three mechanical hypoventilation conditions were used for three agonal periods, which were defined as the interval between the start of hypoventilation and the time when systolic arterial blood pressure reached < 50 mmHg, i.e., < 10, 30-60, and 150-200 min for very short (VS), short (S), and long (L) groups (n = 5 rats/group). After flushing the lung, heart-lung blocks were reperfused ex vivo for 120 min; physiological data were obtained throughout the reperfusion process. RESULTS: Pulmonary vascular resistance was significantly higher throughout reperfusion in group L than in the other two groups (p < 0.05). After reperfusion, oxygenation was worse and pulmonary edema was more severe in group L than in group S (p < 0.05). Potassium concentrations in the perfusates were significantly higher in group L than in group VS. Histological analysis revealed more severe injury in group L than in the other two groups. CONCLUSIONS: Long agonal periods may lead to deterioration of donor lung function; short intervals may not significantly affect donor lung function. PMID- 30471048 TI - Mitral valve repair versus replacement with preservation of the entire subvalvular apparatus. AB - OBJECTIVE: This study aimed to evaluate the outcomes of mitral valve (MV) repair versus MV replacement with preservation of the entire subvalvular apparatus. METHODS: We retrospectively searched our dedicated in-hospital database for patients who underwent MV surgery between 2012 and 2017. RESULTS: A total of 82 patients were divided into a group that underwent MV replacement (n = 35) and a group that underwent MV repair (n = 47). Patients undergoing MV replacement were significantly older (p < 0.01). Mortality at 30 days was not significantly different [MV replacement: n = 1 (2.9%), MV repair: n = 0 (0%); p = 0.43]. The single case of 30-day mortality after MV replacement was due to acute aortic dissection. The total cohort did not show significant differences in long-term survival (p = 0.07). There were no cardiac-related deaths in this cohort. Postoperative left ventricular end-diastolic diameter (MV replacement: 45.4 +/- 6.2 mm, MV repair: 45.6 +/- 5.8 mm; p = 0.89), left ventricular end-systolic diameter (MV replacement: 29.6 +/- 7.1 mm, MV repair: 29.4 +/- 5.2 mm; p = 0.89), and ejection fraction (MV replacement: 59.2 +/- 11.4%, MV repair: 62.0 +/- 6.8%; p = 0.17) were not significantly different. CONCLUSIONS: This study found that MV replacement had operative mortality, long-term survival, and complication rates similar to those of MV repair. There were no cardiac-related deaths in this cohort. MV replacement with preservation of the entire subvalvular apparatus does not seem to be inferior to MV repair. PMID- 30471049 TI - Angiographic appearance of patent saphenous vein grafts more than 25 years after coronary artery bypass grafting. AB - Nine patients with ten angiographical patent saphenous vein grafts (SVG) more than 25 years after coronary artery bypass grafting (CABG) at Kawasaki Medical School Hospital between 1976 and 1992 were reviewed. Patent SVG disease was assessed using the FitzGibbon classification, and clinical characteristics which might affect the longevity of SVG were retrospectively evaluated. The mean duration between surgery and current coronary angiography was approximately 30 years (25-35 years). There were two perfectly patent SVGs (FitzGibbon AI, 35 and 32 years after surgery), both of which were bypass grafts to the left anterior descending arteries (LAD). The other eight grafts exhibited some vein graft disease (BII:3, BIII:5). The sequential anastomosis was performed for 5 SVGs. The SVGs bypassed to the good run-off LAD, sequential bypass, strict medical management including cessation of smoking and body weight control may contribute to the slow progression of vein graft disease after CABG. PMID- 30471050 TI - Comparison of lead failure manifestation of Biotronik Linox with St. Jude Medical Riata and Medtronic Sprint Fidelis lead. AB - PURPOSE: To compare lead failure manifestation and lead performance of the Biotronik Linox/Sorin Vigila defibrillator lead (Linox group) with the St. Jude Medical Riata/Riata ST (Riata group) and Medtronic Sprint Fidelis defibrillator leads (Fidelis group). METHODS: We assessed the performance of all aforementioned leads implanted at our center and investigated the manifestation of lead failures. RESULTS: Of 93 Linox, 86 Riata, and 81 Fidelis leads implanted at our center, 11 (12%), 22 (26%), and 25 (31%) leads failed during a median follow-up of 46, 61, and 84 months, respectively. Inappropriate shocks were delivered in 64% (Linox), 5% (Riata), and 32% (Fidelis) of lead failures; a device alert was noted in none (Linox), 5% (Riata), and 52% (Fidelis); and lead failure was a coincidental finding in 36% (Linox), 91% (Riata), and 16% (Fidelis) of cases (p < 0.001). Non-physiological high rate signals were observed in 73% (Linox), 27% (Riata), and 80% (Fidelis) of lead failures (p = 0.001) and damaged lead integrity was found in 36% (Linox), 73% (Riata), and 24% (Fidelis) of cases (p = 0.064). Lead survival at 5 years was 88%, 92%, and 71% for Linox, Riata, and Fidelis group, respectively. CONCLUSIONS: The most frequent clinical manifestation of lead failure was inappropriate shocks for Linox, coincidental finding for Riata and device alert for Fidelis leads. Non-physiological high rate signals were frequently observed in Linox and Fidelis lead failures whereas in Riata lead failures, a damaged lead integrity was the predominant finding. PMID- 30471052 TI - TSPYL5-mediated inhibition of p53 promotes human endothelial cell function. AB - Testis-specific protein, Y-encoded like (TSPYL) family proteins (TSPYL1-6), which are members of the nucleosome assembly protein superfamily, have been determined to be involved in the regulation of various cellular functions. However, the potential role of TSPYL family proteins in endothelial cells (ECs) has not been determined. Here, we demonstrated that the expression of TSPYL5 is highly enriched in human ECs such as human umbilical vein endothelial cells (HUVECs) and human pluripotent stem cell-differentiated ECs (hPSC-ECs). Importantly, TSPYL5 overexpression was shown to promote EC proliferation and functions, such as migration and tube formation, by downregulating p53 expression. Adriamycin induced senescence was markedly blocked by TSPYL5 overexpression. In addition, the TSPYL5 depletion-mediated loss of EC functions was blocked by p53 inhibition. Significantly, TSPYL5 overexpression promoted angiogenesis in Matrigel plug and wound repair in a mouse skin wound healing model in vivo. Our results suggest that TSPYL5, a novel angiogenic regulator, plays a key role in maintaining endothelial integrity and function. These findings extend the understanding of TSPYL5-dependent mechanisms underlying the regulation of p53-related functions in ECs. PMID- 30471051 TI - Antiepileptic and psychiatric medication in a nationwide cohort of patients with glioma WHO grade II-IV. AB - INTRODUCTION: Glioma is the most common intracranial primary brain tumor. Patients with glioma often suffer from epilepsy, anxiety and depression. Aims of this study were to identify risk factors for drug-treated anxiety and depression, and to determine the use of psychiatric medication in a national glioma cohort. METHODS: Data from the Cancer Registry of Norway on all persons diagnosed with glioma WHO grade II-IV 2004-2010 were linked with data from the Norwegian Prescription Database. Cox regression analysis was used to assess risk factors for drug-treated anxiety and depression. Standardized incidence ratios were calculated for psychiatric medication dispensed to glioma patients and compared to the general population. RESULTS: The glioma cohort consisted of 1056 males and 772 females. Of the 1828 patients, 565 had glioma grade II-III, and 1263 had grade IV. The patients with glioma grade II-III who were treated with levetiracetam had an increased risk for drug-treated anxiety compared to patients without levetiracetam; hazard ratio 2.8 (95% confidence interval 1.7-4.9). Female gender increased the risk for drug-treated anxiety compared to males in patients with glioma grade IV; hazard ratio 1.5 (95% confidence interval 1.2-2.0). Antidepressants were less frequently dispensed to patients with glioma grade II III and epilepsy than to the general population. CONCLUSIONS: Patients with glioma grade II-III on levetiracetam had an increased risk for drug-treated anxiety. The subgroup of patients with glioma grade II-III and epilepsy received less antidepressants than the general population. PMID- 30471053 TI - Long-term outcomes of renal function after radioactive iodine therapy for thyroid cancer according to preparation method: thyroid hormone withdrawal vs. recombinant human thyrotropin. AB - PURPOSE: Long-term effects of iatrogenic hypothyroidism on renal function from thyroid hormone withdrawal during radioactive iodine therapy (RAIT) have not been studied, especially in subjects with mildly impaired renal function. We compared renal function in thyroid cancer subjects according to preparation method of either thyroid hormone withdrawal (THW) or injection of recombinant human thyrotropin (rhTSH). METHODS: This retrospective study enrolled 241 thyroidectomized patients (rhTSH group, n = 87 and THW group, n = 154). Changes in glomerular filtration rate (GFR) were measured prior to surgery, at the time of RAIT, and during a regular follow-up at least one year after RAIT. RESULTS: Baseline renal function was comparable between the rhTSH group and the THW group (91.4 mL/min/1.73 m2 vs. 92.4 mL/min/1.73 m2). At the time of RAIT, GFR was significantly decreased in the THW group (70.6 mL/min/1.73 m2, -23.6%), whereas renal function was preserved in the rhTSH group (85.4 mL/min/1.73 m2, -6.6%). In the THW group, renal function was fully recovered within 6 months after RAIT and was maintained up to 24 months, even in subjects with baseline GFR less than 90 mL/min/1.73 m2. CONCLUSIONS: THW for RAIT preparation induced considerable reduction in renal function, but this change was transient. In contrast, injection of rhTSH did not decrease renal function, making it a good option for RAIT preparation for subjects with renal dysfunction. PMID- 30471054 TI - Trends in Hospital Visits for Generic and Brand-Name Warfarin Users in Quebec, Canada: A Population-Based Time Series Analysis. AB - BACKGROUND: Federal standards authorize the commercialization of generic medicines after bioequivalence versus the brand-name originator has been demonstrated. For drugs with narrow therapeutic indexes, such as warfarin, the accepted difference in bioavailability is <= 10%. No systematic pharmacovigilance studies are conducted once generics become available. OBJECTIVE: We aimed to assess the impact of the arrival of generic warfarin on hospital visit trends (hospital admissions or emergency room consultations) in warfarin users. METHODS: This was an observational interrupted time series analysis (2 January 1996 to 1 January 2016). Using the Quebec Integrated Chronic Disease Surveillance System, we included all patients who were aged >= 66 years, publicly covered and using brand-name or generic warfarin (N = 280,158). We estimated rates of hospital visits in 6-month periods, 5 years before and up to 15 years after the arrival of generic warfarin. Periods before and after were compared using segmented regression models for all users along with exploratory (generic vs. brand name)/subgroup analyses (cardiovascular comorbidities and socioeconomic status). RESULTS: Generic warfarin arrived on the market on 2 January 2001. Over the 20 year period of the study, the mean rate of hospital visits was 113 for 100 brand name or generic users per 6-month period and was similar before and after the arrival of the generics. Up to 15 years after the arrival of the generics, the rates of hospital visits were 10% higher for generic than for brand-name users, which was confirmed by subgroup analyses. CONCLUSIONS: Overall, we observed no impact on hospital visits after the arrival of generic warfarin in all the population treated with any type of warfarin. However, a higher crude rate of hospital visits among generic users than brand-name users remains to be validated using a different methodology and specific outcomes. PMID- 30471055 TI - Janina Scarlet: Therapy Quest: An Interactive Journey Through Acceptance and Commitment Therapy : Little, Brown Book Group, London, 2018, 208 pp, ISBN: 978-1 47213-968-9. PMID- 30471056 TI - The Causal Relationship between Childhood Adversity and Developmental Trajectories of Delinquency: A Consideration of Genetic and Environmental Confounds. AB - An extensive line of research has found that children exposed to multiple forms of early life adversity are more likely to engage in high levels of delinquent behavior during adolescence. Several studies examining this association have used a range of multivariate statistical techniques capable of controlling for observable covariates. Fewer studies have used family-based research designs to additionally control for unobservable confounds, such as genetic and shared environmental influences, that may be associated with exposure to childhood adversity and delinquency. The current study analyzes self-report data on 2534 full-siblings (50% female) from the National Longitudinal Survey of Youth 1997 to conduct a sibling-comparison analysis to provide a rigorous test of the causal hypothesis that exposure to childhood adversity causes differences in developmental patterns of delinquent behavior. Results from multivariate latent growth curve models revealed that childhood adversity was associated with higher starting levels of delinquency during adolescence and slower rates of decline from adolescence to emerging adulthood. Results from multivariate sibling comparison models, however, revealed that siblings exposed to higher levels of childhood adversity reported higher starting levels of delinquent behavior, but not slower declines over time, suggesting that childhood adversity may not be directly associated with long-term patterns of delinquent behavior after genetic and shared environmental factors are taken into account. Implications of these results for future research are discussed. PMID- 30471057 TI - Profiles of Coping with Ethnic-Racial Discrimination and Latina/o Adolescents' Adjustment. AB - The approaches Latina/o youth use for coping with discrimination have important consequences for their adjustment. Yet, little research has examined how adolescents draw on different coping strategies and how patterns of strategies may differentially predict their outcomes. The current investigation examined adolescents' patterns of coping strategies, changes in these patterns over time, and whether profile membership or transitions in profile membership related to adolescent adjustment. Among a longitudinal sample of Latina/o adolescents (N = 323, 49.5% female, Mage = 15.31 years), three profiles of coping strategies emerged: Passive and Moderately Proud, Confrontative, and Proactive. Latent Transition Analysis showed that these profiles were stable over time, that a majority of youth remained in the same profile of strategies across three years, and that the profiles were differentially related to adolescents' adjustment. The findings showed that individuals in the Proactive profile reported higher self esteem and academic motivation than adolescents drawing on different repertoires of coping strategies. These results provide new insights regarding the concurrence of strategies Latina/o youth use to cope with ethnic-racial discrimination and suggest that the adoption of proactive strategies as part of a repertoire of coping strategies could potentially reduce the negative effects of discrimination among adolescents. PMID- 30471058 TI - Alpine accentors as monitors of atmospheric long-range lead and mercury pollution in alpine environments. AB - Mercury and lead are deposited in the West Carpathians as long-range transported air pollution. The Alpine accentor (Prunella collaris) was recognized as a cost effective biomonitor, and used to investigate the bioavailability of contaminants in large alpine areas. The outer tail feathers and blood of the alpine accentors were used for assessment of atmospheric mercury and lead contamination, respectively. Mean mercury levels in feathers of accentors averaged at 1.15 MUg/g (SE = 0.105, n = 40). There were no temporal variations in mercury concentrations. Mean blood lead levels were at 5.2 MUg/dL (SE = 0.5, n = 27), showing a slight decreasing trend from July to October. Juveniles were not more susceptible to lead accumulation than adults. Bone lead concentrations that increase with age reflect a bioaccumulation effect. A statistically significant negative correlation was found between the length of erythrocytes and the concentration of lead, which may show the first symptoms of microcytosis. In comparison to aquatic ecosystems, the biogeochemical factors that influence methylmercury availability in alpine habitats are not yet completely known and require further investigation. Our findings show that birds in alpine terrestrial ecosystems may contain surprisingly high levels of methylmercury. The mercury levels in the feathers of accentors probably indicate that alpine autotrophs make sufficient amounts of mercury available to the terrestrial food web. The blood lead levels of accentors likely approach the threshold level for further hematological effects. We found a clear tendency in erythrocytes to change their shape from ellipsoid to smaller and rounder with increasing amounts of lead in their blood. The shape of bird erythrocytes appears to be a very sensitive indicator of critical levels of lead in the alpine environment. PMID- 30471059 TI - Characterization of blaNDM-harboring, multidrug-resistant Enterobacteriaceae isolated from seafood. AB - Carbapenem-resistant Enterobacteriaceae (CRE) have evolved into a major challenge to antibiotic therapy worldwide. The problem is more confounding when wider dissemination of CRE occurs in the community and the environment. In this study, six blaNDM-harboring Enterobacteriaceae, four Klebsiella pneumoniae, and two Escherichia coli, isolated from seafood, were characterized with respect to their antibiotic resistance and the genetic factors responsible for these resistances. The isolates were resistant to all beta-lactam antibiotics, quinolones, trimethoprim-sulfamethoxazole, chloramphenicol, and tetracycline and were susceptible to colistin, polymixin B, fosfomycin, and tigecycline. Four isolates harbored New Delhi metallo beta-lactamase (blaNDM-5 genes, while one isolate each harbored blaNDM-1 and blaNDM-2 genes, respectively. The blaNDM genes in all the isolates were flanked by an upstream, truncated ISAba125, and downstream bleMBL trpF genes. Conjugation experiments showed that the NDM plasmids were readily transmissible. Further, the two blaNDM-positive E. coli isolates belonged to the multidrug-resistant ST131 clone. This study highlights the growing danger of seafood as carriers of multidrug-resistant bacteria leading to their wider dissemination in the community. PMID- 30471060 TI - Does dual reduction in chemical fertilizer and pesticides improve nutrient loss and tea yield and quality? A pilot study in a green tea garden in Shaoxing, Zhejiang Province, China. AB - Tea tree (Camellia sinensis) is a valuable and popular cash crop widely planted in tropical and subtropical areas of China. To increase tea yield and quality, high rates of chemical fertilizer and pesticide application have generally been used; however, increasing usage of fertilizers and pesticides does not always proportionally increase tea yield. Indeed, excessive nutrient inputs may cause serious agricultural non-point source pollution. A pilot study on dual reduction in fertilizers and pesticides was conducted in a green tea plantation in Shaoxing, Zhejiang Province, to explore the environmental effects of different fertilizer and pesticide managements (e.g., changes in soil properties and nutrient accumulation, nutrient inputs in runoff water) and to reveal the potential effects of the interaction of these two managements on tea yield and quality. Traditional formulas and rates of chemical fertilizers and pesticides were used as the baselines (100% usage); replacement with different proportions of organic fertilizer (i.e., 20%, 50% and 80%) and direct pesticide reductions of 30%, 50%, and 80% were tested. The results showed that proper management with organic fertilizer replacement can effectively mitigate soil acidification and nutrient deficiency in tea plantations, increase soil organic matter (OM) and ammonium nitrogen (NH4-N) contents, and promote tea yield and quality. Moreover, managements with organic fertilizer replacement can markedly reduce the inputs of ammonium nitrogen (NH4-N), nitrate nitrogen (NO3-N), total phosphorus (TP), and total potassium (TK) in runoff water. Soil nutrient accumulation was the highest while the runoff nutrient input was the lowest at 20% organic fertilizer replacement. Experimental spraying of bifenthrin and chlorfenapyr revealed that these pesticides were mainly trapped by the tea leaves and rarely entered the soil or water bodies. Although pesticide reduction treatments can effectively decrease pesticide residues in tea leaves, differences in pesticide residue between various treatments were not obvious due to the rapid degradation of pesticides. Multivariate analysis of variance showed that 50% of the variation in tea yield, bud density, polyphenols, and caffeine can be explained by interactions between fertilizers and pesticides. Combinations of 20% or 50% organic fertilizer replacement and 30% or 50% pesticide application reduction are appropriate for both mitigating nutrient loss and balancing tea yield and quality, especially the combination of 50% organic fertilizer replacement and 50% pesticide reduction, which produced the best results. This study demonstrates the feasibility of dual reductions in fertilizers and pesticides for mitigating environmental hazards while maintaining the yield and quality of tea. PMID- 30471061 TI - Graphene oxide wrapped copper-benzene-1,3,5-tricarboxylate metal organic framework as efficient absorbent for gaseous toluene under ambient conditions. AB - The ultrasonic-assisted hydrothermal and ethanol activation method was proposed to synthesize copper-benzene-1,3,5-tricarboxylate (Cu-BTC) metal organic framework and Cu-BTC/graphene oxide (GO) composites (Cu-BTC@GO). The dynamic adsorption behavior of toluene on two adsorbents was studied and compared with that of GO and reduced graphene oxide (RGO). The Cu-BTC@GO exhibited high adsorption capacity (183 mg/g) for toluene, which is nearly three times as much as that of Cu-BTC (62.7 mg/g) with the GO mass fraction of 20%. Furthermore, the adsorption of toluene on Cu-BTC@GO composites was positively correlated with the initial concentration of toluene and the adsorbent dosage, and negatively correlated with the temperature. The adsorption data of toluene on Cu-BTC@GO composites were well in accordance with pseudo-first kinetics model. Langmuir model had a better fit than Freundlich model. The adsorption thermodynamic results showed that the adsorption process was mainly physical adsorption and the adsorption process was spontaneous at low temperature. After five adsorption desorption cycles, the adsorption efficiency can still reach 82.1%.This study will help to draw a promising roadmap to describe the adsorption performance of Cu-BTC@GO composites for toluene. PMID- 30471062 TI - Exposure to ambient PM2.5 during pregnancy and preterm birth in metropolitan areas of the state of Georgia. AB - A number of studies has pointed to air pollution as an additional factor that could be associated with preterm birth. We assessed in this study the association between exposure to PM2.5 in ambient air during pregnancy and preterm birth in metropolitan areas of the state of Georgia, where the rate of preterm birth has been among the highest in the nation over the years. Birth data were obtained from the National Center for Health Statistics natality dataset. The study population consisted of 53,094 singleton live births between January 1 and December 31, 2004 in nine metropolitan counties of Georgia. Preterm birth was defined as birth, which occurs before 37 weeks of gestation. County-level daily air quality index (AQI) data obtained from the US Environmental Protection Agency (EPA) was used to estimate individual exposure levels of PM2.5 for each study participant based on the county of residence for the duration of the pregnancy. A multivariate logistic regression analysis was conducted to assess the association, adjusting for potential confounders. Of the infants whose mothers resided in the nine metropolitan counties of Georgia, 4543 (8.6%) were born preterm. A higher rate of preterm birth (9.8%) was observed in infants whose mothers were exposed to ambient PM2.5 with AQI values > 50 than the ones with AQI <= 50 (EPA standard for good air quality conditions). Mothers with exposure to PM2.5 at average AQI values greater than 50 during the entire pregnancy were at increased risk of preterm birth (odds ratio 1.15; 95% CI 1.07, 1.25), after adjusting for sex of infant, mother's age, race/ethnicity, education, marital status, prenatal care, cigarette smoking, alcohol consumption, and season of conception. The study provides more evidence on the role of PM2.5 in preterm birth. Reducing exposure to ambient particulate matter, especially in urban areas, for pregnant women would be necessary to improve the health of infants. PMID- 30471063 TI - Spatial variation in the effects of air pollution on cardiovascular mortality in Beijing, China. AB - Due to lack of data from multiple air quality monitoring stations, studies about spatial association between concentrations of ambient pollutants and mortality in China are rare. To investigate the spatial variation of association between concentrations of particulate matter less than 10 MUm in aerodynamic diameter (PM10) and nitrogen dioxide (NO2) and cardiovascular mortality in Beijing, China, we collected data including daily deaths, concentrations of PM10 and NO2, and meteorological factors from January 1, 2009, to December 31, 2010, in all 16 districts of Beijing. Generalized additive model (GAM) and generalized additive mixed model (GAMM) were used to examine the citywide and district-specific effects of PM10 and NO2 on cardiovascular mortality. The citywide effect derived from GAMM was lower than that derived from GAM and the strongest effects were identified for 2-day moving average lag 0-1. For every 10 MUg/m3 increases in concentrations of PM10 and NO2, the corresponding daily cardiovascular mortality increases in 0.31% (95%CI 0.15%, 0.46%) and 1.63% (95%CI 1.11%, 2.13%), respectively. The death risk associated with air pollutants varied across different geographic districts in Beijing. We found spatially varied adverse effects of air pollution on cardiovascular deaths in Beijing. But there was insufficient evidence to show the significant spatial heterogeneity in mortality effects of PM10 and NO2 in this study. PMID- 30471064 TI - Metal content in edible crops and agricultural soils due to intensive use of fertilizers and pesticides in Terras da Costa de Caparica (Portugal). AB - Soils and different vegetable species in Costa de Caparica (Portugal) are subject to the intensive use of inorganic fertilizers and pesticides. Thus, the concentrations of As, Cu, Fe, Mn, Pb, and Zn were evaluated. Lettuce, spinach, and potatoes collected in station 9 cause reason for concern due to their high Pb concentrations close to 20 MUg g-1 which is probably related to an intensive use of copper and iron sulphate fertilizers. Additionally, the consumption of Portulaca oleracea collected in stations 3 and 4 must be avoided due to the high concentrations of Zn, and even Cu. The derived estimated daily intake (EDI) dose of Zn will be a risk to human consumption if P. oleracea was the single basis of a soup, although the addition of other ingredients might lower the tolerable upper intake (TUI) value of 39 mg/day of P. oleracea, to admissible levels, i.e., not exceeding 25 mg/day. Pumpkin collected in station 1 contained 44.1 MUg g-1 Cu and a TUI value of 9.8 mg/day, when the recommendation must not exceed 5.0 mg/day. In this context, it is strongly advised to not include this vegetable in household menus. PMID- 30471065 TI - Integrated comparisons of thorium(IV) adsorption onto alkali-treated duckweed biomass and duckweed-derived hydrothermal and pyrolytic biochar. AB - In order to remove aqueous radionuclides and find an appropriate method for the disposal of wild duckweed in eutrophic water body, alkali-treated duckweed biomass and duckweed-based hydrothermal biochar (hydrochar) and pyrolytic biochars of 300 and 600 degrees C were prepared. Their physicochemical properties were characterized carefully. The adsorption isothermal data fitted well with the Langmuir model and the maximum Langmuir adsorption capacities were 104.1, 96.3, 86.7, and 63.5 mg/g for hydrochar, modified biomass, and 300 and 600 degrees C biochars, respectively. The adsorption kinetic data fitted well with the pseudo-second-order kinetic equation. The sorption data of fixed-bed column also confirmed the high efficient removal of Th(IV) and fitted well with the Thomas model. The duckweed-based hydrothermal biochar is a low-cost adsorbent for Th(IV) removal, and it is also a resource utilization technology of the duckweed collected from eutrophic water body. PMID- 30471066 TI - Conversion from Twice-Daily Prograf(r) to Once-Daily Advagraf(r) in Multi-ethnic Asian Adult Renal Transplant Recipients With or Without Concomitant Use of Diltiazem: Impact of CYP3A5 and MDR1 Genetic Polymorphisms on Tacrolimus Exposure. AB - BACKGROUND AND OBJECTIVES: Tacrolimus is the mainstay of immunosuppression in renal transplantation. Given that once-daily administration improves patient compliance, 1:1 dose conversion from twice-daily Prograf(r) to once-daily Advagraf(r) is recommended. Although cytochrome P450 (CYP) 3A5 and multi-drug resistance 1 (MDR1) polymorphisms influence tacrolimus concentrations, it is unknown if these impact on conversion. This study investigated the change in the pharmacokinetics of tacrolimus after conversion from Prograf(r) to Advagraf(r) and examined the impact of CYP3A5 and MDR1 C3435T polymorphisms on those pharmacokinetics. METHODS: A prospective open-label pharmacokinetic study of 1:1 conversion from Prograf(r) to Advagraf(r) with or without diltiazem was conducted on 26 stable renal transplant recipients. Blood samples were collected over 24 h during each phase, tacrolimus concentrations were assayed, and noncompartmental pharmacokinetic analysis was performed. All participants were genotyped for CYP3A5*3 and MDR1 C3435T. RESULTS: After conversion, without diltiazem, the area under the concentration-time curve at steady state from 0 to 24 h after dose administration (AUCss, 0-24) was significantly reduced [median 224 (range 172 366) vs. 184 (104-347) ng.h/mL, p = 0.006, n = 26]. A decrease in tacrolimus exposure (median 21%) was only evident among CYP3A5 expressors [227 (172-366) vs. 180 (104-347) ng.h/mL, p = 0.014, n = 18], not among non-expressors [215 (197 290) vs. 217 (129-281) ng.h/mL, p = 0.263, n = 8]. In contrast, among CYP3A5 expressors receiving diltiazem, AUCss, 0-24 did not change significantly upon conversion [229 (170-296) vs. 221 (123-342) ng.h/mL, p = 0.575, n = 10]. An independent effect was not evident for MDR1 C3435T polymorphism. CONCLUSION: The high prevalence of CYP3A5 polymorphism among Asians may lead to a significant reduction in tacrolimus exposure with 1:1 dose conversion of Prograf(r) to Advagraf(r). These results advocate for CYP3A5 determination prior to conversion, and suggest that 1:1.25 conversion should be used for CYP3A5 expressors and 1:1 conversion for other patients. PMID- 30471067 TI - Neoadjuvant CAPOX and bevacizumab alone for locally advanced rectal cancer: long term results from the N-SOG 03 trial. AB - BACKGROUND: Neoadjuvant chemotherapy (NAC) alone for locally advanced rectal cancer (LARC) remains an experimental treatment, and the efficacy in terms of long-term outcome has not been fully elucidated. The N-SOG 03 trial examined the safety and efficacy of neoadjuvant CAPOX and bevacizumab (Bev) without radiotherapy in patients with poor-risk LARC. METHODS: Thirty-two patients with MRI-defined LARC received neoadjuvant CAPOX and Bev followed by curative resection between 2010 and 2011. The overall survival (OS), progression-free survival (PFS), and local-relapse rate (LRR) were calculated using the Kaplan Meier method, and the risk factors were evaluated by multivariate analysis using the Cox proportional hazard models. This trial is registered with UMIN, number 000003507. RESULTS: In the entire cohort, the 5-year OS was 81.3%. Because of disease progression during chemotherapy, 3 patients ultimately did not undergo curative surgery. As a result, 29 patients underwent R0/1 resection. Among these 29 patients, the 5-year OS, PFS, and LRR were 89.7%, 72.4% and 13.9%, respectively. In multivariate analysis, cT4b tumor was an independent poor prognostic factor for OS and LRR, and ypT4b tumor and absence of N down-staging were independent poor prognostic factors for PFS. CONCLUSIONS: Patients with cT4b tumor were not suitable for NAC alone. However, the long-term outcomes of the other patients were satisfactory, and NAC alone might be an option for treatment of LARC. N down-staging was likely to bring favorable PFS, even in patients with cStage III. PMID- 30471068 TI - Brain CT and MRI medical image fusion using convolutional neural networks and a dual-channel spiking cortical model. AB - The aim of medical image fusion is to improve the clinical diagnosis accuracy, so the fused image is generated by preserving salient features and details of the source images. This paper designs a novel fusion scheme for CT and MRI medical images based on convolutional neural networks (CNNs) and a dual-channel spiking cortical model (DCSCM). Firstly, non-subsampled shearlet transform (NSST) is utilized to decompose the source image into a low-frequency coefficient and a series of high-frequency coefficients. Secondly, the low-frequency coefficient is fused by the CNN framework, where weight map is generated by a series of feature maps and an adaptive selection rule, and then the high-frequency coefficients are fused by DCSCM, where the modified average gradient of the high-frequency coefficients is adopted as the input stimulus of DCSCM. Finally, the fused image is reconstructed by inverse NSST. Experimental results indicate that the proposed scheme performs well in both subjective visual performance and objective evaluation and has superiorities in detail retention and visual effect over other current typical ones. Graphical abstract A schematic diagram of the CT and MRI medical image fusion framework using convolutional neural network and a dual channel spiking cortical model. PMID- 30471069 TI - Comparison of Skin Cancer Incidence in Caucasian and Non-Caucasian Liver Vs. Lung Transplant Recipients: A Tale of Two Regimens. AB - BACKGROUND: Organ transplantation is a significant risk factor for the development of skin cancer. The impact of skin type, immunosuppressive regimens, and photosensitizing agents requires further study. OBJECTIVE: The objective of this study was to compare skin cancer development between Caucasian and non Caucasian transplant recipients at the University of Southern California. METHODS: We performed a retrospective chart review of lung and liver transplantations to determine the incidence of post-transplant skin cancer. Participants included patients who underwent lung or liver transplantation between 2005 and 2013 at our institution. Patients included in the study were limited to those who survived through the study observation period. RESULTS: We analyzed 475 patients who underwent transplantation, including 370 liver transplant recipients and 105 lung transplant recipients. Among these, 46.3% identified as Caucasian, while 53.7% were non-Caucasian. Over a mean follow-up of 7.9 years, 11.8% of Caucasian patients developed at least one skin cancer, compared with 2.7% of non-Caucasians (p < 0.001). However, irrespective of race, skin cancer development was significantly greater in lung compared with liver transplant recipients (20.0% vs. 3.2%, p < 0.001). The standard immunosuppressive and prophylactic regimens were mycophenolate mofetil and tacrolimus based for both transplants. Mycophenolate mofetil was maintained throughout the course in lung transplant patients, whereas this agent was reduced and terminated when possible in liver transplant recipients. In addition, during the years examined, voriconazole, a known photosensitizing agent, was used in lung transplant recipients to prevent aspergillosis. CONCLUSIONS: Fair skin type increases post transplant skin cancer development, irrespective of the immunosuppressive regimen. A higher risk of skin cancer is associated with different regimens; in particular photosensitizing agents may increase risk in transplant recipients. PMID- 30471070 TI - New Techniques to Study Intracellular Receptors in Living Cells: Insights Into RIG-I-Like Receptor Signaling. AB - This review discusses new developments in Forster resonance energy transfer (FRET) microscopy and its application to cellular receptors. The method is based on the kinetic theory of FRET, which can be used to predict FRET not only in dimers, but also higher order oligomers of donor and acceptor fluorophores. Models based on such FRET predictions can be fit to observed FRET efficiency histograms (also called FRET spectrograms) and used to estimate intracellular binding constants, free energy values, and stoichiometries. These "FRET spectrometry" methods have been used to analyze oligomers formed by various receptors in cell signaling pathways, but until recently such studies were limited to receptors residing on the cell surface. To study complexes residing inside the cell, a technique called Quantitative Micro-Spectroscopic Imaging (Q MSI) was developed. Q-MSI combines determination of quaternary structure from pixel-level apparent FRET spectrograms with the determination of both donor and acceptor concentrations at the organelle level. This is done by resolving and analyzing the spectrum of a third fluorescent marker, which does not participate in FRET. Q-MSI was first used to study the interaction of a class of cytoplasmic receptors that bind viral RNA and signal an antiviral response via complexes formed mainly on mitochondrial membranes. Q-MSI revealed previously unknown RNA mitochondrial receptor orientations, and the interaction between the viral RNA receptor called LGP2 with the RNA helicase encoded by the hepatitis virus. The biological importance of these new observations is discussed. PMID- 30471071 TI - Nutritional and Antioxidant Properties of Physalis peruviana L. Fruits from the Argentinean Northern Andean Region. AB - Physalis peruviana L. fruits have gained great interest in different producing countries because they are good source of nutrients and bioactive compounds. However, the nutritional characterization and bioactive properties of both cultivated and wild fruits of P. peruviana growing in Argentina have not been conducted so far. The results provided clear difference in physicochemical, nutritional and bioactive characteristics of cultivated and wild fruits of P. peruviana from Argentinean Northern Andean region. Cultivated fruits showed a higher content of K, Mg and Cu and bioactive compounds as vitamin C than wild fruits. Besides, cultivated fruits displayed a high antiradical activity towards ABTS?+ and FRAP. In addition, both cultivated and wild fruits exhibited a great antioxidant activity measured as the free radical scavenging activity against DPPH? (effective concentration that scavenged 50% of the radicals is 0.64 and 1.65 mg/mL, respectively). The findings point out that the nutritional properties and bioactive compounds (vitamin C and beta-carotene) of cultivated and wild fruits were comparable to those from countries with a production tradition. Outstandingly, the antioxidant performance of fruits growing in Argentinean Northern Andean region is remarkable in comparison with those reported in other producing zones, which can be ascribed to suitable ecological conditions. PMID- 30471072 TI - Is it Possible to Significantly Modify Blood Pressure with a Combined Nutraceutical on Top of a Healthy Diet? The Results of a Pilot Clinical Trial. AB - INTRODUCTION: Beyond the well-known effects on blood pressure (BP) of the dietary approaches to stop hypertension (DASH) and the Mediterranean diets associated to a correct lifestyle, often a lifestyle change is not simple and can show only long-time results: in this sense, a possible support might be derived from the use of some anti-hypertensive supplements or nutraceuticals, which may provide a significant reduction in blood pressure. AIM: We conducted a randomized, double blind, placebo-controlled clinical trial in a group of 36 pre-hypertensive and first-degree hypertensive patients. METHODS: The treatment period with a mix of bioactive substances (BPLN(r), containing a donor of nitric oxide, magnesium, and vitamins) or placebo was 16-week long and was preceded by 4 weeks of diet stabilization. RESULTS: At the end of the intervention, patients treated with the nutraceutical product showed a significant reduction of all morning pressure parameters and of evening systolic blood pressure, both versus the baseline and versus the group treated with placebo. These effects were maintained even after the first 16 weeks of treatment, confirming that the preliminary results were not due to simple changes in volume and do not lead to adaptation/tachyphylaxis. No patient complained of any side effects while taking the active treatment and placebo. CONCLUSIONS: The tested nutraceutical composite reduces systolic and diastolic blood pressure in the medium term, leading to a significant reduction in the estimated cardiovascular risk in a sample of patients with pre hypertension or first-degree hypertension. PMID- 30471073 TI - A large Number of Metastatic Subcutaneous Nodules: A Complication of Percutaneous Biopsy for Atypical Renal Cell Carcinoma. AB - A 68-year-old man underwent ultrasound-guided needle biopsy of a suspicious renal mass. Just two weeks later, a large number of subcutaneous nodules was found in patient's chest-back, neck and axilla. pathology analysis was found to be metastatic subcutaneous nodules, These features suggest that tumor seeding have occurred during the needle biopsy. Despite needle tract seeding is a rare event, this rare complication should be taken into consideration before contemplating its use in a patient. PMID- 30471074 TI - Evaluation of Oxidative Stress in Testis and Sperm of Rat Following Induced Varicocele. AB - PURPOSE: Oxidative stress (OS) plays a central role in the pathophysiology of varicocele (VC), however, comprehensive studies concomitantly assessing semen parameter along with chromatin status, oxidative stress, and enzymatic antioxidants in both testis and sperm are limited. Therefore, this study aims to assess these parameters in varicocelized rats. MATERIALS AND METHODS: For this study, 30 Wistar rats were randomly divided into three groups: Control group (I); sham-operated group (II) and left varicocele group (III). Left varicocele was induced and two months after surgery, we evaluated sperm parameters, persistent histone, DNA integrity and lipid peroxidation in sperm and also oxidant/antioxidant markers in testis. RESULTS: The results showed that sperm concentration, motility, and normal morphology significantly decreased in varicocele group compared to other groups (P<0.001). Also, we observed a significant increase in persistent histone and DNA damage of sperm cells in varicocele rats (P<0.05). In addition, oxidant assessment analysis showed that ROS level was higher in testis tissue and sperm cells from the left varicocele rats compared to the control group (P<0.05). CONCLUSION: This results clearly show that increase of testicular temperature in varicocele condition has a negative effect on spermatogenesis and increased oxidative stress and reduce in antioxidant capacity hand in hand lead to the production of sperm with damaged chromatin which reduces the fertility potential and may jeopardize the future health of the progeny. PMID- 30471075 TI - Virtual Three-Dimensional Magnetic Resonance Fetal Cystoscopy: A Novel Modality for Precise in Utero Evaluation of Urinary Tract. AB - Urogenital anomalies are the most prevalent anomalies detected during pregnancy. Timely detection of these conditions could facilitate proper post-natal management and improve outcomes. In some cases, precise delineation of fetal urinary tract utilizing ultrasonography is not feasible. Moreover, sometimes the ultrasound study is technically limited. Magnetic resonance imaging could clarify the diagnosis in these situations. Prenatal ultrasonography indicated hydronephrosis and a 14 mm cystic lesion at right ureterovesical junction in a 25 week fetus. However, fetal magnetic resonance urography was not able to precisely clarify the condition and extension of ureterocele into the urethra. Fetal magnetic resonance virtual cystoscopy clearly demonstrated anatomy and extension of ureterocele. This modality provides three-dimensional cystoscopic-like view of urinary bladder and facilitates postnatal management. PMID- 30471077 TI - Salvage autologous fascial sling after failed anti-incontinence surgeries: Long term follow up. AB - OBJECTIVE: To evaluate long term outcomes of autologous pubovaginal fascial sling (AFPVS) as a salvage procedure following different types of failed anti incontinence surgeries. MATERIALS AND METHODS: We retrospectively reviewed medical records of patients who had undergone salvage AFPVS after any kind of anti-incontinence surgery from 2005-2015 at our medical center. Patients were contacted by telephone. Revised Urinary Incontinence Scale (RUIS) was used to determine the success rate. RESULTS: A total of 40 patients out of 51 were successfully contacted. Mean patient age was 50.8+/- 9.8 years (range30-75) and mean follow up was 62.6+/-32.4 months (range12-120). Of 40 patients, 14(35%) had pure SUI and 26(65%) complained of mixed urinary incontinence. A total of 15(37.5%) patients had a failed Burch colposuspention, 5(12.5%) TVT, 8(20%) TOT, 3 (7.5%) AFPVS and five (12.5%) patients had history of failed mini-sling procedure. Four (10%) patients had undergone more than one anti incontinence surgeries. Overall success rate was 65% in our study. New onset urge urinary incontinence was detected in 25% of patient which was negatively associated with satisfaction and recommendation. There was no statistically significant correlation between mixed urinary incontinence, type or number of previous failed surgeries with success however presence of pure SUI had a strongCOCLUSION: Autologous pubovaginal fascial sling might be considered as a safe and efficacious salvage surgical option following failed midurethral slings, Burch colposuspention and even AFPVS itself. It will provide reasonable long term results with no major complications. PMID- 30471076 TI - Does Mantoux Test Result Predicts BCG Immunotherapy Efficiency and Severe ToXxicity in Non-Muscle Invasive Bladder Cancer. AB - PURPOSE: To evaluate on a large group of patients whether Mantoux tuberculin skin test (TST) result is associated with BCG immunotherapy effectiveness and whether it can predict occurrence of moderate to severe toxicity. MATERIAL AND METHODS: We analysed group of 823 patients with intermediate and high risk NMIBCs who were treated with BCG. The study included 412 patients with the history TST and 411 without TST. A standard dose of Statens Serum Institute tuberculin RT23 was used. The reaction was read 48-72 hours later by evaluating the diameter of palpable induration. The size of the induration was considered positive when the measurement was greater than or equal to 6 mm and excessively positive when bigger than 26 mm. Whole BCG immunotherapy schedule consisted of 27 instillations. RESULTS: The patients were followed for median 61 months. The 5 years recurrence and progression free survival (RFS, PFS) did not differ between the groups in both total study population and tumour subgroup analysis. TST result in both total study population and in subgroups was not statistically associated with RFS, PFS and cancer specific survival.The moderate-to-severe toxicity was observed in 181(44%) TST patients, and in 196(47%) patients without TST. Incidence of toxicity was not statistically different and also not statistically associated with TST result in any of the tumour subgroups of TST group. CONCLUSION: This study shows, that TST does not have value in prediction of bladder cancer recurrence, progression nor cancer specific survival. Also it doesn't have a value in predicting therapy toxicity. PMID- 30471078 TI - Decoding Gestural Iconicity. AB - Speakers frequently perform representational gestures to depict concepts in an iconic fashion. For example, a speaker may hold her index finger and thumb apart to indicate the size of a matchstick. However, the process by which a physical handshape is mentally transformed into abstract spatial information is not well understood. We present a series of experiments that investigate how people decode the physical form of an articulator to derive imaginary geometrical constructs, which we call "gesture form." We provide quantitative evidence for several key properties that play a role in this process. First, "profiling," the ability to focus on a structural subunit within the complex form of the physical hand. Second, "perspective," for which we show that one and the same handshape seen from different perspectives can lead to different spatial interpretations. Third, "selectivity," the fact that gestures focus on specific spatial features at the expense of others. Our results provide a first step toward mapping out the process of how representational gestures make the communication of spatial information possible. PMID- 30471079 TI - Teamwork using strain imaging in the echocardiographic assessment of right ventricular systolic function: A cardiac magnetic resonance imaging correlation study. AB - AIM: The aim of this study was to investigate whether conventional echocardiographic assessment of right ventricular (RV) systolic function can be improved by the addition of RV strain imaging. Additionally, we also aimed to investigate whether dedicated reading sessions and education can improve echocardiographic interpretation of RV systolic function. METHODS: Readers of varying expertise (staff echocardiologists, advanced cardiovascular imaging fellows, sonographers) assessed RV systolic function. In session 1, 20 readers graded RV function of 19 cases, using conventional measures. After dedicated education, in session 2, the same cases were reassessed, with the addition of RV strains. In session 3, 18 readers graded RV function of 20 additional cases, incorporating RV strains. Computer simulations were performed to obtain 230 random teams. RV ejection fraction (RVEF) by cardiac magnetic resonance (CMR) was the reference standard. RESULTS: Correlation between RV GLS and CMR-derived RVEF was moderate: Spearman's rho: 0.70, n = 19, P < 0.001 (first two sessions); 0.55, n = 20, P < 0.05 (third session). Individual readers' assessment moderately correlated with RVEF (Spearman's rho first session: 0.67 +/- 0.2; second session: 0.61 +/- 0.2; and third session: 0.68 +/- 0.09). Team estimates of RV systolic function showed consistently better correlation with RVEF, which were improved further by averaging across all readers. RV strain parameters influenced echocardiographic interpretation, with a net reclassification index of 8.0 +/- 3.6% (P = 0.014). CONCLUSIONS: The RV strain parameters showed moderate correlations with CMR-derived RVEF and appropriately influenced echocardiographic interpretation of RV systolic function. "Wisdom of the crowd" applied by averaging echocardiographic assessments of RV systolic function across teams of echocardiography readers, further improved echocardiographic assessment of RV systolic function. PMID- 30471080 TI - Neural microvascular pericytes contribute to human adult neurogenesis. AB - Consistent adult neurogenic activity in humans is observed in specific niches within the central nervous system. However, the notion of an adult neurogenic niche is challenged by accumulating evidence for ectopic neurogenic activity in other cerebral locations. Herein we interface precision of ultrastructural resolution and anatomical simplicity of accessible human dental pulp neurogenic zone to address this conflict. We disclose a basal level of adult neurogenic activity characterized by glial invasion of terminal microvasculature followed by release of individual platelet-derived growth factor receptor-beta mural pericytes and subsequent reprogramming into NeuN+ local interneurons. Concomitant angiogenesis, a signature of adult neurogenic niches, accelerates the rate of neurogenesis by amplifying release and proliferation of the mural pericyte population by ~10-fold. Subsequent in vitro and in vivo experiments confirmed gliogenic and neurogenic capacities of human neural pericytes. Findings foreshadow the bimodal nature of the glio-vascular assembly where pericytes, under instruction from glial cells, can stabilize the quiescent microvasculature or enrich local neuronal microcircuits upon differentiation. PMID- 30471081 TI - Italian validation of the functional difficulties questionnaire (FDQ-9) and its correlation with major determinants of quality of life in adults with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorder. AB - The 2017 nosology defines the new criteria for hypermobile Ehlers-Danlos syndrome (hEDS), which is now considered one end of a continuous spectrum encompassing isolated, nonsyndromic joint hypermobility (JH) and hypermobility spectrum disorders (HSDs). Preliminary data indicate a link between JH and neurodevelopmental disorders and, in particular, developmental coordination disorder (DCD) in children. Assessing DCD in adults is difficult and the recently described functional difficulties questionnaire 9 (FDQ-9) is one of the few available tools. The aims of this study are to (a) validate FDQ-9 written in Italian and present normal values in 230 Italian controls; (b) explore the relationship of FDQ-9 with the brief pain inventory, composite autonomic symptom score 31, multidimensional fatigue inventory, attention deficit/hyperactivity disorder self-report version 1.1, and the SF-36 for quality of life in 105 Italian adults with hEDS/HSD. Validation of the FDQ-9 in Italian was carried out by translation, cross-cultural adaptation and test/retest reliability analysis. A case-control study was performed comparing the FDQ-9 outcome between 105 patients and 105 sex- and age-matched controls. Fifty-nine percent of the patients resulted positive compared to the 3.8% of controls (p value < .00001). In patients, FDQ-9 positive result associated with positive attention deficit/hyperactivity disorder self-report version 1.1 (OR = 4.04). Multivariate regression analysis comparing FDQ-9 with the other questionnaires demonstrated a strong association between positive FDQ-9 and the number of painful joints. Our preliminary data open wider management and therapeutic perspectives for coordination difficulties in hypermobile individuals. PMID- 30471082 TI - Negative parenting modulates the association between mother's DNA methylation profiles and adult offspring depression. AB - This study aimed to examine whether the relationship between mothers' DNA methylation profiles and offspring's depression is modulated by negative parenting. The participants were 35 African-American mother-offspring dyads. Young adult offspring (19 females; age = 17-29.5 years) were assessed on depressive symptoms, and mothers (36-51 years) were assessed on negative parenting. Methyl-binding domain (MBD) sequencing was used to assay genome-wide DNA methylation in peripheral T lymphocytes. Controlling for the effect of offspring's DNA methylation, mothers' DNA methylation was positively associated with offspring's depression. Hypermethylation of a subset of the epigenetic markers was associated with increased negative parenting. Negative parenting was positively correlated with offspring's depression as well, suggesting that negative parenting may be a modulator between the mother's epigenome and offspring's depression. This study is one of the first investigations of the modulating role of parenting behavior in associations between the mother's epigenome and offspring's depression. PMID- 30471083 TI - Syphilitic balanitis of Follmann: two case reports. PMID- 30471084 TI - Levels of type 1 diabetes care in children and adolescents for countries at varying resource levels. AB - Optimal care for children and adolescents with type 1 diabetes is well-described in guidelines such as those of the International Society for Pediatric and Adolescent Diabetes. High-income countries can usually provide this, but the cost of this care is generally prohibitive for lower-income countries. Indeed, in most of these countries, very little care is provided by government health systems, resulting in high mortality, and high complications rates in those who do survive. As lower-income countries work towards establishing guidelines-based care, it is helpful to describe the levels of care that are potentially affordable, cost-effective, and result in substantially improved clinical outcomes. We have developed a Levels of Care concept with three tiers: "Minimal Care", "Intermediate Care", and "Comprehensive (Guidelines-based) Care". Each tier contains levels, which describe insulin and blood glucose monitoring regimens, requirements for HbA1c testing, complications screening, diabetes education, and multidisciplinary care. The literature provides various examples at each tier, including from countries where the Life for a Child and the Changing Diabetes in Children programs have assisted local diabetes centres to introduce Intermediate Care. Intra-clinic mean HbA1c levels range from 12.0-14.0% (108-130 mmol/mol) for the most basic level of Minimal Care, 8.0-9.5% (64-80 mmol/mol) for Intermediate Care, and 6.9-8.5% (52-69 mmol/mol) for Comprehensive Care. Countries with sufficient resources should provide Comprehensive Care, working to ensure that it is accessible by all in need, and that resulting HbA1c levels correspond with international recommendations. All other countries should provide Intermediate Care, while working towards the provision of Comprehensive Care. This article is protected by copyright. All rights reserved. PMID- 30471085 TI - Is there an association between indoor allergens and the severity of atopic dermatitis? AB - BACKGROUND: Atopic dermatitis (AD) is a multifactorial inflammatory skin disease with frequent hypersensitivity to allergens. However, the role of exposure to indoor allergens on AD severity is unclear. METHODS: Children aged 0-17 years with active AD from central Chile were recruited; disease severity was evaluated with SCORAD and POEM scores. A home environment survey was applied to parents. Bedroom dust samples were collected for all subjects and analyzed by multiplex assay to quantify dust mite (Der p1, Der f1), dog (Can f1), cat (Fel d1), and alternaria alternata (Alt a1) allergens. RESULTS: Twenty-five children aged 3.9 +/- 3.8 years were included. Fifty-two percent were female. Mean SCORAD was 29 +/ 14 (range 11-61), and mean POEM was 10.7 +/- 6.2. No direct association was found between tobacco exposure, pet ownership, aerosol use, visible dust, or home carpets/rugs with SCORAD (all P > 0.05). Dust samples from all homes had Can f1 and Fel d1 allergens, regardless of pet ownership. Homes that had indoor dogs or cats had significantly higher amounts of these allergens (P < 0.001). Forty percent of homes had dust mite allergens, and none had alternaria alternata. Children with AD living in homes with elevated dust mite and animal dander allergen concentrations had higher SCORAD than those from homes with low allergen concentrations (40 +/- 13 vs. 26 +/- 13, P = 0.025). CONCLUSIONS: High concentrations of indoor allergens may influence AD severity in children. Further studies assessing indoor allergens and allergen sensitization are warranted to fully evaluate the role of indoor allergens on AD. PMID- 30471086 TI - Subclinical atherosclerosis in psoriatic disease: relation to endocan, TNF-alpha, age of onset, and body fat. AB - BACKGROUND: Psoriasis is a common multisystem inflammatory disease with several associated comorbidities. Serological markers to detect associated subclinical atherosclerosis in psoriatic patients are needed. We aimed to study serum endocan levels in psoriasis vulgaris and its relation to severity of psoriasis, systemic inflammation, associated atherosclerosis, obesity, and the possible factors affecting its level in psoriatic patients. METHODS: This study was conducted on 30 moderate-severe psoriasis vulgaris patients and 30 healthy controls. Body mass index, body fat percent, and PASI assessments were done. Serum endocan and tumor necrosis factor-alpha levels were measured by ELISA. Carotid artery intima-media thickness measurement by high-resolution ultrasound was performed. RESULTS: Psoriasis patients showed significantly higher serum tumor necrosis factor-alpha and endocan levels (P1 = 0.008, P2 = 0.003). Additionally, there was a statistically significant difference between mean carotid artery intima-media thickness of both groups (P = 0.005). Serum endocan levels positively correlated with PASI score (P = 0.002), tumor necrosis factor-alpha levels (P < 0.001), mean carotid artery intima-media thickness (P = 0.001), and body mass index (P < 0.001) in the patients group. Additionally, the age of onset of disease negatively correlated with serum endocan (P = 0.003). CONCLUSION: Serum endocan is a promising marker of severity of psoriasis and associated atherosclerosis. Early onset psoriasis is associated with higher serum endocan levels. Body mass index is positively correlated with serum endocan levels. The positive correlation of endocan and tumor necrosis factor-alpha supports the regulatory effect of the cytokine on endocan production and suggests the role of endocan as an inflammatory marker. PMID- 30471087 TI - Protective Effects of Astragaloside IV Combined with Budesonide in Bronchitis in Rats by Regulation of Nrf2/Keap1 Pathway. AB - BACKGROUND This study was conducted to evaluate the effects of astragaloside IV and budesonide on bronchitis in rats and to explore the mechanism involved. MATERIAL AND METHODS Eighty Sprague-Dawley (SD) rats were randomly divided into 5 groups, including a Bronchitis model group (BM), a Budesonide group (BG), an Astragaloside IV group (AG), an Astragaloside IV combined with Budesonide group (CG), and a blank control group (BC). Lung tissue was stained with hematoxylin and eosin (H&E). The activity of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) were detected by enzyme-linked immunosorbent assay (ELISA). The nuclear factor erythroid 2 [NF-E2] related factor 2 (Nrf2), Kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1 (Keap1), BTB and CNC homology 1 (Bach1), B cell lymphoma-2(Bcl-2), and BCl-2-associated X protein (Bax) mRNA and protein were examined by RT-PCR and Western blot, respectively. RESULTS Compared with the Bronchitis model group, the lung tissue lesions in the Budesonide group, Astragaloside IV group, and Astragaloside IV combined with Budesonide group were effectively ameliorated and the airway resistance was significantly decreased. The activities of SOD, GSH-Px, and CAT were increased after treatment with drugs, while the content of MDA was decreased. The levels of Nrf2, Keap1, and Bcl-2 proteins were increased and the levels of Bach1 and Bax were decreased after treatment with Budesonide and Astragaloside IV. CONCLUSIONS Astragaloside IV combined with budesonide can ameliorate the lesions caused by bronchitis in rats through activating the Nrf2/Keap1 pathway, which plays a protective role on anti oxidative stress injury. PMID- 30471089 TI - Generic Drugs in the United States: Policies to Address Pricing and Competition. AB - The cost of prescription drugs in the U.S. continues to be a source of concern for patients, caregivers, and policymakers. Drug prices typically decline rapidly once generic drugs receive U.S. Food and Drug Administration (FDA) approval and enter the market, but the past decade has witnessed rising costs and shortages of generic drugs. We describe the strategies employed by brand-name manufacturers to undermine generic competition and the reasons underlying the price increases of off-patent drugs, some of which continue to lack any competition from generic versions, and others that have increased in price despite having generic versions. We discuss the FDA's role in addressing drug prices and promoting competition, including recent agency policies to modify its process of reviewing generic drug applications and prioritize applications for off-patent drugs with few competitors. We also examine proposed policy solutions and research areas that could help address the price increases of off-patent drugs. This article is protected by copyright. All rights reserved. PMID- 30471088 TI - Amyloid precursor protein-mediated mitochondrial regulation and Alzheimer's disease. AB - Despite clear evidence of a neuroprotective physiological role of amyloid precursor protein (APP) and its non-amyloidogenic processing products, APP has been investigated mainly in animal and cellular models of amyloid pathology in the context of Alzheimer's disease. The rare familial mutations in APP and presenilin-1/2, which sometimes drive increased amyloid beta (Abeta) production, may have unduly influenced Alzheimer's disease research. APP and its cleavage products play important roles in cellular and mitochondrial metabolism, but many studies focus solely on Abeta. Mitochondrial bioenergetic metabolism is essential for neuronal function, maintenance and survival, and multiple reports indicate mitochondrial abnormalities in patients with Alzheimer's disease. In this review, we focus on mitochondrial abnormalities reported in sporadic Alzheimer's disease patients, and the role of full-length APP and its non-amyloidogenic fragments, particularly soluble APP alpha (sAPPalpha), on mitochondrial bioenergetic metabolism. We do not review the plethora of animal and in vitro studies using mutant APP/presenilin constructs or experiments using exogenous Abeta. In doing so, we aim to invigorate research and discussion around non-amyloidogenic APP processing products and the mechanisms linking mitochondria and complex neurodegenerative disorders such as sporadic Alzheimer's disease. PMID- 30471090 TI - Risk of Mortality in Individuals with Hip Fracture and Traumatic Brain Injury. AB - OBJECTIVES: To estimate the prevalence of diagnosed traumatic brain injury (TBI) in individuals hospitalized with hip fracture and examine its association with all-cause mortality. DESIGN: Nested cohort study. SETTING: National sample of Medicare beneficiaries from 2006 to 2010. PARTICIPANTS: Beneficiaries aged 65 and older hospitalized with hip fracture. MEASUREMENTS: TBI at the time of hip fracture was defined using International Classification of Diseases, Ninth Revision, Clinical Modification codes. The main outcome was all-cause mortality during follow-up. RESULTS: Prevalence of TBI in individuals with hip fracture was 2.7%. Absolute risk of mortality attributable to TBI in individuals with hip fracture was 15/100 person-years. TBI was significantly associated with risk of death in multivariable analysis (hazard ratio=1.24, 95% confidence interval=1.14 1.35). CONCLUSION: TBI was associated with greater risk of mortality in individuals with hip fracture. Practitioners should consider evaluating for presence of TBI in this vulnerable population. PMID- 30471091 TI - A HS6ST2 gene variant associated with X-linked intellectual disability and severe myopia in two male twins. AB - X-Linked Intellectual Disability (XLID) refers to a clinically and genetically heterogeneous neurodevelopmental disorder, in which males are more heavily affected than females. Among the syndromic forms of XLID, identified by additional clinical signs as part of the disease spectrum, the association between XLID and severe myopia has been poorly characterized. We used Whole Exome Sequencing (WES) to study two Italian male twins presenting impaired intellectual function and adaptive behavior, in association with severe myopia and mild facial dysmorphisms. WES analysis detected the novel, maternally inherited, mutation c.916G>C (G306R) in the X-linked Heparan Sulfate 6-O- Sulfotransferase 2 (HS6ST2) gene. HS6ST2 transfers sulphate from adenosine 3'-phosphate, 5'-phosphosulphate (PAPS) to the 6th position of the N-sulphoglucosamine (GlcNS) residue in Heparan Sulfate (HS) proteoglycans. Low HS sulfation levels are associated with defective optic disc and stalk morphogenesis during mammalian visual system development. The c.916G>C variant affects the HS6ST2 substrate binding site and its effect was considered "deleterious" by in-silico tools. An In-vitro enzymatic assay showed that the HS6ST2 mutant isoform had significantly reduced sulphotransferase activity. Taken together, the results suggest that mutant HS6ST2 is possibly involved in the development of myopia and cognitive impairment, characteristics of the probands reported here. This article is protected by copyright. All rights reserved. PMID- 30471092 TI - Targeted panel sequencing in adult patients with left ventricular non-compaction reveals a large genetic heterogeneity. AB - Left ventricular non-compaction (LVNC) is a cardiomyopathy that may be of genetic origin, however few data are available about the yield of mutation, the spectrum of genes and allelic variations. The aim of this study was to better characterize the genetic spectrum of isolated LVNC in a prospective cohort of 95 unrelated adult patients through the molecular investigation of 107 genes involved in cardiomyopathies and arrhythmias. Fifty-two pathogenic or probably pathogenic variants were identified in 40 patients (42%) including 31 patients (32.5%) with single variant and 9 patients with complex genotypes (9.5%). Mutated patients tended to have younger age at diagnosis than patients with no identified mutation. The most prevalent genes were TTN, then HCN4, MYH7, and RYR2. The distribution includes 13 genes previously reported in LVNC and 10 additional candidate genes. Our results show that LVNC is basically a genetic disease and support genetic counseling and cardiac screening in relatives. There is a large genetic heterogeneity, with predominant TTN null mutations and frequent complex genotypes. The gene spectrum is close to the one observed in dilated cardiomyopathy but with specific genes such as HCN4. We also identified new candidate genes that could be involved in this sub-phenotype of cardiomyopathy. This article is protected by copyright. All rights reserved. PMID- 30471093 TI - beta-adrenoceptors as drug targets in melanoma: novel preclinical evidence for a role of beta3-adrenoceptors. AB - Stress plays a role in tumorigenesis through catecholamines acting at beta adrenoceptors including beta1-, beta2- and beta3-adrenoceptors and the use of beta-adrenoceptor antagonists seems to counteract tumor growth and progression. Preclinical evidence and meta-analysis data demonstrate that melanoma shows a positive response to beta-adrenoceptor blockers and in particular to propranolol acting mainly at beta1- and beta2-adrenoceptors. Although evidence suggesting that beta3-adrenoceptors may play a role as a therapeutic target in infantile hemangiomas has been recently reviewed, a comprehensive analysis of the available data from preclinical studies supporting a possible role of beta3-adrenoceptors in melanoma was not available. Here, we review literature data demonstrating that propranolol may be effective in counteracting melanoma growth and we provide preclinical evidence that beta3-adrenoceptors may also play a role in the pathophysiology of melanoma thus opening the door for further clinical assays trying to explore beta3-adrenoceptor blockers as novel alternatives for its treatment. PMID- 30471094 TI - Hypoglycemic Effects of Glimepiride in Sulfonylurea Receptor Deficient Rat. AB - BACKGROUND AND PURPOSE: Sulfonylureas (SUs) were suggested to have an insulin independent blood glucose decreasing activity due to extrapancreatic effect, however, lack of adequate in vivo evidences makes this statement controversial. Here we aimed to evaluate whether glimepiride exists extrapancreatic blood glucose-lowering activity in vivo. EXPERIMENTAL APPROACH: Sulfonylurea receptor deficient (SUR1-/- ) rat was created by TALEN technique. High-fat diet and low dose streptozotocin were used to establish type 2 diabetic models, and which were then randomly divided into four groups: glimepiride, gliclazide, metformin and saline. All rats were treated for 2-weeks. KEY RESULTS: Glimepiride decreased blood glucose level and increased insulin sensitivity without elevating insulin level. Gliclazide showed similar effects as glimepiride. Both agents were weaker than metformin. Further mechanistic investigations revealed that glimepiride increased hepatic glycogen synthesis and decreased gluconeogenesis, which were accompanied with the activation of AKT in liver. Moreover, glimepiride increased both total and membrane GLUT4 levels in muscle and fat, which might be attributed to insulin receptor-independent IRS-1/AKT activation. CONCLUSION AND IMPLICATIONS: Glimepiride possesses extrapancreatic blood glucose-lowering effect in vivo, which might be attributed to its direct effect on insulin-sensitive tissues. Therefore, the combination of glimepiride with multiple insulin injection should not be excluded per se. PMID- 30471095 TI - B cell specific-peroxisome proliferator-activated receptor gamma deficiency augments contact hypersensitivity with impaired regulatory B cells. AB - Nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-gamma) activation can prevent immunoinflammatory disorders and diabetes. B cells play protective roles during inflammation as well. However, the roles of endogenous PPAR-gamma on the regulatory property of B cells to relieve inflammations remain unknown. Here, we developed B cell-specific PPAR-gamma knockout (B-PPAR-gamma-/- ) mice and found that the conditional deletion of PPAR-gamma in B cells resulted in exaggerated contact hypersensitivity (CHS). Meanwhile, IFN-gamma of CD4+ , CD8+ T cells was up-regulated in B-PPAR-gamma-/- mice in CHS. This showed the regulatory function of B cells in B-PPAR-gamma-/- mice declined in vivo. While splenic CD5+ CD1dhi regulatory B cell numbers and peripheral regulatory T cell numbers were not changed in naive B-PPAR-gamma-/- mice. Loss of PPAR-gamma in B cells also did not affect either CD86 or FasL expression in splenic CD5+ CD1dhi regulatory B cells after activation. Notably, IL-10 production in CD5+ CD1dhi regulatory B cells reduced in B-PPAR-gamma-deficient mice. In addition, functional IL-10 producing CD5+ CD1dhi regulatory B cells decreased in B-PPAR gamma-/- mice in CHS model. These were in accordance with augmented CHS. The current work indicated the involvement of endogenous PPAR-gamma in the regulatory function of B cells by disturbing the expansion of IL-10 positive regulatory B cells. This article is protected by copyright. All rights reserved. PMID- 30471096 TI - Roles of phosphatase and tensin homolog in skeletal muscle. AB - The phosphatase and tensin homolog (PTEN), originally identified as a tumor suppressor, is an important regulator of the PI3K-Akt pathway. PTEN plays crucial roles in various cellular processes, including cell survival, cell growth, cell proliferation, cell differentiation, and cell metabolism. In metabolic tissues, PTEN expression affects insulin sensitivity and glucose homeostasis. In skeletal muscle, the deletion of PTEN regulates muscle development and protects the mutant mice from insulin resistance and diabetes. Notably, the regulatory role of PTEN in skeletal muscle stem cells has been recently reported. In this review, we mainly discuss the role of PTEN in regulating the development, glucose metabolism, stem cell fate decision, and regeneration of skeletal muscle. PMID- 30471097 TI - The relative strengths of rapid and delayed density dependence acting on a terrestrial herbivore change along a pollution gradient. AB - 1.Animal populations vary in response to a combination of density dependent and density independent forces, which interact to drive their population dynamics. Understanding how abiotic forces mediate the form and strength of density dependent processes remains a central goal of ecology, and is of increasing urgency in a rapidly changing world. 2.Here, we report for the first time that industrial pollution determines the relative strength of rapid and delayed density dependence operating on an animal population. We explored the impacts of pollution and climate on the population dynamics of an eruptive leafmining moth, Phyllonorycter strigulatella, around a coal fired power plant near Apatity, northwestern Russia. Populations were monitored at 14 sites over 26 years. 3.The relative strengths of rapid and delayed density dependence varied with distance from the power plant. Specifically, the strength of rapid density dependence increased while the strength of delayed density dependence decreased with increasing distance from the pollution source. Paralleling the increasing strength of rapid density dependence, we observed declines in the densities of P. strigulatella, increases in predation pressure from birds and ants, and declines in an unknown source of mortality (perhaps plant antibiosis) with increasing distance from the power plant. 4.In contrast to the associations with pollution, associations between climate change and leafminer population densities were negligible. 5.Our results may help to explain the outbreaks of insect herbivores that are frequently observed in polluted environments. We show that they can result from the weakening of rapid (stabilizing) density dependence relative to the effects of destabilizing delayed density dependence. Moreover, our results may explain some of the variation reported in published studies of animal populations in polluted habitats. Variable results may emerge in part because of the location of the study sites on different parts of pollution gradients. Finally, in a rapidly changing world, effects of anthropogenic pollution may be as, or more, important than are effects of climate change on the future dynamics of animal populations. This article is protected by copyright. All rights reserved. PMID- 30471098 TI - Effects of FOSL1 silencing on osteosarcoma cell proliferation, invasion and migration through the ERK/AP-1 signaling pathway. AB - Osteosarcoma (OS), as the most frequent primary malignancy of bone, is characterized by the presence of malignant mesenchymal cells. In the current study, our aim was to explore the possible effects Fos-like antigen-1 (FOSL1) had on the silencing regarding OS cell proliferation, invasion, and migration through the activation of the extracellular-signal-regulated kinase (ERK)/activator protein-1 (AP-1) signaling pathway. After the collection of OS on top of already having the adjacent normal tissue samples, the protein positive expression rate of FOSL1 was then measured by implementing the use of immunohistochemistry and discovered that FOSL1 was robustly expressed in OS. Later, to better grasp the impact FOSL1 projects on OS and its underlying mechanism, we determined the OS related genes as well as the ERK/AP-1 signaling pathway related genes expression by using a reverse-transcription quantitative polymerase chain reaction and western blot assay techniques. The results of the aforementioned two experiments revealed that the FOSL1 depletion had downregulated the expression of OS related genes by simultaneously downregulating the ERK/AP-1 signaling pathway. Moreover, cell proliferation, cycle, apoptosis, invasion, and migration of FOS1 were all tested by using a cell counting kit-8 assay, flow cytometry, Transwell assay, and scratch test, and these results presented that silencing of the FOSL1 gene inhibited OS cell proliferation, invasion, and migration. Our findings revealed a novel mechanism by which FOSL1 depletion played a significantly negative role in the OS progression through the regulation of the ERK/AP-1 signaling pathway. Functional suppression of FOSL1 might be a future therapeutic strategy regarding OS. PMID- 30471099 TI - Circulating visfatin levels and cancers risk: A systematic review and meta analysis. AB - Visfatin levels have been reported to be abnormal in many types of cancers. However, epidemiological studies yielded inconsistent results. Therefore, a meta analysis was performed to assess the association between circulating visfatin levels and cancer risk. A systematic search was conducted for relevant studies in health-related electronic databases up to March 2018. Data related to standard mean difference (SMD) and overall odds ratio (ORS) were collected and analyzed. Summary SMD and pooled OR with 95% CIs were calculated using a random-effect model. Funnel plot and Egger's linear regression test were conducted to examine the risk of publication bias. A total of 27 studies with 2,693 cases and 3,040 healthy controls were included in meta-analysis for pooling SMD analysis. The results of the meta-analysis showed a significant higher visfatin levels in patients with various cancers than in controls, with a pooled SMD of 0.88, 95% CI = 0.56-1.20, p = 0.000. In subgroup, metaregression, Galbraith plot, and sensitivity analysis showed no substantial difference among all the analyzed factors. Data from 14 studies were also used for pooling ORs analysis. Metaresults revealed that high visfatin levels were associated with cancer risk (OR = 1.24, 95% CI: 1.14-1.34, p = 0.000). No evidence of publication bias was observed for pooling ORs and SMD analysis. This meta-analysis indicated a significant association between high circulating visfatin levels and increased risk of various cancers. Visfatin may represent a potential biomarker for early detection of cancers who may benefit from preventive treatment.Note. PMID- 30471100 TI - Doppler ultrasonographic assessment of fetal middle cerebral artery peak systolic velocity in gestational diabetes mellitus. AB - OBJECTIVE: To compare Doppler ultrasonographic measurements of the fetal middle cerebral artery peak systolic velocity (MCA PSV) among women with or without gestational diabetes mellitus (GDM). METHODS: A cross-sectional study was conducted among pregnant women who presented for prenatal care at a single hospital in Brazil between September 11, 2015, and January 6, 2017. Patients were stratified into a group of patients with GDM and a control group of women without GDM. One Doppler ultrasonographic assessment was performed per participant. This measurement was made after diagnosis but before the start of treatment among women in the GDM group. Fetal ultrasonographic and biometric variables assessed included MCA PSV, MCA pulsatility index, umbilical artery pulsatility index, the MCA-to-umbilical artery ratio, abdominal circumference, and weight. RESULTS: The study included 238 women, 115 in the GDM group and 123 in the control group. The median MCA PSV was 1.02 in the GDM group and 1.08 in the control group (P=0.036). No statistically significant between-group differences were found for the other fetal ultrasonographic variables or for the fetal biometric variables assessed. None of the maternal or fetal parameters assessed displayed a linear correlation with MCA PSV. CONCLUSION: Doppler ultrasonographic measurements of MCA PSV were lowered among the fetuses of women diagnosed with GDM. This article is protected by copyright. All rights reserved. PMID- 30471101 TI - Roles of miRNA-1 and miRNA-133 in the proliferation and differentiation of myoblasts in duck skeletal muscle. AB - MicroRNA (miRNA)-1 and miRNA-133 are derived from the same bicistronic pairs with roles in skeletal muscle development. Many investigations have focused on the role of miRNA-1 and miRNA-133 in the regulation of skeletal muscle development in mammals and fish. However, the mechanisms of miRNA-1 and miRNA-133 underlying the differences in skeletal muscle development between different breeds are not well known. Our study found that the weights of body and breast at 42 days of age were greater in Cherry Valley ducks than in Putian ducks and the areas of breast muscle fibers increased with age; the areas of muscle fibers of Cherry Valley ducks were always greater than those of Putian ducks. Besides, quantitative reverse-transcriptase polymerase chain reaction analysis revealed that relatively high levels of miRNA-1 and miRNA-133 were detected in heart, breast, and leg muscles compared with the liver, spleen, lung, kidney, and the expression levels of miRNA-1 and miRNA-133 remained stable in the embryo stage, and in the growth period, the fluctuation in miRNA expression levels in Putian ducks was considerably higher than that in Cherry Valley ducks, especially from 7 to 28 days. However, in the late growth period, the expression of miRNA-1 and miRNA-133 of Cherry Valley duck was higher than that of Putian duck, which may indicate that miRNA-1 and miRNA-133 play a more important role during the growth period. To determine the function of miRNA-1 and miRNA-133 in skeletal muscle development, we found that the overexpression of miRNA-1, but not miRNA-133, promoted fusion of adjacent myoblasts. By contrast, a repressor of miRNA-1 promoted, whereas a miRNA-133 inhibitor inhibited, myoblast proliferation. Accordingly, the expression levels of myocyte enhancer factor 2D (MEF2D) and myogenic differentiation ( MYOD) were significantly increased by an miRNA-1 mimic and the miRNA-133 inhibitor. In addition, we found that the expression levels of miRNA-1 significantly affected the expression of histone deacetylase 4 ( HDAC4), and miRNA-133 affected serum response factor ( SRF) and transforming growth factor beta receptor 1 ( TGFBR1) levels. However, dual-luciferase reporter assays revealed that only miRNA-1 directly inhibited pGL- HDAC4 luciferase reporter activity, whereas miRNA-133 did not affect pGL- SRF or pGL- TGFBR1 fluorescence activity. Taken together, these results suggest that miRNA-1 targets HDAC4 to promote the differentiation of duck myoblasts and miRNA-133 may affect SRF and TGFBR1 expression to promote proliferation, which indicates that miRNA-1 and miRNA-133 play different important roles in skeletal muscle development. PMID- 30471102 TI - Effect of Age on Opioid Prescribing, Overdose, and Mortality in Massachusetts, 2011 to 2015. AB - OBJECTIVES: To examine the effect of age on the likelihood of PIP of opioids and the effect of PIP on adverse outcomes. DESIGN: Retrospective cohort study. SETTING: Data from multiple state agencies in Massachusetts from 2011 to 2015. PARTICIPANTS: Adult Massachusetts residents (N=3,078,163) who received at least one prescription opioid during the study period; approximately half (1,589,365) aged 50 and older. MEASUREMENTS: We measured exposure to 5 types of PIP: high dose opioids, coprescription with benzodiazepines, multiple opioid prescribers, multiple opioid pharmacies, and continuous opioid therapy without a pain diagnosis. We examined 3 adverse outcomes: nonfatal opioid overdose, fatal opioid overdose, and all-cause mortality. RESULTS: The rate of any PIP increased with age, from 2% of individuals age 18 to 29 to 14% of those aged 50 and older. Older adults also had higher rates of exposure to 2 or more different types of PIP (40 49, 2.5%; 50-69, 5%; >=70, 4%). Of covariates assessed, older age was the greatest predictor of PIP. In analyses stratified according to age, any PIP and specific types of PIP were associated with nonfatal overdose, fatal overdose, and all-cause mortality in younger and older adults. CONCLUSION: Older adults are more likely to be exposed to PIP, which increases their risk of adverse events. Strategies to reduce exposure to PIP and to improve outcomes in those already exposed will be instrumental to addressing the opioid crisis in older adults. PMID- 30471103 TI - Multimorbidity and Mental Health-Related Quality of Life and Risk of Completed Suicide. AB - BACKGROUND: Physical functioning indexed multimorbidity is strongly associated with long-term mortality, but its role in poor mental health has not been quantified. METHODS: A total of 252 002 community-dwelling adults in the Nurses' Health Study (NHS), NHS II, and Health Professionals Follow-up Study (HPFS) prospective cohorts reported physician-diagnosed diseases and the Short Form-36 over 8 years and had 24-year follow-up for suicide mortality. We quantified multimorbidity using a multimorbidity-weighted index (MWI). We used multivariable adjusted proportional hazards models with competing risks for suicide mortality and mixed-effects models to estimate mental health-related quality of life (HRQOL). RESULTS: Multimorbidity was associated with an increased risk of suicide mortality in an approximately linear manner, with roughly two- to threefold higher risk in adults with the highest vs lowest quartile MWI in adjusted models: NHS hazard ratio (HR) = 3.01 (95% confidence interval [CI] = 1.48-6.11); NHS II HR = 3.04 (95% CI = 1.82-5.09); HPFS HR = 1.74 (95% CI = 1.08-2.81). Greater MWI was associated with worse mental HRQOL 8 years later across all scales and the mental component summary (MCS) in a dose-response manner. This association was attenuated but persisted after adjustment for baseline mental HRQOL and other covariates. Adults with the highest quartile MWI had lower MCS in adjusted models compared with those with the lowest quartile MWI: NHS beta = -0.61 (95% CI = 0.78 to -0.44); NHS II beta = -1.25 (95% CI = -1.44 to -1.06). CONCLUSION: Multimorbidity is associated with substantially higher suicide mortality risk and worse mental HRQOL across all available scales, even when indexed to physical functioning. These results highlight the substantial mental health burden imposed by multimorbidity at all ages and sexes. PMID- 30471104 TI - Amino acids stimulate glycyl-tRNA synthetase nuclear localization for mammalian target of rapamycin expression in bovine mammary epithelial cells. AB - Amino acids are required for the activation of mammalian target of rapamycin (mTOR) to increase cell growth, protein and lipid synthesis, and inhibit autophagy. However, the mechanism through which amino acids activate the mTOR signaling is still largely unknown. In our previous study, we discovered that glycyl-tRNA synthetase (GlyRS) is a key mediator of amino-acid-induced mTOR expression and activation in bovine mammary epithelial cells (BMECs). Here we show that amino acids stimulate GlyRS nuclear localization for mTOR expression in BMECs. Met stimulates GlyRS nuclear localization, and the nuclear GlyRS is cleaved into a C-terminus-containing truncated form. We prove that GlyRS has a bipartite nuclear leading sequences, and GlyRS is phosphorylated at Thr544 and Ser704 in the cytoplasm under the stimulation of amino acids (Met, Leu, and Lys). The nuclear GlyRS physically binds to nuclear factor kappa B1, triggers its phosphorylation, thereby enhancing mRNA expression of its target genes including mTOR, S6K1, and 4EBP1. We further demonstrate that GlyRS is required for the inhibition of autophagy by Met. Thus our work elucidates that amino acids trigger GlyRS phosphorylation and nuclear localization to enhance the mRNA expression of mTOR. PMID- 30471105 TI - Microtia patients: Auricular chondrocyte ECM is promoted by CGF through IGF-1 activation of the IGF-1R/PI3K/AKT pathway. AB - OBJECTIVE: To explore the effectiveness of the insulin-like growth factor 1 receptor (IGF-1R)/PI3K/AKT pathway in promoting the synthesis of the auricular chondrocyte extracellular matrix (ECM) using concentrated growth factor (CGF). METHODS: Chondrocytes isolated from the remnant auricular cartilage of microtia patients were randomly divided into different experimental and control groups, then stimulated with a reagent. IGF-1 released by CGF was quantified by enzyme linked immunosorbent assay. Glycosaminoglycan (GAG), proteoglycan, and type II collagen (COLAII) were examined by histological and immunohistological analysis. Expression levels of IGF-1R, pIGF-1R, PI3K, pPI3K, AKT, pAKT, COLAII, and Aggrecan were detected by western blot analysis technique and gene expression was tested by real-time polymerase chain reaction. RESULTS: CGF significantly stimulated the synthesis of COLAII and Aggrecan and increased the phosphorylation levels of IGF-1R, PI3K, and AKT. Small interfering RNA IGF-1 blocked ECM synthesis, COLAII and Aggrecan gene expression, and IGF-1R/PI3K/AKT activation. Inhibitor AG1024 and LY294002 significantly inhibited ECM synthesis and the phosphorylation of IGF-1R, PI3K, and AKT. CONCLUSION: CGF-released IGF-1 stimulates the synthesis of the auricular chondrocyte ECM via the IGF-1R/PI3K/AKT signaling pathway. PMID- 30471106 TI - Caspase-1-dependent mechanism mediating the harmful impacts of the quorum-sensing molecule N-(3-oxo-dodecanoyl)-l-homoserine lactone on the intestinal cells. AB - N-(3-oxododecanoyl)-l-homoserine lactone (3-oxo-C12-HSL), a quorum-sensing (QS) molecule produced by Gram-negative bacteria in the gastrointestinal tract, adversly impacts host cells. Our previous study demonstrated that 3-oxo-C12-HSL induced a decrease in cell viability via cell apoptosis and eventually disrupted mucin synthesis from LS174T goblet cells. However, the molecular mechanism underlying cell apoptosis and whether pyroptosis was involved in this process are still unknown. In this study, we emphasized on the caspases signal pathway and sterile inflammation to reveal the harmful effects of 3-oxo-C12-HSL on LS174T goblet cells. Our data showed that 3-oxo-C12-HSL is a major inducer of oxidative stress indicated by a high level of intracellular reactive oxygen species (ROS). However, TQ416, an inhibitor of paraoxonase 2, can effectively block oxidative stress. A higher ROS level is the trigger for activating the caspase-1 and 3 cascade signal pathways. Blockade of ROS synthesis and caspase-1 and 3 cascades can obviously rescue the viability of LS174T cells after 3-oxo-C12-HSL treatment. We also found that paralleled with a higher level of ROS and caspases activation, an abnormal expression of proinflammatory cytokines was induced by 3-oxo-C12-HSL treatment; however, the blockage of TLRs-NF-kappaB pathway cannot restore cell viability and secretary function. These data collectively indicate that 3-oxo-C12 HSL exposure induces damages to cell viability and secretary function of LS174T goblet cells, which is mediated by oxidative stress, cell apoptosis, and sterile inflammation. Overall, the data in this study will provide a better understanding of the harmful impacts of some QS molecules on host cells and their underlying mechanism. PMID- 30471107 TI - Cancer stem cells as a therapeutic target in bladder cancer. AB - Bladder cancer is one of the most prevalent genitourinary cancers responsible for about 150,000 deaths per year worldwide. Currently, several treatments, such as endoscopic and open surgery, appended by local or systemic immunotherapy, chemotherapy, and radiotherapy are used to treat this malignancy. However, the differences in treatment outcome among patients suffering from bladder cancer are considered as one of the important challenges. In recent years, cancer stem cells, representing a population of undifferentiated cells with stem-cell like properties, have been eyed as a major culprit for the high recurrence rate in superficial papillary bladder cancer. Cancer stem cells have been reported to be resistant to conventional treatments, such as chemotherapy, radiation, and immunotherapy, which induce selective pressure on tumoral populations resulting in selection and growth of the resistant cells. Therefore, targeting the therapeutic aspects of cancer stem cells in bladder cancer may be promising. In this study, we briefly discuss the biology of bladder cancer and then address the possible relationship between molecular biology of bladder cancer and cancer stem cells. Subsequently, the mechanisms of resistance applied by cancer stem cells against the conventional therapeutic tools, especially chemotherapy, are discussed. Moreover, by emphasizing the biomarkers described for cancer stem cells in bladder cancer, we have provided, described, and proposed targets on cancer stem cells for therapeutic interventions and, finally, reviewed some immunotargeting strategies against bladder cancer stem cells. PMID- 30471108 TI - KCNQ1OT1 facilitates progression of non-small-cell lung carcinoma via modulating miRNA-27b-3p/HSP90AA1 axis. AB - Long noncoding RNA KCNQ1OT1 participates in the regulation of imprinted genes within the kcnq1 domain. But its roles in carcinogenesis and metastasis remain largely elusive. Herein, we evaluated its potential in non-small-cell lung cancer (NSCLC) progression. We demonstrated that the KCNQ1OT1 level was upregulated in NSCLC tissues and cell lines. High KCNQ1OT1 level correlated with poor overall and progression-free survival in NSCLC patients. KCNQ1OT1 facilitated proliferation, migration, and invasion in H460 cells. Furthermore, knockdown of KCNQ1OT1 reduced the expression of HSP90AA1. KCNQ1OT1 presented a positive correlation with HSP90AA1 which predicted the tumor progression in NSCLC from The Cancer Genome Atlas database. Intriguingly, KCNQ1OT1 modulated HSP90AA1 expression by sponging miR-27b-3p. MiR-27b-3p counteracted the effect of KCNQ1OT1 on HSP90AA1 expression, H460 cell migration, and invasion. These data revealed a role for KCNQ1OT1 as an oncogene through miR-27b-3p/HSP90AA1 axis during NSCLC progression. PMID- 30471109 TI - LncRNA miR143HG suppresses bladder cancer development through inactivating Wnt/beta-catenin pathway by modulating miR-1275/AXIN2 axis. AB - Although increasing long noncoding RNAs (lncRNAs) have been identified by high throughput sequencing, their functions in human cancer remain largely unknown. The function of lncRNA miR143HG has not been explored before. In the present study, we found that miR143HG expression was significantly downregulated in bladder cancer tissues (BCa) compared with normal tissues. We showed that miR143HG high expression was associated with a high survival rate in BCa patients. Gain-of-function assays demonstrated that miR143HG overexpression suppressed the proliferation, arrested cell cycle progression, and attenuated migration and invasion of BCa cells in vitro. In vivo assay illustrated that ectopic expression of miR143HG inhibited BCa growth in vivo. Mechanistically, miR143HG was identified to inhibit the level of miR-1275, whereas miR-1275 directly targeted AXIN2, a negative regulator of the Wnt/beta-catenin pathway. Restoration of miR-1275 or knockdown of AXIN2 significantly rescued the proliferation, migration, and invasion abilities of BCa cells. In summary, our findings demonstrated that miR143HG/miR-1275/AXIN2 axis regulates BCa development by modulating the Wnt/beta-catenin pathway. PMID- 30471110 TI - Macrophage CD40-signaling drives experimental autoimmune encephalomyelitis. AB - The co-stimulatory CD40L-CD40 dyad plays a major role in multiple sclerosis (MS). CD40 is highly expressed on MHCII+ B cells, dendritic cells and macrophages in human MS lesions. Here we investigated the role of the CD40 downstream signaling intermediates TRAF2 and TRAF6 in MHCII+ cells in experimental autoimmune encephalomyelitis (EAE). Both MHCII-CD40-Traf2-/- and MHCII-CD40-Traf6-/- mice showed a reduction in clinical signs of EAE and prevented demyelination. However, only MHCII-CD40-Traf6-/- mice displayed a decrease in myeloid and lymphoid cell infiltration into the central nervous system (CNS) that was accompanied by reduced levels of TNF-alpha, IL-6, and IFN-gamma. As CD40-TRAF6 interactions predominantly occur in macrophages, we subjected CD40flfl LysMcre mice to EAE. This myeloid specific deletion of CD40 resulted in a significant reduction in EAE severity, reduced CNS inflammation and demyelination. In conclusion, the CD40 TRAF6 signaling pathway in MHCII+ cells plays a key role in neuro-inflammation and demyelination during EAE. Concomitant with the fact that CD40-TRAF6 interactions are predominant in macrophages, depletion of myeloid CD40 also reduces neuro-inflammation. CD40-TRAF6 interactions thus represent a promising therapeutic target for multiple sclerosis. PMID- 30471111 TI - Sleep disordered breathing in children disrupts the maturation of autonomic control of heart rate and its association with cerebral oxygenation. AB - KEY POINT SUMMARY: Sleep disordered breathing (SDB) affects 4 - 11% of children and is associated with adverse neurocognitive, behavioural and cardiovascular outcomes, including reduced autonomic control. The relationship between heart rate variability (HRV; a measure of autonomic control), and age found in non snoring control children was absent during sleep in children with SDB. Age significantly predicted increasing cerebral oxygenation during wake in non snoring control children, whereas during sleep, HRV significantly predicted decreasing cerebral oxygenation. Cerebral oxygenation was not associated with either age or HRV in children with SDB during both wake and sleep. SDB significantly disrupts the normal maturation of autonomic control and the positive association between autonomic control and cerebral oxygenation found in non-snoring children, and we speculate that the dampened autonomic control exhibited by children with SDB may have an attenuating effect on cerebral autoregulation via the moderating influence of HRV on cerebral blood flow. ABSTRACT: Background The repetitive episodes of hypoxia that are features of sleep disordered breathing (SDB) in children are associated with alterations in autonomic control of heart rate in an age dependent manner. We aimed to relate heart rate variability (HRV) parameters to age and measures of cerebral oxygenation in children (3-12 y) with SDB and non-snoring controls. Methods Children (SDB, n = 117; controls, n = 42; 3-12 y) underwent overnight polysomnography. Total (TP), low (LF) and high frequency (HF) power, tissue oxygenation index (TOI) and fractional tissue oxygen extraction (FTOE) were analysed during wake and sleep. Pearson's correlations determined the association between age and HRV parameters, and multiple linear regressions between HRV, age and cerebral oxygenation parameters. Results During wake, age had a positive association with LF power reflecting increased parasympathetic and sympathetic activity with increasing age for both control and SDB groups. This association was also evident during sleep in controls, but was absent in children with SDB. In controls, during wake TOI had a positive, and FTOE a negative association with age. During sleep, TP, LF and HF power were significant, negative determinants of TOI and positive determinants of FTOE. These associations were not seen in children with SDB during wake or sleep. Conclusion SDB disrupts the normal maturation of the autonomic control of heart rate and the association between HRV and cerebral oxygenation exhibited by non-snoring control children of primary school age. These results highlight the impact SDB has on cardiovascular control and the potential impact on adverse cardiovascular outcomes. This article is protected by copyright. All rights reserved. PMID- 30471112 TI - Garcinol suppresses RANKL-induced osteoclastogenesis and its underlying mechanism. AB - Osteoclasts (OCs) are multinuclear giant cells responsible for bone resorption, and an excessive bone resorption by OCs plays an important role in osteoporosis. Commonly used drugs for the treatment of osteoporosis have severe side effects. As such, identification of alternative treatments is essential. Garcinol, a polyisoprenylated benzophenone extracted from the fruit of Garcinia indica, has shown a strong antitumor effect through the nuclear factor-kappaB (NF-kappaB) and mitogen-associated protein kinases (MAPK) signaling pathways. However, the role of garcinol in the osteoclastogenesis is still unclear. Here, we demonstrated that garcinol can inhibit the receptor activator of NF-kappaB ligand (RANKL) induced osteoclastogenesis, osteoclastogenesis-related gene expression, the f actin ring, and resorption pit formation. In addition, garcinol abrogated RANKL induced osteoclastogenesis by attenuating the degradation of the MAPK, NF-kappaB, and PI3K-AKT signaling pathway as well as downstream factors c-jun, c-fos, and NFATC1. In vivo, suppression of osteoclastogenesis by garcinol was evidenced by marked inhibition of lipopolysaccharide-induced bone resorption. In conclusion, our data demonstrated that garcinol inhibited the RANKL-induced osteoclastogenesis by suppressing the MAPK, NF-kappaB, and PI3K-AKT signaling pathways and thus has potential as a novel therapeutic option for osteolytic bone diseases. PMID- 30471113 TI - The Na+ /H+ exchanger NHE1 localizes as clusters to cryptic lamellipodia and accelerates collective epithelial cell migration. AB - KEY POINTS SUMMARY: Exogenous NHE1 expression stimulated collective migration of epithelial cell sheets Stimulation with epidermal growth factor (EGF), a key morphogen, primarily increased migration of the front row of cells, whereas NHE1 increased that of submarginal cell rows, and the two stimuli were additive Accordingly, NHE1 localized not only to the leading edges of leader cells, but also in cryptic lamellipodia in submarginal cell rows NHE1 expression disrupted the morphology of epithelial cell sheets and 3D cysts ABSTRACT: Collective cell migration plays essential roles in embryonic development, in normal epithelial repair processes, and in many diseases including cancer. The Na+ /H+ Exchanger 1 (NHE1, SLC9A1) is an important regulator of motility in many cells and has been widely studied for its roles in cancer, yet its possible role in collective migration of normal epithelial cells has remained unresolved. Here, we show that NHE1 expression in MDCK-II kidney epithelial cells accelerated collective cell migration. NHE1 localized to the leading edges of leader cells, as well as to cryptic lamellipodia in submarginal cell rows. Epidermal growth factor (EGF), a kidney morphogen, increased displacement of the front row of collectively migrating cells and reduced the number of migration fingers. NHE1 expression increased number of migration fingers and increased displacement of submarginal cell rows, resulting in additive effects of NHE1 and EGF. Finally, NHE1 expression resulted in disorganized development of MDCK-II cell cysts. Thus, NHE1 contributes to collective migration and epithelial morphogenesis, suggesting roles for the transporter in embryonic and early postnatal development. This article is protected by copyright. All rights reserved. PMID- 30471114 TI - Challenges and advances in atomistic simulations of potassium and sodium Ion channel gating and permeation. AB - Ion channels are implicated in many essential physiological events such as electrical signal propagation and cellular communication. The advent of K+ and Na+ ion channel structure determination has facilitated numerous investigations of molecular determinants of their behavior. At the same time, rapid development of computer hardware and molecular simulation methodologies has made computational studies of large biological molecules in all-atom representation tractable. The concurrent evolution of experimental structural biology with biomolecular computer modeling has yielded mechanistic details of fundamental processes unavailable through experiments alone, such as ion conduction and ion channel gating. The following is a short survey of the atomistic computational investigations of K+ and Na+ ion channels, focusing on KcsA and several voltage gated channels from the KV and NaV families, that have garnered many successes and engendered several long-standing controversies regarding the nature of their structure-function relationship. We review the latest advancements and challenges facing the field of molecular modeling and simulation regarding the structural and energetic determinants of ion channel function and their agreement with experimental observations. This article is protected by copyright. All rights reserved. PMID- 30471115 TI - The role of HSP27 in the development of drug resistance of gastrointestinal malignancies: Current status and perspectives. AB - Heat-shock protein 27 (HSP27) is a chaperone molecule that plays a critical role in the refolding and activity of several proteins responsible for cancer cell drug toxicity. Upregulation of HSP27 is associated with decreased drug sensitivity as well as poorer survival in gastrointestinal (GI) malignancies. It is, therefore, possible that HSP27 may be of value in the assessment of prognostic and therapeutic efficacy in the treatment of GI cancers. Pharmacological and biological inhibitors of HSP27 enhance tumor cell chemosensitivity. This review summarizes the potential role of HSP27 in chemotherapy drug resistance and the therapeutic potential of HSP27 inhibitors as a novel strategy in the treatment of GI cancers. PMID- 30471116 TI - An overview of microRNAs: Biology, functions, therapeutics, and analysis methods. AB - MicroRNAs (miRNAs) are a class of small noncoding RNAs, which function in posttranscriptional regulation of gene expression. They are powerful regulators of various cellular activities including cell growth, differentiation, development, and apoptosis. They have been linked to many diseases, and currently miRNA-mediated clinical trial has shown promising results for treatment of cancer and viral infection. This review provides an overview and update on miRNAs biogenesis, regulation of miRNAs expression, their biological functions, and role of miRNAs in epigenetics and cell-cell communication. In addition, alteration of miRNAs following exercise, their association with diseases, and therapeutic potential will be explained. Finally, miRNA bioinformatics tools and conventional methods for miRNA detection and quantification will be discussed. PMID- 30471117 TI - Mechanical properties and quality parameters of Chitosan-edible algae (Palmaria palmata) on eady-to-eat strawberries. AB - BACKGROUND: Strawberry is a fruit appreciated for its taste, flavour, and juiciness; however, it is highly perishable during postharvest, handling and storage, producing important physical damage and vitamin and other phytonutrients' loss. For this reason, this study aimed at determining the applicability of edible coatings as an environmentally friendly strategy to improve strawberry fresh appearance and extend its shelflife. RESULTS: The effectiveness of edible coatings formulated with chitosan (CHC) or chitosan and algae (Palmaria palmata Kuntze) (CH-PC) were investigated on quality and nutritional parameters for ready to eat strawberry processed and storage at 4 degrees C during 10 days. CHC controlled significantly (p<0.05) the gradual decline of strawberry, reducing its respiration rate, microbial load and nutritional loss. The addition of P. palmata to the edible coating significantly (p<0.05) enhanced anthocyanin and ascorbic acid content. CONCLUSION: These results suggest that CH-PC could be used in the strawberry postharvest industry to slowdown senescence, while reducing product loss and enhancing its nutritional value. This article is protected by copyright. All rights reserved. PMID- 30471118 TI - Nutritional and meat quality characteristics of seven primal cuts from 9-month old female veal calves: a preliminary study. AB - BACKGROUND: Beef is a highly nutritious and valuable food. In order to complete its nutritional information, in this study was determined the chemical and physico-chemical parameters and fatty acids, amino acids and minerals contents in seven primal cuts from veal carcasses (shoulder clod [SC], inside round [IR], eye of round [ER], bottom round [BR], heel of round [HR], knuckle [KK] and tenderloin [TL]). RESULTS: The intramuscular fat content was higher and the cholesterol content was lower in TL than in the other cuts. The colour parameters also varied in the different primal cuts. The L* and b* values were highest in ER. Cooking losses were significantly (P<0.001) affected by the cut of meat ranging from 20.85% in HR to 29.01% in ER. Determination of the shear force values permitted us to establish more tender muscle (TL with shear force 16.45 N/cm2 ) and less tender muscle (IR with shear force 47.27 N/cm2 ). The nutritional indices and fatty acid profile indicated that HR is the healthiest cut. All cuts evaluated provide important levels of dietary amino acids, although the contents of both essential and non-essential amino acids were highest in HR. Finally, K, Zn and Fe were affected by the type of veal cut. CONCLUSION: All primal cuts of veal provide important nutrients for human diets. The information of this research allows consumers to make healthful food choices, creating diets aimed at trying to correct deficiencies and providing objective data that differentiate between differently priced cuts of veal. This article is protected by copyright. All rights reserved. PMID- 30471119 TI - Oxidative stability of emulsions fortified with iron: the role of liposomal phospholipids. AB - BACKGROUND: Interest in supplementing food with iron to counteract dietary deficiencies has been on the rise in recent years. A major challenge is the pro oxidant activity of soluble iron, which compromises the chemical stability of the enriched food products. This problem could be mitigated by encapsulating iron, to physically keep it separated from oxidisable substrates, such as unsaturated fatty acids. In the present work, the physical and chemical stability of surfactant- or protein-stabilized oil-in-water emulsions fortified with iron was investigated. RESULTS: Iron (ferrous sulfate) was successfully incorporated in liposomes at high encapsulation efficiency (89%). The obtained liposomes were added to emulsions stabilized with either Tween 20, or whey protein isolate (WPI), and the oxidative stability thereof was monitored, and compared to emulsions with free iron. Tween 20-stabilised emulsions were more stable against oxidation than WPI-stabilized emulsions, and furthermore lipid oxidation was substantially higher in emulsions containing iron (either free, or encapsulated in liposomes) than in blank emulsions. This shows that liposomal encapsulation did not inhibit the pro-oxidant activity of iron. CONCLUSION: Despite the high encapsulation efficiency of iron in our liposomes, these systems are not suitable to supplement model foods with iron because of the associated deleterious chemical reactivity. This is most probably due to the phospholipids used as encapsulation material being prone to oxidation, which may actively contribute to the oxidative process. These aspects are normally not taken into account but we showed that they are of utmost importance, and should be taken as a starting point in the design of delivery systems. This article is protected by copyright. All rights reserved. PMID- 30471120 TI - Biotic elicitation as a tool to improve berry (Strawberry and Raspberry) extract potential on metabolic syndrome related enzymes in vitro. AB - BACKGROUND: Raspberry and strawberry are among the high added value food products relevant for human health due to abundance of polyphenols. Polyphenols are secondary metabolites and therefore, devoted to improve plant adaptation so polyphenol profile can ba triggered by different stimulus like beneficial bacteria. The aim of this study was two-fold, i) to evaluate the ability of two bacterial strains to modulate secondary metabolism in strawberry and raspberry, and ii) to explore the ability of plant extracts to modify enzymes' activities related to metabolic syndrome. RESULTS: Total phenolics and anthocyanins contents were higher in strawberries than in raspberries, despite similar antioxidant capacity. Strawberry extracts performed better on the tested enzymes, except on alpha-glucosidase inhibition capacity. Bacillus amyloliquefaciens stabilized effects of extracts in different time points, while the Pseudomonas fluorescens modified plant metabolism after more inoculations (spring) in both species, improving effects of raspberry extracts on alpha-glucosidase, COX1 and COX2, and of strawberry on alpha-amylase and COX1. CONCLUSION: These two fruits are a good choice to be included in the diet since they improve the activity of metabolic syndrome related enzymes. Delivering either strain along plant growth modifies bioactives' profiles, improving effects of fruit extracts over human health. This article is protected by copyright. All rights reserved. PMID- 30471121 TI - Identification and characterization of the rice pre-harvest sprouting mutants involved in molybdenum cofactor biosynthesis. AB - In cereal crops, ABA deficiency during seed maturation phase causes pre-harvest sprouting (PHS), and molybdenum cofactor (MoCo) is required for ABA biosynthesis. Here, two rice PHS mutants F254 and F5-1 were characterized. In addition to the PHS, these mutants showed pleiotropic phenotypes such as twisting and slender leaves, and then died when the seedling developed to four or five leaves. Map based cloning showed that OsCNX6 and OsCNX1 encoding homologs of MoaE and MoeA were responsible for F254 and F5-1 mutants, respectively. Genetic complementation indicated that OsCNX6 not only rescued the PHS and seedling lethal phenotype of cnx6 mutant, but also recovered the MoCo-dependent enzyme activities such as xanthine dehydrogenase (XDH), aldehyde oxidase (AO), nitrate reductase (NR), and sulfite oxidase (SO). Expression pattern showed that OsCNX6 was richly expressed in seed during embryo maturation by qRT-PCR and RNA in situ hybridization. Furthermore, the OsCNX6 overexpression plants can significantly enhance the MoCo dependent enzyme activities, and improved the osmotic and salt stress tolerance without unfavorable phenotypes. Collectively, these data described that OsCNX6 participated in MoCo biosynthesis, and is essential for rice development, especially for seed dormancy and germination, and OsCNX6 could be an effective target for improving abiotic stress tolerance in rice. This article is protected by copyright. All rights reserved. PMID- 30471122 TI - Quantitative Risk Assessment of Listeria monocytogenes in Bulk Cooked Meat from Production to Consumption in China: A Bayesian Approach. AB - BACKGROUND: To estimate the public health risk related to cooked meat in bulk products contaminated with Listeria monocytogenes, a generic Bayesian network (BN) risk assessment model was developed to simulate influencing factors and processes of products from the industry level to the consumer level. To quantify the model, parameter values of prior distributions were acquired from literature, websites and expert opinions. Using the Markov chain Monte Carlo (MCMC) simulation approach, posterior probability distributions were calculated according to the incorporated evidence, which allowed us to predict various risks affected by processing variability from production to consumption. RESULTS: The average risk of listeriosis from consuming cooked meat in bulk products is 8.40*10-7 , 2.58*10-8 , 8.24*10-7 , and 1.05*10-6 per meal for children, young people, elderly people and pregnant women, respectively. The estimated mean number of listeriosis cases is 5 per 100,000 people per year in China. CONCLUSION: Although only a conceptual BN model is given, it manifests the principles and characteristics of mathematical methods. Additionally, the BN model can provide significant benefits for quantitative risk assessment by incorporating all available data as well as by updating beliefs. This article is protected by copyright. All rights reserved. PMID- 30471123 TI - Updating the Chemiluminescence Oxygen-Aftereffect Method for Determining the Rate Constant of the Peroxy-Radical Self-Reaction: Oxidation of Cyclohexene. AB - Updating the facile chemiluminescence oxygen-aftereffect method, most suitable for determining the rate constant (kt ) of the peroxy-radical self-reaction (main chemiluminescence channel), pertained to considering the sensitivity of such a method towards a disturbing influence of the peroxy radicals of the initiator of the chain oxidation process. Such a disturbance may derive from the side chemiluminescent reaction, which involves peroxy radicals of both hydrocarbon and initiator. To examine the applicability and limitations of the chemiluminescence method under present scrutiny, cyclohexene was used as the model oxidizable hydrocarbon substrate. Computer simulations of the reaction and chemiluminescence kinetics has demonstrated the validity of the considered methodology at the value of the rate constant of the propagation of the overall chain process by peroxy radicals of the initiator higher than 1 M-1 s-1 . Despite that the chemiluminescence time profile and the stationary level of the total chemiluminescence intensity depend on the kinetics of the side chemiluminescence channel and on the ratio of the excited-state generation yields in the mentioned reaction channel and in the main chemiluminescence process, the value of kt assessed by the oxygen-aftereffect method has been found independent of variation of these characteristics. This article is protected by copyright. All rights reserved. PMID- 30471124 TI - Application of variance-based uncertainty and sensitivity analysis to biological modeling in carbon ion treatment plans. AB - PURPOSE: In ion beam therapy, biological models to estimate the relative biological effectiveness (RBE) and subsequently the RBE-weighted dose (RWD) are needed in treatment planning and plan evaluation. The required biological parameters as well as their dependency on ion species and ion energy can typically not be determined directly in experiments for in vivo situations. For that reason they are often derived from in vitro data and biological modeling and subject to large uncertainties. We present a model-independent Monte Carlo (variance-) based uncertainty and Sensitivity Analysis (SA) approach to quantify the impact of different input uncertainties on a simulated carbon ion treatment plan. METHOD: The influences of different input uncertainties are examined by variance-based SA methods. In this Monte Carlo approach, a function is evaluated 103 -105 times. For each of those runs all inputs are changed simultaneously, using random numbers according to their associated uncertainties. Variance-based statistic formalisms then rank the input parameter/uncertainty pairs according to their impact on the result of the function. The method of SA includes an uncertainty analysis and was applied to a two-field spot scanning carbon ion treatment plan for two commonly used biological models and two representative tissue parameter sets. RESULTS: Based on an exemplary patient case the application of variance-based SA for biological measures, relevant in (carbon) ion therapy, is demonstrated. A voxel-wise calculation for 2.9.105 voxels takes ~6 h. A structure based SA, which adds an uncertainty band to a RWD-volume histogram (RW-DVH) and shows how to decrease the uncertainty in the most effective way, can be calculated in 0.1 - 1.5 h (depending on the size of the structure). The uncertainties in RBE, RWD or RW-DVH are broken down to the impact of different uncertainties in the (biological) model input. Biological uncertainties have a higher impact on the resulting RBE and RWD than uncertainties in the physical dose. Excluding the physical dose from the SA only slightly decreased the overall uncertainty, emphasizing the necessity to include biological uncertainties into treatment plan evaluation. CONCLUSION: Variance based SA is a powerful tool to evaluate the impact of uncertainties in (carbon) ion therapy. The number of input parameters that can be examined at once is only limited by computation time. A Monte Carlo derived, comprehensive uncertainty quantification and a corresponding sensitivity analysis are implemented and provide new information for treatment plan evaluation. A possible future application is a SA-based biologically robust treatment plan optimization using the additional uncertainty information as presented here. This article is protected by copyright. All rights reserved. PMID- 30471125 TI - Women's stereotype threat-based performance motivation and prepotent inhibitory ability. AB - According to the mere effort account of performance, stereotype threat motivates disproval of the negative performance stereotype, which in turn potentiates the overproduction of prepotent responses. In mathematics (maths), prepotent responding facilitates solve type question (e.g., equations) performance, but reduces comparison type question (e.g., estimations) performance. Problematically, the mere effort account indexes performance motivation as task performance. Also, this account posits that performance reduction on non prepotent tasks derives from the overproduction of prepotent responses, as opposed to failed inhibition of prepotent responses associated with the alternative, namely, the working memory interference perspective. We investigated motivational and prepotent responding as applied to stereotype threat. In Experiment 1, a maths question selection task indexed motivation (independently of performance). Stereotype threat led female test takers to select more solve than comparison maths questions, in accord with the mere effort account. In Experiment 2, higher inhibitory ability protected overall maths performance following stereotype threat, but it did not protect non-prepotentiated comparison question performance (inconsistent with the working memory interference perspective). The results support the mere effort account. PMID- 30471126 TI - Cherenkov imaging for linac beam shape analysis as a remote electronic quality assessment verification tool. AB - PURPOSE: A remote imaging system tracking Cherenkov emission was analyzed to verify that the linear accelerator (linac) beam shape could be quantitatively measured at the irradiation surface for Quality Audit (QA). METHODS: The Cherenkov camera recorded 2D dose images delivered on a solid acrylonitrile butadiene styrene (ABS) plastic phantom surface for a range of square beam sizes, and 6 MV photons. Imaging was done at source to surface distance (SSD) of 100cm and compared to GaF film images and linac light fields of the same beam sizes, ranging over 5*5cm2 up to 20*20cm2 . Line profiles of each field were compared in both X and Y jaw directions. Each measurement was repeated on 2 different Clinac2100 machines. An inter-reader comparison of the beam width interpretation was completed using procedures commonly employed for beam to light field coincidence verification. Cherenkov measurements are also done for beams of complex treatment plan and isocenter QA. RESULTS: The Cherenkov image widths matched with the measured GaF images and light field images, with accuracy in the range of +/-1mm standard deviation. The differences between the measurements were minor and within tolerance of geometrical requirement of standard linac QA procedures conducted by human set up verification, which had a similar error range. The measurement made by the remote imaging system allowed for beam shape extraction of radiation fields at the SSD location of the beam. CONCLUSIONS: The proposed Cherenkov image acquisition system provides a valid way to remotely confirm radiation field sizes and provides similar information to that obtained from the linac light field or GaF film estimates of the beam size. The major benefit of this approach is that with a fixed installation of the camera, testing could be done completely under software control with automated image analysis, potentially simplifying conventional QA procedures with appropriate calibration of boundary definitions, and the natural extension to capturing dynamic treatment beamlets at SSD could have future value, such as verification of beam plans with complex beam shapes, like IMRT or "star-shot" QA for the isocenter. This article is protected by copyright. All rights reserved. PMID- 30471127 TI - Ultrasound assisted low-temperature drying of kiwifruit. Effects on drying kinetics, bioactive compounds and antioxidant activity. AB - BACKGROUND: Low-temperature drying is considered to be a promising technique for food processing which preserves thermolabile compounds and might be intensified by acoustic assistance. The effect of acoustic assistance (20.5 kW/m3 ) during low-temperature drying of kiwifruit (at 5, 10 and 15 degrees C, and 1 m/s) on drying kinetics, bioactive compounds (such as ascorbic acid, vitamin E and total polyphenols) and antioxidant activity, was studied. RESULTS: Drying time was shortened by a 55-65 % when using power ultrasound. A diffusion model was used to evaluate the drying kinetics. The effective diffusion coefficient increased by 154+/-30 % and the external mass transfer coefficient increased by 158+/-66 % when ultrasound was applied during drying, compared with drying without ultrasound application. With regard to bioactive compounds and antioxidant activity, although samples dried at 15 degrees C presented significantly higher (p<0.05) losses (39-54 % and 57-69 %, respectively) than samples dried at 5 degrees C (14-43 % and 23-50 %, respectively) when ultrasound was not applied, the application of ultrasound during drying at 15 degrees C significantly reduced (p<0.05) those losses in all quality parameters (15-47 % and 47-58 %, respectively). CONCLUSION: Overall, low-temperature drying of kiwifruit was enhanced by acoustic assistance preserving bioactive compounds and antioxidant activity, especially at 15 degrees C. This article is protected by copyright. All rights reserved. PMID- 30471128 TI - Role of arginine deiminase in thymus atrophy during experimental S. pyogenes infection. AB - Expression of gene of arginine deiminase (AD) allows adaptation of S. pyogenes to adverse environmental conditions. AD activity can lead to L-arginine deficiency in the host cells' microenvironment. Bioavailability of L-arginine is an important factor regulating the functions of the immune cells in mammals. By introducing a mutation into S. pyogenes M46-16 we obtained a strain with inactivated arcA/sagp gene (M49-16 delArcA), deficient in AD. This allowed elucidating the function of AD in pathogenesis of streptococcal infection. The virulence of the parental and mutant strains was examined in a murine model of subcutaneous streptococcal infection. L-arginine concentration in the plasma of mice infected with S. pyogenes M49-16 delArcA remained unchanged in course of the entire experiment. At the same time mice infected with S. pyogenes M49-16 demonstrated gradual diminution of L-arginine concentration in the blood plasma, which might be due to the activity of streptococcal AD. Mice infected with S. pyogenes M49-16 delArcA demonstrated less intensive bacterial growth in the primary foci and less pronounced bacterial dissemination as compared with animals infected with the parental strain S. pyogenes M46-16. Similarly, thymus involution, alterations in apoptosis, thymocyte subsets and Treg cells differentiation were less pronounced in mice infected with S. pyogenes M49-16 delArcA than in those infected with the parental strain. The results obtained showed that S. pyogenes M49-16 delArcA, unable to produce AD, had reduced virulence in comparison with the parental S. pyogenes M49-16 strain. AD is an important factor for the realization of the pathogenic potential of streptococci. This article is protected by copyright. All rights reserved. PMID- 30471129 TI - Learning-based CBCT Correction Using Alternating Random Forest Based on Auto context Model. AB - PURPOSE: Quantitative Cone Beam CT (CBCT) imaging is increasing in demand for precise image-guided radiotherapy because it provides a foundation for advanced image-guided techniques, including accurate treatment setup, online tumor delineation and patient dose calculation. However, CBCT is currently limited to patient setup only in the clinic because of the severe issues in its image quality. In this study, we develop a learning-based approach to improve CBCT's image quality for extended clinical applications. METHODS AND MATERIALS: An auto context model is integrated into a machine learning framework to iteratively generate corrected CBCT (CCBCT) with high image quality. The first step is data preprocessing for the built training dataset, in which uninformative image regions are removed, noise is reduced, and CT and CBCT images are aligned. After a CBCT image is divided into a set of patches, the most informative and salient anatomical features are extracted to train random forests. Within each patch, alternating random forest is applied to create a CCBCT patch as the output. Moreover, an iterative refinement strategy is exercised to enhance the image quality of corrected CBCT. Then, all the CCBCT patches are integrated to reconstruct final CCBCT images. RESULTS: The learning-based CBCT correction algorithm was evaluated using the leave-one-out cross-validation method applied on a cohort of 12 patients' brain data and 14 patients' pelvis data. The mean absolute error (MAE), peak signal-to-noise ratio (PSNR), normalized cross correlation (NCC) indexes and spatial non-uniformity (SNU) in the selected regions of interest (ROIs) were used to quantify the proposed algorithm's correction accuracy and generated the following results: mean MAE = 12.81+/-2.04 HU and 19.94+/-5.44 HU, mean PSNR = 40.22+/-3.70 dB and 31.31+/-2.85 dB, mean NCC = 0.98+/-0.02 and 0.95+/-0.01, and SNU = 2.07+/-3.36% and 2.07+/-3.36% for brain and pelvis data. CONCLUSION: Preliminary results demonstrated that the novel learning-based correction method can significantly improve CBCT image quality. Hence, the proposed algorithm is of great potential in improving CBCT's image quality to support its clinical utility in CBCT-guided adaptive radiotherapy. INDEX TERMS: CBCT correction, adaptive radiotherapy, alternating random forest, feature selection. This article is protected by copyright. All rights reserved. PMID- 30471130 TI - SMARTWOMANTM : FEASIBILITY ASSESSMENT OF A SMARTPHONE APP TO CONTROL CARDIOVASCULAR RISK FACTORS IN VULNERABLE DIABETIC WOMEN. AB - SMARTWOMANTM was designed to develop and assess the feasibility of a smartphone app to control cardiovascular risk factors in vulnerable diabetic women. Fourteen African American women with diabetes and without known cardiovascular disease were enrolled. A weight-scale, glucometer, sphygmomanometer, and FitBitTM were synchronized to the smartphone and text messaging was provided. Patients were able to follow instructions for app use and device prompts. Follow-up was 6 months. Weekly device reporting was 85% for blood glucose, 82.5% for daily steps, and 77% for systolic blood pressure. Patient engagement levels were 85-100% at 1 month and 50-78% at month 6. The majority reported text messages to be useful, easy to understand, and appropriate in frequency. The women indicated on the exit questionnaire that study participation increased their motivation and ability to take charge of their health. Use of a smartphone app to control cardiovascular risk factors appears feasible in a population of vulnerable indigent African American diabetic women, resulted in increased patient satisfaction and positive reinforcement to healthy behaviors, and warrants a larger clinical outcome trial. This article is protected by copyright. All rights reserved. PMID- 30471131 TI - A fast, linear Boltzmann transport equation solver for computed tomography dose calculation (Acuros CTD). AB - PURPOSE: To improve dose reporting of CT scans, patient-specific organ doses are highly desired. However, estimating the dose distribution in a fast and accurate manner remains challenging, despite advances in Monte Carlo methods. In this work, we present an alternative method that deterministically solves the linear Boltzmann transport equation (LBTE), which governs the behavior of x-ray photon transport through an object. METHODS: Our deterministic solver for CT dose (Acuros CTD) is based on the same approach used to estimate scatter in projection images of a CT scan (Acuros CTS). A deterministic method is used to compute photon fluence within the object, which is then converted to deposited energy by multiplying by known, material-specific conversion factors. To benchmark Acuros CTD, we used the AAPM Task Group 195 test for CT dose, which models an axial, fan beam scan (10 mm thick beam) and calculates energy deposited in each organ of an anthropomorphic phantom. We also validated our own Monte Carlo implementation of Geant4 to use as a reference to compare Acuros against for other common geometries like an axial, cone-beam scan (160 mm thick beam) and a helical scan (40 mm thick beam with table motion for a pitch of 1). RESULTS: For the fan-beam scan, Acuros CTD accurately estimated organ dose, with a maximum error of 2.7% and RMSE of 1.4% when excluding organs with < 0.1% of the total energy deposited. The cone-beam and helical scans yielded similar levels of accuracy compared to Geant4. Increasing the number of source positions beyond 18 or decreasing the voxel size below 5*5*5 mm3 provided marginal improvement to the accuracy for the cone-beam scan but came at the expense of increased run time. Across the different scan geometries, run time of Acuros CTD ranged from 8 to 23 seconds. CONCLUSIONS: In this digital phantom study, a deterministic LBTE solver was capable of fast and accurate organ dose estimates. This article is protected by copyright. All rights reserved. PMID- 30471132 TI - Pulmonary metastasis of mesonephric-like adenocarcinoma arising from the uterine body: a striking mimicry of follicular thyroid carcinoma. AB - Mesonephric adenocarcinoma (MNAC) is a rare neoplasm that presumably develops from the mesonephric remnants, occurring mostly in the uterine cervix and, to a lesser extent, the vagina, uterine body, ovary, and para-adnexal soft tissues. Histologically, MNAC exhibits a variety of architectural growth patterns, even within the same tumour, including tubular, glandular, papillary, solid, and retiform, and therefore may be confused with more common carcinomas of Mullerian origin. Moreover, the tubules with luminal eosinophilic secretions, a common characteristic of MNACs, may result in consideration of thyroidal carcinoma when tumours spread beyond the pelvis. Immunohistochemistry can identify the mesonephric nature of the tumour, that is, negative for hormone receptors and positive for CD10, calretinin, and GATA binding protein 3 (GATA3) in variable degrees This article is protected by copyright. All rights reserved. PMID- 30471133 TI - The inhibition mechanism of epsilon-Polylysine against Bacillus cereus emerging in surimi gel during refrigerated storage. AB - BACKGROUND: Refrigeration is a common method in the process and storage of surimi products. However, refrigerated surimi products are susceptible to microbial contamination, that lead to deterioration of products and shorten the shelf life. Therefore, the aims of the present study were to evaluate the effects of epsilon polylysine (epsilon-PL) on spoilage bacteria in surimi products, and to investigate the antibacterial mechanism of Bacillus cereus, which is the dominant bacterium in spoilage bacteria. RESULTS: A high degree of polymerization (20~30K) epsilon-PL proved able to decrease the total colonies number in surimi products and showed an obvious antibacterial effect against B. cereus. After epsilon-PL treatments, the distinct broken areas on the bacterial surfaces and the aggregations of cells were observed by scanning electron microscope (SEM). The intracellular materials such as small molecules, soluble proteins and deoxyribonucleic acids in the cells were analyzed, which revealed the destructive effects of epsilon-PL on bacterial cells. Experiments with propidium iodide (PI) infiltration experiments verified that the permeability of cell membranes was enhanced by epsilon-PL treatment. CONCLUSION: These results indicated that epsilon-PL could destroy the cell membranes and change the permeability of B. cereus, and subsequently the cell contents leaked out to achieve antibacterial effects. This article is protected by copyright. All rights reserved. PMID- 30471134 TI - Clinical and Translational Pharmacological Aspects of the Management of Fibrous Dysplasia of Bone. AB - Fibrous dysplasia (FD) is a genetic, non-inheritable rare bone disease caused by a post-zygotic activating mutation of the alpha subunit of the stimulatory G protein (Galphas) causing increased abnormal bone formation leading to pain, deformity and fractures. To date, no cure has been identified for FD/MAS and treatment is symptomatic and aimed at decreasing pain and/or local bone turnover. Various drugs have been used to achieve clinical improvement in FD/MAS patients including bisphosphonates and denosumab, however further translational studies are also warranted to address unresolved pathophysiological issues and explore novel pharmacological targets for the management of FD/MAS. In this article, we review literature on the medical treatment of FD/MAS, discuss the unresolved pathophysiological issues and explore novel pharmacological targets for the management of FD/MAS. PMID- 30471135 TI - Intravenous single administration of amiodarone and breastfeeding. AB - Amiodarone treatment is contraindicated during breastfeeding. As the regional pharmacovigilance center, we were contacted for information relative to the possibility of breastfeeding after single intravenous administration of 450 mg amiodarone to a breastfeeding woman. A monitoring of amiodarone concentration in plasma and milk was performed in the mother. At day 4, milk concentration of amiodarone reached a peak (233 MUg/L) and milk to plasma ratio was determined to 3.5. Milk concentration was still detectable at day 10 (132 MUg/L). The maximal relative infant dose was estimated to be 0.6% of the maternal weight-adjusted dosage, corresponding to 0.18% of the usual posology used in children by parenteral route. The review of the literature retrieved one publication suggesting that a single intravenous administration of 150 mg of amiodarone to a mother represents a negligible infant risk based on low breast milk concentration. The French National Pharmacovigilance database query did not disclose any case of side effects during breastfeeding after a single dose of amiodarone. A very limited exposition of breastfed newborns to amiodarone, as well as a low risk of side effects, is expected after a single administration of amiodarone to their mothers. This article is protected by copyright. All rights reserved. PMID- 30471136 TI - Diagnosis and treatment of alcohol use disorder in patients with end-stage alcoholic liver disease. AB - Almost 14-30% of the world's population is affected by alcohol use disorder (AUD), and excessive alcohol consumption represents the most common cause of liver disease in the western world. The clinical picture of alcoholic end-stage liver disease is rendered extremely complex as manifestations such as alcohol withdrawal syndrome, craving and physical dependence, as well as extrahepatic alcohol-related diseases merge with the complications of advanced cirrhosis. This makes AUD recognition and assessment difficult and its management arduous as many drugs commonly employed to treat complications such as alcohol withdrawal syndrome are often contraindicated by the presence of hepatic encephalopathy or hepatorenal syndrome. Reaching and maintaining abstinence represent the mainstay of managing patients with AUD and end-stage liver disease. Psychosocial interventions are an essential component of treatment to reach these goals. However, these interventions alone often prove insufficient in AUD patients and even more frequently in those with end-stage liver disease because of inadequate adherence due to poor functional and physical status. Thus, pharmacological treatments need to be associated, but the available options are greatly limited in end-stage liver disease because many GABA-ergic drugs can favor the development of hepatic encephalopathy, while drugs undergoing extensive liver metabolism should be avoided or used with the greatest caution. Because of these limitations, the management of end-stage AUD is extremely challenging and requires an integrated multidisciplinary approach. This article is protected by copyright. All rights reserved. PMID- 30471137 TI - How does Toxoplasmosis affect the maternal-fetal immune interface and pregnancy? AB - Toxoplasma gondii is a zoonotic parasite which, depending on the geographical location, can infect between 10 to 90% of humans. Infection during pregnancy may result in congenital toxoplasmosis. The effects on the fetus vary depending on the stage of gestation in which primary maternal infection arises. A large body of research has focused on understanding immune response to toxoplasmosis, although few studies have addressed how it is affected by pregnancy or the pathological consequences of infection at the maternal-fetal interface. There is a lack of knowledge about how maternal immune cells, specifically macrophages are modulated during infection and the resulting consequences for parasite control and pathology. Herein, we discuss the potential of T. gondii infection to affect the maternal-fetal interface and the potential of pregnancy to disrupt maternal immunity to T. gondii infection. This article is protected by copyright. All rights reserved. PMID- 30471138 TI - Pharmacogenetics of artemether-lumefantrine influence on nevirapine disposition: clinically significant drug-drug interaction? AB - AIMS: In this study the influence of first-line antimalarial drug artemether lumefantrine on the pharmacokinetics of the antiretroviral drug nevirapine was investigated in the context of selected single nucleotide polymorphisms (SNPs) in a cohort of adult HIV-infected Nigerian patients. METHODS: This was a two-period, single sequence crossover study conducted in two stages. In stage 1, 150 HIV infected patients receiving nevirapine-based antiretroviral regimens were enrolled and genotyped for 7 SNPs. Sparse pharmacokinetic sampling was conducted to identify SNPs independently associated with nevirapine plasma concentration. Patients were categorised as poor, intermediate and extensive metabolisers based on the numbers of alleles of significantly associated SNPs. Intensive sampling was conducted in selected patients from each group. In stage 2, patients received standard artemether-lumefantrine treatment with nevirapine and intensive pharmacokinetic sampling was conducted on day 3. RESULTS: No clinically significant changes were observed in key nevirapine pharmacokinetic parameters, the 90% confidence interval for the measured changes falling completely within the 0.80-1.25 no-effect boundaries. However, the number of patients with trough plasma nevirapine concentration below the 3,400 ng ml-1 minimum effective concentration increased from 10% without artemether-lumefantrine (all extensive metabolisers) to 21% with artemether-lumefantrine (14% extensive, 4% intermediate, and 3% poor metabolisers). CONCLUSIONS: This approach highlights additional increase in the already existing risk of suboptimal trough plasma concentration, especially in extensive metabolisers when nevirapine is co administered with artemether-lumefantrine. PMID- 30471139 TI - Perspectives on shared reading among a sample of Latino parents. AB - BACKGROUND: Pediatric professionals promote shared reading to facilitate school readiness yet relatively few studies examine how parents from underserved communities consider this issue in their daily lives. We sought to understand shared reading within the broader context of parenting among Latino parents. METHODS: We conducted in-depth interviews, purposively sampling Spanish-speaking, Latina mothers of children age <= 3 years from an urban Federally Qualified Health Center. Interviews were recorded, transcribed, and analyzed iteratively. We allowed themes to emerge from data rather than impose an a priori framework. We sought disconfirming evidence within interviews and collected additional data to ensure no new themes were identified (saturation). RESULTS: We achieved saturation after 12 interviews. The median child age was 1.4 years. We identified 4 major themes: (1) All participants reported engaging in literacy promoting activities such as conversations, storytelling, play, and singing even if they did not read to their children daily. (2) Parents' attitudes regarding early learning and development influenced the extent to which parents engaged in shared reading with their child. (3) Participants described feelings that they ought to read daily with their children but were not and cited a variety of barriers. (4) Parents who engaged in frequent shared reading described it as a joyful and relaxed experience; parents who did not engage in shared reading described reading as instructing children or engaging in drills (e.g. teaching letters). CONCLUSION: Urban, Latina mothers who did not read regularly with their children nonetheless recognized its importance suggesting that existing programs have raised awareness even among underserved families. Refinement of messaging may be needed to move past raising awareness to facilitating shared reading for some parents. PMID- 30471140 TI - The efficiency of acoustic radiation force impulse imaging for the staging of graft fibrosis after liver transplantation. AB - AIM: Liver biopsy is the gold standard for assessing liver fibrosis (LF) after liver transplantation (LT), but its invasiveness limits its utility. This study aimed to evaluate the usefulness of liver stiffness measurement (LSM) via acoustic radiation force impulse (ARFI) imaging to assess LF after LT. METHODS: Between September 2013 and January 2017, 278 patients who underwent liver biopsy after LT in Kyoto University Hospital were prospectively enrolled. Liver stiffness measurement was performed via ARFI imaging; its value was expressed as shear wave velocity (Vs) [m/s]. The LF was evaluated according to the METAVIR scores (F0-F4). The diagnostic performance of Vs for F2<= and F3<= was assessed and compared with that of laboratory tests using receiver operating characteristic (ROC) analysis. RESULTS: The median Vs values increased according to the progression of LF (F0: 1.18+/-0.27, F1: 1.35+/-0.42, F2: 1.55+/-0.54, F3: 1.84+/-0.50). The Vs had the highest area under the ROC curve (AUROC) for the prediction of both F2<= and F3<= fibrosis (F2: 0.77 and F3: 0.85). With the cut off value of Vs >1.31, sensitivity, specificity, positive predictive value, and negative predictive value were 89.4%, 53.3%, 37.3%, and 94.2% in predicting F2<=, respectively. Vs diagnosed LF better than any laboratory tests regardless of the type of primary disease. CONCLUSIONS: ARFI helps assess graft LF after LT. The high sensitivity suggested that ARFI may reduce the frequency of liver biopsies by detecting patients who are unlikely to have significant fibrosis after liver transplantation. (Unique trial number: UMIN R000028296). PMID- 30471141 TI - N-acetylcysteine prevents glutathione decrease and does not interfere with paracetamol antinociceptive effect at therapeutic dosage: a randomized double blind controlled trial in healthy subjects. AB - Paracetamol (APAP) may lead to hepatic changes even at therapeutic dosages. Glutathione (GSH) plays a pivotal role in APAP metabolism as it allows the detoxification of a toxic metabolite. N-Acetylcysteine (NAC) is APAP antidote, is also largely used as a mucoactive drug and is often associated with APAP. This study aims at evaluating if 1- NAC modifies APAP pain efficacy and 2- NAC prevents glutathione depletion with APAP at therapeutic doses. This double-blind randomized controlled study (NCT02206178) was carried out in 24 healthy volunteers. APAP was given for 4 days (1 gram x4 daily) with NAC or with placebo. Thermal pain tests, whole blood GSH and hepatic enzymes (ASAT, ALAT) were measured before (D0) and after (D4) oral APAP-NAC or APAP-placebo intake. ANOVA for repeated measures adapted to cross-overdesign was performed and a two-tailed type I error was fixed at 5%. The primary endpoint was the area under the curve (0-240min) of pain intensity (Numerical Scale) after thermal pain stimulation using Pathway-Medoc(r) . APAP antinociceptive effect was similar in both groups. GSH was maintained to its baseline value in the APAP/NAC group but diminished in the APAP/placebo group (p=0.033). This study shows for the first time that APAP antinociceptive effectiveness is not influenced by NAC. It also shows that the effect of APAP at therapeutic dosage on GSH may be counteracted by NAC. These issues are particularly important for patients as APAP is often prescribed for years as a first-line pain treatment and further trials in patients are now warranted. This article is protected by copyright. All rights reserved. PMID- 30471142 TI - Coriander essential oil and linalool - interactions with antibiotics against Gram positive and Gram-negative bacteria. AB - The aim of this study was to evaluate the antibacterial activity of coriander essential oil and its major constituent, linalool, in combination with antibiotics against Gram-positive (methicillin-susceptible and methicillin resistant Staphylococcus aureus, Staph. epidermidis) and Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli). The chemical composition of coriander essential oil was analyzed by gas chromatography with flame ionization and mass spectrometry detection. The antibacterial activity of coriander essential oil, linalool and their combinations with antibiotics were assessed by the broth microdilution and checkerboard assays, respectively. Thirty-four compounds were identified in coriander essential oil, linalool (70.11%) being predominant. Coriander essential oil and linalool showed synergistic interactions with antibiotics (oxacillin, amoxicillin, gentamicin, ciprofloxacin, tetracycline) against both Gram-positive and Gram-negative bacteria. In these synergistic combinations, minimum inhibitory concentrations of antibiotics were markedly reduced; even antibiotic resistance reversal activity was recorded. These findings are very promising for the development of new therapeutic options for bacterial infections. This article is protected by copyright. All rights reserved. PMID- 30471143 TI - A comparison of two ketamine doses for field anaesthesia in horses undergoing castration. AB - BACKGROUND: Ketamine at 2.2 mg/kg given i.v. is often used to induce anaesthesia for surgical procedures in horses under field conditions. Commonly, additional doses are needed to complete the surgery. We hypothesised that surgical conditions would be improved when 5 mg/kg of ketamine was used to induce anaesthesia, while induction and recovery qualities would not differ from those when 2.2 mg/kg ketamine was used. OBJECTIVE: To compare the anaesthetic effects of two ketamine doses (5 mg/kg and 2.2 mg/kg) during field anaesthesia for castration of horses. STUDY DESIGN: Prospective, randomised, blinded, clinical study. METHOD: Seventy-seven client-owned Icelandic horses presenting for castration under field conditions were studied. Pre-anaesthetic medication was xylazine (0.7 mg/kg) butorphanol (25 MUg/kg) and acepromazine (50 MUg/kg) injected i.v. Anaesthesia was induced with either 2.2 mg/kg (K2.2) or 5 mg/kg (K5) i.v. of ketamine mixed with diazepam (30 MUg/kg). The quality of induction, surgical conditions and recovery were compared using subjective and objective measures, and the number of additional ketamine doses recorded. RESULTS: Ketamine 5 mg/kg provided better surgical conditions and a more rapid induction. Recovery quality was subjectively better in K2.2. Five horses in K2.2 and two in K5 required additional ketamine doses. MAIN LIMITATIONS: While the pre-anaesthetic sedation and benzodiazepine doses were consistent among horses, the level of sedation and muscle relaxation achieved before induction differed. CONCLUSION: A ketamine dose of 5 mg/kg can be used to improve the quality of field anaesthesia for castration in Icelandic horses. Although recovery quality is subjectively poorer with this dose, no adverse events were observed during recovery. This article is protected by copyright. All rights reserved. PMID- 30471144 TI - Sirt5 is dispensable for BrafV600E -mediated cutaneous melanoma development and growth in vivo. AB - Sirt5 is known to functionally regulate mitochondrial proteins by altering posttranslational modifications, including lysine desuccinylation. While roles for Sirt5 as either a tumor promoter or suppressor, or in chemoresistance, have been implicated in other cancers, the function of Sirt5 in cutaneous melanoma has not been well examined. Therefore, to determine whether Sirt5 is necessary for BrafV600E -mediated melanoma formation and/or disease progression, we crossed a genetically engineered murine melanoma model (TyrCre ERT 2/+ ; BrafLSL -V600E/+ ; Ptenflox/flox ) to Sirt5-/- knockout animals. In addition, we tested for synergism with a selective BRAF (V600E) inhibitor in Sirt5-/- mouse melanoma cells. Taken together, this report demonstrates that, in these models, Sirt5 is dispensable for BrafV600E -mediated cutaneous melanoma formation and growth in vivo, and does not improve sensitivity to a selective BRAF inhibitor. This article is protected by copyright. All rights reserved. PMID- 30471145 TI - Gram Scale Synthesis of Isolated Monodisperse Gold Nanorods. AB - While the gold nanorods (AuNRs) possess unique properties, the scale-up synthesis of isolated AuNRs in gram quantity remains a challenge. Nearly all previously reported methods produce aqueous solutions of CTAB-coated AuNRs in milligram quantities with the yield of ~20-30 %. This report describes the synthesis of monodisperse functionalized AuNRs (sigma~5%) in gram quantities. Our approach is to increase the concentration of HAuCl4.3H20 in the growth solution to produce larger quantities of starting AuNRs and further reduce the remaining Au (I) ions onto the surface of AuNRs. The slow and controlled addition of reducing agent ascorbic acid (AA) continues the conversion of Au (I) to Au (0) (via disproportionation reaction) onto the surface of nanorods maintaining their uniform morphology without creating any unwanted impurities of various shapes. In addition, this approach significantly narrows the size distribution due to the continuous growth of partially grown AuNRs during the initial stage of the synthesis. To isolate one-gram quantity of AuNRs and make them functionalized for further chemical reactions, a ligand exchange approach was utilized where surfactant CTAB was replaced with 4-mercaptophenol. The thiol group from 4 mercaptophenol forms a covalent bond to the surface of AuNRs leaving free functional OH groups available for further chemical coupling reactions. PMID- 30471146 TI - Identifying key needs for the integration of social-ecological outcomes in arctic wildlife monitoring. AB - For effective monitoring in social-ecological systems to meet needs for biodiversity, science, and humans, desired outcomes must be clearly defined and routes from direct to derived outcomes understood. The Arctic is undergoing rapid climatic, ecological, social, and economic changes and requires effective wildlife monitoring to meet diverse stakeholder needs. To identify stakeholder priorities concerning desired outcomes of arctic wildlife monitoring, we conducted in-depth interviews with 29 arctic scientists, policy and decision makers, and representatives of Indigenous organizations and NGOs. Using qualitative content analysis, we identified and defined desired outcomes and documented links between outcomes. Using network analysis, we investigated the structure of perceived links between desired outcomes. We identified 18 desired outcomes from monitoring and classified them as either driven by monitoring information, monitoring process, or a combination of both. Highly cited outcomes were make decisions, conserve, detect change, disseminate, and secure food. These reflect key foci of arctic monitoring. Infrequently cited outcomes (e.g., govern) were emerging themes. Three modules comprised our outcome network. The modularity highlighted the low strength of perceived links between outcomes that were information driven or primarily information driven (e.g., detect change, make decisions, conserve or secure food) and process driven and derived outcomes (e.g., cooperate, learn, educate). The outcomes expand monitoring community and disseminate created connections between these modules. We identified key desired outcomes from monitoring that are widely applicable to social-ecological systems within and outside the Arctic, particularly those with wildlife subsistence economies. Attributes and motivations associated with outcomes can guide future development of integrated monitoring goals for biodiversity conservation and human needs. Our results demonstrate the disconnect between information and process driven goals and how expanding the monitoring community and better integrating monitoring stakeholders will help connect information derived and process derived outcomes for effective ecosystem stewardship. This article is protected by copyright. All rights reserved. PMID- 30471147 TI - Reduced Late Mismatch Negativity and Auditory Sustained Potential to Rule-Based Patterns in Schizophrenia. AB - Complex rule-based auditory processing is abnormal in individuals with long-term schizophrenia (SZ), as demonstrated by reduced mismatch negativity (MMN) to deviants in rule-based patterns and reduced auditory sustained potential (ASP) that appears when grouping tones together. Together this suggests deficits later in the auditory processing hierarchy in Sz. Here, MMN and ASP were elicited by deviations from a complex zig-zag pitch pattern that cannot be predicted by simple linear rules. Twenty-seven SZ and 26 matched healthy controls (HC) participated. Frequent groups of patterns contained eight tones that zig-zagged in a two-up one-down pitch-based paradigm. There were two deviant patterns: the final tone was either higher in pitch than expected (creating a jump in pitch) or was repeated. Simple MMN to pitch-deviants among repetitive tones was measured for comparison. Sz exhibited a smaller pitch MMN compared to HC as expected. HC produced a late MMN in response to the repeat and jump-deviant and a larger ASP to the standard group of tones, all of which were significantly blunted in SZ. In Sz, the amplitude of the late complex MMN was related to neuropsychological functioning, whereas ASP was not. ASP and late MMN did not significantly correlate in HC or in Sz, suggesting that they are not dependent on one another and may originate within distinct processing streams. Together this suggests multiple deficits later in the auditory sensory-perceptual hierarchy in Sz, with impairments evident in both segmentation and deviance detection abilities. This article is protected by copyright. All rights reserved. PMID- 30471148 TI - Efficacy of the GMALL-B-ALL/NHL2002 Protocol in Burkitt Leukaemia/Lymphoma and Aggressive Non-Hodgkin-Lymphomas with or without CNS-Involvement. AB - OBJECTIVES: The GMALL-B-ALL/NHL2002 protocol is effective in Burkitt lymphoma/leukaemia (BL). Its role in other aggressive lymphomas and in patients with simultaneous central nervous system (CNS) and peripheral involvement is unclear. METHODS: This is a retrospective outcome analysis in 76 patients with BL (n=26), B-lymphoblastic lymphoma (B-LBL; n=3), diffuse large B-cell lymphoma (DLBCL; n=31), mantle-cell lymphoma (MCL; n=6), transformed B-cell non-Hodgkin lymphomas (tB-NHL; n=7) and T-cell NHL (T-NHL; n=3) treated with the GMALL-B ALL/NHL2002 protocol. RESULTS: 73.1% of scheduled chemotherapy cycles were administered. Treatment was discontinued in 38 patients (50.0%) due to progression (n=14), toxicities (n=11), scheduled treatment change (n=6) and unknown reasons (n=7). All BL/B-LBL patients were treated first-line and at a median follow-up of 124.7 months median progression free survival was not reached. In DLBCL, median PFS was 68.4 months in first-line treated patients and 3.7 months in relapsed/refractory patients. CNS involvement was present in 10 non BL/B-LBL cases and did not have a negative impact on survival in first-line treated patients but was fatal in all relapsed/refractory patients. CONCLUSION: This study confirmed the activity of the GMALL-B-ALL/NHL2002 protocol in BL/B LBL. It was also effective in first-line treated non-BL/B-LBL lymphomas with and without simultaneous CNS-/peripheral involvement, but ineffective in relapsed/refractory disease. This article is protected by copyright. All rights reserved. PMID- 30471149 TI - Financial gain- and loss-related BOLD signals in the human ventral tegmental area and substantia nigra pars compacta. AB - Neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) play central roles in reward-related behaviours. Non-human animal studies suggest that these neurons also process aversive events. However, our understanding of how the human VTA and SNC responds to such events is limited and has been hindered by the technical challenge of using fMRI (functional magnetic resonance imaging) to investigate a small structure where the signal is particularly vulnerable to physiological noise. Here we show, using methods optimised specifically for the midbrain (including high resolution imaging, a novel registration protocol, and physiological noise modelling), a BOLD (blood oxygen level dependent) signal to both financial gain and loss in the VTA and SNC, along with a response to nil outcomes that are better or worse than expected in the VTA. Taken together, these findings suggest that the human VTA and SNC are involved in the processing of both appetitive and aversive financial outcomes in humans. This article is protected by copyright. All rights reserved. PMID- 30471150 TI - Stable (BIII-Subporphyrin-5-yl)dicyanomethyl Radicals. AB - Stable BIII-subporphyrin-substituted dicyanomethyl radicals were synthesized by SNAr reaction of meso-bromo or meso-chlorosubporphyrins with malononitrile followed by oxidation with PbO2. Different from previously reported dicyanomethyl radicals that underwent sigma- or pi-dimer formation both in the solid state and in solutions, subporphyrin-stabilized dicyanomethyl radicals exist as monomers in solutions even at low temperature. DFT calculations revealed efficient spin delocalization over the whole subporphyrin. In the solid state, these radicals form weak pi-dimers with antimagnetic interactions depending on the crystal packing structures. PMID- 30471151 TI - Posterior open-wedge anterior longitudinal ligament release (POWAR): cadaveric technique analysis. AB - INTRODUCTION: Anterior column release is a powerful surgical technique for achieving spinopelvic balance in adult patients with sagittal plane deformities. We present an alternative strategy for focal deformity correction from a posterior-only approach. The purpose of this study was to evaluate the feasibility and efficacy of a novel surgical technique called posterior open wedge diskectomy and anterior longitudinal ligament (ALL) release (POWAR). MATERIALS AND METHODS: A cadaveric torso underwent POWARs at the L1-L4 intervertebral disc spaces. Baseline measurements of end-plate angle (EPA), anterior intervertebral disc height (ADH), and posterior intervertebral disc height (PDH) were obtained. These measurements were repeated after three stages of correction: posterior column compression alone, posterior column compression following Schwab grade 2 osteotomies, and posterior column compression following POWAR. A second cadaver underwent posterolateral spinal dissection to demonstrate the pertinent anatomical features relevant to this novel procedure. RESULTS: With each stage of correction, a sequential increase in EPA and ADH and a decrease in PDH were demonstrated. The large increase in ADH seen following POWAR confirmed successful release of the ALL. In situ investigation of the aorta and inferior vena cava following anterior exposure revealed no injury to the great vessels or surrounding structures. Ex vivo testing of the aorta and inferior vena cava took place at the L3-4 level. This testing demonstrated no injury or tears to either vessel. CONCLUSIONS: POWAR is a new surgical technique that can provide an alternative to three-column osteotomy for surgeons performing spinal reconstructions in adults through an open, posterior-only approach. This article is protected by copyright. All rights reserved. PMID- 30471152 TI - Transient c-Src suppression during endodermal commitment of human iPSCs results in abnormal profibrotic cholangiocyte-like cells. AB - Directed differentiation of human induced pluripotent stem cells (iPSCs) toward hepatobiliary lineages has been increasingly used as models of human liver development/diseases. As protein kinases are important components of signaling pathways regulating cell fate changes, we sought to define the key molecular mediators regulating human liver development using inhibitors targeting tyrosine kinases during hepatic differentiation of human iPSCs. A library of tyrosine kinase inhibitors was used for initial screening during the multi-stage differentiation of human iPSCs to hepatic lineage. Among the 80 kinase inhibitors tested, only Src inhibitors suppressed endoderm formation while none had significant effect on later stages of hepatic differentiation. Transient inhibition of c-Src during endodermal induction of human iPSCs reduced endodermal commitment and expression of endodermal markers including SOX17 and FOXA2 in a dose dependent manner. Interestingly, the transiently treated cells later developed into profibrogenic cholangiocyte-like cells expressing both cholangiocyte markers such as CK7 and CK19 and fibrosis markers including Collagen1 and SMA. Further analysis of these cells revealed co-localized expression of collagen and YAP (a marker associated with bile duct proliferation/fibrosis), and an increased production of IL-6 and TNF-alpha. Moreover, treatment with verteporfin, a YAP inhibitor, significantly reduced expression of fibrosis markers. In summary, these results suggest that c-Src has a critical role in cell fate determination during endodermal commitment of human iPSCs, and its alteration in early liver development in human may lead to increased production of abnormal YAP expressing profibrogenic proinflammatory cholangiocytes, similar to those seen in livers of patients with biliary fibrosis. SIGNIFICANCE STATEMENT: Using human iPSCs, we discovered that a protein kinase c-Src is important for endoderm formation and that a transient alteration of its activity in the early stage of liver development results in abnormal fibrotic-biliary cells resembling those observed in patients with biliary fibrosis. Since it is not feasible to study early endoderm formation in human fetus, this study provides a basis for establishing human-specific experimental systems for studying abnormal liver development which may potentially associated with liver fibrosis and cirrhosis. (c) AlphaMed Press 2018. PMID- 30471153 TI - Mg-dechelatase is involved in the formation of photosystem II but not in chlorophyll degradation in Chlamydomonas reinhardtii. AB - The STAY-GREEN (SGR) gene encodes a Mg-dechelatase that catalyzes the conversion of chlorophyll (Chl) a to pheophytin (Pheo) a. This reaction is the first and most important regulatory step in the chlorophyll degradation pathway. Conversely, Pheo a is an indispensable molecule in photosystem (PS) II, suggesting the involvement of SGR in the formation of PSII. To investigate the physiological functions of SGR, we isolated Chlamydomonas sgr mutants by screening an insertion-mutant library. The sgr mutants had reduced maximum quantum efficiency of PSII (Fv/Fm) and reduced Pheo a levels. These phenotypes were complemented by the introduction of the Chlamydomonas SGR gene. Blue-native polyacrylamide gel electrophoresis and immunoblotting analysis showed that although PSII levels were reduced in the sgr mutants, PSI and light-harvesting Chl a/b complex levels were unaffected. Under nitrogen starvation conditions, Chl degradation proceeded in the sgr mutants as in wild type, indicating that Chlamydomonas SGR is not required for Chl degradation and primarily contributes to the formation of PSII. In contrast, in the Arabidopsis sgr triple mutant (sgr1 sgr2 sgrL), which completely lacks SGR activity, PSII was synthesized normally. These results suggest that the Arabidopsis SGR participates in Chl degradation, while the Chlamydomonas SGR participates in PSII formation in spite of the same catalytic property. This article is protected by copyright. All rights reserved. PMID- 30471154 TI - LmCDA1 organizes the cuticle by chitin deacetylation in Locusta migratoria. AB - Cells produce an extracellular matrix (ECM) with a stereotypic organization that is important for tissue function. The insect cuticle is a layered ECM that mainly consists of the polysaccharide chitin and associated proteins adopting a quasi crystalline structure. Our understanding of the molecular mechanisms deployed during construction of the highly ordered protein-chitin ECM so far is limited. In this study, we report on the role of the chitin deacetylase LmCDA1 in the organization of the protein-chitin ECM in the migratory locust Locusta migratoria. LmCDA1 localizes predominantly to the apical tier of the protein chitin ECM, but is also found in lower regions. Reduction of LmCDA1 function correlates with lower amounts of chitin and impedes conversion of chitin to chitosan by deacetylation. Establishment of the quasi-crystalline architecture of the protein-chitin ECM is, however, independent of LmCDA1 activity, but dependent on another chitin deacetylase, LmCDA2, which has no detectable effects on chitin deacetylation and, as shown previously, no influence on chitin content. Our data reveal that LmCDA1 and LmCDA2 act in parallel and independently from each other in defining the dimensions of the cuticle. Both enzymes are non-uniformly distributed within the protein-chitin matrix suggesting a site-autonomous function. This article is protected by copyright. All rights reserved. PMID- 30471155 TI - Screening system for EGFR mutation detection in cytology cell-free DNA of cerebrospinal fluid based on assured sample quality. AB - BACKGROUND: The cobas(r) EGFR Mutation Test v2 designed for cell-free DNA (cfDNA) is approved as a companion diagnostic for osimertinib therapy. The aim of this study was to evaluate the concordance of EGFR mutation detection between paired primary or recurrent samples, and cerebrospinal fluid (CSF) cytology samples of lung cancer patients. METHODS: A total of 26 lung cancer patients with supernatant cytology cfDNA in CSF was analyzed for EGFR mutations using the cobas(r) EGFR Mutation Test v2.0 designed for cfDNA, and the concordance rates between CSF cfDNA and primary or recurrent samples were investigated. RESULTS: Of the 26 CSF cytology cfDNA samples, 46.1% (12/26) were valid and 53.9% (14/26) were invalid. Sensitivity, specificity and accuracy between the valid CSF cfDNA samples and primary or recurrent samples for detection of EGFR mutation, including T790M were 87.5%, 100.0% and 91.7%, respectively. Amounts of both inflammatory cells and tumor cells in CSF cytology were higher in the valid evaluation samples than in the invalid samples (p<0.05), and mutant EGFR was detected in 80.0% (4/5) of the valid CSF cytology cfDNA samples with a negative cytology diagnosis. CONCLUSIONS: The cobas(r) EGFR Mutation Test v2.0 can accurately detect EGFR mutations, including T790M, from supernatant cfDNA of CSF cytology samples. Utilization of supernatant cytology cfDNA in CSF will allow us to perform both EGFR mutation analysis and cytopathological diagnosis at the same time. This represents a new role of cytology in patient treatment, based on assured sample quality. This article is protected by copyright. All rights reserved. PMID- 30471157 TI - Insulin in the ventral tegmental area reduces cocaine-evoked dopamine in the nucleus accumbens in vivo. AB - Mesolimbic dopamine circuits, implicated in incentive motivation, are sensitive to changes in metabolic state such as weight loss and diet-induced obesity. These neurons are important targets for metabolic hormones such as leptin, glucagon like peptide-1, ghrelin and insulin. Insulin receptors are located on dopamine neurons in the ventral tegmental area (VTA) and we have previously demonstrated that insulin induces long-term depression of excitatory synapses onto VTA dopamine neurons. While insulin can decrease dopamine concentration in somatodendritic regions, it can increase dopamine in striatal slices. Whether insulin directly targets the VTA to alter dopamine release in projection areas, such as the nucleus accumbens (NAc), remains unknown. The main goal of the present experiments was to examine NAc dopamine concentration following VTA administration of insulin. Using in-vivo fast-scan cyclic voltammetry (FSCV) to detect rapid fluctuations in dopamine concentration, we showed that intra-VTA insulin via action at insulin receptors reduced pedunculopontine nucleus (PPTg) evoked dopamine release in the NAc. Furthermore, intra-VTA insulin reduced cocaine-potentiated NAc dopamine. Finally, intra-VTA or intranasal insulin decreased locomotor responses to cocaine, an effect blocked by an intra-VTA administered insulin receptor antagonist. Together, these data demonstrate that mesolimbic dopaminergic projections are important targets of the metabolic hormone, insulin. This article is protected by copyright. All rights reserved. PMID- 30471156 TI - Child and Adolescent Psychiatry in the Far East; a 5-year follow up on the Consortium on Academic Child and Adolescent Psychiatry in the Far East (CACAP-FE) study. AB - AIM: Data pertaining to Child and Adolescent Psychiatry (CAP) training systems are limited as extant research was mostly derived from a one-time data collection. This 5-year follow-up survey collects updated information on CAP training systems in the Far East, allowing for the tracking of system changes over the past 5 years. METHODS: Data were obtained from 18 countries, or functionally self-governing areas, in the Far East, 17 of which were also included in the original study. An online questionnaire was completed by leading CAP professionals in each country. Questions were expanded in the present study to capture the contents of CAP training. RESULTS: When compared to data from the original study, there has been progress in CAP training systems in the last 5 years. Specifically, there was an increase in the number of countries having CAP training programs and national guidelines for the training. In addition, the number of CAP departments/divisions affiliated with academic institutions/universities increased. Findings from 12 of 18 countries in the present study provided data on clinical contents. All informants of the present study reported the need for more child and adolescent psychiatrists and allied professionals. CONCLUSIONS: Despite progress in CAP training systems over the last 5 years, needs for more workforce in child and adolescent mental health care in all the relevant areas in this region have yet to be adequately addressed. Continued national efforts and international collaborations are imperative to develop and sustain new CAP training systems while facilitating improvements in existing programs. This article is protected by copyright. All rights reserved. PMID- 30471158 TI - The population genomics of multiple tsetse fly (Glossina fuscipes fuscipes) admixture zones in Uganda. AB - Understanding the mechanisms that enforce, maintain, or reverse the process of speciation is an important challenge in evolutionary biology. This study investigates the patterns of divergence and discusses the processes that form and maintain divergent lineages of the tsetse fly Glossina fuscipes fuscipes in Uganda. We sampled 251 flies from 18 sites spanning known genetic lineages and the four admixture zones between them. We apply population genomics, hybrid zone, and approximate Bayesian computation to the analysis of three types of genetic markers: 55,267 double digest restriction-site associated DNA (ddRAD) SNPs to assess genome wide admixture, 16 microsatellites to provide continuity with published data and accurate biogeographic modeling, and a 491 bp fragment of mitochondrial cytochrome oxidase I and II to infer maternal inheritance patterns. Admixture zones correspond with regions impacted by the reorganization of Uganda's river networks that occurred during the formation of the West African Rift system over the last several hundred thousand years. Because tsetse fly population distributions are defined by rivers, admixture zones likely represent both old and new regions of secondary contact. Our results indicate that older hybrid zones contain mostly parental types, while younger zones contain variable hybrid types resulting from multiple generations of interbreeding. These findings suggest that reproductive barriers are nearly complete in the older admixture zones, while nearly absent in the younger admixture zones. Findings are consistent with predictions of hybrid zone theory: Populations in zones of secondary contact transition rapidly from early to late stages of speciation, or collapse all together. This article is protected by copyright. All rights reserved. PMID- 30471159 TI - The mediating role of sleep in the relationship between Indigenous status and body mass index in Australian school-aged children. AB - AIM: Associations between sleep duration and obesity and between obesity and chronic illness are established. Current rates of obesity for all Australian people are rising. Recent reports indicate that high body mass index (BMI) is a leading contributor to overall burden of disease for Indigenous Australians. Understanding the factors that contribute to higher rates of obesity in Indigenous people is critical to developing effective interventions for reducing morbidity and premature mortality in this population. To explore the effect of sleep duration on the relationship between Indigenous status and BMI in Australian children. METHODS: 716 non-Indigenous and 186 Indigenous children aged 5-12 years in the Australian Health Survey 2011-2013. Primary carers were interviewed regarding children's sleep times; BMI was derived from measurement. RESULTS: Analysis of covariance revealed that regardless of a number of demographic and socio-economic status markers, sleep duration and Indigenous status were independent predictors of BMI. However when both predictors were considered together, only sleep duration remained predictive of BMI. CONCLUSIONS: Sleep duration plays an important mediating role in the relationship between Indigenous status and BMI in this Australian sample. Modification of sleep duration for Indigenous children may lead to longer-term positive health outcomes. PMID- 30471160 TI - Enhanced cecropin B2 production via chitin-binding domain and intein self cleavage system. AB - In this study, various constructs and hosts were used to produce high levels of cecropin B2 (cecB2). To mitigate cecB2's toxic inhibition of host cells, various cecB2 constructs were built. Results showed that the combination of a chitin binding domain and an intein self-cleavage motif in front of cecropin B2, without a His-tag, was best for cecB2 expression. E. coli ER2566 was the best host, and 2YT was the best medium for cultivation. Under these conditions, a cecB2 yield of 98.2 mg/L could be obtained after purification. The purified cecB2 expressed a wide antimicrobial effect on most Gram-negative strains, including multidrug resistant Acinetobactor baumannii and Staphylococcus aureus. This study provides a systematic approach to the efficient production of the antimicrobial peptide (AMP) cecB2 via the recombinant E. coli process, which is expected to be an efficient way for the production of other AMPs. PMID- 30471161 TI - Offline consolidation supersedes prior knowledge benefits in children's (but not adults') word learning. AB - Prior linguistic knowledge is proposed to support the acquisition and consolidation of new words. Adults typically have larger vocabularies to support word learning than children, but the developing brain shows enhanced neural processes that are associated with offline memory consolidation. This study investigated contributions of prior knowledge to initial word acquisition and consolidation at different points in development, by teaching children and adults novel words (e.g., ballow) that varied in the number of English word-form "neighbours" (e.g., wallow, bellow). Memory for the novel word-forms was tested immediately after training, the next day, and one week later, to assess the time course of prior knowledge contributions. Children aged 7-9 years (Experiments 1, 3) and adults (Experiment 2) recalled words with neighbours better than words without neighbours when tested immediately after training. However, a period of offline consolidation improved overall recall and reduced the influence of word form neighbours on longer-term memory. These offline consolidation benefits were larger in children than adults, supporting theories that children have a greater propensity for consolidating phonologically distinctive language information. Local knowledge of just a single word-form neighbour was enough to enhance learning, and this led to individual differences in word recall that were related to adults' global vocabulary ability. The results support the proposal that the relative contributions of different learning mechanisms change across the lifespan, and highlight the importance of testing theoretical models of word learning in the context of development. This article is protected by copyright. All rights reserved. PMID- 30471162 TI - "Stroke-like" events after brain radiotherapy: a large series with long-term follow-up. AB - BACKGROUND: Patients with history of brain radiotherapy can experience acute "stroke-like" syndromes related to the delayed effects of brain radiation, including "Stroke-like Migraine Attacks after Radiation Therapy (SMART)", "Peri Ictal Pseudoprogression (PIPG)", and "Acute Late-onset Encephalopathy after Radiation Therapy (ALERT)" syndrome. The aim of this study is to collect evidence on the long-term outcome and treatment of these conditions, whose knowledge is undermined by their rarity and fragmented description. METHODS: Cases were collected, both prospectively and retrospectively, among six neuro-oncology departments. Inclusion criteria were: 1) history of brain radiotherapy (completed from at least 6 months); 2) new onset of acute/subacute neurological symptoms; 3) exclusion of all etiologies unrelated to brain irradiation. A review of current literature on "stroke-like" syndromes was performed to corroborate our findings. RESULTS: Thirty-two patients with acute neurological conditions attributed to the delayed effects of radiation were identified, including 26 patients with "stroke like" syndromes. Patients with "stroke-like" syndromes commonly presented with a mosaic of symptoms, including focal deficits (77%), encephalopathy (50%), seizures (35%) and headache (35%). Seventy-three percent of them had acute consistent MRI alterations. Treatment included high-dose steroids in 65% of cases. Twenty-two patients recovered completely (85%). Sixteen patients (62%) experienced relapses (median follow-up: 3.5 years). Literature review identified 87 additional "stroke-like" cases with similar characteristics. CONCLUSIONS: "Stroke-like" events related to brain irradiation may be associated with permanent sequelae. Steroids are often administered on empirical grounds, as they are thought to accelerate recovery. Relapses are common, highlighting the need to elaborate adequate prevention strategies. This article is protected by copyright. All rights reserved. PMID- 30471163 TI - Lifestyle patterns and endocrine, metabolic and immunological biomarkers in European adolescents: The HELENA study. AB - OBJECTIVE: To evaluate the association of lifestyle patterns related to physical activity (PA), sedentariness and sleep with endocrine, metabolic and immunological health biomarkers in European adolescents. METHODS: The present cross-sectional study comprised 3528 adolescents (1845 girls) (12.5 -17.5 years) enrolled in the Healthy Lifestyle in Europe by Nutrition in Adolescence Study. Cluster analysis was performed by including body composition, PA by accelerometry, self-reported sedentary behaviors and sleep duration. We also measured endocrine, metabolic and immunological biomarkers. RESULTS: Three cluster solutions were identified: 1- (light-PA time, moderate-vigorous-PA time and sedentary time); 2- (light-PA time, moderate-vigorous-PA time, sedentary time and sleep time); 3- (light-PA time, moderate-vigorous-PA time, sedentary time and body composition). In addition, each cluster solution was defined as: "healthy", "medium healthy" and "unhealthy" according to the presented rating. Analysis of variance showed that overall the healthiest groups from the three clusters analyzed presented a better metabolic profile. A decision tree analysis showed that leptin had a strong association with cluster 3 in both boys and girls, HDL-c had the strongest association with clusters 1 and 3 in boys. Cortisol had the strongest association with cluster 1. HOMA index (homeostatic model assessment) and C3 showed a strong association with cluster 3 in girls. CONCLUSIONS: Our results support the existence of different interactions between metabolic health and lifestyle patterns related to PA, sedentariness and sleep, with some gender specific findings. These results highlight the importance to consider multiple lifestyle related health factors in the assessment of adolescents' health in order to plan favourable strategies. This article is protected by copyright. All rights reserved. PMID- 30471164 TI - Remodeling of cholinergic input to the hippocampus after noise exposure and tinnitus induction in guinea pigs. AB - OBJECTIVES: To investigate remodeling of hippocampal cholinergic inputs after noise exposure and determine the relevance of these changes to tinnitus. METHODS: To assess the effects of noise exposure on the hippocampus, guinea pigs were exposed to unilateral noise for two hours and 2 weeks later, immunohistochemistry was performed on hippocampal sections to examine vesicular acetylcholine transporter (VAChT) expression. To evaluate whether the changes in VAChT were relevant to tinnitus, another group of animals was exposed to the same noise band twice to induce tinnitus, which was assessed using gap-prepulse Inhibition of the acoustic startle (GPIAS) 12 weeks after the first noise exposure, followed by immunohistochemistry. RESULTS: Acoustic Brainstem Response (ABR) thresholds were elevated immediately after noise exposure for all experimental animals but returned to baseline levels several days after noise exposure. ABR wave I amplitude-intensity functions did not show any changes after 2 or 12 weeks of recovery compared to baseline levels. In animals assessed two-weeks following noise-exposure, hippocampal VAChT puncta density decreased on both sides of the brain by 20%-60% in exposed animals. By 12 weeks following the initial noise exposure, changes in VAChT puncta density largely recovered to baseline levels in exposed animals that did not develop tinnitus, but remained diminished in animals that developed tinnitus. These tinnitus-specific changes were particularly prominent in hippocampal synapse-rich layers of the dentate gyrus and areas CA3 and CA1, and VAChT density in these regions negatively correlated with tinnitus severity. CONCLUSIONS: The robust changes in VAChT labeling in the hippocampus two weeks after noise exposure suggest involvement of this circuitry in auditory processing. After chronic tinnitus induction, tinnitus-specific changes occurred in synapse-rich layers of the hippocampus, suggesting that synaptic processing in the hippocampus may play an important role in the pathophysiology of tinnitus. This article is protected by copyright. All rights reserved. PMID- 30471165 TI - Non-hypoxic pharmacological stabilisation of Hypoxia Inducible Factor 1alpha: effects on dopaminergic differentiation of human neural stem cells. AB - Parkinson's disease is a neurodegenerative disease resulting in degeneration of midbrain dopaminergic neurons. Exploratory studies using human fetal tissue or predifferentiated stem cells have suggested that intracerebral transplantation of dopaminergic precursor cells may become an effective treatment for patients with Parkinson's disease. However, strategies for dopaminergic stem cell differentiation vary widely in efficiency, and better methods still need to be developed. Hypoxia Inducible Factor 1 (HIF-1) is a transcription factor involved in the regulation of genes important for cellular adaption to hypoxia and low glucose supply. HIF-1 is to a large degree regulated by the availability of oxygen as in its presence, the subunit HIF-1alpha is degraded by HIF prolyl hydroxylase enzymes (HPHs). Stabilisation of HIF-1alpha through inhibition of HPHs has been shown to increase dopaminergic differentiation of stem cells and to protect dopaminergic neurons against neurotoxins. This study investigated the effects of non-competitive (FG-0041) and competitive (Compound A and JNJ 42041935) HIF-1alpha stabilising compounds on the dopaminergic differentiation of human neural stem cells. Treatment with all HPH inhibitors at high oxygen tension (20%) resulted in HIF-1alpha stabilisation as assessed by immunocytochemistry for HIF-1alpha and detection of increased levels of vascular endothelial growth factor in the conditioned culture medium. Following 10 days of HIF-1alpha stabilisation, the cultures displayed a slightly reduced proliferative activity and significantly increased relative levels of tyrosine hydroxylase-positive dopaminergic neurons. In conclusion, HIF-1alpha stabilisation may represent a promising strategy for the generation of dopaminergic neurons intended for use in experimental in vitro studies and cell replacement therapies. This article is protected by copyright. All rights reserved. PMID- 30471166 TI - Exposure to the fungicide captan induces DNA base alterations and replicative stress in mammalian cells. AB - The classification of the fungicide captan (CAS Number: 133-06-2) as a carcinogen agent is presently under discussion. Despite the mutagenic effect detected by the Ames test and carcinogenic properties observed in mice, the genotoxicity of this pesticide in humans is still unclear. New information is needed about its mechanism of action in mammalian cells. Here we show that Chinese Hamster Ovary (CHO) cells exposed to captan accumulate Fpg-sensitive DNA base alterations. In CHO and HeLa cells, such DNA lesions require the XRCC1-dependent pathway to be repaired and induce a replicative stress that activated the ATR signalling response and resulted in double-strand breaks and micronuclei. The replicative stress is characterized by a dramatic decrease in DNA synthesis due to a reduced replication fork progression. However, impairment of the XRCC1-related repair process did not amplify the replicative stress, suggesting that the fork progression defect is independent from the presence of base modifications. These results support the involvement of at least two independent pathways in the genotoxic effect of captan that might play a key role in carcinogenesis. This article is protected by copyright. All rights reserved. PMID- 30471167 TI - Evidence for a Sensitive Period in the Effects of Early Life Stress on Hippocampal Volume. AB - Exposure to stress has been causally linked to changes in hippocampal volume (HV). Given that the hippocampus undergoes rapid changes in the first years of life, stressful experiences during this period may be particularly important in understanding individual differences in the development of the hippocampus. One hundred seventy-eight early adolescents (ages 9-13 years; 43% male) were interviewed regarding exposure to and age of onset of experiences of stress; the severity of each stressful event was rated by an objective panel. All participants underwent structural magnetic resonance imaging, from which HVs were automatically segmented. Without considering the age of onset for stressful experiences, there was a small but statistically significant negative association of stress severity with bilateral HV. When considering the age of onset, there was a moderate and significant negative association between stress severity during early childhood (through age 5 years) and HV; there was no association between stress severity during later childhood and HV (age 6 years and older). We provide evidence of a sensitive period through age 5 years for the effects of life stress on HV in adolescence. It will be important in future research to elucidate how reduced HV stemming from early life stress may contribute to stress related health outcomes. This article is protected by copyright. All rights reserved. PMID- 30471168 TI - Skeletal muscle performance in metabolic disease: microvascular or mitochondrial limitation or both? AB - One of the clearly established health outcomes associated with chronic metabolic diseases (e.g., type II diabetes mellitus) is that the ability of skeletal muscle to maintain contractile performance during periods of elevated metabolic demand is compromised as compared to the fatigue-resistance of muscle under normal, healthy conditions. While there has been extensive effort dedicated to determining the major factors that contribute to the compromised performance of skeletal muscle with chronic metabolic disease, the extent to which this poor outcome reflects a dysfunctional state of the microcirculation, where the delivery and distribution of metabolic substrates can be impaired, versus derangements to normal metabolic processes and mitochondrial function, versus a combination of the two, represents an area of considerable unknown. The purpose of this manuscript is to present some of the current concepts for dysfunction to both the microcirculation of skeletal muscle as well as to mitochondrial metabolism under these conditions, such that these diverse issues can be merged into an integrated framework for future investigation. Based on an interpretation of the current literature, it may be hypothesized that the primary site of dysfunction with earlier stages of metabolic disease may lie at the level of the vasculature, rather than at the level of the mitochondria. This article is protected by copyright. All rights reserved. PMID- 30471169 TI - Reduced Lateral Orbitofrontal Cortex (OFC) Volume and Suicide Behavior in Youth with Bipolar Disorder. AB - OBJECTIVES: Structural abnormalities in cortical and subcortical regions, including the orbitofrontal cortex (OFC), are altered during brain development in adolescents with bipolar disorder (BD), which may increase risk for suicide. Few studies have examined the neural substrates of suicidal behavior in BD youth. The aim of the present study was to investigate the relationship between suicide behavior and the OFC in youth with BD. METHODS: Thirty-seven participants with BD and 26 non-psychiatric controls, ages 13 to 21 years, completed a diagnostic interview and mood rating scales. Lifetime symptoms of suicide ideation and behavior were examined using the Columbia Suicide Severity Rating Scale. Participants underwent magnetic resonance imaging on a 3T Siemens Verio scanner. Morphometric analysis of brain images was performed using FreeSurfer. RESULTS: Eighteen participants with BD had a history of suicide attempt (SA). Bipolar youth with a history of SA showed reduced left lateral OFC volumes compared to controls, but there was no difference between BD attempters and non-attempters. Controls and BD non-attempters had significantly greater OFC cortical thickness than BD attempters. Additionally, there was a significant negative correlation between OFC volumes and suicide lethality, demonstrating that as suicide lethality increased, OFC volume in BD youth was reduced. CONCLUSIONS: The OFC is involved in decision-making, impulsivity, and reward circuitry which have shown to be impaired in BD. Reduced OFC volume and its association with lethality of suicide suggest that suicide behavior in BD may be related to the emerging neuroanatomical substrates of the disorder, particularly abnormalities of the OFC. This article is protected by copyright. All rights reserved. PMID- 30471170 TI - Compliance with international guidelines for chronic inflammatory neuropathies. AB - ERare diseases' management guidelines are produced with the primary aim of improving practice and standards of care for patients and may represent a useful framework for clinical practice. The EFNS/PNS (European Federation of Neurological Societies/Peripheral Nerve Society) guidelines for CIDP (chronic inflammatory demyelinating polyneuropathy) and MMN (multifocal motor neuropathy) were last published in 2010 (1, 2). Enthusiasm of the audience for whom they are produced, arguably primarily non-sub-specialists, is however largely unexplored. Compliance to these guidelines by neuromuscular and/or peripheral nerve specialists has not been investigated. This article is protected by copyright. All rights reserved. PMID- 30471171 TI - Carborane-based analogues of 5-lipoxygenase inhibitors co-inhibit heat shock protein 90 in HCT-116 cells. AB - 5-Lipoxygenase converts arachidonic acid to leukotrienes that are involved in inflammation and angiogenesis. The introduction of carboranes can improve the pharmacokinetic behavior of metabolically less stable pharmaceutics. We here report the syntheses of several carborane-based inhibitors of the 5-lipoxygenase pathway. The isosteric replacement of phenyl rings by carboranes leads to improved cytotoxicity for several melanoma and colon cancer cell lines. For the colon cancer cell line HCT-116 the co-inhibition of heat shock protein 90 could be detected. PMID- 30471172 TI - Effect of prolonged treatment with phosphodiesterase-5-inhibitors on endothelial dysfunction in vascular diseases and vascular risk conditions: a systematic review analysis and meta-analysis of randomized double-blind placebo-controlled trials. AB - OBJECTIVE: To challenge the argument that continuous use of phosphodiesterase-5 selective inhibitors may reduce endothelial cell dysfunction in patients with vascular diseases or vascular risk conditions. DESIGN: This study included systematic reviews and meta-analysis of randomized double-blind placebo controlled trials dealing with a prolonged use of phosphodiesterase-5 selective inhibitors. The risk of bias and quality of trials were assessed by the Cochrane algorithm. Fixed or random effect models, standardized mean differences, and heterogeneity were estimated in the study. DATA SOURCES: Systematic search for randomized double-blind placebo-controlled trials was done in PubMed, Scopus, CINAHL, Science direct and the Cochrane Library. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomized double-blind placebo-controlled trials reporting measures of endothelial cell dysfunction and/or endothelial cell activation were included. RESULTS: On the whole, 469 subjects were allocated to the phosphodiesterase-5 selective inhibitor group while 463 were assigned to the placebo group in 13 randomized double-blind placebo-controlled trials. Flow mediated dilation of the brachial artery was found to improve after the administration of phosphodiesterase-5 selective inhibitors (p<0.0001). The results were questioned by the elevated and uncorrectable heterogeneity (I2 =92%) and the asymmetry of the funnel plot suggested a publication bias. Phosphodiesterase-5 selective inhibitors have no effect on endothelial cell dysfunction, as assessed in the resistance vessels by digital arterial tonometry. The blood level of endothelin-1 was observed to be decreased in phosphodiesterase 5 selective inhibitors arm (p=0.03), although the effect disappeared once the publication bias and heterogeneity were corrected. The effect of phosphodiesterase-5 selective inhibitors on biomarkers of endothelial cell activation was found to be inconsistent. CONCLUSIONS: The results on the benefits of a prolonged use of phosphodiesterase-5 selective inhibitors, with the objective of lowering endothelial cell dysfunction in patients with vascular diseases or vascular risk conditions are not convincing. This is due to the overall low quality of evidence, giving an unclear scientific support to this treatment. This article is protected by copyright. All rights reserved. PMID- 30471173 TI - Treatment of Perianal Sepsis, a Detailed Treatise for Trainees (Video Vignette ESCP Trainee Video). AB - For many surgeons, the drainage of a perianal abscess is the first operation they perform unsupervised. However, this risks an adverse outcome if the young surgeon has not been well trained. Most surgeons believe perianal sepsis is caused by cryptoglandular infection. Even though this theory is convenient and likely, contrary evidence also exists. This article is protected by copyright. All rights reserved. PMID- 30471174 TI - Barrier to Proton Transfer in the Dimer of Formic Acid: a Pure Rotational Study. AB - The rotational spectra of three C-deuterated isotopologues of the dimer of formic acid have been measured, thanks to the small dipole moment induced by asymmetric H->D substitution(s). For the DCOOH-HCOOH species the concerted double proton transfer of the two hydroxyl hydrogens takes place between two equivalent minima and generates a tunneling splitting of 331.2(6) MHz. This splitting can be reproduced by a 3D model with a barrier of 2559 cm-1 (30.6 kJ/mol) as obtained from ab initio calculations. PMID- 30471175 TI - First Aid Toolkit for Anal Fistulas, a Detailed Treatise for Trainees (Video Vignette ESCP Trainee Video). AB - Fistula surgery is often performed by trainees. However, an inexperienced trainee may lay open a fistula that could be treated by a more conservative approach. There is considerable national and international variation and the present video will not attempt to define superior methods, but rather highlight matters of debate. This article is protected by copyright. All rights reserved. PMID- 30471176 TI - Clinical use of topical hypertonic saline eye drops in a quaternary referral eye care centre over 5 years in Sydney, Australia. AB - No abstract is available for this article. This article is protected by copyright. All rights reserved. PMID- 30471177 TI - Reflections on the Sulphonylurea Story. A Drug Class at Risk of Extinction? Or A Drug Class Worth Reviving? AB - Sulphonylureas (SU) were discovered in 1942 when French researchers observed severe hypoglycaemia in patients receiving sulphonamide treatment for typhoid fever 1 . It was recognised that sulphonamide-induced hypoglycaemia mimicked the action of insulin 2,3 . SU were introduced to clinical practice in the 1950s. This article is protected by copyright. All rights reserved. PMID- 30471178 TI - Rh6 gene modulates the visual mechanism of host utilization in fruit fly Bactrocera minax. AB - BACKGROUND: Vision plays a critical role in host location and oviposition behavior for herbivorous insects. However, the molecular mechanisms underlying visual regulation in host recognition and oviposition site selection in insects remains unknown. The aim of this study was to explore the key visual genes that linked to the host plant location of the fruit fly, Bactrocera minax. RESULTS: Using a host specialist fruit fly, B. minax, which lays eggs only into immature green citrus fruit, we undertook behavioral, transcriptomic and RNAi research to identify the molecular basis for host fruit color recognition. In laboratory and field assays we found that adults prefer green over other colors, and this preference is significantly increased in sexually mature over immature flies. Furthermore, we identified that the Rh6 gene, responsible for green spectral sensitivity, has elevated expression in mature flies over immature flies. RNAi suppression of Rh6 eliminated the preference for green, resulting in a significant decrease in the number of eggs laid by B. minax in green unripe citrus. CONCLUSION: These results show Rh6 gene modulates the visual mechanism of host utilization in B. minax, providing for a genetic basis for visual host location in a non-model insect herbivore. This article is protected by copyright. All rights reserved. PMID- 30471179 TI - Association of HLA-DPA1 and HLA-DPB1 polymorphisms with spontaneous HBsAg seroclearance in Caucasians. AB - BACKGROUND AND AIMS: Acute hepatitis B virus (HBV) infections may clear spontaneously or become chronic and run through different phases. The single nucleotide polymorphisms (SNPs) rs3077, rs9277535 and rs9277534 within the human leukocyte antigen (HLA)-DP gene have been found to be associated with HBV susceptibility and persistence in Asians. However, evidence for the influence of these variants in Caucasians has been limited so far. The aim of our study was to investigate the impact of these polymorphisms on the outcome of HBV infections in a large Caucasian population. METHODS: In this case-control study, we retrospectively analyzed 1,111 Caucasian individuals, including 618 with chronic HBV infections (CHB), 239 with spontaneous HBsAg seroclearance (SC) and 254 healthy controls (HC). The rs3077, rs9277535 and rs9277534 SNPs were genotyped by a polymerase chain reaction from blood samples and melting curve analysis. RESULTS: A significant difference in the allele distributions was observed only for the rs3077 SNP between the HC and the CHB group as well as between the SC and CHB group. The rs3077-C allele was associated with a lower probability for spontaneous HBsAg seroclearance in comparison to the rs3077-T allele (OR 0.704, 95% CI 0.509-0.974; p=0.033). No association of the three SNPs with the stages of chronic HBV infection was found. CONCLUSION: This is the first study demonstrating an association of the rs3077-T allele with spontaneous HBsAg seroclearance in Caucasians. Further studies are needed to elucidate the role of HLA-DP variants in disease pathogenesis and their potential role for individualized disease management. This article is protected by copyright. All rights reserved. PMID- 30471180 TI - Association of intrauterine exposure to aspirin and blood pressure at seven years of age: a secondary analysis. AB - OBJECTIVE: To examine whether maternal aspirin use during pregnancy is associated with childhood blood pressure. DESIGN/SETTING: A secondary analysis of the Collaborative Perinatal Project, a prospective cohort study including 12 U.S. academic medical centres between 1959 and 1976. POPULATION: Singleton births among women with detailed medication information. METHODS: We carried out linear and multivariate logistic regression analysis to assess the associations between maternal aspirin exposure and childhood blood pressure at age seven years. MAIN OUTCOME MEASURES: Offspring blood pressure at age seven years. RESULTS: A total of 15,793 women were exposed to aspirin four weeks before the last menstrual period or during pregnancy. In utero aspirin exposure may be associated with an 11% (95% confidence interval(CI): 0.85, 0.93) and 20% (95% CI: 0.76, 0.84) reduced risk of having high systolic blood pressure (SBP) and diastolic blood pressure (DBP) at seven years of age and a mean decrease of 0.62 mmHg for SBP and 1.04 mmHg for DBP at seven years of age. Compared to children born to mothers without aspirin exposure, those whose mothers were exposed to aspirin for at least seven days during pregnancy had approximately 10% and 27% reduced risk of high SBP and DBP, respectively, and a mean reduction of 0.61 mmHg and 1.27 mmHg in SBP and DBP at seven years of age. The earlier the aspirin exposure occurred during pregnancy, the lower the risk of childhood high blood pressure. CONCLUSION: In utero exposure to aspirin may have long-term benefits for childhood blood pressure. This article is protected by copyright. All rights reserved. PMID- 30471181 TI - Misdecoding of Rare CGA Codon by Translation Termination Factors, eRF1/eRF3, Suggests Novel Class of Ribosome Rescue Pathway in S. cerevisiae. AB - The CGA arginine codon is a rare codon in Saccharomyces cerevisiae. Thus, full length mature protein synthesis from reporter genes with internal CGA codon repeats are markedly reduced, and the reporters, instead, produce short-sized polypeptides via an unknown mechanism. Considering the product size and similar properties between CGA sense and UGA stop codons, we hypothesized that eukaryote polypeptide-chain release factor complex eRF1/eRF3 catalyzes polypeptide release at CGA repeats. Herein, we performed a series of analyses and report that the CGA codon can be, to a certain extent, decoded as a stop codon in yeast. This also raises an intriguing possibility that translation termination factors eRF1/eRF3 rescue ribosomes stalled at CGA codons, releasing premature polypeptides, and competing with canonical tRNAICG to the CGA codon. Our results suggest an alternative ribosomal rescue pathway in eukaryotes. The present results suggest that misdecoding of low efficient codons may play a novel role in global translation regulation in S. cerevisiae. This article is protected by copyright. All rights reserved. PMID- 30471182 TI - Identification of autoimmune type 1 diabetes and multiple organ-specific autoantibodies in adult-onset non-insulin requiring diabetes in China: a population based multicenter national wide survey. AB - AIMS: We previously reported in China, using a hospital-based national survey, a high frequency of adult-onset autoimmune diabetes. Here, in a population-based, multicenter nation-wide study, in phenotypic type 2 diabetes (T2D) patients, we investigate the prevalence of adult-onset autoimmune diabetes (ADM) and predisposition to autoimmune diseases by quantifying serum organ-specific autoantibodies MATERIALS AND METHODS: We included a nationally representative sample of 46 239 adults aged 20 years or older from 14 provinces, of whom 4671 had diabetes plus 1000 control subjects with normal glucose tolerance (NGT). Participants were screened centrally for autoantibodies to glutamic acid decarboxylase (GADA), protein tyrosine phosphatase-like protein (IA2A), and zinc transporter isoform-8 (Znt8A) and designated ADM where positive. We then assayed autoantibodies to thyroid peroxidase (TPOA), tissue transglutaminase (tTGA), and 21-hydroxylase (21-OHA) in randomly-selected subjects with ADM and age-, sex matched non-ADM T2D controls plus NGT controls RESULTS: Post-normalization, standardized prevalence of ADM was 6.0 (5.3-6.8) % in initially non-insulin requiring adult-onset diabetes subjects, corresponding to 6 million adults in China, in whom adjusted antibody positivity was TPOA 16.3(10.8-21.8) %, tTGA 2.1(0.0-4.2) %, and 21-OHA 1.8 (-0.2-3.8) %. Those GADA-positive ADM subjects had high risk for TPOA positivity (odds ratio 2.39; p=0.0031) and tTGA positivity (6.98; p=0.027), while those positive for IA2A had high risk for tTGA positivity (19.05; p=0.001). CONCLUSIONS: A proportion of phenotypic T2D patients in China have adult-onset autoimmune diabetes with diabetes-associated autoantibodies and they may be at risk of developing other organ-specific autoimmune diseases. Therefore, it may be clinically relevant to consider screening such Chinese populations. This article is protected by copyright. All rights reserved. PMID- 30471184 TI - The Impact of Social Support Networks on Family Resilience in an Australian Intensive Care Unit: A Constructivist Grounded Theory. AB - PURPOSE: This article discusses the findings of a grounded theory of family resilience in an Australian intensive care unit (ICU) with a specific focus on families' experiences of their interactions with other members within their own family, and the families of other patients in the ICU. DESIGN: A constructivist grounded theory methodology was adopted. Data were collected using in-depth interviews with 25 family members of 21 critically ill patients admitted to a tertiary-level ICU in Australia. FINDINGS: The core category regaining control represents the families' journey toward resilience when in ICU. The major categories represent facilitators for, and barriers to, regaining control. One of the main facilitators is drawing strength, and it explains the manner with which families receive social support from their own and other family members to help them cope. CONCLUSIONS: This study offers a framework to improve patient- and family-centered care in the ICU by facilitating families' ability to manage their situation more effectively. Social support offered by family members facilitates the families' ability to regain control. An ICU family resilience theoretical framework, situated within the context of the Australian healthcare system, adds to what is currently known about the families' experiences in the ICU. CLINICAL RELEVANCE: The relationships that develop between families in the ICU may provide a source of social support; however, not all families welcome interactions with other ICU families, and it may cause further emotional distress. Further research is warranted to determine whether families suffer a secondary stress reaction from incidental interactions with other patients' families in the ICU. Furthermore, when family members pull together and offer social support to each other, they are better able to regain control. This process contributes to an ICU family resilience framework. PMID- 30471183 TI - High levels of coagulation factors and venous thrombosis risk: strongest association for factor VIII and von Willebrand factor. AB - BACKGROUND: Coagulation factors are essential for robust clot formation. However, elevated levels of procoagulant factors are associated with in increased risk for venous thrombosis. The precise contribution of these factors to the development of venous thrombosis (VT) is not yet understood. OBJECTIVES: We determined thrombosis risk for the highest levels of 8 selected coagulation factors. Furthermore, we analysed which of these coagulation factors had the strongest impact on the supposed association. METHODS: We used data of 2377 patients with a first VT and 2940 control subjects in whom fibrinogen, von Willebrand factor (VWF), factor (F)II-, FVII-, FVIII-, FIX-, FX- and FXI levels were measured. RESULTS: The odds ratios (ORs) for the various coagulation factor levels (>99th percentile vs <25th percentile) varied between 1.8 and 4, except for FVIII (OR 23.0; 95%CI, 14.7-36.0) and VWF (OR 24.0; 95%CI, 15.3-37.3). Adjustment for FVIII and VWF in a mediation analysis attenuated the risks of the other factors to unity, with the exception of FIX and FXI (remaining ORs between 1.7 and 1.9). Conversely, the ORs for FVIII- and VWF levels remained high when adjusted for all other procoagulant factors (FVIII: 16.0; 95%CI, 9.7-26.3; VWF: 17.6; 95%CI, 10.7 28.8). CONCLUSIONS: Our results imply that the observed relationship between VT and coagulation factor levels can be largely explained by FVIII and VWF. FVIII and VWF levels were also associated with the highest VT risk. This article is protected by copyright. All rights reserved. PMID- 30471185 TI - Spatio-temporal variation of alkaloids in Annona purpurea and the associated influence on their antifungal activity. AB - Annona purpurea grows in areas of low elevation in deciduous forests of Mexico, areas which have marked rainy and dry seasons. This species produces more than 30 bioactive alkaloids that could have potential in the control of phytopathogens. This research provides data on the variation of the content and number of alkaloids during an annual cycle and the associated inhibitory potential of the compounds against three phytopathogenic fungi. For one year, alkaloidal extracts of stems and leaves were obtained every two months. The extract profiles were determined by gas chromatography with tandem mass spectrometry and their antifungal activity was examined in vitro. The alkaloids annomontine and oxopurpureine, obtained from the roots and leaves, respectively, were also evaluated individually. The yields, profiles and activities of the extracts, as well as the abundance of annomontine and oxopurpureine in the extracts, were contrasted with the seasonality and phenological phases of the plant. The data indicate that the alkaloid content was higher at the height of the dry season. High yields also occurred during flowering. The strongest inhibitory effect was obtained from the root extracts during the last month of dry season. This finding seems to be explained by the higher chemodiversity of alkaloids in extracts from this season. Annomontine and oxopurpureine inhibited all three phytopathogens; however, they were not solely responsible for the activity of A. purpurea. PMID- 30471186 TI - Transcription factor FTZ-F1 and cis-acting elements mediate expression of CYP6BG1 conferring resistance to chlorantraniliprole in Plutella xylostella. AB - BACKGROUND: Cytochrome P450-mediated detoxification plays an important role in insecticide resistance development. Previous studies demonstrated that the over expression of CYP6BG1 was responsible for permethrin resistance in Plutella xylostella, and our experiments also showed that the up-regulation of this gene is associated with chlorantraniliprole resistance in P. xylostella. However, the transcriptional regulation involved in the expression of CYP6BG1 remains unknown. To further investigate the regulation of CYP6BG1 expression, the promoters of this gene were cloned and analyzed from a susceptible and in four different resistant populations of P. xylostella. RESULTS: In this study, firstly the promoter region of P. xylostella CYP6BG1 was compared in five populations and 3 types of 5'-flanking region were found. Second, the region between -562 and +49 of CYP6BG1 in a field population (TH) of P. xylostella showed the highest promoter activity and could be induced by chlorantraniliprole. Third, the transcriptional factor FTZ-F1, that is an orphan nuclear receptor and binds to the fushi tarazu (ftz) gene, was predicted by two online softwares Alggen and Jaspar. It proved to regulate the expression of CYP6BG1 by RNAi. The expression levels of FTZ-F1 and CYP6BG1 could be induced by chlorantraniliprole and were significantly higher in the resistant populations. CONCLUSIONS: These data are in a better understanding of the transcriptional regulation of an important insecticide detoxification enzyme gene, and therefore, this will help in understanding the molecular mechanisms of insecticides resistance in P. xylostella. This article is protected by copyright. All rights reserved. PMID- 30471187 TI - Impact of chronic lead exposure on liver and kidney function and hematologic parameters. AB - BACKGROUND: Lead, one of the most widely used metals because of its beneficial physical properties, has been reported to adversely influence several different organs and organ systems. The aim of the present study was to examine the effect of lead exposure on liver and renal function and haematologic parameters METHODS: This was a case-cohort study comparing adults with occupational, environmental or opium-related lead exposure with blood lead levels [BLL] >10MUg/dl (High blood lead level (HBLL) group and age- and gender-matched normal healthy subjects (Low blood lead level [LBLL] group with BLL<10MUg/dl). The complete blood count and concentrations of serum creatinine, urea, aspartate aminotransferase (AST), alanine aminotransferase (ALT) were recorded for subsequent investigation. RESULTS: The mean BLL was significantly higher in the HBLL than the LBLL groups (51.36+/-44.72 vs. 4.17+/-1.97 MUg/dl). The Spearman's rho revealed a significant association between BLL and urea (r=0.25, p<0.001), creatinine (r=0.16, p=0.02), AST (r=0.42, p<0.001) and ALT(r=0.27, p<0.001). The median [IQR] serum urea (34 mg/dl [27-221]) vs (30 [27-36]), creatinine (0.9 mg/dl [0.8-1]) vs (0.8 [0.7 0.9]), ALT (25 mg/dl [16-49]) vs (22 [16-30]) and AST concentrations (29 mg/dl [20-42]) vs (20 [18-24]), were all significantly higher (p<0.05) in the HBLL group compared to the LBLL group. The median [IQR] hemoglobin (12.6 g/dl [10.4 15.4]) vs (15.2 [14.6-16.3] and hematocrit (36.9% [31-44.8]) vs (45.6 [43.6 48.2]) were both significantly lower (p<0.001) in the HBLL group than the LBLL group. CONCLUSION: The results indicated that people with chronic lead exposure with BLLs greater than10 MUg/dl are at risk of renal, liver and haematologic impairments. This article is protected by copyright. All rights reserved. PMID- 30471188 TI - Deciphering the Human Gut Microbiome of Urolithin Metabotypes: Association with Enterotypes and Potential Cardiometabolic Health Implications. AB - SCOPE: The gut microbiota ellagitannin-metabolizing phenotypes (i.e., urolithin metabotypes [UMs]) are proposed as potential cardiovascular disease (CVD) risk biomarkers because the host blood lipid profile is reported to be associated with specific UMs. However, the link for this association remains unknown so far. METHODS AND RESULTS: The gut microbiome of 249 healthy individuals is analyzed using 16S rDNA sequencing analysis. Individuals are also stratified by UMs (UM-A, UM-B, and UM-0) and enterotypes (Bacteroides, Prevotella, and Ruminococcus). Associations of UMs discriminating bacteria with CVD risk markers are investigated. Distribution and gut microbiota composition of UMs and enterotypes are not coincident. Almost half of the discriminating genera between UM-A and UM B belongs to the Coriobacteriaceae family. UM-B individuals present higher blood cholesterol levels and higher alpha-diversity, including Coriobacteriaceae family, than those of UM-A. Coriobacteriaceae, whose abundance is the highest in UM-B, is positively correlated with total cholesterol, LDL cholesterol, and body mass index. CONCLUSIONS: Results herein suggest that the family Coriobacteriaceae could be a link between individuals' UMs and their blood cholesterol levels. Further research is needed to explore the mechanisms of the host metabolic phenotype, including cholesterol excretion products, to modulate this bacterial family. PMID- 30471189 TI - Human Study on the Kinetics of 2'R-Ochratoxin A in the Blood of Coffee Drinkers. AB - SCOPE: The aim of this study is to obtain a deeper knowledge of the kinetics of 2'R-ochratoxin A (2'R-OTA), the thermal degradation product of the mycotoxin ochratoxin A (OTA). To investigate the correlation between the amount of this compound in roasted coffee and human blood samples, a human study is performed. METHODS AND RESULTS: An 18-week human study is carried out. During the first eight weeks, all known 2'R-OTA-containing food sources are excluded from the diet and the reduction of 2'R-OTA in venous blood is analyzed. Afterwards, participants are allowed to consume coffee with known OTA and 2'R-OTA concentrations. On a biweekly scale, 2'R-OTA and OTA blood levels are determined. After eight weeks of fasting on 2'R-OTA-containing foods, the 2'R-OTA blood concentration decreased by about 10%. Based on this, a long biological half-life of over seven months is estimated. In the 24 h urine samples collected before and after the coffee fasting period, only traces of 2'R-OTA are detected. CONCLUSION: Results show that 2'R-OTA has a more than seven-fold higher biological half-life in human blood compared to OTA (approx. 35 days). The reason for the long persistence of 2'R-OTA in human blood is still unclear and further research is needed. PMID- 30471190 TI - Metal-ion Binding to Host Defense Peptide Piscidin 3 Observed in Phospholipid Bilayers by Magic Angle Spinning Solid-state NMR. AB - Cationic antimicrobial peptides (AMPs) are essential components of the innate immune system. They have attracted interest as novel compounds with the potential to treat infections with multi-drug resistant bacteria. In this study, we investigate piscidin 3 (P3), an AMP that was first discovered in the mast cells of hybrid striped bass. Prior studies have shown that P3 is less active than its homolog piscidin 1 (P1) against planktonic bacteria. However, it has the advantage of being less toxic to mammalian cells and more active on biofilms and persister cells. Both peptides cross bacterial membranes and co-localize with intracellular DNA but P3 is more condensing to DNA while P1 is more membrane active. Recently, we showed that both peptides coordinate Cu2+ through an amino terminal copper and nickel (ATCUN) motif. We also demonstrated that the bactericidal effects of P3 are linked to its ability to form radicals that nick DNA in the presence of Cu2+. Since metal binding and membrane crossing by P3 is biologically important, we apply solid-state NMR spectroscopy to uniformly 13C 15N-labeled peptide samples to structurally characterize the ATCUN motif of P3 bound to bilayer and coordinated to Ni2+ and Cu2+. These experiments were supplemented with density functional theory calculations. Taken together these results refine the arrangement of not only the backbone but also side chain atoms of an AMP simultaneously bound to metal ions and phospholipid bilayers. PMID- 30471191 TI - Comparing severity scores in exacerbations of chronic obstructive pulmonary disease. AB - INTRODUCTION: Prognostic scores help identify patients at a high risk of mortality in exacerbations of COPD. The DECAF score has been reported to perform better than other severity scores in predicting mortality from exacerbations of COPD in studies including patients with pneumonia. OBJECTIVE: To compare the performance of DECAF with other prognostic scores: CURB-65, CRB-65, and BAP-65, in predicting 30-day mortality in patients hospitalised with exacerbations of COPD without pneumonia. METHODS: Data from hospital admission of 423 patients from two cohorts of patients with exacerbations of COPD without consolidation on chest radiographs were used to compile the CURB-65, CRB-65, BAP-65, and DECAF scores. The performance of each prognostic score in predicting 30-day mortality was studied using receiver-operating-curve analysis. RESULTS: Thirty-one patients (7%) died within 30 days of hospital admission. 100 patients (24%) did not have DECAF scores due to incomplete laboratory data while all 423 patients had the other scores available for analysis. All scores predicted mortality with similar areas under the receiver-operating characteristic curve (CURB-65=0.69, CRB 65=0.64, BAP-65=0.64, DECAF= 0.65, p = 0.186). CONCLUSION: In patients hospitalised with exacerbations of COPD without pneumonia, simple clinical scores that rely on fewer laboratory measures perform at least as well as DECAF in predicting early mortality. This article is protected by copyright. All rights reserved. PMID- 30471192 TI - Computational Methods and Tools to Predict Cytochrome P450 Metabolism for Drug Discovery. AB - In this review we present important, recent developments in the computational prediction of cytochrome P450 (CYP) metabolism in the context of drug discovery. We discuss in silico models for the various aspects of CYP metabolism prediction, including CYP substrate and inhibitor predictors, site of metabolism predictors (i.e. metabolically labile sites within potential substrates) and metabolite structure predictors. We summarise the different approaches taken by these models, such as rule-based methods, machine learning, data mining, quantum chemical methods, molecular interaction fields and docking. We highlight the scope and limitations of each method and discuss future implications for the field of metabolism prediction in drug discovery. This article is protected by copyright. All rights reserved. PMID- 30471193 TI - Alternative digestion approaches improve histone modification mapping by mass spectrometry in clinical samples. AB - PURPOSE: Profiling histone posttranslational modifications (PTMs) in clinical samples holds great potential for the identification of epigenetic biomarkers and the discovery of novel epigenetic targets. MS-based approaches to analyze histone PTMs in clinical samples usually rely on SDS-PAGE separation following histone enrichment in order to eliminate detergents and further isolate histones. However, this limits the digestions options and hence the modification coverage. EXPERIMENTAL DESIGN AND RESULTS: The aim of this study is the implementation of a procedure involving acetone protein precipitation followed by histone enrichment through a C18 StageTip column to obtain histone preparations suitable for various in-solution digestion protocols. Among them, the Arg-C digestion, which allows profiling histone H4 modifications, and the Prop-PIC method, which improves the detection of short and hydrophilic peptides, are tested. This approach is validated on different types of samples, including formalin-fixed paraffin embedded pathology tissues, and employed to profile histone H4 modifications in cancer samples and normal tissues, identifying previously reported differences, as well as novel ones. CONCLUSIONS AND CLINICAL RELEVANCE: This protocol widens the number of applications available in the toolbox of clinical epigenomics, allowing the investigation of a larger spectrum of histone marks in patient samples. PMID- 30471195 TI - Chlamydia trachomatis Impairs Host Base Excision Repair by Downregulating Polymerase Beta. AB - Chlamydia trachomatis infections have been associated with ovarian cancer by several epidemiological studies. Here, we show that C. trachomatis infected primary human ovarian epithelial cells display elevated oxidative DNA damage. Base excision repair, an important cellular mechanism to repair oxidative DNA lesions, was impaired in infected primary ovarian and in several other types of cells. Polymerase beta was downregulated in infected cells associated with upregulation of microRNA-499a (miR-499a). Stabilizing polymerase beta by inhibiting miR-499a significantly improved repair. Moreover, downregulation of tumor suppressor p53 also resulted in attenuated repair in these cells. Thus, our data show that downregulation of polymerase beta by direct inhibition through miR 499a and downregulation of p53 debilitates the host cell base excision repair during C. trachomatis infection. PMID- 30471196 TI - Inverse analysis to estimate site-specific parameters of mathematical model for simulating pesticide dissipations in paddy test systems. AB - BACKGROUND: In Japan, while experimental data for the dissipation behavior of paddy pesticides under a standardized test system are available, the application of a mathematical model is limited. This paper proposes a new model calibration procedure for inversely deriving the model parameters from the experimental data. This procedure is tested in the open software R by running an improved Pesticide Concentration in Paddy Field-1 (PCPF-1) model with R packages to analyze the dissipation of simetryn and molinate in flooded lysimeters and paddy fields. RESULTS: The model fitting was performed by a random minimization routine. Furthermore, the uncertainties of the model parameters envisioned by the global sensitivity analysis were successfully reduced using the Markov-chain Monte-Carlo technique. The calibrated simulation was validated at each test plot by confirming multiple statistical indices (i.e., Nash-Sutcliffe efficiency: 0.88 1.00; percent bias: <+/-5%). The dissipation pathways of two herbicides were quantitatively clarified by the mass balance of calibrated simulations and the effect of the unexpected herbicide runoff was quantified. The case study showed that the adjustment of daily percolation rate in the lysimeter experiment is the key to simulate the actual paddy field condition more accurately, especially in a case where pesticides show higher water solubility and soil mobility. CONCLUSION: The developed procedure can analyze the experimental data with acceptable accuracy and extract the unobservable information quantitatively. Our approach is applicable to the optimization of not only the model but also future experimental design. This article is protected by copyright. All rights reserved. PMID- 30471194 TI - Reductive Metabolism of Xanthohumol and 8-Prenylnaringenin by the Intestinal Bacterium Eubacterium ramulus. AB - SCOPE: The intestinal microbiota transforms a wide range of available substrates, including polyphenols. Microbial catabolites of polyphenols can contribute in significant ways to the health-promoting properties of their parent polyphenols. This work aims to identify intestinal metabolites of xanthohumol (XN), a prenylated flavonoid found in hops (Humulus lupulus) and beer, as well as to identify pathways of metabolism of XN in the gut. METHODS AND RESULTS: To investigate intestinal metabolism, XN and related prenylated flavonoids, isoxanthohumol (IX), and 8-prenylnaringenin (8PN) were added to growing cultures of intestinal bacteria, Eubacterium ramulus and E. limosum. Liquid chromatography coupled with mass spectrometry was used to identify metabolites of the flavonoids from the cultures. The metabolic capacity of E. limosum appears to be limited to O-demethylation. Evidence from the study indicates that E. ramulus hydrogenates XN to form alpha,beta-dihydroxanthohumol (DXN) and metabolizes the potent phytoestrogen 8PN into the chalcones, O-desmethylxanthohumol (DMX) and O desmethyl-alpha,beta-dihydroxanthohumol (DDXN). CONCLUSION: Microbial metabolism is likely to affect both activity and toxicity of XN and derivatives. This study along with others highlights that attention should be focused on metabolites, in particular, products of intestinal microbial metabolism. PMID- 30471197 TI - Impact of Intrauterine Growth Restriction on the Capillarisation of the Early Postnatal Rat Heart. AB - Capillarisation plays a key role in the growth of the developing heart. We therefore hypothesised that impaired heart development following intrauterine growth restriction (IUGR) may arise from inadequate myocardial capillary growth. The aims of the study were to examine the effect of IUGR on the growth and diffusion radius of intramyocardial capillaries in rats at postnatal day 1. Uteroplacental insufficiency was induced in rats in late gestation (E18, term=E22) by bilateral uterine artery and vein ligation (Restricted offspring n=12; 6 males and 6 females); offspring from sham-operated dams were used as Controls (n=10; 5 males and 5 females). At postnatal day 1, the hearts were immersion-fixed and heart volume, capillary length density, capillary diffusion radius and total capillary length were stereologically determined. Restricted offspring were significantly smaller at birth, with a concomitant reduction in heart volume and total myocardial capillary length compared to Controls. Capillary growth was not impaired relative to heart size, with no significant differences in capillary length density or diffusion radius in the myocardium of Restricted and Control offspring. There were no sex differences in any of the parameters examined. In conclusion, there was no evidence to indicate that microvascular development is compromised in the heart of IUGR offspring at one day after birth. Total myocardial capillary length, however, was significantly reduced in the growth restricted offspring and further longitudinal studies are required to elucidate the long-term impact, particularly following hypertrophic cardiac growth. This article is protected by copyright. All rights reserved. PMID- 30471198 TI - Student and foundation doctor perspectives on promoting entry to ENT specialist training. PMID- 30471199 TI - Risk factors associated with pseudoaldosteronism in patients with chronic hepatitis: A retrospective cohort study. AB - Glycyrrhizin is used to treat chronic hepatitis, but it also plays an important role in pseudoaldosteronism. Multidrug resistance-associated protein 2 is important for glycyrrhizin excretion. Dysfunction of this transporter increases the serum levels of direct-bilirubin, glycyrrhizin, and its metabolites. Hence, elevated direct-bilirubin levels could predict the risk of pseudoaldosteronism. This study aimed to evaluate the relationship between elevated direct-bilirubin levels and hypokalaemia, which is the most sensitive marker of pseudoaldosteronism. This retrospective cohort study was conducted in a Japanese university hospital. The occurrence of hypokalaemia, defined as a serum potassium level of <= 3.5 mEq/L after the administration of a glycyrrhizin-containing medication, and a further decline of >= 0.5 mEq/L or an increase of >= 0.5 mEq/L after discontinuing the glycyrrhizin-containing medication were examined in patients with chronic hepatitis between January 2009 and December 2015. This analysis involved 1392 patients, including 596 women. Hepatitis C virus infections were the most common cause of chronic hepatitis in this study. Seventy nine patients received glycyrrhizin (exposed group; mean age 60.5 +/- 14.2) and 1313 did not receive glycyrrhizin (control group; mean age 58.3 +/- 15.8 years). Synergistic effects of glycyrrhizin-containing medications and elevated direct bilirubin levels were associated with hypokalaemia. Elevated direct-bilirubin levels and hypoalbuminaemia were associated with hypokalaemia in the exposed group. Older age, female sex, high daily glycyrrhizin dosage, longer duration of glycyrrhizin intake, and potassium-lowering medications were not associated with hypokalaemia after the model adjustment. Elevated direct-bilirubin levels and hypoalbuminaemia may predict pseudoaldosteronism caused by glycyrrhizin. This article is protected by copyright. All rights reserved. PMID- 30471201 TI - Regulatory mechanisms of T cell activation-From basic research discoveries to a new principle of cancer therapy and the Nobel Prize. PMID- 30471200 TI - MALDI-Imaging for Classification of Epithelial Ovarian Cancer Histotypes from a Tissue Microarray using Machine Learning Methods. AB - PURPOSE: Precise histological classification of epithelial ovarian cancer (EOC) has immanent diagnostic and therapeutic consequences, but remains challenging in histological routine. The aim of this pilot study was to examine the potential of MALDI-Imaging mass spectrometry in combination with machine learning methods to classify EOC histological subtypes from tissue microarray. EXPERIMENTAL DESIGN: Formalin-fixed-paraffin-embedded tissue of 20 patients with ovarian clear-cell, 14 low-grade serous, 19 high-grade serous ovarian carcinomas and 14 serous borderline tumors were analysed using MALDI-Imaging. Classifications were computed by linear discriminant analysis (LDA), support vector machines with linear (SVM-lin) and radial basis function kernels (SVM-rbf), a neural network (NN), and a convolutional neural network (CNN). RESULTS: MALDI-Imaging and machine learning methods results in classification of EOC histotypes with mean accuracy of 80% for LDA, 80% SVM-lin, 74% SVM-rbf, 83% NN and 85% CNN. Based on sensitivity (69%-100%) and specificity (90-99%), CCN and NN were most suited to EOC classification. CONCLUSION AND CLINICAL RELEVANCE: The pilot study demonstrates the potential of MALDI-Imaging derived proteomic classifiers in combination with machine learning algorithms to discriminate EOC histotypes. Applications might support the development of new prognostic parameters in the assessment of EOC. This article is protected by copyright. All rights reserved. PMID- 30471202 TI - Indocyanine Green labeling for optical and photoacoustic imaging of Mesenchymal Stem Cells after in vivo transplantation. AB - The transplantation of Mesenchymal Stem Cells (MSCs) holds great promise for the treatment of a plethora of human diseases, but new non-invasive procedures are needed to monitor the cell fate in vivo. Already largely used in medical diagnostics, the fluorescent dye Indocyanine Green (ICG) is an established dye to track limited numbers of cells by optical imaging, but it can be visualized also by Photoacoustic Imaging (PAI), which provides a higher spatial resolution than pure near infrared fluorescence imaging (NIRF). Because of its successful use in clinical and preclinical examinations, we chose ICG as PAI cell labeling agent. Optimal incubation conditions were defined for an efficient and clinically translatable MSC labeling protocol, such that no cytotoxicity or alterations of the phenotypic profile were observed, and a consistent intracellular uptake of the molecule was achieved. Suspensions of ICG-labeled cells were both optically and optoacoustically detected in vitro, revealing a certain variability in the photoacoustic spectra acquired by varying the excitation wavelength from 680 to 970 nm. Intramuscular engraftments of ICG-labeled MSCs were clearly visualized by both PAI and NIRF over few days after transplantation in the hindlimb of healthy mice, suggesting that the proposed technique retains a considerable potential in the field of transplantation-focused research and therapy. Stem cells were labeled with the FDA approved fluorescent dye Indocyanine Green (ICG), and detected by both photoacoustic and optical imaging, enabling to monitor the cell fate safely, in dual modality, and with good sensitivity and improved spatial resolution. This article is protected by copyright. All rights reserved. PMID- 30471203 TI - Assessment of lateral mitral, septal and tricuspid myocardial performance indices by tissue Doppler imaging in asthmatic children. AB - INTRODUCTION: Recurrent hypoxia makes asthmatics at risk for pulmonary hypertension and ventricular dysfunction. Early stages of these cardiovascular diseases cannot be detected by conventional echocardiography. Tissue Doppler imaging has been introduced recently as a more sensitive & more accurate tool for investigating cardiovascular diseases. OBJECTIVE: investigating ventricular functions in asymptomatic asthmatic children using tissue Doppler echocardiography. METHOD: 50 asthmatic children and 50 controls were examined by conventional echocrdiography. Tissue Doppler echocardiography was performed to measure the myocardial performance (Tei) index at the lateral mitral, septal & tricuspid annuli. RESULTS: Septal Tei indices among patients & uncontrolled asthmatics were significantly higher than healthy subjects & controlled asthmatics respectively (P<0.05). Septal & tricuspid Tei indices were significantly higher among severe asthmatics & patients with concomitant nasal allergy than those with mild asthma & those without concomitant nasal allergy respectively (P<0.05). Septal Tei index correlated negatively with daily inhaled corticosteroid dose (r = -0.412, p = 0.003) and foreced expiratory volume in the 1st second/ forced vital capacity(r = -0.877, p<0.001). Lateral Tei index correlated positively with the patient age (r= 0.312, p= 0.027) and duration of asthma (r = 0.359, p=0.011). CONCLUSION: Tei index can detect subclinical ventricular dysfunction in asthmatics and is affected by asthma duration, control and severity. It can be used for future scoring of asthma severity. Septal annulus seems to be the best location for assessing Tei index in asthmatics. This article is protected by copyright. All rights reserved. PMID- 30471204 TI - MALDI Imaging for Proteomic Painting of Heterogeneous Tissue Structures. AB - PURPOSE: To present matrix-assisted laser desorption/ionization (MALDI) imaging as a powerful method to highlight various tissue compartments. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded (FFPE) tissue of a uterine cervix, a pancreas, a duodenum, a teratoma, and a breast cancer tissue microarray (TMA) are analyzed by MALDI imaging and by immunohistochemistry (IHC). Peptide images are visualized and analyzed using FlexImaging and SCiLS Lab software. Different histological compartments are compared by hierarchical cluster analysis. RESULTS: MALDI imaging highlights tissue compartments comparable to IHC. In cervical tissue, normal epithelium can be discerned from intraepithelial neoplasia. In pancreatic and duodenal tissues, m/z signals from lymph follicles, vessels, duodenal mucosa, normal pancreas, and smooth muscle structures can be visualized. In teratoma, specific m/z signals to discriminate squamous epithelium, sebaceous glands, and soft tissue are detected. Additionally, tumor tissue can be discerned from the surrounding stroma in small tissue cores of TMAs. Proteomic data acquisition of complex tissue compartments in FFPE tissue requires less than 1 h with recent mass spectrometers. CONCLUSION AND CLINICAL RELEVANCE: The simultaneous characterization of morphological and proteomic features in the same tissue section adds proteomic information for histopathological diagnostics, which relies at present on conventional hematoxylin and eosin staining, histochemical, IHC and molecular methods. PMID- 30471205 TI - Discovery of a novel HLA-B*27 variant, B*27:168, by sequence-based typing in a Taiwanese blood donor. AB - Nucleotide substitutions at residues 409 and 412 of HLA-B*27:06 result in a novel allele, HLA-B*27:168. This article is protected by copyright. All rights reserved. PMID- 30471206 TI - Characterization of the novel HLA-DQA1*04:05 allele by sequencing-based typing. AB - HLA-DQA1*04:05 differs from HLA-DQA1*04:01:01:01 by one nucleotide substitution at codon 26 in exon 2. This article is protected by copyright. All rights reserved. PMID- 30471207 TI - Anatomical variation in maxillary sinus ostium positioning: implications for nasal-sinus disease. AB - Among humans, superiorly located maxillary sinus ostia (MSO) result in drainage complications and maxillary sinus (MS) disease. While previous studies investigate maxillary sinusitis frequency or MSO-position relative to specific nasal landmarks, few explore MSO-position to overall MS dimensions. This study investigates whether MSO-position relates to MS size/shape and if sex-based differences exist. Twenty-nine landmarks, placed on magnetic resonance images (MRIs) of 109 individuals (males=57; females=52), captured maximum dimensions of the cranium, MS, nasal cavity, and MSO-position relative to the MS floor (MSO_MSF) and nasal floor (MSO_NCF). Landmark coordinates were used to calculate centroid sizes and 13 linear distances; distances were size standardized by cranial centroid-size. Principal components (PC) analysis on 3D-coordinates indicates that variation in MSO-position relates to superior-inferior MS positioning within the face (PC1 22% variance) and MS height (PC2 12% variance). Regression analyses indicate that MS size (r2 =0.502; P<0.001) and height (r2 =0.589; P<0.0001) strongly contribute to MSO_MSF: larger, taller MSs exhibit greater MSO_MSFs. Sex-based differences were not evident in PC shape-analyses nor among size-standardized dimensions. However, Mann-Whitney U tests indicate females have absolutely smaller MSs (P=0.001) and MSO_MSF distances (P=0.001). Further, regressions indicate females exhibit lower MSO_MSFs for a similar MS height. Overall, MSOs superiorly placed relative to the MS floor correlate with larger, taller MSs and/or sinuses positioned inferiorly within the face. While craniofacial surgeons/clinicians should be aware of potential sex-based differences in MS size and MSO position, this study does not suggest that higher incidences of female-reported sinusitis relate to sex-based differences in MS anatomy. This article is protected by copyright. All rights reserved. PMID- 30471208 TI - Effect of hormone modulations on donor-derived spermatogenesis or colonization after syngeneic and xenotransplantation in mice. AB - BACKGROUND: Cytotoxic cancer treatments, such as irradiation, can cause permanent sterility in male mammals owing to the loss of spermatogonial stem cells. In animal models, spermatogenesis could be restored from transplanted spermatogonial stem cells. Previously, we showed that transient suppression of FSH, LH, and testosterone in the recipient with a gonadotropin-releasing hormone antagonist (GnRH-ant), given immediately after irradiation, enhanced spermatogenesis from transplanted spermatogonial stem cells in mice and monkeys. OBJECTIVES: To explore improvements in the preparation of the recipient for efficient and reliable spermatogenic recovery from spermatogonial stem cell transplantation, so that it can be used effectively in clinical practice. MATERIALS AND METHODS: In mouse recipients, we evaluated the effects of hormone suppression given after germ cell depletion was complete, which is a more clinically relevant model, and also the importance of total androgen ablation and maintenance of FSH levels. Three regimens, GnRH-ant, GnRH-ant plus flutamide (androgen receptor antagonist), and GnRH-ant plus FSH, were administered prior to and around the time of transplantation of testis cells from immature mice or from prepubertal monkeys. RESULTS: Treatment with GnRH-ant resulted in a fourfold increase in spermatogenic recovery from GFP-marked transplanted mouse cells. Total androgen ablation with the addition of flutamide, started two weeks before transplantation, did not further enhance recovery. Surprisingly, FSH supplementation, started around the time of transplantation, actually reduced spermatogenic recovery from transplanted spermatogonial stem cells in GnRH-ant-treated mice. When prepubertal monkey testicular cells were transplanted into nude mice that were given the same hormone treatments, the numbers of donor-derived colonies were independent of hormone treatment. DISCUSSION AND CONCLUSION: The enhancements in spermatogenic recovery may only occur when syngeneic or closely related donor-recipient pairs are used. These results are useful in further investigations in choosing a hormone suppression regimen in combination with spermatogonial transplantation as a treatment to restore fertility in primates after cytotoxic therapy. PMID- 30471209 TI - Identification of the novel HLA-A*30:02:01:04 allele in a Saudi individual. AB - HLA-A*30:02:01:04 differs from HLA-A*30:02:01:01 by a single nucleotide substitution (G?C) at position 3222. This article is protected by copyright. All rights reserved. PMID- 30471210 TI - Diversity and characterisation of polymorphic 3' untranslated region haplotypes of MICA and MICB genes. AB - MICA and MICB genes encode ligands that interact with the NK cell activating receptor, NKG2D. These ligands display a highly polymorphic allelic repertoire, although the true functional significance of this polymorphism remains elusive. We previously reported additional polymorphism in the 5'UTR proximal promoter region of these genes by sequencing international histocompatibility workshop (IHW) cell line DNA promoter and coding regions. The current study extends this analysis by further characterising the 3'UTR region of the same IHW reference panel to achieve a more complete understanding of MICA and MICB haplotype diversity and possible functional relevance. We found 17 extended MICA haplotypes encompassing the coding region and 3'UTR, including 4 novel haplotypes identified in IHW cell line DNA. This increased to 21 when also considering the 5'UTR proximal promoter region. Analysis of the MICB 3'UTR revealed two novel sequences in cell lines KLO and WIN designated MICB-UTR8 and UTR9, respectively. A total of 11 MICB haplotypes were identified in this study and 5 were unique. This study, characterising MICA/B 3'UTR polymorphism utilising IHW reference cell lines, could be useful for future studies investigating the role of microRNA in posttranscriptional repression of gene expression and for immunotherapy strategies to combat cancer progression. This article is protected by copyright. All rights reserved. PMID- 30471211 TI - The mid-fusiform sulcus (sulcus sagittalis gyri fusiformis). AB - In the human brain, the mid-fusiform sulcus (MFS; sulcus sagittalis gyri fusiformis) divides the fusiform gyrus (FG) into lateral and medial partitions. Recent studies show that the MFS is identifiable in every hemisphere and is a landmark that identifies (a) cytoarchitectonic transitions among four areas of the FG, (b) functional transitions in many large-scale maps, and (c) the location of fine-scale functional regions. Thus, simply identifying the MFS in a person's brain provides researchers with knowledge regarding: (a) how cells are organized across layers within a particular cortical location, (b) how functional representations will be laid out in cortex, and (c) the precise location of functional regions from cortical folding alone. The predictive power of the MFS can guide future studies examining the anatomical-functional organization of the FG, as well as the development of translational applications for different patient populations. Nevertheless, progress has been slow in incorporating the MFS into the broader anatomical community and into neuroanatomical reference sources. For example, even though the MFS is a rare structural-functional landmark in human association cortex as just described, it is not recognized in the recently published Terminologia Neuroanatomica (TNA). In this review, I collate the anatomical and functional details of the MFS in one place for the first time. Together, this paper serves as a comprehensive reference regarding the anatomical and functional details of the MFS, as well as provides a growing number of reasons to include the MFS as a recognized neuroanatomical structure in future revisions of the TNA. This article is protected by copyright. All rights reserved. PMID- 30471212 TI - Skull Morphology of the lizard Ptychoglossus vallensis (Squamata: Alopoglossidae) with comments on the variation within Gymnophthalmoidea. AB - In recent years, major changes have been proposed for the phylogenetic relationships within the Gymnophthalmoidea, including the description of Alopoglossidae. Recent studies relied primarily on molecular data, and have not accounted for evidence from alternative sources, such as morphology. In this study, we provide a detailed bone-by-bone description of the skull of Ptychoglossus vallensis and compare this species with other gymnophthalmoideans. The description was based on 10 cleared-and-stained specimens, four disarticulated skulls, and computed microtomography (MUCT) data of P. vallensis. Most recent phylogenetic hypothesis for the Gymnophthalmoidea was used as a framework to compare the skull of P. vallensis with other species of the Alopoglossidae, the Gymnophthalmidae, and the Teiidae. Marked similarities between alopoglossids and gymnophthalmids were observed in contrast to teiids, probably due to convergence generated by the miniaturization process. We also qualitatively analyzed the kinesis of the skull of P. vallensis concluding that is highly akinetic, a trait commonly evolved in fossorial, primarily burrowing squamates. We also describe one unique osteological feature for Alopoglossidae that is not known in any other squamate group. This article is protected by copyright. All rights reserved. PMID- 30471213 TI - AIP1 suppresses transplant arteriosclerosis through inhibition of vascular smooth muscle cell inflammatory response to IFNgamma. AB - IFNgamma-induced vascular smooth muscle cells (VSMCs) inflammatory response plays a key role in transplant arteriosclerosis (TA). However, the mechanisms regulating this process remains poorly defined. Here we show that ASK1 interacting protein 1 (AIP1) deletion markedly augments the expression of IFNgamma-induced chemokines in mouse aortic allografts. Subsequently, donor arterial grafts from AIP1 deficient mice exhibited an accelerated development of TA. Furthermore, AIP1 knockdown significantly increased IFNgamma signaling activation in cultured VSMCs and thus enhances chemokines production in response to IFNgamma. Together, we conclude that AIP1 functions as an inhibitor of VSMCs inflammation by regulating IFNgamma signaling and therefore suppresses TA progression. Our findings suggest that AIP1 might be a potential therapeutic target for chronic transplant rejection. This article is protected by copyright. All rights reserved. PMID- 30471214 TI - Early Life Trauma Predicts Affective Phenomenology and the Effects are Partly Mediated by Staging Coupled with Lowered Lipid-Associated Antioxidant Defences. AB - Background Early life trauma (ELT) may drive mood disorder phenomenology, nitro oxidative pathways and impairments in semantic memory. There are no data regarding the impact of ELT on affective phenomenology and whether these pathways are mediated by staging or lowered lipid-associated antioxidant defences. Methods This study examined healthy controls (n=54) and patients with affective disorders including major depression, bipolar disorder and anxiety disorders (n=118). ELT was assessed using the Child Trauma Questionnaire. In addition, we measured affective phenomenology and assayed advanced oxidation protein products; malondialdehyde, paraoxonase 1 (CMPAase) activity, high-sensitivity C-reactive protein (hsCRP), and high-density lipoprotein (HDL) cholesterol. Results ELT was associated into with increased risk for mood and comorbid anxiety disorders and a more severe phenomenology, including staging characteristics, depression and anxiety severity, suicidal behaviours, type of treatments, disabilities, body mass index, smoking behaviour and hsCRP, as well as lowered health-related quality of life, antioxidant defences and semantic memory. The number of mood episodes and CMPAase/HDL-cholesterol levels could be reliably combined into a new vulnerability staging-biomarker index, which mediates in part the effects of ELT on affective phenomenology and oxidative stress. Moreover, the effects of female sex on mood disorders and affective phenomenology are mediated by ELT. Discussion The cumulative effects of different ELT drive many aspects of affective phenomenology either directly or indirectly through effects of staging and/or lipid-associated antioxidant defences. The results show that children, especially girls, with ELT are at great risk to develop mood disorders and more severe phenotypes of affective disorders. PMID- 30471215 TI - A study of biological and lifestyle factors, including within-subject variation, affecting concentrations of growth differentiation factor 15 in serum. AB - Background Growth differentiation factor 15 (GDF-15) is an emerging cardiovascular biomarker, and a fully automated immunoassay has recently become available. The objectives of the study were to identify biological and lifestyle factors affecting serum GDF-15 concentrations and derive robust reference intervals, and to estimate GDF-15 within-subject biological variation and derived indices. Methods A presumably healthy population of 533 questionnaire-screened adults was used to identify the biological and lifestyle determinants of serum GDF-15. Following stringent exclusion criteria, a final group of 173 individuals was selected to establish GDF-15 reference interval. Twenty-six healthy volunteers were enrolled in the biological variation substudy. Results Using a multiple regression model, age, B-type natriuretic peptide and C-reactive protein as well as smoking status were significantly related to serum GDF-15 concentrations. The upper reference limit (URL) for serum GDF-15 concentrations (90% confidence interval [CI]) was 866 ng/L (733-999 ng/L), with no sex-related difference. Although GDF-15 tended to increase with age, the weak dependence of marker from age does not justify age-related URL. The within-subject CV was 6.3% (95% CI, 4.5%-8.5%), with no sex difference in intraindividual variances. The reference change value (RCV) for GDF-15 was 23%, and two are the specimens required to ensure that the mean GDF-15 result is within +/-10% of the individual's homeostatic set point. Conclusions By identifying the main factors influencing serum GDF-15 concentrations, we robustly established the URL to be applied in adult population. As intraindividual variation of GDF-15 is relatively low, monitoring longitudinal changes in its concentrations over time using RCV can be a good alternative for interpreting GDF-15 in clinical setting. PMID- 30471216 TI - Circulating platelet-neutrophil aggregates as risk factor for deep venous thrombosis. AB - Background Platelet-neutrophil aggregates (PNAs) are fundamental mechanisms linking hemostasis and inflammatory processes. Elevated level of PNAs have been reported in inflammatory diseases and coronary artery diseases. However, studies on the correlation between PNAs formation and deep venous thrombosis (DVT) are not available. Methods A total of 92 participants were involved in this study, including 32 cases with DVT and 60 cases without DVT. Blood samples coagulated by K2-EDTA or sodium citrate were prepared for blood cell count and blood smears. PNAs and platelet activation were measured using flow cytometry. The correlation between platelet activation level and PNAs level was analyzed by linear regression. Receiver operating characteristic (ROC) analysis was performed, assessing the prognostic performance of PNAs to predict potential risk of DVT occurrence. Results PNAs was found in the blood smears of patients with DVT. Significant increased level of PNAs was identified in DVT group (medium 8.43%, interquartile range [IQR] 4.11%-15.69%), compared with that in control group (5.16%, IQR 2.40-9.60, p<0.01). The DVT group also showed a dramatic elevated level of total platelet activation (medium 16.06%, IQR 6.04-22.05) vs. control group (11.26%, IQR 5.54-19.99, p<0.05). The PNAs level was correlated with total platelet activation (r2=0.58, p<0.0001). A significantly high odds ratio (OR) of DVT occurrence was identified when the level of PNAs was higher than 7.4% (OR 3.60, 95% confidence interval [CI] 1.463-8.838, p<0.01). Conclusions An elevated level of PNAs was associated with risk of DVT occurrence, which might be a suitable marker predicting DVT development. PMID- 30471217 TI - Creatine kinase elevation: a neglected clue to the diagnosis of polymyositis. A case report. PMID- 30471218 TI - Analytical barriers in clinical B-type natriuretic peptide measurement and the promising analytical methods based on mass spectrometry technology. AB - B-type natriuretic peptide (BNP) is a circulating biomarker that is mainly applied in heart failure (HF) diagnosis and to monitor disease progression. Because some identical amino acid sequences occur in the precursor and metabolites of BNP, undesirable cross-reactions are common in immunoassays. This review first summarizes current analytical methods, such as immunoassay- and mass spectrometry (MS)-based approaches, including the accuracy of measurement and the inconsistency of the results. Second, the review presents some promising approaches to resolve the current barriers in clinical BNP measurement, such as how to decrease cross-reactions and increase the measurement consistency. Specific approaches include research on novel BNP assays with higher-specificity chemical antibodies, the development of International System of Units (SI) traceable reference materials, and the development of structure characterization methods based on state-of-the-art ambient and ion mobility MS technologies. The factors that could affect MS analysis are also discussed, such as biological sample cleanup and peptide ionization efficiency. The purpose of this review is to explore and identify the main problems in BNP clinical measurement and to present three types of approaches to resolve these problems, namely, materials, methods and instruments. Although novel approaches are proposed here, in practice, it is worth noting that the BNP-related peptides including unprocessed proBNP were all measured in clinical BNP assays. Therefore, approaches that aimed to measure a specific BNP or proBNP might be an effective way for the standardization of a particular BNP form measurement, instead of the standardization of "total" immunoreactive BNP assays in clinical at present. PMID- 30471219 TI - Need of a dedicated isotopic internal standard for accurate 3-epi-25(OH)D3 quantification by LC-MS/MS. PMID- 30471220 TI - Impact of adipose tissue on prostate cancer aggressiveness - analysis of a high risk population. AB - Background We investigated whether visceral adiposity is associated with more aggressive disease at prostatectomy. Materials and methods Four hundred and seventy-four patients referred for postoperative adjuvant or salvage radiotherapy were included in this study. Primary endpoints were positive surgical margins (pSM) or extracapsular extension (ECE). Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were manually contoured. Univariate and multivariate logistic regression was performed. Results In univariate analysis, VAT volume (p = 0.006), adipose tissue ratio (VAT/SAT, p = 0.003), density of the SAT (p = 0.04), as well as age (p < 0.001) were associated with pSM. In the univariate analysis, SAT density was associated with a trend towards a higher rate of ECE (p = 0.051) but visceral fat volume (p = 0.01), as well as the adipose tissue ratio (p = 0.03) were both protective factors. None of the adipose tissue measurements or BMI had an influence on biochemical recurrence or overall survival (all p >= 0.5). Conclusions SAT-volume and increased SAT-density were generally associated with more aggressive prostate cancers whereas VAT as a protective factor. These findings emphasize a possible mechanism for the association between obesity and prostate cancer aggressiveness. PMID- 30471221 TI - Optimal and/or Efficient Two treatment Crossover Designs for Five Carryover Models. AB - Crossover designs robust to changes in carryover models are useful in clinical trials where the nature of carryover effects is not known in advance. The designs have been characterized for being optimal and efficient under no carryover-, traditional-, and, self and mixed carryover- models, however, ignoring the number of subjects, which has significant impact on both optimality and administrative convenience. In this article, adding two more practical models, the traditional, and, self and mixed carryover models having carryover effect only for the new or test treatment, a 5M algorithm is presented. The 5M algorithm based computer code searches all possible two treatment crossover designs under the five carryover models and list those which are optimal and /or efficient to all the five carryover models. The resultant exhaustive list consists of optimal and/or efficient crossover designs in two, three, and four periods, having 4 to 20 subjects of which 24 designs are new optimal for one of the established carryover models, and 34 designs are optimal for newly added models. PMID- 30471222 TI - Hypoglycemic and antioxidant effects of oral administration of garlic extract in the livers of type 1 diabetic rats. AB - Background Liver dysfunction is a predominant complication of diabetes. Herbal remedies such as garlic are commonly used for reducing diabetic complications. In this study the effect of garlic extract on glucose level, liver enzymes activities in the serum and nitric oxide (NO) level, oxidative stress status, and histology in the liver tissues of streptozotocin-induced diabetes (type 1) was investigated. Methods Twenty-four adult male Wistar rats were randomized and divided into four groups: control rats, diabetic rats, diabetic rats treated with garlic, and garlic-treated normal rats. Glucose level and liver enzymes activities were determined by colorimetric assay in the serum. NO levels by Griess method, oxidative stress parameters including malondialdehyde (MDA), total oxidative status (TOS), and total antioxidant capacity (TAC) by spectrophotometric method, and histopathological examination by hematoxylin and eosin staining method were evaluated in the liver tissues. Results Glucose level, liver enzymes activities, MDA, TOS, and NO levels were increased and TAC level decreased significantly in diabetic rats in comparison with control rats (p<0.01); whereas, after oral administration of garlic, glucose level, liver enzymes activities, MDA, TOS, and NO levels were decreased and TAC level increased significantly near to the normal levels (p<0.05). Conclusion The results showed the hypoglycemic and antioxidant effects of garlic in the livers of type 1 diabetic rats. PMID- 30471223 TI - Alpha-synuclein in salivary gland as biomarker for Parkinson's disease. AB - Estimates of the accuracy of clinical diagnosis of Parkinson's disease (PD) range between 46% and 90%, the accuracy of diagnosis dependent on prolonged clinical observation and clinical response to levodopa. For this reason, we need reliable diagnostic biomarkers. The cardinal hallmark of PD is alpha-synuclein aggregation in the brain. Demonstrating pathological alpha-synuclein in live patients would be useful for identifying and monitoring PD patients. By autopsy studies and in vivo studies, the presence of alpha-synuclein has been demonstrated even outside the central nervous system and the gastro-enteric tract appears to be the most promising candidate tissue for biopsy-taking and the esophagus and salivary glands appear to be the area with the highest concentration of alpha-synuclein. The purpose of our study is to conduct a review to determine the utility of salivary gland biopsy for the histological diagnosis of PD. A computerized medline study was carried out through the use of pubmed: using the MeSH terms: 'salivary gland biopsy for PD', 'PD and dysphagia', 'alpha-synuclein and salivary gland'. We found 9 articles about minor salivary glands and submandibular gland biopsy for diagnosis of PD. According to the results of this review, the submandibular gland biopsy is the test with the increased sensitivity and specificity compared to the biopsy of the minor salivary glands (sensitivity: 0.85 and 0.37 respectability and specificity: 0.96 and 0.94 respectively). New studies are necessary on a wider population to confirm these results. PMID- 30471224 TI - Suppression of Apoptosis in Human Umbilical Vein Endothelial Cells (HUVECs) by Klotho Protein is Associated with Reduced Endoplasmic Reticulum Oxidative Stress and Activation of the PI3K/AKT Pathway. AB - BACKGROUND Klotho protein has been shown to act as a hormone on the cardiovascular system, and to have specific protective effects on vascular endothelial cells. The aim of this study was to investigate the mechanisms of the anti-oxidative and anti-apoptotic effects of klotho protein on hydrogen peroxide (H2O2)-induced apoptosis and endoplasmic reticulum oxidative stress in human umbilical vein endothelial cells (HUVECs). MATERIAL AND METHODS HUVECs were cultured in vitro and treated with H2O2. The MTT assay evaluated cell viability of H2O2-treated HUVECs, and flow cytometry measured cell apoptosis. An enzyme linked immunosorbent assay (ELISA) measured the levels of nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), and interleukin (IL)-6. Western blot was used to detect the expression of the proteins, 78 kD glucose-regulated protein (GRP78), CCAAT-enhancer-binding protein homologous protein (CHOP), caspase-3, caspase-9, caspase-12, and AKT. The effects of LY294002, a pharmacological inhibitor of PI3K, were evaluated. RESULTS Klotho protein increased the viability of H2O2-treated HUVECs and reduced the expression of NO, TNF-alpha, and IL-6. Klotho protein reduced the rate of apoptosis of H2O2-treated HUVECs and downregulated the expression of proteins associated with endoplasmic reticulum oxidative stress, GRP78 and CHOP, and the expression of the apoptotic proteins, caspase-3, caspase-9, and caspase-12, and activated the phosphorylation of AKT. The addition of LY294002 inhibited klotho protein downregulation of GRP78, CHOP, caspase-3, caspase-9, and caspase-12 expression. CONCLUSIONS In HUVECs, klotho protein suppressed apoptosis mediated by endoplasmic reticulum oxidative stress by activation of the PI3K/AKT pathway. PMID- 30471225 TI - Lack of correlation between serum 25(OH)D level and endoscopy-based chronic rhinosinusitis in Korean adults. AB - BACKGROUND: Several previous studies have shown that serum 25(OH)D deficiency is associated with increased risk of chronic rhinosinusitis (CRS) in adults and also correlated with disease severity. We aimed to investigate the correlation between serum 25(OH)D level and endoscopy-based CRS in adults using the Korean National Health and Nutrition Examination Survey. METHODS: The data were based on the Korean National Health and Nutrition Examination Survey from 2008 to 2011. Diagnosis of endoscopy-based CRS was based on endoscopic findings of mucopurulent rhinorrhea in the middle meatus or nasal polyps, with nasal symptoms satisfying symptom-based CRS based on European Position Paper on Rhinosinusitis and Nasal Polyps 2012 criteria. Nasal symptoms included nasal obstruction, anterior/posterior nasal drip, facial pain, and the loss of smell. Serum 25(OH) D level was defined as deficient (less than 20 ng/mL), insufficient (20-29.9 ng/mL), or sufficient (less than or equal to 30 ng/mL). RESULTS: The serum 25(OH)D level in the CRS group was 19.293 'plus or minus' 7.035 ng/mL, which was higher than that of the control group (18.057 'plus or minus' 6.56 ng/mL, p = 0.0072). Among symptom combinations of endoscopy-based CRS, some combinations with mucopurulent rhinorrhea at the middle meatus were significantly related to normal serum 25(OH)D level. CONCLUSION: Low serum 25(OH)D level might not be associated with increased prevalence of CRS in Korean adults; rather, patients with CRS showed higher serum 25(OH)D levels than the control group. Thus, these results, contradicting those of previous studies, should be further verified in other countries to investigate the role of the serum 25(OH)D in CRS. PMID- 30471226 TI - Clinical efficacy of intranasal drug delivery by nebulization in chronic rhinosinusitis: a systematic review. AB - BACKGROUND: Treatment of chronic rhinosinusitis (CRS) aims to treat the underlying inflammation or infection. Although the optimal modality of administration remains controversial, inhalation route is usually preferred. The aim of this systematic review was to summarize the efficacy of intranasal corticoisteroids or antibiotics delivery by nebulization on symptoms, histology, endoscopy scores, nasal obstruction, clinical outcomes and quality of life in CRS. METHOD: This systematic review followed the PRISMA guidelines. Randomized controlled, comparative and cohort studies evaluating effects of treatment by nebulization in sinusitis were identified and reviewed from two databases (PubMed and Scopus). Two reviewers independently assessed study quality and reviewed the selected studies. RESULTS: 600 references were retrieved and 12 studies evaluating 377 patients were included in the systematic review. Different devices were used. Efficacy of nasal delivery by nebulization was systematically observed on symptoms and size of polyps and frequently on inflammatory parameters in all studies. The presence of polyps improved the efficacy of the nebulization. This way of delivery appears not convincing regarding antibiotics. Few side effects were noted in the retrieved studies and only for nebulized antibiotics. CONCLUSIONS: This systematic review highlighted that based on the present literature nebulization is not better than nasal spray to the delivery of corticosteroids due to the positive results on symptoms, endoscopic appearance and histological outcomes. For antibiotics delivery, the nebulization is not of added value. PMID- 30471227 TI - Similar survival outcome after endoscopic and open approaches for sinonasal mucosal melanoma. AB - BACKGROUND: To describe a cohort of sinonasal mucosal melanoma (SNMM) patients, and to assess if choice of surgical approach (open versus endoscopic) has impact on survival. METHODOLOGY: Adequate data on clinical presentation, treatment, and recurrence pattern were available for 58 consecutive patients treated for SNMM at the Helsinki University Hospital (HUH) between 1983 and 2016. RESULTS: The 5-year disease-specific survival (DSS) was 27% and overall survival 25% for the whole cohort. The 3-year DSS for patients treated with curative intent with endoscopic surgery was comparable to open surgery (56% and 51%, respectively). Patients with tumours arising from the paranasal sinuses and patients with Stage IV disease had significantly worse prognosis compared with other locations and Stage III patients. All patients who had disease persistence at three months after primary treatment succumbed to SNMM. Post-operative radiotherapy did not affect survival significantly, but a trend towards improved local control was observed. CONCLUSIONS: Local control after endoscopic surgery was comparable to open surgery. Small tumours without local or locoregional spread had improved prognosis, independent of surgical approach. Disease persistence after treatment with curative intent led to death invariably. PMID- 30471228 TI - The potential application of Concentrated Growth Factor in regenerative endodontics. AB - AIM: To investigate the potential application of concentrated growth factor (CGF) to promote pulp regeneration of immature teeth. METHODOLOGY: CGF clots produced from peripheral blood samples were investigated histologically by haematoxylin eosin (HE) staining and evaluated morphologically by scanning electron microscope (SEM). The cytokines were extracted from the CGF and representative cytokines were quantified by enzyme-linked immuno sorbent assay (ELISA). The biological effects of the CGF on human stem cells from the apical papilla (SCAPs) were then investigated and quantified, including cell proliferation, cell migration, mineralized nodule formation, and the gene expression of alkaline phosphatase (ALP), dentine sialophosphoprotein (DSPP) and dentine matrix protein (DMP)-1. The results were analysed statistically using one-way analysis of variance (ANOVA). RESULTS: CGF had a complex three-dimensional structure with a high density of platelets and nucleated cells. Representative growth factors including PDGF-BB, IGF-1, TGF-beta1, bFGF, and VEGF were detected. The growth rate and migratory cell numbers of the CGF groups were significantly greater than those in the control groups (p<0.05). The mineralization areas in the CGF groups were significantly larger than those in the control groups (p<0.05). The expression levels of ALP,DSPP and DMP-1 were significantly up-regulated after induction by CGF (p<0.05). CONCLUSIONS: CGF promoted the proliferation, migration and differentiation of SCAPs and could be a promising bio-material applied in regenerative endodontics. This article is protected by copyright. All rights reserved. PMID- 30471230 TI - Perspective. PMID- 30471229 TI - Deep sequencing of small RNAs from 11 tissues of grass carp Ctenopharyngodon idella and discovery of sex-related microRNAs. AB - This research identified 169 known microRNAs (mirNA) mirNAs, 380 novel mirNAs, and 30,538 targets in 11 tissues (blood, brain, derma, gill, heart, intestine, kidney, liver, muscle, pronephros, and spleen) from grass carp Ctenopharyngodon idella with high-throughput sequencing (HTS). Transcripts per million (TPM) expression analysis detected 41 brain-enriched mirNAs (accounting for 61.19% of all tissue-enriched mirNAs). Real-time quantitative PCR (rt-qPCR) confirmed that 21 of 24 randomly selected tissue-enriched mirNAs from the TPM analysis were indeed tissue-enriched (P < 0.05), suggesting the HTS and TPM analyses were reliable. Nine of the 41 brain-enriched mirNAs are complementary to members of the double-sex and mab-3 related transcription factor family (dmrt) involved in sex differentiation. rt-qPCR revealed that cid-mir-138 was more highly expressed in testis than in ovary (P < 0.01), while the reverse was true for target gene dmrt4a (P < 0.01). This opposite expression pattern suggested the direct participation of cid-mir-138-dmrt4a in neuroendocrine mechanisms related to brain pituitary networks during sex development. The discovery of mirNAs from 11 C. idella tissues expands the available fish mirNA database, and enhances our understanding of the role of sex-related mirNAs in tissue differentiation and maintenance of specific tissue functions in fishes. This article is protected by copyright. All rights reserved. PMID- 30471231 TI - Monkeyflowers (Mimulus): new model for plant developmental genetics and evo-devo. AB - Contents Summary I. Introduction II. The system III. Regulation of carotenoid pigmentation IV. Formation of periodic pigmentation patterns V. Developmental genetics of corolla tube formation and elaboration VI. Molecular basis of floral trait variation underlying pollinator shift VII. Outlook Acknowledgements References SUMMARY: Monkeyflowers (Mimulus) have long been recognized as a classic ecological and evolutionary model system. However, only recently has it been realized that this system also holds great promise for studying the developmental genetics and evo-devo of important plant traits that are not found in well-established model systems such as Arabidopsis. Here, I review recent progress in four different areas of plant research enabled by this new model, including transcriptional regulation of carotenoid biosynthesis, formation of periodic pigmentation patterns, developmental genetics of corolla tube formation and elaboration, and the molecular basis of floral trait divergence underlying pollinator shift. These examples suggest that Mimulus offers ample opportunities to make exciting discoveries in plant development and evolution. PMID- 30471232 TI - Changes in serum levels of leucine-rich alpha2-glycoprotein predict prognosis in primary biliary cholangitis. AB - AIMS: A noninvasive biomarker for patients with primary biliary cholangitis (PBC) is needed. The association between leucine-rich alpha 2 glycoprotein (LRG) and PBC has not been investigated. We aimed to assess the predictive value of LRG for the development of cirrhosis-related conditions in PBC. METHODS: We retrospectively reviewed clinical data of 129 individuals with biopsy-confirmed PBC. LRG was analyzed by enzyme-linked immunosorbent assays using stored sera at biopsy (N = 129) and after treatment (N = 80). RESULTS: LRG levels decreased significantly after treatment (55.8 MUg/mL vs 39.8 MUg/mL, P < 0.001). LRG and delta-LRG were not associated with transaminase or histological findings. Delta LRG > 0 (hazard ratio [HR] 4.61, P = 0.013), delta-LRG > 0 and an AST/platelet ratio index (APRI) > 0.76 (HR 458, P < 0.001) were associated with the development of a cirrhosis-related condition. Patients with a delta-LRG > 0 and an APRI > 0.76 had a significantly increased rate of developing cirrhosis-related conditions (P < 0.001). CONCLUSIONS: Changes in LRG levels after treatment predicted PBC prognosis but were not associated with histological stage. Changes in LRG in addition to the APRI may be a useful tool for clinicians as a noninvasive biomarker. PMID- 30471233 TI - Absence of Intestinal Microbiota during Gestation and Lactation Does Not Alter the Metabolic Response to a Western-type Diet in Adulthood. AB - SCOPE: Microbiota composition in early life is implied to affect the risk to develop obesity in adulthood. It is unclear whether this risk is due to long lasting microbiome-induced changes in host metabolism. This study aims to identify whether the presence or total absence of early-life microbiota affects host metabolism in adulthood. METHODS AND RESULTS: The effects of a germ-free (Former GF) versus conventional status during gestation and lactation on the metabolic status in adult offspring are compared. Upon conventionalization at weaning, all mice were metabolically challenged with a Western-type diet (WTD) at 10 weeks age. Between age 10 and 30 weeks, a former GF status does not notably affect overall body weight gain, cholesterol metabolism, glucose tolerance or insulin sensitivity at adult age. However, Former GF mice have lower bile flow and bile acid secretion in adulthood, but similar bile acid composition. CONCLUSIONS: A germ-free status during gestation and lactation does not substantially affect key parameters of the metabolic status before 10 weeks of age on chow diet or in adulthood following a WTD challenge. These data imply that microbiota in early life does not critically affect adult metabolic plasticity. PMID- 30471234 TI - A nanoparticle-coupled T2 peptide induces immune tolerance and ameliorates chronic prostatitis/ chronic pelvic pain syndrome (CP/CPPS) in mice model. AB - Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a complex disease of unclear etiology. Precise treatment of CP/CPPS is not available due to lack of specific cause; however, autoimmunity is the most valid theory. We develop a new treatment strategy that involves synthesis and coupling of biodegradable nanoparticles to antigenic T2 peptide to induce immune tolerance in CP/CPPS mice models. 50 male C57BL/6 mice were randomized into five groups, i.e. naive, Model, PLGA-PEMA, PLGA-PEMA-OVA323-339 , and PLGA-PEMA-T2 group. All groups except naive were injected subcutaneously on day 0 with 0.2ml of T2 peptide with CFA to generate valid CP/CPPS models. After successful induction of CP/CPPS, Model group, PLGA-PEMA, PLGA-PEMA-OVA and PLGA-PEMA-T2 groups were treated with 0.15 mL of normal saline, 0.2mg of PLGA-PEMA and PLG-PEMA-T2 and 0.3mg PLGA-PEMA-OVA nanoparticles respectively on day 28. Hematoxylin and eosin staining, and ELISA were used to evaluate the variation in CP/CPPS manifestations and seral level of IL-10 in each group. Pain threshold and voiding behavior were also recorded for every group. Mice treated with PLGA-PEMA-T2 exhibited enhanced pain threshold, reduced urine frequency, and prostate pathology. Furthermore, serum level of inflammatory mediators (TNF-alpha and CRP) were reduced and anti-inflammatory IL 10 was enhanced in PLGA-PEMA-T2 group as compared to other groups. Our results demonstrate that PLGA-PEMA-T2 nanoparticle ameliorates disease manifestations in CP/CPPS mice models and upregulates IL-10 which is essential for tolerance induction. This strategy highlights the new therapeutic approach utilizing biodegradable nanoparticles for the treatment of CP/CPPS. This article is protected by copyright. All rights reserved. PMID- 30471235 TI - Carbon balance and source-sink metabolic changes in winter wheat exposed to high night-time temperature. AB - Carbon loss under high night-time temperature (HNT) leads to significant reduction in wheat yield. Growth chamber studies were carried out using six winter wheat genotypes, to unravel post-heading HNT (23o C) induced alterations in carbon balance, source-sink metabolic changes, yield and yield related traits compared to control (15o C) conditions. Four of the six tested genotypes recorded a significant increase in night respiration after four days of HNT exposure, with all the cultivars regulating carbon loss and demonstrating different degree of acclimation to extended HNT exposure. Metabolite profiling indicated carbohydrate metabolism in spikes and activation of the TriCarboxylic Acid (TCA) cycle in leaves as important pathways operating under HNT exposure. A significant increase in sugars, sugar-alcohols, and phosphate in spikes of the tolerant genotype (Tascosa) indicated osmolytes and membrane protective mechanisms acting against HNT damage. Enhanced night respiration under HNT resulted in higher accumulation of TCA cycle intermediates like isocitrate and fumarate in leaves of the susceptible genotype (TX86A5606). Lower grain number due to lesser productive spikes and reduced grain weight due to shorter grain-filling duration determined HNT induced yield loss in winter wheat. Traits and mechanisms identified will help catalyze the development of physiological and metabolic markers for breeding HNT-tolerant wheat. PMID- 30471236 TI - Caregiver Communication About Cancer: Development of a mhealth resource to support family caregiver communication burden. AB - OBJECTIVE: The aim of this study is to illustrate an evidence-based and theoretically informed mhealth resource (smartphone app) designed to provide communication support for informal cancer caregivers (friends or family members). METHODS: An eight-step process was conducted: (a) review of existing print resources; (b) selection of theoretical framework for content development; (c) integration of stakeholder feedback and literacy assessment into an alpha print model; (d) review of existing mhealth resources; (e) development of prototype; (f) assessment of caregiver acceptability (n=5); (g) assessment of quality and perceived impact by cancer providers (n=26); and (h) acceptability testing with caregivers (n=6). RESULTS: Key stakeholders were integrated throughout development and user testing of this iOS smartphone app. The smartphone app consists of talking tips and resources for caregiver communication with the patient, family, far away family, and healthcare providers, as well as general information sharing features. CONCLUSIONS: This study demonstrates feasibility and development of an evidence-based and theory-driven mhealth resource to support caregiver communication about cancer. This is the first theory-driven mhealth application created to support the communication burden experienced by cancer caregivers. A larger study is needed to establish the efficacy of the app as an intervention for caregivers. PMID- 30471237 TI - Defining Treatment Effects: A Primer for Non-Statisticians. AB - It would often be of interest to know the effect of a drug, compared to control, in people who take the drug. However, different people will likely take drug and control. Then comparing takers of drug to takers of control does not yield a drug effect. Drug effects in drug takers can be estimated, but first they must be carefully defined. This article is protected by copyright. All rights reserved. PMID- 30471238 TI - Examining peer support and survivorship for African American women with breast cancer. AB - OBJECTIVE: More than 3.5 million female breast cancer (BrCa) survivors live in the United States, and the number continues to grow. Health status and quality of life amongst survivors is variable, and African American (AA) survivors suffer disproportionately from BrCa morbidity and mortality. Emerging evidence suggests peer support is an effective strategy to promote positive survivorship outcomes for AA BrCa survivors. This study aimed to explore the role of peer support in the BrCa experiences of AA survivors. METHODS: Working collaboratively with The Breakfast Club, Inc. (BCI), a community-based BrCa peer support organization, we conducted a quasi-experiment to compare the BrCa experiences of AA survivors. We conducted in-depth interviews with two survivor groups (N=12 per group), categorized according to receiving peer support during their BrCa experiences. RESULTS: Survivors who received peer support reported greater access to and utilization of alternative support sources, more capacity to process BrCa-related stress, and improved quality of life and adjustment to life as BrCa survivors compared to those who did not receive peer support. CONCLUSIONS: Peer relationships provide consistent, quality social support. Consistent peer support helps survivors cope with the continued stress of BrCa, with implications for psychosocial health and quality of life. Findings expand our current understanding of peer support and may enable public health and clinical practitioners to better recognize and intervene with those for whom additional support services are needed. PMID- 30471239 TI - Energy-resolved mass spectrometry for differentiation of the fluorine substitution position on the phenyl ring of fluoromethcathinones. AB - A reliable method for structural analysis is crucial for the forensic investigation of new psychoactive substances (NPSs). Towards this end, mass spectrometry is one of the most efficient and facile methods for the identification of NPSs. However, the differentiation among 2-, 3-, and 4 fluoromethcathinones (o-, m-, and p-FMCs), which are ring-fluorinated positional isomers part of the major class of NPSs referred to as synthetic cathinones, remains a challenge. This is mostly due to their similar retention properties and nearly identical full scan mass spectra, which hinder their identification. In this study, we describe a novel and practical method for differentiating the fluorine substitution position on the phenyl ring of FMCs, based on energy resolved mass spectrometry (ERMS) using an electron ionization-triple quadrupole mass spectrometer. ERMS measurements showed that the three FMC positional isomers exhibited differences in relative abundances of both the fluorophenyl cation (m/z 95) and the fluorobenzoyl cation (m/z 123). The logarithmic plots of the abundance ratio of these two cations (m/z 95 to m/z 123) as a function of the collision energy (CE) followed the order of o-FMC < p-FMC < m-FMC at each CE, which allowed the three isomers to be unambiguously and reliably differentiated. The theoretical dissociation energy calculations confirmed the relationship obtained by ERMS analyses, and additional ERMS measurements of methylmethcathinone positional isomers showed that the differences in abundance among the FMCs were attributed to the differences in their collision-induced dissociation reactivities arising from the halogen-induced resonance effects on the phenyl ring. Moreover, the method for differentiation described herein was successfully applied to the actual samples containing seized drugs. We expect that the described methodology will also contribute significantly to the reliable and accurate structural identification of NPSs in the fields of therapeutic, clinical, and forensic toxicology. PMID- 30471240 TI - Quantitative Urinary Proteome Reveals Potential Biomarkers for Ureteropelvic Junction Obstruction. AB - PURPOSE: Ureteropelvic junction obstruction (UPJO) is a common obstructive disease. To investigate useful urinary biomarkers in UPJO children, the urinary proteome in UPJO infants is analyzed and it is compared with normal controls. EXPERIMENTAL DESIGN: A tandem mass tag (TMT)-based quantitative proteomics study is performed to analyze the proteome of bladder urine (BU) and pelvis urine (PU) from unilateral UPJO infants with differential renal function less than 40% and they are compared with normal control urine (CON). GO analysis is then utilized to analyze general characterization of the proteins. Proteomic results are verified by western blot. RESULTS: There are 81 and 186 proteins significantly changed in BU and PU groups, respectively, as compared to the CON group. Fifty proteins overlaps are found between these two sets of statistically significant differential proteins. These 50 common differential proteins are involved in multiple biological processes. The increased urinary abundance of Fetuin-A, AGP1, AGP2, Alpha-1-microglobulin/Bikunin Precursor (AMBP), and prostaglandin-H2D isomerase (PGDS) are verified by western blot analysis. CONCLUSIONS AND CLINICAL RELEVANCE: This proteomic analysis indicates that urinary Fetuin-A, AGP1, AGP2, protein AMBP, and PGDS may serve as noninvasive potential biomarkers and these proteins can help to further yield pathological mechanisms involved in UPJO. PMID- 30471241 TI - Comparison of topical 5-fluorouracil and interferon alfa-2b as primary treatment modalities for ocular surface squamous neoplasia. AB - PURPOSE: To compare the efficacy of topical 5-fluorouracil 1% (5FU) and interferon alfa-2b 1 MIU/mL (IFN) eye drops as primary treatment modalities for ocular surface squamous neoplasia (OSSN). DESIGN: Retrospective, comparative, interventional case series. METHODS: Fifty-four patients who received 5FU and 48 patients who received IFN as primary therapy for OSSN were included. Primary outcome measures were the frequency of clinical resolution and time to OSSN recurrence by treatment modality. Secondary outcome was the frequency of side effects with each therapy. RESULTS: The mean age of patients was 68 years. More Hispanics were treated with 5FU. In a univariable analysis, frequency of OSSN resolution was higher with 5FU (96.3%, n = 52) than with IFN (81.3%, n = 39), p=0.01. In a multivariable analysis, treatment modality did not remain a significant predictor of resolution. In patients whose OSSN resolved, time to resolution was similar with both agents, (5FU - mean 6.6 months, standard deviation (SD) 4.5 versus IFN - mean 5.5 months, SD 2.9, p = 0.17). Of the 52 eyes whose OSSN resolved with 5FU, 11.5 % of lesions (n=6) recurred while of the 39 eyes whose OSSN resolved with IFN, 5.1% of lesions (n = 2) recurred, p=0.46. Kaplan Meier survival curves of OSSN recurrence were similar between groups (log rank=0.16). One-year recurrence rates were 11.4% with 5FU and 4.5% with IFN. Eyelid edema (p=0.04) and tearing (p=0.02) were more significant with 5FU. CONCLUSIONS: This is the first direct comparison study between 5FU and IFN eye drops as primary treatment modalities for OSSN. Both modalities resulted in a high frequency of tumor resolution and low recurrence rates and are effective treatment options for OSSN. PMID- 30471242 TI - Assessment of the Impact of an Endpoint Committee in the Ocular Hypertension Treatment Study. AB - PURPOSE: To assess the impact of a masked Endpoint Committee on estimates of the incidence of primary open angle glaucoma (POAG), treatment efficacy and statistical power of the Ocular Hypertension Treatment Study-Phase 1, 1994-2002 (OHTS-1). DESIGN: Retrospective inter-rater reliability analysis of endpoint attribution by the Endpoint Committee METHODS: After study closeout, we re calculated estimates of endpoint incidence, treatment efficacy and statistical power using all-cause endpoints and POAG endpoints. To avoid bias, only the first endpoint per participant is included in this report. RESULTS: The Endpoint Committee reviewed 267 first endpoints from 1,636 participants. The Endpoint Committee attributed 58% (155 of 267) of the endpoints to POAG. The incidence of all-cause endpoints vs. POAG endpoints was 19.5% and 13.2% respectively in the observation group and 13.1% and 5.8% respectively in the medication group. Treatment effect for all-cause endpoints was a 33% reduction in risk (relative risk = 0.67, 95% CI of 0.54-0.84) and a 56% reduction in risk for POAG endpoints (relative risk = 0.44, 95% CI of 0.31-0.61). Post-hoc statistical power for detecting treatment effect was 0.94 for all-cause endpoints and 0.99 for POAG endpoints. CONCLUSION: Endpoint Committee adjudication of endpoints improved POAG incidence estimates, increased statistical power, and increased calculated treatment effect by 23%. An Endpoint Committee should be considered in therapeutic trials when common ocular and systemic co-morbidities, other than the target condition, could compromise study results. PMID- 30471243 TI - Detection of anti-adalimumab antibodies in a RA responsive cohort of patients using three different techniques. AB - Reliable monitoring of clinical relevant anti-drug antibodies is fundamental in the follow-up of patients under adalimumab treatment. The aim of this study is to compare anti-adalimumab antibodies by using three methods based on different technologies. A cross-sectional study was performed in 50 patients with rheumatoid arthritis (RA) treated with adalimumab. Anti-adalimumab antibodies were detected in patients' sera by different techniques: bridging ELISA, reporter gene assay (RGA), and surface plasmon resonance (SPR). Results showed that all methods recognized anti-adalimumab antibodies and the percentage of positives fluctuated among the assays. Five (10%) of the 50 patients were positive in ELISA, 4 (8%) in RGA, and 6 (12%) in SPR. Among positive patients, 4 were positive in the three assays, one patient uniquely in ELISA, and two in SPR. Spearman correlation between ELISA and RGA showed good agreement (Spearman r = 0.800). No correlation between RGA and SPR was observed (Spearman r = 0.108). Similar results were obtained between ELISA and SPR (Spearman r = - 0.241). Summarizing, ELISA, RGA and SPR recognized anti-adalimumab antibodies in few RA patients, showing good agreement among the methodology employed. On the other hand, differences observed between SPR and ELISA or RGA highlight the relevance of the employed technologies in anti-drug antibody identification. PMID- 30471244 TI - Assessment of conventional PCR and real-time PCR compared to the gold standard method for screening Streptococcus agalactiae in pregnant women. AB - Group B Streptococcus (GBS) is a causative agent of invasive neonatal infections. Maternal colonization by GBS is a necessary condition for vertical transmission, with efficient screening of pregnant women playing an essential role in the prevention of neonatal infections. In this study, we aimed to compare the performance of conventional polymerase chain reaction (PCR) and real-time PCR (qPCR) assays as screening methods for GBS in pregnant women against the microbiological culture method considered as the gold-standard. A total of 130 samples from pregnant women were analyzed for sensitivity, specificity, positive predictive value, and negative predictive value. Statistical analysis was performed using the SPSS software, version 20.0. The verified colonization rate was 3.8% with the gold-standard, 17.7% with conventional PCR assay, and 29.2% with the qPCR test. The trials with conventional PCR and qPCR had a sensitivity of 100% and a specificity of 85.6% and 73.6%, respectively. The qPCR assay had a better performance compared to the gold-standard and a greater detection rate of colonization by SGB compared to conventional PCR assay. With its quick results, it would be suitable for using in routine screenings, contributing to the optimization of preventive approaches to neonatal GBS infection. PMID- 30471245 TI - Constrained-induced movement therapy promotes motor function recovery by enhancing the remodeling of ipsilesional corticospinal tract in rats after stroke. AB - Constraint-induced movement therapy (CIMT), which forces the use of the impaired limb by restraining the unaffected limb, has been used extensively for the recovery of limb motor function after stroke. However, the underlying mechanism of CIMT remains unclear. Diffusion tensor imaging (DTI) is a well-known neuroimaging technique that reflects the microstructure of white matter tracts and potential changes associated with different treatments. The aim of this study is to use DTI imaging to determine how corticospinal tract (CST) fibers remodel in ischemic rats with CIMT. In the present study, rats were randomly divided into three groups: a middle cerebral artery occlusion group (MCAO), a therapeutic group (MCAO+CIMT), and a sham-operated group (sham). A plaster cast was used to restrict the unaffected limb of the rats in the MCAO+CIMT group for 14 days. The Catwalk system was used to assess the limb motor function of rats. Fractional anisotropy (FA) and the average diffusion coefficient (ADC) of the CST were quantified through DTI. The expression of the c-Jun-N-terminal kinase signaling pathway (JNK) was examined after 14 days of CIMT. We found that CIMT could accelerate and enhance motor function recovery, and the MCAO+CIMT group showed significantly increased FA values in the ipsilesional posterior limb of internal capsule (PLIC) compared with the MCAO group. In addition, we found no significant difference in the ratio of phosphorylated-JNK/total-JNK among the three groups, whereas the expression of P-JNK decreased significantly in the chronic phase of stroke. In conclusion, CIMT-induced functional recovery following ischemic stroke through facilitation of the remodeling of ipsilesional CST, and restoration after ischemic stroke may be associated with the declining value of the ratio of P JNK/JNK. PMID- 30471246 TI - Long non-coding RNAs and cervical cancer. AB - Cervical cancer is determined as the second highest number of deaths factor in female cancers. Here is a need to find new biomarkers for detection and preliminary prognosis, metastasis. To find new treatment to enhance the survival of cervical cancer patients, pivotal actions are necessitated to be implemented. Long non-coding RNAs (lncRNAs) appear to be the crucial modulators in various processes and critically influence the oncogenesis. The commencement and general review actions of the following lncRNAs HOTAIR, H19, XIST, CCHE1, EBIC, MALAT1, ANRIL, LET, NEAT1, BLACAT1, UFC1, SNHG16 and SNHG20 are focused in this review article. Roles of the lncRNAs in cervical cancer in terms of prognosis and tumor progression, invasion and metastasis, apoptosis, and radio-resistance are pointed out. In this review the utilization of lncRNAs as biomarkers in cervical cancer prognosis for metastasis is discussed. An overview of this review will be useful for selection of biomarkers in diagnosis, prognosis, and targeted therapy of cervical cancer in the future. PMID- 30471247 TI - Clomiphene citrate induces nuclear translocation of the TFEB transcription factor and triggers apoptosis by enhancing lysosomal membrane permeabilization. AB - The autophagy-lysosome pathway plays a central role in cellular homeostasis by regulating the cellular degradative machinery. The transcription factor EB (TFEB) regulates the biogenesis and function of both lysosomes and autophagosomes, and enhancement of TFEB function has emerged as an attractive therapeutic strategy for lysosome-related disorders. However, little is known about the role of TFEB activation in regulating the cellular fate. Here, we describe that clomiphene citrate (CC), a selective estrogen receptor modulator, promotes nuclear translocation of TFEB and increases lysosomal biogenesis in HeLa and MDA-MB-231 cells. Treatment with CC inhibits cell viability and causes apoptosis by increasing the release of proteases cathepsin B (CatB) and cathepsin D (CatD) from lysosomes into the cytosol. In contrast, knockdown of TFEB rescues the cells from CC-induced cell death. Furthermore, CC-induced TFEB activation also enhances the autophagy flux in HeLa cells. Knockdown of autophagy-related gene 7 (ATG7) significantly decreases the CC-induced CatB and CatD release and cell death, suggesting that autophagy contributes to the lysosomal membrane permeabilization (LMP) caused by CC. Altogether, these findings have broad implications for our understanding of TFEB function and provide new insights into CC pharmacological therapy. PMID- 30471248 TI - Diagnostic value of cerebro-spinal fluid biomarkers in dementia with lewy bodies. AB - Dementia with Lewy Bodies (DLB) is the second most common form of dementia after Alzheimer's disease (AD), accounting for 15% to 20% of neuropathologically defined cases. Two-thirds of the patients affected are not or misdiagnosed because of the clinical similarity of these two pathologies. In this review, we evaluate the discriminatory power of cerebrospinal fluid (CSF) biomarkers by focusing more specifically on differential diagnosis between DLB and AD. We focus on the AD biological biomarkers used in clinical routine as well as the biomarkers under study and more particularly the alpha-synuclein assay. Thus, among the AD biomarkers (t-Tau, phospho-Tau181, Abeta42 and Abeta40) used routinely, t-Tau and phospho-Tau181 have shown excellent discrimination whatever the clinical stages severity. Abeta42 level is pathological in DLB patients at the demented stage, but is almost not impacted at the prodromal stage. Alpha synuclein assay in the CSF has also an interest in the discrimination between DLB and AD but not in segregation between DLB and healthy elderly subjects. Thus, globally the biological diagnosis on CSF basis makes it possible, to separate the DLBs from the ADs. In addition, the development of biomarkers such as phospho alpha-synuclein and oligomeric alpha-synuclein should help to reinforce this discrimination power. PMID- 30471249 TI - Applicability of liver stiffness measurement based nomograms to the assessments of hepatitis B related significant fibrosis and cirrhosis. AB - BACKGROUND: We evaluated liver fibrosis in patients with chronic hepatitis B (CHB) and mildly raised alanine transaminase (ALT) activities between 1-2 times the upper limit of normal (ULN) which was near the threshold for initiating treatment. METHODS: Nomogram-Fibrosis and Nomogram-Cirrhosis were elaborated with variables independently associated with significant fibrosis and cirrhosis determined by multivariate logistic regression. Calibration, receiver operator characteristic (ROC) and decision curves were applied to comparing nomograms with aspartate aminotransferase (AST) to platelet count (PLT) ratio index (APRI), age AST-PLT-ALT index (FIB-4) and liver stiffness measurement (LSM). RESULTS: The Nomogram-Fibrosis was constructed with LSM, PLT, and gamma-glutamyl transpeptidase (GGT). Nomogram-Cirrhosis contained one more variable of age other than Nomogram-Fibrosis. The calibration demonstrated that the assessments of significant fibrosis or cirrhosis by nomograms were in line with liver biopsy. The AUROC of Nomogram-Fibrosis was 0.788, lager than APRI (0.586), FIB-4 (0.656) and LSM (0.735). The AUROC of Nomogram-Cirrhosis was 0.889, larger than APRI (0.642), FIB-4 (0.725) and LSM (0.837). Furthermore, the decision curve analysis suggested the most net benefits were provided by the nomograms. CONCLUSIONS: Nomogram-Fibrosis and Nomogram-Cirrhosis could be promising tools for recognizing significant fibrosis and cirrhosis for CHB patients with mild raised ALT activities. PMID- 30471250 TI - Functional gene expression of dopamine receptors in the male reproductive organ during sexual maturation in the honey bee (Apis mellifera L.). AB - Dopamine is a potential integrator between the central nervous system and reproductive system in insects. To test for a possible action of dopamine on the male reproductive organ via hemolymph in honey bees, relative expression levels of dopamine receptor genes and second messenger levels responding to dopamine in the reproductive organ were quantified. Protein content of the three parts of the reproductive organ (testes, seminal vesicles, and mucus glands) differed depending on the age of bees: the protein content of the testes decreased, whereas that of the seminal vesicles and mucus glands increased as males aged. Relative expression levels of dopamine receptor genes (Amdop1, Amdop2, Amdop3 and Amgpcr19) in each part of the reproductive organ were detected and were lower than those in the brain. Expression of all these genes was significantly higher in the seminal vesicles than in testes and mucus glands. Expression of Amgpcr19 was significantly higher in testes of 8-day-old males than in males of other ages, and was highest in the seminal vesicles of 4-day-old males. Cyclic adenosine monophosphate (cAMP) levels responding to dopamine in seminal vesicles were significantly higher in 10-3 M dopamine immersion than in 10-4 M, 10-5 M dopamine, and controls. However, no significant differences in cAMP levels between control and dopamine immersion were detected in testes and mucus glands. These results suggest that the dopamine receptors in seminal vesicles can be driven by dopamine for reproduction, including sperm transfer and storage in the male reproductive organ. PMID- 30471251 TI - Validation study of neurotrophin-3-releasing chitosan facilitation of neural tissue generation in the severely injured adult rat spinal cord. AB - It was previously reported that a tube holding chitosan carriers loaded with neurotrophin-3 (NT-3), after insertion into a 5 mm long transection gap in the adult rat spinal cord, triggered de novo neural tissue generation and functional recovery. Here, we report an effort to validate these findings using stringent blinding methodologies, which are crucial for robustness in reproducing biomedical studies. Radio frequency identification (RFID) chips were utilized to label rats that were randomly assigned into three experimental groups: transection with chitosan-NT-3 implant (C-NT3), transection only (T-controls), and laminectomy only (S-controls), blinding the experimenters to the treatments. Three months after surgery, animals only known by their RFID were functionally, electrophysiologically, and anatomically assessed. The data were then collected into the proper groups and statistically analyzed. Neural tissue with nestin-, Tuj1-, and NeuN-positive cells was found bridging the transection gap in C-NT3 rats, but not in T-controls. Motor- and somatosensory-evoked potentials were detected in C-NT3 rats and S-controls, but not in T-controls. Hind limb movement was significantly better in C-NT3 rats compared with T-controls. Our validation study indicates that C-NT3 implants facilitate neural tissue generation, at least in part, by eliciting endogenous neurogenesis. Our data support the use of C-NT3 implants for tissue remodeling in the injured spinal cord. PMID- 30471252 TI - Perspective: Mutations in Recessive Congenital Ichthyoses Illuminate the Origin and Functions of the Corneocyte Lipid Envelope. AB - The corneocyte lipid envelope (CLE), a monolayer of pi-hydroxyceramides, whose function(s) remain(s) uncertain, is absent in autosomal recessive congenital ichthyoses (ARCI) with mutations in enzymes that regulate epidermal lipid synthesis. Secreted lipids fail to transform into lamellar membranes in certain ARCI epidermis, suggesting the CLE provides a scaffold for the extracellular lamellae. But since cornified envelopes (CEs) are attenuated in these ARCI, the CLE may also provide a scaffold for subjacent CE formation, evidenced by restoration of CEs after CLE 'rescue.' We provide multiple lines of evidence that the CLE originates as lamellar body (LB) limiting membranes fuse with the plasma membrane: i) ABCA12 patients and Abca12-/- mice display normal CLEs; ii) CLEs are normal in Netherton syndrome, despite destruction of secreted LB contents; iii) CLEs are absent in VSP33B-negative patients; iv) limiting membranes of LBs are defective in lipid-synthetic ARCI; and v) lipoxygenases, lipase activity and LIPN co-localize within putative LBs. PMID- 30471253 TI - Three-dimensional optical clearing and imaging of pruritic atopic dermatitis and psoriasis skin reveals downregulation of epidermal innervation. PMID- 30471254 TI - Color and spatial frequency differentially impact early stages of perceptual expertise training. AB - The current study examined the role of color and spatial frequency on the early acquisition of perceptual expertise after one week of laboratory training with bird stimuli. Participants learned to categorize finches (or warblers) at the subordinate species level (e.g., purple finch) and categorize warblers (or finches) at the more general family level. Training images were presented in their natural colors across 6 sessions. Participants completed a subordinate level species matching task prior to training, one day after training and one week after training while event-related potentials (ERPs) were recorded. Bird images were presented in either their natural congruent color, incongruent color, grayscale, low spatial frequency (LSF < 8 cycles per image) or high spatial frequency (HSF > 8 cycles per image). Replicating previous training studies, performance benefited more from subordinate- than basic-level training. Before training, any color helped performance, but color congruence effects (congruent > incongruent) only emerged after subordinate-level training. Spatial frequency manipulations did not interact with training. The N170 ERP component was sensitive to spatial frequency manipulations, but not color. N170 spatial frequency effects did not interact with training, and training effects generalized to all manipulations except the LSF images. Like performance, color congruence effects on the N250 were only observed after subordinate level training. These results are consistent with previous reports suggesting that effects of perceptual expertise training on performance are more clearly indexed by N250 than N170 effects. Taken together, our behavioral and ERP results show that color plays an important role in both low- and high- level visual processing, supporting surface-plus-edge-based theories for object processing and recognition. PMID- 30471255 TI - Allosteric Modulation of Binding Specificity by Alternative Packing of Protein Cores. AB - Hydrophobic cores are often viewed as tightly packed and rigid, but they do show some plasticity and could thus be attractive targets for protein design. Here we explored the role of different functional pressures on the core packing and ligand recognition of the SH3 domain from human Fyn tyrosine kinase. We randomized the hydrophobic core and used phage display to select variants that bound to each of three distinct ligands. The three evolved groups showed remarkable differences in core composition, illustrating the effect of different selective pressures on the core. Changes in the core did not significantly alter protein stability, but were linked closely to changes in binding affinity and specificity. Structural analysis and molecular dynamics simulations revealed the structural basis for altered specificity. The evolved domains had significantly reduced core volumes, which in turn induced increased backbone flexibility. These motions were propagated from the core to the binding surface and induced significant conformational changes. These results show that alternative core packing and consequent allosteric modulation of binding interfaces could be used to engineer proteins with novel functions. PMID- 30471256 TI - A New Mechanism for High-Affinity Uptake of C4-Dicarboxylates in Bacteria Revealed by the Structure of Rhodopseudomonas palustris MatC (RPA3494), a Periplasmic Binding Protein of the Tripartite Tricarboxylate Transporter (TTT) Family. AB - C4-dicarboxylates play a central role in cellular physiology as key metabolic intermediates. Under aerobic conditions, they participate in the citric acid cycle, while in anaerobic bacteria, they are important in energy-conserving fermentation and respiration processes. Ten different families of secondary transporters have been described to participate in C4-dicarboxylate movement across biological membranes, but only one of these utilizes an extracytoplasmic solute binding protein to achieve high-affinity uptake. Here, we identify the MatBAC system from the photosynthetic bacterium Rhodopseudomonas palustris as the first member of the tripartite tricarboxylate transport family to be involved in C4-dicarboxylate transport. Tryptophan fluorescence spectroscopy showed that MatC, the periplasmic binding protein from this system, binds to l- and d-malate with Kd values of 27 and 21 nM, respectively, the highest reported affinity to date for these C4-dicarboxylates, and to succinate (Kd = 110 nM) and fumarate (Kd = 400 nM). The 2.1-A crystal structure of MatC with bound malate shows a high level of substrate coordination, with participation of two water molecules that bridge hydrogen bonds between the ligand proximal carboxylic group and the main chain of two conserved loops in the protein structure. The substrate coordination in MatC correlates with the binding data and explains the protein's selectivity for different substrates and respective binding affinities. Our results reveal a new function in C4-dicarboxylate transport by members of the poorly characterized tripartite tricarboxylate transport family, which are widely distributed in bacterial genomes but for which details of structure-function relationships and transport mechanisms have been lacking. PMID- 30471257 TI - Preparing For A Post-Roe World. AB - Changes in the make-up of the Supreme Court make an overturn of the Roe v Wade decision a realistic possibility. In order to mitigate any adverse health consequences that could result from a change in the law, all stakeholders in women's health have to start to plan for that contingency. These stakeholders include physicians, nurse midwives, nurses, their professional organizations, health advocacy groups, health policy experts, and legislators. Among the tasks for physicians and their professional organization, we include education about the management of women injured by unsafe abortions, post residency training for physicians with reduced access to residency training in abortion, and planning for the management of medically complicated pregnancies that are often currently terminated (e.g. Eisenmenger's syndrome). In this piece we argue for preparation for a potential post-Roe world. PMID- 30471258 TI - Incidence and Risk Factors of Early Post-Operative Small Bowel Obstruction in Patients Undergoing Hysterectomy for Benign Indications. AB - BACKGROUND: Small bowel obstruction (SBO) is a major cause of postoperative mortality and morbidity following abdominal and pelvic surgery with 225,000 to 345,000 annual admissions. SBO may be classified based on onset from day of surgery. Early SBO occurs within the first 30 days following surgery, while late SBO, occurs after the initial 30-day postoperative window; the majority of either type of bowel obstruction is believed to be secondary to intra-abdominal adhesions. Early SBO warrants special attention due to the difficulty in distinguishing between mechanical and non-mechanical obstruction during this period. While conservative management often leads to resolution of non-mechanical obstruction and some partial SBO, surgical management is associated with a higher rate of complications compared to surgery for late SBO due to the presence of hypervascular adhesions in the early postoperative period. The current literature regarding SBO, and early SBO in particular, following hysterectomy is limited. Given that approximately 400,000 hysterectomies are performed annually, understanding the risks factors associated with SBO following these types of surgeries is imperative to improving patient outcomes. OBJECTIVE: The objective of this study was to evaluate the incidence of and risk factors for early small bowel obstruction (SBO) after hysterectomy for benign indications. STUDY DESIGN: This was a retrospective cohort study using data from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database from 2014 to 2016. Current Procedural Terminology codes were used to identify patients undergoing hysterectomy for benign indications with or without concomitant colpopexy, lysis of adhesions (LOA), adnexectomy, or appendectomy. Patient demographics, clinical and surgical factors were obtained. Patients were then stratified to those with and without and SBO. Pairwise comparison was performed using the Wilcoxon rank-sum test and Fisher's exact tests. Multivariable logistic regression was used to identify significant independent predictors of SBO RESULTS: Out of 47,937 hysterectomies, SBO occurred in 286 patients at a rate of 5.9 per 1000 hysterectomies. Comparing patients with and without SBO, those with an obstruction were older (49 years vs 46 years, p<0.001), more likely to smoke (21.0% vs 15.8%, p=0.02), have a history of prior abdominal surgery, (73.4% vs 65.4%, p=0.005), to have medical comorbidities such as hypertension and dyspnea. Patients experiencing SBO were also more likely to undergo abdominal hysterectomy (72.0% vs 21.2%, p<0.001), adhesiolysis (5.2% vs 2.1%, p<0.001), appendectomy (1.7% vs 0.5%, p=0.02) and cystotomy repair (1.0% vs 0.3%, p= 0.002). After logistic regression, route of hysterectomy was not a significant risk factor for SBO, while wound class >3 (aOR=5.96, 95%CI: 2.71-12.99) and perioperative transfusion (aOR=5.01, 95%CI: 3.54-7.13) were the most significant risk factors. Additional risk factors for early SBO included non-white race (aOR= 1.84, 95%CI: 1.33-2.48), increasing age (aOR=1.04, 95%CI: 1.02-1.05), prior abdominal or pelvic surgery (aOR=1.49, 95%CI: 1.17-2.03), operating times exceeding 170 minutes (aOR=1.90, 95%CI: 1.37-2.58), uterine weight greater than 250 grams (aOR=1.54, 95%CI: 1.11-2.14), lysis of adhesions (aOR=2.10, 95%CI: 1.23-3.66), and concurrent appendectomy (aOR=2.64, 95%CI: 1.06-). CONCLUSIONS: Early small bowel obstruction is a rare complication of benign hysterectomy. While route of hysterectomy was not found to be a significant risk factor for early SBO, variables typically associated with abdominal hysterectomy compared to minimally invasive hysterectomy, including higher wound class, larger uteri, and perioperative transfusion (a marker of intraoperative blood loss), were strongly correlated with subsequent development of early obstruction. PMID- 30471259 TI - Responsiveness and Minimally Important Difference of SF-6D and EQ-5D Utility Scores for the Treatment of Pelvic Organ Prolapse. AB - BACKGROUND: Utility preference scores are standardized generic health related quality of life (HRQOL) measures that quantify disease severity and burden and summarize morbidity on a scale from 0 (death) to 1 (optimum health). Utility scores are widely used to measure HRQOL and in cost-effectiveness research. OBJECTIVE: To determine the responsiveness, validity properties and minimal important difference (MID) of utility scores, as measured by the Short Form 6D (SF-6D) and EuroQol (EQ-5D), in women undergoing surgery for pelvic organ prolapse (POP). STUDY DESIGN: This study combined data from four large U.S. multicenter surgical trials enrolling 1,321 women with pelvic organ prolapse. We collected condition-specific quality of life data using the Pelvic Floor Distress Inventory (PFDI) and Pelvic Floor Impact Questionnaire (PFIQ). A subset of women completed the SF6D; women in two trials also completed the EQ5D. Mean utility scores were compared from baseline to 12 months after surgery. Responsiveness was assessed using effect size (ES) and standardized response mean (SRM). Validity properties were assessed by 1) comparing changes in utility scores at 12 months between surgical successes and failures as defined in each study and 2) correlating changes in utility scores with changes in the PFDI and PFIQ. MID was estimated using both anchor-based (SF-36 general health global rating scale "somewhat better" vs. "no change") and distribution-based methods. RESULTS: The mean SF-6D score improved 0.050, from 0.705 +/- 0.126 at baseline to 0.761 +/- 0.131 at 12 months, p<0.01. The mean EQ-5D score improved 0.060, from 0.810 +/- 0.15 at baseline to 0.868 +/- 0.15 at 12 months, p<0.01. ES (0.13-0.61) and SRM (0.13-0.57) were in the small to moderate range, demonstrating responsiveness of the SF-6D and EQ-5D similar to other conditions. SF-6D and EQ-5D scores improved more for prolapse reconstructive surgical successes than failures. The SF-6D and EQ-5D scores correlated with each other (r=0.41; n=645) and with condition specific instruments. Correlations with the PFDI and PFIQ and their prolapse subscales were in the low to moderate range (r=0.09-0.38), similar to other studies. Using the anchor-based method, the MID was 0.026 for SF-6D and 0.025 for EQ-5D, within the range of MIDs reported in other populations and for other conditions. These findings were supported by distribution-based estimates. CONCLUSION: The SF-6D and EQ-5D have good validity properties and are responsive preference-based utility and general HRQOL measures for women undergoing surgical treatment for prolapse. The MIDs for SF-6D and EQ-5D are similar and within the range found for other medical conditions. PMID- 30471260 TI - Changing disparities in teen birth rates and repeat birth rates in Georgia: implications for teen pregnancy prevention. AB - OBJECTIVE: To understand teen birth trends in Georgia by racial and geographic factors. STUDY DESIGN: We analyzed overall birth and repeat teen birth rates by race, urban/rural status, and adequacy of obstetric care from 2008-2016 using vital records from all Georgia counties. RESULTS: Overall birth rates among teens analyzed decreased dramatically in Georgia, from 45.63 births per 1000 teens in 2008-2010 to 26.28 per 1000 teens in 2014-2016. Repeat birth rates followed a similar decline, from 9.40 to 4.53 repeat births per 1000 teens over the same time period. These rates decreased in all sub-groups of teens, however to varying degrees. The difference in birth and repeat birth rates between black and white teens decreased four-fold during this time period, whereas the declines in these rates for teens living in rural versus urban counties and with inadequate versus adequate obstetric care were less pronounced. CONCLUSION: While remarkable reductions in teen birth and repeat birth rates have occurred since 2008, these declines have not been equally experienced by all groups of teens. IMPLICATIONS: Our analysis suggests that persistent disparities in teen birth and repeat birth rates exist, particularly in areas with limited or threatened access to reproductive health care. Applying targeted teen pregnancy prevention initiatives to these areas could help ensure equitable health and social outcomes for teens. PMID- 30471261 TI - Effect of contraceptive choice on rapid repeat pregnancy. AB - OBJECTIVE: To describe the prevalence of rapid repeat pregnancy (RRP), defined as repeat pregnancy within 18months of delivery, in a large health system, and to determine the impact of contraceptive method on RRP. STUDY DESIGN: Retrospective cohort. RESULTS: The prevalence of rapid repeat pregnancy among patients who delivered in August 2014 (n=804) was 27.2%. After controlling for age and sociodemographic characteristics, women experiencing RRP were less likely to have used long-acting reversible contraception (LARC) (aOR 0.45, 95%CI 0.24-0.85, p=.014; RRP in 19% of implant and 18% of IUD users), and more likely to have been prescribed a progestin-only pill (aOR 5.106, 95%CI 2.157-12.083, p<.001; RRP in 53% of users) compared to women choosing all other reversible contraceptive methods. CONCLUSIONS: Postpartum LARC decreases the odds of RRP, while a prescription for progestin-only pills is not protective. PMID- 30471262 TI - Steroid reservoir loss during removal of perforated Levonorgestrel 52mg intrauterine device. AB - A 22-year-old G1P1 Caucasian female had hysteroscopic removal of a perforated intrauterine device during which the steroid reservoir of the intrauterine device was lost. Isolated steroid reservoirs are radiolucent on plain film radiography. We located the reservoir in the peritoneal cavity with magnetic resonance imaging and removed it via laparoscopy. PMID- 30471263 TI - An in-depth analysis of the use of shared decision making in contraceptive counseling. AB - OBJECTIVE(S): Shared Decision Making (SDM) has emerged as a useful tool to promote patient-centered communication and is highly applicable to contraceptive decision making. Little is known about how SDM is operationalized in contraceptive counseling. This study aimed to explore and describe how SDM is used in the contraceptive counseling context. METHODS: We analyzed a selection of transcripts from a larger study of 342 audio-recorded visits in which contraceptive counseling occurred in the San Francisco Bay Area. A previous study team had identified 106 transcripts that demonstrated principles of SDM. We randomly selected 40 transcripts from this group for deeper analysis. We coded transcripts using directed content analysis to understand the process of SDM in the context of contraceptive counseling. We focused on how the previously identified phases of SDM (information sharing, deliberation, and decision making) occurred in these visits and identified emerging themes. RESULTS: Rather than consisting of distinct phases, our analysis found that in contraceptive counseling, the information sharing and deliberation stages of SDM were largely integrated in an iterative back and forth process between patient and provider. The final decision-making phase was directed by the patient, who retained the final choice. CONCLUSION: Our analysis found that the use of SDM in the contraceptive counseling context reflected the intimacy and complexity of contraceptive decision making. These findings can be used as a foundation for future work to develop training designed to integrate SDM in a manner appropriate to the context of contraception, including prioritizing patient autonomy and acknowledging pre-existing preferences of patients. PMID- 30471264 TI - Predictors of Post-abortion Contraception Use in Cambodia. AB - OBJECTIVE: To evaluate which characteristics collected at the point of abortion are associated with contraceptive use over the extended post-abortion period for women in Cambodia. METHODS: The study includes a cohort of 500 women who attended a Marie Stopes International Cambodia clinic for an induced abortion. The primary outcomes are use of effective contraception>=80% of the time over the four and 12 month period post-abortion. We conducted a bivariate analysis to assess the association between each characteristic and the outcome, followed by multivariable modelling to identify the strongest predictors of the outcomes. RESULTS: Nearly 44% of the women used contraception for more than 80% of the time during both follow-up periods. Several socio-demographic and reproductive factors were crudely associated with the outcomes. In the multivariable model, prior use of contraception, intention to use post-abortion contraception, increased number of children and medical abortion were associated with increased contraceptive use over the year post-abortion. Occupation was a predictor at four months only, and abortion method at 12months only. CONCLUSIONS: The models were satisfactory in predicting the outcome of contraceptive continuation both at four and 12months. The paper sets out a methodology for modelling these predictors that can help inform more client-centred counselling and services for women. IMPLICATIONS: Factors known when attending a clinic for induced abortion can help inform more targeted and client-centred post-abortion family planning counselling and services for women in Cambodia. PMID- 30471265 TI - Misalignment of sexual and reproductive health priorities among older Latino adolescents and their mothers. AB - OBJECTIVE: The study describes maternal and adolescent perspectives on sexual decision-making and the role of mothers in shaping use of contraception for the prevention of unplanned pregnancies and STIs among older Latino adolescents. STUDY DESIGN: Researchers used a semi-structured interview guide to conduct focus group discussions with 21 mother-adolescent Latino dyads (n=42). Latino adolescents ages 17-19 were eligible for the study. We recruited families from the South Bronx, New York City using area sampling methodology. For analysis of qualitative data, we used the framework method involving open coding, identification of dominant themes, refining of codebooks, and indexing. RESULTS: Overwhelmingly, results suggest asymmetric priorities and preferences regarding maternal involvement in older adolescent sexual and contraceptive decision making. Mothers primarily employed practices designed to prevent adolescent sexual activity. Most teens reported already having experienced sexual debut and were currently sexually active. Adolescents expressed a strong interest in practical support for sexual decision-making, including maternal guidance regarding effective access to and use of contraception. Mothers offered limited guidance or support with such matters. Maternal views focused entirely on the health and social consequences of sex, in lieu of specific guidance on contraception for older sexually active adolescents. The findings highlight a missed opportunity for Latino mothers to support their older adolescent children to prevent unplanned pregnancies, STIs, and HIV. CONCLUSION: Mothers have the potential to positively shape adolescent contraceptive decision-making and behavior. Misalignment of priorities between mothers and adolescents diminishes the potential of reducing adolescent sexual and reproductive health (SRH) disparities. IMPLICATIONS: Mothers are influential in reducing adolescent SRH risk. However, asymmetric priorities among Latino adolescents and their mothers regarding support for SRH reduces likelihood of reducing adolescent negative SRH outcomes and supporting adolescent health. Programs supporting better alignment of maternal guidance and adolescent SRH needs are warranted. PMID- 30471266 TI - Papillae revisited and the nature of the adhesive secreting collocytes. AB - Ascidian papillae (palps) constitute a transient sensory adhesive organ that assures larval settlement and the onset of metamorphosis to the filterfeeding adult. Despite the importance of papillae for the ascidian development, their cellular composition is only roughly described. For Ciona intestinalis/robusta, a clear definition of cell numbers and discriminative molecular markers for the different cell types is missing. While some attention was given to neural cell types and their connectivity little is known about the adhesive producing collocytes. We converge serial-section electron microscopy and confocal imaging with various marker combinations to document the 3D organization of the Ciona papillae. We show the papillar development with 4 axial columnar cells (ACCs), 4 lateral primary sensory neurons (PSNs) and 12 central collocytes (CCs). We propose molecular markers for each cell type including novel ones for collocytes. The subcellular characteristics are suggestive of their role in papillar function: the ACCs featuring apical protrusions and microvilli, also contain neuroactive and endocytic vesicles indicative of a chemosensory role. They are clearly distinct from the ciliated glutamatergic PSNs. CCs encircle the ACCs and contain microvilli, small endocytic vesicles and notably a large numbers of adhesive granules that, according to element analysis and histochemistry, contain glycoproteins. Interestingly, we detect two different types of collocyte granules, one of them containing fibrous material and larger quantities of polysaccharides. Consistently, carbohydrate specific lectins label the papillar apex, the granules within CCs and the adhesive plaques upon larval attachment. We further propose CCs to derive from an evolutionary ancient neurosecretory cell type. Our findings contribute to understanding the development of the anterior ('new head') region of the Ciona larva and notably the adhesive secreting cells which has implications for developmental biology, cell differentiation and evolution, but also bioadhesion. PMID- 30471267 TI - Transcriptional regulation of Rab32/38, a specific marker of pigment cell formation in Ciona robusta. AB - Through a myriad of pigments stored in different pigment cells, animal pigmentation represents a crucial process to face disparate environmental and ecological challenges. Rab32 and Rab38 proteins are conserved small GTPases that, in vertebrates, are involved in the transport of key melanogenic enzymes, as tyrosinase (tyr) and tyrosinase-related protein (tyrp), to the melanosomes in formation. We provide a survey on Rab32/38 evolution and its regulatory logics during pigment cell formation in Ciona robusta. Our phylogeny supports the existence of a single Rab32/38 gene in tunicates, which is probably the unique transporter for tyrosinase family members in this clade. Different deletions allow us to identify the minimal cis-regulatory element able to recapitulate the endogenous gene expression during pigment cell development in C. robusta. In this conserved region, we identified two putative binding sites for the transcription factor Mitf, which is known for its conserved role as regulator of pigmentation in vertebrates. Mutational analysis revealed that both Mitf binding sites are essential for the activity of this regulatory region and we demonstrated that Mitf misexpression is able to induce ectopic activation of the Rab32/38 regulatory region in vivo. Our results strongly indicate that Mitf is involved in the regulation of Rab32/38 activity during Ciona pigment cell development. PMID- 30471268 TI - Accuracy of algorithms to identify pulmonary arterial hypertension in administrative data: a systematic review. AB - BACKGROUND: The diagnosis of pulmonary arterial hypertension (PAH) is challenging, and there is significant overlap with the more heterogenous diagnosis of pulmonary hypertension (PH). Clinical and research efforts that rely on administrative data are limited by current coding systems that do not adequately reflect the clinical classification scheme. The aim of this systematic review is to investigate current algorithms to detect PAH using administrative data and to appraise the diagnostic accuracy of these algorithms against a reference standard. METHODS: We conducted comprehensive searches of MEDLINE, Embase, and Web of Science from their inception. We included English-language articles that applied an algorithm to an administrative or electronic health record database to identify PAH in adults. RESULTS: Of 2,669 unique citations identified, 32 studies met all inclusion criteria. Only four of these studies validated their algorithm against a reference standard. Algorithms varied widely, ranging from single International Classification of Diseases (ICD) codes to combinations of visit, procedure, and pharmacy codes. ICD codes alone performed poorly, with positive predictive values ranging from 3.3% to 66.7%. The addition of PAH-specific therapy and diagnostic procedures to the algorithm improved the diagnostic accuracy. CONCLUSIONS: Algorithms to identify PAH in administrative databases vary widely and few are validated. The sole use of ICD codes performs poorly, potentially leading to biased results. ICD codes should be revised to better discriminate between PH groups, and universally accepted algorithms need to be developed and validated to capture PAH in administrative data, better informing research and clinical efforts. PMID- 30471269 TI - Effect of Combined beta-Lactam / Macrolide Therapy on Mortality According to the Microbial Aetiology and Inflammatory Status of Patients with Community - Acquired Pneumonia. AB - BACKGROUND: Antibiotic combinations that include macrolides have shown lower mortality rates than beta-lactams in monotherapy or combined with fluoroquinolones in patients with community-acquired pneumonia (CAP). However, this effect has not been studied according to the levels of C-reactive protein (CRP) in CAP with identified microbial cause. OBJECTIVES: In patients with CAP and known microbial cause we aimed to evaluate 30 day mortality of a beta-lactam plus macrolide (BL+M) compared to a fluoroquinolone alone with or without a beta lactam (FQ+/-BL) METHODS: We analysed a prospective observational cohort of patients with CAP admitted to Hospital Clinic of Barcelona between 1996 to 2016. We only included patients with known microbial cause. RESULTS: Of 1,715(29%) patients with known aetiology, a total of 932 patients (54%) received BL+M. Despite a lower crude mortality in the BL+M group in the overall population (BL+M 5% vs. FQ+/-BL 8% p=0.015), after adjusted by a propensity score and baseline characteristics, the combination of BL+M had a protective effect on mortality only in patients with high inflammatory response (C-reactive protein >15 mg/dL) and pneumococcal CAP, (adjOR 0.28, 95%CI 0.09 to 0.93). No benefits on mortality were observed for the population without high inflammatory response and pneumococcal CAP or with other etiologies. CONCLUSIONS: The combination of a beta lactam with a macrolide was associated with a decreased mortality in patients with pneumococcal CAP and, in patients with high systemic inflammatory response. When both factors occurred together, BL+M were protective for mortality in the multivariate analysis. PMID- 30471270 TI - Solriamfetol for the treatment of excessive sleepiness in obstructive sleep apnea: A placebo-controlled randomized-withdrawal study. AB - BACKGROUND: Excessive sleepiness is a common symptom of obstructive sleep apnea (OSA), which often persists despite primary OSA therapy. This phase 3 randomized withdrawal trial evaluated solriamfetol (JZP-110) for the treatment of excessive sleepiness in adults with OSA. METHODS: After 2 weeks of clinical titration (n=174) and 2 weeks of stable dosing (n=148), participants who reported improvement on the Patient Global Impression of Change (PGI-C) and had numerical improvements on the Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) were randomized to placebo (n=62) or solriamfetol (n=62) for 2 additional weeks; 13.4% of participants did not enter the Randomized-Withdrawal phase due to not meeting the criteria for improvement during the Stable-Dose phase. Co-primary endpoints were change from weeks 4 to 6 in MWT and ESS. RESULTS: In the modified intent-to-treat population (n=122), MWT mean sleep latencies and ESS scores were improved from baseline to week 4 (from 12.3-13.1 to 29.0-31.7 minutes and from 15.3-16.0 to 5.9-6.4, respectively). From weeks 4 to 6, solriamfetol-treated participants maintained improvements (least squares [LS] mean [SE] changes of -1.0 [1.4] minutes on MWT and -0.1 [0.7] on ESS), whereas placebo-treated participants worsened (LS mean change of -12.1 [1.3] minutes on MWT and 4.5 [0.7] on ESS); LS mean differences between treatments were 11.2 minutes (95% CI 7.8, 14.6) and -4.6 (95% CI -6.4, -2.8) on MWT and ESS, respectively. Fewer solriamfetol participants reported worsening on the PGI-C from weeks 4 to 6 (20% versus 50%; P=.0005). The most common adverse events included headache, dry mouth, nausea, dizziness, and insomnia. CONCLUSIONS: This study demonstrated maintenance of solriamfetol efficacy and safety over 6 weeks. (clinicaltrials.gov identifier NCT02348619; EudraCT number 2014-005515-16). PMID- 30471271 TI - Incorporating Innovation and New Technology into Cardiothoracic Surgery. AB - The appropriate implementation of new technology, root cause analysis of "imperfect" outcomes and the continuous reappraisal of postgraduate training are needed to improve the care of tomorrow's patients. Healthcare delivery remains one of the most expensive sectors in the United States and the application of new and expensive technology that is necessary for the advancement of this complex specialty must be aligned with providing the best care for our patients. There are a several pathways to innovation; one is partnering with industry and the other is the investigational laboratory. Innovation and the funding thereof come from both the public and the private sector. The majority of new trials that are likely to impact cardiothoracic surgery are industry sponsored trials to meet the requirements necessary for regulatory approval. Cost considerations are paramount when considering integration of innovative technology and treatments into a clinical cardiothoracic surgical practice. The value of any new innovation is determined by the quality divided by the cost, and lean initiatives maximize this equation. The importance and implications of conflict of interest (COI) has been a concern for physicians particularly when new technology or procedures are being incorporated into clinical practice and full disclosures by medical professionals and others involved are essential. Our "societies" and "associations" provide a platform for presentation and peer-reviewed discussion of new procedures, innovations, and trials, etc. and provide a venue for the sharing of knowledge on the highest quality patient care through education and research. PMID- 30471272 TI - Experimental Pig Heart Xenotransplantation - Recent Progress and Remaining Problems. PMID- 30471274 TI - A brief history of studies of ventricular twisting: a tribute to Dr Gerald Buckberg. PMID- 30471273 TI - Patient-specific multiscale modeling of the Assisted Bidirectional Glenn. AB - BACKGROUND: First-stage palliation of neonates with single-ventricle physiology is associated with poor outcomes and challenging clinical management. Prior computational modeling and in vitro experiments introduced the assisted bidirectional Glenn (ABG), which increased pulmonary flow and oxygenation over the bidirectional Glenn (BDG) and the systemic-to-pulmonary shunt in idealized models. In this study, we demonstrate that the ABG achieves similar performance in patient-specific models and assess the influence of varying shunt geometry. METHODS: In a small cohort of single-ventricle pre-stage 2 patients, we constructed 3-dimensional in silico models and tuned lumped parameter networks (LPN) to match clinical measurements. Each model was modified to produce virtual BDG and ABG surgeries. We simulated the hemodynamics of the stage-1 procedure, BDG, and ABG using multiscale computational modeling, coupling a finite-element flow solver to the LPN. Two levels of pulmonary vascular resistances (PVR) were investigated: baseline (low) PVR of the patients, and doubled (high) PVR. The shunt nozzle diameter, anastomosis location, and shape were also manipulated. RESULTS: The ABG increased the pulmonary flow rate and pressure by 15-20%, which was accompanied by a rise in SVC pressure (2-3 mmHg) at both PVR values. Pulmonary flow rate and SVC pressures were most sensitive to the shunt nozzle diameter. CONCLUSIONS: Patient-specific ABG performance was similar to prior idealized simulations and experiments, with good performance at lower PVR values in the range of measured clinical data. Larger shunt outlet diameters and lower PVR led to improved ABG performance. PMID- 30471275 TI - Continuous suction isoperistaltic gastroesophagostomy for esophageal perforation. AB - Esophageal perforation is a surgical emergency with significant morbidity. Management of this condition is complex and constantly evolving. This is the first case series describing repair of esophageal perforation with the use of an isoperistaltic gastroesophagostomy tube connected to continuous suction. We present three patients successfully managed using this technique. PMID- 30471276 TI - A 20 Year Experience with Resection of Primary Cardiac Tumors and Metastatic Tumors of the Heart. AB - BACKGROUND: Cardiac tumors are uncommon, occurring in less than one percent of the population, and are comprised of numerous tumor types. Management of certain tumors types such as sarcoma have evolved and improved in the recent era. We evaluate the outcomes of patients who underwent resection of benign or malignant cardiac tumors with a focused review of cardiac sarcomas. METHODS: Institutional data was reviewed from 1997 to 2017 and 180 patients who underwent tumor resection were identified. Outcomes and survival were examined based on tumor type. RESULTS: Two-thirds (119/180) of patients had benign tumors. Of 61 malignant tumors, 23 were sarcomas, 24 were cavo-atrial tumors and eight were T4 lung tumors. In the sarcoma group, operative mortality was 2/23 (9.1%). Neoadjuvant therapy was administered to 8/23 (34.8%) with R0 resection achieved in 5/8 (62.5%). R0 resection was successful in 7/15 (46.7%) without neoadjuvant therapy. Mean survival with neoadjuvant therapy was 2.76+/-3.85 years versus 1.28+/-1.31 years without (p=0.428). Mean survival with R0 resection was 2.79+/ 4.23 years compared to 1.64+/-1.63 years without (p=0.407). In the T4 lung tumor group, operative mortality was zero and R0 resection was achieved in 6/8 (75%). The cavo-atrial tumors were mostly renal cell carcinoma resected with a mortality of 4.5%. CONCLUSIONS: Cardiac tumors are comprised of diverse tumor types. Indications for, and benefits of, resecting benign tumors and many malignant tumor types are clear and operative outcomes are generally good. Cardiac sarcomas benefit from neoadjuvant therapy, which improves the rate of complete resection, thus improving survival. PMID- 30471277 TI - Immunoglobulin G4 related disease association with an isolated anterior mediastinal tumor. AB - We treated a patient with immunoglobulin G4-related disease (IgG4-RD) exhibiting an isolated anterior mediastinal mass with high 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) accumulation, which mimicked thymoma. The 71-year-old male who had a 47 mm anterior mediastinal mass shadow, was referred to our department. As positron emission tomography(PET) revealed the mass to have a high level of FDG accumulation, we diagnosed it as suspected thymoma; thoracoscopic resection of the tumor was then performed. Immunohistological findings, however, yielded a diagnosis of IgG4-RD. Despite its rarity, IgG4-RD should be borne in mind as a potential diagnosis in case of isolated anterior mediastinal mass shadow. PMID- 30471278 TI - Response to Adding Post-Operative Adjuvant Radiation In N2 lung cancer. PMID- 30471279 TI - Thermosensitive chitosan-gelatin-based hydrogel containing curcumin-loaded nanoparticles and latanoprost as a dual-drug delivery system for glaucoma treatment. AB - Elevated intraocular pressure (IOP) in glaucoma is due to impairment of aqueous humor drainage via the uveoscleral or trabecular outflow pathway. Latanoprost reduces IOP by increasing the uveoscleral outflow. Despite its potency, long-term daily application of it may cause undesirable side effects and many require more than one medication for IOP control. Recent studies have suggested that oxidative stress in the trabecular meshwork (TM) play an important role in the pathogenesis of impaired trabecular outflow facility. Curcumin, a natural phenolic compound, possesses anti-oxidant and anti-inflammation properties. In this study, we developed a thermosensitive hydrogel containing latanoprost and curcumin-loaded nanoparticles (CUR-NPs), and evaluated its possible therapeutic effects with cultured human TM cells under oxidative stress. The results demonstrated that 20 MUM of CUR-NPs might be the optimal concentration to treat TM cells without causing cytotoxicity. Using the newly developed system, both latanoprost and CUR NPs displayed a sustained-release profile. Treatment with this hydrogel containing CUR-NPs effectively decreased the oxidative stress-mediated damage in TM cells via decreasing inflammation-related gene expression, mitochondrial reactive oxygen stress (ROS) production and apoptosis level. The in vivo biocompatibility revealed no signs of inflammation or damage after topical application of developed hydrogel in rabbits. These results suggest that this dual-drug delivery system might enhance both trabecular and uveoscleral outflow and is promising to develop into a novel treatment for glaucoma. PMID- 30471280 TI - Biomechanical changes to Descemet's membrane precede endothelial cell loss in an early-onset murine model of Fuchs endothelial corneal dystrophy. AB - Early-onset Fuchs endothelial corneal dystrophy (FECD) has been associated with nonsynonymous mutations in collagen VIII alpha2 (COL8A2), a key extracellular matrix (ECM) protein in Descemet's membrane (DM). Two knock-in strains of mice have been generated to each express a mutant COL8A2 protein (Col8a2L450W/L450W and Col8a2Q455K/Q455K) that recapitulate the clinical phenotype of early-onset FECD including endothelial cell loss, cellular polymegathism and pleomorphism, and guttae. Due to abnormalities in ECM protein composition and structure in FECD, the stiffness of DM in Col8a2 knock-in mice and wildtype (WT) controls was measured using atomic force microscopy at 5 and 10 months of age, coinciding with the onset of FECD phenotypic abnormalities. At 5 months, only sporadic guttae were identified via in vivo confocal microscopy (IVCM) in Col8a2Q455K/Q455K mice, otherwise both strains of Col8a2 transgenic mice were indistinguishable from WT controls in terms of endothelial cell density and size. By 10 months of age, Col8a2L450W/L450W and Col8a2Q455K/Q455K mice developed reduced corneal endothelial density, increased endothelial cell area and guttae, with the Col8a2Q455K/Q455K strain exhibiting a more severe phenotype. However, at 5 months of age, prior to the development endothelial cell abnormalities, Col8a2L450W/L450W and Col8a2Q455K/Q455K mice knock-in mice had reduced tissue stiffness of DM that was statistically significant in the Col8a2Q455K/Q455K mice when compared with wildtype controls. These data indicate that alterations in the tissue compliance of DM precede phenotypic changes in endothelial cell count and morphology, and may play a role in onset and progression of FECD. PMID- 30471281 TI - Emerging role of Unfolded Protein Response (UPR) mediated proteotoxic apoptosis in diabetes. AB - Endoplasmic reticulum (ER) is a crucial single membrane organelle that acts as a quality control system for cellular proteins as it is intricately involved in their synthesis, folding and trafficking to the respective targets. Type 2 diabetes is characterized by enhanced blood glucose level that promotes insulin resistance and hampers cellular glucose metabolism. Hyperglycemia provokes mitochondrial ROS production and glycation of proteins which exert a tremendous load on ER for conventional refolding of misfolded/unfolded and nascent proteins that perturb ER homeostasis resulting in apoptotic cell death. Impairment in ER functions is suspected to be through specific ER membrane-bound proteins known as Unfolded Protein Response (UPR) sensor proteins. Conformational changes in these proteins induce oligomerization and cross-autophosphorylation which facilitate processes required for the restoration of ER homeostatic imbalance. Multiple studies have reported the involvement of UPR mediated autophagy and apoptotic pathways in the progression of metabolic disorders including diabetes, cardiac ischemia/reperfusion injury and hypoxia-mediated cell death. In this review, the involvement of UPR pathways in the progression of diabetes associated complications have been addressed, which underscores molecular crosstalks during neuropathy, nephropathy, hepatic injury and retinopathy. A better understanding of these molecular interventions may reveal advanced therapeutic approaches for preventing diabetic comorbidities. The article also highlights the importance of phytochemicals that are emerging as novel ER stress inhibitors and are being explored for targeted interaction in preventing cell death responses during diabetes. PMID- 30471282 TI - Immunoregulatory Siglec ligands are abundant in human and mouse aorta and are up regulated by high glucose. AB - AIM: Inflammation is a driving force in development of atherosclerosis, and hyperglycemia is a significant risk factor for angiopathy. Siglec-9, expressed on human neutrophils and macrophages, engages specific glycan ligands on tissues to diminish ongoing inflammation. MATERIALS AND METHOD: Siglec-9 ligands on human aorta were characterized and the effects of high glucose exposure on the expression of ligands for Siglec-9 on human umbilical vein endothelial cells (HUV EC-C) in vitro and ligands for the comparable siglec (Siglec-E) on mouse aorta in vivo were studied. KEY FINDINGS: Siglec-9 ligands were expressed broadly on human aorta, as well as on HUV-EC-C. Siglec-9 ligands on HUV-EC-C were sharply up regulated under high glucose exposure in vitro, as were Siglec-E ligands on the aortas of hyperglycemic mice. Exposure of HUV-EC-C to high-glucose resulted in consistent inhibitory changes in co-cultured macrophages including increased apoptosis and decreased phagocytosis. Control of Siglec-9 ligand expression on HUV-EC-C was downstream of changes in an enzyme involved in their biosynthesis, UDP-galactose-4-epimerase (GALE) and increased cellular N-acetylgalactosamine. The alteration of GALE was associated with the regulatory microRNA hsa-let-7f. SIGNIFICANCE: We conclude that exposure to high-glucose results in up-regulation of immune inhibitory Siglec-9 sialoglycan ligands on aorta and HUV-EC-C cells downstream of altered GALE and GalNAc expression, resulting in up-regulation of apoptosis and decrease of phagocytic activity of macrophages. Changes in Siglec-9 sialoglycan ligand expression on vascular endothelial cells may be a natural response to the initial steps of atherosclerosis and might be a potential target to regulate inflammation in diabetic angiopathy. PMID- 30471283 TI - Osthole decreases tau protein phosphorylation via PI3K/AKT/GSK-3beta signaling pathway in Alzheimer's disease. AB - AIM: Alzheimer's disease (AD), a neurodegenerative disease, was characterized by the loss of memory and progressive cognitive deterioration. Up to now, there has no effective drugs to cure or delay the state of illness. Increasing evidence indicates that hyperphosphorylated tau protein plays a pivotal role in the occurrence and development of AD. Therefore, in present study, we aim to investigate whether osthole (OST) could decrease hyperphosphorylated tau protein in AD and the underlying mechanism. MAIN METHODS: The ability of learning and memory was detected by Morris Water Maze. The pathological changes were detected by H&E staining. The percentage of cells apoptosis was detected by TUNEL assay in vivo and Flow Cytometry in intro. The expressions of tau protein and related proteins in PI3K/Akt/GSK-3beta signaling pathway were detected by Western Blot. KEY FINDINGS: We found that OST could significantly improve learning and memory dysfunction, ameliorate the histology structure of damaged neural cells in hippocampal area. Moreover, we also found that OST could decrease tau protein phosphorylation as well as inhibit cells apoptosis. To explore the underlying mechanism, we used LY294002 to block PI3K/Akt/GSK-3beta signaling pathway, the results from Western bolt showed that the expression of related proteins in PI3K signaling pathway were decreased with LY294002 treated. SIGNIFICANCE: Taken together, the results indicated that OST could decrease phosphorylated tau levels via activation of PI3K/Akt/GSK-3beta signaling pathway. Thus, this study demonstrated that OST might be a potential candidate for the treatment of AD. PMID- 30471284 TI - Rhein ameliorates lipopolysaccharide-induced intestinal barrier injury via modulation of Nrf2 and MAPKs. AB - AIMS: In this study, we explored the underlying mechanisms of protective effects of rhein against intestinal barrier injury in a rat model, induced by intraperitoneal injection of lipopolysaccharide (LPS). MAIN METHODS: Twenty-four male rats were assigned equally to three groups. Rats were given an oral administration of rhein (66.7 mg/kg/day) or not for three continuous days. LPS or saline were injected intraperitoneally in an hour after the last oral administration. The rats were sacrificed at 7 h after LPS or saline administration. Both blood samples and intestinal samples were collected. KEY FINDINGS: Rhein pretreatment markedly inhibited the levels of serum diamine oxidase (DAO), D-lactate (D-lac) and intestinal histological damage, significantly recovered the levels of intestinal DAO, ZO-1 and occludin. Additionally, rhein suppressed LPS-induced intestinal inflammation and oxidative stress, by decreased serum and intestinal, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and nitric oxide levels, up-regulated intestinal catalase, glutathione peroxidase (GSH-Px) activities and HO-1 expression, and down-regulated malondialdehyde (MDA) level in the small intestine. Finally, rhein inhibited JNK, p38 MAPK phosphorylation and activated Nrf2 pathway. SIGNIFICANCE: Rhein could exert the anti-inflammatory and anti-oxidative effects against LPS induced intestinal barrier injury by suppressing p38 MAPK and JNK and activating Nrf2 pathway. PMID- 30471285 TI - Host associations and climate influence avian haemosporidian distributions in Benin. AB - A majority of avian haemosporidian diversity likely remains undiscovered, and each new recovery helps to further elucidate distributional patterns of diversification. We conducted the first known sampling of avian haemosporidians, Haemoproteus, Leucocytozoon, and Plasmodium from Benin located in tropical West Africa. We sampled 222 birds of 77 species and across distinct ecoregions with varied habitats. Haemosporidians were detected in 113 of 222 individuals, resulting in a 50.9% infection rate. By molecular analysis, we recovered a high number of novel lineages, 52.9%, and characterized the multivariate variables which influence the distributions of haemosporidian genetic lineages, including host associations and bioclimatic variables. We introduced a novel visualization method to better capture the multivariate environment of haemosporidians, and this approach resulted in the recovery of intra-generic distribution patterns of diversity, although no patterns were recovered at the genus level. Our results remain descriptive in nature, but show the promise of predictive strength with an increase in sampling localities with future work. Assessing host and bioclimatic variables at a larger geographic scale and across multiple ecoregions will help to elucidate processes regulating the distribution of haemosporidian diversity. PMID- 30471286 TI - Clonal and atypical Toxoplasma strain differences in virulence vary with mouse sub-species. AB - The severe virulence of Toxoplasma gondii in classical laboratory inbred mouse strains contradicts the hypothesis that house mice (Mus musculus) are the most important intermediate hosts for its transmission and evolution because death of the mouse before parasite transmission equals death of the parasite. However, the classical laboratory inbred mouse strains (Mus musculus domesticus), commonly used to test Toxoplasma strain differences in virulence, do not capture the genetic diversity within Mus musculus. Thus, it is possible that Toxoplasma strains that are severely virulent in laboratory inbred mice are avirulent in some other mouse sub-species. Here, we present insight into the responses of individual mouse strains, representing strains of the genetically divergent Mus musculus musculus, Mus musculus castaneus and Mus musculus domesticus, to infection with individual clonal and atypical Toxoplasma strains. We observed that, unlike M. m. domesticus, M. m. musculus and M. m. castaneus are resistant to the clonal Toxoplasma strains. For M. m. musculus, we show that this is due to a locus on chromosome 11 that includes the genes that encode the interferon gamma (IFNG)-inducible immunity-related GTPases (Irgs) that can kill the parasite by localizing and subsequently vesiculating the parasitophorous vacuole membrane (PVM). However, despite the localization of known effector Irgs to the Toxoplasma PVM, we observed that some atypical Toxoplasma strains are virulent in all the mouse strains tested. The virulence of these atypical strains in M. m. musculus could not be attributed to individual rhoptry protein 5 (ROP5) alleles, a secreted parasite pseudokinase that antagonizes the canonical effector Irgs and is indispensable for parasite virulence in laboratory inbred mice (M. m. domesticus). We conclude that murine resistance to Toxoplasma is modulated by complex interactions between host and parasite genotypes and may be independent of known effector Irgs on murine chromosome 11. PMID- 30471287 TI - Deep amplicon sequencing as a powerful new tool to screen for sequence polymorphisms associated with anthelmintic resistance in parasitic nematode populations. AB - Parasitic gastrointestinal nematodes contribute to significant human morbidity and cause billions of dollars per year in lost agricultural production. Control is dependent on the use of anthelmintic drugs which, in the case of livestock parasites, is severely compromised by the widespread development of drug resistance. There are now concerns regarding the emergence of anthelmintic resistance in parasitic nematodes of humans in response to the selection pressure resulting from mass drug administration programs. Consequently, there is an urgent need for sensitive, scalable and accurate diagnostic tools to detect the emergence of anthelmintic resistance. Detecting and measuring the frequency of resistance-associated mutations in parasite populations has the potential to provide sensitive and quantitative assessment of resistance emergence from an early stage. Here, we describe the development and validation of deep amplicon sequencing as a powerful new approach to detect and quantify the frequency of single nucleotide polymorphisms associated with benzimidazole resistance. We have used parasite communities in sheep to undertake a proof-of-concept study of this approach. Sheep provide an excellent host system, as there are multiple co infecting trichostrongylid nematode species, each likely with a varying prevalence of benzimidazole resistance. We demonstrate that the approach provides an accurate measure of resistance allele frequencies, and can reliably detect resistance alleles down to a frequency of 0.1%, making it particularly valuable for screening mutations in the early stages of resistance. We illustrate the power of the technique by screening UK sheep flocks for benzimidazole resistance associated single nucleotide polymorphisms at three different codons of the beta tubulin gene in seven different parasite species from 164 populations (95 from ewes and 69 from lambs) in a single MiSeq sequencing run. This approach provides a powerful new tool to screen for the emergence of anthelmintic resistance mutations in parasitic nematode populations of both animals and humans. PMID- 30471288 TI - Avian malaria on Madagascar: prevalence, biodiversity and specialization of haemosporidian parasites. AB - Previous studies about geographic patterns of species diversity of avian malaria parasites and others in the Order Haemosporida did not include the avian biodiversity hotspot Madagascar. Since there are few data available on avian malaria parasites on Madagascar, we conducted the first known large-scale molecular-based study to investigate their biodiversity. Samples (1067) from 55 bird species were examined by a PCR method amplifying nearly the whole haemosporidian cytochrome b gene (1063 bp). The parasite lineages found were further characterized phylogenetically and the degree of specialization was determined with a newly introduced host diversity index (Hd). Our results demonstrate that Madagascar indeed represents a biodiversity hotspot for avian malaria parasites as we detected 71 genetically distinct parasite lineages of the genera Plasmodium and Haemoproteus. Furthermore, by using a phylogenetic approach and including the sequence divergence we suspect that the detected haemosporidian lineages represent at least 29 groups i.e. proposed species. The here presented Hd values for each parasite regarding host species, genus and family strongly support previous works demonstrating the elastic host ranges of some avian parsites of the Order Haemosporida. Representatives of the avian parasite genera Plasmodium and Leucocytozoon tend to more often be generalists than those of the genus Haemoproteus. However, as demonstrated in various examples, there is a large overlap and single parasite lineages frequently deviate from this rule. PMID- 30471289 TI - Quantification of Silicone oil and its degradation products in aqueous pharmaceutical formulations by 1H-NMR Spectroscopy. AB - During the past years there has been an increasing focus on the presence of silicone oil as a contaminant in pharmaceutical formulations kept in pre-filled syringes. As the pre-filled syringes are coated on the inner wall with silicone oil (PDMS) there is a potential risk that the oil can migrate from the inner surface of the primary packing material into the aqueous solution. Several studies have demonstrated that presence of silicone oil as droplets in a high concentrated protein formulation can cause protein aggregation. Hence, since the use of silicone coated primary packing material for protein formulations are increasing, the call for an easy and quantitative method for determination of silicone oil and its degradation products in pharmaceutical formulations is therefore needed. Several analytical techniques have in the past been developed with the aim of detecting the presence of silicone oil and degradation products hereof. Most of these methods require hydrolyzation-, derivatisation- and/or extraction-steps followed by e.g. GC-MS analysis. Applying these methods can cause a loss in detection or an overestimation of the hydrolytic degradation products of silicone oil, i.e. trimethylsilanol and dimethylsilanediol. The two silanols are highly hydrophilic and prefers the aqueous environment. Analysis of an aqueous formulation obtained from a pre-filled syringe by 1H-NMR spectroscopy provides data about the content and levels of silicone oil and the two silanols even in levels below 10 ppm. The 1H-NMR method offers an easy and direct, quantitative measurement of samples intended for clinical use and samples kept at elevated temperature for a prolonged time-period (i.e. stability studies). The result of the study presented here showed dimethylsilanediol to be the main silicone compound present in the aqueous formulation when kept in baked-on pre filled syringes. The degradation product dimethylsilanediol, in full accordance with expected hydrolytic degradation of silicone oil, increased during storage and with elevated temperature. In addition, the method can be applied to acqueous samples where PDMS has been added as e.g. the major constituent of antifoam. PMID- 30471290 TI - Characterization of the partition rate of ibuprofen across the water-octanol interface and the influence of common pharmaceutical excipients. AB - This work reports the measurement of the partition rate of a model drug, ibuprofen, from aqueous solutions into octanol with the absence and presence of common pharmaceutical excipients including glucose, lactose, maltoheptaose, HPMC, PVP, PVP-VA, HPMCAS, sodium dodecyl sulfate, Tween 80, and sodium taurocholate at varying concentrations. This attempts to assess the kinetic aspect of IBU partitioning across the water-octanol interface by applying a mechanistic model and to characterize the interfacial resistance. A significant reduction of the Pi across the water-octanol interface was observed with extremely low concentration of the selected excipients in the aqueous media. These results reveal the presence of a surface excess of adsorbed excipients at the water-octanol interface. The retardation of the Pi of IBU was found to be sensitive to (1) the molecular weight and/or the degree of polymerization of these excipients, (2) the hydrodynamic condition of the experimental method, and (3) the pH of the aqueous media. Retardation of the Pi of IBU in the presence of excipients observed in this study is proposed by a steric obstruction mechanism through the adsorbed surface excess layer of excipients located at the water-octanol interface. PMID- 30471291 TI - Editorial. PMID- 30471292 TI - The Mechanistic Impact of N-Glycosylation on Stability, Pharmacokinetics and Immunogenicity of Therapeutic Proteins. AB - N-glycosylation is one of major post-translational modifications in nature and it is essential for protein structure and function. As hydrophilic moieties of glycoproteins, N-glycans play important roles in protein stability. They protect the proteins against proteolytic degradation, aggregation and thermal denaturation through maintaining optimal conformations. There are extensive evidences showing the involvement of N-glycans in the pharmacodynamics and pharmacokinetics of recombinant therapeutic proteins and antibodies. Highly sialylated complex-type glycans enable the longer serum half-lives of proteins against uptake through hepatic asialoglycoprotein receptor and mannose receptor for degradation in lysosomes. Moreover, the presence of non-human glycans results in clearance through pre-existing antibodies from serum and induces IgE-mediated anaphylaxis. N-glycans also facilitate or reduce the adverse immune responses of the proteins through interacting with multiple glycan-binding proteins, including those specific for mannose or mannose 6-phosphate. Due to the glycan impacts, a few therapeutic proteins were glycoengineered to improve the pharmacokinetics and stability. Thus, N-glycosylation should be extensively investigated and optimized for each individual protein for better efficacy and safety. PMID- 30471293 TI - Development and evaluation of a physiologically-based pharmacokinetic model for predicting the effects of anti-FcRn therapy on the disposition of endogenous IgG in humans. AB - This work scaled up a previously developed physiologically-based pharmacokinetic (PBPK) model to predict the effects of anti-FcRn agents on the disposition of endogenous IgG in human subjects. Simulations were performed with the scaled model to predict the effects of single and multiple-dose administration of anti FcRn monoclonal antibodies (anti-FcRn mAb, 1 - 256 mg/kg) and high dose intravenous immune globulin (IVIG, 0.4 - 2 g/kg). The model was evaluated for prediction accuracy through comparison to the effects of rozanolixizumab, an anti FcRn mAb under current clinical evaluation, on the disposition of endogenous IgG in healthy human subjects. The model provided reasonably accurate predictions of the effects of rozanolixizumab. Prediction errors for the maximum reduction in endogenous IgG concentrations were -8.50% (90% model prediction interval: -14.0% 1.44%), 3.33% (90% model prediction interval: -13.9% - 21.2%), and 6.85% (90% model prediction interval: -35.2% - 10.5%) for rozanolixizumab doses of 1, 4, and 7 mg/kg. Model simulations predict that anti-FcRn therapies will exhibit greater dose-potency in healthy volunteers than in patients with elevated IgG production rates (e.g., as typically found in autoimmune disease). The model appears to have potential for use in assessing and predicting novel dosing strategies for anti FcRn therapies. PMID- 30471294 TI - Zinc reduces antiseizure activity of neurosteroids by selective blockade of extrasynaptic GABA-A receptor-mediated tonic inhibition in the hippocampus. AB - Zinc is an abundant trace metal in the hippocampus nerve terminals. Previous studies demonstrate the ability of zinc to selectively block neurosteroid sensitive, extrasynaptic GABA-A receptors in the hippocampus (Carver et al, 2016). Here we report that zinc prevents the seizure protective effects of the synthetic neurosteroid ganaxolone (GX) in an experimental model of epilepsy. GABA gated and tonic currents were recorded from dissociated dentate gyrus granule cells (DGGCs), CA1 pyramidal cells (CA1PCs), and hippocampal slices from adult mice. Antiseizure effects of GX and the reversal of these effects by zinc were evaluated in fully-kindled mice expressing generalized (stage 5) seizures. In electrophysiological studies, zinc blocked the GABA-evoked and GX-potentiated GABA-gated chloride currents in DGGCs and CA1PCs in a concentration-dependent fashion similar to the competitive GABA-A receptor antagonists bicuculline and gabazine. Zinc completely blocked GX potentiation of extrasynaptic tonic currents, but not synaptic phasic currents. In hippocampus kindling studies, systemic administration of GX produced a dose-dependent suppression of behavioral and electrographic seizures in fully-kindled mice with complete seizure protection at the 10 mg/kg dose. However, the antiseizure effect of GX was significantly prevented by intrahippocampal administration of zinc (ED50, 150 MUM). The zinc antagonistic response was reversible as animals responded normally to GX administration 24 h post-zinc blockade. These results demonstrate that zinc reduces the antiseizure effects of GX by selectively blocking extrasynaptic deltaGABA-A receptors in the hippocampus. These pharmacodynamic interactions have clinical implications in neurosteroid therapy for brain conditions associated with zinc fluctuations. PMID- 30471295 TI - Mechanical allodynia and enhanced responses to capsaicin are mediated by PI3K in a paclitaxel model of peripheral neuropathy. AB - Paclitaxel chemotherapy treatment often leads to neuropathic pain resistant to available analgesic treatments. Recently spinal Toll-like receptor 4 (TLR4) and the transient receptor potential cation channel subfamily V member 1 (TRPV1) were identified to be involved in the pro-nociceptive effect of paclitaxel. The aim of this study was to investigate the role of phosphatidylinositol 3-kinase (PI3K) and serine/threonine kinases in this process, with the use of their antagonists (wortmannin, LY-294002 and staurosporine). The single paclitaxel administration (8 mg/kg i.p.) in mice induced robust mechanical allodynia measured as reduced threshold to von Frey filament stimulation and generated reduced tachyphylaxis of capsaicin evoked responses, recorded as changes in mEPSC frequency in patch-clamp recordings of dorsal horn neurons activity in vitro, for up to eight days. Paclitaxel application also induced increased Akt kinase phosphorylation in rat DRG neurons. All these paclitaxel-induced changes were prevented by the the wortmannin in vivo pretreatment. Acute co-application of wortmannin or LY-294002 with paclitaxel in spinal cord slices also attenuated the paclitaxel effect on capsaicin evoked responses. Staurosporine was effective in the acute in vitro experiments and on the first day after the paclitaxel treatment in vivo, but in contrast to wortmannin it did not have a significant impact later. Our data suggest that the inhibition of PI3K signaling may help alleviate pathological pain syndromes in the paclitaxel-induced neuropathy. PMID- 30471296 TI - Graphene quantum dots inhibit T cell-mediated neuroinflammation in rats. AB - We investigated the therapeutic capacity of nano-sized graphene sheets, called graphene quantum dots (GQD), in experimental autoimmune encephalomyelitis (EAE), an animal model of immune-mediated central nervous system (CNS) damage. Intraperitoneally administered GQD (10 mg/kg/day) accumulated in the lymph node and CNS cells of Dark Agouti rats in which EAE was induced by immunization with spinal cord homogenate in complete Freund's adjuvant. GQD significantly reduced clinical signs of EAE when applied throughout the course of the disease (day 0 32), while the protection was less pronounced if the treatment was limited to the induction (day 0-7 post-immunization) or effector (from day 8 onwards) phase of the disease. GQD treatment diminished immune infiltration, demyelination, axonal damage, and apoptotic death in the CNS of EAE animals. GQD also reduced the numbers of interferon-gamma-expressing T helper (Th)1 cells, as well as the expression of Th1 transcription factor T-bet and proinflammatory cytokines tumor necrosis factor, interleukin-1, and granulocyte-macrophage colony-stimulating factor in the lymph nodes and CNS immune infitrates. The protective effect of GQD in EAE was associated with the activation of p38 and p42/44 mitogen-activated protein kinases (MAPK) and Akt in the lymph nodes and/or CNS. Finally, GQD protected oligodendrocytes and neurons from T cell-mediated damage in the in vitro conditions. Collectively, these data demonstrate the ability of GQD to gain access to both immune and CNS cells during neuroinflammation, and to alleviate immune-mediated CNS damage by modulating MAPK/Akt signaling and encephalitogenic Th1 immune response. PMID- 30471297 TI - Moderate sex between protocells can balance between a decrease in assortment load and an increase in parasite spread. AB - Sexual reproduction is widespread in nature despite the different kinds of cost that it entails. We do not know exactly when the first sexual process took place and especially why it was beneficial at first. It is clearer why sex is advantageous for the prokaryotes and eukaryotes but the benefit of sex for protocells with individually replicating ribozymes is not yet fully understood. In this context sex is the simple horizontal gene transfer among two protocells that undergo transient fusion. Many authors argue that horizontal gene transfer (HGT) was very common in the early stage of evolution. However, HGT is a risky mechanism considering both the disruption of optimal compositions and the spread of parasites among protocells. In order to test the effects of HGT on the fitness of a protocell population, we explored by numerical simulations those conditions under which fusion might have been beneficial. We investigated multiple conceivable types of fusion in the stochastic corrector model framework and we considered the spread of parasites in every case. Protocells contain up to five species of unlinked, essential ribozymes; if a protocell has the same amount of each, it reaches maximum fitness. Fusion is dangerous not only due to the spread of parasites but also because it can ruin the cells with balanced ribozyme composition. We show that fusion can restore the ribozyme composition of the protocells under certain circumstances (high gene count, intermediate split size and low rate of fusion) and thus it can decrease the effect of the genetic load. Fusion could have been a useful early mechanism in contributing to the reliable coexistence of the different ribozymes before the spread of the chromosomes. PMID- 30471298 TI - Asymmetric evolutionary games with environmental feedback. AB - Models in evolutionary game theory traditionally assume symmetric interactions in homogeneous environments. Here, we consider populations evolving in a heterogeneous environment, which consists of patches of different qualities that are occupied by one individual each. The fitness of individuals is not only determined by interactions with others but also by environmental quality. This heterogeneity results in asymmetric interactions where the characteristics of the interaction may depend on an individual's location. Interestingly, in non-varying heterogeneous environments, the long-term dynamics are the same as for symmetric interactions in an average, homogeneous environment. However, introducing environmental feedback between an individual's strategy and the quality of its patch results in rich eco-evolutionary dynamics. Thus, individuals act as ecosystem engineers. The nature of the feedback and the rate of ecological changes can relax or aggravate social dilemmas and promote persistent periodic oscillations of strategy abundance and environmental quality. PMID- 30471299 TI - A primer set for comprehensive amplification of V-genes from rhesus macaque origin based on repertoire sequencing. AB - Recombinant antibodies serve as therapeutic molecules for a broad range of applications. High affinity antibodies are typically isolated following an active and effective immunization. Human-like antibodies may be obtained from immunized nonhuman primates (NHP), such as rhesus macaque, when immunized human origin is not available. For the isolation of such antibodies, strategies like phage and yeast display, are employed. These strategies are primarily based on the amplification of the rearranged variable (V) regions coded by mRNA, obtained from lymphatic source of immunized animals. To amplify these genomic sequences, designated set of primers are required, ideally covering the immune animal V-gene repertoire. Such primer sets are commonly designed based on the germline repertoire of specific animals according to immunoglobulin databases. However, In case of rhesus macaque, however, the known immunoglobulin germline V-gene database is still limited. The emergence and continuous improvements in high throughput sequencing (HTS) technologies now enable the profiling of an immune repertoire for both basic and applicative studies, among which is the identification and expression of novel alleles. We report here on the profiling of non-immunized rhesus macaque (Macaca mulatta) expressed antibody repertoire, using HTS and advanced tailored bioinformatics tools. This analysis resulted in 32,480 and 73,354 complete heavy and light variable gene (VH and VL) sequences, respectively. Further analysis of these sequences, using the IgDiscover tool, resulted in the identification of 102, 214 and 48 inferred VH, Vkappa and Vlambda germline sequences, respectively, of which over 50% are novel alleles. This dataset, together with other recently published datasets, enabled the design of a comprehensive primer set (v2018), which demonstrated the broadest coverage of rhesus macaque germline genes identified up to date. The newly designed primer set was confirmed for its extent of coverage of the V-genes in various datasets of rhesus macaque germlines as well as the expressed repertoire mapped in this study. Among other things, an improvement of 28% and 50% in the coverage of the VH and VL expressed repertoire was demonstrated in comparison to a primer set we have previously designed. This primer set can be further used for various applications that require the complete coverage of the NHP V-gene repertoire. PMID- 30471300 TI - Wide spectrum of referral routes for acute hepatitis E infections. PMID- 30471301 TI - A secreted-Cu/Zn superoxide dismutase from Microplitis bicoloratus reduces reactive oxygen species triggered by symbiotic bracovirus. AB - In the parasitoid/polydnavirus/host system, polydnaviruses protect larva development in the host hemocoel by suppressing the host immune response. However, the negative effects on the parasitoid and the strategy of the parasitoid to deal with this disadvantage are still unknown. Microplitis bicoloratus bracovirus induces granulocyte apoptosis to suppress immune responses, resulting in an apoptotic haemolymph environment in which immature M. bicoloratus larva develop. Here, we determined the transcriptional profiles of immature M. bicoloratus across five time-points throughout the immature developmental process from egg to third instar. Dynamic gene expression pattern analysis revealed clear rapid changes in gene expression characteristic of each developmental stage, indicating faster sequential unambiguous functional division during development. Combined with the proteome of the host haemolymph, immature parasitoids likely secreted a Cu/Zn superoxide dismutase to reduce reactive oxygen species generation by symbiotic bracovirus. These data established a basis for further studies of parasitoid/host interactions and identified a novel positive self-protection mechanism for the parasitoid. PMID- 30471302 TI - Phosphoenolpyruvate carboxykinase is involved in antiviral immunity against Bombyx mori nucleopolyhedrovirus. AB - Phosphoenolpyruvate carboxykinase (PEPCK) has cytoplasmic isoform (PEPCK-C) and a mitochondrial isoform (PEPCK-M). PEPCK-C plays an important role in gluconeogenesis, but the function of PEPCK-M is largely unknown. In this study, we cloned two isoforms of PEPCK (BmPEPCK-1 and BmPEPCK-2; both of PEPCK-M) from the lepidopteran model Bombyx mori. BmPEPCK-1 and BmPEPCK-2 were adjacently located in the silkworm genome, and both contained 13 exons. The main difference in the sequences was the 13th exon and 3'UTR. The expression of BmPEPCK-1 was higher than that of BmPEPCK-2, the overexpression of which did not affect BmNPV proliferation. The expression levels of BmPEPCK-2 and ATG6/7/8/13 decreased after BmNPV infection. Overexpression of BmPEPCK-2 increased the expression of ATG6/7/8 and significantly decreased viral fluorescence and content, suggesting that BmPEPCK-2 suppressed the multiplication of BmNPV by increasing ATGs expression. These results revealed that PEPCK-M has an important function in antiviral immunity. PMID- 30471303 TI - IgE-class-specific immunosuppression in offspring by administration of anti-IgE to pregnant mice. AB - Environmental events in early in life are critical to development of allergic diseases later in life. We found IgE-class-specific immunosuppression in offspring whose mothers had been administered anti-IgE during pregnancy. PMID- 30471304 TI - Vaccination of non-allergic individuals with recombinant hypoallergenic fragments of birch pollen allergen Bet v 1: Safety, effects and mechanisms. AB - This is the first double-blind, placebo-controlled study showing that vaccination with recombinant hypoallergenic allergen-derivatives is safe and induces sustained allergen-specific IgG responses which block allergic patients IgE binding to the allergen. PMID- 30471305 TI - Transcriptome profiling of refractory atopic keratoconjunctivitis by RNA sequencing. AB - We found upregulation of 47 immunoglobulin genes and 22 S. aureus infection related genes in refractory atopic keratoconjunctivitis tissue by RNA-seq analysis, suggesting that lymphoid neogenesis and stimuli from infection are essential components of the disorder. PMID- 30471306 TI - Carbofuran hampers oligodendrocytes development leading to impaired myelination in the hippocampus of rat brain. AB - During the mammalian brain development, oligodendrocyte progenitor cells (OPCs) are generated from neuroepithelium and migrate throughout the brain. Myelination is a tightly regulated process which involves time framed sequential events of OPCs proliferation, migration, differentiation and interaction with axons for functional insulated sheath formation. Myelin is essential for efficient and rapid conduction of electric impulses and its loss in the hippocampus of the brain may result in impaired memory and long-term neurological deficits. Carbofuran, a carbamate pesticide is known to cause inhibition of hippocampal neurogenesis and memory dysfunctions in rats. Nonetheless, the effects of carbofuran on OPCs proliferation, fate determination, maturation/differentiation and myelination potential in the hippocampus of the rat brain are still completely elusive. Herein, we investigated the effects of sub-chronic exposure of carbofuran during two different time periods including prenatal and adult brain development in rats. We observed carbofuran hampers OPCs proliferation (BrdU incorporation) and oligodendroglial differentiation in vitro. Similar effects of carbofuran were also observed in the hippocampus region of the brain at both the time points. Carbofuran exposure resulted in reduced expression of key genes and proteins involved in the regulation of oligodendrocyte development and functional myelination. It also affects the survival of oligodendrocytes by inducing apoptotic cell death. The ultrastructural analysis of myelin architecture clearly depicted carbofuran-mediated negative effects on myelin compaction and g-ratio alteration. Conclusively, our study demonstrated that carbofuran alters myelination potential in the hippocampus, which leads to cognitive deficits in rats. PMID- 30471307 TI - Bright near-infrared fluorescence bio-labeling with a biliprotein triad. AB - Biliproteins have extended the spectral range of fluorescent proteins into the near-infrared region (NIR, 700-770 nm) of maximal transmission of most tissues and are also favorable for multiplex labeling. Their application, however, presents considerable challenges to increase their stability under physiological conditions and, in particular, to increase their brightness while maintaining the emission in near-infrared regions: their fluorescence yield generally decreases with increasing wavelengths, and their effective brightness depends strongly on the environmental conditions. We report a fluorescent biliprotein triad, termed BDFP1.1:3.1:1.1, that combines a large red-shift (722 nm) with high brightness in mammalian cells and high stability under changing environmental conditions. It is fused from derivatives of the phycobilisome core subunits, ApcE2 and ApcF2. These two subunits are induced by far-red light (FR, 650-700 nm) in FR acclimated cyanobacteria. Two BDFP1.1 domains engineered from ApcF2 covalently bind biliverdin that is accessible in most cells. The soluble BDFP3 domain, engineered from ApcE2, binds phytochromobilin non-covalently, generating BDFP3.1. This phytochromobilin chromophore was added externally; it is readily generated by an improved synthesis in E. coli and subsequent extraction. Excitation energy absorbed in the FR by covalently bound biliverdins in the two BDFP1.1 domains is transferred via fluorescence resonance energy transfer to the non-covalently bound phytochromobilin in the BDFP3.1 domain fluorescing in the NIR around 720 nm. Labeling of a variety of proteins by fusion to the biliprotein triad is demonstrated in prokaryotic and mammalian cells, including human cell lines. PMID- 30471308 TI - Cross-Species Examination of Single- and Multi-Strain Probiotic Treatment Effects on Neuropsychiatric Outcomes. AB - Interest in elucidating gut-brain-behavior mechanisms and advancing neuropsychiatric disorder treatments has led to a recent proliferation of probiotic trials. Yet, a considerable gap remains in our knowledge of probiotic efficacy across populations and experimental contexts. We conducted a cross species examination of single- and multi-strain combinations of established probiotics. Forty-eight human (seven infant/child, thirty-six young/middle-aged adult, five older adult) and fifty-eight non-human (twenty-five rat, twenty-seven mouse, five zebrafish, one quail) investigations met the inclusion/exclusion criteria. Heterogeneity of probiotic strains, substrains, and study methodologies limited our ability to conduct meta-analyses. Human trials detected variations in anxiety, depression, or emotional regulation (single-strain 55.6%; multi-strain 50.0%) and cognition or social functioning post-probiotic intake (single-strain 25.9%; multi-strain 31.5%). For the non-human studies, single- (60.5%) and multi strain (45.0%) combinations modified stress, anxiety, or depression behaviors in addition to altering social or cognitive performance (single-strain 57.9%; multi strain 85.0%). Rigorous trials that confirm existing findings, investigate additional probiotic strain/substrain combinations, and test novel experimental paradigms, are necessary to develop future probiotic treatments that successfully target specific neuropsychiatric outcomes. PMID- 30471309 TI - Motion prediction at low contrast. AB - Accurate motion prediction is fundamental for survival. How does this reconcile with the well-known speed underestimation of low-contrast stimuli? Here we asked whether this contrast-dependent perceptual bias is retained in motion prediction under two different saccadic planning conditions: making a saccade to an occluded moving target, and real-time gaze interaction with multiple moving targets. In a first experiment, observers made a saccade to the mentally extrapolated position of a moving target (imagery condition). In a second experiment, observers had to prevent collisions among multiple moving targets by glancing at them through a gaze-contingent display or by hitting them with the touchpad cursor (interaction condition). In both experiments, target contrast was manipulated. We found that, whereas saccades to the imagined moving target were systematically biased by contrast, the gaze interaction performance, as measured by missed collisions, was generally unaffected - even though low-contrast targets looked slower. Interceptive actions increased at low contrast, but only when the gaze was used for interaction. Thus, perceptual speed underestimation transfers to saccades made to imagined low-contrast targets, without however necessarily being detrimental to effective performance when real-time interaction with multiple targets is required. This differential effect of stimulus contrast suggests that in complex dynamic conditions saccades are rather tolerant to visual speed biases. PMID- 30471310 TI - A simple method for direct isolation of N-acyl-L-homoserine lactone mediated biofilm-forming rhizobacteria from roots. AB - Plant-associated bacteria produce quorum sensing (QS) signals for community (biofilm) formation and functioning in the rhizosphere. The QS-positive biofilm forming rhizobacteria that excel benefits to the plants are now gaining increase importance for agricultural use due to their high competitiveness. However, there is no method available to distinguish these bacteria from the roots of a plant to ease the isolation. Currently, all the plant-associated bacteria have to be isolated, purified and subsequently screened for the QS activity using biosensor strains. This study describes a direct isolation method for N-acyl-homoserine lactone (AHL) type quorum sensing signal producing bacteria from the plant root. In this method, the root sample collected from the field was overlaid directly with the bacterial growth medium seeded with the biosensor reporter, Chromobacterium violaceum (CV026). The AHL produced by QS positive rhizobacteria residing on the surface of the root will be recognized by violacein production of CV026. The bacterial isolates recovered from rice root using this method were further confirmed for the QS activity and biofilm formation. All the QS-positive strains produced N-butyryl DL-homoserine lactone (a C4-AHL type) signal in the culture medium and had biofilm formation during in vitro culturing. The 16S rRNA gene sequences of these QS-positive biofilm-forming rhizobacteria revealed that these strains are phylogenetically close to Pseudomonas siluiensis, Aeromonas hydrophila and A. caviae. Therefore, this could be a simple, rapid and straightforward procedure for isolation and characterization of quorum-sensing rhizobacteria from plant roots. PMID- 30471311 TI - Effects of 5-HT7 receptor antagonists on behaviors of mice that detect drugs used in the treatment of anxiety, depression, or schizophrenia. AB - 5-HT7 receptors have been suggested to play a role in the regulation of psychiatric disorders. The experimental literature however is not fully consistent on this possibility. Two selective 5-HT7 receptor antagonists, DR-4004 and SB-269970, were evaluated in mouse models used to detect drugs used to treat anxiety, depression, or schizophrenia. A 5-HT-induced hypothermia assay was used to define the doses of DR-4004 and SB-269970 predicted to impact 5-HT7 receptors in the brain in vivo. 5-HT produced hypothermia in wildtype mice by either i.p. or i.c.v. routes but did not in 5-HT7 receptor knockout mice. 5-HT-induced hypothermia was not attenuated by drugs selectively blocking alpha1 or 5-HT1A receptors. Doses of DR-4004 and SB-269970 that blocked 5-HT-induced hypothermia, did not display significant anxiolytic-like (elevated plus maze; vogel conflict) or antidepressant-like efficacy (tail-suspension test) in mouse models. These compounds did demonstrate some antipsychotic-like properties in the PCP-induced hyperactivity assay and anxiolytic/anti-stress effects in the stress-induced cGMP assay. Negative findings were substantiated by positive control drugs that were active in each assay system. We conclude that 5-HT-induced hypothermia can be used to estimate blockade of central 5-HT7 receptors. Effects of DR-4004 and SB 269970 in animal models are generally consistent with the experimental literature that the evidence is mixed or not robust regarding the potential efficacy of 5 HT7 receptor antagonism in the treatment of anxiety, depression, or schizophrenia. PMID- 30471312 TI - Adverse drug reactions of anticancer drugs derived from natural sources. AB - Cancer, a life threatening disease adversely affects huge population worldwide. Naturally derived drug discovery has emerged as a potential pathway in search of anticancers. Natural products-based drugs are generally considered safe, compared to their synthetic counterparts. A systematic review on adverse drugs reactions (ADRs) of the anticancer natural products has not been performed till date. We reviewed anticancer drugs, derived from plants, microbes and marine sources with their mechanistic action and reported ADRs. PubMed, ScienceDirect and Scopus were searched through Boolean information retrieval method using keywords "natural products", "cancer", "herbal", "marine drugs" and "adverse drug reaction". We documented ADRs of natural products based anticancer agents, mechanisms of action and chemical structures. It was observed that majority of the natural products based anticancer drugs possess ample adverse effects, dominantly hematological toxicities, alopecia, neurotoxicity and cardiotoxicity. These findings deviate from the preconceived notion about safer nature of herbal drugs. We also came across some anti-cancer natural products with less/no reported adverse events like Cabazitaxel and Arglabin. Comprehensive pharmacovigilance studies are needed to report ADRs and thereby predicting safety of anti-cancer drugs, either originated from natural sources or chemically synthesized. PMID- 30471313 TI - Comment on "Trends in phototherapy utilization among Medicare beneficiaries in the United States, 2000 to 2015". PMID- 30471314 TI - Time to Reconsider the Role of Sentinel Lymph Node Biopsy in Melanoma. PMID- 30471315 TI - A review of smartphone applications for promoting sun protection practices. PMID- 30471316 TI - Association between atopic dermatitis and extra-cutaneous bacterial and mycobacterial infections: A systematic review and meta-analysis. AB - BACKGROUND: Atopic dermatitis (AD) is associated with increased bacterial colonization and infection of skin, and multiple risk factors for extra-cutaneous infections. However, previous studies found conflicting results about whether AD is associated with increased extra-cutaneous infections. OBJECTIVES: To determine whether extra-cutaneous bacterial and mycobacterial infections are increased in AD. METHODS: A systematic review was performed of all published observational studies with controls in MEDLINE, EMBASE, GREAT, Cochrane, and Web of Science that assessed extra-cutaneous infections in AD. Pooled meta-analysis was performed using random-effects weighting. RESULTS: Overall, 7 studies met inclusion criteria. All 7 studies found increased odds of at least one extra cutaneous infection in AD, including endocarditis, meningitis, encephalitis, bone and joint infections, and sepsis. In pooled meta-analysis, AD in children and adults was associated with higher odds of ear infection (odds ratio [95% confidence interval]: 1.29 [1.16-1.43]), strep throat (2.31 [1.66-3.22]) and urinary tract infection (2.31 [1.66-3.22]), but not pneumonia (1.72 [0.75-3.98]). No publication bias was detected. LIMITATIONS: Individual level data were not available. CONCLUSIONS: AD patients have higher odds of extra-cutaneous infections. Future studies are needed to confirm these associations and determine their mechanisms. PMID- 30471317 TI - Implementation of influenza point-of-care-testing and patient-cohorting during a high-incidence season: a retrospective analysis of impact on infection prevention and control and clinical outcomes. AB - BACKGROUND: During high-incidence influenza seasons, a robust infection prevention and control policy is imperative to reduce nosocomial transmission of influenza. AIM: To assess the impact of Emergency Department (ED) influenza point of-care-testing (POCT) and influenza-ward patient-cohorting on infection prevention and control and clinical outcomes. METHODS: Influenza POCT was operational in our adult ED from 21st January 2018 and an influenza-ward from 25th January 2018. A retrospective 'before-after' analysis was performed with pre intervention defined as 1st November 2017-20th January 2018 and post-intervention 21st January-30th April 2018. Primary outcome was rate of hospital-acquired influenza (HAI). Secondary outcomes included antiviral prescription and length of stay. The length of time inpatients remain influenza RNA detected by polymerase chain reaction (PCR) was also analysed. PMID- 30471318 TI - Quorum sensing inhibitors as antipathogens: biotechnological applications. AB - The mechanisms through which microbes communicate using signal molecules has inspired a great deal of research. Microbes use this exchange of information, known as quorum sensing (QS), to initiate and perpetuate infectious diseases in eukaryotic organisms, evading the eukaryotic defense system by multiplying and expressing their pathogenicity through QS regulation. The major issue to arise from such networks is increased bacterial resistance to antibiotics, resulting from QS-dependent mediation of the formation of biofilm, the induction of efflux pumps, and the production of antibiotics. QS inhibitors (QSIs) of diverse origins have been shown to act as potential antipathogens. In this review, we focus on the use of QSIs to counter diseases in humans as well as plants and animals of economic importance. We also discuss the challenges encountered in the potential applications of QSIs. PMID- 30471319 TI - DeepSeeNet: A deep learning model for automated classification of patient-based age-related macular degeneration severity from color fundus photographs. AB - PURPOSE: In assessing the severity of age-related macular degeneration (AMD), the Age-Related Eye Disease Study (AREDS) Simplified Severity Scale predicts the risk of progression to late AMD. However, its manual use requires the time-consuming participation of expert practitioners. While several automated deep learning (DL) systems have been developed for classifying color fundus photographs of individual eyes by AREDS severity score, none to date has utilized a patient based scoring system that employs images from both eyes to assign a severity score. DESIGN: DeepSeeNet, a DL model, was developed to classify patients automatically by the AREDS Simplified Severity Scale (score 0-5) using bilateral color fundus images. PARTICIPANTS: DeepSeeNet was trained on 58,402 and tested on 900 images from the longitudinal follow up of 4,549 participants from AREDS. Gold standard labels were obtained using reading center grades. METHODS: DeepSeeNet (composed of three sub-networks) simulates the human grading process by first detecting individual AMD risk factors (drusen size; pigmentary abnormalities) for each eye and then calculating a patient-based AMD severity score using the AREDS Simplified Severity Scale. MAIN OUTCOME MEASURES: Overall accuracy, specificity, sensitivity, Cohen's kappa, area under the curve (AUC). The performance of DeepSeeNet was compared to that of retinal specialists. RESULTS: DeepSeeNet performed better on patient-based, multi-class classification (accuracy=0.671; kappa=0.558) than retinal specialists (accuracy=0.599; kappa=0.467) with high AUCs in the detection of large drusen (0.94), pigmentary abnormalities (0.93) and late AMD (0.97), respectively. DeepSeeNet also outperformed retinal specialists in the detection of large drusen (accuracy 0.742 vs 0.696; kappa 0.601 vs 0.517) and pigmentary abnormalities (accuracy 0.890 vs 0.813; kappa 0.723 vs 0.535) but showed lower performance in the detection of late AMD (accuracy 0.967 vs 0.973; kappa 0.663 vs 0.754). CONCLUSIONS: By simulating the human grading process, DeepSeeNet demonstrated high accuracy with increased transparency in the automated assignment of individual patients to AMD risk categories based on the AREDS Simplified Severity Scale. These results highlight the potential of deep learning systems to assist and enhance clinical decision-making processes in AMD patients such as early AMD detection and risk prediction for developing late AMD. DeepSeeNet is publicly available on https://github.com/ncbi-nlp/DeepSeeNet. PMID- 30471320 TI - Anti-rheumatoid arthritis effects in adjuvant-induced arthritis in rats and molecular docking studies of Polygonum orientale L. extracts. AB - BACKGROUND AND PURPOSE: Polygonum orientale L. (family: Polygonaceae), named Hongcao in China, has effects of dispelling wind and dampness, promoting blood circulation, and relieving pain. Our group has already studied and confirmed that POEa and POEe (ethyl acetate and ethyl ether extract of P. orientale, respectively) had anti-inflammatory and analgesic effects in early research, which was mainly relevant to the existence of flavonoids. According to the clinical application of P. orientale in traditional Chinese medicine, it has long been used for rheumatic arthralgia and rheumatoid arthritis. Therefore, our group further explored whether flavonoids of P. orientale have anti-rheumatoid arthritis effect and how does they play this role. METHODS: Dried small pieces of the stems and leaves of P. orientale were decocted with water and partitioned successively to obtain POEa and POEe, respectively. The anti-rheumatoid arthritis effect of P. orientale was studied by using a Freund's complete adjuvant (FCA) induced arthritis (AIA) in a rat model. The levels of PGE2, TNF-alpha, and IL 1beta in serum of AIA rats were detected by enzyme linked immunosorbent assay (ELISA) to explore its mechanisms. In addition, we computationally studied the relationships between the 15 chemical components of POEa and POEe, and the currently focused 9 target proteins of rheumatoid arthritis by molecular docking. RESULTS: Pharmacological experiments showed that POEa and POEe significantly ameliorate symptoms of rheumatoid arthritis via reducing paw swelling volume, arthritis score, and thymus and spleen indices, as well as increasing body weight in AIA rats. Simultaneously, the concentrations of PGE2, TNF-alpha, and IL-1beta were significantly decreased by POEa and POEe. Histopathology revealed noticeable reduction in bone and cartilage, synovial hyperplasia, inflammatory cell infiltration, cartilage surface erosion, and joint degeneration by POEa and POEe treatment. In addition, the molecular docking studies showed that docking scores of 14 chemical compositions (including 12 flavonoids and 2 phenolic acids) of POEa and POEe with anti-rheumatoid arthritis protein targets were better than the complexed ligands of the anti-rheumatoid arthritis protein targets. Among them, six flavonoids in POEa and POEe had more docking protein targets (n >= 3). Five anti-rheumatoid arthritis targets including high-temperature requirement A1 protease (HtrA1), janus kinase 1 (JAK1), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (i-NOS), and prostaglandin E2 (PGE2) had better docking score compared with the complexed ligands. Moreover, most of the chemical components in POEa and POEe showed strong interaction with HtrA1. CONCLUSIONS: The flavonoids of P. orientale have anti-rheumatoid arthritis effect. In addition, the molecular docking results indicate that quercetin, catechol, orientin, and other six flavonoids may be closely related to HtrA1, JAK1, COX-2, i-NOS, and PGE2 protein target receptors. It suggests that these chemical compositions form strong protein-ligand complexes with these protein targets, especially HtrA1 to exert anti-rheumatoid arthritis. Further experimental studies show that mechanisms of anti-rheumatoid arthritis effects may also be relevant to inhibit the levels of PGE2, TNF-alpha, and IL-1beta in serum. Therefore, our group can further explore the possible active ingredients and mechanisms of the anti-rheumatoid arthritis effects of flavonoids, and focus on the inhibition of the expression of inflammatory factors and the TGF-beta1/Smad signaling pathway associated with HtrA1 protein target receptors, which can provide a direction and powerful reference for the action mechanism and drug research of anti-rheumatoid arthritis of flavonoids in P. orientale. PMID- 30471321 TI - Heterogeneity of gestational diabetes - Do we take MODY into consideration as much as we should? PMID- 30471322 TI - Reprint of: Development of a risk engine relating maternal glycemia and body mass index to pregnancy outcomes. AB - AIMS: To develop a risk "engine" or calculator, integrating the risks of hyperglycemia, maternal BMI and other basic demographic data commonly available at the time of the pregnancy oral glucose tolerance test (OGTT), to predict an individual's absolute risk of specific adverse pregnancy outcomes. METHODS: Data from the Brisbane HAPO cohort was analysed using logistic regression to determine the relationship between four clinical outcomes (primary CS, birth injury, large for-gestational age, excess neonatal adiposity) with different combinations of OGTT results and maternal demographics (age, height, BMI, parity). Existing sets of international GDM diagnostic criteria were also applied to the cohort. RESULTS: 191 (15.3%) women were diagnosed as GDM by one or more existing criteria. All international criteria performed poorly compared to risk models utilising OGTT results only, or OGTT results in combination with maternal demographics. CONCLUSIONS: The risk engine's empirical performance on receiver - operator curve analysis was superior to the existing GDM diagnostic criteria tested. This concept shows promise for use in clinical practice, but further development is required. PMID- 30471323 TI - A fluorescent 3D cell culture assay for high throughput screening of cancer drugs down-regulating survivin. AB - Survivin, a member of inhibitor of apoptosis family, is currently undergoing intensive investigations as a promising cancer marker due to its overexpression in multiple tumor tissues and close relationship with chemotherapy resistance. In this study, a novel 3D survivin promoter assay was developed, using enhanced green fluorescent protein (EGFP) as the reporter to assess survivin promoter activity for cancer drug screening. Breast cancer MCF-7 cells were engineered to express EGFP controlled by a human survivin promoter and a CMV promoter, respectively. These cells were cultured in three-dimensional (3D) polymer-based scaffolds on a 40-microbioreactor platform (40-MBR) with real-time monitoring of EGFP signals. The EGFP production driven by the survivin promoter was strongly correlated with survivin transcriptional level in MCF-7 cells treated with YM155, a small-molecule survivin promoter suppressant. Moreover, the potential inhibition effects of doxorubicin and cisplatin on survivin and their cytotoxicity were also evaluated in this system. This study demonstrated the potential application of the novel 3D survivin promoter-EGFP reporter assay for high-throughput screening of chemicals down-regulating survivin as a molecular target for cancer therapy. PMID- 30471324 TI - Sex differences in risk factors for vascular contributions to cognitive impairment & dementia. AB - Vascular contributions to cognitive impairment and dementia (VCID) is the second most common cause of dementia. While males overall appear to be at a slightly higher risk for VCID throughout most of the lifespan (up to age 85), some risk factors for VCID more adversely affect women. These include female-specific risk factors associated with pregnancy related disorders (e.g. preeclampsia), menopause, and poorly timed hormone replacement. Further, presence of certain co morbid risk factors, such as diabetes, obesity and hypertension, also may more adversely affect women than men. In contrast, some risk factors more greatly affect men, such as hyperlipidemia, myocardial infarction, and heart disease. Further, stroke, one of the leading risk factors for VCID, has a higher incidence in men than in women throughout much of the lifespan, though this trend is reversed at advanced ages. This review will highlight the need to take biological sex and common co-morbidities for VCID into account in both preclinical and clinical research. Given that there are currently no treatments available for VCID, it is critical that we understand how to mitigate risk factors for this devastating disease in both sexes. PMID- 30471325 TI - Single dose of 17beta-estradiol provides transient neuroprotection in female juvenile mice after cardiac-arrest and cardiopulmonary resuscitation. AB - Each year there are approximately 7000 out of hospital cardiac arrests in the pediatric population, with 30% resuscitation rate and a 6-10% rate of survival to hospital discharge. Survivors of cardiac arrest exhibit learning and memory deficits that are devastating during the school years. Delayed neuronal cell death occurs in the hippocampus following cardiac arrest and likely contributes to memory impairments. Circulating endogenous estrogen in young adult females has been shown to provide protection against ischemic cell death, as does chronic exogenous administration of 17beta-estradiol (E2). Chronic estrogen benefit can have undesirable feminizing effects, particularly in pre-adolescents. Here, we tested if a single-dose of E2 is neuroprotective in our pediatric cardiac arrest mouse model performed in juvenile mice. We subjected P21P25 C57Blk6 male and female mice to 8 min of cardiac arrest followed by cardiopulmonary resuscitation (CA/CPR). This developmental stage preceded the hormonal onset and serum estradiol and testosterone levels were not different in males and females. A single dose of E2 (100MUg/kg) or vehicle was administered 30 min after resuscitation. Neuronal cell death measured 3 days after CA/CPR showed reduced hippocampal cell death in E2-treated females, but not males. Benefit of E2 in females was blocked by the P38 MAPK inhibitor, SB203580. Hippocampal-dependent memory function was equally impaired in E2-and vehicle-treated females measured in the contextual fear conditioning task at 7 days. Our findings demonstrate female-specific transient neuroprotection with E2 that does not provide sustained functional benefit. PMID- 30471326 TI - Analysis of gut microbiota in long-lived older adults and their relatives: A gradual change with ageing. AB - Promoting the health span and lifespan of humans is the ultimate proposition of medical science. Several lifespan-reducing chronic diseases are associated with alterations in the gut microbiota (GM) composition. We aimed to identify the particular age-related GM trajectory in older Chinese adults and investigated the characteristic gut bacterial taxa of long-lived Chinese individuals. Faecal samples from 375 older adults (centenarians or adults nearly 100 years old and their younger immediate relatives) from a longevity area in East China were analysed by 16S-rRNA sequencing. The GM in the extreme-aged older adult group differed from that in the younger older adult group. GM community richness and some particular bacterial taxa (e.g., Escherichia-Shigella, Alistipes and Parabacteroides) are positively associated with ageing, whereas some other bacterial taxa (e.g., Prevotella_9 and Faecalibacterium) are negatively associated with ageing. The GM community diversity is positively associated with ageing in those from 50-59 to 90-59 to 90-99 years old and negatively associated with ageing in those from 90-99 to 100-99 to 109 years old. Our results indicate that the GM composition of healthy older adults changed gradually with ageing. Certain bacterial taxa stand out as the most characteristic of long-lived Chinese and may contribute to the longevity of these adults. PMID- 30471327 TI - Monitoring multiple cortical regions during walking in young and older adults: Dual-task response and comparison challenges. AB - Performance of several tasks simultaneously (dual-tasks) is common in everyday walking. Studies indicate that dual-task walking performance declines with age together with cognitive function, but neural mechanisms underpinning deficits remain unclear. Recent developments in mobile imaging techniques, such as functional near infrared spectroscopy (fNIRS), allow real-time monitoring of cortical activity during walking. This study aimed to: 1) examine activity in motor and cognitive cortical regions when walking with a dual-task in young and older adults; and 2) determine the effect of cognition on dual-task cortical activity changes. Seventeen young (20.3 +/- 1.2 years) and eighteen older adults (72.6 +/- 8.0 years) performed dual-task conditions, lasting 5 min, with alternating 30-second experimental blocks. The primary outcome was cortical activity, assessed by measuring changes in oxygenated haemoglobin (HbO2) concentrations. Cortical regions of interest (ROI) included motor regions (premotor cortex (PMC), supplementary motor area (SMA), primary motor cortex (M1)), and cognitive regions (prefrontal cortex (PFC)). Cognitive domains were assessed using standard tests and accelerometers were used to extract gait features. Cortical activity increased with a dual-task in PMC, SMA and M1 but not in PFC regions across groups, with response most evident with initial task exposure. Older adults did not increase SMA activity with a dual-task to the same level as young adults. Dual-task cortical response was consistently associated with greater executive function across groups. In conclusion, both young and older adults responded in a similar manner to dual-task conditions. Dual-task walking activated multiple motor regions in both groups, but no significant change occurred for cognitive region activation. Cortical activation with a dual task related to executive function. PMID- 30471328 TI - The food craving experience: Thoughts, images and resistance as predictors of craving intensity and consumption. AB - The Elaborated-Intrusion Theory of Desire (Kavanagh, Andrade, & May, 2005) suggests that cravings are made up of two distinct stages whereby an initial, seemingly spontaneous craving-related thought is sufficiently intrusive and pleasant for it then to be elaborated with vivid mental imagery. Previous questionnaire studies have investigated the craving experience with a particular focus on the role of imagery. The present study sought to provide a fuller account of the craving process by investigating the role of craving-related thoughts alongside imagery in predicting craving intensity. Further, the present study sought to investigate predictors of craving-related consumption, including spontaneous strategies used to resist cravings. Two-hundred and forty-nine women completed an online questionnaire which asked about their most recent food craving experience. Results showed that around a third of participants reported craving-related thoughts and about half reported craving-related imagery. Craving related imagery appeared to be a more important predictor of craving intensity than craving-related thoughts; however, neither predicted craving-related consumption. One resistance strategy, 'recognised it was just a thought', was successful in decreasing the likelihood of eating in response to craving. Theoretical and practical implications are discussed in the context of the Elaborated-Intrusion Theory. PMID- 30471329 TI - Sampling arterial input function (AIF) from peripheral arteries: Comparison of a temporospatial-feature based method against conventional manual method. AB - It is often difficult to accurately localize small arteries in images of peripheral organs, and even more so with vascular abnormality vasculatures, including collateral arteries, in peripheral artery disease (PAD). This poses a challenge for manually sampling arterial input function (AIF) in quantifying dynamic contrast-enhanced (DCE) MRI data of peripheral organs. In this study, we designed a multi-step screening approach that utilizes both the temporal and spatial information of the dynamic images, and is presumably suitable for localizing small and unpredictable peripheral arteries. In 41 DCE MRI datasets acquired from human calf muscles, the proposed method took <5 s on average for sampling AIF for each case, much more efficient than the manual sampling method; AIFs by the two methods were comparable, with Pearson's correlation coefficient of 0.983 +/- 0.004 (p-value < 0.01) and relative difference of 2.4% +/- 2.6%. In conclusion, the proposed temporospatial-feature based method enables efficient and accurate sampling of AIF from peripheral arteries, and would improve measurement precision and inter-observer consistency for quantitative DCE MRI of peripheral tissues. PMID- 30471330 TI - Influence of excess ligand on Nephrogenic Systemic Fibrosis associated with nonionic, linear gadolinium-based contrast agents. AB - BACKGROUND: The molecular structure, charge, thermodynamic and kinetic stability are approximately the same for gadodiamide and gadoversetamide, the main substantive difference is that gadodiamide is manufactured with 5% free ligand to form Omniscan(r) and gadoversetamide with 10% free ligand to form OptiMARK(r). PURPOSE: To determine the relative risk of Nephrogenic Systemic Fibrosis (NSF) between gadodiamide (Omniscan(r)) and gadoversetamide (OptiMARK(r)) and to explore the potential contribution of the amount of excess ligand added to their commercial formulations. MATERIALS AND METHODS: In this retrospective observational study, the number of doses and NSF cases associated with these agents were calculated based on two different approaches: the number of doses was determined based on pharmaceutical companies' information, and the number of unconfounded NSF cases was obtained from the previously published literature based on a legal database. A second analysis estimates the number of doses and NSF cases from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). RESULTS: Approximately 87 million and 12 million doses of Omniscan(r) and OptiMARK(r), respectively, have been administered worldwide since their original approval for use in the various countries throughout the world. A total of 197 and 8 unconfounded cases of NSF have been reported with Omniscan(r) and OptiMARK(r), rendering an incidence of 2.3/million and 0.7/million for these agents, respectively. The FAERS analysis suggested reported incidences of 13.1/million and 5.0/million. CONCLUSION: There is an approximately 3-fold greater incidence of NSF from Omniscan(r) than OptiMARK(r). The difference in incidence might reflect the lesser quantity of added free ligand to the formulation of Omniscan(r). PMID- 30471331 TI - Therapy resistance mediated by cancer stem cells. AB - Cancer stem cells (CSC) possess abilities generally associated with embryonic or adult stem cells, especially self-renewal and differentiation. The CSC model assumes that this subpopulation of cells sustains malignant growth, which suggests a hierarchical organization of tumors in which CSCs are on top and responsible for the generation of intratumoral heterogeneity. Effective tumor therapy requires the eradication of CSC as they can support regrowth of the tumor resulting in recurrence. However, eradication of CSC is difficult because they frequently are therapy resistant. Therapy resistance is mediated by the acquisition of dormancy, increased DNA repair and drug efflux capacity, decreased apoptosis as well as the interaction between CSC and their supporting microenvironment, the CSC niche. This review highlights the role of CSC in chemo- and radiotherapy resistance as well as possible ways to overcome CSC mediated therapy resistance. PMID- 30471332 TI - Genetic variability and oncogenic risk association of human papillomavirus type 58 E6 and E7 genes in Taizhou area, China. AB - It is well recognized that the association of human papillomavirus (HPV) and cervical carcinogenesis is based on the presence of HPV DNA sequence. The E6 and E7 oncoproteins encoded by high-risk HPV types play a key role in carcinogenesis. HPV58 type accounts for a larger share of cervical disease in China, whereas data on HPV58 genetic variability in China is limited. We aimed to evaluate the diversity of HPV58 genetic variants by sequencing the entire E6 and E7 genes. Phylogenetic trees were constructed by Maximum likelihood method by MEGA 5.05 software. In this study, the overall HPV infection rate was 22.6% (2891/12780) in Southeast China and the prevalence of HPV58 infection rate was 2.6% (335/12780). 26 nucleotides substitutions were observed in E6 and E7 genes with 10 novel substitutions and 17 non-synonymous substitutions. We obtained 25 distinct variation patterns which the accession GenBank numbers as MH348918-MH348942. All of HPV58 variants belong to lineage A, while no lineage B, C and D were detected in Taizhou area, Southeast China. The sublineage A1, A2, and A3 variants were found in 136 (68.3%), 39 (19.6%), and 24 (12.1%) of HPV58 isolates, respectively. The sublineage A3 variants with T20I/G63S substitutions at E7 oncoprotein carried a significantly higher risk for high-grade cervical intraepithelial neoplasia (CIN2 or worse, CIN2+) when compared with other HPV58 variants (odds ratio = 4.41, P < 0.05). Nevertheless, there was no association between HPV58 (sub) lineages and cervical lesions. These data provide the critical characteristics of HPV58 variants to assist further investigation of carcinogenic association and the development of next generation vaccines and diagnostic assays in China. PMID- 30471333 TI - RNA-Seq analysis of gynoecious and weak female cucumber revealing the cell cycle pathway may regulate sex determination in cucumber. AB - This study aims to investigate key genes involved in molecular regulatory networks of cucumber sex determination. Genome-wide high-throughput RNA sequencing was performed for young apical buds of gynoecious and weak female cucumber at three growth stages (one-leaf one-bud, three-leaf one-bud, and five leaf one-bud). Seven comparisons from the same cultivar at three different stages and at the same stage between the two cultivars were analyzed, and the results revealed that compared with differentially expressed genes (DEGs) in weak female cucumber, more genes were upregulated at the one-leaf one-bud stage and downregulated at the three-leaf one-bud stage in gynoecious cucumber. In addition, there were four kinds of gene expression trends (0, 1, 6, and 7), which were significantly enriched in gynoecious cucumber, while only two kinds of gene expression trends (5 and 6) were significantly enriched in weak female cucumber. Together with the data of the Gene Ontology (GO), pathway, gene expression trends and qRT-PCR, nine genes were identified and considered as candidate genes that may be involved in sex differentiation regulation in cucumber. These genes included Cs-MCM6, Cs-ACT3, Cs-XRCC4, Cs-MCM2, Cs-CDC45, Cs-Dpri, Cs-H2B, Cs-CDC20 and Cs-CNGC1. Among these genes, five genes (Cs-MCM6, Cs-MCM2, Cs-CDC45, Cs-Dpri, and Cs-CDC20) were involved in the cell cycle pathway, suggesting that the cell cycle pathway may play an important role in sex determination in cucumber. PMID- 30471334 TI - A comparative assessment of the CLP calculation method and in vivo testing for the classification of plant protection products. AB - In Europe, animal testing for the purpose of regulatory plant protection product (PPP) assessment should be undertaken only as a last resort. Nevertheless, there is a need to improve the acceptance of alternative methods, which has been slow due to a lack of data regarding the predictivity of in vivo effects. The CLP calculation method is an alternative method based on the concentration addition of all adverse substances in a mixture. It is often applied as a conservative approach for the estimation of toxicodynamic interactions. However, PPPs consist of pesticides and co-formulants, which in combination can also exhibit altered toxicokinetic properties. Our analysis revealed that oral and inhalation toxicity was underestimated for approximately 45% of the in vivo classified products by the CLP calculation method as compared to in vivo testing. With regard to skin and eye irritation, the CLP calculation method underestimated the irritating potential in 22% and 6% of PPPs, respectively. Based on specific concentration limits, skin sensitisation was underestimated in 34% of PPPs. Similar false negative rates have been reported for PPP in vitro testing. Hence, we suggest the development of an integrated assessment strategy, weighing all available information and considering relevant parameters influencing predictivity and uncertainty. PMID- 30471335 TI - Multi-dimensional in vitro bioactivity profiling for grouping of glycol ethers. AB - High-content screening data derived from physiologically-relevant in vitro models promise to improve confidence in data-integrative groupings for read-across in human health safety assessments. The biological data-based read-across concept is especially applicable to bioactive chemicals with defined mechanisms of toxicity; however, the challenge of data-derived groupings for chemicals that are associated with little or no bioactivity has not been explored. In this study, we apply a suite of organotypic and population-based in vitro models for comprehensive bioactivity profiling of twenty E-Series and P-Series glycol ethers, solvents with a broad variation in toxicity ranging from relatively non toxic to reproductive and hematopoetic system toxicants. Both E-Series and P Series glycol ethers elicited cytotoxicity only at high concentrations (mM range) in induced pluripotent stem cell-derived hepatocytes and cardiomyocytes. Population-variability assessment comprised a study of cytotoxicity in 94 human lymphoblast cell lines from 9 populations and revealed differences in inter individual variability across glycol ethers, but did not indicate population specific effects. Data derived from various phenotypic and transcriptomic assays revealed consistent bioactivity trends between both cardiomyocytes and hepatocytes, indicating a more universal, rather than cell-type specific mode-of action for the tested glycol ethers in vitro. In vitro bioactivity-based similarity assessment using Toxicological Priority Index (ToxPi) showed that glycol ethers group according to their alcohol chain length, longer chains were associated with increased bioactivity. While overall in vitro bioactivity profiles did not correlate with in vivo toxicity data on glycol ethers, in vitro bioactivity of E-series glycol ethers were indicative of and correlated with in vivo irritation scores. PMID- 30471336 TI - Macrobrachium rosenbergii nodavirus (MrNV)-CP-RNA-2 DNA vaccine confers protective immunity in giant freshwater prawn Macrobrachium rosenbergii against MrNV infection. AB - Macrobrachium rosenbergii Nodavirus (MrNV) causes white tail disease (WTD) in Giant freshwater prawn Macrobrachium rosenbergii which leads to immense economic losses in hatcheries and farms. In the present study, we cloned the capsid protein gene of MrNV-CP-RNA-2 (1146 bp) into a DNA vaccine vector pVAX1 to form MrNV-CP-RNA-2- pVAX1. The bacterial transformant, containing the MrNV-CP gene, was coated on the fish diet pellets and fed to juvenile M. rosenbergii for 40 days. After the vaccine delivery, group of M. rosenbergii were challenged with virulent MrNV on 20 and 40th days post-vaccination (dpv) respectively and monitored for the survival. The non-vaccinated M. rosenbergii succumbed to death (100%) within 5 days, whereas the MrNV-CP-RNA-2- pVAX1 treated groups had the survivals of 60 and 80% in 20 and 40 dpv respectively (P <= 0.001). To study the MrNV infection level, double step PCR was performed at different dpv. The results revealed that in 20 dpv group, the infection was decreased to 65% and in 40 dpv group the infection decreased to 69% from control diet fed prawns (P < 0.001). Haematological parameters like coagulation time, total haemocyte count (THC) and oxyhaemocyanin levels were performed for the control and vaccinated prawns. The vaccination helped to decrease the time of coagulation, improved THC and oxyhaemocyanin levels at a significant level (p < 0.001) when compared to the non vaccinated group. The immunological parameters like prophenol oxidase (ProPO), superoxide anion and intra-agar lysozyme activity were also performed and the results revealed that the level of proPO, superoxide anion and lysozyme activities were significantly (P <= 0.05) increased in 20 and 40 dpv groups respectively, when compared with the non-vaccinated groups. Based on the vaccination trials, the DNA vaccine construct MrNV-CP-RNA-2-pVAX1 effectively improved the survival against MrNV challenge, helped to decrease viral load and enhanced the immune system to protect the prawn from MrNV infection. This vaccine construct is highly useful to protect the M. rosenbergii from MrNV infection. PMID- 30471337 TI - Dietary administration of Bacillus amyloliquefaciens R8 reduces hepatic oxidative stress and enhances nutrient metabolism and immunity against Aeromonas hydrophila and Streptococcus agalactiae in zebrafish (Danio rerio). AB - Zebrafish (Danio rerio) are an excellent model for assessing the beneficial effects of probiotics before applying them in aquaculture. This study evaluated the effects on zebrafish of dietary supplementation with the probiotic Bacillus amyloliquefaciens R8, which heterologously expresses xylanase from rumen fungi. Nutrient metabolism, hepatic oxidative stress, and innate immunity against pathogen infections were investigated. Treated zebrafish received feed supplemented with B. amyloliquefaciens R8 for 30 days and then were compared to zebrafish that were fed a control diet. The treated fish showed significant increases in xylanase activity in the intestines. The livers of the treated fish showed increased mRNA expressions of glycolysis-related genes of hexokinase, glucokinase, glucose-6-phosphatase, and pyruvate kinase; and higher enzyme activities of 3-hydroxyacyl-coenzyme A dehydrogenase and citrate synthase which are associated with fatty acid beta-oxidation and mitochondrial integrity. The livers of treated fish also showed decreased mRNA expressions of oxidative stress related genes (SOD, Gpx, NOS2, and Hsp70) and an apoptotic gene (tp53), as well as increased expression of an anti-apoptotic gene (bcl-2). The probiotics-treated fish had increased expression of innate immune-related genes (IL-1beta, IL-6, IL 21, TNF-alpha, and TLR-1, -3, and -4). Following challenge with Aeromonas hydrophila and Streptococcus agalactiae, treated fish showed increased a higher survival rate than control fish. Overall, results showed that the administration of xylanase-expressing B. amyloliquefaciens R8 can potentially improve nutrient metabolism and hepatic stress tolerance, and enhance immunity and disease resistance against A. hydrophila and S. agalactiae in zebrafish. PMID- 30471338 TI - Selective growth inhibition of Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans by antisense peptide nucleic acids. AB - Peptide nucleic acids (PNA) are DNA/RNA analogs in which the sugar-phosphate backbone is replaced by N-2-aminoethylglycine. PNA are widely used for experimental antisense therapy due to their strong affinity to mRNA. By targeting specific genes, protein synthesis and the growth of bacteria or cancer cells can be inhibited by PNA. Here, we report the design and evaluation of antisense PNA for selective growth inhibition of Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, potent pathogens associated with periodontitis. Antisense PNA against groEL and acpP were prepared with carrier peptide (KFFKFFKFFK). Anti groEL PNA for P. gingivalis specifically inhibited growth in a dose-dependent manner, and growth was inhibited for 5 h at a concentration of 3 MUM. Anti-groEL PNA for A. actinomycetemcomitans inhibited growth for 2 h at a concentration of 3 MUM with reduced GroEL protein expression. Anti-acpP PNA did not show a marked growth inhibitory effect on either species. Although further studies are needed to develop more effective antisense PNA for both species, anti-groEL PNA may be potentially useful species-specific antibacterial tools against oral pathogens. PMID- 30471339 TI - Choosing a Reduced Intensity Conditioning Regimen for Allogeneic Stem Cell Transplantation, Fludarabine Busulfan versus Fludarabine Melphalan: A Systematic Review and Meta-analysis. AB - Fludarabine with busulfan (FB) or melphalan (FM) are two more commonly used reduced intensity conditioning regimens for allogeneic stem cell transplantation (HCT).We present a systematic review and meta-analysis of studies comparing these two RIC regimens. We searched electronic databases from inception through November 1st, 2017 for literature search to identify relevant studies. DerSimonian random effects model was used to measure efficacy outcomes; hazard ratios and corresponding 95% confidence interval are reported. Seven studies, including a total of 1,955 patients, met criteria for inclusion of which 6 were included in the overall pooled analysis due to repetition of some patients in two studies. Three studies were included in the subgroup analysis of acute myelogenous leukemia (AML)/ myelodysplastic syndrome (MDS) and two in the subgroup analysis of lymphoid malignancies. Overall survival and progression free survival were not statistically significantly different between the two RIC regimens in analysis of all studies. However, overall survival was better with FM in subgroup analysis of AML/MDS studies (HR 0.83; 95% CI .73 - .95). Non relapse mortality was lower with FB (HR 0.64; 95% CI 0.46 - 0.89) while relapse was lower with FM (HR 1.52, 95% CI 1.13 - 2.06) in the analysis of all studies. This meta analysis shows that FB and FM are associated with a similar overall survival in patients undergoing HCT. Relapse rates are lower with FM but at the cost of higher non-relapse mortality. PMID- 30471340 TI - ETANERCEPT AS TREATMENT OF STEROID-REFRACTORY ACUTE GRAFT VERSUS HOST DISEASE IN PEDIATRIC PATIENTS. AB - INTRODUCTION: Corticosteroids are the standard of care for first line treatment of patients who develop grades II-IV of acute Graft-versus-Host Disease (a-GvHD), but the optimal second-line treatment has not been determined yet. We prospectively evaluated the use of anti-TNFalpha monoclonal antibody Etanercept (ET) as second line treatment in children with steroid-refractory a-GvHD. MATERIALS AND METHODS: Twenty-five children with either malignant or non malignant diseases experiencing grade II-IV steroid-refractory (SR)-a-GvHD received ET as second line treatment. ET was administered after a median of 14 days (5-135 days) from onset of a-GvHD. RESULTS: Seventeen out of 25 patients (68%) developed complete or partial response (CR or PR) to ET. Overall response rate (ORR) (CR or PR) was 78% of patients with cutaneous SR-a-GvHD, 78% with gastro-intestinal a-GvHD, and 57% with hepatic a-GvHD. On day +100 after the start of ET, 52% of children were in CR, 16% in PR, while the remaining 32% failed to respond. Overall Survival (OS) in responders was 76.5% and 16.7% in non responders (p=0.004). Transplant-related mortality (TRM) at 5 years was 34.1% (95% CI; 18.6%- 57.1%). CONCLUSION: In our experience, ET proved to be effective as second line treatment in children with SR-a-GvHD. PMID- 30471341 TI - Prevention of Hepatic Stellate Cell Activation using JQ1- and Atorvastatin-Loaded Chitosan Nanoparticles as a Promising Approach in Therapy of Liver Fibrosis. AB - Preventing hepatic stellate cell (HSC) activation represents a promising approach to resolve liver fibrosis. Several drugs have been reported to delay/prevent HSCs activation, however with limited clinical benefits. The latter may be in part attributed to the limited ability of such drugs in targeting more than one pathway of HSC activation. Added to that, is their inability of reaching their target cell in sufficient amounts to induce a therapeutic effect. In this work, chitosan NPs were loaded with JQ1 and atorvastatin, two drugs that have been reported to prevent HSCs activation, however via different mechanisms. NPs were then modified with different densities of retinol (Rt) for active targeting of HSCs. The NP HSCs targeting ability as a function of Rt density was assessed in vitro on primary HSCs and in vivo in carbon tetrachloride (CCl4) induced fibrotic mouse models. In vitro NPs modified with a low Rt density (LRt-NPs) showed ~2 folds enhanced HSCs uptake in comparison to unmodified NPs, whereas NPs modified with a high Rt density (HRt-NPs) showed ~0.8 folds change in uptake relative to unmodified NPs. Similarly, in vivo LRt-NPs showed higher accumulation in fibrotic livers in comparison to healthy livers whereas HRt-NPs and unmodified NPs showed lower accumulation in fibrotic livers relative to healthy controls respectively. Finally, the ability of drug-loaded NPs in preventing HSCs activation was assessed by monitoring the reduction in alpha-smooth muscle actin (alpha-SMA) expression by Western blot. NPs loaded with both JQ1 and atorvastatin showed reduction in alpha-SMA expression. In addition, a synergistic reduction in alpha SMA was observed when cells were co-treated with JQ1 and atorvastatin loaded NPs. PMID- 30471342 TI - Acquired Gerbode type defect after bioprosthetic aortic valve replacement. PMID- 30471343 TI - Structural insights into the catalytic mechanism of 5-methylthioribose 1 phosphate isomerase. AB - 5-Methylthioribose 1-phosphate isomerase (M1Pi) is a crucial enzyme involved in the universally conserved methionine salvage pathway (MSP) where it is known to catalyze the conversion of 5-methylthioribose 1-phosphate (MTR-1-P) to 5 methylthioribulose 1-phosphate (MTRu-1-P) via a mechanism which remains unspecified till date. Furthermore, although M1Pi has a discrete function, it surprisingly shares high structural similarity with two functionally non-related proteins such as ribose-1,5-bisphosphate isomerase (R15Pi) and the regulatory subunits of eukaryotic translation initiation factor 2B (eIF2B). To identify the distinct structural features that lead to divergent functional obligations of M1Pi as well as to understand the mechanism of enzyme catalysis, the crystal structure of M1Pi from a hyperthermophilic archaeon Pyrococcus horikoshii OT3 was determined. A meticulous structural investigation of the dimeric M1Pi revealed the presence of an N-terminal extension and a hydrophobic patch absent in R15Pi and the regulatory alpha-subunit of eIF2B. Furthermore, unlike R15Pi in which a kink formation is observed in one of the helices, the domain movement of M1Pi is distinguished by a forward shift in a loop covering the active-site pocket. All these structural attributes contribute towards a hydrophobic microenvironment in the vicinity of the active site of the enzyme making it favorable for the reaction mechanism to commence. Thus, a hydrophobic active-site microenvironment in addition to the availability of optimal amino-acid residues surrounding the catalytic residues in M1Pi led us to propose its probable reaction mechanism via a cis-phosphoenolate intermediate formation. PMID- 30471344 TI - Single base resolution mapping of 2'-O-methylation sites in human mRNA and in 3' terminal ends of small RNAs. AB - The post-transcriptional modification 2'-O-Methyl (2'OMe) could be present on the ribose of all four ribonucleosides, and is highly prevalent in a wide variety of RNA species, including the 5' RNA cap of viruses and higher eukaryotes, as well as internally in transfer RNA and ribosomal RNA. Recent studies have suggested that 2'OMe is also located internally in low-abundance RNA species such as viral RNA and mRNA. To profile 2'OMe on different RNA species, we have developed Nm seq, which could identify 2'OMe sites at single base resolution. Nm-seq is particularly useful for identifying 2'OMe sites located at the 3' terminal ends of small RNAs. Here, we present an optimized protocol for Nm-seq and a protocol for applying Nm-seq to identify 2'OMe sites on small RNA 3' terminal ends. PMID- 30471345 TI - Optimization of Second Window Indocyanine Green for Intraoperative Near-Infrared Imaging of Thoracic Malignancy. AB - BACKGROUND: Near-infrared (NIR) imaging using the second time window of indocyanine green (ICG) allows localization of pulmonary, pleural, and mediastinal malignancies during surgery. Based on empirical evidence, we hypothesized that different histological tumor types fluoresce optimally at different ICG doses. STUDY DESIGN: Patients with thoracic tumors biopsy-proven or suspicious for malignancy were enrolled in an NIR imaging clinical trial. Patients received a range of ICG doses one day prior to surgery: 1 mg/kg (n=8), 2 mg/kg (n=8), 3 mg/kg (n=13), 4 mg/kg (n=8), and 5 mg/kg (n=8). Intraoperatively, NIR imaging was performed. The endpoint was to identify the highest tumor-to background fluorescence ratio (TBR) for each tumor type at each dose. Final pathology confirmed tumor histology. RESULTS: Of 45 patients, 41 had malignancies (18 non-small cell lung cancer (NSCLC), 3 pulmonary neuroendocrine tumors, 13 thoracic metastases, 3 thymoma, 3 mesothelioma). At doses of 4-5 mg/kg, the TBR from primary NSCLC versus other malignancies was no different (2.70 vs. 3.21, P=1.00). At doses of 1-3 mg/kg, the TBR was greater for the non-NSCLCs (3.19 vs. 1.49, P=0.0006). Background fluorescence from the heart or ribs was observed in 1/16 cases at 1-2 mg/kg, 5/13 cases at 3 mg/kg, and 14/16 cases at 4-5 mg/kg; this was a major determinant of dose optimization. CONCLUSION: This is the first study to demonstrate that the optimal NIR contrast agent dose varies by tumor histology. Lower dose ICG (2-3 mg/kg) is superior for non-primary lung cancers, and high dose ICG (4-5 mg/kg) is superior for lung cancers. This will have major implications as more intraoperative imaging trials surface in other specialties, will significantly reduce costs, and may facilitate wider application. PMID- 30471346 TI - High fat diet increases cognitive decline and neuroinflammation in a model of orexin loss. AB - Midlife obesity is a risk factor for cognitive decline and is associated with the earlier onset of Alzheimer's disease (AD). Diets high in saturated fat potentiate the onset of obesity, microglial activation, and neuroinflammation. Signaling deficiencies in the hypothalamic peptide orexin and/or orexin fiber loss are linked to neurodegeneration, cognitive impairment, and neuroinflammation. Prior studies show that orexin is neuroprotective, suppresses neuroinflammation, and that treatment with orexin improves cognitive processes in orexin/ataxin-3 (O/A3) mice, a transgenic mouse model of orexin neurodegeneration. Our overall hypothesis is that loss of orexin contributes to high fat diet (HFD)-induced hippocampal neuroinflammation and cognitive decline. To examine this, we tested male O/A3 mice (7-8 mo. of age) in a two-way active avoidance (TWAA) hippocampus dependent memory task. We tested whether (1) orexin loss impaired cognitive function; (2) HFD worsened cognitive impairment; and (3) HFD increased microglial activation and neuroinflammation. O/A3 mice showed significant impairments in TWAA task learning vs. wild type (WT) mice (increased escapes p < 0.05, reduced avoidances p < 0.0001). Mice were then placed on HFD (45% total fat, 31.4% saturated fat) or remained on normal chow (NC; 4% total fat and 1% saturated fat), and TWAA was retested at 2 and 4 weeks. Learning impairment was evident at both 2 and 4 weeks in O/A3 mice fed HFD for following diet exposure vs. WT mice on normal chow or HFD (increased escapes, reduced avoidances p < 0.05). Additionally, O/A3 mice had increased gene expression of the microglial activation marker Iba-1 (measured via qRT-PCR, p < 0.001). Further characterization of the microglial immune response genes in hippocampal tissue revealed a significant increase in CX3 chemokine receptor 1 (CX3CR1), tumor necrosis factor-alpha (TNF-alpha) and the mitochondria-associated enzyme immune responsive gene-1 (Irg1). Collectively, our results indicate that orexin loss impairs memory, and that HFD accelerates hippocampus-dependent learning deficits and the onset of neuroinflammation. PMID- 30471347 TI - Synthesis and evaluation of 13C-labeled 5-5-dimethyl-1-pyrroline-N-oxide aimed at in vivo detection of reactive oxygen species using hyperpolarized 13C-MRI. AB - Effective means to identify the role of reactive oxygen species (ROS) mediating several diseases including cancer, ischemic heart disease, stroke, Alzheimer's and other inflammatory conditions in in vivo models would be useful. The cyclic nitrone 5,5-Dimethyl-1-pyrroline-N-oxide (DMPO) is a spin trap frequently used to detect free radicals in vitro using Electron Paramagnetic Resonance (EPR) spectroscopy. In this study, we synthesized 13C-labeled DMPO for hyperpolarization by dynamic nuclear polarization, in which 13C NMR signal increases more than 10,000-fold. This allows in vivo 13C MRI to investigate the feasibility of in vivo ROS detection by the 13C-MRI. DMPO was 13C-labeled at C5 position, and deuterated to prolong the T1 relaxation time. The overall yield achieved for 5-13C-DMPO-d9 was 15%. Hyperpolarized 5-13C-DMPO-d9 provided a single peak at 76 ppm in the 13C-spectrum, and the T1 was 60 s in phosphate buffer making it optimal for in vivo 13C MRI. The buffered solution of hyperpolarized 5-13C-DMPO-d9 was injected into a mouse placed in a 3 T scanner, and 13C-spectra were acquired every 1 s. In vivo studies showed the signal of 5 13C-DMPO-d9 was detected in the mouse, and the T1 decay of 13C signal of hyperpolarized 5-13C-DMPO-d9 was 29 s. 13C-chemical shift imaging revealed that 5 13C-DMPO-d9 was distributed throughout the body in a minute after the intravenous injection. A strong signal of 5-13C-DMPO-d9 was detected in heart/lung and kidney, whereas the signal in liver was small compared to other organs. The results indicate hyperpolarized 5-13C-DMPO-d9 provided sufficient 13C signal to be detected in the mouse in several organs, and can be used to detect ROS in vivo. PMID- 30471348 TI - Mortality from Heart Failure and Dementia in the United States: CDC WONDER 1999 2016. AB - BACKGROUND: Heart failure and dementia are diseases of the elderly that result in billions of dollars in annual healthcare expenditure. With the aging of the United States population, and increasing evidence of shared risk factors, there is a need to understand the conditions' shared contributions to nationwide mortality. The objectives of our study are to estimate the burden of mortality from heart failure and dementia and characterize the demographics of affected individuals. METHODS AND RESULTS: This is a retrospective study using National Vital Statistics Data from 1999-2016 provided by the Centers for Disease Control and ICD-10 codes for heart failure and dementia defined by the Medicare Chronic Conditions Data Warehouse. From 1999 to 2016, deaths contributed by heart failure and dementia totaled 214,706 and comprised 4.00% of all heart failure deaths and 9.04% of all dementia deaths. Women were more affected than men, with higher age adjusted mortality rates (per 1,000,000 person-years): 38.67, 95% CI: 38.47-38.87 vs. 32.90, 95% CI: 32.65-33.15, p<0.001. Whites were affected more than Blacks, with age-adjusted mortality rates (per 1,000,000 person-years): 38.00, 95% CI: 37.83-38.16 vs. 31.06, 95% CI: 30.54-31.59, p<0.001. However, under the age of 65 years, higher crude mortality rates (per 1,000,000 person-years) were reported in men (0.20, 95% CI 0.18-0.22) compared with women (0.15, 95% CI 0.13-0.16, p<0.001). CONCLUSIONS: This study provides insight into temporal trends and nationwide mortality rates reported for heart failure and dementia. Our results suggest a disproportionate burden on populations over 85 years, Whites, and women. PMID- 30471349 TI - Characterization of a third ghrelin receptor, GHS-R3a, in channel catfish reveals novel expression patterns and a high affinity for homologous ligand. AB - A novel third channel catfish growth hormone secretagogue (ghrelin) receptor, GHS R3a, gene was characterized. Identification and analysis of the genomic organization of channel catfish GHS-R3a revealed differences in exon/intron structure relative to the previously published GHS-R1a and GHS-R2a sequences. Amino acid sequence alignment of catfish GHS-R3a with -R1a and -R2a revealed 48 and 52% sequence identity, respectively. Phylogenetic analysis predicted a new clade of GHS-R3a receptors found only in fish, with representation in the teleost infradivisions Osteoglossomorpha, Clupeomorpha, and Euteleostei. In functional analyses, homologous catfish ghrelin increased intracellular Ca2+ concentration in human embryonic kidney (HEK) 293 cells stably expressing catfish GHS-R3a. On the contrary, intracellular Ca2+ concentration was unaffected by treatment with the synthetic growth hormone secretagogues GHRP-6 and hexarelin. Realtime PCR results indicated high expression of GHS-R3a in the brain and gonads, demonstrating tissue specificity among the catfish GHS-Rs. The effects of fasting and refeeding on all three ghrelin receptors were evaluated in catfish brain, pituitary, stomach, and Brockmann bodies. Most notably, GHS-R3a was the only receptor observed to significantly increase (2.9-6.3-fold) in brain, pituitary, and stomach within 4 days of fasting (P < .05). Stomach GHS-R1a also increased (P < .05) after 4 days; however, GHS-R2a was only elevated in brain and pituitary after refeeding for 1 week. Expression of all three ghrelin receptors were elevated (P < .05) in the Brockmann bodies after 2 weeks of fasting and returned to prefasting levels following refeeding. Together with the previously published characterization of GHS-R1a and -R2a, these results establish three ghrelin receptors, each altered by energy state, in channel catfish and add to the growing body of information on GHS-R evolution and function. PMID- 30471350 TI - Light intensity and suppression of nocturnal plasma melatonin in Arctic charr (Salvelinus alpinus). AB - The problem of early sexual maturation among farmed Arctic charr and other salmonids can be effectively reduced by 24 h light overwinter, provided it is bright enough to over-ride interference from the natural daylength cycle. To determine the threshold light intensity to suppress the nocturnal elevation of plasma melatonin, three groups of individually tagged fish (n = 26-28/group ca. 1040 g) were reared on 12 h light: 12 h dark (LD 12:12) and subjected to nighttime light intensities of either 50-65, 0.1-0.3 or 0 (control) lux for five months (November to April). Daytime light intensity was 720-750 lx. Diel plasma melatonin profiles in both November and April were similar; mean daytime levels ranged from 20 to 100 pg/ml, and nighttime levels were inversely proportional to light intensity. In the control group at 0 lx, plasma melatonin increased about four-fold after lights-off, ranging between 320 and 430 pg/ml. Nighttime light intensity of 0.1-0.3 lx halved plasma melatonin levels to 140-220 pg/ml, and 50 65 lx further reduced the levels to one quarter of the control group, 68-108 pg/ml. Among the lit groups, daytime plasma melatonin levels were about 20-30 pg/ml, significantly lower than the nocturnal levels suggesting the diel hormonal rhythm was not completely abolished. Fish grew steadily from about 1100 g to 1600 g between November and April, independent of light intensity (P = .67). Overall, the study demonstrated the sensitivity of pineal melatonin hormone to different light intensities in Arctic charr. PMID- 30471351 TI - Reconsidering the central role of mucins in dry eye and ocular surface diseases. AB - Mucins are key actors in tear film quality and tear film stability. Alteration of membrane-bound mucin expression on corneal and conjunctival epithelial cells and/or gel-forming mucin secretion by goblet cells (GCs) promotes in ocular surface diseases and dry eye disease (DED). Changes in the mucin layer may lead to enhanced tear evaporation eventually contributing to tear hyperosmolarity which has been associated with ocular surface inflammation. Inflammatory mediators in turn may have a negative impact on GCs differentiation, proliferation, and mucin secretion. This sheds new light on the position of GCs in the vicious circle of DED. As contributor to ocular surface immune homeostasis, GC loss may contribute to impaired ocular surface immune tolerance observed in DED. In spite of this, there are no tools in routine clinical practice for exploring ocular surface mucin deficiency/dysregulation. Therefore, when selecting the most appropriate treatment options, there is a clear unmet need for a better understanding of the importance of mucins and options for their replacement. Here, we comprehensively revisited the current knowledge on ocular surface mucin biology, including functions, synthesis, and secretion as well as the available diagnostic tools and treatment options to improve mucin-associated homeostasis. In particular, we detailed the potential link between mucin dysfunction and inflammation as part of the uncontrolled chronic inflammation which perpetuates the vicious circle in DED. PMID- 30471352 TI - Genome-wide DNA methylation analysis in primary antiphospholipid syndrome neutrophils. AB - Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thromboembolic events and pregnancy loss. We sought to characterize the DNA methylation profile of primary APS in comparison to healthy controls and individuals with SLE. In primary APS neutrophils compared to controls, 17 hypomethylated and 25 hypermethylated CpG sites were identified. Notable hypomethylated genes included ETS1, a genetic risk locus for SLE, and PTPN2, a genetic risk locus for other autoimmune diseases. Gene ontology analysis of hypomethylated genes revealed enrichment of genes involved in pregnancy. None of the differentially methylated sites in primary APS were differentially methylated in SLE neutrophils, and there was no demethylation of interferon signature genes in primary APS as is seen in SLE. Hypomethylation within a single probe in the IFI44L promoter (cg06872964) was able to distinguish SLE from primary APS with a sensitivity of 93.3% and specificity of 80.0% at a methylation fraction of 0.329. PMID- 30471353 TI - Mullerian aplasia with severe hematometra: A case report of diagnosis and management in a low resource setting. AB - BACKGROUND: Mullerian aplasia or Mayer-Rokitansky-Kuster-Hauser syndrome is described as congenital absence of the proximal vagina with or without absence of the cervix and uterus, most often recognized following the onset of primary amenorrhea. CASE: An 18-year-old female presented to a free medical clinic in Arcahaie, Haiti with primary amenorrhea, abdominal distention and cyclic monthly abdominal pain. Physical exam was significant for uterus palpable superior to the umbilicus, absence of vagina, and rectal exam without palpable vagina or cervix. Transabdominal and transperineal ultrasounds did not reveal hematocolpos. Exploratory laparotomy revealed severe endometriosis with bilateral hematosalpinges, markedly distended uterus, no proximal vagina, and normal ovaries. Uterine specimen was filled with blood and no clear cervix was present. SUMMARYAND CONCLUSIONS: Diagnosis of vaginal and cervical agenesis is complicated in low resource settings and treatment must be modified when subspecialty care and consistent follow-up are not available. PMID- 30471354 TI - Vti Proteins: Beyond Endolysosomal Trafficking. AB - Vti proteins are conserved from yeast to humans and regulate intracellular membrane trafficking by providing one specific SNARE domain, the Qb SNARE, to the four helical SNARE bundle that drives membrane fusion. Two mammalian Vti genes, Vti1a and Vti1b are reported to regulate distinct aspects of endolysosomal trafficking and retrograde transport to the Golgi, but have also been implicated in synaptic vesicle secretion. In this review, we summarize the current evidence for the role of Vti proteins in intracellular trafficking in different cells. We propose that, despite some unique aspects, the two mammalian VTI genes have largely redundant functions in neurosecretory cells and recycle molecules required for the sorting of regulated cargo to the Golgi. Defects in this recycling also lead to defects in synaptic transmission and dense core vesicle secretion. PMID- 30471355 TI - A Timeline of Motor Preparatory State Prior to Response Initiation: Evidence from Startle. AB - Response preparation in simple reaction time (RT) tasks has been modeled as an increase in neural activation to a sub-threshold level, which is maintained until the go-signal. However, the amount of time required for response preparation following a warning signal (WS) is currently unclear, as experiments typically employ long foreperiods to ensure maximal preparation. The purpose of the present experiments was to examine the time course of motor preparation in a simple RT task when given a limited amount of time to engage in preparatory processing. In Experiment 1, participants completed wrist extension movements in a simple RT paradigm with a short (500 ms) fixed foreperiod, and a long (8.5-10.5 s) inter trial interval. To probe response preparation, a startling acoustic stimulus (SAS), which involuntarily triggers the release of sufficiently prepared responses, was randomly presented during the foreperiod at one of six equally spaced time points between 0 and 500 ms prior to the go-signal. Results showed that the long inter-trial interval was not always effective at preventing participants from engaging in preparatory processing between trials; thus, in Experiment 2 participants performed wrist flexion or extension movements in an instructed delay paradigm, where the required movement was cued by the WS. Results showed that the proportion of startle trials where the intended response was elicited by the SAS at short latency significantly increased until 100 ms prior to the go-signal, indicating response preparation can take up to 300-400 ms following the WS in a simple RT task with a short fixed foreperiod. PMID- 30471356 TI - The First Mating Experience Induces New Neurons in the Olfactory Bulb in Male Mice. AB - In rodents, neurogenesis in the olfactory bulbs (OBs) is enhanced by exposure to olfactory enriched environments including sexually relevant odors. In the present study we evaluated whether sexual stimulation in male mice increases the number of newly generated cells that reach the OB and whether these cells differentiate into neurons. To this end, we used sexually naive male C57BL mice randomly assigned to one of three groups: (1) control, in which animals were left alone in their home cages; (2) exposure, in which animals were exposed to a receptive female precluding any physical contact; and (3) mating, in which males copulated with females. Males were given three injections of the DNA synthesis marker 5 bromo-2'-deoxyuridine (BrdU) 2 h before, at the end and 2 h after the test. Fifteen days after BrdU administration, brains were removed and processed to identify new cells and evaluate if they had differentiated into neurons in the granular (GR), mitral (MI) and glomerular (GL) cell layers of the main and accessory OB (MOB and AOB, respectively). We found an increase in the percentage of new cells that differentiate into neurons in the GL cell layer of the MOB of males from the mating group compared with those from the exposure and control groups. No differences were found in the number of new cells or percentage of new neurons in the rest of the analyzed regions. In male mice, the first sexual experience increases the percentage of new cells that differentiate into neurons in the GL cell layer of the MOB. PMID- 30471357 TI - Direct Intracellular Signaling by the Carboxy terminus of NMDA Receptor GluN2 Subunits Regulates Dendritic Morphology in Hippocampal CA1 Pyramidal Neurons. AB - N-methyl-d-aspartate receptors (NMDARs) are glutamatergic receptors that take part in excitatory synaptic transmission and drive functional and structural neuronal plasticity, including activity-dependent changes in dendritic morphology. Forebrain NMDARs contribute to neuronal plasticity in at least two ways: through calcium-mediated processes or via direct intracellular postsynaptic signaling. Both properties are regulated by the GluN2 subunits. However, the separate contributions of these properties to the regulation of dendritic morphology are unknown. We created transgenic mice that express chimeric GluN2 subunits and examined the impact on pyramidal cell dendritic morphology in hippocampal region CA1. Golgi-Cox impregnation and transgenic expression of green fluorescent protein were employed to visualize dendritic arbors. In adult mice with a predominantly native GluN2A background, overexpression of the GluN2B carboxy terminus increased the total path of the dendritic arbor without affecting branch number or tortuosity. Overexpressing the amino terminus and transmembrane domains of GluN2B had little effect. It may be inferred from these results that NMDAR-dependent intracellular signaling regulates dendritic morphology of hippocampal pyramidal cells more so than calcium conductance dynamics. The findings add to the understanding of NMDAR-mediated signaling in hippocampal neurons and support re-investigation of the molecular underpinnings of NMDAR involvement in postnatal dendrite maturation. PMID- 30471358 TI - Coordinated existence of multiple gangliosides is required for cartilage metabolism. AB - OBJECTIVE: Gangliosides, ubiquitously existing membrane components that modulate transmembrane signaling and mediate cell-to-cell and cell-to-matrix interactions, are key molecules of inflammatory and neurological disorders. However, the functions of gangliosides in the cartilage degradation process remain unclear. We investigated the functional role of gangliosides in cartilage metabolism related to osteoarthritis (OA) pathogenesis. DESIGN: We generated knockout (KO) mice by targeting the beta1, 4-N-acetylgalactosaminyltransferase (GalNAcT) gene, which encodes an enzyme of major gangliosides synthesis, and the GD3 synthase (GD3S) gene, which encodes an enzyme of partial gangliosides synthesis. In vivo OA and in vitro cartilage degradation models were used to evaluate the effect of gangliosides on the cartilage degradation process. RESULTS: The GalNAcT and GD3S KO mice developed and grew normally; nevertheless, OA changes in these mice were enhanced with aging. The GalNAcT KO mice showed significantly enhanced OA progression compared to GD3S mice in vivo. Both GalNAcT and GD3S KO mice showed severe IL-1alpha-induced cartilage degradation ex vivo. Phosphorylation of MAPKs was enhanced in both GalNAcT and GD3S KOs after IL-1alpha stimulation. Gangliosides modulated by GalNAcT or GD3S rescued an increase of MMP-13 induced by IL-1alpha in mice lacking GalNAcT or GD3S after exogenous replenishment in vitro. CONCLUSION: These data show that the deletion of gangliosides in mice enhanced OA development. Moreover, the gangliosides modulated by GalNAcT are important for cartilage metabolism, suggesting that GalNAcT is a potential target molecule for the development of novel OA treatments. PMID- 30471359 TI - Yeast chemogenomic screen identifies distinct metabolic pathways required to tolerate exposure to phenolic fermentation inhibitors ferulic acid, 4 hydroxybenzoic acid and coniferyl aldehyde. AB - The conversion of plant material into biofuels and high value products is a two step process of hydrolysing plant lignocellulose and next fermenting the sugars produced. However, lignocellulosic hydrolysis not only frees sugars for fermentation it simultaneously generates toxic chemicals, including phenolic compounds which severely inhibit yeast fermentation. To understand the molecular basis of phenolic compound toxicity, we performed genome-wide chemogenomic screens in Saccharomyces cerevisiae to identify deletion mutants that were either hypersensitive or resistant to three common phenolic compounds found in plant hydrolysates: coniferyl aldehyde, ferulic acid and 4-hydroxybenzoic acid. Despite being similar in structure, our screen revealed that yeast utilizes distinct pathways to tolerate phenolic compound exposure. Furthermore, although each phenolic compound induced reactive oxygen species (ROS), ferulic acid and 4 hydroxybenzoic acid-induced a general cytoplasmic ROS distribution while coniferyl aldehyde-induced ROS partially localized to the mitochondria and to a lesser extent, the endoplasmic reticulum. We found that the glucose-6-phosphate dehydrogenase enzyme Zwf1, which catalyzes the rate limiting step of pentose phosphate pathway, is required for reducing the accummulation of coniferyl aldehyde-induced ROS, potentially through the sequestering of Zwf1 to sites of ROS accumulation. Our novel insights into biological impact of three common phenolic inhibitors will inform the engineering of yeast strains with improved efficiency of biofuel and biochemical production in the presence hydrolysate derived phenolic compounds. PMID- 30471360 TI - Lipid engineering combined with systematic metabolic engineering of Saccharomyces cerevisiae for high-yield production of lycopene. AB - Saccharomyces cerevisiae is an efficient host for natural-compound production and preferentially employed in academic studies and bioindustries. However, S. cerevisiae exhibits limited production capacity for lipophilic natural products, especially compounds that accumulate intracellularly, such as polyketides and carotenoids, with some engineered compounds displaying cytotoxicity. In this study, we used a nature-inspired strategy to establish an effective platform to improve lipid oil-triacylglycerol (TAG) metabolism and enable increased lycopene accumulation. Through systematic traditional engineering methods, we achieved relatively high-level production at 56.2mg lycopene/g cell dry weight (cdw). To focus on TAG metabolism in order to increase lycopene accumulation, we overexpressed key genes associated with fatty acid synthesis and TAG production, followed by modulation of TAG fatty acyl composition by overexpressing a fatty acid desaturase (OLE1) and deletion of Seipin (FLD1), which regulates lipid droplet size. Results showed that the engineered strain produced 70.5mg lycopene/g cdw, a 25% increase relative to the original high-yield strain, with lycopene production reaching 2.37g/L and 73.3mg/g cdw in fed-batch fermentation and representing the highest lycopene yield in S. cerevisiae reported to date. These findings offer an effective strategy for extended systematic metabolic engineering through lipid engineering. PMID- 30471361 TI - Community Resource Needs Assessment Among Families Presenting to a Pediatric Emergency Department. AB - OBJECTIVE: To identify community resource needs among families presenting to a pediatric emergency department (PED). METHODS: A convenience sample of English and Spanish-speaking caregivers residing in Los Angeles County who presented to the PED of a large urban children's hospital were surveyed. The needs assessment survey assessed demographics, food insecurity, and previous and anticipated need for 12 common community resources. RESULTS: Of 768 caregivers who completed the survey, 75% identified as Hispanic/Latinx. Across all survey participants, 83% used at least one resource in the past, and 67% anticipated needing at least one resource in the next 12 months. Low cost/free health clinics were the most common resources used in the past and needed for the future. Caregivers with younger children tended to need baby formula/breastfeeding and women's health resources, while caregivers with older children tended to need safe housing, subsidized utilities, and counseling/therapy. Many families who needed resources in the past and for the future resided south of the children's hospital, where median household income was relatively lower than in other areas of the county. A pattern of heightened use emerged among caregivers who primarily spoke Spanish. On average, caregivers reported feeling comfortable approaching hospital staff about community resources. CONCLUSIONS: We found significant needs for community resources among families who presented to an urban PED. Needs were particularly salient among Spanish-speaking families and families living in close proximity to the children's hospital. Findings from this study help to inform future work connecting families to community resources. PMID- 30471363 TI - Seaweed allergy. PMID- 30471362 TI - Fish-allergic patients tolerate ray based on the low allergenicity of its parvalbumin. AB - BACKGROUND: Clinical reactions to bony fish species are common in fish-allergic patients and caused by parvalbumins of the beta-lineage. Cartilaginous fish such as rays and sharks contain mainly alpha-parvalbumins and their allergenicity is not well understood. OBJECTIVE: We investigated the allergenicity of cartilaginous fish and their alpha-parvalbumins in individuals allergic to bony fish. METHODS: Sensitization to cod, salmon and ray among cod- and/or salmon allergic patients (n=18) was explored by prick-to-prick testing (PPT). Clinical reactivity to ray was assessed in 11 patients by food challenges or clinical work up. IgE-binding to beta-parvalbumins (cod, carp, salmon, barramundi, tilapia) and alpha-parvalbumins (ray, shark) was determined by IgE-ELISA. Basophil activation tests (BAT) and skin prick tests (SPT) were performed with beta-parvalbumins from cod, carp and salmon, and alpha-parvalbumins from ray and shark. RESULTS: Tolerance of ray was observed in 10/11 patients. PPT to ray was markedly lower than to bony fish (median wheal diameter 2 mm with ray vs. 11 mm with cod and salmon). IgE to alpha-parvalbumins was lower (median 0.1 kU/L for ray and shark) than to beta-parvalbumins (median >=1.65 kU/L). Furthermore, alpha-parvalbumins demonstrated a significantly reduced basophil activation capacity compared to beta-parvalbumins (e.g. ray vs. cod, p<0.001, n=18). SPT further demonstrated lower reactivity to alpha- compared to beta-parvalbumins. CONCLUSION: Most bony fish-allergic patients tolerated ray, a cartilaginous fish, due to low allergenicity of its alpha-parvalbumin. A careful clinical work-up and in vitro IgE-testing for cartilaginous fish will improve patient management and may introduce an alternative to bony fish into patients' diet. PMID- 30471364 TI - Adenosine receptor agonists deepen the inhibition of platelet aggregation by P2Y12 antagonists. AB - Several adenosine receptor (AR) agonists have been shown in the past to possess anti-platelet potential; however, the adjunctive role of AR agonists in anti platelet therapy with the use of P2Y12 receptor inhibitors has not been elucidated so far. This in vitro aggregation-based study investigates whether the inhibition of platelet function mediated by cangrelor or prasugrel metabolite can be potentiated by AR agonists. It evaluates the effect of non-selective (2 chloroadenosine), A2A-selective (UK 432097, MRE 0094, PSB 0777) and A2B-selective AR agonists (BAY 60-6583) on platelet function in relation to their toxicity, specificity towards adenosine receptor subtypes, structure and solubility. UK 432097, 2-chloroadenosine, MRE 0094 and PSB 0777 were found to be more or less potent inhibitors of ADP-induced platelet aggregation when acting alone, and that they remained non-cytotoxic to the cells. These AR agonists were also effective in the potentiation of the effects exerted by P2Y12 antagonists. Considering the estimated IC50 value, UK 432097, showing a relatively high binding affinity to the A2A adenosine receptor, has been identified as the most potent anti aggregatory agent. This compound diminished platelet aggregation at nanomolar concentrations and further augmented platelet inhibition by P2Y12 antagonists by approx. 60% (P < .01). Our results indicate the importance of adenosine receptors as therapeutic targets and point out challenges and potential benefits of therapeutic use of a combined therapy of P2Y12 antagonist and AR agonist in cardioprotection. Our comparative analysis of the effects of AR agonists on platelet response in plasma and whole blood may indirectly suggest that other blood morphology elements contribute little to the inhibition of platelet function by AR agonists. PMID- 30471365 TI - Effects of three common lumbar interbody fusion procedures for degenerative disc disease: A network meta-analysis of prospective studies. AB - OBJECTIVES: Lumbar interbody fusion (LIF) is a treatment option for patients with degenerative disc disease (DDD). However, the effects of the most common LIF procedures-posterior LIF, transforaminal LIF, and anterior LIF-for the treatment of patients with DDD remain controversial. This study evaluated the pain and function caused by the LIF procedures for the treatment of patients with DDD. METHODS: Cochrane library, EMBASE, Ovid Medline, and PubMed were searched from inception to July 17, 2018. We only included prospective studies comparing the LIF procedures for treating patients with DDD. Pain score, Oswestry disability index (ODI) score, and operative time were analyzed in a contrast-based consistency model. Results are reported in weighted mean difference (WMD) and 95% confidence interval (CI). RESULTS: This study included eight prospective studies that recruited 503 patients for the LIF procedures. Minimally invasive posterior LIF resulted in lower pain scores than open transforaminal LIF (WMD: -1.45, 95% CI: -2.27 to -0.63) and open posterior LIF (WMD: -0.61, 95% CI: -1.10 to -0.12). It also resulted in a lower ODI score than open transforaminal LIF (WMD: -15.34, 95% CI: -21.76 to -8.91), anterior LIF (WMD: -15.64, 95% CI: -26.37 to -4.91), minimally invasive transforaminal LIF (WMD: -11.63, 95% CI: -16.86 to -6.40), and open posterior LIF (WMD: -10.93, 95% CI: -16.07 to -5.79). Small study effects were not detected in any consistency models. CONCLUSIONS: Although minimally invasive posterior LIF has longer operative time than anterior LIF, it is associated with lower pain and ODI scores. Therefore, minimally invasive posterior LIF may be a superior LIF procedure for patients with DDD. PMID- 30471366 TI - Man against the machine - Differences in surgical risk evaluation. A cohort prospective study. AB - BACKGROUND: The aim of this study was to compare the assessment provided by the ACS Surgical Risk Calculator with the assessments provided by senior and resident anesthesiologists. METHODS: The study is prospective and controlled. Before the surgical procedure a resident anesthesiologist collected data needed to perform pre-operative assessment. Then, based on this data, a risk assessment was carried out by resident and senior anesthesiologists and by the online ACS Surgical Risk Calculator. Then the three evaluations were compared. Demographic and clinical data were gathered to determine risk factors and complication rates. RESULTS: One hundred patients who were scheduled for a surgical procedure were recruited for the study. A difference was found among the different estimations. In most parameters the resident anesthesiologists more resembled the ACS assessment than the senior anesthesiologists. The following differences in risk assessment were found: possible complication in the course of the surgery (4.4% ACS calculator, 1% senior anesthesiologists, 2.2% resident anesthesiologists), and for a life threatening complication (3.6% ACS calculator, 0.5% senior anesthesiologists, 2.4% resident anesthesiologists). In assessing death, urinary tract and surgical sites infections the seniors difference to the ACS calculator was statistically significant (p < 0.05). Seniors resembled better cardiac complications (p < 0.05) and both resident and senior anesthesiologists failed to resemble the ACS calculator in assessing return to the operating room and pneumonia (p < 0.05). CONCLUSIONS: Both senior and resident anesthesiologists failed to estimate the surgical risks based on preoperative data. Further study involving the surgeons and comparing the estimated to the actual complication rates are needed. PMID- 30471367 TI - Selective castration-resistant prostate cancer photothermal ablation with CuS nanoplates. AB - OBJECTIVE: To explore new therapies for castration-resistant prostate cancer (CRPC) to improve patients' quality of life and extend life. MATERIALS AND METHODS: The synthesis, morphology analysis, phase analysis, spectral analysis and photothermal conversion test were referenced to our previous articles. Then NIR-light-driven CuS nanoplates to inhibit the growth of prostate cancer cells in vivo and in vitro was carried out. Transmission electron microscope, mCherry-LC3 syncytial virus labelling, acridine orange staining and autophagy protein were used to detect the autophagy caused by CuS nanoplates and chloroquine was used to inhibit the process of autophagy. RESULTS: The CuS nanoplates prepared in this study feature low cytotoxicity, simple preparation and high photothermal conversion efficiency. Driven by 980nm near-infrared light, CuS nanoplates could inhibit the growth of prostate cancer cells in vivo and in vitro, while triggering the autophagy and cytoprotection of prostate cancer cells. CONCLUSIONS: CuS nanoplates are a kind of commendable photothermal therapy agent in CRPC treating. Autophagy inhibition enhances the photothermal efficiency of CuS nanoplates, which indicates favorable application prospects in the treatment of advanced prostate cancer. PMID- 30471368 TI - Partially obstructed longitudinal vaginal septum presenting in adulthood with complaint of urinary incontinence. AB - A longitudinal vaginal septum can be obstructive or non-obstructive. We report on an adult woman who presented with involuntary fluid loss per vagina and had a partially obstructive longitudinal vaginal septum. A 36 year-old nulliparous female presented with malodorous, clear, leakage per vagina that she described as "urinary incontinence". Examination revealed a fluid filled fluctuant anterior vaginal wall with a draining sinus. Imaging revealed a solitary right kidney with duplicated ectopic fluid filled ureters inserting into a partially obstructed left hemivagina with a longitudinal vaginal septum. A longitudinal vaginal septum may present in adulthood with the complaint of urinary incontinence. PMID- 30471369 TI - Traumatic penile pseudoaneurysm after straddle injury presenting with life threatening anemia: A unique case and a diagnostic challenge. AB - Partial urethral disruption after blunt perineal trauma can be initially managed with urethral catheterization. Lower urinary tract symptoms after catheter removal should raise suspicion for urethral stricture and requires further investigation. Lesser known complications require high index of suspicion to prevent life threatening sequelae. In this report, we describe a case of blunt perineal trauma and partial urethral disruption in a pediatric patient presenting with refractory anemia due to a penile artery pseudoaneurysm. We discuss an unusual presentation, challenging diagnosis and management of this rare condition. PMID- 30471371 TI - Urologic Management of Priapism Secondary to Chronic Myeloid Leukemia. PMID- 30471370 TI - Factors that Influence Selection of Urinary Diversion among Bladder Cancer Patients in Three Community-Based Integrated Health Care Systems. AB - OBJECTIVES: To assess the relative contributions of patient and surgeon factors for predicting selection of ileal conduit (IC), neobladder (NB), or continent pouch (CP) urinary diversions (UD) for patients diagnosed with muscle invasive/high-risk non-muscle invasive bladder cancer. This information is needed to enhance research comparing cancer survivors' outcomes across different surgical treatment options. METHODS: Bladder cancer patients age >=21 years with cystectomy/UD performed from 1/2010 to 6/2015 in three Kaiser Permanente regions were included. All patient and surgeon data were obtained from electronic health records. A mixed effects logistic regression model was used treating surgeon as a random effect and region as a fixed effect. RESULTS: Of 991 eligible patients, 794 (80%) received IC. 169 surgeons performed the surgeries and accounted for a sizeable proportion of the variability in patient receipt of UD (ICC=.26). The multilevel model with only patient factors showed good fit (AUC=.93, Hosmer Lemeshow test p=.44), and older age, female sex, eGFR<45, 4+ comorbidity index score, and stage III/IV tumors were associated with higher odds of receiving an IC vs. NB/CP. However, including surgeon factors (annual cystectomy volume, specialty training, clinical tenure) had no association (p=.29). CONCLUSIONS: In this community setting, patient factors were major predictors of UD received. Surgeons also played a substantial role, yet clinical training and experience were not major predictors. Surgeon factors such as beliefs about UD options and outcomes should be explored. PMID- 30471372 TI - Effect of chitosan based glycolipid-like nanocarrier in prevention of developing acquired drug resistance in tri-cycle treatment of breast cancer. AB - Multi-cycle treatment strategies were frequently applied in anti-tumor therapy in clinic. However, numerous tumors developed drug resistance during this process, and few researches paid attention to the multi-cycle treatment process when a nano carrier was adopted. In this research, a glycolipid-like nanocarrier encapsulating anti-tumor drug doxorubicin (DOX) was adopted to perform a long term drug stimulation in vitro cell line and a tri-cycle treatment on xenograft tumors to explore its effect in process of developing drug resistance. As expected, tumors treated by free doxorubicin hydrochloride (DOX.HCl) showed obvious increase of P-glycoprotein, while for tumors treated by nanocarrier encapsulated doxorubicin, the P-glycoprotein level stayed low as untreated group. Further exploration found that MDR1 gene transcription got involved in the resistance induction mechanism as its mRNA levels in DOX.HCl stimulated cells were thousands of times of those in parent cell. It concluded that tri-cycle therapy with the glycolipid-like nanocarrier would not result in acquired drug resistance. These results also implied that nano-drug delivery possessed ability in avoiding acquiring drug resistance ability during long-term treatment which may have potential use in clinic. PMID- 30471373 TI - Development of porous particles using dextran as an excipient for enhanced deep lung delivery of rifampicin. AB - This study aimed to develop a dry powder inhaler (DPI) formulation for enhanced deep lung delivery of rifampicin using dextrans of different molecular weights. Porous particles were formed by a spray-drying method, which was designed based on the Peclet number. The morphology of particles containing both rifampicin and dextran was dependent on the dextran concentration. The D50 values of SDPs containing rifampicin and dextran 40 or 70 at ratios of less than 1:10 were below 5 MUm. The specific surface area values of spray-dried particles containing rifampicin and dextran 40 or 70 of more than 1:10 were over 20 m2/g, assuming that an increase in specific surface area was indicative of an increase in the formation ratio of a porous structure. DPI formulations that contained higher amounts of dextran had higher rifampicin contents. Thus, the formulations containing a dextran: rifampicin ratio of 1:20 had approximately 100% drug encapsulation. The formation of the porous particles can be explained by the related Peclet number, which correlates with the viscosity and surface tension of the ethanol-water solution used in preparing the particles. It was noted that the existence ratio of the porous particles increased as the viscosity of the mixed solution was increased. Furthermore, an increase in the proportion of dextran resulted in higher rifampicin loading into the particles and the formation of finer particle fractions (FPF) (<7.0 MUm at a rate of 28.3 L/min, <4.8 um at a rate of 60.0 L/min). The formulations containing rifampicin and both dextrans at a ratio of more than 1:10 consisted of approximately 50% FPF at a rate of 28.3 L/min and 60.0 L/min. The results indicate that dextran is suitable to obtain porous particles via spray-drying. Additionally, the existence ratio of the porous particles can be improved by increasing the viscosity of the solution used in the preparation of the particles. PMID- 30471374 TI - Glutathione-sensitive PEGylated curcumin prodrug nanomicelles: Preparation, characterization, cellular uptake and bioavailability evaluation. AB - The anti-tumor efficacy of curcumin can be markedly improved by nano-drug self delivery systems with high drug loading capacity and smart stimulus-triggered drug release in tumor cells. Herein, a type of novel, glutathione (GSH) responsive, PEGylated prodrug nano-micelles (PPNMs) was prepared by self-assembly of curcumin-s-s-vitamin E/mPEG2k-DSPE mixture. The PPNMs (entrapment efficiency: 96.7%) was acceptably stable in water with a mean particle size of 29.84 nm. Compared with curcumin-loaded mPEG2k-DSPE nano-micelles (CUR-NMs), PPNMs showed a higher drug loading (1.68% vs 27.3%) and remarkably improved the chemical stability of curcumin in phosphate buffer saline (PBS) (pH = 7.4), 10% FBS culture medium, and rat plasma. In vitro release study showed that PPNMs could redox responsively control the release of curcumin from the prodrug. Moreover, PPNMs showed a cytotoxicity in HepG2 cells similar to that of the free curcumin; however, when the HepG2 cells were pretreated with 1 mM GSH, PPNMs displayed a markedly enhanced cytotoxicity and cellular uptake than the free curcumin. After intravenous injection, PPNMs showed an increased half-life in blood circulation (10.6-fold) and bioavailability (107-fold) compared with the free curcumin injection. Altogether, the prodrug nano-micelles represent a promising preparation for sustained and controlled delivery of curcumin with enhanced antitumor activity. PMID- 30471375 TI - A big data approach to pharmaceutical flow properties. AB - Flowability is a key consideration during the formulation and process development of oral solid dosage forms as it can have a critical impact on product quality. With a limited number of examples available in the literature, there is a need to better understand and share the typical flow properties of pharmaceutical materials. Here, historical data (3909 experiments) from a shear cell apparatus were extracted and analysed. These data were composed of different material types, including APIs, excipients, blends and granules from nearly a decade of development projects. APIs were found to have poor flow properties (ffc <2), while other materials (excipients, blends and granules) generally had good flow properties. This analysis provided an enhanced understanding of the typical flow properties of pharmaceutical materials. By combining these data with information on the process and achieved drug load, it was possible to characterise our current operating space as a process flow map which could be used to focus future development. PMID- 30471376 TI - Fabrication of the polyphosphates patched cellulose sulfate-chitosan hydrochloride microcapsules and as vehicles for sustained drug release. AB - Polyphosphates are important polyanionic electrolytes that play a major role in stabilization and consolidation of colloids surface and interior microstructures. In this study, the polyelectrolyte complexes (PEC) microcapsules (sodium cellulose sulfate-chitosan hydrochloride, sample 1), and the patched ones via sodium tripolyphosphate (sample 2), sodium pyrophosphate (sample 3) and sodium hexametaphosphate (sample 4) were fabricated under mild conditions. The effects of polyphosphates on the formation of the PEC microcapsules were investigated systematically. Scanning electron microscope (SEM) and confocal laser scanning microscope (CLSM) observation showed that both of the sample 2 and sample 3 had more compact interior microstructures with higher fluorescence intensity, compared with the sample 4 with macroporous ones and sample 1 with irregular ones. Fourier transform-infrared spectroscopy (FT-IR) and thermogravimetric analysis (TGA) showed the electrostatic interactions occurred among the -NH3+ groups, -SO3- groups, HP3O104- groups, P2O74- groups and H2PO4- groups, and the sample 2 and sample 3 had a more thermal stability comparatively. The sample microcapsules showed good capacity of drug loading and encapsulation efficiency (max. 66.9 +/- 4.6% and 74.2 +/- 5.1%). In the in vitro release studies showed that the sample 2 and sample 3 had a larger accumulative drug release rate of 5 aminosalicylic acid (5-ASA) at the same time point and released completely at 12 h; the drug release mechanisms analysis indicated that the sample 1 and sample 3 were mainly diffusion controlled, while the sample 2 and sample 4 were followed the mechanism of non-Fickian transport. Under the polyphosphate's consolidation, the PEC microcapsules fabricated with sustained drug release profiles could be used as the promising drug vehicles. PMID- 30471377 TI - Bioassay-guided isolation of active compounds from Adenosma buchneroides essential oil as mosquito repellent against Aedes albopictus. AB - ETHNOPHARMACOLOGICAL RELEVANCE: A folk herb Adenosma buchneroides found in the previous ethnobotanical investigation plays an important role as an insect repellent among the Aini people in southwest of China, but the active compounds responsible for repellent activity of the plant have not yet been investigated. AIM OF THE STUDY: The main purpose of the study is to identify the active components of the essential oil which responsible for its repellent activity against Aedes albopictus to support the usage of the plant as mosquito repellent by Aini people. In addition, to supply a class of potential alternatives characterized carvacrol analogues to develop natural repellent products. MATERIAL AND METHODS: The essential oil from aerial part of Ad. buchneroides was extracted by hydrodistillation. A systematic bioassay-guided isolation of repellent compounds from the essential oil was conducted through chromatographic fractionation combined with in-cage mosquito repellent bioassay. The identification of the essential oil components was accomplished by GC-MS and GC FID techniques. The structural elucidation of compounds was performed on the basis of IR, HR-ESI-MS and NMR. Larvicidal activity and cytotoxicity of all repellent compounds also tested by larval bioassays and MTS assays, respectively. Structure-activity relationship (SAR) of carvacrol analogues was investigated by in-cage mosquito repellent bioassay. RESULTS: The essential oil of the plant showed strong mosquito repellent activity with minimum effective dosage (MED) of 0.019 +/- 0.007mg/cm2, compared to reference standard N,N-diethyl-3 methylbenzamide (DEET) (0.031 +/- 0.014mg/cm2). 26 compounds representing 97.8% of the essential oil were identified. Carvacrol, carvacrol methyl ether and a new fragrant compound, adenosmin A (1) were found to be repellent compounds by systematic bioassay-guided isolation, with MEDs in the range of 0.011 0.125mg/cm2. An investigation on SAR of carvacrol analogues led to the discover of three analogues with further lower MEDs (0.002-0.009mg/cm2) than that of DEET, and other three compounds with similar MEDs (0.029-0.039mg/cm2) to that of DEET. Carvacrol (LD50 of 24.8 ppm) was the best larvicide among tested repellent compounds. The essential oil and repellent compounds against seven mammalian cell lines revealed low or no cytotoxicity. CONCLUSIONS: Scientific evidences reported here validate the plant's traditional use as insect repellent and imply promising application of the essential oil and carvacrol analogues as natural mosquito repellents. PMID- 30471378 TI - Chinese medicine CGA formula ameliorates liver fibrosis induced by carbon tetrachloride involving inhibition of hepatic apoptosis in rats. AB - ETHNOPHARMACOLOGICAL REVELVANCE: CGA consisting of Cordyceps sinensis mycelia polysaccharide, gypenosides and amygdalin, was demonstrated to be the effective components formula in Fuzheng Huayu (FZHY) capsule, a traditional Chinese medicine approved by China food and drug administration for treatment of liver fibrosis and to inhibit transforming growth factor-beta1 (TGF-beta1) signaling, previously. AIM OF THE STUDY: To evaluate the effects of CGA on hepatic apoptosis in liver fibrosis induced by carbon tetrachloride (CCl4). MATERIALS AND METHODS: The hepatic injury and histology was detected by serum biomarker assay and hematoxylin-eosin staining. The hepatic collagen was illustrated by Sirius red staining and hydroxyproline (Hyp) concentration. The hepatic stellate cells (HSCs) activation and hepatic apoptosis was visualized by immunohistochemical analysis of alpha-smooth muscle actin (alpha-SMA) and terminal deoxynucleotidyl transferase-mediated dUPT nick-end labeling (TUNEL) assay respectively. The protein expression of collagen type I (Col-I), alpha-SMA, TGF-beta1, Fas, tumor necrosis factor receptor 1 (TNF-R1), cleaved-caspase-8, cleaved-caspase-10, cleaved-caspase-9, cleaved-caspase-3, mitochondrial Bcl-2, Bcl-2 associated X protein (Bax), Bcl-2 homologous antagonist/killer (Bak), cytochrome C and cytoplasmic cytochrome C was detected by western-blot. RESULTS: CGA or FZHY ameliorated liver histological changes, decreasing serum alanine aminotransferase, aspartate aminotransferase, hepatic Hyp, TUNEL positive-stained area, and down-regulated the protein expression of alpha-SMA, TGF-beta1, Col-I, Fas, TNF-R1, cleaved-caspase-8, cleaved-caspase-10, cleaved-caspase-9, and cleaved-caspase-3, mitochondrial Bax, Bak, and cytoplasmic Cytochrome C, while restored the expression of mitochondrial Bcl-2 and cytochrome C. CONCLUSION: CGA formula ameliorates liver fibrosis induced by CCl4, which is correlated to its inhibition on hepatic apoptosis. PMID- 30471379 TI - TOXICITY OF THE DIFFERENT VEGETATIVE STAGES OF Amorimia pubiflora TO SHEEP. AB - Toxic plants containing monofluoroacetate (MFA) cause sudden death in livestock in Australia, South Africa and Brazil, causing economic losses to producers. The objective of this study was to determine the amount of MFA present in young leaves, mature leaves, senescent leaves, and seeds of Amorimia pubiflora harvested at different times of the year and to determine their toxic effect on sheep. Samples of Amorimia pubiflora were collected during April, August and December of 2015 and March of 2016, separated according to the vegetative stage (young leaves, seeds, mature leaves, and senescent leaves), dried in an oven, and administered in daily doses of 5 g/kg/body weight (bw) of fresh leaves to sheep through ruminal cannulae. The experiment was divided into four stages according to the time of collection of the plant so that each sheep received a different vegetative stage of the plant (young leaves, mature leaves, and senescent leaves). Only in the second stage of the experiment was it possible to collect A. pubiflora seeds, which were administered using the same method used for the administration of the leaves. The sheep were dosed with the plant until they showed clinical signs of toxicosis or until the plant was no longer available. Aliquots of leaves and seeds of A. pubiflora were analyzed for MFA concentration. The seeds and young leaves had higher concentrations of MFA than did the mature (harvested in August and December) and senescent (harvested in December) leaves. However, all vegetative stages of the plant were toxic and caused fatal poisoning. The results of our study showed that A. pubiflora is toxic to sheep even when MFA concentrations are low, demonstrating that the presence of this substance is a risk factor for the occurrence of poisoning. Knowing the toxic principle and its variations allow us to determine the conditions for the occurrence of plant toxicosis as well as possible treatment, control, and prophylaxis methods, contributing significantly to the reduction of economic losses on farms due to plant poisoning. PMID- 30471380 TI - Re-evaluation of paralytic shellfish toxin profiles in cyanobacteria using hydrophilic interaction liquid chromatography-tandem mass spectrometry. AB - To date Paralytic shellfish toxin (PST) variants in cyanobacteria have primarily been characterized using high performance liquid chromatography coupled with fluorescence detection. In this study we re-evaluated the PST profiles of five cyanobacterial cultures (Dolichospermum circinale AWQC131C, Aphanizomenon sp. NH 5, Raphidiopsis raciborskii T3, Scytonema cf. crispum CAWBG524 and CAWBG72) and one environmental sample (Microseria wollei) using hydrophilic interaction liquid chromatography coupled with electrospray ionization tandem mass spectrometry. A total of 35 different PST variants were detected. D. circinale contained the highest number of variants (23), followed by S. cf. crispum CAWBG72 (21). Many of the variants detected in the cultures/environmental sample had not been reported from these strains previously: D. circinale (14 variants), S. cf. crispum CAWBG72 (16), S. cf. crispum CAWBG524 (9), Aphanizomenon sp. (9), R. raciborskii (7), and M. wollei (7). Of particular interest was the detection of M-toxins (Aphanizomenon sp., R. raciborskii, D. circinale). These have previously only been identified from shellfish where they were thought to be metabolites. Well characterized PST variant profiles are essential for research investigating the genetic basis of PST production, and given that the toxicity of each variants differs, it will assist in refining risk assessments. PMID- 30471381 TI - The analgesic effect of intraarticular OnabotulinumtoxinA in a female murine model of collagenase induced chronic degenerative monoarthritis. AB - PURPOSE: We previously reported the efficacy of intraarticular (IA) rimabotulinumtoxinB (BoNT/B) in a murine model of chronic degenerative arthritis pain. This study aimed to measure the analgesic effects of onabotulinumtoxinA (BoNT/A) on collagenase induced chronic degenerative arthritis joint pain. METHODS: Chronic degenerative arthritis was produced by IA injection of 10 MUl collagenase (Col) (10 IU) into the left knee of C57BL/6J female mice 4 weeks prior to pain assessment. IA BoNT/A was injected 3 days before testing. Arthritis pain was measured as evoked pain scores (EPS) and spontaneous pain behaviors with an advanced dynamic weight bearing (ADWB) device. EPS was a tally of fights and vocalizations exhibited in one minute with knee palpation. Percent body weight and percent time spent on each limb was quantified. All mice were 12 weeks old at the time of examination. RESULTS: IA Col increased EPS and reduced ADWB measures of percent weight bearing on the left hind limb compared to naive mice. BoNT/A treatment reduced EPS and increased weight bearing on the left hind limb. The improvements were not significant compared to the Col group. There was no significant difference in time spent on the left hind limb between any treatment groups. Forelimb ADWB measures of percent weight and time in arthritic mice significantly increased compared to nonarthritic animals. Treatment with BoNT/A in the arthritic limb decreased this offloading; however, statistical analysis only showed significance in weightbearing. CONCLUSION: IA Col monoarthritis increased evoked and spontaneous pain behaviors in female mice after four weeks. Treatment with IA BoNT/A decreased pain behaviors but only forelimb weight bearing showed a significant improvement. This led us to conclude that treatment with BoNT/A is not an effective analgesic for the treatment of chronic degenerative knee arthritis in murine models. PMID- 30471382 TI - A C-type lectin from Bothrops leucurus snake venom forms amyloid-like aggregates in RPMI medium and are efficiently phagocytosed by peritoneal macrophages. AB - Lectins are carbohydrate-binding proteins that play important roles in the immune system. Under specific conditions, lectins can form amyloids, proteinaceous aggregates rich in cross beta-strand structures. A Ca++-dependent lectin, isolated from Bothrops leucurus snake venom (BLL) has demonstrated relevant biological activities such as antibacterial and antitumor activity. In this work, we aimed to study the interaction of BLL with macrophages. The formation of amyloid structures by BLL in a cell culture medium, the effects of the lectin on macrophage morphology and cytokine production were investigated. BLL amyloid-like fibrils in RMPI medium, pH 7.2, at 37 degrees C was confirmed by binding of Congo Red, Thioflavin T and electron microscopy. Neither binding of amyloid markers nor fibrillar structures were found when the lectin was incubated in RPMI plus galactose, the specific BLL-binding carbohydrate. Several phagocytic compartments containing fibrillar structures were observed in BLL-treated macrophages in RPMI medium for 24 h; these compartments showed an apple-green birefringence after Congo Red staining and were positive for thioflavin S and anti-amyloid antibody, indicating the presence of amyloid-like fibrils. No fibrillar material and no labeling were observed when the macrophages were treated with BLL plus galactose or cytochalasin B, an inhibitor of phagocytosis. BLL did not affect the viability of the cells. A significant release of proinflammatory (TNF-alpha, IL-6, INF-Upsilon and IL-1beta) and regulatory (IL 10) cytokines was observed in BLL-treated macrophages. Taken together, our results shed light on the structural organization of BLL, improving knowledge about the interaction of lectin with macrophages. The phagocytosis of amyloid like aggregates together with the proinflammatory response induced by BLL may open new perspectives for the use of this lectin as an interesting model to study cytokines and the production of other mediators as well as understand the mechanisms occurring in human immune cells during amyloid protein deposition. PMID- 30471383 TI - The impact of a competitive learning environment on hormonal and emotional stress responses and skill acquisition and expression in a medical student domain. AB - The concept of competition has implications for educational contexts, as hormonal and emotional changes under competitive stress can modulate learning and memory processes. This study examined the impact of a competitive learning environment and associated hormonal and emotional responses on skill acquisition and expression in a medical domain. Using a cross-over design, sixteen male medical students participated in a competitive (in pairs facing each other) and non competitive (alone) learning situation. In each treatment, an instructional video was followed by a timed straight-line suture evaluation with anxiety and competitiveness recorded. Salivary testosterone (T) and cortisol (C) were assessed at rest, before and after evaluation to quantify changes in T (DeltaT) and C (DeltaC). These procedures were followed by two sessions of self-directed training before retesting. Paired learning produced a larger positive DeltaT (5.9 7.8% vs. 2.0-5.3%) and DeltaC (7.6% vs. 3.3%), which was accompanied by more anxiety and elevated competitiveness (p < .01). Anxiety declined and suturing abilities improved over time (p < .001), irrespective of the learning approach, with resting C concentrations decreasing when learning alone (p < .05). Some DeltaT and DeltaC measures correlated (r = 0.40 to 0.65) with anxiety and competitive desire with paired learning only, whereas the DeltaC was linked to suturing performance (r = -0.35) when learning alone. In summary, a tacit competition in a natural learning situation promoted more pronounced hormonal and emotional responses. However, skill acquisition and its expression improved to a similar extent in both situations of competitive and non-competitive assessment. Different adaptive pathways for skill expression and development emerged from this work. PMID- 30471384 TI - Psychological responses, muscle damage, inflammation, and delayed onset muscle soreness to high-intensity interval and moderate-intensity continuous exercise in overweight men. AB - We compared in-task affect to HIIE and MICE, and its relationship with time spent at different metabolic domains, perceived exertion (RPE), self-efficacy, enjoyment, and future intention of exercise in overweight inactive men. Muscle damage and soreness, and inflammation were assessed post-exercise. Fifteen participants (28.9 +/- 5.0 yr; 29.2 +/- 3.8 kg/m2) completed a HIIE (10 * 1 min at 100% Vmax, 1 min recovery) and MICE (20 min at 55-59% VO2reserve) session. Affect, alertness, RPE, and self-efficacy were assessed in-task, and enjoyment and future intention post-task. At baseline, 24 and 48 h, creatine kinase, lactate dehydrogenase, interleukin-6 and -10, tumor necrosis factor alpha, and muscle soreness were assessed. Affect (-3.1 +/- 1.8 vs. 0.8 +/- 1.8, P < .001) and self-efficacy (70 +/- 15 vs. 90 +/- 15%, P < .001) were lower, while RPE and alertness were higher in HIIE compared to MICE (Ps <= .02). Affect was negatively correlated with RPE in HIIE (r = -0.90) and MICE (r = -0.72), and time spent above respiratory compensation point in HIIE (r = -0.59). Affect was positively correlated with self-efficacy in MICE (r = 0.74). Enjoyment, future intention, muscle damage and soreness, and inflammation were similar between HIIE and MICE post-exercise. Therefore, in-task HIIE was experienced as unpleasant compared to MICE, but the psychological and physiological responses post-task were similar in overweight inactive men. PMID- 30471385 TI - Exposure to high solar radiation reduces self-regulated exercise intensity in the heat outdoors. AB - High radiant heat load reduces endurance exercise performance in the heat indoors, but this remains unconfirmed in outdoor exercise. The current study investigated the effects of variations in solar radiation on self-regulated exercise intensity and thermoregulatory responses in the heat outdoors at a fixed rating of perceived exertion (RPE). Ten male participants completed 45-min cycling exercise in hot outdoor environments (about 31 degrees C) at a freely chosen resistance and cadence at an RPE of 13 (somewhat hard). Participants were blinded to resistance, pedal cadence, distance and elapsed time and exercised at three sunlight exposure conditions: clear sky (mean +/- SD: 1072 +/- 91 W.m-2; HIGH); thin cloud (592 +/- 32 W.m-2; MID); and thick cloud (306 +/- 52 W.m-2; LOW). Power output (HIGH 96 +/- 22 W; MID 103 +/- 20 W; LOW 108 +/- 20 W) and resistance were lower in HIGH than MID and LOW (P < .001). Pedal cadence was lower, the core-to-skin temperature gradient was narrower, body heat gain from the sun (SHG) was greater and thermal sensation was higher with increasing solar radiation and all variables were different between trials (P < .01). Mean skin temperature was higher in HIGH than MID and LOW (P < .01), but core temperature was similar between trials (P = .485). We conclude that self-regulated exercise intensity in the heat outdoors at a fixed RPE of somewhat hard is reduced with increasing solar radiation because of greater thermoregulatory strain, perceived thermal stress and SHG. This suggests that reduced self-selected exercise intensity during high solar radiation exposure in the heat may prevent excessive core temperature rise. PMID- 30471386 TI - Innovative Behavior in Nursing Context: A Concept Analysis. AB - PURPOSE: The aim of this study was to understand the concept of innovative behavior and its theoretical and practical implications for nursing. METHODS: Walker and Avant's (2005) eight step modification of Wilson's (1963) classic concept analysis procedure was used to explore the antecedents, attributes, and consequences of innovative behavior in the literature. Electronic searches were conducted in PubMed, Google Scholar, OVID Medline, Science Direct, and ERIC databases using "innovative behavior" or "innovative work behavior", "innovativeness", "innovation", "leadership", "healthcare", and "nursing" as keywords with no limitation on publication date. RESULTS: Organizing the framework on Walker and Avant's method of concept analysis; defining attributes to innovative behavior were opportunity exploration, idea generation, idea search, idea communication, promotion of idea, idea championing, application, and overcoming obstacles. Antecedents to innovative behavior categorized into three groups; organizational characteristics, work environmental characteristics, and individual characteristics. Consequences of innovative behavior included job productivity, lower levels of job burnout, job satisfaction, solving the organizational problems, organizational commitment, organizational efficiency, and effectiveness. CONCLUSIONS: Eight dimensions including opportunity exploration, idea generation, idea search, idea communication, idea promotion, championing, application, and overcoming obstacles were analyzed. We suggest promoting innovative behavior through leadership and management in nursing. Future research should focus on developing instruments and conducting empirical studies on innovative behavior in nursing research and practice. PMID- 30471387 TI - Cerebral blood flow changes after a day of wake, sleep, and sleep deprivation. AB - Elucidating the neurobiological effects of sleep and wake is an important goal of the neurosciences. Whether and how human cerebral blood flow (CBF) changes during the sleep-wake cycle remain to be clarified. Based on the synaptic homeostasis hypothesis of sleep and wake, we hypothesized that a day of wake and a night of sleep deprivation would be associated with gray matter resting CBF (rCBF) increases and that sleep would be associated with rCBF decreases. Thirty-eight healthy adult males (age 22.1 +/- 2.5 years) underwent arterial spin labeling perfusion magnetic resonance imaging at three time points: in the morning after a regular night's sleep, the evening of the same day, and the next morning, either after total sleep deprivation (n = 19) or a night of sleep (n = 19). All analyses were adjusted for hematocrit and head motion. rCBF increased from morning to evening and decreased after a night of sleep. These effects were most prominent in bilateral hippocampus, amygdala, thalamus, and in the occipital and sensorimotor cortices. Group * time interaction analyses for evening versus next morning revealed significant interaction in bilateral lateral and medial occipital cortices and in bilateral insula, driven by rCBF increases in the sleep deprived individuals and decreases in the sleepers, respectively. Furthermore, group * time interaction analyses for first morning versus next morning showed significant effects in medial and lateral occipital cortices, in anterior cingulate gyrus, and in the insula, in both hemispheres. These effects were mainly driven by CBF increases from TP1 to TP3 in the sleep deprived individuals. There were no associations between the rCBF changes and sleep characteristics, vigilant attention, or subjective sleepiness that remained significant after adjustments for multiple analyses. Altogether, these results encourage future studies to clarify mechanisms underlying sleep-related rCBF changes. PMID- 30471388 TI - Disease progression timeline estimation for Alzheimer's disease using discriminative event based modeling. AB - Alzheimer's Disease (AD) is characterized by a cascade of biomarkers becoming abnormal, the pathophysiology of which is very complex and largely unknown. Event based modeling (EBM) is a data-driven technique to estimate the sequence in which biomarkers for a disease become abnormal based on cross-sectional data. It can help in understanding the dynamics of disease progression and facilitate early diagnosis and prognosis by staging patients. In this work we propose a novel discriminative approach to EBM, which is shown to be more accurate than existing state-of-the-art EBM methods. The method first estimates for each subject an approximate ordering of events. Subsequently, the central ordering over all subjects is estimated by fitting a generalized Mallows model to these approximate subject-specific orderings based on a novel probabilistic Kendall's Tau distance. We also introduce the concept of relative distance between events which helps in creating a disease progression timeline. Subsequently, we propose a method to stage subjects by placing them on the estimated disease progression timeline. We evaluated the proposed method on Alzheimer's Disease Neuroimaging Initiative (ADNI) data and compared the results with existing state-of-the-art EBM methods. We also performed extensive experiments on synthetic data simulating the progression of Alzheimer's disease. The event orderings obtained on ADNI data seem plausible and are in agreement with the current understanding of progression of AD. The proposed patient staging algorithm performed consistently better than that of state-of-the-art EBM methods. Event orderings obtained in simulation experiments were more accurate than those of other EBM methods and the estimated disease progression timeline was observed to correlate with the timeline of actual disease progression. The results of these experiments are encouraging and suggest that discriminative EBM is a promising approach to disease progression modeling. PMID- 30471389 TI - BOLD-fMRI reveals the association between renal oxygenation and functional connectivity in the aging brain. AB - Aging is accompanied by a decline in physical and cognitive function. Vascular aging may provide a major influence on these measures. The purpose of this study was to explore the relationship between renal oxygenation and functional connectivity of the aging brain because of the anatomic and hemodynamic similarities between cerebral and renal vessels. Fifty-two healthy older adults were recruited to undergo a BOLD-fMRI scan of the brain and kidneys, and forty four healthy younger subjects were recruited as the control group. First, cerebral functional connectivity density (FCD) was used to evaluate functional connectivity. Renal medullary and cortical R2* values were extracted respectively, and the ratio of medullary and cortical R2* values (MCR) was calculated. Then, the association between brain FCD and renal MCR was analyzed. Compared with younger adults, the elderly group showed higher renal medullary R2* and MCR, which might reflect a slight abnormality of renal oxygenation with aging. The older subjects also showed enhanced FCD in bilateral motor-related regions and decreased FCD in regions of the default mode network (DMN). The findings indicated that the functional connectivity in the DMN and motor cortices was vulnerable to aging. Moreover, the altered brain FCD values in the watershed regions, DMN and motor cortices were significantly correlated with the renal MCR value in the elderly group. The association between renal oxygenation abnormalities and spontaneous activity in the brain might reflect vascular aging and its influence on the kidney and brain during aging to some extent. This study provided a new perspective for understanding the relationship between tissue oxygenation and brain functional connectivity. PMID- 30471390 TI - Biodegradation of polyvinyl alcohol using cross-linked enzyme aggregates of degrading enzymes from Bacillus niacini. AB - In this study, polyvinyl alcohol (PVA)-degrading bacteria were screened from sludge samples using PVA as a sole source of carbon. A novel strain was obtained and identified as Bacillus niacini based on the analysis of a partial 16S rDNA nucleotide sequence and morphological characteristics. PVA-degrading enzyme (PVAase) from Bacillus niacini was immobilized as cross-linked enzyme aggregates (CLEAs) via precipitation with ammonium sulfate followed by glutaraldehyde cross linking. The effects of precipitation and cross-linking on PVAase-CLEAs activity were investigated and characterized. 70% ammonium sulfate and 1.5% glutaraldehyde were used for precipitation and 1-h cross-linking reaction. The activity recovery of PVAase-CLEAs was approximately 90% starting from free PVAase, suggesting non purification steps are required for extended use. No significant differences in optimum pH and temperature values of the PVAase were recorded after immobilization. The PVAase-CLEAs showed a ball-like morphology and enhanced PVA degradation efficiency in comparison with the free PVAase in solution. Furthermore, the PVAase-CLEAs exhibited excellent thermal stability, pH stability and storage stability compared to free PVAase. The PVAase-CLEAs retained about 75% of initial PVAase activity after 4 cycles of use. These results suggest that this CLEA is potentially usable for PVA degradation in industrial applications. PMID- 30471391 TI - Generation of humanized single-chain fragment variable immunotherapeutic against EGFR variant III using baculovirus expression system and in vitro validation. AB - Epidermal growth factor receptor variant III (EGFRvIII) is known to be specifically expressed in cancer cells and associated with tumor virulence. The receptor provides an opportunity for both specifically targeting the tumor cells as well as for potentially controlling and inhibiting tumor progression. In this study, humanized anti-EGFRvIII single-chain fragment variable (hscFv) was expressed in insect cell culture system to accommodate post-translational glycosylations crucial for the fragment stability and efficacy. Target specific binding of the developed fragment to EGFRvIII expressing cell lines and EGFRvIII positive glioblastoma patient samples was evaluated by immunocytochemistry and immunohistochemistry respectively. Downstream intracellular signaling mechanisms related to the action of the developed antibody fragment on growth/metabolism of the cell was evaluated in U87-EGFRvIII human glioblastoma cell lines. It was observed that the hscFv bound specifically to EGFRvIII in mutant expressing cells. Functionally, hscFv was found to confer anti-proliferative properties in EGFRvIII expressing cell lines by downregulating phosphorylation of EGFR/EGFRvIII, Lyn, PI3K and GLUT3 involved in proliferation and metabolism. This study demonstrated the significance of hscFv as a potential immunotherapeutic agent as well as a targeting agent for specific delivery of drugs to EGFRvIII expressing cancer cells. PMID- 30471392 TI - Potential application of medical cotton waste for self-reinforced composite. AB - The present work mainly deals with the efficacy of the waste medical grade cotton (MGC) used for the sustainable self-reinforced composite (SRC). MGC waste was exposed in the autoclave for destroying all microorganisms including infected bacteria's and virus followed by scoured and bleached for removing blood stains and foreign materials. SRC film was prepared by selective dissolved fibre surface of waste MGC into a dissolved microcrystalline cellulose (DMCC) matrix solution prepared by lithium chloride/N,N-dimethylacetamide (LiCl/DMAc) solvent system. The tensile strength of SRC films was significantly improved up to 252 MPa, and it was higher than that of the DMCC film. In the FTIR study, no peak was found in 1620 cm-1 in SRC confirming that the LiCl/DMAc has been completely removed. SEM study also revealed the presence of partial dissolution of the surface of MGC which merged with DMCC matrix in the SRC. The XRD results displayed higher crystallinity SRC than DMCC film. The thermal stability of SRC as determined by TGA improved compared to the DMCC film from 225 degrees C for DMCC to 250-283 degrees C for SRC films. Therefore, these prominent results revealed the potential utilization of a sustainable resource, waste MGC in producing environmentally friendly SRC films with high-performance properties. PMID- 30471394 TI - Study on the interaction between calcium ions and alkaline protease of bacillus. AB - The interaction between Ca2+ and alkaline protease has been studied. Enzyme activity measurements demonstrated that Ca2+ with a suitable concentration could increase the activity of alkaline protease. Particle size and zeta potential measurements showed that Ca2+ bound to alkaline protease by electrostatic interaction. The combination of Ca2+ and alkaline protease promoted the structure of alkaline protease to become more stable, which was favorable for the increase of enzyme activity. Fluorescence spectra showed that alkaline protease had two Ca2+ binding sites and potent binding force to Ca2+. Thermodynamic parameters DeltaH, DeltaS and DeltaG obtained by fluorescence spectra confirmed that the interaction between Ca2+ and alkaline protease was also electrostatic interaction and the binding process could proceed spontaneously. The results of molecular docking were also consistent with the conclusions obtained from the zeta potential and fluorescence spectrum measurements. In addition, the washing performance test showed that the detergent added with Ca2+ and alkaline protease had the best washing performance on protein-contaminated swatches JB02 and blood swatches. PMID- 30471393 TI - Comparisons of the restoring and reinforcement effects of carboxymethyl chitosan silk fibroin (Bombyx Mori/Antheraea Yamamai/Tussah) on aged historic silk. AB - This work presents the results of the reinforcement effects of regenerated silk fibroin solutions (SF) of Bombyx-Mori, Antheraea-Yamamai and Tussah on aged historic silk. Furthermore, Carboxymethyl-chitosan (CMC) was utilized as reinforcement and antibacterial filler to further improving the mechanical properties and antibacterial effects. To clarify the rationale behind this process, comprehensive characterization was applied, and a speculative explanation was provided. The results showed that Bombyx-mori and Tussah have better restoring effects than Antheraea-yamamai. CMC has good compatibility to the SF, and the addition of CMC has significantly contributed to the improvement the mechanical properties and thermal stability of the restored silk, which is due to the formation of chemical bonding, strong hydrogen bonding and the construction of polymer network structure. The enhancement of crystallinity and reduction of beta-turns structure indicate that the micro-defects in the crystallization zone of the aged silk has been restored, and the ordered arrangement in the long-range ordered structure has been improved within a certain range. It was found that the CMC acted as antifungal agents when introduced on the aged historic silk, reducing the growth of Aspergillus niger, Aspergillus flavus and Paecilomyces variotii to a certain extent, which were commonly found in storage areas of libraries. PMID- 30471395 TI - Mahua oil-based polyurethane/chitosan/nano ZnO composite films for biodegradable food packaging applications. AB - Biodegradable food packaging films were fabricated from Mahua oil-based polyurethane (PU) and chitosan (CS), incorporated with different proportions of zinc oxide nanoparticles. The structure and properties of the solvent-cast films were evaluated. PU/CS with 5% nano ZnO composite film showed improved tensile strength and stiffness. The incorporation of zinc oxide nanoparticles enhanced the antibacterial properties, barrier properties and hydrophobicity of the film. The weight loss of PU/CS/5% nano ZnO biodegradable film was 86% after 28 days in the soil. The shelf life period of carrot pieces wrapped with the composite film was extended up to 9 days. The film containing zinc oxide nanoparticles was effective in reducing the bacterial contamination when compared to the commercial polyethylene film. In essence, the composite film possessed all desirable characteristics to be considered as a food packaging material that has been fabricated from low environmental impact bio-polyol based polyurethane. PMID- 30471396 TI - Effect of different non-conventional extraction methods on the antibacterial and antiviral activity of fucoidans extracted from Nizamuddinia zanardinii. AB - In the current study, fucoidans from brown alga Nizamuddinia zanardinii were isolated with conventional and non-conventional extraction procedures to evaluate the effects of recently introduced technologies on biochemical characteristics and saccharide composition of the extracts, along with their antibacterial, antiviral and cytotoxic properties. The results demonstrated that subcritical water extraction showed the highest fucoidans yield (13.15%), while the lowest yield was obtained using ultrasound extraction method (3.6%). The polysaccharide chains consisted of fucose, galactose, glucose, mannose and xylose, whose molar percentages differed according to the extraction method used. The weight mean average molecular weight of fucoidans varied between 444 and 1184 kDa. The FT-IR spectroscopy confirmed the presence of sulfate esters by bending vibration of COS and stretching vibration of SO peaks at 818 and 1250 cm-1, respectively. Antibacterial assays showed that microwave- and subcritical water-extracted fucoidans inhibited the growth of E.coli and that enzyme-ultrasound, ultrasound microwave and subcritical water extracted fucoidans exhibited inhibitory effects against P. aeruginosa at 2 mg/mL. Antiviral studies revealed that all the extracted fucoidans exerted strong antiviral activity against HSV-2 infection, with EC50 values in the 0.027-0.123 MUg/mL range; indeed the viscozyme-extracted macromolecules displayed the best selectivity index. PMID- 30471397 TI - Peyer's patch-immunomodulating glucans from sugar cane enhance protective immunity through stimulation of the hemopoietic system. AB - The aim of the present study was chemical clarification of in vitro Peyer's patch immunomodulating polysaccharides in sugar cane molasses, and evaluation of in vivo modulating activity on immune function of T lymphocytes in Peyer's patches and on microenvironment of hemopoietic system. Five kinds of glucans, comprising of dextranase-sensitive and activity-related d-glucosyl moieties, were purified as in vitro Peyer's patch-immunomodulating polysaccharides from the molasses. Oral administration of a glucan-enriched subfraction induced IL-2 and GM-CSF producing T lymphocytes in Peyer's patches, resulting in enhancement of IL-6 production in a hemopoietic microenvironment to boost neutrophil numbers in the peripheral blood stream. Oral administration of purified glucan or glucan-enrich sub-fraction of sugar cane reduced the number of Plasmodium berghei- or P. yoelii infected erythrocytes in a murine infection model, using polysaccharide alone or via co-administration with the antimalarial drug, artesunate. These results suggested that Peyer's patch-immunomodulating glucans enhanced protective immunity through axis of Peyer's patches-hemopoietic system. PMID- 30471398 TI - Cationic and anionic dyes removal by low-cost hybrid alginate/natural bentonite composite beads: Adsorption and reusability studies. AB - Using the extrusion method, novel hybrid beads were prepared from natural bentonite and alginate. Alginate to clay ratios was varied (1/1; 1/2 and 1/3) and used to eliminate two dyes (methylene blue and Congo red).Adsorbents were characterized by Fourier transformed infrared spectroscopy, X-ray diffraction, Brunauer-Emmett-Teller method (BET) from N2 adsorption-desorption isotherm at 77 K, and the point of zero charge (pHPZC). The adsorption of methylene blue and Congo red was studied according to different parameters. The results showed that isotherms were well described by the Langmuir model justifying monolayer and homogeneous adsorption. Kinetics were well followed the pseudo-second-order model. Adsorption capacities of MB onto A-B 1/1 and CR onto A-B 1/3 were 1171 and 95.55 mg/g respectively. MB adsorption on A-B 1/1 and CR adsorption on A-B 1/3 were endothermic and exothermic respectively. Regeneration study showed that dyes were successfully desorbed from A-B 1/1 and A-B 1/3 with removal percentages of 99.65% and 86.2% respectively in the first cycle. Hybrid alginate-bentonite composites are low-cost, effective and regenerable for a wide variety of dyes. PMID- 30471399 TI - Cellulose nanocrystals from rice and oat husks and their application in aerogels for food packaging. AB - This study describes the valorization of rice and oat husks by obtaining cellulose nanocrystals for the production of aerogels for food packaging applications. Commercial cellulose was used as a control sample. Nanocrystals from cellulose were obtained by enzymatic hydrolysis and mechanical treatment at high pressure. The morphology, particle size, functional groups, crystallinity, and thermal properties of the cellulose nanocrystals were analyzed. The morphology, functional groups, crystallinity, water absorption capability, and zeta potential of aerogels were also analyzed. Cellulose nanocrystals show different structural properties and crystallinity depending on the source of the cellulose. The average diameter of the nanocrystals varied from 16.0 to 28.8 nm. The aerogels prepared with cellulose nanocrystals showed a porous and uniform structure with a water absorption capacity between 264.2% and 402.8% at 25 degrees C. The aerogel of oat cellulose nanocrystals showed a larger pore size than that of eucalyptus cellulose nanocrystals, and this may have influenced the lowest water absorption capacity of the aerogels of eucalyptus cellulose nanocrystals. These results show that agroindustrial residues have promising applications in various industrial fields and could be used as aerogel absorbers of water in food packaging. PMID- 30471400 TI - Natural killer cell-mediated anticancer effects of an arabinogalactan derived from rice hull in CT26 colon cancer-bearing mice. AB - Rice hull polysaccharides (RHPS) have been reported to activate innate immunity in mice. This study investigated the effects of RHPS on natural killer (NK) cell mediated cytotoxicity in vitro and the possible underlying anticancer mechanisms in vivo. The results showed that sustained exposure to RHPS increased NK-92MI cell-mediated cytotoxicity in a time- and concentration-dependent manner. In addition, RHPS upregulated the expression of Fas ligand, TNF-related apoptosis inducing ligand, perforin, and granzyme B of NK-92MI cells and induced the secretion of IFN-gamma and TNF-alpha. In the in vivo experiment, colon cancer CT26-bearing mice were used to investigate the effects of RHPS in cytotoxicity and anticancer. The results revealed that RHPS inhibited cancer weight and volume in CT26-bearing mice and significantly upregulated splenic cytotoxicity and NK cell population. Moreover, RHPS treatment increased NK-cell infiltration in tumors. Thus, RHPS can enhance NK-cell activation in vivo and in vitro, thereby exhibiting anticancer activity. PMID- 30471401 TI - Expression of ChiA74?sp and its truncated versions in Bacillus thuringiensis HD1 using a vegetative promoter maintains the integrity and toxicity of native Cry1A toxins. AB - Our objective was to determine whether a recombinant chitinase ChiA74?sp of Bacillus thuringiensis and its truncated versions (ChiA74?sp-60, ChiA74?sp-50) could be produced in B. thuringiensis HD1 with no detrimental effect on the size and insecticidal activity of the native bipyramidal Cry crystal. chiA-p, the promoter used to drive chitinase gene expression, was active during vegetative growth of Cry-B. HD1 recombinants showed increases from ~7- to 12-fold in chitinase activity when compared with parental HD1 and negligible or no effect on the volume of bipyramidal crystals was observed. HD1/ChiA74?sp-60 showed increases from 20% to 40% in the yield of Cry1A per unit of culture medium when compared with parental HD1 and HD1/ChiA74?sp-50, HD1/ChiA74?sp. Inclusion bodies presumably composed of the enzyme attached to native Cry1A crystals of recombinant strains were observed; these inclusions were likely responsible for the enhancements in chitinase activity. Western blot analysis using polyclonal anti-ChiA74?sp showed a weak signal with proteins of ~50 kDa in sporulated and lysed cells of recombinant strains. Bioassays against Spodoptera frugiperda using sporulated/lysed samples of the recombinant strains did not show statistically significant differences in LC50s when compared with HD1. PMID- 30471402 TI - In Vitro Activity of Cefiderocol, a Siderophore Cephalosporin, Against Gram Negative Bacilli Isolated by Clinical Laboratories in North America and Europe in 2015-2016: SIDERO-WT-2015. AB - Cefiderocol (S-649266) is a parenteral siderophore cephalosporin currently in Phase III of clinical development. In this study, we determined the in vitro susceptibility of a 2015-2016 collection of 8,954 clinical isolates of Gram negative bacilli (GNB), provided by 100 clinical laboratories in North America and Europe, to cefiderocol and comparators using the Clinical and Laboratory Standards Institute broth microdilution method. Iron-depleted cation-adjusted Mueller-Hinton broth was used to test cefiderocol. The concentration of cefiderocol inhibiting 90% of isolates (MIC90) was 0.5 (North America; n=2,470) and 1 mg/L (Europe; n=3,543) for Enterobacteriaceae, 0.5 (North America; n=619) and 0.5 mg/L (Europe; n=921) for Pseudomonas aeruginosa, 1 (North America; n=308) and 2 mg/L (Europe; n=664) for Acinetobacter spp., 0.5 (North America; n=165) and 0.25 mg/L (Europe; n=175) for Stenotrophomonas maltophilia, and 0.12 (North America; n=40) and 0.5 mg/L (Europe; n=49) for Burkholderia cepacia complex spp. Cefiderocol MICs were <=4 mg/L for 99.9% (6,005/6,013) of Enterobacteriaceae, 99.9% (1,539/1,540) of P. aeruginosa, 96.4% (937/972) of Acinetobacter spp., 99.4% (338/340) of S. maltophilia, and 94.4% (84/89) of Burkholderia cepacia complex spp. isolates tested. Against meropenem-nonsusceptible isolates, MICs to cefiderocol were <=4 mg/L for 99.6% (245/246) of Enterobacteriaceae, 99.7% (394/395) of P. aeruginosa, 96.1% (540/562) of Acinetobacter spp., and 87.1% (27/31) of B. cepacia complex spp. We conclude that cefiderocol demonstrated potent in vitro activity (MIC, <=4 mg/L) against the vast majority (99.4%, 8,903/8,954) of clinical isolates of GNB in a recent (2015-2016), multi-continent collection, including carbapenem-nonsusceptible isolates. PMID- 30471403 TI - CLINICAL CHARACTERISTICS AND PROGNOSIS OF INFECTIONS CAUSED BY OXA-48 CARBAPENEMASE PRODUCING ENTEROBACTERIACEAE IN PATIENTS TREATED WITH CEFTAZIDIME AVIBACTAM. AB - BACKGROUND: Ceftazidime-avibactam has in vitro activity against Gram-negative bacilli that produce class A, C and some class D beta-lactamases, and has been successfully used in the treatment of infections caused by cephalosporin and carbapenem-resistant Enterobacteriaceae. However, actual experience in the treatment of OXA-48 carbapenemase-producing Enterobacteriaceae (CPE) is limited. OBJECTIVE: To review the characteristics and prognosis of OXA-48 CPE infections treated with ceftazidime-avibactam since the introduction of the drug in our Centre in October 2014 until December 2016. METHODS: Retrospective assessment of episodes of infection caused by OXA-48 CPE treated with ceftazidime-avibactam, analysing the data collected from the diagnosis of the infection until 90 days after the end of treatment. RESULTS: Twenty-four episodes were analysed. Ceftazidime-avibactam was given as the initial definitive treatment in 15 (62.5%) and as salvage therapy in 9 (37.5). Intraabdominal (7, 29%), urinary (6, 25%) and respiratory (5, 21%) were the most common sources. The 30- and 90-day mortality rates were 8.3% and 20.8%, respectively. Clinical cure at 30 days was achieved in 62.5 % of episodes. Four (16.7%) patients had adverse events, two of them related to impaired renal function. Among patients who finished the treatment with ceftazidime-avibactam, 7 of them (35%) were diagnosed of recurrence of infection within 90 days of the end of treatment. CONCLUSIONS: In our experience, ceftazidime-avibactam is an effective drug for the treatment of infections due to OXA-48 CPE and as per our study's results a better safety profile than the current best available therapy could be expected. PMID- 30471405 TI - Beta-amyloid short- and long-term synaptic entanglement. AB - Beta-amyloid (Abeta) is a peptide that derives from the proteolytic cleavage of the amyloid precursor protein (APP) by several secretases. Since its isolation and sequencing from Alzheimer's disease (AD) brains, Abeta has been intensively investigated in the context of AD as the main pathogenic marker responsible for neurodegenerative processes. During the last three decades, results from several independent studies have converged to form the so-called amyloid cascade hypothesis of AD and several therapeutic strategies designed to modulate the APP amyloidogenic pathway have been developed. However, none of the clinical trials targeting Abeta culminated in a significant clinical outcome, thus challenging the concept that targeting Abeta, at least within the time window so far explored in clinical trials, may have a therapeutic effect. However, besides its presence in AD brains, brain cells produce Abeta, thus suggesting that, under normal conditions, the peptide may have a role in the regulation of brain functions, which is consistent with its ubiquitous presence and normal synthesis. Taking into account that Abeta has been found to exhibit a dual role strictly correlated with its concentration (neuromodulatory/neuroprotective vs neurotoxic), we discuss emerging evidence indicating that physiological concentrations of Abeta peptide modulate synaptic activity. The review examines the physiological effects of Abeta on acute synaptic activities and the functional interplay existing between Abeta and different neurotransmitter systems, i.e. cholinergic, glutamatergic, GABAergic, catecholaminergic, serotoninergic, and peptidergic. The review also provides an insight into the different mechanisms through which Abeta affects synaptic activity, focusing in particular on Abeta interaction with the key synaptic proteins that regulate the neurotransmitter release machinery. These interactions may help to identify or recognize alterations in neurotransmitter activity and correlated behaviors as predictive signs for the development of AD and to understand the limitations of current interventions and the failure so far of amyloid targeted therapies. PMID- 30471406 TI - Understanding antidepressant tachyphylaxis. PMID- 30471404 TI - Prevalence and determinants of latent tuberculosis infection among frontline tuberculosis healthcare workers in southeastern China: a multilevel analysis by individuals and health facilities. AB - OBJECTIVES: Healthcare workers (HCWs) suffered high risks for latent tuberculosis infection (LTBI) and the baseline prevalence of LTBI remain unknown among frontline TB HCWs in southeastern China. We ained to assess the prevalence of LTBI among TB HCWs and to analyze associated factors for LTBI at both individual and institutional levels. METHODS: Based on a cross-sectional study design, we selected 31 out of 89 TB designated hospitals in Zhejiang Province of China. We collected information on TB infection control measures through field visits in each selected hospital. We recruited all TB HCWs from selected hospitals to answer a questionnaire and to take LTBI tests by a TB interferon-gamma release assay (IGRA). Univariate analyses and a generalized linear mixed model (GLIMMIX) were applied to analyze associated factors at both individual and hospital levels. RESULTS: A total of 487 TB HCWs were recruited in 31 TB designated hospitals, while 33.9% of them were tested LTBI positive. At the institutional level, a low level of TB epidemic, regular infection control training for HCWs, and regular maintenance of ultraviolet disinfection equipment were found significantly associated with lower LTBI rate among HCWs. At the individual level, we identified alcohol use, more years working on TB, and longer weekly contact duration with TB patients as risk factors for LTBI among HCWs. CONCLUSIONS: LTBI rate among frontline TB HCWs was high in southeastern China. Factors at the institutional and individual levels could both affect the LTBI prevalence among HCWs. PMID- 30471407 TI - Reply to Dr. Sharma' "Understanding antidepressant tachyphylaxis". PMID- 30471408 TI - The role of microbiota in the pathogenesis of lupus: Dose it impact lupus nephritis? AB - Systemic lupus erythematosus (SLE) is a complex, inflammatory, and autoimmune disease triggered by complicated interactions of different factors. A major contributor to morbidity and mortality in SLE is lupus nephritis (LN). To date, the cause of SLE and LN is incompletely understood but a combination of genetic and environmental factors is thought to be involved. In recent years, there have been attempts to consider the intestinal microbial profiles, microbiota, and its role in the pathogenesis of the disease. The composition and elements of gut microbiota have major roles in antibody production, shaping the human B cell repertoire, homeostasis of different populations of helper T cell and Th17:Treg balance, and regulation of the levels of different Th17 cell subpopulations. Disturbance of gut microbiota, called dysbiosis, leads to the development of autoimmunity. To date, few studies have characterized the microbiota composition in SLE. In this review, we will highlight novel findings describing the effect of genetic, epigenetic, and environmental factors on gut microbiota and immune system. Moreover, we will discuss the possible association between SLE and microbiota composition and concerning how its changes may contribute to the onset of SLE and LN. Interest in this area has been grown to consider the microbiome as a potential therapeutic target in future. PMID- 30471409 TI - Paris Saponin II inhibits colorectal carcinogenesis by regulating mitochondrial fission and NF-kappaB pathway. AB - Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality worldwide. Accumulating evidence suggests that mitochondrial dynamics are closely implicated in carcinogenesis including CRC. Paris Saponin II (PSII), a major steroidal saponin extracted from Rhizoma Paris polyphylla, has emerged as a potential anticancer agent. However, the effects of PSII on CRC and its underlying mechanisms remain unknown. In the present study, we found PSII induced apoptosis and inhibited colony formation in HT 29 and HCT 116 cells, and cell cycle arrest in G1 phase. PSII inhibited the phosphorylation of ERK1/2 and mitochondrial translocation of dynamin-related protein 1 (Drp1) by dephosphorylating Drp1 at Ser616, leading to the suppression of mitochondrial fission. PSII also suppressed NF-kappaB activation as a result of the inhibition of IKKbeta and p65 translocation. Drp1 knockdown remarkably downregulated the nuclear expression of p65 and its target genes cyclin D1 and c-Myc in HCT 116 cell, confirming the link between mitochondrial fission and NF-kappaB pathway. Silencing of Drp 1 enhanced the inhibitory effects of PSII on p65 phosphorylation and the expressions of cyclin D1 and c-Myc, revealing that the inhibitory effects of PSII on cyclin D1 and c-Myc were relevant in the suppression of Drp1 and NF kappaB activation. An in vivo study demonstrated PSII remarkably decreased the xenograft tumor size and suppressed the phosphorylation of ERK1/2 and Drp1 at Ser616. Taken together, our results suggested that PSII could inhibit colorectal carcinogenesis, at least in part, by regulating mitochondrial fission and NF kappaB pathway. PMID- 30471410 TI - RGD-modified polymer and liposome nanovehicles: Recent research progress for drug delivery in cancer therapeutics. AB - Over the past few decades, as the demand for cancer treatment has increased, more rational treatment options (considering size, mode of administration, biocompatibility, efficacy, etc.) and plenty of specifically active targeted nanovehicles have been developed. Integrin receptors targeting are one of the most frequently used approaches because of its highly expressed in cancer cells. In particular, the arginine-glycine-aspartic acid (RGD) peptide and its derivatives have been widely used as ligands for integrin to increase direct targeting capabilies. Polymers as well as liposomes are commonly used as nanovehicles for drug delivery. A variety of work is focused on the RGD-modified polymer and liposome nanovehicles for cancer therapeutics. The goal of this article is to review the published literature in recent years concerning the RGD modified liposome and polymer nanovehicles to highlight its successful designs for improving cancer therapy and discuss the current challenges as well as the possible development prospects. PMID- 30471411 TI - Synthesis and structure-activity-relationship of 3,4-Diaryl-1H-pyrrolo[2,3 b]pyridines as irreversible Inhibitors of mutant EGFR-L858R/T790M. AB - The epidermal growth factor receptor (EGFR) is a well-validated drug target for the treatment of non-small cell lung cancer. Here we present an optimization approach and preliminary structure-activity relationship for 1H-pyrrolo[2,3 b]pyridines as covalent irreversible mutant EGFR inhibitors. We synthesized a focused library to investigate the effect of different aromatic substituents in the 4-position of this scaffold, interacting with the gatekeeper. We determined the activity of the synthesized compounds mutant EGFR enzyme assays and determined the selectivity over the wild type. PMID- 30471412 TI - The pH-dependence of lipid-mediated antimicrobial peptide resistance in a model staphylococcal plasma membrane: A two-for-one mechanism of epithelial defence circumvention. AB - The mechanisms of membrane defence by lysylphosphatidylglycerol (LPG), were investigated using synthetic biomimetic mono- and bilayer models of methicillin resistant S. aureus ST239 TW, based on its lipid composition in both pH 7.4 (28% LPG) and pH 5.5 (51% LPG) cultures. These models incorporated a stable synthetic analogue of LPG (3adLPG) to facilitate long-duration biophysical studies, which were previously limited by the lability native LPG. Both increased 3adLPG content and full headgroup ionization at pH 5.5, increased bilayer order and dampened overall charge, via the formation of neutral ion pairs with anionic lipids. Ion pair formation in air/liquid interface lipid monolayers elicited a significant condensing effect, which correlated with the inhibition of subphase-injected magainin 2 F5W partitioning. In fluid phase lipid vesicles, increasing the proportion of 3adLPG from 28 to 51 mol% completely inhibited the adoption of the membrane-active alpha-helical conformation of the peptide, without the need for full headgroup ionization. Neutron reflectivity measurements performed on biomimetic PG/3adLPG fluid floating bilayers, showed a significant ordering effect of mild acidity on a bilayer containing 30 mol% 3adLPG, whilst peptide binding/partitioning was only fully inhibited in a bilayer with 55 mol% 3adLPG at pH 5.5. These findings are discussed with respect to the roles of LPG in resistance to human epithelial defences in S. aureus and the continued evolution of this opportunistic pathogen's virulence. PMID- 30471413 TI - Hypothalamic cell diversity: non-neuronal codes for long-distance volume transmission by neuropeptides. AB - Volume transmission is a mode of intercellular communication using cerebral liquor to deliver signal molecules over long distances and allow their action for extended periods. For hypothalamic neuropeptides, nerve endings amongst ependymal cells are seen as a site of release into the cerebrospinal fluid. Recent single cell RNA-seq data identify tanycytes and ventricular ependyma as alternative sources by being unexpectedly rich in neuroactive substances. This notion, coupled with circuit analysis showing regionalized innervation of periventricular ependyma by intrahypothalamic neurons, could allow for the integration of hypothalamic neuronal activity patterns with brain-wide activity changes upon metabolic challenges through phasic volume transmission primed by neuron-ependyma coupling. Here, we discuss emerging data for an ependymal interface and its breaches in neuropsychiatric disease. PMID- 30471414 TI - "Interneurons and principal cell firing in human limbic areas at focal seizure onset". PMID- 30471415 TI - Pharmacokinetics and efficacy of PT302, a sustained-release Exenatide formulation, in a murine model of mild traumatic brain injury. AB - Traumatic brain injury (TBI) is a neurodegenerative disorder for which no effective pharmacological treatment is available. Glucagon-like peptide 1 (GLP-1) analogues such as Exenatide have previously demonstrated neurotrophic and neuroprotective effects in cellular and animal models of TBI. However, chronic or repeated administration was needed for efficacy. In this study, the pharmacokinetics and efficacy of PT302, a clinically available sustained-release Exenatide formulation (SR-Exenatide) were evaluated in a concussive mild (m)TBI mouse model. A single subcutaneous (s.c.) injection of PT302 (0.6, 0.12, and 0.024 mg/kg) was administered and plasma Exenatide concentrations were time dependently measured over 3 weeks. An initial rapid regulated release of Exenatide in plasma was followed by a secondary phase of sustained-release in a dose-dependent manner. Short- and longer-term (7 and 30 day) cognitive impairments (visual and spatial deficits) induced by weight drop mTBI were mitigated by a single post-injury treatment with Exenatide delivered by s.c. injection of PT302 in clinically translatable doses. Immunohistochemical evaluation of neuronal cell death and inflammatory markers, likewise, cross validated the neurotrophic and neuroprotective effects of SR-Exenatide in this mouse mTBI model. Exenatide central nervous system concentrations were 1.5% to 2.0% of concomitant plasma levels under steady-state conditions. These data demonstrate a positive beneficial action of PT302 in mTBI. This convenient single, sustained-release dosing regimen also has application for other neurological disorders, such as Alzheimer's disease, Parkinson's disease, multiple system atrophy and multiple sclerosis where prior preclinical studies, likewise, have demonstrated positive Exenatide actions. PMID- 30471416 TI - Deciphering microbiome and neuroactive immune gene interactions in schizophrenia. AB - The body's microbiome represents an actively regulated network of novel mechanisms that potentially underlie the etiology and pathophysiology of a wide range of diseases. For complex brain disorders such as schizophrenia, understanding the cellular and molecular pathways that intersect the bidirectional gut-brain axis is anticipated to lead to new methods of treatment. The means by which the microbiome might differ across neuropsychiatric and neurological disorders are not known. Brain disorders as diverse as schizophrenia, major depression, Parkinson's disease and multiple sclerosis appear to share a common pathology of an imbalanced community of commensal microbiota, often measured in terms of a leaky gut phenotype accompanied by low level systemic inflammation. While environmental factors associated with these disease states might contribute to intestinal pathologies, products from a perturbed microbiome may also directly promote specific signs, symptoms and etiologies of individual disorders. We hypothesize that in schizophrenia, it is the putatively unique susceptibility related to genes that modulate the immune system and the gut-brain pleiotropy of these genes which leads to a particularly neuropathological response when challenged by a microbiome in dysbiosis. Consequences from exposure to this dysbiosis may occur during pre- or post-natal time periods and thus may interfere with normal neurodevelopment in those who are genetically predisposed. Here, we review the evidence from the literature which supports the idea that the intersection of the microbiome and immune gene susceptibility in schizophrenia is relevant etiologically and for disease progression. Figuring prominently at both ends of the gut-brain axis and at points in between are proteins encoded by genes found in the major histocompatibility complex (MHC), including select MHC as well as non-MHC complement pathway genes. PMID- 30471418 TI - Decreased pallidal vesicular monoamine transporter type 2 availability in Parkinson's disease: The contribution of the nigropallidal pathway. AB - To date, the contribution of the nigropallidal pathway degeneration to Parkinson's disease (PD) motor symptoms has received little attention and is generally poorly understood in spite of solid evidence that the globus pallidus (GP) receives a dense neuronal projection from the substantia nigra. To explore the dopaminergic (DA) changes of the GP in PD, we measured the availability of vesicular monoamine transporter 2 (VMAT2) using [11C]DTBZ and positron emission tomography in 30 PD patients and 12 controls. PD patients were classified in two groups based on severity of disease. VMAT2 reduction was found to be significant in the external GP (GPe) regardless of the disease stage, while the internal GP (GPi) showed reduction only in more severe patients. Pallidal VMAT2 binding correlated with dopaminergic changes in the striatum, with the GPe showing a stronger association than GPi. Our findings showed DA terminals in the GPe and GPi may be differentially vulnerable in different stages of the disease, possibly playing a distinctive role in the development of motor complications with GPi DA deficiency contributing more to later-stage symptoms. PMID- 30471417 TI - Motor neuron degeneration, severe myopathy and TDP-43 increase in a transgenic pig model of SOD1-linked familiar ALS. AB - Amyotrophic Lateral Sclerosis (ALS) is a neural disorder gradually leading to paralysis of the whole body. Alterations in superoxide dismutase SOD1 gene have been linked with several variants of familial ALS. Here, we investigated a transgenic (Tg) cloned swine model expressing the human pathological hSOD1G93A allele. As in patients, these Tg pigs transmitted the disease to the progeny with an autosomal dominant trait and showed ALS onset from about 27 months of age. Post mortem analysis revealed motor neuron (MN) degeneration, gliosis and hSOD1 protein aggregates in brainstem and spinal cord. Severe skeletal muscle pathology including necrosis and inflammation was observed at the end stage, as well. Remarkably, as in human patients, these Tg pigs showed a quite long presymptomatic phase in which gradually increasing amounts of TDP-43 were detected in peripheral blood mononuclear cells. Thus, this transgenic swine model opens the unique opportunity to investigate ALS biomarkers even before disease onset other than testing novel drugs and possible medical devices. PMID- 30471420 TI - Dietary fibers in osteoarthritis: what are the evidences? PMID- 30471419 TI - Urate and Osteoarthritis: Evidence For a Reciprocal Relationship. AB - Hyperuricemia is a common condition, and in a subset of patients leads to gout, the most common inflammatory arthritis. Osteoarthritis is the most common form of arthritis overall, and gout and osteoarthritis frequently coexist in the same patient. However, the relationship between the two remains poorly defined. More particularly, the impact of osteoarthritis on the development of gout, and the impact of gout on the development of osteoarthritis, remain to be determined. Additionally, whether hyperuricemia mediates osteoarthritis in the absence of gout is uncertain. Here, we review the evidence linking gout and osteoarthritis, with a special focus on the role of hyperuricemia in the presence or absence of gout. Since disease modifying agents are currently available for hyperuricemia and gout but not for osteoarthritis, a contributory role for urate in the pathogenesis of osteoarthritis could have important clinical implications. PMID- 30471421 TI - Singular Case of Osteolytic Lesions Revealing Transformation of Myeloproliferative Syndrome to Acute Leukemia. AB - Hematological malignancies can cause bone lesions, of which the most common are the punched-out foci of osteolysis seen in multiple myeloma. However, osteosclerotic lesions are more common. We report the unusual case of a patient with myeloproliferative syndrome in whom the development of osteolytic lesions revealed transformation to acute leukemia. In 2007, this 82-year-old man with essential thrombocythemia since 1994 developed primary polycythemia with the JAK2 mutation V617 F. In July 2017, he was evaluated for an osteolytic lesion in the right humerus with incipient fracturing. Bone marrow smear results provided only limited information, due to the myelofibrosis, showing 7% of blast cells with no plasmacytosis. No solid malignancies were identified by imaging studies. Examination of a right humeral biopsy specimen taken during internal fixation showed myeloproliferative syndrome with osteosclerosis and grade-3 myelofibrosis, as well as a malignant proliferation of large cells carrying the leukocyte cluster of differentiation antigens CD45, CD 43, CD4, and CD34. The diagnosis was transformation of the myeloproliferative syndrome to acute myeloid leukemia. The development of an osteolytic lesion during the course of myeloproliferative syndrome is an exceedingly rare event that should suggest acute leukemic transformation. PMID- 30471422 TI - New data in causes of autoinflammatory diseases. AB - The spectrum of factors known to mediate autoinflammation has broadened recently to include not only interleukin-1 (IL-1) and interferon, but also abnormalities that impair NF-kappaB pathway negative regulation. The NF-kappaB pathway is activated upon contact of a ligand with tumor necrosis factor receptor 1 (TNFR1) and plays a pivotal role in triggering the inflammatory process by producing major cytokines such as IL-1, IL-6, and TNF. Negative regulation of the NF-kappaB pathway, which is essential to stop the inflammatory process, depends on the level of ubiquitination of the proteins associated with TNFR1 and of other intermediate compounds. A20 and otulin are proteins that influence the level of ubiquitination, and a deficiency in either can result in NF-kappaB activation with overproduction of proinflammatory cytokines. Similar to Behcet's disease, A20 haploinsufficiency manifests as oral and genital ulcers and, more rarely, as uveitis. However, transmission is dominant, symptom onset occurs at a younger age, and severe gastrointestinal involvement is at the forefront of the clinical picture. Clinical presentations are extremely diverse. Over their lifetime, affected patients simultaneously or sequentially experience autoinflammatory and autoimmune manifestations. Mild immune deficiency predominantly affecting humoral responses is less common. Otulin deficiency results in systemic inflammatory manifestations at a very young age, with panniculitis, lipodystrophy, and inflammatory bowel disease. The main differential diagnosis is proteasome associated autoinflammatory syndrome. The treatment of A20 haploinsufficiency and otulin deficiency is challenging and remains unstandardized. The symptoms respond to high-dose glucocorticoid therapy. TNF antagonists and IL-1 antagonists have shown some measure of efficacy. PMID- 30471423 TI - Stromal extracellular matrix is a microenvironmental cue promoting resistance to EGFR tyrosine kinase inhibitors in lung cancer cells. AB - The acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a critical problem in lung cancer clinic, but the underlying mechanisms have remained incompletely understood. Although the TKI-induced or -selected genetic changes are known to drive resistance, resistance also occurs in tumor cells without genetic changes through poorly-characterized processes. Here, we show that the extracellular matrix (ECM) from various components of the tumor microenvironment, including neighboring tumor cells and fibroblasts, may be the driver of resistance in the absence of genetic changes. Unlike genetic changes, which may evolve during relatively long time of chronic EGFR TKI treatment to drive resistance, briefly culturing on de-cellularized ECM, or co-culturing with the ECM donor cells, immediately confers resistance to tumor cells that are otherwise sensitive to EGFR TKIs. We show evidence that collagen in the ECM may be its primary constituent driving resistance, at least partly through the collagen receptor Integrin-beta1. Intriguingly, such effect of ECM and collagen is dose-dependent and reversible, suggesting a potential clinic-relevant application for targeting this effect. Collectively, our results reveal that the stromal ECM acts as a microenvironmental cue promoting EGFR TKI resistance in lung cancer cells, and targeting collagen and Integrin-beta1 may be useful for treating resistance, especially the resistance without clearly-defined genetic changes, for which effective therapeutics are lacking. PMID- 30471424 TI - TNFalpha stimulates NO release in EA.hy926 cells by activating the CaMKKbeta-AMPK eNOS pathway. AB - Previously we showed that a mild stimulation of EA.hy926 cells with tumour necrosis factor alpha (TNFalpha) activated mitochondrial biogenesis, probably as a mechanism preventing cell death. This was accompanied by an increased phosphorylation of eNOS and elevation of NO release. The aim of the present study was to explain the biochemical basis of this effect. Our results indicate that eNOS is the only enzyme catalysing NO generation in EA.hy926 cells, and TNFalpha stimulates its activity by activating AMP-activated protein kinase (AMPK). Inhibition of AMPK with Compound C prevents the TNFalpha-induced activatory phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 and reduces the NO release. AMPK is activated by phosphorylation catalysed by liver kinase B1 (LKB1) and calcium/calmodulin-dependent protein kinase kinase beta (CaMKKbeta), which are phosphorylated and thereby activated in the presence of TNFalpha. Moreover, CaMKKbeta catalyses an activatory phosphorylation of sirtuin 1, which could deacetylate and activate eNOS both directly and indirectly by an elevating the LKB1 activity. TNFalpha hardly increases the nuclear fraction of sirtuin 1, thus its major activity is probably attributed to the cytosolic pool. This is in line with the elevated activity of eNOS. We conclude that the increased AMPK-dependent phosphorylation of eNOS at least partially explains the stimulation of NO generation by TNFalpha in EA.hy926 cells. PMID- 30471425 TI - Additional pathways of sterol metabolism: Evidence from analysis of Cyp27a1-/- mouse brain and plasma. AB - Cytochrome P450 (CYP) 27A1 is a key enzyme in both the acidic and neutral pathways of bile acid biosynthesis accepting cholesterol and ring-hydroxylated sterols as substrates introducing a (25R)26-hydroxy and ultimately a (25R)26-acid group to the sterol side-chain. In human, mutations in the CYP27A1 gene are the cause of the autosomal recessive disease cerebrotendinous xanthomatosis (CTX). Surprisingly, Cyp27a1 knockout mice (Cyp27a1-/-) do not present a CTX phenotype despite generating a similar global pattern of sterols. Using liquid chromatography - mass spectrometry and exploiting a charge-tagging approach for oxysterol analysis we identified over 50 cholesterol metabolites and precursors in the brain and circulation of Cyp27a1-/- mice. Notably, we identified (25R)26,7alpha- and (25S)26,7alpha-dihydroxy epimers of oxysterols and cholestenoic acids, indicating the presence of an additional sterol 26 hydroxylase in mouse. Importantly, our analysis also revealed elevated levels of 7alpha-hydroxycholest-4-en-3-one, which we found increased the number of oculomotor neurons in primary mouse brain cultures. 7alpha-Hydroxycholest-4-en-3 one is a ligand for the pregnane X receptor (PXR), activation of which is known to up-regulate the expression of CYP3A11, which we confirm has sterol 26 hydroxylase activity. This can explain the formation of (25R)26,7alpha- and (25S)26,7alpha-dihydroxy epimers of oxysterols and cholestenoic acids; the acid with the former stereochemistry is a liver X receptor (LXR) ligand that increases the number of oculomotor neurons in primary brain cultures. We hereby suggest that a lack of a motor neuron phenotype in some CTX patients and Cyp27a1-/- mice may involve increased levels of 7alpha-hydroxycholest-4-en-3-one and activation PXR, as well as increased levels of sterol 26-hydroxylase and the production of neuroprotective sterols capable of activating LXR. PMID- 30471427 TI - Monoclonal Antibody Targeting the Matrix Metalloproteinase 9 Prevents and Reverses Paclitaxel-Induced Peripheral Neuropathy in Mice. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling condition accompanying several cancer drugs, including the front-line chemotherapeutic agent paclitaxel. Although CIPN can force dose reduction or even discontinuation of chemotherapy affecting survival in cancer patients, there is no FDA-approved treatment for CIPN. CIPN in mice is characterized by neuropathic pain (e.g., mechanical allodynia) in association with oxidative stress and neuroinflammation in dorsal root ganglia (DRGs), as well as retraction of intraepidermal nerve fibers. Here, we report that paclitaxel-induced mechanical allodynia is associated with transcriptional increased in matrix metalloproteinase (MMP) 2 and 9, and decreased of metallopeptidase inhibitor 1 (TIMP1), a strong endogenous MMP9 inhibitor. Consistently, MMP9 protein levels are increased in DRG neurons in vivo and in vitro after paclitaxel treatment and demonstrated, for the first time, that intrathecal injections of exogenous TIMP1 or a monoclonal antibody targeting MMP9 (MMP9 mAb) significantly prevented and reversed paclitaxel-induced mechanical allodynia in male and female mice. Analyses of DRG tissues showed that MMP9 mAb significantly decreased oxidative stress and neuroinflammatory mediators IL-6 and TNFalpha, as well as prevented paclitaxel-induced loss of intraepidermal nerve fibers. These findings suggest that MMP signaling plays a key role in paclitaxel-induced peripheral neuropathy and MMP9 mAb may offer new therapeutic approaches for the treatment of CIPN. Perspective: Chemotherapy-induced peripheral neuropathy (CIPN) remain ineffectively managed in cancer patients potentially leading to the discontinuation of an otherwise life-saving treatment. Here, we demonstrate that a monoclonal antibody targeting the matrix metalloproteinase 9 (MMP9) alleviates neuropathic pain and several mechanisms linked to CIPN. This study is particularly relevant since a humanized MMP9 antibody is already in advanced clinical trials for the treatment of colitis and cancer, and it may be straightforwardly repurposed for the relief of CIPN. PMID- 30471426 TI - Common binding sites for cholesterol and neurosteroids on a pentameric ligand gated ion channel. AB - Cholesterol is an essential component of cell membranes, and is required for mammalian pentameric ligand-gated ion channel (pLGIC) function. Computational studies suggest direct interactions between cholesterol and pLGICs but experimental evidence identifying specific binding sites is limited. In this study, we mapped cholesterol binding to Gloeobacter ligand-gated ion channel (GLIC), a model pLGIC chosen for its high level of expression, existing crystal structure, and previous use as a prototypic pLGIC. Using two cholesterol analogue photolabeling reagents with the photoreactive moiety on opposite ends of the sterol, we identified two cholesterol binding sites: an intersubunit site between TM3 and TM1 of adjacent subunits and an intrasubunit site between TM1 and TM4. In both the inter- and intrasubunit sites, cholesterol is oriented such that the 3 OH group points toward the center of the transmembrane domains rather than toward either the cytosolic or extracellular surfaces. We then compared this binding to that of the cholesterol metabolite, allopregnanolone, a neurosteroid that allosterically modulates pLGICs. The same binding pockets were identified for allopregnanolone and cholesterol, but the binding orientation of the two ligands was markedly different, with the 3-OH group of allopregnanolone pointing to the intra- and extracellular termini of the transmembrane domains rather than to their centers. We also found that cholesterol increases, whereas allopregnanolone decreases the thermal stability of GLIC. These data indicate that cholesterol and neurosteroids bind to common hydrophobic pockets in the model pLGIC, GLIC, but that their effects depend on the orientation and specific molecular interactions unique to each sterol. PMID- 30471428 TI - Activation of KCNQ channels prevents paclitaxel-induced peripheral neuropathy and associated neuropathic pain. AB - Paclitaxel-induced peripheral neuropathy (PIPN) and associated neuropathic pain are the most common and serious adverse effects experienced by cancer patients receiving paclitaxel treatment. These effects adversely impact daily activities and consequently the quality of life, sometimes forcing the suspension of treatment and negatively influencing survival. Patients are usually at high risk of developing PIPN if paclitaxel induces acute pain, which strongly suggests that an acute increase in the excitability of nociceptors underlies the chronic alterations of PIPN. KCNQ/Kv7 channels are widely expressed in the primary sensory neurons to modulate their excitability. In the present study, we show that targeting KCNQ/Kv7 channels at an early stage is an effective strategy to attenuate the development of PIPN. We found that paclitaxel did not decrease the expression level of KCNQ/Kv7 channels in the primary sensory neurons as detected by qRT-PCR and Western blotting. However, retigabine, which is a specific KCNQ/Kv7 channel opener, significantly attenuated the development of PIPN, as shown by both morphologic and behavioral evidence. We also observed that retigabine had no obvious effect on the chemosensitivity of breast cancer cells to paclitaxel. While retigabine has been approved by the FDA as an anticonvulsant, our study suggests that this drug can be repurposed to attenuate the development of PIPN. Perspective: Paclitaxel-induced peripheral neuropathy and associated neuropathic pain are severe and resistant to intervention. The results of our study demonstrated that retigabine (a clinically available medicine) can be used to attenuate the development of paclitaxel-induced peripheral neuropathy. PMID- 30471429 TI - Incident chronic spinal pain and depressive disorders: Data from the National Comorbidity Survey. AB - This study examined pre-existing depression as a risk factor for the development of chronic spinal pain, and pre-existing chronic spinal pain as a risk factor for the development of depression. Data from the National Comorbidity Survey, a stratified sample of 5001 participants evaluated in 1990-1992 (NCS-1) and again in 2000-2001 (NCS-2) were used to address these associations. Cox regression was used to estimate hazard ratios and time-to-incidence after NCS-1. Participants with antecedent acute or chronic depressive disorders at NCS-1 were more likely to develop chronic spinal pain in the ensuing 10 years compared to participants without depressive disorders. Those with antecedent chronic spinal pain at NCS-1 were more likely to develop dysthymic disorder than subjects without chronic spinal pain at NCS-1, however, antecedent chronic spinal pain was not associated the subsequent development of major depressive disorder. These results suggest that both pain and depression are associated with the development of the other condition. In particular, chronic depression is more strongly linked to chronic spinal pain than is acute depression. The results are discussed in terms of the need to assess the presence of both disorders given the presence of one. Perspective: Chronic spinal pain and depressive disorders, especially chronic depression, increase the likelihood for the subsequent development of the other condition. The results underscore the need to routinely assess for the presence of both disorders given the presence of one in order to mitigate the effects of developing comorbid conditions. PMID- 30471430 TI - Role of adiponectin as a modulator of testicular function during aging in mice. AB - The mechanisms by which testicular functions decline with aging remain largely speculative. Our recent finding showed the importance of adiponectin in the regulation of testicular functions, whereas its concentration declines during male infertility. Thus, the aim of present study was to explore the potential role of adiponectin during aging. The changes in adiponectin, adiponectin receptors, and insulin receptor proteins expression in the testis were evaluated and compared with the testicular parameters, mass, and testosterone level in the mice from early post-natal to late senescence period. Further, the current study has examined the effect of exogenous adiponectin treatment on testicular functions in aged mice. The results showed a significant decline in adiponectin/adiponectin-receptors expression simultaneously with a significant decline in testicular mass, insulin receptor expression and testosterone synthesis in the testis of aged mice. Exogenous treatment of adiponectin to aged mice resulted in marked improvements in testicular mass, histological features (cells proliferation), insulin receptor expression, testicular glucose uptake, anti-oxidative enzymes activity and testosterone synthesis as compared with the control. Based on these findings, it may be concluded that a marked decline in adiponectin synthesis and action results in decreased insulin sensitivity (development of insulin resistance) and increased oxidative stress which consequently suppresses testicular functions during aging. This study further showed that treatment with adiponectin ameliorates reduced testicular functions by enhanced expression of insulin receptor in the testis of senescent mice. It is thus hypothesized that systemic adiponectin treatment could be a promising therapeutic strategy for improvement of testosterone production and sperm counts during aging. PMID- 30471431 TI - Habu coagulotoxicity: Clinical implications of the functional diversification of Protobothrops snake venoms upon blood clotting factors. AB - Venom can affect any part of the body reachable via the bloodstream. Toxins which specifically act upon the coagulation cascade do so either by anticoagulant or procoagulant mechanisms. Here we investigated the coagulotoxic effects of six species within the medically important pit viper genus Protobothrops (Habu) from the Chinese mainland and Japanese islands, a genus known to produce hemorrhagic shock in envenomed patients. Differential coagulotoxicity was revealed: P. jerdonii and P. mangshanensis produced an overall net anticoagulant effect through the pseudo-procoagulant clotting of fibrinogen; P. flavoviridis and P. tokarensis exhibit a strong anticoagulant activity through the destructive cleavage of fibrinogen; and while P. elegans and P. mucrosquamatus both cleaved the A-alpha and B-beta chains of fibrinogen they did not exhibit strong anticoagulant activity. These variations in coagulant properties were congruent with phylogeny, with the closest relatives exhibiting similar venom effects in their action upon fibrinogen. Ancestral state reconstruction indicated that anticoagulation mediated by pseudo-procoagulant cleavage of fibrinogen is the basal state, while anticoagulation produced by destructive cleavage of fibrinogen is the derived state within this genus. This is the first in depth study of its kind highlighting extreme enzymatic variability, functional diversification and clotting diversification within one genus surrounding one target site, governed by variability in co-factor dependency. The documentation that the same net overall function, anticoagulation, is mediated by differential underlying mechanics suggests limited antivenom cross-reactivity, although this must be tested in future work. These results add to the body of knowledge necessary to inform clinical management of the envenomed patient. PMID- 30471432 TI - SHP2 regulates intramembranous ossification by modifying the TGFbeta and BMP2 signaling pathway. AB - SHP2 is a ubiquitously expressed protein tyrosine phosphatase, which is involved in many signaling pathways to regulate the skeletal development. In endochondral ossification, SHP2 is known to modify the osteogenic fate of osteochondroprogenitors and to impair the osteoblastic transdifferentiation of hypertrophic chondrocytes. However, how SHP2 regulates osteoblast differentiation in intramembranous ossification remains incompletely understood. To address this question, we generated a mouse model to ablate SHP2 in the Prrx1-expressing mesenchymal progenitors by using "Cre-loxP"-mediated gene excision and examined the development of calvarial bone, in which the main process of bone formation is intramembranous ossification. Phenotypic characterization showed that SHP2 mutants have severe defects in calvarial bone formation. Cell lineage tracing and in situ hybridization data showed less osteoblast differentiation of mesenchymal cells and reduced osteogenic genes expression, respectively. Further mechanistic studies revealed enhanced TGFbeta and suppressed BMP2 signaling in SHP2 ablated mesenchymal progenitors and their derivatives. Our study uncovered the critical role of SHP2 in osteoblast differentiation through intramembranous ossification and might provide a potential target to treat craniofacial skeleton disorders. PMID- 30471433 TI - Bioassay-guided isolation of a Mycobacterium tuberculosis bioflim inhibitor from Arisaema sinii Krause. AB - Mycobacterium tuberculosis biofilms harbour drug-tolerant bacteria. Identification of drugs that inhibit biofilm formation could enable the dramatic shortening of tuberculosis treatments using standard antibiotics. Arisaema sinii Krause is used to treat pulmonary and lymphatic tuberculosis by Dong People of China. Current study was aimed to purify the active components against M. tuberculosis biofilms from Arisaema sinii extract by using bioassay-guided isolation. (E)-2-(methyl (phenyl) amino) ethyl 2-(2-hydroxyundecanamido)-7, 11 dimethyl-3-oxotetradec-4-enoate, compound 1, was identified as the active component. It could inhibit mycobacterial biofilm formation, disperse the preformed biofilms, and disrupt the mature biofilms at concentration of 4, 8, and 32 MUg/ml, respectively. At the dose of 32 MUg/ml, it could potentiate the bactericidal activity of isoniazid against M. tuberculosis in mature biofilms. The results of this study indicate that compound 1 might be a novel lead compound against mycobacterial biofilm formation. PMID- 30471434 TI - Characterization of oral mucosa lesions and prevalence of yeasts in diabetic patients: A comparative study. AB - BACKGROUND: There is no data available on the prevalence of oral mucosal lesion and candida infection among DM patients which necessitate conducting a local or nation-wide study to assess the oral mucosa lesions and candida prevalent in diabetic patients in Riyadh, Saudi Arabia. OBJECTIVES: The objective of the present study was to characterize oral mucosa lesions, and the prevalence of yeasts in diabetic patients and their association with the risk factors in comparison with a group of non-diabetic controls. METHODS: Study design: A cross sectional comparative study was conducted assuming 50% of the diabetic patients have oral lesions compared to nondiabetic patients and a power of 80% with 5% level of significance, the minimum required sample size was estimated to be 115 in each group. The buccal swabs were collected to isolate Candida species from the individual patient with a current and former history of diabetes. The laboratory findings were collected and the clinical examination of the oral mucosa was processed at the department of microbiology. RESULTS: The results inferred a significant presence of oral mucosa alterations in the diabetic group. A majority of the patients were suffering from type 2 diabetes for the past 10 years. C. albicans was the predominant yeast, followed by. C. tropicalis and C. krusei nonalbicans species that were most frequently isolated. Diabetes and smoking habit were the two risk factors for oral mucosa alterations. CONCLUSIONS: The study found a significant presence of oral mucosa alterations in the diabetic group and the fungal infection tended to be more in the diabetic group with a high incidence of C. albicans. The presence of diabetes and smoking habit were two risk factors identified as significant for oral mucosa alterations. The significant variation in education level in groups indicates that education would help to enhance the prognosis in diabetic patients and healthcare behavior. PMID- 30471435 TI - Dyspnea on exertion provokes unpleasantness and negative emotions in women with obesity. AB - PURPOSE: While dyspnea on exertion (DOE) is a common complaint in otherwise healthy obese women, less is known about feelings of unpleasantness and/or negative emotions provoked by DOE. We examined whether ratings of perceived breathlessness (RPB) during exercise were associated with ratings of unpleasantness and negative emotions (depression, anxiety, frustration, anger, and fear) in obese women. METHODS: Seventy-four women (34 +/- 7 yrs, 36 +/- 4 kg/m2, 46 +/- 5% body fat) performed 6 min of constant-load cycling (60 W); RPB (0-10 scale), and unpleasantness and negative emotions (visual analog scales, 10 cm) were assessed at the end. RESULTS: RPB were significantly correlated with unpleasantness and negative emotions (p < 0.05). The strongest correlations were between RPB and unpleasantness (r = 0.61, p < 0.001), and RPB and anxiety (r = 0.50, p < 0.001). CONCLUSIONS: DOE can significantly provoke unpleasantness and negative emotions during exercise in obese women. This may affect their willingness to engage in regular physical activity. PMID- 30471436 TI - Glutamate metabotropic receptors in the lateral hypothalamus/perifornical area reduce the CO2 chemoreflex. AB - It has been shown that the lateral hypothalamus/perifornical area (LH/PFA) exerts an important role on arousal-state variations of the central chemoreflex, but the mechanisms that underlie LH/PFA chemoreception are poorly understood. Here we asked whether glutamate inputs on metabotropic receptors in the LH/PFA modulate the hypercapnic ventilatory response. We studied the effects of microinjection of a glutamate metabotropic receptor (mGluR) antagonist ((+)-alpha-Methyl-4 carboxyphenylglycine; MCPG; 100 mM) and a selective Group II/III mGluR antagonist ((2S)-2-Amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid; LY341495; 5 mM) into the LH/PFA of conscious rats on ventilation in room air and in 7% CO2, during wakefulness and sleep, in the dark and light periods of the diurnal cycle. Microinjection of MCPG and LY341495 increased the hypercapnic ventilatory response in both the light and the dark period during wakefulness, but not during sleep, (p < 0.001). Our data suggest that glutamate, acting on Group II/III metabotropic receptors in the LH/PFA, exerts an inhibitory modulation of the hypercapnic ventilatory response in awake rats. PMID- 30471437 TI - A resistant cowpea (Vigna unguiculata [L.] Walp.) genotype became susceptible to cowpea severe mosaic virus (CPSMV) after exposure to salt stress. AB - In nature, plants are simultaneously challenged by biotic and abiotic stresses. However, little is known about the effects of these combined stresses for most crops. This work aimed to evaluate the responsed of the virus-resistant cowpea genotype BRS-Marataoa to the exposure of salt stress combined with CPSMV infection. Cowpea plants were exposed to 200 mM NaCl either simultaneously (SV plant group) or 24 h prior to the CPSMV infection [S(24 h)V plant group]. Physiological, biochemical, and proteomic analyses at 2 and 6 days post salt stress (DPS) revealed that cowpea significantly reprogrammed its cellular metabolism. Indeed, plant size, photosynthetic parameters (net photosynthesis, transpiration rate, stomatal conductance, and internal CO2 partial pressure) and chlorophyll and carotenoid contents were reduced in S(24 h)V compared to SV. Moreover, accumulation of viral particles at 6 DPS in S(24 h)V was observed indicating that the salt stress imposed prior to virus infection favors viral particle proliferation. Proteomic analysis showed differential contents of 403 and 330 proteins at 2 DPS and 6 DPS, respectively, out of 733 differentially abundant proteins between the two plant groups. The altered leaf proteins are involved in energy and metabolism, photosynthesis, stress response, and oxidative burst. BIOLOGICAL SIGNIFICANCE: This is an original study in which a virus resistant cowpea genotype (BRS-Marataoa) was (i) exposed simultaneously to 200 mM NaCl and inoculation with CPSMV (SV plant group) or (ii) exposed to 200 mM NaCl stress 24 h prior to inoculation with CPSMV [S(24 h)V plant group]. The purpose was to shed light on how this CPSMV resistant cowpea responded to the combined stresses. Numerous key proteins and associated pathways were altered in the cowpea plants challenged with both stresses, but unexpectedly, the salt stress imposed 24 h prior to CPSMV inoculation allowed viral proliferation, turning the cowpea genotype from resistant to susceptible. PMID- 30471439 TI - Intrasaccular Flow Disruption with WEB device: Current place and results in the management of intracranial aneurysms. PMID- 30471438 TI - Neurosurgical resection and stereotactic radiation versus stereotactic radiation alone in patients with a single or solitary brain metastasis. AB - BACKGROUND: Brain metastases commonly manifest in cancer patients, with approximately 20-50% presenting with one intracranial lesion. Among patients with one, small brain metastasis and controlled or absent extracranial disease, it remains unclear if aggressive intracranial management utilizing neurosurgical resection and cavity stereotactic radiation (SRS/SRT) rather than SRS/SRT alone is beneficial. In patients with controlled or absent extracranial disease and one brain metastasis <=2 cm in size, we evaluated the impact of surgery plus SRS/SRT compared to SRS/SRT on oncologic outcomes including overall survival. METHODS: We retrospectively identified 86 patients with controlled or absent extracranial disease and one brain metastasis <=2 cm in size treated between 2000-2015 at our institution. We examined differences in rates of local and distant failure, use of salvage treatment, and other oncologic outcomes including all-cause mortality (ACM). RESULTS: Baseline characteristics were similar between cohorts. Median follow-up of surviving patients was 38 months. On multivariable analysis, surgical resection plus cavity SRS/SRT was associated with a lower risk of ACM (HR 0.44, 95% CI: 0.19-1.00, p=0.05) when compared to SRS/SRT alone. One and two year rates of overall survival were 100% and 88% versus 74% and 52% for surgery plus cavity SRS/SRT versus SRS/SRT alone, respectively. CONCLUSIONS: Aggressive, local therapy including neurosurgical resection may benefit patients with one brain metastasis in the context of controlled or absent systemic disease, even if the lesion in question is small. Further studies are needed to evaluate these associations. PMID- 30471440 TI - A virtual, three-dimensional temporal bone model and its educational value for neurosurgical trainees. AB - OBJECTIVE: Learning complex neuroanatomy is an arduous yet important task for every neurosurgical trainee. As technology has advanced, various modalities have been created to aid our understanding of anatomy. This study sought to assess the educational value of a virtual, three-dimensional (3D) temporal bone model. METHODS: The 3D temporal bone model was created with assistance of computer graphic designers and published online. Its educational value as a teaching was tool was assessed by querying 73 neurosurgery residents at four institutions and was compared to that of a standard, two-dimensional (2D) temporal bone resource. Data was collected via a survey and significance amongst responses was analyzed via a univariate chi-square test. RESULTS: The survey response rate was 37%. Greater than 90% of residents preferred to study with the 3D model compared with the 2D resource and felt that the 3D model allowed them understand the anatomy more realistically (p = .001). Moreover, greater than 90% of residents believed that reviewing the 3D model prior to an actual surgery could lead to improved operative efficiency and safety (p = .001). CONCLUSIONS: This study demonstrates the utility of a novel, 3D temporal bone model as a teaching tool for neurosurgery residents. The model contains accurate anatomic structures and allows user interaction via a virtual, immersive environment. PMID- 30471441 TI - Addressing the global burden of neurosurgical disease beyond the operating theatre. PMID- 30471442 TI - Delayed myelopathy in patients with traumatic pre-ganglionic brachial plexus avulsion injuries. AB - BACKGROUND: Cervical and upper thoracic nerve root avulsions are pre-ganglionic lesions that occur after extreme traction of the brachial plexus. The tearing of the roots from the spinal cord pia leads not only to immediate and permanent deficits, but also to delayed neurologic complications. Symptomatic myelopathy may present in a late fashion due to chronic sequelae from the inciting traumatic event. There has yet to be a unifying theory that explains the causes of delayed spinal cord dysfunction after preganglionic brachial plexus injury. In this paper, we propose a collective mechanism for the development of delayed spinal cord injury. MATERIALS AND METHODS: An institutional database search as well as a literature review was performed for patients presenting with delayed myelopathy after brachial plexus injury. RESULTS: There were 454 adult patients with traumatic brachial plexus injury and spinal cord injury from 1997-2018 identified in the institutional search. Seventy-four (74) patients had delayed presentation of new myelopathic findings on physical examination developed six months or greater after the initial presentation. In these 74 patients with delayed myelopathic symptoms, there were radiologic findings of spinal cord herniation, syringomyelia, superficial siderosis, or pathologic intradural or extradural CSF collections from traumatic dural tears. Each of these pathologies was present in isolation or combination in our patient population. CONCLUSIONS: Four overlapping etiologies appear to compose the primary foundation for delayed spinal cord dysfunction after brachial plexus injury. This paper highlights this continuum by institutional case examples and literature review. PMID- 30471443 TI - Unruptured intracranial aneurysms: Who to treat? PMID- 30471444 TI - The impact of unmet communication and education needs on neurosurgical patient and caregiver experiences of care: A qualitative exploratory analysis. AB - OBJECTIVE: To describe neurosurgical patient and caregiver perceptions of provider communication, the impact of patient education, and their understanding of information given to them throughout the neurosurgical care trajectory. METHODS: We organized focus groups comprised of patients and caregivers who had been hospitalized on the neurosurgical service at five urban academic tertiary referral hospitals within a large university health system. During focus groups, we used semi-structured questions to answer the study questions. Content analysis was used to analyze the data. RESULTS: Forty-three patients and caregivers took part in five focus groups. In total we identified 12 coding categories (or topics) that were associated with patient and family information needs. Despite the fact all patients were receiving care within the same health system, often with the same care team and clinical environments, their experiences often could not have been more different. We found stark variation in how patients and caregivers described the quality of communication and patient education they received which impacted on their satisfaction. Satisfied patients and caregivers generally felt well informed and reported good understanding of the clinical care plan throughout the perioperative course, while dissatisfied patients struggled with unanswered questions, unmet information needs and a sense of confusion throughout their care experience. CONCLUSIONS: Our study describes several unmet needs, finds inconsistencies in how information is delivered and a lack of patient-and-caregiver-centered approaches to communication. Neurosurgery groups should identify unmet needs at their institution and implement strategies and interventions to improve the patient and caregiver experience. PMID- 30471445 TI - Multiple intracranial meningiomas: a case series and review of the literature. AB - OBJECTIVE: Review the data published on the subject to create a more comprehensive natural history of multiple meningiomas (MM). METHODS: a review of the MM published in the literature up to now was carried out through a Medline search up to August 2018. The use of the "multiple meningiomas" keyword returned 278 papers; and the parameters analyzed in our present cohort were searched on those publications. Papers without: detailed description of clinical findings, neuroimaging confirmation of tumor multiplicity, follow-up at least of 5 years; and clear description of clinical finding were excluded. Added our sample in this analyzes. Our series was added in this review. RESULTS: 293 patients with MM were analyzed, 220 females, and 73 males, with a total of 932 tumors (3.1 tumors per patient). The majority of tumors were located in the convexity (653 - 74.5%). The total number of tumors treated was 429 (43.9%): 338 (78.8%) by surgical resection and 91 (21.2%) by radiotherapy. Histopathological description was available in 303 cases out of 429, being grade I in 272 (90.3%) cases, with predominance of meningothelial subtype (30.7%). Tumor recurrence were described in 32 (8.07%) among 397 and only 10 deaths (3.4%) out of 281 reported cases, where this parameter was evaluated. CONCLUSION: WHO grade I predominance was observed among multiple meningiomas in similarity to single meningiomas. Only a fraction of MMs patients (43.89%) needed treatment. A benign tumor behavior was corroborated by with the observed low frequency of recurrence and mortality. PMID- 30471446 TI - Closed Loop Neuromodulation: Listen to the Body. PMID- 30471447 TI - Spinal Cord Injury from Spinal Tumors: Prevalence, Management, and Outcomes. PMID- 30471448 TI - Tracheostomy as a risk factor for paroxysmal sympathetic hyperactivity in severe traumatic brain injury. AB - BACKGROUND: Paroxysmal sympathetic hyperactivity (PSH) is an uncommon complication of severe traumatic brain injury (sTBI). Clinical risk factors for PSH have not been fully characterized, especially on tracheostomy which is usually recommended for patients with sTBI to facilitate the treatment. PURPOSE: We aimed to examine the effect of tracheostomy on PSH incidence in sTBI. METHODS: This single-centered, retrospective study was conducted based on consecutive patients with sTBI admitted to the Shanghai Changzheng Hospital from January 1, 2013 to March 31, 2018. Potential risk factors related to the occurrence of PSH was explored by univariate analysis. Multivariate logistic regression analysis was conducted to determine the independence associated with PSH development. RESULTS: A total of 17 patients with PSH was identified among 120 patients with sTBI (14.16%). Three risk factors were found to be significantly associated with PSH by univariate and multivariate analysis: 1) tracheostomy [odds ratio (OR), 5.368; 95% confidence interval (CI), 1.102-26.151; P=0.038]; 2) Age (OR, 0.916; 95%CI, 0.874-0.960; P<0.001); 3) hydrocephalus (OR, 6.715; 95%CI, 1.708-26.408; P=0.006). CONCLUSIONS: Our results suggested that tracheostomy was independently associated with an increased incidence of PSH. PMID- 30471450 TI - Memantine: From Alzheimer Disease to Traumatic Brain Injury. PMID- 30471449 TI - Partial vertebrectomies without instrumented stabilization during en bloc resection of primary bronchogenic carcinomas invading the spine: feasibility study and results on spine balance. AB - OBJECTIVE: It is unknown if spinal instrumentation is required to prevent deformity after partial vertebrectomy in the treatment of primary bronchogenic carcinomas invading the spine (PBCIS). In this study, we focus on the postoperative spine deformity in patients operated for partial vertebrectomies without instrumentation during en bloc PBCIS resection. Our objective was to determine if deformity depends on the type of vertebral resection and if any vertebral resection threshold can be observed to justify additional spinal instrumentation. METHODS: This is a retrospective study, including all patients with PBCIS operated without spinal instrumentation from 2009 to 2018. Partial vertebrectomies were classified into categories A, B and C depending on vertebral resection. Patients had a long-term radiological follow-up assessing the spine deformity evolution. RESULTS: Eighteen patients were included. The median follow up was 27 months. Four patients underwent a secondary posterior instrumentation surgical procedure due to progressive spinal deformity. A low-risk group of deformation was characterized as type A resection and type B resection on less than three vertebrae. CONCLUSION: There are no validated criteria to justify a systematic spinal instrumentation when performing a partial vertebrectomy during en bloc resection of PBCIS. Performed alone without spine instrumentation, both type A and type B resections on less than three resected vertebrae were not subject to sagittal and coronal deformity even after a long follow-up, emphasizing that a systematic stabilization is not needed in this low-risk group. These results could help to reduce the perioperative morbidity of these procedures that are usually long and complex. PMID- 30471451 TI - Lysophospholipids induce fibrillation of the repeat domain of Pmel17 through intermediate core-shell structures. AB - Lipids often play an important role in the initial steps of fibrillation. The melanosomal protein Pmel17 forms amyloid in vivo and contains a highly amyloidogenic Repeat domain (RPT), important for melanin biosynthesis. RPT fibrillation is influenced by two lysolipids, the anionic lysophosphatidylglycerol (LPG) and zwitterionic lysophosphatidylcholine (LPC), both present in vivo at elevated concentrations in melanosomes, organelles in which Pmel17 aggregate. Here we investigate the interaction of RPT with both LPG and LPC using small-angle X-ray scattering (SAXS), isothermal titration calorimetry (ITC), electron microscopy, fluorescence and circular dichroism (CD) spectroscopy. Under non-shaking conditions, both lipids promote fibrillation but this is driven by different interactions with RPT. Each RPT binds >40 LPG molecules but only weak interactions are seen with LPC. Above LPG's criticial micelle concentration (cmc), LPG and RPT form connected micelles where RPT binds to the surface as beads on a string with core-shell structures. Binding to LPG only induces alpha-helical structure well above the cmc, while LPC has no measurable effect on the protein structure. While low (but still super-cmc) concentrations of LPG strongly promote aggregation, at higher LPG concentrations (10 mM), only ~ one RPT binds per micelle, inhibiting amyloid formation. ITC and SAXS reveal some interactions between the zwitterionic lipid LPC and RPT below the cmc but little above the cmc. Nevertheless, LPC only promotes aggregation above the cmc and this process is not inhibited by high LPC concentrations, suggesting that monomers and micelles cooperate to influence amyloid formation. PMID- 30471452 TI - Distortions of perceived volume and length of body parts. AB - We experience our body as a 3D, volumetric object in the world. Measures of our conscious body image, in contrast, have investigated the perception of body size along one or two dimensions at a time. There is, thus, a discrepancy between existing methods for measuring body image and our subjective experience of having 3D body. Here we assessed in a sample of healthy adults the perception of body size in terms of its 1D length and 3D volume. Participants were randomly assigned to two groups using different measuring units (other body part and non-body object). They estimated how many units would fit in a perceived size of body segments and the whole body. The patterns of length and volume misperception across judged segments were determined as their perceived size proportional to their actual size. The pattern of volume misperception paints the representation of 3D body proportions resembling those of a somatosensory homunculus. The body parts with a smaller actual surface area relative to their volume were underestimated more. There was a tendency for body parts underestimated in volume to be overestimated in length. Perceived body proportions thus changed as a function of judgement type while showing a similarity in magnitude of the absolute estimation error, be it an underestimation of volume or overestimation of length. The main contribution of this study is assessing the body image as a 3D body representation, and thus extending beyond the conventional 'allocentric' focus to include the body on the inside. Our findings highlight the value of studying the perceptual distortions "at the baseline", i.e., in healthy population, so as to advance the understanding of the nature of perceptual distortions in clinical conditions. PMID- 30471453 TI - Porcine endemic diarrhea virus infection regulates long noncoding RNA expression. AB - Long noncoding RNAs (lncRNAs) have been implicated in various life processes. However, the lncRNA expression and potential functions in porcine endemic diarrhea virus (PEDV) infection and host defense are still poorly understood. In this study, we investigated the lncRNA expression profiles during PEDV infection in intestinal porcine epithelial cell-jejunum 2 (IPEC-J2) cell lines by next generation sequencing and identified 6188 novel lncRNAs. The functional annotation analysis revealed that these lncRNAs might be associated with many immunity-related genes. We next selected candidate lncRNAs related to immune response pathways and further identified their differential expression in PEDV infected IPEC-J2 cells and newborn piglets. Our results demonstrated that PEDV infection regulated lncRNA expression patterns in both the IPEC-J2 cell line and piglet ileum. These findings provide the first large-scale survey of lncRNAs associated with PEDV infection, specifically the lncRNAs responsible for the activation of the immune system within the ileum. PMID- 30471454 TI - Association Between Black Race and Presentation and Liver-related Outcomes of Patients With Autoimmune Hepatitis. AB - INTRODUCTION: & Aims: Small studies have found that black patient with autoimmune hepatitis (AIH) patients present with more aggressive disease. We aimed to characterize the presentation and outcome in black and white patients with AIH. METHODS: We performed a retrospective study, collecting information from databases of patients with AIH attending the Institute of Liver studies at King's College Hospital, London (1971-October 2015, the Royal Free Hospital, London (1982 through December 2016) and the multicenter Dutch Autoimmune Hepatitis Study Group cohort (2006-August 2016). We identified 88 black patients with AIH and we compared their clinical characteristics and outcomes to 897 white patients with AIH. RESULTS: Black patients presented at a younger age (median 38 years vs 45 years) (P=.007), had higher IgG levels (mean 31.0 mg/dL vs 27.5 mg/dL) (P=.04), but there were no significant differences between groups in auto-antibody profiles, international AIH Group scores, or sex distribution of disease. A higher proportion of black patients had systemic lupus erythematosus (10%) than white patients (2%) (P=<.001). There was no significant difference in proportions of patients with a response to standard therapy (86% for black patients vs 91% for white patients; P=.20) or in rate of relapse (57% vs 50%; P=.3). Despite this, black patients had an increased risk of liver transplantation and liver related death (hazard ratio 2.4, 95% CI, 1.4-4.0; P<.001). Overall mortality was similar between the two groups. CONCLUSION: In a comparison of black and white patients with AIH in Europe, we found that black patients present at a younger age, have higher levels of IgG levels, and a greater proportion have SLE. We also found black patients to have a greater risk of liver transplantation and liver related mortality, indicating more aggressive disease. PMID- 30471455 TI - Differences in Outcomes Reported by Patients With Inflammatory Bowel Diseases vs Their Health Care Professionals. AB - BACKGROUND & AIMS: Inflammatory bowel disease (IBD) scoring systems combine patient-reported data with physicians' observations to determine patient outcomes, but these systems are believed to have limitations. We used real-world data from a large IBD cohort in Switzerland to compare results between patients and healthcare professionals' from scoring systems for Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We collected data from the Swiss IBD cohort, beginning in 2006, using 2453 reports for 1385 patients (52% female, 58% with CD). During office visits, physicians asked patients about signs and symptoms and recorded their answers (health care professional-reported outcomes). On a later date, patients received a questionnaire at home (independently of the medical visit), complete it, and sent it back to the data center. Patients also completed the short form 36 and IBD quality of life (QoL) questionnaires. We calculated Cohen's kappa (kappa) statistics to assess the level of agreement in scores between patients and health care professionals (Deltat between reports collected less than 2 months apart). We used Spearman correlation coefficients (r) to compare general well-being (GWB) and QoL scores determined by patients vs health care professionals. Our primary aim was to investigate the overall and individual level of agreement on signs and symptoms reported by health care professionals vs patients. RESULTS: The best level of agreement (although moderate) was observed for number of stools last week in patients with CD (kappa=0.47), and nocturnal diarrhea in patients with UC (kappa=0.52). Agreement was low on level of abdominal pain (kappa=0.31 for patients with CD and kappa=0.37 for patients with UC) and GWB (kappa=0.23 for patients with CD and kappa=0.26 for patients with UC). Patients reported less severe abdominal pain and worse GWB (CD) or better GWB (UC) than that determined by health care professionals. Patient self-rated GWB correlated with IBD quality of life (r=0.68 for patients with CD and r=0.70 for patients with UC) and SF-36 physical scores (r=0.55 for patients with CD and r=0.60 for patients with UC); there was no correlation between health care professional-rated GWB and QoL. CONCLUSION: In a comparison of patient vs health care provider-reported outcomes in a Swiss IBD cohort, we found that health care professionals seem to misinterpret patients' complaints. Patients self-rated GWB correlated with QoL scores, indicating that reporting GWB in a single question is possible and relevant, but can vary based on how the data are collected. PMID- 30471456 TI - Histologic Analysis of Endoscopic Ultrasound-guided Through the Needle Microforceps Biopsies Accurately Identifies Mucinous Pancreas Cysts. AB - BACKGROUND & AIMS: It is a challenge to accurately assess pancreatic cystic lesions (PCLs) and determine their risk. We compared the yield of tissue acquired with endoscopic ultrasound (EUS)-guided microforceps (through the needle tissue biopsy, or TTNB) with that of samples collected by EUS-guided fine-needle aspiration (EUS-FNA), and the accuracy of analyses of each sample type in the diagnosis of mucinous PCLs. METHODS: We performed a prospective open-label study of 114 consecutive adults (56.1% women; mean age, 64.2 years) undergoing EUS-FNA evaluation of PCLs (mean size, 35 mm) at 7 centers, from June 20, 2016 through August 31, 2018. Samples were collected from each cyst by FNA and microforceps; samples collected by FNA were analyzed by cytology and samples collected by TTNB were analyzed by histology. Acquisition yield was defined as percentage of specimens collected that were adequate for cytologic or histologic analysis. Diagnoses of mucinous cysts were made based on identification of pancreatic mucinous epithelium by cytology analysis of FNA samples or histologic analysis of TTNB samples. Surgical specimens were used as reference standard when available. RESULTS: The EUS-guided microforceps were successfully inserted into 97.4% (111/114) of PCLs. Tissue acquisition yield was significantly higher with TTNB (95/114; 83.3%) than FNA (43/114; 37.7%) (P<.001). Sixty-one PCLs were determined to be mucinous based on TTNB analysis (53.5%) vs 11 with FNA analysis (9.6%) (P<.001). Among PCLs categorized as equivocal, based on level of carcinoembryonic antigen, TTNB analysis found 50% (41/82) to be mucinous and FNA analysis found 8.5% (7/82) to be mucinous (P<.001). Findings from analyses of samples collected by TTNB were 100% concordant with findings from histologic analysis of surgical specimens (14/14), whereas only 3/14 findings from analysis of samples collected by FNA were in agreement with findings from surgical specimens (21.4%) (P<.001). Four of 5 mucinous PCLs with advanced neoplasia (80%) were detected with TTNB compared to none with FNA (P=.04). Self-limited intra-cystic bleeding occurred in 7 patients (6.1%) and acute pancreatitis in 6 patients (5.3%). CONCLUSION: In a multicenter prospective study of patients undergoing EUS-FNA for evaluation of PCLs, we found TTNB collection of tissues for histologic analysis to be safe and feasible, with an acquisition yield of 83.3%. Histologic analysis of samples collected by TTNB identified a larger proportion of mucinous PCLs compared to cytologic analysis of samples collected by FNA-even among samples categorized as equivocal, based on level of carcinoembryonic antigen. More samples collected by TTNB than FNA were found to have advanced neoplasia. Clinicaltrials.gov no: NCT02979509. PMID- 30471458 TI - Accuracy of Non-invasive Scoring Systems in Assessing Risk of Death and Liver related Endpoints in Patients With Non-alcoholic Fatty Liver Disease. AB - BACKGROUND AND AIMS: Several non-invasive scoring systems have been developed to determine risk of advanced fibrosis in non-alcoholic fatty liver disease (NAFLD). We examined the association between 4 scoring systems and incident severe liver disease and overall mortality in a large cohort of patients with biopsy-proven NAFLD. METHODS: We performed a retrospective analysis of data from 646 patients with biopsy-proven NAFLD, recruited from 2 hospitals in Sweden, from 1971 through 2009. The NAFLD fibrosis score (NFS), FIB-4, APRI, and BARD scores were calculated at the time of the liver biopsy. Based on each score, patients were assigned to categories of low, intermediate, or high risk for advanced fibrosis. Overall mortality and severe liver disease (cirrhosis, decompensated liver disease, liver failure, or hepatocellular carcinoma) were ascertained through linkage with national registers until the end of 2014. Cox regression, area under the receiver operating characteristic (AUROC) curve, and C-statistic analyses were used to study the predictive capacity of each scoring system. RESULTS: During a mean follow-up time of 19.9+/-8.7 years, there were 214 deaths and 76 cases of severe liver disease. For overall mortality, AUROC curve values were: NFS, 0.72 (95% CI, 0.68-0.76); FIB-4, 0.72 (95% CI, 0.68-0.76); BARD, 0.62 (95% CI, 0.58-0.66); and APRI, 0.52 (95% CI, 0.47-0.57). For severe liver disease, AUROC curve values were: NFS, 0.72 (95% CI, 0.66-0.78); FIB-4, 0.72 (95% CI, 0.66 0.79); BARD, 0.62 (95% CI, 0.55-0.69); APRI, 0.69 (95% CI, 0.63-0.76). C statistics for all scores were of moderate capacity to predict outcomes. CONCLUSIONS: In a retrospective analysis of data from 646 patients with biopsy proven NAFLD, we found the NFS and the FIB-4 scores to most accurately determine risk of overall death or severe liver disease. However, the AUROC values for these scoring systems are not high enough for use in the clinic; new systems are needed to determine prognoses of patients with NAFLD. PMID- 30471457 TI - Low Frequency of Lymph Node Metastases in Patients in the United States With Early-stage Gastric Cancers That Fulfill Japanese Endoscopic Resection Criteria. AB - BACKGROUND & AIMS: In the West, early gastric cancer is increasingly managed with endoscopic resection (ER). This is, however, based on the assumption that the low prevalence and risk of lymph node metastases observed in Asian patients is applicable to patients in the United States. We sought to evaluate the frequency of and factors associated with metastasis of early gastric cancers to lymph nodes, and whether the Japanese ER criteria are applicable to patients in the US. METHODS: We performed a retrospective study of 176 patients (mean age 68.5 years; 59.1% male; 58.5% Caucasian) who underwent surgical resection with lymph node dissection of T1 and Tis gastric adenocarcinomas, staged by pathologists, at 7 tertiary care centers in the US from January 1, 1999 through December 31, 2016. The frequency of lymph node metastases and associated risk factors were determined. RESULTS: The mean size of gastric adenocarcinomas was 23.0+/-16.6 mm most were located in the lower-third of the stomach (67.0%), invading the submucosa (55.1%), and moderately differentiated (31.3%). Lymphovascular invasion was observed in 18.2% of lesions. Overall, 20.5% of patients had lymph node metastases. Submucosal invasion (odds ratio, 3.9; 95% CI 1.4-10.7) and lymphovascular invasion (odds ratio, 4.6; 95% CI, 1.8-12.0) were independently associated with increased risk of metastasis to lymph nodes. The frequency of lymph node metastases among patients fulfilling standard and expanded Japanese criteria for ER were 0 and 7.5%, respectively. CONCLUSION: The frequency of lymph node metastases among patients with early gastric cancer in a US population is higher than that of published Asian series. However, early gastric cancer lesions that meet the Japanese standard criteria for ER are associated with negligible risk of metastasis to lymph nodes, so ER can be recommended for definitive therapy. Expanded criteria cancers appear to have a higher risk of metastasis to lymph nodes, so ER may be considered for select cases. PMID- 30471459 TI - Predictive capacity for mortality and severe liver disease of the relative fat mass algorithm. AB - INTRODUCTION: The relative fat mass (RFM) is a new tool that estimates body fat composition better than body mass index (BMI). However, it is unknown if this new scoring system is better than currently available alternatives to BMI in predicting incident outcomes. METHODS: We used data on 27,617 persons from the Malmo Diet and Cancer cohort. The RFM, BMI and other body composition variables were calculated. Persons were passively followed in national registers for incident cases of severe liver disease (defined as ICD coding for cirrhosis, decompensated cirrhosis, hepatocellular carcinoma and death in liver disease) and overall mortality. Multivariable Cox regression and C-statistics was used to investigate which variables that best associated with relevant outcomes. RESULTS: During a median follow-up of 19.8 years, 8,074 persons died and 508 persons developed severe liver disease. Based on hazard ratios and C-statistics, the RFM was slightly better than BMI in predicting both mortality and severe liver disease, but measures taking abdominal adiposity into account, including waist circumference performed even better. CONCLUSIONS: The RFM outperformed BMI in predicting future mortality and severe liver disease. However, the RFM was not superior compared to currently available body composition measurements in a population-based cohort. PMID- 30471460 TI - Improving post-operative patient reported benefits and satisfaction following spinal fusion with a single pre-operative education session. AB - BACKGROUND CONTEXT: Patient expectations have been demonstrated to influence recovery following spine surgery. Addressing patient expectations specifically in regards to pain and post-surgical healing is an important factor in improving recovery patterns. Pre-surgical education can potentially help manage patient expectations. PURPOSE: The primary objective was to determine if participation in a single preoperative multidisciplinary educational session would result in reduced patient dissatisfaction with surgical expectations. A secondary objective was to determine if participation resulted in improvements in post-surgical pain, disability, and reductions in emergency room visits following surgery. STUDY DESIGN: A retrospective cohort study utilizing data from the Canadian Spine Outcomes and Research Network (CSORN) registry and hospital electronic medical records. PATIENT SAMPLE: Participants were patients receiving elective spinal fusion for 2-5 levels (N = 206). Cohort 1 included patients who participated in preoperative multidisciplinary education (n= 103). Cohort 2 included patients who opted out of the educational session (n= 103). OUTCOME MEASURES: Outcomes measured included the Oswestry Disability Index (ODI), NRS scales for back and leg pain (NRS-B/NRS-L), CSORN questions pertaining to patient satisfaction with surgery and whether or not the surgery met expectations. Electronic chart review quantified emergency room visits following surgery. METHODS: Spinal fusion patients are encouraged to attend a one time, two-hour education session 3-6 weeks prior to their surgery. The education session includes interactive discussions with nursing, physiotherapy and occupational therapy staff concentrating on what patients should expect, how to best prepare for surgery and proper care post-surgery. A one-way ANOVA was conducted for continuous variables of interest (age, number of levels operated on, ASA score and number of visits to the emergency room following surgery). Chi-squared analysis was conducted for categorical variables of interest (pathology, gender, patient satisfaction, and patient expectations). A 2 (Cohort; education: no education) x 2 (Time; baseline: follow-up) repeated measure ANOVA was conducted for NRS-B, NRS-L, and ODI. Significance was set at p<0.05. RESULTS: Patients (n=103) who took part in the pre-surgical education sessions were significantly more satisfied with their surgery compared to the control cohort (p = 0.014). Patients (n=103) who did not participate in the education session failed to have their expectations met in terms of improvement in daily activities (p = 0.03), improvement in walking capacity (p = 0.03) and their expectation of back pain reduction (p = .001). There was a statistically significant effect of participation in the educational session reducing postoperative back pain (p = 0.03), although this improvement did not reach a minimally clinically important difference. Number of visits to the emergency room in the 12 weeks following spine surgery was significantly lower (p = 0.04) for patients in the education cohort. CONCLUSIONS: Reduced emergency room utilization, improved patient satisfaction, achievement of expected improvements and alleviation of back pain were documented with greater success following participation in a single 2-hour educational session prior to surgery. A single education session is a viable tool for improving patient outcomes due to its low administrative burden. PMID- 30471461 TI - Domain-specific classification-pretrained fully convolutional network encoders for skin lesion segmentation. AB - BACKGROUND AND OBJECTIVE: Fully convolutional neural networks have been shown to perform well for automated skin lesion segmentation on digital dermatoscopic images. Our concept is that transferring encoder weights from a network trained on a classification task on images of the same domain may contain useful information for segmentation. METHODS: We trained a fully convolutional network where ResNet34 layers are reused as encoding layers of a U-Net style architecture. We entered the encoding layers i) with He uniform ("random") initialization, ii) pretrained ImageNet weights, or iii) after fine-tuning ResNet34 for skin lesion classification. After transferring the layers to the fully convolutional network architecture we trained for a binary segmentation task using official ISIC 2017 challenge data. RESULTS: Pretraining of ResNet34 layers with either ImageNet or fine-tuning for skin lesion classification achieved a higher Jaccard than random initialization (0.763 and 0.768 vs 0.740) on the ISIC 2017 test-set. This improved performance warrants further exploration on how to implement cross-task learning for skin lesion segmentation. In additional experiments we found that post-processing with fully connected conditional random fields consistently decreased Jaccard on ISIC 2017 test-set images despite reasonable visual results. Further exploration of the test-set revealed that conditional random field - post-processing decreased segmentation performance only if ground truth annotations consisted of simple shapes but increased it if shapes were complex. CONCLUSIONS: Our findings suggest that domain specific pretraining of encoders can be helpful when there are only few ground truth masks available for segmentation training, but may not be of additional benefit to ImageNet pretraining given enough segmentation training data. Complexity of ground truth annotations have a large impact on segmentation metrics and should be taken into account in skin lesion segmentation research. PMID- 30471462 TI - Supervised learning for bone shape and cortical thickness estimation from CT images for finite element analysis. AB - Knowledge about the thickness of the cortical bone is of high interest for fracture risk assessment. Most finite element model solutions overlook this information because of the coarse resolution of the CT images. To circumvent this limitation, a three-steps approach is proposed. 1) Two initial surface meshes approximating the outer and inner cortical surfaces are generated via a shape regression based on morphometric features and statistical shape model parameters. 2) The meshes are then corrected locally using a supervised learning model build from image features extracted from pairs of QCT (0.3-1 mm resolution) and HRpQCT images (82 um resolution). As the resulting meshes better follow the cortical surfaces, the cortical thickness can be estimated at sub-voxel precision. 3) The meshes are finally regularized by a Gaussian process model featuring a two-kernel model, which seamlessly enables smoothness and shape-awareness priors during regularization. The resulting meshes yield high-quality mesh element properties, suitable for construction of tetrahedral meshes and finite element simulations. This pipeline was applied to 36 pairs of proximal femurs (17 males, 19 females, 76 +/- 12 years) scanned under QCT and HRpQCT modalities. On a set of leave-one out experiments, we quantified accuracy (root mean square error = 0.36 +/- 0.29 mm) and robustness (Hausdorff distance = 3.90 +/- 1.57 mm) of the outer surface meshes. The error in the estimated cortical thickness (0.05 +/- 0.40 mm), and the tetrahedral mesh quality (aspect ratio = 1.4 +/- 0.02) are also reported. The proposed pipeline produces finite element meshes with patient-specific bone shape and sub-voxel cortical thickness directly from CT scans. It also ensures that the nodes and elements numbering remains consistent and independent of the morphology, which is a distinct advantage in population studies. PMID- 30471463 TI - Reproducibility and intercorrelation of graph theoretical measures in structural brain connectivity networks. AB - Diffusion-weighted magnetic resonance imaging can be used to non-invasively probe the brain microstructure. In addition, recent advances have enabled the identification of complex fiber configurations present in most of the white matter. This has improved the investigation of structural connectivity with tractography methods. Whole-brain structural connectivity networks, or connectomes, are reconstructed by parcellating the gray matter and performing tractography to determine connectivity between these regions. These complex networks can be analyzed with graph theoretical methods, which measure their global and local properties. However, as these tools have only recently been applied to structural brain networks, there is little information about the reproducibility and intercorrelation of network properties, connectivity weights and fiber tractography reconstruction parameters in the brain. We studied the reproducibility and correlation in structural brain connectivity networks reconstructed with constrained spherical deconvolution based probabilistic streamlines tractography. Diffusion-weighted data from 19 subjects were acquired with b = 2800 s/mm2 and 75 gradient orientations. Intrasubject variability was computed with residual bootstrapping. Our findings indicate that the reproducibility of graph theoretical metrics is generally excellent with the exception of betweenness centrality. A reconstruction density of approximately one million streamlines is necessary for excellent reproducibility, but the reproducibility increases further with higher densities. The reproducibility decreases, but only slightly, when switching to a higher order in constrained spherical deconvolution. Moreover, in binary networks, using sufficiently high threshold values improves the reproducibility. We show that multiple network properties and connectivity weights are highly intercorrelated. The experiments were replicated by using a test-retest dataset of 44 healthy subjects provided by the Human Connectome Project. In conclusion, our results provide guidelines for reproducible investigation of structural brain networks. PMID- 30471464 TI - Motion artifact recognition and quantification in coronary CT angiography using convolutional neural networks. AB - Excellent image quality is a primary prerequisite for diagnostic non-invasive coronary CT angiography. Artifacts due to cardiac motion may interfere with detection and diagnosis of coronary artery disease and render subsequent treatment decisions more difficult. We propose deep-learning-based measures for coronary motion artifact recognition and quantification in order to assess the diagnostic reliability and image quality of coronary CT angiography images. More specifically, the application, steering and evaluation of motion compensation algorithms can be triggered by these measures. A Coronary Motion Forward Artifact model for CT data (CoMoFACT) is developed and applied to clinical cases with excellent image quality to introduce motion artifacts using simulated motion vector fields. The data required for supervised learning is generated by the CoMoFACT from 17 prospectively ECG-triggered clinical cases with controlled motion levels on a scale of 0-10. Convolutional neural networks achieve an accuracy of 93.3% +/- 1.8% for the classification task of separating motion-free from motion-perturbed coronary cross-sectional image patches. The target motion level is predicted by a corresponding regression network with a mean absolute error of 1.12 +/- 0.07. Transferability and generalization capabilities are demonstrated by motion artifact measurements on eight additional CCTA cases with real motion artifacts. PMID- 30471465 TI - The status of MAPK cascades contributes to the induction and activation of Gata4 and Nkx2.5 during the stepwise process of cardiac differentiation. AB - Cardiac differentiation in vitro is a complex, stepwise process that is rigidly governed by a subset of transcription factors and signaling cascades. In this study, we investigated the cooperation of cardiac-specific transcription factors Gata4 and Nkx2.5, as well as mitogen-activated protein kinase (MAPK) cascades. P19 embryonic carcinoma cells were induced into spontaneously beating cardiomyocytes utilizing a two-step protocol that comprised an early stage and a late stage of differentiation. During early-stage differentiation in suspension culture, P19 cells aggregated to form embryoid bodies (EBs), and the Gata4 and Nkx2.5 genes were induced. However, Gata4 expressed at the early stage of differentiation was incapable of activating downstream gene expression, as it was localized in the cytoplasm and prone to degradation. After EBs were plated for late-stage differentiation in adherent culture, the MAPK cascades were highly activated and contributed to the activation of Gata4 and Nkx2.5. Specifically, we revealed that p38 signaling participated in regulating the localization and stabilization of Gata4 and Nkx2.5. Additionally, the JNK cascade regulated late stage cardiac differentiation; JNK kinase reduced Gata4 stabilization and conversely alleviated Nkx2.5 degradation by direct interaction and phosphorylation of Nkx2.5. Finally, we found that the C-terminal domain of Nkx2.5 was required for its stabilization under conditions of oxidative stress and JNK activation. Overall, our results indicated that the induction and activation of Gata4 and Nkx2.5 during early- and late-stage cardiac differentiation was closely associated with the function of the MAPK signaling cascades. PMID- 30471466 TI - NanoBRET ligand binding at a GPCR under endogenous promotion facilitated by CRISPR/Cas9 genome editing. AB - Bioluminescence resonance energy transfer (BRET) is a versatile tool used to investigate membrane receptor signalling and function. We have recently developed a homogenous NanoBRET ligand binding assay to monitor interactions between G protein-coupled receptors and fluorescent ligands. However, this assay requires the exogenous expression of a receptor fused to the nanoluciferase (Nluc) and is thus not applicable to natively-expressed receptors. To overcome this limitation in HEK293 cells, we have utilised CRISPR/Cas9 genome engineering to insert Nluc in-frame with the endogenous ADORA2B locus this resulted in HEK293 cells expressing adenosine A2B receptors under endogenous promotion tagged on their N terminus with Nluc. As expected, we found relatively low levels of endogenous (gene-edited) Nluc/A2B receptor expression compared to cells transiently transfected with expression vectors coding for Nluc/A2B. However, in cells expressing gene-edited Nluc/A2B receptors we observed clear saturable ligand binding of a non-specific fluorescent adenosine receptor antagonist XAC-X-BY630 (Kd = 21.4 nM). Additionally, at gene-edited Nluc/A2B receptors we derived pharmacological parameters of ligand binding; Kd as well as Kon and Koff for binding of XAC-X-BY630 by NanoBRET association kinetic binding assays. Lastly, cells expressing gene-edited Nluc/A2B were used to determine the pKi of unlabelled adenosine receptor ligands in competition ligand binding assays. Utilising CRISPR/Cas9 genome engineering here we show that NanoBRET ligand binding assays can be performed at gene-edited receptors under endogenous promotion in live cells, therefore overcoming a fundamental limitation of NanoBRET ligand assays. PMID- 30471467 TI - Visualization of the electrical activity of the cauda equina using a magnetospinography system in healthy subjects. AB - OBJECTIVE: To establish a method to measure cauda equina action fields (CEAFs) and visualize the electrical activities of the cauda equina in a broadly aged group of healthy adults. METHODS: Using a 124-channel magnetospinography (MSG) system with superconducting interference devices, the CEAFs of 43 healthy volunteers (22-64 years of age) were measured after stimulation of the peroneal nerve at the knee. Reconstructed currents were obtained from the CEAFs and superimposed on the X-ray image. Conduction velocities were also calculated from the waveform of the reconstructed currents. RESULTS: The reconstructed currents were successfully visualized. They flowed into the L5/S1 foramen about 8.25-8.95 ms after the stimulation and propagated cranially along the spinal canal. In 32 subjects (74%), the conduction velocities of the reconstructed currents in the cauda equina could be calculated from the peak latency at the L2-L5 level. CONCLUSIONS: MSG visualized the electrical activity of the cauda equina after peroneal nerve stimulation in healthy adults. In addition, the conduction velocities of the reconstructed currents in the cauda equina could be calculated, despite previously being difficult to measure. SIGNIFICANCE: MSG has the potential to be a novel and noninvasive functional examination for lumbar spinal disease. PMID- 30471468 TI - Fibromyalgia: Increased reactivity of the muscle membrane and a role of central regulation. AB - OBJECTIVE: Fibromyalgia (FM) is characterized by widespread muscle pain and central neural deregulation. Previous studies showed increased muscle fiber conduction velocity (CV) in non-painful muscles of FM patients. This study investigates the relationship between central activation and the CV in FM. METHODS: Twenty-two females with primary FM and 21 controls underwent surface electromyography of the non-painful biceps brachii. Mean CVs were calculated from the motor unit potential velocities (CV-MUPs), and the CV-MUPs' statistical distributions were presented as histograms. The amount of muscle activity (average rectified voltage, ARV) was measured. RESULTS: The CV was higher in the FM-group than in the controls (P = 0.021), with CV-MUPs generally shifted to higher values, indicative of increased muscle membrane propagation speeds. The largest increase in the CV of the FM-group occurred when adopting and maintaining a limb position at only 5% of maximum strength (P < 0.001); the CV did not, as normal, increase with greater force. However, the ARV in both groups similarly increased with force. CONCLUSIONS: In fibromyalgia patients, the muscle membrane propagation speed increases independently of the force load or amount of muscle activity produced. When adopting a limb position, the patients show an augmented muscle membrane reaction, suggesting deregulation from higher neural centers. SIGNIFICANCE: These findings contribute to understanding fibromyalgia. PMID- 30471469 TI - Effect of aging on bioaccessibility of DDTs and PCBs in marine sediment. AB - Hydrophobic legacy contaminants like dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs) were banned almost half a century ago. While their residues still remain in many environmental compartments, they have undergone extensive aging and likely have lower bioaccessibility (the available fraction) compared to fresh residues. However, risk assessment relies heavily on the use of total chemical concentration, rather than accounting for age diminished bioaccessibility, likely leading to overestimated risks. In this study, we used 24 h Tenax desorption to measure the potential bioaccessibility of DDTs and PCBs in two sediment cores taken from the Palos Verdes Shelf Superfund site in the Pacific Ocean. The total concentrations of DDTs and PCBs from the core located at the sewage outfall (8C) were as high as 41,000-15,700 MUg/kg (dry weight, dw) and 530-2600 MUg/kg dw, respectively, while those from a location 7 km northeast of the outfall (3C) were 2-3 orders of magnitude lower. Bioaccessibility estimated by 24-h Tenax-aided desorption (F24h) decreased in the order of DDD > DDE > DDT for DDT derivatives, and PCB 52 > PCB 70 > PCB 153 for PCB congeners, showing a negative correlation with their log Kow. Due to the extensive aging, F24h values were <20% of the total chemical concentration for most contaminants and <5% for DDT, DDE and PCB 153, suggesting that aging greatly diminished their bioavailability. However, a quantitative relationship between F24h and sediment age along the vertical profile was not found, likely because the contaminant residues had undergone aging before their offsite transport and deposition onto the ocean floor. As the use of man-made chemicals such as DDT and PCBs was discontinued in the U.S. many decades ago, the reduction in their bioavailability due to aging may be universal and should be taken into consideration to avoid overly conservative risk predictions or unnecessary mitigation interventions. PMID- 30471470 TI - Intentional binding coincides with explicit sense of agency. AB - Sense of agency, a feeling of generating actions and events by oneself, stems from action-outcome congruence. An implicit marker of sense of agency is intentional binding, which is compression of subjective temporal interval between action and outcome. We investigated relationships between intentional binding and explicit sense of agency. Participants pressed a key triggering auditory (Experiment 1) or visual outcome (Experiment 2) that occurred after variable delays. In each trial, participants rated their agency over the outcome and estimated the keypress-outcome temporal interval. Results showed that delays decreased agency ratings and intentional binding. There was inter-individual correlation between sensitivities to outcome delay (i.e., regression slope) of agency rating and intentional binding in the auditory but not visual domain. Importantly, we found intra-individual correlations between agency rating and intentional binding on a trial-by-trial basis in both outcome modalities. These results suggest that intentional binding coincides with explicit sense of agency. PMID- 30471471 TI - Dispositional mindfulness attenuates the emotional attentional blink. AB - Emotional stimuli have been shown to automatically hijack attention, hindering the detection of forthcoming targets. Mindfulness is defined as a present moment non-judgemental attentional stance that can be cultivated by meditation practices, but that may present interindividual variability in the general population. The mechanisms underlying modification in emotional reactivity linked to mindfulness are still a matter of debate. In particular, it is not clear whether mindfulness is associated with a diminished emotional response, or with faster recovery. We presented participants with target pictures embedded in a rapid visual presentation stream. The targets could be preceded by negative, neutral or scrambled critical distractors. We showed that dispositional mindfulness, in particular the Non-reacting facet, was related to faster disengagement of attention from emotional stimuli. These results could have implications for mood disorders characterised by an exaggerated attentional bias toward emotional stimuli, such as anxiety and post-traumatic stress disorders. PMID- 30471472 TI - Effectiveness of home based intervention program in reducing mortality of hip fracture patients: A non-randomized controlled trial. AB - PURPOSE: The study was done to investigate whether a postoperative intervention program is effective in reducing mortality and improving mobility in two comparative hip fracture patients over one year postoperatively. METHODS: A non randomized controlled trial study with an intervention group of hip fracture patients and historical control group with 12 months follow up. One hundred twenty four admitted hip fracture patients to the Trauma Unit of Assiut University Hospitals, aged 50 years and older were included from 1st July to 31st December 2014. They were divided into 64 and 60 patients as intervention and control groups respectively. Weight, height and bone mineral density were measured and baseline characteristics were taken. The intervention was a postoperative care program in the form of education sessions with an explanatory leaflet on discharge for nutrition and physical exercise program at home. Follow up phone calls were done at 3 months, 6 months and one year postoperatively by one assessor. Physical mobility was assessed by 24 items Western Ontario And McMaster Universities Osteoarthritis Index (WOMAC). RESULTS: Mortality was significantly higher in the control group, WOMAC score was significantly better among intervention group through follow up. By multivariate Cox survival analysis, advancing age, no intervention, osteoporosis, postoperative complications, chest infections and heart attacks were significant predictors for mortality. CONCLUSION: A significant improvement in mobility and reduction of mortality was achieved by application of a postoperative care program that could be incorporated into the hip fracture patients' care pathway. PMID- 30471473 TI - Enzymatically triggered shape memory polymers. AB - Cytocompatible shape memory polymers activated by thermal or photothermal triggers have been developed and established as powerful "smart material" platforms for both basic and translational research. Shape memory polymers (SMPs) that could be triggered directly by biological activity have not, in contrast, been reported. The goal of this study was to develop an SMP that responds directly to enzymatic activity and can do so under isothermal cell culture conditions. To achieve this goal, we designed an SMP with a shape fixing component, poly(epsilon-caprolactone) (PCL), that is vulnerable to enzymatic degradation and a shape memory component, Pellethane, that is enzymatically stable - as the shape fixing component undergoes enzymatically-catalyzed degradation, the SMP returns to its original, programmed shape. We quantitatively and qualitatively analyzed material properties, shape memory performance, and cytocompatibility of the enzymatically-catalyzed shape memory response. The results demonstrate enzymatic recovery, as contraction of tensile specimens, using bulk enzymatic degradation experiments and show that shape recovery is achieved by degradation of the PCL shape-fixing phase. The results further showed that both the materials and the process of enzymatic shape recovery are cytocompatible. Thus, the SMP design reported here represents both an enzyme responsive material capable of applying a programmed shape change or direct mechanical force and an SMP that could respond directly to biological activity. STATEMENT OF SIGNIFICANCE: Cytocompatible shape memory polymers activated by thermal or photothermal triggers have become powerful "smart material" platforms for basic and translational research. Shape memory polymers that could be triggered directly by biological activity have not, in contrast, been reported. Here we report an enzymatically triggered shape memory polymer that changes its shape isothermally in response to enzymatic activity. We successfully demonstrate enzymatic recovery using bulk enzymatic degradation experiments and show that shape recovery is achieved by degradation of the shape-fixing phase. We further show that both the materials and the process of enzymatic shape recovery are cytocompatible. This new shape memory polymer design can be anticipated to enable new applications in basic and applied materials science as a stimulus responsive material. PMID- 30471474 TI - In vitro and in vivo studies of electroactive reduced graphene oxide-modified nanofiber scaffolds for peripheral nerve regeneration. AB - Graphene, as a promising biomaterial, has received great attention in biomedical fields due to its intriguing properties, especially the conductivity and biocompatibility. Given limited studies on the effects of graphene-based scaffolds on peripheral nerve regeneration in vitro and in vivo under electrical stimulation (ES), the present study was intended to systematically investigate how conductive graphene-based nanofibrous scaffolds regulate Schwann cell (SC) behavior including migration, proliferation and myelination, and PC12 cell differentiation in vitro via ES, and whether these conductive scaffolds could guide SC migration and promote nerve regeneration in vivo. Briefly, the reduced graphene oxide (RGO) was coated onto ApF/PLCL nanofibrous scaffolds via in situ redox reaction of the graphene oxide (GO). In vitro, RGO-coated ApF/PLCL (AP/RGO) scaffolds significantly enhanced SC migration, proliferation, and myelination including myelin-specific gene expression and neurotrophic factor secretion. The conditioned media of SCs cultured on AP/RGO scaffolds under ES could induce the differentiation of PC12 cells in a separate culture. In addition, PC12 cells cultured on the conductive AP/RGO scaffolds also showed elevated differentiation upon ES. In vivo implantation of the conductive AP/RGO nerve guidance conduits into rat sciatic nerve defects exhibited a similar healing capacity to autograft, which is the current gold standard in peripheral nerve regeneration. In view of the performance of AP/RGO scaffolds in modulating cell functions in vitro and promoting nerve regeneration in vivo, it is expected that the graphene-based conductive nanofibrous scaffolds would exhibit their potential in peripheral nerve repair and regeneration. STATEMENT OF SIGNIFICANCE: Despite the demonstrated capability of bridging the distal and proximal peripheral nerves, it remains a significant challenge with current artificial nerve conduits to achieve the desired physiological functions, e.g., the transmission of electrical stimuli. Herein, we explored the possibility of combining the conductive properties of graphene with electrospun nanofiber to create the electroactive biomimetic scaffolds for nerve tissue regeneration. In vitro and in vivo studies were carried out: (1) In vitro, the conductive nanofibrous scaffolds significantly promoted SC migration, proliferation and myelination including myelin specific gene expression and neurotrophicfactor secretion, and induced PC12 cell differentiation with electrical stimulation. (2) In vivo, the conductive nerve guidance conduit exhibited similar effects with the gold standard autograft. In view of the performance of this conductive scaffold in modulating the cell functions in vitro and promoting nerve regeneration in vivo, it is expected that the graphene-modified nanofibrous scaffolds will exhibit their potential in peripheral nerve repair and regeneration. PMID- 30471475 TI - Blood interactions with nano- and microfibers: Recent advances, challenges and applications in nano- and microfibrous hemostatic agents. AB - Nanofibrous materials find a wide range of applications, such as vascular grafts, tissue-engineered scaffolds, or drug delivery systems. This phenomenon can be attributed to almost arbitrary biomaterial modification opportunities created by a multitude of polymers used to form nanofibers, as well as by surface functionalization methods. Among these applications, the hemostatic activity of nanofibrous materials is gaining more and more interest in biomedical research. It is therefore crucial to find both materials and nanofiber structural properties that affect organism responses. The present review critically analyzes the response of blood elements to natural and synthetic polymers, and their blends and composites. Also assessed in this review is the incorporation of pro coagulative substances or drugs that can decrease bleeding time. The review also discusses the main animal models that were used to assess hemostatic agent safety and effectiveness. STATEMENT OF SIGNIFICANCE: The paper contains an in-depth review of the most representative studies recently published in the topic of nanofibrous hemostatic agents. The topic evolved from analysis of pristine polymeric nanofibers to multifunctional biomaterials. Furthermore, this study is important because it helps clarify the use of specific blood-biomaterial analysis techniques with emphasis on protein adsorption, thrombogenicity and blood coagulation. The paper should be of interest to the readers of Acta biomaterialia who are curious about the strategies and materials used for the development of multifunctional polymer nanofibers for novel blood-contacting applications. PMID- 30471476 TI - Enhanced extracellular vesicle production and ethanol-mediated vascularization bioactivity via a 3D-printed scaffold-perfusion bioreactor system. AB - Extracellular vesicles (EVs) have garnered significant interest in the biotechnology field due to their intrinsic therapeutic properties as well as their ability to serve as vehicles for bioactive cargo. However, the lack of an established biomanufacturing platform and limited potency of EVs in vivo remain critical bottlenecks for clinical translation. In this study, we utilized a 3D printed scaffold-perfusion bioreactor system to assess the response of dynamic culture on extracellular vesicle production from endothelial cells (ECs). We also investigated whether ethanol conditioning, which was previously shown to enhance vascularization bioactivity of EC-derived EVs produced in standard 2D culture conditions, could be employed successfully for the same purpose in a 3D production system. Our results indicate that dynamic culture in a perfusion bioreactor significantly enhances EV production from human ECs. Moreover, the use of ethanol conditioning in conjunction with dynamic culture induces pro vascularization bioactivity of EC-derived EVs that is correlated with increased EV levels of pro-angiogenic lncRNAs HOTAIR and MALAT1. Thus, this study represents one of the first reports of rationally-designed EV potency enhancement that is conserved between static 2D and dynamic 3D EV production systems, increasing the potential for scalable biomanufacturing of therapeutic EC-derived EVs for a variety of applications. STATEMENT OF SIGNIFICANCE: Extracellular vesicles (EVs) have substantial therapeutic potential in a variety of applications. However, translation of EV-based therapies may be hindered by biomanufacturing challenges. EV production to date has predominantly involved the use of tissue culture flasks. Here, we report, for the first time, the use of a tubular perfusion bioreactor system with an integrated 3D-printed biomaterial scaffold for EV production from human endothelial cells. This system increases EV yield by over 100-fold compared to conventional tissue culture systems. Further, we show that an ethanol-conditioning approach that our group previously developed in 2D culture for enhancing EV potency is compatible with this new system. Thus, potency enhancement of EVs for vascularization applications is possible even with significantly increased production rate. PMID- 30471477 TI - Gentle cyclic straining of human fibroblasts on electrospun scaffolds enhances their regenerative potential. AB - The extracellular matrix of fascia-like tissues is a resilient network of collagenous fibers that withstand the forces of daily life. When overstretched, the matrix may tear, with serious consequences like pelvic organ prolapse (POP). Synthetic implants can provide mechanical support and evoke a host response that induces new matrix production, thus reinforcing the fascia. However, there is considerable risk of scar formation and tissue contraction which result in severe complications. Matrix producing fibroblasts are both mechanosensitive and contractile; their behavior depends on the implant's surface texture and mechanical straining. Here we investigate the effect of both in a newly-designed experimental setting. Electrospun scaffolds of Nylon and PLGA/PCL and a non porous PLGA/PCL film were clamped like a drumhead and seeded with fibroblasts of POP patients. Upon confluency, scaffolds were cyclically strained for 24 or 72 h at 10% and 0.2 Hz, mimicking gentle breathing. Non-loading condition was control. Strained fibroblasts loosened their actin-fibers, thereby preventing myofibroblastic differentiation. Mechanical loading upregulated genes involved in matrix synthesis (collagen I, III, V and elastin), matrix remodeling (alpha-SMA, TGF-beta1, MMP-2) and inflammation (COX-2, TNF-alpha, IL8, IL1-beta). Collagen genes were expressed earlier under mechanical loading and the ratio of I/III collagen increased. Matrix synthesis and remodeling were stronger on the electrospun scaffolds, while inflammation was more prominent on the non-porous film. Our findings indicate that mechanical straining enhances the regenerative potential of fibroblasts for the regeneration of fascia-type tissues and limit the risk of scar tissue formation. These effects are stronger on an electrospun texture. STATEMENT OF SIGNIFICANCE: Pelvic organ prolapsed is a dysfunctional disease in female pelvic floor that can reduce the quality of life women. Currently, trans-vaginal knitted meshes are used to anatomically correct the dysfunctional tissues. However, the meshes can create sever adverse complications in some patients (e.g. chronic pain) in longer-term. As an alternative, we developed nanofibrous matrices by electrospinning based on different materials. We designed an in-vitro culture system and subjected cell-seeded matrices to cyclic mechanical loading. Results revealed that gentle straining of POP-cells on electrospun matrices, advances their regenerative potential at morphological and gene expression levels. Our findings, provide a proof-of-concept for using electrospun matrices as an alternative implant for pelvic floor repair, given that the parameters are designed efficiently and safely. PMID- 30471478 TI - Blood Coagulation Response and Bacterial Adhesion to Biomimetic Polyurethane Biomaterials Prepared with Surface Texturing and Nitric Oxide Release. AB - A dual functional polyurethane (PU) film that mimics aspects of blood vessel inner surfaces by combining surface texturing and nitric oxide (NO) release was fabricated through a soft lithography two-stage replication process. The fabrication of submicron textures on the polymer surface was followed by solvent impregnation with the NO donor, S-nitroso-N-acetylpenicillamine (SNAP). An in vitro plasma coagulation assay showed that the biomimetic surface significantly increased the plasma coagulation time and also exhibited reduced platelet adhesion and activation, thereby reducing the risk of blood coagulation and thrombosis. A contact activation assay for coagulation factor XII (FXII) demonstrated that both NO release and surface texturing also reduced FXII contact activation, which contributes to the inhibition of plasma coagulation. The biomimetic surface was also evaluated for bacterial adhesion in plasma and results demonstrate that this combined strategy enables a synergistic effect to reduce bacterial adhesion of Staphylococcus epidermidis, Staphylococcus aureus, and Pseudomonas aeruginosa microorganisms. The results strongly suggest that the biomimetic modification with surface texturing and NO release provides an effective approach to improve the biocompatibility of polymeric materials in combating thrombosis and microbial infection. STATEMENT OF SIGNIFICANCE: Developed a dual functional polyurethane (PU) film that mimics blood vessel inner surface by combining surface texturing and nitric oxide (NO) release for combatting biomaterial associated thrombosis and microbial infection. Studied the blood coagulation response and bacterial adhesion to such biomimetic PU surfaces, and demonstrated that the combination of surface texturing and NO release synergistically reduced the platelet adhesion and bacterial adhesion in plasma, providing an effective approach to improve the biocompatibility of biomaterials used in blood-contacting medical devices. The NO releasing surface significantly inhibits the plasma coagulation via the reduction of contact activation of FXII, indicating the multifunctional roles of NO in improving the biocompatibility of biomaterials in blood-contacting medical devices. PMID- 30471479 TI - People with musculoskeletal shoulder pain demonstrate no signs of altered pain processing. AB - BACKGROUND: Central sensitisation may contribute to persistent musculoskeletal shoulder pain. Few studies have provided a comprehensive sensory and psychosocial evaluation of this population. OBJECTIVE: To comprehensively assess whether sensory function and psychosocial aspects are impaired in people with shoulder pain and whether age, gender and clinical outcomes are related to impaired sensory function. STUDY DESIGN: Observational case-control study. METHODS: Twenty three participants with musculoskeletal shoulder pain and 23 age- and gender matched healthy participants were included. Static (pressure and thermal pain thresholds) and dynamic (temporal summation) quantitative sensory testing was performed bilaterally at the shoulder and remote tibialis anterior muscle. Conditioned pain modulation was measured at the affected/matched shoulder. Shoulder function (SPADI), depression, anxiety and stress (DASS-21) and health related quality of life (EQ-5D-5L) were also measured. Comparisons were performed between body regions and groups. Age and gender were included as factors in analyses. Clinical outcomes were tested for correlation with sensory measures. RESULTS: Shoulder pain group had higher local pressure pain threshold (i.e., hypoalgesia; p = 0.03; Z = 0-5.04), higher SPADI score (p < 0.01; Z = -5.76) and higher EQ-5D-5L (p < 0.01; Z = 5.23) compared to the control group. There was no difference between groups for thermal pain sensitivity, dynamic sensory testing or psychological measures. CONCLUSION: People with shoulder pain demonstrated mechanical hypoalgesia, increased upper limb disability and poorer quality of life compared with healthy controls. Central sensitisation seems not be a characteristic of musculoskeletal shoulder pain although it could be present in a subgroup of patients. PMID- 30471480 TI - Vaccine nanoparticles displaying recombinant Ebola virus glycoprotein for induction of potent antibody and polyfunctional T cell responses. AB - The recent outbreaks of Ebolavirus (EBOV) in West Africa underscore the urgent need to develop an effective EBOV vaccine. Here, we report the development of synthetic nanoparticles as a safe and highly immunogenic platform for vaccination against EBOV. We show that a large recombinant EBOV antigen (rGP) can be incorporated in a configurational manner into lipid-based nanoparticles, termed interbilayer-crosslinked multilamellar vesicles (ICMVs). The epitopes and quaternary structure of rGP were properly maintained on the surfaces of ICMVs formed either with or without nickel nitrilotriacetic acid (NTA)-functionalized lipids. When administered in mice, rGP-ICMVs without NTA-lipids efficiently generated germinal center B cells and polyfunctional T cells while eliciting robust neutralizing antibody responses. This study suggests the potential of vaccine nanoparticles as a delivery platform for configurational, multivalent display of large subunit antigens and induction of neutralizing antibody and T cell responses. PMID- 30471481 TI - Behind women's body image-focused shame: Exploring the role of fears of compassion and self-criticism. AB - PURPOSE: Recent studies seem to support that being open to compassion from self and others is key for psychological and social well-being. In particular, findings indicated that fears of affiliative emotions are associated with negative affect and difficulties in threat regulation. The current study examined a path model which tested the direct and indirect effect of fears of compassion on both externalized and internalized body image-related shame, and the potential mediator role of self-criticism on these relationships. METHODS: In this study participated 651 Portuguese women, aged between 18 and 55, from the general population who completed a set of self-report measures of fears of compassion, self-criticism, and body image-related shame. RESULTS: The tested model accounted for 53% of externalized and 45% of internalized body image shame's variance and revealed an excellent fit. Findings corroborated the plausibility of the hypothesized model suggesting that fears of self-compassion and receiving compassion from others are positively associated with body image shame, and that self-criticism is a significant mediator of these associations, even when controlling for the effects of age and BMI. CONCLUSIONS: These findings highlight the relevance of addressing fears of compassion and critical forms of self relating in the understanding and management of body image-related difficulties. This study seems to have important clinical implications by suggesting the pertinence of the cultivation of compassionate abilities and attitudes, as adaptive self-regulatory strategies to target body image difficulties. PMID- 30471482 TI - Histological evaluation of vital organs of the livebearer Jenynsia multidentata (Jenyns, 1842) exposed to glyphosate: A comparative analysis of Roundup(r) formulations. AB - Roundup formulations are herbicides whose active principle is glyphosate. However, these formulations are potentially more toxic to non-target organisms than pure glyphosate. This study aimed to evaluate and compare the toxic potential of the Roundup formulations through histological alterations in fish. Thus, males and females of the neotropical fish species Jenynsia multidentata (Jenyns, 1842) were exposed for 24 or 96 h to the Roundup Original(r) (RO), Roundup Transorb(r) (RT) or Roundup WG(r) (RWG) formulations, at a fixed concentration of 0.5 mg/L of glyphosate. This concentration is close to the maximum glyphosate limits found in the environment and is non-lethal to J. multidentata. The three formulations caused histological damage to the liver, gills and brain of J. multidentata, which increased over the exposure time. Differences in the histological alterations between females and males were observed in the liver and brain. Females were more tolerant to RO and RT than RWG. Males did not exhibit these differences in sensitiveness with formulations. The RWG caused more damage in the liver and gills and RT in the brain. Overall, there were differences in the toxicity of RO, RT and RWG and the toxic effect was presented through histological damage, reinforcing the usefulness of histological biomarkers for Roundup(r) toxicity. The comparison of the toxic potential of glyphosate-based herbicides is important because it could give support to the governmental organizations to set protective rules for the water ecosystems and human health, as well as to reduce the use of highly toxic formulations in agriculture. PMID- 30471483 TI - Capacitively coupled electrical stimulation of rat chondroepiphysis explants: A histomorphometric analysis. AB - The growth plate is a cartilaginous layer present from the gestation period until the end of puberty where it ossifies joining diaphysis and epiphysis. During this period several endocrine, autocrine, and paracrine processes within the growth plate are carried out by chondrocytes; therefore, a disruption in cellular functions may lead to pathologies affecting bone development. It is known that electric fields impact the growth plate; however, parameters such as stimulation time and electric field intensity are not well documented. Accordingly, this study presents a histomorphometrical framework to assess the effect of electric fields on chondroepiphysis explants. Bones were stimulated with 3.5 and 7 mV/cm, and for each electric field two exposure times were tested for 30 days (30 min and 1 h). Results evidenced that electric fields increased the hypertrophic zones compared with controls. In addition, a stimulation of 3.5 mV/cm applied for 1 h preserved the columnar cell density and its orientation. Moreover, a pre hypertrophy differentiation in the center of the chondroepiphysis was observed when explants were stimulated during 1 h with both electric fields. These findings allow the understanding of the effect of electrical stimulation over growth plate organization and how the stimulation modifies chondrocytes morphophysiology. PMID- 30471484 TI - Not quite anyone's guess: Brexit, forensic science and legal medicine. AB - A few months before 29th March 2019 - the date when the UK is due to leave the EU ('Brexit') - the nature of the future UK-EU relationship is highly uncertain. Some of the consequences of the new relationship - whatever form it takes - for legal cooperation and everything (including forensic science and legal medicine) that underpins it can be anticipated. Further analysis, however, of the scope and significance of Brexit for the professional and academic scientific and clinical work covered by this journal is needed urgently. This commentary ends with an invitation to its readers to join a new academic and professional network (including professional corporate bodies and NGOs) intended to help facilitate this. PMID- 30471485 TI - The Danger of a single story about forensic humanitarianism. AB - Since the mid-1980s, forensic scientists have played a crucial role in the international response to mass violence, contributing evidence to war crimes tribunals and identifying bodies to end the tortuous uncertainty of loved ones. Recently, experts at the International Committee for the Red Cross have described these activities using the term "humanitarian forensic action," applying it from the field's origins in Argentina to the multiple organizations and types of projects that exist today. This article cautions against any account of the history of humanitarian forensic action, or its contemporary landscape, that is so simple and unified. It points to divergent mandates, working methods, and even definitions of humanitarianism, focusing especially on new ways in which forensic scientists are addressing the mass suffering caused by structural violence. PMID- 30471486 TI - Twenty-five year trends (1986-2011) in hospital incidence and case-fatality rates of ventricular tachycardia and ventricular fibrillation complicating acute myocardial infarction. AB - BACKGROUND: Long-term trends in the incidence rates (IRs) and hospital case fatality rates (CFRs) of ventricular tachycardia (VT) and ventricular fibrillation (VF) among patients hospitalized with acute myocardial infarction (AMI) have not been recently examined. METHODS: We used data from 11,825 patients hospitalized with AMI at all 11 medical centers in central Massachusetts on a biennial basis between 1986 and 2011. Multivariable adjusted logistic regression modeling was used to examine trends in hospital IRs and CFRs of VT and VF complicating AMI. RESULTS: The median age of the study population was 71 years, 57.9% were men, and 94.7% were white. The hospital IRs declined from 14.3% in 1986/1988 to 10.5% in 2009/2011 for VT and from 8.2% to 1.7% for VF. The in hospital CFRs declined from 27.7% to 6.9% for VT and from 49.6% to 36.0% for VF between 1986/1988 and 2009/2011, respectively. The IRs of both early (<48 hours) and late VT and VF declined over time, with greater declines in those of late VT and VF. The incidence rates of VT declined similarly for patients with either an ST-segment elevation myocardial infarction (STEMI) or non-STEMI, whereas they only declined in those with VF and a STEMI. CONCLUSIONS: The hospital IRs and CHRs of VT and VF complicating AMI have declined over time, likely because of changes in acute monitoring and treatment practices. Despite these encouraging trends, efforts remain needed to identify patients at risk for these serious ventricular arrhythmias so that preventive and treatment strategies might be implemented as necessary. PMID- 30471487 TI - Synthesis and antioxidant activity of new lipophilic dihydropyridines. AB - Dihydropyridines (DHPs) obtained from Hantzsch multicomponent reactions are an important pharmaceutical class of compounds marketed as antihypertensive (e.g., nifedipine, nitrendipine, and amlodipine) drugs. This study synthesized new symmetrical and unsymmetrical long-chain fatty DHPs using multicomponent reactions under metal-free conditions with sulfamic acid as a catalyst. The DHPs were tested for antioxidant activity using three different methods. The insertion of a long chain into the DHP core contributed to antioxidant potential, and compounds derived from nitro aldehydes have better antioxidant potential than the antihypertensive drug nifedipine. In addition, fatty analogs to nifedipine derived from palmitic and oleic chains showed similar antioxidant activity to the common standards butylated hydroxytoluene and vitamin E. These results showed that our new synthesized products may find novel applications as antioxidant additives or for tools for use in drug discovery. PMID- 30471488 TI - Liaison psychiatry: Suicide management. PMID- 30471489 TI - Household food insecurity and breakfast skipping: Their association with depressive symptoms. AB - Household food insecurity limits families' access to sufficient and varied safe foods, which may result in problems such as insufficient food intake and nutritional imbalance. This may lead to health issues such as obesity, chronic illness, mental health problems, and even poor quality of life. Breakfast skipping is a risk factor for eating disorders which is related to diseases such as metabolic disorder and depressive symptoms. This study examined household food insecurity and breakfast skipping and their association with depressive symptoms. In this study, we used data from the 2015 Korean Community Health Survey. Study participants were a total of 225,965 people aged 18 years or older who answered questions related to eating habits. Multiple logistic regression analyses were used to identify factors associated with depressive symptoms. Those in households with low food security and very low food security were more likely to experience depressive symptoms. Individuals that skip breakfast 2 days or more per week were more likely to experience depressive symptoms. Our study suggests that those living in households with lower food security and who skip breakfast often should pay more attention to their mental health. PMID- 30471490 TI - Snaps+: Peer-to-peer and academic support in developing clinical skills excellence in under-graduate nursing students: An exploratory study. AB - Peer to peer learning is not a new concept. It has proven to be a valuable approach to enhance deeper learning, improve critical thinking and problem solving. It has been used in the clinical environment, the classroom and the clinical skills laboratory. The aim of this study was to evaluate the effectiveness of student nurse assisted in practice sessions (SNAPS+) with the addition of an experienced nursing academic. Using an eight item Likert scale questionnaire together with three open ended questions, this study found that having a nursing academic present in supporting the peer teachers helped improve confidence in practicing clinical skills and was an effective teaching approach to support student learning and by also providing a critical eye over the skills being practiced. Content analysis revealed to central themes - 'being and feeling supported' and 'feeling more able and competent at undertaking essential nursing skills. The results suggest that overall the nursing students found the SNAPS+ supportive in allowing the time and space to practice skills in an informal manner. The implications for practice could include an evaluation as to whether there is any effect on student success in the clinical placement environment after attending SNAPS+ sessions. PMID- 30471491 TI - Naphthalene degradation by Fe2+/Oxone/UV - Applying an unconventional kinetics model and studying the reaction mechanism. AB - This study shows the degradation of naphthalene (Nap) in aqueous solution using Oxone process mediated by Fe2+ with UV-A irradiation (FOU). To elucidate the role of different parameters, Fe2+/Oxone (FO), Fe2+/UV (FU), Oxone/UV (OU) and direct photolysis processes were studied, separately. The degradation efficiency under different dosage of Fe2+, Oxone, initial probe compound concentration and solution pH were evaluated. It is concluded that FOU process has significantly better degradation capacity and efficiency. More than 90% of 0.125 mM Nap was removed in 20 min, under the optimal conditions of FOU ([Fe2+]0 = 0.250 mM, [Oxone]0 = 0.250 mM, wavelength = 350 nm and pH = 2.8). A mathematical model is proposed to describe the two-stage reaction kinetics involving Oxone. To alleviate the problems of radical surge at the initial stage and a radical deficit at later stage, a stepwise addition of oxidants was conducted and achieved a higher removal performance. Besides, the decay pathways of Nap under FOU process were proposed by using LC-ESI/MS analysis. The TOC content was found to be increased initially and decreased after 2 h reaction. It is clarified that the TOC increment was contributed by the partially degraded intermediates rather than the persistent Nap, since the latter was not completely combustible in the TOC analyzer, demonstrating that the FOU process is effective in degrading Nap into more degradable products such naphthoic acids and aldehydes. PMID- 30471492 TI - Low-temperature anaerobic digestion enhanced by bioelectrochemical systems equipped with graphene/PPy- and MnO2 nanoparticles/PPy-modified electrodes. AB - Bioelectrochemical systems (BESs) with graphene (Gr)/polypyrrole (PPy)- and MnO2 nanoparticles (NPs)/PPy-modified electrodes were developed to enhance low temperature anaerobic digestion (LTAD) of low-strength wastewater. At 20 degrees C, the chemical oxygen demand removal efficiencies and CH4 yield of the BESs with Gr/PPy (R2) and MnO2 NPs/PPy (R3)-modified electrodes were 12.7% and 25.6%, and 43.9% and 66.3%, respectively, higher than those of the control (R1, without modification). Although the performance of all reactors decreased as temperature dropping to 12 degrees C, the CH4 yield rates of R2 and R3 were still 22.8% and 39.0% higher than that of R1. Further analysis indicated that the modified electrodes might stimulate the metabolic activity of the anaerobic digester sludge. Scanning electron microscopy observation showed that the modified electrodes had higher specific surface area, favoring the attachment and formation of dense biofilms on the surface of electrodes. 16S rRNA gene sequencing results demonstrated that H2-consuming methanogens dominated in the BESs and the influence of Gr/PPy and MnO2 NPs/PPy differed on the microbial community structure of biofilms. These findings justify the wider use of Gr and MnO2 NPs in electrode modification to assist LTAD using BESs. PMID- 30471493 TI - Influence of nalidixic acid on tandem heterotrophic-autotrophic kinetics in a "NIPHO" activated sludge reactor. AB - This work analyzes the effect of nalidixic acid (NAL) on the kinetics of the heterotrophic and autotrophic biomass growth within a "NIPHO" activated sludge reactor treating municipal wastewater. Thus, the effect of this chemical in the degradation rates of carbon and nitrogen sources and net biomass growth rate is evaluated. Activated sludge samples were taken at three different operation conditions, changing the values of hydraulic retention time (2.8-3.8 h), biomass concentration (1400-1700 mgVSS L-1), temperature (12.6-14.8 degrees C), and sludge retention time (11.0-12.6 day). A respirometric method was applied to model the kinetic performance of heterotrophic and autotrophic biomass in absence and presence of NAL, and a multivariable statistical analysis was carried out to characterize the influence of the operation variables on the kinetic response of the system, which was finally optimized. The results showed that there was no inhibitory effect of NAL on heterotrophic biomass, with an increase of net heterotrophic biomass growth rate from 1.70 to 6.73 mgVSS L-1 h-1 at the most favorable period. By contrast, the autotrophic biomass was negatively affected by NAL, reducing the value of net autotrophic biomass growth rate from 25.37 to 10.29 mgVSS L-1 h-1 at the best operation conditions. In general, biomass concentration and temperature had the highest influence on the degradation rate of carbon and nitrogen sources, whereas hydraulic retention time and sludge retention time were the most influential on net heterotrophic and autotrophic biomass growth rates. PMID- 30471494 TI - Flocculating properties and potential of Halobacillus sp. strain H9 for the mitigation of Microcystis aeruginosa blooms. AB - Microcystis aeruginosa can cause harmful algal blooms in freshwaters worldwide. It has already seriously affected human lives and prevented the use of water resources. Therefore, there is an urgent need to develop ecofriendly and effective methods to control and eliminate M. aeruginosa in aquatic environments. In this study, Halobacillus sp. strain H9, a bacterium that showed high M. aeruginosa flocculation activity, was isolated and selected to assess its potential for the removal of M. aeruginosa. The analyses of flocculation activity and mode indicated that the strain H9 induced M. aeruginosa flocculation by secreting active flocculating substance rather than by directly contacting algal cells. A 5% concentration of the H9 supernatant could efficiently flocculate M. aeruginosa cells with a density of up to 5 * 107 cells/mL. Dramatic increases in the zeta potential indicated that charge neutralization could be the mechanism of the flocculation process. The strain H9 flocculated M. aeruginosa with no damage to the algal cell membrane, and did not result in microcystin being released into the surrounding environment. The flocculated algal culture was less toxic to zebrafish larvae, suggesting an environmentally friendly benefit of the H9 supernatant. In addition to M. aeruginosa, the H9 strain was also able to flocculate two other species causing harmful algal blooms, Phaeocystis globose and Heterosigma akashiwo. Furthermore, the flocculation activity of the H9 supernatant was stable at different temperatures and over a wide pH range. These characteristics give the H9 strain great potential for mitigating the influences of harmful algal blooms. PMID- 30471495 TI - Uptake of phosphate by Synechocystis sp. PCC 6803 in dark conditions: Removal driving force and modeling. AB - Rapid uptake of inorganic phosphate (Pi) by microalgae should occur through two processes operating in parallel: onto extracellular polymeric substances (EPS) and intracellular polymeric substances (IPS). Most previous studies focused only on overall Pi uptake and ignored the roles of EPS. We investigated the two-step removal of Pi by Synechocystis sp. PCC 6803 in dark conditions (i.e., without incorporation of Pi into newly synthesized biomass). We also developed a model to simulate both steps. Experimental results with Synechocystis confirmed that Pi in the bulk solution was removed by the two uptake mechanisms operating in parallel, but with different kinetics. All uptake rates decreased with time, and the Pi uptake rate by IPS was much higher than that by EPS at all times, but EPS had a larger maximum Pi-storage capacity -- 33-48 mgP/gCODEPS versus 15-17 mgP/gCODIPS. Synechocystis had a maximum Pi-storage capacity in the range of 22-28 mgP/g dry biomass. Protein in EPS and IPS played the key role for binding Pi, and biomass with higher protein content had greater Pi-storage capacity. Furthermore, biomass with low initial stored Pi had faster Pi-uptake kinetics, leading to more Pi removed from the bulk solution. This work lays the foundation for using microalgae as a means to remove Pi from polluted water and for understanding competition for Pi in microbial communities. PMID- 30471496 TI - Comparative study of polycyclic aromatic hydrocarbons (PAHs) and heavy metals (HMs) in corals, surrounding sediments and surface water at the Dazhou Island, China. AB - This study investigated polycyclic aromatic hydrocarbons (PAHs) content in corals (Acropora sp.), surficial sediments, and surface seawater, and heavy metals (HMs) contents in corals and sediments from Dazhou Island, Hainan, China. Concentrations of PAHs in seawater and sediment seasonally ranged from 191.5 ng L 1 to 587.7 ng L-1, and from 37.9 ng g-1 to 233 ng g-1, while levels in corals were higher (185.2-545.0 ng g-1) compared to those found in sediments, demonstrating bioaccumulation of PAHs by corals. A similar seasonally variation of PAHs was observed in water/sediments and corals, and the proportions of low molecular weight PAHs (LPAHs) in seawater and corals were higher. Pyrolytic and petrogenic contaminations were identified to be the main sources of PAHs. Lower HMs concentrations were detected in corals (9.8-39.4 MUg g-1) than in sediments (65.0-83.3 MUg g-1), but HMs bioaccumulation still occurs in corals. Higher concentrations of HMs in sediment and corals were detected in March and December, especially Mn and Zn. Application of an enrichment factor showed that Cu in corals was delivered from non-crustal materials, and anthropogenic inputs were possibly the main sources. According to Biota Sediment Accumulation Factor, corals could strongly bioaccumulate LPAHs and Cd, and PAHs at a higher (p < 0.05) rate than HMs. There was a lack of correlation between the accumulation of PAHs and HMs in corals based on the cluster analysis. Dual hierarchical clustering analysis result revealed that feeding, instead of symbiosis, might be the main process responsible for the bioaccumulation of PAHs and HMs. PMID- 30471497 TI - Cobalt oxide loaded graphitic carbon nitride as adsorptive photocatalyst for tetracycline removal from aqueous solution. AB - The treatment of antibiotic-containing wastewater is of great importance due to the potential threats of antibiotics to human and the ecosystem. We reported the preparation of cobalt oxide loaded graphitic carbon nitride (CoO/g-C3N4) by an impregnation-calcination method for tetracycline (TC) removal from aqueous solution. The developed CoO/g-C3N4 exhibited high adsorption capacity and fast adsorption kinetic for TC due to the complexation of TC with surface loaded CoO. In particular, 7%CoO/gC3N43 sample presented a maximum TC adsorption capacity of 391.4 mg g-1. It was found that Langmuir and pseudo-second order kinetic models fitted TC adsorption process well. Further photocatalytic studies showed that CoO loaded g-C3N4 was active for TC photodegradation, although the photocatalytic reaction rate constant was lower than that of native g-C3N4. CoO nanoparticles loading on g-C3N4 played the major role of adsorption sites rather than cocatalyst for photocatalysis. We believe that the developed CoO/g-C3N4 could be a potential adsorptive photocatalyst for antibiotic pollutants removal from wastewater. PMID- 30471498 TI - Heat stress upregulates G-T mismatch binding activities in zebrafish (Danio rerio) embryos preexposed and nonexposed to a sublethal level of cadmium (Cd). AB - G-T mispair frequently appears in eukaryotic DNA due to the spontaneous deamination of 5-methylcytosine paired with guanine and is therefore an important target for DNA mismatch repair (MMR). Our earlier studies showed the downregulation of G-T binding activities in cadmium (Cd)-exposed (Danio rerio) embryos. Since elevation of water temperature was reported to increase Cd toxicity in zebrafish, this study explored whether heat stress affected zebrafish mismatch binding capacity in the absence or presence of Cd. Heat stress (37 degrees C for 30 min) induced heat shock protein 70 mRNA expression in embryos at 10 and 24 h post fertilization (hpf). Heat stress weakly upregulated normal G-T sensing machinery and inhibited G-T recognition activity in embryos preexposed to 3 MUM Cd for 9 h. Either heat shock or a 23-h Cd treatment alone caused a 1.7 fold stimulation of G-T binding capacity in 24 hpf embryos and heat stress of Cd preexposed embryos further enhanced G-T binding activity to 2.5 fold of control. Normal and Cd-downregulated loop binding activities in 10 and 24 hpf embryos were almost unreactive to heat shock. Heat stress-upregulated G-T sensing in nonexposed, but not in Cd-preexposed, 24 hpf embryos correlated with stronger gene activities encoding MMR-linked mismatch detecting factors MutS homolog 2 and 6 plus a higher DNA binding activity of the transcription factor Sp1 that regulates msh2/msh6 expression. Our results suggested the importance of heat shock response in facilitating the correction of G-T mismatch in developing zebrafish even under Cd exposure. PMID- 30471499 TI - Detection of artificial sweeteners and iodinated X-ray contrast media in wastewater via LC-MS/MS and their potential use as anthropogenic tracers in flowing waters. AB - The detection of wastewater impact on stream chemistry is often hindered by high background concentrations of ubiquitous solutes. In the present study we tested the applicability of artificial sweeteners (AS) and iodinated X-ray contrast media (ICM) as tracers to detect this impact by examining wastewater treatment plant (WWTP) effluents and surface water samples. The developed direct injection LC-MS/MS method enabled the detection of these anthropogenic micropollutants in aqueous samples down to trace level concentrations. The 2-h-composite sampling of WWTP effluent revealed fluctuating ICM concentrations between and within days with highest concentrations at the end of the week. Diatrizoic acid (DTZ) and iopromide (IOP) were the predominant ICM with concentrations up to 7 MUg/L. Concentrations of the AS acesulfame (ACE) fluctuated between 0.5 MUg/L and 1 MUg/L. Concentrations of AS and ICM in surface water were both associated with wastewater impact. DTZ contamination was more widespread whereas some sampling points exhibited a more pronounced contamination with non-ionic ICM. Surface water was frequently contaminated with AS. Particularly ACE was detected in every surface water sample indicating that it is chemically stable and that inputs to the aquatic environment via WWTP effluents are widespread. The broad application of ACE as food additive enables its application as a tracer throughout Germany. Furthermore, the developed LC-MS/MS method enables rapid detection of ACE down to the low ng/L-range. Nonetheless, DTZ or IOP could be used in addition to ACE to verify anthropogenic influences on natural waters. PMID- 30471500 TI - Response of microorganisms in biofilm to sulfadiazine and ciprofloxacin in drinking water distribution systems. AB - Effects of sulfadiazine and ciprofloxacin on microorganisms in biofilm of drinking water distribution systems (DWDSs) were studied. The results verified that the increases of 16S rRNA for total bacteria and bacterial genus Hyphomicrobium were related to the promotion of antibiotic resistance genes (ARGs) and class 1 integrons (int1) in DWDSs with sulfadiazine and ciprofloxacin. Moreover, the bacteria showed higher enzymatic activities in DWDSs with sulfadiazine and ciprofloxacin, which resulted in more production of extracellular polymeric substances (EPS). The higher contents of EPS proteins and secondary structure beta-sheet promoted bacterial aggregation and adsorption onto surface of pipelines to form biofilm. EPS can serve as a barrier for the microorganisms in biofilm. Therefore, the biofilm bacterial communities shifted and the 16S rRNA for total bacteria increased in DWDSs with antibiotics, which also drove the ARGs promotion. Furthermore, the two antibiotics exhibited stronger combined effects than that caused by sulfadiazine and ciprofloxacin alone. PMID- 30471501 TI - Genome-wide transcriptional response of microRNAs to the benzo(a)pyrene stress in amphioxus Branchiostoma belcheri. AB - Amphioxus, a cephalochordate found in sand habitats in shallow in-shore seawaters, has been widely used as a model in comparative immunology of chordates. However, the role of microRNAs (miRNAs) in amphioxus under abiotic stress, particularly xenobiotics with strong toxicity, remains largely unknown. Here, a widespread marine contaminant, benzo(a)pyrene (BaP) is used to evaluate its toxic effects on miRNA expression of amphioxus. Six small RNA libraries were sequenced from Branchiostoma belcheri. A total of 144 known and 157 novel miRNAs were identified using deep sequencing and bioinformatics approaches. A total of 58 differentially expressed miRNAs (DEMs) were screened, including 25 up- and 33 down-regulated DEMs under BaP stress. Target genes possibly regulated by DEMs were predicted, and their functional enrichment analyses were performed. Targets of DEMs are primarily involved in xenobiotic and cellular homeostasis, catabolic and transport process. They could be largely linked to nine immune- and toxin detoxification-related pathways, including metabolism of xenobiotics by cytochrome P450, drug metabolism-other enzymes, and drug metabolism-cytochrome P450, etc. Furthermore, quantitative real-time PCR (qRT-PCR) analysis for 12 key BaP-responsive DEMs validates the accuracy of deep sequencing. Experiments were then conducted to investigate their expression responses to BaP stress at different time intervals in detail to further determine their expression dynamic in responses of B. belcheri towards BaP exposure. This study, to the best of our knowledge, investigates the regulatory roles of miRNAs in the toxicological response of amphioxus for the first time, providing valuable information for the protection of lone existing cephalochordate amphioxus. PMID- 30471502 TI - Cement plant emissions and health effects in the general population: a systematic review. AB - Adverse health effects of cement plant exposure have been found in occupational contexts but are less defined for the general population living near plants. We aimed to summarize the evidence on the health effects of people exposed to ambient air pollution by cement plants. A systematic review using Embase, PubMed and Web of Science was performed. We included only non-occupational studies with a comparison group that focused on adverse health outcomes and biomarkers of internal dose or subclinical effect associated with cement plant exposure. Selection of articles was performed by two authors independently. Of 1491 articles identified by the initial search, 24 were included: 17 of them were included in the analysis of adverse health outcomes and 9 in the analysis of biomarkers of internal dose or subclinical effects. The studies were very heterogeneous in study design, measure of cement plant exposure, outcome detection, measure of association and adjustment for confounding. Almost all the studies found positive associations between cement plant exposure and respiratory diseases and symptoms. An excess risk of cancer incidence and mortality in both children and adults mainly concerning respiratory tract cancers was also reported in some studies. Higher values of heavy metals and of a biomarker of renal toxicity were found in the exposed compared to unexposed populations. In conclusion, there is some evidence for a possible role of cement plant exposure on health adverse effects, although many studies had serious or critical risk of bias and overall level of certainty was low. PMID- 30471503 TI - Determination of emerging chlorinated byproducts of diazepam in drinking water. AB - Diazepam (DZP) is often found in source water and drinking water at dozens of nanograms per liter levels. The transformation of DZP in water chlorination disinfection process has aroused new concern because the toxic disinfection byproducts (DBPs) might be produced. However, the DBPs of DZP have not been fully identified, and their occurrence levels in drinking water have not been reported. In our chlorination experiment, five emerging DBPs of diazepam: (5-chloro-2 (methylamino) phenyl) (phenyl)methanone (BP-246), 6-chloro-1-methyl-4 phenylquinazolin-2(1H)-one (BP-271), N-(2-benzoyl-4,6-dichlorophenyl)formamide (BP-294), methyl-(2-benzoyl-4-chlorophenyl) (methyl)carbamate (BP-304 (1)) and 6 chloro-4-methoxy-1-methyl-4-phenyl-1,4-dihydro2H -benzo[d][1,3]oxazin-2-one (BP 304 (2)), were tentatively identified by high-resolution mass spectrometry and further characterized by nuclear magnetic resonance spectroscopy. We developed a trace analytical method for the analysis of these five DBPs in drinking water based on solid-phase extraction (SPE) followed liquid chromatography coupled with electrospray ionization tandem mass spectrometric detection. Ultrahigh sensitivities were achieved with limits of detection as low as 7 pg per liter. The recoveries at different spiking levels were all higher than 80% except for that of BP-246. Four of the DBPs and DZP were detected in real drinking water samples at concentrations ranging from several to dozens of nanograms per liter with relatively high detection frequencies. This is the first report on the existence of DZP-DBPs in drinking water. The method and results will be useful for further studies on the occurrence, toxicity, human exposure and control measures of these DBPs. PMID- 30471504 TI - Effects of hydraulic loading rate and organic load on the performance of a pilot scale hybrid VF-HF constructed wetland in treating secondary effluent. AB - This study evaluated the performance of a pilot-scale hybrid constructed wetland system for secondary effluent and investigated bulk organic matter characteristics. The hybrid constructed wetland consisted of a vertical-flow (VF) bed followed by a horizontal-flow (HF) bed. We also investigated the effects of hydraulic loading rates and influent organic load on the performance of the pilot scale VF-HF hybrid constructed wetland. The results showed a high removal efficiency for suspended solids (>95%) and organic matter as determined by total organic carbon (>98.5%) and dissolved organic carbon (>70%), but no significant change in nitrogen removal was observed. The wetland treatment efficiency for suspended solids and organic matter showed a good buffer capacity even when hydraulic loading rates increased from 750 to 1500 L m-2 d-1 and 500-1000 L m-2 d 1 during the VF and HF stages, respectively. Moreover, there was no significant change in the performance when influent organic load increased eight-fold. Fluorescence excitation-emission matrix and liquid chromatography-organic carbon detection (LC-OCD) were used to investigate the dissolved organic matter characteristics in the hybrid VF-HF constructed wetland. Fluorescence excitation emission matrix spectroscopy showed that both protein- and humic-like substances did not significantly change in the effluent when hydraulic loading rates and organic load increased by two- and eight-fold, respectively. Biopolymers determined using LC-OCD were effectively removed via the VF and HF stage wetlands, indicating the occurrence of biodegradation. Fluorescence excitation emission matrix spectroscopy and LC-OCD provided the fate of dissolved organic matter characteristics in the hybrid VF-HF constructed wetland. PMID- 30471505 TI - Stability of U(VI) doped calcium silicate hydrate gel in repository-relevant brines studied by leaching experiments and spectroscopy. AB - The stability of calcium silicate hydrate (C-S-H) gel doped with uranium to form calcium uranium silicate hydrate (C-U-S-H) gel was investigated in 2.5 M NaCl, 2.5 M NaCl/0.02 M Na2SO4, 2.5 M NaCl/0.02 M NaHCO3 or 0.02 M NaHCO3 solutions relevant to the geological disposal of radioactive waste. The C-U-S-H gel samples were synthesized by direct U(VI) incorporation and characterized with time resolved laser-induced luminescence spectroscopy (TRLFS), infrared (IR) spectroscopy, powder X-ray diffraction (XRD), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Time-dependent pH changes as well as the Ca, Si and U release from C-U-S-H gels into the brines, determined by inductively coupled plasma mass spectrometry (ICP MS), were monitored for three calcium-to-silicon (C/S) ratios (0.99, 1.55 and 2.02) over 32 d. Subsequently, changes of the U(VI) speciation and C-S-H mineralogy caused by leaching were investigated with TRLFS, IR spectroscopy and XRD. Results indicated that composition and pH value of the leaching solution, the presence of portlandite as well as formation and solubility of calcite as secondary phase determine the U(VI) retention by C-S-H gel under high saline and alkaline conditions. At high ionic strengths, the Ca release from C-S-H and secondary phases like calcite is increased. Under hyperalkaline conditions only small amounts of U(VI) were released during leaching. A decrease of the pH due to the additional presence of carbonate was linked with an increased U(VI) release from C-S-H gel leading to the formation of aqueous calcium uranyl carbonate in the supernatant solution. PMID- 30471506 TI - Enhanced organic removal for shale gas fracturing flowback water by electrocoagulation and simultaneous electro-peroxone process. AB - Colloids and organics in shale gas fracturing flowback water (SGFFW) during shale gas extraction are of primary concerns. Coagulation combined with oxidation might be a promising process for SGFFW treatment. In this study, a novel electrocoagulation-peroxone (ECP) process was developed for SGFFW treatment by simultaneous coagulation and oxidation process with a Al plate as the anode and a carbon-PTFE gas diffusion electrode as the cathode, realizing the simultaneous processes of coagulation, H2O2 generation and activation by O3 at the cathode. Compared with electrocoagulation (EC) and peroxi-electrocoagulation (PEC), COD removal efficiency mainly followed the declining order of ECP, PEC and EC under the optimal current density of 50 mA cm-2. The appearance of medium MW fraction (1919 Da) during ozonation and PEC but disappearance in ECP indicated that these intermediate products couldn't be degraded by ozonation and PEC but could be further oxidized and mineralized by the hydroxyl radical produced by the cathode in ECP, demonstrating the hydroxyl radical might be responsible for the significant enhancement of COD removal. The pseudo-first order kinetic model can well fit ozonation and EC process but not the PEC and ECP process due to the synthetic effect of coagulation and oxidation. However, the proposed mechanism based model can generally fit ECP satisfactorily. The average current efficiency for PEC was 35.4% and 12% higher than that of ozonation and EC, respectively. This study demonstrated the feasibility of establishing a high efficiency and space-saving electrochemical system with integrated anodic coagulation and cathodic electro-peroxone for SGFFW treatment. PMID- 30471507 TI - Link between von Willebrand factor multimers, relapses and coronary microcirculation in patients with thrombotic thrombocytopenic purpura in remission. AB - INTRODUCTION: ADAMTS13 deficiency results in unusually large von Willebrand factor (ULVWF) multimers in the circulation and a higher risk of microthrombi due to high shear stress. In patients treated for acquired thrombotic thrombocytopenic purpura (TTP), a persistently severe ADAMTS13 deficiency (<10%) in remission is associated with more relapses. A reduced plasma ADAMTS13 activity and increased VWF levels are associated with a higher risk of myocardial infarction. Assessing coronary flow reserve (CFR) enables a better cardiovascular risk stratification: a lower CFR correlates inversely with cardiovascular risk. The aim of the study was to establish whether patients with TTP in remission have an impaired coronary microcirculation, in terms of a lower CFR, and whether there is any correlation between ADAMTS13 activity, the presence of ULVWF multimers, and the occurrence of relapses. METHODS: The clinical information and hemostatic parameters of 24 patients with TTP in remission managed at our center were analyzed. The CFR was assessed in a subgroup of the TTP patients and compared with a control group consisting of 50 healthy volunteers. RESULTS: The CFR was statistically lower in patients in remission of TTP than in controls, but there were no differences between TTP patients with normal and lower CFR. The occurrence of relapses correlated with the presence of ULVWF multimers and with a residual ADAMTS13 activity. CONCLUSIONS: When compared with healthy controls, TTP patients in remission have an impaired coronary microcirculation and the occurrence of relapses in the former reveal the presence of ULVWF multimers. PMID- 30471508 TI - Incidence, risk factors, and outcomes of venous thromboembolism after oncologic surgery: A systematic review and meta-analysis. AB - BACKGROUND: The risk and prognosis of VTE associated with oncologic surgery need to be quantified to guide patient management. We aimed to examine the availability of data and to report the incidence of venous thromboembolism (VTE) in cancer patients after surgery, as well as the clinical outcomes of VTE following oncologic surgery. METHODS: We searched multiple databases for terms related to VTE after oncologic surgery from inception to November 1, 2017. A random-effects meta-analysis was done to calculate the pooled incidence of VTE. RESULTS: Of the 8611 citations identified, 136 studies including 1,481,659 patients met the eligibility criteria. The overall incidence of VTE was estimated to be 2.3% (95% CI 2.1-2.5). Bone and soft tissue cancer (10.6%, 95% CI 2.9-18.2) and lung cancer (8.1%, 95% CI 3.7-12.6) were associated with the highest and second highest risk of postoperative VTE, respectively. Age (standardized mean difference [SMD] = 0.46, 95% CI 0.40-0.53; I2 = 93.8%), radiation (OR 1.29, 95% CI 1.03-1.62; I2 = 34.6%), transfusion (OR 1.96, 95% CI 1.48-2.59; I2 = 57.0%), and operative time (SMD = 1.12, 95% CI 1.07-1.16; I2 = 100%) were possible risk factors for postoperative VTE. Patients with VTE versus those without had increased odds of all-cause fatal events (11.15, 95% CI 4.07-30.56; I2 = 92.0%). CONCLUSIONS: The risk of VTE after oncologic surgery remains high, and this risk varied according to the cancer type, study region, surgical location, and thromboprophylactic strategy. VTE is associated with increased mortality at the early stage of cancer surgery. PMID- 30471509 TI - Molecular design of potent, hydrophilic tyrosinase inhibitors based on the natural dihydrooxyresveratrol skeleton. AB - In this study, dihydrooxyresveratrol glucosides 3-6 were synthesized for the first time to the best of our knowledge by the Wittig reaction and Schmidt glycosylation as key steps for the purpose of developing novel hydrophilic tyrosinase inhibitors. Results obtained from inhibitory studies revealed 50% inhibitory concentration (IC50) values of 12.80 MUM and 2.63 MUM for 4-resorcinol glucosides 3 and 4, respectively. The IC50 value of 4 was approximately 4 times greater than that of kojic acid, which is a typical tyrosinase inhibitor. In contrast, 5-resorcinol glucosides 5 and 6 exhibited tyrosinase-inhibitory activity; however their IC50s were not estimated within 100 MUM. These results suggested that the discovering 4-resorcinol structure of dihydrooxyresveratrol glucoside is crucial for inducing potent tyrosinase-inhibitory activity. PMID- 30471510 TI - A versatile synthesis of alphaGalCer and its analogues exploiting a cyclic carbonate as phytosphingosine 3,4-diol protecting group. AB - A convenient synthetic strategy to alphaGalCer and some relevant analogues by using a handily protected phytosphingosine is reported here. The conversion of the phytosphingosine amino group to azide and the protection of 3,4-diol as cyclic carbonate group, cleavable in mild basic conditions but resistant to acidic treatment, afforded quickly an excellent glycosyl acceptor. Its glycosylation with a proper galactosyl donor, gave a versatile intermediate in high yield and excellent stereoselectivity. To demonstrate the potentiality of the intermediate, three immunologically relevant compounds were chosen as model targets: alphaGalCer, dansyl alpha-galactosylceramide and 7DW8-5. These products were easily obtained in few steps and high yields to validate the synthetic route. PMID- 30471511 TI - T cell Subsets in Peripheral Blood of Women with Recurrent Implantation Failure. AB - The objective of this study was to determine whether there are any differences in the T cell composition and the expression of specific factors (i.e., IRF4, TBX21, GATA3, and GITR) of T cells between women with Repeated Implantation Failure (RIF) and fertile women. We observed a decrease in circulating Tregs and exhausted CD8 + T cells in RIF patients when compared to the controls whereas exhausted Treg and Th17 cells were more frequent. Using real-time PCR, we determined that the expression of IRF-4 and TBX21 was significantly elevated in the cases. In contrast, mRNAs encoding GATA3 and GITR were reduced. Furthermore, the expression of some miRNAs involved in T cell differentiation and their target gene candidates were examined in T cells from women with RIF and fertile control women. The patients showed significant up-regulation of miR-25, miR-93, and miR 326. miR-155 and miR-146a demonstrated significant down-regulation in RIF patients. The results revealed that the expression pattern of target genes was in line with data for miRNAs expression from purified Treg and Th17 cells. The findings of real-time PCR analysis provided insights into the genetic pathways underlying this aberration in the proportions of T cell subsets. Our data suggest that a combination of higher pro-inflammatory Th17 and exhausted Treg cells, and lower Treg and exhausted CD8 + T cells may co-exist in the peripheral blood of women with RIF. Moreover, the expression level of transcription factors and miRNAs controlling T cell differentiation may differ in women with RIF influencing pregnancy outcomes in these women. PMID- 30471512 TI - Growth-inhibitory effects of TGFalphaL3-SEB chimeric protein on colon cancer cell line. AB - BACKGROUND: TGFalphaL3-SEB chimeric protein is a synthetic protein, which is produced by combining the third loop (L3) of transforming growth factor-alpha (TGF-alpha) with staphylococcal enterotoxin type B. To the best of our knowledge, anti-cancer activity of this chimeric protein against colon cancer that overexpresses epidermal growth factor receptor (EGFR) has not yet been studied. Thus, in the present study, the anti-tumor effects of TGFalphaL3-SEB chimeric protein on HT-29 colon cancer cells were evaluated. MATERIALS AND METHODS: The TGFalphaL3-SEB chimeric protein was previously designed and cloned in Escherichia coli (E. coli) [1,2]. The level of expression and the purity of this novel protein were examined for further analysis. For this purpose, the cells were treated with different concentrations (25, 50 and 75 MUg/ml) of TGFalphaL3-SEB and then the proliferation was detected using the MTT assay. The apoptosis inducing potential of TGFalphaL3-SEB in HT-29 and HEK-293 cells was evaluated by flow cytometry using Annexin V/PI double staining method; in addition, bax/bcl2 mRNA ratio, caspase-3 and caspase-9 activity were also assessed. RESULTS: In the present study, TGFalphaL3-SEB chimeric protein was produced in E. coli. After effective purification, its growth inhibitory effect was evaluated. Our results indicated that the incubation of HT-29 colon cancer cell with 25, 50 and 75 MUg/ml of TGFalphaL3-SEB for 24 h leads to significant reduction of proliferation in a dose-dependent manner (P < 0.05). Further analysis indicated that exposure of EGFR expressing HT-29 cells to TGFalphaL3-SEB leads to significant increase of the caspase-3 and caspase-9 activity in a concentration-dependent manner (P < 0.05). Bax/bcl-2 ratio also confirmed that TGFalphaL3-SEB has the pro-apoptotic effect. Flow cytometry analysis of TGFalphaL3-SEB treated cells showed that in addition to apoptotic cells, necrotic cells were also increased significantly at the concentration of 25, 50 and 75 MUg/ml (P < 0.05). CONCLUSION: In conclusion, our results demonstrated that TGFalphaL3-SEB chimeric protein induced cell death through both mechanisms of apoptosis and necrosis in HT-29 colon cancer cells. This paper has highlighted that TGFalphaL3-SEB has the potential to target EGFR expressing cancer cell. PMID- 30471513 TI - Antidiabetic and antihyperlipidemic effects of ethanolic Ferula assa-foetida oleo gum-resin extract in streptozotocin-induced diabetic wistar rats. AB - The present study was conducted to investigate the hypoglycemic and hypolipidemic activity of ethanolic ferula assa-foetida oleo-gum-resin extract (FAOGRETE) and also its effects on liver and kidney function in streptozotocin (STZ)-induced diabetic rats. For this purpose, 42 male Wistar rats were divided into six groups (n = 7). Diabetes was induced in four groups by a single-dose of STZ at 55 mg/kg body weight, administrated intraperitoneal. After 42 days of treatment, fasting blood sugar (FBS) levels, serum insulin, biochemical parameters such as total cholesterol, triglycerides, low and high density lipoprotein cholesterol were measured. In addition the markers of liver and kidney function, such as glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, alkaline phosphatase, serum creatinine and urea levels were determined. The study showed that the ethanolic extract at 150 mg/kg body weight (b.w) had a significant antidiabetic activity after 42 days of treatment as the FBS levels decreased significantly while the serum insulin levels increased. Moreover, a significant decrease in the liver and kidney function markers in treated rats indicated the protective effect of the ethanolic extract against liver and kidney damage, while body weight increased. The serum concentrations were normal in normal control and healthy group treated with FAOGRETE. The results of this study showed that FAOGRETE can regulate hyperglycemia and complications of diabetes. Antidiabetic and hypolipidimic activities of FAOGRETE are probably related to its antioxidant activity. Phenolic and flavonoid compounds like ferulic acid, umbelliferone, and quercetin may play an important role in its mechanism of action. PMID- 30471514 TI - Thinking styles and self-determination among university students who are deaf or hard of hearing and hearing university students. AB - This study explores how students' thinking styles are related to their self determination. The Thinking Styles Inventory-Revised II and the American Institutes for Research (AIR) Self-Determination Scale were administered to 913 university students (480 who were deaf or hard-of-hearing and 433 hearing) in mainland China. Results showed that, among all participants, those with Type I styles (i.e., more creativity-generating, less structured, and cognitively more complex) had higher levels of self-determination, while those with Type II styles (i.e., more norm-favoring, more structured, and cognitively more simplistic) had lower levels of self-determination. The contributions, limitations, and implications of this study are discussed. PMID- 30471515 TI - Determination of residue levels of the avicide 3-chloro-4-methylaniline hydrochloride in red-winged blackbirds (Agelaius phoeniceus) by gas chromatography-tandem mass spectrometry. AB - The avicide 3-chloro-4-methylanaline hydrochloride (chloro-p-toluidine hydrochloride, CPTH, DRC-1339) is used to control pest bird species that damage agricultural crops. A specific and sensitive gas chromatography-tandem mass spectrometry method was developed and validated for the determination of CPTH in avian breast muscle, GI tract, kidney, and liver. Tissue samples were extracted with a solution of acidified water and acetonitrile. The sample was made basic and cleaned up with a combination of liquid-liquid partitioning and solid phase extraction. Separation was achieved using a HP-5 ultra-inert GC column (15 M, 0.25 MUm film) with detection on a triple quadrupole mass spectrometer in multiple reaction monitoring (MRM) mode. The monitored transition for CPTH was m/z 140.9 -> 106.2 for quantitation and 139.9 -> 105.2 and 139.9 -> 77.2 for confirmation. The linear range was 5 to 5000 ng/mL. The precision for the determination of CPTH in all tissues averaged 7.2% and the accuracy averaged 6.7%. The recovery of CPTH fortified at 5 different levels averaged 101% in liver, 98.8% in GI tract, 92.9% in breast muscle, and 87.9% in kidney. The established method was successfully used to determine CPTH residue levels in red winged blackbirds exposed to three different doses of CPTH. PMID- 30471516 TI - Untargeted lipidomic evaluation of hydric and heat stresses on rice growth. AB - Environmental stresses are the major factors that limit the geographical distribution of plants. As a consequence, plants have developed different strategies to adapt to these environmental changes among which can be outlined the maintenance of membranes' integrity and fluidity. Lipids are key molecules for this environmental adaptation and a comprehensive understand of the molecular mechanisms underlying is still required. Here, lipidome changes in Japanese rice (Oryza sativa var. Japonica) upon heat and hydric stresses are assessed using an untargeted approach based on liquid chromatography coupled with mass spectrometry (LC-MS). The obtained data were analyzed using different multivariate data analysis tools. A total number of 298 lipids responded to these abiotic stresses, and 128 of them were tentatively identified. Diacylglycerols (DG), triacylglycerols (TG), phosphatidylcholines (PC) and phosphatidylethanolamines (PE) were the most altered lipid families heat and hydric stress. Interpretation of the obtained results showed relevant changes related to the unsaturation degree in the identified lipids. In the case of heat stress, a decrease in the unsaturation degree of lipids can be linked to an increase in the cell membranes' rigidity. In contrast, the hydric stress produced an increase in the lipids unsaturation degree causing an increase in the cell membranes' fluidity, in an attempt to adapt to these non-optimal conditions. PMID- 30471517 TI - HIV-RNA decay in paired blood and semen samples of subjects receiving their first dolutegravir-based ART regimen. AB - BACKGROUND AND OBJECTIVES: We aimed to investigate to what extent a first-line DTG-based ART regimen reduces HIV-RNA in semen compared to plasma. STUDY DESIGN: In this prospective, observational study, ART-naive, HIV-infected males starting their first ART regimen with DTG plus TDF/FTC or ABC/3TC were enrolled. Paired blood (BP) and seminal plasma (SP) samples were collected at baseline (T0) and at week-2/4/12/24 after ART initiation. Sexually transmitted infections (STI) were ruled out before enrolment. RESULTS: Median baseline HIV-RNA levels were lower in SP compared to BP (657 versus 38.200 copies/ml, p < 0.001), three subjects had undetectable semen HIV-RNA. After 12 weeks of treatment, HIV-RNA was below the quantification limit in both BP and SP of 11 pts (61.1%). Discordant results were obtained in 6 subjects (33.3%), showing quantifiable HIV-RNA in blood only (2 cases) and in semen only (4 cases). Finally, one subject had a positive HIV-RNA in SP/BP. At W24, only in 2/16 subjects (12.5%) HIV-RNA was detectable in semen, while in the others it was negative on SP/BP. No concurrent STI was found in subjects with detectable VL in semen. CONCLUSIONS: DTG demonstrated effectiveness in reducing VL with different kinetics in blood and semen, despite seminal viral suppression after 6 months of ART was not obtained in the totality of subjects. PMID- 30471518 TI - Moieties of plant-derived compounds responsible for outward current production and TRPA1 activation in rat spinal substantia gelatinosa. AB - BACKGROUND: Transient receptor potential ankyrin-1 (TRPA1) channels expressed in the central terminal of dorsal root ganglion neurons in the spinal substantia gelatinosa (SG) play a role in modulating nociceptive transmission. Although plant-derived compounds exhibiting antinociception (such as eugenol, carvacrol and thymol) activate TRPA1 channels to enhance spontaneous excitatory transmission while hyperpolarizing membranes in SG neurons without TRPA1 activation, specific chemical moieties involved in synaptic modulation are unknown. METHODS: We examined the effects of other plant-derived compounds (guaiacol, vanillin, vanillic acid and p-cymene) on holding current and spontaneous excitatory transmission at -70 mV by applying the whole-cell patch clamp technique to SG neurons in adult rat spinal cord slices. RESULTS: None of the compounds affected the frequency or amplitude of spontaneous excitatory postsynaptic current. Guaiacol and vanillic acid had no effect on holding currents, while vanillin and p-cymene produced an inward and outward current, respectively, in some neurons tested. Synaptic modulation was also observed within the same neuron as the activities of eugenol, carvacrol, thymol, and the chemically-related plant-derived compound zingerone occurred. CONCLUSION: A substituted group in eugenol and zingerone, but not in guaiacol, vanillin or vanillic acid, as well as an OH bound to the benzene ring of carvacrol and thymol, but not p-cymene, play a role in producing outward current and TRPA1 activation. Thus, the binding of such chemical moeties to the benzene ring of plant-derived compounds appears necessary to modulate nociceptive transmission in the SG. This information provides insight for the development of new analgesics based on plant-derived compounds. PMID- 30471519 TI - Awareness, attitudes, skills and training needs of psychiatrists working with adults with intellectual disability in managing epilepsy. AB - PURPOSE: Comorbid epilepsy is found in 22.5% of people with intellectual disability (ID). Responding to the continuing lack of clarity to the role of the ID psychiatrist in the United Kingdom with regards to epilepsy care, the Royal College of Psychiatrists (RCPsych) published the College Report (CR) 203 in May 2017. This proposed a three-tiered model of competency in ID epilepsy care, with minimum acceptable standards described as Bronze and greater expertise as Silver and Gold. This article documents the perceptions of ID psychiatrists as to their skills and training needs, and the perceived impact of CR203 on the profession. METHODS: An e- questionnaire, matching the standards on CR203 and encouraging comments was designed, reviewed and approved by the RCPsych ID executive faculty. The survey was sent by email to all UK-registered RCPsych ID Faculty members via the RCPsych communications. RESULTS: Of the expected 332 ID psychiatrists in the UK, 141 responses were received (42.4%). Key findings included that ID psychiatrists as a group have an interest in epilepsy but Bronze standards were frequently unmet, with variation across the UK. There was a noted lack of agreement on role among ID psychiatrists again linked to geographical variation. Regional disparity correlated to population density and proximity to tertiary neurological centres. CONCLUSION: There are significant implications on training, both pre- and post- accreditation for the ID psychiatry speciality. The CR203 standards appear to be steps in the right direction to help define the role ID psychiatrists have in the delivery of epilepsy care. PMID- 30471520 TI - What if my colleague was wrong and I was right? The impact of counterfactual mindsets and interpersonal focus on written communication and decision making in a hidden profile task. AB - Past research on counterfactual mindsets (CFMs) has mainly focused on how those influence dealing with own information, without addressing the potential impact of CFMs on responses to others' information. Thus, this study examined how CFMs combined with an interpersonal focus influence responses to others' statements in a decision making context. Results reveal that a CFM combined with an interpersonal focus leads to more biased communication in response to others' information, thereby reinforcing own preferences. No such effect was observed in an intrapersonal focus or a control condition. A congruency between induction and application context thus seems to make the application of CFMs more likely. We discuss our findings in relation to previous work on counterfactual thinking and the mindset literature in general. PMID- 30471521 TI - Multiple representations in visual working memory simultaneously guide attention: The type of memory-matching representation matters. AB - Whether multiple visual working memory (VWM) representations can simultaneously become active templates to guide attention is controversial. The single-item template hypothesis argues that only one VWM representation can be active at a time, whereas the multiple-item-template hypothesis argues that multiple VWM templates can simultaneously guide attention. The present study examined the two hypotheses in three (out of four) experiments, using three different types of memory objects: Experiment 1: shapes; Experiment 2: colors; and Experiment 3: colored shapes. Participants were required to hold one (memory-1) or two objects (memory-2) in VWM while performing a tilted line search task. Zero (match-0), one (match-1), or two (match-2) memory stimuli reappeared as distractors in the search array. Guidance effects were found for each type of memory stimuli. More importantly, the guidance effect for memory-2/match-2 trials was significantly larger than that for memory-2/match-1 and memory-1/match-1 trials when holding two colors or two colored shapes in VWM, which is in line with the multiple-item template hypothesis. However, the pattern of simultaneous guidance effect is not perfectly found for two memory shapes, which may indicate that a reliable simultaneous guidance effect from two representations in VWM can be observed only when the memory-matching stimuli is more effective in guiding attention. Experiment 4 directly compared the guidance effect induced by feature-based matches (partial matching) with the guidance effect induced object-based matches (complete matching) in memory-set-size 2. Reliable guidance effects in match-1 and match-2 trials for object-based matches but not for feature-based matches confirmed the crucial role of the type of memory-matching stimuli in guiding attention. PMID- 30471522 TI - Multi-action Pt(IV) anticancer agents; do we understand how they work? AB - Pt(IV) complexes act as prodrugs that are activated inside cancer cells releasing cytotoxic Pt(II) drugs such as cisplatin as well as two axial ligands. These ligands can be used to confer favorable pharmacological properties to the prodrug. They can be innocent spectators, targeting agents or bioactive moieties. When the ligands are bioactive moieties such as enzyme inhibitors or antiproliferative agents, the prodrug attacks several cellular targets at the same time acting as a multi-action prodrug. These compounds are very potent and often overcome resistance to cisplatin. Despite solid rationalization and careful design, often there is no correlation between the ability of the bioactive ligand to inhibit the target enzyme and the cytotoxicity. This might be because most bioactive ligands affect several cellular functions and not only the ones they were designed to inhibit. Thus, even "dual action" prodrugs might in reality be multi-action prodrugs. This class of multi-action Pt(IV) prodrugs seems to have great potential in the attempts to overcome resistance. PMID- 30471523 TI - Meal-specific dietary patterns and their contribution to overall dietary patterns in the Japanese context: Findings from the 2012 National Health and Nutrition Survey, Japan. AB - OBJECTIVE: Most studies on dietary patterns have focused on the total daily intake of foods without differentiating intake at specific eating occasions. The aim of this study was to identify meal-specific (breakfast, lunch, and dinner) dietary patterns and examine their contribution to overall dietary patterns, using data from the 2012 National Health and Nutrition Survey, Japan. METHODS: Dietary intake was assessed with a 1-d weighed dietary record for 15 618 Japanese adults >=20 y of age. RESULTS: Using principal component analysis based on daily consumption of 22 food groups, four overall dietary patterns were identified: vegetable/fruit/fish/pulse, bread/dairy, meat/fat, and noodle/seasoning patterns. Four meal-specific dietary patterns, which were independently identified in the same manner based on consumption at each eating occasion, were as follows: * Breakfast: rice/vegetable/fish/pulse/seasoning, bread/dairy/fruit/sugar, meat/egg/fat, and tea/coffee patterns; * Lunch: bread/dairy, noodle/seasoning, meat/fat, and vegetable/pulse/potato/sugar patterns; and * Dinner: meat/vegetable/seasoning, noodle/alcoholic beverage, fish/sugar/alcoholic beverage, and other grains/fat patterns. The major contributors to interindividual variation in the vegetable/fruit/fish/pulse overall dietary pattern included the rice/vegetable/fish/pulse/seasoning breakfast (28%), the vegetable/pulse/potato/sugar lunch (15%), and the fish/sugar/alcoholic beverage dinner (19%). For other overall dietary patterns, the major contributors were generally patterns with similar characteristics, namely the bread/dairy/fruit/sugar breakfast (33%) and the bread/dairy lunch (24%) for the bread/dairy overall dietary pattern; the meat/egg/fat breakfast (13%), the meat/fat lunch (33%), the meat/vegetable/seasoning dinner (28%), and the other grains/fat dinner (11%) for the meat/fat overall dietary pattern; and the noodle/seasoning lunch (51%) and the noodle/alcoholic beverage dinner (25%) for the noodle/seasoning overall dietary pattern. CONCLUSION: Major meal-specific dietary patterns were identified in the Japanese context, which differentially contributed to major overall dietary patterns. PMID- 30471524 TI - Effect of alpha-lipoic acid supplementation on lipid profile: A systematic review and meta-analysis of controlled clinical trials. AB - Several studies have shown the effect of alpha-lipoic acid (ALA) on lipid profile. However, findings remain controversial. This systematic review and meta analysis was conducted to systematically summarize the available clinical trials that examined the effects ALA supplementation on the lipid profile of adults. A systematic search through PubMed and Scopus was done for studies published in English up to April 2017. Effect sizes were combined with fixed- or random effects analysis, where appropriate. Between-study heterogeneity was evaluated by Cochran's Q test and I2. Eleven clinical trials with 452 adults (51.5% women, 48.5% men) were included in this meta-analysis. Combining effect sizes of 10 studies on serum triacylglycerol (TG) concentrations revealed a significant effect of ALA supplementation on serum TG compared with the placebo group (weighted mean difference [WMD], -29.185 mg/dL; 95% confidence interval [CI], 51.454 to -6.916; P = 0.010). We also found significant changes in serum total cholesterol and low-density lipoprotein (WMD, -10.683 mg/dL; 95% CI, -19.816 to 1.550; P = 0.022, WMD, -12.906 mg/dL; 95% CI, -22.133 to -3.679; P = 0.006, respectively). Significant changes were not observed in serum high-density lipoprotein (WMD, -0.092 mg/dL; 95% CI, -3.014 to 2.831; P = 0.025). Supplementation dosage and body mass index were potential sources of heterogeneity, in which those with body mass index >30 kg/m2 who received >600 mg/d ALA showed better improvements in lipid profile. Our findings showed that supplementation with ALA significantly decreased the serum concentrations of TG, total cholesterol, and low-density lipoprotein but did not affect serum levels of high-density lipoprotein in adults. PMID- 30471525 TI - Diet quality of patients with acute coronary syndrome receiving public and private health care. AB - OBJECTIVE: The aim of this study was to investigate the quality of the diets consumed by patients with acute coronary syndrome (ACS) who received public and private health care. METHODS: This observational, prospective, longitudinal cohort study evaluated patients with ACS who attended three private and one public cardiology reference hospitals. Information about dietary parameters during the 6 mo before the acute ACS event was collected at admission and 180 d later using a semiquantitative food frequency questionnaire. Diet quality was assessed using the Alternative Healthy Eating Index (2010), and a multilinear regression model was developed to evaluate the associated variables. RESULTS: The 581 volunteers included in this study comprised 325 (55.9%) and 256 (44.1%) patients treated at private and public hospitals, respectively. Although the dietary index increased significantly after ACS (P < 0001), diet quality remained unsatisfactory, particularly in terms of reductions in the consumption of cardioprotective components (vegetables, fruits, and eicosapentaenoic and docosahexaenoic fatty acids). Compared with patients receiving private health care, those attending a public hospital reported lower dietary quality (P < 0.001). The best diet quality was found to correlate with female sex (P < 0.001), receipt of dietary guidance at hospital discharge (P < 0.001), private health care (P < 0.001), a stable relationship status (P, 0.016), and older age (P < 0.001). CONCLUSION: The overall post-ACS diet quality remained unsatisfactory, especially in terms of cardioprotective components and among patients receiving public health care. Sociodemographic factors and the assistance model/quality were determinants of the observed differences in dietary quality. PMID- 30471526 TI - Diet quality, physical activity, and their association with metabolic syndrome in Korean adults. AB - OBJECTIVE: The aim of ths study was to investigate the combined association of overall diet quality and physical activity (PA) on the risk for metabolic syndrome (MetS) in Korean adults. METHODS: This cross-sectional study extracted the data on 1008 adults (384 men and 624 women) 20 to 64 y of age. Dietary quality was assessed using a recommended food score (RFS) modified for a Korean diet. The total PA was summed to obtain a metabolic equivalent task score. Participants were classified according to the recommended levels of PA and RFS. Multiple logistic regression analysis was applied to determine the associations of RFS and PA with the prevalence of MetS after adjustment for potential confounders. RESULTS: About 21% of men and 19% of women were reported to have MetS. Nearly 5% of both sexes reached the recommended level of diet quality and PA. In men, a significantly reduced odds ratio (OR) for MetS (OR, 0.16; 95% confidence interval [CI], 0.09-0.93) and hypertriglyceridemia (OR, 0.25; 95% CI, 0.04-0.99) was found in those with better diet quality, within the strata of high PA. In women, compared with inactive individuals with poor diet quality, the OR for abdominal obesity in those with a better diet quality and who were active was 0.21 (95% CI, 0.05-0.86). CONCLUSIONS: Both diet quality and PA are associated with a lower risk for hypertriglyceridemia in men and abdominal obesity in women. These findings suggest that a sex-specific pattern of association between MetS and lifestyle factors (diet and PA) should be considered in clinical practice. PMID- 30471527 TI - Polyphenols regulating microRNAs and inflammation biomarkers in obesity. AB - Obesity is one of the most prevalent health problems worldwide. It is a complex disease that is generally accompanied by insulin resistance, increases in oxidative stress and inflammation biomarkers, and potentially, microRNA (miRNA) dysregulation. Polyphenols may act on obesity and its metabolic consequences. Circulating miRNAs have been studied as potential biomarkers for inflammatory and metabolic diseases, and their use may improve the diagnostic tools currently available and the ability to diagnose specific diseases. To our knowledge, data regarding the link between the consumption of polyphenols from food sources, miRNA expression, and inflammation biomarkers related to obesity is scarce, and most data available describing this relationship are found in cancer studies. This review focuses on the polyphenols that modulate the metabolism, inflammation, or both related to obesity to understand the extent to which miRNA expression can be modulated by dietary interventions. PMID- 30471528 TI - Insights about urinary hippuric and citric acid as biomarkers of fruit and vegetable intake in patients with kidney stones: The role of age and sex. AB - OBJECTIVES: Urinary hippuric acid (HA) and citrate can represent useful biomarkers of fruit and vegetable (FAV) intake in nephrolithiasis. However, their clinical significance across the life span has been poorly investigated. The aim of this study was to investigate the association between the two biomarkers with FAV intake across different age groups and sexes in a large group of stone formers (SFs). METHODS: SFs undergoing baseline 24-h urinary collection for metabolic profile of lithogenic risk at our institution were consecutively enrolled for a 6-y time span (N = 1185; 625 men). HA and citrate excretions were determined by ion chromatography and ultraviolet method, respectively. SFs completed a food frequency questionnaire on the intake of FAV. Stepwise logistic regression was applied to investigate factors associated with very low FAV (<=1 servings/d) and analysis of covariance to compare citrate and HA excretion across age groups and sexes. RESULTS: Very low FAV intake prevalence declined with age (Ptrend < 0.001), and was inversely associated with HA and citrate excretion (P < 0.001) in a stepwise logistic regression model. A significant increasing trend was verified for both biomarkers across age groups until the age of 65 for HA (P < 0.001) and 55 for citrate (P < 0.001). Citrate excretion significantly declined after the age of 65, and was higher in women than men in adult age groups, regardless of FAV intake. CONCLUSIONS: Both urinary citrate and HA were positively associated with FAV intake in SFs. However, unlike HA, citrate excretion was significantly influenced by the female sex and by older age. PMID- 30471529 TI - The influence of maternal dietary patterns on gestational weight gain: A large prospective cohort study in China. AB - OBJECTIVE: The relationship between dietary patterns and gestational weight gain (GWG) in different pregnancy stages has rarely been reported among the Asian population. The aim of this study was to examine the relationship between dietary patterns and GWG in Chinese pregnant women. METHODS: Participants were women from the Born in Guangzhou Cohort Study who completed a validated food frequency questionnaire at 24 to 27 wk gestation (N = 5733). Dietary patterns were generated by cluster analysis. Maternal prepregnancy weight was self-reported; weights during pregnancy were extracted from medical records. Regression analyses were performed to test the associations between dietary patterns and total GWG and GWG rates (linear regression), and the adequacy of GWG (logistic regression). RESULTS: According to food consumption frequency, six dietary patterns were generated: "richer in cereals," "richer in vegetables," "richer in meats," "richer in fruits," "richer in fish, beans, nuts, and yogurt," and "richer in milk and milk powder." Compared with women following the richer in cereals pattern, those who followed the richer in fruits pattern had a significantly higher GWG (beta = 0.592; 95% confidence interval [CI], 0.166-1.018) and total rate of GWG; those who followed the richer in fish, beans, nuts, and yogurt" pattern had a greater GWG rate in the second trimester, and also had a decreased risk for inadequate GWG (odds ratio, 0.797; 95% CI, 0.638-0.997). CONCLUSION: Consuming a variety of foods and frequent consumption of fruits during pregnancy contributes to a more rapid increase in GWG among pregnant women in China. Findings may be useful in pregnancy weight monitoring. PMID- 30471530 TI - Evaluation of vascular and kidney injury biomarkers in Mexican children exposed to inorganic fluoride. AB - Exposure to inorganic fluoride (F) has been implicated in cardiovascular and kidney dysfunction mainly in adult populations. However, limited epidemiological information from susceptible populations, such as children, is available. In this study we evaluated the relationship of F exposure with some vascular and kidney injury biomarkers in children. A cross-sectional study was conducted in 374 Mexican schoolchildren. Dental fluorosis and F concentrations in the water and urine were evaluated. The glomerular filtration rate (eGFR) and the urinary concentrations of kidney injury molecule 1 (KIM-1) and cystatin-C (uCys-C) were examined to assess kidney injury. The carotid intima media thickness (cIMT) and serum concentrations of vascular adhesion molecule 1 (VCAM-1), intracellular adhesion molecule 1 (ICAM-1), endothelin 1(ET-1) and cystatin-C (sCys-C) were measured to assess vascular alterations. High proportions of children exposed to F were observed (79.7% above 1.2 ppm F in urine) even in the low water F exposure regions, which suggested additional sources of F exposure. In robust multiple linear regression models, urinary F was positively associated with eGFR (beta = 1.3, p = 0.015), uCys-C (beta = -8.5, p = 0.043), VCAM-1 (beta = 111.1, p = 0.019), ICAM-1 (beta = 57, p = 0.032) and cIMT (beta = 0.01, p = 0.032). An inverse association was observed with uCys-C (beta = -8.5, p = 0.043) and sCys-C (beta = -9.6, p = 0.021), and no significant associations with ET-1 (beta = 0.069, p = 0.074) and KIM-1 (beta = 29.1, p = 0.212) were found. Our findings revealed inconclusive results regarding F exposure and kidney injury. However, these results suggest that F exposure is related to early vascular alterations, which may increase the susceptibility of cardiovascular diseases in adult life. PMID- 30471531 TI - Detection and location of second mesiobuccal canal in permanent maxillary teeth: A cone-beam computed tomography analysis in a Taiwanese population. AB - OBJECTIVES: The aim of this study was to analyze the incidence, symmetry, concurrence of second mesiobuccal canal (MB2) and determine geometric relationships between each orifice of maxillary first and second molars by cone beam computed tomography (CBCT) analysis. METHODS: A total of 216 qualified individuals' (503 teeth) CBCT image were enrolled in the present study. The consistency of bilateral symmetry and concurrent appearance of MB2 canals were analyzed among individuals with contralateral and adjacent molar teeth. The inter orifice distances and angulations of first and second molars were also measured. RESULTS: The overall incidence of MB2 canal of maxillary molars was 39.2%, in which 45.9% and 32.3% in the first and second molars, respectively. The distribution of MB2 canal in contralateral molar teeth has significant gender difference in second molars (p = 0.024) while analyzing the frequency of MB2 canal appearing in contralateral molar pairs. The simultaneous occurrence of MB2 canal was 22.4% for contralateral molars, and the prevalence of concurrent appearance of MB2 canal in the adjacent molars was 43.4%. After adjusting for gender, age, and tooth type, the inter-orifice distances of mesiobuccal to palatal (odds ratios = 1.891) and to distobuccal (odds ratios = 1.448) canals, demonstrated significant differences between molars with and without MB2 canals. CONCLUSIONS: The clinical significance of the results presents critical information on the geometric features, including inter-orifice distances and angulations between each orifice in maxillary molar teeth. Further studies should be conducted to investigate the exact anatomic coordination between each orifice and its impact on access preparation and external crown morphology. PMID- 30471532 TI - Tackle reverse solute flux in forward osmosis towards sustainable water recovery: reduction and perspectives. AB - Forward osmosis (FO) has emerged as a potentially energy-efficient membrane treatment technology to yield high-quality reusable water from various wastewater/saline water sources. A key challenge remained to be solved for FO is reverse solute flux (RSF), which can cause issues like reduced concentration gradient and loss of draw solutes. Yet no universal parameters have been developed to compare RSF control performance among various studies, making it difficult to position us in this "battle" against RSF. In this paper, we have conducted a concise review of existing RSF reduction approaches, including operational strategies (e.g., pressure-, electrolysis-, and ultrasound-assisted osmosis) and advanced membrane development (e.g., new membrane fabrication and existing membrane modification). We have also analyzed the literature data to reveal the current status of RSF reduction. A new parameter, mitigation ratio (MR), was proposed and used together with specific RSF (SRSF) to evaluate RSF reduction performance. Potential research directions have been discussed to help with future RSF control. This review intends to shed more light on how to effectively tackle solute leakage towards a more cost-effective and environmental friendly FO treatment process. PMID- 30471533 TI - Microbiome of drinking water: A full-scale spatio-temporal study to monitor water quality in the Paris distribution system. AB - The microbiological water quality of drinking water distribution system (DWDS) is of primary importance for human health. High-throughput sequencing has gained more and more attention in the last decade to describe this microbial diversity in water networks. However, there are few studies describing this approach on large drinking water distribution systems and for extended periods of time. To fill this gap and observe the potential subtle variation in microbiota of a water network through time and space, we aimed to apply high-throughput sequencing of the 16S rRNA gene approach to characterize bacterial communities of the Paris' DWDS over a one-year period. In this study, the Paris network, composed of four different DWDSs, was sampled at 31 sites, each month for one year. The sampling campaign was one of the largest described so far (n = 368) and the importance of key spatio-temporal and physico-chemical parameters was investigated. Overall, 1321 taxa were identified within the Paris network, although only fifteen of them were found in high relative abundance (>1%) in all samples. Two genera, Phreatobacter and Hyphomicrobium were dominant. The whole bacterial diversity was not significantly affected between the four DWDSs (spatial parameter) and by physico-chemical parameters. However, the bacterial diversity was slightly modified over the one-year period (temporal parameter) as we were able to observe DWDS microbiome perturbations, presumably linked to a preceding flood event. Comparison of high-throughput sequencing of the 16S rRNA gene amplicons vs. cultivation-based techniques showed that only 1.8% of bacterial diversity was recovered through cultivation. High throughput sequencing has made it possible to monitor DWDS more accurately than conventional methods by describing the whole diversity and detecting slight fluctuations in bacterial communities. This method would be further used to supervise drinking water networks, to follow any perturbations due to internals events (such as treatments) or external events (such as flooding). PMID- 30471534 TI - The natural activation ability of subsurface media to promote in-situ chemical oxidation of 1,4-dioxane. AB - The ability of soils and sediments to promote in-situ activation of persulfate and persulfate combined with hydrogen peroxide was investigated for treatment of 1,4-dioxane (dioxane). Experiments were conducted with both batch-reactor and column systems to examine reaction rates and activation mechanisms. Four soils and aquifer sediments were used. ICP-MS and XRD analyses were used to characterize geochemical properties of the solutions and sediments, while EPR spectroscopy was used to characterize radical formation. For the batch experiments, degradation of dioxane was significantly greater in the presence of each of the four subsurface geomedia compared to the controls with no geomedia. This indicates that all four geomedia induced oxidant activation, thereby enhancing dioxane degradation. Dioxane degradation was significantly enhanced by the addition of peroxide to the persulfate solution. It is hypothesized that iron associated with the geomedia is primarily responsible for activation, and that the degree of degradation enhancement relates in part to dissolved-phase iron content. EPR results indicate that manganese oxides and soil organic matter may also have contributed to some degree to persulfate activation, and that manganese oxides enhanced activation of peroxide under the study conditions. Approximately 10% of dioxane was degraded in the miscible-displacement experiments, consistent with the short residence time compared to dioxane's half-life. The pseudo first order rate coefficients obtained from the batch and column experiments were similar. The results of this study indicate that subsurface geomedia can induce activation of persulfate and peroxide to enhance in-situ chemical oxidation applications. PMID- 30471535 TI - Prevention of UF membrane fouling in drinking water treatment by addition of H2O2 during membrane backwashing. AB - Although conventional coagulation pre-treatment can mitigate the fouling of ultrafiltration (UF) membrane when treating raw waters, it is insufficient to restrict the development of irreversible fouling and reversible fouling to a low level. In this paper we demonstrate that the intermittent addition of H2O2 into the membrane tank during backwash events (after coagulation pre-treatment) successfully prevented the development of any significant membrane fouling. Laboratory-scale tests were undertaken using two membrane systems operated in parallel over 60 days, one serving as a reference coagulation-ultrafiltration (CUF) process, and the other receiving the H2O2 (CUF-H2O2), with a decreasing dose in three successive phases: 10, 5 and 2 mg/L. The results showed that the addition of H2O2 (via a separate dosing tube) during a 1 min backwash process (at 30 min intervals) reduced the growth of bacteria in the membrane tank, and the associated concentrations of soluble microbial products (SMP, including protein and polysaccharide). This resulted in a much reduced cake layer, which contained significantly less high MW organic matter (>50%), such as EPS, thereby improving the interaction between particles in the cake layer and/or particles and the membrane surface. There was also less organic matter, of all MW fractions, adsorbed in the membrane pores of the CUF-H2O2 system. The addition of H2O2 in the membrane tank appeared to alter the nature of the organic matter with a conversion of hydrophobic to hydrophilic fractions, which induced less organics adsorption within the hydrophobic PVDF membrane pores, and a reduced bonding ability for particles. There was no physico-chemical evidence of any deterioration of the membrane from exposure to H2O2, which indicates the feasibility of applying this novel method of fouling control for full-scale UF based water treatment processes. PMID- 30471536 TI - Identification of urinary metabolites of the synthetic cannabinoid 5F-CUMYL P7AICA in human casework. AB - Synthetic cannabinoids belong to one of the largest groups of new psychoactive substances (NPS) and are challenging regarding analytical detection because of the often complete metabolic degradation of the parent compounds. 5F-CUMYL-P7AICA contains a 7-azaindole moiety and appeared first on the market in 2015. In the frame of abstinence control cases, possible 5F-CUMYL-P7AICA metabolites were detected in three urine samples. The samples were reanalyzed using liquid chromatography-high resolution mass spectrometry (LC-HRMS) and human phase I and II metabolites were identified. Major in vivo biotransformation steps of 5F-CUMYL P7AICA in humans were oxidative defluorination followed by carboxylation, and monohydroxylation followed by sulfation and glucuronidation. Evaluation of the metabolites as marker for 5F-CUMYL-P7AICA consumption revealed the defluorinated and carboxylated metabolite to be important for sensitive detection. For higher specificity, additional monitoring of a monohydroxylated metabolite is recommended. Comparison with previously published in vitro metabolism data revealed good accordance of the results, with exception of a of the dihydroxylated metabolites from the in vitro assays, which were not detected in the in vivo samples. PMID- 30471537 TI - Corrigendum to: "Structural and spectroscopic characterization of DMF complexes with nitrogen, carbon dioxide, ammonia and water. Infrared matrix isolation and theoretical studies" [Spectrochim. Acta, Part A: 190 (2018) 423-432]. PMID- 30471538 TI - Investigation of binding interactions between BSA and [EPMpyr][Sal] through spectroscopy studies, thermophysical and thermodynamic properties. AB - The intensity of research, probing the interactions between proteins and ionic liquid (IL), has been increasing and parallels the fast-growing applications of ILs in biotechnology. The specific aspects which have attracted the involvement of researchers are stabilization, separation, biochemical and enzymatic reactions of proteins. In this work the synthesis of IL, epoxypropyl and N-methyl substituted 2-oxopyrrolidinium cation with salicylate anion, [EPMpyr][Sal], and its interaction with aqueous BSA{BSA(aq)-[EPMpyr][Sal]}. Measurements of thermophysical properties (density (rho), and speed of sound (u)) showed that both moderately strong and weak interactions occur on treatment of BSA with that chosen IL. H-bond formation, dipole-dipole interactions and ionic interactions occurring in this system were investigated via thermophysical and thermodynamic properties as well as spectroscopic data. Thermodynamic data (excess molar volume (VmE), isentropic compressibility (ks), deviation in isentropic compressibility (?ks) and intermolecular free length (Lf)) showed that there were stronger interaction between IL and BSA at higher temperature. The data from all the studies were correlated with Redlich Kister polynomial equation. The blue shift observed in the fluorescent spectra was interpreted to indicate that thetryptophan (Trp) residue of BSA moves to a more hydrophobic environment. It was also observed that the addition of more IL to BSA resulted in denaturation of BSA due to high hydrophobic nature of IL. Circular dichroism studies show that there were significant changes in the fine structure of BSA on interaction with IL. From the FTIR spectra the position of H-bond in the secondary structure of BSA was deduced. PMID- 30471539 TI - Evaluating the impact of a healthy corner store initiative on food access domains. AB - Healthy Corner Store Initiatives (HCSIs) are one food access strategy that aims to improve food environments by supporting local food stores in expanding their healthy offerings. This study presents the evaluation results from one such HCSI. Fresh Foods Here evaluated its network of eight stores in Columbus, Ohio between November 2013 and August 2014. Data from invoices, inventories, rapid market assessments, and customers surveys were analyzed for evidence of impact on the service delivery and personal domains of food access. For some indicators, initial gains were concentrated between pre- and interim evaluation periods, followed by either a leveling off or decline between interim and post. However, overall results were promising, with increases noted in the number of healthy items ordered by store owners, in daily foot traffic and transactions, and in consumer confidence for certain healthy behaviors. Lessons learned concerning the operation and evaluation of HCSIs are shared. PMID- 30471540 TI - From EBIC images to qualitative minority carrier diffusion length maps. AB - A novel method is presented with the aim to perform minority carrier diffusion length map on cross-sectional samples. The method is based on one Electron-Beam Induced Current (EBIC) acquisition and on the analyze of the EBIC signal slope variation on each scanned points. This method is applied on a pinned photodiode array realized on a low doped silicon epitaxy, and the electron diffusion length map which is extracted is in good accordance with our expectation taking into account the doping distribution of the device. A TCAD simulation also confirms quantitatively the measured diffusion length map. Advantages and drawbacks of this method are discussed in this study. PMID- 30471541 TI - Compressibility of arterial wall - Direct measurement and predictions of compressible constitutive models. AB - Volumetric compressibility and Poisson's ratios of fibrous soft tissues are analyzed in this paper on the basis of constitutive models and experimental data. The paper extends the previous work of Skacel and Bursa (J Mech Behav Biomed Mater, 54, pp. 316-327, 2016), dealing with incompressible behaviour of constitutive models, to the area of compressibility. Both recent approaches to structure-based constitutive modelling of anisotropic fibrous biomaterials (based on either generalized structure tensor or angular integration) are analyzed, including their compressibility-related aspects. New experimental data related to compressibility of porcine arterial layer are presented and compared with the theoretical predictions of analyzed constitutive models. The paper points out the drawbacks of recent models with distributed fibres orientation since none of the analyzed constitutive models seems to be capable to predict the experimentally observed Poisson's ratios and volume change satisfactory. PMID- 30471542 TI - Enhanced corrosion resistance and bonding strength of Mg substituted beta tricalcium phosphate/Mg(OH)2 composite coating on magnesium alloys via one-step hydrothermal method. AB - To overcome the defect of high degradation rate of magnesium (Mg), bioactive coatings with compact structure, sufficient bonding strength and enhanced corrosion resistance are essential for Mg-based biodegradable implants. In this study, a dense Mg-substituted beta-tricalcium phosphate and magnesium hydroxide (beta-TCMP/Mg(OH)2) composite coating was prepared on AZ31 alloy via one-step hydrothermal method. The influences of hydrothermal temperature on its composition, microstructure of the surface and interface, bonding strength and corrosion behavior were evaluated. The results showed that the compact composite coating synthesized at 140 degrees C not only possessed a crack-free bilayered structure with an adequate bonding strength (more than 20.88 +/- 1.60 MPa), but also got an extreme high impedance (1197.003 +/- 152.817 kOmega cm2) so that significantly enhanced the corrosion resistance and inhibited the formation of pitting corrosion. Furthermore, the in vitro immersion test suggested that the composite coating slower the initial degradation rate of Mg alloys and enhanced its surface bioactivity to some extent. PMID- 30471543 TI - Modulations of dendritic Ca2+ spike with weak electric fields in layer 5 pyramidal cells. AB - Weak electric fields (EFs) modulate input/output function of pyramidal cells. Dendritic Ca2+ spike is an important cellular mechanism for coupling synaptic inputs from different cortical layers, which plays a critical role in neuronal computation. This study aims to understand the effects of weak EFs on Ca2+ spikes initiated in the distal dendrites. We use a computational model to simulate dendritic Ca2+ spikes and backpropagating action potentials (APs) in layer 5 pyramidal cells. We apply uniform EFs (less than 20 mV/mm) to the model and examine how they affect the threshold for activation of Ca2+ spikes. We show that the effects of weak field on synaptically evoked Ca2+ spikes depend on the timing of synaptic inputs. When distal inputs coincide with the onset of EFs within a time window of several milliseconds, field-induced depolarization facilitates the initiation of Ca2+ spikes, while field-induced hyperpolarization suppresses dendritic APs. Sustained field-induced depolarization leads to the inactivation of Ca2+ channels and increases the threshold of Ca2+ spike. Sustained field induced hyperpolarization de-inactivates Ca2+ channels and reduces the threshold of Ca2+ spike. By altering the threshold of backpropagation activated Ca2+ firing, field-induced depolarization increases the degree of coupling between inputs of the soma and distal dendrites, while field-induced hyperpolarization results in a decrease of coupling. The modulatory effects of weak EF are governed by the field direction with respect to the cell. Our study explains a fundamental link between field-induced polarization, dendritic Ca2+ spike, and somato dendritic coupling. The findings are crucial to interpret how weak EFs achieve specific modulation of cellular activity. PMID- 30471544 TI - Landfill leachate treatment in Brazil - An overview. AB - The management of municipal solid waste (MSW) presents an ever increasing and more complex challenge in global terms. The disposal of MSW in landfills generates leachate, a liquid highly polluting to the aquatic environment. This review describes the state-of-the-art approaches to treatments applied to leachate in Brazil, highlighting the new technologies and alternatives that are still in the research phase, and compares the leachate treatment technologies applied around the world with the current scenario in Brazil. In Brazilian landfills, along with other technologies, the biological process is commonly applied, since this is a simple and economical approach and often it is the only technique used in small municipalities. The sanitary landfills in large Brazilian cities located in the states of Sao Paulo and Rio de Janeiro, invest in or outsource landfill activities, where apply advanced treatment technologies, such as membrane filtration. The use of membrane filtration technology in these cases reveals similarities with leachate treatments applied in the developed countries of North America and Europe. Brazilian researchers have highlighted the need to use efficient and economically viable technologies for the treatment of leachate in Brazilian landfills. However, the current scenario of MSW management in Brazil shows deficiencies related to the monitoring of sanitary landfills and limited information is available on the performance of leachate treatment systems. PMID- 30471546 TI - Modelling built infrastructure heights to evaluate common assumptions in aquatic conservation. AB - Built infrastructure, such as dams and weirs, are some of the most impactful stressors affecting aquatic ecosystems. However, data on the distribution and characteristics of small built infrastructure that often restrict fish movement, impede flows, and retain sediments and materials, remain limited. Collection of this necessary information is challenged by the large number of built infrastructure with unknown dimensions (e.g., height), which means scientists and practitioners need to make assumptions about these characteristics in research and decision-making. Evaluating these common assumptions is essential for advancing conservation that is more effective. We use a statistical modelling approach to double the number of small (<=5 m high) built infrastructure with height values in France. Using two scenarios depicting common assumptions (all infrastructure without height data are impassable, or all are passable for all species) and one based on our modelled heights, we demonstrate how assumptions can influence our understanding of river fragmentation. Assuming all built infrastructure without height data are passable results in a 5-fold reduction in estimated river fragmentation for fish species that cannot pass built infrastructure >=1.0 m. The opposite is true for fish species that cannot pass >=2.0 m, where assuming all built infrastructure without height data are impassable results in a 7-fold increase in fragmentation compared to the scenario with modelled heights to attribute built infrastructure passability. Our findings suggest that modelled height data leads to better understanding of river fragmentation, and that knowledge of different fish species' abilities to pass a variety of built infrastructure is essential to guide more effective management strategies. Our modelling approach, and results, are of particular relevance to regions where efforts to both remediate and remove built infrastructure is occurring, but where gaps in data on characteristics of built infrastructure remain, and limit effective decision making. PMID- 30471545 TI - Mobility of Pb, Zn, Ba, As and Cd toward soil pore water and plants (willow and ryegrass) from a mine soil amended with biochar. AB - Mine soils often contain metal(loid)s that may lead to serious environmental problems. Phytoremediation, consisting in covering the soil with specific plants with the possible addition of amendments, represents an interesting way of enhancing the quality of mine soils by retaining contaminants and reducing soil erosion. In order to study the effect of an assisted phytoremediation (with willow and ryegrass) on the properties of soil pore water (SPW), we investigated the impact of amendment with biochar (BC) combined with the planting of willow and ryegrass on the behavior of several metal(loid)s (Pb, Zn, Ba, As, and Cd) in a mine soil. Data on the physicochemical parameters and concentrations of the different metal(loid)s in both SPW and in plant tissues of willow and ryegrass highlight the importance of BC for SPW properties in terms of reductions in soluble concentrations of Pb and Zn, although there was no effect on the behavior of As and Cd. BC also increased soluble concentrations of Ba, probably related to ion release by the BC. By improving major ions available in mine soil, BC improved the lifetime of plants and enhanced their growth. Plant development did not appear to significantly affect the physicochemical parameters of SPW. Willow and ryegrass growing on soil with BC incorporated Cd and Ba into their tissues. The influence of plants on the behavior of metal(loid)s was noticeable only for ryegrass growing in soil with 2% BC, where it modified the behavior of Pb and Ba. PMID- 30471547 TI - Education and knowledge determine preference for bark beetle control measures in El Salvador. AB - Extensive outbreaks of bark beetles have affected not only large parts of coniferous forests in the Northern Hemisphere, but also - largely absent from global attention - native pine forests of Central America. As such outbreaks frequently spark management debates among residents, land managers, forest owners and the public, the social acceptance of bark beetle control measures has become crucial for modern land management. However, the sociological and psychological determinants of the preference for specific bark beetle control measures outside protected areas remain unclear. To determine the acceptability of bark beetle control measures in El Salvador, we assessed how demographic variables, attitude towards the bark beetle, education, and self-reported knowledge affected the preference for different bark beetle control measures in a survey of government employees and local forest owners using a quantitative questionnaire survey. Cumulative link mixed models revealed that the general preference for control measures increased with increasing self-reported knowledge about the bark beetle but decreased with increasing level of respondent education and an increasing positive attitude towards the bark beetle. Respondents generally preferred beetle control measures on small areas than on large areas. Preferences for control measures did not differ between government employees and forest owners, with controlled burning and chemical control significantly less accepted than stand thinning or salvage logging. We discuss the most preferred control measures considering recent scientific evidence of their efficacy and conclude that the current bark beetle outbreak should be controlled through logging of pines weakened by fire in the short-term and by stand thinning in the medium-term to prevent further outbreaks. PMID- 30471548 TI - A novel device to assess hip strength: Concurrent validity and normative values in male athletes. PMID- 30471549 TI - Clinically measured hip muscle capacity deficits in people with patellofemoral pain. AB - OBJECTIVE: To evaluate differences in clinical measures of hip abductor and extensor capacity (strength, endurance and power) in people with patellofemoral pain (PFP) compared to asymptomatic controls. DESIGN: Cross-sectional. SETTINGS: Laboratory. PARTICIPANTS: Thirty-two physically active people (16 with PFP and 16 controls). MAIN OUTCOME MEASURES: Strength was evaluated isometrically using a hand-held dynamometer and dynamically using 10 repetitions maximum (10RM) tests. Power was assessed using a linear position transducer. Endurance was assessed using maximum number of repetitions. RESULTS: The PFP group had significant deficits compared to the control group in isometric strength (21-25%) for hip abduction (ES = 0.98) and extension (ES = 0.85); in 10RM (15-18%) for hip abduction (ES = 0.72) and extension (ES = 0.85); and in power (24-31%) for hip abduction (ES = 0.80), and extension (ES = 0.94). No difference was identified for hip abduction and extension in endurance tests. CONCLUSION: Clinical assessments can identify deficits in isometric and dynamic hip strength, as well as power in people with PFP. Hip muscle capacity deficits in people with PFP including strength and power highlight a potential need for more progressive resistance training in this population. PMID- 30471550 TI - Is a brief self-report version of the Columbia severity scale useful for screening suicidal ideation in Chilean adolescents? AB - BACKGROUND: Given the high rates of suicide in the adolescent population and the reluctance of this population to seek help, developing proactive and effective strategies to timely detect individuals at high risk for suicide in non-clinical contexts is a worldwide recognized need. A series of brief self-report questionnaires have been developed for this purpose, however there are few studies providing evidence on their capability to accurately classify suicidal risk levels in specific populations. One of the instruments frequently used to evaluate suicide risk is the Columbia-Suicide Severity Rating Scales (C-SSRS). The goal of this study is to provide psychometric evidence about the accuracy of the Suicidal Ideation subscale (SI) of the C-SSRS to classify suicidal risk levels in a sample of Chilean adolescents using Item Response Theory (IRT). METHODS AND MATERIALS: Through the two parameter logistic model (2-PLM), we analyzed the capability of a self-report questionnaire addressing suicidal ideation (SI) to differentiate and classify participants according to their SI severity levels. We tested two main parameters: difficulty (localization) and discriminating power of 6 items extracted and adapted from the Columbia-Suicide Severity Rating Scales (C-SSRS). We administered this questionnaire to a general sample of 1645 adolescents aged 13 to 18. RESULTS: Our results show that the items differentiate symptoms addressing suicidal thoughts according to their severity, providing an accurate classification of the SI risk level. CONCLUSIONS: These findings support the usage of the C-SSRS in Chilean adolescents. Further research is needed to test its predictive value in different populations. PMID- 30471551 TI - Synthesis and evaluation of third generation vitamin D3 analogues as inhibitors of Hedgehog signaling. AB - The Hedgehog (Hh) pathway is a developmental pathway with therapeutic potential as a target for a variety of cancers. In recent years, several vitamin D-based compounds have been identified as potent inhibitors of Hh signaling. These analogues contain aromatic phenol A-ring mimics coupled to the CD-ring side chain of vitamin D3 through modified seco-B regions. To continue structure-activity relationship studies on this class of Hh pathway inhibitors, multiple series of vitamin D-based analogues that contain an amine-based seco-B tether and/or incorporate a hydroxyl moiety on C-25 were designed and synthesized. These compounds were evaluated in multiple cell lines for their anti-Hh activity, and we identify analogues 16, 21, 22 as potent vitamin D-based Hh inhibitors (IC50 values of 110-340 nM). We also performed a series of mechanism of action studies in knockout cell lines to further explore whether these analogues inhibit the Hh pathway through a known Hh pathway component or the vitamin D receptor. While the specific cellular target that mediates these effects remains elusive, our studies suggest multiple cellular targets may mediate the anti-Hh activity of this scaffold. PMID- 30471552 TI - Childhood maltreatment and alcohol use in young adulthood: the role of self regulation processes. AB - INTRODUCTION: Childhood maltreatment has been linked to later alcohol use and disorders. Few studies have examined the pathways linking child maltreatment to alcohol use during the transition to adulthood. Currently, minimal understanding of such developmental pathways limits the success of alcohol prevention and intervention efforts for this highly vulnerable population. The present study examined if individual differences in self-regulation processes are critical factors that mediate the association between childhood maltreatment and risk for alcohol use. METHOD: Young adults (N = 335; mean age = 21.7), who were recruited from the community, completed self-report measures of childhood maltreatment, different facets of self-regulation processes, and alcohol use. Multiple structural equation modeling (SEM) analyses were performed to specify the roles of two related, but different, self-regulation processes (i.e., behavioral self control and behavioral dysregulation) in linking child maltreatment to four different patterns of drinking behaviors, including drinking frequency, binge drinking, alcohol-related problems, and alcohol dependence. Common risk factors for alcohol use, such as psychological symptoms and peer alcohol use, were also entered into the models. RESULTS: We found that behavioral dysregulation particularly plays a mediating role in the associations between childhood emotional abuse and problematic alcohol use during young adulthood. CONCLUSION: The results of this research suggest that self-control processes would be potentially useful targets to prevent problematic alcohol use among young people who have had exposure to childhood maltreatment. PMID- 30471553 TI - Changes in the prevalence and correlates of cocaine use and cocaine use disorder in the United States, 2001-2002 and 2012-2013. AB - To present nationally representative data on changes in the prevalences of 12 month cocaine use, cocaine use disorder (CocUD) and 12-month CocUD among 12-month cocaine users between 2001 and 2002 and 2012-2013. Data were derived from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) and the 2012-2013 NESARC-III. Between 2001 and 2002 and 2012-2013, prevalences of 12-month cocaine use and DSM-IV CocUD significantly increased and 12-month CocUD among 12-month users significantly decreased. Increases in risk of cocaine use were seen across nearly all sociodemographic subgroups while increases in CocUD were observed among women, those in the oldest age group, Whites, individuals with the lowest incomes and highest education, and those residing in urban areas. Prevalence of CocUD among users significantly declined overall and among men, individuals aged 30-44 years old, the never-married, respondents with incomes between $20,000 and $34,000, and those residing in the Midwest. Increases in coca cultivation in Colombia in recent years together with increases in the purity of cocaine entering the U.S. portend more significant increases in the rates of cocaine use and CocUD in the U.S. along with increases in cocaine-related morbidity and mortality. The results of this study support the continued monitoring of cocaine use and CocUD in the U.S., especially in view of the narrowing of the gender gap and shifts in race-ethnic, age and socioeconomic differentials seen between 2001 and 2002 and 2012-2013. PMID- 30471554 TI - Hookah Use among Russian adolescents: Prevalence and correlates. AB - Hookah use among adolescents is increasing globally. No prior studies in the published literature have examined hookah use among youth in the Russian Federation. We assessed demographic, psychological and behavioral factors associated with lifetime and past 30-day hookah use among Russian youth. This cross-sectional study was conducted in three areas of Bashkortostan, Russia. In 2015, we surveyed Russian high school students (n = 716) on socio-demographic characteristics, tobacco (cigarettes, e-cigarettes, hookah) and drug use (alcohol, marijuana, and other illicit drugs), coping strategies, and getting in trouble (self and/or family). We estimated hookah use prevalence and performed bivariate analyses prior to fitting two multilevel models evaluating lifetime and past 30-day hookah use. Within this sample, 34.92% and 9.36% were lifetime and last 30-day hookah users, respectively. Lifetime hookah use was associated with older age (OR = 1.29), higher anger coping (OR = 1.41), school troubles (OR = 2.30), lifetime cigarette (OR = 1.59), e-cigarette (OR = 4.62), alcohol (OR = 5.61), and marijuana use (OR = 8.05). Additionally, past 30-day hookah use was associated with older age (OR = 1.71), lifetime use of alcohol (OR = 5.39), school troubles (OR = 5.82), and anger coping strategies (OR = 1.40). Hookah use is currently high among Russian youth in Bashkortostan and is associated with other risky behaviors. Effective interventions targeting multiple substances and coping strategies are needed. Social media campaigns encouraging cessation and advocating against its use at home may be beneficial in curbing hookah use among youth. PMID- 30471556 TI - Greater progression of coronary artery calcification is associated with clinically relevant cognitive impairment in type 1 diabetes. AB - BACKGROUND AND AIMS: We assessed the predictive role of coronary artery calcification (CAC) in clinically relevant cognitive impairment in 148 middle aged individuals with childhood-onset type 1 diabetes (T1D) from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. METHODS: Baseline CAC was measured in 1996-98 and repeated 4-8 years later. Per extensive neuropsychological testing in 2010-15, 28% (41/148) of participants met the study definition of clinically relevant cognitive impairment (two or more of 7 select test scores >=1.5SD worse than demographically appropriate published norms). Logistic regression models with backward selection were constructed for statistical analysis. RESULTS: Mean age and T1D duration at first CAC measure were 37 and 29 years, respectively. A greater burden of initial CAC was associated with cognitive impairment determined 14 years later. Compared to Agatston score = 0, odds ratio (OR) and 95% confidence intervals (CI) of 0<-100, 100<-300 and >300 were 1.4 (0.6, 3.6), 2.3 (0.6, 9.7), and 7.9 (1.6, 38.5), respectively. With both initial and progression of CAC in the multivariable model, backward selection retained only CAC progression, showing it was significantly associated with cognitive impairment (OR [95% CI]: 1.7 [1.1, 2.9]). In those with an initial CAC>0, CAC density was marginally, inversely, associated with cognitive impairment when controlling for CAC volume (OR [95%CI]: 0.3 (0.1, 1.2), p value = 0.078). CONCLUSIONS: Greater CAC burden was associated with clinically relevant cognitive impairment in middle-aged adults with childhood onset T1D. CAC progression appears to be a more powerful predictor than initial calcification. PMID- 30471555 TI - NUtraceutical TReatment for hYpercholesterolemia in HIV-infected patients: The NU TRY(HIV) randomized cross-over trial. AB - BACKGROUND AND AIMS: Despite hypercholesterolemia has been recognized to increase cardiovascular risk in human immunodeficiency virus (HIV)-infected patients, cholesterol-lowering therapy is underused in this population, due to fear of drug drug interactions with antiretroviral therapy (ART). We investigated the effects of a nutraceutical combination (NC) on lipid profile, proprotein convertase subtilisin/kexin type 9 (PCSK9), subclinical inflammation and arterial stiffness in ART-treated HIV-infected patients. METHODS: This was a prospective randomized open-label trial with a cross-over design including 30 stable HIV-infected patients on ART with low-density lipoprotein cholesterol (LDL-C) >115 mg/dL, not taking lipid-lowering treatment. After a 3-week lipid stabilization period, the effects associated with 3 months of an oral NC containing red yeast rice and berberine vs. no active treatment (noNC) were assessed for plasma total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), lipoprotein(a), PCSK9, high-sensitivity C-reactive protein (hs CRP) levels and aortic pulse wave velocity (aPWV). RESULTS: At baseline, significant correlations between PCSK9 levels, age (rho = -0.51, p=0.004), waist circumference (rho = 0.36, p=0.005) and CD4+ cell count (rho = -0.40, p=0.027) were observed. NC treatment effects corrected for noNC were significant for TC ( 14%, p<0.001), LDL-C (-19%, p<0.001), PCSK9 (-12%, p=0.02), hs-CRP (-14%, p=0.03) and aPWV (-6%, p=0.005). No significant effects were observed for HDL-C, TG and lipoprotein(a). NC treatment was safe and no significant alterations in muscle, liver and immunovirological parameters were observed. No carry over effect was recorded. CONCLUSIONS: The tested NC significantly reduced plasma cholesterol and PCSK9 levels, attenuated subclinical inflammation and improved arterial stiffness in stable HIV-infected patients on ART. PMID- 30471557 TI - Epidemiology of disseminated intravascular coagulation in sepsis and validation of scoring systems. AB - PURPOSE: We investigated the epidemiology and outcome of disseminated intravascular coagulation (DIC) in patients with sepsis. MATERIALS AND METHODS: We analyzed data from a multicenter observational study (Japan Septic Disseminated Intravascular Coagulation [JSEPTIC-DIC] study) conducted in 42 intensive care units in Japan. DIC scores were calculated using two scoring systems: the International Society on Thrombosis and Haemostasis (ISTH) and Japanese Association for Acute Medicine (JAAM) criteria. We compared demographics and clinical characteristics of patients with and without DIC, and performed multivariable logistic regression analyses to assess the association of diagnosis and scores for DIC with in-hospital mortality. RESULTS: Of 1895 eligible patients, 1162 (61%) and 554 patients (29%) were diagnosed as having DIC by the JAAM and ISTH criteria, respectively. Patients with DIC had higher in-hospital mortality compared with those without DIC (33% vs. 20% in JAAM and 38% vs. 24% in ISTH). However, in multivariable analysis, the JAAM score (odds ratio 1.026, 95% confidence interval 0.958-1.097; p = 0.465) and the ISTH score (odds ratio 1.049, 95% confidence interval 0.969-1.135; p = 0.238) did not have an independent association with in-hospital mortality. CONCLUSIONS: Patients with sepsis and DIC have high mortality. However, the DIC are not independently associated with in hospital mortality. PMID- 30471558 TI - Incidence and risk factors for alopecia in survivors of critical illness: A multi centre observational study. AB - PURPOSE: To investigate the incidence, nature and risk factors for patient reported alopecia in survivors of critical illness. MATERIALS AND METHODS: A multi-centre, mixed methods observational study in the intensive care units (ICU) of ten hospitals in Wales. All patients with an ICU stay of 5 days or more, able to give consent were included. Demographic variables and risk factors were collected. A pre-designed survey was completed at three months post-ICU discharge. Statistical analysis included numbers and percentages (categorical variables) and medians and interquartile ranges (continuous variables). Comparisons between patients with and without alopecia were made using Fisher's Exact test (categorical variables) and Mann Whitney U test (continuous variables). Multivariate logistic regression analysis was used to determine the risk factors for alopecia. RESULTS: The survey was completed by 123 patients with alopecia reported in 44 (36%) patients. The only risk factor for alopecia on analysis was sepsis / septic shock (p < .001; OR: 5.1, 95%CI: 2.1-12.4). CONCLUSIONS: Limited research exists examining the incidence, nature and risk factors for patient-reported alopecia in adult survivors of critical illness. The results of this study highlight the need to discuss the potential for alopecia with survivors of critical illness, who had sepsis / septic shock. PMID- 30471559 TI - Renal resistive index as predictor of acute kidney injury after major surgery: A systematic review and meta-analysis. AB - PURPOSE: To determine the efficacy of Doppler renal resistive index in the prediction of acute kidney injury after major surgery. METHODS: A systematic review and meta-analysis of cohort studies was conducted. Medline (1966-2018), Scopus (2004-2018), Clinicaltrials.gov (2008-2018) and Google Scholar (2004-2018) databases were systematically searched. Prospective studies that examined the diagnostic accuracy of renal resistive index in postoperative acute kidney injury were included. RESULTS: The meta-analysis was based on 10 studies, including a total number of 911 patients. Patients who developed acute kidney injury presented higher renal resistive index values preoperatively (MD: 0.02, 95% CI: [0.00-0.03]), immediately after surgery (MD: 0.07, 95% CI: [0.04-0.11]) and 24 hours postoperatively (MD: 0.07, 95% CI: [0.04-0.09]). The pooled sensitivity was 81.8%, the specificity 77.6% and the area under the curve 0.866. Fagan's nomogram indicated that the post-test probability was increased to 60.6% (positive test) and decreased to 9.5% (negative test), when the pre-test probability was 30%. CONCLUSIONS: Renal resistive index represents a useful marker with fair performance in the prediction of postoperative acute kidney injury. Future cohorts should establish the optimal timing of measurement and evaluate the most appropriate cut-off value that should be used in the clinical setting. PMID- 30471560 TI - Red blood cell transfusion in acute brain injury subtypes: An observational cohort study. AB - PURPOSE: Optimal red blood cell (RBC) transfusion thresholds in acute brain injury (ABI) are poorly defined. MATERIALS AND METHODS: We conducted a retrospective cohort study of adult patients with ABI and moderate anemia (Hb 7 10 g/dL) in a neurological intensive care unit (ICU) at an academic medical center between 2008 and 2015. Transfused and non-transfused patients were matched based on age, ABI subtype, pre-transfusion hemoglobin, and ICU length of stay (LOS) at the time of RBC transfusion. Multivariable regression analyses were performed to assess the relationship between RBC transfusion and hospital LOS, hospital mortality, ICU LOS, ICU mortality, and 24 h change in sequential organ failure assessment (SOFA) scores. RESULTS: 2638 patients met inclusion criteria, with 225 (8.5%) receiving RBC transfusion. Acute ischemic stroke was the most prevalent ABI diagnosis (43.3%) then intracranial hemorrhage (25.6%), subarachnoid hemorrhage (16.5%), and traumatic brain injury (TBI) (14.6%). In multivariable analyses, RBC transfusion was associated with longer hospital and ICU LOS, and higher SOFA scores. Each ABI subtype had similar results, except for TBI which showed no difference in hospital LOS. Mortality was not significantly different. CONCLUSIONS: In moderately anemic patients with ABI, RBC transfusion was associated with longer hospital and ICU LOS. Prospective investigations are necessary to further assess these relationships. PMID- 30471561 TI - Lacosamide versus phenytoin for the prevention of early post traumatic seizures. AB - PURPOSE: To compare the efficacy and safety of lacosamide versus phenytoin for seizure prophylaxis following TBI. MATERIALS AND METHODS: All TBI patients who received prophylaxis with either phenytoin or lacosamide were retrospectively identified. The incidence of seizures within the first 7 days of injury were compared along with adverse effects requiring drug discontinuation. A planned sub group analysis was performed for patients with severe TBI (GCS < 9). RESULTS: There were 481 patients (phenytoin, n = 116; lacosamide, n = 365). Demographics were similar but age (50 +/- 21 vs 58 +/- 22 years, P < .001) and initial GCS (11.3 +/- 4.3 vs 12.5 +/- 3.8, P = .010) were lower in the phenytoin group. The need for mechanical ventilation was higher (53% vs 38%, P = .004). Seizures occurred in 0.9% of the phenytoin group and 1.4% of the lacosamide group (P = 1.00). ADEs were significantly higher with phenytoin (5.2% vs 0.5%, P = .003). This difference remained significant upon multivariate analysis [OR(95% CI) = 9.4(1.8-48.9)]. Subgroup analysis for patients with severe TBI revealed no difference in seizures (phenytoin, 0% vs lacosamide, 1.5%; P = 1.00) but more ADEs with phenytoin (12.5% vs 0%, P = .010). CONCLUSION: There was no difference between lacosamide and phenytoin in the prevention of early post traumatic seizures in patients following TBI. Lacosamide may have a more tolerable side effect profile. PMID- 30471562 TI - Vitamin E delta-tocotrienol inhibits TNF-alpha-stimulated NF-kappaB activation by up-regulation of anti-inflammatory A20 via modulation of sphingolipid including elevation of intracellular dihydroceramides. AB - Nuclear factor-kappaB (NF-kappaB) regulates inflammation and cell survival, and is considered a potential target for anti-inflammatory and anti-cancer therapy. delta-Tocotrienol (deltaTE), a vitamin E form, has been shown to inhibit NF kappaB, but the mechanism underlying this action is not clear. In the present study, we show that deltaTE inhibited TNF-alpha-induced activation of NF-kappaB and LPS-stimulated IL-6 in a dose- and time-dependent manner in Raw 264.7 macrophages. deltaTE potently inhibited TNF-alpha-induced phosphorylation of transforming growth factor beta-activated kinase 1 (TAK1), an upstream kinase essential for the activation of NF-kappaB. Interestingly, deltaTE significantly increased the expression of A20 and to a less extent, cylindromatosis (CYLD), both of which are inhibitors of NF-kappaB. The importance of induction of A20 in deltaTE's anti-NF-kappaB effect is validated in A20 knockout cells where deltaTE's inhibition of NF-kappaB was largely diminished. In pursuit of the cause for A20 induction, we found that deltaTE treatment caused rapid and persistent elevation of dihydroceramides, while decreased ceramides initially but increased ceramides during prolonged treatment. These changes of sphingolipids were accompanied by increased cellular stress markers. Importantly, deltaTE's induction of A20 and inhibition of NF-kappaB activation were partially counteracted by myriocin, a potent inhibitor of de novo synthesis of sphingolipids, indicating a critical role of sphingolipid modulation in deltaTE mediated effects. Since dihydroceramide has been shown to induce A20 and inhibit NF-kappaB in RAW cells, we conclude that that deltaTE inhibits NF-kappaB activation by enhancing its negative regulator A20 as a result of modulating sphingolipids especially elevation of dihydroceramides. PMID- 30471563 TI - Secretion of a gastrointestinal hormone, cholecystokinin, by hop-derived bitter components activates sympathetic nerves in brown adipose tissue. AB - Matured hop bitter acids (MHBA) are oxidation products from bitter components in hops, which are used widely as food materials to add flavor and bitterness in beer production. Our previous study has shown that MHBA induces thermogenesis in brown adipose tissue (BAT) via sympathetic nerves in rodents and reduces body fat in healthy adults. However, it is unclear how MHBA affects the sympathetic nervous system. In this study, we demonstrate that MHBA treatment of enteroendocrine cells increases Ca2+ levels and induces the secretion of the gastrointestinal hormone, cholecystokinin (CCK), in a dose-dependent manner. These effects were eliminated by Ca2+ depletion from the medium or blockers of L type voltage-sensitive Ca2+ channels during pretreatment. Induction of CCK secretion by MHBA was also confirmed using isolated rat small intestines. Elevation of the sympathetic nerve activity innervating BAT (BAT-SNA) and BAT temperature by MHBA administration in rats was blocked by pretreatment with a CCK receptor 1 (CCK1R) antagonist. Moreover, the intraperitoneal injection of CCK fragment elevated BAT-SNA, and this increase was blocked by subdiaphragmatic vagotomy. These results demonstrate that MHBA induces CCK secretion in the gastrointestinal tracts and elevates BAT-SNA via CCK1R and vagal afferent nerves. In addition, MHBA increases BAT temperature via CCK1R. Our findings reveal a novel mechanism of the beneficial metabolic effects of food ingredients. PMID- 30471564 TI - Blueberry polyphenols extract as a potential prebiotic with anti-obesity effects on C57BL/6 J mice by modulating the gut microbiota. AB - Polyphenols are known for their various health benefits. Blueberries are dietary sources of polyphenols with reported health benefits. However, the role of blueberry polyphenols in alleviating obesity is not completely understood. This study investigated the potential positive effect of blueberry polyphenol extract (PPE) on high-fat diet (HFD)-induced obesity in C57BL/6 J mice by modulation of the gut microbiota. Four-week-old C57BL/6 J mice were fed a normal-fat diet or HFD with or without PPE or Orlistat for 12 weeks. Mice fed HFD exhibited increased body weight and adipose tissue weight and disordered lipid metabolism. In contrast, PPE inhibited body weight gain and returned lipid metabolism to normal. Furthermore, 16S rRNA gene sequencing of the fecal microbiota suggested that PPE changed the composition of the gut microbiota in C57BL/6 J mice and modulated specific bacteria such as Proteobacteria, Deferribacteres, Actinobacteria, Bifidobacterium, Desulfovibrio, Adlercreutzia, Helicobacter, Flexispira, and Prevotella. Orlistat also improved obesity and metabolic alterations of HFD mice and modulated the composition of the gut microbiota. Our findings suggest that PPE, as a potential prebiotic agent, influences the gut microbiota to positively affect HFD-induced obesity in C57BL/6 J mice. PMID- 30471565 TI - An integrated microfluidic device with solid-phase extraction and graphene oxide quantum dot array for highly sensitive and multiplex detection of trace metal ions. AB - An integrated microfluidic device, consisting of a solid-phase extraction (SPE) unit for metal ion pretreatment, a micropump, a micromixer, and a detachable graphene oxide quantum dot (GOQD) array chip was constructed for selective and sensitive detection of As3+, Cd2+, and Pb2+. The entire process could be sequentially and automatically completed by actuating a pneumatic micropump. Effect of the pH for metal ion capture and pumping scheme for recovery efficiency were investigated on a chip. The ion As3+, Cd2+, and Pb2+ whose concentrations ranged from 10-2 uM to 102 uM were successfully recovered with high efficiency over 80%. Monoplex and multiplex detection of As3+, Cd2+, and Pb2+ were then executed on a GOQD array chip. The target metal ions were specifically captured on the DNA aptamer linked GOQD array, which results in the fluorescence quenching of GOQD due to the electron transfer from the GOQD to metal ions under the laser irradiation. The proposed integrated SPE-GOQD array based microdevice could perform As3+, Cd2+, and Pb2+ detection with detection limits of 5.03 nM, 41.1 nM, and 4.44 nM, respectively. Simultaneous multiplex detection for binary or ternary mixture of As3+, Cd2+, and Pb2+ was performed, and the proposed integrated microdevice also showed high recovery values ranging from 83.52% to 128.3% from the environmental samples. PMID- 30471566 TI - A facile electrochemical aptasensor for lysozyme detection based on target induced turn-off of photosensitization. AB - The quantification of proteins is essential in fundamental research or clinical applications. Here, we developed a facile electrochemical aptasensor based on target-induced turn-off of photosensitization for label-free and ultrasensitive detection of protein (exemplified by lysozyme). EB (ethidium bromide) molecules that were embedded in dsDNA between lysozyme binding aptamer and complementary DNA immobilized on the electrode, could photo-cleave the dsDNA via singlet oxygen (O21) during photosensitization, resulting in a high voltammetry current of the [Fe(CN)6]3-/4-. Upon recognition of the lysozyme by aptamer, the EB molecules were released from dsDNA, and its photosensitization activity was turned off. As a result, more amount of complementary DNA was retained on the Au nanoparticles modified carbon nanotube paste electrode (AuNPs-CNPE), leading to a declined voltammetry current. Such a sensing strategy allowed detection of 10 pM-1 uM lysozyme with a low detection limit (about 2 pM). Besides, the sensor was free of labeling procedure as well as extra signal amplification step, and the CNPE modification was quite simple, only with AuNPs. The sensor also showed excellent selectivity toward lysozyme in the presence of interfering proteins, such as thrombin, bovine serum albumin, myoglobin, etc. The proposed sensor was applied to the determination of lysozyme in urine samples with the recoveries ranging from 96.6% to 101%. The proposed biosensor holds a great promise in developing other electrochemical sensors based on photosensitization. PMID- 30471567 TI - Development of cardiac troponin-I biosensor based on boron nitride quantum dots including molecularly imprinted polymer. AB - The cardiac Troponin-I (cTnI) is one of the subunits of cardiac troponin complexes and a pivotal biochemical marker of acute myocardial infarction (AMI). Due to its myocardial specificity, cTnI is widely used for the diagnosis of AMI diseases. In this study, a novel imprinted biosensor approach based on boron nitride quantum dots (BNQDs) was presented for cTnI detection in plasma samples. Various characterization methods such as scanning electron microscope (SEM), transmission electron microscope (TEM), x-ray diffraction (XRD), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) were used for all characterizations of nanomaterials. After the characterization analysis, cTnI imprinted electrode was developed in the presence of 100.0 mM pyrrole containing 25.0 mM cTnI. After that, the analytical studies of cTnI in plasma samples were performed by using cTnI imprinted biosensor. The results of the study have revealed that 0.01-5.00 ng mL-1 and 0.0005 ng mL-1 were found as the linearity range and the detection limit (LOD). Moreover, the selectivity of cTnI imprinted glassy carbon electrode (GCE) was investigated for plasma sample analysis in the presence of other nonspecific and specific proteins including cardiac myoglobin (MYG), bovine serum albumin (BSA) and cardiac troponin T (cTnT), respectively. Furthermore, the prepared biosensor was examined in terms of stability, repeatability, reproducibility and reusability. Finally, the imprinted biosensor was applied to the plasma samples having high recovery. PMID- 30471568 TI - Enhanced colorimetric detection of norovirus using in-situ growth of Ag shell on Au NPs. AB - Norovirus (NoV) is a leading cause of acute gastroenteritis. The low infectious dose and environmental stability of NoV facilitate its effective transmission through a variety of modes such as food, water and person-to-person. The available enzyme-linked immunosorbent assay (ELISA) for NoV detection has low sensitivity due to the low catalytic activity of the peroxidase used, and thus, a reliable ultrasensitive bioassay is needed. In this study, we apply the enhanced peroxidase-like activity of silver ion-incorporated gold nanoparticles (Au/Ag NPs) in a colorimetric bioassay for NoV detection. NoV was captured by anti-NoV genogroup II antibodies, which were immobilized on the surface of a 96-well microtiter plate and formed a sandwich structure among anti-NoV Ab, NoV and Ab-Au NP. Then, Ag ion-containing hydroquinone was added to form Au/Ag core/shell NPs. When H2O2/3,3',5,5'-tetramethylbenzidine (TMB) solution was added to the wells, Ag ions were liberated from the surface of Au/Ag NPs and enhanced the oxidation of TMB. These reactions enhanced the oxidation of TMB and developed an intense blue color. The Au/Ag NPs were shown to exhibit higher affinity and catalytic efficiency for H2O2 and higher catalytic velocity based on the kcat of up to 7 fold compared with Au NPs. The bioassay was then optimized to detect clinically isolated NoV using NoV-like particles (NoV-LPs). NoV-LPs were detected with a limit of detection of 10.8 pg/mL, corresponding to 1000- and 100-fold higher sensitivity compared to the gold-immunoassay and horseradish peroxidase-based ELISA, respectively. Clinically isolated NoV GII.4 and NoV GII.3 were detected in the range of 102-106 copies of viral RNA/mL fecal solution with a detection limit of 13.2 copies/mL fecal solution for NoV GII.4, equivalent to 132 copies of viral RNA/g feces and indicating significantly higher sensitivity compared to commercial immunoassay kits. This bioassay represents a workable detection assay for low concentrations of NoV that is applicable for early-stage diagnosis for public hygiene. PMID- 30471569 TI - On the nature of the superspreaders. AB - This is a review article on the basic and the latest achievements on superspreading. The complete and fast spreading of droplets on many surfaces in the nature is a special phenomenon discovered in 1960s. Intensive studies on this phenomenon have been conducted since that time, but the mechanism of superspreading remained not completely unveiled till nowadays. Here we scrutinized the basic literature on superspreading from the last 25 years and also present results related to superspreaders acquired in the present work. The literature on superspreading can be divided to the following groups: (i) works on the properties of the trisiloxane surfactants; (ii) works on the mechanisms of superspreading; (iii) MD simulations; (iv) works on the effect of the trisiloxane surfactants on thin liquid films. There is a number of review articles published in the last decade collecting mainly works from groups (i) and (ii). The works on MD simulations (iii) and the effects on trisiloxane surfactants on thin liquid films (iv) are still few despite they are important from scientific view point. We conducted our own study on the effect of the superspreaders on foam films in rectangular frame and confirmed that the superspreaders cause powerful Marangoni effect within the foam films. Such a strong Marangoni effect has been never observed with the ordinary surfactants. With this work of ours we scrutinized and collected the basic works from the groups (i)-(iv) on the superspreading and added our own investigation on the distinguishable effects of superspreaders and non-superspreaders on thin foam films. The work could be useful to both beginners and specialists in the field of wetting/de-wetting and superspreading. PMID- 30471570 TI - Associations of plasma testosterone with clinical manifestations in acute panic disorder. AB - The probable implication of testosterone in the neurobiology of anxiety disorders, and particularly panic disorder (PD), is poorly studied. We explored for potential differences concerning testosterone (T) plasma levels and the ratio testosterone/cortisol (T/C) between medication-free, consecutively-referred patients with acute exacerbation of PD comorbid with agoraphobia (PDA) (N = 40; females = 24; age = 31.4 +/- 7.1 years) and healthy controls (N = 80; females = 48; matched for age). Moreover, we investigated for potential associations of T levels and T/C ratio with the severity of acute PDA psychopathology in the patients of the sample. Psychometric measures included panic attacks' number during last three weeks (PA-21days), the Agoraphobic Cognitions Questionnaire (ACQ) and the Hamilton Anxiety Rating Scale (HARS). Male patients -but not female ones- demonstrated significantly lower T levels compared to controls. Moreover, in male patients, a significant inverse association emerged between T/C ratio and PA-21days, so that lower T/C ratio is associated with significantly more panic attacks. On the contrary, female patients demonstrated significant positive associations: (a) between T levels and PDA-related pathological cognitions (ACQ); (b) between the T/C ratio and both PA-21days and anxiety symptoms' severity (HARS). The results of the study suggest that testosterone is significantly associated to the severity of clinical manifestations of acute panic disorder, although in a different fashion concerning the two genders. PMID- 30471571 TI - Stress reactivity in preschool-aged children: Evaluation of a social stress paradigm and investigation of the impact of prenatal maternal stress. AB - Prenatal maternal stress is an established risk factor for somatic and psychological health of the offspring. A dysregulation of the hypothalamic pituitary-adrenal (HPA) axis in offspring has been suggested as an important mechanism. However, the impact of prenatal stress on stress reactivity in preschool-aged children is not yet well understood. This is partly due to the fact that for this age group there is no stress test as well established as for older children and adults. In the present work a previously published stress test (Kryski et al., 2011) was evaluated in a large sample of 45-month-old children (n = 339). Furthermore, the relation between measures of prenatal maternal stress and cortisol reactivity was investigated. Prenatal stress was defined as psychopathology (self-report available for n = 339; expert-rating available for a subsample of n = 246) and perceived stress (n = 244) during pregnancy. The stress paradigm elicited significant increases in salivary cortisol 30 and 40 min after the test, and 60.8% of the children were classified as responders. Lower cortisol levels after the stress test were observed in the group of children with prenatal stress defined as maternal psychopathology (both self-reported and expert-rated). Maternal perceived stress as a continuous measure was not significantly associated with cortisol levels. However, when comparing children in the highest quartile of maternal perceived stress to all other children, significantly lower cortisol values were observed in the prenatally stressed group. The present study confirms the paradigm by Kryski et al. as an effective stress test for preschool aged children. Moreover, it provides further evidence that prenatal stress impacts HPA axis reactivity. Future studies should target the timing, nature, and intensity of prenatal stressors and their effect on the stress response in offspring at different developmental stages. PMID- 30471572 TI - Abnormal postural behavior in patients with functional movement disorders during exposure to stress. AB - BACKGROUND: Patients affected by functional (psychogenic) movement disorders (FMD) have abnormal processing of stress responses. However, little is known about the influence of this abnormal stress processing on automatic motor defense behavior, such as freeze response. Our aim was thus to investigate stress-induced postural motor responses in FMD. METHODS: Nine FMD patients and thirteen healthy controls were engaged in the Trier Social Stress Test, while we measured the movement of their body by means of accelerometers and gyroscopes attached to the thorax. Standard deviation of thorax acceleration, reflecting the variability of movement amplitude (body sway), was compared across groups over time in a 2 * 2 ANOVA design. Higuchi's fractal dimension (HFD), reflecting the complexity of movement pattern over time, was also analyzed. Salivary cortisol and alpha amylase samples were collected before and after the experiment, as stress biomarkers. Pearson's correlation coefficients were calculated between these biomarkers and movement parameters. RESULTS: A significant interaction effect was found, showing that healthy controls reduced their thorax sway over time during exposure to stress (from 0.027 +/- 0.010 m/s2 to 0.023 +/- 0.008 m/s2, effect size of Cohen's d = 0.95), whereas patients with FMD did not. This change in body sway in controls over time negatively correlated with salivary cortisol values (rho = -0.67, p = 0.012). A significant group effect revealed that FMD patients had an overall larger body sway (0.038 +/- 0.013 m/s2) compared to controls (0.025 +/- 0.009 m/s2 - effect size of Cohen's d = 1.29) and a lower HFD (1.602 +/- 0.071) than controls (1.710 +/- 0.078 - Cohen's d = 1.43). CONCLUSIONS: Patients with FMD failed to show a reduction of body sway over time, i.e., freeze response observed in the controls, thus suggesting an impairment in the automatic defense behavior. Moreover, our analysis found a lower complexity of movement (HFD) in FMD, which deserves future research in order to verify whether this could represent a characteristic trait of the disorder. PMID- 30471573 TI - Biochar amendment to further reduce methylmercury accumulation in rice grown in selenium-amended paddy soil. AB - Methylmercury (MeHg) accumulation in rice is an emerging food safety issue in China and other countries; however, mitigation methods are scarce. Here, the effects of selenium (Se) and multiple applications of Se and biochar on rice MeHg bioaccumulation were investigated using pot and microcosm experiments. We report that Se amendment was still effective in reducing MeHg levels in paddy soil and rice grain after three years of aging. Biochar amendment (0.5% w/w) further decreased grain (brown rice) MeHg levels by 82-87%. The grain MeHg level decrease following the combination of Se and biochar amendment could be partly attributed to inhibition of net MeHg production in soil by Se. In addition, biochar decreased not only net MeHg production but also MeHg bioavailability in the soil, which could be due to organosulfur compounds in the biochar. Our findings suggest that multiple applications of Se and biochar could be a novel remediation strategy to mitigate MeHg accumulation in rice. PMID- 30471574 TI - Enhanced adsorption performance of gaseous toluene on defective UiO-66 metal organic framework: Equilibrium and kinetic studies. AB - In this study, defective UiO-66 materials modified with Cetyltrimethylammonium bromide (CTAB) surfactant were successfully synthesized by a simple approach. Adsorption and desorption performance as well as the corresponding kinetics of toluene vapor for UiO-66 and the modified materials were intensively studied. The physical and chemical properties of the sample were obtained by a series of characterization techniques. As indicated by the experiments, the number of missing-linker defect sites in UiO-66 were influenced by the CTAB concentration. The presence of the defect sites was served as the main active adsorption sites for efficient toluene vapor adsorption. In result, adsorptive capacity of toluene over CTAB-U-0.5 was improved to 275 mg g-1, which was much higher than that of UiO-66 (151 mg g-1). The effects of adsorption temperature, initial toluene concentration and relative humidity on the adsorption capacity of 1000 ppm toluene on UiO-66 were further explored. Furthermore, as-prepared CTAB-modified UiO-66 materials were used for reprocessing cycles, which showed excellent regeneration performance. PMID- 30471575 TI - Graphitic carbon nitride (g-C3N4) nanosheets functionalized composite membrane with self-cleaning and antibacterial performance. AB - Membrane fouling significantly impedes membrane performance and thus short lifespan of the membrane. Membranes that functionalized with photocatalytic activity are deemed as an effective and novel approach to settle membrane fouling. The membranes with self-cleaning and antibacterial performance were fabricated via facilely filtering g-C3N4 nanosheets onto polyacrylonitrile (PAN) porous substrates. The g-C3N4 nanosheets were exfoliated by acid etching and ultrasound treatment, and the exfoliated nanosheets was verified by Fourier transform infrared spectra, Atomic force microscopy and X-ray diffraction. The g C3N4 nanosheets functionalized composite membranes have a water permeability of 11.70 L m-2 h-1 bar-1 and a good antibacterial activity. In addition, the membranes could be restored their original permeability and their surfaces were close to initial color even after three cycles rejecting dyes and post treatment under irradiation with visible light. Besides, the degradable and antimicrobial mechanisms of the membranes were investigated respectively. These g-C3N4 nanosheets composite membranes with self-cleaning and antimicrobial properties have a potential feasibility in water treatment, and provide an alternative method for fabricating self-cleaning membranes. PMID- 30471576 TI - Crossflow electrochemical filtration for elimination of ibuprofen and bisphenol a from pure and competing electrolytic solution conditions. AB - For the first time, a crossflow electrochemical filtration system containing multiwalled carbon nanotubes (MWNTs) blended with buckypaper as a flat sheet dual membrane electrode was investigated for the removal of two contaminants of emerging concern, Ibuprofen and Bisphenol A. Breakthrough experiments revealed that a crossflow configuration could be highly efficient in eliminating both contaminants at applied DC potentials of 2 and 3 V over an extended period, from pure salt electrolyte as well as from synthetic secondary wastewater effluent. The shear flow provided consistent surface coverage resulting in excellent sorption performance. The long residence time of the two contaminants within the membrane (18.3 s) was sufficient enough to allow for almost complete degradation of phenolic aromatic products and quinoid rings and the resulting formation of aliphatic carboxylic acids, which was more evident at a higher applied potential (3 V). The formation of the non-toxic aliphatic carboxylic acids is a clear indication of the superior electrochemical performance of the crossflow mode over the dead-end flow-through system. Moreover, this study provides an in-depth understanding of different factors such as filter surface area and residence time that can greatly affect the removal of the contaminants considered. PMID- 30471577 TI - SLC-0111 enaminone analogs, 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides, as novel selective subnanomolar inhibitors of the tumor-associated carbonic anhydrase isoform IX. AB - SLC-0111, an ureido substituted benzenesulfonamide, is a selective carbonic anhydrase (CA, EC 4.2.1.1) IX inhibitor that is currently in Phase I/II clinical trials for the treatment of advanced hypoxic tumors complicated with metastases. Herein we report the synthesis of two series of 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides 5a-i and 6a-j as SLC-0111 enaminone congeners. The prepared enaminones were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO2 hydrase assay. All these isoforms were inhibited by the enaminones reported here in variable degrees. The target tumor-associated isoform hCA IX was undeniably the most affected one (KIs: 0.21-7.1 nM), with 6- to 21 fold enhanced activity than SLC-0111 (KI = 45 nM). All the prepared enaminones displayed interesting selectivity towards hCA IX over hCA I (SI: 32 - >35714), hCA II (SI: 2 - 1689) and hCA IV (SI: 11 - >45454). Of particular interest, bioisosteric replacement of phenyl tail with the bulkier 2-naphthyl tail, sulfonamide 6h, achieved the higher II/IX selectivity herein reported with SI of 1689. PMID- 30471578 TI - Synthesis and biological evaluation of new N-benzylpyridinium-based benzoheterocycles as potential anti-Alzheimer's agents. AB - A novel series of benzylpyridinium-based benzoheterocycles (benzimidazole, benzoxazole or benzothiazole) were designed as potent acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. The title compounds 4a-q were conveniently synthesized via condensation reaction of 1,2-phenylenediamine, 2 aminophenol or 2-aminothiophenol with pyridin-4-carbalehyde, followed by N benzylation using various benzyl halides. The results of in vitro biological assays revealed that most of them, especially 4c and 4g, had potent anticholinesterase activity comparable or more potent than reference drug, donepezil. The kinetic study demonstrated that the representative compound 4c inhibits AChE in competitive manner. According to the ligand-enzyme docking simulation, compound 4c occupied the active site at the vicinity of catalytic triad. The compounds 4c and 4g were found to be inhibitors of Abeta self aggregation as well as AChE-induced Abeta aggregation. Meanwhile, these compounds could significantly protect PC12 cells against H2O2-induced injury and showed no toxicity against HepG2 cells. As multi-targeted structures, compounds 4c and 4g could be considered as promising candidate for further lead developments to treat Alzheimer's disease. PMID- 30471579 TI - Synthesis and evaluation of new 4-oxoquinazolin-3(4H)-yl)benzoic acid and benzamide derivatives as potent antibacterial agents effective against multidrug resistant Staphylococcus aureus. AB - Treatment of nosocomial and community acquired Staphylococcus aureus infections has become more challenging due to the egression of multi-drug resistance. This has spurred the need for rapid development of new therapeutic agents which can effectively negate the resistance mechanisms. In our current work, several new 4 oxoquinazolin-3(4H)-yl)benzoic acid and benzamide derivatives were synthesized and examined for their antimicrobial activity against ESKAP pathogen panel and pathogenic mycobacteria. In the primary screening, compounds 4a, 4b, 6'a, 6'b, 6'h, 6'i and 6'j were found to demonstrate selective and potent inhibitory activity against Staphylococcus aureus (MICs = 0.25-0.5 ug/mL). When tested against Vero cells, all the compounds were found to be non toxic possessing favourable selectivity index (SI > 10), which encouraged us for carrying out further studies. Compound 6'a (SI > 40) was tested against a number of multiple clinical strains of multi-drug resistant S. aureus and was found to exhibit potent activity, irrespective of the resistant status of the strain. Besides, compound 6'a also exhibited concentration dependent bactericidal activity and synergized with the FDA approved drugs tested. The interesting results obtained suggest the potential utility of the newly synthesized compounds for treatment of multidrug resistant S. aureus infections. PMID- 30471580 TI - Synthesis and biological evaluation of new 2,4,6-trisubstituted pyrimidines and their N-alkyl derivatives. AB - A series of new 2,4,6-trisubstituted pyrimidines and their N-alkyl bromide derivatives were prepared based upon methoxy substituted azachalcones as the starting materials. All newly synthesized compounds were screened for their anti proliferative, cytotoxic, antibacterial activities and DNA/protein binding affinity. In vitro cell proliferation inhibitory and cell cytotoxic effects of 2,4,6-trisubstituted pyrimidines (1-9) and their N-alkyl bromide derivatives (2a c, 3a-c,5a-c,6a-c, 8a-c, 9a-c) were obtained with the help of the 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) cell proliferation, LDH cytotoxicity detection, and microdilution assays. The antimicrobial activity for these compounds was also evaluated following the European Pharmacopoeia 8.0 protocol. The interactions of these compounds with DNA or bovine serum albumin were investigated by the spectrophotometric titration method. When the cytotoxic analysis and anticancer properties of the compounds were examined, most of the compounds significantly exhibited an anti-proliferative potency on cancer cells (IC50 ~ 2-10 ug/mL) and caused a cytotoxic effect as low as control drugs, 5 fluorouracil, and cisplatin (~7-15%). Because the compound-DNA adducts are hyperchromic or hypochromic, they caused variations in their spectra. This situation shows they can be linked to DNA by the groove binding mode at a binding constant range of 2.0 * 104 and 2.4 * 105 M-1. The antimicrobial screening results revealed that our new compounds for some human Gram(+) and Gram(-) pathogen bacteria showed remarkable activity with MIC values between <7.81 and 125 ug/mL. Overall, incorporation of alkyl chain to pyrimidines in the generation of N-alkyl bromides has resulted in showing differences in DNA/protein binding affinity, along with anti-proliferative and cytotoxic activity in favor of new compounds. PMID- 30471581 TI - Profiles and potential health risks of heavy metals in soil and crops from the watershed of Xi River in Northeast China. AB - Heavy metal soil contamination is a major environmental concern in China and has drawn significant public attention in recent years. The present study assessed the human health risk of four heavy metals (cadmium, lead, mercury, and zinc) through soil exposure and dietary intake in the watershed of Xi River, west of Shenyang, Liaoning Province, northeast China. Concentrations of Cd, Pb, Hg, and Zn were determined in 411 soil samples and 59 crop samples collected from this area. The health risks of heavy metal exposure via soil ingestion, inhalation, dermal contact, and dietary intake of crops were further estimated; total hazard index values were 1.15, 1.33, and 2.03 for the adult male, adult female, and children, respectively, and the total cancer risk was 3.7 * 10-3 for the local residents. Among the four investigated heavy metals, Cd was the primary pollutant posing health risks. The estimated non-carcinogenic and carcinogenic risks posed by the studied heavy metals were above the acceptable levels proposed by the U.S. EPA. Dietary intake of contaminated crops was identified as the predominant pathway for human heavy metal exposure in this area, suggesting that soil heavy metals can cause more harm when transported to the food chain. Overall, our findings suggest that the Xi River watershed is unsuitable for growing agricultural products, and more effective controls should be taken to curb future heavy metal pollution in the area. PMID- 30471582 TI - Ecotoxicity response of chlorpyrifos in Aedes aegypti larvae and Lactuca sativa seeds after UV/H2O2 and UVC oxidation. AB - Chlorpyrifos (CP) is an organophosphate pesticide widely used in agriculture known to cause neurological and immunological effects in addition to interfering in the reproduction and development of organisms. In this study, CP degradation by UV/H2O2 process and UVC radiation was investigated, and the ecotoxicity and phytotoxicity was evaluated using bioassays of Aedes aegypti larvae and Lactuca sativa seeds. CP degradation was monitored by HPLC-DAD, and kinetic parameters were calculated for all processes evaluated. Results demonstrated that both processes are efficient, showing a reduction of over 97% of initial CP after 20 and 60 min of UV/H2O2 and UVC radiation, respectively. However, samples treated by UV/H2O2 process demonstrated increase of toxicity, leading to larvae mortality (>90% of organisms) and inhibition effects in seed root growth. The relationship between increased toxicity and the CP byproducts formed was not confirmed due to its low concentration. However, the direct influence of acetonitrile solvent, specifically their toxic byproducts, was observed. This study provides insights into parent compound abatement using oxidative treatment and the changes in toxicity due to the transformation of CP byproducts and complex mixtures (acetonitrile as solvent and hydrogen peroxide). PMID- 30471583 TI - Reward activation in childhood predicts adolescent substance use initiation in a high-risk sample. AB - BACKGROUND: Substance use at an early age conveys substantial risk for later substance-related problems. A better understanding of early risk factors could result in more timely and effective intervention. This study investigated the predictive utility of the brain's response to reward anticipation as a risk factor for early substance use initiation. METHODS: Participants were 34 children (25 male) at high risk for alcohol and other substance use disorders from a longitudinal functional magnetic resonance imaging study, scanned at a mean age of 10.5 years (SD = 1.2) when participants were substance-naive. We used a monetary incentive delay task to examine the hemodynamic response of the nucleus accumbens to gain and loss anticipation. Logistic regression was used to test the hypothesis that these brain response patterns would have predictive utility over and above early externalizing behaviors and family history of substance use disorder, two key risk factors for substance use problems, in differentiating those who initiated substance use before age 16 (n = 18) and those who did not (n = 16). RESULTS: Greater nucleus accumbens activation during monetary gain anticipation in childhood increased the likelihood of initiating substance use during early adolescence (p = .023). The model that comprised neural data in addition to early externalizing behaviors and family history showed significantly better fit than the model without neural data (chi22 = 7.38, p = .025). CONCLUSIONS: Heightened gain anticipation activation in the nucleus accumbens may predispose individuals to early substance use, beyond the risk conveyed by other known factors. PMID- 30471584 TI - Stimulus effects of propylene glycol and vegetable glycerin in electronic cigarette liquids. AB - BACKGROUND: Little is known about the behavioral effects of non-nicotine ingredients in electronic cigarette liquids. Propylene glycol (PG) and vegetable glycerin (VG) are the most common humectants used in electronic cigarette liquids. These ingredients may influence stimulus effects (e.g., visibility of exhalant, taste, or smell), which have played a role in the abuse liability of conventional cigarettes. In the current study, the stimulus effects of aerosol from liquids varying only in PG and VG content were assessed. METHODS: Sixteen electronic cigarette users completed five sessions (one practice and four testing sessions). Following one hour of nicotine deprivation, two sampling puffs from liquid formulations containing 100/0, 75/25, 50/50, 25/75, and 0/100% PG/VG concentrations were administered in random order during five assessments, each separated by 20 min. Measures included self-reported stimulus effects and breakpoint on a multiple-choice procedure with options consisting of sampled puffs or varying amounts of money. RESULTS: VG content was associated with greater reports of visibility of the exhalant (i.e., "cloud"). Liquids with only PG or VG engendered lower reports of inhalation sensations (e.g., throat hit) and greater reductions of systolic blood pressure compared to mixtures of PG and VG. There was no effect of liquid formulation on the multiple-choice procedure, but puffs were rarely chosen over even the smallest monetary option ($0.05), suggesting minimal reinforcing efficacy. CONCLUSIONS: Liquids containing greater concentrations of VG are more capable of producing visible exhalant and mixtures of PG and VG engender greater airway sensory effects than either ingredient alone. PMID- 30471585 TI - Effectiveness and safety of Rituximab in demyelinating diseases spectrum: An Italian experience. AB - BACKGROUND: Rituximab (RTX), a monoclonal antibody targeting the CD20+ B lymphocytes, deserves major attention as therapeutic option in the treatment of demyelinating disorders of the central nervous system (DDCNS). We reported our clinical experience with the use of RTX in terms of efficacy and safety in persons suffering from DDCNS. METHODS: An Italian single-center observational analysis of patients who underwent RTX treatment between 2011 and 2017 was performed at MS center of Catania, Italy. No evidence of disease activity (NEDA) was applied to evaluate the response to RTX. CD19+ and CD20+ counts were collected along therapy. RTX-related adverse events were recorded. RESULTS: Eleven patients with MS, four with NMOSD and two with NMO were enrolled. Out of them, 4/17 were naive to previous treatments. According to NEDA status, 11/17 got NEDA3 status at the follow-up. Six patients had relapses (two had a single relapse and four had multiple relapses). One patient with primary progressive MS and one with relapsing remitting MS stopped RTX, the last one for severe lymphopenia. CONCLUSIONS: RTX showed efficacy to impact DDCNS worsening with an acceptable safety profile. PMID- 30471586 TI - Animal exposure over the life-course and risk of multiple sclerosis: A case control study within two cohorts of US women. AB - BACKGROUND: Whether animal exposure and specifically the timing of such exposure alters multiple sclerosis (MS) risk is unclear. We examined whether animal exposure was associated with MS risk, and whether risk differed by the participants' age. METHODS: We conducted a case-control study within the Nurses' Health Study ((NHS)/NHSII cohorts). Overall, 151 women with MS and 235 controls, matched by age and study cohort, completed an animal exposure history questionnaire. Animal exposure pre-MS onset was assessed as 'any' exposure, then by the participants age, and animal family. Conditional logistic regression was used to estimate relative MS risks, adjusted (adj.RR) for potential confounders. RESULTS: 'Any' animal exposure was reported by 136 (90.1%) MS cases compared to 200 (85.1%) matched controls, with dog exposure being the most common [120 (79.5%) cases vs. 170 (72.3%) controls]. There was no association between 'any' animal exposure and MS risk (adj.RR:1.52;95%CI:0.76-3.04). However, both 'any' animal and specifically dog exposure at ages 10-14 years were associated with an increased MS risk (adj.RR:1.67;95%CI:1.05-2.66 and 1.76;95%CI:1.12-2.78, respectively). CONCLUSION: Animal exposure, and specifically dog exposure, in early adolescence was associated with an increased risk of MS. Further work is needed to confirm this finding. PMID- 30471587 TI - Changes in connectivity and hydrological efficiency following wildland fires in Sierra Madre Oriental, Mexico. AB - Fire modifies soil surface, and hence soil hydrological properties change after wildland fires. High fire severity causes partial or total removal of vegetation, reduction of soil aggregate stability and increased water repellency, which are associated with high runoff and erosion. The spatial connection among these runoff sources is an important factor to consider when evaluating fire-induced changes on hillslope and catchment hydrology, as fire generates connected areas of bare soil, which may increase hydrological connectivity and hence post-fire runoff and erosion. The aim of this study was to quantify changes in hydrological connectivity and efficiency in two burned areas in central Mexico. By integrating rainfall simulation and spatial analysis, an index of connectivity (IC) and the lateral hydrological efficiency index (LHEI) were computed based on land/cover use, fire severity and topography within 287 burned sub-basins. Post-fire IC and LHEI were compared with the pre-fire scenario, and the relationship between LHEI and the proportion of burned area was assessed at the sub-basin level. Thresholds of the burned area per fire severity needed to increase LHEI were determined by a classification tree. The index of connectivity and LHEI were higher after wildland fires. The burned area was positively related with LHEI, and at least 43.3% of area burned with high severity is sufficient to produce the highest LHEI. The results are evidence of the effect of fire on hydrological connectivity and efficiency which adds to the understanding of fire-hydrology relations and can be used for integrated catchment management, ecological restoration and risk assessment. PMID- 30471588 TI - Comparison of chemical composition and airborne bacterial community structure in PM2.5 during haze and non-haze days in the winter in Guilin, China. AB - Haze is a typical type of air pollution and frequently has occurred in the winter in Guilin city recently, but information relating to chemical compositions and airborne bacterial community structure of atmospheric particulate matter (PM2.5) during haze days remains very limited. In this study, the PM2.5 concentration, chemical components including water-soluble ions and metal elements, and bacterial community compositions of PM2.5 on both haze and non-haze days were characterized, and the relationships between them were studied. The results showed that levels of the secondary aerosol particles of SO42-, NO3-, and NH4+ in haze PM2.5 associated with local fuel combustion and vehicle emissions were significantly higher than non-haze samples. Similar trends were observed for the detected trace metal elements. High-throughput sequencing results indicated that higher PM2.5 concentration caused lower bacterial richness and diversity. However, the airborne bacterial community structure remained stable, and no significant difference was found between haze and non-haze PM2.5. Firmicutes, Proteobacteria, and Bacteroidetes were the most abundant phyla accounting for a total of 97.2% on average. In contrast to non-haze PM2.5, the bacterial community structure of haze PM2.5 was mostly positively correlated with SO42-, NO3-, NH4+, K+, and Cl-, suggesting these secondary aerosol particles were probably of great importance on haze pollution and variability of the bacterial compositions of PM2.5. PMID- 30471589 TI - Alleviating Na+ effect on phosphate and potassium recovery from synthetic urine by K-struvite crystallization using different magnesium sources. AB - Human urine is characterized by high concentrations of nitrogen (N), phosphorus (P) and potassium (K), of which the P and K can be recovered as K-struvite crystals. This study first investigated the formation of Na-struvite because of the high Na+ present in the urine. From the results, the optimal pH for the Na struvite crystallization was observed to be 12, and the rise in the Na+ concentration distinctly favored the Na-struvite formation. As magnesium needed to be added to induce the K-struvite crystallization, several magnesium sources including MgCl2, Mg sacrificial electrode and Mg(OH)2 were applied to recover P and K from synthetic urine. The findings indicated that when MgCl2 was used as the magnesium source, the K removal could be slightly enhanced by prolonging the reaction time, which would correspondingly decrease the Na concentration in the precipitates; besides, the intermittent addition of MgCl2 could noticeably improve the removal efficiency of K by 6%, but simultaneously raise the Na content in the precipitates recovered. With respect to the use of the Mg sacrificial electrode, the recovery efficiencies of the P and K from synthetic urine were close to those with the use of MgCl2. However, when Mg(OH)2 was used as the magnesium source, the recovery efficiencies of P and K achieved only roughly 50%, which was much lower than those noted when MgCl2 and the Mg sacrificial electrode were employed. A comprehensive analysis revealed that the MgCl2 was the best magnesium source for the K-struvite crystallization, followed by the Mg sacrificial electrode and Mg(OH)2. PMID- 30471590 TI - Are secondary forests second-rate? Comparing peatland greenhouse gas emissions, chemical and microbial community properties between primary and secondary forests in Peninsular Malaysia. AB - Tropical peatlands are globally important ecosystems with high C storage and are endangered by anthropogenic disturbances. Microbes in peatlands play an important role in sustaining the functions of peatlands as a C sink, yet their characteristics in these habitats are poorly understood. This research aimed to elucidate the responses of these complex ecosystems to disturbance by exploring greenhouse gas (GHG) emissions, nutrient contents, soil microbial communities and the functional interactions between these components in a primary and secondary peat swamp forest in Peninsular Malaysia. GHG measurements using closed chambers, and peat sampling were carried out in both wet and dry seasons. Microbial community phenotypes and nutrient content were determined using phospholipid fatty acid (PLFA) and inductively-coupled plasma mass spectrometry (ICSPM) analyses respectively. CO2 emissions in the secondary peat swamp forest were > 50% higher than in the primary forest. CH4 emission rates were ca. 2 mg m-2 h-1 in the primary forest but the secondary forest was a CH4 sink, showing no seasonal variations in GHG emissions. Almost all the nutrient concentrations were significantly lower in the secondary forest, postulated to be due to nutrient leaching via drainage and higher rates of decomposition. Cu and Mo concentrations were negatively correlated with CO2 and CH4 emissions respectively. Microbial community structure was overwhelmingly dominated by bacteria in both forest types, however it was highly sensitive to land-use change and season. Gram positive and Gram-negative relative abundance were positively correlated with CO2 and CH4 emissions respectively. Drainage related disturbances increased CO2 emissions, by reducing the nutrient content including some with known antimicrobial properties (Cu & Na) and by favouring Gram-positive bacteria over Gram-negative bacteria. These results suggest that the biogeochemistry of secondary peat swamp forest is fundamentally different from that of primary peat swamp forest, and these differences have significant functional impacts on their respective environments. PMID- 30471591 TI - Environmental pollution of soil with PAHs in energy producing plants zone. AB - Polycyclic aromatic hydrocarbons (PAHs) are widely distributed environmental toxicants primarily formed during the incomplete combustion of organic materials (for example, coal, oil, gasoline and wood). Power energy plants are the main sources of organic contaminants including PAHs. The purpose of the present research was to study the Novocherkassk Electric Power Station (NEPS) emission effects of PAHs accumulation in soils. The regional levels, types (groups) and spatial distribution of 16 priority PAHs were investigated. The monitoring sites were located on fallow lands of the 20 km around NEPS. PAHs extraction from collected soil samples was performed using the ecologically clean express-method of subcritical water extraction. The total PAHs content gradually increased in soil of the studied territories during 2016-2017 due to an increase in contaminants emission. Accordingly 16 priority PAHs were determined in the soil samples collected from the sites located to the northwest from NEPS in direction of predominant winds. The 5-km zone situated in direction of predominant winds was highly subjected to PAHs contamination, with maximal accumulation at a distance of 1.6 km from the source. The ratio of high- and low-molecular weight PAHs content in soils of monitoring sites was taken as an index of environmental soil contamination. The high-molecular weight PAHs concentration prevailed in monitoring sites soils situated in direction of predominant winds from NEPS, while the concentration of low-molecular weight PAHs prevailed in the monitoring sites soils situated around NEPS. Soil properties also influenced PAHs accumulation. Polyarenes content in Haplic Chernozems and Haplic Chernozems (Stagnic) was higher versus Fluvisols. This study provides the understanding and model the fate of PAHs in regional technogenic landscape. PMID- 30471592 TI - Using the multidimensional synthesis methods with non-parameter test, multiple time scales analysis to assess water quality trend and its characteristics over the past 25 years in the Fuxian Lake, China. AB - Fuxian Lake is one of the most important conservation areas in the southwest of China. Understanding the water-quality trend and characteristics is the basis of area protection for Fuxian Lake. This study combines of the Mann-Kendall, Mann Kendall-Sneyers, water pollution index (WPI), the trophic state index and time series analysis to detect and characterize the water quality with a set of indicators: transparency (SD), permanganate index (IMn), total phosphorus (TP), total nitrogen (TN), biochemical oxygen demand (BOD5), ammonia nitrogen (NH3-N) and chlorophyll-a (Chl.a). Then, the characteristics are discussed on the scales of long-period, sections divided by the change point, and monthly data. Results show that the water quality of Fuxian Lake is at a good level but decreases consistently. Especially, the increasing trends of IMn, BOD5, and Chl.a pass the confidence limit of the Z value of 2.56. The year of 2007 was designated as the change point. The characteristics of pollution and typical components vary in the long-period series, between the two sections divided by the change point, and in the monthly data. In the long period, the TN and TP are typical pollution components. However, the IMn, BOD5, and Chl.a are typical components as the large changes of a 99.1% and 89.5% increase after the change point with respect to the former values, respectively. On the scale of monthly data of a typical year, the pollution grade and components varies within the years. The multidimensional synthesis methodology established by employing evaluation index systems from the aspects of pollution level, multi-attributes and the trophic state status could also be applied to detect and characterize the water quality of other water bodies. The results of the Fuxian Lake study can provide the base information and decision-making support for water quality management and area protection. PMID- 30471593 TI - Diversity and density patterns of large old trees in China. AB - Large old trees are keystone ecological structures that provide vital ecosystem services to humans. However, there are few large-scale empirical studies on patterns of diversity and density of large old trees in human-dominated landscapes. We present the results of the first nationwide study in China to investigate the patterns of diversity and density of large old trees in human dominated landscapes. We collated data on 682,730 large trees >=100 years old from 198 Chinese regions to quantify tree species diversity, tree density and maximum tree age patterns. We modelled the effects of natural environmental variables (e.g. climate and topography) and anthropogenic variables (e.g. human population density and city age) on these measures. We found a low density of large old trees across study regions (0.36 trees/km2), and large variation in species richness among regions (ranging from 1 to 232 species). More than 95% of trees were <500 years old. The best fit models showed that: (1) Species diversity (species richness adjusted by region size) was positively associated with mean annual rainfall and city age; (2) Density of clustered trees, which are mostly remnants of ancient woods, was negatively influenced by human population density and rural population (% of total population). In contrast, the density of scattered trees, which are mostly managed by local people, was positively correlated with mean annual rainfall and human population density. To better protect large old trees in cities and other highly-populated areas, conservation policy should protect ancient wood remnants, mitigate the effects environmental change (e.g. habitat fragmentation), minimize the negative effects of human activities (e.g. logging), and mobilize citizens to participate in conservation activities (e.g. watering trees during droughts). PMID- 30471594 TI - New approach for the simultaneous detection of somatic coliphages and F-specific RNA coliphages as indicators of fecal pollution. AB - Two groups of coliphages have been recently included in different water management policies as indicators of viral fecal pollution in water and food: somatic coliphages, which infect E. coli through cell wall receptors, and F specific RNA coliphages, which infect through the F-pili. Somatic coliphages are more abundant in fecally contaminated waters, except reclaimed waters, those disinfected by UV irradiation, and some groundwater samples that show a higher level of F-specific coliphages. Somatic coliphages are morphologically similar to DNA enteric viruses while F-specific coliphages are similar to RNA viruses such as norovirus and hepatitis A viruses, which are the viral pathogens of concern in sewage. The use of strains sensitive to both types of phages has been proposed for total coliphage enumeration, thereby avoiding double analysis. The standardized methods available for coliphage detection are robust and cost effective, but the introduction of ready-to-use methods would facilitate routine implementation in laboratories. The fastest available tool for somatic coliphage enumeration is the recently developed Bluephage, which uses a modified beta glucuronide-overexpressing E. coli strain unable to take up the glucuronide substrate. The overexpressed enzyme accumulates inside the bacterial cells until released by phage-induced cell lysis, whereupon it encounters its substrate and the medium changes from yellow to blue. The present method uses E. coli strain CB12, sensitive to somatic coliphages and F-specific coliphages due to the expression of the F-pili. The Bluephage approach incorporating CB12 detects both types of coliphages in a time range of 1:30 to 4:00 h, as assayed with coliphages from raw sewage, river water, sludge and mussels. This strategy can be applied to obtain qualitative and quantitative results and is applicable to microplates as well as to large sample volumes (100 ml). Moreover it can provide monitoring of water bodies at real time, as for example for ambient recreational beach monitoring. PMID- 30471595 TI - A high-resolution map of soil pH in China made by hybrid modelling of sparse soil data and environmental covariates and its implications for pollution. AB - The soil's pH is the single most important indicator of the soil's quality, whether for agriculture, pollution control or environmental health and ecosystem functioning. Well documented data on soil pH are sparse for the whole of China - data for only 4700 soil profiles were available from China's Second National Soil Inventory. By combining those data, standardized for the topsoil (0-20 cm), with 17 environmental covariates at a fine resolution (3 arc-second or 90 m) we have predicted the soil's pH at that resolution, that is at more than 109 points. We did so by parallel computing over tiles, each 100 km * 100 km, with two machine learning techniques, namely Random Forest and XGBoost. The predictions for the tiles were then merged into a single map of soil pH for the whole of China. The quality of the predictions were assessed by cross-validation. The root mean squared error (RMSE) was an acceptable 0.71 pH units per point, and Lin's Concordance Correlation Coefficient was 0.84. The hybrid model revealed that climate (mean annual precipitation and mean annual temperature) and soil type were the main factors determining the soil's pH. The pH map showed acid soil mainly in southern and north-eastern China, and alkaline soil dominant in northern and western China. This map can provide a benchmark against which to evaluate the impacts of changes in land use and climate on the soil's pH, and it can guide advisors and agencies who make decisions on remediation and prevention of soil acidification, salinization and pollution by heavy metals, for which we provide examples for cadmium and mercury. PMID- 30471596 TI - Impact of rice-fish/shrimp co-culture on the N2O emission and NH3 volatilization in intensive aquaculture ponds. AB - How to reduce the gaseous nitrogen (N) pollution (N2O and NH3) of intensive aquaculture ponds to atmosphere has gained increasing attention for the sustainable development of aquaculture. In this study, we constructed a new rice fish/shrimp co-culture system in aquaculture ponds by using a specially developed high-stalk rice variety, and performed a 2-year field experiment to investigate the effect of this system on the N2O and NH3 emissions from yellow catfish and freshwater shrimp ponds. The results showed that the mean emission factors of N2O and NH3 to the total N input in feed was 0.18% and 0.89% for catfish monoculture pond, and 2.46% and 13.45% for shrimp monoculture pond, respectively. Rice fish/shrimp co-culture not only reduced the N2O and NH3 emission from rice platform of catfish and shrimp ponds, but also mitigated the N2O and NH3 emission from the ditch without rice planted. The total amount of N2O and NH3 were respectively mitigated by 85.6% and 26.0% for catfish pond, and by 108.3% and 22.6% for shrimp pond, as compared with that of monoculture ponds. Co-culture system was more effective on the mitigation of gaseous N loss in the catfish than shrimp ponds. PMID- 30471597 TI - Use of estuarine resources by top predator fishes. How do ecological patterns affect rates of contamination by microplastics? AB - This study assessed the seasonal patterns of habitat utilization, feeding ecology and microplastic contamination in different ontogenetic phases of sympatric snooks (Centropomus undecimalis and C. mexicanus) inhabiting a tropical estuary. More than 50% of snooks, in all ontogenetic phases, ingested microplastics (1.5 +/- 0.1 and 1.4 +/- 0.1 particles ind-1). Juveniles migrated to nursery grounds in the upper estuary, during the early dry (C. undecimalis 6.5 +/- 2.8 ind-1) (p < 0.01) and early rainy seasons (C. mexicanus 4.1 +/- 1.9 ind-1). There, they fed mostly on invertebrates (Polychaeta) (p < 0.01), and became contaminated by microplastics (C. undecimalis: 0.8 +/- 0.4 particles ind-1; C. mexicanus: 1.7 +/- 0.5 particles ind-1). Sub-adults of both species forage principally in the estuarine habitats after shifting their diet from invertebrates (shrimps) in the upper reaches (1806.4 +/- 1729.6 mg ind-1) to pelagic fishes (R. bahiensis) in seaward habitats (2507.7 +/- 1758.4 mg ind-1). During feeding continues the contamination by microplastics (3.1 +/- 0.8 part. ind-1). Adults use the adjacent coastal as feeding and spawning grounds during the rainy season. In this phase, snooks are mostly piscivorous (R. bahiensis: up to 5303.8 +/- 3213.4 mg ind-1), but also ingest penaeid shrimp as complementary item (up to 175.9 +/- 156.7). Microplastics contamination rates increased towards the adult phase, with maximum contamination coinciding with peaks of fish ingestion, suggesting trophic transfer of microplastics. The lower estuary and adjacent coastal zone were important contamination sites, especially during the rainy season (up to 3.1 +/- 0.8 part. ind-1) (p < 0.01), when fishery activities is intense and river basin runoff increases. Consequently, the availability of microplastics is higher during this time of year in the lower portion of the estuary. Snooks had similar prey preferences, but the use of different habitats along the life cycle of each species avoids overlaps in estuarine use and minimizes competition. PMID- 30471599 TI - Profiles of bacterial assemblages from microplastics of tropical coastal environments. AB - Plastic waste is a global issue of an increasing concern in aquatic ecosystems. Microplastics form a large proportion of plastic pollution in marine environments. Although microplastics are prevalent, their distribution along the coasts of tropical regions is not well studied. Microplastic pieces (1-5 mm) were collected from two distinct regions along the coastlines of Singapore, from the northern coast in the Johor Strait and the southern coast in the Singapore Strait. Microplastics were present in concentrations ranging from 9.20-59.9 particles per kg of dry sand sediment. The majority of microplastics identified were foam particles (55%) and fragments (35%). Microplastics were significantly more abundant on heavily populated beaches compared to pristine beaches. High throughput sequencing was used to profile the communities of bacteria on the surfaces of microplastic particles. The structure of the microbial communities was primarily characterised by Proteobacteria and Bacteroidetes and were distinct across sites. Hydrocarbon-degrading genera such as Erythrobacter were dominant in areas with heavy shipping and pollution. Potential pathogenic genera such as Vibrio and Pseudomonas were also identified. This study highlights the diverse bacterial assemblages present on marine microplastic surfaces and the importance of understanding the bacterial plastisphere. PMID- 30471598 TI - Time trends in the impact attributable to cold days in Spain: Incidence of local factors. AB - BACKGROUND: While numerous studies have shown that the impact of cold waves is decreasing as result of various processes of adaptation, far fewer have analysed the time trend shown by such impact, and still fewer have done so for the different provinces of a single country, moreover using a specific cold waves definition for each. This study thus aimed to analyse the time trend of the impact of cold days on daily mortality in Spain across the period 1983-2003. METHODS: For study purposes, we used daily mortality data for all natural causes except accidents in ten Spanish provinces. The time series was divided into three subperiods. For each period and province, the value of Tthreshold was obtained via the percentile corresponding to the cold day's definition for that province obtained in previous studies. Relative Risks (RRs) and Population Attributable Fraction (PARs) were calculated using Generalised Linear Models (GLMs) with the Poisson regression link. Seasonalities, trends and autoregressive components were controlled. Global RRs and ARs were calculated with the aid of a meta-analysis with random effects for each of the periods. RESULTS: The results show that the RRs for Spain as a whole were 1.12 (95% CI: 1.08 1.16) for the first period, 1.15 (95% CI: 1.09 1.22) for the second and 1.18 (95% CI: 1.10 1.26) for the third. The impact of cold days has risen slightly over time, though the differences were not statistically significant. These findings show a clearly different behaviour pattern to that previously found for heat. CONCLUSION: The results obtained in this study do not show a downward trend for colds days. The complexity of the biological mechanisms involved in cold-related mortality and the lack of robust results mean that more research must be done in this particular field of public health. PMID- 30471600 TI - Assessing the fate of brown trout (Salmo trutta) environmental DNA in a natural stream using a sensitive and specific dual-labelled probe. AB - Environmental DNA (eDNA) analysis in the aquatic environment has emerged as a promising tool for diagnosis of the ecological status in comprehensive monitoring strategies and might become useful in context of the European Water Framework Directive (WFD) and other legislations to derive stressor-specific indicators. Despite many studies having made significant progress for the future use of eDNA in terms of ecosystem composition and detection of invasive/rare species in inland waters, much remains unknown about the transport and fate of eDNA under natural environmental conditions. We designed a specific dual-labelled probe to detect brown trout (Salmo trutta, L.) eDNA and used the probe to describe the fate of eDNA released from an aquaculture facility into the low mountain range stream Wehebach, Germany. The probe was shown to be specific to brown trout, as ponds housing rainbow trout (Oncorhynchus mykiss) did not test positive. Even though we observed different strengths of eDNA signals for three ponds containing different brown trout quantities, no significant correlation was found between biomass (kg/L) and eDNA quantity. Our results indicate that the release of DNA from brown trout might be life stage and/or age-dependent. The effluents of the aquaculture facility were a source of high levels of eDNA which resulted in the greatest abundance of brown trout eDNA directly downstream of the facility. Despite the natural occurrence of brown trout in the Wehebach, as shown by ecological investigations conducted by authorities of the federal state of North Rhine-Westphalia (Germany) and personal observations, we observed a significant decrease of relative abundance of eDNA in the Wehebach within the first 1.5 km downstream of the aquaculture. Our results suggest that concentrations of eDNA in running waters rapidly decrease under natural conditions due to dilution and degradation processes, which might have important implications for the utility of eDNA in environmental research. PMID- 30471601 TI - Improved arsenic phytoextraction by combined use of mobilizing chemicals and autochthonous soil bacteria. AB - Proper plant selection and application of suitable strategies are key factors to ensure the effectiveness of a reclamation via phytoremediation approach. In this study, micro- and meso-cosm scale experimentation has been realized to address a persistent contamination by arsenic on a disused industrial site through an assisted phytoremediation intervention. Three crop species, namely Brassica juncea, Helianthus annuus and Zea mays, have been considered and the addition of K2HPO4, a common mobilizing agent for As, or (NH4)S2O3, a promising additive for As mobilization in case of mercury co-presence, evaluated. The use of these additives significantly enhanced the bioavailability of the target contaminant and therefore its phytoextraction up to 80%. Furthermore, in order to maximize the extraction efficiency of the plants, the influence of five indigenous Plant Growth Promoting Bacteria (PGPB), in combination with the mobilizing agents, was measured. The addition of the microbial consortium led to a further increase in the total uptake of arsenic, especially in B. juncea (up to 140%). The combined strategy supports and enhances the arsenic phytoextraction together with an improvement of the soil quality, as shown by phytotoxicity tests. PMID- 30471602 TI - Distribution of clinically relevant antibiotic resistance genes in Lake Tai, China. AB - Lake Tai is China's third largest freshwater lake and an important water resource for agriculture, industrial sectors, and as drinking water for several large cities. In this study, the occurrence of five antibiotic resistance genes (sul1, blaTEM, blaNDM-1, blaCTX-M-32, mcr-1) was investigated in water and sediment samples collected from Lake Tai. Antibiotic resistances are currently increasing, posing a significant threat to public health. The sulfonamide resistance gene sul1 was highly abundant in all analyzed water and sediment samples. In addition, the two beta-lactamase genes blaTEMand blaNDM-1 - encoding clinically relevant antibiotic resistances - were detected in 67.1 and 7.3% of the water samples and in 70.7 and 15.4% of the sediment samples. The third beta-lactamase gene, blaCTX M-32, was only detected in water samples (13.4%), while the colistin resistance gene mcr-1 was not detected in any of the samples. No significant variations between different sampling sites or time points could be observed. The investigation of drinking water treatment at Lake Tai, using lake water as influent, showed a significant reduction of the antibiotic resistance genes through the treatment process. Microbial source tracking showed only low fecal contamination by humans, ruminants, and pigs, indicating the relevance of other sources such as fish farms. Overall, our results provide important insights into the occurrence and abundance of antibiotic resistance genes in the Lake Tai water system and their elimination via drinking water treatment. PMID- 30471603 TI - Mixotrophic acidophiles increase cadmium soluble fraction and phytoextraction efficiency from cadmium contaminated soils. AB - A profound concern in developing microbially-assisted phytoextraction is that introduced microbes not only remove heavy metals from contaminated soils but also enhance metal uptake into plant tissues from the treated soils. Cadmium (Cd) removal efficiencies were compared after leaching with deionized water (CK), acidified basal salts medium (acid control), cell-free spent medium (spent bioleaching) and mixotrophic acidophiles (two-step bioleaching). Two-step bioleaching using the mixotrophic acidophiles removed 34% of total Cd and 87% of available Cd, significantly more than CK (3% and 4%), acid control (12% and 51%) and spent bioleaching (26% and 75%). Pot experiments of water spinach growing in four treated soils were conducted to evaluate the Cd uptake performance in plants. Notably, the mixotrophic acidophiles increased Cd concentration in plant tissues by 78% compared to the CK group. More interestingly, the mixotrophic acidophiles were not colonized in soils but caused the compositional increase of indigenous microbes such as the genera of Alicyclobacillus, Clostridium sensu strict and Streptacidiphilus. Meanwhile, two-step bioleaching had little effects on soil structure and physicochemical properties determined by the spectroscopy characteristics analysis. These results implied that the mixotrophic acidophiles facilitated the development of microbially-assisted phytoextraction technology. PMID- 30471604 TI - Factors associated with exposure of pregnant women to perfluoroalkyl acids in North China and health risk assessment. AB - Perfluoroalkyl acids (PFAAs) have been frequently found in blood of pregnant women, but the predictors and potential health risk have not been well studied in China. We recruited 534 pregnant women in Tangshan City of Hebei Province in North China between 2013 and 2014 and measured five PFAAs in serum during their early term of pregnancy, including perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), perfluoro-n undecanoic acid (PFUdA), and perfluorononanoic acid (PFNA). We explored the factors associated with the levels of serum PFAAs and assessed associated health risks. Food consumption information was obtained by food frequency questionnaire covering 100 items. Multiple linear regression model was used to determine the associations of sociodemographic, anthropometric, and food factors with the concentrations of serum PFAAs. Some PFAAs in serum were positively associated with age and body mass index (BMI). Consumption of beans, aquatic products, and eggs was positively associated with the concentrations of several PFAAs after adjusting for important covariates. Pregnant women who ate more cereal, vegetables, mushrooms and alga tended to have lower levels of serum PFOA, PFOS and PFNA. The Hazard index (HI) for reproductive toxicity and developmental toxicity was below 0.8, and the HI for hepatotoxicity beyond 1 was found in 0.37% of pregnant women. These results suggested that age, BMI, and some food consumption were predictors for the exposure to PFAAs in Chinese pregnant women. More attention should be paid to the hepatotoxicity for these exposures. PMID- 30471605 TI - Spatial assessment of major and trace element concentrations from Lower Athabasca Region Trout-perch (Percopsis omiscomaycus) otoliths. AB - The Lower Athabasca Region (LAR) is home to the largest bitumen deposit in Alberta, and has seen industrial development related to the extraction and processing of bituminous sands since the late 1960s. Along with industrial and economic growth related to oil sands development, environmental concerns have increased in recent decades, including those about potential effects on fish. We measured major and trace element concentrations in Trout-perch otoliths from the Athabasca and Clearwater Rivers in the LAR, to illustrate spatial variations and identify possible industrial impacts. Both laser ablation ICP-MS and solution based ICP-MS methods were employed. Of the trace elements enriched in bitumen (V, Ni, Mo and Re), only Ni and Re were above the limits of detection using at least one of the methods. The only significant differences in element concentrations between upstream and downstream locations were found for Li, Cu, and Pb which were more abundant upstream of industry. For comparison and additional perspective, otoliths from the same fish species, but taken from the Batchawana River in northern Ontario, were also examined. The fish from Alberta yielded greater concentrations of Ba, Bi, Li, Mg, Na, Re, Sc, Th and Y, but the Ontario fish had more Cr, Rb and Tl, likely because of differences in geology. PMID- 30471607 TI - A meta-decision-analysis approach to structure operational and legitimate environmental policies - With an application to wetland prioritization. AB - Environmental policies are implemented in complex socio-economic settings, where numerous stakeholders hold different and potentially conflicting values. In addition to being scientifically well-founded, the experts' recommendations on which these policies are based therefore also need to be operational and legitimate. Multi-criteria decision-analysis (MCDA) is often used to solve management problems, but studies in the literature rarely place importance on the way stakeholders perceive researchers' interventions (which implies a lack of legitimacy), and most managers lack the skills to reproduce routinely the operations involved (which implies a lack of operationality). We use MCDA methodology in a different approach: "meta-decision-analysis" (Meta-DA). As researchers, instead of striving to identify the best way for us to solve managers' problems, we identify the actors (the decision-aid providers, DAPs) who are best placed to help managers, and we provide DAPs with the necessary tools. Implementing this approach involves three tasks: T1-identifying a legitimate DAP who will provide decision-aid to managers in routine policy implementations; T2- identifying, among the decisions involved in solving managers' problems, those for which managers and the stakeholders concerned consider that some actors have particular legitimacy; T3-designing tools that are compatible with both the DAP's skills and legitimacy constraints. We applied this approach, structured around T1 3, to wetland prioritization in a French administrative region (Bourgogne-Franche Comte). This application illustrates the feasibility and usefulness of our approach. Our approach entails recommendations for various kinds of actors involved in environmental policies: For researchers, it provides a research agenda to develop new applications of MCDA. For managers and potential DAPs, it suggests that, for some of the problems they face collectively, they should seek the help of researchers to implement a Meta-DA approach. For policy-makers, it suggests that, by encouraging Meta-DA, for example through dedicated funding schemes, they could improve the effectiveness of environmental policies. PMID- 30471606 TI - Evaluation of the bio-protection mechanism in diffusive exchange permeable reactive barriers for the treatment of acid mine drainage. AB - This research studied the bio-protection mechanism based on chemical gradients in diffusive exchange permeable reactive barriers, evaluating the thickness of the reactive layers in the treatment of concentrated acid mine drainage (AMD). Six bench-scale reactors were constructed with reactive layer thicknesses of 2.5, 5, and 7.5 cm in duplicate. The reactors were first fed a sulfated solution for 55 days, followed by concentrated AMD for 166 days. The change of feed to AMD mainly affected the reactors with thinner 2.5 cm layers in comparison to the reactors with 5 and 7.5 cm layers. Cu and Zn removal efficiency was practically 100% in all the reactors; however, in the thinner layer reactors, metal breakthrough occurred towards the end of the experiment concurrently with inhibitory metal concentrations in the reactive layers. On the contrary, the reactors with layer thicknesses of 5 and 7.5 cm evaluated did not present toxic concentrations of these metals at any of the monitoring points. The bio-protection criterion qD correctly predicted that the thin-layer reactor would be the most affected by the toxicity of AMD. The criterion also indicated that all the reactors should fail. Nevertheless, the fault in the thinner layer reactor registered in the effluent after >150 days; therefore, the possibility of failure in the 5 and 7.5 cm thickness reactors is not rejected, as it could have occurred if the experiment had continued. PMID- 30471608 TI - Particle emissions from fused deposition modeling 3D printers: Evaluation and meta-analysis. AB - Fused deposition modeling (FDM) 3D printers, the most popular choice among home hobbyists, have been shown to release volatile organic chemicals (VOCs) and billions of airborne particles per minute, indicating the potential for consumer inhalation exposure and consequent health risks. Publications on FDM 3D printer emissions however, contain large heterogeneity of testing methods and analytical procedures making it difficult to reach overall conclusions for particle characteristics or particle number emission rates across the field. In this publication, data were collected over the printing time from 3D printer emission studies including particle count diameters (PCDs) (nanometers), particle number concentrations (PNCs) (particles/cm3), and particle number emission rates (PNERs) (particles min-1). Despite heterogeneity in methods, the majority of particles released were reported as ultrafine in size (i.e., <100 nm) indicating that using both acrylonitrile butadiene styrene (ABS) and poly-lactic acid (PLA) may present a risk of exposure to respirable particles. Mean PNC emitted in 3D printing tests ranged over several orders of magnitude across publications with overall means of 300,980 particles/cm3 for ABS and 65,482 particles/cm3 for PLA. Although mean PNC data were available from only 7 of the 16 papers reviewed, ABS resulted in greater particle numbers than PLA suggesting increased exposure to ultrafine particles. A linear mixed model was fitted for mean PNCs to further explore the impact of nozzle temperature and filament material. Finally, the PNER calculation method especially regarding losses, varied widely across studies, and directly impacted the PNERs reported. To strengthen direct comparability of results going forward, it is recommended that standard emissions testing protocols be developed for FDM 3D printers and particle influxes and losses be more uniformly calculated. PMID- 30471609 TI - Cabbage-shaped zinc-cobalt oxide (ZnCo2O4) sensing materials: Effects of zinc ion substitution and enhanced formaldehyde sensing properties. AB - Exploiting chemical sensors (CSs) with high-activity sensitive materials is very important for the detection of volatile organic compounds (VOCs). Co-containing spinel oxides are potential candidates for sensing layers. However, the intrinsic activity always hinders their further progress of sensing performances such as sensitivity and selectivity. Here, a facile strategy is successfully developed for the substitution of Co cations into Zn cations in Co3O4 without sacrificing multi-shelled hollow structure. The synthesized cabbage-shaped ZnCo2O4 exhibited the enhanced formaldehyde sensing capability compared to the Co3O4 counterpart. The sensitivity to 100 ppm formaldehyde for ZnCo2O4-sensors is 7.4 at 180 degrees C, which is 6.2 times higher than that of Co3O4-sensors. In addition, the ZnCo2O4-sensors also show the fast response/recovery time (9/12 s) compared to Co3O4-sensors (55/63 s). Interestingly, Zn2+ introduction can facilitate the accumulation of holes and generate more defective oxygen and adsorbed oxygen effectively. Consequently, remarkably improved sensitivity, selectively and fast response/recovery process are demonstrated for the ZnCo2O4-based sensors. The results offer crucial insights in realization of highly sensitive spinel oxide materials for CSs. PMID- 30471610 TI - Colorimetric determination of Hg2+ in environmental water based on the Hg2+ stimulated peroxidase mimetic activity of MoS2-Au composites. AB - A colorimetric assay is described for sensitive determination of Hg2+ ions based on the MoS2-Au composites as peroxidase mimetics, which are synthesized by microwave-assisted solvothermal method. The addition of Hg2+ stimulates their peroxidase-like activity, along with lower Michaelis constant toward the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) with H2O2, allowing the composites for direct determination of Hg2+. A broad linear response is obtained ranging from 20 nM to 20 MUM with a detection limit (LOD) of 5 nM. The superior peroxidase-like activity is attributed to the large surface area of MoS2 nanosheets and the synergistic catalytic effect of MoS2 and Au. The Hg2+ stimulation effect implies the strong interaction between Hg2+ and MoS2-Au, where the XPS results confirm the presence of metallic Hg0, indicative of an Au-Hg amalgam. This colorimetric assay is successfully applied for the determination of Hg2+ in environmental water (tap water and Yellow River water) with excellent selectivity over interfering cations. PMID- 30471611 TI - KOH activation of wax gourd-derived carbon materials with high porosity and heteroatom content for aqueous or all-solid-state supercapacitors. AB - Biomass precursors with natural porous structure and multifarious heteroatoms are desirably sustainable precursors for synthesis of carbon materials for energy and environmental applications. Herein, we reported wax gourd based porous carbons (WGPCs) with developed micro/mesoporous structures via potassium hydroxide (KOH) chemical activation. The optimized material that is denoted as WGPC-4 exhibits high specific surface area (2919 m2 g-1) with oxygen and nitrogen contents of 17.9 at.% and 1.0 at.%, respectively. In a three-electrode system, the WGPC-4 electrode presents high specific capacitance of 333 F g-1 at current density of 1 A g-1. Meanwhile, the assembled symmetrical cell using aqueous electrolyte (0.5 M Na2SO4) has high specific capacitance (167 F g-1 at 1 A g-1), stable cycling characteristics (93% capacitance retaining after 5000 runs) and excellent energy density of 19.2 Wh kg-1. Furthermore, these WGPC-4 electrodes were assembled into an all-solid-state supercapacitor using KOH/polyvinyl alcohol (PVA) gel as solid electrolyte, whose specific capacitance is 258 F g-1 at 1 A g-1, retention at the 2500th run is 87% and energy density is 13.0 Wh kg-1 under a high power density. These materials with excellent structural characteristics are an ideal candidate for high-performance supercapacitors. PMID- 30471612 TI - Effect of triblock copolymer surfactant composition on flow-induced phase inversion emulsification in a tapered channel. AB - HYPOTHESIS: Phase inversion emulsification (PIE) is a process that inverts the dispersed and continuous phases of an emulsion and is useful for preparing emulsions that are challenging to produce using conventional techniques. A recent work has shown that PIE can be induced by flowing an emulsion through a tapered channel. Although prior studies have shown that flow-induced PIE (FIPIE) is influenced by the flow conditions and wetting properties of the channel surface, little is known about the effect of surfactant structure on FIPIE. We hypothesize that FIPIE is affected by the composition and structure of the surfactant used for emulsion stabilization. EXPERIMENTS: We use Pluronics, a series of ABA triblock copolymers composed of hydrophilic poly(ethylene oxide) (PEO) and hydrophobic poly(propylene oxide) (PPO) with various lengths (A = PEO, B = PPO), as model surfactants to test this hypothesis. We observe that triblock copolymer surfactants with long PEO blocks suppress FIPIE. A scaling analysis based on a polymer brush model qualitatively agrees with the experimental observation. We also show that for small molecular weight Pluronics, FIPIE is significantly suppressed when Pluronics with large PPO blocks are used. FINDINGS: Our results strongly indicate that the steric repulsion provided by the PEO blocks as well as the dilatational elasticity provided by the PPO blocks are key factors that control the FIPIE process. PMID- 30471613 TI - Double conductivity-improved porous Sn/Sn4P3@carbon nanocomposite as high performance anode in Lithium-ion batteries. AB - Carbon encapsulated porous Sn/Sn4P3 (Sn/Sn4P3@C) composite is conveniently prepared by one-step electrochemical dealloying of Sn80P20 alloy in mild conditions followed by growing one carbon layer. Controllable dealloying of the Sn80P20 alloy results in the formation of bicontinuous spongy Sn4P3 nanostructure with a part of residued metallic Sn atoms embedded in the porous skeleton. A uniform carbon layer is deposited on the nanoporous Sn/Sn4P3 to prevent the nanostructure's pulverizing and agglomerating during lithium ion insertion/extraction. Upon double conductivity modification from metallic Sn matrix and carbon layer, the as-made composite displays superior lithium-storage performances with much higher specific capacity as well as better cycling stability compared with pure porous Sn4P3. It offers a specific capacity of 837 mA h g-1 after 100 cycles at a rate of 100 mA g-1. Even after 700 cycles at the higher rate of 1000 mA g-1, the specific capacity still maintains as high as 589 mA h g-1. The Sn/Sn4P3@C material possesses promising application potential as an alternative anode in the lithium storage fields. PMID- 30471614 TI - Apparent contact angles for reactive wetting of smooth, rough, and heterogeneous surfaces calculated from the variational principles. AB - Apparent steady contact angles inherent for reactive wetting of flat, rough and chemically heterogeneous solid surfaces are calculated from the variational analysis of the reactive wetting problem. The surface (2D) and linear (1D) contributions to the free energy of the reactive wetting system constitute the apparent contact angle, whereas the bulk contributions such as external fields and heat release do not influence the apparent contact angles of reactive wetting. When the interfacial tensions constitute the apparent contact angle, the equilibrium contact angles are independent on the dimensions of droplets. When the line tension is taken into account, the apparent steady contact angle depends on the radius of the contact area. The Wenzel and Cassie-like regimes of reactive wetting are considered. Reactive wetting of porous surfaces is addressed. The Cassie impregnating reactive wetting regime is treated. PMID- 30471615 TI - Presence of trophoblast in the uterine lumen affects VEGF-C expression in porcine endometrium. PMID- 30471616 TI - Generation of a human iPS cell line from a patient with retinitis pigmentosa due to EYS mutation. AB - Retinitis pigmentosa (RP) is an inherited retinal degenerative disease. Mutations in EYS have been associated with autosomal recessive RP. The human iPS cell line, CABi002-A, derived from peripheral blood mononuclear cells from a patient carrying a heterozygous double mutation in EYS gene was generated by non integrative reprogramming technology, using hOCT3/4, hSOX2, hc-MYC and hKLF4 reprogramming factors. Pluripotency and differentiation capacity were assessed by immunocytochemistry and RT-PCR. This iPSC line can be further differentiated towards the affected cells to understand the pathophysiology of the disease and test new therapeutic strategies. PMID- 30471617 TI - Quercetin inhibits Mrgprx2-induced pseudo-allergic reaction via PLCgamma-IP3R related Ca2+ fluctuations. AB - An allergic reaction is a potentially fatal hypersensitivity response caused by mast cell activation, particularly histamine and lipid mediators. Histamine release caused by reaction to drugs is considered a pseudo-allergic reaction. Quercetin is known for its anti-allergic immune effect. However, at present, its anti-pseudo-allergic effect and its mechanism are less investigated. Therefore, the purpose of this study was to evaluate the anti-pseudo-allergic effect of Quercetin in vivo and to explore the mechanism in vitro. The anti-pseudo-allergic activity of Quercetin was evaluated in vivo using a mouse model, while Quercetin mechanism of action was examined in vitro using HEK293 cells expressing Mrgprx2, a mast cell specific receptor, and LAD2 mast cell line. Our in vivo results showed that Quercetin could attenuate Evans blue leakage in the paws and hind paw thickness in C57BL/6 mice in a dose-dependent manner, and could significantly inhibit serum histamine and chemokines release. In addition, it suppressed calcium mobilization and attenuated the release of histamine and MCP-1 in peritoneal mast cells in a dose-dependent manner. Furthermore, it inhibited the vasodilation due to histamine, the release of eosinophils, and the percentage of degranulated mast cells, indicating that Quercetin antagonized mast cell mediators in vivo, histamine-induced vasodilation and eosinophil release. In vitro results showed that Quercetin reduced pseudo-allergic induced calcium influx, suppressed degranulation and chemokines release in a similar way as dexamethasone (100 MUM) (mast cell stabilizer) in LAD2 mast cell line. In addition, Quercetin inhibited Mrgprx2-induced both calcium influx and pseudo allergic reaction in HEK293 cells expressing Mrgprx2. C48/80, a histamine promoter, and Substance P (a neuropeptide) EC50 was higher when combined with Quercetin compared to the EC50 of these compounds alone, suggesting that Quercetin could inhibit Mrgprx2-induced pseudo-allergic reaction. Furthermore, Quercetin decreased PLCgamma-IP3R signaling pathway activation induced by C48/80 in LAD2 mast cell line. In Mrgprx2 knockdown LAD2 cells, the effect of Quercetin (200 MUM) reduced C48/80 induced calcium flux and the release of beta hexosaminidase, histamine, MCP-1 and IL-8 compared with non-atopic control (NC) transfected LAD2 human mast cells, suggesting that Quercetin anti-pseudo-allergic effect was related to Mrgprx2. The docking results showed that Quercetin had a good binding affinity with Mrgprx2 similar to the one of Substance P and C48/80. Therefore, Quercetin inhibited Mrgprx2-induced pseudo-allergic reaction via PLCgamma-IP3R associated Ca2+ fluctuations. Our results validated Quercetin as an effective small molecule inhibiting Mrgprx2-induced pseudo-allergic reaction via PLCgamma-IP3R associated Ca2+ fluctuations, thus highlighting a potential candidate to suppress Mrgprx2 induced pseudo-allergic related diseases. PMID- 30471618 TI - The effect of high glucose-based peritoneal dialysis fluids on thioredoxin interacting protein expression in human peritoneal mesothelial cells. AB - BACKGROUND: It has been demonstrated that thioredoxin-interacting protein (TXNIP) interacted with NACHT, LRR and PYD domains-containing protein 3 (NLRP3) and participated in the NLRP3 inflammasome activation. Our previous study has demonstrated that in human peritoneal mesothelial cells (HPMCs), exposure to high glucose-based peritoneal dialysis (PD) solutions induced mitochondrial reactive oxygen species (ROS) production, activation of NLRP3 inflammasome and IL-1beta expression. This study aimed to investigate the effect of high glucose-based PD fluids on the TXNIP expression and the underlying mechanisms by which TXNIP-NLRP3 interaction mediates the inflammatory injury to HPMCs in high glucose-based PD fluids conditions. METHODS: TXNIP gene and protein expression was detected by real-time polymerase chain reaction (RT-PCR) and immunoblot. Immunoprecipitation was used to evaluate the interaction between TRX1 and TXNIP, TXNIP and NLRP3. ROS production and IL-1beta expression was examined by flow cytometry and immunoblot and enzyme-linked immunosorbent assay (ELISA) respectively. RESULTS: It was identified that high glucose-based PD solutions enhance the level of TXNIP gene and protein in cultured HPMCs and a rat-based PD model. We also found that ROS generation induced by high glucose-based PD solutions disrupts the TRX1-TXNIP association, while promoting the binding of TXNIP to NLRP3 in HPMCs. Furthermore, the application of a ROS inhibitor (APDC) to HPMCs blocked the high glucose-based PD solution-induced TXNIP-NLRP3 binding, in addition to ROS production and IL 1beta expression. CONCLUSION: The results of the present study revealed a novel mechanism underlying high glucose-containing PD-mediated peritoneal inflammatory injury, supporting the attenuation of ROS generation as a potential therapeutic strategy to alleviate such pathology. PMID- 30471619 TI - The effects of habitual footwear in gait outcomes in people with Parkinson's disease. AB - BACKGROUND: Gait is impaired in individuals with Parkinson's disease (PD). Although the effect of habitual footwear on gait spatiotemporal parameters has already been established in neurologically healthy individuals, its effects on people with PD is unknown. RESEARCH QUESTION: This study aimed to investigate the impact of habitual footwear on the step spatiotemporal parameters in people with PD. METHODS: Sixteen individuals with PD (G-PD) and 15 neurologically healthy individuals (G-HC) were assessed. Participants walked on an 8 m long pressure sensitive walkway at their preferred speed with and without their habitual footwear (3 trials per condition). Footwear included flip-flops, shoes, sneakers and sandals. The average, variability and asymmetry for step length, width, duration, and velocity and the percentage time in the swing and stance phases were calculated. RESULTS: The results showed in both groups a reduced percentage time in the swing phase and an increased step width, duration and length with footwear (F(1,29)>5.64; p<0.02). Additionally, habitual footwear increased step width variability in G-PD and G-HC (F(1,29)=3.97; p=0.06). Interestingly, only G HC showed a higher step length asymmetry in the footwear condition than in the barefoot condition (p=0.02). Finally, only when habitual footwear was used, G-HC showed a higher step velocity asymmetry than G-PD (p=0.04). SIGNIFICANCE: These results indicate a negative influence of footwear on gait spatiotemporal parameters in both groups. Furthermore, footwear induced differences between groups. These findings indicate that footwear use is an influencing factor in studies comparing people with PD and healthy elderly. Further data are needed before definitive recommendations are made. PMID- 30471620 TI - Population bottlenecks in multicomponent viruses: first forays into the uncharted territory of genome-formula drift. AB - Multicomponent viral systems face specific challenges when enduring population bottlenecks. These systems can lose coding information due to the lack of co encapsidation of all the genetic information, at least in a proportion of the capsids in a population. Moreover, bottlenecks can also impact one of the main potential advantages of multicomponent systems: the regulation of gene expression through changes in gene copy frequencies at the population level. How these systems cope with population bottlenecks is far from being clear. Here, two non exclusive scenarios are described. In the first scenario, population bottlenecks during host infection allow for the isolation of within-host populations with different gene frequencies, leaving the door opened for the selection of populations with adaptive gene frequencies. The second scenario postulates that viruses could influence bottleneck size, at least at certain steps of their life cycle, to limit random changes in gene frequencies. Examples of viral mechanism impacting bottleneck size at cell infection are available and, intriguingly, they can lead to either increases or reductions in bottleneck size. This situation opens the way for putative trade-offs on both gene frequencies and bottleneck sizes that could differ among multicomponent systems. PMID- 30471621 TI - Peer influence or projection bias? Predicting respondent delinquency with perceptual measures of peer delinquency in 22 samples. AB - INTRODUCTION: The current study was designed to determine whether the peer influence effect is the direct result of respondents projecting their own delinquency onto peers in a process referred to as projection bias. METHODS: Data from 22 gender-homogeneous U.S. and British samples (Ns = 154 to 4098) of individuals under the age of 17 at the time of initial assessment were used to create partial correlations between perceptual measures of peer delinquency and subsequent respondent offending, controlling for concurrent respondent offending. RESULTS: Significant partial correlations surfaced between peer delinquency and subsequent respondent offending in 21 out of 22 samples, for a significant pooled effect size (rp1o2.o1) of 0.158 (95% CI = 0.124-.193). Although the peer offending relationship, controlling for prior offending, was moderated by data recentness-with less recent samples (>16 years old) achieving a higher pooled effect size than more recent samples (<=16 years old)-a small but significant pooled effect size was recorded for both more and less recent samples. CONCLUSIONS: These results are inconsistent with projection bias as a complete explanation for the peer influence effect and suggest that perceived peer delinquency has a demonstrable and meaningful effect on future offending in adolescents. Despite the lack of support for the projection hypothesis, there is still a need to include additional variables in the analyses (i.e., direct measures of peer delinquency and differential respondent opportunities to observe peer behavior) while entertaining alternative explanations of the perceived peer delinquency-future offending relationship (i.e., hearsay and rejecting delinquency/non-delinquency). PMID- 30471622 TI - The importance of self-efficacy and educational aspirations for academic achievement in resource-limited countries: Evidence from Ghana. AB - INTRODUCTION: Research on the influence of academic self-efficacy and educational aspirations on academic performance is underdeveloped in resource-limited countries. This study replicates and expands on earlier research that investigated a complex network of relationships between academic self-efficacy, educational aspirations, and academic performance. METHODS: Data from 4282 adolescents in Ghana and path analysis were used to test the causal pathways, and path invariance analysis was used to assess the moderation role of gender. Instrumental variable techniques were used to validate the path models. RESULTS: Increase in academic self-efficacy indirectly accounts for improvement in academic performance through the mediational role of educational aspirations. The effects of self-efficacy on educational aspirations, and educational aspirations were stronger for boys than for girls. CONCLUSIONS: These findings suggest that in resource-limited countries where the financial burden of schooling tends to be a demotivating factor, interventions that target adolescents' academic self efficacy may be an effective means to boost educational aspirations and academic performance. Interventions should be tailored to meet the needs of all students so that all children can think of school as an important part of their lives and aspire to achieve, now and in the future. PMID- 30471623 TI - A case report of epiploic appendagitis as a mimic of acute cholecystitis. AB - INTRODUCTION: Epiploic appendagitis is a rare cause of acute abdominal pain. It's presentation often mimics other causes of acute abdominal pain. It is important for clinicians to be aware of an epiploic appendagitis since a delay in diagnosis can lead to unnecessary hospital stay, antibiotic usage and surgical intervention [1-4]). We present a case of epiploic appendagitis mimicking acute cholecystitis in a rural community hospital. CASE REPORT: A 54 Caucasian male self-presents to the emergency department on a Saturday with severe right upper quadrant pain. He was initially diagnosed as acute cholecystitis and managed with antibiotics. Due to limitations with out-of-hours radiology, an ultrasound (US) scan was performed two days after admission. This US showed no evidence of cholecystitis or gallstones. A computed tomography (CT) scan was subsequently performed which revealed a diagnosis of epiploic appendagitis. The patient was discharged with analgesia and anti-inflammatories. DISCUSSION: Epiploic appendagitis can mimic common pathologies causing acute abdominal pain. Unlike its mimics, epiploic appendagitis is a self-limiting condition and its initial management remains conservative. It is diagnosed with imaging studies such as CT scans. It is important for clinicians to be aware of an epiploic appendagitis as a cause for abdominal pain since a delay in diagnosis can lead to unnecessary hospital stay, antibiotic usage and surgical intervention [1-4]. CONCLUSION: A diagnosis of epiploic appendagitis should remain on the list of differential diagnosis for acute abdominal pain. A prompt diagnosis of epiploic appendagitis avoids unnecessary surgical intervention and antibiotic usage. PMID- 30471624 TI - Usefulness of intraoperative neuromonitoring for preservation of an extralaryngeal bifurcation of the recurrent laryngeal nerve: A case report. AB - INTRODUCTION: Recurrent laryngeal nerve injury is a major complication of thyroid surgery. An endotracheal tube with electromyography electrodes attached to it was recently developed for intraoperative neuromonitoring during thyroid surgery. Here we describe the successful identification and preservation of an extralaryngeal bifurcation of the recurrent laryngeal nerve by intraoperative neuromonitoring in a patient undergoing thyroid surgery. PRESENTATION OF CASE: A 56-year-old woman presented for evaluation of a neck swelling found during a medical examination. Computed tomography (CT) revealed a tumor with a 5-cm diameter in the left thyroid lobe. Fine needle aspiration cytology revealed a Bethesda category III finding. Left thyroid lobe resection was scheduled. During surgery, the left recurrent laryngeal nerve was found to be adhered to the tumor. Careful exploration and intraoperative neuromonitoring allowed us to identify and preserve an extralaryngeal bifurcation of the recurrent laryngeal nerve. DISCUSSION: The recurrent laryngeal nerve can demonstrate various anomalies and bifurcations. Failure to notice and correctly identify extralaryngeal bifurcation leads to recurrent laryngeal nerve injury. Motor branch injury has a particularly large effect. Intraoperative neuromonitoring has been reported to be useful for identifying and preserving the recurrent laryngeal nerve and its aberrations as well as the external branch of the superior laryngeal nerve during thyroid surgery. CONCLUSION: The findings from this case suggest that an extralaryngeal bifurcation of the recurrent laryngeal nerve can be identified and safely preserved by intraoperative neuromonitoring. PMID- 30471625 TI - Video-assisted thoracoscopic surgery for bilateral intralobar pulmonary sequestration. AB - INTRODUCTION: Intralobar pulmonary sequestration (ILS) is a rare congenital malformation, and is supplied by an aberrant systemic artery. The conventional surgical resection for ILS is lobectomy through an open thoracotomy. However, lobectomy might lead to a significantly compromised pulmonary function. There have been some reports on the feasibility or advantages of the VATS approach in recent years. We report a rare case where we performed a two staged segmentectomy and wedge resection of the affected lesions using a VATS approach for bilateral ILS, and achieved a successful outcome. CASE PRESENTATION: A 30-year-old woman was diagnosed with pneumonia. Chest CT showed multiple cystic masses containing fluid, in the posterobasal segment of the right lung and a hyper infiltrated area in the identical segment of the left lung. 3D CT angiography showed that the area of the right sided lesion received its blood supply from the left gastric artery and the area of the left sided lesion from the proximal celiac artery. The patient was diagnosed with bilateral ILS, and a staged, sequential lung resection was planned using the VATS approach. Anatomical basilar segmentectomy with VATS minithoracotomy for the right ILS, and resection of only the sequestrated lung by VATS for the left ILS were performed. CONCLUSIONS: It is important to plan the surgical treatment strategy for bilateral ILS for the preservation of respiratory function. Limited resection using the VATS approach for bilateral ILS can be performed safely and might be useful as a minimally invasive surgery. PMID- 30471626 TI - Melanotic neuroectodermal tumour of infancy: A report of two cases. AB - INTRODUCTION: Melanotic neuroectodermal tumour of infancy (MNTI) is a benign tumour of infancy, most commonly affecting the head and neck region. First described in 1918, less than 500 cases have been reported in the literature. MNTI is aggressive in nature & has a high rate of recurrence. PRESENTATION OF CASES: In this retrospective case series, we report two cases of MNTI that presented at our unit; both cases were managed by wide excision and have been followed up uneventfully for over two years. DISCUSSION: MNTI has a recurrence rate of up to 20%. Patient's age can play a significant role in recurrence rate. Although this neural crest tumour is somewhat rare in the literature, there is a consensus with regards to surgical management; the gold standard remains to be wide excision with safety margin. Select cases may benefit from adjuvant and neoadjuvant therapy. CONCLUSION: Owing to its locally aggressive nature and high recurrence rate, prompt diagnosis and surgical intervention is advised in cases of MNTI. Further understanding of this tumour is needed on a microscopic level in order to determine clear prognostic factors. PMID- 30471627 TI - Neoplasm of a supernumerary undescended testis: A case report and review of the literature. AB - INTRODUCTION: Polyorchidism, defined as the presence of more than two testicles, is a rare congenital abnormality of the male genital tract. There is no consensus regarding the management of supranumerary testis (SNT) due to its rareness. To the best of our knowledge, this is the first report of leiomyoma in SNT. PRESENTATION OF CASE: We report the case of a 41-year-old man with two right testes sharing a common vas deferens and separate epididymides. Orchiectomy of right testes was performed. Pathology examination found that the superior testis was the site of a leiomyoma and the lower tesits was the site of an intratubular germ cell neoplasia (IGCN). Orchiopexy and biopsy were later performed for the left testis. Histology was compatible with IGCN. We opted for follow-up to avoid risks of hypogonadism. DISCUSSION: Polyorchidism is usually asymptomatic and found incidentally during surgery for inguinal hernia, undescended testes as in our case, torsion, hydrocele or testicular tumor. If the SNT is scrotal, and there is no other indication for surgery, most authors recommend conservative management with regular ultrasound follow-up. If nonscrotal SNT is found incidentally during surgery, orchiectomy could be performed because of increased risk of malignancy. Treatment of IGCN includes surveillance, orchiectomy, or low dose external radiation. CONCLUSION: Different factors come into account for polyorchidsm management: the drainage system, the fertile potential of the supernumerary gonad, and its localization. In cases of uncomplicated polyorchidism, a conservative treatment, with US or MRI follow-up seems to be a rational choice without surgical complications. PMID- 30471628 TI - Freestanding hierarchical vascular structures engineered from ice. AB - The ability to engineer a synthetic hierarchical vascular network is one of the most demanding and unaddressed challenges in tissue engineering and regenerative medicine. A material that is both structurally rigid and biocompatible is needed to fabricate freestanding hierarchical vascular structures with defined dimensions and geometry. This is particularly important for creating commercially viable and easily suturable synthetic vasculature. Here, we present the surprising discovery that ice is a versatile material which satisfies these requirements. We demonstrate utilizing ice as a sacrificial scaffold, onto which a diverse range of materials were coated, including tropoelastin, polycaprolactone (PCL), silk, and polydimethylsiloxane (PDMS). We present ice facilitating the fabrication of freestanding hierarchical vascular structures with variable lumen dimensions, and validate the vascular application of these vessels by demonstrating their mechanical tunability, biocompatibility, and permeability to nutrient diffusion. This adaptable technology delivers engineered synthetic vasculature and has potential wider applications encompassing tissue engineering bespoke structures. PMID- 30471629 TI - Enhanced repair of meniscal hoop structure injuries using an aligned electrospun nanofibrous scaffold combined with a mesenchymal stem cell-derived tissue engineered construct. AB - Damage to the meniscal hoop structure results in loss of biomechanical function, which potentially leads to the extrusion of the meniscus from the weight bearing area. However, there have been no established, effective treatments for such injuries. The purpose of this study was to investigate the applicability of cell seeded nanofibrous scaffolds to repair the damaged meniscal hoop structure along with the prevention of subsequent cartilage degeneration using a rabbit model. Meniscal radial defects (5 mm width) in the medial meniscus were treated by wrapping and suturing with either an aligned electrospun nanofibrous scaffold alone or a scaffold combined with a tissue engineered construct (TEC) derived from synovial mesenchymal stem cells (MSCs), with the scaffold fiber direction matching that of the meniscal circumferential fibers. The MSC-based TEC-combined nanofibrous scaffolds contributed significantly to the prevention of meniscal extrusion and exerted a chondroprotective effect, compared with either scaffold alone or the untreated control groups. Also, meniscal defects treated with such TEC-combined nanofibrous scaffolds were consistently repaired with a fibrocartilaginous tissue. In this study, we have demonstrated the feasibility of a combined TEC-nanofibrous scaffold to repair the meniscal hoop structure, and prevent the progression to cartilage degeneration, as a potential tissue engineering method. PMID- 30471630 TI - Amyloid beta-positive subjects exhibit longitudinal network-specific reductions in spontaneous brain activity. AB - Amyloid beta (Abeta) deposition and cognitive decline are key features of Alzheimer's disease. The relationship between Abeta status and changes in neuronal function over time, however, remains unclear. We evaluated the effect of baseline Abeta status on reference region spontaneous brain activity (SBA-rr) using resting-state functional magnetic resonance imaging and fluorodeoxyglucose positron emission tomography in patients with mild cognitive impairment. Patients (N = 62, [43 Abeta-positive]) from the Alzheimer's Disease Neuroimaging Initiative were divided into Abeta-positive and Abeta-negative groups via prespecified cerebrospinal fluid Abeta42 or 18F-florbetapir positron emission tomography standardized uptake value ratio cutoffs measured at baseline. We analyzed interaction of biomarker-confirmed Abeta status with SBA-rr change over a 2-year period using mixed-effects modeling. SBA-rr differences between Abeta positive and Abeta-negative subjects increased significantly over time within subsystems of the default and visual networks. Changes exhibit an interaction with memory performance over time but were independent of glucose metabolism. Results reinforce the value of resting-state functional magnetic resonance imaging in evaluating Alzheimer''s disease progression and suggest spontaneous neuronal activity changes are concomitant with cognitive decline. PMID- 30471631 TI - Localised GPCR signalling as revealed by FRET biosensors. AB - Forster resonance energy transfer (FRET) biosensors have provided much evidence for compartmentalised signalling following activation of G protein-coupled receptors (GPCRs). This localised signalling occurs within distinct plasma membrane microdomains and at sub cellular locations including endosomes, mitochondria, Golgi and the nucleus. Notable advances linking compartmentalisation to physiology have been made in two major areas: linking compartmentalised cAMP production by the beta2-adrenoceptor to excitation contraction coupling in the heart; and selectively antagonising GPCRs within early endosomes to provide more efficacious inhibition of pain transmission. Important technological advances are also highlighted, including various approaches for the local activation of receptors, and the rational design of a FRET biosensor with a functional affinity that is not affected by the addition of a targeting sequence. PMID- 30471632 TI - The comparative study of island sign and the spot sign in predicting short-term prognosis of patients with intracerebral hemorrhage. AB - OBJECTIVES: It is well known that early hematoma expansion is associated with short-term prognosis of patients with intracranial hemorrhage (ICH). And spot sign is recognized as a reliable computed tomography angiography (CTA) predictor for early hematoma expansion. Recently, island sign is also reported as a novel computed tomography (CT) predictor for early hematoma growth. Here, we compared the predictive abilities of these two signs for short-term outcomes of ICH patients. PATIENTS AND METHODS: All the ICH patients were retrospectively identified. Clinical characteristics and radiological parameters were obtained from electronic medical records. Hematoma expansion, spot sign and island sign were assessed by two senior neurologists according to the initial and follow-up CT scans. 3-months prognoses were estimated according to Glasgow outcome scale (GOS). Multivariate logistic regression analyses were employed to explore the associations of short-term prognosis on island sign, spot sign and other clinical variables. RESULTS: There were 283 ICH patients included. 113 of them presented with early hematoma expansions. 66 of them exhibited island sign, while spot sign occurred in 85 patients. Univariate analyses demonstrated that GCS score at admission (OR: 0.464, 95%CI: 0.395-0.547), hematoma volume (OR:1.062, 95%CI: 1.041-1.083), interventricular extension(OR:9.528, 95%CI: 3.915-23.187), island sign (OR: 4.595, 95%CI: 2.404-8.784) and spot sign (OR: 4.052, 95%CI: 2.297 7.147) were correlated with 3-months morbidity. Moreover, multivariate logistic regression analyses further revealed that both spot sign (OR: 3.413, 95%CI: 1.570 7.422) and island sign (OR: 7.564, 95%CI: 2.969-19.273) were strongly associated with 3-months poor outcome and have comparable predictive values (AUC: 0.636 vs. 0.622, P = .58). However, spot sign exhibited a superior predictive ability for 3 months mortality compared to island sign (OR: 2.713, 95%CI: 1.570-4.217 vs. OR: 2.362, 95%CI: 1.238-3.899, AUC: 0.700 vs. 0.603, P < .01). CONCLUSIONS: Island sign is not just a convenient and reliable predictor for short-term prognosis of ICH patients, but also could be used as an indicator for accurate diagnosis and aggressive treatment. PMID- 30471633 TI - Estimated glomerular filtration rate predicts incident stroke among Ghanaians with diabetes and hypertension. AB - BACKGROUND: Sub-Saharan Africa is currently experiencing a high burden of both chronic kidney disease (CKD) and stroke as a result of a rapid rise in shared common vascular risk factors such as hypertension and diabetes mellitus. However, no previous study has prospectively explored independent associations between CKD and incident stroke occurrence among indigenous Africans. This study sought to fill this knowledge gap. METHODS: A prospective cohort study involving Ghanaians adults with hypertension or type II diabetes mellitus from 5 public hospitals. Patients were followed every 2 months in clinic for 18 months and assessed clinically for first ever stroke by physicians. Serum creatinine derived estimated glomerular filtration rates (eGFR) were determined at baseline for 2631 (81.7%) out of 3296 participants. We assessed associations between eGFR and incident stroke using a multivariate Cox Proportional Hazards regression model. RESULTS: Stroke incidence rates (95% CI) increased with decreasing eGFR categories of 89, 60-88, 30-59 and <29 ml/min corresponding to incidence rates of 7.58 (3.58-13.51), 14.45 (9.07-21.92), 29.43 (15.95-50.04) and 66.23 (16.85 180.20)/1000 person-years respectively. Adjusted hazard ratios (95%CI) for stroke occurrence according to eGFR were 1.42 (0.63-3.21) for eGFR of 60-89 ml/min, 1.88 (1.17-3.02) for 30-59 ml/min and 1.52 (0.93-2.43) for <30 ml/min compared with eGFR of >89 ml/min. Adjusted HR for stroke occurrence among patients with hypertension with eGFR<60 ml/min was 3.69 (1.49-9.13), p = .0047 and among those with diabetes was 1.50 (0.56-3.98), p = .42. CONCLUSION: CKD is dose-dependently associated with occurrence of incident strokes among Ghanaians with hypertension and diabetes mellitus. Further studies are warranted to explore interventions that could attenuate the risk of stroke attributable to renal disease among patients with hypertension in SSA. PMID- 30471634 TI - Mollaret meningitis. PMID- 30471635 TI - A fast and simple FIA-chemiluminescence method for the evaluation of Roselle flowers as scavenger of the free radicals generated by UV irradiated antibiotics. AB - This work proposes a new method for the in vitro evaluation of the effect of UV irradiation on the production of free radicals and other reactive species during the photodecomposition of drugs. The method was based on the UV irradiation of antibiotics molecules to generate excited states that undergo to homolytic bond cleavages. These reactive species can be detected by their ability to oxidize the luminol, producing the electronically excited aminophtalate, which decays to the ground state releasing electromagnetic radiation in the visible zone of the spectrum. This method was applied to penicillin G, nafcillin, azlocillin and neomycin dissolved in water. It was found that the intensity of the luminol chemiluminescence emission (CL) was proportional to the concentration and dependent on the molecular structure of these drugs. Under the optimized conditions, it was found that penicillin and azlocillin were the most susceptible to photodegradation, while neomycin sulfate was the less affected by the UV light. It was observed that the addition to the antibiotics dissolutions of a hydro-alcoholic extract of petals of calyxes of Roselle reduced the CL intensity, indicating that the extract was able to scavenge the free radicals in the irradiated drugs. This result suggest that its addition to the antibiotics can help in the protection against the radicals formed during the exposition to solar light of patients treated with topic similar antibiotics. PMID- 30471636 TI - Development and validation of a gas chromatography-mass spectrometry method for opiates and cocaine in human bone. AB - A method based on gas chromatography-mass spectrometry (GC-MS) is described for the determination of opioids (6-monoacetylmorphine, morphine, methadone and tramadol) and cocaine and its major metabolite in human bone. After the addition of nalorphine as internal standard, pulverized samples were incubated in acetonitrile for 1 h under ultrasounds. After adjusting the pH of the samples to 6, they were subjected to solid phase extraction and the analytes were eluted using 2 ml of dichloromethane/isopropanol/ammonia (78:20:2). Chromatography was performed on a fused silica capillary column and analytes were determined in the selected-ion-monitoring (SIM) mode. The assay was validated in the range 0.3-1 ng/mg (depending on the drug) to 150 ng/mg, the mean absolute recoveries ranging from 66% to 110%, the matrix effect from 62% to 121% and process efficiency from 61% to 89% depending on the analyte. The intra- and inter-assay accuracy values were always better than 20%. The validated method was then successfully applied to real bone samples from forensic cases in which toxicological analysis for these drugs in blood was positive. Drugs were detected in bone in 12 of the 15 blood positive results. The approximate concentration range was 3-5 ng/g for 6 monoacetylmorphine, 3-7 ng/g for morphine, 14-28 ng/g for methadone and 6 ng/g and 11 ng/g for tramadol and benzoylecgonine. PMID- 30471637 TI - Influence of loading rate and limb position on patellar tendon mechanical properties in vivo. AB - BACKGROUND: The aims of this study were to clarify the changes of patellar tendon length during isometric knee joint extension and the double leg squat position using ultrasonography. METHODS: The left legs of 17 healthy adults were investigated. Isometric knee extension motion was performed at three positions of knee flexion 30 degrees (knee 30 degrees ), knee flexion 60 degrees (knee 60 degrees ), knee flexion 90 degrees (knee 90 degrees ), and at each limb position, 0% (0% peak torque (PT)), 40% (40% PT), 50% (50% PT), and 60% (60% PT) of the maximum knee joint extension torque were executed at random. Both double leg squat motions were randomly performed in three positions: hip flexion 30 degrees , knee flexion 30 degrees , ankle dorsiflexion 10 degrees (squat 30 degrees ); hip joint flexion 60 degrees , knee joint flexion 60 degrees , ankle dorsiflexion 20 degrees (squat 60 degrees ); and hip joint flexion 90 degrees , knee joint flexion 90 degrees , ankle dorsiflexion 30 degrees (squat 90 degrees ). Ultrasonography was used to measure patellar tendon length. FINDINGS: There were no significant changes in patellar tendon length and strain between knee flexion angles of 30 degrees , 60 degrees , and 90 degrees in isometric knee joint extension and the double leg squat limb position. INTERPRETATION: The loading rate and limb position do not appear to affect the length and strain of the patellar tendon. PMID- 30471638 TI - Negative Regulation of BOK Expression by Recruitment of TRIM28 to Regulatory Elements in Its 3' Untranslated Region. AB - BCL-2-related ovarian killer (BOK) is a pro-apoptotic BAX-like member of the BCL 2 family with suggested tumor suppressor activity. The molecular mechanisms regulating BOK expression are poorly understood and fail to explain a frequent lack of concordance between protein and transcript levels. Here, we describe a potent post-transcriptional mechanism that negatively regulates BOK expression mediated by conserved (AU/U)-rich elements within its 3' UTR. Using proteomics approaches we identified TRIM28 as a key component associating with U-rich elements in the human BOK 3' UTR, resulting in a dramatic reduction of BOK expression. TRIM28 is overexpressed in several cancers, correlating with poor patient outcome, whereas the BOK locus is frequently deleted or its expression downregulated in human cancers. Data mining indicated that, for certain cancers, high TRIM28 and low BOK expression are significantly correlated in the stratum of patients with the worst survival, suggesting that this mechanism might be of potential therapeutic value. PMID- 30471640 TI - Glutathione S-transferase M1 and T1 null allele frequencies among Indonesian ethnics toward improved disease risk assessment. AB - Genetic variations in the glutathione S-transferase genes GSTT1 and GSTM1 have been widely studied, and homozygous deletions or null genotypes have been reported in different populations. Previous studies suggest that individuals who are homozygous-null at the GSTM1 or GSTT1 locus may have an increased risk of environmentally related cancers and drug-induced hepatotoxicity. The aim of the present study was to determine the GSTM1 and GSTT1 polymorphisms in 154 healthy, unrelated individuals from the Javanese-Sundanese and Malay ethnic populations of Indonesia to provide a resource for improving the prognosis of possible susceptibilities in specific populations. The subjects were genotyped for the presence of GSTM1 and GSTT1 using the multiplex polymerase chain reaction technique. The GSTM1-null genotype was more frequent among Javanese-Sundanese ethnics (99%) than among the Indonesian Malay (67.2%). Similarly, Javanese Sundanese ethnics showed a higher frequency of the GSTT1-null genotype (66.7%) than the Indonesian Malay (36.2%). Analysis of the combined distribution of the GSTM1 and GSTT1 genes revealed that 66.7% of the individuals from the Javanese Sundanese population lack both the genes, whereas only 21.1% of the Indonesian Malay is GSTM1-null and GSTT1-null. This study contributes significant information on the variability of GSTT1 and GSTM1 gene polymorphisms worldwide, which can provide new knowledge about the relationship between ethnicity and the prevalence of certain diseases. PMID- 30471639 TI - Ultralow Pt Catalyst for Formaldehyde Removal: The Determinant Role of Support. AB - Supported Pt catalyst has been intensively investigated for formaldehyde elimination owing to its superior reactivity at room temperature (RT). However, the high Pt content is challenging because of its high cost. Herein, we report PbO-supported Pt catalysts with only 0.1 wt % Pt, which can achieve complete conversion of formaldehyde and reliable stability at RT under demanding conditions. Both experiments and simulations demonstrate that PbO interacts strongly with the Pt species, resulting in tight Pb-O-Pt bonding at the metal/support interface and concomitant activation of the surface lattice oxygen of the support. Moreover, PbO exhibits an extremely high capacity of formaldehyde capture through methylene glycol chemisorption rather than the common hydroxyl associated adsorption, presenting a different reaction mechanism because the active surface lattice oxygen in the vicinity of Pt species offers improved reactivity. This work provides a valuable example for the design of an efficient catalyst for formaldehyde and potentially oxidation of other carbohydrates. PMID- 30471641 TI - Modulating ROS to overcome multidrug resistance in cancer. AB - The successful treatment of cancer has significantly improved as a result of targeted therapy and immunotherapy. However, during chemotherapy, cancer cells evolve and can acquire "multidrug resistance" (MDR), which significantly limits the efficacy of cancer treatment and impacts patient survival and quality of life. Among the approaches to reverse MDR, modulating reactive oxidative species (ROS) may represent a strategy to kill MDR cancer cells that are mechanistically diverse. ROS in cancer cells play a central role in regulating and inducing apoptosis, thereby modulating cancer cells proliferation, survival and drug resistance. The levels of ROS and the activity of scavenging/anti-oxidant enzymes in drug resistant cancer cells are typically increased compared to non-MDR cancer and normal cells. Consequently, MDR cancer cells may be more susceptible to alterations in ROS levels. Numerous studies suggest that compounds modulating cellular ROS levels can enhance MDR cancer cell death and sensitize MDR cancer cells to certain chemotherapeutic drugs. In the current review, we discuss the critical and targetable redox-regulating enzymes, including mitochondrial electron transport chain (ETC) complexes, NADPH oxidases (NOXs), enzymes related to glutathione metabolism, glutamate/cystine antiporter xCT, thioredoxin reductases (TrxRs), nuclear factor erythroid 2-related factor 2 (Nrf2), and their roles in regulating cellular ROS levels, drug resistance as well as their clinical significance. We also discuss and summarize the findings in the past decade regarding the efficacy of ROS modulators for the treatment of MDR cancer alone or as sensitizing compounds. Compounds that are efficacious in modulating ROS generation represent a prominent class of drug candidates that warrants evaluation in clinical trials for patients harboring MDR cancers. PMID- 30471642 TI - Antiviral phytocompounds target envelop protein to control Zika virus. AB - Zika virus infection causes serious birth defects, including microcephaly, when expectant mothers are infected during pregnancy. Zika outbreaks have been reported in the Pacific Islands, South America, the Caribbean, Africa and parts of South East Asia. Currently, there is no specific treatment available for Zika virus infection. Hence, the current study is focused to identify natural phytocompounds to control Zika virus from few endemic anti-viral herbs by in silico approach. Molecular interactions, Pharmacokinetic Study, Molecular dynamic simulation and annealing were carried out with the phytocompounds and checked using Lipinski filter. The interactions between the phytocompounds and Envelope protein (PDB id: 5JHM) of Zika virus was assessed with SYBYL-X 1.3. The results showed that tannic acid from Terminalia arjuna had better interaction, total score, CScore (6.792 and 5) and formed more number of Hydrogen bonds within 2.5 A bond length, best activity in pharmacokinetic study, Molecular dynamic simulation and annealing temperature at 310 K. Our results suggested that tannic acid can be utilized as lead candidate to control Zika virus infection. PMID- 30471643 TI - One-step continuous/semi-continuous whole-cell catalysis production of glycolic acid by a combining bioprocess with in-situ cell recycling and electrodialysis. AB - Bioprocess for successive bio-production of glycolic acid (GA) from ethylene glycol (EG) using Gluconobacter oxydans is hindered by strong end-product inhibitory effect. Based on the model of compressed oxygen supplied-sealed stirred tank reactor (COS-SSTR), we developed a new system by attaching an ultrafiltration instrument and electrodialysis cell to in-situ separate GA, including conductivity meter to control automatic EG feeding. The combined bioprocess was therefore set up as compressed oxygen supplied cell catalysis ultrafiltration-electrodialysis (COS-CUE). In comparison with the conventional resin and electrodialysis separation process, this device simplified the whole bioprocess. We realized the potential of combined bioprocess for producing GA without EG through continuous/semi-continuous 'one-step' process. Finally, 288.4 g GA was obtained at the yield of 96.5% and average productivity of 4.0 g/L/h in 72 h, with an increment of 148.8% and 20.9% in production compared with batch and cell-recycling fermentation. PMID- 30471645 TI - Elucidating the impact of influent pollutant loadings on pollutants removal in agricultural waste-based constructed wetlands treating low C/N wastewater. AB - In this study, the common agricultural wastes (wheat straw, apricot pit and walnut shell) were exploited as the potential organic substrates in subsurface flow CWs (SSFCWs) with intermittent aeration to investigate the impacts of the varied influent loadings on the removal performance of pollutants. The results indicated that an application of agricultural wastes in CWs presented the different role in improving removal efficiency as influent pollutant loadings increased. In middle and high influent pollutant loadings, CWs with walnut shell strengthened the denitrification process significantly, and could achieve preferable purification of COD (97.36%), NH4+-N (98.83%), TN (51.78%), and TP (80.33%), respectively. However, N2O emission fluxes were higher in CWs with agricultural biomass and increased clearly as the influent pollutant loadings increasing. The results indicated that combination of agricultural material addition and aeration could be an appropriate intensifying strategy in SSFCWs especially for treating medium-strength low-carbon wastewaters. PMID- 30471644 TI - Lignin-first biomass fractionation using a hybrid organosolv - Steam explosion pretreatment technology improves the saccharification and fermentability of spruce biomass. AB - For a transition to a sustainable society, fuels, chemicals, and materials should be produced from renewable resources. Lignocellulosic biomass constitutes an abundant and renewable feedstock; however, its successful application in a biorefinery requires efficient fractionation into its components; cellulose, hemicellulose and lignin. Here, we demonstrate that a newly established hybrid organosolv - steam explosion pretreatment can effectively fractionate spruce biomass to yield pretreated solids with high cellulose (72% w/w) and low lignin (delignification up to 79.4% w/w) content. The cellulose-rich pretreated solids present high saccharification yields (up to 61% w/w) making them ideal for subsequent bioconversion processes. Moreover, under high-gravity conditions (22% w/w) we obtained an ethanol titer of 61.7 g/L, the highest so far reported for spruce biomass. Finally, the obtained high-purity lignin is suitable for various advanced applications. In conclusion, hybrid organosolv pretreatment could offer a closed-loop biorefinery while simultaneously adding value to all biomass components. PMID- 30471646 TI - Distribution of mast cells within the mouse heart and its dependency on Mitf. AB - Although mast cell distribution has been described in both human and canine hearts, cardiac mast cells in mice have yet to be categorically localized. We therefore sought to describe mast cell distribution within the mouse heart and characterize their dependence on the Microphthalmia-associated transcription factor (Mitf). Cardiac mast cells were visualized using Toluidine Blue and avidin staining, and their distribution within the heart described. Cardiac mast cells were most prevalent in the epicardium (50%) or myocardium (45%). Less frequently, mast cells were noted in the endocardium (5%). Within the myocardium, 31% of the mast cells had perivascular location. By studying two different Mitf mutant strains, Mitfmi-vga9 and MitfMi-wh, we demonstrated that these mutations led to near-complete deficiency of cardiac mast cells. Accordingly, expression of the mMCP-4 and mMCP-5 genes was lost and chymase enzyme activity was severely reduced. Additionally, hearts from mice heterozygous for these Mitf mutations contained significantly fewer mast cells compared to wild-type mice. Our results demonstrated that the distribution of cardiac mast cells in mice is different from humans and dogs. Cardiac mast cells are dependent on Mitf expression, with loss-of-function mutation in the Mitf gene leading to near-complete lack of cardiac mast cells. Loss of a single Mitf allele is sufficient for relative mast cell deficiency. PMID- 30471647 TI - European Breast Cancer Council manifesto 2018: Genetic risk prediction testing in breast cancer. AB - European Breast Cancer Council manifesto and supporting article on genetic risk prediction testing in breast cancer, presented at the 11th European Breast Cancer Conference in Barcelona, Spain. PMID- 30471648 TI - Genetic counselling and testing of susceptibility genes for therapeutic decision making in breast cancer-an European consensus statement and expert recommendations. AB - An international panel of experts representing 17 European countries and Israel convened to discuss current needs and future developments in BRCA testing and counselling and to issue consensus recommendations. The experts agreed that, with the increasing availability of high-throughput testing platforms and the registration of poly-ADP-ribose-polymerase inhibitors, the need for genetic counselling and testing will rapidly increase in the near future. Consequently, the already existing shortage of genetic counsellors is expected to worsen and to compromise the quality of care particularly in individuals and families with suspected or proven hereditary breast or ovarian cancer. Increasing educational efforts within the breast cancer caregiver community may alleviate this limitation by enabling all involved specialities to perform genetic counselling. In the therapeutic setting, for patients with a clinical suspicion of genetic susceptibility and if the results may have an immediate impact on the therapeutic strategy, the majority voted that BRCA1/2 testing should be performed after histological diagnosis of breast cancer, regardless of oestrogen receptor and human epidermal growth factor receptor 2 (HER2) status. Experts also agreed that, in the predictive and therapeutic setting, genetic testing should be limited to individuals with a personal or family history suggestive of a BRCA1/2 pathogenic variant and should also include high-risk actionable genes beyond BRCA1/2. Of high-risk actionable genes, all pathological variants (i.e. class IV and V) should be reported; class III variants of unknown significance, should be reported provided that the current lack of clinical utility of the variant is expressly stated. Genetic counselling should always address the possibility that already tested individuals might be re-contacted in case new information on a particular variant results in a re-classification. PMID- 30471649 TI - Impact of dose interruption on the efficacy of lenvatinib in a phase 3 study in patients with radioiodine-refractory differentiated thyroid cancer. AB - BACKGROUND: In the phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT), lenvatinib significantly improved efficacy outcomes versus placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). Lenvatinib-treated patients had more adverse events (AEs), which were generally managed with dose modifications, including dose interruption. This exploratory post hoc analysis investigated the impact of dose interruption on lenvatinib efficacy. METHODS: Dose modifications were required for grade 3 or intolerable grade 2 AEs in SELECT. Lenvatinib-treated patients were dichotomised based on the duration of dose interruption relative to total treatment duration: shorter dose interruption (<10% of total treatment duration) and longer dose interruption (>=10%). RESULTS: At the time of primary data cut-off (November 15, 2013; median follow-up, 17.1 months), the median progression-free survival (PFS) for the shorter dose-interruption group had not yet been reached, whereas median PFS for the longer dose-interruption group was 12.8 months (95% confidence interval [CI], 9.3-16.5). Compared with placebo, the hazard ratios for PFS in the shorter and longer dose-interruption groups were 0.14 (95% CI, 0.09-0.20) and 0.31 (95% CI, 0.22-0.43), respectively. In a multivariate model, dose interruption was significantly associated with lenvatinib efficacy, even after adjustment for patient characteristics. CONCLUSIONS: Lenvatinib improved efficacy outcomes versus placebo in patients with RR-DTC, regardless of the duration of dose interruption; however, those with shorter dose interruptions had a greater magnitude of benefit versus those with longer interruptions. This analysis highlights the importance of timely management of lenvatinib toxicities to minimise dose interruptions and maximise lenvatinib efficacy in patients with RR DTC. CLINICALTRIALS. GOV NUMBER: NCT01321554. PMID- 30471650 TI - Efficacy of adjuvant chemotherapy after resection of pulmonary metastasis from colorectal cancer: a propensity score-matched analysis. AB - BACKGROUND: Pulmonary metastases from colorectal cancer are resected due to the favourable 5-year overall survival rates of 30-60% reported in many studies. However, the efficacy of subsequent adjuvant chemotherapy remains unclear. PATIENT AND METHODS: We retrospectively collected clinical data of 1237 patients who underwent surgical resection of pulmonary metastasis from colorectal cancer at 46 Japanese institutions between 2004 and 2008. Patients with non-curative resection, pre-operative chemotherapy, extra-thoracic metastasis, complications after surgery, and inadequate data were excluded. Then, a 1:1 propensity score nearest-neighbour matching between patients with and without adjuvant chemotherapy was performed, considering relevant co-variables, and survival of patients between groups was compared. RESULTS: Data of 524 patients (surgery alone, 269 patients; surgery with adjuvant chemotherapy, 255 patients) were used for matching. From each group, 192 patients with similar background characteristics between groups were selected. Adjuvant chemotherapies included fluoropyrimidine alone (71%), an oxaliplatin-containing regimen (23%), or an irinotecan-containing regimen (6%). In the surgery alone and adjuvant chemotherapy groups, 5-year overall survival rates were 68% and 69%, and 5-year disease-free survival rates were 40% and 34%, respectively. There were no significant differences between the two groups in terms of overall survival (hazard ratio [HR]: 1.00, 95% confidence interval [CI]: 0.69-1.45, P = 1.00) and disease-free survival (HR: 1.07, 95% CI: 0.82-1.39, P = 0.62). CONCLUSIONS: Adjuvant chemotherapy after curative resection of lung-limited metastasis from colorectal cancer did not show a survival benefit in the propensity score-matched analysis and should not be recommended without further clinical trials. PMID- 30471651 TI - TAS-118 (S-1 plus leucovorin) versus S-1 in patients with gemcitabine-refractory advanced pancreatic cancer: a randomised, open-label, phase 3 study (GRAPE trial). AB - BACKGROUND: In our previous randomised phase 2 study for patients with gemcitabine-refractory advanced pancreatic cancer, S-1 plus leucovorin improved progression-free survival compared with S-1 alone. Here, we evaluated the efficacy of TAS-118 (S-1 plus leucovorin) versus S-1 in overall survival (OS). PATIENTS AND METHODS: This randomised, open-label, phase 3 study was conducted at 58 centres in Japan and Korea. Patients with metastatic pancreatic cancer that progressed during first-line gemcitabine-based chemotherapy or recurred during or after post-operative gemcitabine-based adjuvant treatment were randomly assigned (1:1) to receive either S-1 (40-60 mg, twice daily for 4 weeks in a 6-week cycle) or TAS-118 (S-1 40-60 mg plus leucovorin 25 mg, twice daily for 1 week in a 2 week cycle). The primary end-point was OS. RESULTS: A total of 603 patients were randomised, and 300 and 301 patients received TAS-118 and S-1, respectively. There was no difference in OS between groups (median OS for TAS-118 versus S-1, 7.6 months versus 7.9 months; hazard ratio [HR], 0.98 [95% confidence interval (CI), 0.82-1.16]; P = 0.756). Progression-free survival was significantly longer with TAS-118 than S-1 (median, 3.9 months versus 2.8 months; HR, 0.80 [95% CI, 0.67-0.95]; P = 0.009). There were interactions between Japan and Korea (P = 0.004) and between unresectable and recurrent disease (P = 0.025) in OS. Incidence, profile and severity of adverse events were similar between groups. CONCLUSION: TAS-118 did not improve OS in patients with gemcitabine-refractory advanced pancreatic cancer compared to S-1. Further studies are needed to find patients who have benefit from adding leucovorin to S-1. PMID- 30471653 TI - Master-slave motion alignment for an open surgical console. AB - BACKGROUND: Open surgical consoles widely employed in minimally invasive surgery have better ergonomics than closed consoles. To enhance surgical robots' ergonomics, operational efficiency and safety, an effective master-slave motion alignment model should be established. METHODS: The kinematic model of the robot system based on laparoscopic camera coordinate system is built in the first place. Then, the relative pose between the operator's eyes and the display is measured by Tobii Eye Tracking Sensor and is subsequently used to improve the master-slave motion alignment model. RESULTS: Robot threading experiments are conducted by two doctors and three testers to verify the kinematic model. As a result, in contrast to the original model, the improved model reduces both operation time and the number of collisions. CONCLUSIONS: The improved master slave motion alignment model, in which the transformation matrix between the operator's eyes and the display is employed, raises the ergonomics, operational efficiency and safety. PMID- 30471652 TI - All-oral ixazomib, cyclophosphamide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma. AB - BACKGROUND: Novel efficacious treatments with long-term tolerability are needed for transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. This phase 2 study evaluated the safety and efficacy of all-oral ixazomib cyclophosphamide-dexamethasone (ICd) followed by single-agent ixazomib maintenance. PATIENTS AND METHODS: Patients were randomised (1:1) to receive 4.0 mg of ixazomib, 300 (Arm A) or 400 (Arm B) mg/m2 of cyclophosphamide (days 1, 8, and 15), and 40 mg of dexamethasone (days 1, 8, 15, and 22) as induction (up to 13 * 28-day cycles), followed by single-agent ixazomib maintenance (28-day cycles) until progressive disease, death, or unacceptable toxicity. Primary end point was complete response (CR) + very good partial response (VGPR) rate for ICd induction. RESULTS: Seventy patients were enrolled (n = 36 Arm A; n = 34 Arm B); median age was 73 years (range, 61-87). At data cut-off, 66% of patients had completed 13 induction cycles followed by ixazomib maintenance. Median overall treatment duration was 19 cycles (range, 1-29); 21% of patients discontinued treatment during induction and 3% during maintenance due to adverse events (AEs). During induction, among 67 response-evaluable patients, CR+VGPR rate was 25%, and overall response rate (ORR) was 73%. Including the maintenance phase, CR+VGPR rate was 33%, and ORR was 76%. Median progression-free survival was 23.5 months (median follow-up: 26.1 months). The most common all-grade AE was neutropenia (31%). Grade >=3 AEs were reported by 73% of patients. Five on-study deaths occurred (not treatment-related). CONCLUSIONS: ICd treatment followed by ixazomib maintenance is tolerable and active in elderly, transplant-ineligible NDMM patients. TRIAL REGISTRATION NUMBER: NCT02046070. PMID- 30471654 TI - The Potential Impact of Hydrocarbons on Mussels in Port au Port Bay, Newfoundland. AB - Since 2012, the scallop fishery in Port au Port Bay, Newfoundland, Canada has experienced a drastic decline, while no decline was observed in adjacent St. George's Bay. Local fishermen have raised concerns about an abandoned oil exploration well in the Port au Port Bay. This study investigated the potential impact of petroleum hydrocarbons on sediments and blue mussels [Mytilus edulis] (a proxy organism for scallops) in the area. Sediments from both bays were characterized for their hydrocarbons and compared to potential petroleum hydrocarbon sources. Mussels were analysed for health indices and their 14C content. The results showed that the concentration of hydrocarbons found in the sediments of the fishing ground was within the range of unpolluted marine sediments and that the hydrocarbons present were likely from a mixture of sources. The health indices of the mussels in Port au Port Bay were similar to the health indices of mussels in St. George's Bay and the 14C content of the mussels from both bays was modern. These data suggest that the Port au Port fishing ground was not solely contaminated from crude oil leaking from an oil exploration well, that the mussels were not contaminated with petroleum hydrocarbons, and that Port au Port mussels were just as healthy as the mussels of St. George's Bay. Therefore, whatever caused the scallop decline was most likely scallop- and bay-specific. During this study a fast and efficient method for extracting petroleum hydrocarbons from sediment using accelerated solvent extraction with integrated silica gel was developed. PMID- 30471655 TI - Modification of Hexachlorobenzene to Molecules with Lower Long-Range Transport Potentials Using 3D-QSAR Models with a Full Factor Experimental Design. AB - In this study, the hexachlorobenzene molecule was modified by three-dimensional quantitative structure-activity relationship (3D-QSAR) models and a full factor experimental design to obtain new hexachlorobenzene molecules with low migration ability. The 3D-QSAR models (comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)) were constructed by SYBLY-X 2.0 software, using experimental data of octanol-air partition coefficients (KOA) for 12 chlorobenzenes (CBs) congeners as the dependent variable, and the structural parameters of CBs as independent variables, respectively. A target molecule (hexachlorobenzene; HCB: its long-distance migration capability leads to pollution of the marine environment in Antarctic and Arctic) was modified using the 3D-QSAR contour maps associated with resolution V of the 210-3 full-factorial experimental design method, and 11 modified HCB molecules were produced with a single chlorine atom (-Cl2) and three chlorine atoms (-Cl1, -Cl3, and -Cl5) replaced with electropositive groups ( COOH, -CN, -CF3, -COF, -NO2, -F, -CHF2, -ONO2, and -SiF3) to increase the logKOA. The new molecules had essentially similar biological enrichment functions and toxicities as HCB but were found to be more easily degraded. A 2D-QSAR model and molecular docking technology indicated that both dipole moments and highest occupied orbital energies of the substituents markedly affected migration and degradation of the new molecules. The abilities of the compounds to undergo long distance migration were assessed. The modified HCB molecules (i.e. 2-CN-HCB, 2 CF3-HCB, 1-F-3-COOH-5-NO2-HCB, 1-NO2-3-CN-5-CHF2-HCB and 1-CN-3-F-5-NO2-HCB) moved from a long-range transport potential of the modified molecules to a relatively low mobility class, and the transport potentials of the remaining modified HCB molecules (i.e. 2-COOH-HCB, 2-COF-HCB, 1-COF-3-ONO2-5-NO2-HCB, 1-F-3 CN-5-SiF3-HCB, 1-F-3-COOH-5-SiF3-HCB and 1-CN-3-SiF3-5-ONO2-HCB) also significantly decreased. These results provide a basic theoretical basis for designing environmentally benign molecules based on HCB. PMID- 30471656 TI - Brominated Flame Retardants, Microplastics, and Biocides in the Marine Environment: Recent Updates of Occurrence, Analysis, and Impacts. AB - Emerging contaminants (ECs) may pose adverse effects on the marine ecosystem and human health. Based on the analysis of publications filed in recent years, this paper provides a comprehensive overview on three prominent groups of ECs, i.e., brominated flame retardants, microplastics, and biocides. It includes detailed discussions on: (1) the occurrence of ECs in seawater, sediment, and biota; (2) analytical detection and monitoring approaches for these target ECs; and (3) the biological impacts of the ECs on humans and other trophic levels. This review provides a summary of recent advances in the field and remaining knowledge gaps to address, to enable the assessment of risk and support the development of regulations and mitigation technologies for the control of ECs in the marine environment. PMID- 30471657 TI - Synthetic Musks: A Class of Commercial Fragrance Additives in Personal Care Products (PCPs) Causing Concern as Emerging Contaminants. AB - Synthetic musks (SMs) are promising fragrance additives used in personal care products (PCPs). The widespread presence of SMs in environmental media remains a serious risk because of their harmful effects. Recently, the environmental hazards of SMs have been widely reported in various environmental samples including those from coastal and marine regions. This paper provides a systematic review of SMs, including their classification, synthetic routes, analysis and occurrence in environmental samples, fate and toxicity in the environment, as well as the associated risk assessment and pollution control. Research gaps and future opportunities were also identified with the hope of raising interest in this topic. PMID- 30471658 TI - Occurrence, Impact, Analysis and Treatment of Metformin and Guanylurea in Coastal Aquatic Environments of Canada, USA and Europe. AB - This review discusses the occurrence, impact, analysis and treatment of metformin and guanylurea in coastal aquatic environments of Canada, USA and Europe. Metformin, a biguanide in chemical classification, is widely used as one of the most effective first-line oral drugs for type 2 diabetes. It is difficult to be metabolized by the human body and exists in both urine and faeces samples in these regions. Guanylurea is metformin's biotransformation product. Consequently, significant concentrations of metformin and guanylurea have been reported in wastewater treatment plants (WWTPs) and coastal aquatic environments. The maximum concentrations of metformin and guanylurea in surface water samples were as high as 59,000 and 4502ngL-1, respectively. Metformin can be absorbed in non-target organisms by plants and in Atlantic salmon (Salmo salar). Guanylurea has a confirmed mitotic activity in plant cells. Analysis methods of metformin are currently developed based on high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). The removal of metformin from aquatic environments in the target regions is summarized. The review helps to fill a knowledge gap and provides insights for regulatory considerations. The potential options for managing these emerging pollutants are outlined too. PMID- 30471659 TI - Characterization of Nitrogen-Containing Polycyclic Aromatic Heterocycles in Crude Oils and Refined Petroleum Products. AB - A large amount of polycyclic aromatic hydrocarbons (PAHs) and their heterocyclic analogues (N, S, O) are released to the marine environment from natural oil seeps, oil spills, bilge discharges and input of land-based sources. Many of these compounds are toxic and have a deleterious effect on marine biota. Nitrogen containing compounds in crude oils are typically present as cyclic compounds such as polycyclic aromatic nitrogen heterocycles (PANHs) and are generally classified into the two categories of nonbasic (N-PANHs) and basic compounds (B-PANHs). Chromatographic analyses of PANHs are easily to be interfered by other oil components without proper sample preparation prior to instrumental analysis. In this work, dual solid phase extraction columns of 3-(isocyanato)propyl functionalized silica gel (Si-NCO) and silica gel were employed to efficiently separate both N-PANHs and B-PANHs from saturated and aromatic petroleum hydrocarbons, which enable simultaneous accurate analyses of these groups with single sample preparation. Crude oils studied contain various concentrations of N PANHs including carbazole, benzocarbazole and B-PANHs including quinolone, acridine and benzoacridine as well as their alkylated homologues. These compounds in light fuel and lubricating oil are generally not detected or are only in trace concentration, but have considerable abundance in heavy fuel oils. Crude oils from different sources and various petroleum products have their unique absolute concentrations and relative distribution patterns of PANHs. Chemical fingerprints of PANHs can provide valuable information for forensic oil spill identification and improve the understanding of the fate, behaviour and chemical degradation of spilled crude oil. PMID- 30471660 TI - Fate and Transport Modelling of Emerging Pollutants from Watersheds to Oceans: A Review. AB - This chapter provides a review of the fate and transport modelling of emerging pollutants (EPs) and discusses the major research challenges. The overwhelming limitation of the past modelling studies has been the lack of data necessary for model validation, thus calling for large-scale field data sampling. The identification and understanding of fate and transport processes and their interactions of the target EPs and the corresponding selection of appropriate parameter values were also challenging. Such limitations and challenges were evidenced by the elaboration of the representative models in the field. The review also reveales that the model parameter values varied significantly with the EPs (and chemical compositions) and media of concerns. Sensitivity analysis was found to be necessary for modelling of those EPs with limited references in the literature. In comparison with traditional water pollutants, the concentrations of many EPs in water bodies are usually low and even at a trace level, leading to uncertainties or inaccuracy in measured data. This could further challenge model calibration and validation, and especially the determination of parameter values when lacking sufficient data support. How to improve the existing models to address such an issue special for EPs is an urgent task for researchers to ensure the accuracy and reliability of modelling results. PMID- 30471661 TI - Preface. PMID- 30471663 TI - Taking a Big Step towards Understanding Locomotion. AB - Locomotion is generated by intrinsically oscillating circuits in the spinal cord that are modulated by information from the brain and periphery. In their seminal 1987 publication, Buchanan and Grillner provided for the first time evidence for excitatory spinal neurons receiving inputs from descending commands and sensory afferents, and synapsing onto motoneurons and commissural inhibitory interneurons. These critical findings established the circuit model for central pattern generators incorporating excitatory interneurons' role in the rhythm production mechanism. PMID- 30471664 TI - Sonic Hedgehog Signaling is Blue: Insights from the Patched Mutant Mice. AB - The Hedgehog (Hh) pathway is a highly conserved signaling system regulating a range of developmental processes. A 1997 paper by Goodrich and colleagues provided major contributions to understanding the Hh pathway by mutating the gene encoding the Hh receptor, Patched, and thereby developing a mouse model for a human cancer predisposition syndrome, known as Gorlin syndrome. These studies provided one of the first genetically engineered mouse models for brain tumors. PMID- 30471662 TI - ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition. PMID- 30471665 TI - The Hard and Soft Wired Nature of the Olfactory Map. AB - Across the animal kingdom, odors are known as potent stimuli that directly steer behavior. In 2007, Hitoshi Sakano and colleagues used the power of mouse genetics to manipulate the odor map in the olfactory bulb. Elegant behavioral, anatomical, and physiological analyses revealed an apparent dichotomy in how the brain interprets the odor map. Their work paved a way to think of behavioral contingencies as part of early olfactory processing, highlighting innate and learned pathways. PMID- 30471666 TI - Theoretically Sparse, Empirically Dense: New Views on Cerebellar Granule Cells. AB - Cerebellar granule cells are a popular target of neuroanatomical hyperbole, being so small and so numerous. Early theorists proposed unique roles for this vast cell population, ideas that continue to be tested through contemporary approaches. In 2017, a cluster of empirical and theoretical papers offered a fresh and singular look into the functions of granule cells and the computational advantages of their idiosyncratic circuit organization. PMID- 30471667 TI - Multicomponent reactions in drug discovery and medicinal chemistry. PMID- 30471668 TI - Macrocycles: MCR synthesis and applications in drug discovery. AB - Macrocycles are an emerging and largely underexploited part of chemical space where potential drugs for difficult genomic targets can be discovered. Macrocycles can have advantages over their natural twins such as better control over synthesis, physicochemical properties and target binding. Fast and convergent synthesis pathways are underdeveloped. Multicomponent reaction (MCR) chemistry is very well suited for the synthesis of a diverse range of macrocycles and is also able to generate great levels of molecular diversity and complexity at low synthetic costs. PMID- 30471669 TI - Multi-component synthesis of fluorophores via catalytic generation of alkynoyl intermediates. AB - This account summarizes recent developments of aggregation-induced emissive and emission solvatochromic fluorophores by multicomponent reactions. Key intermediates are catalytically generated alkynoyl derivatives that are directly transformed into luminophores in a one-pot fashion. The conciseness in combination with ready access to tailored chromophore libraries makes this synthetic methodological concept superior over classical multistep syntheses. PMID- 30471671 TI - Integrating biocatalysis and multicomponent reactions. AB - While often multicomponent reactions (MCR) are used for the diversity-oriented synthesis of racemic (or achiral) molecular entities, this short review describes two alternative approaches for accessing enantiopure products exploiting the power of biocatalysis. Enzymes or microorganisms may be used for preparing enantiopure MCR inputs or for resolving racemic (or achiral) MCR adducts. PMID- 30471670 TI - Petasis three-component reactions for the synthesis of diverse heterocyclic scaffolds. AB - The Petasis three-component reaction (PR) of hydroxy aldehydes, amines and boronic acids is an important multi-component reaction for the synthesis of structurally diverse scaffolds and biologically interesting small molecules. The reaction has been significantly explored in the past decade, and many new variants have emerged, such as asymmetric, traceless and four-component approaches. The excellent stereoselectivity, high yield and broad functional group tolerance altogether make this reaction ideal for fragment and compound collection synthesis, since orthogonal chemical handles can be incorporated for subsequent scaffold formation and appendage modification. Herein we present a selection of recent variations on the PR theme for the synthesis of scaffolds of relevance to medicinal chemistry. PMID- 30471673 TI - Homologation of Ugi and Passerini reactions using ynamides. AB - Being important biological and pharmacological units, beta-amino amides and beta acyloxy amides have a privileged position in both academia and industry. Developing a methods to prepare them has gained attention. Ynamides, which possess dual nucleophilic and electrophilic properties, are similar to isonitriles. In this review, usage of ynamides in the single reactant replacement approach of Ugi and Passerini reactions to develop two new multicomponent reactions to get various beta-amino amides and beta-acyloxy amides is reported. PMID- 30471672 TI - Arynes and isocyanides: Two close-knit partners in multicomponent reactions. AB - Despite benzyne has been known since 1940, this fascinating species has received much attention only over the last decades. The renaissance of interest in aryne chemistry is ascribable to the seminal discovery that arynes can be generated in situ from stable and commercially available precursors under mild and neutral conditions. Thanks to their high reactivity, arynes are key intermediates in countless chemical transformations ranging from cycloadditions to insertions and, among all these approaches, multicomponent reactions (MCRs) are currently standing out in this field. In particular, this short article is focused on MCRs involving the concomitant use of benzyne and isocyanides. Furthermore, the first overview on aryne MCRs triggered by alpha-isocyanoacetamides is presented. PMID- 30471674 TI - Borylated reagents for multicomponent reactions. AB - Over the past two decades, there has been an increasing interest in the therapeutic potential of organoboron reagents due to the discovery of bortezomib (Velcade). This has motivated synthetic chemists to develop novel routes for the preparation of heteroatom-rich boron-containing molecules (BCMs). In particular, the development of borylated building blocks has provided facile access to difficult-to-access heteroatom-rich BCMs. In this review, we will discuss the methods used to prepare boron-containing molecules of biological relevance from multicomponent reactions with borylated building blocks. PMID- 30471675 TI - Gold-catalyzed post-MCR transformations towards complex (poly)heterocycles. AB - Post multicomponent reaction (MCR) transformations are one of the most successful methods leading to high structural diversity and molecular complexity. A well known MCR, the Ugi reaction typically affords a linear peptide backbone, enabling post-Ugi transformations as an elegant solution to rigidify the Ugi adduct into more drug-like species. Not surprisingly, the development of such transformations leading to new structural frameworks has expanded rapidly over the last few years. These reactions have reached an impressive level of performance and versatility, particularly in amalgamation with gold catalysis. This review outlines the developments achieved in the past decade, highlighting the modifications that are performed in a sequential or domino fashion with emphasis on major concepts, synthetic applications of the derived products as well as mechanistic aspects. PMID- 30471676 TI - Recent advances of the Povarov reaction in medicinal chemistry. AB - The Povarov multicomponent reaction consists on the condensation of an aniline, an aldehyde, and an activated olefin to generate a tetrahydroquinoline adduct with 3 diversity points. Hereby, we report the main features of this transformation and its uses in medicinal chemistry. Relevant examples of the impact of Povarov adducts in different therapeutic areas are provided. PMID- 30471677 TI - An introduction to psychedelic neuroscience. AB - This chapter is an introduction to the volume "Psychedelic Neuroscience" of Elsevier's Progress in Brain Research addressing the neurobiological mechanisms of psychedelic drugs, the resulting changes in brain activity and integration of traditional viewpoints. As the field is relatively new, there are discrepancies in the literature related to classification, composition and effects of the various psychedelics. Currently, psychedelics are grouped according to their neuro-receptor affinities into classic and atypical psychedelics, each with individual treatment potentials and abilities to elicit potent acute experiences and long-lasting changes in neurobiology through concurrent activation of several neuromodulatory systems. There is disparity in psychedelic brain imaging studies, delineating what is neural activity and hemodynamic needs further investigation for us to understand the brain "state" changes that are apparent. The psychedelic brain "state" is often compared to acute psychosis and we review the psychedelic animal models of psychosis and human brain imaging studies and contrast these to psychosis. The term "psychedelic" means mind-revealing and psychedelics have exceptional anti-amnesic effects and are able to "make conscious" that which was previously unconscious through changes in brain "state," but also there is growing evidence which demonstrates the role of epigenetic mechanisms. This supports traditional therapeutic use of psychedelics to heal ancestral trauma. Details of these mechanisms are provided along with suggestions for further research. PMID- 30471678 TI - A case report SPECT study and theoretical rationale for the sequential administration of ibogaine and 5-MeO-DMT in the treatment of alcohol use disorder. AB - Ibogaine is a plant-derived alkaloid and dissociative psychedelic that demonstrates anti-addictive properties with several substances of abuse, including alcohol. 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring psychedelic known to occasion potent mystical-type experiences and also demonstrates anti-addictive properties. The potential therapeutic effects of both compounds in treating alcohol use disorder require further investigation and there are no published human neuroimaging findings of either treatment to date. We present the case of a 31-year-old male military veteran with moderate alcohol use disorder who sought treatment at an inpatient clinic in Mexico that utilized a sequential protocol with ibogaine hydrochloride (1550mg, 17.9mg/kg) on day 1, followed by vaporized 5-MeO-DMT (bufotoxin source 50mg, estimated 5-MeO-DMT content, 5-7mg) on day 3. The patient received SPECT neuroimaging that included a resting-state protocol before, and 3 days after completion of the program. During the patient's ibogaine treatment, he experienced dream-like visions that included content pertaining to his alcohol use and resolution of past developmental traumas. He described his treatment with 5-MeO-DMT as a peak transformational and spiritual breakthrough. On post-treatment SPECT neuroimaging, increases in brain perfusion were noted in bilateral caudate nuclei, left putamen, right insula, as well as temporal, occipital, and cerebellar regions compared to the patient's baseline scan. The patient reported improvement in mood, cessation of alcohol use, and reduced cravings at 5 days post-treatment, effects which were sustained at 1 month, with a partial return to mild alcohol use at 2 months. In this case, serial administration of ibogaine and 5-MeO-DMT resulted in increased perfusion in multiple brain regions broadly associated with alcohol use disorders and known pharmacology of both compounds, which coincided with a short-term therapeutic outcome. We present theoretical considerations regarding the potential of both psychedelic medicines in treating alcohol use disorders in the context of these isolated findings, and areas for future investigation. PMID- 30471679 TI - Advances and challenges in neuroimaging studies on the effects of serotonergic hallucinogens: Contributions of the resting brain. AB - The effects of hallucinogenic drugs on the human brain have been studied since the earliest days of neuroimaging in the 1990s. However, approaches are often hard to compare and results are heterogeneous. In this chapter, we summarize studies investigating the effects of hallucinogens on the resting brain, with a special emphasis on replicability and limitations. In previous studies, similarities were observed between psilocybin, LSD, and ayahuasca, with respect to decreases in cerebral blood flow and increases in global functional connectivity in the precuneus and thalamus. Additionally, LSD consistently decreased functional connectivity within distinct resting state networks. Little convergence was observed for connectivity between networks and for blood flow in other brain regions. Although these studies are limited by small sample sizes and might be biased by unspecific drug effects on physiological parameters and the vascular system, current results indicate that neuroimaging could be a useful tool to elucidate the neuronal correlates of hallucinogenic effects. PMID- 30471680 TI - Neurocognitive effects of cannabis: Lessons learned from human experimental studies. AB - The following chapter offers an overview of results of experimental studies conducted among healthy individuals examining the effects of acute administration of Delta9-THC and other cannabinoids, alone or in combination, on brain function and behavior, also as a function of previous cannabis exposure. In light of their methodological design, these studies have advanced the understanding of the neurobiological mechanisms increasing the risk of long-lasting cognitive dysfunction as well as psychosis in regular cannabis users. Also, direct and indirect evidence supports an alteration of different neurotransmitters, such as dopamine, glutamate, and gamma-aminobutyric acid, in modulating the manifestation of neurocognitive dysfunction and psychosis in the context of both acute and chronic cannabis exposure. Future multimodal neuroimaging studies will integrate the longitudinal information to track the long-term changes in brain neurochemistry and neurophysiology as well as other potential biomarkers induced by sustained cannabis use. PMID- 30471681 TI - Ibogaine as a treatment for substance misuse: Potential benefits and practical dangers. AB - Ibogaine is an indole alkaloid found in the root bark of the Iboga shrub native to west Africa possessing hallucinogenic properties. For centuries it has been used in religious ceremonies and to gain spiritual enlightenment. However, since the early 1960s, its apparent ability to reduce craving for psychoactive substances including alcohol, cocaine, methamphetamine, opiates, and nicotine has led to its use in detoxification treatments. In many instances, clients receive treatment in non-medical settings, with little by way of robust scientific clinical trials. This chapter provides an overview of the potential benefits that could arise from such research. This is balanced against the serious adverse effects that can occur due to undiagnosed health conditions and/or concomitant use of other drugs. A detailed update is provided of the 33 deaths known to have occurred, including 5 in the UK. Looking forward, there is a need to develop better opiate detoxification treatment against a background of increasing opioid related fatalities. A congener of ibogaine, 18-MC, appears to be safer and is to undergo clinical trials. In the meantime, would-be consumers and treatment providers must make more careful, detailed risk-assessments before using ibogaine. Treatment outcomes, including deaths, need to be accurately recorded and published. PMID- 30471682 TI - The renaissance in psychedelic research: What do preclinical models have to offer. AB - Human research with psychedelics is making groundbreaking discoveries. Psychedelics modify enduring elements of personality and seemingly reduce anxiety, depression, and substance dependence in small but well-designed clinical studies. Psychedelics are advancing through pharmaceutical regulatory systems, and neuroimaging studies have related their extraordinary effects to select brain networks. This field is making significant basic science and translational discoveries, yet preclinical studies have lagged this renaissance in human psychedelic research. Preclinical studies have a lot to offer psychedelic research as they afford tight control of experimental parameters, subjects with documented drug histories, and the capacity to elucidate relevant signaling cascades as well as conduct invasive mechanistic studies of neurochemistry and neural circuits. Safety pharmacology, novel biomarkers, and pharmacokinetics can be assessed in disease state models to advance psychedelics toward clinical practice. This chapter documents the current status of psychedelic research, with the thematic argument that new preclinical studies would benefit this field. PMID- 30471683 TI - d-Lysergic acid diethylamide, psilocybin, and other classic hallucinogens: Mechanism of action and potential therapeutic applications in mood disorders. AB - Depression and anxiety are psychiatric diagnoses commonly associated with low quality of life and low percentage of responsiveness by patients treated with currently available drugs. Thus, research into alternative compounds to treat these disorders is essential to guarantee a patient's remission. The last decade has witnessed a revamped interest for the application of psychedelic medicine for the treatment of mental disorders due to anecdotal reports and clinical studies which show that low doses of d-lysergic acid diethylamide (LSD) and psilocybin may have antidepressant effects. LSD and psilocybin have demonstrated mood modulating properties likely due to their capacity to modulate serotonergic (5 HT), dopaminergic (DA) and glutamatergic systems. LSD, belonging to the category of "classic halluginogens," interacts with the 5-HT system through 5HT1A, and 5HT2A receptors, with the DA system through D2 receptors, and indirectly also the glutamatergic neurotransmission thought the recruitment of N-methyl-d-aspartate (NMDA) receptors. Randomized clinical studies have confirmed its antidepressant and anxiolytic effects in humans. Thus, in this chapter, we will review the pharmacology of psychedelic drugs, report the most striking clinical evidence which substantiate the therapeutic potentials of these fascinating compounds in mood disorders, and look into the horizon of where psychedelic medicine is heading. PMID- 30471684 TI - Common neural signatures of psychedelics: Frequency-specific energy changes and repertoire expansion revealed using connectome-harmonic decomposition. AB - The search for the universal laws of human brain function is still on-going but progress is being made. Here we describe the novel concepts of connectome harmonics and connectome-harmonic decomposition, which can be used to characterize the brain activity associated with any mental state. We use this new frequency-specific language to describe the brain activity elicited by psilocybin and LSD and find remarkably similar effects in terms of increases in total energy and power, as well as frequency-specific energy changes and repertoire expansion. In addition, we find enhanced signatures of criticality suggesting that the brain dynamics tune toward criticality in both psychedelic elicited states. Overall, our findings provide new evidence for the remarkable ability of psychedelics to change the spatiotemporal dynamics of the human brain. PMID- 30471685 TI - Phase Separation of Intrinsically Disordered Proteins. AB - There is growing interest in the topic of intracellular phase transitions that lead to the formation of biologically regulated biomolecular condensates. These condensates are membraneless bodies formed by phase separation of key protein and nucleic acid molecules from the cytoplasmic or nucleoplasmic milieus. The drivers of phase separation are referred to as scaffolds whereas molecules that preferentially partition into condensates formed by scaffolds are known as clients. Recent advances have shown that it is possible to generate physical and functional facsimiles of many biomolecular condensates in vitro. This is achieved by titrating the concentration of key scaffold proteins and solution parameters such as salt concentration, pH, or temperature. The ability to reproduce phase separation in vitro allows one to compare the relationships between information encoded in the sequences of scaffold proteins and the driving forces for phase separation. Many scaffold proteins include intrinsically disordered regions whereas others are entirely disordered. Our focus is on comparative assessments of phase separation for different scaffold proteins, specifically intrinsically disordered linear multivalent proteins. We highlight the importance of coexistence curves known as binodals for quantifying phase behavior and comparing driving forces for sequence-specific phase separation. We describe the information accessible from full binodals and highlight different methods for-and challenges associated with-mapping binodals. In essence, we provide a wish list for in vitro characterization of phase separation of intrinsically disordered proteins. Fulfillment of this wish list through key advances in experiment, computation, and theory should bring us closer to being able to predict in vitro phase behavior for scaffold proteins and connect this to the functions and features of biomolecular condensates. PMID- 30471686 TI - Using NMR Chemical Shifts to Determine Residue-Specific Secondary Structure Populations for Intrinsically Disordered Proteins. AB - Protein disorder is a pervasive phenomenon in biology and a natural consequence of polymer evolution that facilitates cell signaling by organizing sites for posttranslational modifications and protein-protein interactions into arrays of short linear motifs that can be rearranged by RNA splicing. Disordered proteins are missing the long-range nonpolar interactions that form tertiary structures, but they often contain regions with residual secondary structure that are stabilized by protein binding. NMR spectroscopy is uniquely suited to detect residual secondary structure in a disordered protein and it can provide atomic resolution data on the structure and dynamics of disordered protein interaction sites. Here we describe how backbone chemical shifts are used for assigning residual secondary structure in disordered proteins and discuss some of the tools available for estimating secondary structure populations with a focus on disordered proteins containing different levels of alpha helical secondary structure which are stabilized by protein binding. PMID- 30471687 TI - Experimental Characterization of Fuzzy Protein Assemblies: Interactions of Paramyxoviral NTAIL Domains With Their Functional Partners. AB - In this chapter we detail various experimental approaches to characterize the fuzziness of complexes made of the C-terminal domain of the nucleoprotein (NTAIL) from three representative paramyxoviruses and of the C-terminal X domain (XD) of the homologous phosphoprotein. We discuss the advantages, the limitations, as well as the caveats of the various methods. We describe experimental data showing that paramyxoviral NTAIL-XD complexes are characterized by a considerable amount of conformational heterogeneity. We also detail recent data that revealed that NTAIL is highly malleable, i.e., it displays a partner-mediated polymorphism. All the results suggest that NTAIL plasticity and fuzziness play a role in the coordination and regulation of the NTAIL interaction network so as to ensure efficient transcription and replication. PMID- 30471688 TI - Characterization of Dynamic IDP Complexes by NMR Spectroscopy. AB - NMR spectroscopy has proven to be a key method for studying intrinsically disordered proteins (IDPs). Nonetheless, traditional NMR methods developed for solving structures of ordered protein complexes are insufficient for the full characterization of dynamic IDP complexes, where the energy landscape is broader and more rugged. Furthermore, due to their high sensitivity to environmental changes, NMR studies of IDP complexes must be conducted with extra care and the observed NMR parameters thoroughly evaluated to enable disentanglement of binding events from ensemble distribution changes. In this chapter, written for the non NMR expert, we start out by outlining sample preparation for IDP complexes, guide through the recording and evaluation of diagnostic 1H,15N-HSQC spectra, and delineate more sophisticated NMR strategies to follow for the particular type of complex. The most relevant experiments are then described in terms of aims, needs, pitfalls, analysis, and expected outcomes, with references to recent examples. PMID- 30471689 TI - Spectroscopic Characterization of Structure-Function Relationships in the Intrinsically Disordered Protein Complexin. AB - Complexins play a critical role in the regulation of neurotransmission by regulating SNARE-mediated exocytosis of synaptic vesicles. Complexins can exert either a facilitatory or an inhibitory effect on neurotransmitter release, depending on the context, and different complexin domains contribute differently to these opposing roles. Structural characterization of the central helix domain of complexin bound to the assembled SNARE bundle provided key insights into the functional mechanism of this domain of complexin, which is critical for both complexin activities, but many questions remain, particularly regarding the roles and mechanisms of other complexin domains. Recent progress has clarified the structural properties of these additional domains, and has led to various proposals regarding how they contribute to complexin function. This chapter describes spectroscopic approaches used in our laboratory and others, primarily involving circular dichroism and solution-state NMR spectroscopy, to characterize structure within complexins when isolated or when bound to interaction partners. The ability to characterize complexin structure enables structure/function studies employing in vitro or in vivo assays of complexin function. More generally, these types of approaches can be used to study the binding of other intrinsically disordered proteins or protein regions to membrane surfaces or for that matter to other large physiological binding partners. PMID- 30471690 TI - Accurate Transfer Efficiencies, Distance Distributions, and Ensembles of Unfolded and Intrinsically Disordered Proteins From Single-Molecule FRET. AB - Intrinsically disordered proteins (IDPs) sample structurally diverse ensembles. Characterizing the underlying distributions of conformations is a key step toward understanding the structural and functional properties of IDPs. One increasingly popular method for obtaining quantitative information on intramolecular distances and distributions is single-molecule Forster resonance energy transfer (FRET). Here we describe two essential elements of the quantitative analysis of single molecule FRET data of IDPs: the sample-specific calibration of the single molecule instrument that is required for determining accurate transfer efficiencies, and the use of state-of-the-art methods for inferring accurate distance distributions from these transfer efficiencies. First, we illustrate how to quantify the correction factors for instrument calibration with alternating donor and acceptor excitation measurements of labeled samples spanning a wide range of transfer efficiencies. Second, we show how to infer distance distributions based on suitably parameterized simple polymer models, and how to obtain conformational ensembles from Bayesian reweighting of molecular simulations or from parameter optimization in simplified coarse-grained models. PMID- 30471691 TI - Methods and Strategies to Quantify Phase Separation of Disordered Proteins. AB - Phase separation has emerged as a new paradigm currently revolutionizing our understanding of cell biology and intracellular organization. Disordered protein domains have recently been demonstrated as integral drivers of phase separation into condensed liquids with emergent material properties. Using in vitro model systems employing purified protein components is necessary to interrogate the molecular mechanisms underlying phase separation; however, these systems pose many experimental challenges. In this chapter we describe general strategies for purifying, handling, imaging, and characterizing the phase behavior of disordered proteins. We further outline methods for the purification of the model P granule protein LAF-1, the construction of phase diagrams, and the quantification of liquid droplet fusion or coalescence. PMID- 30471692 TI - Probing Differential Binding Mechanisms of Phenylalanine-Glycine-Rich Nucleoporins by Single-Molecule FRET. AB - Phenylalanine-glycine-rich nucleoporins (FG-Nups) are intrinsically disordered proteins, constituting the selective barrier of the nuclear pore complex. They are highly dynamic under physiological conditions and studying their interaction with nuclear transport receptors (NTRs) is key to understanding the molecular mechanism of nucleocytoplasmic transport. Distinct conformational features of FG Nups interacting with diverse NTRs can be detected by multiparameter single molecule fluorescence energy transfer (smFRET), which is a powerful technique for studying the dynamics and interactions of biomolecules in solution. Here we provide a detailed protocol utilizing smFRET to reveal differential binding mechanisms of FG-Nups to NTRs, with a focus on practical considerations on sample preparation of unglycosylated and glycosylated FG-Nups, site-specific dual labeling, smFRET measurements, and data analysis. PMID- 30471693 TI - Fluorescence Depolarization Kinetics to Study the Conformational Preference, Structural Plasticity, Binding, and Assembly of Intrinsically Disordered Proteins. AB - Fluorescence depolarization kinetics measured by the time-resolved fluorescence anisotropy decay serves as a sensitive and powerful methodology to study the conformational dynamics of macromolecules. This methodology allows us to delineate the different modes of biomolecular motional dynamics including the local, segmental, and global rotational dynamics on the timescale ranging from picoseconds to nanoseconds. In this chapter, we describe the principles and applications of this methodology to obtain unique molecular insights into the intrinsically disordered proteins (IDPs). Fluorescence depolarization kinetics, when performed in a site-specific manner, can offer a reliable tool to monitor the intrinsic backbone torsional dynamics of expanded IDPs and is capable of discerning the conformational preference of IDPs. Additionally, the time-resolved fluorescence anisotropy measurements allow us to investigate the mechanism of binding and assembly of a wide range of IDPs that are involved in crucial function and disease. PMID- 30471695 TI - Stopped-Flow Kinetic Techniques for Studying Binding Reactions of Intrinsically Disordered Proteins. AB - Intrinsically disordered proteins are abundant in signaling processes such as transcription. Suitable binding and unbinding rates of proteins with their partners are critical for allowing them to perform their biological roles. Understanding how these are achieved, and indeed designing strategies for intervening or modulating related biological processes, therefore requires kinetic studies. In this chapter, we describe stopped-flow-based methods for determining association and dissociation rate constants for pairs of macromolecular binding partners. We describe how to select the simplest appropriate model to describe the interaction, and highlight cases where it is possible to distinguish between induced fit and conformational selection binding mechanisms. Finally, we go on to describe methods for examining the role of electrostatic forces in binding processes, and for describing the transition state for binding processes that have folding associated with them. PMID- 30471694 TI - Building, Characterization, and Applications of Cuvette-FCS in Denaturant-Induced Expansion of Globular and Disordered Proteins. AB - Fluorescence correlation spectroscopy (FCS) is a single-molecule sensitive technique with widespread applications in biophysics. However, conventional microscope-based FCS setups have limitations in performing certain experiments such as those requiring agitations such as stirring or heating, and those involving measurements in solvents with the mismatch of refractive indices. We have recently developed an FCS setup that is suitable for performing measurements inside regular cuvettes. The cuvette-FCS is suitable for performing single molecule measurements in experiments that are regularly performed in spectrofluorometers but are generally avoided in microscope-based FCS. Here we describe building and characterization of the performance of the cuvette-FCS setup in detail. Finally, we have used a natively folded protein and an intrinsically disordered protein to demonstrate and describe how cuvette-FCS can be applied conveniently to measure urea-dependent expansion of hydrodynamic size of proteins. PMID- 30471696 TI - The Use of Mass Spectrometry to Examine IDPs: Unique Insights and Caveats. AB - A sizeable proportion of active protein sequences lack structural motifs making them irresolvable by NMR and crystallography. Such intrinsically disordered proteins (IDPs) or regions (IDRs) play a major role in biological mechanisms. They are often involved in cell regulation processes, and by extension can be the perpetrator or signifier of disease. In light of their importance and the shortcomings of conventional methods of biophysical analysis to identify them and to describe their conformational variance, IDPs and IDRs have been termed "the dark proteome." In this chapter we describe the use of ion mobility-mass spectrometry (IM-MS) coupled with electrospray ionization to analyze the conformational diversity of IDPs. Using the LEA protein COR15A as an exemplar system and contrasting it with the behavior of myoglobin, we outline the methods for analyzing an IDP using nanoelectrospray ionization coupled with IM-MS, covering sample preparation, purification; optimization of mass spectrometry conditions and tuning parameters; data collection and analysis. Following this, we detail the use of a "toy" model that provides a predictive framework for the study of all proteins with ESI-IM-MS. PMID- 30471698 TI - Visualization and Quantitation of Phase-Separated Droplet Formation by Human HP1alpha. AB - The ability of the heterochromatin protein-1 (HP1) to phase separate into droplets suggests new mechanisms of gene organization in the cell nucleus. An accumulating body of work suggests that other nuclear proteins also display phase separation behaviors in vitro. To understand the mechanistic and biological significance of such droplet formation a rigorous biophysical characterization of this behavior is necessary. Herein we describe procedures for imaging HP1 droplets by brightfield microscopy, and two methods to quantify phase separation. PMID- 30471697 TI - Characterizing Time-of-Day Conformational Changes in the Intrinsically Disordered Proteins of the Circadian Clock. AB - Circadian rhythms are 24-h oscillations conserved in nearly all living organisms that allow for the anticipation of daily environmental changes. These rhythms are maintained by a molecular clock comprised of a transcriptional/translational negative feedback loop. Many of the proteins that organize this feedback loop are intrinsically disordered proteins (IDPs), which lack a fixed or ordered three dimensional structure. Little is known about the impact of intrinsic disorder in clock proteins and this lack of comprehension is compounded by the fact that sophisticated techniques to understand the inherent nature of IDPs are only now emerging. Here, we add to that conversation by describing our novel protocol to track the conformation of a core clock protein (FREQUENCY) in a vital clock model organism (Neurospora crassa). Our protocol, CiRcadian nAtive FasT parallel proteolYsis (CRAFTY), utilizes a parallel proteolysis approach in native conditions to determine the conformational shifts in FREQUENCY over time, providing biologically relevant information and contributing to our understanding of the importance of disorder in the circadian clock. PMID- 30471699 TI - Assessing Allostery in Intrinsically Disordered Proteins With Ensemble Allosteric Model. AB - Intrinsically disordered (ID) proteins have been shown to play a major role in signaling in a broad range of proteins, using a process known as allostery, wherein the protein can integrate one or a number of inputs to regulate its function. The disorder-mediated allostery can be understood energetically with ensemble allosteric model (EAM). In this model, the molecule without effectors is considered as an ensemble of preexisting conformations, and effector binding is treated as an energetic perturbation of the ensemble to redistribute the microstates that are favorable or unfavorable to the second binding partner. As it only considers the intrinsic energetics of the system and does not depend on a crystallographic structure, it can be applied to both structured proteins, ID proteins, and mixed proteins with both structured and ID domains. Simulation with EAM on the basis of experimental data can help quantitatively explain experimental observations, as well as to make predictions to direct future research. This has recently been illustrated with the case of human glucocorticoid receptor, a multidomain transcription factor that contains both structured and disordered regions. In this chapter, we describe the assays for measuring the transcriptional activity, binding affinity to cognate DNA, conformational stability, either on single domain or tandem coupled domains in the GR two-domain isoforms. We then explain how these data are utilized as input parameters or constraints in the EAM for quantitative estimates of stabilities and coupling energies for each domain through global minimization method. PMID- 30471701 TI - Generating Novel Materials Using the Intrinsically Disordered Protein Ubx. AB - The development of functionalized materials is needed to enable diverse applications. Protein-based materials are typically biocompatible and biodegradable and can exhibit a wide variety of useful mechanical properties. Most importantly, gene fusion enables facile incorporation of active proteins into the materials. However, many protocols rely on denaturing conditions to stimulate materials formation. These conditions would be expected to inactivate any appended functional proteins. This chapter describes methods to create protein fibers and films in a mild aqueous buffer near neutral pH. This facile, inexpensive single-pot approach to materials assembly does not require any special equipment. Also included in this chapter are methods to fuse fibers to form fiber bundles, and to use fibers for cell culture. Although these methods were developed to generate materials from the Drosophila Hox transcription factor Ultrabithorax, they may also work for other self-assembling proteins, many of which have sequence features in common with Ubx. PMID- 30471700 TI - A Tethered Vesicle Assay for High-Throughput Quantification of Membrane Fission. AB - Membrane fission, which divides membrane surfaces into separate compartments, is essential to diverse cellular processes including membrane trafficking and cell division. Quantitative assays are needed to elucidate the physical mechanisms by which proteins drive membrane fission. Toward this goal, several experimental tools have been developed, including visualizing fission products using electron microscopy, measuring membrane shedding from a lipid reservoir, and observing fission of individual membrane tubes pulled from giant vesicles. However, no existing assay of membrane fission provides a quantitative, high-throughput measure of the distribution of vesicle curvatures generated by fission-driving proteins. Toward addressing this challenge, here we describe a novel approach that uses confocal fluorescence imaging to quantify the diameter distribution of membrane vesicles that have been tethered to a coverslip surface following exposure to fission-driving proteins. We employ this assay to measure the progressive appearance of high curvature fission products upon exposure of vesicles to increasing protein concentration. Results from this approach are in quantitative agreement with measurements from electron microscopy, but can be collected with considerably greater throughput, enabling examination of a broad range of experimental conditions. Using the tethered vesicle approach, we have recently found that membrane-bound intrinsically disordered proteins are surprisingly potent drivers of membrane fission. The capacity to drive fission arises from steric pressure generated when disordered domains with large hydrodynamic radii bind to membranes at high local densities. More broadly, the experimental tools described here have the potential to improve our mechanistic understanding of membrane fission in diverse biophysical contexts. PMID- 30471702 TI - Challenges in the Structural-Functional Characterization of Multidomain, Partially Disordered Proteins CBP and p300: Preparing Native Proteins and Developing Nanobody Tools. AB - The structural and functional characterization of large multidomain signaling proteins containing long disordered linker regions represents special methodological and conceptual challenges. These proteins show extreme structural heterogeneity and have complex posttranslational modification patterns, due to which traditional structural biology techniques provide results that are often difficult to interpret. As demonstrated through the example of two such multidomain proteins, CREB-binding protein (CBP) and its paralogue, p300, even the expression and purification of such proteins are compromised by their extreme proteolytic sensitivity and structural heterogeneity. In this chapter, we describe the effective expression of CBP and p300 in a eukaryotic host, Sf9 insect cells, followed by their tandem affinity purification based on two terminal tags to ensure their structural integrity. The major focus of this chapter is on the development of novel accessory tools, single-domain camelid antibodies (nanobodies), for structural-functional characterization. Specific nanobodies against full-length CBP and p300 can specifically target their different regions and can be used for their marking, labeling, and structural stabilization in a broad range of in vitro and in vivo studies. Here, we describe four high-affinity nanobodies binding to the KIX and the HAT domains, either mimicking known interacting partners or revealing new functionally relevant conformations. As immunization of llamas results in nanobody libraries with a great sequence variation, deep sequencing and interaction analysis with different regions of the proteins provide a novel approach toward developing a panel of specific nanobodies. PMID- 30471703 TI - Probing RNA Structure in Liquid-Liquid Phase Separation Using SHAPE-MaP. AB - RNA is an integral component of many biological condensates. A variety of features of RNAs are linked to their function in biological phase separation. Length and negative charge provide fairly generic chemical inputs that drive condensation while sequence has been shown to influence both the molecular identity and biophysical properties of droplets. mRNA sequence guides the secondary structure of the polymers and RNA secondary structure licenses-specific RNA-RNA interactions and the recruitment of RNA-binding proteins. Here, we describe a method for directly probing the structure of mRNAs in the context of RNP-droplets formed via LLPS. PMID- 30471704 TI - Characterization of the Binding of Small Molecules to Intrinsically Disordered Proteins. AB - Intrinsically disordered proteins (IDPs) comprise a large fraction of eukaryotic proteomes. IDPs are prevalent in cellular regulation, signaling networks, and disease pathways. The abundance and activity of IDPs is tightly controlled at multiple levels, and their dysregulation is associated with disease. Because of the importance of IDPs in both normal and disease states of the cell, IDPs are attractive targets for modulation by small molecules both to understand their biology and to provide potential drug leads. Multiple screens have successfully identified small molecules that bind to IDPs. Here, we describe how surface plasmon resonance, NMR, and fluorescence methods can be used to characterize the direct binding affinity between small molecules and IDPs. We describe how these techniques can contribute to identifying previously unknown small-molecule binding sites on IDPs. PMID- 30471706 TI - The Use of 13C Direct-Detect NMR to Characterize Flexible and Disordered Proteins. AB - NMR spectroscopy remains the only experimental technique that provides (near) atomistic structural information for intrinsically disordered proteins (IDPs), but their sequence and structure characteristics still pose major challenges for high-resolution spectroscopy. Carbon-13 direct-detect NMR spectroscopy can overcome poor spectral dispersion and other difficulties associated with traditional 1H-detected NMR of nonaggregating disordered proteins. This chapter presents spectroscopic protocols suitable for complete characterization of IDPs that rely exclusively on 13C direct-detect experiments. The protocols described span initial characterization and chemical shift assignment; structure constraint through residual dipolar coupling and paramagnetic relaxation enhancement measurements; and assessment of intramolecular dynamics through 15N spin relaxation. The experiments described empower investigators to establish molecular mechanisms and structure-function relationships for IDPs and other proteins characterized by high internal flexibility. PMID- 30471705 TI - Targeting the Intrinsically Disordered Proteome Using Small-Molecule Ligands. AB - Intrinsically disordered proteins (IDPs) and regions (IDRs) make up a significant part of the proteome and facilitate a wide range of physiological and pathological functions that are only beginning to be understood. As such, they are highly attractive targets for drug development and bioengineering. However, their inability to adopt well-defined structures provides significant obstacles for developing ligands that regulate their behaviors. In this chapter, we review how the conformational flexibility of IDPs and their propensity to phase separate make them tractable targets for small-molecule manipulation. We also describe both theoretical and experimental approaches to characterize disordered proteins, including novel thermodynamic and single-molecule techniques that help identify complimentary partners of IDPs and their ability to shift protein ensembles toward preferred conformations. PMID- 30471707 TI - Preface. PMID- 30471708 TI - Comparison of predictive powers of functional and anatomic dosimetric parameters for radiation-induced lung toxicity in locally advanced non-small cell lung cancer. AB - PURPOSE: To investigate the predictive value of the perfusion (Q) single-photon emission computed tomography (SPECT)-weighted dose-function histogram (DFH) obtained mid-treatment (mid-Tx) with radiotherapy (RT) for radiation-induced lung toxicity (RILT) in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: The study population consisted of NSCLC patients who were undergoing RT treatment and enrolled in prospective imaging studies. Q-SPECT was performed prior to and during RT (at ~40-45 Gy). A baseline dose-volume histogram (DVH) and mid-Tx DVH based on simulation CT as well as a baseline DFH and mid-Tx DFH based on Q-SPECT were calculated. Only patients with stage III NSCLC and visible functional lung (FL) changes on the mid-Tx scan were eligible for this enriched analysis. RILT was graded according to a reported scale. RESULTS: Forty-two stage III NSCLC patients met the criteria for inclusion. The accumulative incidence of grade >=2 RILT was 31% in this high-risk population. Significant differences in functional metrics such as functional lung volume FV5-FV20 at increments of 5 Gy and functional MLD (FMLD) were observed between patients with and without grade >=2 RILT (p < 0.05). Similar results were also obtained for anatomical metrics from V5-V20 and MLD (p < 0.05). The areas under the receiver operating characteristic curves (AUCs) ranged from 0.724to 0.812 for baseline DVH parameters, from 0.745 to 0.830 for mid-Tx DVH parameters, from 0.764 to 0.878 for baseline DFH parameters, and from 0.767 to 0.891 for mid-Tx DFH parameters. Further principal components analysis showed that the AUCs were 0.814/0.817 and 0.790/0.857 for baseline/mid-Tx DVH and baseline/mid-Tx DFH, respectively. CONCLUSIONS: Mid-Tx DFH parameters based on Q-SPECT were significantly elevated in patients with grade >=2 RILT in this study population. Among the metrics compared, mid-Tx DFH seemed to have better predictive accuracy, but this difference did not reach statistical difference. PMID- 30471709 TI - Meta-Analysis Comparing Mitral Valve Repair Versus Replacement for Degenerative Mitral Regurgitation Across All Ages. AB - Although current guidelines recommend mitral valve repair (MVr) over mitral valve replacement (MVR) for patients with mitral regurgitation (MR), it is unclear if it should be also recommended in elderly patients with limited life expectancy. This study was conducted to compare the results of MVr with those of MVR to determine the optimal treatment option for patients with degenerative MR, particularly according to the patient's age. A literature search of 5 electronic databases was performed. The primary outcome was all-cause mortality. The secondary outcomes included early mortality and freedom from reoperation. A metaregression analysis and subgroup analysis were performed according to the mean age of the study population. Twelve retrospective studies (2,950 and 1,252 patients in the MVr and MVR groups, respectively) were selected. Pooled analyses demonstrated that the risk of all-cause mortality was significantly higher in the MVR group than in the MVr group both in all studies and in studies presenting adjusted results (hazard ratio[95% confidence interval] = 1.57[1.39 to 1.77] and 1.53[1.34 to 1.74], respectively). This benefit was similar across all ages when the metaregression analysis and the subgroup analysis were performed (p = 0.879 and 0.123, respectively). Early mortality and risk of reoperation were also higher in the MVR group than in the MVr group (risk ratio[95% confidence interval] = 4.51[3.12 to 6.51] and hazard ratio[95% confidence interval] = 1.47[1.09 to 1.98], respectively). In conclusion, this study indicates that MVr is beneficial compared with MVR in patients with degenerative MR regardless of patients' age in terms of all-cause mortality. PMID- 30471710 TI - Effect of Cardiac Resynchronization Therapy on Left Ventricular Remodeling in Patients With Cardiac Sarcoidosis. AB - Cardiac resynchronization therapy (CRT) has been shown to be beneficial in patients with medically refractory heart failure. Although it has been found to be effective in a wide range of etiologies for nonischemic cardiomyopathy, its role in improving remodeling and survival of patients with cardiac sarcoidosis (CS) remains undefined. We performed a retrospective review of all patients at our institution with CS who underwent implantation of a CRT device from 2007 to 2017. The outcomes of this population were compared with the outcomes of a cohort of patients with nonischemic cardiomyopathy with an etiology other than sarcoidosis. Nineteen patients in our institution with CS underwent CRT implantation during the time period. This group was compared with 311 consecutive patients with other etiologies of nonischemic cardiomyopathy who underwent CRT implantation. CRT improved left ventricular ejection fraction (LVEF) from 28.8% to 35.9% (p <0.05) in CS, whereas it improved LVEF from 25% to 36.6% (p <0.01) in non-CS group (difference in means of 0.13). CRT significantly improved diastolic and systolic LV diameters, mitral regurgitation, and right ventricular systolic function in non-CS patients but failed to improve same parameters in CS patients. In conclusion, CRT significantly improved LVEF in patients with CS. There is no significant evidence that survival outcomes of CRT patients with CS are significantly worse than other etiologies of nonischemic cardiomyopathy. PMID- 30471711 TI - Aortic arch reconstruction in the Norwood operation: It is more than just geometry. PMID- 30471712 TI - Dual antiplatelet therapy after coronary artery bypass graft surgery: Fewer stones remain unturned. PMID- 30471713 TI - Hope should not spring eternal. PMID- 30471714 TI - Left sinus of Valsalva aneurysm: Rare disease, rarer presentation. PMID- 30471715 TI - rhIGF-1/rhIGFBP-3 in Preterm Infants: A Phase 2 Randomized Controlled Trial. AB - OBJECTIVE: To investigate recombinant human insulin-like growth factor 1 complexed with its binding protein (rhIGF-1/rhIGFBP-3) for the prevention of retinopathy of prematurity (ROP) and other complications of prematurity among extremely preterm infants. STUDY DESIGN: This phase 2 trial was conducted from September 2014 to March 2016. Infants born at a gestational age of 230/7 weeks to 276/7 weeks were randomly allocated to rhIGF-1/rhIGFBP-3 (250 ug/kg/ 24 hours, continuous intravenous infusion from <24 hours of birth to postmenstrual age 296/7 weeks) or standard neonatal care, with follow-up to a postmenstrual age of 404/7 weeks. Target exposure was >=70% IGF-1 measurements within 28-109 ug/L and >=70% intended therapy duration. The primary endpoint was maximum severity of ROP. Secondary endpoints included time to discharge from neonatal care, bronchopulmonary dysplasia, intraventricular hemorrhage, and growth measures. RESULTS: Overall, 61 infants were allocated to rhIGF-1/rhIGFBP-3, 60 to standard care (full analysis set); 24 of 61 treated infants achieved target exposure (evaluable set). rhIGF-1/rhIGFBP-3 did not decrease ROP severity or ROP occurrence. There was, however, a 53% decrease in severe bronchopulmonary dysplasia in the full analysis set (21.3% treated vs 44.9% standard care), and an 89% decrease in the evaluable set (4.8% vs 44.9%; P = .04 and P = .02, respectively) for severity distribution between groups. There was also a nonsignificant trend toward decrease in grades 3-4 intraventricular hemorrhage in the full analysis set (13.1% vs 23.3%) and in the evaluable set (8.3% vs 23.3%). Fatal serious adverse events were reported in 19.7% of treated infants (12/61) and 11.7% of control infants (7/60). No effect was observed on time to discharge from neonatal care/growth measures. CONCLUSIONS: rhIGF-1/rhIGFBP-3 did not affect development of ROP, but decreased the occurrence of severe bronchopulmonary dysplasia, with a nonsignificant decrease in grades 3-4 intraventricular hemorrhage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01096784. PMID- 30471716 TI - MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance. AB - To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome sequencing data, and tested ciliogenesis in two affected individuals. The brain malformation comprised posterior predominant lissencephaly and midline crossing defects consisting of absent anterior commissure and a striking W-shaped brainstem malformation caused by small or absent pontine crossing fibers. We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects. We studied cilium formation and found a higher proportion of mutant cells with short cilia than of control cells with short cilia. A ninth child had similar lissencephaly but only subtle brainstem dysplasia associated with a heterozygous de novo missense variant in the spectrin repeat domain of MACF1. Thus, we report variants of the microtubule-binding GAR domain of MACF1 as the cause of a distinctive and most likely pathognomonic brain malformation. A gain-of-function or dominant-negative mechanism appears likely given that many heterozygous mutations leading to protein truncation are included in the ExAC Browser. However, three de novo variants in MACF1 have been observed in large schizophrenia cohorts. PMID- 30471719 TI - [Osteosarcopenia: A narrative review]. AB - Osteosarcopenia is a phenotype resulting from the combination of sarcopenia and low bone mineral density. Based on the relationship between bone and muscle, this phenotype is associated with a higher risk of falls, fractures, dependence, and health care costs than its individual components. Given its characteristics, it can be considered as a new geriatric syndrome. Therefore, understanding its pathophysiology and diagnosis, as well as its non-pharmacological and pharmacological management is a task of great importance. The problem in addressing this phenotype arises from the tradition of managing sarcopenia and osteoporosis separately. There is also a lack of consensus on what to call it (sarco-osteopenia, sarco-osteoporosis, osteosarcopenia). The aim of this review is to outline the epidemiology, pathophysiology, diagnoses, adverse events, and management of osteosarcopenia. PMID- 30471718 TI - Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects. AB - Dysfunction of motile monocilia, altering the leftward flow at the embryonic node essential for determination of left-right body asymmetry, is a major cause of laterality defects. Laterality defects are also often associated with reduced mucociliary clearance caused by defective multiple motile cilia of the airway and are responsible for destructive airway disease. Outer dynein arms (ODAs) are essential for ciliary beat generation, and human respiratory cilia contain different ODA heavy chains (HCs): the panaxonemally distributed gamma-HC DNAH5, proximally located beta-HC DNAH11 (defining ODA type 1), and the distally localized beta-HC DNAH9 (defining ODA type 2). Here we report loss-of-function mutations in DNAH9 in five independent families causing situs abnormalities associated with subtle respiratory ciliary dysfunction. Consistent with the observed subtle respiratory phenotype, high-speed video microscopy demonstrates distally impaired ciliary bending in DNAH9 mutant respiratory cilia. DNAH9 deficient cilia also lack other ODA components such as DNAH5, DNAI1, and DNAI2 from the distal axonemal compartment, demonstrating an essential role of DNAH9 for distal axonemal assembly of ODAs type 2. Yeast two-hybrid and co immunoprecipitation analyses indicate interaction of DNAH9 with the ODA components DNAH5 and DNAI2 as well as the ODA-docking complex component CCDC114. We further show that during ciliogenesis of respiratory cilia, first proximally located DNAH11 and then distally located DNAH9 is assembled in the axoneme. We propose that the beta-HC paralogs DNAH9 and DNAH11 achieved specific functional roles for the distinct axonemal compartments during evolution with human DNAH9 function matching that of ancient beta-HCs such as that of the unicellular Chlamydomonas reinhardtii. PMID- 30471717 TI - Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus. AB - Motile cilia move body fluids and gametes and the beating of cilia lining the airway epithelial surfaces ensures that they are kept clear and protected from inhaled pathogens and consequent respiratory infections. Dynein motor proteins provide mechanical force for cilia beating. Dynein mutations are a common cause of primary ciliary dyskinesia (PCD), an inherited condition characterized by deficient mucociliary clearance and chronic respiratory disease coupled with laterality disturbances and subfertility. Using next-generation sequencing, we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9 in individuals from PCD clinics with situs inversus and in one case male infertility. DNAH9 and its partner heavy chain DNAH5 localize to type 2 ODAs of the distal cilium and in DNAH9-mutated nasal respiratory epithelial cilia we found a loss of DNAH9/DNAH5-containing type 2 ODAs that was restricted to the distal cilia region. This confers a reduced beating frequency with a subtle beating pattern defect affecting the motility of the distal cilia portion. 3D electron tomography ultrastructural studies confirmed regional loss of ODAs from the distal cilium, manifesting as either loss of whole ODA or partial loss of ODA volume. Paramecium DNAH9 knockdown confirms an evolutionarily conserved function for DNAH9 in cilia motility and ODA stability. We find that DNAH9 is widely expressed in the airways, despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract. In summary, DNAH9 mutations reduce cilia function but some respiratory mucociliary clearance potential may be retained, widening the PCD disease spectrum. PMID- 30471720 TI - Endoscopic microanatomy of the normal gastrointestinal mucosa with narrow band technology and magnification. AB - The development of high-definition endoscopes with optical zoom, along with the use of the digital chromoendoscopy and staining, has given endoscopists the possibility to study the microanatomy of the gastrointestinal mucosa in vivo. The recognition of the changes in the microstructure of the surface and microvascular architecture such as those that occur in neoplastic lesions allow us to characterize these lesions in order to decide on the best course of clinical action. The current greater availability of endoscopes with optical zoom in western countries has allowed the use of this technology in routine clinical practice to spread. In this article we review the basic concepts of magnifying endoscopy and the normal endoscopic microanatomy of the oesophageal, gastric, duodenal, ileal and colonic mucosa. PMID- 30471721 TI - Simulated training program in abdominal paracentesis for undergraduate medical students. AB - BACKGROUND AND AIMS: Abdominal paracentesis is an area that every general physician should know about, and the current learning model is unsafe for patients. Simulation allows students to develop their skills prior to clinical confrontation with minimal risks. The aims of this study were to design and evaluate a paracentesis simulation workshop for undergraduate students. METHODS: A workshop was implemented using a specially designed and validated simulation model for abdominal paracentesis. The simulated technique considered the recognition of materials, operator equipment, asepsis, anesthesia, puncture and obtaining liquid, collecting samples for analysis, withdrawal of the material and occlusion. A 24-point direct observation checklist was administered to assess the student. We assessed two students at the beginning of the workshop and all the students at the end. A perception survey was applied to attendees at the end of the workshop. RESULTS: 247 students were included and a workshop that involved 8 students per session was held. Students significantly improved their skills comparing pre- and post-evaluation results [13.36+/-4.46 (55.7%) vs. 22.3+/-1.83 (92.9%) respectively (n=69) p<0.001]. The students' perception questionnaire (n=38) showed that the training sessions were highly valued, averaging 4.8+/-0.38 on a Likert scale of 1-5. CONCLUSIONS: Simulated training in abdominal paracentesis is a very good teaching method. This teaching methodology should be highly recommended as an educational strategy in medicine because it could accelerate the acquisition of clinical skills in a safe learning environment. PMID- 30471722 TI - Nitrogen-improved photosynthesis quantum yield is driven by increased thylakoid density, enhancing green light absorption. AB - A nitrogen supply is necessary for all plants. The multifaceted reasons why this nutrient stimulates plant dry weight accumulation are assessed herein. We compared tomato plants grown in full sunlight and in low light environments under four N doses and evaluated plant growth, photosynthetic and calorimetric parameters, leaf anatomy, chloroplast transmission electron microscopy (TEM) and a high resolution profile of optical leaf properties. Increases in N supplies allow tomato plants to grow faster in low light environments (91.5% shading), displaying a robust light harvesting machinery and, consequently, improved light harvesting efficiency. Ultrastructurally, high N doses were associated to a high number of grana per chloroplast and greater thylakoid stacking, as well as high electrodensity by TEM. Robust photosynthetic machinery improves green light absorption, but not blue or red. In addition, low construction and dark respiration costs were related to improved total dry weight accumulation in shade conditions. By applying multivariate analyses, we conclude that improved green light absorbance, improved quantum yield and greater palisade parenchyma cell area are the primary components that drive increased plant growth under natural light-limited photosynthesis. PMID- 30471723 TI - Visualization of soluble carbohydrate distribution in apple fruit flesh utilizing MALDI-TOF MS imaging. AB - To confirm availability of Matrix-assisted laser desorption/ionization time-of flight (MALDI-TOF) mass spectrometry imaging (MSI) for visualizing distribution of soluble carbohydrates in apple (Malus domestica) fruits a horizontal fruit flesh specimen was cut from a matured 'Fuji' fruit, mounted on a glass slide, lyophilized and then ion intensities of individual soluble carbohydrates were probed around the specimen using a MALDI-TOF MSI apparatus automatically. Contents of soluble carbohydrates in adjacent tissue of the same fruit were also determined using HPLC to compare the distribution of individual carbohydrate based on the ion intensities from MALDI-TOF MSI with those from HPLC. Positive correlation (P < 0.001, R2 > 0.95) was confirmed between the concentration of each standard carbohydrate and the relative ion intensity of MALDI-TOF mass spectrometry (MS), and thus it seems possible to use the ion intensity of MALDI TOF MS for determining the relative concentration of carbohydrates in a sample. Singly charged ions attached with a potassium ion only were detected from the apple fruit specimen when DHB was used as a matrix for MALDI-TOF MSI. Graded increase of sucrose content from center to cortex side of the fruit flesh was confirmed by both MALDI-TOF MSI and HPLC. When pseudo color images on the distribution of individual carbohydrates based on the results from MALDI-TOF MSI were compared with the content of carbohydrates in the adjacent 16 tissue blocks quantified using HPLC, strong (P < 0.001, R2 = 0.6222) and weak (P < 0.10, R2 = 0.2123) correlation was confirmed between the brightness and the content of sucrose and sorbitol, respectively. These facts indicate that distribution of sucrose and sorbitol in apple fruit tissue can be visualized using MALDI-TOF MSI. Thus, MALDI-TOF MSI will be useful for examining carbohydrate metabolism during the maturing of apple fruit. PMID- 30471724 TI - Mini review: Revisiting mobile RNA silencing in plants. AB - Non-cell autonomous RNA silencing can spread from cell to cell and over long distances in animals and plants. This process is genetically determined and requires mobile RNA signals. Genetic requirement and molecular nature of the mobile signals for non-cell-autonomous RNA silencing were intensively investigated in past few decades. No consensus dogma for mobile silencing can be reached in plants, yet published data are sometimes inconsistent and controversial. Thus, the genetic requirements and molecular signals involved in plant mobile silencing are still poorly understood. This article revisits our present understanding of intercellular and systemic non-cell autonomous RNA silencing, and summarises current debates on RNA signals for mobile silencing. In particular, we discuss new evidence on siRNA mobility, a DCL2-dependent genetic network for mobile silencing and its potential biological relevance as well as 22 nt siRNA being a mobile signal for non-cell-autonomous silencing in both Arabidopsis and Nicotiana benthamiana. This sets up a new trend in unravelling genetic components and small RNA signal molecules for mobile silencing in (across) plants and other organisms of different kingdoms. Finally we raise several outstanding questions that need to be addressed in future plant silencing research. PMID- 30471725 TI - A HD-ZIP II HOMEBOX transcription factor, PpHB.G7, mediates ethylene biosynthesis during fruit ripening in peach. AB - Homeobox transcription factors belong to a superfamily that has been widely studied in plant growth and development, but little is known regarding their role in fruit development and ripening. Using a genome-wide expression analysis of homeobox (HB) genes and quantitative real-time PCR, a HD-ZIP II member, PpHB.G7, which presented higher levels of expression in ripening fruits than in developing fruits in all of the tested cultivars, was isolated from peach. Transient transformations showed that PpHB.G7 affects ethylene production and the expression of ethylene biosynthesis genes (PpACS1 and PpACO1). Both dual luciferase and yeast one-hybrid assays confirmed that PpHB.G7 interacts with the promoters of PpACS1 and PpACO1. Thus, PpHB.G7 mediates ethylene biosynthesis by stimulating PpACS1 and PpACO1 activities. Furthermore, we also found that the other eight HB genes were differentially expressed in the developing fruits, with seven of these genes belonging to the HD-ZIP family. These results suggest that the HB genes in the HD-ZIP family play important roles in fruit development and ripening. PMID- 30471726 TI - A DREB1 gene from zoysiagrass enhances Arabidopsis tolerance to temperature stresses without growth inhibition. AB - The DREB (dehydration-responsive element binding) protein family comprises transcription factors that can increase the survivability of a plant under abiotic stresses by regulating expression of multiple genes and altering downstream metabolism at the cost of growth retardation and developmental delay. In this study, a gene for the DREB1-type transcription factor, designated ZjDREB1.4, was isolated from zoysiagrass (Zoysia japonica Steud.), a popular warm season turfgrass. This gene contains a conserved AP2/ERF DNA-binding domain flanking the signature sequence of DREB1 and belongs to a DREB1 branch in the grass family that expands in the warm-season species. The expression of ZjDREB1.4 was significantly induced by chilling stress (4-15 degrees C), moderately induced by salt stress, and only slightly induced by drought stress. The product of ZjDREB1.4 was targeted to the nucleus and showed strong transactivation activity but weak binding to the DRE with ACCGAC as the core sequence. The ZjDREB1.4 protein bound to GCCGAC more preferentially than to ACCGAC. Overexpression of ZjDREB1.4 in Arabidopsis induced the expression of multiple genes including a part of the CBF-regulon, and moderately increased the levels of proline and soluble sugars under normal growth conditions. The transgenic Arabidopsis plants showed an increase in tolerance to high and freezing temperature stresses without obvious growth inhibition and with only a few days delay in bolting. ZjDREB1.4 is potentially useful for producing transgenic plants that are tolerant to high temperature and/or cold stresses with few negative effects. PMID- 30471728 TI - Ionizing radiation manifesting DNA damage response in plants: An overview of DNA damage signaling and repair mechanisms in plants. AB - Plants orchestrate various DNA damage responses (DDRs) to overcome the deleterious impacts of genotoxic agents on genetic materials. Ionizing radiation (IR) is widely used as a potent genotoxic agent in plant DDR research as well as plant breeding and quarantine services for commercial uses. This review aimed to highlight the recent advances in cellular and phenotypic DDRs, especially those induced by IR. Various physicochemical genotoxic agents damage DNA directly or indirectly by inhibiting DNA replication. Among them, IR-induced DDRs are considerably more complicated. Many aspects of such DDRs and their initial transcriptomes are closely related to oxidative stress response. Although many key components of DDR signaling have been characterized in plants, DDRs in plant cells are not understood in detail to allow comparison with those in yeast and mammalian cells. Recent studies have revealed plant DDR signaling pathways including the key regulator SOG1. The SOG1 and its upstream key components ATM and ATR could be functionally characterized by analyzing their knockout DDR phenotypes after exposure to IR. Considering the potent genotoxicity of IR and its various DDR phenotypes, IR-induced DDR studies should help to establish an integrated model for plant DDR signaling pathways by revealing the unknown key components of various DDRs in plants. PMID- 30471727 TI - Transcriptomic and physiological analyses reveal drought adaptation strategies in drought-tolerant and -susceptible watermelon genotypes. AB - Drought stress has become one of the most urgent environmental hazards for horticultural crops. In this research, we analyzed watermelon adaptation strategies to drought stress in drought-tolerant (M20) and -susceptible (Y34) genotypes via transcriptomic and physiological analyses. After drought stress, a total of 6228 and 4311 differentially expressed genes (DEGs) were observed in Y34 and M20, respectively. Numerous DEGs were involved in various defense responses such as antioxidation, protein protection, osmotic adjustment, wax accumulation, hormone signaling, and melatonin biosynthesis. Accordingly, the contents of ABA, melatonin, wax, and some osmoprotectants were increased by drought stress in both Y34 and especially M20. Exogenous application of melatonin or ABA induced wax accumulation and drought tolerance and melatonin may function upstream of ABA. In comparison to Y34, M20 was more able to activate ABA signaling, melatonin biosynthesis, osmotic adjustment, antioxidation, and wax accumulation under drought stress. These stronger responses confer M20 tolerance to drought. Photosynthesis and most DEGs involved in photosynthesis and cell growth were decreased by drought stress in both M20 and especially Y34. For drought susceptible genotypes, growth retardation may be an important mechanism for saving and redistributing resources in order to reprogram stress signaling networks. PMID- 30471729 TI - Functional screening of salt tolerance genes from a halophyte Sporobolus virginicus and transcriptomic and metabolomic analysis of salt tolerant plants expressing glycine-rich RNA-binding protein. AB - Sporobolus virginicus is a halophytic C4 grass found worldwide, from tropical to warm temperate regions. One Japanese genotype showed a salinity tolerance up to 1.5 M NaCl, a three-fold higher concentration than the salinity of sea water. To identify the key genes involved in the regulation of salt tolerance in S. virginicus, we produced 3500 independent transgenic Arabidopsis lines expressing random cDNA from S. virginicus and screened 10 lines which showed enhanced salt tolerance compared with the wild type in a medium containing 150 mM NaCl. Among the selected lines, two contained cDNA coding glycine-rich RNA-binding proteins (SvGRP1 and SvGRP2). This is the first reports on the function of GRPs from halophytes in salt tolerance though reports have shown GRPs are involved in diverse biological and biochemical processes including salt tolerance in Arabidopsis and some other glycophytes. Transcriptomic analysis and GO enrichment analysis of SvGRP1-expressing Arabidopsis under salt stress revealed upregulation of polyol and downregulation of glucosinolate and indole acetic acid biosynthesis/metabolic pathways. Metabolomic analysis of the SvGRP1-transformant suggested that the increase in 3-aminoppropanoic acid, citramalic acid, and isocitric acid content was associated with enhanced salt tolerance. These findings could provide novel insight into the roles of GRPs in plant salt tolerance. PMID- 30471731 TI - The involvement of cytokinin and nitrogen metabolism in delayed flag leaf senescence in a wheat stay-green mutant, tasg1. AB - In the present study on a wheat stay-green mutant, tasg1, we found that its delayed senescence at the late filling stage was related to the high cytokinin (CK) and N contents. RNA sequencing suggested that several genes may be responsible for the different senescence processes between wild-type (WT) and tasg1 plants. WT and tasg1 seedlings were treated with NH4NO3, lovastatin, and 6 benzylaminopurine (BAP), and the results suggested that the feedback of CK with N content regulated the leaf senescence in the tasg1 plants. Furthermore, a knock out of the candidate gene cisZOGT1 (catalytic O-glucosylation in cis-zeatin) in the wheat mutant pool 'Kronos' exhibited delayed senescence at the late grain filling stage. Overall, our results suggested the cisZOGT1 gene has an important role in regulating wheat leaf senescence by regulating CK and N metabolism. At the same time, CK and N metabolism involved in delayed flag leaf senescence of tasg1 may be by a feedback pattern. PMID- 30471730 TI - MORF2 tightly associates with MORF9 to regulate chloroplast RNA editing in Arabidopsis. AB - RNA editing in chloroplasts and mitochondria is performed by hypothetical editosomes. The MORF family proteins are essential components of these editosomes. In Arabidopsis, MORF2 and MORF9 are involved in the editing of most sites in chloroplasts. In this work, we performed immunoprecipitation and mass spectrometry assays of transgenic lines expressing MORF2-4xMYC and MORF9-4xMYC to identify interacting proteins. We found that MORF2 and MORF9 are present in the same complex. Blue-Native PAGE analysis of chloroplast protein complexes also revealed that both MORF2 and MORF9 are part of a complex of approximately 140 kDa, suggesting the existence of tight MORF2-MORF9 interaction in chloroplasts. The editing of ndhD-1 (ndhD-C2) site was reported to be blocked in both morf2 and morf9. RNA immunoprecipitation assays showed that MORF2 and MORF9 are tightly associated with the editing site of ndhD-1. However, in an RNA-EMSA assay MORF2 and MORF9 could not directly bind to transcripts harboring the editing site of ndhD-1. Taken together, these results indicate that the MORF2-MORF9 heterodimer is the core members of editosomes in chloroplasts, while they are not responsible for RNA editing site recognition. PMID- 30471732 TI - Physiological role of beta-carotene monohydroxylase (CYP97H1) in carotenoid biosynthesis in Euglena gracilis. AB - Some carotenoids are found in the Euglena gracilis, including beta-carotene, diadinoxanthin, diatoxanthins, and neoxanthin as the major species; however, the molecular mechanism underlying carotenoid biosynthesis in E. gracilis is not well understood. To clarify the pathway and regulation of carotenoid biosynthesis in this alga, we functionally characterized the cytochrome P450 (CYP)-type carotene hydroxylase gene EgCYP97H1. Heterologous in vivo enzyme assay in E. coli indicated that EgCYP97H1 hydroxylated beta-carotene to beta-cryptoxanthin. E. gracilis cells suppressing EgCYP97H1 resulted in marked growth inhibition and reductions in total carotenoid and chlorophyll contents. Analysis of carotenoid composition revealed that suppression of EgCYP97H1 resulted in higher level of beta-carotene, suggesting that EgCYP97H1 is physiologically essential for carotenoid biosynthesis and thus normal cell growth. To our knowledge, this is the first time EgCYP97H1 has been suggested to be beta-carotene monohydroxylase, but not beta-carotene dihydroxylase. Moreover, during light adaptation of dark grown E. gracilis, transcript levels of the carotenoid biosynthetic genes (EgCYP97H1, geranylgeranyl pyrophosphate synthase EgcrtE, and phytoene synthase EgcrtB) remained virtually unchanged. In contrast, carotenoid accumulation in E. gracilis grown under the same conditions was inhibited by treatment with a translational inhibitor but not a transcriptional inhibitor, indicating that photo-responsive carotenoid biosynthesis is regulated post-transcriptionally in this alga. PMID- 30471733 TI - Identification and characterization of a pyridoxal 5'-phosphate phosphatase in tobacco plants. AB - Pyridoxal 5'-phosphate (PLP), the catalytically active form of vitamin B6, is an important cofactor for many biochemical transformations. PLP is also a very reactive molecule, and the most well-established mechanism for maintaining low levels of free PLP is its dephosphorylation by phosphatases. In our previous study, the crude enzyme extract from tobacco leaves rapidly hydrolyzed PLP at a pH optimum of 5.5. Using PLP as a substrate, a novel acid phosphatase was purified from tobacco leaves and characterized. Whether there is a PLP specific phosphatase in plants is still unknown. In this study, a cDNA clone sharing 34.72% homology with human PLP phosphatase sequences was identified from N. tabacum and characterized. The cDNA encodes a polypeptide of 319 amino acid residues, and the recombinant enzyme purified from E. coli exhibited maximum catalytic activity for PLP at pH 7.5. The properties of the purified enzyme, including pH optimum, metal requirement, optimum substrate and inhibitors were similar to those of human PLP phosphatase. Subcellular localization analysis showed that the PLP phosphatase is mainly located in chloroplast. We down regulated the gene expression with plant RNA interference technology and found that the down-regulation has a greater impact on the transcription of genes encoding vitamin B6 metabolic enzymes. Our study further suggested that the PLP phosphatase plays an important role for maintaining PLP homeostasis within the chloroplast in plants. PMID- 30471734 TI - Lsi1 modulates the antioxidant capacity of rice and protects against ultraviolet B radiation. AB - Silicon (Si) enhances the resistance of rice to biotic and abiotic stress. In rice, the accumulation of Si is controlled by the low silicon rice 1 (Lsi1) gene; overexpression of Lsi1 (Lsi1-OX) increases Si uptake and accumulation, while the reverse is observed in Lsi1-RNA interference (Lsi1-RNAi) transgenic rice. When the two transgenic rice lines and wild-type (WT) rice were exposed to ultraviolet (UV)-B radiation, the Lsi1-OX or Lsi1-RNAi rice showed differential microRNA (miRNA) expression, compared to WT rice. These miRNAs were predicted to target genes involved in light signal transduction and cell detoxification. The greatest capacities of ascorbate peroxidase, superoxide dismutase, peroxidase, and phenylalanine ammonia lyase (PAL) and highest contents of phenolics, flavonoids, and proline were found in Lsi1-OX rice, followed by WT rice and Lsi1-RNAi transgenic rice. A further comparison of the transcript levels of individual PAL genes revealed that the expression of PAL2-2 (Os02g0626400) was positively regulated by Lsi1. Our results demonstrate that Lsi1 overexpression or interference causes changes in both miRNA expression and antioxidant capacity in rice, and therefore modulates rice tolerance to UV-B radiation. Furthermore, we demonstrated that PAL2-2 was positively regulated by Lsi1 during this process. PMID- 30471735 TI - Patient Selection for Kidney Transplant. AB - The incidence of end-stage renal disease has continued to increase. Similarly, the number of patients living with a functioning renal allograft has also increased. Transplantation has improved with advances in surgical techniques, immunosuppression, and better control of comorbid conditions. Transplantation is transformative and offers the greatest potential for restoring a healthy, productive, and durable life to appropriately selected patients. This article describes factors to address in selection of renal transplant candidates and discusses commonly encountered perioperative events. Paramount to selecting appropriate candidates is the collaboration between a multidisciplinary team focused on a systematic process guided by protocols and common practices. PMID- 30471736 TI - Small Bowel Transplantation. AB - Intestinal and multivisceral transplants are complex technical procedures that present unique challenges in the field of solid organ transplantation. This review aims to highlight the indications, techniques, outcomes, and complications specific to intestinal transplantation. PMID- 30471737 TI - Is This Organ Donor Safe?: Donor-Derived Infections in Solid Organ Transplantation. AB - Infection is an inevitable complication of solid organ transplantation. Unrecognized infection may be transmitted from a donor and result in disseminated disease in the immunosuppressed host. Recent outbreaks of deceased donor-derived infections resulting in high rates of mortality and severe morbidity have emphasized the need to be cautious in using donors with possible meningoencephalitis. Screening of organ donors for potential transmissible infections is paramount to improving transplantation outcomes. PMID- 30471739 TI - Safe Living Following Solid Organ Transplantation. AB - Living safely after organ transplantation starts before transplant and continues after transplant. To minimize a solid organ transplant (SOT) recipient's risk for infection and risk for injury, it is important to plan for numerous potential exposures after transplant. These include potential exposure to others with viral or bacterial illness, potential exposure to food and water sources, participation in recreational activities, resuming sexual activity, living with pets, and opportunities for travel, especially internationally. Addressing these risks head on ensures that an SOT recipient and their providers can plan accordingly and anticipate measures that will assist with maintaining such health. PMID- 30471738 TI - Composite and Multivisceral Transplantation: Nomenclature, Surgical Techniques, Current Practice, and Long-term Outcome. AB - The successful development of multivisceral and composite visceral transplantation is among the milestones in the recent history of human organ transplantation. All types of gastrointestinal transplantation have evolved to be the standard of care for patients with gut failure and complex abdominal pathologic conditions. The outcome has markedly improved over the last 3 decades owing to technical innovation, novel immunosuppression, and better postoperative care. Recent data documented significant improvement in the long-term therapeutic indices of all types of visceral transplantation close to that achieved with thoracic and solid abdominal organs. PMID- 30471740 TI - Living Kidney Donation: Strategies to Increase the Donor Pool. AB - End-stage renal disease (ESRD) is a significant health care burden. Although kidney transplantation is the optimal treatment modality, less than 25% of waiting list patients are transplanted because of organ shortage. Living kidney donation can lead to better recipient and graft survival and increase the number of donors. Not all ESRD patients have potential living donors, and not all living donors are a compatible match to recipients. Kidney paired exchanges allow incompatible pairs to identify compatible living donors for living donor kidney transplants for multiple recipients. Innovative modifications of kidney paired donation can increase the number of kidney transplants, with excellent outcomes. PMID- 30471742 TI - Liver Transplantation: Patient Selection, Perioperative Surgical Issues, and Expected Outcomes. AB - Liver transplant rates are at an all-time high, with nearly 8000 liver transplants in 2015. Despite the increasing number of liver transplants performed per year, there is a widening gap of supply and demand on limited donor resources. Patient selection is a complex but necessary process to evaluate patients who will benefit from liver transplant while minimizing futile transplants. Efforts should also continue to focus on minimizing perioperative complications resulting in retransplantations and more targeted immunosuppression to minimize side effects and prolong patient survival. PMID- 30471741 TI - Posttransplant Malignancy. AB - Posttransplant malignancy is a leading cause of death after solid organ transplantation (SOT). Recipients of SOT are at significantly higher risk of multiple cancers compared with the general population, most notably nonmelanoma skin cancer and posttransplant lymphoproliferative disorders. Risk factors for posttransplant malignancy include history of malignancy, immunosuppression, oncogenic viral infections, sun exposure, and disease-specific associations. Early detection and treatment of malignancies can improve survival. PMID- 30471743 TI - Pediatric Abdominal Organ Transplantation. AB - Pediatric liver and kidney transplantation have become the standard and accepted treatment for children with end-stage renal and liver disease. Since the first successful kidney transplant in 1954 by Dr Joseph Murray and the first liver transplant by Dr Thomas Starzl, the scope of indications for visceral organ transplantation as well as the range of recipient and donor ages has expanded. The first pediatric liver and kidney transplants, simultaneous multivisceral transplants, living-donor and donation-after-cardiac-death organs have evolved rapidly into the standard of care for end-stage renal and liver failure in children. PMID- 30471744 TI - Pancreas Transplantation: Indications, Techniques, and Outcomes. AB - Pancreas transplantation treats insulin-dependent diabetes with or without concurrent end-stage renal disease. Pancreas transplantation increases survival versus no transplant, increases survival when performed as simultaneous pancreas kidney versus deceased-donor kidney alone, and improves quality of life. Careful donor and recipient selection are paramount to good outcomes. Several technical variations exist for implantation: portal versus systemic vascular drainage and jejunal versus duodenal versus bladder exocrine drainage. Complications are most frequently technical in the first year and immunologic thereafter. Graft rejection is challenging to diagnose and is treated selectively. Islet cell transplantation currently has inferior outcomes to whole-organ pancreas transplantation. PMID- 30471745 TI - Transplant 2018. PMID- 30471746 TI - A new stage in the diagnosis of Alzheimer's Disease. PMID- 30471747 TI - CRUSADE: Is it still a good score to predict bleeding in acute coronary syndrome? AB - INTRODUCTION: Major bleeding is a serious complication of acute coronary syndrome (ACS) and is associated with a worse prognosis. The CRUSADE bleeding score is used to stratify the risk of major bleeding in ACS. OBJECTIVE: To assess the predictive ability of the CRUSADE score in a contemporary ACS population. METHODS: In a single-center retrospective study of 2818 patients admitted with ACS, the CRUSADE score was calculated for each patient and its discrimination and goodness of fit were assessed by the area under the receiver operating characteristic curve (AUC) and by the Hosmer-Lemeshow test, respectively. Predictors of in-hospital major bleeding (IHMB) were determined. RESULTS: The IHMB rate was 1.8%, significantly lower than predicted by the CRUSADE score (7.1%, p<0.001). The incidence of IHMB was 0.5% in the very low risk category (rate predicted by the score 3.1%), 1.5% in the low risk category (5.5%), 1.6% in the moderate risk category (8.6%), 5.5% in the high risk category (11.9%), and 4.4% in the very high risk category (19.5%). The predictive ability of the CRUSADE score for IHMB was only moderate (AUC 0.73). The in-hospital mortality rate was 4.0%. Advanced age (p=0.027), femoral vascular access (p=0.004), higher heart rate (p=0.047) and ticagrelor use (p=0.027) were independent predictors of IHMB. CONCLUSIONS: The CRUSADE score, although presenting some discriminatory power, significantly overestimated the IHMB rate, especially in patients at higher risk. These results question whether the CRUSADE score should continue to be used in the stratification of ACS. PMID- 30471748 TI - A multiparametric MRI-based machine learning to distinguish between uterine sarcoma and benign leiomyoma: comparison with 18F-FDG PET/CT. AB - AIM: To compare the performance of machine learning using multiparametric magnetic resonance imaging (mp-MRI) and positron-emission tomography (PET) to distinguish between uterine sarcoma and leiomyoma. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and informed consent was waived. Sixty-seven consecutive patients with uterine sarcoma or leiomyoma who underwent pelvic 3 T MRI and PET were included. Of 67 patients, 11 had uterine sarcomas and 56 had leiomyomas. Seven different parameters were measured in the tumours, from T2-weighted, T1-weighted, contrast-enhanced, and diffusion-weighted MRI, and PET. The areas under the receiver operating characteristic curves (AUC) with a leave-one-out cross-validation were used to compare the diagnostic performances of the univariate and multivariate logistic regression (LR) model with those of two board-certified radiologists. RESULTS: The AUCs of the univariate models using MRI parameters (0.68-0.8) were inferior to that of the maximum standardised uptake value (SUVmax) of PET (0.85); however, the AUC of the multivariate LR model (0.92) was superior to that of SUVmax, and comparable to that of the board-certified radiologists (0.97 and 0.89). CONCLUSION: The diagnostic performance of the machine learning using mp-MRI was superior to PET and comparable to that of experienced radiologists. PMID- 30471749 TI - Understudied Skin Characteristics Awaiting Genetic Breakthroughs. AB - Skin is the human body's largest organ and the first to contact various environments. There are considerable variations of normal skin characteristics within and between populations. For example, skin containing more melanin looks darker, people with reduced axial sweating tend to have less body odor, and skin with higher lipid and water content has an improved barrier. For decades, dermatologists have been developing new methods to measure differences in normal skin characteristics. However, most of these studies were carried out at the clinical level. Research at the molecular level, in contrast, has become more common only in the last decade. PMID- 30471750 TI - Srcasm Regulates Tyrosine Kinases in Skin Cancer: Implications for Precision Medicine. AB - Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in humans, with an incidence of approximately 700,000 cases per year in the United States (Rogers et al., 2010). It is known that cSCC is strongly associated with sun exposure, specifically UVB and UVA, as well as other risk factors, such as human papillomavirus infection, immunodeficiency, and specific medications (Ratushny et al., 2012). However, the precise sequence of biological events leading to tumor development remains unknown. With projected higher incidence of patients with cSCCs in the future, there is a strong need to elucidate the molecular pathways that regulate formation of cSCCs. PMID- 30471752 TI - Introduction to the 2016 JID Beijing Workshop: Precision Medicine in Dermatology. AB - On May 23-25, 2016, investigators from the United States, Europe and China came together for a meeting on "Precision Medicine in Dermatology" at the Beijing Landmark Hotel. This meeting brought together investigators in cutaneous biology from the United States, Europe, and China in a forum to exchange scientific ideas and foster new collaborations. The meeting was hosted and organized by Heng Gu, Yong Cui, and Xuejun Zhang. John Seykora, with valuable assistance from Barbara Gilchrest and Elizabeth Blalock, organized the European and American speakers. The meeting speakers represented 4 universities in the United States, 3 universities from Europe, and 12 institutions in China. There were approximately 200 attendees, and 68 abstracts were submitted. PMID- 30471751 TI - Heritable Ectopic Mineralization Disorders: Pathomechanisms and Potential Treatment. AB - Pseudoxanthoma elasticum (PXE), a prototype of heritable ectopic mineralization disorders, is an autosomal recessive disease characterized by deposition of calcium hydroxyapatite in the skin, eyes, and cardiovascular system, with protean manifestations (Li et al., 2016; Li and Uitto, 2013; Neldner, 1988). The classic form of PXE is late-onset and slow-progressing, and the major clinical problems relate to loss of vision and development of cardiovascular complications (Neldner, 1988). The classic form of PXE is caused by loss-of-function mutations in the ABCC6 gene encoding ATP-binding cassette subfamily C, member 6 (ABCC6), a putative transmembrane efflux transporter protein expressed primarily in the liver and kidneys. The metabolic hypothesis concerning PXE postulates that the absence of functional ABCC6 activity, primarily in the liver, results in deficiency of circulating factor(s) that is physiologically required to prevent ectopic mineralization under normal calcium and phosphate homeostasis (Li et al., 2016) (Figure 1). However, the factor(s) transported by ABCC6 from the intracellular milieu to the extracellular space have not been identified. PMID- 30471753 TI - A Promising Generation: Future Academic Leadership of China. AB - With the world's largest population at 1.3 billion and a rising number of foreigners, China requires physicians and a healthcare system that meets the needs of a large and diverse population. Along with rapid economic and technological advancements, the Medical Administration Division of the National Health and Family Planning Commission remarked that medical services through online appointments and payments have improved its efficacy over the past 2 years. According to the official report from the National Health and Family Planning Commission of the People's Republic of China website, China has so far established a total of 25,000 hospitals and 981,000 community health centers, that includes 17,100 dermatologists and 190,000 residents in training. PMID- 30471754 TI - Teledermatology in China: History, Current Status, and the Next Step. AB - Telemedicine, as defined by the World Health Organization, is the use of communication technologies in healthcare for the exchange of medical information for diagnosis, treatment, prevention, research, evaluation, and education over a distance (World Health Organization, 1998). Since the 1990s, with the rapid development of modern communication technology, telemedicine, which can be used by almost all medical specialties, has likely entered its "golden age," However, some of the more visual medical specialties may be more suitable, such as teleradiology, telepathology, and teledermatology. PMID- 30471755 TI - Precision Medicine for Heritable Skin Diseases-The Paradigm of Epidermolysis Bullosa. AB - The 2016 JID Beijing Workshop, held in the context of the 5th National Congress of Investigative Dermatology of the Chinese Society of Dermatology, had the thematic focus on "Precision Medicine in Dermatology." This theme was extremely timely, yet forward-looking, due to the fact that precision medicine is one of the fastest growing paradigms of contemporary medicine (Box 1). PMID- 30471756 TI - Expanded Genome-Wide Association Study Meta-Analysis of Psoriasis Expands the Catalog of Common Psoriasis-Associated Variants. AB - Psoriasis is a complex immune-mediated disease of skin and joints with a prevalence of about 2%. Previous genetic association studies have identified more than 60 psoriasis susceptibility loci, 47 of which were identified in Caucasians. To further understand the genetic architecture of this disease, we conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts (seven GWAS and one Immunochip dataset), with a combined effective sample size of more than 39,000 individuals. Approximately half (n = 22) of the 47 European-origin loci were identified in cohorts containing a large proportion (>=50%) of samples genotyped using the Immunochip (Bowes et al., 2015; Stuart et al., 2015; Tsoi et al., 2012a, 2015), a platform that focuses on genetic variants from promising signals identified in previous association studies of autoimmune diseases (Stuart et al., 2015). However, restricting analysis to markers genotyped (~110,000) (Tsoi et al., 2012b) or well-imputed (~700,000) (Tsoi et al., 2015) on the Immunochip limits exploration of the full genome for susceptibility loci. PMID- 30471757 TI - Major Histocompatibility Complex and Psoriasis. AB - Major histocompatibility complex (MHC), also known as human leukocyte antigen (HLA) in humans, is one of the most genetically diverse regions in the genome of various species. The human MHC contains about 400 genes in a ~7.6-Mb span located on the short arm of the chromosomal region 6p21.3. According to the NHGRI-EBI Catalog of published genome-wide association studies (http://www.ebi.ac.uk/gwas/) in HLA region, more than 500 associations have been identified for about 200 traits or phenotypes, including primary immune deficiencies, autoimmune diseases, susceptibility to infections, malignancies, and psychiatric conditions (Welter et al., 2014). For example, multiple sclerosis is associated with HLA-DRB1*1501 (Handunnetthi et al., 2010); the control of HIV viral load is associated with variants near HLA-C (Kulpa and Collins, 2011). Some acute drug reactions are associated with specific HLA alleles. Carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis have been strongly associated with HLA B*1502 in Han Chinese population and HLA-A*3101 in European populations (Chung et al., 2004; McCormack et al., 2011). The HLA-B*13:01 is associated with the development of the dapsone hypersensitivity syndrome among patients with leprosy (Zhang et al., 2013). PMID- 30471758 TI - The Aberrant Epigenetic Modifications in the Pathogenesis of Psoriasis. AB - Psoriasis is a chronic and recurrent inflammatory skin disease that is characterized by abnormal keratinocyte proliferation, vascular hyperplasia, and infiltration of inflammatory cells into the dermis and epidermis. It is generally accepted that the central pathogenesis of psoriasis is dysfunction of T lymphocytes, which are affected by the complex interplay between genetic and environmental factors, including trauma, infections, stress, drugs, smoking, and alcohol consumption (Nestle et al., 2009). The environmentally induced epigenetic changes, including DNA methylation, histone modification, and microRNAs, have been shown to be involved in the pathogenesis of this disease (Zhang et al., 2012). PMID- 30471759 TI - Investigation of Psoriasis Susceptibility Loci in Psoriatic Arthritis and a Generalized Pustular Psoriasis Cohort. AB - Psoriasis is a common skin disease affecting 1-3% of the population (Gelfand et al., 2005; Ferrandiz et al., 2001). Approximately 30% of patients with psoriasis develop psoriatic arthritis (PsA), an inflammatory arthritis associated with psoriasis (Haroon et al., 2013; Prey et al., 2010). Generalized pustular psoriasis (GPP) affects about 1.3% of psoriasis patients. Recently, numerous novel susceptibility loci for psoriasis vulgaris (PsV) have been discovered thorough the application of genome-wide association studies (GWASs). Among them, the major histocompability complex is the locus with the strongest effect. Outside the major histocompability complex region, the novel susceptibility loci of PsV can be incorporated into an integrated pathogenic model comprising distinct signaling networks affecting skin barrier function, innate immune responses involving NF-kappaB signaling, and adaptive immune responses involving CD8 T cells and IL-23/IL-17-mediated lymphocyte signaling. Compared with PsV, only three GWASs were performed in PsA (Ellinghaus et al., 2012; Huffmeier et al., 2010; Stuart et al., 2015), accompanied with other candidate gene studies, most of the PsA susceptibility loci have been proved to be associated with PsV. However, the genetic study of GPP is quite different. Up to now, IL36RN is the only associated gene of GPP that has been widely verified. The data are based on homozygosity mapping and direct sequencing in consanguineous Tunisian multiplex families with autosomal recessive GPP (Marrakchi et al., 2011). Some researchers suggested that GPP and PsV are etiologically distinct clinical entities (Capon, 2013), challenging the traditional understanding of psoriasis. The percentages of IL36RN-negative patients have been reported to range from 51% (Li et al., 2013) to 84% (Setta-Kaffetzi et al., 2013), implying that additional risk loci, genetic interactions, and other factors may account for the other GPP cases. Recently, more than 10 GWASs of PsV have identified a number of susceptibility loci, making PsV GWASs a rich source of potential risk loci for other subtypes of psoriasis. Here, we use information emerging form PsV GWASs to make inferences about the genetic etiology of PsA and GPP in a Chinese population. PMID- 30471760 TI - Targeted Therapy of Melanoma. AB - In recent years, the treatment of advanced melanoma has been revolutionized by the introduction of new innovative approaches, namely mutation-based targeted therapy and immune checkpoint blockade by CTLA4 and PD-1/PD-L1 inhibitors. The decade-long era of chemotherapy with very low response rates of 5-20% and short median survival rates of 6-9 months has been left in favor of new therapies with response rates ranging between 40% and 70% and median overall survival rates of 2 years and longer (Heppt et al., 2015, Larkin et al., 2014, Long et al., 2015, Long et al., 2016, Schadendorf et al., 2015). PMID- 30471761 TI - How Bad Is the Hedgehog? GLI-Dependent, Hedgehog-Independent Cancers on the Importance of Biomarkers for Proper Patients Selection. AB - Hedgehog (HH) signaling plays an important role both during embryonic development and adult life. It is involved in the regulation of cell differentiation, cell proliferation and tissue polarity, as well as in the maintenance of stem cells, tissue repair, and regeneration (Briscoe and Therond, 2013; Jiang and Hui, 2008). Three ligands, Indian, Sonic, and Desert HH, can activate this pathway. Binding of HH ligands to their receptor, PTCH1 (Figure 1) lift its inhibition on SMO, resulting in activation and nuclear translocation of GLI transcription factors (Javelaud et al., 2012). The vertebrate GLI gene family is composed of three distinct genes GLI1, GLI2, and GLI3, encoding Kruppel-like transcription factors. GLI proteins exhibit distinct regulations, biochemical properties, and target genes. GLI3 acts as the main repressor of the pathway in the absence of HH ligands, whereas, in their presence, GLI2 is the main HH effector that drives the expression of GLI1 (Briscoe and Therond, 2013). PMID- 30471762 TI - Multifunctional Nanoparticle Approach for Targeting Melanoma. AB - Malignant melanoma is the most aggressive and lethal form of skin cancer with an increasing incidence worldwide. In the past 5 years, the Food and Drug Administration has approved six targeted therapies or immunotherapies for the treatment of metastatic melanoma (Chapman et al., 2011; Falchook et al., 2012; Hauschild et al., 2012; Hodi et al., 2010; Ribas et al., 2015; Topalian et al., 2014). For the first time, interventions improve survival of this deadly disease. However, rapid resistance to BRAF/MEK inhibitors and lower rates of objective response or immune-related side effects for anti-CTLA-4 or anti-PD-1 monoclonal antibodies limited their widespread clinical applications. PMID- 30471763 TI - CD147 Is a Novel Chemotherapy or Prevention Target in Melanoma. AB - CD147, also named as BSG, was first identified from F9 embryonal carcinoma cells (Miyauchi et al., 1990) and the human BSG locus on chromosome 19p13.3 containing 10 exons (Belton et al., 2008; Kaname et al., 1993; Liao et al., 2011), which encodes four alternatively spliced transcripts:CD147/Bsg-1,2,3,4 (Kaname et al., 1993; Liao et al., 2011). Bsg-1 has three Ig-like domains (CD147/Bsg-1) (Hanna et al., 2003; Ochrietor et al., 2003), while CD147/Bsg-3,4 contains a single Ig-like domain (Belton et al., 2008; Liao et al., 2011). Evidence shows that CD147/Bsg-2 is the most abundant and best characterized splice product, which contains two Ig like domains (Weidle et al., 2010). Analysis of amino acids showed that CD147 contains a single-chain type I transmembrane domain composed of a 21-amino acid signal sequence, an extracellular domain consisting of 186 amino acids with two Ig-like domains and a cytoplasmic domain of 41 residues (Kanekura et al., 2010; Yurchenko et al., 2005). There are three glycosylation sites at three conserved asparagine (Asn 44, 152, and 186) in the CD147 N-terminal domain (Fadool et al., 1993; Tang et al., 2004; Yu et al., 2006), which could explain the molecular mass of CD147 shifts from a predicted molecular weight of about 27 kDa to 40-65 kDa with Western blotting. Inhibition of glycosylation by specific inhibitors showed that on carbohydrate side groups bearing beta-1,6-branched, polylactosamine-type sugars, fucosylations are the major glycosylation type in N-glycosylation of CD147 (Ni et al., 2014; Riethdorf et al., 2006; Tang et al., 2004). In addition, N-glycosylation of CD147 has been identified as low glycosylated (approximately 32 kDa) or high glycosylated (approximately 45-65 kDa). The fully glycosylated mature CD147 (high-glycosylated CD147) is translocated to the plasma membrane, while low-glycosylated CD147 is the precursor of high-glycosylated CD147 in the endoplasmic reticulum, which requires additional modification in the Golgi prior to being expressed on the cell surface; high levels of glycosylation are a primary biochemical property of CD147 (Jia et al., 2006; Jiang et al., 2014; Ni et al., 2014; Tang et al., 2004). PMID- 30471764 TI - Is the Nervous System More Important Than the Immune System in Itch and Atopic Dermatitis? AB - Atopic dermatitis is a common cutaneous disorder characterized by severe itch, chronic inflammation, and increased nerve fiber density. It has been assumed that the neural changes are in response to ongoing inflammation. We used in vivo imaging over time of fluorescently labeled peripheral sensory nerves during epicutaneous sensitization to ovalbumin in an allergic mouse model of atopic dermatitis. Visualization of cutaneous nerve branches and blood vessels sequentially over months revealed that peripheral sensory nerves begin to pathfind within 48 hours of antigen exposure. Innervation density and arbor complexity of neuropeptidergic fibers in the skin increased within days. Neural sprouting preceded changes in vascularization, vascular permeability, and immune infiltration. Blocking neural activation during periods of sensitization prevented ovalbumin-induced changes in neural recruitment and pattern reorganization, as well as subsequent inflammatory infiltrates and scratching behavior. These data implicate different roles for recently identified itch molecules in modulating various steps in the inflammatory response. Thus, in contrast to the traditional view that neural changes are reactive to inflammation and scratching, these data suggest that allergic stimulation in a chronic eczema model requires neural recruitment and activation early in the process for the elaboration and maintenance of the inflammatory cascade. PMID- 30471765 TI - Genetic Profiles for Systemic Lupus Erythematosus in Han Chinese Population: From Genome-Wide Association Study to Exome-Wide Association Study. AB - Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disease characterized by loss of tolerance to self-antigens, complement activation, dysregulated type 1 IFN responses, and immune-mediated tissue damage. The clinical features of SLE are pleomorphic, affecting virtually any organ system, such as skin, joints, central nervous system, or kidneys. Currently, the etiology and pathogenesis of SLE are not fully understood. Generally, it is considered that genetic factors, immune abnormalities, sex hormones, and environmental factors are associated with SLE, and mainly caused by genetic and environmental interactions, typical for a complex disease with multiple susceptibility genes. Therefore, identification of SLE susceptibility loci through molecular genetics methods may help build the foundation for identifying individuals and groups susceptible to SLE, early prevention, new drug development, and individualized treatment promoting precision medicine. PMID- 30471766 TI - Functional and Mechanistic Insights into the Pathogenesis of P63-Associated Disorders. AB - The p53 family member p63 is a master regulator of gene expression in stratified epithelia, such as the epidermis. One of the main functions of p63 is to sustain mechanical resistance, positively regulating several epidermal genes involved in cell-matrix adhesion and cell-cell adhesion (Ferone et al., 2015). PMID- 30471767 TI - Omega-6 fatty acids, inflammation and cardiometabolic health: Overview of supplementary issue. PMID- 30471768 TI - Higher baseline expression of the PTGS2 gene and greater decreases in total colonic fatty acid content predict greater decreases in colonic prostaglandin-E2 concentrations after dietary supplementation with omega-3 fatty acids. AB - This study evaluated whether mRNA expression of major genes regulating formation of prostaglandin (PG)E2 in the colon and colonic fatty acid concentrations are associated with the reduction in colonic mucosal PGE2 after dietary supplementation with omega-3 (omega-3) fatty acids. Supplementation with omega-3 fatty acids was done for 12 weeks using personalized dosing that was expected to reduce colonic PGE2 by 50%. In stepwise linear regression models, the omega-3 fatty acid dose and baseline BMI explained 16.1% of the inter-individual variability in the fold change of colonic PGE2 post-supplementation. Increases in mRNA gene expression after supplementation were, however, modest and were not associated with changes in PGE2. When baseline expression of PTGS1, PTGS2 and HPGD genes was included in the linear regression model containing dose and BMI, only PTGS2, the gene coding for the inducible form cyclooxygenase, was a significant predictor. Higher relative expression of PTGS2 predicted greater decreases in colonic PGE2, accounting for an additional 13.6% of the inter individual variance. In the final step of the regression model, greater decreases in total colonic fatty acid concentrations predicted greater decreases in colonic PGE2, contributing to an additional 18.7% of the variance. Overall, baseline BMI, baseline expression of PTGS2 and changes in colonic total fatty acids together accounted for 48% of the inter-individual variability in the change in colonic PGE2. This is consistent with biochemical data showing that fatty acids which are not substrates for cyclooxygenases can activate cyclooxygenase-2 allosterically. Further clinical trials are needed to elucidate the factors that regulate the fatty acid milieu of the human colon and how this interacts with key lipid metabolizing enzymes. Given the central role of PGE2 in colon carcinogenesis, these pathways may also impact on colon cancer prevention by other dietary and pharmacological approaches. PMID- 30471769 TI - Low omega-3 index and polyunsaturated fatty acid status in patients with chronic fatigue syndrome/myalgic encephalomyelitis. AB - BACKGROUND: Several studies have suggested that low levels of omega-3 fatty acids (n-3 PUFAs) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are associated with cardiovascular risk, major depression, sleep problems, inflammation and other health-related issues. So far, however, erythrocyte PUFA status in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) has not been established. This study aimed to determine whether n-3 PUFA content and omega-3 index are associated with measures in CFS/ME patients. PATIENTS AND METHODS: PUFA levels and omega-3 index were measured in 31 Spanish CFS/ME patients using the HS-Omega-3 Index method. Demographic and clinical characteristics and self-reported outcome measures were also recorded. RESULTS: A low mean omega-3 index (5.75%) was observed in 92.6% of the sample. Omega-3 index was inversely correlated with the AA/EPA ratio (p = 0.00002) and the BMI (p = 0.0106). In contrast, the AA/EPA ratio was positively associated with the BMI (p = 0.0038). No association for FIS-40 and PSQI measures was found (p > 0.05). CONCLUSION: The low omega-3 index found in our CFS/ME patients may indicate increased risks for cardiovascular health, which should be further investigated. A low omega-3 index also suggests a pro-inflammatory state in these patients. Attempts should be made to increase the omega-3 index in CFS/ME patients, based on intervention trials assessing a potential therapeutic value. PMID- 30471770 TI - Docosahexaenoic acid levels in erythrocytes and their association with the University Selection Test Outcomes in Chile. AB - The aim of this study was to quantitate the relative impact of DHA and AA levels in erythrocytes, anthropometric parameters and socio-economic status of school age children, of both genders, graduated from high school in Chile, on the scholastic achievement in the University Selection Test (Prueba de Seleccion Universitaria, PSU) both language scholastic achievement (LSA) and mathematics scholastic achievement (MSA). A representative sample of 671 school-age young graduated from high school in 2013, 550 and 548 of them took the PSU for LSA and MSA, respectively. Only school-age young with high (n = 91) and low (n = 69) SA in both tests were considered. A total of 122 school-age children agreed to participate in the study and were divided as follows: Group 1: high PSU outcome (n = 70; males n = 48) and Group 2: low PSU outcome (n = 52; males n = 23). Data were analyzed by means of SAS software. Independently of gender, DHA, socio economic status and head circumference-for-age Z-score were the most relevant parameters explaining both LSA (R2 = 0.650; p < 0.0001) and MSA outcomes (R2 = 0.700; p < 0.0001). These results can be useful for nutrition, health and education planning, in order to protect children starting from an early age and thus increase their school outcomes. PMID- 30471771 TI - Comparison of breast milk fatty acid composition from mothers of premature infants of three countries using novel dried milk spot technology. AB - Long chain polyunsaturated fatty acid (LCPUFA) intake during infancy has been associated with many health benefits, and the LCPUFA intake of breastfed infants is largely dependent on the composition of breast milk. The conventional method for breast milk fatty acid profiling is complicated by the need for cold-chain transportation and storage, and the newly developed dried milk spot (DMS) technology overcomes these difficulties. This study aimed to determine the accuracy, sensitivity and applicability of the DMS method developed based on the PUFAcoatTM technology. Two hundred breast milk samples were analyzed using the conventional method and compared with the DMS method. In order to evaluate the usefulness of DMS for large scale international studies, we analyzed another 786 breast milk samples collected from mothers of preterm infants who participated in a large clinical trial conducted in Australia, New Zealand and Singapore. Fatty acids were measured using capillary gas chromatography and results were reported as weight percentage of total fatty acids. Strong correlations and tight variation were observed in total saturated, monounsaturated, n-6 and n-3 PUFAs between the conventional and DMS methods. The DMS method proved to be sensitive in differentiating the breast milk fatty acid profiles of women consuming different habitual diets as evidenced by the differences between the breast milk fatty acid composition between Australian and Singaporean population. This study demonstrates that the DMS and the conventional method provide interchangeable results, and the DMS method is a particularly useful tool for large-scale studies. PMID- 30471772 TI - Antiemetic doses of dexamethasone and their effects on immune cell populations and plasma mediators of inflammation resolution in healthy volunteers. AB - INTRODUCTION: The synthetic glucocorticoid dexamethasone is a commonly administered antiemetic. It has immunosuppressive effects and may alter postoperative blood glucose concentrations. Dexamethasone can effect key enzymes involved in inflammation resolution that is an active process driven by specialised lipid mediators of inflammation resolution (SPM). The purpose of this study in healthy volunteers was to examine whether dexamethasone effects cell populations and synthesis of SPM that are critical for the resolution of inflammation. METHODS: Thirty-two healthy volunteers were randomly allocated to receive saline (Control) or dexamethasone 2 mg, 4 mg or 8 mg intravenously. Venous blood samples were collected at baseline before administration of treatment, and at 4 h, 24 h and one-week post-treatment. At each time point, measurements included blood glucose and macrophage migration inhibition factor (MMIF), full blood count including lymphocyte subsets, monocytes, neutrophils, eosinophils and basophils by flow cytometry, and plasma SPM using liquid chromatography tandem mass spectrometry. The effect of dexamethasone dose and time on all measures was analysed using linear mixed models. RESULTS: There was a dose-dependent increase in neutrophil count after dexamethasone that persisted for 24 h. In contrast, there was a dose-dependent reduction in counts of monocytes, lymphocytes, basophils and eosinophils 4 h after dexamethasone, followed by a rebound increase in cell counts at 24 h. Seven days after administration of dexamethasone, all cell counts were similar to baseline levels. MMIF concentration, glucose and natural killer cell counts were not significantly affected by dexamethasone. There was a significant gender effect on plasma SPM such that levels of 17-HDHA, RvD1, 17R-RvD1 and RvE2 in females were on average 14%-50% lower than males. In a linear mixed model that adjusted for neutrophil count, there was a significant interaction between the dose of dexamethasone and time, on plasma 17R-RvD1 such that plasma 17R-RvD1 fell in a dose-dependent manner until 4 h after administration of dexamethasone. There were no significant effects of dexamethasone on the other plasma SPM (18-HEPE, RvE2, 17-HDHA, RvD1, RvD2 and 14-HDHA) measured. DISCUSSION: This is the first study in healthy volunteers to demonstrate that commonly employed antiemetic doses of dexamethasone affect immune cell populations and plasma levels of 17R-RvD1 an SPM with anti-nociceptive properties. If similar changes occur in surgical patients, then this may have implications for acute infection risk in the post-operative period. PMID- 30471773 TI - Association between blood polyunsaturated fatty acid levels and depressive symptoms in breast cancer survivors. AB - In contrast to the cumulative evidence suggesting the inverse association of n-3 polyunsaturated fatty acids (PUFAs) with depression, few studies have examined the association of n-6 PUFAs with depression. In particular, no study has examined the relationship between n-6 PUFAs and depression in cancer patients. Thus, we conducted this cross-sectional study to comprehensively examine the association of n-3 and n-6 PUFAs with depressive symptoms in breast cancer survivors. Adults who had been diagnosed with invasive breast cancer and were not undergoing chemotherapy were enrolled. Blood PUFA composition was determined using capillary blood. Depressive symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS). Among 126 participants, the mean age (standard deviation) was 58 (11) years and 47% had stage I cancer. Multiple regression analysis controlling for possible confounders revealed that the level of total n-6 PUFAs and linoleic acid was significantly associated with the HADS total score (beta = 0.175, p = 0.046 for total n-6 PUFAs; beta = 0.174, p = 0.048 for LA). No significant associations were found for other PUFAs. These findings provide the first evidence suggesting that a higher blood level of total n-6 PUFAs and linoleic acid is significantly associated with higher depressive symptoms among breast cancer survivors. Further studies should examine the positive effects of a reduction in n-6 PUFAs on depressive symptoms in breast cancer survivors using prospective studies, including randomized control trials. PMID- 30471775 TI - Selective and validated kinetic spectrophotometric method for the determination of irbesartan in pure and pharmaceutical formulations. AB - A novel-coupling reagent is used for the simple and sensitive kinetic spectrophotometric determination of irbesartan (IRB) in pure or pharmaceutical formulations. The method utilizes an oxidative coupling reaction based on oxidation of 3-methyl-2-benzothiazolinone hydrazone hydrochloride monohydrate (MBTH) with Ce(IV) in 2% sulfuric acid medium, followed by coupling the produced electrophilic intermediate (diazonium salt of the reagent) with IRB to give greenish-blue colored product (1:1, stoichiometry) having maximum absorption at 629nm and the colored species is stable for more than 1h. The initial rate and fixed time (at 35min) methods are adopted for determination of IRB concentration. The linearity is in the ranges of 5.0-40.0MUg/mL and 2.0-45.0MUg/mL and the limit of detection is 0.46 and 0.40MUg/mL for initial rate and fixed time methods, respectively. Molar absorptivity for the method was found to be 1.50*104L/molcm. The validated kinetic methods can be successfully applied to the analysis of IRB in bulk and tablet dosage form and in the routine quality control analysis. The percentage recoveries were above 100% for both methods. The excipients did not interfere in the analysis. PMID- 30471774 TI - Evaluating a Media Strategy to Provide Health Messages to Medically Underserved Populations. AB - For nearly every category of chronic disease, blacks with African American ancestry (AAs) bear a disproportionate disease burden in comparison to their non Hispanic white (NHW) counterparts. The purpose of this study was to evaluate perceptions of a radio-based health communication strategy, geared towards AA adults and the medically underserved. The radio broadcast, titled "Closing the Gap in Healthcare, Inc. (CGHI)," is delivered by a well-known AA male physician in South Carolina. The mission of CGHI is to decrease health disparities in a four-county area of the South Carolina coastal region, defined as the "Lowcountry," by providing evidence-based health information to a broad community audience via radio broadcast messaging. To evaluate the impact of the CGHI, investigators conducted 12 focus groups (FGs) with community members from the broadcast coverage area to evaluate responses to FG questions based on 11 attributes of effective health communication. Potential FG participants were identified/recruitd via a South Carolina-based marketing firm. The FGs conducted in the Sea Islands were culturally and racially homogenous. The investigators developed a FG interview guide. Before each FG started, the informed consent process was administered to each participant. Each two-hour FG was digitally recorded. PMID- 30471776 TI - The role of women throughout the history of Nephrology. PMID- 30471777 TI - MYH9 Associated nephropathy. AB - MYH9 related diseases are caused by mutations in the MYH9 gene and constitute a rare group of genetic entities. Its inheritance follows an autosomal dominant pattern. The MYH9 gene, encodes the nonmuscle myosin heavy chain IIA, expressed in different tissues and especially in podocytes and mesangial cells. The disorder is characterized by the presence of macrothrombocytopenia, leukocyte inclusions and a variable risk of developing renal failure, hearing loss and early-onset cataracts. We describe the case of a 27-year-old Caucasian woman, diagnosed initially with idiopathic thrombocytopenic purpura. After a detailed family history and the appearance of renal involvement and hearing loss, genetic testing allowed to make the diagnosis of nephropathy associated with MYH9 mutation. This case is an example of the delayed diagnosis of uncommon diseases and highlights the usefulness genetic testing. A review of the disease is provided. PMID- 30471778 TI - PYY(3-36) and exendin-4 reduce food intake and activate neuronal circuits in a synergistic manner in mice. AB - Peptide YY(3-36) ((PYY(3-36)) and glucagon like peptide 1 (GLP-1) in combination reduce food intake and body weight in an additive or synergistic manner in animal models and in humans. Nevertheless, the mechanisms behind are not completely understood. The present study aims to investigate the effect of combining PYY(3 36) and the GLP-1 receptor agonist exendin-4 (Ex4) by examining acute food intake and global neuronal activation as measured by c-fos in C57BL/6 J mice. An additive reduction in food intake was found 1.5 h after s.c dosing with the combination of PYY(3-36) (200 MUg/kg) and Ex4 (2.5 MUg/kg). This was associated with a synergistic enhancement of c-fos reactivity in central amygdalar nucleus (CeA), rostral part of the mediobasal arcuate nucleus (ARH), supratrigeminal nucleus (SUT), lateral parabrachial nucleus (PB), area postrema (AP) and nucleus tractus solitarius (NTS) compared to vehicle, PYY(3-36) and Ex4 individually dosed mice. The regions activated by Ex4 individually and PYY(3-36) and Ex4 in combination resembled each other, but the combination group had a significantly stronger c-fos response. Twenty-five brain areas were activated by PYY(3-36) and Ex4 in combination compared to vehicle versus nine brain areas by Ex4 individually. No significant increase in c-fos reactivity was found by PYY(3-36) compared to vehicle dosed mice. The neuronal activation of ARH and the AP/NTS to PB to CeA pathway is important for appetite regulation while SUT has not previously been reported in the regulation of energy balance. As PYY(3-36) and Ex4 act on different neurons leading to recruitment of different signalling pathways within and to the brain, an interaction of these pathways may contribute to their additive/synergistic action. Thus, PYY(3-36) boosts the effect of Ex4 possibly by inducing less inhibition of neuronal activity leading to an enhanced neuronal activity induced by Ex4. PMID- 30471779 TI - Distal splenorenal and mesocaval shunting at the time of pancreatectomy. AB - BACKGROUND: When pancreatic neoplasms occlude or encase the superior mesenteric portal-splenic vein confluence with abutment of the posterior lateral wall of the superior mesenteric artery, a mesocaval shunt with or without a distal splenorenal shunt allows for safe dissection of the porta hepatis and separation of the pancreatic tumor from the superior mesenteric artery. Herein we report long-term results of the largest known series of portosystemic shunts performed at the time of pancreatectomy. METHODS: All patients who underwent pancreatic resection with a mesocaval shunt or distal splenorenal shunt were identified from our prospective database. Demographics, perioperative treatment, and outcomes were reviewed. RESULTS: A total of 34 patients underwent mesocaval shunt or distal splenorenal shunt, including 25 at the time of pancreatoduodenectomy, 6 during total pancreatectomy, and 3 after prior pancreatectomy. There were 15 mesocaval shunts, 16 distal splenorenal shunts, 2 combined mesocaval/distal splenorenal shunts, and 1 distal splenoadrenal vein shunt. The mesocaval group included 11 temporary and 6 permanent (3 delayed) shunts. Median operative time was 9 hours (range 6.5-13), median estimated blood loss was 950 mL (range 200 5,000), and median duration of hospital stay was 11 days (range 7-35). Four patients experienced complications that required intervention (Clavien-Dindo grade >=III), but there were no 90-day mortalities. For patients with adenocarcinoma, median overall survival was 31 months at a median follow-up of 19 months. All but 1 shunt (distal splenorenal) were patent at last follow-up. CONCLUSION: Mesenteric venous shunting facilitates a safe and complete tumor resection in patients who require a complex pancreatectomy, many of whom would otherwise be deemed inoperable. PMID- 30471780 TI - What is transplant oncology? PMID- 30471781 TI - Re: Hepatectomy versus stereotactic body radiotherapy for primary early hepatocellular carcinoma. PMID- 30471782 TI - Does Rest Time before Ultrasonography Imaging Affect Quadriceps Femoris Muscle Thickness, Cross-Sectional Area and Echo Intensity Measurements? AB - In the work described here, our aim was to determine, in an elderly population, changes in muscle thickness (MT), cross-sectional area (CSA) and echo intensity (EI) of the quadriceps muscles at four time points (0, 5, 10 and 15 min; i.e., T0, T5, T10 and T15, respectively) after changing from a standing to supine position. Twenty-one elderly participants (14 men: 68.1 +/- 4.6 y; 8 women: 66.8 +/- 4.1 y) were evaluated at four time points. Rectus femoris CSA (RFCSA), MT and EI of the quadriceps femoris (QF) muscles were assessed. EI significantly increased from T0 to T5, T10 and T15 (p < 0.001), whereas no differences were observed between T5 and T15 in the rectus femoris (RFEI), vastus intermedius (VIEI) and quadriceps femoris (QFEI). No differences were observed between any time points in the RFCSA and MT of QF muscles. In summary, these results suggest that periods >5 min are not necessary to obtain consistent MT and EI measurements of quadriceps femoris muscles in the elderly population. PMID- 30471783 TI - Biomarkers: Another help tool to predict bacteriemia in the emergency department. PMID- 30471784 TI - Clinical utility of pleural fluid YKL-40 as a marker of malignant pleural effusion. AB - Pleural effusion is a common presenting feature of malignancy. Malignant pleural effusion is primarily diagnosed by pleural fluid cytology, pleural biopsy, and tumor markers. The glycoprotein YKL-40 is a new tumor marker that has shown to have a good diagnostic accuracy to detect malignant pleural effusion. However, there are only a few studies that have evaluated pleural fluid YKL-40 for detecting malignant pleural effusions. Hence, we conducted this study to evaluate the utility of pleural fluid YKL-40 to detect malignant pleural effusion. This is a cross-sectional study conducted between February 2016 and December 2017 in a tertiary care referral hospital. One hundred and forty-seven consecutive patients with pleural effusion were included in the study. These patients were divided into 3 groups, viz malignant, tuberculous, and parapneumonic pleural effusion, based on clinical features, radiological examination, and pleural fluid analysis. Pleural fluid YKL-40 levels were measured using enzyme-linked immunosorbent assay. Out of the 147 consecutive patients included in the study, 47 patients (31.97%) had malignant pleural effusion, 51 patients (34.69%) had tuberculous pleural effusion, and 49 patients (33.33%) had parapneumonic pleural effusion. The median pleural fluid YKL-40 level was higher in malignant pleural effusion (114.80 ng/mL) compared to tuberculous (93.17 ng/mL) and parapneumonic pleural effusion (89.87 ng/mL; P < 0.05). A diagnostic cut-off for pleural fluid YKL-40 value of 99.76 ng/mL detected malignant pleural effusion with 83% sensitivity, 87% specificity, positive predictive value (PPV) of 75%, negative predictive value (NPV) of 91.58%, and diagnostic accuracy of 85.71%. The level of pleural fluid YKL-40 is significantly elevated in malignant pleural effusion. In lymphocytic pleural effusions presenting with low adenosine deaminase levels and high YKL-40 levels, a thorough diagnostic search for malignancy is warranted. PMID- 30471785 TI - Polymerase Chain Reaction Assay Using the Restriction Fragment Length Polymorphism Technique in the Detection of Prosthetic Joint Infections: A Multi Centered Study. AB - BACKGROUND: PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) techniques have been used for the diagnosis of bacteria in some infections. In this study, we aimed to evaluate the diagnostic accuracy of PCR for the diagnosis of prosthetic joint infections (PJI) and to identify isolated microorganisms, using the RFLP method. METHODS: During January 2015 to January 2018, patients who were suspected of having PJI after arthroplasty surgery or were candidates for revision surgery due to loosening of implant entered the study. Patients who had 1 major criterion or 3 minor criteria for PJI based on the Philadelphia Consensus Criteria (PCC) on Periprosthetic Joint Infection were considered as cases of PJI. Both culture results and PCR findings, were cross compared with results of the PCC (as the gold standard criteria). RESULTS: Overall, 76 samples were included in the study. Mean (standard deviation) age of patients was 66.72 +/- 11.82 years. Overall, 57.9% of patients were females. Prevalence of PJI was 50% based on the PCC. Sensitivity, specificity, positive predictive value, negative predictive value, and general efficacy of PCR for detection of PJI was 97.4%, 100%, 100%, 97.4%, and 98.7%, respectively. Sensitivity, specificity, positive predictive value, negative predictive value, and general efficacy of culture was 31.6%, 100%, 65.7%, 100%, and 59.4%, respectively. We isolated a broad range of bacteria using PCR-RFLP including Gram positive cocci such as Staphylococcus sp., Streptococcus sp., and Enterococcus sp., and Gram-negative bacilli such as Enterobacteriaceae sp., Pseudomonas sp. Citrobacter sp., as well as Chlamydophila pneumonia, Stenotrophomonas maltophilia, Brucella melitensis, non-gonococcal Neisseria, Kingella kingae, Bacteroides ovatus, and Proteus mirabilis from PJI patients. CONCLUSION: Inhere, for the first time, we showed that PCR-RFLP is a powerful tool for identifying the type of bacteria involved in PJI, and can be used for follow-up of patients suspected of PJI and those with a history of antibiotic use. PCR-RFLP may be able to substantially decrease detection time of PJI among PCR-based methods, while allowing more accurate identification of the bacteria involved. PMID- 30471786 TI - Corrigendum to "A large-scale serological survey of Akabane virus infection in cattle, yak, sheep and goats in China" [Vet. Microbiol. 207 (2017) 7-12]. PMID- 30471787 TI - Changes in the biochemical and nutrient composition of seafood due to ocean acidification and warming. AB - Ocean acidification and warming may threaten future seafood production, safety and quality by negatively impacting the fitness of marine species. Identifying changes in nutritional quality, as well as species most at risk, is crucial if societies are to secure food production. Here, changes in the biochemical composition and nutritional properties of the commercially valuable oysters, Magallana gigas and Ostrea edulis, were evaluated following a 12-week exposure to six ocean acidification and warming scenarios that were designed to reflect the temperature (+3 degrees C above ambient) and atmospheric pCO2 conditions (increase of 350-600 ppm) predicted for the mid-to end-of-century. Results suggest that O. edulis, and especially M. gigas, are likely to become less nutritious (i.e. containing lower levels of protein, lipid, and carbohydrate), and have reduced caloric content under ocean acidification and warming. Important changes to essential mineral composition under ocean acidification and warming were evident in both species; enhanced accumulation of copper in M. gigas may be of concern regarding consumption safety. In light of these findings, the aquaculture industry may wish to consider a shift in focus toward species that are most robust to climate change and less prone to deterioration in quality, in order to secure future food provision and socio-economic benefits of aquaculture. PMID- 30471788 TI - Characterizing ENDS use in young adults with ecological momentary assessment: Results from a pilot study. AB - INTRODUCTION: Ecological Momentary Assessment (EMA) allows for assessment of electronic nicotine delivery systems (ENDS) use in real-time. This EMA study aimed to 1) describe study participation rates; 2) evaluate the concordance of EMA and survey items measuring frequency and quantity of ENDS use; and 3) assess the relationships between EMA items measuring frequency and quantity of ENDS use with ENDS dependence, measured at baseline and with saliva cotinine collected at follow-up. METHODS: Fifty young adult ENDS users completed baseline surveys, EMAs (i.e., random, event-based, daily diaries), and follow-up questionnaires over a 14-day period. Spearman correlations were conducted to determine concordance of survey items. Linear regression models assessed the relationships between EMA ENDS use characteristics (e.g., puffs, number of days used, quantity of e-liquid) with dependence items at baseline and saliva cotinine at follow-up. RESULTS: Overall completion for the prompted EMAs (random and daily diaries) was 68%. Correlations between EMA measures assessing ENDS use ranged from weak (rho = 0.02; NS) to strong (rho = 0.69, p < .001); EMA to follow-up items ranged from weak (rho = 0.16; p < .05) to moderate (rho = 0.54; p < .001). Significant associations were found between ENDS use measured via random and daily diary EMAs and saliva cotinine at follow-up after controlling for cigarette smoking (B = 0.70-1.76; p < .01), but not for event-based EMAs. Items measuring frequency/quantity of use from random EMAs were consistently associated with ENDS dependence at baseline (B = 0.74-1.58; p < .01). CONCLUSION: EMA represents a promising methodology to capture real-time ENDS use behaviors, primarily through daily diary and random EMAs. PMID- 30471789 TI - Modified metabolites mapping by liquid chromatography-high resolution mass spectrometry using full scan/all ion fragmentation/neutral loss acquisition. AB - Modified metabolites play important roles in diagnostic monitoring, oxidative response and physiological regulation. Comprehensive analytical methods are greatly needed for improving the coverage of modified metabolites and studying their physiological function. Here, a novel nontargeted profiling method for mapping modified metabolites was developed by liquid chromatography-high resolution mass spectrometry with full scan/all ion fragmentation/neutral loss (FS/AIF/NL) data acquisition. Modified metabolites were unbiasedly defined with less false positive results by mixed standards verification. Thirteen types of modified metabolites in urine were analyzed at the same time, and 198 of 307 modified metabolites at positive mode and 166 of 366 modified metabolites at negative mode were putatively identified. The modified metabolites profiling method was applied for investigating the metabolic differences between the patients with breast cancer and health controls. As a result, many modified metabolites with glucuronidation, ribosylation and indole acetylation modification were significantly up-regulated in breast cancer and four modified metabolites including 7-methylguanosine, N4-acetylcytidine, dihyroxy-1H-indole glucuronide I and indole-3-acetic acid-O-glucuronide were identified as potential biomarkers for the diagnose of breast cancer. PMID- 30471790 TI - A simple liquid chromatography-high resolution mass spectrometry method for the determination of glyphosate and aminomethylphosphonic acid in human urine using cold-induced phase separation and hydrophilic pipette tip solid-phase extraction. AB - Recently, the phenomenon of acute poisoning events caused by glyphosate (GLY) had frequently occurred all over the world. The present work reported a simple liquid chromatography-high resolution mass spectrometry (LC-HRMS) method for direct determination of GLY and its metabolite aminomethylphosphonic acid (AMPA) in human urine by combining cold-induced phase separation (CIPS) with hydrophilic pipette tip solid-phase extraction (PTSPE). First, a urine sample was mixed with acetonitrile at a 80% concentration to precipitate proteins. After centrifugation, the mixture was performed a CIPS at -20 degrees C to enrich GLY and AMPA (six-fold) in the lower water phase which was further performed PTSPE procedure. PTSPE as a miniaturized procedure of SPE, combined with a manual accu jet(r) Pro Pipette Controller, was used to extract GLY and AMPA, in which a new type of hydrophilic adsorbent (HILIC powder) based on amide-modified silica was selected as the adsorption of GLY and AMPA. The key factors including the type and the amount of adsorbent, the loading extraction solution, the type and volume of eluent, and the number of aspirating/dispensing cycles were investigated in detail. Meanwhile, the selectivity and sensitivity of GLY and AMPA analysis were improved by the use of LC-HRMS based on targeted single ion monitoring (tSIM) mode without tedious derivatization. This method made a full use of the advantages of these techniques by combining efficient enrichment, effective extraction and selective separation in a simple way. Finally, a comprehensive validation of the method was rigorously executed and the results indicated that the validated method afforded desired linearity, precision, accuracy, and sensitivity. PMID- 30471791 TI - The influence of model order reduction on the computed fractional flow reserve using parameterized coronary geometries. AB - Computational fluid dynamics (CFD) models combined with patient-specific imaging data are used to non-invasively predict functional significance of coronary lesions. This approach to predict the fractional flow reserve (FFR) is shown to have a high diagnostic accuracy when comparing against invasively measured FFR. However, one of the main drawbacks is the high computational effort needed for preprocessing and computations. Hence, uncertainty quantification may become unfeasible. Reduction of complexity is desirable, computationally inexpensive models with high diagnostic accuracy are preferred. We present a parametric comparison study for three types of CFD models (2D axisymmetric, Semi-3D and 3D) in which we study the impact of model reduction on three models on the predicted FFR. In total 200 coronary geometries were generated for seven geometrical characteristics e.g. stenosis severity, stenosis length and vessel curvature. The effect of time-averaged flow was investigated using unsteady, mean steady and a root mean square (RMS) steady flow. The 3D unsteady model was regarded as reference model. Results show that when using an unsteady or RMS flow, predicted FFR hardly varies between models contrary to using average flows. The 2D model with RMS flow has a high diagnostic accuracy (0.99), reduces computational time by a factor 162,000 and the introduced model error is well below the clinical relevant differences. Stenosis severity, length, curvature and tapering cause most discrepancies when using a lower order model. An uncertainty analysis showed that this can be explained by the low variability that is caused by variations in stenosis asymmetry. PMID- 30471792 TI - Bayesian inverse kinematics vs. least-squares inverse kinematics in estimates of planar postures and rotations in the absence of soft tissue artifact. AB - A variety of inverse kinematics (IK) algorithms exist for estimating postures and displacements from a set of noisy marker positions, typically aiming to minimize IK errors by distributing errors amongst all markers in a least-squares (LS) sense. This paper describes how Bayesian inference can contrastingly be used to maximize the probability that a given stochastic kinematic model would produce the observed marker positions. We developed Bayesian IK for two planar IK applications: (1) kinematic chain posture estimates using an explicit forward kinematics model, and (2) rigid body rotation estimates using implicit kinematic modeling through marker displacements. We then tested and compared Bayesian IK results to LS results in Monte Carlo simulations in which random marker error was introduced using Gaussian noise amplitudes ranging uniformly between 0.2 mm and 2.0 mm. Results showed that Bayesian IK was more accurate than LS-IK in over 92% of simulations, with the exception of one center-of-rotation coordinate planar rotation, for which Bayesian IK was more accurate in only 68% of simulations. Moreover, while LS errors increased with marker noise, Bayesian errors were comparatively unaffected by noise amplitude. Nevertheless, whereas the LS solutions required average computational durations of less than 0.5 s, average Bayesian IK durations ranged from 11.6 s for planar rotation to over 2000 s for kinematic chain postures. These results suggest that Bayesian IK can yield order of-magnitude IK improvements for simple planar IK, but also that its computational demands may make it impractical for some applications. PMID- 30471793 TI - Smoothing can systematically bias small samples of one-dimensional biomechanical continua. AB - The quality with which smoothing algorithms perform is often assessed in simulation by starting with a known 1D datum, adding noise, smoothing the noisy data, then quantifying the difference between the smoothed data and known datum, often using mean-square error (MSE). While effectively summarizing overall difference, MSE fails to capture localized, one-sided errors. This paper describes how smoothing noisy 1D data using a variety of algorithms can introduce systematic bias, and quantifies this bias using the false positive rate (FPR): the probability that a smoothing algorithm will yield a dataset whose 1D mean differs significantly from its true 1D datum. A simulation study was conducted involving six 1D datum continua, and four smoothing algorithms whose parameters were systematically manipulated along with sample size and noise amplitude. Approximately ten million simulation iterations were evaluated. FPRs were calculated at alpha=0.05, based on the calculated smoothness of the resulting datasets. Results showed that FPRs were much higher than the expected value of alpha, and in many cases approached 100%. FPRs were highest with aggressive smoothing parameters, large sample sizes and small noise amplitudes, irrespective of both smoothing algorithm and the 1D datum. These results suggest that smoothing 1D biomechanical data can introduce statistical bias with relatively high probability. The implications are experiment-specific because the biomechanical meaning of 1D changes can vary vastly between datasets. Smoothing induced bias should be a cause for general concern when small 1D changes have non trivial biomechanical consequences. PMID- 30471794 TI - Usefulness of the preoperative prognostic nutritional index score as a predictor of the outcomes of lung transplantation: A single-institution experience. AB - BACKGROUND & AIMS: There is increasing evidence that preoperative nutritional status is a predictor of disease severity and mortality after lung transplantation (LTX). This study aimed to evaluate preoperative nutritional assessment as a predictor of LTX outcomes. METHODS: We included 132 patients who underwent single or double LTX at Severance Hospital, Yonsei University, between October 2010 and April 2016. The Prognostic Nutritional Index (PNI) scores were calculated as follows: 10 * serum albumin value (g/dL) + 0.005 * peripheral lymphocyte count (/mm3). The optimal cut-off PNI score for the prediction of postoperative overall survival was set at 41.15 using receiver operating characteristics analysis. The efficacies of PNI and other clinical factors in predicting LTX outcomes were determined using univariate and multivariate Cox proportional hazard analyses. RESULTS: Patients with PNI <41.15 (PNI-low group) were older, had higher preoperative C-reactive protein levels, and had lower nutritional status scores than did those in the PNI-high group (PNI >= 41.15). Based on Kaplan-Meier analysis, the overall survival rate was significantly better in the PNI-high group (78.3%) than in the PNI-low group (28.6%) (P < 0.001). Age, sex, body mass index, use of preoperative mechanical ventilation, C reactive protein level, neutrophil-to-lymphocyte ratio, and PNI score were independent prognostic factors. Survival was significantly higher in the PNI-high group (hazard ratio: 0.220; P < 0.001) than in the PNI-low group, and incidence of complications >= grade IV was higher in the PNI-low group than in the PNI-high group (P < 0.001). Multivariate regression analysis showed that preoperative PNI score was significantly associated with postoperative survival, even after adjusting for other confounding factors. CONCLUSIONS: Our findings suggest that PNI is a useful prognostic marker for the identification of high-risk lung transplant recipients. Preoperative nutritional assessment using PNI may provide useful information for reducing postoperative morbidity and mortality. PMID- 30471796 TI - The Epidemic of Poor Oral Hygiene. PMID- 30471795 TI - Acute consumption of Andalusian aged wine and gin decreases the expression of genes related to atherosclerosis in men with high cardiovascular risk: Randomized intervention trial. AB - BACKGROUND: Atherosclerosis is an inflammatory disease. Previous studies have suggested the beneficial effects of moderate consumption of alcoholic beverages on reducing cardiovascular risk (CVR). The aim of this study was to evaluate the effects of acute consumption of Andalusian aged wine (AAW) and gin by analyzing the expression of genes related to the appearance and progression of atherosclerosis in men with high CVR. METHODS: We performed an open, randomized, controlled, crossover trial including 41 men with high CVR between 55 and 80 years age, who received a single dose of AAW or gin (0.5 g ethanol/kg). The expression of 10 genes related to atherosclerosis was determined by RT-PCR at baseline and 4 h after the intervention. RESULTS: Gene expression analysis 4 h after consumption of each alcoholic beverage showed a significant decrease in Toll-like receptors 4 and 6 (TLR4, TLR6) and Caspase-1 (p < 0.05 all). Additionally, TLR2, Interleukin-1 receptor, chemokine receptor 3 and inflammasome expression decreased after AAW intake (p < 0.05, all) while only chemokine receptor 5 decreased after gin consumption (p = 0.039). CONCLUSION: The decrease in the expression of several genes related to the appearance and progression of atherosclerosis was greater after AAW than gin intake, suggesting that the phenolic content of AAW may play a protective role against atherosclerosis. PMID- 30471797 TI - Psychosocial Care Is Basic, Improves Medical Outcomes, and Can Be Taught-But Must Be Better Understood. PMID- 30471798 TI - Practical Guidelines for Physicians in Promoting Oral Health in Frail Older Adults. AB - Good oral health in old age is particularly important for maintaining adequate oral function, preventing pain and discomfort, controlling localized or systemic inflammation, sustaining social interaction, and preserving quality of life. Given that oral health is an integral part of general health and well-being, and that major chronic systemic and oral diseases share common risk factors, oral health prevention and promotion should be embedded within routine medical assessment and care provision. The role of medical physicians, particularly primary care physicians, geriatricians, and elderly care physicians, in community and long-term care facilities in assessing and promoting oral health in frail older adults is critical and has been emphasized in recent European recommendations. All physicians should appreciate the importance of oral health and incorporate an initial oral health screening into routine medical assessment and care. A short interview with patients and carers on current oral health practices may help to assess the risk for rapid oral health deterioration. The interview should be followed by an oral health assessment, using validated tools, for nondental health care providers. Based on these findings, the physician should decide on necessary follow-up procedures, which may include oral health counseling and/or dental referral. Oral health counseling should include advice on daily oral, mucosal, and denture hygiene; denture maintenance; dietary advice; smoking cessation; limitation of harmful alcohol consumption; management of xerostomia; and frequent dental review. To enable physicians to perform the tasks recommended in this publication, appropriate teaching at both undergraduate and postgraduate levels must be delivered in addition to provision of appropriate continuing education courses. PMID- 30471799 TI - Music Therapy in Parkinson's Disease. AB - OBJECTIVES: Parkinson's disease (PD) is a chronic progressive neurologic disorder involving degeneration of the dopaminergic system. Its clinical manifestations include motor and nonmotor symptoms. Several nonpharmacologic therapies, such as music therapy (MT), have recently been developed in order to improve the clinical manifestations of this disease. The aim of this narrative literature review is to analyze the scientific evidence for the therapeutic effects of music in PD. DESIGN: We undertook a search in the databases of PubMed, PsycINFO, Scopus, MEDLINE, and Science Direct. SETTINGAND PARTICIPANTS: Inclusion criteria were articles including persons with PD rehabilitated with an MT intervention. MEASURES: Keywords used were music therapy, Parkinson's disease, auditory cueing, non-motor symptoms, motor symptoms, and quality of life. RESULTS: We detected a total of 27 articles, all of which analyzed the therapeutic effects of MT in PD. Of these, 20 studies analyzed the effects in motor symptoms (16 showed beneficial effects and 4, nonbeneficial effects); 9 studies analyzed the effects in nonmotor symptoms, 7 of which demonstrated beneficial effects; and 8 studies analyzed the effects on quality of life, with 6 reporting benefits. None of the articles analyzing nonmotor symptoms and quality of life showed negative effects. CONCLUSIONS/IMPLICATIONS: Most of the studies analyzed demonstrated that MT has beneficial effects for the nonpharmacologic treatment of motor and nonmotor symptoms and quality of life of persons with PD. The use of music as a therapeutic tool combined with conventional therapies should be taken into account. PMID- 30471800 TI - Improving Nursing Home Residents' Oral Hygiene: Results of a Cluster Randomized Intervention Trial. AB - OBJECTIVE: A 2-year cluster randomized trial of Mouth Care Without a Battle (MCWB) was conducted in nursing homes (NHs) to determine if recommended mouth care practices provided by NH staff could improve residents' oral hygiene and denture outcomes. DESIGN: Cluster randomized trial of NHs. SETTING AND PARTICIPANTS: Seven MCWB NHs and 6 control NHs. A total of 219 NH residents completed baseline and 24-month oral examinations and, if applicable, denture assessments (control = 98, intervention = 121). INTERVENTION: The intervention consisted of training NH staff in the MCWB protocol, and providing support in its use for 2 years. MEASURES: Descriptive data from the Minimum Data Set and clinical oral health assessments: the Plaque Index for Long-Term Care (range 0 3), the Gingival Index for Long-Term Care (range 0-4), and the Denture Plaque Index (range 0-4), with lower scores indicating better oral health. RESULTS: There were no significant demographic or health differences between groups at baseline. Residents' mean age (standard deviation) was 77.8 years (13.5), 71% were female, and 49% had cognitive impairment. At 24 months, there were significant improvements in oral and denture hygiene in the intervention group compared with control (all P < .05) with mean changes in indices that were 0.44 (Plaque Index for Long-Term Care), 0.55 (Gingival Index for Long-Term Care), and 0.67 (Denture Plaque Index) points lower in intervention NHs than control NHs. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Training NH staff to attend to residents' oral hygiene and denture care had a sustained, favorable impact on residents' oral and denture hygiene after 24 months compared with usual care. The protocol, MCWB, can be used by direct caregivers to improve the oral hygiene and denture care of NH residents. PMID- 30471801 TI - Social Frailty Predicts Incident Disability and Mortality Among Community Dwelling Japanese Older Adults. AB - OBJECTIVE: To determine the prevalence of social frailty and its relation to incident disability and mortality in community-dwelling Japanese older adults. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: 6603 community dwelling adults aged 65 years and older who were living independently in a city in Shiga prefecture in 2011. OUTCOMES: The outcomes were incident disability and mortality. We defined incident disability using new long-term care insurance (LTCI) service requirement certifications, and the follow-up period was 6 years after the mailed survey. MEASUREMENTS: The 4-item social frailty screening questionnaire was developed and included general resources, social resources, social behavior, and fulfillment of basic social needs. We categorized the respondents into 3 groups based on the level of social frailty. Additionally, we assessed physical/psychological frailty by the frailty screening index and other demographic variables. RESULTS: The prevalences of social frailty, social prefrailty, and social robust were 18.0%, 32.1%, and 50.0%, respectively. During the 6-year follow-up period, 28.1% of those with social robust, 36.9% of those with social prefrailty, and 48.5% of those with social frailty died or experienced incident disability. Those with social prefrailty [adjusted hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.16-1.41] and social frailty (adjusted HR 1.71, 95% CI 1.54-1.90) had significantly elevated risks for incident disability and mortality based on multivariate analyses that used social robust as the reference. Furthermore, the combination of social frailty and physical/psychological frailty is more likely to result in incident disability and mortality compared to social frailty or physical/psychological frailty alone. CONCLUSIONS/IMPLICATIONS: Community-dwelling older adults with both social frailty and physical/psychological frailty are at higher risk of death or disability over 6 years than are older adults with only one type of frailty or no frailty. Screening and preventive measures for social frailty are suggested for healthy aging. PMID- 30471802 TI - Effect of an Educational and Organizational Intervention on Pain in Nursing Home Residents: A Nonrandomized Controlled Trial. AB - OBJECTIVES: To determine whether an intervention based on education and professional support to nursing home (NH) staff would decrease the number of residents with a pain complaint, and to determine whether the intervention would improve pain management. DESIGN: Nonrandomized controlled trial. NHs were nonrandomly allocated either to a strong intervention group consisting in audit, feedback, and collaborative work on quality indicators with a hospital geriatrician, or to a light intervention group (LIG) consisting in audit and feedback only. SETTING: One hundred fifty-nine NHs located in France. PARTICIPANTS: A subgroup of 3722 residents. MEASURES: Information on pain complaint and pain-related covariates at the resident-related and at the NH level were recorded by NH staff at baseline and 18 months later. These covariates were included in a mixed-effects logistic regression on resident's pain complaint. Pain management was compared between intervention groups by chi-square tests. RESULTS: A greater reduction of residents with a pain complaint after the strong intervention (odds ratio 0.69, 95% confidence interval 0.53, 0.90) and a better pain management (47.6% gold standard, vs 30.6% in the LIG, P < .001) than controls. CONCLUSION/IMPLICATIONS: Combining educational and organizational measures, evaluating pain as a patient-reported outcome and as a process endpoint, and implementing a broad-spectrum intervention were original approaches to improve quality of care in NHs. Our results support nonspecific, collaborative, educational, and organizational interventions in NHs to decrease residents' pain complaint and improve pain management. PMID- 30471804 TI - Long-term Care for Older Adults in Africa: Pay Attention to the Situation of Older Women. PMID- 30471803 TI - Educating Nursing Home Staff in Dementia Sensitive Communication: Impact on Antipsychotic Medication Use. AB - OBJECTIVES: An educational program to enhance communication in nursing home dementia care increased person-centered communication by staff and resulted in reduced resident behavioral symptoms measured as resistiveness to care. The purpose of this analysis was to evaluate effects on resident antipsychotic medication use in participating nursing homes. The National Partnership to Improve Dementia Care set a goal of reducing antipsychotic medications in nursing homes by 15% during the study period. DESIGN: A post hoc analysis of Nursing Home Compare data was used to evaluate change in antipsychotic medication rates in nursing homes receiving the communication education versus the corresponding statewide average change. SETTING AND PARTICIPANTS: Eleven nursing homes participated in a cluster-randomized controlled trial from 2011 to 2013 in one Midwestern state. MEASURES: Antipsychotic medication rates were abstracted from Nursing Home Compare data sets. Antipsychotic medication rates were compared for each participating nursing home for the 2 quarters before and the 2 quarters after the communication intervention. To control for other factors supporting reduction in antipsychotic use, changes in the participating nursing homes were compared to the state average change for the corresponding quarters using a 1 sample t test. RESULTS: Antipsychotic medication use decreased on average by 4.88 percentage points (22.9%) in participating nursing homes compared to the state average decrease of 0.68 percentage points (2.7%) during the same period (P = .06). CONCLUSIONS: A clinically meaningful reduction in antipsychotic medication usage occurred in the nursing homes that received communication education. Measurable changes in communication and behavioral symptoms were reflected in reductions in antipsychotic medication usage. Improving staff communication has the potential to reduce inappropriate antipsychotic medication use in long-term care. PMID- 30471805 TI - Corrigendum to "The role of technical protocols and partnership engagement in developing a decision support framework for fisheries management" [J. Environ. Manag. 223 (2018) 503-516]. PMID- 30471806 TI - Ductal Carcinoma of the Prostate: An Uncommon Entity With Atypical Behaviour. AB - AIMS: Ductal adenocarcinoma is a rare variant of prostate cancer, and as such clinical outcomes and best management are not well defined. This series demonstrates the atypical presentation and unusual clinical behaviour of ductal adenocarcinoma and proposes management guidelines to assist clinicians. MATERIALS AND METHODS: A retrospective review of pure (nine patients) and mixed (18 patients) ductal adenocarcinoma of the prostate referred to the Departments of Radiation Oncology of the Sydney Cancer Centre, Royal Prince Alfred Hospital and Northern Sydney Cancer Centre, Royal North Shore Hospital, between 2000 and 2015. RESULTS: Twenty-seven patients were treated with definitive radiotherapy, nine patients (33%) with pure ductal and 18 (67%) with mixed ductal-acinar adenocarcinoma. The median follow-up was 38 months. Four patients (15%) failed locally, all of whom received less than 80 Gy, or no brachytherapy boost. Five patients (19%) failed distantly, four with biopsy-proven lung metastases. All distant failures occurred with a prostate-specific antigen (PSA) < 3 ng/ml. CONCLUSION: This series shows the atypical clinical presentation of this entity, as well as its propensity to metastasise to unusual sites. Relapse may occur at low absolute PSA values and is often asymptomatic. Ductal cancer should not simply be regarded as a high Gleason grade cancer. We propose management guidelines, including regular computed tomography examinations (rather than relying solely on PSA levels) as part of the follow-up for patients with any component of ductal adenocarcinoma. PMID- 30471807 TI - Corrigendum to "Vitamin D status in children with epilepsy treated with levetiracetam monotherapy", [Epilepsy Res. 148 (2018) 116]. PMID- 30471808 TI - A large national comparative study of clinicopathological features and long-term survivals between esophageal gastrointestinal stromal tumor and leiomyosarcoma. AB - BACKGROUND: Esophageal gastrointestinal stromal tumors (E-GIST) and leiomyosarcoma (E-LMS) are rare tumors. Previous studies are limited to small number of patients. We sought to study these two tumors using a large national database. METHODS: The National Cancer Data Base 2004-2014 was queried for patients with E-GIST and E-LMS. The primary outcome was overall survival (OS). Univariate and multivariable Cox regression models were used to investigate OS predictors. RESULTS: We found 141 E-GIST and 38 E-LMS patients, with esophagectomy and systemic treatment rate of 55% and 49% for E-GIST and 50% and 26% for E-LMS. The 5-year OS of E-GIST and E-LMS were 62% and 23%, respectively, p < 0.001. In multivariable analysis, young age, tumor <10 cm, esophagectomy, and E-GIST were associated with superior OS. There was a higher median and mean OS with neoadjuvant vs. upfront surgery for E-GIST group (98 and 111 vs 79 and 80 months). CONCLUSION: E E-GIST has superior OS compared to E-LMS. Esophagectomy is the cornerstone treatment modality. Further studies are needed to evaluate the role of neoadjuvant therapy in E-GIST patients. PMID- 30471809 TI - Early ambulation after colorectal oncologic resection with perineal reconstruction is safe and effective. AB - BACKGROUND: Post-operative bedrest is common following perineal reconstruction despite little supporting data. We sought to determine the safety of early ambulation following colorectal oncologic resection and flap-based perineal reconstruction. METHODS: A retrospective cohort study was conducted with two cohorts: standard bedrest (BC) and early ambulation (EAC). Ambulation capacity was objectively assessed. Regression analysis was performed to determine the effects of ambulation timing on 60-day reoperations or readmissions and other surgical outcomes. RESULTS: There were 57 participants. Those in the EAC were significantly more ambulatory on post-operative days one through three (p < 0.0001). There was no significant difference in 60-day reoperations (25% BC versus 9% EAC, p = 0.14) or readmissions (33% BC versus 15% EAC, p = 0.12). Early ambulation significantly reduced minor complication rates (38% BC versus 9% EAC, p = 0.02). CONCLUSIONS: Early ambulation following perineal reconstruction is safe and may potentially decrease wound complications. SUMMARY AND KEYWORDS: Institution of early ambulation protocols is rapidly becoming the standard of care for many oncological surgery patients. In cases requiring perineal reconstruction with vascularized flaps, however, there is no data to uproot the historical practice of mandatory bedrest. Our study demonstrates that the benefits of early ambulation are attainable in these patients without compromising reconstructive outcomes. PMID- 30471810 TI - Impact of recreational and medicinal marijuana on surgical patients: A review. AB - BACKGROUND: As medicinal and recreational marijuana use broadens across the United States, knowledge of its effects on the body will become increasingly important to all health care providers, including surgeons. DATA SOURCES: We performed a literature review of Pubmed for articles discussing the basic science related to cannabinoids, as well as articles regarding cannabinoid medications, and cannabis use in surgical patients. CONCLUSIONS: The primary components in the cannabis plant, tetrahydrocannabinol (THC) and cannabidiol (CBD), have been made available in numerous forms and formulations to treat multiple medical conditions, and recreational access to marijuana is increasing. Of particular importance to the surgeon may be their effects on prolonging intestinal motility, decreasing inflammation, increasing hunger, mitigating pain, and reducing nausea and vomiting. Perioperative use of medicinal or recreational marijuana will become increasingly prevalent, and the surgeon should be aware of the positive and negative effects of these cannabinoids. PMID- 30471811 TI - Reduction of surgical site infections in colorectal surgery: A 10-year experience from an independent academic medical center. AB - BACKGROUND: Surgical site infections (SSI) are a source of patient morbidity and increased cost. In 2007, our organization discovered an SSI rate of 18% after colorectal surgery (CRS), corresponding to an ACS NSQIP benchmarked high outlier. METHODS: From 2007 to 2016, surgeons championed a stepwise, multidisciplinary improvement pathway for SSI reduction. NSQIP was used to track SSI rates and estimate cost savings. RESULTS: From 2007 to 2016, 1508 patients underwent CRS at our facility. In 2007, our SSI rate was 18%. In 2016, the SSI rate was 7%, corresponding to a NSQIP benchmarked exemplary performance. 54 patients avoided the morbidity of a SSI. The expense of SSI reduction implementation was $180,000. Cost savings was estimated at $1.3 million. CONCLUSIONS: Our approach reduced SSI rates by 58% over ten years. We observed a significant morbidity reduction and cost savings. Our strategy could be adopted within other medical centers focused on CRS SSI improvement. PMID- 30471812 TI - Radiotherapy dose escalation in locally advanced NSCLC - The limits of conventional radiochemotherapy. PMID- 30471813 TI - Optimization of CT protocols using cause-and-effect analysis of outliers. AB - The aim of this study was to implement an outlier marking and analysis methodology to optimize CT examination protocols. CT Head examination data, including dose metrics along with technical parameters, were stored in an automatic dose registry system. Reference dose metrics distribution was obtained throughout a 1-year period. Outlier thresholds were calculated taking into account the specific shape of the distribution, by using a robust measure of the skewness; the medcouple parameter. Subsequently, outliers from a 4-month period were marked and Cause-and-Effect analysis was carried out by a multidisciplinary dose committee. Reference Dose metrics distributions were obtained from 3690 CT Head examinations. Both CTDIvol and DLP showed a certain degree of skewness, with a medcouple value of 0.05 and 0.11, respectively. All of the upper-outliers fell within 3 identifiable groups of causes, ordered by relative importance: i) inadequate protocol selection, ii) arms or objects in the field-of-view, and iii) abnormal scanning region diameter. Regarding the lower-outliers, 90% were attributable to the inclusion of additional series in the original head protocol and the remaining 10% to unknown causes. Also, a general Cause-and-Effect diagram for outliers was elaborated. While the Dose Reference Level method applies to the general performance of a CT protocol and allows comparison with other centers, the outlier method represents a step further in the optimization process. The proposed method focuses on detecting incorrect utilization of the CT, which mainly arises from inadequate knowledge of CT technology. PMID- 30471814 TI - Dosimetric impact of Acuros XB dose-to-water and dose-to-medium reporting modes on VMAT planning for head and neck cancer. AB - PURPOSE: To assess the dosimetric impact of switching from the Analytical Anisotropic Algorithm (AAA) to Acuros XB (AXB) for both dose-to-medium (Dm) and dose-to-water (Dw) in VMAT for H&N patients. To study whether it should be linked to a change in the dose prescriptions to the PTVs and in the constraints to the OARs. METHODS: 110H&N patients treated with VMAT were included. Calculations were performed with AAA and AXB. PTV54, PTV60, PTV70, spinal cord, brainstem, brain, larynx, oral cavity, cochleas, parotid glands and mandible were delineated. Clinically-relevant dose-volume parameters were compared. Paired t-tests were used to analyze the differences in mean values. The Pitman-Morgan dispersion test was computed to evaluate inter-patient variability of these differences. RESULTS: AAA overestimated all dose-volume parameters compared to AXB Dm (0.2 Gy to 2.4 Gy). No systematic trend was observed in the differences between AAA and AXB Dw ( 5.3 Gy to 0.6 Gy). Dose-volume parameters were significantly higher for AXB Dw compared to AXB Dm (0.1 Gy to 6.6 Gy). In all cases, the largest absolute differences (4%-14%) were found for maximum absorbed doses to the cochleas and the mandible. The number of parameters with significant inter-patient variability was greater when switching from AAA to AXB Dw than from AAA to AXB Dm. CONCLUSIONS: There are important differences between AXB and AAA in VMAT planning for H&N cancer. The systematic differences and their inter-patient variability identified may help to facilitate decision-making about the dose prescriptions to the PTVs and the constraints to the OAR. PMID- 30471815 TI - A novel pencil beam model for carbon-ion dose calculation derived from Monte Carlo simulations. AB - An accurate kernel model is of vital importance for pencil-beam dose algorithm in charged particle therapy using precise spot-scanning beam delivery, in which an accurate depiction of the low dose envelope is especially crucial. Based on the Monte Carlo method, we investigated the dose contribution of secondary particles to the total dose and proposed a novel beam model to depict the lateral dose distribution of carbon-ion pencil beam in water. We demonstrated that the low dose envelope in single-spot profiles in water could be adequately modelled with the addition of a logistic distribution to a double Gaussian one, which was verified in both single carbon-ion pencil beam and superposed fields of different sizes with multiple pencil beams. Its superiority was mainly manifested at medium depths especially for high-energy beams with small fields compared with single, double and triple Gaussian models, where the secondary particles influenced the total dose considerably. The double Gaussian-logistic model could reduce the deviations from 4.1%, 1.7% to 0.3% in the plateau and peak regions, and from 19.2%, 4.9% to 1.2% in the tail region compared for the field size factor (FSF) calculations of 344 MeV/u carbon-ion pencil beam with the single and double Gaussian models. Compared with the triple Gaussian one, our newly-proposed model was on a par with it, even better than it in the plateau and peak regions. Thus our work will be helpful for improving the dose calculation accuracy for carbon ion therapy. PMID- 30471817 TI - Medical physics workforce: A global perspective. AB - PURPOSE: The International Organization for Medical Physics (IOMP) performed a detailed study following the first survey published in 2015 with the particular objectives: 1) gather data on global medical physicists (MPs) workforce, 2) identify differences between geographical regions and, 3) investigate whether there is a gender dimension in higher hierarchy positions. METHODS: An online questionnaire was send to IOMP members and contact points in countries where no professional MPs society existed. Information requested: total number (N) of MPs (men and women), N of current elected executive board (EB) of societies and women proportion in the board, president gender and number of women presidents for the last 10 years. IOMP archives were also investigated for data on gender composition related to chairs of committees, officers and IOMP awardees. RESULTS: Ninety three countries reported 29,179 MPs, from which 8702 were women (29.8%) and 20,477 men. The most dense MPs population was in Europe (34%), followed by North America (33%) and Asia/Oceania (24%). Societies EB women members constitute 21-40%, but rarely reach the presidential position. The IOMP archived data show that women MP representation decreases in higher hierarchy positions. CONCLUSIONS: Global MPs production does not meet clinical needs especially in Latin America/Caribbean and Africa (6% of total MPs workforce and small number of MPs/million of population). Rough estimations showed that approximately 58,950 MPs will be required by 2035. Women representation is away from the United Nations and European Commissions goals. Women representation in higher hierarchy position is low. PMID- 30471816 TI - Novel Monte Carlo dose calculation algorithm for robotic radiosurgery with multi leaf collimator: Dosimetric evaluation. AB - PURPOSE: At introduction in 2014, dose calculation for the first MLC on a robotic SRS/SBRT platform was limited to a correction-based Finite-Size Pencil Beam (FSPB) algorithm. We report on the dosimetric accuracy of a novel Monte Carlo (MC) dose calculation algorithm for this MLC, included in the PrecisionTM treatment planning system. METHODS: A phantom was built of one slab (5.0 cm) of lung-equivalent material (0.09...0.29 g/cc) enclosed by 3.5 cm (above) and 5 cm (below) slabs of solid water (1.045 g/cc). This was irradiated using rectangular (15.4 * 15.4 mm2 to 53.8 * 53.7 mm2) and two irregular MLC-fields. Radiochromic film (EBT3) was positioned perpendicular to the slabs and parallel to the beam. Calculated dose distributions were compared to film measurements using line scans and 2D gamma analysis. RESULTS: Measured and MC calculated percent depth dose curves showed a characteristic dose drop within the low-density region, which was not correctly reproduced by FSPB. Superior average gamma pass rates (2%/1 mm) were found for MC (91.2 +/- 1.5%) compared to FSPB (55.4 +/- 2.7%). However, MC calculations exhibited localized anomalies at mass density transitions around 0.15 g/cc, which were traced to a simplification in electron transport. Absence of these anomalies was confirmed in a modified build of the MC engine, which increased gamma pass rates to 96.6 +/- 1.2%. CONCLUSIONS: The novel MC algorithm greatly improves dosimetric accuracy in heterogeneous tissue, potentially expanding the clinical use of robotic radiosurgery with MLC. In-depth, independent validation is paramount to identify and reduce the residual uncertainties in any software solution. PMID- 30471818 TI - A multicenter dosimetry study to evaluate the imaging dose from Elekta XVI and Varian OBI kV-CBCT systems to cardiovascular implantable electronic devices (CIEDs). AB - The increasing use of daily CBCT in radiotherapy has raised concerns about the additional dose delivered to the patient, and it can also become a concern issue for those patients with cardiovascular implantable electronic devices (CIEDs) (Pacemaker [PM] and Implantable Cardioverter Defibrillator [ICD]). Although guidelines highly recommend that the cumulative dose received by CIEDs should be kept as low as possible, and a safe threshold based on patient risk classification needs to be respected, this additional imaging dose is not usually considered. Four centers with different dosimetry systems and different CBCT imaging protocols participated in this multicenter study to investigate the imaging dose to the CIEDs from Elekta XVI and Varian OBI kV-CBCT systems. It was found that although imaging doses received by CIEDs outside the CBCT field are negligible, special attention should be paid to this value when CIEDs are inside the field because the daily use of CBCT can sometimes contribute considerably to the total dose received by a CIED. PMID- 30471819 TI - Investigations of line scanning proton therapy with dynamic multi-leaf collimator. AB - PURPOSE: Scanning proton therapy has dosimetric advantage over passive treatment, but has a large penumbra in low-energy region. This study investigates the penumbra reduction when multi-leaf collimators (MLCs) are used for line scanning proton beams and secondary neutron production from MLCs. METHODS: Scanning beam plans with and without MLC shaping were devised. Line scanning proton plan of 36 energy layers between 71.2 and 155.2 MeV was generated. The MLCs were shaped according to the cross-sectional target shape for each energy layer. The two dimensional doses were measured through an ion-chamber array, depending on the presence of MLC field, and Monte Carlo (MC) simulations were performed. The plan, measurement, and MC data, with and without MLC, were compared at each depth. The secondary neutron dose was simulated with MC. Ambient neutron dose equivalents were computed for the line scanning with 10 * 10 * 5 cm3 volume and maximum proton energy of 150 MeV, with and without MLCs, at lateral distances of 25-200 cm from the isocenter. The neutron dose for a wobbling plan with 10 * 10 * 5 cm3 volume was also evaluated. RESULTS: The lateral penumbra width using MLC was reduced by 23.2% on average, up to a maximum of 32.2%, over the four depths evaluated. The ambient neutron dose equivalent was 18.52% of that of the wobbling beam but was 353.1% larger than the scanning open field. CONCLUSIONS: MLC field shaping with line scanning reduced the lateral penumbra and should be effective in sparing normal tissue. However, it is important to investigate the increase in neutron dose. PMID- 30471820 TI - Dependency of prescribed CT dose on table height, patient size, and localizer acquisition for one clinical MDCT. AB - PURPOSE: The purpose of this study was to quantify the effect that table height, patient size, and localizer acquisition order may have on AEC prescribed dose. METHOD AND MATERIALS: Three phantoms were used for this study: the Mercury Phantom, acrylic sheets, and an anthropomorphic phantom. A lateral (LAT) and a posterior-anterior (PA) localizer was acquired for each phantom at different table heights on a MDCT scanner (GE Discovery CT750 HD). AEC scan acquisitions were prescribed for each combination of phantom, localizer orientation, and table height +/-4 cm with the center position; the displayed CTDIvol was recorded. Based on the institutional dose monitoring program, the relationship between change in CTDIvol and change in table height were studied for LAT and AP localizers for clinical exams. RESULTS: For all phantom scans based on the PA localizer, the percent change in ranged between -18% and 42% for table heights 4 cm below and above proper centering; while for the LAT localizer, the percent change in CTDIvol from ideal were no greater than 12% different for +/-4 cm differences in table height. Change in CTDIvol and change in table height displayed a strong linear relationship for AP localizer exams (P = 0.002), and weak correlation for LAT localizer exams (P = 0.12). CONCLUSIONS: Since uncertainty in vertical patient positioning is inherently greater than lateral positioning, the LAT localizer should be utilized to precisely and reproducibly deliver the intended amount of radiation prescribed by CT protocols. PMID- 30471821 TI - A computer-aided diagnosis scheme of breast lesion classification using GLGLM and shape features: Combined-view and multi-classifiers. AB - PURPOSE: To address high false-positive results of FFDM issue, we make the first effort to develop a computer-aided diagnosis (CAD) scheme to analyze and distinguish breast lesions. METHOD: The breast lesion regions were first segmented and depicted on FFDM images from 106 patients. In this work, 11 gray level gap-length matrix texture features and 12 shape features were extracted form craniocaudal view and mediolateral oblique view, and then Student's t-test, Fisher-score and Relief-F were introduced to select features. We also investigated the effect of three factors, i.e., discretisation, selection methods and classifier methods, of the classification performance via analysis of variance. Finally, a classification model was constructed. Spearman's correlation coefficient analysis was conducted to assess the internal relevance of features. RESULTS: The proposed scheme using Student's t-test achieved an area under the receiver operating characteristic curve (AUC) value of 0.923 at 512 bins. The AUC values are 0.884, 0.867, 0.874 and 0.901 for the low gray-level gaps emphasis (LGGE), solidity, extent, and the combined set, respectively. Solidity and extent depicts the correlation coefficient of 0.86 (P < 0.05). CONCLUSIONS: We present a new CAD scheme based on the contribution of the significant factors. The experimental results demonstrate that the presented scheme can be used to successfully distinguish breast carcinoma lesions and benign fibroadenoma lesions in our FFDM dataset and the MIAS dataset, which may provide a CAD method to assist radiologists in diagnosing and interpreting screening mammograms. Moreover, we found that LGGE, solidity and extent features show great potential for breast lesion classification. PMID- 30471822 TI - Design of lymphedema ultrasound phantom with 3D-printed patient-specific subcutaneous anatomy: A-mode analysis approach for early diagnosis. AB - The secondary lymphedema is mostly caused due to injury of lymphatic system during cancer treatment and its psychological and cosmetic issues are very critical for patients since it can cause severe thickening and swelling of lesions, mostly upper and lower limbs. Therefore, early diagnosis of the secondary lymphedema is more important to treat the symptoms in advance. The amplitude-mode (A-mode) ultrasound is suggested as an early diagnostic modality because it is relatively more cost-effective, portable, and easy to use than other previous diagnostic modalities. In order to see features of the A-mode ultrasound forearly diagnosis of lymphedema, ultrasound lymphedema phantoms were designed and fabricated with patient-specific subcutaneous honeycomb structures at the sub-stages of the international society of lymphedema (ISL) stage II and gelatin- or gelatin-salt based phantom materials. The patent-specific honeycomb structures were segmented from computed tomography (CT) venography images using various image process technologies and printed using a three dimensional (3D) printer for which its printing material shows similar acoustic impedance range with human subcutaneous tissues. The lymphedema phantoms showed similar subcutaneous anatomical features to those of patient's imagesin brightness mode (B-mode) ultrasound examination, and acoustic information originated from the stage-specific honeycomb structures was well represented in A-mode ultrasound examination. In particular, the A-mode wave form well represented stage-specific honeycomb information even with higher impedance value of fibrous fat region. Such stage-specific wave form information of A-mode ultrasound for the corresponding stage-specific lymphedema phantoms at the ISL stage II can be useful for further development of an A-mode ultrasound applications for early diagnosis of the secondary lymphedema. PMID- 30471823 TI - Minimizing the potential of cancer recurrence and metastasis by the use of graphene oxide nano-flakes released from smart fiducials during image-guided radiation therapy. AB - An increasing number of studies show that cancer stem cells become more invasive and may escape into blood stream and lymph nodes before they have received a lethal dose during radiation therapy. Recently, it has been found that graphene oxide (GO) can selectively inhibit the proliferative expansion of cancer stem cells across multiple tumor types. In this study, we investigate the feasibility of using GO during radiotherapy to synergistically inhibit cancer stem cells, and lower the risk of cancer metastasis and recurrence. We hypothesize that graphene oxide nano-flakes (GONFs) released from newly-designed radiotherapy biomaterials (fiducial) can reach targeted tumor cells within 14-21 days. These are the typical time periods between the implantation of the fiducial and the start of image-guided radiation therapy. To test this hypothesis, the spatial-temporal diffusion of GONFs in soft tissue is investigated as a function of different particle sizes. Toxicity of GONFs to normal (HUVEC) and cancer (A549) cells has been assessed using the MTT assay. In addition, the survival fraction of A549 cells treated with GONFs is determined via clonogenic assay during radiotherapy. The diffusion study shows that only GONFs sizes of 50 and 200 nm could achieve the desired concentration of 50 MUg/mL for 2 cm diameter tumor after 14 and 21 days respectively. The clonogenic and the MTT assay confirm the additional benefit of GONFs in killing lung cancer cells during radiotherapy. This work avails ongoing in vivo studies that use GONFs to enhance the treatment outcome for cancer patients during radiation therapy. PMID- 30471824 TI - Monte Carlo investigation on the effect of air gap under bolus in post-mastectomy radiotherapy. AB - OBJECTIVES: To investigate the dosimetric effect of air gaps under bolus on skin dose for left-sided post-mastectomy radiotherapy with loco regional involvement. METHODS: Eight patients were planned retrospectively with volume modulated arc therapy (VMAT) and conventional static Field-in-Field (FinF) methods. Three different setups were applied for the 5-mm bolus over the chest wall having 0, 5 or 10 mm air gap under the bolus. The dose calculation was performed using Monte Carlo (MC) simulation. In addition, Analytic Anisotropic Algorithm (AAA) was used to demonstrate the differences observed in clinical setting. RESULTS: The investigated air gaps under the bolus had minimal effect on surface dose for FinF plans (relative difference <= 2.6%), whereas for VMAT plans the surface dose decreased 13.6% when compared to the case with no air gap. In both FinF and VMAT, the largest differences between AAA and MC were seen at the surface where AAA underestimated the dose by 1.5 Gy (p < 0.05) on average; while the dose in the target volume excluding the surface was relatively similar being on average 0.3 Gy (p > 0.05) larger with AAA than with MC calculations. CONCLUSIONS: The surface dose was significantly lower with VMAT technique than with FinF technique. Possible air gaps under the bolus reduced the surface dose significantly further for VMAT but not for FinF treatments, which may have clinical impact on recurrence rate. AAA was shown to underestimate the surface dose when compared to MC calculation. PMID- 30471825 TI - Neonatal brain: Fabrication of a tissue-mimicking phantom and optimization of clinical Tau1w and T2w MRI sequences at 1.5 T. AB - PURPOSE: Tomicron fabricate a tissue-mimicking phantom simulating the MR relaxation times of neonatal gray and white matter at 1.5 T, for the optimization of clinical Tau1 weighted (T1w) and T2 weighted (T2w) sequences. METHODS: Numerous agarose gel solutions, doped with paramagnetic Gadopentetic acid (Gd DTPA) ions, underwent quantitative relaxometry with a Turbo-Inversion-Recovery Spin-Echo (TIRSE) sequence and a Car-Purcell-Meiboom-Gill (CPMG) sequence for T1 and T2 measurements, respectively. Twenty samples which simulated the spectrum of relaxation times of neonatal brain parenchyma were selected. Reproducibility was tested by refabrication and relaxometry of the relevant samples while stability was tested by six sets of quantitative relaxometry scans during a 12-month period. RESULTS: "Neonatal gray matter equivalent"(0.6%w/v agarose-0.10 mM Gd DTPA), accurately mimicked relaxation times of neonatal gray matter: T1 = (1134 +/- 7)ms, T2 = (200 +/- 7)ms. "Neonatal white matter equivalent"(0.3%w/v agarose 0.03 mM Gd-DTPA), accurately mimicked relaxation times of neonatal white matter: T1 = (1654 +/- 9)ms, T2 = (376 +/- 4)ms. Coefficient of variation of T1 and T2 relaxation times measurements remained less than 5% during 12 months. Sequences were modified according to maximum relative contrast (RC) between neonatal gray and white matter equivalents. Optimized T2wTSE and T1wTSE parameters were TR/TE = 9500 ms/280 ms and TR/TE = 1200 ms/10 ms, respectively for a MAGNETOM Vision/Sonata Hybrid 1.5 T system. Quantitative relaxometry at different 1.5 T MR systems resulted in inter-system T1, T2 measurement deviations of 12% and 3%, respectively. CONCLUSION: A precise, stable and reproducible phantom for the neonatal brain was fabricated. Subsequent optimization of clinical T1w and T2w sequences based on maximum RC between neonatal gray and white matter equivalents was scientifically supported with robust relaxometry. The procedure was applicable in different 1.5 T systems. HIGHLIGHT: TR & TE optimization of neonatal brain at 1.5 T was based on relaxometry of a stable, reproducible phantom. PMID- 30471826 TI - Pareto-optimal plans as ground truth for validation of a commercial system for knowledge-based DVH-prediction. AB - PURPOSE: Treatment plans manually generated in clinical routine may suffer from variations and inconsistencies in quality. Using such plans for validating a DVH prediction algorithm might obscure its intrinsic prediction accuracy. In this study we used a recently published large database of Pareto-optimal prostate cancer plans to assess the prediction accuracy of a commercial knowledge-based DVH prediction algorithm, RapidPlan. The database plans were consistently generated with automated planning using an independent optimizer, and can be considered as aground truth of plan quality. METHODS: Prediction models were generated using training sets with 20, 30, 45, 55 and 114 Pareto-optimal plans. Model-20 and Model-30 were built using 5 groups of randomly selected training patients. For 60 independent Pareto-optimal validation plans, predicted and database DVHs were compared. RESULTS: For model-114, differences between predicted and database mean doses of more than +/- 10% in rectum, anus and bladder, occurred for 23.3%, 55.0%, and 6.7% of the validation plans, respectively. For rectum V65Gy and V75Gy, differences outside the +/-10% range were observed in 21.7% and 70.0% of validation plans, respectively. For 61.7% of validation plans, inaccuracies in predicted rectum DVHs resulted in a deviation in predicted NTCP for rectal bleeding outside +/-10%. With smaller training sets the DVH prediction performance deteriorated, showing dependence on the selected training patients. CONCLUSION: Even when analysed with Pareto-optimal plans with highly consistent quality, clinically relevant deviations in DVH predictions were observed. Such deviations could potentially result in suboptimal plans for new patients. Further research on DVH prediction models is warranted. PMID- 30471827 TI - Comparison of Two Pediatric Early Warning Systems: A Randomized Trial. AB - PURPOSE: Pediatric early warning systems (PEWS) are used to detect clinical deterioration in hospitalized children. Few PEWSs have been validated in multicenter studies and the performance in many single-center studies varies. We wanted to compare two PEWS in a multicenter study. DESIGN AND METHODS: Randomized multicenter unblinded trial conducted at all pediatric departments in the Central Denmark Region. A random sample of 16,213 pediatric patients (31,337 admissions) were enrolled from November 2014 to March 2017. Patients were randomized to The Bedside PEWS or CDR PEWS. The primary outcome was the sum of hospitalized children experiencing in-hospital clinical deterioration requiring transfer to a higher level of care. RESULTS: Of the 21,077 pediatric patients who met the inclusion criteria, 16,213 (from 31,337 admissions) were enrolled. 22 unplanned transfers to a higher level of care were identified: 14 in The Bedside PEWS group and 8 in the CDR PEWS group, a non-statistical difference (P = 0.20). No significant difference in predicting unplanned transfer to a higher level of care (P = 0.78) were detected and no significant difference was observed in the secondary outcomes. CONCLUSIONS: The CDR PEWS prevents as many critical events as The Bedside PEWS. Shorter median time to PEWS reassessment when CDR PEWS was used and fewer reassessments being done to late could reflect that the CDR PEWS was more acceptable to staff. PRACTICE IMPLICATIONS: The results from this study should be interpreted with caution as very few patients experiencing clinical deterioration and further studies should also focus on challenges trying to evaluate PEWS. PMID- 30471828 TI - Novel racemosin B derivatives as new therapeutic agents for aggressive breast cancer. AB - Carbazole derivatives show anti-cancer activity and are of great interest for drug development. In this study, we synthesized and analyzed several new alkylamide derivatives of racemocin B, a natural indolo[3,2-a]carbazole molecule originally isolated from the green alga Caulerpa racemose. Several alkylamide derivatives were found to exhibit moderate to strong growth inhibition against human breast cancer cell lines. They induced G2/M cell cycle arrest and apoptosis in the aggressive triple-negative breast cancer cell line MDA-MB-231. Among these derivatives, compound 25 with the lowest IC50 induced cell death by suppressing autophagy. This was accompanied by inhibition of autophagic flux and accumulation of autophagy protein 1 light chain 3, LC3II, and p62. The novel alkylamide derivative offers a potential new treatment for human breast cancer. PMID- 30471829 TI - The synthesis of 4-arylamido-2-arylaminoprimidines as potent EGFR T790M/L858R inhibitors for NSCLC. AB - A series of 4-arylamido-2-arylaminoprimidines bearing acrylamide pharmacophore were synthesized as potent EGFRT790M/L858R inhibitors among which 9c (IC50 = 0.5872 nM), 9d (IC50 = 2.213 nM), or 9h (IC50 = 12.57 nM) showed more potent anti EGFRT790M/L858R activity compared with AZD-9291 (IC50 = 20.80 nM) and possessed high SI displaying 307.6, 56.5, or 12.5 for EGFRT790M/L858R over the wild-type respectively. 9h also showed pretty good activity against H 1975 cells with an IC50 of 1.664 MUM and exhibited low toxicity against the normal HBE cells (IC50 > 20 MUMU). 9h had moderate selectivity for H 1975 over A 431 (SI = 7.0) and the other selected cell lines. Morphological staining results further indicated that 9h could promote apoptosis. Hence, 9h was a promising compound for further investigation as a potential EGFRT790M/L858R inhibitor for the treatment of NSCLC. PMID- 30471830 TI - QSAR of 1,4-benzoxazin-3-one antimicrobials and their drug design perspectives. AB - Synthetic derivatives of 1,4-benzoxazin-3-ones have been shown to possess promising antimicrobial activity, whereas their natural counterparts were found lacking in this respect. In this work, quantitative structure-activity relationships (QSAR) of natural and synthetic 1,4-benzoxazin-3-ones as antimicrobials were established. Data published in literature were curated into an extensive dataset of 111 compounds. Descriptor selection was performed by a genetic algorithm. QSAR models revealed differences in requirements for activity against fungi, gram-positive and gram-negative bacteria. Shape, VolSurf, and H bonding property descriptors were frequently picked in all models. The models obtained for gram-positive and gram-negative bacteria showed good predictive power (Q2Ext 0.88 and 0.85, respectively). Based on the models generated, an additional set of 1,4-benzoxazin-3-ones, for which no antimicrobial activity had been determined in literature, were evaluated in silico. Additionally, newly designed lead compounds with a 1,4-benzoxazin-3-one scaffold were generated in silico by varying the positions and combinations of substituents. Two of these were predicted to be up to 5 times more active than any of the compounds in the current dataset. The 1,4-benzoxazin-3-one scaffold was concluded to possess potential for the design of new antimicrobial compounds with potent antibacterial activity, a multitarget mode of action, and possibly reduced susceptibility to gram negatives' efflux pumps. PMID- 30471831 TI - Crestal bone loss around dental implants placed in head and neck cancer patients treated with different radiotherapy techniques: a prospective cohort study. AB - The aim of this prospective cohort study was to evaluate how the radiation technique can affect crestal bone loss and the implant survival rate in head and neck cancer patients treated with radiotherapy. In this study, the type of radiotherapy treatment, i.e. three-dimensional conformal radiotherapy (3D-CRT) or intensity modulated radiation therapy (IMRT), was the predictor variable. The primary outcome variable was crestal bone loss, recorded at implant placement and after 3, 6, 12, and 24 months. A descriptive analysis and ANOVA test were performed; significance was set at P<0.05. Thirty-two patients were enrolled and a total of 113 dental implants placed in irradiated residual bone. There was no statistically significant difference in crestal bone loss levels between the groups at any of the intervals (P>0.05), except after 6 months (P=0.028). The cumulative dental implant survival rate was 94.7%. After 24 months, the mean marginal bone loss was 0.83+/-0.12mm in the 3D-CRT group and 0.74+/-0.15mm in the IMRT group (P=0.179). The data suggest that the different radiation techniques did not affect the outcomes of implant-supported prosthetic rehabilitation, as related to crestal bone loss and implant survival. However, long-term follow-up studies are necessary to evaluate the real influence of the radiotherapy technique on dental implants. PMID- 30471832 TI - Repeat A2 Into B Kidney Transplantation After Failed Prior A2 Into B Transplant: A Case Report. AB - Kidneys from donors with blood type A2 can be successfully transplanted into blood type B and O recipients without the need for desensitization if the recipient's starting anti-A hemagglutinin titer is within an acceptable range. National kidney allocation policy now offers priority for eligible B recipients to receive A2 or A2B deceased donor kidneys, and therefore, the frequency with which A2 or A2B to B transplants will occur is expected to increase. The precise mechanisms by which antibody-mediated rejection is averted in these cases despite the presence of both circulating anti-A antibody and expression of the A2 antigen on the graft endothelium are not known. Whether this process mirrors proposed mechanisms of accommodation, which can occur in recipients of ABO incompatible transplants, is also not known. Repeated exposure to mismatched antigens after retransplantation could elicit memory responses resulting in antibody rebound and accelerated antibody-mediated rejection. Whether this would occur in the setting of repeated A2 donor exposure was uncertain. Here we report the case of a patient with history of a prior A2 to B transplant which failed owing to nonimmunologic reasons; the patient successfully underwent a repeat A2 to B transplant. Neither rebound in anti-A2 antibody nor clinical evidence of antibody-mediated rejection were observed after the transplant. Current kidney allocation will likely enable more such transplants in the future, and this may provide a unique patient population in whom the molecular mechanisms of incompatible graft accommodation may be investigated. PMID- 30471833 TI - Intraoperative Management of a Patient With Impaired Cardiac Function Undergoing Simultaneous ABO-Compatible Liver and ABO-Incompatible Kidney Transplant From 2 Living Donors: A Case Report. AB - BACKGROUND: Combined liver and kidney transplant is a very complex surgery. To date, there has been no report on the intraoperative management of patients with impaired cardiac function undergoing simultaneous ABO-compatible liver and ABO incompatible kidney transplant from 2 living donors. CASE REPORT: A 60-year-old man underwent simultaneous ABO-compatible liver and ABO-incompatible kidney transplant from 2 living donors because of IgA nephropathy and alcoholic liver cirrhosis. The preoperative cardiac findings revealed continuous aggravation, shown by large left atrial enlargement, severe left ventricular hypertrophy, a very prolonged QT interval, and a calcified left anterior descending coronary artery. Severe hypotension with very weak pulsation and severe bradycardia developed, with an irregular junctional rhythm noted immediately after the liver graft was reperfused. Although epinephrine was administered as a rescue drug, hemodynamics did not improve, and central venous pressure and mean pulmonary arterial pressure increased to potentially fatal levels. Emergency phlebotomy via the central line was performed. Thereafter, hypotension and bradycardia recovered gradually as the central venous pressure and mean pulmonary arterial pressure decreased. The irregular junctional rhythm returned to a sinus rhythm, but the QTc interval was slightly more prolonged. Because of poor cardiac capacity, the volume and rate of fluid infusion were increased aggressively to maintain appropriate kidney graft perfusion after confirming vigorous urine production of the graft. CONCLUSIONS: A heart with impaired function due to both end-stage liver and kidney diseases may be less able to withstand surgical stress. Further study on cardiac dysfunction will be helpful for the management of patients undergoing complex transplant surgery. PMID- 30471834 TI - The Incidence and Risk Factors of Posttransplantation Diabetes Mellitus in Living Donor Kidney Transplantation: A Single-Center Retrospective Study in China. AB - BACKGROUND: Posttransplantation diabetes mellitus (PTDM) is a frequent metabolic complication following solid organ transplantation and was proven to be associated with adverse outcome. This study aimed to identify the incidence and risk factors of PTDM under the background of relative-living renal transplantation in China. METHODS: We conducted a retrospective cohort study that included 358 recipients who underwent relative-living donor kidney transplantation in the Organ Transplant Institute of 309th Hospital of People's Liberation Army between January 1, 2010, and December 31, 2014. PTDM was defined based on American Diabetes Association criteria. Demographics and laboratory results were compared between patients with PTDM and non-PTDM; multivariate analysis was performed using a logistic regression model. RESULTS: One hundred ten out of a total of 358 recipients were diagnosed with PTDM (30.72%) within 3 years after transplantations. Seven risk factors for PTDM were identified in multivariate analysis: body mass index >=25 (odds ratio [OR] 1.905, 95% confidence interval [CI]: 1.114-3.258), family history of diabetes (OR 1.898, CI: 1.051-3.258), hypomagnesemia pretransplantation (OR 1.871, CI: 1.133-3.092), acute rejection episodes in 3 months posttransplantation (OR 2.312, CI: 1.015 5.268), tacrolimus use (OR 1.952, CI: 1.169-3.258), impaired fasting glucose diagnosed pretransplantation (OR 1.807, CI: 1.091-2.993), and hyperglycemia in the first week posttransplantation (OR 1.856, CI: 1.133-3.043). CONCLUSION: Our study suggests high body mass index, family diabetes history, hypomagnesemia pretransplantation, acute rejection episodes within the first 3 months after transplantation, tacrolimus use, impaired fasting glucose diagnosed pretransplantation, and hyperglycemia within the first week after transplantation are independent risk factors of PTDM in relative-living donor transplantation. PMID- 30471835 TI - [Mortality due to medical and surgical complications, economic crisis and health spending in Spain, 2002-2013]. AB - OBJECTIVE: To describe the evolution of mortality risks for complications due to medical care or surgery between the periods prior to (2002-2007) and after (2008 2013) the beginning of the economic crisis for Spain and by autonomous region, and to analyse the relationship between the changes in the risks of death and the socioeconomic impact of the crisis and the variation in health spending. METHOD: Ecological study based on age-standardized mortality rates, synthetic index of vulnerability as a socioeconomic indicator and variation in health expenditure as an indicator of health expenditure. The relative risk of death between periods was estimated with Poisson regression models. RESULTS: The number of deaths increased for Spain in the period studied. Although the relationship between the increase in public investment in health and the decrease in mortality due to this cause has not been clearly demonstrated, it was possible to determine that the autonomous regions with the lowest increase in health expenditure had rates higher than the rest throughout the period, and that the most vulnerable to the crisis and with the lowest increase in spending presented the greatest increase in the risk of death between the periods. CONCLUSIONS: Given the increase in these deaths, due to avoidable failures of the system, it is necessary to continue investigating this cause of mortality. PMID- 30471836 TI - [Public health services: reading their available reports]. AB - The objective of this study is to analyze the performance of regional public health services in Spain using the information accessible in their annual reports. A search of these was conducted, and 9 were obtained from the 17 Autonomous Communities. Their analysis shows some variation in the structure of the organizations providing public health services, as well as in the published contents and in the indicators used for management. The service portfolio, annual objectives and resources allocated are not always detailed. If the evaluation of public services and its dissemination are basic for transparency and quality management, there is much room for improvement. The compilation of annual reports by public health services is not systematic, and those that exist provide insufficient information for a comparative analysis of their activity, effectiveness and efficiency. PMID- 30471838 TI - A Role for the E3 Ubiquitin Ligase NEDD4 in Keloid Pathogenesis. AB - The molecular pathomechanisms that drive keloid formation are only partially understood. Genetic studies have provided evidence for a genetic predisposition to keloid formation, and a keloid risk allele has been reported in the gene locus for the E3 ubiquitin ligase NEDD4. Fujita et al. (2018) explore the consequences of this genetic risk allele in NEDD4 for inflammation in the skin and for keloid pathogenesis. This study implicates a specific transcript variant of NEDD4, NEDD4 TV3, as a regulator of NF-kappaB/STAT3-mediated inflammation and provides evidence that an increase in NEDD4-TV3 promotes keloid formation. PMID- 30471837 TI - Urban organic community gardening to promote environmental sustainability practices and increase fruit, vegetables and organic food consumption. AB - OBJECTIVE: To describe the environmental practices of participants in an urban organic community garden at the beginning of their gardening experience and after a period of six months, and to discover their opinion about how this activity influenced the consumption of vegetables, fruits and organic food. METHOD: Interviews using structured questionnaires were conducted twice with 115 city dwellers: when they started in the vegetable garden and about 6 months later. The questionnaire included questions related to environmental practices. The second evaluation also included questions related to the consumption of organic food, vegetables and fruit. RESULTS: This research showed significant behavioural transformation, including positive outcomes in environmental practices such as recycling and trying to persuade friends or family to recycle, compost leftovers or choose to walk/bike to save petrol. In the opinion of the participants, activities in the organic community garden helped to increase consumption of fruits, vegetables and organic food. CONCLUSION: The study results reinforce the hypothesis that an organic community vegetable garden can induce significant, positive behavioural changes among its users. In particular this research suggests horticulture is associated with positive improvements in personal environmental behaviours, awareness of the environment's high social priority and increased consumption of organic food, fruit and vegetables. PMID- 30471839 TI - Targeting PAR2 with Pepducins. AB - Itch, inflammation, and atopic dermatitis are associated with activation of PAR2. Affecting PAR2 activity presents a number of challenges. Here, a cell-penetrating peptide, termed a pepducin, circumvents these challenges by preventing the receptor from coupling to G proteins. The pepducin modulates several models of itch, inflammation, and atopic dermatitis. PMID- 30471840 TI - Uterine intravascular adenomyomatosis: a bizarre hybrid lesion? PMID- 30471841 TI - FDG-PET/CT findings, the vital clue to rare diagnosis of herpes simplex virus lymphadenitis simulating Richter transformation. PMID- 30471842 TI - Hepatitis B virus (HBV) genome detection and genotyping in virally suppressed patients using nested polymerase chain reaction-based Sanger sequencing. AB - Hepatitis B virus (HBV) genotypes have important clinical implications. Current genotyping methods are less sensitive in patients with ultra-low HBV viral load. We report a highly sensitive and specific nested polymerase chain reaction (PCR) assay for genotyping patient HBV. Total DNA derived from plasma of 14 (HBsAg+ and/or HBsAg-) HBcAb+ patients was used for HBV-specific nested PCRs targeting the preC/C, X/BCP/preC, and surface regions. All patients were treated with long term nucleos(t)ide analogues (NAs), and 12/14 have undetectable viremia (clinical PCR: sensitivity >10 IU/mL). Surface amplicons were sequenced, aligned with reference genomes, and used in phylogenetic tree construction to determine genotype. HBV DNA was detected in 14/14, including 3 occult (HBsAg-/HBcAb+) cases. Genotypes identified were 6/14 B, 6/14 C, and 2/14 D. This assay in virologically suppressed patients may be useful for future studies requiring genotype prior to assessment of immunomodulatory and/or direct acting anti-viral therapeutics in patients on potent NAs. PMID- 30471843 TI - Molecular phylogeny and diversity of sea pens (Cnidaria: Octocorallia: Pennatulacea) with a focus on shallow water species of the northwestern Pacific Ocean. AB - The order Pennatulacea, commonly known as sea pens, are colony-forming benthos belonging within subclass Octocorallia (Anthozoa, Cnidaria). Sea pens are found worldwide from shallow to deep waters, and they are important components in sandy and muddy environments. Thus far, there has been only one molecular study focusing on the phylogenetic relationships within the order Pennatulacea, which mainly treated deep-sea species, and thus information on shallow water species is still lacking. On a regional scale, the diversity of sea pens in the northwestern Pacific, including Japan and Palau, has not been well investigated. In this research, we aimed to: (1) more accurately resolve the phylogenetic relationships of sea pens with the inclusion of shallow water species, and (2) obtain a better understanding of the diversity of sea pens in Japan and Palau. Specimens were collected by SCUBA and dredging from the Ryukyu Islands in southern Japan, and from mainland Japan and Palau, and identified to at least the genus level by their morphological traits. Construction of phylogenetic trees with concatenated sequences including the mitochondrial mutS-like protein DNA mismatch repair gene mtMutS and the NADH dehydrogenase subunit 2 ND2 region were performed. The p distances of mtMutS were calculated for estimation of species number following McFadden et al. (2011). Molecular data for 12 families and 20 genera of sea pens were used in this study. This most comprehensive study including shallow water taxa provided us with more knowledge of phylogenetic relationships. The resulting phylogenetic trees showed a topology distinguished by four large clades (clades 1 4). Families Veretillidae and Echinoptilidae are shown as not the earliest diverging taxa. Virgulariidae and Scleroptilidae are shown as polyphyletic groups, and our results reconfirm that families Pennatulidae, Kophobelemnidae and Umbellulidae are not monophyletic groups. Overall, we collected and examined an estimated 18 species from the Ryukyu Islands, 16 species from mainland Japan, and five species from Palau. Some of these specimens represented new records from Ryukyu Islands and Palau. Previous records of these sea pens did not exist likely due to a lack of diversity research in sandy and muddy areas. These results demonstrate that many sea pens discoveries likely remain in shallow waters of the Pacific. PMID- 30471844 TI - Prism adaptation changes resting-state functional connectivity in the dorsal stream of visual attention networks in healthy adults: A fMRI study. AB - Unilateral spatial neglect (USN) can be defined as a failure to orient to contra lesional stimuli in the absence of either sensory or motor defects. Although the behavioral and clinical effects of prism adaptation (PA) are widely accepted, its underlying mechanisms are still controversial. However, recent neuroimaging and neurophysiological studies support the idea that PA affects the visual attention and sensorimotor networks including in the parietal cortex and cerebellum. We investigate the effect of PA on functional connectivity (FC) in attention and sensorimotor networks, evaluating changes of resting-state FC before and after PA in healthy individuals using functional magnetic resonance imaging (fMRI). MR sessions were conducted before PA, after PA (Post1), and 1 h after PA (Post2). The FC between the right frontal eye (FEF) field and the right intraparietal sulcus was significantly decreased at Post1 and that between the right FEF and the right anterior cingulate cortex was significantly increased after PA and recovered within 1 h. This is the first study to demonstrate transient changes of resting-state FC in the right dorsal attention network (DAN) by PA in healthy adults using fMRI. These results will contribute to the elucidation of the underling mechanism of PA therapy and to devising new therapies for USN and/or other higher cortical dysfunctions. PMID- 30471845 TI - New alert criteria for intraoperative somatosensory evoked potential monitoring. PMID- 30471846 TI - Long-term intraocular pressure changes after femtosecond laser-assisted cataract surgery in healthy eyes and glaucomatous eyes. AB - PURPOSE: To examine the long-term effect of femtosecond laser-assisted cataract surgery on intraocular pressure (IOP) in healthy (control) and glaucomatous eyes. SETTING: University of Colorado, Aurora, Colorado, and Vanderbilt University, Nashville, Tennessee, USA. DESIGN: Retrospective case series. METHODS: The study comprised patients aged 18 to 89 years meeting the inclusion criteria. Combination procedures were excluded. The main outcome measure was the change in the mean IOP from baseline to postoperatively. RESULTS: Of the 504 eyes meeting the criteria, 278 were in the glaucoma/glaucoma suspect group and 226 in the control group. Both groups had an initial mean increase in IOP 1 day postoperatively (control: +2.0 mm Hg; 95% confidence interval [CI], 1.4-2.6; glaucoma/glaucoma suspect: +3.4 mm Hg; 95% CI, 2.5-4.2) (both P < .001). The increase was significantly higher in the glaucoma/glaucoma suspect group. The IOP returned to baseline levels at 1 week. At 1 month, both groups had a significant decrease in IOP that persisted until year 1 in the control group and through 3 years in the glaucoma group. The number of IOP medications was unchanged in the glaucoma group during follow-up. The glaucoma/glaucoma suspect group achieved significantly greater IOP lowering than the control group after 6 months. CONCLUSIONS: Control eyes and eyes with glaucoma had an initial mean IOP rise 1 day after femtosecond laser-assisted cataract surgery. This was followed by a significant decrease starting at 1 month. The reduction was sustained through 3 years in the glaucoma group. PMID- 30471847 TI - Scleral-sutured intraocular lenses: Single-surgeon technique for suture-preloaded intraocular lens insertion through a small-incision corneal wound. AB - For scleral intraocular lens (IOL) fixation, suture-loaded IOLs have traditionally been folded in half with a forceps and delivered intraocularly through 3.5 to 4.0 mm corneal wounds. We describe a technique in which a suture loaded scleral IOL is inserted through a small-incision corneal wound using 2 widely available ocular surgery tools; that is, a C or D cartridge and a Bowman nasolacrimal duct probe. This technique is easy to replicate and can be performed without an assisting surgeon. PMID- 30471848 TI - Trial-based cost-effectiveness analysis of toric versus monofocal intraocular lenses in cataract patients with bilateral corneal astigmatism in the Netherlands. AB - PURPOSE: To evaluate the cost-effectiveness of toric versus monofocal intraocular lens (IOL) implantation in cataract patients with bilateral corneal astigmatism. SETTING: Two ophthalmology clinics in the Netherlands. DESIGN: Prospective cost effectiveness analysis. METHODS: Resource-use data were collected over a 6-month postoperative period. Consecutive patients with bilateral age-related cataract and 1.25 diopters or more of corneal astigmatism were included in the economic evaluation. Patients were randomized to phacoemulsification with bilateral toric or monofocal IOL implantation. All relevant resources were included in the cost analysis. The base-case analysis was performed from a societal perspective based on quality-adjusted life years (QALYs). The main outcome was the incremental cost effectiveness ratio. RESULTS: The analysis comprised 77 consecutive patients (33 toric IOL; 44 monofocal IOL). Societal costs were higher in the toric IOL group (?3203 [$3864]) than in the monofocal IOL group (?2796 [US$3373]). QALYs were slightly lower in the toric IOL group (0.30 versus 0.31; P = .75). Toric IOLs were therefore inferior to monofocal IOLs from a cost-effectiveness perspective. The cost-effectiveness probability ranged from 1% to 15%, assuming a ceiling ratio for the incremental cost-effectiveness ratio of ?2500 to ?20 000 per QALY. CONCLUSIONS: From a societal perspective, bilateral toric IOL implantation in cataract patients with corneal astigmatism was not cost-effective compared with monofocal IOL implantation. Copayment by patients should therefore be considered. PMID- 30471850 TI - In vitro and schematic model eye assessment of glare or positive dysphotopsia type photic phenomena: Comparison of a new material IOL to other monofocal IOLs. AB - PURPOSE: To compare the glare-type photic phenomena for a new intraocular lens (IOL) to other monofocal IOLs, and to investigate how IOL design features might affect these phenomena. SETTING: Alcon Laboratories, Inc., Fort Worth, Texas; John A Moran Eye Center, University of Utah, Salt Lake City, USA. DESIGN: Schematic model eye evaluation and in vitro study. METHODS: Five monofocal IOL models (Clareon CNA0T0, Tecnis ZCB00, enVista MX60, Eternity W-60, and Vivinex XY1) were used to evaluate glare or positive dysphotopsia-type phenomena. Optical simulations of incoming light were generated using nonsequential ray-tracing software based on a collimated light source for various off-axis angles of illumination. The simulation analyses were verified using a laboratory in vitro bench-top glare measurement system. RESULTS: The Clareon and Vivinex IOLs produced focused off-axis images with negligible peripheral glare characteristics. The Tecnis and enVista IOLs produced dispersed images with additional glare characteristics at 45 degrees of off-axis illumination and higher. The Eternity IOL showed the highest edge-reflected glare characteristic, likely because of its straight optic edge geometry. The laboratory bench images and glare intensity profiles were consistent with the simulation data. CONCLUSIONS: In vitro and nonsequential ray-tracing evaluations showed that straight optic edges and peripheral nonimaging optic geometry might contribute to positive dysphotopsia. The IOL designs with optic edge curvature and full functional optics demonstrated the lowest level of glare-type photic phenomena. Only clinical studies can confirm whether the differences observed between the IOLs in vitro are clinically significant. PMID- 30471849 TI - Increased postoperative anterior chamber inflammation secondary to heat-resistant endotoxins. AB - PURPOSE: To evaluate the cause of clusters of increased postoperative anterior chamber inflammation after uneventful cataract surgery, and to examine its relation to the presence of endotoxins in sterile consumables. SETTING: Tertiary eye center in north India. DESIGN: Single-center retrospective case series. METHODS: All cataract surgeries performed at the tertiary eye center over 12 weeks (October 1, 2017 to December 31, 2017) were noted. Any patient with a "severe reaction" postoperatively was monitored closely and the postoperative drug regimen was altered accordingly. "Severe reaction" was defined as any patient with more than 4+ cells and/or fibrin with or without hypopyon. The Hospital Infection Control committee was informed, and a root cause analysis was performed to determine the cause. All the consumables were recalled and replaced. The samples were sent for microbiological evaluations. RESULTS: Of the 781 cataract surgeries performed, 81 patients had a severe reaction. Most patients were men (71%) and the mean age of the patients was 63 years. Twelve patients had fibrin, 3 of whom presented with hypopyon. Because all samples were negative of any growth, endotoxin tests were performed. All the samples were found to be negative, except for the ophthalmic viscosurgical device (OVD), which showed positive endotoxin levels. The OVD was changed and the anterior chamber reactions ceased to occur. CONCLUSION: A careful, stepwise approach is necessary when investigating clusters of increased postoperative anterior chamber reactions after uneventful surgery. A high degree of suspicion is important to rule out all possible reasons and in the absence of any identifiable cause, sterile consumables should be checked for endotoxins. PMID- 30471851 TI - Identification of LEM-14 inhibitor of the oncoprotein NSD2. AB - The NSD family (NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1) are histone lysine methyltransferases (HMTases) essential for chromatin regulation. The NSDs are oncoproteins, drivers of a number of tumors and are considered important drug targets but the lack of potent and selective inhibitors hampers further therapeutic development and limits exploration of their biology. In particular, MMSET/NSD2 selective inhibition is being pursued for therapeutic interventions against multiple myeloma (MM) cases, especially in multiple myeloma t(4;14)(p16.3;q32) translocation that is associated with a significantly worse prognosis than other MM subgroups. Multiple myeloma is the second most common hematological malignancy, after non-Hodgkin lymphoma and remains an incurable malignancy. Here we report the discovery of LEM-14, an NSD2 specific inhibitor with an in vitro IC50 of 132 MUM and that is inactive against the closely related NSD1 and NSD3. LEM-14-1189, a LEM-14 derivative, differentially inhibits the NSDs with in vitro IC50 of 418 MUM (NSD1), IC50 of 111 MUM (NSD2) and IC50 of 60 MUM (NSD3). We propose LEM-14 and derivative LEM-14-1189 as tools for studying the biology of the NSDs and constitute meaningful steps toward potent NSDs therapeutic inhibitors. PMID- 30471852 TI - Requirement of Rab21 in LPS-induced TLR4 signaling and pro-inflammatory responses in macrophages and monocytes. AB - Lipopolysaccharide (LPS) induces macrophage/monocyte activation and pro inflammatory cytokines production by activating Toll-like receptor 4 (TLR-4) signaling. Rab GTPase 21 (Rab21) is a member of the Rab GTPase subfamily. In the present study, we show that LPS induced TLR4 and Rab21 association and endosomal translocation in murine bone marrow-derived macrophages (BMDMs) and primary human peripheral blood mononuclear cells (PBMCs). In BMDMs, shRNA-mediated stable knockdown of Rab21 inhibited LPS-induced expression and production of pro inflammatory cytokines (IL-1beta, IL-6 and TNF-alpha). Conversely, forced overexpression of Rab21 by an adenovirus construct potentiated LPS-induced IL 1beta, IL-6 and TNF-alpha production in BMDMs. Further studies show that LPS induced TLR4 endosomal traffic and downstream c-Jun and NFkappaB (nuclear factor kappa B) activation were significantly inhibited by Rab21 shRNA, but intensified with Rab21 overexpression in BMDMs. Finally, in the primary human PBMCs, siRNA induced knockdown of Rab21 significantly inhibited LPS-induced IL-1beta, IL-6 and TNF-alpha production. Taken together, we suggest that Rab21 regulates LPS-induced pro-inflammatory responses by promoting TLR4 endosomal traffic and downstream signaling activation. PMID- 30471853 TI - Light-dependent suppression of COP1 multimeric complex formation is determined by the blue-light receptor FKF1 in Arabidopsis. AB - CONSTITUTIVELY PHOTOMORPHOGENIC1 (COP1), a multifunctional E3 ligase protein with many target proteins, is involved in diverse developmental processes throughout the plant's lifecycle, including seed germination, the regulation of circadian rhythms, photomorphogenesis, and the control of flowering time. To function, COP1 must form multimeric complexes with SUPPRESSOR OF PHYA1 (SPA1), i.e., [(COP1)2(SPA1)2] tetramers. We recently reported that the blue-light receptor FKF1 (FLAVIN-BINDING, KELCH REPEAT, F-BOX1) represses COP1 activity by inhibiting its homodimerization, but it is not yet clear whether FKF1 affects the formation of COP1-containing multimeric complexes. To explore this issue, we performed size exclusion chromatography (SEC) of Arabidopsis thaliana proteins and found that the levels and composition of COP1-containing multimeric complexes varied throughout a 24-h period. The levels of 440-669 kDa complexes were dramatically reduced in the late afternoon compared to the morning and at night in wild-type plants. During the daytime, the levels of these complexes were reduced in FKF1 overexpressing plants but not in fkf1-t, a loss-of-function mutant of FKF1, suggesting that FKF1 is closely associated with the destabilization of COP1 multimeric protein complexes in a light-dependent manner. We also analyzed the SEC patterns of COP1 multimeric complexes in transgenic plants overexpressing mutant COP1 variants, including COP1L105A (which forms homodimers) and COP1L170A (which cannot form homodimers), and found that COP1 multimeric complexes were scarce in plants overexpressing COP1L170A. These results indicate that COP1 homodimers serve as basic building blocks that assemble into COP1 multimeric complexes with diverse target proteins. We propose that light-activated FKF1 inhibits COP1 homodimerization, mainly by destabilizing 440-669 kDa COP1 complexes, resulting in the repression of CONSTANS-degrading COP1 activity in the late afternoon in long days, but not in short days, thereby regulating photoperiodic flowering in Arabidopsis. PMID- 30471854 TI - Nobiletin reduces LPL-mediated lipid accumulation and pro-inflammatory cytokine secretion through upregulation of miR-590 expression. AB - Nobiletin has protective effects on cardiovascular diseases, but the mechanism is not clear. In this study, we examined whether nobiletin affects the expression of miR-590/LPL and its relative effects on lipid accumulation and pro-inflammatory cytokine secretion in human THP-1 macrophages. RT-qPCR analysis showed that nobiletin increased the expression of miR-590. Western blot analysis showed that nobiletin-suppressed LPL expression was enhanced by miR-590 mimic and abrogated by miR-590 inhibitor. Oil Red O staining and high-performance liquid chromatography assays showed that nobiletin attenuated lipid accumulation in macrophages. Treatment with nobiletin and miR-590 mimic decreased cellular lipid accumulation, whereas treatment with miR-590 inhibitor increased cellular lipid accumulation. ELISA illustrated that nobiletin alleviated pro-inflammatory cytokine secretion in macrophages as measured by, which was reduced by miR-590 mimic and increased by miR-590 inhibitor. In conclusion, nobiletin may alleviate lipid accumulation and secretion of pro-inflammatory cytokines by enhancing the inhibitory effect of miR-590 on LPL expression, suggesting a promising strategy for potential drug development for atherosclerosis. PMID- 30471855 TI - Screening and bioinformatics analysis of mRNA, long non-coding RNA and circular RNA expression profiles in mucoepidermoid carcinoma of salivary gland. AB - Mucoepidermoid carcinoma (MEC) of salivary gland is a disease characterized by high rate of diatant metastasis, and associated with poor outcomes. However, the molecular mechanisms underlying the MEC remain poorly understand. Here, we simultaneously detected, for the first time, the expression profiles of mRNAs, lncRNAs, and circRNAs in four pairs of MEC and matched non-carcinoma tissues by microarrays. A total of 3612 mRNA, 3091 lncRNAs, and 284 circRNAs were altered during the pathogenesis of MEC. The functions of these differentially expressed RNAs were predicted by Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Co-expression networks of lncRNA-mRNA and circRNA-miRNA were conducted to uncovered the hidden ceRNA mechanisms. Moreover, NONHSAT154433.1 that associated with ADAM12 and hsa_circ_0012342 were further screened and confirmed using qRT-PCR analysis. In conclusion, this study provides a systematic perspective on the potential function of non-coding RNAs (ncRNAs) in the molecular mechanisms of MEC. Among these, NONHSAT154433.1 and hsa_circ_0012342 might be served as potential prognostic biomarkers and therapeutic target of MEC. PMID- 30471857 TI - Hepatitis B virus X protein related lncRNA WEE2-AS1 promotes hepatocellular carcinoma proliferation and invasion. AB - Hepatitis B virus X protein (HBx) is involved in the initiation and progression of hepatocellular carcinoma (HCC) by regulating the host protein-coding genes. In this study, we showed that HBx altered the expression of lncRNAs to promote the progression of HCC. lncRNA microarray and quantitative reverse-transcription polymerase chain reactions (qRT-PCRs) were performed to identify lncRNAs that were differentially regulated by HBx in HCC cells and tissues. Protein, mRNA, and lncRNA expression analyses; cell cycle and apoptosis analyses; loss/gain-of function analysis were performed to delineate the consequences of WEE2-AS1 upregulation in HCC cells. WEE2-AS1 over-expressed in HCC and was positively correlated to hepatitis B virus (HBV) infection, hepatic vascular invasion, poor tumor differentiation and poor patient prognosis. WEE2-AS1 also accelerated the proliferation, migration, invasion and cell cycle progression of HCC cells. Fermitin family member 3 (FERMT3) was a downstream target of WEE2-AS1. In conclusion, there is a preliminary HBx-WEE2-AS1- FERMT3 pathway which may serve as a therapeutic target for HBV-associated HCC. PMID- 30471856 TI - Megaplasmid - A promising tool for higher protein production. AB - Recombinant proteins have an increasing demand due to their application spanning across different fields. Hence, investigating strategies to increase the yield of recombinant proteins are highly significant. To achieve high yield, optimization of various parameters such as temperature, pH, aeration, inducer concentration, etc. are necessary. However, these parameters maximize the product yield of only the single open reading frame (ORF). A conventional single ORF would produce limited transcripts. Our strategy describes the generation of a tandem repeat of ORF and vector backbone, termed as megafragment (MF), followed by circularization and retaining of megaplasmid (MP) in E. coli, thereby, maximizing the protein production. We demonstrate the generation of megafragment through concatemer chain reaction and devised a method to purify megafragment from other shorter fragments. Linker was added to either end of the ORF to mediate homologous recombination and then transformed into E. coli cells to circularize the megafragment to form megaplasmid (ligase-free cloning technology). Megaplasmid can be a promising tool for higher protein expression as compared to single ORF containing plasmids. Also, E. coli BLR (DE3) and recA null strains were used here for demonstrating megaplasmid expression in the cell. The novelty of this work is the maintenance of the megaplasmid during the expression, which enables the expression of proteins at a high level. PMID- 30471858 TI - Analysis of gene co-expression networks and function modules at different developmental stages of chicken breast muscle. AB - The development of poultry muscle fibers after hatching is closely related to meat quality and production efficiency. It is necessary to identify functional modules (groups of functionally related genes) related to muscle development at different developmental stages, and to investigate their relationships based on the weighted gene co-expression network analysis (WGCNA) methods. Accordingly, we investigated the co-expression associations between genes related to chicken breast muscle at four different developmental stages (between 2 and 14 weeks of age), and systematically analyzed the network topology in Jinmao Hua chicken. As a result, 2341 differentially expressed genes were identified and subjected to co expression analysis. Four modules were identified to be related to a particular growth stage for the development of breast muscle. A series of genes with the highest connectivity were identified in the pink (2 weeks), yellow (6 weeks), green (10 weeks) and black modules (14 weeks), respectively, and visualized by Cytoscape. These hub genes (FGF, MAPKAPK5, NRG1, SCD, ACSL1, PPAR etc.) were mainly enriched in 15 pathways, such as MAPK signaling pathway, NRG/ErbB signaling pathway, and insulin signaling pathway. They shared biological functions related to development of breast muscle and adipogenesis. This is the first study of gene network with different stages of muscle development in Jinmao Hua chicken to observe co-expression patterns. It may contribute to the underlied molecular mechanisms of chicken breast muscle development. PMID- 30471859 TI - Effect of site-specific amino acid D-isomerization on beta-sheet transition and fibril formation profiles of Tau microtubule-binding repeat peptides. AB - d-amino acid-containing proteins have been found in several human tissues, and the spontaneous accumulation of d-amino acids in proteins is thought to be involved in age-dependent diseases including dementia. Tau, a microtubule associated protein, is a major component of neurofibrillary tangles in Alzheimer's disease. Site-specific amino acid D-isomerization in Tau has been observed in the brains of patients with Alzheimer's disease. Here, we conducted amino acid D-isomerization at specific sites in microtubule-binding repeat peptides of Tau (Tau R2 and R3) and examined the effects on Tau structure and fibril formation. Our results demonstrate that amino acid D-isomerization in Tau R2 peptides decreased the rates of beta-sheet transition and fibril formation compared with those of the wild-type peptide composed of all l-amino acids. In contrast, Tau R3 peptides that had undergone amino acid D-isomerization at either Asp314, Ser316, or Ser324 showed increased rates of beta-sheet transition and fibril formation compared with those of the wild-type Tau R3 peptide. PMID- 30471860 TI - X-ray structure and characterization of a thermostable lipase from Geobacillus thermoleovorans. AB - Thermo-alkalophilic bacterium, Geobacillus thermoleovorans secrets many enzymes including a 43 kDa extracellular lipase. Significant thermostability, organic solvent stability and wide substrate preferences for hydrolysis drew our attention to solve its structure by crystallography. The structure was solved by molecular replacement method and refined up to 2.14 A resolution. Structure of the lipase showed an alpha-beta fold with 19 alpha-helices and 10 beta-sheets. The active site remains covered by a lid. One calcium and one zinc atom was found in the crystal. The structure showed a major difference (rmsd 5.6 A) from its closest homolog in the amino acid region 191 to 203. Thermal unfolding of the lipase showed that the lipase is highly stable with Tm of 76 degrees C. 13C NMR spectra of products upon triglyceride hydrolysate revealed that the lipase hydrolyses at both sn-1 and sn-2 positions with equal efficiency. PMID- 30471861 TI - Identification of WWP1 as an obesity-associated E3 ubiquitin ligase with a protective role against oxidative stress in adipocytes. AB - White adipose tissue (WAT) is not only the main tissue for energy storage but also an endocrine organ that secretes adipokines. Obesity is the most common metabolic disorder and is related to alterations in WAT characteristics, such as chronic inflammation and increasing oxidative stress. WW domain containing E3 ubiquitin protein ligase 1 (WWP1) is a HECT-type ubiquitin E3 ligase that has been implicated in various pathologies. In the present study, we found that WWP1 was upregulated in obese WAT in a p53-dependent manner. To investigate the functions of WWP1 in adipocytes, a proteome analysis of WWP1 overexpression (OE) and knockdown (KD) 3T3-L1 cells was performed. This analysis showed a positive correlation between WWP1 expression and the abundance of several antioxidative proteins. Thus, we measured reactive oxygen species (ROS) in WWP1 OE and KD cells. Consistent with the proteome results, WWP1 OE reduced ROS levels, whereas KD increased them. These findings indicate that WWP1 is an obesity-inducible E3 ubiquitin ligase that can protect against obesity-associated oxidative stress in WAT. PMID- 30471863 TI - Overexpressing kringle 1 domain of hepatocyte growth factor with adeno-associated virus inhibits the pathological retinal neovascularization in an oxygen-induced retinopathy mouse model. AB - Current clinical treatments for ocular neovascularization are characterized by high possibility of damaging healthy tissues and high recurrence rates. It is necessary to develop new treatment methods to control neovascularization with a stable and effective effect. Kringle1 domain of hepatocyte growth factor (HGFK1) has anti-angiogenesis activity. Here, we established oxygen-induced retinopathy (OIR) model to study if using adeno-associated virus (AAV) as a delivery system to overexpression HGFK1 in retinal cells could benefit retinal neovascularization. We show that, overexpressed exogenous gene was mainly expressed in the inner and outer nuclear layer of the retina. Compared with control mice, the mice pretreated with rAAV-HGFK1 at P3 showed relatively normal vascular branches examined by fluorescence fundus angiography. Subsequent H&E staining and immunohistochemical staining of CD31 of the eye tissue sections showed that the mice received rAAV-HGFK1 had a relatively normal distribution of vascular endothelial cells. Additionally, immunohistochemical staining indicated a lower expression of VEGF in the eye tissues of rAAV-HGFK1 treated OIR mice. Further in vitro studies showed that HGFK1 could inhibit the proliferation but promote the apoptosis of bovine retinal microvascular endothelial cells (BRECs) under the presence of VEGF. Moreover, HGFK1 could inhibit VEGF induced ERK activation but promote p38 activation in BRECs. Therefore, we propose that intravitreal injection of rAAV-HGFK1 might be used to improve the retinal neovascularization and HGFK1 may function through regulating VEGF signaling pathway to inhibit neovascularization. PMID- 30471862 TI - Effects of myeloid sirtuin 1 deficiency on hypothalamic neurogranin in mice fed a high-fat diet. AB - Hypothalamic inflammation has been known as a contributor to high-fat diet (HFD) induced insulin resistance and obesity. Myeloid-specific sirtuin 1 (SIRT1) deletion aggravates insulin resistance and hypothalamic inflammation in HFD-fed mice. Neurogranin, a calmodulin-binding protein, is expressed in the hypothalamus. However, the effects of myeloid SIRT1 deletion on hypothalamic neurogranin has not been fully clarified. To investigate the effect of myeloid SIRT1 deletion on food intake and hypothalamic neurogranin expression, mice were fed a HFD for 20 weeks. Myeloid SIRT1 knockout (KO) mice exhibited higher food intake, weight gain, and lower expression of anorexigenic proopiomelanocortin in the arcuate nucleus than WT mice. In particular, KO mice had lower ventromedial hypothalamus (VMH)-specific neurogranin expression. However, SIRT1 deletion reduced HFD-induced hypothalamic neurogranin. Furthermore, hypothalamic phosphorylated AMPK and parvalbumin protein levels were also lower in HFD-fed KO mice than in HFD-fed WT mice. Thus, these findings suggest that myeloid SIRT1 deletion affects food intake through VMH-specific neurogranin-mediated AMPK signaling and hypothalamic inflammation in mice fed a HFD. PMID- 30471864 TI - Each liver X receptor (LXR) type has a different purpose in different situations. AB - LXRs, which are nuclear receptors, have 2 isoforms-LXRalpha and LXRbeta. Generally, LXRalpha is expressed in the liver, kidney, and a limited number of other organs, whereas LXRbeta is thought to be expressed ubiquitously. Nevertheless, no clear consensus has been reached on the role of each in kidney lipid metabolism. Many researchers have reported that lipids accumulate in renal tubular epithelial cells during nephrosis. The nephrosis model we used showed the presence of urinary protein 4 days after the induction of illness. Additionally, the model maintained high levels of urinary protein from day 7-14. Lipid accumulation was clearly verified at day 4 and extreme accumulation was observed at day 7. We observed increased expression of LXRalpha from an early stage of nephrosis. To explore the role of increased LXRalpha in diseased kidney in vitro, NRK52E, normal kidney tubular epithelial cells, were forced to overexpress LXRalpha. These cells showed significantly lower lipid accumulation than mock cells did. In contrast, LXRbeta knockdown lead to increased lipid accumulation in mock cells, and constancy in overexpressing cells. In normal kidneys, LXRbeta is expressed stably to control mainly the intracellular lipids. However, with increasing intracellular lipid accumulation, expression of LXRalpha and its downstream gene, ABCA1, was upregulated, followed by lipid excretion in an LXRalpha-dependent manner. This phenomenon strongly suggests the importance of LXRalpha in lipid metabolism in the diseased kidney. PMID- 30471865 TI - PPE65 of M. tuberculosis regulate pro-inflammatory signalling through LRR domains of Toll like receptor-2. AB - Our understanding of the PE/PPE family of proteins in M. tuberculosis (Mtb) pathogenesis is still evolving and their critical roles in the host immunomodulation are still in the discovery process. Earlier studies from our group have shown that TLR2-LRR domain plays an important role in regulating cytokine signalling by PPE proteins. The importance of TLR2-LRR domain 16-20 in the regulation of PPE17-induced pro-inflammatory signalling has been established recently. However, it is yet to find whether other PPE protein also targets the TLR2-LRR 16-20 domain for induction of pro-inflammatory responses. In the current study, we have explored the structural parameters and possible role of PPE65 in generating pro-inflammatory signalling molecules mediated through IRAK3 downstream of TLR2-LRR domain 16-20. This study conceptualizes the functional characteristics of PPE65 in infection condition and might possibly provide valuable information in exploring this protein as an immunomodulator in Mtb infection. PMID- 30471866 TI - Rab11-FIP2 suppressed tumor growth via regulation of PGK1 ubiquitination in non small cell lung cancer. AB - Mounting evidence has shown that the Rab11-FIP2 has critical roles in cancer cell growth. However, the clinical significance of Rab11-FIP2 in Non-small cell lung cancer (NSCLC) remains to be fully elucidated. In this study, we investigated the expression of Rab11-FIP2 using immunohistochemistry in 150 patients with NSCLC. We found that its expression level in NSCLC was much lower than that in the corresponding adjacent normal tissues. The DNA methylation data revealed that Rab11-FIP2 were significantly hypermethylated in NSCLC. The methylation level in the gene body was negatively correlated with the expression level of Rab11-FIP2 in NSCLC. Furthermore, enforced expression of Rab11-FIP2 dramatically reduced cancer cell proliferation and tumorigenesis, indicating a tumor suppressor role of PGK1 in NSCLC progression. Mechanistic investigations showed that Rab11-FIP2 interacted with the glycolytic kinase PGK1 and promoted its ubiquitination in NSCLC cells, leading to inactivation of the oncogenic AKT/mTOR signaling pathway. Overall, our data indicate that reduced expression of Rab11-FIP2 by DNA hypermethylation plays an important role in NSCLC tumor growth. PMID- 30471867 TI - Seroprevalence of Dengue and Zika Virus in Blood Donations: A Systematic Review. AB - The presence of antibodies to Zika virus (ZIKV) and dengue virus (DENV) can be detected in blood donations. Donation-based surveillance provides an alternative strategy to estimate population prevalence by detecting antibodies that are circulating. To estimate population prevalence, we conducted a systematic review of literature on the seroprevalence of ZIKV and DENV antibodies in blood donations. We searched PubMed and Web of Science for studies that reported the seroprevalence of ZIKV and DENV in blood donations. The title and abstract of each study were screened by 2 reviewers simultaneously for possible inclusion, and the full text of selected studies was reviewed to ensure that they met inclusion criteria (used primary data collection, reported evidence of immunoglobulin M (IgM) or immunoglobulin G (IgG) antibodies in the blood supply, and included a representative sample of the total population). Immunoglobin test measuring levels of antibodies to IgM and IgG and number of positive cases were extracted from each study. No exclusions were made based on language or country. Our initial search identified 1890 studies after excluding duplicates, of which 76 were assessed for full text eligibility to ensure that they met our final inclusion criteria. There were 14 studies included in our review; 11 examined the seroprevalence of DENV, and 3 examined ZIKV. The highest seroprevalence by IgM was 2.82% for DENV and 0.53% for ZIKV. Our results indicate that the seroprevalence of ZIKV and DENV antibody presence in countries with active transmission is higher than reports by traditional surveillance in some countries. This finding is expected due to the large percentage of asymptomatic cases. The highest seroprevalence was observed for IgG, which can persist over long periods of time compared to IgM. Screening of blood donations may help supplement traditional surveillance measures, especially during outbreak settings. PMID- 30471869 TI - Predictive Processes and the Peculiar Case of Music. AB - We suggest that music perception is an active act of listening, providing an irresistible epistemic offering. When listening to music we constantly generate plausible hypotheses about what could happen next, while actively attending to music resolves the ensuing uncertainty. Within the predictive coding framework, we present a novel formulation of precision filtering and attentional selection, which explains why some lower-level auditory, and even higher-level music syntactic processes elicited by irregular events are relatively exempt from top down predictive processes. We review findings providing unique evidence for the attentional selection of salient auditory features. This formulation suggests that 'listening' is a more active process than traditionally conceived in models of perception. PMID- 30471868 TI - Cognitive Training Does Not Enhance General Cognition. AB - Due to potential theoretical and societal implications, cognitive training has been one of the most influential topics in psychology and neuroscience. The assumption behind cognitive training is that one's general cognitive ability can be enhanced by practicing cognitive tasks or intellectually demanding activities. The hundreds of studies published so far have provided mixed findings and systematic reviews have reached inconsistent conclusions. To resolve these discrepancies, we carried out several meta-analytic reviews. The results are highly consistent across all the reviewed domains: minimal effect on domain general cognitive skills. Crucially, the observed between-study variability is accounted for by design quality and statistical artefacts. The cognitive-training program of research has showed no appreciable benefits, and other more plausible practices to enhance cognitive performance should be pursued. PMID- 30471870 TI - Coming of Age in the Shadow of the Taliban: Education, Child Marriage, and the Future of Afghanistan From the Perspectives of Adolescents and Their Parents. AB - OBJECTIVE: To understand adolescent and parental attitudes toward education, child marriage, and the changes in matriculation for boys and girls over one generation. METHODS: Two-staged household sampling method was used in six provinces with low educational enrollment in Afghanistan during 2016. Final sample included 910 adolescents aged 12-15 years and 454 parents. Data analysis included k-Nearest Neighbour imputation for missing values. Response percentages were compared by two-tail proportional z-test for two-sample comparison or Chi squared test for multiple groups comparison with adjusted p values. RESULTS: Adolescents reported highly valuing education but considered boys to be greater beneficiaries than girls. Over 90% of parents concur expecting their children to complete at least secondary education independent of the child's sex with more than a third (37.89%) indicating that marriage should be postponed until at least high school completion. Likewise, both boys and girls believe marriage of girls under age 18-years limits future educational opportunities as well as increases risks of domestic violence and loss of freedom. Whereas a generation ago four-out of-five parents of today's adolescents were not in school, today that has reversed; and among 12-15 year olds in the provinces studied, 75% were in school at the time of the survey. CONCLUSIONS: In the most disadvantaged provinces of Afghanistan, almost all young adolescents surveyed (98.8%) were not married and the majority were in school while an equal percent of their parents had no formal education. Additionally, both parents report that education of their sons and daughters is highly valued; and, for two-fifths, they believe marriage should occur after completion of secondary school. PMID- 30471871 TI - Can High Schools Be an Effective Setting to Promote Healthy Lifestyles? Effects of a Multiple Behavior Change Intervention in Adolescents. AB - PURPOSE: The main aim was to examine the effects of a school-based intervention on multiple health behaviors in adolescents, such as 24-hour movement behaviors (i.e., physical activity, sedentary time, and sleep duration), diet, and substance consumption (i.e., alcohol and tobacco). Another aim was to examine intragender differences in the effectiveness of the programme. METHODS: A quasi experimental design was carried out in two secondary schools throughout one academic year. A final sample of 210 students participated: 105 in the control (Mage = 13.07 +/- 0.63) and 105 in the experimental school (Mage = 13.05 +/- 0.59). A multicomponent school-based intervention was conducted by teachers in the experimental school via curricular (i.e., tutorial action plan, interdisciplinary project, and school break) and extracurricular (i.e., family involvement, institutional and noncurricular activities, and dissemination of health information and events) actions to promote adolescents' healthy lifestyles. Physical activity and sedentary time were measured by accelerometers, and the rest of health behaviors by using self-reported scales. RESULTS: Experimental school students showed a significant improvement in meeting specific and general combinations of 24-hour movement guidelines, sedentary screen time levels, nap duration, (un)healthy diet scores, breakfast intake, and soft drink consumption compared to both control school students and their baseline values (p >.05). Active commuting and substance consumption rates only showed a significant improvement compared to control school students (p >.05). Although the intervention programme was effective in improving health-related behaviors in both genders, a large effect size was observed in boys. CONCLUSIONS: Conducting multiple health behavior interventions becomes essential to improve adolescents' healthy lifestyles. PMID- 30471872 TI - NK cells suppress CD8+ T cell immunity via NKG2D in severe aplastic anemia. AB - The roles of natural killer (NK) cells in shaping the immune system had raised wide interests. Here we intended to explore the regulatory functions of NK cells on CD8+ T cells in severe aplastic anemia (SAA) using human participants and lymphocyte infusion-induced bone marrow failure (BMF) mouse model. In SAA patients, NK cells had over-expressions of NKG2D and NKp46, under-expression of NKG2A and enhanced cytotoxicity. NK cells limited autologous CD8+ T cell immunity in an effector/target ratio manner. The suppression was dependent on the existence of NKG2D. We also observed upregulated MICA expression on activated CD8+ T cells, which were susceptible to NK cell mediated lysis in SAA. Animal model concurred with the data from patients. Infusion of NK cells suppressed the proliferation of CD8+ T cells and decreased IFN-gamma production. In conclusion, NK cells served NKG2D-dependent immunoregulatory roles by attenuating autologous CD8+ T cell response in SAA. PMID- 30471873 TI - Spontaneous spinal epidural hematoma mimicking Guillain-Barre Syndrome. AB - BACKGROUND: The initial symptoms of Guillain-Barre Syndrome (GBS) can be similar to a case of spontaneous spinal epidural hematoma (SSEH) located at the cervicothoracic junction. Therefore, SSEH may be misdiagnosed as GBS. CASE REPORT: A previously healthy 6-year-old girl presented with a 2-day history of progressive pain in the lower extremities and an inability to walk. On initial evaluation, she was completely paraparetic in the lower extremities. Deep tendon reflexes were absent in the lower extremities, and Babinski reflexes were positive on both sides. She exhibited reduced response to light touch and pinprick with a sensory level below T10, and experienced difficulty during urination. However, the strength, sensation and flexion of upper extremities were normal. Because her presentation and examinations were consistent with GBS, we initiated intravenous immunoglobulin therapy. The next day, she also developed pain and muscle weakness of the right upper extremity. Three days after admission, respiratory depression progressed rapidly. Spinal MRI showed a mass extending from the level of C7-T3, with spinal cord compression. The patient underwent an emergency laminectomy with evacuation of hematoma, and was diagnosed with SSEH. Sixty days after admission, she was transferred to the rehabilitation hospital with severe neurologic sequelae of paralysis in both legs. CONCLUSION: SSEH might have severe consequences, including neurologic deficits and risk of death. This case report serves to raise the awareness of SSEH that mimics the initial presentation of GBS. PMID- 30471874 TI - Preparation of Si-SiOx nanoparticles from volatile residue produced by refining of silicon. AB - Residual Si was produced on a furnace wall when upgraded metallurgical grade Si was refined by electron beam melting. It was then recycled to prepare Si-SiOx nanoparticles with an average size of 100 nm by planetary ball milling. The obtained Si-SiOx nanoparticles mainly consist of amorphous Si, crystalline Si and amorphous SiOx, which was confirmed by XRD, FTIR, XPS and TEM. SiOx is mainly composed of SiO2 and SiO1.35. Distilled water used as a grinding aid not only enhances milling efficiency, but also plays a key role in obtaining SiOx. During refining of upgraded metallurgical grade Si, the deposition pattern of residual Si on furnace wall agrees with model of three-dimension growth. Growth of Si-SiOx nanoparticles is the mutual effect of distilled water and ball milling. Si-SiOx nanoparticles were doped into phenolic resin pyrolysis carbon as anode materials for lithium ion batteries, and 10% doping was observed to improve the specific capacity. After 500 cycles, specific capacity of delithiation remained around 550 mA h/g. It suggests the residual Si is a value-added by-product, and it can be recycled as anode materials for lithium ion batteries. PMID- 30471875 TI - [Hemorrhagic syndrome due to a heparin-like anticoagulant in a patient with systemic lupus erythematosus]. AB - INTRODUCTION: In systemic lupus erythematosus, hemostasis disorders are mainly thrombotic, but more rarely hemorrhagic. CASE REPORT: A 25-year-old man presented with a macrophagic activation syndrome revealing a systemic lupus erythematosus, secondarily complicated by a hemorrhagic syndrome ; biological investigations revealed an increase thrombin time and an activated partial thromboplastin time, normalized by protamin neutralization in vitro, thus confirming the presence of a heparin-like anticoagulant. The hemostasis balance normalized after the specific treatment of lupus. CONCLUSION: This rare anomaly of hemostasis balance has been described in blood cancers and solid cancers. This is the first description of a case associated with an autoimmune connective tissue disorder such as lupus. After one year of follow-up, no diagnosis of blood or solid cancer was made. PMID- 30471876 TI - Assessing Maternity Care Providers' Knowledge of the Management of Hepatitis B in Pregnancy. AB - OBJECTIVE: This study sought to evaluate maternity care providers' knowledge of the management of hepatitis B virus (HBV) in pregnancy. METHODS: A total of 71 maternity care providers from obstetrics, family practice, and midwifery who were practicing at a tertiary women's hospital in Canada completed a survey assessing their demographics and knowledge of the management of HBV in pregnancy. Descriptive statistics were used to assess the survey responses. RESULTS: Of 71 participants, 28% were obstetricians, 35% were family doctors, and 37% were midwives. Most participants (72%) had seen fewer than pregnant patients with HBV in the last 2 years. Correctly, 100% of participants indicated that all pregnant patients should be screened for HBV in pregnancy, and 99% indicated that infants should receive post-exposure prophylaxis. Incorrectly, 25.4% of participants indicated that pregnancy is a contraindication to HBV immunization, 90.1% indicated the recommended timeline for infant serological follow-up, and participants were largely divided on which investigations were needed for a pregnant patient with HBV. Only 23.9% of participants indicated the current recommended viral load for consideration of antiviral treatment in pregnancy. CONCLUSION: Maternity care providers in our cohort had a strong understanding of the fundamentals of caring for pregnant patients with HBV. Continuing education should emphasize the safety of HBV vaccination in pregnancy, novel investigations in pregnancy, current evidence on the use of antivirals in pregnancy, and appropriate timelines for infant serological follow-up. PMID- 30471877 TI - Effectiveness and Accuracy of Tests for Preterm Delivery in Symptomatic Women: A Systematic Review. AB - This study systematically reviewed evidence on the effectiveness and accuracy of predictive tests for preterm delivery among symptomatic women. The study included English-language systematic reviews (SRs) on any predictive test for preterm delivery among symptomatic women and primary studies for placental alpha microglobulin-1. PubMed, Wiley Cochrane Library, the Centre for Reviews and Dissemination Database, the National Guidelines Clearinghouse, and the TRIP database were searched for SRs, PubMed and PubMed Central via the Wiley Cochrane Library were searched for primary studies. One reviewer performed study selection, with input from a second reviewer when needed. One reviewer appraised study quality and extracted: study characteristics (i.e., country, funding source, study design [primary studies] or synthesis method [SRs], study appraisal method [SRs]), population characteristics, index test(s) and cut-off points used, comparator(s) or reference standard(s), and outcomes. A second reviewed a random 10% sample. The authors synthesized the findings narratively. Of 451 unique records, the review included 22 (17 SRs, five primary studies). For effectiveness, there was evidence for use of transvaginal sonographic cervical length assessment (15-25 mm cut point) in reducing incidence of preterm delivery at <37 weeks (relative risk 0.64; 95% CI 0.44-0.94, one SR of three trials; n = 287) but lack of support for cervicovaginal fetal fibronectin. In terms of accuracy, one high-quality study within a best-evidence SR showed that cervical length measurement was useful to predict delivery within 48 hours (LR+ 6.43, 95% CI 5.17-8.00; LR- 0.03, 95% CI 0.00-0.42; n = 510) and 7 days (LR+ 8.61, 95% CI 6.65-11.14; LR- 0.03, 95% CI 0.00-0.18; n = 510). Accuracy of placental alpha microglobulin-1 testing was not supported for most end points. In conclusion, some evidence supports the effectiveness of cervical length as a predictor of preterm delivery in symptomatic women. Evidence for most tests is limited in quality and quantity. PMID- 30471878 TI - Reduction of resource utilization in children with blunt solid organ injury. AB - BACKGROUND/PURPOSE: Nonoperative management of blunt solid organ injuries continues to progress and improve cost-effective utilization of resources while maximizing patient safety. The purpose of this study is to compare resource utilization and patient outcomes after changing admission criteria from a grade based protocol to one based on hemodynamic stability. METHODS: A retrospective review of isolated liver and spleen injuries was done using prospectively collected trauma registry data from 2013 to 2017. The 2 years preceding the change were compared to the 2 years after protocol change. All analyses were performed using SAS 9.4. RESULTS: There were 121 patients in the preprotocol cohort and 125 patients in the postprotocol cohort. Baseline demographics were similar along with injury mechanisms and severity. The ICU admission rate decreased from 40% to 22% (p = 0.002). There were no adverse events on the floor and no patient needed to be transferred to the ICU. CONCLUSIONS: A protocol for ICU admission based on physiologic derangement versus solely on radiologic grade significantly reduced admission rates to the ICU in children with solid organ injury. The protocol was safe and effectively reduced resource utilization. LEVEL OF EVIDENCE: Level II, prospective comparison study. PMID- 30471879 TI - The role of illness uncertainty in the relationship between disease knowledge and patient-reported outcomes among adolescents and adults with congenital heart disease. AB - BACKGROUND: Greater general disease knowledge predicts better patient-reported outcomes (PROs) among congenital heart disease (CHD) survivors, but higher illness uncertainty is associated with elevated emotional distress and poorer well-being among patients with chronic disease. OBJECTIVES: This study explored the relationship of illness uncertainty and disease knowledge with emotional distress and health-related quality of life (HRQoL) among patients with CHD. METHODS: Individuals with CHD (N = 169, ages 15-39) completed self-report measures of disease knowledge (general and risk-related), illness uncertainty, depressive and anxiety symptoms, and HRQoL. Pearson correlations and regressions analyses were utilized. RESULTS: Greater risk-related knowledge was associated with greater anxiety (b = .41, p = .03, 95% CI = [.04, .77]) and poorer emotional HRQoL (b = -.53, p = .03, 95% CI = [-1.02, -.05]) when illness uncertainty was higher. CONCLUSION: When individuals with CHD feel uncertain about their disease course and outcomes, knowledge about future cardiovascular risks may result in higher levels of distress. PMID- 30471881 TI - Reply to Jeremy Y.C. Teoh, Thomas R.W. Herrmann, and Marek Babjuk's Letter to the Editor re: Valeria Panebianco, Yoshifumi Narumi, Ersan Altun, et al. Multiparametric Magnetic Resonance Imaging for Bladder Cancer: Development of VI RADS (Vesical Imaging-Reporting and Data System). Eur Urol 2018;74:294-306. PMID- 30471880 TI - mTOR inhibitors may benefit kidney transplant recipients with mitochondrial diseases. AB - Mitochondrial diseases represent a significant clinical challenge. Substantial efforts have been devoted to identifying therapeutic strategies for mitochondrial disorders, but effective interventions have remained elusive. Recently, we reported attenuation of disease in a mouse model of the human mitochondrial disease Leigh syndrome through pharmacological inhibition of the mechanistic target of rapamycin (mTOR). The human mitochondrial disorder MELAS/MIDD (Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes/Maternally Inherited Diabetes and Deafness) shares many phenotypic characteristics with Leigh syndrome. MELAS/MIDD often leads to organ failure and transplantation and there are currently no effective treatments. To examine the therapeutic potential of mTOR inhibition in human mitochondrial disease, four kidney transplant recipients with MELAS/MIDD were switched from calcineurin inhibitors to mTOR inhibitors for immunosuppression. Primary fibroblast lines were generated from patient dermal biopsies and the impact of rapamycin was studied using cell-based end points. Metabolomic profiles of the four patients were obtained before and after the switch. pS6, a measure of mTOR signaling, was significantly increased in MELAS/MIDD cells compared to controls in the absence of treatment, demonstrating mTOR overactivation. Rapamycin rescued multiple deficits in cultured cells including mitochondrial morphology, mitochondrial membrane potential, and replicative capacity. Clinical measures of health and mitochondrial disease progression were improved in all four patients following the switch to an mTOR inhibitor. Metabolomic analysis was consistent with mitochondrial function improvement in all patients. PMID- 30471882 TI - Does the Evidence Support Adolescent Varicocelectomy? PMID- 30471883 TI - Reply to Ashwin Shinde, Richard Li, Arya Amini, and Scott Glaser's Letter to the Editor re: Liselotte M.S. Boeve, Maarten C.C.M. Hulshof, Andre N. Vis, et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2018.09.008: Future Steps for Definitive Therapy in Metastatic Prostate Cancer: Lessons from the HORRAD TrialUntil Randomised Controlled Trials Prove Different, Treat the Patient, Not His Imaging Results. PMID- 30471884 TI - In the Line of Fire: Should Urologists Stop Prescribing Fluoroquinolones as Default? AB - Fluoroquinolone use might be associated with serious side effects. Urologists should always consider these potential risks associated with fluoroquinolones and participate in a shared-decision making process with each patient. It is critical to strictly follow guidelines when prescribing fluoroquinolones. PMID- 30471885 TI - Re: Are We Improving Erectile Function Recovery After Radical Prostatectomy? Analysis of Patients Treated over the Last Decade. PMID- 30471886 TI - Re: Friederike Haidl, David Pfister, Axel Heidenreich. Re: Prostatic Artery Embolization in the Treatment of Localized Prostate Cancer: A Bicentric Prospective Proof-of-Concept Study of 12 Patients. Mordasini L, Hechelhammer L, Diener PA, et al. J Vasc Interv Radiol 2018;29:589-97. Eur Urol 2018;74:525-6: Could Morphologic Changes in Periprostatic Arteries Have an Influence on Prostatic Artery Embolization? PMID- 30471887 TI - Reply to Jie Gu, Dongjie Li, and Xiaobo Zhang's Letter to the Editor re: Guido Giusti, Silvia Proietti, Moises E. Rodriguez-Socarras, et al. Simultaneous Bilateral Endoscopic Surgery (SBES) for Patients with Bilateral Upper Tract Urolithiasis: Technique and Outcomes. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2018.06.034. PMID- 30471888 TI - Analysis of complications and clinical outcomes in the treatment of segmental tibial fractures according to the method of internal fixation. AB - BACKGROUND/OBJECTIVE: We compared and analysed not only the clinical and radiological results of surgery but also the complications according to the definitive fixation method. METHODS: We retrospectively reviewed the medical records and radiographs of all segmental tibial fracture patients treated with either intramedullary nailing or minimally invasive plate osteosynthesis between 2010 and 2017. We enrolled 69 patients. RESULTS: The patients' mean age was 48.6 years (25-74). Forty-nine patients had open fractures (Type I, 20; Type II, 9; Type III, 20) and six had acute compartment syndrome. The initial stabilisation method was intramedullary nailing in 28 patients (40.6%). The time to definitive fixation was longer in the minimally invasive plate osteosynthesis group (mean, 8.8 days; range, 0-27) than that in the intramedullary nailing group (mean, 3.9 days; range, 0-35), with a statistically significant difference (p = 0.001). Thirteen patients developed nonunion (five with minimally invasive plate osteosynthesis and eight with intramedullary nailing, p = 0.076). Complications were noted in 18 patients (26.1%), including five with infection. There was no significant difference in the clinical and radiological outcomes according to the definitive fixation method. A multivariate logistic regression analysis indicated that age (odds ratio, 1.112; 95% confidence interval, 1.022-1.210; p = 0.013) and smoking (odds ratio, 13.976; 95% confidence interval, 1.599-122.150; p = 0.017) correlated with the occurrence of complications. CONCLUSIONS: The results of our study suggest that if soft-tissue handling and restoration of bony alignment are successful, both intramedullary nailing and minimally invasive plate osteosynthesis will be effective treatment methods for segmental tibial fractures. PMID- 30471889 TI - In gratitude. PMID- 30471890 TI - Ignaz Semmelweis: the "Savior of Mothers": On the 200th anniversary of his birth. PMID- 30471891 TI - Placenta Accreta Spectrum. AB - Placenta accreta spectrum, formerly known as morbidly adherent placenta, refers to the range of pathologic adherence of the placenta, including placenta increta, placenta percreta, and placenta accreta. The most favored hypothesis regarding the etiology of placenta accreta spectrum is that a defect of the endometrial myometrial interface leads to a failure of normal decidualization in the area of a uterine scar, which allows abnormally deep placental anchoring villi and trophoblast infiltration. Maternal morbidity and mortality can occur because of severe and sometimes life-threatening hemorrhage, which often requires blood transfusion. Although ultrasound evaluation is important, the absence of ultrasound findings does not preclude a diagnosis of placenta accreta spectrum; thus, clinical risk factors remain equally important as predictors of placenta accreta spectrum by ultrasound findings. There are several risk factors for placenta accreta spectrum. The most common is a previous cesarean delivery, with the incidence of placenta accreta spectrum increasing with the number of prior cesarean deliveries. Antenatal diagnosis of placenta accreta spectrum is highly desirable because outcomes are optimized when delivery occurs at a level III or IV maternal care facility before the onset of labor or bleeding and with avoidance of placental disruption. The most generally accepted approach to placenta accreta spectrum is cesarean hysterectomy with the placenta left in situ after delivery of the fetus (attempts at placental removal are associated with significant risk of hemorrhage). Optimal management involves a standardized approach with a comprehensive multidisciplinary care team accustomed to management of placenta accreta spectrum. In addition, established infrastructure and strong nursing leadership accustomed to managing high-level postpartum hemorrhage should be in place, and access to a blood bank capable of employing massive transfusion protocols should help guide decisions about delivery location. PMID- 30471893 TI - Diagnostic histochemistry in neuropathology. AB - Neuropathologists have a long and storied history of utilizing histochemistry in the characterization and diagnosis of neurological diseases. This review considers stains that are used for the identification of neurons, neuritic processes and axons, myelin sheaths, neuroglial cells, and connective tissue in the nervous system. Rapid histochemical-smear methods for intraoperative diagnosis are also discussed, along with possible roles for lectin-histochemistry in diagnostic neuropathology. PMID- 30471892 TI - Should adult neurologists play a role in the management of the most common psychiatric comorbidities? Practical considerations. AB - Despite the high prevalence and negative impact of psychiatric comorbidities on the life of adults with epilepsy, significant unmet mental health care need exists because of a variety of factors, including poor access to mental health care providers. A potential solution to address access barriers is neurologist driven diagnosis and management of common psychiatric conditions in epilepsy, of which mood and anxiety disorders are the most common. In this manuscript, patient selection criteria and practical treatment strategies are outlined for common mood and anxiety disorders that can be safely managed by neurologists. This article is part of the Special Issue "Obstacles of Treatment of Psychiatric Comorbidities in Epilepsy". PMID- 30471894 TI - Sarcoidosis deaths in the United States: 1999-2016. AB - BACKGROUND: It has been over a decade since a comprehensive study has been published that has examined sarcoidosis deaths at the national level. The purpose of this study was to analyze sarcoidosis as the underlying cause of death using current national death certificate data. Results from this project can be used to evaluate and compare trends of sarcoidosis reported deaths across the U.S. METHODS: Mortality data from 1999 to 2016 were provided by the National Vital Statistics System (NVSS) with sarcoidosis (ICD-D86.X) as the underlying cause of death from all resident death certificates filed in the 50 states and the District of Columbia (DC). Data were analyzed using CDC WONDER, a web-based public health database and analysis tool. Queries were used to generate number of deaths, along with unadjusted and age-adjusted death rates with 95% confidence intervals and standard errors for groups including year, census region, gender, age group, race/ethnicity and state. Joinpoint regression analysis was used to test the significance of trends in race and gender-specific rates for the 1999 2016 study period. RESULTS: From 1999 to 2016, there were a total of 16,665 sarcoidosis reported deaths in the U.S. The overall age-adjusted mortality rate increased from 2.1 (deaths per 1,000,000) in 1999 to 3.1 in 2002, but then remained relatively stable thereafter until the end of the study period. Female deaths increased 32.0% (from 2.5 to 3.3 per 1,000,000), while male deaths increased 73.3% (from 1.5 to 2.6 deaths per 1,000,000). The highest age-adjusted death rates were among black females (17.0 deaths per 1,000,000), and black males (12.4 deaths per 1,000,000). At the regional level, the southern U.S. had the highest overall mean age-adjusted mortality rate (3.7 deaths per 1,000,000), while black females in the Midwest (18.7 per 1,000,000) had the highest race specific reported death rate. DISCUSSION: The detected increase in the total number of deaths and age-adjusted rates of sarcoidosis deaths in the U.S. is a serious health concern. Factors that contribute to sarcoidosis deaths remain uncertain and more epidemiological research studies are needed to compliment current bench science to explore and examine factors that contribute to this multifactorial, chronic disease. PMID- 30471896 TI - [The treatment of mucormycosis (zygomycosis) in the 21st century]. AB - Infections due to zygomycetes, caused by mucorales and entomophthorales, are characterized by angioinvasion and invasion of neighboring organs or structures. Mucorales most commonly cause rhinocerebral, pulmonary, cutaneous or disseminated infection and its spread is favored by several diseases (such as diabetes or chronic kidney disease) and risk factors (neutropenia, immunosuppression, iron overload). They have a high mortality rate, and the key to success in their treatment are early diagnosis, prompt administration of antifungal treatment, and extensive surgical debridement. Currently, isavuconazole constitutes an option for the treatment of those mucormycosis refractory to liposomal amphotericin B. Due to its pharmacokinetic and pharmacodynamic characteristics and its low toxicity, it is also the best choice for maintenance therapy. PMID- 30471895 TI - [Microbiological diagnosis of invasive mycosis]. AB - The prognosis of invasive fungal infections (IFI) depends on the speed of diagnosis and treatment. Conventional diagnostic methods are of low sensitivity, laborious and too slow, leading to the need for new, faster, and more efficient diagnostic strategies. There are several techniques for diagnosing a candidemia that are faster than the conventional blood culture (BC). Once yeast growth in BC is detected, species identification can be speeded up by mass spectrometry (30minutes), commercialised molecular techniques (60-80minutes) or fluorescent in situ hybridization (90minutes). The combined detection of biomarkers (antimicellium, mannan and anti-mannan or beta-glucan) has shown to be of greater use than their individual use. Commercialised nucleic acid amplification techniques (Septifast(r), T2Candida(r)) are very reliable alternatives to BC. The detection of the capsular antigen of Cryptococcus, by means of latex agglutination or immuno-chromatography, is a valuable technique for cryptococcosis diagnosis. Direct microscopic examination and culture of representative specimens is used for the conventional diagnosis of IFI by filamentous fungi. Detection of galactomannan and beta-glucan are considered diagnostic criteria for probable invasive aspergillosis and probable IFI, respectively, despite the lack of specificity of the latter. The detection of fungal volatile organic compounds in breath is an interesting diagnostic strategy in pulmonary infections. Although widely used, nucleic acid detection techniques are not considered diagnostic criteria for IFIs caused by moulds in consensus documents, due to their lack of standardisation. However, they are the only alternative to culture methods in invasive infections by Scedosporium/Lomentospora, Fusarium, zygomycetes, or dematiaceous fungi. PMID- 30471897 TI - Effects of Separation on Children's Neurodevelopment. PMID- 30471898 TI - An Unusual Case of Recurrent Facial Nerve Palsy. PMID- 30471899 TI - The road to long-term survival: Surgical approach and longitudinal treatments of long-term survivors of advanced-stage serous ovarian cancer. AB - OBJECTIVE: It is unclear if the types of surgical procedures performed on long term survivors (LTS) of high-grade serous ovarian carcinoma (HGSOC) contribute to prolonged survival. In this case-control study we review the surgical procedures performed on LTS and describe their individual longitudinal disease courses. METHODS: Women with FIGO stage III-IV high-grade serous cancer of the ovary, fallopian tube or peritoneum were selected from the University of Chicago ovarian cancer database. LTS were those surviving >7 years and controls were short-term survivors (STS) living 1-2 years. Patients with non-serous histology, low grade, and low malignant potential tumors were excluded. RESULTS: We identified 450 women with stage III/IV HGSOC including 45 LTS and 78 STS. LTS showed a trend towards lower disease burden, yet underwent more aggressive surgical treatment. Interestingly, only 15 LTS (34%) were debulked to microscopic disease and 9 LTS (21%) underwent suboptimal debulking. Two LTS (5%) recurred within 12 months. LTS had heterogeneous clinical courses with 13 (29%) never experiencing a recurrence with 143 months median follow-up and 32 (71%) experiencing a recurrence with 115 months median follow-up. Of the women who recurred, 19 (59%) underwent at least one surgery for recurrence. CONCLUSIONS: Aggressive surgical treatment intended to achieve microscopic disease, primary debulking surgery, preservation of sensitivity to chemotherapy, and recurrence amenable to secondary debulking are associated with long-term survival. However, clinicopathologic data are insufficient to predict long-term survival of HGSOC. Biologic characterization of these patient's tumors likely holds the key to understanding their unusually favorable courses. PMID- 30471900 TI - Beyond prophylaxis: Extended risk of venous thromboembolism following primary debulking surgery for ovarian cancer. AB - OBJECTIVE: To determine the incidence and risk factors for venous thromboembolism (VTE) within six months after primary debulking surgery (PDS) for epithelial ovarian cancer (EOC). METHODS: In a historical cohort, we estimated the cumulative incidence of clinically diagnosed VTE within 6 months among consecutive women who underwent PDS for EOC at a single institution from 1/1/2003 to 12/31/2011. We evaluated perioperative variables as potential risk factors of VTE within 6 months during the postoperative period using univariate and multivariable Cox proportional hazards models. RESULTS: Among 860 women without an immediate history (past 30 days) of a VTE, the cumulative incidence of VTE was 7.5% (95% CI, 5.7-9.3) by 30 days and 13.8% (95% CI, 11.4-16.2) by 6 months following surgery. Macroscopic residual disease (adjusted HR 1.99 [95% CI 1.35 2.94] vs microscopic), increasing estimated blood loss (1.25 [1.05-1.49] per doubling), longer hospital length of stay (3.00 [1.57-5.75]), and experiencing a cardiac event within 30 postoperative days (2.72 [1.55-4.80]) were independently associated with subsequent VTE within 6 months. In-hospital VTE prophylaxis included heterogeneous approaches; dual prophylaxis did not impact 30-day or 6 month VTE rates. CONCLUSIONS: VTE occurred in 1 in 7 women with EOC within 6 months of PDS-a substantial risk of VTE that extends into the adjuvant chemotherapy period. Novel prophylactic measures should be explored in these women at high risk for VTE. PMID- 30471901 TI - The effect of the transition period and postpartum body weight loss on macrophage infiltrates in bovine subcutaneous adipose tissue. AB - The transition period in dairy cattle is characterized by a rapid increase in metabolic demands due to the onset of lactation in parallel with a voluntary drop in dry matter intake, which slowly increases compared with the rapidly increasing milk production. The resulting deficit in energy intake is largely met by lipolysis of adipose tissue stores liberating nonesterified fatty acids (NEFA) as energy substrates to support milk production and for the synthesis of milk fat. Previous work in cattle and other species has documented an increase in adipose tissue macrophages (ATM) during periods of feed restriction and lipolysis; however, alterations in ATM during the transition period have only recently received interest because of the role that adipose tissue remodeling and inflammation may play during this time. The primary objective of this study was to evaluate the number of macrophages in subcutaneous adipose tissue from dairy cattle at multiple time points throughout the transition period. Secondary objectives included the evaluation for potential associations of ATM with changes in body condition score (BCS) and concentrations of circulating NEFA and beta hydroxybutyrate. Holstein cows (n = 25) were enrolled in the study 28 d before expected parturition and fed the same prepartum and postpartum rations for ad libitum consumption. On d 10 before expected parturition, and on d 4 and 21 after calving, subcutaneous adipose tissue biopsies were taken from the paralumbar fossa and preserved in formalin. Paraffin-embedded sections of tissue from each of the 25 cows at the 3 time points (total of 75 samples) were labeled with an immunohistochemical marker of macrophages, ionized calcium-binding adapter molecule 1 (Iba1, also known as allograft inflammatory factor 1). The number of Iba1-positive cells, the number of crown-like structures, and the number of immunopositive aggregates were enumerated in each sample. The number of Iba1 positive macrophages increased by 60 and 93% on d 4 and 21, respectively, when compared with the average prepartum number. Additionally, cows that lost >=0.50 points of BCS had a 57 and 52% higher number of ATM on d 4 and 21 postpartum, respectively, when compared with cows that lost <=0.25 points of BCS. No association was found between ATM numbers and NEFA and beta-hydroxybutyrate concentrations or milk production in early lactation. Cows experiencing a more pronounced decrease in BCS postpartum had the largest increase in adipose tissue macrophage counts, suggesting that a greater degree of adipose tissue remodeling during the period of greatest nutrient deficit may be associated with higher numbers of ATM. PMID- 30471902 TI - Expression patterns of hepatic genes involved in lipid metabolism in cows with subclinical or clinical ketosis. AB - Dairy cows with ketosis are characterized by high blood concentrations of ketone bodies and hepatic lipid metabolism disorder. The discrepancies in the abundance of mRNA encoding a variety of hepatic candidate genes in varying degrees of ketotic cows represent specific responses of the liver to the challenge of fatty acids and ketone bodies. Importantly, the expression disorder of hepatic genes involved in lipid metabolism plays a promoting role in the onset and progression of ketosis. Thus, the aim of this study was to investigate the expression patterns of genes involved in the hepatic fatty acids uptake, transport, activation, beta-oxidation, synthesis, and esterification in the cows with subclinical ketosis (SCK) or clinical ketosis (CK). Twenty-four cows were selected into control [n = 8, beta-hydroxybutyrate (BHB) <=0.6 mM], SCK (n = 8, 3.0 > BHB >= 1.2 mM), and CK (n = 8, BHB >=3.0 mM) groups according to the blood BHB concentration and clinical symptoms. The accumulation of hepatic lipid, as indicated by triglycerides (TG) contents and Oil Red O and hematoxylin and eosin staining, was pronouncedly exacerbated in the tCK group compared with the control and SCK groups. The hepatic mRNA expression of fatty acids transport and activation genes, liver fatty acid-binding protein (FABP1) and long-chain acyl CoA synthetase 1 (ACSL1), were both significantly higher in the SCK and CK groups than in the control group. The expression levels of peroxisome proliferator activated receptor alpha (PPARA) and its target genes, carnitine palmitoyltransferase 1A (CPT1A) and carnitine palmitoyltransferase 2 (CPT2), were significantly elevated in the SCK group but reduced in the CK group compared with control group. Furthermore, the gene expression level of sterol regulatory element-binding protein 1 (SREBP1) and the protein expression level of sterol regulatory element-binding protein 1c and its target genes, acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD1), and TG synthesis genes, diacylglycerol acyltransferase 1 (DGAT1) and diacylglycerol acyltransferase 2 (DGAT2), were significantly higher in the CK group relative to the control group. In short, the present data indicated that hepatic fatty acids uptake, transport, and activation are significantly increased in cows with SCK and CK, hepatic fatty acids beta-oxidation is significantly increased in SCK cows but markedly decreased in CK cows, and hepatic fatty acids and TG synthesis are significantly increased in CK cows, thereby inducing the hepatic steatosis in CK cows. PMID- 30471903 TI - Short communication: Validation of a test-day milk test for beta-hydroxybutyrate for identifying cows with hyperketonemia. AB - Subclinical ketosis is a common metabolic disorder affecting dairy cattle that results in a greater risk for the development of subsequent metabolic and infectious disease. Canwest Dairy Herd Improvement (DHI; Guelph, ON, Canada) has begun to use an infrared test (MilkoScan FT600, Foss Analytical A/S, Hillerod, Denmark) applied to metered composite milk samples to detect beta-hydroxybutyrate (BHB) levels as a herd surveillance test for hyperketonemia. However, the test has not been compared with the gold standard, serum BHB as determined in a reference diagnostic laboratory. The objective of this cross-sectional diagnostic accuracy study was to validate the DHI milk BHB test to identify cows with hyperketonemia as determined by quantification of BHB in serum. A total of 316 cows from 17 dairy herds in southwestern Ontario had a milk and blood sample taken. Milk was collected at a routine DHI test, and blood from the same cow was sampled within 24 h of the milk test. The BHB concentration in milk was determined using the DHI milk BHB test, and serum was sent to the Animal Health Laboratory at the University of Guelph (Guelph, ON, Canada). A nonparametric receiver operating characteristic curve was generated to compare DHI milk BHB concentrations with serum BHB concentrations. Overall, a total of 34 cows (11%) had a level of serum BHB >=1.2 mmol/L. The concentration of DHI milk BHB was moderately correlated with the concentration of serum BHB, yielding a coefficient of determination value of 0.61. The optimal cut point for determining hyperketonemia (>=1.2 mmol/L) on the DHI milk BHB test was >=0.14 mmol/L, yielding a sensitivity of 81% and specificity of 92%. The performance of the DHI milk BHB test varied depending on the days in milk (DIM) of the cows tested, with a higher specificity being found in cows that were <=25 DIM compared with cows tested >25 DIM. If the herd-level prevalence of hyperketonemia was >=14%, the DHI milk BHB test had an improved sensitivity when compared with a herd-level prevalence of <14%. This study demonstrates that the DHI milk BHB test is a reliable measure for evaluating hyperketonemia using routine DHI milk samples and could be used as a herd-level monitoring tool for ketosis when evaluating nutritional management or preventative medicine strategies. PMID- 30471904 TI - Evaluation of tetracycline in milk following extra-label administration of topical tetracycline for digital dermatitis in dairy cattle. AB - Digital dermatitis (DD) is a painful infectious foot lesion commonly treated topically with extra-label tetracycline. Our objectives were to determine the concentrations of tetracycline in milk and plasma and to calculate a withdrawal interval following topical application at various doses. Another objective was to evaluate agreement between tests for measuring tetracycline in milk. A randomized block trial was conducted on 2 farms, where 50 cows with active DD lesions on 2 feet were allocated to 1 of 5 treatment groups (n = 10 cows per group). Treatment groups consisted of topical applications of tetracycline hydrochloride, in a paste or as a powdered form under a bandage, at 3 different dosing levels (2, 5, and 25 g) on each of the 2 affected feet. Following enrollment and treatment, samples were collected from milk, teat skin, and blood every 8 to 24 h for up to 7 d postdosing. Concentrations of tetracycline were measured by liquid chromatography-mass spectrometry and milk samples were further tested using the Charm ROSA TET test (Charm Sciences Inc., Lawrence, MA). Tetracycline was present in milk, plasma, and teat skin from all treatment groups. Tetracycline concentrations varied depending on time of sampling, method of application, and dosing level. At 8 h post-treatment, 11% of cows had tetracycline present in milk higher than 100 ng/mL (ppb) but none higher than 300 ng/mL. The 25-g treatment group had the longest estimated withdrawal interval, the highest observed concentrations (210-244 ng/mL) of tetracycline present in milk, and the longest observed consecutive period of tetracycline presence (from 8 to 72 h) among all treatment groups. Compared with liquid chromatography-mass spectrometry, the Charm test had a sensitivity of 77 and 100% for measuring tetracycline in milk at >=30 and >=100 ng/mL, respectively. Post-treatment samples of the teat skin were taken from 15 cows on 6 occasions, and every cow had tetracycline present in at least 1 of those 6 samples. This confirms an association between topical DD treatment with tetracycline and contamination of the teat. A total of 22% of blood samples had detectable tetracycline, and the majority (63%) occurred at 8 h post-treatment. At 100 ng/mL, the estimated cow-level milk withdrawal interval ranged from 0 to 70 h. At 300 ng/mL, the estimated cow-level withdrawal interval ranged from 0 to 34 h, and was 0 h at the bulk tank level. We recommend that conservative measures be adopted after extra-label use of topical tetracycline for DD treatment, including using a low dose and strategic post-treatment testing for tetracycline-class drugs in milk. PMID- 30471905 TI - Formulation, process conditions, and biological evaluation of dairy mixed gels containing fava bean and milk proteins: Effect on protein retention in growing young rats. AB - Food formulation and process conditions can indirectly influence AA digestibility and bioavailability. Here we investigated the effects of formulation and process conditions used in the manufacture of novel blended dairy gels (called "mixed gels" here) containing fava bean (Vicia faba) globular proteins on both protein composition and metabolism when given to young rats. Three mixed dairy gels containing casein micelles and fava bean proteins were produced either by chemical acidification (A) with glucono-delta-lactone (GDL) or by lactic acid fermentation. Fermented gels containing casein and fava bean proteins were produced without (F) or with (FW) whey proteins. The AA composition of mixed gels was evaluated. The electrophoretic patterns of mixed protein gels analyzed by densitometry evidenced heat denaturation and aggregation via disulfide bonds of fava bean 11S legumin that could aggregate upon heating of the mixtures before gelation. Moreover, fermented gels showed no particular protein proteolysis compared with gel obtained by GDL-induced acidification. Kinetics of acidification were also evaluated. The pH decreased rapidly during gelation of GDL-induced acid gel compared with fermented gel. Freeze-dried F, A, and FW mixed gels were then fed to 30 young (1 mo old) male Wistar rats for 21 d (n = 10/diet). Fermented mixed gels significantly increased protein efficiency ratio (+58%) and lean mass (+26%), particularly muscle mass (+9%), and muscle protein content (+15%) compared with GDL-induced acid gel. Furthermore, F and FW formulas led to significantly higher apparent digestibility and true digestibility (+7%) than A formula. Blending fava bean, casein, and whey proteins in the fermented gel FW resulted in 10% higher leucine content and significantly higher protein retention in young rats (+7% and +28%) than the F and A mixed gels, respectively. Based on protein gain in young rats, the fermented fava bean, casein, and whey mixed proteins gel was the most promising candidate for further development of mixed protein gels with enhanced nutritional benefits. PMID- 30471906 TI - Efficient and accurate computation of base generation allele frequencies. AB - Allele frequencies are used for several aspects of genomic prediction, with the assumption that these are equal to the allele frequency in the base generation of the pedigree. The current standard method, however, calculates allele frequencies from the current genotyped population. We compared the current standard method with BLUP and general least squares (GLS) methods explicitly targeting the base population to determine whether there is a more accurate and still efficient method of calculating allele frequencies that better represents the base generation. A data set based on a typical dairy population was simulated for 325,266 animals; the last 100,078 animals in generations 9 to 12 of the population were genotyped, with 1,670 SNP markers. For the BLUP method, several SNP genotypes were analyzed with a multitrait model by assuming a heritability of 0.99 and no genetic correlation among them. This method was limited by the time required for each BLUP to converge (approximately 6 min per BLUP run of 15 SNP). The GLS method had 2 implementations. The first implementation, using imputation on the fly and multiplication of sparse matrices, was very efficient and required just 49 s and 1.3 GB of random access memory. The second implementation, using a dense full A22-1 matrix, was very inefficient and required more than 1 d of wall clock time and more than 118.2 GB of random access memory. When no selection was considered in the simulations, all methods predicted equally well. When selection was introduced, higher correlations between the estimated allele frequency and known base generation allele frequency were observed for BLUP (0.96 +/- 0.01) and GLS (0.97 +/- 0.01) compared with the current standard method (0.87 +/- 0.01). The GLS method decreased in accuracy when introducing incomplete pedigree, with 25% of sires in the first 5 generations randomly replaced as unknown to erroneously identify founder animals (0.93 +/- 0.01) and a further decrease for 8 generations (0.91 +/- 0.01). There was no change in accuracy when introducing 5% genotyping errors (0.97 +/- 0.01), 5% missing genotypes (0.97 +/- 0.01), or both 5% genotyping errors and missing genotypes (0.97 +/- 0.01). The GLS method provided the most accurate estimates of base generation allele frequency and was only slightly slower compared with the current method. The efficient implementation of the GLS method, therefore, is very well suited for practical application and is recommended for implementation. PMID- 30471907 TI - Association of peripartum plasma insulin concentration with milk production, colostrum insulin levels, and plasma metabolites of Holstein cows. AB - The main objective of this study was to assess associations between plasma insulin concentration around parturition and production in Holstein cows. Primiparous and multiparous cows (n = 267) were enrolled. Blood samples were collected within 12 h after parturition (d 0), and on d 3 and 10 after calving. In addition, blood samples were collected 7 d before (-7 d) the expected date of parturition and colostrum samples were collected within 8 h after parturition from a subset of cows to measure insulin concentration (n = 47). All samples were harvested from 0630 to 1100 h and were used to quantify insulin, nonesterified fatty acids (NEFA), and beta-hydroxybutyrate. The plasma concentrations of insulin on d -7 and 0 were not correlated with insulin levels in colostrum. Cows were grouped according to plasma insulin concentration based on the median as low insulin (L-INS) or high insulin (H-INS) on d 0 (median = 0.35 ng/mL; range 0.2 to 1.2), 3 (median = 0.32 ng/mL; range 0.2 to 1.6), and 10 (median = 0.30 ng/mL; range 0.2 to 0.8). We detected that cows in the L-INS group on d 0 (L-INS = 0.57 +/- 0.02; H-INS = 0.49 +/- 0.02 mmol/L), d 3 (L-INS = 0.56 +/- 0.02; H-INS = 0.49 +/- 0.02 mmol/L), and d 10 (L-INS = 0.61 +/- 0.03; H-INS = 0.55 +/- 0.03 mmol/L) had higher NEFA concentrations compared with cows in the H-INS group. Compared with H-INS cows, milk yield was higher for cows classified as L-INS on d 0 (L-INS = 40.75 +/- 0.69; H-INS = 38.41 +/- 0.64 kg) and d 10 (L-INS = 40.95 +/- 0.74; H INS = 38.66 +/- 0.64 kg). Moreover, fat-corrected milk was higher for cows classified as L-INS on d 0 (L-INS = 40.59 +/- 2.36; H-INS = 37.73 +/- 2.31 kg) and d 10 (L-INS = 41.00 +/- 2.42; H-INS = 38.65 +/- 2.28 kg) compared with H-INS cows, and energy-corrected milk was higher for L-INS cows compared with H-INS cows regardless of the day (d 0, L-INS = 44.50 +/- 0.70 vs. H-INS = 41.67 +/- 0.64 kg; d 3, L-INS = 43.65 +/- 0.74 vs. H-INS = 40.88 +/- 0.72 kg; d 10, L-INS = 44.09 +/- 0.73 vs. H-INS = 40.55 +/- 0.68 kg). We conclude that low plasma insulin concentration during early lactation is associated with higher milk yield in the long term. PMID- 30471908 TI - Evaluation of a filter system to harvest plasma for identification of failure of passive transfer in newborn calves. AB - The objective of this study was to evaluate a filter system to harvest plasma to assess failure of passive transfer (FPT) in newborn calves. Blood samples (n = 227) for serum and plasma harvesting were collected via jugular vein puncture from Holstein calves aged 1 to 7 d from 4 commercial dairy herds in Northeast Germany. Serum IgG concentrations were determined using a sandwich ELISA. Failure of passive transfer was defined as IgG concentrations <10 mg/mL and used as a gold standard. One handheld optical refractometer (Euromex Holland, Arnhem, the Netherlands) and 2 digital Brix refractometers (device 1: HI 96801 digital refractometer, Hanna Instruments, Woonsocket, RI; device 2: Misco PA201, Misco, Solon, OH) were used to analyze total proteins in serum or plasma. The colostrum uptake of the calf can thus be monitored and calves with FPT can be identified. Serum was obtained through centrifugation. Plasma was obtained through either a filter system or centrifugation. For plasma filtration, approximately 2 mL of lithium heparin blood was injected into the inlet reservoir of a plasma filter (2 Drop-Filter, Pharmadoc, Lubeck, Germany) using a disposable syringe. Receiver operating characteristic curve analyses were used to determine optimum thresholds for each of the 3 devices using different media. Sixty-seven (30%) calves had FPT. For the handheld optical refractometer, the optimum threshold was 5.6 g/dL [sensitivity 70.1%; specificity 80.0%; positive predictive value (PPV) 60.1%; negative predictive value (NPV) 86.2%; area under the curve (AUC) 0.85] using serum. For centrifuged plasma, the optimum threshold was 6.3 g/dL (sensitivity 82.1%; specificity 68.1%; PPV 52.5%; NPV 89.9%; AUC 0.84), and for filtered plasma, the threshold was 6.0 g/dL (sensitivity 56.7%; specificity 90.0%; PPV 70.9%; NPV 82.9%; AUC 0.80). For device 1, the optimum threshold was 8.9% Brix (sensitivity 82.1%; specificity 63.8%; PPV 48.7%; NPV 89.5%; AUC 0.81), 9.4% Brix (sensitivity 76.1%; specificity 73.7%; PPV 55.4%; NPV 87.8%; AUC 0.80), using serum and centrifuged plasma, respectively. For device 2, the optimum threshold was 8.7% Brix (sensitivity 74.6%; specificity 76.2%; PPV 57.4%; NPV 87.5%; AUC 0.83), 9.5% Brix (sensitivity 80.6%; specificity 70.6%; PPV 54.0%; NPV 89.5%; AUC 0.83), and 9.2% Brix (sensitivity 58.2%; specificity 87.5%; PPV 66.6%; NPV 83.0%; AUC 0.80) using serum, centrifuged plasma, and filtered plasma, respectively. Based on the AUC, the 3 devices yielded comparable test characteristics to identify calves with FPT. In conclusion, a filter system can be used to facilitate the evaluation of FPT as a point of care technique in calves without the need for serum centrifugation. PMID- 30471909 TI - Hypertonic milk replacers increase gastrointestinal permeability in healthy dairy calves. AB - Hypertonic milk replacers are commonly used in animal production systems and their effect on the gastrointestinal system of young animals is insufficiently studied. Total lactose inclusion or its partial replacement with dextrose increases intestinal osmotic pressure, which may compromise gastrointestinal barrier function. In this experiment, we investigated the effect of increased osmolality of calf milk replacer (CMR) on gastrointestinal permeability in 30 Holstein Friesian (n = 17) or crossbred (n = 13) bull calves. The osmolality of CMR increased as result of a gradual replacement of lactose by monosaccharides (dextrose and galactose). Calves were acquired from dairy farms that followed a standardized protocol for colostrum management, including 3 feedings of colostrum in the first 24 h. Calves were then transported to the research facility between 0 and 3 d of age, fed a milk replacer with 0% dextrose twice daily for the first 2 wk of age, and subsequently exposed to their respective treatments from 3 until 7 wk of age. Meal size was 3.2 L at 3 wk of age and increased to 3.5 L at 7 wk of age. No solids were provided throughout the study and calves had ad libitum access to water. Treatments included 4 levels of dextrose inclusion (replacing lactose): 0% (L1, n = 5), 13.3% (L2, n = 5), 26.7% (L3, n = 5), and 40% (L4, n = 5) and an additional treatment (G+D, n = 10) that included 20% galactose and 20% dextrose and matched the galactose supply of L1 and the osmolality of L4. Carbohydrates were exchanged based on hexose equivalents. Across treatments, the estimated osmolality ranged from 439 (L1) to 611 mOsm/kg (L4 and G+D). Gastrointestinal permeability was assessed by fractional urinary recovery of indigestible markers (lactulose, d-mannitol, and Cr-EDTA) delivered as a single dose at 3 and 7 wk of age. Marker recoveries were expressed as percentage of oral dose and assessed in 6-h and 24-h quantitative urinary collections. Increasing the osmolality of the CMR linearly increased urinary Cr-EDTA and lactulose recoveries at 3 and 7 wk of age. Lactulose and Cr-EDTA recoveries did not differ between G+D and L4, suggesting that the source of monosaccharide (dextrose and galactose) in CMR had no effect on gastrointestinal permeability. The observed increase in gastrointestinal permeability to large molecules (Cr-EDTA and lactulose) with increased osmolality suggests that hypertonic CMR may compromise gastrointestinal barrier function. PMID- 30471910 TI - Probiotic Lactobacillus gasseri SBT2055 improves insulin secretion in a diabetic rat model. AB - The probiotic Lactobacillus gasseri SBT2055 (LG2055) has a protective effect against metabolic syndrome in rats and humans. Metabolic syndrome increases the risk of type 2 diabetes mellitus. In this study, Goto-Kakizaki rats were used as a diabetic model and fed diets containing LG2055-fermented or nonfermented skim milk for 4 wk. Indices of diabetes such as blood glucose levels, serum glucagon levels, plasma levels of insulin, C-peptide, and glucagon-like peptide-1, tissue glycogen contents, and pancreatic mRNA levels were measured. The plasma C-peptide levels and pancreatic mRNA levels of insulin genes (Ins1 and Ins2) and Pdx1 (a transcriptional factor of insulin genes) were increased in LG2055 diet-fed rats. The increase in insulin secretion corresponded to an improvement in serum and pancreatic inflammatory status, associated with decreases in serum levels of serum amyloid P and pancreatic levels of granulocyte colony-stimulating factor. Insulin resistance in Goto-Kakizaki rats was ameliorated by increased glycogen storage in the liver and quadriceps femoris muscles and decreased serum free fatty acid levels. This improvement may be related to the increased cecal production of short-chain fatty acids. In conclusion, dietary LG2055 improved insulin secretion in diabetic rats by improving the inflammatory status in the pancreas and serum. PMID- 30471911 TI - The effects of relative gain and age on peripheral blood mononuclear cell mitochondrial enzyme activity in preweaned Holstein and Jersey calves. AB - Mitochondria are central to metabolism, nutrition, and health, but many factors can influence their efficiency. The objectives of this study were to determine if the mitochondrial enzyme activities of citrate synthase, complex I, complex IV, and complex V from peripheral blood mononuclear cells in Holstein and Jersey dairy calves were affected by age or relative gain as a percent of initial weight. Twenty-three Holstein and 23 Jersey heifer calves were enrolled between 3 and 6 d of age and whole blood samples were collected via jugular venipuncture at 1, 2, and 8 wk of age. Crude mitochondrial extracts were obtained from the peripheral blood mononuclear cell fraction at each time point and subsequently assayed for enzymatic activity. Age-dependent changes in activity were observed in complex V for both breeds. In Jersey calves complex IV and citrate synthase activity differed with age. Complex I activity was greater for high relative gain Jerseys and tended to be greater for high relative gain Holstein calves. Holstein calves had greater incidence of scours compared with Jersey calves, and in both breeds scouring calves exhibited greater complex V activity compared with those without scours. These data suggest that age and immune challenge in the form of scours affect mitochondrial complex V activity. Additionally, complex I activity may serve as a marker for calf growth potential because it was influenced by relative gain and not age. PMID- 30471912 TI - Short communication: Milk urea nitrogen as a predictor of urinary nitrogen and urea nitrogen excretions of late-lactation dairy cows fed nitrogen-limiting diets. AB - Our objectives were to assess the relationships between milk urea N (MUN), serum urea N (SUN), urine N (UN), and urinary urea N (UUN) in late-lactation cows fed N limiting diets and compare these relationships with those previously established. Data were from a pen-based study in which 128 Holstein cows had been assigned to 1 of 16 pens in a randomized complete block design to assess the effects of diets containing 16.2, 14.4, 13.1, and 11.8% crude protein (CP, dry matter basis) during a 12-wk period. At least half of the cows in each pen were randomly selected to collect pen-level samples of serum and urine in wk 3, 7, and 11, when wk in lactation averaged 35, 39, and 43, respectively. A mixed model was developed to study the relationship of MUN with SUN, UN, and UUN. Week of lactation did not affect the relation between MUN and SUN across dietary treatments. However, we found a week * MUN interaction, suggesting that between wk 35 and 43 of lactation, UN excretion decreased from 89 to 73 g/d (-17 g/d) when MUN was 6.0 mg/dL (11.8% dietary CP) but increased from 142 to 149 g/d (+7 g/d) when MUN was 13.3 mg/dL (16.2% dietary CP). These effects were essentially due to changes in UUN excretion, which declined from 54 to 37 g/d (-17 g/d) and increased from 112 to 117 g/d (+5 g/d) when MUN was 6.0 and 13.3 mg/dL, respectively. When MUN was 11.2 mg/dL (15% dietary CP), UN and UUN excretions remained constant over time. Based on root mean squared prediction error and the concordance correlation coefficient, these data did not conform to most previously published prediction equations because of both mean and slope biases. The discrepancy could have resulted from difference in study design (cow vs. pen as experimental unit), dietary treatments (energy vs. N-limiting diets), frequency of measurement and duration of adaptation period (single measurement after 1 to 3 wk of adaptation vs. repeated measurements over a 12-wk period), method for determining urine volume (total collection vs. spot sampling), and the assay used to measure MUN. However, our data captured changes in kidney physiology that warrant further studies of long-term renal adaptation to N limiting diets. PMID- 30471913 TI - Genetics and genomics of reproductive disorders in Canadian Holstein cattle. AB - In Canada, reproductive disorders known to affect the profitability of dairy cattle herds have been recorded by producers on a voluntary basis since 2007. Previous studies have shown the feasibility of using producer-recorded health data for genetic evaluations. Despite low heritability estimates and limited availability of phenotypic information, sufficient genetic variation has been observed for those traits to indicate that genetic progress, although slow, can be achieved. Pedigree- and genomic-based analyses were performed on producer recorded health data of reproductive disorders, including retained placenta (RETP), metritis (METR), and cystic ovaries (CYST) using traditional BLUP and single-step genomic BLUP. Genome-wide association studies and functional analyses were carried out to unravel significant genomic regions and biological pathways, and to better understand the genetic mechanisms underlying RETP, METR, and CYST. Heritability estimates (posterior standard deviation in parentheses) were 0.02 (0.003), 0.01 (0.004), and 0.02 (0.003) for CYST, METR, and RETP, respectively. A moderate to strong genetic correlation of 0.69 (0.102) was found between METR and RETP. Averaged over all traits, sire proof reliabilities increased by approximately 11 percentage points with the incorporation of genomic data using a multiple-trait linear model. Biological pathways and associated genes underlying the studied traits were identified and will contribute to a better understanding of the biology of these 3 health disorders in dairy cattle. PMID- 30471915 TI - Symposium review: Intravital imaging of the lactating mammary gland in live mice reveals novel aspects of milk-lipid secretion. AB - Milk fat comprises membrane-coated droplets of neutral lipid, which constitute the predominant source of lipids for survival of the suckling neonate. From the perspective of the dairy industry, they are the basis for the manufacture of butter and essential ingredients in the production of cheese, yogurt, and specialty dairy produce. To provide mechanistic insight into the assembly and secretion of lipid droplets during lactation, we developed novel intravital imaging techniques using transgenic mice, which express fluorescently tagged marker proteins. The number 4 mammary glands were surgically prepared under a deep plane of anesthesia and the exposed glands positioned as a skin flap with intact vascular supply on the stage of a laser-scanning confocal microscope. Lipid droplets were stained by prior exposure of the glands to hydrophobic fluorescent BODIPY (boron-dipyrromethene) dyes and their formation and secretion monitored by time-lapse subcellular microscopy over periods of 1 to 2 h. Droplets were transported to the cell apex by directed (superdiffusive) motion at relatively slow and intermittent rates (0-2 um/min). Regardless of size, droplets grew by numerous fusion events during transport and as they were budding from the cell enveloped by apical membranes. Surprisingly, droplet secretion was not constitutive but required an injection of oxytocin to induce contraction of the myoepithelium with subsequent release of droplets into luminal spaces. These novel results are discussed in the context of the current paradigm for milk fat synthesis and secretion and as a template for future innovations in the dairy industry. PMID- 30471914 TI - Methyl donor supplementation suppresses the progression of liver lipid accumulation while modifying the plasma triacylglycerol lipidome in periparturient Holstein dairy cows. AB - Co-supplementation of methyl donors may lower hepatic lipid content in transition cows. To define the ability of methyl donor supplementation (MDS) to reduce hepatic lipid content and modify the plasma lipidome, 30 multiparous Holstein cows (2.04 +/- 0.69 lactations; 689 +/- 58 kg of body weight; 3.48 +/- 0.10 units of body condition score) were fed a ration with or without rumen-protected methyl donors (22 g/d of Met, 10 g/d of choline chloride, 3 g/d of betaine, 0.96 g/d of riboflavin, and 14 mg/d of vitamin B12) from d -28 before expected calving through d 14 postpartum. Cows were randomly enrolled based on predefined selection criteria (body condition score and parity). Base diets without MDS were formulated for gestation (15.4% crude protein with a predicted Lys-to-Met ratio of 3.25; 1.44 Mcal of net energy for lactation/kg of dry matter) and lactation (16.6% crude protein with a predicted Lys-to-Met ratio of 3.36; 1.64 Mcal of net energy for lactation/kg of dry matter). Blood sampling occurred from d -28 relative to expected calving through d 14 postpartum. Liver tissue was biopsied at d -28 relative to expected calving and on d 5 and 14 postpartum. In addition to routine analyses, serum AA concentrations on d 10 and 12 were quantified using mass spectrometry. Plasma triacylglycerol (TAG) and cholesteryl esters (CE) were qualitatively measured using time-of-flight mass spectrometry. Data were analyzed using a mixed model with repeated measures. Dry matter intake and milk yield were not modified by MDS. The transition from d -28 relative to expected parturition to d 14 postpartum was characterized by increased plasma fatty acid (0.15 to 0.71 mmol/L) and beta-hydroxybutyrate (0.34 to 0.43 mmol/L) levels and liver lipid content (3.91 to 9.16%). Methyl donor supplementation increased the serum Met level by 26% and decreased the serum Lys-to-Met ratio by 21% on d 10 and 12, respectively. Moreover, the increase in hepatic lipid content from d 5 through 14 postpartum was suppressed with MDS relative to control (3.57 vs. -0.29%). Dietary MDS modified the TAG and CE lipidome. For example, MDS increased plasma TAG 46:3 (carbon number:double bond) by 116% relative to control cows on d 5 postpartum. Moreover, MDS tended to increase plasma CE 34:6. In contrast, MDS lowered plasma TAG 54:8 by 39% relative to control cows on d 5 postpartum. We concluded that in the absence of gains in dry matter intake and milk and milk protein yields, dietary MDS slows the progression of hepatic lipid accumulation and modifies the plasma TAG lipidome in transition cows. PMID- 30471916 TI - Interactome and Proteome Dynamics Uncover Immune Modulatory Associations of the Pathogen Sensing Factor cGAS. AB - Viral DNA sensing is an essential component of the mammalian innate immune response. Upon binding viral DNA, the cyclic-GMP-AMP synthase (cGAS) catalyzes the production of cyclic dinucleotides to induce type I interferons. However, little is known about how cGAS is homeostatically maintained or regulated upon infection. Here, we define cytoplasmic cGAS interactions with cellular and viral proteins upon herpes simplex virus type 1 (HSV-1) infection in primary human fibroblasts. We compare several HSV-1 strains (wild-type, d109, d106) that induce cytokine responses and apoptosis and place cGAS interactions in the context of temporal proteome alterations using isobaric-labeling mass spectrometry. Follow up analyses establish a functional interaction between cGAS and 2'-5' oligoadenylate synthase-like protein OASL. The OAS-like domain interacts with the cGAS Mab21 domain, while the OASL ubiquitin-like domain further inhibits cGAS mediated interferon response. Our findings explain how cGAS may be inactively maintained in cellular homeostasis, with OASL functioning as a negative feedback loop for cytokine induction. PMID- 30471917 TI - The Heart-Lung Dilemma in COPD: A Tale of Two Cities. PMID- 30471918 TI - Atypical Mycobacteria in Bronchiectasis. When do we Treat it? PMID- 30471919 TI - Do daily dynamics in rumination and affect predict depressive symptoms and trait rumination? An experience sampling study. AB - BACKGROUND AND OBJECTIVES: Rumination has been shown to prospectively predict the onset of depression. However, it is unclear how rumination and affect in daily life influence the development of depressive symptoms. The present study examined whether the structure of dynamics in rumination and affect could prospectively predict depressive symptoms and trait rumination in an undergraduate sample (n = 63). METHODS: The main index used was entropy, which reflects the instability of a system's structure. Momentary rumination and affect were assessed eight times per day for a period of seven days. Additionally, depressive symptoms and trait rumination were measured at the beginning of the experiment and at six weeks follow-up. RESULTS: The results showed that entropy significantly predicted trait rumination at follow-up (and depressive symptoms at trend level) while taking into account baseline depressive symptoms and trait rumination. LIMITATIONS: The follow-up measurements conducted six weeks after the baseline were relatively short. Further research may test the predictive effect of the structure over a longer period and confirm its effect by using different indices that describe the structure. CONCLUSIONS: These findings indicate that examining the structure of the dynamics in momentary rumination and affect holds promise for understanding the risk for depression. PMID- 30471920 TI - Crosstalk between Estrogen Signaling and Breast Cancer Metabolism. AB - Estrogens and estrogen receptors (ERs) regulate metabolism in both normal physiology and in disease. The metabolic characteristics of intrinsic breast cancer subtypes change based on their ER expression. Crosstalk between estrogen signaling elements and several key metabolic regulators alters metabolism in breast cancer cells, and enables tumors to rewire their metabolism to adapt to poor perfusion, transient nutrient deprivation, and increased acidity. This leads to the selection of drug-resistant and metastatic clones. In this review we discuss studies revealing the role of estrogen signaling elements in drug resistance development and metabolic adaptation during breast cancer progression. PMID- 30471921 TI - MT1-MMP Binds Membranes by Opposite Tips of Its beta Propeller to Position It for Pericellular Proteolysis. AB - Critical to migration of tumor cells and endothelial cells is the proteolytic attack of membrane type 1 matrix metalloproteinase (MT1-MMP) upon collagen, growth factors, and receptors at cell surfaces. Lipid bilayer interactions of the substrate-binding hemopexin-like (HPX) domain of MT1-MMP were investigated by paramagnetic nuclear magnetic resonance relaxation enhancements (PREs), fluorescence, and mutagenesis. The HPX domain binds bilayers by blades II and IV on opposite sides of its beta propeller fold. The EPGYPK sequence protruding from both blades inserts among phospholipid head groups in PRE-restrained molecular dynamics simulations. Bilayer binding to either blade II or IV exposes the CD44 binding site in blade I. Bilayer association with blade IV allows the collagen triple helix to bind without obstruction. Indeed, vesicles enhance proteolysis of collagen triple-helical substrates by the ectodomain of MT1-MMP. Hypothesized side-by-side MT1-MMP homodimerization would allow binding of bilayers, collagen, CD44, and head-to-tail oligomerization. PMID- 30471922 TI - Structural Survey of Broadly Neutralizing Antibodies Targeting the HIV-1 Env Trimer Delineates Epitope Categories and Characteristics of Recognition. AB - Over the past decade, structures have been determined for broadly neutralizing antibodies that recognize all major exposed surfaces of the prefusion-closed HIV 1-envelope (Env) trimer. To understand this recognition and its implications, we analyzed 206 antibody-HIV-1 Env structures from the Protein Data Bank with resolution suitable to define interaction chemistries and measured antibody neutralization on a 208-strain panel. Those with >25% breadth segregated into almost two dozen classes based on ontogeny and recognition and into six epitope categories based on recognized Env residues. For paratope, the number of protruding loops and level of somatic hypermutation were significantly higher for broad HIV-1 neutralizing antibodies than for a comparison set of non-HIV-1 antibodies (p < 0.0001). For epitope, the number of independent sequence segments was higher (p < 0.0001), as well as the glycan component surface area (p = 0.0005). The unusual characteristics of epitope and paratope delineated here are likely to reflect respectively virus-immune evasion and antibody-recognition solutions that allow effective neutralization of HIV-1. PMID- 30471923 TI - Mechanism of Enhanced Immature Dengue Virus Attachment to Endosomal Membrane Induced by prM Antibody. AB - Dengue virus (DENV) particles are released from cells in different maturation states. Fully immature DENV (immDENV) is generally non-infectious, but can become infectious when complexed with anti-precursor membrane (prM) protein antibodies. It is unknown how anti-prM antibody-coated particles can undergo membrane fusion since the prM caps the envelope (E) protein fusion loop. Here, we determined cryoelectron microscopy (cryo-EM) maps of the immDENV:anti-prM complex at different pH values, mimicking the extracellular (pH 8.0) or endosomal (pH 5.0) environments. At pH 5.0, there are two structural classes with fewer antibodies bound than at pH 8.0. These classes may represent different maturation states. Molecular simulations, together with the measured high-affinity pr:antibody interaction (versus the weak pr:E interaction) and also the low pH cryo-EM structures, suggest how antibody:pr complex can dislodge from the E protein at low pH. This exposes the E protein fusion loop enhancing virus interaction with endosomes. PMID- 30471924 TI - The Preprotein Binding Domain of SecA Displays Intrinsic Rotational Dynamics. AB - SecA converts ATP energy to protein translocation work. Together with the membrane-embedded SecY channel it forms the bacterial protein translocase. How secretory proteins bind to SecA and drive conformational cascades to promote their secretion remains unknown. To address this, we focus on the preprotein binding domain (PBD) of SecA. PBD crystalizes in three distinct states, swiveling around its narrow stem. Here, we examined whether PBD displays intrinsic dynamics in solution using single-molecule Forster resonance energy transfer (smFRET). Unique cysteinyl pairs on PBD and apposed domains were labeled with donor/acceptor dyes. Derivatives were analyzed using pulsed interleaved excitation and multi-parameter fluorescence detection. The PBD undergoes significant rotational motions, occupying at least three distinct states in dimeric and four in monomeric soluble SecA. Nucleotides do not affect smFRET detectable PBD dynamics. These findings lay the foundations for single-molecule dissection of translocase mechanics and suggest models for possible PBD involvement during catalysis. PMID- 30471925 TI - A cadaveric model of anterior compartment leg syndrome: Subcutaneous minimally invasive fasciotomy versus open fasciotomy. AB - OBJECTIVE: Because of disabling sequelae of open fasciotomy in anterior compartment syndrome (ACS) of the leg, we wanted to describe and validate a cadaveric model of ACS. We hypothesized that, first, anterior compartment syndrome (ACS) could be reproduced in cadaveric leg and, second, fasciotomy without complete skin incision could lower the intramuscular pressure (IMP) in an equivalent range to complete dermatofasciotomy. MATERIALS AND METHODS: Lower limb ACS was reproduced by progressive injection of physiologic serum in the anterior compartment of 23 fresh frozen cadaveric legs with monitoring of IMP, in order to reach a maximal stabilised IMP higher than 30mmHg. Subcutaneous minimally invasive fasciotomy was performed on 14 legs through 5 transversal mini-incisions of the skin (2cm) along the axis from the tibial tuberosity to the posterior aspect of the lateral malleolus. Standard open fasciotomy of the anterior compartment was performed on the remaining 9 legs as control. IMP was measured after the skin incisions and after every fasciotomy through skin incisions in the first group and after skin and fascia incisions in the control group. RESULTS: A maximal IMP of 43+/-2mmHg was obtained by injection of 177+/-9ml physiologic serum into the anterior compartment of the leg. In the control open fasciotomy group, the skin incision alone did not lower IMP significantly, whereas fasciotomy lowered IMP to 10+/-1mmHg, which is statistically different from maximal IMP (p<0.001). In the subcutaneous fasciotomy group, complete fasciotomy lowered significantly the IMP to 11+/-4mmHg (p<0.001), without statistical difference with the control group. DISCUSSION: This cadaveric model is effective to reproduce the hyperpressure encountered in ACS. In this model, IMP release after fasciotomy is as efficient through minimally invasive subcutaneous incision as with control open fasciotomy. This in vitro technique appears as an attractive alternative treatment in anterior compartment syndrome of the leg. It should be tested in the other compartments of the leg and its in vivo feasibility in acute conditions has to be clarified. LEVEL OF EVIDENCE: III, control laboratory study. PMID- 30471927 TI - A long biliopancreatic and short alimentary limb results in more weight loss in revisional RYGB surgery. Outcomes of the randomized controlled ELEGANCE REDO trial. AB - BACKGROUND: For a number of years the laparoscopic adjustable gastric band has been one of the leading bariatric procedures with good short-term outcomes. However, inadequate weight loss, weight regain, and other band-related complications in the long term led to an increase in revisional Roux-en-Y gastric bypass (RYGB) procedures. Lengthening the biliopancreatic limb, a relatively simple and safe adjustment of the standard technique, could improve the results of the revisional procedure. OBJECTIVES: The aim of this randomized controlled trial was to evaluate the effect of a long biliopancreatic limb RYGB (LBP-GB) and standard RYGB (S-GB) as revisional procedure after laparoscopic adjustable gastric band. SETTING: General hospital specialized in bariatric surgery METHODS: One hundred forty-six patients were randomized in 2 groups; 73 patients underwent an S-GB (alimentary/biliopancreatic limb 150/75 cm), and 73 patients underwent LBP-GB (alimentary/biliopancreatic limb 75/150). Weight loss, remission of co morbidities, quality of life, and complications were assessed during a period of 4 years. RESULTS: Baseline characteristics between the groups were comparable. At 48 months the follow-up rate was 95%. Mean total weight loss after 24 months was 27% for LBP-GB versus 22% S-GB (P = .015); mean total weight loss after 48 months was 23% and 18%, respectively (P = .036). No significant differences in other parameters were found between the groups. CONCLUSIONS: A LBP-GB as revisional procedure after a failing laparoscopic adjustable gastric band improves short- and long-term total weight loss compared with an S-GB. Together with future modifications this technically simple adjustment of the RYGB could significantly improve disappointing results after revisional surgery. PMID- 30471926 TI - Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes. AB - Microglia, the resident immune cells of the brain, rapidly change states in response to their environment, but we lack molecular and functional signatures of different microglial populations. Here, we analyzed the RNA expression patterns of more than 76,000 individual microglia in mice during development, in old age, and after brain injury. Our analysis uncovered at least nine transcriptionally distinct microglial states, which expressed unique sets of genes and were localized in the brain using specific markers. The greatest microglial heterogeneity was found at young ages; however, several states-including chemokine-enriched inflammatory microglia-persisted throughout the lifespan or increased in the aged brain. Multiple reactive microglial subtypes were also found following demyelinating injury in mice, at least one of which was also found in human multiple sclerosis lesions. These distinct microglia signatures can be used to better understand microglia function and to identify and manipulate specific subpopulations in health and disease. PMID- 30471928 TI - Preoperative liver shrinking diet for bariatric surgery may impact wound healing: a randomized controlled trial. AB - BACKGROUND: In bariatric surgery, preoperative very low-calorie diets (VLCD) may better meet the technical demands of surgery by shrinking the liver. However, diets may affect tissue healing and influence bowel anastomosis in an as-yet undefined manner. OBJECTIVE: This randomized controlled trial aimed to examine the effect on collagen deposition in wounds in patients on a 4-week VLCD before laparoscopic gastric bypass. SETTING: University hospital. METHODS: The trial was undertaken in patients undergoing laparoscopic Roux-en-Y gastric bypass, with a control group (n = 10) on normal diet and an intervention group (n = 10) on VLCD (800 kcal) for 4 weeks. The primary outcome measured was expression of collagen I and III in skin wounds, with biopsies taken before and after the diet and 7 days postoperatively as a surrogate of anastomotic healing. Secondary outcome measures included liver volume and fibrosis score, body composition, operating time, blood loss, hospital stay, and complications. RESULTS: Patients in both groups were similar in age, sex, body mass index (53.4 versus 52.8 kg/m2), co-morbidities, liver volume, and body composition. Expression of mature collagen type I was significantly decreased in diet patients compared with controls after 4 weeks of diet and 7 days after surgery. This was significant decrease in liver volume (23% versus 2%, P = .03) but no difference in operating times (129 versus 139 min, P = .16), blood loss, length of stay, or incidence of complications. CONCLUSIONS: Preoperative diets shrink liver volume and decrease expression of mature collagen in wounds after surgery. Whether the latter has a detrimental effect on clinical outcomes requires further evaluation. PMID- 30471929 TI - What echocardiographic findings suggest a pericardial effusion is causing tamponade? AB - BACKGROUND: Pericardial tamponade is neither a clinical nor an echocardiographic diagnosis alone. The echocardiogram carries diagnostic value and should be performed when there is suspicion for tamponade based on the history and physical exam. A pericardial effusion uncovered on point-of-care ultrasound (POCUS) may be mistaken for tamponade and thereby lead to inappropriate and invasive management with pericardiocentesis. OBJECTIVE: This narrative review will summarize the echocardiographic findings and associated pathophysiology that support the diagnosis of pericardial tamponade. It will provide a succinct description of the core findings for which emergency physicians should evaluate at the bedside, along with potential pearls and pitfalls in this evaluation. Labeled images and video clips are included. DISCUSSION: The core echocardiographic findings of pericardial tamponade consist of: a pericardial effusion, diastolic right ventricular collapse (high specificity), systolic right atrial collapse (earliest sign), a plethoric inferior vena cava with minimal respiratory variation (high sensitivity), and exaggerated respiratory cycle changes in mitral and tricuspid valve in-flow velocities as a surrogate for pulsus paradoxus. CONCLUSION: The emergency physician must recognize and understand the core echocardiographic findings and associated pathophysiology that suggest pericardial tamponade. Together with the history and clinical exam, these findings can help make the overall diagnosis and determine management. PMID- 30471930 TI - Tenecteplase utility in acute ischemic stroke patients: A clinical review of current evidence. AB - INTRODUCTION: Acute ischemic stroke is a leading cause of disability in the United States. Treatment is aimed at reducing impact of cerebral clot burden and life-long disability. Traditional fibrinolytic treatment with recombinant tissue plasminogen activator (tPA) has shown to be effective but at high risk of major bleeding. Multiple studies have evaluated tenecteplase as an alternative to tPA. OBJECTIVE: This review evaluates literature and utility of tenecteplase for treatment of acute ischemic stroke. DISCUSSION: Tenecteplase is modified, third generation fibrinolytic with greater specificity for fibrin bound clots. Current data in acute myocardial infarction suggest decreased bleeding events compared to alteplase. Multiple trials have investigated superiority of tenecteplase compared to tPA for treatment of acute ischemic stroke. Current guidelines designate tenecteplase as an alternative treatment for mild acute ischemic stroke patients based on recent literature. CONCLUSION: Recent emerging literature and limited recommendation guidance from governing medical societies leave many emergency medicine providers to weigh benefit versus risk of fibrinolytic therapy and tenecteplase's place in therapy. This review evaluates the available literature regarding tenecteplase and its utility in the treatment of acute ischemic stroke patients. PMID- 30471931 TI - Assessing the CT findings and clinical course of ED patients with first-time versus recurrent acute pancreatitis. AB - STUDY OBJECTIVES: The primary objective of this study was to compare Emergency Department patients with first-time versus recurrent acute pancreatitis. METHODS: This study was a retrospective chart review of patients with a diagnosis of acute pancreatitis who presented to a single academic urban emergency department from 2012 to 2016. Criteria for inclusion were clinical symptoms of pancreatitis, age greater than or equal to 18 years, ED diagnosis of acute pancreatitis, and an abdominal CT scan within 24 h of triage. Exclusion criteria were traumatic mechanism and pregnancy. Charts were reviewed by a minimum of two trained abstractors using structured data collection sheets and discrepancies were resolved by a third abstractor. Patients with first time acute pancreatitis versus recurrent acute pancreatitis were compared to determine differences in characteristics, management and disposition. RESULTS: 250 patients were included in the study. Of these, 165 patients had first-time acute pancreatitis and 85 patients had recurrent acute pancreatitis. Demographics, vital signs and initial lab values were the same in both groups. Patients with recurrent acute pancreatitis were more likely to have significant findings on CT (Modified CT Severity Index, 2.09 versus 1.43, p < 0.05), more likely to require IV opiates (96% versus 75%, p < 0.001) and less likely to need ICU admission (8% versus 19%, p = 0.03). CONCLUSION: ED patients with recurrent acute pancreatitis demonstrated more significant findings on CT compared to patients with first-time acute pancreatitis but were less likely to require ICU admission. PMID- 30471932 TI - Increased access to urgent care centers decreases low acuity diagnoses in a nearby hospital emergency department. AB - OBJECTIVE: We studied the impact four new urgent care centers (UCCs) had on a hospital emergency department (ED) in terms of overall census and proportion of low acuity diagnoses from 2009 to 2016. We hypothesized that low acuity medical problems frequently seen in UCCs would decrease in the ED population. Since Medicaid was not accepted at these UCCs, we also studied the Medicaid vs non Medicaid discharged populations to see if there were some differences related to access to urgent care. METHODS: We conducted a retrospective review of computerized billing data. We included all patients from 2009 to 2016 who were seen in the ED. We used the Cochran-Armitage Trend Test to examine trends over time. RESULTS: As hypothesized, the proportion of ED patients with a diagnosis of pharyngitis decreased significantly over this time period from 1% to 0.6% (p < 0.0001). The rate of bronchitis in the total ED population also decreased significantly (0.5% to 0.13%, p < 0.0001).When we looked at the discharged patients with and without Medicaid, we found that significantly more Medicaid than non-Medicaid patients presented with pharyngitis to the ED with an increasing trend from 2009 to 2016: OR = 2.33, p < 0.0001. The overall census of the ED rose over the period 2009 to 2016 (80,478 to 85,278/year). Overall admission rates decreased significantly: 36.9% to 34.5% (p < 0.0001). CONCLUSION: With the introduction of four new urgent care centers (UCCs) within 5 miles of the hospital, the ED diagnoses of pharyngitis and bronchitis, two of the most common diagnoses seen in UCCs, decreased significantly. Significantly more Medicaid discharged patients presented to the ED with pharyngitis than in the non Medicaid discharged group, likely because Medicaid patients had no access to UCCs. PMID- 30471933 TI - Central venous catheter placement after ultrasound guided peripheral IV placement for difficult vascular access patients. AB - OBJECTIVES: Ultrasound guided peripheral intravenous catheters (USPIV) are frequently utilized in the Emergency Department (ED) and lead to reduced central venous catheter (CVC) placements. USPIVs, however, are reported to have high failure rates. Our primary objective was to determine the proportion of patients that required CVC after USPIV. Our secondary objective was to determine if classic risk factors for difficult vascular access were predictive of future CVC placement. METHODS: We performed a retrospective review for patients treated at a large academic hospital. Patients were identified by electronic health record and were restricted to age older than 21 years, had received USPIV, and admittance. Exclusion criteria included an existing CVC. Descriptive statistics, t-tests, chi square proportions, and logistic regression were performed to test associations. RESULTS: Of 363 eligible patients, 20 were excluded allowing for 343 for analysis. Of 343, 45 (13.1% 95% CI 9.9-17.1%) required CVC after USPIV. For secondary outcomes, no expected characteristics (diabetes, end-stage renal disease, IV drug abuse, peripheral vascular disease, or sickle cell disease) were predictive of CVC placement. The only predictive variables were admission to ICU/stepdown and length of stay. Each additional day of hospitalization had an OR 1.11 (95% CI 1.06-1.16%) of having a CVC placed. CONCLUSION: Of those admitted after USPIV placement, approximately 7 out of every 8 patients did not require a subsequent CVC. Of the nearly 1 in 8 patients that required a CVC, factors associated with CVC placement were admission to a higher level of care and length of stay. PMID- 30471935 TI - "Flip-over flap" in two-stage cleft palate repair. AB - PURPOSE: This study served to evaluate a two-stage concept in cleft palate repair, including key use of a triangular hinge ("flip-over") flap, in order to prevent palatal fistulae. It uses data from a prospective registry established in 1991. MATERIALS AND METHODS: The concept entails Furlow soft palate repair (at 1 year of age) and hard palate closure (at 4 years) by a three-pronged approach [paring of the edges with or without postero-lateral relaxing incisions, peninsula (Veau) flap(s)], plus a triangular hinge flap. The latter is elevated from the oral layer of the already-repaired soft palate, stays based anteriorly, and is flipped over to close the posterior nasal layer defect. The case series is compared with data from the literature. RESULTS: The palatal fistula rate for Veau II to IV types (two-stage surgeries) was 4.3%. The overall fistula rate in the cleft population (Veau I-IV) was 2.9%. Meta-analyses describe 4.9 and 8.6% on average. There was no difference between sample A in which the flip-over flaps were used only when modified Veau flaps were indicated (until 2006) and sample B in which it was used regardless of the technique of hard palate closure applied (2006-2018). The fistula rate decreased to zero after 2010, which may reflect also an influence of other factors such as the interpositioning of a collagen membrane and also of improved surgical judgment. CONCLUSIONS: Using a flip-over flap in two-stage cleft palate repair may contribute to prevent fistula formation at the hard/soft palate junction. LEVEL OF EVIDENCE: III. PMID- 30471934 TI - Prognostic value of lactate in prehospital care as a predictor of early mortality. AB - BACKGROUND: Prehospital Emergency Medical Services must attend to patients with complex physiopathological situations with little data and in the shortest possible time. The objective of this work was to study lactic acid values and their usefulness in the prehospital setting to help in clinical decision-making. STUDY DESIGN: We conducted a longitudinal prospective, observational study on patients over 18 years of age who, after being evaluated by the Advanced Life Support Unit, were taken to the hospital between April and June 2018. We analyzed demographic variables, prehospital lactic acid values and early mortality (<30 days). The area under the curve of the receiver operating characteristic was calculated for the prehospital value of lactic acid. RESULTS: A total of 279 patients were included in our study. The median age was 68 years (interquartile range: 54-80 years). Overall 30-day mortality was 9% (25 patients). The area under the curve for lactic acid to predict overall mortality at 30 days of care was 0.82 (95% CI: 0.76-0.89). The lactate value with the best sensitivity and specificity overall was 4.25 mmol/L with a sensitivity of 84% (95% CI: 65.3-93.6) and specificity of 70% (95% CI: 65.0-76.1). CONCLUSIONS: The level of lactic acid can be a complementary tool in the field of prehospital emergencies that will guide us early in the detection of critical patients. PMID- 30471936 TI - Evaluation of accuracy and sensory outcomes of mandibular reconstruction using computer-assisted surgical simulation. AB - PURPOSE: To introduce a modified protocol for mandibular reconstruction and evaluate the protocol using a standardized assessment method. METHOD: This retrospective study involved a case series of nine patients who underwent mandibular reconstruction between 2015 and 2017. The modular protocol comprised three novel modifications in terms of computer-assisted surgical simulation (CASS); surgical template (ST), and surgical procedure. The standardized postoperative evaluation consisted of operation time, part comparison analysis (PCA), facial symmetry, and mechanical quantitative sensory testing. RESULTS: The surgery successfully removed the affected mandible and preserved the inferior alveolar neurovascular bundle (IANB). PCA revealed that the mean error and standard deviation were 0.92 and 0.96 mm, respectively, for all mandibular surface sites. Follow-up results showed good facial symmetry, existence of sensation in lower lip, and no significant differences in pulp vitality between both sides (p = 0.181). Also, the results showed a reduction in the overall operating time. CONCLUSION: The modified mandibular reconstruction method used in this study could repair lateral mandibular defects and preserve the sensory function of the chin and lower lip. PMID- 30471937 TI - Treatment of end stage temporomandibular joint disorder using a temporomandibular joint total prosthesis: The Slovenian experience. AB - PURPOSE: The aim of this study was to analyse treatment results after alloplastic temporomandibular joint replacement surgery. MATERIALS AND METHODS: Twelve patients who met the inclusion criteria underwent operation between the years 2012 and 2016 at the Department of Maxillofacial and Oral Surgery of the University Medical Centre Ljubljana, Slovenia. Seven patients had posttraumatic sequelae, 4 osteoarthritis and 1 psoriatic arthritis. We inserted 12 temporomandibular joint prostheses (Biomet- Lorenz). A retrograde analysis of the patients, subjective assessment of the pre- and postoperative temporomandibular pain, opening the mouth, the ability to chew food, and quality of life (VAS scale, 0-10) was performed. Additionally, we evaluated the inter-incisal distance pre- and postoperatively. Complications that occurred were also included in our evaluation. RESULTS: During final examinations, at least 15 months after the surgery (on average 39.5 months), we observed an improved ability to open the mouth in all patients. The average preoperative inter-incisal distance was 22 mm (15-30 mm); the average postoperative distance was 37.5 mm (32.3-1.8 mm), (p < 0.001). The analysis of pain and other subjective variables (opening the mouth, the ability to chew, quality of life) showed a statistically significant improvement (p < 0.001). CONCLUSION: According to our initial experience, replacement of the temporomandibular joint with a total prosthesis is a safe and effective treatment method. PMID- 30471938 TI - Electrochemotherapy - A locoregional therapy with well-established palliative effect in patient with large recurrent lesion of head and neck. AB - BACKGROUND: Electrochemotherapy (ECT) is a well established treatment strategy for skin tumors of different histology. The aim of this study was to evaluate the feasibility and efficacy of electrochemotherapy in the palliative setting in patients with head and neck malignancies, already treated with surgery and/or radio-chemotherapy with no other therapeutic option. METHODS: Thirty-six patients with a loco-regional M0/M1 relapse with no other therapeutic option not suitable for a cure with a radical intent by surgery or RT and not suitable for systemic therapy and/or already treated with it, were admitted to electrochemotherapy (ECT) protocol treatment. ECT was performed according ESOPE guidelines. Clinical features, treatment response, and adverse effects were evaluated 15, 30 days and then every months after the treatment. RESULTS: An overall response of 100% was observed. Only 3 patients out 36 showed a CR. Overall survival probability at 12 months was 41.6% (median OS: 9 months). In all patient, an improvement of quality of life in terms of pain, bleeding events were observed, while need for medical assistance or dressing was significantly reduced 1 month after electrochemotherapy (p < 0.001). CONCLUSIONS: Electrochemotherapy is an effective palliative treatment of non-resectable head and neck malignancies able. Due to the ECT limited side effects, its early use would be desirable to obtain a better local control of the disease and improve quality of life of patients. PMID- 30471940 TI - A patient-centred care and engagement program in intensive care reduces adverse events and improves patient and care partner satisfaction. PMID- 30471939 TI - Clinical supervision and ward orientation predict new graduate nurses' intention to work in critical care: Findings from a prospective observational study. AB - INTRODUCTION: Clinical supervision and transitional support programs are important in supporting the successful transition and retention of new graduate nurses and their intention to work in specialty settings. However, little is known about which elements of support programs influence this intention. This study aimed to examine new graduate nurses' perceptions of clinical supervision and the practice environment, and how these influenced their intention to stay in critical and non-critical care areas following their transitional support program. METHODS: Between May 2012 and August 2013, new graduate nurses (n = 87) were surveyed towards the end of their 12-month transitional support program. In addition to demographic and ward details, participants completed the Manchester Clinical Supervision Scale (MCSS) and the Practice Environment Scale Australia (PES-AUS). The 'Intention to Stay in a Clinical Specialty' survey was used to measure new graduate nurses' intention to remain working in their current ward or unit. RESULTS: Predictors of new graduate nurses' intention to stay in their current ward/unit were not having to practise beyond personal clinical capability (AOR: 4.215, 95% CI: 1.099-16.167) and working in a critical care specialty (AOR: 6.530, 95% CI: 1.911-22.314). Further analysis of those nurses who indicated an intention to remain in critical care revealed that high satisfaction with clinical supervision (AOR: 3.861, 95% CI: 1.320-11.293) and high satisfaction with unit orientation (AOR: 3.629, 95% CI: 1.236-10.659) were significant predictors. CONCLUSION: While this study identified that new graduates who worked within their scope of practice were more likely to report their intention to remain in their current ward, new graduates assigned to critical care were six times more likely to indicate their intention to remain than new graduates in other wards/units. Ensuring new graduate nurses assigned to critical care areas receive good unit orientation and clinical supervision increases their intention to remain in this setting. PMID- 30471941 TI - Postoperative CD4 counts predict anastomotic leaks in patients with penetrating abdominal trauma. AB - INTRODUCTION: The influence of trauma- and surgical stress-induced decrease of CD4 count on anastomotic leaks after penetrating abdominal trauma has to date not been investigated. A prospective study was performed to explore the effect of CD4 count 24 h after surgery on the anastomotic leak rate and to identify risk factors for anastomotic leaks. METHODS: This was a prospective study including 98 patients with small or large bowel resection and subsequent anastomosis due to penetrating abdominal trauma. Univariate analysis identified risk factors for the development of anastomotic leak and also investigated the predictive value of the CD4 count for this complication. RESULTS: Of the 98 patients 23 patients (23%) were HIV-infected. The overall leak rate was 13%. Univariate analysis including all potential risk factors with p-values<0.05 identified six factors leading to a significantly higher rate of anastomotic complications: postoperative CD4 count<250 cells/MUl, postoperative albumin <30 g/L, penetrating abdominal trauma index>=25, gunshot wound as mechanism of injury, blood transfusion requirement >6units and delayed anastomosis after damage control surgery. Survival rates were analysed with the chi2 test and did not show a significantly higher mortality rate in patients with low CD4 count. The negative impact of trauma and subsequent surgery on the cell mediated immunity was demonstrated by the fact that 55 (73%) of the HIV-negative patients had a CD4 count less than 500 cells/MUl 24 h postoperatively. HIV-infection had no significant influence on the leak rate, however all HIV infected patients that developed an anastomotic leak died. CONCLUSION: A low post-operative CD4 count is a predictor for anastomotic leaks irrespective of HIV-serostatus. Low postoperative serum albumin, high injury severity, gunshot wound as mechanism of injury, blood transfusion requirement >6 units and delayed anastomosis were further risk factors for anastomotic complications. Postoperative CD4 count and serum albumin should be considered in the decision making process of performing an anastomosis or diverting stoma for patients after "clip and drop" of the bowel as part of damage control surgery. PMID- 30471942 TI - Treatment of femoral neck fractures in patients 45-64 years of age. AB - INTRODUCTION: Young patients with femoral neck fractures are optimally treated with reduction and stable fixation, while patients over the age of sixty-five are often treated with arthroplasty. This study analyzes in-hospital outcomes associated with total hip arthroplasty, hip hemiarthroplasty and internal fixation for treatment of femoral neck fractures in patients aged 45-64. METHODS: Records of patients between the ages of 45-64, from 2002 to 2014, sustaining femoral neck fractures and treated with internal fixation, hip hemiarthroplasty or total hip arthroplasty were obtained from the Nationwide Inpatient Sample (NIS). Examined variables were age, sex and Charlson Comorbidity Index (CCI). Outcome measures included hospital length of stay (LOS), complications, and inpatient hospitalization charge. RESULTS: From 2002-2014 74,678 femoral neck fractures were available for analysis. THA use increased from 5.3% of operatively managed fractures in 2002 to 22.3% of operatively managed fractures in 2014 (p < 0.0001). Patients undergoing THA had higher hospital cost, higher in hospital complication rates and longer length of stay than patients undergoing internal fixation (p < 0.0001). The in-hospital mortality for patients undergoing a hip hemiarthroplasty was higher (1.2%) than either total hip arthroplasty (0.2%) or internal fixation (0.5%) (P = 0.007). CONCLUSION: This study demonstrates that the use of total hip arthroplasty in treatment of femoral neck fractures in patients from the age of 45-64 increased 4.2-fold over the study period. This treatment is associated with increased hospital cost, length of stay and complications. Additionally, as age increased in our study population, there was a stepwise increase in the use of arthroplasty, and it appears that hemiarthroplasty is being used with a different patient population. PMID- 30471943 TI - Ultra-fine Pd nanoparticles confined in a porous organic polymer: A leaching-and aggregation-resistant catalyst for the efficient reduction of nitroarenes by NaBH4. AB - Porous organic polymers (POPs) containing nitrogenous substituents have potential practical applications as heterogeneous catalysts based upon controlled porous structure and surface-anchored noble metal nanoparticles (NMNPs). In this work we prepared a POP material from piperazine and cyanuric chloride starting materials (PC-POP). The PC-POP material contains numerous triazinyl moieties, thus rendering the pores hydrophobic. Subsequently, by means of a novel reverse double solvent approach (RDSA), microdroplets of Pd(AcO)2/CH2Cl2 were introduced into the hydrophobic pores of PC-POP in an aqueous environment; Pd(II) was rapidly reduced by NaBH4 to form ultra-fine Pd NPs and confined within the pores of PC POP at high dispersity. The extensive porosity and dispersity of the Pd NPs made the active sites readily accessible, and led to efficient mass transfer. Thus, Pd@PC-POP exhibits superior catalytic performance in catalytic reduction of various nitroarenes. Furthermore, Pd@PC-POP has excellent recyclability, without significant loss of activity nor leaching of Pd active sites during 10 successive reaction cycles. This work points to a practical and cost-effective approach to preparation of POP materials, and also for confining ultra-fine NMNPs in POPs for use as catalysts. PMID- 30471944 TI - Reproducibility of Voice Parameters: The Effect of Room Acoustics and Microphones. AB - INTRODUCTION: Computer analysis of voice recordings is an integral part of the evaluation and management of voice disorders. In many practices, voice samples are taken in rooms that are not sound attenuated and/or sound-proofed; further, the technology used is rarely consistent. This will likely affect the recordings, and therefore, their analyses. OBJECTIVES: The objective of this study is to compare various acoustic outcome measures taken from samples recorded in a sound proofed booth to those recorded in more common clinic environments. Further, the effects from six different commonly used microphones will be compared. METHODS: Thirty-six speakers were recorded while reading a text and producing sustained vowels in a controlled acoustic environment. The collected samples were reproduced by a Head and Torso Simulator and recorded in three clinical rooms and in a sound booth using six different microphones. Newer measures (eg, Pitch Strength, cepstral peak prominence, Acoustic Voice Quality Index), as well as more traditional measures (eg Jitter, Shimmer, harmonics-to-noise ratio and Spectrum Tilt), were calculated from the samples collected with each microphone and within each room. RESULTS: The measures which are more robust to room acoustic differences, background noise, and microphone quality include Jitter and smooth cepstral peak prominence, followed by Shimmer, Acoustic Voice Quality Index, harmonics-to-noise ratio, Pitch Strength, and Spectrum Tilt. CONCLUSIONS: The effect of room acoustics and background noise on voice parameters appears to be stronger than the type of microphone used for the recording. Consequently, an appropriate acoustical clinical space may be more important than the quality of the microphone. PMID- 30471945 TI - Upshaw-Schulman syndrome diagnosed during pregnancy complicated by reversible cerebral vasoconstriction syndrome. AB - Upshaw-Schulman syndrome (USS) is an inherited type of thrombotic thrombocytopenic purpura (TTP) that is extremely rare, but often diagnosed during pregnancy. Reversible cerebral vasoconstriction syndrome (RCVS) is the transient stenosis of several cerebral arteries that is frequently diagnosed post-partum. We describe a 28-year-old woman with USS complicated by RCVS after delivery that was treated by plasma exchange with a good outcome. She was referred to our hospital with thunderclap headache, anemia and thrombocytopenia that occurred immediately postpartum. She was diagnosed with TTP and multiple cerebral infarctions. Plasma exchange promptly improved her symptoms on hospital day 3. Moreover, multiple stenoses of cerebral arteries indicating RCVS were resolved. Since her sister also had an episode of thrombocytopenia during pregnancy, inherited TTP was suspected and genetic analyses confirmed USS. Pregnancy is a risk for not only TTP, but also RCVS. Endothelial damage might be an underlining cause and vasospasm after delivery is a trigger of RCVS. Plasma exchange was effective against both TTP and RCVS. PMID- 30471946 TI - Preoperative autologous blood donation in placenta previa patients. AB - OBJECTIVE: The aim of this study was to evaluate the usability of preoperative autologous blood donation (PAD) in pregnant women with placenta previa. STUDY DESIGN: We retrospectively reviewed 142 pregnancies with placenta previa from completed 32 weeks of gestation who underwent a caesarean delivery in University clinical centre Ljubljana, over a five-year period. RESULT: Although more than two thirds of pregnant women met the criteria for PAD, it was justified for approximately 13.6% of them. The decrease in haemoglobin level after PAD was only 4.5 +/- 6.7 g/l on average and did not induce anaemia. CONCLUSION: Although our study shows that PAD is not reasonable for the majority of all pregnant women with placenta previa who met the criteria for PAD from our study, we believe that with the implementation of Patient Blood Management it still has its prospects of clinical application. However, further prospective studies are needed to find risk factors for increased surgical bleeding to make a proper patient selection for PAD. PMID- 30471947 TI - Interventions Guiding Advance Care Planning Conversations: A Systematic Review. AB - BACKGROUND: Advance care planning (ACP) is a communicative process of defining preferences for future medical care. Conversation guides support professionals to conduct ACP conversations, yet insight into essential components is limited. OBJECTIVES: To evaluate the content, rationale, and empirical evidence on the effect of ACP interventions based on conversation guides. METHODS: MEDLINE, Embase, PsycINFO, and CINAHL were searched from January 1, 1998, to February 23, 2018, to identify peer-reviewed articles describing or evaluating ACP interventions based on scripted conversation guides. A thematic analysis of the guides was performed. Data on intervention characteristics, underlying rationale, and empirical evidence were extracted by 2 authors independently using a predesigned form. Assessment of risk of bias and quality of reporting was performed using Cochrane tools and COREQ, respectively. RESULTS: Eighty-two articles reporting on 34 unique interventions met the inclusion criteria. Analysis of the conversation guides revealed a framework for ACP conversations consisting of 4 phases: preparation, initiation, exploration, and action. Exploration of patient's perspectives on illness, living well, end-of-life (EOL) issues, and decision making formed the core part of the guides. Their design was often expert-based, without an underlying theoretical background. Empirical evidence on the effect of the interventions was based on heterogeneous outcome measures. Dyad congruence and preference documentation rates increased among intervention subjects in most studies. The studies showed varying effects on knowledge of ACP, decisional conflict, quality of communication, and preferences concordant care. Qualitative research showed that participants appreciate the importance and benefits of ACP conversations, yet perceive them as difficult and emotional. CONCLUSION: ACP conversation guides address a diversity of themes regarding illness, EOL issues, and decision making. There is a focus on the exploration of patient's perspectives and preferences. Evidence on the translation of explorative information into specific treatment preferences and consequences for care as provided is limited. PMID- 30471948 TI - Effectiveness of Different Topical Treatments in the Healing of Pressure Injuries: A Network Meta-analysis. AB - OBJECTIVES: Pressure injuries (PIs) are one of the most common types of complex wounds and impose a huge economic burden on the healthcare system and the patients. A plethora of topical treatments is widely available for PI treatment, yet there is a paucity of evidence with regard to the most effective treatment. The objective of this study was to compare the effect of various topical treatments and identify the best treatment choice(s) for PI healing. DESIGN: Systematic review and network meta-analysis. SETTING AND PARTICIPANTS: All published randomized controlled trials that compared the effectiveness of 2 or more of the following dressing groups: basic, foam, active, hydroactive, and other wound dressings. MEASURES: The outcome was the relative risk (RR) of complete healing following treatment and the generalized pairwise modeling framework was used to generate mixed treatment effects against hydroactive wound dressing, currently the standard of treatment for PIs. All treatments were then ranked by their point estimates. RESULTS: 40 studies (1757 participants) comparing 5 dressing groups were included in the analysis. All dressings groups ranked better than basic (ie, saline gauze or similar inert dressing). The foam [RR 1.18; 95% confidence interval (CI) 0.95-1.48] and active wound dressing (RR 1.16; 95% CI 0.92-1.47) ranked better than hydroactive wound dressing in terms of healing of PIs when the latter was used as the reference group. CONCLUSIONS/IMPLICATIONS: There was substantial uncertainty around the point estimates; however, evidence from our analysis supports the use of hydroactive wound dressings to replace basic dressings. Foam and active wound dressing groups seem promising and therefore need further investigation. High-quality, rigorously conducted research about the clinical effectiveness of the topical treatments in these 2 groups developed in consultation with health professionals, patients, and their carers is needed to identify if indeed foam and active wound dressings provide advantages over hydroactive dressings. PMID- 30471949 TI - Unravelling the apoptotic mechanisms in T-lymphocytes in an animal model for pollen induced airway allergy and studying the impact of specific immunotherapy. AB - Asthma is a chronic inflammatory disorder of the airways, increasing in prevalence worldwide. Reduced T cell apoptosis may interfere with the down regulation of an immune response resulting in T cell accumulation contributing to the chronic inflammation of asthma. Most studies focused so far on apoptosis of eosinophils but the detailed role of T lymphocytes apoptosis in allergic diseases is unclear yet. The present experimental study was designed to discern the modulation of various apoptotic proteins of splenic T lymphocytes in a previously established rat model of Alstonia scholaris pollen induced airway allergy. Flowcytometry, immunoblotting, and immunofluorescence imaging techniques were employed for the present investigation. Annexin-V studies registered early apoptotic rate of lymphocytes with allergen sensitization and challenge which was corrected following mucosal immunotherapy. The study demonstrates that allergen sensitization and challenge reduced apoptosis of splenic T-lymphocytes via Fas mediated extrinsic pathway, Bax/Bcl2 regulated intrinsic pathway and also perforin/granzyme mediated pathway which were normalized following allergen specific intranasal immunotherapy. Inadequate T cell apoptosis in asthma appears to interfere with normal T cell elimination, resulting in T cell accumulation, which contributes to chronic inflammation and may be the major underlying cause for tissue damage which can be modulated by intranasal immunotherapy. Thus the apoptosis inducing effect of allergen immunotherapy necessitates more studies to elaborate on its effects on various effector cells of airway inflammation. PMID- 30471950 TI - Comments on "Enhanced removal of Cr(V?) from aqueous solution by supported ZnO nanoparticles on biochar derived from waste water hyacinth". AB - A mistake of using pseudo-first-order kinetic equation for testing kinetic parameters of adsorption has been pointed out, as well as inappropriate citations for the adsorption kinetic models. Further, this discussion gives a correct pseudo-first-order kinetic equation and makes a suggestion for citing the original papers for the pseudo-second-order and intra-particle diffusion kinetic equations. PMID- 30471951 TI - Reply to: "Comment on "Mean platelet volume and long-term cardiovascular outcomes in patients with stable coronary artery disease" ". PMID- 30471952 TI - Bridging the treatment gap in patients at 'extreme' cardiovascular risk: Evidence from a lipid clinic. PMID- 30471953 TI - Concomitant administration of a fully liquid ready-to-use DTaP-IPV-HB-PRP-T hexavalent vaccine with a meningococcal ACWY conjugate vaccine in toddlers. AB - Invasive meningococcal disease caused by Neisseria meningitidis is a life threatening disease. Several countries now include meningococcal serogroup C (MenC) conjugate and, more recently, a meningococcal serogroup ACWY conjugate (MenACWY) vaccination in their national immunization schedules. DTaP-IPV-HB-PRP-T is a hexavalent vaccine that provides protection against six diseases. The phase III, open-label, randomised, multicentre study enrolled healthy toddlers who received the DTaP-IPV-HB-PRP-T vaccine (at 2, 3 and 4 months) with or without a MenC vaccine (at 2 and 4 months) in the primary series study. At 12 months of age, 312 toddlers were randomised to receive DTaP-IPV-HB-PRP-T co-administered with MenACWY-TT vaccine (Group A; n = 104); DTaP-IPV-HB-PRP-T vaccine alone (Group B; n = 105); or MenACWY-TT vaccine alone (Group C; n = 103). At 12 months of age, there were no notable differences in terms of antibody persistence for any DTaP-IPV-HB-PRP-T vaccine antigen, whether MenC-TT conjugate vaccine was co administered or not during the primary series. Following booster vaccination, immune responses to DTaP-IPV-HB-PRP-T and MenACWY-TT vaccines were not affected by co-administration. One month after vaccination, the immune responses elicited by both vaccines were high, whether administered concomitantly or separately. The administration of MenC vaccine during infancy did not preclude the use of a MenACWY-TT vaccine for booster vaccination. Even though the reactogenicity after co-administration was somewhat higher, the results of this study support the concomitant administration of the DTaP-IPV-HB-PRP-T vaccine with a MenACWY-TT conjugate vaccine when given from 12 months of age. The clinical trial registration numbers are: clinicaltrial.gov: NCT01839175; EudraCT: 2012-005547 24. PMID- 30471954 TI - Impact of implementing a technology platform in community pharmacies to increase adult immunizations rates. AB - Over the course of this project, we utilized pharmacists at 159 community pharmacies in Nebraska and Iowa to administer vaccinations to adults 19 years of age or older with the objective of improving immunization rates in both states. We implemented a pharmacy-based technology platform and partnered with public health via the state immunization registries of both states to ensure that immunizations provided at the pharmacy were transmitted to the statewide registry, for which reporting is currently voluntary for health care providers. After using the technology platform for one year, an increase of immunization rates for influenza, herpes zoster, and pertussis vaccination rates by 37%, 12%, and 74%, respectively, was recorded in comparison to the prior year numbers. However, there was about 16% decrease in vaccination rates for pneumococcal vaccine. For the first time, the project's participating pharmacies in Nebraska reported immunization counts to their state's immunization registries. This project leveraged community pharmacies as healthcare destinations to achieve further gains in increasing immunization rates, improving the health of adults, and creating a community-wide network for prevention. PMID- 30471955 TI - The HSV-1 live attenuated VC2 vaccine provides protection against HSV-2 genital infection in the guinea pig model of genital herpes. AB - BACKGROUND: Although development of an HSV vaccine is a priority there is currently no vaccine available. The recent failure of subunit vaccines suggest that presentation of more antigens via a live attenuated vaccine may be required for protection. We therefore evaluated VC2, a live attenuated HSV vaccine, engineered to be unable to enter into neuronal axons. METHODS: VC2 pathogenesis was first evaluated in guinea pigs following intravaginal inoculation. VC2 was then evaluated as a prophylactic and therapeutic vaccine and compared protection to a gD2 vaccine adjuvanted with MPL/Alum in the guinea pig model of genital HSV 2. The guinea pig model allows evaluation of acute and recurrent disease, as well as vaginal shedding acutely and during episodes of recurrent activation. RESULTS: VC2 was significantly attenuated in guinea pigs compared to the wild type strain, 17syn+. It replicated poorly at the inoculation site, did not produce any genital disease and rarely infected the neural tissue. After prophylactic vaccination, the VC2 vaccine decreased the clinical severity of acute and recurrent HSV-2 disease and shedding and decreased the quantity of virus in the DRGs. When compared to gD2+MPL/Alum, VC2 was somewhat more effective especially as it relates to neural tissue infection. VC2 was not effective as a therapeutic vaccine. CONCLUSION: The live attenuated prophylactic HSV vaccine, VC2, was effective in the guinea pig model of genital HSV-2. Its decreased ability to infect neural tissues provides advantages over other live attenuated vaccines. PMID- 30471956 TI - Prioritization of risk groups for influenza vaccination in resource limited settings - A case study from South Africa. AB - BACKGROUND: Due to competing health priorities, low- and middle-income countries (LMIC) may need to prioritize between different influenza vaccine risk groups. Risk group prioritization may differ in LMIC based upon programmatic feasibility, country-specific prevalence of risk conditions and influenza-associated morbidity and mortality. METHODS: In South Africa, we collected local disease burden data (both published and unpublished) and published vaccine efficacy data in risk groups and healthy adults. We used these data to aid policy makers with risk group prioritization for influenza vaccination. We used the following formula to assess potential vaccine averted disease in each risk group: rate of influenza associated hospitalization (or death) per 100,000 population * influenza vaccine efficacy (VE). We further estimated the cost per hospital day averted and the cost per year of life saved by influenza vaccination. RESULTS: Pregnant women, HIV-infected adults, and adults and children with tuberculosis disease had among the highest estimates of hospitalizations averted per 100,000 vaccinated and adults aged 65 years and older had the highest estimated deaths averted per 100,000 vaccinated. However, when assessing both the cost per hospital day averted (range: USD148-1,344) and the cost per year of life saved (range: USD112 1,230); adults and children with TB disease, HIV-infected adults and pregnant women had the lowest cost per outcome averted. DISCUSSION: An assessment of the potential disease outcomes averted and associated costs may aid policymakers in risk group prioritization for influenza vaccination. PMID- 30471957 TI - Observational studies of non-specific effects of Diphtheria-Tetanus-Pertussis vaccines in low-income countries: Assessing the potential impact of study characteristics, bias and confounding through meta-regression. AB - INTRODUCTION: It has been suggested that some vaccines have effects beyond protection against the diseases they target, called non-specific effects (NSEs). In 2016, a systematic review by Higgins et al., commissioned by the WHO Strategic Advisory Group of Experts (SAGE) on immunization, estimated the relative risk (RR) of all-cause mortality after whole-cell Diphtheria-Tetanus-Pertussis (DTwP) vaccination to be 1.38 (95% CI: 0.92-2.08), and described these potential NSEs as inconsistent. However, the selection of studies for meta-analysis, based on their proneness to bias and confounding, was debated. OBJECTIVE: To identify study characteristics and postulated risks of bias and confounding that might have impacted the RR of all-cause mortality after DTwP vaccination in observational studies conducted in low-income countries. METHODS: Based on methodological considerations on study design and analysis, we systematically assessed all 17 DTwP studies from the Higgins et al. review for risk of selection bias, exposure and outcome misclassification, confounding and differential co-interventions. We used meta-regression to assess the impact of study characteristics and the postulated risks of bias and confounding on the RR estimates, and looked for outlying and influential risk estimates. Permutation tests were performed to control for false-positive findings. RESULTS: The overall RR of all-cause mortality after DTwP vaccination including all but one outlying and influential study was 1.32 (95% CI: 0.83-2.08). Based on uni-variable meta-regression, we found that study location (p = 0.01), studies using the landmark approach (p = 0.015) and studies at high risk of exposure misclassification (p = 0.036) were significantly associated with increased RR estimates whereas studies at high risk of selection bias (p = 0.059) showed borderline significance. The results further suggest these effect modifiers are clustered in studies conducted in West-Africa. CONCLUSION: The increased RR of all-cause mortality after DTwP might be confined to West-African countries and/or certain postulated risks of bias might have inflated these RRs. PMID- 30471958 TI - Evaluating new rabies post-exposure prophylaxis (PEP) regimens or vaccines. AB - The development of human rabies vaccines has evolved dramatically from the first crude nerve tissue vaccine produced then administered in the presence of Louis Pasteur in 1885. New cell culture technology has enabled highly potent and well tolerated rabies vaccines to be produced that have reduced the volume and number of doses required to save human lives after exposure. However, these highly potent vaccines are still unaffordable to many patients living at risk of exposure on a daily basis. The cost of post-exposure prophylaxis (PEP) is not only related to the direct cost of rabies biologicals and equipment but is also associated with indirect costs that patients incur as a result of travel, loss of work time (income loss), and accommodation over the period of time that a PEP regimen requires to be completed. This paper summarizes the particular criteria that the SAGE Working Group and WHO personnel reviewed as part of the evaluation process for recommending the new one-week intradermal vaccination regimen (2-2-2 0-0) for rabies post-exposure prophylaxis. These criteria included: Cost effectiveness; evaluation of number of doses; seroconversion after vaccination; efficacy; safety; and patient follow-up. PMID- 30471959 TI - [Efficacy and toxicity of immune checkpoint inhibitors in elderly patients - 5th edition of the congress of pharmacology of anticancer drugs]. AB - Physiological aging causes qualitative or quantitative immune system decline, also called immunosenescence. Older people with cancer are often ineligible for chemotherapy. The new immunotherapies (with PD1, PDL1 and CTLA4 checkpoint inhibitors) have proven their effectiveness in many tumor types regardless of age and are often better tolerated than chemotherapy. In the older population, the subgroup data from the different pivotal studies show fairly reassuring efficacy and safety data, despite the frequent lack of power given the small population included. There remains, however, some doubt that age may be a risk factor for hyperprogression. Studies focusing on older subjects and dedicated meta-analysis seem necessary to obtain more accurate data. PMID- 30471961 TI - Preoperative Vascular Interventions to Improve Donor Leg Perfusion: A Report of Two Fibula Free Flaps Used in Head and Neck Reconstruction. AB - PURPOSE: For reconstruction of head and neck defects, the fibula free flap is the first choice at many institutions. The main contraindication for fibula harvest is the lack of 3-vessel runoff, which leads to postoperative vascular compromise of the lower extremity. Atherosclerosis is the most common disease, which can limit the use of this donor site. In general, vascular interventions, which include angioplasty, atherectomy, and stenting, have been used to fix arterial supplies using endovascular methods. The purpose of this study was to report on the outcome of a preliminary cohort of patients after vascular interventions to re-establish vessel patency to allow safe use of the free fibula free flap in head and neck reconstruction. MATERIALS AND METHODS: A single-institution retrospective case review using electronic medical records was designed. The study population was composed of patients who underwent a fibula free flap procedure for head and neck reconstruction from 2015 through 2017. Inclusion criteria were patients who underwent conventional angiography and required vascular interventions. There were no specific exclusion criteria. The primary outcome of interest was vascular compromise of the donor site. Additional variables of interest included success of reconstruction and perioperative donor or recipient site complications. RESULTS: Two patients who underwent preoperative vascular interventions of the superficial femoral artery and posterior tibial artery were identified. The mean age was 65 years, and these patients underwent resection and reconstruction for mandibular carcinoma. For these patients, fibula flaps were harvested from the left lower extremity and included skin paddles. The fibula flaps survived and the donor feet maintained adequate perfusion. One patient had poor take of the split-thickness skin graft. No long-term functional deficit was noted. CONCLUSIONS: Vascular interventions could be a safe method to re-establish vascular flow and 3-vessel runoff for select patients initially unable to undergo fibula free flap harvest. PMID- 30471960 TI - Neoadjuvant therapy and major arterial resection for potentially reconstructable arterial involvement by stage 3 adenocarcinoma of the pancreas. AB - BACKGROUND: Stage 3 pancreatic ductal adenocarcinoma (PDAC) is defined by arterial involvement. This study objective was to evaluate outcomes for patients with stage 3 PDAC with potentially reconstructable arterial involvement, considered for neoadjuvant therapy (NAT) and pancreatic resection, and to compare outcomes following arterial (AR) and non-arterial resection (NAR). METHODS: This study included patients from 2009 to 2016 with biopsy-proven stage 3 PDAC who were offered NAT before surgical exploration. AR was performed if required to achieve R0 resection. Time to event outcomes were analysed from diagnosis date. RESULTS: 87/89 patients (97.8%) received NAT (chemotherapy 41.6%, chemotherapy/radiotherapy 56.2%). 46/89 (51.7%) underwent exploration; 31 underwent resection (AR n = 20, NAR n = 11). AR patients had longer operative time (681 vs. 563 min, p = 0.006) and more blood loss (1600 vs. 575 mL, p = 0.0004), with no difference for blood transfusion, pancreatic fistula, length of stay, reoperation, or mortality. R0 rate was 30/31. Post-resection 90-day mortality was 3.2%. Median overall survival was statistically comparable between the AR and NAR groups (19.7 vs. 28.4 months, p = 0.41). CONCLUSIONS: AR had comparable clinical and oncologic outcomes to NAR. Following careful selection and non-progression after NAT, major AR may cautiously be considered if required to obtain a negative resection margin. PMID- 30471962 TI - Circulating MiRNA Dynamics in ST-Segment Elevation Myocardial Infarction-driven Cardiogenic Shock. PMID- 30471963 TI - Protective effect of ginsenoside Rg1 on LPS-induced apoptosis of lung epithelial cells. AB - Sepsis-induced acute lung injury (ALI) is a life-threatening medical condition with high mortality and morbidity in the critical care units. Though, it was commonly accepted that inflammation and apoptosis of lung epithelial cells played an essential role in the pathogenesis of ALI, the underlying mechanism remain unknown. In our study, we found that LPS-induced cell apoptosis could be counteracted by elevated cell autophagy. In LPS-treated MLE-12 cells, suppression of autophagy via 3-MA could aggravate LPS-induced apoptosis, while activation of autophagy via Rapamycin could effectively impair the apoptosis of MLE-12 cells induced by LPS. In order to further discover the molecular regulation mechanism between apoptosis and autophagy in LPS-treated MLE-12 cells, we demonstrated that autophagy could induced the expression of Nrf2, followed with the decrease of p p65. Targeted inhibition of Nrf2 could induce enlarged cell apoptosis via increasing the level of p-p65. In addition, we demonstrated that ginsenoside Rg1 protected MLE-12 cells from LPS-induced apoptosis via augmenting autophagy and inducing the expression of Nrf2. Our data implicates that activation of autophagy and Nrf2 by ginsenoside Rg1 may provide a preventive and therapeutic strategy for ALI. PMID- 30471964 TI - What are the clinical implications of knee crepitus to individuals with knee osteoarthritis? An observational study with data from the Osteoarthritis Initiative. AB - BACKGROUND: Crepitus is a common clinical feature of knee osteoarthritis. However, the importance of crepitus in the overall clinical presentation of individuals with knee osteoarthritis is unknown. OBJECTIVE(S): (A) To compare function, pain and quality of life between individuals with knee osteoarthritis with and without crepitus; (B) to compare whether individuals with knee osteoarthritis in both knees, but crepitus in just one, differ in terms of function pain, and knee strength. METHODS: Setting: Observational study. PARTICIPANTS: (A) A total of 584 participants with crepitus who had the same Kellgren-Lawrence grade on both knees were matched for gender, body mass index and Kellgren-Lawrence grade to participants without crepitus on both knees. (B) 361 participants with crepitus in only one knee and with the same Kellgren Lawrence grade classification on both knees were included. MAIN OUTCOME MEASURE(S): A - Self-reported function, pain, quality of life, 20-m walk test and chair-stand test. B -Knee extensor and flexor strength, self-reported function and pain. RESULTS: A - Individuals with crepitus had lower self-reported function, quality of life and higher pain compared to those without crepitus (3 11%; small effect=0.17-0.41, respectively). No difference was found in objective function between groups. B - Self-reported function was lower in the limb with crepitus compared to the limb without crepitus (15%; trivial effect=0.09). No difference was found in pain and knee strength between-groups. CONCLUSION(S): Individuals with knee osteoarthritis and knee crepitus have slightly lower self reported physical function and knee-related quality of life (small or trivial effect). However, the presence of knee crepitus is not associated with objective function or knee strength. PMID- 30471965 TI - EMG breakthrough during cortical silent period in congenital hemiparesis: a descriptive case series. AB - BACKGROUND: The cortical silent period is a transient suppression of electromyographic activity after a transcranial magnetic stimulation pulse, attributed to spinal and supraspinal inhibitory mechanisms. Electromyographic breakthrough activity has been observed in healthy adults as a result of a spinal reflex response within the cortical silent period. OBJECTIVES: The objective of this case series is to report the ipsilesional and contralesional cortical silent period and the electromyographic breakthrough activity of 7 children with congenital hemiparesis. METHODS: TMS was delivered over the ipsilesional and contralesional primary motor cortices with resting motor threshold and cortical silent period measures recorded from first dorsal interosseous muscle. RESULTS: Seven children (13+/-2 years) were included. Ipsilesional and contralesional resting motor thresholds ranged from 49 to 80% and from 38 to 63% of maximum stimulator output, respectively. Ipsilesional (n=4) and contralesional (n=7) cortical silent period duration ranged from 49 to 206ms and 81 to 150ms, respectively. Electromyographic breakthrough activity was observed ipsilesionally in 3/4 (75%) and contralesionally in 3/7 (42.8%) participants. In the 3 children with ipsilesional breakthrough activity during the cortical silent period, all testing trials showed breakthrough. Contralesional breakthrough activity was observed in only one of the analyzable trials in each of those 3 participants. The mean peak amplitude of breakthrough activity ranged from 45 to 214MUV (ipsilesional) and from 23 to 93MUV (contralesional). CONCLUSION: Further research is warranted to understand the mechanisms and significance of electromyographic breakthrough activity within the cortical silent period in congenital hemiparesis. Understanding these mechanisms may lead to the design of tailored neuromodulation interventions for physical rehabilitation. TRIAL REGISTRATION: NCT02250092 (https://clinicaltrials.gov/ct2/show/NCT02250092). PMID- 30471966 TI - Does the speed of aquatic therapy exercise alter arm volume in women with breast cancer related lymphoedema? A cross-over randomized controlled trial. AB - OBJECTIVE: To identify whether slow aquatic exercise in the form of modified Ai Chi is more effective than conventional (faster pace) aquatic therapy at reducing arm volume in women with or at risk of breast cancer related lymphoedema. METHODS: Randomized, cross-over controlled trial with concealed allocation and blinded assessment. Eighteen women with a history of breast cancer related lymphoedema were recruited. Participants received two intervention sessions (randomized order) with one week apart. Interventions were a 50min conventional aquatic intervention or a 50min modified Ai Chi. Arm volume was measured as the difference between affected and unaffected arm; bio-impedance was measured as an index of extracellular fluid; satisfaction was measured via a 12 question form. Outcomes were measured before, immediately after and one hour after intervention. RESULTS: Comparison between interventions showed larger decreased arm volume of 140mL (95%CI 17-263) immediately after intervention in favor of the Ai Chi intervention, however it was not sustained at 1h follow-up. A post hoc analysis showed 72% of participants had a decrease in arm volume immediately after Ai Chi compared to 28% immediately after conventional aquatic therapy; with a number needed to treat of 3 (95%CI 1.4-6.6). There were no differences between interventions for bio-impedance. Satisfaction was good for both interventions. CONCLUSION: Slow pace aquatic exercise is more effective than conventional aquatic exercise immediately after intervention for arm volume. Also, undesirable increase in arm volume seems to subside after 1h, which can be beneficial if therapy does not address arm volume. TRIAL REGISTRATION: ACTRN12614000557639 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=126140005576 9). PMID- 30471967 TI - Evidence of stabilizing exercises for low back- and pelvic girdle pain - a critical review. AB - BACKGROUND: Pregnancy-related low back pain (LBP) and pelvic girdle pain (PGP) have been associated with an alteration in the strategy for lumbopelvic stabilization. Different core stabilization approaches exist, the evidence is however controversial. METHODS: This paper discusses how to improve the evidence of exercises for women suffering from LBP and PGP during and after pregnancy. Exercises should be understood in a context, where the bio-psycho-social perspective directs the prescription of exercises, targeting both psychological and physical factors. The type of exercise probably should be individually tailored to the needs and capability of the individual and it is not only about the most appropriate exercise, it is about dosage and delivery of the exercises, and it is about performance. To promote adherence the use of patient preferences, with self-defined movement goals, may be a motivational basis for behavior change. Communication skills may facilitate positive beliefs and provide a motivational foundation for empowerment, self-efficacy and for self-management. To learn by discovery where the patient learns through their own experiences, might motivate the patients to active engagement and to behavioral change. Adherence probably will increase when the patients understand the aim and the rationale behind the exercises they are prescribed. However, with high adherence to exercises that maintains an inappropriate motor pattern, LBP and PGP possibly could proceed into chronicity. CONCLUSION: Exercises need to be meaningful to the patient, relevant for daily activities, individualized according to patient preferences, guided and supervised to secure performance and quality. PMID- 30471968 TI - Updates to our web-based infection prevention data toolkits. PMID- 30471969 TI - Spores on wheels: Wheelchairs are a potential vector for dissemination of pathogens in health care facilities. AB - In a hospital and affiliated long-term care facility, we found that shared wheelchairs were frequently contaminated with health care-associated pathogens, including Clostridium difficile spores. A network graph of 851 wheelchair transports over 3 days demonstrated frequent movement between inpatient wards and outpatient clinics, radiology, and physical therapy. These results highlight the potential for shared wheelchairs to serve as a vector for pathogen transmission. PMID- 30471970 TI - Knowledge, attitudes, and practices of bedside nursing staff regarding antibiotic stewardship: A cross-sectional study. AB - BACKGROUND: Nursing engagement in antibiotic stewardship programs (ASPs) remains suboptimal. The purpose of this study was to determine the knowledge, attitudes, and practices of nursing staff members regarding ASPs and identify barriers to their participation in such programs. METHODS: This cross-sectional study was conducted at Virginia Commonwealth University Health System, an 860-bed tertiary care academic center located in Richmond, Virginia, where a well-resourced ASP has been in place for 2 decades. A survey consisting of 12 questions was administered to nursing staff via REDCap (Research Electronic Data Capture) in February 2018. RESULTS: A total of 159 survey responses were included in the study. The results demonstrated gaps in knowledge regarding antibiotic stewardship (AS) and highlighted the importance of improving communication between nurses and ASPs. Overall, 102 (64.15%) of the study participants indicated familiarity with AS. Time constraints and concerns over physician pushback were identified as major barriers to participation. CONCLUSIONS: Many nurses were unaware of our center's ASP. Nurses identified activities falling within their daily workflow as potential areas for contribution to ASPs. Key barriers to participation were also identified. These data will inform efforts to engage nursing in AS activities at our medical center. PMID- 30471971 TI - Clostridioides difficile colonization and infection in patients with newly diagnosed acute leukemia: Incidence, risk factors, and patient outcomes. AB - BACKGROUND: The frequency, risk factors, and outcomes for Clostridioides difficile infection (CDI) in patients with newly diagnosed acute leukemia (AL) admitted for induction therapy are unclear. METHODS: We studied 509 consecutive patients with AL admitted between 2006 and 2017 and conducted a prospective C difficile surveillance and ribotyping analysis in a subset of these. RESULTS: The incidence of CDI was 2.2/1,000 inpatient days during induction, and CDI was rare after discharge. CDI was highest in patients with acute myelogenous leukemia. A hospitalization shortly before admission and administration of a greater number of antibiotics increased the risk for CDI. No single class of antibiotics conveyed an increased risk. All cases were successfully treated, and CDI was not associated with an increase in length of stay, costs, or mortality. In a subgroup analysis, 16% of patients with acute myelogenous leukemia and 4% with other leukemia types were colonized on admission. Colonization was associated with a higher risk of CDI. Ribotyping of available isolates showed 27 different strain types with 014/020 and 027 being the most frequent. CONCLUSIONS: The number of antibiotics administered are a major risk factor for CDI in patients with AL. However, CDI appears to have minimal clinical impact in this population. PMID- 30471972 TI - Are ball pits located in physical therapy clinical settings a source of pathogenic microorganisms? AB - Clinical, therapeutic ball pits commonly used by physical therapists to provide sensory stimulation to children were investigated for microbial colonization. Due to the permissive and hospitable environment provided by these ball pits, microorganisms can accumulate to levels that increase the ease of transmission to exposed individuals. Our study found considerable microbial colonization in ball pits located in clinical settings, including 8 opportunistic pathogenic bacteria and 1 opportunistic pathogenic yeast. PMID- 30471973 TI - Does chlorhexidine mouthwash reduce the rate of oral colonization by gram negative bacteria in patients with chemotherapy? A placebo-controlled trial. AB - The presence of gram-negative bacteria in the oral cavity is an undesirable occurrence in patients undergoing chemotherapy. Our aim was to investigate the antibacterial effect of 0.12% chlorhexidine mouthwash in chemotherapy patients with a randomized, double-blind, placebo-controlled trial. There were no significant differences between oral colonization rates; there may be local factors that interfere with chlorhexidine activity. PMID- 30471974 TI - A pilot study to assess the impact of an educational patient hand hygiene intervention on acquisition of colonization with health care-associated pathogens. AB - Patient hand hygiene is a commonsense measure that has been associated with reductions in colonization or infection with bacterial and viral pathogens in quasi-experimental studies. We conducted a nonblinded pilot randomized trial to assess the impact of an educational patient hand hygiene intervention on acquisition of colonization by selected health care-associated pathogens in hospitalized patients. For patients with negative admission cultures, the intervention did not reduce the new acquisition of colonization by pathogens compared with that of standard care. PMID- 30471975 TI - Hazards from physical attributes of the home environment among patients on outpatient parenteral antimicrobial therapy. AB - BACKGROUND: Outpatient parenteral antimicrobial therapy (OPAT) requires that patients and their caregivers administer antimicrobial medications in the home via venous catheters. Hazards from physical attributes of the home environment may impede safe performance of OPAT tasks. METHODS: We performed a qualitative study, including semistructured telephone interviews and contextual inquiries, of patients performing OPAT tasks inside the home. Eligible participants were discharged from 2 academic medical centers in Baltimore, Maryland, on OPAT. We coded interview transcripts and contextual inquiry forms based on a model of health care work systems. RESULTS: Twenty-nine patients underwent semistructured telephone interviews, and 14 patients underwent contextual inquiry. We identified hazards including bathing, animal or pets, extremes in temperature, household clutter, indoor soil and food exposures, outdoor soil, and travel. Patients often developed strategies to mitigate these hazards. DISCUSSION: Multiple hazards related to the home environment could have led to harm, and in the absence of specific guidance, patients developed strategies to mitigate these hazards. CONCLUSIONS: Educational interventions to improve OPAT should incorporate an understanding of hazards that may occur in the home environment. PMID- 30471976 TI - A multicenter point prevalence survey of health care-associated infections in Pakistan: Findings and implications. AB - BACKGROUND: Health care-associated infections (HAIs) are seen as a global public health threat, leading to increased mortality and morbidity as well as costs. However, little is currently known about the prevalence of HAIs in Pakistan. Consequently, this multicenter prevalence survey of HAIs was conducted to assess the prevalence of HAIs in Pakistan. METHODS: We used the methodology employed by the European Centre for Disease Prevention and Control to assess the prevalence of HAIs in Punjab Province, Pakistan. Data were collected from 13 hospitals using a structured data collection tool. RESULTS: Out of 1,553 hospitalized patients, 130 (8.4%) had symptoms of HAIs. The most common HAI was surgical site infection (40.0%), followed by bloodstream infection (21.5%), and lower respiratory tract infection (14.6%). The prevalence of HAI was higher in private sector hospitals (25.0%) and among neonates (23.8%) and patients admitted to intensive care units (33.3%). Patients without HAIs were admitted mainly to public sector hospitals and adult medical and surgical wards. CONCLUSIONS: The study found a high rate of HAIs among hospitals in Pakistan, especially surgical site infections, bloodstream infections, and lower respiratory tract infections. This needs to be addressed to reduce morbidity, mortality, and costs in the future, and further research is planned. PMID- 30471977 TI - Exploring patient perceptions of contact precautions. PMID- 30471978 TI - An approach to sample size calculation for research on duration of untreated psychosis. PMID- 30471979 TI - Characteristics and outcomes of young people with substance induced psychotic disorder. AB - BACKGROUND: Substance induced psychotic disorders (SIPD) have been historically considered as associated with better clinical and functional outcomes than other psychotic diagnoses. As a result, treatments for those with SIPD are often considerably less intensive, yet this is not based on evidence. The present study aimed to examine whether differences exist between those with SIPD and other first episode psychosis (FEP) diagnoses in regards to demographic and clinical factors, and to determine the symptomatic, clinical and functional outcomes in those with SIPD. METHODS: This study included all young people aged 15-24 who presented with a FEP to the Early Psychosis Prevention and Intervention Centre between 01/01/2011 and 31/12/2013. Group differences were analysed with independent samples t-tests and chi-square analyses and equivalent non-parametric tests as appropriate. Where applicable, odds ratios were calculated. RESULTS: 544 young people presented with a FEP and 10.3% (N = 56) were diagnosed with SIPD. Individuals with SIPD were more likely to be male, unemployed, and have a comorbid substance use disorder. There were no significant differences between groups regarding duration of untreated psychosis, severity of psychotic symptoms, time to remission, or rates of relapse. Those with SIPD were less likely to be employed or engaged in study at discharge and 35.7% of those with SIPD had a change of diagnosis to a schizophrenia spectrum or bipolar disorder after a median of 84 weeks. CONCLUSION: Young people diagnosed with SIPD should be an important focus of early intervention services and receive comparable treatment to those with other psychotic diagnoses. PMID- 30471980 TI - Goal-directed planning and action impairments in schizophrenia evaluated in a virtual environment. AB - Planning and executing goal-directed behaviours are critical final steps in translating motivation into action. Amotivation is a key feature of schizophrenia, but its impact on goal-directed functioning has not been extensively studied in an objective and ecologically valid manner. To address this, we investigated goal-directed planning and action in schizophrenia using a virtual reality task, the Multitasking in the City Test (MCT). The MCT was administered to 49 outpatients with schizophrenia and 55 healthy controls, and required participants to complete a series of errands in a virtual city. Ability to complete the task as directed was assessed by a performance score based on errands completed and errors committed. Task efficiency was evaluated by the total distance travelled, and an index of path efficiency comparing an optimal route with the traversed route. Schizophrenia participants had lower performance scores, travelled farther, and had reduced path efficiency compared to healthy controls. Greater distance travelled and lower path efficiency in schizophrenia were related to amotivation. Path efficiency in schizophrenia was also related to neurocognition, including planning ability; notably, this relationship appeared to be independent of the relationship with amotivation. Individuals with schizophrenia demonstrated impaired goal-directed planning and action in the context of a simulated everyday errands task, both in terms of reduced capacity to complete errands and reduced efficiency in doing so. The latter may manifest as diminished real-world motivated and functional behaviour in patients with schizophrenia and indicates a specific deficit in the execution of planned behaviour. PMID- 30471981 TI - Prediction of annual drinking water quality reduction based on Groundwater Resource Index using the artificial neural network and fuzzy clustering. AB - Drought is one of the most significant natural phenomena affecting different aspects of human life and the environment. Due to water scarcity, prediction of water quality reduction is very crucial for urban and rural communities. This study contributes by applying artificial neural network and modified fuzzy clustering techniques to estimate the drops in potential drinking water quality in the GIS environment. In this research, the probability of occurrence of adverse annual changes in the water quality of drinking water is estimated. The model was tested using real instances of the southeast aquifers, the regions of the central parts of the IRAN and especially the significant portions of the aquifers of the east area. To validate the model, the data adequacy test and the standardization of the drought index are used. The results of the lowest available water quality and the highest drought using ANNs show that the qualitative stress conditions in large part of the country's aquifers are in unfavorable conditions. Evidence from this research shows that the aquifers in these areas are expected to have severe drought stress and poor quality class status. Also, the computational results indicate that the modified clustering method increases the efficiency of the prediction model as against the previous research. The outcomes do not show a relatively favorable state of drinking water quality for some aquifers in the country. However, the conditions for quantitative changes in the depth of water, based on the predicted results of ANN, are considered critical. The generated maps demonstrate that about 64% of the study area is subjected to a severe deterioration in the quality of drinking water if the current trend continues in the exploitation of aquifers. As a result, the main finding the present study is that the probability of groundwater quality decline is significant in many aquifers in the country. PMID- 30471982 TI - Molecular cloning and functional characterization of an O-methyltransferase catalyzing 4'-O-methylation of resveratrol in Acorus calamus. AB - Resveratrol and its methyl ethers, which belong to a class of natural polyphenol stilbenes, play important roles as biologically active compounds in plant defense as well as in human health. Although the biosynthetic pathway of resveratrol has been fully elucidated, the characterization of resveratrol-specific O methyltransferases remains elusive. In this study, we used RNA-seq analysis to identify a putative aromatic O-methyltransferase gene, AcOMT1, in Acorus calamus. Recombinant AcOMT1 expressed in Escherichia coli showed high 4'-O-methylation activity toward resveratrol and its derivative, isorhapontigenin. We purified a reaction product enzymatically formed from resveratrol by AcOMT1 and confirmed it as 4'-O-methylresveratrol (deoxyrhapontigenin). Resveratrol and isorhapontigenin were the most preferred substrates with apparent Km values of 1.8 MUM and 4.2 MUM, respectively. Recombinant AcOMT1 exhibited reduced activity toward other resveratrol derivatives, piceatannol, oxyresveratrol, and pinostilbene. In contrast, recombinant AcOMT1 exhibited no activity toward pterostilbene or pinosylvin. These results indicate that AcOMT1 showed high 4'-O-methylation activity toward stilbenes with non-methylated phloroglucinol rings. PMID- 30471983 TI - The Itch-Scratch Cycle: A Neuroimmune Perspective. AB - Relentless, repetitive itching and scratching is a debilitating feature of many chronic inflammatory skin disorders such as atopic dermatitis. While well known clinically, this itch-scratch cycle has historically lacked in-depth mechanistic understanding. However, recent advances at the interface of itch neurobiology and skin immunology have shed new light on this phenomenon. In this review, we highlight recent advances in our understanding of the neuroimmunology of chronic itch centered around three key points of entry into the itch-scratch cycle: the epithelial barrier, the immune system, and the peripheral nervous system. Furthermore, we explore novel neuro-epithelial-immune interactions that may represent promising therapeutic paradigms. PMID- 30471984 TI - Editorial commentary on "Atherosclerosis and immunity: A perspective". PMID- 30471985 TI - Editorial commentary: Extracellular vesicles in cardiovascular diagnosis and therapy. PMID- 30471986 TI - Editorial commentary: Ecology of cardio-metabolic diseases: Low-income countries also matter. PMID- 30471987 TI - Toxicokinetics and bioaccumulation of polycyclic aromatic compounds in wood frog tadpoles (Lithobates sylvaticus) exposed to Athabasca oil sands sediment. AB - We performed accumulation-elimination experiments of polycyclic aromatic compounds (PACs) in wood frog tadpoles (Lithobates sylvaticus) using river sediment from Canada's Athabasca oil sands region. The PACs in wood frog tadpoles were ~2x higher on average when the animals were in direct contact with PAC contaminated sediment than when they were separated from the sediment with a screen and exposed only to aqueous PACs. These results suggest that sediment exposure/ingestion contributes as much to PAC accumulation in tadpoles as exposure via aqueous pathways. Alkyl-substituted PAC concentrations in exposed tadpoles exceeded those of the unsubstituted (parent) PACs by about 10 * . Bioaccumulation factors ranged between 0.01 and 4.93, with parent PACs having higher bioaccumulation factors than alkylated PACs. Wood frog tadpoles efficiently eliminated and metabolized most parent and alkyl-substituted PACs, though some compounds (e.g., C4-naphthalenes) had higher bioaccumulation potential and may serve as effective markers of exposure. Here we present a comprehensive analysis of the toxicokinetics and bioaccumulation of PACs (52 analytes) in amphibian larvae, and highlight the importance of sediment exposure when considering the bioaccumulation and potential biological impact of PACs in benthic and epibenthic organisms. PMID- 30471988 TI - What are the components of effective chronic condition self-management education interventions for children with asthma, cystic fibrosis, and diabetes? A systematic review. AB - OBJECTIVE: To articulate the components of educational interventions that help children learn about managing their asthma, cystic fibrosis, or diabetes, relevant to their age/developmental status. METHODS: A systematic review of chronic condition self-management (CCSM) educational interventions that included age/developmentally appropriate components, published before 27 January 2018, including evidence level and quality assessments. Teaching approaches were extracted and translated into practical components. RESULTS: Twenty education interventions were identified, published across 30 studies. Most studies (n = 20/30) were based on the theories of Piaget and Bandura. Similar teaching approaches were used across conditions, incorporating sequenced curriculum and a variety of active elements. Age/developmentally appropriate interventions resulted in improvements in the CCSM capabilities of children. Outcomes were improved when compared with usual care. For very young children, educational interventions were directed at parents/families. As children reached school age, interventions increasingly became child-focused, promoting autonomy. Integrated play and reinforcement were common. Adolescent interventions placed greater emphasis on communication, problem-solving, and role division. CONCLUSION: Eight key components were identified: structured and sequenced curricula; reinforcement; active participation; collaboration; autonomy; feedback; multiple exposures; and, problem-solving. Different components are relevant to specific life stages. PRACTICE IMPLICATIONS: Clinicians require age/developmentally appropriate practical education tools to provide effective paediatric health care. PMID- 30471989 TI - Self-Reported Adherence to High Reliability Practices Among Participants in the Children's Hospitals' Solutions for Patient Safety Collaborative. AB - BACKGROUND: Application of high reliability principles has the potential to transform the health care industry to perform with a higher level of safety than is present today. The purpose of this study was to quantitatively assess and describe the extent and variability of integration of high reliability practices among a collaborative of children's hospitals using the High Reliability Health Care Maturity (HRHCM) model. METHODS: A survey instrument based on the HRHCM model was developed to determine the extent of integration of high reliability practices across hospitals participating in the Children's Hospitals' Solutions for Patient Safety (CHSPS) network. The survey was distributed with instructions for completion to obtain a single organizational response, which was then used to quantify the extent to which high reliability attributes were implemented at each organization. RESULTS: Of the 95 institutions in the CHSPS at the time of the study, 46 provided a complete response to the survey (48.4% response rate). The overall mean score for high reliability was 42.3 (range: 28-53), which places the cohort in the stage of approaching high reliability. Of the responding organizations, none fell into the beginning stage, while 15.2% landed in the developing, 4.3% in the advancing, and 80.4% in the approaching high reliability stages. CONCLUSION: Understanding high reliability attributes and assessing the location of individual and collaborative-wide sites along the high reliability continuum using this maturity model identify opportunities for organizations as they progress on their high reliability journey. Our results suggest opportunity in all domains of the high reliability maturity model for the majority of participating children's hospitals. PMID- 30471990 TI - Feasibility of using auditory event-related potentials to investigate learning and memory in nonverbal individuals with Angelman syndrome. AB - The combination of intellectual, communicative, and motor deficits limit the use of standardized behavioral assessments of cognition in individuals with Angelman syndrome (AS). The current study is the first to objectively evaluate learning and memory in AS using auditory event-related potentials (ERP) during passive exposure to spoken stimuli. Fifteen nonverbal individuals with the deletion subtype of AS (age 4-45 years) completed the auditory incidental memory paradigm. Auditory ERPs were recorded in response to a sequence of unfamiliar nonwords, in which one randomly selected stimulus was repeated multiple times and the rest were presented once. Larger parietal responses within 200-500 ms for the repeated nonword compared to novel distracters were associated with caregiver reports of more adaptive communication skills. These findings demonstrate good tolerability of ERP procedures (94% success rate) and indicate that persons with AS can acquire new information following repeated auditory exposure, even in the absence of explicit memorization instructions. Strong associations between the caregiver reports of adaptive functioning and neural indices of auditory learning and memory support the utility of brain-based measures for objectively evaluating higher-order information processing in nonverbal persons with neurodevelopmental disorders. PMID- 30471991 TI - Further to the right: Viewing distance modulates attentional asymmetries ('pseudoneglect') during visual exploration. AB - Previous studies showed that the small leftward bias found in healthy humans' spatial judgments of lines ("pseudoneglect") shifts to the right with increasing distance between stimuli and observer. In this study, we investigated whether such a modulation of attentional asymmetry can also be observed in free visual exploration. Participants freely explored photographs of naturalistic scenes for 7 s in near (60 cm) and far (140 cm) space. After an initial leftward bias, followed by a compensatory rightward bias, gaze positions were significantly more leftward in near compared to far space (around 4 s from scene onset). Our results show that the modulation of attentional asymmetries by viewing distance previously reported for spatial judgments generalizes to free visual exploration, and we revealed the temporal dynamics of these asymmetries by fine-grained eye movement analysis. In contrast, an effect of viewing distance was reduced or absent when eye movements are under strong top-down control, as in systematic serial visual search (Sensitive Negelct Test). Finally, there was no effect of viewing distance in the landmark task (as also reported in a minority of other studies), suggesting that this effect may depend on specific, yet unidentified task characteristics. PMID- 30471992 TI - Immunotherapy, Cancer and Rheumatological Diseases: A Review of the Literature and a Series of Cases in a University Hospital. AB - The appearance in the field of oncology of therapeutic molecules in the form of monoclonal antibodies, whose objective is to stimulate the patient's own immune system to be responsible for destroying cancer cells, has revolutionized the treatment of many cancers in recent years. This type of therapy, called immunotherapy, is also characterized by presenting side effects in the form of autoimmune diseases that we are still beginning to understand. From the point of view of the immune-mediated rheumatological side effects, we can find musculoskeletal manifestations, mechanical, inflammatory or systemic autoimmune diseases. The therapeutic approach to these side effects remains uncertain due to the absence of clinical trials and validated recommendations. The multidisciplinary management is crucial to successfully treat such cases. In the following manuscript, we will describe our case reports of rheumatologic immune related adverse events in a university hospital. PMID- 30471993 TI - The Neuronal Basis of an Illusory Motion Percept Is Explained by Decorrelation of Parallel Motion Pathways. AB - Both vertebrates and invertebrates perceive illusory motion, known as "reverse phi," in visual stimuli that contain sequential luminance increments and decrements. However, increment (ON) and decrement (OFF) signals are initially processed by separate visual neurons, and parallel elementary motion detectors downstream respond selectively to the motion of light or dark edges, often termed ON- and OFF-edges. It remains unknown how and where ON and OFF signals combine to generate reverse-phi motion signals. Here, we show that each of Drosophila's elementary motion detectors encodes motion by combining both ON and OFF signals. Their pattern of responses reflects combinations of increments and decrements that co-occur in natural motion, serving to decorrelate their outputs. These results suggest that the general principle of signal decorrelation drives the functional specialization of parallel motion detection channels, including their selectivity for moving light or dark edges. PMID- 30471994 TI - foxF-1 Controls Specification of Non-body Wall Muscle and Phagocytic Cells in Planarians. AB - Planarians are flatworms capable of regenerating any missing body part in a process requiring stem cells and positional information. Muscle is a major source of planarian positional information and consists of several types of fibers with distinct regulatory roles in regeneration. The transcriptional regulatory programs used to specify different muscle fibers are poorly characterized. Using single-cell RNA sequencing, we define the transcriptomes of planarian dorsal ventral muscle (DVM), intestinal muscle (IM), and pharynx muscle. This analysis identifies foxF-1, which encodes a broadly conserved Fox-family transcription factor, as a master transcriptional regulator of all non-body wall muscle. The transcription factors encoded by nk4 and gata4/5/6-2 specify two different subsets of DVM, lateral and medial, respectively, whereas gata4/5/6-3 specifies IM. These muscle types all express planarian patterning genes. Both lateral and medial DVM are required for medial-lateral patterning in regeneration, whereas medial DVM and IM have a role in maintaining and regenerating intestine morphology. In addition to the role in muscle, foxF-1 is required for the specification of multiple cell types with transcriptome similarities, including high expression levels of cathepsin genes. These cells include pigment cells, glia, and several other cells with unknown function. cathepsin+ cells phagocytose E. coli, suggesting these are phagocytic cells. In conclusion, we describe a regulatory program for planarian muscle cell subsets and phagocytic cells, both driven by foxF-1. FoxF proteins specify different mesoderm-derived tissues in other organisms, suggesting that FoxF regulates formation of an ancient and broadly conserved subset of mesoderm derivatives in the Bilateria. PMID- 30471995 TI - Hypothalamic Neurons that Regulate Feeding Can Influence Sleep/Wake States Based on Homeostatic Need. AB - Eating and sleeping represent two mutually exclusive behaviors that satisfy distinct homeostatic needs. Because an animal cannot eat and sleep at the same time, brain systems that regulate energy homeostasis are likely to influence sleep/wake behavior. Indeed, previous studies indicate that animals adjust sleep cycles around periods of food need and availability. Furthermore, hormones that affect energy homeostasis also affect sleep/wake states: the orexigenic hormone ghrelin promotes wakefulness, and the anorexigenic hormones leptin and insulin increase the duration of slow-wave sleep. However, whether neural populations that regulate feeding can influence sleep/wake states is unknown. The hypothalamic arcuate nucleus contains two neuronal populations that exert opposing effects on energy homeostasis: agouti-related protein (AgRP)-expressing neurons detect caloric need and orchestrate food-seeking behavior, whereas activity in pro-opiomelanocortin (POMC)-expressing neurons induces satiety. We tested the hypotheses that AgRP neurons affect sleep homeostasis by promoting states of wakefulness, whereas POMC neurons promote states of sleep. Indeed, optogenetic or chemogenetic stimulation of AgRP neurons in mice promoted wakefulness while decreasing the quantity and integrity of sleep. Inhibition of AgRP neurons rescued sleep integrity in food-deprived mice, highlighting the physiological importance of AgRP neuron activity for the suppression of sleep by hunger. Conversely, stimulation of POMC neurons promoted sleep states and decreased sleep fragmentation in food-deprived mice. Interestingly, we also found that sleep deprivation attenuated the effects of AgRP neuron activity on food intake and wakefulness. These results indicate that homeostatic feeding neurons can hierarchically affect behavioral outcomes, depending on homeostatic need. PMID- 30471997 TI - Cortical Response to the Natural Speech Envelope Correlates with Neuroimaging Evidence of Cognition in Severe Brain Injury. AB - Recent studies identify severely brain-injured patients with limited or no behavioral responses who successfully perform functional magnetic resonance imaging (fMRI) or electroencephalogram (EEG) mental imagery tasks [1-5]. Such tasks are cognitively demanding [1]; accordingly, recent studies support that fMRI command following in brain-injured patients associates with preserved cerebral metabolism and preserved sleep-wake EEG [5, 6]. We investigated the use of an EEG response that tracks the natural speech envelope (NSE) of spoken language [7-22] in healthy controls and brain-injured patients (vegetative state to emergence from minimally conscious state). As audition is typically preserved after brain injury, auditory paradigms may be preferred in searching for covert cognitive function [23-25]. NSE measures are obtained by cross-correlating EEG with the NSE. We compared NSE latencies and amplitudes with and without consideration of fMRI assessments. NSE latencies showed significant and progressive delay across diagnostic categories. Patients who could carry out fMRI based mental imagery tasks showed no statistically significant difference in NSE latencies relative to healthy controls; this subgroup included patients without behavioral command following. The NSE may stratify patients with severe brain injuries and identify those patients demonstrating "cognitive motor dissociation" (CMD) [26] who show only covert evidence of command following utilizing neuroimaging or electrophysiological methods that demand high levels of cognitive function. Thus, the NSE is a passive measure that may provide a useful screening tool to improve detection of covert cognition with fMRI or other methods and improve stratification of patients with disorders of consciousness in research studies. PMID- 30471996 TI - Decision Making through Integration of Sensory Evidence at Prolonged Timescales. AB - When multiple pieces of information bear on a decision, the best approach is to combine the evidence provided by each one. Evidence integration models formalize the computations underlying this process [1-3], explain human perceptual discrimination behavior [4-9], and correspond to neuronal responses elicited by discrimination tasks [10-14]. These findings suggest that evidence integration is key to understanding the neural basis of decision making [15-18]. But while evidence integration has most often been studied with simple tasks that limit deliberation to relatively brief periods, many natural decisions unfold over much longer durations. Neural network models imply acute limitations on the timescale of evidence integration [19-23], and it is currently unknown whether existing computational insights can generalize beyond rapid judgments. Here, we introduce a new psychophysical task and report model-based analyses of human behavior that demonstrate evidence integration at long timescales. Our task requires probabilistic inference using brief samples of visual evidence that are separated in time by long and unpredictable gaps. We show through several quantitative assays how decision making can approximate a normative integration process that extends over tens of seconds without accruing significant memory leak or noise. These results support the generalization of evidence integration models to a broader class of behaviors while posing new challenges for models of how these computations are implemented in biological networks. PMID- 30471998 TI - Dip1 Co-opts Features of Branching Nucleation to Create Linear Actin Filaments that Activate WASP-Bound Arp2/3 Complex. AB - When activated by Wiskott-Aldrich syndrome proteins (WASP), Arp2/3 complex nucleates branched actin filaments important for processes like cellular motility and endocytosis [1]. WASP-mediated activation of Arp2/3 complex requires a preformed actin filament, ensuring that activation by WASP creates branched instead of linear filaments. However, this biochemical requirement also means that assembly of branched actin networks must be primed with an initial seed filament [2-4]. We recently described a class of activators called WISH/DIP/SPIN90 (WDS) proteins, which, unlike WASP, activate Arp2/3 complex without a preformed filament [4]. Although this property may allow WDS proteins to serve as seed filament generators, it is unknown whether actin filaments nucleated by WDS-activated Arp2/3 complex can activate WASP-bound Arp2/3 complex. Further, despite their potential importance as branched actin network initiators, little is known about how WDS proteins turn on Arp2/3 complex. Here, we use two color single-molecule total internal reflection fluorescence (TIRF) microscopy to show that Dip1, the S. pombe WDS protein [5], co-opts features of branching nucleation to activate Arp2/3 complex. Specifically, it activates Arp2/3 complex to nucleate linear filaments analogous to the branch created by WASP-mediated activation. The barbed ends of Dip1-Arp2/3 nucleated filaments are free to elongate, and their pointed ends remain anchored to Dip1-bound Arp2/3 complex. The linear filaments nucleated by Dip1-bound Arp2/3 complex activate WASP-bound Arp2/3 complex as potently as spontaneously nucleated or branched actin filaments. These observations provide important insights into the regulation of Arp2/3 complex by its activators and the molecular basis for initiation of branched actin networks. PMID- 30471999 TI - Coincidence Detection of Membrane Stretch and Extracellular pH by the Proton Sensing Receptor OGR1 (GPR68). AB - The physical environment critically affects cell shape, proliferation, differentiation, and survival by exerting mechanical forces on cells. These forces are sensed and transduced into intracellular signals and responses by cells. A number of different membrane and cytoplasmic proteins have been implicated in sensing mechanical forces, but the picture is far from complete, and the exact transduction pathways remain largely elusive. Furthermore, mechanosensation takes place alongside chemosensation, and cells need to integrate physical and chemical signals to respond appropriately and ensure normal tissue and organ development and function. Here, we report that ovarian cancer G protein coupled receptor 1 (OGR1) (aka GPR68) acts as coincidence detector of membrane stretch and its physiological ligand, extracellular H+. Using fluorescence imaging, substrates of different stiffness, microcontact printing methods, and cell-stretching techniques, we show that OGR1 only responds to extracellular acidification under conditions of membrane stretch and vice versa. The level of OGR1 activity mirrors the extent of membrane stretch and degree of extracellular acidification. Furthermore, actin polymerization in response to membrane stretch is critical for OGR1 activity, and its depolymerization limits how long OGR1 remains responsive following a stretch event, thus providing a "memory" for past stretch. Cells experience changes in membrane stretch and extracellular pH throughout their lifetime. Because OGR1 is a widely expressed receptor, it represents a unique yet widespread mechanism that enables cells to respond dynamically to mechanical and pH changes in their microenvironment by integrating these chemical and physical stimuli at the receptor level. PMID- 30472000 TI - Pseudogenization and Resurrection of a Speciation Gene. AB - A persistent question in evolutionary biology is how complex phenotypes evolve and whether phenotypic transitions are reversible. Multiple losses of floral pigmentation have been documented in the angiosperms, but color re-gain has not yet been described, supporting that re-gain is unlikely. Pollinator-mediated selection in Petunia has resulted in several color shifts comprised of both losses and gains of color. The R2R3-MYB transcription factor AN2 has been identified as a major locus responsible for shifts in pollinator preference. Whereas the loss of visible color has previously been attributed to repeated pseudogenization of AN2, here, we describe the mechanism of an independent re gain of floral color via AN2 evolution. In P. secreta, purple color is restored through the improbable resurrection of AN2 gene function from a non-functional AN2-ancestor by a single reading-frame-restoring mutation. Thus, floral color evolution in Petunia is mechanistically dependent on AN2 functionality, highlighting its role as a hotspot in color transitions and a speciation gene for the genus. PMID- 30472001 TI - The complex molecular genetics of arrhythmogenic cardiomyopathy. PMID- 30472002 TI - Fetal growth, stillbirth, infant mortality and other birth outcomes near UK municipal waste incinerators; retrospective population based cohort and case control study. AB - BACKGROUND: Some studies have reported associations between municipal waste incinerator (MWI) exposures and adverse birth outcomes but there are few studies of modern MWIs operating to current European Union (EU) Industrial Emissions Directive standards. METHODS: Associations between modelled ground-level particulate matter <=10 MUm in diameter (PM10) from MWI emissions (as a proxy for MWI emissions) within 10 km of each MWI, and selected birth and infant mortality outcomes were examined for all 22 MWIs operating in Great Britain 2003-10. We also investigated associations with proximity of residence to a MWI. Outcomes used were term birth weight, small for gestational age (SGA) at term, stillbirth, neonatal, post-neonatal and infant mortality, multiple births, sex ratio and preterm delivery sourced from national registration data from the Office for National Statistics. Analyses were adjusted for relevant confounders including year of birth, sex, season of birth, maternal age, deprivation, ethnicity and area characteristics and random effect terms were included in the models to allow for differences in baseline rates between areas and in incinerator feedstock. RESULTS: Analyses included 1,025,064 births and 18,694 infant deaths. There was no excess risk in relation to any of the outcomes investigated during pregnancy or early life of either mean modelled MWI PM10 or proximity to an MWI. CONCLUSIONS: We found no evidence that exposure to PM10 from, or living near to, an MWI operating to current EU standards was associated with harm for any of the outcomes investigated. Results should be generalisable to other MWIs operating to similar standards. PMID- 30472003 TI - Effects of oral isotretinoin therapy on the nasal cavities. AB - INTRODUCTION: Isotretinoin (13 cis-retinoic acid) is the most effective treatment for acne vulgaris and is the only treatment option that can provide either remission or a permanent cure. OBJECTIVE: The aim of this study was to use both subjective and objective methods to assess the nasal complaints of patients with severe acne who received oral isotretinoin therapy. METHODS: Fifty-four subjects were enrolled in the study. All the subjects were assessed with subjective (NOSE and VAS questionnaires) and objective (rhinomanometry and saccharine) tests to determine the severity of their nasal complaints. RESULTS: The mean severity scores (min: 0; max: 100) for nasal dryness/crusting and epistaxis were 0.47+/ 1.48 (0-5); 0.35+/-1.30 (0-5) at admission, 3.57+/-4.45 (0-10); 2.26+/-4.71 (0 20) at the first month, and 4.28+/-6 (0-20); 2.26+/-4.71 (0-20) at the third month of the treatment respectively. Total nasal resistance of 0.195+/-0.079 (0.12-0.56)Pa/cm3/s at admission, 0.21+/-0.084 (0.12-0.54)Pa/cm3/s at the first month, and 0.216+/-0.081 (0.14-0.54)Pa/cm3/s at the third month. CONCLUSION: Oral isotretinoin therapy can cause the complaint of nasal obstruction. In addition, nasal complaints, such as dryness/crusting and epistaxis, significantly increase in patients during the therapy schedule. PMID- 30472004 TI - Endoscopic evaluation of middle ear anatomic variations in autopsy series: analyses of 204 ears. AB - INTRODUCTION: Microsurgery of the ear requires complete evaluation of middle ear surgical anatomy, especially the posterior tympanic cavity anatomy. Preoperative assessment of the middle ear cavity is limited by the permeability of eardrum and temporal bone density. Therefore, middle ear exploration is an extremely useful method to identify structural abnormalities and anatomical variations. OBJECTIVE: The aim of this study is to determine anatomic variations of the middle ear in an autopsy series. METHODS: All evaluations were performed in the Forensic Medicine Institute Morgue Department. The cases over 18 years of age, with no temporal bone trauma and history of otologic surgery included in this study. RESULTS: One hundred and two cadavers were included in the study. The mean age was 49.08+/ 17.76 years. Anterior wall prominence of the external auditory canal was present in 27 of all cadavers (26.4%). The tympanic membrane was normal in 192 ears (94%) while several eardrum pathologies were detected in 12 ears (6%). Agenesis of the pyramidal eminence and stapedial tendon was found in 3 ears. While the ponticulus was bony ridge-shaped in 156 of 204 ears (76.4%), it was bridge-shaped in 25 ears (12.3%). The ponticulus was absent in 23 ears (11.3%). While complete subiculum was present in 136 of all ears (66.7%), incomplete subiculum was present in 21 ears (10.3%). Subiculum was absent in 47 ears (23%). Facial dehiscence was found in 32 ears and the round window niche was covered by a pseudomembrane in 85 ears (41.6%). A fixed footplate was present in 7.4% of all ears, and no persistent stapedial artery was seen in any cases. CONCLUSION: The pseudomembrane frequency covering the round window niche was found different from reports in the literature. In addition, the frequency of the external auditory canal wall prominence has been reported for the first time. PMID- 30472005 TI - A call for mentorship in otolaryngology. PMID- 30472006 TI - [Glaucopsia after occupational exposure to amines]. PMID- 30472007 TI - RNA interference of endoglucanases in the formosan subterranean termite Coptotermes formosanus shiraki (Blattodea: Rhinotermitidae) by dsRNA injection or ingestion. AB - Termites obtain energy and nutrition from wood and wood-related materials by utilizing endogenous and symbiotic cellulases. Endoglucanase is one of the key cellulases in cellulose digestion. Previous studies have shown that the inhibition of the cellulase enzyme system would be a plausible approach for termite control. In the present study, we studied the effect of RNAi on termites by targeting a conserved region of five endoglucanase genes from Coptotermes formosanus (CfEGs). Both dsRNA injection and oral delivery resulted in significant gene silencing of CfEGs and consequently led to mortality, reduced enzyme activity, and reduced weight compared to control worker termites. An injection dose of 150 ng and a feeding dose of 2 MUg/cm2 provided for the best RNAi efficiency. dsCfEG was further combined with flufenoxuron, an insect growth regulator used to manage/suppress subterranean termites, and when fed to workers, caused a lower enzyme activity compared to the dsCfEG- or flufenoxuron-only treatment. The weight loss (~0.598 mg) and mortality (~28%) observed in the combined dsCfEG and flufenoxuron treatment differed significantly from those observed in the flufenoxuron-only treatment (~0.208 mg and ~16%, respectively). Although the effects of these dsCfEG treatments on mortality were insufficient to serve as termiticides, dsCfEGs could be used in combination with other treatments to increase efficacy. This study provides a research basis for the use of RNAi in termiticides. PMID- 30472008 TI - Spare to share? How does interindividual variation in metabolic rate influence food sharing in the honeybee? AB - A central benefit of group living is the cooperative acquisition and sharing of resources but the costs associated with these processes can set up a potential conflict between individual and group level fitness. Within a honeybee colony, the task of resource acquisition is relegated to the foragers and any interindividual differences in their metabolic rate and the consequent carbohydrate demand may pose a constraint on the amount of resources they can contribute to the colony. We investigated whether the carbohydrate demand of a forager is a function of her metabolic rate and if this impacts the amount of food she shares with the nestmates. Our results show that the sucrose consumption rates of foragers with high metabolic rates did not meet their carbohydrate demand, placing them at an energy deficit while those with lower metabolic rates had an energy surplus. Our food sharing experiments showed a trend but did not detect a significant difference among individuals with different consumption rates in terms of the amount of food they shared with their nestmates. These results suggest that honeybee foragers with different metabolic rates are likely to differ in terms of whether they have an energy surplus or deficit, but more long-term datasets may be required to detect how this may influence food sharing. PMID- 30472010 TI - Efficient Generation of Small Intestinal Epithelial-like Cells from Human iPSCs for Drug Absorption and Metabolism Studies. AB - The small intestine plays an important role in the absorption and metabolism of oral drugs. In the current evaluation system, it is difficult to predict the precise absorption and metabolism of oral drugs. In this study, we generated small intestinal epithelial-like cells from human induced pluripotent stem cells (hiPS-SIECs), which could be applied to drug absorption and metabolism studies. The small intestinal epithelial-like cells were efficiently generated from human induced pluripotent stem cell by treatment with WNT3A, R-spondin 3, Noggin, EGF, IGF-1, SB202190, and dexamethasone. The gene expression levels of small intestinal epithelial cell (SIEC) markers were similar between the hiPS-SIECs and human adult small intestine. Importantly, the gene expression levels of colonic epithelial cell markers in the hiPS-SIECs were much lower than those in human adult colon. The hiPS-SIECs generated by our protocol exerted various SIEC functions. In conclusion, the hiPS-SIECs can be utilized for evaluation of drug absorption and metabolism. PMID- 30472009 TI - Human Oligodendrogenic Neural Progenitor Cells Delivered with Chondroitinase ABC Facilitate Functional Repair of Chronic Spinal Cord Injury. AB - Treatment of chronic spinal cord injury (SCI) is challenging due to cell loss, cyst formation, and the glial scar. Previously, we reported on the therapeutic potential of a neural progenitor cell (NPC) and chondroitinase ABC (ChABC) combinatorial therapy for chronic SCI. However, the source of NPCs and delivery system required for ChABC remained barriers to clinical application. Here, we investigated directly reprogrammed human NPCs biased toward an oligodendrogenic fate (oNPCs) in combination with sustained delivery of ChABC using an innovative affinity release strategy in a crosslinked methylcellulose biomaterial for the treatment of chronic SCI in an immunodeficient rat model. This combinatorial therapy increased long-term survival of oNPCs around the lesion epicenter, facilitated greater oligodendrocyte differentiation, remyelination of the spared axons by engrafted oNPCs, enhanced synaptic connectivity with anterior horn cells and neurobehavioral recovery. This combinatorial therapy is a promising strategy to regenerate the chronically injured spinal cord. PMID- 30472012 TI - Eye illustrations in sketch pads (18th century). PMID- 30472013 TI - Author's reply. PMID- 30472011 TI - MYC Induces a Hybrid Energetics Program Early in Cell Reprogramming. AB - Cell reprogramming is thought to be associated with a full metabolic switch from an oxidative- to a glycolytic-based metabolism. However, neither the dynamics nor the factors controlling this metabolic switch are fully understood. By using cellular, biochemical, protein array, metabolomic, and respirometry analyses, we found that c-MYC establishes a robust bivalent energetics program early in cell reprogramming. Cells prone to undergo reprogramming exhibit high mitochondrial membrane potential and display a hybrid metabolism. We conclude that MYC proteins orchestrate a rewiring of somatic cell metabolism early in cell reprogramming, whereby somatic cells acquire the phenotypic plasticity necessary for their transition to pluripotency in response to either intrinsic or external cues. PMID- 30472014 TI - In Response to: "A Prospective Study of Stingray Injury and Envenomation Outcomes". PMID- 30472015 TI - The Effect of a Clinical Decision Support for Pending Laboratory Results at Emergency Department Discharge. AB - BACKGROUND: Health care systems often implement changes within the electronic health record (EHR) to improve patient safety and reduce medical errors. OBJECTIVE: To compare the proportion of emergency department (ED) encounters with laboratory tests resulting subsequent to patient discharge before and after a clinical decision support was implemented. METHODS: In 2015, our institution added an EHR dialogue when placing ED discharge orders, requiring providers to declare whether all laboratory results had been reviewed. To determine the effectiveness of this initiative, we searched the EHR to identify the proportion of ED encounters with laboratory tests resulting after discharge in pre- (January to June 2015) and post-intervention (January to June 2016) periods. RESULTS: There were 67,287 discharged patients during the study periods. In the pre- and post-intervention periods, respectively, 6.9% (95% confidence interval [CI] 6.7 7.2%) and 7.9% (95% CI 7.6-8.2%) of encounters had laboratory tests resulting after discharge, with an absolute difference of 0.9% (95% CI 0.5-1.3%). Of these patients with laboratory tests resulting after ED discharge, in 92% the provider inaccurately marked "yes" or "not applicable" to the EHR dialogue prompt. CONCLUSIONS: This workflow intervention was associated with an increase in the proportion of laboratory tests resulting after ED discharge; inaccurate answers to the EHR dialogue were pervasive. EHR workflow interventions do not always accomplish their intended goals, and their implementation should be considered thoughtfully. PMID- 30472016 TI - Simultaneous Intraoperative Delivery of Inhaled Epoprostenol and Nitric Oxide in a Neonate for Atrial Septal Defect Closure: First Report of a Novel Technique. PMID- 30472017 TI - The Year in Cardiothoracic and Vascular Anesthesia: Selected Highlights from 2018. PMID- 30472018 TI - The Influence of Naproxen on Biological Factors in Leukocyte-Rich Platelet-Rich Plasma: A Prospective Comparative Study. AB - PURPOSE: To quantify and compare normative catabolic and anabolic factor concentrations in leukocyte-rich platelet-rich plasma (LR-PRP) at various time points, including baseline, 1 week after initiating naproxen use, and after a 1 week washout period. METHODS: Asymptomatic healthy donors aged between 18 and 70 years were recruited (average age, 36.6 years; range, 25-64 years). Subjects were excluded from the study if they were actively taking any prescribed medications or nonsteroidal anti-inflammatory drugs (NSAIDs) or if they had any of the following at present or previously: blood or immunosuppression disorders, cancer, osteonecrosis, rheumatoid arthritis, avascular necrosis, NSAID intolerance, gastrointestinal or peptic ulcer disease, or kidney dysfunction. The anabolic factors vascular endothelial growth factor, fibroblast growth factor 2, platelet derived growth factor AB (PDGF-AB), and platelet-derived growth factor AA (PDGF AA) and the catabolic factors interleukin (IL) 1beta, IL-6, IL-8, and tumor necrosis factor alpha in LR-PRP were measured. Peripheral blood was drawn at 3 time points: baseline, after 1 week of naproxen use, and after a 1-week washout period. RESULTS: The angiogenic factors PDGF-AA (44% decrease in median) and PDGF AB (47% decrease) significantly declined from baseline (P < .05) after 1 week of naproxen use. There was a significant recovery (P < .05) of PDGF-AA (94% increase) and PDGF-AB (153% increase) levels after the 1-week washout period, with a return to baseline levels. The catabolic factor IL-6 also had a significant decline from baseline (77% decrease in median, P < .05) after 1 week of naproxen use. After a 1-week washout period, the IL-6 level was similar to the baseline level (130% increase, P < .05). CONCLUSIONS: Naproxen use diminished several biological factors in LR-PRP; however, a 1-week washout period was sufficient for the recovery of PDGF-AA, PDGF-AB, and IL-6 to return to baseline levels. Tumor necrosis factor alpha, IL-1beta, IL-8, vascular endothelial growth factor, and fibroblast growth factor 2 did not show differences between the 3 time points of data collection. Discontinuing NSAIDs for a minimum of 1 week before LR-PRP treatment may improve certain biological factor levels. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 30472019 TI - Full-Thickness Rotator Cuff Tears: What Is the Rate of Tear Progression? A Systematic Review. AB - PURPOSE: To systematically review the literature and determine the rate of radiographic tear progression of nonoperatively treated full-thickness rotator cuff tears. METHODS: The PubMed, Embase, and Cochrane Library databases were systematically reviewed to identify all articles related to nonoperatively treated rotator cuff tears. English-language studies of Level I through IV evidence examining chronic, full-thickness rotator cuff tears in adults were included. Partial-thickness tears were excluded. Rotator cuff tears were analyzed according to the presence or absence of symptoms. The primary outcome was radiographic tear progression defined as an increase in tear size of 5 mm or greater on magnetic resonance imaging or ultrasound. RESULTS: Eight studies were included for statistical analysis, and 411 tears were analyzed for progression. No difference in the rate of tear progression was detected between the asymptomatic and symptomatic groups (40.6% at 46.8 months and 34.1% at 37.8 months, respectively; P = .65). Calculation of the number needed to treat showed that for an 8% retear rate at 2-year follow-up, approximately 7 patients with rotator cuff tears would have to undergo operative repair to prevent 1 tear from progressing radiographically. CONCLUSIONS: This study showed that with the data available, asymptomatic and symptomatic rotator cuff tears carry similar rates of tear progression over time. Most of these tears will not progress significantly over short- to intermediate-term follow-up. LEVEL OF EVIDENCE: Level IV, systematic review of Level I through IV evidence. PMID- 30472021 TI - Effectiveness and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation Patients with Hypertrophic Cardiomyopathy: A Nationwide Cohort Study. AB - BACKGROUND: Chronic anticoagulation is recommended in patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF). Non-vitamin K antagonist oral anticoagulants (NOACs) are an alternative to warfarin, but there are limited data to support their use in patients with HCM and AF. We sought to compare thromboembolic events, bleeding, and mortality between NOAC and warfarin in patients with HCM and AF. METHODS: From the Korean National Health Insurance Service (NHIS) database during the period from January 1, 2011 to December 31, 2016, we identified a warfarin-treated group of patients with HCM and AF (n = 955) who were compared with a 1:2 propensity-matched NOAC treated group (n = 1,504). RESULTS: After a median follow-up of 15 months, the incidence rates of ischemic stroke and major bleeding were similar between NOAC- and warfarin treated patients with HCM and AF. NOAC-treated patients had lower incidence rates for all-cause mortality (5.11 and 10.13 events per 100 person-years for NOAC and warfarin groups) and the composite of fatal cardiovascular events (0.77 and 1.80 events per 100 person-years). Compared with warfarin, use of NOACs was associated with a significantly lower risk of all cause-mortality (hazard ratio [HR]: 0.43, 95% confidence interval [CI]: 0.32-0.57) and composite fatal cardiovascular events (HR: 0.39, 95% CI: 0.18-0.82). CONCLUSIONS: Compared with warfarin, patients with HCM and AF on NOACs had similar stroke and major bleeding risks, but lower all-cause mortality and composite fatal cardiovascular events. Our data suggest that patients with HCM and AF can be safely and effectively treated with NOACs. PMID- 30472020 TI - KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance. AB - Members of the KDM5 histone H3 lysine 4 demethylase family are associated with therapeutic resistance, including endocrine resistance in breast cancer, but the underlying mechanism is poorly defined. Here we show that genetic deletion of KDM5A/B or inhibition of KDM5 activity increases sensitivity to anti-estrogens by modulating estrogen receptor (ER) signaling and by decreasing cellular transcriptomic heterogeneity. Higher KDM5B expression levels are associated with higher transcriptomic heterogeneity and poor prognosis in ER+ breast tumors. Single-cell RNA sequencing, cellular barcoding, and mathematical modeling demonstrate that endocrine resistance is due to selection for pre-existing genetically distinct cells, while KDM5 inhibitor resistance is acquired. Our findings highlight the importance of cellular phenotypic heterogeneity in therapeutic resistance and identify KDM5A/B as key regulators of this process. PMID- 30472022 TI - Multimodal remote monitoring of high cardiovascular risk OSA patients initiating CPAP: a randomized trial. AB - BACKGROUND: The management of patients with high cardiovascular risk and obstructive sleep apnea (OSA) must target not only improving adherence to continuous positive airway pressure (CPAP) but should also include strategies aimed at reducing blood pressure (BP) and increasing physical activity. The study aims to evaluate the effectiveness of an integrated intervention using remote patient telemonitoring in reducing BP in high cardiovascular risk OSA patients. METHODS: In a multicenter, open, randomized trial, OSA patients were randomly assigned at CPAP initiation to usual care or multimodal telemonitoring for 6 months. Telemonitoring used electronic equipment collecting information about BP, symptoms, CPAP side effects and physical activity with home care providers pre specified protocoled actions. The primary effectiveness outcome was assessed using home self-measured BP (HBP) on 3 consecutive days. Secondary outcomes included CPAP compliance, symptoms and physical activity. RESULTS: Of 306 patients aged 61.3 [54.1;66.1] (median [IQR]) years; predominantly male 226 (74%) with a body mass index of 32.0 [28.7;35.6] kg/m2 and an apnea hypopnea index of 46 [35;61] events/hour, 149 received usual care and 157 telemonitoring. After 6 months of CPAP, HBP did not differ significantly between groups. In secondary analyses, there was no significant difference in steps per day, but a significant increase in CPAP adherence, and an improvement in daytime sleepiness and quality of life in favor of the multimodal telemonitoring. CONCLUSION: In OSA patients with high cardiovascular risk, multimodal telemonitoring was not superior to usual CPAP care for improving home blood pressure. However, telemonitoring improved adherence and patient-centered outcomes. PMID- 30472024 TI - A Review of Sleep-Related Violence: The Demographics of Sleep Forensics Referrals to a Single Center. AB - This review of Sleep-Related Violence reports the nature of the underlying sleep suspected conditions encountered and helps establish the spectrum of sleep related behaviors resulting in forensic consequences. This information may begin to bridge the gap between the differing medical and legal concepts of automatisms (complex motor behaviors occurring in the absence of conscious awareness and therefore without culpability). Increasingly, sleep medicine professionals are asked by legal professionals whether a sleep-related condition could possibly have played a role in a forensic-related event. Inasmuch as sleep medicine is a relatively young field, there is scant information to address these questions. The three most prevalent criminal allegations of the 351 consecutive possible sleep forensic-related referrals to a single sleep medicine center over the past 11 years were sexual assault, homicide/manslaughter or attempted murder, and Driving Under the Influence (DUI). The overwhelming possible sleep disorder implicated was sexsomnia, accounting for 41%, or 145 out 351 cases. Of the 351 referrals 111 were accepted following thorough case review. In general cases not accepted were declined on the basis of little or no merit or contamination by alcohol intoxication. Of those cases accepted, the proposed initial claim that a sleep phenomenon was operant was supported in approximately 50% - mostly (Non Rapid Eye Movement) NREM disorders of arousal. No cases were felt to be due to (Rapid Eye Movement Sleep Behavior Disorder) RBD. PMID- 30472023 TI - Efficacy of Pirfenidone in the Context of Multiple Disease Progression Events in Patients With Idiopathic Pulmonary Fibrosis. AB - BACKGROUND: Declines in percent predicted forced vital capacity (% predicted FVC), declines in 6-minute walk distance (6MWD), and respiratory hospitalizations are events associated with disease progression and mortality in idiopathic pulmonary fibrosis (IPF). The incidence of multiple events in the same patient over 12 months of pirfenidone treatment is unknown. METHODS: Patients who received pirfenidone 2403 mg/day (n = 623) or placebo (n = 624) in the ASCEND (Study 016; NCT01366209) and CAPACITY (Studies 004 and 006; NCT00287716 and NCT00287729) phase III trials were included in this post hoc analysis. Disease progression events were defined as relative decline in % predicted FVC >= 10%, absolute decline in 6MWD >= 50 m, respiratory hospitalization, or death from any cause. The incidence of disease progression events over 12 months was assessed. RESULTS: The most frequent disease progression events were declines in % predicted FVC (pirfenidone vs. placebo, 202 vs. 304 events) and declines in 6MWD (pirfenidone vs. placebo, 265 vs. 348 events). Fewer patients who received pirfenidone had > 1 progression event compared with placebo (17.0% vs. 30.1%; P < 0.0001). Death following >= 1 progression event occurred less frequently in the pirfenidone group than in the placebo group (2.1% vs. 6.3%; P = 0.0002). CONCLUSIONS: Pirfenidone significantly reduced the incidence of multiple progression events and death after a progression event over 12 months of treatment compared with placebo. These findings suggest that continued treatment with pirfenidone confers a benefit despite the occurrence of any single disease progression event. PMID- 30472025 TI - The general public's knowledge of diabetes mellitus: A cross-sectional study in Cameroon. AB - OBJECTIVE: To assess the general public's level of knowledge on diabetes mellitus (DM) and identify related sources of information in Cameroon. STUDY DESIGN: This was a cross-sectional study conducted in 2015 in two health facilities in Yaounde and Edea. METHODS: We included consenting adults, except health professionals. The level of knowledge on DM was evaluated on 24 points corresponding to 24 questions addressing either DM definition, signs and symptoms, risk factors or complications. RESULTS: Overall, 1524 persons (40.2% males) were included. Almost 99% of respondents had already heard of DM, but only 16.3% had ever received education on DM. The median score for the global knowledge was 79% (IQR 67-88). A person in the close entourage (71.3%) or a health professional (58.8%) constituted the major sources of information; school (13.3%) and media (television (23.6%), newspaper/magazine (10.0%), radio (9.6%) and internet (6.8%) were less common. Younger ages (<45years), lower levels of education, semi-urban residency, were independently associated with a lower level of knowledge on DM. CONCLUSIONS: The general public's level of knowledge on DM may be satisfactory, though needing to be improved. Schools and media should be capitalized to educate people on DM, targeting especially young adults and the less educated. PMID- 30472026 TI - Synthesis and anti-neuroinflammatory activity of N-heterocyclic analogs based on natural biphenyl-neolignan honokiol. AB - Novel isoxazole and pyrazole analogs based on natural biphenyl-neolignan honokiol were synthesized and evaluated for their inhibitory activities against nitric oxide production in lipopolysaccharide-activated BV-2 microglial cells. The isoxazole skeleton was constructed via nitrile oxide cycloaddition from oxime 3 and pyrazole was generated by condensation of 4-chromone and alkylhydrazine. Among the analogs, 13b and 14a showed stronger inhibitory activities with IC50 values of 8.9 and 1.2 uM, respectively, than honokiol. PMID- 30472027 TI - Synthesis and biological activities evaluation of sanjuanolide and its analogues. AB - Sanjuanolide, psorachalcone A and its seven new analogues were synthesized via a combinatorial strategy by aldol reaction. In order to investigate the effect between electron density in pi-conjugated systems and biological activities, several electron-withdrawing and electron-donating groups were introduced at C-4 and the phenolic hydroxyl groups of sanjuanolide. The two natural products and its seven new analogues were investigated for their inhibitory effects against five cancer cell lines. Moreover, the hydroxyisoprenyl group may be important to maintain the biological activities of sanjuanolide. PMID- 30472028 TI - Syncope in the Pediatric Patient: A Case Report. PMID- 30472029 TI - Watch Me Grow: A Well-Child Examination Protocol to Improve Preventive Care in Dominican Children. AB - INTRODUCTION: Morbidity and mortality rates among Dominican children are a serious health concern worsened by a lack of preventive care that hinders early identification and avoidance of illnesses. The purpose of this study was to improve health outcomes in Dominican children by implementing a well-child examination (WCE) protocol entitled "Watch Me Grow." METHODS: A quantitative, descriptive methodology was used. Twelve adults involved in pediatric care with the Foundation for Peace organization in the Dominican Republic were designated to receive WCE protocol education, and 159 children received WCEs and health promotion teaching. RESULTS: No statistically significant improvement in WCE knowledge was noted. The most common abnormal findings were unhealthy weight (47.8%), dental caries (46.5%), low vision (17.0%), and elevated blood pressure (15.7%). DISCUSSION: The WCE protocol facilitated early identification of many pediatric health concerns and may help diminish the potential future impact of illnesses on Dominican children. PMID- 30472030 TI - Cryptococcal meningoencephalitis in an elderly immunocompetent non-HIV-infected patient. PMID- 30472031 TI - [Phenotypic and molecular detection of carbapenemase-producing Klebsiella pneumoniae strains]. PMID- 30472032 TI - Alcohol drinking patterns and liver cirrhosis risk: analysis of the prospective UK Million Women Study. AB - BACKGROUND: Alcohol is a known cause of cirrhosis, but it is unclear if the associated risk varies by whether alcohol is drunk with meals, or by the frequency or type of alcohol consumed. Here we aim to investigate the associations between alcohol consumption with meals, daily frequency of consumption, and liver cirrhosis. METHODS: The Million Women Study is a prospective study that includes one in every four UK women born between 1935 and 1950, recruited between 1996 and 2001. In 2001 (IQR 2000-03), the participants reported their alcohol intake, whether consumption was usually with meals, and number of days per week it was consumed. Cox regression analysis yielded adjusted relative risks (RRs) for incident cirrhosis, identified by follow-up through electronic linkage to routinely collected national hospital admission, and death databases. FINDINGS: During a mean of 15 years (SD 3) of follow-up of 401 806 women with a mean age of 60 years (SD 5), without previous cirrhosis or hepatitis, and who reported drinking at least one alcoholic drink per week, 1560 had a hospital admission with cirrhosis (n=1518) or died from the disease (n=42). Cirrhosis incidence increased with amount of alcohol consumed (>=15 drinks [mean 220 g of alcohol] vs one to two drinks [mean 30 g of alcohol] per week; RR 3.43, 95% CI 2.87-4.10; p<0.0001). About half of the participants (203 564 of 401 806) reported usually drinking with meals and, after adjusting for amount consumed, cirrhosis incidence was lower for usually drinking with meals than not (RR 0.69, 0.62-0.77; p<0.0001; wine-only drinkers RR 0.69, 0.56-0.85; all other drinkers RR 0.72, 0.63-0.82). Among 175 618 women who consumed seven or more drinks per week, cirrhosis incidence was greater for daily consumption than non-daily consumption (adjusted RR 1.61, 1.40-1.85; p<0.0001). Daily consumption, together with not drinking with meals, was associated with more than a doubling of cirrhosis incidence (adjusted RR 2.47, 1.96-3.11; p<0.0001). INTERPRETATION: In middle-aged women, cirrhosis incidence increases with total alcohol intake, even at moderate levels of consumption. For a given weekly intake of alcohol, this excess incidence of cirrhosis is higher if consumption is usually without meals, or with daily drinking. FUNDING: UK Medical Research Council and Cancer Research UK. PMID- 30472033 TI - Alcohol drinking patterns and risk of liver disease in women. PMID- 30472034 TI - Glucose, fructosamine, and insulin measurements in saliva of dogs: variations after an experimental glucose administration. AB - The aim of this study was to evaluate if glucose, fructosamine, and insulin levels can be measured in saliva of dogs and assess the changes in these compounds after an experimental glucose administration. Automated spectrophotometric assays for glucose and fructosamine and an ELISA assay for insulin measurements were validated in saliva of dogs, by evaluating precision, accuracy, and limits of detection. In addition, an intravenous glucose bolus was administrated to 10 beagles and fasting serum and saliva samples were obtained immediately before and 5, 10, 20, 30, and 45 min after glucose infusion. The results of the between-run imprecision gave mean CVs of 6.16, 9.40, and 3.10% for glucose, fructosamine, and insulin, respectively. Linearity under dilution showed coefficient of correlation of 0.999, 0.994, and 0.990 for glucose, fructosamine, and insulin, respectively. The LDs were 0.04 mg/dL, 4.08 MUmol/L, and 0.02 MUg/mL for glucose, fructosamine, and insulin, respectively. The glucose administration caused an increase in serum and salivary levels of glucose with a peak in salivary levels at 30 min and of insulin with a peak in salivary levels at 45 min, while fructosamine did not change. No correlations between serum and salivary concentrations were found for any compound. It is concluded that glucose, fructosamine, and insulin can be measured in saliva of dogs, and an experimental administration of glucose in this species can lead to increases in glucose and insulin in saliva. PMID- 30472035 TI - Compound 48/80 reduces the crop-emptying rate, likely through a histamine associated pathway in chicks. AB - Infectious conditions are associated with reduced food passage through the digestive tract in both mammals and chicks; however, the precise mechanism mediating this response in chicks remains unclear. The purpose of the present study was to determine if mast cells, a blood cell type which plays an important role in the immune system, might affect food passage through the digestive tract in chicks. Specifically, we performed intraperitoneal (IP) injections of compound 48/80, an inducer of mast cell degranulation, and measured crop emptying. The IP injection of compound 48/80 significantly reduced the crop-emptying rate, but it did not affect the proventriculus to small intestine transit rate or the number of defecations. We also found that IP-injected histamine, which is secreted by mast cells, also reduced the crop-emptying rate. In addition, IP injection of 2 pyridylethylamine (histamine H1 receptor agonist), but not dimaprit, (R)-(-) alpha-methylhistamine, and VUF8430 (histamine H2, H3, and H4 receptor agonists, respectively), reduced the crop-emptying rate, implying that histamine reduces the crop emptying rate via the histamine H1 receptor. Finally, we found that IP injection of compound 48/80 reduced mRNA expression of histidine decarboxylase, a rate-limiting enzyme for histamine synthesis, in the esophagus and proventriculus at 1 h and the proventriculus and duodenum at 3 h after the injection. In sum, the present study suggests that the degranulation of mast cells causes a reduction in the crop-emptying rate, possibly via the histamine pathway in chicks. PMID- 30472036 TI - Comparing subjective and objective neighbourhood deprivation and their association with health over time among older adults in England. AB - The importance of neighbourhood on individual health is widely documented. Less is known about the relative role of objective and subjective reports of neighbourhood conditions, how their effect on health changes as people age, and whether they moderate each other's impact on health. This study uses the English Longitudinal Study of Ageing (ELSA) to determine whether older adults report worse self-rated health as they age, and whether this differs between objective and subjective measures of neighbourhood. ELSA data contain 53,988 person-years across six waves collected biannually between 2002 and 03 and 2012 and 13. Objective neighbourhood conditions are measured by the 2004 Index of Multiple Deprivation, and subjective neighbourhood conditions are captured by a summative neighbourhood dissatisfaction score. We find both objective and subjective neighbourhood composite scores independently predict poor health. There is no change over time in the probability of reporting poor health by baseline objective or subjective neighbourhood scores, suggesting neighbourhood effects do not compound as older adults age. There is no moderating effect of area dissatisfaction on the relationship between neighbourhood deprivation and health. The findings provide little support for causal neighbourhood effects operating in later life and indicate different causal pathways through which objective and subjective neighbourhood deprivation impact on health. PMID- 30472037 TI - Improvement of microvascular endothelial dysfunction induced by exercise and diet is associated with microRNA-126 in obese adolescents. AB - OBJECTIVE: Microvascular endothelial dysfunction, which is at the early stage of atherosclerosis, precedes macrovascular endothelial dysfunction. The study is aimed to investigate the mechanism underlying the improvement of microvascular endothelial dysfunction by exercise and diet in obese adolescents. METHODS: A quasi-randomized study was carried out with 2 cohorts: the experimental group (57 obese male adolescents; age: 15.38 +/- 2.82 years, BMI: 33.21 +/- 4.23 kg/m2) completed a 6-week exercise program with dietary intervention, and control group (10 normal weight adolescents; age: 15.38 +/- 2.82 years, BMI: 23.21 +/- 4.23 kg/m2) maintained sedentary. Clinical characteristics, circulating NO, ET-1 and microRNA-126 (miR-126) levels were measured before and after 6 weeks. The Reactive Hyperemia Index (RHI) was measured using EndoPAT-2000 system. RESULTS: After 6-weeks intervention, obese adolescents' body circumferences and glucolipid metabolism are significantly improved. RHI (p < 0.01) and serum levels of NO/ET-1 (p < 0.01) are significantly increased, while microRNA-126 significantly decreased (p < 0.01). DeltaMiR-126 were positive correlated with DeltaBMI (r = 0.60, p < 0.01), DeltaRHI (r = 0.69, p < 0.05), and DeltaNO/ET-1 (r = -0.68, p < 0.05). CONCLUSIONS: Combination of exercise and diet control can effectively improve glycolipid metabolism of obese adolescents, and thus their microvascular endothelial function, which might be related to changes in serum miRNA-126. PMID- 30472038 TI - Comparison of organ-specific endothelial cells in terms of microvascular formation and endothelial barrier functions. AB - Every organ demonstrates specific vascular characteristics and functions maintained by interactions of endothelial cells (ECs) and parenchymal cells. Particularly, brain ECs play a central role in the formation of a functional blood brain barrier (BBB). Organ-specific ECs have their own morphological features, and organ specificity must be considered when investigating interactions between ECs and other cell types constituting a target organ. Here we constructed angiogenesis-based microvascular networks with perivascular cells in a microfluidic device setting by coculturing ECs and mesenchymal stem cells (MSCs). Furthermore, we analyzed endothelial barrier functions as well as fundamental morphology, an essential step to build an in vitro BBB model. In particular, we used both brain microvascular ECs (BMECs) and human umbilical vein ECs (HUVECs) to test if organ specificity of ECs affects the formation processes and endothelial barrier functions of an engineered microvascular network. We found that microvascular formation processes differed by the source of ECs. HUVECs formed more extensive microvascular networks compared to BMECs while no differences were observed between BMECs and HUVECs in terms of both the microvascular diameter and the number of pericytes peripherally associated with the microvasculatures. To compare the endothelial barrier functions of each type of EC, we performed fluorescence dextran perfusion on constructed microvasculatures. The permeability coefficient of BMEC microvasculatures was significantly lower than that of HUVEC microvasculatures. In addition, there were significant differences in terms of tight junction protein expression. These results suggest that the organ source of ECs influences the properties of engineered microvasculature and thus is a factor to be considered in the design of organ-specific cell culture models. PMID- 30472039 TI - Production of F0 mice from embryonic stem cells injected eight-cell stage embryos which stored at refrigeration temperature. AB - At refrigeration temperature, mouse embryos can retain their developmental ability for a couple of days. Previous research reports have focused on the effect of cool temperature on the development of 2-cell stage embryos, morulae or blastocysts and determined that the embryo still has the ability to produce offspring after about 48 h storage at refrigeration temperature. Here we examined whether refrigeration temperature affects the development of the eight-cell stage and if the stored eight-cell stage embryo can still be used as a host embryo for ES cell injection. Our results show that eight-cell stage embryos can develop into blastocysts and yield pups after cold storage for 24 and 48 h. After ES cell injection, stored eight-cell stage embryos can support ES cells developing to F0 pups. In summary, cool storage can preserve the developmental ability of eight cell stage embryos for at least 48 h, allowing transportation of the embryos at refrigeration temperature between different labs and their subsequent use as host embryos for ES cell injection. PMID- 30472040 TI - Bifunctional and recyclable Dawson-type polyoxometalates catalyze oxidative degradation of lignocellulose to selectively produce phthalates. AB - Acid-redox bifunctional Dawson-type polyoxometalates K6P2W18O62 (P2W18) and K10P2W17O61 (P2W17) were introduced as the new-type catalysts in oxidative decomposition of lignocellulose. The lignin and hemicellulose ingredients of lignocellulose could be decomposed by P2W17 to produce diisobutyl phthalate with the selectivity of 75.67% and other aromatic and aliphatic compounds under mild conditions, evidently differed from other POMs-catalyzed lignocellulose depolymerization in which aromatic ketones and phenols were the main compounds. Diisobutyl phthalate was obtained from the oxidation of Calpha-OR and alpha-OH of the phenyl structure. The catalyst could be recycled for three times without obvious deactivation. This is the first report of lignocellulose decomposition catalyzed by Dawson-type polyoxometalates to selectively produce phthalates. PMID- 30472041 TI - Evaluation of Prostate Cancer Stage Groups Updated in the 8th Edition of the American Joint Committee on Cancer Tumor-Node-Metastasis Staging Manual. AB - INTRODUCTION: The American Joint Committee on Cancer (AJCC) tumor, node, metastasis classification system (TNM) staging manual has been updated and provides more specified stage grouping for prostate cancer (PCa). We aimed to validate the updated AJCC stage groups for PCa using a radical prostatectomy (RP) cohort. PATIENTS AND METHODS: We analyzed the data of 3032 patients previously treated with RP for localized PCa. We stratified patients into stage groups according to the 8th edition of the AJCC manual and compared biochemical recurrence (BCR)-free survival using Kaplan-Meier analyses. RESULTS: There were 217 patients in stage group I, 33 in IIA, 1101 in IIB, 535 in IIC, 129 in IIIA, 781 in IIIB, and 236 in IIIC. There were no significant differences in BCR-free survival between stage groups IIC and IIIA (P = .875). Subsequently, the low Gleason score (GS) IIIA subgroup (GS <= 3 + 4, P = .025) showed superior BCR-free survival than the IIC group, and the high-GS IIIA subgroups (GS >= 4 + 3, P = .004) showed a poorer BCR-free survival than the IIC group. Furthermore, there were no significant differences between groups I and IIA (P = 330) and between groups IIA and IIB (P = .942). Our new staging system provided a better ability to discriminate the prognosis of each group. However, our study has several limitations, such as retrospective design, relatively short follow-up period, and need for further validation. CONCLUSION: The current AJCC prognostic groups show some contradictory results, particularly concerning prognosis of the IIC and IIIA groups. We suggest that GS be given more weight than serum prostate-specific antigen level in stage group stratification. PMID- 30472042 TI - Long-term histological change in chronic hepatitis C patients who had received peginterferon plus ribavirin therapy with sustained virological response. AB - BACKGROUND: The improvement in liver histology is an important aim in the management of hepatitis C virus (HCV) infection. Previous studies suggest that antiviral treatment could reduce the progression of hepatic fibrosis, especially in patients with sustained virological response (SVR). However, most studies were limited by short-term evaluations and the liver stiffness was assessed by non invasive methods. In our study, we performed a paired liver biopsy study aimed at analyzing the long-term histological changes in patients with SVR. METHODS: We included 31 patients who had been previously treated with peginterferon plus ribavirin. All patients achieved SVR and had received pre- and post-treatment liver biopsies. The histological appearance of fibrosis and inflammation were assessed with METAVIR scoring system and Histological Activity Index (HAI) criteria. We analyzed several factors associated with the histological response. RESULTS: The median interval between two biopsies was 93.0 months. The percentage of patients with fibrosis regression, stable, and progression were 19%, 45%, and 36%. A total of 71% of patients achieved inflammation improvement, whereas 6% and 23% of patients had stable disease and disease-progression, respectively. We showed that the patients without baseline advanced fibrosis and those having a lower baseline HAI score had higher risk of fibrosis worsening. Baseline fibrosis and necroinflammation status did not influence HAI change significantly. CONCLUSION: The progression of hepatic fibrosis and inflammation can be reversed in some patients who had long-term virological suppression. Patients with advanced baseline fibrosis and higher inflammatory stages seemed to receive more histologic benefit from successful antiviral treatments. PMID- 30472043 TI - Promoting dentinogenesis of DPSCs through inhibiting microRNA-218 by using magnetic nanocarrier delivery. AB - PURPOSE: The purposes of this study are to explore the roles of microRNA-218 (miR 218) delivered by a newly designed magnetic nanocarrier: GCC-Fe3O4 (GCC-Fe) in dentinogenesis potentials of human dental pulp stem cells (DPSCs). METHODS: Human DPSCs were obtained from impacted wisdom teeth of healthy donors under the permission of National Taiwan University Hospital institutional review board (NTUH IRB). Meanwhile, the transfection efficiency of GCC-Fe was evaluated. After transfecting miR-218 (GFm) and miR-218 inhibitor (GFmi) into DPSCs for 24 h, the dentinogenesis potentials of DPSCs were then evaluated with Alizarin Red S (ARS) staining with or without induction for 1, 4, and 9 days. Possible signaling pathway was further investigated by Western Blotting. RESULTS: We found that the magnetic GCC-Fe3O4 nanocarrier was serum endurable with about 90% transfection efficiency in DPSCs under normal culture condition. Results of ARS staining indicated that miR-218 was negatively regulating dentinogenesis potentials of DPSCs after induction. When the miR-218 inhibitor was delivered, calcium deposits in DPSCs were increased significantly. We also discovered that the effects of miR 218 were further regulated through the MAPK/ERK pathway. CONCLUSION: We identified that miR-218 had a negative regulation role in the dentinogenesis of DPSCs. By inhibiting miR-218, the mineralization potentials of DPSCs were promoted after induction. In addition, we also confirmed that the highly efficient magnetic GCC-Fe3O4 nanocarrier not only was suitable for gene manipulation in biomedical studies, but also ideal for future clinical applications due to its serum endurable property. PMID- 30472044 TI - Shear wave elastography of median nerve at wrist and forearm. Heterogeneity of normative values: Response to authors. PMID- 30472045 TI - Microscope assisted surgery for dupuytrens disease. PMID- 30472046 TI - Donor limb assessment after vascularized groin lymph node transfer for the treatment of breast cancer-related lymphedema: Clinical and lymphoscintigraphy findings. AB - INTRODUCTION: Vascularized lymph node transfer is an established treatment for secondary lymphedema. Different donor sites of lymph node flap have been described. In our institute, vascularized groin lymph node (VGLN) flap is the workhorse flap for treating breast cancer-related lymphedema (BCRL). Potential complications of VGLN flap harvesting include seroma formation, thigh dysaesthesia, and iatrogenic lymphedema. METHODS: Between August 2013 and June 2016, 30 consecutive patients with a mean age of 60 years underwent VGLN transfer for BCRL. Reverse mapping of lower limb lymphatics with patent blue solution was performed in all cases. The donor limb conditions were assessed clinically with limb circumference measurement and radiologically with lymphoscintigraphy. Postoperative lymphoscintigraphy findings and transport indexes were compared between the donor and nonoperated limbs. RESULTS: The mean follow-up period was 22.11 +/- 7.83 months. Three (10%) patients developed groin seroma and 18 (60%) patients complained of transient thigh dysaesthesia. There was no clinically detectable donor limb lymphedema. Lymphoscintigraphy was performed at a mean of 13 months after operation. The mean transport indexes of the nonoperated limbs and donor limbs were 2.04 and 3.32, respectively. For the donor limbs, all patients had normal distribution pattern of contrast uptake. No dermal backflow pattern was demonstrated. CONCLUSION: With good knowledge of groin anatomy and meticulous surgical skills, VGLN flap can be harvested without causing major consequence to the donor limb. PMID- 30472047 TI - Should we be imaging soft tissue masses of the hand and wrist? PMID- 30472048 TI - Trunk postural control during unstable sitting differs between patients with patellofemoral pain syndrome and healthy people: A cross-sectional study. AB - BACKGROUND: Patellofemoral pain syndrome (PFPS) is a common orthopedic problem with a high prevalence among young women. Patients with PFPS have altered trunk muscle activity, impaired postural control and greater displacement of the center of pressure (COP) while standing. Training in unstable sitting, by putting more emphasis on trunk sensory receptors, may improve trunk proprioception by minimizing the role of the lower extremities. The aim of this study was to compare trunk postural control in healthy persons and in patients with PFPS. METHODS: Twenty-one women diagnosed with PFPS and 21 healthy women volunteered to participate in this cross-sectional study. The participants were asked to maintain trunk postural balance on an unstable sitting device, and COP indices of trunk postural control were compared between groups. RESULTS: All COP indices (e.g., mean anterior-posterior and lateral COP displacement, mean COP velocity and mean area of COP displacement) were significantly increased in participants with PFPS in comparison to healthy controls (P < 0.001). The effect sizes of all the indices were greater than 0.80. CONCLUSIONS: Trunk postural control is impaired in patients with PFPS, and this finding has clinical implications for rehabilitation in patients with PFPS. Adding seated postural control training to conventional physical therapy management in patients with PFPS may have beneficial effects by emphasizing trunk proprioception while minimizing the role of the lower extremities. PMID- 30472049 TI - Sub-total duodenectomy for secondary duodenum neoplastic invasion. PMID- 30472050 TI - Relevance of early CT scan diagnosis of blunt diaphragmatic injury: A retrospective analysis from the Northern French Alps Emergency Network. AB - INTRODUCTION: Diaphragmatic rupture following blunt trauma occurs rarely. Classically described after high-velocity accidents, ruptures are often associated with multiple organ injuries. The diagnosis is sometimes difficult. The goal of this study was to analyze and to discuss the modalities of early radiologic diagnosis and management of these injuries. PATIENTS AND METHODS: This multicenter retrospective study included patients seen between 2009 and 2017 within the Northern Alpine Emergency Network [REseau Nord Alpin des Urgences (RENAU)]. Clinical, radiologic and surgical data from all patients sustaining blunt diaphragmatic rupture were studied. RESULTS: Thirty-one patients (18 men and 13 women), median age 44, were included. The principle mechanism of injury was road or traffic accidents for 22 patients. Diaphragmatic rupture occurred on the left side in 23 patients. Diagnosis was delayed in two patients, at 11 days and three months after the initial accident. Chest X-rays were diagnostic in 18 of 29 patients. CT scan was the reference investigation since it was performed in all patients and confirmed the diagnosis in 26 instances. Repair was surgical via a midline laparotomy in 27 patients, via laparoscopy in three, and via thoracoscopy in one. Three patients died. CONCLUSION: At urgent surgical exploration in the unstable blunt trauma patient, the surgeon should keep in mind the relatively poor diagnostic performance of chest X-rays. Accurate diagnosis relies on routine inspection of the diaphragmatic cupolas. In the stable trauma victim, contrast-enhanced abdomino-thoracic CT with reconstruction can lead to early diagnosis, which allows for repair under optimal conditions, whether by laparotomy, laparoscopy or thoracoscopy, according to local conditions and expertise. PMID- 30472051 TI - Place of death and factors associated with hospital death in patients who have died from liver disease in England: a national population-based study. AB - BACKGROUND: Liver disease is a major cause of mortality, with high numbers of hospital deaths, and disproportionately affects people younger than 65 years. This study aims to examine the place of death and factors associated with hospital death for people who died from liver disease. METHOD: We did a national population-based, observational study using the National Death Registration Database from the Office for National Statistics, 2001-14. All non-accidental adult deaths (hospital and non-hospital) from liver disease in England were included. Explanatory variables were underlying cause of death, contributory causes of death (number and specific causes), age at death, sex, marital status, year of death, index of multiple deprivation, rural or urban settlement, and residential region. We applied modified Poisson regression models to assess the strength of association between hospital death and explanatory variables using an adjusted prevalence ratio (PR). FINDINGS: 135 953 decedents were included, of whom 56 065 (41.2%) died from alcohol-related liver disease. Annual deaths from liver disease increased from 7811 in 2001, to 11 017 in 2014. Hospitals were the main place of death (66.9% [95% CI 66.6-67.1]) for patients who died from liver disease. The proportion of hospital deaths reduced from 71.5% in 2001 to 60.0% in 2014. After adjusting for sociodemographic factors, patients who died from alcohol-related liver disease had the highest chance of hospital death; people who died from liver cancer were less likely to die in hospital than people with alcohol-related liver disease (adjusted PR 0.61 [95% CI 0.60-0.61]). People with four or more contributory causes of death were more likely to die in hospital than those with no contributory causes (1.45 [1.42-1.47]). Patients with sepsis (1.24 [1.23-1.25]), hepatorenal syndrome (1.22 [1.21-1.22]), and peritonitis (1.18 [1.17-1.20]) had higher chances of hospital death than those without these respective contributory causes, and those with alcohol-related disorders (0.67 [0.66-0.69]) had lower chances of hospital death. INTERPRETATION: The high risk of hospital death in patients with sepsis, hepatorenal syndrome, or peritonitis warrants further investigation, and the low chance of hospital death in patients with alcohol-related disorders also needs to be explored. Prevention strategies and end-of-life care services are urgently needed to prevent and tackle harms from liver disease. FUNDING: National Institute of Health Research Health Services and Delivery Research Programme, and Collaboration for Leadership in Applied Health Research and Care South London. PMID- 30472052 TI - Unmet needs in end-of-life care for chronic liver disease. PMID- 30472053 TI - Corrective osteotomy and in situ fusion for late-presenting nonunion of lateral condyle fractures of the humerus in adults. AB - BACKGROUND: Late presentation of lateral condylar fractures of the humerus is not an uncommon problem in children, and to lesser extent, in adults. The various surgical interventions for repairing the fracture, correcting the deformity, or even performing anterior transposition of the ulnar nerve as a single procedure or in combination, especially in adults, is still a controversial topic, with a paucity of literature regarding this. There is a risk of loss of the available preoperative range of motion, nonunion, and avascular necrosis. METHODS: In 19 patients with late presentation of lateral humeral condyle fracture, we assessed the results of only corrective osteotomy and internal fixation with lateral incision without anterior transposition of the ulnar nerve with regard to deformity correction, union, and functional results using the Mayo Elbow Performance Score with at least 24 months of follow-up. All patients (14 men, 5 women; average age, 29.1 years) had Milch type 2, 18 patients presented with cubitus valgus deformity, 1 presented with cubitus varus deformity, and 8 patients had tardy ulnar nerve symptoms. RESULTS: Late-presenting lateral condylar fractures could be managed surgically with our procedure alone even if they have a tardy ulnar neuritis, with excellent results in 17 patients and good results in 2 patients. CONCLUSION: In situ fusion, deformity correction, and internal fixation is a valuable method for the management of late-presenting lateral condylar fractures in adults. PMID- 30472054 TI - Midterm results of anatomic total shoulder arthroplasty with a third-generation implant. AB - BACKGROUND: Anatomic total shoulder arthroplasty (TSA) provides reliable, reproducible, and durable results; however, outcomes of many modern TSA systems are lacking. The present study reports early to midterm results of a third generation TSA system using a traditional-length press-fit humeral stem and cemented glenoid. METHODS: A retrospective review was conducted of TSA patients with minimum 2-year clinical follow-up. Patient-reported outcome measures, including Simple Shoulder Test, American Shoulder and Elbow Surgeons Total, visual analog scale for pain, 12-Item Short Form Health Survey, and Single Assessment Numeric Evaluation, as well as measured active motion (forward elevation, external and internal rotation), were recorded at preoperative and postoperative intervals. Preoperative midglenoid axial computed tomography scans were used to evaluate eccentric glenoid wear, humeral head subluxation, and glenoid version. Most recent postoperative radiographs were used to evaluate glenoid loosening, humeral loosening, lesser tuberosity union, and medial calcar resorption. Patient satisfaction at final follow-up was reported as excellent, good, satisfied, or unsatisfied. RESULTS: There were 267 patients who met inclusion criteria, with a mean age of 70.9 years and mean clinical follow-up of 47 months. Average glenoid retroversion was 9.7 degrees , and 27% had eccentric glenoid wear. At final follow-up, measured motion and nearly all patient-reported outcome measures showed significant improvements, with 75.6% of patients rating their satisfaction as excellent. No patient was considered "at risk" for humeral stem loosening. Glenoid radiolucencies were seen in 13.5% of shoulders (7 gross loosening). Five patients were revised to reverse TSA. CONCLUSION: TSA using a third-generation traditional-length press-fit stem and cemented glenoid provides excellent early to midterm outcomes with low rates of loosening and high rates of excellent satisfaction. PMID- 30472056 TI - Protocatechuic acid inhibits TGF-beta1-induced proliferation and migration of human airway smooth muscle cells. AB - Protocatechuic acid (3, 4-dihydroxybenzoic acid, PCA) is a major metabolite of anthocyanins and was reported to possess anti-allergic response. However, the effects of PCA on airway smooth muscle cells (ASMCs) proliferation and migration remain unclear. Therefore, this study aims to investigate the effects of PCA on proliferation and migration of ASMCs. ASMCs were pre-incubated with various concentrations of PCA for 30 min before stimulation with transforming growth factor-beta1 (TGF-beta1) for different times. Cell proliferation was determined using the colony formation assay. Cell migration was detected using the Transwell chamber assay. The levels of type I collagen, fibronectin, phosphorylated Smad2, Smad2, phosphorylated Smad3 and Smad3 were detected by western blot analysis. Our results demonstrated that PCA inhibited the proliferation and migration of ASMCs, as well as suppressed the expression levels of type I collagen and fibronectin in ASMCs induced by TGF-beta1. Furthermore, PCA obviously down-regulated the phosphorylation levels of Smad2/3 in ASMCs exposed to TGF-beta1. Taken together, the present results have revealed that PCA inhibits asthma airway remodeling by suppressing proliferation and extracellular matrix (ECM) protein deposition in TGF-beta1-mediated ASMCs via the inactivation of Smad2/3 signaling pathway. Therefore, PCA may be useful for the prevention or treatment of asthma airway remodeling. PMID- 30472055 TI - Development and validation of a new elbow-specific scoring system for patients with elbow stiffness: the Shanghai Elbow Dysfunction Score. AB - BACKGROUND: Clinical scoring systems are increasingly important and popular for the evaluation of orthopedic patients. Elbow stiffness commonly causes functional impairment and upper-limb disability. The purpose of this study was to develop and validate a new elbow-specific assessment score to evaluate joint function in patients with elbow stiffness. METHODS: The new system, the Shanghai Elbow Dysfunction Score (SHEDS), was developed in 3 portions: elbow motion capacities, elbow-related symptoms, and patient satisfaction level. A total of 73 patients with elbow stiffness were prospectively included. Intraclass correlation coefficients and Cronbach alpha values were calculated for test-retest reliability and internal consistency, respectively. Construct validity was assessed by correlating the SHEDS with previously validated scoring systems. Effect sizes (ES) and standardized response means (SRMs) were calculated for responsiveness. RESULTS: Positive reliability with an intraclass correlation coefficient of 0.83 and adequate homogeneity with a Cronbach alpha value of 0.74 were found for the SHEDS. Good to excellent validity using Spearman correlation coefficients (SCCs) were determined for the total (0.51-0.82), motion (0.65 0.89), and symptom (0.35-0.53) scores. Responsiveness was large for the total ES, 3.48; SRM, 2.96), motion (ES, 2.54; SRM, 2.08), and symptom (ES, 1.26; SRM, 1.14) scores. There were no ceiling or floor effects. Significant positive correlations were found between patient satisfaction levels and the final scores (SCC, 0.62), as well as the score changes of the SHEDS (SCC, 0.42). CONCLUSION: Our results suggest that the newly developed SHEDS is an excellent, comprehensive, valid scoring system to evaluate joint function in patients with elbow stiffness. PMID- 30472057 TI - MiR-532 downregulation of the Wnt/beta-catenin signaling via targeting Bcl-9 and induced human intervertebral disc nucleus pulposus cells apoptosis. AB - OBJECTIVE: Intervertebral disc degeneration was characterized with aberrant intervertebral disc nucleus pulposus cells apoptosis. MiR-532 was reported to be up-regulated in the patients with intervertebral disc degeneration. However, the role of miR-532 in intervertebral disc degeneration remains unclear. Thus, current study aim to investigate the effects of miR-532 on human intervertebral disc nucleus pulposus cells. METHODS: Quantitative PCR was firstly used to evaluate the level of miR-532 expression in intervertebral disc nucleus pulposus cells. Then, luciferase reporter assays was used to confirm the target genes of miR-532. The effects of miR-532 on cell proliferation were assayed using EdU transfection. Next, apoptosis level was examined by flow cytometry utilizing Annexin V-FITC/PI double staining, and the protein expression in cells was detected with Western blotting. Finally, The expression of beta-catenin protein was demonstrated by fluorescence confocal microscopy and the interaction between beta-catenin and Bcl-9 was detected by co-immunoprecipitation. RESULTS: MiR-532 was significantly upregulated in patient with intervertebral disc degeneration. In addition, intervertebral disc nucleus pulposus cells apoptosis was significantly increased in miR-532 mimics treated group. Moreover, Bcl-9 was confirmed to be a direct target of miR-532 via luciferase reporter assays and western blot assays. CONCLUSION: MiR-532 downregulation of the Wnt/beta-catenin signaling via targeting Bcl-9 and induced human intervertebral disc nucleus pulposus cells apoptosis. PMID- 30472058 TI - A microRNA-29 mimic (remlarsen) represses extracellular matrix expression and fibroplasia in the skin. AB - MicroRNA-29 negatively regulates fibrosis, and miR-29 is downregulated in multiple fibrotic organs and tissues, including in the skin. miR-29 mimics prevent pulmonary fibrosis in mouse models but have not previously been tested in the skin. This study aimed to identify pharmacodynamic (PD) biomarkers of miR-29 in mouse skin, to translate those biomarkers across multiple species and to assess the PD activity of a miR-29b mimic (remlarsen) in a clinical trial. miR-29 biomarkers were selected based on gene function and mRNA expression using quantitative reverse transcriptase polymerase chain reaction (QRT-PCR). Those biomarkers comprised multiple collagens and other miR-29 direct and indirect targets and were conserved across species; remlarsen regulated their expression in mouse, rat and rabbit skin wounds and in human skin fibroblasts in culture, while a miR-29 inhibitor reciprocally regulated their expression. Biomarker expression translated to clinical proof-of-mechanism; in a double-blinded, placebo-randomized, within-subject controlled clinical trial of single and multiple ascending doses of remlarsen in normal healthy volunteers, remlarsen repressed collagen expression and the development of fibroplasia in incisional skin wounds. These results suggest that remlarsen may be an effective therapeutic to prevent formation of a fibrotic scar (hypertrophic scar or keloid) or to prevent cutaneous fibrosis, such as scleroderma. PMID- 30472059 TI - Civilian-Military Trauma Partnerships and the Visiting Surgeon Model for Maintaining Medical Readiness. AB - OBJECTIVE: The main objective of this paper is to create a model to predict the amount of trauma experience at a level 1 trauma center a visiting surgeon can expect to obtain with near certainty, in a specific amount of time, to maintain trauma skills. DESIGN: The trauma database of level 1 trauma center (Saint Louis University Hospital, a military civilian partnership site) was examined to identify all urgent trauma cases between 1 October 2015 and 30 September 2017. Using retrospective data, a prospective hypothesis of a mixture of various case exposures a visiting surgeon may experience was made using Monte Carlo statistical methods, various probabilities for wartime relevant specialties were examined. SETTING: Saint Louis University Hospital, a level 1 trauma and tertiary referral center. PARTICIPANTS: Trauma patients between the dates October 1, 2015 and September 30, 2017 that underwent an operation at Saint Louis University Hospital. RESULTS: Orthopedics and general/trauma surgery had the largest number of urgent trauma cases with an average daily amount of 1.03 and 0.49 cases, respectively. Using Monte Carlo methods, various scenarios and probabilities were tabulated. For example, a general surgeon on shift for 10 days could expect to experience 4.9 (95% confidence interval 1-11) urgent cases or a visiting surgeon would require twenty-six 24-hour shifts in the summer to have a 95% certainty to experience at least 10 cases. CONCLUSIONS: Other than for orthopedics, prolonged training timelines would be required to expose a visiting surgeon to multiple operative trauma cases. Though a specific number of cases to achieve "readiness" is undefined, a visiting-surgeon model may be unacceptable if a large number of cases are required prior to military deployment. This predictive model could be extrapolated to other centers and assist in identifying adequate settings and durations of trauma training sites. PMID- 30472060 TI - Multilevel Quality Improvement Teams: An Alternative Approach for Surgical Academic Training Programs to Meet ACGME Core Competency Milestones. AB - BACKGROUND: Quality improvement (QI) activities are an integral part of residency training. We started the process to implement team-based, multilevel QI project streams within our academic surgical residency by studying resident perceptions. OBJECTIVE: Our residency carried out 6 QI projects in line with the American Council for Graduate Medical Education competencies. A resident survey was completed in 2016 to measure resident perceptions of an individual versus team based QI project approach. METHODS: This was a descriptive study looking at resident's preference for team projects and ongoing projects within the training program. We started in 2014 utilizing Wait's Team Action Projects in surgery paradigm to conduct 6 QI projects. After initiation of projects, we allotted 2 full years to pass prior to assessing resident perceptions via a 12-item survey. RESULTS: Notably, this was a descriptive study aiming to capture resident perceptions on team-based QI and the foundational elements necessary to create and sustain such projects by integrating into our curriculum from the intern year. In 2016, 40 residents completed surveys (72.7% response rate), all (100%) opined that they preferred team-based approaches over individual ones, and 75% were on board to move forward with only a team-based approach in the future. CONCLUSIONS: This was a pivotal start to adopting a team-based QI project strategy in the future and laid a solid foundation to build upon. We found residents in our program desire to work within teams early on to develop effective solutions to clinical problems. Residents perceived that the team-based model resulted in an improved resident experience with the QI process and improved patient care. We hope to publish a series of articles updating our progress as we move forward in this endeavor. PMID- 30472062 TI - The 2019 version of the gene table of neuromuscular disorders (nuclear genome). PMID- 30472061 TI - Crowdsourced Assessment of Inanimate Biotissue Drills: A Valid and Cost-Effective Way to Evaluate Surgical Trainees. AB - OBJECTIVE: Providing feedback to surgical trainees is a critical component for assessment of technical skills, yet remains costly and time consuming. We hypothesize that statistical selection can identify a homogenous group of nonexpert crowdworkers capable of accurately grading inanimate surgical video. DESIGN: Applicants auditioned by grading 9 training videos using the Objective Structured Assessment of Technical Skills (OSATS) tool and an error-based checklist. The summed OSATS, summed errors, and OSATS summary score were tested for outliers using Cronbach's Alpha and single measure intraclass correlation. Accepted crowdworkers then submitted grades for videos in 3 different compositions: full video 1* speed, full video 2* speed, and critical section segmented video. Graders were blinded to this study and a similar statistical analysis was performed. SETTING: The study was conducted at the University of Pittsburgh Medical Center (Pittsburgh, PA), a tertiary care academic teaching hospital. PARTICIPANTS: Thirty-six premedical students participated as crowdworker applicants and 2 surgery experts were compared as the gold-standard. RESULTS: The selected hire intraclass correlation was 0.717 for Total Errors and 0.794 for Total OSATS for the first hire group and 0.800 for Total OSATS and 0.654 for Total Errors for the second hire group. There was very good correlation between full videos at 1* and 2* speed with an interitem statistic of 0.817 for errors and 0.86 for OSATS. Only moderate correlation was found with critical section segments. In 1 year 275 hours of inanimate video was graded costing $22.27/video or $1.03/minute. CONCLUSIONS: Statistical selection can be used to identify a homogenous cohort of crowdworkers used for grading trainees' inanimate drills. Crowdworkers can distinguish OSATS metrics and errors in full videos at 2* speed but were less consistent with segmented videos. The program is a comparatively cost-effective way to provide feedback to surgical trainees. PMID- 30472063 TI - Changes in melatonin concentrations in seminal plasma are not correlated with testosterone or antioxidant enzyme activity when rams are located in areas with an equatorial photoperiod. AB - In temperate climates, photoperiod and melatonin regulate ram reproduction, modulating hormonal secretions, sperm quality, and seminal plasma composition. Information on the effect of an equatorial photoperiod (12L:12D) on ram reproduction, however, is scarce, and no data on hormonal concentrations and antioxidant enzyme activity in seminal plasma have been reported. Thus, the variation was investigated of melatonin and its relationship with testosterone and antioxidant enzyme activity in the seminal plasma of three sheep breeds in Colombia, when there was a consistent photoperiod during two dry and two rainy seasons per year. Semen was collected once a week from 12 mature rams (four of each breed: Colombian Creole, Hampshire, and Romney Marsh). Seminal plasma was obtained by centrifugation. The concentration of melatonin and testosterone were quantified along with the enzymatic activity of glutathione peroxidase (GPx), glutathione reductase (GRD), and catalase (CAT). Correlation analyses between melatonin and testosterone concentrations or enzymatic activity were also performed. Melatonin concentration was affected by season (P < 0.05) but not breed, with lesser concentrations in the first rainy season. Testosterone concentration, however, was affected by breed and season, with greater concentrations (P < 0.01) in the Hampshire and Romney Marsh rams during the second dry season. Regarding antioxidant enzyme activity, there was only seasonal variation in GPx activity (P < 0.05). When correlation analyses were used for data assessments, there was a negative correlation between melatonin and testosterone concentrations in Hampshire rams. In conclusion, melatonin concentrations in seminal plasma of rams that were located in an area with an equatorial photoperiod was affected by the climatological season but there was no positive correlation with testosterone concentration or antioxidant enzyme activity. PMID- 30472064 TI - In vitro production of sex preselected cattle embryos using a monoclonal antibody raised against bull sperm epitopes. AB - Sex preselection has always generated great interest among livestock producers. Among the prevalent sperm sorting methods, there is much evidence that sex sorting has a negative effect on sperm quality with an altered pattern of sperm motility, ultimately reducing the period of cell viability. In this study, we have established a new approach for the preselected embryo production by using WholeMom(r); a monoclonal antibody developed against bull sperm epitopes for simple and easy separation of X- and Y-sperm. There were no significant differences (P > 0.05) in the percentage of presumptive zygotes between the control and the X-sperm sorted group, but there was a difference in early cleaving embryos with there being 81.2 +/- 1.4%, 78.3 +/- 1.0%, and 66.7 +/- 1.1% for the control, X-sperm sorted, and Y-sperm sorted groups, respectively. Similarly, the percentage of embryos that developed to the blastocyst stage (Day 7) were also greater (P < 0.05) in the control and X-sperm sorted group compared with the Y-sperm sorted group being 34.8 +/- 1.0%, 32.1 +/- 0.8%, and 23.7 +/- 1.0% in the control, X-sperm sorted, and Y-sperm sorted groups, respectively. Furthermore, B-SRY F2 and B-SRY R2 gene expression data indicated there was a detection accuracy of 81.0% for the female embryos and 72.5% for the male embryos produced in vitro. In conclusion, in cattle in vitro derived embryo production using pre-selected sexed semen and subsequent embryo transfer can facilitate the mass production of individuals that are genetically superior. PMID- 30472065 TI - Protective effects of trehalose on frozen-thawed ovarian granulosa cells of cattle. AB - In this study, trehalose was investigated for its cryoprotective effects on ovarian granulosa cells (bGCs) of cattle. Five concentrations of trehalose at 0, 0.2, 0.4, 0.6 and 0.8 mol/L were added to the cryopreservation medium of bGCs, and the effects on the quality of frozen-thawed bGCs were assessed. The results indicate that the use of cryopreservation medium containing 0.2 and 0.4 mol/L of trehalose resulted in a greater rate of bGC viability compared to those of other groups (P<0.05). Culturing with trehalose at 0.2 and 0.4 mol/L increased 17beta- estradiol (E2)and decreased progesterone (P4)production (P < 0.05) in post-thawed bGCs. Compared with the control group, the intracellular Ca2+ concentrations of frozen-thawed bGCs were less in all treatment groups (P<0.05), and the least Ca2+ concentration was observed in the group containing 0.4 mol/L trehalose. The plasma membrane potentials of frozen-thawed bGCs were greater in the groups with 0.2 and 0.4 mol/L trehalose, and the group treated with 0.4 mol/L trehalose had the greatest membrane potential in comparison to other groups (P < 0.05). The relative abundance of the CYP19 mRNA in frozen-thawed bGCs was greater in the groups containing 0.2, 0.4 and 0.6 mol/L trehalose, and relative abundances of FSHR and BCL2 mRNA were greater in the group of bGCs treated with 0.2 mol/L trehalose (P<0.05). Trehalose treatment at 0.4, 0.6 and 0.8 mol/L had an inhibitory effect on BAX gene transcription in frozen-thawed bGCs (P<0.05). In summary, trehalose exhibited a greater cryoprotective effect on bGCs than basic cryopreservation medium. PMID- 30472066 TI - Improvement of pharmacokinetic properties of therapeutic antibodies by antibody engineering. AB - Monoclonal antibodies (mAbs) have become an important therapeutic option for several diseases. Since several mAbs have shown promising efficacy in clinic, the competition to develop mAbs has become severe. In efforts to gain a competitive advantage over other mAbs and provide significant benefits to patients, innovations in antibody engineering have aimed at improving the pharmacokinetic properties of mAbs. Because engineering can provide therapeutics that are more convenient, safer, and more efficacious for patients in several disease areas, it is an attractive approach to provide significant benefits to patients. Further advances in engineering mAbs to modulate their pharmacokinetics were driven by the increase of total soluble target antigen concentration that is often observed after injecting a mAb, which then requires a high dosage to antagonize. To decrease the required dosage, several antibody engineering techniques have been invented that reduce the total concentration of soluble target antigen. Here, we review the various ways that antibody engineering can improve the pharmacokinetic properties of mAbs. PMID- 30472067 TI - Gazing at Cell Wall Expansion under a Golden Light. AB - In plants, cell growth is constrained by a stiff cell wall, at least this is the way textbooks usually present it. Accordingly, many studies have focused on the elasticity and plasticity of the cell wall as prerequisites for expansion during growth. With their specific evolutionary history, cell wall composition, and environment, brown algae present a unique configuration offering a new perspective on the involvement of the cell wall, viewed as an inert material yet with intrinsic mechanical properties, in growth. In light of recent findings, we explore here how much of the functional relationship between cell wall chemistry and intrinsic mechanics on the one hand, and growth on the other hand, has been uncovered in brown algae. PMID- 30472068 TI - Resources for Crop Production: Accessing the Unavailable. AB - An acute imbalance between human population and food production is projected, partially due to increasing resource scarcity; dietary shifts and the current course of technology alone will not soon solve the problem. Natural ecosystems, typically characterized by high species richness and perennial growth habit, have solved many of the resource-acquisition problems faced by crops, making nature a likely source of insights for potential application in commercial agriculture. Further research on undomesticated plants and natural ecosystems, and the adaptations that enable them to meet their needs for N, P, and water, could change the face of commercial food production, including on marginal lands. PMID- 30472069 TI - Tacrolimus inhibits Th1 and Th17 responses in MuSK-antibody positive myasthenia gravis patients. AB - Muscle specific tyrosine kinase antibody positive myasthenia gravis (MuSK- MG) is characterized by autoantibodies against the MuSK protein of the neuromuscular junction resulting in weakness of bulbar and proximal muscles. We previously demonstrated that patients with MuSK-MG have increased pro-inflammatory Th1 and Th17 responses. Tacrolimus, an immunosuppressant used in AChR-MG and transplantation patients, inhibits T cell responses through interference with IL 2 transcription. The therapeutic efficacy and immunological effect of tacrolimus in MuSK-MG is unclear. In the current study we examined the proliferation, phenotype and cytokine production of CD4+ and CD8+ T cells in peripheral blood mononuclear cells of MuSK-MG following a 3-day in vitro culture with or without tacrolimus. We determined that tacrolimus profoundly suppressed CD4 and CD8 T cell proliferation and significantly suppressed Th1 and Th17 responses, as demonstrated by a reduced frequency of IFN-gamma, IL-2, and IL-17 producing CD4 T cells and reduced frequencies of IFN-gamma and IL-2 producing CD8 T cells. Tacrolimus also inhibits pathogenic Th17 cells coproducing IL-17 and IFN-gamma. In addition, tacrolimus suppressed follicular T helper cell (Tfh) and regulatory T helper cell (Treg) subsets. These findings provide preliminary support for tacrolimus as a potential alternative immunosuppressive therapy for MuSK-MG. PMID- 30472070 TI - Direct transdifferentiation of human Wharton's jelly mesenchymal stromal cells into cholinergic-like neurons. AB - Barckground Alzheimer's disease (AD) is mainly caused by cellular loss and dysfunction of the basal forebrain cholinergic neurons and cholinergic axons in the cortex leading to slowly progressive decline in learning and memory performance. Unfortunately, no definitive treatment to halt neural cell loss exists to date. Therefore, it is necessary to obtain an unlimited source of cholinergic neurons for future pharmacological applications in AD. Human mesenchymal stromal cells (hMSCs) represent a unique source of cholinergic-like neurons (ChLNs). New method hWJ-MSCs were incubated with Cholinergic-N-Run medium for 4 and 7 days. Results hWJ-MSCs cultured with Cholinergic-N-Run medium differentiated into ChLNs in 4 days as evidenced by high levels of protein expression of the neuronal markers ChAT, VAChT, AChE, MAP2, beta-Tubulin III, NeuN, TUC-4, NF-L and no expression of the immature marker SOX2, the dopaminergic marker TH, GABAergic marker GAD67 and glial marker GFAP. Comparison with existing method(s) The hWJ-MSCs form ChLNs (e.g., ~26% IF+) within 20 days by using complex conditioned mediums that are expensive and time-consuming. We report for the first time, to our best knowledge, a direct method of hWJ-MSCs transdifferentiation into ChLNs (~76% ChAT /VAChT assessed by immunofluorescence microscopy and flow cytometry) in an economic, efficient and timely fashion. Conclusions The fastest method to obtain ChLNs from hWJ-MSCs takes only four days using the one-step incubation medium Cholinergic-N-Run. PMID- 30472071 TI - Denoising high angular resolution diffusion imaging data by combining singular value decomposition and non-local means filter. AB - BACKGROUND: High angular resolution diffusion imaging (HARDI) data is typically corrupted with Rician noise. Although larger b-values help to retrieve more accurate angular diffusivity information, they also lead to an increase in noise generation. NEW METHOD: In order to sufficiently reduce noise in HARDI images and improve the construction of orientation distribution function (ODF) fields, a novel denoising method was developed in this study by combining the singular value decomposition (SVD) and non-local means (NLM) filter. Similar 3D patches were first recruited into a matrix from a search volume. HARDI signals in the matrix were then re-estimated using the SVD low rank approximation, and a NLM filter was employed to filter out any residual noise. RESULTS: The performance of the proposed method was evaluated against the state-of-the-art denoising methods based on both synthetic and real HARDI datasets. Results demonstrated the superior performance of the developed SVD-NLM method in denoising HARDI data through preserving fine angular structural details and estimating diffusion orientations from improved ODF fields. CONCLUSION: The proposed SVD-NLM method can improve HARDI quantitative computations, such as MRI brain tissue segmentation and diffusion profile estimation, that rely on the quality of imaging data. PMID- 30472072 TI - Revision surgery in carpal tunnel syndrome: a retrospective study comparing the Canaletto(r) device alone versus a combination of Canaletto(r) and Dynavisc(r) gel. AB - The aim of our study was to demonstrate the benefits of combining the Canaletto(r) implant with carboxymethylcellulose/polyethylene oxide gel in the surgical treatment of carpal tunnel syndrome (CTS) recurrences. Our case series included 39 patients (40 hands, one bilateral case) who underwent revision surgery for recurrent CTS (28 cases) or resistant CTS (12 cases). The mean age of the patients was 56 years. The Canaletto(r) only was implanted in the first 21 cases (group I). In the following 19 cases (group II), Dynavisc(r) gel was added to the protocol and applied around the median nerve when the Canaletto(r) was implanted. At 12 months' follow-up (group I) and 11 months' follow-up (group II), the pre-versus post-operative difference between the average values of the DN4 neuropathic Pain Score was 0.55/10 in group I and 2.25/10 in group II; the Pain Score was 2.23/10 (in group I) and 2.52/10 (in group II); the Quick DASH Score was 18.98/100 (group I) and 19.06/100 (in group II); the hand grip strength was 19.55% (group I) and 28.53% (group II); the sensory nerve conduction velocity was 8.67 m/s (group I) and 10.27 m/s (group II); the distal motor latency was 1.05 m/s (group I) and 1.75 m/s (group II). Nine patients recovered from hypoesthesia in both groups, 5 patients regained satisfactory trophism of the thenar muscles in group I and 3 patients in group II. No improvement whatsoever was noted in 2 patients in group II, despite the electromyogram being normal. One patient from group II suffered an infection that required revision surgery to remove the Canaletto(r); this led to a moderate improvement. Our results show that when resistant or recurrent CTS is diagnosed, the combined treatment of an anti adhesion gel such as Dynavics(r) around the median nerve with the Canaletto(r) implant after performing secondary neurolysis leads to satisfactory post operative outcomes. Compared to other techniques described in the current literature, our technique is less invasive, quicker and associated with minimal morbidity of the surgical site. PMID- 30472073 TI - Epidemiology of gunshot wounds to the hand. AB - Due to increased gun availability/prevalence in current times, low-velocity firearm injuries have risen dramatically. This study describes the epidemiology of gunshot wounds (GSW) to the hand. We identified all patients (January 2005 - August 2015) who presented to our Level 1 trauma center with GSW's to the hand. Analysis of each record was performed to collect epidemiological variables. Cross sectional analyses were performed to quantify the results. Following inclusion/exclusion criteria, 97 patients were selected. Individuals who sustained GSW's to the hand were typically male (93.8%) between the ages of 18 and 30 (48.5%). Injuries were mostly self-inflicted (81.4%), and isolated (89.7%) to the digits (55.7%) or metacarpals (35.1%) of the left hand (74.2%). Most were fired from BB/pellet guns (45.4%) or handguns (33.0%), while cleaning/loading them (65.1%). Over one-half of patients (58.8%) were uninsured. Surgery was required in 35.1% of patients. Patients shot with something other than a BB/Pellet gun (e.g., handgun, shotgun) required surgery significantly more than those shot with a BB/Pellet gun (P < 0.0001). An odds ratio further describing this relationship was 0.13 (P = 0.0002), reflecting an 87% reduction in the odds of surgery for individuals shot by a BB/pellet vs. a different type of gun. The typical GSW to the hand involves a middle-aged male receiving an isolated injury to the digits or metacarpals of the left hand, from a BB/Pellet gun or handgun while they are cleaning/loading the firearm. Patients sustaining injury by a BB/pellet gun are least likely to require surgery. PMID- 30472074 TI - Detection of HER2-positive Circulating Tumor Cells Using the LiquidBiopsy System in Breast Cancer. AB - BACKGROUND: Most previous studies of circulating tumor cells (CTCs) are based on the CellSearch platform, but CellSearch has a number of limitations. This study aimed to use the LiquidBiopsy system and immunofluorescence to test the human epidermal growth factor receptor 2 (HER2) status of CTCs in patients with breast cancer. MATERIALS AND METHODS: The LiquidBiopsy system was used to detect HER2 positive (HER2+) cells in whole blood by microfluidic immunomagnetic bead screening and immunofluorescence assay, according to the manufacturer;s instructions. HER2 expression on CTCs was assessed using the Ariol system, calibrated through spiking experiments of 100 cells (BT474, SKBR3, A431, and MDA MB-231) and 2.5 * 107 white blood cells/mL from healthy donors. Seventy-one patients with breast cancer and 107 non-cancer donors consented to provide blood. RESULTS: Based on breast cancer cell lines experiments, HER2+ CTCs were defined as CTCs with HER2 immunofluorescence intensity >= 3.5 times higher than the CD45 immunofluorescence intensity (100% sensitivity and 99.9% specificity). Among the 71 patients with breast cancer, 31 (43.7%) had HER2+ tumor. Among the HER2+ patients, 41.9% (13/31) were found to be HER2+ based on CTC >= 1, and 25.8% (8/31) were positive based on CTC >= 3. In HER2-negative patients by pathologic examination, 1 (2.5%) patient was found to have >= 3 HER2+ CTCs, whereas 15 (37.5%) patients had >= 1 HER2+ CTC. HER2+ CTCs were detected at all stages, even in early breast cancer, but the detection rate was higher in metastatic breast cancer. CONCLUSION: This proof-of-concept study strongly suggests that HER2+ CTCs can be detected using the LiquidBiopsy system. PMID- 30472075 TI - The potent small molecule integrin antagonist THR-687 is a promising next generation therapy for retinal vascular disorders. AB - Integrins are associated with various eye diseases such as diabetic retinopathy (DR) and wet age-related macular degeneration (AMD) and implicated in main pathologic disease hallmarks like neovascularization, inflammation, fibrosis and vascular leakage. Targeting integrins has the potential to attenuate these vision threatening processes, independent of anti-vascular endothelial growth factor (VEGF) responsiveness. The current investigation characterized THR-687 as a novel pan RGD (arginylglycylaspartic acid) integrin receptor antagonist able to compete for binding with the natural ligand with nanomolar potency (e.g. alphavbeta3 (IC50 of 4.4 +/- 2.7 nM), alphavbeta5 (IC50 of 1.3 +/- 0.5 nM) and alpha5beta1 (IC50 of 6.8 +/- 3.2 nM). THR-687 prevented the migration of human umbilical vein endothelial cells (HUVECs) into a cell-free area (IC50 of 258 +/- 113 nM) as well as vessel sprouting in an ex vivo mouse choroidal explant model (IC50 of 236 +/- 173 nM), and was able to induce the regression of pre-existing vascular sprouts. Moreover, combined intravitreal and intraperitoneal administration of THR-687 potently inhibited VEGF-induced leakage in the mouse retina. In addition, THR-687 injected intravitreally at 3 different dose levels (0.45 mg, 2.25 mg or 4.5 mg/eye) potently inhibited neovascularization-induced leakage in the cynomolgus laser-induced choroidal neovascularization (CNV) model. These data suggest that THR-687 is a promising drug candidate for the treatment of vision-threatening retinal vascular eye diseases such as DR and wet AMD. PMID- 30472076 TI - Neocortical Topology Governs the Dendritic Integrative Capacity of Layer 5 Pyramidal Neurons. AB - The structure of the neocortex varies across the neocortical mantle to govern the physical size of principal neurons. What impact such anatomical variation has on the computational operations of principal neurons remains unknown. Here, we demonstrate within a functionally defined area that neocortical thickness governs the anatomical, electrophysiological, and computational properties of the principal output neurons of the neocortex. We find that neocortical thickness and the size of layer 5B pyramidal neurons changes as a gradient across the rostro caudal axis of the rat primary visual cortex. Simultaneous somato-dendritic whole cell recordings and compartmental modeling revealed that the electrical architecture of principal neurons was not preserved; rather, primary visual cortex site-dependent differences in intracellular resistivity accentuated a gradient of the electrical behavior of layer 5B pyramidal neurons to influence the emergence of active dendritic computations. Our findings therefore reveal an exquisite relationship between neocortical structure and neuronal computation. PMID- 30472077 TI - Higher-Order Thalamocortical Inputs Gate Synaptic Long-Term Potentiation via Disinhibition. AB - Sensory experience and perceptual learning changes receptive field properties of cortical pyramidal neurons (PNs), largely mediated by synaptic long-term potentiation (LTP). The circuit mechanisms underlying cortical LTP remain unclear. In the mouse somatosensory cortex, LTP can be elicited in layer 2/3 PNs by rhythmic whisker stimulation. We dissected the synaptic circuitry underlying this type of plasticity in thalamocortical slices. We found that projections from higher-order, posterior medial thalamic complex (POm) are key to eliciting N methyl-D-aspartate receptor (NMDAR)-dependent LTP of intracortical synapses. Paired activation of cortical and higher-order thalamocortical inputs increased vasoactive intestinal peptide (VIP) and parvalbumin (PV) interneuron (IN) activity and decreased somatostatin (SST) IN activity, which together disinhibited the PNs. VIP IN-mediated disinhibition was critical for inducing LTP. This study reveals a circuit motif in which higher-order thalamic inputs gate synaptic plasticity via disinhibition. This motif may allow contextual feedback to shape synaptic circuits that process first-order sensory information. PMID- 30472078 TI - Surgical outcome of patients with vesicoureteral reflux from a single institution in reference to the ESPU guidelines: a retrospective analysis. AB - INTRODUCTION: Vesicoureteral reflux (VUR) is an anatomic or functional disorder, and it is a condition associated with renal scarring, hypertension, and end-stage renal disease. Renal damage can be prevented by appropriate medical and surgical intervention for selected patients. OBJECTIVES: The objective of this study was to retrospectively analyze the surgically treated patient group of this study in reference to the risk analysis criteria used in European Association of Urology (EAU), European Society for Paediatric Urology (ESPU) guidelines to see the outcome of the study management protocol within the last 15 years in respect to this risk analysis. STUDY DESIGN: A total of 686 patients who were operated upon in a single institution for VUR between 1997 and 2016 were retrospectively analyzed. According to the criteria in EAU/ESPU guidelines, the patients were classified into three groups: low, medium, and high risk. Risk factors were compared between the groups. RESULTS: The patient numbers for low, medium, and high risk were 92 (13.4%), 485 (70.7%), and 109 (15.9%), respectively. In the high-risk group, surgeons tended to do more ureteroneocystostomy (UNC) (82.6%), whereas in the low-risk group, surgeons tended to do more subureteric injection (STING) (76.1%). The success rates for STING and UNC were found to be 75% and 93%, respectively. Although there was a difference in success rates among patients treated with STING or UNC, this difference was not statistically significant in success rates regarding risk groups for patients treated with STING or UNC. DISCUSSION: The most recent guideline was that which was published by the EAU/ESPU organization in 2012. This guideline is established based on the risk analysis. The analysis revealed that patients in the low-risk group tended to undergo endoscopic surgery treatment method, whereas patients in the high-risk group tended to undergo open surgery. Therefore, the study management over the last 10 years has been mainly in line with the current recommendations. CONCLUSION: The analysis shows that when the patients are classified according to the EAU/ESPU risk classification, surgeons tended to perform more endoscopic and more open surgery for the low- and high-risk groups, respectively. Although each surgical modality had similar success rates in each group, open surgical results were overall much higher than those of endoscopic surgery in each group. This was a specifically important finding in high-risk group where the endoscopically treated group of patients was small in number, and the need for a definitive correction is essential in this group because of increased risk of renal injury. PMID- 30472079 TI - Properties of a recombinant GH49 family dextranase heterologously expressed in two recipient strains of Penicillium species. AB - The dexA gene encoding Penicillium funiculosum dextranase (GenBank accession MH581385) belonging to family 49 of glycoside hydrolases (GH49) was cloned and heterologously expressed in two recipient strains, P. canescens RN3-11-7 and P. verruculosum B1-537. Crude enzyme preparations with the recombinant dextranase content of 8-36% of the total secreted protein were obtained on the basis of new Penicillium strains. Both recombinant forms of the dextranase were isolated in a homogeneous state using chromatographic techniques. The purified enzymes displayed very similar properties, that is, pI 4.55, activity optima at pH 4.5 5.0 and 55-60 degrees C and a melting temperature of 60.7-60.9 degrees C. They were characterized by similar specific activities (1020-1340 U/mg) against dextrans with a mean molecular mass of 20, 70 and 500 kDa, as well as similar kinetic parameters in the hydrolysis of 70 kDa dextran (Km = 1.10-1.11 g/L, kcat = 640-680 s-1). However, the recombinant dextranases expressed in P. canescens and P. verruculosum had different molecular masses according to the data of SDS PAGE (~63 and ~60 kDa, respectively); this was the result of different N glycosylation patterns as MALDI-TOF mass spectrometry analysis showed. The main products of dextran hydrolysis at its initial phase were isomaltooligosaccharides, while after the prolonged time (24 h) the reaction system contained isomaltose and glucose as the major products and minor amounts of other oligosaccharides. PMID- 30472080 TI - Biological applications of tethered bilayer lipid membranes. AB - Lipid membranes have an essential role in most physiological processes including cell protection, cell-to-cell communication and regulation of intracellular signaling. These multiple roles of biological membranes prompted the study and the development of artificial lipid membranes with the primary aim to reconstitute the natural functions in vitro and understand the interaction between all membrane components at the molecular level. Tethered bilayer lipid membranes (tBLMs) are emerging as the ideal experimental platform for functional and structural studies on membrane-associated proteins due to their peculiar properties such as their stability and fluidity of both leaflets in the phospholipid bilayer. tBLMs have been used in many studies, ranging from the analysis of membrane structure and function, studies of the membrane-protein and membrane-peptide interactions, as well as applications as biosensors and energy generating devices. This review describes all the uses of tBLMs as a tool to investigate biological functions, pointing out limitations of this methodology and future applications once optimization of the technique will be achieved. PMID- 30472081 TI - Molecular detection of Leucocytozoon (Apicomplexa: Haemosporida) in black flies (Diptera: Simuliidae) from Thailand. AB - Information regarding vector-parasite association is necessary for fully understanding the epidemiology of vector borne diseases yet, this information is lacking in the case of Leucocytozoonosis in the Oriental region, despite a high incidence of the disease. In this study, we used a molecular approach based on mitochondrial cytochrome b (cyt b) sequence to detect the parasite, Leucocytozoon, in potential black fly (Simuliidae) vectors in Thailand. A total of 404 wild caught black flies representing six morphological species of two subgenera were examined.- Gomphostilbia (Simulium asakoae complex, S. chumpornense) and Simulium (S. chamlongi, S. nodosum, S. nigrogilvum). Forty-four black fly specimens from two species of the Gomphostilbia were positive for Leucocytozoon. Most (35) of these were found in a village where high numbers of domestic chicken were kept, consistent with the possibility that chickens are a host of Leucocytozoon species found in black flies. Sixteen haplotypes were identified among 44 cyt b sequences. Comparisons of the sequences with previous reports revealed that the 11 haplotypes obtained in this study were identical or very similar to unknown Leucocytozoon found in infected domestic chickens. Four haplotypes are genetically similar to L. schoutedeni and one haplotype is genetically very different from existing cyt b sequences in public database. Our results indicate that two black fly species of the subgenus Gomphostilbia in Thailand are possible vectors of Leucocytozoon transmitted among poultry and wild birds in the country. PMID- 30472082 TI - Efficacy of Montanide (IMS 3015) as an adjuvant for an inactivated Rift Valley fever (RVF) vaccine in sheep. AB - This study was conducted to evaluate an adjuvant, Montanide (IMS 3015), in improving the quality of Rift Valley fever (RVF) vaccine relative to the traditional adjuvant, aluminum hydroxide gel. Vaccinated sheep were evaluated using biochemical analysis, kidney function tests, liver function tests, and immunological tests. Sheep vaccinated with Montanide (IMS 3015) adjuvant showed significantly higher total protein, total globulin, and gamma globulin concentrations from the second week until the fifth month than the controls. Conversely, albumin concentration and the A/G ratio significantly decreased during this period. Kidney function and liver function tests revealed no differences among any of the groups. There was a significant increase in lymphocyte proportion and a decrease in neutrophil proportion in sheep vaccinated with the Montanide (IMS 3015) adjuvant. Lymphocyte cell proliferation was significantly different in sheep vaccinated with the Montanide (IMS 3015) adjuvant from that in controls. Neutralizing indices were significantly higher in sheep vaccinated with the Montanide (IMS 3015) adjuvant than in controls. The current study showed that sheep vaccinated with inactivated RVF virus with Montanide (IMS 3015) as an adjuvant were protected and no pathological symptoms or biochemical changes were detected. Moreover, the vaccine induced rapid onset of immunological responses with long durations unlike inactivated RVF vaccine with aluminum hydroxide gel. PMID- 30472083 TI - Erratum to "Surgical outcomes in the treatment of temporal bone cerebrospinal fluid leak: A systematic review" [Auris Nasus Larynx 45 (2018) 903-910]. PMID- 30472084 TI - Effect of long spinal fusion including the pelvis on activities of daily living related to lumbar spinal function in adults with spinal deformity. AB - BACKGROUND: Spinal sagittal malalignment is managed by long spinal fusion including the pelvis, which reduces lumbar spine range of motion and impairs the activities of daily living. This study aimed to evaluate the changes in activities of daily living after long spinal fusion in adults with spinal deformity, and clarify the improvement or deterioration in the specific activities of daily living postoperatively. METHODS: We retrospectively reviewed 40 adults who underwent long spinal fusion in a single institution between 2014 and 2016 (female/male, 39/1; mean age, 68.5 years; range, 52-79 years). Each patient undertook three self-assessed health-related quality of life measures preoperatively and again at 2-years postoperatively: Oswestry Disability Index (ODI), Scoliosis Research Society (SRS)-22 questionnaire, and Japanese Orthopaedic Association back pain evaluation questionnaire (JOABPEQ). Radiographic outcomes were measured preoperatively and at 2 years postoperatively. RESULTS: Total ODI and all SRS-22 domains were improved at 2 years postoperatively. The JOABPEQ scores were also improved in all domains, except lumbar function. The change in pelvic incidence minus lumbar lordosis correlated with improvements in total ODI, SRS-22 function, and self-image scores. At 2 years postoperatively, satisfaction was correlated with total ODI, all SRS-22 domains, and the JOABPEQ pain domain. Subclass analysis of the JOABPEQ lumbar function domain at 2 years postoperatively revealed that 65% of patients had difficulty 'putting on socks or stockings', 42% had great difficulty 'bending forward, kneeling, or stooping', 32% reported improvement in 'sit to stand', and 32% reported deterioration in 'putting on socks or stockings' after surgery compared with before surgery. The JOABPEQ lumbar function domain was not correlated with the SRS-22 satisfaction domain. CONCLUSIONS: Despite restricting lumbar function, spinopelvic fusion improves health-related quality of life. Surgeons and patients should discuss potential changes and limitations in the activities of daily living after long spinal fusion including the pelvis. PMID- 30472085 TI - Is the Bohler angle reliable for operative reduction of calcaneus fracture? AB - BACKGROUD: To evaluate reliability of Bohler angle in doing operative reduction of fractured calcaneus, and compare its value over other image lines of hindfoot when surgeons determine whether the injured calcaneus is reduced close to pre injured state. METHODS: Eighteen of postoperative lateral radiographs were obtained and edited with two versions; one of which anterior of calcaneus erased not to check Bohler angle, the other of which peri-calcaneus structure such as talus erased only to check Bohler angle. Four orthopaedic surgeons were asked to determine the two sets of images whether the injured calcaneus is reduced close to pre-injured state in independent two sessions. Intra-, interobserver reliability, diagnosis test including specificity, sensitivity, positive and negative predictive values were assessed. RESULTS: Intra- and interobserver reliability, Kappa value, ranged from 0.110 to 0.723 regardless the kind of the test. Sensitivity and specificity of both two tests were not significantly different in both trials, either. Positive and negative predictive values also showed similar pattern. The probability that observer determine the specific image as an acceptable reduction of calcaneus-less than 5 degrees of difference of the Bohler angle between post-reduction and pre-injured state-of two tests, was not significantly different in both trials (p = 0.40, 0.24, respectively). CONCLUSIONS: Bohler angle is known as one of the most objective markers for calcaneus fracture, but was not accurate as a sole reference in intra-operative reduction in this study. Therefore, surgeons should take into account the other radiographic features in surgery. LEVELS OF EVIDENCE: IV, case series. PMID- 30472086 TI - Cardiovascular sequelae of sleep apnea: In your brain and in your gut. PMID- 30472087 TI - High PARP-1 expression predicts poor survival in acute myeloid leukemia and PARP 1 inhibitor and SAHA-bendamustine hybrid inhibitor combination treatment synergistically enhances anti-tumor effects. AB - BACKGROUND: PARP-1 plays a critical role in DNA damage repair and contributes to progression of cancer. To explore the role of PARP-1 in acute myeloid leukemia (AML), we analyzed the expression of PARP-1 in AML and its relation to the clinical prognosis. Then, we investigated the efficacy and mechanism of PARP inhibitor BMN673 (Talazoparib) combined with NL101, a novel SAHA-bendamustine hybrid in vitro and in vivo. METHODS: The expression of PARP-1 in 339 cytogenetically normal AML (CN-AML) cases was evaluated using RT-PCR. According to the expression of PARP-1, the clinical characteristics and prognosis of the patients were grouped and compared. The combination effects of BMN673 and NL101 were studied in AML cells and B-NSG mice xenograft model of MV4-11. FINDINGS: We found patients in high PARP-1 expression group had higher levels of blast cells in bone marrow (P = .003) and white blood cells (WBC) in peripheral blood (P = .008), and were associated with a more frequent FLT3-ITD mutation (28.2% vs 17.3%, P = .031). The overall survival (OS) and event free survival (EFS) of the high expression group were significantly shorter than those in the low expression group (OS, P = .005 and EFS, P = .004). BMN673 combined with NL101 had a strong synergistic effect in treating AML. The combination significantly induced cell apoptosis and arrested cell cycle in G2/M phase. Mechanistically, BMN673 and NL101 combinatorial treatment promoted DNA damage. In vivo, the combination effectively delayed the development of AML and prolonged survival. INTERPRETATION: High PARP-1 expression predicts poor survival in CN-AML patients. The synergistic effects of PARP inhibitor BMN673 in combination with SAHA bendamustine hybrid, NL101, provide a new therapeutic strategy against AML. FUND: National Natural Science Foundation of China and Zhejiang Provincial Key Innovation Team. PMID- 30472088 TI - Neural stem cell derived extracellular vesicles: Attributes and prospects for treating neurodegenerative disorders. AB - Neural stem cell (NSC) grafting in conditions such as aging, brain injury, and neurodegenerative diseases promotes regeneration, plasticity and functional recovery. Recent studies have revealed that administration of NSC-derived extracellular vesicles (NSC-EVs) via non-invasive approaches can also afford therapeutic benefits. This review confers the properties and therapeutic promise of EVs secreted by NSCs. NSC-EVs enriched with specific miRNAs mediate multiple functions in physiological and pathological conditions, which include modulation of the proximate microenvironment, facilitating the entry of viruses into cells, functioning as independent metabolic units, operating as a microglial morphogen and influencing the diverse aspects of brain function in adulthood including the process of aging. Due to their anti-inflammatory, neurogenic and neurotrophic effects, NSC-EVs are also useful for treating multiple neurodegenerative diseases. Although only a few studies have demonstrated the efficacy of NSC-EVs to treat brain impairments, the promise is enormous. Moving forward, the use of well-characterized NSC-EVs generated in specific culture conditions and NSC-EVs that are engineered to carry the desired miRNAs, mRNAs and proteins have great promise for treating brain injury and neurogenerative diseases. Notably, the possibility of targeting NSC-EVs to specific neuronal types or brain regions would enable managing of diverse neurodegenerative conditions with minimal side effects. PMID- 30472089 TI - Evidence for positive selection of hepatitis A virus antigenic variants in vaccinated men-having-sex-with men patients: Implications for immunization policies. AB - BACKGROUND: A huge outbreak in the men-having-sex-with-men (MSM) has hit Europe during the years 2016-2018. Outbreak control has been hampered by vaccine shortages in many countries, and to minimize their impact, reduction of antigen doses has been implemented. However, these measures may have consequences on the evolution of hepatitis A virus (HAV), leading to the emergence of antigenic variants. Cases in vaccinated MSM patients have been detected in Barcelona, opening the possibility to study HAV evolution under immune pressure. METHODS: We performed deep-sequencing analysis of ten overlapping fragments covering the complete capsid coding region of HAV. A total of 14578255 reads were obtained and used for the analysis of virus evolution in vaccinated versus non-vaccinated patients. We estimated maximum and minimum mutation frequencies, and Shannon entropy in the quasispecies of each patient. Non-synonymous (NSyn) mutations affecting residues exposed in the capsid surface were located, with respect to epitopes, using the recently described crystal structure of HAV, as an indication of its potential role in escaping to the effect of vaccines. FINDINGS: HAV evolution at the quasispecies level, in non-vaccinated and vaccinated patients, revealed higher diversity in epitope-coding regions of the vaccinated group. Although amino acid replacements occurring in and around the epitopes were observed in both groups, their abundance was significantly higher in the quasispecies of vaccinated patients, indicating ongoing processes of fixation. INTERPRETATION: Our data suggest positive selection of antigenic variants in some vaccinated patients, raising concerns for new vaccination polices directed to the MSM group. PMID- 30472090 TI - Defined Paraventricular Hypothalamic Populations Exhibit Differential Responses to Food Contingent on Caloric State. AB - Understanding the neural framework behind appetite control is fundamental to developing effective therapies to combat the obesity epidemic. The paraventricular hypothalamus (PVH) is critical for appetite regulation, yet, the real-time, physiological response properties of PVH neurons to nutrients are unknown. Using a combination of fiber photometry, electrophysiology, immunohistochemistry, and neural manipulation strategies, we determined the population dynamics of four molecularly delineated PVH subsets implicated in feeding behavior: glucagon-like peptide 1 receptor (PVHGlp1r), melanocortin-4 receptor (PVHMc4r), oxytocin (PVHOxt), and corticotropin-releasing hormone (PVHCrh). We identified both calorie- and state-dependent sustained activity increases and decreases in PVHGlp1r and PVHCrh populations, respectively, while observing transient bulk changes of PVHMc4r, but no response in PVHOxt, neurons to food. Furthermore, we highlight the role of PVHGlp1r neurons in orchestrating acute feeding behavior, independent of the anti-obesity drug liraglutide, and demonstrate the indispensability of PVHGlp1r and PVHMc4r, but not PVHOxt or PVHCrh neurons, in body weight maintenance. PMID- 30472091 TI - Reduced area of the normal lung on high-resolution computed tomography predicts poor survival in patients with lung cancer and combined pulmonary fibrosis and emphysema. AB - BACKGROUND: This study aimed to determine the radiologic predictors and clarify the clinical features related to survival in patients with combined pulmonary fibrosis and emphysema (CPFE) and lung cancer. METHODS: We retrospectively reviewed the medical chart data and high-resolution computed tomography (HRCT) findings for 81 consecutive patients with CPFE and 92 primary lung cancers (70 men, 11 women; mean age, 70.9 years). We selected 8 axial HRCT images per patient, and visually determined the normal lung, modified Goddard, and fibrosis scores. Multivariate analysis was performed using the Cox proportional hazards regression model. RESULTS: The major clinical features were a high smoking index of 54.8 pack-years and idiopathic pulmonary fibrosis (n = 44). The major lung cancer profile was a peripherally located squamous cell carcinoma (n = 40) or adenocarcinoma (n = 31) adjacent to emphysema in the upper/middle lobe (n = 27) or fibrosis in the lower lobe (n = 26). The median total normal lung, modified Goddard, and fibrosis scores were 10, 8, and 8, respectively. TNM Classification of malignant tumors (TNM) stage I, II, III, and IV was noted in 37, 7, 26, and 22 patients, respectively. Acute exacerbation occurred in 20 patients. Multivariate analysis showed that a higher normal lung score and TNM stage were independent radiologic and clinical predictors of poor survival at the time of diagnosis of lung cancer. CONCLUSIONS: A markedly reduced area of normal lung on HRCT was a relevant radiologic predictor of survival. PMID- 30472092 TI - Structural Mechanisms of Cooperative DNA Binding by Bacterial Single-Stranded DNA Binding Proteins. AB - Bacteria encode homooligomeric single-stranded (ss) DNA-binding proteins (SSBs) that coat and protect ssDNA intermediates formed during genome maintenance reactions. The prototypical Escherichia coli SSB tetramer can bind ssDNA using multiple modes that differ by the number of bases bound per tetramer and the magnitude of the binding cooperativity. Our understanding of the mechanisms underlying cooperative ssDNA binding by SSBs has been hampered by the limited amount of structural information available for interfaces that link adjacent SSB proteins on ssDNA. Here we present a crystal structure of Bacillus subtilis SsbA bound to ssDNA. The structure resolves SsbA tetramers joined together by a ssDNA "bridge" and identifies an interface, termed the "bridge interface," that links adjacent SSB tetramers through an evolutionarily conserved surface near the ssDNA binding site. E. coli SSB variants with altered bridge interface residues bind ssDNA with reduced cooperativity and with an altered distribution of DNA binding modes. These variants are also more readily displaced from ssDNA by RecA than wild-type SSB. In spite of these biochemical differences, each variant is able to complement deletion of the ssb gene in E. coli. Together our data suggest a model in which the bridge interface contributes to cooperative ssDNA binding and SSB function but that destabilization of the bridge interface is tolerated in cells. PMID- 30472093 TI - Investigation of nervous necrosis virus (NNV) replication in vitro using RNA in situ hybridization. AB - Nervous necrosis virus (NNV) belongs to the genus Betanodavirus of family Nodaviridae. Its genome consists of two RNA segments, RNA1 and RNA2. Several studies have investigated NNV detection by in situ hybridization (ISH), but these have typically focused on the detection of the RNA2 gene. In this study, we localized both RNA1 and RNA2 NNV segments in viral-infected cells by ISH, using labeled RNA probes (RNA-ISH). Also, immunocytochemistry (ICC) assay was carried out for localization of viral particle by targeting the coat protein. Further, viral quantification assays were performed by quantitative RT-PCR and viral infectivity (TCID50) in SSN-1 cells. Viral segments were observed by RNA-ISH at 6 h post infection (hpi), while NNV particles were detected at 24 hpi by ICC. Use of double labeling RNA-ISH revealed the co-expression of the two viral segments in the same area of the cells, while RNA1 was also detected separately. Comparison of the level of viral genomic segments and viral infectivity revealed significantly more copies of RNA1 at each time points than copies of RNA2 and greater NNV titers. The results suggest that RNA1 might be expressed in the early stages of replication, with RNA2 expressed later. The virions then assemble through initially expressed viral genomic segments. Even though infectious particles displayed very efficient packaging, the RNA1 segment was still over produced. PMID- 30472094 TI - The autographa californica multiple nucleopolyhedrovirus Ac12: A non-essential F box-like protein that interacts with cellular SKP1 component of the E3 ubiquitin ligase complex. AB - The Autographa californica multiple nucleopolyhedrovirus (AcMNPV) ac12 gene, which is conserved in ten other baculovirus, codes a predicted 217 amino acid protein of unknown function. In this study, we investigated the role of ac12 during baculovirus infection, by generating an ac12 knockout virus. The transfection of the recombinant genome in insect cells resulted in unaltered viral dispersion and occlusion body production when compared to the control bacmid. This finding demonstrates that ac12 is a non-essential gene. Transmission and scanning electron microscopy (SEM) analyses showed that ac12 knockout virus produced occlusion bodies morphologically similar to those obtained with the control and capable to occlude virions. However, a slight but significant size difference was detected by SEM observation of purified occlusion bodies. This difference suggests that ac12 may be involved in regulatory pathways of polyhedrin production or occlusion body assembly without affecting either viral occlusion or oral infectivity in Rachiplusia nu larvae. This was evidenced by bioassays that showed no significant differences in the conditions tested. A qPCR analysis of viral gene expression during infection evidenced regulatory effects of ac12 over some representative genes of different stages of the viral cycle. In this study, we also showed that ac12 is transcribed at early times after infection and remains detectable up to 72 hours post-infection. The mRNA is translated during the infection and results in a protein that encodes an F-box domain that interacts in vivo and in vitro with S phase kinase associated protein 1 (SKP1) adaptor protein, which is potentially involved in protein ubiquitination pathways. PMID- 30472095 TI - Neurotoxicity of anesthetics: Mechanisms and meaning from mouse intervention studies. AB - Volatile anesthetics are widely used in human medicine and generally considered to be safe in healthy individuals. In recent years, the safety of volatile anesthesia in pediatric patients has been questioned following reports of anesthetic induced neurotoxicity in pre-clinical studies. These studies in mice, rats, and primates have demonstrated that exposure to anesthetic agents during early post-natal periods can cause acute neurotoxicity, as well as later-life cognitive defects including deficits in learning and memory. In recent years, the focus of many pre-clinical studies has been on identifying candidate pathways or potential therapeutic targets through intervention trials. These reports have shed light on the mechanisms underlying anesthesia induced neurotoxicity as well as highlighting the challenges of pre-clinical modeling of anesthesia induced neurotoxicity in mice. Here, we summarize the data derived from intervention studies in neonatal mouse models of anesthetic exposure and provide an overview of mechanisms proposed to mediate anesthesia induced neurotoxicity in mice based on these reports. The majority of these studies implicate one of three mechanisms: reactive oxygen species (ROS) mediated stress and signaling, growth/nutrient signaling, or direct neuronal modulation. PMID- 30472096 TI - Genitourinary tuberculosis in Taiwan: A 15-year experience at a teaching hospital. AB - BACKGROUND: Genitourinary tuberculosis (GUTB) is rare but fatal if not diagnosed early. The purpose of this study was to investigate the outcomes of GUTB in Taiwan. METHODS: We retrospectively reviewed medical records of 57 patients who were diagnosed as GUTB from January 2002 to December 2016, over a 15-year period. Demographic data and clinical manifestations were recorded for analysis. RESULTS: There were 37 males and 20 females with a median age of 71 years. Kidney (24.6%) was the most involved organ. Fever (56.1%) was the major presentation. Sixteen (28.1%) patients presented unfavorable outcome. Compared with the favorable outcome group, the unfavorable outcome group had more malignancy (p = 0.013), fever (p = 0.020), anemia (p = 0007), thrombocytopenia (p = 0.003), and hypoalbuminemia (p = 0.015). In a multivariate analysis, fever (odds ratio: 42.716, 95% confidence interval: 1.032-1767.569; p = 0.048) was identified as prognostic factors for unfavorable outcome. CONCLUSION: GUTB is often in advanced stages with a high mortality in Taiwan. Establishing a diagnosis is difficult and requires thorough investigation. Fever is associated with unfavorable outcome. PMID- 30472097 TI - VANGL2 protein stability is regulated by integrin alphav and the extracellular matrix. AB - Vang-like 2 (VANGL2) is a four-pass transmembrane protein required for a variety of polarized cell behaviors underlying embryonic development. Recent data show human VANGL2 interacts with integrin alphav to control cell adhesion to extracellular matrix proteins. The goal of this study was to further define the functional relationship between integrin alphav and VANGL2. We demonstrate integrin alphav regulates VANGL2 protein levels both in vitro and in the zebrafish embryo. While integrin alphav knockdown reduces VANGL2 expression at membrane compartments, it does not affect VANGL2 transcription. Knockdown of integrin beta5, but not beta1 or beta3, also decreases VANGL2 protein levels. Inhibition of protein translation using cycloheximide demonstrates that integrin alphav knockdown cells have increased VANGL2 degradation while interference with either proteasome or lysosome function restores VANGL2. We further show integrin activation and stimulation of cell-matrix adhesion using MnCl2 fails to influence VANGL2. However, MnCl2 treatment stabilizes VANGL2 protein expression levels in the presence of cycloheximide. In the converse experiment, blockage of integrin mediated cell-matrix adhesion using a cyclic RGD peptide causes a reduction in VANGL2 protein levels. Together, our findings support a model where integrin alphav and cellular interactions with the extracellular matrix are required to maintain VANGL2 protein levels and thus function at the plasma membrane. PMID- 30472098 TI - EVI-1 modulates arsenic trioxide induced apoptosis through JNK signalling pathway in leukemia cells. AB - High expression of the oncogene ecotropic viral integration site-1 (EVI-1) is an independent negative prognostic indicator of survival in leukemia patients. This study aimed to examine the effects of arsenic trioxide (ATO) on EVI-1 in acute myeloid leukemia (AML). Mononuclear cells were isolated from the bone marrow and peripheral blood of AML patients and healthy donors. EVI-1 expression in hematopoietic cells was evaluated by RT-qPCR and Western blot analysis. EVI-1 was highly expressed in both primary AML and leukemia cell lines (THP-1 and K562). ATO down-regulated EVI-1 mRNA in zebrafish in vivo as well as in primary leukemia cells and THP-1 and K562 cells in vitro. Additionally, ATO treatment induced apoptosis, down-regulated both EVI-1 mRNA and oncoprotein expression, increased the expression of pro-apoptosis proteins, and decreased the expression of anti apoptotic proteins in leukemia cells in vitro. EVI-1 expression in leukemia cells (THP-1 and K562) transduced with EVI-1 siRNA was significantly reduced. Silencing EVI-1 had a significant effect on the activation of the JNK pathway and the induction of leukemia cell apoptosis. ATO may downregulate EVI-1 mRNA and oncoprotein levels and block the inhibitory effects of EVI-1 on the JNK pathway, which activates the JNK apoptotic pathway, thereby leading to the apoptosis of EVI-1 in AML patients. PMID- 30472099 TI - A multinested PCR for detection of the equine piroplasmids Babesia caballi and Theileria equi. AB - Two haemoparasites, Theileria equi and Babesia caballi, cause equine piroplasmosis (EP), one of the most prevalent tick-borne diseases in horses. The main aim of the present study was to develop and evaluate a multinested PCR (mn PCR) for simultaneous detection of the equine piroplasmids T. equi and B. caballi, by amplification of five genetic markers (18S rRNA, beta-tubulin, cytB, EMA-1 and RAP-1). This novel assay detected a high prevalence of equine piroplasmids in 235 horse blood samples collected in Castilla-Leon and Extremadura, Spain. The overall prevalence of infection with equine piroplasmids by mn-PCR was 72.8% (171/235), with 66.0% (155/235) of the animals positive for T. equi and 29.4% (69/235) positive for B. caballi. The seroprevalence obtained by cELISA for the same set of samples was lower than the infection prevalence recorded by mn-PCR, for either of the two equine piroplasmids (62.6%) as well as for T. equi alone (61.7%) or B. caballi alone (3.8%). There was high agreement among the mn-PCR and cELISA assays for diagnosis of EP caused by T. equi (kappa = 0.83) but not for B. caballi (kappa = 0.06). A phylogenetic analysis based on the RAP-1 gene of B. caballi showed that the strains from Spain clustered with those from Israel. PMID- 30472100 TI - Thymol action on cells and tissues of the synganglia and salivary glands of Rhipicephalus sanguineus sensu lato females (Acari: Ixodidae). AB - Thymol is a monoterpene present in plants of the families Lamiaceae, Verbenaceae and Apiaceae. Despite its proven acaricidal activity, little is known about the mechanism of action of thymol in ticks. Thus, the aim of this study was to perform a morpho-histochemical analysis of the synganglion and salivary glands of partially engorged females of the brown dog tick, Rhipicephalus sanguineus sensu lato (s.l.), exposed to thymol at different concentrations. Five groups were established: Control Group I (distilled water), Control Group II (ethanol 30%), Group III (thymol 1.25 mg/mL), Group IV (thymol 2.5 mg/mL) and Group V (thymol 5.0 mg/mL). The females were exposed to the treatments by the immersion method and subsequently kept in a climatic chamber (27 +/- 1 degrees C and relative humidity 80 +/- 10%) for five days. After this period, the synganglion and salivary glands were removed, and the hematoxylin/eosin morphological technique was applied. The von Kossa staining method with counterstaining neutral red was performed on the salivary glands. The results showed that females exposed to thymol had damaged synganglia, with pyknotic nuclei and vacuoles in the cortex and subperineurial regions, as well as rupture of the neural lamellae. The salivary glands showed type I acini with a dilated lumen. Cells with extremely vacuolated cytoplasm and fragmented nuclei were observed in type II and III acini. Type II acini of the females exposed to thymol revealed different calcium staining when compared to the Control Groups I and II. We therefore conclude that the salivary glands and synganglion are subject to changes in morphology and calcium levels when exposed to thymol at concentrations of 1.25, 2.5 and 5.0 mg/mL, demonstrating that this monoterpene has acaricidal potential on partially engorged females of R. sanguineus (s.l.). PMID- 30472101 TI - Bladder filling to promote subperitoneal hydrodissection during percutaneous thermal ablation of parietal abdominal tumor. PMID- 30472102 TI - Introduction to special issue Trends and Perspectives in Forensic Genetics 2018. PMID- 30472103 TI - Resting gamma power during the postnatal critical period for GABAergic system development is modulated by infant diet and sex. AB - Gamma band activity (30-50 Hz) plays an essential role in brain development and function, but neither the early postnatal development nor subject and environmental factors influencing this development have been reported. We documented the development of resting gamma power using high density EEG recordings obtained each month from postnatal month 2 to 6 in 518 healthy infants who were breast-fed (170; 85 boys), fed milk formula (186; 97 boys), or fed soy formula (162; 90 boys). Gamma power was determined for 44 sites distributed over major brain regions and analyses were adjusted for background variables relevant to neurodevelopment. The results show gamma power follows a gradually increasing function across this time period that varies in topographic magnitude and is differentially influenced by subject and environmental variables-among which gestation, head circumference, and infant diet-sex interactions figure most prominently. Relationships between gamma power and standardized measures of infant behavioral development appear to be emerging but are in flux during this time. Since this postnatal period is considered critical in the development of the GABAergic system underlying the generation of gamma activity, the observed findings may reflect organizational changes that will influence the future development of gamma-related behavioral and neurocognitive functions. PMID- 30472104 TI - IP-10 is highly involved in HIV infection. AB - Interferon-gamma (IFN-gamma)-induced protein 10 (IP-10 or CXCL-10) is a chemokine involved in trafficking immune cells to inflammatory sites. Numerous studies have reported abnormally high plasma IP-10 levels in the context of human immunodeficiency virus (HIV) infection, and IP-10 is considered an important pro inflammatory factor in the HIV disease process. The data regarding the roles of IP-10 in HIV infection required collation; this review summarizes the biological characteristics of IP-10, the positive association between plasma IP-10 levels and HIV disease progression, the effect of IP-10 on human immune cells, and potential related mechanisms. This review provides important insights into the role of IP-10 in HIV monitoring and treatment. PMID- 30472105 TI - Genetic polymorphisms in interleukin 13 gene with the susceptibility to nasopharyngeal carcinoma in a Chinese population. AB - Although inflammation is emerging as a candidate risk factor in tumorigenesis of nasopharyngeal carcinoma (NPC). In particular, Interleukin (IL) 13 involved inflammatory diseases and cancers. Single nucleotide polymorphisms in IL-13 have been associated with multiple cancers. The study analyzed genetic polymorphisms in IL-13 aiming to investigate its' potential susceptibility with the NPC. The genotyping of polymorphisms (rs20541, rs1295687 and rs2069744) was examined by Snapshot SNP and DNA sequencing. All SNPs were within Hardy-Weinberg equilibrium and each appeared in three genotypes in NPC and controls. Adjusted logistic regression showed that the TT genotype of rs20541 increased the risk of lymph node metastasis (TT vs. CC: OR = 2.87, 95%CI, 1.33-6.18, P = 0.007). CT/CC genotypes were associated with the decreased the risk of lymph node metastasis in NPC (CT/CC vs. TT: OR = 0.32, 95%CI, 0.16-0.65, P = 0.002). The concentration of IL-13 was significantly elevated in NPC patients compared with controls (P = 0.012). Moreover, significant differences were detected in the T-C-T haplotype distribution between NPC patients and controls (OR = 2.47, 95%CI, 1.06-5.78, P = 0.031). Our results, the first report, provide evidence that rs20541 polymorphisms may affect the lymph node metastasis of NPC patients in Chinese population. PMID- 30472106 TI - Visceral white adipose tissue and serum proteomic alternations in metabolically healthy obese patients undergoing bariatric surgery. AB - Metabolically healthy obesity is characterized as a comorbidity-free obesity status, however the exact pathogenetic mechanisms implicated in its transition to unhealthy obesity have not yet been unveiled. Our aim was to investigate the effect of metabolic health on the proteomic profile both in serum and visceral fat of morbidly obese subjects. 28 patients undergoing bariatric surgery were prospectively enrolled. They were divided into two groups: metabolically healthy (MHO, n = 18) and unhealthy (MUO, n = 10) obese patients. 30 biomarkers were measured in serum and visceral adipose tissue with the use of targeted proteomic analysis (Luminex assays). TNF weak inducer of apoptosis (TWEAK) (p = 0.043), TNF related apoptosis inducing ligand (TRAIL) (p = 0.037), Growth differentiation factor-15 (GDF-15) (p = 0.04), Resistin (RETN) (p = 0.047), Matrix metalloproteinase-9 (MMP-9) (p = 0.011) and C-terminal telopeptide (ICTP) (p = 0.022) were up-regulated in the MUO group in the visceral white adipose tissue. Moreover, C-C motif ligand-3 (CCL-3) (p = 0.056), Interleukin-20 (IL-20) (p = 0.04), Prokineticin-1 (PROK-1) (p = 0.028) and TWEAK (p = 0.016) were found to be suppressed in the serum of MHO group. Significant correlations between serum and adipose tissue levels of certain cytokines were also observed, while 16 biomarkers were associated with BMI. Our results indicate metabolic health substantially attenuates the expression of TWEAK, TRAIL, GDF-15, RETN, MMP-9 and ICTP expression locally, in the visceral white adipose tissue, and the expression of CCL-3, IL-20, PROK-1 and TWEAK in the peripheral blood. Intriguingly, different cytokines -except for TWEAK- are up-regulated in each site, suggesting that obesity is not a homogenous but a multi-dimensional disease. PMID- 30472107 TI - Metabolic regulation of infection and inflammation. AB - Immunometabolic framework provides a way to understand the immune regulation via cell intrinsic metabolic fluxes and metabolites during infections, tumors, and inflammatory disorders. During these diseases, the immune cells are activated requiring more energy and moderating their metabolic functions. The two categories of metabolic alterations are therefore causally associated with energy derivation and cellular functions. Pathogens, tumors and inflammation target energy metabolism, primarily glucose uptake, glucose catabolism, gluconeogenesis for continuing lipid metabolism through mainstream pathways such as glycolysis, tricarboxylic acid cycle, mitochondrial respiration and pentose phosphate pathway. Many biosynthetic pathways such as those of cholesterol, ceramide, sphingolipids, and fatty acids are altered explaining the metabolic interface in molecular pathogenesis in various infectious and non-infectious inflammatory diseases. The emerging immune-metabolic framework also identifies the key regulatory elements such as metabolites, signalling intermediates and transcription factors. These regulatory elements play key roles in deciding the fate of an infection, tumor or autoimmune diseases. The original research articles and the review articles in this Special issue of Cytokine on "Infection, Inflammation and Immunometabolomes" highlight these aspects of metabolic reprogramming and the role of some 'metabolomic regulators' in controlling the outcome of infectious and non-infectious diseases. In this Editorial, we introduce the readers to these articles discussing the elements in immune metabolic framework. PMID- 30472108 TI - Curing diffuse large B-cell lymphomas in elderly patients. AB - In older patients lymphoma is a frequent disease and diffuse large B-cell lymphoma (DLBCL) represents >60% of all lymphomas. Elderly patients with DLBCL are a heterogeneous population and the definition of elderly varies within the literature. Even though the combination of rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone (R-CHOP) is considered standard therapy for DLBCL, management of elderly patients remains challenging. Accurate selection of patients able to tolerate proper immune-chemotherapy is crucial and the comprehensive geriatric assessment based on age, comorbidities and functional abilities of daily living, may help to discriminate among fit, unfit or frail patients. Unfit and frail patients need to be treated with chemotherapy at reduced intensity. Novel compounds with a favorable toxicity profile may represent a promising first-line therapeutic option in combination with standard immune-chemotherapy or as single agent in the relapse/refractory setting. PMID- 30472109 TI - Defensins, a novel type of animal toxin-like potassium channel inhibitor. AB - The classical potassium channel inhibitors are toxin peptides from venomous animals, and whether there are peptide inhibitors from other species is an open question. Due to both the independent and interdependent relationships between the spear (peptide inhibitors) and the shield (potassium channels), human defensins were first identified by our group as endogenous potassium channel inhibitors. Encouraged by the discovery of human defensins as potassium channel inhibitors, defensins from invertebrates and fungi were successively found by our group to be potassium channel inhibitors. In addition, a plant defensin was reported to be a potassium channel inhibitor. Since defensins are widely produced by vertebrate, invertebrate, plant and fungi species, the recent work established a new research field on defensin-potassium channel interactions. Here, we review the current work on defensins from vertebrate, invertebrate, plant and fungi species as inhibitors of potassium channels and discuss future work in this research field. PMID- 30472110 TI - Biochemistry and pharmacology of proteins and peptides purified from the venoms of the snakes Macrovipera lebetina subspecies. AB - The isolation and characterization of individual snake venom components is important for a deeper understanding of the pathophysiology of envenomations, for improving the therapeutic procedures of patients, and it also opens possibilities for the discovery of novel toxins that might be useful as tools for understanding cellular and molecular processes. This review provides a summary of the different toxins that have been isolated and characterized from the venoms of Vipera lebetina (Macrovipera lebetina) subspecies Macrovipera lebetina cernovi, Macrovipera lebetina lebetina, Macrovipera lebetina obtusa, Macrovipera lebetina transmediterranea, Macrovipera lebetina turanica, the snake species causing the majority of human envenomings in Central Asia (Middle East) and North Africa. The venoms of these snakes contain proteins belonging to different families: Zn2+- metalloproteinases, serine proteinases, L-amino acid oxidase, 5'-nucleotidase, phosphodiesterase, phosphomonoesterase, nucleases, hyaluronidase, phospholipase A2, C-type lectin-like protein, disintegrin, DC-fragment, cystein-rich secretory protein, proteinase inhibitors, nerve growth factor (NGF), vascular endothelial growth factor (VEGF), low molecular weight peptides. Their main biochemical properties, toxic and pharmacological actions have been described. In this review we will provide an overview of the proteins and peptides from the venoms of M. lebetina subspecies, their biochemical, pharmacological and structural features and their role in snake venom toxinology. A lot of contributions have been made for better understandings of these venomous snakes, their venom, and their pharmacological effects. Many of these components are also fascinating models for drug design. PMID- 30472111 TI - Reliability and Agreement of Various InBody Body Composition Analyzers as Compared to Dual-Energy X-Ray Absorptiometry in Healthy Men and Women. AB - BACKGROUND: Bioelectrical impedance analysis has evolved over the years to include the use of multiple frequencies and impedance measurements to improve the accuracy and reliability of body composition estimates. The purpose of this investigation was to evaluate the reliability of the InBody230, InBody720, and InBody770 to measure body fat percent (BF%), fat mass (FM), and fat-free mass (FFM) in the general population and to compare results to dual-energy X-ray absorptiometry (DXA). METHODS: A total of 31 males and 36 females participated in 2 d of testing separated by 24-72 h. Each visit consisted of a DXA scan, and analysis with the InBody230, InBody720, and InBody770. RESULTS: All 3 bioelectrical impedance devices (InBody230, InBody720, and InBody770) were reliable in men and women as indicated by high intraclass correlation coefficients for BF% (>=0.98), FM (>=0.98), and FFM (>=0.99) and low standard error of measurement for BF% (0.77%-0.99%), FM (0.54-0.87 kg), and FFM (0.58-0.84 kg) and minimum difference for BF% (2.12%-2.73%), FM (1.49-2.39 kg), and FFM (1.60-2.32 kg), respectively. When examining the agreement between the 3 InBody analyzers with DXA, systematic bias (underestimation of BF% and FM and overestimation of FFM) was present for all comparisons (p < 0.05) while proportional bias was present for FM in women and FFM in men. However, there was small individual error for all comparisons as indicated by the standard error of estimate and 95% limits of agreement. CONCLUSION: The InBody analyzers produce small individual error, which suggest these methods can be used as a surrogate when DXA is not available; however, practitioners should be aware of the systematic bias for all comparisons and proportional bias for FM in women and FFM in men. Furthermore, findings revealed that the research grade models, InBody720 and InBody770, added minimal benefit over the portable InBody230 when assessing BF%, FM, and FFM. PMID- 30472112 TI - Making waves: Comparing Morris water task performance in rats and prairie voles. AB - Spatial processing is a critical component for survival. This domain of information processing has been extensively studied in rats and mice. Limited work has examined the capacity of other rodent species, like the prairie vole (Microtus ochrogaster), to process spatial information. The Morris water task (MWT) is a classic spatial task that has been used to examine spatial cognition in rodents. This task involves an animal developing configural relationships between extra-maze cues and the location of a hidden platform to successfully escape from a pool of water. The current study compared performance in the MWT between rats and prairie voles. Rats were observed to outperform prairie voles in key aspects of the task including latency to find the platform, directness of swim paths to the platform, and degrees of heading error. These results may be attributed to potential interspecies differences in spatial cognition, stress reactivity, physiology, or motivation. This study provides the foundation for future work investigating the spatial cognition of prairie voles and the factors that contribute to water task performance in rodents. PMID- 30472113 TI - Behavioral characterization of DAT-KO rats and evidence of asocial-like phenotypes in DAT-HET rats: The potential involvement of norepinephrine system. AB - Dopamine (DA) is a key neurotransmitter of the central nervous system, whose availability is regulated by the dopamine transporter (DAT). Deletion of DAT gene leading to hyperdopaminergia was previously performed on mouse models. This enabled recapitulation of the core symptoms of Attention-Deficit / Hyper-activity Disorder (ADHD), which include hyperactivity, inattention and cognitive impairment. We used recently developed DAT knockout (DAT-KO) rats to carry out further behavioral profiling on this novel model of hyperdopaminergia. DAT-KO rats display elevated locomotor activity and restless environmental exploration, associated with a transient anxiety profile. Furthermore, these rats show pronounced stereotypy and compulsive-like behavior at the Marble-Burying test. Homozygous DAT-KO rats mantain intact social interaction when tested in a social preference task, while heterozygous (HET) rats show high inactivity associated with close proximity to the social stimulus. Ex-vivo evaluation of brain catecholamines highlighted increased levels of norepinephrine in the hippocampus and hypothalamus exclusively of heterozygous rats. Taken together, our data present evidence of unexpected asocial tendencies in heterozygous DAT-KO rats associated with neurochemical alterations in norepinephrine neurotransmission. We shed light on the behavioral and neurochemical consequences of altered DAT function in a higher, more complex model of hyperdopaminergia. Unraveling the role of DA neurotransmission in DAT-KO rats has very important implications in the understanding of many psychiatric illnesses, including ADHD, where alterations in DA system have been demonstrated. PMID- 30472114 TI - Responses to executive demand in young adulthood differ by APOE genotype. AB - Despite evidence of a relationship between Apolipoprotein E (APOE) epsilon4+ and later-life cognitive decline, the lifespan effects of carrying an epsilon4+ allele on cognitive ageing are not well understood. Evidence of epsilon4+ advantages in early-life are inconsistent, but not inconsiderable. We explored the proposal that APOE epsilon4+ cognitive advantages arise only in response to complex and sensitive tasks targeting specific executive functions. We systematically manipulated executive demand within verbal fluency, decision making, prospective memory, and sustained attention tasks. Participants aged 18 25 years (21 epsilon4+, 63 epsilon33) also completed a measure of subjective effort. Under low executive demand, epsilon4+ made fewer verbal fluency word repeats compared to epsilon33 carriers. Under high executive demand, epsilon4+ showed lower costs associated with performing concurrent tasks, greater switching errors, and more verbal fluency root repetition errors. Overall, epsilon4+ appeared to be showing working memory updating advantages under conditions of low executive demand, more effective resource allocation under elevated levels of executive demand, and errors indicating different strategy use compared to epsilon33 carriers, including speed-accuracy trade-offs. PMID- 30472115 TI - The Anti-amyloid Compound DO1 Decreases Plaque Pathology and Neuroinflammation Related Expression Changes in 5xFAD Transgenic Mice. AB - Self-propagating amyloid-beta (Abeta) aggregates or seeds possibly drive pathogenesis of Alzheimer's disease (AD). Small molecules targeting such structures might act therapeutically in vivo. Here, a fluorescence polarization assay was established that enables the detection of compound effects on both seeded and spontaneous Abeta42 aggregation. In a focused screen of anti-amyloid compounds, we identified Disperse Orange 1 (DO1) ([4-((4-nitrophenyl)diazenyl)-N phenylaniline]), a small molecule that potently delays both seeded and non-seeded Abeta42 polymerization at substoichiometric concentrations. Mechanistic studies revealed that DO1 disrupts preformed fibrillar assemblies of synthetic Abeta42 peptides and decreases the seeding activity of Abeta aggregates from brain extracts of AD transgenic mice. DO1 also reduced the size and abundance of diffuse Abeta plaques and decreased neuroinflammation-related gene expression changes in brains of 5xFAD transgenic mice. Finally, improved nesting behavior was observed upon treatment with the compound. Together, our evidence supports targeting of self-propagating Abeta structures with small molecules as a valid therapeutic strategy. PMID- 30472117 TI - Differences in the Conformational Energy Landscape of CDK1 and CDK2 Suggest a Mechanism for Achieving Selective CDK Inhibition. AB - Dysregulation of the cell cycle characterizes many cancer subtypes, providing a rationale for developing cyclin-dependent kinase (CDK) inhibitors. Potent CDK2 inhibitors might target certain cancers in which CCNE1 is amplified. However, current CDK2 inhibitors also inhibit CDK1, generating a toxicity liability. We have used biophysical measurements and X-ray crystallography to investigate the ATP-competitive inhibitor binding properties of cyclin-free and cyclin-bound CDK1 and CDK2. We show that these kinases can readily be distinguished by such inhibitors when cyclin-free, but not when cyclin-bound. The basis for this discrimination is unclear from either inspection or molecular dynamics simulation of ligand-bound CDKs, but is reflected in the contacts made between the kinase N- and C-lobes. We conclude that there is a subtle but profound difference between the conformational energy landscapes of cyclin-free CDK1 and CDK2. The unusual properties of CDK1 might be exploited to differentiate CDK1 from other CDKs in future cancer therapeutic design. PMID- 30472116 TI - (ADP-ribosyl)hydrolases: Structural Basis for Differential Substrate Recognition and Inhibition. AB - Protein ADP-ribosylation is a highly dynamic post-translational modification. The rapid turnover is achieved, among others, by ADP-(ribosyl)hydrolases (ARHs), an ancient family of enzymes that reverses this modification. Recently ARHs came into focus due to their role as regulators of cellular stresses and tumor suppressors. Here we present a comprehensive structural analysis of the enzymatically active family members ARH1 and ARH3. These two enzymes have very distinct substrate requirements. Our data show that binding of the adenosine ribose moiety is highly diverged between the two enzymes, whereas the active sites harboring the distal ribose closely resemble each other. Despite this apparent similarity, we elucidate the structural basis for the selective inhibition of ARH3 by the ADP-ribose analogues ADP-HPD and arginine-ADP-ribose. Together, our biochemical and structural work provides important insights into the mode of enzyme-ligand interaction, helps to understand differences in their catalytic behavior, and provides useful tools for targeted drug design. PMID- 30472118 TI - Protease-Mediated Protein Quality Control for Bacterial Acid Resistance. AB - The periplasm of food-borne enteric pathogens is perhaps the only internal space of living species that can be severely acidified (pH 1-3), which occurs when these pathogens pass through the acidic human stomach. Whereas the periplasmic chaperoning systems are known to deal with such a harsh unfolding stress, other protein quality control mechanisms remain unexplored. Here we report a protease mediated degradation mechanism that facilitates bacterial acid resistance. The genetic analysis revealed that mutant in degP encoding an HtrA family serine protease rendered Escherichia coli highly acid vulnerable. Combining genetically encoded trifunctional probe with 2D-based comparative proteomics, we identified its substrates. We further demonstrated that DegP directly bound to diverse aggregation-prone periplasmic proteins upon acid stress and these pre-mixed DegP substrate co-aggregates were subsequently digested by proteolytic-rescued DegP during acid recovery. DegP represents an unprecedented "acid protease" that maintains protein homeostasis in coping with acid-induced protein unfolding stress within E. coli periplasm. PMID- 30472119 TI - Dual embryonic origin of the mammalian enteric nervous system. AB - The enteric nervous system is thought to originate solely from the neural crest. Transgenic lineage tracing revealed a novel population of clonal pancreatic duodenal homeobox-1 (Pdx1)-Cre lineage progenitor cells in the tunica muscularis of the gut that produced pancreatic descendants as well as neurons upon differentiation in vitro. Additionally, an in vivo subpopulation of endoderm lineage enteric neurons, but not glial cells, was seen especially in the proximal gut. Analysis of early transgenic embryos revealed Pdx1-Cre progeny (as well as Sox-17-Cre and Foxa2-Cre progeny) migrating from the developing pancreas and duodenum at E11.5 and contributing to the enteric nervous system. These results show that the mammalian enteric nervous system arises from both the neural crest and the endoderm. Moreover, in adult mice there are separate Wnt1-Cre neural crest stem cells and Pdx1-Cre pancreatic progenitors within the muscle layer of the gut. PMID- 30472121 TI - Management of spontaneous temporal bone cerebrospinal fluid leak: A 30-year experience. AB - PURPOSE: The goal of this study was to describe the incidence of and our long term results in the management of spontaneous temporal bone CSF leak and to determine if there is any association with an increase in body mass index (BMI). METHODS: This was an Institutional Review Board (IRB) approved retrospective review of 58 patients who underwent repair of spontaneous temporal bone CSF leaks by a single surgeon at a tertiary care academic medical center between 1988 and 2017. Patients with CSF leaks due to trauma, iatrogenic injury, or chronic infection were excluded. Surgical approaches included middle cranial fossa, transmastoid, or a combination of both. Cases were divided into three decades. Patient demographics, clinical features, audiologic results, imaging studies, operative findings, complications, and long-term results were reviewed with a specific emphasis on the potential correlation with BMI. RESULTS: The average BMI was 32. There was a statistically significant increase in BMI between the two most recent decades (p = 0.044). The middle cranial fossa was the most commonly utilized approach. Multiple tegmen defects were often noted on imaging and intraoperatively. CONCLUSION: There is an increase in the incidence of spontaneous CSF leaks possibly associated with an increase in BMI in the United States over the last 30 years. PMID- 30472120 TI - Prognostic factors and survival outcomes for head and neck cutaneous adnexal cancers. AB - OBJECTIVES: Malignant cutaneous adnexal tumors (MCAT) are rare and comprise a heterogeneous group of cancers. There have been several studies reviewing prognostic factors of these tumors, but no studies focusing on the head and neck. This study aimed to review a large population based database to evaluate prognostic factors that could impact survival. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was utilized to identify patients with MCAT of the head and neck. Both overall and disease specific survival were the main outcome measures for the study. Univariate and multivariate analyses were performed to evaluate the association of suspected prognostic factors with survival. RESULTS: The five-year OS and DSS were 72.6 and 95.5%, respectively. A favorable factor for OS was surgical resection ([HR] 0.324; P = 0.001), while unfavorable factors for OS include older age (1.051; P < 0.001), higher tumor grade (1.254; P = 0.049), larger tumor size (1.293; P = 0.003), and positive nodal involvement (3.323; P = 0.002). A favorable factor for DSS was surgical resection (0.026; P < 0.001). Unfavorable factors for DSS include older age (1.058; P = 0.046), larger tumor size (2.528; 1.565-4.085; P < 0.001), and positive nodal involvement (4.761; P = 0.022). CONCLUSION: Review of the SEER database shows good 5-year OS and DSS rates, similar to those cited in other studies. We identified several prognostic factors associated with survival, while histologic sub-type does not seem to be associated with survival. Surgical resection is the mainstay of treatment. PMID- 30472122 TI - Radiographic findings in young adults with asymmetric sensorineural hearing loss. AB - PURPOSE: To evaluate radiographic findings in US Navy recruits found to have asymmetric sensorineural hearing loss (ASNHL) during routine medical screening. MATERIALS AND METHODS: Retrospective analysis of US Navy recruits receiving screening audiometry and medical suitability evaluation from January 2011 to October 2016. Single-institution, institutional review board-approved study of US Navy recruits screened for hearing loss over a six-year period. All recruits with ASNHL were evaluated by an otolaryngologist and received diagnostic radiographic evaluation. Audiometric and imaging results were retrospectively reviewed for this population and compared to common screening criteria. RESULTS: ASNHL was identified in 674 of 228,504 total recruits screened. This population was 91% male and between 17 and 29 years old (mean age 21.1). Six-hundred fifty-three (97%) met criteria for further ASNHL evaluation. Subjective hearing loss was reported in only 6% of patients. Six-hundred sixty-one (99%) received magnetic resonance imaging of the internal auditory canals. Intracranial pathology was identified in 43 (6.3%) patients and 2 (0.3%) had a causative intracranial lesion corresponding to ASNHL. No patients were found to have a vestibular schwannoma. CONCLUSIONS: In a population of healthy young adults with audiometric proven ASNHL, 0.3% had radiographic proven intracranial pathology explaining the hearing loss. Intracranial masses may be less likely to cause ASNHL in this population; further research is needed to determine appropriate MRI screening methods for young adults with ASNHL. PMID- 30472123 TI - Preemptive intravenous ibuprofen application reduces pain and opioid consumption following thyroid surgery. AB - OBJECTIVE: The primary aim of this study was to investigate the effects of preemptive a single dose IV ibuprofen on postoperative 48 h opioid consumption and postoperative pain in patients undergoing thyroidectomy. METHODS: The study included 40 patients aged 18 to 65, scheduled for elective thyroidectomy. Patients were randomly divided into 2 groups. Control group (n = 20) received 100 mL saline solution 15 min before surgery, while study group (n = 20) received 800 mg IV ibuprofen in 100 mL saline. The same general anesthesia protocol was applied in both groups, and all operations were performed by the same surgical team using the same technique. Postoperative analgesia was assessed using a visual analogue scale (VAS) and the amount of consumption of 48 h postoperative fentanyl with patient-controlled analgesia (PCA) and additional analgesia requirements were recorded. When additional analgesia was required, 1000 mg IV paracetamol was used. RESULTS: VAS scores in the ibuprofen group were found lower than the control group in the all-time points (p < 0.05). Opioid consumption in the 48 h was significantly higher in the control group than the ibuprofen group (p < 0.001). Using of rescue analgesia was significantly higher in the control group than the ibuprofen group, statistically (p < 0.05). A significant difference was observed between two groups in terms of side effects of fentanyl consumption (nausea and vomiting) (p < 0.001). CONCLUSION: To use preemptive a single dose IV ibuprofen decreases pain scores and postoperative opioid consumption in patients following thyroidectomy. Additionally, this application increase the patient comfort reducing nausea and vomiting in early postoperative period. PMID- 30472124 TI - The fragility of statistically significant results in otolaryngology randomized trials. AB - OBJECTIVES: The American Academy of Otolaryngology-Head and Neck Surgery regards randomized controlled trials as class A evidence. A novel method to determine the robustness of outcomes in trials is the fragility index. This index represents the number of patients whose status would have to change from a non-event to an event to make a statistically significant result non-significant. METHODS: Investigators included otolaryngology journals listed in the top 10 of one or both of Google Scholar Metrics and Clarivate Analytics' Journal rankings. For inclusion, a randomized controlled trial needed to report a one-to-one random assignment of participants to condition, contain two parallel arms or have used a two-by-two factorial design, and report at least one statistically significant dichotomous outcome. RESULTS: Sixty-nine trials met inclusion criteria. The median fragility index was three events (interquartile range 1-7.5). Median sample size was 72 (interquartile range 50-102.5). Modest correlations were observed between fragility index and total sample size (r = 0.27) and fragility index and event rate (r = 0.46). Investigators found no correlation between fragility index and impact factor or Science Citation Index. In 39% (27/69) of trials, the number lost to follow-up was equal to or greater than the fragility index. CONCLUSION: A median fragility index of 3 indicates that three people, on average, are needed to alter the outcomes in otolaryngology trials. This indicates that the results of two-group randomized controlled trials reporting binary endpoints published in otolaryngology journals may frequently be fragile. PMID- 30472126 TI - Slowly progressive facial paralysis: Intraneural squamous cell carcinoma of unknown primary. AB - BACKGROUND: In this report, we present a unique case of intraneural squamous cell carcinoma of unknown primary found within the facial nerve and the proposed algorithms for diagnosis and management of progressive idiopathic facial paralysis. CASE PRESENTATION: A 66-year-old female with a previous history of basal cell carcinoma presented with right-sided progressive facial paralysis. Repeated magnetic resonance imaging as well as targeted workup failed to reveal a diagnosis. 20 months following symptom onset, after the patient's facial function slowly progressed to a complete paralysis, repeat magnetic resonance imaging revealed enhancement at the stylomastoid foramen. The patient underwent superficial parotidectomy, transmastoid facial nerve decompression and resection of descending and proximal extratemporal facial nerve segments, as well as great auricular nerve interposition grafting. Intraoperatively, frozen sections from the surface of the facial nerve, and the proximal and distal segments of the facial nerve following resection, were negative for malignancy. The final pathology revealed infiltrating poorly differentiated squamous cell carcinoma of the facial nerve with negative margins. CONCLUSION: In cases of slowly progressive facial paralysis the clinician needs to consider malignancy until proven otherwise. Without an identifiable primary malignancy, early algorithmic assessment of presenting characteristics may facilitate expedited clinical decision making and surgical management of malignancy involving the facial nerve. In cases of slowly progressive facial paralysis, when the time comes for surgical exploration and biopsy, head and neck surgeons must be aware that malignancy can exist entirely within the facial nerve, without pathologic changes on the surface of the nerve or in the surrounding tissue. PMID- 30472125 TI - Clinical characteristics of internal carotid artery pseudoaneurysms in the sphenoid sinus. AB - BACKGROUND: Internal carotid artery (ICA) pseudoaneurysms are associated with high mortality if lack of proper management. Patients with ICA pseudoaneurysms in the sphenoid sinus often visit a hospital's ear, nose and throat (ENT) department due to nasal bleeding. In such cases, simple examination and therapy will lead to misdiagnosis. OBJECTIVE: This study sought to investigate the clinical characteristics, diagnostic methods and treatment of ICA pseudoaneurysms in the sphenoid sinus. METHODS: Various data, including clinical features, imaging examination results, and treatment and prognosis information, were collected and analyzed for 8 patients who visited the Department of Otolaryngology, Head & Neck Surgery of West China Hospital from March 2008 to January 2017. RESULTS: The patients included 6 males and 2 females (ages 16 to 56 years). Repeated epistaxis was a common symptom in six of the eight patients (6/8), whereas monocular blindness and binocular blindness were observed in the other two patients. Head trauma was found to play a role in the induction of ICA pseudoaneurysms, given that five patients (5/8) exhibited a specific history of head injury. CT examination tended to result in misdiagnosis, whereas MRI and digital subtraction angiography (DSA) were helpful for obtaining a definite diagnosis with all diagnoses were confirmed via DSA. Coated stent intervention was performed in five patients, while carotid artery ligation was performed in two patients in emergency situations: one of whom exhibited paraplegia, but recovery was ultimately observed after rehabilitation. Moreover, failure of coated stent intervention in one patient was resolved via additional unilateral common carotid artery ligation. Furthermore, one patient with vision loss experienced vision restoration. One patient discontinued treatment for personal reasons and was lost to follow-up. No recurrence was observed in the other 7 patients. CONCLUSION: ICA pseudoaneurysms in the sphenoid sinus are uncommon. To accurately identify ICA pseudoaneurysms, collaboration between otolaryngologists and imaging specialists is essential. On the other hand, both surgical and interventional treatments can achieve good results; therefore, otolaryngologists should enhance their cooperation with neurosurgery and intervention departments. Accurate diagnosis and rapid treatment are keys to managing ICA pseudoaneurysms. PMID- 30472127 TI - Unassisted percutaneous tracheostomy: A new flow chart decision making based on simple physical conditions. AB - INTRODUCTION: Percutaneous dilatation tracheostomy (PDT) has several advantages over traditional surgical tracheostomy. However, it is still performed using bronchoscopy guidance. OBJECTIVE: To suggest the safety of unassisted PDT, without bronchoscopy guidance, based on bed-side screening flow chart evaluation. MATERIAL AND METHODS: 180 consecutive UCI patients referred to tracheostomy were submitted to Avalo's Screening Chart (ASC), in order to decide surgical technique. RESULTS: 161 patients were referred to unassisted PDT (un PDT) and 19 to surgical tracheostomy (ST) due to nonfulfillment of ASC steps. 10 patients submitted to unassisted PDT presented early complications, 8 presented mild bleeding and 2 false tracts. None of 6 months follow up patients presented long term complications. CONCLUSION: The authors suggest unPDT is a safety surgical method in UCI patients who were submitted and approved to an easy anatomical and clinical screening chart (ASC). PMID- 30472128 TI - Response to letter. PMID- 30472129 TI - Commentary on letter to editor titled "surgical management of patients with Eagle syndrome". PMID- 30472130 TI - Clinical features and outcomes in young adults with oral tongue cancer. AB - OBJECTIVE: To evaluate outcomes and survival in young patients with oral tongue cancer (OTC). METHODS: Retrospective chart review of patients aged 18-40 with OTC treated between 2000 and 2016. Tumor characteristics of p16 expression, perineural invasion (PNI), and lymph-vascular invasion (LVI) were evaluated. Recurrence-free (RFS) and overall survival (OS) data were analyzed according to Kaplan-Meier method with univariate analysis. RESULTS: A total of 23 patients were identified: 12 with early stage disease (ESD, stage I), and 11 with advanced stage disease (ASD, stage III or IV), (17 men and 6 women). Mean age at presentation was 34.5 years (+/-5 months) and mean follow-up was 46.6 months. For all patients, 5-year RFS was 62% and OS 66%. RFS for ESD was 73% and ASD 25% (log rank p = 0.011). OS for ESD was 100% and ASD 55% (log rank p = 0.012). 22% indicated tobacco use >5 pack-years and 9% heavy alcohol use. Factors associated with worse OS were neck disease (log rank p = 0.073), positive margins (log rank p = 0.001), and LVI (log rank p = 0.002). Factors associated with worse RFS were chemotherapy or radiation therapy prior to surgery (log rank p = 0.002), neck disease (log rank p = 0.047), positive margins (log rank p = 0.039), and PNI (log rank p = 0.001). Expression of p16 was observed in five cases and was not significantly associated with OS or RFS. CONCLUSION: In young patients with OTC, factors associated with worse outcomes are similar to known predictors in older patients. Expression of p16 was not statistically associated with improved OS. OS in patients with ESD was excellent (100%), and significantly worse for ASD. PMID- 30472131 TI - In vitro analysis of growth patterns of invasive fungal species on commonly used endonasal hemostatic agents. AB - OBJECTIVE: Previous studies have not examined the potential role of endonasal hemostatic agents in facilitating growth of fungal species. We aim to determine the possibility of these to serve as a nutrient source for fungal growth. METHODS: Cultures of Aspergillus, Fusarium, and Mucor were harvested and placed in solution in sterile saline at standardized high and low concentrations. Thrombin gelatin matrix, carboxyl methylcelluose, and potato starch derivative agents were prepared following manufacturer instructions and applied to two separate Petri dishes per agent. Each substrate was then inoculated with either high or low concentrations of fungal species. Negative and positive control plates with each organism were included. Dishes were sealed, incubated, and examined daily for fourteen days for microscopic and macroscopic growth. RESULTS: Thrombin gelatin matrix was relatively resilient to growth, although Fusarium growth was noted on all packing material by day three. Carboxyl methylcellulose also supported growth of high-concentration Mucor appreciated on day five. The potato starch derivative supported fulminant growth of all fungal species. CONCLUSIONS: Endonasal hemostatic agents may be nutrient sources that facilitate growth of fungal species. This may be a consideration in a surgeon's decision to use a hemostatic agent. Prompt initial post-operative debridement may be warranted in select patients. Our findings serve as a model for further testing of fungal growth on other hemostatic materials. Future studies are needed to confirm the clinical significance of these findings in vivo. PMID- 30472132 TI - Laryngeal inflammatory response to smoke and vape in a murine model. AB - PURPOSE: To build a murine model for tobacco smoke and electronic cigarette vapor exposure to characterize the inflammatory and immune responses in the larynx. MATERIALS AND METHODS: In this pilot study, twenty-four wild-type C57BL/6 mice were divided into four groups: smoke, vapor with nicotine, vapor without nicotine, and air only. Following daily exposure for 4 months, larynges were dissected and processed with cytokine detection arrays. Each laryngeal cytokine level between the four different groups was analyzed statistically by using statistical analysis software (SAS) to calculate the analysis of variance (ANOVA). RESULTS: IL-4 was the only cytokine found to achieve statistically significant different levels in this study, with elevated levels of IL-4 in the tobacco smoke and vapor with nicotine groups compared to the levels found in the vapor without nicotine and air only groups (p = 0.0418). While statistically non significant, prominent findings revealed up-regulation of TGF-beta2 and TGF-beta3 in the smoke group, but near-normal levels of TGF-beta2 and TGF-beta3 and suppression of IL-10 in the vapor groups (p > 0.05). CONCLUSION: The potential utility of the murine model is established for studying the inflammatory and immune effects of tobacco smoke and vapor on the mammalian larynx. IL-4 levels in mice larynges were significantly elevated in the tobacco smoke and vapor with nicotine groups. PMID- 30472133 TI - Multi-specialty knowledge on surgical a management: Implementation of an educational initiative. AB - PURPOSE: Deficiencies in airway management knowledge can result in harm, especially in tracheostomy patients. Our objective is to assess the degree of knowledge in different medical specialties, before and after targeted airway education. MATERIALS AND METHODS: A lecture on tracheostomy management was prepared for Otolaryngology, Anesthesia, Emergency Medicine, General Surgery, Oral and Maxillofacial Surgery (OMFS), Internal Medicine (IM), and Family Medicine (FM). Before the lecture, a 12-question quiz on surgical airway knowledge was administered, and demographics from participants collected. Immediately following the lecture, participants were asked to retake the quiz. Performance was assessed. Population baseline characteristics included, specialty, years of practice, and previous education. RESULTS: A paired t-test evaluating pre- and post-lecture results showed a 34.2% improvement for all participants (n = 168) overall (2.7 points, p < 0.001). Providers with more years of practice performed better. Otolaryngology and OMFS performed the highest on the baseline test while FM and IM performed the lowest. The providers who reported previous standardized training from the hospital system, informal instruction on the ward, or had the topic covered in their degree program performed better compared to those without previous education (ANOVA, 3.5 points, p < 0.01). Providers who underwent formal training in their degree program performed the best. A Likert scale with self-assessment of comfort with surgical airway correlated positively with the performance on the quiz. CONCLUSION: Variability in tracheostomy knowledge based on specialty and years of training exists. We demonstrate that formal education on tracheostomy and surgical airways improved quantitative measures of knowledge. PMID- 30472134 TI - Patient preferences regarding the communication of biopsy results in the general otolaryngology clinic. AB - OBJECTIVES: To determine the preferred methods of communicating biopsy results for patients in our comprehensive otolaryngology clinic, and to examine factors associated with preferring remote vs. in-person communication of results. STUDY DESIGN: Cross-sectional study. SETTING: Academic comprehensive otolaryngology clinic. SUBJECTS AND METHODS: A survey instrument was administered to 107 consecutive adult otolaryngology patients undergoing head and neck fine needle aspiration biopsy from March 1, 2017 to April 30, 2018 assessing their health literacy using the Brief Health Literacy Score and their preferred method of notification of biopsy results (in-person vs. remote). RESULTS: 69% of patients preferred remote notification of their biopsy results (either by telephone or via an online portal). 54% of patients prioritized clear explanation of the results as the most important factor when communicating a malignant result. Adequate health literacy was associated with lower odds of preferring in-person notification (adjusted odds ratio 0.11, 95% CI 0.03 to 0.39). Patients who prioritized clear explanation of the results were more likely to prefer in-person notification (adjusted OR 4.13, 95% CI 1.31 to 14.88). CONCLUSIONS: A significant proportion of patients in our comprehensive otolaryngology clinic undergoing fine needle aspiration biopsy preferred remote communication of their biopsy results. Patients most valued clear explanations from the provider and prompt receipt of the result when communicating malignant results. This highlights the need for individualized results communication plans, for patients undergoing biopsy. PMID- 30472135 TI - Analysis of the role of thyroidectomy and thymectomy in the surgical treatment of secondary hyperparathyroidism. AB - PURPOSE: Parathyroidectomy can be subtotal or total with an autograft for the treatment of renal hyperparathyroidism. In both cases, it may be extended with bilateral thymectomy and total or partial thyroidectomy. Thymectomy may be recommended in combination with parathyroidectomy in order to prevent mediastinal recurrence. Also, the occurrence of thyroid disease observed in patients with hyperparathyroidism is poorly understood and the incidence of cancer is controversial. The aim of the present study was to report the experience of a single center in the surgical treatment of renal hyperparathyroidism and to analyse the role of thyroid and thymus surgery in association with parathyroidectomy. MATERIALS AND METHODS: We analysed parathyroid surgery data, considering patient demographics, such as age and gender, and surgical procedure data, such as type of hyperparathyroidism, associated thyroid or thymus surgery, surgical duration and mediastinal recurrence. Histopathological results of thyroid and thymus samples were also analysed. RESULTS: Medical records of 109 patients who underwent parathyroidectomy for secondary hyperparathyroidism were reviewed. On average, thymectomy did not have impact on time of parathyroidectomy (p = 0.62) even when thyroidectomy was included (p = 0.91). Intrathymic parathyroids were detected in 7.5% of the thymuses removed and papillary carcinoma was detected in 20,8% of thyroid tissue samples. Two patients showed recurrence of supernumerary intrathymic parathyroids and a single case of mediastinitis was observed. CONCLUSIONS: Parathyroidectomy with thymectomy and/or thyroidectomy has an important role in the treatment of renal hyperparathyroidism since thyroid cancer can frequently occur and require surgery. Thymectomy should be considered to avoid recurrence and a risky re-operation. PMID- 30472136 TI - Poorly differentiated plasmacytoid squamous cell carcinoma: Case report of a rare malignancy. AB - Plasmacytoid squamous cell carcinoma is an especially aggressive variant of squamous cell carcinoma that has previously been described in the literature as a variant of oral cancers and most extensively, in vulvular [3], transitional cell, and urothelial carcinomas [2,13,15-20]. In this case report, we present a 36-year old man with 6 to 8 weeks of a progressively enlarging mass over the lateral third of his clavicle, acromion process, and deltoid. The mass was resected, and the supraclavicular defect was reconstructed using an anterolateral thigh free flap. Final pathology determined the specimen was an invasive poorly differentiated squamous cell carcinoma with spindle cell and plasmacytoid features of cutaneous origin. Plasmacytoid squamous cell carcinomas have previously been described in the oral cavity, but in no other subsite of the head and neck. This article describes the patient's case and provides a literature review of the available reports related to plasmacytoid variant of squamous cell carcinoma. PMID- 30472137 TI - A Multimodality Review of Adrenal Tumors. AB - Adrenal tumors are very commonly encountered in the practice of radiology. They may arise from the adrenal gland itself, either the cortex or the medulla, or they could be secondary lesions. They may be benign or malignant. The functioning adrenal tumors lead to hypersecretion of adrenal hormones leading to clinical syndromes. Computed tomography is the most common imaging modality used for the initial evaluation of adrenal tumors. Magnetic resonance imaging and functional scintigraphic techniques are frequently used for atypical presentations or further evaluation. We present a multimodality review of common and uncommon adrenal tumors. We highlight their characteristic and specific imaging features which help us in making a diagnosis and suggesting an appropriate follow up for further management. The spectrum of adrenal tumors is wide with varying appearances on different imaging modalities. Imaging techniques used for adrenal tumor imaging have their own strengths and weaknesses as it relates to the final diagnosis. It is important to be familiar with imaging characteristics of adrenal tumors for appropriate diagnosis and management. Differentiation of benign (leave alone) tumors from malignant (surgical) ones along with appropriate disposition of incidentalomas are some of the challenges facing the radiologist. PMID- 30472138 TI - Image Quality of ECG-Triggered High-Pitch, Dual-Source Computed Tomography Angiography for Cardiovascular Assessment in Children. AB - PURPOSE: Evaluate the feasibility and determinants of image quality of ECG triggered High-Pitch Dual-Source Computed Tomography Angiography (CTA) for cardiovascular assessment in Children. MATERIAL AND METHODS: All children that underwent ECG-triggered High-Pitch Dual-Source CTA between August 2014 and September 2017 were identified. Scanner parameters and patients' information were retrieved. Objective image quality was evaluated measuring the Hounsfield units (HU) and standard deviation of regions of interests in the left ventricle, ascending and descending aorta. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. Qualitative image quality was recorded independently by two pediatric radiologist blinded using a three-point scale: 1 - good image quality, 2 - mild artifacts, 3 - poor image quality. Continuous variables were presented as mean +/- standard deviation. The interobserver agreement and non parametric test were used. RESULTS: 93 patients (mean age 5.6 +/- 7.1 years) were selected. Average cardiovascular attenuation, SNR and CNR were 406.2 +/- 146.3 HU, 24.2 +/- 16.0 HU and 52.1 +/- 38.6 HU, respectively. Average image quality was 1.51 +/- 0.48 and the inter-observer agreement was excellent (k = 0.8). Worse subjective quality scores were associated with lower age, height, weight, BSA, lower contrast dose and slower injection rates (p < 0.05). Higher heart rate was associated with high attenuation (p < 0.05), however, SNR and CNR did not show an association with heart rate (p = 0.80). CONCLUSIONS: ECG-triggered High-Pitch Dual-Source cardiac CTA is feasible and provides good or excellent image quality for the evaluation of cardiovascular diseases in children. PMID- 30472139 TI - Impact of Overlying Personal Items on CT Dose with Use of Automated Tube Current Modulation-Pilot Investigation. AB - PURPOSE: To determine the incidence and impact of overlying radiopaque personal items (e.g., cellular phones, zippers) on CT dose and image quality with use of automated tube current modulation. METHODS: Topogram images from 100 consecutive adult outpatient CT abdomen pelvis studies were retrospectively reviewed, and the number and type of overlying radiopaque personal items were recorded. Additionally, an anthropomorphic phantom was imaged with overlying personal items 1) present in topogram and axial images; 2) present in topogram but removed prior to axial acquisition; and 3) present in topogram positioned outside the field of view of the axial acquisition. dose length product (DLP) and CT dose index volume (CTDIvol) were compared to acquisitions performed without overlying personal items. Image noise was evaluated by assessing the standard deviation of Hounsfield units at the level of the overlying personal item. RESULTS: Overlying personal items were visible in topogram images for 55% of CT exams and included underwires (38% of exams), zippers (7%), and cellular phones (1%). DLP increased when a cellular phone was present in the topogram whether or not it was removed before axial image acquisition (3.7% p = 0.002, combined AutomA and SmartmA), and image noise increased (144%, p = 0.002; AutomA). No increase in dose or image noise was observed with overlying zippers or underwires or when any object was visible in the topogram outside the field of view of the axial images. CONCLUSIONS: Overlying personal items were observed in the majority of abdominopelvic CT scans. Large overlying radiopaque personal items resulted in increased dose and increased image noise. Removal of all overlying personal items will result in optimized dose and image quality. PMID- 30472140 TI - NAD binding by human CD38 analyzed by Trp189 fluorescence. AB - The NAD-glycohydrolase/ADP-ribosyl cyclase CD38 catalyzes the metabolism of nicotinamide adenine dinucleotide (NAD) to the Ca2+ mobilizing second messengers ADP-ribose (ADPR), 2'-deoxy-ADPR, and cyclic ADP-ribose (cADPR). In the present study, we investigated binding and metabolism of NAD by a soluble fragment of human CD38, sCD38, and its catalytically inactive mutant by monitoring changes in endogenous tryptophan (Trp) fluorescence. Addition of NAD resulted in a concentration-dependent decrease in sCD38 fluorescence that is mainly caused by the Trp residue W189. Amplitude of the fluorescence decrease was fitted as one site binding curve revealing a dissociation constant for NAD of 29 MUM. A comparable dissociation constant was found with the catalytically inactive sCD38 mutant (KD 37 MUM NAD) indicating that binding of NAD is not significantly affected by the mutation. The NAD-induced decrease in Trp fluorescence completely recovered in case of sCD38. Kinetics of recovery was slowed down with decreasing temperature and sCD38 concentration and increasing NAD concentration demonstrating that recovery in fluorescence is proportional to the enzymatic activity of sCD38. Accordingly, recovery in fluorescence was not observed with the catalytically inactive mutant. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech. PMID- 30472141 TI - Characterization of tear production in subjects with dry eye disease during intranasal tear neurostimulation: Results from two pivotal clinical trials. AB - PURPOSE: The intranasal tear neurostimulator (ITN) activates the nasolacrimal pathway, which is involved with basal and bolus tear secretion. These studies characterized the acute and long-term effectiveness of the ITN in stimulating tear production in subjects with dry eye disease (DED). METHODS: Study 1: Randomized, double-masked, dual-controlled, 1-day crossover. Study 2: Single-arm, open-label, 180-day prospective cohort. Eligible subjects had basal unstimulated Schirmer test (with anesthesia) <=10 mm and intranasal cotton swab-stimulated Schirmer test at least 7 mm greater in the same eye, and Ocular Surface Disease Index(r) >=13 and >= 23, in Studies 1 and 2, respectively. Study 1: Subjects (n = 48) received three randomized test applications: active intranasal, extranasal (active control), and sham intranasal (inactive control) stimulation, 3 min/application with 1-hour minimum between applications. Primary outcome measure was the difference in Schirmer test scores during active intranasal and control applications. Study 2: Subjects (n = 97) performed intranasal neurostimulation for <=3 min/application, 2-10 times/day. Primary outcome measure was the difference in Schirmer scores (stimulated minus unstimulated) at day 180. Both studies recorded device-related adverse events (AEs). RESULTS: Study 1: Schirmer scores (mean +/- SEM) were significantly greater (p < 0.0001) with active intranasal (25.3 +/- 1.5 mm) vs extranasal (9.5 +/- 1.2 mm) and sham (9.2 +/- 1.1 mm) applications. Study 2: Schirmer scores were significantly greater (p < 0.0001) with ITN stimulation vs unstimulated at day 180 (17.3 +/- 1.3 mm vs 7.9 +/- 0.7 mm). No serious device-related AEs were reported in either study. CONCLUSION: The ITN was well-tolerated and effective in stimulating tear production with acute and long-term use in DED. CLINICALTRIALS. GOV IDENTIFIER: NCT02680158 and NCT02526290. PMID- 30472142 TI - Information seeking mechanism of neural populations in the lateral prefrontal cortex. AB - In addition to primary rewards such as food and water, humans continuously seek information in daily life. Whereas the neural mechanisms for processing primary rewards have been clarified in detail in the homeostatic system, those for information seeking remain poorly understood. Although studies in psychology and economics have suggested several criteria with which information is assessed in human information seeking, the neural mechanism that assesses information remains unknown. The suggested criteria include the value of information (VOI; Hubbard, 2010), Shannon information, and the probability gain (Baron, 1985), which are defined as reduction of expected cost, reduction in expected entropy, and expected improvement of identifying correct response, respectively. We examined which criterion the nervous system uses to assess information. We recorded neuronal activity from the lateral prefrontal cortices (lPFCs) of monkeys while the animals performed information seeking tasks. We found that activity of the lPFC neurons was correlated with information that the animals expected to receive, and that more neurons encoded the VOI than did the two other criteria. Further, using principal component analysis, we found that the responses of entire neuronal populations could encode the three criteria. Finally, using a "targeted dimensionality reduction" analysis (Mante et al., 2013), we found that the population responses could encode information values assessed with the VOI longer than the probability gain, but not Shannon information. These findings suggest that the lPFC is involved in assessing information, and the assessment is primarily based on the criterion of the VOI, which captures reduction in expected cost. PMID- 30472143 TI - Physiologically Based Absorption Modeling to Predict Bioequivalence of Controlled Release and Immediate Release Oral Products. AB - Physiologically based absorption modeling was conducted to predict bioequivalence (BE) for immediate release (IR) and controlled release (CR) formulations. In case of the CR formulation of a BCS class 1 drug, sensitivity analyses were conducted to investigate the impact of gastrointestinal (GI) transit time and absorption scaling factors in caecum and colon on formulation PK. The regional absorption profiles of the test and reference formulations were compared to provide additional confidence on the BE predictions. For IR formulation of BCS class 2b drug, the sensitivity of dissolution rate, precipitation time and human permeability were evaluated. Finally for both cases, population simulations were conducted in crossover manner to investigate BE between formulations, and compared with the observed data. These case studies highlight the utility of absorption modeling in prediction of BE. Such modeling can be used for development of innovator and generic products, as well as to address questions arising during regulatory reviews. PMID- 30472144 TI - Lipid nanocapsules decorated and loaded with cannabidiol as targeted prolonged release carriers for glioma therapy: in vitro screening of critical parameters. AB - The therapeutic potential of cannabinoids has been truly constrained heretofore due to their strong psychoactive effects and their high lipophilicity. In this context, precisely due to the lack of psychoactive properties, cannabidiol (CBD), the second major component of Cannabis sativa, arises as the phytocannabinoid with the most auspicious therapeutic potential. Hence, the incorporation of CBD in lipid nanocapsules (LNCs) will contribute to overcome the dosing problems associated with cannabinoids. Herein, we have prepared LNCs decorated and loaded with CBD for glioma therapy and screened in vitro their critical parameters. On the one hand, we have encapsulated CBD into the oily core of LNCs to test their in vitro efficacy as extended-release carriers against the human glioblastoma cell line U373MG. The in vitro antitumor effect was highly dependent on the size of LNCs due to its pivotal role in the extent of CBD release. Effectively, a comparison between two differently-sized LNCs (namely, 20-nm and 50-nm sized carriers) showed that the smaller LNCs reduced by 3.0-fold the IC50 value of their 50-nm sized counterparts. On the other hand, to explore the potential of this phytocannabinoid to target any of the cannabinoid receptors overexpressed in glioma cells, we decorated the LNCs with CBD. This functionalization strategy enhanced the in vitro glioma targeting by 3.4-fold in comparison with their equally-sized undecorated counterparts. Lastly, the combination of CBD-loading with CBD-functionalization further reduced the IC50 values. Hence, the potential of these two strategies of CBD incorporation into LNCs deserves subsequent in vivo evaluation. PMID- 30472145 TI - Role of DNA repair genes XRCC3 and XRCC1 in predisposition to type 2 diabetes mellitus and diabetic nephropathy. AB - INTRODUCTION: Increasing number of experimental and clinical studies suggest a strong relationship between hyperglycemia, oxidative stress, DNA damage and diabetic nephropathy (DN). Also, epidemiologic studies remark an enhanced risk of cancer with type 2 diabetes. This research aims to assess whether the X-ray cross complementing group 3 (XRCC3) gene T241M polymorphism (rs861539) and X-ray cross complementing group 1 (XRCC1) gene A399G polymorphism (rs25487) are related with predisposition to type 2 diabetes mellitus (T2DM) and to diabetic nephropathy in Turkish population. MATERIALS AND METHODS: Polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) was performed to identify the distribution of genotypes and frequency of alleles of T241M polymorphism of the XRCC3 gene (XRCC3 T241M) and A399G polymorphism of the XRCC1 gene (XRCC1 A399G). The study population included 238 subjects residing in Istanbul, Turkey; 116 with T2DM, 50 with DN and 72 with normal glucose metabolism. RESULTS AND CONCLUSION: Polymorphic Gln allele of XRCC1 gene was significantly related with T2DM and DN (OR 3.09, 95% CI 1.14-8.40 and OR 3.29 95% CI 1.23-8.80, respectively) however, there was no statistical association of XRCC3 T241M with T2DM or DN. The results of this study suggest that XRCC1 399Gln polymorphism is related with an increased susceptibility to T2DM and DN in the studied Turkish population. PMID- 30472146 TI - Neuroinflammation and aberrant hippocampal plasticity in a mouse model of emotional stress evoked by exposure to ultrasound of alternating frequencies. AB - Emotional stress is a form of stress evoked by processing negative mental experience rather than an organic or physical disturbance and is a frequent cause of neuropsychiatric pathologies, including depression. Susceptibility to emotional stress is commonly regarded as a human-specific trait that is challenging to model in other species. Recently, we showed that a 3-week-long exposure to ultrasound of unpredictable alternating frequencies within the ranges of 20-25 kHz and 25-45 kHz can induce depression-like characteristics in laboratory mice and rats. In an anti-depressant sensitive manner, exposure decreases sucrose preference, elevates behavioural despair, increases aggression, and alters serotonin-related gene expression. To further investigate this paradigm, we studied depression/distress-associated markers of neuroinflammation, neuroplasticity, oxidative stress and the activity of glycogen synthase kinase-3 (GSK-3) isoforms in the hippocampus of male mice. Stressed mice exhibited a decreased density of Ki67-positive and DCX-positive cells in the subgranular zone of hippocampus, and altered expression of brain-derived neurotrophic factor (BDNF), its receptor TrkB, and anti-apoptotic protein kinase B phosphorylated at serine 473 (AktpSer473). The mice also exhibited increased densities of Iba-1 positive cells, increased oxidative stress, increased levels of interleukin-1beta (IL-1beta), interleukin-6 (IL-6) in the hippocampus and plasma, and elevated activity of GSK-3 isoforms. Together, the results of our investigation have revealed that unpredictable alternating ultrasound evokes behavioural and molecular changes that are characteristic of the depressive syndrome and validates this new and simple method of modeling emotional stress in rodents. PMID- 30472147 TI - Noradrenergic terminals are the primary source of alpha2-adrenoceptor mediated dopamine release in the medial prefrontal cortex. AB - In various psychiatric disorders, deficits in dopaminergic activity in the prefrontal cortex (PFC) are implicated. Treatments involving selective augmentation of dopaminergic activity in the PFC primarily depend on the inhibition of alpha2-adrenoreceptors singly or in combination with the inhibition of the norepinephrine transporter (NET). We aimed to clarify the relative contribution of dopamine (DA) release from noradrenergic and dopaminergic terminals to DA output induced by blockade of alpha2-adrenoreceptors and NET. To this end, we assessed whether central noradrenergic denervation modified catecholamine output in the medial PFC (mPFC) of rats elicited by atipamezole (an alpha2-adrenoreceptor antagonist), nisoxetine (an NET inhibitor), or their combination. Intraventricular administration of anti-dopamine-beta-hydroxylase saporin (aDBH) caused a loss of DBH-positive fibers in the mPFC and almost total depletion of tissue and extracellular NE level; however, it did not reduce tissue DA level but increased extracellular DA level by 70% in the mPFC. Because noradrenergic denervation should have caused a loss of NET and reduced NE level at alpha2-adrenoceptors, the actual effect of an aDBH-induced lesion on DA output elicited by blockade of alpha2-adrenoceptors and NET was evaluated by comparing denervated and control rats following blockade of alpha2-adrenoceptors and NET with atipamezole and nisoxetine, respectively. In the control rats, extracellular NE and DA levels increased by approximately 150% each with 3 mg/kg atipamezole; 450% and 230%, respectively, with 3 mg/kg nisoxetine; and 2100% and 600%, respectively, with combined atipamezole and nisoxetine. In the denervated rats, consistent with the loss of NET, nisoxetine failed to modify extracellular DA level, whereas atipamezole, despite the lack of NE-induced stimulation of alpha2 adrenoceptors, increased extracellular DA level by approximately 30%. Overall, these results suggest that atipamezole-induced DA release mainly originated from noradrenergic terminals, possibly through the inhibition of alpha2-autoreceptors. Furthermore, while systemic and local administration of the alpha2-adrenoceptor agonist clonidine into the mPFC of the controls rats reduced extracellular NE level by 80% and 60%, respectively, and extracellular DA level by 50% and 60%, respectively, it failed to reduce DA output in the denervated rats, consistent with the loss of alpha2-autoreceptors. To eliminate the possibility that denervation reduced DA release potential via the effects at dopaminergic terminals in the mPFC, the effect of systemic administration of the D2-DA antagonist raclopride (0.5 mg/kg IP) on DA output was analyzed. In the control rats, raclopride was found to be ineffective when administered alone, but it increased extracellular DA level by 380% following NET inhibition with nisoxetine. In the denervated rats, as expected due to the loss of NET, raclopride-alone or with nisoxetine-increased DA release to approximately the same level as that observed in the control rats after NET inhibition. Overall, these results suggest that noradrenergic terminals in the mPFC are the primary source of DA released by blockade of alpha2-adrenoreceptors and NET and that alpha2-autoreceptors, and not alpha2-heteroreceptors, mediate DA output induced by alpha2-adrenoceptor blockade. PMID- 30472148 TI - Entorhinal cortex stimulation induces dentate gyrus neurogenesis through insulin receptor signaling. AB - Deep brain stimulation (DBS) has been established as a therapeutically effective method to treat pharmacological resistant neurological disorders. The molecular and cellular mechanisms underlying the beneficial effects of DBS on the brain are not yet fully understood. Beside numerous suggested mechanisms, regulation of neurogenesis is an attractive mechanism through which DBS can affect the cognitive functions. Considering the high expression of insulin receptors in hippocampus and also impaired neurogenesis in diabetic brain, the present study aimed to examine the role of insulin receptor signaling in DBS induced neurogenesis. High frequency stimulation was applied on the entorhinal cortex of rats and then neurogenesis markers in the dentate gyrus region of the hippocampus were examined using molecular and histological methods in the sham, DBS and insulin receptor antagonist-treated groups. In parallel, the changes in insulin receptor signaling in the hippocampus and spatial learning and memory performance were also assessed. DBS promoted adult hippocampal neurogenesis and facilitated the spatial memory concomitant with changes in insulin receptor signaling parameters including IR, IRS2 and GSK3beta. Application of insulin receptor antagonist attenuated the DBS-induced neurogenesis. Our data emphasize that entorhinal cortex stimulation promotes adult hippocampal neurogenesis and facilitates spatial learning and memory at least partly through insulin receptors. Notably, GSK3beta inhibition can play a major role in the downstream of insulin receptor signaling in DBS induced neurogenesis. PMID- 30472149 TI - Lipid metabolism in Alzheimer's disease. AB - Since the metabolic disorder may be the high risk that contribute to the progress of Alzheimer's disease (AD). Overtaken of High-fat, high-glucose or high cholesterol diet may hasten the incidence of AD in later life, due to the metabolic dysfunction. But the metabolism of lipid in brain and the exact effect of lipid to brain or to the AD's pathological remain controversial. Here we summarize correlates of lipid metabolism and AD to provide more foundation for the daily nursing of AD sensitive patients. PMID- 30472150 TI - Dopamine in the hippocampal dentate gyrus modulates spatial learning via D1-like receptors. AB - Increasing evidence supports that dopamine (DA) plays an important role in the hippocampal function via activation of D1-like receptors (D1Rs). As the entry structure of the hippocampal formation, the hippocampal dentate gyrus (DG) is critically involved in spatial learning and memory. Despite a number of studies investigated how DA influences CA1 plasticity and learning, there are fewer studies examining the influence of DA signaling to the DG. To investigate the roles of DA and D1Rs of the DG in modulation of spatial learning and memory, the spatial learning and memory abilities of rats were measured by Morris water maze (MWM), and then the concentration of DA in the DG region was determined by in vivo brain microdialysis and HPLC. Next, the effects of local microinjection of SCH23390 (an antagonist of D1Rs) on extracellular levels of excitatory amino acids (EAAs), including glutamate (Glu) and aspartate (Asp), were measured in the DG region during MWM test in freely-moving conscious rats. During the place navigation trial of MWM test, the escape latency was decreased with the increase in training days, and DA concentration in the DG was significantly increased. In SCH23390 group rats, the escape latency was increased in place navigation trial and the percentage of time spent in target quadrant and the number of platform crossings were decreased in spatial probe trial during MWM test, compared with vehicle group. Furthermore, in vehicle group rats, the extracellular levels of Glu and Asp in the DG were significantly increased during place navigation trial of MWM test, and these responses were partly inhibited by microinjection of SCH23390. Our results suggest that DA activation of D1Rs in the hippocampal DG promotes spatial learning and memory, in part by modulating the responses of EAAs during spatial learning. PMID- 30472151 TI - Purinergic signaling in Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by three major histopathological markers: amyloid-beta (Abeta) plaques, neurofibrillary tangles and gliosis in the central nervous system (CNS). It is now accepted that neuroinflammatory events in the CNS play a crucial role in the development of AD. This review focuses on neuroinflammatory signaling mediated by purinergic receptors (P1 adenosine receptors, P2X ATP-gated ion channels and G protein-coupled P2Y nucleotide receptors) and how therapeutic modulation of purinergic signaling influences disease progression in AD patients and animal models of AD. PMID- 30472152 TI - Effect of dimethyl fumarate on neuroinflammation and apoptosis in PTZ kindling model in rats. AB - OBJECTIVE: Role of apoptosis and neuroinflammation have been well established in the pathogenesis of epilepsy. It has been reported that the activation of nuclear factor-erythroid 2-related factor-2 (Nrf2) contributes to the attenuation of inflammation by inhibiting nuclear factor-kB (NF-kB) pathway. Therefore, the present study was designed to evaluate anti-inflammatory, anti-apoptotic and anti oxidative role of dimethyl fumarate (DMF), an activator of Nrf2, in chemical kindling model in rats. METHODS: Chemical kindling model was established in Wistar rats by intraperitoneal (i.p.) administration of pentylenetetrazole (PTZ). Animals were treated with DMF (60 mg/kg) to activate the Nrf2 antioxidant response element (ARE) pathway. The animals were assessed for seizure score, neuronal damage and inflammatory cytokines levels (IL-1beta, IL-6 and TNF-alpha) in hippocampus. The mRNA levels of various genes (Nrf2, HO-1, NQO1, Bcl2, Bax, Caspase 3, NF-kB, IL-6, IL-1beta and TNF-alpha) were quantified by real-time PCR. The expression of anti-oxidative (Nrf2), apoptotic (Bax, Bcl2) and inflammatory (NF-kB) proteins were analysed by western blot. Immunohistochemistry (Bax) and electron microscopy were done to assess apoptosis. RESULT: The results showed reduction in the seizure score, percentage of kindled rats and neurological damage score in DMF treated rats. The levels of pro-inflammatory cytokines were also decreased by DMF treatment. DMF downregulated the expression of inflammatory (NF-kB) and apoptotic (Bax, Caspase-3) genes and protein. DMF treatment increased the gene expression of Nrf2, HO-1, NQO1, Bcl-2 and protein expression of Nrf2 and Bcl2. CONCLUSION: DMF demonstrated anti-apoptotic, anti-inflammatory and anti oxidative effect in hippocampus, which might be regulated by increased level of antioxidant response elements. PMID- 30472153 TI - Correlates and outcomes of alcohol use after single solid organ transplantation: A systematic review and meta-analysis. AB - BACKGROUND: Reviews on alcohol use in transplant recipients focus on liver recipients and their risk of post-transplant rejection, but do not assess alcohol use in kidney, heart, or lung transplant recipients. This systematic review and meta-analysis aims to synthesize the evidence on correlates and outcomes of any alcohol use and at-risk drinking after solid organ transplantation (Tx). METHODS: We searched 4 databases for quantitative studies in adult heart, liver, kidney and lung Tx recipients, investigating associations between post-Tx alcohol use and correlates and/or clinical, economic or quality of life outcomes. Paper selection, data extraction and quality assessment were performed by 2 reviewers independently. A pooled odds ratio (OR) was computed for each correlate/outcome reported >=5 times. RESULTS: Of the 5331 studies identified, 76 were included in this systematic review (93.3% on liver Tx; mean sample size 148.9 (SD = 160.2); 71.9% male; mean age 48.9 years (SD = 6.5); mean time post-Tx 57.7 months (SD = 23.1)). On average, 23.6% of patients studied used alcohol post-transplant. Ninety-three correlates of any post-Tx alcohol use were identified, and 9 of the 19 pooled ORs were significantly associated with a higher odds for any post-Tx alcohol use: male gender, being employed post-transplant, smoking pre-transplant, smoking post-transplant, a history of illicit drug use, having first-degree relatives who have alcohol-related problems, sobriety <6 months prior to transplant, a history of psychiatric illness, and having received treatment for alcohol-related problems pre-transplant. On average 15.1% of patients had at-risk drinking. A pooled OR was calculated for 6 of the 47 correlates of post-Tx at risk drinking investigated, of which pre-transplant smoking was the only correlate being significantly associated with this behavior. None of the outcomes investigated were significantly associated with any use or at-risk drinking. CONCLUSION: Correlates of alcohol use remain under-investigated in solid organ transplant recipients other than liver transplantation. Further research is needed to determine whether any alcohol use or at-risk drinking is associated with poorer post-transplant outcomes. Our meta-analysis highlights avenues for future research of higher methodological quality and improved clinical care. PROTOCOL REGISTRATION: PROSPERO protocol CRD42015003333. PMID- 30472154 TI - Pre- and post-transplant factors associated with body weight parameters after liver transplantation - A systematic review and meta-analysis. AB - BACKGROUND: Weight gain and obesity can increase liver transplant (LTx) recipients' disease burden. We aimed to summarize and synthesize the evidence on pre- and post-transplant factors related to post-LTx BMI, weight gain, and obesity. METHODS: For this systematic review and meta-analysis we searched Medline (PubMed), Cochrane library, CINAHL, PsycINFO, and EMBASE for quantitative studies on 6 classes of factors (i.e., genetic, sociodemographic, behavioral, biomedical, psychological, and environmental) linked to body weight parameters in adult first-time LTx patients. A 19-item instrument was used for quality assessment. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for relationships investigated in >=5 studies. Factors investigated in <5 studies were summarized and described. RESULTS: Of 16,495 articles retrieved, 43 assessed factors in LTx. These examined 82 mainly biomedical and sociodemographic factors. However, variation between definitions allowed inclusion of only 2 factors (i.e., tacrolimus, cyclosporine) in our meta-analyses of 6 studies examining a shared parameter for body weight (median patient sample: 171 (range: 63-455); Europe n = 3; United States n = 3; publication years: 1997-2015). Neither tacrolimus (OR, 0.75; 95% CI, 0.47-1.21; p = 0.24) nor cyclosporine (OR, 1.40; 95% CI, 0.89-2.18; p = 0.14) were related significantly with post-LTx obesity. CONCLUSIONS: Evidence on modifiable factors related to post-LTx body weight parameters is still scarce, as definition variability limits data extraction and pooling for meta-analyses. To facilitate future research, studies should apply theoretical frameworks to guide their study design, select variables of interest and systematically examine interrelationships among selected factors. PMID- 30472155 TI - Leverage points. PMID- 30472156 TI - Quantitative Clonal Analysis and Single-Cell Transcriptomics Reveal Division Kinetics, Hierarchy, and Fate of Oral Epithelial Progenitor Cells. AB - The oral mucosa is one of the most rapidly dividing tissues in the body and serves as a barrier to physical and chemical insults from mastication, food, and microorganisms. Breakdown of this barrier can lead to significant morbidity and potentially life-threatening infections for patients. Determining the identity and organization of oral epithelial progenitor cells (OEPCs) is therefore paramount to understanding their roles in homeostasis and disease. Using lineage tracing and label retention experiments, we show that rapidly dividing OEPCs are located broadly within the basal layer of the mucosa throughout the oral cavity. Quantitative clonal analysis demonstrated that OEPCs undergo population asymmetrical divisions following neutral drift dynamics and that they respond to chemotherapy-induced damage by altering daughter cell fates. Finally, using single-cell RNA-seq, we establish the basal layer population structure and propose a model that defines the organization of cells within the basal layer. PMID- 30472158 TI - IKZF2 Drives Leukemia Stem Cell Self-Renewal and Inhibits Myeloid Differentiation. AB - Leukemias exhibit a dysregulated developmental program mediated through both genetic and epigenetic mechanisms. Although IKZF2 is expressed in hematopoietic stem cells (HSCs), we found that it is dispensable for mouse and human HSC function. In contrast to its role as a tumor suppressor in hypodiploid B-acute lymphoblastic leukemia, we found that IKZF2 is required for myeloid leukemia. IKZF2 is highly expressed in leukemic stem cells (LSCs), and its deficiency results in defective LSC function. IKZF2 depletion in acute myeloid leukemia (AML) cells reduced colony formation, increased differentiation and apoptosis, and delayed leukemogenesis. Gene expression, chromatin accessibility, and direct IKZF2 binding in MLL-AF9 LSCs demonstrate that IKZF2 regulates a HOXA9 self renewal gene expression program and inhibits a C/EBP-driven differentiation program. Ectopic HOXA9 expression and CEBPE depletion rescued the effects of IKZF2 depletion. Thus, our study shows that IKZF2 regulates the AML LSC program and provides a rationale to therapeutically target IKZF2 in myeloid leukemia. PMID- 30472157 TI - Integrative Proteomic Profiling Reveals PRC2-Dependent Epigenetic Crosstalk Maintains Ground-State Pluripotency. AB - The pluripotent ground state is defined as a basal state free of epigenetic restrictions, which influence lineage specification. While naive embryonic stem cells (ESCs) can be maintained in a hypomethylated state with open chromatin when grown using two small-molecule inhibitors (2i)/leukemia inhibitory factor (LIF), in contrast to serum/LIF-grown ESCs that resemble early post-implantation embryos, broader features of the ground-state pluripotent epigenome are not well understood. We identified epigenetic features of mouse ESCs cultured using 2i/LIF or serum/LIF by proteomic profiling of chromatin-associated complexes and histone modifications. Polycomb-repressive complex 2 (PRC2) and its product H3K27me3 are highly abundant in 2i/LIF ESCs, and H3K27me3 is distributed genome-wide in a CpG dependent fashion. Consistently, PRC2-deficient ESCs showed increased DNA methylation at sites normally occupied by H3K27me3 and increased H4 acetylation. Inhibiting DNA methylation in PRC2-deficient ESCs did not affect their viability or transcriptome. Our findings suggest a unique H3K27me3 configuration protects naive ESCs from lineage priming, and they reveal widespread epigenetic crosstalk in ground-state pluripotency. PMID- 30472159 TI - Mitochondrial quality control in the cardiac system: An integrative view. AB - Recent studies have led to the discovery of multiple mitochondrial quality control (mQC) processes that operate at various scales, ranging from the degradation of proteins by mitochondrial proteases to the degradation of selected cargos or entire organelles in lysosomes. While the mechanisms governing these mQC processes are progressively being delineated, their role and importance remain unclear. Converging evidence however point to a complex system whereby multiple and partly overlapping processes are recruited to orchestrate a cell type specific mQC response that is adapted to the physiological state and level of stress encountered. Knowledge gained from basic model systems of mQC therefore need to be integrated within organ-specific (patho)physiological frameworks. Building on this notion, this article focuses on mQC in the heart, where developmental metabolic reprogramming, sustained contraction, and multiple pathophysiological conditions pose broadly different constraints. We provide an overview of current knowledge of mQC processes, and discuss their implication in cardiac mQC under normal and diseased conditions. PMID- 30472160 TI - Tetrahydrocurcumin epigenetically mitigates mitochondrial dysfunction in brain vasculature during ischemic stroke. AB - The objectives of this study are to identify the mechanism of mitochondrial dysfunction during cerebral ischemic/reperfusion (I/R) injury and the therapeutic potential of tetrahydrocurcumin (THC) to mitigate mitochondrial dysfunction in experimental stroke model. In our study, 8-10 weeks old male C57BL/6 wild-type mice were subjected to middle cerebral artery occlusion (MCAO) for 40 min, followed by reperfusion for 72 h. THC (25mg/kg-BW/day) was injected intraperitoneally once daily for 3 days after 4 h of ischemia. The experimental groups were: (i) sham, (ii) I/R and (iii) I/R + THC. We noticed that THC treatment in ischemic mice significantly improved the functional capacity and motor co-ordination along with reduced neuroscore, infarct volume, brain edema and microvascular leakage in brain parenchyma. The study revealed that level of total homocysteine (tHcy), homocysteine metabolizing enzymes, mitochondrial oxidative stress were significantly altered in I/R mice compared to sham. We also observed alteration in mitochondrial transition pore, ATP production and O2 consumption in the ischemic brain as compared to sham. Further, elevated matrix metalloproteinases-9 (MMP-9) activity and reduced tight junction protein expressions intensified the brain vascular impairment in I/R mice compared to sham. Interestingly, we found that levels of mitophagy markers, fusion and fission proteins were significantly altered. However THC treatment in I/R mice almost normalized the above functional and molecular changes. Mechanistic study demonstrated that DNA Methyltransferase 1 (DNMT1) expression was higher and was associated with reduced mitochondrial tissue inhibitor of metalloproteinases 2 (TIMP-2) expression through hyper-methylation of CpG island of TIMP-2 promoter in I/R mice compared to sham. However, administration of epigenetic inhibitor, 5 Azacytidine (5-Aza) abrogated I/R induced hyper-methylation of TIMP-2 promoter and maintaining the extracellular matrix (ECM) integrity. In conclusion, this study suggests that THC epigenetically ameliorates mitochondrial dysfunction in brain vasculature during Ischemic Stroke. PMID- 30472161 TI - Targeting the terminase: An important step forward in the treatment and prophylaxis of human cytomegalovirus infections. AB - A key step in the replication of human cytomegalovirus (HCMV) in the host cell is the generation and packaging of unit-length genomes into preformed capsids. Enzymes required for this process are so-called terminases, first described for double-stranded DNA bacteriophages. The HCMV terminase consists of the two subunits, the ATPase pUL56 and the nuclease pUL89, and a potential third component pUL51. The terminase subunits are essential for virus replication and are highly conserved throughout the Herpesviridae family. Together with the portal protein pUL104 they form a powerful biological nanomotor. It has been shown for tailed dsDNA bacteriophages that DNA translocation into preformed capsid needs an extraordinary amount of energy. The HCMV terminase subunit pUL56 provides the required ATP hydrolyzing activity. The necessary nuclease activity to cleave the concatemers into unit-length genomes is mediated by the terminase subunit pUL89. Whether this cleavage is mediated by site-specific duplex nicking has not been demonstrated, however, it is required for packaging. Binding to the portal is a prerequisite for DNA translocation. To date, it is a common view that during translocation the terminase moves along some domains of the DNA by a binding and release mechanism. These critical structures have proven to be outstanding targets for drugs to treat HCMV infections because corresponding structures do not exist in mammalian cells. Herein we examine the HCMV terminase as a target for drugs and review several inhibitors discovered by both lead directed medicinal chemistry and by target-specific design. In addition to producing clinically active compounds the research also has furthered the understanding of the role and function of the terminase itself. PMID- 30472162 TI - Progress in human picornavirus research: New findings from the AIROPico consortium. AB - Several research groups in Europe are active on different aspects of human picornavirus research. The AIROPico (Academia-Industry R&D Opportunities for Picornaviruses) consortium combined the disciplines of pathogenesis, diagnostics and therapy development in order to fill the gaps in our understanding of how picornaviruses cause human disease and how to combat them. AIROPico was the first EU consortium dedicated to human picornavirus research and development, and has largely accelerated and improved R&D on picornavirus biology, diagnostics and therapy. In this article, we present the progress on pathogenesis, diagnostics and treatment strategy developments for human picornaviruses resulting from the structured, translational research approach of the AIROPico consortium. We here summarize new insights in protection against infection by maternal or cross protective antibodies, the visualisation of interactions between virus and neutralizing antibodies by cryoEM structural imaging, and the outcomes from a picornavirus-infected human 3D organoid. Progress in molecular detection and a fast typing assay for rhinovirus species are presented, as well as the identification of new compounds potentially interesting as therapeutic compounds. PMID- 30472163 TI - Meta-analyses of cavum septum pellucidum in mood disorders in comparison with healthy controls or schizophrenia. AB - The cavum septum pellucidum (CSP) is a neurodevelopmental abnormality significantly more prevalent in subjects with schizophrenia (SCZ) than in healthy controls (HC). Using meta-analyses, we tested the hypotheses whether CSP would be more frequent in subjects with mood disorders when compared with HC or SCZ. We performed a search in MEDLINE and EMBASE followed by 10 meta-analyses of magnetic resonance imaging studies which examined the association of CSP in bipolar disorders (BD), major depressive disorder (MDD) or mood disorders (MD; considering MDD and BD combined) with either HC or SCZ. Nine studies were included, comprising 692 cases (363 with BD, 182 with MDD and 147 with MD), 463 with SCZ and 630 HC. CSP of any size was significantly associated with BD (OR = 2.07, 95% CI: 1.48-2.90) when compared with HC. Large CSP showed a trend to be associated with BD when compared with HC, but the association was not statistically significant (OR = 1.92, 95% CI 0.64-5.78). Large CSP was significantly associated with subjects with SCZ when compared with subjects with MD (OR = 0.57, 95% CI: 0.36-0.92). There was no association between CSP and MDD in comparison to HC or subjects with SCZ. Cortical structures are known to be altered in mood disorders. The present metanalysis found that certain midline brain abnormalities, such as CSP, are also associated with BD. PMID- 30472164 TI - Efficacy, acceptability and tolerability of antipsychotics in patients with schizophrenia and comorbid substance use. A systematic review and meta-analysis. AB - Patients with schizophrenia and substance related comorbidity or substance induced psychotic disorder are difficult to treat. Although the prevalence of a comorbid substance use is approximately 40% in schizophrenia, such patients are usually excluded from clinical trials. We therefore performed a random-effects meta-analysis of all randomized controlled antipsychotic drug trials in this patient subgroup. We searched multiple databases up to May, 2018. The primary outcome was the reduction of substance user; secondary outcomes were craving, mean reduction of substance use, overall change in schizophrenia symptoms, positive and negative symptoms, response, dropouts, quality of life, social functioning, weight gain, sedation, prolactin, extrapyramidal side effects and use of antiparkinsonian medication. We identified 27 references from 19 RCTs published from 1999 to March 2017 including 1742 participants. The most frequent types of substance abuse were cannabis (8 studies) and cocaine (6 studies) use/dependence. Clozapine was superior to other antipsychotics for reduction of substance use and risperidone to olanzapine for craving. Olanzapine, clozapine and risperidone showed superiority for symptom reduction compared to some other drugs. When reported, results of side-effects followed known patterns. The evidence-base is considerable (19 RCTs), however, firm conclusions cannot be drawn due to small sample sizes of individual studies and insufficient reporting. PMID- 30472165 TI - Endoplasmic reticulum stress and development of insulin resistance in adipose, skeletal, liver, and foetoplacental tissue in diabesity. AB - Diabesity is an abnormal metabolic condition shown by patients with obesity that develop type 2 diabetes mellitus. Patients with diabesity present with insulin resistance, reduced vascular response to insulin, and vascular endothelial dysfunction. Along with the several well-described mechanisms of insulin resistance, a state of endoplasmic reticulum (ER) stress, where the primary human targets are the adipose tissue, liver, skeletal muscle, and the foetoplacental vasculature, is apparent. ER stress characterises by the activation of the unfolded protein response via three canonical ER stress sensors, i.e., the protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1alpha (IRE1alpha), and activating transcription factor 6. Slightly different cell signalling mechanisms preferentially enable in diabesity in the ER stress-associated insulin resistance for adipose tissue (IRE1alpha/X-box binding protein 1 mRNA splicing/c-jun N-terminal kinase 1 activation), skeletal muscle (tribbles-like protein 3 (TRB3)/proinflammatory cytokines activation), and liver (PERK/activating transcription factor 4/TRB3 activation). There is no information in human subjects with diabesity in the foetoplacental vasculature. However, the available literature shows that pregnant women with pre-pregnancy obesity or overweight that develop gestational diabetes mellitus (GDM) and their newborn show insulin resistance. ER stress is recently reported to be triggered in endothelial cells from the human umbilical vein from mothers with pre-pregnancy obesity. However, whether a different metabolic alteration to obesity in pregnancy or GDM is present in women with pre-pregnancy obesity that develop GDM, is unknown. In this review, we summarised the findings on diabesity-associated mechanisms of insulin resistance with emphasis in the primary targets adipose, skeletal muscle, liver, and foetoplacental tissues. We also give evidence on the possibility of a new GDM-associated metabolic condition triggered in pregnancy by maternal obesity, i.e. gestational diabesity, leading to ER stress-associated insulin resistance in the human foetoplacental vasculature. PMID- 30472166 TI - Interactions between gut permeability and brain structure and function in health and irritable bowel syndrome. AB - Changes in brain-gut interactions have been implicated in the pathophysiology of chronic visceral pain in irritable bowel syndrome (IBS). Different mechanisms of sensitization of visceral afferent pathways may contribute to the chronic visceral pain reports and associated brain changes that characterize IBS. They include increased gut permeability and gut associated immune system activation, and an imbalance in descending pain inhibitory and facilitatory mechanisms. In order to study the involvement of these mechanisms, correlations between gut epithelial permeability and live bacterial passage, and structural and functional brain connectivity were measured in women with moderate-to-severe IBS and healthy women. The relationships between gut permeability and functional and anatomical connectivity were significantly altered in IBS compared with the healthy women. IBS participants with lower epithelial permeability reported increased IBS symptoms, which was associated with increased functional and structural connectivity in endogenous pain facilitation regions. The findings suggest that relationships between gut permeability and the brain are significantly altered in IBS and suggest the existence of IBS subtypes based on these interactions. PMID- 30472167 TI - Large-scale brain functional network topology disruptions underlie symptom heterogeneity in children with attention-deficit/hyperactivity disorder. AB - Accumulating evidence suggests brain network dysfunction in attention deficit/hyperactivity disorder (ADHD). Whether large-scale brain network connectivity patterns reflect clinical heterogeneity in ADHD remains to be fully understood. This study aimed to characterize the differential within- and between network functional connectivity (FC) changes in children with ADHD combined (ADHD C) or inattentive (ADHD-I) subtypes and their associations with ADHD symptoms. We studied the task-free functional magnetic resonance imaging (fMRI) data of 58 boys with ADHD and 28 demographically matched healthy controls. We measured within- and between-network connectivity of both low-level (sensorimotor) and high-level (cognitive) large-scale intrinsic connectivity networks and network modularity. We found that children with ADHD-C but not those with ADHD-I exhibited hyper-connectivity within the anterior default mode network (DMN) compared with controls. Additionally, children with ADHD-C had higher inter network FC between the left executive control (ECN) and the salience (SN) networks, between subcortical and visual networks, and between the DMN and left auditory networks than controls, while children with ADHD-I did not show differences compared with controls. Similarly, children with ADHD-C but not ADHD I showed lower network modularity compared with controls. Importantly, these observed abnormal inter-network connectivity and network modularity metrics were associated with Child Behavioral Checklist (CBCL) attention-deficit/hyperactivity problems and internalizing problems in children with ADHD. This study revealed relatively greater loss of brain functional network segregation in childhood ADHD combined subtype compared to the inattentive subtype, suggesting differential large-scale functional brain network topology phenotype underlying childhood ADHD heterogeneity. PMID- 30472168 TI - Biomarkers of Parkinson's disease: Striatal sub-regional structural morphometry and diffusion MRI. AB - Parkinson's disease (PD) is a progressive neurological disorder that has no reliable biomarkers. The aim of this study was to explore the potential of semi automated sub-regional analysis of the striatum with magnetic resonance imaging (MRI) to distinguish PD patients from controls (i.e., as a diagnostic biomarker) and to compare PD patients at different stages of disease. With 3 Tesla MRI, diffusion- and T1-weighted scans were obtained on two occasions in 24 PD patients and 18 age-matched, healthy controls. PD patients completed one session on and the other session off dopaminergic medication. The striatum was parcellated into seven functionally disparate sub-regions. The segmentation was guided by reciprocal connections to distinct cortical regions. Volume, surface-based morphometry, and integrity of white matter connections were calculated for each striatal sub-region. Test-retest reliability of our volume, morphometry, and white matter integrity measures across scans was high, with correlations ranging from r = 0.452, p < 0.05 and r = 0.985, p < 0.001. Global measures of striatum such as total striatum, nucleus accumbens, caudate nuclei, and putamen were not significantly different between PD patients and controls, indicating poor sensitivity of these measures, which average across sub-regions that are functionally heterogeneous and differentially affected by PD, to act as diagnostic biomarkers. Further, these measures did not correlate significantly with disease severity, challenging their potential to serve as progression biomarkers. In contrast, a) decreased volume and b) inward surface displacement of caudal-motor striatumthe region first and most dopamine depleted in PDdistinguished PD patients from controls. Integrity of white matter cortico striatal connections in caudal-motor and adjacent striatal sub-regions (i.e., executive and temporal striatum) was reduced for PD patients relative to controls. Finally, volume of limbic striatum, the only striatal sub-region innervated by the later-degenerating ventral tegmental area in PD, was reduced in later-stage compared to early stage PD patients a potential progression biomarker. Segmenting striatum based on distinct cortical connectivity provided highly sensitive MRI measures for diagnosing and staging PD. PMID- 30472169 TI - Ex vivo detection of calcium phosphate and calcium carbonate in rat blood serum. AB - The total calcium (tCa) in blood serum comprises free Ca2+ ions (fCa), protein bound calcium (prCa), and complexed calcium by small anions (cCa). The cCa fraction, in addition to fCa, has been indicated to have some physiological activity. However, there is little evidence for the structure of its constituents. Here we report an ex vivo detection of the cCa constituents by synchrotron X-ray absorption near-edge structure spectroscopy. We collected the data directly on rat blood serum and, by making use of the reference samples, derived a spectrum that exhibits the features of cCa constituents. Among the features are those of the complexes of calcium phosphate and calcium carbonate. The detected complexes in the cCa fraction are mainly Ca(eta2-HPO4)(H2O)4 and Ca(eta1-HCO3)(H2O)5+, in which HPO42- and HCO3- serve as bidentate and unidentate ligands, respectively. The remained H2O molecules on the coordination sphere of Ca2+ enable these complexes to behave partially like aquated Ca2+ ions in protein binding. Besides, as the dominant part of prCa, albumin-bound calcium (albCa) exhibits a spectrum that closely resembles that of fCa, indicating weak interactions between the protein carboxyl groups and calcium. The weak-bound cCa and albCa, along with fCa and the relevant anions, compose a local chemical system that could play a role in maintaining the calcium level in blood. PMID- 30472170 TI - Variation in human hair ultrastructure among three biogeographic populations. AB - Human scalp hairs are often examined microscopically to study the variation and diversity among a range of visible morphological traits. In this study, we focused on the ultrastructure of human scalp hair within its keratinized matrix, emphasizing, the density and distribution of melanosomes, variation in cuticle thickness within populations, and the relationship of hair fiber ultrastructure with biogeographic ancestry. We used transmission electron microscopy (TEM) to visualize hair cross-sections and generate micron-scale resolution images for analysis of particle morphology and the layered hair matrix. Our results revealed considerable variation in all parameters examined, including the relationship of ultrastructure to biogeographic ancestry. Among the three metapopulations studied (European, African, and East Asian), we identified hair cross-sectional shape, cuticle dimensions, and melanosome distribution as traits that reveal statistically significant ancestry-related patterns. This study establishes trait patterns in hair morphology and ultrastructure among three biogeographically defined metapopulations to improve the current understanding of human variation in hair form and establish a foundation for future studies on the genetic and developmental bases of phenotypic variation in hair ultrastructure related to genotype. PMID- 30472171 TI - Pig enamel revisited - Incremental markings in enamel of wild boars and domestic pigs. AB - The nature and periodicity of incremental markings in pig enamel is currently debated. To broaden the basis for a correct interpretation of growth marks in pig enamel, we analyzed their periodicity in teeth of wild boars and domestic pigs. For that, the numbers of enamel incremental markings were recorded in ground sections and compared with crown formation times for the respective teeth derived from literature data on tooth development and eruption in Sus scrofa. Our study revealed that laminations with a daily periodicity are the dominant incremental feature of pig enamel. In wild boar M3s, daily enamel secretion (apposition) rates ranged between a minimum of 6.1 um in the inner and a maximum of 30.6 um in the outer enamel. Long-period (supra-daily) incremental markings were present as perikymata at the outer enamel surface (OES). Contrary to the situation in primate enamel, in pig enamel the long-period incremental lines terminating in perikyma grooves were mostly structurally indistinguishable from the daily laminations. Typically, five sub-daily increments were present between successive laminations. The incremental pattern in pig enamel can be misinterpreted if the laminations are mistaken for long-period markings (striae of Retzius) and the sub daily growth marks for daily prism cross-striations. The findings of the present study demonstrate the critical importance of correctly characterizing the incremental markings and their periodicity in enamel, and caution against an uncritical transfer of the interpretation of the nature of incremental markings in primate enamel to other mammalian taxa. PMID- 30472172 TI - Electronic Decision support for Improvement of Contemporary Therapy for Stroke Prevention. AB - BACKGROUND: Despite ample clinical trial data demonstrating that oral anticoagulation (OAC) treatment is highly effective in reducing stroke for patients with atrial fibrillation (AF), OAC treatment remains underutilized in current clinical practice. Targeting hospitalist and emergency department providers with electronic decision support represents a potential quality improvement opportunity in the use of OAC medication in AF patients. METHODS: We conducted a 3-center study in which 2 sites utilized an electronic alert (EA) embedded in the electronic health record and 1 site provided usual care. The EA calculated the CHA2DS2-VASc score for clinicians. Patients were tracked following discharge from either the emergency department or hospital. We hypothesized that the EA would increase the rate of OAC use by 15% compared to usual care, with a study sample size of 360 patients. Study exclusions included severe heart valve disease, advanced renal disease, and severe dementia. The primary endpoint was OAC use at the time of hospital discharge or 30 days after hospital discharge (whichever was the last observation recorded). RESULTS: Among 309 patients included for analysis (mean age 70.2 years), the median CHA2DS2-VASc score was 3.5. The frequency of OAC use at follow-up at the usual care hospital was 55.9% (95% confidence interval 47.4-67.9). At the 2 EA sites, the rate of OAC use at the last observation point was 43.9% (P = .06). Aspirin use at follow-up was similar at the usual care site and the EA sites (53.8% versus 46.3%). The rate of OAC use in patients greater than 75 years was 60.0% in the usual care site and 48.4% (P = .09) at the EA sites. CONCLUSIONS: The EA in our study was not sufficient to ameliorate therapeutic inertia in the use of OAC for stroke prevention in AF. PMID- 30472173 TI - Asymptomatic Coronary Artery Disease in Japanese Patients With the Acute Ischemic Stroke. AB - OBJECTIVE: To investigate the prevalence and outcomes of asymptomatic coronary artery disease (CAD) in patients with the first episode of ischemic stroke. METHODS: Patients admitted to our hospital between November 2001 and January 2009 for the episode of an acute ischemic stroke/transient ischemic attack were included. Stress-Tl-201 scintigraphy was performed and followed by coronary angiography (CAG). The prevalence and risks for asymptomatic CAD, and long-term outcomes were studied. RESULTS: Of 1309 patients, only 15 (1.1%) patients presented with a history of CAD. Excluding 406 patients because of severity, systemic infection, early transfer to another hospital, or a refusal to participate, myocardial scintigraphy was performed in 903 patients (mean age, 72 +/- 10 years, male 63.9%), and myocardial ischemia was diagnosed in 214 patients (23.7%). Of these patients, 76 patients underwent CAG, and showed significant stenosis (>75%) of a coronary artery in 61 (80.3%) patients. The risk factors for positive scintigraphy findings and CAG were high-grade premature complexes via Holter monitoring (P < .0001), enlarged left ventricle (P = .0051) and wall motion abnormalities (P = .0014) observed on echocardiography, and carotid artery stenosis observed in magnetic resonance angiography imaging (P < .0001). During the follow-up periods of 83 +/- 47 months and of 91 +/- 47 months, 17.2% of scintigraphy-positive and 2.8% of scintigraphy-negative patients developed episodes of myocardial ischemia, respectively (P < .001). CONCLUSIONS: Symptomatic CAD was rare in Japanese patients with the first episode of ischemic stroke, but asymptomatic CAD was identified by stress Tl-201 myocardial scintigraphy in one-quarter of the patients. Positive scintigraphy was associated with asymptomatic CAD and future cardiac events. PMID- 30472174 TI - Primary Thrombectomy Versus Combined Mechanical Thrombectomy and Intravenous Thrombolysis in Large Vessel Occlusion Acute Ischemic Stroke. AB - Mechanical thrombectomy (MT) in combination with intravenous thrombolysis (IVT) is the standard of care for patients with acute ischemic stroke with anterior circulation large vessel occlusion. The particular benefit of IVT in these patients is unknown. We performed a retrospective analysis of patients submitted to MT at our center between January 2015 and June 2017. Functional outcome was prospectively assessed using modified Rankin scale (mRS) at 3 months. A total of 234 patients were enrolled, 152 (65%) in the combined treatment group and 82 (35%) in the direct MT group. Patients receiving combined treatment had a higher frequency of intracranial internal carotid artery occlusion (48 [31.6%] versus 16 [19.5%], P = .048) and significantly less strokes of cardioembolic etiology (72 [47.4%] versus 57 [69.5%], P = .01). Other baseline characteristics did not differ between the 2 groups. Good functional outcome at 3 months (mRS 0-2) was trending toward being higher in patients in the combined treatment group (98 [64.9%] versus 42 [52.5%], P = .066). Rates of symptomatic intracranial hemorrhage (5 [3.3%] versus 4 [4.9%], P = .723) and mortality (15 [9.9%] versus 14 [17.5%], P = .099) did not differ between groups. In multivariate logistic regression analysis, we did not find a statistically significant association between the use of IVT and any of the outcomes studied. Our results suggest that combined treatment carries similar effectiveness and safety than direct MT. Randomized controlled trials regarding this subject are warranted. PMID- 30472175 TI - Different Types of Family History of Stroke and Stroke Risk: Results Based on 655,552 Individuals. AB - BACKGROUND: Many studies concentrated on the relationships between different types of family history and stroke, but they have not arrived at an unified conclusion. We conducted a comprehensive systematic review to further evaluate the associations. METHODS: Different databases were searched for related studies published from 1990 to August 2017. The relative risk was considered as the common measure of association across different studies. Heterogeneity of effects across studies was quantified by I2. RESULTS: Sixteen published studies (total participants: 655,552) were eligible in this study. The pooled multifactorial adjusted relative risk (RR) (95% confidence interval [CI]) was 1.40 (1.18, 1.67) for individuals with paternal history, 1.36 (1.20, 1.53) for those with maternal history, and 1.44 (1.17, 1.77) for those with sibling history. Based on cohort studies, the pooled adjusted RRs (95%CIs) for paternal, maternal, and sibling history were 1.33 (1.11-1.59), 1.28 (1.14-1.45), and 1.24 (1.01-1.51), respectively, all of which were smaller than those based on case-control and cross-sectional studies. In studies with large sample size, the respective adjusted RR (95%CI) of stroke for paternal, maternal, and sibling history was 1.30 (1.09, 1.56), 1.30 (1.18, 1.44), and 1.26 (1.02, 1.56), which was lower than that in studies with small sample size. CONCLUSIONS: Each type of family history of stroke was associated with an increased stroke risk. We could not find significant differences among stroke risks relating to different types of family history of stroke. Thus, paternal, maternal, and sibling history require our equal attention in the stroke prevention and control work. PMID- 30472177 TI - Improving the provision of rabies post-exposure prophylaxis. PMID- 30472176 TI - The Effect of Anti-Vascular Endothelial Growth Factor Agents on Intraocular Pressure and Glaucoma A Report by the American Academy of Ophthalmology. AB - PURPOSE: To assess the effect of intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents on immediate and long-term intraocular pressure (IOP) elevation and glaucoma. METHODS: Literature searches of the PubMed and Cochrane databases, last conducted in April 2018, yielded 253 unique citations. Of these, 41 met the inclusion criteria and were rated according to the strength of evidence. Two articles were rated level I, 17 were rated level II, and 15 were rated level III; an additional 7 were excluded owing to poor study design and lack of relevance to the topic under evaluation. RESULTS: The studies that reported on short-term IOP elevation (i.e., between 0 and 60 minutes) showed that an immediate increase in IOP is seen in all patients when measured between 0 and 30 minutes of intravitreal injection and that the IOP elevation decreases over time. The data on long-term IOP elevation were mixed; 7 studies reported that between 4% and 15% of patients developed sustained elevation of IOP at 9 to 24 months after injection, whereas 6 studies found no long-term change in IOP from 1 to 36 months after injection. Pretreatment with glaucoma medications, anterior chamber tap, vitreous reflux, longer intervals between injections, and longer axial lengths were associated with lower IOP elevations after injection. Data were mixed on the relationship between IOP rise and the type of intravitreal injection, number of intravitreal injections, pre existing glaucoma, and globe decompression before injection. There were no data on the onset or progression of glaucoma in the studies reviewed in this assessment. CONCLUSIONS: Intravitreal injection of anti-VEGF agents results in an immediate and transient rise in IOP. A long-term increase in IOP may be seen as well, and further studies are needed to determine at-risk populations. Although there is some suggestion in the literature, there is currently insufficient data to determine the impact of intravitreal anti-VEGF injections on glaucoma progression. Even though pretreatment with glaucoma medications, performing anterior chamber paracentesis, or increasing the interval between injections may reduce the impact of transient IOP elevation, the clinical significance and associated risks of these interventions are unknown. PMID- 30472179 TI - Scabies outbreaks in care homes for the elderly - Authors' reply. PMID- 30472178 TI - The potential effect of improved provision of rabies post-exposure prophylaxis in Gavi-eligible countries: a modelling study. AB - BACKGROUND: Tens of thousands of people die from dog-mediated rabies annually. Deaths can be prevented through post-exposure prophylaxis for people who have been bitten, and the disease eliminated through dog vaccination. Current post exposure prophylaxis use saves many lives, but availability remains poor in many rabies-endemic countries due to high costs, poor access, and supply. METHODS: We developed epidemiological and economic models to investigate the effect of an investment in post-exposure prophylaxis by Gavi, the Vaccine Alliance. We modelled post-exposure prophylaxis use according to the status quo, with improved access using WHO-recommended intradermal vaccination, with and without rabies immunoglobulin, and with and without dog vaccination. We took the health provider perspective, including only direct costs. FINDINGS: We predict more than 1 million deaths will occur in the 67 rabies-endemic countries considered from 2020 to 2035, under the status quo. Current post-exposure prophylaxis use prevents approximately 56 000 deaths annually. Expanded access to, and free provision of, post-exposure prophylaxis would prevent an additional 489 000 deaths between 2020 and 2035. Under this switch to efficient intradermal post-exposure prophylaxis regimens, total projected vaccine needs remain similar (about 73 million vials) yet 17.4 million more people are vaccinated, making this an extremely cost effective method, with costs of US$635 per death averted and $33 per disability adjusted life-years averted. Scaling up dog vaccination programmes could eliminate dog-mediated rabies over this time period; improved post-exposure prophylaxis access remains cost-effective under this scenario, especially in combination with patient risk assessments to reduce unnecessary post-exposure prophylaxis use. INTERPRETATION: Investing in post-exposure vaccines would be an extremely cost-effective intervention that could substantially reduce disease burden and catalyse dog vaccination efforts to eliminate dog-mediated rabies. FUNDING: World Health Organization. PMID- 30472180 TI - Ischemic-type biliary lesions: A leading indication of liver retransplantation with excellent results. AB - BACKGROUND: Liver retransplantation (RLT) is the only life-saving treatment option for patients with a failing graft, but it remains a major challenge because of inferior outcomes and technical difficulties. METHODS: This study aimed to evaluate the outcomes of and risk factors for adult RLT in a single center, focusing on the etiology of graft failure. Between 1987 and 2011, 1592 liver transplants (LTs) and 143 RLTs (9%) were performed at our institution. RESULTS: The 1-, 5- and 10-year patient survival rates after RLT were 60%, 52% and 39%, and the graft survival rates were 55%, 46% and 32%. The 90-day mortality rate was 32%, mainly due to septic complications (45% of deaths). Ischemic-type biliary lesions (ITBL) were the leading indication for RLT (23%), and patient survival was significantly better in patients retransplanted for ITBL than for any other indication (P<0.02). Indications other than ITBL (P=0.015), the transfusion of more than 7 units (P=0.006) and preoperative dialysis (P=0.005) were the three parameters associated with poor survival after RLT. CONCLUSION: Patients with ITBL benefit the most from elective RLT. PMID- 30472181 TI - Potassium permanganate - an odd cause of caustic injury. PMID- 30472182 TI - Connexin 43 (Cx43) in Cancer: Implications for Therapeutic Approaches via Gap Junctions. AB - Gap junctions are membrane channels found in all cells of the human body that are essential to cellular physiology. Gap junctions are formed from connexin proteins and are responsible for transfer of biologically active molecules, metabolites, and salts between neighboring cells or cells and their extracellular environment. Over the last few years, aberrant connexin 43 (Cx43) expression has been associated with cancer recurrence, metastatic spread, and poor survival. Here we provide an overview of the general structure and function of gap junctions and review their roles in different cancer types. We discuss new therapeutic approaches targeting Cx43 and potential new ways of exploiting gap junction transfer for drug delivery and anti-cancer treatment. The permeability of Cx43 channels to small molecules and macromolecules makes them highly attractive targets for delivering drugs directly into the cytoplasm. Cancer cells overexpressing Cx43 may be more permeable and sensitive to chemotherapeutics. Because Cx43 can either act as a tumor suppressor or oncogene, biomarker analysis and a better understanding of how Cx43 contextually mediates cancer phenotypes will be required to develop clinically viable Cx43-based therapies. PMID- 30472183 TI - Electrochemotherapy with cisplatin increases survival and induces immunogenic responses in murine models of lung cancer and colorectal cancer. AB - Electrochemotherapy is an emerging treatment modality for cancer patients which can effectively reduce tumour burden and induce immunogenic cell death. Electrochemotherapy is most commonly used with bleomycin as the drug of choice, here we examine the efficacy of electrochemotherapy with cisplatin. Electrochemotherapy with cisplatin was found to effectively reduce tumour growth in a range of murine models and induce significant intratumoural recruitment of myeloid and humoral immune cells. Following the observations of immune system mobilisation, we have shown an ability of electrochemotherapy to reduce metastatic potential as determined by tumour burden in the lung, and to exert an abscopal effect by reducing growth at distal untreated secondary tumours. PMID- 30472184 TI - Inhibition of tankyrase by a novel small molecule significantly attenuates prostate cancer cell proliferation. AB - Tankyrase (TNKS) is a crucial mediator of Wnt signal transduction and has been recognized as a novel molecular target for Wnt-pathway dependent cancer. TNKS is stabilized by the ubiquitin-specific protease 25 (USP25). The effect of disruption of the interaction between TNKS and USP25 by small molecules on prostate cancer proliferation is unknown. In this study we conducted a hierarchical virtual screening with more than 200,000 compounds on the characterized structures of the USP25/TNKS-ARC5 protein complex. In silico analysis and in vitro validation revealed that a small molecule, called C44, binds to the protein-protein interaction (PPI) interface of TNKS and USP25. We show that C44 disrupts the interaction between TNKS and USP25 leading to a higher half-life of AXIN and the breakdown of -catenin protein. We also show that the selective inhibition of the TNKS-USP25 interaction by C44 significantly reduces proliferation of prostate cancer cells in vitro and in vivo. Our study reveals a new PPI inhibitor that lowers the stability of TNKS protein and inhibits Wnt pathway signaling. C44 is a promising new drug for the treatment of Wnt-pathway dependent prostate cancer. PMID- 30472185 TI - Hybrids by tumor-associated macrophages * glioblastoma cells entail nuclear reprogramming and glioblastoma invasion. AB - Hybrid formation is a fundamental process in normal development and tissue homeostasis, while the presence and the biological role of hybrids between tumor associated macrophages (TAMs) and glioblastoma (GBM) cells remain elusive. In this study, we observed that TAM-GBM cell hybrids existed in human GBM specimens as demonstrated by co-expression of glioma biomarkers (GFAP, IDH1R132H and PDGFRA) and macrophage biomarkers (CD68 and CD14). Furthermore, TAM-GBM cell hybrids could also be found in C57BL/6 mice orthotopically inoculated with mouse GBM cells labeled with RFP and after co-culture of bone marrow-derived macrophages from GFP-expressed mice with RFP-labeled GBM cells. The hybrids underwent nuclear reprogramming with unique gene expression profile as compared to parental cells. Moreover, glioma invasion-associated genes were enriched in the hybrids that possessed higher invasiveness, and more hybrids in the invasive margin of GBM were observed as compared to GBM core area. Our data demonstrate the presence of TAM-GBM cell hybrids that enhance GBM invasion. With a better understanding of TAM-GBM cell hybrids, new therapeutic strategies targeting GBM will be developed to treat GBM patients. PMID- 30472186 TI - The PEAK1-PPP1R12B axis inhibits tumor growth and metastasis by regulating Grb2/PI3K/Akt signalling in colorectal cancer. AB - Pseudopodium enriched atypical kinase 1 (PEAK1), a novel non-receptor tyrosine kinase, was recently implicated in cancer pathogenesis. However, its functional role in colorectal cancer (CRC) is not well known. Herein, we demonstrated that PEAK1 was frequently downregulated in CRC and significantly associated with tumor size, differentiation status, metastasis, and clinical stage. PEAK1 overexpression suppressed CRC cell growth, invasion, and metastasis in vitro and in vivo, whereas knockout had the opposite effects. Further evaluation revealed that PEAK1 expression was positively correlated with protein phosphatase 1 regulatory subunit 12B (PPP1R12B) in CRC cell lines and clinical tissues, and this protein was found to suppress activation of the Grb2/PI3K/Akt pathway. Moreover, PPP1R12B knockdown markedly abrogated PEAK1-mediated tumor suppressive effects, whereas its upregulation recapitulated the effects of PEAK1 knockout on cell behaviours and the activation of signalling. Mechanistically, PI3K and Akt inhibitors reversed impaired the effect of PEAK1 function on cell proliferation, migration, and invasion. Our results provide compelling evidence that the PEAK1 PPP1R12B axis inhibits colorectal tumorigenesis and metastasis through deactivation of the Grb2/PI3K/Akt pathway, which might provide a novel therapeutic strategy for CRC treatment. PMID- 30472187 TI - Arginine Citrullination at the C-Terminal Domain Controls RNA Polymerase II Transcription. AB - The post-translational modification of key residues at the C-terminal domain of RNA polymerase II (RNAP2-CTD) coordinates transcription, splicing, and RNA processing by modulating its capacity to act as a landing platform for a variety of protein complexes. Here, we identify a new modification at the CTD, the deimination of arginine and its conversion to citrulline by peptidyl arginine deiminase 2 (PADI2), an enzyme that has been associated with several diseases, including cancer. We show that, among PADI family members, only PADI2 citrullinates R1810 (Cit1810) at repeat 31 of the CTD. Depletion of PADI2 or loss of R1810 results in accumulation of RNAP2 at transcription start sites, reduced gene expression, and inhibition of cell proliferation. Cit1810 is needed for interaction with the P-TEFb (positive transcription elongation factor b) kinase complex and for its recruitment to chromatin. In this way, CTD-Cit1810 favors RNAP2 pause release and efficient transcription in breast cancer cells. PMID- 30472188 TI - OTUB2 Promotes Cancer Metastasis via Hippo-Independent Activation of YAP and TAZ. AB - The transcriptional regulators YAP and TAZ play important roles in development, physiology, and tumorigenesis and are negatively controlled by the Hippo pathway. It is yet unknown why the YAP/ TAZ proteins are frequently activated in human malignancies in which the Hippo pathway is still active. Here, by a gain-of function cancer metastasis screen, we discovered OTUB2 as a cancer stemness and metastasis-promoting factor that deubiquitinates and activates YAP/TAZ. We found OTUB2 to be poly-SUMOylated on lysine 233, and this SUMOylation enables it to bind YAP/TAZ. We also identified a yet-unknown SUMO-interacting motif (SIM) in YAP and TAZ required for their association with SUMOylated OTUB2. Importantly, EGF and oncogenic KRAS induce OTUB2 poly-SUMOylation and thereby activate YAP/TAZ. Our results establish OTUB2 as an essential modulator of YAP/TAZ and also reveal a novel mechanism via which YAP/TAZ activity is induced by oncogenic KRAS. PMID- 30472189 TI - Nucleosome Turnover Regulates Histone Methylation Patterns over the Genome. AB - Recent studies have indicated that nucleosome turnover is rapid, occurring several times per cell cycle. To access the effect of nucleosome turnover on the epigenetic landscape, we investigated H3K79 methylation, which is produced by a single methyltransferase (Dot1l) with no known demethylase. Using chemical induced proximity (CIP), we find that the valency of H3K79 methylation (mono-, di , and tri-) is determined by nucleosome turnover rates. Furthermore, propagation of this mark is predicted by nucleosome turnover simulations over the genome and accounts for the asymmetric distribution of H3K79me toward the transcriptional unit. More broadly, a meta-analysis of other conserved histone modifications demonstrates that nucleosome turnover models predict both valency and chromosomal propagation of methylation marks. Based on data from worms, flies, and mice, we propose that the turnover of modified nucleosomes is a general means of propagation of epigenetic marks and a determinant of methylation valence. PMID- 30472190 TI - Promoter Distortion and Opening in the RNA Polymerase II Cleft. AB - Transcription initiation requires opening of promoter DNA in the RNA polymerase II (Pol II) pre-initiation complex (PIC), but it remains unclear how this is achieved. Here we report the cryo-electron microscopic (cryo-EM) structure of a yeast PIC that contains underwound, distorted promoter DNA in the closed Pol II cleft. The DNA duplex axis is offset at the upstream edge of the initially melted DNA region (IMR) where DNA opening begins. Unstable IMRs are found in a subset of yeast promoters that we show can still initiate transcription after depletion of the transcription factor (TF) IIH (TFIIH) translocase Ssl2 (XPB in human) from the nucleus in vivo. PIC-induced DNA distortions may thus prime the IMR for melting and may explain how unstable IMRs that are predicted in promoters of Pol I and Pol III can open spontaneously. These results suggest that DNA distortion in the polymerase cleft is a general mechanism that contributes to promoter opening. PMID- 30472191 TI - ATP-Dependent Dynamic Protein Aggregation Regulates Bacterial Dormancy Depth Critical for Antibiotic Tolerance. AB - Cell dormancy is a widespread mechanism used by bacteria to evade environmental threats, including antibiotics. Here we monitored bacterial antibiotic tolerance and regrowth at the single-cell level and found that each individual survival cell shows different "dormancy depth," which in return regulates the lag time for cell resuscitation after removal of antibiotic. We further established that protein aggresome-a collection of endogenous protein aggregates-is an important indicator of bacterial dormancy depth, whose formation is promoted by decreased cellular ATP level. For cells to leave the dormant state and resuscitate, clearance of protein aggresome and recovery of proteostasis are required. We revealed that the ability to recruit functional DnaK-ClpB machineries, which facilitate protein disaggregation in an ATP-dependent manner, determines the lag time for bacterial regrowth. Better understanding of the key factors regulating bacterial regrowth after surviving antibiotic attack could lead to new therapeutic strategies for combating bacterial antibiotic tolerance. PMID- 30472192 TI - Comparative Analysis of Droplet-Based Ultra-High-Throughput Single-Cell RNA-Seq Systems. AB - Since its establishment in 2009, single-cell RNA sequencing (RNA-seq) has been a major driver behind progress in biomedical research. In developmental biology and stem cell studies, the ability to profile single cells confers particular benefits. Although most studies still focus on individual tissues or organs, the recent development of ultra-high-throughput single-cell RNA-seq has demonstrated potential power in characterizing more complex systems or even the entire body. However, although multiple ultra-high-throughput single-cell RNA-seq systems have attracted attention, no systematic comparison of these systems has been performed. Here, with the same cell line and bioinformatics pipeline, we developed directly comparable datasets for each of three widely used droplet based ultra-high-throughput single-cell RNA-seq systems, inDrop, Drop-seq, and 10X Genomics Chromium. Although each system is capable of profiling single-cell transcriptomes, their detailed comparison revealed the distinguishing features and suitable applications for each system. PMID- 30472194 TI - The effect of physical strain on breeders patients with obstructive sleep apnea syndrome. AB - AIM: The purpose of this study was to investigate the cardiopulmonary exercise testing (CPET) in breeders patients with obstructive sleep apnea syndrome (OSAS). METHOD: Thirty-two male participants (Age: 42.2 +/- 7.3yrs, BMI: 29.5 +/- 2.2 kg/m2) underwent full overnight polysomnography (PSG) and were divided into two groups (OSAS group: n = 20 vs. Control group: n = 12). 72-hours after the PSG study, they were subjected to CPET. The Independent t-test was used to measure the differences between the groups. Pearson's correlation coefficient was used among the parameters of CPET and PSG study. RESULTS: The results showed difference between the groups (OSAS vs. Control) during CPET in end-tidal, CO2 pressure in the peak of the exercise (38.7 +/- 3.0 vs. 35.4 +/- 5.5 mmHg, p = 0.031) and mean arterial pressure (122.7 +/- 10.6 vs. 113.7 +/- 11.8 mmHg, p = 0.035). Correlation results showed differences between the physical strain and the polysomnography study in physical strain parameters "walking duration per day with the herd" and oxygen desaturation index during sleep (r = 0.370, p = 0.037) and minimum oxygen saturation during sleep (r=-.374, p = 0.035), in the parameter "milking duration" and apnea (r = 0.392, p = 0.048), AHI (r = 0.374, p = 0.035) and oxygen desaturation index during sleep (r = 0.434, p = 0.013). The physical strain parameter "working hours per day" wasn't related to any parameter of the polysomnography study. CONCLUSION: The daily physical activity may have a protective role during the course of the disease in patients with OSAS. PMID- 30472193 TI - Transcriptome Landscape of Human Folliculogenesis Reveals Oocyte and Granulosa Cell Interactions. AB - The dynamic transcriptional regulation and interactions of human germlines and surrounding somatic cells during folliculogenesis remain unknown. Using RNA sequencing (RNA-seq) analysis of human oocytes and corresponding granulosa cells (GCs) spanning five follicular stages, we revealed unique features in transcriptional machinery, transcription factor networks, and reciprocal interactions in human oocytes and GCs that displayed developmental-stage-specific expression patterns. Notably, we identified specific gene signatures of two cell types in particular developmental stage that may reflect developmental competency and ovarian reserve. Additionally, we uncovered key pathways that may concert germline-somatic interactions and drive the transition of primordial-to-primary follicle, which represents follicle activation. Thus, our work provides key insights into the crucial features of the transcriptional regulation in the stepwise folliculogenesis and offers important clues for improving follicle recruitment in vivo and restoring fully competent oocytes in vitro. PMID- 30472195 TI - Accuracy and reliability of mandibular digital model registration with use of the mucogingival junction as the reference. AB - OBJECTIVE: The aim of the study was to validate a method of mandibular digital model (DM) registration, acquired from an intraoral scanner, compared with high resolution voxel-based cone beam computed tomography (CBCT) registration with use of the mucogingival junction as the reference. STUDY DESIGN: Pre- and post treatment CBCT and DM images from 12 adults were randomly selected from an initial sample of 40 patients who had undergone orthodontic treatment. The DM registration was performed in 6 steps: (1) construction of 3-dimensional (3-D) volumetric label maps of CBCT scans, (2) voxel-based registration of CBCT scans, (3) prelabeling of CBCT images, (4) approximation and registration of DM models to the corresponding CBCT models, (5) mucogingival-junction registration of pretreatment and post-treatment DM images, and (6) measurements. The Mann-Whitney U test was used to calculate the significance of differences between the CBCT and DM registrations. The intraclass correlation coefficient (ICC) was performed to assess reproducibility of the registration method. RESULTS: When registered CBCT models and registered DM models were compared, no statistically significant differences in the measurements were found (right-left P = .267; anterior posterior P = .238; superior-inferior P = .384; and 3-D P = .076). ICC showed excellent intra- and inter-rater correlation (ICC > 0.90). CONCLUSIONS: The method of DM registration of the mandible with use of the mucogingival junction as the reference is accurate, reliable, and reproducible. PMID- 30472196 TI - Low N-terminal pro-brain natriuretic peptide levels are associated with non alcoholic fatty liver disease in patients with type 2 diabetes. AB - AIM: Natriuretic peptides (NPs) have emerged as important regulators of lipid metabolism. Reduced levels of NPs are reported in obesity and in patients with type 2 diabetes (T2D). This NP deficiency may affect their ectopic fat distribution and lead to high risk of non-alcoholic fatty liver disease (NAFLD). METHODS: In this cross-sectional study, the association between N-terminal pro-B type natriuretic peptide (NT-proBNP) and liver fat content was quantified using 1H-magnetic resonance spectroscopy in 120 patients with T2D. RESULTS: NAFLD (defined as liver fat content >= 5.6%) was found in 57 (48%) of the T2D patients, who also had significantly lower NT-proBNP (P = 0.002) levels compared with patients without NAFLD, but did not differ as regards the presence of cardiovascular disease (CVD) or in kidney function. After adjusting for potential confounders (age, gender, HbA1c, BMI, HOMA2-IR, CVD, eGFR), the odds ratio for the presence of NAFLD was increased by 2.9 (P = 0.048) for NT-proBNP levels < 45 ng/L. In a multivariable linear regression model, the relationship with NT-proBNP was further analyzed as a continuous variable, and was independently and inversely associated with increasing liver fat content after full adjustment (P = 0.031). CONCLUSION: Reduced plasma NT-proBNP levels are independently associated with high liver fat content in patients with T2D. The present study suggests that NP deficiency may play a role in the development of NAFLD in T2D. PMID- 30472197 TI - Temporality in chronic diseases and adherence to long-term therapies: From philosophy to science and back. AB - This narrative review exhibits the construction and validation of a hypothesis to explain how treatment non-adherence in people with chronic disease, a major issue in contemporary medicine, occurs. I propose that non-adherence to long-term therapies is at least in part due to failure to prioritize the future, which is caused by a condition I dub disruption in time projection. This article gives the rationale for this hypothesis, which is largely grounded on philosophical arguments. Then, it demonstrates the plausibility of the hypothesis: on the one hand, it is consistent with certain epidemiological data found in the literature. On the other, it is possible to predict the underlying mechanisms of this lack of prioritization from recent achievements of neuro-economics and neuroscience. Next, it reviews empirical data that provide an experimental verification for this explanatory hypothesis. Finally, a general evolutionary and philosophical meaning for adherence is proposed, considering the advantages of its preconditions, namely, patience and foresight. PMID- 30472198 TI - Peritoneal carcinomatosis in colorectal cancer: Defining predictive factors for successful cytoreductive surgery and hyperthermic intraperitoneal chemotherapy - A pilot study. AB - BACKGROUND: Peritoneal carcinomatosis originating from colorectal cancer (PC-CRC) carries a dismal prognosis. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) have been offered to those patients with substantial health and economic burden, nevertheless not all patients are fitting this treatment modality and outcome is generally still poor. OBJECTIVE: To elicit predictive factors associated with the success of CRS and HIPEC in PC-CRC patients. PATIENTS AND METHODS: This is a pilot study including 30 consecutive patients with PC-CRC; 20 of them (66.7%) presented with metachronous peritoneal disease. All patients were planned for CRS and HIPEC with Mitomycin-C after receiving preoperative systemic chemotherapy for 3 months. RESULTS: On exploration, CRS and HIPEC were successful in 17 patients (56.6%) who had completeness of cytoreduction score 0-1 (CC-0/1), whereas failure (CC-2) was encountered in 13 patients (43.3%). The presence of ascites, extensive peritoneal disease (PCI > 20) was significantly correlated with failure to achieve CRS and HIPEC (p < 0.001); also, the primary rectal site showed a trend towards significance (p = 0.08). The cumulative overall survival (OS) and progression free survival (PFS) at 2 years were 66.6 and 62.6%, respectively. Patients who achieved CC-0/1 had significantly prolonged OS compared to CC-2 (p < 0.001). On multivariate analysis, the CC score and the original site were independent prognostic factors for OS (p = 0.04 and 0.02, respectively). CONCLUSION: In patients with PC-CRC, malignant ascites and PCI > 20 are poor prognostic factors associated with failure to accomplish CRS with consequent poor survival. PMID- 30472199 TI - The prognostic impact of loss of chromosome 7 material detected by fluorescence in situ hybridization (FISH) in myeloid malignancies. AB - BACKGROUND: Monosomy 7 (-7) or deletion in its long arm [del(7q)] is among the most common chromosomal abnormalities in myeloid malignancies. There are prognostic variations between -7 and del(7q) in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). AIM: To describe the clinical characteristics, response to treatment, and survival of patients with primary AML and MDS having 7 or del(7q) detected by fluorescence in situ hybridization (FISH). PATIENTS AND METHODS: The study was conducted on 53 patients with primary AML and MDS. They were tested for chromosome 7 abnormality using FISH technique. RESULTS: Thirty one patients had chromosome 7 abnormality and 22 did not. Lower complete remission and higher death rates were observed in patients with -7 (47.6% and 62%, respectively) when compared to patients with del(7q) (70% and 40%, respectively) with no significant difference (p = 0.218 and 0.101, respectively). The median overall survival (OS) of patients with -7, del(7q) and normal chromosome 7 were 32.0, 43.0 and 50.0 months, respectively, with significant statistical difference (p = 0.001). This difference was evident between patients with -7 and those with normal chromosome 7 (p = 0.001), and less evident between patients with -7 and those with del(7q) (p = 0.021). CONCLUSION: Chromosome 7 analysis has clear impact on the outcome of myeloid malignancies. The prognostic variations between -7 and del(7q) is attributed to multiple factors. Cases with del(7q) have better outcome than cases with -7. FISH provides a powerful tool for detecting and monitoring patients with chromosome 7 abnormalities. PMID- 30472200 TI - Prenatal propofol exposure downregulates NMDA receptor expression and causes cognitive and emotional disorders in rats. AB - The impacts of prenatal propofol on cognition and emotion of offspring remain elusive. In the present study, pregnant rats in the second trimester were anesthetized with propofol. Neuronal apoptosis and proliferation was determined in fetuses and postnatal rats by detecting caspase-3 and BrdU expression. The offspring were subjected to several behavior tests. Then the pyramidal neurons in hippocampus and the expression of NR1, NR2A, and NR2B subunits of NMDA receptor and PSD-95 in frontal cortex were examined. Propofol exposure significantly increased the number of caspase-3+ cells in lateral ganglionic eminence and hippocampus compared with control group (P < 0.001). The number of BrdU+ cells in the subventricular zone (SVZ) and dentate gyrus (DG) was also reduced in propofol group (P < 0.001). In propofol group, the swimming distance and time in the quadrant were shorter,but longer out of the quadrant.The number of escapes was less than those of the control group. Prenatal propofol exposure also decreased the sucrose preference, reduced the numbers of grooming, crossing, and rearing of the pups, and increased the fecal particle numbers and immobility time (P < 0.05). There were fewer and shorter dendritic branches of pyramidal neurons in the CA1 and CA3 of offspring. The expression of NR1, NR2A, NR2B, and PSD-95 in the frontal cortex was downregulated by propofol exposure (P < 0.001). These data suggested that prenatal propofol exposure impairs neuronal development, which may be associated with depression- and anxiety-like behaviors and cognitive disorders in offspring. PMID- 30472201 TI - Hydralazine protects against renal ischemia-reperfusion injury in rats. AB - In this study, we investigated whether hydralazine could reduce renal ischemia and reperfusion (I/R) injury in rats. Renal I/R was induced by a 70-min occlusion of the bilateral renal arteries and a 24-h reperfusion, which was confirmed by the increased the mortality, the levels of blood urea nitrogen (BUN), blood creatinine (Cr), renal tissue NO and the visible histological damage of the kidneys. Apoptosis was evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) staining. Furthermore, the serum levels of malonaldehyde (MDA), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) were significantly elevated in renal I/R group, while the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) levels were suppressed. However, intragastric pretreatment with hydralazine at doses of 7.5-30 mg/kg before renal I/R significantly limited the increase in mortality, BUN, Cr, oxidative stress, inflammatory factors, histological damage and apoptosis in the kidneys. In addition, hydralazine also increased p-AKT, Bcl-2 expression and decreased iNOS, Bax, cleaved caspase-3 expression in the kidneys. In conclusion, hydralazine reduced renal I/R injury probably via inhibiting NO production by iNOS/NO pathway, inhibiting oxidative stress, inflammatory response and apoptosis by a mitochondrial-dependent pathway. PMID- 30472202 TI - AS2762900-00, a potent anti-human IL-23 receptor monoclonal antibody, prevents epidermal hyperplasia in a psoriatic human skin xenograft model. AB - Interleukin (IL)-23 is thought to be critical in the pathogenesis of psoriasis, and anti-IL-23 monoclonal antibodies (mAbs) have been approved for the treatment of psoriasis. We speculated that an anti-IL-23 receptor mAb might have greater efficacy than an anti-IL-23 mAb in the treatment of local inflamed lesions with high IL-23 levels. We previously generated an anti-human IL-23 receptor mAb, AS2762900-00, which potently blocked IL-23-induced cell proliferation, regardless of the concentration of IL-23. Here, we evaluated the therapeutic potential of AS2762900-00 in the treatment of psoriasis. Compared with untreated control, AS2762900-00 significantly reduced the epidermal thickness of lesions in a clinically relevant psoriatic human skin xenograft model. The expression of inflammatory genes including genes downstream of IL-23 signaling in the lesion tended to be lower in the AS2762900-00 group than the untreated group, suggesting that the inhibitory effects of AS2762900-00 in the psoriatic human skin xenograft model might occur via blockade of IL-23 signaling pathways. Further, AS2762900-00 showed an inhibitory effect on signal transducer and activator of transcription 3 (STAT3) phosphorylation as a downstream signal of IL-23 receptor activation in whole blood from patients with psoriasis. We also confirmed that AS2762900-00 inhibited IL-23-induced STAT3 phosphorylation in a concentration-dependent manner using whole blood from healthy donors. These data suggest that AS2762900-00 is a promising drug candidate for the treatment of psoriasis. In addition, STAT3 phosphorylation in whole blood may be a useful biomarker for the evaluation of the pharmacodynamic effects of AS2762900-00 in healthy volunteers in clinical development. PMID- 30472203 TI - LncRNA XIST promotes the epithelial to mesenchymal transition of retinoblastoma via sponging miR-101. AB - Accumulating evidence demonstrated that abnormal expression of long non-coding RNAs (lncRNAs) was closely associated with cancer development including retinoblastoma (RB). LncRNA X inactive specific transcript (XIST) has been found to function as an oncogene or a tumor suppressor in several cancers. However, the role and underlying mechanism of XIST in RB have not been clarified. The expression of XIST, microRNA (miR)- 101, zinc finger E-box binding homeobox (ZEB) 1, and ZEB2 was detected in human RB tissues and cell lines. The effects of XIST on the proliferation, migration, invasion, epithelial to mesenchymal transition (EMT), and apoptosis of RB cells were evaluated after downregulation of XIST. Furthermore, the mechanism of XIST was mainly focused on miR-101/ZEB1 or ZEB2 signaling. We found the expression of XIST, ZEB1 and ZEB2 was increased, whereas miR-101 was reduced in RB tissues and cells. Knockdown of XIST significantly suppressed the proliferation, migration, invasion and EMT, but promoted the apoptosis and caspase-3 activity. Moreover, we found that XIST functioned as a competing endogenous RNA (ceRNA) for miR-101 to regulate the de-repression of its endogenous targets ZEB1 and ZEB2. In conclusion, these findings suggest that XIST may facilitate the progression of RB through acting as a ceRNA for miR-101 to mediate the expression of ZEB1 and ZEB2. This may provide novel therapeutic options for RB. PMID- 30472204 TI - Identification and validation of potential target genes in papillary thyroid cancer. AB - Thyroid cancer (TC) is one of the most common endocrine malignancies, and the incidence of TC has almost tripled over the past three decades. This increase may partially own to overdiagnosis and approximately 15-30% of cytological indeterminate thyroid nodules cannot be evaluated by means of fine-needle aspiration. The present study aimed to identify potential crucial genes of PTC and provide new sights into improving the diagnosis of thyroid lesions for future study. We adopted an integrated analysis of Gene expression profiles of PTC patients and adjacent normal controls and data from The Cancer Genome Atlas databases (TCGA). The differentially expressed genes (DEGs) were screened using the Limma package in R software. Connectivity Map (CMap) was used to predict potential drugs for PTC. STRING and Cytoscape software were employed to perform GO, KEGG pathway enrichment analysis and module analysis for DEGs. RT-qPCR was used to validate hub genes screened using module analysis. A total of 218 DEGs were screened, including 55 down-regulated and 163 up-regulated DEGs. GO analysis showed that these DEGs were primary enriched in cell adhesion, extracellular region and glycosaminoglycan binding. KEGG pathway analysis revealed that DEGs primarily participated in ECM-receptor interaction. PPI network and module analysis identified seven-hub genes, including FN1, SERPINA1, ECM1, MMRN1, PROS1, CFD, TIMP1. RT-qPCR results validated that the expression levels of seven-hub genes were consistent with the bioinformatics analysis. These findings have identified seven-hub genes which may helpful for the development of gene panel for thyroid nodules diagnosis. PMID- 30472205 TI - Amputation neuroma of the vagal nerve simulating celiac lymph node enlargement: diagnosis with EUS-FNA. PMID- 30472206 TI - An uncommon diagnosis done by colonoscopy. PMID- 30472207 TI - Integrative Analysis of Zika Virus Genome RNA Structure Reveals Critical Determinants of Viral Infectivity. AB - Zika virus (ZIKV) strains can be classified into the ancestral African and contemporary Asian lineages, with the latter responsible for recent epidemics associated with neurological conditions. To understand how Asian strains lead to exacerbated disease, a crucial step is identifying genomic variations that affect infectivity and pathogenicity. Here we use two high-throughput sequencing approaches to assess RNA secondary structures and intramolecular RNA-RNA interactions in vivo for the RNA genomes of Asian and African ZIKV lineages. Our analysis identified functional RNA structural elements and a functional long range intramolecular interaction specific for the Asian epidemic strains. Mutants that disrupt this extended RNA interaction between the 5' UTR and the E protein coding region reduce virus infectivity, which is partially rescued with compensatory mutants, restoring this RNA-RNA interaction. These findings illuminate the structural basis of ZIKV regulation and provide a resource for the discovery of RNA structural elements important for ZIKV infection. PMID- 30472208 TI - FAF1 Regulates Antiviral Immunity by Inhibiting MAVS but Is Antagonized by Phosphorylation upon Viral Infection. AB - Mitochondrial antiviral signaling protein (MAVS) is an adaptor of the innate immune receptor retinoic acid-inducible gene 1 (RIG-I) that links recognition of viral RNA to antiviral signaling. Upon interacting with RIG-I, MAVS undergoes lysine 63-linked poly-ubiquitination by the E3 ligase TRIM31 and subsequently aggregates to activate downstream signaling effectors. We find that the scaffold protein FAF1 forms aggregates that negatively regulate MAVS. FAF1 antagonizes the poly-ubiquitination and aggregation of MAVS by competing with TRIM31 for MAVS association. FAF1 knockout mice are more resistant to RNA virus infection, and FAF1 deficiency in myeloid cells results in enhanced innate signaling and reduced viral load and morbidity in vivo. Upon virus infection, the kinase IKKE directly phosphorylates FAF1 at Ser556 and triggers FAF1 de-aggregation. Moreover, Ser556 phosphorylation promotes FAF1 lysosomal degradation, consequently relieving FAF1 dependent suppression of MAVS. These findings establish FAF1 as a modulator of MAVS and uncover mechanisms that regulate FAF1 to insure timely activation of antiviral defense. PMID- 30472210 TI - Mitotic Catastrophe Causes Podocyte Loss in the Urine of Human Diabetics. AB - Mitotic catastrophe (MC) is a major cause of podocyte loss in vitro and in vivo. We evaluated urine samples (a total of 184 from diabetic patients n=41) from diabetic patients and determined the presence of podocytes in the urine and studied their characteristics, specifically asking whether apoptosis versus MC is present. We also evaluated diabetic glomeruli in renal biopsies by electron microscopy (n=54). A battery of stains including anti-podocalyxin (PCX) were used. PCX+podocytes (PCX+podo) showed nuclear morphologies such as ai) mononucleated, normal shape (8.7%), ii) large and abnormal shape (3.8 %), iii) multinucleated with or without micronucleoli (31.2%), iv), mitotic spindles (8.2%), v) single nucleus and denucleation combined (10.3%), and vi) denucleation only (37.0%). Large size/abnormal shape, multinucleation, mitotic spindles, and a combination of single nucleus and denucleation were considered as features of MC (53.5%). Dual staining of PCX+podo were positive for Glepp 1 (50%), whereas none of PCX+podo were positive for nephrin, podocin, leucocyte, and parietal epithelial cell markers (cytokeratin 8), annexin V, cleaved caspase-3, and Tunel. Ten percent of PCX+podo were positive for phosphorylated vimentin. Electron microscopy identified cellular and nuclear podocyte changes characteristic of The majority of urine podocytes in diabetic patients show MC and not apoptosis. This non-invasive approach may be clinically useful in determining progressive diabetic nephropathy or response to therapeutic intervention. PMID- 30472209 TI - Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and Visual Impairment. AB - Farber Disease (FD) is a debilitating lysosomal storage disorder characterized by severe inflammation and neurodegeneration. FD is caused by mutations in the ASAH1 gene resulting in deficient acid ceramidase (ACDase) activity. Patients with ACDase deficiency exhibit a broad clinical spectrum. In classical cases, patients develop hepatosplenomegaly, nervous system involvement, and childhood mortality. Ocular manifestations include decreased vision, a grayish appearance to the retina with a cherry red spot, and nystagmus. That said, the full effect of ACDase deficiency on the visual system has not been studied in detail. We previously developed a mouse model that is orthologous for a known patient mutation in Asah1 that recapitulates human FD. Herein we report evidence of a severe ocular pathology in Asah1P361R/P361R mice. Asah1P361R/P361R mice exhibit progressive retinal and optic nerve pathology. Through non-invasive ocular imaging and histopathological analyses of these Asah1P361R/P361R animals, we revealed progressive inflammation, the presence of retinal dysplasia, and significant storage pathology in various cell types in both the retina and optic nerves. Lipidomic analyses of retinal tissues revealed an abnormal accumulation of ceramides and other sphingolipids. Electroretinograms and behavioral tests showed decreased retinal and visual responses. Taken together, these data suggest that ACDase deficiency leads to sphingolipid imbalance, inflammation, dysmorphic retinal and optic nerve pathology, and severe visual impairment. PMID- 30472211 TI - Mild traumatic brain injury in mice beneficially alters lung NK1R and structural protein expression to enhance survival after Pseudomonas aeruginosa infection. AB - Mild traumatic brain injury (mTBI) in a murine model increases survival to a bacterial pulmonary challenge compared to blunt tail trauma (TT). We hypothesize Substance P and its receptor, the neurokinin 1 receptor (NK1R; official name TACR1), play a role in the increased survival of mTBI mice. Mice were subjected to mTBI or TT and 48 hours post-trauma, the levels of NK1R mRNA and protein were significantly up-regulated in mTBI lungs. Examination of the lung 48 hours post injury by microarray showed significant differences in the expression of 433 gene sets between groups, most notably genes related to intercellular proteins. Despite down-regulated gene expression of connective proteins, the presence of an intact pulmonary vasculature was supported by normal histology and BAL protein levels. To determine if these mTBI-induced lung changes benefited in vivo responses, two chemotactic stimuli (a CXCL1 chemokine and a live Pseudomonas aeruginosa infection) were administered 48 hours post-trauma. For both stimuli, mTBI mice recruited more neutrophils to the lung four hours post-instillation (KC: mTBI = 6.3 +/- 1.3 vs TT = 3.3 +/- .7 neutrophils/mL; Psd: mTBI = 9.4 +/- 1.4 vs TT = 5.3 +/- 1.1 neutrophils/mL). This study demonstrates that the downstream consequences of mTBI on lung NK1R levels and connective protein expression enhance neutrophil recruitment to a stimulus which may contribute to increased survival. PMID- 30472212 TI - Dietary phytochemicals in the regulation of epithelial to mesenchymal transition and associated enzymes: A promising anticancer therapeutic approach. AB - Epithelial to mesenchymal transition (EMT) is a biological phenomenon that plays a primordial role for initiation of metastasis. It renders cancer cells with increased self-renewal and tumor-initiating capabilities and exacerbated resistance to apoptosis and chemotherapy. Hence, regulation of EMT stands out to be an important strategy in controlling the behavior of malignant cells. Despite the enormous amount of preclinical data on the implication of EMT in cancer progression, there is still lack of routine clinical translation at therapeutic levels. The need of EMT-modulating drugs with high efficacy and low cytotoxicity has led to studies involving the evaluation of the efficacy of a plethora of various classes of phytochemicals present in dietary sources of fruits and vegetables. This review summarizes the role of these different classes of phytochemicals, their natural/synthetic analogs, and their nano-formulations in regulation of EMT in various preclinical models through attenuation of primary signaling pathways. Numerous proteins, transcription factors and enzymes targeted by various classes of phytochemicals in repression of EMT has been presented in this review. Additionally, we have critically analyzed the existing literature and provided views on new direction for accelerating the discovery of novel drug candidates which could be cautiously administered without concomitant effects. PMID- 30472213 TI - Detection of RET rearrangements in papillary thyroid carcinoma using RT-PCR and FISH techniques - A molecular and clinical analysis. AB - INTRODUCTION: Oncogenic BRAF and RAS mutations as well as multiple known (and yet unknown) RET fusion oncogenes comprise the majority of causative molecular alterations in papillary thyroid carcinoma (PTC). Apparently "mutation-negative" PTCs encompass a heterogenous group impeding analysis of prognostic significance of underlying genetics. MATERIAL AND METHODS: BRAF wild type PTC tissue of 56 patients was analyzed using two established methods: hybrid-specific RT-PCR for the predominant rearrangement RET/PTC1 and fluorescent in situ hybridization (FISH). Clinical features of the cases with and without RET rearrangement were compared (patient age, gender, tumor size, focality, lymph node affection, and iodine avidity). RESULTS: RT-PCR revealed RET/PTC1 rearrangements in five of 56 tumors (9%). FISH confirmed these, and identified four additional RET rearrangements (9/56; 16%). Loss of the iodine avidity only occurred in cases of RET/PTC hybrids (7/9 tumors), but not in RET/PTC-negative PTCs (0/41 tumors with available uptake information; p = 0.029). The risk to develop lymph node metastases was eight times higher in presence of RET rearrangements (p = 0.010). CONCLUSIONS: FISH analysis, in contrast to hybrid-specific RT-PCR, revealed infrequent and unknown RET fusion genes. The presence of RET rearrangements was associated with a significantly elevated risk to develop iodine refractory disease and lymph node metastases. Of note, significant clinical discrimination was only achievable when taking the FISH results into account; differences would have been missed when using the RT-PCR method only. Increasing evidence of the clinical impact of RET/PTC-positivity may influence the decision on the extent of surgical resection, especially on lymph node dissection, in PTCs. PMID- 30472214 TI - The number and ratio of positive lymph nodes are independent prognostic factors for patients with major salivary gland cancer: Results from the surveillance, epidemiology, and End Results dataset. AB - INTRODUCTION: To investigate whether the positive lymph node number (PLNN) and positive lymph node ratio (PLNR) could predict the prognosis of patients with major salivary gland cancer (MSGC) and to identify the optimal cutoff points for these variables that stratify patients according to their risk of survival. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify all patients with MSGC between 1988 and 2014. A logistic regression analysis was carried out to evaluate the risk factors for lymph node metastasis (LNM) in MSGC. The X-tile program was used to identify the cutoff values for the PLNN and PLNR in MSGC patients with LNM. Cox proportional hazards regression models were performed to identify the predictors of cancer-specific survival (CSS). RESULTS: In the SEER database, 8668 eligible patients were identified and 3046 of them had LNM. The logistic regression analysis indicated that older age, male sex, larger tumor size, higher grade, tumor extension and high-risk pathology were associated with LNM. The X-tile program showed that a PLNN>4 and a PLNR>0.15 were prognostic indicators of CSS. A multivariable analysis indicated that, after the factors that might potentially affect the prognosis were adjusted for, the PLNN and PLNR were still associated with CSS. CONCLUSIONS: Our Results demonstrated that the PLNN and PLNR were independent prognostic indicators for MSGC patients with lymph node metastasis. PMID- 30472215 TI - Testing a behavioral intervention to improve adherence to adjuvant endocrine therapy (AET). AB - Adjuvant endocrine therapy (AET) is used to prevent recurrence and reduce mortality for women with hormone receptor positive breast cancer. Poor adherence to AET is a significant problem and contributes to increased medical costs and mortality. A variety of problematic symptoms associated with AET are related to non-adherence and early discontinuation of treatment. The goal of this study is to test a novel, telephone-based coping skills training that teaches patients adherence skills and techniques for coping with problematic symptoms (CST-AET). Adherence to AET will be assessed in real-time for 18 months using wireless smart pill bottles. Symptom interference (i.e., pain, vasomotor symptoms, sleep problems, vaginal dryness) and cost-effectiveness of the intervention protocol will be examined as secondary outcomes. Participants (N = 400) will be recruited from a tertiary care medical center or community clinics in medically underserved or rural areas. Participants will be randomized to receive CST-AET or a general health education intervention (comparison condition). CST-AET includes ten nurse delivered calls delivered over 6 months. CST-AET provides systematic training in coping skills for managing symptoms that interfere with adherence. Interactive voice messaging provides reinforcement for skills use and adherence that is tailored based on real-time adherence data from the wireless smart pill bottles. Given the high rates of non-adherence and recent recommendations that women remain on AET for 10 years, we describe a timely trial. If effective, the CST-AET protocol may not only reduce the burden of AET use but also lead to cost effective changes in clinical care and improve breast cancer outcomes. Trials registration: ClinicalTrials.gov, NCT02707471, registered 3/3/2016. PMID- 30472216 TI - MRI-based evaluation of structural degeneration in the ageing brain: Pathophysiology and assessment. AB - Advances in MRI technology have significantly contributed to our ability to understand the process of brain ageing, allowing us to track and assess changes that occur during normal ageing and neurological conditions. This paper focuses on reviewing structural changes of the ageing brain that are commonly seen using MRI, summarizing the pathophysiology, prevalence, and neuroanatomical distribution of changes including atrophy, lacunes, white matter lesions, and dilated perivascular spaces. We also review the clinically accessible methodology for assessing these MRI-based changes, covering visual rating scales, as well computer-aided and fully automated methods. Subsequently, we consider novel assessment methods designed to evaluate changes across the whole brain, and finally discuss new directions in this field of research. PMID- 30472217 TI - Artificial intelligence for aging and longevity research: Recent advances and perspectives. AB - The applications of modern artificial intelligence (AI) algorithms within the field of aging research offer tremendous opportunities. Aging is an almost universal unifying feature possessed by all living organisms, tissues, and cells. Modern deep learning techniques used to develop age predictors offer new possibilities for formerly incompatible dynamic and static data types. AI biomarkers of aging enable a holistic view of biological processes and allow for novel methods for building causal models-extracting the most important features and identifying biological targets and mechanisms. Recent developments in generative adversarial networks (GANs) and reinforcement learning (RL) permit the generation of diverse synthetic molecular and patient data, identification of novel biological targets, and generation of novel molecular compounds with desired properties and geroprotectors. These novel techniques can be combined into a unified, seamless end-to-end biomarker development, target identification, drug discovery and real world evidence pipeline that may help accelerate and improve pharmaceutical research and development practices. Modern AI is therefore expected to contribute to the credibility and prominence of longevity biotechnology in the healthcare and pharmaceutical industry, and to the convergence of countless areas of research. PMID- 30472219 TI - Protein measurements in venous plasma, earlobe capillary plasma and in plasma stored on filter paper. AB - In this study, levels of inflammatory protein biomarkers in venous plasma, plasma derived from capillary blood from the earlobe, and capillary plasma stored as dried plasma spots (DPS) were compared. Samples from 12 male individuals were assessed with a panel of 92 inflammation-related proteins using multiplex proximity extension assay. Correlations between sample types varied greatly between analytes. A high correlation of rho > 0.8 was observed between capillary plasma and DPS for 32 analytes. At this level of correlation, 13 analytes correlated between venous and capillary plasma and 5 analytes in the comparison of venous blood with DPS. PMID- 30472218 TI - MicroRNAs and Mild Cognitive Impairment: a systematic review. AB - BACKGROUND: The diagnosis of MCI is mainly clinical. Several biomarkers have been proposed, but mostly for research purposes, as they are based on invasive procedures (i.e. CSF). As a consequence, rapid and non-invasive biomarkers are needed to improve diagnosis. The objective of this systematic review is to summarize available evidence on the use of miRNAs as biomarkers in subjects with MCI. METHODS: Relevant literature published up to June 2018 was retrieved searching the databases PubMed, ISI Web of Knowledge and the Cochrane Database. Only studies considering miRNAs and a diagnosis of MCI were included. Data were extracted using a specifically-designed standardized form, and their methodological quality was assessed using QUADAS-2 and QUIPS. RESULTS: Twenty-one studies of 153 retrieved articles met the predefined inclusion/exclusion criteria. Studies included a number of participants ranging from 6 to 330. More than 40 miRNAs resulted as dysregulated, and miR-206 was the only miRNA that was found as differentially expressed in patients with MCI by more than two studies. However, these results have either not yet been confirmed in other independent cohorts, or data are still inconsistent. Inconsistencies among included studies could be due to several issues including the selection of participants, pre analytical and analytical procedures, and statistical analyses. PMID- 30472220 TI - A molecularly imprinted electrochemical nanobiosensor for prostate specific antigen determination. AB - Prostate Specific Antigen (PSA) is a biomarker employed for detection of prostate cancer. An electrochemical nanobiosensor is designed and fabricated using a molecularly imprinted polymer for the simple and fast PSA detection. The imprinted polymer served as a PSA artificial receptor fabricated by electrochemical polymerization of pyrrole on screen-printed gold electrode in the presence of PSA. PSA was a molecular template for the polymer. The fabricated nanobiosensor was evaluated by differential pulse voltammetry and using K3[Fe(CN)6]/K4[Fe(CN)6] as an electrochemical marker. The factors influencing the performance of the sensor including electropolymerization cycle umbers (to control the thickness of the polymer film) and time of PSA binding were optimized to attain the best sensitivity. The binding affinity of the nanobiosensor surface was examined by the Freundlich isotherm with Freundlich constant and exponent of 0.89 ng mL-1 and 10.93, respectively. The nanobiosensor demonstrated a fast rebinding rate and a high capacity of PSA recognition with detection limit of 2.0 pg mL-1. PMID- 30472221 TI - Surface-tailored anti-HER2/neu-solid lipid nanoparticles for site-specific targeting MCF-7 and BT-474 breast cancer cells. AB - CAB51, a compact antibody against human epithelial growth receptor 2 (HER2, ErbB2), has been linked to cationic Solid Lipid Nanoparticles (SLN) via streptavidin-biotin interaction and their targeting potential evaluated against breast cancer cells. The amount of streptavidin and biotinylated antibody was optimised by monitoring the mean complex size (intensity weighed average diameter), polydispersity index and immediate stability in phosphate buffer saline (PBS). The effect on MCF-7 and BT-474 cells was evaluated at concentrations of 0.01 mg/mL and 0.1 mg/mL (counted as solid lipid). Streptavidin adsorption onto SLN surface had no influence on cell viability. Linking the antibody showed a synergistic effect on cell viability at lowest concentration tested (0.01 mg/mL) which was lower than that observed after exposure to SLN alone or antibody alone. At the higher tested concentration (0.1 mg/mL), the observed toxicity was entirely governed by the inherent toxicity of the SLN themselves. Streptavidin adsorption had no effect on accumulation in cells, while the antibody-containing complexes showed clearly increased internalisation in both cell lines. In HER2/neu positive BT-474 higher internalisation was observed than in HER2/neu negative MCF-7. PMID- 30472223 TI - Pifithrin-alpha enhancing anticancer effect of topotecan on p53-expressing cancer cells. AB - p53 is generally known as an effective anti-cancer molecular, but it is lost or mutated in more than 50% of human tumors. It is still a controversial issue whether the activity of p53 really benefits for treating cancers, we wondered what would happen if the endogenous p53 was inhibited before treated with topotecan (TPT) on p53 positive tumor cells. In this study, pifithrin-alpha (PFTalpha), a p53 inhibitor, was used 2 h before treated with TPT on three kinds of cancer cell lines including MCF7, BGC823 and HepG2 cells. The IC50s of TPT for MCF7, BGC823 and HepG2 cells after 10 MUMU PFTalpha pretreated, was 4.8 to 14.4 folds lower than the effect of TPT alone. It was demonstrated that PFTalpha decreases the p-p53 levels and p-p53 activity, not affects p53 expression in p53 positive tumor cells. PFTalpha enhanced anticancer effect of TPT on cells was found mainly by two ways. Firstly, it increased the TPT accumulation in cells and nucleus and promoted the inhibition of TPT on activity of Topo I, and induced more DNA damage. Secondly, PFTalpha decreased formation of p53/mdm2 complex responsible for p53 degradation by inhibiting the protein expression of mdm2, so p53 degradation was decreased in cytoplasm and p53 accumulation was increased in nucleus, which induced more cells undergo apoptosis. So, the crosstalk between p53 and TPT played a pivotal role for enhancing anticancer effects of PFTalpha and TPT on p53 positive cancer cells. These findings provide a new idea for drug design and combination chemotherapy of cancers. PMID- 30472222 TI - The effect of thiamine-coating nanoparticles on their biodistribution and fate following oral administration. AB - Thiamine-coated nanoparticles were prepared by two different preparative methods and evaluated to compare their mucus-penetrating properties and fate in vivo. The first method of preparation consisted of surface modification of freshly poly(anhydride) nanoparticles (NP) by simple incubation with thiamine (T-NPA). The second procedure focused on the preparation and characterization of a new polymeric conjugate between the poly(anhydride) backbone and thiamine prior the nanoparticle formation (T-NPB). The resulting nanoparticles displayed comparable sizes (about 200 nm) and slightly negative surface charges. For T-NPA, the amount of thiamine associated to the surface of the nanoparticles was 15 MUg/mg. For in vivo studies, nanoparticles were labelled with either 99mTc or Lumogen(r) Red. T NPA and T-NPB moved faster from the stomach to the small intestine than naked nanoparticles. Two hours post-administration, for T-NPA and T-NPB, >30% of the given dose was found in close contact with the intestinal mucosa, compared with a 13.5% for NP. Interestingly, both types of thiamine-coated nanoparticles showed a greater ability to cross the mucus layer and interact with the surface of the intestinal epithelium than NP, which remained adhered in the mucus layer. Four hours post-administration, around 35% of T-NPA and T-NPB were localized in the ileum of animals. Overall, both preparative processes yielded thiamine decorated carriers with similar physico-chemical and biodistribution properties, increasing the versatility of these nanocarriers as oral delivery systems for a number of biologically active compounds. PMID- 30472224 TI - Repeatability of Regional Lung Ventilation Quantification Using Fluorinated (19F) Gas Magnetic Resonance Imaging. AB - RATIONALE AND OBJECTIVES: To assess the repeatability of global and regional lung ventilation quantification in both healthy subjects and patients with chronic obstructive pulmonary disease (COPD) using fluorinated (19F) gas washout magnetic resonance (MR) imaging in free breathing. MATERIAL AND METHODS: In this prospective institutional review board-approved study, 12 healthy nonsmokers and eight COPD patients were examined with 19F dynamic gas washout MR imaging in free breathing and with lung function testing. Measurements were repeated within 2 weeks. Lung ventilation was quantified using 19F gas washout time. Repeatability was analyzed for the total lung and on a regional basis using the coefficient of variation (COV) and Bland-Altman plots. RESULTS: In healthy subjects and COPD patients, a good repeatability was found for lung ventilation quantification using dynamic 19F gas washout MR imaging on a global (COV < 8%) and regional (COV < 15%) level. Gas washout time was significantly increased in the COPD group compared to the healthy subjects. CONCLUSION: 19F gas washout MR imaging provides a good repeatability of lung ventilation quantification and appears to be sensitive to early changes of regional lung function alterations such as normal aging. PMID- 30472225 TI - New and Old Biomarkers for Diagnosis and Management of Chronic HBV Infection. AB - Tests to detect the presence and activity of hepatitis B virus (HBV) are the cornerstones of diagnosis and management. Assays that detect or measure serum levels of HB surface antigen, HB surface antibody, and HB core antibody are used to identify patients with exposure to HBV, whereas other tests provide information on the level of virus replication, the presence of specific variants, and presence of virus reservoirs. Newer diagnostic tests, used only in research settings so far, aim to quantify levels of intrahepatic HBV replication. Other tests have been developed to detect HBV infection in resource-limited settings. We review point of care tests (essential in global screening efforts), standard diagnostic tests used in routine clinical management, and newer tests that might be used in clinical trials of agents designed to cure HBV infection. PMID- 30472226 TI - Beyond Hospital Rankings: How Do We Measure Academic Strength in Gastroenterology/Hepatology Divisions? PMID- 30472227 TI - High Mucosal Plasma Cell Numbers and Low Serum TREM-1 Levels May Predict Nonresponsiveness to Anti-Tumor Necrosis Factor Therapy in Inflammatory Bowel Disease. PMID- 30472228 TI - Reply. PMID- 30472229 TI - Reply. PMID- 30472230 TI - How to Approach a Patient With Refractory or Recurrent Benign Esophageal Stricture. PMID- 30472231 TI - Atg5 in Pancreatic Tumorigenesis and Progression: Dosage Matters. PMID- 30472232 TI - Reply. PMID- 30472233 TI - Thiopurine Therapy in Inflammatory Bowel Diseases: Making New Friends Should Not Mean Losing Old Ones. PMID- 30472234 TI - Reply. PMID- 30472235 TI - Histone Demethylase JMJD2D Interacts with Beta-catenin to Induce Transcription and Activate Colorectal Cancer Cell Proliferation and Tumor Growth in Mice. AB - BACKGROUND & AIMS: Wnt signaling contributes to development of colorectal cancer (CRC). We studied interactions between lysine demethylase 4D (KDM4D or JMJD2D) and beta-catenin, a mediator of Wnt signaling, in CRC cell lines and the effects on tumor formation in mice. METHODS: We obtained colorectal tumor specimens and surrounding non-tumor colon tissues (controls) from patients undergoing surgery in China; levels of JMJD2D were measured by immunohistochemical or immunoblot analysis. JMJD2D expression was knocked down in CRC (CT26, HCT116, and SW480 cells) using small hairpin RNAs and cells were analyzed in viability, flow cytometry, colony formation, and transwell migration and invasion assays. Cells were also grown as tumor xenografts in nude mice or injected into tail veins or spleens of mice and metastases were measured. We also performed promoter activity, co-immunoprecipitation, and chromatin immunoprecipitation assays. We also performed studies with Apcmin/+ and JMJD2D-knockout mice; these mice were crossed and colorectal tumor formation in offspring (Apcmin/+;Jmjd2d+/+ and Apcmin/+;Jmjd2d-/-) was analyzed. JMJD2D-knockout and wild-type (control) mice were given azoxymethane followed by dextran sodium sulfate (DSS) to induce colitis-associated colorectal cancer; some mice were given the JMJD2D inhibitor 5 c-8HQ or vehicle to examine the effects of 5-c-8HQ on intestinal tumor formation. RESULTS: Levels of JMJD2D were significantly higher in human colorectal tumors than in control tissues and correlated with levels of proliferating cell nuclear antigen. JMJD2D knockdown reduced CRC cell proliferation, migration, and invasion as well as growth of xenograft tumors and formation of metastases in mice. JMJD2D was required for expression of beta-catenin in CRC cell lines; ectopic expression of JMJD2D increased the promoter activities of genes regulated by beta-catenin (MYC, cyclin D1, MMP2, and MMP9). We found that JMJD2D and beta-catenin interact physically, and JMJD2D demethylated H3K9me3 at promoters of beta-catenin target genes. JMJD2D-knockout mice developed fewer colitis-associated colorectal tumors than control mice and their tumor tissues had lower levels of beta-catenin, MYC, cyclin D1, and proliferating cell nuclear antigen than tumors from control mice. Apcmin/+;Jmjd2d-/- mice developed fewer and smaller colon tumors than Apcmin/+ mice. Mice given 5-c-8HQ developed smaller and fewer colitis-associated tumors, with lower levels of cell proliferation, than mice given vehicle. Apcmin/+ mice given 5-c-8HQ also developed fewer tumors in intestines and colons than mice given vehicle. CONCLUSIONS: Levels of the histone demethylase JMJD2D are increased in human colorectal tumors, compared to non-tumor colon tissues. JMJD2D interacts with beta-catenin to activate transcription of its target genes and promote CRC cell proliferation, migration, and invasion as well as formation of colorectal tumors in mice. PMID- 30472236 TI - Efficacy and Safety of Abrilumab in a Randomized, Placebo-Controlled Trial for Moderate to Severe Ulcerative Colitis. AB - BACKGROUND & AIMS: alpha4beta7 integrin is a validated target in inflammatory bowel disease. This randomized, phase 2b, placebo-controlled, double-blind study evaluated the efficacy and safety of the anti-alpha4beta7 antibody abrilumab in patients with moderate-to-severe ulcerative colitis (UC) despite treatment with conventional therapies. METHODS: Patients (total Mayo Score 6-12, rectosigmoidoscopy score >=2) with inadequate response or intolerance to conventional therapies were randomized to receive subcutaneous abrilumab (7, 21, or 70 mg) on day 1, weeks 2 and 4, and every 4 weeks; abrilumab 210 mg on day 1; or placebo. The primary endpoint was remission (total Mayo Score <=2 points, no individual subscore >1 point) for the 2 highest dosages at week 8. Key secondary endpoints were response and mucosal healing (centrally read) at week 8. RESULTS: Among 354 patients who received >=1 dose of investigational product (placebo n=116, 7 mg n=21, 21 mg n=40, 70 mg n=98, 210 mg n=79), non-adjusted remission rates at week 8 were 4.3%, 13.3%, and 12.7% for placebo, abrilumab 70-mg and 210 mg groups, respectively (p<0.05 70 mg and 210 mg vs placebo); odds of achieving remission were significantly greater with abrilumab 70 mg (OR=3.35 [90% CI 1.41, 7.95], P=0.021) and 210 mg (OR=3.33 [90% CI 1.34, 8.26], P=0.030) than placebo. Response and mucosal healing rates with these dosages were also significantly greater versus placebo. Higher baseline alpha4beta7 levels on naive CD4+ T cells were a prognostic indicator for overall outcome, but not a predictive biomarker of abrilumab response. There were no cases of progressive multifocal leukoencephalopathy or deaths. CONCLUSIONS: Abrilumab treatment for 8 weeks induced remission, clinical response, and mucosal healing in patients with moderate-to-severe UC. PMID- 30472237 TI - Autophagy and its role in gastric cancer. AB - Autophagy, which is tightly regulated by a series of autophagy-related genes (ATGs), is a vital intracellular homeostatic process through which defective proteins and organelles are degraded and recycled under starvation, hypoxia or other specific cellular stress conditions. For both normal cells and tumour cells, autophagy not only sustains cell survival but can also promote cell death. Autophagy-related signalling pathways include mTOR-dependent pathways, such as the AMPK/mTOR and PI3K/Akt/mTOR pathways, and non-mTOR dependent pathways, such as the P53 pathway. Additionally, autophagy plays a dual role in gastric carcinoma (GC), including a tumour-suppressor role and a tumour-promoter role. Long-term Helicobacter pylori infection can impair autophagy, which may eventually promote tumourigenesis of the gastric mucosa. Moreover, Beclin1, LC3 and P62/SQSTM1 are regarded as autophagy-related markers with GC prognostic value. Autophagy inhibitors and autophagy inducers show promise for GC treatment. This review describes research progress regarding autophagy and its significant role in gastric cancer. PMID- 30472238 TI - Membrane protein carbonylation of Plasmodium falciparum infected erythrocytes under conditions of sickle cell trait and G6PD deficiency. AB - Deficiency of glucose-6-phosphate dehydrogenase (G6PD) and sickle cell trait (SCT) are described as the polymorphic disorders prevalent in erythrocytes. Both are considered the result of the selective pressure exerted by Plasmodium parasites over human genome, due to a certain degree of resistance to the clinical symptoms of severe malaria. There exist in both a prooxidant environment that favors the oxidative damage on membrane proteins, which probably is part of molecular protector mechanisms. Nevertheless, mechanisms are not completely understood at molecular level for each polymorphism yet, and even less if are commons for several of them. Here, synchronous cultures at high parasitemia levels of P. falciparum 3D7 were used to quantify oxidative damage in membrane proteins of erythrocytes with G6PD deficient and SCT. Carbonyl index by dot blot assay was used to calculate the variation of oxidative damage during the asexual phases. Besides, protein carbonylation profiles were obtained by Western blot and complemented with mass spectrometry using MALDI-TOF-TOF analysis. Erythrocytes with G6PD deficient and SCT showed higher carbonyl index values than control and similar profiles of carbonylated proteins; moreover, cytoskeletal and stress response proteins were identified as the main targets of oxidative damage. Therefore, both polymorphisms promote carbonylation on the same membrane proteins. Finally, these results allowed to reinforce the hypothesis of oxidative damage in erythrocyte membrane proteins as molecular mechanism of human adaptation to malaria infection. PMID- 30472239 TI - Stabilization of d-lactate dehydrogenase diagnostic enzyme via immobilization on pristine and carboxyl-functionalized carbon nanotubes, a combined experimental and molecular dynamics simulation study. AB - The most important mode of enzyme inactivation is thermal inactivation. Immobilization technology is an efficient approach to elongate the life-time of enzymes. d-lactate dehydrogenase (D-LDH) was stabilized at high temperatures with immobilization on CNT and fCNT. The kinetic and thermodynamic parameters, optimum temperature and pH, and the intrinsic fluorescence of free and immobilized enzymes were examined in the present study. Also, an attempt was made to investigate the effect of CNT and fCNT on the adsorption and conformation of d lactate dehydrogenase using molecular dynamics (MD) simulations. In comparison with free enzyme, the immobilized enzyme displayed an improved stability at high temperatures and, therefore, the immobilized enzyme is suitable for use in the industry because most reactions in the industry happen at high temperatures. Results of the present study showed that the adsorption of enzyme on CNT is mediated through the van der Waals and pi-pi stacking interactions, whereas in the adsorption of enzyme on fCNT in addition to hydrophobic interactions, the hydrogen bonding between enzyme and functional groups of fCNT is involved. Moreover, RMSD, RMSF and secondary structure analysis indicate that the fCNT protects the conformation of enzyme more than CNT. Therefore, D-LDH can be efficiently immobilized upon the fCNT compared to the pristine CNT. PMID- 30472240 TI - Inorganic polyphosphate protects against lipopolysaccharide-induced lethality and tissue injury through regulation of macrophage recruitment. AB - Sepsis is an etiologically complex and often fatal inflammatory process involving a multitude of cytokine signaling pathways. Tumor necrosis factor alpha (TNFalpha) acts as a central regulator of the acute-phase inflammatory response by recruiting immune cells, including circulating monocyte/macrophages, to sites of infection or tissue damage. Inorganic polyphosphate (polyP), a linear polymer of orthophosphate residues, has been found in almost all cells and tissues, but its functions in immunity remain largely unknown. In this study, we show that pre or post-treatment of mice with polyP150 (average chain length of 150 phosphate residues) markedly increases survival from lipopolysaccharide (LPS)-induced shock and inhibits macrophage recruitment to the liver and lungs, resulting in protection against tissue injury. In accord with these in vivo results, pretreatment of cultured peritoneal macrophages with polyP150 inhibited chemotaxis and actin polarization in response to TNFalpha. PolyP150 also inhibited phosphorylation of stress-activated protein kinases c-Jun N-terminal kinase (JNK) and p38, two downstream signaling molecules of the TNFalpha cascade, thereby preventing cyclooxygenase-2 gene expression by macrophages. These findings suggest that polyP150 inhibits recruitment of macrophages into organs by regulating the TNFalpha-JNK/p38 pathway, which may, in turn, protect against multi-organ dysfunction and lethality induced by LPS. Our findings identify polyP regulation as a novel therapeutic target for sepsis. PMID- 30472241 TI - Age-related changes in Ki-67 and DCX expression in the BALB/ c mouse (Mus Musculus) brain. AB - Several studies have identified age as one of the strongest regulators of neurogenesis in the mammalian brain. However, previous age-related studies focused mainly on changes in neurogenesis during different stages of adulthood and did not describe changes in neurogenesis through the different life history stages of the animal. The aim of this study was therefore to determine time course changes in neurogenesis in the male BALB/c mouse brain at postnatal ages 1 week to 12 weeks, spanning juvenile, sub adult and adult life history stages. To achieve this, Ki-67 and DCX immunohistochemistry was used to assess changes in cell proliferation and neuronal incorporation respectively. Ki-67 expression was mainly observed in the olfactory bulb, rostral migratory stream, sub ventricular zone of lateral ventricle and the sub granular zone of the dentate gyrus. In addition, fewer Ki-67 positive cells were also observed in the neocortex, cerebellum and tectum. DCX was expressed in similar regions as Ki-67 except for the cerebellum and tectum. Expression of both Ki-67 and DCX sharply decreased with advancing age or life history stages in the sub ventricular zone, rostral migratory stream and sub granular zone of the BALB/c mouse brain. Neurogenesis therefore persists throughout all life history stages in the BALB/c mouse brain although it decreases with age. PMID- 30472242 TI - The AbaR antibiotic resistance islands found in Acinetobacter baumannii global clone 1 - Structure, origin and evolution. AB - In multiply resistant Acinetobacter baumannii, complex transposons located in the chromosomal comM gene carry antibiotic and heavy metal resistance determinants. For one type, known collectively as AbaR, the ancestral form, AbaR0, entered a member of global clone 1 (GC1) in the mid 1970s and continued to evolve in situ forming many variants. In AbaR0, antibiotic and mercuric ion resistance genes are located between copies of a cadmium-zinc resistance transposon, Tn6018, and this composite transposon is in a class III transposon, Tn6019, carrying arsenate/arsenite resistance genes and five tni transposition genes. The antibiotic resistance genes in the AbaR0 and derived AbaR3 configurations are aphA1b, blaTEM, catA1, sul1, tetA(A), and cassette-associated aacC1 and aadA1 genes. These genes are in a specific arrangement of fragments from well-known transposons, e.g. Tn1, Tn1721, Tn1696 and Tn2670, that arose in an IncM1 plasmid. All known GC1 lineage 1 isolates carry AbaR0 or AbaR3, which arose around 1990, or a variant derived from one of them. Variants arose via deletions caused by one of three internal IS26s, by recombination between duplicate copies of sul1 or Tn6018, or by gene cassette addition or replacement. A few GC2 isolates also carry an AbaR island with different cassette-associated genes, aacA4 and oxa20. PMID- 30472243 TI - Outcomes for cancer patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - BACKGROUND/PURPOSE: The incidence of cardiovascular disease in cancer patients is rising. The risk of in-hospital complications for cancer patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) is not well defined. METHODS/MATERIALS: A retrospective single center cohort assessing STEMI patients with a history of cancer (n = 58) and without a history of cancer (n = 551) who underwent primary PCI between January 1, 2012 and June 30, 2017 was conducted. The primary outcome was a composite of in-hospital complications including reinfarction, cardiogenic shock, new heart failure, stroke, new atrial fibrillation, ventricular tachycardia/fibrillation, cardiac arrest, bleeding, new dialysis requirement, mechanical circulatory support, hospice requirement, and in-hospital mortality. RESULTS: Overall in hospital complications occurred in 229 (37.6%) patients. There was no significant difference in overall complications in patients with a history of cancer (39.7%), compared to those without a cancer history (37.4%) (adjusted OR 0.84 [0.46-1.51], p = 0.58; unadjusted OR 1.10 [0.61-1.92], p = 0.73); there were no differences exhibited in any of the individual complications. Patients with a history of cancer were significantly more likely to be readmitted within 30 days (12.7% vs. 5%; p = 0.03) and receive bare metal stents (50% vs. 30.4%; p = 0.004) as compared to patients without a history of cancer. CONCLUSIONS: There was no significant difference for in-hospital complications in patients with a history of cancer and those without a history of cancer undergoing primary PCI for STEMI. Patients with a history of cancer were more likely to readmitted within 30 days and receive bare metal stents. SUMMARY: The risk of in-hospital complications for cancer patients with STEMI undergoing primary PCI is not well defined. In a single-center retrospective cohort, there was no significant difference for in hospital complications between patients with a history of cancer and those without a history of cancer undergoing primary PCI for STEMI. PMID- 30472244 TI - Dealing With Binary Repeated Measures Data. PMID- 30472245 TI - Final Episode (or Not). PMID- 30472246 TI - Message from the Editor-in-Chief. PMID- 30472247 TI - Analysis of spliceosome dynamics by maximum likelihood fitting of dwell time distributions. AB - Colocalization single-molecule methods can provide a wealth of information concerning the ordering and dynamics of biomolecule assembly. These have been used extensively to study the pathways of spliceosome assembly in vitro. Key to these experiments is the measurement of binding times-either the dwell times of a multi-molecular interaction or times in between binding events. By analyzing hundreds of these times, many new insights into the kinetic pathways governing spliceosome assembly have been obtained. Collections of binding times are often plotted as histograms and can be fit to kinetic models using a variety of methods. Here, we describe the use of maximum likelihood methods to fit dwell time distributions without binning. In addition, we discuss several aspects of analyzing these distributions with histograms and pitfalls that can be encountered if improperly binned histograms are used. We have automated several aspects of maximum likelihood fitting of dwell time distributions in the AGATHA software package. PMID- 30472248 TI - Ancestral transcriptome inference based on RNA-Seq and ChIP-seq data. AB - With the help of high-throughput NGS (next-generation sequencing) technologies, ancestral transcriptome reconstruction is helpful to understand the complexity of transcriptional regulatory systems that underlies the evolution of multiple cellular metazoans with sophisticated functions and distinctive morphologies. To this end, we report a new method of ancestral state inference. The new method used Ornstein-Uhlenbeck (OU) model, which is more biologically realistic, to replace the Brownian motion (BM) model and is suitable for multi-transcriptome data. Implemented in the free R package, AnceTran is specially designed for RNA seq and ChIP-seq data, which is feasible. It should be noticed that our work will be integrated to a unified, statistically-sound phylogenetic framework to study the evolution of many other molecular phenomes such as proteomics, chromatin accessibility, methylation status, and metabolomics. We exemplify our method by a case study, using the ChIP-seq binding data of three liver-specific transcription factors and the RNA-seq liver expression data in four closely related mice species, and some technical issues are discussed. PMID- 30472249 TI - Combining Single Molecule Counting with Bead-Based Multiplexing to Quantify Biological Inflammation Time Course Following Skeletal Muscle Injury. AB - Bead-based analysis methods allow for the exploration of a variety of complex biological processes. In particular, these techniques can be applied to better understand how peripheral muscle injury contributes to systemic inflammation. Understanding how these two processes affect one another can give additional insight concerning how changes in inflammation effect readiness to perform in exercise and work environments. The present method sought to combine the strengths of bead-based multiplexing with the precision and low-end detection of single molecule counting (SMC) methods. We used performance of an extreme aerobic exercise session (i.e. half-marathon race) to cause a defined quantity of lower body muscle injury and a systemic inflammatory response lasting up to 24 hours. Using a high-sensitivity, multiplex assay (Milliplex; Millipore-Sigma) we were able to identify 9 of 21 cytokines that were significantly elevated at either 4 or 24 hours post half-marathon performance. Despite the known role of IL-1beta, IL-6, and TNF-alpha in the pro-inflammatory response, they did not appear to change based on the multiplex analysis. We thus, conducted further analysis using an SMC assay and found increases in IL-1beta, IL-6, and TNF-alpha at 4h compared to 24h post exercise. This method approach demonstrates how combining two common, bead-based protein assays can increase the amount of meaningful biological information that can be collected. We anticipate that this approach will be useful in a variety of inflammation-associated disease states. PMID- 30472250 TI - Combined Bead-Based Multiplex Detection of RNA and Protein Biomarkers: Implications for Understanding the Time Course of Skeletal Muscle Injury and Repair. AB - Biological response to skeletal muscle injury time course is generally classified as initial (elevated within first 4-h), delayed (elevated at 24-h), and/or prolonged (elevated at 4-h and sustained to 24-h). Accurate description of this process requires the ability to measure a robust set of RNA and protein biomarkers, yet such an approach is not common and not always feasible. This method proposes a novel experimental approach that focuses on the use of bead based multiplex detection to measure mRNA, lncRNA, cytokines, soluble cytokine receptors, and myokines at 4-h and 24-h post muscle injury. We used an extreme aerobic exercise session (half-marathon race) to create a consistent muscle injury stimulus via oxidative stress and eccentric contractions. Venous blood samples were analyzed to determine the change in 90 targets. Specifically, we identified 14 mRNA, 2 lncRNA, 4 cytokines, and 5 myokines that had only an initial response (change at 4-h). We identified 2 mRNA, 2 cytokines, 13 soluble cytokine receptors, and 1 myokine that had only a delayed response (change at 24 h). Finally, we identified 18 mRNA, 4 lncRNA, 6 myokines and 15 cytokines that had a prolonged response (change at 4-h and sustained at 24-h). We found 4 targets to be undetectable or having no response relative to muscle injury recovery. These findings demonstrate the interplay between RNA and protein biomarkers in response to skeletal muscle injury. This novel experimental application of bead-based multiplexing is applicable to a variety of clinical models that involve muscle injury and/or wasting. PMID- 30472252 TI - Developing potential biomarkers through bedside-to-bench translation. PMID- 30472251 TI - Early inhibition of endothelial retinoid uptake upon myocardial infarction restores cardiac function and prevents cell, tissue, and animal death. AB - Physiologically, following myocardial infarction (MI), retinoid levels elevate locally in the infarcted area. Whereas therapeutic systemic application of retinoids was shown to reduce the progression of ventricular dilatation and the onset of heart failure, the role of acute physiologically increased retinoids in the infarction zone is unknown to date. To reveal the role of local retinoids in the MI zone is the central aim of this study. Using human cell culture and co culture models for hypoxia as well as various assays systems, lentivirus-based transgene expression, in silico molecular docking studies, and an MI model in rats, we analysed the impact of the retinoid all-trans retinoic acid (ATRA) on cell signalling, cell viability, tissue survival, heart function, and MI-induced death in rats. Based on our results, ATRA-mediated signalling does aggravate the MI phenotype (e.g. 2.5-fold increased mortality compared to control), whereas 5' methoxyleoligin (5ML), a new agent which interferes with ATRA-signalling rescues the ATRA-dependent phenotype. On the molecular level, ATRA signalling causes induction of TXNIP, a potent inhibitor of the physiological antioxidant thioredoxin (TRX1) and sensitizes cells to necrotic cell death upon hypoxia. 5ML mediated prevention of ATRA effects were shown to be based on the inhibition of cellular ATRA uptake by interference with the cholesterol (and retinol) binding motif of the transmembrane protein STRA6. 5ML-mediated inhibition of ATRA uptake led to a strong reduction of ATRA-dependent gene expression, reduced ROS formation, and protection from necrotic cell death. As 5ML exerted a cardioprotective effect, also independent of its inhibition of cellular ATRA uptake, the agent likely has another cardioprotective property, which may rely on the induction of TRX1 activity. In summary, this is the first study to show i) that local retinoids in the early MI zone may worsen disease outcome, ii) that inhibition of endothelial retinoid uptake using 5ML may constitute a novel treatment strategy, and iii) that targeting endothelial and myocardial retinoid uptake (e.g. via STRA6 inhibition) may constitute a novel treatment target in acute MI. PMID- 30472254 TI - Greetings from the new editor-in-chief of human pathology. PMID- 30472253 TI - Cloning and characterization of zebrafish K2P13.1 (THIK-1) two-pore-domain K+ channels. AB - Two-pore-domain potassium (K2P) channels conduct background potassium currents in the heart and other tissues. K2P currents are involved in the repolarization of action potentials and stabilize the resting membrane potential. Human K2P13.1 (THIK-1) channels are expressed in the heart and have recently been implicated in atrial fibrillation. The in vivo significance of K2P13.1 currents in cardiac electrophysiology is not known. We hypothesized that Danio rerio (zebrafish) may serve as model to elucidate the functional role of cardiac K2P13.1 channels. This work was designed to characterize zebrafish orthologs of K2P13.1. Two zkcnk13 coding sequences were identified by DNA database searches and amplified from zebrafish cDNA. Human and zebrafish K2P13.1 proteins exhibit 70% (K2P13.1a) and 66% (K2P13.1b) identity. Kcnk13 expression in zebrafish was studied using polymerase chain reaction. Zebrafish kcnk13a and zkcnk13b mRNAs were detected in brain and heart. Human and zebrafish K2P13.1 currents were analyzed in the Xenopus oocyte expression system by voltage clamp electrophysiology. Zebrafish K2P13.1a polypeptides were non-functional, while zK2P13.1b channels exhibited K+ selective, outwardly rectifying currents. Zebrafish and human K2P13.1 currents were similarly activated by arachidonic acid and reduced by barium, mexiletine, lidocaine, and inhibition of phospholipase C. In conclusion, zebrafish K2P13.1b channels and their human orthologs exhibit structural and regulatory similarities. Zebrafish may be used as in vivo model for the assessment of physiology and therapeutic significance of K2P13.1. PMID- 30472256 TI - Validation of the 2007 Kidney Disease Outcomes Quality Initiative Clinical Practice Guideline for the Diagnosis of Diabetic Nephropathy and Nondiabetic Renal Disease in Chinese Patients. AB - AIMS: Diabetes mellitus (DM) has overtaken infection and immunological factors as the most common cause of end-stage renal disease. The 2007 Kidney Disease Outcomes Quality Initiative (KDOQI) guideline is a widely accepted guideline for the clinical diagnosis of diabetic nephropathy (DN) and non-diabetic renal disease (NDRD). Our study sought to verify its diagnostic ability in the Chinese population. METHODS: We included 773 patients with DM who underwent a renal biopsy at the Chinese PLA General Hospital from 2007 to 2016. All patients were divided into three groups according to their pathological findings: isolated DN, isolated NDRD, and DN combined with NDRD. RESULTS: Good sensitivity and poor specificity were found for the prediction of NDRD in the Chinese population. Rapidly decreasing estimated glomerular filtration rate, systemic disease, refractory hypertension, and the existence of "grey area" patients may have contributed to the poor diagnostic ability. CONCLUSIONS: The diagnostic ability of the 2007 KDOQI guideline for DN and NDRD was unsatisfactory. The high sensitivity and low specificity of the guideline made it more suitable as screening criteria rather than as diagnostic criteria. PMID- 30472255 TI - Comparative exoproteome profiling of an invasive and a commensal Staphylococcus haemolyticus isolate. AB - Staphylococcus haemolyticus is a skin commensal emerging as an opportunistic pathogen. Nosocomial isolates of S. haemolyticus are the most antibiotic resistant members of the coagulase negative staphylococci (CoNS), but information about other S. haemolyticus virulence factors is scarce. Bacterial membrane vesicles (MVs) are one mediator of virulence by enabling secretion and long distance delivery of bacterial effector molecules while protecting the cargo from proteolytic degradation from the environment. We wanted to determine if the MV protein cargo of S. haemolyticus is strain specific and enriched in certain MV associated proteins compared to the totalsecretome. The present study shows that both clinical and commensal S. haemolyticus isolates produce membrane vesicles. The MV cargo of both strains was enriched in proteins involved in adhesion and acquisition of iron. The MV cargo of the clinical strain was further enriched in antimicrobial resistance proteins. Data are available via ProteomeXchange with identifier PXD010389. BIOLOGICAL SIGNIFICANCE: Clinical isolates of Staphylococcus haemolyticus are usually multidrug resistant, their main virulence factor is formation of biofilms, both factors leading to infections that are difficult to treat. We show that both clinical and commensal S. haemolyticus isolates produce membrane vesicles. Identification of staphylococcal membrane vesicles can potentially be used in novel approaches to combat staphylococcal infections, such as development of vaccines. PMID- 30472257 TI - Obstructing nephrolithiasis in an 84-year-old patient with a diaphragmatic herniated ureter. AB - Diaphragmatic herniations of the ureter are a rare occurrence overall, with fewer than 10 cases reported. Obstructing nephrolithiasis in the setting of diaphragmatic ureteral herniation has sparsely been documented. Management options to consider include ureteroscopy and laser lithotripsy to alleviate obstruction in herniated ureters. The abnormal path of the ureter and surrounding structures pose unique risks that require careful attention and a high level of operator skill. We present imaging of an 84-year-old woman incidentally found to have right ureteral herniation through the diaphragm with an obstructing 8 mm stone in the right proximal ureter with moderate hydronephrosis. PMID- 30472258 TI - Pure Single-Site Robot-Assisted Partial Nephrectomy Using The SP(r) Surgical System: Initial Clinical Experience. AB - OBJECTIVES: To describe the technique of pure single-site trans-peritoneal robotic partial nephrectomy using the da Vinci SP(r) surgical system. METHODS: Three consecutive patients who were diagnosed with contrast-enhanced renal masses amenable of partial nephrectomy were scheduled for robot-assisted partial nephrectomy to be performed using the SP(r) Surgical System. Data collection received institutional review board approval (IRB 13-780). Subjects were provided with informed consent explaining the adoption of the novel surgical platform. The procedures were performed by reproducing the steps of the standard institutional multi-arms robotic approach to partial nephrectomy. RESULTS: The surgeries were successfully performed. There was no need for conversion to standard multi-ports robotic approach nor need for additional ports placement. All the procedures were completed according to a pure single-site approach. No intraoperative complications occurred. The total robotic operative time averaged 180 min. The warm ischemia time averaged 25 min. Blood loss averaged 180 mL. One patient had postoperative acute bleeding and underwent angioembolization. All patients had negative surgical margins. CONCLUSIONS: The feasibility of pure single-site transperitoneal robot-assisted partial nephrectomy using the novel SP(r) surgical system is demonstrated. Further studies are needed to confirm the results reported herein. PMID- 30472259 TI - BRIEF REPORT: Association of PALB2 Messenger RNA Expression with platinum docetaxel efficacy in advanced non-small cell lung cancer. AB - INTRODUCTION: PALB2, the partner and localizer of BRCA2, is essential for homologous recombination repair. We examined messenger ribonucleic acid (mRNA) levels of DNA-repair genes including PALB2, RNF8, RIF1, ATM, and 53BP1 as predictive biomarkers for cisplatin-docetaxel in the European phase III BRCA1 RAP80 expression customization (BREC) phase III clinical trial (NCT00617656). METHODS: The study was a pre-specified secondary objective of the BREC trial. We assessed mRNA levels of PALB2 and four more DNA repair genes, RNF8, RIF1, ATM and 53BP1, as biomarkers in tissue from 177 cisplatin-docetaxel treated NSCLC patients. We examined the relationship of gene expression levels with progression free survival (PFS), overall survival (OS) and response. RESULTS: In 177 (median age 62 years; 140 men; 91 adenocarcinoma) NSCLC patients, only high PALB2 mRNA expression was predictive in the PFS Cox-regression analysis (Hazard ratio [HR], 0.63; 95% Confidence Interval [CI], 0.42-0.83; p=0.0080). PALB2 was also predictive of OS (HR, 0.68; 95% CI, 0.42-0.90; p=0.0266). Among 158 patients evaluable for response, high PALB2 was predictive of response to cisplatin docetaxel. Specifically, an objective response rate of 77% to cisplatin-docetaxel was observed for patients with high PALB2 mRNA expression compared to only 23 % for those with low PALB2 mRNA expression (p=0.0448). CONCLUSIONS: High PALB2 mRNA expression identified NSCLC patients who significantly benefited from cisplatin docetaxel chemotherapy in the European BREC phase III clinical trial. The combination of chemotherapy with immunotherapy becomes a new standard of care, and a predictive marker of response to chemotherapy may accurately guide therapeutic decision making. PMID- 30472260 TI - Emerging role of 12/15-Lipoxygenase (ALOX15) in human pathologies. AB - 12/15-lipoxygenase (12/15-LOX) is an enzyme, which oxidizes polyunsaturated fatty acids, particularly omega-6 and -3 fatty acids, to generate a number of bioactive lipid metabolites. A large number of studies have revealed the importance of 12/15-LOX role in oxidative and inflammatory responses. The in vitro studies have demonstrated the ability of 12/15-LOX metabolites in the expression of various genes and production of cytokine related to inflammation and resolution of inflammation. The studies with the use of knockout and transgenic animals for 12/15-LOX have further shown its involvement in the pathogenesis of a variety of human diseases, including cardiovascular, renal, neurological and metabolic disorders. This review summarizes our current knowledge on the role of 12/15-LOX in inflammation and various human diseases. PMID- 30472261 TI - Znfl1s are essential for patterning the anterior-posterior axis of zebrafish posterior hindbrain by acting as direct target genes of retinoic acid. AB - RA (retinoic acid) signaling is essential for the patterning the hindbrain of vertebrates. Although hundreds of potential RA targets genes are identified, the ones other than hox genes playing roles in patterning anterior-posterior axis of hindbrain by mediating RA signaling remains largely unknown. Previously, we reported that znfl1s play essential roles in the formation of posterior neuroectoderm in zebrafish embryos. Here, we revealed that znfl1s play a critical role in patterning the posterior axis of hindbrain by maintaining the homeostasis of RA signaling in zebrafish embryos. Knocking down znfl1s shortened the length of the posterior hindbrain in a similar way of reducing RA signaling in zebrafish embryos and the defective posterior hindbrain was effectively rescued by elevating RA signaling. By performing mutagenesis assays and chromatin immunoprecipitation assays on the promoter of znfl1s, we demonstrated that znfl1s are direct target genes of RA to mediate RA signaling through a functional DR1 RA response element. Taken together, our results showed that Znfl1s are essential for patterning the anterior-posterior axis development of posterior hindbrain by acting as direct target genes of RA signaling. PMID- 30472262 TI - MNP triggers nasal allergy by modulating dendritic cell properties. AB - Exposure to MNP generates Th2 response-inducing dendritic cells. Transfer of OVA/MNP-primed dendritic cells induces nasal allergy. Inhibition of Bcl2L12 prevents nasal allergy development. PMID- 30472263 TI - Effect of particle size and polymer loading on dissolution behavior of amorphous griseofulvin powder. AB - The effect of particle size on the dissolution behavior of the particles of amorphous solid dispersions (ASDs) of griseofulvin (GF), with 0-50% Kollidon(r) VA 64 as a crystallization inhibitor is investigated. Both the final dissolved GF concentration, and the dissolution rate of GF ASDs were found to be inversely proportional to the particle size. The solution concentrations for the smallest (45-75 MUm) size group with different polymer loading were significantly higher than those for the largest (250-355 MUm) group regardless of the initial GF amount. Specifically, the dissolution rate of GF ASDs with 50% polymer loading for the finest group was 2.7 times higher than for the largest group under supersaturating conditions. The rates of dissolution and recrystallization were assessed through surface concentration (Cs)and Avrami recrystallization rate kinetics, where the solid state recrystallization was confirmed using Raman spectroscopy. Outcomes indicated that particle size reduction enhanced ASD drug loading by reducing the amount of polymer necessary as finest size ASDs initially dissolve faster, negating their higher recrystallization rate. Kollidon(r) VA 64 at 30% loading was sufficient to inhibit the GF recrystallization. Overall, the combination of particle size reduction and recrystallization inhibition is effective for improved dissolution behavior of GF ASDs. PMID- 30472264 TI - Evaluation of Pyrrolobenzodiazepine-Loaded Nanoparticles: A Targeted Drug Delivery Approach. AB - We describe the development and evaluation of pyrrolobenzodiazepines (PBDs) in poly(DL-lactide-co-glycolide) (PLGA) and lipid (LNP) nanoparticle drug delivery systems. We have established that the partition coefficient (LogP) of PBD is a key influencer of the encapsulation efficiency in nanoparticle systems, with higher LogP values associated with higher encapsulation efficiencies toward increased drug payload delivery and better antitumor efficacy. Cytotoxicity assays demonstrated that compounds with higher LogP values demonstrated higher 50% inhibitory concentration values than the free drug. In vivo efficacy studies in mice demonstrated that a single injection of nanoparticle PBD formulations could inhibit tumor growth for nearly 3 weeks, whereas the free drug failed to inhibit growth. Importantly, mice treated with PBD-loaded nanoparticles did not experience significant loss of body weight. These data demonstrate that nanoparticles containing PBD molecules can be used as an alternative to the widely used antibody drug conjugate approach in delivering cytotoxic PBDs. PMID- 30472265 TI - Bioavailability Enhancement of Polymyxin B with novel drug delivery: Development and Optimization using Quality-by-Design Approach. AB - Polymyxin- B (Poly-B) is an effective antibiotic used to treat infections mainly caused due to sensitive gram-negative infections. They belong to the group of cyclic peptide antibiotics and are minimally absorbed from the gastrointestinal tract (GIT). This arise the need for bioavailability enhancement and is achieved in the present case using niosomes as carrier system. The Poly-B niosomes had been developed using span-60 and cholesterol while optimization is achieved with Quality-by-Design (QBD) approach. In this QBD approach, three independent variables [Span 60: Cholesterol, vol. of PBS (%), amount of drug (mg)], each at three levels were studied. A total of 17 runs were suggested by the model which was further analyzed by optimizing three different responses (particle size, zeta potential, entrapment efficiency (EE %). The results had clearly shown that the optimum formulation selected by QBD was based on the criteria of attaining the maximum value of EE% and low value of size and zeta potential. Poly-B niosomes were further examined by in-vitro antifungal, rat creatinine and cytotoxicity assay. The pharmacokinetics and scintigraphy studies were also performed for in vivo behavior of Poly-B. PMID- 30472266 TI - Systems Modeling of Bortezomib and Dexamethasone Combinatorial Effects on Bone Homeostasis in Multiple Myeloma Patients. AB - Osteolytic bone disease is one of the most debilitating manifestations of multiple myeloma (MM). Bortezomib is a proteasome inhibitor that shows both anticancer and bone anabolic properties and is being evaluated for its positive effects in MM patients with skeletal complications. Dexamethasone is a potent corticosteroid that is often given in combination with bortezomib for its antineoplastic effects; however, bone loss and osteoporosis are major adverse effects of long-term steroid-based therapies. In this study, a small systems pharmacological model was developed to integrate the bone anabolic effects of bortezomib with the osteolytic activity of dexamethasone in MM patients with bone disease. The final model parameters were all estimated with good precision. The interaction model is based on codifying multiple regulatory mechanisms of drug action and provides a platform for probing optimized bortezomib and dexamethasone combination dosing regimens to minimize skeletal side effects during myeloma therapy. PMID- 30472267 TI - Taming hemodialysis-induced inflammation: Are complement C3 inhibitors a viable option? AB - Owing to an increasing shortage of donor organs, the majority of patients with end-stage kidney disease remains reliant on extracorporeal hemodialysis (HD) in order to counter the lifelong complications of a failing kidney. While HD remains a life-saving option for these patients, mounting evidence suggests that it also fuels a vicious cycle of thromboinflammation that can increase the risk of cardiovascular disease. During HD, blood-borne innate immune systems become inappropriately activated on the biomaterial surface, instigating proinflammatory reactions that can alter endothelial and vascular homeostasis. Complement activation, early during the HD process, has been shown to fuel a multitude of detrimental thromboinflammatory reactions that collectively contribute to patient morbidity. Here we discuss emerging aspects of complement's involvement in HD induced inflammation and put forth the concept that targeted intervention at the level of C3 might constitute a promising therapeutic approach in HD patients. PMID- 30472268 TI - Effects of different treatment methods on properties of potato starch-lauric acid complex and potato starch-based films. AB - The effects of different treatment methods on the physicochemical properties of potato starch (PS) and PS-based films were studied. The complexing indices of PS lauric acid (LA) complexes followed the order: pullulanase debranching (PD) > ultrasound treatment (UT) > dimethyl sulfoxide heating (DSH) > Control. Light microscopy showed that PS-LA complexes exhibited irregularly shaped fragments. X ray diffraction indicated that the diffraction intensity of the PD sample was stronger than that of the other samples. The melting enthalpies (?H) of the DSH, UT and PD samples were higher than that of the Control. PD sample had the lowest enzymatic-hydrolysis rate among all of the tested samples. PS-LA composite films showed higher tensile strength, lower elongation at break, and lower moisture permeability than native starch-based film, and the films prepared by PD method had the highest tensile strength and lowest water vapour permeability among all of the tested films. PMID- 30472269 TI - Investigation of the properties of N-[(2-hydroxy-3-trimethylammonium) propyl] chloride chitosan derivatives. AB - N-[(2-Hydroxy-3-Trimethylammonium) Propyl] Chitosan Chloride Derivatives (HTCC), based on low molecular weight crab chitosan, were synthesized by the alkylation reaction with a degree of substitution of 10-98%. The chemical structure was confirmed by 1H NMR and IR-spectra. Physical and chemical characteristics and a number of properties were defined. All HTCC derivatives were soluble at pH 7.4. HTCCs have an inhibitory capacity on the growth of the studied microorganisms. The introduction of quaternary ammonium groups into chitosan molecule contributed to the increase of antibacterial activity of derivatives. HTCC53 showed fungicidal activity and at a concentration of 500 mg/ml completely inhibited the growth of mycelial fungi F. oxysporum, A. alternata and C. herbarum. When studying the ability of HTCCs to absorb DPPH radicals, it was found that samples of HTCC10 and HTCC40 showed high inhibitory capacity at a concentration of >15 mg/ml. It was shown that the chelating ability of HTCCs decreased by reducing the number of free amino groups. HTCC10-HTCC53 demonstrated the maximum values of chelating ability at a concentration of 4-10 mg/ml. Due to the solubility at neutral pH values and the properties shown, obtained chitosan derivatives can be used in clinical practice, pharmaceutical and food industries in the future. PMID- 30472271 TI - Food-riders may improve the chain of survival in out-of-hospital cardiac arrests by delivering CPR and AEDs. PMID- 30472270 TI - A polysaccharide isolated from Sphallerocarpus gracilis protects PC12 cells against hydrogen peroxide-induced injury. AB - Sphallerocarpus gracilis is a medicinal and edible plant in China with high nutritional value. We examined the structure and bioactivity of a new polysaccharide fraction purified from S. gracilis named SGP-1. This polysaccharide possessed an average molecular weight of 4.916 * 105 and was primarily composed of arabinose, mannose and glucose in a molar ratio of 1.08:94.54:4.38. Atomic force microscopy indicated that SGP-1 adopts a sphere like chain conformation. Bioactivity tests showed that SGP-1 significantly protected PC12 cells from oxidative injury caused by H2O2 and enhanced superoxide dismutase and glutathione peroxidase activities. Moreover, SGP-1 reduced PC12 apoptosis by inhibiting Caspase-3 and Caspase-9 activities. These results provide a scientific basis for the further use of SGP-1 as a novel functional component in the treatment of oxidative damage-derived diseases. PMID- 30472272 TI - Neuro-metabolite profiles of rodent models of psychiatric dysfunctions characterised by MR spectroscopy. AB - Neuroimaging endophenotypes in animal models provide an objective and translationally-relevant alternative to cognitive/behavioral traits in human psychopathologies. Metabolic alterations, such as those involved in the glutamate cycle, have been proposed to play a preponderant role in both depression and schizophrenia. Chronic Mild Unpredictable Stress (CMUS) and sub-chronic administration of NMDA receptor antagonist generate animal models of depression and schizophrenia, respectively. The models are based on etiologically-relevant factors related to the induction and support of these psychopathologies. To test metabolic alterations within the glutamate-cycle and in other major neurochemicals, single-voxel Magnetic Resonance Spectroscopy was recorded within the hippocampus in both rat models and control animals. Surprisingly, altered glutamate-related metabolites were observed in the CMUS model, but not NMDA-based model, as indicated by decreased glutamine and increased GABA levels. However, both models presented elevated total visible choline and inositol levels relative to controls. These results indicate the presence cell membrane metabolic alterations and inflammatory processes shared in both models, comparable to evidence presented in schizophrenia and depression and other comparable animal models. These translationally-relevant biomarkers may thus form the basis for drug-development targets in both psychopathologies. PMID- 30472273 TI - Partial restoration of physiological UP-state activity by GABA pathway modulation in an acute brain slice model of epilepsy. AB - In addition to reducing seizures, anti-epileptic treatments should preserve physiological network activity. Here, we used a thalamocortical slice preparation displaying physiological slow oscillations to investigate the effects of anticonvulsant drugs on physiological activity and epileptiform activity in two pharmacological epilepsy models. Thus, we compared the effects of GABA pharmacology on spontaneous physiological and pathological events in slices of the mouse barrel cortex. We show that both reducing inhibition using GABAAR blockers and enhancing excitation by lowering Mg2+ concentration allow for the transition from physiological slow oscillations to epileptiform activity. Our results indicate that GABABR antagonists have pro-convulsive properties by increasing event duration in the low inhibition model and event frequency in the high excitation model. Moreover, we show that GABABR agonists and GABA uptake blockers, known for their anticonvulsant properties, act primarily on epileptiform burst frequency and allow for a partial restoration of physiological events. As a proof of principle, these results indicate that a slice model with spontaneous network events may be a useful pipeline to investigate the effects of anti-epileptic drugs on both epileptiform and physiological network activity. PMID- 30472274 TI - ? PMID- 30472275 TI - Undisclosed conflicts of interest in German-language textbooks of anesthesiology, critical care, and emergency medicine. AB - BACKGROUND: Medical textbooks are important throughout postgraduate internship, residency and fellowship programs but authors' conflicts of interest (COI) are rarely disclosed. In anesthesiology, two high-profile cases of research fraud/unethical publishing have previously been identified. This study evaluated whether anesthesiology textbooks in German include controversial recommendations on hydroxyethyl starch (HES) and whether authors had undisclosed COI. METHODS: Forty-five anesthesiology, critical care, and emergency medicine electronic textbooks (January 2015-August 2017) were identified on the websites of German, Austrian, and Swiss publishers. Six textbooks were excluded (irrelevant content; compilation of peer-reviewed articles). Content on HES ('Kolloid', 'Hydroxyathylstarke', 'Hydroxyethylstarke', 'HES', 'HAES') and COI ('Interessenkonflikt') was electronically searched; subject lists were manually searched. Recommendations on HES were analyzed in the context of indications/warnings/international guidelines. Potential COI for authors of controversial recommendations were searched on PubMed/EMBASE (January 2016-May 2018). RESULTS: COI statements were absent in 38/39 textbooks (present for 1/553 authors; 0.2 %). Twelve textbooks did not discuss HES for volume resuscitation. HES was recommended in 13 textbooks; many recommendations were controversial (10/39 textbooks, 26 %; 25/553 authors, 5 %). Journal COI statements were available for 18/25 authors; 7 authors had financial/other COI, including 4/18 (22 %) with ties to HES manufacturers. CONCLUSIONS: Recommendations on volume resuscitation with HES are highly controversial in German-language electronic textbooks; about one-quarter of relevant textbooks are inconsistent with regulatory authority or international guideline criteria. Undisclosed potential COI of textbook authors making controversial recommendations of HES were frequent, linking roughly one in five authors to the HES-producing industry. Against this background, COI statements must become part of standard textbook publication ethics. PMID- 30472276 TI - [Analysis of individual quality categories from quality management systems and their influence on the overall system]. AB - INTRODUCTION: According to Sect. 135a (2) of the Fifth Book of the German Social Code (SGB V), all physicians, psychotherapists and medical care centers are obliged to introduce an intra-institutional quality management system (QM system). The legislator instructed the Federal Joint Committee (G-BA) to develop basic requirements in a quality management guideline (QM-RL). Factor analysis was used to examine whether individual quality categories had a significant influence on the scores of QM systems. METHODS: The random sample was collected in Saxony and included a total of 24 medical practices because these practices were made available for analysis by the Saxon Association of Statutory Health Insurance Physicians. First, two primary units (family physicians/specialists) were established from the population. In the following step, one sample per QM system was drawn for each primary unit. In total, there were twelve family physicians and twelve specialists, or eight practices per QM system. The analysis was performed using three self-constructed questionnaires (physician, employee and patient). The individual items were developed independently of a QM system (26 quality categories with 40 questions per survey group). For the analysis, the arithmetic mean was calculated in the individual groups of questions. Factor analysis was used to investigate which quality categories per QM system had a significant influence on the evaluations. The Kaiser-Meyer test was used to measure the data's suitability for factor analysis, also Bartlett's test relating to significance and the cumulative percentage of total of variance were applied. RESULTS: In the first step, the quality categories having a significant influence on the overall evaluation of the QM system are presented. Regarding the DIN EN ISO 9001, 18 quality categories have a significant influence on the overall result; in QEP and QisA, 17 quality categories each have a significant influence on the overall result. The quality categories 'continuous professional development and qualification', 'hygiene and cleaning', 'quality management system', 'quality objectives', and 'procurement and storage' do not define an influence on the overall rating in any of the QM systems. Finally, eleven relevant quality categories were discovered which have an influence on all the QM systems. CONCLUSION: 17 quality categories have a significant influence on the overall rating based on sample documents, flow charts, process flows, interview guidelines, maintenance protocols, or job advertisements. There are also eleven categories with a significant and pronounced effect on all three QM systems. PMID- 30472277 TI - Impaired enzymatic reactive aldehyde-detoxifying capacity and glutathione peroxidase activity in the aged human arterial tissue. AB - It is not known whether aging alters the enzymatic reactive aldehyde- and lipid hydroperoxide-detoxifying capacity of the human arterial tissue favoring vascular oxidative stress. To address this issue, we studied the specific enzymatic activities of class 1, 2 and 3 aldehyde dehydrogenase (ALDH1, ALDH2 and ALDH3), glutathione S-transferase (isozyme A4-4, GSTA4-4) and aldose reductase (AR), namely the major reactive aldehyde-scavenging enzymes, together with the activity of the lipid hydroperoxide-removing enzyme glutathione peroxidase (GSH-Px), in superior thyroid arteries (STA) specimens obtained in the thyroid surgery setting in aged subjects (age 72.3 +/- 3.6 years) and young adult controls (age 31.9 +/- 3.5 years). Vascular lipid peroxidation was also studied by assessing in STA fluorescent damage products of lipid peroxidation (FDPL), which reflect oxidant induced 4-hydroxynonenal and lipid hydroperoxide formation. Remarkably, the activities of ALDH1, ALDH2, ALDH3, GSTA4-4, AR and GSH-Px were significantly lower, and FDPL levels higher, in the arterial tissue of the aged subjects than in that of the young adult controls. Moreover, the enzymatic activities were inversely and significantly correlated with the levels of FDPL in the arterial tissue of both the aged and young subjects, highlighting their vascular antioxidant/antilipoperoxidative role in vivo. Thus, aging impairs the enzymatic reactive aldehyde-detoxifying capacity and GSH-Px activity of the human arterial tissue eventually favoring vascular oxidative stress. PMID- 30472279 TI - Pediatric Chief Residents' Experiences as Inpatient Attending Physicians. AB - BACKGROUND: Some pediatric chief residents perform supervisory clinical duties during chief residency, but these activities are highly variable and descriptions are limited. Our goals were to characterize inpatient service performed by pediatric chief residents and to explore factors that influence their experiences as inpatient attending physicians. METHODS: Pediatric chief residents at ACGME accredited programs in 2016 were invited to complete a 40-item electronic questionnaire about their inpatient service obligation as well as attitudes regarding this experience. Data were analyzed using chi-square, ANOVA tests, and logistic regression. Open-ended responses underwent content analysis. RESULTS: There were 116 completed surveys from a national sample of 223 (response rate 52%); 66% served as inpatient attending physicians during chief residency. On average, chief residents spent 5.5 weeks (range 1-16) in this role with a daily census of 11.5 patients (range 5-20). Those entering primary care were significantly less likely to spend time as an inpatient attending compared with chiefs entering fellowship or hospital medicine (45.7 vs. 67.3 vs. 83.3%, p=0.01). Overall, 92% regarded their inpatient clinical experience positively and indicated they would like the same (40%) or more time (52%) in this role. The average favorability rating was 8.2 out of 10 and this was not associated with clinical workload or career choice. CONCLUSIONS: Most chief residents serve as inpatient attending physicians during chief residency. They rate their inpatient experience positively despite wide variability in clinical experiences, patient population, and clinical load. Further studies should examine the value of this experience and its impact on chief residents' future practice. PMID- 30472278 TI - Achilles tendon thickening is associated with disease severity and plaque vulnerability in patients with coronary artery disease. AB - BACKGROUND: Tendon xanthomas are accumulations of collagen and macrophages, which contain cholesterol esters and a marker of high risk for coronary artery disease (CAD). OBJECTIVE: The aim of the article was to clarify whether the presence of Achilles tendon thickening (ATT) was associated with disease severity and plaque vulnerability in patients with CAD. METHODS: A total of 241 consecutive patients who underwent percutaneous coronary intervention and ATT assessment were analyzed. ATT was defined as Achilles tendon thickness of >=9 mm on radiograph. The severity of CAD and plaque vulnerability was assessed by the findings on angiogram and optical coherence tomography, respectively. RESULTS: ATT was found in 44 patients (18.2%). The frequency of multivessel disease (79.6% vs 58.4%, P = .009) and left main lesion (13.6% vs 3.1%, P = .004) was significantly higher in patients with ATT (ATT group) than in patients without ATT (no ATT group). Multivariate logistic regression analyses demonstrated that the presence of ATT was independently associated with the presence of multivessel disease (odds ratio, 2.33; 95% confidence interval, 1.08-5.46; P = .031). The ATT group had a higher prevalence of intimal vascular channels (50.0% vs 24.7%, P = .018) and macrophage accumulation (58.3% vs 33.3%, P = .028) in culprit plaque than the no ATT group. CONCLUSIONS: Patients with the presence of ATT had a higher prevalence of multivessel coronary disease and left main coronary artery disease than with patients without ATT. The presence of ATT was also associated with vulnerable features, including intimal vascular channels and macrophage accumulation in culprit plaques. PMID- 30472281 TI - Echocardiographic Changes in Patients Implanted with a Fully Magnetically Levitated Left Ventricular Assist Device (HeartMate 3). AB - BACKGROUND: The HeartMate3 (HM3) is a Conformitee Europeenne mark-approved left Ventricular (LV) assist device (LVAD) with fully-magnetically levitated rotor and features consisting of wide range operational speeds, wide flow paths and artificial pulse. We performed a hemodynamic-echocardiographic speed optimization evaluation in HM3 implanted patients to achieve optimal LV- and right-ventricular (RV) shape. METHODS: Sixteen HM3 patients underwent pump speed ramp-tests with right-heart catheterization. Three-dimensional echocardiographic (3DE) LV and RV datasets (Philips) were acquired, and volumetric (TomTec) and shape (custom software) analyses were performed (LV: sphericity, conicity; RV: septal and free wall curvatures). Data were recorded at up to 13 speed settings. Speed changes were in 100 RPM steps, starting at 4600 RPM ramping up to 6200 RPM. RESULTS: 3DE was feasible in 50% of the patients. Mean original speed was 5306 +/- 148-rpm. LV end-diastolic diameter (-0.15 +/- 0.09cm/100rpm) and volumes (EDV: 269 +/- 109mL to 175 +/- 90mL, ESV: 234 +/- 111mL to 146 +/- 81mL) progressively decreased as the shape became less spherical and more conical, while RV volumes initially remained stable, but at higher speeds increased (EDV: from 148 +/- 64mL to 181 +/ 92 mL, ESV: 113 +/- 63 mL to 130 +/- 69 mL). On average, the RV septum became less convex (bulging towards the LV) at the highest speeds. CONCLUSION: LV- and RV-shape changes were noted in HM3 supported patients. While a LV volumetric decrease and shape improvement was consistently noted, RV volumes grew in response to increase in speed above a certain point. A next concern would be whether understanding of morphological and function changes in LV and RV during LVAD speed change assessed by using 3DE helps optimize LVAD speed settings and improve clinical outcomes. . PMID- 30472280 TI - Prognostic Value of Left Atrial Functional Measures in Heart Failure with Reduced Ejection Fraction. AB - BACKGROUND: The prognostic value of LA functional measures in heart failure patients with reduced ejection fraction (HFrEF) is unclear. Hence, this study investigated the prognostic value of left atrial (LA) functional measures such as the left atrial emptying fraction (LAEF) and the minimal LA volume in comparison to left atrial volume index (LAVI) in HFrEF patients. METHODS AND RESULTS: A total of 818 HFrEF patients with left ventricular ejection fractions <45% underwent echocardiography. LA volumes were determined by the area-length method from the apical 2 chamber and apical 4 chamber view. LAEF, MinLAVI (minimal LA volume indexed to body surface area) and LAVI was calculated. End-point was all cause mortality. During a median follow-up of 3.3 years (IQR: 1.8-4.6 years), 121 patients died (14.8%). Follow-up was 100%. In a final multivariable model adjusting for clinical and echocardiographic parameters, LAEF, but not MinLAVI or LAVI, was an independent predictors of all-cause mortality in HFrEF patients (LAEF: HR 1.11, p=0.033, per 5% decrease)(MinLAVI: HR 1.03, p=0.57, per 5mL/m2 increase)(LAVI: HR 1.06, p=0.16, per 5 mL/m2 increase). CONCLUSION: LAEF is an independent predictor of all-cause mortality in HFrEF patients after multivariable adjustment. LAEF provides incremental prognostic value over LAVI in risk stratification of HFrEF patients. PMID- 30472282 TI - Right ventricular and pulmonary vascular function are influenced by age and volume expansion in healthy humans. AB - BACKGROUND: Patients with heart failure (HF) often show signs of RV dysfunction. The function of RV coupled with the pulmonary circulation (tricuspid annular plane systolic excursion [TAPSE]: pulmonary artery systolic pressure [PASP]) has been shown to divide HF patients into distinct prognostic strata, however less is known about which factors influence this prognostic marker, and whether these factors can be modified. We sought to obtain normative values and discern the individual effects of age, gender, and fluid overload on right ventricular (RV) function. METHODS: Sixty healthy subjects aged 20-80 years were enrolled in this prospective study. Right heart catheterization with hemodynamic measurements were performed at rest and following a rapid saline infusion (10 ml/kg, 150 ml/min). Linear regression and Spearman correlation models were used to estimate associations between TAPSE:PASP and relevant variables. RESULTS: In healthy persons of all ages, the normative TASPE:PASP ratio was median (5th-95th percentile) 1.25 (0.81-1.78) mm/mmHg. The correlation between progressive age and declining TAPSE:PASP was significant (r: -0.35, p=0.006). Gender did not influence TAPSE:PASP (p=0.30). Rapid fluid expansion increased central venous pressure from 5 +/- 2 mmHg to 11 +/- 4 mmHg after fluid infusion (p<0.0001). This resulted in a 32% decrease in the TAPSE:PASP ratio after fluid infusion, compared to baseline (p<0.0001). CONCLUSIONS: The TAPSE:PASP ratio was affected by age, but not gender. TAPSE: PASP is not only a reflection of intrinsic RV function and pulmonary vascular coupling, but fluid status dynamically affects this index of RV function. Normative values with invasive measurements were obtained for future assessment of HF patients. PMID- 30472283 TI - Ventral craniovertebral junction arachnoid cyst in an elderly patient- a case report of a unique occurrence at extremes of age. AB - BACKGROUND: Craniovertebral junction arachnoid cysts are uncommon. Amongst the ones reported, ventrally located arachnoid cysts at extremes of age are even rarer. We report a successfully managed case of a ventrally placed arachnoid cyst in an 88-year-male by an unconventional surgical approach. CASE DESCRIPTION: An 88-year-male presented to us with complaints of tingling and numbness in both upper limbs and lower limbs. He had weak handgrips on both sides. Spinal magnetic resonance imaging (MRI) showed a contrast non-enhancing cystic lesion over the anterior lip of foreman magnum displacing the cervicomedullary junction posteriorly which was homogenous hypointense on T1 weighted images and hyperintense on T2 weighted images. The lesion was excised through the posterior approach. The cyst contents were drained out followed by complete wall excision. A complete improvement in clinical symptoms and an absence of neurological deficits were noted in the patient. CONCLUSION: Arachnoid cysts are congenital lesions and can present at extremes of age. Ventrally placed small symptomatic arachnoid cyst can be managed successfully through posterior approach especially in the elderly population. PMID- 30472284 TI - Super Giant GH-secreting pituitary adenoma in a young woman: from the ventricles to the nose. AB - BACKGROUND: Giant pituitary adenomas (GPA) are rare tumors that can have a devastating impact on a patient's life. They require a well studied therapeutic approach that often combines different strategies. METHODS: A 29-year-old woman was diagnosed with the largest GH-secreting pituitary adenoma reported in literature, to the best of the authors knowledge. The tumor was removed with a combined approach: endoscopic endonasal trans-sphenoidal and trancortical transventricular. All available acromegaly drugs were used. RESULTS: After two surgeries, a large part of the tumor was removed. Both post-operative courses were uneventful. Since the disease was still active, medical therapy was initiated. The combination of pasireotide, pegvisomant and cabergoline permitted satisfactory control of hormonal levels. CONCLUSIONS: Giant adenomas, larger than 4 cm, are very rare pituitary tumors. Therefore, in order to achieve the best clinical results they require complex management which involves a multidisciplinary team which includes: ENT surgeons, endocrinologists, radiation therapists, ophthalmologists and neurosurgeons. PMID- 30472285 TI - Changing hands: Why being ambidextrous is a trait that needs to be acquired and nurtured in neurosurgery. PMID- 30472286 TI - Did Ibn Zuhr (Avenzoar) postulate before Vesalius that liquid collects in ventricles in the hydrocephalus? AB - OBJECTIVES: This study aimed to present and evaluate the part of Avenzoar's Liber Teisir that pertains to hydrocephalus. Avenzoar was an Andalusian physician prominent in the history of medicine because of the broadness of his observations and original methods. His most important work is recognized to be the Al-Taysir fi al-Mudawat wa al-Tadbir (On Preventive Regimen and Treatment), and its Latin version, Alteisir scilicet regiminis et medelae, was in use for centuries in Europe. METHODS: The Arabic (Rabat, 1991) and Latin (Venice, 1530) versions of Avenzoar's Al-Taysir were perused, relevant sections separately translated into English, and both translations then compared. An English version was prepared and is given in the results section. RESULTS: The location of liquid collection was described as the anterior ventricles of the brain and around the brain in the section titled "On the humidity in the anterior ventricles and around the brain." CONCLUSION: Avenzoar might have noted one of the earliest records on the clinical state called "idiopathic adult hydrocephalus," and postulated liquid collection in the ventricles of brain in hydrocephalus before Vesalius. PMID- 30472287 TI - Antibiotic discovery: History, methods and perspectives. AB - Antibiotic resistance is considered a major public health issue. Policies recommended by the World Health Organization include research on new antibiotics. No new class was discovered since daptomycin and linezolid in the 1980s and only optimization or combination of already known compounds has been recently commercialized. Antibiotics are natural products of soil-living organisms. Actinobacteria and fungi are the source of about two thirds of the antimicrobial agents currently used in human medicine; they were mainly discovered during the golden age of antibiotic discovery. This era declined after the 1970s due to the difficulty of cultivating fastidious bacterial species under laboratory conditions. Various strategies such as rational drug design have not led to date to the discovery of new antimicrobial agents. However, new promising approaches, e.g. genome mining or CRISPR Cas9 are now being developed. The recent rebirth of culture methods from complex samples has, as a matter of fact, permitted the discovery of teixobactin from a new species isolated from the soil. Recently, many Biosynthetic Gene Clusters were identified from Human-associated microbiota, especially from the gut and oral cavity. As an example, the antimicrobial lugdunine was recently discovered in the oral cavity. The repertoire of human gut microbiota has recently substantially increased, with the discovery of hundreds of new species. The exploration of the repertoire of prokaryotes associated with human beings using genome mining or newer culture approaches could be promising strategies for discovering new classes of antibiotics. PMID- 30472289 TI - Emergence of NDM-7-Producing Multidrug-Resistant Enterobacter hormaechei sequence type ST78 in Spain, a high-risk international clone. PMID- 30472288 TI - Population pharmacokinetic modelling of total and unbound flucloxacillin in non critically ill patients to devise a rational continuous dosing regimen. AB - OBJECTIVE: The objective was to describe the population pharmacokinetics of total and unbound flucloxacillin in non-critically ill patients and to devise a rational continuous dosing regimen for this population. METHODS: Total and unbound flucloxacillin pharmacokinetics in 30 non-critically ill patients receiving intravenous flucloxacillin were analyzed using non-linear mixed effects modelling. A Monte-Carlo simulation was used to assess the fraction of the population reaching effective unbound flucloxacillin levels as well as the fraction reaching potential neurotoxic exposure for various continuous dosing regimens. RESULTS: The observed protein binding varied between 64.6 and 97.1% . The unbound fraction was significantly associated with serum albumin and concentration dependent. The parameter estimates of the final model were: Cltotal 122 l/h, Clrenal 1.41 l/h, Vc 190 l, Vp 33.9l, Q 16.8 l/h, Kd 9.63 mg/l, thetaBmax 177 mg/l,thetaalb 0.054. A continuous dose of 6g/24hours was sufficient for 100% of the population to obtain a unbound concentration of > 0.25 mg/l. With 14g/24hours, 91.2% of the population was predicted to reach concentrations of > 2 mg/l, the clinical breakpoint for S. aureus. Potential toxic unbound flucloxacillin levels were reached in 2.0% of the population with 6g/24 hours and 24.1% with 14g/24 hours. CONCLUSIONS: Our study showed that a continuous infusion of 6g/24hours flucloxacillin is sufficient to treat the most infections in non critically ill patients. With this dosing regimen an unbound serum concentration flucloxacillin > 0.25 mg/l is reached in 100% of the patients, with minimal chance of neurotoxicity. PMID- 30472290 TI - Population pharmacokinetics and dosing optimization of latamoxef in neonates and young infants. AB - There has been recent renewed interest in historical antibiotics because of the increased antibiotic-resistant bacterial strains. Latamoxef, a semi-synthetic oxacephem antibiotic developed in 1980s, has been brought back into use for treatment of infections in newborns recently, however, it is still used off-label in neonatal clinical practice due to the lack the evidence-based dosing regimen. Our study was performed to evaluate the pharmacokinetics of latamoxef in neonates and young infants and to provide an evidence-based dosing regimen for newborns based on developmental pharmacokinetics-pharmacodynamics (PK-PD). Opportunistic blood samples from newborns treated with latamoxef were collected for determination of latamoxef concentration by high-performance liquid chromatography with UV detection. Population PK-PD analysis was conducted using NONMEM and R software. A total of 165 plasma samples from 128 newborns (postmenstrual age range: 28.4 to 46.1 weeks) were available for analysis. A two compartment model with first order elimination showed the best fit with the data. Current body weight, birth weight, and postnatal age were identified as significant covariates influencing latamoxef clearance. Simulation indicates that the current dosing regimen (30 mg/kg q12h) is adequate with MIC of 1 mg/L. For MIC of 4 mg/L, to achieve a target rate of 70% of patients having a free antimicrobial drug concentration exceeding the MIC during 70% of the dosing interval, 30 mg/kg q8h were required. Based on the developmental PK-PD analysis of latamoxef, a rational dosing regimen of 30 mg/kg q12h or q8h was required in newborns, depending on the pathogen. PMID- 30472291 TI - The antimetabolite 3-bromopyruvate selectively inhibits Staphylococcus aureus. AB - The rise in antibacterial resistance jeopardizes current therapeutic strategies to control infections, soliciting the development of novel antibacterial drugs with new mechanisms of action. In this work we report the discovery of a potent and selective anti-staphylococcal activity of 3-bromopyruvate (3BP), an antimetabolite in preclinical development phase as an anticancer drug. 3BP showed bactericidal activity against Staphylococcus aureus, with active concentrations comparable to those reported to be effective against cancer cells. In contrast, no relevant activity was observed against other ESKAPE bacteria (Enterococcus faecium, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.). The anti-staphylococcal activity of 3BP was confirmed using a panel of human and veterinary strains, including multidrug-resistant isolates. 3BP showed highest antibacterial activity under conditions which increase 3BP stability (acidic pH) or promote S. aureus fermentative metabolism (anaerobiosis), although 3BP was also able to kill metabolically-inactive cells. 3BP showed synergism with gentamicin, and also disrupted preformed S. aureus biofilms, at concentrations only slightly higher than those inhibiting planktonic cells. This study unravels novel antibacterial and anti-biofilm activities for the anticancer drug 3BP, thus paving the way for further pre-clinical studies. PMID- 30472292 TI - Intrapulmonary pharmacokinetics of antibiotics used to treat nosocomial pneumonia caused by gram-negative bacilli: a systematic review. AB - BACKGROUND: . Knowledge of antibiotic concentrations achievable in the epithelial lining fluid (ELF) will help guide antibiotic dosing for treating patients with gram-negative bacillary ventilator-associated pneumonia (VAP). OBJECTIVE: . To compare: (1) the ELF:serum penetration ratio of antibiotics in patients with pneumonia, including VAP, and also healthy study participants and (2) the ELF and/or tracheal aspirate antibiotic concentrations following intravenous and nebuliser delivery. METHODS: . Web of Science, EMBASE and PubMed databases were searched and a systematic review undertaken. RESULTS: . Fifty-two studies were identified. ELF penetration ratios for aminoglycosides and most beta-lactam antibiotics administered intravenously were between 0.12 and 0.57, whereas intravenous colistin may be undetectable in the ELF. In contrast, estimated mean fluoroquinolone ELF penetration ratios of as much as 1.31 were achieved. Importantly, ELF penetration ratios appear reduced in critically-ill patients with pneumonia compared with healthy volunteers receiving intravenous ceftazidime, levofloxacin and fosfomycin; thus, dose adjustment is likely required in the critically-ill. Unlike the systemic administration route, nebulisation of antibiotics achieves high ELF concentrations. Nebulised 400 mg twice-daily amikacin resulted in a median peak ELF steady-state concentration of 976.01 mg/L (interquartile range 410.3 - 2563.1 mg/L). Similarly, nebulised 1 million international units of colistin resulted in a peak ELF concentration of 6.73 mg/L (interquartile range 4.80 - 10.10 mg/L). CONCLUSION: . Further pharmacokinetic studies investigating the mechanisms for ELF penetration in infected patients and healthy controls are needed to guide antibiotic dosing in VAP and when potential benefits of nebulised therapy might be realised. PMID- 30472293 TI - Fecal microbiota transplantation shortens the colonization period and allows the re-entry of patients carrying carbapenamase-producing bacteria into medical care facilities. AB - BACKGROUND: Colonization with carbapenemase producing Enterobacteriaceae or Acinetobacter (CPE/A) is associated with complex medical care requiring implementation of specific isolation policies and limitation of patient discharge to other medical facilities. Fecal Microbiota Transplantation (FMT) has been proposed in order to reduce the duration of gut colonization. OBJECTIVES: We investigated whether a dedicated protocol of FMT could reduce the negativation time of CPE/A intestinal carriage in patients whose medical care has been delayed due to such colonization. METHOD: We performed a matched case-control retrospective study between patients who received FMT treatment and those who did not among CPE/A colonized patient addressed for initial clustering at our institute. We adjusted two controls per case based on sex, age, bacterial species and carbapenemase type. The primary outcome was the delay in negativation of rectal-swab cultures. RESULTS: At day 14 post-FMT, 8/10 (80%) treated patients were cleared for intestinal CPE/A carriage. In the control group, 2/20 (10%) had a spontaneous clearance at day 14 after CPE/A diagnostic. FMT led patients to reduce the delay of decolonization (median 3 days post-FMT for treated patients versus 50.5 days after the first documentation of digestive carriage for control patients) and discharge from the hospital (median 19.5 days post-FMT for treated patients versus 41 for control patients). CONCLUSION: FMT is a safe and time saving procedure to discharge CPE/A-colonized patients from the hospital. A standardized protocol including 5 days of antibiotic treatment, bowel cleansing and systematic indwelling devices removal should improve the effectiveness of the protocol. PMID- 30472294 TI - Recruited bone marrow derived cells, local stromal cells and IL-17 at the front line of resistance development to anti-VEGF targeted therapies. AB - Although anti-angiogenic agents targeting VEGF have shown affordable beneficial outcomes in several human cancer types, in most pre-clinical and clinical studies, these effects are transient and followed by rapid relapse and tumor regrowth. Recently, it has been suggested that recruited bone marrow derived cells (BMDCs) to the tumor-microenvironment together with stromal cells play an important role in development of resistance to anti-VEGF therapies. Additionally, acquired resistance to anti-VEGF therapies has shown to be mediated partly through overexpression of different pro-angiogenic cytokines and growth factors including G-CSF, IL-6, IL-8, VEGF and FGF by these cells. Alongside, IL-17, a pro inflammatory cytokine, mostly secreted by infiltrated CD4+ T helper cells, has shown to mediate resistance to anti-VEGF therapies, through recruiting BMDCs and modulating stromal cells activities including endothelial cells, tumor associated macrophages and cancer associated fibroblasts. Here, we examined the role of BMDCs, tumor stromal cells, IL-17 and their negotiation in development of resistance to anti-VEGF targeted therapies. PMID- 30472295 TI - Ameliorative effect of gallic acid on sodium arsenite-induced spleno-, cardio- and hemato-toxicity in rats. AB - AIM: Arsenic is an important toxic chemical affecting millions of people around the world. Exposure to inorganic arsenic results in various health problems including skin lesions, hypertension, hematological disturbance, cardiovascular disease, spleen enlargement and cancer. Gallic acid (GA) is an important phenolic compound possessing various pharmacological properties including anti inflammatory, antioxidant and free radical scavenging activities. The present study investigated effects of GA against sodium arsenite (SA)-induced spleno-, cardio- and hemato-toxicity. MAIN METHODS: Thirty-five adult male Wistar rats were randomly divided into five groups; group I received normal saline (2 ml/kg/day, p.o.) for 21 days, group II received SA (10 mg/kg/day, p.o.) for 14 days, group III and IV were treated with GA (10 and 30 mg/kg/day, respectively) for 7 days prior to receive SA and treatment was continued up to 21 days in parallel with SA administration, group V received GA (30 mg/kg/day, p.o.) for 21 days. The level of MDA, NO and glutathione (GSH) and the activity of glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase were measured in heart and spleen tissues. Creatine kinase-MB (CK-MB) activity and hematological and histopathological parameters were also assessed. KEY FINDINGS: GA significantly decreased SA-induced elevation of MDA and NO levels and reduction of GSH level and GPx and SOD activity in heart and spleen tissues. Furthermore, GA improved SA induced alteration in hematological and histopathological parameters and reduced SA-induced elevation of serum CK-MB activity. SIGNIFICANCE: Our results suggest that GA inhibits SA-induced spleno-, cardio- and hemato-toxicity through reducing oxidative stress. PMID- 30472296 TI - Geniposide protects PC-12 cells against oxygen and glucose deprivation-induced injury by up-regulation of long-noncoding RNA H19. AB - AIMS: Hypoxic-ischemic encephalopathy (HIE) is a common brain injury disease in neonates, which can lead to neonatal disability and death. Geniposide (GEN) is a main ingredient of Gardenia jasminoides whose anti-tumor, anti-inflammatory and anti-apoptotic effects have been reported in various diseases. However, the effect of GEN on HIE remains uninvestigated. This study aimed to clarify the protective effect of GEN on PC-12 cells against oxygen and glucose deprivation (OGD)-induced injury. MAIN METHODS: PC-12 cells were subjected to OGD treatment, cell viability, cell cycle-associated factors, apoptosis and apoptosis-associated factors were then determined. The different concentrations of GEN were used to stimulate PC-12 cells, and the effects of GEN on cell proliferation and apoptosis in OGD-treatment cells were assessed. Subsequently, relative expression level of H19 was analyzed in PC-12 cells after treatment with GEN. After this, si-H19 was transfected into PC-12 cells to explore the regulatory effect of H19 on PC-12 cells after treatment with GEN and OGD. Besides, PI3K/AKT and Wnt/beta-catenin pathways were examined by western blot assay. KEY FINDINGS: OGD significantly inhibited cell viability, decreased CyclinD1, CDK4 and CDK6 expression, induced apoptosis and up-regulated Cleaved-Caspase-9/-7/-3 expression in PC-12 cells. GEN treatment obviously alleviated OGD-induced cell injury. Additionally, H19 expression was up-regulated by GEN, and H19 knockdown reversed the protective effect of GEN on PC-12 cells against OGD-induced injury. Finally, GEN activated PI3K/AKT and Wnt/beta-catenin pathways by regulating H19 in OGD-insulted PC-12 cells. SIGNIFICANCE: The findings suggested that GEN protected PC-12 cells against OGD-induced injury by up-regulation of H19. PMID- 30472297 TI - Tilianin mediates neuroprotection against ischemic injury by attenuating CaMKII dependent mitochondrion-mediated apoptosis and MAPK/NF-kappaB signaling. AB - AIMS: Tilianin, a naturally occurring flavonoid glycoside, possesses versatile biological activities including antioxidant, anti-inflammatory, energy collecting and anti-hypoxic effects. Little is known about the mechanisms underlying the effect of tilianin against ischemic injury in neuronal cells. We aimed to determine the potential targets and mechanisms of tilianin treatment behind the crosstalk pathways induced by oxygen-glucose deprivation (OGD). MAIN METHODS: We used an in silico docking model for interaction mode analysis and in vitro models for mechanistic exploration and target verification. Protein changes were measured using cellular immunofluorescence and ELISA techniques. KEY FINDINGS: The ability of tilianin to promote recovery of OGD-induced neurocytotoxic injury was demonstrated by maintenance of cell viability, membrane integrity and nuclear homogeneity. Tilianin treatment was also found to balance the concentrations of proapoptotic and antiapoptotic proteins that had been modified by OGD-induced mitochondrial dysfunction. Of these intersectional cascades, Ca2+/calmodulin dependent protein kinase II (CaMKII) was found to bind efficiently with tilianin. This presented a certain binding score along with down-regulation of ox-CaMKII and p-CaMKII in SH-SY5Y cells affected by OGD. Importantly, after utilizing KN93, one specific CaMKII inhibitor, tilianin-mediated neuroprotection against OGD was abolished. This effect was accompanied by upregulation of mitochondrial function. Thus, the beneficial effects of tilianin toward mitochondrion-mediated apoptosis and p38/JNK/NF-kappaB-associated inflammatory pathways were reversed following CaMKII inhibition. SIGNIFICANCE: Our study indicated that attenuation of CaMKII linked signaling mediated through mitochondria and p38/JNK/NF-kappaB inflammatory pathways is a key mechanism by which tilianin exerts its neuroprotective effects against cerebral ischemia. PMID- 30472298 TI - Carvacrol ameliorates experimental autoimmune encephalomyelitis through modulating pro- and anti-inflammatory cytokines. AB - AIM: The inflammatory process is a key step in multiple sclerosis (MS) development. Carvacrol exhibits various anti-inflammatory properties. We aimed to assess the Carvacrol effects on clinical manifestations and production of pro inflammatory (IFN-gamma, IL-6 and IL-17) and anti-inflammatory (TGF-beta, IL-4, and IL-10) cytokines in experimental autoimmune encephalomyelitis (EAE) as MS animal model. MAIN METHODS: EAE mice were treated with 5, 10 mg/kg dose of Carvacrol or vehicle, as the control EAE group, every other day until day-21 post EAE induction. On day22, the leukocyte infiltration within the CNS was estimated using hematoxylin-eosin staining. The cytokine production by splenocytes was determined after in vitro stimulating with myelin oligodendrocyte protein (MOG). KEY FINDINGS: The EAE clinical scores in 5 and 10 mg/kg Carvacrol-treated mice were lower than untreated group (P < 0.001 and P < 0.01, respectively). The amounts of IFN-gamma and IL-6 production by splenocytes of 5 and 10 mg/kg Carvacrol-administered mice were lower than control group (P < 0.001, and P < 0.01 for IFN-gamma respectively; P ? 0.05 for IL-6). Splenocytes of 5 and 10 mg/kg Carvacrol-treated mice produced higher levels of TGF-beta than untreated mice (P < 0.001). in splenocytes of 5 mg/kg Carvacrol-treated group the IL-10 production was higher while IL-17 secretion was lower than control group (both with P < 0.01). SIGNIFICANCE: Carvacrol exhibits modulatory effects on expression of pro- and anti-inflammatory cytokines. It ameliorates EAE clinical and pathological consequences and therefore its potentials may be considered in treating MS patients. PMID- 30472299 TI - Palpha-syn* mitotoxicity is linked to MAPK activation and involves tau phosphorylation and aggregation at the mitochondria. AB - We recently identified a truncated and phosphorylated form of alpha-synuclein, palpha-syn*, as a key neurotoxic alpha-synuclein species found in cultured neurons, as well as in mouse and Parkinson's disease patients' brains. Small palpha-syn* aggregates localize to mitochondria and induce mitochondrial damage and fragmentation. Herein, we investigated the molecular basis of palpha-syn* induced toxicity. By immunofluorescence, we found phosphorylated MKK4, JNK, ERK5 and p38 MAPKs in palpha-syn* inclusions. pJNK colocalized with palpha-syn* at mitochondria and mitochondria-associated ER membranes where it was associated with BiP and pACC1, markers for the ER and energy deprivation, respectively. We also found that palpha-syn* aggregates are tightly associated with small ptau aggregates of similar size. Palpha-syn*/ptau inclusions localized to areas of mitochondrial damage and to mitophagic vesicles, showing their role in mitochondrial toxicity, mitophagy induction and their removal along with damaged mitochondrial fragments. Several MAPKs may act cooperatively to phosphorylate tau, notably JNK, p38 and GSK3beta, a non-MAPK that was also found phosphorylated in the vicinity of palpha-syn*/ptau aggregates. These results add insight into the mechanisms by which palpha-syn* exerts its toxic effects that include the phosphorylation of several kinases of the MAPK pathway, as well as the formation of ptau at the mitochondrial membrane, likely contributing to mitotoxicity. Thus palpha-syn* appears to be the trigger of a series of kinase mediated pathogenic events and a link between alpha-syn pathology and tau, another protein known to aggregate in Parkinson's disease and other synucleinopathies. PMID- 30472300 TI - Isotropically weighted intravoxel incoherent motion brain imaging at 7T. AB - Perfusion magnetic resonance imaging (MRI) is a promising non-invasive technique providing insights regarding the brain's microvascular architecture in vivo. The scalar perfusion metrics can be used for quantitative diagnostics of various brain abnormalities, in particular, in the stroke cases and tumours. However, conventional MRI-based perfusion approaches such as dynamic contrast-enhanced perfusion imaging or arterial spin labelling have a few weaknesses, for instance, contrast agent deposition, low signal-to-noise ratio, limited temporal and spatial resolution, and specific absorption rate constraints. As an alternative, the intravoxel incoherent motion (IVIM) approach exploits an extension of diffusion MRI in order to estimate perfusion parameters in the human brain. Application of IVIM imaging at ultra-high field MRI might employ the advantage of a higher signal-to-noise ratio, and thereby the use of higher spatial and temporal resolutions. In the present work, we demonstrate an application of recently developed isotropic diffusion weighted sequences to the evaluation of IVIM parameters at an ultra-high 7T field. The used sequence exhibits high immunity to image degrading factors and allows one to acquire the data in a fast and efficient way. Utilising the bi-exponential fitting model of the signal attenuation, we performed an extensive analysis of the IVIM scalar metrics obtained by a isotropic diffusion weighted sequence in vivo and compared results with a conventional pulsed gradient sequence at 7T. In order to evaluate a possible metric bias originating from blood flows, we additionally used a truncated b-value protocol (b-values from 100 to 200 s/mm2 with the step 20 s/mm2) accompanied to the full range (b-values from 0 to 200 s/mm2). The IVIM scalar metrics have been assessed and analysed together with a large and middle vessel density atlas of the human brain. We found that the diffusion coefficients and perfusion fractions of the voxels consisting of large and middle vessels have higher values in contrast to other tissues. Additionally, we did not find a strong dependence of the IVIM metrics on the density values of the vessel atlas. Perspectives and limitations of the developed isotropic diffusion weighted perfusion are presented and discussed. PMID- 30472301 TI - Magnetic resonance imaging in the presence of projectiles and projectile fragments: Artefacts, image quality, rotation and movement. AB - BACKGROUND AND PURPOSE: Gunshot injuries have been considered a contraindication for MRI because of the risk of secondary dislodgement of retained metallic foreign bodies. The objective of our study was to provide a systematic overview of the behaviour of projectiles and fragments in order to aid decision-making regarding the use of MRI in clinical practice. MATERIALS AND METHODS: Ferromagnetic (n = 2) and non-ferromagnetic (n = 5) projectiles and fragments that were lodged in soft tissue (porcine masseter muscles) were examined using standard protocols at 1, 1.5 and 3 T, to simulate clinical situations as realistically as possible. CT was performed before and after every MRI to assess rotation and movement. Artefacts and image quality were analysed using Likert type scales. RESULTS: Ferromagnetic projectiles were of poorer quality and showed larger artefacts and did not provide benefit for clinical practice compared to images of non-ferromagnetic material. Image quality of non-ferromagnetic projectiles varied widely (from very good to moderate) depending on the composition of the projectiles. Field strength (1 T to 3 T) had no relevant influence on image quality. CONCLUSIONS: Non-ferromagnetic projectiles are not a contraindication for MR imaging since there is no potential risk of secondary dislodgement. Image quality and the extent of artefacts, however, strongly depend on the type of ammunition used. The presence of ferromagnetic projectiles in or near vital anatomic structures is a contraindication for MRI because these objects may exhibit movement in response to magnetic fields. Knowledge of the type of projectile used appears to be important in order to guide patient management before an examination is performed. So, the production and use of projectiles suitable for MRI should be favored in the future, knowing that this will be hard to fulfil. PMID- 30472302 TI - Liposomal Bupivacaine vs. Bupivacaine Hydrochloride with Lidocaine During Midurethral Sling Placement: a Randomized Controlled Trial. AB - STUDY OBJECTIVE: The primary objective was to study the effects of liposomal bupivacaine (LB) compared to bupivacaine HCL with lidocaine on postoperative day 1 pain scores. DESIGN: A randomized control trial (Canadian Task Force classification level 1). SETTING: An academic medical center within the department of female pelvic medicine and reconstructive surgery. PATIENTS: Fifty seven patients undergoing a midurethral sling by a fellowship-trained Urogynecologic surgeon and a fellow in female pelvic medicine and reconstructive surgery. INTERVENTIONS: 57 patients were enrolled to participate in this study. There were 24 patients randomized to receive liposomal bupivacaine and 33 to receive a mixture of bupivacaine and lidocaine during the placement of a retropubic midurethral sling. MEASUREMENTS AND MAIN RESULTS: Patients were given a dairy of pain scales and asked to record their level of pain using the provided Visual Analog Scales (VAS) scored on a 100 mm Likert scale. Patients recorded their pain 4 hours after hospital discharge, the night of surgery, and their most intense pain each day thereafter for 7 days postop. In addition patients recorded total opioid and NSAID consumption daily for 1 week postoperative. Finally, a quality of recovery was assessed using the Quality of Recovery-15 questionnaire (QoR-15) scores. The median pain score in the experimental group was 20 mm (0-80) versus 30 mm (0-60) in the comparative group (p=.046). The POD 1 QoR-15 scores were significantly lower in the LB group, 124 (54-150) vs 144 (68-150) p=.007. There no significant differences in opioid and NSAID consumption, the remaining pain scores or POD 7 QoR-15 scores. CONCLUSION: The results suggest use of liposomal bupivacaine during a retropubic midurethral sling placement does not provide a clinically significant difference in POD 1 pain scores when compared to immediate active Bupivacaine HCL and lidocaine. Institutional review board number 883788-9, May 2016 ClinicalTrials.gov ID NCT02875015, April 2016 https://clinicaltrials.gov/ct2/show/NCT02875015. PMID- 30472303 TI - Abnormal Uterine Bleeding in a Patient with Klippel-Trenaunay Syndrome. PMID- 30472304 TI - The cerebral endothelial cell as a key regulator of inflammatory processes in sterile inflammation. AB - Cerebral endothelial cells accomplish numerous tasks connected to the maintenance of homeostasis of the central nervous system. They create a barrier between the central nervous system and peripheral blood and regulate mechanotransduction, vascular permeability, rheology, thrombogenesis, and leukocyte adhesion. In pathophysiological conditions (e.g., stroke or ischemia-reperfusion injury) the endothelial functions are impaired, leading to increased vascular permeability, vascular inflammation, leukocyte-endothelium interactions, and transendothelial migration, driving CNS inflammation and neuronal destruction. This review describes the current knowledge on the regulatory roles of endothelial cells in neuroinflammatory processes. PMID- 30472305 TI - Exploring the relationship between Endothelin-1 and peripheral inflammation in multiple sclerosis. AB - BACKGROUND: Identifying pathways linking neuroinflammation and neurodegeneration is essential to help prevent disability progression in people with multiple sclerosis (MS). Endothelin-1 (ET-1) is a potent vasoconstrictor thought to contribute to cerebral hypoperfusion and tissue damage in MS. Its link with the neuroinflammatory process remains poorly investigated. OBJECTIVES: To determine plasma ET-1 levels in treatment-naive people with MS and controls, and the relationship between ET-1 and other peripheral immune mediator levels as potential markers of the disease process. METHODS: This is a retrospective study that included specimens previously collected from 35 treatment-naive patients with clinically isolated syndrome highly suggestive of MS or definite MS and 35 sex- and age-matched controls. ET-1 plasma levels were measured by enzyme-linked immunosorbent assay (ELISA), and plasma cytokine levels [interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12(p70), IL-13, interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha] were simultaneously measured by Multiplex assay. RESULTS: ET-1 levels were significantly increased in MS patients compared to controls. No significant difference in cytokine levels between the groups were found. However, a significant increase in IFN-gamma/IL-4 ratio was observed in patients with MS in comparison with controls, suggestive of Th1 skewed response. Binary logistic regression was performed to ascertain the effects of age, sex, ET 1 and cytokine levels on the likelihood of MS diagnosis. In the final model, ET 1, IL-4 and IFN-gamma levels remained as predictors of MS. There was no significant correlation between ET-1 and cytokine levels. CONCLUSIONS: Patients with MS presented increased levels of ET-1 and an immune response biased towards a Th1 profile. Although both ET-1 and Th1 cytokine profile were predictors of MS diagnosis, ET-1 levels were not associated with peripheral immune markers, suggesting that these changes may occur independently. PMID- 30472307 TI - Biomaterials of PVA and PVP in medical and pharmaceutical applications: Perspectives and challenges. AB - Poly(vinyl alcohol) (PVA) has attracted considerable research interest and is recognized among the largest volume of synthetic polymers that have been produced worldwide for almost one century. This is due to its exceptional properties which dictated its extensive use in a wide variety of applications, especially in medical and pharmaceutical fields. However, studies revealed that PVA-based biomaterials present some limitations that can restrict their use or performances. To overcome these limitations, various methods have been reported, among which blending with poly(vinylpyrrolidone) (PVP) showed promising results. Thus, our aim was to offer a systematic overview on the current state concerning the preparation, properties and various applications of biomaterials based on synergistic effect of mixtures between PVA and PVP. Future trends towards where the biomaterials research is headed were discussed, showing the promising opportunities that PVA and PVP can offer. PMID- 30472306 TI - A comprehensive review on histone-mediated transfection for gene therapy. AB - Histone has been considered to be an effective carrier in non-viral gene delivery due to its unique properties such as efficient DNA binding ability, direct translocation to cytoplasm and favorable nuclear localization ability. Meanwhile, the rapid development of genetic engineering techniques could facilitate the construction of multifunctional fusion proteins based on histone molecules to further improve the transfection efficiency. Remarkably, histone has been demonstrated to achieve gene transfection in a synergistic manner with cationic polymers, affording to a significant improvement of transfection efficiency. In the review, we highlighted the recent developments and future trends in gene delivery mediated by histones or histone-based fusion proteins/peptides. This review also discussed the mechanism of histone-mediated gene transfection and provided an outlook for future therapeutic opportunities in the viewpoint of transfection efficacy and biosafety. PMID- 30472308 TI - The impact of low to moderate chronic intermittent ethanol exposure on behavioral endpoints in aged, adult and adolescent rats. AB - The average age of the population in the United States and other countries is increasing. Understanding the health consequences in the aged population is critical. Elderly individuals consume ethanol, often at elevated rates, and in some cases in a binge episode. The present study sought to investigate if binge like ethanol exposure in aged male rats produced differential health and behavioral effects compared to adult male and adolescent male rats. Subjects were exposed to either 1.0 g/kg or 2.0 g/kg ethanol every other day via intraperitoneal injection for 20 days and tested on a variety of behavioral measures and body weight. Binge like ethanol exposure produced differential effects on body weight between aged and adolescent and adult rats. In addition, aged rats had significantly longer loss of righting reflex and demonstrated a trend toward tolerance following the 2.0 g/kg exposure. No significant effects on anxiety-like behavior as measured by open arm entries, depressive-like symptoms as measured by immobility in the forced swim test or cognitive performance as measured by latency and pathlength in the Morris water maze were found. These results demonstrate that aged animals are differentially sensitive to the impact of chronic intermittent ethanol exposure in some, but not all behaviors. Future research is needed to understand the mechanisms of these differential effects. PMID- 30472309 TI - Assessment of Interleukin-6 Signaling Effects on Behavioral Changes Associated with Acute Alcohol Intoxication in adult male rats. AB - Recent studies have demonstrated unique brain cytokine signatures associated with acute ethanol intoxication (increased IL-6) and withdrawal (increased IL-1beta and TNFalpha). The purpose of the present studies was to examine the potential functional role of increased central interleukin-6 (IL-6). We utilized two tests of ethanol sensitivity to establish a potential role for IL-6 after high (3.5-4.0 g/kg i.p) or moderate (2.0 g/kg i.p) doses of ethanol: loss of righting reflex (LORR) and conditioned taste aversion (CTA), respectively. Briefly, guide cannula were implanted into the third ventricle of adult male Sprague-Dawley rats. In the first experiments, rats were infused with: 25, 50, 100, or 200 ng of IL-6; or 0.3, 3.0, or 9.0 MUg of the JAK/STAT inhibitor AG490 30 min prior to a high dose ethanol challenge. Although sleep time was not affected by exogenous IL-6, infusion of AG490 increased latency to lose the righting reflex relative to vehicle infused rats. Next, we assessed whether IL-6 was sufficient to produce a CTA. Moderately water-deprived rats received i.c.v. infusions of 25, 50, or 100 ng IL-6 immediately after 60 min access to 5% sucrose solution. 48 hr later, rats were returned to the context and given 60 min access to sucrose solution. IL-6 infusion had no significant effect on sucrose intake when all rats were considered together. However, a median split revealed that low sucrose-consuming rats significantly increased their drinking on test day, an effect that was not seen in rats that received 50 or 100 ng of IL-6. In the last study, AG490 had no effect on ethanol-induced CTA (2 g/kg). Overall, these studies suggest that IL-6 had only a minor influence on ethanol-induced behavioral changes, yet phenotypic differences in sensitivity to IL-6 were apparent. These studies are among the first to examine a potential functional role for IL-6 in ethanol-related behaviors, and may have important implications for understanding the relationship between acute ethanol intoxication and its associated behavioral alterations. PMID- 30472310 TI - Create Better Health: A Practical Approach to Improving Cooking Skills and Food Security. PMID- 30472312 TI - Fresh Conversations, a SNAP-Ed Program for Older Adults: Feedback From Program Facilitators. AB - OBJECTIVE: As part of a statewide Supplemental Nutrition Assistance Program Education program evaluation, Fresh Conversations (FC) facilitators (ie, educators) provided input into a new delivery model. METHODS: The researchers interviewed 25 FC facilitators. Interviews were recorded, transcribed verbatim, and analyzed for common themes. RESULTS: Most facilitators were women with at least 1 year of FC experience. Key motivators for serving as an FC facilitator included alignment with current employment responsibilities and gerontology interest. Training was viewed as helpful, thorough, and self-explanatory. Implementation challenges included recruitment, public speaking, and time management. Nearly all stated that FC content was important and that other seniors at other congregate meal sites would be interested in FC. CONCLUSIONS AND IMPLICATIONS: Findings suggest that facilitators were pleased with FC; however, their experiences might be further improved through enhanced training. Further exploration into community food and nutrition program educators' feedback is needed to ensure these programs meet their needs as well as those of the audience. PMID- 30472311 TI - Development and Testing of Program Evaluation Instruments for the iCook 4-H Curriculum. AB - OBJECTIVE: To develop and test the validity of program outcome evaluation instruments for cooking, eating, and playing together for obesity prevention during iCook 4-H. DESIGN: Instrument development for both youth and adults through pre-post testing of items newly constructed and compiled to address key curriculum constructs. Testing occurred throughout program intervention and dissemination to determine dimensionality, internal consistency and test-retest reliability, and validity. SETTING: A 5-state out-of-school program in cooperative extension and other community sites. PARTICIPANTS: Youths aged 9-10 years; adults were main food preparers; the first phase involved 214 dyads and the second phase, 74 dyads. MAIN OUTCOME MEASURE(S): Youth measures were cooking skills, culinary self-efficacy, physical activity, and openness to new foods. Adult measures were cooking together, physical activity, and eating together. ANALYSIS: Exploratory factor analysis to determine initial scale structure and confirmatory factor analysis to confirm factor structures. Longitudinal invariance tests to see whether the factor structure held over time. Test-retest reliability was determined by Pearson r and internal consistency was determined by coefficient Omega and Cronbach alpha. Validity testing was determined by Pearson r correlations. RESULTS: Youth cooking skills, openness to new foods, and adult eating together and cooking together showed strong evidence for dimensionality, reliability, and validity. Youth physical activity and adult physical activity measures showed strong evidence for dimensionality and validity but not reliability. The youth culinary self-efficacy measure showed strong evidence for reliability and validity but weaker evidence for dimensionality. CONCLUSIONS AND IMPLICATIONS: Program outcome evaluation instruments for youths and adults were developed and tested to accompany the iCook 4-H curriculum. Program leaders, stakeholders, and administrators may monitor outcomes within and across programs and generate consistent reporting. PMID- 30472313 TI - Prevalence and co-occurrence of unhealthy lifestyle habits and behaviours among secondary school students in Tuscany, central Italy. AB - OBJECTIVES: Unhealthy habits acquired during adolescence may persist in adulthood and eventually increase the risk of chronic illnesses. STUDY DESIGN: We reported on a survey conducted in 2013-2015 among secondary school students in Tuscany, central Italy. METHODS: We compared the prevalence of self-reported lifestyle characteristics and overweight/obesity between genders and age groups (14-16 vs 17-21 years). We partitioned each gender- and age-specific stratum into groups based on cigarette smoking and engagement in sport activities, and compared the prevalence of other unhealthy lifestyles across groups using Poisson regression. RESULTS: Overall, 2167 students (53.3% males, mean age 16.8 years) were included. Males were more frequently overweight/obese than females. Cigarette smoking increased with age and did not differ by gender. Males were more likely to engage in sport activities, drink alcoholic beverages and adopt other unhealthy lifestyle habits, whereas females reported a more frequent use of painkillers. Cigarette smoking was the single lifestyle characteristic most consistently associated with other unhealthy habits. CONCLUSIONS: The prevalence and patterns of co-occurrence of unhealthy lifestyle habits varied by gender and age group among secondary school students in Italy. Our findings should be taken into account when planning public health initiatives aiming to combat obesity and tackle unhealthy lifestyles among secondary school students in Italy. PMID- 30472314 TI - Bruno's Score. AB - Many of our experiences in hospice and palliative care medicine are challenging. We support dying patients and their families as they struggle with the transition from life to death, and continue to support those in mourning. Many times, in America, it is difficult to even appreciate a glimmer of spiritual grace as our patients die. We easily remain stuck in the material, and distance ourselves from the spiritual. Some exits are quite graceful, however. I present the case of an exceptional person, who enjoyed an exceptional life and had an exceptionally graceful dying process and death, in hopes that his story may encourage other healers as much as he inspired me. Bruno was a composer and cognitive musicologist, whose art forms of light and music simultaneously move and challenge virtually all of the people and other artists he interfaced with and taught, including his talented wife and family, his friends, his acquaintances, his students, his colleagues, and his deans. He embodied theories as diverse as mathematical strange loops, continually paradoxical / recursive illusory art, contrapuntal fugues, and artificial intelligence. Bruno's spirituality was uncommonly profound. It spanned and interconnected many eclectic faith traditions, theologies, and philosophies, including Taoism, Greek mythology, distributed cognition, mathematics, and Tibetan Buddhism. It resonated strongly with Zen and Christian mysticism. Some of Bruno's being and transformation to non being was obvious; some of it was inscrutable. PMID- 30472315 TI - Multicenter Study of the psychometric properties of the new Demoralization Scale (DS-II) in Spanish-speaking advanced cancer patients. AB - CONTEXT: Demoralization is a state of existential distress in patients with advanced illness, typically with coping difficulties, feelings of loss of sense and purpose in life and despair, among other things. The DS-II is an evaluation tool for this syndrome, which has recently been reformulated on a shorter scale. OBJECTIVE: To obtain a Spanish version of the DS-II and to assess its psychometric properties in advanced cancer patients in Spain and a number of Latin American countries. METHODS: Following a translation- back translation process, a validation study and a confirmatory analysis using structural equation models with their corresponding latent constructs was undertaken. Patients completed the DS-II in Spanish (DS-II (es)), the Hospital Anxiety and Depression Scale (HADS) and the Edmonton Symptom Assessment System-revised (ESAS-r). Reliability was studied according to internal consistency; construct validity and concurrent validity with the HADS and the ESAS-r; discriminant validity using the Karnofsky Performance Status scale; and feasibility, with response ratio and required time. Cut-off points were established, and sensitivity and specificity were studied. RESULTS: The DS-II (es) was obtained. 150 patients completed the validation study The confirmatory analysis showed coherence and all items correlated positively with their subscales and with the overall scale. Cronbach's Alpha for the DS-II (es) was 0.88, for the sense and purpose subscale 0.83, and for the coping ability 0.79. .Demoralization correlated significantly with emotional distress (rho=0.73, p<0.001). The tool distinguished between patients with diverse functional levels (rho=-0.319, p=0.001). Cut-off points at 10 and 20 out of 32 were established. The scale showed high sensitivity (81.97%) and specificity (80.90%). The prevalence of demoralization was 33% in our sample. CONCLUSION: The Spanish version of the new Kissane DS-II demoralization scale has shown to be valid, reliable and feasible with adequate psychometric properties. PMID- 30472316 TI - Development of a Simulation-Based Mastery Learning Curriculum for Breaking Bad News. AB - INTRODUCTION: Physician communication impacts patient outcomes. However, communication skills, especially around difficult conversations, remain suboptimal and there is no clear way to determine the validity of entrustment decisions. The aims of this study are to (a) describe the development of a simulation-based mastery learning (SBML) curriculum for breaking bad news (BBN) conversation skills; and (b) set a defensible minimum passing standard (MPS) to ensure uniform skill acquisition among learners. INNOVATION: An SBML BBN curriculum was developed for fourth-year medical students. An assessment tool was created to evaluate the acquisition of skills involved in a BBN conversation. Pilot testing was completed to confirm improvement in skill acquisition and set the MPS. OUTCOMES: A BBN assessment tool containing a 15-item checklist and 6 scaled items was developed. Students' checklist performance improved significantly at post-test compared to baseline (65.33%, SD=12.09% vs 88.67%, SD=9.45%, p<0.001). Students were also significantly more likely to have at least a score of 4 (on a 5-point scale) for the 6 scaled questions at post-test. The MPS was set at 80%, requiring a score of 12 items on the checklist and at least 4 out of 5 for each scaled item. Using the MPS, 30% of students would require additional training after post-testing. COMMENTS: We developed an SBML curriculum with a comprehensive assessment of BBN skills and a defensible competency standard. Future efforts will expand the mastery model to larger cohorts and assess the impact of rigorous education on patient care outcomes. PMID- 30472317 TI - Pre-treatment psychoneurological symptoms and their association with longitudinal cognitive function and quality of life in older breast cancer survivors. AB - CONTEXT: Symptoms affect quality of life (QOL), functional status, and cognitive function in cancer survivors, but older survivors are understudied. OBJECTIVES: To identify prototypical pre-systemic therapy psychoneurological symptom clusters among older breast cancer survivors, and determine whether these symptom clusters predicted cognition and QOL over time. METHODS: Women with newly diagnosed non metastatic breast cancer (n=319) and matched non-cancer controls (n=347) aged 60+ completed questionnaires and neuropsychological tests before systemic therapy and 12- and 24-months later. Latent class analysis identified clusters of survivors based upon their pre-therapy depression, anxiety, fatigue, sleep disturbance, and pain. Linear mixed-effects models examined changes in objective cognition, perceived cognition, and functional status (instrumental activities of daily living (IADL) disability, functional well-being, and breast cancer-specific QOL) by group, controlling for covariates. RESULTS: Nearly one-fifth of older survivors were classified as having a high pre-therapy symptoms (n=51; 16%); the remainder had a low symptoms (n=268; 84%); both groups improved over time on all outcomes. However, compared to the low symptom group and controls, survivors with high symptoms had lower baseline objective cognition and lower perceived cognition at baseline and 24-months, lower functional well-being at baseline and 12-months, greater IADL disability at baseline, and lower breast cancer-specific QOL at all time points (all p<0.05). CONCLUSION: Nearly one-fifth of older breast cancer survivors had high psychoneurological symptoms at diagnosis, which, predict clinically meaningful decrements in perceived cognition and function in the first 24 months post-diagnosis. Pre-treatment psychoneurological symptom clusters could identify survivors for monitoring or intervention. PMID- 30472318 TI - FAmily CEntered (FACE) Advance Care Planning among African-American and non African-American Adults Living with HIV in Washington, DC: A Randomized Controlled Trial to Increase Documentation & Health Equity. AB - CONTEXT: No prospective studies address disease-specific Advance Care Planning (ACP) for adults living with HIV/AIDS. OBJECTIVE: To examine the efficacy of FAmily-CEntered (FACE) ACP in increasing advance care planning and advance directive documentation in the medical record. METHODS: Longitudinal, two-arm, randomized controlled trial with intent-to-treat design recruited from 5 hospital based outpatient HIV clinics in Washington, DC. Adults living with HIV and their surrogate decision makers (N=233 dyads) were randomized to either an intensive facilitated two-session FACE ACP (Next Steps: Respecting Choices goals of care conversation and Five Wishes advance directive) or Healthy Living Control (conversations about developmental/relationship history and nutrition). RESULTS: Patients (n=223) mean age: 51 years, 56% male, 86% African-American. One hundred ninety-nine dyads participated in the intervention. At baseline, only 13% of patients had an advance directive. Three months post-intervention, this increased to 59% for the FACE ACP group versus 17% in the control group (p<0.0001). Controlling for race, the odds of having an advance directive in the medical record in the FACE ACP group was approximately 7 times greater than controls (Adjusted Odds Ratio=6.58, 95% C.I: 3.21-13.51, p<0.0001). Among African Americans randomized to FACE, 58% had completed/documented advance directives versus 20% of controls (p<0.0001). CONCLUSIONS: The FACE ACP intervention significantly improved ACP completion and advance directive documentation in the medical record among both African-American and non-African-American adults living with HIV in Washington, D.C., providing health equity in ACP which can inform best practices. PMID- 30472319 TI - SEC14L2, a lipid-binding protein, regulate HCV replication in culture with inter- and intra- genotype variations. AB - BACKGROUND & AIMS: Since the discovery of HCV, efficient viral replication of clinical isolates in cell culture was a challenge. This status quo changed with SEC14L2 mediated viral replication of clinical isolates in cell culture. Given the role of SEC14L2 in HCV replication, we aimed to study a large number of HCV positive sera carrying genotypes 1-4, to identify viral factors associated with efficient replication in cell culture. Additionally, we investigated whether 13 single nucleotide polymorphisms (SNPs) of SEC14L2 have an impact on RNA replication of natural occurring HCV isolates. METHODS: We generated Huh-7.5 cell lines overexpressing SEC14L2 or 13 coding SNPs and tested 73 different HCV positive sera for in vitro replication. Furthermore, we genotyped a cohort of 262 patients with chronic HCV for the common SNP (rs757660) and investigated its effect on the clinical phenotype. RESULTS: HCV isolates from genotype 1, 2, 3 and 4 replicate in Huh-7.5 cells overexpressing SEC14L2. Interestingly, only subgenomic replicons from genotypes 1 and 3 showed enhanced replication whereas genotypes 2 and 4 remained unaffected. Furthermore, replication was independent from viral load. Importantly, all tested SNPs supported HCV RNA replication in vitro, while one SNP was associated with decreased SEC1L2 expression and viral RNA. All SNPs exhibited comparable cellular cholesterol and vitamin E abundance in naive Huh-7.5 cells. CONCLUSIONS: This large screen of natural HCV isolates of 4 genotypes underscores the relevance of SEC14L2 as an in vitro HCV host factor. Additionally, SEC14L2 variants appear to recapitulate the wild type enhancement of HCV replication. Variant rs191341134 showed a decreased effect due to lowered stability, whereas variant rs757660, a high prevalence mutant, showed similar phenotype to the wild type. LAY SUMMARY: Until the year 2015, consistent replication of patient derived isolates of hepatitis C virus (HCV) in an in vitro model remained a limitation in HCV research. In 2015 a group of authors identified a protein named SEC14L2 that enabled the replication of isolates in a human hepatoma cell line named Huh-7.5. We implemented this model in our laboratory and performed a large screen encompassing 73 isolates of 4 different HCV genotypes. Additionally, we replaced the natural SEC14L2 with 13 different mutants to test if the protein variation could significantly alter its HCV replication enhancing functions. We showed that different genotypes of HCV react differently to the presence of this protein and the variants of the protein mimic the behaviour of the wild type. PMID- 30472320 TI - Evolutionary biology of human hepatitis viruses. AB - Hepatitis viruses are major threats to human health. During the last decade, highly diverse viruses related to human hepatitis viruses were found in animals other than primates. Here, we compare the unique biological properties and infection patterns of human hepatitis viruses and their animal homologues. We describe both surprising conservation and striking differences of infection patterns between human hepatitis viruses and their animal homologues, including transmission routes, liver tropism, oncogenesis, chronicity and envelopment. We discuss the potential for translation of newly discovered hepatitis viruses into preclinical animal models for drug testing, oncogenesis and vaccine development. Finally, we re-evaluate the evolutionary origins of human hepatitis viruses and discuss the past and present zoonotic potential of their animal homologues. PMID- 30472322 TI - Diabetes Care for Patients Experiencing Homelessness: Beyond Metformin and Sulfonylureas. AB - On any given night in the United States, an estimated 553,742 people are homeless. Applying a broader definition of homelessness that includes unstably housed people, an estimated 1.5% of Americans experience homelessness in a given year. Rates of diabetes are increasing amongst individuals experiencing homelessness. The social, psychological, and physical challenges of homelessness not only contribute to the rate of diabetes, but also complicate management. Unstable housing, limited medical resources, food insecurity, and competing priorities are barriers to diabetes care among patients experiencing homelessness. Homeless patients with diabetes more frequently develop specific comorbidities that require special attention, such as cardiovascular disease, substance abuse, depression, and foot wounds. The Affordable Care Act gave states the option to expand Medicaid to those earning up to 138% of the federal poverty level. This addressed a gap in coverage for low-income individuals not eligible for Medicaid or employer sponsored insurance. With increased insurance coverage, this has increased the variety of medications available to treat hyperglycemia from type 2 diabetes beyond metformin, sulfonylureas, and insulin. Several of the newer classes of medications have advantages for patients experiencing homelessness but also have special considerations in this vulnerable patient population. This narrative review will provide a review of dipeptidyl peptidase-4 inhibitor (DPP-4) inhibitors, glucagon-like peptide (GLP)-agonists, sodium glucose cotransporter (SGLT)-2 inhibitors, and thiazolidinediones (TZDs) in individuals experiencing homelessness. PMID- 30472321 TI - Real-life effectiveness and safety of Glecaprevir/Pibrentasvir in 723 patients with chronic hepatitis C. AB - BACKGROUND AND AIMS: Efficacy and safety of Glecaprevir/Pibrentasvir (G/P) among hepatitis C virus (HCV) infected patients have been only investigated in clinical trials, and no real-life data are available yet. The aim of our study was to investigate effectiveness and safety of G/P in an Italian real-life setting. METHODS: All HCV patients consecutively starting G/P between October 2017 and January 2018 within the NAVIGATORE-Lombardia Network were analyzed. G/P was administered according to drug label (8, 12 or 16 weeks). Fibrosis was staged either histologically or by liver stiffness measurement (LSM). Sustained virological response (SVR) was undetectable HCV-RNA 12 weeks after the end of treatment (EOT). RESULTS: 723 patients (50% males) were treated with G/P, 89% for 8 weeks. Median age was 58 years, BMI 23.9 Kg/m2, LSM 6.1 kPa, 84% F0-2, 16% Interferon-experienced. HCV-RNA was 1,102,600 IU/ml, and HCV genotype was 1 in 49% (32% 1b), 2 in 28%, 3 in 10% and 4 in 13%. Median eGFR was 90.2 ml/min, PLT 209 x 103/mm3 and albumin 4.3g/dl. SVR were 94% at ITT and 99.3% at PP analysis (8-week vs. 12-16-week: 99.2% vs. 100%). Five patients failed therapy due to post treatment relapse; post-treatment NS5A RAS was detected in one case. SVR rates were lower in males and in HCV-3 patients treated for 8 weeks (p=0.022), but independent of treatment duration, fibrosis stage, baseline HCV-RNA, HIV co infection, CKD stage and viral kinetics. Mild adverse events were reported in 8.3% of the patients, and 0.7% of them prematurely withdrew treatment. Three patients died of drug-unrelated causes. CONCLUSIONS: In a large real-life cohort of Italian patients, G/P administered for 8 or 12-16 weeks confirmed excellent effectiveness and safety. PMID- 30472324 TI - Cognitive abilities with a tiny brain: Neuronal structures and associative learning in the minute Nephanes titan (Coleoptera: Ptiliidae). AB - Revealing the effect of brain size on the cognitive abilities of animals is a major challenge in the study of brain evolution. Analysis of the effects of miniaturization on brain function in the smallest insects is especially important, as they are comparable in body size to some unicellular organisms and next to nothing is known about their cognitive abilities. We analyse for the first time the structure of the brain of the adult featherwing beetle Nephanes titan, one of the smallest insects, and results of the first ethological experiments on the capacity of learning in this species. N. titan is capable of associative learning, in spite of the structural modification in its nervous system and the greatly reduced number of neurons compared to the nervous systems of larger insects. Microinsects can become useful model organisms for neurobiology. On the one hand, the structural simplicity and extremely small size of their central nervous system make it possible to study it very efficiently. On the other hand, their learning capacity and retained principal cognitive abilities make them suitable objects for behavioural experiments. PMID- 30472323 TI - Intranasal delivery of hGDNF plasmid DNA nanoparticles results in long-term and widespread transfection of perivascular cells in rat brain. AB - The intranasal route of administration allows large therapeutics to circumvent the blood-brain barrier and be delivered directly to the CNS. Here we examined the distribution and pattern of cellular transfection, and the time course of transgene expression, in the rat brain after intranasal delivery of plasmid DNA nanoparticles (NPs) encoding hGDNF fused with eGFP. Intranasal administration of these NPs resulted in transfection and transgene expression throughout the rat brain, as indicated by eGFP ELISA and eGFP-positive cell counts. Most of the transfected cells were abluminal and immediately adjacent to capillaries and are likely pericytes, consistent with their distribution by perivascular transport. Intranasal administration of these plasmid DNA NPs resulted in significant, long term transgene expression in rat brain, with highest levels at 1week and continued expression for 6months. These results provide evidence in support of intranasal DNA NPs as a non-invasive, long-term gene therapy approach for various CNS disorders. PMID- 30472325 TI - Upregulation of human glycolipid transfer protein (GLTP) induces necroptosis in colon carcinoma cells. AB - Human GLTP on chromosome 12 (locus 12q24.11) encodes a 24 kD amphitropic lipid transfer protein (GLTP) that mediates glycosphingolipid (GSL) intermembrane trafficking and regulates GSL homeostatic levels within cells. Herein, we provide evidence that GLTP overexpression inhibits the growth of human colon carcinoma cells (HT-29; HCT-116), but spares normal colonic cells (CCD-18Co). Mechanistic studies reveal that GLTP overexpression arrested the cell cycle at the G1/S checkpoint via upregulation of cyclin-dependent kinase inhibitor-1B (Kip1/p27) and cyclin-dependent kinase inhibitor 1A (Cip1/p21) at the protein and mRNA levels, and downregulation of cyclin-dependent kinase-2 (CDK2), cyclin-dependent kinase-4 (CDK4), cyclin E and cyclin D1 protein levels. Assessment of the biological fate of HCT-116 cells overexpressing GLTP indicated no increase in cell death suggesting induction of quiescence. However, HT-29 cells overexpressing GLTP underwent cell death by necroptosis as revealed by phosphorylation of human mixed lineage kinase domain-like protein (pMLKL) via receptor-interacting protein kinase-3 (RIPK-3), elevated cytosolic calcium, and plasma membrane permeabilization by pMLKL oligomerization. Overexpression of W96A GLTP, an ablated GSL binding site mutant, failed to arrest the cell cycle or induce necroptosis. Sphingolipid assessment (ceramide, monohexosylceramide, sphingomyelin, ceramide-1-phosphate, sphingosine, and sphingosine-1-phosphate) of HT-29 cells overexpressing GLTP revealed large decreases (>5-fold) in sphingosine 1-phosphate with minimal change in 16:0-ceramide, tipping the 'sphingolipid rheostat' (S1P/16:0-Cer ratio) towards cell death. Depletion of RIPK-3 or MLKL abrogated necroptosis induced by GLTP overexpression. Our findings establish GLTP upregulation as a previously unknown suppressor of human colon carcinoma HT-29 cells via interference with cell cycle progression and induction of necroptosis. PMID- 30472327 TI - Managing Cross-Reactivity in Those with Peanut Allergy. AB - Peanut is an allergenic legume that can cross-react with other plant-based foods, notably other legumes and tree nuts. Peanut allergic individuals can be both co sensitized as well as co-allergic to such items, requiring foresight when eliciting a clinical history of reaction, in the diagnostic evaluation of such allergies, and in the counseling of patients as to food avoidances after a diagnosis is made. Legume allergens belong to the Fabaceae family and encompass the cupin, prolamin, PR-10, and LTP families, which mediate cross-sensitization including that between peanut and tree nut. Among legumes, the most common patterns of clinical cross-reactivity are between peanut and lupine, peanut and soy, as well as chickpea and lentil, though this is highly dependent upon geography and prevalence of these foods in the diet. Issues of cross sensitization may exist between peanut and certain tree nuts, as well as among tree nuts though such patterns do not always result in clinically relevant allergy. Molecular diagnostic testing may be a future tool to help parse out the aforementioned patterns, but oral food challenges are still the gold standard for accurate diagnosis. Though potential desensitization treatments have emerged for peanut allergy, these have not been developed for other legumes and most tree nuts, and desensitization to peanut has not proven to have an effect on legume cross-sensitization. PMID- 30472326 TI - Whole-genome resequencing of a world-wide collection of rapeseed accessions reveals genetic basis of their ecotype divergence. AB - Rapeseed (Brassica napus L.), an important oilseed crop, has adapted to diverse climate zones and latitudes by forming three main ecotype groups, namely winter, semi-winter and spring types. Genomic variations underlying these ecotypes are largely unknown. Here, we report the global pattern of genetic polymorphisms of rapeseed by resequencing a world-wide collection of 991 germplasm accessions. A total of 5.56 or 5.53 million single nucleotide polymorphisms (SNPs) and 1.86 or 1.92 million InDels were identified by mapping reads to the reference genomes of 'Darmor-bzh' or 'Tapidor', respectively. We generated allelic drifting paths that show splits and mixtures of the main populations. The genetic diversity and linkage disequilibrium parameters indicate an asymmetric evolution of the two subgenomes of B. napus. The selective-sweep analysis revealed genetic changes in genes orthologous to those regulating various aspects of plant development and response to stresses. Further genome-wide association study identified SNPs in promoter regions of FLOWERING LOCUS T and FLOWERING LOCUS C orthologs, which specifically corresponded to different rapeseed ecotypes. Our study provides important insights into genomic footprints of the evolution of rapeseed and the flowering time divergence among three ecotypes, and will facilitate screening of molecular markers for accelerating rapeseed breeding. PMID- 30472328 TI - Seroprevalence of anti-HEV antibodies in migrants hosted at one shelter in Sardinia. PMID- 30472329 TI - Aortic valve interventions in children: still only scratching the surface. PMID- 30472330 TI - A Novel Multiplex droplet digital PCR Assay to Identify and Quantify KRAS Mutations in Clinical Specimens. AB - Recurrent activating point mutations in KRAS are critical drivers in pancreatic cancer and have been attributed to resistance to anti-epidermal growth factor receptor therapy in colorectal cancer. Although KRAS genotyping provides limited clinical utility in the diagnosis and management of pancreatic cancer patients at present, inferences about the fractional abundance of KRAS mutations may inform on tumor purity in traditionally challenging clinical specimens and their potential use in precision medicine. KRAS genetic testing has indeed become an essential tool to guide treatment decisions in colorectal cancer, but there is an unmet need for methods standardization. Here, we present a unique droplet digital PCR method that enables the simultaneous detection and quantification of KRAS exon 2, 3, and 4 point mutations and copy number alterations. We have validated 13 mutations (G12S, G12R, G12D, G12A, G12V, G12C, G13D, G60V, Q61H, Q61L, A146V, A146T, and A146P) and focal KRAS amplifications by conducting this assay in a cohort of 100 DNA samples extracted from fresh frozen tumor biopsies, formaldehyde-fixed, paraffin-embedded tissue, and liquid biopsy specimens. Despite its modest lower limit of detection (around 1%), this assay will be a rapid cost-effective means to infer the purity of biopsy specimens carrying KRAS mutations and can be utilized in non-invasive serial monitoring of circulating tumor DNA to evaluate clinical response and/or detect early signs of relapse. PMID- 30472331 TI - Is blur sensitivity altered in children with progressive myopia? AB - School aged children with progressive myopia show large accommodative lags to blur only cue and is suggestive of a large depth of focus (DOF). While DOF measures are lacking in this age group, their blur detection and discrimination capacities appear to be similar to their non-myopic peers. Accordingly, the current study quantified DOF and blur detection ability in progressive myopic children showing large accommodative lags compared to their non-myopic peers and adults. Blur sensitivity measures were taken from 12 children (8-13years, 6 myopes and 6 emmetropes) and 6 adults (20-35years). DOF was quantified using step changes in the lens induced defocus while the subjects viewed a high contrast target through a Badal lens at either 2 or 4D demand. Blur detection thresholds (BDT) were tested using a similar high contrast target in a 2-alternate forced choice paradigm (2AFC) at both the demands. In addition to the large accommodative lags, micro fluctuations and DOF were significantly larger in myopic children compared to the other groups. However, BDTs were similar across the three groups. When limited to blur cues, the findings of a large DOF coupled with large response lags suggests that myopes are less sensitive to retinal defocus. However, in agreement to a previous study, refractive error had no influence on their BDTs suggesting that the reduced sensitivity to the defocus in a myopic eye appears to be compensated by some form of an adjustment in the higher visual processes to preserve the subjective percept even with a poor retinal image quality. PMID- 30472332 TI - Identification of the alternative oxidase gene and its expression in the copepod Tigriopus californicus. AB - In addition to the typical electron transport system (ETS) in animal mitochondria responsible for oxidative phosphorylation, in some species there exists an alternative oxidase (AOX) pathway capable of catalyzing the oxidation of ubiquinol and the reduction of oxygen to water. The discovery of AOX in animals is recent and further investigations into its expression, regulation, and physiological role have been hampered by the lack of a tractable experimental model organism. Our recent DNA database searches using bioinformatics revealed an AOX sequence in several marine copepods including Tigriopus californicus. This species lives in tidepools along the west coast of North America and is subject to a wide variety of daily environmental stresses. Here we verify the presence of the AOX gene in T. californicus and the expression of AOX mRNA and AOX protein in various life stages of the animal. We demonstrate that levels of the AOX protein increase in T. californicus in response to cold and heat stress compared to normal rearing temperature. We predict that a functional AOX pathway is present in T. californicus, propose that this species will be a useful model organism for the study of AOX in animals, and discuss future directions for animal AOX research. PMID- 30472334 TI - A systematic review of the role of parents in the development of anxious cognitions in children. AB - Anxious cognitions and parental behavior are important in the development of child anxiety. The current review aims to appraise the literature on the relationship between parental factors and chid anxious cognitions. Online database searches of PsycInfo, Scopus, ProQuest Dissertations and Web of Science were systematically searched using key terms related to 'parent', 'child', 'anxiety' and 'cognitions'. Included studies (N = 13) were quality assessed and study findings were appraised in line with cognitive behavioral frameworks of the parental pathways to the development of anxious cognitions in children. Reviewed studies confirmed that parental factors have a role in the development of their children's anxious cognitions by modelling fearful responses, reducing their child's autonomy, and indirectly via their own expectations about their child. Limitations of the literature are considered, including issues of measurement. Future research should consider multi-modal assessment of parental factors and examine parental behavior and child anxious cognitions in the context of real life threatening events. PMID- 30472333 TI - Acanthamoeba keratitis in Mexico: Report of a clinical case and importance of sensitivity assays for a better outcome. AB - Acanthamoeba keratitis (AK) is a sight-threatening corneal infection. The early symptoms include redness, pain, photophobia and intense tearing. Chronic infection usually progresses to stromal inflammation, ring ulcers, corneal opacification and hypopyon. Here we document an AK case in a high myopic 38-year old woman from Mexico City, with a history of wearing contact lenses while swimming. Corneal scrapes cultures were positive only for amoebae, consequently a treatment including netilmicin 0.3% and oral itraconazole 100 mg/12 h was prescribed. The infection was resolved after 8 months, leaving a slight leucoma outside the visual axis, with a visual acuity of 20/150. In the laboratory, the amoebic isolate was axenized in PYG medium, with an optimal growth at 30 degrees C, and was identified morphologically as Acanthamoeba polyphaga according to the taxonomic criteria of Page (1988) and placed in the T4 group by genotyping. The virulence of this strain (40%) was determined by intranasal inoculation of 1 * 106/20 MUl trophozoites in BALB/c mice recovering from brain, proving their invasion ability and by the interaction with monolayers of epithelial cells of the established MDCK line of canine kidney origin (1:2 ratio of interaction), at 1, 3, 6, 8 and 24 h; trophozoites migrated to cell junctions inducing few lytic zones. In addition to the biological characterization, in vitro drug sensitivity tests were performed using chlorhexidine, itraconazole, netilmicin and voriconazole. Results revealed that voriconazole was the most effective compound. A. polyphaga remains as one of the most frequently isolated species producing AK. The treatment of AK case using netilmicin and oral itraconazole solved the disease, but the healing process was wide-ranging (8 months). The use of voriconazole and chlorhexidine may be an alternative treatment of future AK cases in Mexico. PMID- 30472335 TI - Hypoglossal schwannomas: A systematic review of the literature. AB - BACKGROUND: Schwannomas of the hypoglossal nerve are rare and account for a very small percentage of non-vestibular schwannomas. OBJECTIVES: In this systematic review of the literature, we examined the epidemiology, symptomatology, management, and outcomes of patients with hypoglossal schwannomas. METHODS: The electronic database Pubmed was searched for all reports of hypoglossal schwannomas with descriptions of symptoms, management, and outcome characteristics. Data was extracted from each study and compiled in a spreadsheet. Continuous variables were reported as means and medians. Categorical variables were reported as proportions. Additional analysis was not done due to inconsistent reporting of outcomes and small sample sizes. RESULTS: A total of 59 studies (94 total individual cases) were included. 64% of patients were female with mean age of 44.6 years. The majority were intracranial/extracranial (50%). The most common symptoms were tongue deviation or speech disturbance (38%) and headaches (33%). Hypoglossal nerve dysfunction was present in 80% of patients. Surgical excision was performed in 93%, with a 15% complication rate. Evidence of residual mass after surgery was noted in 29%. Permanent hypoglossal nerve deficits occurred in 67%. Recurrence of tumor burden was reported in 6 studies, with median time to recurrence of 16.5 months. CONCLUSION: Current evidence suggests overall favorable outcomes with surgical resection of hypoglossal schwannomas, with a large percentage of patients experiencing mild and usually well-tolerated neurologic deficit. Limitations of this study include the use of retrospective data taken from case reports/series with highly selected patients, selective reporting, and absence of control groups. PMID- 30472336 TI - Psychiatric symptoms in migraine patients and their attitudes towards psychological support on stigmatization. AB - OBJECTIVE: Although migraine patients experience more psychological problems when compared to the general population, they are usually not treated. The reasons for non-treatment of these problems are not clear. The anxiety and concern of migraine patients about stigmatization may also prevent them to express psychological symptoms. The present study aimed to investigate the attitudes and behavior of migraine patients about receiving psychological help and their concerns about stigmatization. MATERIAL AND METHOD: The study group included 50 18-49 years old patients diagnosed with migraine in the neurology clinic and the control group included 50 healthy individuals with similar age, gender socio demographic characteristics with the study group. Attitude Scale Towards Seeking Professional Help (ASPH-SF), Self-Stigma in Seeking Professional Help Scale (SSPHS), Intentions to Seek Psychological Help Scale (ISHP), Stigma Scale for Receiving Psychological Help (SSRPH) and Symptom Checklist (SCL-90-R) were applied to all participants. FINDINGS: The comparison of the patient and control groups based on SCL-90-R findings demonstrated that the patient group scores in somatization, anxiety (p = 0.000), depression (p = 0.003), anger (p = 0.02), interpersonal sensitivity (p = 0.006), phobia (p = 0.001), paranoid thoughts (p = 0.012), psychosis (p = 0.031) subscales and additional subscale (p = 0.014) and general symptom index (p = 0.001) scores were higher. Based on SCL 90, it was found that patients with higher levels of symptoms had higher social stigma scores when compared to patients with lower symptom levels (p = 0.007). Migraine patients with high symptom levels were found to have significantly lower rates of seeking psychiatric help (14% vs 33%) when compared to the control group. There was no difference between the patient and control groups based on ASPH-SF, SSPHS, ISPH and SSRPH scale scores. CONCLUSION: Although migraine patients exhibit higher levels of psychiatric symptoms when compared to healthy individuals, it was determined that only a minority of these patients receive psychiatric treatment. Especially patients with high level of psychiatric symptoms could have sought less psychiatric help due to the concerns of stigmatization. PMID- 30472337 TI - 0.075% capsaicin lotion for the treatment of painful diabetic neuropathy: A randomized, double-blind, crossover, placebo-controlled trial. AB - OBJECTIVE: A randomized, double-blinded, crossover, placebo controlled trial was conducted to evaluate the efficacy and safety of 0.075% capsaicin lotion for treating painful diabetic neuropathy (PDN). PATIENTS AND METHODS: PDN subjects were randomized to receive 0.075% capsaicin/placebo for 8 weeks, then crossing over to the other treatment after a 4-weeks washout period. Primary endpoint was the change in visual analog scale score of pain severity. Secondary outcomes were score changes in Neuropathic Pain Scale, short-form McGill Pain Questionnaires, and proportions of patients with pain score reductions of 30% and 50%, and adverse events. RESULTS: A total of 42 subjects were enrolled, 27 completed at least an 8-week treatment period. Intention-to-treat analysis showed no significant improvement in pain control with capsaicin lotion compared with placebo for all pain measures and proportion of patients who had 30% or 50% pain relief, respectively. Per protocol analysis were consistent. Capsaicin lotion was well tolerated but local skin reactions were common. CONCLUSION: In patients with PDN, the efficacy of 0.075% capsaicin lotion was similar to placebo but was well tolerated. More work is needed to assess different capsaicin formulations. PMID- 30472338 TI - Primary intraspinal non-Hodgkin's lymphoma: Case report and review of literature. AB - We present the unique case of an 67-year-old female patient with primary intraspinal B-cell non-Hodgkin's lymphoma without cerebral manifestation mimicking myelitis in clinical presentation and neuroradiological diagnostic. It illustrates the broad spectrum of differential diagnoses for paraplegia and the importance of rapid interdisciplinary diagnostic work-up since the neurologic status after treatment mainly depends on the delay of treatment. Review of existing literature suggests combined radio- and chemotherapy as well as high dose intravenous methotrexate or rituximab. The rising incidence of spinal lymphomas especially in patients with acquired immunodeficiency underlines the importance of fast diagnosis and initiation of treatment of this rare entity. PMID- 30472340 TI - Glioblastoma with bilateral extraocular muscle infiltration preceded by evidence of vascular tropism. AB - We present a case of bilateral synchronous orbital muscle infiltration of extra neural glioblastoma metastases with evidence of focal treatment response. The orbital infiltration was preceded by evidence of leptomeningeal disease, and followed by further symptomatic perineural spread of tumor along the second and third division of the trigeminal nerve and into the masticator space. PMID- 30472339 TI - Splitting of the semispinalis capitis muscle as a less invasive approach for atlantoaxial fusion - A technical note. AB - PURPOSE: Atlantoxial fusion with screw rod constructs traditionally requires subperiostal dissection of the C1/C2 muscle attachments, which may lead to postoperative axial neck pain and intraoperative blood loss. We evaluate a potentially less invasive, muscle splitting approach for atlantoaxial fusion in a cadaver model. METHODS: A technical feasibility study was performed in a human cadaveric specimen with standard surgical instruments and an operating microscope. Surgically relevant anatomical structures as well as final exposure of the C1, C1/C2 and C2 screw entry points are demonstrated. RESULTS: Following a midline skin incision, blunt mobilization and downward retraction of the trapezius and splenius capitis muscle is followed by a longitudinal split of the semispinalis capitis muscle. At the lower border of the rectus capitis posterior major and the obliquus capitis inferior muscle the entry points for C1 lateral mass, C1/C2 transarticular and C2 pedicle screw are exposed. CONCLUSION: Minimal invasive splitting of the semispinalis capitis muscle allows adequate exposure of the screw entry points of C1, C1/C2 and C2 while preserving the intrinsic muscles of the back at the craniocervical junction. PMID- 30472341 TI - Neuroendoscopic hematoma removal with a small craniotomy for acute subdural hematoma. AB - The present study evaluated the safety and effectiveness of neuroendoscopic hematoma removal with a small craniotomy for the treatment of acute subdural hematoma (ASDH). Five patients (4 men and 1 woman) with ASDH underwent neuroendoscopic surgery with a small-size craniotomy between October 2016 and June 2018. The mean age was 87.4 years (range, 82-94). The eligibility criteria were as follows: 1) the presence of symptoms; 2) no moderate or massive brain contusion or edema; and 3) inability to use a large craniotomy because of poor general condition or absence of an anesthesiologist. After performing the small craniotomy, a 4-mm rigid endoscope was inserted and the hematoma was evacuated. Endoscopic surgery was performed under general or local anesthesia. The bleeding origin was a cortical artery in 2 cases, a bridging vein in 2 cases, and unknown in 1 case. The hematoma was completely removed without re-bleeding and the procedure was lifesaving in all cases. Three patients were discharged with independent gait following rehabilitation whereas 2 patients died due to causes unrelated to ASDH. Despite some surgical limitations, neuroendoscopic hematoma evacuation of ASDH is a safe and effective method that minimizes operative complications in some cases. Small craniotomy was sufficient for inserting and maneuvering ordinal neurosurgical instruments. This technique should be considered carefully before surgery in cases of ASDH. PMID- 30472342 TI - Evaluating the suitability of the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) computerized neurocognitive battery for short-term, serial assessment of neurocognitive functioning. AB - BACKGROUND: Computerized Neurocognitive Testing (CNT) is frequently used for serial assessment of athletes following concussion. The Immediate Post-Concussion Assessment for Cognitive Testing (ImPACT) is a commonly used CNT with well documented test-retest reliability in healthy samples for intervals ranging from one month to two years. However, previous research has not explored use of ImPACT for other serial testing methodologies such as immediately before and after an experimental trial/intervention where administration on the same day may be necessary. PURPOSE: To examine the suitability of ImPACT for short-term, serial assessment of neurocognitive functioning. STUDY DESIGN: Prospective, repeated measures research design. METHODS: Forty-two healthy, college-aged individuals completed ImPACT twice, with a one-hour break between assessments. Reliability was assessed using Pearson correlation coefficients, intraclass correlation coefficients (ICCs), reliable change indices (RCIs) and regression-based methods (RBM). RESULTS: No significant increases in mean ImPACT composite or symptom scores were observed between assessments. ICCs ranged from 0.34 to 0.74 (single)/0.51 to 0.85 (average). Across two test administrations, 92-100% and 93 98% of participants' change scores fell within cutoffs when utilizing the RCI and RBM, respectively. CONCLUSION: The ICCs for ImPACT composite and factor scores across the one-hour administration were consistent with previous studies. Only a small percentage of scores fell outside of RCI and RBM cutoffs. These statistical metrics suggest that ImPACT has sufficient reliability when repeating administration within one-hour. PMID- 30472343 TI - Cervical paraspinal muscle compartment pressure after laminoplasty: A cadaveric study. AB - Axial neck pain is a common complaint after cervical laminoplasty and the causes are still not well-understood. We hypothesized that abnormal paracervical muscle compartment pressures might be one of them. The cervical paraspinal muscle compartment pressures of 10 cadavers were measured in six different areas under four different conditions. The posterior cervical area was divided into two sides: open side and hinge side. Then each side was divided into upper, middle, and lower areas. The compartment pressures of each area were measured under four different conditions: before and after dissection of posterior paravertebral (paraspinal) muscles, after laminoplasty and after laminoplasty with removal of the spinous processes. There was a statistically significant difference between the pressures after dissection versus after laminoplasty on the hinge side at all upper, middle and lower areas [p < 0.01, <0.001 and =0.009 respectively]. There was a difference in the pressures after laminoplasty between the open and hinge sides [p < 0.001, <0.001 and =0.023 respectively]. We also found the following significant differences: the pressures between before dissection and after laminoplasty on the hinge side, as well as between after laminoplasty and after removal of the spinous process on the hinge side in the upper and middle areas [p < 0.001, =0.0016 and p = 0.002, =0.023 respectively]. Cervical paraspinal muscle compartment pressures on the hinge side were significantly increased after laminoplasty. This may be a contributor to axial neck pain following laminoplasty. The pressure was then significantly decreased after removal of the spinous processes. PMID- 30472344 TI - Outcomes of intraparenchymal hemorrhage after direct oral anticoagulant or vitamin K antagonist therapy: A systematic review and meta-analysis. AB - Direct Oral Anticoagulants (DOAC) are increasingly used as an alternative to vitamin-K antagonists (VKA) for anticoagulation and have shown lower rates of intracranial hemorrhage; however, there is disagreement in the literature over the outcomes of the intraparenchymal hemorrhages (IPH) associated with DOACs, and clinical concern regarding the lack of standardized reversal strategies for DOACs. Thus, the aim of this meta-analysis was to compare mortality, hematoma volume, and risk of hematoma expansion in patients who developed an IPH on DOACs versus VKA. A systematic review of the literature was conducted in accordance with the PRISMA guidelines. Studies were selected that reported on mortality, hematoma expansion, and hematoma volume in DOAC-associated IPH. Pooled risk ratios (RR) were calculated for mortality and hematoma expansion and pooled mean difference (MD) was calculated for hematoma volume (ml) using random-effect models. 15 studies reporting on 1238 patients were included in the systematic review. Eleven of these compared DOAC-IPH to VKA-IPH and were pooled quantitatively. DOAC-IPH was not associated with increased mortality risk (RR: 0.95, 95%-CI: 0.72 -1.27) or increased hematoma expansion risk (RR: 0.92; 95%-CI: 0.75-1.12) compared to VKA-IPH. The hematoma volume of DOAC- IPH was statistically significantly smaller than VKA-IPH (MD: -12.14 ml; 95%-CI: -15.38; 8.89). In conclusion, DOAC-IPH was not associated with increased mortality or hematoma expansion compared to VKA-IPH and may be associated with a smaller hematoma volume. PMID- 30472345 TI - Clinical-radiographic correlates of Artery of Percheron infarcts in a case series of 6 patients. AB - Bilateral thalamic strokes due to Artery of Percheron (AOP) occlusion are rare but have been previously reported in the literature. It is due to a rare anatomic variant where a solitary arterial trunk from the proximal segment of either posterior cerebral artery (PCA) supplies bilateral thalami and midbrain. Despite its description in the literature, these strokes are usually missed and patient's symptoms are not thought to be secondary to a vascular etiology. Through this report we aim to describe the clinical and radiographic features seen in these patients. We describe a series of 6 patients who present with varying levels of somnolence and oculomotor nerve palsies who had an occlusion of the AOP with bilateral thalamic infarcts with midbrain involvement. These clinical presentations, combined with the "V" sign on MRI are important in making the diagnosis. PMID- 30472346 TI - Peroxisome proliferator-activated receptor-gamma activation attenuates harmaline induced cognitive impairments in rats. AB - Cognitive and motor disturbances are serious concerns of the tremors induced by motor disorders. Despite the lack of effective clinical treatment, some potential therapeutic agents have been used to alleviate the cognitive symptoms in the animal models of tremor. Recent studies have shown that PPAR-gamma agonists have neuroprotective effects. In the current study, the effects of pioglitazone (PIO), a peroxisome proliferator-activated receptor gamma agonist, on harmaline-induced motor and cognitive impairment were studied. Male Wistar rats were divided into vehicle (normal saline), PIO (20 mg/kg i.p.), harmaline (10 mg/kg, i.p.) and PIO + harmaline (PIO injected 2 h before harmaline) groups. Open field, rotarod, wire grip, foot print and Morris water maze tests were used to evaluate the motor and cognitive performance. The results indicated that administration of PIO attenuated harmaline-induced locomotor, anxiety-like behaviors, and spatial learning and memory impairments, but it partially decreased the tremor score. The neuroprotective and anxiolytic effects of PIO demonstrated in the current study can offer the PPAR-gamma receptor agonism as a potential therapeutic agent in the treatment of patients with tremor that manifest mental dysfunction. PMID- 30472347 TI - Peri-electrode edema after deep brain stimulation. AB - Peri-electrode edema can occur after deep brain stimulation (DBS). The diagnosis and management of peri-electrode edema may be challenging. We herein report non infectious peri-electrode edema after the placement of DBS electrodes in patients with Parkinson's disease (PD). Fifteen patients who underwent DBS surgery between 2010 and 2018 at Sapporo Medical University were included to identify post operative peri-electrode edema. Pre- and post-operative CT and MRI were retrospectively analyzed. Six patients showed hyperintensity around the electrodes on FLAIR/T2 MRI without neurological deficits. Two patients showed limited FLAIR and DWI hyperintensities in deep white matter, and microvessels may have been occluded in these patients. In five patients, MRI revealed extensive FLAIR or T2 hyperintensity in surface white matter around the electrodes without vessel injury, whereas DWI showed no abnormal signals. The eosinophil count was increased in one of these five patients. Peri-electrode edema after DBS surgery is not an uncommon phenomenon, and includes two types: (1) limited edema in deep white matter and (2) extensive edema in surface white matter. Different mechanisms may be associated with these types of edemas. PMID- 30472348 TI - Multimodal hyper-connectivity of functional networks using functionally-weighted LASSO for MCI classification. AB - Recent works have shown that hyper-networks derived from blood-oxygen-level dependent (BOLD) fMRI, where an edge (called hyper-edge) can be connected to more than two nodes, are effective biomarkers for MCI classification. Although BOLD fMRI is a high temporal resolution fMRI approach to assess alterations in brain networks, it cannot pinpoint to a single correlation of neuronal activity since BOLD signals are composite. In contrast, arterial spin labeling (ASL) is a lower temporal resolution fMRI technique for measuring cerebral blood flow (CBF) that can provide quantitative, direct brain network physiology measurements. This paper proposes a novel sparse regression algorithm for inference of the integrated hyper-connectivity networks from BOLD fMRI and ASL fMRI. Specifically, a least absolution shrinkage and selection operator (LASSO) algorithm, which is constrained by the functional connectivity derived from ASL fMRI, is employed to estimate hyper-connectivity for characterizing BOLD-fMRI-based functional interaction among multiple regions. An ASL-derived functional connectivity is constructed by using an Ultra-GroupLASSO-UOLS algorithm, where the combination of ultra-least squares (ULS) criterion with a group LASSO (GroupLASSO) algorithm is applied to detect the topology of ASL-based functional connectivity networks, and then an ultra-orthogonal least squares (UOLS) algorithm is used to estimate the connectivity strength. By combining the complementary characterization conveyed by rs-fMRI and ASL fMRI, our multimodal hyper-networks demonstrated much better discriminative characteristics than either the conventional pairwise connectivity networks or the unimodal hyper-connectivity networks. Experimental results on publicly available ADNI dataset demonstrate that the proposed method outperforms the existing single modality based sparse functional connectivity inference methods. PMID- 30472349 TI - Mental health and environmental factors associated with falls in the elderly in North India: A naturalistic community study. AB - AIM: To determine the prevalence of falls and to assess its relationship with cognitive deficits, depression, visual impairment and self-reported hearing impairment among the elderly. METHODS: This was a community-based, cross sectional study conducted in 52 villages in the Naraingarh and Barara block of Ambala district which involved 468 participants. A pretested predesigned questionnaire was used to collect data regarding demographic profile, falls, and physical morbidities. Geriatric Depression Scale-Hindi, Hindi-mini-mental state examination, Snellen chart, Katz- Activity of Daily Living were used to collect data for depression, cognitive decline, vision and activity of daily living respectively. RESULTS: The prevalence of falls was found to be 28.7%. An association was found between falls and slippery floors in the houses, hearing loss, vertigo, hypertension, use of multiple medications, depression and functional disability in univariate analysis. On multivariate regression analysis, slippery floors (OR = 2.28), use of multiple medications (OR = 1.71), hearing loss(OR = 1.83) and presence of depression (OR = 1.62) were found to be independent risk factors with falls. CONCLUSION: There is high prevalence of falls among the elderly and these are commonly related to preventable factors. Appropriate environmental modifications and exercise programs can help reduce the rate of falls as well as injuries related to falls among the elderly. PMID- 30472350 TI - Mortality rate is associated with aripiprazole once-monthly and oral asenapine administration. PMID- 30472351 TI - Effects of sensory manipulations on the dynamical structure of center-of-pressure trajectories of children with cerebral palsy during sitting. AB - AIM: To investigate the effects of manipulating visual information and the compliance of the support surface on the area of sway and dynamical trajectories of center-of-pressure (CoP) in children with CP and children with typical development during static sitting. METHODS: 32 typical children, 14 children with mild CP and 12 with moderate-to-severe CP were tested for CoP sway during static sitting under four sensory conditions: (1) eyes open on a rigid surface; (2) eyes closed on a rigid surface; (3) eyes open on foam; (4) eyes closed on foam. RESULTS: Children with moderate-to-severe CP showed greater regularity and local stability of dynamical CoP trajectories and lower complexity in their motor patterns than typical children and children with mild CP. Moreover, removing vision and sitting on a compliant surface reduced the regularity of CoP trajectories. CONCLUSION: Children with CP were able to adjust the structure and complexity of their postural control responses to sensory challenges, although the structure of their postural responses was poorer than in typical children. PMID- 30472352 TI - Integrated process for anaerobically digested swine manure treatment. AB - An integrated three-step process was proposed for the treatment of the anaerobically digested swine manure (ADSM). The flocculation and struvite precipitation were used as the pre-treatment to remove the particles and reduce phosphorus to balance the condition for the algae growth. In the biological step, the 40% group (2.5* dilution) represented the optimal cultivation condition for the A + B co-cultivation, with the highest biomass concentration of 2.325 +/- 0.16 g/L and performed well with nutrients removal (COD: 9770 +/- 184 mg/L; TN: 235 +/- 5.4 mg/L; TP: 25.3 +/- 0.8 mg/L). 94.8% of the biomass from the 40% group could naturally settle down in 30 min which is good for harvest. The activated carbon adsorption was applied as the advanced treatment to resolve the issues with the dark color and residual compounds. After these processes, the removal efficiencies of COD, TN, TP and NH4-N reached 97.2%, 94.0%, 99.7% and 99.9%, respectively. PMID- 30472354 TI - General distributed activation energy model (G-DAEM) on co-pyrolysis kinetics of bagasse and sewage sludge. AB - In this work, pyrolysis kinetic evolution of mixture of bagasse and sewage sludge with 10%, 30% and 50% (respect to dry initial weight). In terms of kinetic mechanism, the uncertainty of the activation energy obtained by mode-free method was barely known. We found that increasing number of heating rates made result more reliable, but the modeling process more dependent on redundant experiments with extra data. We adapted a novel general distributed activation energy model (G-DAEM) with 5 pseudocomponents for the analysis of kinetic evolution with proposing a more applicable approximation to the general temperature integral. The G-DAEM was trained by data for 20 K/min, and the predictions were performed on data for 15 K/min and 25 K/min. The predictions were well matched to the experimental data. The G-DAEM enhances modeling efficiency of kinetics and provides a effective pathway for high precise model of complicated co-pyrolysis process. PMID- 30472355 TI - The impact of asthma and its treatment on growth: an evidence-based review. AB - OBJECTIVES: To assess the impact of asthma and its treatment (inhaled corticosteroids and other control medications) on growth. DATA SOURCES: The authors searched PubMed (up to August 24, 2018) and screened the reference lists of retrieved articles. Systematic reviews and meta-analysis were selected. If there was no such article, the authors selected either randomized clinical trials or observational studies. DATA SYNTHESIS: A total of 37 articles were included in this review. The findings from 21 studies suggest that asthma per se, especially more severe and/or uncontrolled cases, can transitorily impair child's growth. Two Cochrane reviews of randomized clinical trials showed a small mean reduction in linear growth (-0.91cm/year for beclomethasone, -0.59cm/year for budesonide, and -0.39cm/year for fluticasone) in the first year of treatment with inhaled corticosteroids in prepubertal children with persistent asthma. The effects were likely to be molecule- and dose-dependent. A recent review showed that most of "real-life" observational studies had not found significant effects of inhaled corticosteroids on growth in asthmatic children. Fifteen studies showed that the maintenance systemic corticosteroids could cause a dose-dependent growth suppression in children with severe asthma, but other controllers (cromones, montelukast, salmeterol, and theophylline) had no significant adverse effects no growth. CONCLUSIONS: Severe and/or uncontrolled asthma can transitorily impair child's growth. Regular use of inhaled corticosteroids may cause a small reduction in linear growth in children with asthma, but the well-established benefits of inhaled corticosteroids in controlling asthma outweigh the potential adverse effects on growth. Use of the minimally effective dose of inhaled corticosteroids and regular monitoring of child's height during inhaled corticosteroids therapy are recommended. PMID- 30472353 TI - Kinetic understanding of nitrogen supply condition on biosynthesis of polyhydroxyalkanoate from benzoate by Pseudomonas putida KT2440. AB - Nitrogen supply is critical to the synthesis of intracellular PHA in various bacteria. However, the specific role of the nitrogen in synthesizing PHA from benzoate, a lignin model compound use for the study of bacteria catabolism of aromatics, is still not clear. In this study, two culture conditions were maintained for Pseudomonas putida KT2440 to produce PHA using benzoate as a carbon source. Under nitrogen-limited and surplus conditions, the accumulation of PHA was to 37.3% and 0.25% of cell dry weight, respectively. A model fit to the kinetics of biomass growth and PHA accumulation showed good agreement with data. GC-MS and NMR showed that PHA contained six hydroxyl fatty acid monomers under nitrogen-limited conditions, while two monomers were identified under nitrogen surplus conditions. The average molecular weight of PHA increased after the nitrogen source was exhausted. These results provide a promising strategy for optimization of lignin to PHA yields. PMID- 30472357 TI - Neonatal septal lesions prevent behavioral defeminization caused by neonatal treatment with estradiol in female rats. AB - Male rats rarely show lordosis, a female sexual behavior, because of strong inhibition of the behavior in the lateral septum. Because neonatal treatment with estradiol (E2) in female rats decreases lordosis, it is believed that the lateral septum is a target of E2 action to defeminize or masculinize the lordosis inhibiting system. Here, we tested the hypothesis that disruption of the lateral septum before E2 treatment prevents the effect of neonatal E2 on lordosis. Female rats that underwent radiofrequency-induced septal lesions or sham operation on postnatal day 4 (PD4, day of birth = PD1) were subcutaneously injected with E2 or sesame oil vehicle alone on PD5. Vaginal opening and smears were checked. After sexual maturation, lordosis tests were performed. The effects of neonatal septal lesions on lordosis in male rats were also observed. Sham-operated and E2-treated female rats showed a reduction in lordosis and irregular estrous cycles. Conversely, septal lesioned and E2-treated females exhibited higher levels of lordosis, although their estrous cycles were irregular. These results suggest that neonatal septal lesions prevent females from being behaviorally defeminized by neonatal E2. Additionally, neonatally septal lesioned males displayed higher levels of lordosis than sham-operated males. These results suggest that E2, which is produced by the aromatization of testicular testosterone in the neonatal period, acts on the lateral septum to organize the lordosis-inhibiting system. PMID- 30472356 TI - Synaptic ATPases system of rat frontal cerebral cortex during aging. AB - Energy metabolism is fundamental to maintain Central Nervous System homeostasis because of high requirement of adenosine triphosphate (ATP), that is necessary to sustain neuronal events. During aging, changes in brain bioenergetics may influence the recovery of cerebral tissue in coping with pathophysiological conditions and pharmacological treatments. For this reason, we have previously studied enzyme catalytic activities related to energy-yielding systems. In the present study, the maximum rates (Vmax) of some enzymatic activities related to energy consumption (ATPases) were evaluated on synaptic plasma membranes (S.P.M.) isolated from frontal cerebral cortex of male Wistar rats aged 2, 6, 12, 18 and 24 months, because of the key role of these enzymes in modulating presynaptic nerve ending homeostasis. The following enzyme activities were evaluated: Na+, K+, Mg2+-ATPase; ouabain-insensitive Mg2+-ATPase; Na+, K+-ATPase; specific Mg2+ ATPase; Ca2+, Mg2+-ATPase; acetylcholinesterase (AChE). The present results show that both the activities of (i) ATPases and (ii) AChE were significantly decreased during aging. Comparing these observations with those previously done on rat striatum on the same functional parameters and in the same experimental settings, ATPases activities were influenced by the age factor in different ways, suggesting that the frontal cerebral cortex independently adapt to the different age-dependent biochemical situations at each single age. Overall, this experimental approach is therefore important to add pieces of information for the understanding of the correlation between aging and brain energy metabolism, and could be a suitable model to assess also drug effects, differentiating between different cerebral areas. PMID- 30472358 TI - Dose-dependent neurorestorative effects of amantadine after cortical impact injury. AB - Numerous pharmacotherapies have been evaluated after experimental traumatic brain injury (TBI). While amantadine (AMT) has shown potential for clinical efficacy, the few studies on its effectiveness have been mixed. It is possible that suboptimal dosing, due to the evaluation of only one dose, may be causing the discrepancies in outcomes. Hence, the goal of the current study was to conduct a dose response of AMT after TBI to determine an optimal behavioral benefit. Anesthetized adult male rats received either a cortical impact of moderate severity or sham injury and then were randomly assigned to receive once daily intraperitoneally injections of AMT (10, 20, or 40 mg/kg) or saline vehicle (VEH, 1 mL/kg) commencing 24 h after injury for 19 days. Motor and cognitive function were assessed on post-operative days 1-5 and 14-19, respectively. There were no statistical differences among the sham groups treated with AMT or VEH so the data were pooled. AMT (20 mg/kg) facilitated beam-balance recovery and spatial learning relative to VEH-treated controls (p < 0.05). No other doses of AMT were effective. These results indicate that dosing should be carefully considered when assessing the effects of pharmacotherapies after TBI so that potential benefits are not inadvertently missed. PMID- 30472359 TI - Activation of peripheral group III metabotropic glutamate receptors inhibits pain transmission by decreasing neuronal excitability in the CFA-inflamed knee joint. AB - Peripheral group III metabotropic glutamate receptors (mGluRs) function to modulate pain signaling in inflammatory states. Here, we established in vivo experimental settings, including dynamic weight bearing test and in vivo single nerve recording, to elucidate how the group III mGluRs contribute to inhibiting pain transmission at the peripheral sensory nerve terminal in inflammatory states (1 and 3 days) elicited by Complete Freund's Adjuvant (CFA). As a result, CFA induced nociceptive behaviors were significantly alleviated after administration of 100 and 200 MUM L-AP4 (l-2-amino-4-phosphonobutylate; group III mGluR agonist). In addition, neuronal discharges evoked by 6- and 26-g von Frey filaments at the nerve significantly decreased after administration of 200 MUM L AP4. However, this event was not observed in non-inflammatory state. These results suggest that the group III mGluRs negatively regulate nociceptive behavior and pain transmission by lessening neuronal firing rates at the peripheral nerve in inflammation. PMID- 30472360 TI - IL-25 promotes Th2-type reactions and correlates with disease severity in the pathogenesis of oral lichen planus. AB - OBJECTIVE: The aim of the present study was to investigate the correlation between IL-25 expression and disease severity, and the potential immunoregulatory role of IL-25 expression in oral lichen planus (OLP). MATERIALS AND METHODS: The oral mucosal tissue samples obtained from OLP patients and healthy controls (HCs) were analyzed for IL-25 expression by real-time quantitative PCR (qPCR) and immunohistochemistry. Recombinant IL-25 was used to stimulate OLP patient-derived CD4 + T cells, and then IL-4 secretion and mRNA expression were evaluated by ELISA and qPCR, respectively. The efficiency of the siRNA-mediated knockdown of IL-25R expression in oral keratinocytes was determined by qPCR and Western blotting. Human oral keratinocyte cells were cultured with the recombinant human cytokines IL-25, IL-17 A and IL-17 F. The production of associated cytokines by keratinocytes was determined by qPCR. Statistical analyses of quantitative data were performed using SPSS software. RESULTS: The IL-25 and IL-4 mRNA levels were elevated and correlated significantly with each other in specific OLP subtype lesions compared to HCs, while the numbers of IL-25 positive cells were also increased in local OLP lesions as compared to HCs. In vitro culture with recombinant IL-25 could significantly promote CD4 + T cells from both subtypes of OLP to produce IL-4 mRNA and remarkably elevate supernatant IL-4 levels in reticular OLP CD4 + T cell cultures, which may be attributed to the elevated expression of IL-25R in local OLP lesions. Statistical analyses demonstrated that the simultaneously increased levels of IL-4, CXCL8 and CCL20 in keratinocytes were induced by IL-25 but not IL-17 A or IL-17 F. Decreasing IL-25R subunit expression by siRNA-mediated knockdown significantly blocked the expression of all cytokine-produced inflammatory mediators in oral keratinocytes. CONCLUSIONS: In OLP lesions, IL-25 can function to mediate the Th2 response in specific disease subtypes, which may be an important cause of OLP disease chronicity and persistent inflammation. PMID- 30472361 TI - Corrigendum to "MMP-3 and MMP-8 in rat mandibular condylar cartilage associated with dietary loading, estrogen level, and aging" [Arch. Oral Biol. 97 (2019) 238 244]. PMID- 30472362 TI - Intraoperative carbon nanoparticles mapping in secondary total thyroidectomy for recurrent thyroid nodules: Results of a 8-criterion case-match study (case control study). AB - BACKGROUND: The extent of total thyroidectomy in the management of multinodular goiter remains unclear. Compared to primary thyroidectomy, secondary total thyroidectomy is more difficult to perform and carries a significantly higher risk of postoperative complications such as recurrent laryngeal nerve (RLN) palsy or hypoparathyroidism. In this study, we aimed to evaluate the efficacy and safety of intraoperative carbon nanoparticle (CN) mapping in patients undergoing secondary total thyroidectomy. METHODS: We performed a case-matched analysis of a prospectively maintained database using 8 specific criteria to compare perioperative outcomes after primary total thyroidectomy to those after secondary total thyroidectomy with intraoperative CN mapping. The criteria included age, sex, operative procedure, RLN/parathyroid glands (PGs) exploration, preoperative vocal cord calcium abnormalities, and pathological results. Thirty-five patients underwent secondary total thyroidectomy with intraoperative CN mapping due to recurrent thyroid nodules or development of nodules suspicious for malignancy after subtotal thyroidectomy. Fifty exact matches for all 8 criteria were identified from the database in our previous study, which included records of 3078 primary thyroidectomies without CNs. Perioperative outcomes, surgical technique, and complications were analyzed. RESULTS: The RLNs were successfully identified in all 35 patients. Among three patients that experienced slight hoarseness, one had an RLN end-to-end anastomosis with subsequent improvement in the during the 12-month follow-up period. Two patients experienced changes in vocal tone, but recovered after several months. Two patients underwent parathyroid auto-transplantations, and subsequently presented with transient hypocalcaemia. Their symptoms gradually remitted within one year. Except for mean operation time, there were no statistically significant differences in complications between the primary total thyroidectomies and the secondary total thyroidectomy with CNs. CONCLUSIONS: Intraoperative CN mapping, expert knowledge of the jugular anatomy, and standardized resection procedures can minimize the incidence of complications such as RLN palsy and hypoparathyroidism after secondary total thyroidectomy. PMID- 30472363 TI - Implementation of midwifery continuity of care models for Indigenous women in Australia: Perspectives and reflections for the United Kingdom. AB - Maternity models that provide midwifery continuity of care have been established to increase access to appropriate services for Indigenous Australian women. Understanding the development and implementation of continuity models for Indigenous women in Australia provides useful insights for the development and implementation of similar models in other contexts such as those for vulnerable and socially disadvantaged women living in the United Kingdom. To ensure better health outcomes for mothers and babies, it is crucial to promote culturally competent and safe public health models in which midwives work collaboratively with the multidisciplinary team. PMID- 30472364 TI - Base excision repair plays an important role in the protection against nitric oxide- and in vivo-induced DNA damage in Trypanosoma brucei. AB - Uracil-DNA glycosylase (UNG) initiates the base excision repair pathway by excising uracil from DNA. We have previously shown that Trypanosoma brucei cells defective in UNG exhibit reduced infectivity thus demonstrating the relevance of this glycosylase for survival within the mammalian host. In the early steps of the immune response, nitric oxide (NO) is released by phagocytes, which in combination with oxygen radicals produce reactive nitrogen species (RNS). These species can react with DNA generating strand breaks and base modifications including deaminations. Since deaminated cytosines are the main substrate for UNG, we hypothesized that the glycosylase might confer protection towards nitrosative stress. Our work establishes the occurrence of genotoxic damage in Trypanosoma brucei upon exposure to NO in vitro and shows that deficient base excision repair results in increased levels of damage in DNA and a hypermutator phenotype. We also evaluate the incidence of DNA damage during infection in vivo and show that parasites recovered from mice exhibit higher levels of DNA strand breaks, base deamination and repair foci compared to cells cultured in vitro. Notably, the absence of UNG leads to reduced infectivity and enhanced DNA damage also in animal infections. By analysing mRNA and protein levels, we found that surviving UNG-KO trypanosomes highly express tryparedoxin peroxidase involved in trypanothione/tryparedoxin metabolism. These observations suggest that the immune response developed by the host enhances the activation of genes required to counteract oxidative stress and emphasize the importance of DNA repair pathways in the protection to genotoxic and oxidative stress in trypanosomes. PMID- 30472365 TI - Mitochondria are a substrate of cellular memory. AB - Cellular memory underlies cellular identity, and thus constitutes a unifying mechanism of genetic disposition, environmental influences, and cellular adaptation. Here, we demonstrate that enduring physicochemical changes of mitochondrial networks invoked by transient stress, a phenomenon we term 'mitoengrams', underlie the transgenerational persistence of epigenetically scripted cellular behavior. Using C2C12 myogenic stem-like cells, we show that stress memory elicited by transient, low-level arsenite exposure is stored within a self-renewing subpopulation of progeny cells in a mitochondrial-dependent fashion. Importantly, we demonstrate that erasure of mitoengrams by administration of mitochondria-targeted electron scavenger was sufficient to reset key epigenetic marks of cellular memory and redirect the identity of the mitoengram-harboring progeny cells to a non-stress-like state. Together, our findings indicate that mnemonic information emanating from mitochondria support the balance between the persistence and transience of cellular memory. PMID- 30472366 TI - Melatonin-induced demethylation of antioxidant genes increases antioxidant capacity through RORalphain cumulus cells of prepubertal lambs. AB - Physical damage and oxidative stress may occur in prepubertal cumulus cells, due to insufficient glutathione synthesis. To determine potential epigenetic mechanisms related to antioxidant effects of melatonin on ovine prepubertal cumulus cells, 30 lambs, 4-wk-old were randomly allocated into two groups: a control (C, n=20) group and a melatonin (M, n=10) group given a subcutaneous implant containing 18mg melatonin. All lambs were superovulated (250 IU FSH and 250 IU eCG). Cumulus cells from germinal vesicle stage cumulus oocyte complexes (COCs) were collected by ovarian follicular aspiration and dissociated with hyaluronidase. Compared to the C group, the M group had greater superovulation, better antioxidant capacity, a higher proportion of fully expanded COCs and a lower proportion of apoptotic cumulus cells (P < 0.05). Melatonin up-regulated mRNA expression of genes for melatonin receptors MT1 and nuclear binding site RORalpha, antioxidants (SOD1, GPx4 and CAT) and cumulus cell expansion (PTX3, HAS2 and PTGS2), as well as Bcl2, but down-regulated expression of Bax (P < 0.05). Regarding epigenetics, there were less methylation at five CpG sites of SOD1, three CpG sites of GPx4 and two CpG sites of CAT in M versus C groups (P < 0.05), leading to lower total methylation of SOD1, GPx4 and CAT promoters region on M group (P < 0.05). In a mechanistic study, addition of MT1 or RORalpha antagonist increased ROS and MDA concentrations, but decreased T-AOC, GPx, CAT and T-SOD concentrations (P < 0.05), whereas there were no significant difference between the melatonin and MT2 antagonist treatment groups for T-AOC, GPx, CAT and T-SOD concentrations. Furthermore, addition of RORalpha agonist decreased total DNA methylation of SOD1, GPx4 and CAT, with no significant difference after MT1 agonist treatment. These studies provided new information regarding epigenetic mechanisms by which melatonin promoted ovine prepubertal cumulus cells antioxidant through RORalpha, both in vitro and in vivo. PMID- 30472367 TI - Activation of cardiac TrkB receptor by its small molecular agonist 7,8 dihydroxyflavone inhibits doxorubicin-induced cardiotoxicity via enhancing mitochondrial oxidative phosphorylation. AB - Brain-derived neurotrophic factor (BDNF)/tropomyosin-related receptor kinase B (TrkB) pathway has been revealed as a novel therapeutic target for several neurological diseases. Recently, small-molecule TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) has received considerable attention as a novel potential candidate for the treatment of various BDNF-implicated human disorders. However, its roles in cardiac diseases are not fully understood. Here, the present study aimed to clarify the effects and mechanisms of 7,8-DHF on doxorubicin (Dox)-induced cardiotoxicity. Kunming mice and H9c2 cells were employed to investigate the functional role of 7,8-DHF both in vivo and in vitro. 7,8-DHF markedly increased cell viability and reduced cell death of Dox-treated cells. Meanwhile, 7,8-DHF significantly increased mitochondrial respiration, membrane potential, and optic atrophy 1 (OPA1) protein expression. 7,8-DHF improved cardiac function and attenuated cardiac injury in Dox mice model. Expression of AMP-activated protein kinase (AMPK) and signal transducers and activators of transcription 3 (STAT3) was restored by 7,8-DHF. Furthermore, the protective role of 7,8-DHF was abolished by ANA-12 (a specific antagonist of TrkB). In elucidating the molecular mechanism, the phosphorylation of Akt was significantly increased while extracellular regulated protein kinase (ERK) was decreased after 7,8-DHF treatment. The regulatory effects of 7,8-DHF on STAT3 and AMPK was reversed by Akt inhibitor. In summary, 7,8-DHF attenuated Dox-induced cardiotoxicity by activating Akt and increasing mitochondrial oxidative phosphorylation and thereby regulating STAT3, AMPK, and ERK signals. The present study enhanced current understanding of TrkB receptor in the cardiovascular system and provided a novel target for prevention and treatment of heart diseases. PMID- 30472368 TI - Performance of the International Myeloma Working Group myeloma frailty score among patients 75 and older. AB - OBJECTIVES: We compared the performance of two frailty scoring systems in predicting survival among older patients with multiple myeloma: the International Myeloma Working Group (IMWG) frailty score (which includes age), and the Fried model for frailty (which does not). METHODS: From 2015 to 2018, all patients aged 75 years and older presenting at our institution with a diagnosis of multiple myeloma were approached for a frailty screening assessment. We first categorized patients' frailty using the Fried model. Then, using available deficit measures, we reclassified frailty using the IMWG approach. We compared the performance of the IMWG strategy to the Fried model in terms of association with overall survival. RESULTS: Of the 98 (92%) patients who consented to a baseline frailty assessment, we found 57% discordance among frailty classification between the two scoring systems. Using the IMWG strategy, 9% of the cohort was "fit," 29% "intermediate-fit," and 62% "frail." Using the Fried model, 29% of the cohort was "robust," 52% "pre-frail," and 19% "frail." Frailty category in the Fried model was predictive of overall survival among our cohort, while frailty category in the IMWG strategy was not (log-rank p = 0.04 vs. 0.34). CONCLUSION: Among our cohort of older patients with myeloma (aged 75 and higher), the Fried model appears to be a better predictor of survival compared to the IMWG strategy. These results suggest that using age as a criterion to identify frailty in older patients with multiple myeloma may limit treatment options for the functionally vigorous. PMID- 30472369 TI - Mathematical thinking in children with developmental language disorder: The roles of pattern skills and verbal working memory. AB - Previous research suggests that children with language disorders often have difficulties in mathematical tasks. In the current study, we investigated two relevant factors - working memory and pattern skills - that may underlie children's poor mathematics performance. Children with developmental language disorder (DLD, n = 18, ages 6-13) and age-matched typically-developing children (n = 18) completed three math tasks that tapped calculation skill and knowledge of concepts. Children also completed a visual pattern extension task and a verbal working memory task. There were four key findings: (1) children with DLD exhibited poorer mathematical knowledge than typically-developing children, both in calculation and on key math concepts, (2) children with DLD performed similarly to typically-developing children on the visual pattern extension task, (3) children with DLD had lower verbal working memory scores than typically developing children, and these differences in working memory accounted in part for their poorer calculation performance, and (4) children's pattern extension scores predicted their arithmetic calculation scores, but not their concept scores. PMID- 30472370 TI - Focus of attention modulates the heartbeat evoked potential. AB - Theoretical frameworks such as predictive coding suggest that the perception of the body and world - interoception and exteroception - involve intertwined processes of inference, learning, and prediction. In this framework, attention is thought to gate the influence of sensory information on perception. In contrast to exteroception, there is limited evidence for purely attentional effects on interoception. Here, we empirically tested if attentional focus modulates cortical processing of single heartbeats, using a newly-developed experimental paradigm to probe purely attentional differences between exteroceptive and interoceptive conditions in the heartbeat evoked potential (HEP) using EEG recordings. We found that the HEP is significantly higher during interoceptive compared to exteroceptive attention, in a time window of 524-620 ms after the R peak. Furthermore, this effect predicted self-report measures of autonomic system reactivity. Our study thus provides direct evidence that the HEP is modulated by pure attention and suggests that this effect may provide a clinically relevant readout for assessing interoception. PMID- 30472371 TI - MR fingerprinting enables quantitative measures of brain tissue relaxation times and myelin water fraction in the first five years of life. AB - Quantitative assessments of normative brain development using MRI are of critical importance to gain insights into healthy neurodevelopment. However, quantitative MR imaging poses significant technical challenges and requires prohibitively long acquisition times, making it impractical for pediatric imaging. This is particularly relevant for healthy subjects, where imaging under sedation is not clinically indicated. MR Fingerprinting (MRF), a novel MR imaging framework, provides rapid, efficient, and simultaneous quantification of multiple tissue properties. In this study, a 2D MR Fingerprinting method was developed that achieves a spatial resolution of 1 * 1 * 3 mm3 with rapid and simultaneous quantification of T1, T2 and myelin water fraction (MWF). Phantom experiments demonstrated that accurate measurements of T1 and T2 relaxation times were achieved over a wide range of T1 and T2 values. MRF images were acquired cross sectionally from 28 typically developing children, 0 to five years old, who were enrolled in the UNC/UMN Baby Connectome Project. Differences associated with age of R1 (=1/T1), R2 (=1/T2) and MWF were obtained from several predefined white matter regions. Both R1 and R2 exhibit a marked increase until ~20 months of age, followed by a slower increase for all WM regions. In contrast, the MWF remains at a negligible level until ~6 months of age for all predefined ROIs and gradually increases afterwards. Depending on the brain region, rapid increases are observed between 6 and 12 months to 6-18 months, followed by a slower pace of increase in MWF. Neither relaxivities nor MWF were significantly different between the left and right hemispheres. However, regional differences in age-related R1 and MWF measures were observed across different white matter regions. In conclusion, our results demonstrate that the MRF technique holds great potential for multi parametric assessments of normative brain development in early childhood. PMID- 30472373 TI - Recruitment of the occipital cortex by arithmetic processing follows computational bias in the congenitally blind. AB - Arithmetic reasoning activates the occipital cortex of congenitally blind people (CB). This activation of visual areas may highlight the functional flexibility of occipital regions deprived of their dominant inputs or relate to the intrinsic computational role of specific occipital regions. We contrasted these competing hypotheses by characterizing the brain activity of CB and sighted participants while performing subtraction, multiplication and a control letter task. In both groups, subtraction selectively activated a bilateral dorsal network commonly activated during spatial processing. Multiplication triggered activity in temporal regions thought to participate in memory retrieval. No between-group difference was observed for the multiplication task whereas subtraction induced enhanced activity in the right dorsal occipital cortex of the blind individuals only. As this area overlaps with regions showing selective tuning to auditory spatial processing and exhibits increased functional connectivity with a dorsal "spatial" network, our results suggest that the recruitment of occipital regions during high-level cognition in the blind actually relates to the intrinsic computational role of the activated regions. PMID- 30472372 TI - Age-related differences in default-mode network connectivity in response to intermittent theta-burst stimulation and its relationships with maintained cognition and brain integrity in healthy aging. AB - The default-mode network (DMN) is affected by advancing age, where particularly long-range connectivity has been consistently reported to be reduced as compared to young individuals. We examined whether there were any differences in the effects of intermittent theta-burst stimulation (iTBS) in DMN connectivity between younger and older adults, its associations with cognition and brain integrity, as well as with long-term cognitive status. Twenty-four younger and 27 cognitively normal older adults were randomly assigned to receive real or sham iTBS over the left inferior parietal lobule between two resting-state functional magnetic resonance imaging (rs-fMRI) acquisitions. Three years later, those older adults who had received real iTBS underwent a cognitive follow-up assessment. Among the younger adults, functional connectivity increased following iTBS in distal DMN areas from the stimulation site. In contrast, older adults exhibited increases in connectivity following iTBS in proximal DMN regions. Moreover, older adults with functional responses to iTBS resembling those of the younger participants exhibited greater brain integrity and higher cognitive performance at baseline and at the 3-year follow-up, along with less cognitive decline. Finally, we observed that 'young-like' functional responses to iTBS were also related to the educational background attained amongst older adults. The present study reveals that functional responses of the DMN to iTBS are modulated by age. Furthermore, combining iTBS and rs-fMRI in older adults may allow characterizing distinctive cognitive profiles in aging and its progression, probably reflecting network plasticity systems that may entail a neurobiological substrate of cognitive reserve. PMID- 30472374 TI - Folate-dactolisib conjugates for targeting tubular cells in polycystic kidneys. AB - The aim of the present study was to develop folic acid (FA) conjugates which can deliver the kinase inhibitor dactolisib to the kidneys via folate receptor mediated uptake in tubular epithelial cells. Dactolisib is a dual inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) and is considered an attractive agent for treatment of polycystic kidney disease. The ethylenediamine platinum(II) linker, herein called Lx, was employed to couple dactolisib via coordination chemistry to thiol-containing FA-spacer adducts to yield FA-Lx-dactolisib conjugates. The dye lissamine was coupled via similar linker chemistry to folate to yield fluorescent FA-Lx-lissamine conjugates. Three different spacers (PEG5-Cys, PEG27-Cys or an Asp-Arg-Asp-Asp-Cys peptide spacer) were used to compare the influence of hydrophilicity and charged groups in the spacer on interaction with target cells and in vivo organ distribution of the final conjugates. The purity and identity of the final products were confirmed by UPLC and LC-MS analysis, respectively. FA-Lx-dactolisib conjugates were stable in serum and culture medium, while dactolisib was released from the conjugates in the presence of glutathione. All three type of conjugates were internalized efficiently by HK-2 cells and uptake could be blocked by an excess of folic acid in the medium, demonstrating FR mediated uptake. FA-Lx-dactolisib conjugates showed nanomolar inhibition of the PI3K pathway (Akt phosphorylation) and mTOR pathway (S6 phosphorylation) in cultured kidney epithelial cells (HK-2 cells). After intraperitoneal administration, all three types conjugates accumulated extensively in kidneys of iKsp-Pkd1del mice with polycystic kidney disease. In conclusion, folate conjugates were successfully prepared by platinum(II) coordination chemistry and accumulated in a target-specific manner in kidney cells and polycystic kidneys. The folate conjugate of dactolisib thus may have potential for targeted therapy of polycystic kidney disease. PMID- 30472375 TI - Insight into long noncoding competing endogenous RNA networks in hepatic fibrosis: The potential implications for mechanism and therapy. AB - Mounting evidence has shown that long noncoding RNAs (lncRNAs) can function as competing endogenous RNAs (ceRNAs) in distinct physiological and pathological states. The activation of hepatic stellate cells (HSCs) is a critical event in the development of hepatic fibrosis (HF). LncRNAs have recently been revealed to be involved in HSC activation as ceRNAs. CeRNA analysis tremendously expands the functional information of proteins, DNA and coding and noncoding RNA. In addition, many validated ceRNA networks, including the traditional ceRNA/mRNA/miRNA, participate in the initiation and progress of HF, and additional work is needed in elucidating the potential of ceRNAs in precancer diagnosis, prognosis and providing new therapeutic methods for HF reversion. PMID- 30472376 TI - Genome-wide identification and characterization of the Dof gene family in cassava (Manihot esculenta). AB - Dof proteins comprise a plant-specific transcription factor family involved in regulation of many plant processes. Despite their diverse roles, little information is available in cassava (Manihot esculenta, Euphorbiaceae), the sixth major staple crop in the world. This study presents the first genome-wide identification of Dof family genes in cassava, resulting in 45 family members that are unevenly distributed across 17 out of the 18 chromosomes. Phylogenetic analysis assigned these genes into eight groups representing four subfamilies. Synteny analysis and BRH (Best Reciprocal Hit) method were also adopted to study evolutionary relationships. Among 21 MeDof duplicates identified, the majority of them were derived from the recent whole-genome duplication (WGD), whereas only one from local duplication. Transcriptional profiling revealed diverse expression patterns among various tissues, and further comparison of conserved motifs and expression profiles revealed divergence of MeDof duplicates. These findings provide valuable information for functional analysis of Dof genes in cassava. PMID- 30472377 TI - Polymorphism rs4787951 in IL-4R contributes to the increased risk of renal cell carcinoma in a Chinese population. AB - OBJECTIVE: Interleukins are important molecules involved in tumor formation. In this study, the association between renal cell carcinoma (RCC) risk and single nucleotide polymorphisms (SNPs) on IL-4/IL-13/IL-4R was assessed. METHODS: We recruited 620/623 cases/controls and conducted a case-control study. Five tagSNPs (i.e., IL-4R rs8832, IL-4R rs4787951, IL-13 rs1881457, IL-13 rs2066960 and IL-13 rs2069744) were selected. Odds ratios (ORs) with their 95% confidence intervals (CIs) were obtained to appraise the association between SNPs and RCC susceptibility. Luciferase report assay and EMSA were conducted to investigate whether SNPs could affect binding affinity of transcription factors to target genes. RESULTS: IL-4R rs4787951T>C was significantly associated with RCC susceptibility. Individuals carrying CC genotypes had a significant increment in RCC risk compared with TT genotype carriers (adjusted OR = 1.57, 95% CI = 1.07 2.28, P = 0.020). By stratified analyses, more pronounced association was found in the female, diabetic or without smoking, drinking and hypertension group. Besides, SNP rs4787951 could influence the binding affinity of IL-4R to transcription factors. Sequence surrounding allele T was prone to bind transcription factor NFATc. CONCLUSIONS: This study revealed that IL-4R rs4787951T>C was associated with susceptibility of RCC and could be a predictive biomarker for RCC risk. PMID- 30472378 TI - Curcumin modulates the angiogenic potential of human endothelial cells via FAK/P 38 MAPK signaling pathway. AB - Many phyto-compounds are found to have anti-angiogenesis property. Curcumin, a natural polyphenol, has been used as medicinal plant for years with different biological activities. Here, we investigated the effect of curcumin on angiogenesis potential of human endothelial cells. Human Umbilical Vein Endothelial Cells (HUVECs) were treated with different concentration of curcumin over a period of 72 h. Cell survival rate was measured by MTT assay. Cell migration and tubulogenesis were studied by scratch and tubulogenesis assays. The expression level of VEGF was monitored by RT-PCR. We also monitored the phosphorylation of FAK and P-38 MAPK by western blotting. Compared to control group, curcumin decreased HUVECs survival rate after 72 h. We found that the migration of HUVECs was decreased after curcumin treatment compared to the control (p < 0.0001). Cell alignment and tubulogenesis activity were found to be inhibited compared to cells from the VEGF group (p < 0.05). The expression level of VEGF was increased in curcumin treated cells at first 24 h time period. Based on data from the current experiment, the protein level of p-FAK/FAK ratio was increased coincided with a decrease in p-P38/P38 ratio treatment with curcumin (p < 0.0001). These data demonstrated that curcumin inhibited HUVECs angiogenesis potential by modulation of FAK/P-38 MAPK signaling pathway. PMID- 30472379 TI - Long non-coding RNA TP73-AS1 promotes colorectal cancer proliferation by acting as a ceRNA for miR-103 to regulate PTEN expression. AB - There is an increasing evidence that long non-coding RNAs (lncRNAs) play an important role in tumorigenesis and cancer progression. This study focused on the functional role of P73 antisense RNA 1T (TP73-AS1), a lncRNA, in colorectal cancer (CRC). We found that TP73-AS1 expression was significantly low in CRC tissues and cells, and high TP73-AS1 expression was negatively associated with TNM stage, prognosis, overall survival, and disease-free survival in the CRC patients. Moreover, TP73-AS1 overexpression dramatically inhibited CRC cell growth, promoted apoptosis, downregulated Bcl-2 levels, and increased caspase-3 expression. Furthermore, TP73-AS1 expression levels were positively associated with PTEN levels in clinical CRC samples. As expected, TP73-AS1 could upregulate PTEN expression in CRC cells. Mechanistically, PTEN was shown to be the target of miR-103. Interestingly, TP73-AS1 overexpression could increase PTEN expression through competitive binding to miR-103. Functionally, our data show that such TP73-AS1-induced PTEN expression through binding to miR-103 facilitated CRC cell proliferation. Thus, we showed that TP73-AS1 inhibits CRC cell growth by functioning as a ceRNA (competing endogenous RNAs) to regulate PTEN levels. Our findings provide new insights into the underlying molecular mechanisms of TP73 AS1-mediated CRC. PMID- 30472380 TI - An insight into non-integrative gene delivery approaches to generate transgene free induced pluripotent stem cells. AB - Over a decade ago, a landmark study that reported derivation of induced Pluripotent Stem Cells (iPSCs) by reprogramming fibroblasts has transformed stem cell research attracting the interest of the scientific community worldwide. These cells circumvent the ethical and immunological concerns associated with embryonic stem cells, and the limited self-renewal ability and restricted differentiation potential linked to adult stem cells. iPSCs hold great potential for understanding basic human biology, in vitro disease modeling, high-throughput drug testing and discovery, and personalized regenerative medicine. The conventional reprogramming methods involving retro- and lenti-viral vectors to deliver reprogramming factors in somatic cells to generate iPSCs nullify the clinical applicability of these cells. Although these gene delivery systems are efficient and robust, they carry an enormous risk of permanent genetic modifications and are potentially tumorigenic. To evade these safety concerns and derive iPSCs for human therapy, tremendous technological advancements have resulted in the development of non-integrating viral- and non-viral approaches. These gene delivery techniques curtail or eliminate the risk of any genomic alteration and enhance the prospects of iPSCs from bench-to-bedside. The present review provides a comprehensive overview of non-integrating viral (adenoviral vectors, adeno-associated viral vectors, and Sendai virus vectors) and DNA-based, non-viral (plasmid transfection, minicircle vectors, transposon vectors, episomal vectors, and liposomal magnetofection) approaches that have the potential to generate transgene-free iPSCs. The understanding of these techniques could pave the way for the use of iPSCs for various biomedical applications. PMID- 30472381 TI - The protective role of intermedin in promoting angiogenesis during renal fibrosis. AB - BACKGROUND: Renal fibrosis promotes the progression of chronic renal disease to end-stage renal disease. Microvascular damage and loss play an important role in renal fibrosis. Intermedin (IMD) is expressed mainly in the heart and kidney. IMD has been shown to increase renal blood flow and reduce the loss of glomerular and surrounding renal tubules, but its role in mediating microvascular damage in renal fibrosis remains to be elucidated. Here, we investigated the effects of IMD on microvascular damage in a renal fibrosis model. METHODS: We created a rat model of unilateral ureteral obstruction (UUO) to clarify the effect of microvascular damage on renal fibrosis and the effect of intermedin on reversing renal vascular injury and promoting angiogenesis. Rats were divided randomly into three groups: sham, UUO, and UUO + IMD. The sham group underwent free ureteral ligation but not occlusion. Rats in the latter two groups underwent UUO, and rats in the IMD group were additionally administered intermedin (100 ng/kg/h) daily. On the 7th, 14th, 21st, and 28th days after surgery, abdominal aortic blood and the obstructed kidneys were harvested from the rats (n = 6) for analysis. RESULTS: IMD was found to protect against renal vascular injury and to increase microvessel density. Molecularly, IMD upregulated vascular endothelial growth factor-vascular endothelial growth factor receptor (VEGF-VEGFR2) pathway activity. The VEGF-VEGFR2 pathway might be the underlying mechanism mediating the protective activities of IMD in promoting angiogenesis, delaying renal fibrosis, and improving renal function. CONCLUSION: IMD could be a potential candidate treatment for renal fibrosis. PMID- 30472382 TI - Bleeding disorders in Adolescents with Heavy Menstrual Bleeding (HMB): The Queensland Statewide Paediatric and Adolescent Gynaecology Service. AB - STUDY OBJECTIVE: Heavy menstrual bleeding (HMB) is a common gynaecological complaint among young females with up to 40% having experienced HMB. Bleeding disorders are increasingly being recognised in adolescents and young adults with HMB. The aim of this study was to determine the prevalence of bleeding disorders in adolescents with HMB, among patients presenting to the Queensland Statewide Paediatric and Adolescent Gynaecology (PAG) Service between July 2007 to July 2017. DESIGN, SETTINGS, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: The study was a retrospective review of 124 adolescent females aged 8 to 18 years with HMB presenting to the Queensland PAG Service, Brisbane, Australia. The primary outcome measure was diagnosis of a bleeding disorder, with secondary outcomes including iron deficiency and/or anaemia and treatment modalities. RESULTS: Screening for bleeding disorders was performed in 62.1% (77/124) of patients with HMB. Twenty-seven adolescents were diagnosed with a bleeding disorder, giving a prevalence of 21.7% (27/124) in those with HMB, and 35% (27/77) with HMB that were screened. Of these 35%, von Willebrand Disease (VWD) was the most common bleeding disorder, found in 51.6% (14/27), followed by inherited platelet function disorders diagnosed in 33.3% (9/27), thrombocytopenia (inherited or acquired) in 11.1% (3/27), and Factor IX deficiency in 3.7% (1/27). Iron deficiency and/or anaemia was diagnosed in 49.5% (53/107) of patients with HMB that were screened for this, and 70.3% (19/27) of those diagnosed with a bleeding disorder. CONCLUSION: Adolescents with HMB presenting to a tertiary PAG service should be screened for bleeding disorders, given the considerably high prevalence in this at-risk population. PMID- 30472383 TI - Reproducibility of visual-field asymmetries: Nine replication studies investigating lateralization of visual information processing. AB - Numerous behavioral studies suggest that the processing of various types of visual stimuli and features may be more efficient in either the left or the right visual field. However, not all of these visual-field asymmetries (VFAs) have been observed consistently. Moreover, it is typically unclear whether a failure to observe a particular VFA can be ascribed to certain characteristics of the participants and stimuli, to a lack of statistical power, or to the actual absence of an effect. To increase our understanding of lateralization of visual information processing, we have taken a rigorous methodological and statistical approach to examine the reproducibility of various previously reported VFAs. We did so by performing (near-)exact replications of nine representative previous studies, aiming for sufficient power to detect the effects of interest, and taking into consideration all relevant dependent variables (reaction times and error rates). Following Bayesian analyses -on our data alone as well as on the combined evidence from the original and replication studies- we find precise and reliable evidence that support VFAs in the processing of faces, emotional expressions, global and local information, words, and in the distribution of spatial attention. In contrast, we find less convincing evidence for VFAs in processing of high and low spatial frequencies. Finally, we find no evidence for VFAs in categorical perception of color and shape oddballs, and in the judgments of categorical and coordinate spatial relations. We discuss our results in the light of their implications for theories of visual lateralization. PMID- 30472384 TI - Oculomotor control after hemidecortication: One hemisphere encodes normal ipsilateral oblique anti-saccades. AB - A critical question in neurology is how the brain reorganizes its structure and function following injury. Here, we consider oculomotor control following a massive brain lesion, a hemispherectomy. We used the oblique anti-saccade task which requires the suppression of a saccade towards a visual cue, flashed anywhere in a patient's seeing hemifield, and the generation, in the dark, of an anti-saccade to a task-dependent location in the opposite blind hemifield; inverting either the horizontal or both horizontal and vertical components. Anti saccades require a visuo-motor vector inversion that normally involves bilateral interactions between frontal, parietal and subcortical structures across both hemispheres. Here, oblique anti-saccades presented a major challenge to the patient's single hemisphere, requiring one site in visual cortex to communicate with an instruction-dependent site in oculomotor cortex. Patients with discrete frontal lobe damage can be strongly impaired in anti-saccades. By contrast, hemispherectomy patients performed oblique anti-saccades normally, contrasting with their permanent contralesional hemianopia and severe hemiparesis. PMID- 30472385 TI - Altered neural dynamics in people who report spontaneous out of body experiences. AB - It has been suggested that individual differences in cortical excitability leading to disruption of the timing and integration of sensory information processing may explain why some people have out of body experiences (OBE) in the absence of any known pathological or psychiatric condition. Here we recorded EEG from people who either had, or had not experienced an OBE in order to investigate the neural dynamics of OBE in the non-clinical population. A screening questionnaire was completed by 551 people, 24% of whom reported having at least one OBE. Participants who were free of any psychiatric or neurological diagnoses, including migraines, were invited to take part in subsequent EEG recording. EEG data were obtained from 19 people who had had an OBE and 20 who had not. Amplitude of the visual P1 ERP deflection and consistency of alpha-band phase locking were significantly reduced in the participants who had had an OBE. We did not find any group differences in resting state power or in visually induced gamma oscillations. These results provide support for the claim that cortical differences, particularly with respect to the timing of visual information processing, may give rise to OBE in clinically healthy individuals. To our knowledge, this study is the first to compare EEG variables obtained from people who have, and have not, had an OBE. PMID- 30472386 TI - Involvement of epigenetic modifications in thyroid hormone-dependent formation of adult intestinal stem cells during amphibian metamorphosis. AB - Amphibian metamorphosis has long been used as model to study postembryonic development in vertebrates, a period around birth in mammals when many organs/tissues mature into their adult forms and is characterized by peak levels of plasma thyroid hormone (T3). Of particular interest is the remodeling of the intestine during metamorphosis. In the highly-related anurans Xenopus laevis and Xenopus tropicalis, this remodeling process involves larval epithelial cell death and de novo formation of adult stem cells via dedifferentiation of some larval cells under the induction of T3, making it a valuable system to investigate how adult organ-specific stem cells are formed during vertebrate development. Here, we will review some studies by us and others on how T3 regulates the formation of the intestinal stem cells during metamorphosis. We will highlight the involvement of nucleosome removal and a positive feedback mechanism involving the histone methyltransferases in gene regulation by T3 receptor (TR) during this process. PMID- 30472387 TI - The association between hearing impairment and neural envelope encoding at different ages. AB - Hearing impairment goes with speech perception difficulties, presumably not only because of poor hearing sensitivity but also because of altered central auditory processing. Critical herein is temporal processing of the speech envelope, mediated by synchronization of neural activity to the envelope modulations. It has been suggested that hearing impairment is associated with enhanced sensitivity to envelope modulations which, in turn, relates to poorer speech perception. To verify this hypothesis, we performed a comparative electrophysiological study in hearing-impaired (HI) and normal-hearing (NH) human listeners of three age groups, investigating neural envelope encoding. HI young and middle-aged adults showed enhanced neural synchronization to envelope modulations relative to NH controls, particularly when stimulus audibility was corrected for. At an older age, the degree of neural synchronization was similar for HI and NH persons, yet HI persons showed a synchronization asymmetry toward the right hemisphere. This study demonstrates that hearing impairment is characterized by changes in the neural encoding of envelope modulations, the nature of which varies with age. PMID- 30472388 TI - A Risk Prediction Model for Invasive Fungal Disease in Critically Ill Patients in ICU. AB - PURPOSE: Developing a risk prediction model for invasive fungal disease based on an analysis of the disease related risk factors in critically ill patients of intensive care unit (ICU), in order to diagnose the invasive fungal disease in the early stages and determine the time of initiating early antifungal treatment. METHODS: The data were collected retrospectively from 141 adult critically ill patients with at least 4 days of general ICU stay at S Hospital, S University during the period from February 2015 to February 2016. Logistic regression was used to develop the risk prediction model. Discriminative power was evaluated by the area under the receiver operating characteristics (ROC) curve (AUC). RESULTS: Sequential organ failure assessment (SOFA) score, antibiotic treatment period, and positive culture of Candida albicans other than normally sterile sites are the three predictors of invasive fungal disease in critically ill patients in ICU. The model performs well with a ROC-AUC of .73. CONCLUSION: The risk prediction model performs well to discriminate between critically ill patients with or without invasive fungal disease. Physicians could use this prediction model for early diagnosis of invasive fungal disease and determination of the time to start early antifungal treatment of critically ill patients in ICU. PMID- 30472390 TI - A novel MyD88 inhibitor attenuates allograft rejection after heterotopic tracheal transplantation in mice. AB - BACKGROUND: After lung transplantation, the major complication limiting the long term survival of allografts is obliterative bronchiolitis (OB), characterized by chronic rejection. Innate immune responses contribute to the development of OB. In this study, we used a murine heterotopic tracheal transplantation mouse model to examine the effects of a newtype of innate immune inhibitor, TJ-M2010-5. METHODS: Syngeneic tracheal grafts were transplanted heterotopically from C57BL/6 mice to C57BL/6 mice. Allografts from BALB/c mice were transplanted to C57BL/6 mice. The allograft recipients were treated with TJ-M2010-5, and anti-mouse CD154 (MR-1). The grafts were harvested at 7, 14, and 28 days and evaluated by histological and real-time RT-PCR analyses. RESULTS: In untreated allografts, almost all epithelial cells fell off at 7 days and tracheal occlusion reached a peak at 28 days. However, the loss of the epithelium and airway obstruction were significantly improved in mice treated with TJ-M2010-5 combined with MR-1. The relative mRNA expression levels of pro-inflammatory cytokines were upregulated in allogeneic tracheal grafts, and treatment with the two drugs reduced the production of pro-inflammatory cytokines and infiltration of inflammatory cells. CONCLUSIONS: In heterotopic tracheal transplantation models, TJ-M2010-5 combined with MR-1 could ameliorate the development of OB. PMID- 30472389 TI - Outcome in ulcerative colitis after switch from adalimumab/golimumab to infliximab: A multicenter retrospective study. AB - BACKGROUND: Anti-TNF therapies infliximab (IFX), adalimumab (ADA), and golimumab (GOL) are approved for treating moderate to severe ulcerative colitis (UC). In UC, only the switch from IFX to ADA has been investigated, reaching no more than 10-43% remission rates at 12 months. AIM: Of the present study was to investigate disease outcome after a switch from subcutaneous (SC) agents to the intravenous (IV) agent (IFX). METHODS: In this retrospective multicentre study, we analysed the charts of UC patients unresponsive/intolerant or with secondary loss of response (LOR) to ADA or GOL who were switched to IFX. We evaluated clinical response and remission together with adverse events at 3, 6, and 12 months follow up. RESULTS: Seventy-six patients were included; 38 patients started ADA and 38 started GOL for a mean therapy duration of 6 +/- 6 months. Indications for switch were adverse events in 3%, primary failure in 79%, and LOR in 18% of patients. Clinical remission was reached by 47%, 50%, and 77% of patients, respectively. Patients that switched for LOR did numerically, but not statistically, better than patients who switched for primary failure. CONCLUSIONS: Our data show a superior remission rate in SC to IV anti-TNF switch in UC compared to the IV to SC switch reported in literature. PMID- 30472391 TI - iTRAQ-based quantitative proteomic analysis reveals potential early diagnostic markers in serum of acute cellular rejection after liver transplantation. AB - Liver transplantation (LT) is the most effective treatment method for advanced stage liver disease but acute cellular rejection (ACR) seriously affects the prognosis of LT. To discover novel diagnostic biomarkers of ACR after LT, Isobaric Tags for Relative and Absolute Quantitation (iTRAQ)-based mass spectrometry was performed to characterize alterations of serum proteins among patients validated to be pathologically ACR or pathologically no-ACR after LT and healthy controls. As a result, 10 differentially expressed proteins were found out between the ACR group and the No-ACR group; 88 differentially expressed proteins were found out between the ACR group and the Healthy Control group; 39 differentially expressed proteins were found out between No-ACR group and Healthy Control group. After analysis and ELISA validation, the results showed that CFHR1, CFHR5 and CFH could be candidate protein biomarkers for the early diagnosis of ACR after LT. PMID- 30472392 TI - An enigmatic case of undiagnosed severe diarrhoea post living donor liver transplant. AB - Graft versus Host Disease (GVHD) after orthotopic liver transplant (OLT), although rare, carries >80% mortality. Early diagnosis, prompt treatment, and aggressive supportive care are imperative to potentially reverse this otherwise fatal ailment. We describe a case of severe diarrhoea post living donor OLT who was diagnosed with acute GVHD. Addition of oral budesonide therapy to systemic corticosteroid therapy controlled the symptoms of diarrhoea. PMID- 30472393 TI - A Combined Modelling of Fuzzy Logic and Time-Driven Activity-based Costing (TDABC) for Hospital Services Costing under Uncertainty. AB - Hospital traditional cost accounting systems have inherent limitations that restrict their usefulness for measuring the exact cost of healthcare services. In this regard, new approaches such as Time Driven-Activity based Costing (TDABC) provide appropriate information on the activities needed to provide a quality service. However, TDABC is not flawless. This system is designed for conditions of relatively accurate information that can accurately estimate the cost of services provided to patients. In this study, the fuzzy logic in the TDABC model is used to resolve the inherent ambiguity and uncertainty and determine the best possible values for cost, capacity, and time parameters to provide accurate information on the costs of the healthcare services. This approach has not yet been tested and used in determining the costs of services of a healthcare setting. Therefore, the aim of this study is to present a new Fuzzy Logic-TDABC (FL-TDABC) model for estimating healthcare service costs based on uncertainty conditions in hospitals. The proposed model is implemented in a sample of the hospital laboratory section and the results are compared with the TDABC system. The TDABC model, by allocating the activity costs including fixed costs and not considering the uncertainty regarding the cost, capacity, and time required for each patient, often estimates the unused capacity and costs with a higher margin of error. The results show that the maximum difference in the prescribed costs was 4.75%, 3.72%, and 2.85% in blood bank, microbiology, and hematology tests, respectively, mostly due to uncertainty in the costs of consumables, equipment and manpower (on average 4.54%, 3.8%, and 3.59%, respectively). Also, The TDABC system, in comparison with the proposed system, estimates the unused capacity of the resource with more error. Cost of unused capacity derived using FL-TDABC were 80% of costs derived using TDABC. In conditions where the information is ambiguous, using the new system in hospitals can lead to a more accurate estimate of the cost compared to the TDABC system. Moreover, it helps hospital managers to make appropriate decisions about the use of capacity, capital budgeting, cost control, and etc. PMID- 30472394 TI - Aggressive behavior and stress response after oxytocin administration in male Norway rats selected for different attitudes to humans. AB - Oxytocin (OXT) is known to influence on social behaviors, including intermale aggression and hypothalamic-pituitary-adrenal (HPA) axis activity. However, there are no data on the effects of oxytocin on intermale aggression and HPA axis activity in rats selected for elimination and enhancement of aggressiveness towards humans. The aim of this study is to elucidate the role of oxytocin in expression of aggressive behavior and stress response in Norway rats selected for elimination (tame) and enhancement (aggressive) of an aggressive-defensive reaction to humans. Oxytocin was administered to males via nasal applications once or for 5 days (daily). Resident-intruder test showed that in aggressive males, single oxytocin administration caused an increase in the latent period of aggressive interactions and a decrease in the percentage of direct aggression time (not including the time of lateral threat postures) as compared to the control aggressive rats administered with saline. After a 5-day oxytocin administration, aggressive animals demonstrated shorter time of aggressive interactions compared to the control rats. Resident-intruder test revealed no significant changes in behavior of tame rats after single oxytocin administration, while multiple administration caused an increase in aggressive behavior in tame rats. Oxytocin applications caused an elevation of corticosterone level after restriction in aggressive males, but did not affect expression of Crh, Crh1 and Crhr2 genes in hypothalamus in either tame or aggressive rats. The data obtained indicate significant role of oxytocinergic system in the behavior formed in the process of selection by reaction to humans. PMID- 30472395 TI - Continuous access to snacks from weaning onwards in female rats causes weight gain, insulin insensitivity, and sustained leptin resistance in adulthood. AB - A large part of the daily intake of children in the U.S. consists of snacks, with the average child consuming three snacks per day. Despite this, little research has been conducted to determine the metabolic and behavioral effects of snacking. Using a developing female rat model, our studies aimed to determine the effects of snacking during development before the protective effects of estrogen on weight gain would be relevant. Additionally, to determine if snack composition is important, we created one healthy and one unhealthy snacking group provided with chow and three snacks each in addition to a chow-only group. We found that both snacking groups experienced increased weight gain, elevated abdominal fat pad mass, prolonged leptin resistance into adulthood, and insulin insensitivity that was not observed in their non-snacking counterparts. These physiological differences were measured despite both snacking groups having a similar caloric intake as the chow-only group throughout the study. In addition to physiological changes, both snacking groups showed a preference for snacks over chow and ate more often during the inactive light phase than typical for rats, with the unhealthy snacking group presenting this behavioral change earlier than the healthy snacking group. Our results suggest that constant access to palatable snacks, which is often the case for children in western countries, alters feeding behaviors in relation to food choice and time of day when eating occurs. Snacking during development seemed to promote signs of metabolic syndrome in adulthood even when excess caloric intake was not observed. Our work further suggests that development is a vulnerable time for palatable snack presentation when prepubertal females lack the protective effects of estrogen and exhibit reduced leptin feedback on food intake. Thus snacking from weaning onward could be a contributor to the current childhood obesity crisis. PMID- 30472396 TI - Influence of water antimicrobials and storage conditions on inactivating MS2 bacteriophage on strawberries. AB - Foodborne illnesses caused by norovirus contaminated fresh produce remain a food safety concern worldwide. In the present study, the impacts of commercial and home processing conditions of strawberries were evaluated for inactivation of the MS2 bacteriophage. MS2 was used as a surrogate of norovirus and was spot inoculated onto strawberries to achieve 6.6 log PFU/g. The inoculated strawberries were washed with tap water, electrolyzed water, or 50 ppm chlorine for 90 s prior to and after storage. After initial washing, the strawberries were separately stored at -20 degrees C and -80 degrees C for 30 days. Change in MS2 populations on strawberries was evaluated by plaque assay method on day 1, 15, and 30 for -20 degrees C and -80 degrees C groups. The results showed that washing strawberries prior to storage resulted in a significant decrease (approximately 1 log PFU/g) of MS2 population regardless of the treatment (p < 0.05). Frozen storage had minor effects on inactivating MS2, which resulted in approximately a 0.5 log PFU/g reduction at the end of storage. Washing frozen berries in electrolyzed water or 50 ppm chlorine on day 30 resulted in an additional 1 log PFU/g decrease in MS2 compared to water alone. These results suggest that washing strawberries with a chemical antimicrobial prior to and post frozen storage may enhance microbial safety. PMID- 30472397 TI - A loop-mediated isothermal amplification (LAMP) assay for the rapid detection of toxigenic Fusarium temperatum in maize stalks and kernels. AB - Fusarium temperatum is an emerging maize pathogen that causes maize ear and stalk rot diseases and produces various mycotoxins including moniliformin, beauvericin, enniatins and fumonisin B1, which poses a potential risk to the human food or animal feed supply chains. Early detection of F. temperatum is crucial to prevent its derived mycotoxins from entering the food chain, and is also a useful tool in disease management practices. Here, we describe a loop-mediated isothermal amplification (LAMP) assay for rapid diagnosis of F. temperatum. The 28S ribosomal DNA sequences (28S rDNA) of F. temperatum were used to design a set of six primers. The reaction conditions were optimized for developing a fast assay with high specificity and sensitivity, and were able to detect the presence of less than 10 pg of target DNA per reaction within 60 min. Furthermore, the resulting amplicons were visualized by adding SYBR Green I to the reaction tubes. Suspected F. temperatum infected maize stalk samples collected from Yunnan province, China were identified using the developed LAMP assay. In conclusion, the method not only provides a rapid and specific screening for the existence of F. temperatum in a bulk of maize samples without using sophisticated equipment, but also is potentially useful for other agriculturally important toxigenic fungi. PMID- 30472399 TI - Motivation matters: Development and validation of the Motivation for Solitude Scale - Short Form (MSS-SF). AB - INTRODUCTION: Motivation is an overlooked but crucial factor in determining whether solitude is psychologically beneficial or risky. This paper describes the development and validation of the Motivation for Solitude Scale - Short-Form (MSS SF), a measure grounded in Self-Determination Theory that differentiates between intrinsic versus extrinsic motivations for solitude. METHODS: Emerging adult (N = 803) and adolescent (N = 176) participants were recruited in four successive samples from the United States for the purposes of scale development and validation. Participants completed an on-line survey that included the MSS-SF and various well-being and personality measures. RESULTS & CONCLUSIONS: Confirmatory Factor Analyses resulted in a two-factor solution, selfdetermined solitude (SDS) and not self-determined solitude (NSDS), and showed the MSS-SF to be reliable with adolescents and emerging adults, with satisfactory convergent and discriminant validity. Engaging in solitude for extrinsic, not self-determined reasons was associated with loneliness, social anxiety, and depressive symptomatology; in contrast, solitude chosen for intrinsic, self-determined reasons was positively correlated with well-being, for emerging adults in particular. The MSS-SF goes beyond preference for solitude to distinguish two distinctly different motivations for solitude, and in so doing, allows researchers to better understand the affordances and risks of being alone for adolescents and emerging adults. PMID- 30472398 TI - Considering the negatively formed identity: Relationships between negative identity and problematic psychosocial beliefs. AB - INTRODUCTION: Developing a firm sense of identity is a critical developmental task in adolescence and emerging adulthood, but little or no empirical research exists regarding individuals who firmly form negative identities and psychosocial beliefs. This study examined the formation of negative identities in youth and its association with psychosocial beliefs in terms of variable-oriented psychosocial facets (i.e., dichotomous beliefs, cynicism, and social distrust) and person-oriented psychosocial profiles. METHODS: A total of 2313 young Japanese people (70.9% were females) aged 18-25 years answered the self-report questionnaire. RESULTS: We consequently found that individuals with negative identities possessed problematic psychosocial facets, such as high dichotomous beliefs and cynicism, as well as low social trust. Furthermore, individuals with negative identities had profile characterized by strong hostility toward others/societies. CONCLUSIONS: Overall, our study provided a comprehensive understanding of how youth with negative identities face difficulty in constructing relationships with society, which has been neglected in prior research. PMID- 30472400 TI - Whole-genome sequencing of an NDM-1- and OXA-58-producing Acinetobacter towneri isolate from hospital sewage in Sichuan Province, China. AB - OBJECTIVES: Acinetobacter spp. carrying the blaNDM-1 gene are frequently reported in the world. However, most reported blaNDM-1 genes are carried by clinical strains. Here we report a carbapenems-resistant A. towneri isolated from hospital sewage in China, co-harbouring blaNDM-1 and blaOXA-58 in the genome. METHODS: The whole genome was sequenced using the Single Molecule Real-Time (SMRT) sequencing platform with Pacific Biosciences RS II sequencer and MiSeq systems. The reads were de novo assembled using the Celera Assembler 8.0. Annotation of genome was achieved using the NCBI Prokaryotic Genome Annotation Pipeline. The genome sequence was analysed by bioinformatics methods. RESULTS: The 2 963 729-bp genome with 41.30% G+C content displayed eleven resistance genes, including blaNDM-1 and blaOXA-58. Meanwhile, two plasmids and nineteen genomic islands were predicted within the genome. CONCLUSION: The whole genome sequence reported here can be compared with other genomes of NDM-1-producing Acinetobacter spp. These data could facilitate further understanding of the specific genomic feature of carbapenems-resistant Acinetobacter spp. in China. PMID- 30472401 TI - Anti-obesity effect of garlic oil on obese rats via Shenque point administration. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Shenque is an acupoint located in the umbilicus and connected with the meridians. Thus, acupoint herbs applied at Shenque plays a pivotal role in the Chinese traditional medicine due to its sensitivity, permeability, and absorption. Many studies reported the use of Shenque point as a successful therapeutic approach. However, the effect of garlic oil (GO) applied at Shenque point to combat obesity is unmet. Consequently, we investigated the potential benefit of GO applied at Shenque point against obesity. AIM OF THE STUDY: To investigate GO effects on obese rats applied at Shenque acupoint and orally administered, and to identify the chemical constituents of GO. MATERIALS AND METHODS: Rats were randomly divided into 2 groups: naive and model group. The model group rats were fed with a high fat diet for 7 weeks to induce obesity, and then they were randomly divided into 5 groups: model, GO Shenque point treated groups (25, 50 and 100mg/kg/day) and oral group (50mg/kg/day). Biochemical indexes in the serum, weight of adipose tissue and liver histopathology were evaluated after 6 weeks of GO treatment using a Hitachi 7080 analyzer (Hitachi, Japan). Moreover, GO chemical components were detected by gas chromatography-mass spectrometer (GC-MS). RESULTS: Compared with the naive rats, model rats exhibited higher body and liver weight, increased fat deposition, higher triglyceride concentration and alveolar development. In contrast, GO Shenque point treated groups showed a substantial decrease in body weight (P = 0.358, 0.028, 0.031, respectively), fat mass, cholesterol (P = 0.004, 0.041, 0.001, respectively), triglyceride (P = 0.001, 0.001, 0.001, respectively), and low density lipoprotein concentrations (P = 0.001, 0.000, 0.001, respectively). The effect was more remarkable than the GO orally administered. In addition, twelve GO organosulfur compounds were identified by GC-MS and diallyl trisulfide (DATS) was detected as the main compound, with a 32.08% concentration. CONCLUSIONS: These findings demonstrated that GO had a significant anti-obesity effect on obese rats by reducing the body weight and protecting the liver from damage, and the effect of Shenque point treatment was better than oral administration, suggesting that GO was an effective weight-loss drug and Shenque point administration might be considered as a new anti-obesity approach. PMID- 30472402 TI - Genus Tetradium L.: a comprehensive review on traditional uses, phytochemistry, and pharmacological activities. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The dried fruit of Tetradium ruticarpum is frequently utilized as a common traditional medicine in China, Japan and Korea. It has been widely used for the treatment of various diseases such as headache, menorrhalgia, dermatophytosis, celialgia, emesis and aphtha and so on. AIM OF THIS REVIEW: Despite the wide biological activities of Tetradium plants, there is no current review summarizing medicinal properties of the genus of plants; thus, this review aims to systematically summarize studies on botanical characteristics, traditional uses, phytochemical ingredients, quality control, pharmacokinetics, pharmacological activities and toxicity of Tetradium species to demonstrate their therapeutic capacity. MATERIALS AND METHODS: Information and materials related to Tetradium species were obtained from scientific databases such as Google Scholar, Wikipedia, Web of Science, PubMed, ScienceDirect, ACS Publications, SciFinder. Information was also gathered from International Plant Names Index, Global Biodiversity Information Facility, Chinese Pharmacopoeia and Traditional Chinese Medicine classics, etc. All studies of this genus were included in this review until July 2018. RESULTS: Tetradium is widely assessed regarding its phytochemistry and biological activities. Approximately 131 chemical compounds, including alkaloids, saponins, phenols and other compounds, have been isolated from Tetradium plants. Among these components, alkaloid evodiamine is the most representative active ingredients of Tetradium plants. These compounds isolated from Tetradium plants exhibit a wide range of biological activities in vitro and in vivo including antitumor, antibacterial, anti inflammatory, insecticide, cardioprotective and lipid-lowering, treating CNS disorders, digestive system regulation and endocrine system improving activities. Furthermore, alkaloids could be used as markers for quality identification and evaluation of medicinal materials and their preparations. Information on evaluating the safety and pharmacokinetics of Tetradium often focuses on the alkaloids, thus further study and clinical data are required to enable the drug safety of the utilization of Tetradium plants. CONCLUSIONS: Phytochemical and pharmacological studies of Tetradium plants have proved Tetradium plants are important medicinal herb resource. However, well-designed randomized clinical trials are necessary to confirm the therapeutic benefits of this genus in clinical settings. PMID- 30472403 TI - Antimicrobial and cytotoxic effects of the Copaifera reticulata oleoresin and its main diterpene acids. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The oleoresin of Copaifera reticulata is a traditional Brazilian remedy used for the treatment of skin and urinary tract infections, respiratory diseases, rheumatism, ulcer and tumours; thus, playing an important role in the primary health care of the indigenous population. AIM: As most previous pharmacological tests used the crude oleoresin and only a few studies so far dealt with enriched fractions or pure chemically defined compounds, the aim of this study was to evaluate systematically the antimicrobial and cytotoxic properties of the Copaifera reticulata oleoresin and to assign traditional uses to specific secondary metabolites. MATERIALS AND METHODS: The oleoresin as well as its neutral and acidic fractions were tested for their activity against six cancer cell lines, two clinically relevant bacterial strains, and two dermatophytes. Both fractions were analysed by GC-MS and UHPLC ELSD, respectively. The antibacterial acidic phase was further fractionated by preparative chromatography to purify and characterize the compounds responsible for the observed pharmacological effect. RESULTS: Whereas the use in anticancer treatment was not supported by our results, the crude oleoresin and its acidic fraction showed antibacterial activity against Enterococcus faecium (IC50 values of 4.2 and 4.8ug/mL, respectively) and methicillin-resistant Staphylococcus aureus (MRSA, IC50 values 5.3 and 7.2ug/mL, respectively). Purification of the acidic fraction resulted in the isolation of two dicarboxylic diterpene acids and the four main diterpene acids of the C. reticulata oleoresin, comprising three different diterpene scaffolds. Interestingly, the activity was not restricted to a particular diterpene-type but rather depended on the compounds' lipophilicity, with the most active constituent showing IC50 values of 1.6 (E. faecium) and 2.5ug/mL (MRSA), respectively. Furthermore, ent-polyalthic acid, the major diterpenoid, was significantly active against dermatophytes with IC50 values of 6.8ug/mL (Trichophyton rubrum) and 4.3ug/mL against (T. mentagrophytes). CONCLUSION: The present study proved the antimicrobial effects of the C. reticulata oleoresin and its diterpenoid constituents, confirming its wide use in folk medicine for the treatment of skin and urinary tract infections. The inhibitory activity of copaiba diterpenoids against dermatophytic fungi as well as the gram-positive bacteria E. faecium and MRSA is being reported for the first time, providing potential lead structures for the treatment of these clinically relevant bacterial strains. PMID- 30472404 TI - Effect of problem and scripting-based learning combining wearable technology on orthopedic operating room nurses' learning outcomes. AB - BACKGROUND: Orthopedic operating room (OR) nurses entail specialized skills and training, which are not part of the regular curricula at most nursing college. Instead, many nursing students' exposure to orthopedic care in the orthopedic range is limited to occasional observational assignments. Additionally, teamwork is an important factor affecting the performance of the orthopedic OR nurses. This results in a knowledge gap in clinical nursing education. Problem and scripting based learning (PSBL) method is a crucial tool of pre-operative prepared improvement. It is easy for surgeon to record surgical video from his own field of vision by wearable technology (WT). Nevertheless, few studies related to combine WT and PSBL been done to investigate features underlying efficiency in training of novice orthopedic OR nurses. OBJECTIVE: This study aimed to evaluate the feasibility of combining WT with PSBL in training of novice orthopedic OR nurses. METHODS: 20 operating room post-graduate-year-1 nurses from the First Hospital of China Medical University were randomly divided into two groups ("conventional training (CT)" group and "WT combining with PSBL" group). Initially the superior orthopedic operating room nurses who immediately followed each procedure filled out a feedback questionnaire of the novice nurses. After finished procedure, novice nurses had a basic understanding of each training method benefits and then filled out the questionnaires. Statistical analysis of the results was performed. RESULTS: Novice nurses of WT&PSBL Group got the better score in most of the preparedness and performance feedback statement. Mean scores of overall total preparedness and performance feedback statement of WT&PSBL Group was higher than CT Group (P <= 0.05). Based on summarizing the questionnaires, the novice nurse in WT- PSBL Group also made significantly better total score than "Conventional training" Group (P <= 0.05). CONCLUSIONS: WT&PSBL method, as a crucial tool for improving pre-operative preparedness and intra-operative performance, can cultivate novice orthopedic operating room nurses' ability to use prior knowledge and cognitive frameworks flexibly to deal with problems during performance. It plays a crucial role in training confident and safe orthopedic operating room nurses. DESIGN: Randomized controlled trial (RCT). PMID- 30472405 TI - Undergraduate nursing students' experiences and attitudes towards working with patients with opioid use disorder in the clinical setting: A qualitative content analysis. AB - BACKGROUND: With the US facing an opioid epidemic, undergraduate nursing students are increasingly encountering patients with opioid use disorder in the clinical setting. Yet, nursing curriculums have not adapted to meet this need. Previous research indicates students are exposed to negative messages that might influence their views about patients with opioid use disorder. OBJECTIVES: The purpose of this study was to examine nursing students' experiences encountering patients with opioid use disorder in the clinical setting, their attitudes about their encounters, and their perceptions of their educational preparedness to care for this population. METHOD: Purposive sampling was used to identify participants. Semi-structured interviews were conducted until saturation. Krippendorff's method for qualitative content analysis was used to cluster units within the data to identify emergent themes. PARTICIPANTS: Eleven senior nursing students from a public university in New England participated. RESULTS: Analysis revealed six themes, including: navigating ethical dilemmas, gaining comfort with time and experience, avoiding the "elephant in the room," learning from real-world scenarios, witnessing discriminatory care, and recognizing bias and stigma. CONCLUSIONS: Students were most likely to experience bias and internal conflict in maternity clinical rotations. Education should include practical communication strategies to reduce avoidance behaviors among nursing students as well as techniques to manage difficult situations and reduce moral distress. Nurses must be mindful of their power to influence students and should model non-judgmental language and behavior. Students ultimately expressed a desire to provide informed and empathetic care. PMID- 30472407 TI - Physiological responses to acute stress and the drive to eat: The impact of perceived life stress. AB - The stress-eating relationship is mediated by the release of cortisol from the hypothalamic pituitary adrenal (HPA) axis. Variability in stress-induced eating, and consequently, obesity, may be explained in part by individual differences in chronic stress, which disrupts the regulatory effects of the HPA axis on stress induced eating. A greater understanding of the physiological mechanisms by which chronic stress affects acute stress-induced eating is critical in order to inform efforts to prevent and treat obesity. The current study examined the relationship between physiological responses to acute stress (cortisol and cardiovascular factors) and the drive to eat (ratings of hunger and desire to eat) in female undergraduates with high and low perceived life stress. Participants (n = 64) rated their perceived life stress in an online screening and, on a separate visit, rated their drive to eat before and after a mental stress task. The present report focused on only participants in the lowest (n = 16) and highest (n = 14) quartiles of perceived life stress. Women with high perceived life stress showed greater stress-induced cortisol responses, but no significant changes in blood pressure or heart rate. The heightened cortisol responses were not associated with hunger and desire to eat, but the cardiovascular responses were positively associated with the drive to eat. Women with low perceived life stress showed no relationships between physiological stress markers and the drive to eat. These results suggest that the cortisol stress response is dissociated from the drive to eat in chronically stressed women, although due to the small sample size the data should be regarded as preliminary. Further studies are needed to explore how cortisol and cardiovascular reactivity affect stress-induced eating. PMID- 30472406 TI - Relationships among nursing student palliative care knowledge, experience, self awareness, and performance: An end-of-life simulation study. AB - BACKGROUND: Palliative care education and experience are needed for student competence in delivering high-quality palliative nursing care. Simulation has been linked to acquired clinical competency among pre-licensure students. A known literature gap is measurement of students' performance during end-of-life simulations. OBJECTIVES: The aim of this study was to determine relationships among previous palliative care nursing experience, knowledge, self-awareness, and performance in nursing students during an end-of-life simulation. DESIGN/SETTING/PARTICIPANTS: A quasi-experimental pretest/posttest design was used to assess these variables with a convenience sample of 75 senior nursing students during an end-of-life simulation at a Midwest Jesuit university. METHODS: Self-awareness was measured with the Frommelt Attitudes Toward Care of the Dying, Form B. The Palliative Care Quiz for Nursing measured participants' knowledge. Participants' performance during the simulation was measured using a modified version of the Creighton Competency Evaluation Instrument(r). Palliative care nursing self-awareness and knowledge were assessed before and after the simulation. Previous end-of-life care experience was assessed with a single demographic question at pretest only. RESULTS: The sample was highly experienced in end-of-life care (93.3% reporting experience pre-simulation). Although pretest self-awareness (M = 124.5; +/-1.3) and knowledge (M = 57.1%; +/-2.2) were higher in students with two or more types of end-of-life experience (n = 42), there were no significant differences (p > .10) in these outcomes by groups pre- or post simulation. Self-awareness (M = 130.1; +/-1.2), knowledge (M = 80.5%; +/-2.6), and performance (M = 94.1%; IQR 87.5 to 100) scores were high for student participants (n = 36) post-simulation, with moderate correlations found between some scores (rpb < -0.40 or 0.40). CONCLUSIONS: Findings support self-awareness and knowledge as antecedents of high quality palliative nursing care. Students demonstrated increased post-simulation knowledge, self-awareness, and quality performance of palliative nursing care regardless of previous end-of-life experience. End-of-life simulation is supported as an education method for increasing palliative care nursing competence and assessing student performance of palliative care nursing interventions. PMID- 30472408 TI - Image super-resolution using progressive generative adversarial networks for medical image analysis. AB - Anatomical landmark segmentation and pathology localisation are important steps in automated analysis of medical images. They are particularly challenging when the anatomy or pathology is small, as in retinal images (e.g. vasculature branches or microaneurysm lesions) and cardiac MRI, or when the image is of low quality due to device acquisition parameters as in magnetic resonance (MR) scanners. We propose an image super-resolution method using progressive generative adversarial networks (P-GANs) that can take as input a low-resolution image and generate a high resolution image of desired scaling factor. The super resolved images can be used for more accurate detection of landmarks and pathologies. Our primary contribution is in proposing a multi-stage model where the output image quality of one stage is progressively improved in the next stage by using a triplet loss function. The triplet loss enables stepwise image quality improvement by using the output of the previous stage as the baseline. This facilitates generation of super resolved images of high scaling factor while maintaining good image quality. Experimental results for image super-resolution show that our proposed multi stage P-GAN outperforms competing methods and baseline GANs. The super resolved images when used for landmark and pathology detection result in accuracy levels close to those obtained when using the original high resolution images. We also demonstrate our methods effectiveness on magnetic resonance (MR) images, thus establishing its broader applicability. PMID- 30472409 TI - CNN cascades for segmenting sparse objects in gigapixel whole slide images. AB - Due to the increasing availability of whole slide scanners facilitating digitization of histopathological tissue, large amounts of digital image data are being generated. Accordingly, there is a strong demand for the development of computer based image analysis systems. Here, we address application scenarios in histopathology consisting of sparse, small objects-of-interest occurring in the large gigapixel images. To tackle the thereby arising challenges, we propose two different CNN cascade approaches which are subsequently applied to segment the glomeruli in whole slide images of the kidney and compared with conventional fully-convolutional networks. To facilitate unbiased evaluation, eight-fold cross validation is performed and finally means and standard deviations are reported. Overall, with the best performing cascade approach, single CNNs are outperformed and a pixel-level Dice similarity coefficient of 0.90 is obtained (precision: 0.89, recall: 0.92). Combined with qualitative and further object-level analyses the obtained results are assessed as excellent also compared to previous approaches. We can state that especially one of the proposed cascade networks proved to be a highly powerful tool providing the best segmentation accuracies and also keeping the computing time at the lowest level. This work facilitates accurate automated segmentation of renal whole slide images which consequently allows fully-automated big data analyses for the assessment of medical treatments. Furthermore, this approach can also easily be adapted to other similar biomedical application scenarios. PMID- 30472410 TI - Severe atherosclerosis in the natural mummy of Girolamo Macchi (1648-1734), "major writer" of Santa Maria della Scala Hospital in Siena (Italy). AB - BACKGROUND AND AIMS: A small crypt in the Santissima Annunziata Church of Santa Maria della Scala Hospital in Siena (Italy) contained three well-preserved mummies, two of which, dated back to the 15th-16th century, were identified as Salimbene Capacci (1433-1497), Rector of the Hospital, and his wife, Margherita Sozzini (?-1511). The third mummy, dressed in clothes of the 17th century, was not initially identified. METHODS: Accurate bibliographical, taphonomic and anthropological studies allowed the identification of the mummy of Girolamo Macchi, who lived between 1648 and 1734 and worked as "major writer", an accountant, for the Hospital. He was present when the corpses of the Rector and his wife were discovered in 1678 and, impressed by this finding, wanted to be buried in the same chapel after his death, which occurred at the age of 86. A complete study, including macroscopic, radiological, isotopic and histological analyses, was performed on the natural mummy of Girolamo. RESULTS: Macroscopic investigation showed a large inguinoscrotal hernia and a good preservation of the internal organs. The circulatory system revealed severe atherosclerosis, with multiple calcifications stenosing the lumen of the vessels, in particular of the lumbar aorta and the iliac arteries. The diagnosis was confirmed by imaging techniques (3D Cone Beam Scan) and by histology. CONCLUSIONS: This case confirms that atherosclerosis is also a disease of ancient times. The presence of atherosclerosis in pre-contemporary individuals could suggest that the disease may not only be uniquely characteristic of a specific diet or lifestyle, but it could be also an inherent component of human ageing. PMID- 30472411 TI - Spanish validation of the telephone assessed Expanded Disability Status Scale and Patient Determined Disease Steps in people with multiple sclerosis. AB - BACKGROUND: The Expanded Disability Status Scale (EDSS) and Patient Determined Disease Steps (PDDS) are two of the most widely disability scales used in multiple sclerosis (MS). When physical visits are unavailable, remote evaluation through telephone interview may be helpful. We aimed to translate both scales into Spanish, and to 1) validate the telephone EDSS and PDDS, and 2) explore the association pattern between both telephone questionnaires. METHODS: 103 patients underwent a neurological examination to generate the EDSS and completed the PDDS questionnaire. Telephone questionnaires (EDSS, PDDS) were performed within 15 days. Feasibility and psychometric properties of both telephone questionnaires included internal consistency, acceptability, inter-rater agreement and validity. Test-retest reliability was evaluated in 36 patients. RESULTS: Both scales showed excellent internal consistency and test-retest reliability. The agreement between conventional and telephone assessments in ambulatory impaired patients (EDSS > 4.0) was good for EDSS (kappa = 0.72) and excellent for PDDS (kappa = 0.93); fully ambulatory patients (EDSS <= 4.0) showed lower values (kappa = 0.24, and 0.54, respectively). Full agreement was higher for telephone PDDS than telephone EDSS (78% vs 44%). Overestimation of disability was more frequent in fully ambulatory patients. Strong correlation was found between telephone questionnaires (rho = 0.88; p < 0.001). The pattern of association was not isomorphic, but a PDDS cut-off of 3 identified with high accuracy patients with ambulatory impairment. DISCUSSION: Telephone EDSS and PDDS questionnaires for Spanish patients are valid tools to assess disability status in MS and offer complementary information. Patients with ambulatory impairment are those who benefit the most from a remote assessment. PMID- 30472412 TI - A rare P2RX7 variant in a Hungarian family with multiple sclerosis. PMID- 30472413 TI - Corpus callosum agenesis and clinically isolated syndrome (CIS): A case report. PMID- 30472414 TI - Emotional processing in RRMS patients: Dissociation between behavioural and neurophysiological response. AB - BACKGROUNG: Multiple sclerosis (MS) results in a broad range of symptoms, including motor, visual, cognitive, and neuropsychiatric deficits. Some studies, considering affective facial expressions to study emotion processing, demonstrated emotion recognition difficulties in MS patients. OBJECTIVE: We investigated the impact of MS on the emotional-behaviour rating and neurophysiological response (Event Related Potentials-ERP) through a battery of affective visual stimuli selected from the International Affective Picture System (IAPS). METHODS: Twenty patients with diagnosis of Relapsing Remitting MS (RRMS) and 20 Healthy Controls (HC) matched by age, gender and education were enrolled. Each of them, after a neuropsychological assessment, were asked to evaluate arousal and valence of affective visual stimuli. RESULTS: Our results showed higher P300 amplitudes in RRMS patients than HC group for pleasant and unpleasant images. Moreover, RRMS patients showed lower Reaction Time (RT) respect HC in valence rating. No other effect did emerge between groups. CONCLUSION: Our study shows early compensatory cerebral mechanisms in RRMS patients throughout emotional information processing, particularly for unpleasant and pleasant stimuli. We hypothesize that this compensatory cerebral mechanism reduces the behavioural dissimilarity between patients and HC. PMID- 30472415 TI - The aromatic amino acid sensor GPR142 controls metabolism through balanced regulation of pancreatic and gut hormones. AB - OBJECTIVES: GPR142, which is highly expressed in pancreatic islets, has recently been deorphanized as a receptor for aromatic amino acids; however, its physiological role and pharmacological potential is unclear. METHODS AND RESULTS: We find that GPR142 is expressed not only in beta- but also in alpha-cells of the islets as well as in enteroendocrine cells, and we confirm that GPR142 is a highly selective sensor of essential aromatic amino acids, in particular Trp and oligopeptides with N-terminal Trp. GPR142 knock-out mice displayed a very limited metabolic phenotype but demonstrated that L-Trp induced secretion of pancreatic and gut hormones is mediated through GPR142 but that the receptor is not required for protein-induced hormone secretion. A synthetic GPR142 agonist stimulated insulin and glucagon as well as GIP, CCK, and GLP-1 secretion. In particular, GIP secretion was sensitive to oral administration of the GPR142 agonist an effect which in contrast to the other hormones was blocked by protein load. Oral administration of the GPR142 agonist increased [3H]-2-deoxyglucose uptake in muscle and fat depots mediated through insulin action while it lowered liver glycogen conceivably mediated through glucagon, and, consequently, it did not lower total blood glucose. Nevertheless, acute administration of the GPR142 agonist strongly improved oral glucose tolerance in both lean and obese mice as well as Zucker fatty rat. Six weeks in-feed chronic treatment with the GPR142 agonist did not affect body weight in DIO mice, but increased energy expenditure and carbohydrate utilization, lowered basal glucose, and improved insulin sensitivity. CONCLUSIONS: GPR142 functions as a sensor of aromatic amino acids, controlling GIP but also CCK and GLP-1 as well as insulin and glucagon in the pancreas. GPR142 agonists could have novel interesting potential in modifying metabolism through a balanced action of gut hormones as well as both insulin and glucagon. PMID- 30472416 TI - AncestryPainter: A Graphic Program for Displaying Ancestry Composition of Populations and Individuals. AB - Ancestry composition of populations and individuals has been extensively investigated in recent years due to advances in the genotyping and sequencing technologies. As the number of populations and individuals used for ancestry inference increases remarkably, say more than 100 populations or 1000 individuals, it is usually challenging to present the ancestry composition in a traditional way using a rectangular graph. To address this issue, we developed a program, AncestryPainter, which can illustrate the ancestry composition of populations and individuals with a rounded and nice-looking graph to save space. Individuals are depicted as length-fixed bars partitioned into colored segments representing different ancestries, and the population of interest can be highlighted as a pie chart in the center of the circle plot. In addition, AncestryPainter can also be applied to display personal ancestry in a way similar to that for displaying population ancestry. AncestryPainter is publicly available at http://www.picb.ac.cn/PGG/resource.php. PMID- 30472418 TI - Borrelial serology does not contribute to the diagnostic work-up of patients with nonspecific symptoms. AB - The short commentary focuses on the diagnosis of Lyme borreliosis with special respect to serological testing. The methods of serological testing are summarized with strong recommendation to use the tests only in patients with sysmptoms consistent with Lyme borreliosis according to clinical case definitions. In the second part there is a brief discussion of the post-Lyme diesease syndrome and nonspecific complaints, as patients with such complaints are frequently suspected to have Lyme borreliosis. The published literature indicates that the aetiology of these symptoms might be based on multiple factors and not on the chronic infection with Borrelia. The final, concluding remarks reflect the need for more effective dissemination of evidence-based knowlegde on Lyme borreliosis and more intensive research on the aetiology of nonspecific symptoms in general. PMID- 30472417 TI - The novel HBx mutation F30V correlates with HCC in vivo, reduces HBV replicative efficiency and enhances anti-apoptotic activity of HBx N-terminus in vitro. AB - OBJECTIVE: We aimed to investigate HBx genetic-elements correlated with HBV related HCC and their impact on i) HBV replicative efficiency, ii) HBx-binding to cccDNA, iii) apoptosis and cell-cycle progression, and iv) HBx structural stability. METHODS: This study included 123 HBV-chronically infected patients: 27 with HCC (77.9% [21/27] genotype-D; 22.1% [6/27] genotype-A) and 96 without HCC (75%-D [72/96]; 25.0%-A [24/96]). HepG2 cells were transfected by wt or mutated linear HBV-genome to assess pre-genomic RNA (pgRNA) and core-associated HBV-DNA levels, HBx-binding onto cccDNA by Chromatine Immune-Precipitations-based quantitative assay, and rate of apoptosis and cell-cycle progression by cytofluorimetry. RESULTS: F30V was the only HBx-mutation correlated with HCC (18.5% [5/27] in HCC versus 1.0% [1/96] in non-HCC, p=0.002). Result confirmed by multivariable-analysis. IN-VITRO: F30V determined a 40% and 60% reduction in pgRNA and core-associated HBV-DNA compared to wt (p<0.05), parallelling with a significant decrease of HBx-binding to cccDNA and decreased HBx-stability. F30V also decreased percentage of apoptotic-cells compared to wt (14.8+/-6.8% vs 19.1+/-10.1%, p<0.01, without affecting cell-cycle progression) and increased the probability of HBx-Ser31 to be phosphorylated by PI3K-Akt kinase (known to promote anti-apoptotic activity). CONCLUSIONS: F30V tightly correlated with HBV induced HCC in-vivo, reduced HBV replicative efficiency by affecting HBx-binding to cccDNA and increased anti-apoptotic HBx activity in-vitro. This suggests that F30V (although hampering HBV replicative-capacity) may promote hepatocytes survival, thus potentially allowing persistent production of viral progeny and initiating HBV-driven hepato-carcinogenesis. Investigation of viral genetic markers associated with HCC is crucial to identify patients at higher HCC-risk deserving intensive liver monitoring, and/or early anti-HBV therapy. PMID- 30472419 TI - A case of leech-associated infection involving an extended-spectrum beta lactamase-producing and extensively drug-resistant Aeromonas hydrophila. AB - Herein, we describe a case of failure of delayed breast reconstruction due to leech-borne infection by extended-spectrum beta-lactamase (ESBL)-producing and extensively-resistant A. hydrophila. In the current era of increasing antibiotic resistance, such infections should be considered to redefine preventive protocols of leeches safety and search of bacterial resistance to antibiotics. PMID- 30472420 TI - Molecular mechanisms of azole resistance in Candida tropicalis isolates causing invasive candidiasis in China. AB - OBJECTIVE: We investigated molecular mechanisms responsible for azole resistance in Candida tropicalis isolates. METHODS: We studied 507 C. tropicalis isolates causing invasive candidiasis from 10 hospitals over five years. Antifungal susceptibility was determined by broth microdilution methods. Point mutations in C. tropicalis ERG11 gene that may confer azole resistance was explored and verified. The expression levels of ERG11, CYTb, MDR1, and CDR1 genes were compared in 20 fluconazole-susceptible, and 20 fluconazole-resistant isolates. RESULTS: Fluconazole-susceptible, susceptible dose-dependent and resistant strains accounted for 76.7% (389/507), 10.5% (53/507) and 12.8% (65/507) of C. tropicalis isolates, respectively. The ERG11 mutation A395T/W occurred in 10.7% (54/507) of isolates, all of which were resistant to fluconazole. The nucleotide mutation C461T/Y was the second most common (50/507 isolates, 9.9%), and all isolates carrying C461T/Y also had the mutation A395T/W. However, the presence of C461T didn't contribute to azole resistant phenotype. Substitutions V125A, Y257H and G464S (<2% of isolates), which were reported for the first time in C. tropicalis, also conferred fluconazole non-susceptible phenotypes. Compared with fluconazole susceptible isolates, fluconazole resistant isolates had higher ERG11 (fold expression level 1.42 versus 0.79, P<0.01) but lower CYTb (fold expression level 1.26 versus 2.67, P<0.01) gene expression levels. Three azole resistant isolates carrying the wild-type ERG11 gene had higher levels of CDR1 and MDR1 expression. CONCLUSIONS: ERG11 missense mutations were the major mechanism responsible for azole resistance in C. tropicalis isolates, but overexpression of ERG11, CDR1 and MDR1 as well as reduced expression of CYTb also contributed to resistance. PMID- 30472421 TI - Epidemiological changes of acute/recent HIV-1 infection in Barcelona, Spain (1997 2015): A prospective cohort study. AB - OBJECTIVE: To describe the epidemiology of acute/recent HIV infection over two decades in Barcelona (Spain). METHODS: Prospective, single-center cohort including all patients with an acute/recent HIV infection (less than 180 days) since 1997. Patients were stratified into four periods. Phylogenetic analysis was performed to determine clusters of transmission. RESULTS: 346 consecutive acute/recently infected patients were included. The annual proportion of recent infections among total new HIV diagnoses increased over time from 1% (29 out of 1964) to 8% (112 out of 1474) (p<0.001). Proportion of MSM in the cohort increased from 62% (18 out of 29) to 89% (100 out of 112) (p<0.001). The proportion of migrants showed a non significant increasing trend (24%- 7 of 29- to 40%-45 of 112) likewise the non-B subtype (0% to 22%-22 of 112). The mean time from infection to diagnosis was 53.6 days [IQR 50; 57], comparable among all periods. Mean time from infection to treatment decreased over the years from 575 [IQR 467; 683] to 471 [IQR 394; 549] days (p<0.001) without significant differences between migrants and non-migrants (133 [IQR 71; 411] vs 208 [IQR 90; 523] days p=0.089). Almost 50% (152 of 311) of recently infected patients were included in a cluster of transmission, and 92% (137 of 149) of them were MSM. CONCLUSION: The MSM population has progressively grown within acutely/recently infected patients in Barcelona, and is frequently involved in transmission clusters. Although the time between diagnosis and treatment has been progressively reduced, the time between infection and diagnosis still needs to be shortened. PMID- 30472423 TI - Clofazimine for the treatment of multidrug-resistant tuberculosis. PMID- 30472422 TI - Diagnostic accuracy of leptospirosis whole-cell lateral flow assays: a systematic review and meta-analysis. AB - BACKGROUND: Leptospirosis is under-diagnosed by clinicians in many high-incidence countries, as reference diagnostic tests are largely unavailable. Lateral flow assays (LFA) that use antigen derived from heat-treated whole cell Leptospira biflexa serovar Patoc have potential to improve leptospirosis diagnosis in resource-limited settings. OBJECTIVES: We sought to summarize estimates of sensitivity and specificity of LFA by conducting a systematic review and meta analysis of evaluations of the accuracy of LFA to diagnose human leptospirosis. DATA SOURCES: On 4 July 2017 we searched three medical databases. STUDY ELIGIBILITY CRITERIA: Articles were included if they were a study of LFA sensitivity and specificity PARTICIPANTS: Patients with suspected leptospirosis INTERVENTIONS: Nil METHODS: For included articles, we assessed study quality, characteristics of participants, and diagnostic testing methods. We estimated sensitivity and specificity for each study against the study-defined case definition as the reference standard, and performed a meta-analysis using a random-effects bivariate model. RESULTS: Our search identified 225 unique reports, of which we included nine (4%) published reports containing 11 studies. We classified one (9%) study as high quality. Nine (82%) studies used reference tests with considerable risk of misclassification. Our pooled estimates of sensitivity (95% confidence intervals) were 79% (70,86%) and specificity 92% (85,96%). CONCLUSIONS: As the evidence base for determining the accuracy of LFA is small and at risk of bias, pooled estimates of sensitivity and specificity should be interpreted with caution. Further studies should use either reference tests with high sensitivity and specificity or statistical techniques that account for an imperfect reference standard. PMID- 30472424 TI - Genomics of Klebsiella pneumoniae ST16 producing NDM-1, CTX-M-15 and OXA-232. AB - OBJECTIVES: Genomic characterization of the internationally spread Sequence Type 16 carbapenem resistant Klebsiella pneumoniae METHODS: The complete genomes of 3 carbapenem producing ST16 K. pneumoniae from Italian patients were analyzed by SNP-based phylogeny, cgMLST, resistance, plasmid and virulence content and compared with 10 genomes of ST16 strains isolated in other countries. Plasmids carrying blaNDM-1 or blaOXA-232 carbapenemase genes were assembled and sequences analyzed. RESULTS: The internationally spread ST16 K. pneumoniae clone showed variability in terms of distribution of NDM-1 and OXA-232 type carbapenemases. In some ST16 strains, up to six plasmids can be simultaneously present in the same cell, including ColE-like plasmids carrying blaOXA-232 and IncF plasmids carrying blaNDM-1. The differences observed in plasmid, resistance and virulence content and core genome, suggested that there is not a unique, highly conserved ST16 clone, but instead different variants of this lineage circulate worldwide. CONCLUSIONS: ST16 K. pneumoniae clone is worldwide spread and may become a high risk clone. PMID- 30472425 TI - Effectiveness of second-dose varicella vaccination as post-exposure prophylaxis: a prospective cohort study. AB - OBJECTIVES: Although administration of a second dose of varicella vaccine (2nd dose VarV) to individuals who have previously received one-dose VarV has been recommended as a post-exposure prophylaxis (PEP) strategy for outbreak control, the effectiveness of this strategy remains unclear. We evaluated the vaccination effectiveness (VE) of 2nd-dose VarV as PEP among students involved in 129 varicella outbreaks in Shanghai, China from 2013 to 2016. METHODS: Students who had received one-dose VarV more than five years prior to varicella exposure were eligible to receive 2nd-dose VarV as PEP. We evaluated the VE using the following formula: VE = [1 - hazard ratio (HR)] * 100%. RESULTS: A total of 6,762 students were eligible for 2nd-dose VarV, of whom 58.6% accepted PEP after varicella exposure. The adjusted VE of 2nd-dose VarV as PEP was 77% (95% confidence interval: 64-85%). In addition, the adjusted VE of 2nd-dose VarV as PEP in affected classrooms with high vaccine uptake was higher than that in classrooms with lower vaccine uptake (87% vs. 69%). The adjusted VE was also higher in students who received 2nd-dose VarV within 3 days of exposure compared with those who received it more than 3 days post-exposure (77% vs. 64%). CONCLUSIONS: These results suggest that administration of 2nd-dose VarV as PEP is an appropriate intervention for outbreak control in countries where two-dose VarV has not been adopted. PMID- 30472426 TI - The quality of studies evaluating antimicrobial stewardship interventions: a systematic review. AB - BACKGROUND: Antimicrobial stewardship aims to optimise antibiotic use and minimise selection of antimicrobial resistance. The methodological quality of published studies in this field is unknown. OBJECTIVES: Our objective was to perform a comprehensive systematic review of antimicrobial stewardship research design and identify features which limit validity and translation of research findings into clinical practice. DATA SOURCES: The following online database was searched: PubMed. STUDY ELIGIBILITY CRITERIA: Studies published between January 1950 and January 2017, evaluating any antimicrobial stewardship intervention in the community or hospital setting, without restriction on study design or outcome. METHODS: We extracted data on pre-specified design quality features and factors that may influence design choices including: (1) clinical setting, (2) age group studied, (3) when the study was conducted, (4) geographical region and (5) financial support received. RESULTS: The initial search yielded 17,382 articles; 1,008 were selected for full-text screening, of which 825 were included. Most studies (675/825, 82%) were non-experimental and 104 (15%) used interrupted time series analysis, 41 (6%) used external controls and 19 (3%) used both. Studies in the community setting fulfilled a median of 5/10 quality features (IQR 3-7) and 3 (IQR 2-4) in the hospital setting. Community setting studies (25%, 205/825) were significantly more likely to use randomisation (OR 5.9 (95%CI 3.8-9.2)), external controls (OR 5.6 (95%CI 3.6-8.5)) and multiple centres (OR 10.5 (95%CI 7.1-15.7)). From all studies, only 48% (398/825) reported clinical and 23% (190/825) reported microbiological outcomes. Quality did not improve over time. CONCLUSIONS: Overall quality of antimicrobial stewardship studies is low and has not improved over time. Most studies do not report clinical and microbiological outcome data. Studies conducted in the community setting were associated with better quality. These limitations should inform the design of future stewardship evaluations so that a robust evidence base can be built to guide clinical practice. PMID- 30472427 TI - Hydroxymethylglutaryl-CoA reductase inhibitors (statins) for the treatment of sepsis in adults - a systematic review and meta-analysis. AB - BACKGROUND: The pleiotropic effect of Hydroxymethylglutaryl-CoA reductase inhibitors (statins) might have a beneficial effect in sepsis through several mechanisms. OBJECTIVES: To assess the efficacy and safety of statins, compared to placebo, for the treatment of sepsis in adults. DATA SOURCES: We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2017, Issue 12), OVID MEDLINE (from 1966 to January 2018), Embase (Ovid SP, from 1974 to January 2018) and LILACS (from 1986 to January 2018). We also searched the trial registries ISRCTN and ClinicalTrials.gov to January 2018. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials comparing the treatment of statins versus placebo in adult patients who were hospitalized due to sepsis. PARTICIPANTS: Adults (16 years and older) hospitalized due to sepsis or that developed sepsis during admission INTERVENTIONS: Treatment with hydroxymethylglutaryl-CoA reductase inhibitors (statins) versus no treatment or placebo. METHODS: We performed a systematic review of all randomized controlled trials published until January 2018, assessing the efficacy and safety of statins in sepsis treatment. Two primary outcomes were assessed: 30-day overall mortality and deterioration to severe sepsis during management. Secondary outcomes were hospital mortality, need for mechanical ventilation and drug related adverse events. RESULTS: Fourteen trials evaluating 2628 patients were included. Statins did not reduce 30-day all-cause mortality neither in all patients (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.83-1.10), nor in a subgroup of patients with severe sepsis (RR 0.97, 95% CI 0.84-1.12). The certainty of evidence for both outcomes was high. There was no change in the rate of adverse events between study arms (RR 1.24, 95% CI 0.94 to 1.63). The certainty of evidence for this outcome was high. CONCLUSIONS: The use of statin therapy in adults for the indication of sepsis is not recommended. PMID- 30472428 TI - Analysis of solvent-exposed and buried co-crystallized ligands: a case study to support the design of novel protein-protein interaction inhibitors. AB - Molecular descriptors have been used to characterize and predict the functions of small molecules, including inhibitors of protein-protein interactions (iPPIs). Such molecules are valuable to investigate disease pathways and as starting points for drug discovery endeavors. iPPIs tend to bind at the surface of macromolecules and the design of such compounds remains challenging. Here, we report on our investigation of a pool of interpretable molecular descriptors for solvent-exposed and buried co-crystallized ligands. Several descriptors were found to be significantly different between the two classes and were further exploited using machine-learning approaches. This work could open new perspectives for the rational design of focused libraries enriched in new types of small drug-like molecules that could be used to prevent PPIs. PMID- 30472429 TI - Artificial intelligence in drug development: present status and future prospects. AB - Artificial intelligence (AI) uses personified knowledge and learns from the solutions it produces to address not only specific but also complex problems. Remarkable improvements in computational power coupled with advancements in AI technology could be utilised to revolutionise the drug development process. At present, the pharmaceutical industry is facing challenges in sustaining their drug development programmes because of increased R&D costs and reduced efficiency. In this review, we discuss the major causes of attrition rates in new drug approvals, the possible ways that AI can improve the efficiency of the drug development process and collaboration of pharmaceutical industry giants with AI powered drug discovery firms. PMID- 30472430 TI - GLS1 Mutant Mice Display Moderate Alterations of Hippocampal Glutamatergic Neurotransmission Associated with Specific Adaptive Behavioral Changes. AB - Significant alterations in glutamatergic neurotransmission have been reported in major depressive disorder (MDD) that could underlie psychiatric traits. Studies were mainly interested in synaptic dysfunction in the prefrontal cortex, a key structure involved in depressive-like behavior, however hippocampus has been shown to be important in MDD. As cognitive deficits such as hippocampus-memory process were observed in MDD, we investigated in a mild hypoglutamatergic model behaviors related to depression and memory, synaptic transmission parameters and glutamatergic state specifically in the hippocampus. We thus characterized these phenotypes in adult male mice partially depleted in glutaminase type 1 or GLS1 (GLS1 HET), the enzyme responsible for glutamate synthesis in neurons, that we previously characterized as displaying moderate lower levels of glutamate in brain. We showed that GLS1 mutant mice display AMPA-R-mediated response deficits after prolonged repetitive stimulation with electrophysiological recording and inability to sustain glutamate release by microdialysis experiments with no consequences on behavioral spatial learning performances. However, their ability to escape from unpleasant but repeated escapable condition was attenuated whereas they were more immobile in the unescapable situation in the FST during re-test. These results show that GLS1 mutant mice display moderate impairments of hippocampal glutamatergic neurotransmission and moderate changes in adaptive behaviors that have been shown to participate to the development of depressive like state. PMID- 30472431 TI - Bilateral Prefrontal Cortex Anodal tDCS Effects on Self-reported Aggressiveness in Imprisoned Violent Offenders. AB - Reduced activity of the frontal lobes, and particularly of the prefrontal cortex, has been related with violent behavior, aggression and crime. The causal importance of prefrontal cortex activity for aggressive behaviors and the self perception of aggressiveness needs however to be clarified. The aim of this study was to explore the effect of an anodal transcranial direct current stimulation protocol (tDCS, 1.5 mA, 15 min), which, according to previous studies, enhances cortical excitability, applied bilaterally over the prefrontal cortex on self reported aggressiveness. Two imprisoned violent offender cohorts, discerned by the degree of aggressiveness (murderers vs. non-murderers), were included in this single-blind sham-controlled study. Self-reported aggressiveness was recorded before and after 3 tDCS sessions (one session per day). Four dimensions of aggression were evaluated by means of the standardized Buss-Perry Aggression Questionnaire (BAQ). In both inmate groups the results revealed an aggression reducing effect of tDCS on the Physical aggression, Anger, and Verbal aggression dimensions of the BAQ. In the Hostility dimension, tDCS significantly reduced aggression only in the group of murderers. These results suggest that modulation of prefrontal cortex excitability by 3 consecutive sessions of tDCS reduces self reported aggressiveness similarly in murderer and non-murderer samples. PMID- 30472432 TI - 8-Cetylcoptisine, a new coptisine derivative, induces mitochondria-dependent apoptosis and G0/G1 cell cycle arrest in human A549 cells. AB - Lung cancer is the worldwide leading cause of cancer-related death. Here, we described the synthesis and the anticancer activity of a novel coptisine derivative 8-cetylcoptisine (CCOP) on lung carcinoma in vitro and in vivo. CCOP inhibited the cell viability of A549, BGC-823, MDA-MB-231, HCT-116 and HepG2 cell lines. In A549 cells, CCOP induced apoptosis, G0/G1 cell cycle arrest and decreased mitochondrial membrane potential (MMP) in a dose-dependent manner. Western blot analysis showed that CCOP increased the expression of Bcl-2 associated X protein (Bax), cleaved caspase 3 and 9, while decreased B-cell lymphoma 2 (Bcl-2), cyclins D and E, cyclin dependent kinases (CDKs) 2, 4 and 6, along with the inactivation of the upstream phosphoinositide 3-kinase (Pi3k)/protein kinase B (Akt) signaling. Further in vivo studies showed that CCOP (10 mg/kg) significantly delayed tumor growth in A549 xenograft nude mice, which is stronger than that of coptisine (100 mg/kg). These data suggested that CCOP could be a candidate for lung cancer therapy. PMID- 30472434 TI - ERRATUM: Haploidentical Related Donor Hematopoietic Stem Cell Transplantation for DOCK8 Deficiency Using Post-Transplantation Cyclophosphamide. PMID- 30472435 TI - The Optimal Killer Cell Immunoglobulin-Like Receptor Donor-We Can Recognize, but Can We Search? PMID- 30472433 TI - Prevalence of Sexually Transmitted Infections (HIV, HBV, HSV-2 and Syphilis) in pregnant women in Ethiopia: Trends over 10 Years (2005-2014). AB - OBJECTIVES: We determined the trend in sero-prevalence of the major STIs (HIV, HBV, HSV-2 and Syphilis) over ten years (2005-2014) in pregnant women in Ethiopia. METHODS: Pregnant women (15-49 years old) who were enrolled in the ANC based national HIV surveillance were included. Serological tests for HIV, HBV, HSV-2 and Syphilis were done on/plasma samples. RESULTS: A total of 4887 pregnant women were included. Results showed a decline in prevalence of these STIs by 40 60% in ten years (2005-2014): HIV (10.5% to 5.5%); Syphilis (2.5% to 1.1%); HBV (12.6% to 6.7%); and HSV-2 (47.5% to 28.5%). In 2014, 109/4887 (2.2%) women had triple infections. The prevalence of HSV-2 in 2005, 2007, and 2009 in the older age group (35-45 years) (47.1%, 47.4%, and 50.0%, respectively) was higher than in the younger (15-24 years) (40.9%. 19.5%, 20.2%, respectively). Age category (X2=22.4, p<0.001), study sites/residence (X2=135.2, p=0.001) and time/years (X2=58.9, p=0.001) were associated with positive HSV-2 test result. CONCLUSIONS: We showed a decline in HIV, HBV, HSV-2 and Syphilis by >40% over years in Ethiopia. However, intermediate endemicity level of HBV and higher prevalence of HIV and HSV-2 by 2014, suggests the need to strengthen prevention strategy for STIs. PMID- 30472436 TI - The prognosis of disseminated intravascular coagulation associated with hematologic malignancy and its response to recombinant human thrombomodulin. AB - INTRODUCTION: Disseminated intravascular coagulation (DIC) is a lethal complication in patients with hematologic malignancies (HMs). DIC can be induced by the HM itself, but also by HM-associated secondary infection; however, whether difference of triggering factor impacts the outcome of DIC in HM patients remains unknown. The objective of this study is to clarify the difference between HM induced DIC and infection-induced DIC in HM patients regarding treatment response and prognosis. METHODS: HM-induced DIC (158 episodes) and infection-induced DIC in HM patients (83 episodes) from a single center were retrospectively analyzed. Recombinant human thrombomodulin (rhTM) was administered in 149 episodes, while the remaining received conventional therapies. RESULTS: In HM-induced DIC, improvement by day 7 was 46% (95% confidence interval [CI], 38-54), and rhTM enhanced the improvement (hazard ratio [HR], 1.7; 95% CI, 1.1-2.4). In contrast, improvement of infection-induced DIC was significantly worse (29%; 95% CI, 20-39 on day 7), and this was not influenced by rhTM (HR, 1.0; 95% CI, 0.50-2.2). Thirty-day survival in HM-induced DIC and infection-induced DIC was 87% (95% CI, 81-92) and 53% (95% CI, 42-63), respectively, and was not affected by treatment. A DIC score (Japanese Ministry of Health and Welfare criteria) of >=5 was a predictor of worse survival in both types of DIC (HR, 2.5; 95% CI, 1.5-3.9). CONCLUSIONS: This study showed the inadequacy of current therapeutic strategies for secondary infection-induced DIC, the prognosis of which was significantly worse than HM-induced DIC, and the limited efficacy of rhTM only in the improvement of HM-induced DIC. PMID- 30472437 TI - ILC2s - resident lymphocytes pre-adapted to a specific tissue or migratory effectors that adapt to where they move? AB - A cardinal feature of the T-cell adaptive immune system is the antigen-dependent activation of naive T cells in secondary lymphoid sites, followed by the migration of the resultant effector cells through the efferent lymph to the blood and then into a peripheral tissue site of infection or tumor growth. In contrast, the current view of innate lymphocytes (ILCs), the innate counterparts of T cells, is that they are tissue-resident cells, adapted to their specific environments during development and performing their effector functions locally upon cytokine stimulation. Here we present recent findings that challenge the latter as defining the properties of ILCs, at least ILC2s. Our studies show that IL-25, administrated experimentally or generated in response to helminth infection, triggers local proliferation and activation of intestinal ILC2s that are the precursors to inflammatory ILC2 (iILC2) cells. These cells downregulate CD69 expression, upregulate S1P receptors and move across the villus lymphatic endothelium in an S1P-depndent manner. They subsequently enter the blood stream, through which they traffic to distant organs such as the liver and lung. In the lung, these iILC2 cells play a crucial role in host defense during the pulmonary stage of helminth infection. In the later stage of infection, a fraction of the iILC2 cells phenotypically convert into lung-resident natural ILC2 (nILC2)-like cells while another fraction homes back to their original location in the small intestine. These data support the view that ILC2s possess properties considered characteristic of adaptive T lymphocytes, namely local activation and distant effector function, but in response to alarm cytokines instead of specific antigen. These findings also raise questions about whether other ILC subsets show similar trafficking potential when suitably challenged, the extent to which such cells show plasticity in adapting to new tissue environments beyond the course of early development, and the relative roles of organ-resident versus migratory ILCs in host defense. PMID- 30472438 TI - Soluble epoxide hydrolase inhibitor, APAU, protects dopaminergic neurons against rotenone induced neurotoxicity: Implications for Parkinson's disease. AB - Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid, play a crucial role in cytoprotection by attenuating oxidative stress, inflammation and apoptosis. EETs are rapidly metabolised in vivo by the soluble epoxide hydrolase (sEH). Increasing the half life of EETs by inhibiting the sEH enzyme is a novel strategy for neuroprotection. In the present study, sEH inhibitors APAU was screened in silico and further evaluated for their antiparkinson activity against rotenone (ROT) induced neurodegeneration in N27 dopaminergic cell line and Drosophila melanogaster model of Parkinson disease (PD). In the in vitro study cell viability (MTT and LDH release assay), oxidative stress parameters (total intracellular ROS, hydroperoxides, protein oxidation, lipid peroxidation, superoxide dismutase, catalase, glutathione peroxidise, glutathione reductase, glutathione, total antioxidant status, mitochondrial complex-1activity and mitochondrial membrane potential), inflammatory markers (IL-6, COX-1 and COX-2), and apoptotic markers (JNK, phospho-JNK, c-jun, phospho-c-jun, pro and active caspase-3) were assessed to study the neuroprotective effects. In vivo activity of APAU was assessed in Drosophila melanogaster by measuring survival rate, negative geotaxis, oxidative stress parameters (total intracellular ROS, hydroperoxides, glutathione levels) were measured. Dopamine and its metabolites were estimated by LC-MS/MS analysis. In the in silico study the molecule, APAU showed good binding interaction at the active site of sEH (PDB: 1VJ5). In the in vitro study, APAU significantly attenuated ROT induced changes in oxidative, pro inflammatory and apoptotic parameters. In the in vivo study, APAU significantly attenuates ROT induced changes in survival rate, negative geotaxis, oxidative stress, dopamine and its metabolites levels (p < 0.05). Our study, therefore, concludes that the molecule APAU, has significant neuroprotection benefits against rotenone induced Parkinsonism. PMID- 30472439 TI - Accuracy of self-reported injuries compared to medical record data. AB - BACKGROUND: Self-reported injury data are frequently used in epidemiologic investigations. These data provide useful information about the activities and mechanisms of injuries because injury cause-coding is often not required for outpatient medical visits. OBJECTIVES: The purpose of this evaluation is to determine the accuracy of self-reported military injuries when compared to injuries in outpatient medical records. METHOD: Injuries reported by survey were compared to diagnoses for injuries (International Classification of Diseases (ICD 9-CM 800-999)) and injury-related musculoskeletal disorders (selected ICD-9-CM 710-739) obtained from medical records. Self-reported injury responses from military personnel were matched to diagnoses by date and body part. A new methodology for including secondary matching body parts was proposed and implemented. RESULTS: Infantry Soldiers (n = 5490) completed surveys that requested details about their most recent injury. About one-quarter (24%, n = 1336) reported injuries on the survey and had an injury diagnosis in their medical record in a six month period. Seventy-five percent of the self-reported injuries (n = 996 of 1336) were confirmed by medical records with a date match within 3 months and an identical or nearby body part. Common self-reported injuries were ankle sprains (10%), knee sprains (9%), lower back strains (4%), shoulder strains (3%), and lower back pain (3%). CONCLUSIONS: A high percentage of self-reported injuries were accurate when compared with medical records, substantiating the use of survey data for the evaluation of injury outcomes. This is the first effort to validate self-reported injuries and musculoskeletal disorders with medical records in a large military population. PMID- 30472440 TI - Advances in online methods for monitoring microbial growth. AB - Understanding the characteristics of microbial growth is of great significance to many fields including in scientific research, the food industry, health care, and agriculture. Many methods have been established to characterize the process of microbial growth. Online and automated methods, in which sample transfer is avoided, are popular because they can facilitate the development of simple, safe, and effective growth monitoring. This review focuses on advances in online monitoring methods over the last decade (2008-2018). We specifically focus on optic- and electrochemistry-based techniques, either through contact measurements or contactless measurement. Strengths and weaknesses of each set of methods are described and we also speculate on forthcoming trends in the field. PMID- 30472442 TI - Ultrasensitive label- and amplification-free photoelectric protocols based on sandwiched layer-by-layer plasmonic nanocomposite films for the detection of alpha-fetoprotein. AB - A label- and amplification-free photoelectric immunosensor based on well-defined layer-by-layer sandwich-structured AuNP/TNW/AuNP composite is proposed for direct and ultrasensitive detection of alpha-fetoprotein (AFP). The AuNP/TNW/AuNP composite is produced by assembling an Au nanoparticle underlayer and anatase TiO2 nanowires (TNW) onto the FTO substrate, followed by decorating Au nanoparticles onto the TNW surface, through a simple sputtering and hydrothermal process. The resulting AuNP/TNW/AuNP electrode exhibits a 14-fold and 2-fold enhancement in photocurrent density under simulated sunlight compared with that of bare TNW and AuNP/TNW, respectively, which benefits from the SPR-induced photoabsorption increment and charge separation improvement in Au nanoparticle and interfacial charge transfer promotion at the TiO2/substrate interface in the Au underlayer. As a proof of concept, the AFP antigen can be quantitatively detected by the proposed AuNP/TNW/AuNP coupled with anti-AFP through the analysis of the photocurrent change. This novel AFP photoelectric immunosensor exhibited sensitive detection of AFP with an ultrahigh sensitivity of 0.001 ng mL-1 and good specific selectivity. Moreover, the practical determination of AFP in human serum is also investigated, demonstrating its applicability and potential attraction for clinical tests and disease diagnosis. PMID- 30472441 TI - Dual mode competitive electrochemical immunoassay for B-type natriuretic peptide based on GS/SnO2/polyaniline-Au and ZnCo2O4/N-CNTs. AB - A sensitive dual mode competitive electrochemical immunosensor for the detection of B-type natriuretic peptide (BNP) was successfully fabricated, which based on differential pulse voltammetry (DPV) and amperometric i-t curve response modes. Polyaniline (PAN) and tin dioxide (SnO2) were loaded on graphene sheets (GS), which could effectively promote the electron transfer process, thereby amplifying the current signal and increasing the sensitivity of the immunosensor. To promote biocompatibility, gold nanoparticles (Au) were incorporated on GS/SnO2/PAN (GS/SnO2/PAN-Au). GS/SnO2/PAN-Au complex was gotten to act as the platform which could provide a clearly DPV signals. N-doped carbon nanotubes (N-CNTs) embellished by ZnCo2O4 quantum dots (ZnCo2O4/N-CNTs) with excellent catalytic properties for the reduction of H2O2 was gotten to act as the label of the antibody-BNP (Ab), providing an obviously current signal through amperometric i-t curve method. A large quantity of BNP could be stable loaded in the modified electrode via GS/SnO2/PAN-Au with excellent electrical conductivity and good biocompatibility, which could compete with target-BNP to combine Ab that labelled by ZnCo2O4/N-CNTs. Under the optimum conditions, the immunosensor exhibited remarkable analytical performance of a linear range from 0.01 pg/mL to 1 ng/mL with a detection limit of 3.4 fg/mL for quantitative detection of BNP (S/N = 3). This method was able to become a universal strategy for other biological detection. PMID- 30472443 TI - MoS2/nitrogen doped graphene hydrogels p-n heterojunction: Efficient charge transfer property for highly sensitive and selective photoelectrochemical analysis of chloramphenicol. AB - Constructing junctions between semiconductors is an effective way to promote charge separation and thus to improve the photoelectrochemical (PEC) performances, and specifically, p-n heterojunction is considered as a very promising structure. Herein, we designed and fabricated MoS2/nitrogen doped graphene hydrogels (MoS2/NGH) p-n heterojunction by a facile one-pot hydrothermal route. The as-fabricaterd MoS2/NGH heterostructures demonstrated the excellent PEC activity, exhibiting enhanced photocurrent intensity by the fast transfer and separation rate of photogenerated electron-hole owing to the construction of p-n heterojunction. Based on the high PEC performances of the MoS2/NGH heterostructure, a novel sensitive PEC sensor was developed for the determination of chloramphenicol (CAP) with the assistance of aptamer. In the presence of target molecules, the as-fabricated PEC sensor could recognize the CAP quickly and then consume the holes in the interface of heterostructures, inhibiting the recombination of photogenerated electron-hole pairs, resulting the enhanced photocurrent. Specially, with the concentration of CAP increased, the photocurrent enhanced gradually. Excellent linearity was obtained in the concentration range from 32.3 ng/L to 96.9 MUg/L, and the limit of detection was 3.23 ng/L. Moreover, the as-fabricated PEC sensor exhibited rapid response, high stability, low-cost and high selectivity, which could be successfully applied to the analysis of CAP in honeycomb samples. PMID- 30472444 TI - Photothermal effects induced by surface plasmon resonance at graphene/gold nanointerfaces: A multiscale modeling study. AB - Surface plasmon resonance (SPR) biosensors have enormous potential in biological recognitions and biomolecular interactions, especially for the real time measurement of disease diagnosis and drug screening. Extensive efforts have been invested to ameliorate the sensing performances, while the photothermal effects, which are induced by the plasmon resonance, have an obvious impact. However, due to the limitations of experimental approaches, the theoretical mechanisms and specific influences of the SPR sensors with photothermal effects are few researched. Here, a multiscale simulation method is developed to investigate the photothermal effects at graphene/gold (Au) nanointerfaces, and to calculate the quantitative contribution of the photothermal effects towards high reliability SPR sensors in order to elucidate their influence on the sensing performances by means of first-principle calculations and molecular dynamics simulations. Our results indicate that the sensitivity and detection accuracy of graphene/Au SPR sensors can be tailored from 0 K to 600 K, due to the tunable dielectric constants of Au and graphene films through temperature variation. By controlling the its material thickness, interfacial combination and lattice strain, an optimized graphene/Au SPR sensor with higher sensitivity, detection accuracy, and reliability to the temperature rising has been achieved. Such multiscale simulation method, which is capable of seeking both the role and the underlying mechanism of the interfacial phenomena, can serve as an excellent guideline for the performance optimization and commercialized application of SPR sensors in the analytical chemistry and biomedical fields. PMID- 30472445 TI - Smartphone based dual mode in situ detection of viability of bacteria using Ag nanorods array. AB - The in-situ and rapid detection of live and dead bacteria is essential for human and environmental care. It has become one of the biggest needs in the biological and medical sciences to prevent infectious diseases, which usually occur in hospitals and field clinics. In the current scenario, antibiotic resistance is one of the severe public health problems, which requires a quick and efficient solution. Here, we report a facile sensitive, portable, user-friendly, cost effective and time saving approach for detection of live, dead and drug-resistant bacteria. The endogenous H2S evolution was targeted to differentiate between live and dead as well as antibiotic resistant bacteria. The silver nanorods (AgNRs) arrays sensors were fabricated by glancing angle deposition technique. The colorimetric and water wettability features of as-synthesized AgNRs are found to be highly sensitive and selective for H2S. E. coli. P. aeruginosa, B. subtilis and S. aureus were used as a model organism in this study. All the bacteria were found to produce H2S by their metabolism process. In order to detect the antibiotic resistant E. coli were grown in the presence of different concentration of ampicillin in Luria broth. A drastic visible change in color as well as wetting of AgNRs array was observed. To make the technique easy, a user friendly and field deployable mobile app 'Colorimetric Detector' was developed. This technique takes only 4-6 h whereas the conventional methods need around 24 h for the same. This dual mode facile and, inexpensive method can be easily scaled up in the field of diagnostics. PMID- 30472446 TI - The terahertz electromagnetically induced transparency-like metamaterials for sensitive biosensors in the detection of cancer cells. AB - A kind of novel biosensor based on the electromagnetic induced transparency like (EIT-like) metamaterials (MMs) have been proposed. It demonstrates that the symmetry-breaking double-splits ring resonators can realize the EIT-like plasmonic resonance, the according transparency window occurs at 1.67 THz. The coupled oscillators model illustrates that with the increase of asymmetry degree of double splits, the coupling between bright and dark mode is enhanced. Consequently, the non-radiative damping gamma2 grows from 1.45 to 1.85 THz and coupling coefficient kappa from 3.46 to 4.49 THz2, while the radiative damping gamma1 decreases from 11.5 to 9 THz. Such EIT-like MMs were evaluated in simulation as the refractive index sensors, which the theoretical sensitivity was calculated to 455.7 GHz/RIU (RIU, Refractive Index Unit) under 11 MUm-thick analyte layer. Meanwhile, the dependence of full width at half maximum (FWHM) on analyte thickness was also studied. In experiments, it is found that the frequency shift Deltaf increases from 50 to 90 GHz when the oral cancer cells (HSC3) concentration improves from 1 * 105 to 7 * 105 cells/ml. The maximum experimental sensitivity approaches 900 kHz/cell ml-1 at 7 * 105 cells/ml. Additionally, the apoptosis of cancer cells under the effect of anti-cancer drug was investigated. It shows that with the increase of anti-cancer drug concentration from 1 to 15 MUM and the extension of drug action duration from 24 to 72 h, the Deltaf changes from 140 to 70 GHz and 140-40 GHz, respectively. Besides, the corresponding FWHM also increases from 237.9 to 305.4 GHz and 237.8 337.6 GHz. The results measured by MMs biosensors and biological method exhibit a relatively good agreement, showing a great potential for cells measurement with the sensitive biosensors based on the EIT-like MMs. PMID- 30472447 TI - Removal of persistent DDT residues from soils by earthworms: A mechanistic study. AB - Earthworms have been reported to enhance DDT (1,1,1-trichloro-2,2-bis(4 chlorophenyl)ethane) removal from soils, but the mechanism underlying is still poorly understood. This study therefore worked on the links between DDT transformation in drilosphere and non-drilosphere matrices and the properties of these matrices in sterile and non-sterile soil columns with and without earthworms to reveal related mechanisms. The results show that earthworms shortened the half-time of DDT in soils from over 14 weeks to about 8 weeks; DDT residues were lower (p < 0.05) and its transformation products were higher (p < 0.05) in drilosphere matrixes than those in their non-drilosphere counterparts; DDD and DDMU was higher (p < 0.05) in the gut, and DDE was higher (p < 0.05) in the burrow; and the bioaccumulation of DDT in earthworm tissues only contributed less than 0.03% to the DDT removal enhanced by earthworms. The results further demonstrate that drilosphere is the hotspot of soil DDT transformation with oxidative degradation dominant in the burrow and reductive dechlorination in the gut, and earthworms enhanced DDT removal mainly by digesting and promoting the microbial degradation of DDT by indigenous microorganisms via improving soil properties. Knowledge of the mechanisms of DDT transformation by earthworms will support the use of earthworms in remediating DDT-contaminated soils. PMID- 30472448 TI - Impact of the implementation of Lisbon low emission zone on air quality. AB - Air pollution is an increasing concern due to the negative impacts on human health, environment, and patrimony. The implementation of a Low Emission Zone (LEZ) is an important air quality policy action to reduce air pollutant emissions. This study aims to assess the air quality improvements in Lisbon with the LEZ implementation, analysing its impact on the air pollutant concentrations. The analysis performed from 2009 to 2016 showed an improvement in air quality. In the Zone 1, the reduction of PM10 and NO2 annual average concentrations were 29% and 12%, respectively, while, in the Zone 2, the reduction of PM10 and NO2 annual average concentrations were 23% and 22%, respectively. The background pollution analysis showed the LEZ effect on the lowest levels of ambient air pollution to which the population is chronically exposed. The achieved reductions of PM10 and NO2 levels were 30.5% and 9.4% in Zone 1, and 22.5% and 12.9% in the Zone 2, respectively. Concluding, this study evidenced an air quality improvement mainly for PM10 and NO2; however, insignificant reductions were observed for NOx and PM2.5. Therefore, stricter restriction standards should be defined, combining with other air quality policy decisions to reduce the population exposure to air pollutants. PMID- 30472449 TI - Performance and microbial community evolution of toluene degradation using a fungi-based bio-trickling filter. AB - Fungi have their unique advantages in capturing and degrading hydrophobic VOCs. To study the performance of fungi-based bio-trickling filters (BTFs) with respect to the degradation of toluene, and the succession process of the fungal colony under different operating conditions, a three-layer BTF packed by dominant Fusarium oxysporum immobilized with ceramic particles were set up. The fungal BTF started quickly within 7 days and restarted less than 7 days after starvation; its average RE was higher than 92.5% when the toluene inlet loading rate (ILR) ranging from 7.0 to 100.9 g m-3 h-1 at steady state. Moreover, the maximum elimination capacity (EC) of 98.1 g m-3 h-1 was obtained at a toluene ILR of 100.3 g m-3 h-1. The microorganism analysis of time and space revealed that the dominant fungi Fusarium were replaced by Paramicrosporidium saccamoebae after a certain evolutionary period. The intermediate layer had more microbes and a more complex community than the other two layers, and was more suitable for the survival of the varieties of microbes. PMID- 30472450 TI - A novel electro-coagulation-Fenton for energy efficient cyanobacteria and cyanotoxins removal without chemical addition. AB - Harmful cyanobacterial bloom is a serious threat to global aquatic ecology and drinking water safety. Electro-Fenton (EF) has emerged as an efficient process for cyanobacteria and cyanotoxins removal, but high consumption of energy and chemicals remain a major bottleneck. This study presents a novel convertible three-electrodes Electro-Coagulation-Fenton process for cyanobacteria and cyanotoxins removal with low energy consumption and no chemicals addition. We for the first time demonstrated the freely alternating between Electrocoagulation (EC) and EF by switching electrodes. The optimal aerated EC was operated at pH 8 and 100 mA to remove 91 +/- 2% of cyanobaterial cells and 15% of Microcystins (MCs). Coagulants generated in EC were adsorbed on cyanobacterial cells to form a protect layer against algae disruption and cyanotoxins releasing. Residual MCs and cyanobaterial cells were completely mineralized by EF at 28 mA with iron ions and H2O2 generated in-situ. Compare to traditional EF, the optimal Electro Coagulation-Fenton process increased total organic carbon (TOC) removal efficiency by 30%, yet energy consumption reduced up to 92%. The novel Electro Coagulation-Fenton process is a promising technology for the efficient treatment of the mixture of suspended solid pollutants and persistent organic pollutants in one system with low energy consumption. PMID- 30472451 TI - A novel process of extracting precious metals from waste printed circuit boards: Utilization of gold concentrate as a fluxing material. AB - Waste printed circuit boards (PCBs) are highly toxic materials because of the hazardous substances that are incorporated into them. An advanced recycling technology based on pyrometallurgical treatment using Au concentrate as a flux material was developed in this study. The benefits of employing roasted gold concentrate (RGC) in the smelting process of waste PCBs were demonstrated through high-temperature experiments. The major oxide compositions of PCBs (CaO, Al2O3, and SiO2) were fluxed using oxidized Au concentrate composed of FetO and SiO2. Quaternary slag systems (CaO-FetO-Al2O3-SiO2) were formed during the smelting process, which rendered the process of separation of oxide impurities from Cu based alloys easier. Precious metals (Au and Ag) were effectively recovered from waste PCBs and Au concentrate in the form of a metal alloy that required further treatment by leaching and extraction. Residual S in the RGC significantly changed the alloy phases. A large quantity of S was formulated into a matte phase, while a small amount of S was dissolved into a Cu-Fe metal alloy. The subsequent hydrometallurgical process was optional. Electrorefining or pressure leaching could be applied depending on the type of Cu alloy. PMID- 30472452 TI - Assembling biochar with various layered double hydroxides for enhancement of phosphorus recovery. AB - Highly efficient and cost-effective adsorbents for phosphate (P) recovery are the key to control eutrophication and recover phosphorus from waste streams to enhance food production. This study assembled corn stalk-derived biochar (BC) with various forms of layered double hydroxides (LDHs) (B-M-LDH) through simultaneous pyrolysis of waste biomass and metal (i.e., Zn/Al, Mg/Al, and Ni/Fe) hydroxide precipitates. Batch sorption experiments evaluated the kinetics and isotherms of phosphate adsorption as well as the influence of pH value and co existing anions. Morphological characterization showed that crystalline LDH flakes were impregnated within the framework of fabricated B-M-LDH composites. Superior P adsorption capacity (152.1 mg (P) g-1) and fast Elovich kinetics (5925 mg g-1 h-1) could be achieved by the B-Zn/Al-LDH composite at pH 5. The P adsorption onto BC-LDHs was pH dependent and subjected to adverse influence of co existing anions. Interlayer anion exchange and surface complexation were probably the predominant adsorption mechanisms at the studied phosphate concentration. Therefore, BC can be functionalized as mineral composites for enhancing P recovery and wastewater treatment. PMID- 30472453 TI - Enhanced visible light photoreduction of aqueous Cr(VI) by Ag/Bi4O7/g-C3N4 nanosheets ternary metal/non-metal Z-scheme heterojunction. AB - In this paper, we successfully constructed a ternary metal/non-metal nanomaterial which can synergize Z-scheme heterojunction and plasmonic metal/semiconductor for enhancing visible light photoreduction of aqueous Cr(VI). The as-formed ternary metal/non-metal nanomaterial was composed of g-C3N4 nanosheets mutual modified by Ag nanoparticles and Bi4O7. In the ternary nanomaterial, g-C3N4 nanosheets and Bi4O7 fabricated Z-scheme heterojunction, g-C3N4 nanosheets and Ag nanoparticles formed plasmonic metal/semiconductor system, synchronously. The photodeposition experiments were designed to indirect demonstrate the Z-scheme heterojunction via photocatalytic oxidation and reduction deposition reactions, AgNO3 was used as the electron acceptor and Pb(NO3)2 as the electron donor, photocatalytic reduction product and oxidation product were selectively deposited on g-C3N4 nanosheets and Bi4O7, respectively, revealing the Z-scheme heterojunction was definite formed. In addition, X-ray photoelectron spectroscopy (XPS), photoluminescence (PL), UV-vis absorption, and Fourier-transform infrared spectroscopy (FTIR) were studied to indicate that the plasmonic metal/semiconductor system was existent in the ternary nanomaterial. The visible light photoreduction of ternary Ag/Bi4O7/g-C3N4 nanosheets was evaluated by photoreducing aqueous Cr(VI). The photoreduction results show that the ternary Ag/Bi4O7/g-C3N4 nanosheets is much higher than the pristine bulk g-C3N4 and g C3N4 nanosheets. PMID- 30472454 TI - Effect of gasification biochar application on soil quality: Trace metal behavior, microbial community, and soil dissolved organic matter. AB - Compared to pyrolysis biochar (PBC), gasification biochar (GBC) differs in both composition and surface functionalities due to the use of an oxidizing purging gas. This work compares the effect of using PBC and GBC as soil amendments on the soil properties, trace metal bioavailability, soil microbial activity, and soil dissolved organic matter (DOM). Biochar-driven reduction of bioavailable metals does not necessarily result in a positive impact on the soil microbial growth. The DOM in the soil was strongly related to the soil microbial activity, as revealed by the strong correlation between the soil dehydrogenase activity (DHA) and soil dissolved organic carbon (r = 0.957, p < 0.01). Three identified fluorescent components (C1, C2, C3) in the soil DOM were closely associated with the soil microbial activity, for instance, with a clear positive correlation between the soil DHA and C1 (r = 0.718, p < 0.05) and a significant negative correlation between the total bacterial fatty acid methyl ester content and C3 (r = -0.768, p < 0.05). The bioavailability of Cd and Zn is not only related to the pH and surface functionalities of the biochar, but also to its aromatic carbon and inorganic mineral composition. This study further demonstrates that a fluorescence excitation-emission matrix coupled with parallel factor analysis is a useful tool to monitor changes in the soil quality after application of biochar, which is greatly relevant to the soil biota. PMID- 30472455 TI - Novel synergy of Si-rich minerals and reactive MgO for stabilisation/solidification of contaminated sediment. AB - Disposal of significant amounts of dredged contaminated sediment poses an economic and environmental problem worldwide. Transforming contaminated sediment into value-added construction materials using low-carbon MgO cement is a sustainable option; however, the weak mechanical strength and unreliable water solubility of MgO cement restrict its practical engineering applications. This study elucidates the potential role of industrial Si-rich minerals in the performance enhancement of MgO-based products via the promotion of magnesium silicate hydrate (M-S-H) gel formation. Quantitative X-ray diffraction and 29Si nuclear magnetic resonance analyses indicated that compositions and crystallinities of the Si-rich minerals significantly influence the formation and polymerisation of the M-S-H gel. Pulverised fly ash was found to be a promising Si-rich mineral for generating polymeric M-S-H gel, whereas incinerated sewage sludge ash samples demonstrated a low degree of polymerisation, and the use of glass powder samples gave a low yield of M-S-H. The formation of M-S-H gel enhanced the compressive strength and water resistance (strength retention after water immersion). Further experiments demonstrated that Si-modified MgO cement can transform dredged sediment into fill materials with satisfactory mechanical properties and contaminant immobilisation. Therefore, the synergy between reactive MgO and Si-rich industrial waste is a novel option for sustainable remediation and environmental applications. PMID- 30472456 TI - A novel integrated biodegradation-microfiltration system for sustainable wastewater treatment and energy recovery. AB - This work assessed the treatment of wastewater generated from three different industries viz., paper and pulp, biomass gasification and dairy by biodegradation followed by membrane filtration. Batch biodegradation was first carried out using wastewater as the potential substrate for oleaginous Rhodococcus opacus with lipid accumulation intracellular; subsequently, a microfiltration system was applied to recover the bacterial biomass grown as well as for residual chemical oxygen demand (COD) removal from the effluent. The combined process showed excellent results in terms of COD removal from the industrial wastewaters, with the values 56.8%, 46.1% and 68.9% for dairy, paper and pulp and biomass gasification wastewaters, respectively, by biodegradation. These values were further improved to 92.7%, 87.6% and 88.2%, respectively, following the microfiltration step performed by employing a low-cost ceramic membrane. In addition, lipids accumulated by the bacterium were extracted and characterized for biodiesel production potential. Lipid characterization using 1H NMR confirmed the presence of saturated fatty acids. Gas chromatography analysis of the transesterified lipids revealed the presence of methyl palmitate and methyl stearate. In addition, the estimated properties of the transesterified product affirmed its potential for biofuel application. PMID- 30472457 TI - The occurrence of microplastic in specific organs in commercially caught fishes from coast and estuary area of east China. AB - It is important to understand where microplastics go in the body of organisms. They can readily affect target organs and transport microplastic-associated chemicals to humans via consumption. The plastics (>20 MUm) in guts and gills of 13 species of fishes from coast estuary areas of China were examined for the presence of microplastics. Muscle and liver were analyzed from a commercial species, the Asian seabass (Lateolabrax maculatus), of which 73% of the suspected items were verified by micro-Fourier Transform Infrared Spectroscopy. We targeted the organ specific distribution of microplastics. Microplastics were detected in gut and gills in 22%-100% and 22%-89% of total individuals, respectively. Microplastics in gut varied from 0.3 to 5.3 items/ind. and varied from 0.3 to 2.6 items/ind in gill, respectively. The size of microplastics in gills were smaller than those found in the guts. No microplastics were detected in the liver or muscle tissue of L. maculatus, and several non-plastic items detected in muscles can be attributed to background contamination. Further research is required using a larger number of specimens and better quality control and quality assurance are required to assess the presence of small microplastics or nanoplastics in fishes internal organs and muscle. PMID- 30472458 TI - Polymer films containing chemically anchored diazonium salts with long-term stability as colorimetric sensors. AB - We have prepared polymeric films as easy-to-handle sensory materials for the colorimetric detection and quantification of phenol derivatives (phenols) in water. Phenols in water resources result from their presence in pesticides and fungicides, among other goods, and are harmful ecotoxins. Colorless polymeric films with pendant diazonium groups attached to the acrylic polymer structure were designed and prepared for use as sensory matrices to detect phenol-derived species in water. Upon dipping the sensory films into aqueous media, the material swells, and if phenols are present, they react with the diazonium groups of the polymer to render a highly colored azo group, giving rise to the recognition phenomenon. The color development can be visually followed for a qualitative determination of phenols. Additionally, quantitative analysis can be performed by two different techniques: a) by using a UV-vis spectrophotometer (limit of detection of 0.12 ppm for 2-phenylphenol) and/or b) by using a smartphone with subsequent RGB analysis (limit of detection of 30 ppb for 2-phenylphenol). PMID- 30472459 TI - Magnetically separable BiOBr/Fe3O4@SiO2 for visible-light-driven photocatalytic degradation of ibuprofen: Mechanistic investigation and prototype development. AB - The increasingly ubiquitous release of emerging refractory pollutants into water is a serious concern due to associated risks. In this study, mesoporous hierarchical BiOBr/Fe3O4@SiO2-a solvothermally synthesized visible-light-driven magnetic photocatalyst-not only exhibited fast kinetics (t1/2 = 8.7 min) in the photocatalytic degradation of ibuprofen in water but also achieved almost complete mineralization over a prolonged irradiation of 6 h. Various reactive species, including O2-, OH, and H2O2, were detected, while the scavenging experiments revealed that eCB--mediated reactions and direct-hole oxidation are the major degradation routes. The magnetically recycled BiOBr/Fe3O4@SiO2 maintained ~80% of its initial photocatalytic activity even after five consecutive cycles. The typically copresent wastewater constituents, including NOM and anions, inhibited the photocatalytic performance to varying extents, and hence necessitated an increase in the photocatalyst dosage to achieve complete ibuprofen degradation in real sewage. Based on the findings of batch experiments, the process was scaled up by developing a 5 L prototype photocatalytic reactor integrated with an electromagnetic separation unit. The results of prototype photocatalytic experiments were comparable to those of batch experiments, and an electromagnetic separation efficiency of ~99% was achievable in 5 min. PMID- 30472460 TI - Short implants (5-8mm) vs Long implants in augmented bone and their impact on peri-implant bone in maxilla and/or mandible : Systematic review. AB - OBJECTIVE: The purpose of this systematic literature review is to determine the impact of implant length on marginal bone loss in atrophied arches. MATERIAL AND METHODS: The systematic search of the literature was carried out using electronic databases PubMed, EbscoHost, Cochrane, as well as a manual search of randomized controlled trials in humans, with a follow-up period of at least 12 months, published between 2005 and 2016, comparing the short implants on the one hand, and the long implants placed in atrophic bone crests having undergone bone augmentation on the other hand. This systematic review followed the guidelines of PRISMA Statement (Preferred Reporting Items for Systematic Reviews and Meta Analyzes). The results of the clinical trials were described according to the PICO criteria. The qualitative analysis was conducted by Jadad scale and the Cochrane Collaboration's tool for assessing risk of bias. RESULTS: Thirteen randomized controlled trials (RCTs) were included in our systematic review. Gradual marginal bone loss (intra-group comparison) was significant regardless of the arcade. The difference in bone loss between short and long implants (inter group comparison) was not significant in the first year, but became significant at the end of the fifth year regardless of the arcade. CONCLUSION: Despite the satisfactory results in relation to short implants, it is appropriate to extend the duration of RCTs up to 10 years in order to support the data collected in our systematic review. PMID- 30472461 TI - Role of MCP-1 and CCR2 in alcohol neurotoxicity. AB - Alcohol abuse causes profound damage to both the developing brain and the adult brain. Prenatal exposure to alcohol results in a wide range of deficits known as fetal alcohol spectrum disorders (FASD). Alcohol abuse in adults is associated with brain shrinkage, memory and attention deficits, communication disorders and physical disabilities. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is one of the key chemokines that regulate the recruitment and activation of monocytes and microglia. Both MCP-1 and its receptor C-C chemokine receptor type 2 (CCR2) expressed in the brain are involved in various neuroinflammatory disorders, such as multiple sclerosis (MS), Alzheimer's disease (AD) and Parkinson's disease (PD). However, the role of MCP-1/CCR2 in alcohol-induced brain damage is unclear. Recent evidence indicates that alcohol exposure increased the activity of MCP 1/CCR2 in both mature and developing central nervous systems (CNS). MCP-1/CCR2 signaling in the brain was involved in alcohol drinking behavior. MCP-1/CCR2 inhibition alleviated alcohol neurotoxicity by reducing microglia activation/neuroinflammation in the developing brain and spinal cord. In this review, we discussed the role of MCP-1/CCR2 signaling in alcohol-induced neuroinflammation and brain damage. We also discussed the signaling cascades that are involved in the activation of MCP-1/CCR2 in response to alcohol exposure. PMID- 30472462 TI - Reinterpreting anomalous competitive binding experiments within G protein-coupled receptor homodimers using a dimer receptor model. AB - An increasing number of G protein-coupled receptors (GPCRs) have been reported to be expressed in the plasma membrane as dimers. Since most ligand binding data are currently fitted by classical equations developed only for monomeric receptors, the interpretation of data could be misleading in the presence of GPCR dimers. On the other hand, the equations developed from dimer receptor models assuming the existence of two orthosteric binding sites within the dimeric molecule offer the possibility to directly calculate macroscopic equilibrium dissociation constants for the two sites, an index of cooperativity (DC) that reflects the molecular communication within the dimer and, importantly, a constant of radioligand competitor allosteric interaction (KDAB) in competitive assays. Here, we provide a practical way to fit competitive binding data that allows the interpretation of apparently anomalous results, such as competition curves that could be either bell-shaped, monophasic or biphasic depending on the assay conditions. The consideration of a radioligand-competitor allosteric interaction allows fitting these curve patterns both under simulation conditions and in real radioligand binding experiments, obtaining competitor affinity parameters closer to the actual values. Our approach is the first that, assuming the formation of receptor homodimers, is able to explain several experimental results previously considered erroneous due to their impossibility to be fitted. We also deduce the radioligand concentration responsible for the conversion of biphasic to monophasic or to bell shaped curves in competitive radioligand binding assays. In conclusion, bell shaped curves in competitive binding experiments constitute evidence for GPCR homodimerization. PMID- 30472463 TI - Ginkgetin, a biflavone from Ginkgo biloba leaves, prevents adipogenesis through STAT5-mediated PPARgamma and C/EBPalpha regulation. AB - Adipogenesis involved in hypertrophy and hyperplasia of adipocytes is responsible for expanding the mass of adipose tissues in obese individuals. Peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein alpha (C/EBPalpha) are two principal transcription factors induced by delicate signaling pathways, including signal transducer and activator of transcription 5 (STAT5), in adipogenesis. Here, we demonstrated a novel role of ginkgetin, a biflavone from Ginkgo biloba leaves, as a STAT5 inhibitor that blocks the differentiation of preadipocytes into adipocytes. During the differentiation of 3T3-L1 cells, ginkgetin treatment during the first 2 days markedly inhibited the formation of lipid-bearing adipocytes. PPARgamma and C/EBPalpha expression was decreased in 3T3-L1 cells during adipogenesis following ginkgetin treatment, whereas no change was observed in C/EBPbeta or C/EBPdelta expression. Inhibition of PPARgamma and C/EBPalpha expression by ginkgetin occurred through the prevention of STAT5 activation during the initiation phase of adipogenesis. In addition, ginkgetin-mediated the inhibition of adipogenesis was recapitulated in the differentiation of primary preadipocytes. Lastly, we confirmed the inhibitory effects of ginkgetin on the hypertrophy of white adipose tissues from high-fat diet-fed mice. These results indicate that ginkgetin is a potential anti-adipogenesis and anti-obesity drug. PMID- 30472464 TI - Revisiting autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) mutations in the nicotinic acetylcholine receptor reveal an increase in efficacy regardless of stochiometry. AB - Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a genetic form of epilepsy that is caused by mutations in several genes, including genes encoding for the alpha4 and beta2 subunits of the nicotinic acetylcholine (nACh) receptor. Pentameric alpha4beta2 nACh receptors are the most abundant nicotinic receptor in the mammalian brain and form two stoichiometries, the (alpha4)3(beta2)2 and (alpha4)2(beta2)3 receptors that differ in their physiological and pharmacological properties. The purpose of this study was to investigate how ADNFLE mutations beta2V287M, beta2V287L or alpha4T293I manifest themselves in different receptor stoichiometries. We expressed wild-type and mutant receptors in Xenopus oocytes and measured the response to ACh and other agonists at both receptor stoichiometries. For all three mutations, the efficacy of ACh at (alpha4)2(beta2)3 receptors was increased. At (alpha4)3(beta2)2 receptors, the efficacy of activation was increased both when two molecules of agonist, either ACh or the site-selective agonist sazetidine-A, were bound at the alpha4-beta2 interfaces, and when a third ACh molecule was bound at the alpha4-alpha4 site. Regardless of stoichiometry, the mutations increased the current elicited by low concentrations of ACh. Further, the smoking cessation agents, nicotine, varenicline and cytisine increased activation of mutant (alpha4)3(beta2)2 receptors, while only nicotine increased activation of mutant (alpha4)2(beta2)3 receptors. Chronic exposure of all agonists reduced ACh-activation levels at low and high ACh concentrations. From this, we concluded that mutations that cause ADNFLE manifest themselves in a change in efficacy regardless of the stoichiometry of the receptor. PMID- 30472465 TI - Hair and fingernail cortisol and the onset of acute coronary syndrome in the middle-aged and elderly men. AB - Cortisol levels in hair and fingernail samples could represent hormone levels that have accumulated over the past weeks and months. In this study, by using retrospective indexes, the associations between cortisol and the onset of acute coronary syndrome (ACS) were investigated among middle-aged and elderly men. We measured hair/fingernail cortisol levels in 73 ACS patients and 93 healthy controls; hair and fingernail samples for ACS patients were collected within a few weeks after the onset of ACS. The results indicated the patients exhibited significantly higher cortisol levels in their hair and fingernails compared with the healthy controls. In multivariate logistic regression analyses, adjusting for the traditional cardiovascular risk factors for ACS, high levels of hair or fingernail cortisol were associated with two- to three-fold increased risk of ACS, compared with low levels. We demonstrated that cortisol exposure over a relatively long period, assessed by hair and fingernail samples, was associated with the onset of ACS. PMID- 30472466 TI - Long-term glucocorticoid levels measured in hair in patients with depressive and anxiety disorders. AB - BACKGROUND: Depressive and anxiety disorders have been linked to a dysregulated hypothalamus-pituitary-adrenal (HPA)-axis. Hair cortisol levels (HairF) reflect integrated long-term cortisol regulation and are therefore promising endocrine markers of chronic (psychological and physical) stress. Our aim was to assess hair cortisol levels in persons with a depressive and/or anxiety disorder and to compare their levels with that of persons in remission and healthy controls. METHODS: Data from 1166 participants of the Netherlands Study of Depression and Anxiety (NESDA) were used, including 266 participants with a recent (1-month) diagnosis of a depressive and/or anxiety disorder, 655 participants with a diagnosis in remission, and 245 healthy controls. HairF was measured in the proximal three cm of scalp hair, using LC-MS/MS. RESULTS: Compared to the healthy controls no differences on HairF or HairE levels were found for depressive and anxiety disorders alone. However the presence of a comorbid depressive and anxiety disorder was significantly associated with increased HairF levels (beta = 0.07; p = .031), as was the severity of depressive symptoms (beta = 0.06; p = .029), but no differences were found on HairE nor the HairF:HairE ratio. CONCLUSIONS: Persons with current diagnosis of comorbid depression and anxiety show moderately higher levels of cortisol than patients with only depression or anxiety, or patients in remission and healthy controls, which may be indicative of a chronic state of hyperactivation of the HPA axis. PMID- 30472468 TI - Crying babies, empathic toddlers, responsive mothers and fathers: Exploring parent-toddler interactions in an empathy paradigm. AB - The ability to display caring responses to another child's distress is a key aspect of early empathy that is facilitated by parental socialization. However, existing studies typically involve lab settings and focus on toddlers' unsupported responses to adult simulations of distress, raising questions about their ecological validity. Framed within the New Fathers and Mothers Study, the current study involved 156 British toddlers (Mage = 24.35 months, SD = 0.73) who were filmed at home with either their mother or father (87 mothers and 69 fathers) in a novel paradigm involving a lifelike crying baby doll. Capitalizing on the inclusion of both fathers and mothers, a key question concerned effects of parent-toddler dyad gender composition on both global ratings of toddlers' displays of empathic concern and more specific indicators, including toddlers' attentional, emotional, and behavioral responses. Whereas parental responses did not differ by either child or parent gender and appeared to be closely attuned to child behavior, toddlers' responses showed effects of both (a) child gender, evident in higher rates of emotion labeling in girls than in boys (even when controlling for language ability), and (b) parent gender, evident in higher levels of empathic concern for girls observed with fathers than for those observed with mothers. These findings are discussed within the context of empathy development and parental socialization. PMID- 30472467 TI - Patients' and clinicians' perspectives of co-use of cannabis and opioids for chronic non-cancer pain management in primary care. AB - BACKGROUND: The prevalence of opioid-associated morbidity and mortality underscores the need for research on non-opioid treatments for chronic non-cancer pain (CNCP). Pain is the most common medical condition for which patients request medical cannabis. Limited research indicates that patients are interested in cannabis as a potential addition to or replacement for opioid medication. This analysis reports on CNCP patient and clinician perceptions about the co-use of cannabis and opioids for CNCP management. METHODS: We interviewed 23 clinicians and 46 CNCP patients, using semi-structured interview guides, from six safety-net clinics across the San Francisco Bay Area, and 5 key stakeholders involved in CNCP management. We used a modified grounded theory approach to code and analyze transcripts. RESULTS: CNCP patients described potential benefits of co-use of cannabis and opioids for pain management and concerns about dosing and addictive potential. Patients reported seeking cannabis when unable to obtain prescription opioids. Clinicians stated that their patients reported cannabis being helpful in managing pain symptoms. Clinicians expressed concerns about the potential exacerbation of mental health issues resulting from cannabis use. CONCLUSION: Clinicians are hampered by a lack of clinically relevant information about cannabis use, efficacy and side-effects. Currently no guidelines exist for clinicians to address opioid and cannabis co-use, or to discuss the risk and benefits of cannabis for CNCP management, including side effects. Cannabis and opioid co-use was commonly reported by patients in our sample, yet rarely addressed during clinical CNCP care. Further research is needed on the risks and benefits of cannabis and opioid co-use. PMID- 30472469 TI - Secretory expression, immunoaffinity purification and metal-binding ability of recombinant metallothionein (ShMT) from freshwater crab Sinopotamon henanense. AB - Metallothioneins (MTs) are a super-family of ubiquitous, low-molecular-weight, cysteine-rich and metal-binding proteins. They are thought to play a predominant role in mediating metal metabolism and antioxidation. However, the accurate functions of MTs remain unclear in the physiological processes due to native proteins deficiency and little information of their metal-binding character. Freshwater crab Sinopotamon henanense is a decapod crustacean widely distributed in northern China, in which only one MT isoform (ShMT) has been reported so far. In order to shed light on the accurate role of ShMT, a novel recombinant ShMT in native form was over-expressed by phoA secreted expression system in Escherichia coli (E. coli). Then the ShMT proteins were purified using a one-step gentle immunoaffinity chromatography with a polyol-responsive mAb (PR-mAb) to ShMT, which was generated by conventional hybridoma technology followed by ELISA elution. The Zn-, Cu-, and Cd-ShMT complexes were prepared by recombinant synthesis in metal-enriched media and reconstitution with metal ions, respectively. Further analysis about metal-binding capacity showed recombinant ShMT has high ability to bind Zn, Cu and Cd metals, although the recombinantly expressed and reconstituted metal-ShMT complexes have different metal-to-protein stoichiometry. Moreover, the affinity of recombinant protein for metal ions has been analyzed using competitive reaction with 5, 5-dithiobis (2-nitrobenzoic acid) (DTNB). The results demonstrated the affinity of recombinant ShMT for metals was as follows: Cu>Cd>Zn. In summary, the experimental procedure we have developed facilitates production of recombinant ShMT with native characteristics for further research and the study of metal-binding ability could help further clarify the accurate functions of ShMT. PMID- 30472470 TI - Comparison of rates of direct and indirect migration of phosphorus flame retardants from flame-retardant-treated polyester curtains to indoor dust. AB - In this study, the pathways for migration of phosphorus flame retardants (PFRs), tris(1,3-dichloroisopropyl) phosphate (TDCPP) and tricresyl phosphate (TCsP) which were detected from curtains often, from flame-retardant-treated polyester curtains to indoor dust were investigated. Two possible migration pathways were compared quantitatively: (1) an indirect pathway in which the PFRs in the curtains first evaporate from the curtains and are then adsorbed onto indoor dust and (2) a direct pathway in which the PFRs are directly transferred to dust placed on the curtains. The contribution of the indirect pathway was evaluated by means of emission cell tests, which showed that the area-specific emission rates from curtains treated with PFRs were 0.044 (TDCPP, Curtain 5), 0.17 (TDCPP, Curtain 8), and 0.060 (TCsP, Curtain 12) MUg m-2 h-1 at 20 degrees C (averaged during 24 h). The contribution of the direct pathway was evaluated by measurement of the time dependence of PFR concentrations on the indoor dust placed on the curtains. These measurements indicated that PFR concentrations on the dust increased with time and that the direct migration rates of PFRs from curtains treated with PFRs were 4.4 (TDCPP, Curtain 5), 12 (TDCPP, Curtain 8), and 7.0 (TCsP, Curtain 12) MUg m-2 h-1 at 20 degrees C (averaged during 24 h), or 71-120 times the indirect migration rate. This result suggests that the direct pathway can be expected to predominate. PMID- 30472471 TI - Seasonal and spatial variations of PM10-bounded PAHs in a coal mining city, China: Distributions, sources, and health risks. AB - Atmospheric polycyclic aromatic hydrocarbons (PAHs) emitted from coal combustion has become the major contributor of atmospheric PAHs in China and caused worldwide concern due to their adverse effects on human health and ecosystem. In this work, the abundance, distribution, source and health risk assessment of ambient PM10-bounded PAHs were studied in all seasons from a typical coal resource city in China. The spatial distribution characteristics of PM10-bounded PAHs were also investigated, which cover 6 functional zones including industrial area, mining area, commercial district, education area, residential area and control area, respectively. The average concentrations (in ng/m3) of 16 EPA priority PAHs in PM10 in spring, summer, autumn and winter were 194 +/- 11.1, 161 +/- 14.0, 183 +/- 14.1 and 213 +/- 19.2, respectively, and with an annual average of 188 +/- 21.8. The composition distribution of PM10-bounded PAHs in each functional zone showed that 4-rings PAHs were dominated in all seasons, followed by 3-rings and 5-rings. Principal component analysis (PCA) and diagnostic ratio indicated that the main PAH sources were coal combustion, traffic and biomass combustion. Health risk assessment analysis (BEQ) suggested that the residential exposure to PAHs in the mining and commercial areas, particularly in winter season, may pose a greater cancer risk than people living in other parts of Huainan city. The maximum BEQ values were found at mining and commercial areas, which were mainly influenced by the emissions from gasoline or diesel vehicles, coal and biomass combustion. Both inhalation and skin contact have great influence on the cancer risk of residents in Huainan city. PMID- 30472472 TI - Composite nanofibers membranes of poly(vinyl alcohol)/chitosan for selective lead(II) and cadmium(II) ions removal from wastewater. AB - The nanofibers membranes were fabricated by poly(vinyl alcohol)/chitosan (PVA/Chi) using an electro-spun technique for selective and high adsorption of lead (Pb(II)) and cadmium (Cd(II)) ions based on the solution acidity. The PVA/Chi NFs membranes were characterized systematically using several instrumentations. In addition, several experimental parameters such as initial metal ions concentration, interaction time, adsorbent dosage, solution pH and the effects of competing ions on Pb(II) and Cd(II) adsorption were evaluated. The adsorption data were also clarified that the PVA/Chi NFs membranes were exhibited high kinetic performances towards the both toxic ions at the optimum conditions. The adsorption data were manipulated using different kinetics models, and it was confirmed that only pseudo-second-order model obeyed the adsorption kinetics for Pb(II) and Cd(II) ions. Similarly, the equilibrium data were well fitted with the Langmuir adsorption isotherms model, and the maximum adsorption capacity was 266.12 and 148.79 mg/g for Pb(II) and Cd(II) ions, respectively. The Pb(II) and Cd(II) ions adsorptions were also measured to know the selectivity with simulated environmental solution, and the data were confirmed the high selectivity to Pb(II) and Cd(II) ions at the optimum condition and the nanofibers membrane shown the potentiality for possible use in efficient removal of the selected toxic ions from waste samples. Thus, the PVA/Chi NFs are considered to be effective and promising materials for Pb(II) and Cd(II) ions from wastewaters with high efficiency. PMID- 30472473 TI - Bioavailability/speciation of arsenic in atmospheric PM2.5 and their seasonal variation: A case study in Baoding city, China. AB - Arsenic (As) can be easily enriched in atmospheric particulate matters (PMs), especially in fine particulate matters (PM2.5). In this study, thirty two PM2.5 samples were collected in four seasons in Baoding, China, where the haze pollution was very serious in recent years. The total contents, species and bioavailability of arsenic in PM2.5 samples were investigated. Species of arsenic in the PM2.5 samples were discriminated as five fractions using a sequential extraction method: non-specifically sorbed fraction (F1), specifically-sorbed fraction (F2), amorphous and poorly-crystalline hydrous oxides of Fe and Al fraction (F3), well-crystallized hydrous oxides of Fe and Al fraction (F4) and residual fraction (F5). Bioavailabilities of arsenic in the PM2.5 samples were evaluated by in vitro tests using both solubility bioavailability research consortium (SBRC) and Gamble's solution extraction methods. The total volume concentrations of As in PM2.5 were significantly higher in winter than the other seasons. However, the highest mass concentration of As was found in spring. Scanning electron microscopy (SEM) characterization indicated that the physical morphology of the particles varied in different seasons. Significant differences of fraction distribution and BFs were found between different seasons. Arsenic in PM2.5 samples mainly presented in F1 with high bioavailability factor (BF), especially for the samples in summer. In vitro tests indicated that arsenic in PM2.5 could be dissolved more easily in gastric phase rather than intestinal and lung phases. There was a significant correlation between species and in vitro tests. Interestingly, a synergy effect was found between F2 and F3. Health risk assessment indicated that arsenic in PM2.5via inhalation exposure for both children and adults could cause adverse effects. Principal component analysis suggested that the arsenic in PM2.5 was from the similar sources between summer and autumn, winter and spring, respectively. PMID- 30472474 TI - Phthalate acid esters (PAEs) accumulation in coastal sediments from regions with different land use configuration along the Persian Gulf. AB - Phthalate acid esters (PAEs) are widely used as plasticizers in various plastic products and have aroused considerable concern over their ubiquitous presence and potentially hazardous effects on the environment. This research provides the first data on PAEs distribution in the sediments of northern part of the Persian Gulf. To determine the concentration of 16 PAEs, 26 samples of sediments were collected from industrial stations (IS), urban stations (US), agricultural stations (AGS), and natural field stations (NS) from Asalouyeh Harbor coasts from Nov 2016 to Jan 2017. The mean values of ?16PAEs in the samples taken from IS, AGS, US, and NS were 78.08, 11.69, 46.56, and 5.180 ug/g, respectively. The results indicated that the mean concentrations of ?16PAEs in the samples taken from IS and AGS areas were significantly higher (p < 0.05) than the ones taken from US and NS areas. The order of PAEs concentrations in sediment samples were as di(2-ethylhexyl) phthalate (DEHP), di-n-butyl phthalate (DnBP), butylbenzyl phthalate (BBP), and di-n-octyl phthalate (DnOP), respectively. DEHP was detected in all collected samples and the mean +/- SD of its concentration in the IS, US, AGS, and NS regions were as 28.15 +/- 4.9, 4.040 +/- 0.53, 11.58 +/- 1.2, and 1.780 +/- 0.78 ug/g, respectively. The major sources of PAEs in the sediments collected from the study region were associated with the industrial and agricultural activities. The findings of this study indicated that the sediments of the Asalouyeh coasts are heavily contaminated with PAEs. They have shown potential ecotoxicological effects on the aquatic organisms and benthic. Therefore, more attention should be paid to prediction of the marine ecosystem in this region by the authorities. PMID- 30472475 TI - Environmental contaminants in fish species from a large dam reservoir and their potential risks to human health. AB - The residue levels of antibiotics, metals and organochlorine pesticides (OCPs) were investigated in six fish species from the Karakaya Dam Reservoir, Turkey. Among monitored antibiotics, only enrofloxacin and ofloxacin were detected in muscle of fish species. Enrofloxacin levels in positive samples ranged from 0.0034 to 0.0073 mg/kg. It was detected in four fish species (trout barb, common carp, chub and Euphrates barbell), while ofloxacin was only found in common carp with the concentration of 0.0072 mg/kg. Both enrofloxacin and ofloxacin levels were below the maximum residue levels. No detectable residues of any OCPs were found in fish species. The highest toxic metal (As, Cd and Pb) content was detected in Euphrates barbell (0.103 mg/kg). Arsenic, Cd, Cr, Cu, Pb and Zn levels were well below the maximum permissible limits. The levels of antibiotics and metals found in fish species in the present study were generally lower than or comparable to those reported in other water bodies. According to estimated daily intake and hazard quotient values, antibiotics and metals detected in these wild fish species do not appear to pose a serious risk to public health. PMID- 30472476 TI - Effects of acute mercury exposure on fatty acid composition and oxidative stress biomarkers in Holothuria forskali body wall. AB - Mercury is one of the most harmful pollutant that threat marine biota. This study assessed the Hg impact on the fatty acid (FA) composition and the antioxidant statues in Holothuria forskali body wall tissue. Specimens were exposed to HgCl2 graded doses (40, 80 and 160 MUg L-1) for 96 h. A decrease in linoleic, arachidonic and eicosapentaenoic acid levels and an increase of docosahexaenoic acid were mainly observed at the nominal tested dose. The exposure to the upper dose promoted oxidative stress with an increase of malondialdehyde, hydrogen peroxide, advanced oxidation protein product, glutathione and non-protein thiols levels. Moreover, a decrease in catalase and an increase in superoxide dismutase and glutathione peroxidase activities were observed. Yet, an increase of the metallothionein level was registered in all treated groups. This study confirmed the Hg toxicity on the redox statue of H. forskali and highlighted the usefulness of the FA composition as an early sensitive bioindicators. PMID- 30472477 TI - Non-aspirin non-steroidal anti-inflammatory drugs in prevention of colorectal cancer in people aged 40 or older: A systematic review and meta-analysis. AB - There is still insufficient data about the risk-benefit profile about recommending non-aspirin, non-steroidal anti-inflammatory drugs (NA-NSAIDs) for colorectal cancer (CRC) prevention, especially in people aged 40 years or older. This study specifically addressed the association between regular NA-NSAIDs use and CRC risk in the population aged 40 years or older, performing a comprehensive systematic review and meta-analysis of all published studies on this topic until April 2018, by a search of PubMed, Scopus and Web of science databases and clinical trial registries. Two reviewers independently selected studies based on predefined inclusion criteria and assessed study quality using the Newcastle Otawa scale. The data was combined with the random effects model. Potential heterogeneity was calculated as Q statistic and I2 value. A total of 23 studies involving more than 1 million subjects contributed to the analysis. Pooled odds ratio (OR) of NA-NSAIDs effects on CRC risk was 0.74 (0.67-0.81), I2 = 75.9%, p < 0.001. Heterogeneity was explained by a number of variables including the quality of the studies. Significant protective effects of NA-NSAIDs use were found for women (risk reduction of 19%), higher doses (risk reduction of 18%), distal colon cancer (risk reduction of 22%) and white people (risk reduction from 31% to 41%). From the results NA-NSAIDs use appears to be CRC chemopreventive for a specific subgroup of the population. PMID- 30472478 TI - In vitro stability of arsenic trioxide-liposome encapsulates for acute promyelocytic leukemia treatment. AB - In this work, we investigated the stability of arsenic trioxide (ATO) used in leukemia treatment, encapsulated with nanoliposome, with the aid of ultrasound treatment. Stability studies of As species were followed by liquid chromatography inductively coupled plasma mass spectrometry (LC-ICP-MS), allowing for the detection of the conversion of low amounts of As(III) to As(V) or the formation of other As species. The influence of storage temperature and time on ATO was evaluated. Low amounts of As(III) to As(V) conversions were observed when the As encapsulated with nanoliposome was incubated at 25 degrees C and 40 degrees C. However, As(III) was stable if the solution was maintained at 5 degrees C, even after 90 days. No formation of other As species was observed, indicating good stability of the encapsulated ATO. Next step of the work will focus on spray drying of ATO nanoliposomes-encapsuleted with the aim of long term stability of As. PMID- 30472479 TI - Is the presence of Central European strains of Raphidiopsis (Cylindrospermopsis) raciborskii a threat to a freshwater fish? An in vitro toxicological study in common carp cells. AB - As yet European strains of Raphidiopsis raciborskii (previously Cylindrospermopsis raciborskii) have not been found to produce known cyanotoxins although their extracts have caused adverse effects in mammals, as shown using in vitro and in vivo experimental models. The present study investigated whether R. raciborskii isolated from Western Poland and Ukraine can affect fish cells using in vitro exposures of hepatocytes and red blood cells (RBC), and brain homogenates obtained from common carp (Cyprinus carpio) to 1.0% and 0.1% extracts of 7 strains. The studied extracts evoked different responses of catalase activity in hepatocytes with both increase and decrease observed under low and high concentrations. The cellular thiol pool was also altered with most extracts inducing a decrease in the activity of glutathione-S-transferase, and Ukrainian strains leading to an increase in glutathione level and a decrease in metallothionein content. All the studied extracts induced comparable reactive oxygen species formation, lipid peroxidation, protein carbonylation and DNA fragmentation in hepatocytes, and all but one increased the activity of caspase 3. Only one extract caused lysosomal membrane destabilization as measured by neutral red retention in RBC. In contrast to extracts of Ukrainian isolates, exposure of brain homogenates to extracts of Polish strains induced an increase in acetylcholinesterase activity suggesting the neurotoxic action of their exudates. The results indicate that both Polish and Ukrainian strains of R. raciborskii may pose a toxicological risk to freshwater fish, and further, that Polish strains may produce compound(s) evoking neurotoxic effects. PMID- 30472480 TI - The evolution and origin of tetrodotoxin acquisition in the blue-ringed octopus (genus Hapalochlaena). AB - Tetrodotoxin is a potent non-proteinaceous neurotoxin, which is commonly found in the marine environment. Synthesised by bacteria, tetrodotoxin has been isolated from the tissues of several genera including pufferfish, salamanders and octopus. Believed to provide a defensive function, the independent evolution of tetrodotoxin sequestration is poorly understood in most species. Two mechanisms of tetrodotoxin resistance have been identified to date, tetrodotoxin binding proteins in the circulatory system and mutations to voltage gated sodium channels, the binding target of tetrodotoxin with the former potentially succeeding the latter in evolutionary time. This review focuses on the evolution of tetrodotoxin acquisition, in particular how it may have occurred within the blue-ringed octopus genus (Hapalochlaena) and the subsequent impact on venom evolution. PMID- 30472481 TI - Copper exposure and seawater acidification interaction: Antagonistic effects on biomarkers in the zooxanthellate scleractinian coral Mussismilia harttii. AB - Coral reefs are threatened by global and local impacts, such as ocean acidification (OA) and metal contamination. Toxicity of metals, such as copper (Cu), is expected to be enhanced with OA. However, the interaction between these environmental stressors is still poorly evaluated. In the present study, the interactive effects of seawater acidification and increasing Cu concentrations were evaluated in a zooxanthellate scleractinian coral (Mussismilia harttii), using biochemical biomarkers involved in the coral calcification process and the photosynthetic metabolism of endosymbionts. Corals were kept under control conditions (no seawater acidification and no Cu addition in seawater) or exposed to combined treatments of reduced seawater pH (8.1, 7.8, 7.5 and 7.2) and environmentally relevant concentrations of dissolved Cu (measured: 1.0, 1.6, 2.3 and 3.2 MUg/L) in a mesocosm system. After 15- and 35-days exposure, corals were analyzed for photochemical efficiency (Fv/Fm), chlorophyll a content, Ca-ATPase and carbonic anhydrase (CA) activity. Results showed that 76% of the interactions between reduced seawater pH and increasing Cu concentrations were antagonistic. Only 24% of these interactions were additive or synergistic. In general, the combination of stressors had no significant deleterious effects in the photosynthetic metabolism of endosymbionts or Ca-ATPase activity. In fact, the lowest dissolved Cu concentration tested had a consistent positive effect on Ca ATPase activity in corals facing any of the reduced seawater pH conditions tested. In turn, potentially deleterious effects on acid-base balance in M. harttii, associated with changes in CA activity, were intensified by the combination of stressors. Findings reported here indicate that Cu toxicity in future OA scenarios can be less severe than previously suggested in this coral holobiont. PMID- 30472482 TI - Brain grey matter volume reduction and anxiety-like behavior in lipopolysaccharide-induced chronic pulmonary inflammation rats: A structural MRI study with histological validation. AB - While there have been multiple fMRI studies into the brain functional changes after acutely stimulated peripheral infection, knowledge for the effect of chronic peripheral infection on whole brain morphology is still quite limited. The present study was designed to investigate the brain structural and emotional changes after peripheral local infection initiated chronic systemic inflammation and the relationship between circulating inflammatory markers and brain grey matter. Specifically, in-vivo T2-weighted MRI was performed on rats with lipopolysaccharide (LPS)-induced chronic pulmonary inflammation (CPI) and those without. Grey matter volume was quantified using diffeomorphic anatomical registration through exponentiated lie (DARTEL) enhanced voxel-based morphometry followed by between-group comparison. Open field experiment was conducted to test the potential anxiety-like behaviors after CPI, along with the ELISA estimated inflammatory markers were correlated to grey matter volume. Guided by image findings, we undertook a focused histological investigation with immunefluorescence and Nissl staining. A widespread decrease of grey matter volume in CPI-model rats was revealed. 8 of the 12 measured inflammatory markers presented differential neuroanatomical correlation patterns with three of the pro inflammatory cytokines (IL-1beta, IL-6 and TNF-alpha) and CRP being the most notable. Lower grey matter volumes in some of the inflammatory markers related regions (amygdala, CA2 and cingulate cortex) were associated with more-severe anxiety-like behaviors. Furthermore, grey matter volumes in amygdala and CA3 were correlated negatively with the expressions of glial proteins (S100beta and Nogo A), while the grey matter volume in hypo-thalamus was changing positively with neural cell area. Overall, the neuroanatomical association patterns and the histopathology underpinning the MRI observations we demonstrated here would probably serve as one explanation for the cerebral and emotional deficits presented in the patients with CPI, which would furthermore yield new insights into the adverse effects the many other systemic inflammation and inflammatory autoimmune diseases would pose on brain morphology. PMID- 30472483 TI - A de novo 2q37.2 deletion encompassing AGAP1 and SH3BP4 in a patient with autism and intellectual disability. AB - Autism spectrum disorders are complex neurodevelopmental syndromes characterized by phenotypic and genetic heterogeneity. Further identification of causal genes may help in better understanding the underlying mechanisms of the disorder, thus improving the patients' management. To date, abnormal synaptogenesis is thought to be one of the major underlying causes of autism spectrum disorders. Here, using oligoarray-based comparative genomic hybridization, we identified a de novo deletion at 2q37.2 locus spanning 1 Mb and encompassing AGAP1 and SH3BP4, in a boy with autism and intellectual disability. Both genes have been described as being involved in endosomal trafficking, and AGAP1 in particular has been shown to be expressed in the developing brain and to play a role in dendritic spine formation and synapse function, making it a potential causative gene to our patient's phenotype. PMID- 30472484 TI - TNFalpha -857 C/T and TNFR2 +587 T/G polymorphisms are associated with cystic fibrosis in Iranian patients. AB - Identification of modifier genes influencing phenotype of cystic fibrosis (CF) patients has become a challenge in CF pathophysiology, prognostic estimations and development of new therapeutic strategies. The aim of this study was to explore the association between four genetic polymorphisms of three modifier genes with CF, by comparing their alleles, genotypes and haplotype frequencies in patients and controls. In this favor, two regulatory polymorphic loci in TNFalpha promoter (-857C/T, rs1799724 and -238A/G, rs361525) and two functional polymorphic loci in TNFR1 (+36A/G, rs767455) and TNFR2 (+587T/G, rs1061622) were genotyped in 70 patients and 79 controls, using PCR-RFLP. Clinical pulmonary data were also recorded from all studied patients. Results indicated that an association was observed between both T allele and CT/TT genotypes of TNFalpha (P = 0.0005, OR = 7.06, 95% CI = 3.71-13.45) with CF under dominant model of inheritance. GG genotype of TNFR2 +587 (P = 0.0005, OR = 4.92, 95%CI = 2.34-10.34) was significantly associated with CF using recessive model. Consistently, more severe pulmonary disorder was found for patients carrying either T dominant allele of TNFalpha -857 or GG genotype of TNFR2 +587 polymorphic sites. Despite an association of A-T and G-T haplotypes with CF, no significant association was found between these haplotypes and clinical parameters of CF. Overall, TNFalpha 857 T allele and GG genotype of TNFR2 +587 were more frequent in CF patients compared to healthy controls and hence, they showed an association with CF and severe pulmonary phenotype in Iranian patients. PMID- 30472485 TI - Biallelic mutations in AP3D1 cause Hermansky-Pudlak syndrome type 10 associated with immunodeficiency and seizure disorder. AB - Several types of Hermansky-Pudlak syndromes (HPS) represent a group of immunodeficiency syndromes that feature both leukocyte defects with partial albinism of hair, skin, and eyes. These conditions share defects in genes that encode proteins involved in the biogenesis, function, and trafficking of secretory lysosomes. Mutations in AP3D1 which encode the main subunit AP-3(delta) were recently reported on one individual and led to Hermansky-Pudlak Syndrome type 10 (HPS10; OMIM 617050). HPS10 is a severe condition that manifests with symptoms of oculocutaneous albinism, neurodevelopmental delays, platelet dysfunction, and immunodeficiency. Herein we report on three affected individuals who presented with severe seizures, developmental delay, albinism, and immunodeficiency. Whole exome sequencing identified homozygosity for a deleterious sequence variant of high impact in AP3D1, c.1978delG, predicting p.Ala660Argfs*54 (NM_001261826.3). We further demonstrated an abnormal storage pathway in the platelets. The current study represents a second confirmation report and implicates AP3D1 mutations as a cause of Hermansky-Pudlak Syndrome type 10. PMID- 30472486 TI - A previously identified missense mutation in STYXL1 is likely benign. AB - Based on a homozygous missense variant p.Pro311Ala found in three siblings of a consanguineous family, mutations in the STYXL1 gene were suggested to cause moderate intellectual disability, epilepsy and complex behavioural abnormalities. We have detected this variant via whole exome sequencing in a homozygous state in two families. Segregation analyses in our families and thorough validation in international genetic databases provides evidence that this variant is most likely benign. This is important information for genetic counselling. The role of STYXL1 variants in human disease needs to be established. PMID- 30472487 TI - PUF60-SCRIB fusion transcript in a patient with 8q24.3 microdeletion and atypical Verheij syndrome. AB - Expression of the fusion genes is considered to be an important mechanism of tumorigenesis. However it is hardly ever discussed in relation to the neurodevelopmental disorders. Here we report on an 18-years-old female patient with 13.1 kb deletion of 8q24.3 fusing the 5'-portion of SCRIB with the 3' portion of PUF60 and presenting with borderline intellectual disability, eye coloboma, short stature, scoliosis, heart defects and interestingly postnatal megalencephaly, in contrast to microcephaly, which is usually associated with 8q24.3 deletion (Verheij syndrome). Using next generation sequencing we mapped the breakpoints at nucleotide resolution and showed that the deletion preserved the reading frame. In contrast to the laborious techniques previously used for the precise mapping of deletion breakpoints, our approach identified an accurate interval very rapidly. We demonstrated the expression of the PUF60-SCRIB fusion gene in patient's cells and suggest that the fusion transcript might be a cause of the atypical clinical presentation. PMID- 30472489 TI - Resting state functional connectivity patterns associated with pharmacological treatment resistance in temporal lobe epilepsy. AB - There are no functional imaging based biomarkers for pharmacological treatment response in temporal lobe epilepsy (TLE). In this study, we investigated whether there is an association between resting state functional brain connectivity (RsFC) and seizure control in TLE. We screened a large database containing resting state functional magnetic resonance imaging (Rs-fMRI) data from 286 epilepsy patients. Patient medical records were screened for seizure characterization, EEG reports for lateralization and location of seizure foci to establish uniformity of seizure localization within patient groups. Rs-fMRI data from patients with well-controlled left TLE, patients with treatment-resistant left TLE, and healthy controls were analyzed. Healthy controls and cTLE showed similar functional connectivity patterns, whereas trTLE exhibited a significant bilateral decrease in thalamo-hippocampal functional connectivity. This work is the first to demonstrate differences in neural network connectivity between well controlled and treatment-resistant TLE. These differences are spatially highly focused and suggest sites for the etiology and possibly treatment of TLE. Altered thalamo-hippocampal RsFC thus is a potential new biomarker for TLE treatment resistance. PMID- 30472488 TI - Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes. AB - The SPECC1L protein plays a role in adherens junctions involved in cell adhesion, actin cytoskeleton organization, microtubule stabilization, spindle organization and cytokinesis. It modulates PI3K-AKT signaling and controls cranial neural crest cell delamination during facial morphogenesis. SPECC1L causative variants were first identified in individuals with oblique facial clefts. Recently, causative variants in SPECC1L were reported in a pedigree reported in 1988 as atypical Opitz GBBB syndrome. Six families with SPECC1L variants have been reported thus far. We report here eight further pedigrees with SPECC1L variants, including a three-generation family, and a further individual of a previously published family. We discuss the nosology of Teebi and GBBB, and the syndromes related to SPECC1L variants. Although the phenotype of individuals with SPECC1L mutations shows overlap with Opitz syndrome in its craniofacial anomalies, the canonical laryngeal malformations and male genital anomalies are not observed. Instead, individuals with SPECCL1 variants have branchial fistulae, omphalocele, diaphragmatic hernias, and uterus didelphis. We also point to the clinical overlap of SPECC1L syndrome with mild Baraitser-Winter craniofrontofacial syndrome: they share similar dysmorphic features (wide, short nose with a large tip, cleft lip and palate, blepharoptosis, retrognathia, and craniosynostosis), although intellectual disability, neuronal migration defect, and muscular problems remain largely specific to Baraitser-Winter syndrome. In conclusion, we suggest that patients with pathogenic variants in SPECC1L should not be described as "dominant (or type 2) Opitz GBBB syndrome", and instead should be referred to as "SPECC1L syndrome" as both disorders show distinctive, non overlapping developmental anomalies beyond facial communalities. PMID- 30472490 TI - Knee mechanics during a change of direction movement in division I athletes following full return to sport from anterior cruciate ligament reconstruction. AB - OBJECTIVES: The objective of this study was to determine whether Division I athletes following anterior cruciate ligament reconstruction (ACLR), and who are medically cleared to return to sport, demonstrate faulty knee mechanics during a change of direction maneuver, as evidenced by the presence of genu valgum on VICON(r) motion analysis system of 5 degrees or greater. STUDY DESIGN: Cross sectional study. SETTING: University. PARTICIPANTS: Ten Division I athletes performed a 90 degrees change of direction movement on both the ACLR and unaffected limbs. MAIN OUTCOME MEASURES: Knee mechanics were assessed using the VICON(r) motion analysis system. Knee position was analyzed in the frontal plane and peak genu valgum position was determined during the functional movement. RESULTS: Eight out of ten athletes (80%) demonstrated genu valgum >= 5 degrees on the ACLR limb during a 90 degrees cutting movement. Fourteen out of twenty (70%) of the knees assessed demonstrated genu valgum >= 5 degrees during a 90 degrees cutting movement. CONCLUSION: Athletes who have fully returned to sport following an ACLR demonstrate substantial genu valgum during a cutting maneuver, which suggests an increased risk for future injury. These results show an increased need during ACL rehabilitation to focus on existing biomechanical deficits during sport-specific movements. PMID- 30472491 TI - The design, development, implementation and evaluation of IRISweb; A rugby specific web-based injury surveillance system. AB - OBJECTIVES: To describe the development, implementation and evaluation of a comprehensive injury surveillance system. DESIGN: The four phases; i) A survey of 58 medical professionals working in amateur rugby. ii) The design of a web-based injury surveillance system (IRISweb). iii) Recruitment of 21 of the top 58 amateur clubs to use IRISweb. iv) An evaluation survey of the 21 participating clubs. SETTING: Irish amateur rugby clubs. PARTICIPANTS: Medical professionals working in amateur rugby. MAIN OUTCOME MEASURES: Phase one investigated the injury monitoring practices in operation prior to the IRIS project. Phase four investigated the effectiveness and usefulness of IRISweb. RESULTS: Twenty-one clubs were recruited, however 2 clubs failed to provide a full season of data (10% dropout rate). Eighty-two percent of the remaining 19 clubs rated IRISweb as 'good' or 'very good'. Facilitators of injury surveillance were; increased player adherence (65%) and notifications to update the system (59%), however, poor player adherence (71%) and medical staff availability (24%) were the main barriers. CONCLUSIONS: The IRIS project is the first prospective long-term injury surveillance system in Irish amateur rugby, effectively tracking injuries to guide future evidence-based injury prevention strategies. This study highlights facilitators and barriers to injury surveillance within amateur sport. PMID- 30472492 TI - Inhibition of the STAT5/Pim Kinase Axis Enhances Cytotoxic Effects of Proteasome Inhibitors on FLT3-ITD-Positive AML Cells by Cooperatively Inhibiting the mTORC1/4EBP1/S6K/Mcl-1 Pathway. AB - FLT3-ITD and FLT3-TKD are the most frequent tyrosine kinase mutations in acute myeloid leukemia (AML), with the former conferring a poor prognosis. We have recently revealed that FLT3-ITD confers resistance to the PI3K/AKT pathway inhibitors by protecting the mTORC1/4EBP1/Mcl-1 pathway through Pim kinases induced by STAT5 activation in AML. The proteasome inhibitor bortezomib has recently been reported as a promising agent for treatment of AML. Here, we show that the proteasome inhibitor bortezomib as well as carfilzomib induces apoptosis through the intrinsic pathway more conspicuously in cells transformed by FLT3-TKD than FLT3-ITD. Mechanistically, bortezomib upregulated the stress-regulated protein REDD1 and induced downregulation of the mTORC1 pathway more distinctively in cells transformed by FLT3-TKD than FLT-ITD, while overexpression of Pim-1 partly prevented this downregulation and apoptosis in FLT3-TKD-transformed cells. Genetic enhancement of the REDD1 induction or pharmacological inhibition of STAT5, Pim kinases, mTORC1, or S6K by specific inhibitors, such as pimozide, AZD1208, PIM447, rapamycin, and PF-4708671, accelerated the downregulation of mTORC1/Mcl-1 pathway to enhance bortezomib-induced apoptosis in FLT3-ITD expressing cells, including primary AML cells, while overexpression of Mcl-1 prevented induction of apoptosis. Thus, FLT3-ITD confers a resistance to the proteasome inhibitors on AML cells by protecting the mTORC1/Mcl-1 pathway through the STAT5/Pim axis, and inhibition of these signaling events remarkably enhances the therapeutic efficacy. PMID- 30472493 TI - The CD25+/CD4+ T cell ratio and levels of CII, CIX and CXI antibodies in serum may serve as biomarkers of pristane-induced arthritis in rats and Rheumatoid Arthritis in humans. AB - OBJECTIVE: Collagen antibodies in serum are involved in the pathogenesis of Rheumatoid Arthritis (RA). The objective of this study was to identify the subtype of collagen antibodies and T cell subtype distribution in pristane induced arthritis (PIA) and to clarify their roles in the initiation and maintenance of arthritis. METHODS: Arthritis was induced in Dark Agouti (DA) rats by injection of pristane. The severity was evaluated by macroscopic and microscopic score systems. The alteration of CD25+/CD4+ T cell ratio in rats was detected by flow cytometry. Collagen type II (CII), CIX, or CXI antibody in serum was determined by ELISA. The levels of Nitric oxide (NO) and tartrate-resistant acid phosphatase (TRAP) were measured by kits. RESULTS: The serum levels of CII, CIX, CXI antibodies were significantly increased in RA patients while slightly increased in PIA rats. The ratio of CD25+/CD4+ T cells was significantly higher in RA rats than that in the control group. The serum levels of NO and TRAP in PIA rats and RA patients were higher than that in the control groups, which suggested that the activity of osteoclast was increased in RA. CONCLUSION: The ratio of CD25+/CD4+ T cells plays a pivotal role in the development of PIA. The serum levels of NO and TRAP are inflammatory and osteoclast activity indicators. The serum levels of CII, CIX and CXI antibodies may serve as the clinical diagnostic indicators. These findings are important to our understanding of the pathogenesis of RA, and may provide biomarkers of RA diagnosis and therapeutic targets for the treatment of RA. PMID- 30472494 TI - Energetically wasteful wave reflections due to impedance mismatching in hypertension and their reversal with vasodilator: Time and frequency domain evaluations. AB - BACKGROUND: Increased pulse wave reflections in hypertension arise due to impedance mismatching and the effective energy transmission to the vasculature is compromised. Their quantification in the time and the frequency domains are compared and the beneficial effect of vasodilator is evaluated in the study. METHODS: A simple, fast time domain method for the resolution of aortic pressure and flow pulses into their forward and reflected components is presented, together with frequency domain reflection coefficient and impedance calculations. Both steady and pulsatile energy components are quantified during induced hypertension (HBP) and subsequent vasodilator (VSD, nitroprusside) treatment in experimental mongrel dogs. Corresponding power generation and usage are also analyzed. RESULTS: Characteristic impedance and peripheral resistance were not statistically different between the methods (p > 0.05). Time domain reflection coefficient identified significant differences among control, HBP and VSD groups (p < 0.05) while the frequency domain method did not adequately differentiate the control and the HBP groups. Impedance calculations were similar between the two methods. Frequency domain calculations of total, mean and pulsatile power were, on average, 32.6 mW higher, 12.8 mW lower and 45.4 mW higher than their respective time domain calculations (p < 0.05). Hypertension increased energy consumption, on average, by 88.8 mJ (p < 0.05) and subsequent VSD decreased the energy consumption, on average, by 99.4 mJ (p < 0.05). CONCLUSION: Impedance mismatching in hypertension which leads to increased wave reflections and significantly increased pulsatile work, could be effectively alleviated through vasodilator therapy. This can be quantified through the time-domain method, which is fast and equally accurate as the time-consuming frequency domain approach. The time domain method to quantify crucial parameters such as stroke work cannot be readily determined using the frequency domain methods. PMID- 30472495 TI - Importance of the heart vector origin point definition for an ECG analysis: The Atherosclerosis Risk in Communities (ARIC) study. AB - AIM: Our goal was to investigate the effect of a global XYZ median beat construction and the heart vector origin point definition on predictive accuracy of ECG biomarkers of sudden cardiac death (SCD). METHODS: Atherosclerosis Risk In Community study participants with analyzable digital ECGs were included (n = 15,768; 55% female, 73% white, mean age 54.2 +/- 5.8 y). We developed an algorithm to automatically detect the heart vector origin point on a median beat. Three different approaches to construct a global XYZ beat and two methods to locate origin point were compared. Global electrical heterogeneity was measured by sum absolute QRST integral (SAI QRST), spatial QRS-T angle, and spatial ventricular gradient (SVG) magnitude, azimuth, and elevation. Adjudicated SCD served as the primary outcome. RESULTS: There was high intra-observer (kappa 0.972) and inter-observer (kappa 0.984) agreement in a heart vector origin definition between an automated algorithm and a human. QRS was wider in a median beat that was constructed using R-peak alignment than in time-coherent beat (88.1 +/- 16.7 vs. 83.7 +/- 15.9 ms; P < 0.0001), and on a median beat constructed using QRS-onset as a zeroed baseline, vs. isoelectric origin point (86.7 +/- 15.9 vs. 83.7 +/- 15.9 ms; P < 0.0001). ROC AUC was significantly larger for QRS, QT, peak QRS-T angle, SVG elevation, and SAI QRST if measured on a time-coherent median beat, and for SAI QRST and SVG magnitude if measured on a median beat using isoelectric origin point. CONCLUSION: Time-coherent global XYZ median beat with physiologically meaningful definition of the heart vector's origin point improved predictive accuracy of SCD biomarkers. PMID- 30472496 TI - Sex-specific long-term blood pressure regulation: Modeling and analysis. AB - Hypertension is a global health challenge: it affects one billion people worldwide and is estimated to account for >60% of all cases or types of cardiovascular disease. In part because sex differences in blood pressure regulation mechanisms are not sufficiently well understood, fewer hypertensive women achieve blood pressure control compared to men, even though compliance and treatment rates are generally higher in women. Thus, the objective of this study is to identify which factors contribute to the sexual dimorphism in response to anti-hypertensive therapies targeting the renin angiotensin system (RAS). To accomplish that goal, we develop sex-specific blood pressure regulation models. Sex differences in the RAS, baseline adosterone level, and the reactivity of renal sympathetic nervous activity (RSNA) are represented. A novel aspect of the model is the representation of sex-specific vasodilatory effect of the bound angiotensin II type two receptor (AT2R-bound Ang II) on renal vascular resistance. Model simulations suggest that sex differences in RSNA are the largest cause of female resistance to developing hypertension due to the direct influence of RSNA on afferent arteriole resistance. Furthermore, the model predicts that the sex-specific vasodilatory effects of AT2R-bound Ang II on renal vascular resistance may explain the higher effectiveness of angiotensin receptor blockers in treating hypertensive women (but not men), compared to angiotensin converting enzyme inhibitors. PMID- 30472497 TI - Genetic algorithm for assigning weights to gene expressions using functional annotations. AB - A method, named genetic algorithm for assigning weights to gene expressions using functional annotations (GAAWGEFA), is developed to assign proper weights to the gene expressions at each time point. The weights are estimated using functional annotations of the genes in a genetic algorithm framework. The method shows gene similarity in an improved manner as compared with other existing methods because it takes advantage of the existing functional annotations of the genes. The weight combination for the expressions at different time points is determined by maximizing the fitness function of GAAWGEFA in terms of the positive predictive value (PPV) for the top 10,000 gene pairs. The performance of the proposed method is primarily compared with Biweight mid correlation (BICOR) and original expression values for the six Saccharomyces cerevisiae datasets and one Bacillus subtilis dataset. The utility of GAAWGEFA is shown in predicting the functions of 48 unclassified genes (using p-value cutoff 10-13) from Saccharomyces cerevisiae microarray data where the expressions are weighted using GAAWGEFA and are clustered using k-medoids algorithm. The related code along with various parameters is available at http://sampa.droppages.com/GAAWGEFA.html. PMID- 30472498 TI - Single-shot real-time sub-nanosecond electron imaging aided by compressed sensing: Analytical modeling and simulation. AB - Bringing ultrafast (nanosecond and below) temporal resolution to transmission electron microscopy (TEM) has historically been challenging. Despite significant recent progress in this direction, it remains difficult to achieve sub-nanosecond temporal resolution with a single electron pulse, in real-time (i.e., duration in which the event occurs) imaging. To address this limitation, here, we propose a methodology that combines laser-assisted TEM with computational imaging methodologies based on compressed sensing (CS). In this technique, a two dimensional (2D) transient event [i.e. (x,y) frames that vary in time] is recorded through a CS paradigm, which consists of spatial encoding, temporal shearing via streaking, and spatiotemporal integration of an electron pulse. The 2D image generated on a camera is used to reconstruct the datacube of the ultrafast event, with two spatial and one temporal dimensions, via a CS-based image reconstruction algorithm. Using numerical simulation, we find that the reconstructed results are in good agreement with the ground truth, which demonstrates the applicability of CS-based computational imaging methodologies to laser-assisted TEM. Our proposed method, complementing the existing ultrafast stroboscopic and nanosecond single-shot techniques, opens up the possibility for single-shot, real-time, spatiotemporal imaging of irreversible structural phenomena with sub-nanosecond temporal resolution. PMID- 30472499 TI - Human skeletal muscle cell atlas: Unraveling cellular secrets utilizing 'muscle on-a-chip', differential expansion microscopy, mass spectrometry, nanothermometry and machine learning. AB - The 'Human Cell Atlas' project has been launched to obtain a comprehensive understanding of all cell types, the fundamental living units that constitute the human body. This is a global partnership and effort involving experts from many disciplines, from computer science, engineering to medicine, and is supported by several private and public organizations, among them, the Chan Zuckerberg Foundation, the National Institutes of Health, and Google, that will greatly benefit humanity. Nearly 37 trillion cells of various shapes, sizes, and composition, are precisely organized to constitute the human body. Humans, like all other living organisms, are dynamic, and therefore a comprehensive understanding of different cells in their various dynamic states is required to provide a reference map for the early diagnosis and various preventive approach to disease, and in the development of precision therapeutics. Skeletal muscles being the most abundant tissue and the largest locomotor and metabolic organ in the human body, requires a global understanding of its structure, composition, and function. The objective of creating a 'Human Skeletal Muscle Cell Atlas', necessitates therefore a comprehensive understanding of the emergent properties of skeletal muscle cell growth, development, structure, function and chemistry, under conditions of activity and inactivity. To achieve this objective would require a very precise yet rapid and cost-effective approach of combined multimodal imaging, including our new and novel 'Differential Expansion Microscopy', our 'Nanoscale Thermometry', combined with 'Mass Spectrometry', 'Motor Protein Motility Assay' and 'Machine Learning' tools. PMID- 30472502 TI - Proteomic profile of histotroph during early embryo development in mares. AB - There is a complex cascade involving proteins during early embryo development and maternal recognition, which is very important for maintenance of a conceptus. The aim of this study was to compare proteomic profile of uterine fluid after ovulation in pregnant and cyclic mares. In the first cycle, samples of uterine fluid of 30 cyclic mares were collected on days 7 (n = 10), 10 (n = 10) and 13 (n = 10) post ovulation and constituted the Cyclic group. In the second cycle, the same mares were bred to a fertile stallion. At days 7, 10 and 13 uterine fluid samples were collected. Immediately after sample collection, the mare's uteri were flushed, and those with an embryo recovered were assigned to the Pregnant group. Of the 30 mares flushed embryos were recovered from 6 mares on day 7, 6 on day 10 and 6 on day 13. Samples from the mares without embryo recovery were excluded from both groups. The uterine fluid samples were processed by two dimensional electrophoresis technique followed by matrix assisted laser desorption/ionization time-of-flight/time-of-flight (MALDI-TOF/TOF) mass spectrometry for the identification of relevant protein spots. From a total of 677 detected spots 19 were identified, 13 more abundant in Pregnant group and 6 in Cyclic group. In summary, pregnant and cyclic mares showed proteins with different abundance. Identified proteins were related to the transport of lipids through the embryo capsule, uterine motility, ATP generation, maternal immunological tolerance, cell proliferation, differentiation, metabolism and angiogenesis. Changes in the proteomic profile of uterine fluid during early embryo development in mares were related with the conceptus presence, suggesting that these alterations may be important for conceptus development and maternal recognition of pregnancy. PMID- 30472503 TI - The mediating role of parental satisfaction between marital satisfaction and perceived family burden among parents of children with psychiatric disorders. AB - Parents of children and adolescents with psychiatric disorders may experience perceived family burden. Although previous research has extensively addressed the contribution of clinical factors to perceived family burden, the contribution of marital and parental factors to family burden has rarely been studied in the context of parents whose children have a psychiatric disorder. The current study therefore examined the associations between marital satisfaction, parental satisfaction, parental efficacy, and perceived family burden among parents of children with psychiatric disorders (age range 5-14). Sixty-three parents of children who were hospitalized in a psychiatric hospital completed several questionnaires on marital satisfaction, parental satisfaction, parental efficacy, and perceived family burden. Results supported a mediating role of parental satisfaction (mediation effect size beta = -0.2, p < 0.05) but not parental efficacy (mediation effect size beta = 0.02, NS) between marital satisfaction and perceived family burden. Implications include the need to further study the parental experience during a child's psychiatric hospitalization and other possible factors related to burden. We would also recommend including family and marital therapy as part of routine care in this context. PMID- 30472505 TI - Subjective age and depressive symptoms among Chinese older adults: A moderated mediation model of perceived control and self-perceptions of aging. AB - Although subjective age has been shown to play an important role in older adults' experiences of depressive symptoms, the mediating and moderating mechanisms underlying this relationship have not been adequately examined. The present study aimed to investigate the mediating role perceived control plays between subjective age and depressive symptoms, as well as the moderating role self perceptions of aging plays in this indirect relationship. To examine this, a cross-sectional study was conducted with 609 Chinese older adults, who completed measures of subjective age, perceived control, self-perceptions of aging, and depressive symptoms. The results indicated that: (1) possessing a younger subjective age is significantly associated with less depressive symptoms; (2) perceived control partially mediates the relationship between subjective age and depressive symptoms; and (3) the indirect effect of subjective age on depressive symptoms, through perceived control, is moderated by self-perceptions of aging, while the mediated path is stronger for older adults with less favorable self perceptions of aging. The findings underscore the importance of identifying the mechanisms that moderate the mediated paths between subjective age and depressive symptoms. PMID- 30472504 TI - Traumatic experiences and cognitive profiles of schizophrenia cases influenced by the BDNF Val66met polymorphism. AB - The association of early trauma exposure with current cognition was examined in a research series of 56 schizophrenia cases with respect to the BDNF Val66Met polymorphism (rs6265, Val66Val, Val66Met, Met66Met), as met allele carriers have reduced neurotrophic activity. The Perceptual Organization Index had a significant negative correlation with trauma exposures only in met carriers, including early physical abuse, general trauma after age 18 years, and physical abuse. Within the Val66Val subgroup, there were no significant correlations between WAIS indices and traumatic experiences. PMID- 30472501 TI - Characterizing Trastuzumab-Induced Alterations in Intratumoral Heterogeneity with Quantitative Imaging and Immunohistochemistry in HER2+ Breast Cancer. AB - The purpose of this study is to investigate imaging and histology-based measurements of intratumoral heterogeneity to evaluate early treatment response to targeted therapy in a murine model of HER2+ breast cancer. BT474 tumor-bearing mice (N = 30) were treated with trastuzumab or saline and imaged longitudinally with either dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) or 18F-fluoromisonidazole (FMISO) positron emission tomography (PET). At the imaging study end point (day 4 for MRI or 7 for PET), each tumor was excised for immunohistochemistry analysis. Voxel-based histogram analysis was performed on imaging-derived parametric maps (i.e., Ktrans and ve from DCE-MRI, SUV from 18F FMISO-PET) of the tumor region of interest to measure heterogeneity. Image processing and histogram analysis of whole tumor slice immunohistochemistry data were performed to validate the in vivo imaging findings. Trastuzumab-treated tumors had increased heterogeneity in quantitative imaging measures of cellularity (ve), with a mean Kolmogorov-Smirnov (K-S) distance of 0.32 (P = .05) between baseline and end point distributions. Trastuzumab-treated tumors had increased vascular heterogeneity (Ktrans) and decreased hypoxic heterogeneity (SUV), with a mean K-S distance of 0.42 (P < .01) and 0.46 (P = .047), respectively, between baseline and study end points. These observations were validated by whole-slice immunohistochemistry analysis with mean interquartile range of CD31 distributions of 1.72 for treated and 0.95 for control groups (P = .02). Quantitative longitudinal changes in tumor cellular and vascular heterogeneity in response to therapy may provide evidence for early prediction of response and guide therapy for patients with HER2+ breast cancer. PMID- 30472506 TI - Complex PTSD and intergenerational transmission of distress and resilience among Tutsi genocide survivors and their offspring: A preliminary report. AB - The research on survivors of genocide has focused on PTSD, but complex PTSD (CPTSD) and its potential effect on intergenerational transmission are understudied. This study assessed complex PTSD and resilience among Tutsi genocide survivors (n = 60, mean age = 52.27 [SD = 6.27]) and their offspring (n = 60, mean age = 21.21 [SD = 1.78]). Offspring of parents suffering from PTSD or CPTSD reported more secondary traumatization symptoms relative to offspring of parents without PTSD (p < 0.0001). Moreover, parental CPTSD was related to lower resilience among both survivors and offspring (p < 0.0001). The current findings suggest that parental CPTSD may have broader influences manifested in offspring lower resilience. PMID- 30472507 TI - Gender differences among homicide offenders with schizophrenia in Hunan Province, China. AB - This study aimed to understand the demographic, clinical and criminological characteristics of Chinese homicide offenders with schizophrenia from a gender based perspective. Information on all homicide offenders with schizophrenia who received forensic psychiatric assessment between 2010 and 2016 in Hunan Province, China, was systematically retrieved (n = 669). Gender differences in the above characteristics were analyzed, and independent correlates of homicide were explored. The male to female ratio of homicide offenders was about 4:1. Proportionally more males were single, unemployed and younger when committing their first crime than was apparent in females. Male perpetrators were more often influenced by delusions. Females were more likely to target their close family members. For males, living in rural areas and having a family history of mental disorder were positively associated with homicide, while having a criminal history and being unemployed were negatively associated. For females, younger age was positively, while being unmarried and unemployment were negatively associated with homicide. Our results indicate significant gender differences among Chinese homicide offenders with schizophrenia in demographic, clinical and criminological characteristics and in independent correlates of homicide. Further research in this field, especially aims at determining risk factors for crime in this population, should take the gender differences into account. PMID- 30472508 TI - Neutrophil/lymphocyte, platelet/lymphocyte and monocyte/lymphocyte ratios in different stages of schizophrenia. AB - The inflammation hypothesis is frequently mentioned in the pathogenesis of schizophrenia. The objective of this study was to compare inflammation markers during relapse and remission periods in patients with schizophrenia. Complete blood count (CBC) of 105 patients diagnosed with schizophrenia who were hospitalized due to psychotic relapse at Ondokuz Mayis University Medical Faculty Psychiatry Service between 2012 and 2016 and 105 healthy control subjects were retrospectively analyzed. Relapse CBC was also compared with remission CBC of the same patients and with the control group. Neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and monocyte/lymphocyte ratio (MLR) of the patients during relapse period were found to be significantly higher when compared with the control group. MLR and PLR were found to be significantly higher in the remission period when compared with the control group. NLR, PLR and MLR values were significantly increased in the relapse period when compared with the remission period of the same patients. The findings of our study support the inflammation hypothesis of schizophrenia. As a result of our study, we believe MLR and PLR are important markers. There is a decrease in inflammatory response in schizophrenia following treatment. PMID- 30472500 TI - Hyperpolarized 13C MRI: Path to Clinical Translation in Oncology. AB - This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) 13C magnetic resonance imaging's (MRI's) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized 13C MRI in 2011, preclinical studies involving [1-13C]pyruvate as well a number of other 13C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1-13C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP 13C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind. PMID- 30472509 TI - The impact of past trauma on psychological distress among Chinese students: The roles of cognitive distortion and alexithymia. AB - Past traumatic events are distressing experiences which can result in the emergence of posttraumatic stress disorders (PTSD) and other psychological symptoms among university students. However, little is known as to whether or not cognitive distortion and alexithymia would influence the severity of these distress outcomes. This study examined a cognitive-emotional framework depicting potential roles that cognitive distortion and alexithymia could play in influencing the relationship between past trauma and psychiatric co-morbidities among university students in China. One thousand one hundred and eleven participants completed the PTSD Checklist for DSM-5, Cognitive Distortion Scale (CDS), Toronto Alexithymia Scale (TAS-20), and General Health Questionnaire (GHQ 28). Results indicated that PTSD following past trauma was significantly associated with increased psychiatric co-morbidities after controlling for covariates. Both alexithymia and distorted cognition mediated the association between PTSD and psychiatric co-morbidities. To conclude, university students can develop PTSD from past trauma and other mental health problems. The severity of psychological distress can be influenced by their distorted perceptions of themselves, the world, and the future, as well as their ability to identify, describe, and express distressing emotions. PMID- 30472510 TI - Course, outcome and diagnosis stability of early-onset schizophrenia in Yunnan Province, China-a three years follow-up study. AB - The aim of the study was to describe diagnostic stability and psychosocial outcomes of subjects with early-onset schizophrenia (EOS). All the subjects who had been hospitalized in the Department of Psychiatry of the First Affiliated Hospital of Kunming Medical University between January 2011 and July 2015 with the diagnosis of International Classification of Diseases (ICD)-10 defined schizophrenia, and discharged from the hospital for more than 12 months were enrolled to the study. The Mini International Neuropsychiatric Interview was applied for life-time ICD -10 diagnoses, and Personal and Social Performance (PSP) for global function evaluation. Altogether 249 patients were targeted for follow-up, in which 101 were followed up and the dropout rate was 59.4%. After average 37.2 +/- 16.2 months, 92 patients (including 1 death) were still met the ICD-10 diagnosis of schizophrenia (F20). In terms of global functioning, 48.5% of patients had good outcome, 43.6% had moderate outcome, and 7.9% had poor outcome. A relatively high diagnostic stability of ICD-10 defined schizophrenia was obtained in the current study .Moreover, our results draw a much more optimistic picture of the outcome for EOS than what has previously been reported from Western counties. PMID- 30472511 TI - Elevated brain-derived neurotrophic factor (BDNF) serum levels in an acute episode of schizophrenia in polish women: Correlation with clinical and metabolic parameters. AB - Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of psychiatric disorders. Schizophrenia is associated with metabolic abnormalities and BDNF regulates energy homeostasis and glucose metabolism in peripheral tissues. The aim of this study was to examine serum levels of BDNF in schizophrenic women during 8 weeks of treatment and control group, and its correlation with clinical and metabolic parameters. The study was performed on a group of 96 women: 55 diagnosed with paranoid schizophrenia according to DSM-IV criteria, and 41 healthy controls. Positive and Negative Syndrome Scale (PANSS) was used to assess the severity of schizophrenia. BDNF serum levels and metabolic parameters: fasting serum glucose, total cholesterol, triglyceride (TG), high density lipoprotein (HDL-C), low-density lipoprotein (LDL-C) were measured at baseline and week 8 of treatment. BDNF serum levels were significantly elevated in medicated patients with schizophrenia comparing to controls. After 8 weeks of antipsychotic treatment, BDNF levels did not significantly change. Increase in TG and TG/HDL-C ratio and a decrease in HDL-C was detected in medicated patients. Correlation between BDNF and lipid profile as well as symptoms severity was found. In our study we detected abnormalities in BDNF levels and lipid profile in medicated schizophrenic women in Polish population. PMID- 30472512 TI - Adolescent type D personality and social networking sites addiction: A moderated mediation model of restorative outcomes and affective relationships. AB - Type D personality denotes the joint tendency towards negative affectivity and social inhibition. The recent research has regarded Type D personality as a risk factor of social networking sites addiction. The current study aimed to test whether restorative outcomes would mediate the relation between Type D personality and social networking sites addiction, and whether affective relationships would moderate simultaneously the mediating process. A valid sample of 679 adolescents (mean age = 13.29 +/- 0.77 years) participated in our paper and-pencil survey. Results showed that, after controlling for age and gender, Type D personality positively correlated with social networking sites addiction, and it increased social networking sites addiction via escalating participants' restorative outcomes. Moreover, only affective relationships with friends moderated the mediating effect: for adolescents with low levels of affective relationships with friends, the indirect effect of Type D personality on social networking sites addiction was significant; contrarily, the indirect effect for high levels of affective relationships with friends was non-significant. The current study indicated that Type D personality as a risk factor interacted with other factors (e.g., affective relationships with friends) to contribute to adolescent social networking sites addiction. The limitations and practical implications were discussed. PMID- 30472513 TI - A complex auxiliary: IL-17/Th17 signaling during type 1 diabetes progression. AB - Type 1 diabetes (T1D) is an autoimmune disease centered around the loss of the beta cells of the islets of Langerhans, and consequent inability of the islets to produce the insulin necessary to maintain glycemic control. While most therapeutic approaches have been centered on insulin replacement, newer approaches to target the underlying immune response have become an area of focus. However, the immune landscape in T1D is extremely complex, and the roles played by individual cytokines during disease progression are incompletely understood, making the development of immunotherapies very difficult. In this review, we discuss the complex auxiliary role played by IL-17, both around the islet and in peripheral tissues such as the gut and kidney, which might influence T1D progression. Through our re-analysis of the key factors involved IL-17 signaling in recently published single-cell sequencing and sorted-cell bulk sequencing datasets, we find supporting evidence for the general existence of the signaling apparatus in islet endocrine cells. We also explore the emerging evidence of IL 17 serving as an influential factor in diabetic complications that affect distal tissues. While anti-IL-17 therapies are emerging as an option for psoriasis and other autoimmune disorders, we highlight here a number of questions that would need to be addressed before their potential applicability to treating T1D can be fully evaluated. PMID- 30472514 TI - Identification of the minimal region of peptide derived from ADP-ribosylation factor1 (ARF1) that inhibits IgE-mediated mast cell activation. AB - Mast cells play a pivotal role in allergic reactions and inflammations. Aggregation of the high affinity IgE receptor (FcepsilonRI) eventually leads to the release of granule components such as histamine, as well as the de novo synthesis of inflammatory cytokines and lipid mediators. These substances are involved in the development of allergy and inflammation. Therefore, efficient inhibitors of mast cell activation would be therapeutically beneficial. We previously demonstrated that the synthetic peptide derived from the NH2-terminal region (2-17: GNIFANLFKGLFGKKE) of a small GTPase ARF1 (ADP-ribosylation factor1) inhibited FcepsilonRI-induced mast cell degranulation. However, detailed structure-activity relationship study of NH2-terminal portion of ARF1 peptide has not been done. In addition, it is still unclear whether the NH2-terminal peptide of ARF1 suppresses FcepsilonRI-induced production of cytokines and lipid mediators such as leukotriene C4 (LTC4) from mast cells. Here we show that amino acid residues K10-K16 are necessary for ARF1 peptide to efficiently inhibit FcepsilonRI-induced activation of bone marrow-derived mast cells (BMMCs), indicated by decreased mast cell degranulation, cytokine secretion and leukotriene release. Furthermore, we show that ARF1 peptide inhibits IgE-mediated passive cutaneous anaphylaxis reaction. Our results suggest that the peptide derived from ARF1 could be developed into a novel anti-allergic agent for therapeutic intervention in allergy and mast cell-related pathologies. PMID- 30472515 TI - How neighborhoods matter in fatal interactions between police and men of color. AB - This article addresses the concern that death by legal intervention is a health outcome disproportionately experienced by boys and men of color, and predicated on the quality of the locations in which encounters with law enforcement occur. Using a more comprehensive cross-verified sample of police homicides from online databases and a nationally representative sample of law enforcement agencies, this study examines whether neighborhood social disorganization, minority threat, and defense of inequality theories help explain the odds that males of color will have a fatal interaction with police (FIP). There are several noteworthy results. First, in support of the defense of inequality thesis, we found that income inequality within the area in which a FIP occurred is related to increased relative odds of fatal injury for males of color and Hispanic males. Second, consistent with the minority threat thesis, we found low levels of racial segregation dramatically reduced the odds of a FIP for Black males while higher levels of segregation increased the odds for Hispanic males. Third, Hispanic males were over 2.6 times as likely as others to be killed by officers from agencies with relatively higher percentages of Hispanic officers. We conclude the study with a discussion of its implications for research and policy. PMID- 30472516 TI - Enabling local public health adaptation to climate change. AB - Local public health authorities often lack the capacity to adapt to climate change, despite being on the 'front lines' of climate impacts. Upper-level governments are well positioned to create an enabling environment for adaptation and build local public health authorities' capacity, yet adaptation literature has not specified how upper-level governments can build local-level adaptive capacity. In this paper we examine how federal and regional governments can contribute to enabling and supporting public health adaptation to climate change at the local level in federal systems. We outline the local level's self-assessed adaptive capacity for public health adaptation in Canadian and German comparative case studies, in terms of funding, knowledge and skills, organizations, and prioritization, drawing upon 30 semi-structured interviews. Based on interviewees' recommendations and complemented by scientific literature, we develop a set of practical measures that could enable or support local-level public health adaptation. We find that adaptive capacity varies widely between local public health authorities, but most report having insufficient funding and staff for adaptation activities. We propose 10 specific measures upper-level governments can take to build local public health authorities' capacity for adaptation, under the interrelated target areas of: building financial capital; developing and disseminating usable knowledge; collaborating and coordinating for shared knowledge; and claiming leadership. Federal and regional governments have an important role to play in enabling local-level public health adaptation, and have many instruments available to them to fulfill that role. Selecting and implementing measures to enable local public health authorities' adaptive capacity will require tailoring to, and consideration, of the local context and needs. PMID- 30472517 TI - Aging well in an aging world: The impact of material conditions, culture, and societal disruptions. AB - The world's population is aging, but quality of life in older adulthood is unequally distributed. Using measures of self-rated health and subjective well being from Wave 6 (2010-2014) of the World Values Survey, we examine the individual and social factors that shape older adulthood in 57 countries. In addition to examining inequalities in health and well-being for older adults between countries, we examine the differences between older (50 and over) and younger adults (under 50) within countries. Aging well is not simply a fact of country wealth or personal income. We conduct multi-level analyses to determine which individual-level factors and which country-level factors impact health and well-being, and how these differ across age. We consider three sets of country level factors: material conditions, culture, and societal disruptions. Overall, we find that older adults feel less healthy than younger adults, but older adults in countries that have experienced a transition to independence during their adulthood feel much less healthy than their under-50 counterparts. The same is true for life satisfaction. Although older adults do not necessarily feel more dissatisfied with their lives than do younger adults, they are much more dissatisfied in countries that transitioned. We conclude with a discussion of the implications of how altered life expectations affect aging. PMID- 30472518 TI - An investigation of the effect of accessibility to General Practitioner services on healthcare utilisation among older people. AB - Equity in access to healthcare services is regarded as an important policy goal in the organisation of modern healthcare systems. Physical accessibility to healthcare services is recognised as a key component of access. Older people are more frequent and intensive users of healthcare, but reduced mobility and poorer access to transport may negatively influence patterns of utilisation. We investigate the extent to which supply-side factors in primary healthcare are associated with utilisation of General Practitioner (GP) services for over 50s in Ireland. We explore the effect of network distance on GP visits, and two novel access variables: an estimate of the number of addresses the nearest GP serves, and the number of providers within walking distance of a person's home. The results indicate that geographic accessibility to GP services does not in general explain differences in the utilisation of GP services in Ireland. However, we find that the effect of the number of GPs is significant for those who can exercise choice in selecting a GP, i.e., those without public health insurance. For these individuals, the number of GPs within walking distance exerts a positive and significant effect on the utilisation of GP services. PMID- 30472520 TI - Severe atypical hand-foot-and-mouth disease in adults due to coxsackievirus A6: Clinical presentation and phylogenesis of CV-A6 strains. AB - BACKGROUND: Typically, hand-foot-and-mouth disease (HFMD) is a mild childhood illness associated with coxsackievirus (CV)-A16, CV-A6, enterovirus (EV)-A71. OBJECTIVES: To identify the viral agents associated with severe cases of atypical HFMD in Italy. STUDY DESIGN: Epidemiologically unrelated cases of severe atypical HFMD admitted to the Emergency Room (ER) of IRCCS San Martino IST (Genoa, Italy) in 2014-2016 were investigated. Serologic screening for viral positivity was performed against exanthem-inducing agents. Ten cases with serology indicative of recent EV infection were selected. Molecular assays were used to detect viral genomes in blood [EVs, Parvovirus B19 (PVB19), herpesviruses (CMV; EBV, HHV-6, 7, -8)]. RESULTS: CV-A6 was detected in 10 cases of severe atypical HFMD. Two cases were also infected with PVB19. Herpesviruses were not detected. Phylogenetic analysis mapped the CV-A6 strains into a single cluster related to two recent isolates from a German and an Asian child. Fever, systemic symptoms, severe vasculitis-like rash, and enanthem were predominant at presentation. Spontaneous recovery occurred in 1-3 weeks. CONCLUSIONS: CV-A6 is emerging as a frequent cause of severe atypical HFMD in Italian adults. This viral agent is disseminating worldwide. Dermatologists must identify the manifold alterations caused by EVs and understand the diagnostic power of current virology methods. PMID- 30472519 TI - "So that's why I'm scared of these methods": Locating contraceptive side effects in embodied life circumstances in Burundi and eastern Democratic Republic of the Congo. AB - Contraceptive side effects (SE) are often portrayed as either unproblematic trade offs for pregnancy prevention or misconceptions and fears that negatively affect individuals' contraceptive decisions. Little attention is given, however, to wider, socially-rooted meanings and rationales for these feared and experienced SE. Through inductive analysis of in-depth interviews conducted with women and men from rural Burundi and South Kivu province, Democratic Republic of the Congo between 2013 and 2016, we locate contraceptive SE narratives in individuals' broader and changing life circumstances. We extracted two conceptual categories related to SE from participants' narratives: 1) bodily symptoms attributed to modern contraception; and 2) social meanings of SE in everyday life. We then situate these narratives in context - sources of knowledge on SE, barriers to addressing SE, and individuals/couples' life circumstances - to understand their embodied realities. Using Krieger's ecosocial theory, our findings suggest that in rural contexts of poverty, uncertainty and power inequities the empirical realities of SE are legitimate concerns stemming from actual or anticipated bodily symptoms located in the embodied life circumstances of individuals and couples. PMID- 30472521 TI - Mce-associated protein Rv0177 alters the cell wall structure of Mycobacterium smegmatis and promotes macrophage apoptosis via regulating the cytokines. AB - The success of Mycobacterium tuberculosis as a pathogen largely contributes to its ability to infect, modify and persist within the host cells. M. tuberculosis Rv0177 is a gene of the mce1 operon (Mammalian cell entry), encoding a conserved hypothetical protein, essential for M. tuberculosis survival and up-regulated within murine macrophages. To explore its function, Rv0177 was heterologously expressed in M. smegmatis. The recombinant protein was located in the cell wall. M. smegmatis recombinant strain expressing Rv0177 altered sliding motility, its cell wall architecture and the permeability. Moreover, M. smegmatis expressing Rv0177 could up-regulate MCP-1 and downregulate the IL-6 expression in RAW264.7 macrophages in comparison to the control. MS_Rv0177 increased the expression of MCP-1 inducible protein (MCPIP) and a C/EBP homologous protein (CHOP) owing to MCP-1. In addition, the JNK signaling pathway was engaged in the interplay between MS_Rv0177 and macrophages. The macrophage caspase-3 activation and cell apoptosis were induced by the recombinant. This provided novel functional cues for the MCE-associated Rv0177. PMID- 30472522 TI - Celastrol inhibits microglial pyroptosis and attenuates inflammatory reaction in acute spinal cord injury rats. AB - Pyroptosis pathway is closely related to inflammation. However, Celastrol effect on pyroptosis pathway after spinal cord injury (SCI) are poorly understood. We studied the anti-inflammatory and neuroprotective effects of Celastrol on acute spinal cord injury in rats, and its anti-inflammatory effects on lipopolysaccharide (LPS)/ATP-induced microgliosis. Our results show that Celastrol can improve the recovery of hindlimb motor function after SCI in Sprague-Dawley (SD) rats, and reduce the cavity area of spinal cord injury along with the neuronal loss. Celastrol simultaneously reduced the activation of microglia (especially M1 microglia) in the spinal cord, inhibited the pyroptosis related proteins (NLRP3 ASC Caspase-1 GSDMD), reduced the release of TNF-alpha IL 1beta and IL-18 inflammatory factors, and increased the release of IL10 cytokines. In vitro studies showed that Celastrol reduced the toxicity resulting from the administration of LPS with ATP to BV-2 cells, inhibited the pyroptosis related proteins (NLRP3 Caspase-1 GSDMD), and inhibited the release of corresponding inflammatory factors. Finally, Celastrol can inhibit the expression of NFkappaB/p-p65 in vitro and in vivo. Our results show that Celastrol can attenuate the inflammatory response of the spinal cord after SCI, which is associated with inhibition of microglial activation and pyroptosis pathway. Further study to explore the use of Celastrol to treat SCI is warranted. PMID- 30472523 TI - Modulation of the Hoffmann reflex in soleus and medial gastrocnemius during stair ascent and descent in young and older adults. AB - BACKGROUND: The Hoffmann (H) reflex can provide relevant information on spinal control of leg muscles during locomotor tasks in young and older adults. RESEARCH QUESTION: Is the H reflex in the leg muscles differently modulated during stair gait in young and older adults? METHOD: The H reflex in soleus (SOL) and medial gastrocnemius (MG) (normalized to the maximal M-wave amplitude obtained during upright standing; Mmax) was recorded in 19 young and 18 older adults during upright standing, and stair ascent and descent of a 3-step staircase. RESULTS: H reflex amplitude during upright standing was greater in young than older adults for SOL (48% vs. 26% Mmax; p = 0.001) and MG (23% vs. 14% Mmax; p = 0.02). When data were averaged across groups during stair ascent, H-reflex amplitude in SOL increased from 15% Mmax at the beginning of the stance phase to 29% Mmax at mid stance, then decreased to be 4% Mmax in the swing phase. During stair descent, H reflex amplitude was maximal (20% Mmax) at the beginning of the stance phase, decreased to 5% Mmax at the end of stance, and increased to 11% Mmax in the swing phase. Similar adjustments were observed for the H reflex in MG for both ascent and descent. H-reflex modulation during gait cycle (relative to upright standing) is less pronounced in older adults (p < 0.05). However, no difference was observed between subgroups of young and older adults matched for H-reflex amplitude in upright standing. In both groups, H-reflex modulation was not associated with changes in background electromyographic activity. SIGNIFICANCE: This study indicates that the H reflex is modulated within the stair gait cycle during ascent and descent. Although its magnitude was slightly reduced, the overall modulation of the H reflex is not affected in healthy older adults. PMID- 30472524 TI - Dynamic alignment using external socket reaction moments in trans-tibial amputees. AB - BACKGROUND: Prosthetic alignment is used to optimize prosthetic functioning and comfort. Spatio-temporal and kinematic gait parameters are generally observed to guide this process. However, they have been shown to be influenced by compensations, which reduces their sensitivity to changes in alignment. Alternatively, the use of moments working at the base of the prosthetic socket, external socket reaction moments (ESRM), has been proposed to quantify prosthetic alignment. RESEARCH QUESTION: To investigate if a predetermined kinetic alignment criterion, 0Nm averaged over the stance phase, can be used to fine-tune prosthetic alignment. METHODS: 10 transtibial amputees were included in this intervention study. Firstly, their prostheses were aligned using conventional alignment procedures. Kinetic parameters and Socket Comfort Score (SCS) were measured in this initial alignment (IA) condition. Subsequently, the coronal plane ESRM during gait was presented to the prosthetist in real time using a Gait Real-time Analysis Interactive Lab. The prosthetist iteratively adapted the prosthetic alignment towards a predetermined average ESRM during the stance phase of 0 Nm. At the Final Alignment (FA), kinetic parameters and SCS were measured again and a paired sample t-test was performed to compare ESRMs and SCSs between alignments. RESULTS: A significant (p < 0.001) change was found in the absolute coronal plane ESRM (mean +/- SD) from IA (|0.104| +/- 0.058 Nm/kg) to FA (|0.012| +/- 0.015 Nm/kg). In addition a significant (p < 0.001) change of the external coronal adduction knee moments was observed from IA (-0,127 +/- 0.079 Nm/kg) to FA (-0.055 +/- 0.089 Nm/kg), however this change was more variable among participants. On average, no significant (p = 0.37) change in the SCS was observed. SIGNIFICANCE: While this study shows the potential of quantifying and guiding alignment with the assistance of kinetic criteria, it also suggests that a sole reliance on the ESRM as a single alignment criterion might be too simple. PMID- 30472525 TI - Effects of foot pronation on the lower limb sagittal plane biomechanics during gait. AB - BACKGROUND: Increased foot pronation may compromise ankle plantarflexion moment during the stance phase of gait, which may overload knee and hip. RESEARCH QUESTION: This study investigated the influence of increased foot pronation on lower limbs angular displacement, internal moments and power in the sagittal plane and ground reaction force and center of pressure displacement during the stance phase of gait. METHODS: Kinematic and kinetic data of 22 participants (10 women and 12 men) were collected while they walked wearing flat (control condition) and laterally wedged sandals to induce foot pronation (inclined condition). We used principal component analysis for data reduction and dependent t-test to compare differences between conditions with alpha = 0.05. RESULTS: The inclined condition increased forefoot range of motion (p < 0.001; effect size = 0.73); increased ankle plantarflexion angle (p < 0.001; effect size = 0.96); reduced ankle plantarflexion moment in mid and terminal stance phases and delayed and increased ankle plantarflexion moment in late stance (p < 0.001; effect size = 0.72); increased range of ankle power during late stance (p = 0.006; effect size = 0.56); reduced knee range of moment (p < 0.001; effect size = 0.76); increased range of knee power in early stance and reduced knee power generation in late stance (p = 0.005; effect size = 0.56); reduced the anterior displacement of the center of pressure (p < 0.001; effect size = 0.82) and increased the ground reaction force in the anterior direction (p = 0.003; effect size = 0.60). SIGNIFICANCE: Increased foot pronation compromises lower limb mechanics in the sagittal plane during the stance phase of gait. These findings are explained by the fact that foot pronation increases foot segments flexibility and compromises foot lever arm function during the stance of gait. PMID- 30472526 TI - Survival of amyotrophic lateral sclerosis patients after admission to the intensive care unit for acute respiratory failure: an observational cohort study. AB - PURPOSE: Amyotrophic lateral sclerosis (ALS) entails a risk of acute respiratory failure (ARF). The decision to admit such patients to the intensive care unit (ICU) is difficult given the inexorable prognosis of ALS. To fuel this discussion, this study describes the ICU and post-ICU survival of ALS-related ARF. MATERIAL AND METHODS: Retrospective cohort analysis over 10 years (university hospital setting, ALS reference center). RESULTS: Of 90 patients (66 men, median age: 67 [IQR 59-71], median interval since ALS diagnosis: 26.5 months [14-53], ALSFRS-R: 19 [12-30], bulbar signs 73%), 48 were managed by noninvasive ventilation (NIV) only, 7 were already tracheotomized upon admission, 12 were tracheotomized during the ICU stay (advance care planning project), 18 were already intubated before admission, 5 received oxygen and physiotherapy only. Median ICU stay was 4 days [2-9] with 20% mortality. Median hospital stay was 10 days [5-22] with 33% mortality. The 3-month and one year mortality wer 46% and 71%. Hospital mortality was higher in patients with more severe respiratory acidosis and higher simplified acute physiology scores on admission. CONCLUSIONS: The prognosis of ALS-related ARF requiring ICU admission resembles that of ARF complicating other conditions with high short-term mortality (e.g. lung cancer). PMID- 30472527 TI - Influence of age on ECT efficacy in depression and the mediating role of psychomotor retardation and psychotic features. AB - OBJECTIVE: To investigate whether older age predicts a higher efficacy of electroconvulsive therapy (ECT) in severely depressed patients. Also, to analyze whether psychomotor disturbance and/or psychotic features might explain the potential higher efficacy of ECT in older age. METHOD: A total of 96 patients with major depressive disorder treated with bilateral ECT were evaluated. The 17 item HAM-D and the MADRS were used to evaluate the efficacy of ECT and time to remission, respectively. Psychomotor disturbance was defined according the HAM-D. RESULTS: Middle-aged (MA; 50-70 years) and older-aged (OA; >=70 years) patients had a non-significant larger symptom reduction compared with young-aged (YA; <50 years) patients. Medium effect size was found in favor of MA (d = 0.44) and small effect size in favor of OA (d = 0.30), when compared to YA. Patients with psychotic features and patients with psychomotor retardation had a significantly larger symptom reduction (p < 0.001 and p = 0.005, respectively; d = 0.88 and d = 0.66, respectively). The association between age and ECT efficacy is mediated by psychomotor retardation (p = 0.049) and in lesser extent by psychotic features (p = 0.071). CONCLUSION: The results show that psychomotor retardation and psychotic features are strong predictors of ECT efficacy and explain the association between age and ECT efficacy. Instead of focusing on the age of a patient, clinicians should focus on the presence of psychomotor disturbances and psychotic features of depression, when considering ECT treatment. PMID- 30472528 TI - Bicycle helmet wearing is associated with closer overtaking by drivers: A response to Olivier and Walter, 2013. AB - There is a body of research on how driver behaviour might change in response to bicyclists' appearance. In 2007, Walker published a study suggesting motorists drove closer on average when passing a bicyclist if the rider wore a helmet, potentially increasing the risk of a collision. Olivier and Walter re-analysed the same data in 2013 and claimed helmet wearing was not associated with close vehicle passing. Here we show how Olivier and Walter's analysis addressed a subtly, but importantly, different question than Walker's. Their conclusion was based on omitting information about variability in driver behaviour and instead dividing overtakes into two binary categories of 'close' and 'not close'; we demonstrate that they did not justify or address the implications of this choice, did not have sufficient statistical power for their approach, and moreover show that slightly adjusting their definition of 'close' would reverse their conclusions. We then present a new analysis of the original dataset, measuring directly the extent to which drivers changed their behaviour in response to helmet wearing. This analysis confirms that drivers did, overall, get closer when the rider wore a helmet. The distribution of overtaking events shifted just over one-fifth of a standard deviation closer to the rider - a potentially important behaviour if, as theoretical frameworks suggest, near-misses and collisions lie on a continuum. The paper ends by considering wider issues surrounding this topic and suggests public health research might be best served by shifting focus to risk elimination rather than harm mitigation. PMID- 30472529 TI - Updated estimates of the relationship between speed and road safety at the aggregate and individual levels. AB - Recent studies of the relationship between the speed of traffic and road safety, stated as the number of fatalities and the number of injury accidents, are reviewed and their results synthesised by means of meta-analysis. All studies were based on data fully or partly for years after 2000. Previously proposed models of the relationship between the speed of traffic and road safety, including the Power Model and an Exponential Model, are supported. Summary estimates of coefficients show that the relationship between speed and road safety remains strong. The Power Model and the Exponential Model both fit the data very well. The relationship between speed and road safety is the same at the individual driver level as at the aggregate level referring to the mean speed of traffic. PMID- 30472530 TI - Semi-autonomous vehicles: Usage-based data evidences of what could be expected from eliminating speed limit violations. AB - The use of advanced driver assistance systems and the transition towards semi autonomous vehicles are expected to contribute to a lower frequency of motor accidents and to have a significant impact for the automobile insurance industry, as rating methods must be revised to ensure that risks are correctly measured. Telematics information and usage-based insurance research are analyzed to identify the effect of driving patterns on the risk of accident. This is used as a starting point for addressing risk quantification and safety for vehicles that can control speed. The effect of excess speed on the risk of accidents is estimated with a real telematics data set. Scenarios for a reduction of speed limit violations and the consequent decrease in the expected number of accident claims are shown. If excess speed could be eliminated, then the expected number of accident claims could be reduced to half of its initial value, applying the average conditions of the data used in this study. As a consequence, insurance premiums also diminish. PMID- 30472531 TI - Comparative study of nomophobia among Spanish and Portuguese nursing students. AB - Nomophobia is the fear of leaving the house without a mobile and being out of mobile phone contact and affects different areas of a person's life, especially in terms of social, work and academic relationships due to a dependence on the use of smartphones. Discovering the prevalence of nomophobia among nursing students is very important, as the misuse of smartphones in clinical practice may cause distractions, affecting the quality of care and putting patient safety at risk. Furthermore, it can lead to poorer academic performance during class. The aim of this study was to compare the levels of nomophobia experienced by nursing students at the University of Almeria, Spain and the Polytechnic Institute of Braganza, Portugal. A comparative descriptive observational study was carried out. A nomophobia questionnaire adapted to the Spanish and Portuguese sociolinguistic context was employed; 258 participants comprised the subjects of study. The main results showed both Spanish and Portuguese nursing students scored higher than average regarding levels of nomophobia. However, the scores gathered from items on the questionnaire were generally higher among the Portuguese population than the Spanish one. The Portuguese students (54.7%) felt more anxious than the Spanish students (35.4%) if their battery ran out. Similarly, the Portuguese population showed a greater need for instant communication with their family and friends. In conclusion, the dimensions explored indicate significant levels of nomophobia among both nursing student populations, with higher levels among the Portuguese population than the Spanish. PMID- 30472532 TI - Ultradian Rhythms in the Transcriptome of Neurospora crassa. AB - In many organisms, the circadian clock drives rhythms in the transcription of clock-controlled genes that can be either circadian (~24-hr period) or ultradian (<24-hr period). Ultradian rhythms with periods that are a fraction of 24 hr are termed harmonics. Several harmonic transcripts were discovered in the mouse liver, but their functional significance remains unclear. Using a model-based analysis, we report for the first time ~7-hr third harmonic transcripts in Neurospora crassa, a well-established fungal circadian model organism. Several third harmonic genes are regulated by female fertility 7 (FF-7), whose transcript itself is third harmonic. The knockout of circadian output regulator CSP1 superimposes circadian rhythms on the third harmonic genes, whereas the knockout of stress response regulator MSN1 converts third harmonic rhythms to second harmonic rhythms. The 460 ~7-hr genes are co-regulated in two anti-phasic groups in multiple genotypes and include kinases, chromatin remodelers, and homologs of harmonic genes in the mouse liver. PMID- 30472534 TI - Screening for physical and behavioral dependence on non-opioid analgesics in a German elderly hospital population. AB - OBJECTIVE: To provide further evidence of dependence on non-opioid analgesics (NOAs). METHODS: Post-hoc-analysis of a cross-sectional study of a >= -65-year old non-demented German general hospital population. Four hundred in-patients (75 +/- 6.4 years; 63% females) were included and screened for current and past dependence on NOAs using a structured interview (SKID-I) based on DSM-IV-TR. The addiction section of SKID-I was expanded to the following NOAs: gabapentinoids, acetaminophen, metamizole, flupirtine, and non-steroidal anti-inflammatory drugs (NSAIDs). RESULTS: We found twenty-eight seniors (7%) who fulfilled the criteria for a NOA-dependence. Of whom, twenty-four and four patients were currently dependent and in remission, respectively. According to SKID-I, twenty-one (75%) patients were mildly, five patients (17.9%) moderately, and two (7.1%) patients severely dependent on NOAs. All patients showed at least one sign of physical dependence (tolerance and/or withdrawal symptoms) and most of them reported additional behavioral dependence symptoms. Whereas there was one dependence on gabapentinoids or acetaminophen only, NSAIDs and metamizole were involved in the majority of cases (n = 25; 89.3%). Of note, ten (35.7%) seniors had a de-novo substance dependence exclusively on NOAs - including 2 females with signs of a de novo dependence on metamizole, a NOA which yet has been not in the focus of addiction medicine. CONCLUSION: This cross-sectional study provides further evidence of the existence of a physical and behavioral dependence on NOAs including NSAIDs. Furthermore, preliminary evidence of a de-novo dependence on metamizole is provided which needs further verification. PMID- 30472533 TI - Keratocytes Generate High Integrin Tension at the Trailing Edge to Mediate Rear De-adhesion during Rapid Cell Migration. AB - Rapid cell migration requires efficient rear de-adhesion. It remains undetermined whether cells mechanically detach or biochemically disassemble integrin-mediated rear adhesion sites in highly motile cells such as keratocytes. Using molecular tension sensor, we calibrated and mapped integrin tension in migrating keratocytes. Our experiments revealed that high-level integrin tension abbreviated as HIT, in the range of 50-100 pN (piconewton) and capable of rupturing integrin-ligand bonds, is exclusively and narrowly generated at cell rear margin during cell migration. Co-imaging of HIT and focal adhesions (FAs) shows that HIT is produced to mechanically peel off FAs that lag behind, and HIT intensity is correlated with the local cell retraction rate. High-level molecular tension was also consistently generated at the cell margin during artificially induced cell front retraction and during keratocyte migration mediated by biotin streptavidin bonds. Collectively, these experiments provide direct evidence showing that migrating keratocytes concentrate force at the cell rear margin to mediate rear de-adhesion. PMID- 30472535 TI - Substance use disorder treatment admissions and state-level prenatal substance use policies: Evidence from a national treatment database. AB - State policies pertaining to prenatal substance use have important implications for health outcomes of pregnant women and their infants. However, little is known about the impact of the various types of state-level prenatal substance use policies (i.e., treatment and supportive services; criminal justice initiatives; and health care provider reporting requirements) on substance use disorder treatment admissions. Using data from the 2002-2014 Treatment Episode Data Set - Admissions, we exploited state-level variation in the implementation of different types of policies to assess their impact on pregnant women's admission to substance use disorder treatment. The study found that state-level prenatal substance use policies focused only on the criminal justice sector were negatively associated with the proportion of women of reproductive age who were pregnant upon admission to treatment. Additionally, the implementation of policies that engaged all three sectors was positively associated with the proportion of women of reproductive age who were pregnant upon admission to treatment. These results were consistent across age groups and for both non Hispanic white women and women of other racial/ethnic groups. The findings imply that states with cross-sector policy engagement around prenatal substance use and policies that take a multifaceted, comprehensive approach are more likely to see an increase in admissions to substance use disorder treatment during pregnancy. PMID- 30472536 TI - Polytobacco use and risk perceptions among young adults: The potential role of habituation to risk. AB - INTRODUCTION: Polytobacco use and experimentation is common among young adults. Additional research is needed to determine how these patterns of use impact perceptions of tobacco-related harm and risk. The current study examined whether a relationship exists between an increased number of tobacco products used and decreases in perceptions of harmfulness and health risk. METHOD: Participants (N = 792) completed a survey assessing current/lifetime tobacco use, perceived absolute harmfulness of tobacco/nicotine products and perceived health risk of smoking. For some analyses, participants were grouped by polytobacco use status. RESULTS: Among participants who ever tried a tobacco product, a greater number of products tried was associated with lower perceptions of harm (all p < .05). For e cigarettes and hookah, nonusers rated tobacco products as more harmful compared to single product, dual, and poly users (all p < .05). Number of products tried predicted perceived harmfulness above and beyond demographic characteristics and polytobacco use status across all products. Similarly, number of products tried predicted perceived health risk above and beyond demographic characteristics and polytobacco use status for both lung cancer and heart disease risk. DISCUSSION: Trying a greater number of tobacco products is associated with lower perceived harmfulness of tobacco products. Prospective studies are needed to determine if experimentation with more tobacco products leads to reductions in perceived risk of tobacco use and subsequent sustained use of tobacco. PMID- 30472537 TI - Age-specific risk of substance use disorders associated with controlled medication use and misuse subtypes in the United States. AB - OBJECTIVE: To examine the age-specific risk of past-year substance use disorders (SUDs) associated with use and misuse of prescription opioids, stimulants, sedatives and tranquilizers. METHODS: The authors analyzed nationally representative data from 114,043 U.S. individuals aged 12 and older in the 2015 2016 National Survey on Drug Use and Health. For each controlled medication class, logistic regression was used to model any past-year SUD as a function of use pattern: no use or misuse, use without misuse, prescription drug misuse (PDM). Among individuals reporting PDM, logistic regression was used to model any past-year SUD as a function of PDM subtype (misuse of someone else's medication only, misuse of one's own medication only, and misuse of one's own and someone else's medication). Analyses were stratified by age group. RESULTS: Controlled medication use was associated with higher odds of any past-year SUD compared to no use in many age groups and medication classes. Compared to non-use, PDM was associated with higher odds of any past-year SUD across virtually all age groups and medication classes. Compared to misuse of one's own medication only, misuse of both someone else's and one's own medication was associated with higher odds of any past-year SUD for many age groups and medication classes among individuals reporting PDM. CONCLUSIONS: Clinicians should screen all controlled medication users for PDM and SUDs. Age-specific screening may be required due to heterogeneity in the prevalence and risks of use and misuse of different medications. Determination of PDM subtype can guide interventions to prevent SUDs. PMID- 30472538 TI - Leisure activity participation in relation to alcohol purchasing and consumption in adolescence. AB - BACKGROUND: Building upon the socioecological perspective, this study examines prospective associations linking leisure activity participation with alcohol purchasing and consumption in early adolescence. METHODS: A total of 1763 seventh graders (age 12-13 years) were recruited from middle schools in urban Taiwan via multi-stage sampling and followed-up 1.5 years later during ninth grade. Information about leisure activities, covariates (i.e., gender, puberty development, family structure, parental educational attainment, monthly allowance, peer drinking, and childhood alcohol experience), and two outcome variables (i.e., alcohol purchasing and drinking behaviors) was gathered via web based self-administered questionnaires. Data concerning alcohol outlets and recreational resource for each community district were retrieved from official statistics and commercial sources. Two-level hierarchical generalized linear models were used to evaluate association estimates. FINDINGS: Five percent of ninth graders ever purchased alcohol and nearly one in seven drank alcohol on three or more occasions (i.e., occasional drinking) in the past year. Sports, unstructured, and organized leisure activities were not linked with illegal alcohol purchasing when community contexts were statistically adjusted; a higher community on-premised alcohol outlet density increased alcohol purchasing by 94% (95% CI = 1.24-3.06). In contrast, unstructured leisure activity participation at 7th grade predicted occasional drinking (adjusted Odds Ratio [aOR] = 5.52; 95% CI = 3.13-9.74). Sports participation was associated with reduced risk of occasional drinking in the communities with high unregulated alcohol outlets (aOR for interaction = 0.58; P < .001). CONCLUSION: Our research provides insights to differential roles of leisure activity participation in shaping adolescents' commercial alcohol access and occasional drinking. Macro-social contexts should be considered in the efforts to reduce underage drinking problems through leisure activities. PMID- 30472539 TI - What is a preattentive feature? AB - The concept of a preattentive feature has been central to vision and attention research for about half a century. A preattentive feature is a feature that guides attention in visual search and that cannot be decomposed into simpler features. While that definition seems straightforward, there is no simple diagnostic test that infallibly identifies a preattentive feature. This paper briefly reviews the criteria that have been proposed and illustrates some of the difficulties of definition. PMID- 30472540 TI - Neurobiology of value-driven attention. AB - What we pay attention to is influenced by reward learning. Converging evidence points to the idea that associative reward learning changes how visual stimuli are processed in the brain, rendering learned reward cues difficult to ignore. Behavioral evidence distinguishes value-driven attention from other established control mechanisms, suggesting a distinct underlying neurobiological process. Recently, studies have begun to explore the neural substrates of this value driven attention mechanism. Here, I review the progress that has been made in this area, and synthesize the findings to provide an integrative account of the neurobiology of value-driven attention. The proposed account can explain both attentional capture by previously rewarded targets and the modulatory effect of reward on priming, as well as the decoupling of reward history and prior task relevance in value-driven attention. PMID- 30472541 TI - The role of alpha oscillations in spatial attention: limited evidence for a suppression account. AB - Covert spatial attention allows us to prioritize visual processing at relevant locations. A fast growing literature suggests that alpha-band (8-12 Hz) oscillations play a key role in this core cognitive process. It is clear that alpha-band activity tracks both the locus and timing of covert spatial orienting. There is limited evidence, however, for the widely embraced view that alpha oscillations suppress irrelevant visual information during spatial selection. Extant evidence is equally compatible with an account in which alpha activity enables spatial selection through signal enhancement rather than distractor suppression. Thus, more work is needed to characterize the computational role of alpha activity in spatial attention. PMID- 30472542 TI - Increasing capacity of an anaerobic sludge digester through FNA pre-treatment of thickened waste activated sludge. AB - Free nitrous acid (FNA) pre-treatment has been previously demonstrated to be effective in enhancing methane production and volatile solids (VS) destruction in the anaerobic digestion of waste activated sludge for an equivalent hydraulic retention time (HRT). We hypothesise that, due to enhancement of hydrolysis kinetics, FNA pre-treatment will also allow reduction in the HRT while retaining performance. This would allow for improvement of capacity constrained digesters. Two anaerobic sludge digesters (control-experiment) were fed with the same thickened waste activated sludge (TWAS) from a full-scale plant for 6 months. With 24 h pre-treatment of TWAS at an FNA concentration of 6.1 mgN/L (NO2-N = 250 mg/L, pH = 5.0, T = 25 degrees C), the HRT for the experimental anaerobic digester was progressively reduced from 15 days to 12 days and then to 7.5 days. In comparison, the control reactor was operated at a constant HRT of 15 days, representing typical loading conditions. With the shortened HRTs, the experimental AD reactor achieved VS destruction at 36.9 +/- 0.8% (12 days) and 36.8 +/- 1.0% (7.5 days), representing 30-40% relative increase in comparison to the control reactor (at 26.5 +/- 0.8% and 28.3 +/- 0.7%, respectively, in the same two periods). This was supported by a similar (31-35%) increase in the methane production per unit of VS fed. The volumetric methane production rate of the experimental digester was increased by 165% at HRT of 7.5 days compared with the control digester at HRT of 15 days. The results demonstrated that FNA pre treatment of TWAS can substantially increase the capacity of an anaerobic sludge digester, with a highly favourable economic outcome. PMID- 30472543 TI - Temporal case study of household behavioural response to Cape Town's "Day Zero" using smart meter data. AB - Faced with the threat of "Day Zero", when it was feared that Cape Town's taps could run dry, consumers reduced household water usage from 540 to 280 L per household per day over the 36 months between January 2015 and January 2018. This paper describes the events that prompted this reduction. We look at how changes in water use were affected by official announcements and by public engagement with this news via the social media activity and internet searches. We analysed the water usage of a subset of middle to high income households where smart hot and cold water meters were installed. For hot water usage patterns we compared meter readings with that in another area unaffected by the drought. We further map our cold water smart meter readings against that of the City of Cape Town's municipal data for domestic freestanding households - a sample of more than 400,000 households. We found that the introduction of Level 5 restrictions had a perverse effect on consumption, possibly due to confusing messages. The most dramatic change in behaviour appears to have been instigated by a media storm and consequent user panic after the release of the City's Critical Water Shortages Disaster Plan in October 2017. However, contradictory communication from national and provincial government eroded some of this gain. The paper concludes with recommendations for demand management in a similar future scenario. PMID- 30472544 TI - Effective removal of emerging dissolved cyanotoxins from water using hybrid photocatalytic composites. AB - Harmful algal blooms are occurring more frequently in fresh water throughout the world. Certain cyanobacteria can produce and release potent toxic compounds, known as cyanotoxins, such as microcystins, cylindrospermopsin, saxitoxin, and anatoxin-a, and as such they have become a human and environmental health concern. Hybrid photocatalytic composites (HPCs) comprising carbon nanotubes on the surface of TiO2 nanotubes were designed in this study. The HPCs have a selective adsorption capacity to cyanotoxins and provide photocatalytic activity to produce reactive oxygen species for the degradation of cyanotoxins. HPCs with 5.2 mg carbon nanotubes/cm2 showed an excellent removal efficiency of microcystins-LR (>95%) at 55.6 L/m2/hr/bar. The HPCs more efficiently removed the relatively larger and more hydrophobic cyanotoxins (i.e., microcystin-LR) than the relatively smaller and more hydrophilic compounds, such as cylindrospermopsin, saxitoxin, and anatoxin-a. With a further increased in the carbon nanotube content to 8.6 mg/cm2, the adsorption capacity of the HPCs for cyanotoxins increased to 70.6% for MC-LR. However, there was significant decrease in the photocatalytic activity of the HPCs for production of reactive oxygen species, and consequently a decrease in the degradation of cyanotoxins. It is considered that this device could be used to provide complete rejection of particles and pathogens, and also to significantly reduce trace organic compounds and harmful algal toxins in emergency water supplies. PMID- 30472545 TI - Free nitrous acid (FNA) induced transformation of sulfamethoxazole in the enriched nitrifying culture. AB - The sulfonamide antibiotics sulfamethoxazole (SMX) has been frequently detected in the wastewater. It has been reported that part of SMX can be transformed by the co-metabolism of ammonia oxidizing bacteria (AOB) during nitrifying process. However, previous studies reported inconsistent or even contradictory results in terms of SMX degradation and/or transformation. Literature study revealed that nitrite may play certain role in SMX transformation, which has been neglected previously. In this study, the transformation behavior of SMX was investigated with and without the presence of nitrite in an enriched nitrifying culture. The results clearly show that the elimination of SMX occurred with the presence/accumulation of nitrite, and a linear regression was observed between SMX elimination efficiency and free nitrous acid (FNA) concentration, indicating that FNA was the major factor responsible for the SMX transformation. By reacting with FNA, SMX transformation products, such as 4-nitro-SMX, desamino-SMX and hydroxylated SMX, were detected. However, when FNA concentration decreased, these intermediates may be retransformed back to SMX. These findings improved our understanding on SMX transformation in a biological system and highlighted the role of nitrite/FNA in the sulfonamide antibiotics degradation. PMID- 30472546 TI - Effective removal of MIB and geosmin using MBBR for drinking water treatment. AB - Biodegradation is an effective method for the removal of taste and odour (T&O) compounds from drinking water sources. In this study, the applicability of a moving-bed biofilm reactor (MBBR) as biological treatment step for the control of MIB and geosmin was studied at pilot-scale. After a 3.5 month acclimation period both T&O compounds could be reliably removed by at least 80%. Biodegradation was found to be the dominant removal mechanism with air stripping contributing up to 25% at shorter HRTs. Also sorption of MIB and geosmin onto carriers and biofilm did occur, simultaneously facilitating the biodegradation process. The biodegradation of MIB and geosmin followed pseudo-first-order kinetics. PMID- 30472547 TI - Exploring wastewater system performance under future threats: Does enhancing resilience increase sustainability? AB - Sustainability and resilience are both key considerations in the design and operation of wastewater systems. However, there is currently a lack of understanding of the relationship between these two goals and of the effects of increasing resilience on sustainability. This paper, therefore, presents a framework for analysis of the effects of resilience-enhancing interventions on sustainability, and applies this to an urban wastewater system. Given that sustainability addresses the long term, the framework includes a novel sustainability assessment approach which captures a continuum of potential future conditions and enables identification of tipping points where applicable. This method allows a wide range of potential futures to be captured whilst removing the need to develop scenarios or future projections. While it may be possible to develop interventions that are beneficial in terms of their effects on both resilience and sustainability, the results obtained from the case study demonstrate that implementing measures designed to increase resilience of an integrated urban wastewater system does not guarantee a universal improvement in sustainability. Therefore, when proposing measures to increase resilience, the potential effects on sustainability should be considered also. It is also shown that the extent of any negative effects on system sustainability can vary significantly depending on future conditions, with the case study intervention (increasing pump capacity) achieving the highest degree of sustainability if rainfall depths or imperviousness in the catchments reduce. However, trade-offs between sustainability indicators are present irrespective of future conditions. Furthermore, while an intervention that enhances resilience may be considered sustainable with respect to specific indicators under current conditions, tipping points exist and it will cease to be sustainable if future threat magnitudes exceed these. PMID- 30472548 TI - Role of hot water temperature and water system use on Legionella control in a tertiary hospital: An 8-year longitudinal study. AB - Although measures to minimize Legionella colonization in sanitary hot water installations are well established, there is little evidence of their long-term effectiveness in hospital buildings. During an 8-year period, hot water in a large hospital building was sampled monthly in areas with suitable dimensioning and recirculation and in areas with dead legs and low-use taps. In the former areas, the percentage of Legionella-negative samples was 83.2% when the temperature was >=55%, 64.9% when between 50.1 degrees C and 54.0 degrees C, and 51.6% when <=50 degrees C (p for trend <0.001). In the highest temperature group, no samples with >=103 cfu/L were observed. In poorly designed areas, only 44.7% of samples were negative, and 28.9% presented >=103 cfu/L although reaching 55 degrees C. In these areas, multivariate analysis showed that if hot water supplies were not used daily, the risk of Legionella colonization was greater than two-fold (odds ratio: 2.84; 95% confidence interval: 1.26-6.41), and the risk of finding Legionella concentrations >=103 cfu/L was more than three-fold (odds ratio: 3.18; 95% confidence interval: 1.36-7.46), regardless the temperature. These findings indicate that the effectiveness of maintaining sanitary hot water at a minimum temperature of 55 degrees C is significantly better than that at 50 degrees C for the environmental control of Legionella but only in installations with suitable dimensioning and recirculation. In installations that do not meet these conditions, high temperatures alone result in insufficient control. PMID- 30472549 TI - Studying the fate of the drug Chlorprothixene and its photo transformation products in the aquatic environment: Identification, assessment and priority setting by application of a combination of experiments and various in silico assessments. AB - Chlorprothixene (CPTX) is an antipsychotic drug of the thioxanthene class. Although it is widely used as a tranquillizer in psychiatry, anesthesiology, pediatrics, and in general medical practice, there is a gap in knowledge regarding its occurrence and fate in the environment. Therefore, we provide for the first-time data on the environmental fate and ecotoxicity of CPTX and its potential photo-transformations products (PTPs). Firstly, two standardized biodegradation tests (Closed Bottle test (CBT) and Manometric Respiratory test (MRT)) were performed to assess CPTX's environmental biodegradability. Then, its photodegradability was studied using Xenon and UV lamps. Effects of different conditions (initial drug concentration, pH, and temperature) were applied during UV-photodegradation. Subsequently, the time courses of CPTX and dissolved organic carbon (DOC) concentrations were monitored throughout the photodegradation tests. After that, high-resolution mass spectrometry was employed to elucidate the structures of the formed photo-transformation products (PTPs). In addition, biodegradation tests were performed for the photolytic mixtures to assess the biodegradability of the PTPs. Finally, the (eco)toxicity assessment for CPTX and its photolytic mixtures was predicted using different (quantitative) structure activity relationship ((Q)SAR) software. CPTX was found to be not readily biodegradable in CBT and MRT. CPTX was not eliminated by irradiation with the Xenon lamp, however primarily eliminated using the UV-lamp. The CPTX elimination during UV-irradiation was faster at lower concentrations. CPTX UV photodegradation was affected by pH value, while not affected by the temperature of the irradiated solution. 13 PTPs were detected in UV-photolysis mixtures. One additional product was detected in CPTX standard solution, and it was degraded simultaneously with CPTX during UV-irradiation. On one hand, Biodegradation assays revealed that UV-photolytic mixtures of CPTX, containing its PTPs, were not better biodegradable than CPTX itself. On the other hand, LC-MS analysis showed some PTPs which were eliminated after the biodegradation tests indicating possible biodegradability of these PTPs. This because those PTPs are present in low concentrations in the photolysis mixture and their effect can be hindered by the effect of CPTX and other non-biodegradable PTPs. QSAR analysis revealed that CPTX and some of its PTPs may have some human and/or eco-toxic properties. In conclusion, the release of CPTX into aquatic environments could be harmful. Therefore, further research focusing on CPTX and its PTPs are strongly recommended. PMID- 30472550 TI - Cell-based therapy against prion diseases. AB - Despite multiple efforts to find treatments, prion diseases are still incurable. The currently available therapeutic strategies are mostly based on compounds to inhibit pathological PrP (PrPSc) accumulation, and cellular PrP (PrPC) conversion into PrPSc. However, they cannot reverse the pathological changes already present in the brain. Cell-based therapeutic strategies could promote the repair of the pre-existing brain damage. The few available data come mostly from preclinical studies using neural stem cells, bone marrow-derived microglia and mesenchymal stem cells, as cell sources. Moreover, the benefits of cell-based therapeutic strategies could be linked not only to the replacement of damaged cells, but also to the secretion of trophic factors by the grafted cells that might modulate inflammation, cell death, or endogenous neurogenesis. PMID- 30472551 TI - Efficacy, safety, and pharmacokinetics of intravenous midazolam in Japanese children with status epilepticus. AB - BACKGROUND: No dosing regimen has been established for the initial treatment of pediatric status epilepticus with intravenous midazolam. We therefore evaluated the efficacy, safety, and pharmacokinetics of bolus and continuous midazolam infusion. METHODS: This open-label, prospective, multicenter study involved 34 Japanese children with status epilepticus unresponsive to diazepam. An initial bolus of 0.15 mg/kg midazolam was given, with additional doses of 0.1-0.3 mg/kg up to a cumulative dose of 0.6 mg/kg. A continuous infusion was initiated at 0.1 mg/kg/h (maximum 0.4 mg/kg/h) for patients at high risk of recurrence or in whom seizure reduction was achieved, and continued for 24 h after seizure cessation. Seizure cessation was assessed based on clinical observation (disappearance of motor symptoms regardless of recovery of consciousness), rather than the disappearance of electroencephalography abnormalities. RESULTS: The seizure cessation rate with bolus midazolam was 88%. The cumulative dose was <=0.3 mg/kg in 90% of patients who responded to bolus administration. Adverse events were observed in three patients; one had mild respiratory depression that required supplemental oxygen and bag-valve-mask ventilation. Elimination half-life was 0.999 +/- 0.241 h in seven patients. Total body clearance ranged from 423 to 1220 mL/h/kg in older children but was notably higher in a 10-month-old infant (2010 mL/h/kg). CONCLUSIONS: The efficacy and safety of midazolam were demonstrated in children with status epilepticus, suggesting that intravenous midazolam is suitable as first-line treatment. PMID- 30472553 TI - Vitamin D supplementation has no effect on cognitive performance after four months in mid-aged and older subjects. AB - BACKGROUND: Low serum 25-hydroxyvitamin D (25(OH)D) levels are associated with impaired cognitive function, but the effect of vitamin D supplementation on cognitive function is uncertain. METHODS: 422 subjects were included in a randomized controlled trial with vitamin D (cholecalciferol) 100,000 IU given as a bolus dose followed by 20,000 IU per week versus placebo for four months. Cognitive function was evaluated with verbal recall test, coding test and tapping test. RESULTS: 374 subjects (mean age 52 years, 198 males) had complete cognitive tests both at baseline and at end of study. Mean baseline serum 25(OH)D level was 34 nmol/L. At baseline there were no significant associations between serum 25(OH)D and the three separate cognitive tests. At the end of the study mean serum 25(OH)D levels were 89 nmol/L and 31 nmol/L in the vitamin D and placebo groups, respectively. At the end of the study, there were no statistically significant differences between the two groups regarding change in the cognitive test scores. Nor did sub-group analyses based on gender, age, baseline serum 25(OH)D and cognitive test scores reveal significant differences between the two groups at the end of the study. CONCLUSIONS: Vitamin D supplementation did not improve cognitive function during a four months intervention in mid-aged and older subjects. TRIAL REGISTRATION: ClinicalTrials.govNCT02750293. PMID- 30472552 TI - Supplementary motor area connectivity and dual-task walking variability in multiple sclerosis. AB - BACKGROUND: Despite the prevalence of dual-task (e.g., walking while talking) deficits in people with multiple sclerosis (MS), no neuroimaging studies to date have examined neuronal networks used for dual-task processing or specific brain areas related to dual-task performance in this population. A better understanding of the relationship among underlying brain areas and dual-task performance may improve targeted rehabilitation programs. The objective of this study was to examine relationships between neuroimaging measures and clinical measures of dual task performance, and reported falls in persons with MS. MATERIALS AND METHODS: All participants completed measures of dual-task performance, a fall history, and neuroimaging on a 3 T MRI scanner. Spearman correlations were used to examine relationships among dual-task performance, falls and neuroimaging measures. RESULTS: Eighteen females with relapsing-remitting MS [mean age = 45.5 +/- 8.2 SD; mean symptom duration = 12.3 +/- 6.7 years; Expanded Disability Status Scale median 2.25 (range 1.5-4)] participated in this study. Structural imaging measures of supplementary motor area (SMA) interhemispheric connectivity were significantly related to dual-task walking variability. CONCLUSIONS: The SMA interhemispheric tract may play a role in dual-task performance. Structural neuroimaging may be a useful adjunct to clinical measures to predict performance and provide information about recovery patterns in MS. Functional recovery can be challenging to objectively report in MS; diffusion tensor imaging could show microstructural improvements and suggest improved connectivity. PMID- 30472554 TI - Acute reaction of arterial blood vessels after experimental subarachnoid hemorrhage - An in vivo microscopic study. AB - Subarachnoid hemorrhage (SAH) results in a rapid decrease of cerebral perfusion. While cerebral perfusion pressure (CPP) may quickly recover, a sustained decrease of cerebral blood flow (CBF) has been observed. Acute vasospasm has been concluded from this mismatch. This study was conducted to visualize and investigate immediate vascular reactions during and after experimental SAH. Male Sprague-Dawley rats were subjected to SAH by the endovascular filament model (n = 7) or served as controls (n = 4). Videomicroscopy was performed via a cranial window. Regions of interest were defined in areas covered by videomicroscopy and arterial diameters measured at defined time-points from 15 min before until 3 h after SAH. Local CBF was monitored over the opposite hemisphere by laser-Doppler flowmetry. Local CBF showed a typical decrease immediately after vessel perforation followed by an incomplete recovery in the 3 h thereafter. Videomicroscopy demonstrated a sharp decrease of the arterial diameter in the first minutes after SAH. In some animals, SAH was followed by a complete disappearance of arterial vessel filling. In the following minutes, arterial filling reappeared or improved, respectively. All animals subjected to SAH showed significant vasospasm in subarachnoid arteries. This is the first study to visualize acute vascular reactions during and immediately after SAH. Although the cranial window technique only covers a part of the cerebral vasculature, it covers cerebral vessels rather distant from the site of endovascular perforation. Therefore, it is likely that acute vasospasm observed in the monitored areas reflects a global vascular reaction. PMID- 30472555 TI - Synthesis and biological evaluation of 1-benzyl-N-(2-(phenylamino)pyridin-3-yl) 1H-1,2,3-triazole-4-carboxamides as antimitotic agents. AB - A library of 1-benzyl-N-(2-(phenylamino)pyridin-3-yl)-1H-1,2,3-triazole-4 carboxamides (7a-al) have been designed, synthesized and screened for their anti proliferative activity against some selected human cancer cell lines namely DU 145, A-549, MCF-7 and HeLa. Most of them have shown promising cytotoxicity against lung cancer cell line (A549), amongst them 7f was found to be the most potent anti-proliferative congener. Furthermore, 7f exhibited comparable tubulin polymerization inhibition (IC50 value 2.04 uM) to the standard E7010 (IC50 value 2.15 uM). Moreover, flow cytometric analysis revealed that this compound induced apoptosis via cell cycle arrest at G2/M phase in A549 cells. Induction of apoptosis was further observed by examining the mitochondrial membrane potential and was also confirmed by Hoechst staining as well as Annexin V-FITC assays. Furthermore, molecular docking studies indicated that compound 7f binds to the colchicine binding site of the beta-tubulin. Thus, 7f exhibits anti-proliferative properties by inhibiting the tubulin polymerization through the binding at the colchicine active site and by induction of apoptosis. PMID- 30472556 TI - First-line onartuzumab plus erlotinib treatment for patients with MET-positive and EGFR mutation-positive non-small-cell lung cancer. AB - INTRODUCTION: The phase II JO28638 study evaluated first-line onartuzumab plus erlotinib in patients with MET-positive advanced, metastatic, or post-operative recurrent non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The study was stopped following termination of the global METLung study (OAM4971g), which showed lack of efficacy in the onartuzumab/erlotinib arm. We present immature efficacy and safety data from JO28638. MATERIALS AND METHODS: Chemotherapy-naive patients aged >= 20 years were enrolled. Patients received onartuzumab (15 mg/kg every 3 weeks) plus erlotinib (150 mg once daily) until progression or unacceptable toxicity. The co-primary endpoints were investigator (INV)-assessed progression-free survival (PFS) and safety. Secondary endpoints: overall response rate (ORR), disease control rate (DCR), overall survival (OS), duration of response (DOR), and pharmacokinetics. Exploratory biomarker analyses were also conducted. RESULTS: 61 patients received treatment. Median age was 67 years and most patients had stage IV NSCLC (71%), MET-IHC score 2 (87%), and exon 19 deletion EGFR mutation (53%). Median PFS (INV) was 8.5 months (95% confidence interval [CI] 6.8-12.4); median OS was 15.6 months (95% CI 15.6-not evaluable); ORR was 68.9% (95% CI 55.7-80.1); median DOR was not reached; DCR was 88.5% (95% CI 77.8-95.3). Pharmacokinetics were similar to previous studies. All patients experienced an adverse event (AE); 26 patients discontinued treatment due to AEs; no grade 5 AEs were reported. No significant correlation was found between biomarkers and efficacy outcomes. CONCLUSION: The results presented are inconclusive due to the early termination of the study. PMID- 30472557 TI - Factors affecting the sorption of halogenated phenols onto polymer/biomass derived biochar: Effects of pH, hydrophobicity, and deprotonation. AB - High-performance biochar synthesized via co-pyrolysis of a polymer and rice straw (RS) was evaluated as a sorbent for ionizable halogenated phenols. Compared with RS-derived biochar, the sorption of 2,4-dichlorophenol (DCP), 2,4-dibromophenol (DBP), and 2,4-difluorophenol (DFP) onto polymer/RS-derived biochar was significantly enhanced by the properties of biochar changing due to polymer residues. According to Langmuir sorption isotherm model maximum sorption capacities for DCP, DBP, and DFP were 25.5-27.8, 22.1-26.5, and 11.5-13.3 mg/g, respectively, 3-5 times higher than those of RS-derived biochar. The removal of the polymer residues and increasing aromaticity of polymer/RS-derived biochar at elevated pyrolysis temperatures affected the sorption capacity of halogenated phenols. The surface charge of biochar and deprotonation of the halogenated phenols according to the solution pH were other factors responsible for sorption onto polymer/RS-derived biochar. Competition with other halogenated phenols, Zn2+, and Cu2+ implied that similar sorption mechanisms existed and that surface complexation and electron donor-acceptor interactions were involved in sorption onto polymer/RS-derived biochar. Our results suggest that co-disposal of thermoplastic and biomass wastes through pyrolysis may be an effective option to produce high-performance upgraded biochar as a sorbent for various types of contaminants. PMID- 30472558 TI - Effect of biochar on heavy metal accumulation in potatoes from wastewater irrigation. AB - In many developing countries water scarcity has led to the use of wastewater, often untreated, to irrigate a range of crops, including tuber crops such as potatoes (Solanum tuberosum L.). Untreated wastewater contains a wide range of contaminants, including heavy metals, which can find their way into the edible part of the crop, thereby posing a risk to human health. An experiment was undertaken to elucidate the fate and transport of six water-borne heavy metals (Cd, Cr, Cu, Fe, Pb and Zn), applied through irrigation water to a potato (cv. Russet Burbank) crop grown on sandy soil, having either received no biochar amendment or having top 0.10 m of soil amended with 1% (w/w) plantain peel biochar. A non-amended control, irrigated with tap water, along with the two contaminated water treatments were replicated three times in a completely randomized design carried out on nine outdoor PVC lysimeters of 1.0 m height and 0.45 m diameter. The potatoes were planted, irrigated at 10-day intervals, and leachate then collected. Soil samples collected two days after each irrigation showed that all heavy metals accumulated in the surface soil; Fe, Pb and Zn were detected at 0.1 m depth, while only Fe was detected at 0.3 m depth. Heavy metals were not detected in the leachate. Tested individually, all portions of the potato plant (tuber flesh, peel, leaf, stem and root) bore heavy metals. Biochar amended soil significantly reduced only Cd and Zn concentrations in tuber flesh (69% and 33%, respectively) and peel compared to the non-amended wastewater control (p < 0.05). Heavy metal concentrations were significantly lower in the tuber flesh than in the peel, suggesting that when consuming potatoes grown under wastewater irrigation, the peel poses a higher health risk than the flesh. PMID- 30472559 TI - Trickling filter technology for biotreatment of nitrogenous compounds emitted in exhaust gases from fishmeal plants. AB - Odour emissions are a major environmental issue associated with fishmeal production. Laboratory-scale biotrickling filters (BTFs) were inoculated with microbial consortia derived from sewage sludge, with the goal to study the biotreatment of low-loads of methylamines and ammonia that are main components of odorous exhaust gases produced by fishmeal processing plants. A BTF packed with ceramic rings was subjected to a real fishmeal plant emission containing trimethylamine (TMA), dimethylamine (DMA) and monomethylamine (MMA). The highest elimination capacities (ECs) obtained were 372 mg TMA m-3 h-1, 5.518 mg DMA m-3 h 1 and 1.038 mg MMA m-3 h-1, with maximal removal efficiencies of 92% (TMA), 83% (DMA) and 95% (MMA) after 30 days operation. In a different experiment, a polyurethane foam packing was employed to treat ammonia (NH3) at low inlet loads, reaching an EC of 47.19 mg N m-3 h-1 with 99.8% efficiency (inlet load of 47.27 mg N m-3 h-1). Likewise, the microbial community of the polyurethane-associated biofilm was diverse and stable during operation. These results suggested that elimination of volatile amino-compounds using BTFs inoculated with a methylotrophic microbial consortium holds potential for odour removal. In addition, sequencing analysis of 16S rDNA gene fragments allowed the identification of heterotrophic ammonia-oxidizing bacteria that are promising candidates to effectively maintain ammonia elimination in a biotreatment operation of nitrogenous compounds present in exhaust gases from fishmeal facilities. PMID- 30472560 TI - Degradation of antibiotics and antibiotic resistance genes in fermentation residues by ionizing radiation: A new insight into a sustainable management of antibiotic fermentative residuals. AB - Antibiotic fermentative residues are categorized into hazardous wastes in China due to the existence of antibiotic resistance genes (ARGs) and residual antibiotics How to treat and manage these wastes is a new challenge. This paper investigated the treatment of erythromycin thiocyanate fermentation (EryTcF) residues using ionizing radiation technology for removing ARGs and antibiotics from the fermentation residues. The results showed that as exposed the EryTcF residues to gamma radiation, the abundance of four macrolide resistance genes (ereA, ermB, mefA and mpfB) decreased 1.0-1.3 log with 90-95% removal, and around 56% of erythromycin was removed at absorbed dose of 30 kGy and room temperature (19-22  degrees C). Direct action of gamma-ray radiation contributed to 42-53% of ARGs removal and indirect action (radicals' reaction) was mainly responsible for erythromycin removal (84%). The positive correlation between total ARGs and Shannon index was observed. The potential ARGs-linked hosts were assigned to genera Aeromonas and Enterobacteriaceae and their abundance decreased by 36-43% at 30 kGy. Radiation has not obvious influence on the nutrient components of residues, such as protein content, suggesting that the radiation treated fermentative residues can be used as fertilizer, which is favorable for the development of recycling economy in antibiotic pharmaceutical factory. The results could provide a new insight into a sustainable management of antibiotic fermentative residuals. PMID- 30472561 TI - Effects of the terms and characteristics of cadres on environmental pollution: Evidence from 230 cities in China. AB - This study investigates the effects of cadres' terms and characteristics on environmental pollution by collecting data of 230 prefecture-level cities in 2002 2014. Results show that (1) the cadres' term shows an "inverted U" effect on environmental pollution, or it shows "first deterioration and later improvement" effect on environment. (2) Highly educated cadres are aware of the importance of environmental protection for sustainable economic development and have negative effects on environmental pollution; also, the aged cadres are less likely to be promoted and thus help to environmental protection. (3) The party congress will cause the cadres to focus on economic growth, thus ignoring environmental protection. (4) The effects of cadres on environmental pollution vary across different regions; the effects in central and western China are more serious than that in eastern China. It enriches the evidence on the relationship between governance and environmental pollution, which is significant to the government's formulation and implementation of policies related to environment protection. PMID- 30472562 TI - Enhanced methane potential of rice straw with microwave assisted pretreatment and its kinetic analysis. AB - Biogas has become an alternative clean source of energy. Agricultural residues being renewable and abundant resources could be efficiently used as a feed for methane production. The recalcitrant behaviour of rice straw marks pretreatment an important step to facilitate the transformation into renewable (methane) energy source. Microwave pretreatment has been considered as one of the most effective method, as it can directly (thermal and nonthermal effects) react with the feedstock and destroy its complex matrix. The present study considered the different temperature and exposure time (i.e., 130-230 degrees C, 2-5 min). Biochemical methane potential was assessed corresponding to the maximum solubilization rate; specific methane yield was obtained as 325.76 mL/g/VS. The total net energy gain of 3288.576 J/g/VS was obtained. The performance parameters were calculated by using different kinetic models. It followed the trend as modified Gompertz > transference function > logistic function models. Field Emission Scanning Electron Microscopy (FESEM) and Fourier Transform Infrared (FTIR) analysis confirmed the breakdown of lignocellulose structure resulting from the rupture of cuticular surface. PMID- 30472563 TI - Anaerobic co-digestion of food waste/excess sludge: substrates - products transformation and role of NADH as an indicator. AB - The process of anaerobic co-digestion is vital importance to resource recovery from organic solid wastes such as food waste and municipal sludge. However, its application is hindered by the limited understanding on the complex substrates products transformation reactions and mechanisms therein. In this study, food waste (FW) and excess sludge (ES) from municipal wastewater treatment were mixed at various ratios (ES/FW 5:0, 4:1, 2:1, 1:1, 1:2, 1:4, w/w), and the co-digestion process was studied in a batch test. The consumption of substrates including soluble proteins and carbohydrates, the variation in the intermediates such as various volatile fatty acids, and the production of hydrogen and methane gases were monitored. The results suggested that 4:1 was likely the optimal ratio where substrates were consumed and biogas generated efficiently, whereas 1:2 and 1:4 caused severe inhibition. Fermentation of ES alone produced mainly acetic and propionic acid, while the addition of FW led to butyric acid type fermentation. Intermediates in the fermentation liquid were tentatively identified, and the levels of NADH quantified using 3D-excitation/emission fluorescence spectrometry. One class of the intermediates, tryptophan-like proteins were correlated to the butyric acid accumulation in ES/FW mixtures, and NADH level was proposed as an indicator of VFAs production activities. PMID- 30472564 TI - Immobilization of trace heavy metals in the electrokinetics-processed municipal solid waste incineration fly ashes and its characterizations and mechanisms. AB - The mass production of municipal solid waste incineration (MSWI) fly ashes has caused severe concerns in regarding to the inherently ecological harm and the decreasing landfilling space. To relieve the heavy metal contamination into the environment and complete a closed-loop electrokinetics (EK), the sequential effects of electrokinetics and alkali activating solidification/stabilization (S/S) technique on the immobilization of HMs in the remnant of MSWI fly ashes were investigated in the research. The compressive strength for the remnant-based solidified product at the proposing time of 18 days was 2.58 MPa, 104.76% higher than that of the MWSI-based specimen with the optimal curing parameters being adopted for the production of the solidified matrices. The leaching concentrations of Zn, Pb, and Cu were 9.74, 0.21, and 0.75 mg/L, correspondingly reduced by 57.84%, 80.19%, and 17.58%, respectively. The opposite correlation between the compressive strength and the leaching concentration was demonstrated for both two groups of the curing samples. The mechanism results showed that the electrokinetics had significantly changed the micromorphology characteristics of MSWI fly ashes and distinctly affected the whole curing process. The cementation and geo-polymerization were comprehensively determined as two of main mechanisms for the immobilization of HMs in the curing matrices. PMID- 30472565 TI - An interface damage model that captures crack propagation at the microscale in cortical bone using XFEM. AB - Reliable tools for fracture risk assessment are necessary to handle the challenge with an aging population and the increasing occurrence of bone fractures. As it is currently difficult to measure local damage parameters experimentally, computational models could be used to provide insight into how cortical bone microstructure and material properties contribute to the fracture resistance. In this study, a model for crack propagation in 2D at the microscale in cortical bone was developed using the extended finite element method (XFEM). By combining the maximum principal strain criterion with an additional interface damage formulation in the cement line, the model could capture crack deflections at the osteon boundaries as observed in experiments. The model was used to analyze how the Haversian canal and the interface strength of the cement line affected the crack trajectory in models depicting osteons with three different orientations in 2D. Weak cement line interfaces were found to reorient the propagating cracks while models with strong interfaces predicted crack trajectories that penetrated the cement line and propagated through the osteons. The presented model is a promising tool that could be used to analyze how local, age-related material changes influence the crack trajectory and fracture resistance in cortical bone. PMID- 30472566 TI - Characterization of low-shrinkage dental composites containing methacrylethyl polyhedral oligomeric silsesquioxane (ME-POSS). AB - The aim of this study was to characterize low-shrinkage dental composites containing methacrylethyl-polyhedral oligomeric silsesquioxane (ME-POSS). Four experimental composites were manufactured, two of which contained organic matrixes of BisGMA-TEGDMA (70/30 wt% - BGC) and BisEMA-TEGDMA (80/20 wt% - BEC). The two other experimental composites replaced BisGMA and BisEMA with 25 wt% of ME-POSS (BGP and BEP). The composites also contained 70 wt% of 0.7 um silanized BaBSi particles. The following properties were evaluated: Degree of conversion (DC%), volumetric polymerization shrinkage (VS%), polymerization shrinkage stress (Pss), flexural strength (FS), Flexural modulus (FM), hardness (KHN), water sorption (Wsp), water solubility (Wsl), diffusion coefficient (D), and wear. The DC% was not influenced by the presence of ME-POSS, with BEC (75.6%) and BEP (74.8%) presenting higher DC% than BGC (60.6%) and BGP (55.6%). The ME-POSS containing composites (BGP and BEP) presented significantly lower VS% and Pss. The FS ranged from 92.7 to 142.0 MPa and the FM from 3.6 to 10.3 GPa. ME-POSS did not influence the KHN. BEC and BEP presented lower Wsp and Wsl when compared to BGC and BGP. D ranged from 1.0 * 10-6 to 7.4 * 10-6 cm2 m-1. Incorporation of ME POSS significantly decreased the wear for both binary matrices (p < 0.05). With the exception of FS and FM for BGP, the incorporation of ME-POSS decreased the VS% and Pss without jeopardizing the other properties of the experimental dental composites. PMID- 30472567 TI - Electrochemical performance and microbial community analysis in air cathode microbial fuel cells fuelled with pyroligneous liquor. AB - Microbial fuels cells (MFCs) have been applied for the degradation of pyroligneous liquor (PL) derived from apple tree branches, at different concentrations. The substrate removal, electrochemical properties, and microbial community characteristics were analysed to evaluate the performance of MFCs. Maximum current density (1.94 A/m2), coulombic efficiency (28%), and phenol removal rate (84%) were achieved with MFCs fed with PL at the optimal concentration of 1 g chemical oxygen demand (COD)/L. The polarisation test, cyclic voltammetry, and electrochemical impedance of the electrode redox reaction further explained how the addition of PL could stimulate formation of the electrochemically active biofilm, at the optimal concentration of 1 g COD/L. The microbial community of the anodic biofilm demonstrated that MFCs fed with 1 g COD/L had the highest relative abundance of the typical electrogenic bacteria Geobacter (33%), followed by Sphaerochaeta (6%) and Clostridium (4%). The results revealed that syntrophic interaction of these functional microorganisms contributed significantly to the PL degradation and electrical current generation. PMID- 30472568 TI - Electricity generation and microbial community in long-running microbial fuel cell for high-salinity mustard tuber wastewater treatment. AB - High-salinity mustard tuber wastewater (MTWW) was utilized to obtain effluent treatment and recover bio-energy simultaneously in a microbial fuel cell (MFC). Since the long-term performance of MFCs in MTWW remains unclear, this study examined electricity generation and the microbial community that developed over a 195-day test. The MFC produced electricity over the entire testing period, with stable power output obtained on days 32-120. In the stable phase, a maximum power density of 12.43 W.m-3 was observed, and the internal resistance, open circuit voltage, and columbic efficiency (CE) were 148 Omega, 756 mV and 36.7 +/- 1.2%, respectively. Chemical Oxygen Demand (COD) and Biochemical Oxygen Demand (BOD) removal continuously increased to 89.0 +/- 1.5% and 98.6 +/- 2.0%, respectively, the maximum rates that were obtained at the end of the experiment, respectively. In addition, 16S rRNA gene sequencing analysis showed that hydrolytic/fermentative bacteria could be considered as the bioanode core microbiome, constituting 36.90% of the microbiome. Sulfate-reducing bacteria (SRB), including Dethiosulfovibrio, Thermovirga, Desulfovibrio, and Desulfuromonas, eventually outcompeted the exoelectrogens completely, causing an irreversible loss in CE. This study provides more ideas for treatment and utilization of high-salinity MTWW. PMID- 30472570 TI - Applicability of AuNPs@N-GQDs nanocomposite in the modeling of the amplified electrochemical Ibuprofen aptasensing assay by monitoring of riboflavin. AB - Here, an ultrasensitive and low-cost electrochemical aptasensing assay is developed based on the applicability of a fabricated nanocomposite from nitrogen doped graphene quantum dots (N-GQDs) and gold nanoparticles (AuNPs). A modified glassy carbon electrode (GCE) with the AuNPs@N-GQDs nanocomposite (AuNPs@N GQDs/GCE) as an efficient platform has some unique properties such as high surface area and electrical conductivity. Furthermore, the prepared platform is capable of more loading of aptamer (Apt) molecules as a biological recognition element of Ibuprofen (IBP) on the modified electrode surface. It is noteworthy that in this study, riboflavin (RF) as a universal green probe is used for the first time for electrochemical detection of IBP. According to the proposed strategy and under the optimum condition, the unprecedented detection limit (LOD) of this assay (33.33 aM) is lower than previously reported analytical methods. The results demonstrate the ability of the nanocomposite for designing of the aptasensor, integrated within the electrode format, to cheaper and simpler detection of the IBP with a specificity and sensitivity sufficient for analysis in real samples. It seems that the proposed strategy based on the AuNPs@N-GQDs nanocomposite can be expanded to other nanomaterials. So, this is expected to have promising implications in the design of electrochemical sensors or biosensors for the detection of various targets. PMID- 30472569 TI - Optimization of the droplet electroporation method for wild type Chlamydomonas reinhardtii transformation. AB - We performed the transformation of a wild type Chlamydomonas reinhardtii by optimizing previously developed droplet EP method. For more effective and faster optimization, we used DNA dying fluorescent molecule (Yo-Pro-1) for finding optimal EP conditions instead of using protein expression based evaluation method. By examining wider range of electrical parameter space together with the analysis of total current flow of EP process, we found optimal EP conditions. The obtained optimal EP conditions were verified by CFP transgene expression experiments. By applying the optimal EP conditions to the transformation of C. reinhardtii, we obtained transformants and analyzed them using PCR. Finally, implications and future work are discussed. PMID- 30472571 TI - Using a data science approach to predict cocaine use frequency from depressive symptoms. AB - BACKGROUND: Depressive symptoms may contribute to cocaine use. However, tests of the relationship between depression and severity of cocaine use have produced mixed results, possibly due to heterogeneity in individual symptoms of depression. Our goal was to establish which symptoms of depression are most strongly related to frequency of cocaine use (one aspect of severity) in a large sample of current cocaine users. We utilized generalized additive modeling to provide data-driven exploration of the relationships between depressive symptoms and cocaine use, including examination of non-linearity. We hypothesized that symptoms related to anhedonia would demonstrate the strongest relationship to cocaine use. METHOD: 772 individuals screened for cocaine use disorder treatment studies. To measure depressive symptoms, we used the items of the Beck Depression Inventory, 2nd Edition. Cocaine use frequency was measured as proportion of self reported days of cocaine use over the last 30 days using the Addiction Severity Index. RESULTS: Models identified 18 significant predictors of past-30-day cocaine use. The strongest predictors were Crying, Pessimism, Changes in Appetite, Indecisiveness, and Loss of Interest. Noteworthy effect sizes were found for specific response options on Suicidal Thoughts, Worthlessness, Agitation, Concentration Difficulty, Tiredness, and Self Dislike items. CONCLUSIONS: The strongest predictors did not conform to previously hypothesized "subtypes" of depression. Non-linear relationships between items and use were typical, suggesting BDI-II items may not be monotonically increasing ordinal measures with respect to predicting cocaine use. Qualitative analysis of strongly predictive response options suggested emotional volatility and disregard for the future as important predictors of use. PMID- 30472572 TI - U.S. county prevalence of retail prescription opioid sales and opioid-related hospitalizations from 2011 to 2014. AB - BACKGROUND: The role of prescription opioids in the opioid crisis has been well established. How the prevalence of prescription opioids relates to opioid hospitalizations has been understudied. Hospitalizations due to opioids are a distinct indicator of opioid misuse, have cost implications for health care systems, and may be an entry point into substance use treatment. METHODS: Administrative data were drawn for counties in 32 U.S. states from 2011 to 2014 to associate retail opioid sales rates with opioid-related hospitalization rates. Data on hospitalizations comes from the Healthcare Cost and Utilization Project. Data on opioid sales come from the Automation of Reports and Consolidated Orders System. Statistical models were run accounting for error in the opioid sales measure and controlled for county and year effects and other factors. Sub analyses explored hospitalizations by metropolitan status and maternal/neonatal stays. As a point of comparison, the analysis estimated the relationship of opioid sales to alcohol hospitalizations. RESULTS: Retail opioid sales rates have a positive relationship with opioid-related hospitalization rates where a one morphine kilogram equivalent (MKE) increase in sales per 10,000 people predicts a 9.0% (CI 4.6%-13.7%) increase in opioid-related hospitalization rates. The relationship is higher in non-metropolitan counties. Maternal and neonatal opioid related hospitalization rates increase by 14.1% (CI 4.9%-24.2%) with a one MKE increase in retail sales rates. There is no statistically significant relationship between opioid sales and alcohol hospitalizations. CONCLUSIONS: Though not causal, results inform understanding of how opioid prescribing relate to adverse consequences of opioid use and misuse. PMID- 30472573 TI - Eye movement data reveal increased attention to combined health warnings on cigarette packs. AB - INTRODUCTION: In 2016 the UK introduced standardised pack design regulations, limiting branding and aiming to increase the salience of health warnings. Existing evidence suggests that the effectiveness of pack design in focusing a smoker's attention toward warnings may depend on how much they smoke. Our study aimed to directly compare attention to branding and warnings between the pre regulation and post-regulation packs in smokers, and to determine whether this was affected by the amount smoked, to assess the effectiveness of the new policies. METHOD: 47 adult smokers were recruited, including daily and non-daily smokers to ensure a wide range in cigarettes smoked per week. Eye movement data were recorded while images of cigarette packs were displayed sequentially on screen. Each trial presented one of two types of cigarette pack; pre-regulation packs with a text health warning, or post-regulation packs compliant with governmental guidance introduced in 2016, with plain branding and a combined pictorial and text health warning. Eye movement data were compared between packs, covarying the number of cigarettes smoked per week. RESULTS: Eye movement analysis revealed that smokers attended more to health warnings and less to branding when looking at post-regulation packs compared with pre-regulation packs. These effects did not relate to number of cigarettes smoked per week. CONCLUSION: Standardised regulations for cigarette packs successfully direct smokers' attention away from branding, and towards health warnings, with no association with cigarettes smoked per week. This study adds to the growing body of evidence advocating broader uptake of similar packaging regulations. PMID- 30472574 TI - Nicotine pre-treatment reduces sensitivity to the interoceptive stimulus effects of commonly abused drugs as assessed with taste conditioning paradigms. AB - BACKGROUND: Drug pre-exposure attenuates sensitivity to the interoceptive stimulus properties of additional subsequently administered drugs in drug-induced conditioned taste avoidance (CTA) and conditioned place preference (CPP) paradigms. Specifically, nicotine, commonly used in conjunction with other addictive substances, attenuates acquisition of ethanol and caffeine CTAs and morphine-induced CPP. METHODS: Because nicotine use is comorbid with a number of substance use disorders, we systematically examined the effects of nicotine pre exposure on two different conditioning paradigms involving integration of the interoceptive stimulus properties of multiple commonly abused drugs, in male and female rats, designed to examine both the aversive and reinforcing properties of these drugs. RESULTS: Nicotine dose-dependently interfered with acquisition of CTA to passively administered morphine, ethanol, and cocaine, but not lithium chloride, demonstrating that the effects of nicotine are not simply a matter of reduced orosensory processing or an inability to learn such associations. Moreover, nicotine-treated rats required higher doses of drug in order to develop CTA and did not show increased acceptance of the taste of self-administered ethanol compared with saline-treated rats. CONCLUSIONS: These data demonstrate that nicotine pre-exposure attenuates sensitivity to the stimulus effects of multiple drugs in two conditioning paradigms, in a manner which is consistent with a reduced ability to integrate the interoceptive properties of abused drugs. Through reducing these stimulus properties of drugs of abuse, concomitant nicotine use may result in a need to increase either the frequency or strength of doses during drug-taking, thus likely contributing to enhanced addiction liability in smokers. PMID- 30472575 TI - Do maternal knowledge and paternal knowledge of children's whereabouts buffer differently against alcohol use? A longitudinal study among Finnish boys and girls. AB - BACKGROUND: Previous research suggests that parental knowledge of the child's activities and whereabouts prevents adolescents' alcohol use. However, evidence on whether the positive effects of maternal and paternal knowledge are distinctive for boys' and girls' alcohol use is inconclusive. We examined whether perceived parental knowledge at age 13 prevents alcohol use at age 16, whether the effect of maternal and paternal knowledge was the same for both genders, and whether paternal knowledge had as strong an effect as maternal knowledge. METHOD: Adolescents answered a school survey in 2011 (age 13) and 2014 (age 16) in Finland (N = 5742). Perceived maternal and paternal knowledge was measured separately using a Parents' Monitoring Scale. The data were analysed via moderation regression modelling using Bayesian estimation. RESULTS: Perceived maternal and paternal knowledge at age 13 predicted boys' and girls' lower alcohol use at age 16. For those who had not used alcohol at age 13, parental knowledge protected against an increase of alcohol use at age 16. Both maternal and paternal knowledge had a shielding effect against the increase of boys' and girls' alcohol use, but maternal knowledge had a stronger shielding effect than paternal knowledge. CONCLUSIONS: Both maternal and paternal perceived knowledge at age 13 buffers against the adverse development of alcohol use at age 16 for both genders. Underlining the importance of parent-child communication and knowledge about the child's activities should be a part of family health counselling and school health services. PMID- 30472576 TI - A content analysis of JUUL discussions on social media: Using Reddit to understand patterns and perceptions of JUUL use. AB - BACKGROUND: JUUL, an electronic cigarette, is estimated to occupy 50% of the e cigarette market and appears to be particularly common among youth. However, there is little research on perceptions of JUUL. The aim of the current study was to examine posts on Reddit specific to JUUL and youth to better understand the context and perceptions of JUUL use. METHODS: This content analysis utilized social media discussions posted between January 2015-May 2017. Public posts on Reddit, a social media platform, were gathered and coded. Posters of discussions relevant to both JUUL and youth were included for analysis. RESULTS: 364 posts were included for quantitative content analysis. Posts were mixed in terms of polarity with many (41.1%) including positive and negative language regarding JUUL. In terms of polarity of youth use, 60% of posts showed negative perceptions of youth use. Among posts by youth, only 37% showed negative perceptions of youth use. Posts included a variety of reasons for using JUUL with the most frequent reason being the popularity of JUUL (34.2%) followed by using it to quit smoking (23.3%) and to feel a buzz (20.2%). Age restrictions were the most common barrier to use. CONCLUSIONS: Posters generally had a nuanced perception of JUUL and identified both positive and negative aspects. Interestingly, while primary reasons for youth use indicate the strong influence of social norms, barriers to use suggest that public health interventions such as age restrictions may curb youth use. Findings can inform prevention efforts and important factors for JUUL initiation. PMID- 30472577 TI - E-cigarette use and respiratory disorder in an adult sample. AB - OBJECTIVES: Little evidence is available on the association of e-cigarettes with health indices. We investigated the association of e-cigarette use with diagnosed respiratory disorder among adults in data from the Behavioral Risk Factor Surveillance Survey (BRFSS). METHODS: The 2016 Hawaii BRFSS, a cross-sectional random-dial telephone survey, had 8087 participants; mean age was 55 years. Items asked about e-cigarette use, cigarette smoking, and being diagnosed by a health professional with (a) asthma or (b) chronic obstructive pulmonary disease. Multivariable analyses tested associations of e-cigarette use with the respiratory variables controlling for smoking and for demographic, physical, and psychosocial variables. RESULTS: Controlling for the covariates and smoking there was a significant association of e-cigarette use with chronic pulmonary disorder in the total sample (AOR = 2.58, CI 1.36-4.89, p < 0.01) and a significant association with asthma among nonsmokers (AOR = 1.33, CI 1.00-1.77, p < 0.05). The associations were stronger among nonsmokers than among smokers. Results were similar for analyses based on relative risk and absolute risk. There was also a greater likelihood of respiratory disorder for smokers, females, and persons with overweight, financial stress, and secondhand smoke exposure. CONCLUSIONS: This is the first study to show a significant independent association of e-cigarette use with chronic respiratory disorder. Several aspects of the data are inconsistent with the possibility that e-cigarettes were being used for smoking cessation by persons with existing respiratory disorder. Theoretical mechanisms that might link e-cigarettes use and respiratory symptoms are discussed. PMID- 30472578 TI - Single stage epilepsy surgery in children and adolescents with focal cortical dysplasia type II - Prognostic value of the intraoperative electrocorticogram. AB - OBJECTIVE: To evaluate prospectively the informative/prognostic value of epileptic discharges in the post-resection ECoGs of children with drug-resistant epilepsies and Focal Cortical Dysplasia type II (FCD-II). METHODS: Included were consecutive patients with focal epilepsies and suspected FCD-II who were planned for single-stage epilepsy surgery based on non-invasive presurgical evaluation results. Intraoperative ECoGs were recorded using a 32-channel system with strip- and/or grid-electrodes. Spikes were defined as transients with a mainly negative component and duration of 20-70 ms. Fast activity was defined as rhythmic bursts of polyspikes >13 Hz. All ECoGs were analysed visually. The significance of both spikes and fast activity in the post-resection ECoG for seizure outcomes 24 months after surgery was evaluated. RESULTS: Data from 18 patients (five girls) were analysed. 10/18 patients (55.6%) showed spikes in their post-resection ECoGs, five of them showed additional fast activity. 24 months after surgery, 12/18 patients (66.7%) were seizure-free. There was a significant correlation between unfavorable seizure outcomes and fast activity in the post-resection ECoGs (p = 0.009), whereas spikes alone were not predictive (p = 0.502). CONCLUSION: Even when recorded with non-sophisticated techniques, presence of fast activity in post-resection ECoGs might be a valid negative outcome-predictor after surgery in paediatric patients with FCD-II associated drug-resistant epilepsies. SIGNIFICANCE: Fast activity recorded with a relatively simple ECoG equipment seems also to have prognostic significance and by this might be an alternative to HFOs recorded with highly sophisticated and expensive technologies. PMID- 30472580 TI - Design optimisation of an energy-dispersive X-ray diffraction analyser. AB - A computer package is described for optimising the design of energy-dispersive X ray diffraction mineral phase analysers. An extensive database of relative analyser performances was created and a series of codes developed to search the database for the optimal design for any target minerals and specified design criteria. The advantage of the package is the speed and ease with which results can be obtained, obviating the need for running tailored Monte Carlo simulations or experiments for individual cases. PMID- 30472579 TI - Optimized deep neural network architecture for robust detection of epileptic seizures using EEG signals. AB - OBJECTIVE: Automatic detection of epileptic seizures based on deep learning methods received much attention last year. However, the potential of deep neural networks in seizure detection has not been fully exploited in terms of the optimal design of the model architecture and the detection power of the time series brain data. In this work, a deep neural network architecture is introduced to learn the temporal dependencies in Electroencephalogram (EEG) data for robust detection of epileptic seizures. METHODS: A deep Long Short-Term Memory (LSTM) network is first used to learn the high-level representations of different EEG patterns. Then, a Fully Connected (FC) layer is adopted to extract the most robust EEG features relevant to epileptic seizures. Finally, these features are supplied to a softmax layer to output predicted labels. RESULTS: The results on a benchmark clinical dataset reveal the prevalence of the proposed approach over the baseline techniques; achieving 100% classification accuracy, 100% sensitivity, and 100% specificity. Our approach is additionally shown to be robust in noisy and real-life conditions. It maintains high detection performance in the existence of common EEG artifacts (muscle activities and eye movement) as well as background noise. CONCLUSIONS: We demonstrate the clinical feasibility of our seizure detection approach achieving superior performance over the cutting edge techniques in terms of seizure detection performance and robustness. SIGNIFICANCE: Our seizure detection approach can contribute to accurate and robust detection of epileptic seizures in ideal and real-life situations. PMID- 30472581 TI - Establishment of a quantitative and qualitative analysis and isolation method for tetracyclic iridoids from Morinda lucida Bentham leaves. AB - A new high performance liquid chromatography (HPLC) method has been established for quantitative and qualitative analysis of three tetracyclic iridoids: ML-2-3 (1), molucidin (2), and ML-F52 (3), which are responsible for anti-trypanosomal and anti-leishmanial activities of Morinda lucida Bentham leaves. Separation of 1 3 from dried 80% aqueous (aq.) ethanol extract was achieved on a reversed-phase cholester column packed with cholesteryl-bonded silica using an acetonitrile-0.1% aq. formic acid mobile phase system. Ultraviolet-visible (UV-VIS) spectroscopy was employed for detection of compounds, and their contents were determined by measuring absorbance at 254 nm. Depending on the above system, several factors potentially affecting the concentration of tetracyclic iridoids were evaluated resulting in several variation on plant organs, seasonality, variation between individual trees, and branch positions within the trees. Moreover, we developed a simple, quick, and effective method for tetracyclic iridoid isolation from M. lucida leaves that consisted of extraction by sonication into 80% aq. ethanol, basic hydrolysis, acid neutralization, liquid-liquid extraction into an organic solvent, and reverse phase open column chromatography. Employing this method, we have succeeded to obtain 1 as a colorless crystal yielding of 0.23%, which was 28 times higher than that of previous isolation method. Setting up methodology in this paper may be important for future in vitro and in vivo studies of tetracyclic iridoids and moreover for their applications in new drug design and development. PMID- 30472582 TI - Simultaneous analysis by LC-MS/MS of 22 ketosteroids with hydroxylamine derivatization and underivatized estradiol from human plasma, serum and prostate tissue. AB - This study describes a validated LC-MS/MS method for assaying 23 steroids within a single run from 150 MUl of human plasma, serum or prostatic tissue homogenate. Isotope-labeled steroids were used as internal standards. Samples were extracted with toluene, and ketosteroids were derivatized with hydroxylamine prior to LC MS/MS analysis. The steroids were separated on a C18 column and methanol was used as an organic solvent with the addition of 0.2 mM ammonium fluoride to improve underivatized estradiol (E2) ionization. Certified reference serums as well as plasma samples, and homogenates of prostate tissue were utilized in the method validation. The specificity of the method was inspected with a total of 27 steroids. The validation proved that the method was suitable for the quantitative analysis of a wide panel of androgens (testosterone, T (3.3 pM-13 nM); androstenedione, A4 (3.3 pM-13 nM); 5alpha-androstanedione, DHA4 (13 pM-13 nM); dehydroepiandrosterone, DHEA (67 pM-133 nM); dihydrotestosterone, DHT (33 pM-33 nM); 11-ketodihydrotestosterone, 11KDHT (13 pM-13nM); 11-ketotestosterone, 11KT (33 pM-6.7 nM); 11beta-hydroxyandrostenedione, 11bOHA4 (33 pM-13 nM); 11beta hydroxytestosterone, 11OHT (13 pM-33 nM)), as well as estrogens (estrone, E1 (3.3 pM-13 nM)), progestagens (17alpha-hydroxypregnenolone, 17OHP5 (32 pM-127 nM); 17alpha-hydroxyprogesterone, 17OHP4 (67 pM-133 nM); progesterone, P4 (3.3 pM-13 nM); pregnenolone, P5 (6.6 pM-13 nM)), and glucocorticoids (cortisol, F (33 pM 134 nM); cortisone E (66 pM-131 nM); corticosterone, B (33 pM-67 nM); 11 deoxycortisol, S (33 pM-66 nM); 21-hydroxyprogesterone, 21OHP4 (32 pM-13 nM)). Furthermore, E2 (335 pM-134 nM) and 11alpha-hydroxyandrostenedione, 11aOHA4 (33 pM-33 nM) could be analyzed if the concentration in the sample was high enough. In addition, aldosterone, A (128 pM-64 nM) and 11-ketoandrostenedione, 11KA4 (33 pM-13 nM) could be analyzed semiquantitatively. The limits of quantification for all compounds ranged from 0.9 to 91 pg/ml, and from 0.009 to 0.9 pg/mg tissue. Compared to our previous method, this new method also permits the analysis of the more challenging steroids, like DHT, DHEA and P5, and a panel of 11-ketosteroids. PMID- 30472583 TI - Authentication and discrimination of green tea samples using UV-vis, FTIR and HPLC techniques coupled with chemometrics analysis. AB - Green tea is a popular beverage consumed worldwide. Its quality should be controlled adequately as the quality is influenced by several factors in addition to adulterations. This study aimed to develop a simple method for assessing the quality of green tea samples obtained from the South and the East Asian regions. The UV-vis, FTIR and HPLC data from 38 samples were subjected to multivariate analyses using the unsupervised recognition techniques comprising Hierarchical Cluster Analysis (HCA) and Principal Component Analysis (PCA). The model for their authentication was constructed and validated by applying the supervised recognition techniques as Soft Independent Modeling of Class Analogy (SIMCA) and Partial Least Square Discriminant Analysis (PLS-DA). The percentages of caffeine in the identified samples were determined using a validated HPLC assay in addition to in vitro determination of their antioxidant activity using DPPH radical-scavenging capacity assay. HCA and PCA based on UV data successfully distributed the tested samples into informative clusters. However, that obtained from visible data could only differentiate samples with respect to their powdered condition. On the contrary, PCA from FTIR and HPLC data could hardly discriminate any of the samples. The models constructed using SIMCA and PLS-DA showed a good class separation between the South and the East Asian samples. The percentages of caffeine in the identified samples and the IC50 in DPPH assay are greatly diverse among all the tested samples. Thus, UV spectroscopy and chemometrics have provided a simple and quick tool for the quality control of commercial green tea samples. PMID- 30472584 TI - Reactive intermediates and bioactivation pathways characterization of avitinib by LC-MS/MS: In vitro metabolic investigation. AB - Avitinib (AC0010) is a third generation inhibitor of the EGFR (epidermal growth factor receptor) that was permitted parallel phase I clinical trials in the US and in 2014. It is estimated to enter in market within two years. In the current study, eight in vitro metabolites were detected and their chemical structures were postulated. The main in vitro phase-I metabolic reaction was N-oxidation in piperazine moiety. The generation of reactive metabolites in avitinib metabolism was investigated using rat liver microsomes while adding capturing agents, viz potassium cyanide for reactive iminium intermediates, GSH for iminoquinones and methoxylamine for aldehyde forming stable adducts which are identifiable by LC MS/MS. Ten reactive intermediates (four iminoquinones, three iminium and three aldehydes) were characterized. The three capturing agents used resulted in proposing four different bioactivation pathways. Upon literature examination, no former articles were found for avitinib metabolism including the produced reactive metabolites. PMID- 30472586 TI - Pharmacokinetic studies unveiled the drug-drug interaction between trans-2,3,5,4' tetrahydroxystilbene-2-O-beta-d-glucopyranoside and emodin that may contribute to the idiosyncratic hepatotoxicity of Polygoni Multiflori Radix. AB - Polygoni Multiflori Radix (PMR) has been a reputable tonifying traditional Chinese medicine for a long history. However, clinical side effects regarding its idiosyncratic hepatotoxicity are occasionally reported. The containing anthraquinones, particularly emodin, could cause liver injury in both in vitro and in vivo experiments. It is well-known that some compounds could influence other compounds' pharmacokinetic parameters significantly. In this work, the influence of trans-2,3,5,4'-tetrahydroxystilbene-2-O-beta-d-glucopyranoside (TSG) on the pharmacokinetic behavior of emodin in rats was evaluated by an ultra-high performance liquid chromatography/triple quadrupole mass spectrometry (UHPLC/MS MS) approach. Pharmacokinetic parameters of emodin, PMR extract, and TSG-free PMR extract (prepared by a component "knock-out" strategy with TSG eliminated), in rats after one-day and seven-day administration were determined and compared. We found that, after seven-day administration of the whole PMR extract (rather than TSG-free extract), emodin in rats was accumulated. And accordingly, the exposure of emodin in rats pre-treated with single TSG for seven days could be significantly enhanced. The results indicate that TSG was able to accelerate the exposure and metabolism of emodin. The effect of TSG on the metabolic activities of cytochrome P450 enzymes was further assessed by an LC-MS cocktail method. The accelerated exposure and metabolism of emodin could result from the up-regulation activity of CYP450s, in particular CYP1A2 isozyme. The findings obtained in this work firstly unveiled DDI between TSG and emodin in the administration of PMR, thus may provide a basis for unveiling the underlying mechanism of PMR-induced liver injury. PMID- 30472585 TI - Development of a method to analyze the complexes of enoxaparin and platelet factor 4 with size-exclusion chromatography. AB - Heparin, a highly sulfated glycosaminoglycan, has been used as a clinical anticoagulant over 80 years. However, heparin-induced thrombocytopenia and thrombosis (HITT) is a serious side effect of heparin therapy, resulting in relatively high risk of amputation and even death. HITT is caused by forming of complexes between heparin and platelet factor 4 (PF4). Enoxaparin, one of the most commonly used low molecular weight heparin (LMWH), were developed in 1980's. The lower molecular weight of enoxaparin reduces the risk of HITT by binding to less PF4. To detect the binding capacity between enoxaparin and PF4 could be an effect way to control this risk before it goes to patients. In this work, a size exclusion chromatography (SEC) method was developed to analyze the patterns of complexes formed between PF4 and enoxaparin. The chromatographic condition was optimized to separate PF4, enoxaparin, ultra-large complexes and small complexes. The linearity and stability of this method were confirmed. The impacts of PF4/enoxaparin mixture ratios and incubation time on the forming complexes were investigated. Four enoxaparin samples were analyzed with this method to verify its practicability. It is a robust, accurate and practicable method, and provides an easy way to monitor the capacity of enoxaparin forming complexes with PF4, suggesting the HITT related quality of enoxaparin. PMID- 30472587 TI - Development of a validated LC-MS/MS method for the in vitro and in vivo quantitation of sunitinib in glioblastoma cells and cancer patients. AB - Sunitinib is a multi-targeted tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor and is currently being investigated against other forms of malignant tumors. Recently great interest has emerged for the application of sunitinib to glioblastoma treatment. In order to have a method with broad applicability it will be of importance to have access to a method that could be applied both in human plasma and cell uptake studies. No method has been reported thus far for the estimation of sunitinib uptake in glioma cells. We therefore set out to develop a method that could be applied for quantifying sunitinib in human plasma and in cell uptake studies. The method was validated and accredited according to ISO 17025:2005 guideline in human plasma and successfully applied to cancer patient plasma. Also, the method was effectively recruited to establish a protocol for the evaluation of sunitinib accumulation into M095K glioma cells. This method could significantly contribute to developmental phases in repurposing this drug in different cancer types. PMID- 30472588 TI - In vivo phenotyping of cytochrome 450 isoforms involved in the metabolism of anti HIV and anti-tubercular drugs in human using cocktail approach: An LC-MS/MS analysis. AB - PURPOSE: In vivo phenotyping of CYP isoforms involved in the metabolism of anti HIV and antitubercular drugs is important to determine therapeutic dose levels in HIV/AIDS-TB coinfections. In this study, we used a cocktail of bupropion, losartan and dapsone for in vivo phenotyping of CYP2B6, CYP2C9 and N acetyltransferase-2 (NAT2) in plasma. CYP2B6 is the main catalyst of anti-HIV efavirenz, while NAT2 is involved in antitubercular drug isoniazid metabolism. CYP2C9 has a significant association with antitubercular drug-induced reactions. The activity level of these isoforms has a significant bearing on therapeutic dose in rapid and poor metabolizers. METHODS: Briefly, a cocktail of probe drugs was administered to human volunteers and the drugs and metabolites were determined by an inhouse LC-MS/MS method in 250 MUl plasma. The mobile phase and drug/metabolite extraction methods were optimized before analysis. Retention time, Cmax and tmax were calculated from the same sample and the values were used for phenotyping the isoforms. RESULTS: Retention time of drugs and metabolites was calculated. The method was sensitive (4.5-8.2 %CV) and no interfering peak was observed in any batch. %Accuracy of the calibrator and QC was 85-115%. %CV of storage stability testing was within FDA approved limits. Cmax and tmax were comparable to the values reported for individual drugs. CONCLUSIONS: This study advocates the use of a cocktail of bupropion, losartan and dapsone for in vivo phenotyping of CYP2B6, CYP2C9 and NAT2, which is important in determining therapeutic dose levels of anti-HIV and anti-TB drugs in HIV/AIDS-TB coinfections. PMID- 30472589 TI - Effect of temperature on the retention of Janus kinase 3 inhibitor in different mobile phase compositions using reversed-phase liquid chromatography. AB - In this study, the thermodynamic dissociation constant (pKa) values of tofacitinib in acetonitrile-water binary mixtures with of 25%, 30%, 35% and 45% (v/v) have been determined at 25-45 degrees C range of temperatures with reversed-phase liquid chromatography (RPLC). The chromatographic determination was achieved on a Kinetex Core-Shell EVO C18-Phenomenex (150 mm x 4.6 mm, 5 MUm) analytical column. For each case pKa values and retention factors of tofacitinib by taking into account the effect of the activity coefficients in hydro-organic water-acetonitrile binary mixtures have been evaluated and which obtain by SOLVER algorithm of spreadsheet program Excel to fit experimental data to the nonlinear expression derived. From these values, the thermodynamic aqueous pKa value of the drug was calculated by different approaches. Thermodynamic parameters standard Gibbs free energy (DeltaG degrees ), standard enthalpy (DeltaH degrees ) and standard entropy (DeltaS degrees ) derived from dissociation constant measurements at six different temperatures were calculated by from linearity plots of IogKa against 1/T (van't Hoff plot). PMID- 30472590 TI - Analysis of phosphodiesterase type 5 inhibitors as possible adulterants of botanical-based dietary supplements: extensive survey of preparations available at the Czech market. AB - Popularity of natural-based preparations supporting the sexual potency significantly increased in recent years, which also led to the increase of illegal use of phosphodiesterase type 5 inhibitor (PDE-5) in sexual performance enhancement products. In this study, a rapid U-HPLC-HRMS/MS method has been developed to simultaneously determine 59 PDE-5 inhibitors and their analogues. Within the development of sensitive method for analysis of 59 PDE-5 inhibitors and their analogues, both sample preparation procedure, as well as separation / detection conditions have been optimized. Extraction efficiency of particular extraction solvents, influence of different mobile phase additives on target analytes separation, as well as impact of various settings of mass analyzer on sensitivity of detection were examined. Data were collected in the 'full MS/data dependent MS/MS' acquisition mode (full MS-dd-MS/MS). Before the U-HPLC-HRMS/MS method was used for analysis of real samples, proper validation had been conducted. The precision of the method expressed as the relative standard deviation (RSD) was <=4.2% and <=5.2% at spiking concentrations 5 MUg/g and 0.25 MUg/g, respectively. The limits of quantification were in the range 0.25 - 0.05 MUg/g and the recovery ranged between 71 and 90%. The optimized method was successfully applied for analysis of 64 real samples, and 10 of them were proved to contain both registered or unregistered synthetic PDE-5 inhibitors. Additionally, the acquired U-HPLC-HRMS/MS fingerprints were demonstrated to serve as an efficient tool for revealing of other type of possible fraud in products labeling. Retrospective mining of markers of herbs declared on dietary supplements packaging allowed to assess the trueness / untruth in the declaration of medical herbs composition. PMID- 30472591 TI - Pharmacokinetics, bioavailability and metabolism of cligosiban, an antagonist of oxytocin receptor, in rat by liquid chromatography hyphenated with electrospray ionization tandem mass spectrometry. AB - Cligosiban is a highly-affinity nonpeptide oxytocin receptor antagonist. In this study, a simple an sensitive LC-MS/MS method was developed and validated for the determination of cligosiban in rat plasma. The plasma samples were pretreated with acetonitrile as precipitant and then separated on an ACQUITY BEH C18 column (2.1 * 50 mm, 1.7 MUm) with 0.1% formic acid in water and acetonitrile as mobile phase. The analytes were monitored using selected reaction monitoring (SRM) mode with transitions at m/z 420.1->248.1 for cligosiban and m/z 304.1->161.1 for IS. The developed method showed good linearity over the concentration range of 1-1000 ng/mL with coefficient of correlation > 0.996. The lower limit of quantification (LLOQ) is 1 ng/mL. The method was validated for selectivity, precision, accuracy, recovery, and stability in accordance with FDA's guidance. The validated assay has been successfully applied to the pharmacokinetic study of cligosiban in rat plasma after intravenous and oral administration. According to the current results, the oral bioavailability of cligosiban was 63.82%. Furthermore, the metabolites present in rat liver microsomes (RLM), human liver microsomes (HLM) and rat plasma were analyzed by UHPLC-LTQ-Orbitrap-MS method, and four metabolites structurally identified based on their accurate masses, and fragment ions. The proposed metabolic pathways of cligosiban were demethylation and glucuronidation. This study is the first report on the pharmacokinetic and metabolic information of cligosiban, which would provide insights into the effectiveness and toxicity of cligosiban. PMID- 30472592 TI - Separation and analysis of flavonoid chemical constituents in flowers of Juglans regia L. by ultra-high-performance liquid chromatography-hybrid quadrupole time of-flight mass spectrometry. AB - The flowers of Juglans regia L. have demonstrated their medicinal value as a part of edible plants. In this study, an analytical methodology for identification of flavonoid chemical constituents in flowers of Juglans regia L. was established using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS). Thirty-six flavonoid compounds were identified based on highly accurate mass measurements, and the mass spectrometric fragmentation pathways of eleven representative compounds were proposed, which was helpful for the identification of different types of flavonoids. The study has laid the foundation for the research and development of effective drugs from flowers of Juglans regia L. PMID- 30472593 TI - Infrared and Raman spectroscopic studies of Mn2+ ions doped in strontium alumino borate glasses: Describes the role of Al2O3. AB - Strontium alumino borate glasses doped with Mn2+ ions (SABM) have been prepared and characterized by XRD, density, Electron paramagnetic resonance (EPR), FT-IR and Raman to investigate the spectral and physical properties of the present glass samples. The FTIR spectra revealed the presence of BO3 and BO4 structural units in SABM glasses. The IR peak at ~467 and ~679 cm-1 assigned as the vibration of metal cations (Sr2+), MnO bond vibrations and bending vibration of AlO in [AlO4] units. The Raman band ~786 cm-1 establishes the presence of AlO4 units. It has been found that an increasing the Al2O3 content increases the bond length of the AlO bond in AlO4 which leads to increase molar volume and decrease density. Differential scanning calorimetry (DSC) studies indicated that the glass transition temperature (Tg) decreases with increase of Al2O3. Evaluated g and A values from EPR spectra gave the conformation about the ionic bonding between the Mn2+ and its neighbouring oxygen ions. PMID- 30472594 TI - Copper nanoclusters-enhanced chemiluminescence for folic acid and nitrite detection. AB - The reaction between diperiodatoargentate(III) (DPA) and folic acid (FA) produced weak chemiluminescence (CL) in acid medium, which was greatly enhanced in the presence of copper nanoclusters (CuNCs). The CL intensity of CuNCs-DPA-FA system increased with the concentration of FA ranging from 0.1 to 10.0 MUM. The proposed CL system was applied for the detection of FA in pharmaceutical formulation and human urine samples. Further, the CL signal of CuNCs-DPA-FA system was inhibited by nitrite, and the inhibited CL intensity was proportional to the nitrite concentration in the range of 1.0-80.0 MUM. The method was successfully applied to determine nitrite in water, pickled vegetable and sausage samples. A possible CL mechanism was briefly discussed. PMID- 30472595 TI - Visual detection of cyanide ion in aqueous medium by a new chromogenic azo azomethine chemosensor. AB - A simple and new chromogenic azo-azomethine chemosensor N'-(5-((2,4-dichloro- phenyl) diazenyl)-2-hydroxylbenzylidene) picolinohydrazide (L) has been synthesized as an effective colorimetric sensor for cyanide ion. The sensing behavior of the probe L towards CN- over other anions was examined by naked-eye, UV-vis spectroscopy and NMR studies. L exhibited a selective sensing ability to CN- in DMSO/H2O(6:4, v:v) binary solution and DMSO/Tris(10 mM, pH = 7.1, 6:4, v:v) buffer solution by changing color from colorless to yellow. The detection limit was calculated to be 6.4 MUM. The recognition mechanism was attributed to deprotonation process according to 1H NMR titration method. Moreover, test strips coated with L were easily fabricated with low cost and could be used to detect CN in aqueous solution conveniently. PMID- 30472596 TI - Toxicity of silver nanoparticles released by Hancornia speciosa (Mangabeira) biomembrane. AB - Recent research has shown that latex from different species is able to produce tissue replacement and regeneration. Particularly, biomembranes obtained from Hancornia speciosa latex (HSB) have shown high angiogenic and osteogenic activity. Considering new materials for wound healing, it would be interesting to develop a product combining antibacterial and antifungal activities. Silver nanoparticles (AgNP) have been commonly used for this purpose in medicinal products and devices for decades. In order to combine angiogenic, antibacterial and antifungal properties on the same platform, we developed an HSB containing 3 concentrations of AgNP. It was observed that the HSB successfully accommodated the AgNP in the matrix and released them in a controlled way. The release dynamics of AgNP by HSB was described by UV-vis absorption spectroscopy. The released nanoparticles were evaluated by Transmission Electron Microscopy (TEM) and Dynamic Light Scattering (DLS) measurements. In addition, the cytotoxic and genotoxic effects were evaluated using the Allium cepa assay. The results showed no cytotoxic effect of HSB-AgNP in all studied concentrations. The genotoxic effect was observed in HSB-AgNP at the two highest concentrations, however not at the lowest concentration. Thus, the addition of AgNP at the lowest concentration can improve the pharmacological activity of HSB without causing a toxic effect on vegetal cells. Therefore, the H. speciosa latex biomembrane presented in this paper combines angiogenic, anti-inflammatory and antibacterial properties and can be considered potentially new biomaterial for wound-healing. PMID- 30472597 TI - A visual and sensitive Hg2+ detection strategy based on split DNAzyme amplification and peroxidase-like activity of hemin-graphene composites. AB - A visual and sensitive Hg2+ detection strategy was developed based on split DNAzyme amplification and hemin-graphene oxide composites (H-GNs). Two split DNAzyme sequences can form two entire enzyme-strands DNA (E-DNA) by T-Hg2+-T interaction. The E-DNA can bind with the loop of molecular beacon (MB) to form Mg2+-dependent DNAzyme structure. The formed DNAzyme can circularly cleave the loop of MB, resulting large amount of DNA fragments. The resultant DNA fragments can prevent H-GNs from aggregation by adsorbing on its surface. Consequently, the supernate with large amount of H-GNs shows dark blue color after chromogenic reaction. This strategy shows a linear range from 50 pM to 1200 pM. The limit detection can be low to 33 pM. This strategy provides a visual and enzyme-free amplification mode for quick and sensitive screen of Hg2+. PMID- 30472598 TI - Fe3+-selective and sensitive "on-off" fluorescence probe based on the graphitic carbon nitride nanosheets. AB - An effective and facile "on-off" fluorescence sensing approach for the determination of Fe3+ ion using a large area and relatively uniform size graphitic carbon nitride nanosheets (GCNS) was developed. The prepared GCNS have blue and stable emission, as well as excellent water dispersion, and were applied as an effective fluorescent probe that based on the quenched fluorescence for selective and sensitive detection of Fe3+ ion. Herein, we explain the ambiguous fluorescence quenching mechanism between the GCNS and Fe3+, which mainly springs from the redox potential and empty d orbital of Fe3+. The redox potential and unfilled d orbit of Fe3+ endow it excellent binding force with GCNS, which generates most obvious fluorescence quenching effect with respect to other metal ions. The limit of detection (LOD) for Fe3+ was found to be about 2.06 MUM. Therefore, the prepared GCNS has the potential to be used as a fluorescent probe for detection. PMID- 30472599 TI - Balancing reactivity and antitumor activity: heteroarylthioacetamide derivatives as potent and time-dependent inhibitors of EGFR. AB - Second- and third-generation inhibitors of EGFR possess an acrylamide group which alkylates Cys797, allowing to overcome resistance due to insurgence of T790M mutation. Less reactive warheads, yet capable to bind the target cysteine, may be useful to design newer and safer inhibitors. In the present work, we synthesized a 2-chloro-N-(4-(phenylamino)quinazolin-6-yl)acetamide (8) derivative as a prototype of EGFR inhibitor potentially able to react with Cys797 by nucleophilic substitution. We then tuned the reactivity of the acetamide fragment by replacing the chlorine leaving group with (hetero)-aromatic thiols or carboxylate esters. Among the synthesized derivatives, the 2-((1H-imidazol-2-yl)thio)acetamide 16, while showing negligible reactivity with cysteine in solution, caused long lasting inhibition of wild-type EGFR autophosphorylation in A549 cells, resulted able to bind recombinant EGFR L858R/T790M in a time-dependent manner, and inhibited both EGFR autophosphorylation and proliferation in gefitinib-resistant H1975 lung cancer cells (expressing EGFR L858R/T790M mutant) at low micromolar concentration. PMID- 30472601 TI - Therapeutic potential of selective histone deacetylase 3 inhibition. AB - Histone deacetylases (HDACs) are closely related to the occurrence and development of a variety of diseases, such as tumor, inflammation, diabetes mellitus, cardiovascular and neurodegenerative diseases. Inhibition of HDACs by developing HDAC inhibitors has achieved significant progress in the treatment of diseases caused by epigenetic abnormalities, and especially in the cancer therapy. Isoform selective HDAC inhibitors are emphasized to be disease specific and have less off-target effects and better safety performances. HDAC3 has been illustrated to play specific role in the development of several diseases, and the discovery of HDAC3 selective inhibitors has exhibited potential in the targeted disease treatment. Herein, we summarize the current knowledge about the prospects of selective inhibition of HDAC3 for the drug development. PMID- 30472600 TI - Synthesis, biological evaluation, and molecular docking investigation of 3 amidoindoles as potent tubulin polymerization inhibitors. AB - A series of novel 3-amidoindole derivatives possessing 3,4,5-trimethoxylphenyl groups were synthesized and evaluated for their antiproliferative and tubulin polymerization inhibitory activities. Some of them demonstrated moderate to potent activities in vitro against six cancer cell lines including MCF-7, MDA-MB 231, BT549, T47D, MDA-MB-468, and HS578T. The most active compound 27 inhibited the growth of T47D, BT549, and MDA-MB-231 cell lines with IC50 values at 0.04, 3.17, and 6.43 MUM, respectively. Moreover, the flow cytometric analysis clearly revealed that compound 27 significantly inhibited growth of breast cancer cells through arresting cell cycle in G2/M phase via a concentration-dependent manner. In addition, the compound also exhibited the most potent anti-tubulin activity with IC50 values of 9.5 MUM, which was remarkable, compared to CA-4. Furthermore, molecular docking analysis demonstrated the interaction of the compound 27 at the colchicine-binding site of tubulin. These preliminary results suggest that compound 27 is a very promising tubulin-binding agent and is worthy of further investigation aiming to the development of new potential anticancer agents. PMID- 30472602 TI - A novel series of napabucasin derivatives as orally active inhibitors of signal transducer and activator of transcription 3 (STAT3). AB - The transcription factor STAT3 is an attractive target for a variety of cancers therapy. Napabucasin, applied in phase III clinical trials for the treatment of a variety of cancers, was regarded as one of the most promising anticancer drug by targeting STAT3. Herein, a novel series of napabucasin derivatives were designed and synthesized, which presented a potent inhibitory activity on a variety of cancers cells. Among the derivatives compound 8q exhibited potent inhibitory activity on U251, HepG2, HT29 and CT26 cells with the IC50 values of 0.22, 0.49, 0.07 and 0.14 MUM, respectively, which was over 10-fold more potent than napabucasin. Treatment with compound 8q decreased protein expression level of total STAT3 and p-STAT3Y705in vitro. The binding of compound 8q with STAT3 were further validated by electrophoretic mobility shift assay and surface plasmon resonance analysis. Compound 8q has a KD of 110.2 nM for full-length STAT3 recombinant protein. Moreover, the aqueous solubility of 8q was over 4.5-fold than that of napabucasin. In addition, compound 8qin vivo significantly reduced tumor growth compared to untreated mice, and exhibited good safety profile, indicating its great potential as an efficacious drug candidate for oncotherapy. PMID- 30472603 TI - Ligand-based design, synthesis and biological evaluation of xanthine derivatives as LSD1/KDM1A inhibitors. AB - Histone lysine specific demethylase 1 (LSD1) has been recognized as an important epigenetic target for disease treatment. To date, a large number of LSD1 inhibitors have been developed, some of which are currently being evaluated in clinical trials for the treatment of cancers, virus infection, and neurodegenerative diseases. In this paper, we for the first time reported the ligand-based design of fragment-like xanthine derivatives as LSD1 inhibitors, of which compound 4 possessed acceptable pharmacological inhibition against LSD1 (IC50 = 6.45 MUM) and favorable fragment-like nature, and therefore could be used as a promising template to design new LSD1 inhibitors. Interestingly, compounds 6c and 6i strongly suppressed growth of MGC-803 cells partly dependent on their LSD1 inhibition, and were also found to be able to inhibit BRD4 and IDO1. The docking studies were performed to rationalize the biochemical potency against LSD1 and to explain the observed activity discrepancy. The proof-of-concept work may provide an example for other natural ligand-based drug design. PMID- 30472604 TI - Optimization of a 1,3,4-oxadiazole series for inhibition of Ca2+/calmodulin stimulated activity of adenylyl cyclases 1 and 8 for the treatment of chronic pain. AB - Adenylyl cyclases type 1 (AC1) and 8 (AC8) are group 1 transmembrane adenylyl cyclases (AC) that are stimulated by Ca2+/calmodulin. Studies have shown that mice depleted of AC1 have attenuated inflammatory pain response, while AC1/AC8 double-knockout mice display both attenuated pain response and opioid dependence. Thus, AC1 has emerged as a promising new target for treating chronic pain and opioid abuse. We discovered that the 1,3,4-oxadiazole scaffold inhibits Ca2+/calmodulin-stimulated cyclic adenosine 3',5'-monophosphate (cAMP) production in cells stably expressing either AC1 or AC8. We then carried out structure activity relationship studies, in which we designed and synthesized 65 analogs, to modulate potency and selectivity versus each AC isoform in cells. Furthermore, molecular docking of the analogs into an AC1 homology model suggests the molecules may bind at the ATP binding site. Finally, a prioritized analog was tested in a mouse model of inflammatory pain and exhibited modest analgesic properties. In summary, our data indicate the 1,3,4-oxadiazoles represent a novel scaffold for the cellular inhibition of Ca2+/calmodulin-stimulated AC1- and AC8 cAMP and warrant further exploration as potential lead compounds for the treatment of chronic inflammatory pain. PMID- 30472605 TI - Synthesis and evaluation of chalcone analogues containing a 4-oxoquinazolin-2-yl group as potential anti-tumor agents. AB - The chalcone motif can be found in many molecules that contribute to essential biological processes, and many chalcone-containing compounds exhibit potent anti cancer activity. Here, we synthesized two series of chalcone analogues (3a-s and 6a-s) based on substituting the chalcone B-ring or A-ring with a 4-oxoquinazolin 2-yl group, and then evaluated them for cytotoxic activity in human colorectal HCT-116 and breast cancer MCF-7 cell lines. Compounds 3a-s (in which a 4 oxoquinazolin-2-yl group functioned as the B-ring) were markedly more cytotoxic than compounds 6a-s (in which 4-oxoquinazolin-2-yl group functioned as the A ring), based on their IC50 values to inhibit proliferation. Compound 3f was found as the most potent among 38 analogues and the mechanism of its cytotoxicity was investigated. Flow cytometry indicated that HCT-116 cells treated with compound 3f resulted in a dose-dependent accumulation of cells in the sub-G1 phase, which is representative of apoptotic cells. Subsequent assays (including Annexin V FITC/PI, AO-EB, MitoSOXTM Red and JC-1 staining) confirmed that 3f exposure induced apoptosis in HCT-116 cells. Immunoblotting analysis indicated that cellular exposure to 3f increased the cleavage of PARP1 and caspases 3, 7, and 9. Taken together, this novel chalcone analogue has a cytotoxic effect on cultured cancer cell-lines that is likely mediated by inducing apoptosis via the mitochondrial death pathway. PMID- 30472606 TI - Low molecular weight PEI-based fluorinated polymers for efficient gene delivery. AB - Fluorinated biomaterials have been reported to have promising features as non viral gene carriers. In this study, a series of fluorinated polymeric gene carriers were synthesized via Michael addition from low molecular weight polyethyleneimine (PEI) and fluorobenzoic acids (FBAs)-based linking compounds with different numbers of fluorine atoms. The structure-activity relationship (SAR) of these materials was systematically investigated. SAR studies showed that fluorine could screen the positive charge of these polymers. However, this shielding effect of fluorine would endow fluorinated polymers with good balance between DNA condensation and release. In vitro transfection results suggested that these fluorinated polymers could mediate efficient gene delivery. Flow cytometry and confocal microscopy studies demonstrated that more efficient cell uptake could be achieved by fluorinated materials with more fluorine atoms. Cytotoxicity assays showed that these fluorinated materials exhibited very low cytotoxicity even at high mass ratios. This study demonstrates that FBA-based fluorinated biopolymers have the potential for practical application. PMID- 30472607 TI - Effect of temperature on the microflora community composition in the digestive tract of the veined rapa whelk (Rapana venosa) revealed by 16S rRNA gene sequencing. AB - The veined rapa whelk, Rapana venosa, a poikilotherm that is susceptible to temperature, is an important and valuable fishery resource in China but a major invader around the world. We studied the effects of abnormal temperature on the digestive tract microflora of R. venosa to investigate how temperature impacts its digestion and ingestion. We characterized the microflora in nine samples by sequencing the 16S rRNA gene. To assess the species diversity within the samples, effective tags were clustered at 97% similarity by default. Mycoplasma was the most abundant genus among the three groups, and the Proteobacteria phylum had the highest diversity. However, the microflora structure in the digestive tract was significantly different at different temperatures. The top five most abundant genera in the samples housed at 16 degrees C were Mycoplasma, Phyllobacterium, Aliivibrio, Psychromonas, and Delftia, whereas those in the samples housed under 22 degrees C were Mycoplasma, Phyllobacterium, Delftia, Spirochaeta_2, and Sphingomonas, and those in the samples housed at 28 degrees C were Mycoplasma, Phyllobacterium, Vibrio, Delftia, and Aliivibrio. The family Flavobacteriaceae was more abundant in R. venosa housed at 22 degrees C and 28 degrees C, whereas a significant decrease in Flavobacteriaceae abundance and a substantial increase in Mycoplasmataceae abundance were observed in R. venosa housed at 16 degrees C. The alteration in the digestive tract microflora might further affect the function of the R. venosa digestive tract. The results presented herein might provide further insight into investigations on the effects of temperature on the digestion and ingestion of gastropods. PMID- 30472608 TI - RNA-Seq analysis of the bioluminescent and non-bioluminescent species of Elateridae (Coleoptera): Comparison to others photogenic and non-photogenic tissues of Elateroidea species. PMID- 30472609 TI - Mechanisms underlying nickel nanoparticle induced reproductive toxicity and chemo protective effects of vitamin C in male rats. AB - The purpose of this research is to go a step further study on the reproductive toxicities and the underlying mechanisms induced by nickel nanoparticles (NiNPs), and the possible protective action of vitamin C. Animal experiment was designed according to the one-generation reproductive toxicity standard, and rats were exposed to NiNPs through gavage. Ultrastructural, reactive oxygen species (ROS), oxidant and antioxidant enzymes, and cell apoptosis-related factors in the testicular tissue were analyzed. In contrast with the control group, the activity of surperoxide dismutase (SOD), catalase (CAT) and gonad-stimulating hormone (GSH) was reduced, while the content of nitric oxide (NO), malondialdehyde (MDA) and ROS was increased in the NiNPs treated animals. As the doses of NiNPs increase, the mRNA of apoptotic related factor Caspase-9, Caspase-8 and Caspase-3 showed an obviously upregulation. Protein expression of Bcl-2-associated X Protein (Bax) and apoptosis inducing factor (AIF) was significantly unregulated. After addition of antioxidants-vitamin C, the toxicity was reduced. Injured testicular tissue indicated that NiNPs exposure could damage the reproductive system. Our results suggest that NiNPs induce significant reproductive toxicities. The cellular apoptosis might be induced by caspase family proteinases, but the regulator factor (factor associated suicide (Fas), B-cell lymphoma-2 (Bcl-2), Bax, BH3-interacting domain death agonist (Bid) and AIF protein) might not be involved in this process. Thus, the mechanism of reproductive toxicity of NiNPs on rat testes involves in the induction of oxidative stress, which further results in cell apoptosis. Antioxidants-vitamin C shows a significant inhibition on the reproductive toxicities induced by NiNPs. PMID- 30472610 TI - Effect of land use and soil properties in the feasibility of two sequential extraction procedures for metals fractionation. AB - Several sequential extraction procedures are widely applied for metals chemical fractionation in the literature. However, their limitations to be used in different soils and metals have not been discussed in detail. This study compares two of the most commonly used extraction methods for metals chemical fractionation: Tessier and BCR. The objectives were to i) assess the differences between concentrations of metals extracted in each fraction by both Tessier and BCR procedures; ii) elucidate if soil properties affected the extraction ability of each fraction from both procedures; and iii) evaluate how land use contributes to different chemical metal distribution. Results indicated that both methods provide similar results when were applied to the same soil, since non-significant differences were found in metal concentrations between both methods at each fraction. Conversely, when we compared among land uses, significant differences were found in the metal concentration between both methods, especially between agricultural/urban/industrial against forest soil. Redundancy analysis showed that in carbonate-rich soils, BCR extraction method could cover up the real concentration of exchangeable metals with those bound to the carbonate phase, being the Tessier method the most suitable one for this kind of soils. Therefore, although sequential extraction is a useful tool to understand the distribution of metals in soil, the method used must be selected according to the land use and specific soil characteristics, taking into account at least, soil carbonate content. PMID- 30472611 TI - Toxicity effects of the organic UV-filter 4-Methylbenzylidene camphor in zebrafish embryos. AB - Ultraviolet (UV) filters are widely used in personal care products and due to their lipophilicity these chemicals tend to bioaccumulate in the aquatic biota. 4 Methylbenzylidene camphor (4-MBC) is one of the most used UV-filters, and it is commonly detected in freshwater fish tissues. This substance is suspected to be an endocrine disruptor due to its interaction with Hypothalamus-Pituitary-Gonadal (HPG) and HP-Thyroid (HPT)-axis. The main objective of this study was to evaluate the effects of 4-MBC on apical endpoints, biochemical markers and on genes involved in endocrine pathways in Danio rerio. Zebrafish embryos were exposed to 4-MBC (0.083-0.77 mg/l) from 0 to 96 h post-fertilization (hpf). Hatching, heart rate and malformations were the apical endpoints assessed. Alterations on neurotransmission and oxidative stress were evaluated through acetylcholinesterase (AChE), catalase (CAT) and glutathione S-transferase (GST) enzymatic activities. Endocrine effects were analysed by the expression of genes involved in HPG and HPT-axis of embryos exposed 96 h to the EC10 of 4-MBC (0.19 mg/l). Exposure to 4-MBC induced morphological abnormalities during embryonic development, including notochord curvature, delayed absorption of yolk sac and pericardial oedema. Concentration of 0.77 mg/l 4-MBC decreased embryo heart rate at 48h. At neurotransmission level, an induction of AChE at concentrations above 0.15 mg/l was observed. Malformations and decreased heart rate along with alterations observed at neurotransmission level might have compromised zebrafish larvae equilibrium. Glutathione S-transferase induction above 0.15 mg/l 4-MBC suggests activation of detoxification processes. Furthermore, observed brain aromatase gene down-regulation by 4-MBC suggests impairment of normal functioning of HPG axis in zebrafish. PMID- 30472612 TI - Quantitative analysis of genetic associations in the biodegradative pathway of PAHs in wetland sediments of the Bohai coast region. AB - The present study characterized the distribution and sources of polycyclic aromatic hydrocarbons (PAHs) in 57 sediment cores collected from estuary and tidal flat wetlands in the Bohai coast region and investigated the molecular degradation mechanism of PAHs. The results showed that the PAH concentrations in estuary sediments were significantly higher than in tidal flat sediments. PAH patterns and pollutant sources were more complicated in estuary sediments. Quantitative response relationships showed that in estuary sediments, the key factors affecting PAH degradation changed from initial dioxygenase genes and C23O to salicylate hydroxylase genes and C23O with an increase in the PAH ring number. In contrast, for tidal flat sediments, the initial dioxygenase genes remained the key factors (nidA and nahAc/nagAc, except only nidA for 5-ring PAHs) related to PAHs with different ring numbers. Non-metric multidimensional scaling (NMDS) analysis revealed that the lower catechol dioxygenase pathway coupled with the upper pyrene dioxygenase pathway. The total polycyclic aromatic hydrocarbon (TPAH) level across the Bohai coast region was most affected by catechol dioxygenation (catA + C23O). Catechol dioxygenation was directly affected by naphthalene dioxygenation/nahG ((nahAc + nagAc)/nahG), indicating that the interaction within the upper pathway coupled with the lower pathway. In addition, TOC had direct positive effects on catechol dioxygenation and nidA. This study improves our understanding of the biodegradative pathway of PAHs with different ring numbers and the response of PAHs to biotic and abiotic factors. PMID- 30472613 TI - UV-light intervened synthesis of imidazo fused quinazoline and its solvatochromism, antioxidant, antifungal and luminescence properties. AB - The photochemical preparation of benzo[4,5]imidazo[2,1-b]quinazoline was assessed under the illumination of UV wavelength (>360 nm). The compound 3,4 dihydronaphthalen-1(2H)-one 1 with 1H-benzo[d]imidazol-2-amine 2 in the existence of KOH/DMF which lead to the aromatized compound 3. The notable remark of this reaction is that the UV irradiation (312 nm) plays a vital part in the formation of compound, 3 in shorter duration (2 h) which resulted in higher yield of 96%. Compound 3 was analyzed by H1, C13 NMR, and HRMS. Solvatochromism impacts of the compound 3 was computed with different solvents (DCM < methanol< DMF < DMSO). The compound, 3 was presented to in-vitro free radical screening strategy. The standard ascorbic acid has less IC50 value - than compound 3. Further, it was subjected to in-vitro fungicidal action against two Aspergillus species (A. flavus & niger). The anti-fungal activity of compound 3 additionally demonstrated great action, when compared antifungal specialist Fluconazole. PMID- 30472614 TI - Catalytic, antibacterial and antibiofilm efficacy of biosynthesised silver nanoparticles using Prosopis juliflora leaf extract along with their wound healing potential. AB - The present study focuses on the catalytic, antibacterial and antibiofilm efficacy of silver nanoparticles (AgNPs) in an easy, rapid and eco-friendly pathway. Herein, we have synthesised AgNPs using an aqueous extract of P. juliflora leaf. The bioactive compounds present in the extract are responsible for the reduction of Ag+ to Ag0. The particle synthesis was first observed by visual color change and then characterized using UV-visible spectroscopy to confirm the formation of AgNPs. The synthesis conditions were then optimised using critical parameters such as reaction time, AgNO3 concentration, extract to AgNO3 ratio and temperature of the reaction. The hydrodynamic size of the AgNPs with Dynamic light scattering (DLS) was 55.24 nm, while, was in the range of 10 20 nm as determined through Transmission Electron Microscopy (TEM). Further, Fourier transform infrared spectroscopy (FTIR) studies were conducted to discern the functional groups or compounds responsible for the reduction of silver nitrate as well as the capping of silver nanoparticles. Later, X-ray diffraction (XRD) results showed crystalline nature of the biosynthesized AgNPs. To evaluate their antibacterial potential, AgNPs were assessed through disc-diffusion assay, which resulted in an appreciable dose-dependent activity. The antibacterial potential was investigated through disc-diffusion assay against E. coli and P. aeruginosa. The Congo red agar (CRA) plate assay successfully revealed the anti biofilm activity against B. subtilis and P. aeruginosa. Further, the catalytic activity of synthesised AgNPs was assessed against azo dyes such a Methylene Blue (MB) and Congo Red (CR) that resulted in its effective degradation of toxic compounds in a short span of time. Further, AgNPs were assessed for their wound healing potential. PMID- 30472615 TI - Evaluation of lesion burden in a bone-by-bone comparison of osteological and radiological methods of analysis. AB - OBJECTIVE: To evaluate differences in lesion identification in skeletal remains with respect to bone type and method of analysis. MATERIALS: 212 mostly 19th century adult skeletons from St. Bride's Church in London. METHODS: Using a standard protocol, an osteologist evaluated each set of remains for lesions. A radiologist used the same system to examine radiographs of the crania, humeri, pelves, tibiae, and femora. RESULTS: Osteological analysis noted more lesions per bone type. All bone types examined showed positive, statistically significant correlations between the number of lesions identified by each analytical method. The humerus, tibia, and femur exhibited the strongest correlations. The pelvis exhibited the weakest correlation. For the cranium and pelvis, males showed stronger correlations. CONCLUSIONS: Sex-related differences in correlations were likely influenced by the presence, in females, of lesions affecting the entire skeleton (e.g., osteoporosis). Greater correlations between analytical modalities were observed for long bones. SIGNIFICANCE: Our findings quantify the contexts in which radiological and osteological evaluations converge and diverge and discuss the implications of these results for lesion burden interpretation. LIMITATIONS: Generalizability, potential subjectivity of evaluative methods. SUGGESTIONS FOR FURTHER RESEARCH: Assessment of another study collection using the same methods, to determine if the similar correlations are observed. PMID- 30472616 TI - One-pot synthesis of silane-modified hyaluronic acid hydrogels for effective antibacterial drug delivery via sol-gel stabilization. AB - A silane-modified hyaluronic acid (HA) hydrogel was prepared using a facile one pot method with 3-glycidyloxypropyl-trimethoxysilane (GPTMS). The sol-gel route, specifically the self-condensation of the silane, was combined with the HA hydrogel system to modify its network structure. Nuclear magnetic resonance (NMR) spectroscopy and X-ray photoelectron spectroscopy (XPS) confirmed the chemical functionalization of GPTMS. The morphological, rheological properties, and enzymatic degradation of the hydrogels were also evaluated. The sol-gel stabilized HA hydrogel exhibited superior mechanical properties and biochemical stability as well as excellent biocompatibility without triggering any negative biological effects. Furthermore, an efficient drug-loading strategy is suggested that uses sol-gel encapsulation without the need for any chemical reagents, resulting in sustained release characteristics. Vancomycin was used as a model drug, and enhanced efficacy was demonstrated in antibacterial tests. The proposed approach is expected to have great potential for biomedical applications, and our findings will provide insight into the structure-property relationship of hydrogels. PMID- 30472617 TI - Modification and crosslinking of gelatin-based biomaterials as tissue adhesives. AB - Tissue adhesives have been developed to overcome the difficulties of conventional wound closure techniques (e.g. sutures and staples), such as the potential for collateral damage and difficulty of stopping body fluid and gas. At the same time, it provides advantages such as simpler implementation, less painful, and does not require removal. However, representative adhesives such as cyanoacrylates and fibrin glues are plagued by cytotoxicity and low adhesion. In this study, we choose instead gelatin as the backbone of adhesive, due to its biocompatibility, biodegradability, and low cost. Firstly, catechol-modified gelatin and phenol-modified gelatin were synthesized via an EDC/NHS chemistry. Then, gelatin-based adhesives were prepared via ruthenium-based photochemistry, including photo-crosslinked gelatin (PG), phenol-modified gelatin (PPG), and catechol-modified gelatin (PCG). We also compared the photo-crosslinked adhesives to the recently reported ion-crosslinked catechol-modified gelatin. Our results indicate that gelatin-based adhesives demonstrate lower swelling index, great degradability, and low cytotoxicity. This shows that gelatin-based adhesives demonstrate great potential for wound closure and healing. PMID- 30472619 TI - Isolation of RNA and beta-NAD by phenylboronic acid functionalized, monodisperse porous silica microspheres as sorbent in batch and microfluidic boronate affinity systems. AB - Monodisperse-porous silica microspheres 5.5 MUm in size were obtained by a staged shape templated hydrolysis-condensation method, with a bimodal pore-size distribution. 3-aminophenylboronic acid (APBA) was covalently attached onto the silica microspheres with a capacity of 0.476 mmol APBA/g microspheres. The boronate affinity isolation behaviour of ribonucleic acid (RNA) containing cis diol at 3'-end was investigated by using APBA attached-silica microspheres as the sorbent in batch fashion. A short-chain diol carrying agent, beta-nicotinamide adenine dinucleotide (beta-NAD) was used as a target molecule with stronger affinity for phenylboronic acid ligand. The maximum equilibrium adsorptions for RNA and beta-NAD were determined as 60 and 159 mg/g sorbent, respectively. By using the synthesized sorbent, phosphate buffer at pH 7.0 containing sorbitol was successfuly used as a mild elution medium for obtaining quantitative desorptions with both RNA and beta-NAD. RNA isolations from mammalian and bacterial cells were successfully performed while protecting the structural integrity of RNA via boronate affinity interaction in batch fashion. A microfluidic boronate affinity system including a microcolumn 300 MUm in diameter was also constructed using APBA attached-silica microspheres as the stationary phase. The breakthrough curves of microfluidic system were obtained by studying with different feed concentrations of RNA and beta-NAD. Quantitative desorptions and satisfactory isolation yields were obtained with RNA and beta-NAD in the microfluidic system. The proposed system is useful for boronate affinity applications in genomics or proteomics in which valuable cis-diols at low concentrations are recovered from low-volume samples. PMID- 30472618 TI - Stable mesoporous silica nanoparticles incorporated with MoS2 and AIE for targeted fluorescence imaging and photothermal therapy of cancer cells. AB - Theranostics for imaging-guided cancer treatment have obtained great attention in recent years for their outstanding capability of both tumor diagnosis and treatment. Molybdenum disulfide (MoS2) nanosheets revealed excellent photothermal conversion efficiency, which could be used as photothermal agents. However, MoS2 nanosheets would often quench or decrease the emission of fluorescence dyes when they were incorporated with these dyes to construct fluorescence-imaging-guided nanotheranostic systems. In this work, MoS2 nanosheets were embedded into mesoporous silica nanoparticles (MSNs), and Aggregation Induced Emission (AIE) fluorogen PhENH2 was chemically modified on the surface of MSNs, which could demonstrate more stable fluorescence emission compared with other MSNs with physically absorbed luminescent molecules. Moreover, folic acid (FA) was also chemically decorated on the nanoparticles to facilitate their targeted bioimaging and photothermal therapy. As expected, the obtained PhENH2-MoS2-FA MSNs could be efficiently taken up by MDA-MB-231 cells than HepG2 cells, owing to the over expressed FA receptors on MDA-MB-231 cells. Meanwhile, these MDA-MB-231 cells could be efficiently killed under an 808 nm laser irradiation. These results indicated that the achieved multifunctional MSNs chemically decorated with AIE fluorogens would demonstrate more stable fluorescence for bioimaging-targeted photothermal therapy of MDA-MB-231 cells, which made them promising nanotheranostics for further cancer treatment. PMID- 30472620 TI - Colloidal properties of protein complexes formed in beta-casein concentrate solutions as influenced by heating and cooling in the presence of different solutes. AB - Monomeric bovine beta-casein self-associates into micelles under appropriate conditions of protein concentration, serum composition and temperature. The present study investigated self-association characteristics of a beta-casein concentrate (BCC) prepared from milk at pilot-scale using membrane filtration. The BCC had a casein:whey protein ratio of 77:23, with ~95% of casein consisting of beta-casein, and the remainder being mostly kappa-CN. BCC was reconstituted to 1.2% protein (a typical level in infant formula) in various liquid media at pH 6.8 and incubated at different temperatures from 4 to 63 degrees C for 30 min. Self-association of beta-casein on heating was thermo-reversible in deionised water, lactose (4, 6 or 8%) or calcium (9 mM) solutions. In most serum phases, BCC became highly opaque after incubation at 63 degrees C, but clarified rapidly during cooling to 25 degrees C. However, in simulated milk ultrafiltrate (SMUF), which has a high ionic strength and is supersaturated in calcium phosphate (CaP), BCC remained opaque during cooling to 25 degrees C, and retained residual turbidity after 15 h of holding at 4 degrees C; if SMUF was prepared without phosphate then turbidity development in BCC solutions was markedly reduced. The complexes responsible for this turbidity development were successfully dissociated with 50 mM trisodium citrate. Analysis of pH during heating and holding at 60 degrees C indicated that SMUF acidified continuously under the period of study, while acidification in BCC/SMUF mixtures terminated after a short period, indicating that the type of CaP formed on heating is altered in the presence of BCC. This study demonstrates that BCC ingredients exhibit pronounced temperature-dependant changes in colloidal properties that are strongly affected by the presence of minerals commonly found in nutritional product formulations. PMID- 30472621 TI - A facile one-pot method to prepare peroxidase-like nanogel artificial enzymes for highly efficient and controllable catalysis. AB - Novel artificial enzymes are highly desired to overcome the shortcomings of natural enzymes during industrial or biological applications. Here we designed and prepared nanogel-based artificial enzymes (NAEs) to mimic natural horseradish peroxidase (HRP) using a facile one-pot, scalable method. The poly(N isopropylacrylamide) (PNIPAM) matrix provided a temperature-responsive and size controllable scaffold for the NAEs, and 1-vinylimidazole (Vim) moieties stabilized the enzymatic centers (Hemin) through coordination interaction. The feeding ratios of the components to prepare NAEs were subsequently studied and optimized to ensure the NAEs possess the highest catalytic activity and stability. The optimized NAEs were quite stable and can maintain their catalytic activities over a broad range of heat or pH treatments, and a long storage period as well. The NAEs are active to catalytic oxidation of several azo compounds and their activities can easily be switched on/off by changing the surrounding temperature. Taken together, these easily made, highly stable, efficient and activity-switchable NAEs could mimic natural HRP while overcoming their shortcomings and have a potential in wastewater treatment and controllable catalysis. PMID- 30472622 TI - Immobilization of functional polymers on poly(4-benzoyl-pxylylene-co-p-xylylene) films via photochemical conjugation for modulation of cell adhesion. AB - Surface modification with functional materials, such as anti-fouling or thermal responsive polymers, on biomedical devices benefits their clinical performance. Simple and versatile technologies, which could be applied to a wide variety of substrates, are still highly desirable. Chemical vapor deposition (CVD) of 4 benzoyl-[2,2]paracyclophane (Benzoyl-PPX) layers attracts much attention because the photoreactive platform could be deposited onto almost every substrate for the conjugation of functional molecules. In this study, poly(ethylene glycol) (PEG) was conjugated onto Benzoyl-PPX via UV illumination. The deposited PEG films could effectively reduce protein adsorption and cell attachment. The low-fouling properties of the PEG films were positively correlated with the molecular weight and concentration of PEG. We found that a PEG film, thicker than 16 nm and with a water contact angle of 30 degrees , is a prerequisite for effective inhibition of cell attachment. We also demonstrated that the PEG coating was stable under acidic and basic environments. Furthermore, poly(N-isopropyl acrylamide), PNIPAAm, could be also tethered on the Benzoyl-PPX via UV illumination, and possessed thermal-responsive properties. Intact cell sheets could be released from the PNIPAAm film by decreasing culture temperature. The results indicate that Benzoyl-PPX is an excellent photoreactive platform for the conjugation of functional polymers for modulation of cell attachment. PMID- 30472623 TI - On the effect of ligand shell heterogeneity on nanoparticle/protein binding thermodynamics. AB - Nonspecific protein adhesion to nanoparticle (NP) has been proven to have important implications in nanomedicine. However, there are only a few examples of careful studies relating protein binding thermodynamics to NP physicochemical features. In particular, a systematic investigation of how NP/protein binding parameters scale with size for sub-10 nm NPs and whether this scaling is affected by the surface feature of NPs remain unaddressed. Previously, we have developed an analytical ultracentrifugation (AUC) based method to determine NP/protein binding thermodynamic parameters that was shown to be particularly effective for sub-10 nm NPs. In this work, we exclusively utilize this method to investigate the binding parameters for a well-defined set of gold NPs with varying size and surface ligand ratios to the model protein human serum albumin. We find that gold NPs with a homogenous distribution of hydrophilic molecules in their ligand shell have a monotonic dependence of their binding constants and of the maximum number of bound proteins as a function of their surface area. On the other hand, a more complex relation is found for particles with patchy ligand shell. The findings of this research highlight the significance of surface morphology on the interplay between protein binding behavior and NP size. PMID- 30472624 TI - Influence of intrauterine dispositive in human papillomavirus clearance. AB - INTRODUCTION: An important inverse relation between IUD use and risk of cervical cancer has been proved. Women who used IUD had half the risk of developing cervical cancer. The mechanism how IUD is a protector factor is still unknown. Could be improving the clearance of HPV infection or stopping progression to cancer from preneoplasic lesion. The aim of the study is to check if IUD increases HPV clearance, that is, checking if after 1 year HPV infection disappears in more patients using IUD than those not using it. STUDY DESIGN: This is a cohort case-control prospective study, carried out in Universitary Hospital La Zarzuela in Madrid, Spain, performed between October 2015 and April 2018. No pregnant women between 25-50 years old, with HPV cervical infection were enrolled. We separated the participants into two groups: an IUD group, with women starting using IUD and non IUD group, with women using any other contraceptive method or none. HPV genotyping of cervical cytology samples were performed initially on enrolment day and one year after. RESULTS: 254 participants were enrolled at the beginning of the study, 85 in the IUD group and 169 in the control group (non IUD). 179 participants completed the study, 54 (31%) in IUD group and 120 participants in non IUD group (69%). 38 women from IUD group cleared HPV infection (69.5%) and 65 women from control group cleared it (54.2%) (p = 0.044). An association in logistic regression was observed in HPV clearance with different factors. Firstly, higher percentage of patients with IUD clear the HPV infection than those in control group significantly associated (OR = 0.698, CI 95%; 0.251-0.998, p = 0.046). Clearance was higher in patients with low-risk HPV infection comparing with high risk HPV (OR = 1.078, CI 95%; 1.126-4.6.281, p = 0.026) and in patients with only one HPV type than those with more than one (OR = 0.194, CI 95%; 0.084-0.403, p < 0.001). CONCLUSIONS: In Spanish women with HPV infection, the HPV clearance between IUD and non IUD groups show results with statistical significance, patients with IUD have higher clearance rates. There were differences also between suffering one HPV type or more than one, and having low-risk HPV or high-risk HPV infection. PMID- 30472625 TI - Proteomics of nucleocytoplasmic partitioning. AB - The partitioning of the proteome between nucleus and cytoplasm affects nearly every aspect of eukaryotic biology. Despite this central role, we still have a poor understanding of which proteins localize in the nucleus and how this varies in different cell types and conditions. Recent advances in quantitative proteomics and high-throughput imaging are starting to close this knowledge gap. Studies on protein interaction are beginning to reveal the spectrum of cargos of nuclear import and export receptors. We anticipate that it will soon be possible to predict each protein's nucleocytoplasmic localization based on its importin/exportin interactions and its estimated diffusion rate through the nuclear pore. This insight is likely to provide us with a fundamental understanding of how cells use nucleocytoplasmic partitioning to encode and relay information. PMID- 30472626 TI - Effect of Lactobacillus acidophilus and Porphyromonas gingivalis on proliferation and apoptosis of gingival epithelial cells. AB - PURPOSE: This study aimed to evaluate the possible antagonistic effects of Lactobacillus acidophilus on Porphyromonas gingivalis, and detect inhibition of Lactobacillus acidophilus on Porphyromonas gingivalis when they are co-cultured with human gingival epithelial cells. MATERIALS AND METHODS: Human gingival epithelial cells were co-cultured with Lactobacillus acidophilus and Porphyromonas gingivalis alone or together. The amount of Porphyromonas gingivalis adhering to or invading the epithelial cells were determined by bacterial counts. The cellular proliferation was assayed by the MTT method. Apoptosis was detected by flow cytometry with apoptosis detection kit. RESULTS: On one hand, Lactobacillus acidophilus reduced the inhibitory effect of Porphyromonas gingivalis on the human gingival epithelial cells proliferation in a dose dependent manner. On the other hand, Porphyromonas gingivalis induced significant apoptosis on human gingival epithelial cells, and Lactobacillus acidophilus inhibited this apoptosis-inducing effect of Porphyromonas gingivalis in a dose dependent manner. CONCLUSIONS: Porphyromonas gingivalis inhibits the proliferation and induces the apoptosis of human gingival epithelial cells. Lactobacillus acidophilus could attenuate this effect in a dose-dependent manner, and it thus reduces the destruction from pathogens. Lactobacillus acidophilus could be an effective candidate for probiotic therapy in periodontal diseases. PMID- 30472627 TI - Combined Puestow and choledocoduodenostomy for concomitant large pancreatic duct and primary choledochal stones: A case series. AB - INTRODUCTION: Multiple and large pancreatic duct stones concomitant with primary choledochal stones is a rare case. Patients usually present with recurrent jaundice and signs of pancreatitis. Endoscopic retrograde cholangiopancreatography (ERCP) is the leading method to manage the patients. But ERCP has difficulties when facing the multiple and large stones PRESENTATION OF CASE: Our first case was a 51-years-old man who was admitted to our surgery unit with a diagnosis of chronic pancreatitis. Plain abdominal radiogram, Abdominal MSCT and Magnetic Resonance Cholangiopancreatography (MRCP) showed opacity suspected as stone at the pancreatic duct and distal part of the common bile duct. The second case was a 48-years-old female with the clinical presentation of left upper quadrant pain and history of chronic pancreatitis and intermittent jaundice. Plain abdominal radiogram and MRCP revealed multiple stones in the main pancreatic duct and common bile duct stones. Our third case was female, 60-years old, who was hospitalized with jaundice and recurrent upper abdominal pain with a history of open cholecystectomy one month previously. Radiologic examination showed multiple stones in the main pancreatic duct and common bile duct. Combined longitudinal pancreatojejunostomy Roux-en-Y and Choledoco-duodenostomy were performed successfully in all cases. Postoperative follow-up showed good recovery of all patients. DISCUSSION: Since ERCP is not proper to be used for multiple and large pancreatic duct stones, we performed a combination of longitudinal pancreatojejunostomy Roux-en-Y and choledoco-duodenostomy to treat the patients and prevent the recurrence. CONCLUSION: The incidence of multiple pancreatic duct stones and large choledochal stones is infrequent. Surgical treatment with combined longitudinal pancreatojejunostomy Roux-en-Y and Choledoco-duodenostomy is safe and effective to resolve jaundice and recurrent pain caused by chronic pancreatitis. PMID- 30472628 TI - Gastric ectopic pancreas mimicking a gastrointestinal stromal tumour: A case report. AB - INTRODUCTION: The diagnosis and management of upper gastrointestinal tract submucosal tumours can be challenging due to the difficulties with adequate pre operative characterization and tissue sampling. PRESENTATION OF THE CASE: A 61 year-old female patient underwent esophagogastroduodenoscopy because of epigastric pain and episodic vomiting. A submucosal tumour was found along the greater curvature in the antrum. On endoscopic ultrasound, the mass was suspected to be a gastrointestinal stromal tumour. The patient was referred for laparoscopic excision. The final histopathological examination confirmed an ectopic pancreas, not a gastrointestinal stromal tumour as thought preoperatively. DISCUSSION: Despite an adequate pre-operative diagnostic workup with endoscopic ultrasonography, the lesion was misdiagnosed as a gastrointestinal stromal tumour and surgery was performed to excise an ectopic pancreas, essentially a benign lesion. CONCLUSION: The case highlights the absence of firm diagnostic criteria to differentiate submucosal gastric lesions. PMID- 30472629 TI - A technique to identify the axillary nerve and its cutaneous branch for triceps nerve-to-deltoid nerve transfer. A case report. AB - INTRODUCTION: Triceps nerve-to-deltoid nerve transfer requires the identification of the axillary nerve in the quadrilateral space. This may be difficult especially for residents-in-training. The senior author is a Professor of Hand Surgery at a teaching institution and has devised a new technique of identification of the axillary nerve and its cutaneous branch using surface land marks and on-table ultrasonography. CASE REPORT: The axillary nerve and the quadrilateral space is first identified using anatomical landmarks. The ultrasound probe is the used to identify the quadrilateral space and the axillary nerve which appears as hyper-echoic oval-shaped structure. The ultrasound probe is then moved to scan the cutaneous branch of the axillary nerve as it branches off the main nerve trunk. Finally, the cutaneous branch is traced superficially till it becomes subcutaneous. This point is marked and the skin incision is made along this marked point. During surgery, the cutaneous branch is followed retrograde to the axillary nerve in the quadrilateral space. DISCUSSION: Ultrasound guidance for localization of various nerves is now routinely done by anesthetists in the Operating Room. This localization is used for nerve blocks and in patients with brachial plexus injuries. Hence, the ultrasound machine and the expertise are already available in the operating room; and no special arrangements with the Radiology Department are needed. CONCLUSION: A technique of identification of the cutaneous branch of the axillary nerve using anatomical landmarks and ultrasonography is described. The localization is accurate and is of help in patients undergoing triceps nerve-to-deltoid nerve transfer. PMID- 30472630 TI - Surgical treatment of giant gist with acute gastrointestinal bleeding: Case report. AB - INTRODUCTION: Gastrointestinal stromal tumors represent about 1% of the tumors of digestive tract. Their presentation consists often of indolent symptoms. However, they can present as surgical emergencies in rare cases. This work presents a case of a giant jejunal GIST that required emergent surgical treatment. CASE PRESENTATION: A 60-year-old male presented with abdominal pain and acute low gastrointestinal bleeding. During observation a palpable mass was detected in the periumbilical region, left hypochondrium and left flank. A non-total colonoscopy was inconclusive. An Angio-CT showed a large exophytic tumor arising from the 4th duodenal segment and first jejunal segment with approximately 20 * 14 x 13 cm, with apparent intratumoral bleeding. Due to haemodynamic instability, the patient was submitted to emergency laparotomy, in which a large tumor was found arising from the first jejunal segment. A segmental enterectomy was performed and the post-operative period ran without complications. The histopathologic exam showed a gastro-intestinal stromal tumor of epithelioid cell nature, with low mitotic count (<5 per 50HPF), categorized as T4N0 stage IIIA. The imunohistochemical analysis revealed positivity for CD117 (c-kit) and DOG-1. The patient started Imatinib therapy, and is free of disease recurrence for 3 years. CONCLUSIONS: This case pretends to review an unusual presentation of a giant jejunal intestinal GISTs as well as its management in an emergent context. PMID- 30472632 TI - Surgical fenestration and rehabilitation of a sports traumatic non-union ischial tuberosity fracture - Case report. AB - INTRODUCTION: Ischial tuberosity fractures and complications may be an under recognized diagnosis in adolescent athletes. Operative interventions differ and may include anchor re-fixations, resections and osteostimulating drilling and partial hamstring releases. This case report illustrates a novel and less invasive management of a non-union following a proximal ischial tuberosity avulsion. This approach has to our knowledge not previously been described. PRESENTATION OF CASE: The patient, a 14 years old female athlete, was complaining of sharp pain in the right side of the groin region, after an acute injury during a handball game. The pain was concentrated at the insertion of the adductor muscle group to the superior pubic ramus and the pubic symphysis. She was referred to our orthopaedic sports clinic after 6 months of unsuccessful conservative treatment. An MRI scan showed an ischial tuberosity non-union with a displacement less than 10 mm. Nine months after injury a surgical procedure was performed with the patient under general anaesthesia. An ultrasound guided fenestration of the non-union of the ischial tuberosity with a 1.6 mm Kirshner wire was performed. The enthesis was fenestrated 10 times, using a 1.2 mm syringe. Finally, a 5 ml local anaesthetic was injected in the area. 17 months after the trauma and 8 months postoperatively the patient had a full return to normal day activities including pain free squats and lunges. Radiologically the non-union was healed. CONCLUSION: This novel and less invasive surgical procedure may therefore be seen as a possible treatment option to non-union of the ischial tuberosity with minimal displacement. PMID- 30472631 TI - Duodenal gastrointestinal stromal tumors appear similar to pancreatic neuroendocrine tumors: A case report. AB - INTRODUCTION: Duodenal gastrointestinal tumors (GISTs) are rare. Duodenal GISTs and pancreatic neuroendocrine tumors (NETs) may appear similar on imaging studies. GISTs arising from the second or third portions of duodenum may be incorrectly diagnosed as pancreatic NETs. PRESENTATION OF CASE: The patient is a 79-year-old man who was referred to our hospital with a history of tarry stools and loss of consciousness. Urgent upper digestive tract endoscopy revealed a bleeding submucosal duodenal lesion, which was controlled using endoscopic clips. Enhanced computed tomography scan showed a hyper-vascular mass 50 mm in diameter, at the pancreatic uncus. The patient underwent a pylorus-preserving pancreaticoduodenectomy. Histologically, the tumor was composed of spindle-shaped cells immunohistochemically positive for c-kit and CD34, and the lesion diagnosed as a duodenal GIST. DISCUSSION: Duodenal GISTs often present with gastrointestinal bleeding, which can necessitate emergency surgery. Surgical resection with regional lymph node dissection is the optimal treatment for pancreatic NETs. In contrast, GISTs are generally treated with a minimal resection and without lymph node dissection. Thus, establishing the diagnosis is important in the management of these tumors. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is effective to establish the diagnosis of these lesions. CONCLUSION: A tumor located in the pancreatic head or mesenteric side of the duodenum cannot always be diagnosed based on imaging, and is ideally diagnosed histologically to guide the extent of resection. While EUS-FNA can establish the diagnosis, the complications of this procedure must be considered. PMID- 30472634 TI - Understanding the kinetics and molecular mechanism of unimolecular gas phase thermal decomposition of the alpha-ketoester methyl benzoylformate using RRKM and BET theories. AB - The RRKM calculation and bonding evolution theory analysis coupled with quantum theory of atoms in molecules have been used to investigate kinetics and molecular mechanism of gas phase thermal decomposition of methyl benzoylformate. The pressure-dependent rate coefficients, by applying different collisional efficiency values, indicated that the atmospheric pressure is in high-pressure limit of fall-off curve and low-pressure limit rate coefficients are in the range of 10-13-10-12 cm3 molec-1 s-1. Temperature dependence of high-pressure limiting of rate coefficient over the temperature range 733 +/- 20% K was estimated to be kinfinityRRKM(CBS-QB3)=2.92*1013s-1exp(227.4kJmol-1/RT) and kinfinityRRKM(PBE1PBE)=2.67*1013s-1exp(232.8kJmol-1/RT). Topological analysis of electron localization function and electron density at the B3LYP/6-311G(d,p) level reveal that the reaction can be occurred as going through seven turning points defined as methyl benzoylformate 8-CF?FF?TSFC?[CF?]-0: methyl benzoate + carbon monoxide. The molecular mechanism can be categorized in three fundamental sections A) heterolytic rupture of O3C8 bond and detachment of methoxy part; B) formation of O3C7 bond via donation bond formation mechanism; and C) heterolytic rupture of C7C8 bond and detachment of carbon monoxide. The electron density rho(3,-1)(r) in the region of bond forming and breaking increases and decreases along the reaction course to reflect bond strengthening and weakening, respectively. AIM parameters revealed that so long as chemical bonds are unformed/ruptured, interactions at related BCPs are covalence in nature, otherwise the nature of chemical bonds are strong shared covalence. PMID- 30472633 TI - A case of intrasplenic displacement of an endoscopic double-pigtail stent as a treatment for laparoscopic sleeve gastrectomy leak. AB - INTRODUCTION: The most frequent and severe complication after laparoscopic sleeve gastrectomy is gastric leak. Nowadays, there is no specific standard recommendation for its management, but the endoscopic placement of a double pigtail drain across the leak has been proven to be effective and minimally invasive. Stent displacement into the abdominal cavity is not common and intrasplenic migration is even more rare. CASE PRESENTATION: We report a case of a 49-year-old woman with intrasplenic displacement of an endoscopic double pigtail stent as a treatment for laparoscopic sleeve gastrectomy leak. DISCUSSION: Pigtail drain migration involving the spleen is rare but may potentially expose the patient to the risk of parenchymal abscess or haemorrhage. Often the clinic does not indicate early this complication. CONCLUSION: We underline the need for a close radiologic follow-up, regardless of clinical conditions, in all patients treated with double-pigtail drain and its early removal in case of migration. PMID- 30472635 TI - Advanced nanonetwork-structured carbon materials for high-performance formaldehyde capture. AB - Facile design and construction of advanced materials for eliminating the indoor formaldehyde pollution is still a great challenge but very desirable to provide clean air for human life. Herein, we report a high-performance formaldehyde adsorbent, i.e., a new type of nanonetwork-structured carbon (NNSC) with a hollow nanosphere as network unit by developing a facile, efficient and post-treatment free strategy. The NNSCs can be easily obtained by a simple carbonization of a mixture, in which natural wheat husk and Teflon are used as carbon precursor and biotemplate-in-situ-remover, respectively. The as-constructed NNSC exhibits a unique three-dimensional interconnected micro-, meso- and macroporous nanonetwork. Benefiting from such a valuable hollow nanosphere-interconnected network structure, the NNSCs show surprising formaldehyde gas adsorption properties including super-high storage capacity, ultrafast adsorption rate and efficient adsorptively active surface. Remarkably, their specific adsorption capacity and maximum adsorption rate are as high as 120.3 mg g-1 m-3 and 44.6 mg g-1 m-3 h-1, which make 18-fold and 41-fold enhancement when compared to activated carbon commercially used for formaldehyde adsorption, respectively. This work highlights an efficient solution to develop high-performance formaldehyde adsorbents by facile and rational construction of novel porous structure, simultaneously to provide a new avenue to high-value advanced materials for challenging environmental issue. PMID- 30472636 TI - Fabrication of silver seeds and nanoparticle on core-shell Ag@SiO2 nanohybrids for combined photothermal therapy and bioimaging. AB - In this study, two core-shell nanohybrids of different morphologies, namely SiO2 coated silver (Ag) with surface-exposed silver seeds (Ag@SiO2@Agseed) and SiO2 coated Ag with surface-exposed Ag nanoparticles (Ag@SiO2@AgNPs), were fabricated using the Stober method. Potential applications in bioimaging and photothermal therapy (PTT) of the two fabricated nanohybrids were also explored. Upon exposure to visible light (400 nm), Ag@SiO2@Agseed with surface-exposed Ag seeds exhibited greater photothermal conversion efficiency than Ag@SiO2@AgNPs. In vitro MTT assays in the dark and subsequent bioimaging using HeLa cells proved the potential biocompatibility of the fabricated core-shell nanohybrids. PTT applications of the two fabricated core-shell nanohybrids were studied by incubating HeLa cells with the nanohybrids, exposure to 400 nm laser, and subsequent staining with annexin V and propidium iodide (PI), and the two core shell nanohybrids gave distinctively different PI staining results. Interestingly, Ag@SiO2@Agseed caused higher cell death upon light exposure compared to Ag@SiO2@AgNPs as the former generated more heat within the cells. These results demonstrated potential bioimaging and PPT applications of the fabricated core-shell nanohybrids and offer a novel candidate for phototherapy based biomedical applications. PMID- 30472637 TI - Enzyme activation by alternating magnetic field: Importance of the bioconjugation methodology. AB - Iron oxide nanoparticles (NPs) are attractive materials for enzyme immobilization and, thanks to their superparamagnetism, can be accessed by remote stimuli. This can be exploited to activate molecules that are not remotely actuable. Here, we demonstrate that thermophilic enzymes chemically linked to NPs can be activated in a "wireless" fashion by an external alternate magnetic field (AMF). To this aim, we have conjugated, with different binding strategies, the thermophilic enzymes alpha-amylase and l-aspartate oxidase to iron oxide NPs obtaining NP enzyme systems with activities depending on the different orientations and stretching of the enzymes. Since enzyme activation occurs without a significant rise of the "overall" temperature of the systems, we have speculated a local NP enzyme heating that does not immediately interest the rest of the solution that remains at relatively low temperature, low enough to allow non-thermophilic enzymes to work together with the NP-conjugated thermophilic enzymes. Nanoactuation of thermophilic enzymes by AMF has potential applications in different fields. Indeed, multi-enzymatic processes with enzymes with different temperature optima could be carried out in the same reaction pot and thermolabile products could be efficiently produced by thermophilic enzymes without suffering for the high temperatures. Moreover, our findings represent a proof of concept of the possibility to achieve a fine-tuning of the enzyme-NP system with the aim to intervene in cell metabolism. PMID- 30472638 TI - Effect of electron-hole separation in MoO3@Ni2P hybrid nanocomposite as highly efficient metal-free photocatalyst for H2 production. AB - Effectiveness and stability of photocatalyst are of importance not only for improving H2 evolution, but also for the realization of enhanced semiconductors property in practical applications. In this study, a novel MoO3@Ni2P hybrid nanostructure is successfully prepared by a two step strategy of one-pot pyrolysis followed by calcination method. The reasonable design and controllable preparation of MoO3@Ni2P make it exhibit much high photocatalytic activities for H2 evolution with about 39.8 and 15.8 times compared to the pure MoO3 and Ni2P. This prominently increased effect is certified by results of various characterization such as SEM, TEM, XRD, XPS, BET, FT-IR, UV-vis DRS, transient photocurrent, steady-state fluorescence, transient-state fluorescence and Mott Schottky studies etc. The investigation indicates that the assembly of Ni2P nanoparticles and MoO3 can provide more active sites and accelerate the transfer of electrons. Moreover, the possible mechanism of photocatalytic H2 generation is proposed. PMID- 30472639 TI - Poly-Target Selection Identifies Broad-Spectrum RNA Aptamers. AB - Aptamer selections often yield distinct subpopulations, each with unique phenotypes that can be leveraged for specialized applications. Although most selections aim to attain ever higher specificity, we sought to identify aptamers that recognize increasingly divergent primate lentiviral reverse transcriptases (RTs). We hypothesized that aptamer subpopulations in libraries pre-enriched against a single RT may exhibit broad-spectrum binding and inhibition, and we devised a multiplexed poly-target selection to elicit those phenotypes against a panel of primate lentiviral RTs. High-throughput sequencing and coenrichment/codepletion analysis of parallel and duplicate selection trajectories rapidly narrowed the list of candidate aptamers by orders of magnitude and identified dozens of priority candidates for further screening. Biochemical characterization validated a novel aptamer motif and several rare and unobserved variants of previously known motifs that inhibited recombinant RTs to varying degrees. These broad-spectrum aptamers also suppressed replication of viral constructs carrying phylogenetically diverse RTs. The poly-target selection and coenrichment/codepletion approach described herein is a generalizable strategy for identifying cross-reactivity among related targets from combinatorial libraries. PMID- 30472641 TI - Genotyping polymorphic microhaplotype markers through the Illumina(r) MiSeq platform for forensics. AB - Microhaplotype markers are emerging forensic genetic markers that have received broad attention in forensics and may supplement existing genetic marker panels. Short tandem repeat polymorphisms (STRPs) and single nucleotide polymorphisms (SNPs) are the general genetic markers at present. Stutter and the high mutation rate of STR markers and the low polymorphism of SNP markers obstruct the solving of certain cases. Kidd proposed microhaplotype markers that encompass 2-4 SNPs. In this study, we screened microhaplotype loci through three criteria, and chose the Illumina(r) MiSeq platform to sequence the new markers. A new nomenclature was proposed and Perl-based tool FLfinder was designed to genotype the microhaplotype marker. After counting the number of haplotypes in samples that were sequenced and calculating common forensic parameters, 13 loci with high polymorphism were reported. Twelve of the 13 loci had an average allele coverage ratio (ACR) of 0.72 to 0.92. Structure analysis showed that 2504 samples (1000 genome project) could be divided into 5 groupings of populations, and each one representing a continental origin. The finding indicates that microhaplotype markers could be used for individual identification and ancestry inference, and a new choice is provided for forensic practice in the future. PMID- 30472640 TI - Characterization of Transcriptome Transition Associates Long Noncoding RNAs with Glioma Progression. AB - Long noncoding RNAs (lncRNAs) have been implicated in cancer biogenesis and prognosis. However, we still lack knowledge on their function during glioma progression. In this study, we analyzed the lncRNA expression profile across 907 glioma patients in grades II, III, and IV. Widespread dynamic expression of lncRNAs during glioma progression was revealed, and we identified 33 onco-lncRNAs and 61 tumor suppressor lncRNAs. We found that the expression of these oncogenic lncRNAs is regulated by grade-specific expressed transcription factors. Based on the "guilt by association" rule, we predicted the potential functions of oncogenic lncRNAs, and the majority of these lncRNAs are involved in cancer hallmarks. Especially we found that CARD8-AS1 regulates the metastatic potential of glioma cell lines in vitro. Integrating clinical information, we identified the 12 protective and 8 risk lncRNAs (such as PWAR6 and CARD8-AS1) in glioma. Finally, an lncRNA-gene functional module was identified to be associated with the survival of patients. The predictive ability of this module signature was further validated in an independent dataset. Our results revealed the dynamic transcriptome transition during glioma progression, indicating that the lncRNA signature could be a useful biomarker that may improve upon our understanding of the molecular mechanisms underlying glioma progression. PMID- 30472642 TI - Pharmaceutical residues in streams near concentrated animal feeding operations of Korea - Occurrences and associated ecological risks. AB - Concentrated animal feeding operations (CAFOs) have been suggested to be the most significant source of pharmaceutical release into the environment. However, limited information is available on the occurrence of veterinary pharmaceutical residues and the associated ecological risks to the aquatic environment near CAFO areas. In this study, ten commonly used veterinary antibiotics, including sulfonamides, tetracyclines, and cephalosporins, along with three analgesics, were measured in water samples collected from the streams that run near two CAFOs in Korea in 2013 (n = 16) and 2014 (n = 10). In addition, the associated ecological risks were estimated by calculating risk quotient. The pharmaceuticals were detected in a higher amount in the samples collected downstream from the CAFO than in those collected upstream. Acetaminophen, sulfamethazine, sulfathiazole, and oxytetracycline were detected at maximum concentrations of 38.8 MUg/L, 21.3 MUg/L, 17.4 MUg/L, and 16.9 MUg/L, respectively. Relatively higher concentrations of pharmaceuticals were observed in locations adjacent to the CAFO and the downstream area, suggesting the influence of the CAFO. Except for acetaminophen, lower concentrations of the target pharmaceuticals were detected in the samples collected during the high-flow season. The concentrations of most of the target pharmaceuticals exceeded the risk quotient of one, suggesting potential ecological effects in the areas affected by CAFOs. Our observations show that the water environment near a CAFO could be heavily affected by veterinary pharmaceuticals and analgesic drugs that are also frequently used among humans. Hence, the ecological consequences of pharmaceutical residues in the water bodies near CAFOs warrant further investigation. PMID- 30472643 TI - Assessment of biochar and zero-valent iron for in-situ remediation of chromated copper arsenate contaminated soil. AB - Chromated copper arsenates (CCA) have been extensively used as wood impregnation agents in Europe and North America. Today, CCA contaminated sites remain abundant and pose environmental risks that need to be properly managed. Using a TRIAD approach that combined chemical, ecotoxicological and ecological assessment of soil quality, we investigated the abilities of biochar and zero-valent iron (ZVI) to remediate CCA contaminated soil in a microcosm experiment. Soil samples from a highly contaminated CCA site (1364, 1662 and 540 MUg g-1 of As, Cu and Cr, respectively) were treated with two different biochars (fine and coarse particle size; 1% w w-1) and ZVI (5% w w-1), both as sole and as combined treatments, and incubated for 56 days at 15 degrees C. In general, bioavailable As (Asbio) and Cu (Cubio) determined by whole-cell bacterial bioreporters corresponded well to water-extractable As and Cu (Aswater and Cuwater). However, in biochar treatments, only Cubio and not Cuwater was significantly reduced. In contrast, under ZVI treatments only Cuwater and not Cubio was reduced, demonstrating the value of complementing analytical with bacterial bioreporter measurements to infer bioavailability of elements to soil microorganisms. The combined fine particle size biochar and ZVI treatment effectively reduced water extractable concentrations of Cr, Cu, and As on site by 45%, 45% and 43% respectively, and led to the highest ecological recovery of the soil bacterial community, as measured using the [3H]leucine incorporation technique. We conclude that the combined application of biochar and ZVI as soil amendments holds promise for in situ stabilization of CCA contaminated sites. PMID- 30472644 TI - National PM2.5 and NO2 exposure models for China based on land use regression, satellite measurements, and universal kriging. AB - Outdoor air pollution is a major killer worldwide and the fourth largest contributor to the burden of disease in China. China is the most populous country in the world and also has the largest number of air pollution deaths per year, yet the spatial resolution of existing national air pollution estimates for China is generally relatively low. We address this knowledge gap by developing and evaluating national empirical models for China incorporating land-use regression (LUR), satellite measurements, and universal kriging (UK). Land use, traffic and meteorological variables were included for model building. We tested the resulting models in several ways, including (1) comparing models developed using forward variable selection vs. partial least squares (PLS) variable reduction, (2) comparing models developed with and without satellite measurements, and with and without UK, and (3) 10-fold cross-validation (CV), Leave-One-Province-Out CV (LOPO-CV), and Leave-One-City-Out CV (LOCO-CV). Satellite data and kriging are complementary in making predictions more accurate: kriging improved the models in well-sampled areas; satellite data substantially improved performance at locations far away from monitors. Variable-selection models performed similarly to PLS models in 10-fold CV, but better in LOPO-CV. Our best models employed forward variable selection and UK, with 10-fold CV R2 of 0.89 (for both 2014 and 2015) for PM2.5 and of 0.73 (year-2014) and 0.78 (year-2015) for NO2. Population weighted concentrations during 2014-2015 decreased for PM2.5 (58.7 MUg/m3 to 52.3 MUg/m3) and NO2 (29.6 MUg/m3 to 26.8 MUg/m3). We produced the first high resolution national LUR models for annual-average concentrations in China. Models were applied on 1 km grid to support future research. In 2015, >80% of the Chinese population lived in areas that exceeded the Chinese national PM2.5 standard, 35 MUg/m3. Results here will be publicly available and may be useful for epidemiology, risk assessment, and environmental justice research. PMID- 30472645 TI - Chemical and organic characteristics of PM2.5 particles and their in-vitro cytotoxic effects on lung cells: The Middle East dust storms in Ahvaz, Iran. AB - There are very few reports about the effect of PM2.5 particles carried by the Middle East dust storms on lung cells. This study aimed to investigate the chemical properties and in-vitro cytotoxic effects of PM2.5 extracts. Water soluble fraction and organic solvent-extractable components of the samples collected from the city of Ahvaz, Khuzestan Province, Iran, during the normal and dust storm days of the winter of 2016 were analyzed and then applied on the human lung epithelial cell line (A549). The chemical properties and the cytotoxicity were analyzed by ICP-OES and Lactase Dehydrogenase (LDH) assay, respectively. The results of the independent t-test showed significantly higher mean cytotoxicity in the samples of normal days than that of dust storm days. It could be due to the fact that the cells were exposed to the same amount of water-soluble extract, whether it be from a normal day or a dust storm day, and since the normal air of Ahvaz is severely affected by traffic and industrial pollutants, its normal day samples showed stronger cytotoxic effect. The results of the Kruskal-Wallis test showed that cytotoxic effect increased with the particulate concentration. The highest cytotoxicity levels observed at 62, 125, and 250 MUg/mL concentrations after 24-h incubation were 17% (belonging to a dust storm day), 37% (belonging to a normal day), and 47% (belonging to a dust storm day), respectively Since PAH compounds were measured in the particulate phase, their amount was naturally correlated with the quantity of particulates. However, it was observed that the samples of normal days contained the species with stronger human carcinogens SigmaPAHs = 0.82 ng/m3.The results of one-way ANOVA showed a significant difference between the incubation times regarding the resulted cytotoxicity levels. In general, as the incubation duration increased, so did the cytotoxicity level. Although normal day particulates had a greater cytotoxic effect on A549 cell line, dust storm days are associated with higher levels of health risk; simply because during dust storms, people inhale much larger amounts of particulates. PMID- 30472646 TI - A nationwide survey of 31 organophosphate esters in sewage sludge from the United States. AB - Organophosphate esters (OPEs) are used as flame retardants and plasticizers in a wide range of consumer products. Nevertheless, studies on the occurrence and inventory of OPEs in sewage sludge are limited. In this study, 20 OP triesters and 11 diesters were measured in 75 archived sewage sludge samples collected from 67 wastewater treatment plants (WWTPs) across the United States (US). The median concentrations of ?20OP-triesters and ?11OP-diesters in sludge were 1290 and 78.4 ng/g dry weight (dw), respectively. Sludge samples originating from the Western and Northeastern US contained higher concentrations of OP triesters than did those from the Midwestern and Southern US. Sludge samples from WWTPs with larger treatment capacity (>38 million liters per day) contained higher concentrations of OP diesters (p < 0.05). OP diesters in sludge originated from two sources, triester degradation and direct inputs. Land application of sludge to US soils was estimated to result in annual mass inputs of 12,400-14,900 kg/year of OP triesters and 663-796 kg/year of OP diesters. A hazard assessment was performed for 14 OPEs found in sludge, which suggested a low level of risk at the current land application practices of sludge. PMID- 30472647 TI - Spatial distribution of the public's risk perception for air pollution: A nationwide study in China. AB - Severe air pollution problems have led to a rise in the Chinese public's concern. Risk perception is one of the most important indicators of the public's concern about air pollution. However, there existed few studies exploring the spatial distribution of risk perception. To fill the gap, psychometric paradigm methods was adopted to assess the public's risk perception of air pollution. A nationwide empirical study was conducted from December 2016 to February 2017 and 10,653 completed questionnaires were collected. According to a series of screening strategies, 9744 qualified questionnaires were included as a sample, which covered 31 China provinces (Hong Kong, Macao and Taiwan were not included in this study). We found that 45% of the respondents were dissatisfied with the current air quality, many respondents concerned a lot about air pollution (76%) and worried about the harmful consequences of being exposed to air pollution (86%). There was significant difference in the public's risk perception and attitude toward air pollution among different regions: the respondents in the northeast region, northern coastal region, eastern coastal region and Middle Yellow river region perceived higher air pollution risk and lower satisfaction with air quality than other regions; and the public's trust in the government increased from coastal regions to inland regions. In addition, the hierarchical linear model (HLM) was used to explore the effects of demographic, environmental and economic factors on public risk perception and attitude toward air pollution. Based on this, the characteristics of sensitive populations regarding air pollution were identified. What's more, we found that PM2.5 has a positive influence on perceived risk factor (PR) and can strengthen the positive correlation between PR and satisfaction with air quality (SAQ). Finally, policy implications behind these results were discussed, which can provide references and lay the foundation for policymakers and subsequent researchers. PMID- 30472648 TI - Could bovine livestock intensification in Pantanal be neutral regarding enteric methane emissions? AB - Bovine livestock is a major anthropogenic greenhouse gas source via enteric methane. Brazilian bovine livestock is also responsible for emissions from land use changes. In contrast, enteric emissions from extensive cattle systems in wetlands might have been overestimated. We provide scientific evidences that the human footprint of bovine products delivered by the Pantanal can be much lower. To assess this, a historical cloud-free imagery of the Landsat-5, spanning 26 years, were processed for mapping spatiotemporal landscapes in a Pantanal farm under cattle intensification studies. Eight landscape categories were identified according to spatiotemporal dynamics of interannual floods. The spatiotemporal map allowed in the field the adoption of stratified random samplings of chamber gas fluxes. The combination of stratified sampled landscapes with Monte Carlo simulations of measured methane emissions in wet and dry soils permitted to integrate landscapes emissions at annual basis with biased uncertainties. Assuming enteric emissions obtained for the Pantanal region, our results suggest that the landscapes methane emissions are 10- to 23-fold superior than the enteric emissions of traditional bovine systems. While enteric emissions seem negligible with respect to net farmland emissions, cattle livestock provide important environmental services like carbon recycling through non-competing herbivory. Moreover, cattle might be making use of a biomass that would undergo decomposition during the flooding phase. Our analysis thus indicate that enteric emissions from traditional bovine systems in flooding farmlands could be considered neutral. By contrast, intensification to improve the stocking rate should be accounted as net anthropogenic emissions. A case study of intensification allowed an increase of 48% in the stocking rate, which is associated with net anthropogenic emissions from 534 bovine animals or about 27 to 63 Mg of enteric CH4 per year. In short, the competition between traditional and distinct levels of cattle intensification will result from a trade-off between public policies and strategic market niches (organic, sustainable) for the optimal landscape management of the Pantanal. PMID- 30472649 TI - Screening of BRCA1/2 deep intronic regions by targeted gene sequencing identifies the first germline BRCA1 variant causing pseudoexon activation in a patient with breast/ovarian cancer. AB - BACKGROUND: Genetic analysis of BRCA1 and BRCA2 for the diagnosis of hereditary breast and ovarian cancer (HBOC) is commonly restricted to coding regions and exon-intron boundaries. Although germline pathogenic variants in these regions explain about ~20% of HBOC cases, there is still an important fraction that remains undiagnosed. We have screened BRCA1/2 deep intronic regions to identify potential spliceogenic variants that could explain part of the missing HBOC susceptibility. METHODS: We analysed BRCA1/2 deep intronic regions by targeted gene sequencing in 192 high-risk HBOC families testing negative for BRCA1/2 during conventional analysis. Rare variants (MAF <0.005) predicted to create/activate splice sites were selected for further characterisation in patient RNA. The splicing outcome was analysed by RT-PCR and Sanger sequencing, and allelic imbalance was also determined when heterozygous exonic loci were present. RESULTS: A novel transcript was detected in BRCA1 c.4185+4105C>T variant carrier. This variant promotes the inclusion of a pseudoexon in mature mRNA, generating an aberrant transcript predicted to encode for a non-functional protein. Quantitative and allele-specific assays determined haploinsufficiency in the variant carrier, supporting a pathogenic effect for this variant. Genotyping of 1030 HBOC cases and 327 controls did not identify additional carriers in Spanish population. CONCLUSION: Screening of BRCA1/2 intronic regions has identified the first BRCA1 deep intronic variant associated with HBOC by pseudoexon activation. Although the frequency of deleterious variants in these regions appears to be low, our study highlights the importance of studying non coding regions and performing comprehensive RNA assays to complement genetic diagnosis. PMID- 30472650 TI - Reducing hospital admissions for adverse drug events through coordinated pharmacist care: learning from Hawai'i without a field trip. PMID- 30472653 TI - Prevention of infections in patients with antineutrophil cytoplasm antibody associated vasculitis: potential role of hydroxychloroquine. PMID- 30472652 TI - Phosphatidylinositol 3-kinase delta pathway: a novel therapeutic target for Sjogren's syndrome. AB - BACKGROUND: The phosphatidylinositol 3-kinase delta isoform (PI3Kdelta) belongs to an intracellular lipid kinase family that regulate lymphocyte metabolism, survival, proliferation, apoptosis and migration and has been successfully targeted in B-cell malignancies. Primary Sjogren's syndrome (pSS) is a chronic immune-mediated inflammatory disease characterised by exocrine gland lymphocytic infiltration and B-cell hyperactivation which results in systemic manifestations, autoantibody production and loss of glandular function. Given the central role of B cells in pSS pathogenesis, we investigated PI3Kdelta pathway activation in pSS and the functional consequences of blocking PI3Kdelta in a murine model of focal sialoadenitis that mimics some features of pSS. METHODS AND RESULTS: Target validation assays showed significant expression of phosphorylated ribosomal protein S6 (pS6), a downstream mediator of the phosphatidylinositol 3-kinase delta (PI3Kdelta) pathway, within pSS salivary glands. pS6 distribution was found to co-localise with T/B cell markers within pSS aggregates and the CD138+ plasma cells infiltrating the glands. In vivo blockade of PI3Kdelta activity with seletalisib, a PI3Kdelta-selective inhibitor, in a murine model of focal sialoadenitis decreased accumulation of lymphocytes and plasma cells within the glands of treated mice in the prophylactic and therapeutic regimes. Additionally, production of lymphoid chemokines and cytokines associated with ectopic lymphoneogenesis and, remarkably, saliva flow and autoantibody production, were significantly affected by treatment with seletalisib. CONCLUSION: These data demonstrate activation of PI3Kdelta pathway within the glands of patients with pSS and its contribution to disease pathogenesis in a model of disease, supporting the exploration of the therapeutic potential of PI3Kdelta pathway inhibition in this condition. PMID- 30472654 TI - Some concerns from Turkey. PMID- 30472655 TI - Fifteen-minute consultation: When medicines don't work-the child with poorly controlled seizures. AB - Drug-resistant epilepsy (DRE) occurs in 20%-30% of children with epilepsy with significant impact on their quality of life. Management of this group of children has greatly improved in the recent years with streamlining of epilepsy surgery services and associated quaternary multimodal evaluation. This article provides a review of DRE in children and management based on recent evidence and published opinion. We have also presented an algorithmic approach to the child with possible DRE. PMID- 30472651 TI - Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial. AB - OBJECTIVE: Regulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential. AIM: We aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases. METHODS: We performed a prospective, open-label, phase I-IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet's disease, granulomatosis with polyangiitis, Takayasu's disease, Crohn's disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation. RESULTS: ld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed. CONCLUSION: The dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases. TRIAL REGISTRATION NUMBER: NCT01988506. PMID- 30472656 TI - Multiple fractures of different ages. AB - A 2-year-old boy, who was previously well, was admitted for limping associated with left knee pain of 1 month duration. There was no history of witnessed trauma or significant infective symptoms. Systemic review was otherwise unremarkable. Prior to his onset of signs, he was able to cruise with support, and had some mild isolated speech delay. There was no significant family history of medical conditions. His main caregivers on weekdays were two sets of grandparents when his parents were working, while his parents took over his care on weekends. Physical examination was normal, except for tenderness of his left knee joint and his inability to weight-bear.An X-ray of his left knee joint showed a healing fracture of the left distal femoral metaphysis with associated bony sclerosis at the fracture margins, as well as periosteal reaction in the distal femur. In addition, there were also areas of lucencies in the left proximal tibia metaphysis (figure 1). edpract;archdischild-2018-316074v1/F1F1F1Figure 1Left distal femur healing fracture with surrounding sclerosis. QUESTION 1: What are the possible causes of his current presentation?Non-accidental injuryVitamin D deficiencyOsteogenesis imperfectaLeukaemiaAll of the above His full blood count revealed mild normochromic normocytic anaemia (haemoglobin 10.9 g/L), total white cell count of 6.70*109/L and platelet count of 144*109/L. The peripheral blood film did not show any blast cells. His liver function test showed mild transaminases (aspartate aminotransferase 106 U/L, alanine aminotransferase 244 U/L). His renal function test, bone panel, uric acid and lactate dehydrogenase levels were all normal. A skeletal survey showed presence of metaphyseal fractures of different ages at several sites, as well as subtle areas of lucencies in the right proximal tibia metaphysis (figures 2 and 3).edpract;archdischild-2018-316074v1/F2F2F2Figure 2Right distal femur healing fracture with surrounding sclerosis.edpract;archdischild-2018 316074v1/F3F3F3Figure 3Possible healing fracture in right proximal humerus, with surrounding sclerosis.He was managed conservatively and subsequently discharged back home to the same caregivers with plans for home monitoring visits by social services.He was readmitted 1 month later for worsening symptoms of 1 week duration. He was unable to crawl and had developed a fever over 1 day. Systemic review was otherwise unremarkable. Other than a mild normochromic, normocytic anaemia, the full blood count was normal.Physical examination was normal, except for a slightly swollen right knee joint.A right knee X-ray showed worsening osteopenia and sclerosis in keeping with a healing fracture. An MRI showed diffuse marrow changes in the femur with patchy enhancement. QUESTION 2: Which further investigation(s) would be useful in establishing his diagnosis?Bone marrow biopsyGenetic testing for osteogenesis imperfectaVitamin C levelBone mineral density test Answers can be found on page 3. PMID- 30472657 TI - Mild form of oculocutaneous albinism type 1: phenotypic analysis of compound heterozygous patients with the R402Q variant of the TYR gene. AB - AIM: Oculocutaneous albinism type 1 (OCA1) is due to TYR mutations. c.1205G>A/p.Arg402Gln (R402Q) is a thermosensitive variant of the TYR gene that has been reported to be responsible for mild forms of OCA1. The aim of our study was to define the phenotype associated with this variant. METHODS: In our retrospective series, among 268 patients diagnosed with OCA1, 122 (45.5%) harboured one pathogenic variant of TYR, and the R402Q variant ensured to be in trans by segregation analysis in 69 patients (25.7%), constituting the 'R402Q OCA1' group. 146 patients harboured two pathogenic variants of the TYR gene other than R402Q. Clinical records were available for 119 of them, constituting the 'Classical-OCA1' group. RESULTS: Most R402Q-OCA1 patients presented with white or yellow-white hair at birth (71.43%), blond hair later (46.97%), a light phototype but with residual pigmentation (69.64%), and blue eyes (76.56%). Their pigmentation was significantly higher than in the classical-OCA1 group. All patients from the R402Q-OCA1 group presented with ocular features of albinism. However the prevalence of photophobia (78.13%) and iris transillumination (83.87%) and the severity scores of iris transillumination, retinal hypopigmentation and foveal hypoplasia were lower in the R402Q-OCA1 group. Visual acuity was higher in the R402Q-OCA1 group (0.38+/-0.21 logarithm of the minimum angle of resolution vs 0.76+/-0.24). Investigations concerning a possible additive effect of the c.575C>A/p.Ser192 (S192Y) variant of TYR in cis with R402Q, suggested by others, showed no significant impact on the phenotype. CONCLUSION: The R402Q variant leads to variable but generally mild forms of albinism whose less typical presentation may lead to underdiagnosis. PMID- 30472658 TI - Clinical relevance of protruded retinal layers in minimum rim width measurement of the optic nerve head. AB - BACKGROUND/AIMS: Optical coherence tomography (OCT) imaging of the optic nerve head minimum rim width (MRW) has recently been shown to sometimes contain components besides extended retinal nerve fibre layer (RNFL). This study was conducted to determine whether excluding these components, termed protruded retinal layers (PRLs), from MRW increases diagnostic accuracy for detecting glaucoma. METHODS: In this cross-sectional study, we included 123 patients with glaucoma and 123 normal age-similar controls with OCT imaging of the optic nerve head (24 radial scans) and RNFL (circle scan). When present, PRLs were manually segmented, and adjusted MRW measurements were computed. We compared diagnostic accuracy of adjusted versus unadjusted MRW measurement. We also determined whether adjusted MRW correlates better with RNFL thickness compared with unadjusted MRW. RESULTS: The median (IQR) visual field mean deviation of patients and controls was -4.4 (-10.3 to -2.1) dB and 0.0 (-0.6 to 0.8) dB, respectively. In the 5904 individual B-scans, PRLs were identified less frequently in patients (448, 7.6%) compared with controls (728, 12.3%; p<0.01) and were present most frequently in the temporal sector of both groups. Areas under the receiver operating characteristic curves and sensitivity values at 95% specificity indicated that PRL adjustment did not improve diagnostic accuracy of MRW, globally or temporally. Furthermore, adjusting MRW for PRL did not improve its correlation with RNFL thickness in either group. CONCLUSION: While layers besides the RNFL are sometimes included in OCT measurements of MRW, subtracting these layers does not impact clinical utility. PMID- 30472659 TI - Success of trabeculectomy surgery in relation to cataract surgery: 5-year outcomes. AB - AIMS: To compare success proportions at 5 years in three surgical groups: group 1, trabeculectomy alone; group 2, trabeculectomy followed by cataract surgery within 2 years; and group 3, trabeculectomy performed on a pseudophakic eye. METHODS: A retrospective cohort study. 194 eyes of 194 patients were identified with at least 5 years' follow-up post trabeculectomy (N=85, 60 and 49 in groups 1, 2 and 3, respectively). MAIN OUTCOME MEASURES: 1. PRIMARY OUTCOME MEASURE: intraocular pressure (IOP) at 5 years post-trabeculectomy surgery, 2.Secondary outcome measure: change in visual acuity at 5 years. RESULTS: At 5 years, the mean IOP (SD) was 12.9 (3.5), 12.5 (4.8) and 12.7 (4.8) mm Hg in groups 1, 2 and 3, respectively. Overall success was almost identical, 58%, 57% and 59% in groups 1, 2 and 3, respectively. There was no significant difference between the groups in terms of percentage IOP reduction, number of medications, proportion restarting medication and reoperation rates at 5 years. Logistic regression for an outcome of failure showed men to be at increased risk of failure OR 1.97 (95% CI 1.10 to 3.52, p=0.02). Nearly 80% of patients retained or improved their vision following their initial trabeculectomy. CONCLUSIONS: The sequence in which surgery is carried out does not appear to affect trabeculectomy function at 5 years, success being similar to trabeculectomy alone. In our study, men may be at increased risk of failure. PMID- 30472660 TI - Characterisation of neonatal seizures and their treatment using continuous EEG monitoring: a multicentre experience. AB - OBJECTIVE: The aim of this multicentre study was to describe detailed characteristics of electrographic seizures in a cohort of neonates monitored with multichannel continuous electroencephalography (cEEG) in 6 European centres. METHODS: Neonates of at least 36 weeks of gestation who required cEEG monitoring for clinical concerns were eligible, and were enrolled prospectively over 2 years from June 2013. Additional retrospective data were available from two centres for January 2011 to February 2014. Clinical data and EEGs were reviewed by expert neurophysiologists through a central server. RESULTS: Of 214 neonates who had recordings suitable for analysis, EEG seizures were confirmed in 75 (35%). The most common cause was hypoxic-ischaemic encephalopathy (44/75, 59%), followed by metabolic/genetic disorders (16/75, 21%) and stroke (10/75, 13%). The median number of seizures was 24 (IQR 9-51), and the median maximum hourly seizure burden in minutes per hour (MSB) was 21 min (IQR 11-32), with 21 (28%) having status epilepticus defined as MSB>30 min/hour. MSB developed later in neonates with a metabolic/genetic disorder. Over half (112/214, 52%) of the neonates were given at least one antiepileptic drug (AED) and both overtreatment and undertreatment was evident. When EEG monitoring was ongoing, 27 neonates (19%) with no electrographic seizures received AEDs. Fourteen neonates (19%) who did have electrographic seizures during cEEG monitoring did not receive an AED. CONCLUSIONS: Our results show that even with access to cEEG monitoring, neonatal seizures are frequent, difficult to recognise and difficult to treat. OBERSERVATION STUDY NUMBER: NCT02160171. PMID- 30472661 TI - Accuracy of real-time delivery room resuscitation documentation. AB - OBJECTIVE: To assess the accuracy of real-time delivery room resuscitation documentation. DESIGN: Retrospective observational study. SETTING: Level 3 academic neonatal intensive care unit. PARTICIPANTS: Fifty infants with video recording of neonatal resuscitation. MAIN OUTCOME MEASURES: Vital sign assessments and interventions performed during resuscitation. The accuracy of written documentation was compared with video gold standard. RESULTS: Timing of initial heart rate assessment agreed with video in 44/50 (88%) records; the documented heart rate was correct in 34/44 (77%) of these. Heart rate and oxygen saturation were documented at 5 min of life in 90% of resuscitations. Of these, 100% of heart rate and 93% of oxygen saturation values were correctly recorded. Written records accurately reflected the mode(s) of respiratory support for 89% 100%, procedures for 91%-100% and medications for 100% of events. CONCLUSION: Real-time documentation correctly reflects interventions performed during delivery room resuscitation but is less accurate for early vital sign assessments. PMID- 30472663 TI - Simplified management protocol for term neonates after prolonged rupture of membranes in a setting with high rates of neonatal sepsis and mortality: a quality improvement study. AB - In low-income and middle-income countries, courses of antibiotics are routinely given to term newborns whose mothers had prolonged rupture of membranes (PROM). Rational antibiotic use is vital given rising rates of antimicrobial resistance and potential adverse effects of antibiotic exposure in newborns. However missing cases of sepsis can be life-threatening.This is a quality improvement evaluation of a protocol for minimal or no antibiotics in term babies born after PROM in Papua New Guinea. Asymptomatic, term babies born to women with PROM >12 hours prior to birth were given a stat dose of antibiotics, or no antibiotics if the mother had received intrapartum antibiotics, reviewed and discharged at 48-72 hours with follow-up. Clinical signs of sepsis within the first week and the neonatal period were assessed. Of 170 newborns whose mothers had PROM, 133 were assessed at 7 days: signs of sepsis occurred in 10 babies (7.5%; 95% CI 4.4% to 13.2%) in the first week. Five had isolated fever, four had skin pustules and one had fever with periumbilical erythema. An additional four (3%) had any sign of sepsis between 8 and 28 days. There was one case of bacteraemia and no deaths. 37 were lost to follow-up, but hospital records did not identify any subsequent admissions for infection. A rate of sepsis was documented that was comparable with other studies in low-income countries. This protocol may reduce antimicrobial resistance and consequences of antibiotic exposure in newborns, provided safeguards are in place to monitor for signs of sepsis. PMID- 30472662 TI - Physical compatibility of pentoxifylline and intravenous medications. AB - OBJECTIVE: To investigate the physical and chemical compatibility of pentoxifylline (PTX) with a wide range of parenteral medications used in the neonatal intensive care setting. DESIGN: PTX and drug solutions were combined in glass phials and inspected visually for physical incompatibility. The chemical compatibility was evaluated on the basis of PTX concentrations. RESULTS: Precipitation, colour change or turbidity was not visible in any of the test mixtures, indicating no observed physical incompatibility or apparent risk of blockage in narrow-bore intravenous tubing. The PTX concentration was approximately 2.5% and 4.5% lower when combined with dopamine and amoxicillin, respectively. The PTX concentration ratios for all other combinations were in the range of 99%-102%. CONCLUSION: In simulated Y-site conditions, physical compatibility testing of PTX and 30 parenteral medications revealed no evidence of precipitation. Based on PTX concentration tests, it could be prudent to avoid mixing PTX with dopamine or amoxicillin. PMID- 30472664 TI - Economic cost of congenital CMV in the UK. AB - OBJECTIVE: Congenital cytomegalovirus (cCMV) is the most common infectious cause of congenital disability. It can disrupt neurodevelopment, causing lifelong impairments including sensorineural hearing loss and developmental delay. This study aimed, for the first time, to estimate the annual economic burden of managing cCMV and its sequelae in the UK. DESIGN: The study collated available secondary data to develop a static cost model. SETTING: The model aimed to estimate costs of cCMV in the UK for the year 2016. PATIENTS: Individuals of all ages with cCMV. MAIN OUTCOME MEASURES: Direct (incurred by the public sector) and indirect (incurred personally or by society) costs associated with management of cCMV and its sequelae. RESULTS: The model estimated that the total cost of cCMV to the UK in 2016 was L732 million (lower and upper estimates were between L495 and L942 million). Approximately 40% of the costs were directly incurred by the public sector, with the remaining 60% being indirect costs, including lost productivity. Long-term impairments caused by the virus had a higher financial burden than the acute management of cCMV. CONCLUSIONS: The cost of cCMV is substantial, predominantly stemming from long-term impairments. Costs should be compared against investment in educational strategies and vaccine development programmes that aim to prevent virus transmission, as well as the value of introducing universal screening for cCMV to both increase detection of children who would benefit from treatment, and to build a more robust evidence base for future research. PMID- 30472665 TI - Parents' and children's comprehension and decision in a paediatric early phase oncology trial: a prospective study. AB - OBJECTIVE: To analyse parents' and children's understanding of consent information and assess their decision-making process in paediatric oncology. DESIGN: Prospective observational study. SETTINGS: Eleven French paediatric oncology units. PATIENTS: Parents and children who have been asked to give consent for participation in an early phase trial. INTERVENTIONS: Thirty-seven children and 119 parents were questioned using an audio-recorded semistructured interview. MAIN OUTCOME MEASURES: The participants' understanding of nine elements of the informed consent was assessed by comparing their answers with the informed consent leaflet. Their decision-making process was also evaluated. RESULTS: Most parents and children had an excellent understanding regarding their participation in a clinical trial (respectively 88.2% and 48.6%), the right to withdraw (76.5% and 43.2%) and the prospects of collective benefits (74.8% and 48.6%). By contrast, less than half of the parents and few of the children correctly understood the alternatives (respectively 47.5% and 27%), the risks related to participation (44.5% and 10.8%), the prospects of individual benefits (33.6% and 10.8%) and the purpose of the clinical trial (12.6% and 2.7%). Twenty six (70.3%) children participated in the decision-making process. Most parents and children felt they had no choice but to participate in the trial to have access to a new anticancer treatment. CONCLUSIONS: What might appear to be a poor understanding of the research protocol may actually correspond to the families' interpretation of the situation as a coping mechanism. All children (except infants) should get age-tailored information in order for them to have a meaningful involvement in research. PMID- 30472666 TI - Disclosing the diagnosis of Down syndrome: the experience of 50 Irish parents. PMID- 30472667 TI - Art of listening. PMID- 30472668 TI - Musculoskeletal anomalies in children with Down syndrome: an observational study. AB - BACKGROUND: Musculoskeletal complications of Down syndrome (DS) are common but infrequently reported. The combination of ligamentous laxity and low muscle tone contributes to increased risk of a number of musculoskeletal disorders and a delay in acquisition of motor milestones. The primary aim of this study was to describe musculoskeletal anomalies reported in a national cohort of children with DS. METHODS: This was an observational study. Children with DS, aged 0-21 years, were invited to attend a musculoskeletal assessment clinic conducted by a paediatric physician. Relevant musculoskeletal history and clinical findings were documented. RESULTS: Over an 18-month period, 503 children with DS were examined (56% male). The median age was 8.1 years (0.6-19.2). Pes planus was almost universal, occurring in 91% of the cohort. A range of other musculoskeletal anomalies were observed, with inflammatory arthritis (7%) and scoliosis (4.8%) occurring most frequently after pes planus. Delay in ambulation was common; the median age to walk was 28 months (12-84). CONCLUSION: Children with DS are at increased risk of a number of potentially debilitating musculoskeletal problems. These conditions can present in variable manners or be completely asymptomatic. Pes planus is common; therefore, early consideration of orthotics and lifelong appropriate supportive footwear should be considered. Delayed ambulation is frequently noted. A significant proportion of children with DS have arthritis; however, despite a high prevalence, it is often missed, leading to delayed diagnosis. An annual musculoskeletal assessment for all children with DS could potentially enable early detection of problems, allowing for timely multidisciplinary team intervention and better clinical outcomes. PMID- 30472669 TI - Management of severe bronchiolitis: impact of NICE guidelines. AB - OBJECTIVE: To understand the impact of the National Institute for Health and Care Excellence (NICE) bronchiolitis guidelines on the management of children referred to paediatric intensive care unit (PICU) with bronchiolitis. DESIGN AND SETTING: Data were collected on all children referred to a regional PICU transport service with the clinical diagnosis of bronchiolitis during the winter prior to the NICE consultation period (2011-2012) and during the winter after publication (2015 2016). Management initiated by the referring hospital was assessed. RESULTS: There were 165 infants referred with bronchiolitis in epoch 1 and 187 in epoch 2. Nebuliser use increased from 28% in epoch 1 to 53% in epoch 2. Increased use of high-flow nasal cannula oxygen and reduction in continuous positive airway pressure use were observed. The use of antibiotics did not change between epochs. CONCLUSION: The use of nebulised therapies has increased in the management of severe bronchiolitis despite national guidance to the contrary. PMID- 30472671 TI - Reasons for failed endovascular recanalization attempts in stroke patients. AB - PURPOSE: Mechanical thrombectomy (MT) is a highly effective therapy in patients with acute ischemic stroke due to large vessel occlusion (LVO). However, complete recanalization of the occluded vessel cannot be achieved in all patients, leading to poor clinical outcome. We analyzed the reasons for failed recanalization to help direct future improvements in therapy. METHODS: 648 consecutive stroke patients with LVO and an MT attempt were retrospectively analyzed for none or minimal recanalization, assessed according to the Thrombolysis in Cerebral Infarction (TICI) score (0/1). Procedural parameters were evaluated in a standardized approach. Among other variables, number of retrieval attempts, devices, duration of the intervention, and rescue methods were analyzed. RESULTS: TICI 0/1 was observed in 72/648 patients (11%). In these patients, the thrombus could not be reached in 21% (n=15/72), was reached but not passed in 21% (n=15/72), and was reached and passed in 58% (n=42/72). Only a minor degree of initial recanalization was achieved in 19% (n=8/42) of patients with a reached occlusion during the course of the intervention. Furthermore, a higher number of passes with a single retriever device led to significant prolongation of the intervention. Therefore, major reasons for failed endovascular recanalization were difficult anatomical access and hard or resistant occlusions that might reflect hard thrombi or pre-existing atherosclerotic stenosis. Procedural complications such as dissection or perforation played a minor role. CONCLUSION: In stroke patients with failed MT attempts, approximately 60% of occlusions can be passed. In such cases, rescue therapy might be considered to improve recanalization and clinical outcome. Further development of access devices might help in the remaining cases where the microcatheter could not be manipulated to or through the occlusion. PMID- 30472670 TI - 5 protein-based signature for resectable lung squamous cell carcinoma improves the prognostic performance of the TNM staging. AB - INTRODUCTION: Prognostic biomarkers have been very elusive in the lung squamous cell carcinoma (SCC) and none is currently being used in the clinical setting. We aimed to identify and validate the clinical utility of a protein-based prognostic signature to stratify patients with early lung SCC according to their risk of recurrence or death. METHODS: Patients were staged following the new International Association for the Study of Lung Cancer (IASLC) staging criteria (eighth edition, 2018). Three independent retrospective cohorts of 117, 96 and 105 patients with lung SCC were analysed to develop and validate a prognostic signature based on immunohistochemistry for five proteins. RESULTS: We identified a five protein-based signature whose prognostic index (PI) was an independent and significant predictor of disease-free survival (DFS) (p<0.001; HR=4.06, 95% CI 2.18 to 7.56) and overall survival (OS) (p=0.004; HR=2.38, 95% CI 1.32 to 4.31). The prognostic capability of PI was confirmed in an external multi-institutional cohort for DFS (p=0.042; HR=2.01, 95% CI 1.03 to 3.94) and for OS (p=0.031; HR=2.29, 95% CI 1.08 to 4.86). Moreover, PI added complementary information to the newly established IASLC TNM 8th edition staging system. A combined prognostic model including both molecular and anatomical (TNM) criteria improved the risk stratification in both cohorts (p<0.05). CONCLUSION: We have identified and validated a clinically feasible protein-based prognostic model that complements the updated TNM system allowing more accurate risk stratification. This signature may be used as an advantageous tool to improve the clinical management of the patients, allowing the reduction of lung SCC mortality through a more accurate knowledge of the patient's potential outcome. PMID- 30472672 TI - Can early neurological improvement after mechanical thrombectomy be used as a surrogate for final stroke outcome? AB - BACKGROUND AND PURPOSE: We aimed to identify the best definition of early neurological improvement (ENI) at 2 and 24 hours after mechanical thrombectomy (MT) and determine its ability to predict a good functional outcome at 3 months. METHODS: This retrospective analysis was based on a prospectively collected registry of patients treated by MT for ischemic stroke from May 2010 to March 2017. We included patients treated with stent-retrievers with National Institute of Health Stroke Scale (NIHSS) score before treatment and at 2 and/or 24 hours after treatment and modified Rankin Score (mRS) at 3 months. Receiver operating characteristic curve analysis was performed to estimate optimal thresholds for ENI at 2 and 24 hours. The relationship between optimal ENI definitions and good outcome at 3 months (mRS 0-2) was assessed by logistic regression. RESULTS: The analysis included 246 patients. At 2 hours, the optimal threshold to predict a good outcome at 3 months was improvementin the NIHSS score of >1 point (AUC 0.83,95% CI 0.77 to 0.87), with sensitivity and specificity 78.3% (62.2-85.7%) and 84.6% (77.2-90.3%), respectively, and OR 12.67 (95% CI 4.69 to 31.10, p<0.0001). At 24 hours, the optimal threshold was an improvementin the NIHSS score of >4 points (AUC 0.93, 95% CI 0.89 to 0.96), with sensitivity and specificity 93.8% (87.7-97.5%) and 83.2% (75.7-89.2%), respectively, and OR 391.32 (95% CI 44.43 to 3448.35, p<0.0001). CONCLUSIONS: ENI 24 hours after thrombectomy appears to be a straightforward surrogate of long-term endpoints and may have value in future research. PMID- 30472673 TI - Predictive value of CT angiography source image ASPECTS in patients with anterior circulation acute ischemic stroke after endovascular treatment: ultimate infarct size and clinical outcome. AB - BACKGROUND AND PURPOSE: The objective of this study was to investigate the predictive value of computed tomographic angiography (CTA) source image Alberta Stroke Program Early CT Score (ASPECTS) on clinical outcome and final infarction extent after endovascular treatment (EVT) in patients with acute ischemic stroke (AIS). METHODS: All eligible patients from January 2014 to March 2018 undergoing EVT due to anterior circulation AIS were retrospectively reviewed. The baseline ASPECTS on initial noncontrast CT (NCCT) and the CTA source image were compared with the follow-up MR diffusion-weighted imaging (DWI) ASPECTS. Receiver operating characteristic (ROC) curve analysis was used to assess the predictive value of CTA ASPECTS for prediction of final infarct extent and good clinical outcome. RESULTS: Our sample included a total of 122 eligible patients (64 males, mean age 70 years) with a median baseline National Institute of Health Stroke Scale (NIHSS) score of 12. Baseline ASPECTS on the CTA source image correlated with follow-up MR DWI ASPECTS better than NCCT ASPECTS (P<0.001). ROC curve analysis revealed baseline CTA ASPECTS (area under the curve [AUC] =0.74, 95% CI: 0.65 to 0.83, P<0.001) can better predict favorable functional outcome than NCCT ASPECTS (AUC=0.64, 95% CI: 0.54 to 0.74, P=0.008). Baseline NIHSS score <15, CTA ASPECTS>=8, and successful recanalization were independent predictors of good clinical outcomes. CONCLUSION: The ASPECTS on the CTA source image provides more information in the prediction of good clinical outcome and final infarction size than NCCT in patients with AIS treated with EVT. PMID- 30472675 TI - Dual suction Headway27 microcatheter thrombectomy for the treatment of distal intracranial arterial occlusion strokes: initial experience with the micro-ADAPT technique. AB - BACKGROUND: Recent studies suggest that the proven benefits of endovascular thrombectomy (EVT) for the treatment of large vessel occlusion (LVO) strokes are transferable to more peripheral distal vessel occlusion (DVO) strokes under certain circumstances. Safely accessing and extracting these thrombi however remains challenging, particularly in more tortuous peripheral arteries. For such cases we have utilized the dual suction Headway27 microcatheter thrombectomy, or micro-ADAPT, technique with the aim of reducing potential trauma associated with negotiating stent retrievers or large bore aspiration catheters into the peripheral intracranial vasculature. We present our experience utilizing the micro-ADAPT in the treatment of DVO strokes. We describe our technique as well as present angiographic and clinical outcomes. METHODS: A retrospective review of our institution's prospectively collected EVT registry for the 12 months spanning July 2017 to June 2018 was undertaken. Data on all cases of micro-ADAPT EVT were collected and analyzed. RESULTS: Micro-ADAPT EVT was performed 14 times over the study period, with a recanalization rate of 79%. DVO strokes in multiple locations were treated, including the A3, M3, P3, and superior cerebellar artery. In cases where an LVO stroke was also present, the mean duration between primary LVO recanalization and secondary DVO micro-ADAPT recanalization was 15.5 min. No complications relating to the micro-ADAPT technique were recorded. No infarcts were present in the territory of the recanalized DVO stroke on day 1 CT in successful micro-ADAPT cases CONCLUSIONS: In the setting of challenging peripheral DVO strokes, the micro-ADAPT technique appears to be a fast and effective technique with a low complication rate. PMID- 30472674 TI - Pipeline embolization device treatment of internal carotid artery terminus aneurysms. AB - BACKGROUND: The pipeline embolization device (PED) is approved for the treatment of large aneurysms of the proximal internal carotid artery (ICA). Its off-label application in treating aneurysms located specifically at the ICA terminus (ICA T) has not been studied. METHODS: We conducted a retrospective chart review of patients from 2011 to 7 treated with PEDs. Out of 365 patients, 10 patients with ICA-T aneurysms were included. Patient demographics, procedural information, follow-up imaging, and clinical assessments were recorded. RESULTS: Mean age was 46.9 years (+/- 8.8), and 6 (60%) patients were women. The mean maximum diameter of the aneurysms treated was 14.7 mm (+/- 10.7) and the mean neck diameter was 9.3 mm (+/- 6.6). Reasons for presentation included six incidental findings, one acute subarachnoid hemorrhage (SAH), and three patients with prior SAH. Kamran Byrne Occlusion Scale scores for the treated aneurysms were as follows: three class IV (complete obliteration), four class III (<50% filling in both height and width for fusiform aneurysms or residual neck for saccular aneurysms), one class II fusiform aneurysm, 1 class 0 saccular aneurysm (residual aneurysm body), and one not classified due to pipeline thrombosis. Two clinically asymptomatic complications were noted: one patient who had a small distal cortical SAH post PED and one patient whose stent was found to be thrombosed on follow-up angiogram. All patients were seen in follow-up, and no patients were found to have worsening of their pre-procedure modified Rankin Scale score. CONCLUSION: The PED has potential for treating ICA-T aneurysms not amenable to conventional treatment strategies. Further studies are warranted to confirm the long term outcomes. PMID- 30472676 TI - Equal performance of aspiration and stent retriever thrombectomy in daily stroke treatment. AB - BACKGROUND: Mechanical thrombectomy with stent retrievers has proved to be safe and effective in endovascular treatment of acute ischemic stroke. Direct aspiration has shown revascularization rates comparable to those of stent retrievers in the recent ASTER and COMPASS trials. However, the efficacy of aspiration in routine clinical practice has not yet been shown. OBJECTIVE: To show that aspiration has clinical and technical outcomes equal to those of stent retriever thrombectomy in daily clinical practice. METHODS: We analysed data of patients with a large vessel occlusion of the anterior circulation registered in the Dutch MR CLEAN Registry between March 2014 and June 2016. Primary outcome was functional outcome measured with the modified Rankin Scale (mRS) score. Secondary outcomes were reperfusion grade, periprocedural complication rate, and procedure duration. Association of treatment technique with functional outcome was estimated with univariable and multivariable ordinal logistic regression analysis and expressed as a common OR (cOR) for a shift towards better outcome on the mRS. RESULTS: As first-line treatment, 207 of 1175 patients (17.6%) were treated with direct aspiration, and 968 (82.4%) by a stent retriever. We observed no differences in functional outcome (adjusted cOR=1.020 (95% CI 0.68 to 1.52)) and periprocedural complications. Successful reperfusion (extended Thrombolysis in Cerebral Infarction >=2b) was similar. Duration of the procedure was shorter with aspiration (57 min (IQR 35-73) vs 70 min (IQR 47-95), p<0.0001). CONCLUSION: Direct aspiration shows clinical outcomes equal to those of stent retriever thrombectomy in our large multicenter real-life cohort. We found no difference in complication rates and shorter procedure times for aspiration. PMID- 30472677 TI - Medina embolization device for the treatment of intracranial aneurysms: 18 months' angiographic results. AB - BACKGROUND AND PURPOSE: The Medina embolization device (MED) is a new flow disruption device combining the design of a detachable coil with an intrasaccular flow disrupter. Safety and short-term angiographic effectiveness of this device have recently been reported. However, long-term angiographic results are lacking. We report herein the 18 months' angiographic outcome in patients treated for a wide-neck intracranial aneurysm with the MED. MATERIALS AND METHODS: Nineteen patients (17 female, mean age 50 years) with 20 wide-neck intracranial aneurysms (six ruptured; 14 unruptured) were treated by the MED between January 2015 and June 2016. Procedure-related complications were systematically recorded; discharge and 6-9 months' follow-up modified Rankin Scale scores were assessed. Angiographic mid-term and long-term follow-up were performed with a mean delay of 6.4+/-1.5 months (n=16 aneurysms) and 17.7+/-4.2 months (n=15 aneurysms), respectively. Occlusion rates were evaluated after the procedure and at the mid term and long-term follow-up using the Roy-Raymond scale. RESULTS: Embolization with the MED was feasible in all except two cases (2/20, 10%). One per-procedural perforation was recorded (1/20, 5%) and one MED deployment failed because of the aneurysm's shape (1/20, 5%). Three cases of thromboembolic complications were observed (3/20, 15%). Only one thromboembolic complication was responsible for clinical sequelae. Grade A occlusion rate was 61% (11/18) after the procedure, 75% at 6 months' follow-up (12/16), and 80% (12/15) at long-term follow-up. Two cases (2/18, 11%) of recanalization at mid-term were documented angiographically. No recanalization occurred between the mid-term and long-term follow-up. CONCLUSION: MED is a hybrid embolization device, combining properties of a conventional coil with those of an intrasaccular flow disrupter. Our series focusing on long-term angiographic follow-up shows a satisfactory long-term occlusion rate. Larger series with longer angiographic follow-up times are warranted to confirm these preliminary results. PMID- 30472678 TI - Motorcycle taxi programme increases safe riding behaviours among its drivers in Kampala, Uganda. AB - BACKGROUND: SafeBoda is a motorcycle taxi company that provides road safety training and helmets to its drivers in Kampala, Uganda. We sought to determine whether SafeBoda drivers are more likely to engage in safe riding behaviours than regular drivers (motorcycle taxi drivers not part of SafeBoda). METHODS : We measured riding behaviours in SafeBoda and regular drivers through: (1) computer assisted personal interview (CAPI), where 400 drivers were asked about their riding behaviours (eg, helmet and mobile phone use) and (2) roadside observation, where riding behaviours were observed in 3000 boda-boda drivers and their passengers along major roads in Kampala. RESULTS: Across the two cross-sectional studies, a higher proportion of SafeBoda drivers than regular drivers engaged in safe riding behaviours. For instance, helmet use among SafeBoda compared with regular drivers was 21% points higher (95% CI 0.15 to 0.27; p<0.001) based on the CAPI and 45% points higher (95% CI 0.43 to 0.47; p<0.001) based on roadside observation. Furthermore, compared with regular drivers, SafeBoda drivers were more likely to report having a driver's license (66.3% vs 33.5 %; p<0.001) and a reflective jacket (99.5% vs 50.5 %; p<0.001) and were less likely to report driving towards oncoming traffic (4% vs 45.7 %; p<0.001) in the past 30 days. CONCLUSION: The SafeBoda programme is associated with increased safe riding behaviours among motorcycle taxi drivers in Kampala. Therefore, the promotion and expansion of such programmes may lead to a reduction in morbidity and mortality due to road injuries. PMID- 30472679 TI - Sampling design and methodology of the Violence Against Children and Youth Surveys. AB - INTRODUCTION: Globally 1 billion children are exposed to violence every year. The Violence Against Children Surveys (VACS) are nationally representative surveys of males and females ages 13-24 that are intended to measure the burden of sexual, physical and emotional violence experienced in childhood, adolescence and young adulthood. It is important to document the methodological approach and design of the VACS to better understand the national estimates that are produced in each country, which are used to drive violence prevention efforts. METHODS: This study describes the surveys' target population, sampling design, statistical considerations, data collection process, priority violence indicators and data dissemination. RESULTS: Twenty-four national household surveys have been completed or are being planned in countries across Africa, Asia, the Caribbean, Central and South America, and Eastern Europe. The sample sizes range from 891 to 7912 among females (72%-98% response rate) and 803-2717 among males (66%-98% response rate). Two face-to-face interviews are conducted: a Household and an Individual Questionnaire. A standard set of core priority indicators are generated for each country that range from prevalence of different types of violence, contexts, risk and protective factors, and health consequences. Results are disseminated through various platforms to expand the reach and impact of the survey results. CONCLUSION: Data obtained through VACS can inform development and implementation of effective prevention strategies and improve health service provision for all who experience violence. VACS serves as a standardised tool to inform and drive prevention through high-quality, comprehensive data. PMID- 30472680 TI - Fatal drowning in the Western Cape, South Africa: a 7-year retrospective, epidemiological study. AB - INTRODUCTION: Drowning is a neglected public health threat in low-income and middle-income countries where the greatest drowning burden is observed. There is a paucity of drowning surveillance data from low-resource settings, particularly in Africa. Understanding local epidemiological factors will enable the development of context-specific drowning prevention initiatives and the appropriate allocation of resources. AIM: The primary aim of this study was to describe the epidemiology of fatal drowning in the Western Cape, South Africa. METHOD: This retrospective study describes fatal drowning incidents captured in the Western Cape vital registration system between 2010 and 2016. Data were obtained from the Forensic Pathology Services of the Western Cape Government. One way analysis of variance was performed to detect a trend in mean drowning mortality rates between 2010 and 2016. chi2 tests for independence were performed to detect differences in the distribution of variables between groups. RESULTS: A total of 1391 fatal drownings occurred in the Western Cape between 2010 and 2016, with an age-adjusted drowning mortality rate of 3.2 per 100 000 population. Rates were fourfold higher in men compared with women. Children, particularly young children aged 0-4 years, and young adult men between 20 and 34 years of age were identified to be at high risk of fatal drowning. Drowning occurred predominantly in large, open bodies of water with concentrations in summer and public holidays. CONCLUSIONS: The Western Cape drowning prevention strategy should prioritise interventions to reduce drowning in children and young adult men, with a targeted focus on festive periods such as public holidays. PMID- 30472681 TI - Preoperative administration of the 5-HT4 receptor agonist prucalopride reduces intestinal inflammation and shortens postoperative ileus via cholinergic enteric neurons. AB - OBJECTIVES: Vagus nerve stimulation (VNS), most likely via enteric neurons, prevents postoperative ileus (POI) by reducing activation of alpha7 nicotinic receptor (alpha7nAChR) positive muscularis macrophages (mMphi) and dampening surgery-induced intestinal inflammation. Here, we evaluated if 5-HT4 receptor (5 HT4R) agonist prucalopride can mimic this effect in mice and human. DESIGN: Using Ca2+ imaging, the effect of electrical field stimulation (EFS) and prucalopride was evaluated in situ on mMphi activation evoked by ATP in jejunal muscularis tissue. Next, preoperative and postoperative administration of prucalopride (1-5 mg/kg) was compared with that of preoperative VNS in a model of POI in wild-type and alpha7nAChR knockout mice. Finally, in a pilot study, patients undergoing a Whipple procedure were preoperatively treated with prucalopride (n=10), abdominal VNS (n=10) or sham/placebo (n=10) to evaluate the effect on intestinal inflammation and clinical recovery of POI. RESULTS: EFS reduced the ATP-induced Ca2+ response of mMphi, an effect that was dampened by neurotoxins tetrodotoxin and omega-conotoxin and mimicked by prucalopride. In vivo, prucalopride administered before, but not after abdominal surgery reduced intestinal inflammation and prevented POI in wild-type, but not in alpha7nAChR knockout mice. In humans, preoperative administration of prucalopride, but not of VNS, decreased Il6 and Il8 expression in the muscularis externa and improved clinical recovery. CONCLUSION: Enteric neurons dampen mMphi activation, an effect mimicked by prucalopride. Preoperative, but not postoperative treatment with prucalopride prevents intestinal inflammation and shortens POI in both mice and human, indicating that preoperative administration of 5-HT4R agonists should be further evaluated as a treatment of POI. TRIAL REGISTRATION NUMBER: NCT02425774. PMID- 30472682 TI - Enteric fungal microbiota dysbiosis and ecological alterations in colorectal cancer. AB - OBJECTIVES: Bacteriome and virome alterations are associated with colorectal cancer (CRC). Nevertheless, the gut fungal microbiota in CRC remains largely unexplored. We aimed to characterise enteric mycobiome in CRC. DESIGN: Faecal shotgun metagenomic sequences of 184 patients with CRC, 197 patients with adenoma and 204 control subjects from Hong Kong were analysed (discovery cohort: 73 patients with CRC and 92 control subjects; validation cohort: 111 patients with CRC, 197 patients with adenoma and 112 controls from Hong Kong). CRC-associated fungal markers and ecological changes were also validated in additional independent cohorts of 90 patients with CRC, 42 patients with adenoma and 66 control subjects of published repository sequences from Germany and France. Assignment of taxonomies was performed by exact k-mer alignment against an integrated microbial reference genome database. RESULTS: Principal component analysis revealed separate clusters for CRC and control (p<0.0001), with distinct mycobiomes in early-stage and late-stage CRC (p=0.0048). Basidiomycota:Ascomycota ratio was higher in CRC (p=0.0042), with increase in Malasseziomycetes (p<0.0001) and decrease in Saccharomycetes (p<0.0001) and Pneumocystidomycetes (p=0.0017). Abundances of 14 fungal biomarkers distinguished CRC from controls with an area under the receiver-operating characteristic curve (AUC) of 0.93 and validated AUCs of 0.82 and 0.74 in independent Chinese cohort V1 and European cohort V2, respectively. Further ecological analysis revealed higher numbers of co-occurring fungal intrakingdom and co-exclusive bacterial-fungal correlations in CRC (p<0.0001). Moreover, co-occurrence interactions between fungi and bacteria, mostly contributed by fungal Ascomycota and bacterial Proteobacteria in control, were reverted to co-exclusive interplay in CRC (p=0.00045). CONCLUSIONS: This study revealed CRC-associated mycobiome dysbiosis characterised by altered fungal composition and ecology, signifying that the gut mycobiome might play a role in CRC. PMID- 30472684 TI - Complexity made simple. PMID- 30472683 TI - Alcoholic and non-alcoholic fatty liver disease and associations with coronary artery calcification: evidence from the Kangbuk Samsung Health Study. AB - OBJECTIVE: Recent evidence suggests that alcoholic fatty liver disease (AFLD) and non-alcoholic fatty liver disease (NAFLD) may differentially affect risk of cardiovascular mortality. To investigate whether early liver disease due to AFLD or NAFLD have similar or dissimilar effects on risk of early coronary artery atherosclerosis, we have investigated the associations between AFLD and NAFLD and coronary artery calcium (CAC). DESIGN: A cross-sectional study was performed in 105 328 Korean adults who attended a health check-up programme. CAC score was assessed using CT, daily alcohol intake was recorded as grams/day and liver fat by ultrasound. Logistic regression model was used to calculate ORs with 95% CIs for prevalent CAC. RESULTS: Both NAFLD and AFLD were positively associated with CAC score. After adjusting for potential confounders, multivariable-adjusted OR (95% CIs) for CAC >0 comparing NAFLD and AFLD to the reference (absence of both excessive alcohol use and fatty liver disease) were 1.10 (95% CI 1.05 to 1.16) and 1.20 (95% CI 1.11 to 1.30), respectively. In post hoc analysis, OR (95% CI) for detectable CAC comparing AFLD to NAFLD was 1.09 (95% CI 1.01 to 1.17). Associations of NAFLD and AFLD with CAC scores were similar in both non-obese and obese individuals without significant interaction by obesity (p for interaction=0.088). After adjusting for homeostasis model assessment of insulin resistance and high-sensitivity C reactive protein, the associations between fatty liver disease and CAC scores remained statistically significant. CONCLUSION: In this large sample of young and middle-aged individuals, early liver disease due to NAFLD and AFLD were both significantly associated with the presence of coronary artery calcification. PMID- 30472685 TI - Comparison of analogue and electronic stethoscopes for pulmonary auscultation by internal medicine residents. AB - BACKGROUND: Electronic stethoscopes are becoming more common in clinical practice. They may improve the accuracy and efficiency of pulmonary auscultation, but the data to support their benefit are limited. OBJECTIVE: To determine how auscultation with an electronic stethoscope may affect clinical decision making. METHODS: An online module consisting of six fictional ambulatory cases was developed. Each case included a brief history and lung sounds recorded with an analogue and electronic stethoscope. Internal medicine resident participants were randomly selected to hear either the analogue or electronic lung sounds. Numbers of correct answers, time spent on each case and numbers of times the recordings were played were compared between the groups who heard each mode of auscultation, with a p value of less than 0.05 indicating statistical significance. RESULTS: 61 internal medicine residents completed at least one case, and 41 residents completed all six cases. There were no significant differences in overall scores between participants who heard analogue and electronic lung sounds (3.14+/-0.10 out of 6 correct for analogue, 3.20+/-0.10 out of 6 for electronic, p=0.74). There were no significant differences in performance for any of the six cases (p=0.78), time spent on the cases (p=0.67) or numbers of times the recordings were played (p=0.85). CONCLUSION: When lung sounds were amplified with an electronic stethoscope, we did not detect an effect on performance, time spent on the cases or numbers of times participants listened to the recordings. PMID- 30472686 TI - Biological pest control using a model-based robust feedback. AB - Biological control is the artificial manipulation of natural enemies of a pest for its regulation to densities below a threshold for economic damage. The authors address the biological control of a class of pest population models using a model-based robust feedback approach. The proposed control framework is based on a recursive cascade control scheme exploiting the chained form of pest population models and the use of virtual inputs. The robust feedback is formulated considering the non-linear model uncertainties via a simple and intuitive control design. Numerical results on three pest biological control problems show that the proposed model-based robust feedback can regulate the pest population at the desired reference via the manipulation of a biological control action despite model uncertainties. PMID- 30472688 TI - Identification of essential proteins based on a new combination of topological and biological features in weighted protein-protein interaction networks. AB - The identification of essential proteins in protein-protein interaction (PPI) networks is not only important in understanding the process of cellular life but also useful in diagnosis and drug design. The network topology-based centrality measures are sensitive to noise of network. Moreover, these measures cannot detect low-connectivity essential proteins. The authors have proposed a new method using a combination of topological centrality measures and biological features based on statistical analyses of essential proteins and protein complexes. With incomplete PPI networks, they face the challenge of false positive interactions. To remove these interactions, the PPI networks are weighted by gene ontology. Furthermore, they use a combination of classifiers, including the newly proposed measures and traditional weighted centrality measures, to improve the precision of identification. This combination is evaluated using the logistic regression model in terms of significance levels. The proposed method has been implemented and compared to both previous and more recent efficient computational methods using six statistical standards. The results show that the proposed method is more precise in identifying essential proteins than the previous methods. This level of precision was obtained through the use of four different data sets: YHQ-W, YMBD-W, YDIP-W and YMIPS-W. PMID- 30472687 TI - Dynamic optimal experimental design yields marginal improvement over steady-state results for computational maximisation of regulatory T-cell induction in ex vivo culture. AB - The isolation of T cells, followed by differentiation into Regulatory T cells (Tregs), and re-transplantation into the body has been proposed as a therapeutic option for inflammatory bowel disease. A key requirement for making this a viable therapeutic option is the generation of a large population of Tregs. However, cytokines in the local microenvironment can impact the yield of Tregs during differentiation. As such, experimental design is an essential part of evaluating the importance of different cytokine concentrations for Treg differentiation. However, currently only single, constant concentrations of the cytokines have been investigated. This work addresses this point by performing experimental design in silico which seeks to maximize the predicted induction of Tregs relative to Th17 cells, by selecting an optimal input function for the concentrations of TGF-beta, IL-2, IL-6, and IL-23. While this approach sounds promising, the results show that only marginal improvements in the concentration of Tregs can be achieved for dynamic cytokine profiles as compared to optimal constant concentrations. Since constant concentrations are easier to implement in experiments, it is recommended for this particular system to keep the concentrations constant where IL-6 should be kept low and high concentrations of TGF-beta, IL-2, and IL-23 should be used. PMID- 30472689 TI - Cancers classification based on deep neural networks and emotional learning approach. AB - In the present era, enormous factors contribute to causing cancer. So cancer classification cannot rely only on doctor's thoughts. As a result, intelligent algorithms concerning doctor's help are inevitable. Therefore, the authors are motivated to suggest a novel algorithm to classify three cancer datasets; colon, ALL-AML, and leukaemia cancers. Their proposed algorithm is based on the deep neural network and emotional learning process. First of all, by applying the principal component analysis, they had a feature reduction. Then, they used deep neural as a feature extraction. Then, they implemented different classifiers; multi-layer perceptron, support vector machine (SVM), decision tree, and Gaussian mixture model. In the end, because in the real world, especially when working on systems biology, unpredictable events, and uncertainties are undeniable, the robustness of their model against uncertainties is important. So they added Gaussian noise to the input features of the first encoder in each dataset, then, they applied the stacked denoising method. Experimental results disclosed that, generally, using emotional learning increased the accuracy. In addition, the highest accuracy was gained by SVM, 91.66, 92.27, and 96.56% for colon, ALL-AML, and leukaemia, respectively. However, GMM led to the lowest accuracy. The best accuracy gained by GMM was 60%. PMID- 30472690 TI - Time-invariant biological networks with feedback loops: structural equation models and structural identifiability. AB - Quantitative analyses of biological networks such as key biological parameter estimation necessarily call for the use of graphical models. While biological networks with feedback loops are common in reality, the development of graphical model methods and tools that are capable of dealing with feedback loops is still in its infancy. Particularly, inadequate attention has been paid to the parameter identifiability problem for biological networks with feedback loops such that unreliable or even misleading parameter estimates may be obtained. In this study, the structural identifiability analysis problem of time-invariant linear structural equation models (SEMs) with feedback loops is addressed, resulting in a general and efficient solution. The key idea is to combine Mason's gain with Wright's path coefficient method to generate identifiability equations, from which identifiability matrices are then derived to examine the structural identifiability of every single unknown parameter. The proposed method does not involve symbolic or expensive numerical computations, and is applicable to a broad range of time-invariant linear SEMs with or without explicit latent variables, presenting a remarkable breakthrough in terms of generality. Finally, a subnetwork structure of the C. elegans neural network is used to illustrate the application of the authors' method in practice. PMID- 30472691 TI - Identifying cancer-related microRNAs based on subpathways. AB - MicroRNAs (miRNAs) are a class of small endogenous non-coding genes that play important roles in post-transcriptional regulation as well as other important biological processes. Accumulating evidence indicated that miRNAs were extensively involved in the pathology of cancer. However, determining which miRNAs are related to a specific cancer is problematic because one miRNA may target multiple genes and one gene may be targeted by multiple miRNAs. The authors proposed a new approach, named miR_SubPath, to identify cancer-associated miRNAs by three steps. The targeted genes were determined based on differentially expressed genes in significant dysfunctional subpathways. Then the candidate miRNAs were determined according to miRNA-genes associations. Finally, these candidate miRNAs were ranked based on their relations with some seed miRNAs in a functional similarity network. Results on real-world datasets showed that the proposed miR_SubPath method was more robust and could identify more cancer related miRNAs than a prior approach, miR_Path, miR_Clust and Zhang's method. PMID- 30472692 TI - Study of cohabitation and interconnection effects on normal and leukaemic stem cells dynamics in acute myeloid leukaemia. AB - On the basis of recent studies, understanding the intimate relationship between normal and leukaemic stem cells is very important in leukaemia treatment. The authors' aim in this work is to clarify and assess the effect of coexistence and interconnection phenomenon on the healthy and cancerous stem cell dynamics. To this end, they perform the analysis of two time-delayed stem cell models in acute myeloid leukaemia. The first model is based on decoupled healthy and cancerous stem cell populations (i.e. there is no interaction between cell dynamics) and the second model includes interconnection between both population's dynamics. By using the positivity of both systems, they build new linear functions that permit to derive global stability conditions for each model. Moreover, knowing that most common types of haematological diseases are characterised by the existence of oscillations, they give conditions for the existence of a limit cycle (oscillations) in a particularly interesting healthy situation based on Poincare Bendixson theorem. The obtained results are simulated and interpreted to be significant in understanding the effect of interconnection and would lead to an improvement in leukaemia treatment. PMID- 30472693 TI - Modelling and simulation of photosystem II chlorophyll fluorescence transition from dark-adapted state to light-adapted state. AB - Green houses play a vital role in modern agriculture. Artificial light illumination is very important in a green house. While light is necessary for plant growth, excessive light in a green house may not bring more profit and even damages plants. Developing a plant-physiology-based light control strategy in a green house is important, which implies that a state-space model on photosynthetic activities is very useful because modern control theories and techniques are usually developed according to model structures in the state space. In this work, a simplified model structure on photosystem II activities was developed with seven state variables and chlorophyll fluorescence (ChlF) as the observable variable. Experiments on ChlF were performed. The Levenberg Marquardt algorithm was used to estimate model parameters from experimental data. The model structure can fit experimental data with a small relative error (<2%). ChlF under different light intensities were simulated to show the effect of light intensity on ChlF emission. A simplified model structure with fewer state variables and model parameters will be more robust to perturbations and model parameter estimation. The model structure is thus expected useful in future green house light control strategy development. PMID- 30472694 TI - Hierarchical parameter estimation of GRN based on topological analysis. AB - Reverse engineering of gene regulatory network (GRN) is an important and challenging task in systems biology. Existing parameter estimation approaches that compute model parameters with the same importance are usually computationally expensive or infeasible, especially in dealing with complex biological networks.In order to improve the efficiency of computational modeling, the paper applies a hierarchical estimation methodology in computational modeling of GRN based on topological analysis. This paper divides nodes in a network into various priority levels using the graph-based measure and genetic algorithm. The nodes in the first level, that correspond to root strongly connected components(SCC) in the digraph of GRN, are given top priority in parameter estimation. The estimated parameters of vertices in the previous priority level ARE used to infer the parameters for nodes in the next priority level. The proposed hierarchical estimation methodology obtains lower error indexes while consuming less computational resources compared with single estimation methodology. Experimental outcomes with insilico networks and a realistic network show that gene networks are decomposed into no more than four levels, which is consistent with the properties of inherent modularity for GRN. In addition, the proposed hierarchical parameter estimation achieves a balance between computational efficiency and accuracy. PMID- 30472695 TI - Modelling and simulation of chlorophyll fluorescence from photosystem II as affected by temperature. AB - Emission of chlorophyll fluorescence (ChlF) from photosystem II (PSII) is affected by both plant status and environmental conditions. In this work, a state space model structure for ChlF from PSII with temperature as a variable model parameter was developed to provide insights into the temperature effects on photosynthesis and greenhouse temperature control. Experiments were carried out at 20, 25, and 30 degrees C to validate the capability and flexibility of the developed model structure. Simulations of ChlF emission were performed for different temperatures. The results demonstrated the effectiveness of the ChlF model structure and the findings are useful for the development of greenhouse temperature control strategies. PMID- 30472696 TI - Stability of cannabinoids in cannabis FM1 flowering tops and oil preparation evaluated by ultra-high performance liquid chromatography tandem mass spectrometry. PMID- 30472697 TI - Cell cycle-dependent and -independent telomere shortening accompanies murine brain aging. AB - Replication-based telomere shortening during lifetime is species- and tissue specific, however, its impact on healthy aging is unclear. In particular, the contribution of telomere truncation to the aging process of the CNS, where replicative senescence alone fails to explain organ aging due to low to absent mitotic activity of intrinsic populations, is undefined. Here, we assessed changes in relative telomere length in non-replicative and replicative neural brain populations and telomerase activity as a function of aging in C57BL/6 mice. Telomeres in neural cells and sub-selected neurons shortened with aging in a cell cycle-dependent and -independent manner, with preponderance in replicative moieties, implying that proliferation accelerates, but is not prerequisite for telomere shortening. Consistent with this telomere erosion, telomerase activity and nuclear TERT protein were not induced with aging. Knockdown of the Rela subunit of NF-kappaB, which controls both telomerase enzyme and subcellular TERT protein allocation, did also not influence telomerase activity or telomere length, in spite of its naive up-regulation selectively under aging conditions. We conclude that telomere instability is intrinsic to physiological brain aging beyond cell replication, and appears to occur independently of a functional interplay with NF-kappaB, but rather as a failure to induce or relocate telomerase. PMID- 30472699 TI - Long-Term Follow-Up of a Case with Dyskeratosis Congenita Caused by NHP2 V126M/X154R Mutation: Genotype-Phenotype Association. AB - Dyskeratosis congenita (DC) is a rare inherited syndrome characterized by classical mucocutaneous features and the presence of other clinical features including bone marrow failure, pulmonary fibrosis, liver cirrhosis, and a predisposition to cancer. The symptoms develop at various ages and may manifest over time. Gene mutations associated with DC, such as DC1, TERC, TERT, TINF2, NHP2, NOP10, ACD, CTC1, NAF1, PARN, POT1, RTEL1, STN1, and WRAP53, have been identified in about 70% of patients. Since the number of patients with DC is small and the effect of genetic pathogenic variant may affect the phenotype, we wanted to present the clinical features and course of illness in a patient with NHP2 gene mutation (compound heterozygote for the NHP2 mutations c.376G>A/c.460T>A; amino acid substitutions: p.Val126Met and p.X154Arg) that occurred as a compound heterozygous state. PMID- 30472698 TI - Phosphatidylcholine could protect the defect of zearalenone exposure on follicular development and oocyte maturation. AB - Zearalenone (ZEA) is a well-known exogenous endocrine disruptor and can lead to severe negative effects on the human and animal reproductive process. Using a follicle culture model, we have previously shown that ZEA exposure significantly affected the follicular development and antrum formation but the underlying mechanisms are not well known. Therefore, in this study, we explored the metabolomic changes of granulosa cell (GC) culture media with or without ZEA exposure. The results showed that ZEA significantly increased phosphatidylcholine or phosphatidyl ethanolamine adducts in culture medium. A comprehensive analysis with the metabolome data from follicular fluid of small and large antral follicles showed that lyso phosphatidylcholine (LPC) was accumulated during follicle growth, but was depleted by ZEA exposure. Exogenous supplement with LPC to the follicle growth media or oocyte maturation media can partly protect the defect of ZEA exposure on follicular antrum formation and oocyte maturation. Taken together, our results demonstrate that ZEA exposure hinders the follicular growth and exogenous LPC can practically protect the defect of ZEA on follicular development and oocyte maturation. PMID- 30472700 TI - Predictors of Renal Outcomes in Sclerotic Class Anti-Neutrophil Cytoplasmic Antibody Glomerulonephritis. AB - BACKGROUND: The prognostic value of the anti-neutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis (GN) classification has been demonstrated in several cohorts with sclerotic class having the worst renal outcome. Relevant published data on factors predicting outcomes in sclerotic ANCA GN is limited. METHODS: Sclerotic ANCA GN patients were recruited from 5 centers worldwide for this retrospective cohort study. We describe the clinical characteristics of this cohort and evaluate predictors of 1-year glomerular filtration rate (GFR) and end stage renal disease (ESRD). Kidney function at 12 months as measured by Modification of Diet in Renal Disease estimated GFR (eGFR) was modeled by simple and multiple linear regression analyses. We used Cox proportional hazards regression modeling to evaluate ESRD-free survival. RESULTS: Of the 50 patients, 92% were Caucasian and 60% male with a mean age of 61 years. While 72% had renal limited disease, 82% were MPO ANCA positive. Kidney biopsies contained a median of 20 (interquartile range [IQR] 15-34) glomeruli with 96% showing moderate to severe interstitial fibrosis. Overall, 96% of patients received immunosuppressive drug therapy and 16% received plasmapheresis. Treatment response was achieved in all but 1 patient. The median (IQR) eGFR at entry was 14.5 (9-19) mL/min/1.73 m2. Over a median (IQR) follow-up of 33.5 (17-82) months, 26 patients reached ESRD. Ten patients died with 6 of the deaths occurring within the first year of diagnosis. The hazard of progression to ESRD was significantly higher in those with lower GFR at study entry (p = 0.003) and with higher degree of tubular atrophy (p = 0.043). CONCLUSIONS: Renal recovery is rare among sclerotic ANCA GN patients requiring dialysis at entry and 12% of patients died in the first year. Entry GFR and tubular atrophy were significant predictors of GFR at 12 months and renal survival in patients with sclerotic class ANCA GN. PMID- 30472701 TI - Trends in the Causes of Death among Kidney Transplant Recipients in the United States (1996-2014). AB - BACKGROUND: Death with graft function remains an important cause of graft loss among kidney transplant recipients (KTRs). Little is known about the trend of specific causes of death in KTRs in recent years. METHODS: We analyzed United States Renal Data System data (1996-2014) to determine 1- and 10-year all-cause and cause-specific mortality in adult KTRs who died with a functioning allograft. We also studied 1- and 10-year trends in the various causes of mortality. RESULTS: Of 210,327 KTRs who received their first kidney transplant from 1996 to 2014, 3.2% died within 1 year after transplant. Cardiovascular deaths constituted the majority (24.7%), followed by infectious (15.2%) and malignant (2.9%) causes; 40.1% of deaths had no reported cause. Using 1996 as the referent year, all-cause as well as cardiovascular mortality declined, whereas mortality due to malignancy did not. For analyses of 10-year mortality, we studied 94,384 patients who received a first kidney transplant from 1996 to 2005. Of those, 22.1% died over 10 years and the causative patterns of their causes of death were similar to those associated with 1-year mortality. CONCLUSIONS: Despite the downtrend in mortality over the last 2 decades, a significant percentage of KTRs die in 10 years with a functioning graft, and cardiovascular mortality remains the leading cause of death. These data also highlight the need for diligent collection of mortality data in KTRs. PMID- 30472702 TI - Itraconazole Attenuates Peritoneal Fibrosis Through Its Effect on the Sonic Hedgehog Signaling Pathway in Mice. AB - BACKGROUND: Peritoneal fibrosis is a devastating complication of peritoneal dialysis. However, its precise mechanism is unclear, and specific treatments have not yet been established. Recent evidence suggests that the sonic hedgehog (SHH) signaling pathway is involved in tissue fibrogenesis. Drugs that inhibit this pathway are emerging in the field of anti-fibrosis therapy. Itraconazole, an anti fungal agent, was also recently recognized as an inhibitor of the SHH signaling pathway. In this study, we used a mouse model to investigate whether the SHH signaling pathway is involved in the development of peritoneal fibrosis and the effects of itraconazole on peritoneal fibrosis. METHODS: Peritoneal fibrosis was induced by intraperitoneal (IP) injection of 0.1% chlorhexidine gluconate (CG) solution every other day for 4 weeks, with or without itraconazole treatment (20 mg/kg, IP injection on a daily basis). Male C57BL/6 mice were divided into 4 groups: saline group, saline plus itraconazole group, CG group, and CG plus itraconazole group. Isotonic saline was administered intraperitoneally to the control group. The peritoneal tissues were evaluated for histological changes, expression of fibrosis markers, and the main components of the SHH signaling pathway. RESULTS: Peritoneal thickening was evident in the CG group and was significantly decreased by itraconazole administration (80.4 +/- 7.7 vs. 28.2 +/- 3.8 um, p < 0.001). The expression of the following SHH signaling pathway components was upregulated in the CG group and suppressed by itraconazole treatment: SHH, patched, smoothened, and glioma-associated oncogene transcription factor 1. The IP injection of CG solution increased the expression of fibrosis markers such as alpha-smooth muscle actin and transforming growth factor-beta1 in the peritoneal tissues. Itraconazole treatment significantly decreased the expression of these markers. CONCLUSION: Our study provides the first evidence that the SHH signaling pathway may be implicated in peritoneal fibrosis. It also demonstrates that itraconazole treatment has protective effects on peritoneal fibrosis through the regulation of the SHH signaling pathway. These findings suggest that blockage of the SHH signaling pathway is a potential therapeutic strategy for peritoneal fibrosis. PMID- 30472703 TI - Vitrectomy Outcomes in Eyes with Tractional Diabetic Macular Edema. AB - PURPOSE: To evaluate pars plana vitrectomy (PPV) outcomes in cases with tractional diabetic macular edema (tDME). METHODS: We conducted a single-center retrospective study with a follow-up of 12 months. Forty-six eyes with tDME of 38 patients submitted to PPV between 2013 and 2015 were assessed. A standard PPV was performed and surgical outcomes were registered at the 3-, 6-, and 12-month follow-up. RESULTS: The baseline median best corrected visual acuity (BCVA) in ETDRS (Early Treatment Diabetic Retinopathy Study) letters and the median central foveal thickness (CFT) were 43.0 letters and 491.0 um, respectively. At the 12 month follow-up, a median decrease in CFT of 232.7 um was observed. A CFT < 300 um was achieved in 65.2% of the cases (52.2% needing no further treatment); a BCVA improvement by >=10 letters was achieved in 60.0%, but there was a decrease of >=10 letters in 13.0% of the cases. DME recurrence was observed in 10.9% of the cases, with a median time of development after vitrectomy of 6 months. As a major postoperative complication, a macular hole was observed in 1 patient (2.1%). CONCLUSIONS: In our series, PPV for tDME induced an improvement in retinal thickening and visual outcome in more than 50% of the cases, with low recurrence rates and a low number of postoperative complications. PMID- 30472704 TI - Urinary Level of Liver-Type Fatty Acid Binding Protein Reflects the Degree of Tubulointerstitial Damage in Polycystic Kidney Disease. AB - BACKGROUND/AIMS: Polycystic kidney disease (PKD) is a common, progressive, and heritable type of kidney disease. Although certain imaging modalities are useful for the diagnosis and staging of PKD, they cannot adequately monitor the severity of interstitial inflammation and fibrosis. Therefore, the present study evaluated the urinary level of liver-type fatty acid binding protein (L-FABP) as a marker of interstitial inflammation and fibrosis in PKD. METHODS: Male PCK/CrljCrl Pkhd1pck/Crl (PCK) rats (n = 34) were used as an animal model of the PKD. Age-and sex-matched Sprague-Dawley rats (SD) (n = 34) were used as controls. Urine samples were obtained from the rats at 8, 12, 16, 20, and 24 weeks of age, and the sera and kidney tissues were obtained at 8, 16, 20, and 24 weeks of age. RESULTS: All PCK rats developed cysts, and the degrees of tubular epithelial cell proliferation and interstitial inflammation increased linearly with age in these model rats relative to the controls. Interstitial fibrosis tended to increase in the PCK rats from 8 to 20 weeks of age, and revealed a peak level at 20 weeks. The urinary L-FABP levels increased linearly with age in the PCK rats, and the levels at 12, 16, 20, and 24 weeks were significantly higher than those in the controls. The urinary levels of L-FABP in the PCK rats correlated significantly with the severity of tubulointerstitial damage; specifically, we observed a significant correlation of the urinary levels at 16 weeks of age with the total kidney volume at 20 weeks. In contrast, both PCK and SD rats exhibited similar serum levels of L-FABP. CONCLUSION: Urinary L-FABP reflects the progression of tubulointerstitial damage, and therefore, may be a useful marker for monitoring the progression of PKD. PMID- 30472705 TI - Role of beta-Estradiol in MCF-7 Breast Cancer Cell Line Based on the Bioinformatics Analysis. AB - BACKGROUND: This study aimed to investigate the action mechanism of beta estradiol in MCF-7 breast cancer (BC) cells. METHODS: The cell samples were sequenced using Hiseq 2000, including 2 MCF-7 controls and 2 samples treated with beta-estradiol. Differentially expressed genes (DEGs) were screened using the NOISeq package in R, followed by the functions and pathways analyses using Database for Annotation, Visualization and Integrated Discovery. DEGs associated with beta-estradiol were selected using the WbeGestalt software, and the corresponding target miRNAs of these genes were analyzed from different miRNA databases. Additionally, protein-protein interaction network of the drug associated genes was constructed using Cytoscape. RESULTS: A total of 1,835 DEGs in BC samples were screened. Thereinto, DEGs associated with BC (17 upregulated and 28 downregulated DEGs) were involved in the regulation of cell proliferation, response to endogenous stimulus, and response to hormone stimulus, while the genes participated in several significant pathways. Cyclin D1, estrogen receptor 1, catechol-O-methyltransferase, and cathepsin D (CTSD; hub genes) were the predicted new genes associated with beta-estradiol. Besides, hsa-miR-140-3p was the only target miRNA of CTSD. CONCLUSION: beta-Estradiol may play a key role in contributing to BC progression and metastasis by regulating the expression of the selected genes. PMID- 30472706 TI - Cutting Edge Bioinformatics and Biostatistics Approaches Are Bringing Precision Medicine and Nutrition to a New Era. PMID- 30472709 TI - Inhibition of microRNA-376b Protects Against Renal Interstitial Fibrosis via Inducing Macrophage Autophagy by Upregulating Atg5 in Mice with Chronic Kidney Disease. AB - BACKGROUND/AIMS: Renal interstitial fibrosis (RIF) is a common feature that facilitates the progression of chronic kidney disease (CKD), and emerging lines of evidence suggest that microRNA-376b (miR-376b) is capable of promoting RIF. In this study, we examined collagen deposition in kidney tissues, the autophagy and mitochondrial reactive oxygen species (ROS) of macrophages, and the apoptosis of kidney fibroblasts (KFBs) after the promotion or suppression of endogenous miR 376b in cultured macrophages and renal fibroblasts obtained from mice with CKD. METHODS: FVB/N mice were prepared to establish a CKD model. A target prediction program and luciferase activity determination were used to confirm that autophagy related gene 5 (Atg5) was a direct target of miR-376b. Macrophages and KFBs were isolated after the treatment to study the mechanisms and functions of miR-376b in relation to Atg5 in CKD. The autophagy level was determined, and KFB proliferation and apoptosis were assessed through MTT and EdU assays and flow cytometry, respectively. RESULTS: Atg5 was confirmed as a direct target of miR 376b. miR-376b and Atg5 exhibited high and low expression in kidney tissues from mice with CKD. The mice treated with a miR-376b inhibitor exhibited reduced collagen deposition, suppressed interstitial fibrosis, a higher level of autophagy, higher ROS production, enhanced apoptosis, and inhibited proliferation of KFBs, which suggested that the downregulation of miR-376b could exert beneficial effects on CKD through Atg5. CONCLUSION: miR-376b downregulation promotes macrophage autophagy to relieve RIF by negatively regulating Atg5 in mice with CKD. Thus, miR-376b might represent a potential focus of future investigations on treatments for CKD. PMID- 30472707 TI - Identifying High-Risk Individuals for Chronic Kidney Disease: Results of the CHERISH Community Demonstration Project. AB - BACKGROUND: Most people with chronic kidney disease (CKD) are not aware of their condition. OBJECTIVES: To assess screening criteria in identifying a population with or at high risk for CKD and to determine their level of control of CKD risk factors. METHOD: CKD Health Evaluation Risk Information Sharing (CHERISH), a demonstration project of the Centers for Disease Control and Prevention, hosted screenings at 2 community locations in each of 4 states. People with diabetes, hypertension, or aged >=50 years were eligible to participate. In addition to CKD, screening included testing and measures of hemoglobin A1C, blood pressure, and lipids. -Results: In this targeted population, among 894 people screened, CKD prevalence was 34%. Of participants with diabetes, 61% had A1C < 7%; of those with hypertension, 23% had blood pressure < 130/80 mm Hg; and of those with high cholesterol, 22% had low-density lipoprotein < 100 mg/dL. CONCLUSIONS: Using targeted selection criteria and simple clinical measures, CHERISH successfully identified a population with a high CKD prevalence and with poor control of CKD risk factors. CHERISH may prove helpful to state and local programs in implementing CKD detection programs in their communities. PMID- 30472708 TI - Antibodies against M-Type Phospholipase A2 Receptor May Predict Treatment Response and Outcome in Membranous Nephropathy. AB - BACKGROUND: Anti-phospholipase A2 receptor (PLA2R) antibodies are specific to the diagnosis of primary membranous nephropathy (pMN). The prevalence of positive antibodies varies among different cohorts. Still there is discrepancy in regard to the association between antibody levels and clinical courses, and the prognostic value of antibodies to treatment responses and kidney outcomes. METHODS: Three hundred fifty-nine consecutive kidney biopsy-proven pMN patients were enrolled. Anti-PLA2R antibodies were detected by immunofluorescence assay (IFA) and enzyme-linked immunosorbent assay (ELISA). RESULTS: The positive rate of anti-PLA2R antibodies in pMN was 65.2% (234/359) by IFA and 56.3% (202/359) by ELISA. The antibody level presented positive correlation with urinary protein excretion (r = 0.164, p = 0.002). Detectable antibodies and a higher level of proteinuria were independent risk factors to no-remission after treatments (OR 3.15, p = 0.004; OR 1.11, p = 0.006) and were independent risk factors to no spontaneous remission (OR 2.20, p = 0.011; OR 1.36, p < 0.001). A higher level of antibodies (hazard ratio 1.002, p = 0.019) was the independent risk factor to kidney dysfunction during follow-up. The antibodies turned negative in 42 out of 52 (80.8%) patients who achieved clinical remission, while they remained positive in all patients of the no-response category (p < 0.001). CONCLUSION: We documented correlations between anti-PLA2R antibody levels and clinical severity in this large Chinese pMN cohort. Antibody positivity and higher antibody level might predict treatment responses and kidney outcomes of pMN. PMID- 30472710 TI - Early Start Peritoneal Dialysis: Technique Survival in Long-Term Follow-Up. AB - BACKGROUND/AIMS: Peritoneal dialysis (PD) has gained interest over the last decade as a viable option for early start dialysis. It is still unknown if shorter break-in periods and less time for proper patient evaluation and training could influence technique survival in comparison to planned-start PD. METHODS: A prospective and observational study that compared technique survival in a cohort of patients who started either early or planned PD. Early start PD was defined as break-in period from 3 to 14 days with no previous nephrologist follow-up or patient training. RESULTS: A total of 154 patients were included (40 as early start PD), followed by a median time of 381 days. Comparing early vs. planned start PD, groups were similar concerning age 56 (40; 70) vs. 48 (32; 63) years, p=0.071, body mass index (BMI) 23.3 +/- 4.2 vs. 23.8 +/- 4.0 kg/m2, p=0.567 and male gender (60 vs. 48%, p=0.201), respectively. Comparing early vs. planned start groups, there were no differences regarding PD dropout for peritonitis (7.5 vs. 11.4%, p=0.764), catheter dysfunction (12.5 vs. 17.5%, p=0.619) and patient burnout (0 vs. 4.4%, p=0.328), respectively. Less patients in early start group quit PD for peritoneal membrane failure in comparison to planned-start group (2.5 vs. 16.7%, p=0.026). In multivariate cox-regression analysis, the only factors independently associated with technique failure were BMI> 25 kg/m2 (p=0.033) and Diabetes Mellitus (p=0.013), whereas no differences regarding early vs. planned PD start were observed (p=0.184). CONCLUSION: Despite the adverse scenario for initiating dialysis, early start PD had similar outcomes in comparison to planned start PD in long-term follow-up. PMID- 30472711 TI - Antibodies Against M-Type Phospholipase Receptor and Prediction of Outcome in Membranous Nephropathy: We are Not There Yet. PMID- 30472712 TI - Variants in APOA5 and ADIPOQ Moderate Improvements in Metabolic Syndrome during a One-Year Lifestyle Intervention. AB - BACKGROUND: Metabolic syndrome (MetS) comprises a cluster of risk factors including central obesity, hypertension, dyslipidemia, and impaired glucose homeostasis. Lifestyle interventions that promote improvements in diet quality and physical activity represent a first line of therapy for MetS. However, varying responses to lifestyle interventions are well documented and may be partially explained by underlying genetic differences. The aim of this study was to investigate if variants in genes previously associated with MetS influence the magnitude of change in MetS risk during a 1-year lifestyle intervention. METHODS: The present study used data collected from the Canadian Health Advanced by Nutrition and Graded Exercise study cohort (n = 159 men and women) to investigate the effect of 17 candidate single nucleotide polymorphisms (SNPs) on response to a 1-year lifestyle intervention. Associations between SNPs and the continuous MetS (cMetS) score, as well as individual MetS components, were examined. RESULTS: Reductions in cMetS score at both 3 months and 1 year were significantly associated with 2 variants: rs662799 (A/G) in apolipoprotein A5 (APOA5) and rs1501299 (G/T) in adiponectin (ADIPOQ). Individuals carrying a minor T allele in rs1501299 experienced a greater reduction in cMetS score at both 3 months and 1 year, whereas major allele AA homozygotes in rs662799 experienced greater reductions in cMetS score during the intervention. No associations were identified between the aforementioned SNPs and individual components of MetS. Both un-weighted and weighted genetic risk scores (GRS) using these 2 SNPs revealed that individuals carrying none of the risk alleles experienced significantly greater reductions in cMetS score after 1 year. CONCLUSIONS: The findings from the current study suggest that individuals with certain genotypes may benefit more from a lifestyle intervention for MetS and that specific variants, either independently or as part of a GRS, could be used as a nutrigenomic tool to tailor the intervention to reduce the risk of MetS. PMID- 30472713 TI - The Role of Renal Vascular Reactivity in the Development of Renal Dysfunction in Compensated and Decompensated Congestive Heart Failure. AB - BACKGROUND/AIMS: Reduction of renal blood flow (RBF) is commonly thought to be a causative factor of renal dysfunction in congestive heart failure (CHF), but the exact mechanism of the renal hypoperfusion is not clear. Apart from the activation of neurohormonal systems controlling intrarenal vascular tone, the cause might be altered reactivity of the renal vasculature to endogenous vasoactive agents. METHODS: To evaluate the role of this mechanism, we assessed by an ultrasonic transient-time flow probe maximum RBF responses to renal artery infusion of angiotensin II (ANG II), norepinephrine (NE) and acetylcholine (Ach) in healthy male rats and animals with compensated and decompensated CHF. CHF was induced by volume overload achieved by the creation of the aorto-caval fistula (ACF) in Hannover Sprague-Dawley rats. RESULTS: Maximum responses in RBF to ANG II were similar in rats studied five weeks (compensated phase) and 20 weeks (decompensated phase) after ACF creation when compared to sham-operated rats. On the other hand, NE elicited larger maximum decreases in RBF in rats with CHF (five and 20 weeks post-ACF) than in sham-operated controls. We observed greater maximum vasodilatory responses to Ach only in rats with a compensated stage of CHF (five weeks post-ACF). CONCLUSION: Greater renal vasoconstrictor responsiveness to ANG II or reduced renal vasodilatation in response to Ach do not play a decisive role in the development of renal dysfunction in ACF rats with compensated and decompensated CHF. On the other hand, exaggerated renal vascular responsiveness to NE may be here a contributing causative factor, active in either CHF phase. PMID- 30472714 TI - Patients with Hypertensive Nephropathy and Chronic Kidney Disease Might Not Benefit from Strict Blood Pressure Control. AB - BACKGROUND/AIMS: In patients with chronic kidney disease (CKD) strict blood pressure (BP) control is reno-protective. However, renal benefits from BP control might depend also on the etiology of CKD. We investigated if maintenance of BP at target is equally effective in subjects with hypertensive nephropathy (HN+) and in those with other nephropathies (HN-). METHODS: We evaluated 148 patients with CKD (stages 3-5) in two visits at least 12 months apart. BP was measured both as office BP and 24h ambulatory blood pressure (ABP). Glomerular filtration rate (eGFR) was estimated with CKD-EPI formula. The slope of eGFR variation (DeltaeGFR) was calculated as: (eGFR1-eGFR0)/months of follow up. RESULTS: Cohort characteristics were: HN-(n=82) and HN+ (n=66), age (71+/-9 vs 74+/-9 years; p=0.09); prevalence of diabetes (57 vs 43%; p=0.19); average follow up (19+/-7 vs 21+/-9 months; p=0.3). HN- and HN+ did not differ regarding both baseline eGFR (34+/-18 vs 35+/-14 ml/min; p=0.97) and DeltaeGFR (0.00+/-0.53 vs -0.06+/-0.35 ml/min/month, p=0.52). The proportion of patients with BP at target at both visits was similar in HN- and HN+ (office BP: HN- 18% and HN+ 27%; p=0.21; ABP: HN- 42% and HN+ 43; p=0.96). In patients with office BP at target at both visits HN- showed a significant improvement of DeltaeGFR respect to HN+ (HN-: 0.240 +/- 0.395 and HN+: -0.140+/-0.313 ml/min/ month; p=0.026). In patients with office BP not at target HN- and HN+ did not show any difference in DeltaeGFR (HN- 0.00+/ 0.47; HN+ -0.030+/-0.420 ml/min/month; p=0.66). ABP was not associated with differences in DeltaeGFR either if it was at target (HN- 0.104+/-0.383 and HN+ 0.00+/-0.476 ml/min/month; p=0.42) or not (HN- -0.057+/-0.503 and HN+ -0.092+/ 0.325 ml/ min/month; p=0.87). CONCLUSION: In patients with CKD and HN+ maintenance of BP targets recommended by current guidelines is less reno protective than it is in HN-. PMID- 30472715 TI - The Karyotype of the Hoatzin (Opisthocomus hoazin) - A Phylogenetic Enigma of the Neornithes. AB - The hoatzin (Opisthocomus hoazin Muller, 1776) is a folivorous bird, endemic to the Amazonian region. It presents some unique characteristics, including wing claws and foregut fermentation, which make its phylogenetic relationship to other birds difficult to determine. There have been various attempts to place it among the Galliformes, Gruiformes, Musophagiformes, Cuculiformes, and Charadriiformes, but phylogenetic analyses always show low supporting values. Nowadays, the hoatzin is included in the monotypic order Opisthocomiformes, but the relationship of this order to other groups of birds is still unclear. Although its karyotype resembles the typical avian model, fissions of the syntenic groups corresponding to chicken chromosomes 1 and 2 and 2 fusions were found. The presence of 18S rDNA clusters in 2 pairs of microchromosomes is another derived character. Hence, different rearrangements were detected in the karyotype of the hoatzin, indicating it has been derived from the putative ancestral karyotype by the occurrence of fissions and fusions. However, as these rearrangements are not exclusive to O. hoazin, they do not clarify the phylogenetic position of this enigmatic species. PMID- 30472716 TI - Machine Learning and Imaging Informatics in Oncology. AB - In the era of personalized and precision medicine, informatics technologies utilizing machine learning (ML) and quantitative imaging are witnessing a rapidly increasing role in medicine in general and in oncology in particular. This expanding role ranges from computer-aided diagnosis to decision support of treatments with the potential to transform the current landscape of cancer management. In this review, we aim to provide an overview of ML methodologies and imaging informatics techniques and their recent application in modern oncology. We will review example applications of ML in oncology from the literature, identify current challenges and highlight future potentials. PMID- 30472717 TI - Global Burden of Neurological Disorders: From Global Burden of Disease Estimates to Actions. PMID- 30472718 TI - Informed Consent in Obligatory Vaccinations? AB - Vaccinations cause controversies for numerous reasons: medical, religious, and even personal. The following paper focuses on one more, underestimated conflict between individual autonomy and public health in regard to obligatory childhood vaccinations. Every medical intervention should be preceded by informed consent; however, informed consent in the case of obligatory vaccinations cannot be voluntary and valid. Moreover, asking parents to sign an informed consent form is paradoxical in a situation where not signing it will lead to legal consequences. Our paper tries to accentuate the issue of involuntariness and invalidity of informed consent in the case of obligatory vaccination and tries to propose a solution that acknowledges requirements for vaccinations and makes parents feel safer coming in and out of a vaccination visit. PMID- 30472719 TI - Comparison of Flattening Filter and Flattening Filter-Free Volumetric Modulated Arc Radiotherapy in Patients with Locally Advanced Nasopharyngeal Carcinoma. AB - BACKGROUND This study aimed to investigate the therapeutic role of flattening filter-free (FFF) mode in volumetric modulated arc therapy (VMAT) compared with flattening filter (FF) mode in patients with locally advanced nasopharyngeal carcinoma (NPC). MATERIAL AND METHODS Ten previously treated patients with NPC underwent treatment re-planning with FFF and FF VMAT. Radiotherapy dose distribution on planning target volume (PTV), organs at risk (OAR), target conformity index (CI), total monitor units (MUs), and therapeutic time were compared. RESULTS Maximum and mean radiotherapy dose in PTV and PGTV (primary lesions of NPC and cervical lymph node metastases) in FFF VMAT planning were significantly increased compared with FF VMAT planning, but PTV and OAR showed no significant differences. The CI value of PTV in FFF VMAT planning was significantly reduced compared with FF planning (P<0.05). No differences were found for the maximum radiotherapy dose in the spinal cord and left and right optic nerve, and the mean radiotherapy dose in the brainstem, left and right parotid gland (P>0.05). The maximum dose in the brainstem in the FFF planning was significantly higher compared with FF planning (P>0.05). The maximum radiotherapy dose in left and right crystalline lens (P<0.05) in FFF planning was significantly reduced compared with FF planning. The total hop count in FFF planning was significantly increased compared with FF planning (P<0.05). CONCLUSIONS Both 6 MV X-ray FFF mode and FF mode in the treatment of patients with NPC showed that FFF VMAT planning provided improved protection for OAR. PMID- 30472721 TI - Estimating the Incidence of Stray Energy Burns during Laparoscopic Surgery based on Two Statewide Databases and Retrospective Rates: An Opportunity to Improve Patient Safety. AB - BACKGROUND: The growth of laparoscopic surgery has increased the use of laparoscopic electrosurgical devices based on radiofrequency current. Despite an improvement in most post-operative outcomes, the use of these devices can be associated with inadvertent thermal or mechanical injuries, also called accidental punctures and lacerations (APLs). APLs can occur through either operator error or system error, including insulation failure or capacitive coupling resulting in stray energy burns. Our aim was to estimate the incidence and-as a result-the impact of laparoscopic APLs. METHODS: A retrospective analysis of the Healthcare Cost and Utilization Project (HCUP) State Inpatient Database (SID) was performed for 2009 in California (CA) and Florida (FL). ICD-9 codes and current procedural terminology were used to query for five common general surgery procedures: appendectomy, cholecystectomy, fundoplication, gastric bypass, and gastroplasty with these procedures cross-referenced for any secondary procedure at the time of the initial surgery indicative of APLs. The c2 test was used for comparisons where appropriate. RESULTS: Overall, 192,794 primary laparoscopic procedures were identified in the HCUP database in CA and FL in 2009, with a similar procedure frequency distribution between CA and FL. Six hundred ninety-four procedures were complicated by APL. Gastric bypass and fundoplication were more commonly associated with APLs. CONCLUSION: In this retrospective analysis of procedures performed in CA and FL, the estimated incidence of APL was 3.6 per 1000 cases. Patient morbidity and mortality were likely related to both pilot-error injuries and stray energy burns during laparoscopy. Possible solutions to reduce surgical complications from APL include educational programs to reduce pilot error and the incorporation of fail-safe technologies to eliminate stray energy burns, such as active electrode monitoring and use of non-radiofrequency current (true cautery). PMID- 30472720 TI - Long Stress Induced Non-Coding Transcripts 5 (LSINCT5) Promotes Hepatocellular Carcinoma Progression Through Interaction with High-Mobility Group AT-hook 2 and MiR-4516. AB - BACKGROUND Long non-coding RNAs (lncRNAs) have been implicated in various human cancer types. However, the underlying mechanisms involved in hepatocellular carcinoma (HCC) progression remain poorly understood. MATERIAL AND METHODS In this study, lncRNA array was used to identify HCC related lncRNAs. RNA immunoprecipitation (RIP) followed mass spectrometry was used to explore lncRNA binding proteins. Western blot, quantitative PCR, tumor sphere formation, migration and viability assay were performed to evaluate the oncogenic role of lncRNAs. RESULTS We identified a novel lncRNA named long stress induced non coding transcripts 5 (LSINCT5) which facilitates HCC progression. LSINCT5 was significantly upregulated in both HCC specimens and cell lines and correlates with poor survival. In vitro experiments showed that LSINCT5 promoted migration and viability of HepG2 and Huh7 cells. The in vivo xenograft mouse model also confirmed an oncogenic role for LSINCT5. RIP in combination with mass spectrometry identified HMGA2 as the LSINCT5 binding partner. LSINCT5 could bind to HMGA2 and decrease proteasome-mediated HMGA2 degradation leading to EMT activation. LSINCT5 also served as a competing endogenous RNA (ceRNA) for miR 4516, resulting in increased STAT3/BclxL expression and attenuated apoptosis. CONCLUSIONS Our data have collectively established a lncRNA LSINCT5 mediated process during HCC carcinogenesis and might have provided novel insight into therapeutic targeting. PMID- 30472722 TI - Incisional Application of Negative Pressure for Nontraumatic Lower Extremity Amputations: A Review. AB - In the environment of diabetes and peripheral vascular disease (PVD), there is a high risk of incisional complications following amputation, including seroma, hematoma, infection, and dehiscence. Incisional negative-pressure wound therapy (iNPWT) is a novel application of negative-pressure wound therapy (NPWT) that may be able to mitigate these complications and reduce the need for revisional surgery (including higher-level major lower-extremity amputations). It may also facilitate an increased rate of healing and earlier return to function. iNPWT has been used successfully in high-risk patients to decrease complications. In highly comorbid patients receiving iNPWT for primary closure of abdominal wall reconstruction, incisional infection rates were reduced from 48% to 7% (p=0.029). Furthermore, the need for revisional surgery was significantly decreased in those treated with iNPWT (48% vs.7%, p<0.001), as was the rate of dehiscence (10.68% vs. 5.32%, p<0.001). Major lower-extremity amputations in the multi-comorbid patient have a 16% incidence of incisional dehiscence. Additionally, the rate of infection has been reported to be as high as 22%. Five-year mortality following major lower-extremity amputation is reported to be 50% or higher. This high mortality rate is due, in part, to wound-healing complications. iNPWT can potentially reduce these healing complications and mortality. As of yet, no prospective, randomized trial has shown reduced morbidity, earlier return to function, or reduced mortality with the use of iNPWT after a lower-extremity amputation. This review presents recent findings regarding the use of iNPWT. Further studies on this topic are needed. PMID- 30472723 TI - Shared Decision-Making to Improve Patient Engagement in Minimally Invasive Hysterectomy. AB - Shared decision-making (SDM) between the patient and physician is receiving increased attention as a way to improve patient satisfaction and value of care. Having a readily implemented tool available to inform conversation may enable SDM at a high-volume gynecologic surgery practice. Our objective was to evaluate the impact of an SDM tool on patients' decision to have minimally invasive gynecology surgery. We conducted a feasibility study using the SDM tool plus a follow-up survey for 100 patients recommended to undergo minimally invasive hysterectomy. Nearly all patients (97%) indicated that they were satisfied with their decision to undergo a minimally invasive procedure, including laparoscopic total and supracervical hysterectomy with or without the aid of the robotic platform. Anecdotally, patients expressed appreciation for the provided materials and the presentation of care options. For the care provider, use of the SDM tool did not add substantial time to the visit. Knowing that comprehensive information was provided to all patients was reassuring. Implementing a shared decision-making model in a gynecological practice is feasible and increases awareness and engagement, as well as satisfaction, among patients electing to have a hysterectomy. PMID- 30472724 TI - Operative Applications of Placental Tissue Matrix in Orthopaedic Sports Injuries: A Review of the Literature. AB - INTRODUCTION: Placental and amniotic membrane-based tissues have gained widespread popularity for their ability to promote healing and tissue regeneration and have manifested multiple applications in wound care, burn treatment, and management of various ocular conditions. Recently, there have been multiple studies that investigated the nonoperative uses of placental tissue based products in orthopaedic sports injuries. However, there is a relative paucity of studies that have attempted to evaluate their adjuvant operative uses. Therefore, the aim of this review was to evaluate the use of placental and amniotic tissue-based products as an adjuvant treatment to the operative management of orthopaedic sports injuries. MATERIALS AND METHODS: A comprehensive literature search was performed on PubMed, EBSCO Host, EMBASE, and SCOPUS. Studies published between January 1, 2000 and June 1, 2018 were reviewed. Inclusion criteria were that studies should have reported on: 1) operative uses of placental tissue matrix therapy in tendons and ligaments injuries; and 2) clinical outcomes; in 3) human subjects. In addition, the following studies were excluded: 1) animal studies; 2) basic science studies; 3) non-English language studies; 4) review studies; and 5) duplicate studies across databases. Additionally, to determine the various product compositions and indications for use, we searched publicly available manufacturer's website content, marketing literature, FDA registration documents, and Center for Medicare and Medicaid Services submissions to assess the key differences for each of the products. RESULTS: Current evidence has led to investigation of various placental and amniotic membrane products used as an adjuvant treatment to surgical reconstruction of various types of tendon injuries, with a demonstrated effectiveness found mostly in the short-term, with follow up ranging between five weeks and two years. In addition, their safety and minimal complication profile have been demonstrated. Marked differences exist among the currently available products due to variations in their formulations, tissue source, processing methodology, sterilization method, preservation and storage methods, indications for use, and FDA regulation. CONCLUSION: Operative uses of placental and amniotic membrane-derived tissues appear to be safe when utilized as an adjuvant or augmentation option along with surgical reconstruction. However, several factors may come into play when considering the diversity of commercially available products. Future clinical trials will need to confirm the safety and demonstrate clearer indications and specific guidelines for use in each clinical scenario involving operative management of tendon injuries. Nevertheless, this review will serve as an up-to-date reference and provide an impetus for future investigations. PMID- 30472725 TI - Behcet's syndrome as a tool to dissect the mechanisms of thrombo-inflammation: clinical and pathogenetic aspects. AB - Behcet's syndrome (BS) is a complex disease with different organ involvement. The vascular one is the most intriguing considering the existence of a specific group of patients suffering from recurrent vascular events involving the venous and, more rarely, the arterial vessels. There are several clinical clues suggesting the inflammatory nature of thrombosis in BS, especially of the venous involvement, thus BS is considered a model of inflammation-induced thrombosis. Unique among other inflammatory conditions, venous involvement (together with the arterial one) is currently treated with immunosuppressants, rather than with anticoagulants. Although many in vitro studies have suggested the different roles of the multiple players involved in clot formation, in vivo models are crucial to study this process in a physiological context. At present, no clear mechanisms describing the pathophysiology of thrombo-inflammation in BS exist. Recently, we focused our attention on BS patients as a human in vivo model of inflammation induced thrombosis to investigate a new mechanism of clot formation. Indeed, fibrinogen displays a critical role not only in inflammatory processes, but also in clot formation, both in the fibrin network and in platelet aggregation. Reactive oxygen species (ROS)-derived modifications represent the main post translational fibrinogen alterations responsible for structural and functional changes. Recent data have revealed that neutrophils (pivotal in the pathogenetic mechanisms leading to BS damage) promote fibrinogen oxidation and thrombus formation in BS. Altogether, these new findings may help understand the pathogenetic bases of inflammation-induced thrombosis and, more important, may suggest potential targets for innovative therapeutic approaches. This article is protected by copyright. All rights reserved. PMID- 30472726 TI - Outcomes of monoamniotic twin pregnancies managed primarily in outpatient care-A Danish multicenter study. AB - INTRODUCTION: Monoamniotic twin pregnancies are high-risk pregnancies, and management by inpatient or frequent outpatient care is recommended. We report the outcomes of a national cohort of monoamniotic twin pregnancies managed primarily as outpatients MATERIAL AND METHODS: We analyzed prospectively recorded data from the Danish Fetal Medicine Database, local databases, and medical records of all monoamniotic twin pregnancies diagnosed at the first trimester scan or later, and managed at the six major fetal medicine centers in Denmark over a 10 year period RESULTS: Sixty-one monoamniotic twin pregnancies were included. Thirteen pregnancies were terminated early. Of the remaining 48 pregnancies with a normal first trimester scan, there were 36 fetal losses (25 spontaneous miscarriages <22+0 weeks, three late terminations and eight intrauterine deaths >22 weeks) and 60 live-born children (62.5%), all of whom were delivered by cesarean delivery at a median gestational age of 33+0 weeks. Three children had minor malformations and there was one pregnancy with twin-to-twin-transfusion-syndrome. After 26+0 weeks, 78.8% were managed as outpatients. Intrauterine death occurred in 3.8% of outpatients and in 28.6% of inpatients (admitted due to complications). At weeks 32, 33, and 34, the prospective risk of intrauterine death was 6.9%, 4.2%, and 5.9%, respectively CONCLUSION: In this nationwide, unselected population, only 62.5% of fetuses with a normal first trimester scan were born alive. In contrast, the mortality was 3.8% after 26 weeks among the 78.8% of the cohort that was managed as outpatients. More knowledge is still needed to predict which pregnancies are at the highest risk of intrauterine death. This article is protected by copyright. All rights reserved. PMID- 30472727 TI - IL-17/IL-17R axis elicits intestinal neutrophil migration, restrains gut dysbiosis and LPS translocation in high-fat diet-induced metabolic syndrome model. AB - Sound evidence supports a role for interleukin-17 (IL-17)-producing delta-gamma (gammadelta) T cells and IL-17-producing helper T cells (Th17) in intestinal homeostasis, especially in intestinal barrier integrity. In the present study, we aimed to evaluate the role of IL-17 cytokine in the regulation of intestinal immunity and obesity-induced metabolic syndrome (MetS) in an experimental murine model. C57BL/6 wild-type (WT) mice and mice lacking the IL-17 cytokine receptor (IL-17RA-/- ) were fed either a control diet (CD) or a high-fat diet (HFD) for nine weeks. Our data demonstrate that IL-17RA-/- mice are protected against obesity, but develop hyperglycemia, hyperinsulinemia and insulin resistance. In parallel, HFD-fed IL-17RA-/- mice display intense inflammation in the ileum compared to WT mice on the HFD. IL-17RA-/- mice fed the HFD exhibit impaired neutrophil migration to the intestinal mucosa and reduced gene expression of the CXCL-1 chemokine and CXCR-2 receptor in the ileum. Interestingly, the populations of neutrophils (CD11b+ Ly6G+ ) and anti-inflammatory macrophages (CD11b+ CX3CR1+ ) are increased in the mesenteric lymph nodes of these mice. IL-17RA-/- mice on the HFD also display increased commensal bacterial translocation into the bloodstream and elevated lipopolysaccharide (LPS) levels in the visceral adipose tissue (VAT). Metagenomic analysis of bacterial 16S gene revealed increased Proteobacteria and Bacteroidetes phyla, the main representatives of gram-negative bacteria, and reduced Akkemansia muciniphila in the fecal samples of IL-17RA-/- mice fed the HFD. Together, these data indicate that IL-17/IL-17R axis drives intestinal neutrophil migration, limits gut dysbiosis and attenuates LPS translocation to VAT, resulting in protection to MetS. This article is protected by copyright. All rights reserved. PMID- 30472728 TI - The evidence for the physiological effects of lactate on the cerebral microcirculation: a systematic review. AB - Lactate's role in the brain is understood as a contributor to brain energy metabolism, but it may also regulate the cerebral microcirculation. The purpose of this systematic review is to evaluate evidence of lactate as a physiological effector within the normal cerebral microcirculation in reports ranging from in vitro experiments to in vivo studies in animals and humans. Following pre registration of a review protocol, we systematically searched the PubMed, EMBASE, and Cochrane databases for literature covering themes of 'lactate', 'the brain', and 'microcirculation'. Abstracts were screened, and data extracted independently by two individuals. We excluded studies evaluating lactate in disease models. 28 papers were identified, 18 of which were in vivo animal experiments (65%), 4 on human studies (14%), and 6 on in vitro or ex vivo experiments (21%). Approximately half of the papers identified lactate as an augmenter of the hyperemic response to functional activation by a visual stimulus or as an instigator of hyperemia in a dose-dependent manner, without external stimulation. The mechanisms are likely to be coupled to NAD+ /NADH redox state influencing the production of nitric oxide. Unfortunately, only 38% of these studies demonstrated any control for bias, which makes reliable generalizations of the conclusions insecure. This systematic review identifies that lactate may act as a dose dependent regulator of cerebral microcirculation by augmenting the hyperemic response to functional activation below 5 mmol/kg, and by initiating a hyperemic response above 5 mmol/kg. This article is protected by copyright. All rights reserved. PMID- 30472729 TI - The confluence of accelerated regulatory and health technology assessment access pathways. AB - There is a growing interest in aligning accelerated regulatory pathways with flexible access and reimbursement pathways to expedite the equitable availability of high-quality, safe and effective medicines that provide a value-based approach to meeting society's most important healthcare needs. The Centre for Innovation in Regulatory Science (CIRS) identified key issues regarding the confluence of regulatory and health technology assessment processes from discussions and presentations given by international regulators, health technology assessment bodies, payers, patient representatives and multinational pharmaceutical company representatives on this topic at CIRS workshops held in 2014 and 2017 that focused on the commonalties and differences across these pathways. Recent publications have also been highlighted. The barriers to and opportunities for aligning stakeholder expectations and needs were investigated and recommendations provided. Early dialogue among the stakeholders is likely the process that will provide the greatest return on investment of time and effort to identify, develop, review, and recommend important new medicines, especially those that address an unmet medical need. This article is protected by copyright. All rights reserved. PMID- 30472730 TI - Gene expression profiling in aggressive digital papillary adenocarcinoma sheds light on the architecture of a rare sweat gland carcinoma. AB - BACKGROUND: Sweat gland carcinomas are rare cutaneous adnexal malignancies. Aggressive digital papillary adenocarcinoma (ADPA) represents a very rare sub entity, thought to arise almost exclusively from sweat glands of the fingers and toes. The aetiology of sweat gland carcinomas and ADPA is largely unknown. ADPAs are most likely driven by somatic mutations. However, somatic mutation patterns are largely unexplored, creating barriers to the development of effective therapeutic approaches to the treatment of ADPA. OBJECTIVE: To investigate the transcriptome profile of ADPA using a sample of eight formalin-fixed, paraffin embedded (FFPE) tissue samples of ADPA and healthy control tissue. METHODS: Transcriptome profiling was performed using the Affymetrix PrimeView Human Gene Expression Microarray and findings were validated via reverse-transcription of RNA and real-time qPCR. RESULTS: Transcriptome analyses showed increased tumour expression of 2,266 genes, with significant involvement of cell cycle, ribosomal and crucial cancer pathways. Our results furthermore point to tumour overexpression of FGFR2 (p = 0.001). CONCLUSIONS: Our results indicate the involvement of crucial oncogenic driver pathways, highlighting cell cycle and ribosomal pathways in the aetiology of ADPA. Suggested tumour-overexpression of FGFR2 raises the hope that targeting the FGF/FGFR axis might be a promising treatment for ADPA and probably for the overall group of sweat gland carcinomas. This article is protected by copyright. All rights reserved. PMID- 30472731 TI - Ultrasound-Guided Therapeutic Scapulothoracic Interval Injections. AB - Scapulothoracic pain is a common ailment, but the underlying cause can be difficult to diagnose in a timely manner, and treatment options are limited. We retrospectively review our experience using ultrasound-guided therapeutic scapulothoracic interval steroid injections to treat scapulothoracic pain and review correlative magnetic resonance imaging findings over a 5-year period. Although a variety of structural causes are known to cause scapulothoracic pain, in our experience, most cases lack correlative imaging findings. Ultrasound guided scapulothoracic interval injections provide a safe, easily performed diagnostic and therapeutic tool for treating patients with periscapular pain, providing at least short-term symptom relief. PMID- 30472732 TI - Concentrations of indomethacin and its metabolite desmethylindomethacin in plasma and urine after repeated indomethacin topical application to Thoroughbreds. AB - BACKGROUND: Repeated topical application of indomethacin is common in Japanese racehorses, despite the lack of pharmacokinetic data. OBJECTIVES: To determine the concentrations of indomethacin and its metabolite desmethylindomethacin in plasma and urine of Thoroughbreds topically treated repeatedly with indomethacin. STUDY DESIGN: In vivo experimental. METHODS: Seven female Thoroughbreds were topically treated 50 g of 1% indomethacin cream per horse to the back and hips (500 mg of indomethacin/head/2400 cm2 , 0.21 g/cm2 ) for 3 consecutive days. Samples were pretreated by protein precipitation for plasma and liquid-liquid extraction with ethyl acetate after hydrolysis with hydrochloric acid for urine. The concentrations of indomethacin and desmethylindomethacin in plasma and urine were measured by liquid chromatography-mass spectrometry. RESULTS: Indomethacin was quantifiable in plasma up to 48-72 h and in urine up to 96 hours after the final application. Desmethylindomethacin was quantifiable in plasma up to 48 hours and in urine up to 72-96 hours after the final application. MAIN LIMITATIONS: The relationship between the local and systemic indomethacin concentrations after the topical application was not clarified. CONCLUSIONS: Pharmacokinetic data were acquired for repeated topical administration of 1% indomethacin cream to Thoroughbreds. Hydrolysing urine samples with hydrochloric acid was effective for the analysis of indomethacin and its metabolite, and indomethacin may be an excellent marker analyte for doping tests. The estimated withdrawal time based on the limit of detection was 342 hours. This article is protected by copyright. All rights reserved. PMID- 30472733 TI - Elevated carbon dioxide plus chronic warming causes dramatic increases in leaf angle in tomato, which correlates with reduced plant growth. AB - Limited evidence indicates that moderate leaf hyponasty can be induced by high temperatures or un-naturally-high CO2 . Here we report that the combination of warming plus elevated CO2 (eCO2 ) induces severe leaf hyponasty in tomato (Solanum lycopersicum L.). To characterize this phenomenon, tomato plants were grown at two levels of CO2 (400 vs. 700 ppm) and two temperature regimes (30 vs. 37o C) for 16-18 days. Leaf hyponasty increased dramatically with warming plus eCO2 , but increased only slightly with either factor alone, and was slowly reversible upon transfer to control treatments. Increases in leaf angle were not correlated with leaf temperature, leaf water stress, or heat-related damage to photosynthesis. However, steeper leaf angles were correlated with decreases in leaf area and biomass, which could be explained by decreased light interception, and thus in situ photosynthesis, as leaves became more vertical. Petiole hyponasty and leaf-blade cupping were also observed with warming + eCO2 in marigold and soybean, respectively, which are compound-leaved species like tomato, but no such hyponasty was observed in sunflower and okra, which have simple leaves. If severe leaf hyponasty is common under eCO2 and warming, then this may have serious consequences for food production in future. PMID- 30472734 TI - Diet-Induced Insulin Resistance Elevates Hippocampal Glutamate as well as VGLUT1 and GFAP Expression in AbetaPP/PS1 Mice. AB - The symptomologies of Alzheimer's disease (AD) develop over decades suggesting modifiable life-style factors may contribute to disease pathogenesis. In humans, hyperinsulinemia associated with type 2 diabetes mellitus increases the risk for developing AD and both diseases share similar age-related etiologies including amyloidogenesis. Since we have demonstrated that soluble Abeta42 elicits glutamate release, we wanted to understand how diet-induced insulin resistance alters hippocampal glutamate dynamics, which are important for memory formation and consolidation. Eight to twelve week-old C57BL/6J and AbetaPP/PS1 mice were placed on either a low-fat diet (LFD) or high-fat diet (HFD) for eight months. A HFD led to significant weight increases as well as impaired insulin sensitivity, glucose tolerance, and learning in both C57BL/6J and AbetaPP/PS1 mice. AbetaPP/PS1 LFD mice had elevated hippocampal basal as well as stimulus-evoked glutamate release that was further increased with consumption of a HFD. Immunohistochemistry indicated an increase in vesicular glutamate transporter 1 and glial fibrillary acidic protein density in hippocampal subregions corresponding with this elevated extracellular glutamate. While no differences in hippocampal plaque load were observed, the elevated astrogliotic response surrounding the plaques in AbetaPP/PS1 HFD mice may have been a compensatory mechanism to control plaque accumulation. These data support that AbetaPP/PS1 mice have chronically elevated extracellular glutamate that is exacerbated by a HFD and that modifiable life-style factors such as obesity-induced insulin resistance can contribute to AD pathogenesis. This article is protected by copyright. All rights reserved. PMID- 30472735 TI - Future research priorities for lichen sclerosus - results of a James Lind Alliance Priority Setting Partnership. AB - Lichen sclerosus (LS) is a chronic, inflammatory genital skin condition affecting men, women and children. Long-term complications include loss of normal anatomy from scarring, and malignant transformation. Uncertainties exist about the cause, diagnosis and management of LS. For example, the aetiology is contested; evidence suggests that chronic irritation by occluded urine is important in males,1 however, autoimmune mechanisms are proposed in females.2 Genetic associations are suggested in both sexes. Existing evidence on which to make recommendations about management and the prevention of malignancy, is generally poor quality. This article is protected by copyright. All rights reserved. PMID- 30472736 TI - Neutrophils mitigate the systemic host response during endotoxemia in mice. AB - Recent studies have suggested that neutrophils can exert anti-inflammatory effects. To determine the role of neutrophils in the acute response to lipopolysaccharide (LPS), component of the gram-negative bacterial cell wall, we challenged neutrophil depleted and control mice with LPS and analyzed the plasma concentrations of biomarkers indicative of the cytokine and chemokine network, activation of coagulation and the vascular endothelium, and cellular injury. We here show that neutrophils serve an anti-inflammatory role upon LPS administration, as reflected by sustained elevations in multiple cytokines and chemokines, and enhanced release of nucleosomes in mice depleted of neutrophils, compared to control mice. This article is protected by copyright. All rights reserved. PMID- 30472737 TI - Technical Note: The Design, Construction, and Evaluation of a Liquid-Based Single Phantom Solution for TG128 Brachytherapy Ultrasound QA. AB - PURPOSE: Since the publication of the AAPM TG128 report for the quality assurance of prostate brachytherapy ultrasound systems, no commercially available phantoms have been developed which satisfy all of the task group recommendations. Current solid phantoms require a separate user-implemented setup using a container with liquid medium to evaluate the alignment between the needle template and the electronic grid, a test of geometric accuracy with critical implications in dosimetric quality. Utilizing a 3D printer, we constructed a cost-effective, liquid-based phantom that provides a complete TG128 solution which improves the efficiency of brachytherapy ultrasound QA. METHODS: The TG128 report was used to guide the design process of the liquid-based phantom. The needle template and electronic grid alignment setup served as the foundation with specific components developed to integrate all remaining tests. Water was chosen as the liquid medium, with speed of sound adjusted to 1540 m/s via salinity per the task group recommendations. The proof of concept was evaluated by comparing the time stamps labelled on QA images between the liquid-based phantom and a commercially available one for both a new and experienced user. RESULTS: A TG128 QA trial run demonstrated that all recommended tests can be completed with the single phantom setup. Evaluation of the time data revealed a total QA duration of 45 minutes (average of two trials) with the liquid-based phantom, compared to 70 and 90 minutes with the commercial phantom for a new and experienced user. CONCLUSIONS: The liquid-based phantom is specifically designed to satisfy the recommendations of the TG128 report. The incorporation of 3D printing allows simple design modifications to adapt the phantom on-the-fly if needed. The resulting product improves the efficiency of brachytherapy ultrasound QA by eliminating the need for multiple phantom setups. This article is protected by copyright. All rights reserved. PMID- 30472738 TI - Preliminary experience of the Q-switched 1064-nm neodymium:yttrium aluminum garnet laser in the treatment of Cafe-au-lait macules. AB - Solitary CALMs are a common finding and they occur in 10-20% of the normal polulation. Although benign, CALMs in exposed parts of the body(face, forearms, neck et al) are cosmetically distressing to patients. Various types of laser devices have been utilized to remove CALMs over the years with high rates of recurrence and adverse events. Based on the theory of selective photothermolysis, the Q-switched lasers were most accepted modality to remove CALMs with higher efficacy and minimal adverse effects. This article is protected by copyright. All rights reserved. PMID- 30472739 TI - Reduced pain thresholds and signs of sensitization in women with persistent pelvic pain and suspected endometriosis. AB - INTRODUCTION: Endometriosis is a gynecological disorder that may cause considerable pelvic pain in women of fertile age. Determining pain mechanisms is necessary in order to optimize the treatment of the disease. The objective of the study was to evaluate pain thresholds in women with persistent pelvic pain with and without confirmed endometriosis, and healthy, unaffected controls, and analyze how pain thresholds in these cohorts related to duration of pelvic pain, quality of life, and symptoms of anxiety and depression. MATERIAL AND METHODS: Pain thresholds for heat, cold, and pressure were assessed with quantitative sensory testing on six locations on a reference group of 55 healthy women and on 37 women with persistent pelvic pain who had been admitted for diagnostic laparoscopy on the suspicion of endometriosis. Validated instruments were applied to assess quality of life and symptoms of anxiety and depression. Data were analyzed by means of uni- and multivariate analysis of variance and Spearman's rank-order correlation. RESULTS: The women with persistent pelvic pain had significantly lower pain thresholds compared with the reference women. No differences were observed in pain thresholds between the women with pain, with (13 women) and without (24 women) biopsy-proven endometriosis. The duration of pelvic pain correlated significantly positively to reduced pain thresholds i.e. the longer the duration, the more sensitization. In the persistent pelvic pain group, pain thresholds for heat correlated significantly with the Short Form Health Survey 36 (SF-36) dimension of bodily pain, while thresholds for cold correlated with SF-36 bodily pain and with symptoms of depression. CONCLUSION: Our results showed widespread alterations in pain thresholds in women with persistent pelvic pain that are indicative of central sensitization and a time dependent correlation. Women with pelvic pain and suspicion of endometriosis should probably be treated more thoroughly in order to prevent or at least minimize the concomitant development of central sensitization. This article is protected by copyright. All rights reserved. PMID- 30472740 TI - Risk of Adverse Maternal and Fetal Outcomes during Pregnancy in Living Kidney Donors: A Matched Cohort Study. AB - BACKGROUND: We examined the risk of adverse pregnancy outcomes in primiparous kidney donors compared to matched controls. METHODS: Fifty-nine women with a history of kidney donation prior to their first pregnancy with normal renal function and no history of kidney disease, diabetes or chronic hypertension were matched 1:4 by age (within 2 years) and race to women with two kidneys using data from an integrated healthcare delivery system. Adverse pregnancy outcomes were defined as preterm delivery (delivery < 37 weeks), delivery via cesarean section, gestational hypertension, preeclampsia/eclampsia, gestational diabetes, length of stay in the hospital > 3 days, infant death/transfer to acute facility and low birth weight (<2,500 gm). RESULTS: Living kidney donors did not have a higher risk of adverse outcomes compared to matched controls. There was a trend towards an increased risk of preeclampsia/eclampsia in kidney donors but it did not reach statistical significance (OR 2.96, 95% CI 0.98-8.94, p=0.06). However, in kidney donors <= 30 years of age, there was a 4-fold increased risk of preeclampsia/eclampsia (OR 4.09, 95% CI 1.07-15.59, p=0.04). CONCLUSION: Overall, the risk of pregnancy-associated complications following kidney donation is small but potential female kidney donors should be counseled on the possible increased risk of preeclampsia. This article is protected by copyright. All rights reserved. PMID- 30472741 TI - Sambucus ebulus extract stimulates cellular responses in cutaneous leishmaniasis. AB - This is the first study aiming to determine the therapeutic effects of the S. ebulus aquatic extract as an antileishmanial herbal drug and evaluate the immune responses in L. major infected BALB/c mice. The antileishmanial activity of S. ebulus aquatic extract was evaluated using MTT test as well as Parasite Rescue and Transformation Assay. Footpad swelling and parasite load of infected mice were measured by several techniques. The immune responses were evaluated by measuring the levels of IFN-gamma, IL-4, nitric oxide, and arginase. The results indicated that S. ebulus can significantly decrease L. major promastigotes and amastigotes viability, but it was not toxic to macrophages. The lesion size, parasite burden, and the level of ARG decreased in the treated infected mice, while the IFN-gamma-to-IL-4 ratio and the level of NO increased significantly. Altogether, the S. ebulus extract is an effective compound for killing Leishmania parasite without excessive toxicity to the host cells and can cure the CL by switching the host immune responses towards Th1 response. Thus, it may be a perfect therapeutic option for CL treatment. This article is protected by copyright. All rights reserved. PMID- 30472742 TI - Heritability of metabolic traits associated with equine metabolic syndrome in Welsh ponies and Morgan horses. AB - BACKGROUND: Equine metabolic syndrome (EMS) is a complex clinical disorder with both environmental and genetic factors contributing to EMS phenotypes. Estimates of heritability determine the proportion of variation in a trait that is attributable to genetics. OBJECTIVES: To provide heritability estimates for nine metabolic traits associated with EMS in two high-risk breeds. STUDY DESIGN: Retrospective cohort study. METHODS: High-density single nucleotide polymorphism (SNP) genotype data was used to estimate the heritability (h2 SNP ) of nine metabolic traits relevant to EMS in a cohort of 264 Welsh ponies and 286 Morgan horses. Traits included measurements of insulin, glucose, non-esterified fatty acids (NEFA), triglycerides, leptin, adiponectin, ACTH, and glucose (GLU-OST) and insulin (INS-OST) following oral sugar challenge. RESULTS: In Welsh ponies, seven of the nine traits had statistically significant h2 SNP estimates that were considered moderately to highly heritable (h2 SNP >0.20) including: triglycerides (0.313; SE = 0.146), glucose (0.408; SE = 0.135), NEFA (0.434; SE = 0.136), INS OST (0.440; SE = 0.148), adiponectin (0.488; SE = 0.143), leptin (0.554; SE = 0.132) and insulin (0.808; SE = 0.108). In Morgans, six of the nine traits had statistically significant h2 SNP estimates that were also determined to be moderately to highly heritable including: INS_OST (0.359; SE = 0.185), leptin (0.486; SE = 0.177), GLU-OST (0.566 SE = 0.175), insulin (0.592; SE = 0.195), NEFA (0.684; SE = 0.164), and adiponectin (0.913; SE = 0.181). MAIN LIMITATIONS: Insufficient population size may have limited power to obtain statistically significant h2 SNP estimates for ACTH (both breeds), glucose and triglycerides in Morgans and GLU-OST in Welsh ponies. CONCLUSIONS: This study provides the first concrete evidence of a genetic contribution to key phenotypes associated with EMS. Eight of these nine traits had moderate to high h2 SNP estimates in this cohort. These data demonstrate that continued research for identification of the genetic risk factors for EMS phenotypes within and across breeds is warranted. This article is protected by copyright. All rights reserved. PMID- 30472744 TI - Spiky follicular Mycosis Fungoides : A trichoscopic feature. AB - We have read with great interest a case report published by Slawinka et al describing trichoscopic spectrum of folliculotropic mycosis fungoides (FMF) [1]. Different trichoscopic aspects were reported by authors as the presence of milky white globules, yellow dots, short hair with split or triangle-shaped end, broken hair and pigtail appearance hair. This article is protected by copyright. All rights reserved. PMID- 30472743 TI - Recognizing that Evidence is Made, not Born. AB - Therapeutic product development, licensing and reimbursement may seem a well oiled machine, but continuing high attrition rates, regulatory refusals and patients' access issues suggest otherwise; despite serious efforts, gaps persist between stakeholders' stated evidence requirements and actual evidence supplied. Evidentiary deficiencies and/or human tendencies resulting in avoidable inefficiencies might be further reduced with fresh institutional cultures/mindsets, combined with a context-adaptable practices framework that integrates emerging innovations. Here, Structured Evidence Planning, Production and Evaluation (SEPPE) posits that evidence be treated as something produced, much like other manufactured goods, for which "built-in quality" (i.e. "people" and "process") approaches have been successfully implemented globally. Incorporating proactive, iterative feedback-and-adjust loops involving key decision-makers at critical points could curtail avoidable evidence quality and decision hazards - pulling needed therapeutic products, with high quality evidence of beneficial performance, through to approvals. Critical for success, however, is dedicated, long-term commitment to systemic transformation. This article is protected by copyright. All rights reserved. PMID- 30472745 TI - Retrospective evaluation of early risk factors in children with different types of micturition disorders. AB - AIM: The etiology of micturition disorders in children is multifactorial and still unclear. The perinatal factors may play a role in the development of children's urinary incontinence. We compared each type of micturition disorders in terms of length of gestation, birthweight, family history of bed-wetting and delivery type. METHODS: Data were from 488 patients of the Department of Pediatrics and Nephrology, Children's Clinical Hospital of the Medical University of Bialystok, and included: age, sex, clinical diagnosis, perinatal history, constipation, history of vesicoureteral reflux, family history of nocturnal enuresis, urodynamic diagnosis, bladder capacity. We performed statistical analysis using Mann-Whitney and Spearman tests. RESULTS: Combined day-time nocturnal incontinence made a higher percentage and nocturnal enuresis made a lower percentage of clinical diagnoses in children with low birthweight compared with group of normal birthweight. In children with micturition disorders lower birthweight was associated with smaller bladder capacity than normal for age. CONCLUSION: Low birth weight might predispose to combined day-time-nocturnal incontinence. We are the first to show that patients suffering from micturition disorders with low birthweight present lower estimated bladder capacity than age matched children. Thus, we assume that low birthweight may have strong clinical relevance in children's micturition disorders. This article is protected by copyright. All rights reserved. PMID- 30472746 TI - Inflammatory functional iron deficiency common in myelofibrosis, contributes to anaemia and impairs quality of life. From the Nordic MPN study Group. AB - OBJECTIVES: The study investigates the hypothesis that inflammation in myelofibrosis (MF) like in myeloma and lymphoma, may disturb iron distribution and contribute to anaemia. METHODS: A cross-sectional study of 80 MF and 23 ET patients was performed. RESULTS: Thirtyfive % of anaemic MF patients had functional iron deficiency (FID) with transferrin saturation <20 and normal or elevated S-ferritin (<500 MUg/L). In ET, FID was rare. In MF patients with FID, 70.6% were anaemic, vs. 29.4% in patients without FID (p=0.03). Hepcidin was significantly higher in MF patients with anaemia, including transfusion-dependent patients, 50.6 vs 24.4 MUg/L (p=0.01). There was a significant negative correlation between Hb and inflammatory markers in all MF patients: IL-2, IL-6 and TNF-alpha, (p <0.01 to 0.03), LD (p=0.004) and hepcidin (p=0.03). These correlations were also seen in the subgroup of anaemic MF patients (Table 4). Tsat correlated negatively with CRP (p<0.001). Symptom burden was heavier in MF patients with FID, and MPN-SAF quality of life scores correlated with IL-6 and CRP. CONCLUSIONS: the inflammatory state of MF disturbs iron turnover, FID is common and contributes to anaemia development and impairment of QoL. Anaemic MF patients should be screened for FID. This article is protected by copyright. All rights reserved. PMID- 30472747 TI - Striatal GABAergic Interneuron Dysfunction in the Q175 Mouse Model of Huntington's Disease. AB - The pathological hallmark of Huntington's disease (HD) is the massive loss of striatal and cortical neurons. Until recently, it was believed that striatal interneurons were spared from degeneration. This view has changed after the demonstration that parvalbumin (PV)-expressing interneurons also are vulnerable in humans. Here we compared morphological and functional changes of striatal fast spiking interneurons (FSIs) and low-threshold spiking (LTS) interneurons in the Q175 mouse model of HD at pre-symptomatic (2 months) and symptomatic (12 months) stages of the disease. Electrophysiological intrinsic and synaptic properties of FSIs were significantly altered in symptomatic mice compared to wildtype (WT) littermates. Overall, FSIs became more excitable with disease progression. Sholl analysis also revealed a significant loss of dendritic complexity and excitatory synaptic inputs. The basic membrane and synaptic properties of LTS interneurons were similar in Q175 and WT mice regardless of disease stage. The resilience of LTS interneurons could be related to their sparsity of excitatory synaptic inputs compared with FSIs. However, in symptomatic mice, a subpopulation of LTS interneurons displayed an increase in action potential firing within oscillating bursts. Thus, we conclude that while both FSI and LTS interneurons demonstrate increases in excitability, the HD mutation differentially affects their membrane and synaptic properties as well as their ability to respond to compensatory challenges presented during the late stage of the disease. Alterations in GABAergic interneuron intrinsic activity and responsiveness to incoming signals may significantly affect SPN output thus contributing to abnormal motor movements in patients afflicted with HD. This article is protected by copyright. All rights reserved. PMID- 30472748 TI - LncRNA33732-RESPIRATORY BURST OXIDASE module associated with WRKY1 in tomato- Phytophthora infestans interactions. AB - Our previous studies indicated that the tomato WRKY1 transcription factor acts a positive regulator during tomato resistance to Phytophthora infestans. However, the molecular mechanism of WRKY1-mediated resistance regulation remains unclear. Here, we used a comparative transcriptome analysis between wild-type and WRKY1 overexpressing tomato plants to identify differentially expressed genes (DEGs) and long non-coding RNA (DELs), and we examined long non-coding RNA (lncRNA)-gene networks. The promoter sequences of the up-regulated DEGs and DELs were analyzed. Among 1073 DEGs and 199 DELs, 1 kb 5'-upstream regions of 59 DEGs and 22 DELs contain the W-box, the target sequence of the WRKY1. The results of promoter-GUS fusion and yeast one-hybrid assay showed that lncRNA33732 were activated by WRKY1 through sequence-specific interactions with the W-box element in its promoter. The overexpression and silencing analysis of lncRNA33732 in tomato showed that lncRNA33732 as a positive regulator enhanced tomato resistance to P. infestans by induction of the expression of RESPIRATORY BURST OXIDASE (RBOH) and increase in the accumulation of H2 O2 . When the expression of RBOH gene was inhibited in tomato plants, H2 O2 accumulation decreased and the resistance impaired. These findings suggest that lncRNA33732 activated by WRKY1 induces RBOH expression to increase H2 O2 accumulation in early defense reaction of tomato to P. infestans attack. Our results provide insights into the WRKY1-lncRNA33732-RBOH module involved in the regulation of H2 O2 accumulation and resistance to P. infestans, as well as provide candidates to enhance broad-spectrum resistance to pathogens in tomato. This article is protected by copyright. All rights reserved. PMID- 30472749 TI - Calcipotriol plus betamethasone dipropionate aerosol foam versus apremilast, methotrexate, acitretin, or fumaric acid esters for the treatment of plaque psoriasis: A matching-adjusted indirect comparison. AB - BACKGROUND: Plaque psoriasis has significant impact on patients' quality of life. Topical therapy is considered the treatment mainstay for mild-to-moderate disease according to guidelines. Calcipotriol/betamethasone dipropionate (Cal/BD) [0.005%/0.05%] aerosol foam is indicated for psoriasis vulgaris treatment in adults. Cal/BD foam trials demonstrated improved efficacy and similar safety in this population. Psoriasis treatment is complicated by the broad range of disease presentation, variability, and therapeutic options; particularly decisions on transition from topical to non-biologic systemic treatment are difficult. Assessing comparative effectiveness of treatment options provides meaningful value to treatment decisions. OBJECTIVE: To compare efficacy of Cal/BD foam individual patient data from pooled trials with efficacy of non-biologic systemic treatments based on aggregated patient characteristics and treatment outcomes. METHODS: Individual data from 4 Cal/BD foam trials in 749 psoriasis patients were pooled to conduct matching-adjusted indirect comparisons. Literature review identified non-biologic systemic treatment trials where methods, populations, and outcomes align with Cal/BD foam trials. Of 3,090 screened publications, 4 studies of apremilast, methotrexate, acitretin, or Fumaric Acid Esters (FAE) were included. RESULTS: After baseline matching, patients treated with 4 weeks of Cal/BD foam had greater Physician's Global Assessment 0/1 response compared to those treated with 16 weeks of apremilast (52.7% vs. 30.4%; P<0.001). Patients treated with Cal/BD foam had significantly greater Psoriasis Area and Severity Index (PASI) 75 response at Week 4 compared to 16 weeks of apremilast treatment (51.1% vs. 21.6%; P<0.001). Cal/BD foam patients demonstrated significantly greater PASI 75 response improvements at Week 4 versus 12 weeks of methotrexate (50.8% vs. 33.5%; P<0.001) or acitretin (50.9% vs. 31.7%; P=0.009), and comparable response to FAE (42.4% vs. 47.0%; P=0.451). CONCLUSIONS: Despite recent treatment advances, unmet needs for psoriasis patients remain. Cal/BD foam offers improved efficacy in baseline matched psoriasis patients compared to apremilast, methotrexate, or acitretin, and comparable efficacy to FAE. This article is protected by copyright. All rights reserved. PMID- 30472750 TI - Sedation and neurodevelopmental outcomes in PICU: identification of study groups. AB - BACKGROUND/AIMS: As little as 30 minutes of exposure to anesthetic and sedative agents may adversely affect the developing brain. Safe, humane management of critically ill infants requires the use of sedative agents, often for prolonged periods. We sought to identify two comparable groups of critical care patients who did or did not receive sedatives, with the aim of designing a long-term neuro development follow-up study. This feasibility study aimed to determine if two comparable groups could be found. METHODS: Infants with respiratory diagnoses having non-invasive ventilation without sedation (Group C) or intubation and ventilation with sedation (Group S) were identified by chart review. Charts of patients fulfilling the above inclusion criteria were searched for exclusion criteria including neurological disease, extreme prematurity, congenital cardiac disease, genetic anomalies. Data was extracted to score pediatric severity of illness scores (PRISM and PELOD) for each patient. These scores were then compared using the absolute scores and by risk strata. RESULTS: Group S included 33 patients and Group C had 39. The absolute PRISM and PELOD scores were different between groups, Comparing the groups in 3 risk strata (PRISM greater or less than 5 or 10) there were no significant differences between groups CONCLUSIONS: It is not possible to randomise infants to sedation or no sedation to investigate neurodevelopmental outcomes. This phase of the project aimed to determine the comparability of 2 groups of PICU patients. These findings indicate that these groups could be enrolled as exposed and control subjects in an outcomes study. This article is protected by copyright. All rights reserved. PMID- 30472751 TI - Impact of Resident Autonomy Clinics in a Dermatology Residency: Improving Residents' Perception of Autonomy. AB - Over recent years, concerns have been raised by residents within the Harvard Combined Dermatology Residency Program regarding lack of autonomy, including not being viewed by patients as the primary provider and lack of independence when formulating plans under the "apprenticeship" model. Literature from both surgical and medical specialties suggests a gradual decline in resident autonomy over time with ramifications on resident satisfaction and preparedness for future practice. Here we describe the actualization of resident-run autonomy clinics within our program and compare two years of survey data to assess resident perception of autonomy before and after implementation. This article is protected by copyright. All rights reserved. PMID- 30472752 TI - A Kiss to drive rhythms in reproduction. AB - Reproduction, like many other biological functions, exhibits marked daily and seasonal rhythms in order to anticipate and adapt breeding activity to environmental challenges. In recent years, studies investigating the neuroendocrine mechanisms driving rhythms in reproduction have unveiled the pivotal role of hypothalamic neurons expressing kisspeptin in integrating and forwarding daily and seasonal cues to the reproductive system. The objective of this review is to summarize the knowledge on the effect and role of this neuropeptide on the mammalian hypothalamo-pituitary-gonadal axis and describe how it is involved in the daily control of ovulation in females and long term adaptation of reproduction in seasonal breeders. This article is protected by copyright. All rights reserved. PMID- 30472753 TI - Oxidosqualene cyclase and CYP716 enzymes contribute to the triterpene structural diversity in the medicinal tree banaba. AB - Pentacyclic triterpenes (PCTs) represent a major class of bioactive metabolites in banaba (Lagerstroemia speciosa) leaves; however, biosynthetic enzymes and their involvement in temporal accumulation of PCTs are still not studied. We employed an integrated approach involving transcriptomics, metabolomics and gene function analysis to identify oxidosqualene cyclases (OSCs) and cytochrome P450 monooxygenases (P450s) that catalyzed sequential cyclization and oxidative reactions towards PCT scaffold diversification. Four monofunctional OSCs (LsOSC1,3-5) converted triterpene precursor 2,3-oxidosqualene to either of lupeol, beta-amyrin and cycloartenol, and a multifunctional LsOSC2 formed alpha amyrin as a major product along with beta-amyrin. Two CYP716 family P450s (CYP716A265, CYP716A266) catalyzed C-28 oxidation of alpha-amyrin, beta-amyrin and lupeol to form ursolic acid, oleanolic acid and betulinic acid, respectively. However, CYP716C55 catalyzed C-2alpha hydroxylation of ursolic acid and oleanolic acid to produce corosolic acid and maslinic acid, respectively. Besides, combined transcript and metabolite analysis suggested major roles for the LsOSC2, CYP716A265 and CYP716C55 in determining leaf ursane and oleanane profiles. Combinatorial expression of OSCs and CYP716s in Saccharomyces cerevisiae and Nicotiana benthamiana led to PCT pathway reconstruction, signifying the utility of banaba enzymes for bioactive PCT production in alternate plant/microbial hosts that are easily tractable than the tree species. This article is protected by copyright. All rights reserved. PMID- 30472754 TI - Abnormal lipid storage related to adipocyte shrinkage in acquired partial lipodystrophy (Barraquer-Simons syndrome). AB - BACKGROUND: Acquired partial lipodystrophy (APL) is characterized by the gradual symmetrical loss of subcutaneous fat starting from the face, spreading towards the upper part of the body and sparing the lower extremities. OBJECTIVE: We report a 33- year-old woman with facial lipodystrophy, loss of buccal fat pads, and breast fat tissue. The subcutaneous fat was preserved in other anatomic regions, and we noted some excess of fat accumulation in the lower abdomen and thighs. She had a low serum level of C3 was positive for a polyclonal immunoglobulin C3NeF in the serum. She was diagnosed with APL. METHODS: We examined fat from lipoatrophic and healthy areas and compared it to subcutaneous fat samples from a healthy control. RESULTS: Using scanning electron microscopy, we saw shrunken adipocytes with numerous small lipid droplets detaching from the surface of the adipocytes as compared to the classic aspect of adipose tissue in the control subject where the cytoplasm is occupied by one big lipid droplet. A loss of contact between adipocytes was observed in the APL patient when compared to the normal network of adipocytes in the control subject. The healthy fat seemed not affected by lipoatrophy; we observed normal sized adipocytes, though their surface was not as regular as in the control samples. CONCLUSION: The significance and mechanism of the electron microscopic findings are unknown, but they suggest adipocyte shrinkage related to a defect in the retaining triglycerides, which could contribute to the pathogenesis of this disorder. This article is protected by copyright. All rights reserved. PMID- 30472755 TI - Dermoscopy of papuloerythroderma of Ofuji. AB - Papuloerythroderma of Ofuji is a clinical entity originally described in 1984, with a predilection in elderly Asian males.1 It is clinically characterized by coalescent flat-topped papules on an erythematous base that spare the skin folds.2 We herein report a new case of papuloerythroderma of Ofuji in a Caucasian male individual, and we describe the characteristic dermoscopic pattern of the syndrome for the first time in the literature. This article is protected by copyright. All rights reserved. PMID- 30472756 TI - Self-reported physical activity during leisure time was favourably associated with body composition in Norwegian adolescents. AB - AIM: We studied the cross-sectional association between self-reported physical activity and body composition in adolescents. METHODS: The Norwegian Fit Futures Cohort Study was conducted in the Tromso and Balsfjord municipalities during 2010 2011. All 1,117 students in their first year of upper secondary high school were invited to attend an examination at the Clinical Research Unit at the University Hospital of Northern Norway and 93% agreed. After exclusions, we analysed 945 participants (51% boys) with a mean age of 16.1 years (range 15.5-17.5 years) with valid measurements. The associations between self-reported weekly hours of physical activity during leisure time and four measures of body composition were explored using linear regression. RESULTS: Self-reported physical activity was significantly associated with the fat mass index (p < 0.03) and lean mass index (p < 0.001) in both genders. The lean mass index increased with higher levels of activity and the fat mass index decreased. Physical activity was not associated with body mass index for either gender, but there was an inverse association with waist circumference in girls (p = 0.04). CONCLUSION: Physical activity was favourably associated with body composition in Norwegian adolescents and showed contrasting associations with the fat mass and lean mass indexes. This article is protected by copyright. All rights reserved. PMID- 30472757 TI - Engineering synucleinopathy-resistant human dopaminergic neurons by CRISPR mediated deletion of the SNCA gene. AB - An emerging treatment for Parkinson's disease (PD) is cell replacement therapy. Authentic midbrain dopaminergic (mDA) neuronal precursors can be differentiated from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (iPSCs). These laboratory-generated mDA cells have been demonstrated to mature into functional dopaminergic neurons upon transplantation into preclinical models of PD. However, clinical trials with human fetal mesenchephalic cells have shown that cell replacement grafts in PD are susceptible to Lewy body formation suggesting host-to-graft transfer of alpha-synuclein pathology. Here we have used CRISPR/Cas9n technology to delete the endogenous SNCA gene, encoding for alpha synuclein, in a clinical-grade hESC line to generate SNCA+/- and SNCA-/- cell lines. These hESC lines were first differentiated into mDA neurons, and then challenged with recombinant alpha-synuclein pre-formed fibrils (PFFs) to seed the formation for Lewy-like pathology as measured by phosphorylation of serine-129 of alpha-synuclein (pS129-alphaSyn). Wild-type neurons were fully susceptible to the formation of protein aggregates positive for pS129-alphaSyn, while SNCA+/- and SNCA-/- neurons exhibited significant resistance to the formation of this pathological mark. This work demonstrates that reducing or completely removing SNCA alleles by CRISPR/Cas9n-mediated gene editing confers a measure of resistance to Lewy pathology. This article is protected by copyright. All rights reserved. PMID- 30472758 TI - Effect of semen and donor factors on multiple ovulation and embryo transfer (MOET) in sheep. AB - Multiple ovulation and embryo transfer (MOET) is an important tool in the sheep industry for increasing numbers of genetically superior individuals. The objective of this study was to evaluate the effect of semen source (frozen or fresh), the number of embryo collection procedures for each donor (NECP), the season in which embryo transfer and collection was performed, and the age and breed of the donor, on the number of recovered embryos and pregnancy rates after embryo transfer. The Alamos Genetics' flushing station database was used. This consisted of 140 embryo collection procedures, from 53 dorper and white dorper sheep donors, aged between one and eight years, totaling 1200 collected embryos. Neither the number of retrieved embryos nor the pregnancy rate was affected by the semen preservation method (fresh or frozen), NECP or the age and breed of donor. The season did not affect the number of collected embryos but had a significant effect (P < 0.05) on the recipient pregnancy rate; with higher pregnancy rates reported in the winter (65.57 +/- 25.33%) compared to spring (37.11 +/- 33.27%), summer (29.95 +/- 28.33%) or autumn (35.03 +/- 31.66%). There is an estimated increase of 98.4% and 71.5% of embryos recovered in the spring and summer seasons respectively when winter is used as reference. The survival of embryos is significantly higher when implanted during the breeding season, more specifically in winter. Embryo collection can be carried out throughout the year in sheep, but there may be a marginal advantage in the use of superovulation and fresh embryo transfer programs in the autumn and winter. This article is protected by copyright. All rights reserved. PMID- 30472759 TI - The relationship between sagittal hoof conformation and hindlimb lameness in the horse. AB - BACKGROUND: Lameness can be multifactorial and may result from the accumulation of multiple seemingly unrelated causes. The identification of factors associated with lameness could be one method to decrease incidence of lameness and prolong the equine athlete's competitive life. OBJECTIVES: To determine if there is an association between hoof balance in the sagittal plane and hindlimb lameness. STUDY DESIGN: Case-control study. METHODS: Eighty client-owned horses with hindlimb lameness (cases) and 80 horses with no detectable hindlimb lameness (controls) were prospectively enrolled following lameness evaluation as either cases (lameness localised with regional anaesthesia) or controls (no hindlimb lameness). Lameness cases were divided based on location (stifle, tarsus, proximal metatarsus, and other sites). Lateromedial radiographs were performed of hind hooves and plantar angle of the distal phalanx (PADP) was determined. The prevalence of negative/neutral PADP and median PADPs were calculated. Conditional logistic regression and Wilcoxon signed rank tests were used to analyse PADPs, and odds ratios were calculated. Significance was set at P<0.05. RESULTS: The mean PADP was significantly smaller in cases compared to controls. The mean PADP was significantly smaller in horses with lameness localised to tarsus and proximal suspensory, but not the stifle. Lameness in horses was associated with a negative/neutral PADP (Odds ratio [OR] 3.87, 95% confidence interval [95%CI] 1.97 7.61, p<0.01), with lameness localised to the tarsus (OR 4.98, 95%CI 1.34-18.54, p = 0.01) and proximal suspensory (OR 5.16, 95%CI 1.11-23.89, p = 0.03) being associated with a negative/neutral PADP. MAIN LIMITATIONS: It is unknown whether the negative/neutral PADP contributed to lameness or lameness resulted in lower PADP. CONCLUSIONS: Horses with hindlimb lameness localised to the distal tarsus and proximal metatarsus, but not the stifle, were more likely to have negative/neutral PADPs. Corrective farriery to improve PADP may be investigated further as one component in the treatment of hindlimb lameness localised to regions proximal to the foot. This article is protected by copyright. All rights reserved. PMID- 30472761 TI - Demand Management and Weekend haematology and clinical biochemistry requests. AB - BACKGROUND: Increasing demand for laboratory testing at weekends is common but little is known about its appropriateness. METHODS: An audit was conducted in a large district hospital of routine haematology and clinical biochemistry requests ordered over 2 weekends. Appropriateness was assessed by review of ordered tests compared with clinical records by a qualified chemical pathologist. RESULTS: Profiles requested on phlebotomy included full blood count (76%), renal profile (91%), C-Reactive protein (41%), liver function tests (18%) and another test in 18%. Phlebotomy was likely unnecessary in 47.5% of episodes while 60.8% of requested assays were graded probably unnecessary or unnecessary. At ward level the number of requests averaged 37 (median 32; range 2-76) totalling 446 separate profiles or assays. There was no difference in phlebotomy requests by ward (P=0.19). Differences were observed in ordered tests (P=0.005) which were caused by one outlier ward with a low request rate. CONCLUSIONS: A large number of unnecessary common tests seem to be carried out at weekends as part of routine care. Implementation of demand management through education and if necessary electronic limitation of requests may be useful to control laboratory workloads. This article is protected by copyright. All rights reserved. PMID- 30472760 TI - Compliance with the guidelines for laboratory monitoring of patients treated with lithium: a retrospective follow-up study among ambulatory patients in the Netherlands. AB - OBJECTIVES: Laboratory monitoring of patients using lithium is important to prevent harm and to increase effectiveness. The aim of this study is to determine compliance with the guidelines for laboratory monitoring of patients treated with lithium overall and within subgroups. METHODS: Patients having at least one lithium dispensing for six months or longer between January 2010 and December 2015 were identified retrospectively using data from the Dutch PHARMO Database Network. Laboratory monitoring was defined as being compliant with the Dutch Multidisciplinary Clinical Guideline Bipolar Disorders when lithium serum levels, creatinine and thyroid-stimulating hormone (TSH) had been measured at least every six months during lithium use. RESULTS: Data were analyzed from 1,583 patients with a median duration of seven six-month periods of lithium use. Results indicated that patients had been monitored over six-month periods for lithium serum levels 65% of the time, for creatinine 73% of the time and for TSH 54% of the time. Just over one seventh (16%) of patients had been monitored in compliance with the guidelines for all three parameters during total follow-up. Especially males, patients aged below 65 years, patients receiving prescriptions solely from general practitioners, prevalent users of lithium, patients without interacting co-medication, and patients without other days with laboratory measurements had been monitored less frequently in compliance with the guidelines. CONCLUSION: A considerable proportion of patients had not been monitored in accordance with the guidelines. Further research is needed to understand the reasons for noncompliance and to implement strategies with the ultimate goal of optimizing safety and effectiveness for patients treated with lithium. This article is protected by copyright. All rights reserved. PMID- 30472762 TI - Anti-Inflammatory Therapy for Atherosclerosis:Interpreting Divergent Results from the CANTOS and CIRT Clinical Trials. AB - Over the past 18 months, two multi-national clinical trials specifically designed to test the inflammation hypothesis of atherothrombosis have been presented. First, the 10,061 patient Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) proved that specific targeting of interleukin-1beta can significantly reduce cardiovascular event rates in the absence of lipid or blood pressure lowering. In CANTOS, canakinumab given at doses of either 150 or 300 mg SC once every three months lowered the inflammatory biomarkers interleukin-6 and C reactive protein (hsCRP) by 35 to 40 percent when compared to placebo, effects that led to a 17 percent reduction in rates of recurrent heart attack, stroke, urgent need for revascularization, or cardiovascular death (P<0.001). This article is protected by copyright. All rights reserved. PMID- 30472764 TI - Ultraviolet b radiation modifies circadian time in epidermal skin and in subcutaneous adipose tissue. AB - BACKGROUND: Recent findings suggest that circadian time regulates cellular functions in the skin and may affect protection against ultraviolet radiation (UVR). It is not known, however, whether UVR through skin directly affects the expression of circadian genes. We investigated the effect of ultraviolet-B (UVB) exposure on cryptochrome circadian clock 1 (CRY1), cryptochrome circadian clock 2 (CRY2), and circadian associated repressor of transcription (CIART) genes. METHODS: Healthy volunteers (n=12) were exposed to narrow-band UVB radiation of 4 standard erythemal dose (SED). Epidermal/dermal and subcutaneous adipose tissue samples were obtained by punch biopsies from irradiated and non irradiated skin 10 cm away from the irradiated site 24 hours after UVB exposure. Gene expression of CRY1, CRY2, and CIART was measured using RT-PCR (TaqMan). RESULTS: UVB radiation affected mRNA expression in the epidermal/dermal skin and in the subcutaneous adipose tissue. It down-regulated expression of CRY2 gene in the epidermal/dermal skin, whereas it up-regulated expression of CRY1 and CIART genes in the subcutaneous adipose tissue. CONCLUSION: We showed for the first time that UVB radiation affects expression of circadian genes in the subcutaneous adipose tissue. Further studies are warranted to understand the mechanisms in detail. This article is protected by copyright. All rights reserved. PMID- 30472763 TI - Correlates of affiliate stigma among family caregivers of people with mental illness: A systematic review and meta-analysis. AB - INTRODUCTION: Many studies have investigated the correlates of affiliate stigma among family caregivers of people with mental illness (PWMI). Thus far, no systematic review or meta-analysis has been conducted to synthesize these results. AIMS /QUESTION: This review aims to identify the correlates of affiliate stigma among family caregivers of PWMI. METHOD: We searched four databases including PubMed, PsychINFO, EMBASE, and Web of Science for studies that investigated the association of affiliate sigma with socio-demographic, psychosocial, and disease-related factors. RESULTS: 22 studies including 3381 participants met the inclusion criteria. Eighteen variables were included for the meta-analysis. For disease-related characteristics, only "disease attribution" and "care time/day" were associated with affiliate stigma. For psychosocial characteristics, "support from others," "burden," "depression," "stress," "distress," and "face concern," were related to affiliate stigma. DISCUSSION: This review is the first to assess the association of affiliate stigma with other characteristics of interest. However, the findings are limited due to a very small number of studies. Researchers should conduct in-depth study in this area and improve the quality of the literature. IMPLICATIONS FOR PRACTICE: Health focused interventions for family caregivers such as respite care, self-help groups, online support program, psychosocial education can mediate the impact of affiliated stigma. This article is protected by copyright. All rights reserved. PMID- 30472765 TI - Post thawing effects of three cryopreservation diluents on rusa deer (rusa timorensis) spermatozoa. AB - The aim of this study was to evaluate home-made and commercial extenders for the cryopreservation of Rusa deer semen. After collection by electroejaculation, six ejaculates were diluted and frozen in TES-based, Tris-based and Triladyl(r) extenders. Subjective motility, viability, morphology, acrosome integrity and membrane functionality were assessed post-thawing and after one hour incubation at 37 degrees C (Thermal stress test). Total and progressive motility, and kinematic parameters were also assessed through CASA system. Post-thawing sperm progressive motility (PM), velocity according to the straight path (VSL) and linearity (LIN) showed significant differences and higher values were detected for spermatozoa diluted with Triladyl(r) and TES (p<0.05) as compared with Tris (PM of Triladyl(r) 14.7% vs 3.2% TES and 2.5% Tris; VSL 56 for Triladyl(r) , 59.2 for TES and 41.7 for Tris; LIN 45.6 for Triladyl(r) , 52 for TES and 36.5 for Tris). Triladyl(r) and TES extender led to better post-thawing sperm parameters, but these preliminary results need to be verified through artificial insemination trials This article is protected by copyright. All rights reserved. PMID- 30472766 TI - Safety of urgent endarterectomy in acute non-disabling stroke patients with symptomatic carotid artery stenosis: an international multicenter study. AB - BACKGROUND & PURPOSE: International recommendations advocate that carotid endarterectomy (CEA) should be performed within two weeks from the index event in symptomatic carotid artery stenosis (sCAS) patients. However, there are controversial data regarding the safety of CEA performed during the first two days of ictus. The aim of this international, multicenter study was to prospectively evaluate the safety of urgent (0-2 days) in comparison to early (3 14 days) CEA in patients with sCAS. METHODS: Consecutive patients with non disabling (mRS-scores<=2) acute ischemic strokes (AIS) or Transient Ischemic Attacks (TIA) due to sCAS (>=70%) underwent urgent or early CEA at five tertiary care stroke centers during a six-year period. The primary outcome events included stroke, myocardial infarction (MI) or death during the 30-day follow-up period. RESULTS: A total of 311 patients with sCAS underwent urgent (n=63) or early (n=248) CEA. The two groups did not differ in baseline characteristics with the exception of crescendo TIAs (21% in urgent vs. 7% in early CEA; p=0.001). The 30 day rates of stroke did not differ (p=0.333) between patients with urgent (7.9%; 95%CI: 3.1%-17.7%) and early (4.4%; 95%CI: 2.4%-7.9%) CEA. The mortality and MI rates were similar between the two groups. The median length of hospitalization was shorter in urgent CEA [6 days (IQR 4-6) vs.10 days(IQR 7-14); p<0.001]. CONCLUSIONS: Our findings highlight that urgent CEA performed within two days from the index event is related to a non-significant increase in the risk of peri procedural stroke. The safety of urgent CEA requires further evaluation in larger datasets. This article is protected by copyright. All rights reserved. PMID- 30472767 TI - Aspirin for recurrence prevention in bipolar disorder - promising, yet clinically understudied? AB - Current available maintenance pharmacotherapy for bipolar disorder (BD) leaves ample room for improvement. Up to 50% of patients with BD do not respond adequately to available treatments and still suffer from manic and/or depressive episodes. In this perspective article, we will give an overview of the neuropharmacodynamics of (low-dose) aspirin, reflect on the published clinical studies and argue that aspirin is a promising, yet understudied option for recurrence prevention This article is protected by copyright. All rights reserved. PMID- 30472768 TI - Emergency care in Kiribati: A combined medical and nursing model for development. AB - OBJECTIVES: To summarise recent developments in emergency care in Kiribati, a developing Pacific Island nation. Multiple donor countries and agencies have partnered in this process. Changes in medical training, staffing models and planned infrastructure developments are all described, with a particular focus on a recent emergency nurse training programme. METHODS: A bespoke nurse education course was developed by external clinical nurse specialists in collaboration with local administrators and clinicians, incorporating WHO Basic Emergency Care course. The nine-day course was delivered to 18 nurses, over a 3-week period to accommodate rostering requirements. Pre- and post-course assessment was undertaken. RESULTS: Quantitative assessment improved from 87.11 +/- 7.46 (mean +/- SD) to 94.89 +/- 5.95 (t = 5.45, P < 0.001). Qualitative scenario-based assessment confirmed marked improvement. CONCLUSIONS: A multifaceted development strategy has proven essential for progression in emergency care. Nurse education is an essential component of this, and the existing model has potential for other similar nations. PMID- 30472769 TI - Different approaches to liver transplantation in propionic acidemia patients. AB - We thank Rammohan et cols for the comment on our paper entitled "The Role of Liver Transplantation in Propionic Acidemia". As the authors highlight, the reported rates of Hepatic Arterial Thrombosis (HAT) in Propionic Acidemia (PA) patients that undergo Liver Transplantation (LT) are higher than in other indications of LT (1). As described in the paper, the rate of HAT in our series is 33% (2/6) similar to those reported by other groups (1-2). The overall incidence of HAT in the last 10 years in our centre for non-PA indications was 3.5% (4/113) (3.7% in whole liver graft transplantation (3/81) and 3.1% in living donor liver transplantation (LDLT) (1/32)). This article is protected by copyright. All rights reserved. PMID- 30472770 TI - Respect, trust and continuity: A qualitative study exploring service users' experience of involvement at a Healthy Life Centre in Norway. AB - BACKGROUND: To meet the challenges caused by non-communicable diseases, Norway has established Healthy Life Centres within primary care to encourage a healthy lifestyle. To promote people's health and ensure high-quality services, user involvement in contemporary health care is regarded as essential. OBJECTIVE: To explore the experience of user involvement among Healthy Life Centre users participating in individual health consultations, followed by physical activity groups and/or diet courses. METHODS: This was a qualitative study based on twenty semi-structured individual interviews conducted between September 2015 and May 2016 at a Healthy Life Centre in Norway. Data were analysed using systematic text condensation. RESULTS: Being respected and having a trustworthy relationship with the professionals were found to be essential for the service users' involvement. Building a trustworthy relationship was disrupted for some service users by a lack of relational continuity. This lack of continuity jeopardized the continuation of professionals' awareness of the service users' challenges and personal goals. The service users' preferred levels of user involvement varied. Some service users did not always want to play an active part and instead wanted the professionals, as "experts," to decide. CONCLUSIONS: The findings imply that the professionals need to assess each service user's desires for involvement and consider how these can be met. Thus, user involvement cannot be understood without considering the particular setting and each individual service user's preferences for involvement. Relational continuity is needed to maintain the service users' challenges and goals throughout the services and to promote health behaviour changes. PMID- 30472771 TI - Therapeutic use of steroids in non-chronic rhinosinusitis olfactory dysfunction: a systematic evidence-based review with recommendations. AB - BACKGROUND: Olfactory loss is a common and debilitating disease with limited treatment options, particularly for olfactory dysfunction not related to sinonasal inflammation. Both topical and systemic steroids have been used as treatments for olfactory loss. This study systematically reviews the literature on the efficacy of steroids for non-chronic rhinosinusitis (CRS)-related olfactory loss and provides recommendations. METHODS: A literature search of PubMed, Ovid, EMBASE, and the Cochrane Database was performed according to Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Inclusion criteria included original data, English-language articles on steroid treatment (topical and systemic) for olfactory loss unrelated to sinonasal inflammation. Data was collected on study design, olfaction dysfunction etiology, clinical outcomes, and level of evidence. Two investigators reviewed all articles independently, with a third acting as a mediator for any disagreements in recommendation. RESULTS: Of 866 abstracts identified, only 15 studies met inclusion criteria and were systematically reviewed. Level 4 evidence suggests oral steroids can improve olfactory loss. Level 1B evidence demonstrates topical steroid rinses improve olfactory dysfunction in a select group of patients. Topical steroid sprays show no improvement across several levels of evidence. CONCLUSION: There is a paucity of high-quality studies demonstrating efficacy of either topical or oral steroids for olfactory dysfunction unrelated to sinonasal disease. The only level 1 evidence suggests using steroid rinses to improve olfactory outcomes in select patients, with weaker evidence supporting use of oral steroids. Topical steroid sprays do not improve olfactory dysfunction in this patient population and are not recommended. PMID- 30472772 TI - Hepatitis C: is eradication possible? AB - Hepatitis C has a relevant global impact in terms of morbidity, mortality and economic costs, with more than 70 million people infected worldwide. In the resolution "Transforming our world: the 2030 Agenda for Sustainable Development" was included as a focus area in the health-related goal with world leaders pledging to 'combat' it by 2030. In response, WHO drafted the Global Viral Hepatitis Strategy carrying the ambitious targets to reduce the number of deaths by two thirds and to increase treatment rates up to 80%. Despite the availability of highly effective therapeutic regimens based on direct acting antivirals many barriers to HCV eradication still remain. They are related to awareness of the infection, linkage to care, availability of the therapeutic drug regimens and reinfection. Overall, if an effective prophylactic vaccine will not be available, HCV eradication appears difficult to achieve in the future. This article is protected by copyright. All rights reserved. PMID- 30472773 TI - Investigating fetal growth restriction and perinatal risks in appropriate for gestational age infants: using cohort and within-sibling analyses. AB - OBJECTIVE: Fetal growth restriction refers to fetuses that fail to reach their growth potential. Studies within siblings may be useful to disclose fetal growth restriction in appropriate for gestational age (AGA) infants. We analysed associations between birth weight percentiles and perinatal risks in AGA infants, using both population-based and within-sibling analyses. DESIGN: Population-based cohort study. SETTING AND SAMPLE: Using nation-wide Swedish registries (1987 2012), we identified 2 134 924 singleton AGA births (10th -90th birth weight percentile for gestational age), of whom 1 377 326 were full siblings. METHODS: Unconditional Poisson regression was used for population analyses, and conditional (matched) Poisson regression for within-sibling analyses. We estimated associations between birth weight percentiles and stillbirth, neonatal mortality and morbidity, using incidence rate ratios (IRRs) with 95% confidence intervals (CIs). RESULTS: Stillbirth and neonatal mortality risks declined with increasing birth weight percentiles, but the declines were larger in within sibling analyses. Compared to the reference group (40th -<60th percentile), IRRs (95% CIs) of stillbirth for the lowest and highest percentile groups (10th -<25th and 75th -90th percentiles, respectively) were 1.87 (1.72-2.03) to 0.76 (0.68 0.85) in population analysis and 2.60 (2.27-2.98) and 0.43 (0.36-0.50) in within sibling analysis. Neonatal morbidity risks in term non-malformed infants with low birth weight percentiles were generally only increased in within-sibling analyses. CONCLUSION: Using birth weight information from siblings may help to define fetal growth restriction in AGA infants. This article is protected by copyright. All rights reserved. PMID- 30472774 TI - Venous thromboembolism in patients with liver diseases: reply. AB - The relationship between liver disease and thromboembolic disease is controversial. (1-4). We conducted a population-based study with several limitations that are inherent to administrative databases. We were unable to measure liver-specific disease severity scales, and different groups could be heterogeneous. This article is protected by copyright. All rights reserved. PMID- 30472775 TI - Participation of actin filaments, myosin and phosphatidylinositol 3-kinase (PI3K) in the formation and polarization of tetraspore germ tube of Gelidium floridanum (Rhodophyta, Florideophyceae). AB - This study aimed to examine evidence of direct interaction among actin, myosin and phosphatidylinositol 3-kinase (PI3K) in the polarization and formation of the tetraspore germ tube of Gelidium floridanum. After release, tetraspores were exposed to cytochalasin B, latrunculin B, LY294002 and BDM for a period of 6 hours. In control samples, formation of the germ tube occurred after the experimental period with cellulose formation and elongated chloroplasts moving through the tube region with the presence of F-actin. In the presence of cytochalasin B, an inhibitor of F-actin, latrunculin B, an inhibitor of G-actin, and BDM, a myosin inhibitor, tetraspores showed no formation of germ tube or cellulose. Spherical-shaped chloroplasts were observed in the central region with a few F-actin filaments in the periphery of the cytoplasm. Tetraspores treated with LY294002, a PI3K inhibitor, showed no formation of the tube at the highest concentrations. Polarization of cytoplasmic contents did not occur, only cellulose formation. It was concluded that F-actin directs the cell wall components and contributes to the maintenance of chloroplast shape and elongation during germ tube formation. PI3K plays a fundamental role in signaling for the asymmetric polarization of F-actin. Thus, F-actin regulates the polarization and germination processes of tetraspores of G. floridanum. This article is protected by copyright. All rights reserved. PMID- 30472776 TI - Spontaneous pre-stimulus oscillatory activity shapes the way we look:A concurrent imaging and eye-movement study. AB - Previous behavioural studies have accrued evidence that response time plays a critical role in determining whether selection is influenced by stimulus saliency or target template. In the present work, we investigated to what extent the variations in timing and consequent oculomotor control are influenced by spontaneous variations in prestimulus alpha oscillations. We recorded simultaneously brain activity using magnetoencephalography (MEG) and eye movements while participants performed a visual search task. Our results show that slower saccadic reaction times were predicted by an overall stronger alpha power in the 500 ms time window preceding the stimulus onset, while a weaker alpha power was signature of faster responses. When looking separately at performance for fast and slow responses, we found evidence for two specific sources of alpha activity predicting correct versus incorrect responses. When saccades were quickly elicited, errors were predicted by stronger alpha activity in posterior areas, comprising the angular gyrus in the temporal-parietal junction (TPJ) and possibly the lateral intraparietal area (LIP). Instead, when participants were slower in responding, an increase of alpha power in frontal eye fields (FEF), supplementary eye fields (SEF) and dorsolateral pre-frontal cortex (DLPFC) predicted erroneous saccades. In other words, oculomotor accuracy in fast responses was predicted by alpha power differences in more posterior areas, while the accuracy in slow responses was predicted by alpha power differences in frontal areas, in line with the idea that these areas may be differentially related to stimulus-driven and goal-driven control of selection. This article is protected by copyright. All rights reserved. PMID- 30472777 TI - Ureaplasma urealyticum pyelonephritis presenting with progressive dysuria, renal failure and neurologic symptoms in an immunocompromised patient. AB - Ureaplasma urealyticum is a bacterial species correlated with urethritis in healthy individuals and invasive infections in immunocompromised patients. We describe a 20-year-old female with history of remote heart transplant on everolimus, mycophenolate and rituximab presenting with progressive urinary tract symptoms, renal failure and neurologic symptoms. An extensive workup ultimately identified Ureaplasma urealyticum infection and the patient successfully recovered after a course of azithromycin and doxycycline. This article is protected by copyright. All rights reserved. PMID- 30472778 TI - High-frequency rTMS and iTBS for spasticity management in secondary-progressive multiple sclerosis. AB - BACKGROUND: The spasticity phenomenon is a significant factor in the development of disability. Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment method for this disorder. AIMS: Our aim was to compare the effects of two protocols of rTMS - the high-frequency (HF) rTMS (20 Hz) and the intermittent theta-burst stimulation (iTBS) - on the level of spasticity and concomitant symptoms in patients with secondary progressive multiple sclerosis (SPMS) with an analysis of the duration of the effects up to 12 weeks after the stimulation course. METHODS: 34 patients with SPMS and lower spastic paraparesis were randomized into 3 groups: 1) high-frequency (HF) rTMS (20 Hz); 2) intermittent theta-burst (iTBS) stimulation; 3) sham-stimulation. Spasticity and spasticity assosiated symptoms were assessed by the Modified Ashworth Scale (MAS), the Subjective Evaluating Spasticity Scale (SESS) and the Numerical Analog Scale (NAS), Modified Fatigue Impact Scale (MFIS) and the pain level scale. RESULTS: MAS was significantly reduced after the stimulation course in the HF-rTMS and iTBS groups. SESS was reduced post-intervention and at the two follow-ups in the iTBS group, while HF-rTMS produced a SESS reduction only at the 2-week follow-up, with no effects in the sham group. Conversely, reductions of pain and fatigue were found in the HF-rTMS group. CONCLUSIONS: The results show that HF-rTMS and iTBS significantly reduce spasticity measured by MAS, in contrast to sham stimulation. Some evidence was found in favor of a longer-lasting effect of iTBS on SESS, and of a reduction in pain and fatigue after HF-rTMS. This article is protected by copyright. All rights reserved. PMID- 30472779 TI - Increasing incidence of nonalcoholic steatohepatitis as an indication for liver transplantation in Australia and New Zealand. AB - Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease affecting at least a quarter of the world's population.1 Although NAFLD and its progressive form, nonalcoholic steatohepatitis (NASH), were once regarded as a problem of the developed Western countries, NAFLD and NASH are now well recognized as important and common causes of liver disease across the globe. This article is protected by copyright. All rights reserved. PMID- 30472780 TI - mTOR kinase inhibition reduces tissue factor expression and growth of pancreatic neuroendocrine tumors. AB - BACKGROUND: Full-length tissue factor (flTF) and alternatively spliced TF (asTF) contribute to growth and spread of pancreatic ductal adenocarcinoma. It is unknown, however, if flTF and/or asTF contribute to pathobiology of pancreatic neuroendocrine tumors (pNET). OBJECTIVE: To assess TF expression in pNET and the effects of mTOR complex 1/2 (mTORC1/2) inhibition on pNET growth. METHODS: Human pNET specimens were immunostained for TF. Human pNET cell lines QGP1 and BON were evaluated for TF expression and responsiveness to mTOR inhibition. shRNA were used to knock down TF in BON. TF cofactor activity was assessed using a two-step FXa generation assay. TF promoter activity was assessed using transient transfection of human TF promoter-driven reporter constructs into cells. Mice bearing orthotopic BON tumors were treated with the mTORC1/2 ATP-site competitive inhibitor sapanisertib / MLN0128 (3 mg/kg, oral gavage) for 34 days. RESULTS: Immunostaining of pNET tissue revealed flTF and asTF expression. BON and QGP1 expressed both TF isoforms, with BON exhibiting higher levels. shRNA directed against TF suppressed BON proliferation in vitro. Treatment of BON with sapanisertib inhibited mTOR signaling and suppressed TF levels. BON tumors grown in mice treated with sapanisertib had significantly less TF protein and co-factor activity, and were smaller compared to tumors grown in control mice. CONCLUSIONS: TF isoforms are expressed in pNET. Sapanisertib suppresses TF mRNA and protein expression as well as TF co-factor activity in vitro and in vivo. Thus, further studies are warranted to evaluate the clinical utility of TF-suppressing mTORC1/2 inhibitor sapanisertib in pNET management. This article is protected by copyright. All rights reserved. PMID- 30472781 TI - One year investigation of the prevalence and diversity of clostridial spores in raw milk from the Tokachi area of Hokkaido. AB - We investigated the seasonal prevalence and diversity of clostridial spores in raw milk from the Tokachi area of Hokkaido. Samples of raw milk were collected quarterly from May 2013 through February 2014. The mean clostridial spore count for the raw milk from 336 milk tankers was 27.6 CFU/100 ml. The clostridial species isolated most frequently from raw milk samples was Clostridium tyrobutyricum. The dominant species was C. tyrobutyricum regardless of the season. The percentage of samples with low spore counts (<10 CFU/100 ml) was highest (60.9%) during winter (February) and lowest (34.5%) in autumn (November). In comparison, the percentage of samples with high spore counts (>100 CFU/100 ml) was highest (5.7%) in autumn (November) and lowest (1.1%) during spring (May). PMID- 30472782 TI - Alexithymia and Temporomandibular Joint and Facial Pain in the General Population. AB - BACKGROUND: Associations of alexithymia with temporomandibular pain disorders (TMD), facial pain, head pain and migraine have been described, but the role of the different dimensions of alexithymia in pain development remained incompletely understood. OBJECTIVES: We sought to investigate the associations of alexithymia and its subfactors with signs of TMD and with facial pain, head pain, and migraine in the general population. METHODS: 1,494 subjects from the general population completed the Toronto Alexithymia Scale-20 (TAS-20) and underwent a clinical functional examination with palpation of the temporomandibular joint and masticatory muscles. Facial pain, migraine and head pain were defined by questionnaire. A set of logistic regression analyses was applied with adjustment for age, sex, education, number of traumatic events, depressive symptoms, and anxiety. RESULTS: Alexithymia was associated with TMD joint pain (Odds Ratio 2.63; 95% confidence interval 1.60-4.32 for 61 TAS-20 points versus the median of the TAS-20 score) and with facial pain severity (Odds Ratio 3.22; 95% confidence interval 1.79-5.79). Differential effects of the subfactors were discovered with difficulties in identifying feelings as main predictor for joint, facial, and head pain, and externally oriented thinking (EOT) as U-shaped and strongest predictor for migraine. CONCLUSION: Alexithymia was moderately to strongly associated with signs and symptoms of TMD. These results should encourage dental practioners using the TAS-20 in clinical practice, to screen TMD, facial or head pain patients for alexithymia and could also help treating alexithymic TMD, facial or head pain patients. This article is protected by copyright. All rights reserved. PMID- 30472783 TI - Preventing Arteriovenous Shunt Failure in Hemodialysis Patients: A Population Based Cohort Study. AB - BACKGROUND: Dialysis adequacy is a major determinant of survival for patients with end-stage renal disease. Good vascular access is essential to achieve adequate dialysis. OBJECTIVES: This study evaluated the impacts of different drugs on the vascular access failure rate of an arteriovenous fistula or an arteriovenous graft and the rate of major bleeding in hemodialysis patients. PATIENTS AND METHODS: We studied patients with end-stage renal disease registered in the Taiwan National Health Insurance program from January 1, 1997 to December 31, 2012. A total of 95,971 patients were enrolled in our study. Vascular access dysfunction was defined as the need for thrombectomy or percutaneous angioplasty. Major bleeding was defined as emergency department visits or hospitalization with a primary diagnosis of gastrointestinal bleeding or intracerebral hemorrhage. The adjusted odds ratio between person-quarters with or without antiplatelet or oral anticoagulant use were calculated using a generalized estimating equation. RESULTS: The odds ratio of vascular access failure was 0.21 (0.11-0.39) for aspirin, 0.76 (0.74-0.79) for clopidogrel, 0.67 (0.59-0.77) for dipyridamole, 0.67 (0.53-0.86) for Aggrenox, and 0.96 (0.90-1.03) for warfarin. The highest odds ratio for intracerebral hemorrhage was 5.33 (1.25-22.72) in younger patients using Aggrenox. The highest odds ratio for gastrointestinal bleeding was 1.34 (1.10-1.64) for clopidogrel. CONCLUSION: Antiplatelet agents but not wafarin might reduce the vascular access thrombosis rate. The gastrointestinal bleeding rate was increased in the group using clopidogrel. Aggrenox should be used with caution in young individuals since it might increase the rate of intracerebral hemorrhage. This article is protected by copyright. All rights reserved. PMID- 30472784 TI - Phenotypic plasticity induced using high ambient temperature during embryogenesis in domesticated zebrafish, Danio rerio. AB - Ambient temperature during early stages of life has a substantial effect on physiological processes, eliciting phenotypic plasticity during zebrafish developmental stages. Zebrafish are known to possess a noteworthy ability to modify their phenotype in dependence of environmental factors. However, there is a poor understanding of the effects of temperature during embryogenesis, which influences the biological function like survival ability and masculinization in later life. Since the middle embryonic phase (pharyngula period) is genetically the most conserved stage in embryogenesis, it is very susceptible to embryonic lethality in developmental processes of vertebrates. Here we tested the effect of transient perturbations (heat shock) during early development (5-24 hours post fertilization; hpf) at 35 degrees C compare to control group at 28 degrees C, on survival ability of zebrafish to study the embryonic and post-embryonic mortality. We studied the variation of heat-induced masculinization among and across the families in response to high temperature. Furthermore morphometric traits of adult zebrafish at different developmental time points were measured in order to estimate the temperature * sex interaction effect. We found the highest embryonic mortality around the gastrula and segmentation periods in both experimental groups, with significantly lower survival ability in the temperature treated group (73.30% +/- 0.58% vs. 70.19% +/- 0.57%, respectively). A higher hatching success was observed in the control group (71.08% +/- 0.61%) compared to the heat-induced group (67.95% +/- 0.60%). A distinct reduction of survival ability was also observed in both experimental groups during the first two weeks after hatching, followed by a reduced level of changes thereafter. We found sex ratio imbalances across all families, with 25.2% more males under temperature treatment. Our study on growth performance has shown a positive effect of increased temperature on growth plasticity, with a greater impact on female fish in response to high ambient temperature. This article is protected by copyright. All rights reserved. PMID- 30472786 TI - Sarcopenia and Frailty in the Prognosis of Patients on the Liver Transplant Waiting List. AB - Sarcopenia and frailty are among the most common features of cirrhosis that contribute significantly to morbidity and mortality; however, sarcopenia is not identical to frailty. Sarcopenia is a critical reduction in skeletal muscle mass associated with poor outcomes. The main components of frailty are sarcopenia and physical impairment, which result in a cumulative decline in physiologic reserve (1, 2). This article is protected by copyright. All rights reserved. PMID- 30472785 TI - Ivacaftor improves rhinologic, psychologic, and sleep-related quality of life in G551D cystic fibrosis patients. AB - BACKGROUND: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that improves pulmonary function in cystic fibrosis (CF) patients with at least 1 copy of the G551D CFTR mutation. The purpose of this study is to evaluate the impact of ivacaftor on chronic rhinosinusitis (CRS) symptoms in this population. METHODS: The G551D Observational (GOAL) study was a multicenter prospective cohort study enrolling CF patients >=6 years with at least 1 G551D mutation. Subjects were provided 20-item Sino-Nasal Outcome Test (SNOT-20) questionnaires prior to ivacaftor therapy and at 1, 3, and 6 months afterward. The impact on rhinologic (R), psychological (P), sleep (S), and ear/facial (E) quality of life (QOL) domains was evaluated separately. RESULTS: Of 153 subjects, 129 (84%) completed all questionnaires. Typical baseline symptom burden was low (75% with scores <1) and degree of improvement (ie, reduced scores) was greater with higher baseline scores. SNOT-20 decreased, reflecting improvement, at all follow-up intervals (1 month: [mean change +/- standard deviation] -0.25 +/- 0.53, p < 0.01; 3 months; -0.29 +/- 0.58, p < 0.01; 6 months: -0.21 +/- 0.58, p = 0.02), but less than the prespecified minimal clinically important difference (0.8). Significant improvement was observed at 1, 3, and 6 months in the R domain (1 month: -0.24, p < 0.01; 3 months: -0.34, p < 0.01; 6 months: -0.25, p < 0.01) and P domain (1 month: -0.25, p < 0.01; 3 months: -0.32, p < 0.01; 6 months: -0.26, p < 0.01), and 1 and 3 months in the S domain (1 months: -0.35, p < 0.01; 3 months: -0.32, p < 0.01; 6 months: -0.18, p = 0.07). There was no improvement in the E domain at any time point. CONCLUSION: Ivacaftor improves QOL in the R, P, and S domains in G551D CF patients, although QOL instruments validated for CRS may not translate well to CF CRS patients because symptom burden was surprisingly low. PMID- 30472787 TI - The influence of clinical experience on dental students' ethical awareness. AB - INTRODUCTION: There has been no structured integration of ethical issues into the dental curriculum and currently no data for certain ethics modules exists in Germany. The study aimed at evaluating the attitudes to ethical issues that affect students at the Dental School in Kiel during patient treatment. MATERIAL AND METHODS: In the summer of 2017, students were recruited from the 6th and 10th semesters. A qualitative study design with interviews was chosen. The dimensions included, for example, experience with ethical issues, definitions and expectations of teaching content and methods. A qualitative content analysis was performed. RESULTS: Twelve and eleven students from semesters (32% each) participated. No student was able to name an ethical question based on his own experience (private/study). The need to address ethical issues was justified solely by personal treatment experiences. DISCUSSION: The study revealed a lack of basic ethical knowledge resulting in a lack of ability to deal with ethical issues. Instead, participants described experiences of psychological pressure, feelings of helplessness. CONCLUSION: The results suggest that ethical theoretical foundations should be taught before the beginning of patient treatment. A didactic combination with clinical facts and case vignettes is recommended. This article is protected by copyright. All rights reserved. PMID- 30472788 TI - Circulating levels of microRNA 423-5p are associated with 90 day mortality in cardiogenic shock. AB - AIMS: The role of microRNAs has not been studied in cardiogenic shock. We examined the potential role of miR-423-5p level to predict mortality and associations of miR-423-5p with prognostic markers in cardiogenic shock. METHODS AND RESULTS: We conducted a prospective multinational observational study enrolling consecutive cardiogenic shock patients. Blood samples were available for 179 patients at baseline to determine levels of miR-423-5p and other biomarkers. Patients were treated according to local practice. Main outcome was 90 day all-cause mortality. Median miR-423-5p level was significantly higher in 90 day non-survivors [median 0.008 arbitrary units (AU) (interquartile range 0.003-0.017) vs. 0.004 AU (0.002-0.009), P = 0.003]. miR-423-5p level above median was associated with higher lactate (median 3.7 vs. 2.4 mmol/L, P = 0.001) and alanine aminotransferase levels (median 68 vs. 35 IU/L, P < 0.001) as well as lower cardiac index (1.8 vs. 2.4, P = 0.04) and estimated glomerular filtration rate (56 vs. 70 mL/min/1.73 m2 , P = 0.002). In Cox regression analysis, miR-423 5p level above median was associated with 90 day all-cause mortality independently of established risk factors of cardiogenic shock [adjusted hazard ratio 1.9 (95% confidence interval 1.2-3.2), P = 0.01]. CONCLUSIONS: In cardiogenic shock patients, above median level of miR-423-5p at baseline is associated with markers of hypoperfusion and seems to independently predict 90 day all-cause mortality. PMID- 30472789 TI - Treatment Outcome of Acute Sacral Nerve Stimulation in Functional Anorectal Pain. AB - BACKGROUND: Sacral nerve stimulation (SNS) has revolutionized the management of certain intractable cases of fecal and urinary incontinence; however, the management of functional anorectal pain (FAP) has appeared in only few studies. OBJECTIVE: The aim of this study was to evaluate the treatment effect of SNS in improving functional anorectal pain symptoms. METHODS: A total of 120 patients with FAP who had SNS temporary placement were investigated at Qianfoshan Hospital between January 2014 and December 2016. Pre- and post-SNS assessment of treatment outcomes were assessed using the visual analogue scale (VAS), anorectal manometry and the score of the MOS item short form health survey (SF-36). RESULTS: A total of 120 patients proceeded to insertion of an acute SNS of the S3 root (2 Hz; 1.50 mA; 0.10 ms). Of these, 75 patients were cured, 41 improved and 4 were ineffective.The total effectiveness rate was 96.7% one year after treatment. There was a significant reduction in the median VAS scale pre-SNS and post-SNS, from 8 to 3, respectively. Patients post-SNS had lower anal maximum contraction pressure (AMCP) and anal rest pressure (ARP) than did patients pre-SNS treatment. Compared with the pretreatment group, there were no substantial differences between anal longest contraction time (ALCT) and rectal rest pressure (RRP). In addition to general health, there was a substantial improvement in the remaining dimension scores of the SF-36. CONCLUSION: The effect of SNS in treating FAP was positive, and the improvement of symptoms was substantial and worthy of clinical promotion. This article is protected by copyright. All rights reserved. PMID- 30472790 TI - Comprehensive behavioral analysis and quantification of brain free amino acids of C57BL/6J congenic mice carrying the 1473G allele in tryptophan hydroxylase-2. AB - AIM: Tryptophan hydroxylase 2 (Tph2) is a rate-limiting enzyme for the biosynthesis of 5-hydroxytryptamine (5-HT, serotonin). Previous studies have reported that C1473G polymorphism of the murine Tph2 gene leads to decreased 5-HT levels in the brain and abnormal behavioral phenotypes, such as impaired anxiety- and depression-like behaviors. In this study, to confirm the effect of the C1473G polymorphism on mouse phenotypes, we conducted a comprehensive battery of behavioral tests and measured the amounts of brain free amino acids involved in the production of 5-HT. METHODS: We obtained C57BL/6J congenic mice that were homozygous for the 1473G allele of Tph2 (1473G) and subjected them and their wild type littermates (1473C) to a battery of behavioral tests. Using reverse-phase high-performance liquid chromatography (HPLC), we measured the amounts of free amino acids in the 5-HT and epinephrine synthetic/metabolic pathways in the frontal cortex, hippocampus, striatum, and midbrain. RESULTS: We failed to detect significant differences between genotypes in depression-like behaviors, anxiety like behaviors, social behaviors, sensorimotor gaiting, or learning and memory, while 1473G mice exhibited a nominally significant impairment in gait analysis, which failed to reach study-wide significance. In the HPLC analysis, there were no significant differences in the amounts of 5-HT, dopamine, norepinephrine, and epinephrine in the frontal cortex, hippocampus, striatum, and midbrain. CONCLUSION: Our findings do not support the idea that congenic C57BL/6J mice carrying the 1473G allele may represent an animal model of mood disorder under normal conditions without stress. PMID- 30472791 TI - Interleukin-4-induced posttranscriptional gene regulation of CCL26 by the RNA binding protein HuR in primary human nasal polyp-derived epithelial cells. AB - BACKGROUND: Much attention on the pathophysiology of nasal polyp (NP) has focused on eosinophils. Interleukin (IL)-4 and eotaxin-3 (C-C motif chemokine ligand 26, or CCL26) levels have been reported to be increased in eosinophilic nasal polyps. The aim of this study was to characterize CCL26 posttranscriptional regulation by the RNA-binding protein HuR in primary human nasal polyp-derived epithelial cells (hNPDECs) challenged with IL-4. METHODS: A prospective, observational study was conducted. Nasal polyp tissues were obtained from eosinophilic (n = 12) and non eosinophilic (n = 10) NP patients, and inferior turbinate (IT) tissues were taken from control subjects (n = 9) and cultured into hNPDECs. Expression of HuR and CCL26 were measured by immunohistochemistry, Western blot analysis, enzyme-linked immunoassay, and real-time polymerase chain reaction (PCR). The nucleocytoplasmic shuttling of HuR in hNPDECs was detected by immunofluorescence. Posttranscriptional regulation of CCL26 by HuR was tested by ribonucleoprotein immunoprecipitation assay (RIP) and dual-luciferase reporter assay. CCL26 mRNA stabilization was measured by quatititative PCR after treatment with actinomycin D. Student's t test and one-way analysis of variance were used. RESULTS: Immunohistochemical data show that both HuR and CCL26 were highly expressed in NP tissues, especially eosinophilic NP tissues (p < 0.05). IL-4 stimulation increased CCL26 mRNA stability, and overexpression and knockdown of HuR affected CCL26 expression. Immunofluorescence data indicate that IL-4 altered the subcellular distribution of HuR. The RIP and dual-luciferase reporter assay results supply strong evidence for HuR binding to CCL26. CONCLUSION: Our results provide strong support for the hypothesis that IL-4-induced expression of CCL26 in hNPDECs relies partly on CCL26 mRNA stabilization mediated by the interaction of HuR with CCL26 3'UTR. PMID- 30472792 TI - Auxiliary partial orthotopic liver transplantation for non-cirrhotic metabolic liver disease: Reigniting interest in an old but new technique. AB - Auxiliary partial orthotopic liver transplantation (APOLT) was initially explored for potentially reversible acute liver failure and noncirrhotic metabolic liver disease (NCMLD)(1, 2). The rationale for APOLT for acute liver failure is native liver regeneration facilitating discontinuation of immunosuppressive therapy(3). This article is protected by copyright. All rights reserved. PMID- 30472793 TI - Managing adverse effects by dose reduction during routine treatment of locally advanced basal cell carcinoma with the hedgehog inhibitor vismodegib: a single center experience. AB - Locally advanced basal cell carcinoma (laBCC) represents an uncommon, difficult to treat form of skin cancer (1,2). The approval of hedgehog inhibitor (HHI) vismodegib in 2012 opened a novel therapeutic option (2-10). "Drug holidays" have been proposed to increase patients' compliance and adherence which is poor due to the high frequency of adverse effects (AE's) of HHI (3-5), however, up to date, the effect of dose reduction during HHI treatment has not been reported. Herein we report the data of a single center's experience in dose adjustment in 13 patients with laBCC treated with vismodegib. This article is protected by copyright. All rights reserved. PMID- 30472794 TI - A Follow-up Survey of Total Intravenous Anesthesia Usage in Children in the U.K. and Ireland. AB - BACKGROUND: Total intravenous anesthesia usage in children remains relatively unpopular in the UK and Ireland. A postal survey by Hill et al in 2008 indicated that only 26% of Consultants used a propofol infusion at least once a month. AIM: Following an increase in teaching and training opportunities in pediatric total intravenous anesthesia in the UK, we repeated the survey amongst Consultant members of Association of Paediatric Anaesthetists of Great Britain and Ireland and Society for Intravenous Anaesthesia, to see if this had affected total intravenous anesthesia usage in children and how practice may have changed. METHODS: We used an anonymous online survey sent to APAGBI and SIVA members. RESULTS: A total of 291 responses were analysed. Total intravenous anesthesia was the default method of anesthesia in 8% of respondents and a further 46% used total intravenous anesthesia at least monthly. Overall total intravenous anesthesia usage had increased in the past year in 53%. The main indications were malignant hyperthermia susceptibility, and postoperative nausea and vomiting. ENT Surgery was the most popular surgical specialty. The main reasons for not using total intravenous anesthesia were that it was too 'fiddly' and lack of confidence in the user. Most respondents used propofol in combination with remifentanil. Over 80% used propofol target-controlled infusion. The potential for propofol related infusion syndrome concerned many, with 74% limiting infusion duration as a result. Bispectral Index was not used routinely by the majority of anesthetists. Even though most anesthetists did not use total intravenous anesthesia routinely, 98% felt they would be confident to anesthetize an MH positive patient using the technique. CONCLUSION: This survey has shown that although total intravenous anesthesia is not the default anesthetic technique for most anesthetists, overall usage in children has more than doubled in the past 10 years, with many happy to use it in a wide variety of patients and procedures. This article is protected by copyright. All rights reserved. PMID- 30472795 TI - Glycoproteomic markers of hepatocellular carcinoma-mass spectrometry based approaches. AB - Hepatocellular carcinoma (HCC) is the third most-common cause of cancer-related death worldwide. Most cases of HCC develop in patients that already have liver cirrhosis and have been recommended for surveillance for an early onset of HCC. Cirrhosis is the final common pathway for several etiologies of liver disease, including hepatitis B and C, alcohol, and increasingly non-alcoholic fatty liver disease. Only 20-30% of patients with HCC are eligible for curative therapy due primarily to inadequate early-detection strategies. Reliable, accurate biomarkers for HCC early detection provide the highest likelihood of curative therapy and survival; however, current early-detection methods that use abdominal ultrasound and serum alpha fetoprotein are inadequate due to poor adherence and limited sensitivity and specificity. There is an urgent need for convenient and highly accurate validated biomarkers for HCC early detection. The theme of this review is the development of new methods to discover glycoprotein-based markers for detection of HCC with mass spectrometry approaches. We outline the non-mass spectrometry based methods that have been used to discover HCC markers including immunoassays, capillary electrophoresis, 2-D gel electrophoresis, and lectin FLISA assays. We describe the development and results of mass spectrometry-based assays for glycan screening based on either MALDI-MS or ESI analysis. These analyses might be based on the glycan content of serum or on glycan screening for target molecules from serum. We describe some of the specific markers that have been developed as a result, including for proteins such as Haptoglobin, Hemopexin, Kininogen, and others. We discuss the potential role for other technologies, including PGC chromatography and ion mobility, to separate isoforms of glycan markers. Analyses of glycopeptides based on new technologies and innovative softwares are described and also their potential role in discovery of markers of HCC. These technologies include new fragmentation methods such as EThcD and stepped HCD, which can identify large numbers of glycopeptide structures from serum. The key role of lectin extraction in various assays for intact glycopeptides or their truncated versions is also described, where various core-fucosylated and hyperfucosylated glycopeptides have been identified as potential markers of HCC. Finally, we describe the role of LC-MRMs or lectin FLISA MRMs as a means to validate these glycoprotein markers from patient samples. These technological advancements in mass spectrometry have the potential to lead to novel biomarkers to improve the early detection of HCC. PMID- 30472796 TI - Patient-reported outcomes for NAFLD/NASH: rational for expanded use. AB - It is estimated that one in four adults around the world has non-alcoholic fatty liver disease (NAFLD), a condition that can lead to non-alcoholic steatohepatitis (NASH), serious liver damage and, ultimately, death. The arrival of new treatment options and prevention strategies for NAFLD/NASH will result in an increasing number of clinical trials targeting this disease. Younossi outlined (1) the increasing importance of including patient-reported outcomes (PROs) in future clinical trials for NAFLD/NASH treatment. We fully agree and wish to underline additional points that deserve consideration when dealing with PROs and NAFLD/NASH. This article is protected by copyright. All rights reserved. PMID- 30472797 TI - An Evaluation of the Quality and Content of Web-based Stoma Information. AB - AIM: Although the internet is commonly the first port of call for medical information it provides unregulated data of variable quality. We aimed to evaluate commonly accessed web-based information on intestinal stomas using validated and novel scoring systems. METHODS: The keywords 'stoma,' 'colostomy,' 'ileostomy' and 'bowel bag' were entered into the most commonly used internet search engines (Google, Bing and Yahoo). The first ten websites from each search were analysed using the validated Journal of the American Medical Association (JAMA) benchmark criteria and DISCERN scoring systems. A novel stoma-specific score was devised and applied. RESULTS: Forty-three unique websites were identified. The majority (49%) were from nonprofit or governmental agencies and 9% were from commercial entities. The mean total DISCERN score for all websites was 42.4+/- 10.2 (maximum possible score=75). The mean JAMA and stoma-specific scores were 2.1+/-1.0 (maximum possible score=4) and 12.9+/-6.1 (maximum possible score=27). The lowest JAMA scores were in the category of attribution with 70% of websites lacking references for the information provided. A total of 88% displayed disclosure/paid advertiser information. Surgery was described in 67%., an image or diagram was provided in 58% and in 72% a stomal therapist/nurse was mentioned. Iinformation on when to seek medical help was provided in 51%. CONCLUSION: Web-based information on stomas is of variable content and quality. Authorship and information sources are often unclear.. Only half provided information on when to seek medical help for complications including high output and dehydration. These findings should be highlighted to patients utilising the internet to obtain information on stomas. This article is protected by copyright. All rights reserved. PMID- 30472798 TI - Combining metabolite profiling with genome-wide association study to reveal response mechanisms of Zea mays seedlings under low-phosphorus conditions. AB - Inorganic phosphorus (Pi) is an essential element in numerous metabolic reactions and signaling pathways, but the molecular details of these pathways remain largely unknown. In this study, metabolite profiles of maize (Zea mays L.) leaves and roots were compared between six low-Pi sensitive lines and six low-Pi tolerant lines under Pi-sufficient and Pi-deficient conditions to identify pathways and genes associated with the low-Pi stress response. Results showed that under Pi deprivation the concentrations of nucleic acids, organic acids and sugars were increased, but the concentrations of phosphorylated metabolites, certain amino acids, lipid metabolites, and nitrogenous compounds were decreased. Secondary metabolites involved in plant immune reactions, including benzoxazinoids and flavonoids, were significantly different under Pi-deficient. Among them, eleven most stable metabolites showed significant differences under low- and normal-Pi conditions based on the coefficient of variation (CV). Isoleucine and alanine were the most stable metabolites for identification of Pi sensitive and Pi-resistant maize inbred lines. Due to the significant correlation between morphological traits and metabolites, five low-Pi responding consensus genes associated with morphological traits and simultaneously involved in metabolic pathways were mined by combining metabolites profiles and GWAS. The consensus genes induced by Pi deficiency in maize seedlings were also validated by RT-qPCR. Moreover, these genes were further validated in recombinant inbred line (RIL) population in which the glucose-6-phosphate-1-epimerase encoding gene mediated yield and correlated traits to phosphorus availability. Together, our results provide a framework for understanding the metabolic processes underlying Pi-deficient and multiple insights into improvement of the Pi-use efficiency in maize. This article is protected by copyright. All rights reserved. PMID- 30472799 TI - Effect of pharmacist intervention on blood conservation therapy in total knee arthroplasty: a retrospective, observational study. AB - BACKGROUND: Total knee arthroplasty (TKA) is associated with blood loss and an increased risk of transfusion. Guidelines for antifibrinolytic drug tranexamic acid (TXA) treatment in TKA patients are available. We evaluated the effects of anticoagulant pharmacist intervention on perioperative blood conservation treatment in TKA patients. METHODS: In a retrospective, observational experimental study, patients admitted for TKA were allocated into the control or pharmacist intervention group. In the intervention phase, multiple interventions of TXA treatment based on guidelines were implemented. The primary end point was blood loss. Other outcomes included postoperative haemoglobin and haematocrit levels, allogeneic blood transfusion, cost savings and safety. RESULTS: A total of 177 patients were included (88 and 89 in the control and intervention group, respectively). In the intervention group, 24.72% orders of TXA dosage, 20.22% orders of drug choice, 26.97% orders of TXA timing, 30.34% orders of TXA administration manner were adjusted. 89 (100%) patients received blood conservation therapy compared with 21 (23.86%) patients in the control group (p < 0.001). Total blood loss was 1133.31 +/- 627.08 ml in the control group compared with 604.34 +/- 459.09 ml in the intervention group (p < 0.001). Postoperative drops in haemoglobin and haematocrit in the control group were greater than in the intervention group (p < 0.001). The rate of allogeneic blood transfusion was 40.91% in the control group compared with 21.35% in the intervention group (p = 0.01). Pharmacist intervention conduced to cost savings resulting from reduced transfusion, but with comparable safety profile. CONCLUSIONS: Anticoagulant pharmacist intervention on blood conservation treatment of TKA patients leads to favourable clinical and economic outcomes. This article is protected by copyright. All rights reserved. PMID- 30472801 TI - Perinatal probiotic intervention prevented allergic disease in a Caesarean delivered subgroup at 13-year follow-up. AB - BACKGROUND: The long-term effects of probiotic intervention for primary prevention of allergic diseases are not well known. We previously reported less eczema until 10 years in our probiotic intervention trial. OBJECTIVE: To investigate the effect of early probiotic intervention on the prevalence of allergic diseases up to 13 years of age. METHODS: Pregnant women (n=1223) carrying a child at a high risk of allergy (at least one parent with allergic disease) were randomised to receive a mixture of probiotics (Lactobacillus rhamnosus GG and LC705, Bifidobacterium breve Bb99 and Propionibacterium freudenreichii) or placebo in a double-blind manner from 36 weeks of gestation until birth. Their infants received the same product for the first six months (registration number NCT00298337). At 13-year follow-up the participants were requested to return a questionnaire and to provide a blood sample. RESULTS: A questionnaire was returned by 642 participants (63.1% of intention-to-treat infants) and 459 provided a blood sample. In the whole cohort there were no statistically significant differences in doctor-diagnosed allergic disease (55.2% and 59.0%, probiotic and placebo group, respectively) or allergic disease (47.9% and 51.6%) based on the ISAAC questionnaire data. Inhalant-specific IgE sensitisation (>0.7 kU/L) was 59.3% in the probiotic group and 49.8% in the placebo group (p=0.040). In a post hoc analysis made in Caesarean-delivered subgroup allergy was reported in 41.5% of the probiotic group and 67.9% of the placebo group (p=0.006), and eczema in 18.9% and 37.5% respectively (p=0.031). In the whole cohort 8.5% of the probiotic group had suffered from wheezing attacks during the previous 12 months vs. 14.7% in the placebo group (p=0.013). There was no statistically significant differences discovered between the characteristics of the participating group and the dropout-group. CONCLUSIONS: Probiotic intervention protected Caesarean-delivered subgroup from allergic disease and eczema, but not the total cohort. This article is protected by copyright. All rights reserved. PMID- 30472800 TI - Determination of Normal Breast and Areolar Skin Elasticity Using Shear Wave Elastography. AB - OBJECTIVES: In this study, we aimed to determine reference values for normal breast and areolar skin elasticity using shear wave elastography. METHODS: The right breasts of 200 female participants were evaluated. The age, weight, body mass index, menopausal status, and parity number of all participants were noted. The elasticity values and thickness of the areolar skin and 4 quadrants of the breast skin of all participants were measured. To assess the reproducibility of shear wave elastography, a randomly selected subgroup of 35 participants was reevaluated by a second observer. RESULTS: The mean age of the participants +/- SD was 48.79 +/- 10.74 years (range, 18-79 years). The mean elasticity measurements for the superior, inferior, lateral, and medial regions of the breast and areolar skin were 33.54, 29.84, 30.16, 29.20, and 31.35 kPa, respectively. The mean of the 4-quadrant measurements of breast skin elasticity was 30.68 +/- 9.11 kPa. Age had a moderate negative correlation with breast skin elasticity (r = -0.353; P < .001) and a weak negative correlation with areolar skin elasticity (r = -0.237; P = .001). The parity number had weak negative correlations with breast (r = -0.150; P = .034) and areolar (r = -0.207; P < .001) skin elasticity. The interobserver agreement varied from good to excellent (intraclass correlation coefficients, 0.67-0.91) for the breast and areolar skin elasticity measurements. CONCLUSIONS: Shear wave elastography is a reproducible imaging modality for evaluations of breast and areolar skin elasticity, and our results may provide important pilot data for evaluations of clinical entities that affect the breast and areolar skin structures. PMID- 30472802 TI - Infant Growth Faltering Linked to Subclinical Mastitis, Maternal Fecal-Oral Contamination and Breastfeeding Practices. AB - Infant growth faltering occurs in breastfed infants < 6 months of age. The possibility that maternal health status contributes to this growth faltering is underexplored. We investigated whether 1) subclinical mastitis (SCM), an asymptomatic inflammation of the breast, 2) maternal intestinal nematode and protozoan infections, indicators of fecal-oral contamination or 3) poor breastfeeding practices increased the odds of stunting (LAZ < -2SD), underweight (WAZ < -2SD) or low head circumference (HCAZ < -2SD) in breastfed infants in rural indigenous communities in Guatemala. Mother-infant dyads (n = 105) were subdivided into those with and without SCM (milk Na:K ratio > 0.6). Maternal and infant anthropometry were measured at the time of breast milk collection. Maternal stool samples were examined for the presence of intestinal nematodes and protozoa. Questionnaires were used to characterize breastfeeding practices (exclusivity, frequency) and support, hygiene (latrine use, household faucet) and infant diarrhea. SCM occurred in 14% of women and was associated with increased odds of infant stunting (OR=4.3; CI 1.1, 15.8), underweight (OR=9.2; CI 1.8, 48.0) and low head circumference (OR=15.9; CI 2.6, 96.9). Maternal pathogenic protozoa and nematodes were uncommon (<4%), but non-pathogenic protozoa were common (e.g. Entamoeba coli (39%)). Entamoeba coli increased the likelihood (OR=3.3; CI 1.02, 10.6) of low head circumference whereas higher breastfeeding frequency lowered its odds (OR=0.74, CI 0.56-0.97). Prevention of SCM may improve early infant growth, but public health measures that increase breastfeeding frequency and reduce fecal-oral contamination may be required to minimize low head circumference. PMID- 30472803 TI - Correlation between disease severity and quality of life in patients with epidermolysis bullosa. AB - There is an increased interest of medical staff to have a more objective evidence of the severity of clinical picture of the patient with epidermolysis bullosa (EB), but also about the patient's quality of life. The goal of these studies is to develop a personalized treatment, based on the patients' needs. The aims of our study were to develop a validated and reliable quality of life questionnaire (QOLEB) in Romania, to assess the health-related quality of life (HRQoL) in Romanian EB patients, and to perform an objective evaluation of the clinical features of patients with EB. This study was observational, analytical, prospective, transversal, cohort type. This article is protected by copyright. All rights reserved. PMID- 30472804 TI - Frontal fibrosing alopecia: a case series of 65 patients seen in a single Italian center. AB - BACKGROUND: Frontal fibrosing alopecia (FFA) is increasing in prevalence worldwide and several series from different countries have been published, in order to detect possible causes of the disease outbreak. OBJECTIVE: To analyze the epidemiological, clinical and trichoscopic features of FFA seen in an Italian Dermatology Unit. METHODS: Clinical, trichoscopy, histopathology and medical details of all patients were compared with literature and general population data. RESULTS: From 2005 to 2017 we diagnosed FFA in 65 Caucasian females, with the number of diagnoses per year progressively rising. Premenopausal onset was detected in 21%. Frontal hair line recession was associated with parietal involvement in 80% of cases, occipital in 12.3% and eyebrows alopecia in 86.1%. In 6 cases eyebrow alopecia preceded hair loss. Non-inflammatory facial papules were detected in 1/3 of the patients. Itching was reported by 2/3 of the patients and was indicative of disease progression. Trichoscopy showed empty follicles/yellow dots, absence of follicular ostia, mild follicular hyperkeratosis, perifollicular erythema and "lonely hair". Scalp lichen plano pilaris was seen in 15 patients, female pattern hair loss in 22. Therapy included short-term treatment with systemic or intralesional corticosteroids followed by therapy with 5alpha-reductase inhibitors of hydroxychloroquine and topical drugs. Arrest of FFA progression was seen in 75% of the patients, while 16 experienced worsening of the hairline despite therapy. CONCLUSIONS: FFA not rarely starts before menopause, loss of the eyebrows can be the first sign of the disease, about 50% of the patients have other autoimmune conditions, FFA severity is not related to its duration, itching, follicular hyperkeratosis and erythema at trichoscopy are signs of disease progression, 25% of the patients show progression of hairline recession despite therapy. This article is protected by copyright. All rights reserved. PMID- 30472805 TI - Physico-chemical stability of Plasma-Lyte 148 (r) and Plasma-Lyte 148 (r) + 5% Glucose with eight common intravenous medications. AB - BACKGROUND: Plasma-Lyte 148 (r) is a balanced, crystalloid intravenous (IV) fluid which is both calcium-free and isotonic. It prevents the hyperchloraemic metabolic acidosis and iatrogenic hyponatraemia seen with use of 0.9% sodium chloride and hypotonic solutions respectively. However, data on compatibility with commonly used drugs is lacking. AIM: To investigate the stability of Plasma Lyte 148 (r) and Plasma-Lyte 148 (r) + 5% Glucose with eight commonly used therapeutic agents when compared with 5% Glucose and 0.9% Sodium Chloride as diluents. We aimed to provide vital data which may facilitate the introduction of what appears to be a safer and more economic fluid. METHOD: Plasma-Lyte 148 (r) and Plasma-Lyte 148 (r) + 5% Glucose were mixed with morphine, midazolam, fentanyl, ketamine, clonidine, aminophylline, salbutamol and furosemide at set concentrations. Comparisons were made to 0.9% Sodium Chloride and 5% Glucose fluid controls. Six repeats of each IV fluid and drug admixture were analysed through high performance liquid chromatography (HPLC), at three time points: 0, 2 and 24 hours. A concentration change of < 5% was defined as chemically stable. Physical stability was assessed by observation of precipitate formation or colour change. pH changes were measured using a Fisherbrand Hydrus 300 pH meter. RESULTS: Relative to starting concentration, all drugs except midazolam were stable to +/- 3%. All examined therapeutic agents were chemically stable at 2 and 24 hours relative to control solutions. No precipitate formed in any of the samples. All Plasma-Lyte 148 (r) and Plasma-Lyte 148 (r) + 5% Glucose drug admixtures remained in a safe, peripheral administration pH range of 5-9 and were closer to the pH of blood than standard fluid-drug admixtures. CONCLUSION: Morphine, fentanyl, ketamine, salbutamol, aminophylline, and clonidine are stable for 24 hours when mixed with Plasma-Lyte 148 (r) and Plasma-Lyte 148 (r) +5% Glucose for administration at concentrations equivalent to those found at a typical Y site with maintenance fluid. Furosemide is stable at lower concentrations than those seen at a Y-site, but midazolam displayed instability. This article is protected by copyright. All rights reserved. PMID- 30472806 TI - Therapeutic effects of lentinan on inflammatory bowel disease and colitis associated cancer. AB - In this study, we investigated the therapeutic potential of lentinan in mouse models of inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Lentinan decreased the disease activity index and macroscopic and microscopic colon tissue damage in dextran sulphate sodium (DSS)-induced or TNBS-induced models of colitis. High-dose lentinan was more effective than salicylazosulfapyridine in the mouse models of colitis. Lentinan decreased the number of tumours, inflammatory cell infiltration, atypical hyperplasia and nuclear atypia in azoxymethane/DSS-induced CAC model. It also decreased the expression of pro-inflammatory cytokines, such as IL-13 and CD30L, in IBD and CAC model mice possibly by inhibiting Toll-like receptor 4 (TLR4)/NF-kappaB signalling and the expression of colon cancer markers, such as carcinoembryonic antigen, cytokeratin 8, CK18 and p53, in CAC model mice. In addition, lentinan restored the intestinal bacterial microbiotal community structure in IBD model mice. Thus, it shows therapeutic potential in IBD and CAC model mice possibly by inhibiting TLR4/NF-kappaB signalling-mediated inflammatory responses and disruption of the intestinal microbiotal structure. PMID- 30472807 TI - Preoperative parafunctional or dysfunctional oral habits are associated with the temporomandibular disorders after orthognathic surgery An observational cohort study. AB - BACKGROUND: Temporomandibular disorders (TMDs) are frequent and disabling, and hence, preventing them is an important health issue. Combining orthodontic and surgical treatments for malocclusions has been shown to affect temporomandibular joint (TMJ) health. However, publications regarding the risk factors that predict negative TMJ outcomes after orthognathic surgery are scarce. OBJECTIVE: Present prospective cohort study was conducted to identify an association between preoperative dysfunctional/parafunctional oral habits and presence of TMD symptoms after orthognathic surgery. METHOD: We included 237 patients undergoing orthodontics and surgical treatment for malocclusions associated with dento facial deformities within the Department of Oral and Maxillofacial Surgery of the University of Lille. Their parafunctional and dysfunctional oral habits were recorded through clinical examination along with presence of TMD symptoms before and after the surgery. According to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) classification, the TMD symptoms studied were myalgia, arthralgia, disc displacement with or without reduction. RESULTS: Multivariate analysis revealed significant associations among bruxism (odds ratio [OR] 3.17 [1.066; 9.432]), lingual interposition (OR 4.241 [1.351; 13.313]), as well as primary swallowing (OR 3.54 [1.225; 10.234]) and presence of postoperative symptoms of myalgia. Moreover, a significant association was observed between presence of any dysfunctional oral habit and postoperative disc displacement with reduction (OR 4.611 [1.249; 17.021]). CONCLUSION: Bruxism and dysfunctional oral habits were shown to be risk factors for presence of TMD symptoms also after combined orthodontic and surgical treatment. Treating such habits before orthognathic surgery should help prevent TMD. This article is protected by copyright. All rights reserved. PMID- 30472808 TI - Effect of proton pump inhibitors on the risk and prognosis of infections in patients with cirrhosis and ascites. AB - BACKGROUND & AIMS: Many patients with cirrhosis use proton pump inhibitors (PPI). We aimed to determine their effects on the risk and prognosis of infections in patients with cirrhosis and ascites. METHODS: We used data from three 1-year trials of satavaptan treatment of ascites (N=1198) to compare incidence and 90 day mortality of first-time infections between users and nonusers of PPI. With standard and marginal structural Cox models we adjusted for differences in gender, age, cirrhosis etiology, MELD score, serum albumin, lactulose use, severity of ascites, and history of spontaneous bacterial peritonitis or variceal bleeding. RESULTS: During the follow-up 446 patients had an infection. At inclusion, 524 patients (44%) used PPI, and 645 (54%) used them at some point during the follow-up. PPI use increased the rate of infections overall (adjusted hazard ratio = 1.43, 95% CI 1.18-1.74), and it also increased the rate of all specific types of infections except upper respiratory tract infections of presumably viral origin. The estimated cumulative risk of infections was 36.4% for PPI users vs. 25.1% for nonusers at 6 months (relative risk = 1.45, 95% CI 1.22-1.73), and 45.2% vs. 37.7% at 1 year (relative risk = 1.20, 95% 0.97-1.40). Use of PPI did not affect mortality during the 90 days following infection (adjusted hazard ratio = 0.83, 95% CI 0.53-1.31). CONCLUSIONS: Approximately half of patients with cirrhosis and ascites use PPI. This use increases their risk of bacterial infections, but does not affect their prognosis after an infection occurs. This article is protected by copyright. All rights reserved. PMID- 30472809 TI - Bisphosphonate use and risk of renal cell carcinoma: a population-based case control study. AB - The purpose of this study was to evaluate the association between the use of bisphosphonates and the risk of developing renal cell carcinoma (RCC). We conducted a case-control study in Denmark, using data linked from population based health and administrative registries. We identified all cases of RCC from 1996 to 2013 and sampled population controls in a 10:1 ratio from the underlying population free of RCC, while matching on sex, birth year and calendar time. Bisphosphonate use before RCC diagnosis, excluding the year leading up to the diagnosis, was measured using outpatient prescription dispensations. We used conditional logistic regression to compute crude and adjusted odds ratios (ORs) comparing ever vs. never bisphosphonate use in doses indicated for treatment of osteoporosis, overall and stratified by sex, with the OR estimating the incidence rate ratio. We also examined the effects by cumulative dose and specific agent. There were 2748 RCC cases and 27,480 controls. The adjusted ORs for ever vs. never bisphosphonate use were 1.07 (95% confidence interval: 0.94-1.22) overall; 1.15 (1.00-1.32) for women; and 0.78 (0.54-1.12) for men. Smoking could not be directly controlled for in the analysis. We found a weak association between use of oral bisphosphonates and risk of renal cell carcinoma in females. The observed association could be due to confounding by cigarette smoking, and future studies are required to assess this association further. This article is protected by copyright. All rights reserved. PMID- 30472810 TI - Sips for little lips- letter to the editor. AB - We write to you in relation to your recent important publication of the consensus statement on clear fluid fasting for elective paediatric general anaesthesia, that emphasises improving fasting times from two hours to one hour prior to surgery[1] . In order to determine the volume of clear fluid to be given, one of the practical interventions advised by the author was to use an age-based banded calculator. This eliminates the need to weigh the child prior to fluid administration. This article is protected by copyright. All rights reserved. PMID- 30472811 TI - Assessment of scatter radiation dose and absorbed doses in eye lens and thyroid gland during digital breast tomosynthesis. AB - Digital breast tomosynthesis (DBT) is an alternative tool for breast cancer screening; however, the magnitude of peripheral organs dose is not well known. This study aimed to measure scattered dose and estimate organ dose during mammography under conventional (CM) and Tomo (TM) modes in a specific DBT system. Optically stimulated luminescence dosimeters (OSLDs), whose responses were corrected using a parallel-plate ionization chamber, were pasted on the surface of custom-made polymethyl methacrylate (PMMA) and RANDO phantoms to measure entrance surface air kerma (ESAK). ESAK measurements were also acquired with a 4.5-cm thick breast phantom for a standard mammogram. Organ dose conversion factors (CFD ) were determined as ratio of air kerma at a specific depth to that at the surface for the PMMA phantom and multiplied by the ratio of mass energy absorption coefficients of tissue to air. Normalized eye lens and thyroid gland doses were calculated using the RANDO phantom by multiplying CFD and ESAK values. Maximum variability in OSLD response to scatter radiation from the DBT system was 33% in the W/Rh spectrum and variations in scattered dose distribution were observed between CM and TM. The CFD values for eye lens and thyroid gland ranged between 0.58 to 0.66 and 0.29 to 0.33, respectively. Mean organ doses for two view unilateral imaging were 0.24 (CM) and 0.18 (TM) MUGy/mAs for the eye lens and 0.24 (CM) and 0.25 (TM) MUGy/mAs for the thyroid gland. Higher organ doses were observed during TM compared to CM as the automatic exposure control (AEC) system resulted in greater total mAs values in TM. PMID- 30472812 TI - Pediatric Asthma Prevalence: The First National Population-based Survey in Iran. AB - BACKGROUND: The actual prevalence of pediatric asthma as a worldwide chronic disease has been surveyed in developed countries. However, no sufficient survey has been conducted in most of the eastern developing countries. Herein, we took measures to evaluate the prevalence of pediatric asthma in Iran. METHODS: In this national cross-sectional study, the prevalence of asthma symptoms was estimated throughout the country; using randomized multistage stratified cluster sampling method in 16410 and 16850 individuals aged 6- to 7- and 13- to 14-year-olds, respectively. A validated questionnaire including core questions of the International Study of Asthma and Allergies in Childhood (ISAAC) was applied between November 2015 and February 2016. RESULTS: The total prevalence of asthma was 10.9% (n=3624) (95% confidence interval [CI]: 10.6% - 11.2%) which was significantly higher among 13- to 14-year-olds compared to younger age group (12.4% vs. 9.4%, p<0.001), males versus females (12.1% vs. 9.8%, p<0.001), and residents of urban compared to rural areas (p=0.003). The prevalence of severe asthma was 3.9%; being significantly more prevalent in higher age groups and male individuals (p<0.001). A significant relationship was found between asthma and passive smoking in both 6- to 7- and 13- to 14-year-olds (p?0.001). CONCLUSIONS: The prevalence of asthma and severe asthma in pediatric population of Iran was similar to other developing countries. It is recommended to pay special attention to urban regions, male individuals, and higher age groups for better controlling of asthma. Nevertheless, further national surveys are necessary to determine the trend of pediatric asthma in Iran. This article is protected by copyright. All rights reserved. PMID- 30472813 TI - Validation of the international Guide for Monitoring Child Development demonstrates good sensitivity and specificity in four diverse countries. AB - AIM: It is of critical importance to have internationally constructed tools to address early childhood development. The aim of this second phase of a two phase study was to examine the GMCD sensitivity and specificity of the Guide for Monitoring Child Development (GMCD) in identifying developmental delay in four diverse countries. METHODS: The first phase of this 2011-2015 back-to-back study included 4,949 children up to 42 months of age from primary healthcare centres in Argentina, India, South Africa and Turkey. Distribution curves were generated to show the ages when the children attained GMCD milestones and those that could be used across sexes and countries were placed in age ranges corresponding to the 85th and 97th percentile point estimates. Phase two examined a separately recruited sample of children in those countries to determine sensitivity and specificity of the GMCD. RESULTS: The validation phase of the 85 milestones in the GMCD identified delayed development in 30% of the 1,731 children in the four countries. The sensitivity and specificity ranged from 0.71-0.94 and 0.69-0.82, respectively, for the total sample and the different age groups. CONCLUSION: The GMCD standardised in four diverse countries has appropriate accuracy for identification of children with developmental delay. This article is protected by copyright. All rights reserved. PMID- 30472814 TI - Bacterioruberin extracts from a genetically modified hyperpigmented Haloferax volcanii strain: Antioxidant activity and bioactive properties on sperm cells. AB - AIMS: To examine the antioxidant activity of Bacterioruberin (Bctr)-rich extracts isolated from a hyperpigmented-genetically modified Haloferax volcanii strain (HVLON3) and to investigate the effect on cold-sensitive ram sperm cells. METHODS AND RESULTS: The strain HVLON3 produces higher Bctr amounts than most haloarchaea (220 +/- 13 mg/g DW). HVLON3-Bctr extract has higher antioxidant activity than beta-carotene (3-fold) as evaluated using 2,2 diphenyl-1-picrylhydrazyl combined with Electron Paramagnetic Resonance analysis (EC50 4.5 x 10-5 mol l-1 vs. 13.9 x 10-5 mol l-1 , respectively). Different concentrations of HVLON3-Bctr extracts were assayed on ram sperm after freezing/thawing and physiologically relevant parameters were examined. Extracts containing 7 and 20 MUmol l-1 Bctr significantly improved cell viability (p<0.0001), total and progressive motility (p<0.0001) and sperm velocities (p=0.0172 for curvilinear velocity VCL, p=0.0268 for average path velocity VAP and p=0.0181 for straight-line velocity VSL) and did not affect other parameters evaluated. CONCLUSIONS: HVLON3 is an excellent source of natural microbial C50 carotenoids with applicability in Biotechnology, Biomedical and Veterinary fields. HVLON3 Bctr-extract improves the quality of cryopreserved ram sperm cells and could be applied to increase insemination yields. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides insight on the bioactive properties of a bioproduct derived from haloarchaea (carotenoids) which are so far underexploited. This article is protected by copyright. All rights reserved. PMID- 30472815 TI - Primary Malignant Melanoma of the Breast: A Report of Two Cases. AB - Primary malignant melanoma of the breast (PMMB) is a rare tumor with only a few case reports available in the literature. We report two cases of PMMB, one with tumor derived from breast parenchyma and the other from breast skin. The first case consisted of atypical epithelioid cells without overt melanocytic differentiation. The tumor cells showed diffuse positivity for S100 protein, tyrosinase, and BRAF (V600E). However, the tumor cells were negative for cytokeratin, epithelial membrane antigen, and HMB-45. The second case showed atypical melanocytic proliferation with heavy melanin pigmentation. The tumor cells were positive for S100 protein, HMB-45, tyrosinase, and BRAF (V600E). These two cases represent two distinct presentations of PMMB in terms of skin involvement, melanin pigmentation, and HMB-45 positivity. Although PMMB is very rare, these cases show that it should be considered in malignant epithelioid neoplasms in the breast parenchyma. PMID- 30472816 TI - Prognostic Role of S100A8 and S100A9 Protein Expressions in Non-small Cell Carcinoma of the Lung. AB - Background: S100A8 and S100A9 have been gaining recognition for modulating tumor growth and metastasis. This study aimed at evaluating the clinical significance of S100A8 and S100A9 in non-small cell lung cancer (NSCLC). Materials and Methods: We analyzed the relationship between S100A8 and S100A9 expressions, clinicopathological characteristics, and prognostic significance in tumor cells and peritumoral inflammatory cells. Results: The positive staining in tumor cells for S100A8 was significantly increased in male (p < .001), smoker (p = .034), other surgical method (p = .024), squamous cell carcinoma (SQCC) (p < .001) and higher TNM stage (p = .022) compared to female, non-smoker, lobectomy, adenocarcinoma (ADC) and lower stage. The proportion of stained tumor cells for S100A8 was related with histologic type (p < .001) and patient sex (p < .027). The proportion of stained inflammatory cells for S100A8 showed correlation with patient age (p = .022), whereas the proportion of stained inflammatory cells for S100A9 showed relation with patient sex (p < .001) and smoking history (p = .031). Moreover, the positive staining in tumor cells, more than 50% stained in tumor cells and less than 30% stained in inflammatory cells for S100A8 and S100A9 suggested a tendency to increase survivability with significantly favorable prognosis in more than 50% stained in tumor cells for S100A9 (hazard ratio, 0.483; 95% confidence interval, 0.265-0.880; p = 0.017) in SQCC, and an opposite trend of survival in ADC. Conclusion: S100A8 and S100A9 expressions might be potential prognostic markers in patients suffering from NSCLC. PMID- 30472817 TI - Adrenal Cortical Neoplasm with Uncertain Malignant Potential Arising in the Heterotopic Adrenal Cortex in the Liver of a Patient with Beckwith-Wiedemann Syndrome: A Case Report. AB - Patients with Beckwith-Wiedemann syndrome (BWS) are predisposed to developing embryonal tumors, with hepatoblastoma being the most common type. Our patient showed hemihypertrophy, macroglossia, and paternal uniparental disomy in chromosome 11 and was diagnosed with BWS. When the patient was nine months old, a 2.5*1.5 cm oval hypoechoic exophytic mass was detected in the inferior tip of his right liver. Preoperative imaging identified it as hepatoblastoma; however, histologic, immunohistochemistry and electron microscopic findings were compatible with adrenal cortical neoplasm with uncertain malignant potential. The origin of the adrenal tissue seemed to be heterotopic. Here, we describe for the first time an adrenal cortical neoplasm with uncertain malignant potential arising in the heterotopic adrenal cortex located in the liver of a patient with BWS. PMID- 30472818 TI - Endoscopic Ultrasound-Guided Biliary Drainage for Unresectable Hilar Malignant Biliary Obstruction. AB - Endoscopic transpapillary biliary drainage is the current standard of care for unresectable hilar malignant biliary obstruction (MBO) and bilateral metal stent placement is shown to have longer patency. However, technical and clinical failure is possible and percutaneous transhepatic biliary drainage (PTBD) is sometimes necessary. Endoscopic ultrasound-guided biliary drainage (EUS-BD) is increasingly being reported as an alternative rescue procedure to PTBD. EUS-BD has a potential advantage of not traversing the biliary stricture and internal drainage can be completed in a single session. Some approaches to bilateral biliary drainage for hilar MBO under EUS-guidance include a bridging method, hepaticoduodenostomy, and a combination of EUS-BD and transpapillary biliary drainage. The aim of this review is to summarize data on EUS-BD for hilar MBO and to clarify its advantages over the conventional approaches such as endoscopic transpapillary biliary drainage and PTBD. PMID- 30472819 TI - Therapeutic Feasibility of Full Endoscopic Decompression in One- to Three-Level Lumbar Canal Stenosis via a Single Skin Port Using a New Endoscopic System, Percutaneous Stenoscopic Lumbar Decompression. AB - Study Design: This retrospective study involved 450 consecutive cases of degenerative lumbar stenosis treated with percutaneous stenoscopic lumbar decompression (PSLD). Purpose: We determined the feasibility of PSLD for lumbar stenosis at single and multiple levels (minimum 1-year follow-up) by image analysis to observe postoperative widening of the vertebral canal in the area. Overview of Literature: The decision not to perform an endoscopic decompression might be due to the surgeon being uncomfortable with conventional microscopic decompression or unfamiliar with endoscopic techniques or the unavailability of relevant surgical tools to completely decompress the spinal stenosis. Methods: The decompressed canal was compared between preoperative controls and postoperative treated cases. Data on operative results, including length of stay, operative time, and surgical complications, were analyzed. Patients were assessed clinically on the basis of the Visual Analog Scale (VAS) score for the back and legs and using the Oswestry Disability Index (ODI). Results: Postoperative magnetic resonance imaging revealed that PSLD increased the canal cross-sectional area by 52.0% compared with the preoperative area at the index segment (p<0.001) and demonstrated minimal damage to the normal soft tissues including muscles and the extent of removed normal bony tissues. Mean improvements in VAS score and ODI were 4.0 (p<0.001) and 40% (p<0.001), respectively. Conclusions: PSLD could be an alternative to microscopic or microendoscopic decompression with various advantages in the surgical management of lumbar stenosis. PMID- 30472820 TI - Stand-Alone Cervical Cages in 2-Level Anterior Interbody Fusion in Cervical Spondylotic Myelopathy: Results from a Minimum 2-Year Follow-up. AB - Study Design: A retrospective review of patients who underwent 2-level anterior cervical discectomy and fusion (ACDF) with standalone polyetheretherketone (PEEK) cages for cervical spondylotic myelopathy (CSM). Purpose: To evaluate the efficacy of stand-alone PEEK cage in 2-level cervical interbody fusion for CSM. Overview of Literature: ACDF is a standard surgical procedure to treat degenerative disc disease. However, the use of additional anterior plating for 2 level ACDF remains controversial. Methods: We reviewed outcomes of patients who underwent 2-level ACDF with stand-alone PEEK cages for CSM over a 7-year period (2007-2015) in a regional hospital. Japanese Orthopaedic Association (JOA) score, fusion rate, subsidence rate, cage migration, and cervical alignment by the C2-7 angle as well as the local segmental angle (LSA) of the cervical spine were assessed. Results: In total, 31 patients (mean age, 59 years; range, 36-87 years) underwent 2-level ACDF with a cage-only construct procedure between 2007 and 2015. The minimum follow-up was 24 months; mean follow-up was 51 months. C3-5 fusion was performed in 45%, C4-6 fusion in 32%, and C5-7 fusion in 23%. Mean JOA score improved from 10.1+/-2.2 to 13.9+/-2.1 (p<0.01) at the 24-month follow-up. Fusion was achieved in all patients. Subsidence occurred in 22.5% of the cages but was not associated with differences in JOA scores, age, sex, or levels fused. Lordosis of the C2-7 angle and LSA increased after surgery, which were maintained for up to 1 year but subsequently disappeared after 2 years, yet the difference was not statistically significant. No cage migration was noted; two patients developed adjacent segment disease requiring posterior laminoplasty 3 years after ACDF. Conclusions: The use of a stand-alone PEEK cage in a 2-level cervical interbody fusion achieves satisfactory improvements in both clinical outcomes and fusion. PMID- 30472821 TI - Comparison of Cortical Ring Allograft and Plate Fixation with Autologous Iliac Bone Graft for Anterior Cervical Discectomy and Fusion. AB - Study Design: A retrospective cohort study. Purpose: To compare the clinical and radiological outcomes of patients who underwent anterior cervical discectomy and fusion (ACDF) supplemented with plate fixation using allograft with those who underwent ACDF using tricortical iliac autograft. Overview of Literature: As plate fixation is becoming popular, it is reported that ACDF using allograft may have similar outcomes compared with ACDF using autograft. Methods: Forty-one patients who underwent ACDF supplemented with plate fixation were included in this study. We evaluated 24 patients who used cortical ring allograft filled with demineralized bone matrix (DBM) (group A) and 17 patients who used tricortical iliac autograft (group B). In radiological evaluations, fusion rate, subsidence of grafted material, cervical lordosis, fused segmental lordosis, and radiological adjacent segment degeneration (ASD) were observed and analyzed with preoperative and postoperative plain radiographs. Clinical outcomes were evaluated using the Neck Disability Index score, Odom criteria, and Visual Analog Scale score of neck and upper extremity pain. Radiological union was determined by dynamic radiographs using cutoff values of 1 mm of interspinous motion as the indication of pseudarthrosis. Results: There was no significant difference in the fusion rate, graft subsidence, cervical lordosis, fused segmental lordosis, and ASD incidence between the groups. Operative time was shorter in group A (136 min) than in group B (141 min), but it was not significant (p>0.05). Blood loss was greater in group B (325 mL) than in group A (210 mL, p=0.013). There was no difference in the clinical outcomes before and after surgery. Conclusions: In ACDF with plate fixation, cortical ring allograft filled with DBM group showed similar radiological and clinical outcomes compared with those of the autograft group. If the metal plate is reinforced, using cortical ring allograft could be a viable alternative to autograft. PMID- 30472822 TI - Does the Surgical Timing and Decompression Alone or Fusion Surgery in Lumbar Stenosis Influence Outcome in Cauda Equina Syndrome? AB - Study Design: A retrospective comparative analysis of 64 patients with cauda equina syndrome (CES), who underwent either decompression alone (NF) or fusion (F) surgery. Purpose: We compared the outcomes and timing effects. Overview of Literature: CES can cause loss of autonomic control of vesicular function and lower limb neurological deficits. Prompt diagnosis and emergency surgery markedly improve outcome. Although decompression only is a mainstream technique, there is guarded recovery of vesicular dysfunction. Decompression ventrally in a narrow window requires manipulation of neural tissue in an already jeopardised critical canal and may accentuate irreversible damages. In F surgery, the adequate exposure leads to a lower neural manipulation. Methods: Until January 2008, we treated CES with decompression (laminectomy and/or discectomy). However, from that month forward, all our single-level CES patients have received a fusion operation. In this study, characteristic categorical variables and outcomes were analysed. Results: In a retrospective analysis of 64 patients, NF (n=37) and F (n=27) who received treatment, we found that both groups improved significantly on follow-up in all objective parameters. Although, the comparison of clinical and functional outcome data between the two groups was statistically insignificant, the average value of objective outcome such as vesicular function, low back pain (LBP), and complications was better for patients in F group compared with NF group. However, the patient satisfaction for the F group was also lower, in view of their residual symptoms and disabilities. Contrary to common perceptions, we found that the timing of surgery does not influence the recovery rate for either approach. Conclusions: Although both the techniques appear to be equally effective, the fusion approach overall showed a definite edge over non-fusion, with respect to reduced incidence of iatrogenic dural tears, LBP, and overall outcome, even despite the lower patient satisfaction. PMID- 30472823 TI - APSS-ASJ Best Clinical Research Award: Is There a Difference between Patients' and Parents' Perception of Physical Appearance in Adolescent Idiopathic Scoliosis? AB - Study Design: Prospective study. Purpose: To compare patients' and parents' perceptions of physical attributes (PAs) of adolescent idiopathic scoliosis (AIS) patients and to report any correlations between their perceptions and Scoliosis Research Society-22r (SRS-22r) scores. Overview of Literature: Few studies have looked into the differences between patients' and parents' perceptions of their appearance. Methods: AIS patient-parent pairs (n=170) were recruited. The patients' and parents' perceptions of six PAs were evaluated: waist asymmetry (WA), rib hump (RH), shoulder asymmetry (SA), neck tilt, breast asymmetry (BrA), and chest prominence. These PAs were ranked, and an aggregate PA (Agg-PA) score was derived from a score assigned to the attribute (6 for the most important PA and 1 for the least important). The patients also completed the SRS-22r questionnaire. Results: Ninety-nine patients (58.2%) and 71 patients (41.8%) had thoracic and lumbar major curves, respectively. WA was ranked first by 54 patients (31.8%) and 50 parents (29.4%), whereas RH was ranked first by 50 patients (29.4%) and 38 parents (22.4%). The overall Agg-PA scores were similar for patients and parents (p>0.05). However, for thoracic major curves (TMCs) >40 degrees , a significant difference was noted between the Agg-PA scores of patients and parents for SA (3.5+/-1.6 vs. 4.2+/-1.6, p=0.041) and BrA (3.0+/-1.6 vs. 2.2+/-1.3, p=0.006). For TMCs <40 degrees , a significant difference was found between the Agg-PA scores of patients and parents for WA (3.7+/-1.6 vs. 4.4+/-1.5, p=0.050). BrA was negatively correlated with total SRS-22r score. Conclusions: There were no significant differences between patients and parents in their ranking of the most important PAs. For TMCs >40 degrees , there were significant differences in the Agg-PA for SA and BrA. Pa!tients were more concerned about BrA and parents were more concerned about SA. Patients' perception of the six PAs had weak correlation with SRS-22r scores. PMID- 30472824 TI - Segmental Spinal Dysgenesis-"Redefined". AB - Study Design: Retrospective single institutional observational study. Purpose: Segmental spinal dysgenesis (SSD), a complex spinal dysraphic state caused by notochord malformation disorders, is named after its morphological presentation where a spine segment is dysgenetic, malformed or absent. This study's objective was to examine and reassess SSD imaging findings and correlate them with an embryological explanation. Overview of Literature: Scott and his colleagues defined SSD as segmental agenesis or dysgenesis of the lumbar or thoracolumbar vertebrae and underlying spinal cord. Tortori-Donati and his colleagues defined it as a morphologic continuum ranging from hypoplasia to an absent spinal cord segment. Methods: Fifteen children, whose imaging findings and clinical features were consistent with SSD, were included in the study. Magnetic resonance imaging (MRI) was performed per institutional spine protocol. Results: Five children (33.3%) presented with a high-ending bulbous cord with no caudal segment, six (40%) presented with a dorsal or lumbar segmental dysgenetic cord with a low lying, bulky caudal cord but without significant spinal canal narrowing, and four (26.6%) presented with segmental caudal dysgenesis with severe kyphoscoliosis, gibbus deformity, and spinal canal narrowing with a normal distal segment (normal or low-lying). Conclusions: SSD is a complex spinal anomaly in children requiring clinical-radiological assessment followed by multidisciplinary management based on the extent and severity of the dysgenetic cord and the type of SSD. MRI plays a crucial role in both diagnosing and classifying SSD prior to surgical treatment to prevent further impairment. PMID- 30472825 TI - Detection of Various Biomarkers and Enzymes via Nanocluster-Based Fluorescence Turn-On Sensing Platform. AB - The profiling of disease-related biomarkers is an essential procedure for the accurate diagnosis and intervention of metabol-ic disorders. Therefore, the development of ultrasensitive and highly selective fluorogenic biosensors for diverse biomarkers is extremely desirable. There is still a considerable challenge to prepare nanocluster-based fluorescence turn-on probes capa-ble of recognizing multiple biomolecules. We herein provide a novel nanocluster-based chemical information processing system (CIPS) for the programmable detecting various metabolites and enzymes. This CIPS consists of the biocatalytic re actions between substrates and their respective oxidases to generate H2O2, which was then employed to synthesize bright fluorescent silver nanoclusters (Ag NCs). Utilizing this system, we are able to accurately probe a series of substrates/ corre-sponding oxidases with high sensitivity and specificity, including glucose/ glucose oxidase, uric acid/ uric acid oxidase, sarco-sine/ sarcosine oxidase, choline/ choline oxidase, xanthine/ xanthine oxidase, and lactic acid/ lactic acid oxidase. Further-more, this metabolite profiling CIPS can integrate with binary logic operations, which create an intelligently tool for the high throughput screening of various diseases in vitro (e.g., diabetes, gout, prostate cancer, cardiovascular disease, and lactic acidosis). PMID- 30472826 TI - Validation of Single Particle ICP-MS for Routine Measurements of Nanoparticle Size and Number Size Distribution. AB - Single particle inductively coupled plasma-mass spectrometry (spICP-MS) is an emerging technique capable of measuring nanoparticle size and number concentration simultaneously, of metal-containing nanoparticles (NPs) at environmental levels. spICP-MS will become an established measurement method once the metrological quality of the measurement re-sults it produces have been proven incontrovertibly. This paper presents the first validation of spICP-MS capabilities for measuring mean NP size and number size distribution of gold nanoparticles (AuNPs). The validation is achieved by: (i) calibration based on the consensus value for particle size derived from six different sizing techniques applied to National Institute of Standards and Technology (NIST) Reference Material (RM) 8013; (ii) comparison with high-resolution scan-ning electron microscopy (HR-SEM) used as a reference method, which is linked to the International System of Units (SI) through a calibration standard characterized by the NIST metrological Atomic Force Microscope; and (iii) evaluating the uncertainty associated with the measurement of the mean particle size to enable comparison of the spICP-MS and HR-SEM methods. After establishing HR-SEM and spICP-MS measurement protocols, both methods were used to characterize commercial AuNP suspensions of three different sizes (30 nm, 60 nm, and 100 nm) with four different coatings and sur-face charge at pH 7. spICP-MS measurements (corroborated by HR-SEM) revealed the existence of two distinct sub-populations of particles in the number size distributions for four of the 60 nm commercial suspensions, a fact that was not apparent in the measurement results supplied by the vendor using transmission electron microscopy. This finding illustrates the utility of spICP-MS for routine characterization of commercial AuNP suspensions regardless of size or coating. PMID- 30472827 TI - Function-Integrated Ru Catalyst for Photochemical CO2 Reduction. AB - Visible-light-driven catalytic reduction of CO2 is at the heart of artificial photosynthesis. Here, we demonstrate the first example of a Ru complex that can function both as a photosensitizer and catalyst for CO2 reduction. The catalyst exhibited excellent activity for CO evolution with a high turnover number (TON, 353 for 24 h), reaction rate (TOF, 14.7 h-1), and product selectivity (97%) under visible-light irradiation. We also succeeded in selective product formation (CO or HCOOH) by changing the basicity of the reaction media. This finding will open new avenues for visible-light-driven photoredox catalysis using Ru-based function integrated photocatalysts. PMID- 30472828 TI - Recent advances in body-on-a-chip systems. AB - Microphysiological systems (MPS, also known as 'organ-on-a-chip', 'body-on-a chip', or 'human-on-a-chip') have emerged over the last fifteen years as attractive systems to probe response to pharmaceutical or chemicals. While applicable to animals, such systems are particularly powerful in predicting human response prior to clinical testing of a drug or as augmentation of clinical studies to test underlying mechanisms. The rate of development of such systems has increased exponentially, particularly over the last three years. Organ-on-a chip systems have evolved in sophistication and ability to model details of organ physiology, allowing better understanding of underlying mechanisms of response to drugs and chemicals. Body-on-a-chip (BOC) systems are multi-organ systems, often designed to emulate human physiological response to drugs and have the potential to capture both efficacy of a drug and potential toxicity in other organs. While the focus has been on human response to pharmaceuticals, such systems can evaluate response to general chemical exposure, which is important in evaluating the safety of chemicals, food ingredients, and cosmetics. Here, we review recent progresses in the development of model systems over the last three years, with particular focus on BOC systems. PMID- 30472829 TI - Proton-transfer based azides with fluorescence off-on response for detection of hydrogen sulfide. An experimental, theoretical and bioimaging study. AB - This work describes the synthesis of photoactive proton transfer compounds based on the benzazolic core containing the azide group. The compounds present absorption in the UV region and fluorescence emission in the visible region of the spectra with large Stokes shift due to a phototautomerism in the excited state (ESIPT). The azide location on the benzazolic structure showed to present a noteworthy role on their photophysics leading to fluorescence quenching. A photophysical study was performed in the presence of NaHS to evaluate their application as H2S sensor. The methodology employed was the reduction of azides to amines using NaHS to mimic H2S, resulting in an off-on response fluorescence mechanism. The observed photophysical features were successfully used to explore the azides as fluorescent probes in biological media. In addition, DFT and TD-DFT calculations with CAM-B3LYP/cc-pVDZ and CAM-B3LYP/jun-cc-pVTZ level respectively were performed in order to understand the photophysics features of azide derivatives, where the main interest was investigate fluorescence quenching experimentally observed in the azide derivatives. PMID- 30472830 TI - Discovery and Characterization of 1-Aminocyclopropane-1-carboxylic Acid Synthase of Bacterial Origin. AB - The guangnanmycins (GNMs) belong to a small group of natural products featuring a 1-aminocyclopropane-1-carboxylic acid (ACC) moiety. While extensively studied in plants, ACC biosynthesis in bacteria remains poorly understood. Here we report inactivation of gnmY in vivo and biochemical characterization of GnmY in vitro, assigning GnmY as the first bacterial free ACC synthase that catalyzes the synthesis of ACC from S-adenosyl methionine. ACC is activated by GnmS and subsequently incorporated into the GNM scaffold by the GNM hybrid nonribosomal peptide synthetase-polyketide synthase system in GNM biosynthesis. GnmS exhibits relaxed substrate specificity, exploitation of which allowed the incorporation of 1-aminocyclobutane-1-carboxylic acid (ACBC) into the GNM scaffold to produce a GNM analogue with a cyclobutane ring at C-17. This study provides new insights into ACC biosynthesis in bacteria. GnmY and GnmS might be portable to engineer other ACC/ACBC-containing natural products. PMID- 30472832 TI - Linear Eyring Plots Conceal a Change in the Rate-Limiting Step in an Enzyme Reaction. AB - The temperature dependence of psychrophilic and mesophilic ( R)-3-hydroxybutyrate dehydrogenase steady-state rates yields nonlinear and linear Eyring plots, respectively. Solvent viscosity effects and multiple- and single-turnover pre steady-state kinetics demonstrate that while product release is rate-limiting at high temperatures for the psychrophilic enzyme, either interconversion between enzyme-substrate and enzyme-product complexes or a step prior to it limits the rate at low temperatures. Unexpectedly, a similar change in the rate-limiting step is observed with the mesophilic enzyme, where a step prior to chemistry becomes rate-limiting at low temperatures. This observation may have implications for past and future interpretations of temperature-rate profiles. PMID- 30472831 TI - Protective Effect of Naringin on DSS-Induced Ulcerative Colitis in Mice. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is an important member of the nuclear receptor superfamily. Previous studies have showed the satisfactory anti-inflammatory role of PPARgamma in experimental colitis models, mainly through negatively regulating several transcription factors such as nuclear factor-kappaB (NF-kappaB). Therefore, regulating PPARgamma and PPARgamma related pathways has a great promise for treating ulcerative colitis (UC). In the present study, our objective was to explore the potential effect of naringin on dextran sulfate sodium (DSS)-induced UC in mice and its involved potential mechanism. We found that naringin significantly relieved DSS-induced disease activities index (DAI), colon length shortening and colonic pathological damage. Exploration on the potential mechanisms demonstrated that naringin significantly activated DSS-induced PPARgamma and subsequently suppressed NF-kappaB activation. PPARgamma inhibitor GW9662 largely abrogated the roles of naringin in vitro. Moreover, DSS-induced the activation of mitogen-activated protein kinase (MAPK) and (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome was inhibited by naringin. Tight junction (TJ) architecture in naringin groups was also maintained by regulating zonula occludens-1 (ZO-1) expression. These results suggested that naringin may be a potential natural agent for protecting mice from DSS-induced UC. PMID- 30472833 TI - DNA Walker-Induced Allosteric Switch for Tandem Signal Amplification with Palladium Nanoparticles/Metal-Organic Framework Tags in Electrochemical Biosensing. AB - A DNA walker as a new molecular machine can walk on defined tracks to directly generate signal indicators in biosensing and biomedical applications. In this work, a tandem signal amplification strategy was developed based on the DNA walker-induced conformation switch for bridging palladium nanoparticles/metal organic framework tags in ultrasensitive electrochemical DNA biosensing. The signal tags were synthesized by in situ reduction of Pd nanocrystals on porphyrinic metal-organic frameworks (PCN-224), and followed by conjugating with streptavidin (SA). The as-prepared Pd/PCN-224-SA tag could electrocatalyze the oxidation of NaBH4 with high efficiency for signal readout. The presence of target DNA released swing arms that were each silenced by a blocker, and then the activated swing arms could hybridize with hairpin DNA. The movement of swing arms was powered by enzymatic cleavage of conjugated oligonucleotides, inducing the allosteric switch from hairpin to SA aptamer. Therefore, Pd/PCN-224-SA tags were brought onto the electrode surface via SA-aptamer biorecognition to generate the enhanced electrochemical signal. The DNA walker-based electrochemical biosensor demonstrated good performance such as a six-order magnitude linear range, femtomolar detection limit and single mismatch differentiation ability. Moreover, the feasibility of the biosensor was identified in serum matrixes. The tandem signal amplification of metal-organic frameworks and DNA walkers provided a new avenue in trace electrochemical biosensing. PMID- 30472834 TI - Silica Nanoparticles with Up-conversion Fluorescence Based on Triplet-Triplet Annihilation Mechanism for Specific Recognition of Apoptosis Cells. AB - Discriminating of live and apoptotic cells is a crucial task in the research of pharmacology, biology, pathology, and medicine science. Recently, up conversion (UC) luminescent materials have appealed much attention due to their unique ability to convert low energy excitation photons to high energy ones. However, UC fluorescence has not been employed in the field of discriminating of live and apoptotic cells. We presented a facile, and cost-less Stober method to fabricate robust silicon na-noparticles (SiO2 UCNPs) exhibiting several merits, such as narrow size distribution, and UC luminescence. SiO2 UCNPs could discriminate live and apoptosis cells by taking advantage of the unique surface property of SiO2 UCNPs for the first time. This work is also the first demonstration of the use of single photon excited UC fluorescence derived from nanoparticles for biological recognition of a specific type of cells. PMID- 30472835 TI - Structural Dynamics of Dimethyl Sulfoxide Aqueous Solutions Investigated by Ultrafast Infrared Spectroscopy: Using Thiocyanate Anion as a Local Vibrational Probe. AB - The microscopic structure of dimethyl sulfoxide (DMSO) aqueous solutions was investigated by FTIR spectroscopy and ultrafast IR spectroscopy. The structural dynamics of the binary mixtures were reflected by using thiocyanate anion (SCN-) as a local vibrational probe. FTIR spectra of SCN- anion showed the hydrogen bond networks of water are affected by the presence of DMSO molecules, and the peak position and bandwidth of SCN- anions are red-shifted and narrowed accordingly due to the weak hydration in the binary mixture. The vibrational lifetime of the SCN- anion showed almost linear enhancement with the increase of DMSO, which can be explained by the weak interaction between SCN- and the hydrophobic groups in DMSO molecule. However, the rotational dynamics of SCN- are slowing down significantly and showed a maximum response at XDMSO (mole fraction) of 0.35, which is mainly caused by the confinement of SCN- anions positioned in the vicinity of the complex structure formed between DMSO and water molecules. The concentration dependent rotational dynamics of water molecules and SCN- anions are having similar behavior, indicated that the complex structure can be formed between water and DMSO molecules due to the strong interaction. The result also demonstrates that the structural inhomogeneity in aqueous solution can be unraveled by monitoring the vibrational relaxation dynamics of SCN- anion serving as the local vibrational probe. PMID- 30472836 TI - Fall Creek Monitoring Station: highly resolved temporal sampling to prioritize the identification of non-target micropollutants in a small stream. AB - The goal of this research was to comprehensively characterize the occurrence and temporal dynamics of target and non-target micropollutants in a small stream. We established the Fall Creek Monitoring Station in March 2017 and collected daily composite samples for one year. We measured water samples by means of high resolution mass spectrometry and developed and optimized a post-acquisition data processing workflow to screen for 162 target micropollutants and group all mass spectral (MS) features into temporal profiles. We used hierarchical clustering analysis to prioritize non-target MS features based their similarity to target micropollutant profiles and developed a high-throughput pipeline to elucidate the structures of prioritized non-target MS features. Our analyses resulted in the identification of 31 target micropollutants and 59 non-target micropollutants with varying levels of confidence. Temporal profiles of the 90 identified micropollutants revealed unexpected concentration-discharge relationships that depended on the source of the micropollutant and hydrological features of the watershed. Several of the non-target micropollutants have not been previously reported including pharmaceutical metabolites, rubber vulcanization accelerators, plasticizers, and flame retardants. Our data provide novel insights on the temporal dynamics of micropollutant occurrence in small streams. Further, our approach to non-target analysis is general, and not restricted to highly resolved temporal data acquisitions or samples collected from surface water systems. PMID- 30472837 TI - Superconductivity and Phase Stability of Potassium-Intercalated p-Quaterphenyl. AB - To explore more novel superconductors, we have synthesized the potassium-doped p quaterphenyl by annealing or just pestling process. The Meissner effect with critical temperatures ranging from 3.5 K to 120 K is found by the magnetic susceptibility measurements in doped samples. The primary superconducting phase with critical temperature of 7.2 K can be reduplicated in the annealed and pestled samples. The charge transfer from metal to molecule is confirmed from the Raman scattering measurements. The X-ray diffraction analysis suggests that the low-temperature superconducting phase is due to the two-electron doping while the high-temperature one corresponds to the high doping content. The occurrence of superconductivity in potassium-doped p-quaterphenyl supports the chain link organic molecules as promising candidates for high temperature superconductors. This work also provides a simple method to synthesize the organic superconductors by pestling without annealing. PMID- 30472838 TI - Catalytic Oxidation of Chlorinated Organics over Lanthanide Perovskites: Effects of Phosphoric Acid Etching and Water Vapor on Chlorine Desorption Behavior. AB - In this article, the underlying effect of phosphoric acid etching and additional water vapor on chlorine desorption behavior over a model catalyst La3Mn2O7 was explored. Acid treatment led to the formation of LaPO4 and enhanced the mobility of lattice oxygen of La3Mn2O7 evidenced by a range of characterization (i.e. X ray diffraction, Temperature-programmed analyses, NH3-IR, etc.). The former introduced thermally stable Bronsted acidic sites that enhanced dichloromethane (DCM) hydrolysis while the latter facilitated desorption of accumulated chlorine at elevated temperatures. The acid-modified catalyst displayed a superior catalytic activity in DCM oxidation compared to the untreated sample, which was ascribed to the abundance of proton donors and Mn(IV) species. The addition of water vapor to the reaction favored the formation and desorption of HCl and avoided surface chlorination at low temperatures. This resulted in a further reduction in reaction temperature under humid conditions (T90 of 380 degrees C for the modified catalyst). These results provide an in-depth interpretation of chlorine desorption behavior for DCM oxidation, which should aid the future design of industrial catalysts for the durable catalytic combustion of chlorinated organics. PMID- 30472839 TI - Cysteine Disulfide Traps Reveal Distinct Conformational Ensembles in Dengue Virus NS2B-NS3 Protease. AB - The dengue virus protease (NS2B-NS3pro) plays a critical role in the dengue viral lifecycle, making it an attractive drug target for dengue-related pathologies including dengue hemorrhagic fever. A number of studies indicate that NS2B-NS3pro transitions between two widely different conformational states: an 'open' (inactive) conformation and a 'closed' (active) conformation. For the past several years , the equilibrium between these states and the resting conformation of NS2B-NS3pro have been debated, although a strong consensus is emerging. To investigate the importance of such conformational states, we developed versions of NS2B-NS3pro that allow us to trap the enzyme in various distinct conformations. Our data from these variants suggests that the enzymatic activity appears to be dependent not only on the movement of NS2B, but may also rely on the flexibility of the protease core. Locking the enzyme into the 'closed' conformation dramatically increased activity, strongly suggesting that the 'closed' conformation is the active conformation. The observed resting state of the enzyme depends largely on the construct used to express the NS2B-NS3pro complex. In an 'unlinked' construct, in which the NS2B and NS3 regions exist as independent, co-expressed polypeptides, the enzyme rests predominantly in a 'closed', active conformation. In contrast, in a 'linked' construct, in which NS2B and NS3 are attached by a 9-amino-acid linker, NS2B-NS3pro adopts a more relaxed, alternative conformation. Nevertheless, even the unlinked construct samples both the 'closed' and other alternative conformations. Given our findings, and its more realistic resemblance to the native enzyme, these data strongly suggest that studies should focus on the 'unlinked' constructs moving forward. Additionally, the results from these studies provide a more detailed understanding of the various poses of the dengue virus NS2B-NS3 protease and should help guide future drug discovery efforts aimed at this enzyme. PMID- 30472840 TI - Intermediate States Directed Chiral Transfer on a Silver Surface. AB - Chiral synthesis on surfaces has acquired tremendous interests. We herein report a novel approach of two-dimensional chiral transfer directed by metal-organic intermediate states on a silver surface. With initial deposition at low temperature, the achiral 4,4'-dihydroxybiphenyl molecules self-assemble into large scale two-dimensional networks with four-fold symmetry via intermolecular hydrogen bonding. Fine controlled annealing, however, leads to the formation of tetramer-like chiral metal-organic hybrids, which self-organize into enantiomeric islands on the Ag(100) surface. Subsequent ortho C-C couplings of the reactants lead to dimer products. Of great importance, the chirality expressions of the dimer products are observed to be transferred directly from that of the tetramer intermediate states. The detailed reaction pathways are rationalized by DFT calculations and synchrotron-based XPS experiments, demonstrating the mechanisms of the chiral transfer. PMID- 30472841 TI - Hydrazonophenol, a food vacuole targeted and ferriprotoporphyrin IX-interacting chemotype prevents drug resistant malaria. AB - Rapid emergence of resistance against the frontline antimalarial drugs essentially warrants for the identification of new-generation antimalarials. Here, we describe the synthesis of (E)-2-isopropyl-5-methyl-4-((2-(pyridin-4-yl) hydrazono) methyl) phenol (18) that binds ferriprotoporphyrin-IX (FeIII-PPIX) (Kd = 33 nM) and offers antimalarial activity against chloroquine-resistant and sensitive strains of Plasmodium falciparum in vitro. Structure-function analysis reveals that compound 18 binds FeIII-PPIX through "-C=N-NH-" moiety and 2-pyridyl substitution at hydrazine counterpart plays a critical role in antimalarial efficacy. Live cell confocal imaging using fluorophore-tagged compound confirms its accumulation inside acidic food vacuole (FV) in P. falciparum. Furthermore, this compound concentration-dependently elevates the pH in FV implicating a plausible interference with FeIII-PPIX crystallization (hemozoin formation) by dual-function; through increasing the pH and by binding free FeIII-PPIX. Different "Off-target" bioassays reduce the possibility of promiscuous nature of compound 18. Compound 18 also exhibits potent in vivo antimalarial activity against chloroquine-resistant P. yoelii and P. berghei ANKA (causing cerebral malaria) in mice with negligible toxicity. PMID- 30472842 TI - Metabolic alterations in postharvest pear fruit as influenced by 1 methylcyclopropene and controlled atmosphere storage. AB - This study assessed the impact of 1-methylcyclopropene (1-MCP) and controlled atmosphere (CA) on the metabolism of targeted amino acids, organic acids and antioxidants in stored 'AC Harrow Crisp' pears, and their relationships to storage disorders. Pears were treated with 0 or 300 nL L-1 1-MCP and stored at 0 degrees C under ambient air or CA. Spectrophotometric assays demonstrated that glutathione levels fluctuated with storage, and were most preserved by 1-MCP under ambient air. HPLC analysis revealed that ascorbate concentrations declined with storage, and were little affected by 1-MCP and CA. Citrate, lactate and fumarate accumulated with storage, but were differentially affected by 1-MCP. Aspartate and glutamate concentrations were greater with 1-MCP; gamma aminobutyrate accumulated in disordered fruit. Principal component analysis demonstrated that alterations in citrate and fumarate, respectively, were correlated with internal breakdown and senescent scald. gamma-Aminobutyrate and alanine were associated with internal cavities. All disorders were associated with antioxidant depletion. PMID- 30472843 TI - Food Authentication: Small Molecule Profiling as a Tool for the Geographic Discrimination of German White Asparagus. AB - For the first time, a non-targeted metabolomics approach by means of ultra performance liquid chromatography coupled to electrospray quadruple time-of flight mass spectrometer (UPLC-qTOF-ESI-MS(/MS)) was chosen for the discrimination of geographical origins of white asparagus samples (Asparagus officinalis). Over a period of four harvesting periods (4 years) approximately 400 asparagus samples were measured. Initially, four different LC-MS methods were used to detect as many metabolites as possible and to assess which method is most suitable. The most relevant marker compounds were linked to the influence of different plant stress parameters and climate effects. Some of the samples were also analyzed by isotope-ratio mass spectrometry (IRMS) which is the current gold standard for the discrimination of the geographical origin of asparagus. In summary, the analysis of the metabolome was proved to be quite suitable to determine the geographical origin of asparagus and seems to provide better interpretable results than IRMS studies. PMID- 30472844 TI - Single-Molecule Observation of the Intermediates in a Catalytic Cycle. AB - The development of catalysts benefits from knowledge of the intermediate steps that accelerate the transformations of substrates into products. However, key transient species are often hidden in ensemble measurements. Here, we show that the continuous single-molecule observation of a reaction in solution can be performed by using a protein nanoreactor that samples the intermediate steps in a catalytic cycle. By monitoring changes in the flow of ionic current through an alpha-hemolysin protein pore, we observed three intermediate metal-ligand complexes in a gold(I)-catalysed reaction that converts an acetylenic acid to an enol lactone, revealing a key transitional coordination complex that had been previously unobserved. A kinetic isotope effect helped assign the various metal ligand species. Measurements of the lifetimes of the intermediates allowed a full kinetic analysis of the metal-catalysed reaction cycle. PMID- 30472845 TI - Reactions of Quinones - Mechanisms, Structures, and Prospects for Food Research. AB - Oxidation of plant phenolics leads to quinones, which are instable intermediates that may react with nucleophiles. Quinones play an important role in the enzymatic browning of fruits and vegetables and may form covalent adducts with amino acids, peptides, and proteins. These reactions may alter both the physico chemical and the immunological properties of food proteins. Quinones trap odoriferous compounds and contribute to the formation of aroma compounds through Strecker degradation of amino acids. Oxidative dimerization of chlorogenic acids in the presence of amino acids leads to the formation of green benzacridines, which are a promising alternative to chlorophylls as food colorants. PMID- 30472846 TI - Rapid quantification of monoclonal antibody titer in cell culture harvests by antibody-induced Z-ELP-E2 nanoparticle crosslinking. AB - Existing assays for the quantification of monoclonal antibody (mAb) cell culture titer often require expensive instruments or reagents and may be limited by the low-throughput or tedious protocols. Here, we developed a quick and cost effective alternative assay based on mAb-induced crosslinking with Z-domain-ELP E2 nanocages functionalized by SpyTag/SpyCatcher conjugation. After mixing mAb samples with a fixed nanoparticle concentration for 10 min, we found that the turbidity, measured by absorbance at 600 nm, exhibited a high signal to background ratio and was proportional to the mAb concentration. A simple logarithmic regression was found to fit (R2 = 0.99) the turbidity data for mAb concentrations between 100-1000 ug/mL. The optimized assay procedure was validated using two industrial mAb cell culture harvests and a bridging study using Octet biolayer interferometry with Protein A sensors confirmed accurate and reproducible results. The assay procedure can be easily adapted to a high throughput format for rapid mAb titer screening. PMID- 30472847 TI - Organic solvent-free, Pd(II)-salan complex-catalyzed synthesis of biaryls via Suzuki-Miyaura cross-coupling in water and air. AB - With use of a Pd(II)-sulfosalan complex as a water-soluble catalyst we have developed an efficient synthesis of biaryls via Suzuki-Miyaura cross-coupling in water under aerobic conditions. The water-insoluble target molecules were isolated by simple filtration in analytical purity after washing with 0.01 M aqueous HCl (20 examples). In most cases, palladium contamination was below 5 ppm considered acceptable for active pharmaceutical ingredients. The established method is scalable, reproducible, and provides biaryl products in isolated yields up to 91%. PMID- 30472848 TI - Flap Endonuclease 1 Mutations A159V and E160D Cause Genomic Instability by Slowing Reaction on Double Flap Substrates. AB - Flap endonuclease 1 (FEN1) is a structure-selective nuclease best known for its roles in the penultimate steps of Okazaki fragment maturation, long-patch base excision repair and ribonucleotide excision repair. To better understand the role of FEN1 in genome maintenance in yeast and mammals, FEN1 active site mutations (A159V and E160D) have been used as tools to dissect its involvement in DNA metabolic pathways. However, discrepancies concerning the biochemistry and molecular etiology of genomic instability when FEN1 function is altered exist. Here, a detailed biochemical and biophysical characterization of mouse FEN1 and mutants is presented. Kinetic measurements showed that the active site mutants A159V and E160D reduce the rates of hydrolysis under multiple- and single turnover conditions on all substrates. Consistent with their dominant negative effects in heterozygotes, neither mutation affects the adoption of the substrate duplex arms in the bent conformation on the enzyme surface, although reductions in substrate binding affinity are observed. The ability of the mutants to induce the requisite local DNA conformational change near the scissile phosphate is adversely affected, suggesting that the ability to place the scissile phosphate optimally in the active site causes the reduction in rates of phosphate diester hydrolysis. Further analysis suggests that the A159V mutation causes the chemistry of phosphate diester hydrolysis to become rate limiting, whereas the WT and E160D proteins are likely rate-limited by a conformational change. Based on these results, the proposed roles of FEN1 in genome maintenance derived from studies involving these mutations are reassessed. . PMID- 30472849 TI - Meta-analysis of Insecticides in U.S. Surface Waters: Status and Future Implications. AB - Agricultural insecticides occur in U.S. surface waters, yet our knowledge of their current and potential future large-scale risks for biodiversity is restricted. Here, we conducted a meta-analysis of measured insecticide concentrations (MICs; n=5817; 1962-2017) in U.S. surface waters and sediments reported in 259 peer-reviewed scientific studies for 32 important insecticide compounds and their degradation products (n=6). To assess overall and substance specific ecological risks and future implications, MICs were compared with official U.S. EPA regulatory threshold levels (RTLs) and insecticide use trends. Approximately half of the MICs, i.e., 49.4% (at 69.7% of the 644 sites covered), exceeded their RTLs, indicating substantial risks to the integrity of U.S. aquatic ecosystems and potential shortcomings of regulatory risk assessment procedures. Overall, pyrethroids had the highest exceedance rate (80.7%; n=1808), followed by organophosphates and carbamates (42.2%, n=2618), and organochlorines (33.3%, n=468). Pronounced increasing use trends were found for neonicotinoids, which exceeded their chronic RTLs, i.e., those of high relevance due to neonicotinoids' persistence in surface waters, for 56.8% of MICs (22.2% for acute RTLs). A regression analysis of insecticide use trends, although to be interpreted with care, indicated a future increase in applied amounts of several high risk insecticides such as pyrethroids and neonicotinoids, suggesting elevated prospective risks for U.S. surface waters, biodiversity, and endangered species. PMID- 30472850 TI - Interlayer-Decoupled Sc-Based Mxene with High Carrier Mobility and Strong Light Harvesting Ability. AB - Two-dimensional (2D) van der Waals (vdW) layered materials offer a unique combination of electronic and structural properties attractive for technological applications. Most of them show strong vdW interactions, which lead to interlayer coupled optoelectronic properties due to quantum confinement. Here we present a systematic computational study of one Mxene, 2D double-metal-layered scandium chloride carbides (Sc2CCl2). Unlike conventional quantum-confined nanosystems, 2D Sc2CCl2 exhibits weak vdW interactions with robust interlayer-decoupled optoelectronic properties and extremely high and anisotropic carrier mobilities of about 1-4.5 * 104 cm2 V-1 s-1 that consequently produce comparatively large drain currents. Specifically, the 2D Sc2CCl2 family has strong light-harvesting ability and could be utilized as efficient donor materials in excitonic solar cells. Overall, in combination with high structural stability against ambient conditions, interlayer-decoupled robust optoelectronic properties potentially relax the requirements for the fabrication of high-quality monolayers and for selection of suitable substrates and suggest promising next-generation optoelectronic applications. PMID- 30472852 TI - Remembering Some of the Giants of Biosensing. PMID- 30472851 TI - Metabolomics Reveals that Crossbred Dairy Buffaloes Are More Thermotolerant than Holstein Cows under Chronic Heat Stress. AB - Heat stress (HS) threatens the worldwide dairy industry by decreasing animal production performance and health. Holstein cows and dairy buffaloes are the most important dairy animals, but their differences in the metabolic mechanism of thermotolerance remain elusive. In this study, we used serum metabolomics to evaluate the differences in thermotolerance between Holstein cows and crossbred dairy buffaloes under chronic heat stress (HS) and thermal-neutral conditions. In response to HS, the body temperatures and respiratory rates were increased more for Holstein cows than for dairy buffaloes (38.78 vs 38.24 degrees C, p < 0.001; 43.6 vs 32.5 breaths/min, p < 0.001). HS greatly affected serum metabolites associated with amino acids, fatty acids, and bile acids. The enriched metabolic pathways of these serum metabolites are closely related to HS. We demonstrated that buffaloes adapt to HS by adopting a metabolism of branched-chain amino acids and ketogenic amino acids and gluconeogenesis, but Holstein cows decrease the effect of HS with citrulline and proline metabolism. Both physiological parameters and serum metabolic profiles indicate that dairy buffaloes are more thermotolerant than Holstein cows, providing the feasibility to vigorously develop the buffalo dairy industry in tropical and subtropical regions. PMID- 30472854 TI - Ordered Particle Arrays via a Langmuir Transfer Process: Access to Any Two Dimensional Bravais Lattice. AB - We demonstrate how to directly transform a close-packed hexagonal colloidal monolayer into non-close packed particle arrays of any two-dimensional symmetry at the air/water interface. This major advancement in the field of nanoparticle self-assembly is based on a simple one-dimensional stretching step in combination with the particle array orientation. Our method goes far beyond existing strategies and allows access to all possible 2D Bravais lattices. A key element of our work is the possibility to macroscopically stretch a particle array in a truly one-dimensional manner, which has not been possible up to now. We achieve this by stretching the nanoparticle array at an air/water interface during the transfer process. The degree of stretching is simply controlled by the wettability of the transfer substrate. To retain the symmetry of the transferred structure, the capillary forces upon drying have to be circumvented. We demonstrate two concepts based on thermal fixation for this. It allows for the first time to fabricate non-close packed, non-hexagonal colloidal monolayers on a macroscopic length scale. PMID- 30472855 TI - Time-dependent dynamic behaviors of a confined liquid to achieve tailored adhesion force with repeated contacts revealed by an AFM. AB - The adhesion forces between two silica surfaces were measured by using an atomic force microscope (AFM) with different experimental parameters in air to investigate the dynamic behavior of a confined liquid. Results show that the adhesion force is time-dependent and increases at first sharply and then slightly with dwell time until the saturation is reached, with a long equilibrium time. This behavior is well explained by a dynamic meniscus model, in which a liquid bridge grows gradually due to liquid film flow with a large viscosity. And, the large viscosity was attributed to the formation of orthosilicic acid and subsequent polymerization. With repeated contacts, the liquid bridge changes into two droplets on both surfaces after separation. The liquid in both forms can be controlled to flow into or out of the contact zone by the experimental parameters to achieve tailored adhesion forces. If the liquid of previous contact remains in the contact zone, the adhesion force increases with repeated contacts and then reaches saturation, which can also be explained by the model qualitatively. However, if the liquid droplets vanish before the next contact, the adhesion force usually decreases or remains unchanged. More liquid will be collected with larger contact time. Meanwhile, the droplets remained on the surfaces are getting smaller until vanished without a contact. Moreover, both piezo velocity and scan distance can be used to control the proportion of contact time. In addition, a viscous force should be considered with a large retraction velocity. The changing trend and magnitude of adhesion force depend on the experimental parameters and their coupling effects. The results may facilitate the anti-adhesion design of small-scale silicon-based systems. PMID- 30472856 TI - Solvent-Assisted Tuning the Size and Shape of CsPbBr3 Nanocrystals via Re Dispersion Process at Ambient Condition. AB - All-inorganic CsPbBr3 perovskite nanocrystals are emerging as a new class of semiconductors with outstanding optoelectronic properties and great potential for various applications, such as, lasing, photon detection, photovoltaics etc. This article provides the effect of solvents on the re-precipitation of CsPbBr3 perovskite at room temperature. The results observed for CsPbBr3 perovskite in various anti-solvent showed various cubes (nano to micro size), self-assembly of nanocubes and nanorods. In addition, all the various size (nano to micro), self assembly of nanocubes and shape-controlled nanorods exhibited band-gap tuning at the green light region. The corresponding microscopy (FE-SEM and HR-TEM) images and photoluminescence quantum yield as well as lifetime decay are presented. To the best of our literature knowledge this is the first report on various solvent assisted studies on CsPbBr3 perovskite nanocrystals. PMID- 30472857 TI - Nanomixing Effects in Glycerol/Dodecanol Pickering Emulsions for Interfacial Catalysis. AB - Pickering emulsions offer a promising platform for conducting interfacial reactions between immiscible reagents. Despite the significant progress in the engineering of amphiphilic catalysts for such reactions, the mechanism behind their enhanced activity is still poorly understood. Herein, using the glycerol/dodecanol system as a case study, we conducted a combined meso- and microscale study of Pickering emulsions stabilized by amphiphilic silica nanoparticles bearing acid centers by marrying Dissipative Particle Dynamics simulations with emulsification experiments. The optimal surface properties of the silica particles in terms of length and density of alkyl chains were identified, matching the experimental results. The local distribution of glycerol and dodecanol near the acid centers was ascertained, unraveling potential reactivity zones near the catalytic acid centers due to an enhanced nanomixing between glycerol and dodecanol. PMID- 30472858 TI - High Strength Antibacterial Chitosan-Cellulose Nanocrystals Composite Tissue Paper. AB - A heightened need to control the spread of infectious diseases prompted the current work in which functionalized and innovative antimicrobial tissue paper was developed with a hydrophobic spray-coating of chitosan (Ch) and cellulose nanocrystals (CNC) composite. It was hypothesized that the hydrophobic nature of chitosan could be counterbalanced by the addition of CNC to maintain fiber formation and water absorbency. Light-weight tissue handsheets were prepared, spray coated with Ch, CNC and their composite coating (ChCNC), and tested for antimicrobial activity against gram-negative bacteria E. coli and a microbial sample from a human hand after using the restroom. Water absorption and strength properties were also analyzed. To activate the surface of cationized tissue paper, a helium gas atmospheric plasma treatment was also employed on the best performing antimicrobial tissue papers. The highest bactericidal activity was observed with ChCNC coated tissue paper, inhibiting up to 98% microbial growth. Plasma treatment further improved the antimicrobial activity of the coatings. Water absorption properties were reduced with Ch but increased with CNC. This "self-disinfecting" bactericidal tissue has the potential to be one of the most innovative products for the hygiene industry because it can dry, clean, and resist the infection of surfaces simultaneously, providing significant societal benefits. PMID- 30472859 TI - Evidence of Pure Spin-Current Generated by Spin Pumping in Interface Localized States in Hybrid Metal-Silicon-Metal Vertical Structures. AB - Due to the difficulty to grow high quality semiconductors on ferromagnetic metals, the study of spin diffusion transport in Si was only limited to lateral geometry devices. In this work, by using ultra-high vacuum wafer-bonding technique, we have successfully fabricated metal-semiconductor-metal CoFeB/MgO/Si/Pt vertical structures. We hereby demonstrate pure spin-current injection and transport in the perpendicular current flow geometry over a distance larger than 2um in n-type Si at room temperature. In those experiments, a pure propagating spin-current is generated via ferromagnetic resonance spin pumping and converted into a measurable voltage by using the inverse spin-Hall effect occurring in the top Pt layer. A systematic study by varying both Si and MgO thicknesses reveals the important role played by the localized states at the MgO/Si interface for the spin-current generation. Proximity effects involving indirect exchange interactions between the ferromagnet and the MgO/Si interface states appears to be a prerequisite to establish the necessary out-of-equilibrium spin-population in Si under the spin-pumping action. PMID- 30472860 TI - Variable Growth and Characterizations of Monolayer Protected Gold Nanoclusters Based on Molar Ratio of Gold and Capping Ligands. AB - Controlling the size of nanoscale entities is important because many properties of nanomaterials are directly related to the size of the particles. Gold nanoparticles represent classic materials and are of particular interest due to their potential application in a variety of fields. In this study, hexanethiol capped gold nanoparticles are synthesized via the Brust-Schiffrin method. Synthesized nanoparticles were characterized by various analytical techniques such as transmission electron microscopy (TEM), scanning tunneling microscopy (STM), UV-Visible absorption spectroscopy (UV-Vis) and electrochemical techniques. We have varied the molar ratio of gold to the protecting agent (hexanethiol) to discover the effect of gold-to-hexanethiol ligand ratio on the size of gold clusters. The clear correlation between cluster size and molar ratio is found that the averaged cluster size decreases from 4.28 +/- 0.83 nm to 1.54 +/- 0.67 nm as the gold-to-ligand molar ratio changes from 1:1 to 1:9. In contrast to a recent report that thiolated gold nanoparticles are under spontaneous disintegration when they are assembled on a gold substrate, our STM experiments proved that these gold nanoparticles can form a stable monolayer or multiple layers on the platinum electrode without observing disintegration within 72 hours. Therefore, our STM experiments demonstrate that the disintegration behavior of gold nanoparticles is related to the type of ligands and the nature of substrate materials. In electrochemical experiments, these gold nanoparticles displayed an electrochemical quantized charging effect, making these nanoparticles useful in the device applications such as electrochemical or biological sensors. PMID- 30472861 TI - Dopant Control of Electron-Hole Recombination in Cesium-Titanium Halide Double Perovskite by Time Domain Ab Initio Simulation: Codoping Supersedes Monodoping. AB - Using nonadiabatic (NA) molecular dynamics combined with time domain density functional theory, we simulate electron-hole recombination in pristine and doped inorganic Pb-free double perovskite Cs2TiBr6. We show that replacing the titanium and/or bromine with silicon and/or chlorine extends the charge carrier lifetime. Importantly, dopants avoid deep traps despite the fact that they do not change the fundamental band gap of Cs2TiBr6, and they decrease the NA electron-phonon coupling and accelerate decoherence arising from the reduced overlap of electron and hole wave functions as well as fast phonon modes induced by light dopants, respectively, suppressing electron-hole recombination. More importantly, codoping can reduce the formation energy of silicon and achieve higher doping concentration, potentially increasing the lifetime further. Our study suggests a rational strategy to reduce energy losses by codoping in design of high performance all-inorganic Pb-free perovskite solar cells. PMID- 30472862 TI - Ferromagnet-Free All-Electric Spin Hall Transistors. AB - The spin field-effect transistor, an essential building block for spin information processing, shows promise for energy-efficient computing. Despite steady progress, it suffers from a low-output signal because of low spin injection and detection efficiencies. We demonstrate that this low-output obstacle can be overcome by utilizing direct and inverse spin Hall effects for spin injection and detection, respectively, without a ferromagnetic component. The output voltage of our all-electric spin Hall transistor is about two orders of magnitude larger than that of previously reported spin transistors based on ferromagnets or quantum point contacts. Moreover, the symmetry of the spin Hall effect allows all-electric spin Hall transistors to effectively mimic n-type and p-type devices, opening a way of realizing the complementary functionality. PMID- 30472863 TI - Molecular detection and genetic diversity of porcine bocavirus in piglets in China. AB - Porcine bocavirus (PBoV) is a recently discovered, non-enveloped and single stranded DNA virus that can infect pigs. In order to understand PBoV infection and its genetic characterization in piglets in Xinjiang China, PBoV was detected by PCR in 156 clinical samples from 1-month-old piglets. PBoV was detected in 9 clinical samples, with a prevalence rate of 5.77% (9/156). Then nonstructural protein NS1 gene was amplified, sequenced and used for phylogenetic analysis. The results showed that the prevalence rate in the sick piglets was 9.33% (7/75), which is significantly higher than that in the healthy piglets (2.47%, 2/81). The nucleotide sequences of NS1 gene share high identities (96.1-99.2%) within the same groups of PBoVs. Phylogenetic analysis based on complete nucleotide sequence of NS1 gene showed that PBoV strains can be classified into three genetic groups, among which group I contains PBoV1 strains, group II contains PBoV2 strains, and group III contains PBoV3, PBoV4 and PBoV5 strains. Porcine/XJ-12, porcine/XJ-27, porcine/XJ-65, and porcine/XJ-145 had close genetic distance with subgroup 1, belonging to group I; strains porcine/XJ-79 and porcine/XJ-134 were clustered with subgroup 2, belonging to group II, while porcine/XJ-8, porcine/XJ-52 and porcine/XJ-96 were clustered with subgroup 3, which belonged to group III. This study demonstrated for the first time that PBoV strains in Xinjiang belong to three subgroups of three different genetic groups, indicating a substantial genetic diversity of the epidemic strains circulating in China, which provided the useful epidemiological data for scientific control and prevention of this disease in farm pigs. Keywords: porcine bocavirus; molecular detection; genetic characterization; piglets. PMID- 30472864 TI - Development of a standard protocol for quantitative polymerase chain reaction to detect adenovirus 36, which is associated with obesity. AB - It has been previously reported that adenovirus 36 (Ad36) infection is associated with obesity in humans and other animals. However, there is no clinically available standard protocol to detect Ad36 DNA. In this study, we developed a method for quantitative and rapid detection of Ad36 DNA. Using a TaqMan probe quantitative polymerase chain reaction (qPCR), we identified that the E3 and E4orf1 regions specifically detect Ad36 DNA, because these regions did not show cross reactivity with other types of adenoviruses. The limit of detection was 379 copy/ml and 384 copy/ml for E3 and E4orf1 regions of Ad36, respectively. The %CV (coefficient of variation) for reproducibility of the assay using adenovirus reference material ranged from 1.07-13.02. After we developed the standard protocol to detect Ad36 DNA, we used mouse as a surrogate model to confirm its clinical applicability. We administered Ad36 to mice via intranasal and oral routes, with intraperitoneal administration as the positive control, to analyze the effect of infection route. Ad36 DNA could be detected in lungs, liver, pancreas, and epididymal fat tissue after intraperitoneal injection, whereas it was found only in lungs after intranasal injection. No Ad36 DNA was detectable in any tested organ after oral injection. This indicates that the main route of infection with Ad36 is intranasal, suggesting that Ad36 is a respiratory virus. The standard protocol for qPCR developed in this study is useful for clinical detection of Ad36 DNA. Keywords: adenovirus 36; real-time PCR; obesity. PMID- 30472865 TI - The time course analysis of morphological changes induced by Chikungunya virus replication in mammalian and mosquito cells. AB - Chikungunya virus (CHIKV), a re-emerging Alphavirus, causes chronic myalgia and arthralgia in infected individuals. However, the exact pathophysiology remains undefined till date. Virus induced time course changes in host cells at the ultrastructural level and host cytoskeleton have been reported for other alphaviruses such as Sindbis and Semliki Forest virus. Few studies have tried to delineate the same for CHIKV leading to some understanding of the replication process. Selective CHIKV infection of progenitor cells involved in muscle repair has been proposed as a cause of myalgia; albeit the outcome of infection on these cells has not been reported. With this background, we investigated CHIKV-induced time course changes in two cell lines - Aedes albopictus (C6/36) and murine myoblasts (C2C12) by transmission electron microscopy (TEM). CHIKV infection of C2C12 cells resulted in cell death, with cells exhibiting well defined apoptotic features. In contrast, mature virions were released from infected C6/36 cells without cytolysis. Double labelling of C2C12 cytoskeletal proteins - such as actin, tubulin and CHIKV revealed that viral nucleocapsids co-localized with these proteins during replication. As the infection progressed, CHIKV disrupted the normal organisation of these cell proteins. CHIKV-induced plasma membrane extensions were observed in infected cells, which so far have been reported only for Sindbis virus. This is a first report describing the time course of morphological changes occurring in host cells as a result of infection with CHIKV at the ultrastructural level. Apoptosis of myoblasts due to CHIKV infection could also be an important factor contributing to the recurrence of myalgia in CHIKV patients. Keywords: Chikungunya; electron microscopy; confocal microscopy; C6/36; C2C12; actin; alpha-tubulin. PMID- 30472866 TI - Virus neutralization study using H120, H52, 793/B antisera against Iranian infectious bronchitis virus genotypes. AB - Infectious bronchitis virus (IBV), a major pathogen of the domestic fowl, exhibits extensive antigenic variation. IBV is a member of the Coronaviridae family and the genus Gammacoronavirus. A new infectious bronchitis virus serotype can emerge from only very few amino acid changes within the major peplomer glycoprotein, namely in its S1 part forming the virion spike. Principally, the serotypes are identified by virus neutralization (VN) tests. This study is aimed to investigate the neutralizing efficiency of H52, H120, and 4/91 antiserum against IBV genotypes (IS-1494, IS-720, 793/B, IR-1) recently circulating in Iran. For the first time, we have used cross-neutralization tests for the serological classification of these isolates. In this study, all antisera failed to neutralize all IBV strains. According to the results of our research, cross protection studies are necessary for the design of a proper vaccination program for IBV circulating genotypes in Iran. The data are useful for the development of new vaccine strategies. Keywords: avian infectious bronchitis; Iran; virus neutralization. PMID- 30472867 TI - Ultra-sensitive detection of papaya ringspot virus using single-tube nested PCR. AB - Aphid-transmitted papaya ringspot virus (PRSV) is the greatest disease threat to the commercial production of papaya worldwide. Specific ultrasensitive assays are important for the early detection of PRSV in the field. We have developed a single-tube nested PCR (STNP) assay to address this need. Two nested PCR primer sets were designed to target the P3 gene of PRSV. The annealing temperatures and concentrations of both primer pairs were optimized to reduce potential competition between primer sets in STNP. The assay is more sensitive than regular RT-PCR as determined by serial dilutions of cDNA and RNA templates and sample extracts from infected plants. STNP is capable of detecting PRSV in plants 7 days post-inoculation, whereas RT-PCR and ELISA are capable of detecting PRSV 14 to 21 days post-inoculation. This new assay can also detect PRSV from virus infected but asymptomatic plants. This system could assist epidemiological studies in the field and in quarantine protocols by enabling early detection of very low PRSV infection rates in the field and in imported plant samples. Keywords: early detection; quarantine protocols. PMID- 30472868 TI - Diagnosis of viral central nervous system infections using antipeptide antibody against viral antigen by ELISA. AB - Viral infections of the central nervous system (CNS) occur sporadically and have been extensively studied because of the potential for permanent neurological damage or death. The neurotropic viruses have been reported to lead to various CNS infections. The objective of the present study is to develop an antigen detection ELISA protocol for detection and quantification of viral antigen in CNS infections by assessing the usefulness of antipeptide antibodies against potential peptides of cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), Japanese encephalitis virus (JEV), dengue (DENV), West Nile virus (WNV) and Chandipura virus (CHPV). A total of 182 cerebrospinal fluid (CSF) samples from confirmed, suspected and non-viral infections of the CNS were evaluated using panels of antipeptide antibodies against synthetic peptides of viral proteins. The cases of confirmed and suspected viral infections of the CNS showed 77% and 11% positivity, respectively, for the detection of viral antigen using antipeptide against synthetic peptides of CMV, EBV, VZV and JEV. The concentration of viral antigen was also obtained by using antipeptide of respective viruses in CSF from both the groups. The viral antigen concentration was also correlated with viral load in confirmed cases of viral infection of the CNS. This study demonstrates the use of antipeptide against synthetic peptide derived from CMV, EBV, VZV and JEV in diagnostics of viral infections of the CNS using patients' CSF samples. Keywords: viral infection of the CNS; synthetic peptide; antipeptide antibody; viral load; antigen concentration. PMID- 30472870 TI - Antiviral activity of hypothiocyanite produced by lactoperoxidase against influenza A and B viruses and mode of its antiviral action. AB - Hypothiocyanite (OSCN-) is a natural component of human saliva and is produced by the lactoperoxidase (LPO)/thiocyanate/hydrogen peroxide (H2O2) system. OSCN- has been previously shown to exhibit antiviral activity against influenza viruses (IFV) A/H1N1/2009 and A/H1N2/2009 in vitro as well as antimicrobial and antifungal activities. We elucidated the antiviral activity of OSCN- against both IFV types A and B and the mode of its antiviral action. OSCN- was produced constantly at 900 +/- 200 MUmol/l in Na3PO4 buffer solution containing NaSCN and LPO in the presence of H2O2 as an original OSCN- solution. In a plaque reduction assay, IFV A/PR/8/34 (H1N1), A/Fukushima/13/43 (H3N2), B/Singapore/222/97, and B/Fukushima/15/93 were exposed to various concentrations of OSCN- for 0 to 30 min before adsorption to MDCK cells, and plaque formation was examined. OSCN- exhibited significant similar antiviral activities against all four viruses without cytotoxicity, and the EC50 values for them were from 57 +/- 16 to 148 +/- 27 MUmol/l regardless of the exposure times. The exposure of MDCK cells to OSCN- before viral adsorption did not affect its anti-IFV activity (EC50: more than 450 MUmol/l), but the exposure after viral adsorption affected it moderately (EC50: 380 +/- 40 MUmol/l). Moreover, the exposure of virus particles to OSCN- at 450 MUmol/l did not affect the hemagglutinin activity of IFV in hemagglutination inhibition assay. These results suggest that the attachment of OSCN- to the viral envelope critically contributes to the mode of antiviral action of OSCN- without interfering with viral adsorption. Keywords: hypothiocyanite; influenza virus type A; influenza virus type B; lactoperoxidase; antiviral activity. PMID- 30472869 TI - Combination of virotherapy with VSV and tumor vaccination significantly enhances the efficacy of antitumor therapy. AB - Oncolytic virotherapy offers the potential to treat tumors both as a single agent and in combination with conventional therapies such as chemotherapy and immunological therapy. Here, we describe an effective treatment regimen which combines virotherapy with immunotherapy. IFN-alpha and co-stimulator IL-2 along with tumor cell lysate vaccination with intratumoral administration of oncolytic vesicular stomatitis virus (VSV) resulted in regression of established TC1 papilloma tumor model in C57BL/6 mice. The remarkable results especially in the group receiving tumor vaccination and virotherapy together (TC1-VSV) were obtained. Combination therapy synergistically enhanced CTL activity against tumor cells and reduced tumor size, although significant reduction in tumor size was observed in both groups receiving VSV or tumor vaccine alone. The presented data suggest that the effectiveness of virotherapy is enhanced when combined with immunotherapy by priming specific CD8 T cells against tumor antigens through tumor vaccination and boosting by exposure of antigens upon virus infection. Keywords: virotherapy; VSV; tumor vaccine; immunotherapy; IFN-alpha; IL-2. PMID- 30472871 TI - Counting of viable C. burnetii cells by quantitative reverse transcription PCR using a recombinant plasmid (pCB-dotA) as a standard. AB - Coxiella burnetii is an intracellular pathogenic bacterium and etiological agent of Q fever in humans. Recently, the bacterium has been set free from the strictly intracellular condition by successful cultivation in acidified citrate cysteine medium. Here, we report a bacterial cell counting method that allows rapid quantification of the absolute or relative number of live cells of C. burnetii in a high throughput manner. The method utilizes TaqMan-based quantitative polymerase chain reaction (qPCR) targeting a single dotA gene for determination of genome equivalent (GE) presented either as DNA or complementary DNA (cDNA) synthesized via reverse transcription. The assay was shown to be specific, sensitive and efficiently reproducible. The quantification was linear over a range of 30 to 3x108 copies. Since there is only one copy of the dotA gene per Coxiella chromosome, the calculated dotA copy numbers can be compared to the number of bacterial cells. Finally, we demonstrated the potential of the method to assess effects of antibiotic on cell viability and to determine the antibiotic tolerant fraction within a cell population. Keywords: Coxiella burnetii; Q fever; real-time polymerase chain reaction; copy number; antibiotic; axenic media; dotA gene. PMID- 30472872 TI - Construction of expression vectors of capsid proteins from goose parvovirus and investigation of the immunogenicity. AB - Goose parvovirus (GPV) is a highly contagious and lethal disease in goslings and Muscovy ducklings, and is of concern to the waterfowl industry. With the aim of comparing the cellular immunogenicity of three capsid proteins of GPV, plasmids of pcDNA3.1(+)-VP1, pcDNA3.1(+)-VP2, and pcDNA3.1(+)-VP3 were constructed, and the recombinant protein VPs were expressed using an eukaryotic expression system. We detected the levels of immune-related genes (CD4, CD8alpha, IL-1beta, IL-6, IFNalpha, IFNgamma, and IFNlambda) in both goose embryo fibroblasts (GEF) and goose peripheral blood mononuclear cells (PBMCs) cellular models. The immune response conferred by a VP2 DNA vaccine in vivo was observed in a time course. Our data suggested that the cellular immune response to VP2 and VP3 was stronger than that to VP1, while VP2 and VP3 shared similar cellular immune reactivity. In addition, vaccination with VP2 plasmid can induce high level of IgY antibody that continued to increase through 28 days post vaccination. Therefore, our findings shed light on the host cellular immune response against GPV capsid proteins. Keywords: GPV; capsid proteins; cellular immune response; humoral immunity. PMID- 30472873 TI - Cell-to-cell transmission of lymphocytic choriomeningitis virus MX strain during persistent infection and its influence on cell migration. AB - Lymphocytic choriomeningitis virus (LCMV) can establish in its host a persistent infection, without any prominent symptoms. Even during this infection, when the infectious virions are not released, the virus still disseminates effectively. A very effective and fast way of infection of neighboring cells utilized by many viruses is cell-to-cell transmission. Viruses use different ways of cell-to-cell spread through the extracellular space or by intracellular means through different protrusions. We have found that LCMV strain MX may use three different types of cell-to-cell transport. Firstly, similar to vaccinia virus, it can use actin to propel the virus towards the neighboring cell. Secondly, virus can travel through the intracellular space inside the tunneling nanotubes, that connect the cells even at longer distances and thirdly, the virus may travel on the surface of the membrane of different protrusions connecting two cells. We have also proved that the cells infected by MX strain of LCMV migrate faster than the uninfected cells or cells infected with a different LCMV strain. In accordance with faster migration, the infected cells form more lamellipodia with high expression of keratin 1. In this work, we have introduced three types of cell-to-cell transmission utilized by strain MX of LCMV and showed that even if the cells are not in tight connection, the virus forces them to migrate faster to join the nearest cell. As we show in this work, the virus may use more than one strategy to move to another cell, while each strategy can substitute another. These ways of transmission are very fast and effective and may have a serious impact on the host. Moreover, targeting the cell-to-cell spread, by inhibiting for instance GTPase dynamin, could be an effective way of virus elimination. Keywords: lymphocytic choriomeningitis virus; transmission; migration; keratin 1; nucleoprotein. PMID- 30472874 TI - MAP9 single nucleotide polymorphism rs1058992 is a risk of EBV-associated gastric carcinoma in Chinese population. AB - Microtubule-associated protein 9 (MAP9) is a mitosis-associated protein involved in bipolar spindle assembly. Following DNA damage, MAP9 stabilizes p53 via p300 and MDM2 (mouse double minute-2 homolog). The dysregulation of MAP9 was considered to be associated with tumorigenesis. Single nucleotide polymorphisms (SNPs) in key genes governing mitosis may particularly increase susceptibility to gastric carcinoma (GC). Our study demonstrated that the CC homozygous genotype of SNP rs1058992 located in the MAP9 gene was significantly correlated with EBV associated GC (EBVaGC) in a recessive genetic model (OR = 2.558, 95% CI = 1.306 5.010, P = 0.043), and the C allele frequency of rs1058992 also showed significant correlation with EBVaGC (OR = 1.904, 95% CI = 1.141-3.179, P = 0.013). These results suggest that the MAP9 rs1058992 polymorphism is associated with risk of EBVaGC. The conversion of lysine to arginine caused by rs1058992 may affect development of EBVaGC; however, further studies in larger populations are needed to fully elucidate its role in EBVaGC. Keywords: SNP; EBV; gastric carcinoma; MAP9. PMID- 30472875 TI - The effects of nucleotide usage in key nucleotide positions +4 and -3 flanking start codon on translation levels mediated by IRES of hepatitis C virus. AB - Internal ribosomal entry site (IRES) functions as a cis-acting RNA element, which drives an alternative and cap-independent translation initiation pathway. Currently, there are few studies on effects of nucleotide usages at key nucleotide positions +4 and -3 flanking start codon mediated by IRES of hepatitis C virus (HCV). Herein, we focus on the effect of nucleotide usages at -3 and +4 positions mediated by HCV IRES. The nucleotide contexts flanking AUG start codon employed by HCV IRES is firstly analyzed. We found that each position in the six nucleotide positions (-4 to +6) flanking start codon of HCV has a strong tendency to select the specific nucleotide. A set of bicistronic expression vectors containing CAT gene, HCV IRES and EGFP gene were constructed, including 16 different nucleotide combinations at position -3 and +4. Each set, in which nucleotide at the -3 and +4 position has been changed into different nucleotides, included 16 types of bicistronic expression vectors. It was found that the purine nucleotide at the position -3 or +4 obviously impacts on HCV IRES-related expression, and IRES-driven translation is potentially influenced by the Kozak rule. Our results suggest that optimization of nucleotides at positions -3 and +4 is a convenient and efficient way to enhance the level of IRES-mediated translation. Keywords: Cap-independent translation; internal ribosomal entry site; hepatitis C virus; bicistronic expression vector; translation efficiency. PMID- 30472876 TI - Nitric oxide inhibits the transcription of E6 gene of human papillomavirus. AB - High-risk human papillomavirus (HPV) is an important pathogenic factor for cervical cancer and understanding the mechanism of HPV gene transcription is important for the prevention and therapy of HPV related cervical cancer. This study aimed to investigate the role of nitric oxide (NO) in the regulation of HPV gene transcription. SiHa cells containing integrated HPV16 were treated with NO donor DETA-NO and cell proliferation and cytotoxicity were determined. HPV gene transcription was detected by real-time PCR. We found no significant cytotoxic effects on SiHa cells when the concentration of DETA-NO was less than 0.5 mmol/l. The transcription of HPV E6 gene was inhibited by DETA-NO in a dose-dependent manner and the best inhibitory effect was observed at 0.5 mmol/l DETA-NO. In addition, ERK inhibitor U0126 decreased the transcription of HPV E6 gene at the concentration of 30 MUmol/l. In conclusion, NO inhibits the transcription of HPV E6 gene and probably involves MAPK signaling pathway. Keywords: SiHa cells; nitric oxide; MAPK pathway; HPV transcription. PMID- 30472877 TI - Similar antibody response observed in single-dose-vaccination vs. revaccination against Aujeszky's disease in wild boar. AB - Wild boar is an important reservoir of Aujeszky's disease virus (ADV). There is concern that transmission of this virus from wild boar to domestic pigs is possible. The aim of this work was to compare the antibody response produced by single dose of a gE-deleted ADV vaccine in wild boar to revaccinated animals, to assess if simple single-dose vaccination plans should be examined as a possible control measure against ADV in wild boar. Twenty-five wild boar (ages ranging between 2.5 to 5 months) were included in this study and distributed in three different groups: a control group (n = 5), a single-dose group (10 animals vaccinated only with one dose (day 0)) and a revaccinated group [10 animals vaccinated (day 0) and revaccinated (day 28)]. Mean antibody titers against ADV were determined in three groups using an ELISA assay at three different time points [day 0 (pre-vaccination), 28 (post 1st dose) and 56 (post 2nd dose)]. At day 28, single-dose and revaccinated groups showed a significant increment of antibody titers whereas antibodies in the control group remained stable. At day 56, revaccinated animals did not show a significant increment and antibody titers were similar to those found in animals vaccinated with one dose. These results indicate that vaccination with one dose produces a similar early antibody response to revaccination and therefore, should be examined as a possible control measure against ADV in wild boar. Keywords: Aujeszky's disease; serology; vaccination; wild boar. PMID- 30472878 TI - Sleep Timing During Adolescence: A Latent Transition Analysis Approach. AB - OBJECTIVE/BACKGROUND: This paper utilized a person-centered approach to examine individual differences in sleep timing cross-sectionally and prospectively in adolescents. PARTICIPANTS: Data from Waves 5 and 6 of the Longitudinal Study of Australian Children were used. At Wave 5, the sample included 3,552 Australian adolescents aged 12-13 years (51% males, 49% females); 84% provided data at two year follow-up (Wave 6). METHODS: Through structured interviews, adolescents provided information on sleep timing (bedtimes, sleep-onset times, and wake times) on weekends and weekdays, and relevant covariates. Latent profile analysis identified sleep profiles at Waves 5 and 6 separately; latent transition analysis examined stability and change in profiles across time. RESULTS: Six sleep timing profiles were identified at age 12-13 years: Early Larks (n = 228; 6.4%); Larks (n = 1257; 35.4%); Intermediate (n = 1311; 36.9%); Owls (n = 351; 9.9%); Variable Owls (n = 308; 8.7%); and, Late Owls (n = 97; 2.7%). Six similar profiles were identified at age 14-15 years. The latent transition analysis indicated that the Early Larks, Larks, and Intermediate profiles were more stable over time compared with the Owls, Variable Owls, and Late Owls profiles. Higher body mass index (BMI) and longer screen time predicted transitions from Larks and Early Larks to the Owls, Variable Owls, and Late Owls profiles. CONCLUSIONS: Many adolescents showed healthy sleep timing, which continued with age. However, the Variable Owls, Owls, and Late Owls profiles reflected less healthy and more variable sleep patterns that may require targeted interventions. PMID- 30472879 TI - Validity of Actigraphy in Young Adults With Insomnia. AB - OBJECTIVE/BACKGROUND: Actigraphy is an inexpensive and objective wrist-worn activity sensor that has been validated for the measurement of sleep onset latency (SOL), number of awakenings (NWAK), wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency (SE) in both middle-aged and older adults with insomnia. However, actigraphy has not been evaluated in young adults. In addition, most previous studies compared actigraphy to in-lab polysomnography (PSG), but none have compared actigraphy to more ecologically valid ambulatory polysomnography. PARTICIPANTS: 21 young adults (mean age = 19.90 +/- 2.19 years; n = 13 women) determined to have chronic primary insomnia through structured clinical interviews. METHODS: Sleep diaries, actigraphy, and ambulatory PSG data were obtained over a single night to obtain measures of SOL, NWAK, WASO, time spent in bed after final awakening in the morning (TWAK), TST, and SE. RESULTS: Actigraphy was a valid estimate of SOL, WASO, TST, and SE, based on significant correlations (r = 0.45 to 0.87), nonsignificant mean differences between actigraphy and PSG, and inspection of actigraphy bias from Bland Altman plots (SOL alpha = 1.52, WASO alpha = 7.95, TST alpha = -8.60, SE alpha = -1.38). CONCLUSIONS: Actigraphy was a valid objective measure of SOL, WASO, TST, and SE in a young adult insomnia sample, as compared to ambulatory PSG. Actigraphy may be a valid alternative for assessing sleep in young adults with insomnia when more costly PSG measures are not feasible. PMID- 30472880 TI - Combined effects of cognitive impairment and pre-frailty on future frailty and death in older Mexican Americans. AB - OBJECTIVES: Impaired cognition and pre-frailty are associated with poor health outcomes. However, research has not examined the combined impact of cognitive impairment and pre-frailty on future frailty and mortality among older Mexican Americans. METHODS: Data for this analysis came from the 2006-2007 and 2010-2011 waves of the Hispanic EPESE. The final sample included 639 Mexican Americans aged >=77 years who were non-frail or pre-frail in 2006-2007. Frailty measure included weight loss, exhaustion, weakness, and slow walking speed. Participants were classified as non-frail (0 criteria) and pre-frail (1 criterion) at baseline. Cognitive impairment was defined as <21 points on the MMSE. At baseline, participants were grouped as: cognitively intact non-frail, cognitively intact pre-frail, cognitively impaired non-frail, and cognitively impaired pre-frail. Logistic and hazard regression models were used to evaluate the odds of being frail in 2010-2011 and risk for 10-year mortality. RESULTS: Cognitively impaired pre-frail participants were more likely to become frail (OR = 4.82, 95% CI = 2.02 11.42) and deceased (HR = 1.99, 95% CI = 1.42-2.78). Cognitively impaired non frail participants had significantly higher risk for mortality (HR = 1.55, 95% CI = 1.12-2.19) but not frailty (OR = 1.29, 95% CI = 0.50-3.11). Being cognitively intact and pre-frail at baseline was not significantly associated with being frail at follow-up (OR = 1.62, 95% CI = 0.83-3.19) or mortality (HR = 1.29, 95% CI = 0.97-1.71). CONCLUSIONS: Comorbid cognitive impairment and pre-frailty is associated with future frailty and mortality in older Mexican Americans. Screening for cognitive impairment may be effective for identifying pre-frail Mexican Americans who are at the highest risk of frailty and mortality. PMID- 30472881 TI - Depression care services and telehealth technology use for homebound elderly in the United States. AB - OBJECTIVES: Despite the increasing evidence for the effectiveness of telehealth technology in screening and treating depression in older adults, they have been slowly adopted by Home Health Care (HHC) agencies. Therefore, this study was conducted to determine how HHC agencies perceive and use telehealth technology for depression care among homebound older adult patients. METHODS: Five-hundred and-sixteen staff from the National Association for Homecare & Hospice (NAHC) member home health care agencies completed the online survey. Questions were asked of HHC staff regarding performance expectancy, effort expectancy, social influences, facilitating conditions, telehealth use and intention to use/continue to use telehealth. RESULTS: The majority had a neutral or positive perception towards telehealth. However, participants from agencies that have yet to use telehealth (mean: 3.25, SD: 1.56) reported a less intention to use the technology for depression care versus those from agencies that did (mean: 4.64, SD: 1.37). This may be partially explained by the finding that only 32% perceived themselves as having the knowledge and 25% as having resources to use telehealth. Additionally, facilitating conditions and social influences were significant predictors of intention to use/continue to use telehealth for depression care (p values < .01). CONCLUSION: Overall, staff had a neutral or positive perception towards telehealth. Factors such as fewer years of experience in using telehealth and a small annual budget may explain a negative perception towards telehealth. Therefore, further education and resources are needed to support telehealth use. Future studies may consider comparing telehealth programs and identifying supporting policies. PMID- 30472882 TI - Visible-light optical coherence tomography-based multimodal system for quantitative fundus autofluorescence imaging. AB - IMPACT STATEMENT: Quantitative fundus autofluorescence imaging with simultaneous visible-light optical coherence tomography-based multimodal technology has potential significant impact on the diagnosis and monitoring the progression of retinal diseases. PMID- 30472883 TI - Trientine selectively delivers copper to the heart and suppresses pressure overload-induced cardiac hypertrophy in rats. AB - IMPACT STATEMENT: Our study reveals that TETA, traditionally regarded as a copper chelator, in lower doses delivers copper selectively to the heart through a mechanism independent of copper transporter-1 or -2. Copper supplementation by a lower dose of TETA suppresses pressure overload-induced cardiac hypertrophy. Since ischemic heart disease and hypertrophic cardiomyopathy are accompanied by myocardial copper loss, this approach of using a lower dose of TETA to supplement copper to the heart would help treat the disease condition of patients with such cardiac events. PMID- 30472884 TI - Brain-derived neurotrophic factor in peripheral blood mononuclear cells and stroke outcome. AB - IMPACT STATEMENT: There are a great number of arguments suggesting that BDNF could be involved in stroke recovery dependent of neuroplasticity. Methods that can enhance BDNF levels in the ischemic brain could therefore have great clinical value. Peripheral blood mononuclear cells (PBMC) that contain BDNF and infiltrate early and sustainably the ischemic brain might be used as a cellular vector to deliver BDNF to the ischemic brain and consequently promote recovery. This work is important in this field to show if this BDNF derived from BDNF could exert a positive action on stroke recovery. Our main results showed that a high BDNF level at day 3 after hospital admission was associated with a 12.4 fold increase in favorable outcome after adjusting for still recognized prognostic markers. The new information in this field is this finding identifies PBMC as an attractive cellular vector to deliver BDNF to the ischemic brain. PMID- 30472885 TI - Comparative evaluation of CacyBP/SIP protein, beta-catenin, and immunoproteasome subunit LMP7 in the heart of rats with hypertension of different etiology. AB - IMPACT STATEMENT: Despite extensive research into the pathogenesis of hypertension and disease-related end organ damage, the mechanisms leading to cardiac complications of hypertensive patients are still not fully elucidated. The aim of the presented research was immunodetection and evaluation of CacyBP/SIP, beta-catenin, and proteasomes in the hearts of rats with hypertension of different etiology. Our results show an innovative and important network of interactions between proteins potentially involved in the development and progression of heart problems in various types of hypertension. This report might contribute to deeper understanding of the role of the CacyBP/SIP protein, beta catenin, and proteasomes in heart function. Our results might also bring new information concerning the intracellular processes and signal pathways involved in the regulation of cardiomyocytes functioning in hypertension state. In addition to cognitive significance, the results of presented studies may contribute to further successes in preventing and treatment of cardiac complications associated with hypertension. PMID- 30472886 TI - Does Type 1 Diabetic Adolescents' Fear of Stigmatization Predict a Negative Perception Insulin Treatment? AB - The purpose of this study was to investigate stigmatization, sociodemographic/diabetes-related characteristics and parents-related characteristics as predictors of a negative perception of insulin treatment in adolescents with type 1 diabetes in Turkey. The study was carried out using a cross-sectional correlation design. The research sample included 80 adolescents with type 1 diabetes who volunteered to take part. A positive perception of insulin treatment (beta = -.38, p < .001), stigmatization (beta = -.24, p = .013), informing others about one's type 1 diabetes (beta = .24, p = .017) and only using insulin when alone in public places (beta = .19, p = .042) were significant predictors of a negative perception of insulin treatment, and these variables explained 35% of the common variance. Diabetes' nurses should take stigmatization into account during their training and plan appropriate measures. Entrepreneurial, randomized, and controlled studies should be conducted to decrease the negative influence of stigmatization on the perception of insulin treatment in individuals with type 1 diabetes. PMID- 30472887 TI - Methomyl induced effect on fortilin and S100A1 in serum and cardiac tissue: Potential biomarkers of toxicity. AB - Methomyl toxicity has been reported as a cause of several accidental and suicidal fatalities. The study is evaluating the effect of lethal methomyl toxicity on fortilin and S100A1 in serum and cardiac tissues. Adult 96 female Sprague-Dawley rats were divided equally into a control (euthanized by cervical dislocation) and a study group (overdosed with methomyl). The levels of fortilin and S100A1 in serum were measured antemortem (to establish the basal levels in serum) and postmortem (to evaluate changes after methomyl exposure) using enzyme-linked immunoassay. S100A1 was immunostained in sections from cardiac tissues. Both proteins in the control were not significantly different ( p > 0.05) compared with the antemortem levels. On the contrast, both biomarkers levels in the intoxicated group were remarkably higher ( p < 0.001) than the control and the antemortem levels. Ventricular tissues from the intoxicated rats presented depleted S100A1 immunostain in cardiomyocytes localized mainly in the epicardium with deeply stained adjacent cardiac fibroblasts. The cardiomyocytes were damaged with a prominent loss of striations compared to normal cardiac tissues from the control. The present outcomes explain to a certain degree the potential toxic effect of methomyl poisoning on the cardiac tissue. Both proteins could be added to the currently available battery of markers for assessing methomyl toxicity. PMID- 30472888 TI - Development and Validation of a Filial Piety Scale for Chinese Elders in Contemporary China. AB - This study was designed to validate the newly developed Filial Piety Scale for Chinese Elders (FPSCE) in measuring elders' filial norms in contemporary China by administering questionnaire survey with 521 elders aged 70 years and older in Beijing, China. Validity and reliability tests were applied. Through exploratory factor analysis and confirmatory factor analysis, a conceptually meaningful three factor model with 12 items was obtained, consisting of "caring for parents," "familial entirety," and "familial aspiration." The FPSCE showed good internal consistency, satisfactory discriminant validity, criterion-related validity, and significant correlations for some variables related to demographic characteristics, health status, and financial condition. The construction of the FPSCE indicates that elders' understanding of filial piety and their expectation of their children may have changed. The FPSCE shows that contemporary elders in China hold less authoritative but more reciprocal stances toward filial piety. The FPSCE can be used to advance the contextualized understanding of filial piety in contemporary Chinese societies, to help facilitate the development of family friendly policies in aging societies, and to meet the challenges associated with an accelerating aging population. PMID- 30472889 TI - Social support, disclosure and stigma and the association with non-adherence in the six months after antiretroviral therapy initiation among a cohort of HIV positive adults in rural KwaZulu-Natal, South Africa. AB - The World Health Organisation (WHO) recommends antiretroviral treatment (ART) initiation at human immunodeficiency virus (HIV) diagnosis. As ART programmes expand, addressing barriers to adherence is vital. Past mixed findings on the association between social support, stigma and non-disclosure with ART adherence highlights the need for further research. The primary aim of this study was to examine how these factors are associated with ART non-adherence in the six months after ART initiation. The secondary aim was to explore how other factors are associated with non-adherence. We conducted secondary analysis of prospective data from HIV-positive adults initiating ART. Social support, disclosure patterns, perceived stigma and other demographic factors were collected at ART initiation and six months follow-up. Logistic regression models were used to examine factors associated with self-reported ART non-adherence in the last six months and the last month before the six month follow-up ("recent"). Non adherence in the last six months was twenty-five percent and recent non-adherence was nine percent. There was no association between non-adherence and social support, stigma or non-disclosure of HIV status. In the final model the odds of non-adherence in the last six months were significantly higher for those: with incomplete ART knowledge (aOR 2.10, 95%CI 1.21-3.66); who visited a healthcare provider for conditions other than HIV (aOR1.98, 95%CI 1.14-3.43); had higher CD4 counts at ART initiation (CD4 100-199:aOR 2.50, 95%CI 1.30-4.81; CD4 >= 200:aOR 2.85, 95%CI 1.10-7.40;referent CD4 < 100 cells/mm3); had tested HIV-positive in the last year (aOR 2.00, 95%CI 1.10-3.72; referent testing HIV-positive outside the last year); experienced a rash/itching secondary to ART (aOR 2.48, 95%CI 1.37 4.52); and significantly lower for those >=48 years (aOR 0.65, 95%CI 0.46-0.90). Early non-adherence remains a concern. Incorporation of adherence monitoring and ART knowledge enhancement into appointments for ART collection may be beneficial. PMID- 30472890 TI - Poor Sleep Associates With Recent Nonsuicidal Self-Injury Engagement in Adolescents. AB - OBJECTIVE/BACKGROUND: Poor sleep has been shown to have multiple negative outcomes during adolescence, in both academic and mental health domains. Several studies have identified the association between poor sleep and suicide risk in adolescents. However, onset of and engagement in nonsuicidal self-injury (NSSI) is also common in this age group, but this behavior has rarely been studied in association with sleep in adolescent samples. In the current study, it was expected that poorer sleep and more symptoms of insomnia would associate with a greater likelihood of recent NSSI engagement and greater NSSI severity. PARTICIPANTS: Data were collected from 387 community adolescents (mean age = 14.19, SD = 1.08), 9% of whom reported NSSI in the past 6 months. The gender breakdown was about even (52% female) and the majority of the sample was White (88.5%). METHODS: Adolescent participants were recruited from middle and high schools for a study on mental health and risk behaviors. Researchers visited schools and administered self-report questionnaires to students in large groups. Measures assessed NSSI engagement and severity features, overall sleep quality, and insomnia symptoms. RESULTS: Results indicated that greater insomnia symptoms, but not overall sleep quality, were significantly associated with greater likelihood of recent NSSI engagement. Sleep variables were not significantly associated with NSSI severity among adolescents with recent NSSI. CONCLUSIONS: Insomnia symptoms seem to be associated with recent engagement in NSSI. Adolescents who report symptoms of insomnia should also be assessed for self-harm behavior. PMID- 30472891 TI - Exploring the role of excess fluoride in chronic kidney disease: A review. AB - This review covers nearly 100 years of studies on the toxicity of fluoride on human and animal kidneys. These studies reveal that there are direct adverse effects on the kidneys by excess fluoride, leading to kidney damage and dysfunction. With the exception of the pineal gland, the kidney is exposed to higher concentrations of fluoride than all other soft tissues. Therefore, exposure to higher concentrations of fluoride could contribute to kidney damage, ultimately leading to chronic kidney disease (CKD). Among major adverse effects on the kidneys from excessive consumption of fluoride are immediate effects on the tubular area of the kidneys, inhibiting the tubular reabsorption; changes in urinary ion excretion by the kidneys disruption of collagen biosynthesis in the body, causing damages to the kidneys and other organs; and inhibition of kidney enzymes, affecting the functioning of enzyme pathways. This review proposes that there is a direct correlation between CKD and the consumption of excess amounts of fluoride. Studies particularly show immediate adverse effects on the tubular area of human and animal kidneys leading to CKD due to the consumption of excess fluoride. Therefore, it is very important to conduct more investigations on toxicity studies of excess fluoride on the human kidney, including experiments using human kidney enzymes, to study more in depth the impact of excess fluoride on the human kidney. Further, the interference of excess fluoride on collagen synthesis in human body and its effect on human kidney should also be further investigated. PMID- 30472892 TI - The effect of conjoint tendon release on gait after direct anterior total hip arthroplasty. AB - INTRODUCTION:: There has been considerable interest in the direct anterior (DA) approach to total hip arthroplasty (THA) recently. To facilitate exposure of the proximal femur it is sometimes necessary to release the conjoint tendon. AIM:: To prospectively investigate whether release of the conjoint tendon has an impact on gait in the early postoperative period. METHODS:: We measured gait velocity, stride length, single-limb support and single-limb support symmetry preoperatively, at discharge from the hospital, and 2, 6 and 12 weeks and postoperatively. Participants also completed the Timed Up and Go and a series of questionnaires (WOMAC, SF-12, Harris Hip Score, and pain VAS) at each visit. RESULTS:: 36 participants undergoing a DA THA with a single surgeon were enrolled in this study. 22 participants had a release of the conjoint tendon during their surgery. We found no differences between the groups for any gait, patient reported or surgical outcomes ( p < 0.05). There was a total of 3 complications reported in the release group, and 1 complication in the group that did not have a release. CONCLUSION:: Although the conjoint tendon has an important role in the biomechanics of the hip, we found release of the conjoint tendon during the DA approach for THA to have no impact on gait or patient reported outcomes within 12 weeks post-surgery. Therefore, if the exposure of the proximal femur is limited, a low threshold for release of the conjoint tendon is recommended to improve visualisation. PMID- 30472893 TI - Is a cementless fixation of the femoral component suitable for metal-on-metal hip resurfacing arthroplasty? AB - BACKGROUND:: Hip resurfacing arthroplasty (HRA) typically uses a hybrid design (cemented femoral component and cementless acetabular shell) but has recently been performed with fully cementless components. There is a paucity of information on the clinical performance of these cementless designs. METHODS:: The UCLA clinical scores, SF-12 quality of life scores, complication rates, survivorship and radiographic signs of loosening or gross stress shielding of 39 hips (39 male patients) implanted with cementless HRA were compared with those of 40 hips (37 male patients) implanted with hybrid HRA during the same time frame. RESULTS:: There were no significant differences in postoperative clinical and quality of life scores, complication rates, or radiographic signs of loosening between the 2 groups. The 5-year Kaplan-Meier survivorship was 97.2% for the cementless group and 100% for the hybrid group. This difference was not significant ( p = 0.3694). There were no femoral component failures in any of the 2 groups. CONCLUSIONS:: At a mean follow-up of 6 years, there is no tangible difference between the performance of cementless HRA compared to hybrid HRA. The absence of learning curve associated with this device and the potential for better preservation of femoral neck bone mineral density suggest that this technology is well suited for young patients with good bone quality seeking to resume an active lifestyle including high-impact activities. PMID- 30472894 TI - Effects of low-level combined static and weak low-frequency alternating magnetic fields on cytokine production and tumor development in mice. AB - We investigated the effects of weak combined magnetic fields (MFs) produced by superimposing a constant MF (in the range 30 - 150 uT) and an alternating MF (100 or 200 nT) on cytokine production in healthy Balb/C male mice exposed 2 h daily for 14 days. The alternating magnetic field was a sum of several frequencies (ranging from 2.5 - 17.5 Hz). The frequencies of the alternating magnetic field were calculated formally based on the cyclotron resonance of ions of free amino acids (glutamic and aspartic acids, arginine, lysine, histidine, and tyrosine). The selection of different intensity and frequency combinations of constant and alternating magnetic fields was performed to find the optimal characteristics for cytokine production stimulation in immune cells. MF with a constant component of 60 MUT and an alternating component of 100 nT, which was a sum of six frequencies (from 5 to 7 Hz), was found to stimulate the production of tumor necrosis factor alpha, interferon-gamma, interleukin-2, and interleukin-3 in healthy mouse cells and induce cytokine accumulation in blood plasma. Then, we studied the effect of this MF on tumor-bearing mice with solid tumors induced by Ehrlich ascite carcinoma cells by observing tumor development processes, including tumor size, mouse survival rate, and average lifespan. Tumor-bearing mice exposed to a combined constant magnetic field of 60 MUT and an alternating magnetic field of 100 nT containing six frequencies showed a strong suppression of tumor growth with an increase in survival rate and enhancement of average lifespan. PMID- 30472895 TI - Long-term systemic treatment with lysergic acid diethylamide causes retinal damage in CD1 mice. AB - As a classical hallucinogen with high potential for abuse, lysergic acid diethylamide (LSD) can cause long-lasting abnormalities in retina, but little is known about the exact mechanism. This study was to investigate effects of long term systemic treatment of LSD at low dose on retinal damage and understand the underlying mechanisms. CD1 mice were treated intraperitoneally with 0.1 mg/kg or 0.2 mg/kg LSD daily for 2 months, mice treated with saline as negative control. Electroretinography (ERG) was used to test the retinal function after LSD treatment. Hematoxylin and eosin staining was used to show the retinal morphology and evaluate the loss of photoreceptor cells. Terminal deoxynucleotidyl transferase dUTP Nick end labeling (TUNEL) assay was used to detect the apoptotic cells. Enzyme-linked immunosorbent assays were used to show the oxidative stress and inflammatory response. Real-time PCR and western blot were applied to measure the gene and protein change to explore the underlying mechanisms. Results demonstrated that 2 months treatment with LSD caused retinal damage, evidenced by decreased ERG response and increased apoptotic photoreceptor cells through increasing oxidative stress and inflammatory response. Our study indicated that long-term systemic administration of LSD caused neurotoxic effects on retinas of CD1 mice, suggesting the potential mechanisms for the retina damage caused by LSD abuse. PMID- 30472896 TI - Berberine suppresses the ectopic expression of miR-133a in endothelial cells to improve vascular dementia in diabetic rats. AB - OBJECTIVE: Vascular dementia is the second leading cause of dementia, which is strongly associated with diabetes. Ectopic expression of miR-133a in endothelial cells is involved in endothelial dysfunction in diabetes. Whether berberine, as a natural product in Coptis chinensis, improves vascular dementia induced by diabetes remains unknown. METHODS: Diabetes and subsequent vascular dementia were induced in rats by injecting streptozotocin (50 mg/kg/day) for five consecutive days. The expression of miR-133a was determined by fluorescence in situ hybridization. The learning and memory were evaluated by step-down, step-through, and morris water maze (MWM) tests. RESULTS: In streptozotocin-injected rats, hyperglycemia dramatically induced miR-133a ectopic expressions in vascular endothelium, reduced GTPCH1 gene expressions and BH4 levels, which were reversed by berberine administration (1.0 g/kg/day, 8 weeks). Hyperglycemia also inhibited acetylcholine-induced vasorelaxation in middle cerebral artery and reduced blood supply to the brain, which were bypassed by berberine. Ex vivo studies indicated that miR-133a agomirs abolished these beneficial effects of berberine on acetylcholine-induced vasorelaxation, while supplement of L-sepiapterin prevented endothelial dysfunction in middle cerebral artery isolated from rats. By performing step-down, step-through, and MWM tests, we observed that hyperglycemia significantly caused the impairments of learning and memory in streptozotocin injected rats. Importantly, these aberrant phenotypes in diabetic rats were normalized by berberine therapy. Finally, berberine reduced miR-133a expression, and increased both BH4 levels and NO production in cultured endothelial cells treated with high glucose. CONCLUSION: Berberine improves vascular dementia in diabetes, which is possibly related to the suppression of miR-133a ectopic expression in endothelial cells. PMID- 30472897 TI - Cognitive and behavioral impairments in German and Chinese ALS populations - a post-hoc comparison of national study data. AB - This study aimed to clarify whether differences between German and Chinese studies using the standardized Edinburgh Cognitive and Behavioural ALS Screen (ECAS), might be explained by differences in translated versions of ECAS, by patient demographic or clinical characteristics or by population-specific factors. Comparisons were performed on data from two previous studies in Germany and China. We found except for spelling task (p = 0.05), no differences between control groups of two countries were detected after adjusting for demographics. In contrast, differences were observed in scores on total ECAS, ALS-specific function such as different executive functions (all p < 0.01) and language (p = 0.02), even after correcting for demographic and clinical variables. Chinese ALS cohort performed worse in executive subfunction scores for sentence completion, alternation, social cognition, digit span and language comprehension; they performed better in spelling. Chinese ALS cohort more frequently exhibited disinhibition (p = 0.02), whereas German cohort more frequently exhibited loss of sympathy (p = 0.01) and stereotyped behavior (p = 0.03). Chinese and German ALS cohorts showed a distinctly different pattern in executive and language function. Most of the differences might be related to distinct differences between populations as only spelling might be affected by different language versions of ECAS. Socio-cultural factors might explain behavioral profile differences. PMID- 30472898 TI - Serotonergic mechanisms in the 6-Hz psychomotor seizures in mice. AB - Serotonin (5-hydroxytrytamine (5-HT)) plays an important role in experimental seizures. Recently, we reported the depletion of 5-HT by parachlorophynylalanine (PCPA) in whole brain to enhance 6-Hz psychomotor seizures in mice. In the present work, we investigated the effect of 5-HT depletion in cortex and hippocampus, brain regions relevant for epilepsy, on behavioral and ultra structural changes following 6-Hz psychomotor seizures in mice. In addition, we studied the effect of sodium valproate (SVP) on behavioral, biochemical, and ultra-structural effects induced by 6 Hz. Behavioral changes induced by 6 Hz stimulation were characterized as the increased duration of Straub's tail, stun position, twitching of vibrissae, forelimb clonus, and increased rearing and grooming. PCPA administration further enhanced while SVP reduced these behaviors in mice. The 6-Hz psychomotor seizure induced ultra-structural changes in both cortex and hippocampus in mice treated with PCPA. Furthermore, PCPA administrations followed by 6Hz-induced seizures were accompanied by reduced hippocampal and cortical 5-HT. SVP attenuated the PCPA-induced ultra-structural changes and alterations of 5-HT content in the mouse brain. The study suggests the involvement of 5-HT in the 6 Hz psychomotor seizures and in the mechanisms of action of SVP against such seizures in mice. PMID- 30472900 TI - Abdominal Obesity is Associated With Lower Bone Mineral Density in Non-Weight Bearing Site in Korean Men. AB - This research aimed to investigate the relationship between abdominal obesity and lower bone mineral density (BMD) at non-weight-bearing site in Korean men using data from the Korea National Health and Nutrition Examination Survey, which is a nationwide cross-sectional survey. The study population ( n = 5,941) was selected from the 2009-2010 survey. Abdominal obesity in men was defined as waist circumference ? 90 cm. Lower BMD state was defined as having T-score of -2.5 or below. To investigate the association, multiple logistic regression analysis was performed. Abdominal obesity was highly associated with lower non-weight-bearing site (lumbar spine [LS]) BMD after adjustment (odds ratio [OR] 1.61, 95% CI [1.06, 2.44], p = .026). Also, abdominal obesity was a risk factor for lower LS BMD, especially in age groups of those in their 20s and those over 60s (OR 5.53, 95% CI [1.27, 24.07], p = .023 for 20s; OR 2.19, 95% CI [1.19, 4.02], p = .011 for 60 years or older). Abdominal obesity in Korean men is associated with lower BMD at non-weight-bearing site (LS), especially in younger and older age groups. Further research might be recommended to prove the mechanism or causality. PMID- 30472901 TI - Effects of technology-mediated mindfulness practice on stress: psychophysiological and self-report measures. AB - Repeated exposure to stressors, even if mild, may alter the efficiency of optimal stress responses and hinder emotion regulation skills. Mindfulness meditation, by strengthening self-regulation and awareness, may optimize the efficiency of physiological, cognitive, and behavioral reactions to stressful events but typically requires notable commitment to practice, which often leads to disengagement. Recent research suggested that such practices may be made more accessible and that the potential for self-enhancement and stress management of meditation might be improved by supporting mental training with wearable neurofeedback devices able to inform the practicer on ongoing modulation of bodily and brain activity. This study aimed at testing the effect of such novel training approach based on the integration of mental training with brain-sensing wearable devices on physiological (heart rate and variability) and subjective markers of stress (perceived stress, anxiety, and mood states). Participants (N = 55) have been randomly divided into an active control (CONTg) and an experimental group (EXPg). Both groups completed a four-week training constituted by brief daily activities based on mindfulness practices. Experimental participants practiced with the support of dedicated brain-sensing devices. By analyzing pre- and post-training assessments, we observed relevantly decreased stress and anxiety measures in EXPg, as well as relevantly decreased mental fatigue and increased vigor. EXPg also showed improved physiological markers of vagal tone both at rest and during exposure to a cognitive stressor. Reported findings add to the limited available literature on potential effects of technology-supported mental training protocols for promoting subjective well-being and enhancing self regulation skills. PMID- 30472899 TI - Development of dual-drug-loaded stealth nanocarriers for targeted and synergistic anti-lung cancer efficacy. AB - Combination chemotherapy is widely exploited for suppressing drug resistance and achieving synergistic anticancer efficacy in the clinic. In this paper, the nanostructured targeting methotrexate (MTX) plus pemetrexed (PMX) chitosan nanoparticles (CNPs) were developed by modifying methoxy polye (thylene glycol) (mPEG), in which PEGylation CNPs was used as stealth nanocarriers (PCNPs) and MTX was employed as a targeting ligand and chemotherapeutic agent as well. Studies were undertaken on human lung adenocarcinoma epithelial (A549) and Lewis lung carcinoma (LLC) cell lines, revealing the anti-tumor efficacy of nanoparticle drug delivery system. The co-delivery nanoparticles (MTX-PMX-PCNPs) had well dispersed with sustained release behavior. Cell counting kit-8 (CCK8) has been used to measure A549 cell viability and the research showed that MTX-PMX-PCNPs were much more effective than free drugs when it came to the inhibition of growth and proliferation. Cell cycle assay by flow cytometry manifested that the MTX-PMX PCNPs exhibited stronger intracellular taken up ability than free drugs at the same concentration. In vivo anticancer effect results indicated that MTX-PMX PCNPs exhibited a significantly prolong blood circulation, more tumoral location accumulation, and resulted in a robust synergistic anticancer efficacy in lung cancer in mice. The results clearly demonstrated that such unique synergistic anticancer efficacy of co-delivery of MTX and PMX via stealth nanocarriers, providing a prospective strategy for lung cancer treatment. PMID- 30472903 TI - Identification of a novel 43-bp insertion in the heparan sulfate 6-O sulfotransferase 3 (HS6ST3) gene and its associations with growth and carcass traits in chickens. AB - Previous studies have revealed a significant association between SNPs found within the heparan sulfate 6-O-sulfotransferase 3 (HS6ST3) gene and obesity. This study identified a novel 43-bp indel polymorphism in intron 1 of HS6ST3 in 1963 chickens from nine different breeds, and three genotypes, designated II, ID and DD, were observed. The frequency of the 'I' (0.62-0.87) allele was higher than that of the 'D' (0.13-0.38) allele. A total of 777 individuals of the Gushi-Anka F2 resource population were used for the analysis of associations according to growth traits, carcass traits, serum variables and meat quality traits. The results showed that the 43-bp indel polymorphism was significantly associated with the body weight at 4 and 6 weeks of age, chest depth at 4 and 12 weeks of age and shank girth at 12 weeks of age (P < 0.05). In terms of the carcass traits, the indel polymorphism was significantly associated with breast muscle weight, heart weight and leg weight (P < 0.05). These findings suggested that this indel polymorphism has the potential to become a new target for the marker assisted selection of chicken growth and carcass traits. PMID- 30472904 TI - Websites Related to Volume 32, Issue 3. PMID- 30472902 TI - Clarithromycin Laurate Salt: Physicochemical Properties and Pharmacokinetics after Oral Administration in Humans. AB - Clarithromycin laurate (CLM-L), a fatty acid salt of clarithromycin (CLM), was prepared by a simple co-melting process. The formation of CLM-L was confirmed using FTIR, 1H NMR, and 13C NMR. Solubility, intrinsic dissolution rate (IDR), and partitioning properties of CLM-L were determined and compared to those of CLM. As expected, CLM-L showed a greater hydrophobicity than CLM with lower aqueous solubility, higher partitioning coefficient, and slower dissolution rate in comparison to CLM. Tablets of CLM-L also showed a significantly slower in vitro release in comparison to CLM tablets. Bioavailability of CLM from CLM-L tablets was evaluated in healthy volunteers and compared to immediate release CLM tablets. Cmax, Tmax and AUC0->infinity of CLM-L tablets and immediate release CLM tablets did not show a significant difference. However, the AUC0->2 for the CLM-L tended to be higher than that of CLM at all-time points. This suggested that the CLM-L exhibited a slight absorption enhancement in comparison to CLM. However, its pharmacokinetic behavior was comparable to that of CLM. PMID- 30472905 TI - Experiences of the effects of physical activity in persons with irritable bowel syndrome (IBS): a qualitative content analysis. AB - OBJECTIVE: Increased physical activity has been tested among patients with irritable bowel syndrome (IBS) in a randomized trial which demonstrated improvement in gastrointestinal (GI) symptoms. The patients' experiences of the effects of physical activity on IBS symptoms are unknown. This knowledge is necessary to enable suitable support from health care professionals. The aim of this study was therefore to explore patients' experiences of the effects of physical activity. MATERIALS AND METHODS: Deep interviews were conducted with 15 patients (10 women and 5 men) aged 31-78 years. Their IBS had lasted for 10-57 years. The transcribed interviews were analyzed through a qualitative content analysis. RESULTS: The analysis of the material revealed three themes; GI symptoms, extra-intestinal symptoms, and quality of life (QOL). In relation to GI symptoms, the patients discussed how physical activity affected these symptoms and how they used physical activity to normalize and control their GI symptoms. Extra-intestinal symptoms were also affected by physical activity, and the patients described how they experienced a general bodily wellbeing as well as improved mood and energy in relation to physical activity. In terms of QOL, the patients discussed their perspectives on physical activity as giving them achievements, being pleasurable, and being strengthening of the self. CONCLUSIONS: Our results emphasize the importance of taking into account the patient's experiences of the effects of physical activity when coaching patients with IBS to be physically active. Using a person-centred approach incorporating, the patient's own experiences and resources is the key to successfully promoting physical activity in the clinic. PMID- 30472906 TI - Edaravone inhibits autophagy after neuronal oxygen-glucose deprivation/recovery injury. AB - Edaravone is an oxygen free radical scavenger that is widely used to treat ischemic injury to the nervous system. The present study investigated the effect of edaravone pretreatment on neurons subjected to oxygen-glucose deprivation/recovery (OGD/R) injury. Common neurons were subjected to oxygen and glucose deprivation for 1 h, followed by oxygen and glucose recovery for 0.5 h, 2 h, 6 h, and 12 h to establish the OGD/R model. Autophagy was assessed by electron microscope observation of autophagosomes, cell immunofluorescence, mRFP-GFP-LC3 virus cell fluorescence and western blotting analyses of the autophagy-related proteins. The findings showed that at OGD/R 2 h autophagy was high. Next, neurons were pretreated with different concentrations of edaravone (0 MUM, 5 MUM, 10 MUM, 25 MUM, 50 MUM, and 100 MUM) before establishing the OGD/R model. Western blotting was used to analyze the expression of autophagy-related proteins. The CCK-8 assay was used to analyze cell viability after pretreatment with different concentrations of edaravone. Optimal inhibition of autophagy was achieved with the concentration of edaravone 50 MUM. Neurons pretreated with 50 MUM edaravone and established OGD/R model were analyzed for autophagy levels. At every OGD/R time point autophagy was lower in neurons pretreated with edaravone than in those not pretreated with the drug. The difference was statistically significant without OGD/R 12 h. Thus, it appears that pretreatment with edaravone may reduce the level of autophagy in neurons subjected to OGD/R injury. PMID- 30472907 TI - Less severe disease in patients with early systemic sclerosis? AB - OBJECTIVES: To evaluate the disease severity and activity in patients with a diagnosis of systemic sclerosis (SSc) after the 2013 ACR/EULAR classification criteria development compared to patients diagnosed before 2013. METHODS: One hundred and fifty-four subjects were included and assigned to the following groups: 120 SSc patients meeting the 1980 ACR criteria and with a diagnosis before 2013 (historical group), and 34 patients diagnosed after 2013, fulfilling the new ACR/EULAR criteria (early SSc group). Disease activity was assessed by the 2001 European Scleroderma Study Group Activity Index (EScSG-AI) and by the revised European Scleroderma Trials and Research group (EUSTAR) activity index. Disease severity was assessed using the Medsger Disease Severity Scale (DSS) and the summed DSS score. RESULTS: The time between the first non-Raynaud's symptom and the diagnosis was shorter in early SSc than in the historical group (p = 0.001). The EScSG-AI and the EUSTAR activity index were similar between groups. The summed DSS score and the general, skin and gastrointestinal tract DSS scores were significantly lower in early SSc than in the historical group. CONCLUSION: SSc patients with a diagnosis after the new ACR/EULAR criteria development were diagnosed earlier and had a less severe disease than historical patients. PMID- 30472908 TI - Risk Factors for Cytomegalovirus Disease with Cytomegalovirus Re-activation in Patients with Rheumatic Disease. AB - OBJECTIVE: To assess risk factors for cytomegalovirus (CMV) disease with CMV re activation in patients with rheumatic disease. METHODS: The clinical data of consecutive patients with rheumatic disease who experienced CMV re-activation were examined. We evaluated the difference in various baseline factors at the first detection of CMV pp65 antigenemia on the development of CMV disease using logistic regression models. The changes of laboratory data in the 4 weeks before CMV re-activation were also assessed. RESULTS: We identified 80 patients (median age [interquartile range] = 65.0 years [51.5-74.0]) with CMV re-activation. Oral candidiasis, serum albumin <=30 g/l, and CMV pp65 positive cell count >5.6/105 polymorphonuclear leukocyte cells were found to be associated with CMV disease (odds ratio [OR] [95% CI] = 9.99 [2.02-49.50], 11.4 [1.94-67.40] and 6.80 [1.63 28.30], respectively). Moreover, decreases in serum albumin level and blood lymphocyte count in the 4 weeks before CMV re-activation also predicted CMV disease (OR [95% CI] = 2.02 [1.07-3.8] and 1.96 [1.09-3.54], respectively). CONCLUSION: In CMV re-activation patients with rheumatic disease, the presence of oral candidiasis, high CMV pp65 positive cell count, and hypoalbuminemia are possible risk factors for CMV disease. PMID- 30472909 TI - LimoRhyde: A Flexible Approach for Differential Analysis of Rhythmic Transcriptome Data. AB - Unraveling the effects of genetic or environmental perturbations on biological rhythms requires detecting changes in rhythmicity across multiple conditions. Although methods to detect rhythmicity in genome-scale data are well established, methods to detect changes in rhythmicity or changes in average expression between experimental conditions are often ad hoc and statistically unreliable. Here we present LimoRhyde (linear models for rhythmicity, design), a flexible approach for analyzing transcriptome data from circadian systems. Borrowing from cosinor regression, LimoRhyde decomposes circadian or zeitgeber time into multiple components to fit a linear model to the expression of each gene. The linear model can accommodate any number of additional experimental variables, whether discrete or continuous, making it straightforward to detect differential rhythmicity and differential expression using state-of-the-art methods for analyzing microarray and RNA-seq data. In this approach, differential rhythmicity corresponds to a statistical interaction between an experimental variable and circadian time, whereas differential expression corresponds to the main effect of an experimental variable while accounting for circadian time. To validate LimoRhyde's performance, we applied it to simulated data. To demonstrate LimoRhyde's versatility, we applied it to murine and human circadian transcriptome datasets acquired under various experimental designs. Our results show how LimoRhyde systematizes the analysis of such data, and suggest that LimoRhyde could prove valuable for assessing how circadian systems respond to perturbations. PMID- 30472911 TI - Neuropsychological outcome following thalamic stroke in adolescence: an identical twin comparison. AB - OBJECTIVE: Medial thalamic stroke in adults commonly results in severe learning and memory impairments and executive dysfunction, particularly during the acute phase. However, there is limited research on the cognitive recovery from thalamic stroke in physically healthy adolescents. This study aimed to fill this gap in the literature by utilizing a monozygotic twin control to investigate the neuropsychological outcomes of bilateral thalamic stroke in adolescence. METHOD: We evaluated an otherwise healthy 17-year-old male with a history of premature birth, developmental delay, and learning disability 2 and 7 months after he sustained a bilateral medial/anterior thalamic stroke of unknown etiology. His identical twin brother served as a case control. RESULTS: The patient presented with improvements in many cognitive skills between assessments, most notably processing speed. Despite some mild improvement, however, he presented with significant deficits in fine motor speed/coordination, spatial perception, and rapid naming. Additionally, he exhibited persistent, severe deficits in verbal learning and memory. Relative sparing of executive functions (i.e., planning and set-shifting) and attention on standardized measures in this case may be explained by good underlying health, limited extra-thalamic damage, and/or recovery of function. The effects of thalamic injury resulted in minimal adaptive dysfunction or deterrence from academic or athletic success for the presented case. CONCLUSIONS: These results suggest risk for deficits in encoding of new verbal information following bilateral thalamic stroke in adolescence, as well as risk for persistent cognitive deficits despite initial improvements. This is consistent with descriptions of anterograde memory impairments in adults with similar lesions. PMID- 30472912 TI - Jatrorrhizine reduces 5-HT and NE uptake via inhibition of uptake-2 transporters and produces antidepressant-like action in mice. AB - 1. Jatrorrhizine is an active ingredient found in various traditional Chinese medicinal plants. Based on our previous finding that jatrorrhizine was a potent inhibitor of OCT2 and OCT3, the aim of the present study was to explore whether jatrorrhizine had an antidepressant-like action via inhibition of uptake-2 transporters. 2. In vitro uptake tests showed that jatrorrhizine strongly inhibited PMAT-mediated MPP+ uptake with an IC50 value of 1.05 MUM and reduced 5 HT and NE uptake mediated by hOCT2, hOCT3, and hPMAT with IC50 values of 0.1-1 MUM (for OCT2 and OCT3) and 1-10 MUM (for PMAT). 3. In mouse synaptosomes, jatrorrhizine suppressed 5-HT and NE uptake in a concentration dependently manner, where the role of uptake-2 inhibition is significant. 4. The antidepressant-like action of jatrorrhizine was evaluated by mouse tail suspension test (TST). The TST showed that one week of jatrorrhizine (5, 10, 20 mg/kg, i.p.) or venlafaxine (20 mg/kg, i.g.) can significantly reduce the duration of immobility when compared with vehicle control group. 5. The concentration of jatrorrhizine show a dose-dependent increase in brain tissues. 6. Our study suggested that jatrorrhizine might be used as an antidepressant agent via inhibition of uptake-2 transporters. PMID- 30472913 TI - Brinzolamide-loaded nanoemulsions: Ex vivo transcorneal permeation, cell viability and ocular irritation tests. AB - The aim of this study was to investigate the corneal penetration of brinzolamide nanoemulsions and evaluate their in vitro and ex vivo irritancy potential. Twelve brinzolamide nanoemulsions were prepared by the spontaneous emulsification method and ex vivo permeability studies were conducted using excised bovine corneas fixed onto Franz diffusion cells. To confirm the safety of the formulations for ophthalmic use, preparations were examined for potential ocular irritancy using a cell viability assay on retinal cells, the hen's egg test-chorioallantoic membrane (HET-CAM) and the bovine corneal opacity-permeability (BCOP) test. Seven brinzolamide nanoemulsions exhibited superior penetration across isolated bovine cornea compared to the marketed brinzolamide suspension. The half maximal inhibitory concentration (IC50) values of various surfactants and oils determined using the sulforhodamine B cell viability assay on retinal cells showed that Transcutol P, Cremophor RH40 and Triacetin were the least toxic excipients and may be safely used in the eye at various concentrations. HET-CAM and BCOP tests revealed that NE6B and NE4C did not results in any irritation and were thus considered safe for ocular use. Our finding suggest that optimized nanoemulsions can be a safe and effective vehicle for ocular delivery of brinzolamide. PMID- 30472914 TI - Clinical potential relevance of metabolic properties of SGLT2 inhibitors in patients with heart failure. AB - INTRODUCTION: Heart failure (HF) affects approximately 2% of the population worldwide, remaining a major cause of hospitalization and mortality despite innovative therapeutic approaches introduced in the past few decades. Type 2 diabetes mellitus (T2D) contributes significantly to end-organ damage and HF related complications and is associated with worse clinical status and increased all-cause and cardiovascular mortality in patients with HF with reduced (HFrEF) or with preserved ejection fraction (HFpEF), compared to HF patients without T2D. Recently, a novel class of antidiabetic drugs has been introduced: sodium glucose co-trasport-2 inhibitors (SGLT2i). Initially designed for patients with T2D to reduce kidney blood glucose resorption, SGLT2i rapidly gained attention among HF specialists since they were able to show a beneficial prognostic impact in patients affected by HF and T2D, even independently from the glycemic control as suggested by the EMPA-REG OUTCOME and CANVAS trials. Areas covered: The present review focuses on the mechanisms and the current clinical evidence supporting the use of SGLT2i in HF patients with T2D. Moreover, the SGLT2i pharmacokinetic and pharmacodynamic properties will be presented in order to better understand the rationale and the design of the ongoing clinical trials investigating directly the effect of this new class of drugs in patients with HF, even independently from T2D. Expert opinion: SGLT2i are emerging as an effective and safe therapy for the treatment of T2D and current evidence has unexpectedly demonstrated a robust cardiovascular protection in HF patients with T2D. Therefore, ongoing clinical trials are investigating directly the effect of this new class of drugs in patients with HF, even independently from T2D. However, it is methodologically disappointing that the mechanisms underlying the encouraging results in cardiovascular protection of this drug class are still not fully understood. A better understanding of the pharmacokinetic and pharmacodynamic properties of SGLT2i is necessary in order to better determine the effect of this new class of drugs in patients with HF. PMID- 30472915 TI - Acute and chronic non-pulmonary complications in adults with cystic fibrosis. AB - INTRODUCTION: Cystic fibrosis (CF) is a genetic disease that primarily affects the respiratory system and often leads to respiratory failure and premature death. Although pulmonary complications contribute to 85% of deaths, non pulmonary complications are responsible for significant morbidity and mortality in adults with CF. Areas covered: This review summarizes acute and chronic non pulmonary complications in CF patients, with emphasis on emerging complications and in the context of the current growth and aging of the CF adult population. It also addresses the potential benefits of CF transmembrane conductance regulator modulator therapy. Complications that occur after solid organ (e.g. lung and/or liver) transplantation have been excluded. The review is based on an extensive search of the available literature, using PubMed and international guidelines, and on the authors' clinical experience. Expert commentary: Acute non-pulmonary complications have been well described but should be recognized and managed carefully. Managing chronic non-pulmonary complications is an important and changing aspect of CF patient care, particularly with the emergence of novel complications in adults. Early detection of non-pulmonary complications is essential to the development of prevention and treatment strategies that aim to further improve the survival and health status of adult CF patients. PMID- 30472916 TI - Antimalarial resistance in lupus: a lesser-explored terrain. PMID- 30472918 TI - Novel Feline Viruses: Emerging significance of gammaherpesvirus and morbillivirus infections. AB - PRACTICAL RELEVANCE:: New technologies capable of sequencing the genetic material In any given biological sample, combined with computer-based algorithms for sequence assembly and analysis, have revolutionised infectious disease research. The rate at which novel viruses are being discovered now exceeds our understanding of their clinical relevance. Novel viruses may contribute to diseases that are major causes of feline morbidity and mortality, including cancer and chronic kidney disease. The identification of new viral pathogens raises the prospect of not only improved patient outcomes through specific treatment but even disease prevention through viral control measures. CLINICAL CHALLENGES:: Clinical challenges: It can be difficult to determine the role of a novel virus in disease development. Disease may be an occasional outcome, often years after infection. A high prevalence of infection in the general population can make disease associations harder to identify and almost impossible to rule out. Host cofactors such as immune dysfunction, genetic background or coinfections may be required for manifestation of disease, and one virus species may be linked to a range of pathological sequelae. Establishing causality relies on evaluating accumulating evidence from multiple investigations, which is often hard to access by practitioners. GLOBAL IMPORTANCE:: The worldwide distribution of gammaherpesvirus and morbillivirus infections in domestic cats underlines the potential of these viruses to negatively impact feline health and welfare globally. EVIDENCE BASE:: This review relies on grade la-III evidence. PMID- 30472917 TI - A three-dimensional human skin model to evaluate the inhibition of Staphylococcus aureus by antimicrobial peptide-functionalized silver carbon nanotubes. AB - OBJECTIVE: To investigate the toxicity and antibacterial application of antimicrobial peptide-functionalized silver-coated carbon nanotubes against Staphylococcus infection using a full thickness human three-dimensional skin model. MATERIALS AND METHODS: The three-dimensional skin formation on the scaffolds was characterized by electron microscopy and investigation of several skin cell markers by real time-reverse transcriptase polymerase chain reaction. Functionalized silver-coated carbon nanotubes were prepared using carboxylated silver-coated carbon nanotubes with antimicrobial peptides such as TP359, TP226 and TP557. Following the characterization and toxicity evaluation, the antibacterial activity of functionalized silver-coated carbon nanotubes against Staphylococcus aureus was investigated using a bacterial enumeration assay and scanning electron microscopy. For this purpose, a scar on the human three dimensional skin grown on Alvetex scaffold using keratinocytes and fibroblasts cells was created by taking precaution not to break the scaffold beneath, followed by incubation with 5 ug/mL of functionalized silver-coated carbon nanotubes re-suspended in minimum essential medium for 2 h. Post 2-h incubation, 200 uL of minimum essential medium containing 1 * 104 colony forming units of Staphylococcus aureus were incubated for 2 h. After incubation with bacteria, the colony forming unit/gram (cfu/g) of skin tissue were counted using the plate count assay and the samples were processed for scanning electron microscopy analysis. RESULTS: MTT assay revealed no toxicity of functionalized silver-coated carbon nanotubes to the skin cells such as keratinocytes and fibroblasts at 5 ug/mL with 98% cell viability. The bacterial count increased from 104 to 108 cfu/g in the non-treated skin model, whereas skin treated with functionalized silver-coated carbon nanotubes showed only a small increase from 104 to 105 cfu/g (1000-fold viable cfu difference). Scanning electron microscopy analysis showed the presence of Staphylococcus aureus on the non-treated skin as opposed to the treated skin. CONCLUSION: Thus, our results showed that functionalized silver coated carbon nanotubes are not only non-toxic, but also help reduce the infection due to their antibacterial activity. These findings will aid in the development of novel antibacterial skin substitutes. PMID- 30472919 TI - Motivation counteracts fatigue-induced performance decrements in soccer passing performance. AB - Recent theories suggest that negative effects of fatigue on performance are determined by perception of effort and motivation rather than being directly caused by reaching physiological limits. In the current experiment, the influence of motivation on fatigue-induced decrements in soccer performance was experimentally investigated. Sixty amateur soccer players performed a validated soccer-passing test before and after a fatigue protocol. Results showed that players' motivation and performance decreased after the fatigue protocol for players in the control group. In contrast, players in the motivation group (i.e., with motivation experimentally induced after the fatigue protocol) were able to uphold their motivation and increase their performance. These results indicate that motivation plays a crucial role in performance under fatigue, as fatigue induced decrements in soccer passing performance can be counteracted by high levels of motivation. Future research may explore the limits of this counteracting effect and extend findings to other relevant performance aspects. PMID- 30472920 TI - Current practice in treating chronic venous disease by Canadian vascular surgeons. AB - OBJECTIVE: To evaluate the practice patterns and interests of vascular surgeons in Canada in the treatment of chronic venous disorder. METHODS: A web-based 19 question survey was sent to 155 active members of the Canadian Society for Vascular Surgery. Questions assessed training background, interest in venous disease, practice site, venous treatments offered, and obstacles to therapy. RESULTS: A total of 64 responses (41%) were acquired. Respondents were roughly equal from academic (55%) and community (45%) sites with an even distribution of years in practice. Only 43% offered full range of therapy, which includes compression stockings, sclerotherapy, vein surgery, and endovenous ablation. The main challenges hindering venous practice include lack of time due to overwhelming arterial pathologies (67%), equipment cost/office space limitations (53%), and lack of knowledge or skills in contemporary procedures (28%). The majority of surgeons felt that their residency and fellowship did not prepare them for an active venous practice (69%). Fifty-four percent of the respondents perceived barriers in getting venous ultrasound imaging for their patients. Only 19% of the surgeons find venous disease interesting. Characteristics of these interested surgeons were analyzed and found to be very different from surgeons who did not expressed interest. An overwhelming 92% of all respondents believe that vascular surgeons should be leaders in delivering care for venous disease. CONCLUSION: The treatment of chronic venous disorder has advanced over the last few decades but significant obstacles exist for Canadian surgeons to deliver venous therapy in accordance with current guidelines. PMID- 30472921 TI - A GEE-type approach to untangle structural and random zeros in predictors. AB - Count outcomes with excessive zeros are common in behavioral and social studies, and zero-inflated count models such as zero-inflated Poisson (ZIP) and zero inflated Negative Binomial (ZINB) can be applied when such zero-inflated count data are used as response variable. However, when the zero-inflated count data are used as predictors, ignoring the difference of structural and random zeros can result in biased estimates. In this paper, a generalized estimating equation (GEE)-type mixture model is proposed to jointly model the response of interest and the zero-inflated count predictors. Simulation studies show that the proposed method performs well for practical settings and is more robust for model misspecification than the likelihood-based approach. A case study is also provided for illustration. PMID- 30472922 TI - Pierre Franco (1505-1578): An Innovative Surgeon of the 16th Century in the Treatment of Hernia and Lithotomy. AB - Pierre Franco (1505-1578) was a brilliant surgeon of the Renaissance, a contemporary of Ambroise Pare. He made an impact on the history of surgery with his innovative approaches in the treatment of hernia, lithotomy, and the use of the suprapubic incision. The purpose of this study is to present a detailed account of his work, innovations, and achievements as well as the impact he made on the surgery of the Renaissance. PMID- 30472923 TI - Investigating Capnography Innovation for Better Patient Monitoring in the Resource Limited Surgical Setting. AB - BACKGROUND: Access to basic anesthetic monitoring in the developing world is lacking, which contributes to the 100 times greater anesthesia-related mortality in low- and middle-income countries. We hypothesize that an environmental sensor with a lower sampling rate could provide some clinical utility by providing CO2 levels, respiratory rate, and support in detection of clinical abnormalities. MATERIALS AND METHODS: A bench-top lung simulation was created to replicate CO2 waveforms, and an environmental sensor was compared with industry-available technology. Sensor response time and respiratory rates were compared between devices. Additionally, an in silico model was created to replicate capnography pathology as waveforms would appear using the environmental sensor. RESULTS AND CONCLUSION: Breath simulations using the bench-top lung simulation produced similar results to industry standards with a degree of variability. Respiratory rates did not differ between the environmental sensor and all other devices tested. Finally, pathological waveforms created in silico carried a certain level of detail regarding ventilatory pathology, which could provide some clinical insight to an anesthesiologist. We believe our prototype is the first step toward making low-cost and portable capnography available in the resource-limited setting, and future efforts should focus on bridging the gap to safer anesthesia and surgery globally. PMID- 30472924 TI - A meta-analysis of the accuracy of embedded performance validity indicators from the repeatable battery for the assessment of neuropsychological status. AB - OBJECTIVE: Meta-analyze the embedded performance validity tests of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), emphasizing two topics: diagnostic accuracy and relationships with demographics. METHOD: Literature was identified through a review of PsycINFO, PubMed, and Google Scholar. Bivariate linear mixed models were used for diagnostic accuracy analyses. Random-effects analysis of correlations with demographic variables was also used for the Effort Index. RESULTS: Diagnostic accuracy analyses utilized 12 studies of the Effort Index (EI; N = 1469) and 6 studies of the Effort Scale (ES; N = 854). The EI was found to have a sensitivity of .44 (95% CI: .28 - .62), specificity of .87 (95% CI: .78 - .93), and diagnostic odds ratio (DOR) of 5.41 (95% CI: 3.74 - 7.58). The ES produced a sensitivity of .67 (95% CI: .50 - .81), specificity of .72 (95% CI: .53 - .85), and DOR of 5.97 (95% CI: 1.70 - 15.30). Meta-analysis of correlations utilized 14 samples of the EI (N = 3781), but insufficient data were available for the ES. Correlations between the EI and age (r = .10, 95% CI: .05 - .16), education (r = -.11, 95% CI: -.18 to -.04), and the RBANS Total Scale (r = -.45, 95% CI: -.62 to -.24) were significant. These results appeared to be robust to publication bias. CONCLUSION: Results support use of the EI over the ES; however, the latter is comparatively less studied and did not have similar variability in reported cut-off scores. ES accuracy statistics were significantly predicted by sample variables, which may be related to its relatively fewer studies. Both measures should be used cautiously in the context of genuine cognitive impairment. PMID- 30472925 TI - Integration of neuropsychology services in a sickle cell clinic and subsequent healthcare use for pain crises. AB - OBJECTIVE: Growing literature has documented the clinical utility of neuropsychological evaluations for predicting functional outcomes, including reduced healthcare service utilization, in a variety of clinical samples. The present study investigates the relationship between the integration of clinical neuropsychology services into an existing outpatient sickle cell clinic and frequency of emergency department (ED) visits and hospitalizations for pain crises. METHOD: Participants included 144 adults diagnosed with sickle cell disease (SCD) who either underwent neuropsychological evaluation (NP+), including interview, neuropsychological testing, and feedback, or treatment as usual (NP-). Medical records were reviewed for a two-year period, one year prior to study enrollment (pre-assessment) and one year post-study enrollment (post-assessment), to track the number of ED visits and hospitalizations related to sickle cell pain crises. RESULTS: When examining pain crises ED visits prior to and following neuropsychological evaluation, there was a significant decrease in ED visits for the NP + group, but no change for the NP - group. No significant changes in pain crises hospitalizations were observed for the NP + and NP - groups. For the NP + group, the decreased incidence of pain crises ED visits and hospitalizations was associated with an estimated total cost savings of $994,821. DISCUSSION: Results highlight that integration of neuropsychology services into an existing outpatient sickle cell clinic may reduce healthcare costs, particularly use of pain crises ED services, for adults with SCD. PMID- 30472926 TI - Field performance evaluation of dual rapid HIV and syphilis tests in three antenatal care clinics in Zambia. AB - This cross-sectional study of 3212 pregnant women assessed the field performance, acceptability, and feasibility of two dual HIV/syphilis rapid diagnostic tests, the Chembio DPP HIV-syphilis Assay and the SD Bioline HIV/syphilis Duo in antenatal clinics. Sensitivity and specificity for HIV and syphilis were calculated compared to the rapid Determine HIV-1/2 with Uni-Gold to confirm positive results for HIV and the Treponema pallidum particle agglutination assay for syphilis. RPR titers >=1:4 were used to define active syphilis detection. Acceptability and feasibility were assessed using self-reported questionnaires. For Chembio, the HIV sensitivity was 90.6% (95%CI = 87.4, 93.0) and specificity was 97.2% (95%CI = 96.2, 97.8); syphilis sensitivity was 68.6% (95%CI = 61.9, 74.6) and specificity was 98.5% (95%CI = 97.8, 98.9). For SD Bioline, HIV sensitivity was 89.4% (95%CI = 86.1, 92.0) and specificity was 96.3% (95%CI = 95.3, 97.1); syphilis sensitivity was 66.2% (95%CI = 59.4, 72.4) and specificity was 97.2% (95%CI = 96.4, 97.9). Using the reference for active syphilis, syphilis sensitivity was 84.7% (95%CI = 76.1, 90.6) for Chembio and 81.6% (95%CI = 72.7, 88.1) for SD Bioline. Both rapid diagnostic tests were assessed as highly acceptable and feasible. In a field setting, the performance of both rapid diagnostic tests was comparable to other published field evaluations and each was rated highly acceptable and feasible. These findings can be used to guide further research and proposed scale up in antenatal clinic settings. PMID- 30472927 TI - Establishment of a Rabbit Model of Giant Abdominal Wall Hernia. AB - PURPOSE: Animal models play an important role in abdominal wall hernia research. However, there is still no standard animal models for abdominal wall hernia. This study aimed to introduce a novel rabbit model of giant abdominal wall hernia. METHODS: Sixteen 1-year-old New Zealand rabbits weighing 3 to 5 kg were used. After general anesthesia, a 5-cm longitudinal incision was made 2 cm lateral to the ventral midline, and a full-thickness laparotomy incision was made en bloc including the peritoneum (except skin). A full-thickness defect of the abdominal wall with a diameter of 3 cm was created. To increase the intraabdominal pressure, constipation was induced by deprivation of water perioperatively. The development of giant abdominal wall hernia was recorded. The bulge area of these rabbits was redissected to assess the hernia 3 months postoperatively. RESULTS: Of the 16 rabbits, 13 (81.25%) rabbits had grade I healing and 3 (18.75%) rabbits had grade III healing. Reversible abdominal bulge at the incisional site was observed in all rabbits 3 to 18 days postoperatively. The average maximum diameter of the bulge was 8.73 +/- 1.00 cm. Redissection of the bulge area showed successful establishment of giant abdominal wall hernia. CONCLUSION: We successfully established a rabbit model of giant abdominal wall hernia, which may provide an easy-to-use tool for the research of abdominal wall hernia. PMID- 30472928 TI - Approach to the patient presenting with metabolic acidosis. PMID- 30472929 TI - The "Penis Police": Lesbian and Feminist Spaces, Trans Women, and the Maintenance of the Sex/Gender/Sexuality System. AB - I provide a textual analysis to show how lesbians determine gender in sexualized spaces. As members work toward recognition, agentic embodiment, and the safeguarding of lesbian spaces, how do members differently determine gender for insiders and outsiders in order to preserve a particular kind of feminism? I show how public narratives of gender, essentialism, and heterosexuality circulate in some lesbian spaces as members use the "penis police" to maintain exclusionary feminism. I expand upon the concept of determining gender to move beyond questions about how gender is socially recognized to an analysis of how gender attribution challenges/maintains the sex/gender/sexuality system. PMID- 30472930 TI - Naturalistic data collection of head posture during smartphone use. AB - Association between smartphone use and head-down tilt posture has not yet been quantitatively evaluated in natural settings. This study aimed to objectively assess the angle and duration of head-down tilt posture of smartphone users during a typical working day via naturalistic data-collection. Thirty-one college students conducted their typical school activities while their head posture and smartphone-app usage records were collected simultaneously for 8 hours. Participants spent 125.9 minutes (median usage duration) on their smartphones with significantly larger head-down tilt (p < 0.05) than when they were not using the phone. Head tilt angle greater than 30 degrees was found to be more common when using the phone, while head tilt less than 20 degrees was more common when they were not using the phone. Study findings provide empirical evidence that supports an association between the duration of smartphone use and the intensity of head-down tilt posture. PMID- 30472931 TI - A novel combined model based on Echo State Network -A case study of PM10 and PM2.5 prediction in China. AB - Particulate Matters such as PM10, PM2.5 may contain heavy metal oxides and harmful substances that threaten human health and environmental quality. In this paper, we propose a new combined neural network algorithm which based on Elman, echo state network (ESN) and cascaded BP neural network (CBP) to predict PM10 and PM2.5. In order to further improve the performance of the prediction result, we use the simulated annealing algorithm (SA) to optimize the parameters in the combination method to form the optimal combination model. And particle swarm optimization (PSO) is used to optimize the parameters in ESN. The chemical species in the atmosphere which include SO2, NO, NO2, O3 and CO in Baiyin, Gansu Province of China are used to test and verify the proposed combined method. The experimental results show that the prediction performance of the combined model presented in this paper is indeed superior to other three neural network models. PMID- 30472933 TI - Notice of Duplicate Publication. PMID- 30472932 TI - The CYRM-R: A Rasch-Validated Revision of the Child and Youth Resilience Measure. AB - The Child and Youth Resilience Measure (CYRM) is one of the most popular measures of resilience. In this paper, we investigate the CYRM using Rasch analysis to explore and improve its psychometric properties, leading to a more robust measure of resilience.Cross-sectional data were obtained from a questionnaire administered to n = 408 individuals in Canada aged 11-19 who were participating in the Pathways to Resilience study. Rasch analysis was applied to these data, resulting in the production of a 17-item, 2-subscale CYRM-R, consisting of intra/interpersonal and caregiver resilience subscales. The subscales demonstrated good fit to the Rasch model by satisfying requirements of unidimensionality, good fit statistics and internal reliability, and a lack of item bias and problematic local dependency. The person separation indices also indicated that the subscales had good ability to differentiate between individuals of varying levels of resilience. In sum, the CYRM-R is a 2-subscale, 17-item Rasch-validated measure of resilience with robust psychometric properties. This revised measure is recommended for researchers and practitioners who are interested in measuring resilience across diverse cultures and contexts. PMID- 30472934 TI - Valorisation of the organic fraction of municipal solid waste. AB - The appropriate selection of treatment or final disposal for municipal solid waste generated by a population depends on multiple characteristics; decision making becomes a challenge for those responsible for its integral management. Therefore, the objective of this research was to evaluate multi-scenarios of valorisation of the organic fraction of municipal solid waste. The methodology used included a sample of 421 houses to determine the generation and composition of the aforementioned municipal solid waste; this data served as input to be able to design four treatment and final disposal scenarios: current situation, composting, anaerobic digestion and landfill. The parameters of humidity, biochemical methane potential and biogas were used. In addition, organic fraction variability and treatment cost were considered. Data analysis included design of experiments with the uncertainty coefficient and predictive equations. The results showed that composting was the scenario that presented the highest coefficient of determination and therefore it would be the best choice to fit the particular conditions of the localities. It is concluded that this applied methodology can be used as a tool in the decision-making process regarding the valorisation of the organic fraction of municipal solid waste and can be replicated at a national and international level. PMID- 30472935 TI - Electrocardiogram in a patient with Paragonimiasis westermani-triggered Takotsubo syndrome. PMID- 30472936 TI - Cross-fertilisation of ideas for a more sustainable fertiliser market: The need to incubate business concepts for harnessing organic residues and fertilisers on biotechnological conversion platforms in a circular bioeconomy. PMID- 30472937 TI - Aspirin in Preeclampsia and Its Molecular Intermediators. PMID- 30472938 TI - Different Pathways to Neurodegeneration. AB - The current issue is dedicated to the studies of neurodegenerative diseases and memory. Molecular mechanisms and mutant genes have already been revealed for many neurodegenerative diseases. However, in many cases the cause of selective death of neurons in different brain regions remains unclear. Genetic predisposition and aging are well established risk factors in many neurodegenerative diseases. A large body of evidence has been obtained that shows an important role of immune factors in the modulation of neurodegenerative processes. The progress in the treatment of neurodegenerative diseases requires new cell models for identification of non-canonical pharmacological targets and development of approaches for memory regulation. Gene therapy technologies based on genome editing and RNA interference methods are among promising approaches for repairing primary molecular defects underlying neurodegenerative pathologies. PMID- 30472939 TI - Changes in Retinal Glial Cells with Age and during Development of Age-Related Macular Degeneration. AB - Age is the major risk factor in the age-related macular degeneration (AMD) which is a complex multifactor neurodegenerative disease of the retina and the main cause of irreversible vision loss in people over 60 years old. The major role in AMD pathogenesis belongs to structure-functional changes in the retinal pigment epithelium cells, while the onset and progression of AMD are commonly believed to be caused by the immune system dysfunctions. The role of retinal glial cells (Muller cells, astrocytes, and microglia) in AMD pathogenesis is studied much less. These cells maintain neurons and retinal vessels through the synthesis of neurotrophic and angiogenic factors, as well as perform supporting, separating, trophic, secretory, and immune functions. It is known that retinal glia experiences morphological and functional changes with age. Age-related impairments in the functional activity of glial cells are closely related to the changes in the expression of trophic factors that affect the status of all cell types in the retina. In this review, we summarized available literature data on the role of retinal macro- and microglia and on the contribution of these cells to AMD pathogenesis. PMID- 30472940 TI - Role of microRNA (miRNA) and Viroids in Lethal Diseases of Plants and Animals. Potential Contribution to Human Neurodegenerative Disorders. AB - Both plants and animals have adopted a common strategy of using ~18-25-nucleotide small non-coding RNAs (sncRNAs), known as microRNAs (miRNAs), to transmit DNA based epigenetic information. miRNAs (i) shape the total transcriptional output of individual cells; (ii) regulate and fine-tune gene expression profiles of cell clusters, and (iii) modulate cell phenotype in response to environmental stimuli and stressors. These miRNAs, the smallest known carriers of gene-encoded post transcriptional regulatory information, not only regulate cellular function in healthy cells but also act as important mediators in the development of plant and animal diseases. Plants possess their own specific miRNAs; at least 32 plant species have been found to carry infectious sncRNAs called viroids, whose mechanisms of generation and functions are strikingly similar to those of miRNAs. This review highlights recent remarkable and sometimes controversial findings in miRNA signaling in plants and animals. Special attention is given to the intriguing possibility that dietary miRNAs and/or sncRNAs can function as mobile epigenetic and/or evolutionary linkers between different species and contribute to both intra- and interkingdom signaling. Wherever possible, emphasis has been placed on the relevance of these miRNAs to the development of human neurodegenerative diseases, such as Alzheimer's disease. Based on the current available data, we suggest that such xeno-miRNAs may (i) contribute to the beneficial properties of medicinal plants, (ii) contribute to the negative properties of disease-causing or poisonous plants, and (iii) provide cross species communication between kingdoms of living organisms involving multiple epigenetic and/or potentially pathogenic mechanisms associated with the onset and pathogenesis of various diseases. PMID- 30472941 TI - Molecular Pathogenesis in Huntington's Disease. AB - Huntington's disease (HD) is a severe autosomal dominant neurodegenerative disorder characterized by a combination of motor, cognitive, and psychiatric symptoms, atrophy of the basal ganglia and the cerebral cortex, and inevitably progressive course resulting in death 5-20 years after manifestation of its symptoms. HD is caused by expansion of CAG repeats in the HTT gene, which leads to pathological elongation of the polyglutamine tract within the respective protein - huntingtin. In this review, we present a modern view on molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. Main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as systemic failure of transcription, mitochondrial dysfunction and suppression of energy metabolism, abnormalities of cytoskeleton and axonal transport, microglial inflammation, decrease in synthesis of brain-derived neurotrophic factor, etc. PMID- 30472942 TI - Genome Editing and the Problem of Tetraploidy in Cell Modeling of the Genetic Form of Parkinsonism. AB - The prevalent form of familial parkinsonism is caused by mutations in the LRRK2 gene encoding for the mitochondrial protein kinase. In the review, we discuss possible causes of appearance of tetraploid cells in neuronal precursors obtained from induced pluripotent stem cells from patients with the LRRK2-associated form of parkinsonism after genome editing procedure. As LRRK2 protein participates in cell proliferation and maintenance of the nuclear envelope, spindle fibers, and cytoskeleton, mutations in the LRRK2 gene can affect protein functions and lead, via various mechanisms, to the mitotic machinery disintegration and chromosomal aberration. These abnormalities can appear at different stages of fibroblast reprogramming; therefore, editing of the LRRK2 nucleotide sequence should be done during or before the reprogramming stage. PMID- 30472943 TI - Pluripotent Stem Cells for Modelling and Cell Therapy of Parkinson's Disease. AB - Studying pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD), requires adequate disease models. The available patient's material is limited to biological fluids and post mortem brain samples. Disease modeling and drug screening can be done in animal models, although this approach has its own limitations, since laboratory animals do not suffer from many neurodegenerative diseases, including PD. The use of neurons obtained by targeted differentiation from induced pluripotent stem cells (iPSCs) with known genetic mutations, as well as from carriers of sporadic forms of the disease, will allow to elucidate new components of the molecular mechanisms of neurodegeneration. Such neuronal cultures can also serve as unique models for testing neuroprotective compounds and monitoring neurodegenerative changes against a background of various therapeutic interventions. In the future, dopaminergic neurons differentiated from iPSCs can be used for cell therapy of PD. PMID- 30472944 TI - Anti-amyloid Therapy of Alzheimer's Disease: Current State and Prospects. AB - Drug development for the treatment of Alzheimer's disease (AD) has been for a long time focused on agents that were expected to support endogenous beta-amyloid (Abeta) in a monomeric state and destroy soluble Abeta oligomers and insoluble Abeta aggregates. However, this strategy has failed over the last 20 years and was eventually abandoned. In this review, we propose a new approach to the anti amyloid AD therapy based on the latest achievements in understanding molecular causes of cerebral amyloidosis in AD animal models. PMID- 30472945 TI - Dynamic Microtubules in Alzheimer's Disease: Association with Dendritic Spine Pathology. AB - Alzheimer's disease (AD) is the most common incurable neurodegenerative disorder that affects the processes of memory formation and storage. The loss of dendritic spines and alteration in their morphology in AD correlate with the extent of patient's cognitive decline. Tubulin had been believed to be restricted to dendritic shafts, until recent studies demonstrated that dynamically growing tubulin microtubules enter dendritic spines and promote their maturation. Abnormalities of tubulin cytoskeleton may contribute to the process of dendritic spine shape alteration and their subsequent loss in AD. In this review, association between tubulin cytoskeleton dynamics and dendritic spine morphology is discussed in the context of dendritic spine alterations in AD. Potential implications of these findings for the development of AD therapy are proposed. PMID- 30472946 TI - Genetic Association between Alzheimer's Disease Risk Variant of the PICALM Gene and Auditory Event-Related Potentials in Aging. AB - Aging and genetic predisposition are major risk factors in age-related neurodegenerative disorders. The most common neurodegenerative disorder is Alzheimer's disease (AD). Genome-wide association studies (GWAS) have identified statistically significant association of the PICALM rs3851179 polymorphism with AD. The PICALM G allele increases the risk of AD, while the A allele has a protective effect. We examined the association of the PICALM rs3851179 polymorphism with parameters of the P3 component of auditory event-related potentials (ERPs) in 87 non-demented volunteers (age, 19-77 years) subdivided into two cohorts younger and older than 50 years of age. We found statistically significant association between the AD risk variant PICALM GG and increase in the P3 latency in subjects over 50 years old. The age-dependent increase in the P3 latency was more pronounced in the PICALM GG carriers than in the carriers of the PICALM AA and PICALM AG genotypes. The observed PICALM-associated changes in the neurophysiological processes indicate a decline in the information processing speed with aging due, probably, to neuronal dysfunction and subclinical neurodegeneration of the neuronal networks in the hippocampus and the frontal and parietal cortical areas. Such changes were less pronounced in the carriers of the PICALM gene A allele, which might explain the protective effect of this allele in the cognitive decline and AD development. PMID- 30472947 TI - Mitochondria with Morphology Characteristic for Alzheimer's Disease Patients Are Found in the Brain of OXYS Rats. AB - Growing evidence suggests that mitochondrial dysfunction is closely linked to the pathogenesis of sporadic Alzheimer's disease (AD). One of the key contributors to various aspects of AD pathogenesis, along with metabolic dysfunction, is mitochondrial dynamics, involving balance between fusion and fission, which regulates mitochondrial number and morphology in response to changes in cellular energy demand. Recently, Zhang et al. ((2016) Sci. Rep., 6, 18725) described a previously unknown mitochondrial phenotype manifesting as elongated chain-linked mitochondria termed "mitochondria-on-a-string" (MOAS) in brain tissue from AD patients and mouse models of AD. The authors associated this phenotype with fission arrest, but implications of MOAS formation in AD pathogenesis remain to be understood. Here we analyze the presence and number of MOAS in the brain of OXYS rats simulating key signs of sporadic AD. Using electron microscopy, we found MOAS in OXYS prefrontal cortex neuropil in all stages of AD-like pathology, including manifestation (5-month-old rats) and progression (12-18-month-old rats). The most pronounced elevation of MOAS content (8-fold) in OXYS rats compared to Wistar controls was found at the preclinical stage (20 days) on the background of decreased numbers of non-MOAS elongated mitochondria. From the age of 20 days through 18 months, the percentage of MOAS-containing neuronal processes increased from 1.7 to 8.3% in Wistar and from 13.9 to 16% in OXYS rats. Our results support the importance of the disruption of mitochondrial dynamics in AD pathogenesis and corroborate the existence of a causal link between impaired mitochondrial dynamics and formation of the distinctive phenotype of "mitochondria-on-a-sting". PMID- 30472948 TI - Cytokines as Mediators of Neuroinflammation in Experimental Autoimmune Encephalomyelitis. AB - Cytokines play a pivotal role in maintaining homeostasis of the immune system and in regulation of the immune response. Cytokine dysregulation is often associated with development of various pathological conditions, including autoimmunity. Recent studies have provided insights into the cytokine signaling pathways that are involved not only in pathogenesis of autoimmune neuroinflammatory disorders, such as multiple sclerosis, but also in neurodegenerative states, for example, Alzheimer's disease. Understanding the exact molecular mechanisms of disease pathogenesis and evaluation of relevant experimental animal models are necessary for development of effective therapeutic approaches. PMID- 30472949 TI - Immunogenetic Factors of Neurodegenerative Diseases: The Role of HLA Class II. AB - An increase in the life expectancy during the last decades in most world countries has resulted in the growing number of people suffering from neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and others. Familial forms of neurodegenerative diseases account for 5-10% of all cases and are caused by mutations in specific genes often resulting in pathological protein deposition. The risk factors for neurodegeneration include trauma, lifestyle, and allelic variants of disease associated genes with incomplete penetrance. Many of these gene variants are located in immunity-related loci, particularly in the human leukocyte antigen locus (HLA class II) coding for proteins of the major histocompatibility complex class II (MHCII). HLA class II plays a key role in the antigen presentation and is expressed in microglial cells. Microglia is a component of innate immunity. On the one hand, microglial cells phagocytize pathological protein deposits; on the other hand, they produce proinflammatory factors accelerating neuronal death. The involvement of adaptive immunity mechanisms (antigen presentation, T cell response, antibody production) in the development of neurodegenerative diseases remains unclear and requires further research, including more detailed studies of the role of identified HLA class II genetic variants. PMID- 30472950 TI - Recovery of Impaired Memory: Expression of c-Fos and Egr-1 Transcription Factors during Restoration of Damaged Engram in the Chick Brain. AB - Impairment of protein synthesis in the brain during learning prevents memory consolidation and results in amnesia, which until recently has been regarded irreversible. However, in some cases impaired memory could be restored by various "reminder" stimuli. The present study is based on the hypothesis that even in behaviorally profound amnesia, some disintegrated fragments of the engram are preserved in the brain and could be re-integrated into the whole system by specific types of stimuli. The aim of the present study was to test this hypothesis in an experimental model of pharmacologically induced memory impairment in young chicks and to reveal the brain areas involved in this process by mapping of reminder-induced expression of transcriptional factors c-Fos and Egr-1. We show that reminder treatment results in the recovery of memory impaired by protein synthesis inhibition during learning and induces c-Fos and Egr-1 expression in the brain regions involved in learning in this behavioral model. The patterns of c-Fos and Egr-1 induced expression in animals with impaired memory differed from the patterns of animals with unimpaired memory and as well as naive animals with no memory. Thus, analysis of activity-induced c-Fos and Egr 1 expression revealed the brain regions that were specifically activated by the reminder treatment. At the behavioral level, this treatment led to memory recovery. Altogether, these results suggest that the reminder-induced transcriptional activity in the brain of amnestic animals occurs in regions maintaining the engram fragments that reintegrate to recover the impaired memory. PMID- 30472951 TI - Enhancement of Declarative Memory: From Genetic Regulation to Non-invasive Stimulation. AB - The problem of memory enhancement is extremely important in intellectual activity areas and therapy of different types of dementia, including Alzheimer's disease (AD). The attempts to solve this problem have come from different research fields. In the first part of our review, we describe the results of targeting certain genes involved in memory-associated molecular pathways. The second part of the review is focused on the deep stimulation of brain structures that can slow down memory loss in AD. The third part describes the results of the use of non-invasive brain stimulation techniques for memory modulation, consolidation, and retrieval in healthy people and animal models. Integration of data from different research fields is essential for the development of efficient strategies for memory enhancement. PMID- 30472952 TI - Erratum to: "Amphipathic CRAC-Containing Peptides Derived from the Influenza Virus A M1 Protein Modulate Cholesterol-Dependent Activity of Cultured IC-21 Macrophages" [Biochemistry (Moscow), 83, 982 (2018)]. AB - This corrects the article DOI: 10.1134/S0006297918080096. PMID- 30472953 TI - ADP-Inhibition of H+-FOF1-ATP Synthase. AB - H+-FOF1-ATP synthase (F-ATPase, F-type ATPase, FOF1 complex) catalyzes ATP synthesis from ADP and inorganic phosphate in eubacteria, mitochondria, chloroplasts, and some archaea. ATP synthesis is powered by the transmembrane proton transport driven by the proton motive force (PMF) generated by the respiratory or photosynthetic electron transport chains. When the PMF is decreased or absent, ATP synthase catalyzes the reverse reaction, working as an ATP-dependent proton pump. The ATPase activity of the enzyme is regulated by several mechanisms, of which the most conserved is the non-competitive inhibition by the MgADP complex (ADP-inhibition). When ADP binds to the catalytic site without phosphate, the enzyme may undergo conformational changes that lock bound ADP, resulting in enzyme inactivation. PMF can induce release of inhibitory ADP and reactivate ATP synthase; the threshold PMF value required for enzyme reactivation might exceed the PMF for ATP synthesis. Moreover, membrane energization increases the catalytic site affinity to phosphate, thereby reducing the probability of ADP binding without phosphate and preventing enzyme transition to the ADP-inhibited state. Besides phosphate, oxyanions (e.g., sulfite and bicarbonate), alcohols, lauryldimethylamine oxide, and a number of other detergents can weaken ADP-inhibition and increase ATPase activity of the enzyme. In this paper, we review the data on ADP-inhibition of ATP synthases from different organisms and discuss the in vivo role of this phenomenon and its relationship with other regulatory mechanisms, such as ATPase activity inhibition by subunit epsilon and nucleotide binding in the noncatalytic sites of the enzyme. It should be noted that in Escherichia coli enzyme, ADP-inhibition is relatively weak and rather enhanced than prevented by phosphate. PMID- 30472954 TI - Advances in the Application of Modified Nucleotides in SELEX Technology. AB - Aptamers are widely used as molecular recognition elements for detecting and blocking functional biological molecules. Since the common "alphabet" of DNA and RNA consists of only four letters, the chemical diversity of aptamers is less than the diversity of protein recognition elements built of 20 amino acids. Chemical modification of nucleotides enlarges the potential of DNA/RNA aptamers. This review describes the latest achievements in a variety of approaches to aptamers selection with an extended genetic alphabet. PMID- 30472955 TI - Calcium-Dependent Desensitization of NMDA Receptors. AB - Glutamate receptors play the key role in excitatory synaptic transmission in the central nervous system (CNS). N-methyl-D-aspartate-activated glutamate receptors (NMDARs) are ion channels permeable to sodium, potassium, and calcium ions that localize to the pre- and postsynaptic membranes, as well as extrasynaptic neuronal membrane. Calcium entry into dendritic spines is essential for long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission. Both LTP and LTD represent morphological and functional changes occurring in the process of memory formation. NMDAR dysfunction is associated with epilepsy, schizophrenia, migraine, dementia, and neurodegenerative diseases. Prolonged activation of extrasynaptic NMDARs causes calcium overload and apoptosis of neurons. Here, we review recent findings on the molecular mechanisms of calcium dependent NMDAR desensitization that ensures fast modulation of NMDAR conductance in the CNS and limits calcium entry into the cells under pathological conditions. We present the data on molecular determinants related to calcium-dependent NMDAR desensitization and functional interaction of NMDARs with other ion channels and transporters. We also describe association of NMDARs with lipid membrane microdomains. PMID- 30472956 TI - Prions and Non-infectious Amyloids of Mammals - Similarities and Differences. AB - Amyloids are highly ordered aggregates of protein fibrils exhibiting cross-beta structure formed by intermolecular hydrogen bonds. Pathological amyloid deposition is associated with the development of several socially significant incurable human diseases. Of particular interest are infectious amyloids, or prions, that cause several lethal neurodegenerative diseases in humans and can be transmitted from one organism to another. Because of almost complete absence of criteria for infectious and non-infectious amyloids, there is a lack of consensus, especially, in the definition of similarities and differences between prions and non-infectious amyloids. In this review, we formulated contemporary molecular-biological criteria for identification of prions and non-infectious amyloids and focused on explaining the differences between these two types of molecules. PMID- 30472957 TI - alphaB-Crystallin Phosphorylation: Advances and Problems. AB - The review is dedicated to phosphorylation of alphaB-crystallin (HspB5), one of ubiquitously expressed small heat shock proteins. We describe the structure and properties of alphaB-crystallin and protein kinases involved in its phosphorylation in different cells and tissues, advantages and drawbacks of pseudophosphorylation mutants in elucidation of the mechanism of alphaB crystallin functioning, effects of phosphorylation on the quaternary structure and intracellular location of alphaB-crystallin, interactions of alphaB crystallin with different elements of the cytoskeleton, and effect of phosphorylation on the chaperone-like activity of alphaB-crystallin. We also discuss the validity of experimental data obtained by overexpression of pseudophosphorylation mutants for understanding the effect of phosphorylation on physiologically important properties of alphaB-crystallin, as well as the question why multiple attempts to phosphorylate alphaB-crystallin in vitro have been unsuccessful so far. PMID- 30472958 TI - Synthesis in Escherichia coli and Characterization of Human Recombinant Erythropoietin with Additional Heparin-Binding Domain. AB - Recombinant human erythropoietin (EPO) with additional N-terminal heparin-binding protein domain (HBD) from bone morphogenetic protein 2 was synthesized in Escherichia coli cells. A procedure for HBD-EPO purification and refolding was developed for obtaining highly-purified HBD-EPO. The structure of recombinant HBD EPO was close to that of the native EPO protein. HBD-EPO contained two disulfide bonds, as shown by MALDI-TOF mass spectrometry. The protein demonstrated in vitro biological activity in the proliferation of human erythroleukemia TF-1 cell test and in vivo activity in animal models. HBD-EPO increased the number of reticulocytes in the blood after subcutaneous injection and displayed local angiogenic activity after subcutaneous implantation of demineralized bone matrix (DBM) discs with immobilized HBD-EPO. We developed a quantitative sandwich ELISA method for measuring HBD-EPO concentration in solution using rabbit polyclonal serum and commercial monoclonal anti-EPO antibodies. Pharmacokinetic properties of HBD-EPO were typical for bacterially produced EPO. Under physiological conditions, HBD-EPO can reversibly bind to DBM, which is often used as an osteoplastic material for treatment of bone pathologies. The data on HBD-EPO binding to DBM and local angiogenic activity of this protein give hope for successful application of HBD-EPO immobilized on DBM in experiments on bone regeneration. PMID- 30472959 TI - Hydrophobic Derivatives of Glycopeptide Antibiotics as Inhibitors of Protein Kinases. AB - As key regulators of cell signaling, protein kinases (PKs) are attractive targets for therapeutic intervention in a variety of diseases. Herein, we report for the first time the inhibitory activity of polycyclic peptides, particularly, derivatives of glycopeptide antibiotics teicoplanin and eremomycin, against a panel of 12 recombinant human protein kinases and two protein kinases (CK1 and CK2) isolated from rat liver. Several of the investigated compounds inhibited various PKs with IC50 values below 10 MUM and caused >90% suppression of the enzyme activity at 10 uM concentration. Kinetic analysis of the protein kinase CK2alpha inhibition by the teicoplanin aglycon analogue (7) demonstrated the non competitive mechanism of inhibition (with regard to ATP). Interestingly, the inhibitory activity of some investigated compounds correlated with the earlier described antiviral activity against HIV, HCV, and other corona- and flaviviruses. PMID- 30472960 TI - Thermodynamic Study of Interactions of Distamycin A with Chromatin in Rat Liver Nuclei in the Presence of Polyamines. AB - We studied the thermodynamics of melting of isolated rat liver nuclei with different degrees of chromatin condensation determined by the concentration of polyamines (PA) and the solution ionic strength, as well as the effect of the antibiotic distamycin A (DM) on melting. Differential scanning calorimetry (DSC) profiles of nuclear preparations contained three peaks that reflected melting of three main chromatin domains. The number of peaks did not depend on the degree of condensation; however, nuclei with more condensed chromatin had a higher total enthalpy. DM stabilized peaks II and III corresponding to the melting of relaxed and topologically strained DNA, respectively, but destabilized peak I corresponding to the melting of nucleosome core histones. At the saturating concentration (DM/DNA molar ratio = 0.1), DM increased Tm of peaks II and III by ~5 degrees C and decreased Tm of peak I by ~2.5 degrees C. Based on the dependence of DeltaH on DM concentration, we established that at low DM/DNA ratio (<=0.03), when DM interacted predominantly with AT-rich DNA regions, the enthalpy of peak II decreased in parallel with the increase in the enthalpy of peak III, which indicated that DM induces structural transitions in the nuclear chromatin associated with the increase in torsional stress in DNA. An increase in free energy under saturation conditions was equal to the change in the free energy of DM interaction with DNA. However, the increase in the enthalpy of melting of the nuclei in the presence of DM was much greater than the enthalpy of titration of nuclei with DM. This indicates a significant increase in the strength of interaction between the two DNA strands apparently due, among other things, to changes in the torsional stress of DNA in the nuclei. Titration of the nuclei with increasing PA concentrations resulted in the decrease in the number of DM binding sites and the non-monotonous dependence of the enthalpy and entropy contribution to the binding free energy on the PA content. We suggested that the observed differences in the thermodynamic parameters were due to the different width of the minor groove in the nuclear chromatin DNA, which depends on PA concentration. PMID- 30472961 TI - SkQ1 Controls CASP3 Gene Expression and Caspase-3-Like Activity in the Brain of Rats under Oxidative Stress. AB - Here, we studied the effect of the mitochondria-targeted antioxidant SkQ1 (plastoquinone cationic derivative) on the CASP3 gene expression and caspase-3 activity in rat cerebral cortex and brain mitochondria under normal conditions and in oxidative stress induced by hyperbaric oxygenation (HBO). Under physiological conditions, SkQ1 administration (50 nmol/kg, 5 days) did not affect the CASP3 gene expression and caspase-3-like activity in the cortical cells, as well as caspase-3-like activity in brain mitochondria, but caused a moderate decrease in the content of primary products of lipid peroxidation (LPO) and an increase in the reduced glutathione (GSH) level. HBO-induced oxidative stress (0.5 MPa, 90 min) was accompanied by significant upregulation of CASP3 mRNA and caspase-3-like activity in the cerebral cortex, activation of the mitochondrial enzyme with simultaneous decrease in the GSH content, increase in the glutathione reductase activity, and stimulation of LPO. Administration of SkQ1 before the HBO session maintained the basal levels of the CASP3 gene expression and enzyme activity in the cerebral cortex cells and led to the normalization of caspase-3 like activity and redox parameters in brain mitochondria. We hypothesize that SkQ1 protects brain cells from the HBO-induced oxidative stress due to its antioxidant activity and stimulation of antiapoptotic mechanisms. PMID- 30472962 TI - The Expression of Matryoshka Gene Encoding a Homologue of Kunitz Peptidase Inhibitor Is Regulated Both at the Level of Transcription and Translation. AB - The gene for Kunitz peptidase inhibitor-like protein (KPILP) contains nested alternative open reading frame (aORF) that controls expression of the maternal mRNA. The content of NbKPILP mRNA in intact leaves of Nicotiana benthamiana plant is low but increases significantly upon extended dark exposure or when foreign nucleic acid is overexpressed in the cells. The NbKPILP gene promoter along with the expressed nested aORF are likely to play an important role in maintaining the levels of NbKPILP mRNA. To elucidate the role of NbKPILP promoter, we isolated a fragment of N. benthamiana chromosomal DNA upstream of the NbKPILP transcription start, sequenced it, and created constructs in which reporter E. coli uidA gene coding for beta-D-glucuronidase (GUS) was placed under control of the NbKPILP promoter. By assessing the efficacy of uidA mRNA synthesis directed by the NbKPILP promoter and 35S promoter of the cauliflower mosaic virus in a transient expression system, we showed that the levels of GUS accumulation were comparable for both promoters. Prolonged incubation of the agroinjected plants in the darkness stimulated accumulation of the uidA mRNA directed by the NbKPILP promoter. Our experiments indicate that along with regulation at the transcriptional level, expression of NbKPILP mRNA can be affected by expression of the nested aORF controlled by the polypurine block (PPB) located upstream of its start codon, since introduction of mutations in the PPB resulted in significant accumulation of the NbKPILP mRNA. Nucleotide replacement in the aORF start codon led to the drastic increase in the amounts of NbKPILP mRNA and its protein product. PMID- 30472963 TI - Does Oxidation of Mitochondrial Cardiolipin Trigger a Chain of Antiapoptotic Reactions? AB - Oxidative stress causes selective oxidation of cardiolipin (CL), a four-tail lipid specific for the inner mitochondrial membrane. Interaction with oxidized CL transforms cytochrome c into peroxidase capable of oxidizing even more CL molecules. Ultimately, this chain of events leads to the pore formation in the outer mitochondrial membrane and release of mitochondrial proteins, including cytochrome c, into the cytoplasm. In the cytoplasm, cytochrome c promotes apoptosome assembly that triggers apoptosis (programmed cell death). Because of this amplification cascade, even an occasional oxidation of a single CL molecule by endogenously formed reactive oxygen species (ROS) might cause cell death, unless the same CL oxidation triggers a separate chain of antiapoptotic reactions that would prevent the CL-mediated apoptotic cascade. Here, we argue that the key function of CL in mitochondria and other coupling membranes is to prevent proton leak along the interface of interacting membrane proteins. Therefore, CL oxidation should increase proton permeability through the CL-rich clusters of membrane proteins (CL islands) and cause a drop in the mitochondrial membrane potential (MMP). On one hand, the MMP drop should hinder ROS generation and further CL oxidation in the entire mitochondrion. On the other hand, it is known to cause rapid fission of the mitochondrial network and formation of many small mitochondria, only some of which would contain oxidized CL islands. The fission of mitochondrial network would hinder apoptosome formation by preventing cytochrome c release from healthy mitochondria, so that slowly working protein quality control mechanisms would have enough time to eliminate mitochondria with the oxidized CL. Because of these two oppositely directed regulatory pathways, both triggered by CL oxidation, the fate of the cell appears to be determined by the balance between the CL-mediated proapoptotic and antiapoptotic reactions. Since this balance depends on the extent of CL oxidation, mitochondria-targeted antioxidants might be able to ensure cell survival in many pathologies by preventing CL oxidation. PMID- 30472964 TI - Inhibition of Cannabinoid Receptor 1 Can Influence the Lipid Metabolism in Mice with Diet-Induced Obesity. AB - A growing number of evidences accumulated about critical metabolic role of cannabinoid type 1 receptor (CB1), carnitine palmitoyltransferase-1 (CPT1) and peroxisome proliferator-activated receptors (PPARs) in some peripheral tissues, including adipose tissue, liver, skeletal muscle and heart. To better understand the interactions of CB1, CPT1 and PPARs in these tissues, 30 diet-induced obese (DIO) C57BL/6J male mice were obtained, weight-matched and divided into two groups (15 in each group): (i) DIO/vehicle mice (D-Veh) and (ii) DIO/SR141716 mice (D-SR) treated with SR141716 (or rimonabant, a selective CB1 receptor blocker) administered orally (10 mg/kg daily). Another 15 mice fed standard diet (STD) formed the STD/vehicle group (S-Veh). At the end of 3-week treatment, mean body weight was 28.4 +/- 0.5, 36.5 +/- 0.8, and 30.3 +/- 1.2 g for the S-Veh, D Veh, and D-SR group, respectively (p < 0.05; D-Veh vs. D-SR). Liver weight in the D-SR group was also decreased significantly compared to the D-Veh group (p < 0.05). Serum levels of total cholesterol, high-density lipoprotein cholesterol, leptin and adiponectin in the D-SR group were ameliorated compared to the D-Veh group (p < 0.05). Both qRT-PCR and Western blot assay revealed that CB1 expression levels were efficiently blocked by SR141716 in subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), skeletal muscles and liver (D-SR vs. D-Veh; p < 0.05), whereas there was no significant difference between S-Veh and D Veh mice (p > 0.05). Simultaneously with the reduction of CB1 expression in the D SR group, the expression levels of CPT1A isoform (protein) in the liver and heart and CPT1B isoform (protein) in the SAT, VAT, liver and skeletal muscles were significantly increased (p < 0.05; D-SR vs. D-Veh). Interestingly, the CPT1A and CPT1B expression levels in heart were detected slightly. The expression levels of PPARalpha in the SAT, VAT, liver and skeletal muscles and PPARgamma in the SAT and skeletal muscles in the D-SR group were significantly increased compared to the D-Veh mice (p < 0.05). However, the PPARbeta expression level differed from that of PPARalpha and PPARgamma. Taken together, these data indicate that the inhibition of CB1 could ameliorate lipid metabolism via the stimulation of the CPT1A and CPT1B expression in vivo. Simultaneously, the PPARalpha and PPARgamma expression levels significantly differed compared to that of PPARbeta in obesity and lipid metabolism-related disorders under blockade of CB1. Both the mechanism of the influence of CB1 inhibition on lipid metabolism in the examined tissues and the specific mechanism of PPARalpha, PPARgamma and PPARbeta involvement in lipid exchange under these conditions remain to be further elucidated. PMID- 30472965 TI - Women living with multi-morbidity in the Greater Accra Region of Ghana: a qualitative study guided by the Cumulative Complexity Model. AB - Defined as the co-occurrence of more than two chronic conditions, multi-morbidity has been described as a significant health care problem: a trend linked to a rise in non-communicable disease and an ageing population. Evidence on the experiences of living with multi-morbidity in middle-income countries (MICs) is limited. In high-income countries (HICs), multi-morbidity has a complex impact on health outcomes, including functional status, disability and quality of life, complexity of health care and burden of treatment. Previous evidence also shows that multi morbidity is consistently higher amongst women. This study aimed to explore the perceptions and experiences of women living with multi-morbidity in the Greater Accra Region, Ghana: to understand the complexity of their health needs due to multi-morbidity, and to document how the health system has responded. Guided by the Cumulative Complexity Model, and using stratified purposive sampling, 20 in depth interviews were conducted between May and September 2015 across three polyclinics in the Greater Accra Region. The data were analysed using the six phases of Thematic Analysis. Overall four themes emerged: 1) the influences on patients' health experience; 2) seeking care and the responsiveness of the health care system; 3) how patients manage health care demands; and 4) outcomes due to health. Spirituality and the stigmatization caused by specific conditions, such as HIV, impacted their overall health experience. Women depended on the care and treatment provided through the health care system despite inconsistent coverage and a lack of choice thereof, although their experiences varied by chronic condition. Women depended on their family and community to offset the financial burden of treatment costs, which was exacerbated by having many conditions. The implications are that integrated health and social support, such as streamlining procedures and professional training on managing complexity, would benefit and reduce the burden of multi-morbidity experienced by women with multi-morbidity in Ghana. PMID- 30472967 TI - Mycobacterium avium pseudo-outbreak associated with an outpatient bronchoscopy clinic: Lessons for reprocessing. AB - We identified a pseudo-outbreak of Mycobacterium avium in an outpatient bronchoscopy clinic following an increase in clinic procedure volume. We terminated the pseudo-outbreak by increasing the frequency of automated endoscope reprocessors (AER) filter changes from quarterly to monthly. Filter changing schedules should depend on use rather than fixed time intervals. PMID- 30472966 TI - Relapse of drunk driving and association with traffic accidents, alcohol-related problems and biomarkers of impulsivity. AB - OBJECTIVE: Individual biological predispositions should play a role in risky driving behaviour. Platelet monoamine oxidase (MAO) activity, dopamine transporter gene (DAT1) and neuropeptide S receptor 1 (NPSR1) gene polymorphisms have been identified as markers of impulsivity, alcohol use and excessive risk taking. We aimed to find out how this knowledge on neurobiology of impulsivity applies to drunk driving and traffic behaviour in general. METHODS: We have longitudinally examined the behaviour of drunk drivers (n = 203) and controls (n = 211) in traffic, in association with their alcohol-related problems, personality measures and the three biomarkers. We analysed differences between the subjects based on whether they had committed driving while impaired by alcohol (DWI) violation in a 10-year time period after recruitment or not and investigated further, what kind of predictive value do the different biomarkers have in committing DWI and other traffic violations and accidents. RESULTS: The original drunk drivers group had lower platelet MAO activity but further DWI was not significantly associated with this measure. Being a NPSR1 T-allele carrier contributed to the risk of repeatedly committing DWI. DAT1 9R carriers in contrast were involved in more traffic accidents by their own fault (active accidents), compared to 10R homozygotes in the whole sample. All groups with DWI also had significantly more alcohol-related problems and higher scores in maladaptive impulsivity compared to controls without DWI. CONCLUSIONS: Established biological markers of alcohol use and impulsivity can be reliably associated with everyday traffic behaviour and help in contributing to the understanding of the need for more personalized prevention activities. PMID- 30472968 TI - Changes in socio-economic status and lipoproteins in Chilean adolescents: a 16 year longitudinal study. AB - OBJECTIVE: The present longitudinal study assessed whether changes in socio economic status (SES) from infancy to adolescence were associated with plasma lipoprotein concentrations in adolescence, of which low HDL-cholesterol (HDL-C) and high LDL-cholesterol (LDL-C), TAG and total cholesterol (TC) concentrations are associated with higher cardiovascular risk. DESIGN: SES, assessed using the modified Graffar Index, was calculated at 1, 5, 10 and 16 years. Principal components factor analysis with varimax rotation extracted two orthogonal SES factors, termed 'environmental capital' and 'social capital'. Generalized linear models were used to analyse associations between environmental and social capital at 1 and 16 years and outcomes (HDL-C, LDL-C, TAG, TC) at 16 years, as well as changes in environmental and social capital from 1-5, 5-10, 10-16 and 1-16 years, and outcomes at 16 years. SETTING: Santiago, Chile.ParticipantsWe evaluated 665 participants from the Santiago Longitudinal Study enrolled at infancy in Fe deficiency anaemia studies and examined every 5 years to age 16 years. RESULTS: Social capital in infancy was associated with higher HDL-C in adolescence. Environmental capital in adolescence was associated with higher LDL-C and TC during adolescence. Changing environmental capital from 1-16 years was associated with higher LDL-C. Changing environmental capital from 1-5 and 1-16 years was associated with higher TC. CONCLUSIONS: Improvements in environmental capital throughout childhood were associated with less healthy LDL-C and TC concentrations in adolescence. We found no evidence of associations between changing environmental capital and HDL-C or TAG, or changing social capital and HDL-C, LDL-C, TAG or TC. PMID- 30472969 TI - Morphological and molecular data for species of Lecithaster Luhe, 1901 and Hysterolecithoides Yamaguti, 1934 (Digenea: Lecithasteridae) from fish of East Asia and phylogenetic relationships within the Hemiuroidea Looss, 1899. AB - Four representatives of the genus Lecithaster and one representative of the genus Hysterolecithoides were found during investigation of the trematode fauna of fish species in Vietnamese, Japanese and eastern coastal waters of the Russian Far East. Based on morphometric data, adult trematodes from Vietnamese Strongylura strongylura and Russian Acanthogobius flavimanus were identified as Lecithaster confusus, trematodes from Vietnamese Hemirhamphus marginatus as L. sayori and from osmerid fishes as L. salmonis. Further, a single specimen of Lecithaster sp. and representatives of Hysterolecithoides epinepheli were found in Vietnamese Siganus fuscescens. Morphological and molecular data, including 18S ribosomal DNA (rDNA) V4 fragment, 28S rDNA D1-D3 fragment, internal transcribed spacers (ITS) and a mitochondrial COI gene fragment were analysed for Lecithaster spp. The results revealed that L. sayori and L. salmonis are not synonyms of L. stellatus and L. gibbosus, respectively, but that Hysterolecithoides frontilatus and H. guangdongensis are junior synonyms of H. epinepheli. The 28S-rDNA-based phylogenetic tree of Hemiuroidea showed a distinct position for the genus Lecithaster with internal differentiation into three subclades, including L. confusus, L. sayori and Lecithaster sp. within the first subclade, L. mugilis and L. sudzuhensis within the second subclade and L. salmonis and L. gibbosus within the third subclade. Bayesian phylogenetic reconstructions of Hemiuroidea showed four clades for members of Hemiuridae and Lecithasteridae. The first clade consisted of Hemiuridae representatives and the second clade represented the genus Lecithaster. The third clade included genera Aponurus and Lecithophyllum (Lecithasteridae) and the fourth clade combined members of lecithasterid Quadrifoliovariinae and Hysterolecithinae and hemiurid Opisthadeninae and Bunocotylidae with high statistical support. PMID- 30472970 TI - Mobile app increases vegetable-based preparations by low-income household cooks: a randomized controlled trial. AB - OBJECTIVE: We built an app to help clients of food pantries. The app offers vegetable-based recipes, food tips and no-cost strategies for making mealtimes healthier and for bargain-conscious grocery shopping, among other themes. Users customize materials to meet their own preferences. The app, available in English and Spanish, has been tested in a randomized field trial. DESIGN: A randomized controlled trial with repeated measures across 10 weeks. SETTING: Clients of fifteen community food pantry distributions in Los Angeles County, USA.ParticipantsDistributions were randomized to control and experimental conditions, and 289 household cooks and one of their 9-14-year-old children were enrolled as participants. Experimental dyads were given a smartphone with our app and a phone use-plan, then trained to use the app. 'Test vegetables' were added to the foods that both control and experimental participants received at their pantries. RESULTS: After 3-4 weeks of additional 'test vegetables', cooks at experimental pantries had made 38 % more preparations with these items than control cooks (P = 0.03). Ten weeks following baseline, experimental pantries also scored greater gains in using a wider assortment of vegetables than control pantries (P = 0.003). Use of the app increased between mid-experiment and final measurement (P = 0.0001). CONCLUSIONS: The app appears to encourage household cooks to try new preparation methods and widen their incorporation of vegetables into family diets. Further research is needed to identify specific app features that contributed most to outcomes and to test ways in which to disseminate the app widely. PMID- 30472971 TI - Reward systems and cognitions in Major Depressive Disorder. AB - A lack of motivation and anhedonia represent frequent and pervasive symptoms in depression, although with poor specificity. Historically described as a response bias, reward-related impairments in depression may account for the important aspects of the cognitive impairments associated with diagnosis of major depressive disorder. Reward processing is a broad psychological construct that can be parsed into 3 distinct components known as "reinforcement learning" (learning), "reward responsiveness" (liking), and "motivation to obtain a reward" (wanting). Depressed patients respond hyposensitively to reward and maladaptively to punishment: this pattern is related to a dysfunction in the frontostriatal systems modulated by the monoamine systems; seems to be observed in medicated and unmedicated patients with depression and in healthy individuals with high levels of anhedonia; and could be observed in patients with a history of depression, even when in full remission. Considered to be cognitive impairments, reward related-impairments may also constitute part of an underlying neurobiological vulnerability to major depressive disorder (MDD). For example, the reward-related impairment is state dependent and, more or less, correlated with symptom severity in some studies but has also been proposed as being trait like, with endophenotype characteristics, possibly contributing to the persistence of the disease or treatment resistance. The 3 core aspects of reward processing have specific neurobiological correlates that involve the ventral and dorsal striatum, lateral habenula, ventral tegmental area, orbitofrontal cortex, anterior cingulate cortex, and ventromedial and dorsolateral prefrontal cortex. These structures underline the important role of the dopaminergic mesolimbic pathway, but glutamate and serotonin could also have an important role, at least in some aspects of reward-related impairments. PMID- 30472972 TI - Dietary sources of salt intake in adults and older people: a population-based study in a Brazilian town. AB - OBJECTIVE: To assess salt intake and its dietary sources using biochemical and self-report methods and to characterize salt intake according to sociodemographic and disease-related variables in a sample of the Brazilian population. DESIGN: Population-based cross-sectional survey. SETTING: Salt intake was assessed by biochemical (24 h urinary Na excretion) and self-report methods (sodium FFQ, 24 h dietary recall, seasoned-salt questionnaire, discretionary-salt questionnaire and total reported salt intake).ParticipantsAdults and older people (n 517) aged 20 80 years, living in Artur Nogueira, Sao Paulo, Brazil. RESULTS: Mean salt intake based on 24 h urinary Na excretion and total reported salt intake was 10.5 and 11.0 g/d, respectively; both measures were significantly correlated. Discretionary salt and seasoned salt were the most important sources of salt intake (68.2 %). Men in the study consumed more salt than women as estimated by 24 h urinary Na excretion (11.7 v. 9.6 g salt/d; P<0.0001). Participants known to be hypertensive added more salt to their meals but consumed less salty ultra processed foods. Waist circumference in both sexes and BMI were positively correlated with salt intake estimated by 24 h urinary Na excretion. In addition, regression analysis revealed that being a young male or having a high waist circumference was a predictor of higher salt intake. CONCLUSIONS: Salt intake in this population was well above the recommended amount. The main source of salt intake came from salt added during cooking. Salt intake varied according to sex and waist circumference. PMID- 30472974 TI - The Risk Reference Panel: a thematic analysis of a multidisciplinary forum for complex cases. AB - Aims and methodTo describe the functions of the Aneurin Bevan University Health Board Risk Reference Panel and characterise the typical referrals presented and outcomes from the panel. A structured thematic analysis was performed on verbatim transcripts of 48 panel sessions. RESULTS: The 79 codes identified were grouped into 16 subthemes. Four principal themes were identified: two characterising cases brought to the panel (childhood risk factors and current presenting difficulties) and two describing advice given (risk management and wider organisational issues). Quotations are given to illustrate cases presented and advice given by the panel.Clinical implicationsThe panel provides a valuable source of special expertise in the management of complex and exceptional cases where risk of harm is significant and clinical teams have ongoing concerns. This paper describes a model of peer-working to support staff and may further reduce the risk of harm associated with mental illness.Declaration of interestNone. PMID- 30472973 TI - Associations between schizophrenia genetic risk, anxiety disorders and manic/hypomanic episode in a longitudinal population cohort study. AB - BACKGROUND: Studies involving clinically recruited samples show that genetic liability to schizophrenia overlaps with that for several psychiatric disorders including bipolar disorder, major depression and, in a population study, anxiety disorder and negative symptoms in adolescence.AimsWe examined whether, at a population level, association between schizophrenia liability and anxiety disorders continues into adulthood, for specific anxiety disorders and as a group. We explored in an epidemiologically based cohort the nature of adult psychopathology sharing liability to schizophrenia. METHOD: Schizophrenia polygenic risk scores (PRSs) were calculated for 590 European-descent individuals from the Christchurch Health and Development Study. Logistic regression was used to examine associations between schizophrenia PRS and four anxiety disorders (social phobia, specific phobia, panic disorder and generalised anxiety disorder), schizophrenia/schizophreniform disorder, manic/hypomanic episode, alcohol dependence, major depression, and - using linear regression - total number of anxiety disorders. A novel population-level association with hypomania was tested in a UK birth cohort (Avon Longitudinal Study of Parents and Children). RESULTS: Schizophrenia PRS was associated with total number of anxiety disorders and with generalised anxiety disorder and panic disorder. We show a novel population-level association between schizophrenia PRS and manic/hypomanic episode. CONCLUSIONS: The relationship between schizophrenia liability and anxiety disorders is not restricted to psychopathology in adolescence but is present in adulthood and specifically linked to generalised anxiety disorder and panic disorder. We suggest that the association between schizophrenia liability and hypomanic/manic episodes found in clinical samples may not be due to bias.Declarations of interestNone. PMID- 30472975 TI - Development of the Healthy Purchase Index (HPI): a scoring system to assess the nutritional quality of household food purchases. AB - OBJECTIVE: To develop an index to assess the nutritional quality of household food purchases based on food expenditures only. DESIGN: A database of monthly food purchases of a convenience sample of low-income households was used to develop the Healthy Purchase Index (HPI). The HPI is the sum of two sub-scores based on expenditure shares of food categories in total household food expenditure: the purchase diversity sub-score and the purchase quality sub-score. The first was adapted from an existing diversity score. The second integrated those food categories identified as the best predictors of the nutritional quality of purchases based on associations between expenditure shares of food categories and two nutritional quality indicators: the mean adequacy ratio (MAR) and the mean excess ratio (MER). Correlation between the HPI and a score assessing adherence to French dietary guidelines (PNNS-GSmod) was performed as a first validation.Setting/ParticpantsFood purchases of 112 households from deprived neighbourhoods of Marseille (France), participating in the Opticourses and Jassur projects (2012-2015). RESULTS: The purchase diversity sub-score reflects the presence in food purchases of five food categories: fruits, vegetables, starches, dairy products, and meat, fish & eggs. The purchase quality sub-score is based on expenditure shares for fruit & vegetables, added fats & seasonings, sweet snacks, cheese, sugary drinks, refined grains and fish, as these were identified as predictors of the nutritional quality of purchases. The HPI was positively associated with the PNNS-GSmod (rs=0.378; P<0.001). CONCLUSIONS: The HPI helps assess the healthiness of household food purchases. PMID- 30472976 TI - ZBI multidimensionality: The salience of worry about performance. PMID- 30472977 TI - Non-alcoholic Steatohepatitis (NASH) Drug Discovery - Building a Consensus on ADME Screening Tools and Clinical Pharmacology Strategies to Aid Candidate Development. AB - Number of drugs with different mechanisms of actions is undergoing clinical trials for non-alcoholic steatohepatitis (NASH). Given the complexity of the disease with respect to pathophysiology in the liver and associated changes in the renal function, it becomes apparent that a clear ADME (absorption, distribution, metabolism and excretion) strategy needs to be put in place for a successful nomination of a drug candidate for NASH. This review discusses using in vitro and in vivo ADME screens to understand the properties of drugs and to establish whether or not the chosen drug(s) can overcome the challenges related hepatic and renal transporters covering both uptake and efflux mechanisms imposed by NASH. A complete panel of in vivo preclinical experiments including a 14C labeled study are proposed in NASH animal models to delineate the problematic areas for early drug development. Furthermore, a framework is provided with respect to the clinical pharmacology studies early in clinical development to characterise in an unbiased manner, the altered pharmacokinetics of drug in NASH patients for optimizing the dose selection for late phase clinical development. Because NASH patients have other co-morbid conditions and are prescribed co medications for treating blood pressure, type 2 diabetes mellitus, obesity, dyslipidemia and many more disorders, it is also suggested to examine the drug drug interaction potential by performing a cocktail probe study to cover a broad range of cytochrome P450 (CYP) enzymes and transporters. PMID- 30472978 TI - Development, Characterization, and Pharmacokinetic Evaluation of a CRV431 Loaded Self-Microemulsifying Drug Delivery System. AB - PURPOSE: The objective of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) formulation for the oral delivery of CRV431, a non immunosuppressive analogue of cyclosporine A. Relative to cyclosporine A, CRV431 is poorly soluble in lipid solvents and thusly presents a challenge for the development of a formulation of sufficient oral bioavailability for clinical use. METHODS: The solubility of CRV431, a cyclosporine derivative, was determined in a range of commonly used surfactants, oils and co-solvents. A pseudo-ternary phase diagram was constructed from the most soluble excipients and prototype formulations, SERIES 1 and SERIES 2 were developed. The pharmacokinetics, following single oral doses of 1 and 3 mg/kg of CRV431 SMEDDS, was studied in healthy human volunteers using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). RESULTS: The maximum drug load for the SERIES 1 formulations was less than 40 mg/ml. Manipulation of the excipient ratios allowed for the development of SERIES 2 formulations, which had higher drug loading capacity and stability for CRV431 compared to SERIES 1. Further improvements allowed for the development of an optimized SMEDDS formulation containing up to 90 mg/ml CRV431 and which generated a microemulsion mean particle size of 25 nm when dispersed into aqueous media. The pharmacokinetics of the optimized CRV431 SMEDDS displayed excellent total body exposure and dose-proportional effects in humans, and high drug levels in the liver of rats. CONCLUSIONS: The developed SMEDDS formulation should allow for effective clinical development of CRV431, targeted to the treatment of liver diseases including hepatitis B (HBV), fibrosis, and hepatocellular carcinoma. PMID- 30472979 TI - Case - Fungal urosepsis after ureteroscopy in a patient on new generation of anti hyperglycemic medication. PMID- 30472980 TI - 30-day readmission after radical cystectomy: Identifying targets for improvement using the phases of surgical care. AB - INTRODUCTION: Postoperative readmissions following radical cystectomy (RC) have gained attention in the past decade. Postoperative and post-discharge complications play a role in readmission rates; however, our ability to predict readmissions remains poor. METHODS: Using the National Surgical Quality Improvement Program database, we identified patients with bladder cancer undergoing RC from 2013-2015. Complications were defined as postoperative and post-discharge. Outcomes were 30-day readmission, post-discharge complications, and post-discharge major complications. Patient, operative, and complication factors were assessed using multivariable logistic regression. RESULTS: We identified 4457 patients who underwent RC; 9.2% of patients experienced a postoperative complication, 18.8% experienced a post-discharge complication, and 20.3% were readmitted. Overweight and obese body mass index (BMI), dependent functional status, chronic obstructive pulmonary disease (COPD), a continent diversion, and duration of operation were associated with post-discharge complications. Postoperative complications were not associated with post discharge complications. Readmission was associated with Black race (odds ratio [OR] 1.5; 95% confidence interval [CI] 1.0-2.1), overweight (OR 1.5; 95% CI 1.2 1.8) and obese BMI (OR 1.5; 95% CI 1.2-1.9), diabetes (OR 1.2; 95% CI 1.0-1.5), COPD (OR 1.4; 95% CI 1.0-1.8), steroid use (OR 1.5; 95% CI 1.0-2.2), a continent diversion (OR 1.4; 95% CI 1.1-1.7), duration of operation (OR 1.1; 95% CI 1.1 1.2), and postoperative complications (OR 1.5; 95% CI 1.2-2.0). The majority of readmissions experienced a post-discharge complication. CONCLUSIONS: Factors that span the preoperative, intraoperative, postoperative, and post-discharge phases of care were identified to increase readmission risk. To improve readmission rates, interventions will have to target factors across the surgical experience. PMID- 30472981 TI - Case - Prostatic abscess in an adolescent. PMID- 30472983 TI - Segmental ureterectomy can be performed safely in patients with urothelial carcinoma of distal ureter. AB - INTRODUCTION: We aimed to compare oncological outcomes by surgery type (segmental ureterectomy [SU] vs. radical nephroureterectomy [RNU]) in a large cohort of patients with upper tract urothelial carcinoma (UTUC) of the distal ureter. METHODS: We performed a retrospective analysis of 219 patients with UTUC of the distal ureter among 931 patients with UTUC who underwent SU and RNU. Clinicopathological outcomes were evaluated. Cancer-specific survival (CSS), overall survival (OS), local recurrence-free survival (RFS), intravesical recurrence-free survival (IVRFS), contralateral recurrence-free survival, and distal metastasis-free survival were assessed by the Kaplan-Meier method and Cox regression, estimating hazard ratios (HR) and 95% confidence intervals (CIs). RESULTS: A total of 179 (81.7%) patients underwent RNU and 40 (18.3%) underwent SU: 85 males (47.5%) with RNU and 17 (42.5%) with SU (p=0.568). The median age with RNU and SU was 71 years (range 31-86) and 70 years (range 46-90), respectively (p=0.499). The T stage of the two groups did not differ (p=0.122), nor did mean tumour length (3.35+/-2.62 vs. 3.25+/-2.14; p=0.953), grade (p=0.075), tumour necrosis (p=0.634), or followup time (months) (58.1+/-8.1 vs. 63.7+/-3.4; p=0.462). The two groups did not differ in CSS (p=0.358) or OS (p=0.206), and surgery type did not predict CSS (HR 0.862; 95% CI 0.469-1.585; p=0.633) or OS (HR 0.764; 95% CI 0.419-1.392; p=0.379). Local RFS was higher with RNU than SU (96.2% vs. 86.0%; p=0.02), but the groups did not differ in IVRFS (p=0.661), contralateral RFS (p=0.183), or distant metastasis-free survival (p=0.078). On multivariate analysis, SU was associated with local RFS (HR 5.069; 95% CI 1.029-24.968; p=0.046) and distant metastasis-free survival (HR 6.497; 95% CI 1.196-35.283; p=0.03). Local RFS was lower with SU than RNU for patients with pT3-4 stage (p=0.006). CONCLUSIONS: Long-term oncological outcomes were equivalent with SU and RNU in patients with UTUC of the distal ureter. SU affected local recurrence survival, especially with advanced tumour stage, and distant metastasis survival. PMID- 30472984 TI - Perceptions on Competence by Design in urology. AB - INTRODUCTION: The Royal College of Physicians and Surgeons of Canada has begun implementing Competence by Design (CBD). However, it is unclear how much urology trainees and faculty know about CBD, their attitudes towards this change, and their willingness to embrace and participate in this new model of training. METHODS: This cross-sectional study was conducted through an online survey, which was administered to all trainees and faculty at Canadian urology programs prior to the implementation of CBD. The final survey consisted of eight demographic questions, 17 five-point Likert items, one visual analog scale question, 11 multiple selection questions, and two open-ended questions. RESULTS: A total of 74 participants (38 faculty and 36 trainees) across 12 universities responded, with a completion rate of 82.4%. This corresponded to an overall response rate of 20.5%. Overall, there was a lack of resounding enthusiasm towards this shift to CBD in urology. Although both trainees and faculty had overall positive perceptions of CBD on assessment, teaching, and readiness, most agreed that this transition will be costly and associated with increased requirements for time, funding, and administrative support. Furthermore, there were significant concerns regarding the lack of valid assessment tools and evidence for the validity of entrustable professional activities. CONCLUSIONS: While this survey has demonstrated an appreciation for the benefits of CBD, challenges are equally anticipated. CBD in urology will be a fertile research area; this study has identified several important educational questions regarding the model's effectiveness and consequences, thus, providing collaborative opportunities among all Canadian programs. PMID- 30472982 TI - Endogenous H2S production deficiencies lead to impaired renal erythropoietin production. AB - INTRODUCTION: Patients suffering from chronic kidney disease (CKD) experience a number of associated comorbidities, including anemia. Relative deficiency in renal erythropoietin (EPO) production is thought to be a primary cause of anemia. Interestingly, CKD patients display low levels of hydrogen sulfide (H2S), an endogenously derived renal oxygen sensor. Previous in vitro experiments have revealed that H2S-deficient renal cell lines produce less EPO than wild-type renal cell lines during hypoxia. METHODS: We postulated that H2S might be a primary mediator of EPO synthesis during hypoxia, which was tested using an in vivo murine model of whole-body hypoxia and in clinical samples obtained from CKD patients. RESULTS: Following a 72-hour period of hypoxia (11% O2), partial H2S knockout mice (lacking the H2S biosynthetic enzyme cystathionine gamma-lyase [CSE]) displayed lower levels of hemoglobin, EPO and cystathionine-beta-synthase (CBS) (another H2S biosynthetic enzyme) compared to wild-type mice, all of which was rescued by exogenous H2S supplementation. We also found that anemic CKD patients requiring exogenous EPO exhibited lower urinary thiosulfate levels compared to non-anemic CKD patients of similar CKD classification. CONCLUSIONS: Together, our results confirm an interplay between the actions of H2S during hypoxia and EPO production. PMID- 30472985 TI - Factors underlying treatment decision-making for localized prostate cancer in the U.S. and Canada: A scoping review using principal component analysis. AB - INTRODUCTION: The purpose of this research is to gather, collate, and identify key factors commonly studied in localized prostate cancer (LPC) treatment decision-making in Canada and the U.S. METHODS: This scoping review uses five databases (Medline, EMBASE, CINAHL, AMED, and PsycInfo) to identify relevant articles using a list of inclusion and exclusion criteria applied by two reviewers. A list of topics describing the themes of the articles was extracted and key factors were identified using principal component analysis (PCA). A word cloud of titles and abstracts of the relevant articles was created to identify complementary results to the PCA. RESULTS: This review identified 77 relevant articles describing 32 topics related to LPC treatment decision-making. The PCA grouped these 32 topics into five key factors commonly studied in LPC treatment decision-making: 1) treatment type; 2) socioeconomic/demographic characteristics; 3) personal reasons for treatment choice; 4) psychology of treatment decision experience; and 5) level of involvement in the decision-making process. The word cloud identified common phrases that were complementary to the factors identified through the PCA. CONCLUSIONS: This research identifies several possible factors impacting LPC treatment decision-making. Further research needs to be completed to determine the impact that these factors have in the LPC treatment decision making experience. PMID- 30472987 TI - Recovery of adenosine-sensitive dormant conduction is but one mechanism of pulmonary vein reconnection. PMID- 30472988 TI - Estimating Metabolic Equilibrium Constants: Progress and Future Challenges. AB - Reaction equilibrium constants (Keqs) are key parameters that impose thermodynamic constraints on the function of a metabolic network. An important approach for Keq estimation is the group contribution method, which utilizes chemical moiety-based estimates of compound formation energies. In this Opinion, we delineate a number of current challenges with the group contribution method, specifically: (i) problems related to the completeness and quality of data necessary for reliable estimation; and (ii) inadequacies of the method to represent the physical properties of compounds. We then highlight a number of promising approaches to deal with the limitations of group contribution methods. Further advancements should lead to more accurate prediction of equilibrium constants and a better representation of cellular function under biophysical constraints. PMID- 30472986 TI - Stepwise response of MeJA-induced genes and pathways in leaves of C. roseus. AB - Catharanthus roseus is a perennial herb known for the production of important terpenoid indole alkaloids (TIAs) in addition to a variety of phenolic compounds. The goal of the present work was to detect the prolonged effects of MeJA (6 uM) treatment across time (up to 24 days) in order to detect the stepwise response of MeJA-induced genes and pathways in leaves of C. rouses. Prolonged exposure of plants to MeJA (6 uM) treatment for different time points (6, 12 and 24 days) indicated that genes in the indole alkaloid biosynthesis pathway and upstream pathways were triggered earlier (e.g., 6 days) than those in the anthocyanin biosynthesis pathway and its upstream pathways (e.g., 12 days). Three enzymes, e.g., T16H, OMT, and D4H, in the six-step vindoline biosynthesis and two enzymes, e.g., TDC and STR, acting consecutively in the conversion of tryptophan to strictosidine, were activated after 6 days of MeJA treatment. Two other key enzymes, e.g., TRP and CYP72A1, acting concurrently upstream of the TIA biosynthesis pathway were upregulated after 6 days. The genes encoding TDC and STR might concurrently act as a master switch of the TIA pathway towards the production of the indole alkaloids. On the other hand, we speculate that the gene encoding PAL enzyme also acts as the master switch of phenylpropanoid biosynthesis and the downstream flavonoid biosynthesis and anthocyanin biosynthesis pathways towards the production of several phenolic compounds. PAL and the downstream enzymes were activated 12 days after treatment. Cluster analysis confirmed the concordant activities of the flower- and silique-specific bHLH25 transcription factor and the key enzyme in the TIA biosynthesis pathway, e.g., STR. Due to the stepwise response of the two sets of pathways, we speculate that enzymes activated earlier likely make TIA biosynthesis pathway a more favourable target in C. roseus than anthocyanin biosynthesis pathway. PMID- 30472989 TI - Greasing the Wheels of Lipid Biology with Chemical Tools. AB - Biological lipids are a structurally diverse and historically vexing group of hydrophobic metabolites. Here, we review recent advances in chemical imaging techniques that reveal changes in lipid biosynthesis, metabolism, dynamics, and interactions. We highlight tools for tagging many lipid classes via metabolic incorporation of bioorthogonally functionalized precursors, detectable via click chemistry, and photocaged, photoswitchable, and photocrosslinkable variants of different lipids. Certain lipid probes can supplant traditional protein-based markers of organelle membranes in super-resolution microscopy, and emerging vibrational imaging methods, such as stimulated Raman spectroscopy (SRS), enable simultaneous imaging of more than a dozen different types of target molecule, including lipids. Collectively, these chemical imaging techniques will illuminate, in living color, previously hidden aspects of lipid biology. PMID- 30472990 TI - The Limits of Enzyme Specificity and the Evolution of Metabolism. AB - The substrate specificity of enzymes is bound to be imperfect, because of unavoidable physicochemical limits. In extant metabolic enzymes, furthermore, such limits are seldom approached, suggesting that the degree of specificity of these enzymes, on average, is much lower than could be attained. During biological evolution, the activity of a single enzyme with available alternative substrates may be preserved to a significant or even substantial level for different reasons - for example when the alternative reaction contributes to fitness, or when its undesirable products are nevertheless dispatched by metabolite repair enzymes. In turn, the widespread occurrence of promiscuous reactions is a consistent source of metabolic 'messiness', from which both liabilities and opportunities ensue in the evolution of metabolic systems. PMID- 30472991 TI - Oral health: a neglected aspect of diabetes care. PMID- 30472992 TI - Systemic effects of periodontitis treatment in patients with type 2 diabetes: a 12 month, single-centre, investigator-masked, randomised trial. AB - BACKGROUND: Chronic inflammation is believed to be a major mechanism underlying the pathophysiology of type 2 diabetes. Periodontitis is a cause of systemic inflammation. We aimed to assess the effects of periodontal treatment on glycaemic control in people with type 2 diabetes. METHODS: In this 12 month, single-centre, parallel-group, investigator-masked, randomised trial, we recruited patients with type 2 diabetes, moderate-to-severe periodontitis, and at least 15 teeth from four local hospitals and 15 medical or dental practices in the UK. We randomly assigned patients (1:1) using a computer-generated table to receive intensive periodontal treatment (IPT; whole mouth subgingival scaling, surgical periodontal therapy [if the participants showed good oral hygiene practice; otherwise dental cleaning again], and supportive periodontal therapy every 3 months until completion of the study) or control periodontal treatment (CPT; supra-gingival scaling and polishing at the same timepoints as in the IPT group). Treatment allocation included a process of minimisation in terms of diabetes onset, smoking status, sex, and periodontitis severity. Allocation to treatment was concealed in an opaque envelope and revealed to the clinician on the day of first treatment. With the exception of dental staff who performed the treatment and clinical examinations, all study investigators were masked to group allocation. The primary outcome was between-group difference in HbA1c at 12 months in the intention-to-treat population. This study is registered with the ISRCTN registry, number ISRCTN83229304. FINDINGS: Between Oct 1, 2008, and Oct 31, 2012, we randomly assigned 264 patients to IPT (n=133) or CPT (n=131), all of whom were included in the intention-to-treat population. At baseline, mean HbA1c was 8.1% (SD 1.7) in both groups. After 12 months, unadjusted mean HbA1c was 8.3% (SE 0.2) in the CPT group and 7.8% (0.2) in the IPT group; with adjustment for baseline HbA1c, age, sex, ethnicity, smoking status, duration of diabetes, and BMI, HbA1c was 0.6% (95% CI 0.3-0.9; p<0.0001) lower in the IPT group than in the CPT group. At least one adverse event was reported in 30 (23%) of 133 patients in the IPT group and 23 (18%) of 131 patients in the CPT group. Serious adverse events were reported in 11 (8%) patients in the IPT group, including one (1%) death, and 11 (8%) patients in the CPT group, including three (2%) deaths. INTERPRETATION: Compared with CPT, IPT reduced HbA1c in patients with type 2 diabetes and moderate-to-severe periodontitis after 12 months. These results suggest that routine oral health assessment and treatment of periodontitis could be important for effective management of type 2 diabetes. FUNDING: Diabetes UK and UK National Institute for Health Research. PMID- 30472993 TI - Deciphering the Sharp Decrease in H7N9 Human Infections. AB - The H7N9 virus has caused five waves of human infections since 2013. However, human infections have almost disappeared in the past year. In a recent study, Shi et al. revealed that the usage of a bivalent H5/H7 vaccine successfully prevented chicken infections, and thus prevented, and nearly eliminated, human infections. PMID- 30472994 TI - The VirE-asy Way to Genetically Transform Plants. AB - Agrobacterium transfers T-DNA and several virulence effector proteins to plant cells. It is not known how and where T-complexes containing these components are assembled. A new study suggests that T-complexes form on the plant plasma membrane, mediated by the effector protein VirE3. PMID- 30472995 TI - A Prediction Tool to Facilitate Risk-Stratified Screening for Squamous Cell Skin Cancer. AB - Cutaneous squamous cell cancers (cSCCs) present an under-recognized health issue among non-Hispanic whites, one that is likely to increase as populations age. cSCC risks vary considerably among non-Hispanic whites, and this heterogeneity indicates the need for risk-stratified screening strategies that are guided by patients' personal characteristics and clinical histories. Here we describe cSCCscore, a prediction tool that uses patients' covariates and clinical histories to assign them personal probabilities of developing cSCCs within 3 years after risk assessment. cSCCscore uses a statistical model for the occurrence and timing of a patient's cSCCs, whose parameters we estimated using cohort data from 66,995 patients in the Kaiser Permanente Northern California healthcare system. We found that patients' covariates and histories explained approximately 75% of their interpersonal cSCC risk variation. Using cross validated performance measures, we also found cSCCscore's predictions to be moderately well calibrated to the patients' observed cSCC incidence. Moreover, cSCCscore discriminated well between patients who subsequently did and did not develop a new primary cSCC within 3 years after risk assignment, with area under the receiver operating characteristic curve of approximately 85%. Thus, cSCCscore can facilitate more informed management of non-Hispanic white patients at cSCC risk. cSCCscore's predictions are available at https://researchapps.github.io/cSCCscore/. PMID- 30472996 TI - Long-Term Increase of Kcnn4 Potassium Channel Surface Expression on B Cells in Pemphigus Patients after Rituximab Treatment. PMID- 30472997 TI - [Imatinib-induced pigmentation of the hard palate]. PMID- 30472998 TI - Alternative Carbon Sources for Isoprene Emission. AB - Isoprene and other plastidial isoprenoids are produced primarily from recently assimilated photosynthates via the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway. However, when environmental conditions limit photosynthesis, a fraction of carbon for MEP pathway can come from extrachloroplastic sources. The flow of extrachloroplastic carbon depends on the species and on leaf developmental and environmental conditions. The exchange of common phosphorylated intermediates between the MEP pathway and other metabolic pathways can occur via plastidic phosphate translocators. C1 and C2 carbon intermediates can contribute to chloroplastic metabolism, including photosynthesis and isoprenoid synthesis. Integration of these metabolic processes provide an example of metabolic flexibility, and results in the synthesis of primary metabolites for plant growth and secondary metabolites for plant defense, allowing effective use of environmental resources under multiple stresses. PMID- 30473000 TI - [French ccAFU guidelines - Update 2018-2020: Retroperitoneal sarcoma]. AB - OBJECTIVE: To update French urological guidelines on retroperitoneal sarcoma. METHODS: Comprehensive Medline search between 2016 and 2018 upon diagnosis, treatment and follow-up of retroperitoneal sarcoma. Level of evidence was evaluated. RESULTS: Chest, abdomen and pelvis CT is mandatory to evaluate any suspected retroperitoneal sarcoma. MRI sometimes helps surgical planning. Before histological confirmation through biopsy, the patient must be registered in the French sarcoma pathology reference network. The biopsy standard should be an extraperitoneal coaxial percutaneous sampling before any retroperitoneal mass therapeutic decision. Surgery is retroperitoneal sarcoma cornerstone. The main objective is grossly negative margins and can be technically challenging. Multimodal treatment risks and benefits must be discussed in multidisciplinary teams. The relapse rate is related to tumor grade and surgical margins. CONCLUSION: Retroperitoneal sarcoma prognosis is poor and closely related to the quality of initial management. Centralization through dedicated sarcoma pathology network in a high-volume center is mandatory. PMID- 30472999 TI - [French ccAFU guidelines - Update 2018-2020: Testicular germ cell tumors]. AB - OBJECTIVE: To update French guidelines concerning testicular germ cell cancer. METHODS: Comprehensive Medline search between 2016 and 2018 upon diagnosis, treatment and follow-up of testicular germ cell cancer and treatments toxicities. Level of evidence was evaluated. RESULTS: Testicular Germ cell tumor diagnosis is based on physical examination, biology tests (serum tumor markers AFP, hCGt, LDH) and radiological assessment (scrotal ultrasound and chest, abdomen and pelvis computerized tomography). Total inguinal orchiectomy is the first- line treatment allowing characterization of the histological type, local staging and identification of risk factors for micrometastases. In case of several therapeutic options, one must inform his patient balancing risks and benefits. Surveillance is usually chosen in stage I seminoma compliant patients as the evolution rate is low between 15 to 20%. Carboplatin AUC7 is an alternative option. Radiotherapy indication should be avoided. In stage I non-seminomatous patients, either surveillance or risk-adapted strategy can be applied. Staging retroperitoneal lymphadenectomy has restricted indications. Metastatic germ cell tumors are usually treated by PEB chemotherapy according to IGCCCG prognostic classification. Lombo-aortic radiotherapy is still a standard treatment for stage IIA. Residual masses should be evaluated by biological and radiological assessment 3 to 4 weeks after the end of chemotherapy. Retroperitoneal lymphadenectomy is advocated for every non-seminomatous residual mass more than one cm. 18FDG uptake should be evaluated for each seminoma residual mass more than 3cm. CONCLUSIONS: A rigorous use of classifications is mandatory to define staging since initial diagnosis. Applying treatments based on these classifications leads to excellent survival rates (99% in CSI, 85% in CSII+). PMID- 30473002 TI - [French ccAFU guidelines - Update 2018-2020: Management of kidney cancer]. AB - OBJECTIVE: To update the French guidelines on kidney cancer. METHODS: A systematic review of the literature between 2015 and 2018 was performed. The most relevant articles regarding the diagnosis, the classification, surgical treatment, medical treatment and follow-up of kidney cancer were retrieved and included in the new guidelines. The guidelines were updated with corresponding levels of evidence. RESULTS: Thoraco-abdominal CT scan with injection is the best radiological exam for the diagnosis of kidney cancer. MRI and contrast ultrasound can be useful in some cases. Percutaneous biopsy is recommended when histological results will affect clinical decision. Renal tumours must be classified according to pTNM 2017 classification and ISUP grade. Metastatic kidney cancers must be classified according to IMDC criteria. Partial nephrectomy is the recommended treatment for T1a tumours and can be done through an open, laparoscopic or robotic access. T1b tumours can be treated by partial or total nephrectomy according to tumour complexity. Radical nephrectomy is the recommended treatment of advanced localized tumours. In metastatic patients: cytoreductive nephrectomy is recommended in case of good prognosis; medical treatment must be offered first in case of intermediate or bad prognosis. Surgical or local treatment of metastases should be considered in case of solitary lesion or oligo-metastases. First-line recommended drugs in metastatic patients include sunitinib, pazopanib, and the association nivolumab/ipilimumab. Cabozantinib can be offered in option in intermediate and bad prognostic patients. Cystic tumours must be classified according to Bosniak Classification. Surgical excision should be offered to patients with Bosniak III and IV lesions. It is recommended to follow patients clinically and with imaging according to tumour aggressiveness. CONCLUSION: These updated recommendations should assist French speaking urologists for their management of kidney cancers. PMID- 30473001 TI - [French ccAFU guidelines - Update 2018-2020: Adrenal cancer]. AB - OBJECTIVE: To update French oncology guidelines concerning adrenal cancer. METHODS: Comprehensive Medline search between 2016 and 2018 upon diagnosis, treatment and follow-up of adrenal cancer to update 2013 guidelines. Level of evidence was evaluated according to AGREE-II. RESULTS: Adrenal cancers are mainly represented by adrenocortical carcinomas (AC), malignant pheochromocytomas (MPC) and adrenal metastases (AM). Medical background of these tumors is either the exploration of hormonal or tumor symptoms, or an adrenal incidentaloma. Etiological explorations are based on hormonal biochemical assessment, morphological and functional imaging and histological analysis. AC and MPC are mostly sporadic but hereditary origin is still possible. The suspicion of AC is driven mainly by radiological signs of malignancy, signs of local invasion or distant metastasis, and type of hormonal secretion but the accurate diagnosis is histological. The diagnosis of MPC is clinical, biological and radiological. The diagnosis of MS involves a percutaneous biopsy. Medical files should be discussed within the COMETE - Adrenal Cancer Network (Appendix 1). Oncological adjuvant treatments are specific for the histological type. In the AC, their indication depends on the risk of recurrence and is based on mitotane, external radiotherapy or chemotherapy. In the MPC, it is based on internal radiotherapy and chemotherapy. Metastatic forms treatment is exceptionally surgical. Debulking is uncommon. For metastatic unresectable AC, treatment is based on mitotane monotherapy or triple chemotherapy. For metastatic unresectable MPC, treatment is based on exclusive metabolic radiotherapy or triple chemotherapy. Recurrences are frequent and sometimes delayed, which justifies a close and long follow-up. CONCLUSION: The curative treatment of Adrenal cancers is surgical provided. This treatment is rarely sufficient alone, the prognosis is then pejorative. PMID- 30473003 TI - Detection of mitochondrial transfer RNA (mt-tRNA) gene mutations in patients with idiopathic pulmonary fibrosis and sarcoidosis. AB - Mitochondrial reactive oxygen species production may lead to tissue injury associated with two respiratory disorders of unknown origin which are shared by common tissue fibrosis, IPF and sarcoidosis. Sequence analysis of 22 mt-tRNA genes and parts of their flanking genes revealed 32 and 45 mutations in 38/40 IPF and 69/85 sarcoidosis patients respectively. 4 novel mutations were identified. 15/32 and 25/45 mutations were exclusively expressed while 12/32 and 17/45 mutations predominantly occurred in IPF and sarcoidosis group respectively, compared to healthy controls. Novel mutation combinations were solely expressed in disease. Hence, a mitochondrial-mediated pathogenic pathway seems to underlie both entities. PMID- 30473005 TI - Sphingolipids in adipose tissue: What's tipping the scale? AB - Adipose tissue lies at the heart of obesity, mediating its many effects upon the rest of the body, with its unique capacity to expand and regenerate, throughout the lifespan of the organism. Adipose is appreciated as an endocrine organ, with its myriad adipokines that elicit both physiological and pathological outcomes. Sphingolipids, bioactive signaling molecules, affect many aspects of obesity and the metabolic syndrome. While sphingolipids are appreciated in the context of these diseases in other tissues, there are many discoveries yet to be uncovered in the adipose tissue. This review focuses on the effects of sphingolipids on various aspects of adipose function and dysfunction. The processes of adipogenesis, metabolism and thermogenesis, in addition to inflammation and insulin resistance are intimately linked to sphingolipids as discussed below. PMID- 30473004 TI - Cell Cycle Heterogeneity Can Generate Robust Cell Type Proportioning. AB - Cell-cell heterogeneity can facilitate lineage choice during embryonic development because it primes cells to respond to differentiation cues. However, remarkably little is known about the origin of heterogeneity or whether intrinsic and extrinsic variation can be controlled to generate reproducible cell type proportioning seen in vivo. Here, we use experimentation and modeling in D. discoideum to demonstrate that population-level cell cycle heterogeneity can be optimized to generate robust cell fate proportioning. First, cell cycle position is quantitatively linked to responsiveness to differentiation-inducing signals. Second, intrinsic variation in cell cycle length ensures cells are randomly distributed throughout the cell cycle at the onset of multicellular development. Finally, extrinsic perturbation of optimal cell cycle heterogeneity is buffered by compensatory changes in global signal responsiveness. These studies thus illustrate key regulatory principles underlying cell-cell heterogeneity optimization and the generation of robust and reproducible fate choice in development. PMID- 30473006 TI - Local and systemic production of proinflammatory chemokines in the pathogenesis of HAM/TSP. AB - BACKGROUND: HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) is related with high proviral load, high proinflammatory cytokine levels, and passage of infected cell from the blood to the central nervous system. We aimed to evaluate the participation of chemokines and adhesion molecules in HAM/TSP pathogenesis. METHODS: CXCL9, CXCL10, sICAM-1, and sVCAM-1 were determined by ELISA in serum and cerebrospinal fluid (CSF) of HTLV-1 infected individuals. The frequency and median fluorescence intensity (MFI) of lymphocytes and monocytes expressing ligands of adhesion molecules (CD11a and CD49d) and a chemokine receptor (CXCR3) were analyzed by flow cytometry. RESULTS: The levels of CXCL9 and CXCL10 in serum of definite HAM/TSP were higher than in serum of probable HAM/TSP and HTLV-1 carriers. Considering the production of chemokines by patients with definite HAM/TSP, CXCL9 levels were higher in serum than in CSF, and CXCL10 production was higher in CSF than in serum. Levels of adhesion molecules in serum and CSF of HTLV-1 infected individuals did not differ. The MFI of CD11a on CD4+, CD8+ and CD14+ cells was lower in definite HAM/TSP than in HTLV-1 carriers and did not differ from probable HAM/TSP and healthy subjects (HS). The frequency of lymphocytes expressing CXCR3 was lower in definite HAM/TSP than in cells of probable HAM/TSP and did not differ from carrier and HS. CONCLUSION: These data point to the participation of proinflammatory chemokines, especially CXCL10, in the pathogenesis of definite HAM/TSP. PMID- 30473007 TI - Pharmacological interactions of phosphate binders. PMID- 30473008 TI - Cyclodextrin-induced acidity modification of substituted cathinones studied by capillary electrophoresis supported by density functional theory calculations. AB - This paper shows that the acidity of substituted cathinones can change in a diversified and poorly predictable manner upon supramolecular interaction with cyclodextrins used as buffer additives in capillary electrophoresis. The direction and range of pKa shifts may be noticeably different for the particular cyclodextrins and cathinones, suggesting a strict correlation with structure. The most interesting results were observed for 2-hydroxyethyl-beta-cyclodextrin, which is capable for inducing the large negative and enantioselective apparent pKa shifts for alpha-pyrrolidinovalerophenone and methylenedioxypyrovalerone, even much above -1.0 pH unit. A thermodynamic analysis was performed, to identify the role of enthalpy and entropy in the formation and deprotonation of the respective diastereomeric complexes. The former process turned out to be driven by an energetically favorable increase in entropy, related probably to a hydrophobic effect. Deprotonation enthalpy in the complexed state, in turn, occurred to be more favorable than in the free molecule state, entailing the large drop in pKa after complexation. The DFT calculations allowed us to identify some structural effects that most likely contribute to these phenomena. At last, we have demonstrated that at low cyclodextrin concentration and pH ensuring partial ionization, pKa shifts contribute to chiral separation of the abovementioned cathinones. This analytically important effect may be helpful in anticipating the most efficient chiral separation mechanism of other systems. PMID- 30473009 TI - Protein adsorption to poly(ethylenimine)-modified sepharose FF: VII. Complicated effects of pH. AB - Previously, we have studied protein adsorption behaviors on a series of poly(ethylenimine) (PEI)-grafted Sepharose FF, and a critical ionic capacity of PEI-grafted resins was observed, above which both protein adsorption capacity (q) and effective pore diffusivity (De) increased drastically. Moreover, reducing the charge density of the PEI-grafted resins from an ionic capacity of 740 mmol/L (FF PEI-L740) to 440 mmol/L (FF-PEI-R440) by neutralization of the amino groups of PEI chains with sodium acetate brought out a three-fold increase of De value at pH 8. In this work, FF-PEI-L740 and FF-PEI-R440 were selected to investigate the complicated effects of pH on protein adsorption behavior using bovine serum albumin (BSA) as the model protein. It was found that, for FF-PEI-L740, both the q and De values decreased significantly when pH decreased from 9 to 5.5, and then increased dramatically at pH 5, and finally decreased remarkably at pH 4.5. The results were considered due to the following causes: The decrease of pH from 9 to 5.5 led to a greatly increased electrostatic repulsion between the PEI chains due to the increased dissociation degree of PEI, which caused the increase in steric hindrance effects and decrease in the bound protein transport by chain delivery. At pH 5, which was near the pI of BSA (~4.9), the presence of few protein charges greatly decreased the electrostatic hindrance effect on protein transport and the high charge density of FF-PEI-L740 provided extensively accessible binding sites and facilitated the happening of chain delivery as well. At pH 4.5, the net charge of BSA shifted to positive, likely charged with PEI, so the overall electrostatic repulsion greatly hindered protein uptake. For FF-PEI-R440, whose charge density was much lower than FF-PEI-L740, its q and De values even increased mildly when pH decreased from 8 to 5.5, because its slightly-increased charge density did not cause much increased electrostatic and steric hindrance effects but provided more binding sites for protein adsorption. At pH 5, the few charges of BSA and the low charge density of FF-PEI-R440 could not afford enough electrostatic interaction for protein binding, resulting in significantly decreased q and De values. Besides, column breakthrough experiments revealed that FF-PEI-R440 kept high dynamic binding capacity (DBC) (>120 mg/mL) at pH 5.5-8, while FF-PEI-L740 offered high DBC (>80 mg/mL) at pH 5, 7 and 8 with a higher salt concentration (100 mmol/L NaCl). These findings demonstrated the excellence of FF-PEI-L740 and FF-PEI-R440 in different conditions, and would help in the design and selection of suitable resins for high-performance protein chromatography. PMID- 30473010 TI - Biotransformation-based metabolomics profiling method for determining and quantitating cancer-related metabolites. AB - The discovery and identification of reliable disease biomarkers and relevant disrupted metabolic pathways is still a major challenge in metabolomics. Here, we proposed a biotransformation-based metabolomics profiling method to identify reliable disease biomarkers by simultaneous quantitation and qualification of cancer-related metabolites and their metabolic pathways via liquid chromatography tandem mass spectrometry (LC-MS/MS). The approach was based on selecting a subset of known cancer-related metabolites from our previous metabolomics work, cancer research literature and biological significance. The metabolic profiling of pathway-related metabolites was developed by predicted multiple reaction monitoring (MRM) of ion pairs based on their chemical structures and biotransformation. Then, a high-throughput quantitative method was established. Overall, this approach enables the sensitive and accurate detection of cancer related metabolites and the identification of other relevant metabolites, which facilitates better data quality and in-depth investigation of dysregulated metabolic pathways. As a proof of concept, the approach was applied to a small cell lung cancer (SCLC) study. The results showed that 43 metabolites were significantly changed, and arginine metabolism was apparently disturbed, which proved the proposed approach could be a powerful tool for discovering reliable disease biomarkers and aberrant metabolic pathways. PMID- 30473011 TI - Aquatic Parasite Cultures and Their Applications. AB - In this era of unprecedented growth in aquaculture and trade, aquatic parasite cultures are essential to better understand emerging diseases and their implications for human and animal health. Yet culturing parasites presents multiple challenges, arising from their complex, often multihost life cycles, multiple developmental stages, variable generation times and reproductive modes. Furthermore, the essential environmental requirements of most parasites remain enigmatic. Despite these inherent difficulties, in vivo and in vitro cultures are being developed for a small but growing number of aquatic pathogens. Expanding this resource will facilitate diagnostic capabilities and treatment trials, thus supporting the growth of sustainable aquatic commodities and communities. PMID- 30473012 TI - Characterization and functional analysis of serpin-28 gene from silkworm, Bombyx mori. AB - Serine protease inhibitors (Serpins) are a broadly distributed superfamily of proteins with a SERPIN domain and participate in several immune responses. In this study, a serpin-28 gene was identified in B. mori and its role in immune regulation was investigated. This gene has an open reading frame of 1065 bp that encodes a 354-amino acid residue polypeptide containing one SERPIN domain with a predicted molecular weight of 40.3 kDa. Recombinant Bmserpin-28 protein was expressed in Escherichia coli and used to raise rabbit anti-Bmserpin-28 polyclonal antibodies. Quantitative real-time PCR analysis revealed that Bmserpin 28 was expressed in all examined tissues, with maximum expression in the fat body and silk gland. Expression pattern of different developmental stages showed that the highest expression level was in the pupae, while the lowest expression level was recorded at the egg stage. After challenge with four different microorganisms (Escherichia coli, Beauveria bassiana, Micrococcus luteus and B. mori nuclear polyhedrosis virus), the expression pattern of Bmserpin-28 was investigated in fat body and haemocyte samples. A substantial upregulation of Bmserpin-28 expression level was recorded following pathogen challenge in both the tested tissues. Furthermore, RNA interference of Bmserpin-28 resulted in significant upregulation of antimicrobial peptide genes. In summary, our results indicated that Bmserpin-28 may be involved in the innate immunity of B. mori. PMID- 30473013 TI - Brain-wide Organization of Neuronal Activity and Convergent Sensorimotor Transformations in Larval Zebrafish. AB - Simultaneous recordings of large populations of neurons in behaving animals allow detailed observation of high-dimensional, complex brain activity. However, experimental approaches often focus on singular behavioral paradigms or brain areas. Here, we recorded whole-brain neuronal activity of larval zebrafish presented with a battery of visual stimuli while recording fictive motor output. We identified neurons tuned to each stimulus type and motor output and discovered groups of neurons in the anterior hindbrain that respond to different stimuli eliciting similar behavioral responses. These convergent sensorimotor representations were only weakly correlated to instantaneous motor activity, suggesting that they critically inform, but do not directly generate, behavioral choices. To catalog brain-wide activity beyond explicit sensorimotor processing, we developed an unsupervised clustering technique that organizes neurons into functional groups. These analyses enabled a broad overview of the functional organization of the brain and revealed numerous brain nuclei whose neurons exhibit concerted activity patterns. PMID- 30473015 TI - Effect of Substrate Stiffness on Mechanical Coupling and Force Propagation at the Infarct Boundary. AB - Heterogeneous intercellular coupling plays a significant role in mechanical and electrical signal transmission in the heart. Although many studies have investigated the electrical signal conduction between myocytes and nonmyocytes within the heart muscle tissue, there are not many that have looked into the mechanical counterpart. This study aims to investigate the effect of substrate stiffness and the presence of cardiac myofibroblasts (CMFs) on mechanical force propagation across cardiomyocytes (CMs) and CMFs in healthy and heart-attack mimicking matrix stiffness conditions. The contractile forces generated by the CMs and their propagation across the CMFs were measured using a bio-nanoindenter integrated with fluorescence microscopy for fast calcium imaging. Our results showed that softer substrates facilitated stronger and further signal transmission. Interestingly, the presence of the CMFs attenuated the signal propagation in a stiffness-dependent manner. Stiffer substrates with CMFs present attenuated the signal ~24-32% more compared to soft substrates with CMFs, indicating a synergistic detrimental effect of increased matrix stiffness and increased CMF numbers after myocardial infarction on myocardial function. Furthermore, the beating pattern of the CMF movement at the CM-CMF boundary also depended on the substrate stiffness, thereby influencing the waveform of the propagation of CM-generated contractile forces. We performed computer simulations to further understand the occurrence of different force transmission patterns and showed that cell-matrix focal adhesions assembled at the CM-CMF interfaces, which differs depending on the substrates stiffness, play important roles in determining the efficiency and mechanism of signal transmission. In conclusion, in addition to substrate stiffness, the degree and type of cell-cell and cell matrix interactions, affected by the substrate stiffness, influence mechanical signal conduction between myocytes and nonmyocytes in the heart muscle tissue. PMID- 30473014 TI - Spatial and Temporal Organization of the Individual Human Cerebellum. AB - The cerebellum contains the majority of neurons in the human brain and is unique for its uniform cytoarchitecture, absence of aerobic glycolysis, and role in adaptive plasticity. Despite anatomical and physiological differences between the cerebellum and cerebral cortex, group-average functional connectivity studies have identified networks related to specific functions in both structures. Recently, precision functional mapping of individuals revealed that functional networks in the cerebral cortex exhibit measurable individual specificity. Using the highly sampled Midnight Scan Club (MSC) dataset, we found the cerebellum contains reliable, individual-specific network organization that is significantly more variable than the cerebral cortex. The frontoparietal network, thought to support adaptive control, was the only network overrepresented in the cerebellum compared to the cerebral cortex (2.3-fold). Temporally, all cerebellar resting state signals lagged behind the cerebral cortex (125-380 ms), supporting the hypothesis that the cerebellum engages in a domain-general function in the adaptive control of all cortical processes. PMID- 30473017 TI - Deciphering the Dynamics of Interlocked Feedback Loops in a Model of the Mammalian Circadian Clock. AB - Mathematical models of fundamental biological processes play an important role in consolidating theory and experiments, especially if they are systematically developed, thoroughly characterized, and well tested by experimental data. In this work, we report a detailed bifurcation analysis of a mathematical model of the mammalian circadian clock network developed by Relogio et al., noteworthy for its consistency with available data. Using one- and two-parameter bifurcation diagrams, we explore how oscillations in the model depend on the expression levels of its constituent genes and the activities of their encoded proteins. These bifurcation diagrams allow us to decipher the dynamics of interlocked feedback loops by parametric variation of genes and proteins in the model. Among other results, we find that REV-ERB, a member of a subfamily of orphan nuclear receptors, plays a critical role in the intertwined dynamics of Relogio's model. The bifurcation diagrams reported here can be used for predicting how the core clock network responds-in terms of period, amplitude and phases of oscillations to different perturbations. PMID- 30473016 TI - Piconewton Mechanical Forces Promote Neurite Growth. AB - Investigations over half a century have indicated that mechanical forces induce neurite growth, with neurites elongating at a rate of 0.1-0.3 MUm h-1 pN-1 when mechanical force exceeds a threshold, with this being identified as 400-1000 pN for neurites of PC12 cells. In this article, we demonstrate that neurite elongation of PC12 cells proceeds at the same previously identified rate on application of mechanical tension of ~1 pN, which is significantly lower than the force generated in vivo by axons and growth cones. This observation raises the possibility that mechanical tension may act as an endogenous signal used by neurons for promoting neurite elongation. PMID- 30473018 TI - The Effects of Neck-Specific Training Versus Prescribed Physical Activity on Pain and Disability in Patients With Cervical Radiculopathy: A Randomized Controlled Trial. AB - OBJECTIVE: To compare the effects of a neck-specific training program to prescribed physical activity with both groups receiving a cognitive behavioral approach, on pain and disability in patients with cervical radiculopathy (CR). DESIGN: Parallel-group randomized clinical trial with follow-up at 3, 6, 12, and 24 months. SETTING: Recruitment and assessments of participants were performed at a university hospital. Interventions were performed in primary care setting at outpatient physiotherapy clinics. PARTICIPANTS: Patients (N=144) with CR were recruited to participate in this clinical trial. INTERVENTIONS: Patients were randomly assigned to 3 months of either of a neck-specific training program or prescribed physical activity. MAIN OUTCOME MEASURES: Primary outcomes included self-rated neck and arm pain as collected by the visual analog scale (VAS). Secondary outcomes were self-rated headache measured with the VAS, the Neck Disability Index, the EuroQol 5D, the Fear Avoidance Beliefs Questionnaire, and the Hospital Anxiety and Depression Scale. Assessments were performed at baseline and at 3-, 6-, 12-, and 24-month follow-up periods. RESULTS: Intention-to-treat and per-protocol analyses showed no significant interaction (group * time) or group effects. There were, however, significant time effects indicating improvement over time for both groups for all outcomes except for levels of depression. CONCLUSIONS: The study revealed that neck-specific training as well as prescribed physical activity both including additional cognitive behavioral approach decreased the pain in patients with CR, that is, participants improved regardless of the intervention received. There is a lack of consensus of how to best manage individuals with CR. However, our findings suggest that CR has a natural favorable long-term outcome when patients are prescribed neck-specific training and exercise in combination with a behavioral approach. PMID- 30473021 TI - Treating Military Service Members and Veterans in the Private Sector: Information and Resources for Clinicians. PMID- 30473020 TI - Implementing the German Model of Work-Related Medical Rehabilitation: Did the Delivered Dose of Work-Related Treatment Components Increase? AB - OBJECTIVES: Work-related components are an essential part of rehabilitation programs to support return to work of patients with musculoskeletal disorders. In Germany, a guideline for work-related medical rehabilitation was developed to increase work-related treatment components. In addition, new departments were approved to implement work-related medical rehabilitation programs. The aim of our study was to explore the state of implementation of the guideline's recommendations by describing the change in the delivered dose of work-related treatments. DESIGN: Nonrandomized controlled trial (cohort study). SETTING: Fifty nine German rehabilitation centers. PARTICIPANTS: Patients (N=9046) with musculoskeletal disorders were treated in work-related medical rehabilitation or common medical rehabilitation. Patients were matched one-to-one by propensity scores. INTERVENTIONS: Work-related medical rehabilitation in 2014 and medical rehabilitation in 2011. MAIN OUTCOME MEASURES: Treatment dose of work-related therapies. RESULTS: The mean dose of work-related therapies increased from 2.2 hours (95% confidence interval [CI], 1.6-2.8) to 8.9 hours (95% CI, 7.7-10.1). The mean dose of social counseling increased from 51 to 84 minutes, the mean dose of psychosocial work-related groups from 39 to 216 minutes, and the mean dose of functional capacity training from 39 to 234 minutes. The intraclass correlation of 0.67 (95% CI, 0.58-0.75) for the total dose of work-related therapies indicated that the variance explained by centers was high. CONCLUSIONS: The delivered dose of work-related components was increased. However, there were discrepancies between the guideline's recommendations and the actual dose delivered in at least half of the centers. It is very likely that this will affect the effectiveness of work-related medical rehabilitation in practice. PMID- 30473019 TI - Does Home-Based Progressive Resistance or High-Intensity Circuit Training Improve Strength, Function, Activity or Participation in Children With Cerebral Palsy? AB - OBJECTIVE: Does home-based progressive resistance or high-intensity circuit training improve strength, function, activity, or participation in children with cerebral palsy (CP)? DESIGN: This was the first study on high-intensity circuit training for children with CP. This study was conducted as a randomized prospective controlled pilot study. SETTING: Evaluation took place at the gait laboratory of the university hospital, training sessions were performed at home. PARTICIPANTS: Children (N=22) with CP (average age: 12y, 10mo, 19 Gross Motor Function Classification System level I, 3 level II) were randomly assigned either to progressive resistance training (PRT) or high-intensity circuit training (HICT). INTERVENTIONS: The PRT group trained with progressive overload, while the HICT group performed as many repetitions as possible within 30-second intervals (8wk, 3 times weekly in both groups). MAIN OUTCOME MEASURES: Outcome measures stretched over all domains of the International Classification of Functioning, Disability and Health and included muscle strength, muscle power sprint test (MPST), timed stairs test (TST), 6-minute walking test, Gait Profile Score (GPS), timed Up and Go test (TUGT) and participation questionnaires. RESULTS: Only the HICT group was able to improve strength. Furthermore, the HICT group scored better in the MPST, while PRT participants improved in the TST and TUGT. The HICT group was able to show improvement in the subscores of the parent-reported participation questionnaire. Other measures of mobility or participation did not change. CONCLUSIONS: Both programs improved function specific to intervention. However, only the HICT group showed significant strength and participation improvements. Compliance was decent in both groups, but the average training unit was shorter in the HICT group. Both exercise programs showed functional benefits, but HICT might be the preferable option for strengthening in highly functional children with CP. PMID- 30473022 TI - Ego-centered relative neighborhood deprivation and reported dietary habits among youth. AB - Dietary habits are important precursors of childhood obesity. Youths' dietary habits may be constrained by the experience of deprivation due to social (e.g., family purchasing power) and physical (e.g., availability of fast food outlets in low-income neighborhoods) factors limiting dietary choices. This study considers whether a Yitzhaki-based index of ego-centered relative neighborhood deprivation explains dietary outcomes (i.e., reported healthful and unhealthful food consumption), adjusting for absolute deprivation. The Yitzhaki index takes into account the total incomes to which a youth is deprived in relation to a meaningful reference group, and the youth's position in the cumulative income distribution of this meaningful reference group. The study also considers whether the impact of deprivation on dietary outcomes is moderated by the experience of symptoms of depression. There was some indication that reported healthful food consumption was highest for youth who experienced low absolute deprivation (p <= 0.01) and low symptoms of depression (p <= 0.01), but high relative deprivation (p <= 0.001). These youth therefore appear to benefit from being both "better off", and living among "better-off" individuals. The results for reported unhealthful food consumption were less robust. The results may therefore suggest that youth who are not detrimentally impacted by their relative deprivation, and who have the financial means to access healthful foods, have improved dietary outcomes. The findings suggest that while absolute deprivation plays a key role in explaining healthful food consumption, additional insights can be gleaned from considering youths' relative deprivation and indicators of their well-being. PMID- 30473023 TI - Targeting glycometabolic reprogramming to restore the sensitivity of leukemia drug-resistant K562/ADM cells to adriamycin. AB - AIMS: Mounting studies have confirmed that cancer cells reprogram their metabolism during early carcinogenesis to develop many other hallmarks, and demonstrated a relationship between aerobic glycolysis and the occurrence of drug resistance. However, the molecular mechanisms and role in tumor drug resistance of aerobic glycolysis remain unclear. MAIN METHODS: We analyzed differentially expressed genes (DEGs) at the RNA level between the multi-drug resistance (MDR) leukemia cell line K562/adriamycin (ADM) and its parental, drug-sensitive K562 cell line. Clustering and enrichment analysis of DEGs was performed. Oxamate, a lactic dehydrogenase inhibitor were used to assess the effect of glycolysis inhibition on ADM susceptibility and the expression of the enriched DEGs in K562/ADM cells. KEY FINDINGS: A total of 1742 DEGs were detected between the K562/ADM and K562 cell lines. The differential expression of unigenes encoding enzymes involved in glycometabolism signifies that there was a greater aerobic glycolysis flux in K562/ADM cells. The PI3K-AKT signaling pathway, which is related to glucose metabolism, showed representative differential enrichment and up-regulation in K562/ADM cells. Oxamate improved and re-sensitized the therapeutic effect of ADM in ADM-resistant cells by inhibiting aerobic glycolysis either directly or indirectly by down-regulation of the AKT-mTOR pathway. SIGNIFICANCE: Our findings suggest that ADM resistance mediated by the increase of aerobic glycolysis, which related to the over-activation of the AKT-mTOR-c-Myc pathway in MDR leukemia cells. Inhibition of aerobic glycolysis and down regulation of signaling pathways involved in aerobic glycolysis represent a potential chemotherapeutic strategy for sensitizing leukemic cells and thereby overcoming MDR. PMID- 30473024 TI - ApoA-1 accelerates regeneration of small-for-size fatty liver graft after transplantation. AB - OBJECTIVES: Apolipoprotein A-1 (ApoA-1) is involved in regulating both lipid and energy metabolism, which may play important roles in liver regeneration, especially for the liver with steatosis. We here intended to investigate the role of ApoA-1 in regeneration of small-for-size fatty liver graft and to explore the underlying mechanism. METHODS: The association of ApoA-1 expression with liver regeneration was studied in rat liver transplantation models using small-for-size normal graft or small-for-size fatty graft. The direct role of ApoA-1 in liver regeneration was studied in mouse hepatectomy model in vivo and hepatocytes in vitro. RESULTS: Compared to small-for-size normal graft, decreased expression of ApoA-1 associated with delayed regeneration were detected in small-for-size fatty liver graft after transplantation. In functional study, the expression of ApoA-1 was decreased in hepatocytes with steatosis and was inversely associated with the concentration of oleic acid. The ApoA-1 administration effectively attenuated hepatocytes steatosis and accelerated hepatocytes proliferation. In mouse model, ApoA-1 treatment promoted liver regeneration at day 2 after major hepatectomy. In addition, the treatment of ApoA-1 increased the expressions of PGC-1alpha and its target genes Tfam, Ucp2 and SDHB. CONCLUSIONS: ApoA-1 may accelerate regeneration of small-for-size fatty liver graft at day 2 after transplantation through regulating mitochondrial function. ApoA-1 may be the potential new therapy of promoting liver regeneration. PMID- 30473025 TI - Continuous zebularine treatment enhances hepatic differentiation of mesenchymal stem cells under liver-specific factors induction in vitro. AB - AIMS: To investigate the effect of zebularine, a stable inhibitor of DNA methylation, on hepatic differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs) under liver-specific factors induction in vitro. MAIN METHODS: BM MSCs were isolated from the mononuclear cell fraction of rabbit bone marrow samples. The identification of these cells was carried out by immunophenotype analysis. The three hepatic differentiation protocols of BM-MSCs were as follows: liver-specific factors (hepatocyte growth factor and epidermal growth factor) without zebularine, liver-specific factors combined with a 24 h zebularine pre treatment, and liver-specific factors combined with continuous zebularine treatment. BM-MSCs cultured in basic medium without the differentiation stimuli were set as the control. Morphological features, liver-specific gene and protein expression, and functional analyses were assessed to evaluate hepatic differentiation of BM-MSCs. Global DNA methylation status was tested for investigating the underlying mechanism. KEY FINDINGS: Flow cytometry immunophenotyping proved the isolated cells with plastic adherence and a spindle shape were CD29, CD90 positive and CD34, CD45 negative. Albumin (ALB) and alpha fetoprotein (AFP) messenger RNA and protein expression, glycogen storage and urea production were significantly higher in the continuous zebularine-treated group than the other groups while the differences between the zebularine-untreated group and 24 h zebularine pre-treated group were not significant. Meanwhile, significant decrease of global DNA methylation was observed in the continuous zebularine-treated group. SIGNIFICANCE: We conclude that continuous zebularine treatment can improve hepatic differentiation of BM-MSCs under liver-specific factors induction in vitro, and the decrease of global DNA methylation maybe involved in this process. PMID- 30473026 TI - p53 as a double-edged sword in the progression of non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) derives from the accumulation of hepatic lipids, which leads to liver steatosis and then triggers non-alcoholic steatohepatitis, sometimes worsening to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Although the molecular mechanisms of NAFLD have been intensively investigated, its pathogenesis remains poorly understood and needs to be clarified. Tumor-suppressor factor p53 has a crucial role in many signaling pathways that induce apoptosis and has become an emerging focus for liver disease research. Recent studies have revealed that p53 is linked to the development of NAFLD and that the regulation of p53 has therapeutic potential. However, the association between p53 and NAFLD remains controversial. Several reports have suggested that activated p53 plays an essential role in the pathogenesis of NAFLD, whereas others have indicated that suppression of p53 activation aggravates liver steatosis. Here, we review the relevant evidence suggesting that these two contrasting processes indicate a dual role of p53 in NAFLD progression and propose that the extent of NAFLD may be key to explaining the contradictory findings. In this review, the crosstalk among p53, lipid metabolism, insulin resistance, inflammation and oxidative stress in NAFLD is discussed, and we suggest that a better understanding of p53 would present a promising potential new strategy for NAFLD prevention and treatment. PMID- 30473027 TI - The NAG Scale: Noble Predictive Scale for Hematoma Expansion in Intracerebral Hemorrhage. PMID- 30473028 TI - Corrigendum to "Predicting Motor and Cognitive Improvement Through Machine Learning Algorithm in Human Subject That Underwent a Rehabilitation Treatment in the Early Stage of Stroke" [J Stroke Cerebrovasc Dis 27/11 (2018) 2962-2972]. PMID- 30473029 TI - Survival trends after inferior vena cava and aortic injuries in the United States. AB - OBJECTIVE: Recent studies have demonstrated an increase in trauma mortality relative to mortality from cancer and heart diseases in the United States. Major vascular injuries such as to the inferior vena cava (IVC) and aortic injuries remain responsible for a significant proportion of early trauma deaths in modern trauma care. The purpose of this study was to explore patterns in epidemiology and mortality after IVC and aortic injuries in the United States. METHODS: A 13 year analysis of the National Trauma Databank (2002-2014) was performed to extract all patients who sustained IVC, abdominal aortic, or thoracic aortic injuries. Demographics, clinical data, and outcomes were extracted. Patients were analyzed according to injury mechanism. RESULTS: A total of 25,428 patients were included in this analysis. Overall, the mean age was 39.8 +/- 19.1 years, 70.3% were male, and 14.1% sustained a penetrating trauma. Although the incidence of all three injuries remained constant throughout the study period, for blunt trauma, mortality decreased over the study period (from 48.8% in 2002 to 28.7% in 2014; P < .001), in particular for thoracic aortic injuries (from 46.1% in 2002 to 23.7% in 2014; P < .001) and abdominal aortic injuries (from 58.3% in 2002 to 26.2% in 2014; P < .001). This decrease in mortality after blunt trauma was accompanied by an increase in endovascular procedures over the study period (from 1.0% in 2002 to 30.4% in 2014; P < .001), in particular for blunt thoracic aortic injuries (from 0.7% in 2002 to 41.4% in 2014; P < .001). When penetrating trauma patients were analyzed, overall there was an increase in mortality (from 43.8% in 2002 to 50.6% in 2014; P < .001), in particular after abdominal aortic injury (from 30.4% in 2002 to 66.0% in 2014; P < .001). Similar trends were observed for IVC injuries. No increase in endovascular use in penetrating trauma was identified (from 0.1% in 2002 to 3.4% in 2014; P < .001). CONCLUSIONS: The present study demonstrates an overall decrease in mortality after blunt aortic injuries in the United States. This decrease was accompanied by an increase in the use of endovascular procedures. After penetrating trauma, however, despite contemporary advances in trauma care, mortality has increased over the study period, in particular after abdominal aortic injury. No increase in endovascular use in penetrating trauma was demonstrated. PMID- 30473030 TI - Radiation doses for endovascular aortic repairs performed on mobile and fixed C arm fluoroscopes and procedure phase-specific radiation distribution. AB - OBJECTIVE: The objective of this study was to analyze radiation risk to patients during endovascular aneurysm repair (EVAR) using mobile C-arm (MA) or fixed C-arm (FA) fluoroscopes and to describe the dose distribution during the different phases of the procedure. METHODS: Patients treated with EVAR using a single stent graft system between November 2009 and June 2016 were included in this study. The patients were divided into one of two groups (MA or FA) according to the type of C-arm used in the procedure. Data regarding patients' demographics and the total amount of contrast agent (CA) used, dose-area product, and fluoroscopy time for the procedures were prospectively recorded. Based on the dose report from the FA system, five standard and two optional phases of the procedure were identified to determine the dose distribution. RESULTS: Overall, 160 patients were included (mean age, 73.30 +/- 8.97 years; 146 men); of these, 107 were treated with an MA system and 53 were treated with an FA system. The mean amounts of CA used were 108.55 +/- 42.28 mL in the MA group and 85.37 +/- 38.79 mL in the FA group (P = .0014). The mean total dose-area product values were 49.93 +/- 38.06 Gy.cm2 in the MA group and 168.34 +/- 146.92 Gy.cm2 in the FA group (P < .0001). There was no significant difference in fluoroscopy time between the groups. Per-phase analysis demonstrated that identification of the proximal landing zone and main body deployment required the most radiation, accounting for 24% of the total radiation dose. Overall, 47.6% of the exposure was due to digital subtraction angiography. CONCLUSIONS: Use of an FA system can significantly reduce the amount of CA needed but may also lead to higher radiation doses in EVAR procedures. Dose monitoring remains crucial for the safety of both patients and operators. A detailed analysis of dose distribution is possible with modern systems, which may improve the quality of monitoring in the future. PMID- 30473032 TI - Predicting work outcome in patients with schizophrenia: Influence of IQ decline. AB - BACKGROUND: Patients with schizophrenia show various trajectories in intelligence. However, whether the degree of IQ decline is associated with functional outcomes remains unclear. The purposes of the study were 1) to determine whether IQ decline was related with work outcome, and 2) to perform predictions for attaining a certain amount of work measured by work hours. METHODS: One hundred and forty patients with schizophrenia and 156 healthy volunteers enrolled in the study. The patients were classified into the deteriorated group or preserved group based on the degree of IQ decline. In addition to current and premorbid intelligence, functional outcomes and clinical conditions were also evaluated. Those variables were compared among the patient groups and healthy adults to select independent variables for logistic regression analyses. Four separate logistic regression analyses were conducted with work hours dichotomized by four criteria (0, 10, 20, or 30 h per week) as dependent variables. RESULTS: IQ decline remained significant in all regression models except the model with the 30 h per week criterion. Social function and psychiatric symptoms were also prominent factors in most models. Predictions were more accurate in the models with higher criteria. Individual probabilities to exceed each criterion were presented based on the equations derived from the regression models. CONCLUSION: Intellectual deterioration, in addition to impaired social function and psychiatric symptoms, may play a key role in work disturbances in patients with schizophrenia. Probability models presented here have strengths in evaluating the ability to work from statistical, clinical, and theoretical viewpoints. PMID- 30473035 TI - Preface: Evidence based care in pediatric surgery. PMID- 30473036 TI - Clinical trials. AB - Clinical trials can be used to generate data on safety, efficacy, and/or effectiveness of treatments. They can be classified based on their purpose, phase, or design. Key components of clinical trial design include: identifying the study question and population; clearly defining the treatment and comparison groups; choosing the method of treatment group allocation; defining the primary and secondary outcomes; performing a power analysis; outlining an analytic plan; and reporting results. Critical issues to consider when either designing a trial or interpreting the results of a trial include evaluating the validity and generalizability of the results and assessing the appropriateness of the control group. Designing and implementing clinical trials in pediatric surgery is challenging, but well-constructed and executed trials are instrumental in improving clinical care. PMID- 30473037 TI - Systematic reviews and meta-analytic techniques. AB - Systematic reviews (SRs) are a form of research methodology that addresses a specific research question by collecting, appraising and summarising all empirical evidence that fits pre-specified eligibility criteria. Systematic reviews have grown exponentially since their emergence in the late 1970 s as evidence-based medicine permeated medical culture. With several key advantages and limitations inherent to their design, all health care providers should be familiar with their basic structure, how to critically appraise them, and how to incorporate their findings into clinical practice. This review will contextualise systematic reviews within the broader framework of other review types, and outline the steps in conducting or appraising a systematic review. This includes the framing of an appropriate question, the search strategy, appraisal of included studies, as well as synthesis and analysis of the acquired data. A focus on SRs in the context of pediatric surgical practice will be emphasized. A concise primer on meta-analytic techniques is also provided, with resources highlighted for further reading. PMID- 30473034 TI - Portuguese consensus document for the management of alpha-1-antitrypsin deficiency. AB - Alpha-1-antitrypsin deficiency (AATD) is a genetic autosomal codominant disorder caused by mutations in SERPINA1 gene. It is one of the most prevalent genetic disorders, although it remains underdiagnosed. Whereas at international level there are several areas of consensus on this disorder, in Portugal, inter hospital heterogeneity in clinical practice and resources available have been adding difficulties in reaching a diagnosis and in making therapeutic decisions in this group of patients. This raised a need to draft a document expressing a national consensus for AATD. To this end, a group of experts in this field was created within the Portuguese Pulmonology Society - Study group on AATD, in order to elaborate the current manuscript. The authors reviewed the existing literature and provide here general guidance and extensive recommendations for the diagnosis and management of AATD that can be adopted by Portuguese clinicians from different areas of Medicine. This article is part of a supplement entitled "Portuguese consensus document for the management of alpha-1-antitrypsin deficiency" which is sponsored by Sociedade Portuguesa de Pneumologia. PMID- 30473038 TI - Research using clinical registries in children's surgical care. AB - Clinical registries provide a valuable opportunity to study specific diagnoses or conditions with a broader scope than possible using individual center-based series and with more clinical detail than typically available in administrative data sources. These registries amass structured data with uniform definitions, thus facilitating reliable adoption and consistent use across contributing sites. By compiling granular data from a multitude of geographically diverse sites, clinical registries allow investigation of rare outcomes, comparison of practice and cost variation, and benchmarking across institutions. Registries may track cohorts of patients over time, providing unique longitudinal follow-up that cannot be obtained from many alternate data sources. As clinical registries become more prevalent, research conducted using these registries is increasing and helping to expand knowledge boundaries in children's surgery. The purpose of this review is to provide an overview of several of the most common clinical registries used in children's surgery and explore the strengths and limits of these tools in the conduct of meaningful health services research. PMID- 30473033 TI - Effects of Delayed Cord Clamping on 4-Month Ferritin Levels, Brain Myelin Content, and Neurodevelopment: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate whether placental transfusion influences brain myelination at 4 months of age. STUDY DESIGN: A partially blinded, randomized controlled trial was conducted at a level III maternity hospital in the US. Seventy-three healthy term pregnant women and their singleton fetuses were randomized to either delayed umbilical cord clamping (DCC, >5 minutes) or immediate clamping (ICC, <20 seconds). At 4 months of age, blood was drawn for ferritin levels. Neurodevelopmental testing (Mullen Scales of Early Learning) was administered, and brain myelin content was measured with magnetic resonance imaging. Correlations between myelin content and ferritin levels and group-wise DCC vs ICC brain myelin content were completed. RESULTS: In the DCC and ICC groups, clamping time was 172 +/- 188 seconds vs 28 +/- 76 seconds (P < .002), respectively; the 48-hour hematocrit was 57.6% vs 53.1% (P < .01). At 4 months, infants with DCC had significantly greater ferritin levels (96.4 vs 65.3 ng/dL, P = .03). There was a positive relationship between ferritin and myelin content. Infants randomized to the DCC group had greater myelin content in the internal capsule and other early maturing brain regions associated with motor, visual, and sensory processing/function. No differences were seen between groups in the Mullen testing. CONCLUSION: At 4 months, infants born at term receiving DCC had greater ferritin levels and increased brain myelin in areas important for early life functional development. Endowment of iron-rich red blood cells obtained through DCC may offer a longitudinal advantage for early white matter development. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01620008. PMID- 30473039 TI - Administrative databases. AB - Administrative healthcare databases are created from records of service utilization and payments for payer or hospital billing purposes. Such databases contain large amounts of information on the diagnoses, procedures, resource utilization, and costs or charges of thousands or even millions of patients. However, the patient populations included and data elements available vary widely by database, resulting in different strengths, limitations, and potential uses for each. Therefore, selection of an administrative database should be guided by the research question of interest. This review discusses important considerations when selecting an administrative healthcare database to use to answer a research question and describes key characteristics of the administrative databases most frequently used for pediatric surgical research. PMID- 30473040 TI - Surveys: Merging qualitative and quantitative research methods. AB - Survey methodologies enable researchers to obtain information not routinely captured in electronic medical records, including how delivery of surgical care is perceived through the lens of a child, a parent or caregiver, or a surgeon. Here we describe the approach to using surveys to aid pediatric surgery practice. This article has two aims, (1) to review key concepts in survey creation, administration, and data management, and (2) to describe previously validated survey instruments in pediatric surgery and how to optimize selection of such instruments. The overarching goal of this primer is to give the pediatric surgeon an understanding of the approach to creating a practical survey to address the unique needs of children who require surgery. PMID- 30473041 TI - An overview of commonly used statistical methods in clinical research. AB - Statistics plays an essential role in clinical research by providing a framework for making inferences about a population of interest. In order to interpret research datasets, clinicians involved in clinical research should have an understanding of statistical methodology. This article provides a brief overview of statistical methods that are frequently used in clinical research studies. Descriptive and inferential methods, including regression modeling and propensity scores, are discussed, with focus on the rationale, assumptions, strengths, and limitations to their application. PMID- 30473042 TI - Learning health systems. AB - Healthcare organizations have invested significant resources into integrating comprehensive electronic health record (EHR) systems into clinical care. EHRs digitize healthcare in ways that allow for repurposing of clinical information to support quality improvement, research, population health, and health system analytics. This has facilitated the development of Learning Health Systems. Learning health systems (LHS) merge healthcare delivery with research, data science, and quality improvement processes. The LHS cycle begins and ends with the clinician-patient interaction, and aspires to provide continuous improvements in quality, outcomes, and health care efficiency. Although, the health sector has been slow to embrace the LHS concept, innovative approaches for improving healthcare, such as a LHS, have shown that better outcomes can be achieved by engaging patients and physicians in communities committed to a common purpose. Here, we explore the mission of a pediatric LHS, such as PEDSnet, which is driven by the distinctive goals of a child's well-being. Its vision is to create a national LHS architecture in which all pediatric institutions can participate. While challenges still exist in the development and adoption of LHS, these challenges are being met with innovative strategies and strong collaborative relationships to reduce system uncertainty while improving patient outcomes. PMID- 30473043 TI - Process improvement strategies: Designing and implementing quality improvement research. AB - Quality improvement (QI) is the practice of continuously evaluating and improving the quality of health care that is delivered to patients. In this article, we will use practical examples to show how quality improvement projects have improved surgical patient care, and can be shared between institutions to accelerate the pace of improvement. We will explain the differences between quality improvement and research, and describe the methodological approach to performing and reporting quality improvement projects. Finally, we will describe ways to disseminate and widely implement changes in clinical practice using QI methodology. Even if they are not initiating and developing QI projects, all surgeons are likely to be affected by improvement initiatives going on in their hospitals, and should understand their valuable contribution to patient care. PMID- 30473044 TI - Positive and negative affect and prostate cancer-specific anxiety in Taiwanese patients and their partners. AB - PURPOSE: Few studies have examined positive and negative affect and prostate cancer-specific anxiety in prostate cancer patients and their partners. Thus, this study explored positive and negative affect and prostate cancer-specific anxiety as well as their associated factors in prostate cancer patients and their partners. METHOD: A prospective repeated-measures design was used. Data were collected from 48 prostate cancer patients and their partners when treatment was determined (before treatment) and at 6, 10, 18, and 24 weeks thereafter. The questionnaire included the Expanded Prostate Cancer Index Composite, the Dyadic Adjustment Scale, the Positive and Negative Affect Schedule, and the Memorial Anxiety Scale for prostate cancer. Generalized estimating equations were used for statistical analysis. RESULTS: Patients with lower relationship satisfaction experienced lower positive affect (beta = 0.279) and higher negative affect (beta = -0.323), and their partners experienced higher prostate specific antigen related anxiety (beta = -0.014). The presence of strong hormonal symptoms aggravated negative affect (beta = -0.010) and prostate cancer-related anxiety (beta = -0.009), but living with children and grandchildren improved prostate cancer-related anxiety (beta = -0.445) and fear of cancer recurrence in patients (beta = -0.232). CONCLUSIONS: There is an interaction between the prostate cancer specific anxiety experienced by patients and that experienced by their partners. The emotional state of patients and their partners should be evaluated, and understandable information should be provided. Care strategies should include encouraging adult children to participate in the patients' care plan, symptom management, and the teaching of coping skills. PMID- 30473045 TI - The role of temperature in the detection and diagnosis of neutropenic sepsis in adult solid tumour cancer patients receiving chemotherapy. AB - PURPOSE: The primary aim of this study was to examine the value of temperature as a diagnostic and prognostic indicator of infection and sepsis in neutropenic patients. A secondary aim was to gain insight into the presenting symptoms reported by these patients at home or on their initial admission assessment. METHODS: A cohort study was carried out using a case note review of 220 emergency admissions to a regional cancer centre. All participants were neutropenic and were diagnosed with infection on admission. The main outcome measures were relationships between Early Warning Scores and temperature values at home, on admission and during the hospital stay. RESULTS: 22% of patients who became acutely unwell did not have a fever. Pearson correlations showed only small associations between highest temperature value at any time point and highest early warning scores (r(202) = 0.176, P = .012). Temperature at home (B = 0.156, P = .336) and temperature on admission (B = 0.200, P = .052) did not predict highest Early Warning Scores. CONCLUSIONS: Body temperature is not a consistently reliable diagnostic or prognostic indicator for outcomes in patients with neutropenia and symptoms of infection. It can assist with early presentation and recognition of infection in many neutropenic patients. However, over-reliance on temperature risks missing the opportunity for early detection and treatment. PMID- 30473046 TI - An exerciSe program to improve depression And sleep Disorders in oncology patients: The SAD study. AB - PURPOSE: The purpose of this study was to determine if a structured supervised outpatient exercise program specifically for cancer patients would be associated with improvements in insomnia and depression after attending for 10-weeks. DESIGN: Descriptive observational study. SAMPLE AND SETTING: 75 adult subjects attended an outpatient hospital based exercise program specifically for cancer patients and coordinated by an exercise physiologist and a physical therapist. METHOD: Two validated instruments were administered to measure insomnia (Athens Insomnia Instrument) and depression (Zung Self-Rating Depression Scale) at baseline (prior to the start of the program) and repeated after 10-weeks of exercise. RESULTS: Forty (53.3%) completed the full 10 week program. Of the 40 that completed the program, an improvement in insomnia scores was seen (p value<0.01) as well as depression scores (p-value = 0.01). Baseline insomnia scores were not different between subjects that did not complete the program compared to those who did (p-value = 0.4401). However, baseline depression scores were higher in subjects who did not complete the program compared to subjects who did (p-value = 0.0462). CONCLUSIONS: Exercise improved depression and insomnia in cancer patients. By improving these symptoms, mortality, morbidity, and costs may be improved in the oncology population. Exercise programs can provide not only the health benefits of exercise, but also give cancer populations support from their peers which may improve their overall quality of life. PMID- 30473047 TI - Factors associated with dexamethasone-induced hiccups in cancer patients undergoing chemotherapy: A case control study. AB - PURPOSE: The purpose of this study was to identify demographic, health- and cancer-related, and physiological factors associated with dexamethasone-induced intractable hiccups in cancer patients. METHOD: This study adopted a retrospective case control design. The study subjects were 168 cancer patients admitted to a university hospital for chemotherapy between October 2011 and December 2016: 58 patients who experienced intractable hiccups while on dexamethasone (cases) and 110 matched patients who received dexamethasone but did not experience hiccups (controls). Data were collected from most recent medical records and included demographic, health- and cancer-related, and physiological factors. RESULTS: Our findings demonstrated that the development of dexamethasone induced hiccups was significantly associated with a male gender, a young age, overweight/obesity, the use of alkylating anticancer agents (particularly as the first anticancer drug), high levels of hemoglobin, serum creatinine, uric acid, and albumin, and an elevated body temperature. CONCLUSIONS: Oncology nurses should be aware of influencing factors of dexamethasone-induced hiccups in cancer patients receiving chemotherapy. Our findings may provide evidence to design oncology nursing strategies that help maximize the benefits of chemotherapy in cancer patients. PMID- 30473048 TI - Assessment of the effects of walking as an exercise intervention for children and adolescents with cancer: A feasibility study. AB - PURPOSE: To examine the effects of walking exercise on exercise tolerance, fatigue, sleep quality, and quality of life (QOL) for children and adolescents with cancer. METHODS: A 6-week walking exercise regimen was implemented in pediatric hematological and oncological wards and in clinics of a medical center in Taiwan. A 6-min walk test (6MWT), fatigue, sleep quality, and QOL were measured at baseline and for six subsequent weeks. RESULTS: Adherence to the walking exercise regimen was achieved by 72-89% of the participants in this study. Significant improvements in exercise tolerance were observed after two weeks and they continued through week 6 (F = 17.07, p < 0.001). Both cognitive fatigue and general fatigue were significantly improved after six weeks of walking exercise (t = 2.41, p = 0.02; t = 2.76, p = 0.01), while sub-scores for sleep/rest fatigue did not improve. No significant impact on sleep quality or QOL was observed. CONCLUSIONS: Walking exercise is a feasible and tolerable intervention that should be considered for children and adolescents with cancer. Here, a 6-week walking exercise regimen increased exercise tolerance and improved fatigue. We recommend that walking exercise should be promoted during hospitalization and at home to alleviate fatigue. PMID- 30473049 TI - Patients' participation during treatment and care of breast cancer - a possibility and an imperative. AB - PURPOSE: To explore how patients experience participation during treatment and care for breast cancer related to their understanding. METHOD: Semi-structured individual interviews with 16 women diagnosed with breast cancer. Interpretative qualitative content analysis was performed. RESULTS: Three main themes describe patient participation. Theme 1 Respectful and personal encounters illustrates how the treatment from health care staff contributed to feelings of being "seen" as a human, a basis for participation. Theme 2 Part-owner in decision making describes the women's varied wishes of participating in treatment decisions. Theme 3 Striving to manage treatment, care and self-care concerns the need to manage self care for well-being. CONCLUSIONS: Patient participation is both a possibility and an imperative. Patients must be recognized as unique human beings with varying needs of participation. Shared learning and understanding in dialogue with health care staff is a prerequisite. A novel approach where patients and health care staff are both partners and participants is presented. PRACTICAL IMPLICATION: The results call for an initiation of training programs supporting pedagogical competence in staff and patients' learning in breast cancer care. Access to health care in the outpatient and the hospital settings is needed long term after treatment to support patient participation. PMID- 30473050 TI - Relationship between subjective taste alteration and weight loss in head and neck cancer patients treated with radiotherapy: A longitudinal study. AB - PURPOSE: To conduct a dynamic and comprehensive evaluation of subjective taste alteration (STA)and identify the association between STA and weight loss in patients with head and neck cancer (HNC) who were treated with radiotherapy. METHODS: STA and weight of 114 patients were recorded at baseline, mid-treatment, post-treatment, and one to two months after radiotherapy (follow-up). Generalized estimating equations (GEE) were used to conduct repeated measures analyses of STA and weight loss at four time-points and assess the relationship between them. RESULTS: The prevalence of STA was 13.2% (baseline), 83.3% (mid-treatment), 92.1% (post-treatment), and 77.9% (follow-up), respectively; the prevalence of >=10% weight loss increased from 1.8% (mid-treatment) to 44.2% (follow-up). The severity of STA was increasingly poor with radiation therapy and did not return to the baseline level at the follow-up. Meanwhile, the weight of patients did not increase at the follow-up. Among the four subscales of STA (decline in basic taste, general taste alterations, phantogeusia and parageusia, and discomfort), only the discomfort score (beta = -2.988; p = 0.005; 95%confidence interval: 5.084-0.891) had a significant effect on weight loss. CONCLUSIONS: The main finding of this study was that STA, particularly the discomfort symptom associated with dietary intake, as a common and persistent symptom among HNC patients during and after radiotherapy, might promote weight loss in patients, which should be afforded greater attention from medical staff. PMID- 30473052 TI - This is an older men's world: A qualitative study of men's experiences with prostate cancer. AB - PURPOSE: Prostate cancer is highly prevalent and invasive among older men. Not knowing their experiences hampers care and support to men with prostate cancer and prostate cancer survivors. This study aims to provide insight into older men's experiences with prostate cancer in order to improve personalised care. METHODS: A qualitative research design through semi-structured interviews with 22 older men with prostate cancer was conducted in two areas of the Netherlands in 2015. Patients were selected through systematic non-probabilistic sampling. The transcripts were analysed with conventional content analysis and affinity diagramming. RESULTS: Four themes emerged from the data: impact of prostate cancer, dealing with prostate cancer and treatment, involvement of and with others, and experiences with professional care and the care trajectory. The way patients dealt with prostate cancer and their experiences with the care they received varied. Overall, hospital care was rated positively, and communication was a crucial determinant of the patient's satisfaction or dissatisfaction. Some patients lacked information about their health status, which may have influenced decision-making processes. Some were reluctant to talk about their disease with other people and sometimes hesitated to ask for help. CONCLUSION: Despite many positive care experiences, some patients felt that the communication, information provision and decision-making were inadequate. Vulnerable patients with severe complications or limited social support may need additional psychosocial care. Lowering the threshold for patients to ask for help and the availability of a professional with expert knowledge about prostate cancer and ageing may decrease unnecessary hardship and increase personal strengths. PMID- 30473051 TI - Health-related quality of life in patients with prostate cancer and their spouses: Results from a longitudinal study. AB - PURPOSE: The purpose of this study was to explore changes in HRQoL (health related quality of life) and identify the associated factors in patients with prostate cancer and their spouses during the year following their diagnosis of prostate cancer. METHODS: The longitudinal study design consisted of 179 patients and 166 spouses, using discretionary sampling, at five Finnish central hospitals. Participants completed a self-reported RAND-36-Item Health Survey at three time points: time of diagnosis and 6 and 12 months later. Changes in HRQoL were analysed using descriptive statistics and non-parametric tests. Linear mixed effects models were used to identify the factors associated with the changes in HRQoL in the patients and their spouses. RESULTS: On average, the HRQoL of patients with prostate cancer changed in physical functioning (p = 0.015), emotional well-being (p = 0.029) and general health (p = 0.038) were statistically significant over the 12-month study period. In spouses, statistically significant changes in HRQoL were not observed. Interaction between the age of participants and changes in HRQoL were statistically significant. CONCLUSIONS: Findings in this study suggest that interventions aimed at improving the HRQoL of patients should support a few different dimensions of HRQoL for the patients themselves than for their spouses. Nurses should pay more attention to elderly couples. PMID- 30473053 TI - A pilot randomised controlled trial of a multimodal supportive care (ThriverCare) intervention for managing unmet supportive care needs in men with metastatic prostate cancer on hormonal treatment and their partner/caregivers. AB - PURPOSE: Men with metastatic prostate cancer experience high levels of unmet supportive care needs in current healthcare delivery. We set out to determine the effectiveness of a multimodality supportive care (ThriverCare) intervention on the prevalence of unmet supportive care needs for men and their partner/caregivers. METHODS: A prospective parallel group, pilot randomised controlled pilot trial in 4 hospitals in Scotland. 38 participants with radiologically proven metastatic prostate cancer disease and 10 partners/caregivers were recruited into the study. A two arm 1:1 study design compared the usual standard of care (SC) approach to SC plus ThriverCare intervention. The primary outcome was the Supportive Care Needs Survey at 3 months of intervention. RESULTS: There was no statistical significant difference in the prevalence of unmet supportive care needs between the intervention group and the usual SC group at baseline p = 0.112, however a statistically significant difference was observed at 3 months, indicating that the prevalence of unmet supportive care needs were less in the intervention group (1.13, SD 2.5) compared to the usual SC (6.17, SD 7.05), p = 0.002. CONCLUSION: ThriverCare appears to improve the supportive care experience of men with metastatic prostate cancer on hormonal treatment and their partner/caregivers. Our results accentuate that no longer one size of care delivery fits all, care must be responsive and adaptable to meet the individual needs of people affected by cancer to thrive. PMID- 30473054 TI - Caregiver burden among Chinese family caregivers of patients with lung cancer: A cross-sectional survey. AB - PURPOSE: To investigate the status of caregiver burden and to identify the factors related to caregiver burden among Chinese family caregivers of patients with lung cancer. METHODS: A cross-sectional design with convenience sampling was used in this study. Participants (N = 116) from the oncology inpatient ward at one teaching hospital in Chengdu were recruited from June 2015 to June 2016. The following measurement tools were used: a demographic questionnaire, the Social Support Rating Scale, the General Self-efficacy Scale, and the Zarit Burden Interview. Multiple linear regression analysis was used to identify factors associated with caregiver burden. RESULTS: The average ZBI score was 38.8 (SD = 13.4). Patient age (p < 0.01), medical and other types of insurance (p < 0.01), disclosure of the diagnosis to patients (p < 0.01), and social support of the caregiver (p < 0.05) were related to caregiver burden. Fifty-three percent of the variance in caregivers' burden was explained by these identified factors. CONCLUSIONS: Caregiver burden was higher among Chinese caregivers of lung cancer patients compared with the results of previous studies. Patient age, medical and other types of insurance, disclosure of cancer diagnosis to the patient, and caregivers' social support are factors associated with caregiver burden. The results suggest that social support, comprehensive healthcare insurance initiatives, and culture-based communication skill training are potential areas for future intervention. PMID- 30473056 TI - In Memoriam: Thomas R. Jerrells Editor Emeritus, Alcohol: An International Biomedical Journal. PMID- 30473055 TI - 67-Gallium SPECT/CT in febrile syndromes of unknown origin. AB - INTRODUCTION AND OBJECTIVE: Febrile syndromes of unknown origin (FSUO) are complex processes in hospital practice. Their management includes an exhaustive medical history and examination, as well as an extensive number of biochemical tests. If these are inconclusive, diagnostic imaging techniques such as SPECT/CT with 67-Gallium Citrate (67Ga-SPECT/CT) could play an important role. We evaluated its role in the management of FSUO in our healthcare area. MATERIAL AND METHODS: We reviewed 57 patients who underwent a 67Ga-SPECT/CT due to a FSUO (32 women and 25 men, age range: 32-83 years old) obtaining scintigraphic findings, previous treatments and final diagnosis. Values of sensitivity, specificity, positive predictive values (VPP) and negative values (NPV) were obtained and compared with the results for PET/CT with 18Fluor-deoxy-glucose (18F-FDG PET/CT) found in the literature. RESULTS: The diagnoses found were: infection in 27/57 (47%), inflammatory disease in 15/57 (26%), neoplasm in 1/57 (1.75%) and patients without final diagnosis in 14/57 (24%). The statistical values of 67Ga-SPECT/CT were: sensitivity, specificity, PPV and NPV of 67%, 93%, 97% y 48%, respectively which were slightly lower than those found for the 18F-FDG PET/CT (86%, 52%, 70% and 92%, respectively). The diagnostic yield was 73% which increased to 80% in the patients who lacked empirical treatment. CONCLUSION: Despite the better results of 18F-FDG PET/CT, 67Ga-SPECT/CT behaved as a useful technique in the management of FSUO. It is advisable to use it if 18F-FDG PET/CT is not available. PMID- 30473057 TI - Adiponectin homolog novel osmotin protects obesity/diabetes-induced NAFLD by upregulating AdipoRs/PPARalpha signaling in ob/ob and db/db transgenic mouse models. AB - BACKGROUND: In metabolic disorders, adiponectin and adiponectin receptors (AdipoR1/R2) signaling has a key role in improving nonalcoholic fatty liver disease (NAFLD) in obesity-associated diabetes. OBJECTIVE: To the best of our knowledge, here, we reported for the first time the underlying mechanistic therapeutic efficacy of the novel osmotin, a homolog of mammalian adiponectin, against NAFLD in leptin-deficient ob/ob and db/db mice. METHODS: The ob/ob and db/db mice were treated with osmotin at a dose of 5 MUg/g three times a week for two weeks. To co-relate the in vivo results we used the human liver carcinoma HepG2 cells, subjected to knockdown with small siRNAs of AdipoR1/R2 and PPARalpha genes and treated with osmotin and palmitic acid (P.A.). MTT assay, Western blotting, immunohistofluorescence assays, and plasma biochemical analyses were applied. RESULTS: Osmotin stimulated AdipoR1/R2 and its downstream APPL1/PPAR alpha/AMPK/SIRT1 pathways in ob/ob and db/db mice, and HepG2 cells exposed to P.A. Mechanistically, we confirmed that knockdown of AdipoR1/R2 and PPARalpha by their respective siRNAs abolished the osmotin activity in HepG2 cells exposed to P.A. Overall, the in vivo and in vitro results suggested that osmotin protected against NAFLD through activation of AdipoR1/R2 and its downstream APPL1/PPAR alpha/AMPK/SIRT1 pathways as shown by the reduced body weight, blood glucose level and glycated hemoglobin, improved glucose tolerance, attenuated insulin resistance and hepatic glucogenesis, regulated serum lipid parameters, and increased fatty acid oxidation and mitochondrial functions. CONCLUSION: Our findings strongly suggest that novel osmotin might be a potential novel therapeutic tool against obesity/diabetes-induced NAFLD and other metabolic disorders. PMID- 30473060 TI - [Technological innovations in dialysis]. AB - The history of dialysis, which started only half a century ago, is rich in developments and technological innovations. Thanks to scientific progress and the development of knowledge in the field of dialysis, patient survival will continue to increase and quality of life will continue to improve. More precise purification, reductions in the size and weight of equipment as well as refinement of filtration membranes are a few of the recent and current breakthroughs, and are challenges for further development. Dialysis has a world of opportunities ahead in terms of optimizing processes and new innovations, continuing the progress made in improving patient treatment conditions. Cet article fait partie du numero supplement Innovations en Nephrologie realise avec le soutien institutionnel de Vifor Fresenius Medical Care Renal Pharma. PMID- 30473058 TI - Unsupervised machine learning of radiomic features for predicting treatment response and overall survival of early stage non-small cell lung cancer patients treated with stereotactic body radiation therapy. AB - BACKGROUND AND PURPOSE: To predict treatment response and survival of NSCLC patients receiving stereotactic body radiation therapy (SBRT), we develop an unsupervised machine learning method for stratifying patients and extracting meta features simultaneously based on imaging data. MATERIAL AND METHODS: This study was performed based on an 18F-FDG-PET dataset of 100 consecutive patients who were treated with SBRT for early stage NSCLC. Each patient's tumor was characterized by 722 radiomic features. An unsupervised two-way clustering method was used to identify groups of patients and radiomic features simultaneously. The groups of patients were compared in terms of survival and freedom from nodal failure. Meta-features were computed for building survival models to predict survival and free of nodal failure. RESULTS: Differences were found between 2 groups of patients when the patients were clustered into 3 groups in terms of both survival (p = 0.003) and freedom from nodal failure (p = 0.038). Average concordance measures for predicting survival and nodal failure were 0.640+/-0.029 and 0.664+/-0.063 respectively, better than those obtained by prediction models built upon clinical variables (p < 0.04). CONCLUSIONS: The evaluation results demonstrate that our method allows us to stratify patients and predict survival and freedom from nodal failure with better performance than current alternative methods. PMID- 30473059 TI - Production of Ga-68 with a General Electric PETtrace cyclotron by liquid target. AB - PURPOSE: In recent years the use of 68Ga (t1/2 = 67.84 min, beta+: 88.88%) for the labelling of different PET radiopharmaceuticals has significantly increased. This work aims to evaluate the feasibility of the production of 68Ga via the 68Zn(p,n)68Ga reaction by proton irradiation of an enriched zinc solution, using a biomedical cyclotron, in order to satisfy its increasing demand. METHODS: Irradiations of 1.7 Msolution of 68Zn(NO3)2 in 0.2 N HNO3 were conducted with a GE PETtrace cyclotron using a slightly modified version of the liquid target used for the production of fluorine-18. The proton beam energy was degraded to 12 MeV, in order to minimize the production of 67Ga through the68Zn(p,2n)67Ga reaction. The product's activity was measured using a calibrated activity meter and a High Purity Germanium gamma-ray detector. RESULTS: The saturation yield of68Ga amounts to (330 +/- 20) MBq/uA, corresponding to a produced activity of68Ga at the EOB of (4.3 +/- 0.3) GBq in a typical production run at 46 uA for 32 min. The radionuclidic purity of the68Ga in the final product, after the separation, is within the limits of the European Pharmacopoeia (>99.9%) up to 3 h after the EOB. Radiochemical separation up to a yield not lower than 75% was obtained using an automated purification module. The enriched material recovery efficiency resulted higher than 80-90%. CONCLUSIONS: In summary, this approach provides clinically relevant amounts of68Ga by cyclotron irradiation of a liquid target, as a competitive alternative to the current production through the68Ge/68Ga generators. PMID- 30473061 TI - [From care management decision to set-up of home dialysis: what are the challenges for the nephrologist in assisting the patient?] AB - Since a couple of years, a new paradigm of care has taken place where the patient plays a major role in the choice of his treatment. Patient information in a context where the doctor-patient relationship has drastically changed and where knowledge is continuously growing, is a challenge for the nephrologist. For the patient who decides to undergo home dialysis, numerous questions arise during the decision-making process. How should treatment alternatives be discussed with the patient? What are the current data available on the different methods? As comfort, quality of life and level of autonomy often drive the choice of care management, home dialysis can be promoted more with appropriate assistance from both the nephrologist and the healthcare team. Cet article fait partie du numero supplement Innovations en Nephrologie realise avec le soutien institutionnel de Vifor Fresenius Medical Care Renal Pharma. PMID- 30473062 TI - [Metabolic complications in chronic kidney disease: hyperphosphatemia, hyperkalemia and anemia]. AB - Metabolic complications of chronic kidney disease (CKD) are frequent; the aims of this review are to present a 2018 update for hyperkalemia, hyperphosphatemia and anemia. Hyperkalemia is defined by a plasma level above 5.0 mmol/L, after ruling out pre-analytical problems such as hemolysis. It is frequent in CKD, most often due to drugs and notably renin/ angiotensin blockers. Chronic hyperkalemia is deleterious, with an increased risk of mortality. Therapeutic strategies to decrease the incidence and severity of hyperkalemia are therefore crucial in nephrology: experts recommend to maintain the renin/angiotensin blockers as long as possible, whilst associating diuretics and potassium binders. There are apparent discrepancies between optimal protein intake and decreased phosphate intake in CKD; this is even more important in dialysis since protein decrease is associated with denutrition and subsequent increased risk of mortality. Nutritional phosphate intake from vegetables are less absorbed; in contrast, phosphate additives are almost completely absorbed in the gastro-intestinal tract. These "hidden" intake may increase the total daily phosphate intake by 1 000 mg. As such in addition to optimized dialysis, phosphate binders should be used but compliance may be challenging on the long-term. Educational programs focused on phosphate are also mandatory in CKD patients. "Absolute" iron deficiency is less frequent than "functional" iron deficiency in CKD patients: both require the use of iron supplementation, and the latter may benefit from additional erythropoietin stimulating agents (ESA) when hemoglobin is below 10 g/dL. Intravenous iron is more efficient to correct iron deficiency both in pre dialysis and dialysis especially in patients with chronic deficiency. Last generation intravenous preparations have largely demonstrated their safety. One indication of iron supplementation one should not forget in nephrology is the patient with moderate CKD and heart failure since the expected benefits are multiple, notably in terms of quality of life, renal function and functional capacity. Cet article fait partie du numero supplement Innovations en Nephrologie realise avec le soutien institutionnel de Vifor Fresenius Medical Care Renal Pharma. PMID- 30473063 TI - [What do registries compared to clinical trials tell us?] AB - The objective of this review is to illustrate the interests of registries in terms of clinical research, using practical examples from the French REIN registry. In addition to their interest in terms of observation and decision making for public health, registries may also be used to compare structures, and to evaluate causality in clinical research. Indeed, even though randomized controlled trials are the gold standard to assess causality, they may be difficult to perform, with an applicability in daily life that remains to be demonstrated since patients are highly selected patients with a very close follow up. In contrast, observational studies from registries have other advantages, and notably high number of patients, low cost, relatively rapid research, focus on specific sub-groups. In the future, data mining with an implementation of a huge number of data for patients (hospitalization data, genetics, ambulatory care, etc.) will dramatically improve the databases. We may even imagine running RCTs directly in registries, with lower costs and patients closer to reality. However, many challenges remain to be solved, and notably the ethical issues of confidentiality and protection of patients in these "mega-databases". Cet article fait partie du numero supplement Innovations en Nephrologie realise avec le soutien institutionnel de Vifor Fresenius Medical Care Renal Pharma. PMID- 30473064 TI - Long-Term Follow-Up in Children With Focal Cortical Dysplasia IIId for Early Brain Injuries, Including Neuropathological Findings. AB - BACKGROUND: Early cerebral injury has a close relationship with epilepsy and focal cortical dysplasia IIId. We investigated children with focal cortical dysplasia IIId who underwent surgery for epilepsy. METHODS: We selected 49 patients from among 260 pediatric patients who had undergone epilepsy surgery, analyzing their clinical materials and pathology data. The selected patients had been followed for more than two years. RESULTS: The 49 patients were divided into seven groups based on different early brain injuries. There was a significant difference (P < 0.05) between Engel class I ratio of cerebral hemorrhage group (84.6%) and that of central nervous system infection group (42.1%) in two to eight years follow-up. The patients with prior cerebral hemorrhage had a wider scope (P < 0.05) of brain damage than those in the brain infection and febrile convulsion groups. Secondary polymicrogyria commonly existed. Neuron islands were located adjacent to polymicrogyria in cerebral hemorrhage and brain trauma patients, and missing neuronal laminations beside the polymicrogyria was noted in others. CONCLUSIONS: In children with focal cortical dysplasia IIId, individuals with cerebral hemorrhage within the perinatal period exhibited a wider range of brain lesions, while the postoperative follow-up outcome was better. Secondary polymicrogyria existed along with focal cortical dysplasia IIId and is related to the developmental lesion. The processes of secondary polymicrogyria caused by different early brain injuries might be different. PMID- 30473065 TI - Correlates of Response to Mail Questionnaires Among Assisted Living Communities in Oregon, 2014-2016. PMID- 30473066 TI - Direct quantification of EGFR variant allele frequency in cell-free DNA using a microfluidic-free digital droplet PCR assay. AB - Analysis of liquid biopsy samples is a promising diagnostic intervention for noninvasive detection and monitoring of cancer genotypes. However, current methods used to assess mutation status are either costly, in the case of next generation sequencing-based assays, or lacking in sensitivity, in the case of bulk quantitative PCR measurements. Digital droplet PCR (ddPCR) is at once a sensitive and low-cost method for detecting rare cancer mutations and measuring their variant allele frequency. In this chapter, we describe a method for conducting ddPCR assays without microfluidics in a process called "particle templated emulsification" (PTE). Using hydrogel particles and a standard benchtop vortexer to rapidly emulsify large volumes, the method forgoes the specialized instrumentation required for conventional ddPCR assays and is capable of high experimental throughput. To assess the quantitative performance of the method, we apply PTE ddPCR to analysis of variant allele frequency in EGFR, a commonly mutated gene in lung adenocarcinomas. PMID- 30473067 TI - Quantifying phenotypes in single cells using droplet microfluidics. AB - This book chapter describes the use of droplet microfluidics to phenotype single cells. The basic process flow includes the encapsulation of single cells with a specific probe into aqueous micro-droplets suspended in a biocompatible oil. The probe is chosen to measure the phenotype of interest. After incubation, the encapsulated cell turns the probe fluorescent and renders the entire droplet fluorescent. Enumerating drops that are fluorescent quantifies the concentration of cells possessing the phenotype of interest. Examining the distribution of fluorescence further allows one to quantify the heterogeneity among the cell population. PMID- 30473068 TI - Modular microfluidics for double emulsion formation. AB - For many engineering applications such as manipulating two phase flows, generating single and double emulsions, and passively propelling liquids through channels, control over the surface energy of microfluidic channels is essential. In particular, double emulsion formation, which benefits from alternating hydrophobic and hydrophilic sections of channel, represents a challenge in fabricating controlled microfluidic channel surface properties. As double emulsions find further applications in single-cell handling and analysis, straightforward methods for generating them increase in value. Here, we present a method for generating double emulsions in microfluidic channels fabricated from modular fluidic blocks. By using a vapor-phase polymer coating technology initiated chemical vapor deposition-we are able to fabricate blocks with varying surface properties. Assembling these blocks together then creates step-like changes in surface energy within a microchannel. PMID- 30473069 TI - Universal anchored-droplet device for cellular bioassays. AB - The ability to encapsulate cells individually in droplets has many potential applications, for example for observing the heterogeneity of behaviors within a population. However, implementing operations on moving droplets require feedback control and instruments that provide precise timing. These technical difficulties impede the adoption of droplet microfluidic protocols in nonspecialist labs. In this chapter we describe an approach to produce and manipulate droplets that remain stationary within a microfluidic chamber, by fabricating a microfluidic device having three-dimensional topography. The method uses microchannels that confine the fluids everywhere except in predefined regions where the channels have a large height, a technique known as "rails and anchors." By relying on the natural tendency of droplets to minimize their surface area, the approach provides a wide range of droplet manipulation tools. This chapter shows how this can be used to produce droplets, and several biological applications are demonstrated. PMID- 30473070 TI - Cell biology at the interface of nanobiosensors and microfluidics. AB - It is at the nanometer scale where biology, chemistry, and material science converge. With recent progresses in nanotechnology, research in cell biology has gained enormous interest from a growing multidisciplinary community of scientists in academia and industry. Many efforts have been made to discover cures for diseases through advancements in nanobiosensors and microfluidics. In this chapter, we give a general introduction to nanobiosensors and microfluidics technology, present key developments in the field, and illustrate the breadth of microfluidics-based sensing strategies available for cell biology. We also provide protocols for fabricating localized surface plasmon resonance (LSPR) based nanobiosensors, and for integration of LSPR with a microfluidic device. Finally, we highlight applications and challenges associated with the use of nanobiosensing and microfluidics technology. This chapter should provide a solid platform for cell biologists to develop simple microfluidic LSPR chips for routine cell-based assays. PMID- 30473072 TI - Viable cell culture in PDMS-based microfluidic devices. AB - Microfluidics has played a vital role in developing novel methods to investigate biological phenomena at the molecular and cellular level during the last two decades. Microscale engineering of cellular systems is nevertheless a nascent field marked inherently by frequent disruptive advancements in technology such as PDMS-based soft lithography. Viable culture and manipulation of cells in microfluidic devices requires knowledge across multiple disciplines including molecular and cellular biology, chemistry, physics, and engineering. There has been numerous excellent reviews in the past 15 years on applications of microfluidics for molecular and cellular biology including microfluidic cell culture (Berthier et al., 2012; El-Ali, Sorger, & Jensen, 2006; Halldorsson et al., 2015; Kim et al., 2007; Mehling & Tay, 2014; Sackmann et al., 2014; Whitesides, 2006; Young & Beebe, 2010), cell culture models (Gupta et al., 2016; Inamdar & Borenstein, 2011; Meyvantsson & Beebe, 2008), cell secretion (Schrell et al., 2016), chemotaxis (Kim & Wu, 2012; Wu et al., 2013), neuron culture (Millet & Gillette, 2012a, 2012b), drug screening (Dittrich & Manz, 2006; Eribol, Uguz, & Ulgen, 2016; Wu, Huang, & Lee, 2010), cell sorting (Autebert et al., 2012; Bhagat et al., 2010; Gossett et al., 2010; Wyatt Shields Iv, Reyes, & Lopez, 2015), single cell studies (Lecault et al., 2012; Reece et al., 2016; Yin & Marshall, 2012), stem cell biology (Burdick & Vunjak-Novakovic, 2009; Wu et al., 2011; Zhang & Austin, 2012), cell differentiation (Zhang et al., 2017a), systems biology (Breslauer, Lee, & Lee, 2006), 3D cell culture (Huh et al., 2011; Li et al., 2012; van Duinen et al., 2015), spheroids and organoids (Lee et al., 2016; Montanez-Sauri, Beebe, & Sung, 2015; Morimoto & Takeuchi, 2013; Skardal et al., 2016; Young, 2013), organ-on-chip (Bhatia & Ingber, 2014; Esch, Bahinski, & Huh, 2015; Huh et al., 2011; van der Meer & van den Berg, 2012), and tissue engineering (Andersson & Van Den Berg, 2004; Choi et al., 2007; Hasan et al., 2014). In this chapter, we provide an overview of PDMS-based microdevices for microfluidic cell culture. We discuss the advantages and challenges of using PDMS based soft lithography for microfluidic cell culture and highlight recent progress and future directions in this area. PMID- 30473071 TI - BET-seq: Binding energy topographies revealed by microfluidics and high throughput sequencing. AB - Biophysical models of transcriptional regulation rely on energetic measurements of the binding affinities between transcription factors (TFs) and target DNA binding sites. Historically, assays capable of measuring TF-DNA binding affinities have been relatively low-throughput (measuring ~103 sequences in parallel) and have required significant specialized equipment, limiting their use to a handful of laboratories. Recently, we developed an experimental assay and analysis pipeline that allows measurement of binding energies between a single TF and up to 106 DNA species in a single experiment (Binding Energy Topography by sequencing, or BET-seq) (Le et al., 2018). BET-seq employs the Mechanically Induced Trapping of Molecular Interactions (MITOMI) platform to purify DNA bound to a TF at equilibrium followed by high coverage sequencing to reveal relative differences in binding energy for each sequence. While we have previously used BET-seq to refine the binding affinity landscapes surrounding high-affinity DNA consensus target sites, we anticipate this technique will be applied in future work toward measuring a wide variety of TF-DNA landscapes. Here, we provide detailed instructions and general considerations for DNA library design, performing BET-seq assays, and analyzing the resulting data. PMID- 30473073 TI - High-throughput microfluidic single-cell trapping arrays for biomolecular and imaging analysis. AB - Single-cell analysis is of critical importance in revealing population heterogeneity, identifying minority sub-populations of interest, as well as discovering unique characteristics of individual cells. Microfluidic platforms work at the scale comparable to cell diameter and is suitable for single-cell manipulation. Here we present a microfluidic trapping array which is able to rapidly and deterministically trap single-cells in highly-packed microwells. This chapter first describes the design and fabrication protocols of the trapping array, and then presents its two representative applications: single-cell mRNA probing when integrated with a dielectrophoretic nanotweezer (DENT), and live cell real-time imaging when combined with fluorescence lifetime imaging microscopy (FLIM). As the single-cell trapping efficiency is determined by the channel design instead of the flow rate, this trapping array can be coupled with different microfluidic sample processing units with different flow rates for various single-cell analyses. PMID- 30473074 TI - Artificial niche microarrays for identifying extrinsic cell-fate determinants. AB - The complex cellular microenvironment plays an important role in determining cell fate. For example, stem cells located in a microenvironment termed niche integrate a wide variety of extrinsic cues to take distinct fate choices. Capturing this multiple-input/multiple-output system in vitro has proven to be very challenging. In order to address this issue, we developed and validated a microfabricated cellular array platform, termed artificial niche microarrays, which is capable of performing high-throughput single-cell assays under physiologically relevant conditions. The platform allows exposing cultured cells to differential signaling cues displayed on soft hydrogel substrates having variable stiffness. The behavior of the seeded cells can be readily quantified across over 2000 multivariate microenvironments. Here we describe a pipeline for performing multifactorial, image-based assays with these artificial niche microarrays. The procedure details the steps from microarray production, cell culture, cell phenotyping, data extraction to statistical analysis. PMID- 30473075 TI - Reconstruction of directed neuronal networks in a microfluidic device with asymmetric microchannels. AB - Microfluidic devices for controlling neuronal connectivity in vitro are extremely useful tools for deciphering pathological and physiological processes occurring in neuronal networks. These devices allow the connection between different neuronal populations located into separate culture chambers through axon selective microchannels. In order to implement specific features of brain connectivity such as directionality, it is necessary to control axonal growth orientation in these devices. Among the various strategies proposed to achieve this goal, one of the most promising and easily reproducible is the use of asymmetric microchannels. We present here a general protocol and several guidelines for the design, production and testing of a new paradigm of asymmetric microchannels geometries based on a "return to sender" strategy. In this method, axons are either allowed to travel between the emitting and receiving chambers within straight microchannels (forward direction), or are rerouted toward their initial location through curved microchannels (reverse direction). We introduce variations of these "arches" microchannels and evaluate their respective axonal filtering capacities. Importantly, one of these variants presents an almost complete filtration of axonal growth in the non-permissive direction while allowing robust axonal invasion in the other one, with a selectivity ratio as high as 99.7%. PMID- 30473076 TI - Single-cell 3D electro-rotation. AB - Single-cell rotation is a fundamental manipulation used in a wide range of biotechnological applications such as cell injection and enucleation. However, there are currently few methods for the 3D rotation of single cells. Here, this chapter presents different biochip platforms based on a dielectrophoresis technique to achieve 3D rotation. In-plane (yaw) and out-of-plane rotation (pitch) can be achieved by applying different AC signal configurations, respectively. This use of 3D rotation facilitates several applications. For example, in-plane rotation can be used to measure the rotation spectra, and this can be used to estimate the dielectric parameters. The out-of-plane rotation can help reconstruct 3D cell models. PMID- 30473077 TI - Preface. PMID- 30473078 TI - A Path Towards Effectively Investigating the Impact of Sex and Gender on Mental Health. PMID- 30473079 TI - The Journal of Cataract & Refractive Surgery: 2018 in Review. PMID- 30473080 TI - Phacoemulsifier occlusion break surge volume reduction. AB - PURPOSE: To compare the volumetric occlusion break surge responses of phacoemulsification units from 1 company over 3 generations under varying vacuum limits and target intraocular pressure (IOP) settings. SETTING: Alcon Research, Ltd., Lake Forest, California, USA. DESIGN: Experimental study. METHODS: Three generations of phacoemulsification units (Infiniti Vision System, Centurion Vision System, and Centurion Vision System with Active Sentry upgrades) were tested. Volumetric surge responses were measured after occlusion breaks at vacuum limits of 200 mm Hg, 300 mm Hg, 400 mm Hg, 500 mm Hg, and 600 mm Hg and target IOPs of 30 mm Hg, 55 mm Hg, and 80 mm Hg. An acrylic test chamber with a piston attached to 3 springs modeled the human eye in this study. The springs were calibrated to mimic volumetric changes in the eye over a wide range of IOPs. RESULTS: Occlusion break surge volumes varied from 17.4 MUL to 153 MUL, corresponding to 7% and 61%, respectively, of the aqueous volume in the average phakic eye and to 4% and 33% of the aqueous volume in the average aphakic eye. CONCLUSION: Occlusion break surge volumes decreased with increasing target IOP, decreasing vacuum limit, and each generational increment in the phacoemulsification system. PMID- 30473081 TI - December consultation #2. PMID- 30473082 TI - Residual error after intraocular lens implantation in an eye that had radial keratotomy and laser in situ keratomileusis: December consultation #1. PMID- 30473083 TI - December consultation #3. PMID- 30473084 TI - December consultation #4. PMID- 30473085 TI - December consultation #5. PMID- 30473086 TI - December consultation #7. PMID- 30473087 TI - December consultation #6. PMID- 30473088 TI - December consultation #8. PMID- 30473089 TI - December consultation #9. PMID- 30473090 TI - December consultation #10. PMID- 30473091 TI - Editor's Comment. PMID- 30473092 TI - Corneal stromal demarcation line after 4 protocols of corneal crosslinking in keratoconus determined with anterior segment optical coherence tomography. PMID- 30473093 TI - Reply. PMID- 30473094 TI - Cystoid macular edema after cataract surgery. PMID- 30473095 TI - Introduction: unique challenges in the care of conjoined twins. PMID- 30473096 TI - Phenotyping of circulating extracellular vesicles (EVs) in obesity identifies large EVs as functional conveyors of Macrophage Migration Inhibitory Factor. AB - OBJECTIVE: Obesity-associated metabolic dysfunctions are linked to dysregulated production of adipokines. Accumulating evidence suggests a role for fat-derived extracellular vesicles (EVs) in obesity-metabolic disturbances. Since EVs convey numerous proteins we aimed to evaluate their contribution in adipokine secretion. METHODS: Plasma collected from metabolic syndrome patients were used to isolate EV subtypes, namely microvesicles (MVs) and exosomes (EXOs). Numerous soluble factor concentrations were measured successively on total, MV- and EXO-depleted plasma by multiplexed immunoassays. RESULTS: Circulating MVs and EXOs were significantly increased with BMI, supporting a role of EVs as metabolic relays in obesity. Obesity was associated with dysregulated soluble factor production. Sequential depletion of plasma MVs and EXOs did not modify plasma levels of these molecules, with the exception of Macrophage Migration Inhibitory Factor (MIF). Half of plasma MIF circulated within MVs, and this MV secretory pathway was conserved over different MIF-producing cells. Although MV-associated MIF triggered rapid ERK1/2 activation in macrophages, these functional MV-MIF effects specifically relied on MIF tautomerase activity. CONCLUSION: Our results emphasize the importance of reconsidering MIF-metabolic actions with regard to its MV-associated form and opening new EV-based strategies for therapeutic MIF approaches. PMID- 30473097 TI - LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. AB - OBJECTIVE: A novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists in type 2 diabetes mellitus (T2DM). METHODS: LY3298176 is a fatty acid modified peptide with dual GIP and GLP-1 receptor agonist activity designed for once-weekly subcutaneous administration. LY3298176 was characterised in vitro, using signaling and functional assays in cell lines expressing recombinant or endogenous incretin receptors, and in vivo using body weight, food intake, insulin secretion and glycemic profiles in mice. A Phase 1, randomised, placebo-controlled, double-blind study was comprised of three parts: a single-ascending dose (SAD; doses 0.25-8 mg) and 4-week multiple ascending dose (MAD; doses 0.5-10 mg) studies in healthy subjects (HS), followed by a 4-week multiple-dose Phase 1 b proof-of-concept (POC; doses 0.5-15 mg) in patients with T2DM (ClinicalTrials.gov no. NCT02759107). Doses higher than 5 mg were attained by titration, dulaglutide (DU) was used as a positive control. The primary objective was to investigate safety and tolerability of LY3298176. RESULTS: LY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist. A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25-15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean [LSM] difference [95% CI]: -49.12 mg/dL [-78.14, -20.12] and -43.15 mg/dL [-73.06, -13.21], respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference [95% CI]: -1.75 kg [-3.38, -0.12], -5.09 kg [-6.72, -3.46] and -4.61 kg [-6.21, 3.01], respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference [95% CI]: -2.62 kg [-3.79, -1.45] and -2.07 kg [-3.25, 0.88], respectively. The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity. CONCLUSIONS: Based on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity. PMID- 30473098 TI - TRPV1 neurons regulate beta-cell function in a sex-dependent manner. AB - : There is emerging evidence to support an important role for the transient receptor potential vanilloid type 1 (TRPV1) sensory innervation in glucose homeostasis. However, it remains unknown whether the glucoregulatory action of these afferent neurons is sex-biased and whether it is pancreatic beta-cell mediated. OBJECTIVE: We investigated in male and female mice whether denervation of whole-body or pancreas-projecting TRPV1 sensory neurons regulates adult functional beta-cell mass and alters systemic glucose homeostasis. METHODS: We used a combination of pharmacological and surgical approaches to ablate whole body or pancreatic TRPV1 sensory neurons and assessed islet beta-cell function and mass, aspects of glucose and insulin homeostasis, and energy expenditure. RESULTS: Capsaicin-induced chemodenervation of whole-body TRPV1 sensory neurons improved glucose clearance and enhanced glucose-stimulated insulin secretion without alterations in beta-cell proliferation and mass, systemic insulin sensitivity, body composition, and energy expenditure. Similarly, denervation of intrapancreatic TRPV1 afferents by pancreas intraductal injection of capsaicin or surgical removal of the dorsal root ganglia projecting into the pancreas lowered post-absorptive glucose levels and increased insulin release upon glucose stimulation. The beneficial effects of TRPV1 sensory denervation on glucose tolerance and beta-cell function were observed in male but not female mice. CONCLUSION: Collectively, these findings suggest that TRPV1 neurons regulate glucose homeostasis, at least partly, through direct modulation of glucose induced insulin secretion and that this regulation operates in a sex-dependent manner. PMID- 30473099 TI - ? PMID- 30473100 TI - ? PMID- 30473101 TI - [History and current challenges of paediatric psychiatry in maternity units]. AB - The legal framework of mother-baby care has evolved over the last thirty years driven by innovative programmes put in place by hospital health professionals. Liaison in perinatal care lies at the crossroads of different temporalities and treatment objectives, and requires constant dialogue between the liaison caregivers and those in maternity. The aim is to form a holding environment facilitating the establishment of an adapted response to the complexity of the clinical situations encountered. PMID- 30473102 TI - [State of play of teenage pregnancies]. AB - Teenage pregnancy represents a global risk. In France, in 2016, 1.14% of pregnancies concerned 15-17 year olds. Rare in our societies, they are socially condemned. A medical-psychological-sociological literature review shows that, beyond the contraceptive failure or the accidental nature evoked, it is essential to spot high risk situations and focus on the meaning behind these teenage pregnancies. PMID- 30473103 TI - [Caregivers' feelings and practices faced with teenage pregnancies]. AB - Teenage pregnancy does not comply with social norms; perceived as a failure, it poses a challenge. How do caregivers support these young girls? Confronted with a variety of situations, they are particularly vigilant with regard to their representations and to literature data. At the same time, practices are based on a transferential relationship similar to a parent-child relationship. The care of a pregnant teenager requires specific adjustments. PMID- 30473104 TI - [Pregnancies with somatic, psychiatric and social entanglements: a complex clinical presentation]. AB - The mother-infant programme of Delafontaine hospital in Saint-Denis operates in a territory characterised by psychosocial deprivation and multiculturalism. The account of the immediate post-partum care of a patient with epilepsy having given birth to twins illustrates the possible unease of the healthcare manager and the need for coordination between the hospital and community teams to offer the mother and infant optimal safety and wellbeing. PMID- 30473105 TI - [Identifying and treating autism spectrum disorders in perinatal care]. AB - Severe forms of autism may be spotted by families in the first year of life, but are still rarely treated before the age of 3. Screening and early treatment are recommended to improve the children's functional prognosis. However, there is still little knowledge among perinatal and early childhood professionals of the symptomatology of autistic disorders. Several points are sensitive: during the first year the symptoms of children at risk are non-specific apart from a lack of desire to form relationships; and the early treatment probably modifies the clinical picture of young patients. Screening tools are rare but are starting to be developed. PMID- 30473106 TI - ? PMID- 30473107 TI - ? PMID- 30473108 TI - Enantioseparation and sensitive analysis of ofloxacin by poly(3,4 dihydroxyphenylalanine) functionalized magnetic nanoparticles-based solid phase extraction in combination with on-line concentration capillary electrophoresis. AB - Chiral separation of low concentrations of pharmaceuticals in biofluids is a challenge task. In this study, a method is developed to enantioseparate trace amount of racemic ofloxacin in urine and bovine blood by combining magnetic solid phase extraction (MSPE) and chiral capillary electrophoresis (CE). Poly(3,4 dihydroxyphenylalanine) modified magnetic nanoparticles (polyDOPA-MNPs) are prepared and used as the adsorbents in MSPE to extract ofloxacin. The polyDOPA MNPs are spherical, about 130 nm in diameter and the polyDOPA shell is about 3 nm. The extraction process of polyDOPA-MNPs for ofloxacin includes 2 min adsorption and 2 min desorption with the assistance of sonication. Under the optimized MSPE conditions (3 mg polyDOPA-MNPs as adsorbents, sample pH 7.0, 75% (v/v) AcOH in methanol as eluent, adsorption time 2 min, desorption time 2 min), the extraction efficiency of ofloxacin is 95%. In chiral CE, pressure-assisted field-enhanced sample injection (PA-FESI) is developed to improve the detection sensitivity of ofloxacin enantiomers. The MSPE/PA-FESI chiral CE method demonstrates a good linearity in the concentration range of 0.01-0.06 MUg/mL, with a detection limit as low as 0.29 ng/mL. The feasibility of the method is verified by the successful determination of trace amounts of ofloxacin enantiomers in spiked urine and bovine blood samples. PMID- 30473109 TI - Simultaneously targeted and untargeted multicomponent characterization of Erzhi Pill by offline two-dimensional liquid chromatography/quadrupole-Orbitrap mass spectrometry. AB - Large-scale targeted and untargeted metabolites characterization can be achieved by feat of different liquid chromatography/mass spectrometry (LC-MS) platforms by multiple MS experiments or using data-independent acquisition followed by precursor-product ions matching based on certain algorithms. The resulting insufficiency in efficiency and availability greatly restricts the applicability of these strategies in large-scale profiling and identification of various metabolites. A strategy simultaneously enabling both the targeted and untargeted metabolites characterization is established on a Q Exactive hybrid quadrupole Orbitrap mass spectrometer, by integrating precursor ions list-triggered data dependent MS2 acquisition (PIL/dd-MS2) of the targeted components and using the "If idle-pick others" (IIPO) function to induce untargeted metabolites fragmentation. A compounds-specific mass defect filter (MDF) algorithm is proposed as a method to generate the PIL. As a proof of concept, this strategy coupled with offline two-dimensional liquid chromatography (2D-LC) was applied to identify the multicomponents of a traditional Chinese medicine formula Erzhi Pill (EZP). A rigid MDF vehicle was elaborated by orthogonal screening of the integer mass and integer mass-dependent dynamic mass defects considering a variation of 20 ppm. The Full MS/dd-MS2 method enabling PIL and IIPO exhibited better performance than Full MS/dd-MS2 and Targeted SIM/dd-MS2 (selected ion monitoring) in respect of the sensitivity in identifying the targeted components and the ability to characterize more untargeted ones. As a consequence, 270 components were separated from EZP, and 146 thereof were selectively characterized. In conclusion, it is a practical, multifaced strategy facilitating the in-depth metabolites profiling and characterization of complex herbal and biological samples. PMID- 30473110 TI - Comprehensive two-dimensional gas chromatography and time-of-flight mass spectrometry detection with a 50 ms modulation period. AB - An ultrafast flow modulation period, PM of 50 ms, for comprehensive two dimensional (2D) gas chromatography (GC * GC) with time-of-flight mass spectrometry (TOFMS) detection is demonstrated, producing narrow peak widths, 2W (4sigma width-at-base on the 2D dimension), demonstrating the potential for ultrafast (2D) separations with high peak capacity. The modulator is a pulse flow valve that injects a narrow pulse of carrier gas at a user defined PM, at the union between the 1D and 2D columns. The raw data produced combines the properties of vacancy chromatography and frontal analysis. Deconvolution of the raw data using unconstrained multivariate curve resolution alternating least squares (MCR-ALS) analysis facilitates identification and quantification for overlapped analyte peaks. The peak profile loadings obtained from MCR-ALS are converted into traditional appearing GC * GC data through a process commonly used with frontal analysis. An 18-component test mixture at seven different injected mass levels was studied. The 2D peaks generated ranged from an 2W of 16 to 36 ms with an average of 26 ms. At an on-column injected mass of 14 ng per analyte, an average mass spectral match value, MV, of 822 was achieved using in-house collected spectra for comparison, with an average match value RSD of 7.1%. Calibration of overlapped test analytes was evaluated using the areas of the MCR ALS loadings, with excellent quantification demonstrated. The advancement demonstrated in modulation performance for GC * GC represents a significant decrease in PM as most commercial modulators have a minimum PM of 1 s, while maintaining the benefits of a duty cycle of essentially 1.0, which promises to enable new chemical analyzer designs, compatible with the vacuum requirements of the TOFMS detector. PMID- 30473111 TI - Selection of egg peptide biomarkers in processed food products by high resolution mass spectrometry. AB - Food allergy is a growing health problem worldwide; thus, there is an urgent need for robust, specific, and sensitive analytical methods for detecting allergens. Mass spectrometry is an alternative to the existing methods, and it can overcome their limitations. One of the first steps in the development of any analytical method is the identification of the analytes to be further studied. In the case of allergen detection by mass spectrometry, the analytes are peptides. In this study, a strategy was developed for identifying potential peptide biomarkers in processed food products. This strategy was applied to processed egg matrices, and 16 potential peptide biomarkers were identified for the further detection and quantification of egg by means of mass spectrometry. With an empirical approach based on dedicated sample preparation, including tandem Lys-C/trypsin enzymatic digestion and high-resolution mass spectrometry analysis, hundreds of peptides from egg proteins were identified. This list of peptides was further refined with a series of criteria, obtained from empirical evidence, to identify the ideal biomarkers for the development of a quantitative method. These criteria include the resistance to food processing and the specificity of the peptides for eggs but also the effects of amino acid modifications and enzymatic digestion efficiency. PMID- 30473112 TI - Semi-quantitative determination of co-eluting impurities in oligonucleotide drugs using ion-pair reversed-phase liquid chromatography mass spectrometry. AB - Continued improvements in understanding RNA biology have led to significant success in the development of antisense oligonucleotide therapeutics, and several oligonucleotide drugs have now been approved. Manufacturing of oligonucleotides may be associated with the production of impurities. Current methods for quantification of impurities that co-elute with the main drug component rely on manual ion extraction and integration of the characteristic mass signal of each impurity. For certain applications however, especially those involving large sets of samples such as those generated in the optimization of oligonucleotide manufacturing processes, a rapid method that provides semi-quantitative determination of impurity levels would be sufficient. In this work, an automated approach has been developed to rapidly determine the relative amounts of co eluting impurities in oligonucleotide samples. The most abundant mass in the isotopic distribution is automatically calculated from the impurity formula and used to detect the presence of the impurities. The principles of the approach are described, and representative examples are given. Impurities determined in different manufacturing lots are compared directly, and by principal component analysis. The ability of the method to determine impurity levels across large sample sets is illustrated for an oligonucleotide drug purification study. PMID- 30473113 TI - Study Designs and the Use of the Canadian Task Force Classification. PMID- 30473114 TI - Modeles d'etude et recours a la classification du Groupe d'etude canadien. PMID- 30473115 TI - Excerpts from the World Medical Literature. PMID- 30473116 TI - Extraits De La Litterature Medicale Mondiale. PMID- 30473117 TI - Preoperative Anemia as a Prognostic Factor in Endometrioid-Type Endometrial Carcinoma. AB - OBJECTIVE: This study sought to determine the frequency of preoperative anemia (hemoglobin level <12 g/dL) and its prognostic significance for clinicopathological factors and survival outcomes in Saudi patients with endometrioid-type endometrial carcinoma (EC). METHODS: A retrospective cross sectional study was conducted at King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. A total of 148 patients who underwent staging surgery for primary EC were retrospectively analyzed for perioperative details regarding clinicopathological factors and survival. RESULTS: The frequency of preoperative anemia was 27.7% (n = 41). Patients with advanced FIGO disease (stages III-IV), unfavourable endometrioid tumour grade II-III, >=50% myometrial invasion, positive lymphovascular space invasion, and tumour recurrence had statistically significant lower mean preoperative hemoglobin levels (two-tailed Mann-Whitney U test; P < 0.05). Patients with preoperative anemia had statistically significant higher rates of advanced FIGO stage III-IV (P = 0.0000), unfavourable grades II-III endometrioid histology (P = 0.0005), >=50% myometrial invasion (P = 0.0016), positive lymphovascular space invasion (P = 0.0019), and tumour recurrence (P = 0.0064) than patients without preoperative anemia (two-tailed chi-square test). In a univariate analysis, patients with preoperative anemia had statistically lower significant mean 5-year disease-free survival (DFS) and overall survival (OS) rates than patients without preoperative anemia (log-rank test; P < 0.0001 and P < 0.0003, respectively). In a multivariate analysis, preoperative anemia was shown to be an independent prognostic factor for 5-year DFS (P = 0.0303), but not OS (P = 0.2588). CONCLUSION: In patients with endometrioid-type EC, the preoperative anemia is fairly common. Moreover, preoperative anemia is correlated with a number of unfavourable clinicopathological factors, as well as poor survival (in terms of DFS and OS) in the univariate analysis. PMID- 30473119 TI - Voices of Postpartum Women: Exploring Canadian Women's Experiences of Inpatient Postpartum Care. AB - OBJECTIVE: To explore and understand postpartum inpatient experiences in a Canadian context. METHODS: Inpatients at BC Women's Hospital & Health Centre were invited to complete a questionnaire during their postpartum stay. Completed responses were obtained from 178 women, representing 44% of all postpartum inpatients during the survey period. RESULTS: Overall, women had positive experiences during their postpartum stay: 93% rated their experience as "excellent" or "very good"; 78% felt that nurses never seemed rushed or too busy to care for them; and 85% of women found the nurses to be very helpful with breastfeeding. Two-thirds of the women had concerns about going home that were related to infant feeding, feeling overwhelmed, and not knowing how to settle their baby. Other areas of improvement pertained to the hospital environment being less restful than desired. Certain groups needed additional support, such as primiparous women, women who had Caesarean deliveries, and women from certain ethnic groups. CONCLUSION: This exploration of women's inpatient postpartum experiences in a Canadian hospital provides valuable information for improving service delivery, including assessing hospital routines, providing information/education, and improving discharge planning. Given that postpartum experiences are not uniform across demographic groups, an alternative or augmented approach to postpartum care may be warranted for some women. PMID- 30473118 TI - Next-Generation Sequencing Using a Cardiac Gene Panel in Prenatally Diagnosed Cardiac Anomalies. AB - OBJECTIVE: Most prenatally identified congenital heart defects (CHDs) are the sole structural anomaly detected; however, there is a subgroup of cases where the specific genetic cause will impact prognosis, including chromosome abnormalities and single-gene causes. Next-generation sequencing of all the protein coding regions in the genome or targeted to genes involved in cardiac development is currently possible in the prenatal period, but there are minimal data on the clinical utility of such an approach. This study assessed the outcome of a CHD gene panel that included single-gene causes of syndromic and non-syndromic CHDs. METHOD: Sixteen cases with a fetal CHD identified on prenatal ultrasound were studied using a 108 CHD gene panel. DNA was extracted from cultured amniocytes. RESULTS: There was no diagnostic pathogenic variant identified in these cases. There was an average of 2.9 reportable variants identified per case and the majority of them were variants of uncertain significance. CONCLUSION: Next generation sequencing has the potential for increased genetic diagnosis for fetal anomalies. However, the large number of variants and the absence of an examinable patient make the interpretation of these variants challenging. PMID- 30473120 TI - Trauma perineal a l'accouchement, intimite, ajustement dyadique et fonction sexuelle de nouveaux couples parentaux. AB - OBJECTIVE: This study focuses on perineal trauma during childbirth and its relationship to postnatal marital and sexual issues as expressed by the sexual function and perceived intimacy of new parent couples in Ontario. METHODS: As part of a retrospective study on perinatal intimate and sexual experiences, 67 Canadian French-speaking couples from Ontario (heterosexual couples with their first child between 6 and 12 months of age) were recruited. They filled out online questionnaires that included questions about the severity of the perineal trauma and validated questionnaires that evaluated perceived sexual intimacy, dyadic adjustment, and sexual function. RESULTS: Mediation analyses based on the actor-partner interdependence model were conducted and revealed that the severity of perineal trauma is linked to the perception of decreased intimacy and to weaker sexual function for the woman. Furthermore, the perception of decreased intimacy and the weak sexual function of the man and the woman are related to a weaker dyadic adjustment for the partners. CONCLUSION: The study emphasizes the importance of supporting women who have experienced perineal trauma due to childbirth, as well as their partners. PMID- 30473121 TI - Gestational Diabetes: Glycemic Control in the Last Two Weeks Before Delivery Contributes to Newborn Insulinemia. AB - INTRODUCTION: Fetal hyperinsulinemia in gestational diabetes mellitus (GDM) not only is important during intrauterine life, a time when it can result in macrosomia, but also at delivery, since it can result in neonatal hypoglycemia and hyperbilirubinemia. The question is, how long before delivery does maternal glycemic control contribute to newborn insulinemia in GDM? METHODS: In 72 women with GDM, we calculated Spearman's rank (rs) correlations between umbilical cord blood C-peptide at birth (a biomarker of insulin secretion), and both maternal glycosylated hemoglobin (HbA1c) and mean blood glucose (MBG) recorded in the last two visits prior to delivery. Iterative correlations were done between umbilical cord blood C-peptide at birth, and maternal glucose control, at 0, 1, 2, 3, 4, and 5 weeks before delivery. RESULTS: At an early visit (32.95 +/- 1.8 weeks), rs = 0.353 (P = 0.07) between HbA1c and C-peptide, whereas rs = 0.244 (P = 0.186) between MBG and C-peptide. At the latest visit (35.04 +/- 1.6 weeks), rs = 0.456 (P = 0.004) between HbA1c versus C-peptide, and rs = 0.359 (P = 0.023) between MBG versus C-peptide. Iterative correlations between MBG and C-peptide became significant at 2 weeks before delivery. CONCLUSION: To further reduce the risk of hypoglycemia and hyperbilirubinemia in infants born to women with GDM, besides applying a strict in-patient glucose control protocol at delivery, it is necessary to improve even more the quality of maternal glucose control during the last 2 weeks prior to delivery. PMID- 30473122 TI - Understanding the Experiences of Obstetrics and Gynaecology Residents Who Take Parental Leave During Training in Canada: A Needs Assessment. AB - OBJECTIVE: This study sought to identify and understand the barriers and supports associated with taking parental leave during obstetrics and gynaecology residency training in Canada, with the aim of helping to direct parental leave policies. METHODS: Participants were recruited by social media, program directors, and through the SOGC. The study included a short demographic questionnaire and a semistructured qualitative interview in person, by either telephone or videoconference. The interviews were recorded, transcribed, and anonymized. Descriptive thematic analysis using the constant comparative method of grounded theory was performed on each transcript by two independent investigators. Codes were applied to each sentence of the transcript to identify the main idea in the text segment. Once coding was complete the investigators looked for relationships among codes to define themes. Data collection continued until a saturation of themes was reached. RESULTS: Fifteen participants from across Canada completed the study. The most significant challenges surrounding parental leave during residency included breastfeeding, difficulty on return to work (skill loss, time management, examination preparation), and work-life balance. The major supports noted included family, colleagues and mentors, adequate childcare, and program flexibility surrounding the leave. Participants' suggestions for alleviating the stressors included a gradual return to work and careful planning surrounding returning rotation. CONCLUSION: Trainees identified formal program supports, non surgical or core initial rotation back, and a gradual return to work as important areas to address in policies surrounding resident parental leave during Canadian obstetrics and gynaecology training. PMID- 30473123 TI - Characteristics and Outcomes of Adolescent Births in Nova Scotia: A Retrospective Cohort Study. AB - OBJECTIVE: This study sought to examine the maternal characteristics and outcomes of adolescent births in Nova Scotia. METHODS: The investigators conducted a retrospective population-based cohort study using the Nova Scotia Atlee Perinatal Database. Maternal characteristics and maternal and neonatal outcomes of singleton live births between 2006 and 2015 were compared between adolescent (aged 12 to 19) and adult (aged 20 to 35) women. Associations were examined using log-binomial regression models. RESULTS: Of the 35 111 births that occurred during the study period, 11% were to adolescent mothers. Compared with adult women, adolescents had higher rates of smoking and substance abuse and were of lower socioeconomic status. Adolescent mothers were more than twice as likely as women aged 20 to 35 to smoke during pregnancy. Adolescent women were significantly less likely to have gestational diabetes, need induction of labour, have an assisted vaginal delivery, require a Caesarean section, have a large-for gestational age infant, or breastfeed at discharge compared with the 20 to 35 age group. Birth of a small-for-gestational age infant and other adverse neonatal outcomes were more frequently seen in adolescents compared with adult women in the unadjusted models, but this difference vanished in models adjusted for sociodemographic factors and smoking. CONCLUSION: This study highlights disparities in socioeconomic characteristics and health behaviours between births in adolescent and adult mothers and suggests that a targeted multidisciplinary approach would be valuable for the pregnant adolescent. The role of antenatal support for pregnant adolescents is reinforced because sociodemographic factors and smoking accounted for differences in neonatal outcomes relative to adult women. PMID- 30473124 TI - Case Report of a Tubo-ovarian Abscess Caused by Candida kefyr. AB - BACKGROUND: Candida species are harmless commensals of hosts, including humans, but they can cause infection when the immune system is compromised. Infections with non-albicans species can occur, ranging from urinary tract infections to sepsis, especially among patients in intensive care units. CASE: The patient, a 37-year-old woman, presented with severe abdominal pain, fever, and vomiting. The patient's symptoms and fever continued in spite of treatment with antibiotics, and she underwent exploratory laparotomy. Cyst content culture results showed that Candida kefyr was present in the cyst. CONCLUSION: To the best of our knowledge, this is the first case report of a tubo-ovarian abscess caused by C. kefyr. Rare pathogens can be found in patients with a tubo-ovarian abscess, so culture of the abscess material is important for determining subsequent treatment, particularly in women who require an operation for tubo-ovarian abscess. PMID- 30473125 TI - No. 366-Gynaecologic Management of Hereditary Breast and Ovarian Cancer. AB - OBJECTIVE: This Committee Opinion outlines the gynaecologic management recommendations for women diagnosed with hereditary breast and ovarian cancer syndrome (HBOC) with respect to screening, contraception, chemoprophylaxis, fertility considerations, risk-reducing surgery, and post-oophorectomy care. INTENDED USERS: This Committee Opinion is designed for gynaecologic oncologists, general gynaecologists, family physicians, genetic counsellors, registered nurses, nurse practitioners, residents, and health care providers. TARGET POPULATION: Adult women (18 years and older) with a pathogenic germline variant in the BRCA1, BRCA2, and other ovarian cancer-associated genes. EVIDENCE: While reviewing evidence, databases searched include Medline, Cochrane, and PubMed. Medical Subject Heading search terms used include BRCA AND gynaecology management, hormone replacement therapy, risk reduction, chemoprophylaxis, fertility from 01/2010 and 10/2017. Literature search was begun 07/2017 and finalized 10/2017. In total 183 studies were identified, and 101 were used. VALIDATION METHODS: The content and recommendations were drafted and agreed upon by the principal authors. The Board of the Society of Obstetricians and Gynaecologists of Canada approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology framework (Table 1). The interpretation of strong and conditional (weak) recommendations is described in Table 2. The Summary of Findings is available upon request. BENEFITS, HARMS, AND COSTS: We may expect a risk reduction of up to 90% in women predisposed to HBOC who undergo risk-reducing bilateral salpingo-oophorectomy. The harms of iatrogenic premature menopause are offset by the benefits of risk reduction. By minimizing potential tubal/ovarian/peritoneal cancers, we can expect savings to the health care system. GUIDELINE UPDATE: Evidence will be reviewed 5 years after publication to decide whether all or part of the opinion should be updated. However, if important new evidence is published prior to the 5-year cycle, the review process may be accelerated for a more rapid update of some recommendations. SPONSORS: This guideline was developed with resources funded by the Society of Obstetricians and Gynaecologists of Canada. RECOMMENDATIONS: PMID- 30473126 TI - No 366 - Prise en charge gynecologique du cancer du sein et de l'ovaire hereditaire. AB - OBJECTIF: La presente opinion de comite enumere les recommandations pour la prise en charge gynecologique des femmes ayant recu un diagnostic de syndrome du cancer du sein et de l'ovaire hereditaire (CSOH) en ce qui a trait au depistage, a la contraception, a la chimioprophylaxie, aux facteurs a considerer pour la fertilite, a la chirurgie de reduction du risque et aux soins post-ovariectomie. UTILISATEURS CIBLES: La presente opinion de comite s'adresse aux gynecologues oncologues, aux gynecologues generalistes, aux medecins de famille, aux conseillers en genetique, aux infirmieres autorisees, infirmieres praticiennes, aux residents et aux autres fournisseurs de soins. POPULATION CIBLE: Les femmes adultes (18 ans et plus) presentant une mutation des genes BRCA1 ou BRCA2 ou d'autres genes associes au cancer de l'ovaire. DONNeES: Pour la revue de la litterature, les bases de donnees Medline, Cochrane et PubMed ont entre autres ete interrogees. Les termes de recherche des Medical Subject Headings utilises ont ete BRCA ET gynaecology management [prise en charge gynecologique], hormone replacement therapy [hormonotherapie substitutive], risk reduction [reduction des risques], chemoprophylaxis [chimioprophylaxie] et fertility [fertilite], et les recherches ont cible les articles publies entre janvier 2010 et octobre 2017. La recherche de publications s'est deroulee de juillet a octobre 2017. Au total, 183 etudes ont ete selectionnees, et 101 ont ete utilisees. VALEURS: Le contenu et les recommandations ont ete rediges et acceptes par les auteurs principaux. Le Conseil d'administration de la Societe des obstetriciens et gynecologues du Canada a approuve la version finale avant publication. La qualite des donnees probantes a ete evaluee au moyen des criteres de l'approche GRADE (Grading of Recommendations Assessment, Development and Evaluation) [tableau 1]. L'interpretation des recommandations fortes et conditionnelles (faibles) est decrite dans le tableau 2. Le resume des conclusions peut etre fourni sur demande. AVANTAGES DeSAVANTAGES, ET COuTS: Nous pouvons nous attendre a une diminution des risques allant jusqu'a 90 % chez les femmes predisposees au CSOH qui subissent une salpingo-ovariectomie bilaterale de reduction du risque. Les mefaits associes a la menopause precoce iatrogene sont compenses par les avantages decoulant de la reduction du risque. En reduisant l'occurrence de cancers des trompes, de l'ovaire et du peritoine, nous pouvons nous attendre a des economies dans le systeme de sante. MIS a JOUR: Une revue des donnees probantes sera menee cinq ans apres la publication de la presente opinion afin de determiner si une mise a jour complete ou partielle s'impose. Cependant, si de nouvelles donnees probantes importantes sont publiees avant la fin du cycle de cinq ans, le processus pourrait etre accelere afin que certaines recommandations soient mises a jour rapidement. COMMANDITAIRE: Cette directive clinique a ete elaboree a l'aide de ressources financees par la Societe des obstetriciens et gynecologues du Canada. PMID- 30473127 TI - No. 164-Consensus Guidelines for the Management of Chronic Pelvic Pain. AB - OBJECTIVE: To improve the understanding of chronic pelvic pain (CPP) and to provide evidence-based guidelines of value to primary care health professionals, general obstetricians and gynaecologists, and those who specialize in chronic pain. BURDEN OF SUFFERING: CPP is a common, debilitating condition affecting women. It accounts for substantial personal suffering and health care expenditure for interventions, including multiple consultations and medical and surgical therapies. Because the underlying pathophysiology of this complex condition is poorly understood, these treatments have met with variable success rates. OUTCOMES: Effectiveness of diagnostic and therapeutic options, including assessment of myofascial dysfunction, multidisciplinary care, a rehabilitation model that emphasizes achieving higher function with some pain rather than a cure, and appropriate use of opiates for the chronic pain state. EVIDENCE: Medline and the Cochrane Database from 1982 to 2004 were searched for articles in English on subjects related to CPP, including acute care management, myofascial dysfunction, and medical and surgical therapeutic options. The committee reviewed the literature and available data from a needs assessment of subjects with CPP, using a consensus approach to develop recommendations. VALUES: The quality of the evidence was rated using the criteria described in the Report of the Canadian Task Force on the Periodic Health Examination. Recommendations for practice were ranked according to the method described in that report (Table 1). RECOMMENDATIONS: The recommendations are directed to the following areas: (a) an understanding of the needs of women with CPP; (b) general clinical assessment; (c) practical assessment of pain levels; (d) myofascial pain; (e) medications and surgical procedures; (d) principles of opiate management; (f) increased use of magnetic resonance imaging (MRI); (g) documentation of the surgically observed extent of disease; (h) alternative therapies; (i) access to multidisciplinary care models that have components of physical therapy (such as exercise and posture) and psychology (such as cognitive-behavioural therapy), along with other medical disciplines, such as gynaecology and anesthesia; G) increased attention to CPP in the training of health care professionals; and (k) increased attention to CPP in formal, high-calibre research. The committee recommends that provincial ministries of health pursue the creation of multidisciplinary teams to manage the condition. PMID- 30473128 TI - No 164 - Directive clinique de consensus pour la prise en charge de la douleur pelvienne chronique. AB - OBJECTIF: Ameliorer La comprehension de la douleur pelvienne chronique (DPC) et fournir des directives cliniques factuelles qui beneficieront aux fournisseurs de soins de sante primaires, aux obstetriciens-gynecologues et aux specialistes de la douleur chronique. FARDEAU DE LA SOUFFRANCE: La DPC est une pathologie debilitante courante qui affecte les femmes. Elle est a l'origine d'importantes souffrances personnelles et de depenses de sante considerables associees aux interventions, dont de multiples consultations et un grand nombre de traitements medicaux et chirurgicaux. Puisque la pathophysiologie sous-jacente de cet etat pathologique complexe est mal comprise, ces traitements n'ont obtenu que des taux de reussite variables. ISSUES: Efficacite des options diagnostiques et therapeutiques (y compris l'evaluation du dysfonctionnement myofascial); soins multidisciplinaires; un modele de readaptation mettant l'accent sur l'obtention d'un fonctionnement superieur malgre la presence d'une certaine douleur (plutot que de chercher a obtenir une guerison totale); et utilisation appropriee des opiaces pour le soulagement de la douleur chronique. PREUVES: Des recherches ont ete menees dans Medline et la base de donnees Cochrane en vue d'en tirer les articles de langue anglaise, publies entre 1982 et 2004, portant sur des sujets lies a la DPC, dont la gestion des soins actifs, le dysfonctionnement myofascial et les options therapeutiques medicales et chirurgicales. Les membres du comite ont analyse la litterature pertinente, ainsi que les donnees disponibles tirees d'une evaluation des besoins des personnes presentant une DPC; ils ont fait appel a une approche de consensus pour l'elaboration des recommandations. VALEURS: La qualite des resultats a ete evaluee au moyen des criteres decrits dans le rapport du Groupe d'etude canadien sur l'examen medical periodique. Les recommandations visant la pratique ont ete classees conformement a la methode decrite dans ce rapport (Tableau 1). RECOMMANDATIONS: Les recommandations visent ce qui suit : (a) comprehension des besoins des femmes presentant une DPC ; (b) evaluation clinique generale ; (c) evaluation pratique des niveaux de douleur ; (d) douleur myofasciale ; (e) medicaments et interventions chirurgicales ; (f) principes de la gestion des opiaces; (g) utilisation accrue de l'imagerie par resonance magnetique (IRM) ; (h) documentation de l'etendue de La maladie constatee au moyen de la chirurgie ; (i) therapies non conventionnelles; (j) acces a des modeles de soins multidisciplinaires faisant appel a des composantes de physiotherapie (comme l'exercice et la posture) et de psychologie (comme La therapie cognitivo- comportementale), conjointement avec d'autres disciplines medicales, telles que La gynecologie et l'anesthesie ; (k) attention accrue portee a La DPC dans La formation des professionnels de La sante ; et (l) attention accrue portee a la DPC dans le domaine des recherches officielles et de haut calibre. Le comite recommande que les ministeres provinciaux de La Sante prennent des mesures en faveur de la creation d'equipes multidisciplinaires pouvant assurer La prise en charge de cette pathologie. Chapitre 2 : Portee et definition de La douleur pelvienne chronique Chapitre 3 : Anamnese, examen physique et evaluation psychologique Chapitre 4 : Explorations Chapitre 5 : Sources de douleur pelvienne chronique Chapitre 6 : Causes urologiques et gastro intestinales de La douleur pelvienne chronique Chapitre 7 : Dysfonctionnement myofasclal Chapitre 8 : Therapie medicale - resultats en matiere d'efficacite Chapitre 9 : Chirurgie - resultats en matiere d'efficacite Chapitre 11 : Prise en charge multidisciplinaire de La douleur chronique Chapitre 14 : Orientations futures. PMID- 30473129 TI - The neuromoral theory of antisocial, violent, and psychopathic behavior. AB - The neuromoral theory of antisocial behaviors argues that impairment to the neural circuitry underlying morality provides a common foundation for antisocial, violent, and psychopathic behavior in children, adolescents, and adults. This article reviews new findings in two research fields since this theory was first proposed: brain mechanisms underlying moral decision-making, and brain systems subserving antisocial behaviors. The neuromoral theory is updated to take into account new empirical findings. Key areas implicated in both moral decision making and the spectrum of antisocial behaviors include fronto-polar, medial, and ventral prefrontal cortical regions, and the anterior cingulate, amygdala, superior temporal gyrus, and angular gyrus / temporoparietal junction. It is hypothesized that different manifestations of antisocial behavior are characterized by differing degrees of neuromoral dysfunction, with primary psychopathy, proactive aggression, and life-course persistent offending being more affected, and secondary psychopathy, reactive aggression, and crimes involving drugs relatively less affected by neuromoral dysfunction. Limitations of the current model, social contextual factors, neural remediation interventions, ascertaining whether the affective or cognitive component of empathy is most implicated, and directions for future research are outlined. One forensic implication of the model is that significant impairment to the neuromoral circuit could constitute diminished criminal responsibility. PMID- 30473130 TI - Managing Toxicity of Intravesical Therapy. AB - Intravesical therapies have shown positive effects both on recurrence and progression of non-muscle-invasive bladder cancer. However, more than 50% of patients experience untoward side effects associated with treatment. In order to reduce the rate of patients who discontinue treatment due to side effects, prevention and effective management of treatment-related toxicity is essential. PMID- 30473131 TI - Tonotopy in calcium homeostasis and vulnerability of cochlear hair cells. AB - Ototoxicity, noise overstimulation, or aging, can all produce hearing loss with similar properties, in which outer hair cells (OHCs), principally those at the high-frequency base of the cochlea, are preferentially affected. We suggest that the differential vulnerability may partly arise from differences in Ca2+ balance among cochlear locations. Homeostasis is determined by three factors: Ca2+ influx mainly via mechanotransducer (MET) channels; buffering by calcium-binding proteins and organelles like mitochondria; and extrusion by the plasma membrane CaATPase pump. We review quantification of these parameters and use our experimentally-determined values to model changes in cytoplasmic and mitochondrial Ca2+ during Ca2+ influx through the MET channels. We suggest that, in OHCs, there are two distinct micro-compartments for Ca2+ handling, one in the hair bundle and the other in the cell soma. One conclusion of the modeling is that there is a tonotopic gradient in the ability of OHCs to handle the Ca2+ load, which correlates with their vulnerability to environmental challenges. High frequency basal OHCs are the most susceptible because they have much larger MET currents and have smaller dimensions than low-frequency apical OHCs. PMID- 30473133 TI - Fractures and bone health monitoring in boys with Duchenne muscular dystrophy managed within the Scottish Muscle Network. AB - There are limited reports of radiologically confirmed fractures and bone health monitoring in with Duchenne muscular dystrophy. We performed a retrospective study of 91 boys, with a median age of 11.0 years, who are currently managed in Scotland with the aim to assess the frequency of radiologically confirmed fractures and report on bone health monitoring in relation to International Care Consensus Guidance. Of these boys, 59 (65%) were receiving glucocorticoid (GC) therapy and 23 (25%) had received previous treatment. Of those currently on GC, 37 (63%) had an assessment of bone mineral density and none had routine imaging for vertebral fractures during the study period. Of the 91 boys, 44 (48%) had sustained at least one symptomatic radiographically confirmed fracture. The probability of sustaining a first symptomatic fracture was 50% by 12.8 years old (95%CI: 12.1, 13.6). The most common sites for non-vertebral fracture were the femur and tibia. In this review of boys with DMD, almost half had sustained at least one radiologically confirmed symptomatic fracture. There is a need for standardized bone health monitoring in DMD that includes routine imaging of the spine to identify vertebral fractures, given the persistence of insult to the skeleton in these boys. PMID- 30473134 TI - Vertical displacement of the centre of mass during walking in people with diabetes and diabetic neuropathy does not explain their higher metabolic cost of walking. AB - People with diabetes display biomechanical gait alterations compared to controls and have a higher metabolic cost of walking (CoW), but it remains unknown whether differences in the vertical displacement of the body centre of mass (CoM) may play a role in this higher CoW. The aim of this study was to investigate vertical CoM displacement (and step length as a potential underpinning factor) as an explanatory factor in the previously observed increased CoW with diabetes. Thirty one non-diabetic controls (Ctrl); 22 diabetic patients without peripheral neuropathy (DM) and 14 patients with moderate/severe Diabetic Peripheral Neuropathy (DPN), underwent gait analysis using a motion analysis system and force plates while walking at a range of matched speeds between 0.6 and 1.6 m/s. Vertical displacement of the CoM was measured over the gait cycle, and was not different in either diabetes patients with or without diabetic peripheral neuropathy compared to controls across the range of matched walking speeds examined (at 1 m/s: Ctrl: 5.59 (SD: 1.6), DM: 5.41 (1.63), DPN: 4.91 (1.66) cm; p > 0.05). The DPN group displayed significantly shorter steps (at 1 m/s: Ctrl: 69, DM: 67, DPN: 64 cm; p > 0.05) and higher cadence (at 1 m/s: Ctrl: 117 (SD1.12), DM: 119 (1.08), DPN: 122 (1.25) steps per minute; p > 0.05) across all walking speeds compared to controls. The vertical CoM displacement is therefore unlikely to be a factor in itself that contributes towards the higher CoW observed recently in people with diabetic neuropathy. The higher CoW in patients with diabetes may not be explained by the CoM displacement, but rather may be more related to shorter step lengths, increased cadence and the associated increased internal work and higher muscle forces developed by walking with more flexed joints. PMID- 30473135 TI - Assessing non-uniform stiffening of the achilles tendon noninvasively using surface wave. AB - Currently, noninvasive cost-effective techniques capable of quantifying non uniform degradation of tendon's mechanical and structural properties associated with localized tendon injuries are not readily available. This study demonstrates the applicability of a simple surface-wave elastography (SURF-E) method for assessing the stiffness of the Achilles Tendon by measuring the propagation velocity of surface waves along the tendon in a much broader range of values than currently available Ultrasound-based or MRI-based elastography methods do. Results from this study confirm the non-uniform stiffening of the AT during passive ankle dorsiflexions. PMID- 30473136 TI - Mechanics of linear microcracking in trabecular bone. AB - Microcracking in trabecular bone is responsible both for the mechanical degradation and remodeling of the trabecular bone tissue. Recent results on trabecular bone mechanics have demonstrated that bone tissue microarchitecture, tissue elastic heterogeneity and tissue-level mechanical anisotropy all should be considered to obtain detailed information on the mechanical stress state. The present study investigated the influence of tissue microarchitecture, tissue heterogeneity in elasticity and material separation properties and tissue-level anisotropy on the microcrack formation process. Microscale bone models were executed with the extended finite element method. It was demonstrated that anisotropy and heterogeneity of the bone tissue contribute significantly to bone tissue toughness and the resistance of trabecular bone to microcrack formation. The compressive strain to microcrack initiation was computed to increase by a factor of four from an assumed homogeneous isotropic tissue to an assumed anisotropic heterogenous tissue. PMID- 30473137 TI - Virtual trial to evaluate the robustness of cementless femoral stems to patient and surgical variation. AB - Primary stability is essential for the success of cementless femoral stems. In this study, patient specific finite element (FE) models were used to assess changes in primary stability due to variability in patient anatomy, bone properties and stem alignment for two commonly used cementless femoral stems, Corail(r) and Summit(r) (DePuy Synthes, Warsaw, USA). Computed-tomography images of the femur were obtained for 8 males and 8 females. An automated algorithm was used to determine the stem position and size which minimized the endo-cortical space, and then span the plausible surgical envelope of implant positions constrained by the endo-cortical boundary. A total of 1952 models were generated and ran, each with a unique alignment scenario. Peak hip contact and muscle forces for stair climbing were scaled to the donor's body weight and applied to the model. The primary stability was assessed by comparing the implant micromotion and peri-prosthetic strains to thresholds (150 MUm and 7000 uepsilon, respectively) above which fibrous tissue differentiation and bone damage are expected to prevail. Despite the wide range of implant positions included, FE prediction were mostly below the thresholds (medians: Corail(r): 20-74 um and 1150-2884 uepsilon, Summit(r): 25-111 um and 860-3010 uepsilon), but sensitivity of micromotion and interfacial strains varied across femora, with the majority being sensitive (p < 0.0029) to average bone mineral density, cranio-caudal angle, post-implantation anteversion angle and lateral offset of the femur. The results confirm the relationship between implant position and primary stability was highly dependent on the patient and the stem design used. PMID- 30473132 TI - The changing epidemiology of invasive pneumococcal disease after PCV13 vaccination in a country with intermediate vaccination coverage. AB - BACKGROUND: We studied the impact of 13-valent pneumococcal conjugate vaccine (PCV13) on the incidence of invasive pneumococcal disease (IPD) and serotype distribution in a region with intermediate levels of vaccination (around 64% in children aged <2 years). METHODS: Surveillance data on IPD cases reported by microbiologists participating in the Microbiological Reporting System of Catalonia during 2006-2014 were analysed. We compared estimated incidence rate (IR) ratios for serotypes included in PCV7, PCV10non7, PCV13non10 and non-PCV13 between the PCV7 (2006-2009) and PCV13 periods (2010-2014). IR were corrected for missing serotypes according to year and age groups: <2 years, 2-4 years, 5-64 years and >=65 years. RESULTS: A total of 9338 IPD cases were reported. Overall IPD incidence declined by 26.2% (from 16.4 to 12.1) in the PCV13 period. The largest decrease was observed in children aged 2-4 years (44.5%, from 37.4 to 20.8). Pneumonia fell in all age groups with the largest reduction in children aged 2-4 years (49.3%) and <2 years (42%). PCV13 serotypes decreased significantly in all age groups, from 52% (31.6 to 15.1) in children aged 2-4 years to 35% (22.8 to 14.8) in adults aged >=65 years. Non-PCV13 serotypes rose by 13% (14.8 to 16.8) in people aged >=65 years. CONCLUSIONS: In a region with intermediate vaccination coverage, the introduction of PCV13 has reduced the overall incidence of IPD, mainly due to the decrease in PCV13 serotypes in all age groups, suggesting herd immunity. Non-PCV13 serotypes have increased in adults aged >=65 years, suggesting serotype replacement. Higher PCV13 vaccination coverage in children will further reduce IPD incidence in all age groups. PMID- 30473138 TI - How much trunk control is affected in adults with moderate-to-severe cerebral palsy? AB - Trunk control (TC) impairment is a typical feature in individuals with cerebral palsy (CP), but there are lack of methods that allow to quantify the extent to which static and dynamic TC is impaired in adults with moderate-to-severe CP. Thus, the aims of this study were to analyze the reliability of a posturography protocol to assess TC in adults with CP, and quantify their degree of TC impairment compared to a control sample of adults without CP. Forty-seven adults with moderate-to-severe CP and nineteen control participants were assessed via a protocol of static and dynamic seated trunk tasks, performed on a stable and an unstable surface placed on a force-plate. The mean radial error was the primary variable measured. A large percentage of CP participants successfully completed the static and dynamic conditions on the stable surface (static: 93.6%; dynamic: 91.5-72.3%); however, this percentage decreased considerably on the unstable surface (51.1-34.0%). The posturography protocol displayed good reliability in adults with CP (0.89 <= ICC <= 0.95; 15.2% <= SEM <= 20.7%). Adults with CP displayed significantly decreased TC in 4/5 tasks on the stable seat, particularly in dynamic conditions (1.71 <= dg <= 1.91). Our results confirmed that TC is significantly affected in CP adults compared with controls without CP of similar age, but they present more difficulties to perform dynamic tasks. Thus, it would be recommend including dynamic in addition to static conditions to obtain a comprehensive assessment of TC impairment in adults with moderate-to severe CP. Additional, these results encourage practitioners to design dynamic activities that challenge trunk control for rehabilitations/training programs. PMID- 30473140 TI - Long-term risk of adverse outcomes after acute kidney injury: a systematic review and meta-analysis of cohort studies using consensus definitions of exposure. AB - Reliable estimates of the long-term outcomes of acute kidney injury (AKI) are needed to inform clinical practice and guide allocation of health care resources. This systematic review and meta-analysis aimed to quantify the association between AKI and chronic kidney disease (CKD), end-stage kidney disease (ESKD), and death. Systematic searches were performed through EMBASE, MEDLINE, and grey literature sources to identify cohort studies in hospitalized adults that used standardized definitions for AKI, included a non-exposed comparator, and followed patients for at least 1 year. Risk of bias was assessed by the Newcastle-Ottawa Scale. Random effects meta-analyses were performed to pool risk estimates; subgroup, sensitivity, and meta-regression analyses were used to investigate heterogeneity. Of 4973 citations, 82 studies (comprising 2,017,437 participants) were eligible for inclusion. Common sources of bias included incomplete reporting of outcome data, missing biochemical values, and inadequate adjustment for confounders. Individuals with AKI were at increased risk of new or progressive CKD (HR 2.67, 95% CI 1.99-3.58; 17.76 versus 7.59 cases per 100 person-years), ESKD (HR 4.81, 95% CI 3.04-7.62; 0.47 versus 0.08 cases per 100 person-years), and death (HR 1.80, 95% CI 1.61-2.02; 13.19 versus 7.26 deaths per 100 person years). A gradient of risk across increasing AKI stages was demonstrated for all outcomes. For mortality, the magnitude of risk was also modified by clinical setting, baseline kidney function, diabetes, and coronary heart disease. These findings establish the poor long-term outcomes of AKI while highlighting the importance of injury severity and clinical setting in the estimation of risk. PMID- 30473141 TI - SERAM guide for the renewal and technological update in radiology. AB - The recent financial crisis has led to a substantial reduction in public investment and technological renovation in Spain, resulting in a significant increase in the rate of obsolescence of diagnostic imaging equipment. The Spanish Society of Medical Radiology, aware of the importance of maintaining appropriate technological measures to ensure the quality of health care, has elaborated a document with the aim of analyzing and promulgating the state of diagnostic imaging technology in Spain (depending on the imaging modality, between 32% and 59% of the equipment is more than 10 years old) as well as of establishing criteria and recommendations to guide the management of technology in medical imaging. PMID- 30473142 TI - Characterization of microRNA profile in IgE-mediated mouse BMMCs degranulation. AB - BACKGROUND: Mast cells play a central role in innate and adaptive immunity by releasing pre-formed and de novo synthesized mediators, which include microRNAs. Although miRNAs have been confirmed to function in cell proliferation, differentiation, apoptosis, and the immune response, their functions are still limited in mast cells degranulation. METHODS: Here, we survey miRNA expression profiles in activated mouse bone marrow-derived mast cells (BMMCs) with a miRNA microarray and compare the profiles to those from resting BMMCs. Partial miRNAs were selected for confirmation by qPCR, and let-7i was selected for function discover in mast cell degranulation process. TargetScan Mouse database were used for target genes prediction, gene ontology (GO) were used for gene molecular function classifications, and Cytoscape software were used to construct gene network of degranulation. RESULTS: We found 13 up-regulated miRNAs and 7 down regulated miRNAs in DNP activated BMMCs by miRNA microarray; and let-7b, let-7c, let-7d, let-7f, let-7i, and miR-652 were up-regulated, and miR-296-3p was down regulated in DNP-stimulated BMMCs by qPCR. In the function research, let-7i can inhibit mast cell degranulation by suppress Exco8 expression. Overall, the data indicate that miRNAs participate in mast cell activation, especial for mast cell degranulation process. PMID- 30473139 TI - Safety and cardiovascular efficacy of spironolactone in dialysis-dependent ESRD (SPin-D): a randomized, placebo-controlled, multiple dosage trial. AB - The safety and efficacy of spironolactone is uncertain in end-stage renal disease. We randomized 129 maintenance hemodialysis patients to placebo (n=51) or spironolactone 12.5 mg (n=27), 25 mg (n=26), or 50 mg (n=25) daily for 36 weeks in a double-blind, placebo-controlled, multiple dosage trial to assess safety, tolerability and feasibility and to explore cardiovascular efficacy. The primary safety endpoints were hyperkalemia (potassium > 6.5 mEq/L) and hypotension requiring emergency department visit or hospitalization. Diastolic function was assessed by Doppler echocardiography. 125 participants (97%) completed dose escalation, with no significant difference in permanent study drug discontinuation between the groups (27.5% in placebo versus 16.7% in the combined spironolactone groups and 28% in the 50 mg group). Hyperkalemia frequency was similar between spironolactone and placebo (0.49 versus 0.50 events per patient year) but demonstrated a significant linear trend due primarily to an increased event rate at the 50 mg dose (0.89 events per patient-year). The primary hypotension outcome was infrequent and similar with spironolactone and placebo (0.11 versus 0 events per patient-year). Gynecomastia was rare and did not differ significantly between groups. Change in diastolic function was similar with spironolactone and placebo. Spironolactone appears safe in carefully monitored maintenance hemodialysis patients, but did not affect cardiovascular parameters in this small study. Hyperkalemia occurs more frequently as dosage increases to 50 mg daily. PMID- 30473143 TI - Coinfection of pneumocystis jiroveci pneumonia and pulmonary aspergillosis in a non-HIV-infected patient. PMID- 30473144 TI - Using groEL as the target for identification of Enterococcus faecium clades and 7 clinically relevant Enterococcus species. AB - BACKGROUND/PURPOSE: Accurate identification is important for effective treatment because Enterococcus species have talents to cope with various antibiotics either by intrinsic resistance or by acquisition of mobile genetic elements. The groEL gene is a permissive target in identification of bacteria. We aimed to develop simple assays based on groEL for identification of enterococci. RESULTS: We continued our previous work and determined groEL gene sequences of Enterococcus species isolated from clinical specimens. Phylogenetic analysis based on groEL revealed that each strain clustered well with their reference strains (bootstrap value 100%), in which Enterococcusfaecium and Enterococcusgallinarum could be split into two clades. The divergence of E. faecium was coincident with hospital associated clade, known as clade A, and community-associated clade, known as clade B. A PCR-restriction fragment length polymorphism (PCR-RFLP) assay was therefore designed to differentiate the two E. faecium clades, based on the specific RsaI cutting sites present in the two clades. To differentiate 7 clinical relevant Enterococcus species, the multiplex PCR assay was designed to identify Enterococcusavium, Enterococcuscasseliflavus, Enterococcusfaecalis, E. faecium, E. gallinarum, Enterococcushirae and Enterococcusraffinosus. Specificity was tested with other Enterococcus species including Enterococcuscecorum, Enterococcusdurans and Enterococcusmundtii. None of these bacterial species generated products of similar size to those of the seven Enterococcus species. CONCLUSION: The simple PCR-RFLP and multiplex PCR assays on the basis of groEL gene provided an alternative way to identify Enterococcus species. PMID- 30473145 TI - Bone Marrow Adiposity- Special Edition. PMID- 30473146 TI - Dimethylsulfoxide, methanol and methylglycol in the seminal cryopreservation of Suruvi, Steindachneridion scriptum. AB - The aim of this study was to analyze the effect of 5%, 7.5%, 10%, 12.5% and 15% dimethylsulfoxide (DMSO), methanol and methylglycol alcohols on the cryopreservation of sperm from Steindachneridion scriptum. Male specimens (n = 15) were obtained from Pisciculture and sperm samples were collected by abdominal massage. Post collection the fresh sperm sample was diluted in the Beltsville Thawing Solution and sperm motility was evaluated. Results indicated that the most precise parameters for total and progressive motility were obtained with the use of methylglycol (all concentrations) and 7.5% and 10% methanol (P < 0.05). The motility of the sperm was sustained for the longest time period when 5%, 7.5% and 15% DMSO was used; similar results were also seen for 5% methanol and methylglycol at 7.5%, 10%, 12.5%, and 15% concentration (P < 0.05). With respect to reactive oxygen species it was observed that the production of ROS decreased only in presence of 5% methylglycol but not when DMSO (5%) was used (P < 0.05). Although the use of methanol (12.5%) allowed for a lesser membrane fluidity as compared to DMSO 12.5% (P < 0.05), membrane functional integrity was greater with 10% and 12.5% DMSO (P < 0.05) as compared to 10% methanol or 5% methylglycol (P > 0.05). Additionally, when major mitochondrial functionalities were assessed it was observed that the values obtained with use of 12.5% and 15% DMSO were comparable to all except 5% methyglycol (P < 0.05). In conclusion, the results of the present study indicate that 7.5% methylglycol was the most effective treatment for the cryopreservation of the S. scriptum sperm. PMID- 30473147 TI - Daily administration of a GnRH analogue enhances sperm quality in bucks during the non-breeding season. AB - The aim of this study was to determine if daily administration of a GnRH analogue (buserelin acetate) to bucks during the non-breeding season increases testosterone concentration and improves sperm quality. Five bucks received a daily dose of buserelin for 10 days, starting on Day 0 (first administration), and another five bucks remained as controls. Testosterone concentrations were greater in treated than in control bucks during the first hours after buserelin administration (P = 0.05), but greater in controls 10 h later (P < 0.01). Sperm mass motility and percentage of motile sperm were greater in treated (3.9 +/- 0.6 and 70.1 +/- 7.9%, respectively) than in control bucks (1.0 +/- 0.6, P < 0.01; 45.0 +/- 7.9%, P < 0.05 respectively) on Day 4. Percentage of sperm with normal morphology tended to be greater in treated than in control bucks (81.8 +/- 6.2% compared with 63.5 +/- 6.4% respectively, P = 0.08). The treatment decreased the percentage of sperm with mid piece defect and with bent tail (7.0 +/- 1.5% compared with 12.0 +/- 1.5%; 8.0 +/- 1.7% compared with 13.5 +/- 1.7%, treated and control bucks, respectively, P = 0.05 for both). The square root percentage of sperm with loose but heads with normal structures tended to be less in treated than control bucks (1.3 +/- 0.3% compared with 0.4 +/- 0.3% respectively, P = 0.06). It was concluded that daily administration of buserelin during the non breeding season led to a rapid increase in testosterone concentration and improved sperm quality. PMID- 30473148 TI - Early fault feature extraction of bearings based on Teager energy operator and optimal VMD. AB - As the fault shock component in vibration signals is extremely sparse and weak, it is difficult to extract the fault features when large-scale, low-speed and heavy-duty mechanical equipment is in the early stage of failure. To solve this problem, an early fault feature extraction method based on the Teager energy operator, combined with optimal variational mode decomposition (VMD) is presented in this study. First, the Teager energy operator was used to strengthen the weak shock component of the original signal. Next, a logistic-sine complex chaotic mapping with variable dimensions was constructed to enhance the global search ability and convergence speed of the pigeon-inspired optimization (PIO) algorithm, which is named the variable dimension chaotic pigeon-inspired optimization (VDCPIO) algorithm. Then, the VDCPIO algorithm is used to search for the optimal combination value of key parameters of VMD. The enhanced vibration signal is decomposed into a set of intrinsic mode functions (IMFs) by the optimized VMD, and then kurtosis for every IMF and mean kurtosis of all IMFs are extracted. According to the average kurtosis, several IMFs, whose kurtosis value is greater than the average kurtosis value, are selected to reconstruct a new signal. Then, envelope spectrum analysis of the reconstructed signal is carried out to extract the early fault features. Finally, experimental verification of the method was performed using the simulated signal and measured signal from a rolling bearing; the experimental results indicate that the method presented in this paper is more effective to extract the early fault features of this kind of mechanical equipment. PMID- 30473149 TI - A robust quantized consensus protocol for discrete-time multi-agent systems with additive noise. AB - This paper investigates the consensus problem of multiple discrete-time integrator agents with communication constraints and additive process noise. It proposes a protocol to achieve the approximate consensus of agents over inter agent communication networks with finite bit rates. Under that protocol, dynamic encoding and decoding algorithms are implemented for each pair of neighboring agents to transmit quantized states at a finite bit rate. With received quantized states of neighboring agents, the control input of each agent is locally computed. Particularly input saturation is introduced into the local controllers of agents and places both lower and upper bounds on the local control inputs of agents. These control input bounds can be known in advance and greatly enhance the robustness of the consensus protocol. Under the proposed protocol, the approximate consensus can be guaranteed at any finite bit rate to encode the states of agents. It is shown that even a single bit per time step is enough for the desired approximate consensus. The additive process noise does not increase the bit rate required for that approximate consensus. Moreover, the proposed consensus protocol can be designed with only an upper bound on the number of agents and is more robust than some previous consensus protocols which may require the global information of the inter-agent network topology, such as the second largest eigenvalue of the Laplacian matrix. Even when some communication links are broken due to communication failure or some nodes leave, the same set of consensus parameters can still robustly guarantee the expected approximate consensus. Simulations are conducted to illustrate the effectiveness of the proposed quantized consensus protocol. PMID- 30473150 TI - A Novel Nesting Protocol to Decrease Readmission and Increase Patient Satisfaction Following Congenital Heart Surgery. AB - BACKGROUND: Pediatric patients post-cardiac surgery have complex care needs requiring extensive discharge education and skill competency by caregivers to transition from the hospital environment to a medical home. The purpose of this quality improvement project was to implement a nesting protocol in the cardiovascular intensive care unit (CVICU) to improve discharge teaching and care coordination, with a goal to reduce readmission rates and increase caregiver satisfaction and understanding. METHODS: A nesting protocol was created to provide clear and consistent guidelines to the multidisciplinary team. Pre- and post-intervention data was collected from caregiver satisfaction surveys, using a Likert scale, to determine understanding of nesting and feeling of preparedness upon discharge. In 2016 and 2017, retrospective chart reviews were performed to evaluate readmission data. SQUIRE 2.0 guidelines were utilized when writing this article (Ogrinc et al., 2015). RESULTS: Caregivers reported an increase in satisfaction and understanding of the nesting process post-intervention with an increase of 4.48%. Readmission rates did not improve from 2016 to 2017. However, only 6 months of 2017 were reviewed. CONCLUSIONS: Readmission is a significant problem for children with complex CHD. Post-discharge care requires caregivers to understand the medical care that their children require. Pre-intervention data revealed deficiencies in understanding regarding care regimens, infection control, and nutrition, which correlated with the most frequent causes for readmission among this population. The protocol developed addressed multiple issues concerning discharge readiness. PMID- 30473151 TI - How Do Youth with Cystic Fibrosis Perceive Their Readiness to Transition to Adult Healthcare Compared to Their Caregivers' Views? AB - PURPOSE: To describe how perceived stages of change for self-care management skills varies by age in youth with cystic fibrosis in preparation for transition to adult healthcare, to compare caregiver perception of youth readiness for self care, and age/frequency of transition discussion with provider. DESIGN AND METHODS: The Transition Readiness Assessment Questionnaire and a modified version (TRAQ-C) for caregivers were used for data collection. Descriptive statistics, simple linear regression, and t-tests were employed. RESULTS: Regression equations suggest that age predicts youth perception of self-care management skill in all five domains on the TRAQ (p <= .009). A paired t-test compared the overall TRAQ and TRAQ-C mean scores between dyads. Youth rated themselves significantly higher in perception of self-care skill management (m = 3.187, sd = 0.769) than caregivers (m = 2.490, sd = 0.788; t = 7.408, df = 51, p < .001). Sixteen was the average age of transition discussion for both youth and caregiver. Reported frequency of discussion varied considerably. CONCLUSIONS: Although increasing age predicts perception of self-care management, many youth age 18-22 were still only contemplating or starting to learn skills. Skill level perceptions between youth and caregiver differed, but scores from all self-care management domains followed a similar trend. Discussions with providers began later than guidelines recommend and were often not recognized as such by youth. PRACTICE IMPLICATIONS: Results underscore the importance of beginning transition discussion and skill evaluation in youth with cystic fibrosis at an early age, incorporating caregivers' perception in the process. PMID- 30473152 TI - Response to a National Issue: Moving Beyond "Back to Sleep" at Three Hospitals. AB - PURPOSE: To measure changes in registered nurse (RN) knowledge/beliefs and practices, parents' recall of infant safe sleep (ISS) teaching, and inpatient infant sleep environments and safety after implementing an ISS initiative. DESIGN AND METHODS: This longitudinal quasi-experimental study took place in three hospitals in the United States. An existing infant safe sleep tool was revised and updated to align with current recommendations on sleep environments. A bundled intervention included educating nurses, changing unit processes and implementing crib cards and room signs. Paired questionnaires surveyed 62 nurses before and 2 months after the intervention. Audits of 462 cribs/sleep environments with parent conversations assessed infant sleep conditions and parents' recall of RN teaching before and after the intervention. RESULTS: After Bonferroni correction, eight of 19 items for RN knowledge/beliefs and self reported practice showed statistically significant improvements with moderate effect sizes. All 11 items for parents' recall of RN teaching showed statistically significant improvements, with odds ratios ranging from 7 to 76. Five of six real-time sleep safety conditions (from crib/sleep environment audits) had statistically significant improvements. Odds ratios ranged from eight to 83. CONCLUSION: An updated educational tool improved nurses' and parents' knowledge and practices related to current and updated safety factors for infant sleep conditions. Inpatient adherence to infant sleep safety recommendations improved. PRACTICE IMPLICATIONS: A two-hour investment of nurses' time yielded statistically significant improvements. Factors critical to the success of the ISS project roll-out are reported. Improvements in parents' recall of teaching and actual sleep environments suggest potential for long-term changes in infant safety at home. PMID- 30473153 TI - The Why Behind the Questions: Question-asking in Parents of Children Newly Diagnosed With Cancer - A Report From the Children's Oncology Group. AB - PURPOSE: For parents of children newly diagnosed with cancer, the exchange of information during initial educational processes is critical. This focused analysis was completed to describe parent question-asking during the new childhood cancer diagnosis timeframe. DESIGN & METHODS: In previous research of new diagnosis education experiences, parents spoke extensively about asking questions. These data, captured in first level coding, were incorporated across higher level codes to describe how parents processed information after their child's cancer diagnosis. Using constant comparative analysis, we returned to our data to complete a focused analysis of our first level code, Asking Questions. Team members independently coded Asking Questions data from 20 parent interviews, followed by team discussions and consensus agreement for code assignment. RESULTS: Parents asked questions to learn, fill an unmet need, or clarify information. Clinicians asked questions to assess parent learning. CONCLUSION: Question-asking is a technique used by parents and clinicians to communicate new information, assess understanding of provided content, and/or to confirm previously provided information. PRACTICE IMPLICATIONS: Clinicians can benefit from carefully listening to patients/parents and reflecting on the type of questions asked in an effort to understand the reason behind the question. This can be used to guide further education. PMID- 30473154 TI - Infant Feeding Practices and Weight Gain in Toddlers Born Very Preterm: A Pilot Study. AB - PURPOSE: Long-term consequences of prematurity are a public health concern. A pattern of slow initial weight gain followed by a period of rapid weight gain has been associated with poor cardiometabolic health outcomes. The purpose of this study was to examine the relationships between infant feeding practices and weight gain in a sample of 18-to-24-month olds corrected age born very preterm. DESIGN AND METHODS: A cross-sectional design was used to examine the relationships between infant feeding practices and weight gain. Estimates of effect sizes and model fit estimates were the primary parameters of interest. RESULTS: Most of the participants received human milk after birth, but most had transitioned to formula before three months. Slightly less than half received complementary foods prior to four months corrected age. Gains in weight and head circumference were rapid after discharge from the neonatal intensive care unit, while gains in length lagged behind. Infant feeding practices did not have a clinically meaningful effect on weight gain. CONCLUSIONS: While the initiation of human milk feedings was encouraging, the duration fell short of recommendations. Practices such as the early introduction of complementary feedings and the addition of rice cereal to the bottle are troubling. Additionally, the rapid increase in weight gain may have a negative impact on future cardiometabolic health. PRACTICE IMPLICATIONS: Clinical recommendations include ensuring support for the use of human milk before and after hospital discharge, close monitoring of physical growth, and ensuring adherence to the guidelines for the introduction of complementary foods. PMID- 30473155 TI - Parents' and Health Professionals' Views of Collaboration in the Management of Childhood Long-term Conditions. AB - PURPOSE: To explore how parents and health professionals view the concept and practice of collaboration in the management of childhood long-term conditions. DESIGNS AND METHODS: A qualitative research approach was adopted; sixteen parents and six health professionals participated in either individual or group interviews. Data analysis was underpinned by the Framework approach and involved an iterative process of reading the transcribed data, identifying and refining key themes until a coherent picture emerged. RESULTS: Two main concepts were identified: expectations of collaboration and mechanisms for collaboration. Health professionals' expectations of collaborative practice were influenced by their knowledge, experience and relative objectivity. They used relationship building with families as a key strategy for collaboration. Parents' expectations of collaboration varied and appeared to be influenced by their experience of living with their child's condition. Parents' needs were often unmet, particularly in relation to support with coordinating or accessing care on behalf of their child. Parents' strategies included resilience, assertiveness, determination and battling for what they needed. CONCLUSION: Parents and professionals valued collaboration as a concept but differed in their expectations of collaborative practice and adopted different mechanisms to foster meaningful collaboration. A better understanding of the unique needs and experiences of parents of a child with a long-term condition is key to developing positive collaborative practice. PRACTICE IMPLICATIONS: Collaborative practice could be enhanced by health professionals' being more responsive to the full range of parent support needs, and being more pro-active about helping them work with the complexities of care systems. PMID- 30473157 TI - The Development and Content Validation of a Self-reported Instrument to Explore the Nurse's Role in Healthcare Transition Planning for Youth and Young Adults With Chronic Illness and/or Disability (NR-HCTP). AB - PURPOSE: To develop an instrument to assess the nurse's role and responsibilities in healthcare transition planning (HCTP) for youth and young adults (YYA) with chronic illness and/or disability (CI/D) that will determine to what extent nurses are involved with providing HCTP services; and identify the specific activities that nurses engage in when providing HCTP services. DESIGN AND METHODS: A panel of seven experts in the field were used to determine content validity. RESULTS: The final NR-HCTP instrument contains a total of 68 items (17 main items, 5 containing sub items) representing activities that nurses engage in when providing HCTP services, their level and extent of involvement, and their level of knowledge in the areas of HCTP. PRACTICE IMPLICATIONS: An exploration of nurse's roles in HCTP for YYA with CI/D allows for discussion of current nursing practices in the transition process. The information obtained may be used to identify gaps in knowledge and practice guidelines, develop nursing core elements and educational materials to support nurses in their role, and inform nursing administrators in the development of appropriate HCTP position descriptions. PMID- 30473156 TI - Improving Quality Through Nursing Participation at Bedside Rounds in a Pediatric Acute Care Unit: A Pilot Project. AB - PROBLEM: Implementation of bedside rounds enhances communication and collaboration between physicians and nurses, resulting in improved clinical outcomes. Yet, the literature demonstrates that it remains difficult for nurses to attend rounds if they don't know when they are happening. PURPOSE: This project aimed to increase nurses' presence and participation at bedside rounds in a pediatric acute care unit, enhance teamwork and collaboration, and improve quality outcomes. DESIGN AND METHODS: Nurses carried a pager so that physicians could alert them of rounds. Perception of teamwork and collaboration was assessed via surveys pre- and post-intervention as well as the annual survey evaluating RN and MD interactions from the National Database of Nursing Quality IndicatorsTM (NDNQI(r)). Other quality outcome measures included length of stay and patient satisfaction through Press GaneyTM surveys. RESULTS: Findings demonstrated that when nurses were notified in advance, their participation in rounds increased from 44.4 to 73%. Length of stay decreased from 2.5 days prior to the project to an average of 2.10 days during the project. Scores on inpatient satisfaction surveys increased from 82.4 to 92.2%, and nursing communication improved from 83.3 to 95.65%. CONCLUSION: Interprofessional collaboration as reflected by the inclusion of nurses at bedside rounds led to positive outcomes in patient care. IMPLICATIONS: Increasing nurses' presence and providing them with a role at rounds is an important step towards fostering teamwork and collaboration with physicians and enhancing team-based care in a pediatric inpatient setting. Further research measuring the impact of interprofessional collaboration in healthcare is needed. PMID- 30473158 TI - Feasibility of Online Mental Wellness Self-assessment and Feedback for Pediatric and Neonatal Critical Care Nurses. AB - PURPOSE: The primary goal of this study was to test the feasibility of an educational online self-assessment of burnout, resilience, trauma, depression, anxiety, and common workplace stressors among nurses working in a pediatric intensive care unit or neonatal intensive care unit setting. The secondary, exploratory objectives were to estimate the prevalence of psychiatric symptoms in this sample and to identify those variables that most strongly predict burnout. DESIGN AND METHODS: Data from optional and anonymous online measures were analyzed for 115 nurses (67.9% aged 25-44; 61.7% Caucasian) working in an urban children's hospital pediatric or neonatal ICU. Multiple linear regressions identified demographic variables and workplace stressors that significantly predicted each of three components of burnout. RESULTS: Most respondents found the educational assessment and feedback to be helpful. Choosing nursing as a second career was associated with better resilience. Having worked in ICU settings longer and being older were both linked to lower levels of anxiety. Predictors of burnout varied across the three burnout subscales. CONCLUSIONS: Implementation of an online self-assessment with immediate educational feedback is feasible in critical care settings. The variability of predictors across the three burnout subscales indicates the need for tailored interventions for those at risk. Future research may include follow-up of nurses to examine changes in scores over time and expansion of the tool for other medical personnel. PRACTICE IMPLICATIONS: An educational online self-assessment can be a helpful tool for pediatric critical care nurses experiencing varying degrees of burnout and distress. PMID- 30473159 TI - Psychometric Validation of the Family Nurse Caring Belief Scale in a Neonatal Nursing Population. AB - PURPOSE: To psychometrically validate and strengthen the construct validity of the Family Nurse Caring Belief Scale (FNCBS) with a sample of neonatal nurses. DESIGN AND METHODS: Confirmatory factor analysis of the 25-item FNCBS, using the factor structure based on the original exploratory principal components analysis, was performed to evaluate the psychometric properties of the FNCBS with the neonatal nurse population. RESULTS: Confirmatory factor analysis (CFA) examined the factor structure of the FNCBS using the sample of neonatal nurses. The chi square test determined overall model fit. Comparative fit index (CFI) and Tucker Lewis index (TLI) were both <0.90 therefore, neither of these indices indicated good fit. The root mean square of error approximation (RMSEA) of the sample data was >0.06 and the standardized root mean square residual (SRMR) of the sample data is >0.08 and, therefore, the data did not demonstrate good fit. In addition, the factor correlations between the four latent variables were small. This suggests there is no parsimony and the sample data with neonatal nurses did not fit the model. CONCLUSION: The findings suggest the FNCBS was not psychometrically validated with the population of neonatal nurses and this study was unable to strengthen the construct validity of the FNCBS beyond the pediatric nurse sample in the original study. IMPLICATIONS FOR PRACTICE: This study highlighted the opportunity for continued research in the area of measuring nurses' beliefs regarding the provision of family-sensitive care to families in crisis and will generate a revision of the FNCBS to incorporate concepts which are important to care for a family unit. PMID- 30473160 TI - Refinement of an Instrument to Measure the Needs of Parents of Sick Children in the Context of Family Centered Care. AB - BACKGROUND AND PURPOSE: The purpose of this study was to refine an instrument to capture the perceived needs of parents whose children are seriously ill. This article describes the psychometric properties of the Parents' Needs Scale (PNS), a translated, revised 22-item short form from an original instrument that was developed and tested on parents of children with cancer in Hong Kong. METHODS: The study was done in three stages that included (a) factor analysis of two samples recruited from clinics in Northern Virginia of parents of children with cancer (n = 74) and end stage renal disease (ESRD) (n = 30); (b) known groups validity testing with two groups of parents recruited in a parallel study on children with special needs (n = 15) and a control group of well children (n = 23); and (c) concurrent validity testing on the subsample of parents of children with special needs using the known measure of Impact on the Family Scale (IFS). Data collection for the stages included mailed questionnaires and follow-up telephone interviews. RESULTS: Exploratory factor analysis using the common factor approach identified two domains: (1) needs related to my child's illness and (2) needs unrelated to my child's illness. The factorial structure was followed by item scaling tests to determine item-level convergence and discriminative validity, as well as scale reliability for the two domains (Cronbach's alpha = 0.93 and 0.90). Domain-level discriminant validity tests yielded significant differences on several expected characteristics of the child and/or family based on the literature. The final 22-item scale was reworded and used to establish known groups validity by comparing the two groups of children with acute illnesses from the previous study with two control groups of parents of children who were well or children with special needs but not acutely ill, yielding significant results on both factors (p < 0.001). A final test of concurrent validity was performed on the parents of children with special needs measures of parent need with their reported impact on the family yielding significant correlations on predicted variables. CONCLUSIONS: The PNS can measure parents' needs with demonstrated psychometric validity and reliability. PMID- 30473161 TI - Care Coordination Using a Shared Plan of Care Approach: From Model to Practice. AB - INTRODUCTION: Children and youth with special health care needs (CYSHCN) need, but do not have, adequate care coordination (CC); CC leads to better pediatric care, improved family/professional experience of care, and enhanced population health. Current CC initiatives are promising but lack adherence to emerging definitions/standards. A Lucile Packard Report provides guidelines for using a Shared Plan of Care (SPoC) as a CC approach; studied implementation is needed. PURPOSE: The studied implementation of the Riley Care Coordination Program (RCCP) set out to: 1) illuminate components of family-centered, interdisciplinary, team based care/coordination and SPoC, use 2) underscore family participation/engagement 3) reveal implementation processes/lessons learned. METHODS: Children (ages 2-10) with neurodevelopmental disabilities were referred by subspecialists; families agreed to participate in RCCP from a children's hospital ambulatory care setting. RCCP team used a five-phase workflow to implement CC: (1) Family Outreach/Engagement 2) Family and Team Pre-Visit Work, 3) Population-Based Teamwork, 4) Planned-Care Visits/SPOC "Co-Production", 5) Ongoing Care Coordination and Community Transfer. Family surveys and SPoC goals informed an evaluation. RESULTS: Children (268) with neurodevelopmental disabilities enrolled/completed the 6-month RCCP; it was a feasible endeavor. The co-produced SPoC supported families/care neighborhood partners to meet goals/unmet needs. Team plan-do-study-act improvement cycles informed RCCP enhancements. DISCUSSION/CONCLUSION: Eliciting/using family goals to drive CC emphasized family priorities; children/families gained interventions, treatments, confidence and navigation skills. Going beyond episodic, reactive care, RCCP achieved better CC with care neighborhood learning partnerships. Investing in this quality care coordination with fidelity to national standards holds promise. PMID- 30473162 TI - Post-Operative Pain and Comfort in Children After Heart Surgery: A Comparison of Nurses and Families Pre-operative Expectations. AB - PURPOSE: Parents' and nurses' expectations about pain control and comfort in children after heart surgery were explored to contribute to evidence-based family centered interventions. DESIGN AND METHODS: 20 nurses and 23 parents from a tertiary pediatric center in the Pacific Northwest, were interviewed about their expectations of children's pain control and comfort experience in the hospital after heart surgery. In this descriptive study, data were collected from semi structured recall interviews and analyzed using content analysis. RESULTS: Most parents expected their child be medicated at a level of not feeling any pain. Many expected their child to remain in a heavily sedated state after the surgery. A few parents did not know what to expect. In contrast, nurses expected children to have controlled pain with intermittent discomfort, yet, tolerating recovery activities. CONCLUSIONS: Although both parents and nurses expect to partner in the comfort care of the child, there is variation on the expectations around the nurse-parent relationship and the operational definition of pain management and comfort. PRACTICE IMPLICATIONS: Awareness of parents' expectations about pediatric post-operative comfort present an opportunity for the development of interventions aimed to enhance alignment of nurse and family strategies for children after heart surgery. Pre-operative preparation for families specific to post-operative recovery and pain management of children hospitalized for heart surgery is needed. PMID- 30473163 TI - Secondary Traumatic Stress in Pediatric Nurses. AB - PURPOSE: Secondary traumatic stress affects many in the helping professions, and has been identified in many nursing specialty areas. The purpose of this study was to expand the knowledge of secondary traumatic stress in pediatric nursing by examining the statistical relationships between secondary traumatic stress, age of the nurse, and years of nursing experience, and coping responses. DESIGN AND METHODS: A convenience sample of Certified Pediatric Nurses (n = 338) were surveyed using the Secondary Traumatic Stress Scale, the Brief COPE, the Marlowe Crowne Social Desirability-Short Form, and a demographics form. Hierarchical multiple linear regression and descriptive statistics were utilized to examine secondary traumatic stress and the other variables of interest. RESULTS: Secondary traumatic stress affected more than half of pediatric nurses surveyed. Age and years of experience did not predict secondary traumatic stress. Looking at coping responses pediatric nurses with higher emotional support and instrumental support scores also demonstrated higher secondary traumatic stress scores. Denial and behavioral disengagement were also associated with an increase in secondary traumatic stress scores. CONCLUSION: Secondary traumatic stress impacts many pediatric nurses. Further research is needed to determine which factors predispose pediatric nurses to secondary traumatic stress and which coping responses help pediatric nurses best manage this stress. PRACTICE IMPLICATIONS: Acknowledging secondary traumatic stress in this population by promoting awareness, and providing educational programs will help to protect nurses' psychological health, and may prevent nurses from leaving the profession due to work-related stress. PMID- 30473164 TI - Special Issue Family Centered or Child Centered Care? Strengths and Challenges to Theoretical and Practice Implementation. PMID- 30473165 TI - Letter to Editor. PMID- 30473166 TI - Diagnostic accuracy of F-18 FDG PET or PET/CT for detection of lymph node metastasis in clinically node negative head and neck cancer patients; A systematic review and meta-analysis. AB - OBJECTIVE: The purpose of the current study was to investigate the diagnostic performance of F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) or positron emission tomography/computed tomography (PET/CT) for the detection of cervical lymph node (LN) metastasis in clinically node negative head and neck squamous cell cancer (cN0 HNSCC) patients through a systematic review and meta analysis. METHODS: The PubMed and EMBASE database, from the earliest available date of indexing through April 30, 2018, were searched for studies evaluating the diagnostic performance of F-18 FDG PET or PET/CT for the detection of LN metastasis in cN0 HNSCC patients. We determined the sensitivities and specificities across studies, calculated positive and negative likelihood ratios (LR+ and LR-), and constructed summary receiver operating characteristic (SROC) curves. RESULTS: Across 18 studies (1044 patients), the pooled sensitivity for F 18 FDG PET or PET/CT for the detection of LN metastasis was 0.58 and a pooled specificity of 0.87 for patient based analysis. Neck side based analysis showed the pooled sensitivity of 0.67 and a pooled specificity of 0.85. Level based study demonstrated the pooled sensitivity of 0.53 and a pooled specificity of 0.97 (95% CI; 0.95-0.98). In meta-regression analysis, no definite variable was the source of the study heterogeneity. CONCLUSION: The current meta-analysis showed the low sensitivity and moderate specificity of F-18 FDG PET/CT for the detection of cervical LN metastasis in cN0 HNSCC patients. Level based analysis of F-18 FDG PET or PET/CT has a high specificity and NPV for the detection of cervical metastatic LN detection. PMID- 30473167 TI - The pedicled levator labii superioris alaeque nasi flap: A durable single-stage option for reconstruction of full-thickness nasal defects. AB - IMPORTANCE: Repair of full-thickness nasal defects can often be associated with multi-stage operations that can result in significant physical and psychological morbidity for patients. We present a single-stage option for reconstruction of these defects. OBJECTIVE: Demonstrate the utility of the pedicled levator labii superioris alaeque nasi flap and consistency of its vascular pedicle. DESIGN: Anatomical study using fresh cadavers. SETTING: Academic medical center. MAIN OUTCOME AND MEASURES: Evaluation of vascular anatomy of pedicled flap and measurements of distances with relationship to facial anatomic landmarks. RESULTS: With few noted anatomic variations, the vascular pedicle of the pedicled levator labii superioris alaeque nasi flap arises from the superior labial artery and is reliably located within 1 cm lateral and inferior of the nasal sill. CONCLUSIONS AND RELEVANCE: As a robust single-stage option, the pedicled levator labii superioris alaeque nasi flap can serve as a powerful option in the arsenal of the reconstructive surgeon. The technique for harvest is simple with attention to a few anatomic variations as described herein, and excellent results can be obtained with proper application. PMID- 30473168 TI - Audiological outcomes in sudden sensorineural hearing loss with presumed inner ear hemorrhage. AB - OBJECTIVE: To explore the hearing outcomes and prognostic factors in patients with sudden sensorineural hearing loss resulting from inner ear hemorrhage. METHODS: 42 patients (22 male and 20 female) were recruited from January 2016 to December 2017. Intravenous methylprednisolone and/or intratympanic corticosteroid were used as salvage therapy. The main measures included systemic risk factors and audiometric outcomes as proposed by American Academy of Otolaryngology-Head and Neck Surgery Hearing Loss Scale. All individuals were assessed at baseline, discharge (2 weeks post-treatment) and at 1, 3 and 6 months. RESULTS: The mean ages of patients were 39.3 +/- 14.8 yrs. Cardiovascular disorders were seen in 19.0-33.3% of cases. Restoration of hearing and speech discrimination abilities were assessed at the first month post-treatment versus initial levels (95.5 +/- 15.5 vs. 109.2 +/- 9.6 dB, p = 0.000; and 17.6 +/- 24.4 vs. 1.3 +/- 4.0%, p = 0.003, respectively). Word recognition scores continued to recover at month 6 (38.7 +/- 35.4%, p = 0.000), whereas puretone ceased to change (90.8 +/- 16.2 dB, p = 0.139). The final percentages of complete, partial and no recovery were 0%, 57.1% and 42.9% respectively. The prognosis was independent of accompanying systemic risk factors as analyzed in this study. Intratympanic intervention was associated with improved word recognition scores, although intravenous corticosteroid was not. CONCLUSIONS: Profound sudden sensorineural hearing loss caused by inner ear hemorrhage often has an unsatisfactory prognosis. However, this cohort did experience partial audiological recovery with delayed onset. Immediate and effective intratympanic corticosteroid may have therapeutic potential for this intractable disease. PMID- 30473170 TI - Letter to the editor: Effect of changing postoperative pain management on bleeding rates in tonsillectomy patients. PMID- 30473169 TI - Update on the diagnostic considerations for neurogenic nasal and sinus symptoms: A current review suggests adding a possible diagnosis of migraine. AB - BACKGROUND: Treatment of rhinosinusitis (RS) is one of the leading reasons for prescriptions of antibiotics, although they often fail to provide symptomatic relief. Appropriately diagnosing and treating patients presenting with RS for whom antibiotic therapy has failed or who have normal CT findings is a controversial topic. One explanation is that what these patients are experiencing is misinformation from the trigeminal nerve and autonomic nervous system. Midfacial pain and pressure with rhinorrhea and nasal congestion do not represent an infectious, or even inflammatory, condition within the sinus or nasal cavities, but a mirage that is best treated as a migraine variant. Observations Although there is not enough research to definitively prove this alternate etiology, we are reaching a tipping point where the clinical implications, real world experience, and evolving literature support this possible alternate etiology. Four key factors support a midfacial migraine that mimics RS: 1) Pathophysiology: current pathophysiology literature offers a model of how migraine attacks could replicate clinical presentations of RS; 2) Clinical presentation: patients with infectious RS and midfacial migraine have similar symptomatic presentation, similar demographics, but poorly correlated radiological information; 3) Diagnosis: clinical studies support the proposition that there are alternative diagnostic tools for distinguishing patients with midfacial migraine; and 4) Prognosis: Select RS patients show significant improvement with migraine treatment. CONCLUSIONS: We encourage medical professionals to consider migraine disease as a form of sensory misinformation and as a possible etiology of RS complaints. Clinicians can ask validated questions to determine if possible migraine could be an underlying cause, and there are standard preventative treatments for migraine that could alleviate patient symptoms. Dysfunctional vasomotor activity may be the root of the disturbances, particularly when antibiotic therapy fails and CT findings are discordant with symptoms. Until there is a diagnostic test for migraine, clinicians need to question a patient's self-diagnosis of rhinosinusitis. More research is needed to definitively answer this important question. PMID- 30473171 TI - Clinical and prognostic value of chaperonin containing T-complex 1 subunit 3 in hepatocellular carcinoma: A Study based on microarray and RNA-sequencing with 4272 cases. AB - Liver cancer is one of the few tumors with a steadily increasing morbidity and mortality; hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. We combined the expression profiles of Chaperonin Containing T complex 1 Subunit 3 (CCT3) in HCC tissues based on microarray and RNA-sequencing data. The CCT3 expression levels were extracted and examined based on 421 samples from The Cancer Genome Atlas (TCGA) (HCC, n = 371; non-HCC, n = 50) and 3851 samples from 31 microarray or RNA-sequencing datasets (HCC, n = 1975; non-tumor = 1876). We used a variety of meta-analytic methods, including SMD forest maps, sensitivity analysis, subgroup analysis and sROC curves, to confirm the final results. Meanwhile, database-derived immunohistochemistry data was used for validation. We also further explained the potential mechanism of CCT3 in HCC through signal pathway analyses and PPI network construction with the CCT3 co expressed genes. The mRNA and protein expression of CCT3 in HCC tissues were higher than in non-HCC tissues. The expression of CCT3 differed between groups when grouped according to clinicopathological parameters, such as race, family history, and histological grade. The results of standardised mean difference (SMD) forest map and summary receiver operating characteristic (sROC) curve revealed that CCT3 was highly expressed in HCC tissues and had a high ability to distinguish between cancer tissues and non-cancer tissues. The main form of CCT3 gene alteration in HCC was mRNA up-regulation and amplification (23%), and the most common mutation type was missense. The mRNA expression of CCT3 in HCC was negatively correlated with DNA methylation. According to the Kyoto Encyclopedia of Genes and Genomes pathway analysis, CCT3 can influence HCC occurrence and development through cell cycle and DNA replication pathways. In summary, this study carries out the staging and prognostic analysis of HCC. It suggests that CCT3 might play an important part in the tumorigenesis and progression of HCC and may have a certain prognostic value in HCC. Moreover, CCT3 might represent a promising biomarker for HCC. PMID- 30473172 TI - Well differentiated papillary peritoneal mesothelioma treated by cytoreduction and hyperthermic intraperitoneal chemotherapy-the experience of the PSOGI registry. AB - BACKGROUND: Well differentiated papillary peritoneal mesothelioma (WDPPM) is a rare variant of mesothelioma which affects mainly women in the reproductive age. The disease may present multifocally and recur after primary resection. Our aim was to describe the outcomes of cytoreduction (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in this disease. METHODS: Patients with histological diagnosis of WDPPM were retrieved from the PSOGI registry. Demographical and clinical data were extracted as well as outcomes data (overall survival (OS) and recurrence free survival (RFS)). RESULTS: We analyzed 45 patients for whom complete data was available. The majority of patients were women (n = 33, 73%) with a median age of 44 years. Preoperative chemotherapy (CT) was administered in 8 patients (18%). Median peritoneal carcinomatosis index was 9 (1-30), and complete cytoreduction was achieved in 69% of patients. There was one case (2%) of postoperative mortality, and 24% rate of severe morbidity. Overall, there were 4 deaths and 5 years OS was 80%. 8 patients (18%) had disease recurrence, all within 5 years from operation. On univariate analysis preoperative CT, high PCI and severe morbidity were associated with reduced RFS. On multivariate analysis, only preoperative CT (HR = 32.6, 95% CI: 2.39-446.2, p = 0.009) and high PCI (HR = 21.7, 95% CI: 1.11-425.7, p = 0.04) remained significant risk factors. CONCLUSIONS: WDPPM can be a lethal disease with substantial recurrence even after aggressive treatment. Patients presenting with extensive disease or disease recurrence after surgical excision are at increased risk for relapse. CRS + HIPEC can be safely applied to WDPPM in specialized centers. PMID- 30473173 TI - Immunosuppressive drugs and the gastrointestinal tract in renal transplant patients. AB - Gastrointestinal (GI) discomfort is common after renal transplantation and can be caused by the use of various immunosuppressive drugs. GI symptoms affect the quality of life, lead to an impaired graft survival and an increased mortality. Moreover, diseases and disturbances of the GI tract also affect the pharmacokinetics of immunosuppressive drugs. This review addresses the interaction between immunosuppressive agents and GI disorders. The GI tract is involved in the metabolism of several immunosuppressive drugs. Calcineurin inhibitors, mTor inhibitors, and corticosteroids are subjected to metabolism by the intestinal cytochrome P450 (CYP3A) and by the drug efflux pump ABCB1. Mycophenolate is partly metabolized in the stomach and intestine and undergoes enterohepatic recirculation. Gastrointestinal disturbances can lead to a modified exposure to immunosuppressive drugs. In the first and second part of this review, we focus on the role of the GI tract in the pharmacokinetics of the immunosuppressive drugs and how to adjust immunosuppressive therapy in patients with vomiting, need for tube feeding, delayed gastric emptying, intestinal resection, and diarrhea. In the third part, we review the GI adverse effects of the various immunosuppressive drugs, with special attention for diarrhea and dyspepsia. Finally, we discuss the effects of drugs used for relief of GI complaints on the exposure to immunosuppressive agents. PMID- 30473174 TI - Quantitative Ultrasound Biomarkers Based on Backscattered Acoustic Power: Potential for Quantifying Remodeling of the Human Cervix during Pregnancy. AB - As pregnancy progresses, the cervix remodels from a rigid structure to one pliable enough to allow delivery of a fetus, a process that involves progressive disorganization of cervical microstructure. Quantitative ultrasound biomarkers that may detect this process include those derived from the backscattered echo signal, namely, acoustic attenuation and backscattered power loss. We recently reported that attenuation and backscattered power loss are affected by tissue anisotropy and heterogeneity in the ex vivo cervix. In this study, we compared attenuation and backscattered power difference in a group of women in early pregnancy (first trimester) with those in a group in late pregnancy (third trimester). We observed a significant decrease in the backscattered power difference in late as compared with early pregnancy, suggesting decreased microstructural organization in late pregnancy, a finding that is consistent with animal models of cervical remodeling. In contrast, we found no difference in attenuation between the time points. These results suggest that the backscattered power difference, but perhaps not attenuation, may be a useful clinical biomarker of cervical remodeling. PMID- 30473175 TI - Dispersion in Tissue-Mimicking Gels Measured with Shear Wave Elastography and Torsional Vibration Rheometry. AB - Dispersion, or the frequency dependence of mechanical parameters, is a primary confounding factor in elastography comparisons. We present a study of dispersion in tissue-mimicking gels over a wide frequency band using a combination of ultrasound shear wave elastography (SWE), and a novel torsional vibration rheometry which allows independent mechanical measurement of SWE samples. Frequency-dependent complex shear modulus was measured in homogeneous gelatin hydrogels of two different bloom strengths while controlling for confounding factors such as temperature, water content and material aging. Furthermore, both techniques measured the same physical samples, thereby eliminating possible variation caused by batch-to-batch gel variation, sample geometry differences and boundary artifacts. The wide-band measurement, from 1 to 1800 Hz, captured a 30% 50% increase in the storage modulus and a nearly linear increase with frequency of the loss modulus. The magnitude of the variation suggests that accounting for dispersion is essential for meaningful comparisons between SWE implementations. PMID- 30473176 TI - Synthesis and evaluation of biological activity for dual-acting antibiotics on the basis of azithromycin and glycopeptides. AB - One of the promising directions of the combined approach is the design of dual acting antibiotics - heterodimeric structures on the basis of antimicrobial agents of different classes. In this study a novel series of azithromycin glycopeptide conjugates were designed and synthesized. The structures of the obtained compounds were confirmed using NMR spectroscopy and mass spectrometry data including MS/MS analysis. All novel hybrid antibiotics were found to be either as active as azithromycin and vancomycin against Gram-positive bacterial strains or have superior activity in comparison with their parent antibiotics. One compound, eremomycin-azithromycin conjugate 16, demonstrated moderate activity against Enterococcus faecium and Enterococcus faecalis strains resistant to vancomycin, and equal to vancomycin's activity for the treatment of mice with Staphylococcus aureus sepsis. PMID- 30473177 TI - A thiol-inducible and quick-response DNA cross-linking agent. AB - Three new 2,4-dinitrobenzenesulfonyl derivatives 1-3 were successfully prepared for the first time using a simple process. They were efficiently triggered by thiols (glutathione and l-cysteine) to release the corresponding phenol derivatives (4-6) within 5 min. The quick response of 1-3 toward thiols was determined by 1H NMR and HPLC. Moreover, our results indicated that 1 could induce DNA cross-linking in the presence of glutathione, probably due to the quinone methide formation of phenol intermediate 4 followed by departure of 2,4 dinitrobenzenesulfonyl group. PMID- 30473178 TI - Increased circulating granzyme B in type 2 diabetes patients with low-grade systemic inflammation. AB - In metabolic diseases, like type 2 diabetes (T2D), adipose tissue (AT) is infiltrated by macrophages and other leukocytes - which secrete many bioactive peptides leading to local and systemic low-grade chronic inflammation - and undergoes remodeling and aberrant fibrosis. Granzyme B (GrB) is a serine protease produced by some leukocytes, including cytotoxic lymphocytes and macrophages. It exerts both intracellular apoptotic function and extracellular functions, leading to tissue injury, inflammation and repair. Elevated circulating GrB levels have been found in aging- and inflammation-associated diseases and a role for GrB in the pathogenesis of several chronic inflammatory diseases has been reported. Aims of this study were to investigate circulating GrB levels in T2D patients in relation to their systemic inflammatory profile and to unravel its correlates. For this cross-sectional study, we recruited 51 consecutive T2D patients referring to our diabetes outpatient clinics (Sapienza University, Rome, Italy) for metabolic evaluations, and 29 sex, age and body mass index comparable non diabetic subjects as control group. Study participants underwent clinical work up; fasting blood sampling was performed for routine biochemistry and for inflammatory profile (CRP, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-alpha, IFN-gamma, GM-CSF, adiponectin, WISP1); serum GrB was measured by Human Granzyme-B Platinum Elisa kit (Affymetrix EBIO). We found that T2D patients had serum levels of GrB significantly higher than the control group (10.17 +/- 12.6 vs 7.2 +/- 14.1 pg/ml, p = 0.03). Moreover, in T2D patients increased GrB correlated with unfavorable inflammatory profile, as described by elevated levels of validated adipokines such as IL-6 (p = 0.04), TNF-alpha (p = 0.019) and WISP1 (p = 0.005). Furthermore, multivariate linear regression analysis showed that increased GrB was associated with T2D diagnosis independently from possible confounders. In conclusion, our results show that increased levels of circulating GrB are associated with T2D diagnosis and correlates with markers of AT-linked systemic inflammation, suggesting a potential role for GrB in the inflammatory and reactive processes occurring in metabolic diseases. PMID- 30473179 TI - The role of C-reactive protein as a predictor of treatment response in patients with ankylosing spondylitis. AB - OBJECTIVES: To determine whether C-reactive protein (CRP) level is predictive of response to tumor necrosis factor-alpha blocker treatment in patients with ankylosing spondylitis (AS) and whether there is an optimal CRP range for treatment initiation. METHODS: In this post hoc analysis, data on etanercept treated patients with AS were pooled from four randomized trials. Week 12 responses (ASAS20, ASAS50, ASDAS-CRP < 1.3, and ASDAS-CRP ? <= 1.1) were evaluated in relationship to baseline CRP levels (normal, defined as <= upper limit of normal [<= ULN]; elevated, > ULN; high, > ULN and <= 3xULN; and very high, > 3xULN), baseline levels of patient-reported outcomes (PROs), and CRP levels at weeks 2, 4, and 8, using univariate and stepwise predictor analyses. In addition, relationships between baseline CRP and other baseline predictors were analyzed using stepwise models of response. RESULTS: Among 867 patients, baseline CRP levels were normal in 371 (43%) patients, high in 299 (34%), and very high in 197 (23%). Very high baseline CRP was a significant predictor for all four week 12 outcomes, compared with normal CRP. Conversely, normal CRP at weeks 2, 4, and 8 was a stronger predictor of week 12 response than elevated CRP. PROs were less consistent predictors of response. In addition, there was a significant association between higher baseline CRP and lower age of disease onset (< 40 years) and between normal CRP and lower disease burden. CONCLUSIONS: In patients with AS, both baseline and post-baseline CRP levels can be predictive of response to treatment at week 12, more consistently than PROs. CLINICAL TRIALS: NCT00421915, NCT00247962, NCT00418548, NCT00356356. PMID- 30473180 TI - Early diagnosis of septic arthritis using synovial fluid presepsin: A preliminary study. AB - Therapeutic outcomes for septic arthritis vary greatly depending on the span of time between disease-onset and surgery. The most important factor is making an early and definitive diagnosis; however, some cases may be difficult to diagnose. We investigated presepsin, a biomarker of sepsis, to determine whether or not presepsin in synovial fluid would be useful for the diagnosis of septic arthritis. We selected 18 patients with septic arthritis including periprosthetic joint infections (SA group) and 28 patients with osteoarthritis (OA group). We measured the concentrations of synovial fluid presepsin, blood presepsin and procalcitonin (PCT) in the two groups. We compared the sensitivities and specificities of synovial fluid presepsin, blood presepsin and PCT. Synovial fluid and blood presepsin and blood PCT were all significantly higher in the SA group. Synovial fluid presepsin exhibited both 100% sensitivity and 100% specificity in the SA group, which were higher rates than those for blood presepsin and PCT. We found that synovial fluid presepsin is markedly elevated in case of septic arthritis, and therefore, it has potential as a new biomarker of septic arthritis. PMID- 30473181 TI - The first nationwide survey of antimicrobial stewardship programs conducted by the Japanese Society of Chemotherapy. PMID- 30473182 TI - Overexpression of CDK7 is associated with unfavourable prognosis in oral squamous cell carcinoma. AB - Increased expression of cyclin-dependent kinase 7 (CDK7), an ubiquitous kinase associated with cell cycle and transcription, contributes to human tumourigenesis and associates with patients' prognosis. In the present study, we sought to investigate the expression pattern of CDK7 and its clinicopathological significance in primary oral squamous cell carcinoma (OSCC). The expression of CDK7 mRNA in OSCC was determined by data mining and interrogation using the Oncomine database. Its protein expression was measured by immunohistochemistry in clinical samples from a retrospective cohort of 113 patients with primary OSCC which were treated at our institution from January 2006 to December 2016. The potential associations between CDK7 abundance and multiple clinicopathological parameters as well as patients' survival were assessed. The 4-nitroquinoline 1 oxide (4NQO)-induced OSCC mouse model was developed to monitor CDK7 expression during cancer initiation and progression. The bioinformatics analyses revealed higher CDK7 mRNA in OSCC samples compared to normal counterparts. Our immunohistochemical staining data revealed significant aberrant overexpression of CDK7 in a large subset of OSCC. Elevated CDK7 expression was found to be significantly associated with higher T-stage (p = 0.009) and reduced overall and disease-free survival (Log-rank test, p = 0.022, 0.010, respectively). Both univariate and multivariate Cox regression analysis identified the expression status of CDK7 as an important independent prognostic factor for patients' survival. Increased CDK7 expression was parallel with OSCC development in the 4NQO-induced animal model. Our findings indicate that aberrant CDK7 overexpression associates with T-stage and reduced survival in OSCC, thus suggesting that it might play critical roles underlying oral tumourigenesis and also serve as a novel biomarker with diagnostic and prognostic significance. PMID- 30473183 TI - Review of the economic evidence presented to the United States Advisory Committee on Immunization Practices, 2012-2016. AB - We identified 16 Advisory Committee on Immunization Practices (ACIP) presentations from 2012 to 2016 that indicated 'cost' or 'economic' content. Characteristics were reviewed, abstracted, and tabulated to quantify and assess the transparency and consistency of economic evidence presented to ACIP. To assess transparency, we documented if each study identified author affiliation, conflicts of interest, study limitations, a clearly described model structure and other model attributes. To assess consistency, we identified the frequency of specific modeling choices, including the perspective, types of health outcomes considered, inclusion of specific types of costs, discount rate, and use of sensitivity analyses. Our results indicate that the content in these presentations appear to be transparent overall and consistent in several important areas, such as study perspective and health outcomes. However, we find the inclusion of particular types of direct costs, indirect costs, program costs, and sensitivity analyses are areas that could improve consistency. PMID- 30473184 TI - Parents' perceptions of childhood immunization in Israel: Information and concerns. AB - BACKGROUND: Immunization has a significant impact in protecting from severe diseases. Various factors that could influence child immunization coverage and parents' decisions about vaccinating their children should be further explored in specific population groups. OBJECTIVES: The current study has two main objectives: to assess the main information sources that affect parental decisions to vaccinate their children and to measure the extent to which these factors differ demographically by exploring the opinions and attitudes within four main population groups in Israel: ultra-Orthodox Jews, all other Jews, non-Bedouin Arabs, and Bedouins. METHODS: 1504 parents, with similar representation among four main population groups, participated in this study. A structured, anonymous, self-administered questionnaire was used. RESULTS: The most influential source on parents' decisions to vaccinate their children was the nurse at Mother and Child Health Clinics (MCHCs). Positive attitudes were shown regarding the key role of immunization in preventing severe diseases, while the most important concern expressed was the potential pain to the child while being vaccinated (rather than the safety of the vaccine). Higher compliance rates were reported among participants with a non-academic education level (chi2 = 12.21, p <0.001), an average level of income (chi2 = 26.66, p <0.001), and a greater level of religiosity (chi2 = 5.13, p <0.01). Multivariate analysis showed that higher reliance on Ministry of Health publications (OR = 2.24, 95% CI = 1.49-3.35) and a belief that vaccinations prevent severe diseases (OR = 1.55, 95% CI = 1.06-2.25) predicted higher vaccination compliance. A concern about unsafe components of the vaccinations predicted lower compliance (OR = 0.41, 95% CI = 0.25-0.66). Bedouins demonstrated the highest compliance rate (99%), were most influenced by all information sources, and demonstrated the most pro-vaccination positions. CONCLUSIONS: The factor that most influenced Israeli parents' decisions to vaccinate their children was their degree of trust in information sources about vaccinations, particularly the nurses at the MCHCs. PMID- 30473185 TI - Evaluation of the safety and immunogenicity of the oral inactivated multivalent enterotoxigenic Escherichia coli vaccine ETVAX in Bangladeshi adults in a double blind, randomized, placebo-controlled Phase I trial using electrochemiluminescence and ELISA assays for immunogenicity analyses. AB - The safety and immunogenicity of the second generation oral enterotoxigenic Escherichia coli (ETEC) vaccine ETVAX, consisting of inactivated recombinant E. coli strains over-expressing the colonization factors (CFs) CFA/I, CS3, CS5 and CS6 and the heat labile toxoid LCTBA, were evaluated in Bangladeshi volunteers. To enable analysis of antibody responses against multiple vaccine antigens for subsequent use in small sample volumes from children, a sensitive electrochemiluminescence (ECL) assay for analysis of intestine-derived antibody secreting cell responses using the antibodies in lymphocyte secretions (ALS) assay was established using Meso Scale Discovery technology. Three groups of Bangladeshi adults (n = 15 per group) received two oral doses of ETVAX with or without double mutant LT (dmLT) adjuvant or placebo in the initial part of a randomized, double-blind, placebo-controlled, age-descending, dose-escalation trial. CF- and LTB-specific ALS and plasma IgA responses were analyzed by ECL and/or ELISA. ETVAX was safe and well tolerated in the adults. Magnitudes of IgA ALS responses determined by ECL and ELISA correlated well (r = 0.85 to 0.98 for the five primary antigens, P < 0.001) and ECL was selected as the ALS readout method. ALS IgA responses against each of the primary antigens were detected in 87-100% of vaccinees after the first and in 100% after the second vaccine dose. Plasma IgA responses against different CFs and LTB were observed in 62-93% and 100% of vaccinees, respectively. No statistically significant adjuvant effect of dmLT on antibody responses to any antigen was detected, but the overall antigenic breadth of the plasma IgA response tended to favor the adjuvanted vaccine when responses to 4 or more or 5 vaccine antigens were considered. Responses in placebo recipients were infrequent and mainly detected against single antigens. The promising results in adults supported testing ETVAX in descending age groups of children. ClinicalTrials.gov Identifier: NCT02531802. PMID- 30473187 TI - Clonazepam improves the symptoms of two siblings with novel variants in the SYNJ1 gene. AB - BACKGROUND: Mutations in the SYNJ1 gene have been associated with early-onset of atypical Parkinson's disease or severe neurodegeneration with intractable seizures. Due to the rarity of the disease, there were limitations in the quality of available treatment options for SYNJ1-related diseases. METHODS: Two affected siblings from a non-consanguineous family were evaluated through a set of clinical and laboratory tests. The genetic screening was performed through exome next generation sequencing. SYNJ1 mutant transcripts were purified and cloned into the vectors for Sanger sequence of single-stranded DNA. Relative level of the SYNJ1 transcript was measured by quantitative PCR. RESULTS: The clinical features were characterized by a triad of symptomatic progression including diplopia, dystonia, and Parkinsonism. The dystonic symptoms were outstanding in the siblings, which preceded the Parkinsonism symptoms and became the main symptoms. Clonazepam resolved the clinical symptoms, especially the severe trunk dystonia and dystonic postures of limbs. Compound heterozygous variants (c.2579 2A > G; p.A860Gfs*5 and c.3845C > A; p.P1282L) were identified in the SYNJ1 gene co-segregating in this family. The proline residue is highly conserved across species and predicted to be damaging by several in silico tools. The splice site variant caused a skip of exon 20 and a significant reduction of the SYNJ1 transcript expression. CONCLUSIONS: Our study expanded the clinical and genetic spectrums of the SYNJ1-related diseases. Although our study was a preliminary observation, it indicated that clonazepam could improve the dystonic symptoms caused by mutations in the SYNJ1 gene. PMID- 30473186 TI - Informing randomized clinical trials of respiratory syncytial virus vaccination during pregnancy to prevent recurrent childhood wheezing: A sample size analysis. AB - BACKGROUND: Early RSV illness is associated with wheeze-associated disorders in childhood. Candidate respiratory syncytial virus (RSV) vaccines may prevent acute RSV illness in infants. We investigated the feasibility of maternal RSV vaccine trials to demonstrate reductions in recurrent childhood wheezing in general paediatric populations. METHODS: We calculated vaccine trial effect sizes that depended on vaccine efficacy, allocation ratio, rate of early severe RSV illness, risk of recurrent wheezing at age 3, and increased risk of RSV infection on recurrent wheezing. Model inputs came from systematic reviews and meta-analyses. For each combination of inputs, we estimated the sample size required to detect the effect of vaccination on recurrent wheezing. RESULTS: There were 81 scenarios with 1:1 allocation ratio. Risk ratios between vaccination and recurrent wheezing ranged from 0.9 to 1.0 for 70% of the scenarios. Among the 57 more plausible scenarios, the lowest sample size required to detect significant reductions in recurrent wheezing was 6196 mother-infant pairs per trial arm; however, 75% and 47% of plausible scenarios required >31,060 and >100,000 mother-infant pairs per trial arm, respectively. Studies with asthma endpoints at age 5 will likely need to be larger. DISCUSSION: Clinical efficacy trials of candidate maternal RSV vaccines undertaken for licensure are unlikely to demonstrate an effect on recurrent wheezing illness due to the large sample sizes likely needed to demonstrate a significant effect. Further efforts are needed to plan for alternative study designs to estimate the impact of maternal RSV vaccine programs on recurrent childhood wheezing in general populations. PMID- 30473188 TI - Targeting Mitochondria to Revive Dysfunctional Regulatory T Cells. AB - Immunometabolism is important to T cell dysfunction in chronic infections. A recent publication in The Journal of Clinical Investigation (2018;128:5083-5094) [1] shows reduced mitochondrial fitness in regulatory CD4+ T cells (Tregs) of patients with HIV and failed immune restoration on antiretroviral therapy (ART). This defect can be reversed by IL-15, revealing a new immunotherapy target for regulatory T cell restoration. PMID- 30473189 TI - Cystic fibrosis is associated with an increased risk of Barrett's esophagus. AB - BACKGROUND: Cystic fibrosis (CF) patients have increased risks of gastrointestinal cancers, including esophageal adenocarcinoma. Gastroesophageal reflux disease (GERD) is highly prevalent in CF and manifests at early ages. CF patients may be at increased risk for long-term sequelae of chronic GERD, including Barrett's esophagus (BE). We aimed to assess whether patients with CF have an increased risk of BE or related neoplasia. METHODS: A matched cohort study was performed of adults with and without CF who had undergone upper endoscopy. Non-CF patients were matched in a 4:1 ratio by age, sex, year of exam, and endoscopist. Odds ratios were calculated for the association between CF and BE or related neoplasia, and multivariable logistic regression modeling was performed to adjust for matching variables and additional potential confounders. RESULTS: 122 CF patients underwent endoscopy, and 488 matched controls were identified. Seven (5.7%) CF patients had BE or related neoplasia, including one GE junction adenocarcinoma. Mean age of affected CF patients was 36.0, and 85.7% had a prior solid organ transplant. The odds of BE was significantly increased in CF patients (OR 2.91, 95% CI 1.08-7.81). The risk remained significantly increased in a multivariable model including matching variables (OR 3.32, 95% CI 1.19-9.22) and in a parsimonious model (OR 2.99, 95% CI 1.06-8.42). CONCLUSIONS: Adults with CF have a 3-fold increased risk of BE or related neoplasia and appears to develop at younger ages. Consideration should be given to screening for BE in select CF patients, especially those who have undergone solid organ transplantation. PMID- 30473190 TI - Dental and periodontal manifestations in patients with cystic fibrosis - A systematic review. AB - BACKGROUND: The oral cavity is an important reservoir of microorganisms and can be a potential source of infection of the respiratory tract in CF patients. The literature on the oral health does not explicitly determine dental problems in these patients. The aim of the study was to systematically review the studies relating to oral status in CF patients. METHODS: A systematic review of papers published from 1997 to 2018 regarding oral status in CF children and adults, carried out in accordance with the Cochrane Collaboration guidelines. RESULTS: The search resulted in 143 studies. Thirteen publications were included in the systematic review. CONCLUSIONS: PMID- 30473191 TI - Ulcerative keratitis due to Kocuria palustris: An emerging pathogen. PMID- 30473192 TI - Neuroimaging Applications in Dystonia. AB - Dystonia is a neurological disorder characterized by involuntary, repetitive movements. Although the precise mechanisms of dystonia development remain unknown, the diversity of its clinical phenotypes is thought to be associated with multifactorial pathophysiology, which is linked not only to alterations of brain organization, but also environmental stressors and gene mutations. This chapter will present an overview of the pathophysiology of isolated dystonia through the lens of applications of major neuroimaging methodologies, with links to genetics and environmental factors that play a prominent role in symptom manifestation. PMID- 30473193 TI - Neuroimaging Applications in Chronic Ataxias. AB - Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) are the main instruments for neuroimaging investigation of patients with chronic ataxia. MRI has a predominant diagnostic role in the single patient, based on the visual detection of three patterns of atrophy, namely, spinal atrophy, cortical cerebellar atrophy and olivopontocerebellar atrophy, which correlate with the aetiologies of inherited or sporadic ataxia. In fact spinal atrophy is observed in Friedreich ataxia, cortical cerebellar atrophy in Ataxia Telangectasia, gluten ataxia and Sporadic Adult Onset Ataxia and olivopontocerebellar atrophy in Multiple System Atrophy cerebellar type. The 39 types of dominantly inherited spinocerebellar ataxias show either cortical cerebellar atrophy or olivopontocerebellar atrophy. T2 or T2* weighted MR images can contribute to the diagnosis by revealing abnormally increased or decreased signal with a characteristic distribution. These include symmetric T2 hyperintensity of the posterior and lateral columns of the cervical spinal cord in Friedreich ataxia, diffuse and symmetric hyperintensity of the cerebellar cortex in Infantile Neuro-Axonal Dystrophy, symmetric hyperintensity of the peridentate white matter in Cerebrotendineous Xanthomatosis, and symmetric hyperintensity of the middle cerebellar peduncles and peridentate white matter, cerebral white matter and corpus callosum in Fragile X Tremor Ataxia Syndrome. Abnormally decreased T2 or T2* signal can be observed with a multifocal distribution in Ataxia Telangectasia and with a symmetric distribution in the basal ganglia in Multiple System Atrophy. T2 signal hypointensity lining diffusely the outer surfaces of the brainstem, cerebellum and cerebrum enables diagnosis of superficial siderosis of the central nervous system. The diagnostic role of nuclear medicine techniques is smaller. SPECT and PET show decreased uptake of radiotracers investigating the nigrostriatal system in Multiple System Atrophy and in patients with Fragile X Tremor Ataxia Syndrome. Semiquantitative or quantitative MRI, SPECT and PET data describing structural, microstructural and functional changes of the cerebellum, brainstem, and spinal cord have been widely applied to investigate physiopathological changes in patients with chronic ataxias. Moreover they can track diseases progression with a greater sensitivity than clinical scales. So far, a few small-size and single center studies employed neuroimaging techniques as surrogate markers of treatment effects in chronic ataxias. PMID- 30473194 TI - Neuroimaging Applications in Functional Movement Disorders. AB - Functional (psychogenic) movement disorders are a subtype of functional neurological disorder, a common and disabling cause of neurological symptoms. Abnormal movement in people with functional movement disorders has specific characteristics (e.g., distractibility, variability, incongruence with deficits caused by neurological disease), allowing positive diagnosis and differentiation from other causes of movement disorder. Attempts to understand the pathophysiology of this disorder have previously focused mainly on the psychological level, emphasizing the importance of psychological trauma and adverse life events. However, the last two decades has seen a broadening of this approach to consider the neurobiological level, and brain imaging has formed a key part of this work. Here we review the available imaging evidence in functional movement disorders and explain how this evidence can help us understand more about the underlying pathophysiology of this common cause of abnormal movement control. PMID- 30473195 TI - Transcranial B-Mode Sonography in Movement Disorders. AB - Applying a 2-4MHz probe at the temporal bone window transcranial B-mode sonography (TCS) enables the depiction of the brain parenchyma through the intact skull. Meanwhile it has been applied for the diagnosis and the differential diagnosis of movement disorders for decades. In the first part of this chapter, we summarize the technical requirements and describe the ultrasound method for optimal TCS examination. Imaging planes and the relevant structures are explained in detail. In the second part of the chapter, we focus on the role of substantia nigra hyperechogenicity for the diagnosis of Parkinson's disease (PD) and prodromal PD. In this part, we also mention the role of TCS in atypical and secondary Parkinsonian syndromes and other movement disorders. Summarizing all these information we explain how TCS can be helpful for the differential diagnosis of movement disorders. The current data show that TCS is an easily applicable and economic imaging method which can be used as an additional tool for the diagnosis of PD with a high sensitivity (>85%), specificity (>80%) and inter-rater reliability (>84%) as well as for the differential diagnosis of movement disorders. Lately, TCS has also been utilized in further areas such as the detection of individuals at risk for PD or the determination of electrode localization in patients with deep brain stimulation. An insufficient temporal bone window especially in the elderly and the necessity of an experienced investigator are limitations of this method. PMID- 30473196 TI - Imaging Transplantation in Movement Disorders. AB - Cell replacement therapy with graft transplantation has been tested as a disease modifying treatment in neurodegenerative diseases characterized by the damage of a predominant cell type, such as substantia nigra dopaminergic neurons in Parkinson's disease (PD) or striatal medium spiny projection neurons in Huntington's disease (HD). The results of these trials are mixed with success in preclinical and pilot open-label trials, which were not consistently reproduced in randomized controlled trials. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) molecular imaging and functional magnetic resonance imaging allow the graft survival, and its relationship with the host tissues to be studied in vivo. In PD, PET with [18F]DOPA showed that graft survival does not necessarily correlate with the clinical improvement and PD patients with worse outcome had lower binding in the ventral striatum and a high serotonin ([11C]DASB PET) to dopamine ([18F]DOPA PET) ratio in the grafted neurons. In HD, PET with [11C]PK11195 showed the graft survival and the clinical responses may be related to the reactive activation of the host inflammatory/immune system. Findings from these studies have been used to refine study protocols and patient selection in current clinical trials, which includes identifying suitable candidates for transplantation using imaging markers and employing multiple and/or novel PET tracers to better assess graft functions and inflammatory responses to grafts. PMID- 30473197 TI - Neuroimaging Applications in Restless Legs Syndrome. AB - Neuroimaging studies provide information useful to understand the pathophysiology of restless legs syndrome. Molecular PET and SPECT imaging findings mainly supported dysfunction of dopaminergic pathways involving not only the nigrostriatal but also mesolimbic pathways. Magnetic resonance imaging (MRI) studies have used different techniques. Studies using iron-sensitive sequences supported the presence of a regionally variable low brain iron content, mainly at the level of substantia nigra and thalamus. The search for brain structural or microstructural abnormalities by voxel-based morphometry, diffusion tensor imaging or cortical thickness analysis has reported none or variable findings in restless legs syndrome patients, most of them in regions belonging to sensorimotor and limbic/nociceptive networks. Functional MRI studies have substantially demonstrated activation or connectivity changes in the same networks. Magnetic resonance spectroscopy studies showed metabolic changes in the thalamus, which is a hub of these networks. In summary, neuroimaging findings in restless legs syndrome support the presence of reduction of brain iron content, of dysfunction of mesolimbic and nigrostriatal dopaminergic pathways, and of abnormalities at level of limbic/nociceptive and sensorimotor networks. PMID- 30473199 TI - Preface. PMID- 30473198 TI - Neuroimaging Applications in Tourette's Syndrome. AB - Tics are neurodevelopmental hyperkinetic symptoms typically associated with unpleasant sensory experiences called premonitory urges. Tourette syndrome (TS) is the primary chronic tic disorder for which medical surveillance is most frequently required, and is associated with a complex phenotypical spectrum encompassing different types of abnormal behaviors. Animal models of tics support their link to phasic activity changes throughout the sensorimotor loop of the cortico-basal ganglia-thalamo-cortical network. Event-related functional magnetic resonance imaging (fMRI) studies on patients with TS showed that the supplementary motor area relays preparatory signals related to tics to the primary motor area and other cortical regions relevant to action monitoring, following which cortico-basal ganglia-thalamo-cortical activation leads to the manifestation of tics. Despite their methodological heterogeneity, structural MRI studies highlighted the existence of anatomical markers of distinct sub phenotypes of the TS spectrum. Initial evidence suggests that combining MRI structural methods and functional intrinsic connectivity assessed during resting state could even discriminate between TS patients and control groups. MR spectroscopy and positron emission tomography studies suggest that TS may be related to a complex interplay between different neurotransmitters (particularly dopamine, GABA and glutamate), but discrepancy across studies prevents firm conclusions. Recent volumetric, cortical thickness and fMRI studies results showed an association between premonitory urges and somatosensory and insular cortical regions, involved in the processing of interoceptive and enteroceptive stimuli and motor output modulation. Finally, both structural and functional MRI studies have provided important support to the subtyping of the TS spectrum with respect to behavioral co-morbidities, in line with a "dimensional approach" to the classification of neuropsychiatric disorders, which is based on the identification of neurocognitive endophenotypes and of their anatomical substrate. PMID- 30473201 TI - Is hypnotherapy helpful for irritable bowel syndrome in primary and secondary care? PMID- 30473200 TI - Oral health, academic performance, and school absenteeism in children and adolescents: A systematic review and meta-analysis. AB - BACKGROUND: The authors conducted a systematic review and meta-analysis to provide a summary estimate of the association between oral health and academic performance. TYPES OF STUDIES REVIEWED: The authors conducted a systematic search of PubMed, Embase, and Google Scholar for studies on oral health, school absence, and academic achievement published in English from January 1945 through December 2017. Exposures included subjectively or objectively measured caries, oral pain, and periodontitis. Outcomes included school absence and school achievement. RESULTS: The authors screened a total of 2,041 studies, from which they extracted data from 14 studies of 139,989 children (12 cross-sectional studies, 1 case control study, and 1 longitudinal study). Five studies had school absence as the primary outcome, and 7 studies had student achievement as the primary outcome. Three studies included both outcomes. The authors found no studies for periodontitis. The average modified Newcastle-Ottawa Scale score was 3.93. The authors rated 10 studies as having a low risk of bias and 4 as having a high risk of bias. Qualitative synthesis suggested that poor oral health may have negative effects on student absenteeism and achievement, but study quality was highly variable. Results from meta-analyses indicated that poor oral health was significantly associated with increased odds of poor academic performance (pooled odds ratio, 1.52; 95% confidence interval, 1.20 to 1.83) and absenteeism (pooled odds ratio, 1.43; 95% confidence interval, 1.24 to 1.63). CONCLUSIONS AND PRACTICAL IMPLICATIONS: Increased focus on the broader implications of improvements in oral health for children, such as educational or socioemotional development, is of further interest to practicing dentists owing to the greater connection between oral health and general health. The authors of this study found that caries or tooth pain had a negative association with academic achievement and school absenteeism. However, study quality was limited by inconsistent exposure and outcome definitions and a predominance of cross sectional designs. Thus, causal conclusions are not supported. PMID- 30473203 TI - Reply to: Perihilar cholangiocarcinoma surgery in octogenarians. PMID- 30473202 TI - Efficacy of individual and group hypnotherapy in irritable bowel syndrome (IMAGINE): a multicentre randomised controlled trial. AB - BACKGROUND: Hypnotherapy for irritable bowel syndrome (IBS) has been used primarily in patients with refractory symptoms in specialised departments and delivered on an individual basis. We aimed to test the hypothesis that hypnotherapy would be more effective than educational supportive therapy, and that group hypnotherapy would be non-inferior to individual hypnotherapy for patients with IBS referred from primary and secondary care. METHODS: We did a multicentre randomised controlled trial (IMAGINE) in 11 hospitals in the Netherlands. Patients with IBS, aged 18-65 years, who were referred from primary or secondary care were randomly allocated (3:3:1) in blocks of six using a computer-based random number table procedure by staff not involved in the treatment to receive six sessions of individual or group hypnotherapy or group educational supportive therapy (control group). The primary outcome was adequate relief of IBS symptoms, with responders defined as patients who reported adequate relief when asked once weekly on three or four occasions in 4 consecutive weeks. We compared hypnotherapy (both groups) with control in the intention-to-treat population (excluding individuals subsequently found to be ineligible for enrolment), and assessed non-inferiority of group hypnotherapy versus individual hypnotherapy in the per-protocol population (with a non-inferiority margin of 15%) at 3 months and 12 months. This trial is registered with ISRCTN, number ISRCTN22888906, and is completed. FINDINGS: Between May 31, 2011, and April 6, 2016, 494 patients referred for psychological treatment for IBS were assessed for eligibility, of whom 354 were randomly allocated to the three groups: 150 to individual hypnotherapy, 150 to group hypnotherapy, and 54 to educational supportive therapy. After exclusion of individuals subsequently found to be ineligible for enrolment, 142 patients in the individual hypnotherapy group, 146 in the group hypnotherapy group, and 54 in the control group were included in the intention-to-treat population. Of these, 22 (15%) patients in the individual hypnotherapy group, 22 (15%) in the group hypnotherapy group, and 11 (20%) in the control group dropped out before or during therapy. In the intention-to-treat analysis, the adequate response rate was 40.8% (95% CI 31.7-50.5) in the individual hypnotherapy group, 33.2% (24.3-43.5) in the group hypnotherapy group, and 16.7% (7.6-32.6) in the control group at 3 months. At 12 months, 40.8% (31.3 51.1) of patients in the individual hypnotherapy group, 49.5% (38.8-60.0) of patients in the group hypnotherapy group, and 22.6% (11.5-39.5) of patients in the control group reported adequate relief. Hypnotherapy was more effective than control at 3 months (odds ratio 2.9, 95% CI 1.2-7.4, p=0.0240) and 12 months (2.8, 1.2-6.7, p=0.0185). In the per-protocol analysis, 49.9% (39.2-60.6) in the individual hypnotherapy group and 42.7% (32.3-53.8) in the group hypnotherapy group had adequate relief at 3 months, and 55.5% (43.4-67.1) of individual and 51.7% (40.2-63.0) of group hypnotherapy patients reported adequate relief at 12 months. Group hypnotherapy was therefore non-inferior to individual hypnotherapy. Eight unexpected serious adverse reactions (six in the individual hypnotherapy group and two in the group hypnotherapy group) were reported, most of which were cancer or inflammatory bowel disease, and were judged by the medical ethics committee as not being related to the therapy. INTERPRETATION: Hypnotherapy should be considered as a possible treatment for patients with IBS in primary and secondary care. Furthermore, group therapy could allow many more patients to be treated for the same cost. FUNDING: None. PMID- 30473204 TI - Risk of severe erectile dysfunction in primary hyperaldosteronism: A population based propensity score matching cohort study. AB - BACKGROUND: An elevated plasma aldosterone level has been reported as an independent risk factor for severe erectile dysfunction in men. The aim of this study was to explore whether primary hyperaldosteronism patients experience erectile dysfunction after targeted treatment. METHODS: We conducted a population based cohort study of men with newly identified primary hyperaldosteronism/aldosterone-producing adenoma from January 1, 1997, to December 31, 2009. Men with essential hypertension and normotension were matched to the primary hyperaldosteronism group according to propensity score matching. RESULTS: We identified 1,067 men with primary hyperaldosteronism (mean age, 46.7 +/- 12.8 years) and matched them with the same number of men with essential hypertension or normotension. During the mean follow-up interval of 5.4 years, the incident rates of total erectile dysfunction were 5.7, 3.9, and 3.1 per 1,000 person-years for the primary hyperaldosteronism, essential hypertension, and normotension groups, respectively. Men with primary hyperaldosteronism exhibited a higher risk of erectile dysfunction compared with men with normotension (competing risks hazard ratio, 1.83), and no difference was seen in comparison with men who have essential hypertension. After adrenalectomy, men who have primary hyperaldosteronism had a higher risk of exhibiting severe erectile dysfunction compared with men who have essential hypertension (competing risks hazard ratio, 2.44) or normotension (competing risks hazard ratio, 2.90). CONCLUSION: Men with primary hyperaldosteronism reported a higher incidence of severe erectile dysfunction than normotension controls despite targeted treatment. The risk of severe erectile dysfunction increased after men who have primary hyperaldosteronism underwent adrenalectomy. This result raises the possibility of severe erectile dysfunction after adrenalectomy and calls for a prospective large-scale study of men who have aldosterone-producing adenoma regarding their erectile function both before and after adrenalectomy. PMID- 30473206 TI - [?Neurodegeneration and poor long-term post-vacuum results in hydrocephaly at idiopathic normal pressure? Contributions by Aragones et al]. PMID- 30473205 TI - Assessment of volume preservation performed before or after partial nephrectomy accurately predicts postoperative renal function: Results from a prospective multicenter study. AB - PURPOSE: Partial nephrectomy (PN) is standard for small renal masses, improving renal function by preserving renal parenchyma compared with radical nephrectomy. Recent work demonstrated that postoperative surgeon assessment of volume preservation (SAVP) and 3D imaging measurements agree and correlate with postoperative function. We hypothesize preoperative assessment of volume preservation (PAVP) with PN based on preoperative imaging will reliably indicate postoperative renal function. MATERIALS AND METHODS: Data were collected from 336 patients undergoing PN for suspected renal cancer by 40 surgeons at 12 centers in Europe and the United States within the Surface-Intermediate-Base International Consortium. Surgeons recorded PAVP and SAVP for individual patients; pre- and postoperative glomerular filtration rate (GFR) was estimated by Chronic Kidney Disease Epidemiology Collaboration equations. Correlations between PAVP, SAVP, and postoperative GFR were assessed with linear regression models. Bland-Altman analysis was used to assess agreement between PAVP and SAVP with a significant cutoff of 5%. RESULTS: Median PAVP was 90% (interquartile range [IQR] 85%-100%) and SAVP was 90% (IQR: 80%-94%). PAVP and SAVP were moderately correlated (R2 = 0.67, P < 0.0001) and deemed "interchangeable" by Bland-Altman analysis at a 5% acceptable rate of difference (95% CI: -5.4, -3.1). Median postoperative GFR was 77.3 (IQR: 56.2, 92.0). Both PAVP (R2 = 0.82, P < 0.0001) and SAVP (R2 = 0.83, P < 0.0001) were correlated with postoperative GFR. Multivariable models utilizing volume-adjusted GFR based on PAVP or SAVP significantly and similarly predicted postoperative GFR (R2 = 0.72 for each). CONCLUSION: Renal function is closely linked to the amount of parenchymal volume preservation, whether estimated prior to surgery (PAVP) or afterward (SAVP). PAVP provides reasonably accurate information for decision-making in patients considering PN. PMID- 30473207 TI - The role of Natural Cycle IVF in assisted reproduction. AB - Natural Cycle IVF (NC-IVF) with and without modifications is being increasingly performed. NC-IVF and conventional gonadotropin-stimulated IVF (cIVF) should not be understood as competing treatments, but as complementary treatments with different target groups and to some extent other indications. NC-IVF is particularly interesting for couples who wish to save money, wish a treatment with as few risks as possible and for women who would like to avoid selection and cryopreservation of embryos. NC-IVF therefore contributes to the concept of individualized and patient-oriented therapy. The time to pregnancy is slightly longer than with conventional IVF. NC-IVF is particularly suitable for younger women and for women with a very low ovarian reserve. In this article, the principles of NC-IVF, i.e. monofollicular IVF without gonadotropin stimulation, are described and the technical differences to cIVF, advantages and disadvantages, perinatal outcome and indications for NC-IVF are highlightened. PMID- 30473208 TI - Towards complication-free assisted reproduction technology. AB - Assisted reproductive technology (ART) has vastly improved over the last 40 years, from a frequently unsuccessful and complicated procedure requiring hospital admission and routine laparoscopy to a fairly simple outpatient technique with relatively high success rates. However, it is important to stress that ART is not without risk and medical complications may still occur. The incidence of most of these ART-related complications is associated with how women undergo ovarian stimulation. For this reason, physicians should be aware that a carefully thought-out ovarian stimulation protocol and cycle monitoring are of paramount importance to maximise the success of the treatment while avoiding potentially life-threating complications to occur in this frequently otherwise healthy patient population. This review discusses the rationale and evolution of ovarian stimulation strategies over the years and the current developments towards finding a balance between the retrieval of a sufficient number of oocytes and ART-related complication prevention. PMID- 30473209 TI - Shared multisensory experience affects Others' boundary: The enfacement illusion in schizophrenia. AB - Schizophrenia has been described as a psychiatric condition characterized by deficits in one's own and others' face recognition, as well as by a disturbed sense of body-ownership. To date, no study has integrated these two lines of research with the aim of investigating Enfacement Illusion (EI) proneness in schizophrenia. To accomplish this goal, the classic EI protocol was adapted to test the potential plasticity of both Self-Other and Other-Other boundaries. Results showed that EI induced the expected malleability of Self-Other boundary among both controls and patients. Interestingly, for the first time, the present study demonstrates that also the Other-Other boundary was influenced by EI. Furthermore, comparing the two groups, the malleability of the Other-Other boundary showed an opposite modulation. These results suggest that, instead of greater Self-Other boundary plasticity, a qualitative difference can be detected between schizophrenia patients and controls in the malleability of the Other Other boundary. The present study points out a totally new aspect about body illusions and schizophrenia disorder, demonstrating that EI is not only confined to self-sphere but it also affects the way we discriminate others, representing a potential crucial aspect in the social domain. PMID- 30473210 TI - Can N-acetylcysteine, varenicline, or the combination prevent psychosis by enhancing mismatch negativity? PMID- 30473211 TI - Social dysfunction in preclinical, at risk stages of psychosis: A developmental view. PMID- 30473212 TI - Maternal transmission of CNTN6 copy number variation suggests mitochondrial disorder. PMID- 30473214 TI - Pravastatin sodium attenuated TREM-1-mediated inflammation in human peripheral blood mononuclear cells. AB - Pravastatin sodium on triggering receptor expressed on myeloid cell-1 (TREM-1) mediated inflammation in human peripheral blood mononuclear cells (PBMCs) has been poorly investigated. In this study, we isolated PBMCs from the peripheral blood samples of patients with chronic obstructive pulmonary disease, treated the cells with pravastatin sodium, and determined a concentration at which more than 90% cells could survive. Then we treated cells with 10 ng/ml of lipopolysaccharide, added with 10, 50, 100 MUM of pravastatin sodium combined with or without LR-12, a known TREM-1 inhibitor. The expression of TREM-1 was determined by quantitative RT-PCR. The levels of TREM-1, IL-6, and TNF-alpha in cell culture supernatant were measured with ELISA. Simultaneously, NF-kappaB signaling pathway-related protein p-p65 and p-IkappaBalpha were detected by Western blot assay. Results demonstrated that pravastatin sodium significantly mitigated lipopolysaccharide-stimulated TREM-1 over-expression at mRNA and protein levels dose-dependently. Elevated IL-6 and TNF-alpha levels changed synchronously. LR-12 inhibited the TREM-1 over-expression and inflammatory factor production but did not show extra synergistic effect to pravastatin. Lipopolysaccharide induced phospho-p65 and -IkappaBalpha over-expression was weakened significantly when cells were treated with pravastatin sodium. In conclusion, pravastatin could inhibit TREM-1-medieted inflammation and NF-kappaB signaling pathway was involved. PMID- 30473213 TI - Abnormalities in the evoked frontal oscillatory activity of first-episode psychosis: A TMS/EEG study. AB - TMS with simultaneous EEG allows assessing the intrinsic oscillatory activity of cortical neurons. We recently showed reduced frontal cortical oscillations in chronic schizophrenia (SCZ). Here we investigated the oscillatory activity of first-episode psychosis (FEP) patients after TMS of a frontal area, the motor cortex. Compared to healthy controls, FEP patients had significantly reduced beta/low gamma oscillations, which were associated to worse clinical symptoms. Altogether, this study demonstrates that TMS/EEG recordings: 1) are feasible in acute, early-course psychotic patients; and 2) reveal intrinsic oscillatory deficits at illness onset, which may help design more effective, early interventions in SCZ. PMID- 30473215 TI - XBP1-s promotes colorectal cancer cell proliferation by inhibiting TAp73 transcriptional activity. AB - Endoplasmic reticulum (ER) stress activation could be found in a wide range of human tumors. ER stress induces the splicing of X-box binding protein 1 (XBP1) to form its splicing variant XBP1-s, which in turn activates various ER stress related genes. XBP1-s is highly expressed in various tumors; however, its role in tumorigenesis is still largely unknown. Herein we showed that XBP1-s suppresses the expression of tumor suppressor TAp73, a member of p53 family with high homology with p53, by directly binds to TAp73 promoter and suppresses its transcriptional activity. We also found that overexpression of TAp73 cancelled the effect of XPB1-s on enhancing colorectal cancer cells proliferation and colony formation potential, indicating that TAp73 is critical for XBP1-s-induced tumorigenesis. Together, our findings not only reveal a novel mechanism of TAp73 aberrant regulation in tumor cells, but also link up tumor cells ER stress with tumor suppressive activity of TAp73. PMID- 30473216 TI - Long noncoding RNA ENST00000455974 plays an oncogenic role through up-regulating JAG2 in human DNA mismatch repair-proficient colon cancer. AB - DNA mismatch repair-proficient colon cancer is the most common type of colon cancer, but its initiation and progression are still unknown. Our previous study has revealed that a long noncoding RNA (lncRNA) ENST00000455974 was significantly associated with TNM stage and distant metastasis in patients with DNA mismatch repair-proficient (pMMR) colon cancer (CC). Here, firstly, we observed that ENST00000455974 was gradual increased across colon normal-adenoma-carcinoma metastasis sequence by quantitative real-time PCR. Secondly, ENST00000455974 showed a better sensitivity and specificity than CEA and CA19-9 in the diagnosis of pMMR CC by drawing the receiver operating characteristic (ROC) curve. Thirdly, a higher level of ENST00000455974 was associated with a poorer patient survival. Furthermore, Knockdown of ENST00000455974 led to reduced proliferation and migration of colon cancer cells. Mechanistically, ENST00000455974 was mainly located in the nucleus of colon cancer cells and it promoted the growth and metastasis of pMMR CC cells through up-regulating JAG2. PMID- 30473217 TI - Adipose mesenchymal stem cell-derived exosomes ameliorate hypoxia/serum deprivation-induced osteocyte apoptosis and osteocyte-mediated osteoclastogenesis in vitro. AB - Age-related skeletal changes is closely associated with imbalanced bone remodeling characterized by elevated osteocyte apoptosis and osteoclast activation. Since osteocytes are the commander of bone remodeling, attenuating increased osteocyte apoptosis may improve age-related bone loss. Exosomes, derived from mesenchymal stem cells, hold promising potential for cell-free therapy due to multiple abilities, such as promoting proliferation and suppressing apoptosis. We aimed to explore the effect of exosomes derived from adipose mesenchymal stem cell (ADSCs-exo) on osteocyte apoptosis and osteocyte mediated osteoclastogenesis in vitro. The osteocyte-like cell line MLO-Y4 was used as a model, and apoptosis was induced by hypoxia and serum deprivation (H/SD). Our results showed that ADSCs-exo noticeably reduced H/SD-induced apoptosis in MLO-Y4 cells via upregulating the radio of Bcl-2/Bax, diminishing the production of reactive oxygen species and cytochrome c, and subsequent activation of caspase-9 and caspase-3. Additionally, ADSCs-exo lowered the expression of RANKL both at the mRNA and protein levels, as well as the ratio of RANKL/OPG at the gene level. As determined by tartrate-resistant acid phosphatase staining, reduced osteoclastogenesis was further validated in bone marrow monocytes cultured under conditioned medium from exosome-treated MLO-Y4. Together, ADSCs-exo could antagonize H/SD induced osteocyte apoptosis and osteocyte-mediated osteoclastogenesis, indicating the therapeutic potential of ADSCs-exo in age-related bone disease. PMID- 30473218 TI - The transcription factor Kruppel-like factor 5 promotes cell growth and metastasis via activating PI3K/AKT/Snail signaling in hepatocellular carcinoma. AB - The transcription factor Kruppel-like factor 5 (KLF5) is highly expressed in many cancers and serves as a prognostic factor. However, the function of KLF5 in hepatocellular carcinoma (HCC) is unclear. In this study, we found that KLF5 was significantly overexpressed in HCC cell lines and specimens, and high KLF5 expression predicted a poor prognosis for HCC patients. Then, we studied the effects of KLF5 on the proliferation, apoptosis, migration and invasion of HCC cells in vitro and vivo. The inhibition of KLF5 markedly inhibited HCC growth and metastasis, while KLF5 overexpression promoted these processes. In addition, we observed that KLF5 could promote the epithelial-mesenchymal transition (EMT) in HCC via the PI3K/AKT/Snail signaling pathway. The silencing of KLF5 in HCC cell lines downregulated the expression of N-cadherin, Vimentin and Snail and increased the expression of the epithelial marker E-cadherin. The expression of MMP2 and MMP9 was also decreased in KLF5-silenced HCC cells. However, opposite results were observed in the KLF5-overexpressing group. These results indicate that KLF5 plays a significant role in HCC progression and metastasis and induces EMT via activating PI3K/AKT/Snail signaling, and the inhibition of KLF5 may be a potential treatment modality for patients with HCC. PMID- 30473219 TI - Role and mechanism of miR-4778-3p and its targets NR2C2 and Med19 in cervical cancer radioresistance. AB - The aim of this study was to investigate the effect of miR-4778-3p on the radiosensitivity of cervical cancer cells and to elucidate the underlying mechanism. Tissue samples were collected from eight patients with cervical cancer prior to chemoradiotherapy. MicroRNA chip analyses, RT-PCR, gene transfection, CCK8, wound healing and Transwell assays, colony-forming assay, western blot, and the Dual-Luciferase Reporter Assay System were used to evaluate the role of miR 4778-3p in cervical cancer radiosensitivity and its relationships with target molecules NR2C2 and Med19. Thirty-two differentially expressed miRNA molecules (fold-change > 2; p < 0.05) associated with cervical cancer radioresistance were identified. The expression of miR-4778-3p was significantly lower in recurrent or metastatic patients than in control subjects. In vitro studies using radioresistant HeLa and SiHa cervical cancer cell lines showed that miR-4778-3p upregulation significantly inhibited cell proliferation, invasiveness, and migration after irradiation. There was also a significant increase in apoptosis and a significant decrease in the proportion of cells at the G2/M phase. Further, miR-4778-3p upregulation led to increased expression of apoptosis-related molecules, such as Bax, Caspase-3, Caspase-8, and Caspase-9. Reporter gene assays showed that miR-4778-3p bound specifically to NR2C2 and Med19 and negatively regulated their expression. Thus, miR-4778-3p reduces the vitality, proliferation, and migration of radioresistant cervical cancer cells and may regulate the radiosensitivity of cervical cancer by targeting and regulating NR2C2 and Med19 expression. PMID- 30473220 TI - Predictors of hepatocellular carcinoma in HCV cirrhotic patients treated with direct acting antivirals. AB - BACKGROUND: Despite the dramatic improvement in viral eradication rates that has been reached with direct antiviral agents (DAAs), the real benefit of viral eradication after DAAs on hepatocellular carcinoma (HCC) development is still controversial. AIM: To prospectively assess the risk of HCC occurrence and early recurrence in a large cohort of DAA-treated HCV-cirrhotic patients and to identify potential predictors of HCC development. METHODS: We analyzed data prospectively collected from 1927 consecutive HCV-infected cirrhotic patients treated with DAA from January to December 2015 in 10 tertiary liver centers in Italy and followed-up for one year after therapy. 161 patients had a previous HCC. RESULTS: 38/161 subjects developed tumor recurrence during the follow-up (recurrence rate = 24.8 per 100-year), patients with SVR had a significantly lower rate of recurrence. Lack of SVR and alpha-fetoprotein (AFP) were independent predictors of HCC recurrence. 50/1766 patients without a previous HCC history developed HCC during follow-up (incidence rate = 2.4 per 100-year). Lack of SVR was the strongest predictor of HCC development. Furthermore, patients with SVR and no stigmata of portal hypertension have a lower incidence rate of HCC (1.0 per 100-year). CONCLUSIONS: SVR is associated with a significant decrease of recurrent or de novo HCC. Baseline AFP and signs of portal hypertension can help to stratify the risk of HCC. PMID- 30473221 TI - Contraceptive knowledge and use among women with intellectual, physical, or sensory disabilities: A systematic review. AB - BACKGROUND: Women spend most of their reproductive years avoiding pregnancy. However, we know little about contraceptive knowledge and use among women with disabilities, or about strategies to improve contraceptive knowledge and decision making in this population. OBJECTIVE: To systematically review published literature on women with disabilities and: 1) contraceptive knowledge; 2) attitudes and preferences regarding contraception; 3) contraceptive use; 4) barriers and facilitators to informed contraceptive use; and 5) effectiveness of interventions to improve informed contraceptive decision-making and use. METHODS: We searched MEDLINE, PsychINFO, the Cochrane Library, CINAHL, and ERIC databases from inception through December 2017. Two reviewers independently reviewed studies for eligibility, abstracted study data, and assessed risk of bias following PRISMA guidance. RESULTS: We reviewed 11,659 citations to identify 62 publications of 54 unique studies (total n of women with disabilities = 21,246). No standard definition of disability existed across studies. The majority of studies focused on women with intellectual disabilities (ID). Women with ID and those who were deaf or hard-of-hearing had lower knowledge of contraceptive methods than women without disabilities. Estimates of contraceptive use varied widely, with some evidence that women with disabilities may use a narrower range of methods. Five of six studies evaluating educational interventions to increase contraceptive knowledge or use reported post-intervention improvements. CONCLUSIONS: Women with disabilities may use a more narrow mix of contraceptive methods and are often less knowledgeable about contraceptives than women without disabilities. Interventions to improve knowledge show some promise. A lack of data exists on contraceptive preferences among women with disabilities. PMID- 30473222 TI - [Sporadic lymphangioleiomyomatosis: A rare cause of bilateral spontaneous pneumothorax in young woman]. AB - Sporadic lymphangioleiomyomatosis is an orphan disease of the young woman. Its clinical manifestations are mainly respiratory, including spontaneous pneumothorax. The management is multidisciplinary. We report the case of a young patient with bilateral spontaneous pneumothorax revealing sporadic lymphangioleiomyomatosis. PMID- 30473223 TI - [Medium and long-term respiratory outcome in patients operated from congenital diaphragmatic hernia: From a series of 56 patients]. AB - INTRODUCTION: Recent advances in prenatal diagnosis, high frequency oscillatory ventilation and pulmonary arterial hypertension (PAH) therapies have progressively improved the survival of patients with congenital diaphragmatic hernia (CDH). However, CDH is associated with high morbidity that affects about half of surviving children. The main sequelae observed are respiratory (asthma, persistent PAH [PPAH], bronchopulmonary dysplasia, respiratory infections) and digestive (gastroesophageal reflux disease [GERD]). METHOD: This retrospective study focuses on the medium and long-term respiratory evolution of a cohort of 56 children with CDH and operated at Strasbourg University Hospital between 1999 and 2017. RESULTS: The mean age at assessment was 6,6 years (minimum: 5 months; maximum: 19 years). Seventeen patients (30 %) had asthmatic manifestations. Pulmonary Function Tests (PFT) showed obstructive patterns in 5/11 patients (2 with post-bronchodilator reversibility), and restrictive impairment in 5/11 patients, 3 of whom had thoracic deformity and/or scoliosis. Thirteen patients (23 %) had bronchopulmonary dysplasia. Few patients had recurrent respiratory infections (3.6 %) and chronic respiratory insufficiency (5.3 %). Thirty-nine patients (70 %) presented with an initial PAH, two of whom progressed to PPAH. Sixteen patients (29 %) had thoracic deformity and/or scoliosis and 48 patients (86 %) had GERD, 10 of whom had fundoplication. CONCLUSION: The long-term respiratory outcome of CDH operated patients is characterized by a moderate prevalence of respiratory symptoms and alterations in PFT that are important to consider in their medical follow-up during adolescence and adulthood. PAH is common in the neonatal period but rarely seems to persist. PMID- 30473224 TI - Differences in hospital outcomes following traumatic injury for patients experiencing immediate transfer to a level I trauma facility versus resuscitation at a critical access hospital (CAH). AB - BACKGROUND: Critical access hospitals (CAH) serve a key role in providing medical care to rural patients. The purpose of this study was to assess effectiveness of CAHs in initial care of trauma patients. METHODS: A 5-year retrospective review was conducted of all adult trauma patients who were transported directly to a level I trauma facility or were transported to a CAH then transferred to a level I trauma facility after initial resuscitation. RESULTS: Of 1478 patients studied, 1084 were transferred from a CAH with 394 transported directly to the level I facility. Patients transported directly to the level I hospital were younger and more severely injured. After controlling for injury severity score, age, GCS, and shock, the odds of mortality did not differ between CAH transfer patients and patients transported directly to a level I facility (OR 0.70, P = 0.20). Transfer from CAH was associated with decreased ICU and hospital days, but not associated with increased ventilator days. CONCLUSION: This study demonstrates that use of a CAH for initial trauma care in rural areas is effective. PMID- 30473225 TI - Preoperative endoscopic retrograde cholangio-pancreatography (ERCP) is a risk factor for surgical site infections after laparoscopic cholecystectomy. AB - BACKGROUND: We sought to examine whether preoperative endoscopic retrograde cholangio-pancreatography (ERCP) increases the risk of surgical site infections (SSI) after laparoscopic cholecystectomy. METHODS: Patients admitted to an academic hospital from 2010 to 2016, who were older than 18 and had a laparoscopic or a laparoscopic converted to open cholecystectomy for complicated biliary tract disease were included. We compared those who had a preoperative ERCP to those who did not. Our primary endpoint was the rate of SSI. RESULTS: A total of 640 patients were included. Of them, 122 (19.1%) received preoperative ERCP and 518 (80.9%) did not. The former had different preoperative diagnoses compared to non-ERCP patients (choledocholithiasis [35.2%-7.0%], acute cholecystitis [31.2%-76.4%], gallstone pancreatitis [20.5%-16.2%], and cholangitis [13.1%-0.4%], p < 0.001). The rate of SSI was higher in the preoperative ERCP group (11.5%-4.0%, p = 0.005). In a multivariable analysis conversion to open (OR = 2.57, 95% CI = 1.06-6.21, p = 0.037) and preoperative ERCP (OR = 3.12, 95% CI = 1.34-7.22, p = 0.008) were the only independent predictors of SSI. CONCLUSION: Preoperative ERCP is associated with a threefold increase in the risk of SSI after laparoscopic cholecystectomy. PMID- 30473226 TI - Comparison of cost and outcomes in patients receiving thoracic epidural versus liposomal bupivacaine for video-assisted thoracoscopic pulmonary resection. AB - BACKGROUND: Thoracic Epidural has long been the most recommended treatment for postoperative pain management in general thoracic surgery. This study compares liposomal bupivacaine (LB) as an alternative method for pain control and compares it to the standard. METHODS: LB was compared to thoracic epidural bupivacaine hydrochloride (TE BH) in 387 patients who underwent video-assisted thoracoscopic pulmonary resection (VATS-R) at our institution. Patients received either continuous TE BH or intraoperative LB at a predetermined dose. A total of 237 patients received TE BH from April 2010 to March 2014 and 143 patients received LB from April 2014 to March 2016. After propensity matching, 95 patients in each group had similar demographics and clinical characteristics including gender, age, race, American Society of Anesthesia (ASA) classification, Zubrod scores, and FEV1 and DLCO percent predicted measurements. Outcome measures included hospital costs, length of stay (LOS), adverse events, postoperative opioid medication use, and pain scores. RESULTS: Compared to the TE BH group, the LB group had significantly lower pain scores (average visual analogue scale the day of surgery: 3.9 versus 4.5, p < 0.05), decreased postoperative opioid medication (morphine equivalent dose during the first 3 days: 344.5 versus 269.5, p < 0.05), and lower total and direct hospital costs ($2906 and $1865 respectively, p < 0.05). Although a shorter LOS in the LB group was not statistically significant (4.3 versus 5.1 days, p = 0.156), more patients in the LB group were discharged directly home than the control group (44.2% versus 28.4%, p < 0.05). There was no difference noted in overall adverse events including 30-day readmissions between the two groups. CONCLUSION: LB is a viable alternative for pain management in patients undergoing VATS-R. With recent scrutiny on healthcare costs and the opioid epidemic, these results are encouraging and should be further investigated. PMID- 30473227 TI - Frailty predicts severe postoperative complications after elective colorectal surgery. AB - BACKGROUND: We aim to clarify if frailty affects severe postoperative complications in elective colorectal surgery. METHODS: Consecutive 269 colorectal cancer patients older than 65 years undergoing curative surgery were enrolled in this study. The relevance of the frailty and sarcopenia to postoperative outcome was assessed. Clinical frailty (CF) was defined as clinical frailty scale (CFS) >= 4. Sarcopenia was assessed by measuring skeletal muscle area using computed tomography. RESULTS: Seventy-eight patients (29%) had CF and 159 patients (59%) had sarcopenia. CF was significantly associated with older age (P = 0.0008), postoperative severe complications (P = 0.001), and postoperative in-hospital stay (P < 0.0001), although sarcopenia was not. Logistic regression analysis revealed that low anterior resection and CF were independent predictors of severe postoperative complications (P = 0.038 and P = 0.001, respectively). CONCLUSION: CF, but not sarcopenia, is a robust predictor of severe postoperative complications in patients with colorectal cancer. PMID- 30473228 TI - Proximal Femoral Allograft-Prosthetic Composites: Do They Really Restore Bone? A Retrospective Review of Revision Allograft-Prosthetic Composites. AB - BACKGROUND: Large bone deficiencies are a challenging problem, historically treated with an allograft-prosthetic composite (APC) or megaprosthesis. There were several advantages of the APC compared with early megaprostheses, including the theoretical benefit of restoring bone stock. To our knowledge, there are no studies that have evaluated this claim. Our purpose was to review our institution's experience with APCs of the proximal femur that underwent revision for an aseptic cause and determine if the allograft bone was retained or removed during the revision procedure. METHODS: We identified 203 proximal femoral allograft prosthetic composites placed from 1988 through 2014. Twenty-seven of these patients underwent a revision because of an aseptic cause. Three categories were devised to classify the amount of allograft retention: type A, complete allograft retention; type B, partial retention; and type C, no allograft retention. RESULTS: The mean time from the initial APC to revision surgery was 5 years. The most common indication for revision included failure of the allograft (loosening or fracture). At the time of revision, there were 3 type A cases (11%), 4 type B cases (15%), and 20 type C cases (74%). Three of the 4 type B cases used the retained allograft as a strut graft around a newly inserted megaprosthesis. CONCLUSION: The results of this study are contradictory to previous literature that suggests APCs restore bone stock. In this series, the allograft was retained in only a small percentage of cases when the APC was revised for an aseptic cause. LEVEL OF EVIDENCE: IV. PMID- 30473229 TI - Anterior Tibial Post Impingement During Stair Climbing: A Kinematic Analysis and Clinical Outcomes. AB - BACKGROUND: Anterior tibial post impingement during gait and stair ambulation was reported in knees with posterior-stabilized prostheses. However, the link between anterior post impingement and knee kinematics and between anterior post impingement and the clinical outcome has not been well investigated. Therefore, the purpose of this study was to assess the anterior impingement to clarify the relevant kinematics and clinical results including patient-reported outcomes. METHODS: We analyzed 40 well-functioning knees in 20 patients with a posterior stabilized prosthesis due to osteoarthritis and who were followed up for 2 years or more. Dynamic lateral radiographs during stair-climbing activity were analyzed using a shape-matching technique, and anterior post impingement and the clinical outcome were assessed. RESULTS: Anterior impingement of the tibial post was observed in 13 knees (33%) during the latter half of the stance phase and at the beginning of the swing phase with the average implant flexion angle of -2.4 degrees . Implant flexion was significantly smaller, while the femoral component was located more posterior in the impingement knees. The posterior tibial slope was significantly greater in the impingement group (6.7 degrees +/- 2.0 degrees , 5.3 degrees +/- 1.9 degrees , respectively; P = .041); however, no significant differences were demonstrated in anteroposterior laxity and patient-derived assessments. CONCLUSION: To avoid anterior post impingement, the posterior tibial slope should be made at 5 degrees or less. Femoral notch-anterior post articulation should be designed to have good congruency in order to act as an anterior stabilizer in the case of impingement at knee extension. PMID- 30473230 TI - Measuring Tibial Component Rotation Following Total Knee Arthroplasty: What Is the Best Method? AB - BACKGROUND: Tibial component malrotation is associated with pain, stiffness, and altered patellofemoral kinematics in total knee arthroplasty (TKA). However, measuring tibial component rotation following TKA is difficult. Proposed protocols utilizing computed tomography (CT) lack validity and can be time consuming. This study aimed to (1) compare the reproducibility of the Berger (two dimensional CT) and Mayo (three-dimensional CT) protocols and (2) validate a simple measurement technique using an anatomical distance on two-dimensional axial CT-the Center of the Tibial tray to the tip of the Tibial Tubercle (CTTT). METHODS: Rotational alignment of 70 TKA patients was evaluated by 3 independent observers using the Berger, Mayo, and CTTT protocols. The inter-rater and intra rater interclass correlation coefficients, mean difference between measurements, and the mean measurement times were calculated. RESULTS: The intra-rater reliability for all 3 protocols was rated as "very good" (Mayo 0.96, Berger 0.85, and CTTT 0.85). The inter-rater reliability for the Mayo and the Berger method was rated as "very good" (0.87 and 0.83, respectively), and the CTTT was rated as "good" (0.79). Comparing the CTTT to the Mayo method produced an r2 value of 0.73 with 92% of CTTT measurements <=6 mm having <9 degrees of tibial component internal rotation and 93% of patients with a CTTT >=10 mm having >=9 degrees internal rotation. CONCLUSION: Three-dimensional CT is the gold standard for measuring tibial component rotational alignment. The CTTT has the strongest correlation to the Mayo method and can be reliably used as a rapid screening tool. PMID- 30473231 TI - The Effectiveness of Repeat Two-Stage Revision for the Treatment of Recalcitrant Total Knee Arthroplasty Infection. AB - BACKGROUND: The gold-standard method in North America for the management of infected total knee arthroplasty is 2-stage revision arthroplasty. This has provided generally a high success rate. However, persistent infection after 2 stage revision knee arthroplasty does occur. The purpose of this study was to predict the success rate of second, 2-stage revision arthroplasty. METHODS: All infected total knee arthroplasty treated between 2000 and 2015 that were operated by a single senior surgeon were reviewed retrospectively. Patients were stratified according to general health and limb status according to the Musculoskeletal Infection Society (MSIS) scoring system. The reinfection rate at the last follow-up was identified. The chi-square test and Fisher exact test were used to compare binary variables. RESULTS: We found a statistical relationship between the higher stage of MSIS score, type of microorganism, flap surgery, and reinfection rate after reimplantation of second two-stage surgery. There is not any statistically significant correlation between age, gender, constraint pattern of prosthesis, number of spacers, and time interval between the first and second stages of second 2-stage surgery with the numbers available in this study. CONCLUSION: Another 2-stage knee revision is an effective method of treatment. However, we found a higher incidence of failure in those patients with poor general health based on the MSIS score, inadequate soft tissue envelope and resistant bacteria. The success of second, 2-stage protocol is best in patients with optimized general health, soft tissue coverage, and antibiotic-sensitive microorganism. Patients who cannot be optimized are most likely to require amputation or knee arthrodesis than another futile 2-stage surgery. PMID- 30473232 TI - Reply to Sanguankeo and Upala on "Sleep disturbances increase the risk of dementia: A systematic review and meta-analysis". PMID- 30473233 TI - Choroidal thickness in healthy eyes using enhanced depth imaging optical coherence tomography and comparison with cases of retinitis pigmentosa. AB - INTRODUCTION: The goal of this study was to measure by spectral domain optical coherence tomography (SD-OCT) with EDI the choroidal thickness in healthy subjects and to compare these parameters with those of patients with retinitis pigmentosa (RP). METHODS: Data were obtained from 60 healthy patients without history or family history of retinal or choroidal disease or glaucoma. A case control study was also conducted on 40 eyes of 20 patients with RP and 40 eyes of 20 healthy refraction- and age-matched controls, selected from among the 60 healthy patients. OCT was used with the EDI protocol. The primary outcome measure was choroidal thickness. RESULTS: Among healthy patients, the overall choroidal thickness was 287.7MUm. Mean choroidal thickness was lower on the nasal side (236.6MUm at 2000MUm from the fovea) compared with the temporal side (262.3MUm at 2000MUm, P=0.002). It also varied according to age, being highest among 20-29 year-old patients and decreasing thereafter with increasing age. Choroidal thickness was significantly higher in healthy patients than in RP patients, regardless of the location (P<0.001). CONCLUSION: This observational study confirms that choroidal thickness varies with age and location. It decreases in subjects with RP and is related to worsening of retinal damage, independently of age-related thinning. Further studies are needed to understand whether choroidal vascular alteration is a cause or a consequence of the degenerative pathology. PMID- 30473234 TI - [In vivo confocal microscopy and optical coherence tomography as innovative tools for the diagnosis of limbal stem cell deficiency (French translation of the article)]. AB - The limbus is the anatomical and functional barrier between corneal and conjunctival epithelia. It is characterized by presence of the limbal stem cell niche which allows corneal homeostasis to be maintained. Limbal stem cell deficiency is characterized by a dual process: insufficient regeneration of corneal epithelium, which cannot therefore assure its function of physiological support, associated with corneal invasion by conjunctival proliferation. Diagnosis is currently made via routine clinical examination, corneal impression cytology and in vivo confocal microscopy (IVCM). Slit lamp examination shows abnormal limbal anatomy, thin and irregular epithelium with late fluorescein staining, and superficial vascularization. With its high resolution, IVCM allows identification of limbal and corneal epithelial changes at a cellular level in en face views, parallel to the corneal surface, but with a restricted viewing field of the corneal surface. It shows a poor transition between the corneal and conjunctival epithelia, associated with a loss of the normal corneal epithelial stratification, low basal cell and sub-basal nerve plexus densities, even with sub-epithelial fibrosis. Optical coherence tomography in central cornea and at the limbus, with scans in different orientations, allows a quick, global and non invasive analysis of normal eyes and those with limbal stem cell deficiency. It shows a thin limbal epithelium, lacking normal thickening, featuring absence of stromal undulations and limbal crypts in cross-sections and sections parallel to the limbus, lack of visible limbal crypts in en face sections, loss of clear transition between the hyporeflective corneal epithelium and the hyperreflective conjunctival epithelium, and hyperreflective sub-epithelial fibrosis. PMID- 30473236 TI - Severe color change in corneal tattoos: Report of 3 cases. AB - INTRODUCTION: Corneal tattooing is a noninvasive technique which appears relatively well-tolerated in the medium term. We report the cases of 3 patients with a significant change in the color of their tattoos performed over 5 years previously. PATIENTS AND METHODS: Three patients with a history of intracorneal tattooing several years previously were studied because of a significant change from their initial color. Each patient's file was reviewed with analysis of slit lamp photographs, OCT and specular microscopy. RESULTS: All three patients experienced a significant color change in their tattoos between 5 and 6 years after surgery. The color had changed to golden-brown. DISCUSSION: Retrospective analysis of the components of the tattoo ink found the presence of iron in the black pigment. We believe that pigments composed of iron oxide are transformed into golden-brown ferric iron oxide in the presence of oxygen in the aqueous environment. The presence of moderate corneal edema in these three cases of multioperated patients could explain, in these specific cases, the occurrence of oxidation typically not described. CONCLUSION: Corneal tattooing remains a simple and very interesting technique when partial or total absence of iris causes significant photophobia. However, the significant changes in color that we report more than 5 years later suggest removing iron from the dyes used for the cornea and limiting its use in cases of limited endothelial prognosis. A long-term evaluation of corneal tattoos appears necessary. PMID- 30473235 TI - Ocular surface adverse events of systemic epidermal growth factor receptor inhibitors (EGFRi): A prospective trial. AB - PURPOSE: Controversy exists regarding the safety of agents that systemically inhibit epidermal growth factor receptor (EGFRi) in oncologic patients in terms of toxicity to the ocular surface. We performed a prospective clinical study comparing the ocular surface toxicity of systemic EGFRi between a case and a control group. METHODS: Patients with lung or colon cancer were divided in two groups: 25 patients treated with systemic EGFRi and 25 control patients without EGFRi treatment. Patients in both groups were chemotherapy naive. Four visits were scheduled in a one year period comparing signs and symptoms in terms of symptom questionnaires (SIDEQ, OSDI and AVS), corneal fluorescein staining (Oxford test), tear production (Schirmer's test) and a quantitative evaluation of conjunctival chemosis and hyperemia. Basal epithelial cell density (CEBD) and corneal subepithelial nerve fiber density (CNFD) were measured and compared using confocal microscopy (Heidelberg Engineering, Germany). The differences in each variable were compared with the analysis of variance (ANOVA). A P value<0.05 was considered significant for all comparisons. RESULTS: No statistically significant differences were found between patients under EGFRi treatment and the age-matched controls in the variables analyzed. When cases and controls were evaluated separately, the case group showed a significantly worse progression of signs (chemosis score, CFS, Schirmer's) as well as in terms of CEBD and CNFD (all P<0.05). CONCLUSION: Systemic EGFRi may increase dry eye signs as well as decrease CEBD and CNFD. This study may help us to understand the true toxicity of EGFRi to the ocular surface. PMID- 30473237 TI - [Omalizumab for severe vernal keratoconjunctivitis]. PMID- 30473238 TI - Incidence of posterior capsular opacification requiring Nd:YAG capsulotomy after cataract surgery and implantation of enVista(r) MX60 IOL. AB - PURPOSE: To evaluate incidence of posterior capsule opacification requiring Nd:YAG capsulotomy over 3 years in a large series of eyes implanted with the enVista(r) MX60 Intraocular Lens (IOL). METHODS: A university-based, single center, observational study of patients' medical records was conducted. Uneventful cataract surgery patients with in-the-bag implantations of the enVista(r) MX60 IOL with a minimum of 24 months follow-up were included in the study. Exclusion criteria were insufficient follow-up (<24 months), intraoperative complications and combined surgery. The primary outcome measure was rate of YAG laser capsulotomy, while secondary outcome measures were time to YAG laser capsulotomy and rate of glistenings. RESULTS: A total of 245 eyes of 143 patients received the MX60 IOL and were followed in the same center. Of these, 226 eyes were included in the study. Mean age was 80.7+/-8.3 years and M/F ratio was 42/101 (29.4/70.6%). The mean preoperative distance (logMAR) visual acuity was 0.67+/-0.5, while postoperatively it was 0.31+/-0.5 and 0.32+/-0.5 at the last visit. The Mean+/-SD follow-up time (min-max) was 35.2+/-7.2, (24-48.4) months. The incidence of Nd:YAG capsulotomy over 3 years was 5/226 (2.2%). Average time between surgery and Nd:YAG capsulotomy was 32.17 months. Univariate analysis of age, gender, presence of comorbidity and baseline visual acuity found no predictive factors for capsulotomy. No glistenings were reported at any postoperative visit. CONCLUSION: The three-year cumulative incidence of PCO requiring Nd:YAG laser capsulotomy was 2.2% for the enVista(r) MX-60 IOL, with no glistenings observed during follow-up. This low rate confirms the excellent safety profile of this IOL. PMID- 30473239 TI - SnapshotDx Quiz: May 2016. PMID- 30473240 TI - Cells to Surgery Quiz: May 2016. PMID- 30473241 TI - Unilateral nasal obstruction alters sweet taste preference and sweet taste receptors in rat circumvallate papillae. AB - Nasal obstruction causes mouth breathing, and affects the growth and development of craniofacial structures, muscle function in the stomatognathic system, and the taste perceptive system. However, the detailed mechanism underlying the effects of nasal obstruction on taste perception has not been fully elucidated. In this study, we investigated this mechanism using the two-bottle taste preference test, immunohistological analysis, and quantification of the mRNA expression of taste related molecules in the circumvallate papillae. Neonatal male Wistar rats were divided randomly into control and experimental groups. Rats in the experimental group underwent unilateral nasal obstruction by cauterization of the external nostril at the age of 8 days. Arterial oxygen saturation (SpO2) was recorded in awake rats using collar clip sensors. Taste preference for five basic taste solutions was evaluated. Immunohistochemical analysis and quantitative real-time polymerase chain reaction (RT-PCR) were conducted to evaluate the expressions of taste-related molecules in the taste cells of the circumvallate papillae. Body weights were similar between the two groups throughout the experimental period. The SpO2 in the 7- to 12-week-old rats in the experimental group was significantly lower than that in the age-matched rats in the control group. In the two-bottle taste preference test, the sensitivities to sweet taste decreased in the experimental group. The mRNA expression of T1R2, T1R3, alpha-gustducin, and PLCbeta2 was significantly lower in the experimental group than in the control group as determined by quantitative RT-PCR, and the immunohistochemical staining for alpha-gustducin and PLCbeta2 was less prominent. These findings suggest that nasal obstruction may affect sweet taste perception via the reduced expression of taste-related molecules in the taste cells in rat circumvallate papillae. PMID- 30473242 TI - Postoperative radiographic findings of an uncemented convertible short stem for anatomic and reverse shoulder arthroplasty. AB - BACKGROUND: Several short-stemmed press-fit humeral components have been developed in recent years for anatomic total shoulder arthroplasty (TSA) as well as reverse shoulder arthroplasty (RSA). Varying radiographic outcomes have been reported, with some studies reporting concerning rates of aseptic loosening. This study analyzed the radiographic findings of a press-fit convertible short-stemmed humeral component in both TSA and RSA. METHODS: There were 150 anatomic TSAs (group 1) and 77 RSAs (group 2) analyzed radiographically at a minimum follow-up of 2 years postoperatively. Plain radiographs were reviewed for stem loosening, alignment, signs of stress shielding, and the filling ratio. RESULTS: At final follow-up, 49% of group 1 and 65% of group 2 had no evidence for radiographic changes. In those with radiographic changes, low bone adaptions were found in 83% and high adaptions in 17% in both groups. Larger stem sizes with higher filling ratios were associated with high radiographic adaptions in both groups (P = .02). The overall filling ratios were higher in group 2 (P = .002). Cortical contact of the stem led to higher bone adaptions (P = .014). CONCLUSIONS: The short humeral component analyzed in this study showed encouraging survival rates without aseptic loosening. Radiographic changes are associated with a higher filling ratio and cortical contact of the stem. Surgeons should aim to achieve fixation with the minimal required canal filling to minimize radiographic changes with the uncemented humeral component used in this study. PMID- 30473243 TI - Preoperative Patient-Reported Outcomes Measurement Information System (PROMIS) scores predict postoperative outcome in total shoulder arthroplasty patients. AB - BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) has recently been validated in orthopedic patients with upper-extremity disease. The purpose of this study was to describe preoperative and postoperative PROMIS scores in total shoulder arthroplasty (TSA) patients, compare PROMIS physical function (PF) scores with clinical functional measurements, and determine whether preoperative PROMIS scores could predict achievement of the minimal clinically important difference (MCID) postoperatively. METHODS: Preoperative and postoperative (>3 months) PROMIS scores in patients who underwent primary anatomic TSA were reviewed. Preoperative and postoperative shoulder forward flexion and external rotation were also collected. PROMIS PF, pain interference (PI), and depression scores were compared. Accuracy analyses determined whether preoperative PROMIS scores from each domain could predict postoperative achievement of the MCID in the same domain. RESULTS: The study included 62 patients. Significant improvements in PROMIS PF, PI, and depression scores, as well as forward flexion and external rotation, were found postoperatively (P < .001). The multivariate model demonstrated that preoperative PROMIS PF, PI, and depression scores were predictive of postoperative achievement of the MCID (area under the receiver operating characteristic curve, 0.70-0.87). Ninety percent cutoff scores showed that patients with a preoperative PF score lower than 31.7, PI score greater than 66.9, and depression score greater than 55.5 were more likely to achieve the MCID. CONCLUSIONS: In TSA patients, preoperative PROMIS PF, depression, and PI scores demonstrated strong to excellent abilities to predict postoperative achievement of the MCID. PROMIS PF scores were responsive to the functional improvements observed clinically. The reported cutoff scores allow surgeons to identify patients with increased or decreased probabilities of achieving a clinically meaningful improvement after TSA. PMID- 30473245 TI - E-cigarette use in Serbia: Prevalence, reasons for trying and perceptions. PMID- 30473244 TI - Comprehensive Validation Study of Quality-of-Life Questionnaire Using Objective Clinical Measures: Breast Cancer Treatment Outcome Scale (BCTOS), Brazilian Portuguese Version. AB - INTRODUCTION: When evaluating a quality-of-life questionnaire (QLQ), many validation studies do not correlate quality-of-life scores with objective measurements of complications associated with treatment. PATIENTS AND METHODS: We performed a cross-sectional observational study with 300 patients submitted to breast-conserving therapy. The patients answered the European Organization for Research and Treatment of Cancer (EORTC) QLQs C-30 and BR23, as well as the Brazilian Portuguese version of the Breast Cancer Treatment Outcome Scale (BCTOS) questionnaire. Retest, internal consistency, factorial analysis, convergent/divergent analysis, and Rasch evaluation were performed. All patients underwent physical evaluations to assess lymphedema, handgrip strength, shoulder range of motion, breast cosmesis, and breast pain, and these groups were compared on the basis of BCTOS scores. Receiver operating characteristic curve determined the predictive value of BCTOS scores associated with clinical practice. RESULTS: The internal consistencies of the BCTOS domains ranged from 0.785 to 0.895. Factor analysis grouped according to the original questionnaire. Convergent validation showed differences in the sexual functioning and sexual enjoyment domains of the EORTC BR23. Analysis of known groups found that in most domains, the scores were higher in patients with lymphedema, strength deficit, shoulder range-of-motion alteration, poor breast cosmesis, breast pain, and axillary lymphadenectomy. Using a cutoff of 1.26, lymphedema was associated with the edema domain; using a cutoff of 1.33, Late Effects Normal Tissue Task Force/Subjective, Objective, Management, Analytic pain was associated with the pain domain; and using a cutoff of 2.37, the cosmetic domain was associated with subjective cosmesis. CONCLUSION: The association of objective measurements in a validation study of quality of life qualified the study and allowed us to develop better parameters for comparisons of results of breast-conserving therapy between populations. PMID- 30473246 TI - Associations of risk factors of e-cigarette and cigarette use and susceptibility to use among baseline PATH study youth participants (2013-2014). AB - INTRODUCTION: Improved understanding of the distribution of traditional risk factors of cigarette smoking among youth who have ever used or are susceptible to e-cigarettes and cigarettes will inform future longitudinal studies examining transitions in use. METHODS: Multiple logistic regression analysis was conducted using data from youth (ages 12-17 years) who had ever heard of e-cigarettes at baseline of the PATH Study (n = 12,460) to compare the distribution of risk factors for cigarette smoking among seven mutually exclusive groups based on ever cigarette/e-cigarette use and susceptibility status. RESULTS: Compared to committed never users, youth susceptible to e-cigarettes, cigarettes, or both had increasing odds of risk factors for cigarette smoking, with those susceptible to both products at highest risk, followed by cigarettes and e-cigarettes. Compared to e-cigarette only users, dual users had higher odds of nearly all risk factors (aOR range = 1.6-6.8) and cigarette only smokers had higher odds of other (non-e cigarette) tobacco use (aOR range = 1.5-2.3), marijuana use (aOR = 1.9, 95%CI = 1.4-2.5), a high GAIN substance use score (aOR = 1.9, 95%CI = 1.1-3.4), low academic achievement (aOR range = 1.6-3.4), and exposure to smoking (aOR range = 1.8-2.1). No differences were observed for externalizing factors (depression, anxiety, etc.), sensation seeking, or household use of non-cigarette tobacco. CONCLUSIONS: Among ever cigarette and e-cigarette users, dual users had higher odds of reporting traditional risk factors for smoking, followed by single product cigarette smokers and e-cigarette users. Understanding how e-cigarette and cigarette users differ may inform youth tobacco use prevention efforts and advise future studies assessing probability of progression of cigarette and e cigarette use. PMID- 30473247 TI - Validation of the electronic cigarette attitudes survey (ECAS) for youth. AB - Electronic cigarette (e-cigarette) use among adolescents has rapidly increased in recent years, especially among Latinx and non-Latinx Black adolescents. Yet, limited research exists on adolescent attitudes that may contribute to the popularity of these products. This is in part due to the lack of measures focused on assessing adolescent attitudes towards e-cigarette use. The aim of this study was to develop a measure of adolescent e-cigarette use attitudes. The sample consisted mainly of Latinx and non-Latinx Black adolescents. Data were collected from 247 youth (M age = 16.0, SD = 1.2), 63.6% were girls, a majority (69.2%) were non-Latinx Black, and 27.1% were Latinx. The Electronic Cigarette Attitudes Survey (ECAS) is comprised of 12 items reflecting attitudes associated with e cigarettes, which were derived from prior theoretical, quantitative, and qualitative work with e-cigarette users. To determine the factor structure, a parallel analysis scree plot and an exploratory factor analysis (EFA) of the ECAS was conducted using half of the sample chosen at random (n = 113). Results supported a one-factor solution. A confirmatory factory analysis (CFA) was conducted on the other randomly chosen half of participants (n = 121). Results confirm a one-factor solution. No significant differences were found on ECAS scores based on race/ethnicity or e-cigarette use status (lifetime e-cigarette use vs. no use). The ECAS represents a viable measure for assessing e-cigarette attitudes among youth. PMID- 30473248 TI - Patient centred consultation, satisfaction and young patients: A cross-country analysis. AB - OBJECTIVES: The aim of this study was to investigate the link between perceived dimensions of patient centred care and the satisfaction of adolescents and young adults within the UK, USA, Australian, Italian, and Chinese healthcare systems. METHODS: One thousand and thirty-four participants (212 from China,206 from Australia,208 from UK, 202 from USA, and 206 from Italy) answered a self-report questionnaire assessing the perceived dimensions of patient centred care. Factor analysis (PFA) was conducted on the data to identify relevant dimensions. One-way ANOVAs were run to identify differences between country samples related to perceived dimensions of patient centredness, and a multi-level multiple regression model was computed to assess the link between satisfaction and dimensions of patient centred care. RESULTS: Countries' mean scores on 'Satisfaction with Care' (PF1) and on 'Psychosocial Context' (PF2) were statistically significant by inspecting the ANOVAs (p < .05). Satisfaction with care was predicted by PF2 and clinical utilization. CONCLUSION: An online survey collected meaningful data on perceptions of healthcare received by respondents from five countries. This initial international study highlights important associations worthy of closer investigation. PRACTICE IMPLICATIONS: Healthcare providers should assess comprehensively the psychosocial context of young patients during consultations. PMID- 30473249 TI - The elicitation and management of multiple health concerns in GP consultations. AB - OBJECTIVE: To describe the nature of patient concerns and to explore if, when and how they are addressed by GPs in the UK. METHODS: Detailed coding and descriptive analysis of 185 video recordings from the EPaC study (Elicitation of Patient Concerns, EPaC) RESULTS: An average of 2.1 concerns were raised per consultation and the most common concerns were musculoskeletal, administrative (e.g. test results and medication related issues), and skin symptoms. GPs who had been trained as part of the EPaC intervention to solicit for additional concerns in the opening phase of the consultation did so 92.6% of the time. In contrast, those in the control arm did so only 7% of the time. However, the particular formulation of the GP soliciting question does not seem to be associated with the likelihood of the patient volunteering an additional concern. CONCLUSIONS: GP consultations are complex encounters in which multiple concerns are dealt with across a wide range of disease areas. GPs can be trained to solicit for problems/concerns early in the consultation. PRACTICE IMPLICATIONS: Soliciting for additional concerns is not routinely done. But very brief training can substantially help in eliciting concerns early in the consultation, which may help with organising the consultation. PMID- 30473250 TI - What are our aims at CMI? PMID- 30473251 TI - Conditional GWAS revealing genetic impacts of lifestyle behaviors on low-density lipoprotein (LDL). AB - BACKGROUND: Accumulation of LDL cholesterol (LDL-c) within artery walls is strongly associated with the initiation and progression of atherosclerosis development. This complex trait is affected by multifactor involving polygenes, environments, and their interactions. Uncovering genetic architecture of LDL may help to increase the understanding of the genetic mechanism of cardiovascular diseases. METHODS: We used a genetic model to analyze genetic effects including additive, dominance, epistasis, and ethnic interactions for data from the Multi Ethnic Study of Atherosclerosis (MESA). Three lifestyle behaviors (reading, intentional exercising, smoking) were used as cofactor in conditional models. RESULTS: We identified 156 genetic effects of 10 quantitative trait SNPs (QTSs) in base model and three conditional models. The total estimated heritability of these genetic effects was approximately 72.88% in the base model. Five genes (CELSR2, MARK2, ADAMTS12, PFDN4, and MAGI2) have biological functions related to LDL. CONCLUSIONS: Compared with the based model LDL, the results in three conditional models revealed that intentional exercising and smoking could have impacts for causing and suppressing some of genetic effects and influence the levels of LDL. Furthermore, these two lifestyles could have different genetic effects for each ethnic group on a specific QTS. As most of the heritability in based model LDL and conditional model LDL|Smk was contributed from epistasis effects, our result indicated that epistasis effects played important roles in determining LDL levels. Our study provided useful insight into the biological mechanisms underlying regulation of LDL and might help in the discovery of novel therapeutic targets for cardiovascular disease. PMID- 30473252 TI - [Health literacy: psychometric behaviour of the HLS-EU-Q16 questionnaire]. AB - OBJECTIVE: To describe the psychometric properties and the level of understanding of the health literacy questionnaire HLS-EU-Q16 in Spanish, implemented in the Health Survey of the Valencian Region (Spain) of 2016. METHOD: Descriptive cross sectional study to describe understanding, reliability, structure and internal consistency of the questionnaire on a sample of 5485 subjects, aged 15 or over, who participated in the survey. RESULTS: The percentages of understanding without much difficulty were high. Reliability was high (intraclass correlation coefficient:.923; kappa:.814). The factorial analysis suggested a unifactorial structure (79.1% of variability explained by the common factor), with high factorial loads. The consistency was high (Cronbach's alpha: 0.982). CONCLUSIONS: The HLS-EU-Q16 in Spanish is a short, adequate and valid instrument to measure the level of health literacy in the population. PMID- 30473253 TI - Use of vasodilators for the treatment of pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: A systematic review. AB - BACKGROUND: There are several medications available to treat pulmonary arterial hypertension (PAH): PAH-targeted drugs. However, in patients with pulmonary veno occlusive disease and pulmonary capillary hemangiomatosis (PVOD/PCH), rare diseases that cause pulmonary hypertension, the effectiveness and safety of vasodilators, including PAH-targeted drugs, are unclear. METHODS: We searched English-language publications listed in three electronic databases (PubMed, Cochrane Library, and the Japan Medical Abstracts Society). Reports with efficacy outcomes (survival, improvement in 6-minute walk distance, and pulmonary vascular resistance) and data on development of pulmonary edema after administration of vasodilators to patients with PVOD/PCH were selected (1966 to August 2015). RESULTS: We identified 20 reports that met our criteria. No randomized controlled or prospective controlled studies were reported. The survival time ranged from 71 minutes to 4 years or more after initiation of vasodilators. Most of the reported cases showed an improvement in the 6-minute walk distance and pulmonary vascular resistance. Pulmonary edema was reported in 15 articles, some cases of which were lethal. CONCLUSIONS: The present study demonstrates the potential efficacy and difficulties in the use of vasodilators in patients with PVOD/PCH; however, drawing a firm conclusion was difficult because of the lack of randomized controlled trials. Further research is needed to ascertain if vasodilator use is beneficial and safe in patients with PVOD/PCH. PMID- 30473254 TI - Pediatric Dog Bite Injuries in Central Texas. AB - PURPOSE: Identify children at greatest risk for dog bite injuries and to provide injury prevention recommendations. METHODS: A retrospective review of patients aged <=18 years treated for dog bite injuries from October 2011 to October 2016 was performed. Data collected included patient demographics, parental presence, time of injury, dog breed and ownership status, injury location and characteristics, need for operative intervention, and hospitalization. RESULTS: One-hundred and two patients met the inclusion criteria. The mean age was 5.84 years, and 43.1% were preschool-aged (2-5 years). Parental presence was reported in 43.6% of cases, and most attacks occurred in the evening (46.8%). Injuries often involved the head-neck region (92.1%), and 72.5% were of major severity. Pet dogs were responsible for 42% of injuries, and pit bull was the most identified breed (36.2%). Most injuries occurred while the child was at home (57.8%) and was petting or playing with the dog (28.4%). Intervention in the operating room was required in 34.3% of patients. Major injury was more likely to require operative intervention (p = 0.015) but was not associated with patient age, sex, pet status, or the need for hospitalization. CONCLUSIONS: Preschool aged children are more likely to be injured by dog bites, and dog bites can result in major injury to the head and neck region. Prevention efforts should focus on dog training, public education (children and adults), vigilant adult supervision, and a zero-tolerance policy. LEVEL OF CLINICAL EVIDENCE: Level IV case series with no comparison group. TYPE OF STUDY: Prognostic. PMID- 30473255 TI - Personalized conciliation of clinical guidelines for comorbid patients through multi-agent planning. AB - The conciliation of multiple single-disease guidelines for comorbid patients entails solving potential clinical interactions, discovering synergies in the diagnosis and the recommendations, and managing clinical equipoise situations. Personalized conciliation of multiple guidelines considering additionally patient preferences brings some further difficulties. Recently, several works have explored distinct techniques to come up with an automated process for the conciliation of clinical guidelines for comorbid patients but very little attention has been put in integrating the patient preferences into this process. In this work, a Multi-Agent Planning (MAP) framework that extends previous work on single-disease temporal Hierarchical Task Networks (HTN) is proposed for the automated conciliation of clinical guidelines with patient-centered preferences. Each agent encapsulates a single-disease Computer Interpretable Guideline (CIG) formalized as an HTN domain and conciliates the decision procedures that encode the clinical recommendations of its CIG with the decision procedures of the other agents' CIGs. During conciliation, drug-related interactions, scheduling constraints as well as redundant actions and multiple support interactions are solved by an automated planning process. Moreover, the simultaneous application of the patient preferences in multiple diseases may potentially bring about contradictory clinical decisions and more interactions. As a final step, the most adequate personalized treatment plan according to the patient preferences is selected by a Multi-Criteria Decision Making (MCDM) process. The MAP approach is tested on a case study that builds upon a simplified representation of two real clinical guidelines for Diabetes Mellitus and Arterial Hypertension. PMID- 30473256 TI - The effect of art therapy on the quality of life in patients with a gynecologic cancer receiving chemotherapy. AB - OBJECTIVES: Most art therapy research has involved patients with malignancies other than gynecologic cancer. The current study aimed to assess the impact of an art therapy intervention on the quality of life (QOL) in patients with gynecologic cancer who were receiving chemotherapy. METHODS: This was a prospective, non-randomized, pilot study. Eligible patients had a primary or recurrent gynecologic malignancy scheduled to be treated with at least 6 cycles of chemotherapy over 18 weeks. The intervention consisted of five sessions of art therapy during the chemotherapy. Patients completed a Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire prior to starting chemotherapy, and again at completion of the fifth session. Differences between the FACT-G scores were examined by paired t-tests. An increase in the mean FACT-G score indicated an improvement in QOL. At each session, the patients completed a separate, supplemental questionnaire to subjectively rate the benefit of the session and to express their experience with the art intervention. RESULTS: Twenty-four patients enrolled. Eight did not complete the study, leaving 16 evaluable patients. The mean FACT-G score pre-chemotherapy was 82.3 (95% CI: 75.5, 89.2), and post-art therapy was 78.6 (95% CI: 71.7, 85.5). The mean change in QOL was -3.7 points (95% CI: -10.7, 3.2, p = 0.270). A supplemental questionnaire indicated that 15 of 16 patients felt that art therapy was beneficial at each session. CONCLUSIONS: FACT-G scores did not significantly change over the course of chemotherapy in patients with gynecologic cancers receiving art therapy. Several published studies have indicated that chemotherapy is associated with a decline in QOL. Our results suggest art therapy may help to prevent or mitigate this decline. PMID- 30473257 TI - Management and prognostic factors of epithelioid trophoblastic tumors: Results from the International Society for the Study of Trophoblastic Diseases database. AB - OBJECTIVE: Epithelioid Trophoblastic Tumor (ETT) is an extremely rare form of Gestational Trophoblastic Neoplasia (GTN). Knowledge on prognostic factors and optimal management is limited. We identified prognostic factors, optimal treatment, and outcome from the world's largest case series of patients with ETT. METHODS: Patients were selected from the international Placental Site Trophoblastic Tumor (PSTT) and ETT database. Fifty-four patients diagnosed with ETT or mixed PSTT/ETT between 2001 and 2016 were included. Cox regression analysis was used to identify prognostic factors for overall survival (OS). RESULTS: Forty-five patients with ETT and 9 patients with PSTT/ETT were included. Thirty-six patients had FIGO stage I and 18 had stages II-IV disease. Patients were treated with surgery (n = 23), chemotherapy (n = 6), or a combination of surgery and chemotherapy (n = 25). In total, 39 patients survived, including 22 patients with complete sustained hCG remission for at least 1 year. Patients treated with surgery as first line treatment had early-stage disease and all survived. Most patients treated with chemotherapy with or without surgery had FIGO stages II-IV disease (55%). They underwent multiple lines of chemotherapy. Eleven of them did not survive. Interval since antecedent pregnancy and FIGO stage were prognostic factors of OS (p = 0.012; p = 0.023 respectively). CONCLUSIONS: Advanced-stage disease and an interval of >=48 months since the antecedent pregnancy are poor prognostic factors of ETT. Surgery seems adequate for early-stage disease with a shorter interval. Advanced-stage disease requires a combination of treatment modalities. Because of its rarity, ETT should be treated in a centre with experience in GTN. PMID- 30473258 TI - Adjuvant therapy in stage III endometrial cancer confined to the pelvis. AB - OBJECTIVE: To review outcomes of patients with stage III endometrial cancer confined to the pelvis treated with adjuvant pelvic radiotherapy (RT) or sequential chemoradiotherapy (CRT). METHODS: Between 1990 and 2012, 144 patients diagnosed with stage IIIA, B or C1 endometrial cancer were treated in our institution. All were treated with total hysterectomy, bilateral salpingo oophorectomy +/- lymph node dissection. Post-operatively, 67 patients received adjuvant RT alone, 37 CRT, 21 chemotherapy alone and 19 had no adjuvant therapy. This analysis focuses on the 104 patients treated with RT or CRT. RESULTS: The median follow-up was 61 months. Forty-six patients (44%) were stage IIIA, 6 (6%) were stage IIIB and 52 (50%) stage IIIC1. The 5-year overall survival (OS), disease-free survival (DFS) and disease-specific survival (DSS) for patients treated by RT alone vs. CRT were, respectively, 67% vs. 61% (p = 0.55); 67% vs. 51% (p = 0.35); and 76% vs. 65% (p = 0.21). Grade 3 disease was an independent predictor for worse OS (HR = 6.01, p = 0.001), DFS (HR = 3.16, p = 0.03), and DSS (HR = 3.77, p = 0.02). In patients with grade 3 disease (n = 49), the 5-year OS was superior for the CRT (42% vs. 56%, p = 0.007). CONCLUSIONS: In patients with stage III endometrial cancer confined to the pelvis, the addition of adjuvant chemotherapy with RT significantly improved OS in grade 3 disease. Grade 3 histology is a strong predictor for poor outcome. Further randomized studies aiming specifically at stage III disease are warranted. PMID- 30473259 TI - Excess Weight in Spain: Current Situation, Projections for 2030, and Estimated Direct Extra Cost for the Spanish Health System. AB - INTRODUCTION AND OBJECTIVES: Excess weight promotes the development of several chronic diseases and decreases quality of life. Its prevalence is increasing globally. Our aim was to estimate the trend in excess weight between 1987 and 2014 in Spanish adults, calculate cases of excess weight and its direct extra costs in 2006 and 2016, and project its trend to 2030. METHODS: We selected 47 articles in a systematic literature search to determine the progression of the prevalence of overweight, nonmorbid obesity, and morbid obesity and average body mass index between 1987 and 2014. We projected the expected number of cases in 2006, 2016, and 2030 and the associated direct extra medical costs. RESULTS: Between 1987 and 2014, the prevalence of overweight, obesity, and morbid obesity increased by 0.28%/y (P=.004), 0.50%/y (P <.001) and 0.030%/y (P=.006) in men, and by 0.10%/y (P=.123), 0.25%/y (P=.078), and 0.042%/y (P=.251) in women. The mean body mass index increased by 0.10 kg/m2/y in men (P <.001) and 0.26 kg/m2/y in women (significantly only between 1987 and 2002, P <.001). We estimated 23 500 000 patients with excess weight in 2016, generating 1.95 billion ?/y in direct extra medical costs. If the current trend continues, between 2016 and 2030, there will be 3 100 000 new cases of excess weight, leading to 3.0 billion ?/y of direct extra medical costs in 2030. CONCLUSIONS: Excess weight in Spanish adults has risen since the creation of population registries, generating direct extra medical costs that represent 2% of the 2016 health budget. If this trend continues, we expect 16% more cases in 2030 and 58% more direct extra medical costs. PMID- 30473260 TI - Rhythmic Sawtooth Electroencephalograph Waveforms in Neonatal Hypoxic Ischemic/Hypoglycemic Encephalopathy. PMID- 30473261 TI - Corrigendum to "Modelling aerobic granular sludge reactors through apparent half saturation coefficients" [Water Res. 146 (2018) 134-145]. PMID- 30473262 TI - Influencing Mindsets and Motivation in Procedural Skills Learning: Two Randomized Studies. AB - OBJECTIVES: An incremental (growth) theory of intelligence (mindset), compared with an entity (fixed) mindset, has been associated with improved motivation and performance. Interventions to induce incremental beliefs have improved performance on non-surgical motor tasks. We sought to evaluate the impact of 2 brief interventions to induce incremental beliefs in the context of learning a surgical task. DESIGN: Two randomized experiments. PARTICIPANTS AND SETTING: Secondary school students participating in medical simulation-based training activities at an academic medical center. INTERVENTIONS: We created 4 instructional messages intended to influence mindsets (two 60-second videos in Study 1, 2 fabricated "journal articles" in Study 2). In each study, one message emphasized that ability improves with practice (incremental); the other emphasized that ability is fixed (entity). After reviewing their randomly assigned message, participants completed a laparoscopic cutting task as many times as they desired. Measurements included performance (product quality, self reported task, and completion time), task persistence (repetitions), and entity beliefs. RESULTS: Two hundred and three students completed Study 1. Postevent entity beliefs (1 = lowest, 6 = highest) were similar between groups (incremental, 2.0 vs entity, 2.0; p = 0.78). Contrary to hypothesis, the incremental video group demonstrated slower time (276 vs 191 seconds; p < 0.0001), lower product quality (7.2 vs 3.8 mm deviation; p < 0.0001), and fewer task repetitions (1.4 vs 1.8; p = 0.02). In Study 2, 113 participants provided outcomes related to mindset beliefs, but only 14 provided usable performance outcomes. Postevent entity beliefs were lower in the incremental article group (1.7 vs 2.4; p < 0.0001). Task time (507 vs 585 seconds; p = 0.40) and quality (7.1 vs 7.5 mm deviation; p = 0.85) were similar between groups. CONCLUSIONS: Brief motivational interventions can influence procedural performance and motivation. We need to better understand motivation and other affective influences on procedural skills learning. Mindset theory shows promise in this regard. PMID- 30473263 TI - Over-gap PCR amplification to identify presence of replication-competent HBV DNA from integrated HBV DNA: An updated occult HBV infection definition. PMID- 30473264 TI - Successful HCV treatment of patients on contraindicated anti-epileptic drugs: Role of drug level monitoring. PMID- 30473265 TI - Does Sericin, as a Novel Pleurodesis Agent, Have Higher Effectiveness Compared to Talcum Powder, Doxycycline, and Silver Nitrate Pleurodesis? AB - INTRODUCTION: The usefulness of sericin as pleurodesis agent has previously been described. Present study aims to compare sericin pleurodesis regarding success, effectiveness, tolerability, and side-effects. METHODS: Adult, 12-week-old Wistar albino rats (n=60), divided to five groups as sericin, talcum-powder, doxycycline, silver-nitrate and control. Agents were administrated through left thoracotomy, rats sacrificed twelve-days after. RESULTS: Highest ratio of collagen fibers was observed in sericin group, and the intensity was higher than talcum-powder group (p<0.05). Compared to silver nitrate, sericin group displayed better mesothelial reaction, and multi-layer mesothelium was also better (p<0.05). Foreign body reaction and emphysema were less frequent in sericin group (p<0.05). The presence of biological tissue in parenchyma was less prominent in sericin group (p<0.05). Foreign body reaction on thoracic wall was less common in sericin group (p<0.05). Presence of biological tissue glue in thoracic wall was less prominent in sericin group (p<0.05). Glomerular degeneration was lower in sericin group compared to the silver nitrate group (p<0.05), and tubular degeneration was less common in sericin group than talcum group (p<0.05). Pericarditis was less common in sericin group compared to the other groups (p<0.05). CONCLUSION: As an intrinsic, natural glue protein, sericin protects the lung parenchyma and tissues, and its glue-like characteristics enable pleurodesis. The success of sericin in pleurodesis was demonstrated in the present study based on investigations of the pleurae. Being cost-effective and better tolerated agent associated with a low potential of side effects, sericin is more effective, less expensive and provides more lung parenchyma protection. PMID- 30473266 TI - Corrigendum to "Chinese version of the clinical learning environment comparison survey: Assessment of reliability and validity" [ Nurse Education Today Volume 71, December 2018, Pages 121-128]. PMID- 30473267 TI - Novel drugs and early polypharmacotherapy in status epilepticus. AB - PURPOSE: Rescue medications for status epilepticus (SE) have a relatively high rate of failure. The purpose of this review is to summarize the evidence for the efficacy of novel drugs and early polypharmacotherapy for SE. METHOD: Literature review. RESULTS: New drugs and treatment strategies aim to target the pathophysiology of SE in order to improve seizure control and outcomes. Changes at the synapse level during SE include a progressive decrease in synaptic GABAA receptors and increase in synaptic NMDA receptors. These changes tend to promote self-sustaining seizures. Current SE guidelines recommend a rapid stepwise treatment using benzodiazepines in monotherapy as the first-line treatment, targeting GABAA synaptic receptors. Novel treatment approaches target GABAA synaptic and extrasynaptic receptors with allopregnanolone, and NMDA receptors with ketamine. Novel rescue treatments used for SE include topiramate, brivaracetam, and perampanel, which are already marketed in epilepsy. Some available drugs not marketed for use in epilepsy have been used in the treatment of SE, and other agents are being studied for this purpose. Early polytherapy, most frequently combining a benzodiazepine with a second-line drug or an NMDA receptor antagonist, might potentially increase seizure control with relatively minor increase in side effects. Although many preclinical studies support novel drugs and early polytherapy in SE, human studies are scarce and inconclusive. Currently, evidence is lacking to recommend specific combinations of these new agents. CONCLUSIONS: Novel drugs and strategies target the underlying pathophysiology of SE with the intent to improve seizure control and outcomes. PMID- 30473268 TI - Neurosurgical approaches to pediatric epilepsy: Indications, techniques, and outcomes of common surgical procedures. AB - Epilepsy is a common pediatric neurological condition, and approximately one third of children with epilepsy are refractory to medical management. For these children neurosurgery may be indicated, but operative success is dependent on complete delineation of the epileptogenic zone. In this review, surgical techniques for pediatric epilepsy are considered. First, potentially-curative operations are discussed and broadly divided into resections and disconnections. Then, two palliative approaches to seizure control are reviewed. Finally, future neurosurgical approaches to epilepsy are considered. PMID- 30473269 TI - Vocal Symptoms in University Professors: Their Association With Vocal Resources and With Work Environment. AB - AIM: Investigating the association among vocal symptoms, vocal resources, and work environment in university professors. METHODS: Online questionnaire answered by 334 professors from a federal public university in Belo Horizonte County, Brazil. The questionnaire addressed sociodemographic data, self-perception about one's voice, vocal resources and work environment, and included the Vocal Signs and Symptoms Questionnaire. Professors presenting five or more vocal symptoms were compared to those who reported fewer symptoms. The association between the number of symptoms and the other variables was assessed through univariate and multivariate logistic regression analyses. RESULTS: The mean of symptoms reported by the herein investigated professors was 3.1 (SD +/- 2.75); 24% (n = 82) of them reported five or more vocal symptoms. Factors such as female sex, incidence of noise, high speaking rate, as well as high fundamental frequency and loud voice, were associated with the incidence of five or more vocal symptoms. CONCLUSIONS: University professors belonging to the female sex, who perceive the noise in the work environment as unsatisfactory, speak fast, or present high fundamental frequency and loud voice reported the largest number of vocal symptoms. It is recommended developing education programs focused on raising professors' awareness about voice-related risk factors and about the importance of improving their communicative performance. PMID- 30473270 TI - [Sante publique France: From surveillance to the prevention of suicidal behavior]. PMID- 30473271 TI - Patient Assessment of Family Function, Glycemic Control and Quality of Life in Adult Patients With Type 2 Diabetes and Incipient Complications. AB - OBJECTIVES: Family affects the perception of diabetes self-management in patients with diabetes. Family-related questionnaires have been used to assess family function, but the Brief Family Assessment Measure (Brief FAM-III) has not been used previously in a diabetes population. We aimed to determine whether the family function is associated with glycated hemoglobin levels and quality of life as potential predictors of diabetes self-management. METHODS: An exploratory study of patients with type 2 diabetes and incipient complications and their relatives using the Brief FAM-III, a self-report questionnaire comprising 3 scales assessing family function according to different perspectives: a general score, a dyadic relationship score and a self-rating score. RESULTS: We included 127 patients: 72.4% males, mean age 65.23 (SD=10.26) years; glycated hemoglobin levels, 6.9% (SD=0.9%); diabetes duration, 9.1 (SD=0.6) years; and body mass index, 30.8 (SD=0.5) kg/m2. Mean FAM-III scores for the 3 scales were 41.7 (SD=1.0), 41.5 (SD=0.9) and 38.5 (SD=1.1), respectively. Correlation coefficients were -0.06 (p=0.37), -0.09 (p=0.18) and -0.12 (p=0.06), showing no significant correlation between scales and glycated hemoglobin levels levels in the 3 perspectives before and after adjustment for confounders. Family function correlated with burden of diabetes at 0.14 (p=0.02), 0.24 (p=0.0003) and 0.16 (p=0.01), respectively, and mental health at -0.21 (p=0.0007), -0.23 (p=0.0005) and -0.25 (p<0.0001), respectively. CONCLUSION: The results of our study suggest that in patients with type 2 diabetes, family function does not predict the level of glycemic control. However, we found an association among healthy family function, low burden of diabetes and strong mental health, issues that are important for the patients' quality of life, compliance with lifestyle factors and diabetes self-management. PMID- 30473272 TI - Metastasis of adenoid cystic carcinoma from a submandibular gland to the larynx. AB - The present article discusses the first reported case of adenoid cystic carcinoma (ACC) metastasis from a submandibular gland to the larynx. Both treatments of distant metastasis of ACC and secondary laryngeal tumor are challenging. Despite its slow progression, ACC is associated with high rates of local recurrence, distant metastasis, and poor prognosis. Patients with secondary laryngeal cancer often have other concurrent metastatic lesions. Therefore, treatment selection should consider the biological behavior of the tumor and characteristics of the laryngeal lesion, along with the general condition and quality of life of the patient. The patient (55-year-old female) had a history of ACC of the right submandibular gland, removed surgically 9 years prior to the present consultation. Follow-up showed multiple pulmonary metastases. The patient complained of dysphonia lasting 3 months. Following the diagnosis of ACC metastasis to the larynx (supraglottic) and a neck lymph node via biopsy, we performed partial laryngectomy, left neck dissection, and tracheotomy. Histopathological examination showed an increase in the tumor grade over time. Two months after discharge, there was no obvious local recurrence or increase in lung metastasis. PMID- 30473273 TI - Erratum to "Protective effect of an astaxanthin nanoemulsion against neomycin induced hair-cell damage in zebrafish" [Auris Nasus Larynx 45 (2018) 20-25]. PMID- 30473274 TI - Molecular mechanism of endocrine-disruptive effects induced by Bisphenol A: The role of transmembrane G-protein estrogen receptor 1 and integrin alphavbeta3. AB - Bisphenol A (BPA) is one of the highest volume industrial products worldwide and has been widely used to make various products as the intermediates of polycarbonate plastics and epoxy resins. Inevitably, general population has been widely exposed to BPA due to extensive use of BPA-containing products. BPA has similar chemical structure with the natural estrogen and has been shown to induce a variety of estrogen-like endocrine effects on organism in vivo or in vitro. High doses of BPA tend to act as antagonist of estrogen receptors (ERs) by directly regulating the genomic transcription. However, BPA at environmentally relevant low-dose always disrupt the biological function via a non-genomic manner mediated by membrane receptors, rather than ERs. Although some studies had investigated the non-genomic effects of low-dose BPA, the exact molecular mechanism still remains unclear. Recently, we found that membrane G protein coupled estrogen receptor 1 and integrin alphavbeta3 and its relative signal pathways participate in the induction of male germ cell proliferation and thyroid transcription disruption by the low-dose BPA. A profound understanding for the mechanism of action of the environmentally relevant BPA exposure not only contributes to objectively evaluate and predict the potential influence to human health, but also provides theoretical basis and methodological support for assessing health effects trigged by other estrogen-like environmental endocrine disruptors. Based mainly on our recent findings, this review outlines the research progress of molecular mechanism on endocrine disrupting effects of environmental low-dose BPA, existing problems and some consideration for future studies. PMID- 30473275 TI - Understanding primary and secondary sources of ambient oxygenated volatile organic compounds in Shenzhen utilizing photochemical age-based parameterization method. AB - Oxygenated volatile organic compounds (OVOCs) are key intermediates in the atmospheric photooxidation process. To further study the primary and secondary sources of OVOCs, their ambient levels were monitored using a proton-transfer reaction mass spectrometer (PTR-MS) at an urban site in the Pearl River Delta of China. Continuous monitoring campaigns were conducted in the spring, summer, fall, and winter of 2016. Among the six types of OVOC species, the mean concentrations of methanol were the highest in each season (up to 13-20ppbv), followed by those of acetone, acetaldehyde and acetic acid (approximately 2 4ppbv), while those of formic acid and methyl ethyl ketone (MEK) were the lowest (approximately 1-2ppbv). As observed from a diurnal variation chart, the OVOCs observed in Shenzhen may have been affected by numerous factors such as their primary and secondary sources and photochemical consumption. The photochemical age-based parameterization method was used to apportion the sources of ambient OVOCs. Methanol had significant anthropogenic primary sources but negligible anthropogenic secondary sources during all of the seasons. Acetone, MEK and acetic acid were mostly attributed to anthropogenic primary sources during each season with smaller contributions from anthropogenic secondary sources. Acetaldehyde had similar contributions from both anthropogenic secondary and anthropogenic primary sources throughout the year. Meanwhile, anthropogenic primary sources contributed the most to formic acid. PMID- 30473276 TI - Sorption of uranyl ions on TiO2: Effects of pH, contact time, ionic strength, temperature and HA. AB - Sorption of U(VI) onto TiO2 as functions of pH, ionic strength, contact time, soil humic acid (SHA), solid-to-liquid ratio and temperature was studied under ambient conditions using batch and spectroscopic approaches. The sorption of U(VI) on TiO2 was significantly dependent on pH and ionic strength. The presence of SHA slightly enhanced the sorption of U(VI) on TiO2 below pH4.0, while it inhibited U(VI) sorption in the higher pH range. U(VI) sorption on TiO2 was favored at high temperatures, and the sorption process was estimated to be endothermic and spontaneous. Reduction of U(VI) to lower valent species was confirmed by X-ray photo-electron spectroscopy analysis. It is very interesting to find that U(VI) sorption on TiO2 was promoted in solutions with higher back ground electrolyte concentrations. In the presence of U(VI), higher back-ground electrolyte made more TiO2 particles aggregate through (001) facets, leading more (101) facets to be exposed. Therefore, the reduction of U(VI) was enhanced by the exposed (101) facets and more U(VI) removal was observed. PMID- 30473278 TI - Macroporous Ni foam-supported Co3O4 nanobrush and nanomace hybrid arrays for high efficiency CO oxidation. AB - Herein, we reported the synthesis of well-defined Co3O4 nanoarrays (NAs) supported on a monolithic three-dimensional macroporous nickel (Ni) foam substrate for use in high-efficiency CO oxidation. The monolithic Co3O4 NAs catalysts were obtained through a generic hydrothermal synthesis route with subsequent calcination. By controlling the reaction time, solvent polarity and deposition agent, these Co3O4 NAs catalysts exhibited various novel morphologies (single or hybrid arrays), whose physicochemical properties were further characterized by using several analytical techniques. Based on the catalytic and characterization analyses, it was found that the Co3O4 NAs-6 catalyst with nanobrush and nanomace arrays displayed enhanced catalytic activity for CO oxidation, achieving an efficient 100% CO oxidation conversion at a gas hourly space velocity (GHSV) 10,000hr-1 and 150 degrees C with long-term stability. Compared with the other Co3O4 NAs catalysts, it had the highest abundance of surface-adsorbed oxygen species, excellent low-temperature reducibility and was rich in surface-active sites (Co3+/Co2+=1.26). PMID- 30473277 TI - Highly selective catalytic reduction of NOx by MnOx-CeO2-Al2O3 catalysts prepared by self-propagating high-temperature synthesis. AB - We first present preparation of MnOx-CeO2-Al2O3 catalysts with varying Mn contents through a self-propagating high-temperature synthesis (SHS) method, and studied the application of these catalysts to the selective catalytic reduction of NOx with NH3 (NH3-SCR). Using the catalyst with 18 wt.% Mn (18MnCe1Al2), 100% NO conversion was achieved at 200 degrees C and a gas hourly space velocity of 15384hr-1, and the high-efficiency SCR temperature window, where NO conversion is greater than 90%, was widened to a temperature range of 150-300 degrees C. 18MnCe1Al2 showed great resistance to SO2 (100 ppm) and H2O (5%) at 200 degrees C. The catalysts were characterized using X-ray diffraction, X-ray photoelectron spectroscopy, Brunauer-Emmett-Teller (BET) analysis, scanning electron microscopy, Fourier transform infrared spectroscopy, and H2 temperature programmed reduction. The characterization results showed that the surface atomic concentration of Mn increased with increasing Mn content, which led to synergism between Mn and Ce and improved the activity in the SCR reaction. 18MnCe1Al2 has an extensive pore structure, with a BET surface area of approximately 135.4m2/g, a pore volume of approximately 0.16cm3/g, and an average pore diameter of approximately 4.6 nm. The SCR reaction on 18MnCe1Al2 mainly followed the Eley Rideal mechanism. The performances of the MnOx-CeO2-Al2O3 catalysts were good, and because of the simplicity of the preparation process, the SHS method is applicable to their industrial-scale manufacture. PMID- 30473279 TI - Antimony speciation in the environment: Recent advances in understanding the biogeochemical processes and ecological effects. AB - Antimony (Sb) is a toxic metalloid, and its pollution has become a global environmental problem as a result of its extensive use and corresponding Sb mining activities. The toxicity and mobility of Sb strongly depend on its chemical speciation. In this review, we summarize the current knowledge on the biogeochemical processes (including emission, distribution, speciation, redox, metabolism and toxicity) that trigger the mobilization and transformation of Sb from pollution sources to the surrounding environment. Natural phenomena such as weathering, biological activity and volcanic activity, together with anthropogenic inputs, are responsible for the emission of Sb into the environment. Sb emitted in the environment can adsorb and undergo redox reactions on organic or inorganic environmental media, thus changing its existing form and exerting toxic effects on the ecosystem. This review is based on a careful and systematic collection of the latest papers during 2010-2017 and our research results, and it illustrates the fate and ecological effects of Sb in the environment. PMID- 30473280 TI - Relations between mercury fractions and microbial community components in seawater under the presence and absence of probable phosphorus limitation conditions. AB - Microbial transformations of toxic monomethylmercury (MMHg) and dissolved gaseous mercury (DGM) at the lower levels of the marine food web are not well understood, especially in oligotrophic and phosphorus-limited seas. To examine the effects of probable phosphorus limitation (PP-limitation) on relations between mercury (Hg) fractions and microorganisms, we determined the total mercury (THg), total methylated mercury (MeHg), DGM, and microbiological and chemical parameters in the Central Adriatic Sea. Using statistical analysis, we assessed the potential microbial effects on Hg transformations and bioaccumulation. Only in the absence of PP-limitation conditions (NO-PP-limitation) is MeHg significantly related to most chemical and microbial parameters, indicating metabolism-dependent Hg transformations. The heterotrophic activity of low nucleic acid bacteria (abundant in oligotrophic regions) seems responsible for most of Hg methylation under NO-PP-limitation. Under these conditions, DGM is strongly related to microbial fractions and chlorophyll a, indicating biological DGM production, which is probably not metabolically induced, as most of these relations are also observed under PP-limitation. MMHg biomagnification was observed through an increased bioaccumulation factor from microseston to mesozooplankton. Our results indicate that Hg transformations and uptake might be enhanced under NO-PP limitation conditions, emphasizing their impact on the transfer of Hg to higher trophic levels. PMID- 30473281 TI - Application of interface material and effects of oxygen gradient on the performance of single-chamber sediment microbial fuel cells (SSMFCs). AB - Single-chamber sediment microbial fuel cells (SSMFCs) have received considerable attention nowadays because of their unique dual-functionality of power generation and enhancement of wastewater treatment performance. Thus, scaling up or upgrading SSMFCs for enhanced and efficient performance is a highly crucial task. Therefore, in order to achieve this goal, an innovative physical technique of using interface layers with four different pore sizes embedded in the middle of SSMFCs was utilized in this study. Experimental results showed that the performance of SSMFCs employing an interface layer was improved regardless of the pore size of the interface material, compared to those without such layers. The use of an interface layer resulted in a positive and significant effect on the performance of SSMFCs because of the effective prevention of oxygen diffusion from the cathode to the anode. Nevertheless, when a smaller pore size interface was utilized, better power performance and COD degradation were observed. A maximum power density of 0.032mW/m2 and COD degradation of 47.3% were obtained in the case of an interface pore size of 0.28MUm. The findings in this study are of significance to promote the future practical application of SSMFCs in wastewater treatment plants. PMID- 30473283 TI - Effects of silver nanoparticles with different dosing regimens and exposure media on artificial ecosystem. AB - Due to the wide use of silver nanoparticles (AgNPs) in various fields, it is crucial to explore the potential negative impacts on the aquatic environment of AgNPs entering into the environment in different ways. In this study, comparative experiments were conducted to investigate the toxicological impacts of polyvinylpyrrolidone-coated silver nanoparticles (PVP-AgNPs) with two kinds of dosing regimens, continuous and one-time pulsed dosing, in different exposure media (deionized water and XiangJiang River water). There were a number of quite different experimental results (including 100% mortality of zebrafish, decline in the activity of enzymes, and lowest number and length of adventitious roots) in the one-time pulsed dosing regimen at high PVP-AgNP concentration exposure (HOE) compared to the three other treatments. Meanwhile, we determined that the concentration of leached silver ions from PVP-AgNPs was too low to play a role in zebrafish death. Those results showed that HOE led to a range of dramatic ecosystem impacts which were more destructive than those of other treatments. Moreover, compared with the continuous dosing regimen, despite the fact that higher toxicity was observed for HOE, there was little difference in the removal of total silver from the aquatic environment for the different dosing regimens. No obvious differences in ecological impacts were observed between different water columns under low concentration exposure. Overall, this work highlighted the fact that the toxicity of AgNPs was impacted by different dosing regimens in different exposure media, which may be helpful for assessments of ecological impacts on aquatic environments. PMID- 30473282 TI - Insight into the critical factors determining the particle number concentrations during summer at a megacity in China. AB - To identify the critical factors impacting the number concentration of particles with the aerodynamic diameters less than 2.5MUm (PNC2.5), the continuous measurement of PNC2.5, chemical components in PM2.5, gaseous pollutants and meteorological conditions were conducted at an urban site in Tianjin in June 2015. Results indicated that the average PNC2.5 was 2839+/-2430 dN/dlogDp 1/cm3 during the campaign. Compared to other meteorological parameters, the relative humidity (RH) had the strongest relationship with PNC2.5, with a Pearson's correlation coefficient of 0.53, and RH larger than 30% influenced strongly PNC2.5. The important influence of secondary reactions on PNC2.5 was inferred due to higher correlation coefficients between PNC2.5 and SO42-, NO3-, NH4+ (r=0.78 0.89; p<0.01) and between PNC2.5 and ratios that represent the conversion of nitrogen and sulfur oxides to particulate matter (r=0.42-0.49; p<0.01). Under specific RH conditions, there were even stronger correlations between PNC2.5 and NO3-, SO42-, NH4+, while those between PNC2.5 and EC, OC were relatively weak, especially when RH exceeded 50%. Principal component analysis (PCA) and Pearson's correlation analysis indicated that secondary sources, vehicle emission and coal combustion might be major contributors to PNC2.5. Backward trajectory and potential source contribution function (PSCF) analysis suggested that the transport of air masses originated from these regions around Tianjin (Liaoning, Hebei, Shandong and Jiangsu) influenced critically PNC2.5. The north of Jiangsu, the west of Shandong, and the east of Hebei were distinguished as major potential source-areas of PNC2.5 by PSCF model. PMID- 30473284 TI - Realizing stable operation of anaerobic ammonia oxidation at low temperatures treating low strength synthetic wastewater. AB - The low activity of Anammox bacteria at low temperatures and competition from nitrite oxidation bacteria (NOB) when treating low strength wastewater have been major bottlenecks in implementing Anammox in mainstream wastewater treatment. By intermittent high strength feeding (IHSF) and stepwise temperature reduction, stable operation of a granular Anammox reactor was realized at low temperatures (down to 15 degrees C) for 28days when treating low strength synthetic wastewater. The nitrogen loading rate reached 1.23-1.34kgN/m3/day, and the total nitrogen removal rate reached 0.71-0.98kgN/m3/day. The IHSF enriched the Anammox sludge in high strength cycles and compensated for sludge loss in low strength cycles, and the high concentration of ammonium in high strength cycles inhibited NOB. The 16SrRNA gene sequencing results revealed that Candidatus Kuenenia was predominant in the reactor at low temperatures. PMID- 30473285 TI - Statistical regression modeling for energy consumption in wastewater treatment. AB - Wastewater treatment is one of critical issues faced by water utilities, and receives more and more attentions recently. The energy consumption modeling in biochemical wastewater treatment was investigated in the study via a general and robust approach based on Bayesian semi-parametric quantile regression. The dataset was derived from a municipal wastewater treatment plant, where the energy consumption of unit chemical oxygen demand (COD) reduction was the response variable of interest. Via the proposed approach, the comprehensive regression pictures of the energy consumption and truly influencing factors, i.e., the regression relationships at lower, median and higher energy consumption levels were characterized respectively. Meanwhile, the proposals for energy saving in different cases were also facilitated specifically. First, the lower level of energy consumption was closely associated with the temperature of influent wastewater, and the chroma-rich wastewater also showed helpful in the execution of energy saving. Second, at median energy consumption level, the COD-rich wastewater played a determinative role in the reduction of energy consumption, while the higher quality of treated water led to slightly energy intensive. Third, the higher level of energy consumption was most likely to be attributed to the relatively high temperature of wastewater and total nitrogen (TN)-rich wastewater, and both of the factors were preferably to be avoided to alleviate the burden of energy consumption. The study provided an efficient approach to controlling the energy consumption of wastewater treatment in the perspective of statistical regression modeling, and offered valuable suggestions for the future energy saving. PMID- 30473286 TI - Factor decomposition of carbon emissions in Chinese megacities. AB - In this article, per capita urban carbon emissions were decomposed into manufacturing, transportation, and construction sectors using logarithmic mean Divisia index (LMDI) method. This new decomposition method can provide information about specific drivers of carbon emissions, including urban growth and resident living standards, rather than general demographic and economic factors identified by traditional methods. Using four Chinese megacities (Beijing, Tianjin, Shanghai, and Chongqing) as case studies, we analyzed the factors that influenced per capita carbon emissions from 2010 to 2015. The results showed that per capita carbon emissions increased in Tianjin and Chongqing whereas decreased in Beijing and Shanghai, and that manufacturing was a key driving force. In these four megacities, energy conservation strategies were successfully implemented despite poor energy structure optimization during 2010 2015. Development of manufacturing and improvement of resident living standards in the cities led to an increase in carbon emissions. The unique dual-core urban form of Tianjin might mitigate the increased carbon emissions caused by the transportation sector. Reductions in carbon emissions could be achieved by further optimizing energy structures, limiting the number of private cars, and controlling per capita construction. PMID- 30473287 TI - Relationship between heavy metals and dissolved organic matter released from sediment by bioturbation/bioirrigation. AB - Organic matter (OM) is an important component of sediment. Bioturbation/bioirrigation can remobilize OM and heavy metals that were previously buried in the sediment. The remobilization of buried organic matter, thallium (Tl), cadmium (Cd), copper (Cu) and zinc (Zn) from sediment was studied in a laboratory experiment with three organisms: tubificid, chironomid larvae and loach. Results showed that bioturbation/bioirrigation promoted the release of dissolved organic matter (DOM) and dissolved Tl, Cd, Cu and Zn, but only dissolved Zn concentrations decreased with exposure time in overlying water. The presence of organisms altered the compositions of DOM released from sediment, considerably increasing the percentage of fulvic acid-like materials (FA) and humic acid-like materials (HA). In addition, bioturbation/bioirrigation accelerated the growth and reproduction of bacteria to enhance the proportion of soluble microbial byproduct-like materials (SMP). The DOM was divided into five regions in the three-dimensional excitation emission matrix (3D-EEM), and each part had different correlation with the dissolved heavy metal concentrations. Dissolved Cu had the best correlation with each of the DOM compositions, indicating that Cu in the sediment was in the organic-bound form. Furthermore, the organism type and heavy metal characteristics both played a role in influencing the remobilization of heavy metal. PMID- 30473288 TI - Effects of redox potential on soil cadmium solubility: Insight into microbial community. AB - Understanding the role of microbes in the solubility of cadmium (Cd) is of fundamental importance for remediation of Cd toxicity. The present study aimed to identify the microbes that involved in regulating Cd solubility and to reveal possible mechanisms. Therefore, microbial communities were investigated through high-throughput sequencing approach, the molecular ecological network was constructed and metagenomes were predicted. Our results indicated that redox conditions affected both the solubility of soil Cd and the microbial communities. Anaerobic microbes, such as Anaerolineaceae, did not only play important roles in shaping the microbial community in soils, but might also be involved in regulating the Cd solubility. Two possible mechanisms that how Anaerolineaceae involved in Cd solubility are (1) Anaerolineaceae are important organic matter degraders under anoxic conditions and (2) Anaerolineaceae can co-exist with methane metabolism microbes, while methane metabolism promotes the precipitation of soluble Cd. Thus, application of Anaerolineaceae in bioremediation of soil Cadmium contamination is a potential approach. The study provided a novel insight into the role of microbial community in the regulation of Cd solubility under different redox conditions, and suggested a potential approach for the remediation of soil Cd contamination. PMID- 30473289 TI - Benthic diatom community response to metal contamination from an abandoned Cu mine: Case study of the Gromolo Torrent (Italy). AB - Environmental contamination has become a global problem of increasing intensity due to the exponential growth of industrialization. One main debated issue is the metal contamination of rivers receiving Acid Mine Drainage (AMD) from active/abandoned mines. In order to assess the quality of lotic systems, diatoms are commonly used, as their assemblage modifies on the basis of changes in environmental parameters. Benthic diatom changes were analyzed along the metal impacted Gromolo Torrent (Liguria, NW Italy) with the aim of understanding the effects of input from the abandoned Libiola Cu mine. The results support the hypothesis that metals from AMD lead to massive changes in diatoms, resulting in low biological diversity and in a shift of dominance, passing from the genera Cymbella and Cocconeis to more tolerant and opportunistic species, such as Achnanthidium minutissimum and Fragilaria rumpens. The high concentrations of labile metals, measured through Diffusion Gradients in Thin-films (DGT) immediately downstream of the two AMD inputs in the torrent, corresponded to a sudden decrease in the presence of diatoms, indicating the possible reaching of acute toxic levels. In particular, A. minutissimum dominated the mining area and was positively correlated with Cu and Zn; whereas F. rumpens bloomed downstream of this area, where the metal content was diluted, and was positively correlated with As and Pb. Finally, an important abundance of Nitzschia palea and teratological forms of A. minutissimum and F. rumpens were observed downstream from the mine, indicating that metals may have an important impact on diatoms up to the torrent mouth. PMID- 30473290 TI - Use of polymeric sub-micron ion-exchange resins for removal of lead, copper, zinc, and nickel from natural waters. AB - This research investigated the removal capacity of polymeric sub-micron ion exchange resins (SMR) for removal of lead, copper, zinc, and nickel from natural waters in competition with natural organic matter (NOM). Polymeric SMR particles were created and tested to ensure that they were adequately dispersed in the solution. They removed little NOM (10% or less) from river water and wastewater, indicating that competition from NOM was not a major concern. SMR were able to remove 82%+/-0.2% of lead, 46%+/-0.6% of copper, 55%+/-20% of zinc, and 17%+/-2% of nickel from river water spiked with 500MUg/L of each. Similarly, in wastewater, they were able to remove 86%+/-0.1% of lead, 38%+/-0.8% of copper, 28%+/-1% of zinc, and 11%+/-1% of nickel. PMID- 30473291 TI - Implications of denitrification in the ecological status of an urban river using enzymatic activities in sediments as an indicator. AB - A better understanding of the effects of a number of environmental factors on denitrification is vital for analyzing its role as nitrogen sink and providing deeper knowledge about the ecological status of a nitrate-rich ecosystem. Since few studies have addressed the occurrence and implications of denitrification in river sediments, and complexity of interactions among all these environmental factors makes comprehension of the process difficult, the potential of sediments from the Deba River to attenuate nitrate excess through denitrification was investigated. For this purpose, we adapted an in vitro method to measure activities of two enzymes contributing to the entire multiple-step nitrate reduction: Nitrate Reductase and Nitrite Reductase. The environmental features that influence both or single enzymatic activities were identified as oxygen availability, regulated directly by the moisture content or indirectly through the aerobic respiration, organic matter and nitrate content of sediments, and electrical conductivity and exchangeable sodium percentage of water. Additionally, our results showed that Nitrate Reductase catalyzes the principal limiting step of denitrification in sediments. Therefore, taking this enzymatic activity as an indicator, the southern part of the Deba River catchment presented low potential to denitrify but nitrate-limited sediments, whereas the middle and northern parts were characterized by high denitrification potential but nitrate rich sediments. In general, this study on denitrifying enzymatic activities in sediments evaluates the suitability of the management of the effluents from wastewater treatment plants and municipal sewages to ensure a good ecological status of the Deba River. PMID- 30473292 TI - Simultaneous removal of arsenic and antimony from mining wastewater using granular TiO2: Batch and field column studies. AB - Coexisting arsenic (As) and antimony (Sb) in mining wastewater is a common and great concern. On-site simultaneous removal of As and Sb from mining wastewater was achieved by using a reusable granular TiO2 column in this study. To evaluate the accuracy of the scale-up procedure, As and Sb adsorption from wastewater was studied in both large (600g TiO2) and small columns (12g TiO2) based on the proportional diffusivity rapid small-scale column tests (PD-RSSCTs) design. The comparable As and Sb breakthrough curves obtained from small and large columns confirmed the accuracy of the PD-RSSCT theory in the design of large-scale columns. Meanwhile, the consistent As and Sb adsorption results from batch and column experiments suggested that TiO2 adsorption for As and Sb can be predicted from bench-scale tests. Charge distribution multi-site complexation (CD-MUSIC) and one-dimensional transport modeling integrated in the PHREEQC program were performed to study the adsorption behaviors of As and Sb on the TiO2 surface. Coexisting ions, such as Ca2+, Mg2+, and Si4+, play an important role in As and Sb adsorption, and the breakthrough curves were well simulated after considering the compound ion effects. The results from this study highlight the surface reactions of As and Sb on TiO2 and provide a practical way for on-site remediation of industrial wastewater. PMID- 30473293 TI - Fabrication of PVDF nanofibrous hydrophobic composite membranes reinforced with fabric substrates via electrospinning for membrane distillation desalination. AB - To improve the mechanical properties of the electrospun nanofibrous membrane, the nonwoven fabrics and spacer fabrics were employed as support substrates to fabricate polyvinylidene fluoride (PVDF) nanofibrous composite membranes. The influences of the substrate on membrane morphology, hydrophobicity, pore size and pore size distribution, porosity, mechanical strength and permeability were comprehensive evaluated. The electrospun composite membranes had a three dimension bead-fiber interconnected open structure and a rough membrane surface. The membrane surface presented a multilevel re-entrant structure and all the water contact angles were above 140 degrees . In contrast with the pure PVDF nanofibrous membrane, the stress at break and the elastic modulus of the composite membranes increased by 4.5-16 times and 17.5-37 times, respectively. Since the spacer fabrics had less resistance to mass transfer, the membranes composited with spacer fabrics exhibited greater permeate fluxes compared with the composite membranes with the nonwoven fabrics as substrates. During the membrane distillation test, the highest permeate flux was up to 49.3kg/m2/hr at the feed temperature of 80 degrees C. The long-time and repeat operation of membrane distillation desalination indicated the fabricated membrane with a good resistance to scaling and wetting. The results suggested the potential of the electrospun composite membrane for membrane distillation application. PMID- 30473294 TI - Validation of a HRGC-ECNI/LRMS method to monitor short-chain chlorinated paraffins in human plasma. AB - Short-chain chlorinated paraffins (SCCPs) are produced in high volume and have the high potential to pose a threat to human health. However, little information is available for SCCP contamination in human blood/plasma/serum, mainly due to the difficulty of sample preparation and quantitative analysis. A method using high resolution gas chromatography coupled with electron capture negative ionization low resolution mass spectrometry (HRGC-ECNI/LRMS) was developed and validated to measure SCCPs in human plasma. The pretreatment process included protein denaturation and lipid elimination, liquid-liquid extraction with a mixture of n-hexane/dichloromethane (1:1, V/V), and cleanup on a multi-layer silica column. The blank controls, including procedural blank, vacuum blood collection tube blank, and instrumental blank, were the most pivotal points for the reliable analysis of SCCPs. The average value of procedural blanks was 9.0ng/g; and the method detection limit (MDL), calculated as the sum of the average procedural blank value and 3 times of the standard deviation of the procedural blanks, was 12.6ng/g plasma. The validated method was applied to measure the concentrations of the total SCCPs (?SCCPs) in 50 plasma samples from a general population. The measured plasma concentrations of ?SCCPs ranged from =30, non-invasive tear film break-up time <10 s), the overall sensitivity was 86%, specificity 94%, positive likelihood ratio 15.0, and negative likelihood ratio 0.15. CONCLUSIONS: The abridged non-invasive dry eye assessment algorithm may be a useful rapid screening instrument for the full TFOS DEWS II diagnostic test battery, of particular benefit in resource or time-constrained settings. PMID- 30473323 TI - Can crude alkaloids extract of Rhazya stricta induce apoptosis in pancreatic cancer: In vitro study? AB - Cancer is a complicateddisease that reveals genetic variability even among the cells within the same tumor. Pancreatic cancer is the 12th cause of cancer deaths over the world. As a result of the incomplete recovery and the many side effects of current clinical treatment approaches, Herbal diet therapy as a single or adjuvant therapy show high significant output in cancer treatment. Our study focused on the role of the crude alkaloid extract of Rhazya stricter (R. stricta) on pancreatic cancer cells using MTT assay. The cytotoxic effect of different concentrations of R. Strict crude alkaloid on the pancreatic cancer cells showed significant decrease in cell viability with dose dependent manner and the effect was observed at higher concentration of crude R. Stricta alkaloids. On the other hand, no significant cytotoxic effect was observed with the normal WISH cells at all R. Stricta crude alkaloid concentrations with IC50. Moving on, in AsPC-1cells under the same concentrations mRNA expression was increased by 1.5 and 6 folds with 10 and 100 MUg/ Ml treatment when compared with control. Under the same experimental conditions, the anti- apoptotic marker Bcl-2 showed high significant decrease in mRNA expression in both PANC-1 and AsPC-1 pancreatic cancer cells. The present study indicated that the crude alkaloids extract of R. stricta significantly induce apoptotic cell death in pancreatic cancer cells. PMID- 30473322 TI - Pellucid marginal degeneration: Detection, discrimination from other corneal ectatic disorders and progression. AB - Pellucid marginal degeneration (PMD) is a non-inflammatory ectatic corneal disease characterized by a narrow band of corneal thinning separated from the limbus by a relatively uninvolved area 1-2 mm in width. It is a rare corneal disorder that shares many clinical characteristics with other corneal ectasias, such as keratoconus, keratoglobus or Terrien marginal degeneration. PMD usually starts later in life than keratoconus and progresses slower than keratoconus. Slit-lamp examination is very useful to distinguish PMD from other corneal ectatic disorders with inflammatory nature. Corneal topographic indices and the classical crab-claw topographic pattern cannot be used as the main tool to distinguish between PMD and keratoconus. New Scheimpflug imaging-based devices have shown the importance and usefulness of the pachymetric map for an appropriate diagnosis of PMD. In addition, biomechanical and densitometric properties have been studied as complementary techniques to help in the diagnosis of PMD. PMID- 30473324 TI - Quantitative Systems Pharmacology: Modelling and simulating drug action in health and disease. PMID- 30473325 TI - Trends, Predictors, and Outcomes of Temporary Mechanical Circulatory Support for Postcardiac Surgery Cardiogenic Shock. AB - Postcardiac surgery cardiogenic shock (PCCS) is seen in 2% to 6% of patients who undergo cardiac surgery. There are limited large-scale data on the use of mechanical circulatory support (MCS) in these patients. This study sought to evaluate the in-hospital mortality, trends, and resource utilization for PCCS admissions with and without MCS. A retrospective cohort of PCCS between 2005 and 2014 with and without the use of temporary MCS was identified from the National Inpatient Sample. Admissions for permanent MCS and heart transplant were excluded. Propensity-matching for baseline characteristics was performed. The primary outcome was in-hospital mortality and secondary outcomes included trends in use, hospital costs and lengths of stay. In the period between 2005 and 2014, there were 132,485 admissions with PCCS, with 51.3% requiring MCS. The intra aortic balloon pump was the predominant device used with a steady increase in other devices. MCS use for more frequent in younger patients, males and those with higher co-morbidity. There was a decrease in MCS use across all demographic categories and hospital characteristics over time. Older age, female sex, previous cardiovascular morbidity and MCS use were independently predictive of higher in-hospital mortality. In 6,830 propensity-matched pairs, PCCS admissions that required MCS use, had higher in-hospital mortality (odds ratio 2.4; p<0.001), higher hospital costs ($98,759 +/- 907 vs $81,099 +/- 698; p<0.001) but not a longer length of stay compared with those without MCS use. In conclusion, in patients with PCCS, this study noted a steady decrease in MCS use. Use of MCS identified PCCS patients at higher risk for in-hospital mortality and greater resource utilization. PMID- 30473326 TI - Usefulness of High Estimated Pulmonary Artery Systolic Pressure to Predict Acute Kidney Injury After Cardiac Valve Operations. AB - High estimated pulmonary artery systolic pressure (ePASP) has been established as a detrimental predictor for adverse outcomes in patients with chronic kidney disease. However, the relation between preoperative high ePASP and the development of cardiac surgery associated acute kidney injury (CSA-AKI) has not been validated. We performed a retrospective cohort study of adult patients who underwent valve surgery in 2015 at Zhongshan Hospital, Fudan University. Right ventricular systolic pressure, a surrogate for pulmonary systolic pressure, was estimated in the study group of 1056 patients by preoperative echocardiography. CSA-AKI was defined based on the Kidney Disease Improving Global Outcomes criteria. The relation between preoperative ePASP and CSA-AKI was demonstrated with the use of multivariate analysis after adjusting for potential risk factors for CSA-AKI. Of these patients, preoperative ePASP was 44.5 +/- 14.9 mm Hg. 401 (38%) patients developed CSA-AKI in which 73 patients (6.9%) suffered from severe AKI (stage II and III). Multivariate analysis showed that preoperative ePASP was independently associated with CSA-AKI (odds ratio per 10 mm Hg increment, 1.099; 95% confidence interval, 1.003 to 1.204; p = 0.042). Preoperative ePASP more than 60 mm Hg was found to be linked with the increasing incidence of AKI by 62% and in-hospital mortality by over 300%, but not linked with severe AKI or renal replacement therapy. In conclusion, an increase in preoperative ePASP was independently and significantly associated with the development of CSA-AKI in patients who underwent valve surgery. Such relation between preoperative ePASP and CSA-AKI could provide a novel therapeutic target against prevention of AKI. PMID- 30473327 TI - Relation of Alcohol Consumption to Left Ventricular Fibrosis Using Cardiac Magnetic Resonance Imaging. AB - Light-to-moderate regular alcohol consumption has been associated with reduced mortality, heart failure, and sudden death, with a well described "U-shaped" relationship. We sought to determine whether markers of diffuse ventricular fibrosis as assessed by cardiac magnetic resonance imaging (CMR) T1 mapping differ between nondrinkers and regular drinkers. We prospectively recruited 165 participants to undergo 3T CMR ventricular T1 mapping which included 120 regular light-to-moderate drinkers (7 to 28 standard drinks per week for >12 months) and 45 age and gender-matched nondrinking controls (1 standard drink ~12 g alcohol). Diffuse ventricular fibrosis was assessed using ShMOLLI T1 mapping sequences performed in mid-short axis. Native T1, postcontrast T1 times and extracellular volume were compared in the left ventricle between regular drinkers and lifelong nondrinkers. In total 165 participants (mean age 59 +/- 12 years, 70% male, 36% hypertension, mean LVEF 58 +/- 11%) underwent CMR. Moderate alcohol intake (mean alcohol intake 16 +/- 6 SDs/week) was associated with lower markers of diffuse ventricular fibrosis: native T1 time 1140 +/- 47 vs 1173 +/- 39 ms, p < 0.001; postcontrast T1 time 470 +/- 47 vs 445 +/- 43 ms, p = 0.01; extracellular volume 25.0 +/- 2.7% vs 27.0 +/- 2.8%, p = 0.003 despite similar LV size (p = 0.55) and mass compared with nondrinkers (p = 0.78). Quantity of alcohol intake and beverage type did not predict lower native T1 times. In conclusion, light-to moderate or "social" alcohol consumption is associated with T1 changes on CMR suggestive of a reduction in diffuse ventricular fibrosis. These preliminary findings may provide some insights into the association between modest alcohol intake and reduction in sudden death and heart failure. PMID- 30473328 TI - Prognostic Significance of Incidental Nonsustained Ventricular Tachycardia Detected on Pacemaker Interrogation. AB - Symptomatic sustained ventricular tachycardia is a life threatening arrhythmia requiring prompt treatment. However, the risk associated with asymptomatic nonsustained ventricular tachycardia (NSVT) detected on routine permanent pacemaker (PPM) interrogation in patients with known cardiac conduction disease is unknown. Our aim is to determine if asymptomatic NSVT detected on PPM interrogation is associated with increased mortality. As part of a prospective observational cohort study, 582 patients with long-term pacemakers were recruited at a tertiary cardiac centre, and followed for 4 +/- 1.96 years (mean +/- standard deviation). At each subsequent pacemaker check, any symptoms and ventricular high-rate episodes were recorded. We excluded 17 patients due to incomplete data. In the remaining 565 patients (57% male, age 74.5 +/- 19.2 years, left ventricular ejection fraction 50.0 +/- 11.3%), NSVT was found in 125 (22.1%) patients with a higher prevalence in males (65% vs 54%; p = 0.033). Those with NSVT were more likely to have had coronary artery disease (p = 0) or previous myocardial infarction (p = 0.015). After correction for baseline variables, NSVT had no impact on survival (n = 52 [42%] vs n = 162 [37%]; log rank p = 0.331, hazard ratio: 0.927, 95% confidence interval: 0.678 to 1.268, p = 0.697). In conclusion, asymptomatic NSVT identified on PPM interrogation does not appear to be associated with increased mortality, thus whether treatment to suppress this arrhythmia is of benefit remains unproven. PMID- 30473329 TI - An evolving technology for an evolving disease: A commentary on NGS-based MRD evaluation in B-ALL. PMID- 30473330 TI - Anatomical site as a parameter in the predictive model of diffuse large B cell lymphoma. PMID- 30473331 TI - Successfully treatment of intercourse anejaculation with psychosexual counseling: A very rare case of situational anejaculation specific to penetrative sex with the wife. AB - Situational anejaculation means that a man can ejaculate in some situations but not in others. Intercourse type of anejaculation means existence of ejaculation by masturbation, but not during sexual intercourse. In some cases, men may be able to ejaculate and attain orgasm with one partner but not with another. Performance anxiety, hostility toward the partner, dysfunctional psychosexual development, and unconscious desire to avoid pregnancy are the possible underlying conditions. We herein reported a case of wife-specific intercourse anejaculation succesfully treated with sexual therapy. According to our best knowledge, this is an important case study in literature about intercourse type of situational anejaculation specific to the patient's wife that was treated with psychosexual counseling. The authors conclude that this clinical course of situational intercourse anejaculation suggests a psychological problem in these patients and sexual therapy is effective. PMID- 30473332 TI - Functional results in the treatment of localized prostate cancer. An updated literature review. AB - Prostate cancer is the second most frequently diagnosed cancer in men. The initial diagnosis is made in increasingly younger patients, so it seems to be essential to guarantee optimal functional results. We carried out a systematic search to define the functional results of each of the therapeutic options for localized prostate cancer. Radical prostatectomy generates a greater negative effect on urinary continence and erectile function compared to active surveillance and radiotherapy. Robotic surgery seems to offer better functional results, especially at the level of erectile function. Urinary and bowel symptoms are more pronounced after radiotherapy compared to other options. Patients must be warned of the possible functional results prior to choice of treatment. PMID- 30473333 TI - Prognostic impact of beta-blocker compared to combined amiodarone therapy secondary to ventricular tachyarrhythmias. AB - OBJECTIVE: The study sought to assess the prognostic impact of treatment with beta-blocker (BB) compared to combined BB plus amiodarone (BB-AMIO) on long-term survival in patients surviving ventricular tachyarrhythmias on admission. BACKGROUND: Data regarding the prognostic outcome of patients presenting with ventricular tachyarrhythmias treated with BB and BB-AMIO is limited. METHODS: A large retrospective registry was used including consecutive patients surviving index episodes of ventricular tachyarrhythmias from 2002 to 2016. Patients treated with BB were compared to patients with BB-AMIO. The primary prognostic endpoint was long-term all-cause death at 3 years. Kaplan-Meier, multivariable Cox regression and propensity score matching analyses were applied. RESULTS: A total of 1354 patients was included, 85% treated with BB, 15% with BB-AMIO. Within the unmatched real-life cohort, uni- and multivariable Cox regression models revealed BB associated with improved long-term survival compared to BB AMIO (univariable: HR = 0.550; p = 0.001, multivariable: HR = 0.712; statistical trend, p = 0.052). After propensity-score matching (n = 186 matched pairs), BB therapy was still associated with improved survival compared to BB-AMIO (mortality rate 18% versus 26%; log rank p = 0.042; HR = 0.634; 95% CI = 0.407 0.988; p = 0.044). Prognostic superiority of BB was mainly observed in patients with LVEF >= 35% (HR = 0.463; 95% CI = 0.215-0.997; p = 0.049) and in those without atrial fibrillation (non-AF) (HR = 0.415; 95% CI = 0.202-0.852; p = 0.017). CONCLUSION: BB therapy is associated with improved secondary long-term prognosis compared to BB-AMIO in patients surviving index episodes of ventricular tachyarrhythmias. PMID- 30473334 TI - Nutritional risk index predicts survival in patients undergoing transcatheter aortic valve replacement. AB - BACKGROUND: Among patients undergoing transcatheter aortic valve replacement (TAVR), prognosis is impacted by nutritional status, but the influence of the nutritional risk index (NRI) is unknown. Here we calculated the NRI to determine the prevalence and prognostic impact in terms of mortality of malnutrition in TAVR patients. METHODS AND RESULTS: This retrospective multicenter study included 941 patients who underwent TAVR between 2008 and 2016 (mean age, 80.7 +/- 6.5 years; 57% female). The NRI was calculated as 1.519 * albumin (g/L) + 41.7 * (real weight [kg] / ideal weight [kg]). The mean NRI was 98.1 +/- 7.0%. The patients were stratified into the following groups based on malnutrition risk: severe (NRI < 83.5; n = 83; 8.82%), moderate (83.5 >= NRI < 97.5; n = 370; 39.32%), mild (97.5 >= NRI < 100; n = 102; 10.84%), and no risk (NRI >= 100; n = 386; 41.02%). During the follow-up period (2.1 +/- 1.1 years), 186 patients died, representing 19.8% of the total cohort. Cox regression models were used to analyze the relationship between NRI and mortality during follow-up. Compared to patients with no or mild nutritional risk, those with moderate or severe nutritional risk had a 45% greater risk of mortality during follow-up (adjusted HR, 1.45; 95% CI, 1.05-1.99; P = 0.021). CONCLUSION: Malnutrition is common among TAVR patients. Our present data indicated that the NRI was independently associated with increased risk of death during long-term follow-up after TAVR. Based on its potential to improve risk prediction, NRI appears to be a promising tool for the clinical assessment of patients who are candidates for TAVR. PMID- 30473335 TI - Comparison of atrial fibrillation in CKD and non-CKD populations: A cross sectional analysis from the Kailuan study. AB - OBJECTIVES: To compare clinical epidemiological features of atrial fibrillation (AF) in chronic kidney disease (CKD) and non-CKD populations. METHODS: This study included 88,312 adults aged >=45 years old from the KAILUAN study. AF was ascertained with a 12-lead electrocardiogram. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 and/or proteinuria. Participants were categorized into non-CKD (eGFR > 60 mL/min/1.73 m2 without proteinuria, n = 66,725) and CKD (n = 21,578) groups. We evaluated the prevalence of AF in both groups, evaluated risk factors for AF using multivariable-adjusted logistic regression analysis. RESULTS: The prevalence of AF among non-CKD and CKD participants was 0.26% and 1.00%, respectively. Multivariable-adjusted analysis showed that older age (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.07 1.10, P < 0.001), smoking (OR: 1.23, 95% CI: 1.07-1.57, P = 0.017), hypertension (OR: 2.14, 95% CI: 1.44-3.17, P < 0.001), diabetes (OR: 1.79, 95% CI: 1.10-2.89, P < 0.001), and larger waist circumference (OR: 1.03, 95% CI: 1.01-1.04, P < 0.001) were significantly associated with AF in the non-CKD group. In the CKD group, older age, smoking, larger waist circumference, reduced eGFR (OR: 0.97, 95% CI: 0.95-0.99, P < 0.001), proteinuria (OR: 2.01, 95% CI: 1.09-3.74, P < 0.001) and raised serum C-reactive protein (1.01, 1.00-1.03, P < 0.001) were significantly associated with AF. CONCLUSIONS: The prevalence of AF in Chinese adults with CKD is higher than that among those without CKD. Risk factors for AF in non-CKD population were not the same compared with those in CKD population, kidney function and inflammatory markers were associated with the prevalence of AF. PMID- 30473336 TI - Associations between risk of overall mortality, cause-specific mortality and level of inflammatory factors with extremely low and high high-density lipoprotein cholesterol levels among American adults. AB - BACKGROUND: The health outcomes associated with extremely low or high plasma concentrations of high-density lipoprotein cholesterol (HDL-C) are not well documented mainly because of the small numbers of participants with such values included in the clinical trials. OBJECTIVE: We prospectively investigated the association between extremely low and high HDL-C with: 1) the risk of overall, coronary heart disease (CHD), cerebrovascular and cancer mortality, and, 2) their link with inflammatory factors. METHODS: Analysis was based on subjects >=18 years old from the National Health and Nutrition Examination Surveys (NHANES). We categorized HDL-C levels as follows: [low HDL-C group <=30 (extremely low), 30-40 (low), and >=40 (reference)] [high HDL-C group = 40-80 (reference), 80-100 (high) and >=100 mg/dl (extremely high). Cox proportional hazard regression models and analysis of covariance accounted for survey design, masked variance and sample weights. RESULTS: After adjustment for age, race and sex, we found that the very low HDL-C category (<30 mg/dl) had a greater risk of total mortality (risk ratio [RR]: 3.00, 95%CI: 2.20-4.09). RR for CHD and stroke mortality was 2.00 and 2.53, respectively; there was no link between cancer and level of HDL-C (p = 0.235). The association between total mortality, CHD and stroke with the level of HDL-C attenuated but remained significant even after adjustment for demographics, dietary, cardiovascular risk factors and treatment for dyslipidemia (all p < 0.001). After adjustments, subjects with extremely high HDL-C levels had a higher risk of mortalities (all p < 0.001). Mexican-American ethnicity, subjects in the low level of HDL-C (30-40 mg/dl) category had higher risk of mortalities than those with a very low level (all p < 0.001). Concentration of C-reactive protein, fibrinogen and white blood count significantly decreased as the level of the HDL C increased; these findings were robust after adjustment for demographics, dietary, cardiovascular risk factors and treatment for dyslipidemia (all p < 0.001); further subjects with extremely high HDL-C levels have a greater levels of inflammatory factors (all p < 0.001). CONCLUSIONS: Both extremely low and high HDL-C levels were associated with greater risk of mortalities (total, CHD and stroke) and higher level of inflammatory factors, while there was no link between level of HDL-C and risk of cancer. Moreover, we found evidence of an HDL-C paradox in Mexican-American ethnicity participants. PMID- 30473337 TI - Predictors of strut coverage of drug eluting stent implantation in diabetic patients. AB - BACKGROUND: Incomplete re-endothelialization of drug eluting stent (DES) segments has been associated with the occurrence of major adverse cardiac events after DES implantation. It is unknown whether on-clopidogrel platelet reactivity (OPR) and/or circulating endothelial progenitor cells (EPC) levels may predict uncovered strut rate in diabetic patients treated by DES implantation. METHODS: One-hundred and five diabetic patients undergoing elective DES implantation were included into the study. EPC levels and OPR were assessed at 24 h (baseline) and 3 months. EPC were evaluated by flow cytometric analysis and defined by the co expression of the markers CD34 and KDR. OPR was assessed using the impedance aggregometer. The degree of DES re-endothelialization was assessed at 3 months by optical coherence tomography. RESULTS: A direct correlation was observed between the uncovered strut rate and OPR both at baseline (r = 0.47: p < 0.001) and at the 3 months (r = 0.25: p = 0.015). On the contrary, we found no significant correlation between EPC level and uncovered strut rate either at baseline (r = 0.02; p = 0.85) or at 3 months (r = -0.06; p = 0.13). By multivariable regression analysis, independent predictors of uncovered strut rate > 5% were complex lesions (OR = 5.35; 95% confidence interval 1.32-17.57; p = 0.027) and OPR at baseline (OR = 4.73; 95% confidence interval 1.04-8.14; p = 0.039). CONCLUSIONS: In diabetic patients treated with DES implantation OPR at baseline and complex lesions are independent predictors of uncovered strut rate at 3 months. PMID- 30473338 TI - Molecular characterization of bovine ephemeral fever virus in Thailand between 2013 and 2017. AB - Bovine ephemeral fever (BEF) is an arthropod-borne disease caused by bovine ephemeral fever virus (BEFV), a negative sense, single-stranded RNA virus. BEFV is endemic in tropical and sub-tropical regions including Thailand, a country in mainland Southeast Asia. However, there are few studies on BEFV and no available information regarding molecular characteristics of BEFV in Thailand. Therefore, the aims of this study were to genetically characterize Thai BEFVs and reveal their evolutions by phylogenetic analysis of G gene ectodomain sequences. From 2013 to 2017, blood samples were collected from bovine that matched with BEF case definition from three regions of Thailand. Thai BEFV G genes and a whole genome of an isolate, East Asia/TH/LRI0045/2016, were sequenced and characterized. Additionally, their phylogenies were constructed. This is the first report on genetics of BEFV in Southeast Asia. G ectodomain encoding region of Thai BEFV found during 2013-2017 are closely related to the second and third sub-clades of East Asia lineage. In addition, we observed mutation in the putative P' ORF of all Thai BEFVs which generated a premature stop codon. Thai G gene sequences are closely related to those of mainland Chinese and Taiwanese isolates. The whole genomic sequences of Thai BEFV and East Asia/China/JT02 L/2002 possess common characteristics, suggesting shared evolutionary relationship between East and Southeast Asian strains. Further studies on relationship between animal translocation, circulation of BEFV in Greater Mekong subregion and acquisition of more G gene sequences may improve understanding of BEFV epidemiology in mainland Southeast Asia. PMID- 30473339 TI - PI3K/Akt/mTOR signaling pathway participates in Streptococcus uberis-induced inflammation in mammary epithelial cells in concert with the classical TLRs/NF-KB pathway. AB - Mammary epithelial cells (MECs) play an important role in debating Streptococcus uberis (S. uberis) infection. Toll like receptor (TLR) engagement leads to the recruitment of phosphatidylinositol 3 kinases (PI3K). In order to investigate the relationship of TLRs/NF-kappaB and PI3K/Akt/mTOR signaling pathways in S. uberis infection in MECs, we challenged MECs (EpH4-Ev) with S. uberis 0140 J and quantified the adaptor molecules in these two signaling pathways, as-well-as proinflammatory cytokines and cell damage. The results indicate that the host's responses to virulent S. uberis infection are complex. In MECs, both TLR2 and TLR4 are detecting S. uberis infection and TLR2 is the principal receptor. The role of the PI3K/Akt/mTOR pathway in inflammatory regulation is independent of the activation of TLRs/NF-kappaB. Cross-talk between PI3K/Akt/mTOR and TLRs/NF kappaB signaling pathways promote inflammation. This study increases our understanding of the molecular defense mechanisms of MECs in S. uberis mastitis, and provides theoretical support for the prevention of this disease. PMID- 30473340 TI - Spotty Liver Disease: A review of an ongoing challenge in commercial free-range egg production. AB - Spotty Liver Disease is an acute infectious disease of layer chickens that was likely first described in the USA and Canada in the 1950s and 1960's. The disease occurs almost exclusively in barn and free-range production systems. Outbreaks usually, but not exclusively occur in young layers (?25 weeks) at peak of lay. Indicators of SLD include an acute drop in egg production of up to 35%, together with increased mortality of up to 15%. A presumptive diagnosis at post mortem is made with the detection of characteristic small yellow-white necrotic hepatic lesions, together with a fibrinous peri-hepatitis, excess pericardial and peritoneal fluid, and usually enteritis with diarrhoea. Histopathology reveals a multifocal acute hepatocellular necrosis with fibrin and occasional haemorrhage. Control measures trialled include use of antibiotics, improved biosecurity and hygiene, as well as management practices directed at reducing stress in flocks. However, none other than treatment with antibiotics has been consistently effective which suggested a bacterial aetiology. In 2015, a novel fastidious thermophilic, microaerobic campylobacter was isolated from symptomatic SLD flocks in the UK. Subsequently, an Australian group isolated and further characterised a genetically similar bacterium and named it Campylobacter hepaticus. The bacterium can be cultured from the liver and bile of infected birds, although recovery from non-sterile organs such as the caecum and duodenum remains elusive. Consequently, the route of transmission remains unconfirmed, although molecular detection by PCR of C. hepaticus DNA in the gastrointestinal tract and faeces of SLD infected birds is highly suggestive of a faecal-oral route. PMID- 30473341 TI - Clostridium perfringens-mediated necrotic enteritis is not influenced by the pre existing microbiota but is promoted by large changes in the post-challenge microbiota. AB - PROBLEM ADDRESSED: Clostridium perfringens is the etiological agent of necrotic enteritis in chickens. As necrotic enteritis is a gastrointestinal disease, the interactions of pathogenic C. perfringens strains with the complex microbiota of the gastrointestinal tract may influence disease development and severity of disease. OBJECTIVE: In this study the interactions of a pathogenic strain of C. perfringens, WER-NE36, with the microbiota of broilers was investigated to determine whether the pre-existing microbiota could influence disease outcomes in the necrotic enteritis challenge model. Methods and approach: Faecal microbiota compositions were measured before and after C. perfringens challenge and caecal microbiota was also characterised at necropsy. The microbiota profiles from individual birds were related back to the degree of necrotic enteritis that each bird developed. RESULTS: Under the experimental conditions used the pre-existing microbiota did not have an effect on disease outcomes. However, C. perfringens challenge was shown to have a significant effect on the microbiota of broilers, regardless of disease status, by displacement of commensal clostridia. CONCLUSIONS: The microbiota signature after challenge resembled that of lower productivity birds, supporting the finding that physically obvious disease (necrotic lesions), as well as dysbiosis, are associated with shifts in gut microbiota and affect broiler performance, increasing costs to the poultry industry. PMID- 30473343 TI - Experimental infection of racing pigeons (Columba livia domestica) with highly pathogenic Clade 2.3.4.4 sub-group B H5N8 avian influenza virus. AB - Reported mass mortalities in wild pigeons and doves during the 2017/2018 Clade 2.3.4.4 HPAI H5N8 outbreaks in South Africa necessitated an investigation of healthy racing pigeons for their susceptibility and ability to transmit a Clade 2.3.4.4 sub-group B virus of South African origin. Pigeons challenged with medium (104.5 EID50) and high doses (106 EID50) but not a low dose (103 EID50) of virus, shed virus in low levels of <103 EID50/ml from the oropharynx and cloaca for up to eight days, with peak shedding around 4 days post challenge. Challenged pigeons were able to transmit the virus to contact pigeons, but not contact chickens. Neither pigeons nor chickens presented clinical disease, and only two pigeons in the group that received the high challenge dose developed influenza A virus specific antibodies. The levels of virus shed by the racing pigeons were well below the published bird infectious dose 50 values for most poultry, especially chickens, therefore the risk that racing pigeons could act as propagators and disseminators through excretion of Clade 2.3.4.4 HPAI H5N8 strains remains negligible. PMID- 30473342 TI - Full-genome characterization by deep sequencing of rotavirus A isolates from outbreaks of neonatal diarrhoea in pigs in Spain. AB - Since early 2017, in Spain there was an apparent increase in reports on rotavirus involvement in neonatal diarrhoea outbreaks, affecting also adult sows. In this study, 16 unrelated outbreaks of diarrhoea in suckling pigs and sows, where rotavirus A was the only pathogen detected, were investigated. Deep-sequencing was performed on total RNA from twenty-four positive faecal samples. Genotyping, phylogenetic and bayesian analyses showed that all isolates had a common ancestor of porcine, or human porcine-like, origin. The new strain was introduced in the population shortly before the onset of the outbreaks. Besides, a high diversification of the VP7 and VP4 genes occurred in a short time. Isolates presented a high number of amino acid changes in the neutralizing epitopes compared to vaccine sequences. The present report illustrates how a new rotavirus A strain may disseminate rapidly and the extremely high diversification that this pathogen may undergo in a short period. PMID- 30473344 TI - High reversion potential of a cell-adapted vaccine candidate against highly pathogenic porcine reproductive and respiratory syndrome. AB - Modified live vaccine (MLV) based on highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) is prone to quick reversion of virulence upon circulating in host animals. The objective of this study was to evaluate the virulence reversion potential of HP-PRRSV MLV and to identify elements within the HP-PRRSV genome contributing to this phenomenon. A blind passage, cell-adaptation strategy was attempted to attenuate a HP-PRRSV strain JX143, which was isolated during the atypical PRRS outbreak in 2006. Two attenuated candidates passage 87 (JXM87) and passage 105 (JXM105) used as MLVs showed the best balance of safety and efficacy in 4 week-old piglets (unpublished data). Two studies were performed during which the candidates were assessed for reversion to virulence through five back passages in susceptible piglets (21 +/- 3 days of age). Both study results showed increase in clinical signs, pyrexia and lung lesions as well as decreased average daily weight gain as of passage 3 in susceptible pigs clearly, and it indicated that both candidates regained virulence, irrespective of the passage level. Increase in respective parameters was accompanied by increase in viremia in piglets: JXM87 virus titer increased from Passage 1 (P1) 4.40 Lg TCID50/mL to P4 5.75 Lg TCID50/mL, and JXM105 virus titer increased from P1 3.78 Lg TCID50/mL to P4 6.42 Lg TCID50/mL. Next generation sequencing (NGS) was performed on clinical samples (serum, lung tissue) from P4 animals. Sequence analysis comparing P4 materials with their parental strains revealed 10 amino acid mutations in 4 proteins for JXM87 and 14 amino acid mutations in 9 proteins for JXM105, respectively. Interestingly, five amino acid mutations were identical for the two candidates, which were located in nsp1beta, GP5a and nsp10 coding regions, suggesting nsp1beta, GP5a and nsp10 could contribute to virulence in HP PRRSV. PMID- 30473345 TI - Multiple bluetongue virus serotypes causing death in Brazilian dwarf brocket deer (Mazama nana) in Brazil, 2015-2016. AB - Bela Vista Biological Sanctuary (RBV) is a protected area of Itaipu Binacional, a hydroelectric power company located on the border of Brazil and Paraguay. A captive population of Brazilian dwarf brocket deer (Mazama nana, Cervidae, Artiodactyla) is maintained for conservation purposes. Despite the reproductive success of the animals, outbreaks of a fatal hemorrhagic disease have been registered over the years, compromising conservation efforts. In order to identify the etiological agents of these hemorrhagic diseases, 32 captive Brazilian dwarf brockets were sampled to investigate bluetongue virus (BTV), epizootic hemorrhagic disease (EHD), and adenovirus hemorrhagic disease (AHD), in 2015. Only one deer (1/32; 3.12%) was seropositive for BTV. After this survey, five animals died in the early autumn of 2015 and 2016, again presenting clinical signs of hemorrhagic disease. Using RT-qPCR, RT-PCR and DNA sequencing, five BTV serotypes (3, 14, 18, 19, and 22) were identified in blood and tissues collected during necropsies. These BTV serotypes had not been previously described or isolated in Brazil, either in wild or domestic ruminants. Additionally, differential diagnosis was performed for EHD and AHD, but all samples were negative for both diseases. The multiple distinct BTV serotypes identified in these outbreaks resulted in a high lethality (100%) of Brazilian dwarf brockets and indicated that various BTV serotypes are circulating in the area. PMID- 30473346 TI - Role of wild birds and environmental contamination in the epidemiology of Salmonella infection in an outdoor pig farm. AB - Foodborne outbreaks caused by Salmonella are often attributed to the pork consumption. Salmonella contamination of retail pork is directly linked to the Salmonella prevalence on farm. In UK, approximately 40% of breeding pigs are kept outdoors. Aim of this study was to investigate the role of wild birds in the epidemiology of Salmonella in one outdoor pig farm. Three sampling visits were carried out at monthly intervals to an outdoor farm consisting of two fields, one left empty of pigs for more than 2 years (field A) while the second (field B) was occupied by pigs during the first visit only. Faeces from wild bird droppings, environmental samples and pig faeces were tested for Salmonella. Salmonella spp. was isolated from environmental samples also in field A that had not been occupied by pigs more than 2 years. Interestingly, the wild bird population accessing the fields increased considerably once the pigs had left the farm and the proportion of Salmonella positive wild bird droppings increased over time with 7.4%, 15.8% and 44.3% at the first, second and third visit, respectively. The levels of Salmonella identified in some of the wild bird droppings were unusually high (105-106 CFU/g) suggesting that Salmonella was actively replicating in the gastrointestinal tract of these birds. Monophasic Salmonella Typhimurium DT193 was the predominant serotype isolated in pigs as well as in wild bird droppings and the environment, suggesting that the pigs were the original source of infection, as this serovar is typically associated with pigs. PMID- 30473347 TI - Pathogenicity differences between a newly emerged TW-like strain and a prevalent QX-like strain of infectious bronchitis virus. AB - TW-like IBV isolates have appeared frequently in recent years in mainland China. In this study, we compared the TW-like IBV GD strain and the predominant QX-like SD strain in terms of serology and pathogenicity to 3-week-old specific-pathogen free chickens. Both strains could cause severe respiratory distress and renal lesions, with a mortality rate were approximately 20%. Virus were continuously shed via the respiratory tract and cloaca. However, the infection pattern of the two isolates were different. The GD strain persisted for a longer duration and caused extensive damages to the tracheas and lungs. Moreover, chickens infected with the GD strain showed inefficient recovery of damaged cilia after infection. Our findings suggested that the newly emerged TW-like IBV GD strain showed obvious differences in pathogenicity, tissue tropism and replication efficiency compared with the QX-like IBV SD strain, with the TW-like GD strain showing stronger tropism to the respiratory tract and a longer duration of clinical signs. PMID- 30473348 TI - Methicillin-resistant Staphylococcus aureus CC22-MRSA-IV as an agent of dairy cow intramammary infections. AB - Methicillin-resistant S. aureus (MRSA) lineages have become major responsible of healthcare- and community-associated infections in human population. Bovine MRSA are sporadically detected in the dairy herd, but its presence enhances the risk of zoonosis. Some lineages are able to lose the specific host tropism, being easily transmitted from animals to humans and vice-versa. The present study aims at clarifying the epidemiology of MRSA intramammary infections in a closed dairy herd, which was running a mastitis control program since years. Quarter milk samples were collected from all lactating cows once a week for 9 weeks and bacteriologically tested. At the end of the follow-up period, also a self-taken nasal swab of the milker was analysed. Three cows (12.5%) were MRSA positive, a fourth showed a transient infection and MRSA was isolated also from the milker's nose. Somatic cell counts of infected quarters fluctuated from 1000 to 1,800,000 cells/mL. The isolates were genotyped using DNA microarrays and identified as the epidemic UK-EMRSA-15 grouping in CC22. All strains carried the genes for beta lactam and macrolide resistance. The milker isolate differed from cow isolates mainly for the absence of the untruncated beta-haemolysin and the presence of the immune evasion cluster. The milker had been volunteering in a nursing home since months, thus playing the role of MRSA vector into the herd. Our results showed the adaptive capacity of such MRSA to the bovine host. Therefore, we suggest that CC22-MRSA should be regarded as a potential cause of reverse zoonosis in dairy cattle herds. PMID- 30473349 TI - PCV2 infection activates the cGAS/STING signaling pathway to promote IFN-beta production and viral replication in PK-15 cells. AB - PCV2 is a single-stranded DNA virus that we previously found to induce IFN-beta production via RIG-I and MDA-5. cGAS is known to be the most important DNA sensor for the recognition of cytosolic DNA; however, it remains unclear whether the interferon production induced by PCV2 is associated with cGAS. In the present study, PCV2 infection was found to increase the level of cGAS and STING expression, promote the release of cyclic dinucleotide cGAMP, and induce STING dimerization and translocation into the nucleus of PK-15 cells. These findings indicate that PCV2 infection activates both cGAS and STING. Furthermore, the knockdown of cGAS and STING decreased both the mRNA expression and promoter activity of IFN-beta, demonstrating that the cGAS/STING signaling pathway contributes to the production of IFN-beta. In addition, a knockdown of cGAS and STING also decreased the PCV2 viral load and infectivity. Therefore, PCV2 infection activates the cGAS/STING signaling pathway to induce IFN-beta production and the knockdown of cGAS and STING decreases viral replication in PK 15 cells. These results provide further insight into the relationship between PCV2 and host innate immunity. PMID- 30473350 TI - Pathologic and molecular findings associated with atypical porcine pestivirus infection in newborn piglets. AB - Atypical porcine pestivirus (APPV) has been associated with congenital tremor (CT) type A-II in newborn piglets. Although the number of APPV-based studies is increasing, the associated pathologic findings in infected piglets are underreported. This study describes the histopathologic features of spontaneous APPV infection in CT-affected piglets and complements a previous report by our group. Four two-day-old piglets with CT were evaluated by histopathology, immunohistochemistry (IHC), and molecular assay. The main histopathologic findings at the brain and spinal cord included neuronal necrosis, gliosis, neuronophagia, satellitosis, demyelination, Wallerian degeneration, and Purkinje cell necrosis. An IHC assay designed to detect the proliferation of glial fibrillary acidic protein (GFAP) in affected areas of the brain and spinal cord revealed that the proliferation of GFAP + cells and fibers was predominant in APPV-infected piglets relative to asymptomatic piglets of the same age group. The RT-nested-PCR assays identified APPV RNA in the cerebrum, cerebellum, and brainstem of all piglets; other viruses known to produce similar manifestations were not detected. These results suggest that the APPV-induced histopathologic findings are predominantly degenerative and necrotic and correlate with our previous findings. Consequently, it is proposed that neuronal necrosis, gliosis, neuronophagia, and satellitosis should be considered as important histologic features of APPV-induced infection in symptomatic CT piglets. PMID- 30473351 TI - Zoonotic potential of atypical enteropathogenic Escherichia coli (aEPEC) isolated from puppies with diarrhoea in Brazil. AB - Recent studies point atypical enteropathogenic Escherichia coli (aEPEC) to be an important agent in childhood diarrhoea in Brazil. aEPEC are commonly found in various animal species, including dogs. Although the true zoonotic risk remains unknown, some strains recovered from dogs present the same serotypes and carry the same virulence genes implicated in human disease. In this study, we compared the virulence and genetic relationship among a set of aEPEC strains previously isolated from diarrheic faeces from companion dogs and humans. A total of 17 strains, 12 from puppies and five from children, were studied. The strains were assessed for: (i) presence of virulence-associated genes (a total of 31 genes) using PCR assays; (ii) genetic relationship by Random Amplified Polymorphic DNA (RAPD), Multilocus Sequence Typing (MLST) and Pulsed-field Gel Electrophoresis (PFGE); and (iii) adherence pattern in intestinal Caco-2 cells. The occurrence of virulence genes was similar between the canine and human isolates presenting the same serotype. The fimbrial genes ecpA and fimH were the most frequently detected, followed by hcpA, tccP, tccP2, lpfA1, lpfA2, astA and toxB genes. Several nle genes were also detected, with one canine strain (O156:H- / ST327) showing all PAI O-122 genes investigated (efa-1, nleB, nleE and ent/espL2). Canine and human strains of the same serotype were grouped into a single cluster by RAPD and PFGE, in which the ST10 and ST206 were identified. Additionally, most of the strains exhibited a localized adherence-like phenotype when interacting with Caco-2 cells. The results showed that some canine aEPEC strains share virulence genes commonly found in human pathogenic strains. Moreover, strains of the same serotype, isolated from dogs and children, share virulence genes and are phylogenetically close, suggesting a potential zoonotic risk. PMID- 30473352 TI - The relationship between clinical signs and microbiological species, spa type, and antimicrobial resistance in bovine mastitis cases in Austria. AB - Bovine mastitis, an inflammation of the udder usually caused by bacteria, is the most common disease in dairy cattle worldwide with a negative economic impact on the dairy industry. In this study 3020 quarter milk samples from 647 dairy cows on 166 Austrian farms were collected and microbial species, spa type for Staphylococcus (S.) aureus and antimicrobial susceptibility were analysed. A multinomial logistic regression model was applied to investigate the effect of possible categorical influencing covariates on the microbiological findings. Additionally, a generalized linear model was used to analyse the effects of genotype and pathogen species on the occurrence of antimicrobial resistance. Staphylococci were the most common (17% of samples) udder pathogens including 32 different S. aureus spa types. The occurrence of pathogen groups was significantly associated with the clinical mastitis score. Enterobacteriaceae isolates had a significantly higher probability of being present in severe mastitis cases compared to streptococci. Benzylpenicillin and tetracycline were the most common resistance in S. aureus including 14% and 11% resistant isolates. Whereas 16% and 13% of coagulase-negative staphylococci (CNS) isolates were resistant to tetracycline and clindamycin. Overall the proportion of Enterobacteriaceae isolates resistant to at least one antibiotic agents was high (55% of isolates), whereas only 3% benzylpenicillin resistant streptococci were detected. Associations were detected between antimicrobial resistance and particular species of Enterobacteriaceae, CNS and specific S. aureus spa types. In conclusion we present in this study data on causative udder pathogen species and their antimicrobial resistance, which are of great importance for mastitis management and prevention. PMID- 30473353 TI - p53 mediated IFN-beta signaling to affect viral replication upon TGEV infection. AB - TGEV can induce IFN-beta production, which in turn plays a vital role in host antiviral immune responses. Our previous studies showed that TGEV infection activated p53 signaling to induce host cell apoptosis, which might influence virus replication. However, whether there be an interaction between p53 and IFN beta signaling in the process of TGEV infection is unknown. In the present study, we used low dose of TGEV to infect p53 wild-type PK-15 cells (WT PK-15 cells) and p53 deficient cells (p53-/- PK-15 cells), to investigate the modulation of IFN signaling and virus replication by p53. The results showed that the IFN-beta expression and production were notably inhibited in p53-/- PK-15 cells compared with that in WT PK-15 cells at early stage of TGEV infection. In addition, TGEV induced the changes in mRNA levels of TRIF, TRAM, MDA5, RIG-I, IPS-1, IRF9, IRF3, ISG15 and ISG20 were notably hindered in p53-/- PK-15 cells before 36 h post infection (p.i.). Moreover, TGEV genomic RNA and sub genomic mRNA (N gene and ORF7) levels showed significant increase in p53-/- PK-15 cells compared with WT PK-15 cells after TGEV infection. And viral titers were observably enhanced in p53-/- PK-15 cells. Furthermore, exogenous IFN-beta and polyinosinic polycytidylic acid (poly (I:C)) treatment markedly inhibited the mRNA levels of TGEV gRNA, N and ORF7 in WT PK-15 cells and p53-/- PK-15 cells compared to control. Taken together, these results demonstrated that p53 may mediate IFN-beta signaling to inhibit viral replication early after TGEV infection. PMID- 30473354 TI - Isolation and genomic characterization of a novel chicken-orign orthoreovirus causing goslings hepatitis. AB - A severe infectious disease characterized by nephritis, hepatitis and splenitis has attacked goslings around Shandong province in China since 2016. A novel chicken-origin avian orthoreovirus (ARV) was isolated with LMH cells from affected goslings named Reo/Goose/SDPY/1116/17 (SDPY-ARV) strain, and the infection was successfully reproduced experimentally. The ARV-SDPY full genome sequencing was conducted using Next-Generation Sequencing (NGS) technique on Illumina HiSeq platform. The complete genome of SDPY-ARV was 23,427 bp in length and consist of 10 dsRNA segments ranged from 1192 bp (S4) to 3958 bp (L1) which encoding 12 viral proteins. Genomic sequence analysis showed that the SDPY-ARV strain is in the same branch with broiler, pheasant-origin ARV isolates, and shares 51.8-96.2% of nucleotide identity of sigmaC gene with them; while only 49.3-50.3% with waterfowl isolates. In addition, the occurrence of 10 segments genetic reassortment of SDPY strain is confirmed among the PA15511, the 1733 and the PA13649 strains from America. In conclusion, the causative agent of gosling hemorrhagic necrotic hepatitis and nephritis occurring in China is a novel chicken-origin goose orthoreovirus. PMID- 30473355 TI - Occurrence of mcr-1 in Escherichia coli from rabbits of intensive farming. AB - The emergence of mobile colistin resistance genes (mcr) is yet another challenge in the fight against antimicrobial resistance, with reports proving the dissemination of these genes in different countries and different environments being of great concern. In the present study, we describe the recovery of three E. coli strains with mcr-1 gene in IncHI2 plasmids from intestinal content of necropsied meat rabbits reared in two intensive production systems in Portugal. Our findings are worrisome, given the high level of dependence on the usage of antibiotics in rabbit rearing and call for the development and implementation of an active surveillance system in this species. PMID- 30473356 TI - Possible pathogenicity of Japanese encephalitis virus in newly hatched domestic ducklings. AB - Japanese encephalitis virus (JEV) is a zoonotic flavivirus that is transmitted by mosquitoes and vertebrate-amplifying hosts, including birds. Domestic ducks are susceptible to JEV infection and develop various levels of viremia. We tested the pathogenicities of seven JEV strains in newly hatched domestic ducklings. All inoculated ducklings showed stunted growth. Two JEV strains caused notable mortalities of 12.7% and 31.7%, respectively, highlighting that some emerged JEV strains may thus be pathogenic in newly hatched domestic ducklings. PMID- 30473357 TI - Porcine reproductive and respiratory syndrome virus induces interleukin-1beta through MyD88/ERK/AP-1 and NLRP3 inflammasome in microglia. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) infection which caused severe reproductive failure and respiratory disorders in swine is accompanied with severe nervous symptoms. Our previous studies demonstrated that microglia, the resident innate immune cells in central nervous system (CNS), could support PRRSV infection and replication in vitro. And PRRSV infection led to the increased expressions of large amounts of proinflammatory cytokines and chemokines which contributed to neuropathogenesis of PRRSV. Interleukin-1beta (IL 1beta) is one of the increased proinflammatory cytokines, which possesses diverse functions in immune response upon virus infection, including activation of innate immune and modulation of adaptive immune responses. Importantly, considerable evidences indicated that 1L-1beta is involved in neuronal injury. Here, we demonstrated that PRRSV infection up-regulated IL-1beta expression at both the mRNA and protein levels in microglia in a dose-dependent manner. Myeloid differentiation primary response gene 88 (MyD88), extracellular signal-regulated kinase1/2 (ERK) and activator protein 1 (AP-1) were involved in PRRSV induced IL 1beta production in microglia. Moreover, NOD-like receptor protein 3 (NLRP3) inflammasome is activated by PRRSV in microglia, which is required for IL-1beta secretion. Taken together, our data indicated that PRRSV infection could induce IL-1beta up-regulation, which was likely mediated by MyD88/ERK/AP-1 and NLRP3 inflammasome. These findings will provide new insights into the molecular mechanisms of IL-1beta production and some implications for neuropathogenesis of PRRSV. PMID- 30473358 TI - Observations on the distribution and persistence of monophasic Salmonella Typhimurium on infected pig and cattle farms. AB - Following a rapid rise in cases of monophasic Salmonella Typhimurium DT193 (mST) in humans and pigs since 2007 a detailed study of the prevalence and persistence of mST on pig and cattle farms in Great Britain (GB) was undertaken. Thirteen commercial pig farms and twelve cattle farms, identified as mST-positive from surveillance data, were intensively sampled over a three year period. Five indoor and eight outdoor pig farms and four beef and eight dairy farms were included. Individual and pooled faecal samples were collected from each epidemiological group and environmental samples throughout each farm and the antimicrobial resistance profile determined for a selection of mST-positive isolates. Indoor pig farms had a higher mST prevalence than outdoor pig farms, and across both cattle and pig farms the juvenile animals had a higher mST prevalence than the adult animals. Overall, mST prevalence decreased with time across all pig farms, from 25% to less than 15% of environmental samples and 22% to 15% of pooled faecal samples; only one organic outdoor breeding farm was Salmonella-negative at the end of the study. Across the cattle farms no mST was detected by the end of the study, apart from one persistent farm. Clearance time of mST was between seven and twenty-five months. Farms were selected based on having the antimicrobial resistance profile ampicillin, streptomycin, sulphonamides and tetracycline (A, S, SU, T), although resistance to trimethoprim-potentiated sulphamethoxazole was also identified on five pig farms sampled. This study provided a detailed insight into the distribution and persistence of mST on individual pig and cattle farms in GB. It has identified variation in mST shedding of individual animals, and the data can be applied to the wider livestock industry when considering the distribution of mST once identified on an individual farm. PMID- 30473359 TI - Seroprevalance of Batai virus in ruminants from East Germany. AB - Batai virus (BATV), a mosquito-transmitted Orthobunyavirus, was first detected in Southwest Germany in anopheline and culicine mosquitoes in 2009. However, little is known about the exposure to BATV infections for farm animals and humans in Germany as almost no systematic surveillance or infection studies have been carried out to date. This may explain why clinical symptoms in animals or humans have not been reported so far. Therefore and since BATV has meanwhile been detected repeatedly in different mosquito species in several regions of Germany, we performed a surveillance study by assaying more than 1300 blood samples from ruminants (goats, bovines, sheep) from six different federal states covering the years 2013 to 2016. Samples were investigated by BATV-specific real-time polymerase chain reaction as well as by virus neutralisation test. BATV-specific RNA was not detected, whereas BATV-specific antibodies were found in livestock from various geographic regions. We have determined the seroprevalence of 38.8% for goats, 44.7% for sheep and 36.4% for bovines in Saxony-Anhalt. The seroprevalence of goats from Brandenburg was 38.6% and of goats from Saxony 28.4%. These results confirm the levels of seroprevalence to BATV, suggesting endemic circulation, in different regions and indicate that ruminants are potential hosts of BATV in East Germany. Furthermore, the role of BATV as segment donor in disease emergence events should not be overlooked. PMID- 30473360 TI - Recent progresses on synthesized LuxS inhibitors: A mini-review. AB - Design and synthesis of LuxS enzyme inhibitors otherwise known as S ribosylhomocysteine analogues, to target quorum sensing in bacteria, has been considerably developed within the last decade. This review presents which molecules have been synthesized to target LuxS enzyme in other words inhibitors of S-ribosylhomocysteinase. It reports their tested biological activity as LuxS inhibitors when available. A systematic overview has been conducted by searching PubMed, Medline, and The Cochrane Library and data extraction of all synthesized S-ribosylhomocysteine analogues has been collected. This mini-review shows limited data to date on this area and should continue to be studied. PMID- 30473361 TI - Drug screening assay based on the interaction of intact Keap1 and Nrf2 proteins in cancer cells. AB - BACKGROUND: The Nrf2-Keap1 interaction is the major regulatory pathway for cytoprotective responses against oxidative and electrophilic stresses. Keap1, a substrate protein of a Cul3-dependent E3 ubiquitin ligase complex, is a negative regulator of Nrf2. The use of chemicals to regulate the interaction between Keap1 and Nrf2 has been proposed as a strategy for the chemoprevention of degenerative diseases and cancers. RESULTS: The interactions between Keap1 and Nrf2 in vitro and in vivo were investigated using fluorescence resonance energy transfer (FRET) and bimolecular fluorescence complementation (BiFC) strategies in our study. Nrf2 with its N-terminal fused to eGFP and Keap1 with its C-terminal fused to mCherry were expressed and purified in vitro. When purified eGFP-Nrf2 and Keap1-mChrry proteins were mixed together, a strong FRET signal could be detected, indicating an efficient energy transfer from eGFP to mCherry. Moreover, the FRET was detected in vivo using confocal microscopy in colon cancer HCT-116 cells that were co-transfected with eGFP-Nrf2 and Keap1-mCherry. Finally, using an eGFP BiFC approach, the Keap1-Nrf2 interaction was also detected in MCF7 cells by transfecting eGFP N-terminal fused to Nrf2 (eN158-Nrf2) and eGFP C-terminal fused to Keap1 (eC159-Keap1). Using the BiFC and FRET systems, we demonstrated that the prototypical Nrf2-activiting compound tBHQ and the antitumor drug F-dUrd might interfere with the intracellular interaction between Keap1 and Nrf2 whereas the 5 Fu have little role in activating the protective response of Nrf2 pathway in cancer cells. CONCLUSIONS: By analyzing the perturbation of the energy transfer between the donor and acceptor fluorophores and the bimolecular fluorescence complementation of eGFP, we can screen potential inhibitors for the interaction between Keap1 and Nrf2. PMID- 30473362 TI - Cathepsin B: Active site mapping with peptidic substrates and inhibitors. AB - The potential of papain-like cysteine proteases, such as cathepsin B, as drug discovery targets for systemic human diseases has prevailed over the past years. The development of potent and selective low-molecular cathepsin B inhibitors relies on the detailed expertise on preferred amino acid and inhibitor residues interacting with the corresponding specificity pockets of cathepsin B. Such knowledge might be obtained by mapping the active site of the protease with combinatorial libraries of peptidic substrates and peptidomimetic inhibitors. This review, for the first time, summarizes a wide spectrum of active site mapping approaches. It considers relevant X-ray crystallographic data and discloses propensities towards favorable protein-ligand interactions in case of the therapeutically relevant protease cathepsin B. PMID- 30473363 TI - Transforming the landscape of liver disease in the UK. PMID- 30473364 TI - Gathering momentum for the way ahead: fifth report of the Lancet Standing Commission on Liver Disease in the UK. AB - This report presents further evidence on the escalating alcohol consumption in the UK and the burden of liver disease associated with this major risk factor, as well as the effects on hospital and primary care. We reiterate the need for fiscal regulation by the UK Government if overall alcohol consumption is to be reduced sufficiently to improve health outcomes. We also draw attention to the effects of drastic cuts in public services for alcohol treatment, the repeated failures of voluntary agreements with the drinks industry, and the influence of the industry through its lobbying activities. We continue to press for reintroduction of the alcohol duty escalator, which was highly effective during the 5 years it was in place, and the introduction of minimum unit pricing in England, targeted at the heaviest drinkers. Results from the introduction of minimum unit pricing in Scotland, with results from Wales to follow, are likely to seriously expose the weakness of England's position. The increasing prevalence of obesity-related liver disease, the rising number of people diagnosed with type 2 diabetes and its complications, and increasing number of cases of end-stage liver disease and primary liver cancers from non-alcoholic fatty liver disease make apparent the need for an obesity strategy for adults. We also discuss the important effects of obesity and alcohol on disease progression, and the increased risk of the ten most common cancers (including breast and colon cancers). A new in-depth analysis of the UK National Health Service (NHS) and total societal costs shows the extraordinarily large expenditures that could be saved or redeployed elsewhere in the NHS. Excellent results have been reported for new antiviral drugs for hepatitis C virus infection, making elimination of chronic infection a real possibility ahead of the WHO 2030 target. However, the extent of unidentified cases remains a problem, and will also apply when new curative drugs for hepatitis B virus become available. We also describe efforts to improve standards of hospital care for liver disease with better understanding of current service deficiencies and a new accreditation process for hospitals providing liver services. New commissioning arrangements for primary and community care represent progress, in terms of effective screening of high-risk subjects and the early detection of liver disease. PMID- 30473365 TI - Promoting school climate and health outcomes with the SEHER multi-component secondary school intervention in Bihar, India: a cluster-randomised controlled trial. AB - BACKGROUND: School environments affect health and academic outcomes. With increasing secondary school retention in low-income and middle-income countries, promoting quality school social environments could offer a scalable opportunity to improve adolescent health and wellbeing. METHODS: We did a cluster-randomised trial to assess the effectiveness of a multi-component whole-school health promotion intervention (SEHER) with integrated economic and process evaluations in grade 9 students (aged 13-14 years) at government-run secondary schools in the Nalanda district of Bihar state, India. Schools were randomly assigned (1:1:1) to three groups: the SEHER intervention delivered by a lay counsellor (the SEHER Mitra [SM] group), the SEHER intervention delivered by a teacher (teacher as SEHER Mitra [TSM] group), and a control group in which only the standard government-run classroom-based life-skills Adolescence Education Program was implemented. The primary outcome was school climate measured with the Beyond Blue School Climate Questionnaire (BBSCQ). Students were assessed at the start of the academic year (June, 2015) and again 8 months later at the end of the academic year (March, 2016) via self-completed questionnaires. This study is registered with ClinicalTrials.gov, number NCT02484014. FINDINGS: Of the 112 eligible schools in the Nalanda district, 75 were randomly selected to participate in the trial. We randomly assigned 25 schools to each of the three groups. One school subsequently dropped out of the TSM group, leaving 24 schools in this group. The baseline survey included a total of 13 035 participants, and the endpoint survey included 14 414 participants. Participants in the SM-delivered intervention schools had substantially higher school climate scores at endpoint survey than those in the control group (BBSCQ baseline-adjusted mean difference [aMD] 7.57 [95% CI 6.11-9.03]; effect size 1.88 [95% CI 1.44-2.32], p<0.0001) and the TSM delivered intervention (aMD 7.57 [95% CI 6.06-9.08]; effect size 1.88 [95% CI 1.43-2.34], p<0.0001). There was no effect of the TSM-delivered intervention compared with control (aMD -0.009 [95% CI -1.53 to 1.51], effect size 0.00 [95% CI -0.45 to 0.44], p=0.99). Compared with the control group, participants in the SM-delivered intervention schools had moderate to large improvements in the secondary outcomes of depression (aMD -1.23 [95% CI -1.89 to -0.57]), bullying (aMD -0.91 [95% CI -1.15 to -0.66]), violence victimisation (odds ratio [OR] 0.62 [95% CI 0.46-0.84]), violence perpetration (OR 0.68 [95% CI 0.48-0.96]), attitude towards gender equity (aMD 0.41 [95% CI 0.21-0.61]), and knowledge of reproductive and sexual health (aMD 0.29 [95% CI 0.06-0.53]). Similar results for these secondary outcomes were noted for the comparison between SM-delivered intervention schools and TSM-delivered intervention schools (depression: aMD 1.23 [95% CI -1.91 to -0.55]; bullying: aMD -0.83 [95% CI -1.08 to -0.57]; violence victimisation: OR 0.49 [95% CI 0.35-0.67]; violence perpetration: OR 0.49 [95% CI 0.34-0.71]; attitude towards gender equity: aMD 0.23 [95% CI 0.02 0.44]; and knowledge of reproductive and sexual health: aMD 0.22 [95% CI -0.02 to 0.47]). However, no effects on these secondary outcomes were observed for the TSM delivered intervention schools compared with the control group (depression: aMD 0.03 [95% CI -0.70 to 0.65]; bullying: aMD -0.08 [95% CI -0.34 to 0.18]; violence victimisation: OR 1.27 [95% CI 0.93-1.73]; violence perpetration: OR 1.37 [95% CI 0.95-1.95]; attitude towards gender equity: aMD 0.17 [95% CI -0.09 to 0.38]; and knowledge of reproductive and sexual health: aMD 0.06 [95% CI -0.18 to 0.32]). INTERPRETATION: The multi-component whole-school SEHER health promotion intervention had substantial beneficial effects on school climate and health related outcomes when delivered by lay counsellors, but no effects when delivered by teachers. Future research should focus on the evaluation of the scaling up of the SEHER intervention in diverse contexts and delivery agents. FUNDING: John D. and Catherine T. MacArthur Foundation, USA and the United Nations Population Fund India Office. PMID- 30473367 TI - Changing school climates to promote adolescent wellbeing: two trials with one goal. PMID- 30473366 TI - Effects of the Learning Together intervention on bullying and aggression in English secondary schools (INCLUSIVE): a cluster randomised controlled trial. AB - BACKGROUND: Bullying, aggression, and violence among children and young people are some of the most consequential public mental health problems. We tested the Learning Together intervention, which involved students in efforts to modify their school environment using restorative practice and by developing social and emotional skills. METHODS: We did a cluster randomised trial, with economic and process evaluations, of the Learning Together intervention compared with standard practice (controls) over 3 years in secondary schools in south-east England. Learning Together consisted of staff training in restorative practice; convening and facilitating a school action group; and a student social and emotional skills curriculum. Primary outcomes were self-reported experience of bullying victimisation (Gatehouse Bullying Scale; GBS) and perpetration of aggression (Edinburgh Study of Youth Transitions and Crime (ESYTC) school misbehaviour subscale) measured at 36 months. We analysed data using intention-to-treat longitudinal mixed-effects models. This trial was registered with the ISRCTN registry (10751359). FINDINGS: We included 40 schools (20 in each group); no schools withdrew. 6667 (93.6%) of 7121 students participated at baseline and 5960 (83.3%) of 7154 at 36 months. Mean GBS bullying score at 36 months was 0.34 (SE 0.02) in the control group versus 0.29 (SE 0.02) in the intervention group, with a significant adjusted mean difference (-0.03, 95% CI -0.06 to -0.001; adjusted effect size -0.08). Mean ESYTC score at 36 months was 4.33 (SE 0.20) in the control group versus 4.04 (0.21) in the intervention group, with no evidence of a difference between groups (adjusted difference -0.13, 95% CI -0.43 to 0.18; adjusted effect size -0.03). Costs were an additional L58 per pupil in intervention schools than in control schools. INTERPRETATION: Learning Together had small but significant effects on bullying, which could be important for public health, but no effect on aggression. Interventions to promote student health by modifying the whole-school environment are likely to be one of the most feasible and efficient ways of addressing closely related risk and health outcomes in children and young people. FUNDING: National Institute for Health Research, Educational Endowment Foundation. PMID- 30473368 TI - Risk factors for early readmission due to surgical complications after treatment of proximal femoral fractures - A Finnish National Database study of 68,800 patients. AB - INTRODUCTION: Hip fracture surgery is associated with a considerable amount medical and surgical complications, which adversely impacts the patient's outcome and/or increases costs. We evaluated what risk factors were associated with the occurrence of early readmission due to surgical complications after hip fracture surgery. MATERIAL AND METHODS: A nationwide database with 68,800 hip fracture patients treated between 1999 and 2011 was studied to uncover the association of readmissions with co-morbidities, fracture types, different hospital types and treatment methods using the Cox proportional hazards model. RESULTS: Early readmission within three months due to hip fracture surgery complications occurred at a rate of 4.6%. Increased occurrence of readmission was found among patients with: heavy alcoholism (HR 1.38; 95% CI: 1.23-1.53); Parkinson's disease (PD; HR 1.22; 95% CI: 1.05-1.42); pre-existing osteoarthritis (HR 2.02; 95% CI: 1.83-2.23); rheumatic disease (HR 1.44; 95% CI: 1.27-1.65); as well as those with a fracture of the femur neck, depression, presence of a psychotic disorder, an operative delay of at least three days, or previous treatment with total hip arthroplasty. CONCLUSION: Our results indicate that there are several factors associated with an increased risk of early readmission. We suggest that in the presence of these factors, the surgical treatment method and postoperative protocol should be carefully planned and performed. PMID- 30473369 TI - Accidental external rotation of distal interlock jig in retrograde femoral nailing can lead to more prominent screws. AB - OBJECTIVE: Symptomatic distal interlocking screws in retrograde femoral nailing are common due the difficulties of imaging the trapezoidal femur. Screws appearing to have appropriate length on imaging may possibly be prominent, creating symptoms. Screw trajectory may influence the degree of this radiographic error. We hypothesize that external rotation of screw trajectory will increase measurement error of screw length. DESIGN: Retrospective. SETTING: Urban Level I Tertiary Trauma Center. PARTICIPANTS: 283 patients with Computer Tomography (CT) scans of the native knee were retrospectively identified. Simulation was done of the trajectory of an interlock at 20 mm and 40 mm proximal to the nail entry point, which represent common screw positions associated/not associated respectively, with removal. The distance between the radiographic medial cortex and the tip of the transverse screw was calculated (D). The angle (Psi) between the transverse trajectory and a modified trajectory aimed at the most medial cortex to avoid radiographic measurement error was calculated. Geometric modeling was utilized to calculate the measurement error (D) in the event of accidental external rotation. The angle of the medial slope was also measured (Theta). INTERVENTION: Review of CT imaging of normal distal femora. MAIN OUTCOME MEASUREMENTS: CT measurements of distal femora. RESULTS: The mean distance (D) at 20/40 mm was 4.21 [95%CI 4.02-4.402] and 2.03 mm [95%CI 1.78-2.83], respectively (p < 0.0001). The mean angle (Psi) between the transverse and modified trajectory at 20/40 mm was 12 degrees [95%CI 11.5-12.5] and 9.60 degrees [95%CI 9-10.2], respectively (p < 0.0001). External rotation by a similar amount nearly triples the measured difference (D). The measured medial slope was significantly increased as screws were placed more proximal (Theta20 mm 46.5 vs Theta40 mm: 48.7 degrees , p < 0.00001). CONCLUSION: The distance between the perceived medial cortex and the tip of the most transverse screw is 4.21 mm and could account for painfully prominent screws. In more proximal screws this distance is decreased. Internal rotation of the screw trajectory 12 degrees can reduce this distance (D), which has implications in nail design. External rotation, amplifies this difference nearly three-fold. Surgeons should avoid external rotation of the aiming arm to prevent prominent screws. PMID- 30473370 TI - Is bone-cement augmentation of screw-anchor fixation systems superior in unstable femoral neck fractures? A biomechanical cadaveric study. AB - OBJECTIVES: Improved fixation techniques with optional use of bone cements for implant augmentation have been developed to enhance stability and reduce complication rates after osteosynthesis of femoral neck fractures. This biomechanical study aimed to evaluate the effect of cement augmentation on implant anchorage and overall performance of screw-anchor fixation systems in unstable femoral neck fractures. METHODS: Ten pairs of human cadaveric femora were used to create standardized femoral neck fractures (Pauwels type 3 fractures; AO/OTA 31-B2) with comminution and were fixed by means of a rotationally stable screw-anchor (RoSA) system. The specimens were assigned pairwise to two groups and either augmented with PMMA-based cement (Group 1, augmented) or left without such augmentation (Group 2, control). Biomechanical testing, simulating physiological loading at four distinct load levels, was performed over 10.000 cycles for each level with the use of a multidimensional force-transducer system. Data was analysed by means of motion tracking. RESULTS: Stiffness, femoral head rotation, implant migration, femoral neck shortening, and failure load did not differ significantly between the two groups (p >= .10). For both groups, the main failure type was dislocation in the frontal plane with consecutive varus collapse). In the cement-augmented specimens, implant migration and femoral neck shortening were significantly dependent on bone mineral density (BMD), with higher values in osteoporotic bones. There was a correlation between failure load and BMD in cement-augmented specimens. CONCLUSION: In screw-anchor fixation of unstable femoral neck fractures, bone-cement augmentation seems to show no additional advantages in regard to stiffness, rotational stability, implant migration, resistance to fracture displacement, femoral neck shortening or failure load. PMID- 30473371 TI - Head, face and neck camel-related injuries: Biomechanics and severity. AB - INTRODUCTION: Large animal-related human injuries are associated with high morbidity and mortality. There are no studies on biomechanics of the camel related head, face, and neck (HFN) injuries. We aimed to study the mechanism, anatomical distribution and severity of camel-related HFN injuries. METHODS: We analyzed our prospectively collected data of patients who were admitted to Al Ain Hospital with camel-related HFN injury during the period of October 2001 to January 2010. RESULTS: Seventy-three patients were studied; all were males having a median (range) age of 28 (5-89) years. Camel kick was the most common mechanism of injury (45%) followed by falling from a camel (22%). Facial fractures were significantly more common in patients who were kicked by a camel. Severe head injuries were significantly more in patients who fell from a camel or who had a car collision with a camel. Car collision with a camel was significantly associated with lower cervical spine fractures (p = 0.017) and severe cervical spine injuries (p = 0.004). Two patients died (overall mortality 3%) CONCLUSIONS: Our study provides an insight into the complex biomechanics and severity of camel related HFN injuries. It is essential to adopt protective measures in our community so as to reduce camel-related HFN injuries. PMID- 30473373 TI - Are athletes able to resume sport at six-month mean follow-up after anterior cruciate ligament reconstruction? Prospective functional and psychological assessment from the French Anterior Cruciate Ligament Study (FAST) cohort. AB - BACKGROUND: The decision to return to sport following anterior cruciate ligament (ACL) reconstruction should not only be based on time since surgery. This study aimed to assess, using isokinetic and neuromuscular (hops) testing in a large group, postoperative objective functional recovery of the knee. The secondary objective was to determine the relationship between psychological, functional scores, and these postoperative tests. METHODS: This prospective study included athletes who underwent surgery between 2013 and 2016 for an isolated full thickness ACL tear. They received a complete evaluation of functional performance of the knee by isokinetic tests performed on a dynamometer to measure quadriceps and hamstring strength, and neuromuscular assessment based on single-leg hop tests. The main judgment criterion was satisfactory functional recovery (yes/no) defined as a difference of <=10% both in the quadriceps 60 degrees /s and the single hop at a minimum of four months of follow-up. RESULTS: A total of 234 athletes were analyzed. The mean age was 28.4 +/- 8.6 years. At 6.5 +/- 1.7 months mean follow-up, 44 (18.5%) patients had satisfactory functional recovery of the knee. The correlations between isokinetic/hop tests and the different scores were variable. During follow-up, two patients presented with a graft tear and two with a contralateral ACL tear, all in the group with unsatisfactory functional recovery. CONCLUSION: At a mean of six months after ACL reconstruction, objective functional recovery of the knee was generally unsatisfactory and this seemed to be a risk factor for recurrent tears. LEVEL OF EVIDENCE: IV; case series. PMID- 30473372 TI - Three-dimensional assessment of lower limb alignment: Accuracy and reliability. AB - INTRODUCTION: Three-dimensional (3D) surgical planning and patient-specific implants are becoming increasingly popular in orthopedics and trauma surgery. In contrast to the established and standardized alignment assessment on two dimensional (2D) long standing radiographs (LSRs) there is neither a standardized nor a validated protocol for the analysis of 3D bone models of the lower limb. This study aimed to create a prerequisite for pre-operative planning. METHODS: According to 2D analysis and after meticulous research, 24 landmarks were defined on 3D bone models obtained from computed axial tomography (CT) scans for a 3D alignment assessment. Three observers with different experience levels performed the test three different times on three specimens. Intraobserver and interobserver variability of the landmarks and the intraclass correlation coefficient (ICC) of the resulting axes and joint angles were evaluated. RESULTS: Overall, the intraobserver and interobserver variability was low, with a mean deviation <5 mm for all landmarks. The ICC of all joint angles and axis deviations was >0.8, except for tibial torsion (ICC = 0.69). All knee joint angles showed excellent ICC (>0.95). CONCLUSIONS: Using the defined landmarks, a standardized 3D alignment assessment with low intraobserver and interobserver variability and high ICC values for the knee joint angles can be performed regardless of examiner's experience. The described method serves as a reliable standardized protocol for a 3D malalignment test of the lower limb. Three dimensional pre-operative analysis might enhance understanding of deformities and lead to a new focus in surgical planning. PMID- 30473374 TI - Gait speed is more challenging than cognitive load on the stride-to-stride variability in individuals with anterior cruciate ligament deficiency. AB - BACKGROUND: Several investigations have studied gait variability of individuals with anterior cruciate ligament (ACL) deficiency; however, the effect of dual tasking on the gait variability of these individuals remained unclear. The aim of the present study was to determine the effect of gait speed and dual-tasking on knee flexion-extension variability in subjects with and without ACL deficiency. METHODS: The knee flexion-extension Lyapunov exponent (LyE) was measured in 22 ACL-deficient (Mean+/-SD) (25.95 +/- 4.69 years) and 22 healthy subjects (24.18 +/- 3.32 years). They walked at three levels of gait speed in isolation or concurrently with a cognitive task. RESULTS: Repeated-measure analyses of variance (ANOVAs) demonstrated that the interaction of group by gait speed was statistically significant. As the gait speed increased from low to high, the knee flexion-extension LyE significantly decreased for the subjects with ACL deficiency (effect size: 0.57, P = 0.01). The interaction of group by cognitive load was not statistically significant (P = 0.07). In addition, the ACL-deficient subjects had statistically slower reaction times than healthy subjects during the dual-task compared with the single-task condition. CONCLUSIONS: The ACL-deficient and healthy individuals had a tendency to maintain safe gait. It seems that the ACL-deficient subjects sacrificed the cognitive task more than the healthy individuals to pay more attention toward gait. Additionally, it seems that the gait speed was more challenging than cognitive load on the stride-to-stride variability in the individuals with ACL deficiency. PMID- 30473375 TI - Older age and female gender are independent predictors of early conversion to total knee arthroplasty after high tibial osteotomy. AB - BACKGROUND: The primary aim was to assess survival of opening wedge high tibial osteotomy (HTO) for medial compartment osteoarthritis. The secondary aim was to identify independent predictors of early conversion to total knee arthroplasty (TKA). METHODS: During the 18-year period (1994-2011) 111 opening wedge HTO were performed at the study centre. Mean age was 45 years (range 18-68) and the majority male (84%). Mean follow-up was 12 (range six to 21) years. Failure was defined as conversion to TKA. Kaplan-Meier, Cox regression and receiver operating curve (ROC) analyses were performed. RESULTS: Forty (36.0%) HTO failed at a mean of 6.3 years (range one to 15). By Kaplan-Meier analysis, the five-year survival rate was 84% (95% confidence interval (CI) 82.6-85.4), 10-year rate 65% (95% CI 63.5-66.5) and 15-year rate 55% (95% CI 53.3-56.7). Cox regression analysis identified older age (hazard ratio (HR) 1.07 for each additional year, 95% CI 1.03-1.11, p b 0.001) and female gender (HR 2.37, 95% CI 1.06-5.33, p = 0.04) as independent predictors of failure. ROC analysis identified a threshold age of 47 years above which the risk of failure increased significantly (area under curve 0.72, 95% CI 0.62-0.81, p b 0.001). Cox regression analysis, adjusting for covariates, identified a significantly greater (HR 2.49, 95% CI 1.26-4.91, p = 0.01) risk of failure in patients aged 47 years old or more. CONCLUSION: The risk of early conversion to TKA is significantly increased in females and those older than 47. These risk factors should be considered pre-operatively when planning intervention for isolated medial compartment osteoarthritis. PMID- 30473376 TI - Impact of PCSK9 loss-of-function genotype on 1-year mortality and recurrent infection in sepsis survivors. AB - BACKGROUND: Reduced activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been associated with decreased short-term death in patients with septic shock. Whether PCSK9 genotype influences long-term outcomes in sepsis survivors is unknown. METHODS: We evaluated the impact of PCSK9 loss-of-function (LOF) genotype on both 1-year mortality and infection-related readmission (IRR) after an index sepsis admission. The Derivation cohort included 342 patients who survived 28 days after a sepsis admission in a tertiary hospital (Vancouver/Canada, 2004-2014), while an independent Validation cohort included 1079 septic shock patients admitted at the same hospital (2000-2006). All patients were genotyped for three common missense PCSK9 LOF variants rs11591147, rs11583680, rs562556 and were classified in 3 groups: Wildtype, single PCSK9 LOF, and multiple PCSK9 LOF, according to the number of LOF alleles per patient. We also performed a meta-analysis using both cohorts to investigate the effects of PCSK9 genotype on 90-day survival. FINDINGS: In the Derivation cohort, patients carrying multiple PCSK9 LOF alleles showed lower risk for the composite outcome 1 year death or IRR (HR: 0.40, P = 0.006), accelerated reduction on neutrophil counts (P = 0.010), and decreased levels of PCSK9 (P = 0.037) compared with WT/single LOF groups. Our meta-analysis revealed that the presence of multiple LOF alleles was associated with lower 90-day mortality risk (OR = 0.69, P = 0.020). INTERPRETATION: The presence of multiple PCSK9 LOF alleles decreased the risk of 1-year death or IRR in sepsis survivors. Biological measures suggest this may be related to an enhanced resolution of the initial infection. FUNDING: Canadian Institutes of Health Research (PJT-156056). PMID- 30473377 TI - Validation of epigenetic markers to identify colitis associated cancer: Results of module 1 of the ENDCAP-C study. AB - BACKGROUND: Chronic inflammation caused by ulcerative colitis (UC) causes a pro neoplastic drive in the inflamed colon, leading to a markedly greater risk of invasive malignancy compared to the general population. Despite surveillance protocols, 50% of cases proceed to cancer before neoplasia is detected. The Enhanced Neoplasia Detection and Cancer Prevention in Chronic Colitis (ENDCaP-C) trial is an observational multi-centre test accuracy study to ascertain the role of molecular markers in improving the detection of dysplasia. We aimed to validate previously identified biomarkers of neoplasia in a retrospective cohort and create predictive models for later validation in a prospective cohort. METHODS: A retrospective analysis using bisulphite pyrosequencing of an 11 marker panel (SFRP1, SFRP2, SRP4, SRP5, WIF1, TUBB6, SOX7, APC1A, APC2, MINT1, RUNX3) in samples from 35 patients with cancer, 78 with dysplasia and 343 without neoplasia undergoing surveillance for UC associated neoplasia across 6 medical centres. Predictive models for UC associated cancer/dysplasia were created in the setting of neoplastic and non-neoplastic mucosa. FINDINGS: For neoplastic mucosa a five marker panel (SFRP2, SFRP4, WIF1, APC1A, APC2) was accurate in detecting pre cancerous and invasive neoplasia (AUC = 0.83; 95% CI: 0.79, 0.88), and dysplasia (AUC = 0.88; (0.84, 0.91). For non-neoplastic mucosa a four marker panel (APC1A, SFRP4, SFRP5, SOX7) had modest accuracy (AUC = 0.68; 95% CI: 0.62,0.73) in predicting associated bowel neoplasia through the methylation signature of distant non-neoplastic colonic mucosa. INTERPRETATION: This multiplex methylation marker panel is accurate in the detection of ulcerative colitis associated dysplasia and neoplasia and is currently being validated in a prospective clinical trial. FUNDING: The ENDCAP-C study was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) Programme (11/100/29). PMID- 30473378 TI - Myofibroblasts in macular fibrosis secondary to neovascular age-related macular degeneration - the potential sources and molecular cues for their recruitment and activation. AB - Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in developed countries. Neovascular AMD (nAMD) accounts for 90% of AMD related vision loss. Although intravitreal injection of VEGF inhibitors can improve vision in nAMD, approximately 1/3 of patients do not benefit from the therapy due to macular fibrosis. The molecular mechanism underlying the transition of the neovascular lesion to a fibrovascular phenotype remains unknown. Here we discussed the clinical features and risk factors of macular fibrosis secondary to nAMD. Myofibroblasts are key cells in fibrosis development. However, fibroblasts do not exist in the macula. Potential sources of myofibroblast precursors, the molecular cues in the macular microenvironment that recruit them and the pathways that control their differentiation and activation in macular fibrosis were also discussed. Furthermore, we highlighted the challenges in macular fibrosis research and the urgent need for better animal models for mechanistic and therapeutic studies. PMID- 30473379 TI - Integrin-linked kinase (ILK) and src homology 2 domain-containing phosphatase 2 (SHP2): Novel targets in EGFR-mutation positive non-small cell lung cancer (NSCLC). AB - BACKGROUND: The activation of multiple signaling pathways jeopardizes the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutation positive non-small cell lung cancer (NSCLC). Integrin-linked kinase (ILK) regulates the interactions between tumor cells and extracellular environment to activate signaling pathways and promote cell proliferation, migration, and epithelial-mesenchymal transition. Src homology 2 domain-containing phosphatase 2 (SHP2) is essential for receptor tyrosine kinase signaling and mitogen-activated protein kinase (MAPK) pathway activation. METHODS: We analyzed tumor ILK, beta receptor subunit glycoprotein 130 (gp130), SHP2, and stromal hepatocyte growth factor (HGF) and interleukin-6 (IL-6) mRNA expression in baseline tumor specimens of advanced EGFR-mutation positive NSCLC patients treated with EGFR TKIs. RESULTS: ILK, when highly expressed, was an independent poor prognostic factor for the progression-free survival of the patients, both in the univariate (hazard ratio [HR for disease progression, 2.49; 95% CI, 1.37-4.52; P = .0020]) and in the multivariate (HR 3.74; 95% CI, 1.33-10.56; P = .0126) Cox regression model. Patients with high SHP2 expression had an almost 13-month shorter progression free survival (P = .0094) and an 18-month shorter overall survival (P = .0182) in comparison to those with low SHP2 mRNA expression. INTERPRETATION: The levels of ILK and SHP2 could be predictive for upfront combinatory therapy of EGFR TKIs plus SHP2 or ILK inhibitors. FUND: A grant from La Caixa Foundation, an Instituto de Salud Carlos III grant (RESPONSE, PIE16/00011), an Instituto de Salud Carlos III grant (PI14/01678), a Marie Sklodowska-Curie Innovative Training Networks European Grant (ELBA No 765492) and a Spanish Association Against Cancer (AECC) grant (PROYE18012ROSE). PMID- 30473380 TI - Association of maternal serum copper during early pregnancy with the risk of spontaneous preterm birth: A nested case-control study in China. AB - BACKGROUND: The effect of maternal copper (Cu) level on the risk of spontaneous preterm birth (SPB) remains debate. Therefore, we conducted a prospective nested case-control study in Shanxi Province to investigate the relationship between maternal serum Cu concentration and SPB risk, as well as the potential mediation effect of lipid metabolism. METHOD: From an overall cohort of 4229 women, 147 women affected by SPB at 20-36 gestational weeks (cases) and 381 women who delivered at >=37 gestational weeks (controls) were included in our nested case control study. Maternal blood samples were collected during 4-22 gestational weeks, and the concentrations of Cu, total cholesterol (TC), and triglycerides (TG) were measured. Information on maternal social demographic characteristics were collected using questionnaires. Unconditional logistic regression models were used to estimate the associations of Cu, TC or TG levels with SPB risk. Linear regressions were used to assess the relationships between concentrations of Cu and TC or TG. RESULTS: Serum Cu concentrations in the case group (median: 184 MUg/dL) were significantly higher than those in the control group (median: 166 MUg/dL, p < 0.0001). Compared to the lowest serum Cu levels, the odds ratios associated with SPB increased to 2.02 (95% confidence interval [CI]: 1.07, 3.82), 3.10 (1.54, 6.22) and 4.18 (2.11, 8.27) in the second, third and fourth quartile respectively, after adjusting for sampling time, maternal age, pre-pregnancy BMI, education, occupation, parity, spontaneous abortion history, folic acid use, medication use, pre-pregnancy passive smoking status, child gender and fasting status. Plasma concentrations of TC and TG were positively associated with SPB risk in a dose-dependent manner. However, when stratified by sampling time, the above-mentioned relationships were significant in the first trimester but not in the second. In addition, plasma concentrations of TC and TG were positively correlated with serum Cu concentrations. CONCLUSIONS: High maternal Cu level in the first trimester may increase the risk of SPB, by potentially increasing plasma concentrations of TC and TG. PMID- 30473381 TI - A picture tells a thousand...exposures: Opportunities and challenges of deep learning image analyses in exposure science and environmental epidemiology. AB - BACKGROUND: Artificial intelligence (AI) is revolutionizing our world, with applications ranging from medicine to engineering. OBJECTIVES: Here we discuss the promise, challenges, and probable data sources needed to apply AI in the fields of exposure science and environmental health. In particular, we focus on the use of deep convolutional neural networks to estimate environmental exposures using images and other complementary data sources such as cell phone mobility and social media information. DISCUSSION: Characterizing the health impacts of multiple spatially-correlated exposures remains a challenge in environmental epidemiology. A shift toward integrated measures that simultaneously capture multiple aspects of the urban built environment could improve efficiency and provide important insights into how our collective environments influence population health. The widespread adoption of AI in exposure science is on the frontier. This will likely result in new ways of understanding environmental impacts on health and may allow for analyses to be efficiently scaled for broad coverage. Image-based convolutional neural networks may also offer a cost effective means of estimating local environmental exposures in low and middle income countries where monitoring and surveillance infrastructure is limited. However, suitable databases must first be assembled to train and evaluate these models and these novel approaches should be complemented with traditional exposure metrics. CONCLUSIONS: The promise of deep learning in environmental health is great and will complement existing measurements for data-rich settings and could enhance the resolution and accuracy of estimates in data poor scenarios. Interdisciplinary partnerships will be needed to fully realize this potential. PMID- 30473382 TI - A risk of bias instrument for non-randomized studies of exposures: A users' guide to its application in the context of GRADE. AB - The objective of this paper is to explain how to apply, interpret, and present the results of a new instrument to assess the risk of bias (RoB) in non randomized studies (NRS) dealing with effects of environmental exposures on health outcomes. This instrument is modeled on the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) instrument. The RoB instrument for NRS of exposures assesses RoB along a standardized comparison to a randomized target experiment, instead of the study-design directed RoB approach. We provide specific guidance for the integral steps of developing a research question and target experiment, distinguishing issues of indirectness from RoB, making individual-study judgments, and performing and interpreting sensitivity analyses for RoB judgments across a body of evidence. Also, we present an approach for integrating the RoB assessments within the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework to assess the certainty of the evidence in the systematic review. Finally, we guide the reader through an overall assessment to support the rating of all domains that determine the certainty of a body of evidence using the GRADE approach. PMID- 30473383 TI - Elimination of short-chain chlorinated paraffins in diet after Chinese traditional cooking-a cooking case study. AB - Short-chain chlorinated paraffins (SCCPs) were listed in the Stockholm Convention in 2017 yet are still used in large-tonnage in China. Diet is the main external exposure pathway of many persistent organic pollutants (POPs), but SCCP diet exposure has not been studied completely thus far. In this study, samples of 122 raw foods were collected from markets in Beijing, cooked with Chinese traditional cooking methods, and analyzed for SCCPs. Overall, SCCP levels in the raw food materials ranged from0.67 to 5100 ng g-1 wet weight (ww). SCCP elimination was found in six out of seven kinds in the cooking case study. Concentrations in the raw food used for cooking ranged from 3.6 to 52 ng g-1 ww, while the corresponding values in the cooked food ranged from 0.67 to 10.8 ng g-1 ww. The SCCP elimination rate ranged from 12% to 93%. The daily average intake of SCCPs for the general population through raw food and cooked food was assessed. The total daily SCCP intake via these foods was 403 and 145 ng kg-1 bw d-1, which suggests that different assessing approaches may result in different estimated SCCP diet exposure amounts. PMID- 30473384 TI - Interlaced proton grid therapy - Linear energy transfer and relative biological effectiveness distributions. AB - PURPOSE: Interlaced beams have previously been proposed for delivering proton grid therapy. This study aims to assess dose-averaged LET (LETd) and RBE-weighted dose (DRBE) distributions of such beam geometries, and compare them with conventional intensity modulated proton therapy (IMPT). METHODS: IMPT plans and four different interlaced proton grid therapy plans were generated for five patient cases (esophagus, lung, liver, prostate, anus). The constant RBE = 1.1 was assumed for optimization. The LETd was subsequently Monte Carlo calculated for each plan and used as input for two LET-dependent variable RBE models. The fulfilment of clinical goals, along with DVH and spatial distribution evaluations, were then assessed and compared. RESULTS: All plans fulfilled the clinical target goals assuming RBE = 1.1. The target coverage was slightly compromised for some grid plans when assuming the variable RBE models. All IMPT plans, and 18 of 20 grid plans, fulfilled all clinical goals for the organs at risk when assuming RBE = 1.1, whereas most plans failed at least one goal when assuming the variable RBE models. Compared with the IMPT plans, the grid plans demonstrated substantially different LETd distributions due to the fundamentally different beam geometries. However, DRBE distributions in the target were similar. CONCLUSIONS: Despite the unconventional beam geometries of interlaced proton grid plans, with resulting alternating dose and LETd patterns, the fulfillment of realistic clinical goals seems to be comparable to regular IMPT plans, both assuming RBE = 1.1 and variable RBE models. In addition, the alternating grid patterns do not seem to give rise to unexpected DRBE hot-spots. PMID- 30473385 TI - Impact of Exon 19 Deletion Subtypes in EGFR-Mutant Metastatic Non-Small-Cell Lung Cancer Treated With First-Line Tyrosine Kinase Inhibitors. AB - BACKGROUND: Common epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs), with exon 19 deletions being associated with better outcome compared to L858R mutations. We aimed to investigate the impact of different exon 19 deletions on patient outcome in EGFR-mutant NSCLC treated with first-line TKIs. PATIENTS AND METHODS: In this retrospective analysis, 106 patients with metastatic NSCLC harboring EGFR exon 19 deletions and treated with first-line TKIs were included. The primary end point was overall survival (OS), the secondary end point progression-free survival (PFS). Analyses were performed by grouping exon 19 deletions according to 2 models: we compared different type of deletion (delE746_A750 vs. deletions other than delE746-A750, defined as "uncommon") or different starting codon of deletion (E746 vs. L747). RESULTS: The frequency of uncommon deletions of exon 19 was 36%. When delE746_A750 (n = 68) was compared to the other deletions in exon 19 (n = 38), no differences were found, either in terms of OS (P = .65) or PFS (P = .65). Similarly, no difference in OS (P = .74) or PFS (P = .99) emerged when comparing the E746 group (n = 81) to the L747 group (n = 25). On multivariate analysis including clinical characteristics and type of deletions (delE746_A750 vs. uncommon deletions or E746 vs. L747), only the presence of brain metastases at diagnosis or during TKI treatment was associated with shorter PFS but not with worse OS. CONCLUSION: Different exon 19 deletions are equally sensitive to first-line EGFR-TKIs in EGFR mutant NSCLC. PMID- 30473386 TI - Hyperkalemia, also in acute heart failure. PMID- 30473387 TI - Sleep Quality and Related Psychosocial Variables Among Renal Transplant Patients. AB - BACKGROUND: Several studies have examined sleep quality in the post renal transplant population of China, but few studies have actually confirmed the related psychosocial variables of sleep quality in renal transplant recipients with home care. OBJECTIVES: This study investigates sleep quality and its related psychosocial variables among renal transplant patients. METHODS: This is a cross sectional study using a convenient sampling approach. Self-report questionnaires were applied to 485 renal transplant patients. All participants completed the General Data Questionnaire, the Pittsburgh Sleep Quality Index (PSQI), the Self Rating Depression Scale, the Three-Dimensional Inventory of Character Strengths, and the Flourishing Scale. RESULTS: A total of 438 valid questionnaires were included in the analysis. The global PSQI score was 5.86 (SD, 3.20), significantly lower than the norm; 128 (29.2%) recipients were classified as having poor sleep quality (global PSQI > 7). In the component score of PSQI, sleep onset latency was the highest; the others from high to low are sleep disturbance, daytime dysfunction, subjective sleep quality, sleep efficiency, sleep duration, and use of hypnotic medication. A total of 19.6% reported sleeping fewer than 6 hours a night, 64.8% reported that they had to get up to use the bathroom, and 50.0% woke up in the middle of the night or early morning at least 1 night per week in the past month. Significant differences in the PSQI scores were observed in renal transplant patients of different sex, age, residence, career, length of post-renal transplant period, comorbidity, kidney function, and depressive symptoms (P < .05). The PSQI scores were positively correlated with depression (Self-Rating Depression Scale) (P < .01) but negatively correlated with inquisitiveness (Three-Dimensional Inventory of Character Strengths-inquisitiveness) and psychological well-being (Flourishing Scale) (P < .01). CONCLUSION: The sleep quality of renal transplant patients was lower than that of the general population. Character strengths and well-being can increase the level of sleep quality in renal transplant patients. Psychosocial intervention is necessary for improving the sleep quality of renal transplant recipients in China. PMID- 30473388 TI - Corrigendum to "Subacute combined degeneration of the spinal cord following nitrous oxide anesthesia: A systematic review of cases" [Clin. Neurol. Neurosurg. 173 (2018) 163-168]. PMID- 30473389 TI - Cell polarization: From epithelial cells to odontoblasts. AB - Cell polarity identifies the asymmetry of a cell. Various types of cells, including odontoblasts and epithelial cells, polarize to fulfil their destined functions. Odontoblast polarization is a prerequisite and fundamental step for tooth development and tubular dentin formation. Current knowledge of odontoblast polarization, however, is very limited, which greatly impedes the development of novel approaches for regenerative endodontics. Compared to odontoblasts, epithelial cell polarization has been extensively studied over the last several decades. The knowledge obtained from epithelia polarization has been found applicable to other cell types, which is particularly useful considering the remarkable similarities of the morphological and compositional features between polarized odontoblasts and epithelia. In this review, we first discuss the characteristics, the key regulatory factors, and the process of epithelial polarity. Next, we compare the known facts of odontoblast polarization with epithelial cells. Lastly, we clarify knowledge gaps in odontoblast polarization and propose the directions for future research to fill the gaps, leading to the advancement of regenerative endodontics. PMID- 30473390 TI - Challenges in implementing and assessing outcomes of school start time change in the UK: experience of the Oxford Teensleep study. AB - OBJECTIVE: Later school start times for adolescents have been implemented in the US and associated benefits found, although no randomised controlled trials (RCT) have been undertaken. The objective of this study was to evaluate the impact of two school interventions in the UK, a delayed start time and a sleep education programme, on students' academic performance, sleep outcomes and health-related quality of life. METHODS: The study had an RCT design to enable an investigation into the differential effects of two interventions or a combination of both: schools were to delay their start time to 10:00am and/or provide a classroom based sleep education programme. The recruitment target was 100 state (non-fee paying) secondary schools. Participants were to be students in Year 10/11 (14-16 year-olds). RESULTS: Despite much media coverage, only two schools volunteered to take part in the RCT. The main challenges faced in recruitment fell under three categories: research design, school, and project-specific issues. The delayed start time and prospect of randomisation to this intervention were the overwhelming reasons cited for not taking part. Facilitators and barriers to research were identified. Recommendations include carrying out a feasibility study prior to a main trial, allowing adequate time for recruitment, involving stakeholders throughout the decision-making process, incorporating independent (fee-paying) schools in recruitment, focusing on students not taking important examinations or involving an older year group with greater independence. CONCLUSION: The Teensleep study provides supporting evidence that evaluating the effects of a change in school start times through an RCT is unfeasible in the UK. PMID- 30473391 TI - Complications of continuous catheter analgesia for postoperative pain management in a tertiary care hospital. Incidence of technical complications and alternative analgesia methods used. AB - BACKGROUND: Continuous invasive analgesia remains the gold-standard method for managing acute post-operative pain after major surgery. However, this procedure is not exempt from complications that may have detrimental effects on the patient and affect the post-operative recovery process. Data of the complications of continuous catheter analgesic techniques (CCATs) and their impact on pain relief are scarce in the literature. MATERIAL AND METHODS: We conducted a prospective longitudinal study and patients who underwent a surgical procedure and received continuous invasive analgesia after surgery were included. Post-operative analgesic strategy, pain scores (NRS), CCAT's characteristics and technical complications were recorded. Patient satisfaction was determined. Descriptive statistics and Student's t-tests were applied for the comparative analyses. RESULTS: We collected data from 106 patients. Mean duration of the CCAT was 47.52+/-21.23hours and 52 patients (49.1%) were controlled in conventional hospitalisation units whereas 54 patients (50.9%) were controlled on intensive or high-dependency care units. The overall incidence of technical complications was 9.43%. The most common complications were catheter displacement (2.38%), inflammation at the IV catheter insertion point (2.38%) and excessive dosing of analgesic drugs (2.38%). Mean NRS scores were <=3 during the permanence of CCATs. Maximum pain intensity was significantly higher in patients who suffered technical complications (mean+/-standard deviation [x +/- SD]: 4.4 +/- 2.8 vs. 2.9 +/- 1.9; P<0.05). Satisfaction levels with the technique and overall satisfaction with the pain management strategy were negatively impacted by the occurrence of complications. CONCLUSIONS: The incidence of technical complications of CCATs was 9.43% and had a negative impact in pain control and patient's satisfaction. PMID- 30473392 TI - Novel method using Hjorth mobility analysis for diagnosing attention-deficit hyperactivity disorder in girls. AB - BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a common childhood neuropsychiatric disorder. Diagnosis of ADHD is based on core symptoms or checklists; however, practitioner subjectivity inevitably results in instances of over- or under-diagnosis. Although an elevated theta/beta ratio (TBR) of the electroencephalography (EEG) band has been approved by the Food and Drug Administration as a factor that may be used in diagnosis of ADHD, several studies have reported no significant differences between the TBR of patients with ADHD and controls. PURPOSE: In this study, a method was developed based on Hjorth Mobility (M) analysis of EEG to compare patients with ADHD and controls. METHODS: Differences in the presentations of ADHD between boys and girls are well established; therefore, separate investigations are required. The present study enrolled 30 girls with ADHD and 30 age-matched controls. RESULTS: The results revealed that the control group had significantly higher Hjorth M values in most brain areas in EEG readings compared with the values for the ADHD group. Compared with TBR, our method revealed a greater number of more significant differences between the girls in the ADHD group and the controls. Moreover, our method can produce the higher average sensitivity (0.796), average specificity (0.796), average accuracy (0.792), and average area under the curve of receiver operating characteristic curve (AUC) value (0.885). Therefore, compared with TBR, Hjorth M possessed the better potential for differentiating between girls with ADHD and controls. CONCLUSION: The proposed method was more accurate than the TBR in diagnosing ADHD. Therefore, Hjorth M may be a promising tool for differentiating between children with ADHD and controls. PMID- 30473393 TI - Glass-based organ-on-a-chip device for restricting small molecular absorption. AB - The use of organ-on-a-chip (OOC) devices is a promising alternative to existing cell-based assays and animal testing in drug discovery. A rapid prototyping method with polydimethylsiloxane (PDMS) is widely used for developing OOC devices. However, because PDMS tends to absorb small hydrophobic molecules, the loss of test compounds in cell-based assays and increases in background fluorescence during observation often lead to biased results in cell-based assays. To address this issue, we have fabricated a glass-based OOC device and characterized the medium flow and molecular absorption properties in comparison with PDMS-based devices. Consequently, we revealed that the glass device generated a stable medium flow, restricted the absorption of small hydrophobic molecules, and showed enhanced cell adhesiveness. This glass device is expected to be applicable to precise cell-based assays to evaluate small hydrophobic molecules, for which PDMS devices cannot be applied because of their absorption of small hydrophobic molecules. PMID- 30473394 TI - Grilling temperature effects on tenderness, juiciness, flavor and volatile aroma compounds of aged ribeye, strip loin, and top sirloin steaks. AB - Ribeye, top loin, and top sirloin steaks were assigned a grilling temperature setting (177 degrees C, 205 degrees C, or 232 degrees C) and consumer panel, Warner-Bratzler shear force, trained sensory panel, and GC/MS - olfactory analyses were performed. No differences (P > 0.05) in consumer overall, tenderness, juiciness, appearance, and flavor liking were detected among steak type or grill temperature. Grill surface temperature had no effect (P > 0.05) on trained panel tenderness scores. Of the volatiles present during an aroma event, pyrazine compounds were most influenced by grill surface temperature. The tenderness and juiciness of steaks grilled at differing temperatures were not perceived to be different by consumers; however, grilling temperature impacted the flavor of the final product by generating more pyrazine compounds. Steaks in this study likely were too tender to have a grilling effect on tenderness, but selecting different grilling temperatures can be used to vary the amount of browning of steaks and/or to modify aroma volatile compounds. PMID- 30473395 TI - Triple O Content Innovations and New Section Editors. PMID- 30473396 TI - The application of 0-1 mixed integer nonlinear programming optimization model based on a surrogate model to identify the groundwater pollution source. AB - The optimization model is presently used for the identification of pollution sources and it is based on non-linear programming optimization. The decision variables in this model are continuous, resulting in a weak recognition of integer variables including pollution source location. In addition, as the number of pollution sources increase, so the calculated load increases exponentially and accuracy decreases. Compared with previous studies, this study makes a series of improvements by adopting a 0-1 mixed integer nonlinear programming optimization model to enable the simultaneous identification of both location (integer variable) and the release intensity (continuous variable) of the pollution source. One of the constraints in the optimization model is a simulation component which requires thousands of calls during the calculation process and therefore requires considerable computational load. To avoid this problem, the Kriging surrogate model is established in this study to reduce computational load, while at the same time ensuring the accuracy of the simulation results. The identification result is solved using a genetic algorithm (GA) and represents the real location of the pollution source, while release intensities are close to actual ones with small relative errors. The Kriging surrogate model is based on a 0-1 mixed integer nonlinear programming optimization model and can simultaneously identify both the location and the release intensity of the pollution source with a high degree of accuracy and by using short computational times. PMID- 30473397 TI - Depression treatment use among stroke individuals with depression: A cross sectional analysis of the Medical Expenditure Panel Survey. AB - BACKGROUND: Depression is the most prevalent psychiatric comorbidity among stroke individuals. Despite the effectiveness of antidepressants and psychotherapy, data on the use of these treatments among stroke survivors is limited. OBJECTIVE: The main objective of this study was to document prevalence of antidepressant use, types of antidepressants utilized, and adherence to antidepressants among stroke individuals. METHODS: Retrospective, cross-sectional data obtained from the Medical Expenditure Panel Surveys (MEPS), for the years 2011, 2013 and 2015, was utilized for this study. Treatment for depression was categorized into three mutually exclusive categories: 1) antidepressants only, 2) antidepressants and psychotherapy (combination), and 3) No treatment. Adherence to antidepressants was measured using the Proportion of Days Covered (PDC) ratio. Adherence between antidepressant only and combination therapy group was compared using Student's t test. A multinomial logistic regression analysis was used to further examine the association between patient characteristics and likelihood of receiving depression treatment. RESULTS: A total of 759 stroke individuals with comorbid depression were identified. Of these, 51.2% utilized only antidepressants, 12.6% utilized a combination treatment of antidepressants and psychotherapy and 31.7% did not receive treatment for depression. Selective Serotonin Reuptake Inhibitors (SSRI's) was the most commonly used antidepressants in the stroke population. Males (P = 0.04), age group of 40-64 years (P < 0.001), and African Americans (P = 0.02) constituted for the highest proportions of untreated stroke survivors. Among treated stroke individuals, adherence was higher for combination therapy users compared to those using antidepressants only (mean PDC = 65.8 +/- 6.89 and 57.6 +/- 3.74, respectively). CONCLUSION: Almost 70% of stroke individuals received some form of treatment for depression and several patient-related factors (gender, age, race, marital status, and comorbidity burden) were associated with the utilization of depression treatment. Future researchers need to investigate the factors responsible for lack of depression treatment in stroke individuals and policy makers should aim for a more patient centered care. PMID- 30473398 TI - A pilot evaluation of incorporating "opt-out" naloxone dispensing within a chain community pharmacy. PMID- 30473399 TI - Effects of the Intravenous Calcimimetic Etelcalcetide on Bone Turnover and Serum Fibroblast Growth Factor 23: Post Hoc Analysis of an Open-Label Study. AB - PURPOSE: Secondary hyperparathyroidism (SHPT) is a serious complication that increases the risk of bone disorders in patients with chronic kidney disease (CKD) undergoing hemodialysis. Etelcalcetide is the first injectable calcimimetic approved for treatment of SHPT, which reduces bone turnover markers and suppresses intact fibroblast growth factor 23 (iFGF-23). This study aimed to explore the associations between etelcalcetide-induced changes in circulating factors and serum iFGF-23 levels. METHODS: This study was a post hoc analysis of data from a previous multicenter, open-label study of etelcalcetide administered to 191 Japanese patients with SHPT undergoing hemodialysis for 52 weeks. Correlations were analyzed between changes from baseline in serum iFGF-23 and serum intact parathyroid hormone (iPTH), corrected calcium, phosphate, bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase-5b (TRACP-5b), and 1alpha,25-dihydroxyvitamin D (1,25[OH]2D) levels at 1, 2, 3, 6, and 12 months. Akaike's Information Criterion (AIC) was calculated using serum iPTH, corrected calcium, phosphate, BAP, TRACP-5b, and 1,25(OH)2D levels as potential predictor variables at each time point. Four models with the smallest AIC at the 3-month time point were chosen as the fitted models to predict changes in iFGF-23 levels, and stepwise multivariate analysis was performed to determine the predictor variables with the greatest contribution to the change in iFGF-23 levels by calculating the partial coefficients of determination. FINDINGS: The etelcalcetide-induced reduction in iFGF-23 was positively correlated with serum levels of corrected calcium and phosphate and negatively with BAP. By calculating the AIC, corrected calcium, phosphate, iPTH, BAP, and TRACP-5b were suggested to be predictors of iFGF-23 levels. Stepwise multivariate analysis found that phosphate, corrected calcium, BAP, and TRACP-5b correlated with iFGF-23, in order from strongest to weakest. IMPLICATIONS: These results suggest that etelcalcetide effectively lowered iFGF-23 and that this reduction may occur via improvements in phosphate, corrected calcium, BAP, and TRACP-5b. Etelcalcetide is thus a promising calcimimetic for decreasing iFGF-23 and improving bone turnover in patients with CKD undergoing hemodialysis with severe SHPT, in addition to decreasing PTH itself. JapicCTI identifier: 142,665. PMID- 30473400 TI - Pharmacovigilance: Challenges in Getting From Here to There. PMID- 30473401 TI - Familial hyperuricaemic nephropathy: New mutation in uromodulin gen. PMID- 30473402 TI - Predicting treatment response to antidepressant medication using early changes in emotional processing. AB - Antidepressants must be taken for weeks before response can be assessed with many patients not responding to the first medication prescribed. This often results in long delays before effective treatment is started. Antidepressants induce changes in the processing of emotional stimuli early in the course of treatment. In the current study we assessed whether changes in emotional processing and subjective symptoms over the first week of antidepressant treatment predicted clinical response after 4-8 weeks of treatment. Such a predictive test may shorten the time taken to initiate effective treatment in depressed patients. Seventy-four depressed primary care patients completed measures of emotional bias and subjective symptoms before starting antidepressant treatment and then again 1 week later. Response to treatment was assessed after 4-6 weeks. The performance of classifiers based on these measures was assessed using a leave-one-out validation procedure with the best classifier then tested in an independent sample from a second study of 239 patients. The combination of a facial emotion recognition task and subjective symptoms predicted response with 77% accuracy in the training sample and 60% accuracy in the independent study, significantly better than possible using baseline response rates. The face based measure of emotional bias provided good quality data with high acceptability ratings. Changes in emotional processing can provide a sensitive early measure of antidepressant efficacy for individual patients. Early treatment induced changes in emotional processing may be used to guide antidepressant therapy and reduce the time taken for depressed patients to return to good mental health. PMID- 30473403 TI - Reply. PMID- 30473404 TI - The contribution of women to pancreatic knowledge. PMID- 30473405 TI - The evolving role of the chaperone in medicine-protection and training: A plastic surgery perspective. PMID- 30473406 TI - Feeding Induces Left Atrial Compression and Impedes Cardiac Filling in Patients With Large Hiatal Hernia. AB - BACKGROUND: Patients with large hiatal hernias (HH) frequently experience postprandial dyspnea. The aim of this study was to evaluate whether feeding induced cardiac compression in these patients using echocardiography. METHODS: Transthoracic echocardiography was performed during fasting and 30 min after feeding (300 g rice pudding) in patients with HHs (n = 32; mean age, 72 +/- 9 years). A subset of patients (n = 15; mean age, 76 +/- 6 years) were evaluated postoperatively. RESULTS: Preoperatively, feeding decreased left atrial (LA) volumes (maximal 27.4 +/- 11.3 vs 19.2 +/- 9.7 mL/m2, P < .001; minimal 13.1 +/- 7.0 vs 6.9 +/- 5.1 mL/m2, P < .001), and increased LA inflow velocities (systolic wave 0.62 +/- 0.14 vs 0.77 +/- 0.17 m/sec, P < .01; diastolic wave 0.46 +/- 0.13 vs 0.59 +/- 0.13 m/sec, P < .01), mitral inflow velocities (E wave 0.79 +/- 0.17 vs 0.94 +/- 0.19 m/sec, P < .01; A wave 0.93 +/- 0.20 vs 1.05 +/- 0.22 m/sec, P < .01), and E/E' ratio (12.1 +/- 2.7 vs 13.7 +/- 3.9, P < .01). Cardiac output (6.3 +/- 1.6 vs 7.24 +/- 2.0 L, P < .01) increased postprandially by marked heart rate augmentation (68.8 +/- 7.0 vs 84.2 +/- 8.4 beats/min, P < .01), with modest stroke volume increase (88.5 +/- 16.7 vs 94.3 +/- 19.5 mL, P = .03). After HH surgery, feeding did not change LA volumes (maximal 52.9 +/- 13.6 vs 53.4 +/- 12.5 mL, P = .89; minimal 28.6 +/- 12.2 vs 27.4 +/- 8.7 mL, P = .59) or E/E' ratio (10.9 +/- 2.1 vs 11.3 +/- 2.3) and induced more modest alterations in LA inflow (systolic wave 0.58 +/- 0.17 vs 0.68 +/- 0.16 m/sec, P = .01; diastolic wave 0.41 +/- 0.12 vs 0.47 +/- 0.13 m/sec, P = .01) and mitral inflow (E wave 0.69 +/- 0.15 vs 0.80 +/- 0.13 m/sec, P < .01; A wave 0.92 +/- 0.13 vs 1.01 +/- 0.18 m/sec, P = .02). Postoperatively, feeding increased cardiac output by substantial stroke volume augmentation (81.9 +/- 16.5 vs 90.8 +/- 16.0 mL, P = .01), with only modest increase in heart rate (69.8 +/- 9.1 vs 75.9 +/- 10.5 beats/min, P < .01). CONCLUSIONS: Feeding produces marked LA compression in patients with HHs, inducing compensatory exaggerated responses in cardiac inflow and hemodynamic status. These compensatory mechanisms improve postoperatively following resolution of LA compression, likely explaining the debility noted preoperatively. PMID- 30473408 TI - Treatment Experiences, Information Needs, Pain and Quality of Life in Men with Metastatic Castrate-resistant Prostate Cancer: Results from the EXTREQOL Study. AB - AIMS: Delaying progression, ameliorating symptoms and maintaining quality of life (QoL) are primary aims of treatment for metastatic castrate-resistant prostate cancer (mCRPC). Real-world rather than clinical trial data about symptoms and side-effects are sparse. In EXTREQOL, patients' QoL, pain and information needs were recorded during treatment. MATERIAL AND METHODS: Men with mCRPC from 20 UK cancer centres starting various systemic mCRPC treatments completed QoL, pain and information needs questionnaires at baseline, 3 and 6 months. RESULTS: In total, 132 patients were recruited. Overall QoL declined significantly by 6 months (Functional Assessment of Cancer Therapy-Prostate [FACT-P] mean = -3.89, 95% confidence interval -6.7 to -1.05, P = 0.007; Trial Outcome Index [TOI] analysis mean = -3.10, 95% confidence interval -5.34 to -0.83, P = 0.007). Those who came off novel therapy and remained on luteinising hormone-releasing hormone agonist therapy alone had worse scores than patients receiving concomitant chemotherapy (Prostate Concerns Subscale mean difference = -4.45, 95% confidence interval 7.06 to -1.83, P = 0.001; TOI mean difference = -5.62, 95% confidence interval 10.97 to -0.26, P = 0.040). At 3 and 6 months, men who reported pain at baseline improved (43%, 40%), but for others pain levels remained the same (45%, 42%) or worsened (13%, 18%). Information regarding supportive care was lacking throughout the period of time on the study. CONCLUSION: Most mCRPC treated patients experience reduced QoL and inadequate pain control. More help with pain management and better information provision regarding supportive care is warranted. PMID- 30473407 TI - Establishment and 12-month progress of the New Zealand Motor Neurone Disease Registry. AB - There are only limited treatments currently available for Motor Neurone Disease, each with modest benefits. However, there is a large amount of research and drug discovery currently underway worldwide. The New Zealand Motor Neurone Disease Registry was established in 2017 to facilitate participation in research and clinical trials, and to aid researchers in planning and recruitment. The NZ MND Registry is an opt in patient registry which collects demographic, contact and clinical data for those who choose to enrol. We report anonymised aggregated data from the first year's enrolment. 12th July 2018, there were 142 participants enrolled in the NZ MND Registry. Participant sex distribution reflects the demographics reported worldwide, but ethnicity is divergent from what is seen in New Zealand overall, with an over-representation of people who identify as New Zealand European. 85.5% of participants are diagnosed with sporadic MND and 6.1% with familial MND. The remainder were participants who have not been diagnosed but have a family history, or positive genetic test for a MND-causing mutation. Levels of disability are reported using ALSFRS-R scores, and show that the majority of participants are within the higher range of the scale. The registry has facilitated entry of patients into three studies to date. The establishment of the NZ MND Registry illustrates a swift launch of a rare disease patient registry. The role of patient registries is an ever changing one, but with clear utility at every point of along the pathway to drug discovery. PMID- 30473409 TI - Predicting wound healing rates and survival with the use of automated serial evaluations of burn wounds. AB - Healing of burn wounds is necessary for survival; however tracking progression or healing of burns is an inexact science. Recently, the relationship of mortality and wound healing has been documented with a software termed WoundFlow. The objective of the current study was to confirm various factors that impact burn wound healing, as well as to establish a timeline and rate of successful healing. A retrospective analysis was performed on adults (n=115) with at least 20% TBSA burn that had at least two computer-based wound mappings. The % open wound (%OW) was calculated over time to document healing trajectory until successful healing or death. Only 2% of patients in the group with successful wound healing died. A decrease in the %OW of 0.8 (IQR: 0.7-1.1) was associated with survival. Disparities in wound healing trajectories between survivors and non-survivors were distinguishable by 2weeks post-injury (P<0.05). When %TBSA was stratified by decile, the 40-49% TBSA group had the highest healing rate. Taken together, the data indicate that wound healing trajectory (%OW) varies with injury severity and survival. As such, automated mapping of wound healing trajectory may provide valuable information concerning patient/prognosis, and may recommend early interventions to optimize wound healing. PMID- 30473410 TI - Cell-based therapies for acute respiratory distress syndrome. PMID- 30473411 TI - Obesity, but not metabolic syndrome, as a risk factor for late-onset asthma in Japanese women. AB - BACKGROUND: Several cross-sectional studies have suggested an association between obesity and asthma. However, few studies have investigated this relationship longitudinally, especially in middle-aged subjects. Although metabolic syndrome is a well-known risk factor for many non-communicable diseases, its contribution to asthma remains controversial. METHODS: From 2008, specific health checkups for metabolic syndrome have been conducted throughout Japan. To seek relationships of obesity and metabolic syndrome with late-onset asthma in Japan, we analyzed data collected from health insurance claims and specific health checkups for metabolic syndrome at three large health insurance societies. Among subjects aged 40-64 years (n = 9888), multivariate logistic regression analyses were performed to investigate the relationships of obesity and metabolic syndrome in fiscal year 2012 (from April 2012 to March 2013) with the incidence of late-onset asthma in the following two years (from April 2013 to March 2015). RESULTS: In women, BMI 25-29.9 kg/m2 or >=30 kg/m2, waist circumference >=90 cm, and waist-to-height ratio >=0.5 were shown to be significant risk factors for asthma, with adjusted odds ratios (95% CI) of 1.92 (1.35-2.75), 2.24 (1.23-4.09), 1.89 (1.30-2.75), and 1.53 (1.15-2.03), respectively. Significance was retained even after adjustment for metabolic syndrome, and there were no significant relationships between metabolic syndrome itself and the incidence of asthma in men or women. CONCLUSIONS: Only the obesity measures, not metabolic syndrome, were shown to be significant risk factors for the incidence of late-onset asthma but only in middle-aged Japanese women, and not in men. PMID- 30473412 TI - Airway innate lymphoid cells in the induction and regulation of allergy. AB - The recent discovery of innate lymphoid cells has revolutionized our understanding of the pathogenesis of immune diseases including allergy and asthma. Innate lymphoid cells (ILCs) are a heterogeneous collection of lymphocytes that lack antigen-specificity (non-T, non-B cells) and potently produce characteristic cytokines of T cell subsets (Th1, Th2, Th17). ILCs are divided into group 1 (ILC1s), group 2 (ILC2s), or group 3 (ILC3s). Similar to Th2 cells, ILC2s produce IL-4, IL-5, and IL-13, among others, and are present in increased numbers in samples from patients with many allergic disorders including asthma and chronic rhinosinusitis (CRS). Animal models have identified that ILC2s contribute to eosinophilic tissue infiltration, airway hyperresponsiveness, mucus production, as well as coordinate adaptive immune responses. Finally, recent studies support regulation of ILC2s by neuro-immune mechanisms as well as demonstrate a significant degree of plasticity between ILC subsets that may impact the immune responses in asthma and allergic airway diseases. Here, we review the current literature on ILC2s in human asthma and allergic airway diseases, as well as highlight some recent mechanistic insights into ILC2 function from in vitro studies and in vivo animal models. PMID- 30473413 TI - Lingual ectopic papillary thyroid carcinoma: Two case reports and review of the literature. AB - Ectopic thyroid occurs when it is not located on the normal thyroid compartment. While 90% of the ectopic thyroids were located at the base of the tongue, only 1% were lingual thyroid carcinoma (LTC). Only 56 LTC cases have been reported so far. Here we reported two cases of LTC. Patient 1 was a 47-year-old female with LTC and co-current sub-hyoid ectopic thyroid. She experienced major hematemesis and dyspnea requiring emergent tracheotomy. Patient 2 was a 61-year old female who was presented with LTC with multiple lymph node metastasis and bilateral lung metastasis. Both of the patients' lingual masses were removed via trans submaxillary excisions. Pathology revealed ectopic papillary thyroid carcinoma. Then they were treated with radio-active iodine (RAI). These patients had full recovery and there were no complications. A review of literature was also presented. PMID- 30473414 TI - Is a bleeding scan prior to single-balloon enteroscopy necessary in patients with obscure gastrointestinal bleeding? AB - BACKGROUND/PURPOSE: To evaluate the efficacy and accuracy of bleeder localization in a pre-enteroscopic bleeding scan in patients with obscure gastrointestinal bleeding (OGIB). METHODS: From January 2009 to December 2014, 98 patients with OGIB undergoing single-balloon enteroscopy (SBE) were enrolled. These patients were classified based on their history of a previous bleeding scan; 56 patients had undergone a previous bleeding scan, whereas 42 had not. The clinical characteristics, endoscopic findings, and rebleeding rate were compared between these two groups. The ability of the bleeding scan to localize the bleeding site was analyzed. RESULTS: The mean age of patients was 56 +/- 22 years; final diagnostic yield, 65.3%; and the most common etiology of OGIB, angiodysplasia (29.6%). There was no significant difference in demographic characteristics, OGIB etiologies, and final diagnostic yields (67.9% vs. 61.2%, bleeding scan vs. control group) between groups. In the bleeding scan group, the rate of positive detection was approximately 80.4%. However, only 26.7% patients with a positive bleeding scan showed correct localization of bleeding. Moreover, the bleeding scan delayed SBE (8.9 days vs. 3.0 days, p < 0.001). During the 24 months of follow-up, 15 patients (15.3%) exhibited rebleeding and needed to be hospitalized, but there was no significant difference between the groups. CONCLUSION: In our study, bleeding scans in patients with OGIB revealed poor localization of the bleeder and delay in performing SBE. Thus, a bleeding scan prior to SBE showed a limited role for patients with OGIB. PMID- 30473415 TI - Leaflet Tear of Trifecta Bioprosthesis. PMID- 30473416 TI - Minimally Invasive Versus Conventional Aortic Root Replacement - A Systematic Review and Meta-Analysis. AB - BACKGROUND: Mini-sternotomy has been proven superior to full sternotomy in aortic valve replacement by providing better perioperative outcomes. We investigated whether such technique provides better outcomes in patients undergoing aortic root surgery. METHODS: A comprehensive electronic literature search was undertaken among the four major databases (PubMed, Ovid, Scopus and EMBASE) to identify all published studies up to June 2018. The search terms used related to mini-sternotomy versus full sternotomy, aortic root, valve sparing, Bentall procedure. Only articles that compared mini against full sternotomy were considered in this analysis. After excluding articles based on title or abstract, the full text articles selected had reference lists searched for any potential further articles to be included in this review. RESULTS: A total of 2,765 patients were analysed from across eight comparative studies that were included in the quantitative analysis of the parameters of interest that fulfilled the criteria for meta-analysis. Mini-sternotomy aortic root replacement was associated with significantly shorter cardiopulmonary bypass time (p=0.009), lower rate of blood transfusion (p=0.01). additionally, they had lower operative mortality (p=0.02), and shorter stay at intensive care and at hospital (p=0.0009, p=0.03 respectively). However, there was no difference between mini-sternotomy and conventional aortic root replacement in terms of aortic cross-clamp time (p=0.28), total operation time (p=0.31), re-exploration rate for bleeding (p=0.28), stroke rate (p=0.90), wound infection rate (p=0.96), and length of mechanical ventilation (p=0.10). CONCLUSION: Mini-sternotomy is a safe, feasible alternative option to full sternotomy in aortic root repair. However, the significant heterogeneity in data points to the need for a larger, well-designed trial to support the currently limited literature evidences. PMID- 30473417 TI - Metabolic surgery ameliorates cardiovascular risk in obese diabetic patients: Influence of different surgical procedures. AB - BACKGROUND: In recent years, bariatric surgery was found to have therapeutic potential for the treatment of type 2 diabetes (T2D) in severely obese patients (body mass index [BMI] >=35 kg/m2) and to reduce cardiovascular disease (CVD) risk and mortality. However, the benefit of CVD risk reduction after metabolic surgery in nonseverely obese T2D patients (BMI <35 kg/m2) remained to be proven. OBJECTIVE: To evaluate the CVD risk after metabolic surgery in T2D patients using The UK Prospective Diabetes Study score. SETTING: Tertiary referral general hospital, Taiwan, Republic of China. METHODS: Outcomes of 392 patients (235 women and 147 men) who had undergone sleeve gastrectomy (87) or gastric bypass (305) for treatment of T2D with 1-year follow-up were assessed. Data were prospectively collected for study, and cerebral and coronary heart disease risk was calculated by using The UK Prospective Diabetes Study risk engine. Outcomes of patients who had undergone different surgical procedures were assessed. RESULTS: One year after surgery, weight and glycemic control with complete and partial remission of T2D were significant in most of the patients. The 10-year coronary heart disease risk and fatal coronary heart disease risk were also reduced from 8.8% to 4.6% and from 4.6% to 2.1%, respectively (both P < .001). Similar CVD risk reduction was seen in both patients with BMI >=35 and BMI <35. Multivariable analysis confirmed that surgical procedure of sleeve gastrectomy was a negative independent predictor of CVD risk reduction after metabolic surgery. CONCLUSION: The present study confirms the efficacy of metabolic surgery for the T2D treatment and reduction of CVD risk up to 50% 1 year after surgery. Gastric bypass surgery has more power on CVD risk reduction than sleeve gastrectomy. PMID- 30473418 TI - Editorial overview: Engineering for viral resistance. PMID- 30473419 TI - Editorial overview: Viruses and cancer. PMID- 30473420 TI - Active rearrangements in the cell wall follow polymer concentration during postharvest withering in the berry skin of Vitis vinifera cv. Corvina. AB - During grape postharvest withering, a worldwide practice used to produce important high-quality wines, the solute concentration increases due to dehydration, and many organoleptic and quality traits, especially related to the berry skin, are affected in a cultivar-specific manner. Nevertheless, a complete comprehension of the underlying processes is still lacking. In this work, we applied ATR-FTIR micro-spectroscopy combined with PCA to monitor cell wall biochemical changes at three stages during postharvest withering on the internal and external sides of the berry skin of the Vitis vinifera cv. Corvina, an important local variety of the Verona province in Italy. The obtained results were integrated by profiling xylogucans and pectins through immunohistochemistry and by genome-wide transcriptomic analysis performed at the same withering stages. Our analysis indicates a gradual passive polymer concentration due to water loss in the first two months of postharvest withering, followed by active structural modifications in the last month of the process. Such rearrangements involve xyloglucans in the internal surface, cuticle components and cellulose in the external surface, and pectins in both surfaces. Moreover, by investigating the expression trend of cell wall metabolism-related genes, we identified several putative molecular markers associated to the polymer dynamics. The present study represents an important step towards an exhaustive comprehension of the postharvest withering process, which is of great interest from both the biological and technological points of view. PMID- 30473421 TI - There is a direct link between allantoin concentration and cadmium tolerance in Arabidopsis. AB - Allantoin, an important intermediate of ureide metabolism, has been the subject of investigation recently due to its dual function in nitrogen recycling and abiotic stress response in plants. Allantoin appears to be the dominant ureide accumulating in response to different abiotic stresses, and mutants containing elevated allantoin concentrations exhibit a stress-tolerant phenotype due to limited reactive oxygen species (ROS) generation. Here we describe the involvement of allantoin in stress response and attempt to explain the regulatory mechanism(s) underlying allantoin function in plants. Growth of wild type Col-0 seedlings in the presence of exogenous allantoin improved root elongation in response to Cd treatment. Allantoin treatment of Col-0 seeds increases superoxide dismutase activity causing an enhanced seed germination and seedling growth following Cd exposure. Additionally, allantoinase-overexpressed (ALNox) lines, with lower levels of allantoin, exhibited more susceptibility to Cd treatment than Col-0 Arabidopsis, implying that there is a positive correlation between allantoin concentration and Cd resistance in plants. Growing ABA-insensitive (abi) mutants on allantoin-containing media and comparison between abi mutants and their wild-type backgrounds demonstrated that the potential regulatory function of allantoin does not require ABA at germination but may be ABA dependent at later stages of seedling growth, suggesting a potential crosstalk between allantoin-mediated stress response and ABA signalling pathway in plants. PMID- 30473422 TI - Anthocyanin accumulation and biosynthesis are modulated by regulated deficit irrigation in Cabernet Sauvignon (Vitis Vinifera L.) grapes and wines. AB - Anthocyanins contents and compositions play an important role in grape berries and wines. Grapevines are widely cultivated in arid and semi-arid areas, and water shortage restricts the development of wine industry. The aim of this work was to gain insight on the effect of regulated deficit irrigation (RDI) on the accumulation and biosynthesis of anthocyanins in Cabernet Sauvignon (Vitis Vinifera L.) grapes and wines. High-performance liquid chromatography (HPLC) was used for anthocyanins profiles analyses and real-time quantitative PCR (qRT-PCR) was used for the genes expressions measurement. The grapevines were treated with 60% (RDI-1), 70% (RDI-2), 80% (RDI-3), 100% (CK, traditional drip irrigation) of their estimated evapotranspiration (ETc) respectively. RDI treatments significantly reduced titration acid and increased pH with higher total soluble solids. RDI-1 treatment increased total anthocyanins contents in berries and wines in both two vintages. RDI-1 and RDI-2 treatments significantly increased the contents of acylated anthocyanins in berries and wines, especially Malvidin-3 acetly-glucoside. RDI treatments significantly increased non-acylated anthocyanins contents in wines, such as Delphinidin-3-gliucoside and Malvidin-3 glucoside. RDI treatments upregulated the expressions of VvPAL, VvC4H, VvCHS, VvF3'H, VvF3'5'H, VvLDOX, and VvOMT in both two vintages. Correlation analysis showed the accumulation of anthocyanins was closely related to the key genes expressions, including VvPAL, VvF3'H, VvF3'5'H etc. The present results provided direct evidence and detailed data to explain that RDI treatments regulated the accumulation of anthocyanins by regulating genes expressions in the anthocyanin synthesis pathway. PMID- 30473423 TI - Disease caused by non-tuberculous mycobacteria in children with cystic fibrosis. AB - Non-tuberculous mycobacterial (NTM) (especially M. abscessus complex) infections pose a considerable challenge in the management of lung disease in patients with cystic fibrosis (CF). The apparent increase in prevalence is likely multifactorial. Emergent evidence of patient-to-patient transmission and isolation of highly resistant strains is a concern for all CF centers around the world. Treatment is often long and burdensome with multiple agents. Treatment side effects are frequent and can cause significant morbidity. Although consensus guidelines provide some direction, many units are faced with the challenges of: finding drug combinations for highly resistant strains; dealing with interruptions of treatment; discussing additional facilitating procedures in the form of gastrostomy and long-term vascular access devices; as well as supporting families emotionally and psychologically through the process. PMID- 30473424 TI - [Assessment of the sound level in the operating room during urological surgery]. AB - OBJECTIVES: In the operating room, a high sound level is associated with a higher risk of complications and affects the communication between the various workers. The objective of this study was to assess the sound level at the operating room during urological procedures. MATERIAL AND METHODS: A monocentric cross-sectional study was carried out in 100 procedures in urology. They were divided into four groups: open surgical procedures, endoscopic procedures, pure laparoscopic procedures, and robotic-assisted laparoscopic procedures. The sound level was measured with the Sound Metter by Examobile application (Bielsko-Biala, Poland) for i-phone(r). RESULTS: For all procedures, mean sound level, mean minimum sound level and mean maximum sound level were 60.31+/-3.3 db, 52.42+/-2.6 db and 81.73+/-2.8 db, respectively. For endourological procedures, they were 61.6+/-4.1 db, 53.4+/-4.1 db and 81.3+/-3.1 db, respectively. For open surgery, they were 59.0+/-1.0 db, 51.6+/-1.8 db and 81.4+/-1.5 db, respectively. For laparoscopic surgery, they were 58.33+/-0.6 db, 50.66+/-1.2 db and 83.33+/-1.5 db, respectively. Robotic-assisted laparoscopic surgery, they were 60.0+/-2.4 db, 52.5+/-2.3 db and 83.56+/-1.8 db, respectively. No difference was found according to the type of surgical approach. However, the sound level in the operating room was increased for endourological procedures using the laser technology as compared to endourological procedures without laser used (58.7+/-1.1 vs. 66.3+/ 0.1 db, P=0.01, respectively). CONCLUSION: The sound level in the operating room during urological procedures was high. For the endourological procedures, the sound level was the highest when the laser technology was used. LEVEL OF EVIDENCE: 3. PMID- 30473425 TI - NuA4 acetyltransferase is required for efficient nucleotide excision repair in yeast. AB - The nucleotide excision repair (NER) pathway is critical for removing damage induced by ultraviolet (UV) light and other helix-distorting lesions from cellular DNA. While efficient NER is critical to avoid cell death and mutagenesis, NER activity is inhibited in chromatin due to the association of lesion-containing DNA with histone proteins. Histone acetylation has emerged as an important mechanism for facilitating NER in chromatin, particularly acetylation catalyzed by the Spt-Ada-Gcn5 acetyltransferase (SAGA); however, it is not known if other histone acetyltransferases (HATs) promote NER activity in chromatin. Here, we report that the essential Nucleosome Acetyltransferase of histone H4 (NuA4) complex is required for efficient NER in Saccharomyces cerevisiae. Deletion of the non-essential Yng2 subunit of the NuA4 complex causes a general defect in repair of UV-induced cyclobutane pyrimidine dimers (CPDs) in yeast; in contrast, deletion of the Sas3 catalytic subunit of the NuA3 complex does not affect repair. Rapid depletion of the essential NuA4 catalytic subunit Esa1 using the anchor-away method also causes a defect in NER, particularly at the heterochromatic HML locus. We show that disrupting the Sds3 subunit of the Rpd3L histone deacetylase (HDAC) complex rescued the repair defect associated with loss of Esa1 activity, suggesting that NuA4-catalyzed acetylation is important for efficient NER in heterochromatin. PMID- 30473426 TI - Wound Disruption Following Caesarean Delivery in Women With Class III Obesity: A Retrospective Observational Study. AB - BACKGROUND: This study sought to identify risk factors associated with wound disruption following CS in women with class III obesity and to determine the value of individualized perioperative care plans in reducing its incidence. METHODS: The study included women with class III obesity who underwent CS after 24 weeks of gestation at Mount Sinai Hospital, Toronto, Ontario between 2011 and 2015 and collected data on demographics, clinical history, and perioperative details. Multivariable logistic regression analysis was performed to identify factors likely to contribute to a higher incidence of wound disruption (level of evidence II-3B). RESULTS: Of the 334 identified cases, in women with a mean BMI of 48.20 +/- 7.52 kg/m2, there were 60 cases of wound disruption (18%). The most common perioperative interventions involved Pfannenstiel skin incisions (75.6%), subcutaneous tissue closure (65.4%), use of pressure dressings (65%), and thromboprophylaxis (71.8%). On bivariable analysis, surgical time >1 hour (24.2% vs. 13.5%; OR 2.03; P = 0.017) and the use of thromboprophylaxis (20.1% vs. 10.6%; OR 2.22, P = 0.031) were associated with increased wound disruption, but these associations were attenuated on multivariable regression analysis. CONCLUSIONS: No single risk factor or perioperative intervention was independently associated with wound disruption. However, the use of individualized perioperative care plans resulted in fewer wound disruptions in our cohort when compared with published literature. PMID- 30473427 TI - Ribosome Stoichiometry: From Form to Function. AB - The existence of eukaryotic ribosomes with distinct ribosomal protein (RP) stoichiometry and regulatory roles in protein synthesis has been speculated for over 60 years. Recent advances in mass spectrometry (MS) and high-throughput analysis have begun to identify and characterize distinct ribosome stoichiometry in yeast and mammalian systems. In addition to RP stoichiometry, ribosomes host a vast array of protein modifications, effectively expanding the number of human RPs from 80 to many thousands of distinct proteoforms. Is it possible that these proteoforms combine to function as a 'ribosome code' to tune protein synthesis? We outline the specific benefits that translational regulation by specialized ribosomes can offer and discuss the means and methodologies available to correlate and characterize RP stoichiometry with function. We highlight previous research with a focus on formulating hypotheses that can guide future experiments and crack the ribosome code. PMID- 30473428 TI - Lactate: A Metabolic Driver in the Tumour Landscape. AB - The presence of lactate in human tumours has been long neglected, confined to the role of a waste product derived from glycolysis and as a biomarker of malignancy. More recently, lactate has been rediscovered as signalling molecule that plays important roles in the regulation of the metabolic pathways, the immune response, and cell-to-cell communication within the tumour microenvironment. This review examines recent discoveries about the functional role of lactate in shaping the behaviour and the phenotype of tumour and tumour-associated cells, and describes potential clinical approaches to target lactate transport and metabolism in tumours. PMID- 30473429 TI - Evaluation of left ventricular filling pressure: Updated recommendations lack new evidence and have severe interpretation issues. PMID- 30473430 TI - Increased cognitive complexity reveals abnormal brain network activity in individuals with corpus callosum dysgenesis. AB - Cognitive reasoning is thought to require functional interactions between whole brain networks. Such networks rely on both cerebral hemispheres, with the corpus callosum providing cross-hemispheric communication. Here we used high-field functional magnetic resonance imaging (7 T fMRI), a well validated cognitive task, and brain network analyses to investigate the functional networks underlying cognitive reasoning in individuals with corpus callosum dysgenesis (CCD), an anatomical abnormality that affects the corpus callosum. Participants with CCD were asked to solve cognitive reasoning problems while their brain activity was measured using fMRI. The complexity of these problems was parametrically varied by changing the complexity of relations that needed to be established between shapes within each problem matrix. Behaviorally, participants showed a typical reduction in task performance as problem complexity increased. Task-evoked neural activity was observed in brain regions known to constitute two key cognitive control systems: the fronto-parietal and cingulo-opercular networks. Under low complexity demands, network topology and the patterns of local neural activity in the CCD group closely resembled those observed in neurotypical controls. By contrast, when asked to solve more complex problems, participants with CCD showed a reduction in neural activity and connectivity within the fronto-parietal network. These complexity-induced, as opposed to resting-state, differences in functional network activity help resolve the apparent paradox between preserved network architecture found at rest in CCD individuals, and the heterogeneous deficits they display in response to cognitive task demands [preprint: https://doi.org/10.1101/312629]. PMID- 30473431 TI - Treatment Outcome, Toxicity, and Predictive Factors for Radioligand Therapy with 177Lu-PSMA-I&T in Metastatic Castration-resistant Prostate Cancer. AB - Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is increasingly being used in metastatic castration-resistant prostate cancer (mCRPC). The objective of this study is to report our clinical experience with RLT using 177-lutetium-labeled PSMA-I&T. A total of 100 patients were treated under a compassionate use protocol with a total number of 319 cycles (median two cycles, range 1-6). Eligibility criteria included previous treatment with abiraterone or enzalutamide, previous taxane-based chemotherapy or chemoineligibility, and positive PSMA-ligand uptake at positron-emission tomography scan. The 177Lu-PSMA-I&T was given 6-8 weekly with an activity of 7.4 GBq up to six cycles. The median number of previous mCRPC regimens was 3 (range 1 6), and 35 patients had visceral metastases. Prostate-specific antigen decline of >=50% was achieved in 38 patients, median clinical progression-free survival (cPFS) was 4.1mo, and median overall survival (OS) was 12.9mo. Subgroup analyses identified an association of visceral metastases with a poor prostate-specific antigen (PSA) response and shorter cPFS and OS, and an association of rising lactate dehydrogenase (LDH) with shorter cPFS and OS. Patients achieving PSA decline of >=50% within 12wk of treatment showed longer cPFS and OS. Treatment emergent hematologic grade 3/4 toxicities were anemia (9%), thrombocytopenia (4%), and neutropenia (6%). Grade 3/4 nonhematologic toxicities were not observed. RLT with 177Lu-PSMA-I&T showed good activity in more than one-third of patients with late-stage mCRPC at low toxicity. Presence of visceral metastases and rising LDH were associated with worse treatment outcome. PATIENT SUMMARY: We analyzed the treatment outcome and toxicity of prostate-specific membrane antigen targeted radioligand therapy in patients with metastatic castration-resistant prostate cancer. We found that a good treatment response could be achieved in a subgroup of patients with few side effects. We also observed that treatment outcome was worse in patients with organ metastases and elevated lactate dehydrogenase in blood tests. PMID- 30473432 TI - Re: Guido Giusti, Silvia Proietti, Moises E. Rodriguez-Socarras, et al. Simultaneous Bilateral Endoscopic Surgery (SBES) for Patients with Bilateral Upper Tract Urolithiasis: Technique and Outcomes. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2018.06.034. PMID- 30473434 TI - Re: Marco Moschini, Emanuele Zaffuto, Pierre I. Karakiewicz, et al. External Beam Radiotherapy Increases the Risk of Bladder Cancer When Compared with Radical Prostatectomy in Patients Affected by Prostate Cancer: A Population-based Analysis. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2018.09.034. PMID- 30473433 TI - Study Protocol for the DETECTIVE Study: An International Collaborative Study To Develop Consensus Statements for Deferred Treatment with Curative Intent for Localised Prostate Cancer. PMID- 30473435 TI - The impact of gynaecological cancer treatment on physical activity levels: a systematic review of observational studies. AB - BACKGROUND: The natural history of physical activity levels during and following gynaecological cancer treatment is not well understood. This is required in order to establish the time at which physical activity levels are lowest in order to target cancer rehabilitation or exercise interventions in gynaecological cancer population accordingly. OBJECTIVES: To conduct a systematic review to evaluate the impact of gynaecological cancer treatments on physical activity levels and to summarise the pattern of changes in physical activity levels over time among patients with gynaecological cancer. METHODS: A comprehensive literature search was performed via MEDLINE (1946-2018), CINAHL (1982-2018), EMBASE (1947-2018), Ovid Emcare (1947-2018), PsycINFO (1806-2018) and the Cochrane Library (1991 2018). Studies were eligible for inclusion if they had assessed changes in physical activity levels during and after gynaecological cancer treatment. The methodological quality of the eligible studies was assessed by two independent reviewers using the Joanna Briggs Institute Critical Appraisal Tools. RESULTS: In total, six studies (three cohort studies and three cross-sectional studies) with 1607 participants were included. All studies used patient-reported physical activity measures. Two of the three cohort studies measured patient-recalled physical activity levels before diagnosis (baseline), and length of follow-up varied across all studies. The majority of participants were treated surgically+/ adjuvant therapy. Physical activity levels decreased at 6 months following surgery when compared with pre-treatment levels. Approximately 91% of participants did not meet physical activity guidelines 2 years following diagnosis, and 58% reported being less physically active 3 years after diagnosis, compared with the pre-diagnosis levels. CONCLUSIONS: Despite the paucity of evidence and limitations in the current body of literature, this review demonstrated that compared to pre-diagnosis, levels of physical activity remain low in gynaecological cancer survivors up to 3 years after diagnosis. More research is warranted to better characterise the pattern of change of physical activity levels across the disease trajectory and identify changes in physical activity patterns by cancer treatments and gynaecological tumour streams in order to target interventions accordingly. PMID- 30473436 TI - Radiology and artificial intelligence: An opportunity for our specialty. PMID- 30473438 TI - Outcomes of children with severe traumatic brain injury. PMID- 30473437 TI - The effects of exercise on transdiagnostic treatment targets: A meta-analytic review. AB - BACKGROUND: The present study meta-analytically reviewed the effects of exercise on four transdiagnostic treatment targets: anxiety sensitivity (AS), distress tolerance (DT), stress reactivity (SR), and general self-efficacy (GSE). METHODS: We conducted systematic searches of peer-reviewed studies in bibliographical databases (Cochrane Library, psychINFO, PubMed) before April 1, 2018. Only randomized controlled trials (RCT) evaluating the effect of exercise on AS, DT, SR, or GSE using at least one validated outcome instrument in a sample of adolescents (>=13 years old) or adults were selected. We employed a meta-analysis of effects using random-effects pooling modeling for each treatment target. RESULTS: The systematic search yielded 28 RCTs meeting eligibility criteria. Exercise interventions had a large effect on reducing AS (six studies, Hedges's g = 0.72, p = .001), a medium effect on increasing GSE (eight studies, Hedges's g = 0.59, p < .001), and a small effect on reducing SR (ten studies, Hedges's g = 0.32, p < .001). Evidence from four studies suggested that exercise interventions had a small but non-significant effect on increasing DT (Hedges's g = 0.21, p = .26). CONCLUSIONS: This meta-analysis provides preliminary evidence exercise can engage certain transdiagnostic targets. Further research is required to optimize exercise intervention parameters to achieve the strongest effects on these important mechanistic variables. PMID- 30473439 TI - Children and young people get rheumatic disease too. PMID- 30473441 TI - A systematic review and meta-analysis of randomized controlled trials to evaluating the trend of cytokines to vitamin A supplementation in autoimmune diseases. AB - BACKGROUND & AIMS: Vitamin A is considered as a supplement that effect on autoimmune diseases. We aimed to systematically review the effect of vitamin A on cytokines in patients with autoimmune disease. METHODS: Two researchers searched Scopus and PubMed until May 2018. Researchers extracted data from 6 eligible published papers. Extracted data included the gene expression of the inflammatory and anti-inflammatory cytokines. RESULTS: Fixed effect analysis of the WMD (95% CI) of the changes in gene expression showed that gene expression of the inflammatory (IL-17, IFN-gamma and T-bet) and anti-inflammatory (TGF-beta and FOXP3) cytokines significantly decreased and increased due to vitamin A supplementation in patients with autoimmune (Multiple sclerosis and atherosclerosis) diseases. CONCLUSIONS: Vitamin A supplementation effects on gene expression and may improve serum level of cytokines and clinical signs of autoimmune disease but there is no adequate evidence. PMID- 30473440 TI - The Pediatric Guideline Adherence and Outcomes (PEGASUS) programme in severe traumatic brain injury: a single-centre hybrid implementation and effectiveness study. AB - BACKGROUND: As far as we know, there are no tested in-hospital care programmes for paediatric traumatic brain injury. We aimed to assess implementation and effectiveness of the Pediatric Guideline Adherence and Outcomes (PEGASUS) programme in children with severe traumatic brain injury. METHODS: We did a prospective hybrid implementation and effectiveness study at the Harborview Medical Center (Seattle, WA, USA). We included children (aged <18 years) with traumatic brain injury (trauma mechanism and image findings). We assessed service provision, adherence to three key performance indicators, and discharge outcomes associated with the PEGASUS programme. The three key performance indicators were early initiation of enteral (oral or tube feeds) or parenteral nutrition; avoidance of any unwanted hypocarbia (PaCO2 <30 mm Hg) without brain herniation; and maintenance of cerebral perfusion pressure (>40 mm Hg) for 72 h after the diagnosis of severe traumatic brain injury. Poisson regression with robust standard errors was used to estimate the association between adhering to key performance indicators and discharge outcomes. FINDINGS: Between May 1, 2011, and July 1, 2017, 199 children (median age 11.9 years [IQR 3.4-16.1]) participated in the PEGASUS programme, of whom 193 (97%) had severe traumatic brain injury and six (3%) had moderate traumatic brain injury. 105 patients contributed data for all three key performance indicators. Adherence to at least one key performance indicator was achieved by 101 (96%) of 105 participants, and 44 (42%) achieved adherence to all three key performance indicators. Programme participants achieved adherence to the key performance indicators of hypocarbia (76 of 105 [72%]), nutrition (162 of 199 [81%]), and cerebral perfusion pressure (128 of 199 [64%]). Adherence to the nutrition key performance indicator was associated with higher discharge survival (relative risk [RR] 2.70, 95% CI 1.54-4.73) and a more favourable discharge disposition (3.05, 1.52-6.11). Adherence to the cerebral perfusion pressure key performance indicator was also associated with higher discharge survival (RR 1.33, 95% CI 1.12-1.59) and favourable disposition (1.53, 1.19-1.96). Adherence to each additional key performance indicator was associated with higher survival (RR 1.27, 1.12-1.44) and a more favourable discharge disposition (1.46, 1.23-1.72), in a dose-response manner. INTERPRETATION: The multilevel, hospital-wide, high-fidelity PEGASUS programme might benefit children and adolescents admitted to the emergency department with severe traumatic brain injury. Cerebral perfusion pressure, nutrition, and hypocarbia targets are essential components of the PEGASUS programme and are associated with favourable discharge outcomes. FUNDING: National Institutes of Health. PMID- 30473443 TI - Is there any optimum value of lepidic parameters for cancer risk and progress? PMID- 30473444 TI - Treatment of malignant gliomas with ketogenic or caloric restricted diets: A systematic review of preclinical and early clinical studies. AB - BACKGROUND & AIMS: Patients with malignant gliomas have a poor prognosis. Diets that lower blood glucose, such as ketogenic or caloric restricted diets (KCRDs), are hypothesized to reduce tumor growth and improve survival. In this systematic review, we summarize preclinical and clinical data on KCRDs in gliomas. METHODS: We searched PubMed and Embase for preclinical and clinical studies on KCRDs in gliomas, and extracted data on surrogate and clinically relevant endpoints, in accordance with PRISMA statement. Quality assessment of clinical studies was performed with use of Cochrane Collaboration's tool. We performed Fisher's exact test to examine associations between surrogate and clinically relevant endpoints. RESULTS: We included 24 preclinical studies, seven clinical studies and one mixed study. Both preclinical and clinical studies were highly heterogeneous. Preclinically, KCRDs reduced tumor growth, but only a small majority of the in vivo studies found improved survival. These effects were stronger in groups with decreased blood glucose than in those with increased ketones, and also when other therapies were used concomitantly. Finally, KCRDs influence multiple molecular biological pathways, including the PTEN/Akt/TSC2 and NF-kB pathway. In clinical studies, KCRDs seem to be safe and feasible in glioma patients. Clinical data were insufficient to draw conclusions regarding efficacy. CONCLUSIONS: KCRDs have positive effects on malignant gliomas in published preclinical studies. Preliminary clinical data suggest that KCRDs are safe and feasible. However, because of the paucity of clinical data, the efficacy of KCRDs for improving survival and quality of life of glioma patients remains to be proven in prospective studies. PMID- 30473442 TI - Plasma 25-hydroxyvitamin D concentrations and risk of incident cancer in adults with hypertension: A nested case-control study. AB - BACKGROUND & AIMS: Evidence from epidemiologic studies on the association of circulating 25-hydroxyvitamin D [25(OH)D] concentrations with the incident risk of cancer has been inconsistent. We aimed to investigate the prospective relationship of baseline plasma 25(OH)D concentrations with the risk of cancer, and to examine possible effect modifiers. METHODS: We employed a nested case control study design, including 231 patients with incident cancer during a median 4.5 years of follow up, and 231 matched controls from the China Stroke Primary Prevention Trial (CSPPT). RESULTS: The prevalence of plasma 25(OH)D <15, <20 and <30 ng/mL was 23.6%, 47.4% and 85.5%, respectively. Overall, there was an inverse relation between risk of cancer and plasma 25(OH)D. The Odds ratios (95% CI) for participants in the second (15.1 to <20.6 ng/mL), third (20.6 to <26.4 ng/mL) and fourth quartiles (>=26.4 ng/mL) were 0.45 (95% CI: 0.25-0.80), 0.53 (95% CI: 0.27 1.06) and 0.55 (95% CI: 0.27-1.10), respectively, compared with those in quartile 1. Conversely, low 25(OH)D (<15.1 ng/mL) concentrations were associated with increased risk of cancer (OR, 2.08; 95% CI: 1.20-3.59) compared to higher concentrations. These associations were consistent across subtypes of cancer. Several potential effect modifiers were identified, including plasma vitamin E concentrations and alcohol intake. CONCLUSIONS: Low plasma 25(OH)D concentrations (<15.1 ng/mL) were associated with increased total cancer risk among Chinese hypertensive adults, compared to higher 25(OH)D concentrations. This finding and the possible effect modifiers warrant additional investigation. PMID- 30473445 TI - Multifocal visual evoked potentials and contrast sensitivity correlate with ganglion cell-inner plexiform layer thickness in multiple sclerosis. AB - OBJECTIVE: To examine the relationship between optical coherence tomography (OCT) macular ganglion cell-inner plexiform layer thickness (GCIPLT), peripapillary retinal nerve fiber layer thickness (RNFLT) and visual function in relapsing remitting multiple sclerosis (RRMS). METHODS: Cirrus OCT, VERIS 60-sector multifocal visual evoked potential (mfVEP) and Pelli-Robson contrast sensitivity (CS) were obtained for 53 eyes with last optic neuritis (ON) > 6 months and 105 non-ON eyes in 90 patients. One eye (43 ON, 73 non-ON) was used for correlations when both had the same history. Global (G, 60 sectors) and central 5.6 degrees (C, 24 sectors) mfVEP amplitude and latency were calculated as mean logSNR and median latency. RESULTS: Eyes showing abnormal mfVEP (amplitude or latency) vs OCT (GCIPLT or RNFLT) was 77% vs 69% (p = 0.33) in ON, 45% vs 22% (p < 0.0005) in non-ON. In ON and non-ON, mfVEP measures and CS correlated with GCIPLT and RNFLT (r = -0.24 to 0.78, p = 0.03-0.0001). In ON, mfVEP amplitude (C,G) correlated better with GCIPLT (r = 0.78, 0.76) than RNFLT (r = 0.43, 0.58; p < 0.001, 0.01). CONCLUSIONS: MfVEP measures and CS correlated well with GCIPLT and RNFLT in ON and non-ON. MfVEP amplitudes were more highly correlated with GCIPLT than RNFLT in ON. MfVEP detected significantly more defects than OCT in non-ON. SIGNIFICANCE: GCIPLT, mfVEP and CS provide useful measures of optic nerve integrity in RRMS. PMID- 30473446 TI - Corrigendum to "The contribution of coping related variables and cardiac vagal activity on dark throwing task performance" [Physiology and Behavior, 179 (2017) 116-125]. PMID- 30473447 TI - [Signs of social inequality in information seeking and evaluation of information among young women with breast cancer - results of a cohort study]. AB - OBJECTIVE: The extent to which cancer patients are well-informed can have manifold effects. The aim of this study was to explore both the sources of information that young breast cancer patients with children use and how they evaluate the information obtained. METHODS: Participants were recruited within a rehabilitation program for young mothers with non-metastatic breast cancer (the Groemitz project "gemeinsam gesund werden"). Data on information seeking, the level of information, socio-demographic data and clinical characteristics were collected using a questionnaire. RESULTS: The patients (n=827) used several additional sources of information - most frequently the internet (69.5%; n=767). The majority felt well informed about their disease and found the information provided easy to understand. A social gradient was observed in relation to media use, information evaluation and obtaining a second opinion. CONCLUSION: To young breast cancer patients, the internet is crucial for obtaining further information. The indication of a social gradient underlines the importance of addressing the information needs of patients with a lower socioeconomic status. PMID- 30473449 TI - [Etiological diagnosis of pulmonary hypertension: A cause of difficult diagnosis]. AB - INTRODUCTION: Schistosomiasis associated pulmonary arterial hypertension belongs to group 1 of the pulmonary hypertension classification and should be considered in any patient with pulmonary hypertension returning from an endemic area. CASE REPORT: A 17-year-old patient was hospitalized for pulmonary hypertension detected during the initial assessment of viral hepatitis B-related cirrhosis with portal hypertension. The initial assessment established the diagnosis of pulmonary hypertension secondary to viral hepatitis B-cirrhosis. The patient's hepatic and haemodynamic condition deteriorated and he was treated with intravenous epoprostenol. This allowed subsequent performance of a liver transplantation. Epoprostenol could then be discontinued. Unexpectedly, histology of the liver explant revealed florid schistosomiasis in addition to hepatitis B cirrhosis. CONCLUSION: The diagnosis of pulmonary arterial hypertension associated with schistosomiasis may be difficult. It is necessary to repeat the serological studies and, sometimes, to obtain a rectal biopsy. The treatment of pulmonary arterial hypertension associated with schistosomiasis is based on specific therapies and antiparasitic treatment. PMID- 30473448 TI - Multiplex TaqMan real-time PCR platform for detection of Neisseria gonorrhoeae with decreased susceptibility to ceftriaxone. AB - A multiplex TaqMan real-time PCR platform was developed in this study for combined detection of opa and/or porA genes (identification of N. gonorrhoeae) and the key mutations (Ala501Val/Thr/Pro, and/or Gly545Ser) in penicillin-binding protein 2 (PBP2) associated with decreased susceptibility to extended-spectrum cephalosporins (ESCs). Firstly, the specificities of the TaqMan probes/primers for the multiplex TaqMan real time PCR platform were confirmed by Basic Local Alignment Search Tool (BLAST) analysis. Then the multiplex PCR platform was performed on 77 isolates with decreased susceptibility to ceftriaxone (CRO) and 100 isolates with full susceptibility to CRO under universal optimized reaction conditions. As a result, based on cultivation-based matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and antimicrobial susceptibility testing in vitro, the multiplex platform had a sensitivity of 100% and a specificity of 95.0% for identifying cultured isolates of Neisseria gonorrhoeae (N. gonorrhoeae, NG, GC) with decreased susceptibility to CRO. When directly screening N. gonorrhoeae with decreased susceptibility to CRO from clinical urogenital swabs, the multiplex platform offered a sensitivity of 96.1% and a specificity of 95.0%. Therefore, on the basis of sample culture and antimicrobial susceptibility testing in vitro, the multiplex TaqMan real time PCR platform has been proven to be a sensitivity of 100% and a specificity of 95.0% useful tool for screening cultured isolates of N. gonorrhoeae with decreased susceptibility to CRO, which can be finished within 2 days. PMID- 30473450 TI - [Features distinguishing ornithosis from avian acute hypersensitivity pneumonitis - a retrospective analysis]. AB - INTRODUCTION: The aim of our study was to compare the features at diagnosis in patients with ornithosis to patients with avian acute hypersensitivity pneumonitis (HP). Clinical, biological and radiological differences could potentially help clinicians to distinguish these diseases. METHODS: We conducted a retrospective study on patients admitted from 2000 to 2016 in three hospitals. Ornithosis was diagnosed based on a positive polymerase chain reaction for Chlamydophila psittaci on respiratory samples and/or a seroconversion while HP was diagnosed on the basis of at least one positive serum precipitin. RESULTS: Twelve patients with HP and 13 patients with ornithosis were identified. Compared to HP, ornithosis occurred more frequently in males (P=0.047), with less previous respiratory diseases (P=0.01), shorter symptom duration (P=0.03), less frequently bilateral crackles (P=0.004), more severe disease requiring more frequently intensive care admission (P=0.005), higher CRP values (P=0.005) and more profound lymphopenia (P=0.02). Ground glass shadowing on CT scan (P=0.001) or bronchiectasis (P=0.03) were more frequently noted in patients with HP. CONCLUSIONS: Our results suggest that patients with ornithosis and HP have important differences in their clinical, biological, and radiological presentation. PMID- 30473451 TI - [Incidental deep vein thrombosis during EBUS]. PMID- 30473452 TI - Factors Affecting the Cost and Profitability of Arthroscopic Rotator Cuff Repair. AB - PURPOSE: To examine the cost metrics and profitability of rotator cuff repairs (RCRs) in a large health care system. METHODS: A retrospective study was performed using value analysis team data from 2 hospitals within a large metropolitan health system from 2010 to 2014. Cost and profit metrics were collected and compared against surgeon volume, surgeon subspecialty training, implant costs, Current Procedural Terminology (CPT) coding, length of stay, and hospital site. RESULTS: A total of 5,899 RCRs were identified with a mean contribution margin of $2,133. Surgical supplies were the largest contributor to direct costs. Hospital site also significantly affected contribution margin ($1,912 at hospital 1 vs $3,129 at hospital 2, P < .001). The number of billed CPT codes was not significantly correlated to contribution margin; however, significant differences were noted in contribution margin and direct cost associated with different CPT code combinations, with arthroscopic RCR with subacromial decompression and distal clavicle excision being the most profitable, at an average contribution margin of $2,147. There was no correlation between surgeon volume and contribution margin or direct cost. CONCLUSIONS: Our overall findings show that improvement in the profitability of arthroscopic RCR for hospital systems is possible, both by examining institutions' direct costs and by providing individual surgeons with cost breakdowns and contribution margin information to improve the profitability of their practice. LEVEL OF EVIDENCE: Level IV, economic and decision analysis. PMID- 30473453 TI - Increasing Numbers of Shoulder Corticosteroid Injections Within a Year Preoperatively May Be Associated With a Higher Rate of Subsequent Revision Rotator Cuff Surgery. AB - PURPOSE: To identify any dose-dependent association between the use of subacromial corticosteroid injections within a year before rotator cuff repair (RCR) and subsequent need for revision rotator cuff surgery. METHODS: Two large administrative databases were queried for patients undergoing arthroscopic RCR. A minimum of 1 year of preoperative database exposure and 2 years of postoperative database follow-up were required for inclusion. Patients were stratified into groups that received 0 (control), 1, 2, or 3 or more ipsilateral corticosteroid shoulder injections within the year prior to RCR. The outcome of interest was ipsilateral revision arthroscopic or open RCR or arthroscopic debridement for a diagnosis of rotator cuff tear within 2 years of the index surgery. Revision rates were compared between groups using a multivariate logistic regression analysis controlling for demographic and comorbidity confounders. RESULTS: A total of 110,567 patients from the Medicare database and 12,892 patients from the private insurance database were included. There was no association between a single injection within the year prior to RCR and revision surgery in either cohort. The use of 2 or more injections was associated with a significant increase in the risk of requiring revision surgery in both the Medicare (odds ratio [OR], 2.76-3.26; P < .0001) and private insurance (OR, 2.53-2.87; P < .0001) populations. CONCLUSIONS: A single shoulder injection within a year prior to arthroscopic RCR was not associated with any increased risk of revision surgery; however, the administration of 2 or more injections was associated with a substantially increased risk of subsequent revision rotator cuff surgery (OR, 2.53-3.26). Although causality cannot be established on the basis of this database review, caution is recommended when considering more than 1 shoulder corticosteroid injection in patients with potentially repairable rotator cuff tears. LEVEL OF EVIDENCE: Level III, retrospective cohort study. PMID- 30473454 TI - Return to Sports After in Situ Arthroscopic Repair of Partial Rotator Cuff Tears. AB - PURPOSE: To evaluate return to sport, clinical outcomes, and complications in a series of athletes with painful partial-thickness rotator cuff tears treated with the arthroscopic in situ repair with a minimum 2-year follow-up. METHODS: Retrospective case series. Seventy-two patients who had undergone an arthroscopic in situ repair for partial-thickness rotator cuff tears were evaluated. We assessed return to sport and the level achieved after surgery. Clinical assessment consisted of glenohumeral range of motion measurement and the American Shoulder and Elbow Surgeons score. Pain was recorded using a visual analog scale. Postoperative complications were also assessed. RESULTS: The mean age was 42.2 years (range, 21-66 years), and the mean follow-up was 54 months (range, 24-113 months). Sixty-one patients (87%) were able to return to sports. Fifty-six patients (80%) returned to the same level they had previous to the injury. The mean interval between surgery and return to competition was 5.6 months. The final functional outcomes were related neither to the type of sports nor to the level of competition before the injury. All active range of motion parameters improved significantly (P < .0001). The American Shoulder and Elbow Surgeons score improved from 43.3 to 88.1, and the visual analog scale scores improved from 6.1 to 1.2 (P < .0001). No significant difference regarding return to sports or functional outcomes was found between articular and bursal-sided tears. Only 5 patients developed a postoperative adhesive capsulitis that responded to physical therapy. CONCLUSIONS: In patients with partial-thickness rotator cuff tears, arthroscopic in situ repair resulted in excellent functional outcomes, with most of the patients returning to sport and at the same level they had before injury. The results were equally favorable in articular and bursal tears. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 30473455 TI - Determination of Threshold Scores for Treatment Success After Arthroscopic Rotator Cuff Repair Using Oxford, Constant, and University of California, Los Angeles Shoulder Scores. AB - PURPOSE: To determine the threshold scores for the Constant-Murley score (CMS); University of California, Los Angeles (UCLA) shoulder score; and Oxford Shoulder Score (OSS) that determine treatment success after arthroscopic rotator cuff (RC) repair. METHODS: Patients who underwent unilateral arthroscopic double-row RC repair by a single surgeon between 2010 and 2015 were prospectively followed up and assessed preoperatively and at 6, 12, and 24 months postoperatively. Perceived pain was measured with a visual analog scale, and functional outcome was assessed by the CMS, UCLA score, and OSS. Treatment success was defined as simultaneous fulfillment of 3 criteria: improvement in pain, expectations for surgery met, and patient satisfied with surgery. Threshold scores were determined by receiver operating characteristic (ROC) analyses, using the various scores as predictors and the defined treatment success as the criterion. RESULTS: The study included a total of 214 patients (96 male and 118 female patients) with a mean age of 60.1 +/- 10 years. Most patients showed improvement in pain (>=88%) and high satisfaction (>=93%) and expectation fulfillment (>=80%) postoperatively. Of the patients, 73% had treatment success at 6 months; 85%, at 12 months; and 80%, at 24 months. ROC analyses showed good prediction of treatment success using the CMS, UCLA score, and OSS at all 3 follow-up time points (area under the ROC curve [AUC] > 0.70), with excellent prediction using the UCLA score at 12 months and 24 months (AUC, 0.811 and 0.805, respectively) and the OSS at 12 months (AUC, 0.820). The following threshold scores were identified: CMS of 59, UCLA score of 21, and OSS of 42 at 6 months; CMS of 61, UCLA score of 26, and OSS of 43 at 12 months; and CMS of 65, UCLA score of 30, and OSS of 46 at 24 months. CONCLUSIONS: The CMS, UCLA score, and OSS have good predictive value in defining treatment success after arthroscopic RC repair. The cutoff scores are time dependent. LEVEL OF EVIDENCE: Level II, development of diagnostic criteria. PMID- 30473456 TI - Abnormal Biomechanics at 6 Months Are Associated With Cartilage Degeneration at 3 Years After Anterior Cruciate Ligament Reconstruction. AB - PURPOSE: To investigate the changes in landing biomechanics over a 3-year period and their correlation with cartilage degenerative changes in the medial tibiofemoral joint of the knee after anterior cruciate ligament reconstruction (ACLR) using magnetic resonance T1rho mapping. METHODS: Thirty-one anterior cruciate ligament-injured patients underwent magnetic resonance imaging of the injured knee before ACLR and 3 years after ACLR, as well as biomechanical analysis of a drop-landing task at 6 months and 3 years after ACLR. Sixteen healthy individuals were recruited and underwent knee magnetic resonance imaging and biomechanical assessment during a drop-landing task. T1rho cartilage relaxation times were calculated for the medial femur and tibia. RESULTS: ACLR patients exhibited increased peak vertical ground reaction force (VGRF), VGRF impulse, peak knee flexion moment (KFM), and KFM impulse from 6 months to 3 years (P < .001 for each). Although the ACLR knees showed significantly lower peak VGRF and KFM at 6 months (P < .001 for both) when compared with the controls, there were no significant differences at 3 years. At 3 years, ACLR patients showed higher T1rho values over the medial femur (P < .001) and tibia (P = .012) when compared with their preoperative values and with healthy control values. Within the ACLR group, side-to-side differences in peak VGRF and sagittal knee biomechanics at 6 months were associated with increased T1rho values from baseline to 3 years. CONCLUSIONS: The results of this longitudinal study show that landing biomechanics are altered after ACLR but biomechanical abnormalities tend to recover at 3 years after ACLR. Differences in lower-extremity mechanics during a landing task at 6 months may be associated with cartilage degeneration at 3 years after anterior cruciate ligament injury and reconstruction. LEVEL OF EVIDENCE: Level II, prospective trial. PMID- 30473457 TI - Knotless Anchors in Acetabular Labral Repair: A Biomechanical Comparison. AB - PURPOSE: To analyze the failure mechanism, stiffness, and pullout strength of acetabular knotless suture anchors. METHODS: Seven suture anchors were tested in high-density (0.48 g/cc) synthetic blocks. The anchors were implanted perpendicular to the bone block. The anchor's suture(s) were tied around a loop of 8 high-strength nonabsorbable sutures and pulled in line with the anchor at a rate of 1 mm/s until failure. The following knotless anchors were tested: Stryker Knotilus 3.5, Arthrex Pushlock 2.9, Linvatec PopLok 2.8, Linvatec PopLok 3.3, ArthroCare SpeedLock HIP (3.4-mm), and Smith & Nephew Bioraptor Knotless 2.9. The standard knot tying Smith & Nephew Bioraptor 2.9 mm served as a baseline for comparison. RESULTS: Stiffness was highest in the Pushlock, the SpeedLock HIP, and Knotilus. At 1 mm displacement, the SpeedLock HIP exhibited significantly higher load than all other anchors, excluding the Pushlock and PopLok 3.3 (P <= .012 for all comparisons). Excluding the SpeedLock HIP and Knotilus, the Pushlock displayed significantly higher load than all other anchors at 2-mm displacement (P <= .015 for all comparisons). Maximum load was the highest for the Knotilus and Bioraptor knotted anchor (P < .001 compared with all other anchors). CONCLUSIONS: All knotless suture anchors used in hip arthroscopy, except for the Knotilus 3.5, failed by suture pullout from the anchor. The 2 anchors with the highest maximum load, the Knotilus 3.5 and knotted Bioraptor 2.9, failed by suture failure; however, these anchors displayed the lowest stiffness and load at 1 mm displacement among all anchors tested. Stiffness and loads at clinically relevant displacements, not maximum load alone, may be most important in predicting anchor clinical performance during the early phases of labral healing. CLINICAL RELEVANCE: Knotless suture anchors tend to fail by suture pullout from the anchor, yet the stiffness of these constructs suggests that minimal displacement of the repair will occur under physiologic loads. PMID- 30473458 TI - Management of Chondral Lesions of the Knee: Analysis of Trends and Short-Term Complications Using the National Surgical Quality Improvement Program Database. AB - PURPOSE: To provide updated surgical trends of cartilage procedures differentiated by the classic groups of palliative, repair, and restorative modalities. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried from 2010-2016 for the following cartilage procedures: chondroplasty, microfracture, arthroscopic osteochondral autograft or allograft transplantation, open osteochondral autograft or allograft transplantation, and autologous chondrocyte implantation. Demographic variables and short-term (30-day) complications were analyzed with 1-way analysis of variance and post hoc analysis. Linear regression analysis was performed to analyze trends over time. RESULTS: A total of 15,609 procedures performed between 2010 and 2016 were analyzed. On average, 342.2 +/- 27.9 cartilage procedures were performed per 100,000 operations. There was a linear increase in the management of overall cartilage procedures per 100,000 operations (P = .002). There were also linear increases in arthroscopic osteochondral autograft transplantation, arthroscopic osteochondral allograft transplantation, open osteochondral autograft transplantation, open osteochondral allograft transplantation, and autologous chondrocyte implantation (P < .001, P = .037, P = .001, P = .006, and P = .002, respectively). Meniscectomy was the most frequently performed concomitant procedure (9.7%-64.2% of cases). Chondroplasty and microfracture showed no change in frequency over time (P = .140 and P = .720, respectively). The overall complication rate was 2.1% for chondroplasty, 1.4% for microfracture, 1.8% for arthroscopic osteochondral autograft transplantation, 1.0% for arthroscopic osteochondral allograft transplantation, 1.4% for open osteochondral autograft transplantation, 1.1% for open osteochondral allograft transplantation, and 0.75% for autologous chondrocyte implantation. Deep vein thrombosis was the most common complication, occurring in 0.4% to 1.0% of cases. No statistically significant difference was found in complication rates between procedures (P = .105). CONCLUSIONS: Cartilage restoration is becoming an increasingly popular modality to address chondral defects. Minimal complication rates suggest that these procedures may be safely performed concomitantly with other interventions. LEVEL OF EVIDENCE: Level IV, retrospective database analysis. PMID- 30473459 TI - Female eye attractiveness - Where beauty meets science. AB - INTRODUCTION: While periorbital and -ocular surgery ranks amongst the most frequently performed plastic surgical procedures, only scarce information exists regarding the contributing factors of aging and its systematic anatomic assessment. The presented study, based on measuring distinct physical landmarks, aimed to gather data to provide a foundation of in-depth periorbital analysis in order to more clearly define female eye attractiveness. METHODS: 80 probands (age range: 30-50 years, M = 38.4 +/- 6.5 years) were asked to judge 60 standardized high-resolution digital pictures of female eye regions in respect to the perceived age (in years) and attractiveness (7-point Likert scale). All photographs were objectively evaluated and measured utilizing a total of 38 distinct landmarks. The data was analyzed by calculating correlations between relevant measured eye area parameters and mean attractiveness ratings including age estimations. RESULTS: Overall, it was found that several specific eye shape features correlate with attractiveness and perceived age. For instance, large visible height of the iris and large upward and lateral inclination of both eye axis and eyebrows correlated moderately to strongly with attractiveness (p < 0.05). CONCLUSION: Regarding the female eye, there exist distinct periorbital anatomic features and landmarks which contribute to a youthful appearance and attractiveness. Knowledge regarding these facts may serve as an important guideline for pre- and post-operative patient analysis. PMID- 30473460 TI - Yield of Echocardiography in the Evaluation of Cerebral Ischemic Events: A Single Center Cohort Study. AB - BACKGROUND: Echocardiography (ECO) is frequently used as a screening test in patients with acute ischemic brain disease. We aimed to evaluate the additional information and therapeutic impact resulting from ECO in these patients. METHODS: We conducted a prospective study performing ECO on consecutive patients with ischemic stroke or transient ischemic attacks, admitted to our centre between February 2013 and May 2017. RESULTS: A total of 696 patients were included (female, 57.3%; mean age, 70 +/- 15.3 years). Seven hundred thirty two echocardiographic examinations were performed (696 transthoracic and 36 transesophageal). Echocardiography yielded findings judged of clinical importance in 142 patients (20.4%, 95% CI 17.5-23.5). The most frequent of these were left atrial volume enlargement or a normal evaluation. Echocardiography findings resulted in changes in the management of 76 patients (10.7% 95% CI 8.8-13.4); initiation of anticoagulation therapy, administration of IV antibiotic therapy, cardiac surgeries, or other pharmacological therapies occurring in 42 cases (6%). The presence of coronary heart disease (OR: 2.64 95% CI 1.34-5.25), atrial fibrillation (OR: 0.24; 95% CI, 0.2-0.69), and admission NIHSS (OR: 1.04; 95% CI, 1.01-1.09), were the variables associated with changes in management. CONCLUSIONS: In unselected patients with acute ischemic stroke ECO had a low yield of additional information, and it changed management in a small percentage of patients. PMID- 30473461 TI - Hamartomas and choristomas in the nervous system. AB - Hamartomas are an overgrowth of mature tissues that normally occur in an area of the body, but with disorganization and often with one element predominating. Choristomas on the other hand, are a mass of tissue histologically normal for a part of the body other than the one in which it is located (heterotopic/ectopic). Many reports use choristoma and heterotopia interchangeably. What is included in the definition of hamartoma or choristoma varies. Malformations may be sometimes considered to be hamartomas and many ectopias could be included in the definition of choristoma. Hamartomas and choristomas can occur anywhere in the body including the nervous system. PMID- 30473462 TI - Hamartomas and other tumor-like malformations of the lungs and heart. AB - Tumor-like malformative lesions are seen throughout the body, and they may be confused with true neoplasms by clinicians and pathologists alike. In the lungs, they are principally represented by hamartomas-which may contain chondroid, adipocytic, fibroblastic, and myxoid tissue, with entrapped bronchiolar epithelium-and congenital pulmonary airway malformations (CPAMs). The latter have been subdivided into 5 groups, based on their histological features, but they basically comprise proliferations of malformed bronchopulmonary tissues of different types. Type 1 lesions have a capacity for malignant transformation in a small proportion of cases. Malformative cardiac tumefactions include rhabdomyoma like hamartomas; fibromatous hamartomas; and mesenchymal ventricular hamartomas, which contain cardiac muscle, smooth muscle, fat, vasogenic tissue, and nerves. Another intracardiac proliferation in the same general category is seen in the interatrial septum, in the region of the atrioventricular node. It comprises randomly-disposed gland-like profiles that are made up of endodermal epithelium. Originally thought to be a form of mesothelial lesion, that abnormality is now classified as an endodermal choristoma. All forms of pulmonary and cardiac malformations are only rarely symptomatic, and the necessity for surgical excision of them depends on the particular details of each case. PMID- 30473463 TI - Increase in serum chloride and chloride exposure are associated with acute kidney injury in moderately severe and severe acute pancreatitis patients. AB - OBJECTIVE: We aimed to evaluate whether early (first 48 h) hyperchloremia and/or the change of serum chloride concentration are associated with acute kidney injury (AKI) in patients with moderately severe and severe acute pancreatitis (MSAP and SAP). METHODS: We retrospectively collected the data of patients with a primary diagnosis of MSAP or SAP from a tertiary center between January 2014 and June 2017. Consecutive chloride levels within the first 48 h after admission were retrieved for further calculation. Logistic regression analysis and receiving operating characteristic (ROC) curve were used to assess the relationship between hyperchloremia and AKI. RESULTS: 145 patients were enrolled for analysis, of whom 33.5% (47/145) developed hyperchloremia during the observation period. The incidence of AKI was significantly higher in the hyperchloremia group (40.4% vs 7.1%; p < 0.001). On multivariate analysis, the increase in serum chloride (Delta[Cl-]) was independently associated with AKI [OR = 1.32 (1.00-1.74)], as was chloride exposure [OR = 1.01 (1.00-1.02)], and these associations were found to be stronger in patients identified as predicted SAP (PSAP). Moreover, even in patients without hyperchloremia, increase in serum chloride (Delta[Cl-]) was still associated with AKI [OR = 1.65 (1.18-2.32)]. Area under the curve of the ROC curve (AUCROC) analysis found that Delta[Cl-] is a good predictor of AKI with an optimal cutoff point at 3.5 mmol/L, showing an AUCROC of 0.81. CONCLUSION: Hyperchloremia is common in patients with AP and Delta[Cl-] and chloride exposure during the first 48 h were independent risk factors for AKI in MSAP and SAP patients. PMID- 30473464 TI - Sarcopenia is a reliable prognostic factor in patients with advanced pancreatic cancer receiving FOLFIRINOX chemotherapy. AB - BACKGROUND/OBJECTIVES: FOLFIRINOX is the reliable treatments for pancreatic cancer, but it has a relatively high toxicity and the selection of suitable patients for this regimen remains challenge. On the other hand, sarcopenia is one of the important prognostic factors of pancreatic cancer. The aim of this study was to investigate the effect of sarcopenia on overall survival (OS) and time to treatment failure (TTF) in patients with pancreatic cancer who received FOLFIRINOX. METHODS: Clinical data of consecutive patients treated with FOLFIRINOX at our institution from 2011 to 2017 was retrospectively reviewed. Skeletal muscle index (SMI) and adipose tissue index (ATI) at the third lumbar spine level was calculated from computed tomography (CT) images. The association between clinical factors (SMI and ATI), and OS and TTF were determined using univariate and multivariate analyses. RESULTS: We assessed 82 patients. The median OS of sarcopenia and the non-sarcopenia patients were 11.3 and 17.0 months, respectively (hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.43 4.32; p = 0.001). Median TTF was 3.0 and 6.1 months in the sarcopenia and the non sarcopenia patients, respectively (HR, 1.67; 95% CI, 1.03-2.71; p = 0.032). Multivariate analyses revealed that sarcopenia (HR, 1.37; 95% CI, 1.01-1.87; p = 0.045) was an independent prognostic factor of OS. High ATI (p = 0.022) and sarcopenic obesity (p = 0.008) were significantly associated with hematologic toxicity. CONCLUSIONS: Sarcopenia is an independent indicator of poor prognosis in patients with pancreatic cancer who received FOLFIRINOX, while ATI and sarcopenic obesity predicted severe hematologic toxicity. PMID- 30473465 TI - High-Density Lipoprotein Components and Functionality in Cancer: State-of-the Art. AB - Cancer is the second leading cause of death in western countries, and thus represents a major global public health issue. Whilst it is well-recognized that diet, obesity, and smoking are risk factors for cancer, the role of low levels of high-density lipoprotein cholesterol (HDL-C) in cancer is less well appreciated. Conflicting evidence suggests that serum HDL-C levels may be either positively or negatively associated with cancer incidence and mortality. Such disparate associations are supported in part by the multitude of high-density lipoprotein (HDL) functions that can all have an impact on cancer cell biology. The aim of this review is to provide a comprehensive overview of the crosstalk between HDLs and cancer, focusing on the molecular mechanisms underlying this association. PMID- 30473467 TI - Flow cytometry and immune thrombocytopenic purpura. AB - Although Immune thrombocytopenic purpura is a common disorder that family physicians, internists and hematologists face in their everyday practice, its diagnosis rests only on "exclusion" and its therapy is based on algorithms where "trial and error" is the rule. Flow cytometry, if simplified and standardized, could provide a quicker and better diagnostic accuracy. Studies of the lymphocyte subset using flow cytometry and more elaborate immune studies are paving the way for a better understanding of the disease and in identification of prognostic markers. Such studies may even help stratify the first-line therapy responder and assist in the use of the arsenal of immune suppressive therapy with better precision. PMID- 30473469 TI - Radiosurgery and risk of intracranial malignancies: more research needed. PMID- 30473468 TI - Risk of radiation-associated intracranial malignancy after stereotactic radiosurgery: a retrospective, multicentre, cohort study. AB - BACKGROUND: A major concern of patients who have stereotactic radiosurgery is the long-term risk of having a secondary intracranial malignancy or, in the case of patients with benign tumours treated with the technique, the risk of malignant transformation. The incidence of stereotactic radiosurgery-associated intracranial malignancy remains unknown; therefore, our aim was to estimate it in a population-based study to assess the long-term safety of this technique. METHODS: We did a population-based, multicentre, cohort study at five international radiosurgery centres (Na Homolce Hospital, Prague, Czech Republic [n=2655 patients]; Ruber International Hospital, Madrid, Spain [n=1080], University of Pittsburgh Medical Center, Pittsburgh, PA, USA [n=1027]; University of Virginia, Charlottesville, VA, USA [n=80]; and NYU Langone Health System, New York, NY, USA [n=63]). Eligible patients were of any age, and had Gamma Knife radiosurgery for arteriovenous malformation, trigeminal neuralgia, or benign intracranial tumours, which included vestibular or other benign schwannomas, WHO grade 1 meningiomas, pituitary adenomas, and haemangioblastoma. Patients were excluded if they had previously had radiotherapy or did not have a minimum follow up time of 5 years. The primary objective of the study was to estimate the incidence of stereotactic radiosurgery-associated intracranial malignancy, including malignant transformation of a benign lesion or development of radiation associated secondary intracranial cancer, defined as within the 2 Gy isodose line. Estimates of age-adjusted incidence of primary CNS malignancies in the USA and European countries were retrieved from the Central Brain Tumor Registry of the United States (CBTRUS) and the International Agency for Research on Cancer (IARC) Global Cancer statistics. FINDINGS: Of 14 168 patients who had Gamma Knife stereotactic radiosurgery between Aug 14, 1987, and Dec 31, 2011, in the five contributing centres, 4905 patients were eligible for the analysis (had a minimum follow-up of 5 years and no history of previous radiation therapy). Diagnostic entities included vestibular schwannomas (1011 [20.6%] of 4905 patients), meningiomas (1490 [30.4%]), arteriovenous malformations (1089 [22.2%]), trigeminal neuralgia (565 [11.5%]), pituitary adenomas (641 [13.1%]), haemangioblastoma (29 [0.6%]), and other schwannomas (80 [1.6%]). With a median follow-up of 8.1 years (IQR 6.0-10.6), two (0.0006%) of 3251 patients with benign tumours were diagnosed with suspected malignant transformation and one (0.0002%) of 4905 patients was considered a case of radiosurgery-associated intracranial malignancy, resulting in an incidence of 6.87 per 100 000 patient-years (95% CI 1.15-22.71) for malignant transformation and 2.26 per 100 000 patient-years (0.11 11.17) for radiosurgery-associated intracranial malignancy. Two (0.0004%) of 4905 patients developed intracranial malignancies, which were judged unrelated to the radiation field. Overall incidence of radiosurgery-associated malignancy was 6.80 per 100 000 patients-years (95% CI 1.73-18.50), or a cumulative incidence of 0.00045% over 10 years (95% CI 0.00-0.0034). The overall incidence of 6.8 per 100 000, which includes institutions from Europe and the USA, after stereotactic radiosurgery was found to be similar to the risk of developing a malignant CNS tumour in the general population of the USA and some European countries as estimated by the CBTRUS and IARC data, respectively. INTERPRETATION: These data show that the estimated risk of an intracranial secondary malignancy or malignant transformation of a benign tumour in patients treated with stereotactic radiosurgery remains low at long-term follow-up, and is similar to the risk of the general population to have a primary CNS tumour. Although prospective cohort studies with longer follow-up are warranted to support the results of this study, the available evidence suggests the long-term safety of stereotactic radiosurgery and could support physicians counselling patients on Gamma Knife stereotactic radiosurgery. FUNDING: None. PMID- 30473470 TI - Derazantinib for intrahepatic cholangiocarcinoma. PMID- 30473471 TI - Expectation affects neural repetition suppression in infancy. AB - Recent work provides evidence that the infant brain is able to make top-down predictions, but this has been explored only in limited contexts and domains. We build upon this evidence of predictive processing in infants using a new paradigm to examine auditory repetition suppression (RS). RS is a well-documented neural phenomenon in which repeated presentations of the same stimulus result in reduced neural activation compared to non-repeating stimuli. Many theories explain RS using bottom-up mechanisms, but recent work has posited that top-down expectation and predictive coding may bias, or even explain, RS. Here, we investigate whether RS in the infant brain is similarly sensitive to top-down mechanisms. We use fNIRS to measure infants' neural response in two experimental conditions, one in which variability in stimulus presentation is expected (occurs 75% of the time) and a control condition where variability and repetition are equally likely (50% of the time). We show that 6-month-old infants exhibit attenuated frontal lobe response to blocks of variable auditory stimuli during contexts when variability is expected as compared to the control condition. These findings suggest that young infants' neural responses are modulated by predictions gained from experience and not simply by bottom-up mechanisms. PMID- 30473472 TI - Statins, diabetes, obesity, nonalcoholic fatty liver disease, and hepatocellular carcinoma. PMID- 30473473 TI - Pediatric sacral nerve stimulator explanation due to complications or cure: a survival analysis. AB - INTRODUCTION: Historically, there have been few treatment options for children with severe refractory bladder and bowel dysfunction (BBD). Sacral neuromodulation (SNM) continues to show promising results in this challenging pediatric population with recalcitrant lower urinary tract symptoms. At the authors institution, they have begun offering explantation to those with persistent improvement after >6 months of having device turned off. The authors hypothesized that (1) SNM explantation for cure increases with extended follow-up and (2) those explanted for cure would have improved symptoms and quality of life when compared to those explanted for complication. MATERIALS & METHODS: The authors retrospectively reviewed all consecutive patients aged <18 years who underwent SNM placements at their institution (2012-2017). They excluded those without the second stage procedure. Reasons for device explantation were categorized as cure (resolution of symptoms with the device turned off for at least 6 months) or a complication (e.g. infection, need for magnetic resonance imaging, or pain). Non-parametric tests and survival analysis were used for analysis to account for differential follow-up time. Of those explanted, surveys were electronically sent to assess BBD severity and overall quality of life. RESULTS: Of 67 children who underwent a first stage procedure, 62 (92.5%) underwent a second stage procedure. 61 met inclusion criteria (68.9% female, 29.5% with previous filum section, median age at implantation 10.3 years). During follow-up (median 2.3 years), 12 patients (19.7%) had the SNM exchanged/revised because of lead fracture/breakage and return of urinary symptoms. To date, 50 patients remain with their SNM implanted, and 11 have been explanted. Adjusting for follow-up time, the risk of explantation was 6.5% at 2 years (2.2% for cure, 4.3% for complications) (Figure 1). Explantation increased to 24.5% at 3 years (16.5% for cure, 8.0% for complications) and 40.4% at 4 years (32.4% for cure, 8.0% for complications). Questionnaires were collected on patients after explant (median 2.2 years), with improvement in those explanted for cure compared to complication (Figure 2). DISCUSSION: Sacral neuromodulation explantation for cure is a novel concept previously not described in the literature. Limitations of this study include the relatively small numbers and lack of objective data in the cohort that remains with SNM device implanted. CONCLUSION: Sacral neuromodulation is a safe, viable option for the pediatric patient with refractory bladder dysfunction. Furthermore, SNM explantation for cure is an option with increasing likelihood after 2 years. PMID- 30473474 TI - Computer-aided diagnosis of congenital abnormalities of the kidney and urinary tract in children based on ultrasound imaging data by integrating texture image features and deep transfer learning image features. AB - INTRODUCTION: Anatomic characteristics of kidneys derived from ultrasound images are potential biomarkers of children with congenital abnormalities of the kidney and urinary tract (CAKUT), but current methods are limited by the lack of automated processes that accurately classify diseased and normal kidneys. OBJECTIVE: The objective of the study was to evaluate the diagnostic performance of deep transfer learning techniques to classify kidneys of normal children and those with CAKUT. STUDY DESIGN: A transfer learning method was developed to extract features of kidneys from ultrasound images obtained during routine clinical care of 50 children with CAKUT and 50 controls. To classify diseased and normal kidneys, support vector machine classifiers were built on the extracted features using (1) transfer learning imaging features from a pretrained deep learning model, (2) conventional imaging features, and (3) their combination. These classifiers were compared, and their diagnosis performance was measured using area under the receiver operating characteristic curve (AUC), accuracy, specificity, and sensitivity. RESULTS: The AUC for classifiers built on the combination features were 0.92, 0.88, and 0.92 for discriminating the left, right, and bilateral abnormal kidney scans from controls with classification rates of 84%, 81%, and 87%; specificity of 84%, 74%, and 88%; and sensitivity of 85%, 88%, and 86%, respectively. These classifiers performed better than classifiers built on either the transfer learning features or the conventional features alone (p < 0.001). DISCUSSION: The present study validated transfer learning techniques for imaging feature extraction of ultrasound images to build classifiers for distinguishing children with CAKUT from controls. The experiments have demonstrated that the classifiers built on the transfer learning features and conventional image features could distinguish abnormal kidney images from controls with AUCs greater than 0.88, indicating that classification of ultrasound kidney scans has a great potential to aid kidney disease diagnosis. A limitation of the present study is the moderate number of patients that contributed data to the transfer learning approach. CONCLUSIONS: The combination of transfer learning and conventional imaging features yielded the best classification performance for distinguishing children with CAKUT from controls based on ultrasound images of kidneys. PMID- 30473475 TI - Robot-assisted resection of ectopic kidney in children: An anatomical illustration. AB - INTRODUCTION: Failure of kidney migration during embryonic life results in an ectopic kidney, with an incidence varying from 1 in 500 to 1 in 1200. Pelvic kidney can be a rare cause of recurrent urinary tract infection (UTI), warranting nephrectomy in some cases. MATERIAL AND METHODS: A 7-year-old girl with a history of recurrent UTIs and vaginal discharge was diagnosed with a dysplastic afunctional ectopic kidney located in the pelvis, with ureter draining into the cervix or vaginal wall. RESULTS: A robot-assisted approach was chosen, with side docking of the robot to allow concurrent vaginoscopic/hysteroscopic exploration. A uterus bicornis was found. The ectopic ureter was dissected toward its drainage in the vaginal wall, where it was sutured and resected. The dysplastic kidney and ureter were removed. Compared to pure laparoscopic approach, dissection deep into the pelvis toward the vaginal wall is aided by the robotic dexterity and facilitates complete resection of the structure, which avoids leaving a ureteric stump into the vaginal wall. CONCLUSIONS: Robot-assisted surgery is a safe and effective option for resection of ectopic kidneys with ectopic ureter in children. Dissection up until the vaginal wall in children is aided by robotic dexterity, making this kind of surgery the ideal indication for robotic-assisted surgery. PMID- 30473476 TI - Late ascended testes: is non-orthotopic gubernacular insertion a confirmation of an alternative embryological etiology? AB - INTRODUCTION: Re-ascended testes account for a proportion of all undescended testes (UDTs); one main hypothesis relating to their etiology relates to a patent processus vaginalis peritonei. The aim was to investigate gubernacular insertion points in boys with late ascended testis as a possible guide to an alternative embryological etiology. PATIENTS AND METHODS: Patients with proven ascended testes were recruited from four different pediatric urology centers between May 2016 and September 2017. All patients were evaluated regarding their gubernacular insertion during orchidopexy. The presence of accompanying patent processus vaginalis and the association between the epididymis and testis were also documented. RESULTS: Seventy-seven children (mean age = 73.1 +/- 41.2 months [range 18-176]) were enrolled into the study. A non-orthotopic gubernacular insertion point was found in 96.1% (n = 74); 34.2% (n = 26) of these were located in the groin and 63.2% (n = 48), high within the scrotum. Figure A. An open processus vaginalis peritonei was found in 35.1%. Twelve patients (15.6%) had small, dysplastic appearing testis with testis-epididymis dissociation. Boys with a higher insertion of the non-orthotopic gubernaculum (n = 48, groin) were operated earlier (mean age at surgery, 62.3 months) compared with those with a gubernacular insertion at a high scrotal site (mean age at surgery, 90.5 months; p = 0.004). Figure B. DISCUSSION: This study revealed that non-orthotopic gubernacular insertion is found in the vast majority of the ascending testis cases. Patent processus vaginalis was accompanying only 35.1% of all children and might be the cause of the ascending testis in this small subgroup of patients in line with the earlier reports [1]. In boys with ascending testes, in this population, the gubernaculum was very likely to insert non-orthotopically. In concordance with previous reports [2] and regarding the finding of a an earlier age at surgery in boys with higher inserting gubernacula, this could provide a logical explanation as to how these testes are initially palpable in the scrotum and then, during body growth are retracted to the groin. CONCLUSION: In 96.1% of the patients, a non-orthotopic gubernacular insertion was found. This points to embryologic etiology, complying well with earlier reports and further underlining the critical importance of timely diagnosis and treatment for this group of patients. PMID- 30473478 TI - Suicidal behaviour recurrence in psychiatric emergency departments of patients without a prior suicide attempt, index and reattempters: A prospective study. AB - INTRODUCTION: There has been little change in the incidence of suicidal behaviour and reattempts in recent years. Evidence is needed on the incidence of suicidal behaviour in the psychiatric population and its follow-up. MATERIAL AND METHOD: A prospective multi-centre case-control study. The sample covered the cases of 440 patients seen as psychiatric emergencies. For this purpose, we used the Vital Adverse Event Scale by Brugha and screening with the Columbia Scale. The sample was divided into three groups: patients without prior suicide attempts, patients with an index attempt and patients with more than one attempt. At two years, the clinical histories of these patients were reviewed, assessing for suicidal behaviour. RESULTS: A total of 49.1% (n=216) of the patients required urgent psychiatric care during the follow-up period, and 2.7% eventually committed suicide. The data shows a differential profile between the three groups analysed. Among them, the group of reattempters required the highest number of interventions regarding suicide behaviour (11.0%; chi2=30.3; d.f.=2; P<.001). Eventually, 6.1% of the patients without prior suicide attempts tried to commit suicide for the first time, and 21.7% (n=60) of the remaining sample repeated their prior attempts. The highest risk of attempt was in the thirty days following the urgent intervention. After this period, risk distribution varied for each group. Three items from the Columbia Scale predict suicide behaviour. CONCLUSIONS: The results show the need for assessing suicidal behaviour for all patients who receive psychiatric urgent care, including during the follow-up period. A more thorough control should be performed during the first months for patients without prior suicide attempts, and longer periods for those patients who have already tried to commit suicide. PMID- 30473477 TI - ECT-induced brain plasticity correlates with positive symptom improvement in schizophrenia by voxel-based morphometry analysis of grey matter. AB - BACKGROUND: Electroconvulsive therapy (ECT) is often considered as an augmentation of antipsychotic treatment for schizophrenia in drug-refractory cases. However, the mechanisms underlying the observed therapeutic effects are still not understood. OBJECTIVE: We aimed to investigate changes in whole brain grey matter volume (GMV) before and after modified ECT. GMV was determined using voxel-based morphometry (VBM) whole brain analysis. Correlations of brain structural changes with clinical improvement were also investigated. METHODS: Twenty-one schizophrenia patients treated with a full course of ECT combined with antipsychotics (ECT group) and 21 schizophrenia patients treated only with antipsychotics (Drug group) were observed in parallel. Magnetic resonance imaging scans were performed at baseline (T1) and follow-up (T2) for each patient. Data were compared to a healthy control group (HC group) of 23 persons who were only scanned at baseline. Demographic data were matched between the three groups. RESULTS: Significant interactions of group by time were found within four brain regions: the left parahippocampal gyrus/hippocampus, right parahippocampal gyrus/hippocampus, right temporal_pole_mid/superior temporal gyrus, and right insula. Post-hoc analysis revealed an increase of GMV across all four regions amongst ECT group, but a decrease of GMV within the Drug group. Furthermore, the ECT group showed a significant positive correlation of GMV change in the right parahippocampal gyrus/hippocampus with a reduction of positive subscore in the positive and negative syndrome scale. Both treatment groups did not differ significantly in terms of GMV from the HC group in these regions either at T1 or at T2. CONCLUSION: Our findings indicate that ECT may induce brain plasticity as indexed by grey matter volume change during the treatment of schizophrenia via distinct mechanics from those by antipsychotic medications. ECT may ameliorate the positive psychotic symptoms of patients suffering from schizophrenia by preferentially targeting limbic brain areas such as the parahippocampal gyrus/hippocampus. PMID- 30473479 TI - Structural changes caused by ultrasound pretreatment: Direct and indirect demonstration in potato cylinders. AB - This work aimed to demonstrate the internal and external structural changes in potato cylinders caused by different times of ultrasound pretreatment. In addition, the structural changes were associated with the viscoelasticity and mass transfer. For which, potato cylinders were immersed in distilled water and pretreated with and without ultrasound (ultrasonic bath of 91 W/L and 25 kHz) up to 120 min. Then, the microstructure was evaluated by stereoscopic observation as a direct method, and by viscoelasticity and mass transfer evaluation (pigment diffusion and drying) as indirect methods. Both external and internal structure of the material were evaluated. As results, it was demonstrated the formation of microchannels inside the potato tissue as well as the surface erosion caused by ultrasound, especially after 60 min of pretreatment. Further, it was observed that the product viscoelasticity is affected by the ultrasound pretreatment reducing the elasticity. In addition, the mass transfer on the cylinders was improved by ultrasound pretreatment. The pigment transfer was enhanced, demonstrating the acoustic erosion at the sample border. Furthermore, the drying process was accelerated by ultrasound, demonstrating the reduction of the internal resistance to water transfer. Finally, it was observed that high structural changes on the potato cylinders can bring some disadvantages such as changes on the color and severe shrinkage. This work concluded that the structural changes caused by ultrasound can be evidenced directly and indirectly. Furthermore, different structural changes took place, on both inside and outside of the vegetable sample. However, despite ultrasound improves further process, especially those that involve mass transfer, the parameters time and ultrasonic power must be optimized to obtain desirable results without reducing the product quality. PMID- 30473480 TI - Antibodies against recombinant alpha-galactosidase A in Fabry disease: Subclass analysis and impact on response to treatment. AB - BACKGROUND: Treatment of Fabry disease (FD) with recombinant alpha-galactosidase A (r-alphaGAL A) is complicated by the formation of anti-drug antibodies in the majority of male patients with the classical disease phenotype. Detailed information regarding antibody subtypes, onset and persistence of antibody development and their effect on treatment efficacy is sparse. METHODS: A retrospective study was carried out in 39 male patients with classical FD, treated with either agalsidase-alfa or agalsidase-beta (mean follow up of 10 years). With six to twelve months intervals plasma-induced in vitro inhibition of enzyme activity, lysoglobotriaosylsphingosine (lysoGb3) levels and renal function were assessed. In a subset of 12 patients, additionally anti- r-alphaGAL A IgM, IgA and IgG1, 2, 3 and 4 levels were analyzed. RESULTS: In 23 out of 39 patients, plasma-induced in vitro inhibition of r-alphaGAL A activity was observed (inhibition-positive). The inhibition titer was strongly negatively correlated to the decrease in lysoGb3: agalsidase-alfa (FElog10(inhibition) = -10.3, P <=.001), agalsidase-beta (FElog10(inhibition) = -4.7, P <=.001). Inhibition-positive patients had an accelerated decline in renal function (FE = 1.21, p = .042). During treatment IgG1 anti-r-alphaGAL A levels increased only in inhibition positive patients (p = .0045). IgG4 anti-r-alphaGAL A antibodies developed in 7 out of 9 inhibition-positive patients. Other antibody subclasses were either not present or too low to quantify. CONCLUSION: Development of inhibiting antibodies against r-alphaGAL A negatively affects the biochemical response to ERT and resulted in an accelerated decline in renal function. The presence of IgG1 and IgG4 anti-r-alphaGAL A antibodies is associated with in vitro alphaGAL A activity inhibition. PMID- 30473481 TI - Novel mutations in the mitochondrial complex I assembly gene NDUFAF5 reveal heterogeneous phenotypes. AB - Primary mitochondrial complex I deficiency is the most common defect of the mitochondrial respiratory chain. It is caused by defects in structural components and assembly factors of this large protein complex. Mutations in the assembly factor NDUFAF5 are rare, with only five families reported to date. This study provides clinical, biochemical, molecular and functional data for four unrelated additional families, and three novel pathogenic variants. Three cases presented in infancy with lactic acidosis and classic Leigh syndrome. One patient, however, has a milder phenotype, with symptoms starting at 27 months and a protracted clinical course with improvement and relapsing episodes. She is homozygous for a previously reported mutation, p.Met279Arg and alive at 19 years with mild neurological involvement, normal lactate but abnormal urine organic acids. We found the same mutation in one of our severely affected patients in compound heterozygosity with a novel p.Lys52Thr mutation. Both patients with p.Met279Arg are of Taiwanese descent and had severe hyponatremia. Our third and fourth patients, both Caucasian, shared a common, newly described, missense mutation p.Lys109Asn which we show induces skipping of exon 3. Both Caucasian patients were compound heterozygotes, one with a previously reported Ashkenazi founder mutation while the other was negative for additional exonic variants. Whole genome sequencing followed by RNA studies revealed a novel deep intronic variant at position c.223-907A>C inducing an exonic splice enhancer. Our report adds significant new information to the mutational spectrum of NDUFAF5, further delineating the phenotypic heterogeneity of this mitochondrial defect. PMID- 30473482 TI - Coexistence of Gaucher Disease and severe congenital neutropenia. AB - Gaucher Disease (GD) is the most common lysosomal storage disorder has traditionally been classified into three clinical phenotypes. Type 3 GD is characterized by neurological involvement but neurological symptoms generally appear later in life than in type 2 disease. Neutropenia is much rarer than other hematological manifestations in GD and has not been scrutinized adequately. Severe congenital neutropenia (SCN) is a rare disease entity which is characterized by a paucity of peripherally circulating neutrophils with arrest of neutrophil maturation at the promyelocyte stage and consequent increased susceptibility to severe and recurrent infections. We report a patient who presented in the first year of life with visceral involvement and severe neutropenia in whom the propositus had a unique coexistence of Gaucher Disease and severe congenital neutropenia associated with a mutation in HAX1. In contrast to his expired siblings he had experienced no severe infections. These clinical observations suggest that enzyme replacement therapy may display a modulating factor with respect to the clinical course of SCN. SYNOPSIS: Our patient is the only report of the combination of Gaucher Disease and Kostmann Syndrome in the literature. The clinical course of our patient is not severe when comparing with exitus siblings and other Kostmann Syndrome patients. But when considering the patient's only clinical difference is ERT, this case is very important to emphasise the role of enzyme replacement therapy in bone marrow. PMID- 30473484 TI - Poverty is a political choice. PMID- 30473483 TI - Contributions of diseases and injuries to widening life expectancy inequalities in England from 2001 to 2016: a population-based analysis of vital registration data. AB - BACKGROUND: Life expectancy inequalities in England have increased steadily since the 1980s. Our aim was to investigate how much deaths from different diseases and injuries and at different ages have contributed to this rise to inform policies that aim to reduce health inequalities. METHODS: We used vital registration data from the Office for National Statistics on population and deaths in England, by underlying cause of death, from 2001 to 2016, stratified by sex, 5-year age group, and decile of the Index of Multiple Deprivation (based on the ranked scores of Lower Super Output Areas in England in 2015). We grouped the 7.65 million deaths by their assigned International Classification of Diseases (10th revision) codes to create categories of public health and clinical relevance. We used a Bayesian hierarchical model to obtain robust estimates of cause-specific death rates by sex, age group, year, and deprivation decile. We calculated life expectancy at birth by decile of deprivation and year using life-table methods. We calculated the contributions of deaths from each disease and injury, in each 5 year age group, to the life expectancy gap between the most deprived and affluent deciles using Arriaga's method. FINDINGS: The life expectancy gap between the most affluent and most deprived deciles increased from 6.1 years (95% credible interval 5.9-6.2) in 2001 to 7.9 years (7.7-8.1) in 2016 in females and from 9.0 years (8.8-9.2) to 9.7 years (9.6-9.9) in males. Since 2011, the rise in female life expectancy has stalled in the third, fourth, and fifth most deprived deciles and has reversed in the two most deprived deciles, declining by 0.24 years (0.10 0.37) in the most deprived and 0.16 years (0.02-0.29) in the second-most deprived by 2016. Death rates from every disease and at every age were higher in deprived areas than in affluent ones in 2016. The largest contributors to life expectancy inequalities were deaths in children younger than 5 years (mostly neonatal deaths), respiratory diseases, ischaemic heart disease, and lung and digestive cancers in working ages, and dementias in older ages. From 2001 to 2016, the contributions to inequalities declined for deaths in children younger than 5 years, ischaemic heart disease (for both sexes), and stroke and intentional injuries (for men), but increased for most other causes. INTERPRETATION: Recent trends in life expectancy in England have not only resulted in widened inequalities but the most deprived communities are now seeing no life expectancy gain. These inequalities are driven by a diverse group of diseases that can be effectively prevented and treated. Adoption of the principle of proportionate universalism to prevention and health and social care can postpone deaths into older ages for all communities and reduce life expectancy inequalities. FUNDING: Wellcome Trust. PMID- 30473485 TI - Dissecting the life expectancy gap in England provides clues on how to reduce it. PMID- 30473486 TI - Tannic acid, a novel histone acetyltransferase inhibitor, prevents non-alcoholic fatty liver disease both in vivo and in vitro model. AB - OBJECTIVE: We examined the potential of tannic acid (TA) as a novel histone acetyltransferase inhibitor (HATi) and demonstrated that TA prevents non alcoholic fatty liver disease (NAFLD) by inhibiting HAT activity. METHODS: The anti-HAT activity of TA was examined using HAT activity assays. An in vitro NAFLD model was generated by treating HepG2 cells with oleic and palmitic acids. Male C57BL/6J mice were fed a control diet (CD) or Western diet (WD) with or without supplementation with either 1% or 3% TA (w/w) for 12 weeks. Finally, the possibility of interacting p300 and TA was simulated. RESULTS: TA suppressed HAT activity both in vitro and in vivo. Interestingly, TA abrogated occupancy of p300 on the sterol regulatory element in the fatty acid synthase and ATP-citrate lyase promoters, eventually inducing hypoacetylation of H3K9 and H3K36. Furthermore, TA decreased acetylation at lysine residues 9 and 36 of histone H3 protein and that of total proteins. Consequently, TA decreased the mRNA expression of lipogenesis related genes and attenuated lipid accumulation in vivo. We observed that NAFLD features, including body weight, liver mass, fat mass, and lipid profile in serum, were improved by TA supplementation in vivo. Finally, we demonstrated the possibility that TA directly binds to p300 through docking simulation between ligand and protein. CONCLUSIONS: Our findings demonstrate that TA, a novel HATi, has potential application for the prevention of NAFLD. PMID- 30473487 TI - Preface. PMID- 30473488 TI - School Lunch Entrees Before and After Implementation of the Healthy, Hunger-Free Kids Act of 2010. AB - BACKGROUND: The Healthy, Hunger-Free Kids Act (HHFKA) 2010 updated standards to increase the nutritional quality of school meals. Studies of HHFKA outcomes have focused primarily on fruit and vegetables, nutrient quality of whole meals, and plate waste. OBJECTIVE: To examine changes in school lunch entree nutrient quality and student selections after HHFKA implementation. DESIGN: Descriptive, longitudinal study analyzing 1.7 million student-selected lunch entrees in eight entree categories. PARTICIPANTS/SETTING: Three middle schools and three high schools in an urban school district in Washington State, from January 2011 to January 2014 (16 months before and 15 months after HHFKA implementation). MAIN OUTCOME MEASURES: Nutritional quality of each entree category was assessed by analyzing mean adequacy ratio, energy density, and energy per serving. Selection was determined by analyzing number of entrees in each category selected by students. STATISTICAL ANALYSES PERFORMED: Comparison of indices of pre- and postimplementation nutritional quality using a combination of Wilcoxon two-sample test with t approximation and a two-sided alternative t test assuming equal variances and t test assuming unequal variances using Satterthwaite approximation. Quantity of entree categories selected was also determined by Satterthwaite approximation. RESULTS: After implementation, there was significant improvement in mean adequacy ratio and energy per serving overall for all entrees combined. There were significant improvements in both mean adequacy ratio and energy per serving for salads, burritos, and pizza in middle schools and for hot sandwiches and burritos in high schools. For energy density, middle schools also had significant decreases for casseroles and salads, with no significant changes found in high schools. The variety of entrees decreased by 44%, and there were significant changes in the proportions of entrees selected from specific food categories. CONCLUSION: Nutritional quality of lunch entrees, variety of entrees available, and student entree selections changed after implementation of HHFKA policy in one urban school district in Washington State. PMID- 30473489 TI - Assessment of the approved Risk Evaluation and Mitigation Strategy programs for New Drug Applications and Biologics Licensing Applications. AB - The Food and Drug Amendments Act of 2007, (FDAAA), granted the United States Food and Drug Administration to require drug manufacturers to develop a Risk Evaluation and Mitigation Strategy, (REMS). Implementation of the FDAAA required drug manufacturers to utilize risk minimization strategies beyond routine labeling for benefit-risk profiles of prescription drugs. The first full year of FDAAA implementation, 2008, through 2016, was reviewed to assess presence of differences in REMS requirements in Center for Drug Evaluation and Research (CDER) New Drug Applications, (NDAs), and Biologics License Applications, (BLAs). The risks present in the current unreleased approved REMS were reviewed to determine any difference in FDA requirements for safety risks identified in the NDA and BLA REMS programs. PMID- 30473491 TI - Demystifying the practice of khafd in the Dawoodi Bohra community: A commentary on the WeSpeakOut report from India. AB - In this commentary, we critique a recent report on female genital cutting (FGC) in the Indian Dawoodi Bohra community titled "The Clitoral hood a contested site: Khafd or female genital mutilation/cutting (FGM/C) in India." Published against the backdrop of possible legislation against FGC in India, the report makes good recommendations and is a useful addition to global literature on FGC. We critique specific sections of the document using relevant literature and informal conversations with the Bohra community in Pakistan, thereby highlighting both its strengths and weaknesses. We also attempt to show that criminalising khafd by conflating it with more drastic forms of cutting may be counterproductive. In conclusion, education and activism from within the community may be more fruitful than the imposition of a law banning khafd. PMID- 30473492 TI - Relationship between autonomy and moral distress in emergency nurses. AB - Reducing nurses' autonomy can impair their decision-making and ability for appropriate interventions. Lowered independence hinders ethical reasoning, which may lead to moral distress. This descriptive correlation study investigates the relationship between professional independence and moral distress in 173 nurses working in emergency departments in Tabriz, Iran. Data were collected using questionnaires designed to assess professional autonomy and moral distress and analysed using descriptive and inferential statistics via the SPSS 13 software. The level of professional autonomy among emergency nurses was low (83.2+/-16.9), and moral distress, moderate (7.43+/-3.52). A statistically significant negative relationship was reported between professional independence and the frequency of moral distress (p=0.018). Bivariate analysis related professional autonomy with the frequency and intensity of moral distress. Multiple regression analysis showed that age significantly predicted moral distress (frequency, intensity, and total scores). Lack of autonomy hinders nurses from functioning effectively and efficiently in practice and even can lead to moral distress. Increasing professional independence and the use of experienced nurses as mentors in emergency settings to support younger nurses can help with the reduction of moral distress. PMID- 30473490 TI - Comparative analysis of novel decynium-22 analogs to inhibit transport by the low affinity, high-capacity monoamine transporters, organic cation transporters 2 and 3, and plasma membrane monoamine transporter. AB - Growing evidence supports involvement of low-affinity/high-capacity organic cation transporters (OCTs) and plasma membrane monoamine transporter (PMAT) in regulating clearance of monoamines. Currently decynium-22 (D22) is the best pharmacological tool to study these transporters, however it does not readily discriminate among them, underscoring a need to develop compounds with greater selectivity for each of these transporters. We developed seven D22 analogs, and previously reported that some have lower affinity for alpha1-adrenoceptors than D22 and showed antidepressant-like activity in mice. Here, we extend these findings to determine the affinity of these analogs for OCT2, OCT3 and PMAT, as well as serotonin, norepinephrine and dopamine transporters (SERT, NET and DAT) using a combination of uptake competition with [3H]methyl-4-phenylpyridinium acetate in overexpressed HEK cells and [3H]citalopram, [3H]nisoxetine and [3H]WIN 35428 displacement binding in mouse hippocampal and striatal preparations. Like D22, all analogs showed greater binding affinities for OCT3 than OCT2 and PMAT. However, unlike D22, some analogs also showed modest affinity for SERT and DAT. Dual OCT3/SERT and/or OCT3/DAT actions of certain analogs may help explain their ability to produce antidepressant-like effects in mice and help account for our previous findings that D22 lacks antidepressant-like effects unless SERT function is either genetically or pharmacologically compromised. Though these analogs are not superior than D22 in discriminating among OCTs/PMAT, our findings point to development of compounds with combined ability to inhibit both low-affinity/high capacity transporters, such as OCT3, and high-affinity/low-capacity transporters, such as SERT, as therapeutics with potentially improved efficacy for treatment of psychiatric disorders. PMID- 30473493 TI - Medical Council of India's new guidelines on admission of persons with specified disabilities: Unfair, discriminatory and unlawful. AB - The Medical Council of India (MCI)'s recent guidelines on admission of persons with specified disabilities into the medical course under the disability quota has escalated into a huge controversy. Multiple litigations have been initiated against MCI by successful National Eligibility cum Entrance Test candidates with disabilities across the country. In light of our new Rights of Persons with Disabilities Act, 2016, and the United Nations Convention on the Rights of Persons with Disabilities, I argue in this essay that these guidelines are unfair, discriminatory and unlawful. I quote Supreme Court judgments on reasonable accommodation, equality and discrimination and highlight the exclusion of doctors with disabilities in policy making. PMID- 30473494 TI - 7th International Conference on Human Values in Higher Education: Education for holistic human health. AB - The 7th International Conference on "Human Values in Higher Education: Education for Holistic Human Health" (ICHVHE-18) was held from April 26 to 28, 2018, at Khesar Gyalpo University of Medical Sciences of Bhutan, Thimphu, Bhutan. This conference also celebrated the 50th year of Indo-Bhutan friendship. ICHVHE-18, was the culmination of the collaborative efforts of eight universities, two from Bhutan and six from India. The ICHVHE is an annual conference aimed at developing a shared vision of holistic, humane education, particularly in institutions of higher learning. The initial plan is to implement human values and education for holistic health in higher education within India and other SAARC nations. Delegates from five SAARC nations, viz, Bhutan, India, Nepal, Bangladesh and Maldives, participated in this conference. Ultimately, the effort is to provide universal human value-based education to every child, globally. PMID- 30473495 TI - Critical reflections on health sector reforms in India: A seminar report. AB - The papers presented at a recent seminar-"Rethinking gender and body in times of health sector reforms in India"-highlighted the urgent need to integrate gender studies into critical health research in order to understand the complex scenario brought about by the health reforms, and its impact on different categories of people. They also stressed on the need for tracing the historiography of public healthcare in India and the need to scrutinise values not just facts, and develop a dialogic process of learning in order to fully grasp multiple issues. PMID- 30473496 TI - Storm in a teacup? General implications of the Cochrane crisis. AB - The crisis that has emerged around the expulsion of Peter Gotzsche from the Cochrane Board seems at first sight to be the outcome of a typical power play. However, the structural issues that have led to the crisis have emerged in a more technical criticism. These include lack of transparency, lack of cooperation of the pharma industry and hostility of institutions. Thus, the watchdog institution for efficacy and effectiveness of pharmaceutical drugs has itself now been hobbled by inefficacy and lack of effectiveness in its operation. What the confrontation shows us is how little control or understanding we (ordinary people) have over what we are given as curative and preventive biomedicine. It demonstrates how we are ignorant about the treatment of our sick bodies by expertise, pharmaceutical industry and medical institutions. The problem is not one of a particular evil actor. It is a problem of our medical culture. While we struggle to find our way through this overall historical situation, we need to listen to ethical experts like Peter Gotzsche who are willing to stick their necks out and speak the truth. PMID- 30473497 TI - Ethical challenges posed by human infection challenge studies in endemic settings. AB - Human infection challenge studies (HCS) involve intentionally infecting research participants with pathogens, often with the ultimate aim of developing new interventions against infectious diseases. Despite ethical concerns about research involving vulnerable populations, there are both scientific and ethical reasons to consider conducting more HCS in low- and middle-income countries where neglected diseases are often endemic. HCS researchers can reduce the risks to participants (and the risks of transmission from participants to others) by controlling multiple factors (eg those related to the laboratory environment, participant selection, the pathogen, and the timing of treatment); but HCS nonetheless raise important ethical issues, some of which may be particularly pertinent to HCS in endemic settings. This article provides background on HCS in general, as well as recent HCS in low- and middle-income countries, and an overview of the ethical issues associated with HCS in endemic settings. PMID- 30473498 TI - An ethical appraisal of the choice of vaccines against Poliomyelitis. AB - Medical ethics is invoked for immunisation of children as it involves an interaction between a healthcare professional and the child. Immunisation under the national immunisation programme is a public health intervention and the common belief is that ethics is not relevant. Two vaccines with contrasting safety and efficacy profiles were available against polio before the national immunisation programme was launched: the inactivated poliovirus vaccine (IPV) and the live attenuated oral poliovirus vaccine (OPV). India chose OPV and excluded IPV. We carried out an ethical appraisal of that choice. Principles of medical ethics comprising four elements-non-maleficence, beneficence, autonomy and justice-was already in vogue at the time. Applying each of them, a head-to-head comparison between IPV and OPV is made. The results clearly show that the choice of vaccine was made without using ethical principles, resulting in serious adverse effects in hundreds of thousands of children. We recommend that medical ethics must be applied to all choices of public health interventions. PMID- 30473499 TI - Development and validation of HPLC method for the determination of Candesartan in human plasma. AB - Candesartan (CAN), an ARB-blocker, antihypertensive, was analyzed in human plasma by a simple, accurate and precise RP-HPLC (reverse phase-High performance liquid chromatography assay method which was then validated for its accuracy, specificity and precision. The mobile phase has a constitution of acetone, diethylamine and distilled water, while Phosphoric acid was used to adjust the pH to 2.5+/-0.1. This mobile phase was run at 1.1ml/min and the fluorescence wavelength was set to 392 nm. A C-18 HPLC, column particle size (5 MUm) Mediterranean Sea (r) L x 1.D. 25cm x 4.6 mm (Supelcosil) , with auto sampler injection volume of 30MUl ,an internal standard Valsartan was utilized for chromatographic detection. Candesartan took a retention time of 6+/-0.5 minutes. This method was validated by the parameters of selectivity, accuracy, precision, repeatability, reproducibility, recovery, linearity and stability. Candesartan's calibration curves were found to be linear in the range of 200ng/ml to 3.125ng/ml and the coefficient of determination (r2) was found to be 0.99. Analytical recovery obtained was above 88%. Hence, this method has been found to be useful for determining Candesartan in plasma. PMID- 30473500 TI - Preformulation study and initial determination of biological Properties of isopropylidene shikimic acid. AB - Isopropylidene shikimic acid (ISA), a new drug derviatived from Shikimic Acid, had been proved to be effective in the cerebral protection after cerebral ischemia and reperfusion. But there was little research on the physical pharmacy and biopharmaceutical properties about the drug. In order to provide some useful data for the pharmaceutical development of ISA, the solubility, stability and Oil/Water partition coefficient (LogP) were determined by the classic preformulation study method, and the transmembrane performance of ISA was studied by Franz -diffusion cell method in vitro. The results showed that ISA was water soluble with a solubility 32.52mg/ml, which could be improved to 44.32 mg/ml by 1% (w/v) sodium dodecylsulfate; the LogP was -0.63; ISA was less stable in water but it was stable when pH greater than 6.0 and unstable when pH less than 6.0; the accumulated permeation rates at 1h were about 50% and more than 80% at 6h. Data obtained by the study indicated that the medium selection and pH control were important for liquid preparation of ISA, and avoiding dissolution and absorption in stomach was critical for the oral solid dosage forms. Mucosal drug delivery systems would be considered, according to the certain hydrophilic lipophilic characters and good transmembrane capability. PMID- 30473501 TI - Industrially relevant cellulase production by indigenous thermophilic Bacillus licheniformis TLW-3 strain: Isolation-molecular identification and enzyme yield optimization. AB - Cellulases are the third largest single industrial bio-robots. These enzymes are employed in industries like pharmaceutical, textile, food processing, paper recycling and detergent manufacturing. In order to produce broadly diversified cellulases, microbes (both bacteria and fungi) have been exploited. Different ecological niches have already been explored for the isolation of cellulolytic microbes. However, there have been no remarkable reports viz a viz to the hot oven ash (for cellulolytic bacterial flora). In this regard, a Bacillus strainTLW 3 was isolated and selected for CMCase production and optimization. The strain was identified as B. licheniformis TLW-3 through 16S rDNA sequencing that was submitted to Gen Bank with accession numberKY440432. The isolate growth and CMCase production conditions were optimized to get the maximum CMCase yield. The highest growth and maximum CMCase production by B. licheniformis TLW-3 were recorded at pH 7 and 50oC, after the incubation period of 72 (hour) at 150rpm. Studies on the various nitrogen and carbon sources on CMCase production showed that the medium having 1% peptone, 0.5% yeast extract and 1% CMC can significantly enhance the enzymatic yield as compared to other (studied) sources. EDTA, Tween-20 and Tween-80 acted as inhibitors for the enzyme production. The present study holds the conviction that the (reported) organism could directly be applied to produce industrial thermophilic CMCase. PMID- 30473502 TI - Biological activities of three medicinal plants from district Mirpur, AJK, Pakistan. AB - Present research work was aimed to investigate the biological activities i.e. antibacterial, antifungal, antioxidant, cytotoxic and antitumor activities of crude methanolic extract of Anagallis arvensis L., Butea monosperma (Lam.) Kuntze and Coronopus didymus (L.) Pers. against Gram positive strains (Bacillus subtilis, Staphylococcus aureus) and gram negative strains (Vibrio cholera, Enterobacter aerogenes, Klebsiella pneumonia, Agrobacterium tumefaciens, Escherichia coli) were screened. Best activity was observed against K. pneumonia and S. aureus by A. arvensis compared with other strains. Butea monosperma exhibited considerable activity against S. aureus, V. cholera, E. aerogenes and K. pneumonia compared with other strains. Methanolic extract of A. arvensis L. inhibited fungal growth against A. niger up to 30.2%. B. monosperma inhibited the growth of A. niger up to 43.5% and against A. fumigatus 27.3%. C. didymus inhibited the A. fumigates up to 27.3% and against A. niger, it inhibited 48%. Brine shrimps lethality bioassay was used to evaluate the cytotoxic activity and LD50 value was calculated by using probit analysis. Potato disc bioassay was designed to screen antitumor activity and data was analyzed by one way ANOVA. PMID- 30473503 TI - Vertebral spine osteoporosis treatment efficacy in local population: A clinical study. AB - In Pakistani population the prevalence of Calcium and vitamin D deficiency is at alarming rate. Previous studies show that globally vertebral osteoporosis is most commonly recognized site causing deterioration to personal life satisfaction. It is very unfortunate that in Pakistan ample amount of research work has not been done in the area, consequently, information on rate of vertebral osteoporosis & fracture are rare in Pakistan. There is no reduction in T-score on supplementation with calcium and vitamin D3 administration. There is reduction in T-score on supplementation with calcium and vitamin D3 administration. The prime objective of the current work was to determine vertebral spine osteoporosis treatment efficacy in local population. This is an intervention experimental study with no control. The study population was selected from the local community; consisting of individuals with vertebral spine osteoporosis, further they were followed for up to 6 months. Data was analyzed by SPSS-22. Tabs Chewable: Calcium: 1250 mg, Cholecalciferol: 125 IU, BD/Day was advised. The mean T-score before and after treatment were recorded as; Mean +/-S.D: 2.890 +/-1.7217 and Mean +/-S.D: -2.456+/-0.8064 respectively. The findings of the current work do not provide support for routine supplementation with calcium and vitamin D3 orally for osteoporosis. PMID- 30473504 TI - In vitro characterization of elementary osmotic tablet containing celecoxib. AB - Oral dosage form has limited control over the release of drug from dosage form, hence effective plasma level concentration do not achieve at site of action. Such unusual pattern of dosing results in inappropriate or erratic blood plasma concentrations. The absorption of drug from conventional dosage form depends on factors such as-Physio-chemical properties of the drug, presence of excipient, physiological factors such as presence or absence of food, PH of the gastrointestinal tract etc. Present study highlights osmotically driven oral drug delivery system (tablet) containing celecoxib as an active ingredient. Patients with long term treatment of NSAID (e.g. Arthritis) and suffering from various gastrointestinal side effect will be benefited from such a dosage form. Majority of controlled release dosage forms available in market are generally matrix based, their principal drug release mechanism was based on drug diffusion through the matrix. Such mechanism is changed by-the pH, presence of food, in the gastrointestinal tract. Body's physiological factors (G.I. motility) also contribute their role in unpredictable absorption. All these factors also affect the release of celecoxib from conventional oral dosage form. Osmotic systems utilize the principle of osmosis as delivery force to release the drug from the dosage form, and the release rate has no effect of the body's pH and other physiological factors, also the various side effects due to long term therapy of NSAIDs are reduced. Batch 6 coated with semipermeable membrane give the maximum of 90.28% release from elementary osmotic tablet in control manner up to 8 hours and following zero order release, other batches e.g. 4and 8 coated with microporous membrane follow first order release. PMID- 30473505 TI - Synthesis, Characterization and evaluation of antioxidant potential of 2, 6 diphenylpiperidine-4-one compounds and their novel imine derivatives. AB - In search of potent molecules having antioxidant activity the present work was designed to synthesize 2, 6-diphenylpiperidine-4-one compounds (1a and 1b) and their imine derivatives (2a, 2b, 3a, and 3b). Compounds 1a and 1b were synthesized by Mannich condensation reaction. The method was found to be simple, convenient with high yield and products were easily separated. Compounds 1a and 1b serves as an intermediate for the preparation of highly functionalized novel imine derivatives. Oxime (2a, 2b) and carbothioamide (3a, 3b) derivatives of 1a and 1b compounds were produced by condensation reaction with hydroxyl amine hydrochloride and thiosemicarbazide respectively. These compounds were characterized by IR, EI-mass and 1HNMR spectroscopy. The antioxidant activity of compounds was analyzed by 1, 1- dipheny1-2-picrylhydrazyl (DPPH) assay method. It was found that substituted aryl derivatives containing phenol and methoxy groups (1b, 2b and 3b) showed better antioxidant activity (IC50 values rang from 1.84 4.53MUg/ml) than unsubstituted aryl derivative (1a, 2a and 3a) (IC50 rang from 6.46-11.13MUg/ml). Compound 1b exhibited excellent antioxidant activity (IC50 1.84+/-0.15MUg/ml) comparable to standard ascorbic acid (IC501.65+/- 0.16MUg/ml). PMID- 30473506 TI - In vitro hypoglycemic potential of spices: Cinnamon and Cumi. AB - Present study evaluates the anti-hyperglycemic potential of two Indian spices Cinnamomum zeylanicum(CZ) and Cumin cyminum(CC) (whole powder and aqueous extracts) using in vitro techniques like glucose adsorption assay, amylolysis kinetics and ex vivo assays like amylase, Sucrase and alpha-glucosidase assay. CZ displayed higher glucose adsorption and glucose diffusion retardation than CC, as shown by glucose adsorption and amylolysis kinetics assay. CZ showed lower inhibition of alpha-amylase and sucrase where as CC has no effect on both the enzymes. In case of alpha-glucosidase, CC had better inhibition than CZ. Further research is needed to understand the mechanism through which both the spices act to regulate the hyperglycemia. PMID- 30473507 TI - Potentiating effect of rifampicin on methimazole induced hepatotoxicity in mice. AB - Methimazole (MMI) is a widely used drug for hyperthyroidism. However, its clinical use is associated with hepatotoxicity. Though the precise mechanism of hepatic damage is still far from clear, role of metabolic activation and reactive metabolites have been implicated. The present study was designed to investigate the role of enzyme induction in bioactivation based hepatotoxicity of methimazole in mice. Thirty male mice were randomly divided into five groups. Hepatotoxicity was induced by single intraperitoneal injection of methimazole (1000mg/kg). Pretreatment with rifampicin which is a potent enzyme inducer was carried out for 6 days prior to administration of methimazole. The extent of hepatic damage was determined by measuring serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) along with histopathological grading of liver samples. The elevated levels of biochemical markers by methimazole were potentiated by pretreatment with rifampicin. This potentiation of hepatic injury was also observed in liver histopathological examination. These findings suggest induction of microsomal enzymes as a potentiating factor of methimazole induced hepatotoxicity. PMID- 30473508 TI - Antimicrobial susceptibility profile, Adherence and invasion to mammalian cells of Brucellamelitensis isolates. AB - Susceptibilities of 66 Brucella isolates were tested in vitro. All isolates were susceptible to doxycycline, gentamic in and streptomycin. In addition, propyl paraben, cresol and benzalkoniumchloride were found to be the most powerful tested preservative, disinfectant and antiseptic, respectively. All isolates adhered to and invaded into Vero cells by variable degrees. Adherence and invasion of most isolates were significantly reduced by: (1) pretreatment of test isolates with trypsin and sodium metaperiodate; (2) pretreatment of Vero cells with lipase, neuraminidase and sodium metaperiodate; (3) Presence of Ca++, Mg++ and 200mM mannose in the assay medium and (4) growth of test isolates in half MICs of different antimicrobial agents. On the other hand, pretreatment of Vero cells with trypsin increased the adherence and invasion of most test isolates. No significant change in adhesion and invasion by changing the temperature from 27 degrees C to 42 degrees Cor the pH from 6 to 8. Log phase cultures showed higher adherence and invasion than stationary phase cultures. PMID- 30473509 TI - Identification of the risk factors of the thyroid cancer by using logit model in Lahore. AB - Thyroid Cancer is a disease, which becomes a cause of death in developing countries. The aim of this study is to investigate all the possible risk factors of thyroid cancer in Pakistan. This study was consisting of 320 individuals, including 160 cases and 160 controls. These subjects were interviewed from the INMOL hospital and Sheikh Zayed Hospital, Lahore. The information was collected regarding the characteristics like age, gender, family history of thyroid cancer, use of iodine-diet, radiation therapy, etc. Descriptive and inferential statistics were used to explore the risk factors of the thyroid cancer. Odds ratio and 95% confidence interval (CI) were computed by using logistic regression model. The result showed that the odds ratio and 95% CI for family history of cancer are 2.222 and (1.281-3.853), for use of iodine diet are 2.619 and (1.492 4.596), for acromegaly disease are 1.947 and (1.123-3.374), for oxidative stress are 6.229 and (3.473-11.172), for red meat are 2.601 and (1.421-4.762), for fast food are 3.177 and (1.745-5.785), for fried food are 2.357 and (1.268-4.382), for the use of fats are 2.531 and (1.265-5.064) and for sea food are 2.050 and (1.127 3.729), respectively. It can be concluded that oxidative stress has 6 times high risk of thyroid cancer with the odd ratio 6.229 and CI (3.473, 11.172). Moreover, fast food, the use of iodine diet, red meat and the seafood are also increased the risk factor of thyroid cancer. PMID- 30473510 TI - Phytochemical composition and antioxidant activity of Tunisian Laurus nobilis. AB - We study the composition of Tunisian laurel leaves essential oil (EO), the fatty acid composition of laurel seed fixed oil and the total phenolics, flavonoids and tannins of laurel leaves methanolic extract. We also evaluated its free radical scavenging activity by the DPPH test. The predominant chemical class in Tunisian Laurus nobilis leaves EO was represented by oxygenated monoterpenes accounting for 64.29% of whole EO with the major compound was 1,8-cineole (46.8%). The predominant fatty acid was oleic acid (C18: 1) with an amount of 42.0%. Total polyphenols were present in the methanolic extract of Laurusnobilis leaves at an amount of 174.1 mg GAE.g-1dry matter. Total flavonoids and total tannins accounted respectively for 149.2mg CE.g-1 dry matter and 24.9mg CEg-1 dry matter. Furthermore, concerning free radical scavenging activity, Laurus nobilis leaves methanolic extract presented a significant IC50 (3mg/mL). PMID- 30473511 TI - Preventive effect of Tongxinluo on endothelial survival and vascular integrity, together with inhibition of inflammatory reaction in rats model of intestine ischemia/reperfusion injury. AB - This study was design to investigate preventive function of Tongxinluo (TXL) capsule on micro vascular function and endothelial survival in rats model of intestine ischemia/reperfusion (I/R) injury. We randomly divided fifty male Sprague-Dawley rats into Sham group, I/R group, TXL0.4+I/R group, TXL0.8+I/R group, TXL1.6+I/R group (10 rats each). Rat intestine I/R injury was carried out using a model of acute superior mesenteric artery occlusion with 30 min ischemia followed by 60 min reperfusion. The distribution of endothelial apoptosis in intestine was determined by CD31+TUNEL immunofluorescent double staining analysis. VE-Cadherin, ANGPTL4, HMGB1 and NF-kappaB were determined by immunohistochemical analysis. I/R induced massively endothelial cell apoptosis, accompanied with reduced expression of adherens junction protein VE-Cadherin and up regulation of inflammatory mediator HMGB1 and NF-kappaB. TXL pretreatment groups (TXL0.4+I/R, TXL0.8+I/R and TXL1.6+I/R group) significantly attenuated endothelial cell apoptosis with a dose-dependent effect. TXL pretreatment could maintain the expression of VE-Cadherin and promote the expression of ANGPTL4 which help to maintain endothelial integrity. TXL pretreatment also exert great influence in inhibiting HMGB1 expression and NF-kappaB expression induced by I/R. It could be concluded from this study that micro vascular dysfunction and endothelial damage play a causal role in rat intestine I/R injury. TXL pretreatment could significantly prevent the I/R induced pathology of endothelial apoptosis, micro vascular integrity disruption and inflammatory reaction. PMID- 30473512 TI - Biowaiver studies of Metronidazole tablets (400mg): An alternative to In-vivo bioequivalence Studies. AB - The aim of the study was to investigate the dissolution behavior of commercially available brands of metronidazole and to provide basic tool to evaluate the comparative effectiveness and interchangeability of generic brands under biowaiver conditions. The dissolution test for six brands of metronidazole 400mg tablets was performed and physical controls were analyzed. Basket Rack methods at 100rpm were used to estimate release pattern of drug. Pharmaceutical parameters of tablets were analyzed. In order to evaluate dissolution profiles, multiple point dissolution were performed and calculated 85.96+/-0.41 to 90.56+/-0.93 % within 15 minutes in pH 1.2,85.50+/-1.40 to 88.99+/-0.80% in pH 4.5 and 85.37+/ 1.94 to 92.79+/-0.89% in pH 6.8 dissolution medium respectively. Five different kinetics have been studied to predict and evaluate the acceptability level of drug release. The results show that Hixson-Crowell, first-order and Weibull demonstrated the drug release with R2> 0.95 that predicted the tablets were pharmaceutically equivalent. One-way ANOVA at p >0.05 level and similarity factors (f2) were used to estimate the discrepancy and intimacy among the brands. It is a need of time to constantly monitor the marketed generic drugs products and their release profiles to confirm their in vitro bioequivalence which can help to reduce the time, cost and unnecessary exposure of healthy subjects to medicines. PMID- 30473513 TI - Ameliorative potential of Cortex Lycii on enzymes involved in carbohydrate metabolism in streptozotocin-nicotinamide induced diabetic rats. AB - Cortex Lycii (root back of Lycium chinense) has is a famous traditional Chinese medicine which displays several pharmacological activities including antioxidant and antidiabetic properties. We investigated the effect of the ethyl acetate fraction (QCL) of Cortex Lycii on the enzymes involved in the metabolism of carbohydrate in diabetic rat models. Streptozotocin-nicotinamide (110 and 65mg/kg body weight, respectively) was used to induce diabetes. Diabetic rats were treated with QCL (100, 200 and 400 mg/kg) and glibenclamide (600 MUg/kg) daily for six weeks. Upon the completion of treatment, fasting blood glucose (FBG), insulin, glycosylated haemoglobin (HbA1c), haemoglobin (Hb), hexokinase, glucose 6-phosphate dehydrogenase, glucose-6-phosphatase, phosphoenolpyruvate carboxykinase and fructose-1,6-bisphosphatase levels were measured by biochemical assays. Likewise, the body weight, food and water intake was monitored and measured. Diabetic rats displayed significant elevation in the blood glucose, glycosylated hemoglobin and a marked decrease in plasma insulin and hemoglobin. Furthermore, the levels of key enzymes including fructose-1,6-bisphosphatase, glucose-6-phosphatase phosphoenolpyruvate carboxykinase were significantly increased while the activity levels of hexokinase, glucose-6-phosphate dehydrogenase and glycogen were significantly down regulated in diabetic rats. However, treatment of diabetic rats with Cortex Lycii led to a significant reduction the FGB, food and water intake and an increase in the plasma insulin level. Treatment with Cortex Lycii also reversed the altered activity profiles of the key enzymes mentioned above in a dose dependent manner. Our results suggested that Cortex Lycii has a promising therapeutic option in the management of diabetic complications relating to glucose homeostasis and carbohydrate metabolism. PMID- 30473514 TI - Phytochemical analysis and antimicrobial activity of aqueous and methanolic extracts of the flowers of Nelumbium speciosum. AB - In present investigation aqueous and methanolic extracts of Nelumbium speciosum flowers were screened for phytochemical constituents and antibacterial activity to ascertain their traditional use. Antimicrobial activity of both extracts was tested by Kirby-Bauer disc diffusion method against four Gram positive strains, viz. Staphylococcus aureus (ATCC25923), Streptococcus agalactiae (13813), Bacillus subtilis (ATCC 6633), Staphylococcus epidermidis (ATCC 12228) and four Gram negative bacterial strains Escherichia coli (ATCC 8739), Pseudomonas aeruginosa (ATCC 27853), Proteus mirabilis (12453) and Klebsiella pneumoniae (10031). Phytochemical analysis showed the presence of tannins, saponins and alkaloids in both extracts while flavonoids and steroids were present only in methanolic extract. Methanolic extract of Nelumbium speciosum flower showed concentration dependent antibacterial activity against all tested strains with maximum zone of inhibition (17.3+/-0.3mm) against P. aeruginosa. Aqueous extract showed concentration dependent activity against S. aureus, E. coli, B. subtilis and S. epidermidis with maximum antibacterial activity against E. coli (14.3+/ 0.3mm). MIC of methanolic and aqueous extracts was in the range of 0.015-0.251 and 0.0625-0.251 mg/mL, respectively. Results showed that methanolic extract of Nelumbium speciosum exhibits superior antibacterial activity than aqueous extract. PMID- 30473515 TI - Preliminary investigations of banana (Musa paradisiaca) starch mucilage as binder in metformin tablet formulation. AB - The binding properties of banana (Musa paradisiaca) starchwas investigated using maize starch BP and polyvinylpyrrolidone (PVP) as standards in the formulation of metformin tablets. Starch from unripe banana fruits was extracted with distilled water. Mucilages of the banana and maize starches and solutions of PVP at 5 and 10 %w/v were used to produce metformin granules by wet granulation and compressed into tablets. Granules and tablets properties were evaluated. Compatibility studies using differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) were also carried out. Granules flow properties was of the order: PVP>banana starch > maize starch. DSC and FTIR analysis reveals no interaction between excipients and metformin. Increase in concentration of banana starch mucilage from 5-10% w/v led to an increase in hardness, disintegration time and decrease in friability of the tablets. Tablets of banana starch mucilages were comparable in tablet properties with those of maize starch mucilages and PVP solutions with no significant differences (p<0.05). The tablets exhibited crushing strength, friability and disintegration time values ranging from 6.75-12.00 kp, 0.82-1.50 % and 11.04-14.51 min, respectively. The tablet parameters met compendial requirements at binder concentrations studied except friability values for tablets of PVP. Results revealed that banana starch could be used as a binding agent in metformin tablet formulation due to its comparable binding property with maize starch BP and PVP. PMID- 30473516 TI - A computational structural analysis of functional attributes of hypodermin A and B proteins: A way forward for vaccine development. AB - Hypodermosis is a parasitic disease of cattle. The pathogenicity of the disease is attributed to Hypodermin proteins (Hypodermin A, Hypodermin B and Hypodermin C). Studies suggest that Hypodermin proteins may be defined as Serine proteases and collagenases. The structure of both proteases Hypodermin A and Hypodermin B were modeled using the Swiss-model server followed by its validation using Procheck, Errat and Verify-3D. Afterwards, both Hypodermin A and Hypodermin B were docked against collagen in order to study its interaction with respective Hypodermin proteins. The structure of both Hypodermin A and Hypodermin B showed more bent towards hydrophobic nature as more beta sheets were present in them. Both structures were also superimposed to check out similarities and differences present between them. Serine, Aspartic acid, Histidine, Glutamic acid and Lysine are found as interacting residues that are involved in hydrogen bonding with collagen. The interactions are found in the active domain region of Hypodermin proteins. The interacting residues were present in the active region of the hypodermin proteins thus validating the docking studies. This study may help in the drug development against hypodermosis with least side effects. PMID- 30473517 TI - WITHDRAWN: Drug compliance and its associated factors among hypertensive patients in Pakistan: A cross-sectional study. AB - Ahead of Print article withdrawn by publisher. PMID- 30473518 TI - Protective effects of Butea frondosa leaves against stress induced immune impairment in sprague dawley rats. AB - Stress is thought to impair immune function through emotional or behavioral manifestations thus the present study was done to assessed the effect of ethanolic extract of Butea frondosa (BF) leaves on behaviour, immunomodulatory activity and brain acetyl cholinesterase activity in normal and stress induced male rats. Neuroprotective effects of BF, doses (100,200,400mg/kg p.o) were measured by assessing the changes in the behaviour and the immunity of the rats. In stress control, the results indicated that the retention transfer latency, time spent in a closed arm, agglutination, total leukocytes counts (TLC), total paw edema ,size of spleen , decreased significantly (p<0.01) while glucose level, size of the kidney and the liver, AChE activity increased significantly (p<0.01) in comparison with normal control. In BF (200mg/kg) treated rats, the results indicated that the time spent in a closed arm (p<0.01), agglutination (p<0.01), TLC (p<0.01), total paw edema (p<0.05), size of spleen(p<0.01), increased significantly while glucose level (p<0.01), size of the kidney and the liver (p<0.01), AChE activity (p<0.01) decreased significantly in comparison with stress control. This study therefore concluded that the ethanolic extract of BF (200mg/kg) showed a protective effect against the stress induced impaired immune system and the psychological disorders. PMID- 30473519 TI - Extraction and isolation of important bioactive compounds from the fruit of Physalis ixocarpa. AB - The current study investigates pharmaceutically important bioactive compounds in the fruits of Physalis ixocarpa. Two different extractions methods were used to study its effect on percent extract yield, recovery of bioactive compounds and antioxidant activity of the extracts. The data indicated that Soxhlet extraction had high efficiency of recovery than maceration method for extracting compounds; percent extract yield and antioxidant activity of the extracts. In maceration, the percent extract yield was found to be in order of water >methanol >ethyl acetate whereas in Soxhlet extraction, it was in order of methanol >water >ethyl acetate. Ethyl acetate extract produced by Soxhlet extraction showed strong antioxidant activity of 59.7% (250ppm) as compared to other extracts. Analysis of ethyl acetate extract showed the presence of Triglyceride. GC-MS study of triglyceride revealed the presence of trilinoleinic acid (9,12-Octadecdienoic acid), tripalmitin (hexadecanoic acid) and trioleinic acid (9-Octa decenoic acid). Four impure and three pure compounds were isolated from crude methanol extract of the fruit. The structure of pure compounds were identified by NMR and characterized as sugar, glucose and fructose. PMID- 30473520 TI - Antibacterial, antifungal and enzyme inhibitory effects of selected plants from Turkey. AB - In this study, antibacterial, antifungal, antihyaluronidase, anticollagenase and antielastase activity of Hypericum bithynicum, Malva neglecta, Morus alba, Rubus discolor, Sambucus ebulus and Smilax excelsa were investigated. Methanol extracts of M. neglecta and R. discolor and all extracts of H. bithynicum were more active against Staphylococcus epidermidis. Similarly, water extracts of M. alba and S. ebulus were more active against Streptococcus pneumonia. Additionally, S. ebulus and S. excelsa had prominent antifungal activity on Candida albicans. Besides, methanol extract of M. neglecta and n-hexane extract of H. bithynicum were determined to have significant anti-hyaluronidase activity. Only R. discolor showed significant anti-elastase effect. PMID- 30473521 TI - Synthesis of 2-Furyl[(4-aralkyl)-1-piperazinyl]methanone derivatives as suitable antibacterial agents with mild cytotoxicity. AB - The aim of the present research work was synthesis of some 2-furyl[(4-aralkyl)-1 piperazinyl]methanone derivatives and to ascertain their antibacterial potential. The cytotoxicity of these molecules was also checked to find out their utility as possible therapeutic agents. The synthesis was initiated by reacting furyl(-1 piperazinyl)methanone (1) in N,N-dimethylformamide (DMF) and lithium hydride with different aralkyl halides (2a-j) to afford 2-furyl[(4-aralkyl)-1 piperazinyl]methanone derivatives (3a-j). The structural confirmation of all the synthesized compounds was done by IR, EI-MS, 1H-NMR and 13C-NMR spectral techniques and through elemental analysis. The results of in vitro antibacterial activity of all the synthesized compounds were screened against Gram-negative (S. typhi, E. coli, P. aeruginosa) and Gram-positive (B. subtilis, S. aureus) bacteria and were found to be decent inhibitors. Amongst the synthesized molecules, 3e showed lowest minimum inhibitory concentration MIC = 7.52+/ 0.MUg/mL against S. Typhi, credibly due to the presence of 2-bromobenzyl group, relative to the reference standard, ciprofloxacin, having MIC = 7.45+/ 0.58MUg/mL. PMID- 30473522 TI - Cellulase-assisted extraction and anti-ultraviolet activity of polysaccharides from the root of Flammulina velutipes on Caenorhabditis elegans. AB - We investigated the cellulase-assisted extraction and anti-ultraviolet activity of water-soluble polysaccharides from the root of Flammulina velutipes on Caenorhabditis elegans. A Box-Behnken design experiment with three factors and three levels, including enzymolysis temperature, microwave time, and microwave power, was designed on the basis of the results of single-factor experiments. For improving the polysaccharide yield of F. velutipes root, the following optimal extraction conditions were used: 52.67 degrees C enzymolysis temperature, 80s microwave time, and 144 W microwave power. Under optimal conditions, the actual measured value of the yield was 2.01% (w/w) and the predicted value was 2.06% (w/w). One fraction (FRP-2) was isolated and purified, and its characteristics were analyzed. The average mean molecular weight of FRP-2 was measured to be 2.60*105 Da, and its monosaccharide composition is mainly glucose. The sugar units are present both in the alpha-configuration and beta-configuration. Moreover, FRP-2 exhibited certain anti-ultraviolet activity to C. elegans when the polysaccharide concentration ranged between 0.05mg/mL and 0.20mg/mL. PMID- 30473523 TI - In vitro analysis of anti-diabetic and anti-oxidative potential of pedicles of fruit-vegetable bottle gourd. AB - The fruit-vegetable Lagenaria siceraria is well known for its ethnomedicinal applications. While other parts of the plant have been studied for their medicinal properties, its fruit pedicles have not been yet explored. The present study therefore aimed to investigate their phenolics, flavonoids, antioxidant potential and alpha-amylase inhibitory properties. The bioactivities of this neglected part of the fruit were promising. Ethyl acetate fraction had the highest total phenolic content (TPC), 4.4MUg/mL Gallic acid equivalent (GAE). The TPC of chloroform and n-butanolic fractions were 3.6 and 2.5 GAE, respectively. Chloroform fraction displayed the highest total flavonoid content (TFC, 295MUg/mL Rutin equivalent). The trend of TFC among the fractions was chloroform > hexane > ethyl acetate > n-butanolic > aqueous. Ethyl acetate fraction was most potent as a DPPH radical scavenger, and showed notable activity even at very low concentration (IC50 2.65mg/mL). It was more potent than ascorbic acid (IC50 4.9mg/mL), the standard used in the study. The methanolic extract itself was more powerful than ascorbic acid. The residual aqueous fraction was the strongest inhibitor of alpha-amylase with IC50 1.35mg/mL, which was comparable to the antidiabetic drug Acarbose (IC50 1.26 mg/mL). The IC50 (mg/mL) of ethyl acetate, hexane and n-butanolic fractions were 2.16,2.05 and 2.44, respectively. The findings indicated that the pedicles of L. siceraria fruits have remarkable antioxidant and alpha-amylase inhibitory potential. Subject to verification by in vivo analysis and clinical trial, consumption of the pedicles of this fruit may be advised to diabetic people. As the aqueous fraction was the most potent inhibitor, a water decoction of the fruit part may safely be recommended for the purpose. PMID- 30473524 TI - Evaluation of fast disintegrating tablets of paracetamol prepared from a blend of croscarmellose sodium and Pleurotus tuber-regium powder. AB - The study investigated the combination effects of the mixture of croscarmellose sodium and Pleurotus tuber-regium powder on the granules and tableting parameters of paracetamol tablets. Five batches (A-E) of paracetamol tablets were formulated using wet granulation method with various combination ratios of croscarmellose sodium and Pleurotus tuber-regium powder as disintegrant incorporated both intra- and extra granularly. Their granule properties such as bulk and tapped densities, angle of repose, Carr's index, Hausner's ratio and post compression parameters such as friability, hardness, disintegration time and drug release profiles were evaluated. The results showed a decrease in disintegration time with increasing concentration of Pleurotus tuber-regium powder with disintegration times < 3.58 min. There was an increase in hardness (values > 4.34 kp) and a decrease in friability (values < 0.6 %) of the tablets with increasing concentrations of Pleurotus tuber-regium. All the tablets exhibited comparable drug release profiles with over 80 % of their drugs released in 1 h. Harder and less friable fast disintegrating tablets of paracetamol can be obtained with Pleurotus tuber regium powder in combination with croscarmellose sodium. The combination of croscarmellose sodium and Pleurotus tuber-regium possesses potentiative effect on their disintegrant activity. PMID- 30473525 TI - Comparative analgesic evaluation of Himalrandia tetrasperma and Wendlandia exserta of family Rubiaceae after induction of pain in mice. AB - Himalrandia tetrasperma and Wendlandia exserta medicinal plants belong to family Rubiaceae commonly known as coffee family were investigated by quantitative analysis of major bioactive compounds and analgesic effect. The analgesic potential was accessed using different parts of H. tetrasperma and W. exserta by induced acetic acid writhing and hot plate test method. Methanolic extracts of these two plants satisfactorily possesses analgesic activity. All the extracts showed good results as compared to standard drug, i.e. aspirin. Seeds of H. tetrasperma possess maximum, i.e. 86.73% inhibition at first phase where as aspirin possesses 52.73%. In second phase, leaves possess 99.8 % inhibition respectively. Hot plate analgesic activity of bark extract displayed maximum activity at 4.5h stage, i.e. 8.6+/-0.40. W. exserta methanolic extract of bark possesses 97.3% inhibition respectively in first phase and 99.8% in second phase. Bark extract displayed maximum activity at 4.5h stage, i.e., 9.7+/-0.5. Quantitative analysis of bark of H. tetrasperma possesses highest value of saponins, i.e. 30.21+/-0.8 where as flavonoids 17.50+/-1.2, phenolic compounds 23.25+/-0.5 and tannins 12.32+/-0.4. The leaf extracts of H. tetrasperma contains maximum value of phenols, i.e. 15.10+/-0.7 where as W. exserta bark possesses significant value of alkaloids, i.e. 16.41+/-0.4 and leaf extracts possesses flavonoids, i.e. 14.51+/-0.3, saponins 12.22+/-0.1 and phenolic compounds 11.31+/ 0.4. The seeds of both plants possess significant value of tannins, i.e. 07.60+/ 0.3. PMID- 30473526 TI - Stability indicating HPLC method for simultaneous quantification of sildenafil citrate and dapoxetine hydrochloride in Pharmaceutical products. AB - A stability-indicating HPLC-UV method for the simultaneous determination of sildenafil citrate and dapoxetine hydrochloride in solution and tablet was developed. The mobile phase was comprised of acetonitrile and 0.2M ammonium acetate buffer. The analyte was eluted at 3.392min and 7.255min for sildenafil citrate and dapoxetine HCl respectively using gradient system at a flow rate of 1.5mL/min. The theoretical plates count was>2000, tailing factor <.30, capacity factor 3.19-7.58 and peak asymmetry factor <.08.The method was linear from 5-180 and 1-40MUg/mL with a correlation coefficient of 0.9999 and 0.9994 for sildenafil citrate and dapoxetine HCl respectively. The drug solution was stable at ambient room temperature (26C) for 48hours.Both drugs were found susceptible to oxidation and the drug content dropped slightly in acid and alkali condition but stable under UV light and heat. No interference from tablet excipients and degradation products was found. PMID- 30473527 TI - In vitro antibacterial activity and phyto-chemistry of samples from the roots of Viola pilosa. AB - Anti-microbial activity and phytochemical analysis of samples from the roots of Viola pilosa was studied against six strains of bacteria. Data indicated that the tested bacterial strain differed in its sensitivity to the root extracts of Viola pilosa. The results showed that Xanthomonas campestris, Bacillus subtilis and S. aureus were more susceptible to butanol extracted fraction. S. aureus was totally resistant to aqueous extracted fraction at all concentrations and .Xanthomonas campestris and Bacillus subtilis were least susceptible to the same fraction at 0.5 mg disc-1. Similarly, ethyl acetate at 2 mg disc-1 concentrations was effective against Pseudomonas aeruginosa and Escherichia coli. Klebsiella pneumoniae was completely resistant to all the tested concentrations. Phytochemical analysis of the different solvent extracted samples suggested the presence or absence of different various metabolites including alkaloids, saponins, tannins, sterols, flavonoids, protein, carbohydrates and fats. PMID- 30473528 TI - In vitro antibacterial susceptibility of different brands of oral levofloxacin 250 mg tablet against Staphylococcus aureus and Escherichia coli. AB - Antibiotics are not only used in morbidity but also help in prevention of infection. The irrational use of broad spectrum antibiotics is now increasing the resistance against pathogens. This present study has been carried out to evaluate the in-vitro antibacterial effect of levofloxacin against clinical isolates. According to Clinical and Laboratory Standards Institute (CLSI) guidelines, minimum inhibitory concentrations 90% (MIC90) of the levofloxacin tested were evaluated by an agar dilution method. Total 63 clinical isolates Staphylococcus aureus (n=34) and Escherichia coli (n=29) were collected from different hospitals at Karachi and were evaluated MIC90 of eleven different brands of levofloxacin tablet (250 mg). Levofloxacin (Reference) was tested against E.coli standard (American Type Culture Collection) (ATCC=25922) with (MIC90; 0.03MUg/ml) and compared with different eleven brands of levofloxacin tablets 250mg (MIC90; 0.5MUg/ml -16.0MUg/ml). Levofloxacin (Reference) sensitivity against S. aureus standard (ATCC=25923) is (MIC90; 0.12MUg/ml) and similarly when it was compared with same levofloxacin tablets (MIC90; 0.5-16.0MUg/ml). It has been concluded by the present study, a large number of strains of bacteria have shown better bactericidal action of different brands of levofloxacin and nearly all commercialized drugs were appropriate for therapeutic use. PMID- 30473529 TI - Report: Wound healing activity of Hymenocallis littoralis - Moving beyond ornamental plant. AB - Spider lily (Hymenocallis littoralis) belongs to Amaryllidaceae family is a well known plant species for its medicinal properties. The inhibitory effects of H. littoralis methanol sonication extracts were evaluated for wound healing activity. This is the first report on the wound healing activity of Malaysian origin H. littoralis. The bulb, flower, root, anther, stem and leaves of H. littoralis methanol sonication extracts were used for scratch-wound assay. The cell line was treated with two different concentrations; 1 and 10MUg/ml of extracts. The extracts were prepared freshly by dissolving in sterile phosphate saline buffer (PBS) and the healing activity was observed from 2, 4, 8, 12, 24, 36 and 48 h. The bulb, root, stem and anther methanol extracts demonstrated active wound healing activities at 1 MUg mL-1at 36 h of treatment. At the low concentration the bulb, root, stem and anther methanol extracts heals the wound compared to leaf and flower extracts. It's demonstrated that these extracts contain effective phytochemical substances which are responsible for wound healing process. This finding suggests the potential application of H. littoralis methanol extract in wound healing activity. PMID- 30473530 TI - Report: Safety and toxicological evaluation of herbal formulation on rodents. AB - Herbal medicines are still most popular, abundant and affordable remedies for curing various ailments. Garlina is one of the herbal formulations of Hamdard Laboratories (waqf) Pakistan used to treat cardiovascular diseases and elevated sugar level. However, there is no scientific data available regarding the potential toxicity. Therefore, the present study was to assess the acute and sub chronic toxicity in rats. The single dose of Garlina 5000mg/kg were administered orally and observed for 14 days. A sub-chronic toxicity test was performed at 2000mg/kg of Garlina daily for 30 days. Control rats received saline. The biochemical, hematological and histopathological analysis was carried out. The acute toxicity LD50 was determined to be <5000mg/kg. The result of acute and sub chronic toxicity revealed no mortality and sign of toxicity. Garlina did not elicit any significant change in body weight, hematological and histopathology analysis when compared to saline treated rats. The relative weight of organs was not affected by the treatment. While the daily dose of Garlina for humans is 20mg/kg. However, the sub-chronic toxicity at 2000mg/kg dose of Garlina exhibited significant increase in gamma glutamyltransferase while total protein significantly decreased. Results obtained from study demonstrated that there is wide margin of safety for the therapeutic use of Garlina and significant decrease in LDL, atherogenic index, GGT and bilirubin direct at the dose of 5000mg/kg further strengthen the use as hypolipidemic and hypoglycemic agent. PMID- 30473531 TI - Report: Effect of macrophage alone or primed with cytokines on Balamuthia mandrillaris interactions with human brain microvascular endothelial cells in vitro. AB - Balamuthia mandrillaris is well known to cause fatal Balamuthia amoebic encephalitis (BAE). Amoebic transmission into the central nervous system (CNS), haematogenous spread is thought to be the prime step, followed by blood-brain barrier (BBB) dissemination. Macrophages are considered to be the foremost line of defense and present in excessive numbers during amoebic infections. The aim of the present investigation was to evaluate the effects of macrophages alone or primed with cytokines on the biological characteristics of Balamuthia in vitro. Using human brain microvascular endothelial cells (HBMEC), which constitutes the BBB, we have shown that Balamuthia demonstrated <90% binding and <70% cytotoxicity to host cells. However, macrophages further increased amoebic binding and Balamuthia-mediated cell cytotoxicity. Furthermore macrophages exhibited no amoebicidal effect against Balamuthia. Zymography assay demonstrated that macrophages exhibited no inhibitory effect on proteolytic activity of Balamuthia. Overall we have shown for the first time macrophages has no inhibitory effects on the biological properties of Balamuthia in vitro. This also strengthened the concept that how and why Balamuthia can cause infections in both immuno-competent and immuno-compromised individuals. PMID- 30473532 TI - Report: Attenuation of apomorphine induced behavioral sensitization in rats pre treated with tryptophan. AB - Psychostimulants substances, some of which are abused by humans, are generally believed to produce sensitization effects when they are repeatedly administered to animals. Apomorphine, a non-narcotic derivative of morphine, having agonistic property for dopamine in order to produce psycho stimulant-like effects. Meanwhile, chronic administration leads to behavioral sensitization. Therefore, present study destine to produce desensitization in animals by the repeated administration of tryptophan (100 mg/kg), thereafter treated with apomorphine (1.0 mg/kg) to observe the intensity of sensitization in rats pre-treated with tryptophan. Apomorphine on acute administration known to increase motor activity whereas repeated treatment of apomorphine initiates the sensitization of motor behavior. It is expected that the intensity of apomorphine induced sensitization would be affected in tryptophan-treated rats. Present study provide the clear-cut evidence that chronic treatment of apomorphine arouses the motor behavior of animals in both novel and anxiolytic model over the saline treated animals, whereas hypo locomotive behavior was seen in animals pre-treated with tryptophan, provides the evidence that preliminary treatment of tryptophan perturbs the apomorphine induced sensitization in animals. The discoveries present an inventive methodology for amplifying the remedial utilization of apomorphine and traditional psychostimulants. PMID- 30473533 TI - Report: A comparative study of loratidine physiochemical properties from different brands. AB - Loratidine is a piperidine derivative resemble to azatadine long acting non sedating commonly used for the treatment of allergic condition like watery or itchy eyes, runny nose, chronic urticaria or throat itching. In the present study different brands of loratidine were evaluated for the weight variation, hardness, friability, disintegration time and dissolution. Dissolution release study performed by using paddle method (USP 2) in 900 ml of 0.1N HCl at 50 rpm. The physicochemical of loratidine did not give any variation. By this study we conclude that all parameter for physicochemical properties like weight variation, hardness of tablets, friability, their disintegration time and the dissolution release study for all the brands of loratidine that are available in Karachi meet the British pharmacopoeia (BP) and United State pharmacopoeia (USP) specification for quality control analysis.Weight variation, hardness and friability value requirement was complied by all brands .Disintegration time for all brands was less than 15 minutes complying the BP/USP recommendation. All brands showed more than 80% drug release within 45 minutes. The present findings suggest that almost all the brands of loratidine meet the BP/USP specification for QC analysis. PMID- 30473534 TI - Report: Incidence of malaria in the population of Korangi creek area, Karachi, Pakistan. AB - Parasites lives on host organism with some or complete metabolic dependence on it, while the haemoparasites inhabit and nourished from blood cells of the host. The current investigation evaluated to raise awareness of blood parasite (Plasmodium spp.) infection in Korangi creek, Karachi, population and to know as to which Plasmodium species was most prevalent. One year data was collected from different hospitals and laboratories of the Korangi creek area, blood slides were prepared under the microscope. Four hundred and eighty one infected slides with Plasmodium were observed amongst them 396 (82.32 percent) had P. vivax and 85 (17.67 percent) had P. falciparum infection. The rate of infection did not vary with gender but had a signification association with age. Highest incidence was recorded in age group 16-40 years for both P. vivax and P. falciparum followed by age group 1-15 years in P. vivax and age group 41-60 years for P. falciparum. It was suggested that protective measures are required to overcome disease that include covering arms and legs, using repellents mosquito nets along with proper dispensing and appropriate treatment. PMID- 30473535 TI - The genetic effect of the ICAM1 (Intercellular Adhesion Molecule 1) rs5498 polymorphism on the susceptibility towards multiple sclerosis. AB - In the present study, we included currently published evidence to comprehensively evaluate the influence of the rs5498 polymorphism within the ICAM1 (Intercellular Adhesion Molecule 1) gene on the genetic risk of multiple sclerosis. STATA 12.0 software was utilized to carry out the heterogeneity assessment, association test, and Begg's test as well as the Egger's tests and sensitivity analyses. A total of eleven high-quality case-control studies were selected from the initially retrieved 2,209 articles. The lack of high heterogeneity led to the use of a fixed-effect model in all genetic models. The results of the association test showed a reduced risk of multiple sclerosis in the allelic G vs. A (Table 2, Passociation = 0.036, OR=0.91) and dominant AG+GG vs AA ( Passociation = 0.042, OR=0.85) but not in other genetic models (all Passociation >0.05). In addition, the negative results were observed in further subgroup analyses based on ethnicity or Hardy-Weinberg equilibrium (HWE) in all genetic models. Data from Begg's and Egger's tests further excluded the presence of remarkable publication bias, while sensitivity analysis data supported stable outcomes. Thus, we conclude that ICAM1 rs5498 may not be related to the risk of multiple sclerosis in Caucasian or Asian populations, which still merits further research. PMID- 30473536 TI - alpha-Pinene regulates miR-221 and induces G2/M phase cell cycle arrest in human hepatocellular carcinoma (HepG2) cells. AB - The naturally occurring compound alpha-pinene induces cell cycle arrest and antitumor activity. We examined effects of alpha-pinene on cell cycle regulation in HepG2 cells to establish a foundation for its development as a novel treatment for hepatocellular carcinoma (HCC). HepG2 cells treated with alpha-pinene exhibited dose-dependent growth inhibition as a result of G2/M-phase cell cycle arrest. Cell cycle arrest was associated with downregulated CDK1 and miR-221 levels and upregulated levels of CDKN1B/p27, gamma-H2AX, phosphorylated ATM, phosphorylated Chk2 and phosphorylated p53. Our observations are consistent with a model in which alpha-pinene inhibits miR221 expression, which leads to G2/M phase arrest and activation of CDKN1B/p27-CDK1 and ATM-p53-Chk2 pathways that suppress human hepatoma tumor progression. Additionally, alpha-pinene was found to trigger oxidative stress and induce apoptosis of HepG2 cells. alpha-pinene therefore represents a potential chemotherapeutic compound for the treatment of HCC . PMID- 30473537 TI - Immediate and persistent antidepressant-like effects of Chaihu-jia-Longgu-Muli tang are associated with instantly upregulated BDNF in the hippocampus of mice. AB - Conventional antidepressants have a disadvantage in delayed onset of efficacy. Here, we aimed to evaluate the rapid and persistent antidepressant-like action of a classic herbal medicine Chaihu-jia-Longgu-Muli decoction (CLM), the contribution of the constituent formula Xiaochaihu decoction (XchD), as well as the action of CLM with hippocampal brain-derived neurotrophic factor (BDNF) overtime. Following a single dose of CLM, tail suspension test (TST), forced swim test (FST) and novelty-suppressed feeding test (NSF) were performed, by which XchD and its interaction with Longgu-Muli or remaining parts of CLM was also examined. BDNF expression in the hippocampus was examined at 30 minutes and 24 hours post a single CLM. A single administration of half of clinic dose of CLM elicited antidepressant effects in TST 30 minutes post-administration, and lasted for 72 hours. Furthermore, CLM also reduced the latency to eat in NSF. A single proportional dose of XchD induced antidepressant effect at 30 minutes and lasted for 48 hours. The effect lasted for 72 hours when combined with either Longgu Muli or the remaining parts of CLM. BDNF expression increased at 30 minutes and persisted at least for 24 hours after a single dose of CLM. PMID- 30473538 TI - Elevated Notch1 enhances interleukin-22 production by CD4+ T cells via aryl hydrocarbon receptor in patients with lung adenocarcinoma. AB - Notch signaling induced interleukin (IL)-22 secretion by CD4+ T cells via retinoid-related orphan nuclear receptor gammat (RORgammat) or aryl hydrocarbon receptor (AhR). Previous studies have demonstrated that Notch-AhR-IL-22 axis took part in the pathogenesis of chronic viral infection, however, its role in cancer have not been fully elucidated. Thus, the aim of current study was to investigate the involvement of Notch-AhR-IL-22 axis in the pathogenesis of lung adenocarcinoma. A total of thirty-seven late-stage lung adenocarcinoma patients and seventeen healthy individuals were enrolled. CD4+ T cells were purified from peripheral bloods and bronchoalveolar lavage fluids (BALF), and were stimulated with gamma-secretase inhibitor (GSI). mRNA corresponding to Notch receptors and transcriptional factors were measured by real-time PCR. IL-22 concentration was investigated by ELISA. The bioactivity (including cellular proliferation, cell cycle, apoptosis, and invasion) of lung adenocarcinoma cell line A549 cells was also assessed in response to recombinant IL-22 stimulation in vitro Notch1 mRNA expression was significantly elevated in CD4+ T cells purified from peripheral bloods and tumor site BALF in lung adenocarcinoma patients. IL-22 expression and RORgammat/AhR mRNA in BALF was also remarkably increased in tumor site. Inhibition of Notch signaling by GSI did not affect cellular proliferation, but reduced IL-22 production in CD4+ T cells from BALF, along with downregulation of AhR, but not RORgammat. Moreover, IL-22 stimulation promoted A549 cells invasion. The current data indicated elevated Notch1 induced higher IL-22 secretion by CD4+ T cells in lung adenocarcinoma patients, and Notch-AhR-IL-22 axis took part in the pathogenesis of lung adenocarcinoma. PMID- 30473539 TI - TIMP-1 inhibits proliferation and osteogenic differentiation of hBMSCs through Wnt/beta-catenin signaling. AB - This study aimed to evaluate the effect of tissue inhibitor of metalloproteinase 1 (TIMP-1) on the proliferation and osteogenic differentiation potential of human bone marrow-derived MSCs (hBMSCs). hBMSCs with stable TIMP-1 overexpression or TIMP-1 knockdown were generated. Osteogenic differentiation was assessed by Alizarin Red S staining, alkaline phosphatase (ALP) activity and expression of specific markers. Compared to the vehicle controls, TIMP-1 knockdown significantly promoted the growth of hBMSCs. TIMP-1 knockdown up-regulated beta catenin and cyclin D1 proteins. During osteogenic differentiation, TIMP-1 knockdown elevated the deposition of calcium nodules, ALP activity and the mRNA levels of the osteogenic markers sex determining region Y-box 9 (Sox9), CCAAT enhancer-binding protein (C/EBP) and peroxisome proliferator-activated receptor gamma (PPARgamma). During osteogenic differentiation, TIMP-1 knockdown significantly enhanced the up-regulation of osteocalcin proteins. Meanwhile, TIMP 1 overexpression attenuated the Wnt/ activator Wnt3a-induced up-regulation cyclin D1 and Runt-related transcription factor 2 (RUNX-2) (during osteogenic differentiation) proteins, while TIMP-1 knockdown restored the inhibitor Dickkopf 1-induced inhibition effect on the expression of beta-catenin, cyclin D1, and RUNX-2. TIMP-1 plays a negative regulatory role in the proliferation and osteogenesis of hBMSCs, at least partially, through Wnt/beta-catenin signaling. PMID- 30473540 TI - Efficacy of liraglutide in treating type 2 diabetes mellitus complicated with non alcoholic fatty liver disease. AB - Type 2 diabetes mellitus (T2DM) complicated with non-alcoholic fatty liver disease (NAFLD) is difficult to treat. This study explored the efficacy of liraglutide in treating T2DM complicated with NAFLD. A total of 127 patients suffering from T2DM complicated with NAFLD were enrolled in this study, and randomly assigned to a Lira group (liraglutide injection: 0.6-1.2 mg/day, 12 weeks, n = 52) or a Met group (oral metformin: 1000-1500 mg/day, 12 weeks, n = 75). During the treatment phase, the values for fasting plasma glucose (FPG), 2 h plasma glucose (2hPG), glycated hemoglobin (HbA1c), Aspartate aminotransferase (AST)/alanine aminotransferase (ALT), and adiponectin (APN) decreased in both the Lira and Met groups, and the levels of Delta2hPG, DeltaAST/ALT, and DeltaAPN in the Lira group were significantly lower than those in the Met group. The values for total cholesterol (TC), triglycerides (TG), low-and high-density lipoproteins (LDL and HDL), ALT, AST, weight, body mass index (BMI), waist to hip ratio (WHR), and C-reactive protein were markedly increased in both groups, and levels of DeltaAST, DeltaALT, Deltaweight, DeltaBMI, DeltaWHR, and DeltaCRP in the Lira group were significantly higher than those in the Met group. An analysis of treatment efficacy showed that liraglutide was better than metformin in its ability to significantly decrease the ALT levels in patients with combined T2DM and NAFLD. Furthermore, liraglutide was more effective than metformin at ameliorating the severity of T2DM complicated with NAFLD, and produced its effects by alleviating liver inflammation and improving liver function. PMID- 30473541 TI - Understanding the full burden of drowning: a retrospective, cross-sectional analysis of fatal and non-fatal drowning in Australia. AB - OBJECTIVES: The epidemiology of fatal drowning is increasingly understood. By contrast, there is relatively little population-level research on non-fatal drowning. This study compares data on fatal and non-fatal drowning in Australia, identifying differences in outcomes to guide identification of the best practice in minimising the lethality of exposure to drowning. DESIGN: A subset of data on fatal unintentional drowning from the Royal Life Saving National Fatal Drowning Database was compared on a like-for-like basis to data on hospital separations sourced from the Australian Institute of Health and Welfare's National Hospital Morbidity Database for the 13-year period 1 July 2002 to 30 June 2015. A restrictive definition was applied to the fatal drowning data to estimate the effect of the more narrow inclusion criteria for the non-fatal data (International Classification of Diseases (ICD) codes W65-74 and first reported cause only). Incidence and ratios of fatal to non-fatal drowning with univariate and Chi2 analysis are reported and used to calculate case-fatality rates. SETTING: Australia, 1 July 2002 to 30 June 2015. PARTICIPANTS: Unintentional fatal drowning cases and cases of non-fatal drowning resulting in hospital separation. RESULTS: 2272 fatalities and 6158 hospital separations occurred during the study period, a ratio of 1:2.71. Children 0-4 years (1:7.63) and swimming pools (1:4.35) recorded high fatal to non-fatal ratios, whereas drownings among people aged 65-74 years (1:0.92), 75+ years (1:0.87) and incidents in natural waterways (1:0.94) were more likely to be fatal. CONCLUSIONS: This study highlights the extent of the drowning burden when non fatal incidents are considered, although coding limitations remain. Documenting the full burden of drowning is vital to ensuring that the issue is fully understood and its prevention adequately resourced. Further research examining the severity of non-fatal drowning cases requiring hospitalisation and tracking outcomes of those discharged will provide a more complete picture. PMID- 30473542 TI - How do palliative care doctors recognise imminently dying patients? A judgement analysis. AB - OBJECTIVES: To identify a group of palliative care doctors who perform well on a prognostic test and to understand how they make their survival predictions. DESIGN: Prospective observational study and two cross-sectional online studies. SETTING: Phase I: an online prognostic test, developed from a prospective observational study of patients referred to palliative care. Phase II: an online judgement task consisting of 50 hypothetical vignettes. PARTICIPANTS: All members of the Association of Palliative Medicine (APM) were eligible (n=~1100). 99 doctors completed the prognostic test and were included in the phase I analysis. The top 20% were invited to participate in phase II; 14/19 doctors completed the judgement task and were included in the phase II analysis. MEASURES: Phase I: participants were asked to give a probability of death within 72 hours (0%-100%) for all 20 cases. Accuracy on the prognostic test was measured with the Brier score which was used to identify the 'expert' group (scale range: 0 (expert)-1 (non-expert)). Phase II: participants gave a probability of death within 72 hours (0%-100%). A mixed model regression analysis was completed using the percentage estimate as the outcome and the patient information included in the vignettes as the predictors. RESULTS: The mean Brier score of all participants was 0.237 (95% CI 0.235 to 0.239). The mean Brier score of the 'experts' was 0.184 (95% CI 0.176 to 0.192). Six of the seven prognostic variables included in the hypothetical vignettes were significantly associated with clinician predictions of death. The Palliative Performance Score was identified as being the most influential in the doctors' prognostic decision making (beta=0.48, p<0.001). CONCLUSIONS: This study identified six clinical signs and symptoms which influenced the judgement policies of palliative care doctors. These results may be used to teach novice doctors how to improve their prognostic skills. PMID- 30473544 TI - Plasma proteome correlates of lipid and lipoprotein: Biomarkers of metabolic diversity and inflammation in children of rural Nepal. AB - Proteins involved in lipoprotein metabolism can modulate cardiovascular health. While often measured to assess adult metabolic diseases, little is known about the proteomes of lipoproteins and their relation to metabolic dysregulation and underlying inflammation in undernourished child populations. The objective of this population study was to globally characterize plasma proteins systemically associated with HDL, LDL and triglycerides in 500 Nepalese children. Abnormal lipid profiles characterized by elevated plasma triglycerides and low HDL cholesterol concentrations were common especially in children with subclinical inflammation. Among 982 proteins analyzed, relative abundance of 11, 12 and 52 plasma proteins were correlated with LDL-cholesterol (r=-0.43~0.70), triglycerides (r=-0.39~0.53) and HDL-cholesterol (r=-0.49~0.79) concentrations, respectively. These proteins included apolipoproteins and numerous unexpected intracellular and extracellular matrix binding proteins, likely originating in hepatic and peripheral tissues. Relative abundance of two-thirds of the HDL proteome varied with inflammation, with acute phase reactants higher by 4~40% and proteins involved in HDL biosynthesis, cholesterol efflux, vitamin transport, angiogenesis and tissue repair lower by 3~20%. Untargeted plasma proteomics detects comprehensive sets of both known and novel lipoprotein-associated proteins likely reflecting systemic regulation of lipoprotein metabolism and vascular homeostasis. Inflammation-altered distributions of the HDL proteome may be predisposing undernourished populations to early chronic disease. PMID- 30473543 TI - Medical device industry: international investigation exposes lax regulation. PMID- 30473545 TI - Community Social Capital and Depressive Symptoms Among Older People in Japan: A Multilevel Longitudinal Study. AB - BACKGROUND: This study aimed to examine the contextual effects of community-level social capital on the onset of depressive symptoms using a longitudinal study design. METHODS: We used questionnaire data from the 2010 and 2013 waves of the Japan Gerontological Evaluation Study that included 14,465 men and 14,600 women aged over 65 years from 295 communities. We also used data of a three-wave panel (2006-2010-2013) to test the robustness of the findings (n = 7,424). Using sex stratified multilevel logistic regression, we investigated the lagged associations between three scales of baseline community social capital and the development of depressive symptoms. RESULTS: Community civic participation was inversely associated with the onset of depressive symptoms (men: adjusted odds ratio [AOR] 0.93; 95% confidence interval [CI], 0.88-0.99 and women: AOR 0.94; 95% CI, 0.88-0.997 per 1 standard deviation unit change in the score), while no such association was found in relation to the other two scales on social cohesion and reciprocity. This association was attenuated by the adjustment of individual responses to the civic participation component. Individual-level scores corresponding to all three community social capital components were significantly associated with lower risks for depressive symptoms. The results using the three wave data set showed statistically less clear but similar associations. CONCLUSIONS: Promoting environment and services enhancing to community group participation might help mitigate the impact of late-life depression in an aging society. PMID- 30473546 TI - Premature mortality due to malignancies of the kidney and bladder in Japan, 1980 2010. AB - BACKGROUND: In the present study, we examined the trends of premature mortality due to kidney and bladder cancers among the Japanese population from 1980 through 2010. METHODS: Mortality data were obtained from the World Health Organization mortality database. Years of life lost (YLL) was estimated using Japanese life tables. Average lifespan shortened (ALSS) was calculated and defined as the ratio of years of life lost relative to the expected lifespan. RESULTS: Over the study period, the age-standardized rates to the World Standard Population for deaths from kidney and bladder cancers were stable. The average years of life lost (AYLL) measure shows decreases of about four and six years of life for kidney cancer in men and women respectively, and decreases of about two years of life for bladder cancer in both sexes. The ALSS shows that patients with kidney cancer lost 21.0% and 24.7% of their lifespan among men and women in 1980, whereas respective losses were 15.3% and 15.8% in 2010. Also, patients with bladder cancer on average lost 13.5% in men and 14.2% in women in 1980 and 10.8% in men and 11.1% in women in 2010. CONCLUSIONS: Our study shows favorable trends in premature mortality for kidney and bladder cancers in Japan over a 30-year period; however, patients with bladder cancer on average lost a smaller proportion of their lifespan compared to those with kidney cancer. The development of a novel ALSS measure is convenient in examination of the burden of premature mortality over time. PMID- 30473547 TI - A Case of Renal Oncocytoma with Renal Venous Tumor Thrombus. AB - Renal oncocytoma is generally regarded as a benign renal tumor. We herein report a case of large renal oncocytoma with renal venous tumor thrombus. The patient may need to be carefully followed up because hematogenous metastasis may occur. PMID- 30473548 TI - Age-associated changes in DNA methylation and expression of the TNFalpha gene in pigs. AB - DNA methylation is an important mediator of gene expression regulation and has been shown to be closely linked to aging. Immune-related genes tend to be influenced by DNA methylation at different ages. To explore DNA methylation changes in the porcine TNFalpha gene and analyze their potential effects on gene expression, we measured the methylation level of the TNFalpha promoter and TNFalpha mRNA expression in the spleen of Meishan piglets at six developmental stages (1, 7, 14, 21, 28 and 35 days old) by bisulfite sequencing PCR and quantitative PCR. The results revealed a trend for TNFalpha promoter methylation level to increase and mRNA expression to decrease with age. Correlation analysis showed a significant negative association between methylation level and mRNA expression (Pearson's r = -0.775, P = 4.87E-07). In addition, the transcription factor Sp1 was revealed to bind with the TNFalpha promoter and regulate TNFalpha expression. DNA methylation in the TNFalpha promoter was found to decrease the promoter's activity, and methylation inhibition could enhance the expression level of TNFalpha, providing functional evidence that promoter methylation controls TNFalpha expression. Together, our data provide insights into age associated changes in promoter methylation of the TNFalpha gene in the spleen and contribute to our understanding of regulatory mechanisms for TNFalpha expression in the immune system of pigs. PMID- 30473549 TI - Determinants Strengthening Japanese Nurses' Intention to Stay at Their Current Hospital. AB - In order to retain nursing staff, it is crucial to have a comprehensive understanding of the factors that motivate nurses to stay at an institution. Toward this aim, we identified a variety of factors that strengthen nurses' intention to stay at their current hospital. A cross-sectional questionnaire survey was conducted at 12 hospitals in the Tohoku and Kanto regions of Japan. Of the 1,034 nurses working in those hospitals, 713 returned the questionnaire (response rate: 69.0%). Of these, we analysed the data of 485 nurses (17.42 +/- 9.83 years of clinical experience, 95.3% female) (valid response rate: 46.9%) who met the inclusion criteria of planning to stay at their current hospital and completing all questionnaire items. An exploratory factor analysis indicated that variables strengthening intention to stay at the current hospital could be grouped into five factors: "comfortable workplace environment," "passive motivational factors," "convenience of hospital location," "favorable work-life balance," and "fulfilment in nursing." Nurses who were married or had children placed a higher priority on a "favorable work-life balance" in remaining at their current workplace. Regular employees or nurses working in the smaller cities tended to display higher "passive motivational factors," which comprised various extrinsic factors. Though extrinsic factors are considered to make only short term contributions to employee retention, they could generate positive synergistic effects when combined with intrinsic motivations such as "fulfilment in nursing." Effective nurse-retention strategies should be developed by capitalizing on the interaction among the five factors that strengthen nurses to stay at their current hospital. PMID- 30473550 TI - China issues the National Essential Medicines List (2018 edition): Background, differences from previous editions, and potential issues. AB - On October 25, 2018, the National Health Commission of China issued the National Essential Medicines List (2018 edition) [NEML (2018)]. The NEML (2018) contains 685 drugs, which consist of 417 chemicals and biological products and 268 Chinese patent medicines. Compared to the 2012 version of the NEML, a total number of 165 drugs were added, representing an increase of 31.7%. The biggest increase (90.9%) is in Chinese patent medicines for surgical use. The NEML (2018) set up the category of pediatric medications for the first time, and 11 cancer drugs were added. The NEML (2018) is characterized by: "basic" to "comprehensive" coverage, it includes both Chinese and Western medicines, it now includes pediatric drugs, and more cancer drugs have been added. There are several issues with the new NEML such as the link between the essential medicines system and the medical insurance system and establishment of firm support for implementation. PMID- 30473551 TI - Forecasting hand, foot, and mouth disease in Shenzhen based on daily level clinical data and multiple environmental factors. AB - Hand, foot, and mouth disease (HFMD) is caused by a group of enteroviruses. It infects millions of children in the Southeast Asian area. An accurate forecasting of outbreaks of HFMD could facilitate public health officials to suggest public health actions earlier. Many researchers tried to develop an early warning system for HFMD to lower the damage caused by a HFMD outbreak. The research data based on daily level could help figure out the relationship between HFMD and environmental factors, but nevertheless is difficult to collect. In this study, we collected the daily clinical data from the Shenzhen Health Information Center and multiple environmental factors to analyze the outbreaks of HFMD. Considering the incubation period of HFMD, we fed the previous 60 days' HFMD rates, 7 days' temperature factors and 7 days' air-quality factors into the tree model, XGBoost. The following conclusions were drawn in this study: i) Compared with the model only using the previous HFMD rate and temperature factors, the addition of the air-quality factors could make the model better, improving MAE nearly 16.7%. ii) By analyzing the Pearson correlation, we found that the temperature showed a positive correlation and the air quality showed a negative correlation for the HFMD outbreaks. Improving the air quality, especially decreasing PM2.5 and PM10 could decrease the risk of HFMD outbreaks. PMID- 30473552 TI - Differential expression of APE1 in hepatocellular carcinoma and the effects on proliferation and apoptosis of cancer cells. AB - This research aimed to investigate the differential expression of apurinic apyrimidinic endonuclease 1 (APE1) in hepatocellular carcinoma (HCC) tissues and cells and the effects on proliferation and apoptosis of cancer cells. Immunohistochemical techniques were used to detect the expression of APE1 in 80 cases of HCC and the corresponding paracancerous tissue microarrays; meanwhile, Western blots were used to detect the expression of APE1 in both human HCC BEL 7402, BEL-7405, HCC-9204, Hep3B, HepG2, SMMC-7721 and Huh-7 cells, and normal hepatocyte L-02 cells. The relationship between APE1 expression and clinical pathological characteristics of HCC was statistically analyzed. APE1 shRNA vector was constructed in Hep 3B cells to establish a stably transfected cell line, using Western blots to determine the interference efficiency. Cell proliferation activity was detected with MTT assays, while apoptosis was detected with the Annexin V-FITC/PI double-labeling technique. The expression of APE1 in HCC tissues and cells was significantly up-regulated, and its expression was significantly different from TNM staging and histopathological grading. Down regulation of APE1 expression significantly reduced the proliferative activity and increased the apoptosis rate of Hep 3B cells. In conclusion, APE1 demonstrates cancer progression potential at the clinical, tissue and cell level. It provides a new idea and theoretical basis for APE1-based clinical diagnosis, prognosis determination and molecular targeted therapy in treatment of HCC. PMID- 30473554 TI - A novel compound heterozygous mutation in the GJB2 gene is associated with non syndromic hearing loss in a Chinese family. AB - Autosomal recessive (AR) non-syndromic hearing loss (NSHL) is the most common form of hereditary deafness. Mutations in the gap junction protein beta 2 (GJB2) gene encoding connexin 26 (Cx26) account for about 50% of cases of ARNSHL. In the current study, a combination of exome sequencing and Sanger sequencing in a Chinese Dong family with ARNSHL allowed identification of a novel compound heterozygous mutation c.240G>C(p. Q80H)/C.109G>A(p.V37I) in exon 2 of the GJB2 gene, which co-segregated with the disease phenotype in this family and was not evident in 100 healthy controls. Bioinformatic analysis revealed that the two mutations in the GJB2 gene were probably pathogenic. Results indicated that the compound heterozygous variants, p.Q80H and p.V37I, in the GJB2 gene are associated with ARNSHL. The Q80H variant was initially identified in patients of Dong Chinese origin with NSHL. The current results broaden the spectrum of GJB2 mutations responsible for NSHL and have important implications for molecular diagnosis, treatment, and genetic counseling for this family. PMID- 30473553 TI - The pregnancy outcomes of intrauterine insemination with husband's sperm in natural cycles versus ovulation stimulated cycles: A retrospective study. AB - To compare the clinical outcomes of intrauterine insemination (IUI) with or without ovulation induction (OI), IUI cycles from January 2008 to December 2017 in Zhoushan Maternity and Child Healthcare Hospital were included, consisting of 455 natural cycles and 536 OI cycles. The overall clinical pregnancy rate did not differ between the two groups (P > 0.05). Stratified by OI medications such as clomiphene (CC), human menopausal gonadotropin (HMG) and follicle stimulating hormone (FSH), the pregnancy rates in HMG, CC, CC+HMG, and FSH/FSH+HMG groups were 11.70%, 13.58%, 15.95%, and 13.46%, respectively, but the difference was not significant compared with natural cycles (P > 0.05). Stratified by infertility etiology, the pregnancy rate was significantly higher in stimulated cycles than natural cycles with ovulation disorders (P < 0.01) and unexplained factors (P < 0.01) while it was significantly lower regarding cervical factors (P < 0.01), endometriosis (P < 0.05), male factor (P < 0.01) and other female factors. There was no strong difference of pregnancy rate for biparental causes (P > 0.05). Stratified by age category, women over 35 had higher pregnancy rate in stimulated cycles compared with natural cycles (18.75 vs. 12.24%; P < 0.05), while women under 35 had no significant difference of pregnancy rate between the two groups (13.65 vs 13.05%; P > 0.05). However, there was no significant difference between each ovarian stimulation group and natural cycle group regardless of the infertility causes or age categories. To conclude, IUI-OI could achieve a higher overall pregnancy rate for women over 35 and infertile patients with ovulation disorders and unexplained factors. PMID- 30473555 TI - Impact of three-dimensional visualization technology on surgical strategies in complex hepatic cancer. AB - Surgical resection is still the mainstay of treatment for primary liver cancer (PLC). It is unclear whether three-dimensional visualization (3DV) preoperative evaluation and simulated liver resection would affect the surgical strategies and improve the R0 resection rates of patients with complex PLC when compared with the 2D evaluation using computed tomography or magnetic resonance imaging. In the study, patients with complex PLC who were subjected to laparotomy underwent both 2D and 3DV evaluation before operation. A comparison between the 2D and 3DV evaluation was compared with the gold standard of laparotomy findings. In this study, of 335 patients with complex PLC, 71 were assessed to have resectable tumors. 2D and 3DV assessments determined 63 and 71 patients to have resectable PLC, respectively. At laparotomy 69 of the 71 patients were found to have resectable PLC, but 2 patients were found to be unresectable because of detection of metastatic lesions on laparotomy, which were not detected either by 2D or 3DV preoperative evaluation. The accuracy, false positive and false negative rates of the 2D and the 3DV preoperative assessments in determining tumor resectability were 85.9%, 2.8%, 11.3%, and 97.2% (p < 0.05), 2.8%, 0%, respectively. The 3DV and 2D preoperative evaluation revealed 17 and 13 patients with vascular anomalies, respectively. There were 4 patients with major vascular anomalies not detected by 2D evaluation, whose surgical strategies were modified by 3DV evaluation. These results suggested 3DV preoperative assessment could lead to better in evaluating tumor resectability, with potential benefit in the modification of surgical strategy for patients with complex PLC. PMID- 30473556 TI - Total laparoscopic versus robot-assisted laparoscopic pancreaticoduodenectomy. AB - In this study, the clinical effectiveness of the robot-assisted laparoscopic pancreatico-duodenectomy (RPD) and Total laparoscopic pancreaticoduodenectomy LPD were retrospectively reviewed. From December 2013 to September 2017, 20 patients underwent robot-assisted laparoscopic pancreaticoduodenectomy and 80 patients underwent Total laparoscopic pancreaticoduodenectomy. The clinical data of the RPDs and the first 20 LPDs were reviewed retrospectively. There is no difference in operative time, estimated blood loss, length of stay, and rates of complications and mortality between the LPD and RPD group. The next 10 cases in the RPD group had shorter operative times (p = 0.03) than the first 10 cases. The estimated blood loss and length of stay were also lower in the next 10 cases; however, these results did not reach statistical significance. Our results show that LPD and RPD are technically safe and feasible. Comparable results were demonstrated between the two groups, while the robotic system seemed to shorten the learning curve of minimally invasive pancreaticoduodenectomy (PD). PMID- 30473557 TI - Bao Yuan decoction and Tao Hong Si Wu decoction improve lung structural remodeling in a rat model of myocardial infarction: Possible involvement of suppression of inflammation and fibrosis and regulation of the TGF-beta1/Smad3 and NF-kappaB pathways. AB - Chronic heart failure (CHF) leads to pulmonary structural remodeling, which may be a key factor for poor clinical outcomes in patients with end-stage heart failure, and few effective therapeutic options are presently available. The aim of the current study was to explore the mechanism of action and pulmonary protective effects of treatment with Bao Yuan decoction combined with Tao Hong Si Wu decoction (BYTH) on lung structural remodeling in rats with ischemic heart failure. In a model of myocardial infarction (MI) induced by ligation of the left anterior descending (LAD) artery, rats were treated with BYTH. Heart function and morphometry were measured followed by echocardiography, histological staining, and immunohistochemical analysis of lung sections. The levels of transforming growth factor-beta1 (TGF-beta1), type I collagen, phosphorylated-Smad3 (p-Smad3), tumor necrosis factor-alpha (TNF-alpha), toll-like receptor 4 (TLR4), active nuclear factor kappaB (NF-kappaB) and alpha smooth muscle actin (alpha-SMA) were detected using Western blotting. Lung weight increased after an infarct with no evidence of pulmonary edema and returned to normal as a result of BYTH. In addition, BYTH treatment reduced levels of type I collagen, TGF-beta1, and alpha SMA expression and decreased the phosphorylation of Smad3 in the lungs of rats after MI. BYTH treatment also reduced the elevated levels of lung inflammatory mediators such as TNF-alpha, TLR4, and NF-kappaB. Results suggested that BYTH could effectively improve lung structural remodeling after MI because of its anti inflammatory and anti-fibrotic action, which may be mediated by suppression of the TGF-beta1/Smad3 and NF-kappaB signaling pathways. PMID- 30473558 TI - Novel compound heterozygous mutations in SLC26A4 gene in a Chinese family with enlarged vestibular aqueduct. AB - In order to investigate the genetic causes of hearing loss in a Chinese proband with nonsyndromic hearing loss and enlarged vestibular aqueduct (EVA), we conducted clinical and genetic evaluations in a deaf proband and her parents with normal hearing. 20 exons and flanking splice sites of the SLC26A4 gene were screened for pathogenic mutations by PCR amplification and bidirectional sequencing. As a control, a group of 400 healthy newborns from the same ethnic background were subjected to SLC26A4 gene screening using the same method. The proband harbored two mutations in the SLC26A4 gene in the form of compound heterozygosity. She was found to be heterozygous for a novel mutation c.574delC (p.Leu192Ter) in exon 5 and for the known mutation c.919-2A>G(c.IVS7-2A>G). Her mother was a heterozygous carrier of the c.919-2A>G mutation, and her father was a heterozygous carrier of the c.574delC and therefore co-segregated with the genetic disease. The c.574delC mutation was absent in 400 healthy newborns. The frameshift mutation causes the leucine (Leu) at amino acid position 192 to become a termination codon, leading to termination of protein sequence coding. This study demonstrates that the novel frameshift mutation c.574delC (p.Leu192Ter) in compound heterozygosity with c.919-2A>G in the SLC26A4 gene is the main cause of deafness in a family. Our study will expand the spectrum of known SLC26A4 mutations in the Chinese population, providing more information on genetic counseling, and diagnosis in hearing loss with EVA. PMID- 30473559 TI - HIV/AIDS responses in China should focus on the impact of global integration. AB - China has made substantial progress in tackling its Human immunodeficiency virus (HIV) epidemic, however, the number of people living with HIV / acquired immunodeficiency syndrome (AIDS) continues to increase, with the number of all cause deaths rising. There are a total 75.6 million people living with HIV and 2.39 million people newly infected with HIV as of December 31, 2017 in China. Besides, while the number of new HIV infections continued to decline in 2017 globally, the data from Chinese Center for Disease Control and Prevention (CCDC) show steady increases in new HIV infections in China. The compound annual growth rate (CAGR) of new HIV infections in China from 2012 to 2017 was 10.29%, and the CAGR of AIDS-related deaths was 5.92%. Moreover, there was a sudden increase in new HIV infections in China from January 2018, showing the compound monthly growth rate (CMGR) of 2018 increased by 9.92% compared to 2017. Given the advance of globalization, it is increasingly important to focus on the impact of global integration for HIV/AIDS responses, facing the increasing challenge of key affected populations such as men who have sex with men (MSM), young people and older people. Certainly, comprehensive strategies for prevention, drug treatment, and even functional cure will also be crucial for curbing the HIV epidemic in China in the new era. PMID- 30473560 TI - Considerations on PCR-based methods for malaria diagnosis in China malaria diagnosis reference laboratory network. AB - Precise diagnosis is a key measurement for malaria control and elimination, traditional microscopy and rapid diagnostic tests cannot satisfy the requirements especially in the low transmission endemic areas or in the malaria elimination phase. Polymerase chain reaction (PCR) with high sensitivity and specificity can be considered as a diagnostic standard while no uniform PCR assay was established due to variations in their performance and lack of formal external quality assurance programs for validation for PCR assays in use. Here, 24 articles including 43 paired comparative evaluations limited to paired comparison of diagnostic performance between real-time PCR and conventional PCR to detect plasmodium in blood samples of human subjects from clinics or the field are systematically summarized. And according to the Landis and Koch classification, nineteen pairs showed almost perfect agreement, followed by 8 pairs of moderate agreement and 4 pairs of good agreement, while the kappa values of 12 pairs couldn't be examined. Moreover, the performance of 14 pairs were completely the same and 8 pairs had no differences, but 14 pairs were significant different including 8 pairs of real-time PCR with better performance than conventional PCR. Therefore, it is still an outstanding issue to choose PCR methods, and more work such as the standardization of materials and methods in use and their availability are needed to settle priority to better promote the role of malaria diagnosis reference laboratories. PMID- 30473561 TI - The importance of non-tuberculous mycobacteria identification in Chinese patients infected with HIV. AB - The increased co-incidence of tuberculosis (TB) and AIDS is compounded by the emergence of opportunistic infections with non-tuberculous mycobacteria (NTM) in patients with HIV/AIDS, and the treatment for these infections differs from that for TB. The high frequency of NTM strains found in patients infected with HIV raises concerns about accurate species identification before deciding proper treatment. A total of 101 isolates from 2014, 137 from 2015, and 162 from 2016 were subjected to 16S rDNA sequencing to identify the species. Forty-one (41/101, 40.6%) were identified as NTM in 2014, 64 (64/137, 46.7%) were identified as NTM in 2015, and 72 (72/162, 44.4%) were identified as NTM in 2016 in Chinese patients infected with HIV. The species of Mycobacteria isolates needs to be rapidly and accurately identified to determine appropriate antibiotic therapy, and this is especially true for patients infected with HIV. PMID- 30473562 TI - Correlation between the use of antibiotics and development of a resistant bacterial infection in patients in the ICU. AB - The current study analyzed the correlation between the use of antibiotics and development of a resistant bacterial infection in 454 patients in intensive care units (ICUs), and this study also examined factors related to development of an infection in order to facilitate more rational use of antibiotics and to reduce the incidence of resistant bacterial infections. Potential subjects were patients who were admitted to the ICU in 2016, and 454 such patients were selected using cluster sampling. Patient information was documented using an original questionnaire, Patients in the ICU with a Resistant Bacterial Infection. The correlation between use of an antibiotic and development of a resistant bacterial infection was examined. The rate of infection significantly increased over time and with receipt of various antibiotics. The development of a resistant bacterial infection was found to correlate with the use of antibiotics. Antibiotics should be used more carefully to reduce the incidence of resistant bacterial infections. PMID- 30473563 TI - The relation between social cohesion and the care burden of family healthcare providers. AB - This study aimed to clarify the relationship between social cohesion and family care burden. The social capital indicators of Kondo et al. and the short version of the Zarit Care Burden Interview Scale in Japanese (J-ZBI_8) were used. Data were analyzed by multiple regression models. Seventy-one caregivers responded. Factors showing statistical significance in the multiple regression analysis included "receipt of emotional support" (p = 0.009) and "instrumental support provided" (p = 0.010). Social support was suggested to have a possible effect on the care burden of the main caregivers to relate to less burden. The gap between the original ideal loss and the social role caused by providing nursing care is likely to increase the degree of care burden. PMID- 30473564 TI - Prescription surveillance for early detection system of emerging and reemerging infectious disease outbreaks. AB - Based on prescriptions filled at external pharmacies, prescription surveillance (PS) in Japan has been reporting the estimated numbers of influenza and varicella patients and people prescribed certain drugs since 2009. Every morning, this system estimates the numbers of patients from the numbers of prescriptions filled nationwide for neuraminidase inhibitors, anti-herpes virus drugs, antibiotic drugs, antipyretic analgesics, and multi-ingredient cold medications. Moreover, it can detect "unexplained" infectious diseases that are not explained as infectious diseases monitored by other surveillance systems. Such "unexplained" infectious diseases might be emerging and re-emerging infectious diseases including bioterrorism attacks, which are reportedly difficult to diagnose, at least in early outbreak stages. To ascertain the system's potential benefits, this study examined schemes to detect "unexplained" infectious diseases using PS information. The numbers of patients prescribed the respective drugs are first regressed on the known infectious diseases, time trends, and dummies for day-of the-week, holidays, and days following a holiday. Known infectious diseases are defined as covered by the National Official Sentinel Surveillance for Infectious Diseases under the Infection Control Law. After the numbers of patients from PS are compared with the predicted numbers of patients, their probabilities of occurrence are calculated. We examined the system's prospective operation from January 2017 through July 2018. The criterion we used to define aberrations varied, from 0.01 to 10-7. For criteria of 0.01 and 10-7 we found 254 and 15 aberrations, respectively. We confirmed its feasibility and effectiveness. PMID- 30473565 TI - Nitrogenase Activity in Thermophilic Chemolithoautotrophic Bacteria in the Phylum Aquificae Isolated under Nitrogen-Fixing Conditions from Nakabusa Hot Springs. AB - The phylum Aquificae comprises chemolithoautotrophic thermophilic to hyperthermophilic bacteria, in which the nitrogenase reductase gene (nifH) has been reported. However, nitrogen-fixing activity has not yet been demonstrated in members of this deeply branching bacterial phylum. We isolated two thermophilic diazotrophic strains from chemosynthetic microbial communities in slightly alkaline hot springs (>=70 degrees C) in Nakabusa, Nagano Prefecture, Japan. A phylogenetic analysis based on 16S rRNA genes identified these strains as members of the genus Hydrogenobacter within Aquificae. Their NifH sequences showed 96.5 and 97.4% amino acid sequence identities to that from Hydrogenobacter thermophilus TK-6. Nitrogenase activity, measured by acetylene reduction, was confirmed in both strains at 70 degrees C. These novel strains grew under semi aerobic conditions by using CO2 as the sole carbon source and N2 as the sole nitrogen source in media containing hydrogen and/or thiosulfate. To the best of our knowledge, this is the first demonstration of active nitrogen fixation in thermophilic bacteria at 70 degrees C and in the phylum Aquificae. PMID- 30473566 TI - Cyanobacterial Catalase Activity Prevents Oxidative Stress Induced by Pseudomonas fluorescens DUS1-27 from Inhibiting Brassica napus L. (canola) Growth. AB - Plant growth-promoting bacteria (PGPB) inhabit the rhizosphere of plants and are capable of enhancing plant growth through a number of mechanisms. A strain of Pseudomonas fluorescens DUS1-27 was identified as a potential PGPB candidate based on its ability to increase the growth of Brassica napus L. (canola) over that of uninoculated control plants in a soil-based system. The same P. fluorescens isolate was found to reduce plant growth in a hydroponic growth system, with plants showing the symptoms of a microbe-associated molecular pattern (MAMP) response to the bacteria. The amperometric quantification of H2O2, fluorescence-based total peroxidase assays, and quantification of catalase gene expression levels using qRT-PCR revealed that oxidative stress reduced plant growth in the hydroponic system. The addition of the cyanobacterium Nostoc punctiforme (known to have high catalase activity levels) in the hydroponic system as a co-inoculant reduced oxidative stress (49.7% decrease in H2O2 concentrations) triggered by the addition of P. fluorescens DUS1-27, thereby enabling plants to grow larger than uninoculated control plants. These results show the advantage of inoculating with multiple bacteria to promote plant growth and, for the first time, demonstrate that N. punctiforme beneficially assists plants under oxidative stress through its catalase activity in planta. PMID- 30473567 TI - Influence of culture conditions on cell proliferation in a microfluidic channel. PMID- 30473568 TI - Electrochemical biosensing system for single cells, cellular aggregates and microenvironments. PMID- 30473569 TI - Cardiac Function and Type of Mitral Valve Surgery Affect Postoperative Blood Flow Pattern in the Left Ventricle. AB - BACKGROUND: To determine the impact of cardiac function and type of mitral valve (MV) surgery on blood flow and energy loss in the left ventricle (LV). Methods and Results: This study enrolled patients with ejection fraction (EF) <35% or >50%; both groups had native (n=27 and n=16), repaired (n=19 and n=33), or prosthetic MVs (n=18 and n=19). They were examined by echocardiography-based vector flow mapping to assess the LV blood flow pattern and energy loss per heartbeat. Among patients with preserved EF, those with native MVs displayed a clockwise vortex and relatively low energy loss. In contrast, MV replacement induced a counterclockwise vortex producing higher energy loss than MV repair, which induced a normal clockwise vortex. This indicated the need for MV repair to minimize LV energy loss after surgery. Among the patients with reduced EF, those with native MVs showed a blood flow pattern similar to those with preserved EF and native MVs; furthermore, those with repaired MVs and half of the patients with prosthetic MVs displayed a clockwise vortex, resulting in no difference in energy loss between the 2 types of MV surgery. CONCLUSIONS: Cardiac function and the type of MV surgery are factors affecting the postoperative LV blood flow pattern. MV replacement resulted in abnormal blood flow with normal cardiac function, whereas advanced cardiomyopathy modified the blood flow pattern post-MV replacement. PMID- 30473570 TI - Distribution of calretinin immunopositive somata and fibers in the rabbit midcingulate cortex. AB - The midcingulate cortex (MCC; area 24') resides in the mid-rostrocaudal part of the cingulate gyrus, and it plays important roles in nociceptive, cognitive and skeletomotor functions. The MCC has recently been shown to consist of four cortical areas (areas a24a', a24b', p24a' and p24b') in the rabbit, based on immunohistochemistry. To further characterize the organization of these areas, here we immunohistochemically identified structures immunopositive (+) for calretinin (CR) as a marker of a subpopulation of inhibitory neurons. CR+ somata were identified as multipolar and bipolar neurons. The multipolar neurons were predominant throughout the MCC. CR+ somata were present mainly in layer (L) 2/3 and L6, and CR+ fibers occurred mainly in L1, L2/3 and L6. However, there were differences in the distribution of CR+ structures in each area. CR+ somata tended to be most densely distributed in area a24a', followed by area p24a', area a24b' and area p24b'. CR+ fibers were most densely distributed in area p24a', followed by area p24b', area a24a' and area a24b'. In addition, only areas p24a' and p24b' enclosed patchy CR+ fibers and terminals in deep L2/3. These results show the distinct distribution of CR+ structures in each area of the MCC in the rabbit, suggesting that CR+ neurons may contribute to information processing for cognitive functions in somewhat different manners in each area of the MCC. PMID- 30473571 TI - Detection of anti-viral antibodies from meat juice of wild boars. AB - Wild boars are a reservoir for many zoonotic pathogens and a good sentinel for surveillance of zoonotic viral infections, but collection of serum samples from wild boars in the field is sometimes difficult and requires special equipment and techniques. In this study, ELISA using meat juices extracted from the heart and diaphragm of wild boars, instead of serum samples, was performed to detect antibodies against zoonotic pathogens, Japanese encephalitis virus and hepatitis E virus. The results of ELISA using meat juice samples were significantly correlated with those using serum samples and meat juice contained one-fifth the antibodies of serum samples. As meat juice is easily collected from wild animals in the field without special equipment and techniques, ELISA using meat juice is a simple and superior method for serological survey of zoonosis among wild animals. PMID- 30473572 TI - Mycobacterial infection induces eosinophilia and production of alpha-defensin by eosinophils in mice. AB - It has been well known in humans that eosinophil infiltration into the site of inflammation and eosinophilia occur in mycobacterial infections. However, the role of eosinophils against the mycobacterium is unclear. We showed in previous study that in situ mouse eosinophils infiltrated into tissues produce alpha defensin, an anti-bacterial peptide. We investigated in this study whether eosinophils reacting to mycobacteria produce alpha-defensin in mice and whether it can be used as a model. We showed that mycobacterial infection induced blood eosinophilia and infiltration of alpha-defensin producing eosinophils that to surround mycobacteria at the site of infection. These findings were usually seen during human mycobacterial infection. We established a good model to study host defense mechanism against mycobacteria through alpha-defensin via eosinophils. PMID- 30473573 TI - Abscisic acid-mediated developmental flexibility of stigmatic papillae in response to ambient humidity in Arabidopsis thaliana. AB - Stigmatic papillae develop at the apex of the gynoecium and play an important role as a site of pollination. The papillae in Brassicaceae are of the dry and unicellular type, and more than 15,000 genes are expressed in the papillae; however, the molecular and physiological mechanisms of their development remain unknown. We found that the papillae in Arabidopsis thaliana change their length in response to altered ambient humidity: papillae of flowers incubated under high humidity elongated more than those under normal humidity conditions. Genetic analysis and transcriptome data suggest that an abscisic acid-mediated abiotic stress response mechanism regulates papilla length. Our data suggest a flexible regulation of papilla elongation at the post-anthesis stage, in response to abiotic stress, as an adaptation to environmental conditions. PMID- 30473574 TI - CORRIGENDUM: Amniotic Fluid Natriuretic Peptide Levels in Fetuses With Congenital Heart Defects or Arrhythmias. PMID- 30473577 TI - X monosomy in the endangered Kiso horse breed detected by a parentage test using sex chromosome linked genes and microsatellites. AB - A routine parentage test as part of a conservation program for Kiso horses identified a possible sex chromosome anomaly in a 7 months-old filly because of an aberrant result using LEX3, an X-linked marker. We then analyzed X-linked markers (LEX26, TKY38, and TKY270), Y-linked markers (Eca.YH12, Eca.YM2, Eca.YA16, and the sex-determining region Y gene), and an X/Y marker (Amelogenin gene). This analysis demonstrated that the filly had not inherited an X chromosome from her sire. A karyotyping analysis confirmed that the filly was 63,XO. As it was suspected that the horse would be sterile, we avoided using the horse as a broodmare; the information should also serve to prevent unnecessary conflict between owners transferring and receiving the horse. PMID- 30473578 TI - Risk factors associated with reproductive performance in Japanese dairy cows: vaginal discharge with flecks of pus or calving abnormality extend time to pregnancy. AB - The present study aimed to determine possible risk factors affecting reproductive performance, especially time taken to establish pregnancy in dairy cows, using Cox's proportional hazard model. The data were collected from 154 Holstein Friesian cows (199 lactations). Cows diagnosed with a vaginal discharge score (VDS) of one or calving abnormality showed significantly delayed pregnancy: hazard ratio (HR)=0.654 (95% confidence interval [CI]: 0.436-0.983; P=0.041) and HR=0.457 (95% CI: 0.270-0.774; P=0.004), respectively. Our study suggested that the occurrence of VDS of one or calving abnormality might be possible risk factors increasing the number of days open and affecting reproductive performance in dairy cows. PMID- 30473579 TI - Application of intracytoplasmic sperm injection to the embryo production in aged cows. AB - Reduction in oocyte quality is a major factor responsible for declining fertility associated with maternal aging in cows. The objective of the present study was to determine whether intracytoplasmic sperm injection (ICSI) could increase the efficiency of embryo production in older cows. We used cows aged 30 to 50 months or >120 months, which were defined as young or aged, respectively. The distribution of cortical granules in oocytes was affected by age as older cows had lower proportion of oocytes with mature cytoplasm containing evenly dispersed cortical granules compared to young cows. Although fertilization rates did not differ significantly between the two groups after in vitro fertilization (IVF), the rate of abnormal fertilization was higher, and the numbers of total and diploid blastocysts were lower for aged cows compared to young cows. However, in the embryos produced by ICSI, there was no significant difference in these parameters between young and aged cows. Although ICSI did not improve the blastocyst development rate, ICSI increased the proportion of diploid blastocysts in aged cows compared to IVF. In conclusion, maternal aging may negatively affect cytoplasmic maturation of bovine oocytes, which could be associated with abnormal fertilization or low developmental competence of oocytes. Our data also suggests beneficial effects of ICSI on the production of chromosomally normal embryos in aged cows. PMID- 30473580 TI - The bacterial load in milk is associated with clinical severity in cases of bovine coliform mastitis. AB - We evaluated the relationship between the severity of coliform mastitis and bacterial load in 106 quarter milk samples. We found no significant relationship between somatic cell count, severity score, and coliform bacterial load in milk in bovine clinical coliform mastitis. Results of the Cochran-Armitage test for trend in milk bacterial load proportions indicated a significant decreasing low group (P<0.001), increasing medium group (P<0.002) and increasing high group (P<0.02) with increasing clinical grade. The present study indicates that the coliform bacterial load in milk is significantly associated with clinical severity states in cases of bovine coliform mastitis, and can be a useful indicator for optimal management of this disease. PMID- 30473581 TI - Correlation Between First Morning Single Void and 24-Hour Urines: The Reliability to Quantify Niacin Status. AB - BACKGROUND The current common practice when using urine as a biomarker for vitamin excretion is to use a 24-hour sample for analysis. Due to the difficulty involved in this process, we attempted to find an alternative solution through the use of a single first morning void. The aim of our study was to investigate if there is a correlation between the first morning single void and the 24-hour collections of urines for the urine metabolite of niacin, N-1-methylnicotinamide (N1MN), and to test the reliability of utilizing a method using first morning single void collections corrected with the concentration of urine creatinine. MATERIAL AND METHODS All urine samples were collected from 30 healthy adult volunteers over the age of 18 years: 20 females and 10 males. Samples were collected after discarding the first morning urine and collecting every other urine voided during the next 24 hours including the first morning urine of the day after in 2 separate vessels. We analyzed the concentration of N1MN by high performance liquid chromatography and the concentration of creatinine by a commercial kit by spectrophotometry. The B3 excretion was expressed as the ratio of N1MN to creatinine. RESULTS We found a significant correlation between the ratios of first morning single void and 24-hour urines. When comparing males and females, the ratio demonstrated a significant correlation as well. CONCLUSIONS Our results demonstrated that it is possible to substitute a 24-hour collection with a first morning single void urine for the estimation of N1MN excretion. PMID- 30473582 TI - Improved Detection of Culprit Pathogens by Bacterial DNA Sequencing Affects Antibiotic Management Decisions in Severe Pneumonia. AB - BACKGROUND Severe pneumonia requiring admission to an intensive care unit carries high morbidity and mortality. Evidence-based management includes early administration of empiric antibiotics against plausible bacterial pathogens while awaiting results of microbiologic cultures. However, in over 60% of pneumonia cases, no causative pathogen is identified with conventional diagnostic techniques. In this case report, we demonstrate how direct-from-sample sequencing of bacterial DNA could have identified the multiple culprit pathogens early in the disease course to guide appropriate antibiotic management. CASE REPORT A previously healthy, 21-year-old man presented with neck pain and fever and rapidly developed acute respiratory distress syndrome (ARDS) requiring mechanical ventilation. He was started on broad-spectrum antibiotics and was found to have septic thrombophlebitis of the left internal jugular vein (Lemierre syndrome), with blood cultures growing Fusobacterium necrophorum. While his antibiotics were narrowed to piperacillin-tazobactam monotherapy, his clinical condition worsened, but repeated efforts to define an additional/alternative respiratory pathogen resulted in negative cultures. He eventually developed bilateral empyemas growing Mycoplasma hominis. Once azithromycin was added to the patient's regimen, he improved dramatically. Retrospective sequencing of consecutive endotracheal aspirates showed Fusobacterium as the dominant pathogen early in the course, but with significant and increasing Mycoplasma abundance several days prior to clinical detection. CONCLUSIONS Had sequencing information been available to the treating clinicians, the causative pathogens could have been detected earlier, guiding appropriate antibiotic therapy and perhaps preventing his clinical complications. Real-time bacterial DNA sequencing has the potential to shift the diagnostic paradigm in severe pneumonia. PMID- 30473583 TI - Effect of Age on Prognosis of Gastric Signet-Ring Cell Carcinoma: A SEER Database Analysis. AB - BACKGROUND Age is a prognostic factor for multiple malignancies. In this study, we aimed to assess the effect of age on the cancer-specific survival (CSS) of patients with gastric signet-ring cell carcinoma (SRC). MATERIAL AND METHODS Information on patients with gastric SRC was extracted from the Surveillance, Epidemiology, and End Results database. Chi-squared tests were used to demonstrate distribution differences, and Kaplan-Meier analysis and Cox regression models were used to analyze the impact of age on CSS. RESULTS A total of 4596 patients were enrolled and divided into 3 subgroups according to age (<45, 45-74, and >74 years old). Higher percentages of T4, N2, and M1 disease were observed in the <45-year-old group (all P<0.001). Kaplan-Meier plots showed that the youngest group had the most favorable 5-year CSS rate (36.3%), which remained true after stratification according to tumor stage. Multivariate Cox regression models demonstrated a poorer survival outcome for >74-year-old than for <45-year-old patients (hazard ratio 1.841, 95% confidence interval 1.636 2.071; P<0.001). CONCLUSIONS Young age is associated with improved survival, even though younger patients generally present with a more advanced-stage disease. PMID- 30473584 TI - Probing drug-DNA interactions using super-resolution force spectroscopy. AB - Atomic magnetometry and ultrasound, as individual techniques, have been used extensively in various physical, chemical, and biomedical fields. Their combined application, however, has been rare. We report that super-resolution force spectroscopy, which is based on the integration of the two techniques, can find unique biophysical applications in studying drug-DNA interactions. The precisely controlled ultrasound generates acoustic radiation force on the biological systems labeled with magnetic microparticles. A decrease in the magnetic signal, measured by an automated atomic magnetometer, indicates that the acoustic radiation force equals the binding force of the biological system. With 0.5 pN force resolution, we were able to precisely resolve three small molecules binding with two DNA sequences and quantitatively reveal the effect of a single hydrogen bond. Our results indicate that the increases in DNA binding force caused by drug binding correlate with the enthalpy instead of free energy, thus providing an alternative physical parameter for optimizing chemotherapeutic drugs. PMID- 30473585 TI - Revisiting the case of R Monocerotis: Is CO removed at R < 20 au??. AB - Context: To our knowledge, R Mon is the only B0 star in which a gaseous Keplerian disk has been detected. However, there is some controversy about the spectral type of R Mon. Some authors propose that it could be a later B8e star, where disks are more common. Aims: Our goal is to re-evaluate the R Mon spectral type and characterize its protoplanetary disk. Methods: The spectral type of R Mon has been re-evaluated using the available continuum data and UVES emission lines. We used a power-law disk model to fit previous 12CO 1->0 and 2->1 interferometric observations and the PACS CO data to investigate the disk structure. Interferometric detections of 13CO J=1->0, HCO+ 1->0, and CN 1->0 lines using the IRAM Plateau de Bure Interferometer (PdBI) are presented. The HCN 1->0 line was not detected. Results: Our analysis confirms that R Mon is a B0 star. The disk model compatible with the 12CO 1->0 and 2->1 interferometric observations falls short of predicting the observed fluxes of the 1431 CO lines suggest the existence of a region empty of CO at R?20 au in the proto-planetary disk. The intense emission of the HCO+ and CN lines shows the strong influence of UV photons on gas chemistry. Conclusions: The observations gathered in this paper are consistent with the presence of a transition disk with a cavity of R in ?20 au around R Mon. This size is similar to the photoevaporation radius that supports the interpretation that UV photoevaporation is main disk dispersal mechanism in massive stars. PMID- 30473586 TI - Through the magnifying glass: ALMA acute viewing of the intricate nebular architecture of OH231.8+4.2. AB - We present continuum and molecular line emission ALMA observations of OH 231.8+4.2, a well studied bipolar nebula around an asymptotic giant branch (AGB) star. The high angular resolution (~0."2-0."3) and sensitivity of our ALMA maps provide the most detailed and accurate description of the overall nebular structure and kinematics of this object to date. We have identified a number of outflow components previously unknown. Species studied in this work include 12CO, 13CO, CS, SO, SO2, QCS, SiO, SiS, H3O+, Na37Cl, and CH3OH. The molecules Na37Cl and CH3OH are first detections in OH 231.8+4.2, with CH3OH being also a first detection in an AGB star. Our ALMA maps bring to light the totally unexpected position of the mass-losing AGB star (QX Pup) relative to the large-scale outflow. QX Pup is enshrouded within a compact (?60 AU) parcel of dust and gas (clump S) in expansion (V exp~5-7 km s-1) that is displaced by ~0."6 to the south of the dense equatorial region (or waist) where the bipolar lobes join. Our SiO maps disclose a compact bipolar outflow that emerges from QX Pup's vicinity. This outflow is oriented similarly to the large-scale nebula but the expansion velocities are about ten times lower (V exp?35km s-1). We deduce short kinematical ages for the SiO outflow, ranging from ~50-80 yr, in regions within ~150 AU, to ~400-500 yr at the lobe tips (~3500 AU). Adjacent to the SiO outflow, we identify a small-scale hourglass-shaped structure (mini-hourglass) that is probably made of compressed ambient material formed as the SiO outflow penetrates the dense, central regions of the nebula. The lobes and the equatorial waist of the mini-hourglass are both radially expanding with a constant velocity gradient (V exp ? r). The mini-waist is characterized by extremely low velocities, down to ~1 km s-1 at ~150 AU, which tentatively suggest the presence of a stable structure. The spatio-kinematics of the large-scale, high-velocity lobes (HV lobes) and the dense equatorial waist (large waist) known from previous works are now precisely determined, indicating that both were shaped nearly simultaneously about ~800-900 yr ago. We report the discovery of two large (~8"*6"), faint bubble-like structures (fish bowls) surrounding the central parts of the nebula. These are relatively old structures although probably slightly (~100-200 yr) younger than the large waist and the HV lobes. We discuss the series of events that may have resulted in the complex array of nebular components found in OH 231.8+4.2 as well as the properties and locus of the central binary system. The presence of ?80 yr bipolar ejections indicate that the collimated fast wind engine is still active at the core of this outstanding object. PMID- 30473587 TI - Values Versus Environmental Knowledge as Triggers of a Process of Activation of Personal Norms for Eco-Driving. AB - Eco-driving can be an effective strategy to save fuel and reduce CO2 emissions on the road. In the current study, we reason that personal norms are important predictors of eco-driving, and that they are activated when people are aware of environmental problems caused by behavior (problem awareness) and believe that they can contribute to the solution of the problem by changing behavior (outcome efficacy). Extending previous research, we aim at testing two antecedents of this norm activation process: values and environmental knowledge. Results revealed that in comparison with knowledge, values-in particular biospheric values-were strongly associated with the intention to eco-drive by being highly related to awareness of problems caused by car use, which in turn was associated with stronger outcome efficacy beliefs and personal norms for eco-driving. Findings indicate that values are more likely to be a motivational force for pro environmental intentions than is environmental knowledge. PMID- 30473588 TI - Respectful leadership: Reducing performance challenges posed by leader role incongruence and gender dissimilarity. AB - We investigate how respectful leadership can help overcome the challenges for follower performance that female leaders face when working (especially with male) followers. First, based on role congruity theory, we illustrate the biases faced by female leaders. Second, based on research on gender (dis-)similarity, we propose that these biases should be particularly pronounced when working with a male follower. Finally, we propose that respectful leadership is most conducive to performance in female leader-male follower dyads compared with all other gender configurations. A multi-source field study (N = 214) provides partial support for our hypothesis. While our hypothesized effect was confirmed, respectful leadership seems to be generally effective for female leaders irrespective of follower gender, thus lending greater support in this context to the arguments of role congruity rather than gender dissimilarity. PMID- 30473589 TI - Technology, Affordances and Occupational Identity Amongst Older Telecommunications Engineers: From Living Machines to Black-Boxes. AB - This article explores the relationship between technology and occupational identity based on working-life biographical interviews with older telecommunications engineers. In the construction of their own working-life biographical narratives, participants attached great importance to the technology with which they worked. The article contends that workers' relationship with technology can be more nuanced than either the sociology of technology literature or the sociology of work literature accommodates. Adopting the concept of affordances, it is argued that the physical nature of earlier electromechanical technology afforded engineers the opportunity to 'fix' things through the skilled application of tools and act as autonomous custodians of 'living' machines: factors that were inherent to their occupational identity. However, the change to digital technology denied the affordances to apply hands-on skill and undermined key elements of the engineering occupational identity. Rather than simply reflecting the nostalgic romanticizing of the past, the biographies captured deterioration in the material realities of work. PMID- 30473590 TI - Stroke Literature Synopses: Basic Science (2018/May). PMID- 30473592 TI - Lot-to-Lot Variation. AB - Lot-to-lot variation affecting calibrators and reagents is a frequent challenge that limits the laboratory's ability to produce consistent results over time. This variation is not without clinical consequence and there are several well documented examples of adverse clinical outcomes. It is important that laboratories have procedures in place for quantification of this inaccuracy, and for determining whether the amount of variation is acceptable for the release of patient results. Various approaches have been taken to the assessment of new lots, including the evaluation protocol published by the Clinical and Laboratory Standards Institute (CLSI). Internal quality control and external quality assurance material is often not commutable, and so the use of native patient samples is preferred. Published evaluation protocols differ significantly in ease of use and statistical rigour, and some may be underpowered to detect a clinically meaningful change between lots. Furthermore, current protocols (including the CLSI protocol) will not detect cumulative shifts between reagent lots. This shortcoming may at least partly be addressed by laboratories adopting moving patient averages or similar quality procedures. Collaboration and data sharing between laboratories and manufacturers also has an important role to play in the detection of lot-to-lot variation. While the laboratory may take steps to evaluate and detect variation, the ideal is to reduce variation between lots at the point of manufacture. Using appropriate acceptance criteria based on medical need or biological variation requirements instead of some arbitrary percentage may go some steps toward achieving this. PMID- 30473591 TI - Biochemical Analysis of Pleural Fluid and Ascites. AB - Biochemical testing of peritoneal and pleural fluids is carried out widely, although the range of tests likely to be useful is limited in comparison to the repertoire of tests available in a modern biochemistry laboratory. Fluids accumulate when pathological processes cause an imbalance between hydrostatic pressure gradients, capillary membrane permeability and lymphatic capacity, resulting in protein-poor transudates or inflammatory exudates. In peritoneal fluid, albumin is the most useful test, for the calculation of the serum-ascites albumin gradient; protein and LDH have a role regarding risk and diagnosis of spontaneous bacterial peritonitis and amylase may be useful in diagnosing fluid accumulation due to pancreatitis. Peritoneal fluid pH and glucose are not indicated analyses. For pleural fluid, protein and LDH are important in distinguishing between transudate and exudate using Light's criteria; albumin and the serum-effusion albumin gradient may have a complementary role in patients already on diuretics. Pleural fluid pH is the most useful marker of infection although LDH and glucose are also used. Pleural fluid amylase is often measured but, if raised, is more likely to reflect a malignant process than pancreatic disease as the former is much more prevalent. Tumour markers in both peritoneal and pleural fluids generally have limited diagnostic accuracy for detecting local malignancy. Limited studies validating standard serum test methods for use with pleural and peritoneal fluids have been published but work is progressing in this area both in Australasia and overseas and opportunities exist for contributing to this effort. PMID- 30473594 TI - Goal Setting in Teams: Goal Clarity and Team Performance in the Public Sector. AB - With the rise of performance management, work in the public sector has changed. An output focus has become more common. Other changes include decentralization and managing organizations more horizontally. Setting performance goals and working in teams exemplify these developments. Despite an extensive literature on goal setting, research on goal setting in teams and empirical studies in public organizations have been largely absent. This study contributes to the fields of public management and teamwork by examining whether and under what team conditions clear goals contribute to team performance in the Dutch public sector. Analyses on survey data (n = 105 teams) show that both goal clarity and self management positively affect team performance. The effect of goal clarity on team performance is not affected by teamwork though, indicated by insignificant moderation effects of self-management and information elaboration. Suggestions are offered for future research to better understand goal setting in public sector teams. PMID- 30473593 TI - Iron electrolysis-assisted peroxymonosulfate chemical oxidation for the remediation of chlorophenol-contaminated groundwater. AB - BACKGROUND: Electrolysis with an iron anode is a novel way to provide ferrous activators for chemical oxidation. The objective of this study is to evaluate the performance of peroxymonosulfate (PMS) for chlorophenol destruction when compared with H2O2 and persulfate (PS), and to see whether the electrolysis mode facilitates the buildup of conditions that favor the activation of PMS and removal of chlorophenols. RESULTS: Ferrous species can effectively activate the PMS over a wide pH range. In comparison with H2O2 and PS, PMS is less sensitive to the solution's pH and possesses stronger oxidation capability at alkaline pHs. The optimal molar ratio of PMS to Fe(II) activator is 1:1 for the destruction of 2,4-dichlorophenol (2,4-DCP). The column experiments show that an acidic zone developed downstream from the anode is favorable to maintain ferrous ions and subsequent activation of PMS. The reactivity of the PMS can be manipulated by varying the electrical currents, and the process demonstrates effectiveness for treating organic contaminants. 2,4-DCP contaminated groundwater shows decreased biotoxicity after the chemical oxidation process without considering the residual PMS. CONCLUSIONS: Iron electrolysis-assisted peroxymonosulfate chemical oxidation can effectively treat the 2,4-dichlorophenol and mixtures of organic contaminants. This process can be engineered as an in situ chemical oxidation method for groundwater remediation. PMID- 30473595 TI - The cost of school holidays for children from low income families. AB - School holidays can be stressful periods for children from low-income families. Poor provision of appropriate childcare, limited access to enrichment activities, and food insecurity mean that children's health and well-being can suffer and their learning stagnate or decline. This article examines and documents the evidence that has emerged on this topic and aims to raise its profile and the impact on children's lives. It makes the case for further academic scrutiny of this unexamined and neglected subject. PMID- 30473596 TI - Molluscan benthic communities at Brijuni Islands (northern Adriatic Sea) shaped by Holocene sea-level rise and recent human eutrophication and pollution. AB - The effects of and the interplay between natural and anthropogenic influences on the composition of benthic communities over long time spans are poorly understood. Based on a 160-cm-long sediment core collected at 44 m water depth in the NE Adriatic Sea (Brijuni Islands, Croatia), we document changes in molluscan communities since the Holocene transgression ~11,000 years ago and assess how they were shaped by environmental changes. We find that (1) a transgressive lag deposit with a mixture of terrestrial and marine species contains abundant seagrass-associated gastropods and epifaunal suspension-feeding bivalves, (2) the maximum-flooding phase captures the establishment of epifaunal bivalve-dominated biostromes in the photic zone, and (3) the highstand phase is characterized by increasing infaunal suspension feeders and declining seagrass-dwellers in bryozoan-molluscan muddy sands. Changes in the community composition between the transgressive and the highstand phase can be explained by rising sea level, reduced light penetration, and increase in turbidity, as documented by the gradual up-core shift from coarse molluscan skeletal gravel with seagrass associated molluscs to bryozoan sandy muds. In the uppermost 20 cm (median age <200 years), however, epifaunal and grazing species decline and deposit-feeding and chemosymbiotic species increase in abundance. These changes concur with rising concentrations of nitrogen and organic pollutants due to the impact of eutrophication, pollution, and trawling in the 20th century. The late highstand benthic assemblages with abundant bryozoans, high molluscan diversity, and abundance of soft-bottom epi- and infaunal filter feeders and herbivores represent the circalittoral baseline community largely unaffected by anthropogenic impacts. PMID- 30473597 TI - Columbus' environmental impact in the New World: Land use change in the Yaque River valley, Dominican Republic. AB - Columbus' arrival in the New World in AD 1492 on the northern coast of Hispaniola was followed by a suite of changes in land-use. We reconstruct environmental change from a 225-cm-long sediment core from site Los Indios from an abandoned and sediment-filled meander of the Yaque River, Cibao Valley, northeastern Dominican Republic. The sediment record starts ca. AD 195 (ca. 1755 cal. yr BP) and the history of the meander infill was monitored by changing grain size distributions, organic matter concentration and pollen from wetland plants. From ca. AD 200 to ca. AD 1525, the pollen record indicates a diverse forest assemblage; however, the presence of pollen from potential crop plants suggest nearby small-scale subsistence crop cultivation. More abundant charcoal after ca. AD 1410 shows Amerindians increasingly used fire. The record of grain size distributions shows that the meander was temporarily part of a low energetic drainage system in which bedload and suspended sediments accumulated. After European colonization of Hispaniola increasing spores of coprophilous fungi evidence that Europeans had introduced during the first decades of colonization cattle in the Cibao Valley which gradually resulted in more open forest. The charcoal record around ca. AD 1650 reflects intensive forest clearing, suggesting that small-scale Pre-Colonial practice of crop cultivation became replaced by large-scale agriculture on the moist and nutrient rich soils along the Yaque River. Further deforestation and signals of erosion suggest that the population of colonists and introduced enslaved labour force must have increased rapidly. After ca. AD 1740 charcoal influx decreased suggesting that last deforestation activities used selective cutting to produce fire wood and timber for construction, rather than burning forest in situ. Two centuries after European colonization, by the 18th century, land-use within the Cibao Valley had become a balance between substantial livestock and crop cultivation (pollen grains have evidenced cereals, maize, and potentially also sugar cane, amaranthaceous crops and tobacco). After ca. AD 1950, swamp vegetation of Typha and Cyperaceae decreased, pointing to an almost fully terrestrialized meander with only few bodies of standing water, reflecting the present-day setting. This multiproxy reconstruction of anthropogenic environmental change shows a clear differentiation between an immediate introduction of livestock and after some 150 years the development of a European style agriculture, providing a context for archaeological investigations. PMID- 30473598 TI - Micropulse P3TM (MP3) Laser for Glaucoma: An Innovative Therapy. AB - How to cite this article: Aquino MC, Lim D, Chew PTK. Micropulse P3TM(MP3) Laser for Glaucoma: An Innovative Therapy. J Curr Glaucoma Pract 2018;12(2):51-52. PMID- 30473599 TI - Outcomes of Resident-versus attending-performed Tube Shunt Surgeries in a United States Residency Program. AB - Introduction: Glaucoma is a chronic optic neuropathy with increasing global prevalence, necessitating trainees in ophthalmology to be well-trained in the surgical modalities used to manage glaucoma. It is also important to not compromise patient safety and treatment efficacy for training and education. The purpose of our analysis is to compare postoperative outcomes of resident versus (vs.) attending performed tube shunt surgeries (TS). Materials and methods: A retrospective, chart review was performed of patients who had undergone TS between 2009 and 2015 at Rutgers University in Newark, New Jersey, USA. Inclusion criteria was patients with a confirmed diagnosis of glaucoma, who underwent either an Ahmed or Baerveldt TS, and had at least two evaluation visits before the surgery to establish baseline characteristics. Exclusion criteria were patients with follow up for less than 1 year. The main outcome measure was the surgical success at 1 year follow up after TS. Surgical success was defined according to recommendations from the Glaucoma Surgical Trials guidelines published by the World Glaucoma Association (WGA):* 20% reduction in IOP and absolute IOP <= 21 mm Hg (criteria 1)* 30% reduction in IOP and absolute IOP <= 18 mm Hg (criteria 2). Results: A total of 120 cases: 60 attending and 60 resident cases that met all the inclusion criteria and none of the exclusion criteria were included. The mean intraocular pressure (IOP) one year post surgery were 15.06 +/- 3.55 and 15.21 +/- 5.17 mm Hg for attendings and residents respectively (p = 0.422). At the 1 year time point, 87% of resident cases and 95% of attending cases met the qualifications of criteria 1 for success. Kaplan Meier analysis was performed and did not show a significant difference in the outcome (p = 0.325). At the 1 year time point, 80% of attending and resident cases met the qualifications of criteria 2 for success. Kaplan-Meier analysis was performed and did not show a significant difference in the outcome (p = 0.401). There were no differences in complication and failure rates between resident and attending performed cases. Resident-performed cases had a longer intraoperative time in comparison to attending performed cases (p = 0.02). Conclusion: Resident performed surgeries are as effective as attending performed surgeries. Resident performed TS does not compromise safety and better prepares future physicians to deliver optimal care. Clinical Significance: Attendings may consider incorporating more resident performed, attending supervised TS procedures into their clinical practice as surgical training to manage common ophthalmological conditions like glaucoma is essential to residency training.How to cite this article: Thangamathesvaran L, Crane E, Modi K, Khouri AS. Outcomes of Resident versus attending-performed Tube Shunt Surgeries in a United States Residency Program. J Curr Glaucoma Pract 2018;12(2):53-58. PMID- 30473600 TI - Potential Savings from Visit Reduction of Continuous Intraocular Pressure Monitoring. AB - Introduction: A continuous method of measuring intraocular pressures (IOP) could be advantageous in the management of glaucoma. This report aims to analyze the potential savings from visit reduction of continuous IOP measurements obtained with an intraocular device. Materials and methods: We constructed a model adapted from a prior study based on the number of glaucoma patients among 5% of the Medicare population. Results: We found that the implementation of a device that continuously measures IOP can result in a reduction of 23.21% in yearly costs from glaucoma outpatient visits. Conclusion: Continuous IOP monitoring has the potential to alleviate the economic burden of the current management structure of patients with glaucoma. Clinical Significance: In an era of elevated healthcare costs, continuous IOP monitoring offers an option to improve the care of glaucoma patients through visit reduction, also resulting in a 23.21% reduction in yearly expenses related to glaucoma clinical visits.How to cite this article: Dong J, Syed ZA, Fan K, Yahya AF, Melki SA. Potential Savings from Visit Reduction of Continuous Intraocular Pressure Monitoring. J Curr Glaucoma Pract 2018;12(2):59 63. PMID- 30473601 TI - Precipitants of 5-Fluorouracil in Trabeculectomy Bleb Management: A Comparative Laboratory Study. AB - Aim: Concerns regarding 5-Fluorouracil (5-FU) corneal toxicity have resulted in various ways of reducing its corneal exposure during post-operative trabeculectomy bleb manipulation. This study investigates the properties of various topical agents used to induce the precipitation of this compound. Materials and methods: This is a double-blind, descriptive, laboratory study comparing five different potential precipitants of 5-FU (proxymetacaine (proxy), oxybuprocaine (oxy), ametho-caine (ameth), fluorescein (flor), proxymetacaine + fluorescein (proxy-flor) to a control group (normal saline). A 0.01 mL of each anonymized agent was applied next to a clear round comparison marker in a transparent sterile container set on a dark background. 5-FU (0.01 mL of 50 mg/mL) was subsequently applied to each agent. The induced changes in transparency were imaged and compared to the transparency of the central marker. For each application, pH changes were also noted. Results: Proxy, flor and proxy + flor did not result in any discernible 5-FU precipitation. Oxy resulted in a moderate visible change, and ameth produced very significant precipitation. Application of proxy, oxy, ameth, and proxy + flor resulted in the neutralization of the 5-FU's alkaline pH. Conclusion: We propose using a cotton-tipped bud dipped in ameth applied at the injection site as the recommended method to avoid 5-FU corneal exposure in these cases. Clinical significance: Practitioners should be aware of the differences in precipitation of 5-FU by different types of topical anesthetics and modify techniques of anesthesia and 5-FU administration accordingly.How to cite this article: Mercieca KJ, Fenerty CH, Steeples LR, Drury B, Bhargava A. Precipitants of 5-Fluorouracil in Trabeculectomy Bleb Management : A Comparative Laboratory StudyJ Curr Glaucoma Pract 2018;12(2):64-66. PMID- 30473602 TI - Efficacy and Adverse Event Profile of the iStent and iStent Inject Trabecular Micro-bypass for Open-angle Glaucoma: A Meta-analysis. AB - Aim: This meta-analysis explores the efficacy and adverse event profile of the iStent, an ab interno implant for the treatment of open-angle glaucoma. Methods: A systematic literature search of Ovid MEDLINE and EMBASE was used to identify peer-reviewed original studies that provided efficacy data on the first or second generation iStent for at least five eyes. Intraocular pressure (IOP) was the primary efficacy endpoint, while the number of medication classes was the secondary outcome. Weighted mean differences were reported for continuous endpoints, while a relative risk was computed for dichotomous variables. Review Results: The search revealed 545 results, of which 1767 eyes from 28 studies were included. The cohort age was 71.4 +/- 5.4 years, and 44.9% of patients were male. There was a significantly greater IOP reduction after the use of two first generation stents compared to one, irrespective of phacoemulsification status (p < 0.001). Additionally, there was a significantly greater IOP reduction following iStent alone relative to phaco-iStent for the first-generation iStent (p < 0.001) and the iStent inject (p < 0.001). For the first generation stent, combined phaco iStent provided a greater level of IOP reduction (p < 0.001) and reduction in the number of medication classes relative to phacoemulsification alone (p < 0.001). In total, 22.5% of eyes that received iStent implantation sustained some type of adverse event. The most common adverse events were intraocular pressure elevation, stent blockage or obstruction, stent malposition and hyphema. Conclusion and Clinical Significance: Statistically significant differences in efficacy outcomes exist between different numbers of stents and the presence or absence of concurrent phacoemulsification.How to cite this article: Popovic M, Campos-Moller X, Saheb H, Ahmed IIK. Efficacy and Adverse Event Profile of the iStent and iStent Inject Trabecular Micro-bypass for Open-angle Glaucoma: A Meta analysis. J Curr Glaucoma Pract 2018;12(2):67-84. PMID- 30473603 TI - Deep Sclerectomy with Porous Collagen in Open-angle Glaucoma, Short-term Study. AB - Aim: To assess the role of porous collagen in deep sclerectomy (DS), with and without trabeculo-Descemet membrane (TDM) rupture. Patients and methods: Forty six eyes with different types of open-angle glaucoma and medically uncontrolled intraocular pressure (IOP) were selected. DS was performed in all cases. Ologen was implanted as a single large piece in the scleral lake and subconjunctival space in all cases with and without TDM rupture. Results: A total sample of 46 open-angle glaucoma patients were included in the study. The mean +/- standard deviation (SD) IOP was 25.6 mm Hg +/- 10.6 (range 12-58 mm Hg) pre-operatively. On follow-up, the mean +/- SD IOP was 6.1 mm Hg +/- 3.7 (range 2-20 mm Hg) 1 day postoperatively and 9.3 mm Hg +/- 4.0 (range 4-23 mm Hg) after 1 month of follow up, at 12 months the IOP was at 12.1 mm Hg +/- 3 (range 8-18 mm Hg). The overall mean +/- SD IOP reduction percentage was 48.3% +/- 21.3 (range 0.0-86.2). Comparing mean IOP reductions at last follow-up between TDM rupture cases and non TDM cases (Mann-Whitney test), the mean +/- SD IOP reduction in TDM rupture patients was 12.1 +/- 8.0 mm Hg (range 2-27) meanwhile, in non-TDM rupture patients it was 14.3 +/- 11.4 mm Hg (range 0-50). However, the difference in IOP reduction between the two groups was not significant. (p = 0.689). Conclusion: Porous collagen can enhance the results of DS; also, it helps to proceed with DS in cases of TDM rupture without converting to trabeculectomy.How to cite this article: Elbably A, Othman TM, Mousa A, Elridy M, Badawy W, Elbably M. Deep Sclerectomy with Porous Collagen in Open-angle Glaucoma, Short-term Study. J Curr Glaucoma Pract 2018;12(2):85-89. PMID- 30473604 TI - Endoscopic Goniosynechialysis for Acute Angle Closure Glaucoma Following Descemet's Stripping Automated Endothelial Keratoplasty. AB - We describe a new modified technique to release the peripheral iridocorneal adhesions that formed after Descemet stripping automated endothelial keratoplasty. The usual technique of goniosynechialysis was modified and performed using endoscopic fiber-optic light and camera probe to aid visualization of the adherent iris tissue and carry out uneventful 270 degrees release of adhesions. The iris tissue was gently pulled away using micro forceps. The modified technique was conceptualized, as the view from the cornea was very poor due to recent lamellar surgery and corneal oedema secondary to poorly controlled intraocular pressure. The blocked trabecular meshwork system was successfully recanalized, which allowed an adequate control of intraocular pressure. The graft survived the insult and cornea gained complete clarity giving the patient the desired vision and improved quality of life. How to cite this article: Rana M, Shah S, Pandey P, Masood I. Endoscopic Goniosynechialysis for Acute Angle Closure Glaucoma Following Descemet's Stripping Automated Endothelial Keratoplasty. J Curr Glaucoma Pract 2018;12(2):90-93. PMID- 30473605 TI - Bilateral Phacomatosis Pigmentovascularis in a Young Male with Developmental Glaucoma and Varicose Veins. AB - Aim: To report a case of bilateral phacomatosis pigmentovascularis (PPV), in a young male,presenting with developmental glaucoma and high myopia along with systemic features of klippel trenanauy weber (KTW) syndrome. Background: The co existence of oculodermal melanocytosis (ODM)and port-wine stain was termed PPV by Ota. Port-wine stain presents as part of Sturge-Weber syndrome (SWS). KTW presents with varicose veins and tissue hypertrophy alongwith port-wine stain. Case Description: A 22-year-old male presented with decreased vision owing to high myopia and advanced glaucoma. Incidental findings noted were pigmentary naevi along with facial port-wine stain, which collectively comprises PPV. Also noted were bilateral varicose veins which are usually seen in association with KTW. In view of advanced visual field damage and inability to control intraocular pressures (IOP) on topical medications, he underwent Glaucoma filtration surgery in both eyes. Intra-operatively care was taken to avoid sudden decompression by controlled anterior chamber paracentesis, and scleral flap closure with releasable sutures was done to prevent hypotony related complications in the immediate postoperative period. Such precautions lead to an uneventful postoperative recovery, and even at 3 years' follow-up, the patient is maintaining IOP in early teens along with a stable visual acuity and visual fields. Conclusion: This case highlights the overlapping features of congenital conditions like oculodermal melanocystosis (ODM), SWS, KTW; presenting in a young male. Systemic features reported less frequently with PPV, included palatal pigmentation and palatal vascular malformations. Clinical Significance: This case re-emphasizes a common origin of these entities, PPV and KTW, from the neural crest cells. Early recognition of the systemic features and timely surgical intervention under appropriate precautions, can be vision salvaging in such cases of developmental glaucoma.How to cite this article: Singh K, Dangda S, Mutreja A, Bhattacharyya M, Jaisingh K. Bilateral Phacomatosis Pigmentovascularis in a Young Male with Developmental Glaucoma and Varicose Veins. J Curr Glaucoma Pract 2018;12(2):94-98. PMID- 30473607 TI - Improving malignancy prediction through feature selection informed by nodule size ranges in NLST. AB - Computed tomography (CT) is widely used during diagnosis and treatment of Non Small Cell Lung Cancer (NSCLC). Current computer-aided diagnosis (CAD) models, designed for the classification of malignant and benign nodules, use image features, selected by feature selectors, for making a decision. In this paper, we investigate automated selection of different image features informed by different nodule size ranges to increase the overall accuracy of the classification. The NLST dataset is one of the largest available datasets on CT screening for NSCLC. We used 261 cases as a training dataset and 237 cases as a test dataset. The nodule size, which may indicate biological variability, can vary substantially. For example, in the training set, there are nodules with a diameter of a couple millimeters up to a couple dozen millimeters. The premise is that benign and malignant nodules have different radiomic quantitative descriptors related to size. After splitting training and testing datasets into three subsets based on the longest nodule diameter (LD) parameter accuracy was improved from 74.68% to 81.01% and the AUC improved from 0.69 to 0.79. We show that if AUC is the main factor in choosing parameters then accuracy improved from 72.57% to 77.5% and AUC improved from 0.78 to 0.82. Additionally, we show the impact of an oversampling technique for the minority cancer class. In some particular cases from 0.82 to 0.87. PMID- 30473606 TI - Prosthetic Foot Selection for Individuals with Lower-Limb Amputation: A Clinical Practice Guideline. AB - Introduction: This guideline was developed to present current evidence and to provide associated clinical recommendations on prosthetic foot selection for individuals with lower-limb amputation. Materials: NA. Methods: The guideline is based upon the best available evidence as it relates prosthetic foot selection during the provision of definitive lower-limb prostheses. Where possible, recommendations are drawn from Cochrane Review, meta-analysis, systematic and narrative literature reviews, and published evidence-based guidelines. Where this standard is unavailable, alternate academic literature has been used to support individual recommendations. Results: Recommendation 1: For patients ambulating at a single speed who require greater stability during weight acceptance because of weak knee extensors or poor balance, a single-axis foot should be considered. Recommendation 2: Patients at elevated risks for overuse injury (i.e., osteoarthritis) to the sound-side lower limb and lower back are indicated for an energy-storage-and-return (ESAR) foot to reduce the magnitude of the cyclical vertical impacts experienced during weight acceptance. Recommendation 3: Neither patient age nor amputation etiology should be viewed as primary considerations in prosthetic foot type. Recommendation 4: Patients capable of variable speed and/or community ambulation are indicated for ESAR feet. Conclusions: These clinical practice guidelines summarize the available evidence related to prosthetic foot selection for individuals with lower limb amputation. The noted clinical practice guidelines are meant to serve only as "guides." They may not apply to all patients and clinical situations. PMID- 30473608 TI - Latent Network Features and Overlapping Community Discovery via Boolean Intersection Representations. AB - We propose a new latent Boolean feature model for complex networks that captures different types of node interactions and network communities. The model is based on a new concept in graph theory, termed the Boolean intersection representation of a graph, which generalizes the notion of an intersection representation. We mostly focus on one form of Boolean intersection, termed cointersection, and describe how to use this representation to deduce node feature sets and their communities. We derive several general bounds on the minimum number of features used in cointersection representations and discuss graph families for which exact cointersection characterizations are possible. Our results also include algorithms for finding optimal and approximate cointersection representations of a graph. PMID- 30473609 TI - Australobiustracheoperspicuus sp. n., the first subterranean species of centipede from southern China (Lithobiomorpha, Lithobiidae). AB - Australobiustracheoperspicuus sp. n. (Lithobiomorpha: Lithobiidae) was recently discovered from the Cave of the brickyard of Gaofeng village, in the Guizhou Province, southwest China, and it is described here. Morphologically the new species is similar to A.magnus (Trozina>, 1894) from north-western China. The new species can be easily distinguished from those by the trachea connected to the valve of the TIII clearly visible from the dorsal side, the absence of ocelli on each side of the cephalic plate, the DaC spine being only present on the XIIIth XVth legs. Numbers of examined specimens, distribution and the main morphological characters and an identification key to the known Chinese species of genus Australobius based on adult specimens is given. PMID- 30473610 TI - First continental troglobiont Cylindroiulus millipede (Diplopoda, Julida, Julidae). AB - The new species of millipede Cylindroiulusvillumi is described from a cave in the Estremenho karst massif in central Portugal. It is the first cave-adapted species of its genus with a strict subterranean life-style in continental Europe, and is the fifth blind species of the genus. The new species is illustrated with photographs and diagrammatic drawings. It is tentatively placed in the purely Iberian Cylindroiulusperforatus-group. The differences between the new species and its relatives are discussed, as well as its adaptations to a subterranean life-style. PMID- 30473611 TI - Description of a new species of Dacus from Sri Lanka, and new country distribution records (Diptera, Tephritidae, Dacinae). AB - A fruit fly survey in the Sinharaja and Knuckles National Parks in Sri Lanka (2016), using traps baited with the male lures methyl eugenol, cue-lure, and zingerone, yielded 21 species of Dacini fruit flies. Of these, three species, viz. Bactroceraamarambalensis Drew, B.dongnaiae Drew & Romig, and B.rubigina (Wang & Zhao), are new country occurrence records, and Dacus (Mellesis) ancoralis Leblanc & Doorenweerd, sp. n. is described as a new species. The Sri Lankan Dacini fruit fly fauna is now comprised of 39 species. PMID- 30473612 TI - Two new species of Satsuma A. Adams, 1868 from Taiwan (Pulmonata, Camaenidae). AB - Two new sinistral species of the genus Satsuma A. Adams, 1868, Satsumasquamigera sp. n. and Satsumaadiriensis sp. n., from southern Taiwan are described. Satsumasquamigera sp. n. is characterized by a microsculpture comprising coarse, irregularly-spaced ridges and dense, easily-dislodged triangular scales on its sinistral shell, an angulated periphery, and partly-opened umbilicus. This species inhabits secondary forests in lowland hills. Satsumaadiriensis sp. n. is characterized by a thin, fragile smooth shell with microsculpture of coarse, loose ridges, a rounded periphery, completely-opened umbilicus, and elongated penial verge formed by two main pilasters. This new species was collected in a mountainous, mid-elevation, broad-leafed forest. PMID- 30473613 TI - Coccomyxagreatwallensis sp. nov. (Trebouxiophyceae, Chlorophyta), a lichen epiphytic alga from Fildes Peninsula, Antarctica. AB - A single-celled green alga Coccomyxagreatwallensis Shunan Cao & Qiming Zhou, sp. nov., isolated from a specimen of Antarctic lichen Psoromahypnorum (Vahl) Gray, is described and illustrated based on a comprehensive investigation of morphology, ultrastructure, ecology and phylogeny. The cells of C.greatwallensis are ovoid to long ellipsoidal and measured 3-5 um * 6-12 um. The new species has distinct ITS rDNA and SSU rDNA sequences and differs from the phylogenetic closely related species C.antarctica, C.arvernensis and C.viridis in cell size, distribution and habitat. PMID- 30473614 TI - Chrysospleniumramosissimum Y.I.Kim & Y.D.Kim (Saxifragaceae), a new species from Korea. AB - This study describes and illustrates Chrysospleniumramosissimum, a new plant species from Mt. Seonjaryeong, located in the central region of the Korean Peninsula. The species is most similar to C.valdepilosum but is readily distinguishable by the presence of yellowish-green bracteal leaves during flowering, highly branched sterile branches, shiny silvery dots on sterile branch leaves and larger tubercles on the seed coat. PMID- 30473615 TI - A new disjunct species of Eriolaena (Malvaceae, Dombeyoideae) from Continental Africa. AB - Eriolaenarulkensii Dorr, sp. nov. is described and illustrated. This attractive shrub is endemic to coastal Mozambique. The new species has apically winged seeds, which place it in a group of Malvaceae (Dombeyoideae) that is found in Asia and Madagascar and which had not previously been found in continental Africa. PMID- 30473616 TI - Two new species of Raphia (Palmae/Arecaceae) from Cameroon and Gabon. AB - Raphia (Arecaceae, Calamoideae) is the most diverse genus of African palms with around 20 species. Two new species from Cameroon and Gabon, Raphiagabonica Mogue, Sonke & Couvreur, sp. nov. and Raphiazamiana Mogue, Sonke & Couvreur, sp. nov. are described and illustrated. Their affinities are discussed and the conservation status of each species is assessed. For both species, distribution maps are provided. Raphiagabonica is restricted to two small populations from central Gabon, where it occurs on hillsides on tierra firme soil, and close to small streams. Its preliminary IUCN status is Endangered, being amongst the five most threatened palm species in Africa. Raphiagabonica potentially belongs to the moniliform section. Raphiazamiana is largely distributed from south Cameroon to south Gabon and is very common. It is also a multi-used palm, from which wine, grubs and construction material are extracted and sold. It generally occurs in large stands in a wide range of ecosystems such as swamps, coastal forests on partially inundated sandy soils and inundated savannahs. Its large stature, hard to access habitat (swamps) and abundant presence might have discouraged botanists to collect it until now. Raphiazamiana belongs to the taxonomically complex raphiate section. PMID- 30473617 TI - Data Leakage and Loss in Biodiversity Informatics. AB - The field of biodiversity informatics is in a massive, "grow-out" phase of creating and enabling large-scale biodiversity data resources. Because perhaps 90% of existing biodiversity data nonetheless remains unavailable for science and policy applications, the question arises as to how these existing and available data records can be mobilized most efficiently and effectively. This situation led to our analysis of several large-scale biodiversity datasets regarding birds and plants, detecting information gaps and documenting data "leakage" or attrition, in terms of data on taxon, time, and place, in each data record. We documented significant data leakage in each data dimension in each dataset. That is, significant numbers of data records are lacking crucial information in terms of taxon, time, and/or place; information on place was consistently the least complete, such that geographic referencing presently represents the most significant factor in degradation of usability of information from biodiversity information resources. Although the full process of digital capture, quality control, and enrichment is important to developing a complete digital record of existing biodiversity information, payoffs in terms of immediate data usability will be greatest with attention paid to the georeferencing challenge. PMID- 30473618 TI - A story of data won, data lost and data re-found: the realities of ecological data preservation. AB - This paper discusses the process of retrieval and updating legacy data to allow on-line discovery and delivery. There are many pitfalls of institutional and non institutional ecological data conservation over the long term. Interruptions to custodianship, old media, lost knowledge and the continuous evolution of species names makes resurrection of old data challenging. We caution against technological arrogance and emphasise the importance of international standards. We use a case study of a compiled set of continent-wide vegetation survey data for which, although the analyses had been published, the raw data had not. In the original study, publications containing plot data collected from the 1880s onwards had been collected, interpreted, digitised and integrated for the classification of vegetation and analysis of its conservation status across Australia. These compiled data are an extremely valuable national collection that demanded publishing in open, readily accessible online repositories, such as the Terrestrial Ecosystem Research Network (http://www.tern.org.au) and the Atlas of Living Australia (ALA: http://www.ala.org.au), the Australian node of the Global Biodiversity Information Facility (GBIF: http://www.gbif.org). It is hoped that the lessons learnt from this project may trigger a sober review of the value of endangered data, the cost of retrieval and the importance of suitable and timely archiving through the vicissitudes of technological change, so the initial unique collection investment enables multiple re-use in perpetuity. PMID- 30473619 TI - A preliminary checklist of soil ants (Hymenoptera: Formicidae) of Colombian Amazon. AB - Background: This paper presents an updated list of soil ants of the Colombian Amazon collected in three different river basins: the Amazon, the Caqueta and the Putumayo. The list includes 10 subfamilies, 60 genera and 218 species collected from TSBF monoliths at four different depths (Litter, 0 - 10 cm, 10 - 20 cm and 20 - 30 cm). This updated list increases considerably the knowledge of edaphic macrofauna of the region, due to the limited published information about soil ant diversity in the Colombian Amazon region. New information: This is the first checklist of soil ant diversity of the Colombian Amazon region. Six new records of species for Colombia are exposed: Acropyga tricuspis (LaPolla, 2004), Typhlomyrmex clavicornis (Emery, 1906), Typhlomyrmex meire (Lacau, Villemant & Delabie, 2004), Cyphomyrmex bicornis (Forel, 1895), Megalomyrmex emeryi (Forel, 1904) and Myrmicocrypta spinosa (Weber, 1937), most of them corresponding to subterranean ants. PMID- 30473620 TI - Incentivising use of structured language in biological descriptions: Author driven phenotype data and ontology production. AB - Phenotypes are used for a multitude of purposes such as defining species, reconstructing phylogenies, diagnosing diseases or improving crop and animal productivity, but most of this phenotypic data is published in free-text narratives that are not computable. This means that the complex relationship between the genome, the environment and phenotypes is largely inaccessible to analysis and important questions related to the evolution of organisms, their diseases or their response to climate change cannot be fully addressed. It takes great effort to manually convert free-text narratives to a computable format before they can be used in large-scale analyses. We argue that this manual curation approach is not a sustainable solution to produce computable phenotypic data for three reasons: 1) it does not scale to all of biodiversity; 2) it does not stop the publication of free-text phenotypes that will continue to need manual curation in the future and, most importantly, 3) It does not solve the problem of inter-curator variation (curators interpret/convert a phenotype differently from each other). Our empirical studies have shown that inter-curator variation is as high as 40% even within a single project. With this level of variation, it is difficult to imagine that data integrated from multiple curation projects can be of high quality. The key causes of this variation have been identified as semantic vagueness in original phenotype descriptions and difficulties in using standardised vocabularies (ontologies). We argue that the authors describing phenotypes are the key to the solution. Given the right tools and appropriate attribution, the authors should be in charge of developing a project's semantics and ontology. This will speed up ontology development and improve the semantic clarity of phenotype descriptions from the moment of publication. A proof of concept project on this idea was funded by NSF ABI in July 2017. We seek readers input or critique of the proposed approaches to help achieve community-based computable phenotype data production in the near future. Results from this project will be accessible through https://biosemantics.github.io/author-driven-production. PMID- 30473621 TI - A new species of Cintractiella (Ustilaginales) from the volcanic island of Kosrae, Caroline Islands, Micronesia. AB - Cintractiella is an unusual genus of smut fungi containing two described species that produce sori as adventitious gall-like spikelets on members of tribe Hypolytreae (subfam. Mapanioideae, Cyperaceae). In September 200, during a botanical expedition on the volcanic island of Kosrae located in the eastern Caroline Islands and within the Federated States of Micronesia, a specimen of Mapaniapacifica was collected displaying Cintractiella-like sori in adventitious spikelets on the host leaves. Sori were hypophyllous, occurring in groups of spikelets composed of olivaceous-brown scale-like leaves, 1-1.5 mm wide and up to 6 mm long. Microscopic comparison with the protologue and drawings of the type material of C.lamii show several differences in teliospore and sori characters between it and the newly collected material on Mapania. To our knowledge, this represents only the second known collection of any member of Cintractiella on vegetative organs of Hypolytreae and a third species for this genus and the only known smut species infecting Mapania, herein described as Cintractiellakosraensis sp. nov. PMID- 30473622 TI - Two new species of Geejayessia (Hypocreales) from Asia as evidenced by morphology and multi-gene analyses. AB - Two new species of Geejayessia are introduced, based on materials collected from central China. Geejayessiaclavata sp. nov. is characterised by gregarious, red brownish to dark red, oval-subglobose to globose perithecia that are formed on a basal stroma; (4-7-)8-spored cylindrical asci; ellipsoidal or rarely broadly ellipsoidal, uniseptate, smooth or finely verruculose ascospores; clavate, aseptate microconidia and absence of macroconidia. Geejayessiasinica sp. nov. is characterised by red to bright red, pyriform, subglobose to globose, perithecia on a basal stroma, collapsing laterally when dry; subcylindrical to clavate asci with a rounded apex; ellipsoidal, uniseptate ascospores; and falcate, multiseptate macroconidia with an arcuate tip. Morphological distinctions of the new species from the related fungi are discussed. This is the first report of Geejayessia from Asia. PMID- 30473623 TI - SARC018_SPORE02: Phase II Study of Mocetinostat Administered with Gemcitabine for Patients with Metastatic Leiomyosarcoma with Progression or Relapse following Prior Treatment with Gemcitabine-Containing Therapy. AB - Histone deacetylase inhibitors (HDACi) can reverse chemoresistance, enhance chemotherapy-induced cytotoxicity, and reduce sarcoma proliferation in cell lines and animal models. We sought to determine the safety and toxicity of mocetinostat and its ability to reverse chemoresistance when administered with gemcitabine in patients with metastatic leiomyosarcoma resistant to prior gemcitabine-containing therapy. Participants with metastatic leiomyosarcoma received mocetinostat orally, 70 mg per day, three days per week, increasing to 90 mg after three weeks if well tolerated. Gemcitabine was administered at 1,000 mg/m2 intravenously at 10 mg/m2/minute on days five and 12 of every 21-day cycle. Disease response was evaluated with CT or MRI. Twenty participants with leiomyosarcoma were evaluated for toxicity. Median time to disease progression was 2.0 months (95% CI 1.54 3.12). Eighteen participants were evaluated for radiologic response by RECIST 1.1. Best responses included one PR and 12 SD. Tumor size reduced in 3 patients. Most common toxicities were fatigue, thrombocytopenia, anemia, nausea, and anorexia. One patient experienced a significant pericardial adverse event. No study-related deaths were observed. Rechallenging with gemcitabine by adding mocetinostat was feasible and demonstrated modest activity in patients with leiomyosarcoma. Further studies are needed to better define the role of HDAC inhibitors in patients with metastatic leiomyosarcoma. PMID- 30473625 TI - The Indonesian general practitioners' perspectives on formal postgraduate training in primary care. AB - Background: To be recognized as a primary care physician (PCP), an Indonesian general practitioner (GP) has to follow a formal postgraduate training in primary care. However, 4 years since the regulation was published, the progress of the training is slow. There is a need to deeply investigate the doctors' perspectives, particularly to explore factors associated with their willingness to follow this training. Aim: This study aims to explore the GPs' views and perspectives related to the formal postgraduate training in primary care that may influence their enrolment in PCP program. Methods: We conducted semi-structured interviews with a topic guide. The study took place in Yogyakarta from January to December 2016. The participants were GPs practicing in Yogyakarta primary care clinics who were recruited using purposive-maximum variation sample design. The interviews were audio-recorded and transcribed. The data were analysed using interpretative phenomenological analysis approach. Results: Nineteen GPs participants were involved in this study. Three major themes were identified, namely unfamiliarity, resistance, and positivism. Almost all the GP participants were unfamiliar with the primary care training program. They were also pessimistic if the training could change the health service in the country while it lacked resources and infrastructures. However, exposure to the training brought positive insights that it could improve the doctors' knowledge and skills in primary care practice. Discussion: The government intention to establish PCP training is currently on the right tract. However, information dissemination and more supports in primary care are also essential. PMID- 30473624 TI - Antiangiogenic Gene Therapy in Cancer. AB - One of the most recent and exciting approaches in cancer gene therapy is the ability to target the developing blood supply of the tumor. An appealing feature of antiangiogenic gene therapy is that the tumor vasculature is a readily accessible target, particularly when the carrier and its gene are administered systemically. This is in contrast to several other gene therapy approaches in which the tumor vasculature represents a major obstacle to achieving high levels of transfection of the tumor cells. Several gene-based viral or non-viral therapies that target tumor angiogenesis have shown efficacy in pre-clinical models. Genes that encode antiangiogenic polypeptides such as angiostatin and endostatin have significantly inhibited tumor growth, inducing a microscopic dormant state. The products of these genes are thought to act extracellularly to inhibit angiogenesis. An alternative approach that investigators have used successfully in tumor-bearing mice is to target angiogenic growth factors or their receptors that are essential for tumor growth. Levels of angiogenic factors such as vascular endothelial growth factor (VEGF) have been reduced by either antisense methods or the use of genes encoding truncated angiogenic decoy receptors. Despite these promising findings of tumor reduction with antiangiogenic gene therapy, advances in the viral and/or non-viral delivery systems are essential for this therapy to have clinical utility. In this review, we will discuss the mechanisms of angiogenesis/antiangiogenesis, and the current status and future directions of antiangiogenic gene therapy. PMID- 30473626 TI - Role of Leptin/Osteopontin Axis in the Function of Eosinophils in Allergic Rhinitis with Obesity. AB - Background: Allergic rhinitis (AR) is characterized by tissue and blood eosinophilia. Previous studies showed enhanced eosinophilia in allergic rhinitis patients with obesity, suggesting an association between obesity and eosinophilia. However, the interaction and mechanism between obesity and eosinophilia is still unclear. Methods: We recruited thirty AR children and 30 controls in this study. Expression of leptin and osteopontin (OPN) proteins in serum was detected, and correlation analysis with eosinophilia was performed. The effect of leptin or OPN on eosinophil apoptosis, adhesion, migration, and activation of eosinophil was examined. Ovalbumin-sensitized mice were established to prove the role of obesity on eosinophil regulation by leptin and OPN. Results: We found that upregulated serum and nasal leptin and OPN expression in AR were positively correlated with eosinophilia and eosinophil cationic protein levels. Leptin or OPN inhibited eosinophil apoptosis, demonstrated as inhibited DNA fragmentation and phosphatidylserine (PS) redistribution (P < 0.05). Leptin and OPN promote expression of cluster of differentiation 18 (CD-18) and intercellular adhesion molecule 1 (ICAM-1) and inhibit expression of ICAM-1 and L-selectin by eosinophils, which contribute to the adhesion of eosinophils. Leptin and OPN mediated migration and activation of eosinophil through phosphatidylinositol-3-OH kinase (PI3K) pathway. Obese AR mice presented with more severe eosinophilia and symptoms compared with nonobese AR mice or control mice. Immunochemistry staining of leptin and OPN of nasal turbinate in obese AR mice was also stronger than those in nonobese AR mice or control mice. Anti-OPN, anti-leptin, and anti-alpha4 treatments reduce nasal eosinophilia inflammation and clinical symptoms in model mice. Conclusion: Our results suggested that in an obese state, upregulation of leptin and OPN regulates apoptosis, adhesion, migration, and activation of eosinophils, and this process may be mediated by the PI3K and anti-alpha4 pathways. PMID- 30473627 TI - Predicting recidivism among youth offenders: Augmenting professional judgement with machine learning algorithms. AB - Summary: Offender rehabilitation seeks to minimise recidivism. Using their experience and actuarial-type risk assessment tools, probation officers in Singapore make recommendations on the sentencing outcomes so as to achieve this objective. However, it is difficult for them to maximise the utility of the large amounts of data collected, which could be resolved by using predictive modelling informed by statistical learning methods. Findings: Data of youth offenders (N = 3744) referred to the Probation Service, Ministry of Social and Family Development for rehabilitation were used to create a random forests model to predict recidivism. No assumptions were made on how individual predictor values within the risk assessment tool and other administrative data on an individual's socio-economic status such as level of education attained and dwelling type collected in line with organisational requirements influenced the outcome. Sixty per cent of the data was used to develop the model, which was then tested against the remaining 40%. With a classification accuracy of approximately 65%, and an Area under the Curve value of 0.69, it outperformed existing models analysing aggregated data using conventional statistical methods. Application: This article identifies how analysis of administrative data at the discrete level using statistical learning methods is more accurate in predicting recidivism than using conventional statistical methods. This provides an opportunity to direct intervention efforts at individuals who are more likely to reoffend. PMID- 30473628 TI - Non-application of the nursing process at a hospital in Accra, Ghana: lessons from descriptive research. AB - Background: Registered nurses in Ghana are trained to plan the care that they provide to their patients in a systematic and organized manner. This scientific approach to care is known as the nursing process. There is evidence that the nursing process is not being practised by professional nurses in Ghana, as expected. This research seeks to explore what informs nursing interventions in the clinical area. Methods: A qualitative study was conducted with ten registered nurses; and this was descriptive in nature. One-on-one interviews were conducted with the research participants, as a means of collecting the data. A semi structured interview guide was used as the data-collecting tool. The collected data were analysed by using latent-content analysis. Three main themes emerged from the data analysis. Results: It was found that registered nurses did not plan their nursing care. The care that the nurses provided was based on routine nursing care and doctors' orders, both verbal and non-verbal; or written communication were the means whereby the care was provided; and that was communicated among the nurses. Conclusion: Registered nurses are taught the nursing process; and they are expected to implement the acquired knowledge in the clinical area. The failure of nurses to practise the expected standard of care results in their relying on the decision of other health-care professionals, such as doctors. This makes registered nurses appear to be assistants to doctors. We, therefore, conclude that nurse leaders must supervise nurses to put into practice what they were taught during their training; so that they can have professional autonomy in their practice as nurses. It is also suggested that nurses must show evidence of using the nursing process in their daily work by the use of the nursing care-plan form. PMID- 30473630 TI - RelB plays an oncogenic role and conveys chemo-resistance to DLD-1 colon cancer cells. AB - Background: Nuclear transcription factor kappa B (NF-kappaB) subunits exhibit crucial roles in tumorigenesis and chemo-sensitivity. Recent studies suggest that RelB, the key subunit of the alternative NF-kappaB pathway, plays a critical role in the progression of diverse human malignancies. However, the significance of RelB in colorectal cancer (CRC) remains unclear. Here, we systematically explored the functions of the alternative NF-kappaB subunit RelB in colon cancer cells and its underlying mechanism. Methods: Stably transfected RelB-shRNA DLD-1 cells were established using Lipofectamine 2000. NF-kappaB DNA-binding capability was quantified using an ELISA-based NF-kappaB activity assay. Cell growth was monitored by an x-Celligence system. Cell proliferation was analyzed by a CCK-8 and a Brdu proliferation assay. Response to 5-FU was assessed by an x-Celligence system. Cell apoptosis and cell cycle was detected using flow cytometry analyses. Cell migration and invasion abilities were detected by an x-Celligence system, Transwell inserts, and wound-healing assays. RelB expression and its clinical significance were analyzed using the CRC tissue microarray. The expression of NF kappaB signaling subunits, AKT/mTOR signaling molecules, cell cycle related proteins, MMP2, MMP9, and Integrin beta-1 were measured by Western blotting analyses. Results: The RelB-silencing inhibited cell growth of DLD-1 cells. The RelB-silencing exerted the anti-proliferative by downregulation of AKT/mTOR signaling. The RelB-silencing caused G0-G1 cell cycle arrested likely due to decreasing the expression of Cyclin D1 and CDK4, concomitant with increased expression of p27Kip1. The RelB-silencing enhanced cytotoxic effect of 5-FU and induced cell accumulation in S-phase. The RelB-silencing impaired the migration and invasion potential of DLD-1 cells, which was related to downregulation of MMP2, MMP9, and Integrin beta-1. Importantly, the RelB expression was correlated with depth of tumor invasion, lymph node metastasis, metastasis stage, and pTNM stage. High-RelB expression was significantly correlated with poor overall survival in CRC patients. Conclusion: Our studies here provided evidence that RelB plays an oncogenic role and conveys chemo-resistance to 5-FU. RelB can be considered as an independent indicator of prognosis in CRC. PMID- 30473629 TI - Water-pipe smoking promotes epithelial-mesenchymal transition and invasion of human breast cancer cells via ERK1/ERK2 pathways. AB - Background: With the increasing popularity of water-pipe smoking (WPS), it is critical to comprehend how WPS may affect women's health. The main goal of this study is to identify the potential outcome of WPS on human breast cancer progression. Methods: Two breast cancer cell lines, MCF7 and BT20, were used in this investigation. We explored the outcome of WPS on cell morphology and cell invasion using inverted microscope and Biocoat Matrigel invasion chambers. On the other hand, Western blot was employed to study the expression patterns of key control genes of cell adhesion and invasion. Results: Our data reveal that WPS induces epithelial-mesenchymal transition (EMT) of MCF7 and BT20 breast cancer cell lines; thus, WPS enhances cell invasion ability of both cell lines in comparison with their matched controls. More significantly, WPS provokes a down- and up-regulation of E-cadherin and focal adhesion kinase (FAK), respectively, which are important key regulators of cancer progression genes. Finally, our data point out that WPS incites the activation of Erk1/Erk2, which could be behind the stimulation of EMT and invasion as well as the deregulation of E-cadherin and FAK expression. Conclusion: Our data show, for the first time, that WPS initiates EMT and stimulates cell invasion of breast cancer cells, which could incite metastatic development in breast cancer patients. Thus, we believe that further studies, both in vitro and in vivo, are required to elucidate the pathogenic outcome of WPS on cancer progression of several human carcinomas including breast. PMID- 30473632 TI - Focus on the role of substance P in chronic urticaria. AB - Background: Emerging data have strengthened the importance of substance P (SP) as a proinflammatory mediator in human pathology. A role for SP in the pathogenesis of urticaria has long been hypothesized. Methods: Literature data regarding the possible role of SP in chronic urticaria/chronic spontaneous urticaria (CSU) have been reviewed and summarized in this manuscript. This review is based on pertinent articles that were retrieved by a selective literature search in the PubMed database. Articles in English published up to July 2018 were taken into consideration. Results: Recent studies in patients with CSU have demonstrated that circulating levels of SP are significantly elevated, in correlation with disease severity, and that SP-positive basophils are upregulated. SP has been shown to trigger degranulation in basophils derived from CSU patients. Moreover, SP can be involved in pseudoallergic reactions and may act as a histamine releasing factor in a subset of patients with CSU. Current evidence suggests that the biological activity of SP can be exerted not only through the conventional NK 1 receptor but also through the recently identified Mas-related G protein-coupled receptors. MRGPRX2 can cause mast cell activation and has been found to be upregulated in the skin of patients with severe chronic urticaria. Conclusions: Many findings seem to support the pathogenic involvement of SP in chronic urticaria/CSU. However, further studies are necessary to elucidate the role of SP as a mediator in CSU pathogenesis and a potential new therapeutic target. PMID- 30473631 TI - Markers of atopic dermatitis, allergic rhinitis and bronchial asthma in pediatric patients: correlation with filaggrin, eosinophil major basic protein and immunoglobulin E. AB - Background: Allergic reactions have been implicated as contributions in a number of atopic disorders, including atopic dermatitis (AD), allergic rhinitis (AR) and bronchial asthma (BA). However, the potential for filaggrin protein, eosinophil major basic protein (MBP) and immunoglobulin E (IgE) to elicit allergic response or to contribute to atopic disorders remains largely unexplored in pediatric patients. This study was undertaken to investigate the status and contribution of filaggrin protein, eosinophil MBP and total IgE in pediatric patients with AD, AR and BA. Methods: Sera from 395 pediatric patients of AD, AR or BA with varying levels of disease activity according to the disease activity index and 410 age matched non-atopic healthy controls were evaluated for serum levels of atopic markers, including filaggrin, eosinophil MBP and IgE. Results: Serum analysis showed that filaggrin levels were remarkably high in pediatric patients with AD, followed by BA and AR, whereas its levels were low in non-atopic pediatric controls. Eosinophil MBP levels in sera of atopic patients were significantly high as compared with their respective controls, but its levels were highest in AR patients, followed by AD and BA. Total IgE in sera of AD patients was markedly high, followed by AR and BA patients, whereas its levels were low in non-atopic pediatric controls. Interestingly, not only was an increased number of subjects positive for filaggrin protein, eosinophil MBP or total IgE, but also their levels were statistically significantly higher among those atopic patients whose disease activity scores were higher as compared with atopic patients with lower disease activity scores. Conclusions: These findings strongly support a role of filaggrin protein, eosinophil MBP and IgE in the onset of allergic reactions in pediatric patients with AD, AR and BA. The data suggest that filaggrin, eosinophil MBP or IgE might be useful in evaluating the progression of AD, AR or BA and in elucidating the mechanisms involved in the pathogenesis of these pediatric disorders. PMID- 30473633 TI - The severity of LPS induced inflammatory injury is negatively associated with the functional liver mass after LPS injection in rat model. AB - Background: High levels of serum lipopolysaccharide (LPS) were observed in sepsis patients with liver injury and high mortality. However, the role of liver in modulation LPS induced inflammatory injury was ill investigated. In the present study, the severity of LPS induced inflammatory response was observed after liver resection or portal branch occlusion to decreasing functional liver mass. The local and systemic damage was observed to investigate the role of liver in modulation inflammatory injury. Methods: First, 30%, 70%, and 90% partial hepatectomy (PH) were performed, and serum TNF-alpha, survival rate, and hepatic LPS uptake was observed. Second, LPS-exposure of the functional liver mass was decreased by selectively blocking the RL prior to LPS-injection, which was given 30 min before a 70% PH, and the inflammatory response was compared in the occluded and the non-occluded liver. The control group was subjected to LPS injection 30 min prior to liver resection without blocking the RL transiently. The serum TNF-alpha, ALT, AST, creatinine levels, and urea levels, survival rate, hepatic LPS uptake, and hepatic inflammatory cytokines was observed. Results: The decreasing of functional liver mass after 90%, 70%, and 30% PH was associated with decreased serum TNF-alpha, survival rate, and increased hepatic LPS uptake after LPS injection. Occluding the right lobes (RL) prior to LPS administration reversed the liver injury caused by 70% PH, indicated by 100% survival rate and decreased liver and kidney injury, and systemic inflammatory response. The induction of inflammatory response in occluding liver lobes were lower than un occluding liver lobes. Conclusions: The severity of the LPS-induced systemic inflammatory injury is determined by functional liver volume. This observation suggests that the liver is the central organ for the initiation of the inflammatory response, and is involved in causing a severe SIRS with systemic damage and death. PMID- 30473634 TI - Contribution of the inflammasome to inflammaging. AB - Background: Inflammation is a natural part of the aging process. This process is referred to as inflammaging. Inflammaging has been associated with deleterious outcomes in the aging brain in diseases such as Alzheimer's disease and Parkinson's disease. The inflammasome is a multi-protein complex of the innate immune response involved in the activation of caspase-1 and the processing of the inflammatory cytokines interleukin (IL)-1beta and IL-18. We have previously shown that the inflammasome plays a role in the aging process in the brain. In this study, we analyzed the brain of young (3 months old) and aged (18 months old) mice for the expression of inflammasome proteins. Results: Our findings indicate that the inflammasome proteins NLRC4, caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and IL-18 are elevated in the cytosol of cortical lysates in aged mice when compared to young. In addition, in the cytosolic fraction of hippocampal lysates in aged mice, we found an increase in NLRC4, caspase-1, caspase-11, ASC and IL-1beta. Moreover, we found higher levels of ASC in the mitochondrial fraction of aged mice when compared to young, consistent with higher levels of the substrate of pyroptosis gasdermin-D (GSDM-D) and increased pyroptosome formation (ASC oligomerization). Importantly, in this study we obtained fibroblasts from a subject that donated his cells at three different ages (49, 52 and 64 years old (y/o)) and found that the protein levels of caspase-1 and ASC were higher at 64 than at 52 y/o. In addition, the 52 y/o cells were more susceptible to oxidative stress as determined by lactose dehydrogenase (LDH) release levels. However, this response was ameliorated by inhibition of the inflammasome with Ac-Tyr-Val-Ala-Asp-Chloromethylketone (Ac YVAD-CMK). In addition, we found that the protein levels of ASC and IL-18 are elevated in the serum of subjects over the age of 45 y/o when compared to younger subjects, and that ASC was higher in Caucasians than Blacks and Hispanics, whereas IL-18 was higher in Caucasians than in blacks, regardless of age. Conclusions: Taken together, our data indicate that the inflammasome contributes to inflammaging and that the inflammasome-mediated cell death mechanism of pyroptosis contributes to cell demise in the aging brain. PMID- 30473636 TI - Management Options for Nocturia at a Large Urology Group Practice. PMID- 30473635 TI - Calcitonin gene-related peptide promotes proliferation and inhibits apoptosis in endothelial progenitor cells via inhibiting MAPK signaling. AB - Background: Calcitonin gene-related peptide (CGRP) contributes to bone formation by stimulating bone marrow stromal cell (BMSC) proliferation and differentiation. However, the proliferative and apoptotic effects of CGRP on bone marrow-derived endothelial progenitor cells (EPCs) have not been investigated. Methods: We tested the effects of CGRP on EPC proliferation and apoptosis by Cell Counting Kit-8, flow cytometry, and studied the effects of CGRP on the expression of proliferation- and apoptosis-related markers in EPCs and the underlying mitogen activated protein kinase (MAPK) signalling pathway by quantitative polymerase chain reaction and western blotting. Results: We detected EPC markers (CD34, CD133 and VEGFR-2) in 7-day cultures and found that CGRP (10- 10-10- 12 M) promoted the proliferation of cultured EPCs, with a peak increase of 30% at 10- 10 M CGRP. CGRP also upregulated the expression of proliferation-associated genes, including cyclin D1 and cyclin E, and increased the percentages of G2/M phase and S-phase cells after incubation 72 h. CGRP inhibited serum deprivation (SD)-induced apoptosis in EPCs after 24 and 48 h and downregulated the expression of apoptosis-related genes, including caspase-3, caspase-8, caspase-9 and Bax. Phosphorylated (p-)ERK1/2, p-p38 and p-JNK protein levels in EPCs treated with CGRP were significantly lower than those in untreated EPCs. Pre-treatment with the calcitonin receptor-like receptor (CRLR) antagonist CGRP8-37 or a MAPK pathway inhibitor (PD98059, SB203580 or SP600125) completely or partially reversed the pro-proliferative and anti-apoptotic effects and the reduced p ERK1/2, p-p38 and p-JNK expression induced by CGRP. Conclusion: Our results show that CGRP exerts pro-proliferative and anti-apoptotic effects on EPCs and may act by inhibiting MAPK pathways. PMID- 30473637 TI - Accuracy in 24-hour Urine Collection at a Tertiary Center. AB - There is a paucity of studies addressing the accuracy of 24-hour urine collection for assessing stone risk parameters. Collection accuracy is thought to be essential for assigning optimal therapy for stone prevention. The objective of this study was to determine factors associated with accurate and inaccurate collections. During a 2-year period (2015-2016), 241 stone formers completed 24 hour urine collections. They were divided into accurate collectors (AC), defined as at least one accurate urine collection, and inaccurate collectors (IC). Accuracy was assessed by 24-hour urine creatinine (Cr) excretion indexed to body weight (normal: males, 20-25 mg Cr/kg; females, 15-20 mg Cr/kg). Demographic data analyzed included age, gender, race, insurance status, partner status, income, and education. Statistical analysis methods included the chi-square test, Fisher's exact test, and the two-group t-test. Average age was 50.7 years at the time of collection; 50.2% were men, 86% were white, and 14% were black. Overall, 51.0% of collections were inaccurate. There was no statistical significance between AC and IC for gender (P = 0.85), race (P = 0.90), insurance status (P = 0.85), recurrence (P = 0.87), stone type (P = 0.57), education (P = 0.35), income (P 5 0.42), or poverty (P = 0.35). Older age (P = 0.017) and having a partner (P = 0.022) were significantly associated with AC. The high rate of inaccurate 24 hour urine collections is a concern. The only factors we identified as influencing collection accuracy were age and partner status. These results underscore the importance of developing methods to improve the accuracy of collecting 24-hour urine samples. PMID- 30473638 TI - Histologic Changes in Prostate Cancer Detected Subsequent to the 2012 United States Preventive Services Task Force (USPSTF) Prostate Cancer Screening Recommendation. AB - We report changes in the histopathology of prostate cancer diagnosed in a large urology group practice after the final United States Preventive Services Task Force (USPSTF) Grade D recommendation against prostate-specific antigen screening. All prostate biopsies performed from 2011 through 2015 in a large urology group practice were retrospectively reviewed; 2012 was excluded as a transition year. The changes in biopsy data in years following the USPSTF decision (2013-2015) were then compared with baseline (2011). A total of 10,944 biopsies were evaluated during the study period. Positive biopsy rates rose from 39.1% at baseline to 45.2% in 2015 (P < 0.01) with a marked shift toward more aggressive cancer throughout the study period. The absolute number of patients presenting with Gleason Grade Group 4 or 5 increased from 155/year at baseline to 231, 297, and 285 in 2013, 2014, and 2015, respectively (P < 0.05), unrelated to age or racial changes over time. Black men represented 16% of the cohort. Since the USPSTF recommendation against prostate cancer screening, trends toward a substantial upward grade migration and increased volume of cancers were noted in a cohort of nearly 11,000 patients in a real-world clinical practice. Additionally, continuing reductions in cancer detection in the United States may exacerbate these trends. PMID- 30473640 TI - ICD-10 Changes for October 1, 2018. PMID- 30473639 TI - LUGPA Celebrates Its 10th Anniversary at Its 2018 Annual Meeting. PMID- 30473641 TI - Azoospermia With Testosterone Therapy Despite Concomitant Intramuscular Human Chorionic Gonadotropin: NYU Case of the Month, July 2018. PMID- 30473642 TI - Endoscopic Management of Ureteral Stricture: NYU Case of the Month, August 2018. PMID- 30473643 TI - Characterization of Colombian Clay and Its Potential Use as Adsorbent. AB - This paper presents a mineralogical and physicochemical characterization of a Colombian clay found in an area with the greatest exploitation potential of smectites and possible use as an adsorbent for the removal of chromium. The clay was characterized by using X-ray diffraction (XRD), cation exchange capacity (CEC), X-ray fluorescence (XRF), Fourier transform infrared spectroscopy (FT-IR), thermal analysis (TGA/DSC), and nitrogen adsorption at 77 K. The homoionized clay was used as an adsorbent for the removal of Cr(III) in an aqueous solution. The homoionized clay was modified with hexadecyltrimethylammonium bromide (HDTMA-Br), and the organoclay obtained was evaluated for the adsorption of Cr(VI) in aqueous solution. The XRD analysis showed that the clay from Armero-Guayabal is primarily constituted by smectite (48 wt%) followed by quartz mineral (21 wt%). The chemical analysis of bulk clay showed that the predominant oxides are SiO2 (55.81 wt%), Al2O3 (16.25 wt%), and Fe2O3 (7.51 wt%), and the nitrogen adsorption indicated that the bulk clay has a specific surface area of 45.1 m2/g. Homoionized clay and organoclay achieved Cr(III) and Cr(VI) removals greater than 85.05 +/- 2.04% (pH between 3 and 4) and 82.93 +/- 1.03% (pH between 3 and 5), respectively, proving the potential of these materials for the removal of heavy metals in an aqueous solution. PMID- 30473644 TI - Fully Automated Delineation of Gross Tumor Volume for Head and Neck Cancer on PET CT Using Deep Learning: A Dual-Center Study. AB - Purpose: In this study, we proposed an automated deep learning (DL) method for head and neck cancer (HNC) gross tumor volume (GTV) contouring on positron emission tomography-computed tomography (PET-CT) images. Materials and Methods: PET-CT images were collected from 22 newly diagnosed HNC patients, of whom 17 (Database 1) and 5 (Database 2) were from two centers, respectively. An oncologist and a radiologist decided the gold standard of GTV manually by consensus. We developed a deep convolutional neural network (DCNN) and trained the network based on the two-dimensional PET-CT images and the gold standard of GTV in the training dataset. We did two experiments: Experiment 1, with Database 1 only, and Experiment 2, with both Databases 1 and 2. In both Experiment 1 and Experiment 2, we evaluated the proposed method using a leave-one-out cross validation strategy. We compared the median results in Experiment 2 (GTVa) with the performance of other methods in the literature and with the gold standard (GTVm). Results: A tumor segmentation task for a patient on coregistered PET-CT images took less than one minute. The dice similarity coefficient (DSC) of the proposed method in Experiment 1 and Experiment 2 was 0.481~0.872 and 0.482~0.868, respectively. The DSC of GTVa was better than that in previous studies. A high correlation was found between GTVa and GTVm (R = 0.99, P < 0.001). The median volume difference (%) between GTVm and GTVa was 10.9%. The median values of DSC, sensitivity, and precision of GTVa were 0.785, 0.764, and 0.789, respectively. Conclusion: A fully automatic GTV contouring method for HNC based on DCNN and PET CT from dual centers has been successfully proposed with high accuracy and efficiency. Our proposed method is of help to the clinicians in HNC management. PMID- 30473645 TI - Patient and Health Care Professional Perspectives: A Case Study of the Lung Cancer Integrated Care Pathway. AB - Introduction: The purpose of this study was to evaluate the perception of the quality of care, considering both patient experience and health care professionals' perceptions as well as patient outcome measures of an integrated lung cancer pathway. Methods: A cross-sectional study was conducted in 2016 at Ferrara University Hospital, Italy. OPportunity for Treatment In ONcology (OPTION) questionnaires were administered to 77 patients, and the Care Process Self-Evaluation Tool (CPSET) questionnaires were given to 38 health care professionals. The effectiveness of the pathway was evaluated by analysing the tool's positive impact on lung cancer surgery volume and 30-day mortality. Results: Seventy-seven patients were enrolled, and 38 health care professionals assessed the CPSET questionnaire. The highest scores were related to "respect" (100%), "satisfaction" (98.7%), and "trust" (97.4%) on the OPTION and to "patient focused vision" (97.2%) and "patient engagement" (94.4%) on the CPSET. The lowest scores were related to "information" (26%) and "cooperation with general practitioner" (17.6%) on the OPTION and "cooperation between the hospital and primary care" (23.5%) for the CPSET. The outcomes analysis shows an increase in the volume of activity and a decrease in 30-day mortality after pathway implementation. Discussion: The lung cancer pathway is a patient-centred intervention that enables care to be shaped for patient needs in order to improve the quality and efficiency of service and clinical outcome. PMID- 30473647 TI - Two Year's Long-term Outcomes of Very Low Birth Weight Infants in Korea. PMID- 30473646 TI - Applications of Metabolomics in the Study and Management of Preeclampsia; A Review of the Literature. AB - Introduction: Preeclampsia represents a major public health burden worldwide, but predictive and diagnostic biomarkers are lacking. Metabolomics is emerging as a valuable approach to generating novel biomarkers whilst increasing the mechanistic understanding of this complex condition. Objectives: To summarize the published literature on the use of metabolomics as a tool to study preeclampsia. Methods: PubMed and Web of Science were searched for articles that performed metabolomic profiling of human biosamples using either Mass-spectrometry or Nuclear Magnetic Resonance based approaches and which included preeclampsia as a primary endpoint. Results: Twenty-eight studies investigating the metabolome of preeclampsia in a variety of biospecimens were identified. Individual metabolite and metabolite profiles were reported to have discriminatory ability to distinguish preeclamptic from normal pregnancies, both prior to and post diagnosis. Lipids and carnitines were among the most commonly reported metabolites. Further work and validation studies are required to demonstrate the utility of such metabolites as preeclampsia biomarkers. Conclusion: Metabolomic based biomarkers of preeclampsia have yet to be integrated into routine clinical practice. However, metabolomic profiling is becoming increasingly popular in the study of preeclampsia and is likely to be a valuable tool to better understand the pathophysiology of this disorder and to better classify its subtypes, particularly when integrated with other omic data. PMID- 30473648 TI - Factors Associated with Vancomycin-Resistant Enterococcus Colonization in Patients Transferred to Emergency Departments in Korea. AB - Background: Vancomycin-resistant enterococci (VRE) infections have become a major healthcare-associated pathogen problem worldwide. Nosocomial VRE infections could be effectively controlled by screening patients at high risk of harboring VRE and thereby lowering the influx of VRE into healthcare centers. In this study, we evaluated factors associated with VRE colonization in patients transferred to emergency departments, to detect patients at risk for VRE carriage. Methods: This study was conducted in the emergency department of a medical college-affiliated hospital in Korea. Every patient transferred to the emergency department and admitted to the hospital from January to December 2016 was screened for VRE using rectal cultures. In this cross-sectional study, the dependent variable was VRE colonization and the independent variables were demographic and clinical factors of the patients and factors related to the transferring hospital. Patients were divided into two groups, VRE and non-VRE, and previously collected patient data were analyzed. Then we performed logistic regression analyses of characteristics that differed significantly between groups. Results: Out of 650 patients, 106 (16.3%) had positive VRE culture results. Significant variables in the logistic analysis were transfer from geriatric long-term care hospital (adjusted odds ration [aOR]: 8.017; 95% confidence interval [CI]: 1.378-46.651), hospital days (4-7 days; aOR: 7.246; 95% CI: 3.229-16.261), duration of antimicrobial exposure (1-3 days; aOR: 1.976; 95% CI: 1.137-3.436), and age (aOR: 1.025; 95% CI: 1.007 1.043). Conclusion: VRE colonization in patients transferred to the emergency department is associated primarily with factors related to the transferred hospitals rather than demographic and clinical characteristics. PMID- 30473649 TI - Impacts of the Journal Evaluation Program of the Korean Association of Medical Journal Editors (KAMJE) on the Quality of the Member Journals. AB - Background: In 1997 the Korean Association of Medical Journal Editors (KAMJE) instituted a program to evaluate member journals. Journals that passed the initial evaluation were indexed in the KoreaMed. Here, we report changes in measures of quality of the KAMJE member journals during the last 20 years. Methods: Quality measures used in the study comprised 3 assessment categories; self-assessment by journal editors, assessment of the journals by KAMJE reviewers, and by Korean health science librarians. Each used detailed criteria to score the journals on a scale of 0 to 5 or 6 in multiple dimensions. We compared scores at baseline evaluation and those after 7 years for 129 journals and compared improvements in journals indexed vs. not-indexed by the Web of Science (Science Citation Index Expanded; SCIE). Results: Among 251 KAMJE member journals at the end of 2015, 227 passed evaluation criteria and 129 (56%) had both baseline and 7-year follow-up assessment data. The journals showed improvement overall (increase in median [interquartile range; IQR] score from baseline, 0.47 [0.64]; 95% confidence interval [CI], 0.44-0.61; P < 0.001) and within each category (median [IQR] increase by editor's assessment, 0.17 [0.83]; 95% CI, 0.04-0.26; P = 0.007; by reviewer's, 0.45 [1.00]; 95% CI, 0.29-0.57; P < 0.001; by librarian's, 1.75 [1.08]; 95% CI, 1.77-2.18, P < 0.001). Before the foundation of KAMJE in 1996, there were only 5 Korean medical journals indexed in the MEDLINE and none in SCIE, but 24 journals in the MEDLINE and 34 journals in SCIE were indexed by 2016. Conclusion: The KAMJE journal evaluation program successfully contributes improving the quality of the member journals. PMID- 30473650 TI - Add-on Eye Movement Desensitization and Reprocessing (EMDR) Therapy for Adults with Post-traumatic Stress Disorder Who Failed to Respond to Initial Antidepressant Pharmacotherapy. AB - This study examined the add-on efficacy of eye movement desensitization and reprocessing (EMDR) therapy among adult civilians with post-traumatic stress disorder (PTSD) who continued to be symptomatic after more than 12 weeks of initial antidepressant treatment. Scores for the Clinician Administered PTSD Scale (CAPS) were rated pre- and post-EMDR and at a 6-month follow-up. After an average of six sessions of EMDR treatment, seven of 14 patients (50%) showed more than a 30% decrease in CAPS score and eight (57%) no longer met the criteria for PTSD. Our results indicate that EMDR could be successfully added after failure of initial pharmacotherapy for PTSD. PMID- 30473651 TI - National Registry Data from Korean Neonatal Network: Two-Year Outcomes of Korean Very Low Birth Weight Infants Born in 2013-2014. AB - Background: The aim of this study was to observe long-term outcomes of very low birth weight infants (VLBWIs) born between 2013 and 2014 in Korea, especially focusing on neurodevelopmental outcomes. Methods: The data were collected from Korean Neonatal Network (KNN) registry from 43 and 54 participating units in 2013 and 2014, respectively. A standardized electronic case report form containing 30 items related to long-term follow up was used after data validation. Results: Of 2,660 VLBWI, the mean gestational age and birth weight were 291/7 +/- 26/7 weeks and 1,093 +/- 268 g in 2013 and 292/7 +/- 26/7 weeks and 1,125 +/- 261 g in 2014, respectively. The post-discharge mortality rate was 1.2%-1.5%. Weight < 50th percentile was 46.5% in 2013 and 66.1% in 2014. The overall prevalence of cerebral palsy among the follow up infants was 6.2% in 2013 and 6.6% in 2014. The Bayley Scales of Infant Developmental Outcomes version II showed 14%-25% of infants had developmental delay and 3%-8% of infants in Bayley version III. For the Korean developmental screening test for infants and children, the area "Further evaluation needed" was 5%-12%. Blindness in both eyes was reported to be 0.2%-0.3%. For hearing impairment, 0.8%-1.9% showed bilateral hearing loss. Almost 50% were readmitted to hospital with respiratory illness as a leading cause. Conclusion: The overall prevalence of long-term outcomes was not largely different among the VLBWI born between 2013 and 2014. This study is the first large national data study of long-term outcomes. PMID- 30473652 TI - Effect of Childbirth Age on Bone Mineral Density in Postmenopausal Women. AB - Background: In postmenopausal women, there is rapid bone loss due to estrogen depletion. In women, reproductive factors such as age at menarche, breastfeeding, and parity are considered risk factors of osteoporosis. Many reports suggest that obesity is associated with a reduced risk of osteoporosis. This nationwide, population-based study aims to identify the association between maternal age and osteoporosis risk in postmenopausal women of different obesity classifications. Methods: We assessed data from the Korean National Health and Nutrition Examination Survey 2010-2012. The study included 1,328 postmenopausal women, after excluding women with missing data for reproductive history among 4,546 postmenopausal women in the survey. Multivariate regression was used to identify the association between childbirth age and postmenopausal bone mineral density after adjustments for confounding factors. Results: The prevalence of postmenopausal osteoporosis was 35.24% (n = 468). After dividing the subjects into obese and non-obese groups based on body mass index (BMI) and waist circumference, there were significant differences between non-osteoporosis and osteoporosis groups with regard to age at first childbirth, age at last childbirth, and parity in the BMI-based general obesity group. The prevalence of osteoporosis was highest in women older than 35 years old at last childbirth. The prevalence of osteoporosis was also greater in women with parity >= 4 compared to those with lower parity levels. Conclusion: Postmenopausal women of older age at last childbirth and higher parity were at increased risk of osteoporosis in the BMI-based non-general obesity group. PMID- 30473653 TI - Differential Signature of Obesity in the Relationship with Acute Kidney Injury and Mortality after Coronary Artery Bypass Grafting. AB - Background: Obesity is related to several comorbidities and mortality, but its relationship with acute kidney injury (AKI) and long-term mortality remain undetermined in patients undergoing coronary artery bypass grafting. Methods: Data from 3,018 patients (age >= 18 years) who underwent coronary artery bypass graft surgery from two tertiary referral centers were retrospectively reviewed between 2004 and 2015. Obesity was defined using the body mass index, according to the World Health Organization's recommendation. The odds and hazard ratios in post-surgical, AKI, and all-cause mortality were calculated after adjustment for multiple covariates. Patients were followed for 90 +/- 40.9 months (maximum: 13 years). Results: Among the cohort, 37.4%, 2.4%, 21.1%, 35.1%, and 4.0% of patients were classified as normal weight, underweight, overweight-at-risk, obese I, and obese II, respectively. Post-surgical AKI developed in 799 patients (26.5%). Patients in the obese groups (overweight-at-risk to obese II) had a higher risk of AKI than did those in the normal-weight group. During the follow up period, 787 patients (26.1%) died. Underweight patients had a higher risk of mortality than did normal-weight patients, whereas overweight-at-risk, obese I, and obese II patients showed better survival rates. Conclusion: After coronary artery bypass graft surgery, obese patients encountered a high risk of AKI, and underweight patients exhibited a low chance of survival. Awareness of both obese and underweight statuses should be raised in these patients. PMID- 30473655 TI - De novo transcriptome assembly of brackish water flea Diaphanosoma celebensis based on short-term cadmium and benzo[a]pyrene exposure experiments. AB - To develop a brackish water flea as a promising model for marine monitoring, Diaphanosoma celebensis were exposed to two pollutants, cadmium (Cd) and benzo[a]pyrene (BaP), which have different chemical characteristics and distinct modes of metabolic action on aquatic animals. Twenty-four hours after exposure to Cd (2 mg/L) or BaP (25 MUg/L), whole body transcriptomes were analyzed. In total, 99.6 Mbp were assembled from nine libraries, resulting in 98,458 transcripts with an N50 of 1883 bp and an average contig length of 968 bp. Functional gene annotations were performed using Gene Ontology, Eukaryotic Orthologous Groups, and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Cd significantly modulated endocrine and digestive enzyme system. Following BaP treatment, DNA repair and circadian rhythm related metabolisms were significantly modulated. Both the chemicals induced stress response and detoxification metabolism. This brackish water flea genomic information will be useful to monitor estuaries and coastal regions, as water fleas have been confirmed as promising sentinel models in freshwater ecosystems. PMID- 30473654 TI - Bone Mineral Density and Osteoporotic Vertebral Fractures in Traditional, Unassisted, Free-Diving Women (Haenyeos). AB - Background: Water pressure and muscle contraction may influence bone mineral density (BMD) in a positive way. However, divers experience weightlessness, which has a negative effect on BMD. The present study investigated BMD difference in normal controls and woman free-divers with vertebral fracture and with no fracture. Methods: Between January 2010 and December 2014, traditional woman divers (known as Haenyeo in Korean), and non-diving women were investigated. The study population was divided into osteoporotic vertebral fracture and non fracture groups. The BMD of the lumbar spine and femoral neck was measured. The radiological parameters for global spinal sagittal balance were measured. Results: Thirty free-diving women and thirty-three non-diving women were enrolled in this study. The mean age of the divers was 72.1 +/- 4.7 years and that of the controls was 72.7 +/- 4.0 years (P = 0.61). There was no statistical difference in BMD between the divers and controls. In divers, cervical lordosis and pelvic tilt were significantly increased in the fracture subgroup compared to the non fracture subgroup (P = 0.028 and P = 0.008, respectively). Sagittal vertical axis was statistically significantly correlated with cervical lordosis (Spearman's rho R = 0.41, P = 0.03), and pelvic tilt (Spearman's rho R = 0.46, P = 0.01) in divers. Conclusion: BMD did not differ significantly between divers and controls during their postmenopausal period. When osteoporotic spinal fractures develop, compensation mechanisms, such as increased cervical lordosis and pelvic tilt, was more evident in traditional woman divers. This may be due to the superior back muscle strength and spinal mobility of this group of women. PMID- 30473656 TI - Construction of a high-density genetic map: genotyping by sequencing (GBS) to map purple seed coat color (Psc) in hulless barley. AB - Background: Colored hulless barley are more suitable in food processing compared to normal (yellow) varieties because it is rich in bioactive compounds and produces higher extraction pearling fractions. Therefore, seed coat color is an important agronomic trait for the breeding and study of hulless barley. Results: Genotyping-by-sequencing single-nucleotide polymorphism (GBS-SNP) analysis of a doubled haploid (DH) mapping population (Nierumuzha * Kunlun10) was conducted to map the purple seed coat color genes (Psc). A high-density genetic map of hulless barley was constructed, which contains 3662 efficient SNP markers with 1129 bin markers. Seven linkage groups were resolved, which had a total length of 645.56 cM. Chromosome length ranged from 60.21 cM to 127.21 cM, with average marker density of 0.57 cM. A total of five loci accounting for 3.79% to 23.86% of the observed phenotypic variation for Psc were detected using this high-density map. Five structural candidate genes (F3'M, HID, UF3GT, UFGT and 5MAT) and one regulatory factor (Ant1) related to flavonoid or anthocyanin biosynthesis were identified.. Conclusions: Five structural candidate genes and one regulatory factor related to flavonoid or anthocyanin biosynthesis have been identified using a high-density genetic map of hulless barley. This study lays the foundation for map-based cloning of Psc but provides a valuable tool for studying marker-trait associations and its application to marker-assisted breeding of hulless barley. PMID- 30473657 TI - A Cooperative Ternary Catalysis System for Asymmetric Lactonizations of alpha Ketoesters. AB - A general and enantioselective N-heterocyclic carbene (NHC)-catalyzed lactonization of simple enals and alpha-ketoesters has been discovered using a new ternary cooperative catalytic system. The highly selective annulation was achieved by using a combination of a chiral NHC, a hydrogen-bond donor, and a metal salt, facilitating self-assembly of the reactive partners. A proposed model for this new mode of NHC chiral relay catalysis is supported by experimental and computational mechanistic studies. PMID- 30473658 TI - Photoacoustic Imaging of Embryonic Stem Cell-Derived Cardiomyocytes in Living Hearts with Ultrasensitive Semiconducting Polymer Nanoparticles. AB - The last decade has seen impressive progress in human embryonic stem cell-derived cardiomyocytes (hESC-CMs) that makes them ideal tools to repair injured hearts. To achieve an optimal outcome, advanced molecular imaging methods are essential to accurately track these transplanted cells in the heart. Herein, we demonstrate for the first time that a class of photoacoustic nanoparticles (PANPs) incorporating semiconducting polymers (SPs) as contrast agents can be used in the photoacoustic imaging (PAI) of transplanted hESC-CMs in living mouse hearts. This is achieved by virtue of two benefits of PANPs. First, strong PA signals and specific spectral features of SPs allow PAI to sensitively detect and distinguish a small number of PANP-labeled cells (2,000) from background tissues in vivo. Second, the PANPs show a high efficiency for hESC-CM labeling without adverse effects on cell structure, function, and gene expression. Assisted by ultrasound imaging, the delivery and engraftment of hESC-CMs in living mouse hearts can be assessed by PANP-based PAI with high spatial resolution (~100 MUm). In summary, this study explores and validates a novel application of SPs as a PA contrast agent to track labeled cells with high sensitivity and accuracy in vivo, highlighting the advantages of integrating PAI and PANPs to advance cardiac regenerative therapies. PMID- 30473659 TI - Challenges and Perspectives of Quantitative Functional Sodium Imaging (fNaI). AB - Brain function has been investigated via the blood oxygenation level dependent (BOLD) effect using magnetic resonance imaging (MRI) for the past decades. Advances in sodium imaging offer the unique chance to access signal changes directly linked to sodium ions (23Na) flux across the cell membrane, which generates action potentials, hence signal transmission in the brain. During this process 23Na transiently accumulates in the intracellular space. Here we show that quantitative functional sodium imaging (fNaI) at 3T is potentially sensitive to 23Na concentration changes during finger tapping, which can be quantified in gray and white matter regions key to motor function. For the first time, we measured a 23Na concentration change of 0.54 mmol/l in the ipsilateral cerebellum, 0.46 mmol/l in the contralateral primary motor cortex (M1), 0.27 mmol/l in the corpus callosum and -11 mmol/l in the ipsilateral M1, suggesting that fNaI is sensitive to distributed functional alterations. Open issues persist on the role of the glymphatic system in maintaining 23Na homeostasis, the role of excitation and inhibition as well as volume distributions during neuronal activity. Haemodynamic and physiological signal recordings coupled to realistic models of tissue function will be critical to understand the mechanisms of such changes and contribute to meeting the overarching challenge of measuring neuronal activity in vivo. PMID- 30473661 TI - Sleep Disturbance in Mild Cognitive Impairment and Association With Cognitive Functioning. A Case-Control Study. AB - Objectives: The aims of the current study are to (1) report the frequency of specific sleep disturbance symptoms in Mild Cognitive Impairment (MCI) and cognitive healthy older persons; (2) examine whether overall poor sleep and specific sleep disturbance symptoms are more common in persons with MCI compared to cognitive healthy older controls and; (3) examine the association between sleep disturbances and performance in general and specific cognitive domains in persons with MCI and separately in cognitive healthy older persons. Methods: Data were collected at the Fondazione Ospedale San Camillo Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Venice, Italy as part of the European VPH DARE@IT project. We included 69 persons with MCI (mean age 75.7; SD = 7.7) and 72 sex-matched cognitively healthy controls (mean age 71.8; SD = 7.0). Participants underwent extensive neuropsychological assessment and evaluation of subjective sleep performance with the Sleep Continuity in Alzheimer's Disease Scale(SCADS). Results: A fifth of MCI patients (21.7%, n = 15) had poor sleep compared to 15.3% (n = 11) of cognitively healthy controls. MCI patients had a 3.2 higher odds of having poor sleep compared to cognitively healthy controls after adjustment for age, education, sex, and general cognitive functioning (Odds Ratio (OR) = 3.2; 95% Confidence Interval (CI) = 1.1-9.2). Persons who reported waking up twice or more during the night had higher odds of being MCI compared to those who never wake or wake only once (OR = 2.6; 95% CI = 1.1-6.1). In MCI patients, poor sleep was associated with better general cognitive functioning and short-term working memory, whereas in cognitive healthy older persons poor sleep was associated with impairment in episodic memory performance and executive functioning. Discussion: Our results confirm previous studies showing that sleep disturbances are common in MCI, and this may be due to an ongoing neurodegenerative process rather than a symptom of cognitive impairment. Future research with objective sleep measurements are needed in MCI as well as interventions to improve sleep with the aim of preventing cognitive decline. PMID- 30473660 TI - Modeling Contextual Modulation of Memory Associations in the Hippocampus. AB - We present a computational model of how memories can be contextually acquired and recalled in the hippocampus. Our adaptive contextual memory model comprises the lateral entorhinal cortex (LEC), the dentate gyrus (DG) and areas CA3 and CA1 in the hippocampus, and assumes external inputs about context that originate in the prefrontal cortex (PFC). Specifically, we propose that there is a top-down bias on the excitability of cells in the DG of the hippocampus that recruits a sub population of cells to differentiate contexts, independent of experienced stimuli, expanding the "pattern separation" role typically attributed to the DG. It has been demonstrated in rats that if PFC is inactivated, both acquisition and recall of memory associations are impaired. However, PFC inactivation during acquisition of one set of memory associations surprisingly leads to subsequent facilitation of the acquisition of a conflicting set of memory associations in the same context under normal PFC operation. We provide here the first computational and algorithmic account of how the absence or presence of the top down contextual biases on the excitability of DG cells during different learning phases of these experiments explains these data. Our model simulates PFC inactivation as the loss of inhibitory control on DG, which leads to full or partial activation of DG cells related to conflicting memory associations previously acquired in different contexts. This causes context-inappropriate memory traces to become active in the CA3 recurrent network and thereby the output CA1 area within the hippocampus. We show that these incongruous memory patterns proactively interfere with and slow the acquisition of new memory associations. Further, we demonstrate that pattern completion within CA3 in response to a partial cue for the recall of previously acquired memories is also impaired by PFC inactivation for the same reason. Pre-training the model with interfering memories in contexts different from those used in the experiments, simulating a lifetime of experiences, was crucial to reproduce the rat behavioral data. Finally, we made several testable predictions based on the model that suggest future experiments to deepen our understanding of brain-wide memory processes. PMID- 30473663 TI - 25-Hydroxyvitamin D Levels and the Risk of Dementia and Alzheimer's Disease: A Dose-Response Meta-Analysis. AB - Background and Purpose: Conclusions of previous cohort studies on the relationship between 25-hydroxyvitamin D level and the risk of dementia and Alzheimer's disease were not consistent. Thus, we performed a dose-response meta analysis to evaluate this relationship by summarizing cohort studies. Methods: Pubmed, Embase, Cochrane, and Web of Science databases were searched for relevant studies. Cohort studies concerning the association between 25-hydroxyvitamin D level and dementia or Alzheimer's disease were included. Results of studies were pooled and the dose-response relationship was determined using a random-effect model. Results: Ten cohort studies, with 28,640 participants were included. A significant inverse relationship was found between 25-hydroxyvitamin D level and the risk of dementia and Alzheimer's disease. In addition, we found a linear dose response relationship in that a 10 nmol/L increase in 25-hydroxyvitamin D level may lead to a 5% decrease in the risk of dementia (relative risk, 0.95; 95% confidence interval, 0.93-0.98) and 7% in the risk of Alzheimer's disease (relative risk, 0.93; 95% confidence interval, 0.89-0.97). Conclusion: Plasma or serum 25-hydroxyvitamin D concentration was inversely related to the risk of dementia and Alzheimer's disease, consistent with a linear dose-response relationship. PMID- 30473662 TI - Early Detection of Alzheimer's Disease Using Non-invasive Near-Infrared Spectroscopy. AB - Mild cognitive impairment (MCI) is a cognitive disorder characterized by memory impairment, wherein patients have an increased likelihood of developing Alzheimer's disease (AD). The classification of MCI and different AD stages is therefore fundamental for understanding and treating the disease. This study aimed to comprehensively investigate the hemodynamic response patterns among various subject groups. Functional near-infrared spectroscopy (fNIRS) was employed to measure signals from the frontal and bilateral parietal cortices of healthy controls (n = 8), patients with MCI (n = 9), mild (n = 6), and moderate/severe AD (n = 7) during a digit verbal span task (DVST). The concentration changes of oxygenated hemoglobin (HbO) in various subject groups were thoroughly explored and tested. Result revealed that abnormal patterns of hemodynamic response were observed across all subject groups. Greater and steeper reductions in HbO concentration were consistently observed across all regions of interest (ROIs) as disease severity developed from MCI to moderate/severe AD. Furthermore, all the fNIRS-derived indexes were found to be significantly and positively correlated to the clinical scores in all ROIs (R >= 0.4, P < 0.05). These findings demonstrate the feasibility of utilizing fNIRS for the early detection of AD, suggesting that fNIRS-based approaches hold great promise for exploring the mechanisms underlying the progression of AD. PMID- 30473664 TI - Black Truffle Aqueous Extract Attenuates Oxidative Stress and Inflammation in STZ Induced Hyperglycemic Rats via Nrf2 and NF-kappaB Pathways. AB - Background and Purpose: Tuber melanosporum (black truffle) has been considered as a medicinal mushroom for a long time. T. melanosporum has the ability to attenuate oxidative stress and in turn diabetes mellitus (DM). DM has become an awfully common chronic unwellness, threatening people's well-being. There are nearly 1 in 10 people in the world affected by diabetes. Oxidative stress plays a crucial role in vascular complications related to DM. Our study aimed to attain an effective treatment method to alleviate oxidative stress by scavenging free radicals and reducing inflammation, to display how truffle aqueous extract (TE) attenuates hyperglycemia. Methods: Streptozotocin (STZ)-induced hyperglycemic rat model was accustomed to check the hypoglycemic effect of black truffle by relating it with Nrf2 and NF-kappaB pathways. Varied biomarkers and inflammatory markers were analyzed. Results: Rats treated with TE showed reduced glucose levels, attenuated oxidative stress through regulation of SOD, CAT, VIT-E, and VIT-C. The gene expression of Nrf2 and NF-kappaB in rats treated with TE was increased to normal group level. The mRNA expression of inflammatory pathway genes and oxidative stress pathway genes in rats treated with TE was brought back normal. Similar results were achieved in the rats treated with standard drug, glibenclamide (GB). TE conjointly inhibits the state of inflammation within the tissues generally littered with the symptoms of hyperglycemia. Conclusion: The results of our study show the hypoglycemic impact of black truffle on STZ-induced hyperglycemia in rats via Nrf2 and NF-kappaB pathways, and both pathways have significant improvement that may support the hypoglycemic impact of truffle. PMID- 30473665 TI - Kinome-Wide siRNA Screening Identifies Src-Enhanced Resistance of Chemotherapeutic Drugs in Triple-Negative Breast Cancer Cells. AB - Background: Chemotherapy is the main treatment for triple-negative breast cancer (TNBC), which lack molecular markers for diagnosis and therapy. Cancer cells activate chemoresistant pathways and lead to therapeutic failure for patients with TNBC. Several kinases have been identified as chemoresistant genes. However, the involvement of kinases in the chemoresistance in TNBC cells is not fully understood. Methods: We employed a kinome siRNA library to screen whether targeting any kinases could increase the chemosensitivity of TNBC cell lines. The effects of kinase on cell viability in various breast cancer cells were validated with ATP level and colony formation. Protein expression and phosphorylation were determined by immunoblotting. The Cancer Genome Atlas (TCGA) dataset was collected to analyze the correlation of Src expression with prognosis of TNBC patients. Results: Primary screening and validation for the initial hits showed that Src kinase was a potential doxorubicin-resistant kinase in the TNBC cell lines MDA-MB-231 and Hs578T. Both siRNA against Src and the Src inhibitor dasatinib enhanced the cytotoxic effects of doxorubicin in TNBC cells. Moreover, phosphorylation of AKT and signal transducer and activator of transcription 3 (STAT3), downstream effectors of Src, were accordingly decreased in Src-silenced or -inhibited TNBC cells. Additionally, TCGA data analysis indicated that Src expression levels in tumor tissues were higher than those in tumor-adjacent normal tissues in patients with TNBC. High co-expression level of Src and STAT3 was also significantly correlated with poor prognosis in patients. Conclusion: Our results showed that Src-STAT3 axis might be involved in chemoresistance of TNBC cells. PMID- 30473666 TI - Caveolin-3 Microdomain: Arrhythmia Implications for Potassium Inward Rectifier and Cardiac Sodium Channel. AB - In human cardiac ventricular myocytes, caveolin-3 functions as a scaffolding and regulatory protein for signaling molecules and compartmentalizes ion channels. Our lab has recently explored this sub-cellular microdomain and found that potassium inward rectifier Kir2.x is found in association with caveolin-3. The three cardiac Kir2.x isoforms (Kir2.1, Kir2.2, and Kir2.3) are the molecular correlates of IK1 in the heart, of which Kir2.1 is the dominant isoform in the ventricle. Kir2.1 channels assemble with Kir2.2 and Kir2.3 forming hetero tetramers that modulate IK1. IK1 sets the resting membrane potential and assists with terminal phase 3 ventricular repolarization. In our studies using native human ventricular tissue, Kir2.x co-localizes with caveolin-3 and significance of the association between Kir2.x and caveolin-3 is emphasized in relation to mutations in the gene which encodes caveolin-3, CAV3, associated with Long QT Syndrome 9 (LQT9). LQT9-associated CAV3 mutations cause decreased current density in Kir2.1 and Kir2.2 as homomeric and heteromeric channels, which affects repolarization and membrane potential stability. A portion of Kir2.1 cardiac localization parallels that of the cardiac sodium channel (Nav1.5). This may have implications for Long QT9 in which CAV3 mutations cause an increase in the late current of Nav1.5 (INa-L) via nNOS mediated nitrosylation of Nav1.5. In iPS-CMs, expression of LQT9 CAV3 mutations resulted in action potential duration (APD) prolongation and early-after depolarizations (EADs), supporting the arrhythmogenicity of LQT9. To evaluate the combined effect of the CAV3 mutants on INa-L and IK1, we studied both ventricular and Purkinje myocyte mathematical modeling. Interestingly, mathematical ventricular myocytes, similar to iPS-CMs, demonstrated EADs but no sustained arrhythmia. In contrast, Purkinje modeling demonstrated delayed-after depolarizations (DADs) driven mechanism for sustained arrhythmia, dependent on the combined loss of IK1 and gain of INa-L. This finding changes the overall assumed arrhythmia phenotype for LQT9. In future studies, we are exploring caveolar micro-domain disruption in heart failure and how this effects Kir2.x and Nav1.5. Here we review the caveolae cardiac microdomain of Kir2.x and Nav1.5 and explore some of the downstream effects of caveolin-3 and caveolae disruption in specific clinical scenarios. PMID- 30473667 TI - Formal Thought Disorders-Historical Roots. AB - In this article the authors intend to review in an intelligible and comprehensive way the historical roots of Formal Thought Disorders. Early descriptions of thought disorders date back to the XIX century with Esquirol, but it was in the first half of the XX century that several authors introduced the main features of the actual concept of Formal Thought Disorders. Emil Kraepelin described akataphasia (inability to find the appropriate expression for a thought) in patients with dementia praecox (a term that some years later was replaced by schizophrenia). Bleuler and Kretschmer also identified in schizophrenic patients a generalized "loosening of associations" and Carl Schneider described several Formal Thought Disorders such as derailment, fusion, omission, suspension and driveling. At the end of the XX century Nancy Andreasen studied the classical descriptions regarding Formal Thought Disorders, reclassified them and also introduced a scale to assess them. Although the specificity of these symptoms in schizophrenia and psychosis has been a source of controversy among the different authors, the importance given to their presence in these mental disorders is universal. We defend that it is crucial that these historical and conceptual elements are grasped in order to assess Formal Thought Disorders for clinical and research purposes. PMID- 30473668 TI - Association Between Plasma Caffeine and Other Methylxanthines and Metabolic Parameters in a Psychiatric Population Treated With Psychotropic Drugs Inducing Metabolic Disturbances. AB - Importance: Multiple studies conducted in the general population identified an association between self-reported coffee consumption and plasma lipid levels. To date, no study assessed whether and which plasma methylxanthines (caffeine and/or its metabolites, i.e., paraxanthine, theophylline, and theobromine) are associated with plasma lipids. In psychiatric patients, an important coffee consumption is often reported and many psychotropic drugs can induce a rapid and substantial increase of plasma lipid levels. Objective: To determine whether plasma methylxanthines are associated with metabolic parameters in psychiatric patients receiving treatments known to induce metabolic disturbances. Design, Setting, and Participants: Data were obtained from a prospective study including 630 patients with metabolic parameters [i.e., body mass index (BMI), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (non HDL-C), and fasting triglycerides (TG)] monitored routinely during psychotropic treatment. Exposures: Plasma methylxanthines levels. Main Outcomes and Measures: Metabolic variables including BMI and plasma lipid levels. Results: Multivariate analyses indicated that BMI, TC, HDL-C, and non-HDL-C increased significantly with increasing total methylxanthines (p corrected <= 0.05). In addition, compared to patients with plasma caffeine concentration in the lowest quartile, those with caffeine concentration in the highest quartile were twice more prone to suffer from non-HDL hypercholesterolemia (p corrected = 0.05), five times more likely to suffer from hypertriglyceridemia (p corrected = 0.01) and four times more susceptible to be overweight (p corrected = 0.01). Conclusions and Relevance: This study showed that plasma caffeine and other methylxanthines are associated with worsening of metabolic parameters in patients receiving psychotropic treatments known to induce metabolic disturbances. It emphasizes that important caffeine consumption could be considered as an additional environmental risk factor for metabolic worsening in patients receiving such treatments. PMID- 30473670 TI - Different Outcomes in the Acquisition of Residual V2 and Do-Support in Three Norwegian-English Bilinguals: Cross-Linguistic Influence, Dominance and Structural Ambiguity. AB - This paper investigates the acquisition of residual verb second (V2) in three corpora consisting of data from Norwegian-English bilinguals (Emma, Emily and Sunniva) in order to determine to what extent these structures are affected by cross-linguistic influence (CLI) from Norwegian V2. The three girls exhibit three different patterns with regard to the relevant constructions. They are very target-like in their use of auxiliaries in the relevant structures. However, when it comes to do-support, Emily and Sunniva are equally target-like, while Emma mainly produces non-target-like structures. These either involve the omission of do, or non-target-like movement of a lexical verb. Furthermore, Emma also allows verb movement across the subject with both lexical verbs and auxiliaries in topicalised structures, suggesting that she has overgeneralised residual V2 across verb types and clause types. Emily, on the other hand, is very target-like in structures involving residual V2 in English, but also allows auxiliaries and dummy-do to move across the subject in topicalised structures, overgeneralising residual V2 to apply to non-subject-initial declaratives. Finally, Sunniva is very precocious and very target-like in all the relevant structures, which may be an indication of acceleration due to CLI from Norwegian V2. We discuss these results with reference to language balance, finding that the measures available to us suggest that the differences between the children cannot straightforwardly be explained by language dominance. Instead, we suggest that these results can be accounted for by ambiguity in the English system, leaving the data open to several possible interpretations when acquired in contact with the consistent V2 system in Norwegian. This has several consequences: (i) the three girls' parsers interpret the input differently, (ii) differences between the three children are qualitative rather than quantitative and (iii) there has to be some mechanism that ensures that the children can 'recover' from these non-target-like grammars. In this paper, we will focus on the first two issues. PMID- 30473671 TI - How Do Career Aspirations Benefit Organizations? The Mediating Roles of the Proactive and Relational Aspects of Contemporary Work. AB - This paper examines how employees' career aspirations benefit organizations, i.e., contribute to strengthening organizational capabilities and connections, by means of two aspects of contemporary work: proactive and relational. Data were collected from alumni of a public university in Amsterdam, the Netherlands, in two waves with a 1-year time lag. The results showed that employees with career aspirations strengthen: (a) organizational capabilities; and (b) organizational connections through their instrumental and psychosocial relationships. Interestingly, although employees' career aspirations were positively associated with taking charge, we did not find that taking charge mediates the relationship between career aspirations and employees' individual contributions to organizational capabilities. This study is the first to examine how individual career aspirations benefit organizations, and it discusses the results in light of their novel contributions to theory and practice. PMID- 30473672 TI - Pre-service and In-service Teachers' Metacognitive Knowledge of Learning Strategies. AB - Research in cognitive psychology has suggested that difficulties are often desirable for learning: learning strategies that create difficulties for learners during practice often produce durable learning. Prominent examples of effective learning strategies that introduce desirable difficulties are testing as a means of learning, spacing study sessions over time, and interleaving practice of different topics. Previous research has suggested that, generally, undergraduates' metacognitive knowledge about the effectiveness of these learning strategies is inaccurate. The goal of the current study was to extend the examination of metacognitive knowledge of learning strategies to pre-service and in-service teachers, and further examine whether teachers' metacognitive knowledge is related to their teaching experience. Pre-service teachers enrolled in a university teacher training program (N = 83) and in-service elementary, junior-high, and high school teachers (N = 82) were presented with learning scenarios and predicted which of two learning strategies would yield the better outcome. Results suggested that, overall, both pre-service and in-service teachers failed to predict the advantages of testing, spacing, and interleaving as learning strategies. Furthermore, their knowledge of learning strategies failed to increase with teaching experience. It is, therefore, recommended that explicit instruction about the benefits of empirically supported learning strategies should be included in teacher training and development programs. PMID- 30473669 TI - Pituitary Volume and Socio-Cognitive Functions in Individuals at Risk of Psychosis and Patients With Schizophrenia. AB - Objectives: Increased pituitary volume, which probably reflects hypothalamic pituitary-adrenal (HPA) hyperactivity, has been reported in patients with schizophrenia and individuals at risk of psychosis. On the basis of potential role of abnormal HPA axis function on cognitive impairments in psychosis, we aimed to examine possible relations between the pituitary volume and socio cognitive impairments in these subjects. Methods: This magnetic resonance imaging study examined the pituitary gland volume in 38 subjects with at-risk mental state (ARMS) [of whom 4 (10.5%) exhibited the transition to schizophrenia], 63 patients with schizophrenia, and 61 healthy controls. Social and cognitive functions of the ARMS and schizophrenia groups were assessed using the Brief Assessment of Cognition in Schizophrenia (BACS), the Schizophrenia Cognition Rating Scale (SCoRS), and the Social and Occupational Functioning Assessment Scale (SOFAS). Results: Both the ARMS and schizophrenia groups had a significantly larger pituitary volume compared to controls. In the schizophrenia group, the pituitary volume was negatively associated with the BACS working memory score. No association was found between the pituitary volume and clinical variables (medication, symptom severity) in either clinical group. Conclusion: Our findings support the notion of common HPA hyperactivity in the ARMS and schizophrenia groups, but abnormal HPA axis function may contribute differently to cognitive deficits according to the illness stages of schizophrenia. PMID- 30473673 TI - Are You Awed Yet? How Virtual Reality Gives Us Awe and Goose Bumps. AB - "Awe" is a category of emotion within the spectrum of self-transcendent experiences. Awe has wellness benefits, with feelings of social interconnectivity and increased life satisfaction. However, awe experiences remain rare in our everyday lives, and rarer in lab environments. We posit that Virtual Reality (VR) may help to make self-transcendent and potentially transformative experiences of awe more accessible to individuals. Here, we investigated how interactive VR as a positive technology may elicit awe, and how features of aesthetic beauty/scale, familiarity, and personalization (self-selection of travel destinations) may induce awe. In this mixed-methods study, participants used an interactive VR system to explore Earth from ground and orbit. We collected: introspective interviews and self-report questionnaires with participants' experience of awe; information on personality traits and gender; and we recorded physiological goose bumps on the skin (using an arm-mounted goose bump camera instrument), which is a documented marker of an awe experience. Results showed that on a scale of 0-100 for self-reported awe, four different interactive VR environments yielded an average awe rating of 79.7, indicating that interactive VR can indeed induce awe. 43.8% of participants experienced goose bumps: awe ratings positively correlated with the occurrence of goose bumps with those who experienced goose bumps having showed significantly higher ratings of awe than those who did not. Most (64%) of the goose bumps occurred when participants self-selected their VR environment. Participant statements from the interviews were characteristic of an awe inspiring experience, revealed themes of social connection, and usability problems with the VR interface. Personality traits yielded no clear correlation to awe ratings, and females appear to experience more goose bumps than males. In summary: (1) Interactive VR can elicit awe, especially within familiar, self selected environments; (2) Physiological goose bumps can be recorded to provide reliable, non-intrusive indications of awe; (3) Care must be taken to design interaction interfaces that do not impede awe; and (4) While personality traits are not correlated to awe ratings, goose bumps were experienced more frequently among females. We aim to conduct future studies using custom VR environments, interfaces, and additional physiological measures to provide further insight into awe. PMID- 30473674 TI - Emotional Intelligence and Mindfulness: Relation and Enhancement in the Classroom With Adolescents. AB - Emotional intelligence (EI) and mindfulness are two constructs that have been separately studied, and the relation between them still remains unclear. Research in this area has not attempted to go further into how enhancing EI and mindfulness together can achieve better improvements in this ability to attend mindfully. To bridge this knowledge gap, our research goal was to study the relationship between EI and the mindfulness competence in our study sample and to assess the impact of implementing EI and a mindfulness competence developmental program (SEA) about participants' mindfulness competence. The sample consisted of 156 students aged 11-14 years old from a Spanish public high school. One hundred and eight participants were randomly assigned to the experimental condition, and the remaining 48 were to the control condition. The instruments used to evaluate EI were the CDE-SEC, EQi-Youth Version and the General Empathy Scale. Mindfulness on the School Scope Scale was used to assess mindfulness competences. Social adaptation was evaluated by using the social abilities and adjustment questionnaire BAS3. All the instruments where answered by the participants and have been adapted to a sample of youths with such age specifications. The results showed that EI and mindfulness were related to many of the variables measured by the instruments. Showing a good mindfulness competence was particularly related to having a good general level of the EI trait, and to many of the assessed social and emotional variables. The data indicated a significant relation between the mindfulness competence and having better general empathy skills or being better socially adjusted to the school context. The data also indicated a significant effect on participants' interior and kinesthetic mindfulness competence after implementing the SEA Program. These findings corroborate the relationship between EI and mindfulness, and the possibility of enhancing mindfulness by applying a direct intervention program in the classroom. PMID- 30473676 TI - Commentary: Visual attention is not deployed at the endpoint of averaging saccades. PMID- 30473675 TI - Adaptation to the Direction of Others' Gaze: A Review. AB - The direction of another person's gaze provides us with a strong cue to their intentions and future actions, and, correspondingly, the human visual system has evolved to extract information about others' gaze from the sensory stream. The perception of gaze is a remarkably plastic process: adaptation to a particular direction of gaze over a matter of seconds or minutes can cause marked aftereffects in our sense of where other people are looking. In this review, we first discuss the measurement, specificity, and neural correlates of gaze aftereffects. We then examine how studies that have explored the perceptual and neural determinants of gaze aftereffects have provided key insights into the nature of how other people's gaze direction is represented within the visual hierarchy. This includes the level of perceptual representation of gaze direction (e.g., relating to integrated vs. local facial features) and the interaction of this system with higher-level social-cognitive functions, such as theory of mind. Moreover, computational modeling of data from behavioral studies of gaze adaptation allows us to make inferences about the functional principles that govern the neural encoding of gaze direction. This in turn provides a foundation for testing computational theories of neuropsychiatric conditions in which gaze processing is compromised, such as autism. PMID- 30473677 TI - Effect of Long-Term Music Training on Emotion Perception From Drumming Improvisation. AB - Long-term music training has been shown to affect different cognitive and perceptual abilities. However, it is less well known whether it can also affect the perception of emotion from music, especially purely rhythmic music. Hence, we asked a group of 16 non-musicians, 16 musicians with no drumming experience, and 16 drummers to judge the level of expressiveness, the valence (positive and negative), and the category of emotion perceived from 96 drumming improvisation clips (audio-only, video-only, and audiovideo) that varied in several music features (e.g., musical genre, tempo, complexity, drummer's expressiveness, and drummer's style). Our results show that the level and type of music training influence the perceived expressiveness, valence, and emotion from solo drumming improvisation. Overall, non-musicians, non-drummer musicians, and drummers were affected differently by changes in some characteristics of the music performance, for example musicians (with and without drumming experience) gave a greater weight to the visual performance than non-musicians when giving their emotional judgments. These findings suggest that besides influencing several cognitive and perceptual abilities, music training also affects how we perceive emotion from music. PMID- 30473678 TI - Blast-Exposed Veterans With Mild Traumatic Brain Injury Show Greater Frontal Cortical Thinning and Poorer Executive Functioning. AB - Objective: Blast exposure (BE) and mild traumatic brain injury (mTBI) have been independently linked to pathological brain changes. However, the combined effects of BE and mTBI on brain structure have yet to be characterized. Therefore, we investigated whether regional differences in cortical thickness exist between mTBI Veterans with and without BE while on deployment. We also examined whether cortical thickness (CT) and cognitive performance differed among mTBI Veterans with low vs. high levels of cumulative BE. Methods: 80 Veterans with mTBI underwent neuroimaging and completed neuropsychological testing and self-report symptom rating scales. Analyses of covariance (ANCOVA) were used to compare blast exposed Veterans (mTBI+BE, n = 51) to those without BE (mTBI-BE, n = 29) on CT of frontal and temporal a priori regions of interest (ROIs). Next, multiple regression analyses were used to examine whether CT and performance on an executive functions composite differed among mTBI Veterans with low (mTBI+BE Low, n = 22) vs. high (mTBI+BE High, n = 26) levels of cumulative BE. Results: Adjusting for age, numer of TBIs, and PTSD symptoms, the mTBI+BE group showed significant cortical thinning in frontal regions (i.e., left orbitofrontal cortex [p = 0.045], left middle frontal gyrus [p = 0.023], and right inferior frontal gyrus [p = 0.034]) compared to the mTBI-BE group. No significant group differences in CT were observed for temporal regions (p's > 0.05). Multiple regression analyses revealed a significant cumulative BE * CT interaction for the left orbitofrontal cortex (p = 0.001) and left middle frontal gyrus (p = 0.020); reduced CT was associated with worse cognitive performance in the mTBI+BE High group but not the mTBI+BE Low group. Conclusions: Findings show that Veterans with mTBI and BE may be at risk for cortical thinning post-deployment. Moreover, our results demonstrate that reductions in CT are associated with worse executive functioning among Veterans with high levels of cumulative BE. Future longitudinal studies are needed to determine whether BE exacerbates mTBI-related cortical thinning or independently negatively influences gray matter structure. PMID- 30473679 TI - The Association Between an Addictive Tendency Toward Food and Metabolic Characteristics in the General Newfoundland Population. AB - Background: Our previous study of 29 obese food addiction (FA) patients found that FA is associated with lipid profiles and hormones which may be a factor in cardiovascular disease (CVD) and insulin resistance (IR). However, there is currently no data available regarding the relationship between FA symptoms and metabolic characteristics of CVD and IR in the general population. We designed this study to investigate the correlation between FA symptoms with lipid profiles and IR in men and women of the general Newfoundland population. Methods: 710 individuals (435 women and 275 men) recruited from the general Newfoundland population were used in analysis. FA symptoms were evaluated using the Yale Food Addiction Scale (YFAS). Glucose, insulin, HDL, LDL, total cholesterol and triglycerides levels were measured. IR was evaluated using the homeostatic model of assessment (HOMA). Participants were grouped by sex and menopausal status. Age, physical activity, calories and total % body fat were controlled. Results: Partial correlation analysis revealed that in men, YFAS symptom counts were significantly correlated with HOMA-beta (r = 0.196, p = 0.021), triglycerides (r = 0.140, p = 0.025) and inversely correlated with HDL (r = -0.133, p = 0.033). After separating by menopausal status, pre-menopausal women exhibited no correlations and post-menopausal women had a significantcorrelation with triglycerides (r = 0.198, p = 0.016). Conclusion: FA is significantly correlated with several markers of metabolic disturbance in men and to a lesser extent, post menopausal women, in the general population. Further research is required to explain sex specific associations and elucidate any potentially causal mechanisms behind this correlation. PMID- 30473680 TI - In situ Immune Signatures and Microbial Load at the Nasopharyngeal Interface in Children With Acute Respiratory Infection. AB - Acute respiratory infection (ARI) is the most frequent cause for hospitalization in infants and young children. Using multiplexed nCounter technology to digitally quantify 600 human mRNAs in parallel with 14 virus- and 5 bacterium-specific RNAs, we characterized viral and bacterial presence in nasopharyngeal aspirates (NPA) of 58 children with ARI and determined the corresponding in situ immune profiles. NPA contained different groups of organisms and these were classified into bacterial (n = 27), viral (n = 5), codetection [containing both viral and bacterial transcripts (n = 21), or indeterminate intermediate where microbial load is below threshold (n = 5)]. We then identified differentially expressed immune transcripts (DEITs) comparing NPAs from symptomatic children vs. healthy controls, and comparing children presenting NPAs with detectable microbial load vs. indeterminate. We observed a strong innate immune response in NPAs, due to the presence of evolutionarily conserved type I Interferon (IFN)-stimulated genes (ISG), which was correlated with total bacterial and/or viral load. In comparison with indeterminate NPAs, adaptive immunity transcripts discriminated among viral, bacterial, and codetected microbial profiles. In viral NPAs, B cell transcripts were significantly enriched among DEITs, while only type III IFN was correlated with viral load. In bacterial NPAs, myeloid cells and coinhibitory transcripts were enriched and significantly correlated with bacterial load. In conclusion, digital nCounter transcriptomics provide a microbial and immunological in situ "snapshot" of the nasopharyngeal interface in children with ARI. This enabled discrimination among viral, bacterial, codetection, and indeterminate transcripts in the samples using non-invasive sampling. PMID- 30473681 TI - In vitro Assessment of the Probiotic Properties and Bacteriocinogenic Potential of Pediococcus pentosaceus MZF16 Isolated From Artisanal Tunisian Meat "Dried Ossban". AB - Pediococcus pentosaceus MZF16 has been isolated from artisanal Tunisian meat so called "Dried Ossban," an original ecological niche, and identified by MALDI-TOF mass spectrometry and 16S rDNA sequencing. This bacterium showed a high tolerance to gastric stress conditions, and toward bile salts. P. pentosaceus MZF16 also demonstrated a hydrophobic surface profile (high adhesion to xylene), autoaggregation, and adhesive abilities to the human intestinal Caco-2/TC7 cell line. These properties may help the bacterium colonizing the gut. Furthermore, MZF16 was found to be resistant to gentamycin and chloramphenicol but did not harbor any transferable resistance determinants and/or virulence genes. The data also demonstrated absence of cytotoxicity of this strain. Conversely, P. pentosaceus MZF16 can slightly stimulate the immune system and enhance the intestinal epithelial barrier function. Moreover, this bacterium has been shown to be highly active against Listeria spp. due to bacteriocin production. Characterization of the bacteriocin by PCR amplification, sequencing and bioinformatic analyses revealed that MZF16 produces a bacteriocin 100% identical to coagulin, a pediocin-like inhibitory substance produced by Bacillus coagulans. To our knowledge, this is the first report that highlights the production of a pediocin 100% identical to coagulin in a Pediococcus strain. As coagulin, pediocin MZF16 has the consensus sequence YYGNGVXCXXXXCXVXXXXA (X denotes any amino acid), which confirms its belonging to class IIa bacteriocins, and its suitability to preserve foods from Listeria monocytogenes development. According to these results, P. pentosaceus MZF16 can be proposed as a probiotic and bioprotective agent for fermented foods, including Tunisian dry meat and sausages. Further investigations will aim to study the behavior of this strain in meat products as a component of functional food. PMID- 30473682 TI - Enhancing the Electricity Generation and Nitrate Removal of Microbial Fuel Cells With a Novel Denitrifying Exoelectrogenic Strain EB-1. AB - Microbial fuel cells (MFCs) have been tentatively applied for wastewater treatment, but the presence of nitrogen, especially nitrate, induces performance instability by changing the composition of functional biofilms. A novel denitrifying exoelectrogenic strain EB-1, capable of simultaneous denitrification and electricity generation and affiliated with Mycobacterium sp., was isolated from the anodic biofilm of MFCs fed with nitrate containing medium. Polarization curves and cyclic voltammetry showed that strain EB-1 could generate electricity through a direct electron transfer mechanism with a maximum power density of 0.84 +/- 0.05 W m-2. Additionally, anodic denitrification, as a concurrent metabolism, was demonstrated with an efficient removal rate of 0.66 +/- 0.01 kg N m-3 d-1 at a COD/N ratio of 3.5 +/- 0.3. Importantly, voltage output was not negatively influenced by nitrate, indicating that the concurrent process of nitrate removal and electricity generation was a limitation of the electron donor rather than an inhibition of the system. Furthermore, various organic materials were successfully utilized as anode donors for strain EB-1, and demonstrated the exciting performances in terms of simultaneous denitrification and electricity generation. Mycobacterium sp. EB-1 thus expands the diversity of exoelectrogens and contributes to the potential applications of MFC for simultaneous energy recovery and wastewater treatment. PMID- 30473683 TI - Strategies for the Preservation, Restoration and Modulation of the Human Milk Microbiota. Implications for Human Milk Banks and Neonatal Intensive Care Units. AB - Studies carried in the last years have revealed that human milk contains a site specific microbiota and constitutes a source of potentially beneficial bacteria to the infant gut. Once in the infant gut, these bacteria contribute to the assembly of a physiological gut microbiota and may play several functions, contributing to infant metabolism, protection against infections, immunomodulation or neuromodulation. Many preterm neonates are fed with pasteurized donor's human milk (DHM) or formula and, therefore, are devoid of contact with human milk microbes. As a consequence, new strategies are required to allow the exposition of a higher number of preterm infants to the human milk microbiota early in life. The first strategy would be to promote and to increase the use of own mother's milk (OMM) in Neonatal Intensive Care Units (NICUs). Even small quantities of OMM can be very valuable since they would be added to DHM in order to microbiologically "customize" it. When OMM is not available, a better screening of donor women, including routine cytomegalovirus (CMV) screening of milk, may help to avoid the pasteurization of the milk provided by, at least, a relevant proportion of donors. Finally, when pasteurized DHM or formula are the only feeding option, their supplementation with probiotic bacteria isolated from human milk, such as lactic acid bacteria or bifidobacteria, may be an alternative to try to restore a human milk-like microbiota before feeding the babies. In the future, the design of human milk bacterial consortia (minimal human milk microbiotas), including well characterized strains representative of a healthy human milk microbiota, may be an attractive strategy to provide a complex mix of strains specifically tailored to this target population. PMID- 30473686 TI - Exopolysaccharide-Derived Carbon Dots for Microbial Viability Assessment. AB - Fluorescent dye staining combined with fluorescence microscopy or flow cytometry is becoming a routine way to monitor microorganism viability that is necessary for food safety, antibiotic development, and human health. However, the conventional live/dead assay dyes suffer from high cost, inconvenient staining steps, and high cytotoxicity, which is urgently needed to overcome. Herein, cheap carbon dots, CDs-EPS605, were reported to successfully assess microbial viability in a convenient way with neglectable cytotoxicity. The fluorescent N-doped CDs EPS605 could be facilely prepared from bacterial amino exopolysaccharide (EPS) by one-step hydrothermal carbonization, which is cost-effective and sustainable. The negatively charged CDs-EPS605 consisted of C, H, O, N, P, and S, and featured various functional groups, including -COOH, -OH, -CONH-, and -NH2. CDs-EPS605 were observed to sensitively and selectively stain dead microorganisms instead of live ones to enable discrimination of live/dead microorganisms. The labeling method with CDs-EPS605 did not require protection from light, or washing, which is convenient. Additionally, CDs-EPS605 displayed better photostability and much less cytotoxicity compared to the commercial counterpart. Altogether, CDs-EPS605 represent a simple, yet powerful staining agent for microbial viability assessment, and at the same time enrich the current applications of microbial EPS. PMID- 30473685 TI - Characterisation of a Hydroxycinnamic Acid Esterase From the Bifidobacterium longum subsp. longum Taxon. AB - Bifidobacterium longum subsp. longum, a common member of the human gut microbiota with perceived positive health effects, is capable of metabolising certain complex, plant-derived carbohydrates which are commonly found in the (adult) human diet. These plant glycans may be employed to favourably modulate the microbial communities in the intestine. Hydroxycinnamic acids (HCAs) are plant phenolic compounds, which are attached to glycans, and which are associated with anti-oxidant and other beneficial properties. However, very little information is available regarding metabolism of HCA-containing glycans by bifidobacteria. In the current study, a gene encoding a hydroxycinnamic acid esterase was found to be conserved across the B. longum subsp. longum taxon and was present in a conserved locus associated with plant carbohydrate utilisation. The esterase was shown to be active against various HCA-containing substrates and was biochemically characterised in terms of substrate preference, and pH and temperature optima of the enzyme. This novel hydroxycinnamic acid esterase is presumed to be responsible for the release of HCAs from plant-based dietary sources, a process that may have benefits for the gut environment and thus host health. PMID- 30473688 TI - Afadin Downregulation by Helicobacter pylori Induces Epithelial to Mesenchymal Transition in Gastric Cells. AB - Afadin is a cytoplasmic protein of the adherens junctions, which regulates the formation and stabilization of both the adherens and the tight junctions. Aberrant expression of Afadin has been shown in cancer and its loss has been associated with epithelial-to-mesenchymal transition (EMT). EMT is characterized by the change from an epithelial to a mesenchymal phenotype, with modifications on the expression of adhesion molecules and acquisition of a migratory and invasive cell behavior. While it is known that Helicobacter pylori disrupts the tight and the adherens junctions and induces EMT, the effect of the bacteria on Afadin is still unknown. The aim of this study was to disclose the effect of H. pylori on Afadin and its impact in the induction of an EMT phenotype in gastric cells. Using two different cell lines, we observed that H. pylori infection decreased Afadin protein levels, independently of CagA, T4SS, and VacA virulence factors. H. pylori infection of cell lines recapitulated several EMT features, displacing and downregulating multiple proteins from cell-cell junctions, and increasing the expression of ZEB1, Vimentin, Slug, N-cadherin, and Snail. Silencing of Afadin by RNAi promoted delocalization of junctional proteins from the cell-cell contacts, increased paracellular permeability, and decreased transepithelial electrical resistance, all compatible with impaired junctional integrity. Afadin silencing also led to increased expression of the EMT marker Snail, and to the formation of actin stress fibers, together with increased cell motility and invasion. Finally, and in line with our in vitro data, the gastric mucosa of individuals infected with H. pylori showed decrease/loss of Afadin membrane staining at cell-cell contacts significantly more frequently than uninfected individuals. In conclusion, Afadin is downregulated by H. pylori infection in vitro and in vivo, and its downregulation leads to the emergence of EMT and to the acquisition of an aggressive phenotype in gastric cells, which can contribute to gastric carcinogenesis. PMID- 30473689 TI - Role of Temperate Bacteriophage phi20617 on Streptococcus thermophilus DSM 20617T Autolysis and Biology. AB - Streptococcus thermophilus DSM 20167T showed autolytic behavior when cultured in lactose- and sucrose-limited conditions. The amount of cell lysis induced was inversely related to the energetic status of the cells, as demonstrated by exposing cells to membrane-uncoupling and glycolysis inhibitors. Genome sequence analysis of strain DSM 20617T revealed the presence of a pac-type temperate bacteriophage, designated Phi20617, whose genomic organization and structure resemble those of temperate streptococcal bacteriophages. The prophage integrated at the 3'-end of the gene encoding the glycolytic enzyme enolase (eno), between eno and the lipoteichoic acid synthase-encoding gene ltaS, affecting their transcription. Comparative experiments conducted on the wild-type strain and a phage-cured derivative strain revealed that the cell-wall integrity of the lysogenic strain was compromised even in the absence of detectable cell lysis. More importantly, adhesion to solid surfaces and heat resistance were significantly higher in the lysogenic strain than in the phage-cured derivative. The characterization of the phenotype of a lysogenic S. thermophilus and its phage-cured derivative is relevant to understanding the ecological constraints that drive the stable association between a temperate phage and its bacterial host. PMID- 30473687 TI - Harnessing Metabolic Regulation to Increase Hfq-Dependent Antibiotic Susceptibility in Pseudomonas aeruginosa. AB - The opportunistic human pathogen Pseudomonas aeruginosa is responsible for ~ 10% of hospital-acquired infections worldwide. It is notorious for its high level resistance toward many antibiotics, and the number of multi-drug resistant clinical isolates is steadily increasing. A better understanding of the molecular mechanisms underlying drug resistance is crucial for the development of novel antimicrobials and alternative strategies such as enhanced sensitization of bacteria to antibiotics in use. In P. aeruginosa several uptake channels for amino-acids and carbon sources can serve simultaneously as entry ports for antibiotics. The respective genes are often controlled by carbon catabolite repression (CCR). We have recently shown that Hfq in concert with Crc acts as a translational repressor during CCR. This function is counteracted by the regulatory RNA CrcZ, which functions as a decoy to abrogate Hfq-mediated translational repression of catabolic genes. Here, we report an increased susceptibility of P. aeruginosa hfq deletion strains to different classes of antibiotics. Transcriptome analyses indicated that Hfq impacts on different mechanisms known to be involved in antibiotic susceptibility, viz import and efflux, energy metabolism, cell wall and LPS composition as well as on the c-di GMP levels. Furthermore, we show that sequestration of Hfq by CrcZ, which was over-produced or induced by non-preferred carbon-sources, enhances the sensitivity toward antibiotics. Thus, controlled synthesis of CrcZ could provide a means to (re)sensitize P. aeruginosa to different classes of antibiotics. PMID- 30473684 TI - Regulatory Hierarchies Controlling Virulence Gene Expression in Shigella flexneri and Vibrio cholerae. AB - Gram-negative enteropathogenic bacteria use a variety of strategies to cause disease in the human host and gene regulation in some form is typically a part of the strategy. This article will compare the toxin-based infection strategy used by the non-invasive pathogen Vibrio cholerae, the etiological agent in human cholera, with the invasive approach used by Shigella flexneri, the cause of bacillary dysentery. Despite the differences in the mechanisms by which the two pathogens cause disease, they use environmentally-responsive regulatory hierarchies to control the expression of genes that have some features, and even some components, in common. The involvement of AraC-like transcription factors, the integration host factor, the Factor for inversion stimulation, small regulatory RNAs, the RNA chaperone Hfq, horizontal gene transfer, variable DNA topology and the need to overcome the pervasive silencing of transcription by H NS of horizontally acquired genes are all shared features. A comparison of the regulatory hierarchies in these two pathogens illustrates some striking cross species similarities and differences among mechanisms coordinating virulence gene expression. S. flexneri, with its low infectious dose, appears to use a strategy that is centered on the individual bacterial cell, whereas V. cholerae, with a community-based, quorum-dependent approach and an infectious dose that is several orders of magnitude higher, seems to rely more on the actions of a bacterial collective. PMID- 30473690 TI - Innate Immune Cells in Immune Tolerance After Liver Transplantation. AB - Currently, liver transplantation is the most effective treatment for end-stage liver disease. Immunosuppressive agents are required to be taken after the operations, which have significantly reduced rejection rates and improved the short-term (<1 year) survival rates. However, post-transplant complications related to the immunosuppressive therapy have led to the development of new protocols aimed at protecting renal function and preventing de novo cancer and dysmetabolic syndrome. Donor specific immune tolerance, which means the mature immune systems of recipients will not attack the grafts under the conditions without any immunosuppression therapies, is considered the optimal state after liver transplantation. There have been studies that have shown that some patients can reach this immune tolerance state after liver transplantation. The intrahepatic immune system is quite different from that in other solid organs, especially the innate immune system. It contains a variety of liver specific cells, such as liver-derived dendritic cells, Kupffer cells, liver sinusoidal endothelial cells, liver-derived natural killer (NK) cells, natural killer T (NKT) cells, and so on. Depending on their specific structures and functions, these intrahepatic innate immune cells play important roles in the development of intrahepatic immune tolerance. In this article, in order to have a deeper understanding of the tolerogenic functions of liver, we summarized the molecular mechanisms of immune tolerance induced by intrahepatic innate immune cells after liver transplantation. PMID- 30473691 TI - Understanding the Multifaceted Role of Neutrophils in Cancer and Autoimmune Diseases. AB - Neutrophils are one of the first immune cell types that are recruited to injury and infection site. As a vital component of the immune system, neutrophils are heterogeneous immune cells known to have phagocytic property and function in inflammation. Recent studies revealed that neutrophils play dual roles in tumor initiation, development, and progression. The multifunctional roles of neutrophils in diseases are mainly due to their production of different effector molecules under different conditions. N1 and N2 neutrophils or high density neutrophils (HDNs) and low density neutrophils (LDNs) have been used to distinguish neutrophils subpopulations with pro- vs. anti-tumor activity, respectively. Indeed, N1 and N2 neutrophils also represent immunostimulating and immunosuppressive subsets, respectively, in cancer. The emerging studies support their multifaceted roles in autoimmune diseases. Although such subsets are rarely identified in autoimmune diseases, some unique subsets of neutrophils, including low density granulocytes (LDGs) and CD177+ neutrophils, have been reported. Given the heterogeneity and functional plasticity of neutrophils, it is necessary to understand the phenotypical and functional features of neutrophils in disease status. In this article, we review the multifaceted activates of neutrophils in cancer and autoimmune diseases, which may support new classification of neutrophils to help understand their important functions in immune homeostasis and pathologies. PMID- 30473693 TI - IgG Induced by Vaccination With Ascaris suum Extracts Is Protective Against Infection. AB - Human ascariasis has a global and cosmopolitan distribution, and has been characterized as the most prevalent neglected tropical disease worldwide. The development of a preventive vaccine is highly desirable to complement current measures required for this parasitic infection control and to reduce chronic childhood morbidities. In the present study, we describe the mechanism of protection elicited by a preventive vaccine against ascariasis. Vaccine efficacy was evaluated after immunization with three different Ascaris suum antigen extracts formulated with monophosphoryl lipid A (MPLA) as an adjuvant: crude extract of adult worm (ExAD); crude extract of adult worm cuticle (CUT); and crude extract of infective larvae (L3) (ExL3). Immunogenicity elicited by immunization was assessed by measuring antibody responses, cytokine production, and influx of tissue inflammatory cells. Vaccine efficacy was evaluated by measuring the reductions in the numbers of larvae in the lungs of immunized BALB/c mice that were challenged with A. suum eggs. Moreover, lung physiology and functionality were tested by spirometry to determine clinical efficacy. Finally, the role of host antibody mediated protection was determined by passive transfer of serum from immunized mice. Significant reductions in the total number of migrating larvae were observed in mice immunized with ExL3 61% (p < 0.001), CUT 59% (p < 0.001), and ExAD 51% (p < 0.01) antigens in comparison with non immunized mice. For the Ascaris antigen-specific IgG antibody levels, a significant and progressive increase was observed with each round of immunization, in association with a marked increase of IgG1 and IgG3 subclasses. Moreover, a significant increase in concentration of IL-5 and IL-10 (pre challenge) in the blood and IL-10 in the lung tissue (post-challenge) was induced by CUT immunization. Finally, ExL3 and CUT-immunized mice showed a marked improvement in lung pathology and tissue fibrosis as well as reduced pulmonary dysfunction induced by Ascaris challenge, when compared to non-immunized mice. Moreover, the passive transfer of specific IgG antibodies from ExL3, CUT, and ExAD elicited a protective response in naive mice, with significant reductions in parasite burdens in lungs of 65, 64, and 64%, respectively. Taken together, these studies indicated that IgG antibodies contribute to protective immunity. PMID- 30473692 TI - A Systematic Review on Novel Mycobacterium tuberculosis Antigens and Their Discriminatory Potential for the Diagnosis of Latent and Active Tuberculosis. AB - Background: Current immunodiagnostic tests for tuberculosis (TB) are based on the detection of an immune response toward mycobacterial antigens injected into the skin or following an in-vitro simulation in interferon gamma-release assays. Both tests have limited sensitivity and are unable to differentiate between tuberculosis infection (LTBI) and active tuberculosis disease (aTB). To overcome this, the use of novel Mycobacterium tuberculosis (M. tuberculosis) stage specific antigens for the diagnosis of LTBI and aTB has gained interest in recent years. This review summarizes current evidence on novel antigens used for the immunodiagnosis of tuberculosis and discrimination of LTBI and aTB. In addition, results on measured biomarkers after stimulation with novel M. tuberculosis antigens were also reviewed. Methods: A systematic literature review was performed in Pubmed, EMBASE and web of science searching articles from 2000 up until December 2017. Only articles reporting studies in humans using novel antigens were included. Results: Of 1,533 articles screened 34 were included in the final analysis. A wide range of novel antigens expressed during different stages and types of LTBI and aTB have been assessed. M. tuberculosis antigens Rv0081, Rv1733c, Rv1737c, Rv2029c, Rv2031 and Rv2628, all encoded by the dormancy of survival regulon, were among the most widely studied antigens and showed the most promising results. These antigens have been shown to have best potential for differentiating LTBI from aTB. In addition, several studies have shown that the inclusion of cytokines other than IFN-gamma can improve sensitivity. Conclusion: There is limited evidence that the inclusion of novel antigens as well as the measurement of other biomarkers than IFN-gamma may improve sensitivity and may lead to a discrimination of LTBI from aTB. PMID- 30473695 TI - Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Dendritic Cell Maturation and Function. AB - Mesenchymal stromal cells (MSCs) are potent regulators of immune responses largely through paracrine signaling. MSC secreted extracellular vesicles (MSC EVs) are increasingly recognized as the key paracrine factors responsible for the biological and therapeutic function of MSCs. We report the first comprehensive study demonstrating the immunomodulatory effect of MSC-EVs on dendritic cell (DC) maturation and function. MSC-EVs were isolated from MSC conditioned media using differential ultracentrifugation. Human monocyte-derived DCs were generated in the absence or presence of MSC-EVs (20 ug/ml) then subjected to phenotypic and functional analysis in vitro. MSC-EV treatment impaired antigen uptake by immature DCs and halted DC maturation resulting in reduced expression of the maturation and activation markers CD83, CD38, and CD80, decreased secretion of pro-inflammatory cytokines IL-6 and IL-12p70 and increased production of anti inflammatory cytokine TGF-beta. MSC-EV treated DCs also demonstrated a diminished CCR 7 expression after LPS stimulation, coupled with a significantly reduced ability to migrate toward the CCR7-ligand CCL21, although they were still able to stimulate allogeneic T cell proliferation in vitro. Through microRNA profiling we have identified 49 microRNAs, which were significantly enriched in MSC-EVs compared to their parent MSCs. MicroRNAs with known effect on DC maturation and functions, including miR-21-5p, miR-142-3p, miR-223-3p, and miR-126-3p, were detected within the top 10 most enriched miRNAs in MSC-EVs, with MiR-21-5p as the third highest expressed miRNA in MSC-EVs. In silico analysis revealed that miR-21 5p targets the CCR7 gene for degradation. To verify these observations, DCs were transfected with miR-21-5p mimics and analyzed for their ability to migrate toward the CCR7-ligand CCL21 in vitro. MiR-21-5p mimic transfected DCs showed a clear trend of reduced CCR7 expression and a significantly decreased migratory ability toward the CCL21. Our findings suggest that MSC-EVs are able to recapitulate MSC mediated DC modulation and MSC-EV enclosed microRNAs may represent a novel mechanism through which MSCs modulate DC functions. As MSCs are currently used in clinical trials to treat numerous diseases associated with immune dysregulation, such as graft-versus-host disease and inflammatory bowel disease, our data provide novel evidence to inform potential future application of MSC-EVs as a cell-free therapeutic agent. PMID- 30473694 TI - Review of the Amphibian Immune Response to Chytridiomycosis, and Future Directions. AB - The fungal skin disease, chytridiomycosis (caused by Batrachochytrium dendrobatidis and B. salamandrivorans), has caused amphibian declines and extinctions globally since its emergence. Characterizing the host immune response to chytridiomycosis has been a focus of study with the aim of disease mitigation. However, many aspects of the innate and adaptive arms of this response are still poorly understood, likely due to the wide range of species' responses to infection. In this paper we provide an overview of expected immunological responses (with inference based on amphibian and mammalian immunology), together with a synthesis of current knowledge about these responses for the amphibian chytridiomycosis system. We structure our review around four key immune stages: (1) the naive immunocompetent state, (2) immune defenses that are always present (constitutive defenses), (3) mechanisms for recognition of a pathogen threat and innate immune defenses, and (4) adaptive immune responses. We also evaluate the current hot topics of immunosuppression and immunopathology in chytridiomycosis, and discuss their respective roles in pathogenesis. Our synthesis reveals that susceptibility to chytridiomycosis is likely to be multifactorial. Susceptible amphibians appear to have ineffective constitutive and innate defenses, and a late-stage response characterized by immunopathology and Bd-induced suppression of lymphocyte responses. Overall, we identify substantial gaps in current knowledge, particularly concerning the entire innate immune response (mechanisms of initial pathogen detection and possible immunoevasion by Bd, degree of activation and efficacy of the innate immune response, the unexpected absence of innate leukocyte infiltration, and the cause and role of late-stage immunopathology in pathogenesis). There are also gaps concerning most of the adaptive immune system (the relative importance of B and T cell responses for pathogen clearance, the capacity and extent of immunological memory, and specific mechanisms of pathogen-induced immunosuppression). Improving our capacity for amphibian immunological research will require selection of an appropriate Bd susceptible model species, the development of taxon-specific affinity reagents and cell lines for functional assays, and the application of a suite of conventional and emerging immunological methods. Despite current knowledge gaps, immunological research remains a promising avenue for amphibian conservation management. PMID- 30473696 TI - Mucosal Barrier and Th2 Immune Responses Are Enhanced by Dietary Inulin in Pigs Infected With Trichuris suis. AB - Diet composition may play a crucial role in shaping host immune responses and commensal gut microbiota populations. Bioactive dietary components, such as inulin, have been extensively studied for their bioactive properties, particularly in modulating gut immune function and reducing inflammation. It has been shown that colonization with gastrointestinal parasitic worms (helminths) may alleviate chronic inflammation through promotion of T-helper cell type (Th) 2 and T-regulatory immune responses and alterations in the gut microbiome. In this study, we investigated if dietary inulin could modulate mucosal immune function in pigs during colonization with the porcine whipworm Trichuris suis. T. suis infection induced a typical Th2-biased immune response characterized by transcriptional changes in Th2- and barrier function-related genes, accompanied by intestinal remodeling through increased epithelial goblet and tuft cell proliferation. We observed that inulin also up-regulated Th2-related immune genes (IL13, IL5), and suppressed Th1-related pro-inflammatory genes (IFNG, IL1A, IL8) in the colon. Notably, inulin augmented the T. suis-induced responses with increased transcription of key Th2 and mucosal barrier genes (e.g., IL13, TFF3), and synergistically suppressed pro-inflammatory genes, such as IFNG and CXCL9. 16S rRNA sequencing of proximal colon digesta samples revealed that inulin supplementation reduced the abundance of bacterial phyla linked to inflammation, such as Proteobacteria and Firmicutes, and simultaneously increased Actinobacteria and Bacteroidetes. Interestingly, pigs treated with both inulin and T. suis displayed the highest Bacteroidetes: Firmicutes ratio and the lowest gut pH, suggesting an interaction of diet and helminth infection that stimulates the growth of beneficial bacterial species. Overall, our data demonstrate that T. suis infection and inulin co-operatively enhance anti-inflammatory immune responses, which is potentially mediated by changes in microbiota composition. Our results highlight the intricate interactions between diet, immune function and microbiota composition in a porcine helminth infection model. This porcine model should facilitate further investigations into the use of bioactive diets as immunomodulatory mediators against inflammatory conditions, and how diet and parasites may influence gut health. PMID- 30473699 TI - Editorial: Current Progress and Challenges in the Development of a B Cell Based Hepatitis C Virus Vaccine. PMID- 30473697 TI - T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses. AB - T-cell exhaustion is a phenomenon of dysfunction or physical elimination of antigen-specific T cells reported in human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections as well as cancer. Exhaustion appears to be often restricted to CD8+ T cells responses in the literature, although CD4+ T cells have also been reported to be functionally exhausted in certain chronic infections. Although our understanding of the molecular mechanisms associated with the transcriptional regulation of T-cell exhaustion is advancing, it is imperative to also explore the central mechanisms that control the altered expression patterns. Targeting metabolic dysfunctions with mitochondrion-targeted antioxidants are also expected to improve the antiviral functions of exhausted virus-specific CD8+ T cells. In addition, it is crucial to consider the contributions of mitochondrial biogenesis on T-cell exhaustion and how mitochondrial metabolism of T cells could be targeted whilst treating chronic viral infections. Here, we review the current understanding of cardinal features of T-cell exhaustion in chronic infections, and have attempted to focus on recent discoveries, potential strategies to reverse exhaustion and reinvigorate optimal protective immune responses in the host. PMID- 30473698 TI - The Key Role of TNF-TNFR2 Interactions in the Modulation of Allergic Inflammation: A Review. AB - Tumor necrosis factor-alpha (TNF) is a pleiotropic cytokine, which is thought to play a major role in the pathogenesis of inflammatory diseases, including allergy. TNF is produced at the early stage of allergen sensitization, and then continues to promote the inflammation cascade in the effector phase of allergic reactions. Consequently, anti-TNF treatment has been proposed as a potential therapeutic option. However, recent studies reveal anti-intuitive effects of TNF in the activation and proliferative expansion of immunosuppressive Tregs, tolerogenic DCs and MDSCs. This immunosuppressive effect of TNF is mediated by TNFR2, which is preferentially expressed by immunosuppressive cells. These findings redefine the role of TNF in allergic reaction, and suggest that targeting TNF-TNFR2 interaction itself may represent a novel strategy in the treatment of allergy. PMID- 30473701 TI - IFNAR2 Is Required for Anti-influenza Immunity and Alters Susceptibility to Post influenza Bacterial Superinfections. AB - Influenza virus infections particularly when followed by bacterial superinfections (BSI) result in significant morbidities and mortalities especially during influenza pandemics. Type I interferons (IFNs) regulate both anti-influenza immunity and host susceptibility to subsequent BSIs. These type I IFNs consisting of, among others, 14 IFN-alpha's and a single IFN-beta, are recognized by and signal through the heterodimeric type I IFN receptor (IFNAR) comprised of IFNAR1 and IFNAR2. However, the individual receptor subunits can bind IFN-beta or IFN-alpha's independently of each other and induce distinct signaling. The role of type I IFN signaling in regulating host susceptibility to both viral infections and BSI has been only examined with respect to IFNAR1 deficiency. Here, we demonstrate that despite some redundancies, IFNAR1 and IFNAR2 have distinct roles in regulating both anti-influenza A virus (IAV) immunity and in shaping host susceptibility to subsequent BSI caused by S. aureus. We found IFNAR2 to be critical for anti-viral immunity. In contrast to Ifnar1 -/- mice, IAV-infected Ifnar2 -/- mice displayed both increased and accelerated morbidity and mortality compared to WT mice. Furthermore, unlike IFNAR1, IFNAR2 was sufficient to generate protection from lethal IAV infection when stimulated with IFN-beta. With regards to BSI, unlike what we found previously in Ifnar1 -/- mice, Ifnar2 -/- mice were not susceptible to BSI induced on day 3 post-IAV, even though absence of IFNAR2 resulted in increased viral burden and an increased inflammatory environment. The Ifnar2 -/- mice similar to what we previously found in Ifnar1 -/- mice were less susceptible than WT mice to BSI induced on day 7 post-IAV, indicating that signaling through a complete receptor increases BSI susceptibility late during clinical IAV infection. Thus, our results support a role for IFNAR2 in induction of anti-IAV immune responses that are involved in altering host susceptibility to BSI and are essential for decreasing the morbidity and mortality associated with IAV infection. These results begin to elucidate some of the mechanisms involved in how the individual IFNAR subunits shape the anti-viral immune response. Moreover, our results highlight the importance of examining the contributions of entire receptors, as individual subunits can induce distinct outcomes as shown here. PMID- 30473702 TI - TACI Contributes to Plasmodium yoelii Host Resistance by Controlling T Follicular Helper Cell Response and Germinal Center Formation. AB - The delay in parasite-specific B cell development leaves people in malaria endemic areas vulnerable to repeated Plasmodium infections. Here, we investigated the role of transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), a molecule involved in the generation of antigen-specific antibody secreting cells, in host response to non-lethal Plasmodium yoelii infection. We found that TACI deficiency not only resulted in higher peak parasitemia levels in P. yoelii challenged mice, but also led to a delay in parasite clearance and anti-P. yoelii Merozoite Surface Protein 1(C-terminal 19 kDa fragment [rMSP-119]) protein and anti-rMSP-119 and anti-P. yoelii IgG antibody development. There was also a delay in the generation of splenic high affinity antibody secreting cells that recognize rMSP-119 protein as compared to wild-type mice. Interestingly, coinciding with the delay in parasite clearance there was a delay in the resolution of T follicular helper (TFH) cell and germinal center (GC) B cell responses in TACI -/- mice. The persistence of TFH and GC B cells is likely a result of enhanced interaction between TFH and GC B cells because inducible costimulator ligand (ICOSL) expression was significantly higher on TACI -/- GC B cells than wild-type cells. The difference in the kinetics of GC reaction appeared to also impact the emergence of plasma cells (PC) because there was a delay in the generation of TACI -/- mice PC. Nevertheless, following the recovery from P. yoelii infection, TACI -/- and wild type mice were both protected from a rechallenge infection. Establishment of protective B cell response was responsible for the resolution of parasitemia because B cells purified from recovered TACI -/- or wild-type mice were equally protective when introduced to naive wild-type mice prior to P. yoelii challenge. Thus, despite the increased susceptibility of TACI -/- mice to P. yoelii infection and a delay in the development of protective antibody levels, TACI -/- mice are able to clear the infection and resist rechallenge infection. PMID- 30473700 TI - ATP and Its Metabolite Adenosine as Regulators of Dendritic Cell Activity. AB - Adenosine (Ado) is a well-studied neurotransmitter, but it also exerts profound immune regulatory functions. Ado can (i) actively be released by various cells into the tissue environment and can (ii) be produced through the degradation of extracellular ATP by the concerted action of CD39 and CD73. In this sequence of events, the ectoenzyme CD39 degrades ATP into ADP and AMP, respectively, and CD73 catalyzes the last step leading to the production of Ado. Extracellular ATP acts as a "danger" signal and stimulates immune responses, i.e. by inflammasome activation. Its degradation product Ado on the other hand acts rather anti inflammatory, as it down regulates functions of dendritic cells (DCs) and dampens T cell activation and cytokine secretion. Thus, the balance of proinflammatory ATP and anti-inflammatory Ado that is regulated by CD39+/CD73+ immune cells, is important for decision making on whether tolerance or immunity ensues. DCs express both ectoenzymes, enabling them to produce Ado from extracellular ATP by activity of CD73 and CD39 and thus allow dampening of the proinflammatory activity of adjacent leukocytes in the tissue. On the other hand, as most DCs express at least one out of four so far known Ado receptors (AdoR), DC derived Ado can also act back onto the DCs in an autocrine manner. This leads to suppression of DC functions that are normally involved in stimulating immune responses. Moreover, ATP and Ado production thereof acts as "find me" signal that guides cellular interactions of leukocytes during immune responses. In this review we will state the means by which Ado producing DCs are able to suppress immune responses and how extracellular Ado conditions DCs for their tolerizing properties. PMID- 30473703 TI - Methanol in Plant Life. AB - Until recently, plant-emitted methanol was considered a biochemical by-product, but studies in the last decade have revealed its role as a signal molecule in plant-plant and plant-animal communication. Moreover, methanol participates in metabolic biochemical processes during growth and development. The purpose of this review is to determine the impact of methanol on the growth and immunity of plants. Plants generate methanol in the reaction of the demethylation of macromolecules including DNA and proteins, but the main source of plant-derived methanol is cell wall pectins, which are demethylesterified by pectin methylesterases (PMEs). Methanol emissions increase in response to mechanical wounding or other stresses due to damage of the cell wall, which is the main source of methanol production. Gaseous methanol from the wounded plant induces defense reactions in intact leaves of the same and neighboring plants, activating so-called methanol-inducible genes (MIGs) that regulate plant resistance to biotic and abiotic factors. Since PMEs are the key enzymes in methanol production, their expression increases in response to wounding, but after elimination of the stress factor effects, the plant cell should return to the original state. The amount of functional PMEs in the cell is strictly regulated at both the gene and protein levels. There is negative feedback between one of the MIGs, aldose epimerase-like protein, and PME gene transcription; moreover, the enzymatic activity of PMEs is modulated and controlled by PME inhibitors (PMEIs), which are also induced in response to pathogenic attack. PMID- 30473705 TI - Validation of a Salivary RNA Test for Childhood Autism Spectrum Disorder. AB - Background: The diagnosis of autism spectrum disorder (ASD) relies on behavioral assessment. Efforts to define biomarkers of ASD have not resulted in an objective, reliable test. Studies of RNA levels in ASD have demonstrated potential utility, but have been limited by a focus on single RNA types, small sample sizes, and lack of developmental delay controls. We hypothesized that a saliva-based poly-"omic" RNA panel could objectively distinguish children with ASD from their neurotypical peers and children with non-ASD developmental delay. Methods: This multi-center cross-sectional study included 456 children, ages 19 83 months. Children were either neurotypical (n = 134) or had a diagnosis of ASD (n = 238), or non-ASD developmental delay (n = 84). Comprehensive human and microbial RNA abundance was measured in the saliva of all participants using unbiased next generation sequencing. Prior to analysis, the sample was randomly divided into a training set (82% of subjects) and an independent validation test set (18% of subjects). The training set was used to develop an RNA-based algorithm that distinguished ASD and non-ASD children. The validation set was not used in model development (feature selection or training) but served only to validate empirical accuracy. Results: In the training set (n = 372; mean age 51 months; 75% male; 51% ASD), a set of 32 RNA features (controlled for demographic and medical characteristics), identified ASD status with a cross-validated area under the curve (AUC) of 0.87 (95% CI: 0.86-0.88). In the completely separate validation test set (n = 84; mean age 50 months; 85% male; 60% ASD), the algorithm maintained an AUC of 0.88 (82% sensitivity and 88% specificity). Notably, the RNA features were implicated in physiologic processes related to ASD (axon guidance, neurotrophic signaling). Conclusion: Salivary poly-omic RNA measurement represents a novel, non-invasive approach that can accurately identify children with ASD. This technology could improve the specificity of referrals for ASD evaluation or provide objective support for ASD diagnoses. PMID- 30473704 TI - FGF10 and the Mystery of Duodenal Atresia in Humans. AB - Background: Duodenal atresia (DA) is a congenital obstruction of the duodenum, which affects 1 in 7000 pregnancies and requires major surgery in the 1st days of life. Three morphological DA types are described. In humans, the association between DA and Down syndrome suggests an underlying, albeit elusive, genetic etiology. In mice, interruption of fibroblast growth factor 10 (Fgf10) gene signaling results in DA in 30-50% of embryos, supporting a genetic etiology. This study aims to validate the spectrum of DA in two novel strains of Fgf10 knock-out mice, in preparation for future and translational research. Methods: Two novel CRISPR Fgf10 knock-out mouse strains were derived and embryos generated by heterozygous plug-mating. E15.5-E19.5 embryos were genotyped with respect to Fgf10 and micro-dissected to determine the presence and type of DA. Results: One twenty seven embryos (32 wild-type, 34 heterozygous, 61 null) were analyzed. No wild-type or heterozygous embryos had DA. However, 74% of Fgf10 null embryos had DA (49% type 1, 18% type 2, and 33% type 3). Conclusion: Our CRISPR-derived strains showed higher penetrance of DA due to single-gene deletion of Fgf10 in mice than previously reported. Further, the DA type distribution in these mice more closely reiterated that observed in humans. Future experiments will document RNA and protein expression of FGF10 and its key downstream signaling targets in normal and atretic duodenum. This includes exploitation of modern, high-fidelity developmental tools, e.g., Fgf10 flox/+-tomatoflox/flox mice. PMID- 30473706 TI - Feasibility, Safety, and Efficacy of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) for Peritoneal Metastasis: A Registry Study. AB - Introduction: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel drug delivery system with superior pharmacological properties for treating peritoneal metastasis (PM). Safety and efficacy results of PIPAC with cisplatin/doxorubicin or oxaliplatin from a registry cohort are presented. Methods: IRB-approved registry study. Retrospective analysis. No predefined inclusion criteria, individual therapeutic recommendation by the interdisciplinary tumor board. Safety assessment with CTCAE 4.0. Histological assessment of tumor response by an independent pathologist using the 4-tied peritoneal regression grading system (PRGS). Mean PRGS and ascites volume were assessed at each PIPAC. Results: A total of 142 PIPAC procedures were scheduled in 71 consecutive patients with PM from gastric (n = 26), colorectal (n = 17), hepatobiliary/pancreatic (n = 9), ovarian (n = 6), appendiceal (n = 5) origin, pseudomyxoma peritonei (n = 4), and other tumors (n = 3). Mean age was 58 +/- 13 years. Patients were heavily pretreated. Mean PCI was 19 +/- 13. Laparoscopic nonaccess rate was 11/142 procedures (7.7%). Mean number of PIPAC/patient was 2. All patients were eligible for safety analysis. There was no procedure-related mortality. There were 2.8% intraoperative and 4.9% postoperative complications. 39 patients underwent more than one PIPAC and were eligible for efficacy analysis, and PRGS could be assessed in 36 of them. In 24 patients (67%), PRGS improved or remained unchanged at PIPAC#2, reflecting tumor regression or stable disease. Ascites was present in 24 patients and diminished significantly under therapy. Median survival was 11.8 months (95% CI: 7.45-16.2 months) from PIPAC#1. Conclusion: PIPAC is feasible, safe, and well-tolerated and can induce histological regression in a significant proportion of pretreated PM patients. This trial is registered with NCT03210298. PMID- 30473707 TI - Oral Health Impact Profile in Celiac Patients: Analysis of Recent Findings in a Literature Review. AB - The increment of recording atypical oral manifestation in young patients often related to systematic disease is today a challenge for the therapists. Sometime, the presence of tooth enamel lesions correlated with soft tissue lesions is just a symptom or a trigger sign for a deeper and undetermined disease. Recently, high impact has been developed toward the influence of the diet as a controlled and modifiable factor in patients affected by celiac pathologies. The celiac disease (CD) is a chronic immune-mediated disorder triggered by the ingestion of gluten that appears in genetically predisposed patients. Gluten is a proline-rich and glutamine-rich protein present in wheat (gliadin), barley (hordein), and rye (secalin). The gluten-free diet (GFD) seems to better influence the oral health status of the CD patients. For this reason, the main objective of this revision was to analyze the international data highlighting the relationship between celiac patients and the oral health impact profile. A comprehensive review of the current literature was conducted according to the PRISMA guidelines by accessing the NCBI PubMed database. Authors conducted the search of articles in the English language published from 2008 to 2018. The first analysis with filters recorded 67 manuscripts accordingly with the selected keywords. Finally, a number of 16 appropriate published papers were comprehended in the review. The studies were different in terms of the structure, findings, outcomes, and diet quality evaluation, and for this reason, it was not possible to accomplish a meta analysis of the recorded data. This manuscript offers some observational evidence to justify the advantages of gluten-free diets related to a better oral health status in the patients involved. PMID- 30473708 TI - Undescended Testes and Laparoscopy: Experience from the Developing World. AB - Background: Cryptorchidism or undescended testes is the most common disorder of the male endocrine glands in children. With the advancements in laparoscopic techniques and instruments, laparoscopic orchidopexy has become the standard procedure in the management of nonpalpable undescended testes. Aim: To evaluate and determine the therapeutic role, sensitivity, and specificity of laparoscopy in localizing nonpalpable testes and the mean operative time, the conversion rate (and reasons thereof), postoperative wound infection, postoperative stay, and time taken for return to daily activities following laparoscopic orchidopexy or orchidectomy. Materials and Methods: This was a prospective study carried out in the Postgraduate Department of Surgery, Government Medical College, Srinagar, J&K, India, from May 2008 to August 2011. All patients who presented to the outpatient department with complaints of absent testes were examined, and the ones with nonpalpable testes were included in the study. Results: The mean operative time for bilateral and unilateral nonpalpable testis was 102.76 and 53.67 minutes, respectively. Minor postoperative wound infections were noted in 4 of our patients. Mean duration of hospital stay was 14.23 hrs for unilateral cases and 16.27 hrs for bilateral cases. Patients who underwent laparoscopic orchidopexy resumed their normal activities within 4 +/- 1 days. Conclusion: Laparoscopy clearly demonstrates the anatomy and provides visual information upon which a definitive decision can be made for further management of the undescended nonpalpable testis. PMID- 30473709 TI - Quantitative Characterization of the Hemorrhagic, Necrotic, Coagulation-Altering Properties and Edema-Forming Effects of Zebra Snake (Naja nigricincta nigricincta) Venom. AB - This study was designed to investigate the cytotoxicity and haemotoxicity of the Western barred (zebra) spitting cobra (Naja nigricincta nigricincta) venom to help explain atypical and inconsistent reports on syndromes by Namibian physicians treating victims of human ophidian accidents. Freeze-dried venom milked from adult zebra snakes was dissolved in phosphate buffered saline (PBS) for use in this study. Haemorrhagic and necrotic activity of venom were studied in New Zealand albino rabbits. Oedema-forming activity was investigated in 10-day old Cobb500 broiler chicks. Procoagulant and thrombolytic activity was investigated in adult Kalahari red goat blood in vitro. The rabbit skin minimum hemorrhagic dose (MHD) for N. n. nigricincta was 9.8MUg. The minimum necrotizing dose (MND) for N. n. nigricincta venom was 12.2MUg. The N. n. nigricincta venom showed linear dose-dependent procoagulant activity on goat blood (p<0.05). Likewise, N. n. nigricincta venom showed linear dose-dependent thrombolytic activity on goat blood (p<0.05, n = 6). Subplantar injection of N. n. nigricincta venom (25MUg, 50MUg, 75MUg, and 100MUg) into chick paw resulted in peak oedema of 35.5%, 38.5%, 42.9%, and 47.5%, respectively, two hours after injection. Paw oedema subsided within five hours to a mean volume ranging from 5% (25MUg venom) to 17.6% (100MUg venom). In conclusion, though N. n. nigricincta belongs to the genus Elapidae, the current study has shown its venom to possess potent hemorrhagic, necrotic (cytotoxic), and paradoxically, both procoagulant and thrombolytic activity. The authors propose further work to fractionate, isolate, and elucidate the structure of the various N. n. nigricincta venom toxins as a prelude to the development of an antivenom. PMID- 30473710 TI - Fasting-Evoked En Route Hypoglycemia in Diabetes (FEEHD): An Overlooked Form of Hypoglycemia in Clinical Practice. AB - Objective: Many patients with diabetes opt to fast for lab tests, especially for lipid profiles, thus missing breakfast. In parallel, recent studies and international guidelines have indicated that routine fasting for lipid panels may not be necessary. Missing breakfast while fasting for lab tests may invoke hypoglycemia, if patients are not properly instructed about adjusting diabetes medications on the night before or on the day of the lab test. Our group described this form of hypoglycemia and introduced the term FEEHD to refer to it (fasting-evoked en route hypoglycemia in diabetes). In a recently published small study, we reported a rate of occurrence of FEEHD of 27.1%. The objective of this study was to evaluate the rate of occurrence of FEEHD in another clinic. Methods: Patients with diabetes were asked to complete a simple, 2-page survey inquiring about hypoglycemic events while fasting for labs in the preceding 12 months. Results: A total of 525 patients completed the surveys out of 572 patients invited (91.8% response rate). A total of 363 patients with complete data were analyzed, with a mean age of 60.6 (SD 12.5) years. A total of 62 (17.1%) patients reported having experienced one or more FEEHD events in the prior 12 months. Of the 269 patients who were at higher risk of FEEHD (on insulin secretagogues or on insulin), 59 (21.9%) reported having experienced FEEHD. Only 33 of FEEHD patients (53%) recalled having contacted their provider regarding the events and only 22 (35%) indicated having received some sort of FEEHD prevention instructions. Conclusion: Our study shows a significant rate of occurrence of FEEHD in the real world (a clinical practice). FEEHD is especially dangerous, as patients often commute (drive) to and from the laboratory facility (potential risk of traffic accidents). Given study limitations, further studies are needed to assess prevalence of FEEHD in other settings and in the general populations. PMID- 30473711 TI - Prevalence of HCV Infection in Household Contacts of Chronic Liver Diseases Cases in Egypt. AB - Background: Egypt has the highest prevalence of HCV infection worldwide. This project aimed at identifying the role of HCV transmission among household contacts to index cases in the persistent high incidence of HCV infection in Egypt. Methods: This cross-sectional study recruited 70 Egyptian cases with chronic liver diseases and their household contacts (140 contacts) from Qalubeyia Governorate. An interview questionnaire was used to collect information on sociodemographic characteristics and risk factors to HCV infection. HCV-RNA was tested using real-time polymerase chain reaction (PCR). Univariate and multivariate analyses were carried out to estimate the risk of HCV infection among contacts. Results: HCV viremia was detected in 85.7% of cases and 20% of contacts. HCV-RNA was detected in higher proportion of household contacts to cases than the general population. Contacts to HCV-positive cases were unlikely exposed to used syringe (P=0.02) and unlikely to have history of Bilharziasis (P=0.001) compared to contacts to HCV-negative cases. HCV-positive contacts were more likely older (P < 0.001) and married (P=0.008) and had higher crowding index (P=0.04) than HCV-negative contacts. Also, HCV-positive contacts were more likely exposed to blood transfusion (P=0.008) and shaving at community barber (P=0.04) and had history of Bilharziasis (P=0.01). The strongest predictors for HCV infection among contacts were old age (OR, 95% CI: 1.08, 1.02 to 1.15; P=0.01) and blood transfusion (8.08, 1.75 to 37.3; P=0.007). Conclusion: Nonetheless, household contacts to HCV cases are exposed to increased risk of HCV infection, and environmental exposure particularly blood transfusion remained a major source of HCV infection. PMID- 30473712 TI - The clinical burden of allergic rhinitis in five Middle Eastern countries: results of the SNAPSHOT program. AB - Background: The SNAPSHOT program provides current data on the allergic rhinitis burden in the adult general population of five Middle Eastern countries (Egypt, Turkey, Kuwait, Saudi Arabia and the United Arab Emirates, the latter three grouped into a Gulf cluster). Methods: A multi-country, cross-sectional, epidemiological program conducted by telephone in a random sample of the adult general population; quotas were defined per country demographics. Subjects were screened for allergic rhinitis using the Score For Allergic Rhinitis questionnaire. Current prevalence (last 12 months) was estimated. Disease severity and control were assessed using the Allergic Rhinitis and its Impact on Asthma classification and Rhinitis Control Assessment Test respectively. Quality of sleep, impact on daily activities and quality of life were measured using the Epworth Sleepiness Scale, Sheehan Disability Scale and EuroQol Five-Dimension questionnaire respectively. Multivariate logistic regression analyses were used to investigate risk factors and co-morbidities. Results: 1808 of 33,486 subjects enrolled in the SNAPSHOT program fulfilled the case definition for allergic rhinitis. Prevalence was 3.6% [95% CI 3.2-4.0%] in Egypt, 6.4% [95% CI 5.9-6.9%] in Turkey and 6.4% [95% CI 6.0-6.9%] in the Gulf cluster. Risk factors identified were country, co-morbid asthma and income. Subjects with allergic rhinitis reported a significantly lower quality of life compared to the general population (p < 0.0001). Overall, 55% of allergic rhinitis subjects were moderate/severe and 33% were uncontrolled. Both these groups reported impaired quality of life and quality of sleep and increased impairment of daily activities compared to mild/well-controlled subjects (p < 0.0001). Conclusions: Although the observed prevalence of allergic rhinitis in these Middle Eastern countries is low compared to western countries, its burden is considerable. Allergic rhinitis in general, and specifically uncontrolled and severe disease, results in a negative impact on quality of life, quality of sleep and daily activities. PMID- 30473713 TI - Fetal cord blood and tissue immune responses to chronic placental inflammation and chorioamnionitis. AB - Background: Chorioamnionitis is a risk factor for future asthma development. Animal models of chorioamnionitis demonstrate increased TH17-to-Treg ratios associated with proinflammatory cytokine elevations. The association of chorioamnionitis on human neonatal immune cells systemically and within tissues is not known. Methods: We enrolled two cohorts to evaluate TH17 and regulatory T cell (Treg) phenotypic markers in chorioamnionitis. From a cohort of 19 live birth infants, we collected cord blood and placenta samples to evaluate for signs of acute and chronic histologic inflammation and cell phenotype characterization. We analyzed a second cohort of stillborn infants with and without chorioamnionitis to classify and enumerate cell infiltrate phenotypes in the spleen, thymus, and lung. We used linear regression analysis determine the association of retinoic acid-related orphan receptor gamma t positive (RORgammat+) and Treg cell frequency with different types of inflammation seen in the live cohort subjects. Using linear mixed models, we evaluated for any associations between chorioamnionitis and T- and B-cell with a logarithmic scale for level of expression of cellular markers. We then performed Wilcoxon rank sum tests to assess the associations between cell count and chorioamnionitis. Results: In the live birth subjects with chronic placental inflammation we observed an increased proportion of RORgammat+ cells in Foxp3+ cells, regardless of the presence of acute inflammation, compared to subjects with neither acute nor chronic inflammation. We also found an increased proportion of RORgammat+ cells within Foxp3+ cells in subjects with acute high stage fetal and maternal inflammation compared to those without acute or chronic inflammation. In the stillborn subjects with chorioamnionitis, we observed a decrease in splenic Foxp3+ cells and an increase in lung CD3+ cells compared with subjects that did not have chorioamnionitis. Conclusion: Exposure to chorioamnionitis in utero may affect immune activation in neonates with an increased frequency of RORgammat+ cells systemically as well as lymphocytic infiltrate in the lung. Our findings suggest an increase in RORgammat+ cells during chorioamnionitis and thus may support the known associations between chorioamnionitis with asthma. PMID- 30473715 TI - Overexpression of Prokineticin 2 in Transgenic Mice Leads to Reduced Circadian Behavioral Rhythmicity and Altered Molecular Rhythms in the Suprachiasmatic Clock. AB - In mammals, the master pacemaker driving circadian rhythms is thought to reside in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. A clear view of molecular clock mechanisms within the SCN neurons has been elucidated. In contrast, much less is known about the output mechanism by which the SCN circadian pacemaker sends timing information for eventual control of physiological and behavioral rhythms. Two secreted molecules, prokineticin 2 (PK2) and vasopressin, that are encoded by respective clock-controlled genes, have been indicated as candidate SCN output molecules. Several lines of evidence have emerged that support the role of PK2 as an output signal for the SCN circadian clock, including the reduced circadian rhythms in mice that are deficient in PK2 or its receptor, PKR2. In the current study, transgenic mice with the overexpression of PK2 have been generated. These transgenic mice displayed reduced oscillation of the PK2 expression in the SCN and decreased amplitude of circadian locomotor rhythm, supporting the important signaling role of PK2 in the regulation of circadian rhythms. Altered molecular rhythms were also observed in the SCN in the transgenic mice, indicating that PK2 signaling also regulates the operation of core clockwork. This conclusion is consistent with recent reports showing the likely signaling role of PK2 from the intrinsically photosensitive retinal ganglion cells to SCN neurons. Thus, PK2 signaling plays roles in both the input and the output pathways of the SCN circadian clock. PMID- 30473716 TI - Beneficial Effects of Qigong Wuqinxi in the Improvement of Health Condition, Prevention, and Treatment of Chronic Diseases: Evidence from a Systematic Review. AB - Purpose: Qigong is a modality of traditional Chinese mind-body medicine that has been used to prevent and cure ailments, to improve health in China for thousands of years. Wuqinxi, a Chinese traditional Qigong that focuses on mind-body integration, is thought to be an effective exercise in promoting physical and mental wellbeing. Thus, we summarized the evidence and aim to unravel effects of Wuqinxi on health outcomes. Methods: We performed a systematic review of Wuqinxi studies published in English or Chinese since 1979. Relevant English and Chinese language electronic data bases were used for literature search. The selection of studies, data extraction, and validation were performed independently by two reviewers. Results: A total of 28 eligible studies were included in this review, among which three are 3 in English and 25 in Chinese. The studies included in this review involve three different experimental designs: (1) 16 RCTs; (2) 2 historical cohort studies; and (3) 10 pretest and posttest studies (PPS). Participants in this review are categorized as either healthy or clinical populations. The results from this systematic review support the notion that Wuqinxi may be effective as an adjunctive rehabilitation method for improving psychological and physiological wellbeing among different age of healthy populations in addition to alleviating and treating diseases among various clinical populations. Conclusion: The results indicated that Wuqinxi has been thought to be beneficial to improve health and treat chronic diseases. However, the methodological problems in the majority of included studies make it difficult to draw firm conclusive statements. More methodologically rigorous designed large scale RCTs with a long-term follow-up assessment should be further conducted to examine the effects of Wuqixi on health-related parameters and disease-specific measures in different health conditions. This systematic review lends insight for future studies on Wuqinxi and its potential application in preventive and rehabilitation medicine. PMID- 30473714 TI - Characterization of tenascin-C as a novel biomarker for asthma: utility of tenascin-C in combination with periostin or immunoglobulin E. AB - Background: Extracellular matrix proteins tenascin-C (TNC) and periostin, which were identified as T-helper cell type 2 cytokine-induced genes in human bronchial epithelial cells, accumulate in the airway basement membrane of asthmatic patients. Although serum periostin has been accepted as a type 2 biomarker, serum TNC has not been evaluated as a systemic biomarker in asthma. Therefore, the objective of this study was to evaluate whether serum TNC can serve as a novel biomarker for asthma. Methods: We evaluated 126 adult patients with mild to severe asthma. Serum TNC, periostin, and total IgE concentrations were quantified using enzyme-linked immunosorbent assays. Results: Serum TNC levels were significantly higher in patients with severe asthma and high serum total IgE levels. Patients with both high serum TNC (> 37.16 ng/mL) and high serum periostin (> 95 ng/mL) levels (n = 20) or patients with both high serum TNC and high serum total IgE (> 100 IU/mL) levels (n = 36) presented higher disease severity and more severe airflow limitation than patients in other subpopulations. Conclusions: To our knowledge, this is the first study to show that serum TNC levels in asthmatic patients are associated with clinical features of asthma and that the combination of serum TNC and periostin levels or combination of serum TNC and total IgE levels were more useful for asthma than each single marker, suggesting that serum TNC can serve as a novel biomarker for asthma. PMID- 30473717 TI - Assessment of Intermingled Phlegm and Blood Stasis Syndrome in Coronary Heart Disease: Development of a Diagnostic Scale. AB - Background: Intermingled Phlegm and Blood Stasis Syndrome (IPBSS) is a common feature in patients with coronary heart disease (CHD). In clinical practice, the diagnostic agreement of clinical doctor of Chinese Medicine (CM) is poor. We previously developed a IPBSS diagnostic scale for use by general practitioner. Objectives: To assess a IPBSS diagnostic scale that we previously developed for use by non-experts. Methods: This is a multicenter, prospective study involving eight study sites across China. Eligible patients were adults (>=18 years) with CHD as demonstrated by a history of myocardial infarction, stenosis, or past coronary revascularization. IPBSS was assessed using a scale that consisted of 14 items in two domains (e.g., phlegm and blood stasis). The score range for each item was 0 to 3 points. Maximum total score was 72 points. Diagnostic accuracy was verified using consensus opinion by two independent experts as reference. Results: A total of 1,142 CHD patients were included. IPBSS was established in 729 subjects using the IPBSS diagnostic scale. In ROC curve analyses, at the optimal cut-off of 25.5, the sensitivity and specificity of the IPBSS scale were 67.6% and 72.4%, respectively. The area under the ROC curve was 0.741 (95%CI: 0.711-0.772). Conclusions: The newly developed IPBSS scoring system showed moderate performance in diagnosing IPBSS in CHD patients. Data from further large scale diagnostic test accuracy studies are warranted. This trial is registered with ChiCTR-OOC-15006599. PMID- 30473718 TI - Acupuncture for Infantile Colic: A Systematic Review of Randomised Controlled Trials. AB - Introduction: Infantile colic is a common condition causing considerable deterioration in the quality of life of both infants and their parents. Minimal acupuncture, a gentle needling technique without strong muscle stimulation, has primarily been used to treat this condition, but the clinical evidence of its efficacy and safety is yet to be established. The objective of this review was to assess clinical evidence of the safety and efficacy of acupuncture for infantile colic. Methods: To identify studies for inclusion, PubMed, Cochrane Library, Google Scholar, China Knowledge Resource Integrated Database, Wanfang, and Oriental Medicine Advanced Searching Integrated System were searched until January 2017. Only randomised controlled trials of infantile colic in patients aged 0 to 25 weeks, who were treated with acupuncture, were included. To assess the quality, the risk of bias was determined for each study by two authors. The intention was to perform a meta-analysis, but this was not possible in this study due to considerable clinical heterogeneity among the included studies. Results: Of the 601 studies identified, only four randomized controlled trials were included in this review. All included studies were conducted in northern European countries. Most studies showed a low risk of bias in most domains. Minimal acupuncture on LI4 or ST36 without strong stimulation was used in all studies. From the narrative analysis, acupuncture appears to be effective in alleviating the symptoms of colic, including crying and feeding and stooling problems, and may have only minor adverse effects. However, clinical evidence could not be confirmed owing to considerable clinical heterogeneity and the small sample sizes of the included studies. Conclusion: There is currently no conclusive evidence on the safety and efficacy of acupuncture for infantile colic. Rigorous full-scale randomized controlled trials will be necessary in future. PMID- 30473719 TI - Comparative morphology and evolution of the cnidosac in Cladobranchia (Gastropoda: Heterobranchia: Nudibranchia). AB - Background: A number of shelled and shell-less gastropods are known to use multiple defensive mechanisms, including internally generated or externally obtained biochemically active compounds and structures. Within Nudipleura, nudibranchs within Cladobranchia possess such a special defense: the ability to sequester cnidarian nematocysts - small capsules that can inject venom into the tissues of other organisms. This ability is distributed across roughly 600 species within Cladobranchia, and many questions still remain in regard to the comparative morphology and evolution of the cnidosac - the structure that houses sequestered nematocysts (called kleptocnides). In this paper, we describe cnidosac morphology across the main groups of Cladobranchia in which it occurs, and place variation in its structure in a phylogenetic context to better understand the evolution of nematocyst sequestration. Results: Overall, we find that the length, size and structure of the entrance to the cnidosac varies more than expected based on previous work, as does the structure of the exit, the musculature surrounding the cnidosac, and the position and orientation of the kleptocnides. The sequestration of nematocysts has originated at least twice within Cladobranchia based on the phylogeny presented here using 94 taxa and 409 genes. Conclusions: The cnidosac is not homologous to cnidosac-like structures found in Hancockiidae. Additionally, the presence of a sac at the distal end of the digestive gland may have originated prior to the sequestration of nematocysts. This study provides a more complete picture of variation in, and evolution of, morphological characters associated with nematocyst sequestration in Cladobranchia. PMID- 30473720 TI - Resting-state brain activity in Chinese boys with low functioning autism spectrum disorder. AB - Background: This study aimed to explore the resting-state fMRI changes in Chinese boys with low functioning autism spectrum disorder (LFASD) and the correlation with clinical symptoms. Methods: The current study acquired resting-state fMRI data from 15 Chinese boys with LFASD and 15 typically developing (TD) boys to examine the local brain activity using the regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) indexes; the researchers also examined these measures and their possible relationships with clinical symptoms using the autism behavior checklist. Results: Results indicated that boys with LFASD exhibited increased ReHo in the right precuneus and inferior parietal gyrus (IPG), increased ALFF in right middle temporal gyrus, angular gyrus and IPG. However, no correlation was found between the ALFF/ReHo score and clinical symptoms in the LFASD group. Conclusions: Some of the brain regions had ReHo/ALFF values that were higher in the boys with LFASD than the TD group and these differentiated brain areas in boys with LFASD were all on the right cerebrum, which supported 'atypical rightward asymmetry' in boys with LFASD. PMID- 30473722 TI - A method to calculate the number of wheat seedlings in the 1st to the 3rd leaf growth stages. AB - Background: The number of cultivated wheat seedlings per unit area allows calculation of plant density. Wheat seedling density provides emergence data and this is useful for improving crop management. The number of wheat seedlings is typically determined by visual counts but this is time-consuming and laborious. Results: We obtained field digital images of 1st to 3rd leaf stage wheat seedlings. The seedlings were extracted using an image analysis technique that calculated the coverage degree of the seedlings and the number of angular points of overlapping leaves. The wheat seedling quantity estimation model was constructed using multivariate regression analysis. The model parameters included coverage degree, number of angular points, variety coefficient, and leaf age. Introduction of the number of angular points increased the accuracy of the single coverage degree model. The R2 value was consistently > 0.95 when the model was applied to different varieties, indicating that the model was adaptable for different varieties. As the leaf stage or density increased, the accuracy of the model declined, but the minimum R2 remained > 0.87, indicating good adaptability of the model to seedlings with different leaf ages and densities. Conclusions: This method is an effective means for counting wheat seedlings in the 1st to the 3rd leaf stages. PMID- 30473721 TI - Perception of donor breast milk and determinants of its acceptability among mothers in a developing community: a cross-sectional multi-center study in south east Nigeria. AB - Background: Due to the health and economic benefits of breast milk, the World Health Organization (WHO) recommends that for infants who cannot receive breast milk from their own mothers, the next preferred option is donated breast milk. This recommendation is however rarely practiced in most developing countries where donor milk is not widely accepted. Methods: This cross-sectional multi center study enrolled mothers attending antenatal or pediatric clinics in six tertiary institution in south-east Nigeria using purposive and convenient sampling method. Data collection was done using pretested questionnaires. The study aimed to assess the knowledge, acceptability and willingness to donate breast milk and/or use donated breast milk for their infants It also explored factors that determine this behavior. Results: A total of 1235 mothers participated; 39% (480/1225) have heard about the concept of donor milk, while only 10% (79/759) and 7% (81/1179), respectively, had adequate knowledge of the concept and policy on donor milk. Sixty percent indicated willingness to use donor milk or donate breast milk if need arises. Respondents with lower age (p = 0.049) and with higher occupational status (p = 0.001) were more likely to have adequate knowledge of donor breast milk, while respondents with lower educational attainment (p = 0.002) and those who are non-Christians (p = 0.004) were more likely to request financial inducement for donating their breast milk. Adequate knowledge of the concept of donor milk (p = 0.001), preference of donor milk to infant formula (p = 0.001) and requirement of financial remuneration (p = 0.001) were the only significant predictors of willingness to donate and/or receive donated breast milk. Conclusion: The knowledge of the concept of donor breast milk and awareness of policies regulating its practice in Nigeria is low, but the prospect of its acceptability is high among mothers surveyed in south-east Nigeria. Targeted public education by relevant government agencies in collaboration with clinicians, community and religious leaders about the concept of donor breast milk to families may help increase the acceptance and practice of donating breast milk and/or use of donated breast milk among mothers in the region. PMID- 30473723 TI - Anther culture in rice proportionally rescues microspores according to gametophytic gene effect and enhances genetic study of hybrid sterility. AB - Background: To investigate plant hybrid sterility, we studied interspecific hybrids of two cultivated rice species, Asian rice (Oryza sativa) and African rice (O. glaberrima). Male gametes of these hybrids display complete sterility owing to a dozen of hybrid sterility loci, termed HS loci, but this complicated genetic system remains poorly understood. Results: Microspores from these interspecific hybrids form sterile pollen but are viable at the immature stage. Application of the anther culture (AC) method caused these immature microspores to induce callus. The segregation distortion of 11 among 13 known HS loci was assessed in the callus population. Using many individual calli, fine mapping of the HS loci was attempted based on heterozygotes produced from chromosome segment substitution lines (CSSLs). Transmission ratio distortion (TRD) from microspores was detected at 6 of 11 HS loci in the callus population. The fine mapping of S 1 and S 19 loci using CSSLs revealed precise distances of markers from the positions of HS loci exhibiting excessive TRD. Conclusions: We demonstrated that AC to generate callus populations derived from immature microspores is a useful methodology for genetic study. The callus population facilitated detection of TRD at multiple HS loci and dramatically shortened the process for mapping hybrid sterility genes. PMID- 30473725 TI - Shape Analysis of the Patellar Bone Surface and Cutting Plane for Knee Replacement Surgery. AB - Geometry of the patella (kneecap) remains poorly understood yet is highly relevant to performing the correct patellar cut to reduce pain and to improve function and satisfaction after knee replacement surgery. Although studies routinely refer to "parallel to the anterior surface" and "the patellar horizon," a quantitative definition of these is lacking and significant variability exists between observers for this irregularly-shaped bone. A 2D-3D shape analysis technique was developed to determine the optimal device configuration for contacting the patellar surface. Axial and sagittal pseudo-X-rays were created from 18 computed tomography (CT) scans of cadaveric knees. Four expert surgeons reviewed three repetitions of the X-rays in randomized order, marking their desired cut plane and their estimate of the anterior surface. These 2D results were related back to the 3D model to create the desired plane. There was considerable variability in perceptions, with intra- and intersurgeon repeatability (standard deviations) ranging from 1.3 degrees to 2.4 degrees . The best configuration of contact points to achieve the desired cutting plane was three pegs centred on the patellar surface, two superior and one inferior, forming a 16 mm equilateral triangle. This configuration achieved predicted cut planes within 1 degrees of the surgeon ranges on all 18 patellae. Implementing this, as was done in a subsequent prototype surgical device, should help improve the success and satisfaction of knee replacement surgery. PMID- 30473724 TI - Histology-guided high-resolution AP-SMALDI mass spectrometry imaging of wheat Fusarium graminearum interaction at the root-shoot junction. AB - Background: Fungal pathogens like Fusarium graminearum can cause severe yield losses and mycotoxin contamination of food and feed worldwide. We recently showed its ability to systemically colonize wheat via root infection. However, the molecular response of wheat to Fusarium root rot (FRR) infection and systemic spread is still unknown. As a molecular camera, mass spectrometry (MS) imaging combines label-free and multiplex metabolite profiling with histopathology. Results: Atmospheric-pressure (AP)-SMALDI-MS imaging was combined with optical microscopy to study wheat-F. graminearum interaction at the root-shoot junction, which is a crucial line of defense against a pathogen that can invade all distal plant parts. To scope the functional, temporal and local aspects of FRR disease spread, metabolic changes were simultaneous visualized in diseased and healthy stem bases of the resistant cultivar Florence-Aurore at 10, 14 and 21 days after root inoculation. Histological information was used to identify disease relevant tissues and to assist the interpretation of molecular images. Detected mycotoxin compounds secreted by F. graminearum showed a route of stem infection that was consistent with observations made by microscopy. The outer epidermis and vasculature of leaf sheath were, at different disease stages, identified as prominent sites of pathogen migration and wheat protection. Wheat metabolites mapped to these relatively small tissues indicated cell wall strengthening and antifungal activity as direct defenses as well as conservation in the wheat reactions to F. graminearum diseases that affect different plant organs. Conclusions: AP-SMALDI-MS imaging at high spatial resolution is a versatile technique that can be applied to basic and applied aspects of agricultural research. Combining the technology with optical microscopy was found to be a powerful tool to gain in-depth information on almost unknown crop disease. Moreover, the approach allowed studying metabolism at the host-pathogen interface. The results provide important hints to an understanding of the complex spatio-temporal organization of plant resistance. Defense-on-demand responses to pathogen ingress were found, which provide opportunities for future research towards an improved resistance that does not negatively impact yield development in the field by saving plant resources and, moreover, may control different Fusarium diseases. PMID- 30473726 TI - The influence of prostatic Cutibacterium acnes infection on serum levels of IL6 and CXCL8 in prostate cancer patients. AB - Background: Chronic prostatic inflammation, caused by Cutibacterium acnes (C. acnes), has been proposed to influence the risk of prostate cancer development. In vitro studies have demonstrated the capacity of C. acnes to induce secretion of Interleukin 6 (IL6) and C-X-C motif chemokine ligand 8 (CXCL8) by prostate epithelial cells. Both these inflammatory mediators have been implicated in prostate cancer pathophysiology. In this cohort study, we aimed to investigate the influence of prostatic C. acnes on serum levels of IL6 and CXCL8. Methods: We recruited 99 prostate cancer patients who underwent radical prostatectomy at Orebro University Hospital. The cultivation of pre-operatively obtained prostate biopsies identified C. acnes in 60 of the 99 patients. Levels of IL6 and CXCL8 in pre-operative serum samples were analyzed using ELISA, and concentrations were compared between prostate cancer patients with and without prostatic C. acnes infection using standard statistical methods. Results: No statistical differences were observed in serum levels of IL6 and CXCL8 between subjects with and without prostatic C. acnes infection. Conclusions: Our results indicate that prostatic C. acnes infection may give rise to low-grade inflammation with little effect on systemic levels of IL6 and CXCL8. PMID- 30473727 TI - Awareness of comfort immediately after a relaxation therapy session affects future quality of life and autonomic function: a prospective cohort study on the expectations of therapy. AB - Background: High expectations regarding therapy are reported to have positive effects on future therapeutic course and related behavior. Some individuals are aware of feelings of comfort immediately after a relaxation therapy session. Methods: Heart rate variability biofeedback (HRV-BF) therapy using a relaxation technique called resonant breathing was administered to 44 family caregivers who felt burdened by their work caring for family members with cancer. We prospectively evaluated how the level of comfort participants were aware of immediately after an initial therapy session affected their expectations regarding the therapy, as well as future quality of life (QOL) and autonomic function. This study was a secondary analysis of a randomized, open-label study titled "Self-care system for family caregivers of cancer patients using resonant breathing with a portable home device". Results: Among the participants, 56.8% were aware of a feeling of comfort immediately after an initial therapy session. Participants were then divided into two groups according to the presence or absence of their awareness of comfort. Expectation levels regarding the therapy were significantly increased in the awareness group after the therapy session (P = 0.003). No main effect between groups was observed for heart rate variability (HRV) during therapy (P = 0.949). Four weeks after the initial therapy session, QOL improved and HRV increased in the awareness group (P < 0.001). Conclusions: Better outcomes in the awareness group were not associated with HRV during therapy. A feeling of comfort immediately after a therapy session may have positive effects on future QOL and autonomic function by raising participants' expectations of the therapy. Trial registration: UMIN000021639. Registered 27 March 2016. PMID- 30473728 TI - Treatment recommendation differences for schizophrenia and major depression: a population-based study in a Vietnamese cohort. AB - Background: In Vietnam, the mental health care infrastructure is on the verge of transformation with an increase in the demand for access to adequate and effective mental health care services. Public attitudes towards mental illness, as well as corresponding treatment options influence help-seeking behaviors of patients and caregivers, affecting the course of their treatment. This study assesses attitudes towards treatment options for depression and schizophrenia, as the two most common psychiatric disorders in Vietnam, accounting for at least 75% of all psychiatric inpatients. Methods: A general population-based survey was conducted in Hanoi, Vietnam between April and August 2013. Participants received a description of a person with symptoms of either depression (n = 326) or schizophrenia (n = 403) and were asked to give recommendations for adequate sources of mental health support and treatment options. Multiple analyses on a single item level compared the likelihood of recommendation between schizophrenia and depression. Results: Overall, respondents recommended health care services, ranging from seeking mental health care professionals, psychotherapists, and psychiatrists for both disorders. Psychotherapy was the most favored treatment method, whereas further treatment options, such as concentration and relaxation exercises, meditation or yoga and psychotropic medication were also endorsed as helpful. For the schizophrenia vignette condition, psychotherapy, visiting a psychiatrist or psychotherapist received stronger endorsement rates as compared to the depression vignette. Furthermore, ECT, Feng Shui-based practices, praying and visiting natural healers were recommended less by respondents for the depression vignette in comparison with the schizophrenia vignette. Conclusions: The Vietnamese public endorsed evidence-based treatment recommendations from a variety of treatments options. Differences in the treatment recommendations between depression and schizophrenia reflected the perceived severity of each disorder. Further developments of the Vietnamese mental health care system concerning mental health care providers, as well as the legal regulations surrounding the provision of psychotherapy are needed. PMID- 30473729 TI - Prevascularization of collagen-glycosaminoglycan scaffolds: stromal vascular fraction versus adipose tissue-derived microvascular fragments. AB - Background: The seeding of scaffolds with the stromal vascular fraction (SVF) of adipose tissue is a common prevascularization strategy in tissue engineering. Alternatively, adipose tissue-derived microvascular fragments (ad-MVF) may serve as vascularization units. In contrast to SVF single cells, they represent a mixture of intact arteriolar, capillary and venular vessel segments. Therefore, we herein hypothesized that the ad-MVF-based prevascularization of scaffolds is superior to the conventional SVF single cells-based approach. Results: SVF single cells and ad-MVF were enzymatically isolated from epididymal fat pads of green fluorescent protein (GFP)+ donor mice to assess their viability and cellular composition using fluorescence microscopy and flow cytometry. Moreover, collagen glycosaminoglycan matrices (Integra(r)) were seeded with identical amounts of the isolates and implanted into full-thickness skin defects within dorsal skinfold chambers of GFP- recipient mice for the intravital fluorescent microscopic, histological and immunohistochemical analysis of implant vascularization and incorporation throughout an observation period of 2 weeks. Non-seeded matrices served as controls. While both isolates contained a comparable fraction of endothelial cells, perivascular cells, adipocytes and stem cells, ad-MVF exhibited a significantly higher viability. After in vivo implantation, the vascularization of ad-MVF-seeded scaffolds was improved when compared to SVF seeded ones, as indicated by a significantly higher functional microvessel density. This was associated with an enhanced cellular infiltration, collagen content and density of CD31+/GFP+ microvessels particularly in the center of the implants, demonstrating a better incorporation into the surrounding host tissue. In contrast, non-seeded matrices exhibited a poor vascularization, incorporation and epithelialization over time. Conclusions: The present study demonstrates that ad-MVF are highly potent vascularization units that markedly accelerate and improve scaffold vascularization when compared to the SVF. PMID- 30473730 TI - Bioconversion of cheese whey permeate into fungal oil by Mucor circinelloides. AB - Background: Oleaginous fungi are efficient tools to convert agricultural waste streams into valuable components. The filamentous fungus Mucor circinelloides was cultivated in whey permeate, a byproduct from cheese production, to produce an oil-rich fungal biomass. Response surface methodology was used to optimize the fermentation conditions such as pH and temperature for increased biomass yield and lipid accumulation. Quantification and characterization of the fungal biomass oil was conducted. Results: Upstream lactose hydrolysis of the whey permeate increased the biomass yield from 2.4 to 7.8 (g dry biomass/L) compared to that of non-hydrolyzed whey permeate. The combination of low pH (4.5) and pasteurization minimized microbial competition, thus favoring fungal growth. A central composite rotatable design was used to evaluate the effects of temperature (22.4-33.6 degrees C) and a lower pH range (3.6-4.7) on biomass yield and composition. The highest biomass yield and oil content was observed at high temperature (33.6 degrees C), while the pH range evaluated had a less pronounced effect. The predictive model was validated at the optimal conditions of 33.6 degrees C and pH 4.5. The fungal biomass yield plateaued at 9 g dry cell weight per liter, while the oil content and lipid yield reached a maximum of 24% dry biomass and 2.20 g/L, respectively, at 168 h. Triacylglycerides were the major lipid class (92%), which contained predominantly oleic (41%), palmitic (23%), linoleic (11%), and gamma-linolenic acid (9%). Conclusions: This study provided an alternative way of valorization of cheese whey permeate by using it as a substrate for the production of value-added compounds by fungal fermentation. The fatty acid profile indicates the suitability of M. circinelloides oil as a potential feedstock for biofuel production and nutraceutical applications. PMID- 30473731 TI - Retraction Note to: Bacterial conversion of depolymerized Kraft lignin. AB - [This retracts the article DOI: 10.1186/s13068-018-1240-7.]. PMID- 30473732 TI - The putative beta-glucosidase BGL3I regulates cellulase induction in Trichoderma reesei. AB - Background: The filamentous fungus Trichoderma reesei (anamorph of Hypocrea jecorina) displays increased cellulase expression while growing on inducers such as lactose or cellulose. However, the mechanism of cellulase induction in T. reesei is not yet completely characterized. Here, a protein annotated as beta glucosidase (BGL3I) was found to be involved in cellulase induction in T. reesei. The effects of BGL3I on cellulase production have not yet been fully understood. Results: Deletion of the bgl3i gene had no influence on the growth of T. reesei, but significantly increased its cellulase activities. Deletion of bgl3i also resulted in decreased extracellular galactosidase activity, but significantly increased transcription of lactose permeases, which might be involved in lactose transport. Furthermore, deletion of bgl3i enhanced the transcription levels of intracellular beta-glucosidases cel1a, cel1b and the regulator xyr1, which are all essential for lactose induction in T. reesei. BGL3I was found to have a relatively high ability to hydrolyze sophorose, which is proposed to be the strongest natural inducer of cellulase synthesis in T. reesei. Conclusions: BGL3I may take part in the complex regulating system of cellulase induction. The deletion of bgl3i offers a new strategy to improve T. reesei strain performance. PMID- 30473733 TI - Reliability of a multi-segment foot model in a neutral cushioning shoe during treadmill walking. AB - Background: Detailed kinematics of the foot has been frequently reported on in the literature, specifically using various multi-segment foot models. It is important to identify the reliability of a multi-segment foot model in a population of mixed genders and activity levels, while walking in commonly used footwear. The main objective of this study was to investigate the between-day reliability and within-session variability of the Oxford Foot Model (OFM) while walking in a neutral cushioning shoe. Methods: A 7-camera Vicon motion capture system was used along with 29 passive reflective markers, placed on the participant to examine the multi-segment foot kinematics of the left foot using the OFM. Windows were cut in New Balance 840 shoes following reports from a previous investigation to maintain shoe integrity during testing. Two walking sessions on separate days were collected for 12 healthy participants, with an average total of 22 gait cycles per day. Results: ICCs ranged from 0.020 to 0.964 for between-day reliability, and within-session ICC values ranged from 0.268 to 0.985. Between-day ICC values of the relative measures (excursion and range of motion (ROM)) were higher than the absolute angle measures (angle at foot strike and peak angle). Largest differences were measured in the transverse plane, and the smallest differences in the sagittal plane. Bland-Altman plots revealed best agreement in the frontal and sagittal planes. SEM values ranged from 0.04 to 3.5 for the between-day reliability. Conclusions: Between-day reliability and within session variability were comparable to previous studies for adults walking barefoot and shod. This research demonstrates that the OFM can produce reliable data when applied to the assessment of a shod foot. PMID- 30473734 TI - Lower bone mineral density in older female endurance skiers - a cross-sectional, observational study. AB - Background: Physical activity (PA) is generally beneficial for bone health, but the effect of high levels of PA over many years, in older women, is unknown. Methods: T-score from Dual-energy X-ray absorptiometry (DXA), and self-reported baseline characteristics were recorded for 24 female, cross-country-skiing competitors, aged 68-76 years, from the Birkebeiner Ageing Study. Data from 647 women in the same age range from the Tromso-6 population study, with recorded DXA findings, were used for comparison. Results: The athletes reported a median(range) of 9(1-34) participations in the 54 km, yearly ski-race, indicating long-term PA. They also reported more moderate and high levels of PA than women in the general population (52% vs. 12 and 30% vs. 0%, respectively). The athletes had lower body mass index (BMI) than the controls (mean BMI 21.7 vs 26.9 kg/m2, p < 0.001). As many as 22/24(92%) of the athletes and 477/647(74%) of the controls had a low bone mineral density (BMD) (T-score < - 1), p 0.048, Pearson chi square test. Odds ratio (OR) of low BMD was 3.9 in athletes vs. controls (p 0.048, logistic regression), but adjusting for BMI largely diminished the effect estimate, which was no longer statistically significant (aOR 1.81, p 0.432). The proportion of self-reported fractures was the same in the two groups. Conclusions: This pilot study suggests that long-term, high levels of PA are associated with low bone mineral density in older women, and the finding might be due to differences in BMI. Despite the lower bone mineral density the athletes did not report more fractures. PMID- 30473736 TI - Successful rituximab treatment of granulomatosis with polyangiitis with cranial neuropathies. AB - Background: In granulomatosis with polyangiitis (GPA), peripheral nerve involvement is common but central nervous system (CNS) involvement is extremely rare and treatment strategy has not been established. We report a case of intravenous cyclophosphamide (IVCY)-resistant GPA with associated cranial neuropathies that was successfully treated with rituximab (RTX). Case presentation: A 37-year-old man with intractable sinusitis had several months of headache, hoarseness, and dysphagia; a month of right-sided deafness and nasal bleeding; and a week of dysarthria, steppage gait, and numbness in the right L5 distribution. A magnetic resonance imaging (MRI) examination of the head showed an infiltrative lesion in the right skull base encasing the carotid sheath. Computed tomography (CT) scan of the chest revealed a 23 mm nodule in the left upper lobe. Histology was inconclusive. Therefore, the patient was diagnosed as GPA. He was treated with glucocorticoids (GC) and IVCY. Three months later, he was readmitted for recurrence of headache and new left-sided hearing loss. He was treated with GC and RTX, and a 1-year remission followed. The molecular mechanism of RTX is not fully understood. In this case, RTX was more effective at rapidly and strongly suppressing B cells than CY. Since the B cell count was proportional to the patient's clinical manifestations, B cells might represent a suitable target for the treatment of GPA with cranial neuropathies. Conclusions: GPA with cranial neuropathies might be useful with RTX as induction therapy. PMID- 30473735 TI - Effects of 10-week walking and walking with home-based resistance training on muscle quality, muscle size, and physical functional tests in healthy older individuals. AB - Background: Older individuals have been shown to present muscle atrophy in conjunction with increased fat fraction in some muscles. The proportion of fat and connective tissue within the skeletal muscle can be estimated from axial B mode ultrasound images using echo intensity (EI). EI was used to calculate the index of muscle quality. Walking, home-based weight-bearing resistance training, and its combinations are considered simple, easy, and practical exercise interventions for older adults. The purpose of this study was to quantify the effects of walking and walking with home-based resistance training on muscle quality of older individuals. Methods: Thirty-one participants performed walking training only (W-group; 72 +/- 5 years) and 33 participants performed walking and home-based resistance training (WR-group; 73 +/- 6 years). This study was a non randomized controlled trial with no control group. All participants were instructed to walk 2 or 3 sets per week for 10 weeks (one set: 30-min continuous walking). In addition, the WR-group performed home-based weight-bearing resistance training. EI was measured as a muscle quality index using axial B-mode ultrasound images of the rectus femoris and vastus lateralis of the mid-thigh. We further averaged these parameters to obtain the EI of the quadriceps femoris (QF). Participants further performed five functional tests: sit-ups, supine up, sit-to-stand, 5-m maximal walk, and 6-min walk. Results: QF EI was significantly decreased in both groups after training (W-group 69.9 +/- 7.4 a.u. to 61.7 +/- 7.0 a.u., WR-group 64.0 +/- 9.5 a.u. to 51.1 +/- 10.0 a.u.; P < 0.05), suggesting improved muscle quality. QF EI was further decreased in the WR-group compared with the W-group. The sit-up test in both groups and the sit-to-stand and 5-m maximal walk tests in the W-group were significantly improved after training. Conclusion: These results suggest that training-induced stimulation is associated with a decrease in EI in some thigh regions. Furthermore, the addition of home based resistance training to walking would be effective for a greater reduction of EI. PMID- 30473737 TI - "Ticking Bomb": The Impact of Climate Change on the Incidence of Lyme Disease. AB - Lyme disease (LD) is the most common tick-borne disease in North America. It is caused by Borrelia burgdorferi and transmitted to humans by blacklegged ticks, Ixodes scapularis. The life cycle of the LD vector, I. scapularis, usually takes two to three years to complete and goes through three stages, all of which are dependent on environmental factors. Increases in daily average temperatures, a manifestation of climate change, might have contributed to an increase in tick abundance via higher rates of tick survival. Additionally, these environmental changes might have contributed to better host availability, which is necessary for tick feeding and life cycle completion. In fact, it has been shown that both tick activity and survival depend on temperature and humidity. In this study, we have examined the relationship between those climatic variables and the reported incidence of LD in 15 states that contribute to more than 95% of reported cases within the Unites States. Using fixed effects analysis for a panel of 468 U.S. counties from those high-incidence states with annual data available for the period 2000-2016, we have found sizable impacts of temperature on the incidence of LD. Those impacts can be described approximately by an inverted U-shaped relationship, consistent with patterns of tick survival and host-seeking behavior. Assuming a 2 degrees C increase in annual average temperature-in line with mid-century (2036-2065) projections from the latest U.S. National Climate Assessment (NCA4)-we have predicted that the number of LD cases in the United States will increase by over 20 percent in the coming decades. These findings may help improving preparedness and response by clinicians, public health professionals, and policy makers, as well as raising public awareness of the importance of being cautious when engaging in outdoor activities. PMID- 30473738 TI - In vitro measurements of hemodynamic forces and their effects on endothelial cell mechanics at the sub-cellular level. AB - This paper presents micro-particle tracking velocimetry measurements over cultured bovine aortic endothelial cell monolayers in microchannels. The objective was to quantify fluid forces and cell morphology at the sub-cellular scale for monolayers subjected to steady shear rates of 5, 10, and 20 dyn/cm2. The ultimate goal of this study was to develop an experimental methodology for in vitro detailed study of physiologically realistic healthy and diseased conditions. Cell topography, shear stress, and pressure distributions were calculated from sets of velocity fields made in planes parallel to the microchannel wall. For each experiment, measurements were made in 3 h intervals for 18 h. It was found that there is a three-dimensional change in cell morphology as a result of applied shear stress. That is, cells flatten and become more wedge shaped in the stream direction while conserving volume by spreading laterally, i.e., in the cross-stream direction. These changes in cell morphology are directly related to local variations in fluid loading, i.e., shear stress and pressure. This paper describes the first flow measurements over a confluent layer of endothelial cells that are spatially resolved at the sub-cellular scale with a simultaneous temporal resolution to quantify the response of cells to fluid loading. PMID- 30473739 TI - The effects of nonignorable missing data on label-free mass spectrometry proteomics experiments. AB - An idealized version of a label-free discovery mass spectrometry proteomics experiment would provide absolute abundance measurements for a whole proteome, across varying conditions. Unfortunately, this ideal is not realized. Measurements are made on peptides requiring an inferential step to obtain protein level estimates. The inference is complicated by experimental factors that necessitate relative abundance estimation and result in widespread non-ignorable missing data. Relative abundance on the log scale takes the form of parameter contrasts. In a complete-case analysis, contrast estimates may be biased by missing data and a substantial amount of useful information will often go unused. To avoid problems with missing data, many analysts have turned to single imputation solutions. Unfortunately, these methods often create further difficulties by hiding inestimable contrasts, preventing the recovery of interblock information and failing to account for imputation uncertainty. To mitigate many of the problems caused by missing values, we propose the use of a Bayesian selection model. Our model is tested on simulated data, real data with simulated missing values, and on a ground truth dilution experiment where all of the true relative changes are known. The analysis suggests that our model, compared with various imputation strategies and complete-case analyses, can increase accuracy and provide substantial improvements to interval coverage. PMID- 30473740 TI - Prevalence and treatment of allergies in rural areas of Bavaria, Germany: a cross sectional study. AB - Background: There is a high prevalence of allergies in Germany, with approximately 20% of the population having at least one allergy and only about 10% of these being treated adequately. We conducted a cross-sectional study in a rural area of Bavaria (Southern Germany) to evaluate the prevalence of allergies and their treatment, because research regarding this topic is currently limited. Methods: Data were collected in 10 offices of non-dermatological doctors using a self-filled questionnaire to ask participants about allergies and treatment. Results: A total of 641 questionnaires were appropriate for analysis. The prevalence of allergies in the Bavarian countryside was higher than that reported for Germany (37.3% vs. 20.0%). Furthermore, almost a third (30.4%) of allergies were not treated at all. The most frequently consulted therapist was found to be a general practitioner. Conclusions: Based on the study results, there is a need for prevention programs and establishment of treatments for certain allergies to minimize long-term health effects. Moreover, more studies are needed to analyze the prevalence of allergies in farmers who had a higher prevalence of allergies compared to previously reported prevalence in literature reviews. Trial registrations: The study was approved by the ethical review committee of the Technical University Munich (EC number 548/16S). PMID- 30473741 TI - Effect of Metronidazole on the Oxidoreductive Processes in the Submandibular and Parotid Glands in Experimental Research. AB - Oxidative stress takes part in the pathomechanisms of many diseases, including oral disorders. The imbalance between oxidative and antioxidative processes may lead to periodontitis, osteitis, or oral cancers. Furthermore, many chemotherapeutics, e.g., metronidazole (MTZ), may also cause toxic reactions and affect oxidative reactions. The research focused on MTZ influence on oxidative destruction in the parotid and submandibular gland tissue in animal experimental model. Therefore, the concentrations of enzymatic and nonenzymatic markers of oxidative stress were measured in these two rat glands in the control and experimental MTZ-treated groups. The material for analysis included parotid and submandibular glands of male Wistar rats, which were treated with metronidazole for 7 days by gastric tube in a dose of 100 mg/kg b.w. On day 8, the material was obtained and frozen in temp. -80 degrees C. Then, the following seven enzymatic and nonenzymatic parameters were measured: GPx, TOS, TAS, SOD, LPO, CAT, and GSH. The data were analysed using Statistica 10.0. Metronidazole treatment in the experimental model showed an increase in LPO, TOS, and TOS/TAS and a decrease in CAT, SOD, GPx, and TAS. The conclusions of this research were made. Metronidazole treatment in a dose of 100 mg/kg b.w. caused imbalance between oxidative and antioxidative reactions in the rat parotid and submandibular glands. An increase was observed in LPO, TOS, and TOS/TAS in both glands exposed to metronidazole. Decreased activity of CAT, SOD, GPx, and TAS was noted, which indicates attenuation of the gland antioxidative protective barrier. PMID- 30473744 TI - AUTOMATIC RENAL SEGMENTATION IN DCE-MRI USING CONVOLUTIONAL NEURAL NETWORKS. AB - Kidney function evaluation using dynamic contrast-enhanced MRI (DCE-MRI) images could help in diagnosis and treatment of kidney diseases of children. Automatic segmentation of renal parenchyma is an important step in this process. In this paper, we propose a time and memory efficient fully automated segmentation method which achieves high segmentation accuracy with running time in the order of seconds in both normal kidneys and kidneys with hydronephrosis. The proposed method is based on a cascaded application of two 3D convolutional neural networks that employs spatial and temporal information at the same time in order to learn the tasks of localization and segmentation of kidneys, respectively. Segmentation performance is evaluated on both normal and abnormal kidneys with varying levels of hydronephrosis. We achieved a mean dice coefficient of 91.4 and 83.6 for normal and abnormal kidneys of pediatric patients, respectively. PMID- 30473743 TI - Combination of Coenzyme Q10 Intake and Moderate Physical Activity Counteracts Mitochondrial Dysfunctions in a SAMP8 Mouse Model. AB - Aging skeletal muscles are characterized by a progressive decline in muscle mass and muscular strength. Such muscular dysfunctions are usually associated with structural and functional alterations of skeletal muscle mitochondria. The senescence-accelerated mouse-prone 8 (SAMP8) model, characterized by premature aging and high degree of oxidative stress, was used to investigate whether a combined intervention with mild physical exercise and ubiquinol supplementation was able to improve mitochondrial function and preserve skeletal muscle health during aging. 5-month-old SAMP8 mice, in a presarcopenia phase, have been randomly divided into 4 groups (n = 10): untreated controls and mice treated for two months with either physical exercise (0.5 km/h, on a 5% inclination, for 30 min, 5/7 days per week), ubiquinol 10 (500 mg/kg/day), or a combination of exercise and ubiquinol. Two months of physical exercise significantly increased mitochondrial damage in the muscles of exercised mice when compared to controls. On the contrary, ubiquinol and physical exercise combination significantly improved the overall status of the skeletal muscle, preserving mitochondrial ultrastructure and limiting mitochondrial depolarization induced by physical exercise alone. Accordingly, combination treatment while promoting mitochondrial biogenesis lowered autophagy and caspase 3-dependent apoptosis. In conclusion, the present study shows that ubiquinol supplementation counteracts the deleterious effects of physical exercise-derived ROS improving mitochondrial functionality in an oxidative stress model, such as SAMP8 in the presarcopenia phase. PMID- 30473745 TI - Designing consensus immunogens to break tolerance to self-antigens for cancer therapy. PMID- 30473746 TI - eIF4A inhibition: ready for primetime? PMID- 30473742 TI - Relevance of Trypanothione Reductase Inhibitors on Trypanosoma cruzi Infection: A Systematic Review, Meta-Analysis, and In Silico Integrated Approach. AB - Due to the rudimentary antioxidant defenses in Trypanosoma cruzi, disruptors of redox balance are promising candidates for new antitrypanosomal drugs. We developed an integrated model based on systematic review, meta-analyses, and molecular modeling to evaluate the effect of trypanothione reductase (TR) inhibitors in T. cruzi infections. Our findings indicated that the TR inhibitors analyzed were effective in reducing parasitemia and mortality due to Trypanosoma cruzi infection in animal models. The most investigated drugs (clomipramine and thioridazine) showed no beneficial effects on the occurrence of infection-related electrocardiographic abnormalities or the affinity and density of cardiac beta adrenergic receptors. The affinity between the tested ligands and the active site of TR was confirmed by molecular docking. However, the molecular affinity score was unable to explain TR inhibition and T. cruzi death in vitro or the antiparasitic potential of these drugs when tested in preclinical models of T. cruzi infection. The divergence of in silico, in vitro, and in vivo findings indicated that the anti-T. cruzi effects of the analyzed drugs were not restricted to TR inhibition. As in vivo studies on TR inhibitors are still scarce and exhibit methodological limitations, mechanistic and highly controlled studies are required to improve the quality of evidence. PMID- 30473747 TI - Decreased expression levels of complement regulator CD55 contribute to the development of bullous pemphigoid. AB - Bullous pemphigoid is a common autoimmune blistering disease of the elderly associated with autoantibody-mediated complement activation, and complement dysregulation is critical for its pathogenesis. As a crucial regulator of the complement system, CD55 has been widely studied in autoimmune diseases. Here, we investigated the involvement of CD55 in bullous pemphigoid, as little is known regarding its role in this disease. We found that CD55 levels were significantly lower in the lesions of patients with bullous pemphigoid (n = 8) compared to those in skin samples from healthy controls (n = 6). Interestingly, CD55 depletion in HaCaT human keratinocytes enhanced autoantibody-mediated complement activation. Moreover, complement activation was blocked by exogenous recombinant CD55 protein in both skin sections and keratinocytes exposed to pathogenic antibodies from patients with bullous pemphigoid. Notably, a significant increase in the expression of TNF-alpha and IFN-gamma, administration of which downregulated CD55 levels in HaCaT cells, was observed in the sera of patients with bullous pemphigoid (n = 38) compared to that in healthy controls (n = 19). We found that ERK1/2 is involved in both TNF-alpha- and IFN-gamma-induced CD55 downregulation. Thus, CD55 deficiency is a crucial factor in bullous pemphigoid pathogenesis, suggesting that increasing CD55 levels may exert a therapeutic effect. PMID- 30473748 TI - Distinct lung cancer subtypes associate to distinct drivers of tumor progression. AB - The main non-small-cell lung cancer (NSCLC) histopathological subtypes are lung adenocarcinomas (LUAD) and lung squamous cell carcinomas (LUSC). To identify candidate progression determinants of NSCLC subtypes, we explored the transcriptomic signatures of LUAD versus LUSC. We then investigated the prognostic impact of the identified tumor-associated determinants. This was done utilizing DNA microarray data from 2,437 NSCLC patients. An independent analysis of a case series of 994 NSCLC was conducted by next-generation sequencing, together with gene expression profiling from GEO (https://www.ncbi.nlm.nih.gov/geo/). This work led us to identify 69 distinct tumor prognostic determinants, which impact on LUAD or LUSC clinical outcome. These included key drivers of tumor growth and cell cycle, transcription factors and metabolic determinants. Such disease determinants appeared vastly different in LUAD versus LUSC, and often had opposite impact on clinical outcome. These findings indicate that distinct tumor progression pathways are at work in the two NSCLC subtypes. Notably, most prognostic determinants would go inappropriately assessed or even undetected when globally investigating unselected NSCLC. Hence, differential consideration for NSCLC subtypes should be taken into account in current clinical evaluation procedures for lung cancer. PMID- 30473750 TI - Retrospective analysis of prognostic factors in patients of papillary thyroid microcarcinoma. AB - We performed a retrospective chart review of 245 patients with papillary thyroid microcarcinoma (PTMC) to define factors linked to central lymph node metastasis and thus prognosis. Univariate and multivariate analyses showed that being male (p < 0.001), age <45 years at diagnosis (p = 0.045), maximum tumor size > 5 mm (p = 0.030), multifocal tumor (p = 0.040) and tumor envelope invasion (p < 0.001) were all independent risk factors for central compartment lymph node metastasis. Unifocal lesions at the thyroid gland's upper pole, middle and lower pole, had lymph node metastasis rates of 22.7%, 14.0% and 35.0%, respectively (p = 0.048). The rate of central lymph node metastasis was much higher when there was bilateral thyroid involvement than with multifocal unilateral lesions (58.6% vs 37.5%; p = 0.040). These results suggest that for patients at low risk of central lymph node metastasis, unilateral thyroid lobe and isthmus resection is sufficient. However, for patients at high risk of central lymph node metastasis, central lymph node dissection increases the likelihood of complete tumor excision. PMID- 30473749 TI - Lipid profiles of prostate cancer cells. AB - Lipids are important cellular components which can be significantly altered in a range of disease states including prostate cancer. Here, a unique systematic approach has been used to define lipid profiles of prostate cancer cell lines, using quantitative mass spectrometry (LC-ESI-MS/MS), FTIR spectroscopy and fluorescent microscopy. All three approaches identified significant difference in the lipid profiles of the three prostate cancer cell lines (DU145, LNCaP and 22RV1) and one non-malignant cell line (PNT1a). Specific lipid classes and species, such as phospholipids (e.g., phosphatidylethanolamine 18:1/16:0 and 18:1/18:1) and cholesteryl esters, detected by LC-ESI-MS/MS, allowed statistical separation of all four prostate cell lines. Lipid mapping by FTIR revealed that variations in these lipid classes could also be detected at a single cell level, however further investigation into this approach would be needed to generate large enough data sets for quantitation. Visualisation by fluorescence microscopy showed striking variations that could be observed in lipid staining patterns between cell lines allowing visual separation of cell lines. In particular, polar lipid staining by a fluorescent marker was observed to increase significantly in prostate cancer lines cells, when compared to PNT1a cells, which was consistent with lipid quantitation by LC-ESI-MS/MS and FTIR spectroscopy. Thus, multiple technologies can be employed to either quantify or visualise changes in lipid composition, and moreover specific lipid profiles could be used to detect and phenotype prostate cancer cells. PMID- 30473751 TI - MiR-192, miR-200c and miR-17 are fibroblast-mediated inhibitors of colorectal cancer invasion. AB - Colorectal cancer remains a leading cause of cancer-related death worldwide. A previous transcriptomics based study characterized molecular subgroups of which the stromal subgroup was associated with the worst clinical outcome. Micro-RNAs (miRNAs) are well-known regulators of gene expression and can follow a non-linear repression mechanism. We set up a model combining piecewise linear and linear regression and applied this combined regression model to a comprehensive colon adenocarcinoma dataset. We identified miRNAs involved in regulating characteristic gene sets, particularly extracellular matrix remodeling in the stromal subgroup. Comparison of expression data from separated (epithelial) cancer cells and stroma cells or fibroblasts associate these regulatory interactions with infiltrating stromal or tumor-associated fibroblasts. MiR-200c, miR-17 and miR-192 were identified as the most promising candidates regulating genes crucial for extracellular matrix remodeling. We validated our computational findings by in vitro assays. Enforced expression of either miR-200c, miR-17 or miR-192 in untransformed human colon fibroblasts down-regulated 85% of all predicted target genes. Expressing these miRNAs singly or in combination in human colon fibroblasts co-cultured with colon cancer cells considerably reduced cancer cell invasion validating these miRNAs as cancer cell infiltration suppressors in tumor associated fibroblasts. PMID- 30473753 TI - Correction: Resistin promotes tumor metastasis by down-regulation of miR-519d through the AMPK/p38 signaling pathway in human chondrosarcoma cells. AB - [This corrects the article DOI: 10.18632/oncotarget.2724.]. PMID- 30473752 TI - Nasal administration of mesenchymal stem cells restores cisplatin-induced cognitive impairment and brain damage in mice. AB - Cognitive impairments are a common side effect of chemotherapy that often persists long after treatment completion. There are no FDA-approved interventions to treat these cognitive deficits also called 'chemobrain'. We hypothesized that nasal administration of mesenchymal stem cells (MSC) reverses chemobrain. To test this hypothesis, we used a mouse model of cognitive deficits induced by cisplatin that we recently developed. Mice were treated with two cycles of cisplatin followed by nasal administration of MSC. Cisplatin treatment induced deficits in the puzzle box, novel object/place recognition and Y-maze tests, indicating cognitive impairment. Nasal MSC treatment fully reversed these cognitive deficits in males and females. MSC also reversed the cisplatin-induced damage to cortical myelin. Resting state functional MRI and connectome analysis revealed a decrease in characteristic path length after cisplatin, while MSC treatment increased path length in cisplatin-treated mice. MSCs enter the brain but did not survive longer than 12-72 hrs, indicating that they do not replace damaged tissue. RNA sequencing analysis identified mitochondrial oxidative phosphorylation as a top pathway activated by MSC administration to cisplatin-treated mice. Consistently, MSC treatment restored the cisplatin-induced mitochondrial dysfunction and structural abnormalities in brain synaptosomes. Nasal administration of MSC did not interfere with the peripheral anti-tumor effect of cisplatin. In conclusion, nasal administration of MSC may represent a powerful, non-invasive, and safe regenerative treatment for resolution of chemobrain. PMID- 30473754 TI - Correction: Simultaneous delivery of olaparib and carboplatin in PEGylated liposomes imparts this drug combination hypersensitivity and selectivity for breast tumor cells. AB - [This corrects the article DOI: 10.18632/oncotarget.25466.]. PMID- 30473755 TI - Correction: Sonoporation by microbubbles as gene therapy approach against liver cancer. AB - [This corrects the article DOI: 10.18632/oncotarget.25875.]. PMID- 30473756 TI - Religious beliefs and climate change adaptation: A study of three rural South African communities. AB - This article argues that religious beliefs significantly influence a community's understanding and experience of climate change adaptation, indicating the need for an inclusion of such information in climate change adaptation education. Data were collected using the Q-method, whereby recurring statements were identified from semi-structured interviews with participants from three rural communities in the North-West province of South Africa: Ikageng, Ventersdorp and Jouberton. The research found that community members who regard themselves as religious (overall of the Christian faith) fall under two groups: the religious determinists or fatalists, who see climate as a natural process that is governed by God, and religious participants who deny this 'naturalness' and acknowledge humans' impact on the climate. PMID- 30473758 TI - Why does network governance fail in managing post-disaster conditions in the Philippines? AB - Disasters are the litmus test of governance. The inherent complexity of disasters places government agencies and societies in vulnerable situations. This study uses the mixed-method approach to social network analysis in evaluating the network structure of the Philippine disaster management and its implications for disaster governance. A survey was conducted among the target 56 identified disaster response-related agencies and organisations from the disaster management networks of the most susceptible areas in the Philippines - Cities of Cagayan de Oro and Iligan, Province of Misamis Oriental and the overall Region 10 disaster response network, aimed at measuring the existing relationships among member agencies. Forty-four agencies and organisations were able to participate in the survey. Also, key informant interviews were conducted among the representatives of the lead agencies, non-government organisations and survivors of Typhoon Washi. The findings revealed that the mandated tall structure and the lead organisation form of network governance as stipulated in Republic Act 10121 does not work in the regional and local disaster management networks in Region 10, particularly during Typhoon Washi in 2010. At the regional level, such structure does not build interdependencies among agencies, while at the local level, disaster response operations are constrained by bureaucratic protocols making disaster management networks ineffective. At the regional level, where many agencies and organisations are involved, the existing less centralised structure of decision-making should be transformed into a highly centralised structure, while disaster operations should be improved through coordination at all levels of disaster operations and intensified collaboration with non-government agencies. PMID- 30473757 TI - Cultural beliefs of time orientation and social self-construal: Influences on climate change adaptation. AB - Climate change is one of the greatest challenges humankind faces and adaptive behaviour is an imperative response to such change. Culture and the resulting worldview are determinants of behaviour and eminent cultural beliefs are that of time orientation (TO) and social self-construal (SSC). To date, no research focuses on these beliefs from an indigenous South African perspective or the manner in which it may subsequently affect a community's adaptation towards climate change. Q-methodology was used to study perspectives and beliefs in three peri-urban communities in South Africa and to investigate the interrelation between themes such as TO, SSC, climate change awareness and climate change causality. It became apparent that the communities are aware of climate change, yet little to no efforts are currently being made to adapt to climatic change. This absence of motivation to adapt may be attributed to limited risk perception and cultural beliefs of TO and SSC. This study aims to contribute to the understanding of cultural beliefs and its impact on climate change adaptation behaviour in the South African context. It is concluded that TO and SSC from an indigenous South African perspective influence community adaptation to climate change. PMID- 30473759 TI - Traditional leadership and the Tokwe-Mukosi induced displacements: Finding the missing link. AB - There is increasing empirical evidence that the relocation of the victims of the Tokwe-Mukosi floods in Zimbabwe was marred by a combination of challenges. These challenges are argued in this article to have resulted from the adoption of Eurocentric models by government and non-governmental organisation technocrats and experts while relegating traditional leadership and the lived experiences of the displaced to the shadows. The writer provides a summary and critique of the Elizabeth Colson-Thayer Scudder four-stage model and Michael Cernea's Impoverishment Risks and Reconstruction Model. This article argues that traditional leadership is the missing link in disaster-induced displacement and its integration can overcome most of the challenges faced by the displaced in Zimbabwe. Traditional leadership in Zimbabwe can be traced to precolonial states and it has survived the colonial and postcolonial epochs. The study was guided by the Afrocentric theoretical framework. The case for the integration of traditional leadership was buttressed by numerous arguments. Among these arguments include proximity of traditional leadership to the displaced, the Zunde raMambo concept and ubuntu, among others. PMID- 30473760 TI - Gallbladder volvulus-acute cholecystitis 'with a twist'. AB - A Caucasian 92-year-old female was admitted to hospital with acute epigastric pain associated with vomiting. Initial investigations revealed mildly raised inflammatory markers, normal liver function tests but a markedly distended gallbladder with prominent wall thickening. The patient was managed with intravenous antibiotics for acute cholecystitis but deteriorated significantly on Day 2 of admission. An emergency laparoscopic cholecystectomy was performed and we found a gangrenous gallbladder secondary to gallbladder volvulus. The patient recovered well in the postoperative period and was discharged home 7 days later. PMID- 30473761 TI - Solitary fibrous tumor of the stomach with high-grade sarcomatous dedifferentiation. AB - Solitary fibrous tumors (SFT) are uncommon fibroblastic mesenchymal neoplasms that display a wide range of histologic behaviors. These tumors, which are estimated to account for 2% of all soft tissue neoplasms, typically follow a benign clinical course. However, it is estimated that 10-30% of SFTs are malignant and demonstrate aggressive behavior with local recurrence and metastasis up to several years after surgical resection. We report a case of SFT arising from the stomach, which is an exceptionally rare finding and has been reported only six times in the literature. Our case was complicated by diagnostic dilemma with GIST, highlighting the challenges of diagnosing and characterizing SFTs. Additionally, this tumor was associated with dedifferentiation into undifferentiated pleomorphic sarcoma. To our knowledge, there are no documented cases of a malignant SFT arising from the stomach to demonstrate dedifferentiation into an undifferentiated pleomorphic sarcoma. PMID- 30473762 TI - Paradoxical embolism through PFO leading to stroke in a gunshot victim with IVC injury. AB - A 23-year-old man presented to the emergency department with multiple gunshot wounds to the chest and abdomen, and was taken to the operating room emergently for exploratory laparotomy due to hemodynamic instability. The patient underwent inferior vena cava (IVC), bowel and ureter repair during the procedure, requiring massive amounts of blood products. The patient transferred to the surgical intensive care unit with a routine post-operative course for approximately the next 7 days before presenting with signs of stroke. The patient was diagnosed with deep vein thrombosis in IVC at the repair site on a follow-up venogram. Upon further work-up with echocardiography, the patient was determined to have a patent foramen ovale (PFO), with paradoxical embolism as the most likely cause of the stroke. We present this unusual case of a GSW leading to stroke due to embolism from a venous source through a PFO. PMID- 30473763 TI - Descending thoracic aortic aneurysm revealing metastasis of a soft tissue fibrosarcoma: a case report and review of the literature. AB - Background: Review of the first documented case of aortic wall metastasis from a limb sarcoma. Case presentation: In a 56-year-old woman with a diagnosis of a high-grade limb fibrosarcoma, an aortic metastasis was revealed by a fast growing aneurysm of the descending thoracic aorta. This was managed with an endoprosthesis. Conclusion: The presence of an aneurysm in a patient with a sarcoma with a high potential for metastasis and poor cardiovascular risk factors should alert physicians. PMID- 27303633 TI - Hypnotic drug risks of mortality, infection, depression, and cancer: but lack of benefit. AB - This is a review of hypnotic drug risks and benefits, reassessing and updating advice presented to the Commissioner of the Food and Drug Administration (United States FDA). Almost every month, new information appears about the risks of hypnotics (sleeping pills). The most important risks of hypnotics include excess mortality, especially overdose deaths, quiet deaths at night, infections, cancer, depression and suicide, automobile crashes, falls, and other accidents, and hypnotic-withdrawal insomnia. Short-term use of one-two prescriptions is associated with greater risk per dose than long-term use. Hypnotics have usually been prescribed without approved indication, most often with specific contraindications, but even when indicated, there is little or no benefit. The recommended doses objectively increase sleep little if at all, daytime performance is often made worse, not better, and the lack of general health benefits is commonly misrepresented in advertising. Treatments such as the cognitive behavioral treatment of insomnia and bright light treatment of circadian rhythm disorders offer safer and more effective alternative approaches to insomnia. PMID- 27303633 TI - Hypnotic drug risks of mortality, infection, depression, and cancer: but lack of benefit. AB - This is a review of hypnotic drug risks and benefits. Almost every month, new information appears about the risks of hypnotics (sleeping pills). The most important risks of hypnotics include excess mortality (especially overdose deaths, quiet deaths at night, and suicides), infections, cancer, depression, automobile crashes, falls, other accidents, and hypnotic-withdrawal insomnia. Short-term use of one-two prescriptions is associated with even greater risk per dose than long-term use. Hypnotics have usually been prescribed without approved indication, most often with specific contraindications, but even when indicated, there is little or no benefit. The recommended doses objectively increase sleep little if at all, daytime performance is often made worse (not better) and the lack of general health benefits is commonly misrepresented in advertising. Treatments such as the cognitive behavioral treatment of insomnia and bright light treatment of circadian rhythm disorders offer safer and more effective alternative approaches to insomnia. PMID- 30473764 TI - Cost-effectiveness of spinal manipulation, exercise, and self-management for spinal pain using an individual participant data meta-analysis approach: a study protocol. AB - Background: Spinal pain is a common and disabling condition with considerable socioeconomic burden. Spine pain management in the United States has gathered increased scrutiny amidst concerns of overutilization of costly and potentially harmful interventions and diagnostic tests. Conservative interventions such as spinal manipulation, exercise and self-management may provide value for the care of spinal pain, but little is known regarding the cost-effectiveness of these interventions in the U.S. Our primary objective for this project is to estimate the incremental cost-effectiveness of spinal manipulation, exercise therapy, and self-management for spinal pain using an individual patient data meta-analysis approach. Methods/design: We will estimate the incremental cost-effectiveness of spinal manipulation, exercise therapy, and self-management using cost and clinical outcome data collected in eight randomized clinical trials performed in the U.S. Cost-effectiveness will be assessed from both societal and healthcare perspectives using QALYs, pain intensity, and disability as effectiveness measures. The eight randomized clinical trials used similar methods and included different combinations of spinal manipulation, exercise therapy, or self management for spinal pain. They also collected similar clinical outcome, healthcare utilization, and work productivity data. A two-stage approach to individual patient data meta-analysis will be conducted. Discussion: This project capitalizes on a unique opportunity to combine clinical and economic data collected in a several clinical trials that used similar methods. The findings will provide important information on the value of spinal manipulation, exercise therapy, and self-management for spinal pain management in the U.S. PMID- 30467516 TI - BgeeDB, an R package for retrieval of curated expression datasets and for gene list expression localization enrichment tests. AB - BgeeDB is a collection of functions to import into R re-annotated, quality controlled and re-processed expression data available in the Bgee database. This includes data from thousands of wild-type healthy samples of multiple animal species, generated with different gene expression technologies (RNA-seq, Affymetrix microarrays, expressed sequence tags, and in situ hybridizations). BgeeDB facilitates downstream analyses, such as gene expression analyses with other Bioconductor packages. Moreover, BgeeDB includes a new gene set enrichment test for preferred localization of expression of genes in anatomical structures ("TopAnat"). Along with the classical Gene Ontology enrichment test, this test provides a complementary way to interpret gene lists. Availability: https://www.bioconductor.org/packages/BgeeDB/. PMID- 30473768 TI - Moving things forward in Hodgkin lymphoma. AB - Arising from the immune system and located primarily in lymphoid organs, Hodgkin lymphoma (HL) is one of the most common cancers in young adults. Risk-adapted first-line treatment usually consisting of multi-agent chemotherapy and often incorporating consolidative radiation therapy aims at long-term cure. Although this is achieved in the vast majority of patients, therapy-related side effects such as organ damage, second cancers, and fatigue constitute considerable sequelae and outweigh HL as the cause of mortality after successful first-line treatment. In addition, intensive conventional therapy is seldom feasible in elderly or frail patients, diminishing chances of cure in this growing population of patients. The rapidly growing understanding of HL biology, innovative clinical trials, and the incorporation of novel drugs might help to overcome these obstacles in the management of HL. In this review, recent advances in the understanding and care of HL will be summarized with a focus on ongoing and future strategies which might help move things forward. PMID- 30473769 TI - Recent advances in managing brain metastasis. AB - Brain metastases are the most common malignancy encountered in the central nervous system (CNS), with up to 30-40% of cancer patients developing brain metastases at some point during the course of their disease. The management of brain metastasis is rapidly evolving and the roles of local therapies such as whole-brain radiation therapy, stereotactic radiosurgery, and resection along with systemic therapies are in flux. An emphasis on the neurocognitive side effects associated with treatment has gained prominence. Novel molecular studies have demonstrated important evolutionary patterns underpinning the development of brain metastasis and leptomeningeal disease, which may be key to unlocking new therapeutic strategies. This article provides a framework for incorporating the results of recent randomized radiotherapy clinical trials into practice, expounds upon the emphasis on cognition being an important driver in therapeutic selection, describes the importance of CNS-penetrating systemic therapies, and provides an overview of the novel molecular insights that will likely set the stage for future developments in this field. PMID- 30473770 TI - Recent advances in understanding dominant spinocerebellar ataxias from clinical and genetic points of view. AB - Abstract Spinocerebellar ataxias (SCAs) are rare types of cerebellar ataxia with a dominant mode of inheritance. To date, 47 SCA subtypes have been identified, and the number of genes implicated in SCAs is continually increasing. Polyglutamine (polyQ) expansion diseases ( ATXN1/SCA1, ATXN2/SCA2, ATXN3/SCA3, CACNA1A/SCA6, ATXN7/SCA7, TBP/SCA17, and ATN1/DRPLA) are the most common group of SCAs. No preventive or curative treatments are currently available, but various therapeutic approaches, including RNA-targeting treatments, such as antisense oligonucleotides (ASOs), are being developed. Clinical trials of ASOs in SCA patients are already planned. There is, therefore, a need to identify valid outcome measures for such studies. In this review, we describe recent advances towards identifying appropriate biomarkers, which are essential for monitoring disease progression and treatment efficacy. Neuroimaging biomarkers are the most powerful markers identified to date, making it possible to reduce sample sizes for clinical trials. Changes on brain MRI are already evident at the premanifest stage in SCA1 and SCA2 carriers and are correlated with CAG repeat size. Other potential biomarkers have also been developed, based on neurological examination, oculomotor study, cognitive assessment, and blood and cerebrospinal fluid analysis. Longitudinal studies based on multimodal approaches are required to establish the relationships between parameters and to validate the biomarkers identified. PMID- 30467520 TI - Status of drowning in Nepal: A study of central police data. AB - Background: Drowning is a serious and mostly preventable injury-related cause of death. Low-and-middle income countries represent over 90% of total drowning deaths worldwide. There is lack of epidemiological studies of drowning in Nepal. The aim of this paper is to describe the status of drowning in Nepal. Methods: Cases of drowning, occurring between 1 January 2013 and 31 December 2015 were extracted from the Daily Incident Recording System of Nepal Police. Drowning cases were extracted and analysed regardless of their intent. Variables on age, sex of the deceased, types of water bodies, geographical locations, season when drowning occurred and activities of deceased were extracted and descriptive analysis was conducted. Results: A total of 1,507 drowning cases were recorded over a 3 year period. The rate of drowning was 1.9 per 100,000 (2.95 for males and 0.92 for females). Majority of drowning occurred among males (76%) and more than half were (53%) under 20 years of age. Mostly drowning occurred in rivers (natural water bodies). The findings provide strong indication that drowning occurs throughout the year in Nepal. Children were highly vulnerable to drowning. The magnitude of drowning was found to be lower than estimated by global burden of disease (GBD) study. Conclusion: The burden of drowning in Nepal is considerable, but mostly unknown to the public. Despite only having access to a limited data source, this study provides useful evidence that comprehensive research in Nepal is needed urgently. PMID- 30443343 TI - Using different methods to process forced expiratory volume in one second (FEV 1) data can impact on the interpretation of FEV 1 as an outcome measure to understand the performance of an adult cystic fibrosis centre: A retrospective chart review. AB - Background: Forced expiratory volume in one second (FEV 1) is an important cystic fibrosis (CF) prognostic marker and an established endpoint for CF clinical trials. FEV 1 is also used in observation studies, e.g. to compare different centre's outcomes. We wished to evaluate whether different methods of processing FEV 1 data can impact on centre outcome. Methods: This is a single-centre retrospective analysis of routinely collected data from 2013-2016 among 208 adults. Year-to-year %FEV 1 change was calculated by subtracting best %FEV 1 at Year 1 from Year 2 (i.e. negative values indicate fall in %FEV 1), and compared using Friedman test. Three methods were used to process %FEV 1 data. First, %FEV 1 calculated with Knudson equation was extracted directly from spirometer machines. Second, FEV 1 volume were extracted then converted to %FEV 1 using clean height data and Knudson equation. Third, FEV 1 volume were extracted then converted to %FEV 1 using clean height data and GLI equation. In addition, year to-year variation in %FEV 1 calculated using GLI equation was adjusted for baseline %FEV 1 to understand the impact of case-mix adjustment. Results: Year-to year fall in %FEV 1 reduced with all three data processing methods but the magnitude of this change differed. Median change in %FEV 1 for 2013-2014, 2014 2015 and 2015-2016 was -2.0, -1.0 and 0.0 respectively using %FEV 1 in Knudson equation whereas the median change was -1.1, -0.9 and -0.3 respectively using %FEV 1 in the GLI equation. A statistically significant p-value (0.016) was only obtained when using %FEV 1 in Knudson equation extracted directly from spirometer machines. Conclusions: Although the trend of reduced year-to-year fall in %FEV 1 was robust, different data processing methods yielded varying results when year to-year variation in %FEV 1 was compared using a standard related group non parametric statistical test. Observational studies with year-to-year variation in %FEV 1 as an outcome measure should carefully consider and clearly specify the data processing methods used. PMID- 30473772 TI - Recent advances in imaging and understanding interstitial cystitis. AB - Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating condition associated with intense pelvic pain and bladder storage symptoms. Since diagnosis is difficult, prevalence estimates vary with the methodology used. There is also a lack of proven imaging tools and biomarkers to assist in differentiation of IC/BPS from other urinary disorders (overactive bladder, vulvodynia, endometriosis, and prostatitis). Current uncertainty regarding the etiology and pathology of IC/BPS ultimately impacts its timely and successful treatment, as well as hampers future drug development. This review will cover recent developments in imaging methods, such as magnetic resonance imaging, that advance the understanding of IC/BPS and guide drug development. PMID- 30473775 TI - Computational assessment of stomach tumor volume from multi-slice computerized tomography images in presence of type 2 cancer. AB - Background: The multi-slice computerized tomography (MSCT) is a medical imaging modality that has been used to determine the size and location of the stomach cancer. Additionally, MSCT is considered the best modality for the staging of gastric cancer. One way to assess the type 2 cancer of stomach is by detecting the pathological structure with an image segmentation approach. The tumor segmentation of MSCT gastric cancer images enables the diagnosis of the disease condition, for a given patient, without using an invasive method as surgical intervention. Methods: This approach consists of three stages. The initial stage, an image enhancement, consists of a method for correcting non homogeneities present in the background of MSCT images. Then, a segmentation stage using a clustering method allows to obtain the adenocarcinoma morphology. In the third stage, the pathology region is reconstructed and then visualized with a three dimensional (3-D) computer graphics procedure based on marching cubes algorithm. In order to validate the segmentations, the Dice score is used as a metric function useful for comparing the segmentations obtained using the proposed method with respect to ground truth volumes traced by a clinician. Results: A total of 8 datasets available for patients diagnosed, from the cancer data collection of the project, Cancer Genome Atlas Stomach Adenocarcinoma (TCGASTAD) is considered in this research. The volume of the type 2 stomach tumor is estimated from the 3-D shape computationally segmented from the each dataset. These 3-D shapes are computationally reconstructed and then used to assess the morphopathology macroscopic features of this cancer. Conclusions: The segmentations obtained are useful for assessing qualitatively and quantitatively the stomach type 2 cancer. In addition, this type of segmentation allows the development of computational models that allow the planning of virtual surgical processes related to type 2 cancer. PMID- 30473771 TI - Recent advances in branching mechanisms underlying neuronal morphogenesis. AB - Proper neuronal wiring is central to all bodily functions, sensory perception, cognition, memory, and learning. Establishment of a functional neuronal circuit is a highly regulated and dynamic process involving axonal and dendritic branching and navigation toward appropriate targets and connection partners. This intricate circuitry includes axo-dendritic synapse formation, synaptic connections formed with effector cells, and extensive dendritic arborization that function to receive and transmit mechanical and chemical sensory inputs. Such complexity is primarily achieved by extensive axonal and dendritic branch formation and pruning. Fundamental to neuronal branching are cytoskeletal dynamics and plasma membrane expansion, both of which are regulated via numerous extracellular and intracellular signaling mechanisms and molecules. This review focuses on recent advances in understanding the biology of neuronal branching. PMID- 30467521 TI - The Congress Impact Factor: A proposal from board members of the World Society of Emergency Surgeons.it (WSES) and Academy of Emergency Medicine and Care (AcEMC). AB - Many scientific congresses and conferences are held every year around the world. The aim of the World Society of Emergency Surgeons.it (WSES) and Academy of Emergency Medicine and Care (AcEMC) was to develop a simple mathematical parameter as an indicator of academic quality and scientific validity of a congress. In this opinion article, a new metric, the Congress Impact Factor (IFc), is proposed taking into consideration the widely used Impact Factor as an indicator of journals' prestige and using H-index analysis. The IFc is derived from the mathematical ratio between the mean H-index of invited lecturers normalized for lecture topic and number of lectures in the conference. In case of multiple sessions, the mean of all IFc is calculated along with its standard deviation. We conclude that the IFc can be a useful measure for evaluating and comparing congress prestige, and may also represent a potentially useful parameter for improving academic curriculum and helping participants to choose the more prestigious meetings for their education. PMID- 30473777 TI - Exploring challenges of health system preparedness for communicable diseases in Arbaeen mass gathering: a qualitative study. AB - Background: Infectious diseases are common problems in mass gatherings, especially when there is a lack of health system preparedness. Since Iran is one of the most important countries on the walking path of Arbaeen and has a vital role in providing health services to pilgrims, the experiences of health challenges by participants is of key importance. The aim of this study is to explore stakeholders' experiences on the health system's preparedness and challenges, and to provide suggestions for preventing infectious diseases during the Arbaeen mass gathering. Methods: A qualitative research method was used with a conventional content analysis approach. The number of participants was 17, including 13 executive managers and 4 health policymakers who entered the study among participants. Semi-structured interviews were used to generate the data. Interviews were analyzed by means of content analysis after face-to-face interviews. Results: Data analysis resulted in the extraction of four main themes and 11 sub-themes. Health infrastructure defects in Iraq has three sub-themes (health abandonment in Iraq, the weaknesses in health culture and problems related to the health system); poor control of the causative factors of infectious diseases has three sub-themes (the underlying factors of the prevalence of contagious diseases, health system response to communicable diseases and ignoring the risks of the Arbaeen ceremony); the low perception of risk in pilgrims has three sub-themes (lack of awareness in pilgrims, fatalism in pilgrims and unhygienic belief in pilgrims); and the ineffectiveness of health education has two sub-themes (training shortage in the targeted group and educational content problems) that shows participant's experiences of the health system's challenges for coping with infectious diseases during the Arbaeen ceremony. Conclusion: Pilgrim-based training, planning and controlling other challenges may change these threats to opportunities and improve the health of participants of the mass gathering of Arbaeen in the region. PMID- 30473778 TI - E-cadherin expression pattern during zebrafish embryonic epidermis development. AB - Background: E-cadherin is the major adhesion receptor in epithelial adherens junctions (AJs). On established epidermis, E-cadherin performs fine-tuned cell cell contact remodeling to maintain tissue integrity, which is characterized by modulation of cell shape, size and packing density. In zebrafish, the organization and distribution of E-cadherin in AJs during embryonic epidermis development remain scarcely described. Methods: Combining classical immunofluorescence, deconvolution microscopy and 3D-segmentation of AJs in epithelial cells, a quantitative approach was implemented to assess the spatial and temporal distribution of E-cadherin across zebrafish epidermis between 24 and 72 hpf. Results: increasing levels of E-cadh protein parallel higher cell density and the appearance of hexagonal cells in the enveloping layer (EVL) as well as the establishments of new cell-cell contacts in the epidermal basal layer (EBL), being significantly between 31 and 48 hpf . Conclusions: Increasing levels of E cadherin in AJs correlates with extensive changes in cell morphology towards hexagonal packing during the epidermis morphogenesis. PMID- 30473779 TI - Burden of cytomegalovirus reactivation post kidney transplant with antithymocyte globulin use in Thailand: A retrospective cohort study. AB - Background: Cytomegalovirus (CMV) is an important cause of infectious complications after kidney transplantation (KT), especially among patients receiving antithymocyte globulin (ATG). CMV infection can result in organ dysfunction and indirect effects such as graft rejection, graft failure, and opportunistic infections . Prevention of CMV reactivation includes pre-emptive or prophylactic approaches. Access to valganciclovir prophylaxis is limited by high cost. Our objective is to determine the burden and cost of treatment for CMV reactivation/disease among KT recipients who received ATG in Thailand since its first use in our center. Methods: We conducted a single-center retrospective cohort study of KT patients who received ATG during 2010-2013. We reviewed patients' characteristics, type of CMV prophylaxis, incidence of CMV reactivation, and outcome (co-infections, graft function and death). We compared the treatment cost between patients with and without CMV reactivation. Results: Thirty patients included in the study had CMV serostatus D+/R+. Twenty-nine patients received intravenous ganciclovir early after KT as inpatients. Only three received outpatient valganciclovir prophylaxis. Incidence of CMV reactivation was 43%, with a median onset of 91 (range 23-1007) days after KT. Three patients had CMV end-organ disease; enterocolitis or retinitis. Infectious complication rate among ATG-treated KT patients was up to 83%, with a trend toward a higher rate among those with CMV reactivation ( P = 0.087). Patients with CMV reactivation/disease required longer duration of hospitalization ( P = 0.018). The rate of graft loss was 17%. The survival rate was 97%. The cost of treatment among patients with CMV reactivation was significantly higher for both inpatient setting ( P = 0.021) and total cost ( P = 0.035) than in those without CMV reactivation. Conclusions: Burden of infectious complications among ATG treated KT patients was high. CMV reactivation is common and associated with longer duration of hospitalization and higher cost. PMID- 30473780 TI - Using zebrafish larval models to study brain injury, locomotor and neuroinflammatory outcomes following intracerebral haemorrhage. AB - Intracerebral haemorrhage (ICH) is a devastating condition with limited treatment options, and current understanding of pathophysiology is incomplete. Spontaneous cerebral bleeding is a characteristic of the human condition that has proven difficult to recapitulate in existing pre-clinical rodent models. Zebrafish larvae are frequently used as vertebrate disease models and are associated with several advantages, including high fecundity, optical translucency and non protected status prior to 5 days post-fertilisation. Furthermore, other groups have shown that zebrafish larvae can exhibit spontaneous ICH. The aim of this study was to investigate whether such models can be utilised to study the pathological consequences of bleeding in the brain, in the context of pre clinical ICH research. Here, we compared existing genetic (bubblehead) and chemically inducible (atorvastatin) zebrafish larval models of spontaneous ICH and studied the subsequent disease processes. Through live, non-invasive imaging of transgenic fluorescent reporter lines and behavioural assessment we quantified brain injury, locomotor function and neuroinflammation following ICH. We show that ICH in both zebrafish larval models is comparable in timing, frequency and location. ICH results in increased brain cell death and a persistent locomotor deficit. Additionally, in haemorrhaged larvae we observed a significant increase in macrophage recruitment to the site of injury. Live in vivo imaging allowed us to track active macrophage-based phagocytosis of dying brain cells 24 hours after haemorrhage. Morphological analyses and quantification indicated that an increase in overall macrophage activation occurs in the haemorrhaged brain. Our study shows that in zebrafish larvae, bleeding in the brain induces quantifiable phenotypic outcomes that mimic key features of human ICH. We hope that this methodology will enable the pre-clinical ICH community to adopt the zebrafish larval model as an alternative to rodents, supporting future high throughput drug screening and as a complementary approach to elucidating crucial mechanisms associated with ICH pathophysiology. PMID- 30473781 TI - Orchestrating a community-developed computational workshop and accompanying training materials. AB - The importance of bioinformatics, computational biology, and data science in biomedical research continues to grow, driving a need for effective instruction and education. A workshop setting, with lectures and guided hands-on tutorials, is a common approach to teaching practical computational and analytical methods. Here, we detail the process we used to produce high-quality, community-authored educational materials that are available for public consumption and reuse. The coordinated efforts of 17 authors over 10 weeks resulted in 15 workshops available as a website and as a 388-page electronic book. We describe how we utilized cloud infrastructure, GitHub, and a literate programming approach to robustly deliver hands-on tutorials to participants of the annual Bioconductor conference. The scripts, raw and published workshop materials, and cloud machine image are all openly available. Our approach uses free services and software and can be adapted by workshop organizers and authors in other contests with appropriate technical backgrounds. PMID- 30473782 TI - Embryonic zebrafish xenograft assay of human cancer metastasis. AB - Cancer metastasis is the most important prognostic factor determining patient survival, but currently there are very few drugs or therapies that specifically inhibit the invasion and metastasis of cancer cells. Currently, human cancer metastasis is largely studied using transgenic and immunocompromised mouse xenograft models, which are useful for analysing end-point tumour growth but are unable to accurately and reliably monitor in vivo invasion, intravasation, extravasation or secondary tumour formation of human cancer cells. Furthermore, limits in our ability to accurately monitor early stages of tumour growth and detect micro-metastases likely results in pain and suffering to the mice used for cancer xenograft experiments. Zebrafish ( Danio rerio) embryos, however, offer many advantages as a model system for studying the complex, multi-step processes involved during cancer metastasis. This article describes a detailed method for the analysis of human cancer cell invasion and metastasis in zebrafish embryos before they reach protected status at 5 days post fertilisation. Results demonstrate that human cancer cells actively invade within a zebrafish microenvironment, and form metastatic tumours at secondary tissue sites, suggesting that the mechanisms involved during the different stages of metastasis are conserved between humans and zebrafish, supporting the use of zebrafish embryos as a viable model of human cancer metastasis. We suggest that the embryonic zebrafish xenograft model of human cancer is a tractable laboratory model that can be used to understand cancer biology, and as a direct replacement of mice for the analysis of drugs that target cancer invasion and metastasis. PMID- 30473783 TI - Phenylalanine intercalation parameters for liquid-disordered phase domains - a membrane model study. AB - Background: Propensity of phenylalanine (Phe) for nonpolar environments drives its intercalation into phospholipid membranes, which has been implicated in metabolic and neurological disorders. The knowledge of Phe intercalation parameters can be instrumental in understanding various membrane processes triggered by interactions with Phe, in particular the early events leading to the formation of nucleation/docking sites for the self-assembly of Phe amyloid fibrils at the membrane surface. Results: In this study, we used monolayers of phosphatidylethanolamine (DPPE) and phosphatidylcholine (DPPC) to mimic the membrane outer leaflet. Its initial interaction with Phe was modeled by injecting Phe into the aqueous phase underneath the monolayer. Constant pressure insertion assays augmented with epifluorescence microscopy imaging were used to monitor Phe intercalation. Our primary goal was to determine the Phe intercalation area, A Phe. Two values were obtained for A Phe, 33 +/- 2 and 48 +/- 3 A2. Conclusions: Phe appeared to discriminate between DPPE and DPPC packing, and use two modes of intercalation. The area of A Phe 33 +/- 2 A2 is consistent with a Phe monomer intercalating into membrane by inserting the phenyl ring nearly normal to the membrane surface. This mode has been found to operate in DPPE membranes. For DPPC membranes however, the value of A Phe = 48 +/- 3 A2 suggests that, from saline, Phe tends to intercalate as a larger species plausibly dragging along a counterion, Na+, in a Na+(Phe) complex. PMID- 30473784 TI - Extended spectrum beta-lactamase mediated resistance in carriage and clinical gram-negative ESKAPE bacteria: a comparative study between a district and tertiary hospital in South Africa. AB - Background: Gram-negative ESKAPE bacteria are increasingly implicated in several difficult-to-treat infections in developed and developing countries. They are listed by the World Health Organization as resistant bacteria of critical priority in research. Objectives: To determine the risk factors, prevalence, phenotypic profiles, genetic diversity and clonal relatedness of extended spectrum beta-lactamase (ESBL)-producing multi-drug resistant (MDR) Gram-negative ESKAPE bacteria in the faecal carriage and clinical samples from patients in an urban, tertiary and a rural, district hospital in uMgungundlovu District, KwaZulu Natal, South Africa. Methods: This study took place in a district and tertiary hospital during a two-months period from May to June 2017 in uMgungundlovu district, South Africa. Rectal swabs collected from hospitalized patients, at admission, after 48 h and at discharge (whenever possible) formed the carriage sample while clinical isolates routinely processed in the microbiological laboratory during the sampling period were also collected and formed the clinical sample. Gram-negative ESKAPE bacteria were screened for ESBL production on selective MacConkey agar and confirmed using ROSCO kits. Minimum inhibitory concentrations were determined, and real-time and multiplex polymerase chain reaction were used to ascertain the presence of bla CTX-M group-1-2-9, bla CTX-M group 8/25, bla SHV, bla TEM, bla OXA-1-like, bla KPC, bla VIM, bla IMP, bla GES and AmpC genes. Genomic fingerprinting was also performed using ERIC-PCR. Risk factors for ESBL-mediating MDR Gram-negative ESKAPE colonization were ascertained by univariate and multivariate logistic regression analyses. Results: Overall prevalence of carriage of ESBL-mediating MDR Gram-negative ESKAPE was 37.21% (16/43), 42.31% (11/26) and 57.14% (4/7) at admission, after 48 h and at discharge respectively. The prevalence of ESBL-mediating MDR Gram-negative ESKAPE bacteria in faecal carriage (46%) was higher than clinical samples (28%). Colonization was mainly associated with the referral from district to tertiary hospital with high statistical significance (OR: 14.40, 95% CI 0.98-210.84). bla CTX-M-group-9, bla CTX-M-group-1 and bla SHV were the main resistance genes identified. Several patients carried more than two different isolates. A Klebsiella pneumoniae (K1) clone was circulating within wards and between hospitals. Conclusion: The study highlights the high prevalence of ESBL-mediating MDR Gram-negative ESKAPE bacteria in carriage and clinical samples among hospitalized patients in uMgungundlovu, South Africa. The wide dissemination of these resistant ESKAPE bacteria in hospitals necessitates improvements in routine screening and reinforcement of infection, prevention and control measures. PMID- 30473785 TI - Intestinal colonization due to Escherichia coli ST131: risk factors and prevalence. AB - Background: Escherichia coli sequence type 131 (ST131) is a successful clonal group that has dramatically spread during the last decades and is considered an important driver for the rapid increase of quinolone resistance in E. coli. Methods: Risk factors for rectal colonization by ST131 Escherichia coli (irrespective of ESBL production) were investigated in 64 household members (18 were colonized) and 54 hospital contacts (HC; 10 colonized) of 34 and 30 index patients with community and nosocomial infection due to these organisms, respectively, using multilevel analysis with a p limit of < 0.1. Result: Colonization among household members was associated with the use of proton-pump inhibitors (PPI) by the household member (OR = 3.08; 95% CI: 0.88-10.8) and higher age of index patients (OR = 1.05; 95% CI; 1.01-1.10), and among HC, with being bed-ridden (OR = 21.1; 95% CI: 3.61-160.0) and having a urinary catheter (OR = 8.4; 95% CI: 0.87-76.9). Conclusion: Use of PPI and variables associated with higher need of person-to-person contact are associated with increased risk of rectal colonization by ST131. These results should be considered for infection control purposes. PMID- 30473787 TI - Bias and estimation under misspecification of the risk period in self-controlled case series studies. AB - The self-controlled case series (SCCS) method is useful for estimating the relative incidence (RI) of acute events, such as adverse events (AEs) during a specified risk period following an exposure (e.g., 6-week period after vaccinations or 30-day period after infection-related hospitalizations). In practice, the "optimal" risk period is unknown and must be specified. To date, two approaches are available to guide the specification of the risk period. Both methods do not fully utilize the nature of the bias due to misspecification, which to date has not been characterized. Thus, we elucidate the bias of SCCS estimate of the RI when the risk period is misspecified. We then propose a novel method that more effectively estimates the optimal risk period and the associated RI of AEs. The new method incorporates information on the functional form of the bias. Efficacy of the proposed approach is illustrated with substantial reduction in bias and variance in simulation studies. The proposed method is illustrated with two SCCS studies to determine the (1) risk of idiopathic thrombocytopenic purpura after measles-mumps-rubella vaccination in children and (2) risk of cardiovascular events after infection-related hospitalizations in older patients on dialysis. PMID- 30473789 TI - Prevalence and factors associated with incomplete immunization of children (12-23 months) in Kwabre East District, Ashanti Region, Ghana. AB - Background: Childhood immunization is one of the most cost effective health interventions but its rate has been declining recently in Ghana. Information on immunization coverage and determinants is needed to improve immunization programmes. The objective of this study was to determine the prevalence and factors associated with incomplete immunization of children (12-23 months) in Kwabre East District, Ghana. Methods: A cross-sectional, community-based survey involving 322 children and their mothers was carried out. Data were collected on socio-demographic characteristics of mothers, childhood immunization history and mothers' knowledge and practices of immunization using a structured questionnaire. Children were classified as incompletely immunized if they failed to receive at least one of 8 vaccine doses: - one dose of Bacillus Calmette Guerin (BCG), 3 doses each of pentavalent, 3 doses of polio and one dose of measles per WHO/UNICEF definition. Chi-square and logistic regression analyses were used to identify the factors associated with incomplete immunisation. Results: The prevalence of incomplete immunization was low (15.5%) suggesting high immunisation coverage but the coverage of the second measles dose, taken at 18 months of age, was the lowest (23.9%). Most of the mothers knew the importance of immunisation (95.7%) and at least one vaccine-preventable disease or symptom (84.9%). Two factors associated with incomplete immunisation in bivariate analyses (community of residence, and mother's knowledge of number of oral polio vaccines given to children) were no longer significant in a logistic regression model. Compared to children in Aboaso, children in Gyamfi Wonoo (AOR = 1.81, 95% CI = 0.80-4.08), Mamponteng (Bonwunu) (AOR = 0.59, 95% CI = 0.24-1.48) and Mamponteng (Town) (AOR = 0.63, 95% CI = 0.26-1.55) had similar odds of incomplete immunisation. Similarly, mother's lack of knowledge of the number of doses of polio vaccine given to children had no effect on the odds of incomplete immunisation (AOR = 0.53, 95% CI = 0.22-1.26). Conclusions: Immunization coverage is high in the Kwabre East district but very few children received the second measles dose. None of the maternal and child factors assessed is associated with immunisation coverage. Further research is needed to identify the determinants of immunisation coverage and the reasons for the low uptake of second measles dose in the study area. PMID- 30473786 TI - Antibiotic consumption and antimicrobial resistance in Poland; findings and implications. AB - Background: The problem of inappropriate use of antibiotics and the resulting growth in antimicrobial resistance (AMR) has implications for Poland and the world. The objective of this paper was to compare and contrast antibiotic resistance and antibiotic utilisation in Poland in recent years versus other European countries, including agreed quality indicators, alongside current AMR patterns and ongoing policies and initiatives in Poland to influence and improve antibiotic prescribing. Methods: A quantitative ten-year analysis (2007-2016) of the use of antibiotics based on European Centre for Disease Prevention and Control (ECDC) data combined with a literature review on AMR rates and antimicrobial stewardship initiatives. Results: The system of monitoring AMR and appropriate strategies to address AMR rates remain underdeveloped in Poland. The role of microbiological diagnostics and efforts to prevent infections is currently underestimated by physicians. Overall, Poland had one of the highest rates of total consumption of antibiotics in the analysed European countries. Total consumption of antibacterials for systemic use and relative consumption of beta-lactamase sensitive penicillins were characterized by small but statistically significant average annual increases between 2007 and 2016 (from 22.2 DIDs to 23.9 DIDs and from 0.8 to 1.3%, respectively). Conclusions: The integrated activities around appropriate antibiotic prescribing in the pre- and post-graduate training of physicians and dentists seem to be particularly important, as well as changes in policies on prescribing antibiotics within ambulatory care. AMR and appropriate prescribing of antibiotics should be the focus of health policy actions in Poland. PMID- 30473788 TI - Exercise inhibits tumor growth and central carbon metabolism in patient-derived xenograft models of colorectal cancer. AB - Background: While self-reported exercise is associated with a reduction in the risk of recurrence in colorectal cancer, the molecular mechanisms underpinning this relationship are unknown. Furthermore, the effect of exercise on intratumoral metabolic processes has not been investigated in detail in human cancers. In our current study, we generated six colorectal patient patient derived xenografts (CRC PDXs) models and treated each PDX to voluntary wheel running (exercise) for 6-8 weeks or no exposure to the wheel (control). A comprehensive metabolomics analysis was then performed on the PDXs to identify exercise induced changes in the tumor that were associated with slower growth. Results: Tumor growth inhibition was observed in the voluntary wheel running group compared to the control group in three of the six models. A metabolomics analysis first revealed that central carbon metabolism was affected in each model irrespective of treatment. Interestingly, comparison of responsive and resistant models showed that levels of metabolites in nucleotide metabolism, known to be coupled to mitochondrial metabolism, were predictive of response. Furthermore, phosphocreatine levels which are linked to mitochondrial energy demands were associated with inhibition of tumor growth. Conclusion: Altogether, this study provides evidence that changes to tumor cell mitochondrial metabolism may underlie in part the benefits of exercise. PMID- 30473790 TI - An examination of risk factors that moderate the body dissatisfaction-eating pathology relationship among New Zealand adolescent girls. AB - Background: Eating disorders (EDs) and their subclinical variants are important health concerns for adolescent girls, and body dissatisfaction is a more common yet often debilitating experience that typically precedes the development of an ED. Despite this fact, little is known about what makes girls who are dissatisfied with their bodies more likely to engage in pathological eating behaviors. The present study explored eating pathology among a sample of adolescent girls from New Zealand and examined a variety of established risk factors that may moderate the relationship between body dissatisfaction (BD) and eating pathology. Methods: Adolescent girls aged between 14 and 18 (N = 231) completed questionnaires assessing eating pathology, BD, negative affect, perfectionism, self-esteem, teasing and sociocultural pressure. Regression analyses tested for moderator effects to examine which variables moderated the relationship between BD and eating pathology. Results: The analyses indicated that high levels of socially prescribed and self-oriented perfectionism, negative affect, perceived pressure from the media, and low levels of self-esteem all strengthened the relationship between BD and eating pathology. Conclusions: The results highlight potential factors that may make adolescent girls who are dissatisfied with their bodies more susceptible to eating pathology. PMID- 30473791 TI - Effects of lipopolysaccharide-induced inflammation on hypoxia and inflammatory gene expression pathways of the rat testis. AB - Background: Bacterial infection and inflammation of the testis impairs fertility, yet an understanding of inflammatory responses of the testis is incomplete. We are interested in identifying gene pathways involved in the detection and clearance of infectious microbes in the male reproductive tract. In previous studies in our lab focused on hypoxia-responsive genes of the testis, preliminary experiments suggested that genes classically categorized as hypoxia genes are also activated during antimicrobial responses. The purpose of this study was to identify hypoxia and inflammatory gene pathways that contribute to antimicrobial protection of the testis and to consider possible cross-talk and interactions between these pathways. Inflammation was induced in Sprague-Dawley rats using P. aeruginosa or E. coli lipopolysaccharide (LPS). Levels of hypoxia-inducible factor-1 (HIF-1alpha) protein and nuclear factor kappa B (NF-kappaB) were measured, and hypoxia and inflammatory gene expression patterns in testis were analyzed by gene expression profiling using real-time quantitative PCR arrays. Results: In LPS-treated rats, HIF-1alpha protein increased with no change in Hif 1alpha mRNA. Western Blot analysis also demonstrated no change in NF-kappaB and inhibitory NFKB alpha (IkappaBalpha) protein levels following LPS treatment. Five hypoxia pathway genes (Angptl4, Egr1, Ier3, Pai1, and Glut1), and 11 inflammatory pathway genes (Ccl12, Cc13, Cd14, Cxcl10, Icam1, Il10, Il1b, Il6, Nfkbia, Tlr2, Tnf) up-regulated after 3 h of inflammation. Angptl4, Ccl12, Cc13, Cd14, Egr1, Nfkbia, Tlr2, and Tnf remained elevated at 6 h. Six genes were up-regulated at 6 h only (Bhlhe40, C3, Jak2, Nlrp3, Slc11a1, Tlr1). One gene (Tlr5) was down regulated after 3 h and no genes at 6 h. Electrophoretic mobility shift assay results suggest a decrease in NF-kappaB binding activity following LPS treatment. Conclusions: Testicular HIF-1alpha is up-regulated following LPS-induced inflammation. In contrast to other tissues, in which HIF-1alpha is up-regulated through transcriptional activation via NF-kappaB, we conclude that HIF-1alpha in the testis is not up-regulated through an increase in Hif-1alpha mRNA or through NF-kappaB-dependent mechanisms. Hypoxia pathway genes and genes involved in Toll like receptor (TLR) and cytokine-mediated signaling comprise major functional categories of up-regulated genes, demonstrating that both hypoxia and classic inflammatory pathways are involved in inflammatory responses of the testis. PMID- 30473792 TI - Vasopressin versus norepinephrine in septic shock: a propensity score matched efficiency retrospective cohort study in the VASST coordinating center hospital. AB - Purpose: It is not clear whether vasopressin versus norepinephrine changed mortality in clinical practice in the Vasopressin and Septic Shock Trial (VASST) coordinating center hospital after VASST was published. We tested the hypothesis that vasopressin changed mortality compared to norepinephrine using propensity matching of vasopressin to norepinephrine-treated patients in the VASST coordinating center hospital before (SPH1) and after (SPH2) VASST was published. Methods: Vasopressin-treated patients were propensity score matched to norepinephrine-treated patients based on age, APACHE II, respiratory, renal, and hematologic dysfunction, mechanical ventilation status, medical/surgical status, infection site, and norepinephrine dose. The propensity score estimated the probability that a patient would have received vasopressin given baseline characteristics. For sensitivity analysis, we then excluded patients who had underlying severe congestive heart failure. The primary outcome was 28-day mortality. Results: Vasopressin- and norepinephrine-treated patients were similar after matching in SPH1 (pre-VASST); vasopressin-treated patients (n = 158) had a significantly higher mortality than norepinephrine-treated patients (n = 158) (60.8 vs. 46.2%, p = 0.009). In SPH2 after matching, the 28-day mortality rates were not significantly different; 31.2% and 26.9% in the vasopressin (n = 93) and norepinephrine (n = 93) groups, respectively (p = 0.518). The day 1 vasopressin dose in SPH1 vs. SPH2 was 0.036 units/min (SD 0.009) vs. 0.032 units/min (SD 0.005), p = 0.001, significantly lower in SPH2 after VASST. Conclusions: Before VASST, vasopressin use was associated with increased mortality compared to norepinephrine in the VASST coordinating center hospital. After VASST, there was no difference in mortality between vasopressin- and norepinephrine-treated patients. This may be the first retrospective propensity-matched cohort study of a sepsis treatment in a center that had previously coordinated a large pivotal randomized controlled trial of that treatment and could be a useful approach for other sepsis therapies. Trial registration: Registration: ISRCTN94845869. PMID- 30473793 TI - High red blood cell distribution width as a marker of hospital mortality after ICU discharge: a cohort study. AB - Background: High red blood cell distribution width (RDW) is associated with worse outcome in diverse scenarios, including in critical illness. The Sabadell score (SS) predicts in-hospital survival after ICU discharge. We aimed to determine RDW's association with survival after ICU discharge and whether RDW can improve the accuracy of the SS. Design: Retrospective cohort study. Setting: general ICU at a university hospital. Patients: We included all patients discharged to wards from January 2010 to October 2016. Methods: We analyzed associations between RDW and variables recorded on admission (age, comorbidities, severity score), during the ICU stay (treatments, complications, length of stay (LOS)), and at ICU discharge (SS). The primary outcome was hospital mortality. Statistical analysis included multivariable logistic regression and receiver operating characteristic curve (ROC) analyses. Results: We discharged 3366 patients to wards; median ward LOS was 7 [4-13] days; ward mortality was 5.2%. Mean RDW at ICU discharge was 15.4 +/- 2.5%. Ward mortality was higher at each quartile of RDW (0.7%, 2.9%, 7.5%, 10.3%; area under ROC 0.81). A logistic regression model with Sabadell score obtained an excellent accuracy for ward mortality (area under ROC 0.863), and the addition of RDW slightly improved accuracy (AUROC 0.890, p < 0.05). Recursive partitioning demonstrated higher mortality in patients with high RDW at each SS level (1.6% vs. 0.3% in SS0, 9.7% vs. 1.1% in SS1, 21.9% vs. 9.7% in SS2), but not in SS3. Conclusion: High RDW is a marker of severity at ICU discharge and improves the accuracy of Sabadell score in predicting ward mortality except in the more extreme SS3. PMID- 30473795 TI - Chronic exposure of Hawaii Island spinner dolphins (Stenella longirostris) to human activities. AB - Habitat selection is strongly influenced by spatial variations in habitat quality and predation risk. Repeated exposure of wildlife to anthropogenic activities in important habitats may affect habitat selection, leading to negative biological consequences. We quantified the cumulative human exposure of a small, genetically isolated and behaviourally constrained spinner dolphin (Stenella longirostris) population, off Hawaii Island, and exposure effects on their daytime cumulative activity budget. Dolphins were exposed to human activities within 100 m for 82.7% of the daytime, with a median duration of 10 min between exposure events. Individual dolphins spent on average 61.7% (s.d. = 6.5) of their daytime resting. Of their total rest time, greater than 90% occurred inside sheltered bays. Despite high levels of human exposure, we did not observe an effect on dolphin resting behaviour. The short intervals between exposure events probably prevent dolphins from returning to a natural resting state before the next event. Consequently, 'control' observations may represent a resting behaviour of a more vigilant nature. Chronic levels of exposure to human activities could lead to rest deprivation, displacement from preferred resting habitats and ultimately negative population level effects. These results have implications for new proposed legislation aiming to reduce dolphin exposure to human activities. PMID- 30473794 TI - An open-label, randomized, phase 3 study of the efficacy and safety of antithrombin gamma in patients with sepsis-induced disseminated intravascular coagulation syndrome. AB - Background: A recombinant form of antithrombin (AT), called AT gamma, is being developed as an alternative to AT derived from human plasma. To compare the efficacy and safety of AT gamma to plasma-derived AT (pAT), we conducted a randomized, open-label, multicenter trial in patients with sepsis-induced disseminated intravascular coagulation (DIC). Methods: Eligible patients, recruited at 30 clinical sites, had been diagnosed with sepsis-induced DIC (by the Japanese Association for Acute Medicine [JAAM] DIC criteria) and AT activity at 70% or below. Patients were randomized 1:1 to either 36 IU/kg/day AT gamma (n = 110) or 30 IU/kg/day pAT (n = 112), both administered intravenously for 5 days. The primary endpoint was recovery from DIC at day 6 or early study withdrawal. DIC recovery was defined as a DIC score of less than four. Secondary endpoints were DIC score, outcome on day 28, sequential organ failure assessment score, acute physiology and chronic health evaluation II score (APACHE II), and plasma AT activity. Adverse events and adverse drug reactions were recorded using MedDRA/J version 16.0. Results: Baseline patient demographics and clinical features were similar in the two treatment groups. On day 6 (or at withdrawal), DIC recovery had occurred in 62 of 110 (56.4%; 95% confidence interval, 46.6 65.8%) patients in the AT gamma group and 59 of 112 (52.7%; 95% confidence interval, 43.0-62.2%) patients in the pAT group. In both treatment groups, DIC recovery rate values tended to be higher when stratified by baseline AT activity rates. All changes in other secondary endpoints were similar in both treatment groups. Safety was also similar in the two treatment groups. Adverse events occurred in 89 of 108 (82.4%) patients in the AT gamma group and 99 of 113 (87.6%) patients in the pAT group. Conclusions: Safety and efficacy were similar for 36 IU/kg/day AT gamma and 30 IU/kg/day pAT. These results confirm that AT gamma is an excellent alternative to pAT for improving outcomes for patients with DIC. Trial registration: ClinicalTrials.gov identifier: NCT01384903; June 2011. PMID- 30473796 TI - Effects of sintering temperature on sensing properties of WO3 and Ag-WO3 electrode for NO2 sensor. AB - Pure WO3 and Ag-WO3 (mixed solid solutions Ag with WO3) have been successfully synthesized by sol-gel method and the influences of calcination temperature on the particle size, morphology of the WO3 and Ag-WO3 nanoparticles were investigated. Powder X-ray diffraction results show that the hexagonal to monoclinic phase transition occurs at calcination temperature varying from 300 degrees C to 500 degrees C. SEM images show that calcination temperature plays an important role in controlling the particle size and morphology of the as-prepared WO3 and Ag-WO3 nanoparticles. The NO2 gas sensing properties of the sensors based on WO3 and Ag-WO3 nanoparticles calcined at different temperatures were investigated and the experimental results exhibit that the gas sensing properties of the Ag-WO3 sensors were superior to those of the pure WO3. Especially, the sensor based on Ag-WO3 calcined at 500 degrees C possessed larger response, better selectivity, faster response/recovery and better longer-term stability to NO2 than the others at relatively low operating temperature (150 degrees C). PMID- 30473797 TI - Evaluating prose style transfer with the Bible. AB - In the prose style transfer task a system, provided with text input and a target prose style, produces output which preserves the meaning of the input text but alters the style. These systems require parallel data for evaluation of results and usually make use of parallel data for training. Currently, there are few publicly available corpora for this task. In this work, we identify a high quality source of aligned, stylistically distinct text in different versions of the Bible. We provide a standardized split, into training, development and testing data, of the public domain versions in our corpus. This corpus is highly parallel since many Bible versions are included. Sentences are aligned due to the presence of chapter and verse numbers within all versions of the text. In addition to the corpus, we present the results, as measured by the BLEU and PINC metrics, of several models trained on our data which can serve as baselines for future research. While we present these data as a style transfer corpus, we believe that it is of unmatched quality and may be useful for other natural language tasks as well. PMID- 30473798 TI - Necessity of the sleep-wake cycle for synaptic homeostasis: system-level analysis of plasticity in the corticothalamic system. AB - Neural field theory is used to study the system-level effects of plasticity in the corticothalamic system, where arousal states are represented parametrically by the connection strengths of the system, among other physiologically based parameters. It is found that the plasticity dynamics have no fixed points or closed cycles in the parameter space of the connection strengths, but parameter subregions exist where flows have opposite signs. Remarkably, these subregions coincide with previously identified regions that correspond to wake and slow-wave sleep, thus demonstrating state dependence of the sign of synaptic modification. We then show that a closed cycle in the parameter space is possible when the plasticity dynamics are driven by the ascending arousal system, which cycles the brain between sleep and wake to complete a closed loop that includes arcs through the opposite-flow subregions. Thus, it is concluded that both wake and sleep are necessary, and together are able to stabilize connection weights in the brain over the daily cycle, thereby providing quantitative realization of the synaptic homeostasis hypothesis. PMID- 30473800 TI - Effect of the second-step voltages on the structural and corrosion properties of silicon-calcium-phosphate (Si-CaP) coatings on Mg-Zn-Ca alloy. AB - The applications of magnesium (Mg) alloys as biodegradable orthopedic implants are mainly restricted due to their rapid degradation rate in the physiological environment. In this study, Si-CaP micro-arc oxidation (MAO) coatings were prepared on a Mg-Zn-Ca alloy by a second-step MAO process at different voltages in order to decrease the degradation rate and increase the bioactivity of the alloy. The microstructure and morphology of the samples were characterized using XRD, FT-IR SEM and EDS. The degradation behaviours of samples were evaluated using electrochemical techniques, and immersion tests in simulated body fluid (SBF). The results indicate that the morphology of the Si-CaP coatings changed significantly with the increase in Ca/P ratio as the second-step voltage increased. The Si-CaP containing coating produced at 450 V could significantly decrease the degradation rate of Mg and caused a slow increase in pH of the SBF solution. The haemolysis test concluded that the coating C3 did not cause a haemolytic reaction. The corrosion resistance of Mg alloy was greatly improved with the Si-CaP coatings, and the Mg alloy with Si-CaP coating prepared at 450 V had the best corrosion resistance, which indicates that the Si-CaP coatings are promising for improving the biodegradation properties of Mg-based orthopedic implants. Haemolysis tests indicated that the Si-CaP coating prepared at 450 V conforms to the given standard (YY/T0127.1-93). PMID- 30473799 TI - Peptides derived from cadherin juxtamembrane region inhibit platelet function. AB - The juxtamembrane domains (JMD) of transmembrane proteins are rich in critical peptide sequences that participate in dynamic cell signalling events. Synthetic JMD peptides derived from cadherin cell adhesion proteins have previously been shown to modulate platelet function. In this study, we aimed to develop functional bioactive agents from bioinformatically identified critical peptide sequences. We synthesized overlapping 12-15 amino acid peptides from E- and N cadherin JMD and assessed their effect on platelet aggregation and platelet ATP secretion. Peptides derived from close to the membrane proximal region inhibit platelet function. Sequential deletion of amino acids from the N- and C-termini of the inhibitory E-cadherin peptides identified the short K756EPLLP763 motif as a critical bioactive sequence. Alanine scanning studies further identified that the di-leucine (LL) motif and positively charged lysine (K) are crucial for peptide activity. Moreover, scrambled peptides failed to show any effect on platelet activity. We conclude that peptides derived from JMD of E-cadherin provide potential lead peptides for the development of anti-thrombotic agents and to enable further understanding of the role of cadherins in platelet function. PMID- 30473801 TI - Native reptiles alter their foraging in the presence of the olfactory cues of invasive mammalian predators. AB - Invasive mammalian predators are linked to terrestrial vertebrate extinctions worldwide. Prey naivete may explain the large impact invasive predators have on native prey; prey may fail to detect and react appropriately to the cues of novel predators, which results in high levels of depredation. In Australia, the feral cat (Felis catus) and the red fox (Vulpes vulpes) are implicated in more than 30 animal extinctions and the naivete of native prey is often used to explain this high extinction rate. Reptiles are one group of animals that are heavily preyed upon by F. catus and V. vulpes. However, very few studies have examined whether reptiles are naive to their cues. In this study, we examine the ability of two native reptile species (Morethia boulengeri and Christinus marmoratus) to detect and distinguish between the chemical cues of two invasive predators (V. vulpes and F. catus) and three native predators (spotted-tailed quoll, Dasyurus maculatus; dingo, Canis lupus dingo; eastern brown snake, Pseudonaja textilis), as well as two non-predator controls (eastern grey kangaroo, Macropus giganteus and water). We conducted experiments to quantify the effects of predator scents on lizard foraging (the amount of food eaten) during 1 h trials within Y-maze arenas. We found both study species reduced the amount they consumed when exposed to predator scents-both native and invasive-indicating that these species are not naive to invasive predators. An evolved generalized predator-recognition system, rapid evolution or learned behaviour could each explain the lack of naivete in some native Australian reptiles towards invasive predators. PMID- 30473803 TI - Noether's symmetry and conserved quantity for a time-delayed Hamiltonian system of Herglotz type. AB - The variational problem of Herglotz type and Noether's theorem for a time-delayed Hamiltonian system are studied. Firstly, the variational problem of Herglotz type with time delay in phase space is proposed, and the Hamilton canonical equations with time delay based on the Herglotz variational problem are derived. Secondly, by using the relationship between the non-isochronal variation and the isochronal variation, two basic formulae of variation of the Hamilton-Herglotz action with time delay in phase space are derived. Thirdly, the definition and criterion of the Noether symmetry for the time-delayed Hamiltonian system are established and the corresponding Noether's theorem is presented and proved. The theorem we obtained contains Noether's theorem of a time-delayed Hamiltonian system based on the classical variational problem and Noether's theorem of a Hamiltonian system based on the variational problem of Herglotz type as its special cases. At the end of the paper, an example is given to illustrate the application of the results. PMID- 30473802 TI - Limb bone scaling in hopping macropods and quadrupedal artiodactyls. AB - Bone adaptation is modulated by the timing, direction, rate and magnitude of mechanical loads. To investigate whether frequent slow, or infrequent fast, gaits could dominate bone adaptation to load, we compared scaling of the limb bones from two mammalian herbivore clades that use radically different high-speed gaits, bipedal hopping (suborder Macropodiformes; kangaroos and kin) and quadrupedal galloping (order Artiodactyla; goats, deer and kin). Forelimb and hindlimb bones were collected from 20 artiodactyl and 15 macropod species (body mass M 1.05-1536 kg) and scanned in computed tomography or X-ray microtomography. Second moment of area (I max) and bone length (l) were measured. Scaling relations (y = axb ) were calculated for l versus M for each bone and for I max versus M and I max versus l for every 5% of length. I max versus M scaling relationships were broadly similar between clades despite the macropod forelimb being nearly unloaded, and the hindlimb highly loaded, during bipedal hopping. I max versus l and l versus M scaling were related to locomotor and behavioural specializations. Low-intensity loads may be sufficient to maintain bone mass across a wide range of species. Occasional high-intensity gaits might not break through the load sensitivity saturation engendered by frequent low-intensity gaits. PMID- 30473804 TI - A temporal shift in trophic diversity among a predator assemblage in a warming Arctic. AB - Climate change is leading to northward shifts in species distributions that is altering interspecific interactions at low- and mid-trophic levels. However, little attention has been focused on the effects of redistributions of species on the trophic ecology of a high trophic-level predator assemblage. Here, during a 22-year period (1990-2012) of increasing sea temperature (1.0 degrees C) and decreasing sea ice extent (12%) in Cumberland Sound, Nunavut, Canada, we examined the trophic structure of a near-apex predator assemblage before (1990-2002) and after (2005-2012) an increase in the availability of capelin-generally an indicator species in colder marine environments for a warming climate. Stable isotopes (delta13C and delta15N) were used in a Bayesian framework to assess shifts in diet, niche size and community-wide metrics for beluga whales (Delphinapterus leucas), ringed seals (Pusa hispida), Greenland halibut (Reinhardtius hippoglossoides) and anadromous Arctic char (Salvelinus alpinus). After 2005, consumption of forage fish increased for all predator species, suggesting diet flexibility with changing abiotic and biotic conditions. An associated temporal shift from a trophically diverse to a trophically redundant predator assemblage occurred where predators now play similar trophic roles by consuming prey primarily from the pelagic energy pathway. Overall, these long term ecological changes signify that trophic shifts of a high trophic-level predator assemblage associated with climate change have occurred in the Arctic food web. PMID- 30473805 TI - Friction-lowering capabilities and human subject preferences for a hydrophilic surface coating on latex substrates: implications for increasing condom usage. AB - Personal lubricants can increase user satisfaction with male condoms by reducing friction and yielding a slippery sensation. However, lubricants pose disadvantages of dilution in physiologic fluids and sloughing away over repeated articulations. To address these drawbacks, a latex surface modification, which becomes lubricious in the presence of physiologic fluid, has been developed and evaluated. This study assesses (i) the frictional performance of the lubricious coating compared to non-coated latex and latex lubricated by personal lubricant, (ii) the level of agreement between human-perceived slipperiness and machine measured friction, and (iii) human preference for a hypothetical male condom containing the lubricious coating. Friction coefficient of the lubricious coating was 53% lower than that of non-coated latex and approximately equal to that afforded by personal lubricant. A touch test and survey of a small population sample (N = 33) revealed a strong correlation (R 2 = 0.83) between human perceived slipperiness and machine-measured friction. A majority of participants (73%) expressed a preference for a condom containing the lubricious coating, agreeing that an inherently slippery condom that remained slippery for a long duration would increase their condom usage. Such a coating shows potential to be an effective strategy for decreasing friction-associated pain, increasing user satisfaction and increasing condom usage. PMID- 30473806 TI - Autonomously shaping natural climbing plants: a bio-hybrid approach. AB - Plant growth is a self-organized process incorporating distributed sensing, internal communication and morphology dynamics. We develop a distributed mechatronic system that autonomously interacts with natural climbing plants, steering their behaviours to grow user-defined shapes and patterns. Investigating this bio-hybrid system paves the way towards the development of living adaptive structures and grown building components. In this new application domain, challenges include sensing, actuation and the combination of engineering methods and natural plants in the experimental set-up. By triggering behavioural responses in the plants through light spectra stimuli, we use static mechatronic nodes to grow climbing plants in a user-defined pattern at a two-dimensional plane. The experiments show successful growth over periods up to eight weeks. Results of the stimuli-guided experiments are substantially different from the control experiments. Key limitations are the number of repetitions performed and the scale of the systems tested. Recommended future research would investigate the use of similar bio-hybrids to connect construction elements and grow shapes of larger size. PMID- 30473807 TI - Fuzzy risk assessment of a deeply buried tunnel under incomplete information. AB - Risk assessment has always been an important part of safety risk research in tunnel and underground engineering. Owing to the characteristics of tunnel construction, to achieve an expected risk control effect, it is necessary to carry out accurate risk assessment research according to the risk assessment concept based on the entire tunnel construction process. At present, because of the frequent occurrences of safety accidents, a variety of risk assessment models have been proposed for different tunnel projects such as subways and railway tunnels, which can be roughly classified into two types: probability-based and fuzzy set theories. However, the existing models may be more suitable for the construction stage, and the design stage lacks a reliable and practical fuzzy risk assessment method. Therefore, based on fuzzy set theory and similarity measure theory, a risk assessment model is proposed to adapt to the characteristics that the risk information is difficult to quantify the fuzziness in the design phase. Firstly, new ideas of fuzzy risk analysis are proposed to overcome deficiencies in existing methods; secondly, a new similarity measure is constructed; then fusing multi-source fuzzy information based on evidence theory, the relationship between similarity measure and mass function is established. Finally, the new method is applied to the Yuelongmen tunnel. Results show that the concept of risk control and the risk assessment model are feasible. PMID- 30473808 TI - Pore pressure evolution and mass loss of broken gangue during the seepage. AB - Broken gangue consists of different particles, and it has more complicated seepage characteristics than intact rock sample. Using the self-designed instrument, the permeability, mass loss and pore pressure of crushed gangue during the seepage are tested. The result shows that permeability parameter k of crushed rock has a polynomial relationship with effective stress sigma' in inverse proportion, and permeability parameter beta of crushed gangue has power exponent relationship with effective stress sigma' increasing in direct proportion. The particle size of 8.0-10.0 mm has a good support effect. The inner pressure of crushed rock is mostly linear distribution along the tube wall. After the seepage, mass loss of broken gangue mainly increases with large particle size out of proportion. PMID- 30473809 TI - Low reversed cyclic loading tests for integrated precast structure of lightweight wall with single-row reinforcement under a lightweight steel frame. AB - Given the development of precast structures for low-rise residential buildings, this study explores a new structure-namely, an integrated precast structure of lightweight recycled concrete wall with single-row reinforcement-under a lightweight steel frame filled with recycled concrete (integrated precast structure for short). The lightweight steel frame and lightweight wall cooperate to bear the forces. The applied concealed bracing, either a rebar bracing or a steel plate bracing, increases the shear resistance of the wall. The lightweight steel frame is designed to bear the vertical loading, whereas the seismic load in the horizontal direction is jointly borne by the frame and wall. This study presents the results of low reversed cyclic loading tests on nine specimens of integrated precast structures. An analysis is then carried out to investigate the mechanical properties of the specimens; based on these results, a formula for the force-bearing performance of the inclined section is developed. The results show satisfactory performance as an integrated piece; the proposed structure has two seismic lines of defence, with the lightweight wall restraint by the side frame being the first line and the steel frame being the second line. Because the failure of the wall can be categorized as shear failure, the restraint of the lightweight steel frame significantly reduces the potential damage of the wall. As the beams and columns of the steel frame tend to bend against failure, the wall filling helps resist sliding. Therefore, the reinforced joints of the connecting beams and columns show no visible signs of damage, indicating that the connection between the beams and columns is reliable. The narrow spacing of rebars and the setting of concealed bracing contribute to the increase in ductility and energy efficiency of the integrated structure and the evident reduction in the failure process. Furthermore, the recycled concrete increases the seismic resistance of the structure. PMID- 30473810 TI - Multi-robot replication of ant collective towing behaviours. AB - In this work, teams of small mobile robots are used to test hypotheses about cooperative transport by ants. This study attempts to explain a decrease in steady-state transport speed with increasing team size that was previously observed in the ant Novomessor cockerelli. Two models of one-dimensional collective towing are compared: one in which transporters with different maximum speeds pull the payload with continuous, variable forces and another in which transporters with identical speeds pull with intermittent, unsynchronized forces. A statistical analysis of ant data supports the hypothesis that ants behave according to the first model, in which the steady-state transport speed is the maximum speed of the slowest teammate. By contrast, the ant data are not consistent with the second model, which predicts constant speed regardless of team size. To verify these predictions, the ant behaviours in each model are translated into decentralized controllers and implemented on teams of two to four robots. The controller for the first model incorporates a real-time reinforcement learning algorithm that successfully reproduces the observed relationship between ant team size and transport speed. The controller for the second model yields the predicted invariance of transport speed with team size. These results show the value of robotic swarms for testing mechanistic hypotheses about biological collectives. PMID- 30473811 TI - Long-term biodegradation of aged saline-alkali oily sludge with the addition of bulking agents and microbial agents. AB - Huge amount of aged oily sludge was generated during the drilling and transportation of crude oil. Sometimes, the sludge exhibited characters of combined pollution, such as saline-alkali oily sludge. Orthogonal experiments of L16(45) were conducted to evaluate the long-term effects of total petroleum hydrocarbons (TPH) concentration, microbial agents (Oil Gator and ZL) and bulking agents (peat and wheat bran) on the biodegradation of aged saline-alkali oily sludge. Compared with the control group, the significant improvement in the removal rate of TPH was exhibited with the addition of microbial agents and bulking agents after 231 days of the experimental period. Based on the values of mean range (R), it was revealed that the predominant influencing factor of the bioremediation was TPH concentration. After biostimulation and bioaugmentation, the quantity of petroleum hydrocarbon-degrading bacteria in the oily sludge increased by 2-4 orders of magnitude. Furthermore, the bioremediation improved the microbial diversity based on the analysis of PCR-DGGE. It was inferred that the addition of microbial agents and bulking agents reconstructed the microbial ecological niche. The principal component analysis indicated that the differentiation of the microbial community was generated by the biostimulation and bioaugmentation in comparison with the control samples. PMID- 30473813 TI - The sintering kinetics of shellfish porcelain reinforced by sepiolite nanofibres. AB - The work investigated the effect of sepiolite nanofibres on mechanical properties and sintering behaviour of shellfish porcelain. Samples of shellfish porcelain reinforced by sepiolite nanofibres were fired in an electric furnace at 1150, 1200 and 1250 degrees C for a period of 80, 100, 120 and 140 min. Sintered samples were characterized by flexural strength, fracture toughness, scanning electron microscopy, transmission electron microscopy and X-ray diffraction. The results showed that 2 wt% sepiolite nanofibres could increase the flexural strength and fracture toughness of the porcelain bodies through the fibre pullout and the weak interface mechanisms. Sintering activation energies were determined according to the linear shrinkage results. It is found that the liquid-phase sintering mechanism of shellfish porcelain with sepiolite nanofibres is a diffusion mechanism. Porcelain without sepiolite is controlled by volume diffusion, and eventually, the grain boundary diffusion began to appear with the increase of sepiolite addition. PMID- 30473812 TI - Cross-cultural differences in implicit learning of chunks versus symmetries. AB - Three experiments explore whether knowledge of grammars defining global versus local regularities has an advantage in implicit acquisition and whether this advantage is affected by cultural differences. Participants were asked to listen to and memorize a number of strings of 10 syllables instantiating an inversion (i.e. a global pattern); after the training phase, they were required to judge whether new strings were well formed. In Experiment 1, Western people implicitly acquired the inversion rule defined over the Chinese tones in a similar way as Chinese participants when alternative structures (specifically, chunking and repetition structures) were controlled. In Experiments 2 and 3, we directly pitted knowledge of the inversion (global) against chunk (local) knowledge, and found that Chinese participants had a striking global advantage in implicit learning, which was greater than that of Western participants. Taken together, we show for the first time cross-cultural differences in the type of regularities implicitly acquired. PMID- 30473814 TI - Multiscale entropy rate analysis of complex mobile agents. AB - Accurate prediction of the motion of objects is a central scientific goal. For deterministic or stochastic processes, models exist which characterize motion with a high degree of reliability. For complex systems, or those where objects have a degree of agency, characterizing motion is far more challenging. The information entropy rate of motion through a discrete space can place a limit on the predictability of even the most complex or history-dependent actor, but the variability in measured encountered locations is inexorably tied to the spatial and temporal resolutions of those measurements. This relation depends on the path of the actor in ways that can be used to derive a general law in closed form relating the mobility entropy rate to different spatial and temporal resolutions, and the path properties within each cell along the path. Correcting for spatial and temporal effects through regression yields the path properties and a measure of mobility entropy rate robust to changes in dimension, allowing comparison of mobility entropy rates between datasets. Employing this measure on empirical datasets yields novel findings, from the similarity of taxicabs to drifters, to the predictable motions of undergraduates, to the browsing habits of Canadian moose. PMID- 30473815 TI - Cue predictability does not modulate bottom-up attentional capture. AB - Attention can be involuntarily captured by physically salient stimuli, a phenomenon known as bottom-up attention. Typically, these salient stimuli occur unpredictably in time and space. Therefore, in a series of three behavioural experiments, we investigated the extent to which such bottom-up attentional capture is a function of one's prior expectations. In the context of an exogenous cueing task, we systematically manipulated participants' spatial (Experiment 1) or temporal (Experiments 2 and 3) expectations about an uninformative cue and examined the amount of attentional capture by the cue. We anticipated larger attentional capture for unexpected compared to expected cues. However, while we observed attentional capture, we did not find any evidence for a modulation of attentional capture by prior expectation. This suggests that bottom-up attentional capture does not appear modulated by the degree to which the cue is expected or surprising. PMID- 30473816 TI - A new chart of hydraulic fracture height prediction based on fluid-solid coupling equations and rock fracture mechanics. AB - The conventional method to predict hydraulic fracture height depends on linear elastic mechanics, and the typical Gulrajani-Nolte chart fails to reflect fracture height when the net pressure in the fracture is too high. Based on fluid solid coupling equations and rock fracture mechanics, a new chart is obtained by the ABAQUS extended finite-element method. Compared with the Gulrajani-Nolte chart, this new chart shows that longitudinal propagation of hydraulic fracture is still finite when the net pressure in the fracture is higher than in situ stress difference between reservoir and restraining barrier. The barrier has a significant shielding effect on the longitudinal propagation of hydraulic fracture, and there is a threshold for an injection rate of fracturing fluid to ensure hydraulic fracture propagates in the barrier. Fracture height decreases with the increase of in situ stress difference. When the ratio of net pressure to in situ stress difference is less than 0.56, the propagation of hydraulic fracture is completely restricted in the reservoir. Hydraulic fracturing parameters in Well Shen52 and Well Shen55 are optimized by using the new chart. Array acoustic wave logging shows that the actual fracture height is at an average error within 14.3% of the theoretical value, which proves the accuracy of the new chart for field application. PMID- 30473817 TI - Morphogenetic mechanism of the acquisition of the dinosaur-type acetabulum. AB - Understanding morphological evolution in dinosaurs from a mechanistic viewpoint requires the elucidation of the morphogenesis that gave rise to derived dinosaurian traits, such as the perforated acetabulum. In the current study, we used embryos of extant animals with ancestral- and dinosaur-type acetabula, namely, geckos and turtles (with unperforated acetabulum), and birds (with perforated acetabulum). We performed comparative and experimental analyses, focusing on inter-tissue interaction during embryogenesis, and found that the avian perforated acetabulum develops via a secondary loss of cartilaginous tissue in the acetabular region. This cartilage loss might be mediated by inter-tissue interaction with the hip interzone, a mesenchymal tissue that exists in the embryonic joint structure. Furthermore, the data indicate that avian pelvic anlagen is more susceptible to paracrine molecules, e.g. Wnt ligand, secreted by the hip interzone than 'reptilian' anlagen. We hypothesize that during the emergence of dinosaurs, the pelvic anlagen became susceptible to the Wnt ligand, which led to the loss of the cartilaginous tissue and to the perforation in the acetabular region. Thus, the current evolutionary-developmental biology study deepens our understanding of morphological evolution in dinosaurs and provides it with a novel perspective. PMID- 30473818 TI - Chromium deposition and poisoning of La2NiO4 cathode of solid oxide fuel cell. AB - Chromium deposition and poisoning of La2NiO4 cathode of solid oxide fuel cell were studied. La2NiO4 cathode showed stable performance in the presence of metallic interconnects. Comparing with the polarization resistance (R p) of La2NiO4 cathode in the absence of metallic interconnects, R p did not change in the presence of metallic interconnect. After electrical conductivity relaxation method, La2NiO4 with high surface oxygen diffusion coefficients working under Cr atmosphere improved the oxygen reduction kinetics and increased cathode O2 reduction reaction rates. No chromium deposition was observed on the La2NiO4 cathode surface after polarization for 20 h at 800 degrees C. The chemical compatibility of La2NiO4/Cr2O3 and La2NiO4/Gd0.1Ce0.9O1.95 (GDC) study indicates that La2NiO4 did not react with Cr2O3 and GDC under the operating temperature. The results indicate that La2NiO4 cathode is a potential chromium-tolerant material of solid oxide fuel cell. PMID- 30473819 TI - Variations in power of opinion leaders in online communication networks. AB - Online social media has completely transformed how we communicate with each other. While online discussion platforms are available in the form of applications and websites, an emergent outcome of this transformation is the phenomenon of 'opinion leaders'. A number of previous studies have been presented to identify opinion leaders in online discussion networks. In particular, Feng (2016 Comput. Hum. Behav. 54, 43-53. (doi:10.1016/j.chb.2015.07.052)) has identified five different types of central users besides outlining their communication patterns in an online communication network. However, the presented work focuses on a limited time span. The question remains as to whether similar communication patterns exist that will stand the test of time over longer periods. Here, we present a critical analysis of the Feng framework both for short-term as well as for longer periods. Additionally, for validation, we take another case study presented by Udanor et al. (2016 Program 50, 481-507. (doi:10.1108/PROG-02-2016-0011)) to further understand these dynamics. Results indicate that not all Feng-based central users may be identifiable in the longer term. Conversation starter and influencers were noted as opinion leaders in the network. These users play an important role as information sources in long-term discussions. Whereas network builder and active engager help in connecting otherwise sparse communities. Furthermore, we discuss the changing positions of opinion leaders and their power to keep isolates interested in an online discussion network. PMID- 30473820 TI - Hunter selection for larger and older male bobcats affects annual harvest demography. AB - Wildlife researchers often rely on demographic data collected from harvested animals to estimate population dynamics. But demographic data from harvested animals may be non-representative if hunters/trappers have the ability and motivation to preferentially select for certain physical traits. Hunter preference is well demonstrated for ungulates, but less so for other wildlife species such as furbearers. We used data from bobcats harvested in Wisconsin (1983-2014) to determine if harvest method and demographics (mass, male:female sex ratio and age) have changed over time, and if bobcat hunters/trappers exhibited selection. Each trait of harvested bobcats that we tested changed over time, and because these selected traits were interrelated, we inferred that harvest selection for larger size biased harvests in favour of older, male bobcats. The selection of older, male bobcats appears primarily driven by hound hunters (hereafter hunters) compared to trappers, with hunters more frequently creating taxidermy mounts from their harvested bobcats. We found an increase in the proportion of bobcats that were harvested by hunting compared to trapping over time, and this was associated with increased selectivity and substantial changes in the characteristics of harvested bobcats. Selection by hunters may bias population models that are based on the demography of harvested bobcats, and accounting for biases that may occur, including from different harvest methods, is critical when using harvest-dependent data. PMID- 30473821 TI - Quantum imploding scalar fields. AB - The d'Alembertian ?phi = 0 has the solution phi = f(v)/r, where f is a function of a null coordinate v, and this allows creation of a divergent singularity out of nothing. In scalar-Einstein theory a similar situation arises both for the scalar field and also for curvature invariants such as the Ricci scalar. Here what happens in canonical quantum gravity is investigated. Two minispace Hamiltonian systems are set up: extrapolation and approximation of these indicates that the quantum mechanical wave function can be finite at the origin. PMID- 30473822 TI - A facile energy-saving route of fabricating thermoelectric Sb2Te3-Te nanocomposites and nanosized Te. AB - A facile energy-saving route is developed for fabricating Sb2Te3-Te nanocomposites and nanosized Te powders. The fabrication route not only avoids using organic chemicals, but also keeps the energy consumption to a minimum. The fabrication procedure involves two steps. Energetic precursors of nanosized powders of Sb and Te are produced at room temperature followed by hot pressing at 400 degrees C under 70 MPa for 1 h. The resulting Sb2Te3-Te nanocomposite exhibits enhanced power factor. The dimensionless figure of merit zT value of the Sb2Te3-Te nanocomposite is 0.29 at 475 K. PMID- 30473823 TI - Effect of alkaline fusion on muscovite decomposition and the vanadium release mechanism from vanadium shale. AB - In order to figure out the decomposition of muscovite and the release mechanism of vanadium from vanadium shale in the alkaline fusion process, the process of vanadium release and roasting kinetics by alkaline fusion was studied. It was found that the addition of sodium hydroxide made the muscovite convert into the sodium silicate and gehlenite. This process promoted the dissolution of silicon and the destruction of muscovite, which could facilitate the release of vanadium. The kinetic analysis indicated that the controlling step of vanadium transformation reaction is changed from chemical reaction control to diffusion control with the increase of roasting time. Compared to the diffusion controlling step, the vanadium related chemical reaction was completed in the first period. The alkaline fusion reaction enhanced the decomposition of muscovite, which could accelerate the release of vanadium and reduce the dependence on high temperature and time in the roasting process. The apparent activation energies of chemical reaction control and diffusion control were 42.24 kJ mol-1 and -9.553 kJ mol-1, respectively. The kinetic model of vanadium extraction from vanadium shale using alkaline fusion could be finally established. PMID- 30473824 TI - Phase transition and switchable dielectric behaviours in an organic-inorganic hybrid compound: (3-nitroanilinium)2(18-crown-6)2(H2PO4)2(H3PO4)3(H2O). AB - An organic-inorganic hybrid compound with an extensive three-dimensional (3D) crystal structure, (3-nitroanilinium)2(18-crown-6)2(H2PO4)2(H3PO4)3(H2O) (1), was synthesized under slow evaporation conditions. Differential scanning calorimetry measurements indicated that 1 underwent a reversible phase transition at ca 231 K with a hysteresis width of 10 K. Variable-temperature X-ray single-crystal diffraction revealed that the phase transition of 1 can be ascribed to coupling of pendulum-like motions of its nitro group with proton transfer in O-H...O hydrogen bonds of the 3D framework. The temperature dependence of its dielectric permittivity demonstrated a step-like change in the range of 150-280 K with remarkable dielectric anisotropy, making 1 a promising switchable dielectric material. Potential energy calculations further supported the possibility of dynamic motion of the cationic nitro group. Overall, our findings may inspire the development of other switchable dielectric phase transition materials by introducing inorganic anions into organic-inorganic hybrid systems. PMID- 30473825 TI - The time geography of segregation during working hours. AB - While segregation is usually evaluated at the residential level, the recent influx of large streams of data describing urbanites' movement across the city allows to generate detailed descriptions of spatio-temporal segregation patterns across the activity space of individuals. For instance, segregation across the activity space is usually thought to be lower compared with residential segregation given the importance of social complementarity, among other factors, shaping the economies of cities. However, these new dynamic approaches to segregation convey important methodological challenges. This paper proposes a methodological framework to investigate segregation during working hours. Our approach combines three well-known mathematical tools: community detection algorithms, segregation metrics and random walk analysis. Using Santiago (Chile) as our model system, we build a detailed home-work commuting network from a large dataset of mobile phone pings and spatially partition the city into several communities. We then evaluate the probability that two persons at their work location will come from the same community. Finally, a randomization analysis of commuting distances and angles corroborates the strong segregation description for Santiago provided by the sociological literature. While our findings highlights the benefit of developing new approaches to understand dynamic processes in the urban environment, unveiling counterintuitive patterns such as segregation at our workplace also shows a specific example in which the exposure dimension of segregation is successfully studied using the growingly available streams of highly detailed anonymized mobile phone registries. PMID- 30473826 TI - Metabolism studies of paeoniflorin in rat liver microsomes by ultra-performance liquid chromatography coupled with hybrid quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS). AB - To explore metabolism mechanism of paeoniflorin in the liver and further understand intact metabolism process of paeoniflorin, a rapid, convenient and effective assay is described using ultra-performance liquid chromatography coupled with hybrid quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF MS/MS). The strategy was confirmed in the following primary processes: firstly, different concentration of paeoniflorin, rat liver microsomes, coenzymes and different incubated conditions were optimized to build a biotransformation model of rat liver microsomes in vitro by high performance liquid chromatography with diode array detection (HPLC-DAD); secondly, the metabolites of paeoniflorin in rat liver microsomes were detected and screened using UPLC-Q-TOF-MS/MS by comparing the total ion chromatogram (TIC) of the experimental group with those of control groups; finally, the molecular formulae and corresponding chemical structures of paeoniflorin metabolites were identified by comparing the MS and MS/MS spectra with the self-constructed database and simulation software. Based on this analytical strategy, 20 metabolites of paeoniflorin were found and 6 metabolites (including four new compounds) were tentatively identified. It was shown that hydrolysis and oxidation were the major metabolic pathways of paeoniflorin in rat liver microsomes, and the main metabolic sites were the structures of pinane and the ester bond. These findings were significant for a better understanding of the metabolism of paeoniflorin in rat liver microsomes and the proposed metabolic pathways of paeoniflorin might provide fundamental support for the further research in the pharmacological mechanism of Paeoniae Radix Rubra (PRR). PMID- 30473827 TI - Electrochemical performance of ZnO-coated Li4Ti5O12 composite electrodes for lithium-ion batteries with the voltage ranging from 3 to 0.01 V. AB - Oxide is widely used in modifying cathode and anode materials for lithium-ion batteries. In this work, a facile method of radio magnetron sputtering is introduced to deposit a thin film on Li4Ti5O12 composite electrodes. The pristine and modified Li4Ti5O12 electrodes are characterized at an extended voltage range of 3-0.01 V. The reversible capacity reaches a high level of 286 mAh g-1, which is a little less than its theoretical capacity (293 mAh g-1). Electrodes modified by ZnO thin films with various thickness show elevated rate capability and improved cycle performance. PMID- 30473828 TI - Thermally induced deterioration behaviour of two dolomitic marbles under heating cooling cycles. AB - Thermally induced deterioration behaviour can cause severe weathering in marbles. Most previous studies focus on the deterioration behaviour of calcitic marbles. Relevant studies of dolomitic marbles are generally carried out under a 'high temperature and low cycling times' condition. Little attention is focused on the deterioration behaviour in dolomitic marbles when they are subjected to a large quantity of heating-cooling cycles under a 'low temperature and high cycling times' condition. This paper presents experimental investigations on the thermally induced deterioration behaviour of two Beijing dolomitic marbles (Qingbaishi Marble (QM) and Hanbaiyu Marble (HM)) under heating-cooling cycles up to 1000 cycling times. The applied temperature range is from -20 degrees C to 60 degrees C which is to simulate the seasonal temperature variations in Beijing city, China. Related properties such as weight loss, three-dimensional microtopography, elastic wave velocity and uniaxial compressive strength were measured at certain cycles. The results indicate that thermally induced deterioration behaviour will result in a continuous weight loss in dolomitic marble samples. Mechanical properties of those two marbles are strongly affected by heating and cooling treatments, which were reflected by the reductions of dynamic Young's modulus and uniaxial compressive strength with an increase of thermal cycles. Compared with QM, HM displays a higher level of thermally induced deterioration which should be due to the abundance of quartz mineral. PMID- 30473829 TI - Vertebral artery fusiform aneurysm geometry in predicting rupture risk. AB - Cerebral aneurysms affect a significant portion of the adult population worldwide. Despite significant progress, the development of robust techniques to evaluate the risk of aneurysm rupture remains a critical challenge. We hypothesize that vertebral artery fusiform aneurysm (VAFA) morphology may be predictive of rupture risk and can serve as a deciding factor in clinical management. To investigate the VAFA morphology, we use a combination of image analysis and machine learning techniques to study a geometric feature set computed from a depository of 37 (12 ruptured and 25 un-ruptured) aneurysm images. Of the 571 unique features we compute, we distinguish five features for use by our machine learning classification algorithm by an analysis of statistical significance. These machine learning methods achieve state-of-the-art classification performance (81.43 +/- 13.08%) for the VAFA morphology, and identify five features (cross-sectional area change of aneurysm, maximum diameter of nearby distal vessel, solidity of aneurysm, maximum curvature of nearby distal vessel, and ratio of curvature between aneurysm and its nearby proximal vessel) as effective predictors of VAFA rupture risk. These results suggest that the geometric features of VAFA morphology may serve as useful non-invasive indicators for the prediction of aneurysm rupture risk in surgical settings. PMID- 30473830 TI - Characterizing the shape patterns of dimorphic yeast pseudohyphae. AB - Pseudohyphal growth of the dimorphic yeast Saccharomyces cerevisiae is analysed using two-dimensional top-down binary images. The colony morphology is characterized using clustered shape primitives (CSPs), which are learned automatically from the data and thus do not require a list of predefined features or a priori knowledge of the shape. The power of CSPs is demonstrated through the classification of pseudohyphal yeast colonies known to produce different morphologies. The classifier categorizes the yeast colonies considered with an accuracy of 0.969 and standard deviation 0.041, demonstrating that CSPs capture differences in morphology, while CSPs are found to provide greater discriminatory power than spatial indices previously used to quantify pseudohyphal growth. The analysis demonstrates that CSPs provide a promising avenue for analysing morphology in high-throughput assays. PMID- 30473831 TI - Rapid detection of cocaine using aptamer-based biosensor on an evanescent wave fibre platform. AB - The rapid detection of cocaine has received considerable attention because of the instantaneous and adverse effects of cocaine overdose on human health. Aptamer based biosensors for cocaine detection have been well established for research and application. However, reducing the analytic duration without deteriorating the sensitivity still remains as a challenge. Here, we proposed an aptamer-based evanescent wave fibre (EWF) biosensor to rapidly detect cocaine in a wide working range. At first, the aptamers were conjugated to complementary DNA with fluorescence tag and such conjugants were then immobilized on magnetic beads. After cocaine was introduced to compete against the aptamer-DNA conjugants, the released DNA in supernatant was detected on the EWF platform. The dynamic curves of EWF signals could be interpreted by the first-order kinetics and saturation model. The semi-log calibration curve covered a working range of 10-5000 uM of cocaine, and the limit of detection was approximately 10.5 uM. The duration of the full procedure was 990 s (16.5 min), and the detection interval was 390 s (6.5 min). The specified detection of cocaine was confirmed from four typical pharmaceutic agents. The analysis was repeated for 50 cycles without significant loss of sensitivity. Therefore, the aptamer-based EWF biosensor is a feasible solution to rapidly detect cocaine. PMID- 30473832 TI - Assessing mesophotic coral ecosystems inside and outside a Caribbean marine protected area. AB - Widespread shallow coral reef loss has led to calls for more holistic approaches to coral reef management, requiring inclusion of ecosystems interacting with shallow coral reefs in management plans. Yet, almost all current reef management is biased towards shallow reefs, and overlooks that coral reefs extend beyond shallow waters to mesophotic coral ecosystems (MCEs; 30-150 m). We present the first detailed quantitative characterization of MCEs off Cozumel, Mexico, on the northern Mesoamerican Reef in the Mexican Caribbean, and provide insights into their general state. We documented MCE biodiversity, and assessed whether MCEs adjacent to a major town and port, where coastal development has caused shallow reef damage, have similar benthic and fish communities to MCEs within a National Park. Our results show that overall MCE communities are similar regardless of protection, though some taxa-specific differences exist in benthic communities between sites within the MPA and areas outside. Regardless of protection and location, and in contrast to shallow reefs, all observed Cozumel MCEs were continuous reefs with the main structural habitat complexity provided by calcareous macroalgae, sponges, gorgonians and black corals. Hard corals were present on MCEs, although at low abundance. We found that 42.5% of fish species recorded on Cozumel could be found on both shallow reefs and MCEs, including 39.6% of commercially valuable fish species. These results suggest that MCEs could play an important role in supporting fish populations. However, regardless of protection and depth, we found few large-body fishes (greater than 500 mm), which were nearly absent at all studied sites. Cozumel MCEs contain diverse benthic and fish assemblages, including commercially valuable fisheries species and ecosystem engineers, such as black corals. Because of their inherent biodiversity and identified threats, MCEs should be incorporated into shallow reef-focused Cozumel National Park management plan. PMID- 30473833 TI - Two sources of bias explain errors in facial age estimation. AB - Accurate age estimates underpin our everyday social interactions, the provision of age-restricted services and police investigations. Previous work suggests that these judgements are error-prone, but the processes giving rise to these errors are not understood. Here, we present the first systematic test of bias in age estimation using a large database of standardized passport images of heterogeneous ages (n = 3948). In three experiments, we tested a range of perceiver age groups (n = 84), and found average age estimation error to be approximately 8 years. We show that this error can be attributed to two separable sources of bias. First, and accounting for the vast majority of variance, our results show an assimilative serial dependency whereby estimates are systematically biased towards the age of the preceding face. Second, younger faces are generally perceived to be older than they are, and older faces to be younger. In combination, these biases account for around 95% of variance in age estimates. We conclude that perception of age is modulated by representations that encode both a viewer's recent and normative exposure to faces. The finding that age perception is subject to strong top-down influences based on our immediate experience has implications for our understanding of perceptual processes involved in face perception, and for improving accuracy of age estimation in important real-world tasks. PMID- 30473834 TI - On critical dynamics and thermodynamic efficiency of urban transformations. AB - Urban transformations within large and growing metropolitan areas often generate critical dynamics affecting social interactions, transport connectivity and income flow distribution. We develop a statistical-mechanical model of urban transformations, exemplified for Greater Sydney, and derive a thermodynamic description highlighting critical regimes. We consider urban dynamics at two time scales: fast dynamics for the distribution of population and income, modelled via the maximum entropy principle, and slower dynamics evolving the urban structure under spatially distributed competition. We identify phase transitions between dispersed and polycentric phases, induced by varying the social disposition-a factor balancing the suburbs' attractiveness-in contrast with the travel impedance. Using the Fisher information, we identify critical thresholds and quantify the thermodynamic cost of urban transformation, as the minimal work required to vary the underlying parameter. Finally, we introduce the notion of thermodynamic efficiency of urban transformation, as the ratio of the order gained during a change to the amount of required work, showing that this measure is maximized at criticality. PMID- 30473835 TI - Interleukin 6 promotes an in vitro mineral deposition by stem cells isolated from human exfoliated deciduous teeth. AB - Interleukin 6 (IL-6) plays various roles including stem cell regulation. The present study investigated the effect of IL-6 on cell proliferation, colony forming unit ability, stem cell marker expression and differentiation ability in stem cells isolated from human exfoliated deciduous teeth (SHEDs). We reported that the isolated cells from dental pulp tissues for deciduous teeth expressed CD44, CD90 and CD105 but not CD45. These cells were able to differentiate into osteoblasts, adipocytes and neuronal-like cells. IL-6 treatment resulted in the significant increase of NANOG, SOX2 and REX1 mRNA expression. However, IL-6 had no effect on cell proliferation and colony forming unit ability. IL-6 did not alter adipogenic and neurogenic differentiation potency. IL-6 supplementation in osteogenic medium led to a significant increase of mineralization. Furthermore, IL-6 upregulated ALP, ANKH and PIT1 mRNA levels. In conclusion, IL-6 participates in the regulation of pluripotent marker expression and is also involved in mineralization process of SHEDs. Hence, IL-6 could be employed as a supplementary substance in culture medium to maintain stemness and to induce osteogenic induction in SHEDs for future regenerative cell therapy. PMID- 30473836 TI - Tasman-PCR: a genetic diagnostic assay for Tasmanian devil facial tumour diseases. AB - Tasmanian devils have spawned two transmissible cancer clones, known as devil facial tumour 1 (DFT1) and devil facial tumour 2 (DFT2). DFT1 and DFT2 are transmitted between animals by the transfer of allogeneic contagious cancer cells by biting, and both cause facial tumours. DFT1 and DFT2 tumours are grossly indistinguishable, but can be differentiated using histopathology, cytogenetics or genotyping of polymorphic markers. However, standard diagnostic methods require specialist skills and equipment and entail long processing times. Here, we describe Tasman-PCR: a simple polymerase chain reaction (PCR)-based diagnostic assay that identifies and distinguishes DFT1 and DFT2 by amplification of DNA spanning tumour-specific interchromosomal translocations. We demonstrate the high sensitivity and specificity of this assay by testing DNA from 546 tumours and 804 normal devils. A temporal-spatial screen confirmed the reported geographic ranges of DFT1 and DFT2 and did not provide evidence of additional DFT clones. DFT2 affects disproportionately more males than females, and devils can be co-infected with DFT1 and DFT2. Overall, we present a PCR-based assay that delivers rapid, accurate and high-throughput diagnosis of DFT1 and DFT2. This tool provides an additional resource for devil disease management and may assist with ongoing conservation efforts. PMID- 30473838 TI - Sand casting safety assessment for foundry enterprises: fault tree analysis, Heinrich accident triangle, HAZOP-LOPA, bow tie model. AB - Sand casting operations, though commonplace, pose a significant threat of explosion accidents. This paper presents a novel sand casting safety assessment technique based on fault tree analysis, Heinrich accident triangle, hazard and operability-layer of protection analysis (HAZOP-LOPA) and bow tie model components. Minimal cut sets and minimal path sets are first determined based on fault tree analysis, then the frequency of sand casting explosion accidents is calculated based on the Heinrich accident triangle. Third, the risk level of venting quality can be reduced by adopting HAZOP-LOPA; the residual risk level of venting quality remains excessive even after adopting two independent protective layers. The bow tie model is then adopted to determine the causes and consequences of venting quality. Five preventative measures are imposed to enhance the venting quality of foundry sand accompanied by 16 mitigative safety measures. Our results indicate that the risk attributable to low foundry sand venting quality can be minimized via bow tie analysis. PMID- 30473837 TI - Hunter-gatherer mobility and technological landscapes in southernmost South America: a statistical learning approach. AB - The present work aims to quantitatively explore and understand the relationship between mobility types (nautical versus pedestrian), specific technological traits and shared technological knowledge in pedestrian hunter-gatherer and nautical hunter-fisher-gatherer societies from the southernmost portion of South America. To that end, advanced statistical learning techniques are used: state-of the-art classification algorithms and variable importance analyses. Results show a strong relationship between technological knowledge, traits and mobility types. Occupations can be accurately classified into nautical and pedestrian due to the existence of a non-trivial pattern between mobility and a relatively small fraction of variables from some specific technological categories. Cases where the best-fitted classification algorithm fails to generalize are found significantly interesting. These instances can unveil lack of information, not enough entries in the training set, singular features or ambiguity, the latter case being a possible indicator of the interaction between nautical and pedestrian societies. PMID- 30473839 TI - Fluorine-doped graphene with an outstanding electrocatalytic performance for efficient oxygen reduction reaction in alkaline solution. AB - Doping carbon materials have proved to be the front runners to substitute for Pt as oxygen reduction reaction (ORR) catalysts. Fluorine-doped graphene (FG) has rarely been used as ORR catalyst because of the difficulty in preparation. Herein, we report FG sheets prepared by a thermal pyrolysis graphene oxide (GO) process in the presence of zinc fluoride (ZnF2) as an efficient electrocatalyst for ORR in the alkaline medium. The results show that the pyrolysis temperature seriously affected the doped fluoride amount and morphology of catalyst. It is found that the FG-1100 catalyst possesses a more positive onset potential, higher current density and better four-electron process for ORR than other FG samples. FG-1100 displays an outstanding ORR catalytic activity that is comparable to that of the commercial Pt/C catalyst. Also, its durability and methanol tolerance ability are superior to those of the commercial Pt/C. The excellent ORR catalytic performance is closely related to its higher doped fluorine amount and wrinkle morphology. The FG catalyst can be developed as a low-cost, efficient and durable catalyst as a viable replacement for the Pt/C catalyst, promoting the commercialization of fuel cells. PMID- 30473840 TI - Strain energy-based rubber fatigue life prediction under the influence of temperature. AB - Aiming at the problem of the fatigue life prediction of rubber under the influence of temperature, the effects of thermal ageing and fatigue damage on the fatigue life of rubber under the influence of temperature are analysed and a fatigue life prediction model is established by selecting strain energy as a fatigue damage parameter based on the uniaxial tensile data of dumbbell rubber specimens at different temperatures. Firstly, the strain energy of rubber specimens at different temperatures is obtained by the Yeoh model, and the relationship between it and rubber fatigue life at different temperatures is fitted by the least-square method. Secondly, the function formula of temperature and model parameters is obtained by the least-square polynomial fitting. Finally, another group of rubber specimens is tested at different temperatures and the fatigue characteristics are predicted by using the proposed prediction model under the influence of temperature, and the results are compared with the measured results. The results show that the predicted value of the model is consistent with the measured value and the average relative error is less than 22.26%, which indicates that the model can predict the fatigue life of this kind of rubber specimen at different temperatures. What's more, the model proposed in this study has a high practical value in engineering practice of rubber fatigue life prediction at different temperatures. PMID- 30473841 TI - A mathematical model of cocoa bean fermentation. AB - Cocoa bean fermentation relies on the sequential activation of several microbial populations, triggering a temporal pattern of biochemical transformations. Understanding this complex process is of tremendous importance as it is known to form the precursors of the resulting chocolate's flavour and taste. At the same time, cocoa bean fermentation is one of the least controlled processes in the food industry. Here, a quantitative model of cocoa bean fermentation is constructed based on available microbiological and biochemical knowledge. The model is formulated as a system of coupled ordinary differential equations with two distinct types of state variables: (i) metabolite concentrations of glucose, fructose, ethanol, lactic acid and acetic acid and (ii) population sizes of yeast, lactic acid bacteria and acetic acid bacteria. We demonstrate that the model can quantitatively describe existing fermentation time series and that the estimated parameters, obtained by a Bayesian framework, can be used to extract and interpret differences in environmental conditions. The proposed model is a valuable tool towards a mechanistic understanding of this complex biochemical process, and can serve as a starting point for hypothesis testing of new systemic adjustments. In addition to providing the first quantitative mathematical model of cocoa bean fermentation, the purpose of our investigation is to show how differences in estimated parameter values for two experiments allow us to deduce differences in experimental conditions. PMID- 30473842 TI - Enrichment of lithium from salt lake brine by forward osmosis. AB - Forward osmosis (FO) is a concentration process based on the natural phenomena of osmosis. It is considered a breakthrough technology that can be potentially used for concentrating solutions and suspensions. The diluted nature of brine restricts the treatment technologies that can be applied. Then, brine concentration by FO could represent a new emerging technology enabling the application of a wider range of treatment alternatives. The performance of concentrated brine depending upon FO membranes was studied at normal temperature and pressure in this research. Cellulose triacetates on radio-frequency-weldable non-woven support (CTA-NW) and a thin-film composite with embedded polyester screen support (TFC-ES) were compared; and their orientations were considered. The brine was from Chaerhan Salt Lake after extracting potassium as the feed solution, NaCl solution or MgCl2 solution as the draw solution. The results indicated that CTA-NW exhibited better concentration performance than TFC-ES, while the water fluxes of the two membranes were exactly the opposite. In the case of CTA-NW in active layer facing feed solution orientation with MgCl2 as the draw solution, the concentration factor of Li+ was nearly 3.0. Quantitative structure-activity relationship of FO membranes and concentration characteristics was correlated, based on results of SEM, FTIR and contact angles studies. The concentration performance could be mainly attributed to the porosity and the thickness of FO membranes; while the water flux was dependent on the hydrophily of FO membrane surface. PMID- 30473843 TI - Removal of toxic metals from aqueous solution by biochars derived from long-root Eichhornia crassipes. AB - Biochars were produced from long-root Eichhornia crassipes at four temperatures: 200, 300, 400 and 500 degrees C, referred to as LEC200, LEC300, LEC400 and LEC500, respectively. The sorption ability of lead, zinc, copper and cadmium from aqueous solutions by four kinds of biochars was investigated. All the biochars had lower values of CEC and higher values of pH. LEC500 was the best one to bind toxic metals which can be reflected in the results of SEM, BET and elemental analyser. It was also found that alkyl, carboxyl, phosphate and cyano groups in the biochars can play a role in binding metals. In addition, the sorption processes of four metals by the biochars in different metal concentration were all excellently represented by the pseudo-second-order model with all correlation coefficients R 2 > 0.95. And the sorption processes of four metals in different temperatures could be described satisfactorily by the Langmuir isotherms. According to calculated results by the Langmuir equation, the maximum removal capacities of Pb(II), Zn(II), Cu(II) and Cd(II) at 298 K were 39.09 mg g-1, 45.40 mg g-1, 48.20 mg g-1 and 44.04 mg g-1, respectively. The positive value of the DeltaH 0 confirmed the adsorption process was endothermic and the negative value of DeltaG 0 confirmed the adsorption process was spontaneous. The sorption capacities were compared with several other lignocellulosic materials which implied the potential of long-root Eichhornia crassipes waste as an economic and excellent biosorbent for eliminating metal ions from contaminated waters. PMID- 30473844 TI - Experiment and simulation study of the effect of ethanol and compound additives on the urea-based selective non-catalytic reduction process under moderate temperature conditions. AB - An experiment and simulation study of the effect of using liquid additives on the selective non-catalytic reduction (SNCR) process is presented, providing a novel way for plants reducing NOX emissions. An experimental study is conducted in an entrained flow reactor, and CHEMKIN is applied for simulation study. Ethanol additive can effectively shift the temperature window of the NOXOUT process to a lower range and the NOXOUT efficiency ranges from 29 to 56% at 700-800 degrees C. Furthermore, ethanol additive has a significant inhibitory effect on ammonia slip. Na2SO4 and C2H5OH can be combined into a compound additive, which has a synergistic effect on NO reduction. The addition of methanol can greatly promote denitrification efficiency from 650 degrees C to 725 degrees C, indicating the potential of compound additives in NO reduction. The HNCO + OH = H2O + NCO pathway is also proven to be enhanced for ethanol decomposition, thereby providing OH*, which is active in NO reduction. Finally, the reaction routes for ethanol on the urea-based SNCR process at the proper temperature are proposed. PMID- 30473845 TI - Vertebral morphometrics and lung structure in non-avian dinosaurs. AB - The lung-air sac system of modern birds is unique among vertebrates. However, debate surrounds whether an avian-style lung is restricted to birds or first appeared in their dinosaurian ancestors, as common osteological correlates for the respiratory system offer limited information on the lungs themselves. Here, we shed light on these issues by using axial morphology as a direct osteological correlate of lung structure, and quantifying vertebral shape using geometric morphometrics in birds, crocodilians and a wide range of dinosaurian taxa. Although fully avian lungs were a rather late innovation, we quantitatively show that non-avian dinosaurs and basal dinosauriforms possessed bird-like costovertebral joints and a furrowed thoracic ceiling. This would have immobilized the lung's dorsal surface, a structural prerequisite for a thinned blood-gas barrier and increased gas exchange potential. This could have permitted high levels of aerobic and metabolic activity in dinosaurs, even in the hypoxic conditions of the Mesozoic, contributing to their successful radiation. PMID- 30473846 TI - Finding the weakest link: mechanical sensitivity in a fish cranial linkage system. AB - Understanding the physical mechanics behind morphological systems can offer insights into their evolution. Recent work on linkage systems in fish and crustaceans has suggested that the evolution of such systems may depend on mechanical sensitivity, where geometrical changes to different parts of a biomechanical system have variable influence on mechanical outputs. While examined at the evolutionary level, no study has directly explored this idea at the level of the mechanism. We analyse the mechanical sensitivity of a fish cranial linkage to identify the influence of linkage geometry on the kinematic transmission (KT) of the suspensorium, hyoid and lower jaw. Specifically, we answer two questions about the sensitivity of this linkage system: (i) What changes in linkage geometry affect one KT while keeping the other KTs constant? (ii) Which geometry changes result in the largest and smallest changes to KT? Our results show that there are ways to alter the morphology that change each KT individually, and that there are multiple ways to alter a single link that have variable influence on KT. These results provide insight into the morphological evolution of the fish skull and highlight which structural features in the system may have more freedom to evolve than others. PMID- 30473848 TI - Research on the mechanical behaviour of shale based on multiscale analysis. AB - In view of the difficulty in obtaining the mechanical properties of shale, the multiscale analysis of shale was performed on a shale outcrop from the Silurian Longmaxi Formation in the Changning area, Sichuan Basin, China. The nano-/micro indentation test is an effective method for multiscale mechanical analysis. In this paper, effective criteria for the shale indentation test were evaluated. The elastic modulus was evaluated at a multiscale and the engineering validation of drilling cuttings was performed. The porosity tests showed that the pore distribution of shale from the nanoscale to macro-pore could be better displayed by the nuclear magnetic resonance test. The micro-scale elastic modulus and hardness increased nonlinearly with the increase in the clay packing density. It was observed that the size effect of the micro-hardness was based on porosity and composition. The partial spalling of shale at the micro-scale could lead to irregular bulges or steps in a load-displacement curve. The elastic modulus of pure clay minerals was 24.2 GPa on the parallel bedding plane and 15.8 GPa on the vertical bedding plane. The contact hardness (pure clay minerals) was 0.51 GPa. The indentation results showed that the micro-elastic modulus of shale obeyed the normal distribution, and the statistical average could predict the macro mechanical properties effectively. The present work can provide a new way to recognize the mechanical behaviour of shale. PMID- 30473847 TI - Magnetoliposomes containing magnesium ferrite nanoparticles as nanocarriers for the model drug curcumin. AB - Magnesium ferrite nanoparticles, with diameters around 25 nm, were synthesized by coprecipitation method. The magnetic properties indicate a superparamagnetic behaviour, with a maximum magnetization of 16.2 emu g-1, a coercive field of 22.1 Oe and a blocking temperature of 183.2 K. These MgFe2O4 nanoparticles were used to produce aqueous and solid magnetoliposomes, with sizes below 130 nm. The potential drug curcumin was successfully incorporated in these nanosystems, with high encapsulation efficiencies (above 89%). Interaction by fusion between both types of drug-loaded magnetoliposomes (with or without PEGylation) and models of biological membranes was demonstrated, using FRET or fluorescence quenching assays. These results point to future applications of magnetoliposomes containing MgFe2O4 nanoparticles in cancer therapy, allowing combined magnetic hyperthermia and chemotherapy. PMID- 30473849 TI - Environmental oestrogens cause predation-induced population decline in a freshwater fish. AB - Understanding population-level effects of environmental stressors on aquatic biota requires knowledge of the direct adverse effects of pollutants on individuals and species interactions that relate to survival and reproduction. Here, we connect behavioural assays with survival trials and a modelling approach to quantify changes in antipredator escape performance of a larval freshwater fish following exposure to an environmental oestrogen, and predict changes in population abundance. We quantified the effects of short-term (21 days) exposure to 17beta-oestradiol (E2) on the antipredator escape performance of larval fathead minnows (Pimephales promelas) and the probability of predation by a natural predator, the bluegill sunfish (Lepomis macrochirus). Compared with unexposed minnows, minnows exposed to environmentally relevant concentrations of E2 that approach total oestrogenic activity of wastewater-dominated environments (38 and 103 ng l-1) had delayed response times and slower escape speeds, and were more susceptible to predation. Incorporating these data into a stage-structured population model demonstrated that enhanced predation mortality at the larval stage can result in population declines. These results indicate that subtle, sub lethal shifts in the behaviour of individuals due to human-mediated environmental change can impact species interactions with measurable population-level effects. Such changes have the potential to alter higher-order trophic interactions and disrupt aquatic communities. PMID- 30473850 TI - Novel elucidation and treatment of pancreatic chronic graft-versus-host disease in mice. AB - Chronic graft-versus-host disease (cGVHD) is a severe complication of allogeneic haematopoietic stem cell transplantation. There is a growing understanding of cGVHD, and several effective therapies for cGVHD have been reported. However, pancreatic cGVHD is a potentially untapped study field. Our thought-provoking study using a mouse model of cGVHD suggested that the pancreas could be impaired by cGVHD-induced inflammation and fibrosis and that endoplasmic reticulum (ER) stress was augmented in the pancreas affected by cGVHD. These findings urged us to treat pancreatic cGVHD through reduction of ER stress, and we used 4 phenylbutyric acid (PBA) as an ER stress reducer. A series of experiments has indicated that PBA can suppress cGVHD-elicited ER stress in the pancreas and accordingly alleviate pancreatic cGVHD. Furthermore, we focused on a correlation between epithelial to mesenchymal transition (EMT) and fibrosis in the cGVHD affected pancreas, because EMT was conceivably implicated in various fibrosis associated diseases. Our investigation has suggested that the expression of EMT markers was increased in the cGVHD-disordered pancreas and that it could be reduced by PBA. Taken together, we have provided a clue to elucidate the pathogenic process of pancreatic cGVHD and created a potentially effective treatment of this disease using the ER stress alleviator PBA. PMID- 30473851 TI - Host species, pathogens and disease associated with divergent nasal microbial communities in tortoises. AB - Diverse bacterial communities are found on every surface of macro-organisms, and they play important roles in maintaining normal physiological functions in their hosts. While the study of microbiomes has expanded with the influx of data enabled by recent technological advances, microbiome research in reptiles lags behind other organisms. We sequenced the nasal microbiomes in a sample of four North American tortoise species, and we found differing community compositions among tortoise species and sampling sites, with higher richness and diversity in Texas and Sonoran desert tortoises. Using these data, we investigated the prevalence and operational taxonomic unit (OTU) diversity of the potential pathogen Pasteurella testudinis and found it to be common, abundant and highly diverse. However, the presence of this bacterium was not associated with differences in bacterial community composition within host species. We also found that the presence of nasal discharge from tortoises at the time of sampling was associated with a decline in diversity and a change in microbiome composition, which we posit is due to the harsh epithelial environment associated with immune responses. Repeated sampling across seasons, and at different points of pathogen colonization, should contribute to our understanding of the causes and consequences of different bacterial communities in these long-lived hosts. PMID- 30473852 TI - Wild jackdaws are wary of objects that violate expectations of animacy. AB - Nature is composed of self-propelled, animate agents and inanimate objects. Laboratory studies have shown that human infants and a few species discriminate between animate and inanimate objects. This ability is assumed to have evolved to support social cognition and filial imprinting, but its ecological role for wild animals has never been examined. An alternative, functional explanation is that discriminating stimuli based on their potential for animacy helps animals distinguish between harmless and threatening stimuli. Using remote-controlled experimental stimulus presentations, we tested if wild jackdaws (Corvus monedula) respond fearfully to stimuli that violate expectations for movement. Breeding pairs (N = 27) were presented at their nests with moving and non-moving models of ecologically relevant stimuli (birds, snakes and sticks) that differed in threat level and propensity for independent motion. Jackdaws were startled by movement regardless of stimulus type and produced more alarm calls when faced with animate objects. However, they delayed longest in entering their nest-box after encountering a stimulus that should not move independently, suggesting they recognized the movement as unexpected. How jackdaws develop expectations about object movement is not clear, but our results suggest that discriminating between animate and inanimate stimuli may trigger information gathering about potential threats. PMID- 30473853 TI - Scaling the phase-planes of social dilemma strengths shows game-class changes in the five rules governing the evolution of cooperation. AB - Game theory has been extensively applied to help explain how cooperative behaviour is promoted in human and animal societies. How do humans and animals establish reciprocity when confronting a social dilemma? In 2006, Nowak theoretically proved that numerous mechanisms and models for evolving cooperative behaviour reported over the last few decades can be distilled into five reciprocity mechanisms (rules). Additionally, universal scaling parameters were proposed to measure two different types of dilemmas, namely, the gamble-intending dilemma (GID) and risk-averting dilemma (RAD). In this work, by drawing a RAD-GID phase-plane diagram for pair-wise games, we prove that these five rules are indeed quite different for the resolution (relaxation) of the two dilemmas. These diagrams also demonstrate whether and when game-class change (resolution of a dilemma) occurs, thus implying how defectors can be eliminated. PMID- 30473855 TI - Opinion formation on dynamic networks: identifying conditions for the emergence of partisan echo chambers. AB - Modern political interaction is characterized by strong partisanship and a lack of interest in information sharing and agreement across party lines. It remains largely unclear how such partisan echo chambers arise and how they coevolve with opinion formation. Here, we explore the emergence of these structures through the lens of coevolutionary games. In our model, the payoff of an individual is determined jointly by the magnitude of their opinion, their degree of conformity with their social neighbours and the benefit of having social connections. Each individual can simultaneously adjust their opinion and the weights of their social connections. We present and validate the conditions for the emergence of partisan echo chambers, characterizing the transition from cohesive communities with a consensus to divisive networks with splitting opinions. Moreover, we apply our model to voting records of the US House of Representatives over a timespan of decades to understand the influence of underlying psychological and social factors on increasing partisanship in recent years. Our work helps elucidate how the division of today has come to be and how cohesion and unity could otherwise be attained on a variety of political and social issues. PMID- 30473854 TI - Insights on decomposition process of c-C4F8 and c-C4F8/N2 mixture as substitutes for SF6. AB - In recent years, many scholars have carried out studies on c-C4F8 and its gas mixture and found it has potential to be used as an environment-friendly insulating medium to replace SF6 in medium-voltage equipment. In this paper, the c-C4F8 and c-C4F8/N2 gas mixture models were built to study its decomposition process by the combination of reactive molecular dynamics method and density functional theory. The yield of the main decomposition products, the reaction pathways and enthalpy under different temperatures were explored. It was found that the decomposition of c-C4F8/N2 mainly produces CF2, F, CF3, CF, C, CF4 and C2F4. c-C4F8 can decompose to C2F4 by absorbing 43.28 kcal/mol, which is the main decomposition path and this process easily occurs under high temperature. There is a dynamic equilibrium process among the various produced radicals, which ensures the insulation performance of system to a certain extent. The decomposition performance of c-C4F8/N2 mixture is better than that of pure c-C4F8 at the same temperature. Relevant results provide guidance for engineering application of the c-C4F8/N2 gas mixture. PMID- 30473856 TI - Preparation and properties of hydrochars from macadamia nut shell via hydrothermal carbonization. AB - Macadamia nut shell (MNS) is a type of waste lignocellulose obtained from macadamia nut production processing. Large MNS wastes caused serious resource waste and environmental pollution. So, preparation of hydrochars from MNS via hydrothermal carbonization (HTC) is of great significance. HTC of MNS was conducted to study the effect of process parameters, including HTC temperature (180-260 degrees C) and residence time (60-180 min) on the properties of hydrochars. Results showed that the increase in HTC temperature and residence time decreased the mass yield of hydrochars and increased the high heating value of hydrochars. Furthermore, the C content of hydrochars increased, whereas the H and O contents decreased. Mass yield of hydrochar is 46.59%, energy yield is 64.55% and the higher heating value is 26.02 MJ kg-1 at a temperature of 260 degrees C and time of 120 min. The surface structure of hydrochars was rougher compared with that of MNS as observed via scanning electron microscopy. The chemical and combustion behaviour of MNS and hydrochars was analysed by Fourier transform infrared spectroscopy, and thermogravimetric analysis indicated that decarboxylation and dehydration reactions were the predominant pathways during the HTC process. Results showed that HTC can facilitate the transformation of MNS into solid fuel. PMID- 30473857 TI - A two-step method for fabricating large-area textile-embedded elastomers for tunable friction. AB - Recently, shape-tunable wrinkles formed on an elastomeric sheet with a textile finely embedded in proximity to the surface have been developed for in situ control of friction depending on various situations. For their actual uses, sheets with a large area are desired. A key challenge on their fabrication is to overcome the non-uniformity of the vertical position of the textile embedded within the elastomeric sheet, which causes substantial reduction in the tunable range of friction. The defect originates from the increased difficulty, as the sheet area is scaled up, of squeezing a viscoelastic precursor liquid due to the use of a deformable elastomeric surface. Here, we report a new two-step method for a textile-embedded elastomeric sheet that avoids using the soft elastomeric surface on the squeezing process and requires post-joining to an elastomeric base sheet. The obtained sheet with a large area (180 * 180 mm), was uniform and showed a large change of friction on its strain-induced transformation between flat and wrinkled states. The relationship between the experimentally controllable parameters and the squeeze film hydrodynamics is theoretically discussed, which is generally applicable to precise embedding micro-objects at the elastomer surface. PMID- 30473860 TI - Effect of components on the curing of glycidyl azide polymer spherical propellant through rheological method. AB - We have conducted a novel study of the influence of energy components (RDX, AP and CL-20) on curing kinetics of glycidyl azide polymer (GAP) spherical propellant based on rheological method. The autocatalytic model was used to describe curing kinetics and the parameters were determined by the model-fitting method. It was found that the incorporation of components hinders the cross linking reaction of GAP spherical propellant. Integral isoconversional method was used on rheological kinetics to investigate the changes of the activation energy and we confirmed that the incorporation of components increased the activation energy. It was also found that such components had no effect on the trend of activation energy curves but shrank the peak value at a = 0.2. Dynamic mechanical analysis (DMA) showed the differences between pure curing system and its components. These findings are potentially helpful to control the curing effectively and optimize the processing schedules. The addition of components decreased alpha translation temperature which means the reduction in cross-links. The differences in the values of loss factor tan delta and beta translation showed that pure curing system has lower resistance for side chain to motion. PMID- 30473859 TI - A novel in situ stress measurement method based on acoustic emission Kaiser effect: a theoretical and experimental study. AB - Measurement of in situ stress is critical to understand the deformation and destruction of the underground space surrounding rock, and dynamic disaster of the coal mine. At present, with the increasing depth of mining, in situ stress parameters are more and more important for coal mine. In this paper, a novel method for in situ stress measurement with Kaiser effect was studied and applied in the Baijiao coal mine. First, we presented a comprehensive analysis method for the identification of Kaiser effect point. Then, a calculation method for in situ stress measurement based on the Kaiser effect on acoustic emissions was suggested. After that, the in situ stress test of Baijiao coal mine is taken as the research object, an experiment using acoustic emissions monitoring during uniaxial compression testing was performed to investigate the mechanical properties and acoustic emissions characteristics. Finally, in situ stress of the study area was calculated using the novel calculation method above and calculation results were verified using stress relief method and hydraulic fracturing method. The results showed that the calculation results obtained using the proposed method were valid and credible. Therefore, the calculation method for in situ stress measurement and the proposed comprehensive analysis method using the Kaiser point could be applied for in situ stress testing using the Kaiser effect method. PMID- 30473858 TI - A global cline in a colour polymorphism suggests a limited contribution of gene flow towards the recovery of a heavily exploited marine mammal. AB - Evaluating how populations are connected by migration is important for understanding species resilience because gene flow can facilitate recovery from demographic declines. We therefore investigated the extent to which migration may have contributed to the global recovery of the Antarctic fur seal (Arctocephalus gazella), a circumpolar distributed marine mammal that was brought to the brink of extinction by the sealing industry in the eighteenth and nineteenth centuries. It is widely believed that animals emigrating from South Georgia, where a relict population escaped sealing, contributed to the re-establishment of formerly occupied breeding colonies across the geographical range of the species. To investigate this, we interrogated a genetic polymorphism (S291F) in the melanocortin 1 receptor gene, which is responsible for a cream-coloured phenotype that is relatively abundant at South Georgia and which appears to have recently spread to localities as far afield as Marion Island in the sub-Antarctic Indian Ocean. By sequencing a short region of this gene in 1492 pups from eight breeding colonies, we showed that S291F frequency rapidly declines with increasing geographical distance from South Georgia, consistent with locally restricted gene flow from South Georgia mainly to the South Shetland Islands and Bouvetoya. The S291F allele was not detected farther afield, suggesting that although emigrants from South Georgia may have been locally important, they are unlikely to have played a major role in the recovery of geographically more distant populations. PMID- 30473861 TI - Vocal behaviour predicts mating success in giant pandas. AB - Surprisingly little is known about how mammal vocal signals are used to achieve behavioural synchrony in the lead up to copulation. The ability to signal short term fluctuations in arousal levels and behavioural intention is likely to be particularly important for synchronizing mating behaviour in asocial species, which must overcome their natural avoidance and aggressive tendencies to mate. Here, we examined vocal behaviour during breeding encounters in captive giant pandas (Ailuropoda melanoleuca) to gain a greater understanding of how close range vocal signalling mediates reproduction in this asocial, and conservation dependent species. Our results revealed that the occurrence of different giant panda vocalizations and acoustic variation within these calls is predictive of successful encounters leading to copulation, as opposed to unsuccessful encounters that do not. In addition, key differences were detected between vocalizations produced during and just prior to copulation. These findings illustrate that vocal exchanges are crucial for achieving behavioural synchrony and signalling intention to mate in giant pandas, and could also provide a valuable tool for breeding programmes, helping conservation managers to assess the likelihood of breeding introductions leading to copulation or potentially injurious failure. PMID- 30473862 TI - Microstructure, local electronic structure and optical behaviour of zinc ferrite thin films on glass substrate. AB - Zinc ferrite thin films were deposited using a radio-frequency-sputtering method on glass substrates. As-deposited films were annealed at 200 degrees C for 1, 3 and 5 h, respectively. X-ray diffraction studies revealed the amorphous nature of as-grown and annealed films. Thickness of as-deposited film is 96 nm as determined from Rutherford backscattering spectroscopy which remains almost invariant with annealing. Transmission electron microscopic investigations envisaged a low degree of crystalline order in as-deposited and annealed films. Thicknesses estimated from these measurements were almost 62 nm. Roughness values of these films were almost 1-2 nm as determined from atomic force microscopy. X ray reflectivity measurements further support the results obtained from TEM and AFM. Near-edge X-ray absorption fine structure measurements envisaged 3+ and 2+ valence states of Fe and Zn ions in these films. UV-Vis spectra of these films were characterized by a sharp absorption in the UV region. All films exhibited almost the same value of optical band gap within experimental error, which is close to 2.86 eV. PMID- 30473864 TI - Synchronous fluorescence as a green and selective tool for simultaneous determination of bambuterol and its main degradation product, terbutaline. AB - A green, sensitive and cost-effective method is introduced in this research for the determination of bambuterol and its main degradation product, terbutaline, simultaneously, relying on the synchronous spectrofluorimetric technique. First derivative synchronous spectrofluorimetric amplitude is measured at Deltalambda = 20 nm, so bambuterol can be quantitated at 260 nm, and terbutaline can be measured at 290 nm, each at the zero crossing point of the other. The amplitude concentration plots were linear over the concentration ranges of 0.2-6.0 ug ml-1 and 0.2-4.0 ug ml-1 for both bambuterol and terbutaline, respectively. Official guidelines were followed to calculate the validation parameters of the proposed method. The low values of limits of detection of 0.023, 0.056 ug ml-1 and limits of quantitation of 0.071, 0.169 ug ml-1 for bambuterol and terbutaline, respectively, point to the sensitivity of the method. Bambuterol is a prodrug for terbutaline, and the latter is considered its degradation product so the established method could be regarded as a stability-indicating one. Moreover, the proposed method was used for the analysis of bambuterol and terbutaline in their single ingredient preparations and the results revealed statistical agreement with the reference method. The suggested method, being a simple and low-cost procedure, is superior to the previously published methods which need more sophisticated techniques, longer analysis time and highly toxic solvents and reagents. It could be considered as an eco-friendly analytical procedure. PMID- 30473865 TI - Indirect effects of climate change altered the cannibalistic behaviour of shell drilling gastropods in Antarctica during the Eocene. AB - The fossil record from Seymour Island, Antarctic Peninsula, provides a record of biotic response to the onset of global climatic cooling during the Eocene. Using drilling traces-small, round holes preserved on prey shells-we examined the effect of a cooling pulse 41 Ma on the cannibalistic behaviour of predatory naticid gastropods. We predicted that cannibalistic attacks would decline in response to the cooling climate, reflecting reduced activity levels, energy requirements and constraints on the chemically aided drilling process of the naticids. Surprisingly, however, cannibalism frequencies did not change. This counterintuitive result is best explained by a sharp reduction in durophagous (shell-crushing) predation in shallow-benthic communities in Antarctica that also occurred as the climate cooled. Reduced durophagous predation may have created a less-risky environment for foraging naticids, stimulating cannibalistic behaviour. The change in the top-down control exerted by shell-crushing predators on naticids may have counteracted the direct, negative effects of declining temperatures on the predatory performance of naticids. Our results suggest that the long-term consequences of climate change cannot be predicted solely from its direct effects on predation, because the temperature can have large indirect effects on consumer-resource interactions, especially where risk-effects dominate. PMID- 30473863 TI - The left ventral premotor cortex is involved in hand shaping for intransitive gestures: evidence from a two-person imitation experiment. AB - The ventral premotor cortex (PMv) is involved in grasping and object manipulation, while the dorsal premotor cortex (PMd) has been suggested to play a role in reaching and action selection. These areas have also been associated with action imitation, but their relative roles in different types of action imitation are unclear. We examined the role of the left PMv and PMd in meaningful and meaningless action imitation by using repetitive transcranial magnetic stimulation (rTMS). Participants imitated meaningful and meaningless actions performed by a confederate actor while both individuals were motion-tracked. rTMS was applied over the left PMv, left PMd or a vertex control site during action observation or imitation. Digit velocity was significantly greater following stimulation over the PMv during imitation compared with stimulation over the PMv during observation, regardless of action meaning. Similar effects were not observed over the PMd or vertex. In addition, stimulation over the PMv increased finger movement speed in a (non-imitative) finger-thumb opposition task. We suggest that claims regarding the role of the PMv in object-directed hand shaping may stem from the prevalence of object-directed designs in motor control research. Our results indicate that the PMv may have a broader role in 'target directed' hand shaping, whereby different areas of the hand are considered targets to act upon during intransitive gesturing. PMID- 30473866 TI - Correction to 'Holographic sol-gel monoliths: optical properties and application for humidity sensing'. AB - [This corrects the article DOI: 10.1098/rsos.172465.]. PMID- 30473867 TI - A dynamics and stability framework for avian jumping take-off. AB - Jumping take-off in birds is an explosive behaviour with the goal of providing a rapid transition from ground to airborne locomotion. An effective jump is predicated on the need to maintain dynamic stability through the acceleration phase. The present study concerns understanding how birds retain control of body attitude and trajectory during take-off. Cursory observation suggests that stability is achieved with relatively little cost. However, analysis of the problem shows that the stability margins during jumping are actually very small and that stability considerations play a significant role in the selection of appropriate jumping kinematics. We use theoretical models to understand stability in prehensile take-off (from a perch) and also in non-prehensile take-off (from the ground). The primary instability is tipping, defined as rotation of the centre of gravity about the ground contact point. Tipping occurs when the centre of pressure falls outside the functional foot. A contribution of the paper is the development of graphical tipping stability margins for both centre of gravity location and acceleration angle. We show that the nose-up angular acceleration extends stability bounds forward and is hence helpful in achieving shallow take offs. The stability margins are used to interrogate simulated take-offs of real birds using published experimental kinematic data from a guinea fowl (ground take off) and a diamond dove (perch take-off). For the guinea fowl, the initial part of the jump is stable; however, simulations exhibit a stuttering instability not observed experimentally that is probably due to the absence of compliance in the idealized joints. The diamond dove model confirms that the foot provides an active torque reaction during take-off, extending the range of stable jump angles by around 45 degrees . PMID- 30473869 TI - Protective effect of soursop (Annona muricata linn.) juice on oxidative stress in heat stressed rabbits. AB - Background: Preventing oxidative stress in heat stressed animals may be possible by increasing antioxidant defence via exogenous administration of antioxidant substrate and/or its precursors. The study aimed to investigate the effect of Soursop juice in mitigating oxidative stress induced by heat stress in rabbit. Methods: Sixty mixed breed rabbit bucks aged 12-18 months old with the average weight of 1826 +/- 8.35 g/rabbit, randomly allotted to experimental treatments of four replicates each, in a completely randomized design during high-temperature humidity index in Ado Ekiti, Southwest Nigeria. Soursop juice (SSJ) was administered via oral drenched daily per kg body weight (BW), to designated treatment 1 to 5; 0.55 mlkg-1BW distilled water (control), 0.55 mlkg-1BW SSJ, 1.11 mlkg-1BW SSJ, 1.67 mlkg-1BW SSJ and 2.22 mlkg-1BW SSJ, respectively. Fastened blood samples were collected at days 28 and 56, and assay for serum protein, cholesterol, triglycerides, superoxide dismutase, catalase, reduced glutathione and lipid peroxidation using standard procedures. Result: Result revealed that SSJ demonstrated hypocholesterolemic effect in a dose-dependent manner throughout the study. Effect of chronic administration of SSJ to heat stressed rabbits proved beneficial, as SSJ reduced serum lipid peroxidation and enhanced antioxidant activity over 8 weeks. Conclusion: Administration of soursop juice to heat-stressed bucks at 2.22 mlkg-1BW offered optimum antioxidant defense against oxidative stress. PMID- 30473868 TI - Association between furosemide in premature infants and sensorineural hearing loss and nephrocalcinosis: a systematic review. AB - Furosemide is a potent loop diuretic commonly and variably used by neonatologists to improve oxygenation and lung compliance in premature infants. There are several safety concerns with use of furosemide in premature infants, specifically the risk of sensorineural hearing loss (SNHL), and nephrocalcinosis/nephrolithiasis (NC/NL). We conducted a systematic review of all trials and observational studies examining the association between these outcomes with exposure to furosemide in premature infants. We searched MEDLINE, EMBASE, CINAHL, and clinicaltrials.gov. We included studies reporting either SNHL or NC/NL in premature infants (< 37 weeks completed gestational age) who received at least one dose of enteral or intravenous furosemide. Thirty-two studies met full inclusion criteria for the review, including 12 studies examining SNHL and 20 studies examining NC/NL. Only one randomized controlled trial was identified in this review. We found no evidence that furosemide exposure increases the risk of SNHL or NC/NL in premature infants, with varying quality of studies and found the strength of evidence for both outcomes to be low. The most common limitation in these studies was the lack of control for confounding factors. The evidence for the risk of SNHL and NC/NL in premature infants exposed to furosemide is low. Further randomized controlled trials of furosemide in premature infants are urgently needed to adequately assess the risk of SNHL and NC/NL, provide evidence for improved FDA labeling, and promote safer prescribing practices. PMID- 30473870 TI - 'Phasing out pig tail docking in the EU - present state, challenges and possibilities'. AB - Background: European legislation dictates that pig tail docking is not allowed to be performed routinely (European Union. Council Directive 2008/120/EC of 18 December 2008 laying down minimum standards for the protection of pigs. OJ L 47, 18.2.2009). Nevertheless, tail docking is still practiced routinely in many European countries, while four countries stopped routine tail docking completely. Tail docking is also practiced in many countries outside Europe.The Federation of Veterinarians of Europe (FVE), the European Association of Porcine Health Management (EAPHM) together with the European Commission carried out an online survey to investigate the situation regarding the practice of pig tail docking and the provision of enrichment material across 24 European countries. It also focuses on the role of the veterinary profession and gives an overview on published literature regarding the challenges and possibilities related to the raising of pigs with intact tails. Results: Fifty-seven (57) usable survey responses from 24 countries were received. On average 77% (median = 95%) of pigs are routinely tail-docked. In Finland, Norway, Sweden, Switzerland, less than 5% of the pigs are tail-docked. According to the respondents, 67% of pigs (median = 76%) across the 24 EU countries surveyed are given suitable enrichment materials. Training of veterinary practitioners, their role in advising the producer and undertaking a risk assessment of tail biting were more positively valued in countries that stopped routine tail docking than in countries that had not stopped routine tail docking. Initiatives such as training from national authorities to encourage abandoning tail docking and routine recording of tail biting at the slaughterhouse were identified as two successful items to promote the raising of pigs with entire tails. Conclusion: In many European countries the majority of the pigs are still routinely tail-docked, which is a violation of the European legislation. To stop routine tail docking it is necessary to raise the awareness and education about risk factors to prevent tail biting. The growing knowledge about the reasons for failing voluntary national initiatives as well as about successful measures taken by some countries to make pig production with intact tails feasible should be distributed throughout the EU pig producing community. The veterinary profession has a significant role to play in raising awareness, facilitate knowledge transfer and to identify risk factors and solutions on farm level for the benefit of pig health and welfare. PMID- 30473871 TI - A randomized controlled feasibility study to evaluate the effects of a goal setting coaching intervention using feedback from an accelerometer on sedentary time in older people at risk of falls (SMART-MOVE): a study protocol. AB - Background: Sedentary behaviour and falls are important interrelated health issues in older people. One in three people aged 65 years and above fall at least once a year and sedentary behaviour has been identified as one of the risk factors for falls. Studies have shown that the duration of sedentary time increases with age. These dual problems need to be addressed effectively as the ageing population grows. Accelerometers enable accurate measurement of sedentary time. This study aims to establish the feasibility and effect of an individualized goal-setting health coaching intervention using feedback initially from an accelerometer and then pedometer over a period of 12 weeks (intervention) compared with providing a one-off advice through a brochure (control), on sedentary time in older people with a recent fall or at risk of one. Methods: A single-blinded randomized controlled feasibility trial involving 80 community dwelling people aged 65 years and above will be conducted with 40 randomized to the intervention and another 40 to control. Primary outcomes will be the feasibility of the intervention and change in total sedentary time at 12 and 24 weeks. Secondary outcomes include a change in fear of falling based on the falls efficacy scale, gait speed, self-reported sedentary time, the proportion of fallers and number of falls. Four focus groups (two from each arm) will be conducted at the end of the study to evaluate the feasibility and effectiveness of this intervention. Feasibility findings will be primarily descriptive. Mean group differences will be examined using independent samples t test for normally distributed data and nonparametric tests (Kruskal-Wallis and Mann-Whitney U) for non-normally distributed data. Differences in frequency of variables will be compared using chi-square test. Analysis of variance (ANOVA) will be used to test the post-intervention difference between the two groups at 12 and 24 weeks. Discussion: The trial will address a key gap in evidence about sedentary behaviour and falls amongst older people and will evaluate the feasibility of an intervention that could be implemented within the primary health care settings. Trial registration: Australian New Zealand Clinical Trials Registry 12617001186347, Registered 11 August 2017. PMID- 30473872 TI - Resolving authorship disputes by mediation and arbitration. AB - Background: Disputes over authorship are increasing. This paper examines the options that researchers have in resolving authorship disputes. Discussions about authorship disputes often address how to prevent disputes but rarely address how to resolve them. Both individuals and larger research communities are harmed by the limited options for dispute resolution. Main body: When authorship disputes arise after publication, most existing guidelines recommend that the authors work out the disputes between themselves. But this is unlikely to occur, because there are often large power differentials between team members, and institutions (e.g., universities, funding agencies) are unlikely to have authority over all team members. Other collaborative disciplines that deal with issues of collaborative creator credit could provide models for scientific authorship. Arbitration or mediation could provide solutions to authorship disputes where few presently exist. Because authors recognize journals' authority to make decisions about manuscripts submitted to the journal, journals are well placed to facilitate alternative dispute resolution processes. Conclusion: Rather than viewing authorship disputes as rare events that must be handled on a case by case basis, researchers and journals should view the potential for disputes as predictable, preventable, and soluble. Independent bodies that can offer alternative dispute resolution services to scientific collaborators and/or journals could quickly help research communities, particularly their most vulnerable members. PMID- 30473873 TI - The Projected Impact of a Neighborhood-scaled Green Infrastructure Retrofit. AB - Climate change and its related factors are increasing the frequency of hurricanes, coastal storms, and urban flooding. Recovery from disasters can be slow, with jurisdictions failing to build back better, wasting time and money without improving resilience to the next disaster. To help attenuate floods and mitigate their impacts, Low Impact Development (LID) and the incorporation of green infrastructure (GI) is gaining in popularity. LID installs more natural methods of absorbing, redirecting, retaining, and filtering water, through GI installations such as rain gardens, detention ponds, and the reduction of impervious surfaces. LID is, however, primarily implemented and evaluated only on a local scale; few studies have assessed the broader impacts of GI on a larger scale. In fact, most performance calculators that evaluate the effects of GI are only useful at the site scale. Further, most advocates of GI propose its use in new developments, without much attention to retrofitting existing, suburban development. This article seeks to determine what the potential effects of retrofitting an existing, suburban neighborhood with GI for flood protection at a larger scale could be, using Sugar Land, Texas, USA as a case site. First, low impact facilities are proposed and schematically designed at a site scale for a typical single-family lot. The volume of rainfall that can be retained on site, due to each incorporated feature, is then derived using the Green Values National Storm Water Management Calculator. Using this data, the total volume of rainfall that could be retained if all residential sites in Sugar Land incorporate similar facilities is then projected. The result show that Sugar Land has the capacity to capture 56 billion liters of stormwater water annually if all residential properties use LID. Additional benefits of the use of GI include reduced heat (37%), improved aesthetics and property values (20%), increased recreational opportunities (18%), improved water quality (12%), improved air quality (5%), increased green collar jobs (4%), reduced damage from harmful gas emissions (3%), and increased energy savings (1%), thereby surpassing conventional storm water management techniques [1]. PMID- 30473874 TI - A new way of teaching an old subject: Pharmacy Law and Ethics. AB - Background: Pharmacy educators are responsible for ensuring that students are equipped with the necessary regulatory knowledge required to deal with ethical challenges that arise in practice. Teaching methods have a strong impact on student learning, making it essential to determine how learning is influenced when changing pedagogy. Objective: To describe students' experience and perceptions of the use of a case-based learning (CBL) activity as an adjunctive method to didactic teaching of pharmacy law and ethics. Method: A survey was conducted among 3rd-year pharmacy students enrolled for a Pharmacy Law and Ethics course at the University of KwaZulu-Natal, Durban, South Africa. The course content was delivered didactically, followed by a CBL activity for which the students were divided into groups and assigned various real-life case studies. Results: Most of the 74 respondents (66%) agreed that the activity was enjoyable and metacognitively useful. A majority (77%) found the activity interactive, and 92% agreed that it enhanced their understanding of pharmacy law concepts. Eighty percent agreed that it facilitated their understanding of law and ethics concepts, and their application to real-life situations. Conclusion: The use of CBL was beneficial to both the individual student's learning experience and the overall class learning process. More importantly, the exercise improved their metacognitive awareness, and suggests the need to consider this method of teaching as part of the formal curriculum to better equip students to deal with ethical issues that will arise in practice. PMID- 30473875 TI - B-cell and T-cell activation in South African HIV-1-positive non-Hodgkin's lymphoma patients. AB - Background: Altered immune mechanisms play a critical role in the pathogenesis of non-Hodgkin's lymphoma (NHL). HIV-1 (HIV) infection is associated with a state of excessive T-cell activation, which can lead to increased T-cell turnover and lymph node fibrosis. Objectives: This study aimed to determine the serum levels of circulating B-cell activation markers, and the expression of T-cell activation and regulatory markers in HIV-positive NHL patients. Method: The serum levels of circulating soluble(s) sCD20, sCD23, sCD27, sCD30 and sCD44 molecules, all of which are biomarkers of B-cell activation, were determined by enzyme-linked immunosorbent assays (ELISA), while biomarkers of T-cell activation (CD8+CD38+) and regulation (FoxP3) were determined by flow cytometry in 141 subjects who were divided into five groups: Combination antiretroviral therapy (ART)-naive HIV positive patients; ART-treated HIV-positive patients; HIV-negative NHL patients; HIV-positive NHL patients on ART; and healthy controls. Results: HIV-positive NHL patients had significantly higher serum levels of sCD20, sCD23, sCD30 and sCD44 than HIV-negative NHL patients, while all five biomarkers were significantly elevated in HIV-positive NHL patients when compared with ART-treated HIV-positive patients. HIV-positive NHL patients had higher CD8+CD38+ and lower FoxP3 expression than HIV-negative NHL and ART-treated HIV-positive patients. Conclusion: B-cell activation is increased in HIV-positive NHL patients and is associated with reduced regulatory T-cell populations and increased CD8+ T-cell activation. PMID- 30473877 TI - Southern African HIV Clinicians Society Guidance on the use of dolutegravir in first-line antiretroviral therapy. PMID- 30473878 TI - Appropriate clinical use of darunavir 800 mg. PMID- 30473876 TI - Guidelines to support HIV-affected individuals and couples to achieve pregnancy safely: Update 2018. PMID- 30473879 TI - Attitudes of prehospital providers on transport decision-making in the management of patients with a suicide attempt refusing care: A survey based on the Mental Health Care Act of 2002. AB - Background: Given the frequency of suicidal patients making attempts prior to a completed suicide, emergency access to mental health care services could lead to significant reduction in morbidity and mortality for these patients. Aim: To describe the attitudes of prehospital providers and describe transport decision making around the management of patients with a suicide attempt. Setting: Cape Town Metropole. Methods: A cross-sectional, vignette-based survey was used to collect data related to training and knowledge of the Mental Health Care Act, prehospital transport decision-making and patient management. Results: Patients with less dramatic suicidal history were more likely to be discharged on scene. Few respondents reported the use of formal suicide evaluation tools to aid their decision. Respondents displayed negative attitudes towards suicidal patients. Some respondents reported returning to find a suicidal patient dead, while others reported patient attempts at suicide when in their care. Eighty per cent of respondents had no training in the management of suicidal patients, while only 7.0% had specific training in the Mental Health Care Act. Conclusion: A critical lack in the knowledge, training and implementation of the Mental Health Care Act exists amongst prehospital providers within the Western Cape. A further concern is the negative feelings towards suicidal patients and the lack of commitment to transporting patients to definitive care. It is essential to urgently develop training programmes to ensure that prehospital providers are better equipped to deal with suicidal patients. PMID- 30473880 TI - Prevalence and factors associated with postnatal depression among women in two rural districts of Manicaland, Zimbabwe. AB - Background: Low- and middle-income countries are disproportionately affected by postnatal depression (PND). High prevalence of PND in urban Zimbabwe has been reported but the situation in rural settings is largely unknown and this is one of the first studies to report prevalence of PND in Chipinge and Mutasa districts. Objectives: This study explored the prevalence and associated factors of PND among women attending postnatal care services in two rural districts of Chipinge and Mutasa, Manicaland, Zimbabwe between August and September 2017. Methods: One hundred and ninety-two women were recruited consecutively as they attended postnatal services at 7 days and 42 days post-delivery. The Diagnostic and Statistical Manual for Mental Disorders, fifth edition criteria was used to classify depression among participants. Prevalence of PND and 95.0% confidence intervals (CIs) were estimated and associations with key socio-demographic and risk factors assessed. Results: The mean age of participants was 23.7 years (standard deviation = 6.14). Pooled prevalence of PND across the two districts was 26.0% (95% CI: 19.04-31.74). There was a higher prevalence of PND in Mutasa (31.0%) as compared to Chipinge (21.48%) but this was not statistically significant (p = 0.142). Having insufficient food in the household, intimate partner violence and having a child with birthweight under 2500 g significantly increased the likelihood of PND twofold: adjusted odds ratio (aOR) = 2.8 (95% CI: 1.2-6.1), aOR = 2.5 (95% CI: 1.2-5.3) and aOR = 2.4 (95% CI: 1.1-5.6), respectively. Conclusion: The high prevalence of PND and its associated risk factors indicates the need for routine screening and targeted interventions for PND in Zimbabwe, especially in rural areas. PMID- 30473881 TI - Level of awareness and treatment of anxiety and depression during pregnancy in southeast Nigeria. AB - Background: Anxiety and depressive disorders are somewhat masked by features of pregnancy; hence many women are ignorant of them and are untreated. Aim: To determine the level of awareness and treatment of anxiety and depression in pregnancy. Setting: The study was carried out at the antenatal clinic of Enugu State University Teaching Hospital, Enugu, Nigeria. Method: This was a cross sectional and descriptive study of 200 pregnant women in consecutive attendance of the antenatal clinic using the Hospital Anxiety and Depression Scale (HADS) and a sociodemographic questionnaire. Results: Of the participants, 23.5% had anxiety and/or depression, 7.5% of them were aware of their condition and only 0.5% of all the participants or 6.7% of those who were aware of their problem received treatment. Conclusion: Anxiety and depression are prevalent among pregnant women. Because of overlap of symptoms of anxiety and depression with those of pregnancy, the awareness is very low; hence many of them suffer immensely without treatment. PMID- 30473882 TI - Risk of manic switch with antidepressants use in patients with bipolar disorder in a Nigerian neuropsychiatric hospital. AB - Background: Depressive disorders are common among those with bipolar affective disorder (BAD) and may necessitate the use of antidepressants. This has been suggested to precipitate manic episodes in some patients. Objectives: This study aims to determine the prevalence of and factors associated with manic switch in patients with BAD being treated with antidepressants. Methods: Case notes of patients who were treated at a Nigerian neuropsychiatric hospital for a BAD from 2004 to 2015 were reviewed. BAD diagnosis was made using ICD-10 criteria. Treatment for bipolar depression included monotherapy (i.e. antidepressants, antipsychotics or mood stabilisers) or combination therapy (mood stabiliser with an antidepressant or a combination of mood stabilisers, antipsychotics and antidepressants). The primary outcome measure was a switch to mania or hypomania within 12 weeks of commencing an antidepressant. Results: Manic or hypomanic switch (MS) was observed in 109 (44.3%) of the participants. Female gender, younger age, number of previous episodes and a past history of psychiatric hospitalisation were all significantly associated with a risk of MS. There was no significant difference in the rate of MS in either those treated with adjunct antidepressants therapy with a mood stabiliser or an antipsychotic or those placed on a combination of antidepressants, antipsychotics and mood-stabilising agents. Conclusion: A large proportion of patients with BAD on antidepressants experience medication-induced manic or hypomanic switch. PMID- 30473883 TI - Effect of Myricetin on Primary Open-angle Glaucoma. AB - Background: Primary open angle glaucoma (POAG) is the most common form of glaucoma, with a multifactorial etiology that results in retinal ganglion cell death and loss of vision. In this study, we assessed the effects of myricetin on the trabecular meshwork cells in POAG. Methods: In the in-vivo model, glaucoma was induced in Sprague-Dawley rats by injecting hyaluronic acid into the anterior chamber of the eye (every week for six-weeks). Treatment group rats were administered myricetin (25, 50 or 100 mg/ kg body weight via oral gavage) each day for of six weeks. Results: POAG TM cells exposed to myricetin (25, 50 or 100 MUM) exhibited significantly lowered reactive oxidative species (ROS) levels and lipid peroxidation products. The expressions of transforming growth factors (TGFbeta1/beta2), vascular endothelial growth factor, and senescence markers (senescence associated-beta-galactosidase, cyclin-dependent kinase inhibitors-p16 and p21) were substantially down-regulated in POAG TM cells exposed to myricetin. Myricetin effectively prevented IOP elevation in glaucoma-induced rats and decreased inflammatory cytokines (IL-1alpha, IL-1beta, IL-6, Il-8, TNF-alpha) in the aqueous humor and POAG TM cells of glaucoma-induced rats. Conclusion: The observations of the study illustrate the protective effects of myricetin in glaucomatous TM cells. PMID- 30473884 TI - P38 Mitogen-activated Protein Kinase and Parkinson's Disease. AB - Parkinson's disease, the second major neurodegenerative disease, has created a great impact on the elder people. Although the mechanisms underlying Parkinson's disease are not fully understood, considerable evidence suggests that neuro inflammation, oxidative stress, mitochondrial dysfunction, cell proliferation, differentiation and apoptosis are involved in the disease. p38MAPK, an important member of the mitogen-activated protein family, controls several important functions in the cell, suggesting a potential pathogenic role in PD. This review provides a brief description of the role and mechanism of p38MAPK in Parkinson's disease. PMID- 30473886 TI - Pediatric HIV Disclosure in Northern India: Evaluation of Its Prevalence, Perceptions amongst Caregivers, and Its Impact on CLHIV. AB - Background: With improving standards of care of children living with HIV (CLHIV), pediatric HIV related mortality rates are declining. New challenges like HIV status disclosure are emerging which need to be addressed to ensure their smooth transition into adulthood. Poor disease disclosure rates are observed in CLHIV globally. Aims: This study was done to assess the prevalence of HIV disclosure in North Indian CLHIV, know the perceptions of caregivers regarding disclosure, and evaluate the impact of disclosure on CLHIV. Methods: It was a questionnaire based cross-sectional study carried out amongst 144 caregivers of CLHIV aged 6-16 years attending the pediatric HIV clinic of a tertiary care teaching hospital. Results: Though the majority (93.8%) caregivers felt that it is important to disclose but only 33% of the children were actually disclosed. Eighty five percent felt that disclosure must be done by one of the family members and correspondingly 73% of the disclosed children were actually disclosed by their parents. Forty seven percent believed that the most appropriate age for disclosure is 10-12 years. The mean age at which disclosure was actually done was 11.06 +/- 1.62 years. Comparison of the disclosed and undisclosed CLHIV revealed that the disclosed group had significantly higher age, longer duration of taking ART, and higher proportion of paternal orphans. Age of the CLHIV was the only significant factor for disclosure. Several reasons were cited by the caregivers for nondisclosure. The caregivers observed improved drug adherence in 47.9% of the children following disclosure. Conclusions: There is a need to develop region specific pediatric HIV disclosure guidelines keeping in mind the caregivers' perceptions. The guidelines must be age appropriate, systematic, and socioculturally acceptable. The most suitable age for disclosure appears to be 10-12 years. Involvement of caregivers and health care providers in the process is a must. PMID- 30473885 TI - HMBG1 as a Driver of Inflammatory and Immune Processes in the Pathogenesis of Ocular Diseases. AB - High-mobility group box 1 (HMGB1) is a nuclear protein that can also act as an extracellular trigger of inflammation, proliferation, and migration in eye diseases. It induces signaling pathways by binding to the receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs) 2, 4, and 9. This proinflammatory activity is considered to be important in the pathogenesis of a wide range of ocular diseases resulting from hemodynamic changes, presence of neovascular endothelial cells, secretion of intraocular immune factors or inflammation, and apoptosis of retinal cell layers. Further work is needed to elucidate in detail how HMGB1 contributes to ocular disease and how its damaging activity can be modulated. In this review, we summarize current knowledge on HMGB1 as a ligand that can evoke inflammation and immune responses in ocular diseases. PMID- 30473888 TI - Prevalence of Extended Spectrum Betalactamase (ESBL) and Metallobetalactamase (MBL) Producing Pseudomonas aeruginosa and Acinetobacter baumannii Isolated from Various Clinical Samples. AB - This study was conducted with an objective to find the prevalence of extended spectrum betalactamase (ESBL) and metallobetalactamase (MBL) in P. aeruginosa and A. baumannii isolates obtained from various clinical samples. It was conducted in the Department of Microbiology, Adesh Institute of Medical Sciences and Research, Bathinda, over a period of two years from July 2014 to June 2016. Clinical specimens including urine, pus, blood, high vaginal swabs, respiratory samples, and various body fluids were processed and P. aeruginosa and A. baumannii isolates were identified by standard protocols. Antibiotic sensitivity testing for all isolates was done using Kirby-Bauer disc diffusion method. Disc potentiation test was performed to check ESBL and MBL production in these bacteria. Maximum ESBL positive isolates of P. aeruginosa were observed among pus samples and maximum MBL positive isolates were detected in tracheal aspirates. A. baumannii showed maximum positivity for ESBL and MBL production in endotracheal secretions. This study gives an alarming sign towards high prevalence of cephalosporin and carbapenem resistance due to production of extended spectrum betalactamases and metallobetalactamases, respectively. Early detection, stringent antibiotic policies, and compliance towards infection control practices are the best defenses against these organisms. PMID- 30473887 TI - Assessment of Respiratory Symptoms and Pulmonary Function Status among Workers of Flour Mills in Addis Ababa, Ethiopia: Comparative Cross-Sectional Study. AB - Background: Flour dust in the respiratory tract affects lung function. Flour dust is a heterogeneous organic substance which can have a tendency to cause respiratory ailments. There is growing consensus on the deleterious effects of flour dust on respiratory symptoms and lung performance of flour mill workers. Methods: The study design was comparative cross-sectional. A total of 54 flour mill workers who work for more than eight-hour shift per day and 54 control subjects matched for sex, age, weight, height, and area of residence were enrolled. Anthropometric measurement was done. Lung function was measured by using a digital portable spirometer (Spiro Pro) based on the ATS guidelines. FVC, FEV1, FEV1/FVC, PEFR, and FEF25% -75% were measured. Productive cough, dry cough, wheeze, and breathlessness were evaluated using BMRC questionnaire guidelines, administered through face-to-face interview. Result: This study showed statistically significant reduction in the mean values of pulmonary function tests in flour mill workers as compared to their matched controls. Reduction of pulmonary function indices in study subjects was significant for FVC (4.25+/-0.93 vs. 5.30+/-0.71, p<0.001), FEV1 (3.46+/-0.86 vs. 4.50+/-0.72, p<0.001), PEFR (5.43+/-2.43 vs. 7.87+/-2.53, p<0.001), and FEF25% -75%, (3.87+/ 1.61 vs. 4.60+/-1.60, p<0.05), but not significant for FEV1/FVC (81.93+/-12.74 vs. 83.40+/-12.50, p>0.05). Flour mill workers developed 27.7% of restrictive type and 11.1% of obstructive type of lung disorders. Percentage prevalence of respiratory symptoms was evaluated as dry cough (27.7% vs. 9.3%), productive cough (11.1% vs. 5.6%), wheeze (14.8% vs. 3.8%), and breathlessness (16.6% vs.7.4%) in flour mill workers and controls, respectively. Conclusion: Based on the results of the present study, occupational exposure to flour dust could cause respiratory dysfunction, thereby reducing lung efficiency. PMID- 30473889 TI - Acute Pancreatitis Mimicking ST-Segment Elevation Myocardial Infarction. AB - Introduction: Electrocardiographic changes imitating myocardial ischemia have been occasionally reported in patients with intra-abdominal pathology including acute pancreatitis. Case Report: A 60-year-old man with no past medical history presented to the emergency department (ED) after a syncopal episode. In ED, his vitals were stable. His ECG showed sinus bradycardia at 53 beats per minute, peaked T waves, 1 mm ST-segment elevation in leads II, III, and aVF, and 2 mm ST elevation in V3 as shown in the figures. With the concern for STEMI, he was taken for left heart catheterization (LHC) emergently, showing nonobstructive coronary artery disease (CAD). His laboratory workup was remarkable for lipase of 25,304 IU/l (normal level 8-78 IU/l). His liver function test and triglyceride level were normal. Troponin was <0.01 ng/ml. A computed tomographic exam of the abdomen revealed acute interstitial pancreatitis with a small discrete fluid collection in the uncinate process. He was treated with aggressive intravenous fluid resuscitation and was discharged on day 3. Discussion: Intra-abdominal pathologies like acute pancreatitis can lead to transient ECG changes mimicking STEMI. It is important to use ECG clues, echocardiographic findings, and clinical judgement to avoid cardiac catheterization, contrast exposure, and associated health care costs. PMID- 30473890 TI - Marine-Lenhart Syndrome: Case Report, Diagnosis, and Management. AB - The coexistence of thyroid functioning nodules and Graves' disease is called Marine-Lenhart syndrome. This condition is estimated to occur in 0.8-2.7% of patients with Graves' disease with few cases reported in the literature. Criteria for the diagnosis are not well defined. Here, we present a case of hyperthyroidism characterized by the presence of stimulating TSH receptor antibodies and severe bilateral exophthalmos. A thyroid uptake and scan revealed an elevated 24-hour iodine-131 uptake and a discrete hot nodule in the upper pole of the right lobe which was also observed with a thyroid ultrasound. The patient was diagnosed with Marine-Lenhart syndrome complicated by thyroid eye disease and was treated with methimazole followed by thyroidectomy and orbital decompression. We review the existing literature and propose criteria for the diagnosis and treatment of this condition. PMID- 30473891 TI - Type 2 Diabetes Mellitus, a Sequel of Untreated Childhood Onset Growth Hormone Deficiency Developing in a 17-Year-Old Patient. AB - In a seminal report, a 17-year-old boy with panhypopituitarism had fatty liver (FL) amelioration with growth hormone (GH). By extension, since hepatic insulin resistance (IR) is key to FL and type 2 diabetes mellitus (T2DM), GH then may ameliorate the IR of T2DM. We present a 17-year-old nonobese female with untreated childhood onset growth hormone deficiency (CO-GHD) who developed type 2 diabetes mellitus (T2DM) and steatohepatitis with bridging fibrosis. Based on height z-score of - 3.1 and a history of radiation therapy as treatment for a medulloblastoma at 7 years of age, GHD was quite likely. GH therapy was, however, not initiated at 15 years of age (when growth was concerning) based on full skeletal maturity. After she developed T2DM, GHD was confirmed and GH was initiated. With its initiation, though insulin dose decreased from 2.9 (~155 units) to 1.9 units/kg/day (~ 100 units), her T2DM was, however, not fully reversed. This illustrates the natural history of untreated CO-GHD and shows that though hepatic IR can be ameliorated by GH, full reversal of T2DM may be prevented with irreversible hepatic changes (fibrosis). Clinicians caring for pediatric patients and otherwise should remember that, even in patients beyond the cessation of linear growth, GH can have a crucial role in both glucose and lipid metabolism. PMID- 30473893 TI - Progressive Intramuscular Haematoma in a 12-Year-Old Boy: A Case of Acquired Haemophilia A. AB - Acquired hemophilia A (AHA) is a rare bleeding disorder due to acquired antibodies against coagulation factor VIII (FVIII). It is rare in children less than 16 years old, and the incidence is 0.45/million/year. An otherwise healthy, 12-year-old boy was admitted to the ward with a history of swelling of the right and left forearms, for 1 day duration. He did not have any history of trauma or bleeding disorder. He had prolonged APPTT level with very high antibody titer against factor VIII. His gene expression for factor VIII was found to be normal. He was managed with FEIBA and recombinant FVII activated complexes and prednisolone 1 m/kg/day regime to control bleeding. AHA is associated with several underlying pathologies such as pregnancy, autoimmune diseases, malignancy, medications and infections; however, up to 50% of reported cases are idiopathic. In contrast to congenital haemophilia A, in which haemarthrosis is the hallmark clinical presentation, patients with AHA mainly bleed in to the skin, muscles, and soft tissues. High mortality rate of more than 20% is either to retroperitoneal or intracranial bleeds. Diagnosis is confirmed on isolated prolongation of activated partial thromboplastin time which does not normalize after addition of normal plasma, reducing the factor VIII levels with evidence of FVIII inhibitor activity. They have normal prothrombin time and platelet functions. Management of AHA involves two aspects, namely, eradication of antibodies and maintaining effective haemostasis during a bleeding episode. PMID- 30473892 TI - Exome Sequencing Identifies a Novel Sorting Nexin 14 Gene Mutation Causing Cerebellar Atrophy and Intellectual Disability. AB - The autosomal recessive cerebellar ataxias (ARCA) affect both the central and the peripheral nervous systems. They are also characterized by a relatively high level of genetic heterogeneity with well over 40 genes already implicated. The present study aimed to identify the gene mutation responsible for a complex phenotype comprising cerebellar ataxia and intellectual disability segregating in an Omani consanguineous family. Homozygosity-guided exome data analysis identified a novel frameshift mutation (c.2319_2322del) within the sorting nexin 14 gene (SNX14), which predicts complete absence of the SNX14 encoded protein. Segregation within the family of the sequence variation is consistent with its pathogenic role. Importantly, loss-of-function mutations in SNX14 have recently been described as a cause of a clinically distinguishable recessive syndrome consisting of cerebellar atrophy, ataxia, coarsened facial features, and intellectual disability. This study expands the genetic diversity of ataxia genes in the Omani population and have important implications for the clinical and molecular diagnosis of this condition in affected individuals. PMID- 30473894 TI - Swimming with the Pigs: A Case of Severe Soft Tissue Infection during a Caribbean Vacation. AB - A 74-year-old man presented to the emergency department with severe right leg cellulitis following a trip to the Bahamas where he swam in both chlorinated pools and the ocean. His blood cultures grew Shewanella species, a marine pathogen known to cause disease in humans, following exposure to seawater. He was treated with cefepime for a total of two weeks without needing any surgical intervention. The patient had complete resolution of infection and was able to return to his activities of daily living. PMID- 30473895 TI - Unusual Case of an Infant with Urinary Tract Infection Presenting as Cholestatic Jaundice. AB - Neonatal jaundice is considered one of the most common reasons for admission to the pediatric medical ward. We report a case of a 1-month-old infant who presented with jaundice but no fever or any other signs of systemic illnesses. Laboratory test results revealed high direct hyperbilirubinemia, and urine culture showed a urinary tract infection with Enterobacter cloacae as the causative agent. He was admitted to the pediatric medical ward where he was treated with a course of antibiotics for 14 days, and cholestasis resolved completely following a course of antibiotics. We conclude that direct hyperbilirubinemia can be related to urinary tract infection in neonates. It is unusual for urinary tract infection to present clinically and biochemically as cholestatic jaundice. PMID- 30473896 TI - Another Case of Multilevel Cervical Disconnection Syndrome Presenting as Neonatal Encephalopathy. AB - Multilevel cervical disconnection syndrome (MCDS) is a rare malformation of the cervical spine previously documented in two toddlers. We present a case of a newborn first thought to have hypoxic-ischemic encephalopathy who was subsequently diagnosed with MCDS. The possibility of in utero presentation of the syndrome in this patient and the categorization of this syndrome in the spectrum of basilar skull/upper cervical malformation syndromes is discussed. PMID- 30473897 TI - Vesicouterine Fistula (VUF) as a Rare Urogenital Complication Managed with Delayed Surgical Repair: A Case Report and Review of the Literature. AB - Vesicouterine fistula (VUF) represents a rare urogenital complication. It is considered to be the least common type of urogenital fistulas. Iatrogenic reasons have been shown to be the most prominent cause, with lower segment caesarean section accounting for approximately two-thirds of the cases. The highest incidence concerns young females of reproductive age. VUF can present with clinical symptoms varying from cyclic hematuria, amenorrhea, and vaginal leakage of urine to secondary infertility and first-trimester abortion. Quality of life (QoL) for patients having this pathology is strongly affected due to the psychological burden. Surgical excision of the fistula remains the mainstay of treatment, as less than 5% of patients respond to conservative therapy. Recently laparoscopic and robotic-assisted VUF repair started gaining ground with comparable results to open surgery. Herein, we presented the successful delayed surgical repair of VUF in a 32-year-old female patient. A review of the published literature was also performed, summarizing all the available evidence regarding this rare clinical entity. PMID- 30473898 TI - Unusual Presentation of Follicular Dendritic Cell Sarcoma as a Cystic Neck Swelling. AB - Follicular dendritic cell sarcoma is a very rare neoplasm that most commonly involves cervical lymph nodes and usually presents as a solid mass. Presentation as a cystic neck mass is very rare. Radiological studies and aspiration cytology are often unreliable, and diagnosis is usually made after thorough clinical and pathological examination along with immunohistochemical analysis. In this article, we report a case of a 42-year-old man who presented with right-sided neck swelling of a 2-month duration. Contrast-enhanced CT showed a cystic lesion in the right side of the neck inferomedial to parotid gland located between medial border of sternocleidomastoid muscle and internal jugular vein. Fine needle aspiration cytology was inconclusive. Patient underwent excision biopsy. Histological examination showed a solid-cystic tumor composed of spindle cells arranged in storiform pattern and showed a positive staining for CD23, CD35, and CD21 that confirmed the diagnosis of follicular dendritic cell sarcoma. PMID- 30473899 TI - Nontraumatic Parapharyngeal Haematoma: A Rare Lesion. AB - Nontraumatic haematoma of parapharyngeal space is very rare and may cause dysphagia and dyspnea. The authors present a case report of a 74-year-old woman with sudden nontraumatic neck swelling without dyspnea and with left pharyngeal bulging and endolaryngeal displacement. Parathyroid hormone elevation and imaging exams confirmed bleeding from a parathyroid adenoma. Symptoms and signs resolved after one week of conservative treatment. There are few cases of parapharyngeal haematomas caused by parathyroid adenomas. Most patients can be managed without emergent surgery, but close airway monitoring is fundamental. PMID- 30473900 TI - Case Report of Atypical Juxtaglomerular Cell Tumor. AB - Juxtaglomerular cell tumor (JGCT) is a rare renal tumor, producing renin and behaving almost in a benign fashion. So far, only three cases have been reported as malignant. We report a rare case with atypical JGCT. A 74-year-old male was referred to our hospital due to hypertension, proteinuria, and hematuria. Abdominal CT revealed a mass measured in 9.7*7.0 cm in the lower portion of the right kidney. Right kidney was removed laparoscopically. Grossly, white to tan tumor with massive hemorrhage and necrosis occupied the lower portion of the right kidney. Microscopically, tumor grew in a solid fashion. Tumor cells were polygonal to ovoid cells with round nuclei and clear to eosinophilic cytoplasm. Mitosis was found in 5 per 10 HPF. Immunohistochemically, tumor cells were stained by vimentin and CD34. Some tumor cells were also positive for renin. Electron micrograph showed near rhomboid crystalline structure in the tumor cells. Because of massive necrosis and mitotic figures, diagnosis of atypical (potentially malignant) JGCT was rendered. Gene mutations for IDH1, PIK3CA, K ras, N-ras, Braf, and EGFR were not found by MBP-QP system. PMID- 30473901 TI - Unilateral Thalamic Venous Infarction in an Infant: A Rare Presentation of Bilateral Deep Cerebral Venous Thrombosis. AB - Cerebral venous thrombosis (CVT) may manifest as superficial cerebral venous thrombosis (SCVT) or deep cerebral venous thrombosis (DCVT). Of the two patterns, DCVT is less commonly observed, although it often results in greater morbidity and mortality due to involvement of the deep gray nuclei. It can present at any age and typically results in edema of the bilateral thalami, with occasional extension into the basal ganglia. Unilateral thalamic infarct is rare and results in an ambiguous imaging pattern. We present the clinical and neuroimaging profile of an acute unilateral thalamic venous infarct in an infant secondary to bilateral DCVT. Early recognition of this atypical pattern will facilitate accurate diagnosis and treatment, and obviate the need for unnecessary interventions. PMID- 30473902 TI - Metastatic Small Cell Carcinoma of the Urinary Bladder That Recurred in the Vagina 6 Years after Radical Cystectomy: A Case Report. AB - Small cell carcinoma (SCC) of the urinary bladder is highly aggressive and portends a poor outcome. Herein, we report a patient with recurrent SCC of the urinary bladder who experienced an unusually long-term disease-free duration after radical cystectomy. The patient was a 60-year-old woman who had undergone transurethral resection followed by radical cystectomy for muscle-invasive bladder cancer (high-grade urothelial carcinoma with adenocarcinomatous differentiation) 6 years prior; the surgical specimen had a negative surgical margin. She was referred to our hospital because of continuous bleeding from her vagina. Magnetic resonance imaging showed a mass located at the anterior wall of her residual vagina, a biopsy of which confirmed a pathological diagnosis of adenocarcinoma. The vaginal tumor and a section of the sigmoid colon were resected en bloc and were pathologically diagnosed as adenocarcinoma and SCC. We reevaluated the initial transurethral resection specimen and found SCC with foci of adenocarcinoma concomitant with high-grade urothelial carcinoma. Local recurrence and metastasis at the pelvic bone occurred 4 months later; although radiation therapy was performed, she died of the progressive disease. PMID- 30473903 TI - A Comparison of Gender Differences in Smoking Behaviors, Intention to Quit, and Nicotine Dependence among Thai University Students. AB - Background: Smoking is the leading cause of preventable death. In Thailand, the prevalence of smoking is about 15-20 times higher among men than women. This study aimed to investigate gender differences among university students concerning smoking behaviors, nicotine dependence, and intention to quit smoking. Methods: A self-administered questionnaire was used to collect information from participants who were current smokers studying at a university in northern Thailand. Snowball sampling was used to recruit participants. Results: Of 364 participants, there were 321 males and 43 females. This study showed higher smoking behaviors among males than females; males were more likely to smoke every day than females (67.0 and 41.9%, respectively, p value=0.002), and the average number of cigarettes daily was higher among males than females (8.4 and 5.5, respectively, p value=0.006). The sources of cigarettes differed between males and females. The nicotine dependence level, as measured by the Fagerstrom Test for Nicotine Dependence, was quite low in both male and female smokers and did not differ significantly (mean score of 2.3+/-2.2 for males, 1.8+/-1.8 for females; p value=0.123). Females were more likely than males toward intention to quit in the next 30 days (51.2 and 34.0%, respectively, p value=0.041). The most common reason for intention to quit was awareness of harm to health, for which females were more concerned than males. Conclusion: Male and female university students who smoked differed in smoking behaviors and intention to quit, but not in nicotine dependence level. The university should provide health promotion to help students quit smoking. PMID- 30473904 TI - Higher education as a platform for capacity building to address violence against women and promote gender equality: the Swedish example. AB - Violence against women is an acknowledged public and global health problem which has adverse consequences for women's health. Education, especially higher education, has long been identified as an important arena for addressing the problem and promoting gender equality. Two measures recently put in place in the Swedish higher education have brought the role of the sector into focus. The first is the inclusion of gender equality as a measurable outcome in quality assurance in higher education. The second measure is the amendment of the Swedish Higher Education Ordinance to include mandatory knowledge of VAW in the degree programme of seven selected relevant professional groups. The potentials of both measures to positively contribute to the gender equality discourse, as well as improving capacity building for the public health workforce who encounter VAW, are discussed. PMID- 30473905 TI - Pregnancy after Aortic Root Replacement in Marfan's Syndrome: A Case Series and Review of the Literature. AB - Objectives We sought to characterize pregnancy-related aortic complications in women with Marfan's syndrome who had prior aortic root replacement. Study Design This is a retrospective case series study and literature review of women with Marfan's syndrome with pregnancy after aortic root replacement. We surveyed women with Marfan's syndrome who had successful pregnancy after aortic root replacement using the Marfan Foundation Website and from two large tertiary care Marfan's clinics. Clinical data, counseling information, and details of pregnancy-related aortic complications were compiled. A literature review was performed assessing aortic outcomes in women with Marfan's syndrome with pregnancy after aortic surgery. Results Fourteen women with 20 pregnancies were identified. Two women had three pregnancies following root replacement for aortic dissection. There were no aortic dissections during the 20 pregnancies. In contrast, aortic dissection was frequently reported in the literature. Conclusions Women with Marfan's syndrome who become pregnant following aortic root replacement remain at risk for distal aortic dissection related to pregnancy. The exact risk is difficult to quantify but is not zero and women should be counseled accordingly. PMID- 30473906 TI - Introduction of Posterior Axilla Sling Traction in Simulated Shoulder Dystocia. AB - Objective Aim of this study was to introduce posterior axilla sling traction (PAST) in delivering providers and nursing staff as an adjunct to the management of shoulder dystocia and evaluate comfort in performing the maneuver. Methods A presimulation questionnaire had given to all participants. A brief training on how to perform PAST was also given. A simulated shoulder dystocia was run where usual maneuvers failed. Participants used PAST for delivery of posterior shoulder, delivery of posterior arm, and to assist with rotation. Participants were then given a post-simulation questionnaire. A Chi-squared test was used to evaluate comfort with performing the procedure pre and post-simulation. Results Data were collected from 43 participants at pre and post-simulation. Designations (attending, resident, midwife, registered nurse) and responses were recorded to the questionnaires. There was a statistically significant increase in the number of providers and nurses who would feel comfortable using PAST for shoulder dystocia management and for rotational maneuvers. Ninety-three percent of participants would consider using PAST in future shoulder dystocia when usual maneuvers failed. Conclusion PAST is an adjunct to management of shoulder dystocia that has not previously been taught in our facility. The majority of participants in our simulation felt comfortable with using PAST. PMID- 30473907 TI - Bromocriptine Use in Peripartum Cardiomyopathy: Review of Cases. AB - Objective This study is to review published cases of peripartum cardiomyopathy (PPCM) treated with bromocriptine and outline pros and cons of the treatment strategy. Data Sources Data were collected from PubMed/MedLine, ClinicalTrials.gov; the years 2007 to 2018 were searched for English-language articles. Search terms: "bromocriptine and peripartum cardiomyopathy", "bromocriptine and cardiomyopathy." Methods of Study Selection This search strategy yielded 171 articles. After excluding duplicates, 86 studies were reviewed. Sixty-one articles involving the treatment of PPCMP were included, and of these, 17 were case reports of patients with PPCMP treated with bromocriptine; these studies were included in this review. Tabulation, Integration, and Results Seventeen of these articles were case reports of patients with peripartum cardiomyopathy treated with bromocriptine that were included. Conclusion Bromocriptine seems to be a promising treatment, there is currently insufficient evidence for universal utilization of bromocriptine for all patients with PPCMP. Addition of bromocriptine to the standard heart failure therapy should be individualized. PMID- 30473908 TI - Intermittent vs Continuous Administration of Nerve Growth Factor to Injured Medial Septal Cholinergic Neurons in Rat Basal Forebrain. AB - Many medial septal neurons of the basal forebrain are dependent on nerve growth factor (NGF) from the hippocampus for survival and maintenance of a cholinergic phenotype. When deprived of their source of NGF by axotomy, medial septal neuronal cell bodies atrophy and lose their cholinergic markers. This is similar to what is observed in the basal forebrain during Alzheimer's disease (AD). In the present study, medial septal neurons were axotomized in female rats by way of a fimbria/fornix lesion. For fourteen days following axotomy, varying NGF doses (1 - 250 MUg/ml) were administered to the lateral cerebral ventricle with either mini-osmotic infusion or daily injection. The responsiveness of medial septal neurons was evaluated with choline acetyltransferase immunohistochemistry. Within the mini-osmotic pumps, NGF activity diminished greatly during the first five days of implantation, but increased dramatically in the CSF after five days of infusion. The responsiveness of medial septal neurons to NGF was dose dependent and the ED50 for NGF injection was determined to be 14.08 MUg/ml compared to 27.60 MUg/ml for NGF infusion. Intermittent injections at varying intervals were evaluated with 30 MUg/ml NGF over a fourteen-day time period (2, 3, 6, or 12 injections). No differences occurred in the number of choline acetyltransferase neurons from rats that received weekly injections to those that received daily injections of NGF. NGF administration has been suggested as a therapy for AD. The results of these studies continue to highlight the need for NGF stability within the delivery system and AD patient CSF, the choice of delivery system, frequency of administration, and the NGF dose for maintaining basal forebrain cholinergic neurons during AD. PMID- 30473909 TI - Anteverting Periacetabular Osteotomy for Acetabular Retroversion. AB - Introduction: The periacetabular osteotomy procedure reorients a retroverted acetabulum into a more anatomically appropriate position. Step 1 Evaluation of Acetabular Retroversion: Evaluate acetabular retroversion on the basis of a combination of radiographic signs. Step 2 Patient Positioning and Skin Incision: After draping and sterile preparation with the patient in a supine position, make an incision following the skin lines of the inguinal fold. Step 3 Exposure of the Deep Muscle Layers and the Pelvic Brim: Detach the abdominal wall muscles from the anterior iliac crest and detach the sartorius muscle and the inguinal ligament to expose the iliac fossa and the pelvic brim. Step 4 Surgical Dissection for Preparation of the Ischial Osteotomy: Detach the iliocapsularis muscle and mobilize it medially to allow access to the infra-articular space and palpation of the ischial bone. Step 5 Incomplete Partial Ischial Osteotomy: Introduce a curved chisel with a crescent-shaped tip into the infra-articular space in order to perform the osteotomy of the ischial bone. Step 6 Osteotomy of the Superior Pubic Ramus: Place subperiosteal blunt retractors around the superior pubic ramus to ensure safe and complete pubic bone osteotomy. Step 7 Supra-Acetabular and Retroacetabular Osteotomy: Start the supra-acetabular horizontal osteotomy at the anterior superior iliac spine and end it 2 cm lateral to the pelvic brim, where the osteotomy is angled 100 degrees distally. Step 8 Mobilization of the Acetabular Fragment: With the help of a spreader and a 4.5-mm threaded Schanz pin, free and mobilize the acetabular fragment. Step 9 Reorientation of the Acetabular Fragment: Perform internal rotation of the acetabular fragment with the help of the threaded Schanz pin. Step 10 Improvement of Anterior Head-Neck Offset Femoral Neck Osteoplasty: Anterior capsulotomy and improvement of anterior head-neck offset is recommended when internal rotation is <30 degrees . Step 11 Anteroposterior Pelvic Radiograph Following Periacetabular Osteotomy: Ideally, a postoperative radiograph should show negative crossover and posterior wall signs while the ischial spine sign typically remains positive. Results: The long-term results of the periacetabular osteotomy in a series of twenty-two patients (twenty-nine hips) with symptomatic acetabular retroversion were evaluated after a mean duration of follow-up of eleven years (range, nine to twelve years).IndicationsContraindicationsPitfalls & Challenges. PMID- 30473910 TI - Essential Surgical Technique for French-Door (Double-Door) Laminoplasty. AB - Introduction: We describe the surgical technique and the pitfalls of French-door laminoplasty. Step 1 Patient Positioning: Position the patient to keep the cervical spine "parallel to the floor" or in the "reverse Trendelenburg position" with only a slight incline and place intraoperative neurological monitors to prevent intraoperative neurological deterioration. Step 2 Surgical Approach: Use the common cervical posterior approach to expose the lamina and ligamentum flavum. Step 3 Create Grooves: Cut the center of each lamina and create bilateral grooves using a high-speed burr. Step 4 Open the Lamina: Open the lamina bilaterally and create a small hole in each one using a high-speed burr. Step 5 Create Bone Struts: Create bone struts from the spinous processes and tie them to each lamina. Step 6 Wound Closure: Perform meticulous closure of the wound to avoid wound-healing complications. Results: In our original study12, we treated forty-six patients with French-door laminoplasty and compared the surgical results of this procedure with those of open-door laminoplasty in a prospective, randomized controlled manner.IndicationsContraindicationsPitfalls & Challenges. PMID- 30473911 TI - Internal Fixation of Posterior Pelvic Ring Injuries Using Iliosacral Screws in the Dysmorphic Upper Sacrum. AB - Introduction: The correct usage of preoperative and intraoperative imaging allows fixation of posterior pelvic ring injuries with safely positioned iliosacral screws in the setting of sacral dysmorphism. Step 1 Preoperative Planning: Obtain CT reformats along the longitudinal axis of the sacrum to determine the orientation and diameter of the osseous corridor for selection of the ideal screw size, length, and trajectory. Step 2 Patient Positioning: Proper positioning enables reduction and accurate iliosacral screw placement. Step 3 Fracture Reduction: Reduction of the posterior pelvic ring confers stability; if closed reduction is unsuccessful, proceed with open reduction. Step 4 Identification of the Entry Point: The entry point for an iliosacral screw into the upper sacral segment of a dysmorphic pelvis lies more posterior and caudal on the outer table of the posterior ilium than does a transsacral screw; adjust the entry point on the basis of inlet and outlet fluoroscopic views. Step 5 Drilling Technique: Insert a stout cannulated drill bit of 4.5 to 5 mm (depending on the core diameter of the intended iliosacral screw) over the Kirschner wire and drill it into the sacral body under fluoroscopic guidance, in accordance with the preoperative plan. Step 6 Screw Insertion: With the guidewire in the ideal position, measure the screw length off the inserted guidewire and advance a tap into the pathway; insert the screw and verify its position on the inlet, outlet, and lateral sacral views. Results: Understanding the three-dimensional anatomy of the posterior pelvic ring is essential to successful reduction and fixation of unstable pelvic injuries with use of percutaneous iliosacral screws.IndicationsContraindicationsPitfalls & Challenges. PMID- 30473912 TI - Crista Supinatoris Fractures of the Proximal Part of the Ulna: Surgical Technique. AB - Introduction: Open reduction and internal fixation of crista supinatoris fractures is required when the elbow is unstable despite appropriate nonoperative management and when a patient is undergoing surgical treatment of a periarticular elbow fracture-dislocation. Step 1 Skin Incision and Surgical Approach: Use a posterior or lateral skin incision according to your preference and then utilize the Kocher interval to access the joint, lateral collateral ligament, and crista supinatoris or, in the setting of a proximal ulnar fracture, use the Boyd interval. Step 2 Management of Associated Injuries: Crista supinatoris fractures have not been identified in isolation; address associated injuries such as radial head/neck fractures, capitellar fractures, and coronoid fractures first. Step 3 Evaluation of Elbow Stability: If elbow instability persists after the concomitant injuries have been addressed, fix the crista supinatoris. Step 4 Exposure of the Crista Supinatoris: Expose the fracture fragment and base of the crista supinatoris. Step 5 Reduction and Fixation of the Crista Supinatoris Fracture: Obtain an anatomic reduction and fixation of the crista supinatoris fracture to appropriately tension the lateral ulnar collateral ligament. Step 6 Reevaluation of Elbow Stability: Gently evaluate the stability of the elbow following repair of the crista supinatoris fracture. Step 7 Postoperative Care: Initiate rehabilitation on the basis of intraoperative stability and concomitant injuries. Results: We recently conducted a retrospective review of the outcomes of twelve patients with a fracture of the crista supinatoris.IndicationsContraindicationsPitfalls & Challenges. PMID- 30473913 TI - Arthroscopic Treatment of Suprascapular Neuropathy from a Suprascapular Notch Cyst Using a Lateral Subacromial Approach. AB - Introduction: We describe a safe surgical technique for arthroscopic decompression of a suprascapular notch cyst in the setting of compressive suprascapular neuropathy. Step 1 Position the Patient: Position the patient in the standard beach-chair position. Step 2 Mark Anatomic Landmarks: Palpate and mark the subcutaneous landmarks of the shoulder in preparation for later arthroscopy. Step 3 Diagnostic Arthroscopy: Create standard anterior and posterior portals for glenohumeral visualization. Step 4 Perform Suprascapular Cyst Decompression Through a Lateral Subacromial Approach: Establish accessory superior and lateral portals and transition to a lateral viewing portal to perform suprascapular notch decompression. Step 5 Release the Transverse Scapular Ligament: Establish a G Portal and release the transverse scapular ligament using arthroscopic scissors. Step 6 Closure: Perform arthroscopic lavage of the subacromial space and glenohumeral joint and close arthroscopic portals. Results: As suprascapular nerve entrapment is a relatively rare entity, with only a limited number of studies from which to draw conclusions regarding the outcomes of arthroscopic suprascapular nerve release, Shah et al. recently reported on their results in twenty-four patients using this surgical technique.IndicationsContraindicationsPitfalls & Challenges. PMID- 30473914 TI - Intracompartmental Pressure Monitoring Using a Handheld Pressure Monitoring System. AB - Introduction: We describe the correct technique for measuring compartment pressure with a handheld device to diagnose compartment syndrome. Step 1 Device Preparation: Proper preparation of the handheld pressure monitoring device (Stryker Surgical, Kalamazoo, Michigan) is critical to ensure that the device performs appropriately. Step 2 Identification of the Compartment of Interest: The needle must be placed in the proper location to appropriately measure a compartment's pressure. Step 3 Injection: Inject saline solution from the pressure monitoring device to clear any soft tissue from the side port on the needle that could result in inaccurate pressure measurements. Step 4 Stabilization and Pressure Reading: The pressure must reach a stable state before it is recorded; different pressure thresholds for decompression have been recommended in the literature. Step 5 Repeat Measurements: As mistakes can be made with any single measurement, accuracy may be improved by repeating steps 1 through 4 and averaging the results. Step 6 Additional Compartments: After the reading is obtained, move on to any additional compartment(s) that need to be evaluated, repeating the steps listed above. Results: The handheld intracompartmental monitoring device with a side-ported needle has been shown to be extremely accurate in the laboratory.IndicationsContraindicationsPitfalls & Challenges. PMID- 30473915 TI - Revision Total Ankle Replacement. AB - Introduction: The technique for revision total ankle replacement described in this article addresses the subsidence and loosening that occur when an Agility total ankle replacement fails. Step 1 Indications and Contraindications: The main indications for revision total ankle arthroplasty include loosening and subsidence of the talar component, with no limit to the extent of subsidence or loss of talar bone stock as neither precludes use of a revision system, particularly when a flat cut on the talus can be made. Step 2 Anterior Incision and Joint Exposure: Make the incision employing the prior anterior midline incision, create full-thickness flaps of tissue to diminish the risk of wound dehiscence, and completely expose and debride the joint as this is critical to revising the total ankle replacement correctly. Step 3 Remove the Talar Component and Polyethylene: Remove the talar component, which is rarely difficult as it is usually loose. Step 4 Remove the Tibial Component: When removing the tibial component, it is critical to preserve as much of the anterior tibial cortex as possible to provide support for the revision tibial component. Step 5 Make the Tibial Bone Cut: Tibial cuts can be made proximal or distal to tibial osseous defects. Step 6 Make the Talar Bone Cut: It is preferable to use a cutting block for the talus that attaches to the tibial guide. Step 7 Managing Loosening and Cavitary Defects: If there is substantial bone loss around the tibia after component removal, consider impaction bone-grafting, as better bone quality makes it is easier to obtain a press fit and allow immediate weight-bearing. Step 8 Place Trial Components: Size the tibia and talus and subsequently insert the tibial and talar trials and polyethylene simultaneously. Step 9 Cementing Technique: In revision settings, manual cement insertion is important because there is no medullary canal to work around. Results: We previously reported the outcomes of revision of failed Agility total ankle replacements (DePuy, Warsaw, Indiana) in forty-one patients.Pitfalls & Challenges. PMID- 30473916 TI - Single-Stage Treatment Protocol for Presumed Aseptic Diaphyseal Nonunion. AB - Introduction: This article describes the general surgical technique for treating presumed diaphyseal nonunion with a one-stage procedure involving intraoperative removal of specimens for culture, revision open reduction and internal fixation (ORIF) with a plate or nail, and bone-grafting. Step 1 Preoperative Evaluation: Take a careful history, evaluate the extremity and wound, and note comorbidities and medications. Step 2 Preoperative Planning: Preoperative planning is essential before revision nonunion surgery. Step 3 Debridement Implant Removal and Cultures: Debride the nonunion site, remove all failed and loose implants, and take specimens for culture; withhold antibiotics until all culture specimens have been obtained. Step 4 Open Reduction and Internal Fixation: Reduce the fracture and use interfragmentary fixation and/or compression, or a bridging plate. Step 5 Postoperative Care: If any of the five cultures are positive, consult an infectious disease specialist with experience in treating musculoskeletal infections. Results: We have used this protocol at our institution for patients with prior fracture surgery who subsequently developed a nonunion, with or without implant failure, that had no obvious infectious etiology.IndicationsContraindicationsPitfalls & Challenges. PMID- 30473917 TI - Distal Tibial Osteotomy without Fibular Osteotomy for Medial Ankle Arthritis with Mortise Widening. AB - Introduction: A patient with medial ankle osteoarthritis and a widened ankle mortise can be treated successfully with an oblique distal tibial osteotomy, without fibular osteotomy, to narrow the mortise and shift the weight-bearing axis to a more normal position. Step 1 Patient Positioning and Preoperative Assessment: With the patient under spinal or general anesthesia, check for mortise widening with a valgus stress test. Step 2 Surgical Approach: Expose the ankle joint through an anterior approach. Step 3 Corrective Osteotomy: Perform an oblique osteotomy of the distal part of the tibia and narrow the widened mortise by shifting the osteotomized fragment. Step 4 Fixation and Bone-Grafting: Stabilize the osteotomy site with a locking plate and apply bone graft to the osteotomy site. Step 5 Closure: Close the soft tissue in layers. Results: Eighteen patients (fifteen female and three male; mean age, fifty-seven years) with symptomatic medial ankle osteoarthritis and mortise widening underwent distal tibial oblique osteotomy without fibular osteotomy between 2008 and 2011.IndicationsContraindicationsPitfalls & Challenges. PMID- 30473918 TI - Percutaneous Fixation of Proximal Humeral Fractures. AB - Introduction: The percutaneous approach to proximal humeral fixation emphasizes minimum dissection with the goal of preserving vascularity of the articular segments and thereby decreasing the risk of osteonecrosis. Step 1 Preoperative Planning: Perform preoperative imaging to assess fracture displacement and comminution in order to confirm that percutaneous treatment is appropriate. Step 2 Closed Fracture Reduction: Attempt closed fracture reduction prior to incision. Step 3 Surgical Approach for Humeral Head and Shaft Reduction: Obtain anatomic humeral head reduction, insert terminally threaded pins, and check pin placement fluoroscopically. Step 4 Tuberosity Fracture Reduction and Fixation of the Tuberosity Fragments: Fix the tuberosity fracture(s). Step 5 Wound Closure: Cut the pins below the skin and irrigate and close the wounds. Step 6 Postoperative Rehabilitation: Begin passive shoulder motion after pin removal, and initiate active motion at six weeks after pin removal. Results: The results of this technique in twenty-seven patients with an average age of 58.8 years (range, forty-two to seventy-six years) at the time of injury were reported previously6.IndicationsContraindicationsPitfalls & Challenges. PMID- 30473919 TI - Surgical Treatment of Severe Cavovarus Foot Deformity in Charcot-Marie-Tooth Disease. AB - Introduction: A successful adjusted treatment algorithm for the correction of cavovarus foot deformity requires soft-tissue balancing procedures, in particular total split posterior tibial tendon transfer (T-SPOTT), in combination with adjunctive corrective procedures depending on the degree of deformity. Step 1 Surgical Preparation: Place the patient in a supine position and follow a standard aseptic surgical disinfection and draping protocol, allowing access to the iliac crest. Step 2 Steindler Release of the Plantar Aponeurosis: Use a medial approach to access and transect the plantar aponeurosis. Step 3 Release the Posterior Tibial Tendon at the Foot: Transect the posterior tibial tendon near its insertion point. Step 4 Retract and Split the Posterior Tibial Tendon at the Calf and Transfer It Through the Interosseous Membrane: Make a medial incision in the distal part of the calf, retract the posterior tibial tendon (and flexor digitorum tendon if necessary), split it longitudinally in half, and pass it through the interosseous space. Step 5 Reveal the Target Tendons and Pull the Posterior-Tibial-Tendon Halves to These Tendons: Expose the anterior tibial and peroneal tendons and pull the posterior-tibial-tendon halves (and flexor digitorum longus tendon of it is being used) to these tendons. Step 6 Chopart or Triple or Lambrinudi Arthrodesis: Perform a Chopart, or triple or Lambrinudi 16 , arthrodesis when osseous correction and stabilization are required for fixed deformities. Step 7 Modified Jones Procedure: If the cavovarus foot displays flexible clawing of the big toe, carry out a modified Jones procedure. Step 8 Extension Osteotomy of the First Metatarsal: If the first metatarsal remains in a fixed plantar flexed position and cannot be corrected with the Jones procedure, perform a dorsal-based wedge extension osteotomy. Step 9 Clawing of the Lesser Toes: Incise the plantar tendons, transect the long flexor tendons, and place a single Hohmann wire through the end of each claw toe. Step 10 Soft-Tissue Equinus Correction Rarely Needed: Depending on the severity of the remaining equinus, correct it with calf muscle or calcaneal tendon lengthening (the more severe the equinus, the more distal the corrective measure). Step 11 Supramalleolar Varus Derotation Osteotomy: If foot external rotation is increased after foot correction, supramalleolar derotation osteotomy should be added to avoid lever arm problems postoperatively. Step 12 Complete the Tendon Transfers: Attach the transferred tendons to their respective target tendons using a Pulvertaft needle with a Pulvertaft weave technique, while keeping the foot in a plantigrade position. Step 13 Wound Closure: Reevaluate the foot and determine if all corrections have been made, perform necessary final radiographic documentation, release the tourniquet, perform hemostasis, clean the wounds, and close them. Step 14 Postoperative Management and Aftercare: The achieved operative correction is only as good as the postoperative treatment allows. Results: Various authors have recommended posterior tibial tendon transfer to the dorsum of the foot to correct foot drop.IndicationsContraindicationsPitfalls & Challenges. PMID- 30473921 TI - Two-Incision Minimally Invasive Approach for the Treatment of Anterior Column Acetabular Fractures. AB - Introduction: We describe an alternative to the Letournel ilioinguinal approach for anterior column acetabular fractures that is performed with a unique retraction device that decreases the rate of soft-tissue complications. Step 1 Position the Patient and Identify the Sites for the Incisions: Identify the sites for both incisions with the help of an image intensifier. Step 2 Make the First Incision to Expose the Anterior Column and the Linea Terminalis Pelvic Brim: Make the first incision to expose the central area of the fracture. Step 3 Make the Second Incision to Expose the Symphysis and the Ipsilateral Pubic Bone: Make the second incision to expose the area for the distal plate fixation. Step 4 Maintain Exposure of the Linea Terminalis Using a Soft-Tissue Retraction System: For better visualization, use a soft-tissue retraction system. Step 5 Reduce the Fracture: Clean and reduce the fracture through the first incision. Step 6 Fix the Fracture: Perform temporary and definitive fixation according to the standards for anterior acetabular fracture fixation. Step 7 Close the Wound: After radiographic documentation in three views, close the wound. Results: We reported the results of a case-control study of the first twenty-six patients operated on with the two-incision minimally invasive technique.IndicationsContraindicationsPitfalls & Challenges. PMID- 30473920 TI - Expansion Thoracoplasty for Thoracic Insufficiency Syndrome Associated with Jarcho-Levin Syndrome. AB - Introduction: Although surgical treatment of spondylothoracic dysplasia (STD) is controversial, we have found that an expansion thoracoplasty using a Vertical Expandable Prosthetic Titanium Rib (VEPTR; DePuy Synthes) results in favorable outcomes, including 100% survivability (at an average follow-up of 6.2 years), increased thoracic spinal length, and decreased requirements for ventilation support. Step 1 Preoperative Preparation: Make anteroposterior and lateral radiographs of the spine. Step 2 Position the Patient for the Procedure: The patient is placed in the prone position. Step 3 The Incision: A curvilinear skin incision is made, starting proximally between the spine and the medial edge of the scapula. Step 4 The Osteotomy: Perform the v-osteotomy. Step 5 Placement of the VEPTR Device: A number-4 VEPTR-I device is wedged in, starting laterally within the osteotomy sites, wedging the osteotomies apart, distracting the superior ribs proximally and the inferior ribs distally, lengthening the hemithorax, and stopping approximately at the posterior axillary line, when there is maximum stress on the superior and inferior ribs, to avoid fracture, and the lamina spreaders are then removed. Step 6 Wound Closure: Insert drains and local anesthetic catheters and close the wound. Step 7 Expansion and Replacement Procedures: Lengthen the devices with the standard VEPTR technique of limited 3 cm incisions every three to six months. Results: VEPTR treatment in patients with STD is associated with increased thoracic spine height and reduced thoracic width to-height ratio, suggesting a greater gain in height than in width. What to Watch For: IndicationsContraindicationsPitfalls & Challenges. PMID- 30473922 TI - Essential Surgical Technique for Arthroscopic Capsular Release in the Treatment of Shoulder Stiffness. AB - Introduction: Among many treatments for shoulder stiffness, which is a common debilitating condition, arthroscopic capsular release is an effective surgical method for patients who have not responded to conservative treatment, as it provides visual control of the capsular release with a lower risk of potential traumatic damage than manipulation under anesthesia. Step 1 Position the Patient: Place the patient either in the lateral decubitus position or in the beach-chair position, depending on one's preference. Step 2 Portal Placement: Create a standard posterior viewing portal, an anterior portal, and a lateral portal for approaching the glenohumeral joint and the subacromial space. Step 3 Remove Rotator Interval Tissue: Begin the capsular release with the rotator interval and middle glenohumeral ligament using a 3.0-mm 90 degrees electrocautery device through the anterior portal. Step 4 Release the Anterior Capsule: Begin the anterior capsular release below the long head of the biceps tendon origin and preserve the glenoid labrum. Step 5 Release the Inferior Capsule: As the electrocautery device may not reach the inferior portion of the inferior glenohumeral ligament, switch the working portal to the posterior portal for an easier approach to the inferior portion. Step 6 Release the Coracohumeral Ligament and the Subscapularis: Begin this procedure with the camera in the lateral portal viewing the anterior portion of the subdeltoid space. Step 7 Postoperative Rehabilitation: The goal for the patient is to achieve an immediate range of motion by performing active-assisted and passive range-of-motion exercises including pendulum circumduction or the pulley exercise. Results: In our recently reported series of seventy-five patients who had a rotator cuff tear with simultaneous shoulder stiffness, treatment with an anterior and inferior capsular release showed favorable results. What to Watch For: IndicationsContraindicationsPitfalls & Challenges. PMID- 30473923 TI - Open Reduction and Internal Fixation of Fractures of the Proximal Part of the Humerus. AB - Introduction: We describe the surgical technique for open reduction and internal fixation (ORIF) of proximal humeral fractures with a locking plate. Step 1 Preoperative Planning: To choose the right candidate, obtain a full understanding of the patient's fracture pattern, activity level and demands, and bone quality; be aware of predictors of complications and poor outcomes. Step 2 Patient Positioning: Place the patient in the beach-chair position with the arm draped free or in a hydraulic device with good access for the image intensifier. Step 3 Approach: The deltopectoral approach is generally preferred because of the exposure obtained, the possibility of distal extension, and the minimal risk of nerve injury. Step 4 Reduction and Fixation of the Tuberosities the Key to Obtaining Marionette-Like Control: The control, reduction, and fixation of the tuberosities are crucial to restore the anterior-posterior force couple of the shoulder and must therefore be done properly no matter what the fracture pattern looks like. Step 5 Fracture Reduction: After carrying out Steps 1 through 4, perform the reduction techniques for the specific fracture type as described below for types that we think suitable for ORIF with a locking plate. Step 6 Fixation Implant-Specific Considerations: Plate length and positioning, humeral head screw placement, distal locking, confirming the screw tip position with the image intensifier, and securing the tuberosities. Step 7 Tenotomy or Tenodesis of the Long Biceps Tendon: Perform a biceps tenotomy if the biceps is displaced out of the groove by the fracture pattern or if you have to open the rotator interval. Step 8 Wound Closure: Do not close the deltopectoral interval. Step 9 Rehabilitation: As the failure rate of ORIF of proximal humeral fractures is high, do not force an active rehabilitation protocol. Results: In our analysis of 269 fractures followed for twelve months, we found that the Constant-Murley score (CMS) and Short Form-36 (SF-36) score improved continuously during the first six months postoperatively.IndicationsContraindicationsPitfalls & Challenges. PMID- 30473924 TI - Tibialis Anterior Tendon Transfer for Relapsing Idiopathic Clubfoot. AB - Introduction: A relapsed idiopathic clubfoot can be effectively treated with transfer of the entire tibialis anterior tendon to the mid-dorsum of the foot following repeated manipulations and serial casts. Step 1 Preoperative Planning: Ensure that the foot has been adequately corrected for tendon transfer by performing both clinical and radiographic evaluation. Step 2 Prepare the Patient: Position the patient supine, induce general anesthesia, and perform a caudal block for postoperative pain management. Step 3 Identify and Release the Tibialis Anterior Tendon from Its Insertion: Identify the tibialis anterior tendon and release its insertion on the medial cuneiform and first metatarsal bones. Step 4 Prepare the Tendon and Surrounding Tissues for Transfer: Release obstructing tissues and prepare the freed tendon for lateral transfer to the mid-dorsum of the foot. Step 5 Prepare the Lateral Cuneiform for Tendon Transfer and Fixation: Identify the lateral cuneiform with fluoroscopy and prepare it for transfer of the tibialis anterior tendon. Step 6 Transfer and Secure the Tendon: Make a subcutaneous path, transfer the tendon, and secure it in the osseous tunnel of the lateral cuneiform. Step 7 Postoperative Care: We apply a long leg cast and restrict patients to non-weight-bearing for six weeks. Results: The tibialis anterior tendon transfer has been used to treat relapsing idiopathic clubfoot with great success for more than fifty years.IndicationsContraindicationsPitfalls & Challenges. PMID- 30473925 TI - Locked Plate Fixation of Proximal Humeral Fractures Through an Extended Deltoid Split Approach with Use of a Shoulder Strap Incision. AB - Introduction: The shoulder strap approach involves an anterolateral deltoid split with use of an inverted U incision, providing excellent lateral exposure for locked plate fixation of complex proximal humeral fractures. Step 1 Positioning of the Patient and the Image Intensifier: Proper positioning of the image intensifier is important for uninterrupted fluoroscopy. Step 2 Skin Incision: The tip of the acromion is a useful landmark and serves as the proximal extent of the incision. Step 3 Raise the Distally Based Fasciocutaneous Flap: Raise a broad based full-thickness fasciocutaneous flap. Step 4 Creation of the Proximal Working Window: Split the deltoid anteriorly to minimize the chances of denervation. Step 5 Identification and Protection of the Axillary Nerve: Leave a cuff of deltoid muscle to protect the axillary nerve. Step 6 Placement of Traction Cuff Sutures: The cuff sutures are helpful in reduction of the proximal fracture segments and improve stability of three and four-part fractures. Step 7 Reduction of the Head and Tuberosity Fragments: Avoid varus reduction and reestablish the relationship between the humeral head and the greater tuberosity. Step 8 Plate Placement: Proper plate positioning is important to maximize the possibility of using all proximal screw options and to minimize chances of impingement. Step 9 Fracture Fixation: As is necessary with all locked internal fixators, reduce the fracture before fixing the plate; the order of fixation may vary with the type of fracture. Results: In our study of fifty patients with a displaced three or four-part fracture treated with this approach, all flaps healed well without any necrosis and no infections were seen.IndicationsContraindicationsPitfalls & Challenges. PMID- 30473926 TI - Surgical Techniques of Eccentric Rotational Acetabular Osteotomy. AB - Introduction: This report describes the operative indications and essential techniques of eccentric rotational acetabular osteotomy for hip dysplasia in patients with either pre-osteoarthritis, early arthritis, or in some cases even advanced osteoarthritis of the hip. Step 1 Patient Positioning: An accurate lateral decubitus position of the pelvis is important. Step 2 Skin Incision: Make a bikini skin incision and elevate the skin flap. Step 3 Transtrochanteric Approach: Make a Y-shaped incision, retract the innominate fossa, and detach the greater trochanter with an oscillating saw. Step 4 Deep Dissection to Mark the Osteotomy Lines: Partially release and divide the rectus femoris, detach the iliacus, and retract the iliopsoas. Step 5 Osteotomy of Ilium and Ischium: It is essential to use an osteotomy guide to perform an accurate spherical osteotomy. Step 6 Osteotomy of the Pubic Bone: The osteotomy of the pubic bone is technically demanding. Step 7 Reorientation of the Acetabular Fragment: The acetabular fragment can be rotated to the intended position as determined by the preoperative planning. Step 8 Reattachment of the Greater Trochanter: Fix the greater trochanter with two AO cancellous screws. Step 9 Postoperative Care: Walking with a walker and partial weight-bearing begins one day after surgery, and full weight-bearing starts at two months postoperatively. Results: The clinical and radiographic outcomes in the first 126 consecutive patients (132 hips) who had undergone eccentric rotational acetabular osteotomy at our institution were retrospectively assessed.IndicationsContraindicationsPitfalls & Challenges. PMID- 30473929 TI - An index of non-sampling error in area frame sampling based on remote sensing data. AB - Agricultural areas are often surveyed using area frame sampling. Using non updated area sampling frame causes significant non-sampling errors when land cover and usage changes between updates. To address this problem, a novel method is proposed to estimate non-sampling errors in crop area statistics. Three parameters used in stratified sampling that are affected by land use changes were monitored using satellite remote sensing imagery: (1) the total number of sampling units; (2) the number of sampling units in each stratum; and (3) the mean value of selected sampling units in each stratum. A new index, called the non-sampling error by land use change index (NELUCI), was defined to estimate non sampling errors. Using this method, the sizes of cropping areas in Bole, Xinjiang, China, were estimated with a coefficient of variation of 0.0237 and NELUCI of 0.0379. These are 0.0474 and 0.0994 lower, respectively, than errors calculated by traditional methods based on non-updated area sampling frame and selected sampling units. PMID- 30473928 TI - The role of neoantigen in immune checkpoint blockade therapy. AB - Immune checkpoint inhibitor induces tumor rejection by activated host immune system. The anti-tumor immune response consists of capture, presentation, recognition of neoantigen, as well as subsequent killing of tumor cell. Due to the interdependence among this series of stepwise events, neoantigen profoundly influences the efficacy of anti-immune checkpoint therapy. Moreover, the neoantigen-specific T cell reactivity is the cornerstone of multiple immunotherapies. In fact, several strategies targeting neoantigen have been attempted for synergetic effect with immune checkpoint inhibitor. Increasing neoantigen presentation to immune system by oncolytic virus, radiotherapy, or cancer vaccine is feasible to enhance neoantigen-specific T cell reactivity in theory. However, some obstacles have not been overcome in practice such as dynamic variation of neoantigen landscape, identification of potential neoantigen, maintenance of high T cell titer post vaccination. In addition, adoptive T cell transfer is another approach to enhance neoantigen-specific T cell reactivity, especially for patients with severe immunosuppression. In this review, we highlighted the advancements of neoantigen and innovative explorations of utilization of neoantigen repertoire in immune checkpoint blockade therapy. PMID- 30473927 TI - The Contribution of Tau, Amyloid-Beta and Alpha-Synuclein Pathology to Dementia in Lewy Body Disorders. AB - Parkinson's Disease (PD) and the closely related Dementia with Lewy Bodies (DLB) are due to the accumulation of pathogenic alpha-synuclein protein in brain cells manifest by heterogeneous motor and non-motor symptoms, including cognitive impairment and dementia. The majority of patients with Parkinson's Disease develop Dementia (PDD) in late stages of the disease and have widespread neocortical distribution of alpha-synuclein pathology at autopsy, compared with PD without dementia, in which neocortical synuclein pathology is less prevalent. These three entities PD, DLB and PDD comprise a clinical spectrum, collectively known as Lewy Body Disorders (LBD). Recent investigations into the neuropathological basis of LBD have demonstrated that while synuclein pathology is the defining feature of these disorders, it is often accompanied by other age related neurodegenerative pathologies. In particular, amyloid plaque and tau tangle pathology characteristic of Alzheimer's Disease (AD) (~50% of all LBD patients have sufficient pathology at autopsy for a secondary neuropathologic diagnosis of AD), appear to contribute to cognitive impairment in LBD, and the combination is associated with a shorter interval between onset of motor symptoms and development of dementia and a shorter life span. Further, the co-occurrence of neocortical alpha-synuclein, tau and amyloid pathologies found at end-stage disease suggests a potential synergistic interaction of these individual pathologies in humans during life, mirroring experimental observations in animal and cell model systems that show how pathogenic species of synuclein fibrils can promote trans-synaptic spread of both tauopathy and synucleinopathy with strain like properties. Newer post-mortem studies using digital methods to measure pathologic burden have highlighted distinct neocortical patterns of areas with relative higher density of tau pathology in LBD compared to AD that support these model data. The emerging field of cerebrospinal fluid and molecular imaging biomarkers of synuclein, amyloid and tau pathologies in LBD is contributing to a greater understanding of how the different pathologies evolve and interact to produce clinical heterogeneity in LBD. Future work to elucidate biologically meaningful clinical subgroups of synucleinopathy and its co-pathology must focus on the full clinicopathological spectrum of LBD and use validated biomarkers, when available, to design clinical trials based on the precise selection of homogeneous patient subgroups to maximize statistical power for detecting the impact of treatment. PMID- 30473930 TI - Genetic evidence supports a distinct lineage of American crocodile (Crocodylus acutus) in the Greater Antilles. AB - Four species of true crocodile (genus Crocodylus) have been described from the Americas. Three of these crocodile species exhibit non-overlapping distributions Crocodylus intermedius in South America, C. moreletii along the Caribbean coast of Mesoamerica, and C. rhombifer confined to Cuba. The fourth, C. acutus, is narrowly sympatric with each of the other three species. In this study, we sampled 113 crocodiles across Crocodylus populations in Cuba, as well as exemplar populations in Belize and Florida (USA), and sequenced three regions of the mitochondrial genome (D-loop, cytochrome b, cytochrome oxidase I; 3,626 base pair long dataset) that overlapped with published data previously collected from Colombia, Jamaica, and the Cayman Islands. Phylogenetic analyses of these data revealed two, paraphyletic lineages of C. acutus. One lineage, found in the continental Americas, is the sister taxon to C. intermedius, while the Greater Antillean lineage is most closely related to C. rhombifer. In addition to the paraphyly of the two C. acutus lineages, we recovered a 5.4% estimate of Tamura Nei genetic divergence between the Antillean and continental clades. The reconstructed paraphyly, distinct phylogenetic affinities and high genetic divergence between Antillean and continental C. acutus populations are consistent with interspecific differentiation within the genus and suggest that the current taxon recognized as C. acutus is more likely a complex of cryptic species warranting a reassessment of current taxonomy. Moreover, the inclusion, for the first time, of samples from the western population of the American crocodile in Cuba revealed evidence for continental mtDNA haplotypes in the Antilles, suggesting this area may constitute a transition zone between distinct lineages of C. acutus. Further study using nuclear character data is warranted to more fully characterize this cryptic diversity, resolve taxonomic uncertainty, and inform conservation planning in this system. PMID- 30473932 TI - Amphibian life history in a temperate environment of the Mexican Plateau: dimorphism, phenology and trophic ecology of a hylid frog, Hyla eximia (=Dryophytes eximius). AB - The study of demographic and life history aspects of an organism provides valuable information for its conservation. Here, we analyze the phenology of the Mountain Treefrog Hyla eximia (= Dryophytes eximius) in a temperate environment of the Mexican Plateau. Females were larger in snout-vent length and body mass than males. The peak period of activity occurred in the rainy season (May September), with amplexus and egg deposition occurring between June and July, and larval development from July to August. A logistic model best explained observed male growth patterns, while the Von Bertalanffy model better described female growth. Notably, males grew faster than females, although females reached a larger overall body size. The diet of this species is made up of 10 prey categories. The index of diet importance indicated that males feed mainly on Coleoptera and Diptera, while females feed on Coleoptera, Diptera, Hemiptera, and Aranea. Both females and males showed a significant abundance of plant material in their stomachs, suggesting that H. eximia might exhibit highly specialized feeding behavior. Reproduction was seasonal, and both female and male reproductive cycles are synchronized with the rainy season. These natural history characteristics provide information to better understand their responses to environmental conditions. PMID- 30473931 TI - Cancer and mTOR inhibitors in kidney transplantation recipients. AB - Background: Previous studies show that mTOR inhibitors decrease the risk of cancer development after kidney transplantation. However, the effect of cumulative doses of mTOR inhibitors on cancer after kidney transplantation is not well known. Methods: In the current study, patients were registered into a national database in Taiwan. Between year 2000 and 2013, 4,563 patients received kidney transplantation. They were divided into two groups, according to mTOR inhibitors usage. The cumulative dose of mTOR inhibitors was recorded. Patients were followed-up until de novo cancer development, death, or the end of 2014. Results: Patients were divided into two groups: mTOR inhibitors users (study group, n = 828) and mTOR inhibitors non-users (control group, n = 3,735). The median follow-up duration was 7.8 years. The risk of de novo cancer (hazards ratio (HR) 0.80, 95% CI [0.60-1.09], p = 0.16) and risk of death (HR 1.14, 95% CI [0.82-1.60], p = 0.43) was not different between mTOR inhibitor user and non-user groups. Neither high- nor low-dose exposure to mTOR inhibitors was associated with increased risk of cancer or mortality. Analysis of cancer subtypes showed no influence by mTOR inhibitors. In addition, the cause of mortality was not significantly different between the two groups. Discussion: We could not find the association of mTOR inhibitors use and risk of de novo cancer development or mortality in patients with kidney transplantation in Chinese patients. Cumulative exposure to mTOR inhibitors did not change the results. PMID- 30473933 TI - First evidence of asexual recruitment of Pocillopora acuta in Okinawa Island using genotypic identification. AB - Okinawa Island is located near the center of the Nansei Islands (~24-31 degrees N), at a relatively high latitude for coral reefs. Nevertheless, more than 80 coral genera (over 400 species) are abundant in the Nansei Islands. Since March, 2017, scleractinian corals have been held in an outdoor tank at the OIST Marine Science Station at Seragaki, Onna with natural sea water flow-through in order to be used in molecular biological and physiological studies. In January, 2018, we found small pocilloporid-like colonies suspected to have originated asexually. We collected 25 small colonies and measured their sizes and weights. Also, we validated the classification and clonality of the colonies using a mitochondrial locus and nine microsatellite loci. Almost all of the small colonies collected in the outdoor tank were <=1 cm in both width and height. The weight of dried skeletons ranged from 0.0287 to 0.1807 g. Genetic analysis determined that they were, in fact, Pocillopora acuta. Only one mitochondrial haplotype was shared and two microsatellite multilocus genotypes were detected (20 colonies of one and four colonies of the other). The mitochondrial haplotype and one microsatellite multilocus genotype for 20 colonies corresponded to those of one P. acuta colony being kept in the tank. One small colony matched both multilocus genotypes. This may have been a chimeric colony resulting from allogenic fusion. These small colonies were not produced sexually, because the only potential parent in the tank was the aforementioned P. acuta colony. Instead, they were more likely derived from asexual planula release or polyp bail-out. Corals as Pocillopora acuta have the capacity to produce clonal offspring rapidly and to adapt readily to local environments. This is the first report of asexual reproduction by planulae or expelled polyps in P. acuta at Okinawa Island. PMID- 30473934 TI - Late Cretaceous sauropod tooth morphotypes may provide supporting evidence for faunal connections between North Africa and Southern Europe. AB - The Cretaceous Kem Kem beds of Morocco and equivalent beds in Algeria have produced a rich fossil assemblage, yielding, amongst others, isolated sauropod teeth, which can be used in species diversity studies. These Albian-Cenomanian (~113-93.9 Ma) strata rarely yield sauropod body fossils, therefore, isolated teeth can help to elucidate the faunal assemblages from North Africa, and their relations with those of contemporaneous beds and geographically close assemblages. Eighteen isolated sauropod teeth from three localities (Erfoud and Taouz, Morocco, and Algeria) are studied here, to assess whether the teeth can be ascribed to a specific clade, and whether different tooth morphotypes can be found in the samples. Two general morphotypes are found, based on enamel wrinkling and general tooth morphology. Morphotype I, with mainly rugose enamel wrinkling, pronounced carinae, lemon-shaped to (sub)cylindrical cross-section and mesiodistal tapering towards an apical tip, shows affinities to titanosauriforms and titanosaurs. Morphotype II, characterized by more smooth enamel, cylindrical cross-section, rectangular teeth with no apical tapering and both labial and lingual wear facets, shows similarities to rebbachisaurids. Moreover, similarities are found between these northwest African tooth morphotypes, and tooth morphotypes from titanosaurs and rebbachisaurids from both contemporaneous finds from north and central Africa, as well as from the latest Cretaceous (Campanian-Maastrichtian, 83.6 Ma-66.0 Ma) of the Ibero-Armorican Island. These results support previous hypotheses from earlier studies on faunal exchange and continental connections between North Africa and Southern Europe in the Cretaceous. PMID- 30473936 TI - A divergence between underlying and final causes of death in selected conditions: an analysis of death registries in Peru. AB - Background: The underlying cause of death is used to study country and global mortality trends and profiles. The final cause of death could also inform the ultimately cause of death in individuals with underlying conditions. Whether there is a pattern between the underlying and final cause of death has not been explored using national death registries. We studied what final causes of death were most common among selected underlying causes using national death registries in Peru, 2015. Methods: Underlying and final causes of death were classified according to their ICD-10 codes. Underlying causes included chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), hypertension (HTN), diabetes, and selected cancers (cervix, breast, stomach, prostate, and lung). Final causes were categorized as: communicable, cardiovascular, and cancers. Descriptive statistics were used. Results: A total of 77,065 death registries were analyzed; cases had a mean age of 69.4 (SD: 19.3) years at death and were mostly men (53.9%). When the underlying cause was HTN, the most frequent final cause was cardiovascular diseases (82.3%). For all the other underlying causes, the most frequent final cause was communicable diseases: COPD (86.4%), CKD (79.3%), cancer (76.5%), and diabetes (68.3%). Conclusions: In four selected underlying causes of death there was a divergence with respect to the final cause, suggesting there was a shift from non-communicable to communicable causes. Although efforts should be deployed to prevent underlying non-communicable diseases, potential communicable complications should not be neglected. PMID- 30473935 TI - Evaluation of 17 microsatellite markers for parentage testing and individual identification of domestic yak (Bos grunniens). AB - Background: Yak (Bos grunniens) is the most important domestic animal for people living at high altitudes. Yak ordinarily feed by grazing, and this behavior impacts the accuracy of the pedigree record because it is difficult to control mating in grazing yak. This study aimed to evaluate the pedigree system and individual identification in polled yak. Methods: A total of 71 microsatellite loci were selected from the literature, mostly from the studies on cattle. A total of 35 microsatellite loci generated excellent PCR results and were evaluated for the parentage testing and individual identification of 236 unrelated polled yaks. A total of 17 of these 35 microsatellite loci had polymorphic information content (PIC) values greater than 0.5, and these loci were in Hardy-Weinberg equilibrium without linkage disequilibrium. Results: Using multiplex PCR, capillary electrophoresis, and genotyping, very high exclusion probabilities were obtained for the combined core set of 17 loci. The exclusion probability (PE) for one candidate parent when the genotype of the other parent is not known was 0.99718116. PE for one candidate parent when the genotype of the other parent is known was 0.99997381. PE for a known candidate parent pair was 0.99999998. The combined PEI (PE for identity of two unrelated individuals) and PESI (PE for identity of two siblings) were >0.99999999 and 0.99999899, respectively. These findings indicated that the combination of 17 microsatellite markers could be useful for efficient and reliable parentage testing and individual identification in polled yak. Discussion: Many microsatellite loci have been investigated for cattle paternity testing. Nevertheless, these loci cannot be directly applied to yak identification because the two bovid species have different genomic sequences and organization. A total of 17 loci were selected from 71 microsatellite loci based on efficient amplification, unambiguous genotyping, and high PIC values for polled yaks, and were suitable for parentage analysis in polled yak populations. PMID- 30473937 TI - CMTCN: a web tool for investigating cancer-specific microRNA and transcription factor co-regulatory networks. AB - Transcription factors (TFs) and microRNAs (miRNAs) are well-characterized trans acting essential players in gene expression regulation. Growing evidence indicates that TFs and miRNAs can work cooperatively, and their dysregulation has been associated with many diseases including cancer. A unified picture of regulatory interactions of these regulators and their joint target genes would shed light on cancer studies. Although online resources developed to support probing of TF-gene and miRNA-gene interactions are available, online applications for miRNA-TF co-regulatory analysis, especially with a focus on cancers, are lacking. In light of this, we developed a web tool, namely CMTCN (freely available at http://www.cbportal.org/CMTCN), which constructs miRNA-TF co regulatory networks and conducts comprehensive analyses within the context of particular cancer types. With its user-friendly provision of topological and functional analyses, CMTCN promises to be a reliable and indispensable web tool for biomedical studies. PMID- 30473938 TI - Microsatellite markers for Corybas (Orchidaceae) species in New Zealand. AB - Premise of the Study: Microsatellite markers were developed for New Zealand species of Corybas (Orchidaceae) to investigate population genetics and species delimitation. Methods and Results: From sequencing a total genomic DNA library (using Illumina MiSeq), we developed 22 microsatellite markers for C. obscurus. The di- and trinucleotide repeat loci were initially trialed on individuals representing seven Corybas taxa (C. "rimutaka," C. confusus, C. hypogaeus, C. macranthus, C. obscurus, C. trilobus, and C. walliae) and had one to eight alleles per locus. Twelve polymorphic markers were further tested on six Corybas populations from three of the seven taxa (C. obscurus, C. "rimutaka," and C. trilobus). Observed and expected heterozygosities ranged from 0-1 and 0-0.859, respectively. The utility of these 12 loci was further validated in five related Corybas species (C. hypogaeus, C. obscurus, C. vitreus, C. walliae, and C. "rimutaka"; 38 individuals) representing populations from across the North and South Islands. The average value for genetic diversity among populations (F ST) of 0.439 shows differentiation among species. Conclusions: These markers will be useful for future studies aimed at delimiting species boundaries and examining the genetic diversity of the New Zealand Corybas species. PMID- 30473939 TI - iNaturalist as a tool to expand the research value of museum specimens. AB - Premise of the Study: Innovative approaches to specimen collection and curation are needed to maximize the utility of natural history collections in a new era of data use. Associated data, such as digital images from the field, are routinely collected with recent herbarium specimens. However, these data often remain inaccessible and are rarely curated alongside the associated physical specimens, which limits future data use. Methods and Results: We leveraged the widely used citizen science platform, iNaturalist, to permanently associate field-collected data to herbarium specimens, including information not well preserved in traditional specimens. This protocol improves the efficiency and accuracy of all steps from the collecting event to specimen curation and enhances the potential uses of specimens. Conclusions: iNaturalist provides a standardized and cost efficient enhancement to specimen collection and curation that can be easily adapted for specific research goals or other collection types beyond herbaria. PMID- 30473940 TI - GC-MS metabolite profiling for specific detection of dwarf somaclonal variation in banana plants. AB - Premise of the Study: The production of banana (Musa spp.; Musaceae) plants is affected by various types of somaclonal variations (SV), including dwarfism. However, methods for specific detection of SV are still scarce. To overcome this, a metabolite-based method for detection of dwarf variants was evaluated. Methods: The gas chromatography-mass spectrometry (GC-MS) metabolite profile of dwarf banana variants was investigated and compared to that of normal-healthy (N) and cucumber mosaic virus (CMV)-infected plants using principal components analysis and partial least squares discriminant analysis (PLS-DA). Results: Significant differences among the sample groups were observed in 82 metabolites. Rhamnose was exclusively present in dwarf plants but allothreonine and trehalose were present in all but SV samples. Cellobiose was only detected in N plants, while 45 other metabolites, including methyl-glucopyranoside, allopyranose, lactose, phenylalanine, and l-lysine were detected in all but CMV-infected samples. PLS-DA models were able to detect SV, CMV, and N plants with 100% accuracy and specificity. Discussion: The GC-MS metabolite profile can be used for the rapid, specific detection of SV at early plant production stages. This is the first metabolite-based characterization and detection of somaclonal variation in plants. PMID- 30473941 TI - Fifteen microsatellite markers for the Appalachian rockcap fern, Polypodium appalachianum (Polypodiaceae), and its relatives. AB - Premise of the Study: Microsatellite markers were developed for Polypodium appalachianum (Polypodiaceae) to facilitate investigation of species boundaries between P. appalachianum and its putative hybrid, P. virginianum, and potentially among other members of the Miocene-age P. vulgare species complex. Methods and Results: Forty-eight primer pairs were designed from Illumina data and screened for successful amplification. Sixteen pairs were genotyped and evaluated for variability within and among three populations in North Carolina, Vermont, and New Hampshire. Twelve of these primer pairs were reliable and polymorphic, exhibiting one to 10 alleles per locus. Cross-species amplification experiments were conducted for P. virginianum and four additional close relatives from the P. vulgare complex in order to maximize information about likely utility within a phylogenetic context. Conclusions: These microsatellite markers will be useful in population genetics and species boundaries studies of P. appalachianum and P. virginianum, and likely in other species within the P. vulgare complex. PMID- 30473942 TI - In silico detection of polymorphic microsatellites in the endangered Isis tamarind, Alectryon ramiflorus (Sapindaceae). AB - Premise of the Study: Alectryon ramiflorus (Sapindaceae) is an endangered rainforest tree known from only two populations. In this study, we identified polymorphic microsatellites, in silico, improving the effectiveness and efficiency of microsatellite development of nonmodel species. The development of genetic markers will support future conservation management of the species. Methods and Results: We used next-generation sequencing and bioinformatics to detect polymorphic microsatellites, in silico, reducing both the time and cost of marker development. A panel of 15 microsatellites, 12 of which were polymorphic, were subsequently characterized in 64 adult trees representing the entire species range. Mean observed heterozygosity and expected heterozygosity were 0.471 and 0.425, respectively. The polymorphism information content across loci ranged from 0.152 to 0.875. Conclusions: The microsatellite markers developed in this study will be useful in gaining an understanding of A. ramiflorus' genetic diversity, level of inbreeding, and population structure and for guiding future restoration and management efforts. PMID- 30473943 TI - Comparing RNA-Seq and microarray gene expression data in two zones of the Arabidopsis root apex relevant to spaceflight. AB - Premise of the Study: The root apex is an important region involved in environmental sensing, but comprises a very small part of the root. Obtaining root apex transcriptomes is therefore challenging when the samples are limited. The feasibility of using tiny root sections for transcriptome analysis was examined, comparing RNA sequencing (RNA-Seq) to microarrays in characterizing genes that are relevant to spaceflight. Methods: Arabidopsis thaliana Columbia ecotype (Col-0) roots were sectioned into Zone 1 (0.5 mm; root cap and meristematic zone) and Zone 2 (1.5 mm; transition, elongation, and growth terminating zone). Differential gene expression in each was compared. Results: Both microarrays and RNA-Seq proved applicable to the small samples. A total of 4180 genes were differentially expressed (with fold changes of 2 or greater) between Zone 1 and Zone 2. In addition, 771 unique genes and 19 novel transcriptionally active regions were identified by RNA-Seq that were not detected in microarrays. However, microarrays detected spaceflight-relevant genes that were missed in RNA-Seq. Discussion: Single root tip subsections can be used for transcriptome analysis using either RNA-Seq or microarrays. Both RNA-Seq and microarrays provided novel information. These data suggest that techniques for dealing with small, rare samples from spaceflight can be further enhanced, and that RNA-Seq may miss some spaceflight-relevant changes in gene expression. PMID- 30473944 TI - Development of 17 novel microsatellite markers for Lycoris aurea and L. radiata (Amaryllidaceae) using next-generation sequencing. AB - Premise of the Study: Lycoris is an ornamental and medicinal plant. We developed microsatellite markers for L. aurea and L. radiata simultaneously by using a hybrid between these two species. Methods and Results: Ion Torrent next generation sequencing produced 1,784,504 reads. Testing 64 primer sets allowed for the development of 17 novel microsatellite markers: 16 for L. aurea, 10 for L. radiata, and nine common markers. Lycoris aurea had one to 12 alleles per locus and observed and expected heterozygosity levels of 0-0.923 and 0.038-0.809, respectively. Lycoris radiata had three to 12 alleles per locus and observed and expected heterozygosity levels of 0-0.909 and 0.127-0.797, respectively. Ten markers were cross-amplified for L. sprengeri. Conclusions: Hybrid sequencing can facilitate the cost-effective development of molecular markers for parental species. The markers developed here are useful for studying Lycoris population structure. PMID- 30473945 TI - How Do Patients Rate Their Radiation Oncologists in the Modern Era: An Analysis of Vitals.com. AB - Introduction The popularity of online physician rating websites has risen substantially. These third-party sites have the potential to significantly influence patients' perception of their healthcare providers. The purpose of this study was to evaluate online ratings of U.S. radiation oncologists (ROs) on Vitals.com, one of the most popular physician rating websites, and the variables that most significantly affect patients' overall rating (OR) of their ROs. Methods The Centers for Medicare and Medicaid Physician Comparable Downloadable File was analyzed to obtain data on all self-identified ROs in the U.S. and Puerto Rico. Patient Review Satisfaction Scores (PRSS) that ranged from one (poor) to five (excellent) for the following variables were recorded: OR, accurate diagnosis, spending appropriate time with patients, ease of appointment, courteous staff, bedside manner, follow-up after visit, promptness, and wait time. Associations among these factors were assessed. Results Of 4,443 self identifying Medicare-accepting ROs, 1,797 (40.4%) ROs who had at least one OR rating and at least one written comment were included in this study. The ROs' mean OR was 4.34 +/- 0.2 (median 4; 30% received a score of 5; 78% received a score greater than 4). OR was found to have a strong correlation with accuracy of diagnosis (r = 0.69), bedside manner (r = 0.71), and spends appropriate time with patients (r = 0.69). With the exception of the number of ratings (p = 0.07), physicians with over 10 years of experience showed statistically significant differences in how much better they scored in each of the variables compared to those with less than 10 years of experience (p < 0.01 for each characteristic). Significant differences in OR were also observed between ROs whose wait times exceeded 20 minutes compared to those with wait times less than 10 minutes (p < 0.01) for all internal and external metrics except for the number of ratings (p = 0.42) and number of reviews (p = 0.88) Conclusion Patients are providing high ratings for their ROs on Vitals.com and are more frequently recommending them to friends and family. Given the rise in popularity of third-party physician rating sites, it is important for ROs to understand the various factors that may influence their online ratings. PMID- 30473946 TI - Non-ischemic Cardiomyopathy Secondary to Left Ventricular Hypertrophy due to Long term Anabolic-androgenic Steroid Use in a Former Olympic Athlete. AB - Currently, the cardiovascular risk associated with the use of anabolic steroids is not well documented. Recent studies have shown that its use may potentiate the development of cardiac dysfunction in the short term. This case report describes an encounter that supports a causal link between anabolic-androgenic steroid use (AAS) and cardiomyopathy later in life. We herein present a case study of a 73 year-old prior Olympic athlete who had misused AAS for 20 years and subsequently was found to have developed a systolic and diastolic cardiomyopathy, presumably due to long-standing left ventricular hypertrophy. A 73-year-old man presented to our medical center with symptoms of lightheadedness and palpitations. He was found to be in ventricular tachycardia and was converted to sinus rhythm with medical pharmacotherapy. Further workup with two-dimensional trans-thoracic echocardiogram and cardiac catheterization showed severe left ventricular (LV) hypertrophy in the absence of hypertension and a combined systolic and diastolic heart failure with reduced ejection fraction in the absence of significant coronary artery disease or dilated cardiac chambers. The patient denies any family or personal history of cardiac issues until the time of presentation. By exclusion, he was diagnosed with a non-ischemic cardiomyopathy secondary to his prior regimented use of anabolic steroids. Although causality can only be inferred, this case presents a potentially delayed long-term cardiac consequences of extreme AAS use over many years. Notably, our patient had remained asymptomatic, until the development of arrhythmias, eventuating in ventricular tachycardia and contributing to heart failure with reduced ejection fraction. Physicians should caution users about the risk of possible long-term cardiac complications linked with AAS use. PMID- 30473947 TI - Challenges and Solutions for Functional Neurosurgery in Developing Countries. AB - Functional neurosurgery techniques remain integral to the neurosurgical treatment armamentarium but data on global implementation remains scarce. In comparison to high-income countries (HIC), low- and middle-income countries (LMIC) suffer from an increased prevalence of diseases like epilepsy, which may be amenable to functional techniques, and therefore, LMIC may benefit from an increased utilization of these treatment modalities. However, functional techniques tend to be expensive and thus difficult to implement in the LMIC setting. A review was performed to assess the current status of functional neurosurgical techniques in LMIC as a starting point for future initiatives. For methodology, a review of the current body of literature on functional neurosurgery in LMIC was conducted through the United States National Library of Medicine Pubmed search engine. Search terms included "functional neurosurgery," "developing countries," "low and middle income," and other related terms. It was found that though five billion people lack access to safe surgical care, the burden of disease amenable to treatment with functional neurosurgical procedures remains unknown. Increasingly, reports of successful, long-term, international neurosurgical collaborations are being reported, but reports in the sub-field of functional neurosurgery are lacking. In conclusion, awareness of global surgical disparities has increased dramatically while global guidelines for functional techniques are currently lacking. A concerted effort can harness these techniques for wider practice. Partnerships between centers in LMIC and HIC are making progress to better understand the burden of disease in LMIC and to create context-specific solutions for practice in the LMIC setting, but more collaborations are warranted. PMID- 30473948 TI - Nitrofurantoin Toxicity: A Near Case of Mistaken Identity. AB - Nitrofurantoin is one of the most utilized antibiotics to treat bladder and urinary tract infections (UTIs). Despite the clinical benefits, it requires vigilant monitoring, as it can cause damage to multiple organs, especially the lungs and the liver. This case is an example of clinical vigilance, which provided tremendous benefit for the patient. PMID- 30473949 TI - Intrinsic CanMEDS Competencies Expected of Medical Students During Emergency Medicine Core Rotation: A Needs Assessment. AB - Objectives There are few high-quality free open-access medical (FOAM) education resources to guide medical students in the development of key non-medical expert skills and competencies during their emergency medicine (EM) clerkship core rotation. In our endeavor to develop a novel online educational EM curriculum for medical students, a needs assessment is required to effectively address needs specifically focused on aptitudes that are deemed to be imperative by educators in the EM academia. Methods An online needs assessment survey was developed and shared with residents, staff, nurses, and program/clerkship directors of Canadian emergency medicine programs by email correspondence and embedding the form on CanadiEM.org. The survey consisted of twelve proposed topics for a potential EM curriculum, which were graded on a five-point Likert scale. Free-typed responses for additional topics were also solicited from participants. Results Over the course of four weeks, 84 participants responded to the survey. Participants outside of North American were excluded (n=10). Most participants were North American staff physicians (n=52), which included residency program directors (n=10) and clerkship directors (n=6), followed by residents (n=14), and nurses (n=8). All 12 topics proposed by the authors were considered important for inclusion in an EM curriculum. Nine additional topics were identified from typed free-text responses. Top ranking topics included: how to present a case to an EM staff or resident, how to chart patient encounters, and how to effectively communicate with nurses and other healthcare professionals. Conclusions This online needs assessment analysis revealed a total of 21 topics that were deemed to be relevant to the development of an online curriculum to foster the development of core competencies of medical students during their EM core rotation. PMID- 30473950 TI - An Unusual Presentation of Spigelian Hernia Incarceration after Colonoscopy. AB - Spigelian hernias are uncommon and predominantly affect the abdominal wall.The incidence of Spigelian hernias after colonoscopy is even rarer with only one case outlined in the surgical literature. This is the case of a 66-year-old man who underwent routine colonoscopy and presented to the hospital with systemic inflammatory response syndrome (SIRS). A computed tomography (CT) scan demonstrated a Spigelian hernia in the location of a prior left ventricular assist device (LVAD) placement. This required surgical resection and resulted in a complicated post-operative course. This case offers a unique perspective on a rare colonoscopic complication not well represented in the literature. It offers the learning point of remaining vigilant for a rare, but potentially deadly, colonoscopic outcome. This case also illustrates the decision-making heuristic of availability bias. PMID- 30473951 TI - True Congenital Pancreatic Cyst: A Rare Entity. AB - Pancreatic cysts are common in adults but rarely seen in children. Out of those seen in children, the majority are pseudocysts. This article presents a unique case of a child diagnosed with a true congenital pancreatic cyst which was ultimately excised completely. PMID- 30473952 TI - Negative Pressure Wound Therapy with Instillation and Dwell Time in the Surgical Management of Severe Hidradenitis Suppurativa. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a physically debilitating disease that greatly impairs the quality of life of affected individuals. Advanced disease is often difficult to treat with topical and systemic therapies. Surgical resection of diseased skin has become paramount in HS management but proposes challenges of wound care and closure. METHODS: Four patients with a total of 12 complex wounds were treated over a three year period. All of the patients were males between the ages of 28 and 61 years. The lesions were located on the buttocks (n=5), chest (n=1), perianal (n=2), perineal (n=2), and axillary regions (n=2). A protocol of wide local excision, followed by negative pressure wound therapy with instillation and dwell time (NPWTi-d) to decrease bioburden and promote angiogenesis of the exposed base, and subsequent skin grafting was used. Patients remained hospitalized between procedures. RESULTS: The original wound area ranged from 210-540 cm2. Skin grafts of comparable sizes were taken from donor sites. The average duration of NPWTi-d placement was 3.5 days and the average time from excision to wound coverage was 4.3 days. The percent of graft uptake ranged from 70%-90%. All patients were resolved of their local disease with no complications. CONCLUSIONS: Surgical management of HS can be complicated by difficult closures. This case series demonstrates that wide local excision followed by NPWTi-d and skin grafting is able to achieve local resolution of disease in HS patients who have failed multiple minimally invasive therapies. PMID- 30473953 TI - Can You Teach Yourself Point-of-care Ultrasound to a Level of Clinical Competency? Evaluation of a Self-directed Simulation-based Training Program. AB - Introduction Self-directed learning in medical professions is established as an effective method of training in certain modalities. Furthermore, simulation technology is becoming widely used and accepted as a valid method of training for various medical skills, with ultrasound being one of the best studied. The use of point-of-care ultrasound (PoCUS) in the practice of emergency medicine is well established, and PoCUS is a core competency of the Royal College of Physicians and Surgeons of Canada emergency medicine standards. The primary goal of our study was to assess the effectiveness of a self-directed simulation-based training program for medical students, in terms of achieving competency in basic PoCUS scans. Methods Fourteen second-year medical students with no prior ultrasound experience were provided access to online study modules created by SonoSim ultrasound training solutions (SonoSim, Santa Monica, CA, US), covering ultrasound theory and methodology, and attended a two-hour introductory session where they were introduced to the study protocol, simulation equipment, and software. Participants then undertook self-directed ultrasound simulation training throughout the year, using the CAE Vimedix PoCUS simulator (CAE Healthcare, Sarasota, FL, US) and the SonoSim ultrasound training solution system. Upon reaching 10 (and 25) scans in each of the four categories (cardiac, abdomen, aorta, and pelvic), a triggered assessment was arranged in which participants scanned a live volunteer under the direct supervision of PoCUS certified physicians. The physicians scored the participant attempts in terms of image acquisition, interpretation, and clinical understanding. No feedback was provided to the participants. Following the study, participants submitted feedback regarding the design of the study and were asked to rank their preferred training program protocols out of a provided list of five different options. Results At the first triggered assessment (after completing only 10 scans in each category), four out of 14 participants were scored as competent in the aorta scan, two out of 14 participants were competent in the pelvic scan, and none of the participants were competent in both the cardiac and abdominal scans. Only nine out of 14 participants completed the second triggered assessment (after completing 25 scans in each category). At the second assessment, only three participants were scored as competent in the aorta scan, two participants were competent in the cardiac scan, and one participant was competent in the pelvic scan. None of the 14 learners completed the final phase of the training and assessment protocol. Feedback following the termination of the study showed that none of the participants supported continuing the study protocol as designed originally, and the preferred study design consisted of a full-day introductory course with live models and simulation, followed by self-directed learning with simulation and live models until 50 scans in each category were achieved. Conclusion We were unable to demonstrate the achievement of competence in PoCUS in medical learners engaged in our combined self-directed simulation-based training program. This is in contrast to the considerable literature supporting self-directed learning and simulation-based learning for other skills. Feedback from faculty, curriculum integration, and alignment with clinical experience may be beneficial. PMID- 30473954 TI - An Overview of the Pathology and Emerging Treatment Approaches for Interstitial Cystitis/Bladder Pain Syndrome. AB - Our article will discuss bladder pain syndrome (BPS), which is the presence of chronic suprapubic pain to bladder filling accompanied by other urinary symptoms, such as frequency, urgency, discomfort with filling, and relief with emptying of the bladder in the absence of infections or other pathology. It is mostly seen in females and occurs in 0.06%-30% of the population. Some of the proposed mechanisms causing BPS include damage to the bladder lining, a problem manifesting in the pelvic musculature, endocrine, neurological, allergic, autoimmune system, and inflammatory system; however, a definite cause has not been yet identified. Two types of this syndrome have been identified, ulcerative and non-ulcerative. In the ulcerative disease, areas of reddened mucosa associated with small vessels radiating towards a central scar (at times, covered by a small clot or fibrin) can be seen. In the non-ulcerative type, a normal bladder mucosa can be observed initially, and the subsequent development of glomerulations after hydrodistension is considered a definite sign of its diagnosis. The diagnosis of BPS is primarily clinical; however, cystoscopy and biopsy can also be performed, if needed. Finally, we will discuss in detail the treatment of BPS, which constitutes three different guidelines (The European Association of Urology (EAU) Guidelines 2017, the American Urology Association (AUA) Guidelines 2014, and The Royal College of Obstetricians and Gynecologists (RCOG) in conjunction with the British Society of Urogynaecologists (BSUG) Guidelines 2016). All are proposing different types of therapy, including conservative, medical, and surgical treatment. PMID- 30473955 TI - Reversible Acute Kidney Injury Associated with Sildenafil Overdose. AB - Sildenafil is a phosphodiesterase type 5 inhibitor that is approved to treat erectile dysfunction and pulmonary hypertension. Generally, sildenafil is safe, with mild side effects. Here, we report a case of acute kidney injury caused by a sildenafil overdose. A 67-year-old man took 400 mg of sildenafil for erectile dysfunction. The patient was found to have acute kidney injury from acute tubular necrosis during hospitalization with a peak serum creatinine of 5.07 mg/dL though his renal function recovered with supportive care. PMID- 30473956 TI - Management of Non-syndromic Multiple Impacted Teeth with Dentigerous Cysts: A Case Report. AB - Impacted teeth may not only interfere with function, but also can act as a source of many pathological lesions such as odontogenic cysts and tumors. One of the most prevalent types of odontogenic cysts associated with erupted, developing or impacted tooth is dentigerous cyst. Multiple impacted teeth with dentigerous cysts in both the maxillary and mandibular arches without the association of any syndromes is a very rare occurrence. In the present article, we report such a non syndrome case of bilateral multiple impacted teeth in both maxilla and mandible with dentigerous cysts treated with enucleation and ridge augmentation with autogenous bone graft harvested from posterior iliac region. Further, dental rehabilitation was carried out with dentures. PMID- 30473957 TI - A Newborn with Simmering Bleeding after Circumcision. AB - We present a case of a healthy male neonate born at term, circumcised on Day 1 of life. Facing ongoing bleeding at the incision site, the baby was transferred to a level III neonatal intensive care unit for further investigation and management. His family history was unremarkable for bleeding disorders. On arrival, the baby was hemodynamically stable with abnormal coagulation values. Further investigations revealed a diagnosis compatible with severe hemophilia A. He deteriorated on Day 2, developing acute severe anemia which required two red blood cell transfusions. This rare but potentially fatal event reminds clinicians to remain extremely vigilant with minor surgical procedures such as circumcision even in the absence of family history. PMID- 30473958 TI - The Intravenous Drug User with a Big Heart. AB - Infective endocarditis is a severe and now more frequently encountered condition given the rise of intravenous (IV) drug use. An IV drug user presented with septic shock and bacterial endocarditis. Upon imaging, a fistulous tract was discovered, communicating from the annulus of the infected mitral valve to a large left ventricular pseudoaneurysm (PA). Presence of valvular vegetation, heart failure, and PA are all independent factors of increased mortality rates. The sheer size of the PA placed this patient at a very high surgical risk, and she was deemed inoperable. She was discharged when stabilized on supportive medical therapy. However, she returned six weeks later in cardiogenic shock with multi-organ failure. Repeat imaging revealed that the PA had significantly increased in size. Despite optimal medical management, the patient's condition deteriorated, and she, unfortunately, succumbed to her illness. PMID- 30473959 TI - Colony-stimulating Factor 3 Receptor Mutated Chronic Neutrophilic Leukemia: A Rare Case Report. AB - Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm, which is characterized by sustained peripheral leukocytosis with neutrophilia, hepatosplenomegaly, and hypercellularity of the bone marrow, with less than 5% myeloblasts along with normal neutrophil maturation and no dysplasia. In 2016, World Health Organization (WHO) included activating mutations in the gene for colony-stimulating factor 3 receptor (CSF3R) as one of the diagnostic criteria with CSF3RT618I being the most common mutation. We report a rare case of CNL (JAK2V617F negative, BCR-ABL1 negative, CSF3RT618I positive) in an elderly female who had an aggressive clinical course of the disease. PMID- 30473960 TI - Evaluation of an Innovative Bleeding Cricothyrotomy Model. AB - Objectives Emergency medicine (EM) residents are required to perform a cricothyrotomy during training as per the Accreditation Council for Graduate Medical Education (ACGME) guidelines. Cricothyrotomy is a rare procedure, comprising 0.45% of emergency department airway management procedures. Procedural competence in utilizing a realistic trainer is of utmost importance. We have developed a cricothyrotomy trainer using a fused deposition modeling (FDM) three dimensional (3D) printer and innovative bleeding tissue to enhance fidelity. We aim to evaluate the trainer's realism. Methods Implementation occurred during a difficult airway educational lab for EM residents in April 2018. Participants completed anonymous written surveys after performing a cricothyrotomy on the trainer. The survey evaluated the realism of the trainer and compared it to other available models by utilizing five-point visual analog scales (VAS). The participants rated their comfort level in performing the procedure pre- and post educational lab on a five-point VAS. Demographic data included postgraduate year, prior clinical cricothyrotomy experience as a primary operator versus as an assistant, and previous trainer experience. The survey included open-response suggestions for trainer improvement. Results Forty-three EM residents completed the survey (82.7%, 43/52). The mean realism rating of the trainer was 3.81 (95% CI = 3.54-4.1). The participants reported previous training on cadaver (62.8%, 27/43), porcine (46.5%, 20/43), and manikin (67.4%, 29/43) models prior to using this trainer. The bleeding cricothyrotomy trainer was rated higher than other models (4.45, 95% CI = 4.28-4.63). Participants noted improved comfort with performing the cricothyrotomy after the educational lab (average improvement of 1.23+/-0.75). Participants specifically commented on the realism of the bleeding and skin texture; however, they also recommended a reduction in the size of the cricothyroid membrane space. Conclusion The innovative bleeding cricothyrotomy trainer has greater fidelity and reported superiority when compared to other commonly used nonbleeding models. This trainer provides a more advanced platform to teach an infrequent yet critical procedural skill to emergency medicine residents. PMID- 30473961 TI - A Meta-analysis of the Association Between Needle Exchange Programs and HIV Seroconversion Among Injection Drug Users. AB - We assessed the association between different levels of needle exchange program (NEP) use and human immunodeficiency virus (HIV) seroconversion in the injecting drug user (IDU) population using meta-analysis to aggregate risk estimates from any reported cohort studies or randomized controlled trials (RCTs) in the literature. We searched the literature for articles published from January 1990 to August 2014 using Medical Subject Headings and other terms from MEDLINE(r) (using Ovid), Embase, ProQuest, the International Aids Society Abstract database, and the European AIDS clinical society database, and the European Conferences Abstract Archive. Articles were included if data were reported from an original study; the study was a prospective cohort or RCT design; estimates for seroconversion (hazard ratios [HRs]) for drug-users with different levels of NEP use, as well as variance data, or the information to calculate these were reported; risk estimates were adjusted for unstable housing, risky sexual behaviors, frequency of injections, cocaine use, and risky needle sharing practices; and the study was published between January 1990 and August 2014. Information abstracted was general study information (i.e., study name, authors, publication year, study site, sample size, length of follow-up, and follow-up intervals, incentives to IDUs for improving compliance/enrollment), outcomes variable measures (seroconversion HR estimates, variance figures, and factors adjusted for), description of the study population (inclusion and exclusion criteria and definitions of comparison groups), type of intervention (NEP program), statistical methods used, and sub-group information. Two prospective cohort studies with a total of 3,172 IDUs were eligible for inclusion. Comparison groups had different levels of NEP-use (e.g., daily use vs. non-daily use and NEP users vs. non-users) from fixed-site NEPs. Our Q-statistic was insignificant with a p-value of 0.401 while the I2 value was 0.0%. A random-effects model was used to aggregate the estimates, and we found an overall significant positive association between NEP-use and HIV seroconversion with an HR estimate of 1.59 (95% confidence interval [CI]: 1.2 to 2.1). According to our results, higher usage of NEPs is associated with a higher risk of HIV seroconversion in the IDU population. The observed association aligns with previous findings of NEP programs being inadequate for HIV control in IDUs. Further research on the topic needs to be done including studies on different NEP designs and how they can be made more effective by combining with other strategies, including the study of IDU characteristics which make them more likely to use safe syringes when they inject. PMID- 30473962 TI - Temozolomide-induced Aplastic Anemia Treated with Eltrombopag and Granulocyte Colony Stimulating Factor: A Report of a Rare Complication. AB - Temozolomide is an alkylating agent used in the treatment for glioblastoma multiforme (GBM), the most frequent primary malignant brain tumor in adults. Temozolomide was approved in March 2005 for treatment of GBM, with the Stupp protocol (radiotherapy and concomitant use of temozolomide). Despite initial studies demonstrating mild and well-tolerated side effects, several recent reports describe severe hematologic adverse effects associated with temozolomide use. We report the case of a 51-year-old female diagnosed with GBM who received the standard treatment protocol of radiotherapy and concomitant temozolomide. The patient developed prolonged pancytopenia. Bone marrow biopsy demonstrated hypocellular bone marrow with diminished trilineage hematopoiesis, suggestive of drug-induced aplastic anemia. Although temozolomide is regarded as a safe drug with few side effects, severe hematologic toxicities have been reported. PMID- 30473963 TI - Cohen Syndrome: Review of the Literature. AB - Cohen syndrome was initially described as a syndrome including obesity, hypotonia, mental deficiency, and facial, oral, ocular and limb anomalies. Leukopenia, especially neutropenia, was later described as a feature of Cohen syndrome. Cohen syndrome is caused by an autosomal recessive (AR) mutation of the vacuolar protein sorting 13 homolog B (VPS13B, also referred to as COH1) gene on chromosome 8q22.2. PMID- 30473964 TI - Contrast-induced Nephropathy Following Percutaneous Coronary Intervention at a Tertiary Cardiac Center in Nepal. AB - Background Contrast-induced nephropathy (CIN) is one of the leading causes of morbidity and mortality including increased financial burden in high risk patients undergoing percutaneous coronary intervention (PCI). Methods This is an observational prospective study. We aimed to study the incidence of CIN in Nepalese populations and compare the outcome to international reprinted values with coronary artery disease (CAD) undergoing PCI. All consecutive patients with CAD undergoing PCI between February 2010 and July 2010 were enrolled in the study. Results One hundred fifty-two patients were enrolled in the study during six months period. Twenty (13.20%) patients developed CIN following PCI. Out of them 70% were diabetics and 30% were non-diabetics. Mean age of patients was 58.5 +/- 23 years; male:female ratio was 2.7:1. Mean contrast volume injected was 160.3 +/- 78.3 mL. Diabetic patients 21.8% (14/64) had significant CIN compared to non-diabetic patients 6.8% (6/88) following PCI (<0.01). Conclusions CIN is a common complication following PCI especially in diabetics. Despite the use of iodinated material we had similar incidence of CIN comparing the incidence of CIN among various radiocontrast compounds used to visualize vessels. None of the patients received hemodialysis as compared to available studies and there was no observed mortality. PMID- 30473965 TI - Neck Cutting Behavior: Paraphilia or Suicide Attempt? A Case Report of Self-harm in the Context of Drug Abuse and Depression. AB - The border between self-harm and suicidal behaviors is not always clear. Self mutilation is a common finding in mood and personality disorders, and cutting of the extremities is more common than cutting of the neck. The case put forth regards a young adult male with a past history of depression and drug abuse who presented to the emergency department with superficial lacerations on his left arm and bilaterally on his neck with a large abscess in his right forearm. The patient reported the cuts on his arm to be from testing the sharpness of a kitchen knife and the cuts on his neck to be the result of sexual activity between him and his girlfriend. Collateral reports were inconsistent with the patient's version of events, and he voluntarily chose to receive psychiatric evaluation. After undergoing hospital rehabilitation, the patient was discharged with the diagnosis of bipolar disorder unspecified due to the findings of chronic mood instability without conclusive evidence of mania or hypomania. The etiology of his neck cutting behavior remained unexplained. PMID- 30473966 TI - A Systematic Review of Marijuana Use and Outcomes in Patients with Myocardial Infarction. AB - The prevalence of marijuana use is increasing after its legalization in a few states of the United States (US). Smoking marijuana is found to be associated with an increased risk of myocardial infarction (MI) immediately after its use. However, knowledge about the impact of marijuana on outcomes following MI is limited. In light of the rapidly shifting landscape regarding the legalization of marijuana for medical and recreational purposes, it is necessary to evaluate the impact of marijuana on the outcomes following MI. In this systematic review, we opted to review the effects of marijuana on in-hospital and long-term outcomes following MI. PMID- 30473968 TI - Spine Injuries Related to Ocean Waves: Case Series of Unusual Injuries. AB - Spine injuries related to ocean wave accidents are little known because they exclusively occur in beach destinations. This unusual type of trauma happens when these patients are slammed or caught by a wave, rolled over, and driven into the water, usually hitting the head on the seabed. Due to the kinematics of ocean wave accidents, spine injuries occur almost exclusively in the subaxial cervical spine. Several cases of spine injuries associated with ocean wave accidents are described. These ocean bathers presented with spinal trauma in levels other than the subaxial cervical spine. Two patients presented with injuries in the upper cervical spine, another patient showed a thoracic fracture, and finally, another patient sustained a lumbar compression fracture. All patients were tourists with minimal experience with swimming in the ocean who very likely ignored the danger of waves. This study shows that spine injuries related to ocean waves can occur at any level of the spine. Therefore, emergency physicians and spine surgeons must be aware of unusual locations of this unique type of trauma. PMID- 30473967 TI - Chronic Kidney Disease and Calciphylaxis: A Literature Review. AB - Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is a rare complication of chronic kidney disease (CKD). Its incidence is increasing due to a better understanding and diagnosis by physicians. Calciphylaxis is a fatal complication of many metabolic disorders. If not managed properly, it can lead to death within a year. This review is an effort to highlight the importance of research on prompt diagnosis and treatment guidelines for calciphylaxis, as it poses a challenge due to its diverse clinical presentation and high mortality rate. PMID- 30473969 TI - Management of Diabetic Ketoacidosis with Dengue Hemorrhagic Fever. AB - Viral hemorrhagic fever is one of the most important emerging infectious diseases. Some viral hemorrhagic fevers include dengue, hantavirus, Ebola infection, and yellow fever. Dengue virus infection results in a wide spectrum of clinical diseases, including dengue hemorrhagic fever, characterized by the transient period of plasma leakage and hemorrhagic tendency. Vascular instability ranges from mild to fatal shock, and hemorrhage varies from none to life threatening. Infection is the predominant precipitating factor for diabetic ketoacidosis. In addition to insulin administration, successful management of diabetic ketoacidosis requires fluid resuscitation. We herein report an adult patient with diabetic ketoacidosis complicated with dengue hemorrhagic fever who developed leakage syndrome. Early recognition of leakage and appropriate fluid management was critical in the diabetic ketoacidosis management of this case. PMID- 30473970 TI - Welcome to the New Era: A Completely Wireless Interventional Procedure. AB - The number of minimally invasive interventional radiology (IR) and interventional cardiology vascular procedures performed increases every year. As the number of vascular procedures increases, the need for advanced technology and innovative devices increases as well. Traditionally, as a general rule, a catheter is used in conjunction with a guidewire in such procedures. The underlying principle of IR is to always use a guidewire prior to any advancement of a catheter. This article describes a revolutionary theory that utilizes a new technology and contradicts this basic principle. Using a steerable microcatheter, a bilateral uterine artery embolization was performed from a wrist access with no guidewire. Furthermore, this technique reduced the procedure time by more than half when compared to standard of care. This technique may be applicable to other IR procedures, which could potentially reduce the time critically ill patients spend in the procedure area outside the intensive care unit. PMID- 30473972 TI - A Route Less Traveled: Anomalous Venous Drainage of the Right Heart. AB - Congenital anomalies of the coronary sinus and veins have been well documented, but only one instance of an anomalous small cardiac vein draining into the superior vena cava (SVC) has been reported. The majority of patients with anomalies of the coronary venous system are asymptomatic, but these variants are important to document as they may have clinically significant implications in the management and possible interventions patients may receive. This report describes an anomalous connection from the coronary venous system to the superior vena cava discovered incidentally in a patient with SVC syndrome and end-stage renal disease (ESRD). This may reflect a congenital variant which accommodated collateral flow to bypass the fully occluded SVC. Alternatively, it may be the result of repeated venoplasty of the stenotic SVC which opened an iatrogenic tract that was maintained and vascularized over time. PMID- 30473971 TI - Postictal Mania Versus Postictal Psychosis. AB - PIM (postictal mania) or PIP (postictal psychosis) usually comes on after a single episode or a seizure cluster of generalized tonic-clonic or complex partial secondarily generalized seizures. Patients maintain a lucid interval of clear consciousness which precedes a psychotic episode. The symptoms may include insomnia, hallucinations, delusions, elated expansive mood, euphoria, and distractibility. We present a case of a 62-year-old male with PIP or mania preceding an episode of seizure. In the light of this case report, we illustrate the importance of being vigilant about the psychotic symptoms in a patient with epilepsy in order to minimize the morbidity. PMID- 30473973 TI - Difficult Patient Encounters: Assessing Pediatric Residents' Communication Skills Training Needs. AB - Introduction Difficult patient encounters (DPEs) are common and can lead to frustration and dissatisfaction among healthcare providers. Pediatric resident physician experiences with DPEs and curricula for enhancing necessary communication skills have not been well described. Materials and methods We used a cross-sectional survey research design for our needs assessment on resident experiences with DPEs. Thirty-three pediatric residents completed this anonymous survey. The survey assessed residents' experiences with and self-efficacy regarding DPEs. Descriptive statistics were used to analyze the quantitative data. Additionally, two authors independently coded free response data to include in the narrative description of the survey results. Results These survey results include the views of 92% of the residents in the program (33/36). Residents reported a greater frequency of difficult encounters in the inpatient setting than the outpatient setting. The majority of residents rated their communication skills during DPEs as "fair" or "good" (70%, 23/33). Residents tended to have lower confidence when discussing chronic pain, managing parental insistence on a plan, and breaking bad news. They generally reported higher levels of anxiety for scenarios involving angry patients and families, families insisting on a plan, and when breaking bad news. Residents cited many challenges, including working with angry and demanding families. Additionally, residents described difficulty with managing discordant opinions between the family and the healthcare team regarding the care plan. Residents expressed a preference for learning how to manage challenging patient encounters using clinical experiences. Simulation, discussion, and observation of role models also rated highly as educational methods for increasing skills, while most residents rated lectures as the least important means of training skills for these difficult encounters. Discussion We found that pediatric residents experience difficult encounters frequently, especially in the inpatient setting. Individual residents vary in their confidence and anxiety levels with different types of difficult encounters and may benefit from not only general communication skills training, but also from targeted training to equip them for the particular contexts they find most challenging. Residents value interactive structured learning activities, including discussion and simulation. Residents most consistently value the opportunity to lead challenging conversations in the clinical setting, especially when followed by effective debriefing and feedback by trained faculty preceptors. Conclusions Next steps include creating a "Difficult Encounters" communication skills curriculum informed by this needs assessment, which aim to enhance patient care as well as increase resident self-efficacy. In addition to the curriculum development for residents, it may be helpful to initiate faculty development on how to supervise resident-led difficult conversations and provide effective debriefing and feedback to promote resident growth. PMID- 30473974 TI - Thromboprophylaxis in Intensive Care Unit Patients: A Literature Review. AB - Thromboembolism is a major complication in hospitalized patients. Intensive care unit (ICU) patients have a greater risk of thrombotic events due to additional risk factors such as immobilization, mechanical ventilation, and central catheters. The diagnosis and management of deep vein thrombosis (DVT) and pulmonary embolism (PE) in critically ill patients are challenging and these conditions are associated with high mortality. Medical thromboprophylaxis with low molecular weight heparin (LMWH) as well as unfractionated heparin (UFH) has been shown to reduce the incidence of thromboembolic events in such patients. For patients with high risk of bleeding, mechanical thromboprophylaxis can be used. Literature database was conducted on Medline for articles published up to 2018 using particular search terms such as thromboprophylaxis and venous thromboembolism in ICU patients. The following review summarizes the existing data regarding thromboprophylaxis in ICU patients with special consideration to the use of mechanical prophylaxis and pharmacologic prophylaxis using heparin products. PMID- 30473975 TI - Endothelial Progenitor Cells and Cardiovascular Correlates. AB - Cardiovascular disease is cited as the underlying cause of death in one out of every three deaths within the United States; this burden on the health care system percolates down to affect patients on an individual level. In part, the problem arises from the low regenerative capacity of cardiovascular system cells, for example, cardiac myocytes, and from oxidative stressors to the human body. Endothelial progenitor cells (EPCs) are a type of stem cell, and various clinical conditions including hypertension and renal failure underlie their dysfunction. EPCs are classified as either early or late outgrowth endothelial progenitor cells depending on the time they appear in circulation and at the site of injury after an inciting event. Their function is paracrine through the release of cytokines, growth factors and chemokines such as interleukin-6 and vascular endothelial growth factor, and they are involved in transdifferentiation into vascular smooth muscle cells and potentially cardiac myocytes. They are beneficial to the modification of cardiovascular cell apoptosis, fibrosis, and contractility. In times of stress, the normal function of endothelial progenitor cells is altered; this creates a maladaptive cycle where stress and failed coping mechanisms enhance each other toward the culmination of cardiovascular disease. The development of the cardiovascular system follows gastrulation in the embryonic period, and the cells that form the system are derived from the mesoderm; being mesoderm, the vascular cells exhibit heterogeneity in their origin and function. The need to understand the molecular and cellular regulatory pathways during development can amalgamate efforts of endothelial cell and cardiovascular system pathophysiology for the advancement of patient cardiovascular reserve and function. PMID- 30473976 TI - Microbiological Profile of Chronic Tonsillitis in the Pediatric Age Group. AB - Introduction Tonsillitis is a very common disease in children. Understanding the microbiology and pathology of chronic tonsillitis is an important step in its management. The aim of the study was to describe the microbiological profile of core tonsillar tissue in chronic tonsillitis in children. Materials and methods Children under 16 years of age with chronic tonsillitis were recruited in the descriptive study. Children with recurrent tonsillitis and recurrent tonsillitis with obstructive symptoms were included. Children who underwent tonsillectomy for obstructive symptoms alone and those who received antibiotics for at least one month prior to surgery were excluded from the study. Dissection and the snare method of tonsillectomy were done on all children. The operated specimen was cut into two halves in a sterile container. The core of the tonsillar tissue was swabbed with two sterile cotton-tipped swabs and sent for the microbiological evaluation of aerobes and anaerobes. The tonsillar tissue was sent for a histopathological examination. Results A total of 106 children were operated for chronic tonsillitis in one year. The mean age of children included in this study was 9.4 years. The duration of symptoms due to tonsillar disease ranged from four weeks to 28 months. There were 48 males and 58 females. Recurrent tonsillitis was the most common indication for tonsillectomy in all children. A total of 301 aerobes and 171 anaerobic microorganisms were isolated from 106 children with chronic tonsillitis. The aerobic bacterial species most often isolated was Streptococcus viridans, which was present in 83 children followed by Group A, beta-hemolytic Streptococci in 67 children. The anaerobic bacterial most often isolated was Peptococcus species in 49 children. Polymicrobial aerobic and anaerobic flora were present in all tonsillar specimens, yielding an average of 4.1 isolates per specimen. The histopathological examination revealed chronic tonsillitis with reactive follicular hyperplasia in all (100%) children. Actinomycosis was associated with non-specific reactive follicular hyperplasia in four specimens. Conclusion Polymicrobial aerobic and anaerobic flora are identified in deep tonsillar tissue in children with tonsillitis. The identification of bacterial isolates from the core tissue in recurrent tonsillitis could dictate the management of chronic tonsillitis. The histopathological examination of the core tissues of the tonsils helps in an accurate identification of organisms that are difficult to culture. PMID- 30473977 TI - Finding a Better Solution for Asthma Control in Children. AB - Asthma is a chronic respiratory condition that is very common among children. With proper management and follow-ups, this condition can be easily controlled in a child. However, there are several factors that are negatively influencing a proper care of asthmatic children throughout the world. In this mini-review, the roles of the parents, the schools and the child himself were analyzed and several possible solutions to improve those hurdles were discussed. PMID- 30473978 TI - Sleep-related Eating Disorder in a Patient with Parkinson's Disease. AB - Sleep disorders constitute a major aspect of the non-motor symptoms of Parkinson's disease (PD). Rapid eye movement (REM) behavior disorders are the most frequently experienced parasomnias in patients with PD. Non-REM sleep disorders like confusional arousals, sleep terrors, sleepwalking, and sleep related eating disorder (SRED) are also associated with PD. Parasomnias can affect the quality of life of the patients as well as the night time sleep of their bed partners. Hence, it is important for physicians to recognize the occurrence of parasomnias in PD. We report an unusual case of PD with SRED along with obstructive sleep apnea (OSA) and REM behavior disorder. To our knowledge, only two cases have been reported in the literature highlighting the association of SRED with PD. We also explain the different night-time eating disorders like nocturnal eating syndrome and binge eating syndrome, which can be seen in PD, and differentiate them from SRED. PMID- 30473979 TI - Multimodality Intraoperative Neurophysiological Monitoring (IONM) in Anterior Hip Arthroscopic Repair Surgeries. AB - Arthroscopic hip surgery is performed routinely for the treatment of various hip disorders. Leg traction during labral tear repair, femoroplasty, and acetabuloplasty for hip stabilization can stretch the peripheral nerves. This may cause temporary or permanent nerve injury. This study illustrates the benefit of utilizing multimodality Intraoperative Neurophysiological Monitoring (IONM) during hip surgical procedures. We performed a retrospective review of 10 arthroscopic hip surgeries with neurophysiological monitoring at one medical center. The patients consisted of six females and four males (mean age: 48.9 years). The procedures were equally divided into left and right-sided procedures. IONM setup included posterior tibial, peroneal, and femoral or saphenous nerve somatosensory evoked potentials (SSEPs), transcranial electrical motor evoked potentials (TCeMEP), train of four (TOF), and electromyography (EMG) from the lower extremities. All patients exhibited changes in IONM data during the surgical procedure. Changes in the latency and amplitude or loss of the lower SSEPs on the surgical side occurred in 36% of the monitorable SSEPs. The surgeon instructed the team to reduce the leg lengthening by removing traction when changes were observed. The SSEPs exhibited a full recovery in 75% of the affected lower extremity SSEPs. In the two instances of nonrecovery, the SSEP responses remained increased in latency or decreased in amplitude at closing, but the waveform was intact. There were five instances of complete loss of the waveform (four in the ipsilateral leg, and one in the contralateral leg) with recovery after traction was reduced. TCeMEP changes occurred in 53% of the ipsilateral lower muscles monitored. Many of the TCeMEP changes were attributed to ischemia of the feet and could not be resolved intraoperatively. Multimodality IONM can be a beneficial and protective tool during surgical procedures involving hip and acetabular areas. Early identification of changes in evoked potentials during hip arthroscopy surgeries can minimize post-operative neurological deficits due to peripheral nerve injury and leg ischemia. PMID- 30473980 TI - Anti-coagulation Drug Warfarin Contributes to Severe Adverse Outcomes in Prolonged Unsupervised Use: A Double-edged Sword. AB - Anti-coagulation medications are widely used in clinical practice, especially in the United States as cardiac-related emergencies are on the rise. An overarching caveat in using anti-coagulation drugs as a long-term treatment regimen, such as warfarin, is that patients are closely monitored by their primary care provider. Routine monthly laboratory examinations are strictly required to assess the international normalized ratio (INR) which measures prothrombin time (PT), providing insight into how long it takes for blood to clot. A 58-year-old Caucasian male presented with non-traumatic acute quadriplegia with cord compression starting at the 3rd cervical (C3) level and continuing throughout the entire spinal cord. Radiological studies revealed severe cervical stenosis from C3 to C7 resulting from a posterior spinal mass, thoracic and lumbar spine studies revealed a compressive posterior acute epidural hematoma (EDH) compressing the thoracic spinal cord from T6 to T10 with signal change, as well as a L4-S1 posterior acute epidural hematoma compressive of the cauda equina. Upon detailed review of our patient's history it became evident that our patient had been on a prolonged and unsupervised warfarin (Coumadin) regimen for congestive heart failure without primary care follow-up or routine laboratory testing. Our patient was a prime surgical candidate for an immediate two-stage decompression, hematoma evacuation and instrumentated fusion surgery. Post operatively, our patient regained leg strength to 2/5 and arm strength to 4+/5. PMID- 30473982 TI - Cerebellopontine Angle Lesions (Part 1). PMID- 30473983 TI - Retrosigmoid Transmeatal Endoscope-Assisted Approach in Semi-Sitting Position for Resection of Vestibular Schwannoma: 2-D operative Video. AB - We present a case of a mid-sized vestibular schwannoma (T3b according to the Hannover classification) that was resected through a retrosigmoid transmeatal approach in semi-sitting position under endoscopic assistance. The patient is a 52-year-old male with acute loss of functional hearing on the right side. Audiometry confirmed a loss of up to 60 dB and lost speech discrimination, there were no associated symptoms such as tinnitus or vertigo. This 2D video demonstrates positioning, OR set-up, anatomical and surgical nuances of the skull base approach and the operative technique for microdissection of the tumor from the critical neurovascular structures, especially the facial and cochlear nerves. A gross total resection was achieved and the patient discharged home after four days with unaltered function of the facial nerve (HB I). At one year follow up there was no indication of residual or recurrence. In summary, the retrosigmoid transmeatal approach is an important and powerful tool in the armamentarium for the microsurgical management of all kinds of vestibular schwannomas. Provided the necessary anesthesiological precautions and intraoperative procedures the semi sitting position is safe and effective. If needed, the approach can be complemented by the use of an endoscope for visualization of the distal internal auditory canal. The link to the video can be found at: https://youtu.be/pPKT4_5nIn0 . PMID- 30473984 TI - Microsurgical Gross Total Resection of a WHO Grade II Cerebellopontine Angle Ependymoma in an Adult. AB - Infratentorial ependymomas that arise in the fourth ventricle and extend into the cerebellopontine angle (CPA) through the foramina of Luschka are well described. However, a primary CPA location of an ependymoma is distinctly uncommon. In this video, we present a 46-year-old man with episodes of dizziness, left-sided tinnitus, imbalance, double vision, and nausea. An magnetic resonance imaging (MRI) scan of the head showed a large mass lesion centered in the CPA with heterogenous enhancement. Differential diagnosis included ependymoma, meningioma, schwannoma of the vestibular nerve, or lower cranial nerves, and choroid plexus papilloma. He underwent microsurgical gross total resection of the tumor via a retrosigmoid approach. Direct stimulation of the cranial nerves was performed throughout the case and there was no attachment of the tumor to any cranial nerve to suggest that this might be a schwannoma. The tumor encased important vasculature, including the posterior-inferior cerebellar artery. The histopathology was a grade II ependymoma. The patient tolerated the surgery well and his postoperative course was uneventful. He remained neurologically intact. He received radiation therapy and there was no recurrent or residual disease on follow-up studies. This video demonstrates important steps of the surgical approach and microsurgical resection techniques for this type of challenging tumor. The link to the video can be found at: https://youtu.be/KK-y6EYh888 . PMID- 30473985 TI - Microsurgical Decompression of Trigeminal Neuralgia Caused by Simultaneous Double Arterial (SCA and AICA) and Petrosal Vein Complex Compression. AB - Trigeminal neuralgia is a chronic pain disorder affecting the face. In approximately 80% of cases, it is most commonly caused, when the root entry zone (REZ) of the trigeminal nerve is compressed by the superior cerebellar artery (SCA). The etiology of the remaining 20% of cases is distributed among venous, arteriovenous malformations, posterior fossa tumors, multiple sclerosis plaque compressions, and other pathologies. Combinations of those compressive factors are very rare. 1 2 3 4 Herein, we present a video clip of microvascular decompression (MVD) in a 73-year-old female, who has failed conservative treatment with 6 medications over 10 years. She was affected by a unique triple compression of the right REZ by the SCA, anterior inferior cerebellar artery (AICA), and petrosal vein complex ( Fig. 1A ). Right-sided microsurgical decompression of the REZ of the trigeminal nerve through standard retrosigmoid craniotomy was performed by the senior author (K.I.A.). The SCA and AICA were separated from the nerve using Teflon pledgets. The petrosal vein complex was coagulated and divided, freeing up the right trigeminal nerve ( Fig. 1B ). The patient was discharged home on the third postoperative day with complete resolution of trigeminal neuralgia. The link to the Video can be found at: https://youtu.be/PYVvImGW0yE . PMID- 30473987 TI - Chronic Urinary Retention due to Fowler's Syndrome. AB - Fowler's syndrome (FS) is a rare cause of chronic urinary retention in teenage girls and young women. We present a case of a 14-year-old girl who presented at our hospital 2 weeks after uncomplicated laparoscopic appendectomy. The girl complained of reduced urinary frequency and prolonged micturition time. Following an acute cystitis 2 months later, she completely lost her ability to void. A comprehensive set of investigations to assess the cause of her urinary retention including a cerebral and spinal magnetic resonance imaging (MRI), and videourodynamics were performed. The diagnostic workup revealed polycystic ovaries and an asensitive and hypotonic bladder with capacity up to 1200 mL and high maximum urethral pressure of 120 cm of water. She did not tolerate clean intermittent catheterization; therefore, a suprapubic catheter was placed. Under this treatment, she suffered recurrent urinary tract infections. Two years later, she was diagnosed with FS on the basis of the medical history, clinical symptoms, and urodynamic findings. Finally, the implantation of a S3 neurostimulator restored her ability to void. PMID- 30473986 TI - Chondrosarcoma in the Petrous Apex: Case Report and Review. AB - Introduction Surgical treatment of petrous apex chondrosarcoma is challenging due to the location of the tumor. Using an endoscopic technique for tumor resection is favored since it provides a minimally invasive approach. Case Presentation A 57 years old female was admitted for acute onset of left abducens nerve palsy and occasional headache mainly on the left side of the retro-orbital area with some radiation to the left occiput. Magnetic resonance imaging (MRI) and computed tomography (CT), at the time of admission, were showed lytic lesion on the left petrous apex and left part of the clivus. Results of metastatic workup were negative. The surgical procedure considered was expanded endoscopic endonasal transclival approach to the left of the petrous apex and reconstruction with a pedicled nasoseptal flap with image guidance system. The pathology confirmed chondrosarcoma on myxoid background. The surgical procedure was uncomplicated. The abducens nerve palsy was resolved in few weeks and no new deficits occurred. Postoperative MRI showed complete resection of the tumor. Conclusion Expanded endoscopic endonasal transclival approach to petrous apex and reconstruction appears to be safe and feasible technique, capable of achieving total removal of identified lesions near the petrous apex. Nonetheless, future studies with a greater number of patients are crucial to confirm and consolidate this initial impression. PMID- 30473989 TI - A Case of Inferior Vena Cava Thrombosis Induced by Left Iliac Vein Stents. AB - Stents have been widely used to restore the patency of the iliac vein in the treatment of its obstruction. However, various complications related to those stents have been reported. This case report covers a 67-year-old male who was diagnosed with left iliofemoral venous post-thrombotic syndrome with recurrent acute deep venous thrombosis. Thrombosis of the inferior vena cava was induced by pronounced extension of left iliac vein stents. Extending stents in this way covers the outlet of the contralateral common iliac vein and may induce thrombosis in the inferior vena cava. PMID- 30473988 TI - The Excised Appendix Tip-To Send or not to Send, That is the Question. AB - A 9-year-old boy, with previous anorectal malformation and neuropathic bladder and bowel, underwent ileocystoplasty, Monti-Mitrofanoff and appendix antegrade colonic enema procedure. The tip of the macroscopically normal appendix was sent for routine histopathology. Microscopy demonstrated a 5-mm well-differentiated neuroendocrine tumor extending into muscularis propria. K i -67 index was <2%. Due to margin involvement, the appendix conduit and surrounding skin were re excised and a tube cecostomy was created through a separate incision. Microscopy revealed no residual neuroendocrine tumor, and no further treatment was required. PMID- 30473990 TI - The current status of decompressive craniectomy in traumatic brain injury. AB - Purpose: This review describes the evidence base that has helped define the role of decompressive craniectomy (DC) in the management of patients with traumatic brain injury (TBI). Recent findings: The publication of two randomized trials (DECRA and RESCUEicp) has strengthened the evidence base. The DECRA trial showed that neuroprotective bifrontal DC for moderate intracranial hypertension is not helpful, whereas the RESCUEicp trial found that last-tier DC for severe and refractory intracranial hypertension can significantly reduce the mortality rate but is associated with a higher rate of disability. These findings have reopened the debate about 1) the indications for DC in various TBI subtypes, 2) alternative techniques (e.g. hinge craniotomy), 3) optimal time and material for cranial reconstruction, and 4) the role of shared decision-making in TBI care. Additionally, the role of primary DC when evacuating an acute subdural hematoma is currently undergoing evaluation in the context of the RESCUE-ASDH randomized trial. Summary: This review provides an overview of the current evidence base, discusses its limitations and presents a global perspective on the role of DC, as there is growing recognition that attention should also focus on low- and middle income countries due to their much greater TBI burden. PMID- 30473993 TI - Addressing antiretroviral therapy-related diagnostic coverage gaps across South Africa using a programmatic approach. AB - Background: A major challenge facing South Africa is the concomitant HIV and tuberculosis epidemics. The National Health Laboratory Service provides testing for staging HIV-positive patients, monitoring patients on antiretroviral therapy (ART) and diagnosing tuberculosis. Not all health districts have equivalent ART related coverage in particular for CD4 and HIV viral load testing. Objectives: The Integrated Tiered Service Delivery Model coverage precinct approach was used to address ART-related testing service coverage gaps in a manner that balances cost, quality and equity. Methods: An algorithm was developed to identify and address ART-related diagnostic coverage gaps. Data was extracted from the corporate data warehouse and Oracle systems for the period of April 2015 to March 2016. Daily test volumes were based on 21.73 working days per month. Data were analysed using MS Excel and mapped using ArcCatalog and ArcMap. Capacity analysis was informed by the available testing-platforms. Results: Health district daily HIV viral load volumes ranged from 2 to 1308 samples. Nineteen candidate laboratories were identified to address the coverage gaps. Following the proximity analysis, testing was consolidated at four candidate laboratories, resulting in 13 revised candidate laboratories. The revised candidate laboratory daily HIV viral load referrals ranged between 5 and 205 samples, with CD4 volumes between 6 and 85 samples. Remaining coverage gaps were identified in seven municipalities. Conclusions: The study demonstrated that the service coverage precinct approach could be used to identify coverage gaps for a defined ART related testing repertoire. PMID- 30473994 TI - Support to address barriers to learning for learners who are deaf. AB - Background: There is great importance in support services for successfully addressing the barriers to learning optimally or learners who are deaf. The study, though conducted in South Africa, has national and international appeal. Objectives: The aim of the study was to identify educator reflections on support services needed for them to address barriers to learning of learners who are deaf. Method: The study used a qualitative design for collecting data in natural settings. A sample size of 11 educators of learners who are deaf was purposively selected from two provinces of South Africa. The study used an open ended individual interview questionnaire. Results: Data was analysed using qualitative content analysis considering the context of the schools in which the study was carried out. Results showed that there was: limited curriculum support in special schools; lack of support and inadequate teaching and learning materials; overcrowding in one school and; limited support of multidisciplinary professionals in most schools. Conclusion: The study provided a framework for support services important for research, policy and practice. Of significance was the relevance of the Universal Design for Learning (UDL) theoretical framework in implementing support services programmes in schools. PMID- 30473991 TI - Cellular senescence in intervertebral disc aging and degeneration. AB - Purpose: Age is a major risk factor for multiple disease pathologies, including chronic back pain, which stems from age-related degenerative changes to intervertebral disc tissue. Growing evidence suggest that the change in phenotype of disc cells to a senescent phenotype may be one of the major driving forces of age-associated disc degeneration. This review discusses the known stressors that promote development of senescence in disc tissue and the underlying molecular mechanisms disc cells adopt to enable their transition to a senescent phenotype. Recent findings: Increased number of senescent cells have been observed with advancing age and degeneration in disc tissue. Additionally, in vitro studies have confirmed the catabolic nature of stress-induced senescent disc cells. Several factors have been shown to establish senescence via multiple different underlying mechanisms. Summary: Cellular senescence can serve as a therapeutic target to combat age-associated disc degeneration. However, whether the different stressors utilizing different signaling networks establish different kinds of senescent types in disc cells is currently unknown and warrants further investigation. PMID- 30473995 TI - Implementation of the 2006 Convention on the Rights of Persons with Disabilities in Zimbabwe: A review. AB - Background: The Convention on the Rights of Persons with Disabilities came into place in 2006, as the main instrument for advancing the human rights of persons with disabilities. For many African states, the Convention came amidst ubiquitous marginalisation and discrimination of persons with disabilities. As expected, the Convention has been hailed as a landmark in the struggle to reframe the needs and concerns of persons with disabilities. Objectives: This article reviews the implementation of the Convention by the Zimbabwean government. Method: The study relies on reviews of extant literature on disability rights. Reviewed documents include the Convention, constitution and other related national laws, policies and measures pertaining to disability rights. Results: This article lauds the state for promulgating a disability-friendly constitution that resembles the Convention to effectuate a human rights approach to disability issues. Relatedly, the state came up with institutions that collaborate with research institutes and disability organisations to conduct research, provide services to persons with disabilities, raise awareness and advocacy and litigate for disability rights. Conclusion: In spite of these efforts, this article shows that Zimbabwe has yet to close the gap on the ideals of the Convention, mainly because of limited resources amongst state-funded institutions for advancing disability issues. The government of Zimbabwe is challenged to domesticate all provisions of the Convention and to provide resources to institutions for progressive realisation of the rights of persons with disabilities. PMID- 30473992 TI - Development of a technology-based behavioral vaccine to prevent adolescent depression: A health system integration model. AB - Efforts to prevent depression have become a key health system priority. Currently, there is a high prevalence of depression among adolescents, and treatment has become costly due to the recurrence patterns of the illness, impairment among patients, and the complex factors needed for a treatment to be effective. Primary care may be the optimal location to identify those at risk by offering an Internet-based preventive intervention to reduce costs and improve outcomes. Few practical interventions have been developed. The models for Internet intervention development that have been put forward focus primarily on the Internet component rather than how the program fits within a broader context. This paper describes the conceptualization for developing technology based preventive models for primary care by integrating the components within a behavioral vaccine framework. CATCH-IT (Competent Adulthood Transition with Cognitive-behavioral, Humanistic and Interpersonal Training) has been developed and successfully implemented within various health systems over a period of 14 years among adolescents and young adults aged 13-24. PMID- 30473996 TI - Perceptions and satisfaction of caregivers regarding rehabilitation services from selected rehabilitation centres in the Western Cape. AB - Background: Understanding caregivers' views on rehabilitation services is important as it may assist in informing healthcare services and patient management. Objectives: The aim of this study was to explore caregivers' perceptions and satisfaction regarding rehabilitation services in the Western Cape, South Africa, and to inform clinical practice and policy in this emerging field. Method: This study used a descriptive, qualitative design using in-depth interviews with conveniently selected participants. Interviews were conducted with 13 caregivers of patients with: amputations (3), cerebrovascular accidents (5) and neuromuscular disorders (5). Thematic content analysis was conducted with the transcripts. Results: Four key themes emerged, which were (1) financial difficulties, (2) caregiver and therapist relationships, (3) facility management and (4) caregiver experience with service delivery. Conclusion: Based on the participants' feedback, the rehabilitation services seem to be meeting the basic rehabilitation needs of the patients; however, the needs of the caregivers require attention. PMID- 30473998 TI - The carry-over effect of an aquatic-based intervention in children with cerebral palsy. AB - Background: Cerebral palsy (CP) is the most common motor disability in childhood. Children with CP are more likely to have lower levels of physical activity than their peers, which has negative implications for their health. However, aquatic exercise can be used to improve levels of fitness among children with CP. Objective: To determine the carry-over effect of an aquatic-based programme (postural control and balance) on land (walking, running and jumping) in children with CP, post aquatic intervention. Method: The study used a pretest-post-test, randomised group, cross-over design. Children aged 8-12 years (n = 10) were divided into intervention (n = 5) and control (n = 5) groups. The intervention group participated in two 30-min sessions a week, while the control group continued with normal activities. Pre- and post-intervention testing was conducted using gross motor function measurement. The 10-point programme of the Halliwick Concept was used. Results: Results demonstrated that the aquatic therapy had a significant effect on gross motor function scores. The aquatic programme-based group showed increased motor function following the intervention, compared to the control group (z = -2.803, p = 0.005). Furthermore, the aquatic based therapy improved the average score for gross motor function measurement, post-intervention. Conclusion: Together with conventional modes of therapy, aquatic-based programmes should be integrated and considered as an essential, ongoing mode of treatment for children with CP, in order to ensure long-term gross motor function improvements. PMID- 30473997 TI - Parents of children with disabilities: A systematic review of parenting interventions and self-efficacy. AB - Background: An increasing body of empirical evidence suggests that early intervention has positive outcomes for parents of children with neurodevelopmental disabilities. Parental self-efficacy has been used as an outcome measure in some empirical studies; however, there is a lack of evidence of the impact of parent training programmes on parenting self-efficacy beliefs. Objectives: This systematic review sought to assess the effectiveness of parenting interventions to increase parental self-efficacy levels in parents of young children with neurodevelopmental disabilities. Method: We conducted a broad literature search, which included grey literature, such as dissertations and unpublished conference presentations, to identify all relevant prospective studies reporting on our study objective. Articles were selected for inclusion using predefined criteria and data were extracted onto a purposely designed data extraction form. Twenty-five articles met our search criteria. We extracted parenting self-efficacy scores before, and on, completion of parenting interventions and performed a meta-analysis using standardised mean difference. We also conducted a risk of bias assessment for all the included studies. Results: Parent training programmes resulted in a statistically significant increase in parental self-efficacy levels (standardised mean difference, 0.60 [95% confidence interval {CI}, 0.38-0.83]; I2, 74%) relative to baseline measurements. Parents of children younger than 5 years demonstrated the highest increase in levels of parental self-efficacy after parenting interventions. Furthermore, this review showed that psychologists and other healthcare practitioners are successfully able to implement training programmes that enhance parenting self-efficacy. Conclusion: Parent training programmes are effective in increasing parental self-efficacy in parents of children with neurodevelopmental disabilities. PMID- 30473999 TI - Part 1: A review of using photovoice as a disability research method: Implications for eliciting the experiences of persons with disabilities on the Community Based Rehabilitation programme in Namibia. AB - Background: Although the Community Based Rehabilitation (CBR) programme in Namibia was formally adopted in 1997, the effectiveness of the programme, including the experiences of persons with disabilities on the programme, has not been assessed to date. Objectives: To explore the need for a qualitative evaluation tool for the CBR programme that can elicit the experiences of persons with disabilities. Methods: A scoping review was conducted on the use of photovoice as a disability research method and its potential use in eliciting the experiences of persons with disabilities participating in the CBR programme. A comprehensive literature search was conducted on electronic databases as a part of the scoping review. Results: Twenty-one studies were selected for review. Six studies followed the exact steps of the traditional photovoice process, and the remaining 15 studies modified the process. Seventeen studies used photovoice as the only research method, 3 combined photovoice with a qualitative method and only one study combined photovoice with a quantitative method. Seven studies had a sample size ranging from 6 to 10 participants as suggested by the traditional photovoice process. The duration of the studies ranged from 2 weeks to 2 years. Thirteen studies investigated life experiences of persons with various disabilities and 17 studies suggested that the photovoice process increases empowerment. Conclusion: Photovoice is a versatile research method and has the potential to be utilised in effectively eliciting the experiences of persons with disabilities on the CBR programme in Namibia. PMID- 30474000 TI - Part 2: The feasibility of utilising photovoice method and the World Health Organization Quality of Life instrument in evaluating the Community-Based Rehabilitation programme in Namibia: A pilot study. AB - Background: Evaluation of Community-Based Rehabilitation (CBR) programmes in Namibia has been primarily quantitative, focusing mainly on outputs, including numbers of persons with disabilities served, referrals made and activities implemented. Little or no evidence is available on experiences and quality of life of persons with disabilities, despite the CBR programme being operational for more than 20 years. The 2011 World Report on Disability recommended the use of appropriate tools to fill the research gap by integrating the experiences of persons with disabilities and their quality of life. Objectives: The overall objective of the larger cohort study is to develop a monitoring and evaluation tool that can measure and integrate the experiences of persons with disabilities and their quality of life within the context of the CBR Programme in Namibia. Method: An adapted photovoice process was conducted with six purposively selected participants over a period of 1 month. The World Health Organization Community Based Rehabilitation (WHO CBR) Matrix was used to identify the themes and subthemes. Participants were requested to complete the World Health Organization Quality of Life (abbreviated version) (WHOQOL-BREF) instrument at the end of the photovoice process to determine their quality of life. Results: Administering the WHOQOL-BREF instrument at the end of the photovoice process measured both the quality of life of persons with disabilities and at the same time indicated the convergence and divergence in the two data collection methods. The study demonstrated a stronger convergence than divergence of the two methods. A feasibility criterion was mapped for future studies. Conclusion: This study demonstrated that photovoice is a flexible method that can be used with a variety of disabilities and has the potential of being combined with the WHOQOL-BREF assessment form. A larger cohort study may consider implementing photovoice and WHOQOL-BREF on multiple study sites and be able to compare results, considering geographical and demographic variables. The feasibility of utilising each method alone and in combination offered valuable insights on future conceptual framing of CBR programme evaluation. This conceptual framing will allow CBR practitioners to appreciate how these two methods contribute to a rigorous process of CBR programme evaluation. PMID- 30474001 TI - Exercise and Prospective Memory. AB - The purpose of this paper was to review the literature to evaluate the potential effects of exercise on prospective memory (PM). A narrative review was employed. In this review, we provide a brief description of PM; indicate the effects of PM on health; evaluate the effects of age and neurological impairment on PM; examine the neural correlates of PM; provide a description of specific components that subserve PM; identify non-behavioral strategies used to enhance PM; and evaluate the literature and plausibility through which exercise behavior may influence PM. Regarding the latter, this paper aims to burgeon the development of a new research paradigm that will play a critical role in patient health, given that memory function, and in particular, the prospective (vs. retrospective) component of memory, is highly sensitive to aging and is critically associated with health status. This is an emerging line of research that has critical implications for patient health. PMID- 30474002 TI - Effects of School-based Health Promotion Intervention on Health Behaviors among School Adolescents in North Lima and Callao, Peru. AB - Background: Multicomponent interventions that include both school and family or community involvements have the potential to cause significant changes in the levels of health in adolescents. To this end, KOICA and Yonsei Global Health Center implemented a school-based health promotion program from 2015 to 2016 in Northern Lima and Callao, Peru. The present study aimed to evaluate the effects of a school-based health promotion intervention on the health behaviors of school adolescents in Peru. Methods: Health behaviors were measured using a standard self-administered questionnaire before and after the introduction of a school based health promotion intervention in 2014 and 2016. The intervention was executed in secondary schools, specifically two schools from Lima and two from Callao, from April 2015 to November 2016. Two schools (one from each area) were selected as control schools. The interventions included health education, screening, and psychological counseling of vulnerable individuals as well as education for teachers and workshops with parents. Results: Descriptive statistics, chi-square test results, and logistic regression values were computed. Sample sizes were 332 and 255 in 2014 and 933 and 599 in 2016 in the intervention and control schools, respectively. Logistic regression analysis revealed significant improvement in the consumption of vegetables and in depression in the intervention schools. Suicide attempts, television-watching, video game use, Internet use, consumption of chips and sugary drinks, and being in fights did not decrease in the intervention group but did increase in the control group. Thus, the intervention might have prevented the worsening of these behaviors in the intervention schools. Conclusion: The intervention had a positive effect on vegetable consumption and feeling depressed as well as on preventing the increase in sedentary behaviors, fighting, and suicide attempts. PMID- 30474003 TI - Health-promoting Lifestyles of Nurses and Its Association with Musculoskeletal Disorders: A Cross-Sectional Study. AB - Background: Work-related musculoskeletal disorders are a significant concern for public health, leading to temporary and permanent disability. Health care workers, including nurses, are at high risk for these disorders. This study aimed to assess the health-promoting lifestyles of nurses and their association with musculoskeletal disorders and symptoms. Methods: This study explored health promoting lifestyles and their association with musculoskeletal symptoms in nurses. In this cross-sectional study, a total of 300 nurses working in the teaching hospitals affiliated with Shiraz University of Medical Sciences (SUMS), were selected using systematic random sampling. Data were collected by two questionnaires, the Health-promoting Lifestyle Profile (HPLP) and the Nordic Musculoskeletal Questionnaire (NMQ). Results: Study findings showed that 47% of the study participants had a moderate level lifestyle. In terms of musculoskeletal symptoms, the most prevalent were reported in the back (88.33%), knees (83.33%), and thighs (71%). Moreover, Pearson correlation analysis revealed significant negative correlations between eating habits and musculoskeletal symptoms and interpersonal relations, while a significant positive correlation was found between nutrition and stress management with musculoskeletal symptoms. Conclusion: Lifestyle variables are a good predictor for nurses' musculoskeletal symptoms. Therefore, knowledge of health-promoting lifestyle behaviors and practice of these behaviors are necessary to reduce musculoskeletal disorders among nurses. PMID- 30474004 TI - Body Mass Index in Master Athletes: Review of the Literature. AB - Background: Masters athletes (MAs) have led a physically active lifestyle for an extended period of time or initiated exercise/sport in later life. Given the benefits of physical activity and exercise we investigated if body mass index (BMI), an indirect health indicator of obesity, was clinically superior in MAs as compared to controls or the general population. Methods: Seven databases (Medline, PubMed, Scopus, Web of Science, CINAHL, PsycINFO, Cochrane) were electronically searched for studies on BMI (kg/m2) or as a percentage of BMI categories (underweight, normal, overweight, obesity) in MAs. Results: Of the initial yield of 7,431 papers, 60 studies met our inclusion criteria and were used in this literature review. Studies identified were classified as: endurance sports (n = 14), runners (n = 14), mixed sports (n = 8), cyclists (n = 4), soccer (n = 4) swimmers (n = 3), non-specific (n = 3), orienteering (n = 2), World Masters Games (n = 2) and individual sports (n = 5). Where BMI was presented for the group of MAs the mean was 23.8 kg/m2 (+/- 1.1) with a range from 20.8 kg/m2 (endurance runners) to 27.3 kg/m2 (soccer players), this was significantly lower (p < 0.001) than controls ( -9.5%, 26.13 +/- 1.7 kg/m2). Where gender specific BMI was reported the mean for male MAs was 23.6 kg/m2 (+/- 1.5) (range 22.4 kg/m2 endurance to 26.4 kg/m2 swimmers) and 22.4 kg/m2 (+/- 1.2) for female MAs (range 20.8 kg/m2 mixed to 24.7 kg/m2 WMG). Conclusion: In most, but not all studies the BMI of MAs was significantly lower than controls. A clinically superior BMI affords MAs reduced risk with regard to a number of cardiometabolic diseases, osteoarthritis and certain types of cancers. PMID- 30474005 TI - The Association between Lower Extremity Muscular Strength and Cognitive Function in a National Sample of Older Adults. AB - Background: We evaluated the association between lower extremity muscular strength and cognition among older adults in the United States. Methods: Data from the 1999-2002 National Health and Nutrition Examination Survey was used to identify 1508 older adults, between 60-85 years. Muscle strengthening activities were assessed via self-report. Participation in physical activity was determined from self-report data. The DSST was used to assess participant executive cognitive functioning tasks of pairing and free recall. A Kin-Com MP isokinetic dynamometer (Chatanooga Group Inc.) was used to assess lower extremity strength, expressed as absolute strength (N), relative strength (N/body weight in kg), and high (<245.75 N) vs. low (<=245.75 N) absolute strength based on the median levels of strength. Results: Lower extremity strength (beta = 0.01; 95% CI: 0.0008-0.03; p = 0.039) was associated with higher cognitive performance, independent of age, muscle strengthening activities, physical activity and other covariates. In an adjusted multivariate logistic regression model, those with high (vs. low) strength had a 34% reduced odds of having low cognitive function (OR = 0.66; 95% CI: 0.46-0.93; p = 0.02). Conclusion: In this nationally representative sample of older adults, there was a positive association between elevated lower extremity muscular strength and cognitive functioning. PMID- 30474006 TI - Prevalence of Nicotine Dependence among Men Aged 21-60 Years in the Rural Field Practice Area of a Tertiary Care Hospital in Tamil Nadu, India. AB - Background: The World Health Organization (WHO) estimated that about 4 million deaths worldwide annually are attributable to tobacco use. Tobacco use is an important risk factor for numerous chronic diseases like cancer, diseases of the lungs, and cardiovascular diseases. Despite this, tobacco use is common throughout the world. Almost 150 million young people are known to use tobacco out of which a majority worldwide began this when they were adolescents. The complex mechanism of nicotine dependency makes it challenging to evaluate dependence or progress towards dependence. The objectives of the study were: (1) To assess the prevalence of nicotine dependence among tobacco users. (2) To study the correlates of nicotine dependence among rural population. Methods: A cross sectional study was conducted using a predesigned and pretested structured proforma. The study was conducted among men of 21-60 years in field visit area of SRM medical college. Karl fagerstrom nicotine dependence questionnaire was used to assess dependence on nicotine. Results: The overall proportion of smokers was 35%. The mean age of initiation of smoking was 20.09 years and the reason was peer pressure, duration of smoking was 11.98 years. 46% of smokers had intention to quit smoking, others gave a reason as addiction (51.6%) for not quitting. Significant association was found between tobacco use and socio-economic parameters such as age group, marital and socio economic status. Conclusion: The proportion of smokers was 35%. Significant determinants of smoking were those aged more than 40 years, those of lower socio economic status. PMID- 30474007 TI - Survival After Childhood Cancer-Social Inequalities in High-Income Countries. AB - Despite substantial improvements in survival from childhood cancer during the last decades, there are indications that survival rates for several cancer types are no longer improving. Moreover, evidence accumulates suggesting that socioeconomic and sociodemographic factors may have an impact on survival also in high-income countries. The aim of this review is to summarize the findings from studies on social factors and survival in childhood cancer. Several types of cancer and social factors are included in order to shed light on potential mechanisms and identify particularly affected groups. A literature search conducted in PubMed identified 333 articles published from December 2012 until June 2018, of which 24 fulfilled the inclusion criteria. The findings are diverse; some studies found no associations but several indicated a social gradient with higher mortality among children from families of lower socioeconomic status (SES). There were no clear suggestions of particularly vulnerable subgroups, but hematological malignancies were most commonly investigated. A wide range of social factors have been examined and seem to be of different importance and varying between studies. However, potential underlying mechanisms linking a specific social factor to childhood cancer survival was seldom described. This review provides some support for a relationship between lower parental SES and worse survival after childhood cancer, which is a finding that needs further attention. Studies investigating predefined hypotheses involving specific social factors within homogenous cancer types are lacking and would increase the understanding of mechanisms involved, and allow targeted interventions to reduce health inequalities. PMID- 30474009 TI - Vaginal microbiome in pregnant women according to trimester and its association with preterm birth: critical appraisal of a cross-sectional study. PMID- 30474010 TI - Isotretinoin exposure in pregnant women in Korea. AB - Objective: Isotretinoin is a notorious teratogen otherwise used for the treatment of acne vulgaris. Some countries, including those in North America and the European Union, implemented the pregnancy prevention program (PPP); however, no PPP has yet been established in South Korea. So the aim of this study was to evaluate the rate of pregnant women exposed to isotretinoin among the callers of the Korean Mother Safe Counseling Center. Methods: This is a prospective cohort study. We evaluated the demographic characteristics, obstetric history, and isotretinoin exposure of pregnant women based on the mother safe registry from April 2010 to July 2016. Results: Among 22,374 callers, 650 (2.9%) pregnant women were exposed to isotretinoin. The mean age was 29.0+/-4.4 years in the isotretinoin-exposed group and 32.0+/-4.2 years in the unexposed group (P<0.001). Moreover, the incidence of pregnancies within 30 days after isotretinoin discontinuation or during isotretinoin intake was 78.9% (513/650). The median duration of isotretinoin exposure was 18 (1-4,231) days. Furthermore, from 2011 to 2015, the incidence of isotretinoin exposure was 2.9+/-1.2 pregnancies per 10,000 births in South Korea. Conclusion: Approximately 80% of pregnant women are exposed to isotretinoin within the recommended 30 days of contraception or during pregnancy. Therefore, the PPP has to be established in South Korea. PMID- 30474008 TI - Post-translational Modifications of the CARMA1-BCL10-MALT1 Complex in Lymphocytes and Activated B-Cell Like Subtype of Diffuse Large B-Cell Lymphoma. AB - Piracy of the NF-kappaB transcription factors signaling pathway, to sustain its activity, is a mechanism often deployed in B-cell lymphoma to promote unlimited growth and survival. The aggressive activated B-cell like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) exploits a multi-protein complex of CARMA1, BCL10, and MALT1 (CBM complex), which normally conveys NF-kappaB signaling upon antigen receptors engagement. Once assembled, the CBM also unleashes MALT1 protease activity to finely tune the immune response. As a result, ABC DLBCL tumors develop a profound addiction to NF-kappaB and to MALT1 enzyme, leaving open a breach for therapeutics. However, the pleiotropic nature of NF-kappaB jeopardizes the success of its targeting and urges us to develop new strategies. In this review, we discuss how post-translational modifications, such as phosphorylation and ubiquitination of the CBM components, as well as, MALT1 proteolytic activity, shape the CBM activity in lymphocytes and ABC DLBCL, and may provide new avenues to restore vulnerability in lymphoma. PMID- 30474011 TI - Safety of delayed umbilical cord clamping in preterm neonates of less than 34 weeks of gestation: a randomized controlled trial. AB - Objective: There is concern regarding the safety of delayed cord clamping (DCC) in babies born at less than 34 weeks' gestation. Therefore, the primary objective of this study was to compare the rates of hyperbilirubinemia and polycythemia during initial 7 days in infants born at less than 34 weeks' gestation and randomized to receive DCC by 120 seconds or early cord clamping (ECC) within less than 30 seconds. Methods: One hundred pregnant women were randomly subjected to DCC or ECC at the time of birth in a tertiary referral hospital setting. Blood samples were obtained from each newborn at 48 hours and 7 days for hematocrit measurement. Serum bilirubin levels were estimated once the infant had clinically significant jaundice or at 72 hours. For the statistical analysis, the chi2 test, student's t-test, or Wilcoxon rank sum test was used. Results: The hematocrit was significantly higher in the DCC group than in the ECC group (P<0.001). None of the babies had polycythemia. Mean total serum bilirubin level was 6.6 mg/dL in the DCC group and 8.7 mg/dL in the ECC group (P<0.001). There was no increased risk of hyperbilirubinemia in the DCC group. Conclusion: DCC benefits preterm neonates with no significant adverse effects. PMID- 30474013 TI - Development of a novel nomogram for predicting ongoing pregnancy after in vitro fertilization and embryo transfer. AB - Objective: This study aimed to develop a nomogram that predicts ongoing pregnancy after in vitro fertilization and embryo transfer (IVF-ET) using patient age and serum hormonal markers. Methods: A total of 284 IVF-ET cycles were retrospectively analyzed. At 14 days post-oocyte pick-up (OPU), the serum human chorionic gonadotropin (HCG) and progesterone levels were measured. The main predicted outcome was ongoing pregnancy. Results: Patient age and serum of HCG and progesterone levels at 14 days post-OPU were good predictors of ongoing pregnancy. The cut-off value and area under the curve (AUC) (95% confidence interval) were 36.5 years and 0.666 (0.599-0.733), respectively, for patient age; 67.8 mIU/mL and 0.969 (0.951-0.987), respectively, for serum HCG level; and 29.8 ng/mL and 0.883 (0.840-0.925), respectively, for serum progesterone level. When the prediction model was constructed using these three parameters, the addition of serum progesterone level to the prediction model did not increase its overall predictability. Furthermore, a high linear co-relationship was found between serum HCG and progesterone levels. Therefore, we developed a new nomogram using patient age and HCG serum level only. The AUC of the newly developed nomogram for predicting ongoing pregnancy after IVF-ET cycles using patient age and serum HCG level was as high as 0.975. Conclusion: We showed that ongoing pregnancy may be predicted using only patient age and HCG serum level. Our nomogram could help clinicians and patients predict ongoing pregnancy after IVF-ET if the serum JCG level was >=5 IU/L at 14 days post-OPU. PMID- 30474012 TI - Risk factors for cytological progression in HPV 16 infected women with ASC-US or LSIL: The Korean HPV cohort. AB - Objective: This study was to identify the risk factors for cytological progression in women with atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL). Methods: We analyzed data from women infected with the human papillomavirus (HPV) who participated in the Korean HPV cohort study. The cohort recruited women aged 20 60 years with abnormal cervical cytology (ASC-US or LSIL) from April 2010. All women were followed-up at every 6-month intervals with cervical cytology and HPV DNA testing. Results: Of the 1,158 women included, 654 (56.5%) and 504 (43.5%) women showed ASC-US and LSIL, respectively. At the time of enrollment, 143 women tested positive for HPV 16 (85 single and 58 multiple infections). Cervical cytology performed in the HPV 16-positive women showed progression in 27%, no change in 23%, and regression in 50% of the women at the six-month follow-up. The progression rate associated with HPV 16 infection was higher than that with infection caused by other HPV types (relative risk [RR], 1.75; 95% confidence interval [CI], 1.08-2.84; P=0.028). The cytological progression rate in women with persistent HPV 16 infection was higher than that in women with incidental or cleared infections (P<0.001). Logistic regression analysis showed a significant relationship between cigarette smoking and cytological progression (RR, 4.15; 95% CI, 1.01-17.00). Conclusion: The cytological progression rate in HPV 16-positive women with ASC-US or LSIL is higher than that in women infected with other HPV types. Additionally, cigarette smoking may play a role in cytological progression. PMID- 30474014 TI - Patient-reported satisfaction after robot-assisted hysterectomy among Korean patients with benign uterine disease. AB - Objective: This study aimed to evaluate patient-reported satisfaction following robot-assisted hysterectomy due to benign uterine disease, and to identify the factors associated. Methods: We used a questionnaire to evaluate patients' satisfaction with robot-assisted hysterectomy. The questions concerned overall patient-reported satisfaction and specific factors affecting satisfaction, including postoperative pain, return to daily life, the hospital experience, wounds, cost, the doctor-patient relationship, whether expectations were met, and whether detailed information was provided. We also collected data from patient records, such as uterine weight, rate of pelvic adhesion, operation time, rate of transfusion, delayed discharge, and readmission. One hundred patients who underwent robot-assisted hysterectomy participated in the study. Seventy-three fully completed questionnaires were returned. Results: The majority of patients (95.9%) were satisfied with robot-assisted hysterectomy. The doctor-patient relationship, whether expectations were met, the hospital experience, wounds, and whether detailed information was provided were statistically significant factors influencing patients' overall satisfaction. Payment of fees and clinical and surgical outcomes did not significantly influence patients' overall satisfaction. Conclusion: Our findings show that most patients reported high levels of satisfaction following robot-assisted hysterectomy, regardless of cost or clinical and surgical outcomes. Therefore, if gynecologists consider robot assisted hysterectomy suitable for patients they need not hesitate based on potential costs; they should feel confident in recommending the procedure to patients. PMID- 30474015 TI - Effect of Menstrugole on primary dysmenorrhea: a randomized clinical trial. AB - Objective: Primary dysmenorrhea occurs in more than 50% of women of reproductive age. This survey evaluated the effects of Menstrugole on the alleviation of primary dysmenorrhea. Methods: This study was performed in western Iran between August 15 and December 15, 2017, in female students with primary dysmenorrhea. The students were randomly divided into 2 groups and received placebo or a Menstrugole capsule for 3 days in each of 2 menstrual cycles. The visual analog scale was used to assess pain severity. The chi2 test, one-way analysis of variance, and the paired t-test were used for statistical evaluation. Results: We compared the severity of pain between the 2 groups. There was a significant change in the mean pain score during the first (P<0.001) and second months (P<0.001) after the use of Menstrugole, compared with that in the placebo group. Conclusion: Menstrugole decreased pain severity in female students, and can be considered by health care providers for treatment of primary dysmenorrhea. PMID- 30474016 TI - Challenging management of chorioamnionitis with placental listeriosis: lessons from 2 cases. AB - Listeriosis is a rare foodborne infection caused by Listeria monocytogenes. It is 12-20 times more prevalent in pregnant women compared to the general population, with a 20-40% mortality rate in neonates. Early treatment with appropriate antimicrobial agents is critical for pregnancy outcomes; however, the infection is difficult to control because the nonspecific clinical manifestations and rarity of the disease often preclude early diagnosis. We encountered 2 cases of pregnancy-associated listeriosis that occurred at 29 and 37 weeks of gestation. Both neonates were delivered by emergent cesarean section due to fetal condition, and one of the preterm infants died immediately after birth. Pregnancy-associated listeriosis should be considered in the management of unexplained fever or inflammatory conditions in pregnant women. PMID- 30474017 TI - Robotic extralevator excision of a retrorectal giant aggressive angiomyxoma. AB - Aggressive angiomyxoma (AA) is a very rare mesenchymal tumor most commonly found in the pelvic and perineal regions. For the complete excision of retrorectal tumors, with extension through the levator muscle into the ischioanal space, open anterior and posterior approaches are typically required. Herein, we report our experience with robotic excision of a giant presacral AA with extralevator extension into the ischioanal space and extraction via Pfannenstiel incision, which we found to be technically feasible, efficacious, and safe to perform. Mayo Clinic Institutional Review Board exemption status was obtained for this study. PMID- 30474018 TI - Immunohistochemistry: sole tool in diagnosing a rare case of primary vaginal amelanotic melanoma. AB - We report a rare case of vaginal amelanotic melanoma. Malignant melanomas are cutaneous and extracutaneous tumors that arise from embryological remnants of neural crest cells/melanocytes. Amelanotic melanomas at such rare locations can be misdiagnosed both clinically and radiologically. Therefore, histopathological examination and immunohistochemistry are mandatory for the diagnosis of these tumors. We diagnosed this case using histopathology and confirmed the diagnosis based on the presence of immunohistochemical markers human melanoma black 45 (HMB45) and S-100. PMID- 30474020 TI - Erratum: Correction of the name of society. AB - [This corrects the article on p. 542 in vol. 61, PMID: 30254990.]. PMID- 30474019 TI - Supernumerary ovary on recto-sigmoid colon with associated endometriosis. AB - A supernumerary ovary is a rare gynecological anomaly, and is usually excised due to its malignant transformation potential. We report a case of a supernumerary ovary and endometriosis situated on the anterior rectosigmoid colon. When laparoscopy was conducted, a firm, 5-cm mass was discovered on the anterior rectosigmoid colon along with normal ovaries. In this case, the discovery of a supernumerary ovary implied the presence of endometriosis. It is unusual for endometriosis and a supernumerary ovary to exist simultaneously. PMID- 30474021 TI - Three-dimensional analysis of changes in airway space after bimaxillary orthognathic surgery with maxillomandibular setback and their association with obstructive sleep apnea. AB - Background: Bimaxillary orthognathic surgery with maxillomandibular setback is often accompanied by changes in airway space. We analyzed the changes in airway space before and after surgery and assessed their association with obstructive sleep apnea. Methods: This study is based on the cohort of 13 adult patients (9 males, 4 females, average age 23.85 years) who underwent bimaxillary orthognathic surgery with maxillomandibular setback.We performed computed tomography and portable polysomnography before and after the surgery to assess changes in airway space and Apnea-Hypopnea Index (AHI) values (total, supine, non-supine). Results: The oropharyngeal airway volume decreased by 29% after the surgery, which was statistically significant (p < .05). The upper airway volume and hypopharyngeal airway volume were decreased, but not significantly (4 and 19%, respectively). The changes in airway surface area were statistically significant at all levels examined (p < .05). Changes in the maximum anteroposterior width of the airway were also significant at all levels (p < .05). However, the changes in maximum lateral width were only statistically significant at C2 level (p < .05). AHI values were increased after the surgery but not significantly at any position. Conclusions: Although bimaxillary surgery with maxillomandibular setback significantly reduces the airway space, it does not affect AHI values or induce obstructive sleep apnea. PMID- 30474022 TI - Invasive Meningococcal Disease in the Vaccine Era. AB - Infection with the meningococcus is one of the main causes of meningitis and septicaemia worldwide. Humans are the only natural reservoir for the meningococcus which is found primarily as a commensal inhabitant in the nasopharynx in ~10% of adults, and may be found in over 25% of individuals during adolescence. Prompt recognition of meningococcal infection and early aggressive treatment are essential in order to reduce mortality, which occurs in up to 10% of those with invasive meningococcal disease (IMD). This figure may be significantly higher in those with inadequate or delayed treatment. Early administration of effective parenteral antimicrobial therapy and prompt recognition and appropriate management of the complications of IMD, including circulatory shock and raised intracranial pressure (ICP), are critical to help improve patient outcome. This review summarizes clinical features of IMD and current treatment recommendations. We will discuss the evidence for immunization and effects of vaccine strategies, particularly following implementation of effective vaccines against Group B meningococcus. PMID- 30474023 TI - An Integrated Care Model With Implementation Roadmap to Improve Chlamydia trachomatis Management and Control in India. AB - Chlamydia trachomatis is the world's most prevalent bacterial Sexually Transmitted infection (STI). It is associated with a wide range of health consequences and sequelae in both the short and long term. Enhanced control of urogenital C. trachomatis infection is particularly important in low- and middle income countries such as India, where most of the burden goes unnoticed and where limited systematic data is available to gauge the current situation. The World Health Organization (WHO) recently issued its latest strategy on STIs, which is aligned with the achievement of the Sustainable Development Goals (SDGs). Taking the WHO framework into account; this paper puts forward an integrated care model to strengthen the management and control of C. trachomatis in India. The model is compiled of five key components of STI management (awareness, prevention diagnosis, treatment and follow-up). The model considers barriers to effective C. trachomatis control into account. The barriers are discussed and compiled into different categories. A roadmap for the implementation of other similar models to enhance C. trachomatis control in the future is provided. PMID- 30474024 TI - Encapsulation of Metal Nanoparticle Catalysts Within Mesoporous Zeolites and Their Enhanced Catalytic Performances: A Review. AB - Metal nanoparticles (NPs) exhibit desired activities in various catalytic reactions. However, the aggregation and sintering of metal NPs usually cause the loss of catalytic performance in practical reaction processes. Encapsulation of catalytically active metal NPs on/within a high-surface-area inorganic support partially resolve such concerns. Microporous zeolites, owing to their rigid frameworks and porous structural features, have been considered as one of ideal inorganic supports. Metal NPs can be easily encapsulated and stabilized within zeolitic frameworks to prevent unwished aggregation during the catalysis. Unfortunately, sole microporous nanochannels (generally <1 nm) in conventional zeolites are not easy to be accessed. The introduction of another set of nanochannel (e.g., mesopore), known as mesoporous zeolites, can greatly improve the mass-transfer efficiency, which is structurally beneficial for most catalytic reactions. The coexistence of micropores and mesopores in inorganic supports provides the synergetic advantages of both fine confinement effect for metal NPs and easy diffusion for organic reactants/intermediates/products. This review focuses on the recent advances in the design and synthesis of mesoporous zeolites encapsulated metal NP catalysts as well as their desired catalytic performances (activity and stability) in organic reactions. We first discuss the advantages of mesoporous zeolites as the supports and present general strategies for the construction of mesoporous zeolites. Then, the preparation methods on how to encapsulate NP catalysts within both microporous and mesoporous zeolites are clearly demonstrated. Third, some recent important cases on catalytic applications are presented to verify structural advantages of mesoporous zeolite supports. Within the conclusion, the perspectives on future developments in metal NP catalysts encapsulated within mesoporous zeolites are lastly discussed. PMID- 30474026 TI - Photogenerated Electrical Fields for Biomedical Applications. AB - The application of electrical engineering principles to biology represents the main issue of bioelectronics, focusing on interfacing of electronics with biological systems. In particular, it includes many applications that take advantage of the peculiar optoelectronic and mechanical properties of organic or inorganic semiconductors, from sensing of biomolecules to functional substrates for cellular growth. Among these, technologies for interacting with bioelectrical signals in living systems exploiting the electrical field of biomedical devices have attracted considerable attention. In this review, we present an overview of principal applications of phototransduction for the stimulation of electrogenic and non-electrogenic cells focusing on photovoltaic-based platforms. PMID- 30474025 TI - Fermentative Production of N-Methylglutamate From Glycerol by Recombinant Pseudomonas putida. AB - N-methylated amino acids are present in diverse biological molecules in bacteria, archaea and eukaryotes. There is an increasing interest in this molecular class of alkylated amino acids by the pharmaceutical and chemical industries. N alkylated amino acids have desired functions such as higher proteolytic stability, enhanced membrane permeability and longer peptide half-lives, which are important for the peptide-based drugs, the so-called peptidomimetics. Chemical synthesis of N-methylated amino acids often is limited by incomplete stereoselectivity, over-alkylation or the use of hazardous chemicals. Here, we describe metabolic engineering of Pseudomonas putida KT2440 for the fermentative production of N-methylglutamate from simple carbon sources and monomethylamine. P. putida KT2440, which is generally recognized as safe and grows with glucose and the alternative feedstock glycerol as sole carbon and energy source, was engineered for the production of N-methylglutamate using heterologous enzymes from Methylobacterium extorquens. About 3.9 g L-1 N-methylglutamate accumulated within 48 h in shake flask cultures with minimal medium containing monomethylamine and glycerol. A fed-batch cultivation process yielded a N methylglutamate titer of 17.9 g L-1. PMID- 30474027 TI - Preventing Translational Scientists From Extinction: The Long-Term Impact of a Personalized Training Program in Translational Medicine on the Careers of Translational Scientists. AB - Far too much biomedical research is wasted and ends in the so called "Valley of Death": the gap that exists between biomedical research and its clinical application. While the translational process requires collaboration between many disciplines, current translational medicine focuses on single disciplines. Therefore, educational pathways that integrate clinical and research skills in interdisciplinary and interprofessional contexts are needed. The Eureka institute (http://www.eurekainstitute.org/) was founded to address these issues. The institute organizes an annual 1-week international certificate course to educate professionals in the domains of translational medicine. Study design: This study set out to investigate the impact of the Eureka certificate course on the alumni, focusing on their ability to engage in translational activities and thus become more proficient translational professionals. An explanatory, mixed-methods study was executed. Data collection: A questionnaire was distributed to collect quantitative data on the number of alumni who were able to apply what they learned during the Eureka course and engage in translational activities. Questionnaire data were also used to inform the semi-structured interviews that were conducted subsequently. Results: Fifty-one percent of the alumni reported that participating in the Eureka course played a role in their decision to change to a different job or in the way they were accomplishing their everyday work. Ten conditions for change that either hampered or supported the Eureka alumni's engagement in translational research activities were identified. Further, the learning outcomes of the Eureka course that impacted the alumni's professional activities were explored using Personal Professional Theory (PPT). The insight that alumni gained in the full translational spectrum and stakeholders involved stimulated reflection on their own role within that pathway. Further, according to the alumni, the course provided them with the skills and confidence to pursue a career as translational professional. These learning outcomes, in combination with conditions that supported alumni's engagement in translational activities, such as supportive professional partners, opportunities to network or collaborate, and a translational work environment, contributed to the large number of alumni that were able to engage in translational activities. PMID- 30474028 TI - Evaluating Clinical Genome Sequence Analysis by Watson for Genomics. AB - Background: Oncologists increasingly rely on clinical genome sequencing to pursue effective, molecularly targeted therapies. This study assesses the validity and utility of the artificial intelligence Watson for Genomics (WfG) for analyzing clinical sequencing results. Methods: This study identified patients with solid tumors who participated in in-house genome sequencing projects at a single cancer specialty hospital between April 2013 and October 2016. Targeted genome sequencing results of these patients' tumors, previously analyzed by multidisciplinary specialists at the hospital, were reanalyzed by WfG. This study measures the concordance between the two evaluations. Results: In 198 patients, in-house genome sequencing detected 785 gene mutations, 40 amplifications, and 22 fusions after eliminating single nucleotide polymorphisms. Breast cancer (n = 40) was the most frequent diagnosis in this analysis, followed by gastric cancer (n = 31), and lung cancer (n = 30). Frequently detected single nucleotide variants were found in TP53 (n = 107), BRCA2 (n = 24), and NOTCH2 (n = 23). MYC (n = 10) was the most frequently detected gene amplification, followed by ERBB2 (n = 9) and CCND1 (n = 6). Concordant pathogenic classifications (i.e., pathogenic, benign, or variant of unknown significance) between in-house specialists and WfG included 705 mutations (89.8%; 95% CI, 87.5%-91.8%), 39 amplifications (97.5%; 95% CI, 86.8-99.9%), and 17 fusions (77.3%; 95% CI, 54.6-92.2%). After about 12 months, reanalysis using a more recent version of WfG demonstrated a better concordance rate of 94.5% (95% CI, 92.7-96.0%) for gene mutations. Across the 249 gene alterations determined to be pathogenic by both methods, including mutations, amplifications, and fusions, WfG covered 84.6% (88 of 104) of all targeted therapies that experts proposed and offered an additional 225 therapeutic options. Conclusions: WfG was able to scour large volumes of data from scientific studies and databases to analyze in-house clinical genome sequencing results and demonstrated the potential for application to clinical practice; however, we must train WfG in clinical trial settings. PMID- 30474029 TI - Pemphigus Foliaceus-Repeated Treatment With Rituximab 7 Years After Initial Response: A Case Report. AB - Pemphigus foliaceus is an autoimmune skin disease mediated by autoantibodies directed against desmoglein-1 located in the upper epidermal layer. Rituximab, a monoclonal anit-CD20 antibody depleting b-cells, offers an effective treatment possibility for therapy-resistant pemphigus foliaceus. Here, we present the case of 55-year-old man who did not respond sufficiently to conventional treatment with prednisolone, azathioprine, and cyclophosphamide, but underwent almost complete remission after rituximab treatment. The patient relapsed 7 years later, and a repeated course of rituximab infusions led to a partial remission. PMID- 30474030 TI - Editorial: Hybrid Biomolecular Modeling. PMID- 30474031 TI - Platelet Function During Extracorporeal Membrane Oxygenation in Adult Patients: A Systematic Review. AB - Background: Hemorrhagic and thromboembolic complications are common during treatment with extracorporeal membrane oxygenation (ECMO), resulting in considerable morbidity and mortality. This emphasizes the clinical relevance of understanding hemostatic changes occurring during ECMO treatment. As platelets are key players in hemostasis, detailed knowledge on how ECMO treatment affects platelet function is of great importance. We therefore aimed to systematically summarize and discuss existing knowledge on platelet function during ECMO treatment in adult patients. Methods: Systematic review complying with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Objectives and methods were specified in a PROSPERO protocol (ID no CRD42018084059). The MEDLINE/PubMed, EMBASE, and Web of Science databases were systematically searched on September 10, 2018. A standardized quality assessment tool was used to assess the risk of bias in included studies. Primary outcome was platelet function during ECMO treatment, measured as platelet adhesion, activation or aggregation. Secondary outcomes were thrombosis, bleeding, and mortality during ECMO treatment. Results: A total of 591 studies were identified, of which seven were eligible for inclusion in the qualitative synthesis. Of these, one study investigated expression of platelet adhesion receptors and found them to be reduced during ECMO treatment; two studies reported a decrease in platelet activation markers during ECMO treatment; and five studies demonstrated reduced platelet aggregation during ECMO treatment. Three studies reported on thrombosis, mortality and/or bleeding during ECMO treatment; no thromboembolic events were reported; all three studies reported frequent bleeding episodes defined on basis of transfusion requirements. An in-hospital mortality of 35-40% and a 30-day mortality of roughly 30% were reported in three different studies. Conclusions: The present systematic review reveals a substantial knowledge gap regarding platelet function during ECMO treatment in adult patients and underscores the demand for more and well-designed studies on this topic. There is suggested evidence of reduced platelet adhesion, decreased platelet activation, and reduced platelet aggregation in adult patients during ECMO treatment. Importantly, platelet aggregation results need to be interpreted in the light of low platelet counts. The associations of platelet function and bleeding and/or thromboembolic complications during ECMO treatment remain to be fully elucidated. PMID- 30474032 TI - The Conundrum of Tricuspid Regurgitation Grading. AB - Findings from early percutaneous tricuspid intervention trials have shown that the severity of tricuspid regurgitation (TR) far exceeded the current definition of severe TR. Also, the improvement in the amount of TR following tricuspid intervention is not accounted for by the current definition of TR as different degrees of severity at the severe end was grouped under the same umbrella term of "severe." There has been a recent call to expand the TR grading system, encompassing two more grades, namely "massive" and "torrential" TR, in the order of increasing severity. This seems appropriate as the patients enrolled in tricuspid intervention trials were found to have TR severity up to 2 grades above the current severe thresholds of effective regurgitant orifice area (EROA) 40 mm2, regurgitant volume (R Vol) 45 ml and vena contracta (VC) width 7 mm. The proposed grade of "massive" is defined by EROA 60-79 mm2, R Vol 60-74 ml and VC 14-20 mm, while "torrential" is defined by EROA >=80 mm2, R Vol >=75 ml, and VC >=21 mm. The grading of TR requires a comprehensive, multi-parametric approach. In particular, quantitative assessment of TR should be performed in patients who require serial monitoring and quantification of treatment effect. PMID- 30474033 TI - The Inhibition Effect of Tert-Butyl Alcohol on the TiO2 Nano Assays Photoelectrocatalytic Degradation of Different Organics and Its Mechanism. AB - The inhibition effect of tert-butyl alcohol (TBA), identified as the *OH radical inhibitor, on the TiO2 nano assays (TNA) photoelectrocatalytic oxidation of different organics such as glucose and phthalate was reported. The adsorption performance of these organics on the TNA photoelectrode was investigated by using the instantaneous photocurrent value, and the degradation property was examined by using the exhausted reaction. The results showed that glucose exhibited the poor adsorption and easy degradation performance, phthalate showed the strong adsorption and hard-degradation, but TBA showed the weak adsorption and was the most difficult to be degraded. The degradation of both glucose and phthalate could be inhibited evidently by TBA. But the effect on glucose was more obvious. The different inhibition effects of TBA on different organics could be attributed to the differences in the adsorption and the degradation property. For instance, phthalate of the strong adsorption property could avoid from the capture of *OH radicals by TBA in TNA photoelectrocatalytic process. PMID- 30474034 TI - The Promotion Effect of Low-Molecular Hydroxyl Compounds on the Nano Photoelectrocatalytic Degradation of Fulvic Acid and Mechanism. AB - Abstract: A significant promotion effect of low-molecular hydroxyl compounds (LMHCs) was found in the nano-photoelectrocatalytic (NPEC) degradation of fulvic acid (FA), which is a typical kind of humic acid existing widely in natural water bodies, and its influence mechanism was proposed. A TiO2 nanotube arrays (TNAs) material is served as the photoanode. Methanol, ethanediol, and glycerol were chosen as the representative of LMHCs in this study. The adsorption performance of organics on the surface of TNAs was investigated by using the instantaneous photocurrent value. The adsorption constants of FA, methanol, ethanediol, and glycerol were 43.44, 19.32, 7.00, and 1.30, respectively, which indicates that FA has the strongest adsorption property. The degradation performance of these organics and their mixture were observed in a thin-layer reactor. It shows that FA could hardly achieve exhausted mineralization alone, while LMHCs could be easily oxidized completely in the same condition. The degradation degree of FA, which is added LMHCs, improves significantly and the best promotion effect is achieved by glycerol. The promotion effect of LMHCs in the degradation of FA could be contributed to the formation of a tremendous amount of hydroxyl radicals in the NPEC process. The hydroxyl radicals could facilitate the complete degradation of both FA and its intermediate products. Among the chosen LMHCs, glycerol molecule which has three hydroxyls could generate the most hydroxyl radicals and contribute the best effective promotion. This work provides a new way to promote the NPEC degradation of FA and a direction to remove humus from polluted water. Graphical Abstract: PMID- 30474035 TI - Various Silver Nanostructures on Sapphire Using Plasmon Self-Assembly and Dewetting of Thin Films. AB - Silver (Ag) nanostructures demonstrate outstanding optical, electrical, magnetic, and catalytic properties and are utilized in photonic, energy, sensors, and biomedical devices. The target application and the performance can be inherently tuned by control of configuration, shape, and size of Ag nanostructures. In this work, we demonstrate the systematical fabrication of various configurations of Ag nanostructures on sapphire (0001) by controlling the Ag deposition thickness at different annealing environments in a plasma ion coater. In particular, the evolution of Ag particles (between 2 and 20 nm), irregular nanoclusters (between 30 and 60 nm), and nanocluster networks (between 80 and 200 nm) are found be depended on the thickness of Ag thin film. The results were systematically analyzed and explained based on the solid-state dewetting, surface diffusion, Volmer-Weber growth model, coalescence, and surface energy minimization mechanism. The growth behavior of Ag nanostructures is remarkably differentiated at higher annealing temperature (750 degrees C) due to the sublimation and temperature-dependent characteristic of dewetting process. In addition, Raman and reflectance spectra analyses reveal that optical properties of Ag nanostructures depend on their morphology. PMID- 30474036 TI - Microbiological testing of adults hospitalised with community-acquired pneumonia: an international study. AB - This study aimed to describe real-life microbiological testing of adults hospitalised with community-acquired pneumonia (CAP) and to assess concordance with the 2007 Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) and 2011 European Respiratory Society (ERS) CAP guidelines. This was a cohort study based on the Global Initiative for Methicillin-resistant Staphylococcus aureus Pneumonia (GLIMP) database, which contains point-prevalence data on adults hospitalised with CAP across 54 countries during 2015. In total, 3702 patients were included. Testing was performed in 3217 patients, and included blood culture (71.1%), sputum culture (61.8%), Legionella urinary antigen test (30.1%), pneumococcal urinary antigen test (30.0%), viral testing (14.9%), acute phase serology (8.8%), bronchoalveolar lavage culture (8.4%) and pleural fluid culture (3.2%). A pathogen was detected in 1173 (36.5%) patients. Testing attitudes varied significantly according to geography and disease severity. Testing was concordant with IDSA/ATS and ERS guidelines in 16.7% and 23.9% of patients, respectively. IDSA/ATS concordance was higher in Europe than in North America (21.5% versus 9.8%; p<0.01), while ERS concordance was higher in North America than in Europe (33.5% versus 19.5%; p<0.01). Testing practices of adults hospitalised with CAP varied significantly by geography and disease severity. There was a wide discordance between real-life testing practices and IDSA/ATS/ERS guideline recommendations. PMID- 30474037 TI - The Swiss Paediatric Airway Cohort (SPAC). AB - Chronic respiratory symptoms, such as cough, wheeze and dyspnoea, are common in children; however, most research has, with the exception of a few large-scale clinical cohort studies, been performed in the general population or in small, highly-selected samples. The Swiss Paediatric Airway Cohort (SPAC) is a national, prospective clinical cohort of children and adolescents who visit physicians for recurrent conditions, such as wheeze and cough, and exercise-related respiratory problems. The SPAC is an observational study and baseline assessment includes standardised questionnaires for families and data extracted from hospital records, including results of clinically indicated investigations, diagnoses and treatments. Outcomes are assessed through annual questionnaires, monthly symptom reporting via mobile phone and follow-up visits. The SPAC will address important questions about clinical phenotypes, diagnosis, treatment, and the short- and long-term prognosis of common respiratory problems in children. The cohort currently consists of 347 patients from four major hospitals (Bern, Zurich, Basel and Lucerne), with 70-80 additional patients joining each month. More centres will join and the target sample size is a minimum of 3000 patients. The SPAC will provide real-life data on children visiting the Swiss healthcare system for common respiratory problems and will provide a research platform for health services research and nested clinical and translational studies. PMID- 30474039 TI - Genomic and Postgenomic Approaches to Understand Environmental Microorganisms. PMID- 30474038 TI - Dynamics of respiratory symptoms during infancy and associations with wheezing at school age. AB - Children with frequent respiratory symptoms in infancy have an increased risk for later wheezing, but the association with symptom dynamics is unknown. We developed an observer-independent method to characterise symptom dynamics and tested their association with subsequent respiratory morbidity. In this birth cohort of healthy neonates, we prospectively assessed weekly respiratory symptoms during infancy, resulting in a time series of 52 symptom scores. For each infant, we calculated the transition probability between two consecutive symptom scores. We used these transition probabilities to construct a Markov matrix, which characterised symptom dynamics quantitatively using an entropy parameter. Using this parameter, we determined phenotypes by hierarchical clustering. We then studied the association between phenotypes and wheezing at 6 years. In 322 children with complete data for symptom scores during infancy (16 864 observations), we identified three dynamic phenotypes. Compared to the low-risk phenotype, the high-risk phenotype, defined by the highest entropy parameter, was associated with an increased risk of wheezing (odds ratio (OR) 3.01, 95% CI 1.15 7.88) at 6 years. In this phenotype, infants were more often male (64%) and had been exposed to environmental tobacco smoke (31%). In addition, more infants had siblings (67%) and attended childcare (38%). We describe a novel method to objectively characterise dynamics of respiratory symptoms in infancy, which helps identify abnormal clinical susceptibility and recovery patterns of infant airways associated with persistent wheezing. PMID- 30474040 TI - Microscopic Monitoring of Erythrocytes Deformation under Different Shear Stresses Using Computerized Cone and Plate Flow Chamber: Analytical Study of Normal Erythrocytes and Iron Deficiency Anemia. AB - Erythrocytes deformation is one of the exciting properties of erythrocytes. It is still under investigation by many of the researchers in different disciplines. The clinicians and researchers are still looking for a simple and efficient method to monitor and tracking the erythrocytes deformation. This research article represented a microscopic technique that could be a helpful tool in evaluation and studying of erythrocytes deformation under different shear stresses. This technique was used to compare the deformation of normal erythrocytes and iron deficiency anemia. Elongation index was calculated and used in the quantitative analysis of erythrocytes deformation. It was found that the deformability of normal erythrocytes was higher than that of iron deficiency anemia. Normal erythrocytes and iron deficiency anemia showed strong negative correlations with the mean cell volume and the mean cell hemoglobin concentration under different shear stresses. This study introduces more understanding of the erythrocytes deformation by using a simple microscopic technique. The elongation index could be used as a measurable parameter to evaluate the deformability of the erythrocyte in normal and abnormal cases. PMID- 30474041 TI - Correlation between Brodsky Tonsil Scale and Tonsil Volume in Adult Patients. AB - Purpose: To evaluate the value of Brodsky tonsil scale in predicting the objective tonsil volume and to identify the potential factors that might interfere with the accuracy of prediction. Methods: A total of 87 adult patients who underwent single tonsillectomy or uvulopalatopharyngoplasty (UPPP) procedure including tonsillectomy in our hospital between Jan 2015 and Dec 2016 were included. The data of Brodsky tonsil scale evaluated preoperatively and objective tonsil volume evaluated postoperatively were collected for analysis. Results: Among the 87 adult patients included, 85 patients underwent bilateral tonsillectomy, while only 2 underwent unilateral procedure. Therefore, a total of 172 tonsils were included. Significant positive correlations were established between Brodsky scale and objective volume for either right (R = 0.647), left (R = 0.664), or overall tonsils (R = 0.654) (all p < 0.001). However, volume overlaps could be found between 2+ and 3+ tonsils. Age [odds ratio (OR) = 4.053, p = 0.003] and body mass index (BMI; OR=1.740, p = 0.044) were found to be independent factors that could influence the consistency between the Brodsky scale and objective volume. As a result, a formula "Index = 1.409+1.399*age+0.554*BMI" was constructed for the evaluation of the consistency. Conclusion: Tonsil grading was significantly correlated with tonsil volume; preoperative tonsil grading that reflected the real tonsil volume was regarded as the protocol for the evaluation of the tonsil size. Age and BMI were independent factors that could affect the consistency between tonsil grade and tonsil volume. A mathematical model was estimated to predict the consistency accurately. PMID- 30474042 TI - Managing Severe Asthma: A Role for the Long-Acting Muscarinic Antagonist Tiotropium. AB - Severe asthma is associated with substantial morbidity and mortality. Therapies must be maximized to gain control of a patient's severe asthma; however, avoiding overtreatment is also important. The mainstays of asthma maintenance treatment are inhaled corticosteroids (ICS) and long-acting beta 2-agonsits (LABAs), with the option of supplementary add-on treatments. New add-on treatments for severe asthma have emerged over the past two decades, including personalized biological therapies that are guided by a patient's asthma phenotype. In addition, the long acting muscarinic antagonist tiotropium has been recommended as an add-on treatment for severe asthma. Phase III clinical trials have shown tiotropium in combination with ICS/LABA to be efficacious in patients with severe asthma. Further analyses of clinical trial data have indicated that there is no benefit in stratifying patients by phenotype to predict tiotropium efficacy. Furthermore, health economic studies suggest tiotropium to be a cost-effective treatment in patients with severe asthma. This review will present the evidence surrounding the role of tiotropium in severe asthma and will discuss the use of tiotropium add-on therapy before personalized medicine strategies in the stepwise process of gaining asthma control. PMID- 30474043 TI - Quality of Life Is Influenced by Body Weight, Education, and Family Income in Adolescents with Chronic Diseases. AB - Objective: To evaluate the health-related quality of life (HRQoL) of adolescents diagnosed with different chronic conditions and to identify demographic, socioeconomic, and health-status outcomes associated with the impairment in HRQoL. Study Design: Cross-sectional study. Methods: We evaluated 276 adolescents (50.7% male) aged 14 +/- 2 years that were assisted by healthcare public service and diagnosed with cancer (CA), type 1 diabetes mellitus (DM1), overweight (OW), asthma (AS), and no chronic health condition-control group (CG). Adolescents and parent-proxy completed age-appropriate self-report and/or parent-proxy report on generic HRQoL measures using PedsQLTM. Results: Adolescents with CA had lower overall HRQoL as well as poorer scores in all dimensions than either healthy participants or other chronic disease sufferers. HRQoL scores reported by parent proxy were similar to those reported by adolescents across all chronic diseases. CG members reported better scores in all dimensions. Maternal education, family income, and marital status of parents were correlated with HRQoL scores in all dimensions. The risk of having an affected HRQoL score was higher in adolescents with CA than in adolescents with other chronic diseases. Conclusions: The likelihood of cancer affecting HRQoL was higher when compared to other chronic diseases, and the OW group had a worse overall score compared to CG. Adolescents with CA, AS, and OW reported worse school dimensions when compared to healthy adolescents. The education of adolescents and their parent-proxy, body weight, and family income influence the dimensions of HRQoL in adolescents with chronic diseases. PMID- 30474044 TI - The Humanistic and Economic Burden Associated with Anxiety and Depression among Adults with Comorbid Diabetes and Hypertension. AB - We conducted a retrospective cross-sectional study to estimate the humanistic and economic burden associated with depression and anxiety among adults with comorbid diabetes and hypertension. Pooled data from the 2013 and 2015 Medical Expenditure Panel Survey were used to include adults (>=18 years old) who were alive and diagnosed with both diabetes and hypertension during the observation period. We assessed the humanistic burden with health-related quality of life (HRQoL) and economic burden with the total annual healthcare expenditures. Depending on the presence/absence of depression and anxiety, the study sample was divided into four groups (i.e., no depression/anxiety, depression only, anxiety only, and depression and anxiety). Multivariable regression analyses were used to evaluate the associations between the depression/anxiety categories and disease burden measures. The incremental burden associated with depression and/or anxiety was estimated with the counterfactual recycled prediction. Of the 4560 adults with comorbid diabetes and hypertension, 13.2% reported depression only, 8.7% reported anxiety only, and 7.7% reported both. Results from adjusted analyses indicated that the presence/absence of depression and anxiety was associated with significantly poorer HRQoL, especially on the mental component. Having either depression or anxiety corresponded to reduced mental component summary scores by more than four points. The reduction was as high as 10.35 points when both conditions occurred. Comparing to adults without depression or anxiety, the per capital incremental annual healthcare expenditures were $4607 for the depression group, $2481 for the anxiety group, and $8709 for adults with both conditions. Furthermore, adults with depression and anxiety were 58% more likely to spend at least 10% of annual household income on healthcare as compared to those with neither the conditions. Our results highlight the needs for integrating cost effective mental health services into diabetes management to improve the HRQoL and reduce healthcare costs for adults with comorbid diabetes and hypertension. PMID- 30474045 TI - Immune System and Chronic Diseases 2018. PMID- 30474046 TI - Evaluation of Tuberculosis Treatment Response With Serial C-Reactive Protein Measurements. AB - Background: Novel biomarkers are needed to assess response to antituberculosis therapy in smear-negative patients. Methods: To evaluate the utility of C reactive protein (CRP) in monitoring response to antituberculosis therapy, we conducted a post hoc analysis on a cohort of adults with symptoms of tuberculosis and negative sputum smears in a high-tuberculosis and HIV prevalence setting in KwaZulu-Natal, South Africa. Serial changes in CRP, weight, and hemoglobin were evaluated over 8 weeks. Results: Four hundred twenty-one participants being evaluated for smear-negative tuberculosis were enrolled, and 33 were excluded. Two hundred ninety-five were treated for tuberculosis (137 confirmed, 158 possible), and 93 did not have tuberculosis. One hundred and eighty-three of 213 (86%) participants who agreed to HIV testing were HIV positive. At week 8, the on treatment median CRP reduction in the tuberculosis group (interquartile range [IQR]) was 79.5% (25.4% to 91.7%), the median weight gain was 2.3% (-1.0% to 5.6%), and the median hemoglobin increase was 7.0% (0.8% to 18.9%); P < .0001 for baseline to week 8 comparison of absolute median values. Only CRP changed significantly at week 2 (median reduction [IQR], 75.1% [46.9% to 89.2%]) in the group with confirmed tuberculosis and in the possible tuberculosis group (median reduction [IQR], 49.0% [-0.4% to 80.9%]). Failure of CRP to reduce to <=55% of the baseline value at week 2 predicted hospitalization or death in both tuberculosis groups, with 99% negative predictive value. Conclusions: Change in CRP may have utility in early evaluation of response to antituberculosis treatment and to identify those at increased risk of adverse outcomes. PMID- 30474048 TI - Conformation-specific detection of calmodulin binding using the unnatural amino acid p-azido-phenylalanine (AzF) as an IR-sensor. AB - Calmodulin (CaM) is a very conserved, ubiquitous, eukaryotic protein that binds four Ca2+ ions with high affinity. It acts as a calcium sensor by translating Ca2+ signals into cellular processes such as metabolism, inflammation, immune response, memory, and muscle contraction. Calcium binding to CaM leads to conformational changes that enable Ca2+/CaM to recognize and bind various target proteins with high affinity. The binding mode and binding partners of CaM are very diverse, and a consensus binding sequence is lacking. Here, we describe an elegant system that allows conformation-specific detection of CaM-binding to its binding partners. We incorporate the unnatural amino acid p-azido-phenylalanine (AzF) in different positions of CaM and follow its unique spectral signature by infrared (IR)-spectroscopy of the azido stretching vibration. Our results suggest that the AzF vibrational probe is sensitive to the chemical environment in different CaM/CaM-binding domain (CaMBD) complexes, which allows differentiating between different binding motifs according to the spectral characteristics of the azido stretching mode. We corroborate our results with a crystal structure of AzF labelled CaM (CaM108AzF) in complex with a binding peptide from calmodulin dependent protein kinase IIalpha identifying the structural basis for the observed IR frequency shifts. PMID- 30474049 TI - Kinetic Characterization of the Shigella Type Three Secretion System ATPase Spa47 Using alpha-32P ATP. AB - ATPases represent a diverse class of enzymes that utilize ATP hydrolysis to support critical biological functions such as driving ion pumps, providing mechanical work, unfolding/folding proteins, and supporting otherwise thermodynamically unfavorable chemical reactions. We have recently shown that the Shigella protein Spa47 is an ATPase that supports protein secretion through its specialized type three secretion apparatus (T3SA), supporting infection of human host cells. Characterizing ATPases, such as Spa47, requires a means to accurately determine enzyme activity (ATP hydrolysis) as a function of time, reaction conditions, and potential cofactors, regulators, inhibitors, etc. Here, we describe a detailed protocol for characterizing the enzyme kinetics of Spa47 using a direct alpha-32P ATPase assay. PMID- 30474047 TI - Salvage Debridement, Antibiotics and Implant Retention ("DAIR") With Local Injection of a Selected Cocktail of Bacteriophages: Is It an Option for an Elderly Patient With Relapsing Staphylococcus aureus Prosthetic-Joint Infection? AB - Local injection of a bacteriophages mix during debridement, antibiotics and implant retention ("DAIR") was performed to treat a relapsing Staphylococcus aureus chronic prosthetic joint infection (PJI). This salvage treatment was safe and associated with a clinical success. Scientific evaluation of the potential clinical benefit of bacteriophages as antibiofilm treatment in PJI is now feasible and required. PMID- 30474050 TI - Technology as a tool in teaching quantitative biology at the secondary and undergraduate levels: a review. AB - Since the publication of the National Research Councils Report BIO2010, e orts have increased to better integrate mathematics and biology in undergraduate education. Unfortunately, equivalent e orts to introduce these quantitative topics at the secondary level have been seldom. This could cause differential success of undergraduate students who come from diverse secondary science backgrounds. Undergraduate courses regularly use technology to integrate these two disciplines, and we believe that technology can similarly be used at the secondary level to prevent quantitative achievement mismatch in undergraduate biology programs. In this paper, we review the current uses of technology to teach quantitative biology at the secondary and undergraduate levels, propose needs for further implementation, and address potential barriers to integrating mathematics and biology using technology. PMID- 30474052 TI - Streptavidin-conjugated gold nanoclusters as ultrasensitive fluorescent sensors for early diagnosis of HIV infection. AB - We have engineered streptavidin-labeled fluorescent gold nanoclusters to develop a gold nanocluster immunoassay (GNCIA) for the early and sensitive detection of HIV infection. We performed computational simulations on the mechanism of interaction between the nanoclusters and the streptavidin protein via in silico studies and showed that gold nanoclusters enhance the binding to the protein, by enhancing interaction between the Au atoms and the specific active site residues, compared to other metal nanoclusters. We also evaluated the role of glutathione conjugation in binding to gold nanoclusters with streptavidin. As proof of concept, GNCIA achieved a sensitivity limit of detection of HIV-1 p24 antigen in clinical specimens of 5 pg/ml, with a detection range up to1000 pg/ml in a linear dose-dependent manner. GNCIA demonstrated a threefold higher sensitivity and specificity compared to enzyme-linked immunosorbent assay for the detection of HIV p24 antigen. The specificity of the immunoassay was 100% when tested with plasma samples negative for HIV-1 p24 antigen and positive for viruses such as hepatitis B virus, hepatitis C virus, and dengue. GNCIA could be developed into a universal labeling technology using the relevant capture and detector antibodies for the specific detection of antigens of various pathogens in the future. PMID- 30474051 TI - Dietary Polysaccharides in the Amelioration of Gut Microbiome Dysbiosis and Metabolic Diseases. AB - The prevalence of metabolic diseases including obesity, diabetes, cardiovascular diseases, hypertension and cancer has evolved into a global epidemic over the last century. The rate of these disorders is continuously rising due to the lack of effective preventative and therapeutic strategies. This warrants for the development of novel strategies that could help in the prevention, treatment and/ or better management of such disorders. Although the complex pathophysiology of these metabolic diseases is one of the major hurdles in the development of preventive and/or therapeutic strategies, there are some factors that are or can speculated to be more effective to target than others. Recently, gut microbiome has emerged as one of the major contributing factors in metabolic diseases, and developing positive modulators of gut microbiota is being considered to be of significant interest. Natural non-digestible polysaccharides from plants and food sources are considered potent modulators of gut microbiome that can feed certain beneficial microbes in the gut. This has led to an increased interest in the isolation of novel bioactive polysaccharides from different plants and food sources and their application as functional components to modulate the gut microbiome composition to improve host's health including metabolism. Therefore, polysaccharides, as prebiotics components, are being speculated to confer positive effects in managing metabolic diseases like obesity and diabetes. In this review article, we summarize some of the most common polysaccharides from plants and food that impact metabolic health and discuss why and how these could be helpful in preventing or ameliorating metabolic diseases such as obesity, type 2 diabetes, hypertension and dyslipidemia. PMID- 30474054 TI - Spatial variations in crop growing seasons pivotal to reproduce global fluctuations in maize and wheat yields. AB - Testing our understanding of crop yield responses to weather fluctuations at global scale is notoriously hampered by limited information about underlying management conditions, such as cultivar selection or fertilizer application. Here, we demonstrate that accounting for observed spatial variations in growing seasons increases the variance in reported national maize and wheat yield anomalies that can be explained by process-based model simulations from 34 to 58% and 47 to 54% across the 10 most weather-sensitive main producers, respectively. For maize, the increase in explanatory power is similar to the increase achieved by accounting for water stress, as compared to simulations assuming perfect water supply in both rainfed and irrigated agriculture. Representing water availability constraints in irrigation is of second-order importance. We improve the model's explanatory power by better representing crops' exposure to observed weather conditions, without modifying the weather response itself. This growing season adjustment now allows for a close reproduction of heat wave and drought impacts on crop yields. PMID- 30474053 TI - Infant cognition includes the potentially human-unique ability to encode embedding. AB - Human cognition relies on the ability to encode complex regularities in the input. Regularities above a certain complexity level can involve the feature of embedding, defined by nested relations between sequential elements. While comparative studies suggest the cognitive processing of embedding to be human specific, evidence of its ontogenesis is lacking. To assess infants' ability to process embedding, we implemented nested relations in tone sequences, minimizing perceptual and memory requirements. We measured 5-month-olds' brain responses in two auditory oddball paradigms, presenting standard sequences with one or two levels of embedding, interspersed with infrequent deviant sequences violating the established embedding rules. Brain potentials indicate that infants detect embedding violations and thus appear to track nested relations. This shows that the ability to encode embedding may be part of the basic human cognitive makeup, which might serve as scaffolding for the acquisition of complex regularities in language or music. PMID- 30474056 TI - Mechanism of large-scale flow reversals in turbulent thermal convection. AB - It is commonly believed that heat flux passing through a closed thermal convection system is balanced so that the convection system can remain at a steady state. Here, we report a new kind of convective instability for turbulent thermal convection, in which the convective flow stays over a long steady "quiet period" having a minute amount of heat accumulation in the convection cell, followed by a short and intermittent "active period" with a massive eruption of thermal plumes to release the accumulated heat. The rare massive eruption of thermal plumes disrupts the existing large-scale circulation across the cell and resets its rotational direction. A careful analysis reveals that the distribution of the plume eruption amplitude follows the generalized extreme value statistics with an upper bound, which changes with the fluid properties of the convecting medium. The experimental findings have important implications to many closed convection systems of geophysical scale, in which massive eruptions and sudden changes in large-scale flow pattern are often observed. PMID- 30474055 TI - Stability of core language skill from infancy to adolescence in typical and atypical development. AB - Command of language is a fundamental life skill, a cornerstone of cognitive and socioemotional development, and a necessary ingredient for successful functioning in society. We used 15-year prospective longitudinal data from the Avon Longitudinal Study of Parents and Children to evaluate two types of stability of core language skill in 5036 typically developing and 1056 atypically developing (preterm, dyslexic, autistic, and hearing impaired) children in a multiage, multidomain, multimeasure, multireporter framework. A single core language skill was extracted from multiple measures at multiple ages, and this skill proved stable from infancy to adolescence in all groups, even accounting for child nonverbal intelligence and sociability and maternal age and education. Language skill is a highly conserved and robust individual-differences characteristic. Lagging language skills, a risk factor in child development, would profitably be addressed early in life. PMID- 30474057 TI - Spatial interference scale as a determinant of microbial range expansion. AB - In microbial communities, social interactions such as competition occur ubiquitously across multiple spatial scales from local proximity to remote distance. However, it remains unclear how such a spatial variation of interaction contributes to the structural development of microbial populations. Here, we developed synthetic consortia, biophysical theory, and simulations to elucidate the role of spatial interference scale in governing ecosystem organization during range expansion. For consortia with unidirectional interference, we discovered that, at growing fronts, the extinction time of toxin-sensitive species is reciprocal to the spatial interference scale. In contrast, for communities with bidirectional interference, their structures diverge into distinct monoculture colonies under different initial conditions, with the corresponding separatrix set by the spatial scale of interference. Near the separatrix, ecosystem development becomes noise-driven and yields opposite structures. Our results establish spatial interaction scale as a key determinant for microbial range expansion, providing insights into microbial spatial organization and synthetic ecosystem engineering. PMID- 30474058 TI - Strain-triggered mechanical feedback in self-organizing optic-cup morphogenesis. AB - Organogenesis is a self-organizing process of multiple cells in three-dimensional (3D) space, where macroscopic tissue deformations are robustly regulated by multicellular autonomy. It is clear that this robust regulation requires cells to sense and modulate 3D tissue formation across different scales, but its underlying mechanisms are still unclear. To address this question, we developed a versatile computational model of 3D multicellular dynamics at single-cell resolution and combined it with the 3D culture system of pluripotent stem cell derived optic-cup organoid. The complementary approach enabled quantitative prediction of morphogenesis and its corresponding verification and elucidated that the macroscopic 3D tissue deformation is fed back to individual cellular force generations via mechanosensing. We hereby conclude that mechanical force plays a key role as a feedback regulator to establish the robustness of organogenesis. PMID- 30474060 TI - Triterpenoids manipulate a broad range of virus-host fusion via wrapping the HR2 domain prevalent in viral envelopes. AB - A trimer-of-hairpins motif has been identified in triggering virus-cell fusion within a variety of viral envelopes. Chemically manipulating such a motif represents current repertoire of viral fusion inhibitors. Here, we report that triterpenoids, a class of natural products, antagonize this trimer-of-hairpins via its constitutive heptad repeat-2 (HR2), a prevalent alpha-helical coil in class I viral fusion proteins. Triterpenoids inhibit the entry of Ebola, Marburg, HIV, and influenza A viruses with distinct structure-activity relationships. Specifically, triterpenoid probes capture the viral envelope via photocrosslinking HR2. Profiling the Ebola HR2-triterpenoid interactions using amino acid substitution, surface plasmon resonance, and nuclear magnetic resonance revealed six residues accessible to triterpenoids, leading to wrapping of the hydrophobic helix and blocking of the HR1-HR2 interaction critical in the trimer-of-hairpins formation. This finding was also observed in the envelopes of HIV and influenza A viruses and might potentially extend to a broader variety of viruses, providing a mechanistic insight into triterpenoid-mediated modulation of viral fusion. PMID- 30474061 TI - A central control circuit for encoding perceived food value. AB - Hunger state can substantially alter the perceived value of a stimulus, even to the extent that the same sensory cue can trigger antagonistic behaviors. How the nervous system uses these graded perceptual shifts to select between opposed motor patterns remains enigmatic. Here, we challenged food-deprived and satiated Lymnaea to choose between two mutually exclusive behaviors, ingestion or egestion, produced by the same feeding central pattern generator. Decoding the underlying neural circuit reveals that the activity of central dopaminergic interneurons defines hunger state and drives network reconfiguration, biasing satiated animals toward the rejection of stimuli deemed palatable by food deprived ones. By blocking the action of these neurons, satiated animals can be reconfigured to exhibit a hungry animal phenotype. This centralized mechanism occurs in the complete absence of sensory retuning and generalizes across different sensory modalities, allowing food-deprived animals to increase their perception of food value in a stimulus-independent manner to maximize potential calorific intake. PMID- 30474059 TI - HIV-1 vaccine design through minimizing envelope metastability. AB - Overcoming envelope metastability is crucial to trimer-based HIV-1 vaccine design. Here, we present a coherent vaccine strategy by minimizing metastability. For 10 strains across five clades, we demonstrate that the gp41 ectodomain (gp41ECTO) is the main source of envelope metastability by replacing wild-type gp41ECTO with BG505 gp41ECTO of the uncleaved prefusion-optimized (UFO) design. These gp41ECTO-swapped trimers can be produced in CHO cells with high yield and high purity. The crystal structure of a gp41ECTO-swapped trimer elucidates how a neutralization-resistant tier 3 virus evades antibody recognition of the V2 apex. UFO trimers of transmitted/founder viruses and UFO trimers containing a consensus based ancestral gp41ECTO suggest an evolutionary root of metastability. The gp41ECTO-stabilized trimers can be readily displayed on 24- and 60-meric nanoparticles, with incorporation of additional T cell help illustrated for a hyperstable 60-mer, I3-01. In mice and rabbits, these gp140 nanoparticles induced tier 2 neutralizing antibody responses more effectively than soluble trimers. PMID- 30474063 TI - The Emerging Role of p27 in Development of Diseases. PMID- 30474062 TI - The emerging spectrum of early life exposure-related inflammation and epigenetic therapy. AB - Early life exposure to a variety of insults during sensitive windows of development can reprogram normal physiological responses and alter disease susceptibility later in life. During this process, Inflammation triggered by a variety of adverse exposures plays an important role in the initiation and development of many types of diseases including tumorigenesis. This review article summaries the current knowledge about the role and mechanism of inflammation in development of diseases. In addition, epigenome alteration related to inflammation and treatment options using epigenetic modifiers are highlighted and discussed. PMID- 30474064 TI - The Role of Prophylactic Octreotide Following Pancreaticoduodenectomy to Prevent Postoperative Pancreatic Fistula: A Meta-Analysis of the Randomized Controlled Trials. AB - Introduction A postoperative pancreatic fistula (POPF) is a major cause of morbidity and mortality following pancreaticoduodenectomy (PD). A pharmacologic approach using perioperative octreotide, a long-acting somatostatin analog having an inhibitory action on pancreatic exocrine secretion, was proposed to reduce the incidence of the POPF. Despite contradictory results in various randomized controlled trials (RCTs), the prophylactic octreotide has been widely used in the last two decades to reduce the POPF. The present meta-analysis aims to assess the effectiveness of the prophylactic octreotide in preventing the POPF following PD. Methods A literature search was performed in the PubMed for the RCTs that compared the prophylactic octreotide with the placebo following PD published prior to October 2016. Review manager (Cochrane Collaboration's software) version RevMan 5.2 was used for analysis. Those RCTs which had compared the prophylactic Octreotide with placebo to reduce the POPF following PD were considered eligible for the meta-analysis. The low quality (Jadad score of two or less) RCTs or those including mixed pancreatic resections without reporting specific pancreaticoduodenectomy outcomes were excluded. The effect size for the dichotomous and the continuous data was displayed as the odds ratio (OR) and the weighted mean difference (WMD), respectively, with their corresponding 95% confidence intervals (CI). A fixed effect or random effects model was used to pool the data according to the result of a statistical heterogeneity test. The heterogeneity between the studies was evaluated using the Cochran Q statistic and the I 2 test, with p < 0.05 indicating significant heterogeneity. Results There were eight RCTs available for the analysis. A total of 959 patients were included in the meta-analysis-492 received the prophylactic octreotide and 467 patients received the placebo. The prophylactic octreotide was not found to significantly decrease the total number of the POPF (OR, 1.03'; 95% CI: 0.73-1.45; p -value 0.85) or the clinically significant POPF (OR, 0.76; 95% CI: 0.35-1.65; p -value 0.49) compared with the placebo. There was also no difference in the duration of hospital stay (WMD, 1.19; 95% CI:1.84-4.23; p -value 0.44) or the postoperative mortality (OR, 2.04; 95% CI: 0.87-4.78; p -value 0.10) between the two groups. The prophylactic octreotide was also not found to significantly delay the gastric emptying (OR, 0.76; 95% CI: 0.41-1.40; p -value 0.38). Conclusion The present meta-analysis does not support the role of the prophylactic octreotide to prevent the POPF following PD. PMID- 30474065 TI - Impact of Graft Steatosis on Postoperative Complications after Liver Transplantation. AB - Background Steatotic grafts are more susceptible to ischemia-reperfusion injury than are normal grafts. Therefore, using steatotic grafts for liver transplantation (LT) is associated with high primary dysfunction and decreased survival rates. The aim of this study is to evaluate the impact of graft steatosis on post LT outcomes. Methods A retrospective cohort analysis of 271 LT recipients from 2005 to 2016 was performed and patients were classified based on two types of steatosis, macrosteatosis (MaS), and microsteatosis (MiS). Each category was subdivided into three groups according to the degree of steatosis: no (< 5%), mild (>=5 to < 30%), and moderate (>=30 to <=60%). The primary hospital stays and 6-month postoperative complications were analyzed by the Clavien-Dindo classification system. Additionally, patient and graft survivals were studied. Results Significant differences were observed in grade III MaS ( p -value = 0.019) and grade V MiS ( p -value = 0.020). A high trend of early graft dysfunction was found in the moderate MaS and MiS groups; however, they were not statistically significant ( p -value = 0.199 and 0.282, respectively). Interestingly, the acute cellular rejection (ACR) rate was found to be inversely proportional to the degree of steatosis in both categories but it did not reach a significant level ( p -value = 0.161 and 0.111, respectively). Conclusion Excellent post LT long-term outcomes using grafts with mild and moderate steatosis were determined. Further studies are needed to evaluate the newly proposed relationship between ACR and steatosis. PMID- 30474066 TI - Outcomes of Biliointestinal Bypass among Iranian Obese Patients. AB - Background There are several surgical approaches to treat obesity not cured with medical approaches. Each method has its advantages and complications. In here, we have conducted a study to evaluate complications of biliointestinal bypass surgery (BIBP). Methods A prospective study was conducted in a private hospital from 2002 to 2016. Those patients, not previously operated for morbid obesity, were eligible. Mean follow-up period was 89 months ( +/- 54 months; range: 73-108 months). Main outcome measures were weight, BMI (body mass index), concentrations of blood lipids and glucose, liver transaminases, and obesity-related comorbidities and complications. Results Twenty-three consecutive patients with morbid obesity, including 16 women (69.7%) and seven men (31.3%) with mean age 38.47 +/- 10 years (range: 26-57 years) underwent surgery. At the end of follow up period, a mean BMI reduction of 12.2 kg/m 2 kg/m 2 ( p < 0.001)] was observed. An excess weight loss (EWL) of 63% ( +/- 34) was achieved at the end of the study. Additionally, total cholesterol and triglyceride levels decreased postoperative significantly. The main long-term complications were flatulence (60%), borborygmus (47.8%), mal odorous stool (30.4%), and diarrhea (21.7%). Revision rate was 4.34%. There were no cases with irreversible hepatic injury, deaths due to the surgery, or progressive renal failure. Conclusion BIBP seems to be a safe, easily reversible, and one of valid therapeutic approaches in morbidly obese patients. BIBP has the potential to achieve durable weight loss and offers an improved quality of life. PMID- 30474067 TI - Enterovesical Fistula Secondary to Transitional Cell Carcinoma of the Bladder. AB - Although fistulae between the urinary bladder and the gastrointestinal tract are not uncommon, those caused by carcinoma of the urinary bladder are rare. This report describes the case of an 85 years old male who was diagnosed with a mass involving the small bowel and the urinary bladder during the course of investigation for recurrent urinary tract infections. At laparotomy, the presence of an enterovesical fistula involving the ileum and bladder was confirmed. Histopathological examination of the resected mass showed poorly differentiated urothelial carcinoma. No early postoperative complications were encountered and postoperative cystography showed healing of the bladder without evidence of leakage. Due to the patient's age and comorbidities, no further oncological treatment was offered. Three months later the patient was readmitted to hospital with a severe pneumonia to which he succumbed. PMID- 30467552 TI - Longitudinal serological measures of common infection in the Avon Longitudinal Study of Parents and Children cohort. AB - Antibodies against pathogens provide information on exposure to infectious agents and are meaningful measures of past and present infection. Antibodies were measured in the plasma of children that are the offspring in a population-based birth cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC). Plasma was collected during clinics at age 5, 7, 11 and 15 years. The antigens examined include: fungal ( Saccharomyces cerevisiae); protozoan ( Toxoplasma gondii and surface antigen 1 of T. gondii); herpes viruses (cytomegalovirus, Epstein-Barr virus, herpes simplex virus type 1); common colds (influenza virus subtypes H1N1 and H3N2); other antigens (measles); animal (feline herpes virus, Theiler's virus); bacteria ( Helicobacter pylori); dietary antigens (bovine casein alpha protein, bovine casein beta protein). Alongside the depth of data available within the ALSPAC cohort, this longitudinal resource will enable the investigation of the association between infections and a wide variety of outcomes. PMID- 30474070 TI - Atypical Presentation of Granulomatosis with Polyangiitis. PMID- 30474069 TI - Approach to Using Trend Arrows in the FreeStyle Libre Flash Glucose Monitoring Systems in Adults. AB - The use of personal continuous glucose monitoring (CGM) has expanded dramatically among individuals with diabetes. CGM systems provide retrospective data, as well as the current glucose value and trend arrow data, which indicate the direction and velocity of changing glucose. In 2017, Aleppo and colleagues developed a simplified approach for adults with diabetes to safely adjust rapid-acting insulin doses using trend arrow information in the Dexcom G5 CGM system. Since then, the FreeStyle Libre and FreeStyle Libre 14-day CGM systems have become available in the United States; however, guidance on using trend arrow data that take the unique features of these systems into consideration is lacking. Specifically, the FreeStyle Libre systems do not have automatic alarms, which impact how the system and trend arrow data are used. The Endocrine Society convened an expert panel to address this gap and develop an approach to adjusting rapid-acting insulin doses for adults using trend arrows in the FreeStyle Libre systems. We based our approach on previous work and expanded upon engagement and scanning recommendations, and we incorporated pre-exercise planning specific to these systems. Our approach provides insulin dose adjustments as discrete insulin units based on an individual's insulin sensitivity and directionality of the trend arrow. We focus on the needs of patients treated with multiple daily injections because these individuals currently make up a greater proportion of individuals on intensive insulin therapy. Our recommendations are intended to provide a safe, practical approach to using trend arrows in the FreeStyle Libre systems. PMID- 30474071 TI - Consumer health-related needs of pregnant women and their caregivers. AB - Objectives: To build effective applications, technology designers must understand consumer health needs. Pregnancy is a common health condition, and expectant families have unanswered questions. This study examined consumer health-related needs in pregnant women and caregivers and determined the types of needs that were not met. Materials and Methods: We enrolled pregnant women <36 weeks' gestational age and caregivers from advanced maternal-fetal and group prenatal care settings. Participant characteristics were collected through surveys, and health-related needs were elicited in semi-structured interviews. Researchers categorized needs by semantic type and whether they were met (ie, met, partially met, or unmet). Inter-rater reliability was measured by Cohen's kappa. Results: Seventy-one pregnant women and 29 caregivers participated and reported 1054 needs, 28% unmet, and 49% partially met. Need types were 66.2% informational, 15.9% logistical, 8.9% social, 8.6% medical, and 0.3% other. Inter-rater reliability was near perfect (kappa=0.95, P < 0.001). Discussion: Common topics of unmet needs were prognosis, life management, and need for emotional support. For pregnant women, these unmet needs focused around being healthy, childbirth, infant care, and being a good mother; caregivers' needs involved caring for the mother, the natural course of pregnancy, and life after pregnancy. Conclusion: Pregnant women and caregivers have a rich set of health-related needs with many not fully met. Caregivers' needs differed from those of pregnant women and may not be adequately addressed by resources designed for mothers. Many unmet needs involved stress and life management. Knowledge about consumer health needs can inform the design of better technologies for pregnancy. PMID- 30474072 TI - Accrual to Clinical Trials (ACT): A Clinical and Translational Science Award Consortium Network. AB - The Accrual to Clinical Trials (ACT) network is a federated network of sites from the National Clinical and Translational Science Award (CTSA) Consortium that has been created to significantly increase participant accrual to multi-site clinical trials. The ACT network represents an unprecedented collaboration among diverse CTSA sites. The network has created governance and regulatory frameworks and a common data model to harmonize electronic health record (EHR) data, and deployed a set of Informatics for Integrating Biology and the Bedside (i2b2) data repositories that are linked by the Shared Health Research Information Network (SHRINE) platform. It provides investigators the ability to query the network in real time and to obtain aggregate counts of patients who meet clinical trial inclusion and exclusion criteria from sites across the United States. The ACT network infrastructure provides a basis for cohort discovery and for developing new informatics tools to identify and recruit participants for multi-site clinical trials. PMID- 30474073 TI - Designing a wrist-worn sensor to improve medication adherence: accommodating diverse user behaviors and technology preferences. AB - Objectives: High medication adherence is important for HIV suppression (antiretroviral therapy) and pre-exposure prophylaxis efficacy. We are developing sensor-based technologies to detect pill-taking gestures, trigger reminders, and generate adherence reports. Materials and Methods: We collected interview, observation, and questionnaire data from individuals with and at-risk for HIV (N = 17). We assessed their medication-taking practices and physical actions, and feedback on our initial design. Results: While participants displayed diverse medication taking practices and physical actions, most (67%) wanted to use the system to receive real-time and summative feedback, and most (69%) wanted to share data with their physicians. Participants preferred reminders via the wrist worn device or mobile app, and summative feedback via mobile app or email. Discussion: Adoption of these systems is promising if designs accommodate diverse behaviors and preferences. Conclusion: Our findings may help improve the accuracy and adoption of the system by accounting for user behaviors, physical actions, and preferences. PMID- 30474074 TI - A Curated Cancer Clinical Outcomes Database (C3OD) for accelerating patient recruitment in cancer clinical trials. AB - Data used to determine patient eligibility for cancer clinical trials often come from disparate sources that are typically maintained by different groups within an institution, use differing technologies, and are stored in different formats. Collecting data and resolving inconsistencies across sources increase the time it takes to screen eligible patients, potentially delaying study completion. To address these challenges, the Biostatistics and Informatics Shared Resource at The University of Kansas Cancer Center developed the Curated Cancer Clinical Outcomes Database (C3OD). C3OD merges data from the electronic medical record, tumor registry, bio-specimen and data registry, and allows querying through a single unified platform. By centralizing access and maintaining appropriate controls, C3OD allows researchers to more rapidly obtain detailed information about each patient in order to accelerate eligibility screening. This case report describes the design of this informatics platform as well as initial assessments of its reliability and usability. PMID- 30474075 TI - The association between method of solicitation and patient permissions for use of surplus tissues and contact for future research. AB - Objective: Obtaining patient permissions for research contact and for surplus tissue use as part of routine clinical practice can improve research participation. This study aims to investigate the difference in patient permissions for use of surplus tissues, and for direct contact for research, using 2 different methods of solicitation. Methods: An opt-in, population-based approach for gathering research permissions was implemented in 2 methods. The first method, applied a 2-item patient questionnaire delivered through the electronic health record patient portal. The questionnaire composed of 2 questions (1) whether de-identified surplus specimens may be used for research and (2) whether patients could be contacted about research. In the second method, the same questionnaire was physically presented in clinic within the clinical workflow. We used 1 to 1 propensity score matching and multivariate logistic regression to estimate the odds of obtaining permission and the difference between the 2 methods of solicitation. Results: The propensity score model matched 8044 observations (4114 submissions in each group). Among the in-clinic submission group, 70.13% provided permission for surplus tissue compared with 66.65% in the patient portal submission group (odds ratio [OR] = 1.20; 95% confidence interval [CI] 1.09-1.32; P < 0.001). Permission for future research contact was similar among in-clinic (65.07%) and patient portal submission (66.65%) groups (OR = 0.94; 95% CI 0.85-1.03; P = 0.175). These trends were consistent among European Americans and African American patients. However, among patients of other race, higher permission for both future contact (OR = 0.58; 95% CI 0.39-0.86; P < 0.007) and surplus tissue use (OR = 0.65; 95% CI 0.43-0.97; P = 0.036) was observed among patient portal submission. Discussion: Our findings suggest that in-clinic solicitation of patient permissions may provide the same opportunity to patients who do not use patient portals and may be associated with higher permission rate for surplus tissue. However, this was primary true for European American and African Americans patients. Patients of other race minorities might respond better to online approaches. Conclusion: Adopting a patient-centric approach that combines in-clinic and portal-based administration may be feasible and promising. Further research is required in this area. PMID- 30474076 TI - Research participation preferences as expressed through a patient portal: implications of demographic characteristics. AB - Objective: As patient portals are increasingly used for research recruitment, it is important to examine the demographic makeup of research registries that are populated via portals and the factors that influence participation in these registries. Methods: We examined the response to a routine research preference questionnaire among patients who were enrolled in a patient portal at an academic health center and characterized the sub-population that responded and was tracked in a research preferences registry. We examined the factors that influence choices in two research preferences: future contact for research opportunities and biobanking of de-identified specimens. Results: Out of 79 834 patients to whom the questionnaire was sent, 32% responded. Of those 74% agreed to future contact and 77% to the biobank preference. We found significantly lower odds of agreement in both preferences in minority populations, especially in the population >65 years of age when stratified by race. Individuals with higher comorbidity indexes had significantly higher odds for agreement. Discussion: The disparities in volunteerism as expressed by agreement to future contact and willingness to participate in biobanking are exacerbated by lower levels of enrollment in the patient portal by minorities, especially in the oldest age group. Future work should examine other socioeconomic factors and the differences across age groups, sicker individuals, and payer categories. Conclusion: Although patient portals can be more efficient for recruitment, researchers have to be cognizant of, and proactively address, potential biases when recruiting participants from these registries. PMID- 30474077 TI - Using electronic health records to characterize prescription patterns: focus on antidepressants in nonpsychiatric outpatient settings. AB - Objective: To characterize nonpsychiatric prescription patterns of antidepressants according to drug labels and evidence assessments (on-label, evidence-based, and off-label) using structured outpatient electronic health record (EHR) data. Methods: A retrospective analysis was conducted using deidentified EHR data from an outpatient practice at a New York City-based academic medical center. Structured "medication-diagnosis" pairs for antidepressants from 35 325 patients between January 2010 and December 2015 were compared to the latest drug product labels and evidence assessments. Results: Of 140 929 antidepressant prescriptions prescribed by primary care providers (PCPs) and nonpsychiatry specialists, 69% were characterized as "on-label/evidence-based uses." Depression diagnoses were associated with 67 233 (48%) prescriptions in this study, while pain diagnoses were slightly less common (35%). Manual chart review of "off-label use" prescriptions revealed that on-label/evidence-based diagnoses of depression (39%), anxiety (25%), insomnia (13%), mood disorders (7%), and neuropathic pain (5%) were frequently cited as prescription indication despite lacking ICD-9/10 documentation. Conclusions: The results indicate that antidepressants may be prescribed for off-label uses, by PCPs and nonpsychiatry specialists, less frequently than believed. This study also points to the fact that there are a number of off-label uses that are efficacious and widely accepted by expert clinical opinion but have not been included in drug compendia. Despite the fact that diagnosis codes in the outpatient setting are notoriously inaccurate, our approach demonstrates that the correct codes are often documented in a patient's recent diagnosis history. Examining both structured and unstructured data will help to further validate findings. Routinely collected clinical data in EHRs can serve as an important resource for future studies in investigating prescribing behaviors in outpatient clinics. PMID- 30474078 TI - Learning relevance models for patient cohort retrieval. AB - Objective: We explored how judgements provided by physicians can be used to learn relevance models that enhance the quality of patient cohorts retrieved from Electronic Health Records (EHRs) collections. Methods: A very large number of features were extracted from patient cohort descriptions as well as EHR collections. The features were used to investigate retrieving (1) neurology specific patient cohorts from the de-identified Temple University Hospital electroencephalography (EEG) Corpus as well as (2) the more general cohorts evaluated in the TREC Medical Records Track (TRECMed) from the de-identified hospital records provided by the University of Pittsburgh Medical Center. The features informed a learning relevance model (LRM) that took advantage of relevance judgements provided by physicians. The LRM implements a pairwise learning-to-rank framework, which enables our learning patient cohort retrieval (L-PCR) system to learn from physicians' feedback. Results and Discussion: We evaluated the L-PCR system against state-of-the-art traditional patient cohort retrieval systems, and observed a 27% improvement when operating on EEGs and a 53% improvement when operating on TRECMed EHRs, showing the promise of the L-PCR system. We also performed extensive feature analyses to reveal the most effective strategies for representing cohort descriptions as queries, encoding EHRs, and measuring cohort relevance. Conclusion: The L-PCR system has significant promise for reliably retrieving patient cohorts from EHRs in multiple settings when trained with relevance judgments. When provided with additional cohort descriptions, the L-PCR system will continue to learn, thus offering a potential solution to the performance barriers of current cohort retrieval systems. PMID- 30474079 TI - Trends in anesthesiology research: a machine learning approach to theme discovery and summarization. AB - Objectives: Traditionally, summarization of research themes and trends within a given discipline was accomplished by manual review of scientific works in the field. However, with the ushering in of the age of "big data," new methods for discovery of such information become necessary as traditional techniques become increasingly difficult to apply due to the exponential growth of document repositories. Our objectives are to develop a pipeline for unsupervised theme extraction and summarization of thematic trends in document repositories, and to test it by applying it to a specific domain. Methods: To that end, we detail a pipeline, which utilizes machine learning and natural language processing for unsupervised theme extraction, and a novel method for summarization of thematic trends, and network mapping for visualization of thematic relations. We then apply this pipeline to a collection of anesthesiology abstracts. Results: We demonstrate how this pipeline enables discovery of major themes and temporal trends in anesthesiology research and facilitates document classification and corpus exploration. Discussion: The relation of prevalent topics and extracted trends to recent events in both anesthesiology, and healthcare in general, demonstrates the pipeline's utility. Furthermore, the agreement between the unsupervised thematic grouping and human-assigned classification validates the pipeline's accuracy and demonstrates another potential use. Conclusion: The described pipeline enables summarization and exploration of large document repositories, facilitates classification, aids in trend identification. A more robust and user-friendly interface will facilitate the expansion of this methodology to other domains. This will be the focus of future work for our group. PMID- 30474081 TI - Partitioning and Classification of RNA Secondary Structures into Pseudonotted and Pseudoknot-free Regions Using a Graph-Theoretical Approach. AB - Dual graphs have been applied to model RNA secondary structures with pseudoknots, or intertwined base pairs. In this paper we present a linear-time algorithm to partition dual graphs into maximal topological components called blocks and determine whether each block contains a pseudoknot or not. We show that a block contains a pseudoknot if and only if the block has a vertex of degree 3 or more; this characterization allows us to efficiently isolate smaller RNA fragments and classify them as pseudoknotted or pseudoknot-free regions, while keeping these sub-structures intact. Applications to RNA design can be envisioned since modular building blocks with intact pseudoknots can be combined to form new constructs. PMID- 30474080 TI - A Layer-by-Layer Approach To Retain a Fluorescent Glucose Sensing Assay within the Cavity of a Hydrogel Membrane. AB - A continuous glucose monitoring device that resides fully in the subcutaneous tissue has the potential to greatly improve the management of diabetes. Toward this goal, we have developed a competitive binding glucose sensing assay based on fluorescently labeled PEGylated concanavalin-A (PEGylated-TRITC-ConA) and mannotetraose (APTS-MT). In the present work, we sought to contain this assay within the hollow central cavity of a cylindrical hydrogel membrane, permitting eventual subcutaneous implantation and optical probing through the skin. A "self cleaning" hydrogel was utilized because of its ability to cyclically deswell/reswell in vivo, which is expected to reduce biofouling and therefore extend the sensor lifetime. Thus, we prepared a hollow, cylindrical hydrogel based on a thermoresponsive electrostatic double network design composed of N isopropylacrylamide and 2-acrylamido-2-methylpropanesulfonic acid. Next, a layer by-layer (LbL) coating was applied to the inner wall of the central cavity of the cylindrical membrane. It consisted of 5, 10, 15, 30, or 40 alternating bilayers of positively charged poly(diallyldimethylammonium chloride) and negatively charged poly(sodium 4-styrenesulfonate). With 30 bilayers, the leaching of the smaller-sized component of the assay (APTS-MT) from the membrane cavity was substantially reduced. Moreover, this LbL coating maintained glucose diffusion across the hydrogel membrane. In terms of sensor functionality, the assay housed in the hydrogel membrane cavity tracked changes in glucose concentration (0 to 600 mg/dL) with a mean absolute relative difference of ~11%. PMID- 30474084 TI - SPEC 2018: International Society of Clinical Spectroscopy. PMID- 30474083 TI - Interleukin-18 has an Important Role in Differentiation and Maturation of Mucosal Mast Cells. AB - A significant amount of correlational evidence has linked increased levels of IL 18 with allergic diseases in both human and animal models, and, as mast cells are major mediators of allergies, we hypothesized that IL-18 may have a role in mast cell biology. Rationale for our hypothesis is based on the evidence that IL-3 deficient mice are not devoid of mast cells, even though IL-3 is a major differentiation and growth factor for mast cells. Accordingly, we cultured IL-18 responsive bone marrow CD34+ cells in vitro under a variety of conditions and cytokine combinations to examine mast cell differentiation and maturation using flow cytometry, quantitative PCR,and immunostaining techniques. Additionally, in vivo mast cell transformation and maturation were also analysed using endogenous IL-18 gene-deficient or Fabpi-IL-18 overexpressed mice. Our data indicate that both IL-3 and IL-18 exposed CD34+ bone marrow precursors differentiate and mature into mast cells. Further, we observed that IL-18 differentiates mast cells independent of IL-3, as pharmacologic blockade of IL-3 does not prevent in vitro IL-18-driven mast cell differentiation. Further, we found that endogenous IL-18 deficiency restricts maturation of IL-3 generated mast cells and IL-18 derived mast cells require IL-3 for their survival. Additionally, we observed IL-18 intestinal overexpression promotes tissue mast cell proliferation and mucosal mast cell development. Taken together, we provide the evidence that IL-18 has an important contributory role in mast cell differentiation, maturation and in vivo development of mucosal mast cells. Therefore, IL-18 may represent a future pharmacologic target for treating mast cell-mediated allergic diseases. PMID- 30474082 TI - A Discussion on the Relationship between Skin Lipid Metabolism and Whole-Body Glucose and Lipid Metabolism: Systematic Review. AB - The obesity epidemic is a costly public health crisis that is not improving. In addition to the stigma and discomfort associated with carrying extra weight (at the expense of range of movement), obesity also goes hand-in-hand with co morbidities like fatty liver disease, diabetes, cardiovascular disease, and increased risk of some forms of cancer. Currently there are no long-lasting treatments for obesity other than diet and exercise, which are not feasible for many populations that may not be equipped with the resources and/or support needed to lead a healthy lifestyle. Although there have been some pharmacological breakthroughs for treating obesity, each FDA-approved drug comes with unpleasant side-effects that make adherence unlikely. As a result, alternate approaches are necessary. In this review, we outline the relationship between skin lipid metabolism and whole-body glucose and lipid metabolism. Specifically, by summarizing studies that employed mice that were genetically modified to interrupt lipid metabolism in the skin. As a result, we propose that skin might be an overlooked, but viable target for combating obesity. PMID- 30474085 TI - Highlights from the Faraday Discussion 296: quantum effects in small molecular systems, 10-12 September 2018, Edinburgh, United Kingdom. AB - Exciting discussions on the impact of quantum effects in small molecular systems took place in the historical city of Edinburgh this fall 2018 in the unique conference format of the Faraday Discussions. During this three day conference meeting close to Holyrood Park, 65 leading experts from all over the world came together to discuss the developments, advances and challenges in the wide field of quantum effects in small molecular systems, either isolated or embedded into clusters, clathrates or cold matrices. The meeting clearly reflected the importance of the accurate description, characterization and prediction of quantum effects in isolated, solvated and complexed molecular systems, while allowing the community to crystallize future perspectives and directions in the field, as well as applications in chemistry, physics, biology, environmental sciences and industry. PMID- 30474086 TI - Hot off the press. AB - A personal selection of 32 recent papers is presented covering various aspects of current developments in bioorganic chemistry and novel natural products such as kadsuraol A from Kadsura longipedunculata. PMID- 30474087 TI - Oscillating dispersed-phase co-flow microfluidic droplet generation: jet length reduction effect. AB - Microdroplet generation methods are assessed by two important criteria of droplet throughput and size dispersity. The widely-used co-flow droplet generation technique is bottlenecked with droplet polydispersity at high throughputs due to transition to an unstable jetting regime at high dispersed-phase (d-phase) flow rates. In this paper, we introduce a novel technique to oscillate the d-phase nozzle inside the continuous phase (c-phase) channel to suppress the jetting effect. The effect of the nozzle oscillation frequency (0-15 Hz) on the jet length was studied at different d-phase (Qd = 1.8, 2.4 and 3.0 ml min-1) and c phase (Qc = 6, 12 and 18 ml min-1) flow rates and d-phase viscosities (1, 2.5, and 6 mPa s). The jet length was directly proportional to the d-phase flow rate and inversely proportional to the oscillation frequency. Oscillation-induced jet length reduction was more significant at high jet velocities, but a less steep jet length reduction was always observed at oscillation frequencies higher than 10 Hz. A maximum jet length reduction of 70.8% was obtained at the highest d phase and lowest c-phase flow rates. Increasing the viscosity of the d-phase resulted in diminishing the effect of oscillation on jet length reduction. Moreover, we observed that nozzle oscillation could disintegrate the long jet into droplets of various sizes that were mostly smaller than the stationary-mode droplets. We hypothesize that oscillating the dispersion nozzle at lower flow rates, without the jetting effect, can simultaneously generate multi-size monodisperse droplets. This active technique can also be implemented into aqueous two-phase systems (ATPSs) in which droplet generation is a difficult task. PMID- 30474088 TI - Relations between the aromaticity and magnetic dipole transitions in the electronic spectra of hetero[8]circulenes. AB - Magnetically induced current densities have been calculated at the second-order Moller-Plesset perturbation theory (MP2) level for seven hetero[8]circulenes and their dicationic and dianionic forms. Calculations of the magnetic dipole transition moments have also been carried out at the algebraic diagrammatic construction (ADC(2)) and the second-order approximate coupled-cluster (CC2) levels. The calculations show that the degree of aromaticity and the size of the magnetic dipole transition moment of the lowest magnetic-dipole allowed excited state are related. We show that neutral hetero[8]circulenes are weakly antiaromatic when the first excited state with a large magnetic dipole transition moment of 10-16 a.u. lies at high energies (~2.8-3.5 eV). For the dications, this transition often lies at much lower energies. Hetero[8]circulene dications with large magnetic dipole transition moments are strongly antiaromatic. The lowest excited states of the hetero[8]circulene dianions have very small magnetic dipole transition moments implying that they are aromatic. PMID- 30474090 TI - Does deamidation of islet amyloid polypeptide accelerate amyloid fibril formation? AB - Mass spectrometry has been applied to determine the deamidation sites and the aggregation region of the deamidated human islet amyloid polypeptide (hIAPP). Mutant hIAPP with iso-aspartic residue mutations at possible deamidation sites showed very different fibril formation behaviour, which correlates with the observed deamidation-induced acceleration of hIAPP aggregation. PMID- 30474089 TI - Kinetics of the reaction of the simplest Criegee intermediate with ammonia: a combination of experiment and theory. AB - The kinetics of the reaction of the simplest Criegee intermediate (CH2OO) with ammonia has been measured under pseudo-first-order conditions with two different experimental methods. We investigated the rate coefficients at 283, 298, 308, and 318 K at a pressure of 50 Torr using an OH laser-induced fluorescence (LIF) method. Weak temperature dependence of the rate coefficient was observed, which is consistent with the theoretical activation energy of -0.53 kcal mol-1 predicted by quantum chemistry calculation at the QCISD(T)/CBS//B3LYP/6 311+G(2d,2p) level. At 298 K, the rate coefficient at 50 Torr from the OH LIF experiment was (5.64 +/- 0.56) * 10-14 cm3 molecule-1 s-1 while at 100 Torr we obtained a slightly larger value of (8.1 +/- 1.0) * 10-14 cm3 molecule-1 s-1 using the UV transient absorption method. These experimental values are within the theoretical error bars of the present as well as previous theoretical results. Our experimental results confirmed the previous conclusion that ammonia is negligible in the consumption of CH2OO in the atmosphere. We also note that CH2OO may compete with OH in the oxidation of ammonia under certain circumstances, such as at night-time, high altitude and winter time. PMID- 30474091 TI - An improved theory of the electric conductance of ionic solutions based on the concept of the ion-atmosphere's smaller-ion shell. AB - Although the electric conductivity of ionic solutions is of great importance in science and technology, complete understanding of the physical factors and principles underlying ion and charge transport in solution has so far been missing. The Debye-Huckel-Onsager (DHO) theory of the equivalent ionic conductivity (lambdai for single ion i, Lambda for a binary electrolyte) is a limiting law of only a few electrolyte valence families, and its extension to solution of finite concentration has not been entirely successful; at most, it has led to semiempirical expressions of lambdai or Lambda vs. concentration (c), incorporating adjustable parameters of no clear physical meaning. Improving the description of the ion atmosphere and including in the conductivity model the smaller-ion shell (SiS) of this atmosphere (D. Fraenkel, Mol. Phys., 2010, 108, 1435) allow now an extension of the DHO theory to a "DHO-SiS" theory that offers analytic expressions for lambdai and Lambda as a function of c without adjustable parameters. The fit with experiment is very good, often excellent, for many electrolytes of the various valence families. lambdai values can be converted to single-ion activity coefficients, gammais, suggesting that the latter ionic factors do have physical validity, contrary to what many literature sources claim. Together with the recently proposed theory of the limiting conductivities, lambda0i and Lambda0 (D. Fraenkel, Mol. Phys., 2018, 116, 2271), the new theory offers a simple and comprehensive ion conductivity treatment that improves upon existing theoretical treatments, with lambdai and Lambda expressed by ionic sizes instead of lambda0i and Lambda0. PMID- 30474092 TI - Quantitative profile-profile relationship (QPPR) modelling: a novel machine learning approach to predict and associate chemical characteristics of unspent ammunition from gunshot residue (GSR). AB - Evidence association in forensic cases involving gunshot residue (GSR) remains very challenging. Herein, a new in silico approach, called quantitative profile profile relationship (QPPR) modelling, is reported. This is based on the application of modern machine learning techniques to predict the pre-discharge chemical profiles of selected ammunition components from those of the respective post-discharge GSR. The obtained profiles can then be compared with one another and/or with other measured profiles to make evidential links during forensic investigations. In particular, the approach was optimised and successfully tested for the prediction of GC-MS profiles of smokeless powders (SLPs) from organic GSR in spent cases, for nine ammunition types. Results showed a high degree of similarity between predicted and experimentally measured profiles, after adequate combination and evaluation of fourteen machine learning techniques (median correlation of 0.982). Areas under the curve (AUCs) of 0.976 and 0.824 were observed after receiver operating characteristic (ROC) analysis of the results obtained in the comparisons between predicted-predicted and predicted-measured profiles, respectively, in the specific case that the ammunition types of interest were excluded from the training dataset (i.e., extrapolation). Furthermore, AUCs of 0.962 and 0.894 were observed in interpolation mode. These values were close to those of the comparison of the measured SLP profiles between themselves (AUC = 0.998), demonstrating excellent potential to correctly associate evidence in a number of different forensic scenarios. This work represents the first time that a quantitative approach has successfully been applied to associate a GSR to a specific ammunition. PMID- 30474093 TI - Nitrogen matters: the difference between PANH and PAH formation. AB - A solid understanding of and a reliable model for the formation pathways of polycyclic aromatic (nitrogen containing) hydrocarbons (PA(N)Hs) is needed to account for their abundance in the interstellar medium and in Titan's atmosphere as well as to mitigate the emission of these carcinogens in our terrestrial environment. We have investigated the phenyl + acrylonitrile reaction mechanism between 600 and 1200 K in a hot microreactor. Radical intermediates (C9H8N), formed by addition, and closed-shell C9H7N products, formed by subsequent hydrogen elimination, are isomer-selectively identified using photoion mass selected threshold photoelectron spectroscopy in conjunction with Franck-Condon simulations. Although quinoline is the most stable product, the calculated potential energy surface and a kinetic model confirm that the reaction is kinetically controlled and yields four open-chain isomers instead. The absence of quinoline is in stark contrast with the isoelectronic phenyl + vinylacetylene reaction that produces naphthalene. Ab initio calculations suggest that this change is brought about by the stability of the nitrile group, which inhibits ring formation. Therefore, it is unlikely that nitrile precursors form nitrogen containing rings, which calls for alternative pathways by which nitrogen atoms can be incorporated in aromatic systems to explain their presence in the ISM and Titan's atmosphere. PMID- 30474094 TI - Protein engineering through chemical, genetic and computational manipulation. PMID- 30474095 TI - The size dependant behaviour of particles driven by a travelling surface acoustic wave (TSAW). AB - The use of travelling surface acoustic waves (TSAW) in a microfluidic system provides a powerful tool for the manipulation of particles and cells. In a TSAW driven system, acoustophoretic effects can cause suspended micro-objects to display three distinct responses: (1) swirling, driven by acoustic streaming forces, (2) migration, driven by acoustic radiation forces and (3) patterning in a spatially periodic manner, resulting from diffraction effects. Whilst the first two phenomena have been widely discussed in the literature, the periodic patterning induced by TSAW has only recently been reported and is yet to be fully elucidated. In particular, more in-depth understanding of the size-dependant nature of this effect and the factors involved are required. Herein, we present an experimental and numerical study of the transition in acoustophoretic behaviour of particles influenced by relative dominance of these three mechanisms and characterise it based on particle diameter, channel height, frequency and intensity of the TSAW driven microfluidic system. This study will enable better understanding of the performance of TSAW sorters and allow the development of TSAW systems for particle collection and patterning. PMID- 30474096 TI - Rate constants for collision-induced emission of O2(a1Deltag) with He, Ne, Ar, Kr, N2, CO2 and SF6 as collisional partners. AB - Rate constants for singlet oxygen collision induced emission of the a1Deltag X3Sigma-g transition at 1.27 MUm were measured for CO2, N2, SF6, and rare gases as collisional partners. Photolysis of ozone by 266 nm laser radiation produced singlet oxygen. We performed direct measurements of pressure dependences of the 1.27 MUm emission intensity for partner gases. The measured rate constants kMa-X in the units of 10-24 cm3 s-1 are as follows: CO2 - 10 +/- 2; N2 - 3.2 +/- 0.6; SF6 - 7 +/- 1; He - 1.1 +/- 0.3; Ne - 1.3 +/- 0.3; Ar - 2.8 +/- 0.6; Kr - 6 +/- 1. The measured values of kMa-X are close to the values calculated from absorption measurements. Considering the known rate constants kMb-a for the b1Sigmag+-a1Deltag transition in the gas phase we found that the ratio kMa-X/kMb a was constant and independent of a collisional partner according to the "spin orbit based" mechanism of intensity borrowing proposed by Minaev (THEOCHEM, 1989, 183, 207). However, this ratio amounted to (1.3 +/- 0.2) * 10-4, which is considerably lower than the theoretically predicted value of (3-6) * 10-4. PMID- 30474097 TI - Recent advances in gold-NHC complexes with biological properties. AB - This tutorial review covers the recent advances made in the study of gold complexes containing N-heterocyclic carbene ligands with biological properties. The great stability, ease of modulation of the electronic properties and excellent sigma-donating capacity displayed by NHCs allow gold-NHC derivatives to reach high stability in biological media and relatively good internalization into cells and for that they have emerged as excellent potential chemotherapeutics. The new gold-NHC derivatives show superior anticancer activity compared to other standards such as Cisplatin or Auranofin. In addition, the application of gold NHC complexes in the treatment of other human diseases as antibacterial, antioxidant and antiparasitic agents is reviewed for the first time. PMID- 30474098 TI - An iminodibenzyl-quinoxaline-iminodibenzyl scaffold as a mechanochromic and dual emitter: donor and bridge effects on optical properties. AB - The influence of phenyl linkage and donor strength on the photophysical properties of new derivatives of quinoxaline-containing iminodibenzyl and iminostilbene moieties is studied. The donor-acceptor derivatives showed dual thermally activated delayed fluorescence (TADF) and room temperature phosphorescence (RTP) despite a large energy gap between the excited singlet and triplet states (ca. 0.5 eV). This extremely rare observation is explained by the twisted and rigidified structure of the iminodibenzyl moiety. PMID- 30474099 TI - An ultrathin iron-porphyrin based nanocapsule with high peroxidase-like activity for highly sensitive glucose detection. AB - For the first time, an ultrathin iron-porphyrin based polymer nanocapsule with multiple peroxidase-like catalytic centers was constructed by covalently assembling iron-porphyrin monomers; this nanocapsule with a single molecule thickness shell acted as a highly efficient artificial enzyme for mimicking peroxidase. On the basis of the peroxidase-like activity of Fe-TPyP based nanocapsules (Fe-TPyP NCs), a highly sensitive colorimetric sensor for glucose determination was fabricated, the limit of detection was found to be as low as 0.098 MUM. This study provided a novel strategy for developing artificial enzymes based on covalently assembled nanostructures. Furthermore, the colorimetric sensor for glucose determination showed potential applications in biomedicine and biology. PMID- 30474100 TI - Ultrasensitive quantification of tumor mRNAs in extracellular vesicles with an integrated microfluidic digital analysis chip. AB - Extracellular vesicles (EVs) present a promising liquid biopsy for cancer diagnosis. However, it remains a daunting challenge to quantitatively measure molecular contents of EVs including tumor-associated mRNAs. Herein, we report a configurable microwell-patterned microfluidic digital analysis platform combined with a dual-probe hybridization assay for PCR-free, single-molecule detection of specific mRNAs in EVs. The microwell array in our device is configurable between the flow-through assay mode for enhanced hybridization capture and tagging of mRNAs and the digital detection mode based on femtoliter-scale enzymatic signal amplification for single-molecule counting of surface-bound targets. Furthermore, a dual-probe hybridization assay has been developed to enhance the sensitivity of the digital single-molecule detection of EV mRNAs. Combining the merits of the chip design and the dual-probe digital mRNA hybridization assay, the integrated microfluidic system has been demonstrated to afford quantitative detection of synthetic GAPDH mRNA with a LOD as low as 20 aM. Using this technology, we quantified the level of GAPDH and EWS-FLI1 mRNAs in EVs derived from two cell lines of peripheral primitive neuroectodermal tumor (PNET), CHLA-9 and CHLA-258. Our measurements detected 64.6 and 43.5 copies of GAPDH mRNA and 6.5 and 0.277 copies of EWS-FLI1 fusion transcripts per 105 EVs derived from CHLA-9 and CHLA 258 cells, respectively. To our knowledge, this is the first demonstration of quantitative measurement of EWS-FLI1 mRNA copy numbers in Ewing Sarcoma (EWS) derived EVs. These results highlight the ultralow frequency of tumor-specific mRNA markers in EVs and the necessity of developing highly sensitive methods for analysis of EV mRNAs. The microfluidic digital mRNA analysis platform presented here would provide a useful tool to facilitate quantitative analysis of tumor associated EV mRNAs for liquid biopsy-based cancer diagnosis and monitoring. PMID- 30474101 TI - Considerations in the Care of Non-Small-Cell Lung Cancer: The Value Imperative. AB - Cancer costs in the United States continue to escalate at an alarming and unsustainable rate. These costs are not driven exclusively by a higher demand for services or by an aging population; rather, a number of systemic failures, highlighted by the Institute of Medicine (IOM), continue to plague our cancer care delivery systems and need to be rectified. Drug costs, plus expensive diagnostic tests, hospital admissions/readmissions, and unreasonable end-of-life care, combine to inflate the total cost of care. Cancer, particularly lung cancer, is one of the most expensive diseases in the United States. While individual oncologists are unlikely to influence costs in the short term, they can become more proficient at evaluating the value derived from new treatment options and maximizing the clinical benefit for their patients. Discussions of cost and patient values need not hinder patient-physician relationships, and, in fact, can strengthen them. This article discusses ways in which the oncologist can incorporate value into the management of patients with lung cancer and comply with the underlying principles of the Choose Wisely Campaign, as well as recent American Society of Clinical Oncology and European Society for Medical Oncology initiatives, to bend the cost curve downwards while maintaining efficacy. PMID- 30474102 TI - Pros and Cons of Dietary Strategies Popular Among Cancer Patients. AB - As many as 48% of cancer patients pursue popular diets, including the alkaline, Paleolithic, ketogenic, vegan, and macrobiotic diets, with the hope that they will improve survival and prevent recurrence. These diets have positive aspects consistent with the dietary guidelines proposed by the American Cancer Society (ACS) and the American Institute for Cancer Research (AICR). All of the diets emphasize eating vegetables, all but the ketogenic diet encourage eating fruit, and all but the vegan diet limit refined grains and alcohol. Both the macrobiotic and the alkaline diets meet the majority of the ACS and AICR guidelines. Negative aspects of these diets include pseudo-scientific rationales for their anti-cancer properties, limited evidence that they improve cancer outcomes, the possibility for nutrient insufficiencies, and elimination of food groups proven beneficial for cancer prevention and general health. Moreover, with nutritional counseling, nutrient insufficiencies and misalignment with cancer clinical guidelines can often be addressed. Clinicians should consider strategies to encourage evidence based dietary changes that encourage positive features of popular cancer diets, while minimizing negative aspects. PMID- 30474103 TI - Role of Temozolomide in the Treatment of Cancers Involving the Central Nervous System. AB - Temozolomide has been available to oncologists for over 30 years. During this time, it has become an integral part of standard therapy in patients with high grade gliomas. Given its ability to traverse the blood-brain barrier, temozolomide has also been evaluated in other cancers that involve the central nervous system (CNS). We review its role in the management of patients with primary brain tumors, brain metastases, leptomeningeal carcinomatosis, and other selected CNS cancers. There is strong evidence that temozolomide is effective in patients with high-grade astrocytomas and oligodendrogliomas. Modest evidence supports its activity in primary CNS lymphomas and aggressive pituitary adenomas. Temozolomide, however, has minimal efficacy in a wide variety of systemic cancers. Given that concentrations of temozolomide in the CNS are only 20% of those in the blood, it is not surprising that it is generally inactive in patients with CNS metastases from solid tumors. PMID- 30474104 TI - Bone-Targeted Therapy in Early Breast Cancer. AB - Aromatase inhibitors (AIs) play an important role in the adjuvant treatment of hormone receptor-positive breast cancer, but they are associated with bone loss and increased fracture risk. Although several guidelines for the management of osteoporosis and osteopenia exist, their algorithms do not account for the use of AIs. In this article, we describe the role of bone-targeted therapies, specifically for managing early breast cancer, by reviewing their bone-specific and cancer-specific benefits. PMID- 30474105 TI - Management of Metastatic Prostate Cancer in Frail/Elderly Patients. AB - As the world population ages, we can expect to care for an increasing number of older cancer patients. Prostate cancer is inherently a condition that affects patients of advanced age. In caring for these patients who have advanced prostate cancer, it is important to first assess the health status of the patient and his goals of care. As this is established, likely through a geriatric assessment, this will inform how to modify or mold the treatment plan to fit a patient's needs and vulnerabilities. These vulnerabilities may surface as patients undergo treatment such as androgen deprivation therapy-the backbone of systemic therapy for advanced disease. Androgen deprivation therapy leads to long-term adverse effects; therefore, providers should carefully consider its use and proactively manage toxicity. It is important to assess patients before starting treatment and to adjust the choice of therapy, or supportive services, in order to maximize benefit and minimize potential harms. PMID- 30474106 TI - Atrial Fibrillation: Considerations for the Use of BTK Inhibitors. PMID- 30474107 TI - Accelerating the Development of Second-Order False Belief Reasoning: A Training Study With Different Feedback Methods. AB - One-hundred-six 5-year-olds' (Mage = 5;6; SD = 0.40) were trained with second order false belief tasks in one of the following conditions: (a) feedback with explanation; (b) feedback without explanation; (c) no feedback; (d) active control. The results showed that there were significant improvements in children's scores from pretest to posttest in the three experimental conditions even when children's age, verbal abilities, or working memory scores were controlled for. The training effect was stable at a follow-up session 4 months after the pretest. Overall, our results suggest that 5-year-olds' failures in second-order false belief tasks are due to lack of experience and that they can be helped over the threshold by exposure to many stories involving second-order false belief reasoning, including why questions. PMID- 30474108 TI - A comparison of two structured taxonomic strategies in capturing adverse events in U.S. hospitals. AB - OBJECTIVE: To compare the Agency for Healthcare Research and Quality's Quality and Safety Review System (QSRS) and the proposed triadic structure for the 11th version of the International Classification of Disease (ICD-11) in their ability to capture adverse events in U.S. hospitals. DATA SOURCES/STUDY SETTING: One thousand patient admissions between 2014 and 2016 from three general, acute care hospitals located in Maryland and Washington D.C. STUDY DESIGN: The admissions chosen for the study were a random sample from all three hospitals. DATA COLLECTION/EXTRACTION METHODS: All 1000 admissions were abstracted through QSRS by one set of Certified Coding Specialists and a different set of coders assigned the draft ICD-11 codes. Previously assigned ICD-10-CM codes for 230 of the admissions were also used. PRINCIPAL FINDINGS: We found less than 20 percent agreement between QSRS and ICD-11 in identifying the same adverse event. The likelihood of a mismatch between QSRS and ICD-11 was almost twice that of a match. The findings were similar to the agreement found between QSRS and ICD-10 CM in identifying the same adverse event. When coders were provided with a list of potential adverse events, the sensitivity and negative predictive value of ICD 11 improved. CONCLUSIONS: While ICD-11 may offer an efficient way of identifying adverse events, our analysis found that in its draft form, it has a limited ability to capture the same types of events as QSRS. Coders may require additional training on identifying adverse events in the chart if ICD-11 is going to prove its maximum benefit. PMID- 30474109 TI - Response to: The GPRC5A frameshift variant c.183del is not associated with increased breast cancer risk in BRCA1 mutation carriers. PMID- 30474110 TI - Long-term muscle changes after hamstring lengthening in children with bilateral cerebral palsy. AB - AIM: To evaluate short-term (1y postoperatively; E1) and long-term (at least 4y postoperatively; E2) changes in hamstring muscle-tendon length (MTL) and lengthening velocity after hamstring lengthening in children with bilateral cerebral palsy (CP). METHOD: Three-dimensional gait analysis was performed in 19 children (16 males, 3 females; 36 limbs; mean age at surgery 9y [SD 3y]; range 6 10y) with flexed knee gait, preoperative ankle dorsiflexion lower than 20 degrees, and CP before bilateral hamstring lengthening (E0), at E1 and E2. Hamstring MTL (normalized by leg length) and velocity were assessed via OpenSim software. RESULTS: MTL increased from E0 to E1 (p=0.004) and decreased from E1 to E2 (p<0.020). Hamstring lengthening velocity did not change. In the subgroup with short, not slow hamstrings, the increase in MTL was maintained at E2. INTERPRETATION: Hamstring lengthening is an efficient procedure to lengthen short and/or slow hamstrings short-term. The desired outcome with maintenance of the postoperative changes in hamstring MTL is only achieved for preoperatively short, not slow hamstrings. WHAT THIS PAPER ADDS: Surgical hamstring lengthening can be confirmed via musculoskeletal modelling in OpenSim software. Surgical hamstring lengthening in cerebral palsy does not change hamstring lengthening velocity. Short, not slow hamstrings present a long-lasting muscle-tendon length (MTL) increase after hamstring lengthening. Changes in MTL after hamstring lengthening cannot be maintained for slow hamstrings. MTL does not change after hamstring lengthening for neither short nor slow hamstrings. PMID- 30474111 TI - Neonatal gut colonisation by Staphylococcus aureus strains with certain adhesins and superantigens is negatively associated with subsequent development of atopic eczema. AB - BACKGROUND: Insufficient early immune stimulation may predispose to atopic disease. Staphylococcus aureus, a skin and gut colonizer, produces the B-cell mitogen protein A and T-cell activating superantigens. Early gut colonization by S. aureus strains that possess the superantigens encoded by enterotoxin gene (egc) cluster and the elastin-binding protein, is negatively associated with development of atopic eczema. OBJECTIVES: To investigate whether these findings could be replicated in a second birth-cohort, FARMFLORA and, secondly, whether nasal colonization by S. aureus also relates to subsequent atopic eczema development. METHODS: Faecal samples and nasal swabs from infants in the FARMFLORA birth-cohort (N=65) were cultured for S. aureus. Individual strains were distinguished by RAPD (random amplified polymorphic DNA) and assessed for adhesin and superantigen gene carriage by PCR. Atopic eczema at 18 months of age was related to nasal and gut S. aureus colonisation patterns during the first 2 months of life (well before onset of eczema). RESULTS: S. aureus colonisation per se was unrelated to subsequent eczema development. However, gut S. aureus strains from the infants who subsequently developed atopic eczema less frequently carried the ebp gene, encoding elastin-binding protein, and superantigen genes encoded by the egc, as compared to strains from children who remained healthy. Nasal colonization by S. aureus was less clearly related to subsequent eczema development. CONCLUSION: The results precisely replicate our previous observations and may suggest that mucosal colonisation by certain S. aureus strains provides immune stimulation that strengthens the epithelial barrier and counteracts the development of atopic eczema. This article is protected by copyright. All rights reserved. PMID- 30474112 TI - Initial and crucial genetic events in intestinal-type gastric intramucosal neoplasia. AB - Gastric cancer (GC) is one of the most common and life-threatening malignancies. The course of disease and tumor aggressiveness vary among GCs, although how early fate is determined and by what factors remains elusive. To solve this question, we collected 43 gastric intramucosal neoplasias (GINs), comprising dysplasia/intraepithelial neoplasia (D/IEN; a premalignant lesion) and minute GC (miGC; <=10 mm) of intestinal histotype, and performed targeted deep DNA sequencing of 67 GC-related genes derived from large-scale data. Gastric D/IEN was classified into low or high grade (LG-D/IEN or HG-D/IEN). The most frequent mutations in D/IENs included APC (19/25; 76%), ARID2 (6/25; 24%), and MUC6 (5/25; 20%). All LG-D/IENs had APC mutation (12/12), and APC hotspot mutations affecting R1450 and E1554 were noted in both LG-D/IEN and HG-D/IEN. ARID2 mutation always co-occurred with APC mutation, whose tumor variant allele frequency (TVAF) was higher than that of ARID2 in D/IEN. APC and TP53 mutations were mutually exclusive in D/IEN (p = 0.031 [main cohort], p = 0.025 [expanding cohort]), and TP53-mutated D/IEN was exclusively HG-D/IEN (4/4). TP53 mutations were highly recurrent (11/14; 79%) in MLH1-positive miGCs, and were detected even in two microscopic lesions measuring 1 and 3 mm respectively. Furthermore, TVAF analyses suggested that TP53 mutation is the initial event in the TP53-mutated miGCs. In contrast, TP53 mutation was absent (0/4) in MLH1-negative small intramucosal carcinoma (8-24 mm). Advanced GC data suggested that early mutations (APC and TP53) may affect the potential of cancerous progression from D/IEN. This study revealed somatic mutational landscape and initial mutations of GINs, and we report for the first time that TP53 mutations precede other mutations in intestinal-type GC. Our results also indicate that molecular subtyping based on APC/TP53 mutations would be a high-priority approach for determining and predicting the malignant potential of GIN, including D/IEN. PMID- 30474113 TI - Impact of leader-member-exchange and team-member-exchange on nurses' job satisfaction and turnover intention. AB - AIM: To investigate the impacts of leader-member exchange and team-member exchange on job satisfaction and turnover intention of nurses. BACKGROUND: Leader member exchange refers to the quality of relationships between leaders and members of a team and studies on this have generally focused on the aspect of member-leader-member exchanges. In nursing, the latter can refer to a situation where nurses (members) evaluate their relationship with their head nurse (leader). Member-leader-member exchange affects job satisfaction and turnover intention of nurses. However, even though all of these types of exchanges are important, few studies have examined their effects on job satisfaction and the turnover intention of nurses. METHODS: Participants in this descriptive study were 40 head nurses and 284 clinical nurses working at three hospitals in Korea. Data were collected from a questionnaire and analysed using hierarchical multiple regression. RESULTS: Leader-leader-member exchange, member-leader-member exchange, and team-member exchange had a positive effect on job satisfaction. However, only leader-leader-member exchange and member-leader-member exchange affected turnover intention. CONCLUSIONS: The impacts of leader-leader-member exchange, team-member exchange, and member-leader-member exchange on job satisfaction were confirmed. To reduce turnover intention, our study found it is more important to improve leader-member exchange than team-member exchange. IMPLICATIONS FOR NURSING PRACTICE: In health organizations, there is an important need to focus on the communication and exchange relationships between leaders and their staff, well as among the members, to increase job satisfaction. This will assist leaders to play an important role in lowering nurses' turnover intention and create an organizational culture in which nurses can communicate well with them. IMPLICATIONS FOR NURSING POLICY: Policy changes are needed so that the components of job performance evaluation for nurse leaders also include attendance at regular programmes, such as training to improve their leadership and communication skills, and consultations with their staff members. PMID- 30474114 TI - Presentation and eustachian tube function test results in children evaluated at a specialty clinic. AB - OBJECTIVES/HYPOTHESIS: Interest in eustachian tube (ET) dysfunction (ETD) has increased with the recent Food and Drug Administration approval of a new device for balloon dilation of the ET (BDET) in adults. However, children have been receiving BDET treatment with ET-specific or sinus balloons around the world and off-label in the United States for years. It is important, therefore, to understand the manifestations of and methods to verify ETD in children. STUDY DESIGN: Retrospective cross-sectional study. METHODS: This is a retrospective study of clinical presentations and results of ET function (ETF) tests in children referred to the ETD clinic. An otorhinolaryngology exam, nasopharyngeal videoendoscopy of the ET orifices during swallow and maneuvers, and ETF tests, including inflation deflation, forced response test, and pressure chamber tests, were performed as applicable. RESULTS: Data for 30 children aged 6.2 to 17.3 years (mean = 12.9 +/- 2.8 years) were analyzed. Of 60 ears, 19 (31.7%) had an intact tympanic membrane (TM), 16 (26.7%) had a patent and two had a blocked ventilation tube, and 23 (38.3%) had a TM perforation. Endoscopy of the nasopharynx revealed a large amount of secretions in 19/45 (42.2%); ET orifices and mucosal inflammation in 22/45 (48.8%); a large amount of adenoid tissue in the fossa of Rosenmuller was noted in 21/45 (46.7%). ETF tests revealed abnormal active function in 43/54 ears (79.6%) and abnormal passive function in 40/54 ears (74.1%). CONCLUSIONS: ETD in children is often associated with residual or regrowth of adenoids and inflammation. Caution should be taken assigning a uniform phenotype and treatment prior to thorough evaluation and testing. LEVEL OF EVIDENCE: 4 Laryngoscope, 2018. PMID- 30474115 TI - Comparison between different isoelectric points of biodegradable gelatin sponges incorporating beta-tricalcium phosphate and recombinant human fibroblast growth factor-2 for ridge augmentation: A preclinical study of saddle-type defects in dogs. AB - BACKGROUND AND OBJECTIVE: It is well known that recombinant human fibroblast growth factor-2 (rhFGF-2) signaling plays an important role in tissue repair and regeneration. rhFGF-2 strongly binds to acidic gelatin via ionic linkages and is gradually released upon gelatin decomposition. On the other hand, the linkage between rhFGF-2 and basic gelatin is so weak that most rhFGF-2 is rapidly released from basic gelatin by simple desorption. Gelatin/beta-tricalcium phosphate (beta-TCP) sponges, which comprise 50 wt% gelatin and 50 wt% beta-TCP in a cross-linked structure, can release rhFGF-2 gradually owing to their electrical features. In a previous study, we reported that new bone height in the test group using rhFGF-2 with acidic gelatin/beta-TCP sponges was significantly greater than that in the control group using acidic gelatin/beta-TCP sponges alone in a ridge augmentation model in dogs. However, whether these results depend on controlled release by the gelatin/beta-TCP sponges remains controversial. In this study, we evaluated the effects of controlled release by comparing acidic and basic gelatin/beta-TCP sponges with different isoelectric points (IEP) on ridge augmentation in dogs. MATERIALS AND METHODS: Twelve weeks after extraction of the maxillary second and third incisors of six dogs, critically sized saddle-type defects (8 mm length * 4 mm depth) were surgically created bilaterally 2 mm from the mesial side of the canine. Acidic gelatin/beta TCP sponges (IEP 5.0) soaked with 0.3% rhFGF-2 were applied to the defect in the acidic group, whereas basic gelatin/beta-TCP sponges (IEP 9.0) soaked with 0.3% rhFGF-2 were applied to the defect in the basic group. Twelve weeks after surgery, biopsy specimens were obtained and subjected to microcomputed tomography (micro-CT) and histological analyses. RESULTS: New bone area detected by micro-CT analysis was significantly smaller in the basic group than in the acidic group. New bone height calculated by histologic sections was significantly lower in the basic group than in the acidic group. The total tissue height was lower in the basic group than in the acidic group. However, the differences between both sites were not significant. CONCLUSIONS: These findings suggest that in ridge augmentation of saddle-type defects, controlled release of rhFGF-2 induces notably more alveolar bone formation than does short-term application of rhFGF-2. PMID- 30474116 TI - The role of microbiota in the development of colorectal cancer. AB - Colorectal cancer is the third largest cancer in worldwide and has been proven to be closely related to the intestinal microbiota. Many reports and clinical studies have shown that intestinal microbial behavior may lead to pathological changes in the host intestines. The changes can be divided into epigenetic changes and carcinogenic changes at the gene level, which ultimately promote the production and development of colorectal cancer. This article reviews the pathways of microbial signaling in the intestinal epithelial barrier, the role of microbiota in inflammatory colorectal tumors, and typical microbial carcinogenesis. Finally, by gaining a deeper understanding of the intestinal microbiota, we hope to achieve the goal of treating colorectal cancer using current microbiota technologies, such as fecal microbiological transplantation. PMID- 30474117 TI - Sequential testicular atrophy involves changes in cellular proliferation and apoptosis associated with variations in aromatase P450 expression levels in Irs-2 deficient mice. AB - Insulin receptor substrate 2 (Irs-2) is an intracellular protein susceptible to phosphorylation after activation of the insulin receptor. Its suppression affects testis development and its absence induces peripheral resistance to insulin. The aim of this study was to identify changes induced by the deletion of Irs-2 in the testicular structure and by the altered expression of cytochrome P450 aromatase, a protein necessary for the development and maturation of germ cells. Adult knockout (KO) mice (Irs-2-/- , 6 and 12 weeks old) and age-matched wild-type (WT) mice were used in this study. Immunohistochemistry and Western blot analyses were performed to study proliferation (PCNA), apoptosis (active caspase-3) and P450 aromatase expression in testicular histological sections. Deletion of Irs-2 decreased the number of epithelial cells in the seminiferous tubule and rete testis. Aberrant cells were frequently detected in the epithelia of Irs-2-/- mice, accompanied by variations in spermatogonia, which were shown to exhibit small hyperchromatic nuclei as well as polynuclear and anuclear structures. The amount of cell proliferation was significantly lower in Irs-2-/- mice than in WT mice, whereas apoptotic processes were more common in Irs-2-/- mice. Aromatase P450 reactivity was higher in 6-week-old KO mice than in WT mice of the same age and was even higher at 12 weeks. Our results suggest that Irs-2 is a key element in spermatogenesis because silencing Irs-2 induces the sequential development of testicular atrophy. The effects are observed mainly in germ cells present in the seminiferous tubule, which may be due to changes in cytochrome P450 aromatase expression. PMID- 30474118 TI - Modulations of bovine hepatic microsomal metabolism of benzimidazoles by secondary plant metabolites. AB - The study was aimed to estimate the effect of plant secondary metabolites present in ruminants diet and phytogenic feed additives on liver microsomal metabolism of albendazole and fenbendazole. The selected phytocompounds comprised of flavonoids (apigenin, quercetin) and saponins (hederagenin, medicagenic acid). The experiments were performed on liver microsomal fraction obtained from routinely slaughtered cows. The intensity of albendazole and fenbendazole metabolism in the presence of flavonoids and saponins was analyzed in equimolar concentration (100 MUM). The obtained results revealed that both flavonoids and saponins intensify the metabolism of albendazole and fenbendazole in bovine microsomes. In the case of albendazole, apigenin and quercetin doubled the amount of degraded drug and the amount of produced albendazole sulfoxide. Additionally, both flavonoids increased the amount of produced albendazole sulfone. Saponins, hederagenin, and medicagenic acid intensified the degradation of albendazole (1.8-fold) and the production of albendazole sulfoxide (twofold). Medicagenic acid inhibited the production of albendazole sulfone. In the case of fenbendazole, the degradation of the drug and the production of oxfendazole were increased four and five times in the presence of saponins and flavonoids, respectively. The enhancement of benzimidazoles' metabolism caused by the studied plant metabolites could change pharmacokinetics and the efficacy of benzimidazoles' treatment in cattle. PMID- 30474119 TI - Anatomical defences against bark beetles relate to degree of historical exposure between species and are allocated independently of chemical defences within trees. AB - Conifers possess chemical and anatomical defences against tree-killing bark beetles that feed in their phloem. Resins accumulating at attack sites can delay and entomb beetles while toxins reach lethal levels. Trees with high concentrations of metabolites active against bark beetle-microbial complexes, and more extensive resin ducts, achieve greater survival. It is unknown if and how conifers integrate chemical and anatomical components of defence or how these capabilities vary with historical exposure. We compared linkages between phloem chemistry and tree ring anatomy of two mountain pine beetle hosts. Lodgepole pine, a mid-elevation species, has had extensive, continual contact with this herbivore, whereas high-elevation whitebark pines have historically had intermittent exposure that is increasing with warming climate. Lodgepole pine had more and larger resin ducts. In both species, anatomical defences were positively related to tree growth and nutrients. Within-tree constitutive and induced concentrations of compounds bioactive against bark beetles and symbionts were largely unrelated to resin duct abundance and size. Fewer anatomical defences in the semi-naive compared with the continually exposed host concurs with directional differences in chemical defences. Partially uncoupling chemical and morphological antiherbivore traits may enable trees to confront beetles with more diverse defence permutations that interact to resist attack. PMID- 30474121 TI - Reliability of low-flow vasoreactivity in the brachial artery of adolescents. AB - PURPOSE: Macrovascular endothelial function is commonly assessed using flow mediated dilation (FMD) and is nitric oxide (NO) dependent. However, the vasoreactivity to low flow during the FMD protocol may complement FMD interpretation. This study aimed to investigate in adolescents: (1) the day-to day reliability of low-flow-mediated constriction (L-FMC) and composite vessel reactivity (CVR); and (2) the relationship between L-FMC and FMD. METHODS: A retrospective analysis of data on 27 adolescents (14.3 +/- 0.6 year, 12 males) was performed. Participants had two repeat measures, on separate days, of macrovascular function using high-resolution ultrasound for assessment of L-FMC, FMD, and CVR. RESULTS: On average, the L-FMC response was vasoconstriction on both days (-0.59 +/- 2.22% and -0.16 +/- 1.50%, respectively). In contrast, an inconsistent response to low flow (vasoconstriction, dilation, or no change) was observed on an individual level. Cohen's Kappa revealed poor agreement for classifying the L-FMC measurement between visits (k = 0.04, P > .05). Assessment of the actual vessel diameter was robust with a coefficient of variation of 1.7% (baseline and peak) and 2.7% (low-flow). The between-day correlation coefficient between measures was r = .18, r = .96 and r = .52 for L-FMC, FMD, and CVR, respectively. No significant correlation between FMD and L-FMC was observed for either visit (r = -.06 and r = -.07, respectively; P > .05). CONCLUSION: In adolescents, the low-flow vasoreactivity is inconsistent between days. Whereas the actual vessel diameter is reproducible, the measurement of L-FMC and CVR has poor between-day reliability compared to FMD. Finally, L-FMC, and FMD are not significantly correlated. PMID- 30474120 TI - The importance of impulsivity and attention switching deficits in perpetrators convicted for intimate partner violence. AB - It has been stated that Attention deficit hyperactivity disorder (ADHD) increases the likelihood of risky behavior such as intimate partner violence (IPV), but the cognitive mechanisms that facilitate or underlie these types of behavior remain unexplained. In this regard, several authors have established that impulsivity and inattentive symptoms might affect basic processes such as emotional decoding and set-shifting abilities, which are important processes for emotional and behavioral regulation. Hence, these symptoms entail a reduction in sensitivity to key contextual stimuli. Accordingly, the main aim of this study was to examine the involvement of impulsivity (assessed by self-reports) and attention switching impairments (assessed with the Attention Switching Task; AST), as well as the associations between these cognitive processes in facial emotion decoding (assessed by the eyes test) and cognitive flexibility impairments (measured by the Wisconsin Card Sorting Test, WCST) in a sample of IPV perpetrators (n = 89; mean age = 40) and a control group matched on socio-demographic characteristics (n = 39; mean age = 41). IPV perpetrators had higher trait impulsivity and greater attention switching costs than controls. Moreover, differences were also found between groups in facial expression decoding and WCST performance, with IPV perpetrators showing lower Eyes Test and WCST scores. Mainly, we observed that the ability to recognize facial expressions was poorer when individuals showed high impulsivity in both groups, but this association was only explained by deficits in attention switching in IPV perpetrators. Our research reinforces the importance of impulsivity and inattentive symptoms as targets for specific cognitive rehabilitation interventions designed to prevent the long-term IPV risk of recidivism. PMID- 30474122 TI - Risk perception of a chronic threat of terrorism: Differences based on coping types, gender and exposure. AB - High levels of risk perception of terrorism (RPT) may impair an individual's quality of life and welfare. To understand the mechanisms responsible for RPT, this study investigated the association of gender and coping styles with individual differences in two key elements of RPT: perceived control and perceived vulnerability. A convenience sample of 400 Israelis (181 men and 219 women) filled out questionnaires on sociodemographic background, RPT and coping. Employing a multidimensional approach for coping, we divided participants into four coping types: problem-focused (n = 65), emotion-focused (n = 70), mixed (n = 122) and minimal (n = 142). The results indicate that problem-focused coping is associated with higher levels of perceived control than other types of coping and mixed coping is associated with higher levels of perceived vulnerability than other coping strategies. Also, interactions between gender and exposure to terrorism contributed to understanding the differences in perceived control. The discussion addresses gender differences in RPT and coping in the context of traditional gender roles. The study concludes with implications for risk management and therapeutic interventions regarding high levels of fear of terrorism. PMID- 30474123 TI - Hypoxia pathway has more impact than inflammation pathway on etiology of infertile men with varicocele. AB - This study aimed to compare main molecular markers of hypoxia (HIF1-alpha and P53) and inflammation (TLR-2, TLR-4 and TNF-alpha) pathways between infertile men with varicocele and fertile individuals. Sperm parameters such as sperm concentration, motility and morphology were assessed according to World Health Organization (Laboratory manual for the examination and processing of human semen. Geneva, Switzerland, 2010) guideline in 20 infertile men with grade II or III varicocele, and 20 fertile men candidate of family balancing. In addition, sperm DNA fragmentation and molecular markers involved in hypoxia and inflammation pathways were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay and real-time PCR respectively. Mean of sperm parameters (concentration, motility and morphology) and DNA integrity were significantly lower in infertile men with varicocele compared to fertile individuals. Unlike markers involved in inflammation pathway, mean expression of markers of hypoxia pathway (HIF1-alpha and P53) was significantly higher in infertile men with varicocele compared to fertile individuals (p < 0.05), and also a significant correlation was observed between expression of HIF1-alpha and P53 (r = 0.461; p = 0.003). Overall, the result of this study suggests higher likelihood of involvement of hypoxia pathway, in comparison with inflammation pathway, in pathogenesis varicocele associated with male infertility. PMID- 30474124 TI - The common rule's 'reasonable person' standard for informed consent. AB - Laura Odwazny and Benjamin Berkman have raised several challenges regarding the new reasonable person standard in the revised Common Rule, which states that informed consent requires potential research subjects be provided with information a reasonable person would want to know to make an informed decision on whether to participate in a study. Our aim is to offer a response to the challenges Odwazny and Berkman raise, which include the need for a reasonable person standard that can be applied consistently across institutional review boards and that does not stigmatize marginal groups. In response, we argue that the standard ought to be based in an ordinary rather than ideal person conception of reasonable person and that the standard ought to employ what we call a liberal constraint: the reasonability standard must be malleable enough such that a wide variety of individuals with different, unique value systems would endorse it. We conclude by suggesting some of the likely consequences our view would have, if adopted. PMID- 30474125 TI - Working in the dead of night: exploring the transition to after-hours duty. AB - CONTEXT: Transitions, although often difficult, represent integral components of medical training. New postgraduate trainees (first-year residents) find themselves in an especially challenging transition as they are expected to fulfil both learning and service expectations concurrently. Workplace learning theory has been suggested as a lens through which to understand this unique educational, yet service-oriented, role. This tension may be further amplified overnight when residents are on-call with little to no support. OBJECTIVES: The aims of this study were to explore the transition from medical student to resident with respect to the on-call experience, and to provide theory-based suggestions to enhance learning during this unique transition. METHODS: We conducted an interpretivist qualitative study by interviewing eight medical students and 10 first-year residents from six different specialty training programmes across four academic sites. Each semi-structured interview was transcribed verbatim and anonymised. Resident interview transcripts were initially coded for major themes, after which medical student interview transcripts were coded for consistencies and discrepancies. RESULTS: Four interrelated themes were identified in students' and residents' descriptions of on-call experiences: (i) shift in responsibility; (ii) supervisory support; (iii) contextual conditions, and (iv) clarity of expectations. Generally, students were not able to anticipate the challenges they would face as residents on-call, and residents perceived the transition as sudden with little emphasis placed on learning. CONCLUSIONS: First-year residents face multiple challenges during on-call, which may prevent optimal learning in this setting. These challenges are amplified by the large gap between the respective roles of medical students and residents. We identified promoters of and barriers to effective learning in this environment and, by using workplace learning theory, provide recommendations for how we might be able to enhance medical students' preparation for and first-year residents' learning during experiences of being on-call. PMID- 30474126 TI - Relationship between Chinese children's imaginary companions and their understanding of second-order false beliefs and emotions. AB - We investigated relationship between Chinese children's imaginary companions (ICs) and their understanding of second-order false beliefs and emotions in 180 children, aged 5-6 years old. We examined the potential differences in second order false belief understanding and emotion understanding between children with and without ICs, children with egalitarian IC relationships and hierarchical IC relationships, as well as children with invisible friends and personified objects. The results revealed that children with ICs had better second-order false belief understanding and emotion understanding than children without ICs. Compared with children with hierarchical relationships, children with egalitarian relationships had better second-order false belief understanding. However, children with invisible friends and personified objects did not differ on their understanding of second-order false beliefs and emotions. The results suggest that compared with IC types, IC status and child-IC relationship qualities may be more relevant to children's theory of mind. It will be interesting for the future researchers to investigate the underlying mechanism of the differences between children with egalitarian IC relationships and hierarchical IC relationships. PMID- 30474127 TI - Prefrontal and temporal cortical thickness in adolescents with traumatic brain injury. AB - AIM: To investigate the impact of traumatic injury on the developing prefrontal temporal adolescent cortex, and correlated brain structural measures with neurocognitive functioning. METHOD: Nineteen adolescents (12 males, 7 females, age range: 11-17y, mean 15y 8mo, standard deviation 1y 7mo, median 15y 11mo) with traumatic brain injury (TBI) were included. Cortical thickness of frontal and temporal lobes was assessed using magnetic resonance imaging. We correlated cortical thickness of prefrontal-temporal regions with age, time since injury, and neurocognitive functioning, and compared these results with a matched control cohort without TBI. RESULTS: We found thinner prefrontal (p=0.039) and temporal cortices (p=0.002) in adolescents with TBI compared to typically developing children. Furthermore, significant age effect was observed on the prefrontal (r= 0.75, p=0.003) and temporal (r=-0.66, p=0.013) cortical thickness in typically developing adolescents, but not in adolescents with TBI. Executive function (measured using the Behaviour Rating Inventory of Executive Function questionnaire, with lower scores meaning higher functioning) was correlated with prefrontal cortical thickness in typically developing adolescents (r=0.72, p=0.009). Opposite trends were found for correlations between cortical thickness and executive function in the TBI and control cohort. INTERPRETATION: Structural maturation in typically developing adolescents correlates with functional development: the older the adolescent, the thinner the prefrontal cortex, the better executive function. In adolescents with TBI we observed an opposite trend, that appeared significantly different from the control group: the thinner the prefrontal and temporal cortex, the worse executive functioning. WHAT THIS PAPER ADDS: Cortical thickness is negatively correlated with age in typically developing adolescents. Prefrontal cortex thickness correlates negatively with executive function in typically developing adolescents. Correlations between cortical thickness and executive functioning rise for adolescents without traumatic brain injury (TBI). Correlations between cortical thickness and executive functioning fall for adolescents with TBI. Adolescents with TBI have a long-term impairment of adaptive functioning in daily living. PMID- 30474128 TI - Prevalence of depressive symptoms among medical students: overview of systematic reviews. AB - CONTEXT: The prevalence of depressive symptoms among medical students has been found to be higher than among other students because of their longer studying time, higher workload and larger financial burden. Despite the availability of reviews examining this, some have focused solely on one country, whereas others used databases containing papers of solely one language; therefore, the results from reviews might not be comprehensive. Against this background, this overview aims to synthesise the results from all the published systematic reviews of depression among medical students, in order to provide a more accurate result. METHODS: A systematic search was conducted of online databases for published systematic reviews or meta-analyses examining the prevalence of depressive symptoms among medical students. The findings of individual studies included in these reviews were extracted and then combined with a random-effects model. Subgroup analysis was conducted by regions. RESULTS: A total of 10 studies were selected in this overview, involving 249 primary studies and 162 450 medical students. MEDLINE was the most popular database used in these studies. The overlapping of primary studies in these reviews was appreciably high, except for three studies that focused on specific countries. The overall pooled prevalence was 27.0% (95% CI, 24.7-29.5%). Significant subgroup differences were detected (p < 0.001). The pooled prevalence among studies in the Western Pacific Region was the lowest, 18.9% (95% CI, 11.7-29.0%), whereas that in Africa (40.9%) was the highest (95% CI, 28.8-54.4%). The top five significant factors associated with depressive symptoms were: (i) year of study; (ii) gender; (iii) personal issues; (iv) family relations or issues, and (v) health status. CONCLUSIONS: Depression affected around a quarter of medical students in general and 40.9% of students in Africa. It is suggested that medical schools and health authorities should introduce preventive measures to curb the high prevalence of depressive symptoms. PMID- 30474129 TI - Erosion of informed consent in U.S. research. AB - This paper evaluates four recent randomized clinical trials in which the informed consent of participants was either not sought at all, or else was conducted with critical information missing from the consent documents. As these studies have been taking place, various proposals to conduct randomized clinical trials without consent have been appearing in the medical literature. Some of the explanations offered for why it is appropriate to bypass consent or disclosure requirements appear to represent a fundamental misunderstanding of applicable government regulations and even the research enterprise. Others are the result of conceptual disagreements about the importance and application of traditional research ethics norms to 'comparative effectiveness research' and modern research environments. Common among these explanations, however, is a failure to appreciate when a research intervention, rather than merely an observation or review of data, is taking place. Review committees and investigators are failing to see, or choosing to ignore, interventions in the lives of research subjects. When these studies have come to light, government agencies with oversight authority have done little or backed down. Prestigious medical journals have published research results knowing that the required consent was not obtained, or they have stood by the published studies even after the inadequacy of consent is discovered. This article critically examines this erosion of consent in theory and practice and calls for restoring the requirement of informed consent to its proper place as a priority in human subjects research. PMID- 30474131 TI - Infantile pyknocytosis. PMID- 30474130 TI - Impact of California's safe patient handling legislation on musculoskeletal injury prevention among nurses. AB - BACKGROUND: This study evaluated the impact of California's safe patient handling (SPH) legislation on musculoskeletal injury prevention among hospital nurses. METHODS: Two serial cross-sectional surveys were conducted using postal and online questionnaires in statewide random samples of California registered nurses in 2013 and 2016. Analysis included hospital nurses who performed patient handling (n = 254 and n = 281, respectively). RESULTS: In 2016, there were significant improvements in nurses' knowledge of a SPH policy in their hospital (87%), receipt of annual SPH training (73%), and availability of lift equipment (80%); 33% perceived their hospital's SPH programs as excellent or very good. Significant prevalence reduction was observed for work-related musculoskeletal symptoms (61% vs 52%; Adjusted Prevalence Ratio = 0.78, 95% CI 0.66-0.91). CONCLUSIONS: Our findings indicate the significant role of SPH legislation with positive impacts on SPH policies and programs at the hospital level and on musculoskeletal health outcomes at the worker level. PMID- 30474132 TI - Compression with the ultrasound probe to prevent malposition of central venous catheter in the ipsilateral internal jugular vein during axillary vein cannulation. PMID- 30474133 TI - Bi-allelic recessive loss-of-function mutations in FIGLA cause premature ovarian insufficiency with short stature. AB - Premature ovarian insufficiency (POI) is a group of heterogeneous disorders characterized by decreased ovarian reserve and increased follicle stimulating hormone (FSH) levels. It is rarely associated with short stature. FIGLA mutations with POI are identified with regards to heterozygosity; till date, only one affected family has been identified with homozygous mutations in FIGLA but without functional evaluation. Here, we described two POI patients from a consanguineous family from China. An 18-year-old girl and her sister presented with primary amenorrhea and increased FSH and luteinizing hormone levels, but the sister also presented with short stature and bone age delay. Whole-genome sequencing analysis identified a recurrent homozygous mutation in the FIGLA gene, c.2T>C (p.Met1Thr), in this family member with POI; this variant was segregated within the pedigree. This change was absent in 382 control subjects, and we did not detect any mutations in 39 other idiopathic POI patients. In vitro functional analysis indicates that the p.Met1Thr mutation does not affect the transcription of the FIGLA gene, but blocks the synthesis of the full-length FIGLA protein. Our results support the notion that bi-allelic recessive loss-of-function effects of FIGLA contribute to POI patients with short stature and expand the FIGLA-related phenotypic spectrum. This article is protected by copyright. All rights reserved. PMID- 30474134 TI - Effect of sodium-glucose cotransporter 2 inhibitor, empagliflozin, and alpha glucosidase inhibitor, voglibose, on hepatic steatosis in an animal model of type 2 diabetes. AB - OBJECTIVE: We investigated the effects of sodium-glucose cotransporter 2 inhibitor, empagliflozin, and alpha-glucosidase inhibitor, voglibose, on hepatic steatosis in an animal model of type 2 diabetes (T2DM). METHODS: Empagliflozin (OLETF-EMPA) or voglibose (OLETF-VOG) was administered to Otsuka Long-Evans Tokushima fatty (OLETF) rats once daily for 12 weeks. Control Long-Evans Tokushima Otsuka (LETO) and OLETF (OLETF-C) rats received saline. RESULTS: Blood glucose levels were significantly suppressed in OLETF-EMPA and OLETF-VOG compared with the OLETF-C group. The liver fat content was significantly higher in the OLETF-C group than in the OLETF-EMPA and OLETF-VOG. Hepatic gene expressions involved in gluconeogenesis (glucose 6-phosphatase [G6Pase], fructose-1,6 bisphosphatase [FBP1], and phosphoenolpyruvate carboxykinase [PEPCK]) and lipogenesis (acetyl-CoA carboxylase [ACC], fatty acid synthase [FAS], and sterol regulatory element-binding transcription factor 1c [SREBP-1c]) were significantly decreased in the OLETF-EMPA group compared with other OLETF groups (OLETF-C and OLETF-VOG). Sirtuin 1 (SIRT1) expression level and SIRT1 activity were markedly reduced in OLETF-C rats; however, its expression increased in the OLETF-EMPA and OLETF-VOG. AMP-activated protein kinase (AMPK) phosphorylation level was remarkably increased by empagliflozin treatment in OLETF rats compared with other OLETF groups. Long-term empagliflozin and voglibose treatment reduced hepatic steatosis with suppression of gluconeogenesis and lipogenesis pathway in OLETF rats. CONCLUSION: We suggest that this metabolic improvement might be related to SIRT1 and AMPK pathway in T2DM. But empagliflozin is thought to have more advantage to prevent hepatic steatosis than voglibose in T2DM. PMID- 30474135 TI - Preoperative Treatment of Anemia and Outcomes in Surgical Jehovah's Witness Patients. PMID- 30474136 TI - The crisis in replicability. PMID- 30474137 TI - Natural exposure to ultraviolet-B radiation in two species of chameleons from Madagascar. AB - Many reptiles require ultraviolet-B radiation between 290 and 315 nm (UV-B) to synthesize vitamin D3 and process dietary calcium. In captivity, exposure to too little or too much UV-B can result in health problems such as metabolic bone disease. While it is recognized that UV-B is necessary to successfully maintain many reptiles in captivity, the actual levels of UV-B that species are exposed to in nature is poorly known. We measured the UV-B exposure of two species of chameleon (Calumma brevicorne and C. nasutum) in the field in Madagascar over a period of four months. We found that both species were exposed to less UV radiation than that which was available in full sun. Only on rare occasions were chameleons observed in areas with a UV Index (UVI) greater than 3.0, and the median UVI for both species was only 0.3. There was no daily temporal pattern in UV exposure for C. nasutum, but C. brevicorne was found in areas with lower UV levels in the late afternoon when compared to late morning. Additionally, C. nasutum males showed higher UV exposure than females in late morning. Our results suggest that both C. brevicorne and C. nasutum can be classified as Ferguson Zone 1 species, and should be provided with a UV-B gradient in captivity that offers access to UV-B radiation as well as adequate shaded refuge. PMID- 30474138 TI - A comprehensive study on donor-matched comparisons of three types of mesenchymal stem cells-containing cells from human dental tissue. AB - BACKGROUND AND OBJECTIVE: Mesenchymal stem cells (MSCs) have been widely used in tissue engineering, such as for regenerating the supporting structures of teeth destroyed by periodontal diseases. In recent decades, dental tissue-derived MSCs have drawn much attention owing to their accessibility, plasticity and applicability. Dental pulp stem cells (DPSCs), periodontal ligament stem cells (PDLSCs) and gingival MSCs (GMSCs) are the most readily available MSCs among all types of dental MSCs. The purpose of this study was to comprehensively compare the characteristics of MSCs from dental pulp (DP), periodontal ligament (PDL) and gingiva (G) in vitro and thus provide insight into optimizing the performance of cells and seed cell selection strategies for tissue regeneration. MATERIALS AND METHODS: In this study, patient-matched (n = 5) cells derived from DP, PDL and G which, respectively, contained DPSCs, PDLSCs and GMSCs were evaluated using multiple methods in terms of their proliferation, senescence, apoptosis, multilineage differentiation and stemness maintenance after long-term passage. RESULTS: Mesenchymal stem cells-containing cells from G (MSCs/GCs) showed superior proliferation capability, whereas patient-matched MSCs-containing cells from PDL (MSCs/PDLCs) exhibited excellent osteogenic and adipogenic differentiation ability; MSCs-containing cells from DP (MSCs/DPCs) achieved mediocre results in both aspects. In addition, MSCs/GCs were the least susceptible to senescence, while MSCs/PDLCs were the most prone to ageing. Furthermore, the biological properties of these three types of cells were all affected after long-term in vitro culture. CONCLUSION: These three types of dental MSCs showed different biological characteristics. MSCs/PDLCs are the best candidate cells for bone regeneration, but the application of MSCs/PDLCs might be limited to certain number of passages. Improving the differentiation of MSCs/GCs remains the key issue regarding their application in tissue engineering. PMID- 30474139 TI - Insight and the no-self in deep brain stimulation. AB - Ethical analyses of the effects of neural interventions commonly focus on changes to personality and behavior, interpreting these changes in terms of authenticity and identity. These phenomena have led to debate among ethicists about the meaning of these terms for ethical analysis of such interventions. While these theoretical approaches have different criteria for ethical significance, they agree that patients' reports are concerning because a sense of self is valuable. In this paper, I question this assumption. I propose that the Buddhist theory of no-self offers a novel approach to making ethical sense of patients' claims following deep brain stimulation. This alternative approach is based on the value of insight into patterns of cause and effect among mental states and actions. PMID- 30474140 TI - Combined testing for herpes simplex virus and Mycobacterium tuberculosis DNA in cerebrospinal fluid of patients with aseptic meningitis in Burkina Faso, West Africa. AB - BACKGROUND: Little is known about the involvement of herpes simplex virus (HSV) or Mycobacterium tuberculosis (MTB) as potentially curable causes of central nervous system (CNS) infections in sub-Saharan Africa. OBJECTIVE: In this study, we developed a PCR assay dedicated to simultaneous testing of HSV1/HSV2 and MTB in Burkina Faso, a country where HSV is neglected as a cause of CNS infection and where TB prevalence is high. METHODS: A consensus HSV1/HSV2 set of primers and probe were designed and combined to primers and probe targeting the IS6110 repetitive insertion sequence of MTB. Analytical performances of the assay were evaluated on reference materials. Cerebrospinal fluid (CSF) collected from subjects with aseptic meningitis was tested for HSV1/HSV2 and MTB DNA. RESULTS: The UL29 gene was chosen as a highly conserved region targeted by the HSV1/HSV2 nucleic acid test. The lower limits of detection were estimated to be 2.45 copies/uL for HSV1, 1.72 copies/uL for HSV2, and 2.54 IS6110 copies per uL for MTB. The PCR was used in 202 CSF collected from subjects suspected of aseptic meningitis. Five samples (2.46%) tested positive, including two children positive for HSV1 (0.99%) and three adults tested positive for MTB (1.47%). CONCLUSION: Using an in-house real-time PCR assay, we showed that both HSV and MTB are etiologic pathogens contributing to aseptic meningitis in Burkina Faso. This molecular test may have clinical utility for early diagnosis for those treatable CNS infections. PMID- 30474141 TI - Ultrastructure features of the surface of the gills and the lower pharyngeal jaw of the Tilapia Zilli, redbelly tilapia (Coptodon Zillii, Gervais, 1848). AB - The present investigation was designed to describe the surface ultrastructure of the gill system of tilapia Zilli. The gill system is formed from four gill arches and each gill arch carries a row of gill filaments on its convex border and two rows of the gill rakers on its concave border. The quadrilateral interbranchial septum has elevated part at the level of the third gill arch. By SEM observations, the gill arch was divided into three regions: rostral, middle and caudal region. The caudal region contained two characteristic structures: oval leaf-like structure and rounded-shaped structure. Each oval leaf-like structure carried two lateral rows of the triangular pointed spines separated by a median groove. All surfaces of gill arches, rakers and filaments were covered with a mosaic of the polygonal pavement cells, in addition to the opening of chloride cells and mucous cells. The gill arch and gill raker had only one appearance of taste buds named type I. Meanwhile, the filaments contained two types of different appearance of the taste buds named: type I and type II. Type I was the main common and similar to that present in gill arch and raker and characterized by its blunt end, while type II had hair-like structures that projected from the volcano-shaped depression. The gill rakers were formed from central axis surrounded by two lateral lobulated regions which carry pointed spines, taste buds and the opening of chloride cells. The surface of triangular lower pharyngeal jaw carries numerous teeth-like papillae which originated from the socket-like depression. PMID- 30474142 TI - What's in a name? Molecular sub-classification of sarcomas creates fresh challenges. AB - This commentary addresses the issue of the classification of sarcomas in the article written by Watson and colleagues published recently in this journal. That article delves into the molecular characterization and distinct phenotypes of some recently described entities (e.g. BCOR-rearranged sarcomas, CIC-fused sarcomas), and describes new groups with common characteristics. This commentary focuses on several questions raised in the article, such as what makes a group of sarcomas become a clinical entity, which should be the main driver of sarcoma classification, how the classification of small round cell sarcomas is expected to evolve and how high-throughput techniques could be applied to sarcoma diagnosis in the short term. PMID- 30474143 TI - Letter to the Editor Regarding Article, "High mobility group box 1 as a biomarker in critically ill patients". PMID- 30474144 TI - The unmet need for better risk stratification of non-proliferative diabetic retinopathy. AB - Diabetic retinopathy is a common microvascular complication of diabetes and remains one of the leading causes of preventable blindness in working-age people. Non-proliferative diabetic retinopathy is the earliest stage of diabetic retinopathy and is typically asymptomatic. Currently, the severity of diabetic retinopathy is assessed using semi-quantitative grading systems based on the presence or absence of retinal lesions. These methods are well validated, but do not predict those at high risk of rapid progression to sight-threatening diabetic retinopathy; therefore, new approaches for identifying these people are a current unmet need. We evaluated published data reporting the lesion characteristics associated with different progression profiles in people with non-proliferative diabetic retinopathy. Based on these findings, we propose that additional assessments of features of non-proliferative diabetic retinopathy lesions may help to stratify people based on the likelihood of rapid progression. In addition to the current classification, the following measurements should be considered: the shape and size of lesions; whether lesions are angiogenic in origin; the location of lesions, including predominantly peripheral lesions; and lesion turnover and dynamics. For lesions commonly seen in hypertensive retinopathy, a detailed assessment of potential concomitant diseases is also recommended. We believe that natural history studies of these changes will help characterize these non-proliferative diabetic retinopathy progression profiles and advance our understanding of the pathogenesis of diabetic retinopathy in order to individualize management of people with diabetic retinopathy. PMID- 30474145 TI - Refining the ethics of preimplantation genetic diagnosis: A plea for contextualized proportionality. AB - Many European countries uphold a 'high risk of a serious condition' requirement for limiting the scope of preimplantation genetic diagnosis (PGD). This 'front door' rule should be loosened to account for forms of PGD with a divergent proportionality. This applies to both 'added PGD' (aPGD), as an add-on to in vitro fertilization (IVF), and 'combination PGD' (cPGD), for a secondary disorder in addition to the one for which the applicants have an accepted PGD indication. Thus loosening up at the front has implications at the back of PGD treatment, where a further PGD rule says that 'affected embryos' (in the sense of embryos with the targeted mutation or abnormality) should not be transferred to the womb. This 'back door' rule should be loosened to allow for transferring 'last chance' affected embryos in aPGD and cPGD cases, provided this does not entail a high risk that the child will have a seriously diminished quality of life. PMID- 30474146 TI - Inhalation exposure to low levels of ethyl tertiary butyl ether: Its genetic effects were significantly modified by ALDH2 activity. AB - Previous experiments showed that high concentrations of ethyl tertiary butyl ether (ETBE) exposure (500-5,000 ppm) significantly resulted in DNA damages in aldehyde dehydrogenase 2 (Aldh2) knockout (KO) mice. This study was aimed to verify the genotoxic effects in three genetic types, Aldh2 KO, heterogeneous (HT), and wild type (WT), of mice exposed to lower concentrations of ETBE (50-500 ppm) by inhalation. Histopathology assessments in the livers, measurements of genotoxic biomarkers in blood and livers, and urinary 8-hydroxydeoxyguanosion (8 OH-dG) for the oxidative DNA damage of whole body were performed. Significant histopathological changes and DNA strand breaks both in hepatocytes and leukocytes were found in HT and KO male mice exposed to >=200 ppm ETBE, but not in 50 ppm ETBE. 8-OH-dG levels either in liver or urine were higher in the HT and KO male mice exposed to >=200 ppm ETBE. The pathological and genetic effects of ETBE were almost at the same extents for HT and KO mice. Thus, 50 ppm could be the no observed adverse effect level for ETBE in HT and KO male mice, which was far lower than the 500 ppm in WT mice. These results suggested that decrease and deficiency of ALDH2 activity would significantly increase the sensitivity to ETBE induced genotoxicity as well as hepatotoxic effects after exposure even to low concentrations of ETBE. Environ. Mol. Mutagen. 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30474147 TI - The impact of high-intensity interval training on the cTnT response to acute exercise in sedentary obese young women. AB - AIMS: This study characterized (1) the cardiac troponin T (cTnT) response to three forms of acute high-intensity interval exercise (HIE), and (2) the impact of 12 weeks of HIE training on the cTnT response to acute exercise in sedentary obese young women. METHODS: Thirty-six sedentary women were randomized to traditional HIE training (repeated 4-min cycling at 90% VO2max interspersed with 3-min rest, 200 kJ/session), work-equivalent sprint interval exercise (SIE) training (repeated 1-min cycling at 120% VO2max interspersed with 1.5-min rest) or repeated sprint exercise (RSE) training (40 * 6-s all-out sprints interspersed with 9-s rest) group. cTnT was assessed using a high sensitivity assay before and immediately, 3 and 4 h after the 1st (PRE), 6th (EARLY), 20th (MID), and 44th (END) training session, respectively. RESULTS: cTnT was elevated (P < 0.05) after all forms of acute interval exercise at the PRE and EARLY assessment with cTnT response higher (P < 0.05) after HIE (307%) and SIE (318%) than RSE (142%) at the PRE assessment. All forms of acute interval exercise at MID and END had no effect on the cohort cTnT concentration post-exercise (all P > 0.05). CONCLUSION: For sedentary obese young women, both HIE and SIE, matched for total work, induced a similar elevation in cTnT after acute exercise with a smaller rise observed after RSE. By the 44th training session, almost no post-exercise cTnT elevation was observed in all three groups. Such information is relevant for clinicians as it could improve medical decision-making. This article is protected by copyright. All rights reserved. PMID- 30474148 TI - The distribution of the proteoglycan FORSE-1 in the developing mouse central nervous system. AB - Glycosylation is a major post-translational modification in which a carbohydrate known as a glycan is enzymatically attached to target proteins which regulate protein folding and stability. Glycans are strongly expressed in the developing nervous system where they play multiple roles during development. The importance of these glycan epitopes in neural development is highlighted by a group of conditions known as congenital disorders of glycosylation which lead to psychomotor difficulties, mental retardation, lissencephaly, microencephaly and epilepsy. One of these glycan epitopes, known as Lewis X, is recognised by the FORSE-1 antibody and is regionally expressed in the developing nervous system. In this study, we report the regional and temporal expression patterns of FORSE-1 immunolabelling during the periods of neurogenesis, gliogenesis and axonogenesis in developing mouse nervous system. We demonstrate the localisation of FORSE-1 on subsets of neuroepithelial cells and radial glial cells, and in compartments corresponding to axon tract formation. These spatial, temporal and regional expression patterns are suggestive of roles in the determination of different cell lineages and in the patterning of white matter during development, and help provide insights into the neuroanatomical regions affected by congenital disorders of glycosylation. PMID- 30474149 TI - 31 P NMR assessment of the phosvitin-iron complex in mayonnaise. AB - Lipid oxidation is the main reason for the limited shelf-life of mayonnaise. One of the main catalysts of this process is iron, which is introduced in its ferric (Fe (III)) form via phosvitin, an egg yolk phosphoprotein rich in phosphoserines. The binding of Fe (III) to phosvitin and its ability to establish a redox couple with Fe (II) is believed to determine the oxidation rate of unsaturated lipids. In this work, a 31 P NMR based method was developed to quantify loading of phosvitin with Fe (III) and its reductive release. Both features could be quantified in model phosvitin solutions by exploiting the paramagnetic broadening of 31 P NMR signal of phosphoserine residues by Fe (III). This method was then successfully applied to quantify the phosvitin-Fe (III) loading in mayonnaise water phase by liquid NMR, whereas 31 P NMR MAS could only provide a qualitative measure. The 31 P NMR method showed a direct relation between loading of the Fe (III)-phosvitin complex and lipid oxidation. PMID- 30474150 TI - Comparative single-dose pharmacokinetics of orally administered florfenicol in rainbow trout (Oncorhynchus mykiss, Walbaum, 1792) at health and experimental infection with Streptococcus iniae or Lactococcus garvieae. AB - This study evaluates changes in the pharmacokinetic behavior of a single oral dose of florfenicol in rainbow trouts experimentally infected with Lactococcus garvieae or Streptococcus iniae. One hundred and fifty fish were randomly divided into three equal groups: 1-healthy fish, 2-fish inoculated with S. iniae (2.87 * 107 CFU/ml, i.p.), and 3-fish inoculated with L. garvieae (6.8 * 105 CFU/ml, i.p.). Florfenicol was administered to all groups at 15 mg/kg by oral gavage. Blood sampling was performed at 0, 2, 3, 6, 8, 12, 24, 48, 72, and 120 hr after drug administration to each group, and plasma concentration of florfenicol was assayed by HPLC method. The MICs of florfenicol were 1.2 MUg/ml and 5 MUg/ml against L. garviae and S. iniae, respectively. Healthy fish showed higher values for most of the PK/PD parameters as compared to fish infected with L. garvieae which was reversed in fish infected with S. iniae. Fish infected with L. garvieae showed decreased relative bioavailability accompanied by increased volume of distribution at steady-state (Vdss ) and total body clearance (ClB ). Infection with S. iniae increased the peak concentration of drug after administration (Cmax) and decreased elimination half-life (T1/2 beta ), central compartment volume (Vc ), and Vdss . In conclusion, infection with these bacteria can affect the pharmacokinetic behavior of florfenicol in rainbow trouts as shown by decreased bioavailability and increased total body clearance and volume of distribution in L. garvieae infection and decreased volume of distribution accompanied by increased Cmax in S. iniae-infected fish. PMID- 30474151 TI - 3D self-gated cardiac cine imaging at 3 Tesla using stack-of-stars bSSFP with tiny golden angles and compressed sensing. AB - PURPOSE: To develop and evaluate an accelerated 3D self-gated cardiac cine imaging technique at 3 Tesla without the use of external electrocardiogram triggering or respiratory gating. METHODS: A 3D stack-of-stars balanced steady state free precession sequence with a tiny golden angle sampling scheme was developed to reduced eddy current effect-related artefacts at 3 Tesla. Respiratory and cardiac motion were derived from a central 5-point self-gating signal extraction approach. The data acquired around the end-expiration phases were then sorted into individual cardiac bins and used for reconstruction with compressed sensing. To evaluate the performance of the proposed method, image quality (1: the best; 4: the worst) was quantitatively compared using both the proposed method and the conventional 3D golden-angle self-gated method. Linear regression and Bland-Altman analysis were used to assess the functional measurements agreement between the proposed method and the routine 2D breath-hold multi-slice technique. RESULTS: Compared to the conventional 3D golden-angle self gated method, the proposed method yielded images with much less streaking artifact and higher myocardium edge sharpness (0.50 +/- 0.06 vs. 0.45 +/- 0.05, P = 0.004). The proposed method provided an inferior image quality score to the routine 2D technique (2.13 +/- 0.35 vs. 1.38 +/- 0.52, P = 0.063) but a superior one to the conventional self-gated method (2.13 +/- 0.35 vs. 3.13 +/- 0.64, P = 0.031). Left ventricular functional measurements between the proposed method and routine 2D technique were all well in agreement. CONCLUSION: This study presents a novel self-gating approach to realize rapid 3D cardiac cine imaging at 3 Tesla. PMID- 30474152 TI - L-theanine ameliorate depressive-like behavior in a chronic unpredictable mild stress rat model via modulating the monoamine levels in limbic-cortical-striatal pallidal-thalamic-circuit related brain regions. AB - L-theanine, originally found in green tea, elicits various physiological effects, such as promoting relaxation, improving concentration and learning ability, and providing antianxiety-like and antidepressant-like properties. This study aims to investigate the effects of L-theanine (2 mg/kg) on monoamine levels in an animal model of depression. The effect of l-theanine on the symptoms of depression was examined through the open-field test, sucrose preference test, and forced swim test. The monoamine neurotransmitters that involve serotonin (5-HT), norepinephrine (NE), and dopamine (DA) were measured in the limbic-cortical striatal-pallidal-thalamic (LCSPT)-circuit related brain regions, including the prefrontal cortex (PFC), nucleus accumbens (NAC), striatum (ST), amygdala, and hippocampus (HIP). L-theanine ameliorated the depressive-like behaviors in the chronic unpredictable mild stress (CUMS) rat model. In the PFC, NAC, and HIP, L theanine administration significantly increased the levels of 5-HT, NE, and DA. In the ST, the levels of 5-HT and DA were increased after the administration of L theanine. However, in the HIP, only the level of DA significantly changed after the treatment of L-theanine. Taken together, these results indicated that L theanine has possibly antidepressant-like effects in the CUMS rat model, which could be mediated by the monoamine neurotransmitters in the LCSPT-circuit related brain regions. PMID- 30474153 TI - Probing carbohydrate metabolism using hyperpolarized 13 C-labeled molecules. AB - Glycolysis is a fundamental metabolic process in all organisms. Anomalies in glucose metabolism are linked to various pathological conditions. In particular, elevated aerobic glycolysis is a characteristic feature of rapidly growing cells. Glycolysis and the closely related pentose phosphate pathway can be monitored in real time by hyperpolarized 13 C-labeled metabolic substrates such as 13 C enriched, deuterated D-glucose derivatives, [2-13 C]-D-fructose, [2-13 C] dihydroxyacetone, [1-13 C]-D-glycerate, [1-13 C]-D-glucono-delta-lactone and [1 13 C] pyruvate in healthy and diseased tissues. Elevated glycolysis in tumors (the Warburg effect) was also successfully imaged using hyperpolarized [U-13 C6 , U-2 H7 ]-D-glucose, while the size of the preexisting lactate pool can be measured by 13 C MRS and/or MRI with hyperpolarized [1-13 C]pyruvate. This review summarizes the application of various hyperpolarized 13 C-labeled metabolites to the real-time monitoring of glycolysis and related metabolic processes in normal and diseased tissues. PMID- 30474155 TI - 'If someone donates $1000, they support you. If they donate $100 000, they have bought you'. Mixed methods study of tobacco, alcohol and gambling industry donations to Australian political parties. AB - BACKGROUND AND AIMS: Business corporations' use of political donations to garner political influence is especially troubling in relation to products that damage human health. We sought to investigate patterns of donations to Australian political parties from tobacco, alcohol and gambling industry actors and the experiences of key informants. DESIGN AND METHODS: We analysed public data on federal and state donations for 10 years to June 2015. We conducted 28 semi structured interviews with current and former politicians, ex-political staffers and other key informants, concerning the role played by political donations of tobacco, alcohol and gambling companies in Australian politics. We examined temporal associations in donations data, and thematically analysed interviews. RESULTS: Australian political parties declared donations of A$14 million (US$11 M) from tobacco ($1.9 M), alcohol ($7.7 M), gambling ($2.9 M) and supermarket ($1.7 M) entities, excluding donations below the $12 800 reporting threshold. Donations to the governing party increased substantially during debates about an alcohol tax and gambling law reform. Alcohol industry donations to major parties spiked ahead of elections. Interviewees identified the function of donations in terms of: (i) buying immediate influence; (ii) building long-term relationships; (iii) exploiting a flawed political system; and (iv) the need to look beyond donations, for example, to favour exchange; and the public's right to know about corporate influence on policy-makers. DISCUSSION AND CONCLUSIONS: The alcohol and gambling industries make substantial donations to influence particular decisions in the short term and build relationships over the long term. Banning corporate donations and publicly funding political parties warrant consideration to safeguard the integrity of public policy-making. PMID- 30474154 TI - Estimating cross-population genetic correlations of causal effect sizes. AB - Recent studies have examined the genetic correlations of single-nucleotide polymorphism (SNP) effect sizes across pairs of populations to better understand the genetic architectures of complex traits. These studies have estimated rhog , the cross-population correlation of joint-fit effect sizes at genotyped SNPs. However, the value of rhog depends both on the cross-population correlation of true causal effect sizes ( rhob ) and on the similarity in linkage disequilibrium (LD) patterns in the two populations, which drive tagging effects. Here, we derive the value of the ratio rhog/rhob as a function of LD in each population. By applying existing methods to obtain estimates of rhog , we can use this ratio to estimate rhob . Our estimates of rhob were equal to 0.55 ( SE = 0.14) between Europeans and East Asians averaged across nine traits in the Genetic Epidemiology Research on Adult Health and Aging data set, 0.54 ( SE = 0.18) between Europeans and South Asians averaged across 13 traits in the UK Biobank data set, and 0.48 ( SE = 0.06) and 0.65 ( SE = 0.09) between Europeans and East Asians in summary statistic data sets for type 2 diabetes and rheumatoid arthritis, respectively. These results implicate substantially different causal genetic architectures across continental populations. PMID- 30474156 TI - A Quantum-Mechanical Map for Bonding and Properties in Solids. AB - A 2D map is created for solid-state materials based on a quantum-mechanical description of electron sharing and electron transfer. This map intuitively identifies the fundamental nature of ionic, metallic, and covalent bonding in a range of elements and binary compounds; furthermore, it highlights a distinct region for a mechanism recently termed "metavalent" bonding. Then, it is shown how this materials map can be extended in the third dimension by including physical properties of application interest. Finally, it is shown how the map coordinates yield new insight into the nature of the Peierls distortion in phase change materials and thermoelectrics. These findings and conceptual approaches provide a novel avenue to tailor material properties. PMID- 30474157 TI - Task-dependent responses to muscle vibration during reaching. AB - Feedback corrections in reaching have been shown to be task-dependent for proprioceptive, visual and vestibular perturbations, in line with predictions from optimal feedback control theory. Mechanical perturbations have been used to elicit proprioceptive errors, but have the drawback to actively alter the limb's trajectory, making it non-trivial to dissociate the subject's compensatory response from the perturbation itself. In contrast, muscle vibration provides an alternative tool to perturb the muscle afferents without changing the hands trajectory, inducing only changes in the estimated, but not the actual, limb position and velocity. Here, we investigate whether upper-arm muscle vibration is sufficient to evoke task-dependent feedback corrections during goal-directed reaching to a narrow versus a wide target. Our main result is that for vibration of biceps and triceps, compensatory responses were down-regulated for the wide compared to the narrow target. The earliest detectable difference between these target-specific corrections is at about 100 ms, likely reflecting a task dependent feedback control policy rather than a voluntary response. This article is protected by copyright. All rights reserved. PMID- 30474158 TI - Abolition of prenatal lipopolysaccharide-induced reproductive disorders in rat male offspring by fulvestrant. AB - During prenatal and early postnatal periods of development, multiple environmental factors have profound and long-lasting effects on the immune and reproductive functions. The aim of this study was to investigate the effects of maternal lipopolysaccharide (LPS) exposure (50 mg/kg, i.p.) at day 12 of pregnancy and estradiol antagonist treatment (fulvestrant, 1.5 mg/kg, s.c. in neck) at postnatal days 5-14 (PND5-14) with high estradiol levels on reproductive parameters in adult rat males. Serum steroid concentrations were measured in male offspring at PND80 by ELISA. Body, testis weights and ano-genital distance (AGD) were recorded at different stages of postnatal development. Testis was also processed to cytohistological studies at PND80. Our results demonstrate that body weight was decreased from PND14 to 30 after prenatal LPS treatment and was increased after fulvestrant treatment. AGD was decreased after prenatal LPS treatment and was increased after fulvestrant injections. Testis weight, testosterone level, seminiferous tubule diameter, and number of Sertoli and spermatid cells were also decreased in rats exposed prenatally to LPS and were restored to the normal control level after fulvestrant treatment. According to results, we can conclude that the development of sexual disorders in males after prenatal immune stress is potentiated by estradiol during the pre-pubertal period. PMID- 30474159 TI - Magnetocaloric materials as switchable high contrast ratio MRI labels. AB - PURPOSE: To develop switchable and tunable labels with high contrast ratio for MRI using magnetocaloric materials that have sharp first-order magnetic phase transitions at physiological temperatures and typical MRI magnetic field strengths. METHODS: A prototypical magnetocaloric material iron-rhodium (FeRh) was prepared by melt mixing, high-temperature annealing, and ice-water quenching. Temperature- and magnetic field-dependent magnetization measurements of wire-cut FeRh samples were performed on a vibrating sample magnetometer. Temperature dependent MRI of FeRh samples was performed on a 4.7T MRI. RESULTS: Temperature dependent MRI clearly demonstrated image contrast changes due to the sharp magnetic state transition of the FeRh samples in the MRI magnetic field (4.7T) and at a physiologically relevant temperature (~37 degrees C). CONCLUSION: A magnetocaloric material, FeRh, was demonstrated to act as a high contrast ratio switchable MRI contrast agent due to its sharp first-order magnetic phase transition in the DC magnetic field of MRI and at physiologically relevant temperatures. A wide range of magnetocaloric materials are available that can be tuned by materials science techniques to optimize their response under MRI appropriate conditions and be controllably switched in situ with temperature, magnetic field, or a combination of both. PMID- 30474160 TI - Cognitive performance in survivors of breast cancer and markers of biological aging. AB - BACKGROUND: Biological aging pathways accelerated by cancer treatments may be a mechanism for cognitive impairment in cancer survivors. The goal of the current study was to examine whether indicators of biological aging, namely elevated levels of DNA damage, reduced telomerase enzymatic activity, and shorter peripheral blood mononuclear cell (PBMC) telomere length (TL) would be related to cognitive function in a cohort of survivors of breast cancer. METHODS: The authors evaluated a cross-sectional sample of 94 women aged 36 to 69 years who were treated for early-stage breast cancer 3 to 6 years previously. Leukocyte DNA damage, PBMC telomerase enzymatic activity, PBMC TL, and the inflammatory marker soluble tumor necrosis factor receptor II (sTNF-RII) were determined from blood samples. Cognitive function was assessed using a neuropsychological test battery and self-report. Linear regression models examined the relationship between biological aging predictors and cognitive outcomes. RESULTS: Both higher DNA damage and lower telomerase were found to be statistically significantly related to lower executive function scores adjusting for age, body mass index, race, years from treatment, and intelligence score (standardized coefficients [B], 0.23 and 0.30; all P values <.05). In addition, lower telomerase activity was associated with worse attention and motor speed scores (B values, 0.30 and 0.24; P <.05). sTNF-RII and TL were found to be unrelated to any of the neurocognitive domains. CONCLUSIONS: The results of the current study suggest a significant association between measures of biological aging and objective measures of cognitive performance in survivors of breast cancer. Future prospective studies are needed to confirm a causal role of biological aging as a driver of declines in cognitive function after cancer treatment. PMID- 30474161 TI - The Risk of Recurrent VTE and Major Bleeding in a Commercially-insured Population of Cancer Patients Treated with Anticoagulation. PMID- 30474162 TI - Response to commentaries: The quest(ion) remains in the search for a meaningful reduction-based end-point. PMID- 30474163 TI - Effects of dietary supplemental phytoncide instead of zinc oxide on growth performance, nutrient digestibility, blood profiles, and faecal microflora in growing pigs. AB - This study was aimed to evaluate the effect of phytoncide (PTC) instead of zinc oxide on growth performance, blood profile, nutrient digestibility and faecal microflora in growing pigs. A total of 120 growing pigs [(Landrace * Yorkshire) * Duroc] with initial body weight 24.48 +/- 1.62 kg were randomly assigned to four dietary treatments for a 6 weeks feeding trials, the treatments as follow: CON (base diet),ZO (CON + 0.03% Zinc Oxide), PTC1 (CON + 0.5% PTC), PTC2 (CON + 1.0% PTC). Compared to basal diet, during weeks 1-3, 3-6, and overall experimental period, the ADG of growing pigs fed phytoncide diet trend to be increased, and fed ZO diet was significantly increased (p < 0.05). During weeks 3-6 and overall experiment period, pigs fed the ZO diet showed improvement in feed intake compared to pigs fed basal diet as a trend. Compared with basal diet, the pigs receiving phytoncide diet significantly increased the digestibility of DM and reduced the concentration of aspartate transaminase in pigs receiving 1.0% phytoncide diet. These results suggested that dietary supplement of phytoncide, Korean pine extract, could be used as an alternative to zinc oxide by decreasing detoxify to soil and plants without influencing the performance of growing pigs. Further study is needed to determine the systemic estimation of the dose of phytoncide. PMID- 30474164 TI - Implementing a new adolescent epilepsy service: Improving patient experience and readiness for transition. AB - AIM: To implement and appraise a new model of care in terms of: patient experience, knowledge of epilepsy, readiness for transition and emotional and behavioural support in a new purpose-built facility for adolescents and young adults. METHODS: The new model of care included: upskilling of neurology staff in adolescent engagement and provision of group education sessions on epilepsy and mental health (MH), along with MH support, in a new purpose-built adolescent facility. Parameters examined pre- and post-attendance at the new clinic included: adolescent experience of service delivery, transition readiness, emotional and behavioural well-being, epilepsy knowledge and medication adherence. RESULTS: A total of 45 adolescents (mean age 15.7 years) attended the new epilepsy clinic between February 2017 and December 2017. Adolescents felt significantly better informed following education in relation to epilepsy and driving, alcohol/street drugs and birth control/pregnancy. There was no significant improvement in self-reported medication adherence, transition readiness or mental well-being at follow-up. While MH education was ranked highly in terms of importance by adolescents and parents at baseline, attendance at MH education and engagement with MH support was low. CONCLUSIONS: This paper documents what is important to young people with epilepsy regarding service delivery. The new adolescent service was well received. Based on feedback from adolescents and parents relating to the service, and the suboptimal uptake of MH supports, the model of care has been revised to reduce attendance burden on families and improve patient experience. PMID- 30474165 TI - The dysphagia stress test for rapid assessment of swallowing difficulties in esophageal conditions. AB - BACKGROUND: Esophageal dysphagia is a common symptom in gastroenterology practice. Current rapid assessment tools are limited to oropharyngeal dysphagia and do not translate well to esophageal conditions. We aim to create a novel tool, the dysphagia stress test (DST), to evaluate swallowing in patients with esophageal disease characterized by dysphagia. METHODS: Adults with eosinophilic esophagitis (EoE), gastroesophageal reflux disease (GERD), achalasia, and dysphagia not otherwise specified (NOS) participated. Patient controls with non esophageal diagnoses and healthy controls were also recruited. Participants completed the DST with five bolus challenges: water, applesauce, rice, bread, barium tablet and rated their swallowing difficulty and pain. A study clinician observed and documented water use and refusal of any challenges. Participants also completed measures of esophageal symptoms, hypersensitivity, and symptom anxiety to evaluate the DST validity. Collinearity of bolus challenges guided item reduction. KEY RESULTS: A total of 132 subjects participated. Both control groups and GERD patients had the best swallowing ability, while achalasia, EOE, and dysphagia NOS scored poorer. About 90% of patients were able to attempt or pass each of the bolus challenges, suggesting high acceptability. Construct validity of the DST is evidenced by modest negative correlations with symptom severity, hypersensitivity, and anxiety. The DST does not appear to be influenced by brain-gut processes. Applesauce, rice, and bread demonstrated collinearity; thus, the DST was reduced to three challenges. CONCLUSIONS & INFERENCES: The DST is the first rapid assessment tool designed for gastroenterology clinics with direct observation of swallowing ability across several conditions to mitigate issues related to patient self-report of esophageal symptoms. PMID- 30474166 TI - Inside-out or outside-in, a new factor in MAG-mediated signaling in the nervous system: An Editorial for 'High-affinity heterotetramer formation between the large myelin-associated glycoprotein and the dynein light chain DYNLL1' on doi:10.1111/jnc.14598. AB - Our nervous system depends on protein-mediated cellular communication and connections for its formation and function. The transmembrane receptor Myelin Associated Glycoprotein (MAG) plays an important role in the wrapping process of myelin around axons and in life-long maintenance of this important bicellular structure. MAG organizes the adhesion and the signalling between the axon and the myelin. But how does MAG do this? Better understanding of this process is required to treat MAG-function associated neurological disorders. This editorial highlights a study by Myllykoski et al. in the current issue of the Journal of Neurochemistry that describes the identification and characterization of a novel intracellular binding partner of MAG. Using cellular, biophysical and structural techniques, the authors show that the dynein light chain, DYNLL1 recognizes and interacts with only one of two splice forms of MAG, L-MAG. DYNLL1 dimerizes L-MAG at the cytosolic side and this has implications for the signalling and adhesive functions of MAG in our nervous system. PMID- 30474167 TI - Combined effects of guanidinoacetic acid, coenzyme Q10 and taurine on growth performance, gene expression and ascites mortality in broiler chickens. AB - High levels of guanidinoacetate acid (GAA) deteriorate growth response in broiler chickens. We propose using coenzyme Q10 , an antioxidant, and taurine (TAU), a methyl donor, to cope with the situation when high level of GAA included in diet. GAA was supplemented at 0 (control), 0.75, 1.5 and 2.25 g/kg in isoenergetic and isonitrogenous diets and fed to broilers (Cobb 500) from 1 to 40 days post-hatch. Three additional diets were prepared by adding CoQ10 (40 mg/kg), TAU (40 mg/kg) or their combination (both CoQ10 and TAU at 40 mg/kg) to the 2.25 g/kg GAA group. The experimental design used was a completely randomized design. While weight gain (p = 0.038) and feed conversion ratio (p = 0.024) improved when GAA added at 1.5 g/kg, higher supplementation (2.25 g/kg) deteriorated these responses. These responses, however, were significantly restored by using CoQ10 , TAU or their combination. Abdominal fat deposition was significantly decreased when TAU added to broiler diets by virtue of upregulating peroxisome proliferator-activated receptor alpha. Supplementing broiler diets with CoQ10 and TAU or their combination significantly decrease ascites mortality. In conclusion, CoQ10 and TAU have shown beneficial effects when high level of GAA included in broiler diets. PMID- 30474168 TI - Importance of sample volume to the measurement and interpretation of plasma osmolality. AB - BACKGROUND: Small sample volumes may artificially elevate plasma osmolality (Posm) measured by freezing point depression. The purpose of this study was to compare two widely different sample volumes of measured Posm (mmol/kg) to each other, and to calculated osmolarity (mmol/L), across a physiological Posm range (~50 mmol/kg). METHODS: Posm was measured using freezing point depression and osmolarity calculated from measures of sodium, glucose, and blood urea nitrogen. The influence of sample volume was investigated by comparing 20 and 250 MUL Posm samples (n = 126 pairs). Thirty-two volunteers were tested multiple times while EUH (n = 115) or DEH (n = 11) by -4.0% body mass. ProtinolTM (240, 280, and 320 mmol/kg) and ClinitrolTM (290 mmol/kg) reference solutions were compared similarly (n = 282 pairs). RESULTS: The 20 MUL samples of plasma showed a 7 mmol/kg positive bias compared to 250 MUL samples and displayed a nearly constant proportional error across the range tested (slope = 0.929). Calculated osmolarity was lower than 20 MUL Posm by the same negative bias (-6.9 mmol/kg) but not different from 250 MUL Posm (0.1 mmol/kg). The differences between 20 and 250 MUL samples of ProtinolTM were significantly higher than ClinitrolTM. CONCLUSIONS: These results demonstrate that Posm measured by freezing point depression will be ~7 mmol/kg higher when using 20 MUL vs 250 MUL sample volumes. Approximately half of this effect may be due to plasma proteins. Posm sample volume should be carefully considered when calculating the osmole gap or assessing hydration status. PMID- 30474169 TI - Arctic browning: Impacts of extreme climatic events on heathland ecosystem CO2 fluxes. AB - Extreme climatic events are among the drivers of recent declines in plant biomass and productivity observed across Arctic ecosystems, known as "Arctic browning." These events can cause landscape-scale vegetation damage and so are likely to have major impacts on ecosystem CO2 balance. However, there is little understanding of the impacts on CO2 fluxes, especially across the growing season. Furthermore, while widespread shoot mortality is commonly observed with browning events, recent observations show that shoot stress responses are also common, and manifest as high levels of persistent anthocyanin pigmentation. Whether or how this response impacts ecosystem CO2 fluxes is not known. To address these research needs, a growing season assessment of browning impacts following frost drought and extreme winter warming (both extreme climatic events) on the key ecosystem CO2 fluxes Net Ecosystem Exchange (NEE), Gross Primary Productivity (GPP), ecosystem respiration (Reco ) and soil respiration (Rsoil ) was carried out in widespread sub-Arctic dwarf shrub heathland, incorporating both mortality and stress responses. Browning (mortality and stress responses combined) caused considerable site-level reductions in GPP and NEE (of up to 44%), with greatest impacts occurring at early and late season. Furthermore, impacts on CO2 fluxes associated with stress often equalled or exceeded those resulting from vegetation mortality. This demonstrates that extreme events can have major impacts on ecosystem CO2 balance, considerably reducing the carbon sink capacity of the ecosystem, even where vegetation is not killed. Structural Equation Modelling and additional measurements, including decomposition rates and leaf respiration, provided further insight into mechanisms underlying impacts of mortality and stress on CO2 fluxes. The scale of reductions in ecosystem CO2 uptake highlights the need for a process-based understanding of Arctic browning in order to predict how vegetation and CO2 balance will respond to continuing climate change. PMID- 30474170 TI - Mortality from liver angiosarcoma, hepatocellular carcinoma, and cirrhosis among vinyl chloride workers. AB - BACKGROUND: Occupational exposure to vinyl chloride monomer (VCM) has been established as a cause of hepatocellular carcinoma (HCC) and liver angiosarcoma (ASL). However, some controversy remains due to conflicting results on liver cirrhosis, and to evidence on HCC based on few confirmed cases. The aim of the study is to clarify the association between VCM exposure and mortality from liver diseases. METHODS: In a cohort of 1658 workers involved in VCM production and polymerization, Poisson regression was adopted to estimate rate ratios (RR) across categories of VCM exposure for mortality due to ASL (n = 9), HCC (n = 31) confirmed by histological/clinical records, and the combination of deaths from liver cirrhosis and from liver cancer with clinical/histological evidence of cirrhosis (n = 63). RESULTS: Cumulative VCM exposure was associated with study outcomes; RRs in the highest compared to the lowest exposure category were: ASL 91.1 (95%Confidence Interval 16.8-497), HCC 5.52 (2.03-15.0), liver cirrhosis 2.60 (1.19-5.67). CONCLUSIONS: The risk of death from liver cirrhosis, as well as from HCC in the largest available series of confirmed cases, increased with VCM exposure. PMID- 30474171 TI - Rituximab maintenance significantly prolongs progression-free survival of patients with newly diagnosed mantle cell lymphoma treated with the Nordic MCL2 protocol and autologous stem cell transplantation. AB - Recently, survival benefit of rituximab maintenance (RM) was confirmed in patients with mantle cell lymphoma (MCL) treated with R-DHAP and autologous stem cell transplant (ASCT). Whether RM improves outcomes in patients treated with other induction regimens is unknown. As part of the NiHiL observational study in patients with malignant lymphomas (GovTrial No. NCT03199066) we analyzed outcome of MCL patients treated with the Nordic MCL2 protocol followed by ASCT and RM or observation. The cohort consisted of 143 consecutive patients with median age 56 years, and with MIPI low, intermediate and high risk in 41%, 38% and 21% patients, respectively. Overall response rate (ORR) after induction in the whole cohort was 93% (67.1% CRs). 138 patients completed induction and 119 were transplanted. ORR after ASCT was 92.4% (81.5% CRs). From 130 patients without progression within 120 days after the last therapy delivery (in 112 pts after stem cell transfer, in 18 pts after the last cycle of induction), 66 initiated RM, and 64 were observed. With a median follow up 4.1 years median PFS was 9.8 years (5-y PFS and OS 66.2% and 74.4%, respectively) and median OS was not reached for the whole cohort. RM compared to observation significantly reduced risk of progression (5-y PFS 82.9% vs. 63.3%, p 0.004, HR 0.36, 95% CI 0.21 - 0.74), but the difference was not significant for OS. There was no difference in PFS in RM group between patients with and without ASCT. MIPI and splenomegaly independently correlated with shorter PFS and OS. This article is protected by copyright. All rights reserved. PMID- 30474172 TI - Immune system responses in Parkinson's Disease: early and dynamic. AB - The neuropathological hallmarks of Parkinson's disease (PD) are the degeneration and death of dopamine-producing neurons in the ventral midbrain, the widespread intraneuronal aggregation of alpha-synuclein (a-syn) in Lewy bodies and neurites, neuroinflammation, and gliosis. Signs of microglia activation in the PD brain postmortem as well as during disease development revealed by neuroimaging, implicate immune responses in the pathophysiology of the disease. Intensive research during the last two decades has advanced our understanding of the role of these responses in the disease process, yet many questions remain unanswered. A transformative finding in the field has been the confirmation that in vivo microglia are able to respond directly to pathological a-syn aggregates but also to neuronal dysfunction due to intraneuronal a-syn toxicity well in advance of neuronal death. In addition, clinical research and disease models have revealed the involvement of both the innate and adaptive immune systems. Indeed, the data suggest that PD leads not only to a microglia response, but also to a cellular and humoral peripheral immune response. Together, these findings compel us to consider a more holistic view of the immunological processes associated with the disease. Central and peripheral immune responses aimed at maintaining neuronal health will ultimately have consequences on neuronal survival. We will review here the most significant findings that have contributed to the current understanding of the immune response in PD, which is proposed to occur early, involve peripheral and brain immune cells, evolve as neuronal dysfunction progresses, and is likely to influence disease progression. This article is protected by copyright. All rights reserved. PMID- 30474173 TI - Genetically Encoding a Lipidated Amino Acid for Extension of Protein Half-life in vivo. AB - Protein therapeutics are increasingly used to treat various diseases, yet they often suffer from short serum half-lives. An emerging attractive strategy is to attach fatty acids onto proteins so as to increase their binding with human serum albumin (HSA) to extend lifetime in vivo. To recombinantly generate fatty acid modified proteins, here we report the genetic encoding of epsilon-N-heptanoyl-L lysine (HepoK), which introduces fatty acid-containing amino acid into proteins with exquisite site-specificity and homogeneity, overcoming issues associated with existing chemical conjugation methods. We demonstrate the efficient expression and purification of HepoK incorporated glucagon-like peptide-1 (GLP1) in E. coli. The resultant GLP1(HepoK) showed stronger binding with HSA than GLP1(WT), without impairing the stimulation of GLP1 receptor in cells. Moreover, GLP1(HepoK) decreased blood glucose level as GLP1(WT) did in mice in vivo, showing longer-lasting effects than GLP1(WT). HepoK thus represents a genetically encoded unnatural amino acid showing beneficial physiological effects in vivo. Genetically encoding fatty acid-containing amino acids will afford a general method for recombinantly producing therapeutic peptides and proteins that bind HSA to achieve longer serum half-life. It will also be useful for expressing site specifically lipidated proteins in vitro and in vivo to investigate the cellular function and pathological effects of this important post-translational modification. PMID- 30474174 TI - Deciphering the mechanisms of phonological therapy in jargon aphasia. AB - BACKGROUND: Severe word production difficulties remain one of the most challenging clinical symptoms to treat in individuals with jargon aphasia. Clinically, it is important to determine why some individuals with jargon aphasia improve following therapy when others do not. We report a therapy study with AM, an individual with severe neologistic jargon aphasia, and provide a subsequent comparison with previous cases, with the purpose of informing both our theoretical and clinical understanding of jargon aphasia. AIMS: To investigate AM's locus of word production deficit and determine the effectiveness of phonological component analysis (PCA) therapy, a phonological cueing therapy, in the re-learning and generalization of naming responses for words. In addition, AM's performance in therapy, linguistic profile and ability to engage with therapy/cues were compared in a retrospective analysis with the background linguistic and therapy data of two other individuals with jargon aphasia (P9 and FF), who responded differentially to PCA. This was undertake to explore possible prognostic indicators of phonological therapy for jargon aphasia. METHODS & PROCEDURES: A battery of linguistic and neuropsychological tests was used to identify AM's word production deficit. A single-subject multiple probe design across behaviours was employed to evaluate the effects of PCA therapy on the re learning and generalization of naming responses. In the retrospective analysis of AM, P9 and FF, we compared differences and similarities in performance on various linguistic tasks, the ability to engage in therapy (i.e., ability to generate and use the cues), as well as to retain and maintain cues. OUTCOMES & RESULTS: AM's locus of deficit was identified in the mapping between semantics and phonology. PCA was found to be effective in improving naming in two of the three treated word lists during the treatment phase; however, these gains were not maintained. Generalization to untreated picture names was not observed. Findings from the retrospective analysis illustrated that oral reading skills, the ability to segment phonological information from words and active engagement with provided cues are likely prerequisites for obtaining robust and long-term gains. CONCLUSIONS & IMPLICATIONS: We demonstrated that phonological therapy could be beneficial for the remediation of naming abilities at least in the re-learning phase; however, maintenance and generalization of these gains were limited. This research helps to elucidate the considerations and evaluations necessary for the appropriateness of phonological therapy and candidacy of individuals with jargon aphasia for this treatment approach. PMID- 30474175 TI - The relationship between the temporal structure of magnetoencephalography recorded brain activity and capacity to form discrete auditory representations. AB - A function of oscillatory brain activity may be to align activity relative to threshold potentials and in doing so provide limited opportunities for representational neuronal assemblies to form. This low-level function could apply across frequency bands and potentially affect the temporal dynamics of experience. To test these possibilities a magnetoencephalography protocol was developed where capacity to form discrete auditory representations over time was assessed relative to oscillatory brain activity. Three sets of pre-registered analyses were conducted. First, the capacity to form representations correlated with the prevalence and durations of activity localized to the auditory cortex. Second, brain oscillations became entrained to stimuli over a broad range of frequencies. Finally, a sequence of gamma (gamma) band events predicted successful discrete representation, where previous research had indicated similar individuation related differences within the alpha (alpha) range. Together, these findings indicate that a low-level function of cortical oscillations, which may apply across a range of frequency bands, is periodically to set conditions in which representational neuronal assemblies can manifest, limiting and so affecting the flow of experience. This article is protected by copyright. All rights reserved. PMID- 30474176 TI - Influence of a membrane-denitrification reactor on the microbial community of an aquaculture recirculation system. PMID- 30474177 TI - Receiving treatment at a specialist centre confers an overall survival benefit for patients with mantle cell lymphoma. PMID- 30474178 TI - Supramolecularly Assembled Nanocomposites as Biomimetic Chloroplasts for Enhancement of Photophosphorylation. AB - Prototypes of natural biosystems provide new opportunities for artificial biomimetic systems to break the limits of natural reactions and achieve output control. However, mimicking unique natural structures and ingenious functions still remains a great challenge. Here, we have integrated multiple biochemical reactions into artificially designed compartments via molecular assembly. First, multicompartmental silica nanoparticles with hierarchical structures that mimic the chloroplasts were obtained by a templated synthesis. Then, photoacid generators and ATPase-liposomes were assembled inside and outside of silica compartments, respectively. Upon light illumination, protons produced by a photoacid generator in the confined space can drive the liposome-embedded enzyme ATPase towards ATP synthesis, which mimics the photophosphorylation process in vitro. The developed methodology enables fabrication of bioinspired nanoreactors for photobiocatalysis and provides insight for understanding sophisticated biochemical reactions. PMID- 30474180 TI - News and ISN. PMID- 30474179 TI - Advances in Light-Emitting Dendrimers. AB - The design of dendrimers with various chromophores has attracted significant attention in light of the dual effect of the luminescence of the chromophores and the morphology of the synthesized dendrimers. Recent developments in this field stem from their wide potential applications, including organic light-emitting diodes, photonic switches and upconversion lasers, as well as sensors and electronic devices. The focus of this comprehensive review is on the design and properties of various classes of light-harvesting dendrimeric materials. PMID- 30474181 TI - The involvement of the canonical Wnt-signaling receptor LRP5 and LRP6 gene variants with ADHD and sexual dimorphism: Association study and meta-analysis. AB - Wnt-signaling is one of the most abundant pathways involved in processes such as cell-proliferation, -polarity, and -differentiation. Altered Wnt-signaling has been linked with several neurodevelopmental disorders including attention deficit/hyperactivity disorder (ADHD) as well as with cognitive functions, learning and memory. Particularly, lipoprotein receptor-related protein 5 (LRP5) or LRP6 coreceptors, responsible in the activation of the canonical Wnt-pathway, were associated with cognitive alterations in psychiatric disorders. Following the hypothesis of Wnt involvement in ADHD, we investigated the association of genetic variations in LRP5 and LRP6 genes with three independent child and adolescent ADHD (cADHD) samples (total 2,917 participants), followed by a meta analysis including previously published data. As ADHD is more prevalent in males, we stratified the analysis according to sex and compared the results with the recent ADHD Psychiatric Genomic Consortium (PGC) GWAS. Meta-analyzing our data including previously published cADHD studies, association of LRP5 intronic rs4988319 and rs3736228 (Ala1330Val) with cADHD was observed among girls (OR = 1.80 with 95% CI = 1.07-3.02, p = .0259; and OR = 2.08 with 95% CI = 1.01-4.46, p = .0026, respectively), whereas in boys association between LRP6 rs2302685 (Val1062Ile) and cADHD was present (OR = 1.66, CI = 1.20-2.31, p = .0024). In the PGC-ADHD dataset (using pooled data of cADHD and adults) tendency of associations were observed only among females with OR = 1.09 (1.02-1.17) for LRP5 rs3736228 and OR = 1.18 (1.09-1.25) for LRP6 rs2302685. Together, our findings suggest a potential sex-specific link of cADHD with LRP5 and LRP6 gene variants, which could contribute to the differences in brain maturation alterations in ADHD affected boys and girls, and suggest possible therapy targets. PMID- 30474182 TI - An in vivo comparative study of the gelatin microtissue-based bottom-up strategy and top-down strategy in bone tissue engineering application. AB - Tissue-engineered bone grafts (TEBGs) represent a promising treatment for bone defects. Nevertheless, drawbacks of the current construction strategy (top-down [TD] strategy) such as limited transmission of nutrients and nonuniform distribution of seeded cells, result in an unsatisfied therapeutic effect on large segmental bone defects. Theoretically, tissue-engineered microtissue (TEMT) based bottom-up (BU) strategy is effective in preserving seed cells and vascularization, thus being regarded as a better alternative for TEBGs. Yet, there are few studies focusing on the comparison of the in vivo performance of TEBGs fabricated by TD or BU strategy. Here, we developed an ectopic bone formation rat model to compare the performance of these two construction strategies in vivo. TEBGs made from gelatin TEMT (BU strategy) and bulk tissue (BT; TD strategy) were seeded with equal number of rat bone marrow-derived mesenchymal stem cells and fabricated in 5 mm polydimethylsiloxane chambers. The grafts were implanted into subcutaneous pockets in the same rat. Four weeks after implantation, microcomputed tomography and hematoxylin and eosin staining results demonstrated that more bony tissue was formed in the microtissue (MT) group than in the BT group. CD31 staining further confirmed that there were more blood vessels in the MT group, indicating that the BU strategy was superior in inducing angiogenesis. This comparative study provides evidence that the BU construction strategy is more effective for in vivo application and bone defect treatment by bone tissue engineering. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 00A: 1-11, 2018. PMID- 30474183 TI - In-depth Proteome Analysis of Ricinus communis Pollens. AB - Pollen grains are the tiny structures vital for sexual reproduction and consequently seed and fruit production in angiosperms, and a source of many allergenic components responsible deleterious implications for health worldwide. Current pollen research is mainly focused on unraveling the molecular mechanisms underlying the pollen germination and tube formation passing from the quiescent stage. In this context, an in-depth proteome analysis of the pollens from Ricinus communis at three different stages i.e. mature, hydrated and in-vitro germinated was performed. This analysis resulted in the identification of 1950 proteins, including 1773, 1313 and 858, from mature, hydrated and germinated pollens, respectively. Based on label-free quantification 164 proteins were found to be significantly differentially abundant from mature to hydrated pollens, 40 proteins from hydrated to germinated while 57 proteins from mature to germinated pollens, respectively. Most of the differentially abundant proteins are related to protein, carbohydrate, and energy metabolism, and signaling. Besides other functional classes, a reasonable number of the proteins were predicted to be allergenic proteins, previously undiscovered. This is the first in-deep proteome analysis of the R. communis pollens and, to the best of our knowledge, one of the most complete proteome dataset identified from the pollens of any plant species, thus providing a reference proteome for the researchers interested in pollen biology. This article is protected by copyright. All rights reserved. PMID- 30474184 TI - Usefulness of longitudinal reconstructed optical coherence tomography images for predicting the need for the reverse wire technique during coronary bifurcation interventions. AB - OBJECTIVES: The aim is to investigate the usefulness of longitudinal reconstructed optical coherence tomography (OCT) images in selecting the reverse wire (RW) technique for inserting a guidewire into a side branch (SB). BACKGROUND: It is sometimes necessary to protect the SB with a guidewire to prevent SB complications in PCI for bifurcation lesions. The RW is a novel method for guidewire insertion into an extremely angulated SB when the standard antegrade wire (AW) approach is difficult. METHODS: This retrospective study included 46 consecutive patients who underwent OCT-guided PCI in bifurcation lesions with significant SB stenosis. Patients were divided into two groups: 36 patients with successful guidewire crossing using the AW (AW group) and 10 patients with unsuccessful AW but successful RW guidewire crossing (RW group). SB angle and branch point (BP) slope, defined as the angle between the line connecting the proximal and distal BPs and the vertical, were measured using longitudinal reconstructed OCT images. RESULTS: The RW group had a significantly larger SB angle and higher BP slope than the AW group (108.7 +/- 11.4 degrees vs. 76.2 +/- 14.9 degrees ; P < 0.0001, 128.7 +/- 31.6 degrees vs. 82.9 +/- 33.6 degrees ; P = 0.0004, respectively). Receiver operating characteristic curve analysis indicated that SB angle >= 100 degrees and BP slope >= 120 degrees are optimal cutoff values for predicting the need for RW (area under the curve 0.97, sensitivity 90.0%, specificity 91.7%; area under the curve 0.83, sensitivity 80.0%, specificity 86.1%, respectively). CONCLUSIONS: Longitudinal reconstructed OCT is useful for selecting the wiring technique for bifurcation lesions. PMID- 30474185 TI - Erythropoietin and ferritin response in native highlanders aged 4-19 years from the Leh-Ladakh region of India. AB - The pivotal role of erythropoietin (EPO) in hypoxic adaptation has led to various studies assessing the EPO and ferritin response in native highlanders from Andes and Tibet. We assessed the relationship between EPO, haemoglobin and ferritin in 335 native highlanders (172 boys and 163 girls, aged 4 to 19 years) from Leh Ladakh, India, who had no history of travel to lowland areas. Complete blood counts, serum EPO and ferritin levels were measured. We stratified study subjects based on age, gender, pubertal status and analysed the EPO and ferritin levels between the stratified groups respectively. The mean EPO level in boys was lower than girls. The mean ferritin level in boys was significantly higher (P = 0.013) than in girls. There was no significant variation in the EPO and ferritin levels amongst the various age groups in our study. Near normal EPO levels since childhood with a negative correlation with haemoglobin is suggestive of a robust adaptive mechanism to high altitude from the early years of life. Low ferritin levels are indicative of decreased iron stores in these native highlanders. PMID- 30474186 TI - Nucleus-localized adiponectin is survival gate keeper through miR-214-mediated AIFM2 regulation. AB - Adiponectin secreted from adipocytes into plasma has anti-aging, anti-obesity, and anti-inflammation effects. Here, we detected intracellular adiponectin localized in the nuclei of human and mouse pluripotent stem cells, mouse germ cells, and some somatic cells. Nucleus-localized (Nu) adiponectin protein is characterized by an N-terminal truncated monomer form in a native state, compared with intact multimer forms of cytoplasm-localized (Cy) adiponectin protein. Doxycycline-induced overexpression of ADIPONECTIN caused cell death in human and mouse Nu-type pluripotent stem cells. Genome-wide gene expression analysis indicated that apoptosis by ADIPONECTIN overexpression was induced in accompany with upregulation of AIFM2 and MEG3. Upregulation of AIFM2 and MEG3 and downregulation of miR-214-3p verified by qPCR analyses after ADIPONECTIN overexpression indicated that the MEG3-miR-214-AIFM2 pathway played a role in the apoptotic cell death of pluripotent cells. Adiponectin-induced cell death was rescued by the treatment with miR-214-3p mimic. Global data analysis demonstrate that Nu adiponectin has a role in microRNA-mediated post-transcription regulation, cell-cell interactions, and chromatin remodeling as a survival gate keeper. This article is protected by copyright. All rights reserved. PMID- 30474187 TI - Testicular spermatozoon is superior to ejaculated spermatozoon for intracytoplasmic sperm injection to achieve pregnancy in infertile males with high sperm DNA damage. AB - The purpose of this study was to compare the clinical outcome of testicular spermatozoon versus ejaculated spermatozoon in the treatment of infertile males with high sperm DNA damage, referred as sperm DNA fragmentation index (DFI), that attending intracytoplasmic sperm injection (ICSI) programme in terms of clinical pregnancy, births delivered as the primary and pregnancy loss and embryo fertilisation as the secondary outcome. A total of 102 males fulfilling the inclusion criteria were enrolled in the present study. Of the 102 males, 61 infertile males underwent testicular spermatozoon combined with ICSI while the remaining 41 males applied ejaculated spermatozoa in their first ICSI cycles, and the data of them were collected and analysed. In a 18-month follow-up, testicular spermatozoon achieved higher pregnancy rate and deliver rate than those in ejaculated sperm group (pregnancy rate, 36% vs. 14.6%, p = 0.017; deliver rate, 38.5% vs. 9.8%, p = 0.001). Nevertheless, there were no significant differences in the number of oocytes aspirated and number of embryos transferred between the two groups. Additionally, the fertilisation rate in the testicular sperm study cohort (70.4%) was also similar to that in the ejaculated sperm group (75.0%). Based on the current data, we conclude that testicular spermatozoon is the prior option in the treatment of infertile males with high sperm DFI in ICSI programme. More high-quality studies with larger samples size are needed in the future due to the relative small size and the nonrandomized design of the present study. PMID- 30474188 TI - Different characteristics and survival in non-small cell lung cancer patients with primary and acquired EGFR T790M mutation. AB - Primary epidermal growth factor receptor (EGFR) T790M mutation can be occasionally identified in previous untreated non-small cell lung cancer (NSCLC) patients. To compare clinical characteristics and outcomes in patients with primary and acquired EGFR T790M mutation, we collected the data of patients diagnosed with EGFR mutation from 2012 to 2017 in Shanghai Chest Hospital. Primary EGFR T790M mutation was identified in 61 patients (1.1%; 95% confidence interval (CI): 0.8%-1.3%) of 5685 TKI-naive EGFR mutant patients. Acquired T790M mutation was detected in 98 patients (50.3%; 95%CI: 43.2%-57.3%) of 195 TKI treated patients. T790M mutation always coexisted with sensitizing EGFR mutations. Primary EGFR T790M always coexisted with 21L858R (46/61) whereas acquired T790M coexisted with 19del (68/98),(p<0.001). Among them, 18 patients with primary T790M mutation received osimertinib and 72 patients with acquired T790M mutation received osimertinib. The median progression-free survival (PFS) of osimertinib was significantly longer in primary T790M group (17.0 months, 95%CI:14.0-20.0months) compared to acquired T790M group (10.0 months, 95%CI:8.6 11.4 months, p=0.022). However, the median overall survival (OS) of acquired T790M mutation patients was significantly longer compared to that of primary T790M mutation patients who received osimertinib (50.4 months vs. 29.9 months, p=0.016). Our findings suggest that primary T790M mutation likely coexists with 21L858R while acquired mutation likely coexists with 19del. Both mutations showed good response to osimertinib. Patients with primary T790M mutation experienced greater benefits from osimertinib. However, patients with acquired T790M mutation had a better overall survival during the entire clinical treatment. This article is protected by copyright. All rights reserved. PMID- 30474189 TI - Engineering Proteases for Mass Spectrometry-based Post Translational Modification Analyses. AB - Protein post-translational modifications (PTMs) are important modulators of virtually all cellular processes, and frequently correlate with not only the rate but also severity of diseases. There has been considerable interest to map all possible PTM sites to be used as drug targets. Current approaches for PTM analysis suffer from a number of challenges; one of which is the lack of a PTM specific cleaving reagent. A central technology for global quantitative PTM analysis, mass spectrometry (MS) based proteomics, is biased toward trypsin due to its high activity and specificity. This bias becomes a problem when a PTM is located at or near tryptic cleavage sites, in which case the PTM might block recognition by trypsin, resulting in missed cleavage and sequence coverage gaps. Reviewed here are recent advances in engineering new proteases for PTM analyses, and how these new proteases are beginning to address current challenges in the field. This article is protected by copyright. All rights reserved. PMID- 30474190 TI - Expression patterns and co-localization of two sensory neuron membrane proteins in Ectropis obliqua Prout, a geometrid moth pest that uses Type-II sex pheromones. AB - Sensory neuron membrane proteins (SNMPs) function as essential cofactors for insect sex pheromone detection. In this study, we report two SNMPs in Ectropis obliqua Prout, a serious geometrid pest that produces typical Type-II sex pheromones. Sequence alignments and phylogenetic analyses showed that EoblSNMP1 and EoblSNMP2 belonged to two distinct SNMP subfamilies. Quantitative real-time PCR suggested that EoblSNMP1 was male antennae-biased, while EoblSNMP2 was highly expressed on male antennae but was also expressed on female antennae and other chemosensory tissues. Additionally, EoblSNMP1 and EoblSNMP2 differed in their developmental expression profiles. In situ hybridization revealed that EoblSNMP1 was sensilla trichodea I specific, whereas EoblSNMP2 was expressed at sensilla trichodea I and sensilla basiconica; furthermore, EoblSNMP1 and EoblSNMP2 were co expressed at sensilla trichodea I but in different cells. This study suggests that EoblSNMP1 is functionally distinct from EoblSNMP2 in E. obliqua; EoblSNMP1 might specifically contribute to the recognition of sex pheromones, while EoblSNMP2 exhibits multiple olfactory roles. Our findings comprehensively reveal the expression patterns of SNMPs in a lepidopteran species that uses Type-II sex pheromones, providing new insights into the functional evolution of SNMPs from lepidopteran moths with Type-I sex pheromones to those with Type-II sex pheromones. This article is protected by copyright. All rights reserved. PMID- 30474191 TI - Utility of HbA1c assessment in people with diabetes awaiting liver transplantation. AB - AIMS: To investigate the relationship between HbA1c and glucose in people with co existing liver disease and diabetes awaiting transplant, and in those with diabetes but no liver disease. METHODS: HbA1c and random plasma glucose data were collected for 125 people with diabetes without liver disease and for 29 people awaiting liver transplant with diabetes and cirrhosis. The median (interquartile range) Model for End Stage Liver Disease score for the study cohort was calculated as 12 (9-17; normal <6). In those with cirrhosis, this was caused by non-alcoholic fatty liver disease, hepatitis C, alcoholic liver disease, hereditary haemochromatosis, polycystic liver/kidneys, cryptogenic/non-cirrhotic portal hypertension and alpha-1-antitrypsin-related disease. RESULTS: The median (interquartile range) age of the diabetes with cirrhosis group was 55 (49-63) years compared to 60 (50-71) years (P=0.13) in the group without cirrhosis. In the diabetes with cirrhosis group there were 21 men (72%) compared with 86 men (69%) in the group with diabetes and no cirrhosis (P=0.82). Of the group with diabetes and cirrhosis, 27 people (93%) were of white European ethnicity, two (7%) were South Asian and none was of Afro-Caribbean/other ethnicity compared with 94 (75%), 16 (13%), 10 (8%)/5 (4%), respectively, in the group with diabetes and no cirrhosis (P=0.20). The median (interquartile range) HbA1c concentrations were 41 (32-56) mmol/mol [5.9 (5.1-7.3)]% vs 61 (52-70) mmol/mol [7.7 (6.9-8.6)%; P<0.001], respectively, in the diabetes with cirrhosis group vs the diabetes without cirrhosis group and the glucose concentrations were 8.4 (7.0-11.2) mmol/l vs 7.3 (5.2-11.5) mmol/l (P=0.17). HbA1c concentration was depressed by 20 mmol/mol (1.8%; P<0.001) in 28 participants with cirrhosis but elevated by 28 mmol/mol (2.6%) in the participant with alpha-1-antitrypsin disorder. Those with cirrhosis and depressed HbA1c concentrations had fewer larger erythrocytes, and higher red cell distribution width and reticulocyte count. This was reflected in the positive association of glucose with mean cell volume (r=0.39) and haemoglobin level (r=0.49) and the negative association for HbA1c concentration (r=-0.28 and r=-0.26, respectively) in the diabetes group. CONCLUSION: HbA1c is not an appropriate test for blood glucose in people with cirrhosis and diabetes awaiting transplant as it reflects altered erythrocyte presentation. This article is protected by copyright. All rights reserved. PMID- 30474192 TI - Detection and quantification of Aeromonas schubertii in Channa maculata by TaqMan MGB probe fluorescence real-time quantitative PCR. AB - Aeromonas schubertii is a major epidemiological agent that threatens cultured snakeheads (Channidae) and has caused great economic losses in fish-farming industries in China in recent years. In present study, a specific TaqMan minor groove binder (MGB) probe fluorescence real-time quantitative PCR (qPCR) assay was developed to rapidly detect and quantify A. schubertii. A pair of qPCR primers and a TaqMan MGB probe were selected from the rpoD gene, which were shown to be specific for A. schubertii. A high correlation coefficient (R2 = 0.9998) in a standard curve with a 103% efficiency was obtained. Moreover, the qPCR method's detection limit was as low as 18 copies/MUl, which was 100 times more sensitive than that of conventional PCR. The detection results for the A. schubertii in pond water and fish tissue were consistent with those of the viable counts. Bacterial load changes detected by qPCR in different tissues of snakeheads infected with A. schubertii showed that the gills and intestines may be the entry for A. schubertii, and the spleen and kidney are major sites for A. schubertii replication. The established method in present study should be a useful tool for the early surveillance and quantitation of A. schubertii. PMID- 30474193 TI - Methylphenidate-induced "Moving Ear Syndrome" in a child with ADHD responding favorably to add-on propranolol. PMID- 30474195 TI - Mycophenolate mofetil in the treatment of pediatric autoimmune central nervous system disease. PMID- 30474194 TI - A murine model of acute lung injury identifies growth factors to promote tissue repair and their biomarkers. AB - Type II alveolar epithelial cells (AEC2s) play a crucial role in the regeneration of type I AECs after acute lung injury. The mechanisms underlying the regeneration of AEC2s are not fully understood. To address this issue, here we investigated a murine model of acute lung injury using mice expressing human Diphtheria Toxin Receptor (DTR) under the control of Lysozyme M promoter (LysM DTR). DT injection induced the depletion of AEC2s, alveolar macrophages, and bone marrow (BM)-derived myeloid cells in LysM-DTR mice, and the mice died within 6 days after DT injection. Apoptotic AEC2s and bronchiolar epithelial cells appeared at 24 hours, whereas Ki67-positive proliferating cells appeared in the alveoli and bronchioles in the lung of LysM-DTR mice at 72 to 96 hours after DT injection. Transfer of wild-type BM cells into LysM-DTR mice accelerated the regeneration of AEC2s along with the upregulation of several growth factors. Moreover, several metabolites were significantly decreased in the sera of LysM DTR mice compared to WT mice after DT injection, suggesting that these metabolites might be biomarkers to predict AEC2s injury. Together, LysM-DTR mice might be useful to identify growth factors to promote lung repair and the metabolites to predict the severity of lung injury. (199 words) This article is protected by copyright. All rights reserved. PMID- 30474196 TI - Flax rhamnogalacturonan lyases: phylogeny, differential expression, and modeling of protein structure. AB - Rhamnogalacturonan lyases (RGLs; EC 4.2.2.23) degrade the rhamnogalacturonan I (RG-I) backbone of pectins present in the plant cell wall. These enzymes belong to polysaccharide lyase family 4, members of which are mainly from plants and plant pathogens. RGLs are investigated, as a rule, as pathogen "weapons" for plant cell wall degradation and subsequent infection. Despite the presence of genes annotated as RGLs in plant genomes and the presence of substrates for enzyme activity in plant cells, evidence supporting the involvement of this enzyme in certain processes is limited. The differential expression of some RGL genes in flax (Linum usitatissimum L.) tissues, revealed in our previous work, prompted us to carry out a total revision (phylogenetic analysis, analysis of expression, and protein structure modeling) of all the sequences of flax predicted as coding for RGLs. Comparison of the expressions of LusRGL in various tissues of flax stem revealed that LusRGLs belong to distinct phylogenetic clades, which correspond to two co-expression groups. One of these groups comprised LusRGL6-A and LusRGL6-B genes and was specifically up-regulated in flax fibers during deposition of the tertiary cell wall, which has complex RG-I as a key non-cellulosic component. The results of homology modeling and docking demonstrated that the topology of the LusRGL6-A catalytic site allowed binding to the RG-I ligand. These findings lead us to suggest the presence of RGL activity in planta and the involvement of special isoforms of RGLs in the modification of RG-I of the tertiary cell wall in plant fibers. This article is protected by copyright. All rights reserved. PMID- 30474197 TI - ALP2 is a functional receptor of Cry1Ac but not Cry2Ab in Helicoverpa zea. AB - Although membrane-bound alkaline phosphatases (ALPs) have been proposed as a receptor for Cry1Ac in a few Lepidopteran speceis, their potential functions as a Cry2Ab receptor are yet to be verified. To determine if ALP2 also serves as a receptor for Cry1Ac and even for Cry2Ab in Helicoverpa zea, we measured the potency of activated Cry1Ac and Cry2Ab against the midgut and fat body cell lines of H. zea and the ovarian cell line of Spodoptera frugiperda (Sf9) expressing H. zea ALP2 (HzALP2) or transfected with HzALP2 double strand RNA (dsRNA). Relative to the control cells, the three cell lines expressing HzALP2 became more susceptibile to Cry1Ac but remained the same to Cry2Ab. By constrast, the two H. zea cell lines transfected with HzALP2 dsRNA were resistant to Cry1Ac while kept susceptible to Cry2Ab. Further RNAi knockdown of HzALP2 in H. zea larvae enhanced larval survival on Cry1Ac-containing diets. These findings indicate that HzALP2 functions as a receptor of Cry1Ac but not Cry2Ab. PMID- 30474198 TI - Protist Biodiversity and Biogeography in Lakes From Four Brazilian River Floodplain Systems. AB - The biodiversity and biogeography of protists inhabiting many ecosystems have been intensely studied using different sequencing approaches, but tropical ecosystems are relatively under-studied. Here we sampled planktonic waters from 32 lakes associated with four different river-floodplains systems in Brazil, and sequenced the DNA using a metabarcoding approach with general eukaryotic primers. The lakes were dominated by the largely free-living Discoba (mostly the Euglenida), Ciliophora, and Ochrophyta. There was low community similarity between lakes even within the same river-floodplain. The protists inhabiting these floodplain systems comprise part of the large and relatively undiscovered diversity in the tropics. This article is protected by copyright. All rights reserved. PMID- 30474200 TI - Nomograms for incident risk of postpartum type 2 diabetes in Chinese women with gestational diabetes. AB - Worldwide the prevalence of type 2 diabetes (T2D) is increasing. Using the 2010 ADA criteria, the burden for China is already especially high. Gestational diabetes mellitus (GDM) is one of the major predictors of subsequent diabetes. A systematic review assessed the risk as seven-fold but the studies were heterogenous2 Incidence varies with socioeconomic status and ethnicity. This article is protected by copyright. All rights reserved. PMID- 30474199 TI - A Quasi-Solid-State Flexible Fiber-Shaped Li-CO2 Battery with Low Overpotential and High Energy Efficiency. AB - The rapid development of wearable electronics requires a revolution of power accessories regarding flexibility and energy density. The Li-CO2 battery was recently proposed as a novel and promising candidate for next-generation energy storage systems. However, the current Li-CO2 batteries usually suffer from the difficulties of poor stability, low energy efficiency, and leakage of liquid electrolyte, and few flexible Li-CO2 batteries for wearable electronics have been reported so far. Herein, a quasi-solid-state flexible fiber-shaped Li-CO2 battery with low overpotential and high energy efficiency, by employing ultrafine Mo2 C nanoparticles anchored on a carbon nanotube (CNT) cloth freestanding hybrid film as the cathode, is demonstrated. Due to the synergistic effects of the CNT substrate and Mo2 C catalyst, it achieves a low charge potential below 3.4 V, a high energy efficiency of ~80%, and can be reversibly discharged and charged for 40 cycles. Experimental results and theoretical simulation show that the intermediate discharge product Li2 C2 O4 stabilized by Mo2 C via coordinative electrons transfer should be responsible for the reduction of overpotential. The as-fabricated quasi-solid-state flexible fiber-shaped Li-CO2 battery can also keep working normally even under various deformation conditions, giving it great potential of becoming an advanced energy accessory for wearable electronics. PMID- 30474201 TI - Impact of concurrent tricuspid regurgitation on mortality after transcatheter aortic-valve implantation. AB - OBJECTIVES: To determine whether concomitant tricuspid regurgitation (TR) is associated with increased mortality in patients with severe aortic stenosis (AS) undergoing transcatheter aortic-valve implantation (TAVI), we performed a meta analysis of currently available studies. METHODS: MEDLINE and EMBASE were searched through May 2018. We included comparative or cohort studies enrolling patients with AS undergoing TAVI and reporting early (in-hospital or 30-day) and late (including early) all-cause mortality in patients stratified by baseline TR grade. An odds ratio (OR) of early mortality and a hazard ratio (HR) of late mortality with its 95% CI for significant versus non-significant (typically, >=moderate versus =moderate versus =moderate) TR is associated with an approximately two-fold increase in both early and midterm all-cause mortality in patients with AS undergoing TAVI. PMID- 30474202 TI - MEDIATOR18 modulates viability of root initial cells. PMID- 30474203 TI - Association of Maternal Prepregnancy Weight with Offspring Adiposity Throughout Adulthood over 37 Years of Follow-up. AB - OBJECTIVE: This study aimed to determine the relation of maternal prepregnancy weight with offspring BMI across adulthood from almost 40 years of follow-up. METHODS: BMI was measured in Framingham Heart Study Offspring cohort participants between 1971 and 2008. The association of maternal prepregnancy weight category (ascertained via direct measure and questionnaire) with serial offspring BMI, overweight, obesity, and change in BMI over time was tested, adjusted for age, sex, and a BMI genetic risk score; secondary models additionally adjusted for physical activity, dietary factors, smoking, education, and familial relatedness. RESULTS: Among 863 participants at initial assessment (83 exposed and 780 controls), mean (SD) age was 33 (10) years, 53% were female, and mean BMI was 24.5 (4.1) kg/m2 . Exposed offspring BMI was higher at every examination cycle, ranging from 1.5 (0.5) to 3.0 (0.5) kg/m2 (P < 0.001), with larger differences at later assessments. The rate of increase in offspring BMI over time was higher in exposed offspring before the age of 50 years (beta [SE] = 0.07 [0.02] kg/m2 per year; P = 0.004) but not after the age of 50 years (-0.05 [0.04] kg/m2 per year; P = 0.2). CONCLUSIONS: Maternal prepregnancy weight is associated with greater offspring BMI throughout adulthood, with more rapid weight acceleration in early and midadulthood. PMID- 30474204 TI - Non-Syndromic Craniosynostosis Mimicking Primary Pseudotumor Cerebri Syndrome. PMID- 30474205 TI - The therapeutic potential of regulatory T lymphocytes in periodontitis: A systematic review. AB - This systematic review aimed to: (a) generate a descriptive synthesis of preclinical studies assessing the therapeutic potential of regulatory T lymphocytes (Tregs) to arrest periodontitis, (b) evaluate the methodological heterogeneity of the reviewed animal studies and (c) assess the risk of bias (RoB) of the included studies. The electronic search for animal studies included the MEDLINE, EMBASE, Web of Science and LILACS databases. In addition, a manual search assessed the high-ranked scientific journals in "periodontics/immunology" and the references listed in the included studies. There were no language, year or publication status restrictions. Two independent reviewers selected and extracted the data, and Cohen's Kappa coefficient was calculated to determine the inter-examiner agreement. The Systematic Review Center for Laboratory Animal Experimentation's (SYRCLE) tool was used to assess the RoB. A total of 21 of the 425 studies obtained from the database search were included. Treg function was mainly described in Porphyromonas gingivalis-induced periodontitis (57.1%) in mice (76.2%), where Treg suppression was strongly related to disease progression and Treg induction was strongly related to immuno-inflammatory response reduction. Of those 21 studies, eight included eight animal experiments using three distinct therapeutic approaches, including: P. gingivalis-driven immunization (n = 3), retinoic acid inoculation (n = 2) and anti-inflammatory molecules in polymeric carriers (n = 3), which could modulate the Treg activity through cytokine production (interleukin-10 and transforming growth factor beta1), CC-chemokine- and CC-chemokine receptor-mediated chemoattraction (CCL22 and CCR4) or Th17-associated receptor activator of nuclear factor kappaB ligand (RANKL) downregulation. However, the studies with animal experiments did not specify the randomization sequences and housing conditions that were used, and therefore, 42.11% of the entries were rated as unclear RoB. Distinct therapeutic strategies involving Tregs could potentially suppress the immuno-inflammatory response and restore alveolar bone homeostasis during periodontitis. Nevertheless, important methodological variability, poor reporting of treatment effect estimates and unclear RoB suggest using caution when assessing the results of these studies. PMID- 30474206 TI - Primary outcomes and mechanism of action of intravascular lithotripsy in calcified, femoropopliteal lesions: Results of Disrupt PAD II. AB - OBJECTIVE: DISRUPT PAD II was designed to evaluate the safety and performance of intravascular lithotripsy (IVL), a novel approach using pulsatile sonic pressure waves, to modify intimal and medial calcium in stenotic peripheral arteries. BACKGROUND: Vascular calcification restricts vessel expansion, increases the risk of vascular complications, and may impair the effect of anti-proliferative therapy. METHODS: Disrupt PAD II was a non-randomized, multi-center study that enrolled 60 subjects with complex, calcified peripheral arterial stenosis at eight sites. Patients were treated with IVL and followed to 12-months. The primary safety endpoint was major adverse events (MAE) through 30 days. The primary effectiveness endpoint was patency at 12 months as adjudicated by duplex ultrasonography (DUS). Key secondary endpoints included acute procedure success, freedom from re-intervention, and functional outcomes. RESULTS: Between June 2015 and December 2015, subjects with moderate or severe calcified arterial lesions were enrolled. The final residual stenosis was 24.2%, with an average acute gain of 3.0 mm. The 30-day MAE rate was 1.7% with one grade D dissection that resolved following stent placement. Primary patency at 12 months was 54.5%, and clinically driven TLR at 12 months was 20.7%. Optimal IVL technique defined by correct balloon sizing and avoiding therapeutic miss, improved 12-month primary patency and TLR outcomes to 62.9% and 8.6%, respectively. CONCLUSIONS: IVL demonstrated compelling safety with minimal vessel injury, and minimal use of adjunctive stents in a complex, difficult to treat population. PMID- 30474207 TI - To Our Readers and Authors. PMID- 30474208 TI - Hamstring lengthening in cerebral palsy and the use of musculoskeletal modelling. PMID- 30474210 TI - Increasing risk of uterine cervical cancer among young Japanese women: Comparison of incidence trends in Japan, South Korea and Japanese-Americans between 1985 and 2012. AB - In Japan, cervical cancer incidence has increased since the late 1990s especially among young women, despite a decreasing trend in most developed countries. Here, we examined age, period and birth cohort trends in cervical cancer incidence rates from 1985 to 2012. Incidence rates were ascertained using three population based cancer registries and analyzed using Joinpoint regression and age-period cohort models. We compared the findings in Japan to trends among Japanese Americans in the Surveillance, Epidemiology, and End Results Registries and among women in South Korea using the Korea Central Registry. Age-standardized incidence rates in Japan decreased by 1.7% per year (95% confidence interval -3.3%, 0.0%) until 1997 and thereafter increased by 2.6% per year (1.1%, 4.2%). Incidence rates increased among women under age 50, were stable among women aged 50-54, and decreased or remained stable among women aged 55 and over. The age-standardized incidence rate ratio by birth cohort showed a U-shaped pattern with the lowest rates in women born in the late 1930s and 1940s. In comparison, women born before 1920 and after 1970 had about double the incidence. Increasing risk in recent birth cohorts was not evident in Japanese-American or South Korean women. The trends in Japan may be attributable to increasing prevalence of human papillomavirus (HPV) infection among young women. Screening and vaccination have been shown to be highly effective and would help reverse these trends. This article is protected by copyright. All rights reserved. PMID- 30474209 TI - Improvement in HCV patients with advanced, compensated liver disease after SVR to antivirals. AB - BACKGROUND: The outcome of patients with chronic hepatitis C virus infection (HCV) and advanced, compensated liver disease after sustained virological response (SVR) to direct-acting antivirals (DAAs) has not yet been completely depicted. We aimed to assess the clinical, biochemical, and instrumental outcome of patients with advanced, compensated chronic HCV-related liver disease with DAAs-induced SVR to DAAs and who had at least 1-year follow-up. MATERIALS AND METHODS: Fifty-two patients with cirrhosis (n=27) and fibrosis stage F3 (n=25) followed-up for a median of 60 weeks after successful DAAs treatment were included. Laboratory work-up, including APRI and FIB-4 scores, liver transient elastography, and measurement of the spleen bi-polar diameter were carried out before treatment and at the end of follow-up. RESULTS: Liver stiffness decreased (P<0.0001) from a median baseline of 15.2kPa (12.0-20.0) to 9.3kPa (7.5-12.0) at follow-up. A liver stiffness value suggestive of the presence (i.e., >=21.0kPa) of clinically significant portal hypertension was found in 13 patients (25.0%) at baseline and in 7 patients (13.5%) at follow-up (P=0.037). Both APRI (P<0.0001) and FIB-4 score (P=0.025) progressively decreased, while platelet count increased [143x109 /L (117-176) to 153 x109 /L (139-186), P=0.003], and spleen bi-polar diameter decreased [120mm (112-123) to 110mm (102-116), P=0.0009] from baseline to the end of follow-up. CONCLUSIONS: In patients advanced, compensated chronic liver disease, liver stiffness significantly improves in the long-term after SVR, and this improvement is accompanied by an amelioration of indirect indices of liver fibrosis and function, and by a decrease in parameters of portal hypertension. This article is protected by copyright. All rights reserved. PMID- 30474211 TI - TCP7 functions redundantly with several Class I TCPs and regulates endoreplication in Arabidopsis. AB - TCP (TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR) proteins, a family of plant-specific transcription factors, play important roles in many developmental processes. However, genetic and functional redundancy among class I TCP limits the analysis of their biological roles. Here, we identified a dominant negative mutant of Arabidopsis thaliana TCP7 named leaf curling-upward (lcu), which exhibits smaller leaf cells and shorter hypocotyls than the wild type, due to defective endoreplication. A septuple loss-of-function mutant of TCP7, TCP8, TCP14, TCP15, TCP21, TCP22, and TCP23 displayed similar developmental defects to those of lcu. Genome-wide RNA-sequencing showed that lcu and the septuple mutant share many misexpressed genes. Intriguingly, TCP7 directly targets the CYCLIN D1;1 (CYCD1;1) locus and activates its transcription. We determined that the C terminus of TCP7 accounts for its transcriptional activation activity. Furthermore, the mutant protein LCU exhibited reduced transcriptional activation activity due to the introduction of an EAR-like repressive domain at its C terminus. Together, these observations indicate that TCP7 plays important roles during leaf and hypocotyl development, redundantly, with at least six class I TCPs, and regulates the expression of CYCD1;1 to affect endoreplication in Arabidopsis. PMID- 30474212 TI - Plant adaptation and speciation studied by population genomic approaches. AB - Ever since Darwin, one of the major challenges in evolutionary biology is to unravel the process and mechanisms of adaptation and speciation. Population genomics-the analysis of whole-genome polymorphism data from large population samples-is a critical approach to study adaptation and speciation, as population genomics datasets enable us to: (1) perform genome-wide association studies (GWAS) to find genes underlying adaptive phenotypic variations; (2) scan the footprints of selection across the genome to pinpoint loci under selection; and (3) infer the structure and demographic history of populations. Here, we review recent studies of plants using population genomics, covering those focusing on interactions with other organisms, adaptations to local climatic conditions, and the genomic causes and consequences of reproductive isolation. Integrative studies involving GWAS, selection scans, functional studies, and fitness measurements in the field have successfully identified loci for adaptation, revealed the molecular basis of genetic trade-offs, and shown that fitness can be predicted by polygenic effects of a number of loci associated with local climate. We highlight the importance of the measurement of fitness and phenotypes in the field, which can be powerful tools when combined with population genomic analyses. PMID- 30474214 TI - Changes in survival and characteristics among older stroke unit patients-1994 versus 2012. AB - OBJECTIVES: Treatment on organized stroke units (SUs) improves survival after stroke, and stroke mortality has decreased worldwide in recent decades; however, little is known of survival trends among SU patients specifically. This study investigates changes in survival and characteristics of older stroke patients receiving SU treatment. MATERIALS & METHODS: We compared 3-year all-cause mortality and baseline characteristics in two cohorts of stroke patients aged >=60 consecutively admitted to the same comprehensive SU in 1994 (n = 271) and 2012 (n = 546). RESULTS: Three-year survival was 53.9% in 1994 and 56.0% in 2012, and adjusted hazard ratio (HR) was 0.99 (95% CI: 0.77-1.28). Adjusted 30-day case fatality was slightly higher in 2012, 18.9% versus 16.2%, HR 1.68 (95% CI: 1.14 2.47). There were no significant between-cohort differences in survival beyond 30 days. Patients in 2012 were older (mean age: 78.8 vs. 76.7 years) and more often admitted from nursing homes. There were higher rates of atrial fibrillation (33.7% vs. 21.4%) and malignancy (19.2% vs. 8.9%), and prescription of antiplatelets (46.9% vs. 26.2%) and warfarin (16.3% vs. 5.5%) at admission. Stroke severity was significantly milder in 2012, proportion with mild stroke 66.1% versus 44.3%. CONCLUSIONS: Three-year survival in older Norwegian stroke patients treated on an SU remained stable despite improved treatment in the last decades. Differences in background characteristics may explain this lack of difference; patients in 2012 were older, more often living in supported care, and had higher prestroke comorbidity; however, their strokes were milder and risk factors more often treated. PMID- 30474213 TI - Comparative transcriptome analysis of Ethiopian indigenous chickens from low and high altitudes under heat stress condition reveals differential immune response. AB - Ethiopia is an ecologically diverse country; the low altitude regions are hot and humid whereas the high altitude regions are cooler. In this study we analyzed the transcriptome response of high altitude (Addis Ababa) and low altitude (Awash) chickens to heat stress conditions that are prevalent in the low altitude regions. The chickens were free ranged for 20 h in an enclosure in Awash, and then the heart, breast muscle and spleen tissues were collected at 6:00 am, 12:00 noon and 6:00 pm to follow a daily circadian cycle. Through RNA-sequencing analysis, we identified differentially expressed genes (DEGs) that were significant (q < 0.05). These DEGs were subjected to protein-protein interaction (PPI) network and gene co-expression network (GCN) analyses to understand their role. KEGG pathway analysis and Gene Ontology analysis of all the identified DEGs and the genes identified from the PPI network and GCN analyses revealed that several immune-related pathways, such as proteasome, focal adhesion, influenza A, the ErbB signaling pathway and glycerophospholipid metabolism, were enriched in response to heat stress. These results suggest that the high altitude chickens were under heat stress and might be immunologically susceptible. Our findings will help in developing a genetic approach to mitigate production loss due to heat stress. PMID- 30474216 TI - Multilevel model with random effects for clustered survival data with multiple failure outcomes. AB - We present a multilevel frailty model for handling serial dependence and simultaneous heterogeneity in survival data with a multilevel structure attributed to clustering of subjects and the presence of multiple failure outcomes. One commonly observes such data, for example, in multi-institutional, randomized placebo-controlled trials in which patients suffer repeated episodes (eg, recurrent migraines) of the disease outcome being measured. The model extends the proportional hazards model by incorporating a random covariate and unobservable random institution effect to respectively account for treatment-by institution interaction and institutional variation in the baseline risk. Moreover, a random effect term with correlation structure driven by a first-order autoregressive process is attached to the model to facilitate estimation of between patient heterogeneity and serial dependence. By means of the generalized linear mixed model methodology, the random effects distribution is assumed normal and the residual maximum likelihood and the maximum likelihood methods are extended for estimation of model parameters. Simulation studies are carried out to evaluate the performance of the residual maximum likelihood and the maximum likelihood estimators and to assess the impact of misspecifying random effects distribution on the proposed inference. We demonstrate the practical feasibility of the modeling methodology by analyzing real data from a double-blind randomized multi-institutional clinical trial, designed to examine the effect of rhDNase on the occurrence of respiratory exacerbations among patients with cystic fibrosis. PMID- 30474215 TI - Synthesis, anticonvulsant screening, and molecular modeling studies of new arylalkylimidazole oxime ether derivatives. AB - Hit, Lead & Candidate Discovery Preclinical Research & Development In this study, 15 new oxime ether derivatives were synthesized and their anticonvulsant activities were screened in vivo. The compounds were synthesized by the reaction of various alkyl halides with 1-(2-naphthyl)-2-(1H-imidazol-1-yl)ethanone oxime. Their anticonvulsant activities were determined using acute (maximal electroshock, subcutaneous metrazol [SCM], and 6 Hz seizure test) and chronic (corneal-kindled mouse) seizure models, their neurotoxic effects were evaluated by models of behavioral toxicity according to the Epilepsy Therapy Screening Program protocol of the NIH. All our compounds were protective in at least one of the tests. Quantification studies were applied to some of the active compounds and the intraperitoneal ED50 values in mice were found between 25.48 and 99.56 mg/kg. Some pharmacokinetic properties of the compounds were predicted in silico and molecular docking studies were performed to provide insights into their possible anticonvulsant mechanism regarding their SCM activity. PMID- 30474217 TI - Ergonomic hazards in otolaryngology. AB - OBJECTIVES/HYPOTHESIS: To evaluate the presence of postural-related strain and musculoskeletal discomfort, along with the level of ergonomics training and the availability of ergonomic equipment among otolaryngology surgeons. STUDY DESIGN: Intraoperative observations and survey study. METHODS: Using the Rapid Entire Body Assessment score system to identify ergonomic hazards, we conducted intraoperative observations assessing operating room personnel during different otolaryngological subspecialty procedures. Based on these findings, otolaryngology surgeons at a single academic institution in the United States were sent a survey that evaluated ergonomic practice, environmental infrastructure, and prior ergonomic training or education. RESULTS: A response rate of 69% was obtained from 70 surgeons, with 72.9% of responding surgeons suffering from some level of back pain, with cervical spine pain being the most common. Interestingly, residents were equally affected when compared to more senior surgeons both in subjective survey reports and from observational risk analysis. Furthermore, 43.8% of surgeons reported suffering from the highest level of pain when standing, whereas only 12.5% experienced pain when sitting. Importantly, 10% stated that pain impacted their work. Only 24% of surgeons had any prior ergonomic training or education. CONCLUSIONS: Our data suggest that pain and disability induced by poor ergonomics are widespread among the otolaryngology community and confirm that surgeons rarely receive ergonomic training in the surgical context. Additionally, intraoperative observational findings identified that the majority of observed surgeons display poor posture, particularly a poor cervical angle and use of ergonomic setups, both of which increase ergonomic risk hazard. These data provide guidance for future interventional studies. LEVEL OF EVIDENCE: NA Laryngoscope, 2018. PMID- 30474218 TI - Wireless body sensor for electrocardiographic monitoring in dogs and cats. AB - OBJECTIVES: To evaluate the diagnostic utility of electrocardiogram data obtained by a wireless sensor from 36 dogs and four cats with suspected arrhythmias caused by cardiac or systemic diseases. MATERIALS AND METHODS: Wireless electrocardiographic recordings were obtained via two precordial electrodes attached to an electrocardiogram sensor connected to a smart device via low-power Bluetooth technology. Cardiac rate, rhythm and duration of P-QRS-T waves were evaluated with VisECG(r) software. Fifteen- to 30-minute wireless recordings were compared to standard electrocardiograms. Furthermore, the wireless sensor was used in 10 dogs and four cats for 24-hour continuous electrocardiogram monitoring at home. RESULTS: When compared to standard electrocardiogram, equivalent results were obtained for heart rate and duration of different waves. Due to the longer recording time, more arrhythmias were diagnosed with the wireless device in 50% (15 of 30) of animals with arrhythmias. Satisfactory recordings were obtained when the dogs were resting, standing or walking but interpretation of the wireless electrocardiogram signal was not possible during strenuous physical activity. CLINICAL SIGNIFICANCE: Wireless electrocardiographic monitoring is a reliable and accurate method for identification of heart rate, arrhythmia and duration of electrocardiogram waves. A higher diagnostic yield of arrhythmias was documented with the wireless sensor due to prolonged monitoring. The device offers a good option for the long-term monitoring of canine and feline cardiac rhythm. PMID- 30474220 TI - A Fluorescent Probe with Aggregation-Induced Emission for Detecting Alkaline Phosphatase and Cell Imaging. AB - Alkaline phosphatase (ALP) is associated with many diseases, and its accurate detection is of great significance. Fluorescent compounds with aggregation induced emission (AIE) feature show beneficial advantages for serving as fluorescent probes. Herein, an AIE-active "turn on" probe for ALP detection was synthesized through incorporating a strong electron-withdrawing group (cyano) in the middle and the recognition moiety phosphate group at the end, thereby rendering a D-A-D structure with a relatively high conjugation degree and good water solubility. It was found that the probe TPE-CN-pho is highly sensitive to ALP in aqueous solution. In the presence of ALP, the hydrophilic phosphate group on the probe is rapidly removed, resulting in a decrease in water solubility and subsequent formation of aggregates, thereby achieving aggregation-induced emission. Moreover, the probe TPE-CN-pho has also been successfully applied to imaging ALP in living cells. PMID- 30474219 TI - Is the caudal auricular axial pattern flap robust? A multi-centre cohort study of 16 dogs and 12 cats (2005 to 2016). AB - OBJECTIVE: To determine the frequency and type of healing complications arising after the use of the caudal auricular axial pattern flap to close defects on the head in dogs and cats. MATERIAL AND METHODS: Multi-centre retrospective cohort study. Centres were recruited by the Association for Veterinary Soft Tissue Surgery Research Cooperative. Medical records of 11 centres were reviewed, and data from all dogs and cats treated with a caudal auricular axial pattern flap were retrieved. The following data were recorded: signalment, reason for reconstruction, flap dimensions, anatomic landmarks used, histological diagnosis, flap healing and whether revision surgery was required. RESULTS: Twenty-eight cases were included: 16 dogs and 12 cats. Flap length: width ratio was approximately 3:1 and flap length extended to the scapular spine in most cases. Optimal wound healing occurred in five of 16 (31%) dogs and six of 12 (50%) cats. Wound dehiscence without flap necrosis occurred in one of 16 (6%) dogs and one of 12 (8%) cats. Wound dehiscence with flap necrosis occurred in 10 of 16 (63%) dogs and five of 12 (42%) cats. Revision surgery was performed in eight of 16 (50%) dogs and three of 12 (25%) cats. CLINICAL SIGNIFICANCE: The caudal auricular axial pattern flap can provide full thickness skin coverage for large defects on the head in dogs and cats. Partial flap necrosis is a common complication, and revision surgery may be required in order to achieve final wound closure. PMID- 30474222 TI - Emerging infectious uveitis: Chikungunya, Dengue, Zika, Ebola. AB - Recently recognised forms of uveitis include intraocular inflammations that occur during or following one of several emerging infectious diseases: chikungunya fever, dengue, Zika virus disease and Ebola virus disease. Anterior, intermediate, posterior and pan- uveitis have been described in individuals infected with chikungunya virus. Persons who contract dengue or Zika viruses also may develop different types of uveitis in the course of the infection: maculopathy is a common manifestation of dengue eye disease, and Zika eye disease may cause hypertensive anterior uveitis or mimic a white dot syndrome. Up to one third of Ebola survivors develop aggressive uveitis, which is frequently associated with vision loss and complicated by cataract. There are no specific anti-viral drugs for these forms of uveitis, and thus treatment is largely supportive. In this article, we summarise the systemic infectious diseases and virology, and describe the clinical presentations, outcomes and management of emerging viral forms of uveitis. PMID- 30474221 TI - High expression of CCR5 in melanoma enhances epithelial-to-mesenchymal transition and metastasis via TGFbeta1. AB - Chemokine receptors are highly expressed in various cancers and play crucial roles in tumor progression. However, their expression patterns and functions in melanoma are unclear. The present study aimed to identify the chemokine receptors that play critical roles in melanoma progression and unravel the underlying molecular mechanisms. We found that the C-C chemokine receptor 5 (CCR5) was more abundant in melanoma cells than normal cells and was positively associated with tumor malignancy in clinical patients. Animal experiments suggested that CCR5 deficiency in B16/F10 or A375 cells suppressed primary tumor growth and lung metastasis, while CCR5overexpression in B16/F0 cells enhanced primary tumor growth and lung metastasis. CCR5 played a critical role in proliferation and migration of melanoma cells in vitro. Importantly, CCR5 was required for maintenance of the mesenchymal phenotype of metastatic melanoma cells. Mechanistically, CCR5 positively regulated expression of Transforming Growth Factor beta1 (TGFbeta1), which in turn induced epithelial-mesenchymal transition (EMT) and migration via PI3K/AKT/GSK3beta signaling. Collectively, our results establish a critical role of CCR5 expressed by melanoma cells in cancer progression and reveal the novel mechanisms controlling this process, which suggests the prognostic value of CCR5 in melanoma patients and provides novel insights into CCR5-targeted strategies for melanoma treatment. PMID- 30474223 TI - Associations between testosterone and metabolic syndrome in depressed and non depressed older men and women. AB - OBJECTIVES: Older age and Major depressive disorder (MDD) are both risk factors for the development of cardiovascular diseases. Testosterone has been associated with MDD and Metabolic Syndrome (MetS) in men, though associations in women are less clear. Therefore, we investigated whether testosterone is associated with MetS and whether this association is different for depressed and non-depressed older men and women. METHODS: In this prospective cohort study, 478 participants (349 patients with MDD and 129 controls) aged between 60 and 93 years from the Netherlands Study of Depression in Older Persons (NESDO) were included. Total testosterone (TT) and sex-hormone binding globulin (SHBG) levels were measured using a second generation radioimmune assay. Free testosterone (FT) was calculated based on TT. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS: A higher risk for MetS was found in men with low FT and TT (Odds Ratio [OR]: 0.67, 95% confidence interval [95%CI]: 0.47-0.95 and OR: 0.51, 95%CI: 0.34-0.75), and in women with high FT (OR: 1.41, 95%CI: 1.08-1.82). Strong associations in the same direction were found with adiposity, glucose and plasma lipid MetS components at baseline, but not with changes in these components at two-year follow-up. The associations did not significantly differ between MDD patients and controls. CONCLUSIONS: Independently of having MDD, low testosterone levels in men, and in contrast, high testosterone levels in women were significantly associated with MetS and its components. PMID- 30474224 TI - Rational Design of IR820- and Ce6-Based Versatile Micelle for Single NIR Laser Induced Imaging and Dual-Modal Phototherapy. AB - Phototherapy as a promising cancer diagnostic and therapeutic strategy has aroused extensive attention. However, single-wavelength near-infrared (NIR) light triggered combinational treatment of photothermal therapy (PTT) and photodynamic therapy (PDT) is still a great challenge. Herein, a multifunctional micelle activated by a single-wavelength laser for simultaneous PTT and PDT as well as fluorescence imaging is developed. Briefly, new indocyanine green (IR820) is conjugated to d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) via the linker 6-aminocaproic acid, and then, chlorin e6 (Ce6) is encapsulated into the micelles formed by TPGS-IR820 conjugates to fabricate TPGS-IR820/Ce6 micelles. As the well-designed TPGS-IR820 conjugate shares a similar peak absorption wavelength with Ce6, this micelle can be applied with a single NIR laser (660 nm). The stable micelles exhibit excellent photothermal conversion efficiency in vitro and in vivo as well as high singlet oxygen generation capacity in tumor cells. After efficient cellular internalization, the as prepared micelles display outstanding anticancer activity upon single NIR laser irradiation in vitro and in vivo. Furthermore, TPGS-IR820/Ce6 micelles show negligible systemic toxicity. The highly safe and effective TPGS-IR820/Ce6 micelles can offer an innovative strategy to construct single NIR light-induced PTT and PDT combined phototherapy nanoplatforms via suitable modification of organic phototherapeutic agents. PMID- 30474225 TI - Mortality after emergency abdominal surgery in a non-metropolitan Australian centre. AB - OBJECTIVE: Emergency abdominal surgery has poorer outcomes and higher mortality rates, compared with elective surgery. Serious morbidity or mortality occurs in up to 40% of patients. No information is available with regard to the outcome of patients undergoing emergency abdominal surgery in rural Australia. METHODS: Patients undergoing emergency abdominal surgery in a 110-bed rural surgical centre in South Australia over a 5 year period (January 2010-December 2014) were included in the study. Patient data were retrieved using the hospital database and review of patient records. RESULTS: A total of 4396 general surgical emergency admissions was recorded. Emergency admissions without intervention, endoscopic intervention only, appendectomy, cholecystectomy or urological or gynaecological diagnoses were excluded from mortality analysis. The remaining 237 patients underwent major abdominal emergency surgery for bowel obstruction (benign and malignant: n = 143, 60%), injury/inflammation/perforation/peritonitis (n = 85, 36%) or haemorrhage/ischaemia (n = 9, 3.8%). Thirty- (n = 9) and 90- (n = 12) day mortality rates were 3.8% and 5.1%, respectively. CONCLUSION: Emergency abdominal surgery can be safely provided in non-metropolitan Australian centres, with a low 30-day mortality rate of 3.8% and a 90-day mortality rate of 5.1%. This compares well with results published by other national and international investigators. PMID- 30474226 TI - Confidence regions for treatment effects in subgroups in biomarker stratified designs. AB - Subgroup analysis has important applications in the analysis of controlled clinical trials. Sometimes the result of the overall group fails to demonstrate that the new treatment is better than the control therapy, but for a subgroup of patients, the treatment benefit may exist; or sometimes, the new treatment is better for the overall group but not for a subgroup. Hence we are interested in constructing a simultaneous confidence interval for the difference of the treatment effects in a subgroup and the overall group. Subgroups are usually formed on the basis of a predictive biomarker such as age, sex, or some genetic marker. While, for example, age can be detected precisely, it is often only possible to detect the biomarker status with a certain probability. Because patients detected with a positive or negative biomarker may not be truly biomarker positive or negative, responses in the subgroups depend on the treatment therapy as well as on the sensitivity and specificity of the assay used in detecting the biomarkers. In this work, we show how (approximate) simultaneous confidence intervals and confidence ellipsoid for the treatment effects in subgroups can be found for biomarker stratified clinical trials using a normal framework with normally distributed or binary data. We show that these intervals maintain the nominal confidence level via simulations. PMID- 30474227 TI - In Vivo Tumor Photoacoustic Imaging and Photothermal Therapy Based on Supra (Carbon Nanodots). AB - Carbon nanodots (CNDs) with high photothermal conversion efficiency are considered as emerging nanomaterials for advanced biomedical applications attributing to their high biocompatibility, low-cost, and unique photophysical properties. In previous work, supra-CNDs are synthesized exhibiting high absorption in the near-infrared (NIR) region and good NIR photothermal conversion performance. In this work, supra-CNDs are explored as a photothermal agent for photothermal therapy (PTT) and a contrast agent for photoacoustic (PA) imaging, respectively. As a result, in vivo tumor PTT is realized under 655 nm laser irradiation via intratumor injecting supra-CNDs. In vivo PA imaging reveals that supra-CNDs can accumulate in the tumor tissue via the blood circulation after intravenous injection. Moreover, in vivo PTT is conducted after intravenous injection and subsequent tumor accumulation of supra-CNDs, and the lives of mice are prolonged due to the tumor growth inhibition after PTT. These attractive properties indicate that the supra-CNDs can be used as biomedical agents for PA imaging and tumor therapy. PMID- 30474228 TI - Oxygen-Assisted Cathodic Deposition of Zeolitic Imidazolate Frameworks with Controlled Thickness. AB - Processing metal-organic frameworks (MOFs) as films with controllable thickness on a substrate is increasingly crucial for many applications to realize function integration and performance optimization. Here, we report a facile cathodic deposition process that enables the large-area preparation of uniform films of zeolitic imidazolate frameworks (ZIF-8, ZIF-71, and ZIF-67) with highly tunable thickness ranging from ~24 nm to hundreds of nanometers. Importantly, this oxygen reduction-triggered cathodic deposition does not lead to the plating of reduced metals (Zn and Co). It is also operable cost-effectively in the absence of supporting electrolyte and facilitates greatly the construction of well-defined submicrometer-sized heterogeneous structures within ZIF films. PMID- 30474229 TI - The association between maternal methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphism and birth defects and adverse pregnancy outcomes. AB - Published studies indicate the MTHFR C677T and A1298C polymorphisms are associated with abnormal homocysteine levels, which may cause various pregnancy complications and birth defects. However, the results obtained from different studies have been inconsistent. Therefore, this meta-analysis explores the association between MTHFR polymorphisms and birth defects and adverse pregnancy outcomes. The Pubmed, ScienceDirect, Embase, China Biology Medicine literature databases and ClinicalTrials were searched. Analyses of public bias, meta regression, subgroups, and sensitivity were used to ensure the robustness of our results. MTHFR C677T was significantly associated with recurrent pregnancy loss in developing countries (OR: 1.34, 95% CI: 1.20~1.50), but not developed countries (OR: 0.87, 95% CI: 0.68~1.11). No significant relationship was found between MTHFR A1298C and recurrent pregnancy loss (OR: 1.04, 95% CI: 0.93~1.18). MTHFR C677T and A1298C were not associated with pre-eclampsia (OR: 1.06 95% CI: 0.97~1.16 and OR: 1.16, 95% CI: 0.97~1.39 respectively), and C677T was not associated with placental abruption (OR: 1.03, 95% CI: 0.87~1.21), intrauterine growth retardation (OR: 1.02, 95% CI: 0.90~1.15) or congenital heart disease (OR: 1.05, 95% CI: 0.89~1.25). MTHFR C677T, but not A1298C, was associated with neural tube defects (OR: 1.24, 95% CI: 1.08~1.42) and Down Syndrome (OR: 1.65, 95% CI: 1.39~1.95). PMID- 30474230 TI - The shifting relationship between weight and pediatric obstructive sleep apnea: A historical review. AB - OBJECTIVES: For more than a century, pediatric obstructive sleep apnea (OSA) was associated with failure to thrive. However, that association has faded over the last few decades. A 21st century child with OSA is much more likely to be overweight than underweight. This raises the question: Has pediatric OSA changed over time, or has the rise of childhood obesity in the United States created a new, separate disease? This literature review explores the historical shift in the relationship between weight and OSA, and the associated changes in treatment. RESULTS: We demonstrate a clear transition in the prevalence of failure to thrive and obesity in the OSA literature in the mid-2000s. What is less clear is whether these two clinical phenotypes should be considered two distinct diseases, or whether subtle differences in one set of pathophysiologic pathways-adenotonsillar hypertrophy, altered inflammation, and increased energy expenditure-can lead to divergent metabolic outcomes. More research is needed to fully elucidate the pathophysiology of OSA in children with obesity. CONCLUSIONS: We may need new and different treatments for obesity-associated OSA as adenotonsillectomy-which is effective at reversing failure to thrive in OSA-is not as effective at treating OSA in children with obesity. One option is drug-induced sleep endoscopy, which could personalize and improve surgical treatment of OSA. There is some evidence that therapies used for OSA in adults (e.g., weight loss and positive airway pressure) are also helpful for overweight/obese children with OSA. Laryngoscope, 2018. PMID- 30474231 TI - New Aggregation-Induced Delayed Fluorescence Luminogens for Efficient Organic Light-Emitting Diodes. AB - Aggregation-induced delayed fluorescence (AIDF) can be regarded as a special case of aggregation-induced emission (AIE). Luminogens with AIDF can simultaneously emit strongly in solid state and fully utilize the singlet and triplet excitons in organic light-emitting diodes (OLEDs). In this work, two new AIDF luminogens, DMF-BP-DMAC and DPF-BP-DMAC, with an asymmetric D-A-D' structure, are designed and synthesized. The characteristics of both luminogens are systematically investigated, including single crystal structures, theoretical calculations, photophysical properties and thermal stabilities. Inspired by their AIDF nature, the green-emission non-doped OLEDs based on them are fabricated, which afford good electroluminescence performances, with low turn-on voltages of 2.8 V, high luminance of 52560 cd m-2, high efficiencies of up to 14.4%, 42.3 cd A-1 and 30.2 lm W-1, and very small efficiency roll-off. The results strongly indicate the bright future of non-doped OLEDs on the basis of robust AIDF luminogens. PMID- 30474232 TI - Longitudinal Reciprocal Associations Between Anxiety, Depression, and Alcohol Use in Adolescent Girls. AB - BACKGROUND: Depression, anxiety, and alcohol misuse predict adverse social, academic, and emotional outcomes, and their relations to one another increase during adolescence-particularly in girls. However, evidence on the directions of these relations is mixed. Longitudinal models of internalizing problem-alcohol use links may identify promising prevention targets. Accordingly, we examined reciprocal associations between anxiety severity and alcohol use, as well as between depression severity and alcohol use, in adolescent girls. METHODS: Data were drawn from a population-based longitudinal study of female adolescents. The current sample comprised 2,100 participants (57.1% Black, 42.9% White) assessed annually between ages 13 and 17. Girls self-reported depression severity, anxiety severity, and frequency of alcohol use (consumption of >=1 full drink) in the past year. Primary caregivers reported on socioeconomic and neighborhood factors; these were included with race, early puberty, and conduct problems (youth-report) as covariates. Anxiety and depression severity were included within a single cross-lagged panel model, along with alcohol use, to isolate their independent and reciprocal links to drinking behavior. RESULTS: Higher depression severity modestly predicted increased likelihood of subsequent alcohol use from ages 13 to 17. However, inconsistent relations emerged for the reverse pathway: Alcohol use modestly predicted decreased depression severity at ages 14 and 16; associations were nonsignificant in other lagged associations. Anxiety severity and alcohol use were not consistently associated. CONCLUSIONS: Results highlight the key role of depression, relative to anxiety, in predicting later alcohol use. Future studies may examine whether depression prevention programs yield secondary reductions in alcohol use in adolescent girls. PMID- 30474233 TI - Allergen-specific IgE in nonatopic dogs. PMID- 30474234 TI - Inclination of the condylar long axis is not related to temporomandibular disc displacement. AB - AIM: The aim of the present study was to correlate the angle formed by inclination of the condylar long axis and median sagittal plane to the presence of internal disc derangement, as well as changes in eccentric mandibular positions. METHODS: The sample consisted of magnetic resonance images of 35 temporomandibular joint (TMJ) acquired with a 1.5T magnetic resonance imaging system with surface coils of 8.5 cm in diameter. Parasagittal images were used according to the following parameters: TMJ disc position with mouth closed, TMJ disc position with mouth open, TMJ disc function, and degrees of rotation and translation of the condyle. Next, we determined the angles between the condyle long axis and median sagittal plane by using axial images. RESULTS: The results showed correlations between TMJ disc position and disc function (P = 0.009), as well as between disc position and degree of condylar rotation (P = 0.008). The main purpose of the present study was to assess the angle of the condylar long axis, with no statistical correlation being found between this variable and disc position (P = 0.787), disc function (P = 0.091), condylar translation (P = 0.808), and condylar rotation (P = 0.115). CONCLUSION: There was no relationship between inclination of the condyle long axis and parameters of internal derangements. PMID- 30474235 TI - A forced-choice preferential looking task for the assessment of vision in dogs: pilot study. AB - OBJECTIVES: To describe preliminary use of a forced-choice preferential looking task for the clinical assessment of vision in dogs. MATERIALS AND METHODS: The vision of 18 pet dogs was investigated in two separate studies using a forced choice preferential looking task: multiple observers watched eye, head and body movements on video recordings to identify cues suggesting when a dog had seen the feature of interest. Human observer reliability was determined using eight dogs and computer-generated stimuli. Visual acuity was assessed using computer generated grating stimuli: in real-time, an observer watched each dog's eye movement patterns and behaviour to decide whether each grating was seen. Stimuli were presented in a step-wise manner and were controlled by the observer. Acuity was estimated as the highest spatial frequency the dog was determined to have seen. RESULTS: Median estimated visual acuity was better at 1 m compared to that at 3 m. Average test time was longer at a 3-m distance than at 1 m. Inter- and intra-observer reliability was better from 1 m than from 3 m. CLINICAL SIGNIFICANCE: Preliminary use of a forced-choice preferential looking task for measurement of visual acuity in dogs has potential use as a clinical tool for the assessment of vision in dogs. PMID- 30474236 TI - Pharmacokinetics and bioavailability of danofloxacin in chukar partridge (Alectoris chukar) following intravenous, intramuscular, subcutaneous, and oral administrations. AB - The aim of the present study was to determine the pharmacokinetics (PKs) and bioavailability of danofloxacin in chukar partridge (Alectoris chukar) following intravenous (IV), intramuscular (IM), subcutaneous (SC), and oral (PO) administrations at a dose of 10 mg/kg. A total of eight clinically healthy chukar partridges weighing 480 +/- 45 g were used for the investigation. The study was performed in a crossover design (2 * 2 * 2 * 2) with a 15-day washout period between two administrations in four periods. The plasma concentrations of danofloxacin were determined using reversed-phase high-performance liquid chromatography. Noncompartmental PK parameters were also estimated. No local or systemic adverse drug effects were observed in any of the chukar partridges. The mean elimination half-life ranged between 8.18 and 12.08 hr and differed statistically among administration routes. The mean peak plasma concentrations of danofloxacin following IM, SC, and PO administrations were 8.05, 9.58, and 3.39 MUg/ml at 0.5, 1, and 4 hr, respectively. Following IM, SC, and PO administrations, the mean bioavailability was 86.33%, 134.40%, and 47.62%, respectively. The mean total clearance and volume of distribution at steady-state following IV administration were 0.13 L hr-1 kg-1 and 0.96 L/kg, respectively. These data, including favorable PKs and the absence of adverse drug effects, suggest that danofloxacin is a useful antibiotic in chukar partridges. PMID- 30474237 TI - Superior Compatibility of C2 N with Human Red Blood Cell Membranes and the Underlying Mechanism. AB - The widespread use of nanomaterials, such as carbon based 2D nanomaterials, in biomedical applications, has been accompanied by a growing concern on their biocompatibility, and in particular, on how they may affect the integrity of cell membranes. Herein, the interactions between C2 N, a novel 2D nanomaterial, and human red blood cell membranes are explored using a combined experimental and theoretical approach. The experimental microscopies show that C2 N exerts a negligible hemolysis effect on the blood cells with a superior compatibility to their cell membranes, when compared with the control system, reduced graphene oxide (rGO), which is found to be highly hemolytic. The molecular dynamics simulations further reveal the underlying molecular mechanisms, which indicate that C2 N prefers to be adsorbed flat on the water-membrane interface. Interaction energy analyses demonstrate the crucial role of Coulombic contributions, originating from the unique electrostatic potential surface of C2 N, in preventing C2 N from penetrating into cell membranes. These findings indicate a high compatibility of C2 N with cell membranes, which may provide useful foundation for the future exploration of this 2D nanomaterial in related biomedical applications. PMID- 30474238 TI - Chronic idiopathic axonal polyneuropathy: Prevalence of pain and impact on quality of life. AB - BACKGROUND AND AIM: Chronic idiopathic axonal polyneuropathy (CIAP) is a term describing axonal neuropathies of insidious onset, with slow or no progression of the disease over at least 6 months and with no etiology being identified despite appropriate investigations. We aimed to establish the prevalence of pain in patients with CIAP and investigate the impact of pain on quality of life (QoL). METHODS: All consecutive patients with CIAP attending a specialist neuropathy clinic were invited to participate. Pain was assessed via the DN4 questionnaire and the visual analogue scale (VAS). Overall Neuropathy Limitations Scale (ONLS) was used to assess the severity of neuropathy. The SF-36 questionnaire was used to measure participants' quality of life. RESULTS: Fifty-five patients with CIAP were recruited (63.6% male, mean age 73.4 +/- 8.7 years). Based on the DN4 questionnaire, peripheral neuropathic pain was present in 33 patients (60.0%). After having adjusted for age, gender and disease severity pain showed significant negative correlations with the energy/fatigue domain of QoL (beta = 0.259, p = 0.049), with the emotional well-being domain (beta = -0.368, p = 0.007) and the general health perception domain (beta = -0.356, p = 0.007). CONCLUSION: Pain is very prevalent in CIAP and is associated with poorer emotional well-being, worse general health perception, and increased fatigue. PMID- 30474240 TI - Adjusting for selection bias in assessing treatment effect estimates from multiple subgroups. AB - This paper discusses a number of methods for adjusting treatment effect estimates in clinical trials where differential effects in several subpopulations are suspected. In such situations, the estimates from the most extreme subpopulation are often overinterpreted. The paper focusses on the construction of simultaneous confidence intervals intended to provide a more realistic assessment regarding the uncertainty around these extreme results. The methods from simultaneous inference are compared with shrinkage estimates arising from Bayesian hierarchical models by discussing salient features of both approaches in a typical application. PMID- 30474239 TI - Justice at any cost? The impact of cost-benefit salience on criminal punishment judgments. AB - This study investigated the effect of cost-benefit salience on simulated criminal punishment judgments. In two vignette-based survey experiments, we sought to identify how the salience of decision costs influences laypeople's punishment judgments. In both experiments (N1 = 109; N2 = 398), undergraduate participants made sentencing judgments with and without explicit information about the direct, material costs of incarceration. Using a within-subjects design, Experiment 1 revealed that increasing the salience of incarceration costs mitigated punishments. However, when costs were not made salient, punishments were no lower than those made when the costs were externalized (i.e., paid by a third party). Experiment 2 showed the same pattern using a between-subjects design. We conclude that, when laypeople formulate sentencing attitudes without exposure to the costs of the punishment, they are prone to discount those costs, behaving as if punishment is societally cost-free. However, when cost information is salient, they utilize it, suggesting the operation of a genuine, albeit labile, punishment preference. We discuss the implications of these findings for psychological theories of decision making and for sentencing policy, including the degree of transparency about the relevant costs of incarceration during the decision process. PMID- 30474241 TI - Hypoxia in sickle cell disease due to right to left shunting. PMID- 30474242 TI - Clinical and neuroimaging risk factors for cognitive decline in community dwelling older adults living in rural Ecuador. A population-based prospective cohort study. AB - OBJECTIVE: There is limited information on factors influencing cognitive decline in rural settings from low and middle income countries. Using the Atahualpa Project cohort, we aimed to assess the burden of cognitive decline in older adults living in a rural Ecuadorian village. METHODS: The study included Atahualpa residents aged >=60 years who had a follow-up Montreal Cognitive Assessment (MoCA) repeated at least one year after baseline. MoCA decline was assessed by multivariable longitudinal linear models, adjusted for demographics, days between MoCA tests, cardiovascular risk factors and neuroimaging signatures of structural brain damage. RESULTS: We included 252 individuals who contributed 923.7 person-years of follow-up (mean: 3.7+/-0.7 years). The mean baseline MoCA was 19.5+/-4.5 points and the follow-up MoCA was 18.1+/-4.9 points (p=0.001). Overall, 154 individuals (61%) had lower MoCA scores at follow-up. The best fitted longitudinal linear model showed a decline of follow-up MoCA from baseline (beta: 0.14; 95% C.I.: 0.07 - 0.21; p<0.001). High glucose levels, global cortical atrophy and white matter hyperintensities were independently and significantly associated with greater MoCA decline. CONCLUSION: This study provides evidence of cognitive decline in older adults living in a rural setting. Main targets for prevention should include glucose control, and the control of factors that are deleterious for the development of cortical atrophy and white matter hyperintensities. PMID- 30474243 TI - Use of TiBrush for surface decontamination at peri-implantitis sites in dogs: Radiographic and histological outcomes. AB - AIM: The aim of the present study was to evaluate the efficacy on the healing of mechanical decontamination of infected implant surfaces performed with a titanium brush. METHODS: Mandibular premolars and first molars were extracted bilaterally in six dogs. After 3 months, two unsubmerged implants were installed on both sides of the mandible. Three months later, peri-implantitis was induced with ligatures for 3 months and then removed. After 1 month, surgical mechanical decontamination of the surfaces was performed either with a rotatory titanium brush or gauzes soaked in saline. Five month later, biopsies were retrieved. Evaluations on X-rays taken of the mesiodistal plane and on histological slides prepared in a buccal-lingual plane were performed. RESULTS: After the induction of peri-implantitis, a mean marginal bone loss of 2.6 +/- 0.6 mm and 1.9 +/- 1.0 mm was observed in the brush and gauze groups by X-ray, respectively. Five months after treatment, a mean gain of marginal bone of 0.6 mm was obtained in both groups. The mean closures of the vertical and horizontal defects were 0.6 mm and 0.6 mm for the brush group, and 0.8 mm and 0.5 mm for the gauze group, respectively. Histologically, a loss of attachment at the buccal aspect of 2.2 +/ 0.9 mm in the brush group and of 2.3 +/- 0.5 mm in the gauze group was found. No statistically-significant differences were found after the treatment. CONCLUSIONS: Mechanical implant surface decontamination performed with a rotatory titanium brush resulted in a marginal bone level gain, yielding a low content of inflammatory infiltrate close to the marginal bone. PMID- 30474244 TI - Apathy and right caudate perfusion in idiopathic normal pressure hydrocephalus: a case-control study. AB - OBJECTIVES: Apathy is prevalent in patients with idiopathic normal pressure hydrocephalus (iNPH), a treatable disorder resulting from ventricular enlargement. We assessed the relationship between apathy and regional cerebral blood flow (rCBF) in patients with iNPH. METHODS: Before lumbo-peritoneal shunt surgery (LPS), 56 iNPH patients were evaluated on apathy and dysphoria subscales of the Neuropsychiatric Inventory (NPI), and were divided into 2 groups according to NPI apathy score: 15 without apathy (iNPH-APA) and 41 with apathy (iNPH+APA). Among iNPH+APA, 29 patients were evaluated for apathy and dysphoria 3 months after LPS, and were divided into 2 groups based on the change in NPI apathy score: 13 with improvement (iNPH+ImpAPA) and 16 without improvement in apathy (iNPH-ImpAPA). N-isopropyl-p-iodoamphetamine single photon emission computed tomography using the autoradiography method was performed before and after LPS, and rCBF was calculated in 22 regions of interest in the frontal cortex, basal ganglia, and limbic system. RESULTS: In iNPH+APA, rCBF in the right caudate nuclei before LPS was significantly lower than that in iNPH-APA (p = 0.004; two sample t-test). Between iNPH-ImpAPA and iNPH+ImpAPA, a significant group-by-shunt interaction was observed for rCBF in only the right caudate nuclei (F1, 28 = 11.75, p = 0.002; two-way repeated-measures analysis of variance), with increased rCBF in iNPH+ImpAPA but not in iNPH-ImpAPA. The significant group-by-shunt interaction persisted if change in NPI dysphoria scores was used as a covariate (F1, 27 = 8.33, p = 0.008). CONCLUSIONS: Our findings suggest that right caudate dysfunction might cause apathy in iNPH patients. PMID- 30474245 TI - Prevalence of CD20+ cutaneous epitheliotropic T-cell lymphoma in dogs: a retrospective analysis of 24 cases (2011-2018) in the USA. AB - BACKGROUND: Limited information is known about the baseline frequency of canine CD20 positive (+ ) cutaneous epitheliotropic T-cell lymphoma. A single canine case report has been published. OBJECTIVES: To characterize the baseline frequency of CD20+ staining in cases of canine cutaneous epitheliotropic T-cell lymphoma; to assess its values as a prognostic indicator. ANIMALS: Skin biopsies from 24 client-owned animals diagnosed with cutaneous epitheliotropic lymphoma were assessed. METHODS AND MATERIALS: A retrospective review of medical records from 2011 to 2018. Clinical histories and previous histological and immunohistochemical slides were collected from 24 dogs and additional immunohistochemical staining was performed as needed to assess cases of cutaneous epitheliotropic T-cell lymphoma for CD3, CD20, CD79a and PAX5 staining characteristics. Staining characteristics were assessed for their statistical relationship to median survival time. RESULTS: Overall median survival time was 189 days following the onset of clinical signs and 99 days following definitive diagnosis; 54% of cases had CD20+ staining. There was no statistically significant correlation between staining characteristics and median survival time from onset of signs (P = 0.54) or from diagnosis (P = 0.61). CONCLUSIONS AND CLINICAL SIGNIFICANCE: Canine cutaneous epitheliotropic lymphoma has a higher instance of CD20 positivity than documented previously. This indicates that CD20 staining may be unsuitable to differentiate T-cell and B-cell cutaneous epitheliotropic lymphoma. This also may have therapeutic implications with the advent of canine CD20 monoclonal antibody therapies. PMID- 30474246 TI - Vitamin D receptor ApaI, TaqI, BsmI, and FokI polymorphisms and psoriasis susceptibility: an updated meta-analysis. AB - BACKGROUND: Vitamin D is considered a regulator of the immune system, and its polymorphisms have been associated with psoriasis in some but not all reports. AIM: To explore whether vitamin D receptor (VDR) polymorphisms are associated with susceptibility to psoriasis. METHODS: Meta-analyses were conducted to determine the associations between psoriasis and the VDR ApaI, TaqI, BsmI and FokI polymorphisms in all participants, and stratified by ethnic group. RESULTS: In total, 16 studies on VDR polymorphisms and psoriasis were included in this meta-analysis, which involved 2086 patients and 2182 controls. The meta-analysis indicated an association between psoriasis and the VDR TaqI TT genotype in Caucasian (OR = 1.29, 95% CI = 1.00-1.66, P < 0.05), but not in Asian (OR = 1.32, 95% CI = 0.89-1.96, P = 0.16) populations. However, no association was found between psoriasis and the VDR TaqI polymorphism using dominant, allele contrast or homozygous contrast models. No association was found between psoriasis and either the VDR ApaI, BsmI or FokI polymorphisms by meta-analyses of the allele contrast, recessive, or dominant models or homozygous contrast models in the overall, Caucasian or Asian populations. CONCLUSION: This meta-analysis showed that polymorphisms in VDR ApaI, BsmI and FokI are not associated with psoriasis susceptibility in overall, Caucasian or Asian populations. However, the VDR TaqI polymorphism is associated with psoriasis susceptibility in Caucasian populations. PMID- 30474247 TI - Retest effects in medical selection interviews. AB - CONTEXT: Repetition of a cognitive ability test is known to increase scores, but almost no research has examined whether similar improvement occurs with repetition of interviews. Retest effects can change the rank order of candidates and reduce the test's criterion validity. Because interviews are widely used to select medical students and postgraduate trainees, and because applicants apply to multiple programmes and often reapply if unsuccessful, the potential for retest effects needs to be understood. OBJECTIVES: This study was designed to identify if retest improvements occur when candidates undertake multiple interviews and, if so, whether the effect is attributable to general interview experience or specific experience and whether repeat testing affects criterion validity. METHODS: We compared interview scores of applicants who were interviewed for one or more of three independent undergraduate medical programmes in two consecutive years and those who were interviewed in both years for the same programme. Correlations between initial and repeat interview scores and a written test of social understanding were compared. RESULTS: General experience (being interviewed by multiple programmes) did not produce improvement in subsequent interview performance. There was no evidence of method effect (having prior experience of the multiple mini-interview process). Specific experience (being interviewed by the same programme across 2 years) resulted in a significant improvement in scores for which regression to the mean did not fully account. Criterion validity did not appear to be affected. CONCLUSIONS: Unsuccessful candidates for medical school who reapply and are re-interviewed on a subsequent occasion at the same institution are likely to increase their scores. The results of this study suggest the increase is probably not attributable to improved ability. PMID- 30474249 TI - 'No one is as invested in your continued good health as you should be:' an exploration of the post-surgical relationships between weight-loss surgery patients and their home bariatric clinics. AB - This article traces the post-surgical relationship between weight-loss surgery (WLS) patients and their home bariatric clinics. Following surgery, there is substantive drop off in patient attendance at both follow-up appointments and support groups. While barriers to follow-up are often discussed with the bariatric literature, patients themselves are typically defined as the problem. Based upon a thematic analysis of 217 blog posts and comments in two top patient led online forums, I demonstrate that bariatric patients tell a more complex story about their post-surgical lives. I argue that WLS patients constitute a population with highly specialised medical needs that is caught between the requirements for living with surgically altered digestive systems and a lack of sufficient post-operative follow-up care from their home bariatric clinics. Although online forums provide spaces for patients to examine these post operative social and clinical experiences in critical terms, seek information and get support, ultimately the conversations serve to underline the value of personal responsibility for post-operative outcomes-a framing that echoes that of the bariatric profession. This framing should be understood within a larger climate of weight-based stigma and discrimination as well as neoliberal healthism. PMID- 30474248 TI - TRANSCRIPTOME AND CYTOGENETIC PROFILING ANALYSIS OF MATCHED IN SITU/INVASIVE CUTANEOUS SQUAMOUS CELL CARCINOMAS FROM IMMUNOCOMPETENT PATIENTS. AB - Although most cutaneous squamous cell carcinomas (cSCCs) develop from actinic keratoses (AK), the key events in this evolution remain unclear. We have combined the results of different genomic and expression array platforms on matched concomitant samples of sun-exposed skin (SES), AK and cSCC from ten immunocompetent patients. Gene expression analysis and copy number alterations were assessed using GeneChip Human Gene 2.0 ST Array(r) (Affymetrix) and CytoScan HD Cytogenetics Solution(r) (Affymetrix) platforms, respectively. Integration of transcriptome and genome results was evaluated using the DR-Integrator tool. Additional studies (qPCR, immunohistochemistry and Western blot) were performed for selected genes. FOSL1 and BNC1 encode transcription factors whose expression was increased in cSCC in the expression array and the qPCR. By immunohistochemistry, FOSL1 showed an intense staining at the invasive front of cSCC samples and BNC1 expression varied from a nuclear (SES) to a cytoplasmic location (cSCC). Western blot analyses confirmed the enhancement of FOSL1 and BNC1. Additionally, the smallest overlapping regions of genomic imbalance (SORIs) involving at least 3 of the samples were selected. One of the SORIs was a deletion in the p24.1 band of chromosome 3, shared by 7 of the cSCCs. A strong correlation in the integration analysis was found for NEK10, a gene contained in the previously mentioned SORI. Loss of NEK10 expression in cSCC was confirmed by immunohistochemistry and Western blot analyses. In addition, functional studies in NEK10 depleted cells were performed. In conclusion, we identified FOSL1 and BNC1, which could act as tumor drivers, and NEK10, which could function as a tumor suppressor, to be differentially expressed during cSCC development. This article is protected by copyright. All rights reserved. PMID- 30474251 TI - Social media and psoriasis treatment: What are people saying on Twitter? AB - Almost half of households use the internet for seeking health related information. Because there is no regulation over the accuracy of this information, disease myths and unconventional remedies may be perpetuated. There are few studies that have used social media as a tool to assess people's perception of psoriasis or its treatment. Our aim was to evaluate commonly discussed psoriasis treatments on the social media site Twitter. This article is protected by copyright. All rights reserved. PMID- 30474250 TI - Therapeutic options in male genital tract inflammation. AB - Chronic inflammatory conditions of the genital tract are still unsatisfactorily recognised in the workup of male infertility due to inappropriate definitions and inconsistent diagnostic criteria. The most popular term used for description of both, infections and inflammation in the genital tract is MAGI (male accessory gland infection). In asymptomatic patients, the diagnosis is primarily based on leucocytospermia (i.e., more than 1 million peroxidase-positive leucocytes per ml ejaculate), although ongoing infections should be identified and distinguished from post-infectious or non-infectious inflammatory disease. In addition to alterations of the basic semen parameters, sperm functions -and DNA integrity may be affected by chronic inflammation of the male genital tract. Despite considerable diagnostic drawbacks and a rather limited database concerning evidence-based therapy, adequate management of affected patients appears mandatory. Antibiotic treatment aims at the eradication or reduction of pathogenic bacteria in the ejaculate. Available studies suggest, that NSAID are effective in chronic inflammatory conditions. Moreover, low-dose corticosteroids, mast cell blockers, and other immune-modulatory compounds as well as a sequential adjuvant treatment with antioxidants can be considered as therapeutic options. PMID- 30474252 TI - Gradient variability in hypertrophic cardiomyopathy: New insights from computer assisted, high fidelity, rest and exercise hemodynamic analysis. AB - OBJECTIVES: This study examines the intrapatient variability in peak instantaneous left ventricular outflow tract (LVOT) gradients and aortic pulse pressures during rest, exercise, and after ventricular ectopy. BACKGROUND: Although the variability in LVOT gradients in patients with hypertrophic cardiomyopathy (HCM) is well known, the predictors of such variation are not. We hypothesized that quantitative invasive analysis of gradient variation could identify useful predictors of maximal gradients. METHODS: Variability in continuously recorded, high-fidelity left ventricular and aortic pressure waveforms were evaluated by computer-assisted analysis in the resting state (N = 659 beats) and during supine exercise (N = 379 beats) in a symptomatic patient with a resting LVOT gradient >30 mmHg and frequent ventricular ectopy. RESULTS: At rest, the peak left ventricular and aortic pressures at the time of the peak instantaneous LVOT gradient for all sinus and postectopic beats followed consistent regression slopes characterizing the potential energy loss between the LV cavity and aorta. During exercise, similar regression slopes were identified, and these converged with the resting slopes at the point of the maximal measured LVOT gradient. Component analysis of the LVOT gradient suggests that resting beat to-beat variability provides information similar to post-ectopic pressures for predicting maximal gradients in obstructive-variant HCM. CONCLUSIONS: Our study suggests that computer-assisted analysis of hemodynamic variability in HCM may prove useful in characterizing the severity of obstruction. Further study is warranted to confirm the reproducibility and utility of this finding in a population with clinically significant exercise-induced gradients. PMID- 30474253 TI - Growth rates of juvenile Boa constrictor under two feeding regimes. AB - Many husbandry routines in zoo herpetology are based on tradition, authoritarianism, anecdote, or speculation. However, relatively few empirical studies underlie many very common practices. We compared growth rates among littermates of Boa constrictor raised under two feeding regimes that were identical in terms of the mass of food ingested, but differed in weekly versus bi weekly schedules. The growth rate of the group fed weekly was greater than the rate for the biweekly group. Snakes fed 10% of their body mass on a weekly regimen grew to a larger size, and at a faster rate, than did snakes fed 20% of their body mass on a biweekly regimen. PMID- 30474254 TI - Complex decision making in medical training: key internal and external influences in developing practical wisdom. AB - CONTEXT: Good judgement and the ability to make complex decisions are key attributes of a skilled professional. There has been limited study of doctors and their decision making, particularly in relation to making complex decisions. The study aims were to understand how trainee doctors develop practical wisdom through investigating their approach to difficult decision making, understanding the influences on the development of practical wisdom, and identifying potential interventions that may help develop this further. METHODS: Constructing an understanding of the process of developing practical wisdom was analysed within a social constructivist frame. The study investigated trainee doctors at different stages of their careers. Qualitative semi-structured interviews were used to explore the approaches doctors take to difficult decision making, as well as the key training influences in learning these skills. Constant comparative analysis was carried out within a grounded theory approach. RESULTS: Key elements emerged from the data regarding the doctors themselves and the environments they worked in that assisted in developing decision making. This led to the construction of a conceptual model setting out the development of practical wisdom among trainee doctors. The model describes a process of gaining experience in decision making, moderated by key external and internal influences. The important roles of self efficacy and agency (relational) are highlighted as key enablers of the process. DISCUSSION: The implications of this model are considered in relation to postgraduate training of doctors. The importance of training doctors to be self regulated learners in learning environments that support their development is highlighted. Aspects of the clinical learning environment (structure) such as rotation structures, the culture, supervision and feedback can all be enhanced. Self-efficacy and relational agency, alongside other internal influences, are key factors in accelerating development of practical wisdom. Other studies have shown that these factors can be improved with targeted interventions. PMID- 30474255 TI - Telomere elongation through hTERT immortalisation leads to chromosome repositioning in control cells and genomic instability in Hutchinson-Gilford Progeria syndrome fibroblasts, expressing a novel SUN1 isoform. AB - Immortalising primary cells with hTERT has been common practice to enable primary cells to be of extended use in the laboratory since they avoid replicative senescence. Studying exogenously expressed hTERT in cells also affords scientists models of early carcinogenesis and telomere behaviour. Control and the premature ageing disease - Hutchinson-Gilford Progeria Syndrome primary dermal fibroblasts, with and without the classical G608G mutation have been immortalised with exogenous hTERT. However, hTERT immortalisation surprisingly elicits genome reorganisation, in disease cells but also in the normal control cells, such that whole chromosome territories normally located at the nuclear periphery in proliferating fibroblasts become mis-localised in the nuclear interior. This includes chromosome 18 in the control fibroblasts and both chromosomes 18 and X in HGPS cells, which physically express an isoform of the LINC complex protein SUN1 that has previously only been theoretical. Additionally, this HGPS cell line has also become genomically unstable and has a tetraploid karyotype, which could be due to the novel SUN1 isoform. Long term treatment with the hTERT inhibitor BIBR1532 enabled the reduction of telomere length in the immortalised cells and resulted in these mis-localised internal chromosomes to be located at the nuclear periphery, as assessed in actively proliferating cells. Taken together, these findings reveal that elongated telomeres lead to dramatic chromosome mis localisation, which can be restored with a drug treatment that results in telomere re-shortening and that a novel SUN1 isoform combined with elongated telomeres leads to genomic instability. Thus, care should be taken when interpreting data from genomic studies in hTERT immortalised cell lines. This article is protected by copyright. All rights reserved. PMID- 30474256 TI - Asymptotic bias of normal-distribution-based maximum likelihood estimates of moderation effects with data missing at random. AB - Moderation analysis is useful for addressing interesting research questions in social sciences and behavioural research. In practice, moderated multiple regression (MMR) models have been most widely used. However, missing data pose a challenge, mainly because the interaction term is a product of two or more variables and thus is a non-linear function of the involved variables. Normal distribution-based maximum likelihood (NML) has been proposed and applied for estimating MMR models with incomplete data. When data are missing completely at random, moderation effect estimates are consistent. However, simulation results have found that when data in the predictor are missing at random (MAR), NML can yield inaccurate estimates of moderation effects when the moderation effects are non-null. Simulation studies are subject to the limitation of confounding systematic bias with sampling errors. Thus, the purpose of this paper is to analytically derive asymptotic bias of NML estimates of moderation effects with MAR data. Results show that when the moderation effect is zero, there is no asymptotic bias in moderation effect estimates with either normal or non-normal data. When the moderation effect is non-zero, however, asymptotic bias may exist and is determined by factors such as the moderation effect size, missing-data proportion, and type of missingness dependence. Our analytical results suggest that researchers should apply NML to MMR models with caution when missing data exist. Suggestions are given regarding moderation analysis with missing data. PMID- 30474257 TI - Shen'ge powder decreases the cardiomyocyte hypertrophy in chronic heart failure by activating the Rho protein/Rho-associated coiledcoil forming protein kinase signaling pathway. AB - OBJECTIVE: The current study aimed to explore the role and the molecular mechanism of Shen'ge powder in cardiomyocyte hypertrophy in chronic heart failure (CHF). METHODS: Sprague-Dawley rats were selected for the study and divided randomly into four groups: control, model, Shen'ge powder, and fasudil group. An inverted microscope was used to determine the diameter of cardiomyocytes in each group. The survival and apoptotic rate of cardiomyocytes in each group was determined by the tetrazolium dye MTT 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. The messenger RNA levels and protein expression of RhoA, Rho-associated coiled-coil forming protein kinase (ROCK), myosin light-chain phosphatase (MLCP), and myosin light-chain kinase (MLCK) were determined by quantitative reverse transcription polymerase chain reaction and Western blot analysis, respectively. RESULTS: CHF increased the diameter and apoptotic rate of cardiomyocytes and decreased the survival rate of cardiomyocytes. The levels of RhoA, ROCK, and MLCK were increased significantly in CHF model rats, and the level of MLCP was decreased. After treating with Shen'ge powder, the expression of RhoA, ROCK, and MLCK decreased dramatically and the expression of MLCP increased. CONCLUSION: Shen'ge powder could reduce cardiomyocyte hypertrophy in CHF by regulating the Rho/ROCK signaling pathway. PMID- 30474258 TI - Analysis of long noncoding RNA expression profiles in the whole blood of neonates with hypoxic-ischemic encephalopathy. AB - Long noncoding RNAs (lncRNAs) have been shown to participate in many biological processes. To investigate the expression profiles of lncRNAs and their potential functions in neonatal hypoxic-ischemic encephalopathy (HIE), we detected the lncRNA and messenger RNA (mRNA) expression in the peripheral blood samples from HIE patients and controls using a microarray. A total of 376 lncRNAs and 126 mRNAs were differentially expressed between the HIE and the non-HIE samples (fold change > 2). Quantitative real-time polymerase chain reaction was used to validate the microarray data. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis were performed to determine the gene function. Furthermore, the lncRNA-mRNA coexpression network was generated to predict the potential targets of lncRNAs. In conclusion, our study first demonstrated the differential expression profiles of lncRNAs in the whole blood of infants with HIE and may provide a new view of the distinct lncRNA functions in HIE. PMID- 30474260 TI - Multiple skin lesions on a background of hypergammaglobulinaemia. PMID- 30474259 TI - Six-months assessment of a hand prosthesis with intraneural tactile feedback. AB - OBJECTIVE: Hand amputation is a highly disabling event, which significantly affects quality of life. An effective hand replacement can be achieved if the user, in addition to motor functions, is provided with the sensations that are naturally perceived while grasping and moving. Intraneural peripheral electrodes have shown promising results toward the restoration of the sense of touch. However, the long-term usability and clinical relevance of intraneural sensory feedback have not yet been clearly demonstrated. METHODS: To this aim, we performed a six months clinical study with three trans-radial amputees who received implants of transverse intrafascicular multichannel electrodes (TIMEs) in their median and ulnar nerves. After calibration, electrical stimulation was delivered through the TIMEs connected to artificial sensors in the digits of a prosthesis to generate sensory feedback, which was then used by the subjects while performing different grasping tasks. RESULTS: All the subjects, notwithstanding their important clinical differences, reported stimulation induced sensations from the phantom hand for the whole duration of the trial. They also successfully integrated the sensory feedback into their motor control strategies while performing experimental tests simulating tasks of real life (with and without the support of vision). Finally, they reported a decrement of their phantom limb pain and a general improvement in mood state. INTERPRETATION: The promising results achieved with all subjects show the feasibility of the use of intraneural stimulation in clinical settings. This article is protected by copyright. All rights reserved. PMID- 30474261 TI - Prevalence, clinical characteristics and prognosis of EBV-positive follicular lymphoma. PMID- 30474263 TI - Hypothalamic Obesity Treatment Demands Thinking Outside the Box. PMID- 30474262 TI - Proximate determinants of Taylor's law slopes. AB - 1.Taylor's law (TL), a commonly observed and applied pattern in ecology, describes variances of population densities as related to mean densities via log(variance)=log(a)+b*log(mean). Variations among datasets in the slope, b, have been associated with multiple factors of central importance in ecology, including strength of competitive interactions and demographic rates. But these associations are not transparent, and the relative importance of these and other factors for TL slope variation is poorly studied. TL is thus a ubiquitously used indicator in ecology, the understanding of which is still opaque. 2.The goal of this study is to provide tools to help fill this gap in understanding by providing proximate determinants of TL slopes, statistical quantities that are correlated to TL slopes but are simpler than the slope itself and are more readily linked to ecological factors. 3.Using numeric simulations and 82 multi decadal population datasets, we here propose, test, and apply two proximate statistical determinants of TL slopes which we argue can become key tools for understanding the nature and ecological causes of TL slope variation. 4.We find that measures based on population skewness, coefficient of variation, and synchrony are effective proximate determinants. We demonstrate their potential for application by using them to help explain covariation in slopes of spatial and temporal TL (two common types of TL). 5.This study provides tools for understanding TL, and demonstrates their usefulness. This article is protected by copyright. All rights reserved. PMID- 30474264 TI - Associated tympanic bullar and cochlear hypertrophy define adaptations to true deserts in African gerbils and laminate-toothed rats (Muridae: Gerbillinae and Murinae). AB - Hearing capabilities in desert rodents such as gerbils and heteromyids have been inferred from both anatomical and ecological aspects and tested with experiments and theoretical models. However, very few studies have focused on other desert adapted species. In this study, a refined three-dimensional morphometric approach was used on three African rodent tribes (Otomyini, Taterillini and Gerbillini) to describe the cochlear and tympanic bullar morphology, and to explore the role of phylogeny, allometry and ecology to better understand the underlying mechanism of any observed trends of hypertrophy in the bulla and associated changes in the cochlea. As a result, desert-adapted species could be distinguished from mesic and semi-arid taxa by the gross cochlear dimensions, particularly the oval window, which is larger in desert species. Bullar and cochlear modifications between species could be explained by environment (bulla and oval window), phylogeny (cochlear curvature gradient) and/or allometry (cochlear relative length, oval window and bulla) with some exceptions. Based on their ear anatomy, we predict that Desmodillus auricularis and Parotomys brantsii should be sensitive to low-frequency sounds, with D. auricularis sensitive to high frequency sounds, too. This study concludes that in both arid and semi-arid adapted laminate-toothed rats and gerbils there is bulla and associated cochlea hypertrophy, particularly in true desert species. Gerbils also show tightly coiled cochlea but the significance of this is debatable and may have nothing to do with adaptations to any specific acoustics in the desert environment. PMID- 30474265 TI - Factors affecting parents' satisfaction with pediatric wards. AB - AIM: To explore the relationship of parental satisfaction with sociodemographic variables and to identify the possible determinants in pediatric and surgical wards of two public pediatric hospitals in Greece. METHODS: The validated Swedish Pyramid Questionnaire that measures parental satisfaction with the quality of care was used. A convenience sample of 352 parents (response rate: 88%) was collected from two major pediatric public hospitals in Athens, Greece, from February to April, 2016. The satisfaction questions focused on eight domains: information on illness, information on routines, accessibility, medical treatment, care processes, staff attitudes, parental participation, and the staff work environment. RESULTS: The parents of the hospitalized children were highly satisfied with the behavior of the healthcare providers and the medical and nursing care that was provided, but they were less satisfied with accessibility in the hospital. The marital status and child's length of stay in the hospital seemed to affect the most dimensions of parental satisfaction, with the married parents whose child's length of stay was short expressing higher levels of satisfaction. CONCLUSION: Healthcare providers' approaches should be modified for parental satisfaction to be improved and parents' sociodemographics while providing health care. Nurses should enhance the quality of nursing care. PMID- 30474266 TI - Brain invasion by chronic lymphocytic leukemia. AB - Brain invasion by chronic lymphocytic leukemia (CLL) is very rare, and only a handful of cases have been reported. We here report a case of 61-year-old woman who had been treated for CLL for 14 years presenting with a progressive mental disturbance. Magnetic resonance imaging (MRI) showed discontinuous ring-enhancing lesions compatible with the "open ring" sign, which was considered a demyelinating disorder, in both the frontal lobes. However, on histological examination of the biopsied specimen, infiltration of small lymphocytes positive for CD5, CD20, and CD23, indicating brain invasion by CLL, was seen. The leukemia cells occupied the Virchow-Robin space and infiltrated into the brain parenchyma. The arterioles in the Virchow-Robin space were compressed and occluded with the tumor cells, while CD163-positive cells infiltrated the brain parenchyma. Myelin staining demonstrated myelinoclasis in the infiltrated brain tissue. The MRI findings in the present case probably reflected myelinoclasis, suggesting rare brain invasion by CLL. The possibility of lymphoma should not be eliminated based on the MRI findings. PMID- 30474267 TI - Genetic variant in the NSDHL gene in a cat with multiple congenital lesions resembling inflammatory linear verrucous epidermal nevi. AB - BACKGROUND: The feline counterpart of human inflammatory linear verrucous epidermal nevus (ILVEN) has been described; however, the possible underlying developmental defect has not been investigated. OBJECTIVE: To report a case of multiple ILVEN-like lesions in a cat with a genetic variant in the NSDHL gene. ANIMALS: A 2-year-old, female, domestic short hair cat with a history of multiple alopecic, verrucous, hyperpigmented and erythematous skin lesions, following Blaschko's lines on the head, the limbs, the trunk and paw pads. METHODS AND RESULTS: According to the clinical and histopathological findings, a diagnosis of multiple ILVEN-like lesions was made. Genetic investigation revealed a heterozygous missense variant in the X-chromosomal NSDHL gene predicted to lead to a loss-of-function of the NSDHL protein. CONCLUSIONS AND CLINICAL IMPORTANCE: To the best of the authors' knowledge, this is the first case of feline ILVEN like lesions in which a genetic cause has been proposed. Future studies to establish a causal relationship between NSDHL variants and skin lesions might lead to pathogenesis-directed treatments. PMID- 30474268 TI - Improving the sustainability of ex situ populations with mate choice. AB - Many breeding programs managed by the Association of Zoos and Aquariums' (AZA) Species Survival Plans(r) (SSPs) are not meeting goals for population size and genetic diversity due to failure of recommended pairs to breed successfully. According to AZA Population Management Center analyses, as many as 80% of recommended breeding pairs fail to produce young before the next breeding and transfer plan is issued. Determining reasons for failure and ensuring that a specific pairing produces offspring can be challenging. Mate incompatibility, one possible reason for failure, might be addressed by allowing mate choice. Although many SSP(r) coordinators and breeding managers, who implement breeding recommendations at their institutions, recognize the potential benefits of mate choice, examples and models for presenting and assessing choice are lacking. Here we review examples from birds, rodents, lagomorphs, marsupials, carnivores, fishes, and insects where mate choice has been incorporated. These examples provide strong evidence that free mate choice and mating with preferred partners increase a variety of reproductive success measurements when compared to assigned mate pairings. We suggest innovative housing and breeding arrangements for better incorporating mate choice into the management strategies for species held ex situ. Further, we discuss the fitness consequences and welfare implications of allowing choice. We advocate for a more systematic use of behavioral research in cooperative breeding programs. Behavioral management for mating can yield more successful programs, thus ensuring SSP(r) genetic and demographic goals are met, while simultaneously improving welfare. PMID- 30474269 TI - Are Vinyl Cations Finally Coming of Age? AB - Ready for the open waters? Recent developments have fundamentally changed our knowledge of vinyl cation reactivity. The myth that they are too reactive for a predictable reaction design has been debunked, and the applicability of their most distinguished feature, namely their carbene-like reactivity, has taken a major leap forwards. Vinyl cations have thus matured into distinct reactive intermediates with a bright future ahead. PMID- 30474270 TI - LncRNA H19/miR-194/PFTK1 axis modulates the cell proliferation and migration of pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge due to its high mortality and morbidity; gene therapy might be a promising treatment for PDAC. The critical role of Wnt-signaling pathway in cancer pathogenesis has been widely recognized; cyclin-dependent kinase 14 (CDK14, PFTK1)-induced low-density lipoprotein receptor-related proteins 5/6 (LRP5/6) phosphorylation is an important issue in Wnt-signaling activation. Long noncoding RNA (LncRNA)-microRNA (miRNA)-messenger RNA (mRNA) modulating the pathogenesis of cancers has been regarded as a major mechanism. In the current study, upregulated lncRNAs positively correlated with PFTK1 were analyzed and selected using The Cancer Genome Atlas (TCGA) database. Of them, lncRNA H19 can activate Wnt signaling in cancers. In PDAC tissues, the expression of H19 and PFTK1 were upregulated; H19 knockdown suppressed the cell proliferation and migration of PDAC, while PFTK1 overexpression partially attenuated the suppressive effect of H19 knockdown. As analyzed by TCGA and predicted by online tools, miR-194 was negatively correlated with PFTK1 and might bind to both H19 and PFTK1, which was further confirmed by luciferase reporter and RNA immunoprecipitation assays. Moreover, the effect of H19 knockdown on PFTK1 protein and the cell proliferation and migration could be partially reversed by miR-194 inhibition; H19/miR-194 axis modulated PDAC cell proliferation and migration through PFTK1 downstream Wnt signaling. Results suggested that rescuing miR-194 expression in PDAC can inhibit lncRNA H19 and PFTK1 expression, subsequently suppressing PDAC cell proliferation and migration. Due to the complexity of the lncRNA-miRNA-mRNA network, further in vivo experiments examining potential side effects are needed in future study to explore the clinical application of these findings. PMID- 30474271 TI - Response to the "Letter to the editor regarding article, 'High-mobility group box 1 as a biomarker in critically ill patients'." PMID- 30474273 TI - Isolated Paresis of Laryngeal Adduction: What Are the Laryngoscopic and Stroboscopic Findings? AB - OBJECTIVES/HYPOTHESIS: This study aimed to describe the videolaryngostroboscopic (VLS) findings in a cohort of patients with isolated paresis of laryngeal adduction and identify predictive variables that may be related to voice recovery. STUDY DESIGN: Chart review and VLS analysis of dysphonic patients diagnosed with isolated paresis of laryngeal adduction by laryngeal electromyography (LEMG). METHODS: Demographic, clinical, VLS, and LEMG findings were analyzed according to the outcome of dysphonia. RESULTS: There were 17 patients, 12 males (70.6%), mean age of 46.6 years, with median dysphonia duration of 4 months (range, 1-60 months) included in the study. In all patients, gross movement of both vocal folds were normal. Laryngoscopy showed limited adduction of the ipsilateral ventricular fold, contralateral interarytenoid region deviation, and vocal fold atrophy in 100%, 94.1%, and 76.5% of patients, respectively. VLS findings included: impairment of glottic closure (94.1%), phase asymmetry (94.1%), and reduced mucosal wave on the affected side (76.5%). Predictors of good voice outcome were sudden onset (P = .012), duration of dysphonia on presentation shorter than 5 months (P = .005), and absence of polyphasic potentials on LEMG (P = .041). CONCLUSIONS: Findings on VLS as described suggest isolated paresis of laryngeal adduction and should warrant indication of LEMG for definite diagnosis. Voice improvement may be related to clinical and LEMG findings. LEVEL OF EVIDENCE: 4 Laryngoscope, 2018. PMID- 30474272 TI - Balancing Biofunctional and Biomechanical Properties with Porous Titanium Reinforced by Carbon Nanotubes. AB - Despite the well-known advantages of the titanium-based implant systems, they still lack an optimal balance between biofunctionality and mechanical strength, especially regarding the modulation of cellular response and a desired implant osseointegration. In this work, we fabricated a nanocomposite based on porous commercially pure grade 4 titanium (c.p. Ti) reinforced with carbon nanotubes (CNT) at 5% and 10% w/w, with the aim of obtaining a nanocomposite with lower stiffness compared to traditional titanium-based implants and with the mechanical strength and bioactivity owed by the CNT. Results obtained by SEM, XPS, and AFM characterization showed that the CNT dispersed and incorporated into the porous c.p. Ti matrix. Interestingly, CNT were associated with a higher twining within neighbor Ti grains, which was indeed consistent with an increased in nano hardness. Biological evaluation by MTT and Comet assay revealed that the nanocomposites did not induce genotoxicity and cytotoxicity on two different cells lines despite the presence of nickel at the surface. Accordingly, a purification step would be required before these CNT can be used for biomedical applications. Our results indicate that incorporation of CNT into porous c.p. Ti is a promising avenue to achieve an adequate balance between biofunctionality and mechanical strength in Ti-based scaffolds for tissue replacement. This article is protected by copyright. All rights reserved. PMID- 30474274 TI - Airborne allergic contact dermatitis caused by wood tars. PMID- 30474275 TI - Chinese version of the Cancer Support Person's Unmet Needs Survey-Sort Form: A psychometric study. AB - OBJECTIVE: Psychometrically rigorous and comprehensive needs assessment measures for Chinese general cancer caregivers are relatively scarce. We described the development and psychometric evaluation of the Chinese version of the Cancer Support Person's Unmet Needs Survey-Short Form (SPUNS-SFC). METHODS: A forward backward translation method was utilised to develop the SPUNS-SFC. The construct validity, internal consistency, convergent validity and discriminant validity of the SPUNS-SFC were evaluated. RESULTS: A total of 1,026 Chinese cancer caregivers completed the SPUNS-SFC. Items 10, 11, 13, 24 and 26 were removed as more than 80% of respondents reported having no unmet needs on these items. Exploratory factor analysis revealed a five-factor structure, which accounted for 78.47% of the total variance, and consisted of the following domains: information, healthcare access and continuity, personal and emotional needs, worries about the future, and financial needs. Internal consistency of the measure was high, with Cronbach's alpha coefficients ranging from 0.87 to 0.95 for the five domains. The measure illustrated adequate evidence of convergent validity, demonstrated by significant correlations with multiple measures of psychological well-being. Known-groups validity was established, as 87.5% of the hypotheses were supported. CONCLUSION: This study indicates the SPUNS-SFC is a reliable and valid measure of the unmet needs of Chinese cancer caregivers. PMID- 30474276 TI - Gelatin nonwovens-based epithelial morphogenesis involves a signaling axis comprising EGF-receptor, MAP kinases ERK 1/2, and beta1 integrin. AB - In biomaterials research, biomechanics which support tissue regeneration steadily gains of importance. Hence, we have previously shown that gelatin-based electrospun nonwoven mats (NWMs) with a distinct modulus of elasticity (3.2 kPa) promotes epithelial morphogenesis. Since molecular mechanisms of this morphogenesis are still unknown, the present study aims at identifying molecules, involved herein. Epithelia established on the NMWs showed persistence of the activated state of the Epidermal Growth Factor Receptor (EGF-R), phosphorylated at the src-specific tyrosine 845 (EGF-RT845 ) throughout the observation period of 10 days. To elucidate whether the observed morphogenesis mechanistically involves EGF-R signaling, we inhibited EGF-R, by employing the EGF-RT845 specific inhibitor Gefitinib (IRESSA(r)). Gefitinib administration yielded a reduced expression of the beta1 integrin subunit, a well-known cell-matrix-interaction receptor, concomitant with down-regulation of p42/44 ERK1/2 MAP-kinase activity. To elucidate whether the observed down-regulation of beta1 is EGF-RT845 dependent or emerging from ERK1/2 signaling, we exposed epithelia, grown on the NWMs, with the ERK1/2-directed inhibitor U0126. In the absence of Gefitinib, inhibition of p42/44 MAP-kinase activity resulted in decreased beta1 integrin protein levels, thus indicating that beta1 expression is dependent on ERK1/2 and not EGF-RT845 . Our results showed the first time that an EGF-R-beta1 integrin signaling axis, including ERK1/2, promotes NWM- elasticity-based epithelial morphogenesis. This article is protected by copyright. All rights reserved. PMID- 30474277 TI - Physiological and Psychological Reactions of Sub-Tropically Acclimatized Subjects Exposed to Different Indoor Temperatures at a Relative Humidity of 70. AB - Thermal comfort, self-reported acute health symptoms, cognitive performance, and physiological reactions were examined at four temperatures (26, 30, 33 and 37 degrees C) at a relative humidity of 70%. Thirty-two sub-tropically acclimatized subjects experienced each condition for 175 min., in balanced order, in a climatic chamber. The perception of heat gradually increased with increasing temperature, but the subjects felt hot only at 37 degrees C. The temperature of 33 degrees C was on average rated as acceptable and only just uncomfortable. The acceptability of air quality decreased linearly with increasing temperature. The intensity of acute health symptoms reported by the subjects increased with increasing temperature, but it was no more than moderate even at the highest temperature; dryness of skin and eye were alleviated. The eardrum temperature, skin temperature and moisture, heart rate, end-tidal carbon dioxide and weight loss increased significantly with increasing temperature, whereas the percentage of adjacent heart inter-beat intervals differing by > 50 ms decreased significantly. These results suggest that the perceived heat, self-reported symptoms, and physiological reactions occurred concurrently. They show additionally that acclimatization to heat may shift the boundary of thermal discomfort to a higher temperature. The role of psychological adaptation and of the contextual aspects of this process still require clarification in future experiments. This article is protected by copyright. All rights reserved. PMID- 30474278 TI - Molecular design approach managing molecular orbital superposition for high efficiency without color shift in thermally activated delayed fluorescent organic light-emitting diodes. AB - Molecular design principle of thermally activated delayed fluorescent (TADF) emitters having a high quantum efficiency and a color tuning capability was investigated by synthesizing three TADF emitters with donors at different positions of a benzonitrile acceptor. The position rendering a large overlap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) enhances the quantum efficiency of the TADF emitter. Regarding the orbital overlap donor attachments at 2 and 6 positions of the benzonitrile were more beneficial than 3 and 5 substitutions. Moreover, an additional attachment of a weak donor at 4 position further increased the quantum efficiency without decreasing the emission energy. Therefore, the molecular design strategy of substituting strong donors at the positions allowing a large molecular orbital overlap and an extra weak donor is a good approach for both a high quantum efficiency and a slightly increased emission energy. PMID- 30474279 TI - CLR-4, a novel conserved transcription factor for cellulase gene expression in ascomycete fungi. AB - Fungal degradation of lignocellulosic biomass requires various (hemi-)cellulases and is an important part of the natural carbon cycle. Although induction of cellulases has been described for some saprobic filamentous fungi, the regulation of cellulase transcription is complex and many aspects are still poorly understood. Here, we identified and characterized the novel cellulase regulation factor NcCLR-4 in Neurospora crassa and its ortholog MtCLR-4 in Myceliophthora thermophila. Deletion of CLR-4 resulted in similarly defective cellulolytic enzyme production and activities. Transcriptome analyses of DeltaNcclr 4/DeltaMtclr-4 revealed the down-regulation of genes encoding (hemi-)cellulases and pivotal regulators (clr-1, clr-2 and xyr-1) and key genes in the cAMP signaling pathway such as adenylate cyclase Nccr-1. Intracellular cAMP levels were markedly lower in DeltaNcclr-4/DeltaMtclr-4 than in wild-type during cellulose utilization. In electrophoretic mobility shift (EMSA) and DNase I footprinting assays, NcCLR-4/MtCLR-4 can directly bound to the promoters of Nccr 1/Mtcr-1 (encoding adenylyl cyclase). EMSAs also demonstrated that NcCLR-4/MtCLR 4 could directly bound to clr-1 (encoding a key cellulase regulator), Mtclr-2 and Mtxyr-1 (encoding biomass deconstruction regulators). These findings about the novel cellulase expression regulators NcCLR-4 and MtCLR-4 enrich our understanding of how cellulose degradation is regulated and provide new targets for engineering fungi to deconstruct plant biomass in biorefineries. PMID- 30474280 TI - Association between asthma, rhinitis and conjunctivitis multimorbidities with molecular IgE sensitization in adults. PMID- 30474282 TI - Occupational rhinitis, asthma, and contact urticaria from IgE-mediated allergy to pork. AB - We describe four cases of slaughterhouse workers with occupational immediate allergy to raw pork allergens, confirmed by positive skin prick testing and specific immunoglobulin E (IgE) antibodies. Our first patient was diagnosed with occupational asthma from raw pork allergens. Two patients were diagnosed with occupational rhinitis caused by raw pork allergens, which was confirmed by a nasal provocation test. One of these also had occupational contact urticaria caused by raw pork meat. We were unable to diagnose an occupational respiratory or skin disease in the fourth patient, despite signs of immediate sensitization to raw pork meat from occupational exposure. Based on proper diagnoses, measures to prevent allergen exposure were taken, which led to the improvement of symptoms in these four patients. The present patient cases highlight the importance of recognition of early signs of occupational allergy and identification of causative allergens in order to allow avoidance of allergens, with the aim of preventing persistence and worsening of symptoms. PMID- 30474281 TI - EDTA-conditioning of circumpulpal dentine induces dentinogenic events in pulpotomized miniature swine teeth. AB - AIM: To investigate pulp responses after pulpotomy and EDTA-conditioning of pulp chamber dentinal walls with or without the placement of a collagenous scaffold in the experimental model of miniature swine teeth. METHODOLOGY: Forty-two fully developed permanent premolars and molars of healthy miniature swines were used. After preparation of pulp exposures through Class I cavities, the tissue of the pulp chamber was completely removed. The haemorrhage was controlled and the root pulp was protected using a polyurethane film. The circumpulpal pulp chamber dentine was treated for 3 min with normal saline (group 1), or 17% EDTA solution (groups 2 and 3). The film was removed and the pulp chamber cavities were left empty (groups 1 and 2), or filled with swine collagenous sponge (group 3). The access cavities were restored with a Teflon disc and glass ionomer. Teeth were evaluated histo-morphologically after 10 weeks. Data were compared using the nonparametric Fisher's exact test. RESULTS: Teeth after treatment of dentine with saline (group 1) were associated with no or only traces of hard tissue formation along the root canal walls. Atubular tertiary dentine deposition in the form of matrix deposition along root canal walls, or dentine bridge formation at the orifice of root canals or complete pulp canal obliteration, were found after treatment of dentine with EDTA in both experiments (groups 2 and 3). Significantly different types of mineralization in the root canals of groups 2 and 3 were seen (p=0.001). Tissue changes in the pulp cavity, characterized by soft tissue growth and osteodentine or atubular tertiary dentine formation, were only seen after EDTA-conditioning of dentine, in 6.2% of the teeth without scaffold and 64.7% of the teeth with scaffold application. Newly deposited mineralized matrix in the pulp chamber was always in continuation with hard tissue deposited in the root canals. CONCLUSIONS: The EDTA-conditioning of pulp cavity dentinal walls after pulpotomy induced dentinogenic events in the root pulp. Application of collagenous scaffold in the pulp cavity enhanced soft tissue growth and mineralized tissue formation along the treated circumpulpal dentine. This article is protected by copyright. All rights reserved. PMID- 30474283 TI - Effect of Syringic acid on antioxidant biomarkers and associated inflammatory markers in mice model of asthma. AB - Preclinical Research & Development Asthma is termed as the induction of chronic inflammation in the airway lumen of lungs due to accumulation of inflammatory cells which affects normal breathing process. Prolonged accumulation of inflammatory cells leads to oxidative stress and suppression of antioxidant activities. Therefore, in our present investigation, a potential phenolic compound, Syringic acid was tested for the suppression of inflammatory markers toward an antiasthmatic activity in ovalbumin (OVA)-induced asthmatic mice model. As a result, the Syringic acid treatment was found to suppress the inflammatory cells; eosinophil, neutrophil, macrophage, lymphocyte, and other inflammatory markers including IL-4, IL-5, IL-13, and TNF-alpha in the BALF of OVA-induced asthmatic mice. Similarly, IgE levels were significantly reduced in the blood serum of Syringic acid treated mice groups. In this context, the IFN-gamma levels were found enhanced in the BALF of Syringic acid treated asthmatic mice groups, expressing an anti-inflammatory response. Enzymatic and nonenzymatic antioxidants such as SOD, CAT, and GSH levels were found high in the Syringic acid treatment than the asthmatic control group, which depicts the antioxidant response of Syringic acid on asthmatic groups. Intriguingly, the ROS, NO2 , NO3 , and MDA levels were inhibited in the BALF of Syringic acid treated mice groups. The airway hyper-reactivity (AHR) was comparatively normal in the Syringic acid treatment as it was severe in the case of asthmatic control group. Consequently, the effect of Syringic acid is prominent in the treatment of asthma by controlling the accumulation of inflammatory cells, other inflammatory markers along with enhancement of antioxidant markers, suppression of ROS and controlling airway hyperreactivity. Hence, Syringic acid may be recommended for clinical trials in the treatment of asthma. PMID- 30474284 TI - The GPRC5A frameshift variant c.183del is not associated with increased breast cancer risk in BRCA1 mutation carriers. PMID- 30474286 TI - Tetra-Aza-Pentacenes via a One-Pot Friedlander Synthesis. AB - Tetra-aza-pentacenes are attractive n-type small molecules for optoelectronic device applications, yet their syntheses are often laborious. Disclosed here is a one-pot Friedlander synthesis of 1,7,8,14 tetraazapentacece (tAP) derivatives (linear and/or bent), fully aromatized in-situ despite the absence of an exogenous oxidant. The photophysics of linear tAPs resembles that of regular pentacene while their crystal structures differ. A LUMO energy of 3.71 eV for di tert butylanisole-substituted linear tAP is similar to that of the well-known acceptor, C60. PMID- 30474285 TI - Multifunctional Delivery Nanosystems Formed by Degradable Antibacterial Poly(Aspartic Acid) Derivatives for Infected Skin Defect Therapy. AB - Nucleic acid (NA)-based therapy is promising for tissue repair, such as skin and bone defect therapy. However, bacterial infections often occur in the process of tissue healing. The ideal treatment of tissue repair requires both anti-infection and simultaneous tissue healing. The epidermal growth factor (EGF) plays an important role in wound healing processes. In this work, degradable antibacterial gene vectors based on tobramycin (clinically relevant antibiotic) conjugated poly(aspartic acid) (TPT) are proposed as multifunctional delivery nanosystems of plasmid encoding EGF (pEGF) to realize the antibacterial therapy and tissue healing of infected skin defects. TPT has low cytotoxicity and good degradability, which is helpful in the NA delivery process. TPT demonstrates good transfection performances and hemocompatibility, as well as excellent antibacterial activities in vitro. The outstanding pEGF delivery ability of TPT and the bioactivity of expressed EGF facilitate the proliferation of fibroblast cells. The effective in vivo infected skin defect therapy is also demonstrated with TPT/pEGF nanocomplexes, where skin tissue healing is promoted. The present work opens new avenues for the design of multifunctional delivery nanosystems with antibacterial ability to treat infected tissue defect. PMID- 30474287 TI - Improvement of the 15 N gas flux method for in situ measurement of soil denitrification and its product stoichiometry. AB - RATIONALE: Field measurement of denitrification in agricultural ecosystems using the 15 N gas flux method has been limited by poor sensitivity because current isotope ratio mass spectrometry is not precise enough to detect low 15 N2 fluxes in the presence of a high atmospheric N2 background. For laboratory studies, detection limits are improved by incubating soils in closed systems and under N2 depleted atmospheres. METHODS: We developed a new procedure to conduct the 15 N gas flux method suitable for field application using an artificially N2 -depleted atmosphere to improve the detection limit at the given precision of mass spectrometry. Laboratory experiments with and without 15 N-labelling and using different flushing strategies were conducted to develop a suitable field method. Subsequently, this method was tested in the field and results were compared with those from the conventional 15 N gas flux method. RESULTS: Results of the two methods were in close agreement showing that the denitrification rates determined were not biased by the flushing procedure. Best sensitivity for N2 +N2 O fluxes was 10 ppb, which was 80-fold better than that of the reference method. Further improvement can be achieved by lowering the N2 background concentration below the values established in the present study. CONCLUSIONS: In view of this progress in sensitivity, the new method will be suitable to measure denitrification dynamics in the field beyond peak events. PMID- 30474288 TI - Sarcopenia in patients with non-alcoholic fatty liver disease: is it a clinically significant entity? AB - Sarcopenia, described as the loss of muscle mass and/or strength, is gaining importance as it can be increasingly related to many chronic diseases. It is also associated with chronic liver disease, and recently it has been more frequently linked to non-alcoholic fatty liver disease (NAFLD) in particular. Both sarcopenia and NAFLD are subject to complex and intermingled pathophysiological processes, of which some are in common. Furthermore, it is presently unclear if sarcopenia directly contributes to NAFLD or vice versa. The mechanisms that are involved may include obesity, insulin resistance, vitamin D deficiency, aging, physical inactivity and certain cytokines. Current clinical evidence is subject to an important heterogeneity in methods and definitions, with additionally also a relative overrepresentation of evidence in Asian ethnicities. Nonetheless, all studies so far point towards the same association between sarcopenia and NAFLD, including an association with NAFLD-severity and NAFLD-related fibrosis. Since the field is in its infancy, clear definitions and further research are needed to aid to improve understanding of the association between NAFLD and sarcopenia. This can eventually lead to additional potential therapeutic interventions. This review attempts to give an overview of the current published literature that links sarcopenia to NAFLD, followed by a discussion of the presumably involved pathophysiological factors, and ends by discussing current unmet needs. PMID- 30474289 TI - Machine learning methods for leveraging baseline covariate information to improve the efficiency of clinical trials. AB - Clinical trials are widely considered the gold standard for treatment evaluation, and they can be highly expensive in terms of time and money. The efficiency of clinical trials can be improved by incorporating information from baseline covariates that are related to clinical outcomes. This can be done by modifying an unadjusted treatment effect estimator with an augmentation term that involves a function of covariates. The optimal augmentation is well characterized in theory but must be estimated in practice. In this article, we investigate the use of machine learning methods to estimate the optimal augmentation. We consider and compare an indirect approach based on an estimated regression function and a direct approach that aims directly to minimize the asymptotic variance of the treatment effect estimator. Theoretical considerations and simulation results indicate that the direct approach is generally preferable over the indirect approach. The direct approach can be implemented using any existing prediction algorithm that can minimize a weighted sum of squared prediction errors. Many such prediction algorithms are available, and the super learning principle can be used to combine multiple algorithms into a super learner under the direct approach. The resulting direct super learner has a desirable oracle property, is easy to implement, and performs well in realistic settings. The proposed methodology is illustrated with real data from a stroke trial. PMID- 30474291 TI - Gaussian Process Regression Models for the Prediction of Hydrogen Bond Acceptor Strengths. AB - We present two approaches for the computation of hydrogen bond acceptor strengths, one by machine-learning and one by a composite quantum-mechanical protocol, both based on the well-established pKBHX scale and dataset. The QM calculations after a necessary linear fit reproduce the complexation free energies in solution with an RMSE of 2.6 kJ mol-1 , not far off the expected error of 2 kJ mol-1 obtained from the comparison of experimental data from two different sources. The second approach is by Gaussian Process Regression (GPR) machine-learning. We describe the hydrogen bond acceptor atoms by a radial atomic reactivity descriptor that encodes their electronic and steric environment. The performance of the GPR model on an external test set corresponds to 3.3 kJ mol-1 , which is also close to the experimental error. We apply the GPR model built on experimental data to model the hydrogen bond acceptor strengths of a series of hydrogen bond acceptor sites of 10 phosphodiesterase 10 A inhibitors. The predicted values correlate well with the experimentally measured IC50 values. PMID- 30474290 TI - Social inequalities in sleep-disordered breathing: Evidence from the CoLaus|HypnoLaus study. AB - Sleep-disordered breathing is a common condition, related to a higher cardiometabolic and neurocognitive risk. The main risk factors for sleep disordered breathing include obesity, craniofacial characteristics, male sex and age. However, some studies have suggested that adverse socioeconomic circumstances and lifestyle-related behaviours such as smoking and alcohol use, may also be risk factors for sleep-disordered breathing. Here, we investigate the associations between socioeconomic status and sleep-disordered breathing, as measured by sleep apnea-hypopnea and oxygen desaturation indexes. Furthermore, we assess whether these associations are explained by lifestyle-related factors (smoking, sedentary behaviour, alcohol use and body mass index [BMI]). We used data from the CoLaus|HypnoLaus study, a population-based study including 2162 participants from Lausanne (Switzerland). Socioeconomic status was measured through occupation and education. Sleep-disordered breathing was assessed through polysomnography and measured using the apnea-hypopnea index (AHI: number of apnea/hypopnea events/hr: >=15/>=30 events), and the >=3% oxygen desaturation index (ODI: number of oxygen desaturation events/hr: >=15/>=30 events). Lower occupation and education were associated with higher AHI and ODI (occupation: AHI30, odds ratio (OR) = 1.88, 95% confidence interval (CI) [1.07; 3.31]; ODI30, OR = 2.29, 95% CI [1.19; 4.39]; education: AHI30, OR = 1.21, 95% CI [0.85; 1.72]; ODI30, OR = 1.26, 95% CI [0.83; 1.91]). BMI was associated with socioeconomic status and AHI/ODI, and contributed to the socioeconomic gradient in SDB, with mediation estimates ranging between 43% and 78%. In this Swiss population-based study, we found that low socioeconomic status is a risk factor for sleep disordered breathing, and that these associations are partly explained by BMI. These findings provide a better understanding of the mechanisms underlying social differences in sleep-disordered breathing and may help implement policies for identifying high-risk profiles for this disorder. PMID- 30474292 TI - Chest X-ray evaluation training: impact of normal and abnormal image ratio and instructional sequence. AB - CONTEXT: Medical image perception training generally focuses on abnormalities, whereas normal images are more prevalent in medical practice. Furthermore, instructional sequences that let students practice prior to expert instruction (inductive) may lead to improved performance compared with methods that give students expert instruction before practice (deductive). This study investigates the effects of the proportion of normal images and practice-instruction order on learning to interpret medical images. It is hypothesised that manipulation of the proportion of normal images will lead to a sensitivity-specificity trade-off and that students in practice-first (inductive) conditons need more time per practice case but will correctly identify more test cases. METHODS: Third-year medical students (n = 103) learned radiograph interpretation by practising cases with, respectively, 30% or 70% normal radiographs prior to expert instruction (practice first order) or after expert instruction (instruction-first order). After training, students performed a test (60% normal) and sensitivity (% of correctly identified abnormal radiographs), specificity (% of correctly identified normal radiographs), diagnostic performance (% of correct diagnoses) and case duration were measured. RESULTS: The conditions with 30% of normal images scored higher on sensitivity but the conditions with 70% of normal images scored higher on specificity, indicating a sensitivity and specificity trade-off. Those who participated in inductive conditions took less time per practice case but more per test case. They had similar test sensitivity, but scored lower on test specificity. CONCLUSIONS: The proportion of normal images impacted the sensitivity-specificity trade-off. This trade-off should be an important consideration for the alignment of training with future practice. Furthermore, the deductive conditions unexpectedly scored higher on specificity when participants took less time per case. An inductive approach did not lead to higher diagnostic performance, possibly because participants might already have relevant prior knowledge. Deductive approaches are therefore advised for the training of advanced learners. PMID- 30474293 TI - Plastidial starch phosphorylase is highly associated with starch accumulation process in developing squash (Cucurbita sp.) fruit. AB - We investigated changes in starch content and starch metabolic enzyme activities in developing and postharvest squash of distinct species, Cucurbita maxima and C. moschata, which accumulate high and low levels of starch, respectively. The total activity of starch phosphorylase in developing fruits significantly correlated (r = 0.99) to the amount of starch among Cucurbita species (C. maxima, C. moschata and C. pepo). Separable activity of a plastidial L-form phosphorylase in C. maxima fruit markedly increased corresponding with starch accumulation. We isolated two genes (CmPhoL1 and CmPhoH1) encoding an L-form and a cytosolic H form Pho from C. maxima fruit. The expression of CmPhoL1 in the fruit dramatically increased at the beginning of starch accumulation. Recombinant CmPhoL1 enzyme showed similar kinetic parameters in both glucan synthesis and phosphorolysis: this enzyme can catalyze the invertible reaction in vitro depending on the concentration of substrates. These results suggest that CmPhoL1 plays a role in the starch accumulation process during squash development, but the aid of other starch synthetic enzymes may be required for in vivo glucan synthesis reaction by CmPhoL1. An importance of plastidial starch phosphorylase in the starch accumulation in the fruit organ was indicated. This article is protected by copyright. All rights reserved. PMID- 30474294 TI - After Salisbury Nerve Agents Revisited. AB - In March 2018 the term Novichok (Hovichokappa) became publically known following an attempted murder of a former Russian spy in Salisbury, UK. Novichok is the name of a group of nerve agents secretly produced by Russia in the later stages of the Cold War. These compounds were never declared under the Chemical Weapons Convention and very little is known about the actual identity and characteristics of these compounds. Structures of some of the Novichoks have been reported by a former Russian chemist, Vil Mirzayanov, previously working at the Russian State Scientific Research Institute of Organic Chemistry and Technology (GOSNIIOKhT). It was in this context claimed that at least two compounds of the Novichok family, known as Novichok-5 and Novichok-7 were 5-8 times more potent than the hitherto most toxic nerve agent, VX. The present study elucidates, applying a series of QSAR models toxicity, skin permeation, pharmacokinetic aspects as well as the environmental fate of a series of Novichoks. Virtually the results from the different studies related to human health point in the same direction, i. e., the Novichoks are significantly less toxic than VX and the skin permeation much lower and less efficient than observed for VX. Hence, the claim by Mirzayanov could not be substantiated. PMID- 30474295 TI - Towards Catalytic Antibiotics: Redesign of Aminoglycosides to Catalytically Disable Bacterial Ribosome. AB - The emergence of multidrug-resistant pathogens that are resistant to the majority of currently available antibiotics is a significant clinical problem. The development of new antibacterial agents and novel approaches is therefore extremely important. We set out to explore the potential of catalytic antibiotics as a new paradigm in antibiotics research. Here we describe our pilot study on the design, synthesis, and biological testing of a series of new derivatives of the natural aminoglycoside antibiotic neomycin B for their potential action as catalytic antibiotics. The new derivatives showed significant antibacterial activity against wild-type bacteria and were especially potent against resistant and pathogenic strains including P. aeruginosa and MRSA. Selected compounds displayed RNase activity even though the activity was not as high and specific as we would have expected. Based on the observed chemical and biochemical data, along with the comparative molecular dynamics simulations of the prokaryotic rRNA decoding site, we postulate that the rational design of the catalytic antibiotics should involve not only their structure but also a comprehensive analysis of the rRNA A-site dynamics. PMID- 30474296 TI - Translating auxin responses into ovules, seeds and yield: Insight from Arabidopsis and the cereals. AB - Grain production in cereal crops depends upon the stable formation of male and female germ cells in the flower. In most angiosperms, the female germ cells are located deep within the ovary, protected by several layers of maternal tissue, including the ovary wall, ovule integuments and nucellus. In the field, germline formation and floret fertility are major determinants of yield potential, contributing to traits such as seed number, weight and size. Despite this, viable gametes are not the sole determinants of yield. Stimuli affecting the timing and duration of reproductive phases, as well as the viability, size and number of cells within reproductive organs also play a role. One key stimulant is the phytohormone auxin, which influences growth and morphogenesis of female tissues during gynoecium development, gametophyte formation, and endosperm cellularization. In this review we consider the role of the auxin signalling pathway during ovule and seed development, first in the context of Arabidopsis and then in the cereals. We summarise the gene families involved and highlight distinct expression patterns that suggest a range of roles in reproductive cell specification and fate. This is discussed in terms of seed production and how targeted modification of different tissues might facilitate improvements. PMID- 30474297 TI - Risk of obstructive sleep apnea in patients with bipolar disorder: A nationwide population-based cohort study in Taiwan. AB - AIM: Previous studies have found a high prevalence of risk factors for obstructive sleep apnea (OSA) in patients with bipolar disorder (BD). The study aims to determine whether BD patients are associated with an increased risk of incident OSA. METHODS: Using the National Health Insurance Research Database (NHIRD) of Taiwan, 3,650 BD patients and 18,250 non-BD controls matched by gender and age were enrolled between 2000-2010 and followed until the end of 2013. Patients who developed OSA confirmed by a polysomnographic examination during the follow-up period were identified. Cox regression analysis was performed to examine the risk of OSA between BD patients and comparative controls. RESULTS: BD patients were prone to develop OSA in the crude analysis (hazard ratio (HR): 1.63, 95% confidence interval (95% CI): 1.07-2.49). After adjusting for demographics and comorbidities, the HR declined and was only marginally significant (HR: 1.54, 95% CI: 0.99-2.37). The stratification analysis by gender revealed that the risk trend with BD and subsequent OSA was mainly contributed by the male with BD (HR: 1.72, 95% CI: 1.02-2.91) and the female with BD weakened the overall association. Additionally, this study found that older age, higher income, living in urbanized areas, and some metabolic comorbidities were potential risk factors for developing OSA. CONCLUSIONS: This study shows that male BD patients are associated with an increased risk of OSA, which has direct implications for the development of targeted prevention interventions or the implementation of a screening algorithm for OSA to reduce its negative health impact. This article is protected by copyright. All rights reserved. PMID- 30474298 TI - Is metabolically healthy obesity a useful concept? AB - Obesity poses significant public health concerns, including Type 2 diabetes mellitus, cardiovascular disease and stroke. Although deleterious metabolic profiles typically accompany individuals with obesity, various epidemiological studies have identified a subset of patients with a favourable metabolic phenotype referred to as the metabolically healthy obese. Metabolically healthy obesity is a novel concept that stratifies obese individuals according to their respective metabolic status. It has important implications for healthcare policies, particularly the efficient allocation of resources in the targeted treatment of obesity and prevention of metabolic ill-health. However, conflicting evidence in the literature regarding its risk profile questions its clinical relevance. In addition, the lack of a unified definition of metabolically healthy obesity and agreement on its progression further impede its utility as a stratification strategy. This review aims to describe current concepts of metabolically healthy obesity within the literature, evidence of this metabolic phenotype, the clinical implications of patient stratification and limitations of the concept. This article is protected by copyright. All rights reserved. PMID- 30474299 TI - A novel simulator model and standardized assessment tools for fine needle aspiration cytology training. AB - OBJECTIVES: Fine needle aspiration (FNA) is an invaluable diagnostic procedure for evaluation of lesions; however, acquisition of diagnostic material is dependent on the skill of the practitioner. We report a novel patient simulator for teaching the FNA procedure and structured assessment tools for educators and learners. METHODS: We created a novel simulator model for FNA training, employed a standardized teaching module, and assessed procedure utility in medical students. Groups of students completed training using a commercial version of the model, and underwent structured evaluation using an Objective Structured Assessment of Technical Skills (OSATS) form, and the Debriefing Assessment for Simulation in Healthcare (DASH) tool. RESULTS: In the initial phase, 178 students rated the training workshop between valuable and essential (4.2 on a 5-point Likert scale). In the second phase, for students evaluated with the OSATS form, the mean overall score was 33 out of 50 (range 26-43). The areas of weakness for the participants were: (a) compression after the FNA procedure, (b) completion of the informed consent, and (c) correct explanation of the procedure to the patient. For the group of students that completed the DASH questionnaire, the results were: 6.2 (assessment by students) and 6.7 (assessment by instructor) out of a maximum of 7. CONCLUSION: A realistic simulation model, in combination with a standardized training program with formal assessment methods is a valuable tool to teach FNA. We here describe a process for teaching the FNA procedure to interested educators and learners. PMID- 30474300 TI - Mosquito bloodmeal preferences in two zoological gardens in Germany. AB - Because they provide a high density and diversity of vertebrate species, small water pools and shaded environments, zoological gardens offer ideal living conditions for numerous mosquito species. Depending on their host preferences and vector competencies, these species may be able to transmit pathogens between native and non-adapted exotic blood host species, thereby causing morbidity and mortality among valuable zoo animals. To determine the extent to which native mosquito species feed on captive and wild animals, as well as on humans, in two German zoological gardens, mosquitoes were collected over two seasons by trapping and aspirating. A total of 405 blood-fed specimens belonging to 16 mosquito taxa were collected. Genetic bloodmeal analysis revealed 56 host species, mainly representing mammals of the zoo animal population, including exotic species previously not known as blood hosts of the mosquito species collected. These results indicate opportunistic feeding patterns with low host-specificity in the analysed mosquitoes, although these could be grouped, according to their bloodmeals, into 'amphibian-', 'non-human mammal-' and 'non-human mammal and human-' feeding species. As the blood-feeding preferences of vector-competent mosquito species are major determinants of vector capacity, information on the blood-feeding behaviour of mosquitoes in zoos is crucial to the success of targeted vector management. PMID- 30474301 TI - MicroRNA-34a inhibit hepatocellular carcinoma progression by repressing hexokinase-1. AB - Hepatocellular carcinoma (HCC) is known as a frequent type of primary cancer in the liver, and it is the third-most common cause of cancer-related death all over the world. However, the molecular mechanism in the progression of HCC is still unclear. The current study was designed to investigate the expression and function of microRNA-34a (miR-34a) in HCC. In HCC tissues and cells, the expression levels of miR-34a were analyzed by quantitative real-time polymerase chain reaction. The association between the level of miR-34a and hexokinase (HK) 1 was also investigated via luciferase reporter assay. Cell viability and proliferation were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay and flow cytometry. To assess whether miR-34a can limit tumor growth in vivo, animal models and terminal deoxynucleotidyl transferase dUTP nick end labeling assay were used for examining the role of miR 34a on the development of HCC and cell apoptosis. The expression level of miR-34a was reduced in HCC samples and cells. The expression of miR-34a was associated with the viability and proliferation capacity of HCC cells, and miR-34a could inhibit HCC cells proliferation by inhibiting HK1. In the mouse model of HCC, volumes and weight of the tumors were significantly decreased by transfection with miR-34a mimic compared with the control group. Furthermore, miR-34a mimics could induce apoptosis in a greater proportion of cells compared with the control group. Taken together, the data may provide some novel insights into the molecular mechanism of miR-34a and HK1 in the progression of HCC. Thus, miR 34a/HK1 axis might be a novel promising therapeutic target for treating HCC. PMID- 30474302 TI - Why phylogenomic uncertainty enhances introgression analyses. PMID- 30474303 TI - Cost-effectiveness analysis of English memory assessment services two years after first consultation for patients with dementia. AB - OBJECTIVES: This paper aims to compare changes over two years in patients' health related quality of life (HRQL) with the health and social care costs of diagnosis and treatment of people newly referred to MAS. METHODS: We analysed observational data from 1318 patients referred to 69 MAS who completed resource use and HRQL questionnaires at baseline, 3, 6, 12 and 24 months. We reported mean differences in HRQL (disease-specific DEMQOL and generic EQ-5D-3L), quality-adjusted life years (QALYs), costs and cost-effectiveness between baseline and 2-year follow up. RESULTS: Two years after referral to MAS, patients reported a higher DEMQOL score (mean gain 4.47, 95% confidence interval: 3.08 to 5.90) and EQ-5D-3L (0.014, -0.011 to 0.039). Mean total costs and QALYs over 24 months was L2 411 (L1721 to L2873) and 0.027 (0.003 to 0.051), respectively. Assuming that patients' HRQL would not have altered over the two years had they not attended MAS, these outcomes suggest an incremental cost-effectiveness ratio of L89 546 (L38123 to L145864) based on changes in EQ-5D-3L. If we assumed that patients' HRQL would have declined by about 10% over this period had they not attended MAS, the cost-effectiveness ratio would be L25 056. The largest MAS (N=32; 46%) with over 50 new patients a month were more likely to be cost-effective than smaller ones (p < 0.01). CONCLUSIONS: Memory assessment services are effective and can be cost-effective for diagnosing and treating people with suspected dementia. Large variations in costs between clinics suggest that many MAS could improve their cost-effectiveness. PMID- 30474304 TI - TRB-J1 usage, in combination with the HLA-A*01:01 allele, represents an apparent survival advantage for uterine corpus endometrial carcinoma: Comparisons with microscopic assessments of lymphocyte infiltrates. AB - The opportunity for the highly efficient recovery of immune receptor recombination data from cancer specimens, including the ready assessment of immune receptor V and J usage, raises the issue of establishing precise values of assessing the immune receptor status as opposed to obtaining basic information regarding lymphocyte infiltration, in the cancer setting. In this report, we obtained the lymphocyte infiltration percentages from the cancer digital slide archive representing uterine corpus endometrial carcinoma (UCEC) and correlated these data with recovery of the immune receptor recombination reads from corresponding UCEC exome files. Results indicated a basic correlation of the recovery of productive T-cell receptor beta (TRB) recombination reads with lymphocyte infiltration percentages. However, the recovery of specific immune receptor recombination reads did not indicate the same survival outcomes as microscope detection of lymphocyte infiltrate percentages. To further exploit the value of recovery of the TRB recombination reads from the UCEC exome files, we determined the survival outcomes for combinations of TRB gene segment usage and HLA class I alleles, with the most important result being that the combination of HLA-A*01:01 and TRB-J1 segment usage reflected a strikingly high survival rate. Overall, this report emphasized the increased value of the knowledge of the immune receptor recombinations, in comparison with basic lymphocyte infiltration percentages, in assessing cancer survival rates. PMID- 30474306 TI - Photobiomodulation Improves the Frontal Cognitive Function of Older Adults. AB - OBJECTIVES: The frontal lobe hypothesis of age-related cognitive decline suggests that the deterioration of the prefrontal cortical regions that occurs with aging leads to executive function deficits. Photobiomodulation (PBM) is a newly developed, non-invasive technique for enhancing brain function, which has shown promising effects on cognitive function in both animals and humans. This randomized, sham-controlled study sought to examine the effects of PBM on the frontal brain function of older adults. METHODS/DESIGNS: Thirty older adults without a neuropsychiatric history performed cognitive tests of frontal function (i.e., the Eriksen flanker and category fluency tests) before and after a single 7.5-min session of real or sham PBM. The PBM device consisted of three separate light-emitting diode cluster heads (633 nm and 870 nm), which were applied to both sides of the forehead and posterior midline, and delivered a total energy of 1349 J. RESULTS: Significant group (experimental, control) * time (pre-PBM, post PBM) interactions were found for the flanker and category fluency test scores. Specifically, only the older adults who received real PBM exhibited significant improvements in their action selection, inhibition ability, and mental flexibility after vs. before PBM. CONCLUSIONS: Our findings support that PBM may enhance the frontal brain functions of older adults in a safe and cost-effective manner. PMID- 30474305 TI - Ni(OH)2 Nanoflakes Supported on 3D Ni3 Se2 Nanowire Array as Highly Efficient Electrodes for Asymmetric Supercapacitor and Ni/MH Battery. AB - Porous Ni(OH)2 nanoflakes are directly grown on the surface of nickel foam supported Ni3 Se2 nanowire arrays using an in situ growth procedure to form 3D Ni3 Se2 @Ni(OH)2 hybrid material. Owing to good conductivity of Ni3 Se2 , high specific capacitance of Ni(OH)2 and its unique architecture, the obtained Ni3 Se2 @Ni(OH)2 exhibits a high specific capacitance of 1689 uAh cm-2 (281.5 mAh g-1 ) at a discharge current of 3 mA cm-2 and a superior rate capability. Both the high energy density of 59.47 Wh kg-1 at a power density of 100.54 W kg-1 and remarkable cycling stability with only a 16.4% capacity loss after 10 000 cycles are demonstrated in an asymmetric supercapacitor cell comprising Ni3 Se2 @Ni(OH)2 as a positive electrode and activated carbon as a negative electrode. Furthermore, the cell achieved a high energy density of 50.9 Wh L-1 at a power density of 83.62 W L-1 in combination with an extraordinary coulombic efficiency of 97% and an energy efficiency of 88.36% at 5 mA cm-2 when activated carbon is replaced by metal hydride from a commercial NiMH battery. Excellent electrochemical performance indicates that Ni3 Se2 @Ni(OH)2 composite can become a promising electrode material for energy storage applications. PMID- 30474307 TI - Synthesized glucocorticoid-induced leucine zipper peptide (GILZ-P) inhibits photoreceptor apoptosis and protects retinal function in light-induced retinal degeneration model. AB - BACKGROUND: This study aimed to investigate the neuroprotective function of a synthesized glucocorticoid-induced leucine zipper peptide (GILZ-p) in a light induced retinal degeneration model. METHODS: The GILZ98-134 peptide was synthesized and injected intravitreally into Sprague Dawley rats. Retinal injury was then induced in the rats by exposing their eyes to constant white light (5000 lux) for 24 h. The activation of retinal caspases-9/3 and the release of cytochrome c from the mitochondria to the cytosol were measured at 1, 3, 5 and 7 days after light injury. Photoreceptor apoptosis was evaluated with TUNEL staining at 3 days after injury. Hematoxylin and eosin staining and electroretinography were used to observe the changes in the retinal morphology and function, respectively, 7 and 14 days after light injury. RESULTS: The intravitreally injected synthesized GILZ-p successfully penetrated to the retina and significantly inhibited the activation of retinal caspase-3 and caspase-9 at 1, 3, 5, and 7 days after light injury, and reduced the number of TUNEL-positive photoreceptors at 3 days after light injury. GILZ-p pretreatment also alleviated cytochrome c release and rescued mitochondria-mediated apoptosis after injury. Simultaneously, GILP-p pretreatment also mitigated the light-induced thinning of the outer nuclear layer and the loss of retinal function at 7 and 14 days after light injury, respectively. CONCLUSION: The synthesized GILZ-p prevented light induced photoreceptor apoptosis and protected retinal function from degeneration, and is therefore a potential therapeutic option for degenerative retinal diseases. PMID- 30474308 TI - Reversible hydrogen uptake/release over sodium phenoxide-cyclohexanolate pair. AB - Hydrogen uptake and release in arene-cycloalkane pairs provide an attractive opportunity for on-board and off-board hydrogen storage. However, the efficiency of arene-cycloalkane pairs currently is limited because of unfavorable thermodynamics for hydrogen release. In this paper, we propose a strategy for optimizing the thermodynamics based on substitution of H in the -OH group of cyclohexanol and phenol with alkali or alkaline earth metals. The enthalpy changes of dehydrogenation decreases substantially, which correlates with the electron delocalized from oxygen to the benzene ring in phenoxides. Theoretical calculations reveal that replacement of H with a metal leads to a reduction in the energy gap of HOMO and LOMO and elongation of the C-H bond in the alpha site in cyclohexanolate, which indicates the cyclohexanol is activated upon metal substitution. Our experimental results demonstrate that sodium phenoxide cyclohexanolate, an air and a water stable pair, can desorb hydrogen at ca. 413K and 373K in the solid form and in an aqueous solution, respectively. Hydrogenation, on the other hand, is accomplished at the temperatures as low as 303K. PMID- 30474309 TI - Managing Liver Dysfunction in Hematology Patients: Switch Antifungals, or use the Tincture of Time? AB - Liver function test (LFT) abnormalities are a common occurrence in hematology patients receiving antifungal therapies. The cause of elevated LFTs is often multifactorial. Posaconazole is associated with elevated LFTs in approximately 5 10% of patients. Recently, DiPippo, et al. demonstrated that switching to isavuconazole in such cases leads to a reduction in LFTs in the majority of patients. However, the LFTs in such patients may have declined with time while continuing on posaconazole therapy. We retrospectively assessed LFT kinetics in 157 AML patients receiving posaconazole for antifungal prophylaxis and found that in 27 patients who developed grade 2 or higher CTCAE hepatotoxicity, 85% (23/27) had lower LFTs at the end of posaconazole therapy, despite continuation in the setting of hepatotoxicity, and this change from maximum LFTs was statistically significant (p<0.0001). Thus, the development of LFT abnormalities while on posaconazole therapy may not warrant a switch to an alternative, potentially less effective antifungal, as hepatotoxicity is often multifactorial and generally resolves with time in the majority of patients. This article is protected by copyright. All rights reserved. PMID- 30474310 TI - Semiparametric transformation models for interval-censored data in the presence of a cure fraction. AB - Mixed case interval-censored data arise when the event of interest is known only to occur within an interval induced by a sequence of random examination times. Such data are commonly encountered in disease research with longitudinal follow up. Furthermore, the medical treatment has progressed over the last decade with an increasing proportion of patients being cured for many types of diseases. Thus, interest has grown in cure models for survival data which hypothesize a certain proportion of subjects in the population are not expected to experience the events of interest. In this article, we consider a two-component mixture cure model for regression analysis of mixed case interval-censored data. The first component is a logistic regression model that describes the cure rate, and the second component is a semiparametric transformation model that describes the distribution of event time for the uncured subjects. We propose semiparametric maximum likelihood estimation for the considered model. We develop an EM type algorithm for obtaining the semiparametric maximum likelihood estimators (SPMLE) of regression parameters and establish their consistency, efficiency, and asymptotic normality. Extensive simulation studies indicate that the SPMLE performs satisfactorily in a wide variety of settings. The proposed method is illustrated by the analysis of the hypobaric decompression sickness data from National Aeronautics and Space Administration. PMID- 30474311 TI - A Malvaceae mystery: A mallow maelstrom of genome multiplications and maybe misleading methods? AB - Previous research suggests that Gossypium has undergone a 5- to 6-fold multiplication following its divergence from Theobroma. However, the number of events, or where they occurred in the Malvaceae phylogeny remains unknown. We analyzed transcriptomic and genomic data from representatives of eight of the nine Malvaceae subfamilies. Phylogenetic analysis of nuclear data placed Dombeya (Dombeyoideae) as sister to the rest of Malvadendrina clade, but the plastid DNA tree strongly supported Durio (Helicteroideae) in this position. Intraspecific Ks plots indicated that all sampled taxa, except Theobroma (Byttnerioideae), Corchorus (Grewioideae), and Dombeya (Dombeyoideae), have experienced whole genome multiplications (WGMs). Quartet analysis suggested WGMs were shared by Malvoideae-Bombacoideae and Sterculioideae-Tilioideae, but did not resolve whether these are shared with each other or Helicteroideae (Durio). Gene tree reconciliation and Bayesian concordance analysis suggested a complex history. Alternative hypotheses are suggested, each involving two independent autotetraploid and one allopolyploid event. They differ in that one entails an allopolyploid origin for the Durio lineage, whereas the other invokes an allopolyploid origin for Malvoideae-Bombacoideae. We highlight the need for more genomic information in the Malvaceae and improved methods to resolve complex evolutionary histories that may include allopolyploidy, incomplete lineage sorting, and variable rates of gene and genome evolution. PMID- 30474312 TI - Influence of background suppression and retrospective realignment on free breathing renal perfusion measurement using pseudo-continuous ASL. AB - PURPOSE: To assess the influence of background suppression and retrospective realignment on physiological noise and image quality in free-breathing renal pseudo-continuous arterial spin labeling (pCASL). METHODS: Ten subjects were scanned at 3T with a pCASL prepared single-slice coronal acquisition through the kidneys under free breathing. Multiple acquisitions were performed with various levels of residual background signal based on optimization of pulse timings to achieve specific background suppression levels (<2%, <5%, <10%, <20%). A retrospective non-rigid motion-correction strategy was also implemented. RESULTS: Decreasing level of residual background signal was associated with higher temporal SNR. The retrospective motion-correction provided an additional but not statistically significant improvement in tSNR. The highest image quality was obtained with the lowest level of residual background signal accompanied by the retrospective motion-correction, although no significant difference in quantitative renal blood-flow could be observed. CONCLUSIONS: Renal perfusion measurement with ASL under free breathing is feasible and robust against physiological noise when using strong background suppression strategies. Finally, retrospective motion-correction further improves image quality but cannot replace background suppression. PMID- 30474313 TI - Morbidity and cause-specific mortality in first-time myocardial infarction with nonobstructive coronary arteries. AB - BACKGROUND: Myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) is receiving increasing interest as a prognostically adverse entity distinct from myocardial infarction with significant coronary artery disease (MI CAD). However, data are still limited regarding long-term cardiovascular morbidity and cause-specific mortality in MINOCA. METHODS: This is a registry based cohort study using data from patients admitted to Swedish coronary care units. We investigated various nonfatal outcomes (recurrent MI, hospitalization for heart failure or stroke) and fatal outcomes (cardiovascular, respiratory or cancer-related mortality) in 4069 patients without apparent acute cardiovascular disease, used as non-MI controls, 7266 patients with first-time MINOCA and 69 267 patients with first-time MI-CAD. RESULTS: Almost all event rates (median follow up 3.8 years) increased in a stepwise fashion across the three cohorts [rates of major adverse events (MAE; composite of all-cause mortality, recurrent MI, hospitalization for heart failure or stroke): n = 268 (6.6%), n = 1563 (21.5%), n = 17 777 (25.7%), respectively]. Compared to non-MI controls, MINOCA patients had an adjusted hazard ratio (HR) of 2.12 (95% confidence interval 1.84-2.43) regarding MAE. MINOCA patients had a substantial risk of cardiovascular mortality and the highest numerical risks of respiratory and cancer-related mortality. Male sex, previous heart failure and chronic obstructive pulmonary disease had a stronger prognostic impact in MINOCA than in MI-CAD. Female MINOCA patients with atrial fibrillation were at particular risk. CONCLUSIONS: Patients with first time MINOCA have a considerable risk of adverse events. This stresses the need for a comprehensive search of the cause of MINOCA, thorough treatment of underlying disease triggers and close follow-up. PMID- 30474314 TI - Biomechanical changes in the cornea following cataract surgery: a prospective assessment with the Corvis-ST. AB - IMPORTANCE: Intraocular pressure is often reduced following cataract surgery. Postoperative changes in corneal stiffness are likely to be at least partly responsible for any reduction in IOP measured with applanation tonometry. BACKGROUND: To determine the effect of cataract surgery and corneal incision size on corneal biomechanics. DESIGN: Prospective randomised trial PARTICIPANTS: One hundred prospectively enrolled patients qualifying for cataract surgery METHODS: Participants were randomised to clear corneal incisions with a 2.20 or 2.85mm keratome. Corvis-ST tonometry and dynamic corneal response measurements were obtained preoperatively, and 3-months postoperatively. Multiple regression analysis was completed using R software. MAIN OUTCOME MEASURES: Corvis-ST biomechanical parameters RESULTS: Ninety-three eyes of 93 patients were included in the final analysis. Mean Corvis-ST biomechanically corrected intraocular pressure decreased by 3.63 mmHg postoperatively (95% confidence interval = 2.97 - 4.35, P <=0.01), and central pachymetry increased by 6.96MUm (4.33 - 9.59, P <=0.01). Independent of IOP and pachymetry changes, mean (+/- standard error) corneal first applanation stiffness parameter reduced by 9.761+/-3.729 (P = 0.01) postoperatively. First applanation velocity increased by 0.007+/-0.002ms, second applanation velocity increased by 0.012+/-0.004ms (P <=0.01), the first applanation deformation amplitude increased by 0.008+/-0.002mm (P <=0.01), and the deflection amplitude at highest concavity increased by 0.030+/-0.069 (P <=0.01). There were no significant differences between different incision size groups. CONCLUSIONS AND RELEVANCE: Corneal stiffness is reduced three months following cataract surgery and is associated with falsely low intraocular pressure measurements. This finding may be important for glaucoma patients and in particular when assessing the effectivity of Minimally Invasive Glaucoma Surgery devices. PMID- 30474315 TI - Gene coexpression network analysis identified potential biomarkers in gestational diabetes mellitus progression. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is one of the most common problems during pregnancy. Lack of international consistent diagnostic procedures has limit improvement of current therapeutic effectiveness. Here, we aimed to screen potential gene biomarkers that might play vital roles in GDM progression for assistance of its diagnostic and treatment. METHODS: Gene expression profiles in four GDM placentae at first trimester, four GDM placentae at second trimester, and four normal placentae were obtained from the publicly available Gene Expression Omnibus (GEO). Weighted gene coexpression network analysis (WGCNA) indicated two gene modules, that is, black and brown module, that was significantly positively and negatively correlated with GDM progression time points, respectively. Additionally, a significant positive correlation between module membership (MM) and degree in protein-protein interaction network of brown module genes was observed. RESULTS: KIF2C, CENPE, CCNA2, AURKB, MAD2L1, CCNB2, CDC20, PLK1, CCNB1, and CDK1 all have degree larger than 50 and MM larger than 0.9, so they might be valuable biomarkers in GDM. Gene set enrichment analysis inferred tight relations between carbohydrate metabolism or steroid biosynthesis related processes and GDM progression. CONCLUSIONS: All in all, our study should provide several novel references for GDM diagnosis and therapeutic. PMID- 30474316 TI - Prenatal diagnosis of familial exudative vitreoretinopathy and Norrie disease. AB - BACKGROUND: Both familial exudative vitreoretinopathy (FEVR) and Norrie disease (ND) are hereditary retinal disorders which can cause severe visual impairment and blindness at a young age. The present study aimed to report the use of antenatal genetic testing and ultrasound in the diagnosis and counseling of FEVR and ND. METHODS: Amniocentesis and ultrasonography were performed in high-risk mothers, with children having FEVR or ND, to predict severe ocular abnormalities. RESULTS: Case 1: A homozygous NDP mutation (c.376T>C, NM_000266) was detected in the proband and his mother. Molecular prenatal analysis of the fetal DNA revealed no mutations. No ocular abnormalities were detected on ultrasonography. The pregnancy progressed uneventfully to a normal outcome. Case 2: A novel heterozygous FZD4 mutation (c.1010dupA, NM_012193) was detected in the proband and his mother. The same mutation was detected in the fetus, but ultrasonography showed no ocular abnormalities. A healthy baby boy with stage 1 FEVR was born after an uneventful pregnancy. Case 3: Deletions of exons 2 and 3 in the NDP were found in the proband and his mother. The same deletion mutation was detected in the female fetus, but the ultrasound scan was normal. The pregnancy progressed uneventfully to a normal outcome. CONCLUSIONS: To our knowledge, antenatal genetic analyses were used in conjunction with ultrasound for the first time, to diagnose FEVR and ND, and predict the postnatal prognoses in at-risk babies. PMID- 30474317 TI - Frontal Cortex Proteome Perturbation after Juvenile Rat Secondhand Smoke Exposure. AB - Secondhand smoke remains a global concern for children's health. Epidemiological studies implicate exposure to secondhand smoke as a major risk factor for behavioral disorders, yet biological causation remains unclear. Model studies have mainly focused on secondhand smoke impacts to prenatal neurodevelopment, yet juvenile exposure represents a separate risk. Using ion mobility-enhanced data independent mass spectrometry, the effect of juvenile secondhand smoke exposure on the prefrontal cortex, a principal part of the brain involved in behavioral control, is characterized. The produced dataset includes 800 significantly responsive proteins within the juvenile orbital frontal cortex, with 716 showing an increase in abundance. The neuroproteomic response reflects a prominent perturbation within the glutamatergic synaptic system, suggesting aberrant, disorganized excitation as observed underlying psychiatric disorders. Also disclosed are impacts to GABAergic and dopaminergic systems. Overall, the dataset provides a wealth of detail, facilitating further targeted research into the causal mechanisms underlying behavioral disorders associated with juvenile exposure to secondhand smoke and other environmental pollutants. All MS data have been deposited to the ProteomeXchange consortium with identifier PXD011744. PMID- 30474318 TI - Dermatitis caused by autochthonous Cercopithifilaria bainae from a dog in Florida, USA: clinical, histological and parasitological diagnosis and treatment. AB - BACKGROUND: Cercopithifilaria bainae is a tick-vectored filarioid nematode associated with erythematous dermatitis in dogs. It has not been reported previously in the United States. HYPOTHESIS/OBJECTIVE: To describe clinical, histological and parasitological diagnosis and treatment of C. bainae in a dog. ANIMALS: An 11-month-old golden retriever/standard poodle mixed breed dog from Florida (USA). METHODS AND MATERIALS: The dog had no travel history within or outside the United States, was presented with a one month history of annular erythematous plaques on the head and ulcers on the medial canthi. Lesions were unresponsive to antibiotic treatment. RESULTS: Histopathological evaluation of skin biopsies revealed an eosinophilic to lymphohistiocytic perivascular dermatitis with multiple microgranulomas and rare 5-10 MUm diameter microfilariae within microgranulomas. Microfilarial morphology was consistent with C. bainae. PCR and sequencing of 18S rRNA and mitochondrial cytochrome oxidase subunit I genes confirmed the nematodes as C. bainae. The dog was treated with a commercial spot-on containing imidacloprid and moxidectin, and clinical resolution occurred. CONCLUSIONS AND CLINICAL IMPORTANCE: To the best of the authors' knowledge, this is the first report of C. bainae in a dog in the United States and the first description of dermatological lesions caused primarily by C. bainae. PMID- 30474319 TI - Patterns of domestic violence against women during pregnancy and the postpartum period in Kathmandu, Nepal. AB - INTRODUCTION: Domestic violence during pregnancy and the postpartum period is a public health problem, which affects not only the health of the mother but also the health of the fetus and child. This study aims to examine the prevalence and patterns of domestic violence during pregnancy and the postpartum period and to identify associated factors in a Nepalese society. METHODS: A cross-sectional study was conducted in a government hospital of Nepal. In each trimester of pregnancy and the postpartum period, 165 women aged 15 to 49 years were recruited. Domestic violence information was elicited using a questionnaire adapted from a World Health Organization (WHO) domestic violence against women instrument. Multiple logistic regression models were used to identify associated factors of domestic violence. RESULTS: The overall prevalence of domestic violence against women during pregnancy and the postpartum period was 26.2% (17.6%, 34.6%, 32.7%, and 20.0% in the first, second, and third trimesters of pregnancy, and the postpartum period, respectively). Associated factors for domestic violence included Janjati ethnicity of the women, 2 to 5 years of married life compared with <2 years, the second and third trimesters of pregnancy compared with the first trimester, low education status of husbands, high controlling behavior of mothers-in-law, and previous history of domestic violence. DISCUSSION: Domestic violence during pregnancy and the postpartum period is common in Nepalese women, especially in the second and third trimesters of pregnancy. PMID- 30474320 TI - Typhoid fever complicated by cholecystitis in a 10-year-old boy. PMID- 30474321 TI - Multilevel States of Nano-Electromechanical Switch for a PUF-Based Security Device. AB - A nano-electromechanical (NEM) switch using multilevel states based on the high security physical unclonable function (PUF) is proposed and experimentally demonstrated. Using the asymmetric random stiction of a silicon nanowire (SiNW), the conventional binary state is simply expanded to a quaternary-state encryption key without increasing chip area. The multiple states are determined by the asymmetrically bent direction and stiction of the SiNW. The experimental results show that the fabricated NEM-PUF with multistates retains unique, random, and robust characteristics, while the key capacity is doubled, even with the same array size footprint. PMID- 30474322 TI - The Use of Hair as a Long-Term Indicator of Low-Dose beta2 -Agonist Treatments in Cattle: Implications for Growth Promoting Purposes Monitoring. AB - The objective of this study was to assess the feasibility of using hair as a long term indicator of cocktail (low-dose beta2 -agonists) treatments in cattle. Six male Simmental cattle were treated with a mixture of low-dose clenbuterol, ractopamine, and salbutamol at dosages of 5.3, 223.3, and 50.0 MUg/kg, respectively. The trial lasted for 112 days and included 28 days of treatment and 84 days of withdrawal. Plasma and urine samples taken during the treatment period contained the highest residues, with maximum concentrations of clenbuterol, ractopamine, and salbutamol in plasma of 1.49 ng/mL (Day 21), 43.78 (Day 14) ng/mL, and 8.07 ng/mL (Day 7), respectively, and in urine of 58.36 ng/mL (Day 28), 3995.77 ng/mL (Day 28), and 503.72 ng/mL (Day 1), respectively. On day 42 of withdrawal, the residues of all three beta2 -agonists in plasma were below the limit of quantification (LOQ; 0.3 ng/mL for clenbuterol, and 0.5 ng/mL for ractopamine and salbutamol), and in urine samples were below or near the LOQ (the highest being ractopamine at 1.10 ng/mL). The highest concentrations of clenbuterol, ractopamine, and salbutamol in hair were 88.36, 1351.92, and 100.58 ng/g, respectively, on day 14 of withdrawal; and the residues were long-lasting, with 7.64, 28.55, and 8.77 ng/g, respectively, on day 84 of withdrawal. The results of this study demonstrate that hair could be utilized as a long-term indicator of the use of a combination of low-dose beta2 -agonists in cattle, which could have implications growth promoting purposes monitoring. PMID- 30474323 TI - Preface for GCC Special Issue on non-coding RNAs, non-coding DNAs and genome editing. PMID- 30474324 TI - Expression of Matrix Metalloproteinases, Tissue Inhibitors of Metalloproteinases, and Interleukins in Vertebral Cartilage Endplate. AB - OBJECTIVE: Turnover of cartilage endplate extracellular matrix (ECM) may play an important role in disc degeneration and low back pain (LBP). However, the expression pattern of pro-inflammatory factors, matrix metalloproteinases (MMP), and tissue inhibitors of metalloproteinases (TIMP) in the cartilage endplates (CEP) of intervertebral discs (IVD) is not understood. We aimed to examine the transcriptional levels of MMP, TIMP, and interleukins (IL), and the correlations between them. METHODS: Thirty degenerated cartilage endplate samples from patients with LBP who underwent lumbar fusion surgery were included in the degenerated group. Ten patients without LBP history who underwent lumbar surgery because of vertebral burst fractures were included in the control group. The degenerative severity of the samples was evaluated by MRI, and hematoxylin-eosin and safranin O-fast green (SO-FG) staining. Real-time polymerase chain reaction (RT-PCR) was used to detect the mRNA levels of MMP-1, MMP-3, MMP-9, MMP-13, TIMP 1, TIMP-2, TIMP-3, IL-1alpha, IL-1beta, and IL-6. The correlations between the levels of these genes were tested using Spearman's rho test. RESULTS: Hematoxylin eosin and SO-FG staining confirmed a decrease in cell number and proteoglycans in the degenerated cartilage endplate. MRI showed significant signal changes in degenerated cartilage endplates. Patients in the degenerated group showed a higher rate of endplate Modic changes when compared with the control group. MMP 3, MMP-9, TIMP-3, IL-1alpha, and IL-1beta were elevated with statistical significance, while MMP-1, MMP-13, TIMP-1, TIMP-2, and IL-6 were changed without statistical significance or remained unchanged. Expression of MMP-3 was positively correlated with IL-1alpha (Spearman coefficient, 0.486; P < 0.05); expression of TIMP-3 was positively correlated with MMP-9, IL-1alpha, and IL 1beta (Spearman coefficient, 0.577, 0.407, and 0.571, respectively; P < 0.05). CONCLUSION: MMP-3, MMP-9, TIMP-3, IL-1alpha, and IL-1beta may play a role in the process of cartilage endplate degeneration. MMP-3 may be regulated by IL-1alpha, and TIMP-3 might be associated with MMP-9 and regulated by IL-1alpha and IL 1beta. PMID- 30474325 TI - Ethics in animal breeding. AB - Ethical breeding involves the use of healthy animals true to their species in behaviour and physical appearance, and when applicable, showing a sustainable performance. The concerns for the species/breed are essential parts of the breeding goals, including preservation of genetic resources within the species/breed, and the health and welfare of the individual animal. Ethical and welfare considerations were often not prioritized in developing new breeds of production or companion animals. As a result, animal breeding practices are increasingly becoming part of the debate on animal welfare. In companion animals, breeding for curiosity or "cuteness" may be a goal in itself, although dogs are also bred for utility. In production animals, breeding focus is on performance, i.e., quantitative entities and financial income, rather than physical appearance. For instance, dairy cows are bred to be larger and to have higher milk yields, sows and ewes to produce more offspring, and horses are designed for riding, racing, and companionship. Overbreeding in relation to current demand of horses, cats, and dogs raises welfare issues due to abandonment or killing of horses and millions of cats and dogs every year. There is variable regulation of health requirements for breeding animals in different countries of the world. In many countries, consumers are becoming increasingly aware of animal welfare issues such as negative effects of certain production traits in farm animals, leading to decreased demand for their meat at a time where increased food production is becoming crucial. Amidst these dilemmas are the veterinarians. This paper deals with issues connected to traditional breeding as well as some of the breeding technologies, and includes food safety, ethics, and animal welfare. PMID- 30474326 TI - Gonadotropin-releasing hormone-modified chitosan as a safe and efficient gene delivery vector for spermatogonia cells. AB - The use of male gonadal tissue as a site for the local delivery of DNA is an interesting concept. Previously, we reported synthesis, physiochemical and biological properties of gonadotropin-releasing hormone (GnRH)-conjugated chitosan as a carrier for DNA delivery to GnRH receptor-overexpressing cells. In this study, the application of modified chitosan as a potential vector for gene delivery to testicular cells was carried out. Transfection efficiency was investigated in mouse-derived spermatogonia cells (GC-1 cells) using green fluorescent protein as a reporter gene. GnRH-conjugated chitosan exhibited higher transfection activity and specificity compared to the unmodified chitosan. Furthermore, the GnRH-modified chitosan showed less cytotoxicity. In conclusion, we have developed and successfully tested the GnRH-modified chitosan for delivery of a transgene of interest to spermatogonia cells in vitro. Such vector could be useful in particular for testis-mediated gene transfer. PMID- 30474328 TI - Body temperature of bitches in the first week after parturition measured by ingestible loggers. AB - The objective of this study was to identify the physiological ranges of body temperature of bitches in the first 7 days after parturition by measurement with ingestible temperature loggers. Twenty bitches swallowed one ingestible temperature logger daily. Bitches were defined to be healthy by spontaneous parturition and leucocyte concentration. Mean core body temperatures of eight healthy bitches were (Mean +/- SD) 38.8 degrees C +/- 0.40 on day 0 p.p., 38.9 degrees C +/- 0.47 on day 1 p.p., 38.9 degrees C +/- 0.35 on day 2 p.p. 38.7 degrees C +/- 0.31 on day 3 p.p., respectively. In the following days, the three remaining healthy bitches showed mean core body temperatures (Mean +/- SD) of 38.8 degrees C +/- 0.30 on day 4 p.p., 38.6 degrees C +/- 0.35 on day 5 p.p., 38.5 degrees C +/- 0.27 on day 6 p.p. and 38.4 degrees C +/- 0.34 on day 7 p.p., respectively. Three out of the eight healthy bitches showed temperatures >=39.5 degrees C. Bitches with leucocytosis showed significant higher mean core body temperatures (39.0 degrees C +/- 0.49) than healthy bitches (38.8 degrees C +/- 0.39) during the first 3 days after parturition (p < 0.01). We conclude that the physiological ranges of body temperature of healthy bitches in the first days after parturition do not differ from those of healthy dogs in general, while the appearance of short episodes of febrile temperatures seems to be physiological. Puerperal bitches with leucocytosis show higher body temperatures increased by only 0.2 degrees C. PMID- 30474327 TI - Vitrification of cat ovarian tissue: Does fragment size matters? AB - The aim of the present study was to investigate whether or not the size of the ovarian fragment influences its resistance to cryostorage. For that purpose, ovaries were collected from 34 queens (various breeds, age 1-5 year) by routine ovariectomy, transported to the laboratory and then sectioned in different sizes (3 mm * 3 mm * 3 mm, 5 mm * 3 mm * 3 mm and 7 mm * 3 mm * 3 mm) and randomly assigned to a control (GC3, GC5 and GC7, respectively) or vitrified (GV3, GV5 and GV7, respectively) groups. Vitrified-warmed fragments were evaluated by histomorphology and immunohistochemistry (for apoptotic rates by using cleaved caspase-3). Histological examination reveals that 72.97% of the follicles in GV3 and 72.58% in GV5 were normal while only 42.86% of the follicles in GV7. The main morphological alteration presented in all groups was a detachment of the epithelial cells. Similarly, immunohistochemistry evaluation using caspase 3 revealed a small proportion of apoptotic cells in GV3 (8.43%) while in GV7 30.43% of the cells expressed cleaved caspase-3. These findings indicate that fragments sectioned in 3 mm * 3 mm * 3 mm (27 mm3 ) seem more adequate for perfusion of the cryoprotectant, causing less damage to the cell after vitrification-warming. PMID- 30474329 TI - Editorial. PMID- 30474330 TI - Accuracy of ultrasonography and fine-needle aspiration cytology in the diagnosis of prostate diseases in dogs. AB - Clinical signs of prostatic diseases in dogs are often non-specific. Appropriate treatment should be based on a detailed investigation using reliable diagnostic tools. The aim of our study was to evaluate the diagnostic value of ultrasonography (US) and fine-needle aspiration (FNA) cytology in dogs' prostate diseases. The mean accuracy of FNA cytology and US were 0.72 and 0.88 (n = 13), respectively. US gland size measurements and actual gland dimensions were highly concordant. Obtained results confirm the high diagnostic value of US and FNA biopsy and in prostatic diseases. Diagnosis based on US is highly reliable; however, it should be combined with clinical signs. Therefore, cytological evaluation of prostate gland material may be performed to differentiate or confirm presumptive diagnosis. PMID- 30474331 TI - Canine ovulation timing: A survey on methodology and an assessment on reliability of vaginal cytology. AB - Ovulation timing in bitches is a routine procedure in small animal practice around the world. It is most frequently used for supporting breeding management, high-risk pregnancy monitoring and determination of the time of parturition. To learn more about how and for what reasons veterinarians interested in small animal reproduction perform canine ovulation timing, an online survey was conducted in 2017. The link to the survey was distributed via the mailing list cafereprod-l@list.cornell.edu and the website, the Twitter account and the Facebook page of EVSSAR. All respondents recommended using quantitative progesterone measurement for ovulation timing alone or in combination with other diagnostic tests. Vaginal cytology was also a commonly used technique. The 63 respondents followed different protocols for sampling and staining vaginal epithelial cells. Interestingly, 50 respondents used vaginal cytology routinely, but only two consider it as a very reliable and another nine as a somewhat reliable test if used alone. In a second project, delegates attending the EVSSAR congress held in Vienna, Austria, in June 2017 had the opportunity to examine seven stained vaginal smear slides under optical microscopy in a blinded approach. The results showed a marked heterogeneity in the identification of vaginal cells and assessment of the time in relation to ovulation. This heterogeneity supports the opinion of survey participants that vaginal cytology alone is not a valid tool for determining the day of ovulation. Results of both projects suggest that there is no standard procedure for the examination of vaginal smears in dogs. It is not recommended to determine the optimal time for mating based on the examination of a single vaginal smear only. According to some comments of survey participants, it is more useful to assess vaginal samples repeatedly and to use the findings to determine when to start progesterone measurement. PMID- 30474332 TI - General and type 2 parvovirus-specific passive immune transfer in puppies - Evaluation by early growth. AB - Failure of passive immune transfer put puppies at a higher risk of neonatal and weaning mortality due to low immune protection against infectious agents. The aim of this study was to investigate the evolution of the general via serum IgG concentration (IgG) and the specific via serum maternally derived canine parvovirus type 2-specific antibody titer (CPV2 MDA) passive immune transfer within the first 4 weeks of age. Furthermore, the relationship between general and specific immune transfer and the possibility of non-invasive evaluation was assessed. Puppies (169) were weighed systematically between birth and Day 28. IgG and CPV2 MDA were assayed in serum samples at 2 and at 28 days of age. At Day 2, there was a positive correlation between IgG and CPV2 MDA (rho = 0.71; p < 0.001). At Day 2, 17.9% (27/151) of puppies presented a deficit of passive immune transfer according to IgG result (defined as IgG < 2.3 g/L) and 25.8% (39/151) of puppies were under the minimal protective CPV2 MDA titer (defined as <1:160). No correlation between IgG and CPV2 MDA was observed at Day 28 (rho = 0.14; p = 0.11). Growth rate within the first 48 hours <-2.7% allowed to distinguish puppies at high risk of the general and specific passive immune failure (Youden's index = 0.79 and 0.75, respectively). The threshold value of early growth rate, although applicable only in puppies non-supplemented with milk replacer, allows identifying via non-invasive way individuals requiring a special care. Further investigation of the mechanism of passive immune transfer in dogs is necessary to understand the relationship between the general and specific immunoglobulin levels. PMID- 30474333 TI - Relationship between motile sperm subpopulations identified in frozen-thawed dog semen samples and their ability to bind to the zona pellucida of canine oocytes. AB - Studies performed on ejaculates from several species have identified discrete subpopulations of motile sperm. In dogs, motile sperm subpopulations have also been described in fresh and frozen-thawed semen. The subpopulation of the most rapid and progressively motile sperm has been suggested to be the most likely source of fertilizing spermatozoa. However, the significance of subpopulation differences among dogs and ejaculates relative to fertility is not known. The aim of this study was to investigate the relationship between the relative proportion of motile sperm subpopulations in frozen-thawed dog semen samples and their ability to bind to the zona pellucida of canine oocytes. Multiple linear regression analysis indicated that the subpopulation of the most rapid and progressively motile sperm was significantly and positively correlated with zona pellucida-binding assays (ZBA) outcomes: each 10% increase in this subpopulation was associated with an increase of 1.5 sperm bound per oocyte. Subpopulations of hyperactivated-like or locally motile sperm were negatively correlated with the ZBA results. It was concluded that subpopulation differences among frozen-thawed dog semen samples determined differences in the number of sperm bound to the ZP of canine oocytes. PMID- 30474334 TI - Ultrasonographic evaluation of ovarian morphology and blood flow in prepubertal and pubertal cats. AB - The aim of this study was to evaluate two-dimensional and Doppler ultrasonographic changes of feline ovaries before and during puberty. Nine, 3 month-old female cats were followed until puberty (Day 1). Two-dimensional and Doppler ultrasound evaluations of the ovaries were carried out on Days -50, -20, 7 and 1. Longitudinal and transverse sections of the ovaries were measured and all anechoic spherical structures were considered to be follicles. The number of follicles >1 mm and the maximum diameter of the largest follicle were recorded. Peak systolic velocity and end diastolic velocity of intraovarian arteries were also measured to automatically calculate the resistive index (RI). The mean ovarian longitudinal diameter increased gradually throughout the study from 8.6 to 10.7 mm (p < 0.05). While four cats presented multiple anechoic spherical structures <1 mm diameter throughout the study, the remaining five animals had these structures only on Days -50 and -20. On Days -20, -7 and 1, the mean number of follicles were 1.4 +/- 0.7, 2.5 +/- 0.8 and 4.8 +/- 1 respectively (p < 0.01). The largest follicles at the same time points were 1.1 +/- 0.2 mm, 1.9 +/- 0.3 mm and 2.6 +/- 0.5 mm respectively (p < 0.05). The RI of the intraovarian arteries declined throughout the study period (p < 0.01). It is concluded that, in female cats, ovarian dimensions, follicle number and intraovarian blood flow increased from 3 months of age to puberty. PMID- 30474335 TI - Pre-pubertal treatment with a GnRH agonist in bitches-Effect on the uterus and hormone receptor expression. AB - Aim of the study was to examine the effect of deslorelin on uterine tissues of eleven pre-pubertal bitches aged 4.2 +/- 0.6 m. Implants containing placebo (sodium chloride 0.9%; n = 4, G I), 4.7 mg (n = 3, GII) or 9.4 mg (n = 4, GIII) deslorelin acetate (Suprelorin(r) ; Virbac, France), were administered subcutaneously. Signs of oestrus, vaginal cytology, serum progesterone (P4) and estradiol-17beta (E2) concentrations were monitored until the occurrence of oestrus. Bitches were ovariohysterectomized and sections from the uterine tissue were subjected to immunohistochemistry (IHC) for detection of GnRH receptor (R), Kisspeptin (KP)10, Kisspeptin receptor (GPR54), androgen receptor (AR), oestrogen receptor (ER) alpha,beta, and progesterone receptor (PR). Tissue sections were scored semi-quantitatively using an immunoreactivity score (IRS) ranging from 0 to 300 (3). Since some animals were ovariohysterectomized before puberty (n = 1 from GII and n = 2 from GIII), and some in metestrus (all controls and 2 from GII and GIII each), results from these animals were separately evaluated and compared to the controls. Results: No abnormalities were seen in uterine tissues. Kisspeptin 10 expression was low in all cell types, highest IRS were seen in the vascular endothelial cells. The GPR54 was mainly detected in the luminal epithelial cells, superficial and deep uterine glands. The expression of GPR54 and ERalpha,beta was especially high in bitches operated prepubertally. No difference was observed between the controls and experimental bitches operated in their first metestrus. The PR and ERalpha,beta were exclusively expressed in superficial and deep uterine glands and luminal surface epithelial cells. The AR and GnRH-R expression was negative in all cells of all groups. We conclude that application of 4.7 or 9.4 mg deslorelin at the age of 4 months did not cause uterine disturbances. GPR54 expression might be influenced by pre-pubertal deslorelin treatment or the changings related to approaching puberty; the latter is supposed in case of ERalpha,beta. PMID- 30474336 TI - Age-related changes in interstitial fibrosis and germ cell degeneration of the canine testis. AB - Fifty-five healthy medium-sized dogs were divided into four groups; young (1-3 years old, n = 14), adult (>3 to 6 years old, n = 12), old (>6 to 9 years old, n = 14) and senile (>9 years old, n = 15). After routine orchiectomy, testes were collected, and the degree of white streak areas on cut surfaces was subjectively assessed. Later, testicular tissue sections were stained with haematoxylin and eosin and Masson's trichrome for evaluation of germ cell degeneration and the proportion of interstitial connective tissue, respectively. Semiquantitative severity scoring of germ cell degeneration and quantitative analysis of spermatogenic cells for spermatic index (SI) and Sertoli cell index (SEI) was performed. The score of white streak on cut surface area of the testes increased with age, being higher (p < 0.05) in senile dogs than other age groups; no difference was found between adult and old dogs. The proportion of testicular interstitial fibrosis was highest (p < 0.05) in senile dogs. Positive correlations between age and white streak area (rho = 0.77, p < 0.01) as well as age and interstitial fibrosis (rho = 0.63, p < 0.01) were observed. The severity of germ cell degeneration gradually increased with age and differed among age groups (p < 0.05). Age positively correlated with atrophy of seminiferous tubules (rho = 0.93, p < 0.01). The SI was lower (p < 0.05) in senile dogs compared to other age groups, and SI was not different among young, adult and old dogs. Conversely, SEI was significantly higher in senile dogs compared to young, adult and old dogs. A negative correlation between age and SI (rho = -0.69) and a positive correlation between age and SEI (rho = 0.68) were significant (p < 0.01). In conclusion, influence of age on testicular interstitial fibrosis and germ cell degeneration/depletion were pronounced in dogs over 9 years old. PMID- 30474337 TI - Nuclear competence and genetic expression of growth differentiation factor-9 (GDF 9) of canine oocytes in 3D culture. AB - To evaluate the ability of a 3D culture system in improving the nuclear and molecular competence of canine oocytes, barium alginate microcapsules were used for in vitro maturation (IVM) and the expression profile of one selected oocyte secreted factor, the growth differentiation factor-9 (GDF-9) was analysed. In Experiment I, canine grade I cumulus-oocyte complexes (COCs) were in vitro matured in 3D microcapsules in a controlled atmosphere for 72 hr, and meiosis resumption rates were compared to those of oocytes cultured in traditional 2D microdrops of medium. In Experiment II, a primer pair specific for canine GDF-9 was designed, and preliminary tested in conventional PCR on genomic DNA. Total RNA content was isolated from oocytes at different time intervals (T0-T24-T48 T72) during in vitro 3D culture, and a reverse transcription to cDNA was performed. The expression of target gene was assessed by quantitative Reverse Transcription Real-Time PCR (qRT-PCR), and the obtained amplicons were sequenced to check the specificity of the analysis. Canine COCs resumed meiosis at higher rates in 3D microcapsules than in 2D microdrops (p < 0.05), even though no significant differences in the proportions of oocytes achieving full maturational stages were obtained. A significant dynamic decrease in GDF-9 expression was recorded during culture: after 72 hr of IVM, the GDF-9 transcription significantly dropped (p = 0.018) compared to 24 and 48 hr. In conclusion, in vitro 3D culture represents an efficient system for IVM of canine oocytes, and the expression profile of GDF-9 well reflects temporal dynamics for the acquisition of developmental competence in this species. PMID- 30474339 TI - Comparison of the characteristics of chinchilla epidydimal semen after collection, storage at 5 degrees C and cryopreservation. AB - The aim of the study was to compare the characteristics of chinchilla epididymal sperm: fresh, stored at liquid state and cryopreserved. Epididymal spermatozoa obtained from 11 males were assessed for subjective motility, concentration, motility parameters measured by CASA, viability, morphology, membrane integrity, acrosome integrity, mitochondrial potential, lipid peroxidation, chromatin structure, apoptotic changes and capacitation. Then half of the spermatozoa were stored at 5 degrees C for 30 hr, and the second half was cryopreserved. After storage and thawing the same parameters as in fresh semen were assessed. Fresh semen showed good quality, with low levels of lipid peroxidation, chromatin fragmentation and capacitation. CASA evaluation showed significantly lower values for MOT, PMOT, RAPID, VCL, VAP and VSL after both storage at liquid state and cryopreservation (p < 0.05). Cold storage did not induce membrane and acrosome damage (p > 0.05), conversely to cryopreservation (p < 0.05). After storage, there was a drop in high mitochondrial potential in live cells (p < 0.05) and an increase in the percentage of non-apoptotic, capacitated cells (p < 0.05). These changes were not seen after cryopreservation (p > 0.05). Lipid peroxidation in live cells and chromatin structure remained unchanged both after storage and cryopreservation (p > 0.05). The study showed that examined methods of semen preservation exerted different patterns of changes in spermatozoa and that sperm quality after both of them allowed for further use of preserved spermatozoa in artificial reproductive techniques. PMID- 30474338 TI - Dog cloning-no longer science fiction. AB - Since the generation of world's first cloned dog, Snuppy, in 2005, somatic cell nuclear transfer (SCNT) in dogs has been widely applied for producing several kinds of dogs with specific objectives. Previous studies have demonstrated that cloned dogs show normal characteristics in growth, blood parameters and behavioural aspect. Also, canine SCNT technique has been applied to propagate working dogs with excellent abilities in fields such as assistance of disabled people, drugs detection and rescue activity. Because dogs have similar habituation properties and share many characteristics including anatomic and physiological aspects with humans, they are also primary candidates for human disease models. Recently, transgenic dogs that express red fluorescent protein gene constitutively and green fluorescent protein gene conditionally have been generated. In addition, transgenic dogs with an overexpression of peroxisome proliferator-activated receptor-alpha in specific muscles were generated to enhance physical performance. In 2017, Snuppy was recloned with markedly increased pregnancy and delivery rates compared to the statistics from when Snuppy was first cloned. Such striking improvements in the cloning of dogs using SCNT procedures suggest that dog cloning could be applied in many fields of biomedical science for human diseases research, and the application of cloning is no longer science fiction. PMID- 30474340 TI - The never-ending search of an ideal culture system for domestic cat oocytes and embryos. AB - In the domestic cat, in vitro fertilization started 40 years ago, but an ideal culture system has yet to be achieved. The physiological microenvironments, which interact with oocytes and embryos promoting their competence, have been investigated. However, recreating in vitro follicle- and oviduct-like conditions is challenging and a matter of both chemistry and physics. This review presents an excursus of the experimental investigations focused on the improvement of feline oocytes and embryos culture through the modulation of chemical and physical factors. Medium supplementation with components of follicular and oviductal fluids, or the use of different co-cultures, supports or substrata have been considered. Innovative and sophisticated systems as "organ-on-a-chip" might lead to the creation of artificial follicles and oviducts and they may represent the ideal combination of chemical and physical factors. Will the search ever end? PMID- 30474341 TI - Neonatal puppy survival after planned caesarean section in the bitch using aglepristone as a primer: A retrospective study on 74 cases. AB - Since most of dystocia end up in caesarean sections (C-sections), the history of any problem during whelping is a good reason to plan in advance a further C section. Our aim was to confirm that on a large sample and over an extended period of time, mortality in puppies <2 weeks of age was low, born after a planned C-section using aglepristone as a primer. Seventy-four C-sections on 59 different bitches were included. Bitches were monitored during oestrus to estimate the day of ovulation by progesterone assays; 60, 61 or 62 days after ovulation, foetal viability was checked by ultrasonography and progesterone plasma level was measured. None of the bitches was at term (progesterone plasma level >2 ng/ml). An injection of aglepristone was performed in late afternoon to block the effect of progesterone, mimicking its drop at the end of pregnancy. The C-section was conducted the following morning. Twenty-one breeds were represented most of which were bulldogs (26%, 21/74) and Great Danes (16%, 13/74). Four hundred and thirty-five puppies were born. A total of 43/435 puppies died within the first 2 weeks (9.89%). None of the puppies showed any external signs of prematurity. The average number of deaths per litter relative to the date after ovulation was similar (0.5 pups per litter at day 60, 0.7 at day 61, 0.4 at day 62). This study shows that planned C-section after an accurate determination of ovulation and using aglepristone as a primer is a safe procedure for bitches and their offspring. It may be offered to owners if a pregnant bitch is "at risk" of dystocia. PMID- 30474342 TI - Uterine two-dimensional and Doppler ultrasonographic evaluation of feline pyometra. AB - The aim of this study was to compare uterine two-dimensional and Doppler ultrasonographic parameters in queens suffering from pyometra from those in early pregnancy. Secondly, the effect of the presence of clinical signs of systemic illness on these parameters was also described. Fourteen post-oestrous queens, with uterine luminal content in the absence of embryos were included. According to their outcome (pyometra surgery or parturition), the queens were retrospectively assigned to one of the following groups: Pyometra (PYO; n = 7) or pregnant (PRG; n = 7). In all the queens, two-dimensional and Doppler ultrasound examinations of the uterus were performed. The presence or absence of clinical signs of systemic illness was recorded. The widest cross-sectional diameter (UD), uterine wall thickness (WT), uterine lumen contents (LC) and uterine artery resistance index (RI) were measured. Uterine horn diameter was higher in PYO group than in PRG group (p < 0.05), while WT (p > 0.1) and LC (p = 0.09) did not differ between groups. Values of RI for PYO and PRG groups were 0.61 +/- 0.03 vs 0.53 +/- 0.09 (p < 0.05), respectively. PYO cats suffering from clinical signs of systemic illness showed larger UD than those without signs (p < 0.01). It is concluded that two-dimensional and Doppler ultrasound might be useful to distinguish queens suffering from pyometra from those in early pregnancy. Secondly, the clinical signs of systemic illness were associated with a larger UD. PMID- 30474343 TI - Manipulation of the oestrous cycle of the bitch-what works... for now. AB - Manipulation of the oestrous cycle of the bitch is a common request of pet owners for different reasons. On one side, clients may be interested in temporally preventing oestrus until the bitch has finished the performance career, or to manage the kennel in the presence of a stud dog and to avoid undesirable breeding. Additionally, clients with no interest to use their animal for breeding, may, for ethical reasons, prefer to avoid elective surgery such as ovariectomy, to control reproduction. On the other side, clients may want to induce oestrus to better control the time of birth, to use a male with limited availability during a specific time, or to reduce the duration of the interoestrous interval in bitches with a long oestrous cycle (>8 months). Both these options for oestrous manipulation are based on hormonal treatments. For oestrous prevention, synthetic progesterone has been used since the 1960s. Induction of oestrus has been established with reliable results using dopamine agonists in the late 1980s and more recently using GnRH agonists. This review is focusing on the current and recently available treatments to manipulate the oestrous cycle in the bitch. PMID- 30474344 TI - Combined typical and atypical long-acting injectable antipsychotics in treatment resistant schizophrenia: two case reports. AB - Real-world data have shown that clozapine and long-acting injectable (LAI) antipsychotics (LAIAs) were more effective than oral antipsychotics in preventing relapse in schizophrenia.1 A treatment dilemma emerges when managing patients with treatment-resistant schizophrenia (TRS) refusing oral antipsychotics, as the treatment of choice, LAI clozapine, is not available. We reported on two patients with TRS successfully managed with combined typical and atypical LAIAs. Informed consents have been obtained from both patients' family. This article is protected by copyright. All rights reserved. PMID- 30474345 TI - TLC-MALDI-TOF-MS-based identification of flavonoid compounds using an inorganic matrix. AB - INTRODUCTION: Thin layer chromatography (TLC) is frequently used to obtain the fingerprint of a plant extract. Although the retardation factor and the response to visualisation give primary information about compound identification, the direct TLC-mass spectrometry (MS) coupling allows a more detailed characterisation of samples. OBJECTIVES: To demonstrate the potential for the flavonoid dereplication using an inorganic matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF-MS) method with and without TLC separation. MATERIAL AND METHODS: Samples derived from wine, apple or rose were deposited on an aluminium-backed silica gel TLC sheet compatible with the MS adapter. Unlike the wine sample, for apple and rose samples compound derivatisation was necessary. These two samples were deposited twice and the plate was cut in two parts. One half was oversprayed with Neu-Peg reagent to visualise flavonoids while the inorganic matrix was deposited on each flavonoid zone on the second half for MS ionisation. RESULTS: Mass spectra obtained for samples without plate development showed numerous ions corresponding to glycosylated flavonoids. The lower m/z observed could be due either to aglycone flavonoids or to in-source fragment ions. After plate development, a separation of many spots was observed and each spot was analysed separately leading to a deeper identification of the present flavonoids. Moreover, isobaric flavonoids with different hRf values could be differentiated. CONCLUSION: TLC-MALDI-TOF-MS using an inorganic matrix enabled the analysis of anthocyanins in positive mode and of flavonols, flavanols, dihydrochalcones and phenolic acids in negative mode, reducing adduct, aggregate forms giving thus simple and reliable spectra for the dereplication approach of flavonoids in complex samples. PMID- 30474347 TI - Exenatide use and Incidence of Pancreatic and Thyroid Cancer: A Retrospective Cohort Study. AB - A retrospective cohort study supplemented with a nested case-control study was performed using two administrative databases from commercial health plans in the US to compare the incidence of pancreatic and thyroid cancer among users of exenatide versus other antidiabetic drugs (OADs). Patients with type 2 diabetes who initiated exenatide or OADs between 6/1/2005 and 6/30/2015 were included. Pancreatic and thyroid cancers were identified using chart-validated algorithms in the cohort study. Cases in the nested case-control study were chart-confirmed pancreatic or thyroid cancers, and controls were sampled using risk-set sampling. The time-fixed analyses comparing 33,629 exenatide initiators to 49,317 propensity score-matched OAD initiators yielded HRs of 0.76 (95% CI, 0.47-1.21) for pancreatic cancer and 1.46 (95% CI, 0.98-2.19) for thyroid cancer. Results in the time-dependent analyses by cumulative duration or dose were similar. Nested case-control analyses yielded RRs of 0.48 (95% CI, 0.25 - 0.91) for pancreatic cancer and 0.87 (95% CI, 0.59 - 1.29) for thyroid cancer. This observational study suggested exenatide use was not associated with an increased risk of pancreatic or thyroid cancer. This article is protected by copyright. All rights reserved. PMID- 30474346 TI - Two-year outcomes of statin therapy in patients with acute myocardial infarction with or without dyslipidemia after percutaneous coronary intervention in the era of new-generation drug-eluting stents within Korean population: Data from the Korea Acute Myocardial Infarction Registry. AB - BACKGROUND: Limited studies focused on long-term outcomes of statin therapy in patients with acute myocardial infarction (AMI) with or without dyslipidemia after percutaneous coronary intervention (PCI) in the era of new-generation drug eluting stents (DES). We thought to investigate 2-year clinical outcomes of statin therapy in these patients. METHODS: A total of 18,137 eligible AMI patients (from the Korea AMI Registry [KAMIR]) were finally enrolled and divided into four groups according to the presence or absence of dyslipidemia and statin therapy (dyslipidemia+/statin- [group A, 309 patients], dyslipidemia+/statin+ [group B, 2094 patients], dyslipidemia-/statin- [group C, 672 patients], dyslipidemia-/statin+ [group D, 15062 patients]). The primary outcome was major adverse cardiac event (MACE) defined as all-cause death, myocardial infarction (MI) and revascularization. RESULTS: During the 2-year follow-up period, the cumulative incidence of MACE in the group A was higher than the group B (adjusted hazard ratio [HR], 2.207; 95% confidence interval (CI), 1.098-3.743; p = .024) and the group D (adjusted HR, 2.110; 95% CI, 1.240-3.593, p = .006). This significantly increased incidence of MACE caused by the higher cumulative incidences of all-cause death and cardiac death (CD) in the group A compared with groups B and D. However, the cumulative incidences of MI and revascularization were not significantly different among these four groups. CONCLUSION: Statin therapy demonstrated significantly reduced incidences of MACE, all-cause death and CD compared with non-users after PCI in AMI patients with or without dyslipidemia during 2-year follow-up period in the era of new-generation DES. PMID- 30474348 TI - Role of HA and BG in Engineering Poly(epsilon-caprolactone) Porous Scaffolds for Accelerating Cranial Bone Regeneration. AB - Effects of varied bioactive fillers on the biological behavior of porous polymer/inorganic composite scaffolds are lack of comprehensive comparison and remain elusive. Moreover, composite scaffolds with high porosity suffer from inferior mechanical performance. Herein, high-pressure molding and salt leaching were employed to prepare poly(epsilon-caprolactone) (PCL) composite porous scaffolds loaded with hydroxyapatite (HA) and bioactive glass (BG), respectively. Structural analysis indicated all the porous scaffolds presented interconnected open-pore structure with the porosity of ~ 87% and pore size of ~ 180 MUm, hinging on the amounts and size of porogen. Compared to PCL/HA scaffolds, PCL/BG scaffolds showed ~ 2.3-fold augment in the water absorption. Attributing to the compact framework, the PCL/HA and PCL/BG porous scaffolds exhibited outstanding compressive modulus, which was notably higher than other PCL composite porous scaffolds reported in literatures. Cells culture results demonstrated that PCL/BG scaffolds displayed higher expression of osteogenic differentiation than PCL and PCL/HA scaffolds. Furthermore, in vivo results showed that more mature bone was formed within PCL/BG scaffolds than PCL/HA scaffolds, manifesting that the introduction of BG accelerated cranial bone regeneration to obtain complete bone healing within a short time. Therefore, these data indicate that PCL/BG scaffolds are more competitive for bone tissue engineering application. This article is protected by copyright. All rights reserved. PMID- 30474350 TI - Seawater recirculation through subducting sediments sustains a deeply buried population of sulfate-reducing bacteria. AB - Subseafloor sulfate concentrations typically decrease with depth as this electron acceptor is consumed by respiring microorganisms. However, studies show that seawater can flow through hydraulically conductive basalt to deliver sulfate upwards into deeply buried overlying sediments. Our previous work on IODP Site C0012A (Nankai Trough, Japan) revealed that recirculation of sulfate through the subducting Philippine Sea Plate stimulated microbial activity near the sediment basement interface (SBI). Here, we describe the microbial ecology, phylogeny, and energetic requirements of population of aero-tolerant sulfate-reducing bacteria in the deep subseafloor. We identified dissimilatory sulfite reductase gene (dsr) sequences 93% related to oxygen-tolerant Desulfovibrionales species across all reaction zones while no SRB were detected in drilling fluid control samples. Pore fluid chemistry revealed low concentrations of methane (<0.25 mM), while hydrogen levels were consistent with active bacterial sulfate reduction (0.51-1.52 nM). Solid phase total organic carbon (TOC) was also considerably low in these subseafloor sediments. Our results reveal the phylogenetic diversity, potential function, and physiological tolerance of a community of sulfate-reducing bacteria living at ~480 m below subducting seafloor. PMID- 30474351 TI - Clinical exigencies, psychosocial realities: negotiating HIV pre-exposure prophylaxis beyond the cascade among gay, bisexual and other men who have sex with men in Canada. AB - INTRODUCTION: Notwithstanding the efficacy of oral pre-exposure prophylaxis (PrEP) in clinical trials, a number of obstacles exist to achieving population level impact among gay, bisexual and other men who have sex with men (GBM). However, few studies have explored the subjective experiences of GBM PrEP users and non-users in the community, outside of clinical trials. The objectives of this study were to explore GBM's experiences of considering, accessing and using (or not using) PrEP, and to understand emerging sexual health, social and community issues among GBM in the PrEP era. METHODS: From October 2015 to March 2016, we purposively sampled PrEP-naive and PrEP-experienced GBM from community organizations and health centres in Toronto, Canada. In-depth, 45- to 90-minute semi-structured interviews explored PrEP perspectives and decision-making, access, initiation, use over time, sexual practices and psychosocial considerations. Interviews were recorded, transcribed verbatim, uploaded into NVIVO, reviewed using thematic analysis and then contrasted with the PrEP cascade. RESULTS: Participants included PrEP users (n = 15) and non-users (n = 14) (mean age = 36.7 years; SD = 8.2), largely gay-identified (86.2%), cisgender male (89.7%) and white (79.3%). Themes indicate not only correspondences, but also limitations of the PrEP cascade by complicating a user/non-user binary and challenging the unilateral presupposition that HIV risk perception leads to PrEP acceptance. Findings further call into question assumptions of a linear stage progression and retention in care as a universal endpoint, instead revealing alternate trajectories of seasonal or intermittent PrEP use and, for some, an end goal of terminating PrEP. GBM's narratives also revealed potent psychological/affective experiences of untethering sex from HIV anxiety; multifaceted PrEP stigma; and challenges to sexual norms and practices that complicate existing behavioural prevention strategies and sexual and social relationships. CONCLUSIONS: An expanded PrEP cascade should consider alternate trajectories of use based on dynamic relationships and behavioural risks that may call for seasonal or intermittent use; systemic barriers in access to and sustaining PrEP; and multiple end goals including PrEP maintenance and discontinuation. Incorporating GBM's lived experiences, evolving preferences, and psychosocial and community-level challenges into PrEP implementation models, rather than a circumscribed biomedical approach, may more effectively support HIV prevention and GBM's broader sexual and psychological health. PMID- 30474353 TI - Dosimetric evaluation of an atlas-based synthetic CT generation approach for MR only radiotherapy of pelvis anatomy. AB - PURPOSE: To investigate the potential of an atlas-based approach in generation of synthetic CT for pelvis anatomy. METHODS: Twenty-three matched pairs of computed tomography (CT) and magnetic resonance imaging (MRI) scans were selected from a pool of prostate cancer patients. All MR scans were preprocessed to reduce scanner- and patient-induced intensity inhomogeneities and to standardize their intensity histograms. Ten (training dataset) of 23 pairs were then utilized to construct the coregistered CT-MR atlas. The synthetic CT for a new patient is generated by appropriately weighting the deformed atlas of CT-MR onto the new patient MRI. The training dataset was used as an atlas to generate the synthetic CT for the rest of the patients (test dataset). The mean absolute error (MAE) between the deformed planning CT and synthetic CT was computed over the entire CT image, bone, fat, and muscle tissues. The original treatment plans were also recomputed on the new synthetic CTs and dose-volume histogram metrics were compared. The results were compared with a commercially available synthetic CT Software (MRCAT) that is routinely used in our clinic. RESULTS: MAE errors (+/ SD) between the deformed planning CT and our proposed synthetic CTs in the test dataset were 47 +/- 5, 116 +/- 12, 36 +/- 6, and 47 +/- 5 HU for the entire image, bone, fat, and muscle tissues respectively. The MAEs were 65 +/- 5, 172 +/ 9, 43 +/- 7, and 42 +/- 4 HU for the corresponding tissues in MRCAT CT. The dosimetric comparison showed consistent results for all plans using our synthetic CT, deformed planning CT and MRCAT CT. CONCLUSION: We investigated the potential of a multiatlas approach to generate synthetic CT images for the pelvis. Our results demonstrate excellent results in terms of HU value assignment compared to the original CT and dosimetric consistency. PMID- 30474352 TI - Ecotoxicological Modeling, Ranking and Prioritization of Pharmaceuticals Using QSTR and i-QSTTR Approaches: Application of 2D and Fragment Based Descriptors. AB - There is a huge lack of experimental data on ecotoxicity of pharmaceuticals, while existing resources are insufficient to gather these data against all possible environmental endpoints. Computational tools such as quantitative structure-toxicity relationship (QSTR) can help us to a great extent to overcome this problem through filling of data gaps. In the current study, QSTR models have been developed for toxicity of 260 diverse pharmaceuticals on three different trophic level species namely algae, daphnia and fish, using partial least squares (PLS) regression approach with 2D descriptors selected through a genetic algorithm approach in order to study underlying chemical features responsible for the observed acute toxicity. The final obtained statistically reliable QSTR models were extensively validated following the OECD guidelines. Interspecies quantitative structure-toxicity-toxicity (QSTTR) models were also developed using genetic algorithm followed by multiple linear regression (GA-MLR) approach to check for the pattern of responses observed as we move across the hierarchy of genetics in different taxonomical class. The obtained interspecies models were finally utilized to fill the data gaps for 260 pharmaceuticals, where experimental data were missing for at least one of the endpoints. Finally, a prioritized list for 7106 existing drug like substances was prepared by predicting their acute toxicity using developed QSTR models. PMID- 30474354 TI - Acquisition of deleterious mutations during potato polyploidization. AB - Potatoes (Solanum tuberosum L.) represent an important tuber crop, worldwide. During its prolonged clonal propagation, numerous deleterious mutations have accumulated in the potato genome, leading to severe inbreeding depression; however, the shaping of this mutation burden during polyploidization and improvement is largely unknown. Here, we sequenced 20 diploid landraces of the Stenotomum group, eight tetraploid landraces, and 20 tetraploid modern cultivars, to analyze variations in their deleterious mutations. We show that deleterious mutations accumulated rapidly during the polyploidization of tetraploid potatoes. This study provides a foundation for future potato improvement. PMID- 30474355 TI - Erratum. PMID- 30474356 TI - How to...analyse qualitative data in different ways. AB - In this paper, the fifth in a series on qualitative research in medical education, we discuss approaches to analysing qualitative data. We focus primarily on analysing transcribed interview and focus group data. We also touch on the analysis of visual data, a potentially fruitful alternative approach. PMID- 30474357 TI - Discovery of a Prenylated Flavonol Derivative as a Pin1 Inhibitor to Suppress Hepatocellular Carcinoma by Modulating MicroRNA Biogenesis. AB - Peptidyl-prolyl cis-trans isomerase Pin1 plays a crucial role in the development of human cancers. Recently, we have disclosed that Pin1 regulates the biogenesis of miRNA, which is aberrantly expressed in HCC and promotes HCC progression, indicating the therapeutic role of Pin1 in HCC therapy. Here, 7-(benzyloxy)-3,5 dihydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-en-1-yl)-4H-chromen-4-one (AF-39) was identified as a novel Pin1 inhibitor. Biochemical tests indicate that AF-39 potently inhibits Pin1 activity with an IC50 values of 1.008 MUm, and also displays high selectivity for Pin1 among peptidyl prolyl isomerases. Furthermore, AF-39 significantly suppresses cell proliferation of HCC cells in a dose- and time-dependent manner. Mechanistically, AF-39 regulates the subcellular distribution of XPO5 and increases miRNAs biogenesis in HCC cells. This work provides a promising lead compound for HCC treatment, highlighting the therapeutic potential of miRNA-based therapy against human cancer. PMID- 30474358 TI - Cone-beam computed tomography investigation of the anatomy of permanent mandibular premolars in a cohort of Caucasians. AB - AIM: The aim of the present study was to evaluate the number of roots and the anatomy of root canal systems of permanent mandibular premolars using images derived from cone-beam computed tomography (CBCT) scans. METHODS: Mandibular CBCT scans of a cohort of Caucasians (Italians) were evaluated using a dedicated software. The number of roots and the anatomy of root canal systems (following the classification by Vertucci) were recorded, and the prevalence of each type was calculated. RESULTS: In total, 112 mandibular scans were evaluated accounting for 97 first premolars and 88 second premolars; 94.2% of first premolars and 96.6% of second premolars had one single root. The most common root canal system configuration was type I for both first premolars (79.2%) and second premolars (95.5%). Moreover, a large variability was observed. CONCLUSIONS: Based on the results, mandibular premolars show a significant heterogeneity in root canal system anatomy that could complicate non-surgical endodontic treatment. PMID- 30474359 TI - Paper Microfluidics for Cell Analysis. AB - Paper microfluidics has attracted much attention since its first introduction around one decade ago due to the merits such as low cost, ease of fabrication and operation, portability, and facile integration with other devices. The dominant application for paper microfluidics still lies in point-of-care testing (POCT), which holds great promise to provide diagnostic tools to meet the ASSURED criteria. With micro/nanostructures inside, paper substrates provide a natural 3D scaffold to mimic native cellular microenvironments and create excellent biointerfaces for cell analysis applications, such as long-term 3D cell culture, cell capture/phenotyping, and cell-related biochemical analysis (small molecules, protein DNA, etc.). This review summarizes cell-related applications based on various engineered paper microdevices and provides some perspectives for paper microfluidics-based cell analysis. PMID- 30474360 TI - Cattle-associated risk factors for human tuberculosis in rural livestock-keeping communities, Uganda. AB - Tuberculosis (TB) is a leading infectious cause of human death worldwide. In cattle, TB infection results in productivity losses, trade barriers and zoonotic transmission via milk, meat or direct contact. We conducted a cross-sectional study in rural communities in Uganda between 2014 and 2016 to evaluate the association between tuberculosis skin test (TST) positivity in humans and cattle associated risk factors: household herd positivity and raw milk consumption. Human and cattle TSTs were performed in communities followed by a survey of household practices. TST data were available on 493 humans, 184 (37.3%) with positive results, and 1,441 cattle, 50 (3.5%) with positive results. We fit separate log binomial generalized estimating equation models for the herd positivity-human TST positivity association, stratified on sex; and for the raw milk consumption-human TST positivity association, stratified on frequency of milk consumption. Having at least one TST-positive bovid in the household's herd was significantly associated with lower risk of TB among men (prevalence ratio [PR] 0.66, 95% CI 0.49, 0.87) but was not significantly associated with TB among women (PR 1.21, 95% CI 0.76, 1.95). This apparent protective effect was contrary to our a priori hypothesis of higher exposure effect among men, the primary caretakers of cattle. This finding may be the result of residual confounding by socioeconomic status; wealthier individuals may be less likely to be TB positive, but more likely to have TST-positive herds by virtue of larger herd sizes, ability to purchase new and possibly infected stock, and propensity to keep more TB-susceptible European breeds. For raw milk consumption, effect estimates were close to one and not statistically significant. Thus, in settings where bovine TB prevalence is low, such as Uganda, cattle-associated zoonotic transmission may be rare, and cattle-associated risk factors may not be important drivers of human TB burden. PMID- 30474361 TI - Limbic encephalitis: Experience of a moroccan center. AB - OBJECTIVES: Histologically defined as an inflammation-degeneration of limbic structures, limbic encephalitis (LE) is a rare disease and often difficult to diagnose particularly in institutions with limited access to laboratory tests such as antineuronal antibodies or HSV-PCR, and functional imaging. We aimed to describe the demographic, clinical, paraclinical, and etiological features of LE, as well as its medium-term prognosis in Moroccan patients. MATERIALS AND METHODS: We collected retrospectively all patients diagnosed with LE in the Department of Neurology of the University Hospital Hassan II of Fez (Morocco) between September 2008 and December 2016. We analyzed their demographic features, clinical manifestations, magnetic resonance imaging and laboratory findings, etiologies, and medium-term prognoses. RESULTS: We included 22 men and 9 women aged 14-76 years (mean age: 45.8 years). In 64.5% of cases, the onset of symptoms was acute. The clinical manifestations included generalized status epilepticus (16.1%), confusional syndrome (29%), epileptic seizures (38.7%), psychiatric disorders (48.4%), and memory disorders (45.2%). The nonlimbic symptoms were nuchal stiffness (22.6%), headaches (9.7%), fever (61.3%), vesicular rash (3.2%), and language disorders (6.5%). The different etiologies found were herpes simplex virus (6.5%), syphilis (16.1%), tuberculosis (3.2%), varicella (3.2%), paraneoplastic autoimmune LE (22.6%), anti-NMDA-R LE (6.5%), and sarcoidosis (3.2%). We found 12 cases (38.7%) of LE without definite etiology and with an incomplete diagnostic workup. The medium-term clinical course includes a complete remission in 45.2% of cases and partial remission in 45.1% of cases. The different sequelae were temporal lobe epilepsy (9.7%), anterograde amnesia (16.1%), and severe cognitive impairment (19.4%). The mortality rate was 9.7% (3 patients). CONCLUSION: Our study shows a wide diversity of etiologies of LE in Morocco with essentially an acute mode of onset of symptoms. PMID- 30474362 TI - Comprehensive evaluation of interventions: eight vital parameters. AB - BACKGROUND: It is critically important to determine the effectiveness of an intervention before it can be translated into clinical practice. However, the future implementation and sustainability of the intervention may be diminished if other intervention parameters are not assessed. This requires obtaining feedback from intervention recipients so interventions will be perceived as appealing, relevant, meaningful and beneficial to them; otherwise recipients may be unlikely to perform them over time, resulting in unsuccessful health outcomes. AIM: To propose the addition of two intervention parameters to the existing six-parameter model and provide examples from recent research of how each parameter can be tested. DISCUSSION: Definitions of the eight parameters are provided and methods for analysing each of them explained. While some studies show necessity, fidelity and cost have unique distinguishing characteristics, other studies indicate feasibility, acceptability and safety have common features, and efficacy and effectiveness are closely associated. CONCLUSION: Researchers frequently examine one or two parameters, but few simultaneously apply the six-parameter model. This model is also missing two vital parameters - efficacy and cost. IMPLICATIONS FOR PRACTICE: Comprehensive and systematic evaluation of all eight intervention parameters is recommended before researchers begin randomised controlled trials and translate them into practice. PMID- 30474363 TI - Conductive Cuprous Iodide Hole-Selective Contacts with Thermal and Ambient Stability for Silicon Solar Cells. AB - Dopant-free carrier-selective contacts are becoming increasingly attractive for application in silicon solar cells, due to the depositions for their fabrication being simpler and occurring at lower temperatures. However, these contacts are limited by poor thermal and environmental stability. In this contribution, the use of the conductive high work function of cuprous iodide, with its characteristic thermal and ambient stability, has enabled a hole-selective contact for p-type silicon solar cells, due to the large conduction band offset and small valence offset at the CuI/p-Si interface. The contact resistivity (~30 mOmega.cm2) of the Ag/CuI (20 nm)/p-Si contact after annealing to 200 degrees C represents the CuI based hole-selective contact with a low resistance and high thermal stability. Microscopic images and elemental mapping of the Ag/CuI/p-Si contact interface revealed that a nonuniform, continuous CuI layer separates the Ag electrode and p-type Si. Thermal treatment at 200 degrees C results in the intermixing of the Ag and CuI layers. As a result, the 200 degrees C thermal process improves the efficiency (20.7%) and stability of the p-Si solar cell, featuring partial CuI hole-selective contact. Furthermore, the devices employing the CuI/Ag contact are thermally stable upon annealing to temperatures up to 350 degrees C. These results not only demonstrate the use of metal iodide instead of metal oxides as hole-selective contacts for efficient silicon solar cells, but also have important implications regarding industrial feasibility and longevity for deployment in the field. PMID- 30474364 TI - The dose-response effect of lycopene on cerebral vessel and neuron impairment induced by hyperlipidemia. AB - To study the dose-response effect of lycopene on vessel and neuron damage in the brain against hyperlipidemia, rats were fed with hypercholesterolemic feed and treated with lycopene orally by gavage at the dose of 5, 25, 45, 65, 85, and 105, 125 mg/kg/bw-1/d-1. At the end of the fourth week, lycopene doses and serum lycopene concentration showed an inverse U-shape curve. Serum lycopene concentration was negatively correlated with the levels of serum TC, TG, LDL-C, as well as the cerebral LDL-C, VEGF, and VCAM-1; Serum lycopene concentration was positively correlated with the expression of Claudin-5 and the number of neurons in hippocampal CA1 and CA3. Lycopene could also reduce the pathologic change of these areas. These results suggested an inverse U-shape relation between dose and serum concentration of lycopene, and intermediate doses were most effective to protect cerebral vessels and neurons from being damaged by hyperlipidemia. PMID- 30474365 TI - Relay Catalysis of Rh (II) and Cobaloxime: Stereoselective Synthesis of Spiroindanones from N-Sulfonyl-1,2,3-triazoles. AB - A novel relay Rh (II)/cobaloxime (III) dual catalysis strategy has been developed for the stereoselective synthesis of indolyl spiroindanones from readily accessible N-sulfonyl-1,2,3-triazoles. This binary-catalyst system enables an aza vinyl carbene initiated Pictet-Spengler-type cyclization and sequential cobaloxime promoted intramolecular Mannich-type reaction cascade. The easily accessible reagents, high diastereoselectivity, and operational simplicity make this reaction a method of choice for the preparation of functionalized spiroindanones, which are difficult to access by other classic reactions in one step. PMID- 30474366 TI - Detachable polyzwitterion coated ternary nanoparticles based on peptide dendritic carbon dots for efficient drug delivery in cancer therapy. AB - In this work, we presented the ternary nanoparticles [pCBMA(CD-D/DOX)] based on peptide dendritic carbon dots (CDs) to realize tumor-specific drug delivery and high efficient cancer therapy. The versatile nanoparticles could achieve "stealth" delivery in blood due to the anti-fouling zwitterion coating. Meanwhile, charge changes of the zwitterions could be moderated during their transportation toward/inside tumor cells, where subtle environmental pH variations acted as potent stimuli to actualize desired functions. In particular, the detachment of the zwitterionic "coat" at tumor site resulted in exposure of the abundant peripheral guanidine groups on peptide dendritic carbon dots (CD D/DOX) owing to the extracellular pH environment (pH 6.8) induced charge conversion. Consequently, the positively charged CD-D/DOX (+7.02 mV) interacted with the negatively charged cancer cell membrane to enhance cellular uptake. After endocytosis, tumor intracellular microenvironments (acidic condition and high glutathione level) could launch effective disintegration of the CD-D/DOX entities due to acid-induced protonation of guanidine groups and glutathione induced cleavage of peptide dendritic components on CDs, and then effective endosomal escape and fast doxorubicin hydrochloride (DOX.HCl) release (73.2 % accumulative release within 4 h) were achieved successively. This strategy enabled a 9.19-fold drug release rate at tumor sites in comparison with the one at the physiological environment. Moreover, the excellent fluorescent property of CDs endowed the pCBMA(CD-D/DOX) fluorescence bioimaging function. In view of the above-mentioned advantages, pCBMA(CD-D/DOX) exhibited outstanding anti-tumor activities both in vitro and in vivo, demonstrating much higher anti-tumor efficacy and less side effects than the free DOX.HCl. PMID- 30474367 TI - Graphene based nanocomposites for efficient photocatalytic hydrogen evolution: insight into the interface toward separation of photogenerated charges. AB - Although the reduced graphene oxide (rGO), as a kind of excellent electron mediator, has been widely applied in the field of photocatalytic H2 evolution, no enough attention is given to study the interface between photocatalyst and rGO, which is the key point to affect the transportation of photogenerated electron. Herein, in order to research the heterojunctions interface, the series of SrTiO3 photocatalysts with different crystal facets were fabricated to load with rGO for photocatalytic H2 evolution. Raman spectrum, X-ray photoelectron spectroscopy (XPS) and density functional theory (DFT) study verified that the rGO mainly anchored on the Ti-O bond of SrTiO3. So, as compared to {001} facets sample, the {110} facets of SrTiO3, exposed more Ti and O atoms, can form stronger bond with the rGO. Additionally, DFT study deduced that the photoinduced electron can also immigrate rapidly from Ti-O bond to the rGO, which was in good agreement with the results of photoelectrochemical and photoluminescence (PL) experiments. Meanwhile, experimentally, the 1 % wt. rGO@SrTiO3 with {110} facets nanocomposite showed the superior photocatalytic hydrogen generation rate (3.82 mmol/h/g), which was 2.2 times and 3.2 times higher than that of pure SrTiO3 with the same facets and 1 % wt. rGO@SrTiO3 with {001} facets, respectively. Both experiments and theoretical calculations at the nanocomposites interface unveiled that the synergetic effect of rGO loading and SrTiO3 facets engineering effectively prompted the separation and immigration of photogenerated electron. This study affords us a rational design of a high efficiency rGO-based heterogeneous photocatalysts for solar energy conversion. PMID- 30474368 TI - One-pot Synthesis of 2-Benzyl/2-Allyl Substituted Thiobenzoazoles Using Transition-metal-free Conditions in Water. AB - A transition-metal-free protocol for the one-pot synthesis of 2-benzyl/2-allyl substituted thiobenzoazoles in water was developed. The cyclization of 2 aminothiophenols, 2-aminophenols, and 1,2-phenylenediamines with tetramethylthiuram disulfide (TMTD) gave mercapto benzoheterocycles, the subsequent C-S coupling with benzyl or allyl halides furnished the desired products in good to excellent yields. This method features transition-metal free, water as solvent, easy performance, mild reaction conditions, wide substrate scope, and good to excellent yields, thus paves an efficient and useful way to establish the library of potentially active drug molecules. PMID- 30474369 TI - A chemiresistor sensor based on azo-polymer and graphene for real-time monitoring of mitochondrial oxygen consumption. AB - In the present study, a chemiresistor sensor based on a poly (Bismarck Brown Y) reduced graphene oxide nanocomposite was developed to analyze the respiratory capacity of the constituent complexes of the electron transport chain. The sensorial platform was characterized using electrochemical impedance spectroscopy, and oxygen detection was accomplished by measuring the resistive properties of the sensor at fixed AC frequency. The impedance decreased significantly in response to small variations of the O2 concentrations tested up to saturation of the electrolyte solution with molecular oxygen. The resistive response of the sensor at 0.1 Hz was linear over the oxygen concentration range from 1.17 x 10-5 mol L-1 to 1.02 x 10-3 mol L-1, with a detection limit of 3.60 x 10-7 mol L-1. Using the new O2 sensing platform, we monitored gradients in static cultures of adherent cells exposed to graded oxygen both at rest and upon metabolic stimulation. Under high dissolved oxygen conditions, the respiration of resting cells dictated that local O2 was moderately reduced, while cell metabolic stimulation triggered a major redistribution of O2. The usefulness of the developed sensor was demonstrated by continuous monitoring of mitochondrial oxygen consumption in various biologic applications. PMID- 30474370 TI - Tea polysaccharides as potential therapeutic options for metabolic diseases. AB - Tea polysaccharides (TPS) are regarded as some of the main bioactive constituents of tea made from the leaves and buds of tea plant (Camellia sinensis L.). An increasing number of studies have demonstrated that TPS can reduce the risk of type 2 diabetes, obesity and other metabolic diseases. However, the potential mechanisms responsible for anti-diabetic and anti-obesogenic activities of TPS remain unclear. Therefore, the cellular and physiological mechanisms that underlie its anti-diabetic and anti-obesogenic effects including anti-oxidant and anti-inflammation effects, inhibition of digestive enzymes, prevention of macronutrient absorption and expression of gene and protein were summarized in this review. Furthermore, the gastrointestinal functions of TPS and the role of gut microbiota in the prevention and treatment of metabolic diseases were discussed. It is expected that the present review will be helpful for enhancing our knowledge about the health-promoting of TPS on metabolic diseases and for stimulating the further works on TPS. PMID- 30474371 TI - Synthesis of 2H-Azirines via Iodine-Mediated Oxidative Cyclization of Enamines. AB - A facile and practical oxidative cyclization reaction of enamines to 2H-azirines has been developed employing molecular iodine. The features of the present synthetic approach include no use of transition metals, mild reaction conditions and simplicity of operation. Under the optimal reaction conditions, a variety of 2H-azirine derivatives were synthesized from simple and readily accessible enamine precursors in an efficient and scalable fashion. PMID- 30474373 TI - Strain tuned topological insulator and Rashba induced anisotropic momentum locked Dirac-cones in two-dimensional SeTe monolayer. AB - Rashba spin-orbit coupling (SOC) in Topological Insulator (TI) is very interesting phenomenon and has received extensive attention in two-dimensional (2D) materials. However, the coexistence of Rashba SOC and band topology, especially for materials with square lattice, is still lacking. Here, by using first-principles calculations, we propose for the first time SeTe monolayer as a 2D candidate with this novel properties. We find that square lattice exhibits anisotropic band dispersions near the Fermi level and Rashba effect related to large SOC and inversion asymmetry, which lead to Dirac semimetal state. Another prominent feature is that SeTe can turn into a topological state under a tensile strain of only 1%, characterized by the Z2 invariant and helical edge states. Our findings demonstrate that SeTe is a promising materials for novel electronic and spintronics applications. PMID- 30474372 TI - Synthesis of l-Deoxyribonucleosides from d-Ribose. AB - The preparation of 2-deoxy-l-ribose derivatives or mirror image deoxyribonucleosides (l-deoxyribonucleosides) from d-ribose is reported. Starting from inexpensive d-ribose, an acyclic d-form carbohydrate precursor was synthesized to study a unique carbonyl translocation process. In this novel radical reaction, not only was the configuration of the sugar transformed from the d-form to the l-form, but also deoxygenation at the C(2) position of the sugar was successfully achieved. This is one of the most practical methods for converting a d-sugar to a 2-deoxy-l-sugar in a one-step reaction. To further identify the reaction product, radical reactions followed by treatment with 1,3 propanedithiol and then benzoylation were performed to afford a dithioacetal derivative. The stereochemistry and configuration of the 2-deoxy-l-ribose dithioacetal derivative were confirmed by its X-ray crystal structure. To further apply this methodology, a diethyl thioacetal derivative was formed, followed by selective benzoyl protection, and an NIS-initiated cyclization reaction to give the desired ethyl S-l-2-deoxyriboside, which can be used as a 2-deoxy-l-ribosyl synthon in the formal total synthesis of various l-deoxyribonucleosides, such as l-dT. PMID- 30474374 TI - Pd-Catalyzed Dearomative Carboxylation of Indolylmethanol Derivatives. AB - By using a new catalytic system (PdCl2[P( n-Bu)3]2 in combination with ZnEt2), various 3-indolylmethanol derivatives were successfully carboxylated with CO2 (1 atm) via dearomatization of the indole nucleus, affording 3-methyleneindoline-2 carboxylates. In contrast, carboxylation of 2-indolylmethanol derivatives afforded unexpected doubly carboxylated products, which are useful synthetic precursors for biologically active compounds. PMID- 30474375 TI - Tethered Bichromophoric Fluorophore Quencher Voltage Sensitive Dyes. AB - Voltage sensitive dyes (VSDs) are used for in vitro drug screening and for imaging of patterns of electrical activity in tissue. Wide application of this technology depends on the availability of sensors with high sensitivity (percent change of fluorescence per 100mV), high fluorescence quantum yield, and fast response kinetics. A promising approach uses a 2-component system consisting of anionic membrane permeable quenchers with fluorophores labeling one side of the membrane; this produces voltage-dependent fluorescence quenching. However, the quencher must be kept at low concentrations to minimize pharmacological effects, thus limiting sensitivity. By developing tethered bichromophoric fluorophore quencher (TBFQ) dyes, where the fluorophore and quencher are covalently connected by a long hydrophobic chain, the sensitivity is maximized and is independent of VSD concentration. A series of 13 TBFQ dyes based on the AminoNaphthylEthenylPyridinium (ANEP) fluorophore and the dipicrylamine anion (DPA) quencher have been synthesized and tested in an artificial lipid bilayer appa-ratus. The best of these, TBFQ1, shows a 2.5 fold change in fluorescence per 100mV change in mem-brane potential, and the response kinetics is in 10-20 ms range. This sensitivity is an order of magnitude better than commonly used VSDs. However the fluorescence quantum yield is only 1.6%, which may make this first generation of TBFQ VSDs impractical for in vivo electrical imaging. Nevertheless, the design principles established here can serve as foundation for improved TBFQ VSDs. We believe this approach promises to greatly enhance our ability to monitor electrical activity in cells and tissues. PMID- 30474376 TI - Eat, Pray, Move: A Pilot Cluster Randomized Controlled Trial of a Multilevel Church-Based Intervention to Address Obesity Among African Americans and Latinos. AB - PURPOSE:: To implement a multilevel, church-based intervention with diverse disparity populations using community-based participatory research and evaluate feasibility, acceptability, and preliminary effectiveness in improving obesity related outcomes. DESIGN:: Cluster randomized controlled trial (pilot). SETTING:: Two midsized (~200 adults) African American baptist and 2 very large (~2000) Latino Catholic churches in South Los Angeles, California. PARTICIPANTS:: Adult (18+ years) congregants (n = 268 enrolled at baseline, ranging from 45 to 99 per church). INTERVENTION:: Various components were implemented over 5 months and included 2 sermons by pastor, educational handouts, church vegetable and fruit gardens, cooking and nutrition classes, daily mobile messaging, community mapping of food and physical activity environments, and identification of congregational policy changes to increase healthy meals. MEASURES:: Outcomes included objectively measured body weight, body mass index (BMI), and systolic and diastolic blood pressure (BP), plus self-reported overall healthiness of diet and usual minutes spent in physical activity each week; control variables include sex, age, race-ethnicity, English proficiency, education, household income, and (for physical activity outcome) self-reported health status. ANALYSIS:: Multivariate linear regression models estimated the average effect size of the intervention, controlling for pair fixed effects, a main effect of the intervention, and baseline values of the outcomes. RESULTS:: Among those completing follow-up (68%), the intervention resulted in statistically significantly less weight gain and greater weight loss (-0.05 effect sizes; 95% confidence interval [CI] = -0.06 to -0.04), lower BMI (-0.08; 95% CI = -0.11 to 0.05), and healthier diet (-0.09; 95% CI = -0.17 to -0.00). There was no evidence of an intervention impact on BP or physical activity minutes per week. CONCLUSION:: Implementing a multilevel intervention across diverse congregations resulted in small improvements in obesity outcomes. A longer time line is needed to fully implement and assess effects of community and congregation environmental strategies and to allow for potential larger impacts of the intervention. PMID- 30474377 TI - Walkable Urban Design Attributes and Japanese Older Adults' Body Mass Index: Mediation Effects of Physical Activity and Sedentary Behavior. AB - PURPOSE:: The purposes of this study were to examine associations between objectively measured walkable urban design attributes with Japanese older adults' body mass index (BMI) and to test whether objectively assessed physical activity and sedentary behavior mediated such associations. DESIGN:: Cross-sectional. SETTING:: Matsudo City, Chiba Prefecture, Japan. PARTICIPANTS:: Participants were 297 older residents (aged 65-84 years) randomly selected from the registry of residential addresses. MEASURES:: Walkable urban design attributes, including population density, availability of physical activity facilities, intersection density, and access to public transportation stations, were calculated using geographic information systems. Physical activity, sedentary behavior, and BMI were measured objectively. ANALYSIS:: The relationships of walkable urban design attributes, Walk Score(r), and BMI were examined by multiple linear regression with adjustment for covariates in all models. Mediation effects of the physical activity and sedentary behavior variables in these relationships were tested using a product-of-coefficients test. RESULTS:: Higher population density and Walk Score(r) were associated with lower BMI. Light and moderate-to-vigorous physical activities partially mediated the relationships between these walkable urban design attributes and BMI. CONCLUSIONS:: Developing active-friendly environmental policies to (re)design neighborhoods may not only promote active transport behaviors but also help in improving residents' health status in non Western contexts. PMID- 30474378 TI - Metacognitive Reflection and Insight Therapy (MERIT) Among People With Schizophrenia: Lessons From Two Case Studies. AB - People with schizophrenia spectrum disorder face a major challenge in the ability to reflect on their own and others' mental activities and about specific psychological problems in their lives. These deficits are associated with increased symptoms and lower functioning. Specific interventions have been designed to enhance these abilities, one of which is metacognitive reflection and insight therapy (MERIT). Several case studies and a recent pilot study have shown increased metacognitive abilities and a decrease in symptoms among clients after MERIT. This article presents two case studies of clients diagnosed with schizoaffective disorder whose psychotherapy, conducted in Israel, incorporated the MERIT protocol. Outcome measures were taken before and after treatment, and metacognitive abilities were assessed at five time points throughout treatment. Clinical implications and limitations are discussed. PMID- 30474379 TI - How often does computed tomography (CT) of the brain demonstrate a cause for psychosis? A 7-year retrospective study at a tertiary metropolitan hospital. AB - OBJECTIVES:: The aim of the study was to determine the diagnostic yield of computed tomography (CT) of the brain for the investigation of psychosis. METHODS:: CT brain requests describing psychosis over a 7-year period at a 500 bed major metropolitan hospital were identified retrospectively. Patients were excluded if they were aged greater than 50 years or if the CT request described focal neurological findings on examination, trauma/falls or known brain tumour, demyelinating disorder, encephalopathy, seizure disorder, congenital brain anomaly, stroke or traumatic brain injury. RESULTS:: A total of 805 patients meeting the inclusion and exclusion criteria were identified, representing the largest published study on this topic. Only 0.4% of patients (3 out of 805) had a potential cause for psychosis demonstrated on CT. None of these patients had their management altered as a result. An additional 0.6% of patients (5 out of 805) had significant pathology that was deemed unrelated to their psychosis. CONCLUSIONS:: The diagnostic value of CT in the setting of psychosis was found to be extremely low in patients meeting the inclusion and exclusion criteria. Given the risk of ionising radiation and the expenditure of time and cost, more judicious use of CT is suggested. PMID- 30474381 TI - [Evaluation of chitosan-based nasal dressing in animal model]. AB - INTRODUCTION: The usefulness of nasal packing after endoscopic sinus surgery is still debated in the literature. AIM: Our aim was to evaluate the effects of a new chitosan-based nasal dressing in animal model. METHODS: Standard mucosal damage was caused in both nostrils during endoscope-assisted procedure in ten rabbits. Chitosan nasal packing was inserted in a randomly selected nasal fossa of each animal, while the other side was left unpacked. Symptoms were evaluated during nasal endoscopy on the 12th postoperative week. The degree of mucosal oedema, crusting, adhesions and the nasal discharge were observed according to the modification of the grading system of Berlucchi et al. The higher scores indicated the worse complaints. RESULTS: Assessing the adhesion formation, 1 point was given (mean: 0.1; standard deviation [SD]: 0.32) for the unpacked side, while in the tamponated side no adhesion formation was observed. The total score of crusting in the non-packed side was lower with 1 point (total score: 9, mean: 0.90; SD: 0.74) than in the chitosan side (total score: 10, mean 1.00; SD: 0.82). Discharge or mucosal oedema were not observed during the follow-up period. The mean rate, measured with electronmicroscopy, was 22.06% (SD: 0.25) in the chitosan side, while in the non-packed side it was 36.11% (SD: 0.48). The differences did not show any significance (p = 0.806). CONCLUSION: During the examinations, none of the animals suffered complications. The symptoms of the packed and the non-packed nasal cavities did not differ significantly on the basis of our examinations. Orv Hetil. 2018; 159(47): 1981-1987. PMID- 30474380 TI - Association between problematic Internet use, sleep disturbance, and suicidal behavior in Chinese adolescents. AB - BACKGROUND AND AIMS: This large-scale study aimed to test (a) associations of problematic Internet use (PIU) and sleep disturbance with suicidal ideation and suicide attempts among Chinese adolescents and (b) whether sleep disturbance mediates the association between PIU and suicidal behavior. METHODS: Data were drawn from the 2017 National School-based Chinese Adolescents Health Survey. A total of 20,895 students' questionnaires were qualified for analysis. The Young's Internet Addiction Test was used to assess PIU, and level of sleep disturbance was measured by the Pittsburgh Sleep Quality Index. Multilevel logistic regression models and path models were utilized in analyses. RESULTS: Of the total sample, 2,864 (13.7%) reported having suicidal ideation, and 537 (2.6%) reported having suicide attempts. After adjusting for control variables and sleep disturbance, PIU was associated with an increased risk of suicidal ideation (AOR = 1.04, 95% CI = 1.03-1.04) and suicide attempts (AOR = 1.03, 95% CI = 1.02 1.04). Findings of the path models showed that the standardized indirect effects of PIU on suicidal ideation (standardized beta estimate = 0.092, 95% CI = 0.082 0.102) and on suicide attempts (standardized beta estimate = 0.082, 95% CI = 0.068-0.096) through sleep disturbance were significant. Conversely, sleep disturbance significantly mediated the association of suicidal behavior on PIU. DISCUSSION AND CONCLUSIONS: There may be a complex transactional association between PIU, sleep disturbance, and suicidal behavior. The estimates of the mediator role of sleep disturbance provide evidence for the current understanding of the mechanism of the association between PIU and suicidal behavior. Possible concomitant treatment services for PIU, sleep disturbance, and suicidal behavior were recommended. PMID- 30474382 TI - [The reliability and validity of the Hungarian version of the Surgical Fear Questionnaire]. AB - INTRODUCTION: Interdisciplinary studies confirm that surgical fear experienced by patients can have a substantial effect on the outcome of the surgery and the healing process after surgery. AIM: The aim of this study was to assess the reliability and validity of the Hungarian version of the Surgical Fear Questionnaire in cancer patients. METHOD: 149 patients were assessed using the Spielberger Anxiety Inventory, the Beck Depression Inventory, the Visual Analogue Scale and the Surgical Fear Questionnaire. RESULTS: The scale showed excellent internal consistency (Cronbach-alfa = 0.878; 0.885). The Surgical Fear Questionnaire scores moderately correlated with anxiety, depression and anticipated pain after surgery. CONCLUSION: The reliability and validity of the Hungarian version of the Surgical Fear Questionnaire in the sample were excellent. The questionnaire turned out to be a useful psychometric tool in the measurement of surgical fear. Orv Hetil. 2018; 159(47): 1988-1993. PMID- 30474383 TI - [Alteration in the expression of platelet microRNAs in diseases with abnormal platelet activation]. AB - MicroRNAs (miRNA) are short, non-coding RNAs consisting of 18-25 nucleotides that regulate posttranscriptionally the gene expression involved in the regulation of physiological processes of the cells. Their key role is to modulate the translation of target mRNAs via binding to complementary sequences within the 3' UTRs of mRNAs resulting in altered protein synthesis or even the degradation of mRNAs. miRNAs are carried not only by cells with nucleus, but also in platelets, red blood cells, and they are present in the circulation, in urine and in other body fluids as well. The fact about functional miRNAs in platelets without nucleus having a half-life of 8-12 days was questioned for a long time, thus it was also obscure whether platelets are able to produce proteins de novo when being exposed to different challenges. In the last few years, several publications have described the expression and function of certain platelet mRNAs with their regulatory miRNAs in terms of regulation of cell activation, especially in diseases in which platelet activation status is elevated, such as in type 2 diabetes mellitus or in sepsis. Apart from their pathophysiological role, miRNAs may be applied as potential new biomarkers in the investigation or differential diagnosis of these clinical conditions. This review article sought to summarize the recent findings about platelet miRNAs focusing on their altered expression in diabetes and sepsis. Orv Hetil. 2018; 159(47): 1962-1970. PMID- 30474384 TI - [Trisomy 9p and clinical heterogeneity: case report of an unusual presentation]. AB - Whole or partial trisomy of the short arm of chromosome 9 (9p) is considered to be one of the more frequent chromosome abnormalities compatible with life. The duplication may affect various organs, however the most common symptoms are certain specific facial dysmorphisms and abnormalities of the fingers, toes and nails. A one month old boy presented with failure to thrive, jaundice, ventricular septal defect (VSD) and dysmorphic face. He displayed symptoms of heart failure. The cardiologic examination revealed a significant VSD, hypoplasia of the aortic arch, pulmonary hypertension, decompensated circulatory failure and moderate left ventricle dysfunction. Routine cytogenetic analysis revealed a supernumerary marker chromosome. Fluorescence in situ hybridization (FISH) identified this as the short arm of chromosome 9. The child's karyotype was determined as 47,XY,+der(9)dup(9)(p10p24)dn. Due to his worsening condition and the high risk of the operation, it was decided to forego the procedure. After a short palliative care the child passed away. The child's clinical presentation and the uncharacteristic severity of his condition show that chromosome abnormalities involving duplicated genetic material are extremely heterogeneous. Thus treatment of each child should be individualized and may also involve difficult ethical considerations. Orv Hetil. 2018; 159(47): 1994-2000. PMID- 30474386 TI - Employing the Sirolimus-Eluting Poly (Propylene Carbonate) Mesh for the Prevention of Arteriovenous Graft Stenosis in Rats. AB - Poly (propylene carbonate, PPC) is a new member of the aliphatic polyester family. An outstanding feature of PPC is that it produces mainly water and carbon dioxide when degraded in vivo, causing minimal side effects. This unique property together with excellent biocompatibility and biodegradability makes PPC a promising material for drug delivery. In this study, we explored the effect of the sirolimus (an inhibitor of cell growth)-eluting PPC mesh on graft stenosis and its possible mechanisms in a rat arteriovenous grafting model. The PPC mesh was prepared by electrospinning. A jugular vein to abdominal aortic autograft transplantation model was established in rats. The graft was then treated by wrapping with the drug mesh or the drug-free mesh or left untreated. Four weeks posttransplantation, neointima was measured with hematoxylin and eosin staining, matrix metalloproteinase-2 (MMP-2), and MMP-9, and proliferating cell nuclear antigen (PCNA) in the grafts were assayed by Western blotting and immunohistochemistry, respectively. In vitro rat aortic adventitial fibroblast cell (RAAFC) migration was assessed using the Boyden chamber assay, and phospho mammalian target of rapamycin (mTOR) levels in RAAFCs were determined by Western blotting. Animals with the drug mesh had an intimal area index of 4.87% +/- 0.98%, significantly lower than that of the blank group (14.21% +/- 2.56%) or the PPC group (15.03% +/- 2.35%, both P < .05). The sirolimus mesh markedly suppressed MMP-2 and MMP-9 expression, decreased PCNA-positive cell numbers, inhibited RAAFC migration, and reduced phospho-mTOR levels. Our data suggest that the sirolimus-eluting PPC mesh might be potentially applied for the management of grafting stenosis. PMID- 30474385 TI - [Studying the health behavior of asthmatic children regarding the dimensions of media and internet usage and self-esteem]. AB - INTRODUCTION: According to the literature, somatic and psychological factors are connected with asthma bronchiale. The health behavior of these patients can be influenced by the virtual world. AIM: We wish to analyze social media and internet usage, self-esteem and sociodemographic data connected to attachment. METHOD: For our research, the Facebook Intensity Scale, the Problematic Internet Usage Questionnaire, the Rosenberg Self-Esteem Scale and a socio-demographic questionnaire were used. We interviewed 175 asthmatic children from the age of 10 to 18 (92 boys, 83 girls). RESULTS: Asthmatic girls, children who went to daycare (under the age of 3) and who were not breastfed use Facebook more than boys, children who stayed at home instead of daycare and who were breastfed (p<0.01). There is no difference in their internet usage. Breastfeeding (even if it only lasted for 1-7 days) can strengthen attachment which is shown in our results regarding social media usage compared with children who were not breastfed (p<0.01). A negative relation with medium strength was found between the number of siblings (rho = -0.400; p<0.01) and the self-esteem and Facebook usage (rho = 0.475; p<0.01). There is a positive correlation between Facebook usage and the size of the place the children live in (rho = 0.492; p<0.01). CONCLUSIONS: Asthmatic youth use social media more frequently which provides social feedback to compensate their self-esteem, especially by girls. As protection factors, we can emphasize the existence of human relationships and the importance of an early mother-child bond. Orv Hetil. 2018; 159(47): 1971-1980. PMID- 30474387 TI - Psychological distress and health-related quality of life in parents of children referred to an outpatient service for children with developmental disorders. AB - OBJECTIVES:: The current study's aim was to measure anxiety, depression and quality of life in parents of children referred for developmental evaluation. METHODS:: The Hospital Anxiety and Depression Scale and the Short Form 36 Health Survey were used to assess anxiety, depression and quality of life, respectively. RESULTS:: One hundred and thirty parents participated in the study, 95 with a child referred for evaluation and 35 with healthy children. Parents of developmentally impaired children reported increased anxiety ( p=0.002) and depression ( p<0.001) and worse social functioning ( p=0.002) and mental health ( p=0.017). Mothers of developmentally impaired children reported significantly increased anxiety symptoms ( p=0.012) and bodily pain ( p=0.046) and lower levels of vitality ( p=0.009), social functioning ( p=0.005) and mental health ( p=0.008). More children in the family correlated with increased anxiety scores ( p=0.021), while higher child age was associated with more anxiety symptoms ( p=0.002), more role limitations due to emotional problems ( p=0.003) and worse mental health ( p=0.002). CONCLUSIONS:: Parenting children with developmental difficulties is associated with significant psychological distress and disturbed quality of life. PMID- 30474388 TI - Combination long-acting injectable (LAI) antipsychotic medication in adolescents with severe psychosis and aggression: a case series. AB - OBJECTIVES:: We examine the use of combination long-acting injectable (LAI) antipsychotic medication for adolescents with severe psychosis and aggression. We discuss benefits and risks with this approach, for a highly challenging small group of young people. METHODS:: A clinical summary is given of three adolescents admitted to a secure adolescent forensic inpatient unit, and the literature is reviewed. RESULTS:: In these adolescents with severe psychosis, aggression and violent offending, combination LAI antipsychotics effectively treated psychosis and enabled transfer to less restrictive settings. Brief Psychiatric Rating Scale (BPRS) scores decreased significantly with treatment, without any severe adverse effects. CONCLUSIONS:: Combination LAI antipsychotics may be an effective treatment for adolescents with severe psychosis and aggression where clozapine is not a realistic therapeutic option. Close monitoring for side-effects, clear documentation of clinical reasoning and appropriate safeguards are important. PMID- 30474389 TI - Hip Hip Hooray, ECT turns 80! AB - OBJECTIVE:: This paper reviews the history of electroconvulsive therapy (ECT) with an emphasis on the Australian context over the past 30 years. The review includes data collection, the contribution of the RANZCP, and changes in legislation. CONCLUSION:: ECT remains the most effective treatment for severe depression. Since the 1950s efforts have been made to make it more effective, tolerable and acceptable. Over the same period, significant social and political forces have acted to have the practice of ECT restricted or banned. Psychiatrists, through the RANZCP and other bodies, have the responsibility to promote quality ECT practice, advocate for patients, carers, and clinicians, counter inaccurate negative portrayals, and lobby for balanced legislation for ECT and other neurostimulation. PMID- 30474390 TI - Prevalence of self-reported computer vision syndrome symptoms and its associated factors among university students. AB - PURPOSE:: To determine the prevalence of symptoms of computer vision syndrome and to identify its associated factors. The secondary objective was to assess knowledge and practices related to preventing computer vision syndrome symptoms. METHODS:: The data for this cross-sectional study were collected through a self administered questionnaire distributed to 713 female undergraduates studying business and medicine in Saudi Arabia. The questionnaire included computer vision syndrome validated symptoms and factors associated with computer vision syndrome development. RESULTS:: The most common symptom due to prolonged computer use was neck or shoulder pain, reported by 82.2% of the subjects. Overall, 66.5% of the subjects suffered from headache and 51.5% from dry eyes, in mild, moderate, or severe form. Business students were 1.6 times as likely as medical students to suffer from computer vision syndrome (odds ratio = 1.65; 95% confidence interval: 1.22, 2.24). The use of electronic devices for more than 5 h (odds ratio = 1.52; 95% confidence interval: 1.07, 2.16) was also associated with experiencing computer vision syndrome symptoms. Regarding computer vision syndrome prevention, factors such as hours of use, screen distance, screen brightness, and room illumination showed statistically significant difference between the two groups (p < 0.0001). CONCLUSION:: The prevalence of computer vision syndrome symptoms was significantly higher among business students, who reported lower awareness and poor practice measures of computer use recommendations. Relevant awareness campaigns focusing on the appropriate use of computers are highly recommended. PMID- 30474391 TI - Transgender ward allocation in single-sex mental health wards: contemporary considerations. AB - OBJECTIVES:: Allocation of transgender patients to single-sex mental health wards in Australasia can be a complex and challenging decision in the absence of adequate awareness, education and policy that prioritize consumer safety and preference. It is a point of care that can go wrong for a transgender person. We examine relevant literature, law and existing principles of care and offer an approach. CONCLUSION:: Transgender individuals experience an excess health burden and have difficulties that are poorly understood by many health practitioners. This is partly the result of both informational and institutional biases. Relevant legal frameworks, while supportive, are still to be translated into policy. We suggest a framework that canvasses the needs of various stakeholders and considers them equally in the decision-making process. PMID- 30474392 TI - Laminar drainage implant. AB - OBJECTIVE:: To assess the feasibility of a novel surgical technique in painful blind eyes. DESIGN:: A prospective safety study conducted at the Federal University of Minas Gerais, Brazil. PARTICIPANTS/SAMPLES:: A total of 15 end stage glaucomatous eyes without light perception vision. METHODS:: After implantation, conjunctival hyperemia, discharge, erosion, aqueous humor leakage, corneal edema, hyphema, anterior chamber cells and depth, dislocation of the implant, and filtering bleb height were assessed by slit-lamp biomicroscopy. Intraocular pressure was measured preoperatively and 24 months following surgery. A numerical rating scale was used to evaluate pain. Anterior segment optical coherence tomography was also assessed. RESULTS:: Laminar drainage implant surgery was performed in all patients without major complications. Mean intraocular pressure was significantly reduced after surgery without hypotensive medication (preoperatively 54.5 +/- 5.1 mmHg vs 24 months after surgery 37.0 +/- 15.4 mmHg, p = 0.003). Subjective ocular pain intensity also reduced (preoperatively 10 vs at 24-month follow-up visits 0). Corneal edema incidence reduced from 85.7% (95% confidence interval: 57.2%-98.2%) to 16.7% (95% confidence interval: 2.1%-48.4%) at the 24-month follow-up. No patients experienced a prolonged flat anterior chamber or erosion of overlying tissues. CONCLUSION:: The surgery was feasible and safe in painful blind eyes. PMID- 30474393 TI - Auditory P300 as a Neurophysiological Correlate of Symptomatic Improvement by Transcranial Direct Current Stimulation in Patients With Schizophrenia: A Pilot Study. AB - BACKGROUND: The reduced amplitude, prolonged latency, and increased intertrial variability of auditory P300 have been consistently reported in relation to the symptomatic severity of schizophrenia. This study investigated whether auditory P300 event-related potentials can be used as an objective indicator of symptomatic improvement by transcranial direct current stimulation (tDCS) in patients with schizophrenia. METHODS: Ten patients with schizophrenia received 20 minutes of 2-mA tDCS twice a day for 5 consecutive weekdays. The anode was placed over the left dorsolateral prefrontal cortex, and the cathode was placed over the left temporo-parietal cortex. The Positive and Negative Syndrome Scale (PANSS) and the auditory P300 were measured for each participant at baseline and after the completion of the tDCS applications. RESULTS: The participants showed significant improvement in the positive and negative symptoms as indexed by change in the PANSS scores by the tDCS. The P300 amplitude, latency, and intertrial variability did not statistically significantly differ after the tDCS application. However, a significant association was observed between the reduced P300 intertrial variability and improvement in the positive symptoms by tDCS. In addition, the changes in both the P300 latency and intertrial variability were significantly correlated with reduced negative symptoms after the tDCS application. CONCLUSIONS: Although this pilot study is limited by the small sample size and lack of a sham control, the results suggest that auditory P300 may be a putative marker reflecting the effect of tDCS on the positive and negative symptoms of schizophrenia. PMID- 30474394 TI - Indoor air-related symptoms and volatile organic compounds in materials and air in the hospital environment. AB - In this case study, hospital workers did suffer from symptoms related to the poor indoor air quality. To investigate reasons for symptoms MM40-survey and house inspection methods were performed. The study consisted of 49 operating rooms and 470 employees. MM-40 survey revealed that over 40% of the staff suffered from skin reactions, over 50% had upper respiratory tract symptoms and 25% suffered headaches. No reason for the staff's symptom could be found in the structural studies of workplaces. The mean air exchange rate of the rooms was 5.51/h. In total 61 materials and 49 indoor air samples were taken. The most frequently found compounds in the material samples were 2-ethyl-1-hexanol and aliphatic hydrocarbons. VOC emissions were high in some of the material samples and they presumably were the one reason for the workers' symptoms observed in some in of the rooms. However, indoor air VOC concentrations were low in most of the cases. According to the linear regression model emissions from flooring material couldn't explain the indoor air concentration of the VOCs. One reason for that was the high ventilation rates of the rooms, which presumably kept VOC levels in indoors low. In addition, VOC concentrations indoors were strongly related to the ongoing healthcare activities in the hospital. PMID- 30474395 TI - Detection of Sapoviruses in two biological lines of Tunisian hospital wastewater treatment. AB - The efficiency of rotating biodisks and natural oxidizing lagoon procedures is investigated at a Tunisian semi-industrial pilot plant, El Menzeh I, where the wastewater is mainly provided by three different neighbouring hospital clinics. Throughout 2011, 102 wastewater samples were collected from the two mentioned wastewater treatment procedures. Results showed that the Sapovirus (SaV) frequency was approximately 29.4% using the real-time reverse transcription polymerase chain reaction (RT-PCR) technique, and about 16.6% using the conventional RT-PCR. Also, the SaV genogroups and genotypes were identified and genotyping revealed that all of the four Tunisian SaV strains obtained belonged to the two genogroups GIV.1 and GGI.3. In addition, two new genotypes, D and C, were detected. A moderate decrease in the SaV frequencies was observed at the exit of the two treatment processes and the SaV removal rate was around 90% in the natural oxidizing lagoons and 94% in the rotating biodisks procedure showing the temperate sensitivity of these viruses to the implemented biological wastewater. Therefore, an urgent disinfection process should be implemented downstream of the two biological treatment procedures for safe release of treated effluent in the different natural environments. Abbreviations: NoV: Noroviruses; SaV: Sapoviruses; EC: Electrical Conductivity; COD: Chemical Oxygen Demand; BOD5: Biological Oxygen Demand; SS: Suspended Solids; NH4-N: Ammonium Nitrogen; P-PO4: Ortho-Phosphate; AlCl3: aluminum chloride. PMID- 30474396 TI - The Protective Effects of Preconditioning With Dioscin on Myocardial Ischemia/Reperfusion-Induced Ventricular Arrhythmias by Increasing Connexin 43 Expression in Rats. AB - Myocardial ischemia-reperfusion (IR) injury is associated with high disability and mortality worldwide. This study was to explore the roles of dioscin in the myocardial IR rats and discover the related molecular mechanisms. Rats were divided into 5 groups: sham, IR, IR + 15 mg/kg dioscin, IR + 30 mg/kg dioscin, and IR + 60 mg/kg dioscin. Heart rate (HR), mean arterial blood pressure (MAP), and rate pressure product (RPP) were evaluated at 10 minutes before ischemia, immediately after ischemia, and at the beginning, middle, and end of reperfusion. Arrhythmia score and myocardial infarct size were examined in rats of all groups. The serum creatine kinase-muscle/brain (CKMB) and cardiac troponin I (cTnI) levels were analyzed via enzyme-linked immunosorbent assay. Protein amount of total connexin 43 (T-Cx43) and phosphorylated connexin 43 (P-Cx43) was evaluated by Western blot. Ischemia reperfusion significantly decreased HR, MAP, and RPP of rats compared to the sham group. However, dioscin significantly attenuated the above phenomena in a dose-dependent manner. Dioscin markedly inhibited IR-induced increase in arrhythmias score, infarct size, and serum CKMB and cTnI levels. In addition, dioscin strikingly induced IR-repressed expression of T-Cx43 and P Cx43. Our results suggested that dioscin pretreatment exhibited protective effects against myocardial IR injury. Moreover, we found that dioscin attenuated myocardial IR-induced ventricular arrhythmias via upregulating Cx43 expression and activation. PMID- 30474397 TI - The role of pars plana vitrectomy in the management of fungal endogenous endophthalmitis. AB - PURPOSE:: To identify the causative microorganism of fungal endogenous endophthalmitis in our tertiary referral uveitis center and review the therapeutic role of pars plana vitrectomy in patients with fungal endogenous endophthalmitis. METHODS:: Seven eyes of six cases were identified as fungal endogenous endophthalmitis through positive cultures of ocular fluids and clinical presentations. The final anatomical and functional results were evaluated. RESULTS:: Four women (66.7%) and two men (33.3%) underwent vitrectomy. Control of infection was achieved early on in all cases. Candida (71.4%) and Aspergillus (28.6%) species were identified as causative fungi in patients with fungal endogenous endophthalmitis. Two patients were reoperated due to reinfection and retinal detachment, respectively. Visual acuity improved in six eyes (85.7%) and worsened in one eye (14.3%). At the final examination, the retina was flat in all cases. No eye developed phthisis bulbi. CONCLUSION:: Candida species are the most common causative organisms of fungal endogenous endophthalmitis in this study. Pars plana vitrectomy in fungal endogenous endophthalmitis may enhance the treatment of infection by removing fungal elements in the vitreous and aid in diagnosis. Vitrectomy may also be an important tool in the management of vision-threatening post-infectious sequelae such as retinal detachment and reinfections. PMID- 30474398 TI - Ergonomic practices and musculoskeletal disorders among ophthalmologists in India: An online appraisal. AB - INTRODUCTION:: Ergonomics in ophthalmology is neither taught during professional training nor does it readily receive consideration or priority in clinical practice. Owing to a high prevalence of musculoskeletal disorders among ophthalmologists, ergonomic awareness, and practices are vital in averting this modern epidemic. OBJECTIVE:: To assess the ergonomic practices and prevalence of self-reported musculoskeletal disorders among ophthalmologists in India. METHOD:: An online survey was conducted among ophthalmologists who were registered with the All India Ophthalmological Society of India using a pre-tested and validated questionnaire. RESULTS:: The prevalence of self-reported musculoskeletal disorder in the 377 participants was 75.3% (284; 95% confidence interval: 70.6-79.5). Low back pain (149, 52.9%) was the most commonly reported symptom. Musculoskeletal disorder-attributed productivity loss was reported by 58.45% (166) of the respondents. Musculoskeletal disorder was most frequently associated with less than 10 years of work experience (odds ratio: 1.2; 95% confidence interval: 1.1 1.3, p = 0.01) and lack of good clinic (odds ratio: 1.7; 95% confidence interval: 1.1-2.7, p = 0.03) and operation room ergonomic practices (odds ratio: 1.8; 95% confidence interval: 1.1-2.9, p = 0.03). Only 27.9% (105) of the respondents had accessed information related to ergonomics in ophthalmic practice. CONCLUSION:: The self-reported musculoskeletal disorder among ophthalmologists in India is quite high and significant enough to cause some degree of productivity loss. It is thus imperative to emphasize the implementation of good ergonomic practices, especially among relatively young ophthalmologists. PMID- 30474399 TI - Metabolic risk in patients participating in residential rehabilitation programs: how are we doing? AB - OBJECTIVES:: To examine the prevalence of metabolic syndrome and its association with clinical, demographic and lifestyle factors in patients with mental illness participating in residential rehabilitation. METHODS:: A physical health audit of all consumers ( n = 364) in publicly funded residential rehabilitation programs in Queensland was carried out in late 2016. Data collection focused on clinical, demographic and lifestyle factors associated with physical health. RESULTS:: Central obesity was identified in 80% of males and 89% of females and half of the patients (49.4%) met criteria for metabolic syndrome (MetS). The prevalence of MetS in Indigenous patients (66.1%) was 20% higher than the rate found in non Indigenous patients (46.1%). Smoking, substance abuse, gender, Indigenous background, length of stay and rarely eating fruit and vegetables were individually associated with MetS. CONCLUSIONS:: The prevalence of MetS in this cohort is almost double that of the general population, while the rate in Indigenous patients is among the highest reported for those with mental illness. Rehabilitation staff are encouraged to engage more fully in the monitoring of physical health status, sharing this information with consumers and primary care providers, and encouraging consumers to play a greater role in managing their physical health. PMID- 30474400 TI - Patterns of discrepancies in different objects of awareness in mild and moderate Alzheimer's disease. AB - OBJECTIVES: Awareness is considered a heterogeneous and non-linear phenomenon in dementia. We aim to investigate patterns of change of different domains of awareness (awareness of cognitive functioning and health condition, activities of daily living, emotional state, social functioning, and relationships) in people with mild and moderate Alzheimer's disease (AD) and aspects related to each domain. METHOD: Cross-sectional assessment of dyads of people with AD (PwAD) and caregivers (n = 128; CDR1 = 74, CDR2 = 54). PwAD completed assessments about quality of life, cognition and their awareness of disease. Caregivers provided information about PwAD and received quality of life and burden of care assessments. RESULTS: Mild AD group showed a mildly impaired awareness (n = 40; 54.05%), while moderate AD group, showed higher presence of moderately impaired awareness (n = 22; 40.74%). There was a significant difference between groups in awareness of cognitive functioning and health condition (p < 0.004), functional activity impairments (p < 0.001) and total score of awareness (p < 0.01). Conversely, awareness of emotional state (p = 0.22) and of social functioning and relationship (p = 0.44) presented no significant difference between groups. Unawareness of functional activity impairments showed higher discrepancy scores between PwAD and caregivers in both groups. CONCLUSIONS: Significant differences were found only in patterns of discrepancies in awareness of cognitive functioning and health condition, of ADL and socio-emotional functioning. Different factors are related to different domains in mild and moderate group, reinforcing the heterogeneity of awareness in dementia. ADL deficits have an important role in awareness phenomenon, independent of the severity of disease. PMID- 30474401 TI - Can lifelike baby dolls reduce symptoms of anxiety, agitation, or aggression for people with dementia in long-term care? Findings from a pilot randomised controlled trial. AB - OBJECTIVES: To compare a lifelike baby doll intervention for reducing anxiety, agitation, and aggression in older people with dementia in long-term care (LTC), with usual facility care; and explore the perceptions of care staff about doll therapy. METHOD: Pilot, mixed-methods, parallel, randomised controlled trial, with follow-up semi-structured interviews. Thirty-five residents from five LTC facilities in Queensland, Australia were randomised to the lifelike baby doll intervention (three, 30-minute, individual, non-facilitated sessions per week) or usual care. Outcomes were changes in levels of anxiety, agitation, and aggression after the 3-week intervention, and short-term effects at week 1. Following intention-to-treat principles, repeated measure MANOVA was undertaken. Qualitative interviews involved five staff. RESULTS: The doll intervention did not significantly reduce residents' anxiety, agitation, or aggression when compared to usual care at weeks 3 (primary outcome) and 1 (secondary outcome). However, there was a significant group-by-time interaction for the outcome of pleasure - the doll group showed a greater increase in displays of pleasure at week 3 compared to baseline than usual care (F(1,31) = 4.400, p = 0.044; Cohen's d = 0.74). Staff perceived benefits for residents included emotional comfort, a calming effect, and providing a purposeful activity. Perceived limitations were that doll therapy may only be suitable for some individuals, some of the time, and the potential for residents to care for the doll at the expense of their health. CONCLUSIONS: Doll therapy can provide some residents with enjoyment and purposeful engagement. Further research should focus on understanding the individual characteristics and circumstances in which residents most benefit. PMID- 30474402 TI - Impact of Design on Emotional, Psychological, or Social Well-Being for People With Cognitive Impairment. AB - AIM:: The objective of this article is to identify and analyze what is known about characteristics in and around the home that support well-being for those with cognitive impairment. This could provide direction for designers of homes in general, but specifically for designers trying to meet the needs of people with cognitive impairment. BACKGROUND:: It has been established that there is a relationship between psychological well-being and a person's environment. Research also shows that particular design aspects can reduce the impact of cognitive impairment. However, there is limited design expertise in the Australian housing market to create supportive spaces which will help to reduce the impact of the disability for those with cognitive impairment. METHOD:: A literature review was carried out to determine the extent and details of what is known about the relationship of home design and its impact on emotional, psychological, or social well-being for people with cognitive impairment. CONCLUSIONS:: The study indicates that researchers in various disciplines understand that pragmatic design inputs such as thermal comfort and adequate lighting are important for people with cognitive impairment. In addition, some researchers have shown or surmise that there are other "intangible" designer controlled elements that have beneficial impacts on people with cognitive impairment. Details of these intangible elements are sparse, and how much they might improve the quality of life for a person with cognitive impairment is not well understood. Further research is required to meet a growing need. PMID- 30474403 TI - Systematic Review of Physical Activity Interventions and Hispanic Adults. AB - INTRODUCTION:: Physical activity (PA) has demonstrated substantial physical and psychological benefits. However, Hispanics engage in less leisure-time PA when compared with other groups, putting them at higher risk for diseases associated with obesity, such as diabetes mellitus type 2. This literature review was conducted to identify best practices with regard to interventions designed to increase PA among Hispanic adults. METHODS:: Extensive searching located 21 randomized controlled studies conducted in the United States. RESULTS:: Common conceptual frameworks were the transtheoretical model and social cognitive theory. Most interventions used educational sessions with a variety of topics and many used promotoras to increase PA. Outcomes were predominantly examined using self-report PA measures. Walking was the most commonly reported PA behavior. Studies with significant results were those that measured moderate-to-vigorous PA and used theory to guide interventions. Male and older participants were underrepresented. CONCLUSIONS:: Effective culturally appropriate PA interventions for Hispanics adults are needed. Particular attention to intervention tailoring based on country of origin could enhance intervention effectiveness. PMID- 30474404 TI - Polymorphisms in Th17-related genes and the pathogenesis of autoimmune thyroid disease. AB - The prognosis of autoimmune thyroid disease (AITD) including Graves' disease (GD) and Hashimoto's disease (HD) is difficult to predict. We previously suggested that Th17 cells may be associated with the pathogenesis of AITD. However, the association between gene polymorphisms in Th17-related genes and the prognosis of AITD was not clarified. To clarify this association, we genotyped 12 polymorphisms in 11 Th17-related genes (IL1Ra, IL6R, IL17R, IL21R, IL23R, CCR6, SOCS3, RORC, IL17A, IL17F and IL21) in 142 HD patients including 58 patients with severe HD and 48 patients with mild HD, 170 patients with GD including 81 patients with intractable GD and 49 patients with GD in remission, and 84 healthy volunteers. The frequency of the IL17F rs763780 T allele was higher in patients with severe HD than in patients with mild HD (p = .008). The frequency of the IL17R rs9606615 T allele was higher in patients with HD than in normal subjects (p = .011). The frequencies of the SOCS3 rs4969170 AA genotype, CCR6 rs3093024 AA genotype, and IL21 rs907715 AA genotype were higher in patients with intractable GD than in patients with GD in remission (p = .035, p = .002 and p = .030, respectively). In conclusion, IL17R rs9607715 and IL17F rs763780 polymorphisms are associated with the susceptibility and severity of HD, respectively. IL21 rs907715, SOCS3 rs4969170 and CCR6 rs3093024 polymorphisms are associated with the intractability of GD. PMID- 30474405 TI - University physicists and the origins of the National Physical Laboratory, 1830 1900. AB - Traditionally, historians have taken it for granted that Britain's National Physical Laboratory (NPL) was created as the result of demands from a "professional" body of university-based physicists for a state-funded scientific institution. Yet paying detailed attention to the history of the NPL's originating institution, Kew Observatory, shows that the story is not so clear cut. Starting in the 1850s, Kew Observatory was partly a center for testing meteorological instruments and other scientific equipment in return for fees. Long after the 1850s, the observatory was run by self-funded devotees of science. Paid university physicists only assumed a dominant role on its governing committee in the last two decades of the nineteenth century, by which time instrument-testing was already the observatory's main role. This paper argues that the rise of the university physicists - together with the desire of some of these physicists for a national institution that tested electrical standards - can only partially explain the origins of the NPL, and that Kew was in some ways a national physical laboratory before there were many physics teaching posts in British universities. This paper is a case study that illustrates a need to reassess the importance of university physicists in shaping British science at the end of the nineteenth century. PMID- 30474406 TI - Family, Health, and Poverty Factors Impacting Suicide Attempts in Cambodian Women. AB - BACKGROUND: Our recent report demonstrates that 5.5% of Cambodian women have previously attempted suicide. Despite these high rates and critical need for intervention, research on suicide attempts in Cambodia is lacking, and life saving information on suicide prevention is therefore unknown. AIMS: This study explores factors impacting Cambodian women suicide attempts. METHOD: A total of 1,801 women participated in the large national survey during which 100 of these women (5.5%) reported at least one suicide attempt. Of the 100 participants 76 provided qualitative reasons for the suicide attempts. Only the 76 who provided the reasons for suicide attempt were included for analysis in this study. RESULTS: Four major themes emerged: (1) family conflict, (2) emotional distress, (3) poverty, and (4) illness. Family conflict, emotional distress, poverty, and illness were all interrelated with each other; for example, women without money were unable to pay for treatment of otherwise treatable illnesses. LIMITATIONS: Owing to the nature of the data collection, member checking could not be conducted. CONCLUSION: Cumulative and intertwined personal, interpersonal, and contextual-level factors impacting suicide attempts included emotional distress, illness, family conflict, and poverty. Findings highlight points of intervention at individual, familial, and contextual levels to prevent suicide. PMID- 30474407 TI - Assessing the Reliability of the CAMS Rating Scale Using a Generalizability Study. AB - BACKGROUND: An important consideration when conducting randomized controlled trials is treatment differentiation. Direct observation helps ensure that providers in different treatment groups are delivering distinct interventions. One direct observation method is the use of a measure to rate clinician performance when delivering an intervention. AIMS: This generalizability study evaluated the reliability of the CAMS Rating Scale (CRS), a measure used to assess delivery of the Collaborative Assessment and Management of Suicidality (CAMS). METHOD: Digitally recorded tapes of clinicians delivering either CAMS or Enhanced Care-As-Usual (E-CAU) were coded using the CRS. Sessions (N = 36) were each coded by two raters, and encompassed four clinicians, four time points, and 34 unique patients across two treatment groups. A reliability coefficient (i.e., G coefficient) and the percentages of variance contributed by each component of the measurement model were obtained. RESULTS: The CRS reliably differentiates CAMS from E-CAU, minimizes measurement error relative to expected variance sources, and continues to demonstrate high inter-rater reliability. LIMITATIONS: The absence of blind raters, a formal training protocol for the rating team, and ratings from all clinician-patient dyads at all time points was a limitation. CONCLUSION: The CRS is a reliable treatment differentiation measure that can play an integral role in studies evaluating CAMS. PMID- 30474408 TI - Examining the Relationship Between Attitudes Toward Suicide and Suicide Attempt History. AB - BACKGROUND: Relatively little is known regarding the relationship between attitudes toward suicide, suicide attempt (SA) history, and future suicidal behaviors. AIMS: Utilizing a sample of firefighters, this study compared attitudes toward suicide between individuals with/without a career SA history and evaluated whether certain attitudes toward suicide are associated with a greater self-reported likelihood of making a future SA. METHOD: US firefighters (N = 818) completed self-report measures. One-way ANOVAs and linear regression analyses were utilized to address study aims. RESULTS: Firefighters with a career SA reported significantly greater normalization/glorification of suicide - yet lower attributions of suicide to isolation/depression - than those without this history. More stigmatizing attitudes toward suicide and greater normalization/glorification of suicide were each significantly associated with greater self-reported future SA likelihood. LIMITATIONS: Data were cross sectional and findings may not be generalizable. CONCLUSION: Firefighters who have made an SA during their firefighting careers may normalize and glorify suicide more than those who have not. These attitudes may be associated with greater self-perceived risk for future SAs. Research is needed to replicate findings and evaluate strategies for targeting potentially harmful beliefs about suicide among SA survivors. PMID- 30474409 TI - Analysis of the Effects on Time Between Divorce Decree and Suicide. AB - BACKGROUND: Divorced individuals carry unique suicide risks, from both acute and chronic exposure to stressors from divorce. AIMS: Several statewide data sets were linked to assess the relationship between divorce and suicide. METHOD: Divorced suicide decedents in the Colorado Violent Death Reporting System, 2004 2015, were matched with divorce decree, using multiple identifiers. Statistically significant differences between the linked cohort and all divorced suicide decedents were assessed using chi-square statistics. Kaplan-Meier survival analyses were conducted assessing which demographics and circumstances had a significant effect on the time between divorce and death. RESULTS: The linkage resulted in 381 divorced suicide decedents linked to a divorce decree. Time between divorce and death ranged from less than 1 year to more than 10 years. Age and intimate partner problems both had significant effects on reducing the survival probability at 1 year and beyond. LIMITATIONS: Only 14% of divorced suicide decedents were linked to a Colorado divorce decree. There were noted significant differences between the linked cohort and the total divorced suicide population. CONCLUSION: Better understanding the relationship between divorce and suicide is imperative to design effective prevention programs for this specific population. PMID- 30474410 TI - Types of Stressors on Nonprofessional Against-Suicide and Pro-Suicide Message Boards. AB - BACKGROUND: Little is known about presenting problems of primary posters (i.e., posters opening the thread) and their responders in nonprofessional against suicide and pro-suicide message boards. AIMS: We aimed to compare problems described in suicide message boards between different types of users (primary posters and respondents) and between against-suicide, neutral, and pro-suicide message boards. METHOD: In all, 1,182 archival threads with 20,499 individual postings from seven nonprofessional suicide message boards supporting an against suicide, neutral, or pro-suicide attitude were randomly selected. Problems mentioned by primary posters and their respondents were coded with content analysis. Differences between pro-suicide, neutral, and against suicide boards, as well as correlations between primary posters and respondents, were calculated. RESULTS: Interpersonal problems were most frequently mentioned by primary posters in against-suicide threads (40.9%) and less frequently in pro-suicide threads (11.8%; p < .001). In pro-suicide boards, the most frequent stressors were suicide method-related (e.g., how to identify a safe method: 26.2% vs. 2.5% in against-suicide boards, p < .001). Primary posters resembled respondents in terms of presenting problems in pro-suicide boards, but not in against-suicide boards. LIMITATIONS: Only self-reported problems were assessed. CONCLUSION: The results confirm a stronger focus on death than on life among users in pro-suicide message boards, and posters with similar problems meet in pro-suicide boards. The posters appear to clearly emphasize social strains over psychiatric problems compared with some professional settings. PMID- 30474411 TI - Toward Automatic Risk Assessment to Support Suicide Prevention. AB - BACKGROUND: Suicide has been considered an important public health issue for years and is one of the main causes of death worldwide. Despite prevention strategies being applied, the rate of suicide has not changed substantially over the past decades. Suicide risk has proven extremely difficult to assess for medical specialists, and traditional methodologies deployed have been ineffective. Advances in machine learning make it possible to attempt to predict suicide with the analysis of relevant data aiming to inform clinical practice. AIMS: We aimed to (a) test our artificial intelligence based, referral-centric methodology in the context of the National Health Service (NHS), (b) determine whether statistically relevant results can be derived from data related to previous suicides, and (c) develop ideas for various exploitation strategies. METHOD: The analysis used data of patients who died by suicide in the period 2013 2016 including both structured data and free-text medical notes, necessitating the deployment of state-of-the-art machine learning and text mining methods. LIMITATIONS: Sample size is a limiting factor for this study, along with the absence of non-suicide cases. Specific analytical solutions were adopted for addressing both issues. RESULTS AND CONCLUSION: The results of this pilot study indicate that machine learning shows promise for predicting within a specified period which people are most at risk of taking their own life at the time of referral to a mental health service. PMID- 30474412 TI - Long-term relationship between unattended automated blood pressure and auscultatory BP measurements in hypertensive patients. AB - AIMS: Unattended automated office blood pressure (uAutoOBP) has attracted more attention since SPRINT trial had been published. However, its long-term relationship to attended office blood pressure (AuscOBP) is not known. MATERIAL AND METHODS: Stable treated hypertensive subjects were examined in four Czech academic hypertension centers. All subjects attended four clinical visits three months apart. uAutoOBP was measured with the BP Tru device; AuscOBP was measured three times with auscultatory method by the physician. 24-hour ambulatory blood pressure monitoring (ABPM) was performed within one week from the second clinical visit. RESULTS: Data on 112 subjects aged 65.6 +/- 10.8 years with mean AuscOBP 128.2 +/- 12.2/78.5 +/- 10.3 mm Hg are reported. Across the four clinical visits, the uAutoOBP was by 10.1/3.7 mm Hg lower than AuscOBP and the mean difference was similar during all four visits (P>=.061). Both uAutoOBP and AuscOBP had similar intra-individual variability during study follow-up as demonstrated by similar intraclass correlation coefficients (ICC, for systolic ICC = 0.50, for diastolic ICC = 0.72). However, the intra-individual variability of the systolic AuscOBP and uAutoOBP difference was high as demonstrated by low ICCs for absolute (ICC = 0.17 [95%CI, 0.09 - 0.25]) and low kappa coefficients for categorized differences (kappa <= 0.16). The main determinant of AuscOBP-uAutoOBP difference was AuscOBP level. The AuscOBP-uAutoOBP difference was poor tool to identify hypertension control categories defined on the basis of AuscOBP and ABPM. CONCLUSIONS: Although mean AuscOBP-uAutoOBP differences were relatively similar across the four clinical visits, intra-individual variability of this difference was high. The AuscOBP-uAutoOBP difference was poor tool to identify hypertension control categories defined on the basis of AuscOBP and ABPM. Therefore, uAutoOBP cannot be used as a replacement for ABPM. PMID- 30474414 TI - Risk Factors and Biomarkers of Poor Outcomes. PMID- 30474415 TI - Introduction to the 2018 Cardiovascular Surgery-Themed Issue. PMID- 30474413 TI - Classic Text No. 117 From Evolutive Paranoia, by August Wimmer (1902): Part 2. PMID- 30474416 TI - Is There a Role for Preoperative Platelet Function Testing in Patients Undergoing Cardiac Surgery During Antiplatelet Therapy? AB - Up to 11% of patients presenting with acute coronary syndromes undergo coronary artery bypass grafting. Guidelines largely recommend a one-size-fits-all preoperative discontinuation period for P2Y12 receptor blockers to avoid bleeding. These recommendations do not account for highly variable pharmacodynamic responsiveness and for variable recovery of platelet reactivity following discontinuation of P2Y12 receptor blockers. Several observational studies have demonstrated that an objective measurement of platelet function among these patients may reduce the waiting period while mitigating the risk of bleeding. Based on these findings, 2 recent guidelines included a Class IIa and IIb recommendation for platelet function testing in patients undergoing cardiac surgery. The following review article describes the rationale for discontinuation of dual antiplatelet therapy before cardiac surgery and the limitations with this approach, available platelet function assays to assess pharmacodynamic effects, and the association between platelet inhibition and other clinical factors with surgery-related bleeding. The information will assist the reader in determining which patients undergoing cardiac surgery might benefit from preoperative platelet function monitoring. PMID- 30474417 TI - New Strategies for Surgical Myocardial Revascularization. AB - We summarize the evidence on the new strategies for coronary artery bypass grafting (CABG). Hybrid CABG implies surgical grafting of the left anterior descending artery and percutaneous treatment of the other target vessels, with the promise of combining the durable benefits of surgery with the less invasive approach of percutaneous coronary interventions. Robotic CABG and minimally invasive CABG are performed through minimal incision or port access with dedicated equipment and instruments. Anaortic coronary artery bypass refers to off-pump CABG using only in-situ grafts. The use of multiple arterial grafts has been shown to improve patency and is potentially associated with better clinical outcomes. All these techniques require dedicated training and are more complex than conventional CABG but can significantly improve the results of surgery. Validation of the results of these new approaches in large randomized trials is a priority for the surgical community. PMID- 30474419 TI - Optimal Treatment of Patients With Left Ventricular Dysfunction and Severe Coronary Artery Disease. PMID- 30474418 TI - Endovascular Fenestration/Stenting First Followed by Delayed Open Aortic Repair for Acute Type A Aortic Dissection With Malperfusion Syndrome. AB - BACKGROUND: Immediate open repair of acute type A aortic dissection is traditionally recommended to prevent death from aortic rupture. However, organ failure because of malperfusion syndrome (MPS) might be the most imminent life threatening problem for a subset of patients. METHODS: From 1996 to 2017, among 597 patients with acute type A aortic dissection, 135 patients with MPS were treated with upfront endovascular reperfusion (fenestration/stenting) followed by delayed open repair (OR). We compared outcomes between the first and second decades and observed mortalities with those expected with an "upfront OR for every patient" approach, determined using prognostic models from the literature (Verona, Leipzig-Halifax, Stockholm, Penn, and GERAADA [German Registry for Acute Aortic Dissection Type A] models). RESULTS: Overall, in-hospital mortality improved between the 2 decades (21.0% versus 10.7%, P<0.001). In the second decade, for patients with MPS initially treated with fenestration/stenting, mortality from aortic rupture decreased from 16% to 4% ( P=0.05), the risk of dying from organ failure was 6.6 times higher than dying from aortic rupture (hazard ratio=6.63; 95% CI, 1.5-29; P=0.01), and 30-day mortality after OR for MPS patients was 3.7%. Compared to the expected mortalities with the upfront OR for every patient models, our observed 30-day and in-hospital mortalities (9% and 11%, respectively) of all patients with acute type A aortic dissection were significantly lower ( P<=0.03). CONCLUSIONS: Immediate OR is the strategy to prevent death from aortic rupture for the majority of patients with acute type A aortic dissection. However, relatively stable (no rupture, no tamponade) patients with MPS benefit from a staged approach: upfront endovascular reperfusion followed by aortic OR at resolution of organ failure. PMID- 30474420 TI - Multiple Arterial Grafting Is Associated With Better Outcomes for Coronary Artery Bypass Grafting Patients. AB - BACKGROUND: Observational studies have shown better survival in patients undergoing coronary artery bypass grafting (CABG) with 2 arterial grafts compared with 1. However, whether a third arterial graft is associated with incremental benefit remains uncertain. We sought to analyze the outcomes of 3 versus 2 arterial grafts during CABG. As a secondary objective, we compared CABG with 2 or 3 arterial grafts (multiple arterial grafts [MAG]) with CABG using a single arterial graft (SAG). METHODS: Retrospective cohort analyses of all patients undergoing primary isolated CABG in Ontario, Canada, from October 2008 to March 2016. Propensity score matching was performed between patients with 3 arterial grafts (3Art group) versus 2 (2Art group). The primary outcome was time to first event of a composite of death, myocardial infarction, stroke, and repeat revascularization (major adverse cardiac and cerebrovascular events). Additional analyses were performed to evaluate the association between MAG versus SAG and long-term outcomes using propensity score matching. RESULTS: Fifty thousand, two hundred thirty patients underwent isolated CABG during our study period; 3044 (6.1%) and 8253 (16.4%) patients had 3 and 2 arterial grafts, respectively, resulting in 2789 propensity score matching pairs for the primary analyses. Mean and maximum follow-up was 4.2 and 8.5 years, respectively. Radial artery grafting was more common in the 3Art versus 2Art group (79.3% versus 65.6%, P<0.01). In hospital outcomes were not significantly different, including death (3Art 0.8% versus 2Art 0.5%, P=0.26). Up to 8 years, there were no differences in major adverse cardiac and cerebrovascular events (3Art 27%, 95% confidence interval [CI], 24% to 30% versus 2Art 25%, 95% CI, 22% to 28%; hazard ratio [HR], 1.08, 95% CI, 0.94-1.25), death (HR, 1.08; 95% CI, 0.90-1.29), myocardial infarction (HR, 1.15; 95% CI, 0.87-1.51), stroke (HR, 1.39; 95% CI, 0.95-2.06), or repeat revascularization (HR, 1.04; 95% CI, 0.82-1.32). When evaluating MAG versus SAG, 8629 patient pairs were formed using propensity score matching. At 8 years, cumulative incidences of major adverse cardiac and cerebrovascular events (HR, 0.82, 95% CI, 0.77-0.88), survival (HR, 0.80; 95% CI, 0.73-0.88), repeat revascularization (HR, 0.79; 95% CI, 0.69-0.90), and myocardial infarction (HR, 0.83; 95% CI, 0.72-0.97) were superior in the MAG group. CONCLUSIONS: CABG with 3 arterial grafts was not associated with increased in-hospital death nor with better clinical outcomes at 8-year follow-up, compared with CABG with 2 arterial grafts. MAG was associated with superior outcomes compared with SAG. PMID- 30474421 TI - Upfront Interventional Radiology for Acute Type A Dissection With Malperfusion Syndrome. PMID- 30474424 TI - Case for Earlier Surgical Myectomy in Patients With Obstructive Hypertrophic Cardiomyopathy. PMID- 30474422 TI - Association Between Variation in Preoperative Care Before Arterial Switch Operation and Outcomes in Patients With Transposition of the Great Arteries. AB - BACKGROUND: The arterial switch operation (ASO) is the gold standard operative correction of neonates with transposition of the great arteries and intact ventricular septum, with excellent operative survival. The associations between patient and surgeon characteristics and outcomes are well understood, but the associations between variation in preoperative care and outcomes are less well studied. METHODS: A multicenter retrospective cohort study of infants undergoing neonatal ASO between January 2010 and September 2015 at hospitals contributing data to the Pediatric Health Information Systems database was performed. The association between preoperative care (timing of ASO, preoperative use of balloon atrial septostomy, prostaglandin infusion, mechanical ventilation, and vasoactive agents) and operative outcomes (mortality, length of stay, and cost) was studied with multivariable mixed-effects models. RESULTS: Over the study period, 2159 neonates at 40 hospitals were evaluated. Perioperative mortality was 2.8%. Between hospitals, the use of adjuvant therapies and timing of ASO varied broadly. At the subject level, older age at ASO was associated with higher mortality risk (age >6 days: odds ratio, 1.90; 95% CI, 1.11-3.26; P=0.02), cost, and length of stay. Receipt of a balloon atrial septostomy was associated with lower mortality risk (odds ratio, 0.32; 95% CI, 0.17-0.59; P<0.001), cost, and length of stay. Later hospital median age at ASO was associated with higher odds of mortality (odds ratio, 1.15 per day; 95% CI, 1.02-1.29; P=0.03), longer length of stay ( P<0.004), and higher cost ( P<0.001). Other hospital factors were not independently associated with the outcomes of interest. CONCLUSIONS: There was significant variation in preoperative care between hospitals. Some potentially modifiable aspects of perioperative care (timing of ASO and septostomy) were significantly associated with mortality, length of stay, and cost. Further research on the perioperative care of neonates is necessary to determine whether modifying practice on the basis of the observed associations translates into improved outcomes. PMID- 30474423 TI - Rapid Self-Assembly of Bioengineered Cardiovascular Bypass Grafts From Scaffold Stabilized, Tubular Bilevel Cell Sheets. AB - BACKGROUND: Cardiovascular bypass grafting is an essential treatment for complex cases of atherosclerotic disease. Because the availability of autologous arterial and venous conduits is patient-limited, self-assembled cell-only grafts have been developed to serve as functional conduits with off-the-shelf availability. The unacceptably long production time required to generate these conduits, however, currently limits their clinical utility. Here, we introduce a novel technique to significantly accelerate the production process of self-assembled engineered vascular conduits. METHODS: Human aortic smooth muscle cells and skin fibroblasts were used to construct bilevel cell sheets. Cell sheets were wrapped around a 22.5-gauge Angiocath needle to form tubular vessel constructs. A thin, flexible membrane of clinically approved biodegradable tissue glue (Dermabond Advanced) served as a temporary, external scaffold, allowing immediate perfusion and endothelialization of the vessel construct in a bioreactor. Subsequently, the matured vascular conduits were used as femoral artery interposition grafts in rats (n=20). Burst pressure, vasoreactivity, flow dynamics, perfusion, graft patency, and histological structure were assessed. RESULTS: Compared with engineered vascular conduits formed without external stabilization, glue membrane stabilized conduits reached maturity in the bioreactor in one-fifth the time. After only 2 weeks of perfusion, the matured conduits exhibited flow dynamics similar to that of control arteries, as well as physiological responses to vasoconstricting and vasodilating drugs. The matured conduits had burst pressures exceeding 500 mm Hg and had sufficient mechanical stability for surgical anastomoses. The patency rate of implanted conduits at 8 weeks was 100%, with flow rate and hind-limb perfusion similar to those of sham controls. Grafts explanted after 8 weeks showed a histological structure resembling that of typical arteries, including intima, media, adventitia, and internal and external elastic membrane layers. CONCLUSIONS: Our technique reduces the production time of self-assembled, cell sheet-derived engineered vascular conduits to 2 weeks, thereby permitting their use as bypass grafts within the clinical time window for elective cardiovascular surgery. Furthermore, our method uses only clinically approved materials and can be adapted to various cell sources, simplifying the path toward future clinical translation. PMID- 30474425 TI - Atezolizumab for the treatment of triple-negative breast cancer. AB - INTRODUCTION: Triple-negative breast cancer (TNBC) is associated with poor prognosis and limited treatment options. However, TNBC is known to be more immunogenic compared to other breast cancer subtypes, with tumor-infiltrating lymphocytes (TILs) playing an important prognostic and predictive role. Furthermore, TNBC has a higher level of programmed cell death-ligand 1 (PD-L1) expression. Therapeutic blockade of PD-L1 using atezolizumab is thus expected to activate and enhance tumor-specific T-cell responses, resulting in improved antitumor activity. Areas covered: This review summarizes the development and the impact of the PD-L1 inhibitor atezolizumab in advanced TNBC; it examines the mechanism of action, pharmacokinetics and the available preclinical and clinical data. Expert Opinion: Atezolizumab, a novel ICPi targeting PD-L1, is an effective and well-tolerated treatment option for metastatic TNBC. In general, TNBC has a high unmet medical need, hence the clinical development of atezolizumab should continue, particularly for TNBC. Indeed, atezolizumab has the potential to substantially augment the therapeutic armamentarium for TNBC. This should lead to improved immunotherapeutic strategies and the enhancement of the outcome for this group of breast cancer patients. PMID- 30474426 TI - The association between circulating endostatin levels and incident myocardial infarction. AB - OBJECTIVE: Increased levels of circulating endostatin have been observed in patients with prevalent ischemic heart disease. However, the association between circulating endostatin, and incident myocardial infarction (MI) is less studied. Our main aim was to study the association between circulating endostatin and incident MI in the community adjusted for established cardiovascular risk factors in men and women. DESIGN: Circulating endostatin was measured in a nested case control study based on three large community-based Swedish cohorts, including 533 MI cases, and 1003 age-, sex- and cohort-matched controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated with adjustments for established cardiovascular risk factors. RESULTS: Higher endostatin was associated with a higher incidence of MI independently of established cardiovascular risk factors (OR 1.19, 95 % CI 1.03-1.37, p = 0.02), but this association was abolished after additional adjustment for C-reactive protein. Sex-stratified analyses suggest that the association was substantially stronger in women as compared to men Conclusions: In our community based sample, higher endostatin predicted incident myocardial infarction predominantly in women but not independently of CRP. Thus, our findings do not support a broad utility of endostatin measurements for the prediction of incident myocardial infarction in clinical practice. PMID- 30474427 TI - Is cardiorespiratory fitness independently associated with the biochemical profile in overweight/obese adults with primary hypertension? The EXERDIET-HTA study. AB - Cardiorespiratory fitness (CRF) is positively associated with enhanced cardiovascular health. This cross-sectional study aimed to determine associations between CRF and the biochemical profile of overweight/obese adults diagnosed with primary hypertension (HTN). Does cardiorespiratory fitness (exposure) positively affect the biochemical profile (outcome) in overweight/obese individuals suffering from HTN? Assessment with anthropometric, ambulatory blood pressure monitoring (24 h), CRF (peak oxygen uptake, VO2peak) and biochemical analysis was performed on 214 participants (138 men, 76 women). A series of linear and logistic regression analyses were conducted. Participants were divided into CRF tertiles (classified as low, moderate and high CRF). The CRF was independently and inversely associated with aspartate aminotransferase (AST; beta = -0.328, p < .05) and alanine aminotransferase (ALT; beta = -0.376, p < .01) concentrations. C reactive protein, AST/ALT ratio, gamma-glutamyl transpeptidase, total cholesterol/high-density lipoprotein cholesterol ratio, glucose, insulin and insulin resistance index (HOMA-IR), were all associated, but not independently, with CRF in linear and/or unadjusted logistic regression models. However, independently, logistic regression revealed that glucose was associated with the moderate CRF group. Findings suggest that a lower CRF is associated with an unhealthy biochemical profile in non-physically active and overweight/obese individuals with HTN. As such, this population should look to increase physical activity in order to improve their CRF and biochemical profile. PMID- 30474428 TI - c-Met kinase inhibitors: an update patent review (2014-2017). AB - INTRODUCTION: The receptor tyrosine kinase c-Met is involved in the formation, metastasis and invasion of various malignant tumors thus it has been an attractive target for anti-tumor drug designing. Many compositions targeting c Met have been developed in pharmaceutical industry for cancer therapy and some of them are in clinical study now. Among them, Crizotinib was the first small molecular inhibitor approved by FDA in 2011. Areas covered: This review briefly summarizes the signal transduction pathway about c-Met, its role in oncogenesis, most recent patents of small-molecule inhibitors and antibodies of c-Met from 2014 to 2017. Expert opinion: To date, some c-Met inhibitors have been launched in the market. In addition, their clinical performances have shown encouraging value in cancer therapy. Many potential agents are still in preclinical or clinical study now and achieve some promising progressions. Some patients have developed resistance to c-Met inhibitors which results in the need to develop inhibitors with novel structures. Development of several potent drugs also tends to be pharmacodynamically active against multiple targets. PMID- 30474431 TI - Impact of rocker sole footwear on plantar pressure distribution during standing and walking in adult obese women. AB - PURPOSE: Obesity increases the stresses applied to the foot. Ergonomic rocker sole shoes increase energy expenditure of standing and walking in obese individuals but could potentially alter plantar pressure distribution. The aim of this study was to compare plantar pressure distribution during standing and walking between rocker sole and flat-bottomed shoes in obese subjects. METHODS: Twenty adult obese women were asked to stand quietly and to walk at their preferred walking speed whilst wearing flat-bottomed or rocker sole shoes. Plantar pressure distribution was assessed using instrumented insoles. RESULTS: During standing, toe pressure and as well as midfoot force were higher with rocker sole than with flat-bottomed shoes (p < 0.05). During walking with rocker sole shoes, mean pressure and maximal force were lower under the toes and the forefoot, but higher under the midfoot and rearfoot regions with respect to flat bottomed shoes (p < 0.05). CONCLUSIONS: While standing with rocker sole shoes, obese subjects showed augmented pressure under the toes whereas forefoot and heel pressure had no significant difference compared to the flat-bottomed shoes. As walking with rocker sole shoes resulted in decreased forces and pressures under the forefoot but increased overload at heel and midfoot regions, obese individuals may not benefit from wearing rocker sole shoes during walking, at least from a plantar pressure distribution perspective. Implications for rehabilitation The use of ergonomic rocker sole shoes causes a redistribution of in-shoe plantar pressures leading to potentially detrimental adjustments that fail to attenuate the obesity-related increase in midfoot pressure during standing, while accentuating this region-specific impairment in dynamic conditions. Rocker sole shoes may best be avoided for walking in obese patients with heel pain or with any midfoot/rearfoot alteration such as medial arch flattening. PMID- 30474430 TI - Laser-assisted delivery enhances topical uptake of the anticancer agent cisplatin. AB - Systemic chemotherapy with the anticancer agent cisplatin is approved for advanced non-melanoma skin cancer (NMSC), but topical treatment is limited by insufficient cutaneous penetration. We studied the impact of ablative fractional laser (AFL) exposure on topical cisplatin's pharmacokinetics and biodistribution in skin, using microscopic ablation zones reaching the mid- (MAZ-MD; 620 MUm depth) and deep dermis (MAZ-DD; 912 MUm depth) (lambda = 10,600 nm, 196 MAZ/cm2). Assessed in an in vitro Franz cell model after 0.5-, 4-, 24 h topical exposure (n = 8), cisplatin delivery was greatly accelerated by AFL, shown by quantitative- and imaging-based inductively coupled plasma-mass spectrometry (ICP-MS). After 30 minutes, cisplatin concentrations were 91.5, 90.8 and 37.8 MUg/cm3 in specific 100-, 500, and 1500 MUm skin layers respectively, contrasting to 8.08, 3.12, 0.64 MUg/cm3 in non-laser-exposed control skin (p < .001; control vs MAZ-MD). Supported by element bioimaging, the greatest relative increases occurred in the deep skin compartment and at later time points. After 24 h, cisplatin concentrations thus rose to 1829, 1732 and 773 MUg/cm3, representing a 25-, 103- and 447-fold enhancement in the 100, 500, and 1500 MUm deep skin layers versus corresponding controls (p < .001; MAZ-MD). A significant difference in cutaneous uptake using MAZ-MD and MAZ-DD was not shown at any time point, though deeper laser channels resulted in increased transdermal cisplatin permeation (p <= .015). In conclusion, AFL is a rapid, practical and existing skin treatment that may provide greatly enhanced uptake of topical cisplatin for treatment of superficial and deep skin cancer. PMID- 30474429 TI - The National Physicians Cooperative: transforming fertility management in the cancer setting and beyond. AB - Once unimaginable, fertility management is now a nationally established part of cancer care in institutions, from academic centers to community hospitals to private practices. Over the last two decades, advances in medicine and reproductive science have made it possible for men, women and children to be connected with an oncofertility specialist or offered fertility preservation soon after a cancer diagnosis. The Oncofertility Consortium's National Physicians Cooperative is a large-scale effort to engage physicians across disciplines - oncology, urology, obstetrics and gynecology, reproductive endocrinology, and behavioral health - in clinical and research activities to enable significant progress in providing fertility preservation options to children and adults. Here, we review the structure and function of the National Physicians Cooperative and identify next steps. PMID- 30474432 TI - Impact of quality improvement strategies on the quality of life of individuals post-stroke: a systematic review. AB - PURPOSE: The purpose of this systematic review was to synthesize and appraise the evidence regarding the impact of quality improvement strategies on quality of life as well as physical and psychological well-being of individuals with stroke. MATERIALS AND METHODS: Studies were identified by searching MEDLINE (OVID interface, 2000 onwards), CINAHL (EBSCO interface, 2000 onwards), EMBASE (OVID interface, 2000 to present), and PsycINFO (OVID interface, 2000 onwards). The Effective Practice and Organization of Care Risk of Bias Tool was applied. Extracted data from the publications included: study characteristics, participant characteristics, the strategy characteristics, the outcomes, and quality appraisal. RESULTS: Our review identified 12 trials that utilized only 4 of the 10 quality improvement strategies included in this review. The most common quality improvement strategy was self-management. Other studies included patient education, team changes, and case management. Only 5 of the 12 studies reported statistically significant improvements in some component of quality of life. CONCLUSIONS: There is a lack of evidence to demonstrate efficacy/effectiveness of patient education, self-management, team changes, and case management approaches on improving the quality of life of stroke survivors. Identifying the essential features of effective and ineffective strategies, especially in the area of self management strategies would be beneficial. Implications for rehabilitation There is a lack of evidence to demonstrate efficacy/effectiveness of patient education, self-management, team changes, and case management approaches on improving the quality of life of stroke survivors. To improve these outcomes, there may be a need to co-create/tailor quality improvement interventions with patients, their caregivers, and providers. The impact of a broader range of quality improvement interventions, including clinician education and patient reminder systems, on quality of life post-stroke should be considered. PMID- 30474433 TI - Rationale and evidence for the incorporation of heparin to the diclofenac epolamine medicated plaster. AB - OBJECTIVE: The nonsteroidal anti-inflammatory drug (NSAID) diclofenac epolamine (DHEP) formulated as a topical patch has demonstrated efficacy and safety in the localized treatment of acute pain from minor strains, sprains, and contusions, and for epicondylitis and knee osteoarthritis. The glycosaminoglycan heparin enhances the activity of topical NSAIDs formulated as a medicated plaster, even in the absence of any significant release of heparin. Therefore, DHEP Plus, a new formulation of the DHEP medicated plaster containing a small amount of heparin sodium as excipient has been developed. METHODS: We reviewed the pivotal and supportive studies of the clinical development program of the new patch and evaluated the role of heparin as an enhancer in the treatment of localized pain/inflammation of musculoskeletal structures, associated with post-traumatic and/or rheumatic conditions. RESULTS: The data were consistent with the concept that heparin increased the clinical activity of the DHEP Plus medicated plaster versus the reference DHEP medicated plaster through improved bioavailability due to enhanced movement of diclofenac from the plaster. Both DHEP formulations have the same dissolution profile, indicating that heparin does not change the physical and chemical characteristics of the plaster. Permeation testing showed that heparin is not released from the DHEP Plus medicated plaster. Efficacy studies showed that the DHEP Plus medicated plaster was significantly more effective in reducing pain than the reference marketed DHEP medicated plaster. CONCLUSIONS: The benefit/risk assessment of DHEP Plus 180 mg medicated plaster is favorable, with a safety profile equal to placebo and improved efficacy over the reference marketed DHEP medicated plaster. PMID- 30474434 TI - Intensified antibiotic treatment of tuberculous meningitis. AB - INTRODUCTION: Meningitis is the most severe manifestation of tuberculosis, resulting in death or disability in over 30% of those affected, with even higher morbidity and mortality among patients with HIV or drug resistance. Antimicrobial treatment of Tuberculous meningitis (TBM) is similar to treatment of pulmonary tuberculosis, although some drugs show poor central nervous system penetration. Therefore, intensification of antibiotic treatment may improve TBM treatment outcome. Areas covered: In this review we address three main areas: available data for old and new anti-tuberculous agents; intensified treatment in specific patient groups like HIV co-infection, drug-resistance and children; and optimal research strategies. Expert commentary: There is good evidence from preclinical, clinical and modelling studies to support use of high-dose rifampicin in TBM, likely to be at least 30mg/kg. Higher dose isoniazid could be beneficial, especially in rapid acetylators. The role of other first and second line drugs is unclear, but observational data suggest that linezolid, which has good brain penetration, may be beneficial. We advocate use of molecular pharmacological approaches, physiologically-based pharmacokinetic (PBPK) modelling and pharmacokinetic-pharmacodynamic (PK-PD) studies to define optimal regimens to be tested in clinical trials. Fortunately, exciting data from recent studies hold promise for improved regimens and better outcome of TBM patients. PMID- 30474435 TI - Misconceptions and current use of contraception among women of reproductive age in six major cities in Nigeria. AB - OBJECTIVES: The aims of this study were to assess the determinants of family planning misconceptions and modern contraceptive use, and the influence of misconceptions on the use of modern contraceptive methods. METHODS: We reviewed and analysed data collected between October 2010 and March 2011 among a representative household sample of 13,575 women of reproductive age (15-49 years) in six urban cities in Nigeria. Multiple linear and logistic regression models were used to examine the predictors of misconceptions and current use of contraception and the association between misconceptions and modern contraceptive use. RESULTS: Catholic women were significantly more likely to have misconceptions compared with Muslim women (beta = 1.09; 95% confidence interval [CI] 0.58, 1.60; p < .001); women with higher education were significantly less likely to have misconceptions about contraception compared with women with no formal education (beta= -0.06; 95% CI -0.96, -0.29; p < .001). Unmarried women living with a partner were not significantly different from those who were not cohabiting (single, separated or widowed) in their current contraceptive use (adjusted odds ratio [OR] 0.91; 95% CI 0.79, 1.04; p > .05). Women with lower misconception scores were significantly more likely to adopt and use modern contraception compared with those with high misconception scores (adjusted OR 0.93; 95% CI 0.92, 0.94; p < .001). CONCLUSION: These findings suggest that programmatic efforts should be geared towards dispelling misconceptions by providing simple factual information related to the benefits of contraception and family planning. PMID- 30474436 TI - The molecular characterization and therapeutic strategies of papillary renal cell carcinoma. AB - INTRODUCTION: Papillary renal cell carcinoma (pRCC) is an important subtype of kidney cancer with a problematic pathological classification and highly variable clinical behavior. In this review, we summarize the current progression on pRCC in molecular level. Our findings highlight the need for molecular markers to accurately subtype pRCC and may lead to the development of more targeted agents and better patient stratification in clinical trials for pRCC. Areas covered: This review highlights the need for molecular markers to accurately subtype PRCC and may lead to the development of more targeted agents and better patient stratification in clinical trials for pRCC. Expert commentary: There are mainly two subtypes of pRCC based on histology. However, little is known about the genetic characterization of the sporadic forms of pRCC and there are currently no standard forms of therapy for patients with advanced disease. Both MET inhibitors and immunotherapy may be effective in advanced pRCC treatment. Therefore, understanding the molecular basis of pRCC and identifying the main goal of treatment is crucial for the selection of the best strategy. PMID- 30474438 TI - Prescribing patterns and healthcare costs of gout. AB - The Longitudinal Health Insurance Database (LHID) 2010 was used to identify gout cases and their number of gout flares. Out of 21,376 gout patients, a total of 3,561 (16.7%) had frequent gout flares (> = 3 gout flares/year). Average all cause healthcare utilization (35.9 visits vs. 30.7 visits; P < 0.001) and gout related utilization (22.7 visits vs. 15.6 visits; p < 0.001) were higher in frequent gout flare patients than in those with infrequent gout flares. The median gout-related cost (USD $369 vs. $285; p < 0.001), but not all-cause costs (P = 0.25), were higher in frequent gout flare patients compared to the infrequent group. Over 55.8% of the flares were treated with colchicine + NSAIDs. In conclusion, patients with frequent gout flares had higher healthcare utilization and gout-related healthcare costs. Colchicine + NSAIDs are commonly used therapy for gout flare. PMID- 30474439 TI - Terlipressin for the treatment of hepatorenal syndrome: An overview of current evidence. AB - Hepatorenal syndrome (HRS) is a serious complication of liver cirrhosis, which is of pre-renal origin due to central volume depletion together with cardiac dysfunction and characterized by oliguria with severe urinary sodium retention and elevated serum creatinine levels. HRS is divided into HRS I, which is rapidly progressive and mostly seen in patients with decompensated liver cirrhosis, and HRS II, which progresses more slowly and is always accompanied by gross ascites. Liver transplantation is the best choice of treatment for HRS but rarely available. Current mainstay pharmacological therapies are vasoconstrictors, such as terlipressin, noradrenaline, and dopamine, in combination with albumin. This paper aims to overview the current evidence regarding outcomes of terlipressin for the treatment of HRS. PMID- 30474443 TI - Treatment outcome and persistence of repigmentation from narrow-band ultraviolet B phototherapy in vitiligo. AB - BACKGROUND: Narrow-band ultraviolet B (NB-UVB) phototherapy is a mainstay treatment in vitiligo. However, data relative to repigmentation outcome, prognostic factors, and duration of repigmentation are limited. OBJECTIVES: To investigate the quantitative repigmentation outcome of NB-UVB phototherapy in vitiligo, the factors associated with favorable prognosis after NB-UVB, and the duration of repigmentation after NB-UVB discontinuation. MATERIALS AND METHODS: Medical records of vitiligo patients who underwent NB-UVB phototherapy at Department of Dermatology, Siriraj Hospital during 2012 to 2016 were retrospectively reviewed. Repigmentation was assessed using Vitiligo Area Scoring Index (VASI) score. RESULTS: Fifty-eight patients were included. All patients received NB-UVB phototherapy twice to three times weekly for a median duration of 12 months. Forty-two patients had non-segmental vitiligo (NSV), and 16 had segmental vitiligo (SV). NSV and SV demonstrated overall improvement in VASI score of -50.0%+/-31.0% and -40.0%+/-28.3%, respectively. Factors predictive of good outcome included type of vitiligo, lesion location, disease duration before NB-UVB, and duration and total number of NB-UVB treatments. Persistence of repigmentation was observed in approximately 80% of cases at one year after discontinuation of NB-UVB. CONCLUSION: NB-UVB phototherapy is an effective treatment for vitiligo, especially NSV. Repigmentation persisted in 80% of patients at 1-year after cessation of phototherapy. PMID- 30474437 TI - Dual-modified natural high density lipoprotein particles for systemic glioma targeting drug delivery. AB - Therapeutic outcome for the treatment of glioma was often limited due to the two barriers involved: the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB). Therefore, the development of nanocarriers that possess both BBB and BBTB permeability and glioma-targeting ability is of great importance for the chemotherapy of glioma. New frontiers in nanomedicine are advancing the research of new biomaterials. Here we constructed a natural high-density lipoprotein particle (HDL)-based drug delivery system with the dual-modification of T7 and dA7R peptide ligand (T7/dA7R-HDL) to achieve the above goals. HDL, the smallest lipoprotein, plays a biological role and is highly suitable as a platform for delivering imaging and therapeutic agents. T7 is a seven-peptide ligand of transferrin receptors (TfR) capable of circumventing the BBB and then targeting glioma. dA7R is a d-peptide ligand of vascular endothelial growth factor receptor 2 (VEGFR 2) overexpressed on angiogenesis, presenting excellent glioma-homing property. 10-Hydroxycamptothecin (HCPT), a hydrophobic anti-cancer drug, was used as the model drug in this study. By combining the dual-targeting delivery effect, the dual-modified HDL displayed higher glioma localization than that of single ligand-modified HDL or free HCPT. After loading with HCPT, T7/dA7R-HDL showed the most favorable anti-glioma effect in vivo. These results demonstrated that the dual-targeting natural nanocarriers strategy provides a potential method for improving brain drug delivery and anti-glioma treatment efficacy. PMID- 30474444 TI - Spotlight on Bortezomib: potential in the treatment of hepatocellular carcinoma. AB - INTRODUCTION: This study reviews the evidence for the use of Bortezomib (BZB), a first-in-class proteasome inhibitor in advanced Hepatocellular carcinoma (HCC). This review aims to delineate the role of BZB within the management of non surgical and metastatic HCC, either as an alternative or as an adjunct to the current treatment paradigm. Areas covered: In addition to BZB pharmacology and mechanism of action, safety and tolerance profiles of the drug obtained from clinical trials are explored. The utility of BZB as a therapeutic agent either alone or in combination with other therapies against HCC, including its application in both preclinical and clinical settings has been reviewed. In particular, we highlight the importance of preclinical evaluation of BZB as a combinatorial agent in synergism with other therapies for the use in the management of HCC. Expert opinion: There has been much interest surrounding the use of BZB, a first-in-class proteasome inhibitor for HCC therapy. The discernment of outcomes of BZB clinical trials for HCC need to take into consideration the disease-specific factors that can affect survival outcomes including patient selection and aetiological differences. Further preclinical testing of BZB in combination with other therapeutic modalities can be important for eliciting enhanced anti-HCC effects. PMID- 30474446 TI - Biotechnological Management of Angiopathic Wounds: Challenges and Perspectives. AB - Angiopathic wound is a wound that develops as a result of a local vascular lesion. Angiogenesis is an important aspect underlying repair, and increased angiogenesis could accelerate and improve the healing outcome. Biotherapy has been used more and more in clinic and brings hope for angiopathic wound treatment, through the rapid recovery of angiogenesis and regulation and correction of the whole wound microenvironment. In this article, we discuss the advantages and disadvantages of various technologies ranging from presentation of angiogenic growth factors, genetic strategies, stem cells, and biomaterials engineering in angiopathic wound treatment. PMID- 30474445 TI - Wireless binaural hearing aid technology for telephone use and listening in wind noise. AB - OBJECTIVE: To assess the speech perception benefits of binaural streaming technology for bilateral hearing aid users in two difficult listening conditions. DESIGN: Two studies were conducted to compare hearing aid processing features relating to telephone use and wind noise. Speech perception testing was conducted in four different experimental conditions in each study. STUDY SAMPLE: Ten bilaterally-aided children in each study. RESULTS: Significant improvements in speech perception were obtained with a wireless feature for telephone use. Significant speech perception benefits were also obtained with wireless hearing aid features when listening to speech in simulated wind noise. CONCLUSIONS: Binaural signal processing algorithms can significantly improve speech perception for bilateral hearing aid users in challenging listening situations. PMID- 30474447 TI - Clinical leadership and integrated primary care: A systematic literature review. AB - BACKGROUND: Leaders are needed to address healthcare changes essential for implementation of integrated primary care. What kind of leadership this needs, which professionals should fulfil this role and how these leaders can be supported remains unclear. OBJECTIVES: To review the literature on the effectiveness of programmes to support leadership, the relationship between clinical leadership and integrated primary care, and important leadership skills for integrated primary care practice. METHODS: We systematically searched PubMed, CINAHL, Embase, PsycINFO until June 2018 for empirical studies situated in an integrated primarycare setting, regarding clinical leadership, leadership skills, support programmes and integrated-care models. Two researchers independently selected relevant studies and critically appraised studies on methodological quality, summarized data and mapped qualitative data on leadership skills. RESULTS: Of the 3207 articles identified, 56 were selected based on abstract and title, from which 20 met the inclusion criteria. Selected papers were of mediocre quality. Two non-controlled studies suggested that leadership support programmes helped prepare and guide leaders and positively contributed to implementation of integrated primary care. There was little support that leaders positively influence implementation of integrated care. Leaders' relational and organizational skills as well as process-management and change-management skills were considered important to improve care integration. Physicians seemed to be the most adequate leaders. CONCLUSION: Good quality research on clinical leadership in integrated primary care is scarce. More profound knowledge is needed about leadership skills, required for integrated-care implementation, and leadership support aimed at developing these skills. PMID- 30474448 TI - Intensity-modulated proton therapy decreases dose to organs at risk in low-grade glioma patients: results of a multicentric in silico ROCOCO trial. AB - BACKGROUND AND PURPOSE: Patients with low-grade glioma (LGG) have a prolonged survival expectancy due to better discriminative tumor classification and multimodal treatment. Consequently, long-term treatment toxicity gains importance. Contemporary radiotherapy techniques such as intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), tomotherapy (TOMO) and intensity-modulated proton therapy (IMPT) enable high-dose irradiation of the target but they differ regarding delivered dose to organs at risk (OARs). The aim of this comparative in silico study was to determine these dosimetric differences in delivered doses. MATERIAL AND METHODS: Imaging datasets of 25 LGG patients having undergone postoperative radiotherapy were included. For each of these patients, in silico treatment plans to a total dose of 50.4 Gy to the target volume were generated for the four treatment modalities investigated (i.e., IMRT, VMAT, TOMO, IMPT). Resulting treatment plans were analyzed regarding dose to target and surrounding OARs comparing IMRT, TOMO and IMPT to VMAT. RESULTS: In total, 100 treatment plans (four per patient) were analyzed. Compared to VMAT, the IMPT mean dose (Dmean) for nine out of 10 (90%) OARs was statistically significantly (p < .02) reduced, for TOMO this was true in 3/10 (30%) patients and for 1/10 (10%) patients for IMRT. IMPT was the prime modality reducing dose to the OARs followed by TOMO. DISCUSSION: The low dose volume to the majority of OARs was significantly reduced when using IMPT compared to VMAT. Whether this will lead to a significant reduction in neurocognitive decline and improved quality of life is to be determined in carefully designed future clinical trials. PMID- 30474449 TI - Study description and baseline characteristics of the population enrolled in a multinational, observational study of teriparatide in postmenopausal women with osteoporosis: the Asia and Latin America Fracture Observational Study (ALAFOS). AB - OBJECTIVE: To describe the study design and baseline patient characteristics of the Asia and Latin America Fracture Observational Study (ALAFOS) to better understand the profile of patients receiving teriparatide during the course of routine clinical practice in Asia, Latin America, the Middle East, and Russia. METHODS: Prospective, observational, non-interventional study in postmenopausal women with osteoporosis who are prescribed teriparatide for up to 24 months, according to local medical standards, with a 12-month post-treatment follow-up. MEASURES: Demographics, risk factors for osteoporosis and fractures, history of fracture, prior osteoporosis medications, comorbidities, physical function, back pain, and quality of life (QoL). RESULTS: 3031 postmenopausal women (mean age 72.5 years) recruited at 152 sites in 20 countries were analyzed; 62.9% had a history of fragility fracture after age 40 (33.0% of patients with spinal, 14.2% with hip fractures). The mean (SD) bone mineral density T-scores at baseline were -3.06 (1.40) and -2.60 (1.05) at the lumbar spine and femoral neck, respectively. At entry, 43.7% of patients were naive to prior osteoporosis treatments; 40.5% of patients reported >=1 fall in the past year. The median (Q1;Q3) EuroQoL Visual Analog Scale (EQ-VAS) for perceived overall health status was 60 (50;80). The mean (SD) worst back pain Numeric Rating Scale in the last 24 hours was 4.6 (3.3). CONCLUSIONS: Our data indicate that patients who were prescribed teriparatide in the ALAFOS participant countries had severe osteoporosis, high prevalence of fractures, disabling back pain, and poor QoL. The frequency of patients receiving prior osteoporosis medications was lower than in previous observational studies conducted in other geographies. PMID- 30474450 TI - Budget impact analysis of secukinumab versus adalimumab in the treatment of ankylosing spondylitis. AB - Background Biologic treatments have enhanced the treatment outcomes of patients with active ankylosing spondylitis (AS). Until recently, TNF-alpha-inhibitors have been the only biologics approved for the treatment of active AS. The objective of this study was to assess the potential financial impact of the first non-TNF-alpha biologic secukinumab (fully human IL-17A-inhibitor) versus adalimumab (TNF-alpha-inhibitor) in the treatment of AS in Finland. Materials and methods In this model-based budget impact analysis, patients were treated either with secukinumab (150mg) or adalimumab (40mg). The number of patients and market share of different biologics were based on national reimbursement registry data. Adalimumab was the most commonly used biologic treatment for AS, and in the base case analysis all adalimumab patients are assumed to switch to secukinumab. Response rates were based on a matching-adjusted indirect comparison between secukinumab and adalimumab. Patients not achieving response were switched to another biologic treatment. Results Treating AS patients with secukinumab instead of adalimumab leads to potential savings of 18.2 million euros within a 5-year time period. The total costs within the follow-up time were 59.5 million euros and 77.7 million euros with and without secukinumab, respectively. According to sensitivity analyses, higher adoption rate of secukinumab corresponds to higher potential savings. Conclusions Secukinumab is a cost-saving treatment option compared with adalimumab in the treatment of AS in Finland. More patients could be treated with a biologic by allocating resources more efficiently. PMID- 30474452 TI - Correction. PMID- 30474451 TI - Reproducibility of the fetal cerebral vessels assessment in full and late term pregnancies. AB - OBJECTIVE: Data concerning feasibility of the fetal cerebral Doppler examination in full term and late term pregnancy is lacking. Our purpose was to perform an evaluation of these arteries with power Doppler ultrasound, calculating the percentage of identification and measurement and the intraobserver reproducibility. METHODS: This was a cross sectional study evaluating a population of 578 normally grown fetuses divided according to the week of examination. The first group included fetuses examined at week 40 (N = 323) and the second fetuses examined at week 41 (N = 255). The three major branches of the internal carotid artery (anterior, middle and posterior cerebral arteries, ACA, middle cerebral artery (MCA), posterior cerebral arteries (PCA)) and their anastomosis (A1, A2, P1, P2) were examined with power Doppler ultrasonography by three independent ultrasonographers. The proportion of vessel identified and measured was calculated and the reproducibility among the three operators was investigated. RESULTS: The major arteries at the circle of Willis were fully identified/measured in 65/56 and 62/48% of fetuses at 40 and 41 weeks. The MCA obtained the higher percentage of identification and measurement at both periods (> 80 and >70%). The entire set of anastomosis were less frequently identified/measured at both periods (50/< 50% of cases), especially in the A2 segment. The best agreement was obtained in the MCA and the worst in the PCA-P1 segment. CONCLUSIONS: At 40 and 41 weeks, the fetal cerebral vessels, especially the MCA, are suitable for power Doppler evaluation, providing an interesting tool to evaluate fetal hemodynamics in full and late term pregnancy. PMID- 30474453 TI - Association between serum progesterone concentration in early pregnancy and duration of pregnancy: a cohort study. AB - OBJECTIVE: To examine the association between progesterone concentration in early pregnancy and duration of pregnancy and risk of preterm delivery. METHODS: Women enrolled in the Born in Guangzhou Cohort Study from 2013-2014, with a singleton pregnancy, who had serum progesterone measured at least one time between 4 and 10 weeks of gestation were included. The association between progesterone concentration both continuous and as categorical variable (quartile) and the risk of preterm delivery was assessed with Cox proportional hazards regression. Differences of length of gestation in four progesterone concentration quartiles were assessed using the Log-rank test. RESULTS: We studied 1860 mother-newborn pairs. The mean overall progesterone concentration was 65.7 +/- 21.3 nmol/L, with mean progesterone concentrations in the four quartiles of 42.4 +/- 6.2 nmol/L (n = 463), 56.2 +/- 3.3 nmol/L (n = 462), 68.9 +/- 4.5 nmol/L (n = 470), and 95.1 +/ 15.3 nmol/L (n = 465). There was no significantly difference in duration of gestation in four progesterone concentration groups (p=.511). There was no relation between progesterone level and preterm delivery (adjusted hazard ratio (HR) per 10 nmol/l progesterone level 1.00 (95% confidence interval (CI) 0.90, 1.11)). After adjusting for potential confounders, the HR of any preterm delivery for quartiles 1, 2 and 3 versus the highest quartile of progesterone level (> 77.3 nmol/L) was 1.04 (95% CI 0.52, 2.07), 1.17 (95% CI 0.60, 2.28), and 1.46 (95% CI 0.76, 2.78), respectively. When analysis was done for spontaneous preterm delivery only, also no association with first trimester progesterone was found. CONCLUSION: Lower first trimester serum progesterone concentration is not associated with reduction of length of gestation or increased risk of preterm delivery. PMID- 30474454 TI - Muscle stretching changes neuromuscular function involved in ankle stability. AB - It has been postulated that the mechanical and neurophysiological effects induced by stretching decrease maximal muscle strength and power. Additionally, the reduction in neural input and muscle stiffness can affect the joint stabilization process. However, there is no evidence available to support this hypothesis. Thus, the aim of this study is to analyze the influence of static stretching on dynamic joint stability. Twenty physically active female university students (22.8 +/- 5.3 years; 58 +/- 8.8 kg; 1.62 +/- 0.07 m) performed a series of static passive stretching exercises for the peroneus longus and brevis muscles (four repetitions of 30 s). Before and after the stretches, electromyography was performed on both muscles during simulated ankle sprain. Mathematical algorithms calculate the latency and the electromyography activity (RMS). After stretching, the latency increased from 66ms to 73 ms (p = 0.003) for the peroneus brevis muscle and from 70 ms to 79 ms (p = 0.001) for the peroneus longus muscle. The RMS, calculated 100 ms after the simulation, decreased in the peroneus brevis muscle, from 25.05 to 18.16 (p = 0.001), and in the peroneus longus muscle, from 22.84 to 15.61 (p = 0.001). Muscle stretching changed the motor responses of both muscles. The increase in latency and the decrease in RMS indicate that static stretching influences the neuromuscular function involved in the joint stabilization process. PMID- 30474455 TI - Development of a research agenda for general practice based on knowledge gaps identified in Dutch guidelines and input from 48 stakeholders. AB - BACKGROUND: Several funding organizations using different agendas support research in general practice. Topic selection and prioritization are often not coordinated, which may lead to duplication and research waste. OBJECTIVES: To develop systematically a national research agenda for general practice involving general practitioners, researchers, patients and other relevant stakeholders in healthcare. METHODS: We reviewed knowledge gaps from 90 Dutch general practice guidelines and formulated research questions based on these gaps. In addition, we asked 96 healthcare stakeholders to add research questions relevant for general practice. All research questions were prioritized by practising general practitioners in an online survey (n = 232) and by participants of an invitational conference including general practitioners (n = 48) and representatives of other stakeholders in healthcare (n = 16), e.g. patient organizations and medical specialists. RESULTS: We identified 787 research questions. These were categorized in two ways: according to the chapters of the International Classification for Primary Care (ICPC) and in 12 themes such as common conditions, person-centred care and patient education, collaboration and organization of care. The prioritizing procedure resulted in top 10 lists of research questions for each ICPC chapter and each theme. CONCLUSION: The process resulted in a widely supported National Research Agenda for General Practice. We encourage both researchers and funding organizations to use this agenda to focus their research on the most relevant issues in general practice and to generate new evidence for the next generation of guidelines and the future of general practice. PMID- 30474457 TI - Cannula-guided snare with endoclip to assist in endoscopic submucosal dissection: an in vivo animal study. AB - BACKGROUND AND OBJECTIVE: Assisted endoscopic submucosal dissection (ESD) with mucosal traction remains a challenge. This study explored an approach to assist in esophageal, gastric, colonic, and rectal ESD through a cannula-guided snare with endoclips (CSC-ESD), and aimed to preliminarily evaluate its feasibility in an in vivo porcine model. MATERIAL AND METHODS: Forty-seven digestive tract mucosae in six pigs were resected using CSC-ESD. The operative time, operative success rate, en bloc resection rate, and intraoperative complications were evaluated. RESULTS: The mean diameter of 12 resected esophageal mucosae was 4.4 +/- 1.7 cm and the mean operative time was 24 +/- 8 min. The mean diameter of 20 resected gastric mucosae was 3.8 +/- 0.9 cm and the operative time was 35 +/- 8 min. The mean diameter of 15 resected colonic and rectal mucosae was 3.6 +/- 1.0 cm and the operative time was 34 +/- 8 min. In all 47 resected mucosae, the en bloc resection rate was 100%, the operative success rate was 100%, and the intraoperative perforation rate was 4.3% (2/47) in the colon. No mucosal bruising or massive bleeding occurred during surgery. CONCLUSION: The results indicated that this novel assistive method is feasible in esophageal, gastric, colonic and rectal ESD. The further research is worthwhile. PMID- 30474456 TI - Effects of Formulation Development Methods on the stability of Model Protein Pharmaceuticals Embedded in Solid Lipid Matrices. AB - This study was conducted to investigate the influence of formulation development methods on the stability (secondary structure, aggregation and biological activity) of protein drugs embedded in lipid matrices. Catalase, horseradish peroxidase and alpha-chymotrypsin were employed as model proteins while, Precirol(r) AT05 (glyceryl palmitostearate) was used as lipid matrix. Protein loaded lipid matrices were prepared using melting and mixing and wet granulation methods. Attenuated total reflectance Fourier transform infrared (ATR FT-IR) spectroscopy, size exclusion chromatography (SEC) and biological activity analyses were performed. ATR FT-IR analysis indicated significant interference of the lipid with the protein amide-I band which was eliminated using spectral subtraction. Wet granulation method induced more changes in protein secondary structure compared to melting and mixing method. SEC analysis gave evidence of protein aggregation for catalase upon adopting the wet granulation method. The biological activity of catalase was found to reduce significantly than other two proteins upon using wet granulation method which might be ascribed to both secondary structure alterations and the formation of aggregates. Horseradish peroxidase and alpha-chymotrypsin did not form any soluble aggregates. In conclusion, melting and mixing method emerged as a better incorporation method compared to wet granulation because of better stability shown by the formulated proteins. PMID- 30474458 TI - "When what is taken for granted disappears": women's experiences and perceptions after a cardiac event. AB - BACKGROUND AND PURPOSE: On entering Cardiac Rehabilitation (CR), the female cardiac population shows greater fear of overexertion and sense of uncertainty than similarly affected men. The purpose of this study was to explore how women experienced the recovery process after a cardiac event and what impact the event had on bodily experiences. METHODS: A qualitative, descriptive design, inspired by a phenomenological approach. Information was collected from 20 women through focus groups and individual in-depth interviews. The material was analyzed with a method of systematic text condensation. RESULTS: The women's recovery after a CE could be a lonely and difficult process. Their own perspectives on what they need in the process is often overlooked, focus being on medical care and clinical recovery in the early phase. Returning home, the women suffered vulnerability, fragility, and insecurity, affecting well-being as well as activity levels. Lack of support and follow-up post-discharge seemed to disturb the progress of the recovery process. CONCLUSIONS: Helping the women regain confidence in their new bodies, supporting the personal recovery processes, and bridging the gap between discharge and enrolling in a CR-program could reduce personal stress and withdrawal, thereby empowering more women to start and complete CR programs. PMID- 30474459 TI - Pre-formulation investigations for establishing a protocol for treosulfan handling and activation. AB - INTRODUCTION: Treosulfan is an alkylating agent that is used for the treatment of ovarian cancer and for conditioning prior to stem cell transplantation. It is a prodrug that is activated non-enzymatically to two active epoxides. OBJECTIVES: To optimize a protocol for both in vivo samples handling and in vitro drug preparation. Treosulfan stability was tested in biological fluids at different conditions as well as for its cytotoxicity on cell lines. RESULTS: Plasma samples can be safely frozen for a short period up to 8h, however; for longer periods, samples should be acidified. Urine samples and cell culture media can be safely frozen regardless their pH. For in vitro investigations, incubation of treosulfan at 37 degrees C for 24h activated 100% of the drug. Whole blood acidification should be avoided for the risk of hemolysis. Finally; treosulfan cytotoxicity on HL-60 cells has increased following pre-incubation for 24h at 37 degrees C compared to K562 cell line. CONCLUSION: The stability profiling of treosulfan provided a valuable reference for handling of biological samples for both in vivo and in vitro studies. These results can be utilized for further investigations concerning the drug kinetics and dynamics in addition to the development of new pharmaceutical formulations. PMID- 30474460 TI - IgG4-related periaortitis/periarteritis: an under-recognized condition that is potentially life-threatening. AB - Periaortitis and periarteritis are one of the clinical features of IgG4-related disease. Such vascular manifestations are reported to be present in 10%-30% of overall IgG4-related disease, and they may also appear as an isolated lesion of IgG4-related disease. As other types of large vessel vasculitis, IgG4-related vasculitis may cause significant clinical consequences. On the other hand, the diagnosis of IgG4-related periaortitis/periarteritis seems to have been made on the basis of different diagnostic criteria in reported studies; thus far, difficulty seems to be present in assessing the true frequency of the disease as well as determining the optimal therapeutic strategy. In this review, in addition presenting the clinical and pathological features of IgG4-related periaortitis/periarteirtis, we would like to discuss on what kind of points should be resolved for the better understanding of vascular involvement of IgG4 related disease in terms of diagnosis and treatment. PMID- 30474461 TI - Predictors of pre-sarcopenia in community-dwelling older adults: a 5-year longitudinal study. AB - OBJECTIVES: Sarcopenia is an aging-induced decrease in muscle mass that increases frailty and fall in elderly people. Pre-sarcopenia corresponds to the preliminary stage of sarcopenia. The purpose of this prospective study is to examine predictors of pre-sarcopenia in health screening. METHODS: The subjects were 124 community residents aged >=60 years (55 males, 69 females, average age 70.2 years) who attended local government health checkups in 2010 and 2015, as part of the Yakumo study, and did not have pre-sarcopenia in 2010. Body mass index (BMI), waist and hip circumferences, grip strength, bone mineral density (BMD), 10-m gait time, back muscle strength, and stride length were measured. Pre-sarcopenia was defined using the appendicular skeletal muscle index (arm and leg skeletal muscle mass/height2). RESULTS: The prevalences of pre-sarcopenia in 2015 in males and females were 21.8% (12/55) and 30.4% (21/69), respectively. BMI, grip strength, BMD, back muscle strength, and osteoporosis deteriorated significantly more in the pre-sarcopenia group (n = 33) compared with controls (n = 91; no pre sarcopenia in 2015). In multivariate analysis, osteoporosis (OR 3.12, 95% CI 1.07 9.09; p < 0.05) was significantly associated with pre-sarcopenia after 5 years. CONCLUSIONS: Establishment of risk factors for future pre-sarcopenia may allow development of evidence-based prevention strategies for this condition. PMID- 30474462 TI - Pitfalls of Frozen Section in Gynecological Pathology: A Rare Case of Ovarian Lymphoma in an HIV-Positive Woman Resembling Dysgerminoma on Frozen Section. AB - Primary lymphoma of the ovary, particularly in an HIV-positive woman, is exceptionally rare, and ovarian lymphoma may not be considered at the time of intraoperative consultation. In this article, we present a case in an HIV positive woman thought to be a dysgerminoma at the time of frozen section, but which was found to be a diffuse large B-cell lymphoma of the ovary. PMID- 30474463 TI - The effects of Para-phenylenediamine (PPD) on the skin fibroblast cells. AB - 1. Para-phenylenediamine (PPD) is the commonest and most well-known component of hair dyes. PPD is found in more than 1000 hair dye formulations and is the most frequently used permanent hair dye component in Europe, North America, and East Asia. PPD containing hair dyes have been associated with cancer and mutagenicity. Apart from that, PPD has potential toxicity which includes acute toxicity such as allergic contact dermatitis and subacute toxicity. 2. In this study, we examined the effects of the PPD composition on the skin-isolated fibroblast cells. Fibroblast cells were isolated from the skin and cell viability, reactive oxygen species (ROS) production, the collapse of mitochondrial membrane potential (MMP), lipid peroxidation, damage to the lysosome and finally release of cytochrome c were examined following the exposure to various concentrations of PPD. 3. Our results showed that exposure to PPD increased reactive oxygen species (ROS) generation, lipid peroxidation (LPO), the collapse of mitochondrial membrane potential (MMP), and cytochrome c release. Our results suggest that PPD can induce damage to the lysosomal membrane. 4. These results showed that PPD composition has a selective toxicity on skin fibroblasts cell and mitochondria are considered one of the goals of its toxicity. PMID- 30474464 TI - The development of environmentally acceptable fluorocarbons. AB - Chlorofluorocarbons (CFCs) were introduced in the 1930s as the safe replacements for the toxic and flammable refrigerants being used at that time. Subsequently, hydrochlorofluorocarbons (HCFCs) were also developed. In addition to refrigerant applications, they were used as foam blowing agents, as solvents and as propellants for many aerosols. In the 1970s and 1980s, concern developed about their environmental impact, specifically on stratospheric ozone depletion. Industry began to consider acceptable replacements. In 1987, many of the governments of the world came together and drafted the Montreal Protocol, calling upon Industry to initially phase out production of the CFCs and later HCFCs. Within 4 months of the signing of the Montreal Protocol, the 15 global major producers joined together to form the Alternative Fluorocarbons Environmental Acceptability Study (AFEAS), which sponsored research into environmental effects and the Program for Alternative Fluorocarbons toxicity Testing, PAFT), which examined the toxicology of potential replacements for the CFCs and HCFCs. Nine replacements were identified by companies and, through this international cooperation; toxicology programs were designed, conducted, and evaluated without duplication of effort and testing; consequently these new products were introduced within less than 10 years. Indeed the Montreal Protocol has been recognized as the most appropriate international treaty to phase-down HFCs. In 2016 the Kigali Amendment to the Montreal Protocol set out a phase-down schedule for the consumption and production of HFCs. In order to reduce the consumption and emissions of high GWP HFCs. Recently lower GWP HFCs and very low GWP HFOs (hydrofluoroolefins and HCFOs (hydrochlorofluoroolefins) have been introduced into a range of applications. Summaries of the toxicology profiles of some of the original CFCs and HCFCs, the replacements and the new post-PAFT replacements are described. The chemicals in this review include CFC-11, CFC-12, CFC-113, CFC-114, HCFC 22, HCFC-123, HCFC-124, HCFC-141b, HCFC-142b, HCF-32, HFC-125, HFC-134a, HFC 143a, HFC-152a, HFC-245ea, HFC-245fa, HFO-1234yf, HFO-1234ze, and HCFO-1233zd. PMID- 30474465 TI - IgG4-related respiratory disease. AB - IgG4-related diseases (IgG4-RDs), such as autoimmune pancreatitis and IgG4 related Mikulicz disease, are often accompanied by intrathoracic lesions, which are called IgG4-related respiratory disease (IgG4-RRD). IgG4-RRD has few subjective symptoms, and is usually detected during workup of patients with extra thoracic lesions of IgG4-RD. IgG4-RRD is characterized by various conditions, including masses, nodules, thickening, and infiltration at numerous sites in the thorax through lymphatic routes. Although elevated serum IgG4 concentrations and pathologic evidence of lymphoplasmacytic infiltrates with abundant IgG4-positive plasma cells are characteristic findings of IgG4-RD, other intrathoracic diseases, such as multicentric Castleman disease and malignancy, may present with similar findings. Developing diagnostic criteria for IgG4-RRD, including clinicoradiological and pathological characteristics, is necessary for its appropriate diagnosis. PMID- 30474466 TI - Developing and Validating an Experience Sampling Measure of Aggression: The Aggression-ES Scale. AB - Experience sampling methodologies are likely to play an important role in advancing our understanding of momentary influences on aggression, including short-term antecedent psychological states and situations. In this study, we evaluate whether a newly developed experiencing sampling measure of aggression, the Aggression Experience Sampler ( Aggression-ES), provides a valid and reliable measure of aggression in experience sampling contexts. Participants were a convenience sample of 23 young adults recruited from the local University community. Data were collected using an experience sampling smartphone application over 8 days. They were analyzed using multilevel structural equation modeling. Our results support the within- and between-person reliability and the criterion validity of the Aggression-ES. The Aggression-ES represents a good choice of measure for use in experience sampling studies of aggression. Further work in other samples will help to provide further validity evidence for the measure. PMID- 30474467 TI - Childhood Maltreatment Experiences, Attachment, Sexual Offending: Testing a Theory. AB - The aim of this study was to empirically examine the theoretical model proposed by Grady, Levenson, and Bolder used to explain the relationships between experiencing trauma, attachment styles, and risk factors associated with sexual offending. The specific risk factors tested were emotional, behavioral, and cognitive regulation deficits. The research questions were as follows: (1) What specific childhood traumatic experiences (physical and sexual abuse and/or other domestic trauma events) are associated with anxious-ambivalent and anxious avoidant attachments? (2) Are anxious-ambivalent and anxious-avoidant attachment styles differentially linked to dysregulation outcomes (emotional, behavioral and cognitive shift, and inhibitions)? (3) Do insecure attachment styles explain why childhood trauma is associated with dysregulation? and (4) Do these early life experiences contribute to sexual offending behavior? The sample included 200 male youth adjudicated for either a sexual or nonsexual crime and living in the community or a residential facility. The average age of the youth was 17.17 years ( SD = 1.81 years). Structural equation modeling was used to determine the direct and indirect relationships between abuse and traumatic experiences, anxious avoidant and ambivalent-anxious attachment styles, and regulation deficits. Authors found a direct relationship between physical abuse and both of the attachment styles, separately. Both anxious-ambivalent and anxious-avoidant attachment styles related similarly to regulation deficits. Separately, anxious ambivalent and anxious-avoidant attachment styles served as mediators between physical abuse and regulation deficits. Sexual abuse predicted the later commission of sexual crimes with no influence from attachment style. Finally, domestic trauma independently predicted regulation deficits in the model that included anxious-ambivalent attachment but had no effect on deficits in the model that included anxious-avoidant attachment. Implications for treatment include the need to consider using attachment-based interventions and prevention strategies, and a trauma-informed approach when working with justice involved youth. Suggestions for future research are also discussed. PMID- 30474468 TI - Myostatin Serum Concentration as an Indicator For Deviated Muscle Metabolism In Severe Burn Injuries. AB - INTRODUCTION:: Patients experiencing thermal injuries with an extent of over 20% of total body surface area suffer from systemic catabolic disease. The thermal trauma-induced loss of muscle mass causes a higher incidence for comorbidities and subsequently a higher mortality. In this study, we aimed to investigate the role of myostatin in the interplay with follistatin during muscle cachexia. METHODS:: Patients with burn injuries (>10% total body surface area) between the ages of 18 and 75 were prospectively included within the first 48 h after trauma to determine deviations of parameters connected to muscle catabolism. In the chronic state of burn injury (9-12 months after trauma), we re-evaluated myostatin and follistatin concentrations as well as muscle strength of the non dominant forearm. RESULTS:: We were able to show a time-dependent alteration (9 12 months after burn injury) of myostatin with an initial decrease ( p < 0.001) and long-term increase ( p < 0.001) after thermal injury in blood serum. For follistatin, a reciprocal correlation was observed ( r = -0.707, p = 0.001). Accordingly, muscle strength of the non-dominant hand and forearm was significantly decreased 9-12 months after injury in post-burn patients compared with healthy patients with a significant correlation to myostatin levels ( r = 0.899, p < 0.001). In addition, initial myostatin serum concentration was predictive for long-term muscle strength impairment. CONCLUSION:: With regard to the muscle metabolism after thermal trauma, our data suggest an acute anabolic response, presumably to spare muscle mass, which is converted to catabolic conditions accompanied by muscle strength reduction in the chronic phase. Myostatin plays a crucial role in this orchestration and initial myostatin concentration may predict the long-term muscle strength. PMID- 30474469 TI - Breast cancer-released exosomes trigger cancer-associated cachexia to promote tumour progression. AB - Emerging evidence supports the pivotal roles of cancer-associated cachexia in biological behaviour of breast cancer. However, the mediators and mechanisms that mediate cancer-induced cachexia remain unclear. Here, we show that breast cancer derived exosomes alter adipocytes and muscle cells in terms of increased catabolism characterized by the release of metabolites. Likewise, tumour cells cocultivated with mature adipocytes or C2C12 exhibit an aggressive phenotype through inducing epithelial-mesenchymal transition. Mechanistically, we show that cancer cell-secreted miR-155 promotes beige/brown differentiation and remodel metabolism in resident adipocytes by downregulating the PPARgamma expression, but does not significantly affect biological conversion in C2C12. In vitro the use of propranolol ameliorates tumour exosomes-associated cachectic wasting through upregulating the PPARgamma expression. These results demonstrate that cancer derived exosomes reprogram systemic energy metabolism and accelerate cancer associated cachexia to facilitate tumour progression. PMID- 30474470 TI - Comparing Injecting Risk Behaviors of Long-Term Injectors with New Injectors in Tehran, Iran. AB - BACKGROUND: Global estimates suggest there are 15.6 million people who inject drugs (PWID) of whom 17.8% are living with HIV.Few studies have characterized newly-onset injectors with long-term injectors and its association with injecting risk behaviors. OBJECTIVES: We examined the relationship between length of injection and risk behaviors among people who inject drugs (PWID) in Tehran, Iran. METHODS: A cross-sectional study was conducted among PWID, from March to August 2016 in Tehran, Iran. PWID were recruited by convenience and snowball sampling from five Drop-in Centers (DIC) located in the south of Tehran. Our primary independent variable was length of injecting career, defined as the number of months since injecting initiation. Those defined as new injectors (were injecting for less than 18 months), and long-term injectors (as injecting drugs for more than 18 months). We reported the adjusted odds ratio (aOR) point estimate and 95% confidence interval (CI95%) as the effect measure. The level of significance used in multiple logistic regression model was 0.05. We used STATA v. 11 for all analyzes. RESULTS: The analytical sample comprised of 500 participants (100% male). Mean (+/-SD) age of PWID with a length of injection history was 31.2 +/- 7.2 years. Overall, 270 (54%) (CI95%: 49.6%, 58.4%) of participants were long-term injectors. The average age of drug use initiation among long-term injectors group was lower as compared to new injectors group (31.2 vs. 29.4, p < 0.001). The odds of distributive syringe sharing among new injectors were two times higher than long-term injectors (AOR = 2.1, 95% CI 1.4 4.7). The odds of receptive syringe sharing were lower among new injectors group (AOR = 0.7, CI95% 0.2-0.87), compared to long-term injectors. New injectors had higher odds of reusing their own syringes (OR = 2.8, 95% CI: 1.4-5.7; p = 0.01). CONCLUSIONS: Improvements in harm reduction service provision can occur through taregted risk reduction education for new injectors focusing on reducing distributive syringe sharing among them. PMID- 30474471 TI - Relationship between serum soluble receptor for advanced glycation end products (sRAGE) and disease activity in rheumatoid arthritis patients. AB - OBJECTIVE: Considering the important role of serum soluble receptor for advanced glycation end product (sRAGE/RAGE)-ligand system in rheumatoid arthritis (RA), this study aimed to evaluate serum sRAGE levels in RA patients compared to healthy subjects and to assess whether there is an association between sRAGE levels and disease characteristics in RA. METHODS: In this cross-sectional study, 60 RA patients according to the ACR/EULAR 2010 criteria and 30 age- and sex matched healthy controls were included. In patients, clinical examination was performed and disease activity score 28 (DAS-28) measure of disease activity was assessed. Serum sRAGE level was measured using ELISA kit. RESULTS: The mean +/- SD age of patients and controls was 54.86 +/- 11.65 and 50.71 +/- 3.72 years, respectively). Serum sRAGE level was significantly higher in RA patients (median [25th and 75th percentiles], 1000.3 [792.00, 1486.8]) compared to healthy controls (median [25th and 75th percentiles], 293.25 [220.35, 364.24]) (p < 0.001). There was significant difference in serum sRAGE level according to the activity of disease (p < 0.001). There were significant positive correlations between serum sRAGE level with disease activity (r = 0.67, p < 0.001), ESR (r = 0.411, p = 0.001) and CRP (r = 0.273, p = 0.035). There were no significant correlations between serum sRAGE level with demographic characteristics as well as biochemical measurements including serum creatinine, BUN, RF, and Anti-CCP (p > 0.05). CONCLUSIONS: Our study revealed higher serum sRAGE levels in RA patients compared to healthy controls, which correlated positively with disease activity. PMID- 30474472 TI - Long noncoding RNA Malat1 is not essential for T cell development and response to LCMV infection. AB - Long noncoding RNAs (lncRNAs) are emerging as critical mediators of various biological processes in the immune system. The current data showed that the lncRNA Malat1 is highly expressed in T cell subsets, but the function of Malat1 in T cell remains unclear. In this study, we detected the T cell development and both CD8+ and CD4+ T cell response to LCMV infection using Malat1-/- mice model. To our surprise, there were no significant defects in thymocytes at different developmental stages and the peripheral T cell pool with ablation of Malat1. During LCMV infection, Malat1-/- mice exhibited normal effector and memory CD8+ T cells as well as TFH cells differentiation. Our results indicated that Malat1 is not essential for T cell development and T cell-mediated antiviral response though it expresses at very high level in different T cell populations. PMID- 30474473 TI - Beta regression in the presence of outliers - A wieldy Bayesian solution. AB - Real phenomena often leads to challenges in data. One of these is outliers or influential values. Especially in a small sample, these values can have a major influence on the modeling process. In the beta regression framework, this issue has been addressed mainly in two ways: the assumption of a different response model and the application of a minimum density power divergence estimation (MDPDE) procedure. In this paper, however, we propose a simple hierarchical Bayesian methodology in the context of a varying dispersion beta response model that is robust to outliers, as shown through an extensive simulation study and analysis of two real data sets. To robustify Bayesian modeling, a heavy-tailed Student's t prior with uniform degrees of freedom is adopted for the regression coefficients. This proposal results in a wieldy implementation procedure which avails practical use of the approach. PMID- 30474474 TI - SAMHD1 inhibits epithelial cell transformation in vitro and affects leukemia development in xenograft mice. AB - Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a mammalian dNTP hydrolase (dNTPase) and functions as a negative regulator in the efficacy of cytarabine treatment of acute myeloid leukemia (AML). We have reported that SAMHD1 knockout (KO) increased the activity of phosphoinositide 3-kinase (PI3K) in AML-derived THP-1 cells and attenuated their ability to form subcutaneous tumors in xenografted immunodeficient mice. However, the functional significance of SAMHD1 in controlling AML leukemogenesis remains unclear. Previous studies show that in vitro transformation of Madin-Darby canine kidney (MDCK) epithelial cells by the Jaagsiekte sheep retrovirus (JSRV) envelope protein requires activation of the PI3K/Akt oncogenic signaling pathway. Using this cell transformation model, we demonstrated that ectopic expression of wild-type human SAMHD1 or a dNTPase-defective SAMHD1 mutant (HD/AA) significantly inhibited MDCK cell transformation, but did not affect cell proliferation. To visualize and quantify THP-1 cell growth and metastasis in xenografted immunodeficient mice, we generated luciferase-expressing stable SAMHD1 KO THP-1 cells and control THP-1 cells, which were injected intravenously into immunodeficient mice. Bioluminescence imaging and quantification analysis of xenografted mice revealed that SAMHD1 KO cell-derived tumors had similar growth and metastatic potential compared with control cells at 35 days post-injection. However, mice xenografted with SAMHD1 KO cells showed greater survival compared with mice injected with control cells. Our data suggest that exogenous SAMHD1 expression suppresses in vitro cell transformation independently of its dNTPase activity, and that endogenous SAMHD1 affects AML tumorigenicity and disease progression in vivo. PMID- 30474476 TI - Efficacy and safety of PD-1 inhibitors for treating advanced melanoma: a systematic review and meta-analysis. AB - AIM: We conducted a meta-analysis to systematically review the efficacy and safety of programmed cell death 1 (PD-1) inhibitors for advanced melanoma. STUDY DESIGN: The relevant studies of the randomized controlled trials in melanoma patients treated with PD-1 inhibitors were retrieved and the systematic evaluation was conducted. Databases were searched till June 2018. RESULTS: PD-1 inhibitors significantly improved the progression-free survival, overall survival and overall response rate in patients with advanced melanoma. Progression-free survival, overall survival and overall response rate did not vary significantly according to PD-L1 status, V-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations and type of drug, but varied significantly by control therapy. PD-1 inhibitors were associated with a decreased risk of adverse events compared with ipilimumab, but an increased risk of immune-related events compared with chemotherapy. CONCLUSION: The PD-1 inhibitors-containing therapy was efficacious in treating advanced melanoma. PMID- 30474477 TI - The forgotten role of adjuvant immune checkpoint inhibitors in preventing melanoma brain metastasis. PMID- 30474475 TI - Risk of fatigue in cancer patients treated with anti programmed cell death-1/anti programmed cell death ligand-1 agents: a systematic review and meta-analysis. AB - AIM: We aimed to assess the incidence and relative risk (RR) of fatigue in cancer patients treated with anti programmed cell death-1 (PD-1) and anti programmed cell death ligand-1 (PD-L1) agents. PATIENTS & METHODS: Eligible studies were selected according to Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statement. Incidence, RR and 95% CIs were calculated using random or fixed-effects models. RESULTS: Thirty-eight studies were included in this analysis, with a total of 11,719 patients. The incidences were 23.4 and 2.1% for all- and high-grade fatigue, respectively. The highest incidence of high grade fatigue was reported by the combination of nivolumab and ipilimumab. Overall RR of high-grade fatigue with anti-PD-1/PD-L1 compared with chemotherapy or targeted therapy was 0.48. CONCLUSION: Treatment with anti-PD-1/PD-L1 agents correlates with lower incidence and RR of fatigue compared with standard therapies. PMID- 30474478 TI - Effects of sacubitril/valsartan on functional status and exercise capacity in real-world patients. AB - BACKGROUND: Sacubitril/valsartan significantly reduced heart failure(HF) hospitalisations and mortality in the PARADIGM-HF-trial. However real-world data on symptomatic and functional improvement are lacking. METHODS: Between December 2016 and January 2018, we retrospectively collected baseline and follow-up data including New York Heart Association (NYHA)-functional class and Cardio-pulmonary exercise data(CPET) in all HF-patients receiving sacubitril/valsartan. Additionally, in patients with an implantable electric cardiovascular device (IECD) enrolled in remote telemonitoring, we quantified patient level activity before and after initiation. RESULTS: A total of 201 patients (82% males) were identified. NYHA-functional class was reassessed after an average of 221 +/- 114 days. Overall, 3.3% of patients improved 2 NYHA classes, 28.7% improved 1 NYHA class, 64% remained stable and 4% deteriorated 1 NYHA class. Patients with symptomatic improvement exhibited a larger reduction in Left Ventricular End Systolic Volume(LVESV) and a larger increase in Left Ventricular Ejection Fraction(LVEF[p-value both <.05]). In total, 110 patients (55%) were equipped with an IECD capable of quantifying outpatient activity-level. On an average of 364 days before sacubitril/valsartan, an activity expressed as %-of-the-day was 13 +/- 2%, vs. 18 +/- 3% the 364 days following sacubitril/valsartan initiation. Signifying a 38% improvement in the out-patient activity level. CPET-data was obtained in paired-fashion in 45 patients (22%). VO2max at baseline (14.7 +/- 3.8 mL/kg/min) did not significantly change at follow-up (14.1 +/- 4.7 mL/min/kg; p = .237). CONCLUSION: Real-world patients exhibit significant symptomatic and functional improvement following the initiation of sacubitril/valsartan. However, larger prospective studies are necessary to assess the impact of sacubitril/valsartan on indices of maximal exercise performance measured during CPET. PMID- 30474479 TI - Dietary plant miRNAs as an augmented therapy: cross-kingdom gene regulation. AB - Cross-kingdom gene regulation by microRNAs (miRNAs) initiated a hot debate on the effective role of orally acquired plant miRNAs on human gene expression. It resulted in the expansion of gene regulation theories and role of plant miRNAs in cross-kingdom regulation of gene expression. This opened up the discussion that "Whether we really get what we eat?" and "Whether the orally acquired miRNAs really have a biologically important consequences after entering our digestive and circulatory system?" The reports of orally acquired plant miRNAs inside human alimentary canal have been a topic of discussion in the scientific community. The cross-kingdom gene regulations have raised our hopes to explore the exciting world of plant miRNAs as therapeutic potential and dietary supplements. However, there are reports which have raised concerns over any such cross-kingdom regulation and argued that technical flaws in the experiments might have led to such hypothesis. This review will give the complete understanding of exogenous application and cross-kingdom regulation of plant miRNAs on human health. Here, we provide update and discuss the consequences of plant miRNA mediated cross kingdom gene regulation and possibilities for this exciting regulatory mechanism as an augmented therapy against various diseases. PMID- 30474480 TI - Increased expression of the proprotein convertase enzyme FURIN in rheumatoid arthritis. AB - OBJECTIVE: FURIN is a proprotein convertase enzyme that inhibits the proinflammatory function of T cells and myeloid cells. Elevated FURIN expression levels have been reported in immune-mediated diseases, such as primary Sjogren's syndrome. Here, we investigated the levels of FURIN in peripheral blood (PB) and synovial fluid (SF) leucocytes from patients with rheumatoid arthritis (RA). METHOD: FURIN mRNA expression in PB and SF cells was determined by quantitative reverse transcription-polymerase chain reaction and FURIN plasma levels were measured using enzyme-linked immunosorbent assay. Associations between FURIN levels and demographic and clinical characteristics of the patients were determined. RESULTS: FURIN levels were significantly elevated in PB and SF mononuclear cells, T cells, and monocytes from RA patients compared to healthy controls. High FURIN levels were significantly associated with the prevailing prednisolone treatment, higher prednisolone doses, and increased C-reactive protein levels and Health Assessment Questionnaire values. CONCLUSION: FURIN is significantly upregulated in RA PB and SF leucocytes, suggesting that it may have a role in the pathogenesis of RA. In addition, our results suggest that elevated FURIN expression is associated with the indicators of more severe RA. PMID- 30474481 TI - Non-small-cell lung cancer homing peptide-labeled dendrimers selectively transfect lung cancer cells. AB - AIM: Lung cancer gene therapies require reagents to selectively transfect lung tumors after systemic administration. MATERIALS & METHODS: We created a reagent called NSCLC-NP by attaching a peptide with binding affinity for lung cancer to polyamidoamine dendrimers. The positively charged dendrimers electrostatically bind negatively charged nucleic acids, inhibit endogenous nucleases and transfect cells targeted by the attached peptide. RESULTS: In vitro, NSCLC-NP complexed to DNA plasmids bound and transfected three human lung cancer cell lines producing protein expression of the plasmid's gene. In vivo, systemically administered NSCLC-NP selectively transfected lung cancer cells growing in RAG1KO mice. CONCLUSION: The capability of NSCLC-NP to selectively transfect lung cancer allows its future use as a vehicle to implement human lung cancer gene therapy strategies. PMID- 30474483 TI - Immunotherapy Foreword 2018. AB - To all of our readers, the Future Medicine editorial office would like to thank you for your continued readership over 2018 and I hope you have a fantastic Christmas and New Year. I would also like to thank our esteemed editorial board, peer reviewers and contributing authors for their continued support. We very much look forward to working with you all in 2019 and seeing the journal continue to progress. In this foreword, we will present some highlights from the last 12 months in addition to looking forward to the year ahead. PMID- 30474482 TI - The behavior of Italian allergists in prescribing allergen immunotherapy for house dust mites allergy. AB - The meeting 'Clinical Evidence, Extracts Quality and Biotechnology Innovation in Allergen Immunotherapy' held in Trieste (Italy) on 1 October 2017 concerned the outcomes of a real-world survey conducted on a group of Italian allergists about allergen immunotherapy (AIT) for house dust mites allergy. It pointed out: allergist's confidence that AIT should be prescribed continuously; tablets seem to be well accepted by patients and effective in most subjects with a fast onset of action (3-6 months); combined score for symptom severity and medication use is universally assessed; there is disagreement about the diagnosis of house dust mites allergy, the quote of AIT prescription, the choice for AIT route of administration, assessment of serum IgE and perception of patient's adherence. PMID- 30474484 TI - Now trending: Coping with non-parallel trends in difference-in-differences analysis. AB - Difference-in-differences (DID) analysis is used widely to estimate the causal effects of health policies and interventions. A critical assumption in DID is "parallel trends": that pre-intervention trends in outcomes are the same between treated and comparison groups. To date, little guidance has been available to researchers who wish to use DID when the parallel trends assumption is violated. Using a Monte Carlo simulation experiment, we tested the performance of several estimators (standard DID; DID with propensity score matching; single-group interrupted time-series analysis; and multi-group interrupted time-series analysis) when the parallel trends assumption is violated. Using nationwide data from US hospitals (n = 3737) for seven data periods (four pre-interventions and three post-interventions), we used alternative estimators to evaluate the effect of a placebo intervention on common outcomes in health policy (clinical process quality and 30-day risk-standardized mortality for acute myocardial infarction, heart failure, and pneumonia). Estimator performance was assessed using mean squared error and estimator coverage. We found that mean-squared error values were considerably lower for the DID estimator with matching than for the standard DID or interrupted time-series analysis models. The DID estimator with matching also had superior performance for estimator coverage. Our findings were robust across all outcomes evaluated. PMID- 30474485 TI - Complications Following 250 Cemented Modular Hip Hemiarthroplasties. AB - BACKGROUND AND AIMS:: Hemiarthroplasty is a common method of treating displaced femoral neck fractures, especially among elderly non-active patients with frailty syndrome. Complications arising from the use of a modern, modular hemiendoprosthesis via a posterior approach have been poorly reported in this population. The aim of this study was to evaluate complications and mortality associated with the use of Lubinus sp II cemented, unipolar hemiarthroplasty prosthesis and posterior approach during a 9-year follow-up. MATERIAL AND METHODS:: All patients (244) who received hemiarthroplasty due to an acute fracture of the femoral neck in Central Finland Hospital, Jyvaskyla, Finland, during 2007 and 2008 were included. Patient records were retrospectively reviewed for intraoperative and postoperative complications. RESULTS AND CONCLUSION:: Women composed 70% (n = 171) of the study population. Mean age was 83 years for women and 80 years for men. A total of 31 (12%) complications were found in 30 patients. These were 12 dislocations (5% of all patients), 5 (2%) periprosthetic fractures, 2 (0.8%) superficial and 5 (2%) deep infections, 1 (0.4%) protrusion of the prosthesis, 2 (0.8%) intraoperative fractures, and 2 (0.8%) partial sciatic nerve palsies. Conversion to total hip replacement was performed in 9 cases (4%) and a reoperation was required in 15 (6%) cases. Mortality rate at 9 years was 78% (95% confidence interval = 72%-83%). The overall rate of complications was acceptable although mortality was high in this comorbid patient population. The need for conversion to total hip arthroplasty and reoperation is low. PMID- 30474486 TI - Noninvasive allergic sinus congestion and resolution assessments using microcomputed tomography imaging. AB - Sinus congestion resultant of allergic rhinosinusitis is associated with development and worsening of asthma and can result in difficulty breathing, headaches, and missed days of school and work. Quantification of sinus congestion is important in the understanding of allergic rhinosinusitis and the development of new drugs for its treatment. Noninvasive microcomputed tomography (micro-CT) was investigated in a guinea pig model of allergic rhinosinusitis to determine its utility to determine accurately the degree of sinus congestion and resolution with anti-inflammatory drug administration. Three-dimensional sinus air-space volume, two-dimensional sinus width, sinus image air-space area, and sinus image sinus perimeter were measured in guinea pigs administered ragweed pollen (RWP), intranasally (i.n.), followed by administration of fluticasone, i.n. To determine their relative accuracy in assessing sinus congestion, the micro-CT image results were compared with the "gold-standard" method of sinus fluid fill-volume (SFFV) measurements. As measured by SFFV method, RWP increased sinus congestion in a RWP concentration-dependent fashion, approaching near-total sinus blockage with concentrations >=22 ug of RWP. At this level of congestion, fluticasone (25-100 ug) progressively decreased sinus congestion in a concentration-dependent fashion. The noninvasive micro-CT methods were found to accurately determine the amount of sinus congestion and resolution, with patterns of increases and decreases of congestion that were nearly identical to the SFFV method. We conclude that noninvasive micro-CT measurements of allergic sinus congestion can be useful as an investigative tool in the assessment of congestion intensity and the development of new drug therapies for its treatment. NEW & NOTEWORTHY Allergic rhinosinusitis afflicts significant portions of the world population, resulting in loss of work productivity and decreased quality of life. Thus the development of methodological approaches, which incorporate accurate and reproducible noninvasive assessments of sinus congestion, are desirable. Microcomputed tomography of the guinea pig sinuses offers a noninvasive evaluation tool in an animal model of IgE-dependent allergy similar to that in humans, with potential relevance toward development of therapeutics for human sinus diseases. PMID- 30474487 TI - Exercise training-induced effects on the abdominal subcutaneous adipose tissue phenotype in humans with obesity. AB - Rodent studies have indicated that physical exercise may improve adipose tissue function. We investigated the effects of a 12-wk supervised, progressive exercise training program on adipocyte morphology and abdominal subcutaneous adipose tissue function in metabolically well-phenotyped subjects with obesity. Men with obesity ( n = 21) participated in a 12-wk supervised, progressive, combined exercise training program consisting of aerobic exercise (30 min at 70% of maximal power output 2 times/wk) and resistance exercise (3 * 10 repetitions at 60% of 1 repeated maximum 1 time/wk), with adjustment of exercise intensity every 4 wk. At baseline and after intervention, abdominal subcutaneous adipose tissue biopsies were collected to determine 1) adipocyte morphology, 2) gene expression of markers for lipolysis, inflammation, browning, adipokines, and mitochondrial biogenesis/function, 3) protein expression of mitochondrial oxidative phosphorylation (OXPHOS) complexes, and 4) ex vivo basal and beta2-adrenergic stimulated lipolysis. The exercise training program, which increased maximal aerobic capacity ( P < 0.001) and muscle strength ( P < 0.001), slightly reduced adipose tissue mass (~0.7 kg, P = 0.021) but did not affect abdominal subcutaneous adipocyte size ( P = 0.744), adipose tissue gene expression of markers for mitochondrial biogenesis and function, browning, lipolysis, inflammation and adipokines, total OXPHOS protein content ( P = 0.789), or beta2 adrenergic sensitivity of lipolysis ( P = 0.555). A 12-wk supervised, progressive exercise training program did not alter abdominal subcutaneous adipocyte morphology and adipose tissue gene/protein expression of markers related to adipose tissue function or beta2-adrenergic sensitivity of lipolysis in male subjects with obesity. NEW & NOTEWORTHY Studies that investigated the effects of exercise training on adipose tissue function in well-phenotyped humans are scarce. We demonstrate that 12 wk of supervised exercise training improved physical fitness and peripheral insulin sensitivity but did not alter abdominal subcutaneous adipocyte morphology, adipose tissue gene and protein expression of markers related to adipose tissue function, or beta2-adrenergic receptor-mediated lipolysis in men with obesity. A prolonged and/or more intense training program may be required to improve human adipose tissue function. PMID- 30474488 TI - Time course of interlimb strength transfer after unilateral handgrip training. AB - "Cross-education" is the increase in strength or functional performance of an untrained limb after unilateral training. A major limitation for clinical translation from unilateral injury includes knowledge on the minimum time for the emergence of crossed effects. Therefore, the primary purpose was to characterize the time course of bilateral strength changes during both "traditional" ( n = 11) and "daily" ( n = 8) unilateral handgrip training in neurologically intact participants. Traditional training included five sets of five maximal voluntary handgrip contractions 3 times/wk for 6 wk whereas daily training included the same number of sessions and contractions but over 18 consecutive days. Three pre- and one posttest session evaluated strength, muscle activation, and reflex excitability bilaterally. Time course information was assessed by recording handgrip force for every contraction in the trained limb and from a single contraction on every third training session in the untrained limb. Six weeks of traditional training increased handgrip strength in the trained limb after the 9th session whereas the untrained limb was stronger after the 12th session. This was accompanied by increased peak muscle activation and bilateral alterations in Hoffmann reflex excitability. Daily training revealed a similar number of sessions (15) were required to induce significant strength gains in the untrained limb (7.8% compared with 12.5%) in approximately half the duration of traditional training. Therefore, minimizing rest days may improve the efficiency of unilateral training when the trained limb is not the focus. Establishing a "dose" for the time course of adaptation to strength training is paramount for effective translation to rehabilitative interventions. NEW & NOTEWORTHY Unilateral handgrip training using a "traditional" protocol (3 times/wk; 6 wk) increased strength bilaterally after 9 (trained arm) and 12 (untrained arm) sessions. "Daily" training (18 consecutive days) increased strength in the untrained limb in a similar number of training sessions, which was accomplished in approximately half the time. Within clinical populations when the focus is on the untrained limb, reducing rest days may optimize the recovery of strength. PMID- 30474490 TI - Modelling of zero-inflation improves inference of metagenomic gene count data. AB - Metagenomics enables the study of gene abundances in complex mixtures of microorganisms and has become a standard methodology for the analysis of the human microbiome. However, gene abundance data is inherently noisy and contains high levels of biological and technical variability as well as an excess of zeros due to non-detected genes. This makes the statistical analysis challenging. In this study, we present a new hierarchical Bayesian model for inference of metagenomic gene abundance data. The model uses a zero-inflated overdispersed Poisson distribution which is able to simultaneously capture the high gene specific variability as well as zero observations in the data. By analysis of three comprehensive datasets, we show that zero-inflation is common in metagenomic data from the human gut and, if not correctly modelled, it can lead to substantial reductions in statistical power. We also show, by using resampled metagenomic data, that our model has, compared to other methods, a higher and more stable performance for detecting differentially abundant genes. We conclude that proper modelling of the gene-specific variability, including the excess of zeros, is necessary to accurately describe gene abundances in metagenomic data. The proposed model will thus pave the way for new biological insights into the structure of microbial communities. PMID- 30474489 TI - Cerebral blood flow regulation and cognitive function in women with posttraumatic stress disorder. AB - Posttraumatic stress disorder (PTSD) is associated with structural and functional alterations in a number of interacting brain regions, but the physiological mechanism for the high risk of cerebrovascular disease or impairment in brain function remains unknown. Women are more likely to develop PTSD after a trauma than men. We hypothesized that cerebral blood flow (CBF) regulation is impaired in women with PTSD, and it is associated with impairment in cognitive function. To test our hypothesis, we examined dynamic cerebral autoregulation (CA) and cognitive function by using a transfer function analysis between arterial pressure and middle cerebral artery blood velocity and the Stroop Color and Word test (SCWT), respectively. We did not observe any different responses in these hemodynamic variables between women with PTSD ( n = 15) and healthy counterparts (all women; n = 8). Cognitive function was impaired in women with PTSD; specifically, reaction time for the neutral task of SCWT was longer in women with PTSD compared with healthy counterparts ( P = 0.011), but this cognitive dysfunction was not affected by orthostatic stress. On the other hand, transfer function phase, gain, and coherence were not different between groups in either the supine or head-up tilt (60 degrees ) position, or even during the cognitive challenge, indicating that dynamic CA was well maintained in women with PTSD. In addition, there was no relationship between cognitive function and dynamic CA. These findings suggest that PTSD-related cognitive dysfunction may not be due to compromised CBF regulation. NEW & NOTEWORTHY Cognitive function was impaired; however, dynamic cerebral autoregulation (CA) as an index of cerebral blood flow regulation was not impaired during supine and 60 degrees head-up tilt in women with PTSD compared with healthy females. In addition, there was no relationship between cognitive function and dynamic CA. These findings suggest that the mechanism of PTSD-related cognitive dysfunction may not be due to CBF regulation. PMID- 30474491 TI - Autism Disparities: A Systematic Review and Meta-Ethnography of Qualitative Research. AB - Racial, ethnic, and socioeconomic disparities associated with autism spectrum disorder (ASD) are evident across many service domains including access to early assessment, diagnosis, and therapeutic interventions. To better understand the complex social and structural factors contributing to these disparities, this article offers a systematic review of peer-reviewed qualitative research conducted from 2010 to 2016 in the United States that investigates autism disparities experienced by marginalized communities. Based on these criteria, we identified 24 qualitative research studies and conducted an analysis using meta ethnography and an intersectional interpretive lens. We identified three interdependent themes contributing to autism disparities, including familial, cultural, and structural barriers. Omissions in the literature were also evident, including a lack of research on underserved adults with ASD and the gendered inequities of caregiving. We discuss the implications of our findings and offer new questions that take an intersectional approach using qualitative research to investigate autism disparities. PMID- 30474492 TI - Rate of anastomotic leakage after rectal anastomosis depends on the definition: Pelvic abscesses are significant. AB - BACKGROUND AND AIMS:: The International Study Group of Rectal Cancer has proposed that a pelvic abscess in the proximity of the anastomosis is considered an anastomotic leak, whether or not its point of origin is detectable. This study describes how the inclusion of pelvic abscesses alters the leakage rate. MATERIAL AND METHODS:: Risk factors and postoperative complications in patients with visible anastomotic leakage ("direct leakage"), pelvic abscesses alone in the vicinity of a visibly intact anastomosis ("abscess leakage"), and no leakage were retrospectively evaluated. RESULTS:: In total, 341 patients operated with anterior resections and who received an anastomosis within 15 cm as measured from the anal verge were included. A total of 37 patients (10.9%) had direct leakage, 13 (3.8%) had abscess leakage, and 291 (85.3%) had no leakage. The overall anastomotic leakage rate was 14.7% (50 patients). In accordance with the grading system outlined by International Study Group of Rectal Cancer, 7 patients (2.1%) experienced Grade A leakage, 19 (5.6%) Grade B, and 24 (7.0%) Grade C. Direct leak patients had more often a reoperation due to anastomotic complications (odds ratio = 19.7, p = 0.001), a permanent stoma (odds ratio = 28.5, p = 0.001), and a longer hospital stay than abscess leak patients (29.0 vs 15.5 days, p = 0.030). CONCLUSION:: Abscess leakage accounted for over one-fourth of the overall leakage rate, raising the leakage rate. Direct leak patients were at a higher risk of requiring a reoperation, permanent stoma, and longer hospital stay than abscess leak patients. Abscess leak patients were at a greater risk for a urinary tract infection, wound infection, and postoperative intestinal obstruction than non leak patients. PMID- 30474493 TI - Platelet-Rich Plasma Versus Hyaluronic Acid Injections for Knee Osteoarthritis: A Propensity-Score Analysis. AB - BACKGROUND AND AIMS:: Intra-articular injections of viscosupplements have been an option in the treatment of knee osteoarthritis. Platelet-rich plasma is an experimental treatment in osteoarthritis. Previous studies have shown that platelet-rich plasma reduces osteoarthritis symptoms in similar proportions as viscosupplements. The aim of this study was to compare platelet-rich plasma versus viscosupplements in terms of symptoms' relief and time to arthroplasty. MATERIAL AND METHODS:: A total of 190 patients included in this retrospective study received either intra-articular injections of platelet-rich plasma (94 patients) or hyaluronic acid (86 patients) between January 2014 and October 2017. Western Ontario and McMaster Universities Osteoarthritis Index, Visual Analogue Scale, and range of motion were measured before injection, at 15 days, 6 months, 12 months, and at last follow-up. We compared outcomes between these two groups using propensity score analysis for risk adjustment in multivariate analysis and for one-to-one matching. RESULTS:: Hyaluronic acid-treated patients experienced a higher arthroplasty rate (36.0% vs 5.3%, p < 0.001), lower range of motion, worse Visual Analogue Scale and Western Ontario and McMaster Universities Osteoarthritis Index scores, and increased risk of any arthroplasty occurrence (log-rank < 0.001) than platelet-rich plasma patients. Cox proportional hazards analysis revealed a tendency to decrease the risk of knee arthroplasty for the patients treated by platelet-rich plasma (hazard ratio = 0.23, 95% confidence interval, 0.05-1.05, p = 0.058). When the treatment method was adjusted for propensity score in the propensity score-matched pairs (n = 78), we found that platelet-rich plasma group still showed significant improvement over the hyaluronic acid group in arthroplasty rate (12.8% vs 41.0%, p = 0.010), Visual Analogue Scale and Western Ontario and McMaster Universities Osteoarthritis Index scores, but not in the range of motion, during the mean follow-up of 16.7 months. CONCLUSION:: Intra-articular injections of platelet-rich plasma associated with better outcomes than hyaluronic acid in knee osteoarthritis. Platelet-rich plasma might prolong the time to arthroplasty and provide a valid therapeutic option in selected patients with knee osteoarthritis not responding to conventional treatments. Further larger studies are needed to validate this promising treatment modality. PMID- 30474494 TI - Nanocolloidal lipidic carriers of olmesartan medoxomil surface-tailored with Concavalin-A for lectin receptor targeting. AB - AIM: The present work involves the development of Concavalin A-conjugated nanostructured lipidic carriers (NLCs) of olmesartan medoxomil for lectin receptor targeting. MATERIALS & METHODS: Excipient selection was performed by drug solubility in solid and liquid lipids. Factor screening was carried out by evaluating the impact of formulation and process variables on the critical quality attributes. Surface modification of NLCs was carried out using Concavalin A and extensively characterized. RESULTS & CONCLUSION: NLCs exhibited the particle size of 273.6 nm, zeta-potential of -30.2 nm, encapsulation efficiency of 73.3% and sustained drug release profile. Nearly 4.2-fold improvement in cell uptake, four- to eightfold increase in Cmax and AUC, and 37% reduction in blood pressure was observed from NLCs over the pure drug. PMID- 30474495 TI - Study on removal effect of Cr(VI) and surface reaction mechanisms by bimetallic system in aqueous solution. AB - Fe/Al bimetallic particles were synthesized by chemical deposition. The materials were characterized by XRD and SEM. The structures of material with lower iron loading are solid ball like with a small amount of zero-valent iron. The structures of material with higher iron loading are porous ball like whose outer surface is almost entirely coated with zero-valent iron and provides more active sites. Different parameters affecting Cr(VI) removal rates were listed as research targets. The results showed that the removal rates can reach more than 90% under optimum conditions. In addition, Cr(VI) removal experiment was in accordance with the pseudo-first-order kinetics. SEM, FT-IR and XPS analysis were characterized after the reaction and the results proved that galvanic cell effect, the properties of reducibility of zero-valent metals, Fe(III)-Cr(III) mix phase hydroxides were the main surface reaction mechanisms for the reaction of Fe/Al bimetal with Cr(VI). PMID- 30474496 TI - Characterization of Gnomoniopsis idaeicola, the Causal Agent of Canker and Wilting of Blackberry in Serbia. AB - Blackberry cane diseases with the symptoms of necrosis, canker, and wilting are caused by several fungi worldwide. Surveys conducted from 2013 to 2016 in Serbia revealed the occurrence of Gnomoniopsis idaeicola, the causal agent of cane canker and wilting, which was found to be distributed in almost half of the surveyed orchards, in three blackberry cultivars, and with disease incidence of up to 80%. Wide distribution and high disease incidence suggest that G. idaeicola has been present in Serbia for some time. Out of 427 samples, a total of 65 G. idaeicola isolates were obtained (isolation rate of 34.19%). Reference isolates, originating from different localities, were conventionally and molecularly identified and characterized. G. idaeicola was detected in single and mixed infections with fungi from genera Paraconiothyrium, Colletotrichum, Diaporthe, Botryosphaeria, Botrytis, Septoria, Neofusicoccum, and Discostroma, and no diagnostically specific symptoms could be related directly to the G. idaeicola infection. In orchards solely infected with G. idaeicola, blackberry plant mortality was up to 40%, and yield loses were estimated at 50%. G. idaeicola isolates included in this study demonstrated intraspecies diversity in morphological, biological, pathogenic, and molecular features, which indicates that population in Serbia may be of different origin. This is the first record of a massive outbreak of G. idaeicola infection, illustrating its capability of harmful influence on blackberry production. This study represents the initial step in studying G. idaeicola as a new blackberry pathogen in Serbia, aiming at developing efficient control measures. PMID- 30474497 TI - Predicting diabetes-related hospitalizations based on electronic health records. AB - OBJECTIVE: To derive a predictive model to identify patients likely to be hospitalized during the following year due to complications attributed to Type II diabetes. METHODS: A variety of supervised machine learning classification methods were tested and a new method that discovers hidden patient clusters in the positive class (hospitalized) was developed while, at the same time, sparse linear support vector machine classifiers were derived to separate positive samples from the negative ones (non-hospitalized). The convergence of the new method was established and theoretical guarantees were proved on how the classifiers it produces generalize to a test set not seen during training. RESULTS: The methods were tested on a large set of patients from the Boston Medical Center - the largest safety net hospital in New England. It is found that our new joint clustering/classification method achieves an accuracy of 89% (measured in terms of area under the ROC Curve) and yields informative clusters which can help interpret the classification results, thus increasing the trust of physicians to the algorithmic output and providing some guidance towards preventive measures. While it is possible to increase accuracy to 92% with other methods, this comes with increased computational cost and lack of interpretability. The analysis shows that even a modest probability of preventive actions being effective (more than 19%) suffices to generate significant hospital care savings. CONCLUSIONS: Predictive models are proposed that can help avert hospitalizations, improve health outcomes and drastically reduce hospital expenditures. The scope for savings is significant as it has been estimated that in the USA alone, about $5.8 billion are spent each year on diabetes-related hospitalizations that could be prevented. PMID- 30474498 TI - Complex contagion leads to complex dynamics in models coupling behaviour and disease. AB - Models coupling behaviour and disease as two unique but interacting contagions have existed since the mid 2000s. In these coupled contagion models, behaviour is typically treated as a 'simple contagion'. However, the means of behaviour spread may in fact be more complex. We develop a family of disease-behaviour coupled contagion compartmental models in order to examine the effect of behavioural contagion type on disease-behaviour dynamics. Coupled contagion models treating behaviour as a simple contagion and a complex contagion are investigated, showing that behavioural contagion type can have a significant impact on dynamics. We find that a simple contagion behaviour leads to simple dynamics, while a complex contagion behaviour supports complex dynamics with the possibility of bistability and periodic orbits. PMID- 30474499 TI - Paraquat exposure and Parkinson's disease: A systematic review and meta-analysis. AB - To reconcile and unify available results regarding paraquat exposure and Parkinson's disease (PD), we conducted a systematic review and meta-analysis to provide a quantitative estimate of the risk of PD associated with paraquat exposure. Six scientific databases including PubMed, Cochrane libraries, EMBASE, Scopus, ISI Web of Knowledge, and TOXLINE were systematically searched. The overall odds ratios (ORs) with corresponding 95% CIs were calculated using a random-effects model. Of 7,309 articles identified, 13 case control studies with 3,231 patients and 4,901 controls were included into our analysis. Whereas, one prospective cohort studies was included into our systematic review. A subsequent meta-analysis showed an association between PD and paraquat exposure (odds ratio = 1.64 (95% CI: 1.27-2.13; I2 = 24.8%). There is a statistically significant association between paraquat exposure and PD. Thus, future studies regarding paraquat and Parkinson's disease are warranted. PMID- 30474500 TI - Rape Disclosure and Depression Among Community Women: The Mediating Roles of Shame and Experiential Avoidance. AB - Many women who disclose a rape encounter victim-blaming responses, which are associated with negative outcomes. The present study examined rape-related shame and experiential avoidance as mediators of the relation between victim-blaming responses to rape disclosure and depression among 103 rape survivors drawn from a community sample. Results revealed that victim-blaming responses were positively associated with depressive symptoms through rape-related shame and experiential avoidance, and shame was indirectly related to depression via avoidance. Findings suggest clinical interventions should focus on rape-related shame and experiential avoidance in targeting depression among rape survivors, and future research should continue to examine how victim-blaming responses to rape disclosure may be related to these factors. PMID- 30474501 TI - Total mesorectal excision for mid-rectal cancer without anastomosis: Low Hartmann's operation or intersphincteric abdomino-perineal excision? AB - BACKGROUND AND AIMS:: In mid-rectal cancer, the low colorectal anastomosis is, although feasible, sometimes avoided. The aim was to compare low Hartmann's procedure with intersphincteric abdomino-perineal excision of the rectum, in patients operated with total mesorectal excision for mid-rectal cancer in whom the low anastomosis was technically feasible but for patient-related reasons undesired. MATERIAL AND METHODS:: A total of 64 consecutive patients with mid rectal cancer who underwent low Hartmann's procedure (n = 34) or intersphincteric abdomino-perineal excision (n = 30) at one colorectal unit were compared regarding patient demography, short-term oncology, surgical outcome at 3 and 24 months, and long-term overall survival. RESULTS:: There were no significant differences between intersphincteric abdomino-perineal excision and Hartmann's procedure regarding age, gender distribution, body mass index, preoperative radiotherapy, tumor level, or cancer stages. Operation time was shorter in Hartmann's procedure as compared with intersphincteric abdomino-perineal excision, median 174 and 256 min, (P < 0.001), and intraoperative blood loss was increased, 600 and 500 mL, respectively (P = 0.045). Number of lymph nodes and circumferential resection margin were comparable. In Hartmann's procedure compared with intersphincteric abdomino-perineal excision, the need for reoperation was 24% and 3%, (P = 0.020), complications classified as Clavien Dindo 3-4 occurred in 32% and 10%, (P = 0.031), pelvic abscess in 21% and 10%, (P = 0.313), and mortality within 90 days was 3% and 0%, respectively, (P = 0.938). In intersphincteric abdomino-perineal excision, the perineal wound was not healed at 3 months in 13%, and in Hartmann's procedure 15% had chronic secretion from the anorectal remnant at 2 years postoperatively. CONCLUSION:: The results from this study suggest that intersphincteric abdomino-perineal excision might be an alternative to Hartmann's procedure in patients with mid-rectal cancer, in whom a low colorectal anastomosis is undesired. PMID- 30474502 TI - Patients' understanding of clinical research: An Italian cancer patient survey. AB - INTRODUCTION:: Patients' awareness of clinical research and their involvement in clinical trials is of great importance, but it is difficult to estimate the extent of knowledge on the research being undertaken. METHODS:: We evaluated the level of knowledge about clinical research using a self-reporting survey distributed to 967 adult patients with cancer attending the Departments of Medical Oncology and Onco-Haematology Units of IRST IRCCS and 4 hospitals in the region of Emilia-Romagna, Italy. The questionnaire was composed of 10 specific items on research knowledge. Patients responding correctly to at least 8 of the 10 items were considered to have a good understanding of clinical research. RESULTS:: The questionnaire was completed by 769 patients (response rate 79.5%). Only 19% of patients were found to have a good understanding of clinical research. Patients with higher education and those who had previous clinical trial experience showed a significantly better understanding. Fifty-three percent of patients said that they would be willing to participate in a trial studying a new drug and 75% expressed an interest in taking part in informative meetings/events about clinical studies. CONCLUSIONS:: Our results show that patients' understanding of clinical research is limited and highlight an interest in learning more. PMID- 30474503 TI - Time to systemic treatment and prognosis in patients with recurrent and metastatic head and neck squamous cell cancer. AB - BACKGROUND:: Delay of systemic treatment in recurrent/metastatic head and neck squamous cell cancer (r/mHNSCC) has never been assessed. Whether time span to start systemic treatment affects survival and whether referral to a medical oncologist is important has not been explored. METHODS:: We analyzed our head and neck database to assess the prognostic impact of time between diagnosis of r/mHNSCC and start of systemic treatment (time to treatment [TTT]). Secondarily, we assessed the prognostic impact of time to referral to a medical oncologist (referral time). For this purpose, we used pairwise correlation analysis and multivariate Cox regression analysis as statistical tests. RESULTS:: A total of 110 patients with r/mHNSCC were evaluable for analysis. TTT correlated significantly with OS from r/mHNSCC diagnosis ( R = .43, p < .0001). A nonsignificant, positive correlation was found between referral time and OS ( R = .17, p = .10). CONCLUSIONS:: Results of this retrospective analysis suggest that longer TTT is not associated with worse prognosis. Referral time seems not to have an impact on prognosis. PMID- 30474504 TI - External accelerated partial breast irradiation for ductal carcinoma in situ: long-term follow-up from a phase 3 randomized trial. AB - INTRODUCTION:: For a long time, accelerated partial breast irradiation (APBI) effectiveness for ductal carcinoma in situ (DCIS) has been debated, due to conflicting published results. Recent encouraging data from phase 3 trials reopened new perspectives for this radiation approach. The aim of the present study was to analyze the long-term efficacy and safety results of the series of patients with DCIS enrolled in the APBI arm of the APBI-IMRT-Florence phase 3 trial (NCT02104895). METHODS:: Patients were treated in a phase 3 randomized trial comparing whole breast irradiation (50 Gy in 25 fractions to the whole breast, plus 10 Gy in 5 fractions to the tumor bed) to APBI (30 Gy in 5 nonconsecutive fractions) using the intensity-modulated radiotherapy technique. RESULTS:: Overall, 22 patients were treated in the APBI arm. Median age was 62 years (mean 59; range 42-75 years). At a median follow-up of 9.2 years (mean 8.8; range 3.8-12.1 years), no contralateral invasive/DCIS occurrence, distant metastasis, or breast cancer-related death were recorded. The 5- and 10-year local recurrence, distant metastasis-free survival, and breast cancer-specific survival were 100%. The 10-year overall survival rate was 90.9%. No late toxicity at 5 and 10 years was recorded. CONCLUSIONS:: Waiting for pending studies and mature follow-up, we confirmed the efficacy and safety of APBI for low-risk DCIS. PMID- 30474505 TI - Telomere Homeostasis and Senescence Markers Are Differently Expressed in Placentas From Pregnancies With Early- Versus Late-Onset Preeclampsia. AB - BACKGROUND:: Early-onset preeclampsia (EOPE; <34 weeks' gestation) usually has more severe morbidity for the mother and fetus compared to late-onset preeclampsia (LOPE). Telomere homeostasis is disrupted in preeclampsia (PE) and senescence markers are increased. The pathophysiologic differences between early and LOPE are not fully unraveled yet. METHODS:: We studied placental biopsies from 7 pregnancies with EOPE, 6 pregnancies with LOPE, and 13 healthy gestational age-matched controls. Telomere length and aggregate formation were assessed using qualitative fluorescence in situ hybridization and electronic quantitative methods. Senescence markers were evaluated including senescence-associated heterochromatin foci, beta-galactosidase (SAbeta-Gal), and P16 staining, as was the expression of P16 complementary DNA (cDNA) using real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS:: There were no differences in maternal age, gravidity, parity, body mass index, and mode of conception between the study and the control groups. The percentage of trophoblasts with short telomeres was higher in placental samples from EOPE (52.61% [12.27%]) versus LOPE (28.72% [10.14%]); both were higher compared to controls (7.53% [5.14%], P = .03). Aggregate formation was enhanced in EOPE (8.72% [2.49%]) compared to LOPE (4.54% [1.45%]); both were higher than in healthy controls (2.72% [1.08%], P = .03). Trophoblasts from EOPE versus LOPE were more likely to stain positive for SAbeta-Gal and P16 compared to controls ( P < .001). P16 cDNA expression assayed by RT-qPCR was 7.51 times higher in EOPE compared to controls and 5.86 times higher than in LOPE. CONCLUSIONS:: Impaired telomere homeostasis and senescence markers are more prominent in EOPE versus LOPE. These findings may contribute to our understanding of the pathophysiology and explain their different clinical presentations and outcomes. PMID- 30474506 TI - RETRACTED ARTICLE: Transcriptional Controls by Nuclear Fat-Soluble Vitamin Receptors through Chromatin Reorganization. PMID- 30474507 TI - Monitoring health inequality in Indonesia. PMID- 30474508 TI - Monitoring within-country health inequalities: the example of Indonesia. PMID- 30474509 TI - Increased stress and altered expression of histone modifying enzymes in brain are associated with aberrant behaviour in vitamin B12 deficient female mice. AB - A sub-optimal nutritional environment from early life can be envisaged as a stressor that translates into mental health problems in adulthood. Considering the widespread prevalence of vitamin B12 deficiency especially amongst women in developing countries and the importance of vitamin B12 in normal brain function, in this study we have elucidated the behavioural correlates of chronic severe and moderate vitamin B12 deficiency in C57BL/6 mouse model established by us earlier. Female weanling mice were assigned to three dietary groups: (a) control AIN-76A diet with cellulose as dietary fibre (b) vitamin B12 restricted AIN-76A diet with pectin as dietary fibre (severe deficiency group) and (c) vitamin B12 restricted AIN-76A diet with cellulose as dietary fibre (moderate deficiency group). The mice received these diets throughout pregnancy, lactation and thereafter. Nest building, maternal care, anxiety and depressive behaviours were evaluated. Oxidative stress, activities of antioxidant enzymes and expression of various histone modifying enzymes in brain were investigated to unravel the probable underlying mechanisms. Our data suggests that both severe and moderate vitamin B12 deficiency induced anxiety and impaired maternal care. However, only severe vitamin B12 deficiency induced depression. Oxidative stress and poor antioxidant defense underlie the deleterious effects of both severe and moderate vitamin B12 deficiency. Altered expression of histone modifying enzymes in the brain of severely deficient mice is suggestive of epigenetic reprogramming. This study suggests that chronic vitamin B12 deficiency leads to behavioural anomalies in female C57BL/6 mice and the severity of these outcomes can be correlated to the level of deficiency. PMID- 30474510 TI - An unusual case of post-cochlear implant performance degradation in a patient with suspected Cogan's syndrome. AB - Cogan's Syndrome is an autoimmune disorder that can affect the ear, eye and other organs. Although rare, Cogan's Syndrome is particularly relevant to the cochlear implant surgeon because the resulting hearing loss is often bilateral and the majority of cases progresses to profound levels where cochlear implantation may be indicated. There are many issues relating to this condition that concern the cochlear implant surgeon. Its rarity, lack of specific laboratory diagnostic tests and variability in the onset and types of manifestation relating to the ear, eye and other organs often pose diagnostic difficulties. Pre-operatively, the cochlear implant surgeon must anticipate and exclude the possibility of cochlear luminal obliteration and ossification. Although the post-implant hearing results are expected to be generally good in Cogan's Syndrome, the possibility of adverse hearing outcomes cannot be ruled out whether in the initial or subsequent post-operative period. The possible side effects of long-term immuno-suppressive therapy on the well-being of the cochlear implant are to be appreciated and managed. A case which posed much difficulty in management is presented and discussed to highlight some of these challenges. PMID- 30474511 TI - Factors Affecting Inferior Vena Cava Filter Retrieval: A Review. AB - OBJECTIVE:: Over the last 2 decades, there has been an exponential rise in placement of retrievable inferior vena cava (IVC) filters, while the retrieval rate has remained steadily low. Approaches to increasing filter retrieval rates have been extensively studied. CONCLUSION:: This review presents an up-to-date review of reported data-driven variables that affect retrieval rates of IVC filters, with a focus on clinical, technical, and process factors. PMID- 30474512 TI - Combination Effects of Forced Mild Exercise and GABAB Receptor Agonist on Spatial Learning, Memory, and Motor Activity in Striatum Lesion Rats. AB - Basal ganglia (BG) lesions cause impairments of different mammalian's movement and cognition behaviors. Motor circuit impairment has a dominant role in the movement disorders. An inhibitory factor in BG is GABA neurotransmitter, which is released from striatum. Lesions in GABAergic neurons could trigger movement and cognition disorders. Previous evidence showed that GABAB receptor agonist (Baclofen) administration in human improves movement disorders and exercise can improve neurodegenerative and cognitive decline; however, the effects of both Baclofen and mild forced treadmill exercise on movement disorders are not well known. The main objective of this study is to investigate the combined effects of mild forced treadmill exercise and microinjection of Baclofen in the internal Globus Pallidus on striatum lesion-induced impairments of spatial learning and motor activity. We used Morris water maze and open filed tests for studying spatial learning, and motor activity, respectively. Results showed that mild exercise and Baclofen microinjection could not lonely affect the spatial learning, and motor activity impairments while the combination of them could alleviate spatial learning, and motor activity impairments in striatum-lesion animals. Our results suggest that striatum lesion-induced memory and motor activity impairments can improve with combination interaction of GABAB receptor agonist and exercise training. PMID- 30474514 TI - Developing novel Ca-zeolite/poly(amino acid) composites with hemostatic activity for bone substitute applications. AB - The novel Ca-zeolite/poly(amino acid) (CaY/PAA) composites for bone substitute applications with hemostatic activity were prepared using the in situ melting polymerization method. In this study, Ca-zeolite (CaY) loaded with Ca2+ was obtained from Y-type zeolite (NaY) by ion-exchange method. The properties of the CaY/PAA composites and PAA, including composition, structure, compressive strength, in vitro degradability in phosphate-buffered solution (PBS), bioactivity, cytocompatibility and in vitro coagulation tests were characterized and investigated. The results showed that compressive strength of the CaY/PAA composites ranged from 145 to 186 MPa, demonstrating sufficient mechanical strength for load-bearing bone substitute. After soaking in PBS for 16 weeks, the weight loss of 25CaY/PAA and 50CaY/PAA were 4.1 and 1.6 wt%, respectively, and the pH values for CaY/PAA composites increased to about 8.0 in 2 weeks and then gradually stabilized around 7.4, indicating good stability in PBS. Scanning electron microscope and energy dispersive spectrometer results showed that the composites were bioactive and new apatite layers attached on their surfaces. Mesenchymal stem cells (MSCs) exhibited high-proliferation in the extract solution of the CaY/PAA composites and were well spread on the surfaces of the composites. Cells on the CaY/PAA composite groups showed higher alkaline phosphatase (ALP) activity indicating the potential to promote cell differentiation. The in vitro coagulation tests showed that CaY/PAA composites have shorter clotting time and better performance of promoting blood coagulation than other samples, presenting improved hemostatic activity. In summary, the results demonstrated that the CaY/PAA composites had good mechanical strength, stability, bioactivity, cytocompatibility and hemostatic activity for bone substitute applications. PMID- 30474513 TI - Cause-specific child mortality performance and contributions to all-cause child mortality, and number of child lives saved during the Millennium Development Goals era: a country-level analysis. AB - BACKGROUND: During the Millennium Development Goal (MDG) era, impressive reductions in the under-5 mortality rate (U5MR) have been observed, although the MDG 4 target was not met. So far, cause-specific progress in child mortality has been analyzed and discussed mainly at the global and regional levels. OBJECTIVES: We aimed to explore annual changes in cause-specific mortality at the country level, assess which causes contributed the most to child mortality reduction in 2000-2015, and estimate how many child lives were saved. METHODS: We used the cause-specific child mortality estimates published by Liu and colleagues. We derived average annual changes in cause-specific child mortality rates and cause specific contribution to overall child mortality in 2000-2015. We estimated the number of cause-specific child deaths averted during the MDG era, assuming that cause-specific child mortality remained the same as in 2000. We targeted the 75 Countdown countries where 95% of maternal and child deaths occurred during the MDG era. RESULTS: Wide disparities existed across causes within countries, both in neonatal and post-neonatal mortality reduction, except for a few countries such as China, Rwanda, and Cambodia. In 20 of the 45 sub-Saharan African countries, malaria was the main contributor to post-neonatal mortality reduction, and pneumonia was the main contributor in only six countries. A single disease often contributed to a substantial proportion of the child mortality reduction, particularly in west and central African countries. Diarrhea-specific post neonatal child mortality reduction accounted for 7.1 million averted child deaths (24.5%), while pneumonia accounted for another 6.7 million averted child deaths (23%). CONCLUSIONS: This study demonstrates country-specific characteristics with regards to cause-wise child mortality that could not be identified by global or regional analyses. These findings provide the global community with evidence for formulating national policies and strategies to achieve the Sustainable Development Goals in child mortality reduction. PMID- 30474515 TI - Determining Whether Geographic Origin and Potato Genotypes Shape the Population Structure of Phytophthora infestans in the Central Region of Colombia. AB - Pathogen variation plays an important role in the dynamics of infectious diseases. In this study, the genetic variation of 279 Phytophthora infestans isolates was assessed using a combination of 12 microsatellite simple-sequence repeat markers. Isolates were collected from 11 different potato cultivars in 11 different geographic localities of the central region of Colombia. The objective of this study was to determine whether populations were differentiated by host genotype or geographic origin. Within a single clonal lineage, EC-1, 76 genotypes were detected. An analysis of molecular variance attributed most of the variation to differences within host genotypes rather than among the host genotypes, suggesting that host cultivars do not structure the populations of the pathogen. Furthermore, the lack of a genetic population structure according to the host cultivar was confirmed by all of the analyses, including the Bayesian clustering analysis and the minimum spanning network that used the Bruvo genetic distance, which suggested that there are no significant barriers to gene flow for P. infestans among potato cultivars. According to the geographic origin, the populations of P. infestans were also not structured, and most of the variation among the isolates was attributed to differences within localities. Only some but not all localities in the north and west of the central region of Colombia showed some genetic differentiation from the other regions. The absence of sexual reproduction of this pathogen in Colombia was also demonstrated. Important insights are discussed regarding the genetic population dynamics of the P. infestans populations of the central region of Colombia that were provided by the results. In Colombia, there is a high genetic variation within the EC-1 clonal lineage with closely related genotypes, none dominant, that coexist in a wide geographic area and on several potato cultivars. PMID- 30474516 TI - Transforming the workplace environment to prevent non-communicable chronic diseases: participatory action research in a South African power plant. AB - BACKGROUND: The workplace is an important setting for the prevention of non communicable diseases (NCDs). Policies for transformation of the workplace environment for occupational health and safety in South Africa have focused more on what to do and less on how to do it. There are no guidelines and little evidence on workplace-based interventions for NCDs. OBJECTIVE: The aim of this study was to learn how to transform the workplace environment in order to prevent and control cardio-metabolic risk factors for NCDs amongst the workforce at a commercial power plant in Cape Town, South Africa. METHODS: The study design utilized participatory action research in the format of a cooperative inquiry group (CIG). The researcher and participants engaged in a cyclical process of planning, action, observation and reflection over a two-year period. The group used outcome mapping to define the vision, mission, boundary partners, outcomes and strategies required. At the end of the inquiry the CIG reached a consensus on their key learning. RESULTS: Substantial change was observed in the boundary partners: catering services (78% of progress markers achieved), sport and physical activities (75%), health and wellness services (66%) and managerial support (65%). Highlights from a 10-point consensus on key learning included the need for: authentic leadership; diverse composition and functioning of the CIG; value of outcome mapping; importance of managerial engagement in personal and organizational change; and making healthy lifestyle an easy choice. CONCLUSION: Transformation included a multifaceted approach and an engagement with the organization as a living system. Future studies will evaluate changes in the risk profile of the workforce, as well as the costs and consequences for the organization. PMID- 30474517 TI - Policy Shift: South Africa's Old Age Pensions' Influence on Perceived Quality of Life. AB - Noncontributory pensions serve as an important resource for poverty-affected households in low- and middle-income countries. This study explores how a recent policy change to pension receipt influences perceived quality of life among older South Africans. We use survey data from the longitudinal World Health Organization Study on global AGEing and adult health and from the Agincourt Health and Socio-Demographic Surveillance System census. We find pension receipt to have a positive impact on both men's and women's perceived quality of life. These findings hold when controlling for prior well-being status. We find a significant moderating factor of physical limitations on the relationship between pension receipt and quality of life. Individuals reporting the highest levels of physical limitation report a larger increase in their quality of life upon pension receipt than those with less severe physical limitations. We conclude that despite the well-documented household income-pooling in this population, pension receipt still leads to a significant positive impact on pensioners' perceived quality of life. PMID- 30474518 TI - Low uptake of hypertension care after community hypertension screening events in Lagos, Nigeria. AB - BACKGROUND: In Lagos, Nigeria, approximately 33% of the population suffers from hypertension, yet antihypertensive treatment coverage is low. To improve access to care, a decentralized pharmacy-based hypertension care model was piloted. This study reports on the recruitment strategies used and is part of a larger study to evaluate the feasibility of the care model. OBJECTIVE: To describe our experience executing three different strategies to recruit hypertensive patients in the program: community hypertension screenings, hospital and pharmacy referral. METHODS: Individuals with elevated blood pressure and no history of cardiovascular disease were referred to the program's recruitment days to see a medical doctor for hypertension diagnosis and enrollment. Individuals were referred from community screenings, tertiary hospital outpatient clinics, and pharmacies participating in the program. For the community screenings, we report the number needed to screen (NNS) to find one individual with elevated blood pressure, the NNS to enroll one individual in the program, and factors associated with enrollment in the program among participants referred. RESULTS: We recruited 226 individuals (69%) in the program via the pharmacies, 97 (30%) via the community screenings, and 2 (<1%) via hospital referral. At the community screenings 3,204 individuals participated, 729 (23%) had elevated blood pressure and 618 (85%) were eligible for referral of whom 142 (23%) visited the recruitment days, and 97 (16%) enrolled. The NNS to find one individual with elevated blood pressure was 5, and the NNS to enroll one individual was 34. Enrollment in the program was associated with advancing age, blood pressure >=160/100 and currently using antihypertensive medication. CONCLUSIONS: Despite the potential attractiveness of community screenings to identify and refer individuals with hypertension, enrollment in the program was low. For future programs we recommend pharmacy referral as individuals seem more inclined to access care through healthcare providers they are familiar with. PMID- 30474519 TI - The new script of nursing: using social media and advances in communication - to create a contemporary image of nursing. AB - BACKGROUND: Inaccurate and cliched images of nurses are well documented and need to be challenged. For too long, the image of nursing has been formed by television and movies, which typically portray the nurse as the doctor's assistant or as a background character rather than an integral member of the interdisciplinary team. METHOD: "The New Script of Nursing", using a multi-media digital approach, was launched by Johns Hopkins University to break through the stereotypical images of nursing and showcase the depth and breadth of the nursing profession. Using a case study method, using temporal limits, the method of the campaign is described and the impact assessed using digital analytics. RESULTS: Within two weeks there were: 23,030 views on Facebook including 1467 reactions, comments and shares; Twitter received 12,208 impressions and 832 engagements; YouTube received 4518 views and 107 views on Instagram. The We Got This website received more than 7000 visitors from Canada, Australia, the United Kingdom, South Africa, Portugal, Lebanon, and Hong Kong. Engagement has been sustained and within nine months, the video on social media received 32,000 views and 400 shares. CONCLUSION: Social media, cellphones, and portable devices enable not just rapid but widespread communication and there is a compelling imperative to engage this media. The accessibility and affordability of social media is empowering and allows the voice of nurses to be heard. Impact Statement: Social media is an accessible, affordable and efficacious method to address misconceptions and inaccuracies of nursing as a profession. Nurses must adopt communication science and social media to profile the profession. PMID- 30474520 TI - Identification of previously untypable RD cell line isolates and detection of EV A71 genotype C1 in a child with AFP in Nigeria. AB - We previously attempted to identify 96 nonpolio enteroviruses (EVs) recovered in RD cell culture from children <15 years with acute flaccid paralysis in Nigeria. We succeeded in identifying 69 of the isolates. Here, we describe an attempt to identify the remaining 27 isolates. Twenty-six (the 27th isolate was exhausted) isolates/samples that could not be typed previously were further analyzed. All were subjected to RNA extraction, cDNA synthesis, enterovirus 5'-UTR-VP2 PCR assay and a modified VP1 snPCR assay. Both the 5'-UTR-VP2 and VP1 amplicons were sequenced, isolates identified and subjected to phylogenetic analysis.Twenty of the 26 samples analyzed were identified. Altogether, 23 (three samples had co infection) EV strains were recovered. These belong to 11 EV (one EVA, nine EVB and one EVC) types which were EVA71 genotype C1 (1 strain), CVB3 (7 strains), CVB5 (1 strain), E5 (2 strain), E11 (3 strains), E13 (2 strain), E19 (1 strain), E20 (1 strain), E24 (2 strains), EVB75 (1 strain) and EVC99 (2 strains). Of the 11 EV types, the 5'-UTR-VP2 assay identified seven while the VP1 assay identified 10. Both assays simultaneously detected 7 of the 11 EV types identified in this study with 100% congruence. We successfully identified 20 of 26 samples that were previously untypable. We also provided evidence that suggests a clade of EVA71 genotype C1 might have been circulating in sub-Saharan Africa since 2008. Finally, we showed that the 5'-UTR -VP2 assay might be as valuable as the VP1 assay in EV identification. PMID- 30474521 TI - Preface. PMID- 30474522 TI - The Effect of Drugs and Genetic Factors on the Development and Progression of the Atherosclerotic Process. PMID- 30474523 TI - Advances in carbon based nanomaterials for bio-medical applications. AB - The unique mechanical, electrical, thermal, chemical and optical properties of carbon based nanomaterials (CBNs) like: Fullerenes, Graphene, Carbon nanotubes, and their derivatives made them widely used materials for various applications including biomedicine. Few recent applications of the CBNs in biomedicine include: cancer therapy, targeted drug delivery, bio-sensing, cell and tissue imaging and regenerative medicine. However, functionalization renders the toxicity of CBNs and makes them soluble in several solvents including water, which is required for biomedical applications. Hence, this review represents the complete study of development in nanomaterials of carbon for biomedical uses. Especially, CBNs as the vehicles for delivering the drug in carbon nanomaterials is described in particular. The computational modeling approaches of various CBNs are also addressed. Furthermore, prospectus, issues and possible challenges of this rapidly developing field are highlighted. PMID- 30474524 TI - Carbon nano-onions: a valuable class of carbon nanomaterials in biomedicine. AB - The development of nanoscale materials is an important area of research as it provides access to materials with unique properties that can be applied to improve quality of life. Multi-layer fullerenes, also known as carbon nano-onions (CNOs) are an exciting class of nanostructures which show great versatility and applicability. They find applications in several fields of technology and biomedicine. This review highlights the potential advantages of CNOs for biomedical applications, which include but are not limited to bioimaging and sensing. Their good biocompatibility renders them promising platforms for the development of novel healthcare devices. PMID- 30474525 TI - Novel Vaccine Candidates against Tuberculosis. AB - Ranking above AIDS, tuberculosis (TB) is the ninth leading cause of death affecting and killing many individuals every year. Drugs' efficacy is limited by serials of problems such as multi-drug resistance (MDR) and extensively-drug resistance (XDR). Meanwhile, the only licensed vaccine BCG (Bacillus Calmette Guerin) existing for over 90 years is not effective enough. Consequently, it is essential to develop novel vaccines for TB prevention and immunotherapy. This paper provides an overall review of the TB prevalence, immune system response against TB and recent progress of TB vaccine research and development. Several vaccines in clinical trials are described as well as LAM-based candidates. PMID- 30474526 TI - The role of TRP channels in allergic inflammation and its clinical relevance. AB - Allergy refers to an abnormal adaptive immune response to non-infectious environmental substances (allergen) that can induce various diseases such as asthma, atopic dermatitis, and allergic rhinitis. In this allergic inflammation, various immune cells, such as B cells, T cells, and mast cells, are involved and undergo complex interactions that cause a variety of pathophysiological conditions. In immune cells, calcium ions play a crucial role in controlling intracellular Ca2+ signaling pathways. Cations, such as Na+, indirectly modulate the calcium signal generation by regulating cell membrane potential. This intracellular Ca2+ signaling is mediated by various cation channels; among them, the transient receptor potential (TRP) family is present in almost all immune cell types, and each channel has a unique function in regulating Ca2+ signals. In this review, we focus on the role of TRP ion channels in allergic inflammatory responses in T cells and mast cells. In addition, the TRP ion channels, which are attracting attention in clinical practice in relation to allergic diseases, and current status of the development of therapeutic agents that target TRP channels are discussed. PMID- 30474527 TI - Enhanced Vitamin K (Menaquinone-7) Production by Bacillus subtilis natto in Biofilm Reactors by Optimization of Glucose-based Medium. AB - BACKGROUND: Benefits of vitamin K have been reported by many studies recently, due to its ability to reduce the risk of cardiovascular diseases and its potential benefits against osteoporosis. Specifically, menaquinone-7 (MK-7), being the most potent form of vitamin K, has definitely received most of the attention. Currently, solid or static liquid fermentation strategies are utilized for industrial production of MK-7 by Bacillus strains. However, these strategies face fundamental operational and scale-up issues as well as intense pellicle and biofilm formations which is problematic in static liquid fermentation, due to heat and mass transfer inefficiencies they create. OBJECTIVE: The purpose of this study was to demonstrate that biofilm reactors will overcome the issues associated with suspended cell reactors when using Bacillus strains to produce MK 7. The expectation is that the use of biofilm reactors will result in a significant increase in the production of MK-7. METHOD: Vitamin K production by Bacillus subtilis natto when grown in a biofilm reactor was evaluated at various concentrations of the three major nutrients, glucose, yeast extract and casein. The data was analyzed using response surface methodology (RSM). RESULTS: The maximum concentration of MK-7 in the biofilm reactors was 20.5+/-0.5 mg/L, which was a 344 % increase when compared to the amount produced in suspended cell reactors containing the same optimum media composition. CONCLUSION: These results demonstrate the potential of utilizing biofilm reactors for MK-7 production on an industrial scale. PMID- 30474529 TI - Saccharomyces cerevisiae (Baker's Yeast) as an Interfering RNA Expression and Delivery System. AB - The broad application of RNA interference for disease prevention is dependent upon production of dsRNA in an economically feasible, scalable, and sustainable fashion, as well as the identification of safe and effective methods for RNA delivery. Current research has sparked interest in the use of Saccharomyces cerevisiae for these applications. This review examines the potential for commercial development of yeast interfering RNA expression and delivery systems. S. cerevisiae is a genetic model organism that lacks a functional RNA interference system, which may make it an ideal system for expression and accumulation of high levels of recombinant interfering RNA. Moreover, recent studies in a variety of eukaryotic species suggest that this microbe may be an excellent and safe system for interfering RNA delivery. Key areas for further research and development include optimization of interfering RNA expression in S. cerevisiae, industrial-sized scaling of recombinant yeast cultures in which interfering RNA molecules are expressed, the development of methods for large scale drying of yeast that preserve interfering RNA integrity, and identification of encapsulating agents that promote yeast stability in various environmental conditions. The genetic tractability of S. cerevisiae and a long history of using this microbe in both the food and pharmaceutical industry will facilitate further development of this promising new technology, which has many potential applications of medical importance. PMID- 30474528 TI - Potential therapeutic agents against Par-4 target for cancer treatment: where are we going? AB - One of the greatest challenges of cancer therapeutics nowadays is to find selective targets successfully. Prostate apoptosis response-4 (Par-4) is a selective tumor suppressor protein with an interesting therapeutic potential due to its specificity on inducing apoptosis in cancer cells. Par-4 activity and levels can be downregulated in several tumors and cancer cell types, indicating poor prognosis and treatment resistance. Efforts to increase Par-4 expression levels have been studied, including its use as therapeutic protein by transfection with adenoviral vectors or plasmids. However, the gene therapy is very complex and still presents many hurdles to be overcome. We decided to review molecules and drugs with capacity to upregulate Par-4 and, thereby, be an alternative to reach this druggable target. In addition, Par-4 localization and function are reviewed in some cancers, clarifying how it can be used as a therapeutic targe. PMID- 30474530 TI - Bone manifestation of faulty perinatal hormonal imprinting: a review. AB - Hormonal imprinting takes place at the first encounter between the developing receptor and its target hormone and the encounter determines the receptor's binding capacity for life. In the critical period of development, when the window for imprinting is open, the receptor can be misdirected by related hormones, synthetic hormones, and industrial or communal endocrine disruptors which cause faulty hormonal imprinting with life-long consequences. Considering these facts, the hormonal imprinting is a functional teratogen provoking alterations in the perinatal (early postnatal) period. One single encounter with a low dose of the imprinter in the critical developmental period is enough for the formation of faulty imprinting, which is manifested later, in adult age. This has been justified in the immune system, in sexuality, in animal behavior and brain neurotransmitters etc. by animal experiments and human observations This review points to the faulty hormonal imprinting in the case of bones (skeleton), by single or repeated treatments. The imprinting is an epigenetic alteration which is inherited to the progeny generations. From clinical aspect, the faulty imprinting can have a role in the pathological development of the bones as well, as in the risk of osteoporotic fractures etc. PMID- 30474531 TI - Human Breast Milk-Acquired Cytomegalovirus Infection: Certainties, Doubts And Perspectives. AB - Breast Milk (BM) is the best source of nutrition for newborns, especially if premature. In fact, its beneficial impact on short- and long-term neonatal outcome has was deeply described. Unfortunately, BM could not be always so safe, especially due to the possible presence of maternal viruses that can shed and transferred to the breastfed neonate. Among these, Cytomegalovirus (CMV) can potentially lead to a serious and acute illness, mostly in case of low gestational age. Some studies also report the association of CMV-acquired infection to an increased risk of structural and functional brain modifications and neurological impairment. Due to these reasons, a strategy to remove CMV from BM with a minimal or absent impact on its beneficial components, would be desirable. Up to now, pasteurization, freezing, ultraviolet- C or microwave irradiation are the available techniques; they show different levels of efficacy and variable effects on BM composition, even if many studies are still needed to fully clarify these implications. In this review, we provide an update of the current evidence about these topics. We focus on the factors promoting CMV shedding through BM; moreover, the possible occurrence of a severe disease in preterm neonates is also described. Finally we investigate the potential effects showed on BM properties by the strategies that prevent or reduce viral transmission, therefore influencing newborns' healthy, and the new techniques which could show a relevant role in the next future, such as metabolomics. PMID- 30474532 TI - Systemic lupus erythematosus and endothelial dysfunction: a close relationship. AB - BACKGROUND: Accelerated atherosclerosis, responsible for premature cardiovascular disease, has been estimated to develop or progress in 10% of systemic lupus erythematosus (SLE) patients each year and to be 6-fold more frequent in SLE compared with the general population. The mechanisms underlying accelerated atherosclerosis in SLE are complex and involve classical and "non-classical" cardiovascular risk factors. Subclinical and disseminated atherosclerosis is associated with endothelial dysfunction and arterial stiffness. OBJECTIVE: The aim of this review is to analyze the association between SLE and endothelial dysfunction. RESULTS AND CONCLUSIONS: Different mechanisms have been proposed to explain the prevalence of endothelial dysfunction in SLE, which are briefly reported in this review: impaired clearance of apoptotic cells, oxidative stress markers, B cell activation with different circulating autoantibodies, different subtypes of T lymphocytes, cytokine cascade. Several studies and meta-analyses show a significant trend towards a prevalence of subclinical accelerated atherosclerosis in patients with SLE compared with healthy controls, since the childhood. Based on general considerations, we suggest a multidisciplinary management to assess endothelial dysfunction at the diagnosis of the disease and to periodically search for and treat the traditional cardiovascular risk factors. Prospective studies are needed to confirm the beneficial of this management. PMID- 30474533 TI - Clinical Management of Medial Patellar Plica Syndrome: Mini Review from Diagnosis to Treatment. AB - Synovial plicae are thickenings of the synovial knee membrane; they are very frequent and often asymptomatic. However, they can become symptomatic due to idiopathic or secondary causes, as trauma and inflammation of the synovial tissue. Currently, synovial plicae are classified as infrapatellar, mediopatellar and suprapatellar. The prevalence of the mediopatellar plica over the other forms of plicae varies between 18% and 60%. The most reported symptom of the mediopatellar plica is pain located medial to the patella above the joint line. Magnetic Resonance Imaging (MRI) is the most useful examination to highlight the presence of the plica, its measurement and exact location. The treatment is initially conservative, i.e., medical treatment and physiotherapy, however when these fail, the plica should be removed surgically via arthroscopy. In the current paper, we aim to report our clinical experience in the management of medial patellar plica syndrome by describing the clinical presentation and diagnosis of this condition as well as its treatment. PMID- 30474534 TI - Biological effects study of Myricitrin and relevant molecular mechanisms. AB - In humans, oxidative stress is thought to be involved in the development of Parkinson' s disease, Alzheimer's disease, atherosclerosis, heart failure, myocardial infarction, depression. Myricitrin, a botanical flavone, is abundantly distributed in the root bark of Myrica cerifera, Myrica esculenta, Ampelopsis grossedentata, Nymphaea lotus, Chrysobalanus icaco, and other plants. Considering the abundance of its natural sources, myricitrin is relatively easy to extract and purify. Myricitrin reportedly possesses effective anti-oxidative, anti inflammatory, and anti-nociceptive activities, and can protect a variety of cells from in vitro and in vivo injuries. Therefore, our current review summarizes the research progress of myricetin in cardiovascular diseases, nerve injury and anti inflammatory, and provides new ideas for the development of myricitrin. PMID- 30474535 TI - Polymyxin resistance mechanisms: from intrinsic resistance to mcr genes. AB - The global spread of carbapenemase-encoding genes among Gram-negative nosocomial pathogens, has led to the revival of polymyxins. Colistin and polymyxin B, despite their serious adverse effects, have become last resort treatment options for multi- or even extensively-drug-resistant bacterial infections due to Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa. Their use however has been followed by an increase in polymyxin resistance rates and the spread of transferable resistance genes limiting further the treatment options and contributing to the emergence of pan-drug-resistance. In the present review, the to-date known polymyxin resistance mechanisms as well as patents related to polymyxin resistance are discussed. PMID- 30474536 TI - Commentary: High-throughput Strategy Accelerates the Progress of Marine Anticancer Peptide Drug Development. PMID- 30474537 TI - Anti-inflammatory effect of Juniperus procera extract in rats exposed to streptozotocin toxicity. AB - BACKGROUND: Chronic inflammation is a critical health issue and implicated in several chronic health problems such as tumors, auto-immune disorder, hypertension or diabetes. However, Juniperus procera is one of the famous ancient plants that been traditionally used to treat several diseases such as hyperglycemia, hepatitis, jaundice, bronchitis, and pneumonia. OBJECTIVE: Current study is an attempt to investigate the anti-inflammatory effect of juniperus procera extract on rats exposed to cytotoxicity caused experimentally by streptozotocin injections. METHOD: Five groups of adult Westar rats (10 rats each) were examined as ( Normal control, Normal rats treated with juniperus procera extract, rats administrated with streptozotocin, rats administrated with streptozotocin and treated with insulin and, rats administrated with streptozotocin and juniperus procera extract). At the end of the experiment, blood was collected from experimented rats. Animals then were killed and small parts of both pancreas and liver were collected for gene expression and histopathological examination. RESULTS: Serum analysis showed a significant increase in glucose, IL-6, IL-2 and TNF-alpha levels in rats exposed to streptozotocin. That change was reduced in rats cotreated with insulin or juniperus procera extract. Moreover, streptozotocin showed a significant upregulation of IL-6, TNF-alpha and A2M genes, while, either insulin or juniperus procera treatment restored that to normal status. Streptozotocin induced inflammation within hepatic tissues which clearly reduced in hepatic tissues of both insulin and junipers cotreated groups. CONCLUSION: Streptozotocin toxicity induces acute inflammation and increases serum glucose, IL-6, IL-2 and TNF-alpha levels. However, juniperus procera extract was significantly prevented that reaction within four weeks experimented frame time. PMID- 30474538 TI - Development and Characterization of Nasal Delivery of Selegiline Hydrochloride Loaded Nanolipid Carriers for the Management of Parkinson's Disease. AB - Introduction Parkinson's disease (PD) is one of the most common age-related neurodegenerative disorders which are marked with the loss of dopaminergic neurons. Present study performed on the nose to brain delivery of selegiline hydrochloride loaded nano lipid carrier, suggests that the nasal route is a good mean of targeting the drug directly into the brain. Method and Materials Nanostructured lipid carriers were prepared by using hot homogenization. Selegiline hydrochloride loaded NLCs and rotenone treatment were given at a dose of 10 mg/kg administered from 14th day to 28th day. Behavioral parameters were determined at 7th, 14th, 21st and 28th day. On the 28th day, animals were sacrificed for biochemical estimation. Result The optimized drug loaded NLC formulation has shown 93+/-5.25% entrapment efficiency and 51.96% loading capacity of. Optimized NLCs formulation has shown 70% release within 10 hours and after that, the release of the drug is sustained up to 22 hours up to 97%. Pharmacological action of the drug was found to restore the behavioral parameters in rotenone-induced rats. Conclusion Nano lipid carrier (NLCs) therapeutics has emerged as a prominent method for the treatment of Parkinson's disease (PD) as it offers targeted delivery and enhances the therapeutic efficacy of neurotherapeutics. It is concluded from the studies that, Selegiline HCl loaded nano lipid carrier which was administered through nasal route have the potential to be used in the management therapy for Parkinson's disease. PMID- 30474539 TI - The prevalence of bacteriospermia in infertile men and association with semen quality in Southwestern Iran. AB - INTRODUCTION: Infertility considered as a social and public health issue and estimated that the most of these infertile couple are residents of developing countries. Infectious diseases including the history of sexually transmitted infections (STIs) may impact on male reproductive function. Therefore, the present study aimed to investigate the prevalence of bacterial contaminants of semen and probable association with sperm quality of infertile men in Iranian population.

Methods: The study population consisted of 200 infertile men and 150 fertile men attending to an infertility Center in southwestern Iran within study period in 2015. The assessment of sperm parameters was according to World Health Organization (WHO) guidelines. The presumptive pathogens were identified using standard microbiology tests and confirmed by specific PCR primers.

Results: The prevalence of bacteriospermia in the semen of the infertile group was significantly higher than that in the fertile group (48% vs. 26.7%, P <0.001). The microbiological analysis of samples showed that the most abundant species of bacteria in semen of infertile men were Chlamydia trachomatis (12.5%) followed by Neisseria gonorrhoeae (11%). On the other hand, in control group Lactobacillus spp. (17.3%) was the most isolated pathogen. Results showed that the presences of N. gonorrhoeae, C. trachomatis, Mycoplasma genitalium, Haemophilus, and Klebsiella was significantly associated with sperm abnormality.

Conclusions: Based on our findings, it seems that bacteriospermia is associated with alterations in properties of semen which may lead to a decrease in the fertilization potential of sperm. Therefore, immediate and appropriate treatment is necessary before investigating every other possible cause of infertility. PMID- 30474540 TI - Repurposing of existing drugs for the bacterial infections: An In silico and In vitro study. AB - BACKGROUND: The emergence of infectious diseases and its resistance to approved drugs is a global threat to human health. The incidence of infectious diseases is increasing day by day and expected to rise exponentially in next 2 decades. Thus, there is a need for new treatment modalities for the treatment of microbial infections. OBJECTIVE: Thus, in the current investigation, we have explored the existing drugs [metformin (Anti-diabetic), propranolol (Anti-hypertensive), and amitriptyline (antidepressant)] for treatment of infectious diseases. RESULTS: An in-silico result of current investigation has shown the good interaction of metformin, propranolol, and amitriptyline towards various targets (Beta lactamase, Penicillin-binding proteins, Staphylokinase protein, Oxidoreductase protein, etc.) of gram positive and gram negative bacteria as that of internal ligand. Further, in-vitro results have shown that the antibacterial activity of metformin, propranolol, and amitriptyline against Bacillus pumilus, Pseudomonas aeruginosa and Staphylococcus aureus. CONCLUSION: The parameters such as Microtiter assay: percentage growth retardation and bacterial growth kinetics, Minimum inhibitory concentration (MIC), Post-antibiotic assay and Biofilm formation have indicated the antibacterial potential of metformin, propranolol, and amitriptyline. However, before starting a clinical trial, complete safety and efficacy profile of drugs in the treatment of infectious diseases should be investigated. PMID- 30474541 TI - Evaluation of salivary Lipid peroxidation as a possible cause of dental caries. AB - BACKGROUND: Tissue destruction can be measured by the level of lipid peroxidation (LP) end products. Since free radicals are very reactive with low survival time, the level of free radicals and oxidative stress activity are measured indirectly by tissue damage end product assessment, i.e. malondialdehyde (MDA) that is a final end product of LP. OBJECTIVE: The aim of this study was to evaluate salivary MDA level as an indicator of oxidative stress; in caries-active and caries-free students. MATERIALS AND METHODS: A total of 100 male and female students, 15-17 years of age, participated in this case-control study. Five mL of whole saliva were obtained. Salivary MDA level was measured spectrophotometrically. Statistical comparisons were performed with Student's t test, using SPSS 13. RESULTS: Salivary MDA level was significantly higher in caries-active group compared to the control caries-free group. MDA was also slightly lower in males. CONCLUSION: Higher MDA level might indicate caries induced oxidative stress. In this study there was a relationship between salivary MDA level and dental caries. Therefore oxidative stress suppression might prevent caries initiation and progression. PMID- 30474542 TI - Does the development of vaccines advance solutions for tuberculosis? AB - BACKGROUND: Mycobacterium tuberculosis (Mtb) is considered as one of the most efficacious human pathogens. The global mortality rate of TB stands at approximately 2 million, while about 8 to 10 million active new cases are documented yearly. It is, therefore, a priority to develop vaccines that will prevent active TB. The vaccines currently used for the management of TB can only proffer a certain level of protection against meningitis, TB, and other forms of disseminated TB in children; however, their effectiveness against pulmonary TB varies and cannot provide life-long protective immunity. Based on these reasons, more efforts are channeled towards the development of new TB vaccines. During the development of TB vaccines, a major challenge has always been the lack of diversity in both the antigens contained in TB vaccines and the immune responses of the TB sufferers. Current efforts are channeled on widening both the range of antigens selection and the range of immune response elicited by the vaccines. The past two decades witnessed a significant progress in the development of TB vaccines; some of the discovered TB vaccines have recently even completed the third phase (phase III) of clinical trial. OBJECTIVE: The objectives of this article are to discuss the recent progress in the development of new vaccines against TB; to provide an insight on the mechanism of vaccine-mediated specific immune response stimulation; and to debate the interaction between vaccines and global interventions to end TB. PMID- 30474543 TI - Ketogenic diet acts on body remodeling and microRNAs expression profile. AB - BACKGROUND: The ketogenic diet (KD) promotes metabolic changes and optimizes energy metabolism. It is unknown if microRNAs (miRs) are influenced by KD in obese subjects. OBJECTIVES: The aim of this study was to evaluate 6 weeks of biphasic KD in obese subjects. We enrolled 36 obese subjects (18 females and 18 males) in stage 1 of Edmonton Obesity Staging System (EOSS) parameter. Blood biochemical parameters were dosed by ADVIA 1800. RESULT: The screening of circulating miRs was performed with the FDA approved platform n-counter flex. Only three miRs, hsa-let-7b-5p, hsa-miR-143-3p and hsa-miR-504-5p were influenced in an equal manner in both sexes. The KD was safe ameliorating both biochemical and anthropometric factors in obese subjects re-collocating them into stage 0 of EOSS parameters. CONCLUSION: The miRs identified here might be a useful tool to monitor low carbohydrate nutritional regimens reflecting indirectly the regulatory biochemical mechanisms and cell signaling to the orchestration of metabolic and signaling pathways. PMID- 30474544 TI - Mismatch between femur and tibia coronal alignment in the knee joint: classification of five lower limb types according to femoral and tibial mechanical alignment. AB - BACKGROUND: Reasons for dissatisfaction with total knee arthroplasty (TKA) include unequal flexion or extension gap, soft tissue imbalance, and patella maltracking, which often occur with mismatch between femoral and tibial coronal bony alignment in the knee joint or extremely varus or valgus alignment. However, lower limb coronal alignment classification is based only on hip-knee-ankle angle (HKAA), leading to oversight regarding a mismatch between femoral and tibial coronal alignment. We aimed to classify alignment of the lower limbs according to the mechanical alignment of the femur and tibia in a healthy population. METHODS: All 214 normal triple films were reviewed retrospectively. HKAA, mechanical lateral distal femoral angle (mLDFA), mechanical medial proximal tibial angle (mMPTA), angle between the femoral anatomical axis and the mechanical axis (AA MA), and knee alignment angle (KAA) were measured. Subjects were categorized into one of five types based on the mechanical alignment of femur and tibia. RESULTS: Mean HKAA, mLDFA, and mMPTA of all subjects were 1.2 degrees , 87.3 degrees , and 85.8 degrees , respectively. All subjects were classified into one of five types with significant differences (p < 0.001). About 61% of subjects showed neutral alignment, of which nearly 40% were type 2 (valgus of the femur and varus of the tibia with oblique joint line: mLDFA 85.0 degrees +/- 1.4 degrees , mMPTA 85.1 degrees +/- 1.2 degrees , TJLA 2.7 degrees +/- 2.4 degrees ) and 60% exhibited neutral alignment with a neutral femur and tibia (type 1). In varus and valgus types, mismatch between the mechanical angle of the femur and tibia was common. Varus alignment, including types 3 (varus of the tibia: mLDFA 88.0 degrees +/- 1.4 degrees , mMPTA 83.5 degrees +/- 1.6 degrees ) and 4 (varus of both the tibia and femur: mLDFA 91.4 degrees +/- 1.4 degrees , mMTPA 85.2 degrees +/- 2.0 degrees ), was found in 30% of subjects. Valgus alignment (type 5 valgus of femur: mLDFA 84.6 degrees +/- 1.6 degrees , mMPTA 88.8 degrees +/- 2.0 degrees ) accounted for 8.9% of all subjects. CONCLUSIONS: Mismatch between mechanical alignment of the femur and tibia was common in varus and valgus alignment types. Joint line obliquity was also observed in 40% of the neutral alignment population. This classification provides a quick, simple interpretation of femoral and tibial coronal alignment, and more detailed guidance for preoperative planning for TKA than the traditional varus-neutral-valgus classification. PMID- 30474545 TI - The influence of radio frequency ablation on intra-articular fluid temperature in the ankle joint - a cadaver study. AB - BACKGROUND: Radio frequency ablation devices have found a widespread application in arthroscopic surgery. However, recent publications report about elevated temperatures, which may cause damage to the capsular tissue and especially to chondrocytes. The purpose of this study was the investigation of the maximum temperatures that occur in the ankle joint with the use of a commercially available radio frequency ablation device. METHODS: Six formalin-fixed cadaver ankle specimens were used for this study. The radio frequency device was applied for 120 s to remove tissue. Intra-articular temperatures were logged every second for 120 s at a distance of 3, 5 and 10 mm from the tip of the radio frequency device. The irrigation fluid flow was controlled by setting the inflow pressure to 10 mmHg, 25 mmHg, 50 mmHg and 100 mmHg, respectively. The controller unit voltage setting was set to 1, 5 and 9. RESULTS: Maximum temperatures exceeding 50 degrees C/122 degrees F were observed for all combinations of parameters, except for those with a pressure of 100 mmHg pressure. The main critical variable is the pressure setting, which is highly significant. The controller unit voltage setting showed no effect on the temperature measurements. The highest temperature was 102.7 degrees C/215.6 degrees F measured for an irrigation flow of 10 mmHg. The shortest time span to exceed 50 degrees C/122 degrees F was 3 s. CONCLUSION: In order to avoid temperatures exceeding 50 degrees C/122 degrees F in the use of radio frequency devices in arthroscopic surgeries of the ankle joint, it is recommended to use a high irrigation flow by setting the pressure difference across the ankle joint as high as feasible. Even short intervals of a low irrigation flow may lead to critical temperatures above 50 degrees C/122 degrees F. LEVEL OF EVIDENCE: Level II, diagnostic study. PMID- 30474546 TI - Association between liver enzymes and bone mineral density in Koreans: a cross sectional study. AB - BACKGROUND: Osteoporosis is a major health concern for both men and women, and associated fractures incur substantial economic burden. While there are a multitude of studies on bone mineral density (BMD) and liver diseases, not many studies have assessed the association between liver enzyme levels and BMD in homogeneous populations. METHODS: The current study investigated the association between serum liver enzyme levels and BMD at various sites in Koreans. Out of 21,517 surveyees of the 5th Korean National Health and Nutrition Examination Survey (2010-2012), 7160 participants' data on BMD, serum liver enzymes, and full covariate data were included for cross-sectional analysis. BMD at the femoral neck, lumbar spine, entire femur, and whole body was assessed using dual energy X ray absorptiometry (DEXA), and liver enzymes included aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma(gamma)-glutamyl transferase (GGT) levels. Differences in participant characteristics by BMD and liver enzyme levels were analyzed, and complex sample design regression analysis adjusted for multiple covariates was performed to assess the relationship between liver enzymes and BMD. RESULTS: Negative associations were seen with GGT and BMD at all sites (P <= 0.02), ALT with lumbar spine (P = 0.0013), and AST with lumbar BMD (P = 0.0009). In particular, GGT presented strong negative associations with BMD in postmenopausal women and elder men. CONCLUSIONS: This study demonstrates a negative relationship between liver enzyme levels and BMD, and suggests that a significant association exists between osteoporosis/decreased BMD and liver disorders. PMID- 30474548 TI - Risk factors of hepatic function alterations in hospitalized adult patients treated with short-term parenteral nutrition receiving the same lipid composition at the same dose. AB - BACKGROUND: High doses and vegetable origin of lipid emulsions (LE) are prominent factors for liver test (LT) alterations in patients treated with parenteral nutrition (PN). This study aims to determine incidence of LT alterations, and risk factors related to these alterations in patients with short term PN with homogenous LE. METHODS: Adult non-critically ill hospitalized patients, with normal LTs at the beginning of PN, receiving 0.8 g/kg/day of an olive/soybean LE were included. A paired Student t-test was applied to compare final with initial LT values. LT variation (end vs start of PN) according to type of surgery and infection was studied by means of an analysis of the variance. Univariate and multivariate analyses were constructed to relate the variations of each of the 4 LTs with the adjustment variables. RESULTS: One hundred eighty one patients (66.57 +/- 12.89 years; 72.4% men), 66.8% suffered from cancer. Final LT values increased from initial values for gamma-glutamyltransferase (GGT) 2.69 +/- 2.49 MUkat/L vs 0.55 +/- 0.36 MUkat/L, alkaline phosphatase (AP) 1.97 +/- 1.49 MUkat/L vs 1.04 +/- 0.33 MUkat/L, and alanine aminotransferase (ALT) 0.57 +/- 0.92 MUkat/L vs 0.32 +/- 0.26 MUkat/L. GGT and AP variations were associated with days of PN; GGT, AP and total bilirubin with surgical patients, AP variations with infection, and GGT with cancer. Multivariate analysis: elevation of GGT, AP and ALT was related to infection, days of PN and surgery. CONCLUSIONS: Factors that increased the risk of LTs elevation during short term PN treatment were duration of PN, surgery, cancer, and infection associated with oxidative stress. PMID- 30474549 TI - Relationship of insulin resistance estimated by triglyceride glucose index to arterial stiffness. AB - BACKGROUND: Insulin resistance (IR) is an important risk factor for subclinical atherosclerosis. This study evaluated the relationship between the triglyceride glucose (TyG) index, which is a simple and reliable surrogate marker for IR, and arterial stiffness. METHODS: This study included 2560 Korean subjects without a previous history of coronary artery disease, stroke, and malignancies who participated in a community-based cohort study. Arterial stiffness was measured using the brachial-ankle pulse wave velocity (baPWV). RESULTS: All participants were stratified into four groups based on the quartile of the TyG index. The prevalence of metabolic syndrome and diabetes significantly increased with increasing TyG index quartile. The mean baPWV was significantly different among all groups (group I [lowest]: 1421 +/- 242 vs. group II: 1480 +/- 244 vs. group III: 1534 +/- 260 vs. group IV [highest]: 1575 +/- 279 cm/s; p < 0.001). The TyG index values were correlated with baPWV (r = 0.224, p < 0.001). Multiple regression analysis showed that age (beta = 0.410), male gender (beta = 0.051), increased blood pressure (beta = 0.266), and TyG index (beta = 0.158) were associated with baPWV (p < 0.05, respectively). TyG index was independently related to baPWV in both non-diabetics and diabetics. CONCLUSIONS: The TyG index is independently associated with arterial stiffness in a relatively healthy Korean population. PMID- 30474547 TI - Impact of heart failure and other comorbidities on mortality in patients with chronic obstructive pulmonary disease: a register-based, prospective cohort study. AB - BACKGROUND: Multimorbidity has already become common in primary care and will be a challenge in the future. Primary care in Sweden participates to a great extent in the care of patients with two severe, chronic conditions: chronic obstructive pulmonary disease (COPD) and heart failure. Both conditions are characterized by high mortality and often coexist. Age, sex, heart failure and other comorbidities are considered to be the major predictors of mortality in patients with COPD. We aimed to study the impact of heart failure, other comorbidities, age and sex on mortality in patients with COPD. METHODS: A register-based, prospective cohort study conducted in Blekinge County in Sweden with about 150,000 inhabitants. The study population was comprised of people aged >=35 years. The data about diagnoses of COPD and heart failure came from the 2007 health care register, in which we found 984 individuals with a diagnosis of COPD. Date of death was collected from January 1st, 2008 -August 31st, 2015. The diagnosis-based Adjusted Clinical Groups (ACG) Case-Mix System 7.1 was used to describe comorbidity. Each individual was assigned one of six comorbidity levels called resource utilization bands (RUB) graded from 0 to 5. RESULTS: Estimated eight year mortality in patients with COPD and coexisting heart failure was seven times higher than in patients with COPD alone - odds ratio 7.06 (95% CI 3.88-12.84). Adjusting for age and male sex resulted in odds ratio 3.75 (95% CI 1.97-7.15). Further adjusting for other comorbidities resulted in odds ratio 3.26 (95% CI 1.70-6.25). The mortality was strongly associated with the highest comorbidity level - RUB 5 where the odds ratio was 5.19 (95% CI 2.59-10.38). CONCLUSION: Heart failure has an important impact on mortality in patients with COPD. The mortality in patients with COPD and coexisting heart failure was strongly associated with age, male sex and other comorbidities. Of those three predictors, only other comorbidities can be influenced. Heart failure and other comorbidities should be recognized early and properly treated in order to improve survival in patients with coexisting COPD and heart failure. PMID- 30474550 TI - Production of a recombinant peroxidase in different glyco-engineered Pichia pastoris strains: a morphological and physiological comparison. AB - BACKGROUND: The methylotrophic yeast Pichia pastoris is a common host for the production of recombinant proteins. However, hypermannosylation hinders the use of recombinant proteins from yeast in most biopharmaceutical applications. Glyco engineered yeast strains produce more homogeneously glycosylated proteins, but can be physiologically impaired and show tendencies for cellular agglomeration, hence are hard to cultivate. Further, comprehensive data regarding growth, physiology and recombinant protein production in the controlled environment of a bioreactor are scarce. RESULTS: A Man5GlcNAc2 glycosylating and a Man8-10GlcNAc2 glycosylating strain showed similar morphological traits during methanol induced shake-flask cultivations to produce the recombinant model protein HRP C1A. Both glyco-engineered strains displayed larger single and budding cells than a wild type strain as well as strong cellular agglomeration. The cores of these agglomerates appeared to be less viable. Despite agglomeration, the Man5GlcNAc2 glycosylating strain showed superior growth, physiology and HRP C1A productivity compared to the Man8-10GlcNAc2 glycosylating strain in shake-flasks and in the bioreactor. Conducting dynamic methanol pulsing revealed that HRP C1A productivity of the Man5GlcNAc2 glycosylating strain is best at a temperature of 30 degrees C. CONCLUSION: This study provides the first comprehensive evaluation of growth, physiology and recombinant protein production of a Man5GlcNAc2 glycosylating strain in the controlled environment of a bioreactor. Furthermore, it is evident that cellular agglomeration is likely triggered by a reduced glycan length of cell surface glycans, but does not necessarily lead to lower metabolic activity and recombinant protein production. Man5GlcNAc2 glycosylated HRP C1A production is feasible, yields active protein similar to the wild type strain, but thermal stability of HRP C1A is negatively affected by reduced glycosylation. PMID- 30474551 TI - Association between serum lipids and low back pain among a middle-aged Japanese population: a large-scale cross-sectional study. AB - BACKGROUND: Abnormal lipid levels have been suggested as a mechanism leading to atherosclerosis of the lumbar vessels, resulting in low back pain (LBP). This study examined whether abnormal lipid levels were associated with LBP among middle-aged adults in Japan. METHODS: The present study included adults between 40 and 64 years old who underwent an annual health checkup. A total of 258,367 eligible participants were analyzed to investigate associations of LBP with low density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and LDL-C/HDL-C ratio. Participants were categorized into two groups according to each of LDL-C, HDL-C, and LDL-C/HDL-C ratio (LDL-C: >= 140 vs. < 140 mg/dL; HDL-C: >= 40 vs. < 40 mg/dL; LDL-C/HDL-C ratio: >= 2.5 vs. < 2.5). Information on LBP was obtained using a self-administered questionnaire. Logistic regression modeling was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for LBP. RESULTS: The prevalence of LBP was 2.2% in men and 2.1% in women. Multivariable analysis adjusting for age, body mass index, and lifestyle factors found significant associations for HDL-C < 40 mg/dL (OR, 1.34; 95%CI, 1.20-1.48 in men; OR, 1.32; 95%CI, 1.02-1.72 in women) and LDL-C/HDL-C ratio >= 2.5 (OR, 1.17; 95%CI, 1.09-1.26 in men; OR, 1.15; 95%CI, 1.03-1.29 in women) with LBP. CONCLUSIONS: Low HDL-C and high LDL-C/HDL-C ratio were significantly associated with LBP in a middle-aged Japanese population. These findings might support the atherosclerosis-LBP hypothesis. PMID- 30474552 TI - Pilot randomized controlled trials in the orthopaedic surgery literature: a systematic review. AB - BACKGROUND: The primary objective of this systematic review is to examine the characteristics of pilot randomized controlled trials (RCTs) in the orthopaedic surgery literature, including the proportion framed as feasibility trials and those that lead to definitive RCTs. This review aim to answer the question of whether pilot RCTs lead to definitive RCTs, whilst investigating the quality, feasibility and overall publication trends of orthopaedic pilot trials. METHODS: Pilot RCTs in the orthopaedic literature were identified from three electronic databases (EMBASE, MEDLINE, and Pubmed) searched from database inception to January 2018. Search criteria included the evaluation of at least one orthopaedic surgical intervention, research on humans, and publication in English. Two reviewers independently screened the pool of pilot trials, and conducted a search for corresponding definitive trials. Screened pilot RCTs were assessed for feasibility outcomes related to efficiency, cost, and/or timeliness of a large scale clinical trial involving a surgical intervention. The quality of the pilot and definitive trials were assessed using the Checklist to Evaluate a Report of a Non-Pharmacological Trial (CLEAR NPT). RESULTS: The initial search for pilot RCTs yielded 3857 titles, of which 49 articles were relevant for this review. 73.5% (36/49) of the orthopaedic pilot RCTs were framed as feasibility trials. Of these, 5 corresponding definitive trials (10.2%) were found, of which four were published and one ongoing. Based on author responses, the lack of a definitive RCT following the pilot trial was attributed to a lack of funding, inadequacies in recruitment, and belief that the pilot RCT sufficiently answered the research question. CONCLUSIONS: Based on this systematic review, most pilot RCTs were characterized as feasibility trials. However, the majority of published pilot RCTs did not lead to definitive trials. This discrepancy was mainly attributed to poor feasibility (e.g. poor recruitment) and lack of funding for an orthopaedic surgical definitive trial. In recent years this discrepancy may be due to researchers saving on time and cost by rolling their pilot patients into the definitive RCT rather than publish a separate pilot trial. PMID- 30474553 TI - Identification and application of a growth-regulated promoter for improving L valine production in Corynebacterium glutamicum. AB - BACKGROUND: Promoters are commonly used to regulate the expression of specific target genes or operons. Although a series of promoters have been developed in Corynebacterium glutamicum, more precise and unique expression patterns are needed that the current selection of promoters cannot produce. RNA-Seq technology is a powerful tool for helping us to screen out promoters with expected transcriptional strengths. RESULTS: The promoter PCP_2836 of an aldehyde dehydrogenase coding gene from Corynebacterium glutamicum CP was identified via RNA-seq and RT-PCR as a growth-regulated promoter. Comparing with the strong constitutive promoter Ptuf, the transcriptional strength of PCP_2836 showed a significant decrease that from about 75 to 8% in the stationary phase. By replacing the native promoters of the aceE and gltA genes with PCP_2836 in the C. glutamicum ATCC 13032-derived L-valine-producing strain AN02, the relative transcriptional levels of the aceE and gltA genes decreased from 1.2 and 1.1 to 0.35 and 0.3, and the activity of their translation products decreased to 43% and 35%, respectively. After 28 h flask fermentation, the final cell density of the obtained strains, GRaceE and GRgltA, exhibited a 7-10% decrease. However, L valine production increased by 23.9% and 27.3%, and the yield of substrate to product increased 43.8% and 62.5%, respectively. In addition, in the stationary phase, the intracellular citrate levels in GRaceE and GRgltA decreased to 27.0% and 33.6% of AN02, and their intracellular oxaloacetate levels increased to 2.7 and 3.0 times that of AN02, respectively. CONCLUSIONS: The PCP_2836 promoter displayed a significant difference on its transcriptional strength in different cell growth phases. With using PCP_2836 to replace the native promoters of aceE and gltA genes, both the transcriptional levels of the aceE and gltA genes and the activity of their translation products demonstrated a significant decrease in the stationary phase. Thus, the availability of pyruvate was significantly increased for the synthesis of L-valine without any apparent irreversible negative impacts on cell growth. Use of this promoter can enhance the selectivity and control of gene expression and could serve as a useful research tool for metabolic engineering. PMID- 30474555 TI - Early postoperative changes of sphingomyelins and ceramides after laparoscopic sleeve gastrectomy. AB - BACKGROUND: This study aimed to determine early postoperative changes of serum sphingomyelin (SM) and ceramide (CER) species following laparoscopic sleeve gastrectomy (LSG). METHODS: Twenty obese patients [mean body mass index (BMI) 45,64 +/- 6,10 kg/m2] underwent LSG and normal weight control patients (mean BMI 31,51 +/- 6,21 kg/m2) underwent laparoscopic cholecystectomy. Fasting blood samples were collected prior to surgery, at day 1 and day 30 after surgery. Circulating levels of C16-C24 SMs, C16-C24 CERs and sphingosine-1-phosphate (S1P) were determined by an optimized multiple reaction monitoring (MRM) method using ultra fast-liquid chromatography (UFLC) coupled with tandem mass spectrometry (MS/MS). Serum activity of neutral sphingomyelinase (N-SMase) was assayed by standard kit methods, and ceramide-1-phosphate (C1P) levels were determined by enzyme-linked immunosorbent assay (ELISA). Lipid profile, routine biochemical and hormone parameters were assayed by standard kit methods. Insulin sensitivity was evaluated using homeostatic model assessment for insulin resistance (HOMA IR). RESULTS: A significant decrease was observed in serum levels of very-long-chain C24 SM, very-long-chain C22-C24 CERs, HOMA-IR, N-SMase and C1P in LSG patients after postoperation day 1 and day 30 compared to preoperation levels. At 30 days postsurgery, BMI was reduced by 11%, fasting triglycerides were significantly decreased, and insulin sensitivity was increased compared to presurgery values. A significant positive correlation was found between HOMA-IR and serum levels of C22-C24 CERs in LSG patients. CONCLUSION: We conclude that very long chain CERs may mediate improved insulin sensitivity after LSG. PMID- 30474554 TI - Feasibility of 3D black-blood variable refocusing angle fast spin echo cardiovascular magnetic resonance for visualization of the whole heart and great vessels in congenital heart disease. AB - BACKGROUND: Volumetric black-blood cardiovascular magnetic resonance (CMR) has been hampered by long scan times and flow sensitivity. The purpose of this study was to assess the feasibility of black-blood, electrocardiogram (ECG)-triggered and respiratory-navigated 3D fast spin echo (3D FSE) for the visualization of the whole heart and great vessels. METHODS: The implemented 3D FSE technique used slice-selective excitation and non-selective refocusing pulses with variable flip angles to achieve constant echo signal for tissue with T1 (880 ms) and T2 (40 ms) similar to the vessel wall. Ten healthy subjects and 21 patients with congenital heart disease (CHD) underwent 3D FSE and conventional 3D balanced steady-state free precession (bSSFP). The sequences were compared in terms of ability to perform segmental assessment, local signal-to-noise ratio (SNRl) and local contrast-to-noise ratio (CNRl). RESULTS: In both healthy subjects and patients with CHD, 3D FSE showed superior pulmonary vein but inferior coronary artery origin visualisation compared to 3D bSFFP. However, in patients with CHD the combination of 3D bSSFP and 3D FSE whole-heart imaging improves the success rate of cardiac morphological diagnosis to 100% compared to either technique in isolation (3D FSE, 23.8% success rate, 3D bSSFP, 5% success rate). In the healthy subjects SNRl for 3D bSSFP was greater than for 3D FSE (30.1 +/- 7.3 vs 20.9 +/- 5.3; P = 0.002) whereas the CNRl was comparable (17.3 +/- 5.6 vs 17.4 +/- 4.9; P = 0.91) between the two scans. CONCLUSIONS: The feasibility of 3D FSE for whole heart black-blood CMR imaging has been demonstrated. Due to their high success rate for segmental assessment, the combination of 3D bSSFP and 3D FSE may be an attractive alternative to gadolinium contrast enhanced morphological CMR in patients with CHD. PMID- 30474556 TI - MicroRNA-382 inhibits cell growth and migration in colorectal cancer by targeting SP1. AB - BACKGROUND: Emerging evidence showed that microRNAs (miRs) play critical roles in human cancers by functioning as either tumor suppressor or oncogene. MIR-382 was found to function as tumor suppressor in certain cancers. However, the role of MIR-382 in colorectal cancer (CRC) is largely unknown. Specificity protein 1 (SP1) is highly expressed in several cancers including CRC and is correlated with poor prognosis, but it is unclear whether or not MIR-382 can regulate the expression of SP1. METHODS: MIR-382 expression level was measured by reverse transcription-quantitative polymerase chain reaction. The connection between MIR 382 and SP1 was validated by luciferase activity reporter assay and western blot assay. Cell counting kit-8 assay and wound-healing assay were conducted to investigate the biological functions of MIR-382 in CRC. RESULTS: In this study, we found MIR-382 expression was downregulated in CRC tissues and cell lines, and the transfection of MIR-382 mimic decreased cell growth and migration. Furthermore, we identified SP1 was a direct target of MIR-382. Overexpression of MIR-382 decreased the expression of SP1, whereas MIR-382 knockdown promoted SP1 expression. We also observed an inversely correlation between MIR-382 and SP1 in CRC tissues. Additionally, we showed that knockdown of SP1 inhibited cell growth and migration and attenuated the effect of MIR-382 inhibitor on cell behaviors. CONCLUSIONS: In conclusion, the present study describes a potential mechanism underlying a MIR-382/SP1 link contributing to CRC development. Thus, MIR-382 may be able to be developed as a novel treatment target for CRC. PMID- 30474557 TI - Non-programmed transcriptional frameshifting is common and highly RNA polymerase type-dependent. AB - BACKGROUND: The viral or host systems for a gene expression assume repeatability of the process and high quality of the protein product. Since level and fidelity of transcription primarily determines the overall efficiency, all factors contributing to their decrease should be identified and optimized. Among many observed processes, non-programmed insertion/deletion (indel) of nucleotide during transcription (slippage) occurring at homopolymeric A/T sequences within a gene can considerably impact its expression. To date, no comparative study of the most utilized Escherichia coli and T7 bacteriophage RNA polymerases (RNAP) propensity for this type of erroneous mRNA synthesis has been reported. To address this issue we evaluated the influence of shift-prone A/T sequences by assessing indel-dependent phenotypic changes. RNAP-specific expression profile was examined using two of the most potent promoters, ParaBAD of E. coli and phi10 of phage T7. RESULTS: Here we report on the first systematic study on requirements for efficient transcriptional slippage by T7 phage and cellular RNAPs considering three parameters: homopolymer length, template type, and frameshift directionality preferences. Using a series of out-of-frame gfp reporter genes fused to a variety of A/T homopolymeric sequences we show that T7 RNAP has an exceptional potential for generating frameshifts and is capable of slipping on as few as three adenine or four thymidine residues in a row, in a flanking sequence-dependent manner. In contrast, bacterial RNAP exhibits a relatively low ability to baypass indel mutations and requires a run of at least 7 tymidine and even more adenine residues. This difference comes from involvement of various intrinsic proofreading properties. Our studies demonstrate distinct preference towards a specific homopolymer in slippage induction. Whereas insertion slippage performed by T7 RNAP (but not deletion) occurs tendentiously on poly(A) rather than on poly(T) runs, strong bias towards poly(T) for the host RNAP is observed. CONCLUSIONS: Intrinsic RNAP slippage properties involve trade offs between accuracy, speed and processivity of transcription. Viral T7 RNAP manifests far greater inclinations to the transcriptional slippage than E. coli RNAP. This possibly plays an important role in driving bacteriophage adaptation and therefore could be considered as beneficial. However, from biotechnological and experimental viewpoint, this might create some problems, and strongly argues for employing bacterial expression systems, stocked with proofreading mechanisms. PMID- 30474558 TI - Universal health coverage for refugees and migrants in the twenty-first century. AB - Migration is a determinant of health. Tackling the health needs of migrants and refugees will require action at the local, national, and global levels. Over the past 12 months, BMC Medicine has published a collection of articles under the title Migrant and Refugee Health ( https://www.biomedcentral.com/collections/migrant-and-refugee-health ) addressing a range of health issues affecting refugees and migrants in their countries of origin, on transit, and in their destination countries. In light of these articles, we herein discuss the complex and wide-ranging healthcare needs of different refugee groups in their destination countries as well as the need for accessible and culturally appropriate health services. PMID- 30474559 TI - Effectiveness of pharmacotherapy for smoking cessation: protocol for umbrella review and quality assessment of systematic reviews. AB - BACKGROUND: In the long term, smoking cessation can decrease the risk of cancer, stroke, and heart attacks and improve overall survival. The aim of the proposed umbrella review is to summarize existing systematic reviews that assessed the effects of pharmacological interventions for smoking cessation and to evaluate the methodological quality of previously conducted systematic reviews. METHODS: Databases such as the Cochrane Library, PubMed, MEDLINE, EMBASE, CINAHIL PsychINFO Web of Science, Conference Papers Index, Scopus, and Google Scholar will be used to retrieve reviews. Systematic reviews which included only randomized control trials will be considered in this review. The primary outcome will be prolonged abstinence from smoking for a minimum of 6 months follow-up, and the secondary outcome will be point abstinence rate from smoking of less than 6 months follow-up but more than 7 days. Methodological quality of the included reviews will be assessed using the Assessment of Multiple Systematic Reviews 2 (AMSTAR 2) tool, which contains 16 domains. Two authors will screen the titles and abstracts of all reviews obtained by the search strategy, assess the full text of selected articles for inclusion, and extract data independently. The quality appraisal will be also assessed by two authors (AM, CC) independently, and Cohen's Kappa statistic will be used to assess inter-ratter agreement. The findings of the study will be narrated qualitatively to describe the effect of different pharmacotherapy on smoking cessation. DISCUSSION: The World Health Organization recommends treatment of tobacco dependence as one approach in its comprehensive tobacco control policy. To date, many trials and systematic reviews have been conducted to assess the effectiveness of pharmacotherapy for smoking cessation. Therefore, the findings of the umbrella review will improve clinical decision-making and be used as a baseline for future studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017080906. PMID- 30474560 TI - Stakeholder involvement in systematic reviews: a scoping review. AB - BACKGROUND: There is increasing recognition that it is good practice to involve stakeholders (meaning patients, the public, health professionals and others) in systematic reviews, but limited evidence about how best to do this. We aimed to document the evidence-base relating to stakeholder involvement in systematic reviews and to use this evidence to describe how stakeholders have been involved in systematic reviews. METHODS: We carried out a scoping review, following a published protocol. We searched multiple electronic databases (2010-2016), using a stepwise searching approach, supplemented with hand searching. Two authors independently screened and discussed the first 500 abstracts and, after clarifying selection criteria, screened a further 500. Agreement on screening decisions was 97%, so screening was done by one reviewer only. Pre-planned data extraction was completed, and the comprehensiveness of the description of methods of involvement judged. Additional data extraction was completed for papers judged to have most comprehensive descriptions. Three stakeholder representatives were co-authors for this systematic review. RESULTS: We included 291 papers in which stakeholders were involved in a systematic review. Thirty percent involved patients and/or carers. Thirty-two percent were from the USA, 26% from the UK and 10% from Canada. Ten percent (32 reviews) were judged to provide a comprehensive description of methods of involving stakeholders. Sixty-nine percent (22/32) personally invited people to be involved; 22% (7/32) advertised opportunities to the general population. Eighty-one percent (26/32) had between 1 and 20 face-to face meetings, with 83% of these holding <= 4 meetings. Meetings lasted 1 h to 1/2 day. Nineteen percent (6/32) used a Delphi method, most often involving three electronic rounds. Details of ethical approval were reported by 10/32. Expenses were reported to be paid to people involved in 8/32 systematic reviews. DISCUSSION/CONCLUSION: We identified a relatively large number (291) of papers reporting stakeholder involvement in systematic reviews, but the quality of reporting was generally very poor. Information from a subset of papers judged to provide the best descriptions of stakeholder involvement in systematic reviews provide examples of different ways in which stakeholders have been involved in systematic reviews. These examples arguably currently provide the best available information to inform and guide decisions around the planning of stakeholder involvement within future systematic reviews. This evidence has been used to develop online learning resources. SYSTEMATIC REVIEW REGISTRATION: The protocol for this systematic review was published on 21 April 2017. Publication reference: Pollock A, Campbell P, Struthers C, Synnot A, Nunn J, Hill S, Goodare H, Watts C, Morley R: Stakeholder involvement in systematic reviews: a protocol for a systematic review of methods, outcomes and effects. Research Involvement and Engagement 2017, 3:9. https://doi.org/10.1186/s40900-017-0060-4 . PMID- 30474561 TI - Is increased carer knowledge of the health care system associated with decreased preventable hospitalizations for people in the community diagnosed with dementia? A systematic review protocol. AB - BACKGROUND: People living with dementia (PLWD) are admitted to hospital twice as often as those without dementia, for ambulatory care sensitive conditions (ACSC) that could have been managed in ambulatory and primary care settings. PLWD are at greater risk of poor outcomes during and following hospital admission. Compared to those without dementia, they are almost twice as likely to die in hospital and two to three times more likely to experience an adverse event. Although some hospitalizations are clinically necessary, there may be a proportion related to ACSC that could be potentially avoided with additional support and education for PLWD and their carers. This study aims to assess the effectiveness of interventions focused on reducing avoidable hospitalization for PLWD by supporting carers to manage the health care needs of the PLWD, via improved awareness and understanding of health and the healthcare system. METHOD: Scientific and gray literature will be searched using a combination of keywords pertaining to dementia, caregivers, education, and support. Included studies will involve community-dwelling PLWD and caregivers, with interventions aimed at improving carer's understanding of the healthcare system and ability to manage the caregiving role. The primary outcome will be hospitalization related to the PLWD and secondary outcomes will be carer burden, stress, wellbeing, and quality of life. All study designs will be considered. Data from included studies will be analyzed using descriptive statistics and content analysis. If the data permits, we will perform a meta-analysis and subgroup analyses, related to the intervention and participant characteristics. DISCUSSION: This review will provide a comprehensive picture of the knowledge available on the subject and identify knowledge gaps in existing literature. The findings may highlight the lack of existing interventions for PLWD and their carers who live in the community and will help stakeholders to identify needs and develop programs targeted to carers and care recipients that prevent avoidable hospitalization for PLWD. SYSTEMATIC REVIEW REGISTRATION: PROSPERO number: 49655 . PMID- 30474562 TI - Lifestyle and fertility: the influence of stress and quality of life on male fertility. AB - BACKGROUND: Male infertility is a widespread condition among couples. In about 50% of cases, couple infertility is attributable to the male partner, mainly due to a failure in spermatogenesis. In recent times, the crucial role that modifiable lifestyle factors play in the development of infertility have generated a growing interest in this field of study, i.e. aging, psychological stress, nutrition, physical activity, caffeine, high scrotal temperature, hot water, mobile telephone use. Several studies have investigated associations between semen quality and the presence of lifestyle stressors i.e. occupational, life events (war, earthquake, etc.) or couple infertility; overall, these studies provide evidence that semen quality is impaired by psychological stress. In this review, we will discuss the impact of quality of life (modifiable lifestyle factors) and psychological stress on male fertility. In addition, the role that increased scrotal temperature along with inappropriate nutritional and physical exercise attitudes exert on male fertility will be presented. CONCLUSION: The decline of male fertility, particularly associated with advancing age, incorrect lifestyles and environmental factors plays an important role on natality, and its consequences on the future on human population makes this an important public health issue in this century. Thus, modification of lifestyle through a structured program of educational, environmental, nutritional/physical exercise and psychological support, combined with the use of nutraceutical antioxidants can prevent infertility and therefore, may help couples to obtain better quality of life and improved possibility to conceive spontaneously or optimize their chances of conception. PMID- 30474563 TI - Erdheim Chester disease in a patient with Burkitt lymphoma: a case report and review of literature. AB - BACKGROUND: Erdheim Chester disease (ECD) is a rare, non-Langerhans cell histiocytosis characterized by widespread tissue infiltration by CD68-positive, CD1a-negative foamy histiocytes. ECD can be difficult to identify, and diagnosis relies on the presence of histiocytes with certain histologic and immunophenotypic features in an appropriate clinical and radiologic setting. Clinical signs and symptoms are variable depending on which organ systems are involved. Most patients have at least skeletal involvement with bone pain as well as fatigue. Other common manifestations include diabetes insipidus, cardiac, periaortic, or retro-orbital infiltration/fibrosis, kidney impairment, xanthelasmas, among others. CASE PRESENTATION: Herein, we describe a case of BRAF mutation positive ECD in a patient with Burkitt lymphoma, and we review recent literature. CONCLUSION: Underlying BRAF and other MAPK pathway mutations are identified in approximately 50% of cases of ECD, which aids in diagnosis as well as enables novel targeted treatments. ECD patients have an increased risk of myeloid neoplasms; however, unlike other histiocytoses, an association with lymphoproliferative disorders has not been recognized. PMID- 30474565 TI - Ageing in patients with chronic HIV infection: impact of hypercoagulation. AB - Ageing is the result of biological events that progressively and irreversibly compromise the function of vital organs and eventually result in death. There is a general perception that ageing is accelerated in people living with HIV, with an increasing body of evidence to support this view. With the introduction of effective antiretroviral therapy, the life expectancy of people living with HIV has improved. Since people with HIV are living longer than previously, while also ageing faster than the general population, there is an increase in HIV-positive patients living with age-related comorbidities. This brief overview of ageing and HIV discusses aspects of the complications of HIV infection as they impact the ageing process. How diseases of age affect patients with HIV provides clues to help unravel the interactions between HIV and ageing that ultimately should help clinicians understand the basis of 'normal' ageing and manage ageing HIV-positive patients more effectively. PMID- 30474564 TI - CITRIC: cold-inducible translational readthrough in the chloroplast of Chlamydomonas reinhardtii using a novel temperature-sensitive transfer RNA. AB - BACKGROUND: The chloroplast of eukaryotic microalgae such as Chlamydomonas reinhardtii is a potential platform for metabolic engineering and the production of recombinant proteins. In industrial biotechnology, inducible expression is often used so that the translation or function of the heterologous protein does not interfere with biomass accumulation during the growth stage. However, the existing systems used in bacterial or fungal platforms do not transfer well to the microalgal chloroplast. We sought to develop a simple inducible expression system for the microalgal chloroplast, exploiting an unused stop codon (TGA) in the plastid genome. We have previously shown that this codon can be translated as tryptophan when we introduce into the chloroplast genome a trnWUCA gene encoding a plastidial transfer RNA with a modified anticodon sequence, UCA. RESULTS: A mutated version of our trnWUCA gene was developed that encodes a temperature sensitive variant of the tRNA. This allows transgenes that have been modified to contain one or more internal TGA codons to be translated differentially according to the culture temperature, with a gradient of recombinant protein accumulation from 35 degrees C (low/off) to 15 degrees C (high). We have named this the CITRIC system, an acronym for cold-inducible translational readthrough in chloroplasts. The exact induction behaviour can be tailored by altering the number of TGA codons within the transgene. CONCLUSIONS: CITRIC adds to the suite of genetic engineering tools available for the microalgal chloroplast, allowing a greater degree of control over the timing of heterologous protein expression. It could also be used as a heat-repressible system for studying the function of essential native genes in the chloroplast. The genetic components of CITRIC are entirely plastid-based, so no engineering of the nuclear genome is required. PMID- 30474566 TI - Quantitative characterization of the urine and serum metabolomes of children is essential for 'omics' studies. AB - Understanding the long-term health impacts of the early-life exposome requires the characterization and assimilation of multi 'omics' data to ultimately link molecular changes to exposures. In this way, markers associated with negative health outcomes, such as increased disease risk, can be ascertained. However, determining the extent and direction of metabolic perturbations relies on comparisons to existing metabolomic reference profiles. While such resources are increasingly available for adult populations, analogous tools for children are decidedly lacking. Lau et al. have compiled robust, translatable quantitative metabolomics data on urine and serum samples for European children across six study locations. Metabolites were associated with body mass index, diet and demographics, and correlated within and between biofluids. As a result, a novel association between urinary 4-deoxyerythronic acid and body mass index was uncovered. This work serves as a crucial reference for future studies in exposomics, and - more broadly - represents a significant step forward for metabolomics by creating the foundation for a comprehensive reference metabolome for children.Please see related article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-018-1190-8. PMID- 30474567 TI - Insights into globalization: comparison of patient characteristics and disease progression among geographic regions in a multinational Alzheimer's disease clinical program. AB - BACKGROUND: Globalization of clinical trials has important consequences for trial planning and interpretation. This study investigated heterogeneity in patient characteristics and outcomes among world regions in the global idalopirdine Phase 3 clinical program. METHODS: Data were pooled from three 24-week randomized controlled trials in patients aged >= 50 years with mild-to-moderate Alzheimer's disease (AD) (n = 2506). Patients received idalopirdine (10, 30, or 60 mg/day) or placebo, added to cholinesterase inhibitor treatment. Patients were categorized into the following regions: Eastern Europe/Turkey (n = 759), Western Europe/Israel (n = 709), USA/Canada (n = 444), South America/Mexico (n = 361), Asia (n = 134), and Australia/South Africa (n = 99). For each region, operational characteristics, baseline demographic and clinical characteristics, adverse events, and mean change from baseline to week 24 in clinical rating scale scores (placebo group only) were summarized using descriptive statistics. RESULTS: Completion rates were 0.86-0.90 in all regions. Heterogeneity among global regions was evident. Protocol deviations were twice as common in South America/Mexico as in USA/Canada (2.64 vs 1.35 per patient screened). Educational level ranged from 9.2 years in South America/Mexico to 13.4 years in USA/Canada. APOE epsilon4 carriage was 80.6% in Australia/South Africa, 63.1% in Western Europe/Israel, and < 60% in other regions. Screening Mini-Mental State Examination scores were higher in Eastern Europe/Turkey (18.0) and USA/Canada (17.5) than in other regions (16.9-17.1). Baseline AD Assessment Scale-Cognitive subscale (ADAS-Cog) scores ranged from 24.3 in USA/Canada to 27.2 in South America/Mexico. Baseline AD Cooperative Study-Activities of Daily Living, 23-item version (ADCS-ADL23) scores ranged from 58.5 in USA/Canada to 53.5 in Eastern Europe/Turkey. In the placebo group, adverse events were 1.6-1.7 times more common in Western Europe/Israel, USA/Canada, and Australia/South Africa than in Eastern Europe/Turkey. On the ADAS-Cog, Australia/South Africa and Western Europe/Israel showed the most worsening among patients receiving placebo (1.56 and 1.40 points, respectively), whereas South America/Mexico showed an improvement (-0.71 points). All regions worsened on the ADCS-ADL23, from -3.21 points in Western Europe/Israel to -0.59 points in Eastern Europe/Turkey. CONCLUSIONS: Regional heterogeneity-in terms of study conduct, patient characteristics, and outcomes-exists, and should be accounted for, when planning and conducting multinational AD clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01955161 . Registered on 27 September 2013. ClinicalTrials.gov, NCT02006641 . Registered on 5 December 2013. ClinicalTrials.gov, NCT02006654 . Registered on 5 December 2013. PMID- 30474568 TI - Chylothorax after hepatectomy: a case report. AB - BACKGROUND: Chylothorax is the accumulation of chyle within the pleural space. Chylothorax can occur as a complication after multiple different types of surgery, most frequently after thoracic surgery, albeit with an incidence rate of less than 1%. Chylothorax after abdominal surgery is extremely rare, and there are only a few case reports. CASE PRESENTATION: A 74-year-old Japanese woman presented with jaundice. She was diagnosed as having hilar cholangiocarcinoma and underwent right hepatectomy, caudate lobectomy, extrahepatic bile duct resection, and lymph node dissection after preoperative percutaneous transhepatic portal vein embolization. Postoperative liver function was normal. She developed chylous ascites on postoperative day 5, for which conservative treatment was initially effective. Dyspnea developed suddenly on postoperative day 42, and she had a massive right pleural effusion and a small amount of ascites. Management with pleural drainage, total parenteral nutrition, and octreotide injections decreased the chylothorax. However, the chylous effusion reaccumulated on postoperative day 57. As conservative treatments ultimately failed, lymphangiography was performed on postoperative day 62. Lymphangiography with Lipiodol (ethiodized oil) revealed extravasation into the pleural space, but the location of the leak was not identified. There was neither obstruction nor dilation of the thoracic duct. A lymphatic leak in her abdominal cavity was not demonstrated. A chest tube was placed after lymphangiography, and the chylothorax was diminished by postoperative day 71. She was discharged on postoperative day 72. Two and a half years after surgery, she is doing well with no evidence of recurrence of either chylothorax or cancer. CONCLUSIONS: Chylothorax can occur after hepatectomy and pleural effusion should raise suspicion for chylothorax. Lymphangiography may be effective for both diagnosis and treatment in the case of chylothorax after hepatectomy. PMID- 30474570 TI - MiR-219-5p inhibits growth and metastasis of ovarian cancer cells by targeting HMGA2. AB - BACKGROUND: Accumulating studies have demonstrated that high-mobility group A2 (HMGA2), an oncofetal protein, plays a role in tumor development and progression. However, the molecular role of HMGA2 in ovarian carcinoma is yet to be established. MicroRNAs (miRNAs), a group of small noncoding RNAs, negatively regulate gene expression and their dysregulation has been implicated in tumorigenesis. The aim of this study was to investigate the potential involvement of a specific miRNA, miR-219-5p, in HMGA2-induced ovarian cancer. METHODS: The ovarian cancer cell line, SKOV3, was employed, and miR-219-5p and HMGA2 overexpression vectors constructed. The CCK-8 kit was used to determine cell proliferation and the Transwell(r) assay used to measure cell invasion and migration. RT-PCR and western blot analyses were applied to analyze the expression of miR-219-5p and HMGA2, and the luciferase reporter assay used to examine the interactions between miR-219-5p and HMGA2. Nude mice were employed to characterize in vivo tumor growth regulation. RESULTS: Expression of miR-219-5p led to suppression of proliferation, invasion and migration of the ovarian cancer cell line, SKOV3, by targeting HMGA2. The inhibitory effects of miR-219-5p were reversed upon overexpression of HMGA2. Data from the luciferase reporter assay showed that miR-219-5p downregulates HMGA2 via direct integration with its 3' UTR. Consistent with in vitro findings, expression of miR-219-5p led to significant inhibition of tumor growth in vivo. CONCLUSION: Our results collectively suggest that miR-219-5p inhibits tumor growth and metastasis by targeting HMGA2. PMID- 30474569 TI - How do orthopaedic surgeons inform their patients before knee arthroplasty surgery? A cross-sectional study. AB - BACKGROUND: Total knee arthroplasty (TKA) is a successful and common procedure. However, 6-28% of patients are dissatisfied postoperatively. The provision of preoperative patient information, inquiring about patients' expectations, and taking a psychiatric history are essential parts of both preoperative evaluation and postoperative outcome. The aim of this study was to investigate how orthopaedic knee surgeons in Sweden inform their patients before surgery. METHODS: A questionnaire was distributed to all knee surgeons performing TKA in Sweden. Responses were received from 60 of the 65 orthopaedic departments performing TKA in Sweden (92%), covering 219 of the approximately 311 knee surgeons at the 65 departments (70%). The answers were analysed with descriptive statistics. A content analysis of the surgeons' opinions was also performed using a thematic method. RESULTS: In terms of information provision, 58% of the surgeons always gave written information while 92% informed orally. Only 44% always asked about the patient's expectations, and only 42% always informed patients about the 20% dissatisfaction rate after TKA. Additionally, 24% never operated on mild indication of arthrosis, 20% always took a psychiatric history, and half never or seldom consulted a psychiatrist. However, all the knee surgeons believed in a psychiatric impact on TKA outcome. Qualitative analysis revealed five common causes of patient dissatisfaction, which in descending frequency were: patients' expectations, choice of patients to operate on, surgical factors, combinations of factors, and insufficient information provision to patients. CONCLUSIONS: Knee surgeons in Sweden have considerable awareness of the importance of preoperative patient information, the impact of patient expectations, and psychiatric illness. However, they need to improve their preoperative routines when it comes to providing written information, asking about the patient's expectations, and psychiatric assessment. PMID- 30474572 TI - Activity of cabozantinib in radioresistant brain metastases from renal cell carcinoma: two case reports. AB - BACKGROUND: Renal cell carcinoma represents 3-5% of adult malignant tumors. Metastases are found in 30-40% of patients and brain metastases occurred in more than 10% of them. Despite significant progress in medical treatment, patients with brain metastases still have a limited survival. Cabozantinib, a tyrosine kinase inhibitor directed against vascular endothelial growth factor receptors, was recently registered for the treatment of metastatic renal cell carcinoma. Almost no data are, however, available on patients with brain metastases. CASE PRESENTATION: Case 1 is a 51-year-old man of North African origin; Case 2 is a 55 year-old European man. Case 1 and Case 2 had metastases of renal carcinoma at initial diagnosis and were treated with vascular endothelial growth factor receptors tyrosine kinase inhibitors. Case 1 had clear cell renal carcinoma and underwent nephrectomy; he then received several lines of tyrosine kinase inhibitor directed against vascular endothelial growth factor receptors and the mTor complex. During the second treatment a brain metastasis was diagnosed and treated with radiosurgery with rapid efficacy. Two years later he received nivolumab, an antibody directed against the programmed death-1 and programmed death-ligand 1 complex, but disease progression was observed with the reappearance of the brain metastasis together with neurologic symptoms. Cabozantinib was administered and induced a rapid clinical improvement as well as tumor regression in all sites including his brain. Sequencing of his tumor evidenced a mutation of the MET gene. Case 2 had a papillary renal carcinoma with brain metastases at time of diagnosis. After radiation of the brain tumors, a vascular endothelial growth factor receptor tyrosine kinase inhibitor was administered for 3 years. The disease was under control in all sites except in his brain; several new brain metastases requiring new radiation treatments developed. The disease finally progressed at all metastatic sites including his brain and he had several neurological symptoms. Cabozantinib was administered and rapidly induced a clinical improvement; a further computed tomography scan and brain magnetic resonance imaging showed significant tumor regressions. No MET gene mutation or amplification was observed in the tumor analysis. CONCLUSIONS: These case reports indicate that cabozantinib was able, first, to reach brain tumors and second, to induce significant regressions in renal carcinoma brain metastases that were resistant to radiation as well as to previous systemic vascular endothelial growth factor receptor tyrosine kinase inhibitors. PMID- 30474571 TI - Tumor-infiltrating CD8+ and FOXP3+ lymphocytes before and after neoadjuvant chemotherapy in cervical cancer. AB - BACKGROUND: Neoadjuvant chemotherapy (NACT) has been recently accepted as an effective alternative in patients with locally advanced cervical cancer. However, little is known about the effects of NACT on the immunological microenvironment in cervical cancers. In this study, we analyzed the alterations of tumor infiltrating lymphocytes (TILs) before and after NACT and analyzed their prognostic significance in advanced cervical cancer patients treated with platinum-based NACT. METHODS: We recruited 137 patients with stage Ib2 and IIa2 cervical cancer retrospectively. Pretreatment biopsy and surgical specimens after NACT were immunostained with CD8 and Foxp3. The densities of intratumoral and peritumoral immunopositive TILs were analyzed separately. RESULTS: Foxp3+ T cells density significantly decreased in both intratumoral (median 28.49 vs. 19.97; Z = - 8.635, p < 0.001) and peritumoral (median 113.53 vs. 82.48; Z = - 3.741, p < 0.001) areas after NACT, whereas CD8+ T cell counts remained stable in both intratumoral (median 121.32 vs. 109.59; Z = - 0.817,p = 0.414) and peritumoral (median 402.56 vs. 390.84; Z = - 1.138,p = 0.255) areas. Patients with pathological complete response (pCR) had significantly lower number of Foxp3+ T cell density after NACT than non-pCR cases in both intratumoral (median16.12 vs. 22.00; Z = - 2.009, p = 0.045) and peritumoral areas(median 63.31 vs. 98.48; Z = 2.469, p = 0.014). Multivariate analyses demonstrated that high ratio of intratumoral CD8/peritumoral Foxp3 in residual tumors was independent prognostic factor for both progression-free survival (HR = 0.297; 95% CI, 0.109-0.810, p = 0.018) and overall survival (HR = 0.078; 95% CI, 0.010-0.598, p = 0.014). CONCLUSIONS: NACT in cervical cancers can induce anti-cancer immunity by altering TILs subsets. An elevated intratumoral CD8/peritumoral Foxp3 ratio after NACT may confer a favorable clinical outcome. PMID- 30474575 TI - Overmedicating vulnerable children in the U.S. PMID- 30474574 TI - The relationship between a trusted adult and adolescent outcomes: a protocol of a scoping review. AB - BACKGROUND: Although documentation of harm towards children and young people has existed for centuries, it was not until the 1960s that it became a specific focus for health professionals. Since that time, the importance of protective social networks has become better understood. The concept of trusted adults has come into sharper focus, with children being encouraged to develop networks of dependable adults to turn to for support in times of need. While many child protection processes highlight risks to younger children, there has been less emphasis on older children. The role of trusted adults may be particularly important during adolescence, due to burgeoning independence, developing sexuality, relationship formation, and associated vulnerabilities. While important choices relating to health and education are made during this period, there is little formal evidence relating to the impact of trusted adults on such outcomes. This review therefore aims to focus on the role and influence of trusted adults for adolescents. METHODS: This study is a scoping review. A broad range of databases will be searched, including MEDLINE, ERIC, Education Abstracts, Web of Science, ASSIA, Sociological Abstracts, and PsycINFO. Predefined inclusion/exclusion criteria will be used, with a focus on outcomes relating to health and education. Two reviewers will blind screen papers independently at all screening stages, with conflicts being resolved by a third reviewer. Quantitative and qualitative studies, as well as unpublished (grey) literature/reports, will be included. We will use the World Health Organization's 'second decade' definition of adolescence. We aim to collate and map evidence in a broad overview and produce meta-analyses of homogenous data. Where this is not possible, a narrative summary will be produced. DISCUSSION: There appears to be sparse knowledge regarding the role of trusted adults for adolescents. Potential benefits to health and wellbeing may impact on educational attainment, and vice versa. These areas are of particular relevance during the second decade, when decisions that affect future direction, achievement, and wellbeing are being made. The increased understanding of the role of trusted adults provided by this review may help to inform practice and policy and lead to potential benefits for the health and education of adolescents. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD 42017076739. PMID- 30474576 TI - The current practice and care of paediatric patients post cardiac catheterisation. AB - BACKGROUND: Literature is lacking to guide standardised care and assessment practices for paediatric patients post cardiac catheterisation. In response to this gap, we sought to describe the current state of practice in cardiology programmes performing paediatric cardiac catheterisations procedures in the United States of America.Materials and methodsA web-based survey was distributed to the Congenital Cardiovascular Interventional Study Consortium Listserv, with representation from 113 identified institutions. A 36-question survey, including fixed-choice and open-ended questions, was developed and piloted for reliability and validity before distribution. Data were summarised descriptively with count and frequency or median and range. RESULTS: Of the 113 identified institutions, 52% (n=59) responded to the survey. Manual pressure is used to achieve haemostasis by 94.9% of the respondents. Pressure dressings are used by a majority of the facilities and the length of time for bed rest is variable, with the majority using 6 hours for arterial access and 4 hours for venous access. Predominantly, respondents use the time of haemostasis as the start time of bed rest while a third of respondents reported using the time the sheath was removed. CONCLUSION: In this study, variation in a number of post catheterisation care and assessment practices for paediatric patients was noted across cardiology programmes. Information from this assessment identifies key opportunities to collaborate in developing standardised practices for the care and assessment of the paediatric patients post catheterisation. PMID- 30474577 TI - Pulmonary effects on exercise testing in tetralogy of Fallot patients repaired with a transannular patch. AB - BACKGROUND: A transannular patch is often used in the contemporary surgical repair of tetralogy of Fallot. This can lead to significant pulmonary insufficiency and increased right ventricular volumes and ultimately pulmonary valve replacement. Cardiopulmonary exercise testing is used to assess exercise capacity in tetralogy of Fallot patients before pulmonary valve replacement. There is only few published literatures on how lung function affects functional capacity in tetralogy of Fallot patients repaired with a transannular patch. METHODS: A retrospective chart review was done from 2015 to 2017 on patients with tetralogy of Fallot who underwent maximal effort cardiopulmonary exercise testing with cycle ergometry and with concurrent pulmonary function testing. Tetralogy of Fallot patients repaired with a transannular patch without pulmonary valve replacement were compared with age, gender, and size-matched normal controls. RESULTS: In the tetralogy of Fallot group, 24 out of 57 patients underwent primary repair with a transannular patch. When compared to the normal controls, they demonstrated abnormal predicted forced expiratory volume in one second (79 +/- 23.1% versus 90.7 +/- 14.1%, p<0.05), predicted maximal voluntary ventilation (74 +/- 18% versus 90.5 +/- 16.2%, p<0.05) while having low-normal predicted forced vital capacity (80.5 +/- 17.2% versus 90.2 +/- 12.4%, p<0.05) and normal breathing reserve percentage (50.3 +/- 11.3% versus 47.5 +/- 17.3%, p = 0.52). Cardiopulmonary exercise testing abnormalities included significantly lower percent predicted oxygen consumption (63.2 +/- 12.2% versus 87 +/- 12.1%, p<0.05), maximal heart rate (171.8 +/- 18.9 versus 184.6 +/- 13.6, p<0.05), and percent predicted maximum workload (61.7 +/- 15.9% versus 88.3 +/- 21.5%, p<0.05). CONCLUSIONS: Tetralogy of Fallot patients repaired with a transannular patch can have abnormal pulmonary function testing with poor exercise capacity in addition to chronotropic incompetence and impaired muscular power. PMID- 30474578 TI - Global spatial assessment of Aedes aegypti and Culex quinquefasciatus: a scenario of Zika virus exposure. AB - Zika virus (ZIKV) is an arbovirus transmitted mainly by Aedes aegypti mosquitoes. Recent scientific evidence on Culex quinquefasciatus has suggested its potential as a vector for ZIKV, which may change the current risk zones. We aimed to quantify the world population potentially exposed to ZIKV in a spatially explicit way, considering the primary vector (A. aegypti) and the potential vector (C. quinquefasciatus). Our model combined species distribution modelling of mosquito species with spatially explicit human population data to estimate ZIKV exposure risk. We estimated the potential global distribution of C. quinquefasciatus and estimated its potential interaction zones with A. aegypti. Then we evaluated the risk zones for ZIKV considering both vectors. Finally, we quantified and compared the people under risk associated with each vector by risk level, country and continent. We found that C. quinquefasciatus had a more temperate distribution until 42 degrees in both hemispheres, while the risk involving A. aegypti is concentrated mainly in tropical latitudes until 35 degrees in both hemispheres. Globally, 4.2 billion people are under risk associated with ZIKV. Around 2.6 billon people are under very high risk associated with C. quinquefasciatus and 1 billion people associated with A. aegypti. Several countries could be exposed to ZIKV, which emphasises the need to clarify the competence of C. quinquefasciatus as a potential vector as soon as possible. The models presented here represent a tool for risk management, public health planning, mosquito control and preventive actions, especially to focus efforts on the most affected areas. PMID- 30474579 TI - Aerobic Fitness Level Moderates the Association Between Cannabis Use and Executive Functioning and Psychomotor Speed Following Abstinence in Adolescents and Young Adults. AB - OBJECTIVES: The high rate of cannabis (CAN) use in emerging adults is concerning given prior research suggesting neurocognitive deficits associated with CAN use in youth. Regular CAN use downregulates endocannabinoid activity, while aerobic exercise upregulates cannabinoid receptor 1 activity and releases endocannabinoids. Here we investigate the influence of regular CAN use on neuropsychological performance, and whether aerobic fitness moderates these effects. METHODS: Seventy-nine young adults (37 CAN users) aged 16-26 participated. Groups were balanced for aerobic fitness level. Exclusion criteria included: left-handedness, past-year independent Axis-I disorders, major medical/neurologic disorders, prenatal issues, or prenatal alcohol/illicit drug exposure. After 3 weeks of abstinence, participants completed a neuropsychological battery and a maximal oxygen consumption test (VO2 max). Multiple regressions tested whether past-year CAN use, VO2 max, and CAN*VO2 max interaction predicted neuropsychological performance, controlling for past-year alcohol use, cotinine, gender, and depression symptoms. RESULTS: Increased CAN use was associated with decreased performance on working memory and psychomotor tasks. High aerobic fitness level was related to better performance on visual memory, verbal fluency, and sequencing ability. CAN*VO2 max predicted performance of psychomotor speed, visual memory, and sequencing ability. CONCLUSIONS: Following monitored abstinence, increased CAN use was associated with poorer performance in working memory and psychomotor speed. Higher aerobic fitness level moderated the impact of CAN on visual memory, executive function and psychomotor speed, as more aerobically fit CAN users demonstrated better performance relative to low-fit users. Therefore, aerobic fitness may present an affordable and efficacious method to improve cognitive functioning in CAN users. (JINS, 2018, 00, 1-12). PMID- 30474580 TI - Making their own money - painted banknotes by Raimundo Camilo, Pearl Blauvelt and other outsider artists. PMID- 30474573 TI - Potential therapy strategy: targeting mitochondrial dysfunction in sepsis. AB - Recently, the definition of sepsis was concluded to be a life-threatening organ dysfunction caused by a dysregulated host response to infection. Severe patients always present with uncorrectable hypotension or hyperlactacidemia, which is defined as septic shock. The new definition emphasizes dysregulation of the host response and multiple organ dysfunction, which is partially attributed to metabolic disorders induced by energy crisis and oxidative stress. Mitochondria are a cellular organelle that are well known as the center of energy production, and mitochondrial damage or dysfunction is commonly induced in septic settings and is a predominant factor leading to a worse prognosis. In the present review, we determine the major mitochondrial disorders from morphology to functions in sepsis. In the following, several clinical or pre-clinical assays for monitoring mitochondrial function are demonstrated according to accumulated evidence, which is the first step of specific therapy targeting to modulate mitochondrial function. Accordingly, various reagents used for regulating mitochondrial enzyme activities and promoting biogenesis have been documented, among which mitochondria-targeted cation, TPP-conjugated antioxidants are the most valuable for future trials and clinical treatment to improve mitochondrial function as they may take advantage of the prognosis associated with septic complications. PMID- 30474581 TI - Auditory and visual hallucination prevalence in Parkinson's disease and dementia with Lewy bodies: a systematic review and meta-analysis. AB - BACKGROUND: Non-motor features of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), such as auditory hallucinations (AH), contribute to disease burden but are not well understood. METHODS: Systematic review and random-effects meta analyses of studies reporting AH associated with PD or DLB. Prevalence of visual hallucinations (VH) in identified studies meeting eligibility criteria were included in meta-analyses, facilitating comparison with AH. Synthesis of qualitative descriptions of AH was performed. PubMed, Web of Science and Scopus databases were searched for primary journal articles, written in English, published from 1970 to 2017. Studies reporting AH prevalence in PD or DLB were screened using PRISMA methods. RESULTS: Searches identified 4542 unique studies for consideration, of which, 26 met inclusion criteria. AH pooled prevalence in PD was estimated to be 8.9% [95% confidence interval (CI) 5.3-14.5], while in DLB was estimated to be 30.8% (+/-23.4 to 39.3). Verbal hallucinations, perceived as originating outside the head, were the most common form of AH. Non-verbal AH were also common while musical AH were rare. VH were more prevalent, with an estimated pooled prevalence in PD of 28.2% (+/-19.1 to 39.5), while in DLB they were estimated to be 61.8% (+/-49.1 to 73.0). Meta-regression determined that the use of validated methodologies to identify hallucinations produced higher prevalence estimates. CONCLUSIONS: AH and VH present in a substantial proportion of PD and DLB cases, with VH reported more frequently in both conditions. Both AH and VH are more prevalent in DLB than PD. There is a need for standardised use of validated methods to detect and monitor hallucinations. PMID- 30474582 TI - Renaming schizophrenia: benefits, challenges and barriers. PMID- 30474583 TI - From the Editors. AB - From org charts to staffing models, community-care outreach programs to surgical unit redesigns and a host of other initiatives, health system leaders and healthcare providers are deeply immersed in formulating plans and setting them in motion. In this issue of Healthcare Quarterly, planning and implementation are firmly in the driver's seat. PMID- 30474584 TI - Integrating Population-Wide Laboratory Testing Data with Audit and Feedback Reports for Ontario Physicians. AB - Audit and feedback reports, distributed by Health Quality Ontario to consenting primary care physicians, provide doctors with a confidential summary of how they manage patients with diabetes; these reports currently lack clinical information. We examined the feasibility of linking the Ontario Laboratories Information System (OLIS), a large provincial database of laboratory test results, with the existing provincial audit and feedback reporting structure to integrate measures of glycemic and cholesterol control among patients with diabetes. We found that we could ascertain glycated hemoglobin (69.9%) and low-density lipoprotein cholesterol (64.1%) test results in the previous year for most patients and that there was wide variation among physicians in the proportion of patients who exceeded clinical thresholds for these measures. Our study highlights the potential value of reporting more clinically rich information to physicians to improve diabetes care and management and demonstrates the feasibility of using OLIS data at the population level to enhance ongoing research and quality improvement. PMID- 30474585 TI - How Canada Compares: Engagement of Seniors in Chronic Condition Management in 11 Countries. AB - Patient engagement is a growing movement that emphasizes the collaboration between patients and their healthcare providers. Patient engagement in chronic condition management is important because its success relies on patients preventing and acting on symptoms outside of their doctor's office. For many chronic conditions, seniors are often affected more than other age groups. Here we highlight how Canadian seniors are engaged in their management of chronic conditions compared to seniors in 10 peer countries. Although more Canadian seniors reported feeling engaged by their regular doctors than the international average, there is room for improvement. PMID- 30474586 TI - Highlights from the 2018 Ted Freedman Awards. AB - In the year 2000, Ted Freedman, former president and CEO of Toronto Mount Sinai Hospital and a founding member of the Healthcare Quarterly editorial advisory board, was the surprised honoree of an annual award launched by the journal in cooperation with Agilent Technologies. The award recognizes those people who inspire, advocate and enable education in healthcare. The winners are honoured with a self-portrait in bronze by award-winning sculptor Amy Switzer of Barrie, Ontario. Ms. Switzer was recovering from brain surgery when she created the bust. PMID- 30474587 TI - Effective Approaches to Integrating Care: A Three-Part Series. AB - This issue of Healthcare Quarterly introduces a three-part series featuring international perspectives on health service delivery models that improve system integration and ensure seamless services and better coordination. The series, developed by Ontario's Change Foundation, will feature Chris Ham, chief executive of the London-based King's Fund think tank; Geoff Huggins, director for health and social care integration in Scotland; and Helen Bevan, chief transformation officer of England's National Health Service. PMID- 30474588 TI - Patient and Staff Engagement in Health System Improvement: A Qualitative Evaluation of the Experience-Based Co-design Approach in Canada. AB - Surveys and interviews were undertaken in Ontario, Canada, with healthcare staff, patients, caregivers and family members to evaluate the adoption and effectiveness of the experience-based co-design (EBCD) approach. EBCD combines patient and staff experiences to identify opportunities for healthcare improvement. Participants reported that EBCD was an effective form of improving experience. Implementation barriers included time, human resources and funding. Suggestions for increased EBCD utilization included funding, training, promotion of success stories, leadership and greater participant involvement. EBCD can be an effective method of identifying and transforming how healthcare services are delivered to improve the patient, caregiver and family experience. PMID- 30474589 TI - Untapped Potential: Engaging in Meaningful Client and Family Partnerships to Drive High-Quality, Safe Care. AB - Holland Bloorview Kids Rehabilitation Hospital developed an innovative framework that fully integrates 17 family and youth leaders into its accreditation preparation process to drive its quality and safety improvements. The hospital established a formalized committee, the Family Leader Accreditation Group (FLAG), where staff and family leaders (FLs), partnered equally to meet, update and share quality and safety initiatives as part of the accreditation preparedness process. The Quality, Safety and Performance (QSP) team was driven to partner more deeply with clients and families to advance quality and safety. PMID- 30474590 TI - It's About Time: Rapid Implementation of a Hub-and-Spoke Care Delivery Model for Tertiary-Integrated Complex Care Services in a Northern Ontario Community. AB - Children with medical complexity (CMC) in rural and northern communities have more difficulty accessing subspecialty health providers than those in urban centres. This article describes an alignment cascade in which leaders engaged peers and staff to rapidly roll out the implementation of a sustainably designed complex care model, integrated in the Champlain Complex Care Program and delivered in Timmins, Ontario. The Provincial Council for Maternal and Child Health's Complex Care for Kids Ontario (CCKO) strategy supports the implementation and expansion of a hub-and-spoke model of interprofessional complex care for CMC and their families. A nurse practitioner is the primary point of contact for the family and oversees coordination and integration of care; regional CCKO programs are committed to building capacity to provide safe, high-quality care for CMC in communities closer to their homes. PMID- 30474591 TI - Market Segmentation as a Tool to Inform Health and Social Services Policy and Planning: The Case of Autism Spectrum Disorder and Intellectual Disability. AB - In the absence of complete public surveillance data, estimating the prevalence and needs of sub-groups of heterogeneous populations is nonetheless critical to properly inform health and social services planning and policy. We thus introduce market segmentation as an innovative tool for health and social services planners and policy makers. Segmentation is a process whereby broad populations are categorized into sub-groups with common characteristics and needs. Using the example of autism spectrum disorder and/or intellectual disability in Quebec, Canada, we triangulate available data and mathematical problem solving to present a portrait of the varying support needs of this under-served, yet growing, population. PMID- 30474593 TI - Corticosteroid therapy alone for the treatment of C3 glomerulonephritis in association with monoclonal gammopathy?. AB - INTRODUCTION: C3 glomerulonephritis (C3GN) is a form of proliferative glomerulonephritis characterized by dominant glomerular C3 deposition. There is currently no consensus guideline on therapy for this disease. Experience with corticosteroids alone is scant in C3GN. We report the experience of treating patients with C3GN in association with monoclonal gammopathy with corticosteroid at a single center. MATERIALS AND METHODS: Corticosteroid therapy alone was used to treat 6 patients with C3GN who were also found to have monoclonal gammopathy at the time of presentation. RESULTS: Median age of this cohort was 65 years. Median estimated glomerular filtration rate (eGFR) by MDRD equation was 31.6 mL/min/1.73m2 at presentation. After a median duration of follow-up of 23.5 months, all patients showed improvement in proteinuria: median proteinuria reduced from 2.3 to 0.5 g/d. Four of 6 patients showed improvement in kidney function. One patient who had required renal replacement therapy recovered renal function. Median eGFR at follow-up was 38.7 mL/min/1.73m2. DISCUSSION: In patients with C3GN in association with monoclonal gammopathy, corticosteroid therapy alone may be a viable treatment option. Work-up should be done to exclude a hematologic neoplasm and inherited complement abnormalities before proceeding to corticosteroid therapy.?. PMID- 30474592 TI - Prognostic models for identifying risk of poor outcome in people with acute ankle sprains: the SPRAINED development and external validation study. AB - BACKGROUND: Ankle sprains are very common injuries. Although recovery can occur within weeks, around one-third of patients have longer-term problems. OBJECTIVES: To develop and externally validate a prognostic model for identifying people at increased risk of poor outcome after an acute ankle sprain. DESIGN: Development of a prognostic model in a clinical trial cohort data set and external validation in a prospective cohort study. SETTING: Emergency departments (EDs) in the UK. PARTICIPANTS: Adults with an acute ankle sprain (within 7 days of injury). SAMPLE SIZE: There were 584 clinical trial participants in the development data set and 682 recruited for the external validation study. PREDICTORS: Candidate predictor variables were chosen based on availability in the clinical data set, clinical consensus, face validity, a systematic review of the literature, data quality and plausibility of predictiveness of the outcomes. MAIN OUTCOME MEASURES: Models were developed to predict two composite outcomes representing poor outcome. Outcome 1 was the presence of at least one of the following symptoms at 9 months after injury: persistent pain, functional difficulty or lack of confidence. Outcome 2 included the same symptoms as outcome 1, with the addition of recurrence of injury. Rates of poor outcome in the external data set were lower than in the development data set, 7% versus 20% for outcome 1 and 16% versus 24% for outcome 2. ANALYSIS: Multiple imputation was used to handle missing data. Logistic regression models, together with multivariable fractional polynomials, were used to select variables and identify transformations of continuous predictors that best predicted the outcome based on a nominal alpha of 0.157, chosen to minimise overfitting. Predictive accuracy was evaluated by assessing model discrimination (c-statistic) and calibration (flexible calibration plot). RESULTS: (1) Performance of the prognostic models in development data set - the combined c-statistic for the outcome 1 model across the 50 imputed data sets was 0.74 [95% confidence interval (CI) 0.70 to 0.79], with good model calibration across the imputed data sets. The combined c-statistic for the outcome 2 model across the 50 imputed data sets was 0.70 (95% CI 0.65 to 0.74), with good model calibration across the imputed data sets. Updating these models, which used baseline data collected at the ED, with an additional variable at 4 weeks post injury (pain when bearing weight on the ankle) improved the discriminatory ability (c-statistic 0.77, 95% CI 0.73 to 0.82, for outcome 1 and 0.75, 95% CI 0.71 to 0.80, for outcome 2) and calibration of both models. (2) Performance of the models in the external data set - the combined c-statistic for the outcome 1 model across the 50 imputed data sets was 0.73 (95% CI 0.66 to 0.79), with a calibration plot intercept of -0.91 (95% CI -0.98 to 0.44) and slope of 1.13 (95% CI 0.76 to 1.50). The combined c-statistic for the outcome 2 model across the 50 imputed data sets was 0.63 (95% CI 0.58 to 0.69), with a calibration plot intercept of -0.25 (95% CI -0.27 to 0.11) and slope of 1.03 (95% CI 0.65 to 1.42). The updated models with the additional pain variable at 4 weeks had improved discriminatory ability over the baseline models but not better calibration. CONCLUSIONS: The SPRAINED (Synthesising a clinical Prognostic Rule for Ankle Injuries in the Emergency Department) prognostic models performed reasonably well, and showed benefit compared with not using any model; therefore, the models may assist clinical decision-making when managing and advising ankle sprain patients in the ED setting. The models use predictors that are simple to obtain. LIMITATIONS: The data used were from a randomised controlled trial and so were not originally intended to fulfil the aim of developing prognostic models. However, the data set was the best available, including data on the symptoms and clinical events of interest. FUTURE WORK: Further model refinement, including recalibration or identifying additional predictors, may be required. The effect of implementing and using either model in clinical practice, in terms of acceptability and uptake by clinicians and on patient outcomes, should be investigated. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12726986. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 64. See the NIHR Journals Library website for further project information. Funding was also recieved from the NIHR Collaboration for Leadership in Applied Health Research, Care Oxford at Oxford Health NHS Foundation Trust, NIHR Biomedical Research Centre, Oxford, and the NIHR Fellowship programme. PMID- 30474594 TI - Risk factors for graft loss in kidney transplant recipients with g3 glomerulitis: A single-center experience?. AB - BACKGROUND: Risk factors for graft loss in kidney transplant recipients with g3 lesions are poorly defined. MATERIALS AND METHODS: We evaluated outcomes in 37 consecutive kidney transplant biopsies diagnosed with g3 glomerulitis based on Banff 2013 criteria in a single-center observational study. RESULTS: The diagnosis of g3 glomerulonephritis was made 6.1 +/- 6.6 years after transplant. The majority of patients were Caucasian (86%), male (65%), and received basiliximab induction (54%). At the time of biopsy, all were on triple therapy with tacrolimus, mycophenolate, and prednisone. Mean serum creatinine (Scr) was 2.85 +/- 2.1 mg/dL. Notably, 20 (54%) were positive for donor-specific antibodies (DSA+) and 8 (22%) were C4d+, while 24 (65%) had transplant glomerulopathy (TG). Treatment included pulse steroids/intravenous immunoglobulin (IVIG) (73%) and rituximab (51%). Patients were followed for up to 4 years after the biopsy. Eleven grafts (30%) were lost during the follow-up. Cox regression analyses determined Scr (HR = 1.63, 95% CI 1.19 - 2.24, p = 0.002), live donor status (HR = 0.18, 95% CI 0.04 - 0.90, p = 0.03), t-score (HR = 2.75, 95% CI 1.30 - 5.81, p = 0.008), and ct-score (HR = 2.19, 95% CI 1 - 4.75, p = 0.04) as significant predictors of graft loss. CONCLUSION: Severe glomerulitis was associated with a high prevalence of TG and graft loss at 4 years. Live donor status, kidney function (Scr), and tubular injury (t- and ct-scores) were independently associated with graft loss. Interventional mechanistic clinical trials are needed to better understand the pathogenesis and outcomes of g3 glomerulitis.?. PMID- 30474595 TI - A case of membranous nephropathy characterized by atypical distribution of phospholipase A2 receptor?. AB - A 77-year-old man was referred to our hospital with persistent proteinuria and progressive lower leg edema. Past history was unremarkable except for hypertension. Autoimmune diseases, infections, and malignancies were excluded based on clinical and laboratory test results. Renal biopsy specimens showed membranous nephropathy with segmental distribution of spikes and bubbling appearance. Double contour formation in glomerular tufts was also observed. There were no proliferative changes in the glomeruli. Interstitial fibrosis and tubular atrophy were moderate, and no interstitial inflammation was observed. Arteries showed moderate sclerotic changes with hyalinosis. Immunohistochemical analysis revealed no thrombospondin type 1 domain-containing 7A reactivity. Immunofluorescence staining showed segmental granular positivity of IgG on glomerular tufts and focal staining of IgG on the tubular basement membranes. IgG deposits (subclass distribution: IgG1, 2+; IgG2, -; IgG3, 1+; IgG4, 2+) and phospholipase A2 receptor type 1 (PLA2R1) immunoreactivity showed similar distributions in both glomeruli and renal tubular basement membranes. Electron microscopy revealed subendothelial edema in partially collapsed glomerulus. No subepithelial dense deposits were observed in the glomeruli under an electron microscope. This is the first documented case of membranous nephropathy (MN) with segmental distribution of PLA2R1 in the glomeruli and focal PLA2R1 positivity in renal tubular basement membranes. Our findings extend the pathological presentation of PLA2R1-associated MN. Future studies are required to examine the mechanistic insights of these atypical histopathological features.?. PMID- 30474596 TI - Identification of new alpha-galactosidase A mutation responsible for Fabry disease: A case report. PMID- 30474597 TI - Redescription of the Siamese shield leech Placobdelloides siamensis with new host species and geographic range. AB - The Siamese shield leech Placobdelloides siamensis (Oka, 1917) Sawyer, 1986 (Euhirudinea: Glossiphoniidae) was collected from five new host species, Southeastern Asian Box Turtle (Cuora amboinensis), Yellow-headed Temple Turtle (Heosemys annandalii), Malayan Snail-eating Turtle (Malayemys macrocephala), Mekong Snail-eating Turtle (M. subtrijuga), and Khorat Snail-eating Turtle (M. khoratensis) and was found for the first time in Udon Thani, Thailand. Examination of live leeches provided, for the first time, data on coloration and the combination of parental care behavior, both carrying cocoons and attaching cocoons to the substrate. This species was separated from its congeners based on the following characters: one pair of eyes; spines at proboscis subterminal; mouth terminal on oral sucker; absent plaque in neck region; gonopores located in furrow and separated by two annuli; distinctly triannulated mid-body segments; crop with seven pairs and branched caeca; caudal sucker slightly over half of maximum body width; and strongly dorsal papillae. Phylogenetic relationships based on the COI and ND1 genes were clarified and demonstrated that the species is distinct from others. The original description was amended and the taxonomic history is discussed. PMID- 30474598 TI - Echinococcus granulosus sensu stricto: silencing of thioredoxin peroxidase impairs the differentiation of protoscoleces into metacestodes. AB - Cystic echinococcosis (CE) is a cosmopolitan parasitic disease caused by infection with the larval stage of Echinococcus granulosus sensu lato. Thioredoxin peroxidase (TPx) may play an essential role in the antioxidant defence system of E. granulosus s.l. as neither catalase nor glutathione peroxidase activities have been detected in the parasite. However, it is not known whether TPx affects the survival and growth of E. granulosus s.l. during development. In this study, three fragments of siRNA specific for EgTPx (siRNA 1/2/3) were designed and transfected into protoscoleces of E. granulosus sensu stricto by electroporation. Quantitative real-time PCR and Western blotting analysis showed that siRNA-3 significantly reduced the expression of EgTPx. Coincidentally, knockdown of EgTPx expression in protoscoleces with siRNA-3 significantly reduced the viability of the parasite under oxidative stress induced by 0.6 mM H2O2. In vitro culture studies showed that protoscoleces treated with siRNA-3 reduced pre-microcyst formation. In vivo experiments showed that injecting mice intraperitoneally with protoscoleces treated with siRNA-3 resulted in a significant reduction in the number, size and weight of CE cysts compared with those of control animals. Silencing of EgTPx led to the impairment of growth of E. granulosus s.s. both in vitro and in vivo, indicating that EgTPx is an important factor for protoscoleces survival and plays an important role in the antioxidant defence against the host during development. PMID- 30474599 TI - A new species of Peniculus (Copepoda: Siphonostomatoida) parasitizing mesopelagic myctophid fish: first discovery of colonization of the genus in deep water. AB - Peniculus hokutoae n. sp. is described on the basis of an ovigerous adult female parasitizing the caudal fin of the myctophid fish Symbolophorus evermanni (Gilbert, 1905), collected from Suruga Bay, Japan. This is the first record of parasitism by this genus on mesopelagic myctophid fish. The new species is easily distinguished from other congeners in: (1) the presence of a conical process anterior to the rostrum; (2) the secondary elongation of the first pedigerous somite; (3) the incorporation of the third and fourth pedigerous somites into the trunk; (4) the unilobate maxillule bearing two unequal apical setae; (5) the lack of any processes on the first segment of the maxilla. Four morphological patterns of the cephalothorax, neck and anterior parts of the trunk can be found in the genus. We infer that initial colonization of a mesopelagic myctophid fish as host is likely to have occurred when the diurnally-migrating myctophid host was feeding in near-surface waters at night and was exposed to infective stages of Peniculus. PMID- 30474600 TI - Molecular characterization of Trypanosoma cruzi samples derived from Triatoma vitticeps and Panstrongylus geniculatus of the Atlantic rainforest, southeast Brazil. AB - BACKGROUND: In rural areas of Espirito Santo state, southeast Brazil, triatomine species attracted by light frequently invade residences. The aim of this study was to investigate the Trypanosoma cruzi discrete typing units (DTUs) harbored by these triatomines. METHODS: Triatomine's intestinal contents were examined, inoculated in mice, and the positive samples were cultivated. Flagellates obtained from infected mice hemoculture were submitted to DNA extraction using a salting-out method and to TcSC5D gene amplification. The amplified samples were sequenced, and polymorphism was analyzed for DTU identification. RESULTS: Three hundred and ninety-four triatomines were identified: Triatoma vitticeps (90.03%), Panstrongylus geniculatus (8.89%), Panstrongylus megistus (0.54%), Panstrongylus diasi (0.27%), and Triatoma tibiamaculata (0.27%). Among the specimens, 251/394 (67.65%) presented flagellated forms similar to T. cruzi. After triatomine intestinal content inoculation into mice, 134 mice presented T. cruzi-like trypomastigotes from Tr. vitticeps and P. geniculatus and 89 samples were positive in hemoculture. Sixty-two samples were analyzed for the TcSC5D gene and TcI, TcII, TcIII, and TcIV DTUs were identified. CONCLUSIONS: We observed T. cruzi DTU diversity in Tr. vitticeps and P. geniculatus, which showed the predominance of TcII and occurrence of TcI, TcIII and TcIV. Triatomines presented high T. cruzi infection rates. Since little is known regarding the possible mammalian hosts that maintain the T. cruzi cycle, further studies are necessary to obtain a better understanding of the parasite transmission cycle in this region. PMID- 30474601 TI - Molecular characterization and protective efficacy of the microneme 2 protein from Eimeria tenella. AB - Microneme proteins play an important role in the adherence of apicomplexan parasites to host cells during the invasion process. In this study, the microneme 2 protein from the protozoan parasite Eimeria tenella (EtMIC2) was cloned, characterized, and its protective efficacy as a DNA vaccine investigated. The EtMIC2 gene, which codes for a 35.07 kDa protein in E. tenella sporulated oocysts, was cloned and recombinant EtMIC2 protein (rEtMIC2) was produced in an Escherichia coli expression system. Immunostaining with an anti-rEtMIC2 antibody showed that the EtMIC2 protein mainly localized in the anterior region and membrane of sporozoites, in the cytoplasm of first- and second-generation merozoites, and was strongly expressed during first-stage schizogony. In addition, incubation with specific antibodies against EtMIC2 was found to efficiently reduce the ability of E. tenella sporozoites to invade host cells. Furthermore, animal-challenge experiments demonstrated that immunization with pcDNA3.1(+)-EtMIC2 significantly increased average body weight gain, while decreasing the mean lesion score and oocyst output in chickens. Taken together, these results suggest that EtMIC2 plays an important role in parasite cell invasion and may be a viable candidate for the development of new vaccines against E. tenella infection in chickens. PMID- 30474602 TI - Will deep brain stimulation increase the incidence of induced psychosis? Post operation follow-ups for 1 hundred patients from 2004-2017. AB - Generally regarding as a safe treatment for Parkinson's disease (PD) for the past 20 years, deep brain stimulation (DBS) is also an example of precision medicine where surgeons need to titrate individual patient's stimulating electrodes one by one down to the scale of micrometer for the maximum therapeutic effect. In order to prevent operation induced psychiatric complications and minimize any other potential side effects, we have followed 103 patients received this treatment provided by a single surgeon in the same medical institution from 2004 to 2017. We identified each patient complaint from nursing care records and complication data from medical charts during the perioperative hospitalization period to see if any of them correlate statistical significantly with the DBS lead placement procedure. Top five frequent complaints including fever, constipation, nausea, headache, wound pain. The majority of post-operative complaints turned out to be the same as general post-operative / post-anesthesia side effects rather than the DBS operation itself. However, a few rare but critical complications such as post operative intracranial hemorrhage (ICH), postoperative epidural hematoma (EDH) were identified as well. These patients' subsequent treatments and prognosis were documented for revising the operating procedure in the future. Our retrospective study reconfirmed that DBS is indeed a relatively safe procedure and improve the life quality of PD patients in general. Hopefully, the through preoperative preparation and careful surgical approach will safeguard the patient's prognosis. PMID- 30474604 TI - The effectiveness of stress-management-based cognitive-behavioral treatments on anxiety sensitivity, positive and negative affect and hope. AB - BACKGROUND AND OBJECTIVE: Anxiety sensitivity, positive and negative affection and hope are the important factors in promoting mental health of students. The purpose of this study was to investigate the effectiveness of stress-management based cognitive-behavioral treatments on anxiety sensitivity, hope, positive and negative affect in female students of Medical Sciences. MATERIALS AND METHODS: This research was a trail study with pre-test, post-test and control group. A sample of 30 subjects, were selected by available sampling and were randomly assigned using Block Randomization Method of two groups (experimental and control groups). Schneider's hope questionnaire, Watson's positive and negative affect questionnaire, Clarke and Tolgman's questionnaire, Reiss et al.'s anxiety sensitivity of the revised index questionnaire, were completed in two stages (pre test and post-test) by all subjects. A 6-session protocol of cognitive-behavioral group treatment was performed only on the experimental group. The data were analyzed using ANOVA and MANOVA analysis of variance. RESULTS: Two experimental and control groups with the mean 22, standard deviationl. 13, average age is 22 years. Stress-management-based cognitive-behavioral treatments were effective on the level of anxiety sensitivity and hope (p <0.016), however, it had no significant positive effect on the amount of positive and negative affect (p <0.016). CONCLUSION: According to the results, it can be concluded that cognitive behavioral treatments are effective on anxiety sensitivity and hope. Therefore, stress-management-based cognitive-behavioral training can reduce students' anxiety sensitivity and increase their hopes for coping with challenges. PMID- 30474603 TI - Comparison of two methods of laparoscopic trocar insertion (Hasson and Visiport) in terms of speed and complication in urologic surgery. AB - BACKGROUND: Nowadays, diverse approaches have been existed for laparoscopic procedures. The most common laparoscopic entry methods included close and direct entry laparoscopy and open (Hasson) laparoscopy. There is no evidence regarding the superiority in safety and initial speed for the use of open and optical laparoscopic entry. Therefore, the sight of current study was to evaluate comparative survey of two methods of laparoscopic trocar insertion (Hasson and VisiportTM) in terms of speed and complications in urologic surgery. METHODS: This expertized base clinical trial study was conducted on 100 patients who underwent urological laparoscopy in Alzahra Hospital, Isfahan, Iran. These patients were randomly divided to two groups (n = 50). One group underwent open laparoscopy and another group Visiport optical trocar. Speed and Complications of urologic surgery was extracted from medical records. Independent T test was used for doing of analysis. RESULTS: The mean age of patients in Hasson and Visiport laparoscopic group was 41.4 +/- 11.2 and 41.6 +/- 15 years old, respectively (p = 0.91). The mean time for initial trocar placement in patients who underwent Visiport trocar system and Hasson laparoscopic technique was 37.7 +/- 15.59 and 95.4 +/- 31.75 seconds. There was gratifying difference between two techniques of laparoscopic trocar insertion (Hasson and Visiport) in terms of speed (p = 0.000). In addition, complications were observed in 8% of patients who underwent Visiport trocar system. However, no complications were observed in Hasson laparoscopy group. CONCLUSION: Visiport optical trocar technique is faster for initial trocar placement than open laparoscopy. However it is associated with complications compared to open laparoscopy. Therefore, there is evidence of benefit in terms of speed for initial trocar placement and harm based on complications in Visiport trocar system. PMID- 30474605 TI - Study of the effect of the essential oil (extract) of rhubarb stem (shoot) on glycosylated hemoglobin and fasting blood glucose levels in patients with type II diabetes. AB - BACKGROUND: Diabetes is a serious chronic disease that can damage the heart, arteries, eyes, kidneys and nerves, leading to death and early disability. Before the discovery of insulin as well as common anti-diabetes drugs, patients with diabetes were treated with medicinal herbs and traditional treatments. One of these effective medicinal herbs is Rhubarb. Rhubarb is prescribed in traditional medicine for various patients, including patients with diabetes. But its effect has not been scientifically reported so far. PURPOSE: This study was conducted with the aim to determine the effectiveness of Rhubarb stem extract on HbA1C and fasting blood glucose in patients with type II diabetes. METHOD: In this experimental study, 80 patients with type II diabetes mellitus in Zabol diabetes center, aged 30-60 years old with fasting blood glucose greater than 140 mg/d/ were selected. Patients were randomly assigned into two groups (n = 40) of treatment with capsules of Rhubarb stem and placebo after matching the oral medications. The patients in both groups were studied for fasting blood glucose and HbA1C before and after 1 month of conducting the study. RESULTS: The mean FBS and HbA1C in rhubarb group before the intervention were 288.80 +/- 94.49 and 9.62 +/- 1.58, respectively, and after the intervention were 226.42 +/- 88.89 and 7.83 +/- 1.50, respectively. According to the statistical paired f-test and Wilcoxon test a significant reduction was found in FBS and HbA1C with rhubarb intervention (p < 0.05). CONCLUSION: In diabetes mellitus, as many factors affect the level of blood glucose, they also contribute to reducing blood glucose level and preventing complications. Therefore, considering the positive effects of rhubarb, it can be recommended to use rhubarb extract as an additional treatment to reduce blood glucose level. PMID- 30474606 TI - Weight loss might be an early clinical manifestation of undiagnosed cancer: a nation-based cohort study. AB - BACKGROUND/AIM: No published nation-based study has examined the relationship between weight loss and cancer in Taiwan. The aim of this study was to investigate whether weight loss is an early clinical manifestation of cancer in Taiwan. METHODS: We conducted a nation-based, retrospective cohort study that analyzed the database of the Taiwan National Health Insurance Program. There were 8210 subjects aged 20 to 84 years with newly diagnosed weight loss selected as the weight loss group from 2000 to 2012, and 32826 randomly selected subjects without weight loss as the non-weight loss group. The weight loss and non-weight loss groups were matched along sex, age, and comorbidities. The incidence of cancer at the end of 2013 was examined in both groups. RESULTS: The weight loss group had a significantly higher incidence of cancer than the non-weight loss group during the first 3 months of follow-up (25.1 vs. 8.39 per 1000 person years, with an incidence rate ratio 2.99, 95% CI 2.82, 3.18). The multivariable Cox proportional hazards regression model revealed that the adjusted HR of cancer was 1.05 for the weight loss group (95% CI 1.04, 1.05) as compared with the non weight loss group. CONCLUSION: Weight loss is associated with a small but statistically significant increase in the hazard of cancer. Weight loss might be an early clinical manifestation of undiagnosed cancer. Physicians should keep in mind the possibility of cancer when people present with weight loss and other possible cancer-related symptoms, particularly during the first 3 months of follow-up. PMID- 30474607 TI - The effect of selenium supplementation on cystine crystal volume in patients with cystinuria. AB - BACKGROUND: Cystinuria as an autosomal recessive sickness is a relatively rare disease. Formation of cystine stones indicates cystinuria. Few studies are considered the cysteine crystal volume in management of cystinuria. Selenium may inhibit organization of crystal stone, growth and stone aggregation. Since the role of selenium on inhibition of cystine crystal formation is not known, the aim of this study was to evaluate the effect of selenium supplementation on cystine crystals volume in patients with cystinuria. MATERIALS AND METHODS: This double blind clinical trial study was conducted on 48 patients in Al-Zahra hospital, Isfahan, Iran from 2015 to 2017. These patients received selenium (200 mg/ daily) for 6 weeks. The urine crystal volume was evaluated before and after treatment. Data were entered SPSS and analyzed by Paired sample T test, Spearman and Pearson coefficient correlation. P- value < 0.05 was considered significant. RESULTS: In current study, mean cystine crystal volume before and after treatment was 6787.4 +/- 11902.6 and 3110.9 +/- 7225.4, respectively. Significant difference was observed before and after treatment in terms of cystine crystal volume (p < 0.001). No relation was observed between the mean cystine crystal volume with sex, age and type of medical procedures (p > 0.05). CONCLUSION: In this study, selenium treatment affected cystine crystal volume. It seems that selenium had the potential value to alleviate the volume of cystine crystal. Therefore, since reducing of cystine crystal volume decreases crystal formation, selenium may be effective to cure patients with cystinuria. However, age, sex and type of medical procedures did not affect cysteine crystal volume. PMID- 30474608 TI - A rare case of extensive cervico-thoracic ossification of the posterior longitudinal ligament causing myelopathy. AB - Ossification of the posterior longitudinal ligament (OPLL) most commonly occurs in the cervical spine, usually involving two to three segments; however, the disease has the potential to occur anywhere in the spine. We encountered a fifty one year old male with progressive unsteadiness and bilateral lower limb weakness for a period of six months which eventually became worse resulting in inability to walk without assistance. Neurological examination revealed normal upper limb function; however, the lower limbs demonstrated motor dysfunction. Signs of myelopathy were elicited and the patient was subjected to detailed radiological evaluation. CT and MRI scans revealed an extensive cervico-thoracic continuous OPLL from C3 to T3 causing significant cord compression. In view of the deteriorating neurological status, extensive C3-T3 laminectomy with instrumented posterolateral fusion was done and the patient recovered without any immediate or delayed C5 palsy. This case highlights a rare occurrence or extensive OPLL involving eight segments at the cervico-thoracic region. This report also discusses surgical strategies for managing such extensive presentations and our technique to prevent C5 palsy. PMID- 30474609 TI - Ion channels and neuropathic pain. AB - Pain behaviors in a Fabry mouse model are associated with the accumulation of a fat molecule that disrupts sodium ion channels in small fiber neurons. PMID- 30474610 TI - Conducting controlled human infection model studies in India is an ethical obligation. AB - Weighing competing obligations and achieving the "greatest balance" of right over wrong guides an individual, an agency or a country in determining what ought to be done in an ethically challenging situation. Conducting controlled human infection model (CHIM) studies in India is one such situation. The ethical challenge in conducting a CHIM study lies in completing the difficult task of introducing standardised, attenuated strains of micro-organisms into normal healthy volunteers, at the same time ensuring the safety of these healthy individuals from potential and completely informed risks in a fashion that is transparent and accountable. The bar is further raised against the background of already fragile public confidence in biomedical research in India; especially when "deliberate" introduction of microbial agents into healthy individuals is involved, with the larger altruistic objective of gain to society as a whole. This paper discusses the uses of CHIM studies with respect to the larger scientific Indian research enterprise of the 21st century. It further explores etic and emic perspectives in conducting such trials in India and seeks to generate an ethical coherence to the justification for conducting CHIM studies in India. The paper deliberates on ethical issues arising out of conducting CHIM studies and reflects on how developing the capacity for CHIM studies in India is likely to strengthen the health research and development sector in the country. PMID- 30474611 TI - The crisis in Cochrane: Evidence Debased Medicine. AB - The mission of the Cochrane Collaboration, established in 1993, was to systematically review medical evidence with a view to producing the best quality and trustworthy evidence. Twenty-five years later, it is in a crisis that centres on the dismissal one of its founders and the question of access to clinical trial data. The original mission aimed at improving health. In the face of stalling life expectancies, the stakes in the current crisis could not be higher. This essay looks at the crisis in the context of the disastrous effects of medication for paediatric depression on children as a consequence of the suppression of adverse findings from clinical trials. PMID- 30474612 TI - Cooperation in confidential withholding of HIV status from partners of sexually active patients: a role for organisational moral agency. AB - An increasingly blurred understanding of the conditions under which clinicians may withhold HIV seropositive status from partners of patients who are sexually active and who do not intend to disclose suggests a critical need to revisit the relationship between the principle of confidentiality, the moral and legal duties to warn at-risk third parties, and the organisational ethics surrounding licit cooperation with wrongdoing in the effort to uphold professional moral responsibility. This essay grounds its argument in two, straightforward premises: (i) the ethical principle of cooperation is an indispensable measure of the moral licitness of instances of complicity with wrongdoing; (ii) some instances of material organisational complicity vis-a-vis confidential withholdings of HIV seropositive status from partners of sexually active patients both meet and successfully employ the standards of the ethical principle of cooperation. Drawing from this syllogism, the essay argues that, in Type II cases, healthcare organisations may (initially and on certain conditions) materially cooperate in withholding the HIV seropositive status of patients from partners with whom patients are sexually active, and to whom patients do not intend to disclose HIV seropositive status, in the effort to honour professional obligations of privacy, confidentiality, and fidelity in a manner that is both legally licit and morally justifiable. PMID- 30474614 TI - Simultaneous motion monitoring and truth-in-delivery analysis imaging framework for MR-guided radiotherapy. AB - Intrafraction motion (i.e. motion occurring during a treatment session) can play a pivotal role in the success of abdominal and thoracic radiation therapy. Hybrid magnetic resonance-guided radiotherapy (MR-gRT) systems have the potential to control for intrafraction motion. Recently, we introduced an MRI sequence capable of acquiring real-time cine imaging in two orthogonal planes (SOPI). We extend SOPI here to permit dynamic updating of slice positions in one-plane while keeping the other plane position fixed. In this implementation, cine images from the static plane are used for motion monitoring and as image navigators to sort stepped images in the other plane, producing dynamic 4D image volumes for use in dose reconstruction. A custom 3D-printed target, designed to mimic the pancreas and duodenum and filled with radiochromic FXG gel, was interfaced to the dynamic motion phantom. 4D-SOPI was acquired in a dynamic motion phantom driven by an actual patient respiratory waveform displaying amplitude/frequency variations and drifting and in a healthy volunteer. Unique 4D-MRI epochs were reconstructed from a time series of phantom motion. Dose from a static 4 cm * 15 cm field was calculated on each 4D respiratory phase bin and epoch image, scaled by the time spent in each bin, and then rigidly accumulated. The phantom was then positioned on an Elekta MR-Linac and irradiated while moving. Following irradiation, actual dose deposited to the FXG gel was determined by applying a R 1 versus dose calibration curve to R 1 maps of the phantom. The 4D-SOPI cine images produced a respiratory motion navigator that was highly correlated with the actual phantom motion (CC = 0.9981). The mean difference between the accumulated and measured dose inside the target was 4.4% of the maximum prescribed dose. These initial results demonstrate that 4D-SOPI is a promising imaging framework enabling simultaneous real-time motion monitoring and truth-in-delivery analysis for integrated MR-gRT systems. PMID- 30474613 TI - A novel ATP6V0A2 mutation causing recessive cutis laxa with unusual manifestations of bleeding diathesis and defective wound healing. AB - OBJECTIVE: Autosomal recessive cutis laxa type IIA (ARCL2A) is a rare congenital disorder characterized by loose and elastic skin, growth and developmental delay, and skeletal anomalies. It is caused by biallelic mutations in ATP6V0A2. Those mutations lead to increased pH in secretory vesicles and thereby to impaired glycosyltransferase activity and organelle trafficking. We aimed to identify the genetic and molecular cause of the unexpected haematological findings in a Turkish family. MATERIALS AND METHODS: We performed clinical, genetic and histological analyses on a consanguineous family afflicted with wrinkled and loose skin, microcephaly, intellectual disability, cleft lip and palate, downslanting palpebral fissures, ectopia lentis, bleeding diathesis and defective wound healing. RESULTS: Linkage analysis using the SNP genotype data yielded a maximal multipoint LOD score of 2.59 at 12q24.21-24.32. Exome sequence analysis for proband led to the identification of novel homozygous frameshift c.2085_2088del (p.(Ser695Argfs*12)) in ATP6V0A2, within the linked region, in the two affected sibs. CONCLUSION: Our patients do not have gross structural brain defects besides microcephaly, strabismus, myopia, growth or developmental delay. Large platelets were observed in patients and unusual electron-dense intracytoplasmic inclusions in fibroblasts and epidermal basal cells were observed in both affected and unaffected family members. Patients do not have any genetic defect in VWF gene but vWF activity to antigen ratios were low. Clinical findings of bleeding diathesis and defective wound healing have not been reported in ARCL2A and hence our findings expand the phenotypic spectrum of the disease. PMID- 30474615 TI - Penetration depth study of the type-I superconductor PdTe2. AB - Superconductivity in the topological non-trivial Dirac semimetal PdTe2 was recently shown to be type-I. We hereby report measurements of the relative magnetic penetration depth, [Formula: see text], on several single crystals using a high precision tunnel diode oscillator technique. The temperature variation [Formula: see text] follows an exponential function for [Formula: see text], consistent with a fully-gapped superconducting state and weak or moderately coupling superconductivity. By fitting the data we extract a [Formula: see text] value of ~500 nm. The normalized superfluid density is in good agreement with the computed curve for a type-I superconductor with nonlocal electrodynamics. Small steps are observed in [Formula: see text], which possibly relates to a locally lower [Formula: see text] due to defects in the single crystalline sample. PMID- 30474616 TI - On the accuracy and efficiency of condensed history transport in magnetic fields in GEANT4. AB - The purpose of this work was to investigate the accuracy and efficiency of electron transport in GEANT4 with and without a magnetic field present. Fano cavity simulations were performed in GEANT4 version 10.02 and 10.04.p01 using two multiple scattering (MSC) algorithms for two slab and one pseudo-ion chamber geometries. An iterative approach was used to optimize the transport parameters to obtain agreement with theory. Similar to previous works, the step lengths had to be severely restricted to obtain agreement with theory when using the Urban MSC model in GEANT4 v10.02. Using the Goudsmit-Saunderson MSC model with the UseSafetyPlus MSC step limitation in GEANT4 v10.04.p01 limited the maximum discrepancy from theory to 0.5%. Minor adjustments to the transport parameters were needed to obtain agreement within 0.16% of theory for all simulation configurations without a magnetic field present. The maximum deviation from theory was within 2% for all simulation configurations in the presence of a magnetic field except for two setups that exhibited discrepancies of up to 10.8%. This anomalous behavior was mitigated by forcing single scattering within the detector gas volume. Further adjustments to the transport parameters resulted in agreement with theory at the 0.21% level. Agreement with theory in the absence of a magnetic field can be obtained without significantly restricting the step size if the Goudsmit-Saunderson MSC model is used with the UseSafetyPlus MSC step limitation in GEANT4 v10.04.p01. The large discrepancies from theory observed for two simulation setups with a magnetic field present were attributed to an issue with energy loss sampling over a step when strict magnetic field transport parameters are used. This problem can be corrected by forcing single scattering within the detector gas volume; however, more work is needed to identify the cause of this anomalous behavior. This work has shown that GEANT4 can perform accurate electron transport with and without a magnetic field present without applying significant step-size reductions. PMID- 30474617 TI - How pump-probe differential reflectivity at negative delay yields the perturbed free-induction-decay: theory of the experiment and its verification. AB - We present a simple but mathematically complete first-principles theory for the pump-probe differential reflectivity experiment at negative delay (probe preceding the pump) to show how it gives information about the perturbed-free induction-decay of coherent polarization. The calculation, involving the optical Bloch equations to describe the induced polarization and the Ewald-Oseen idea to calculate the reflected signal as a consequence of the free oscillations of perturbed dipoles, also explicitly includes the process of lock-in detection of a double-chopped signal after it has passed through a monochromator. The theory giving a closed form expression for the measured signal in both time and spectal domains is compared with experiments on high quality GaAs quantum well sample. The dephasing time inferred experimentally at 4 K compares remarkably well with the inverse of the absorption linewidth of the continuous-wave photoluminescence excitation spectrum. Spectrally-resolved signal at negative delay calculated from our theoretical expression nicely reproduces the coherent spectral oscillations observed in our experiments, although exact fitting of the experimental spectra with the theoretical expression is difficult on account of multiple resonances. PMID- 30474618 TI - Revisiting the single-energy CT calibration for proton therapy treatment planning: a critical look at the stoichiometric method. AB - Despite extensive research in dual-energy computed tomography (CT), single-energy CT (SECT) is still the standard imaging modality in proton therapy treatment planning and, in this context, the stoichiometric calibration method is considered to be the most accurate to establish a relationship between CT numbers and proton stopping power. This work revisits the SECT calibration for proton therapy treatment planning, with special emphasis on the stoichiometric method. Three different sets of tissue-substitutes of known elemental composition (Gammex, CIRS and Catphan) were scanned with the same scanning protocol. A stoichiometric fit was performed for each set of tissue-substitutes. Based on that, the CT number, relative electron density and relative proton stopping power were calculated for ICRU 46 biological tissues and the different sets of tissue substitutes. Despite common belief, it was found that the stoichiometric fit depends on the elemental composition of the tissue-substitutes used in the calibration, leading to differences in relative stopping power up to 3.5% for cortical bone. In addition, according to Rutherford et al (1976 Neuroradiology 11 15-21) parametrization of the atomic cross-section, CT numbers of Gammex tissue substitutes and ICRU 46 biological tissues were found to be similar within the whole energy range relevant to computed tomography. Consequently, it was found that, for Gammex tissue-substitutes, the CT calibration curve resulting from the stoichiometric method agrees with that obtained by simple interpolation of experimental data. In conclusion, the stoichiometric method for SECT calibration seems to depend on the tissue-substitutes used for calibration-which could be regarded as an additional source of uncertainty in proton range for bone tissues. Furthermore, Gammex tissue-substitutes appear to be a good representative of biological tissues within the energy range relevant to computed tomography-making the stoichiometric method unnecessary. PMID- 30474619 TI - Spin dependence of crossed Andreev reflection and electron tunneling induced by Majorana fermions. AB - We investigate spin dependence of the nonlocal transport induced by Majorana fermions in a one-dimensional ferromagnet-ferromagnetic-insulator-superconductor ferromagnetic-insulator-ferromagnet junction on the edge of a two-dimensional topological insulator. The results show that coupled Majorana fermions lead to the nonlocal transport processes including electron tunneling and crossed Andreev reflection, which can be tuned by adjusting the spin polarizations of the Majorana fermions. By manipulating the bands in the two ferromagnets, the nonlocal transport can be selected as either pure electron tunneling or pure crossed Andreev reflection, the transmission probability of which could be 100%. Furthermore, the pure electron tunneling and the pure crossed Andreev reflection are well controlled by the spin directions of the electron states in the two ferromagnets. PMID- 30474621 TI - Optimization of a table-top x-ray fluorescence computed tomography (XFCT) system. AB - Pencil beam x-ray fluorescence computed tomography (XFCT) has typically used a single spectrometer and prohibitively long scan times. However, detecting backscattered fluorescent x-rays from gold nanoparticles (AuNPs) using multiple spectrometers greatly reduces image noise and scan time. The arrangement of eight spectrometers for combined K-shell and L-shell XFCT was investigated along with a variety of conditions. A 2.5 cm-diameter cylindrical water phantom containing 4 mm-diameter vials with 0.1%-2% AuNP concentrations by weight was modeled by TOPAS, a GEANT4-based Monte Carlo software. The phantom was irradiated to 30 mGy by a 0.5 mm Pb-filtered 120 kVp and 1 mm Al-filtered 30 kVp 1 mm2 x-ray pencil beam to yield respective Au K-shell and L-shell fluorescent x-rays, with 50 0.5 mm translation and 2-degree rotation steps. Eight CdTe and silicon drift detector (SDD) spectrometers were placed 2.25 cm away from the isocentre. The respective energy resolution was applied to the detected energy spectra and the spectra were corrected for detector response before extracting the fluorescence signal. Three CdTe and SDD spectrometer configurations (isotropic/backscattered grid/backscattered row arrangements), two CdTe crystal sizes (9 mm2/25 mm2), two scanning techniques (moving/stationary spectrometers) and five vial-edge depths (0-4 mm) were considered in optimizing the contrast-to-noise ratio (CNR) for each XFCT image reconstructed with a maximum-likelihood expectation maximization (MLEM) algorithm. The isotropic spectrometer arrangement had AuNP detection sensitivities of 0.106% for K-shell and 0.132% for L-shell XFCT at 4 mm depth. Comparatively, the backscattered grid arrangement had the best AuNP sensitivity of 0.055% and 0.095%. The highest K-shell (0.044%) and L-shell (0.004%) AuNP sensitivities were found for vials at 0 mm depth. Using stationary spectrometers or the 9 mm2 CdTe crystal compromised the CNR. For the best-case arrangement, L shell XFCT is superior at vial-edge depths less than 3.0 mm. This work demonstrated the importance of spectrometer arrangement and vial depth for improving AuNP sensitivity and will guide the design for our table-top XFCT system. PMID- 30474620 TI - How to harmonize SUVs obtained by hybrid PET/CT scanners with and without point spread function correction. AB - State of the art point-spread function (PSF) corrections implemented in positron emission tomography/computed tomography (PET/CT) reconstruction improved image quality and diagnostic performance but caused an increase in the standardized uptake value (SUV) compared to a conventional OSEM reconstruction system. The EANM suggested one produce two reconstructions, one optimised for maximum lesion detection and one for semi-quantitative analysis. In this work we investigated an alternative methodology, using a single reconstruction data set together with a post-reconstruction algorithm for SUV harmonization. Data acquisition was performed on a Siemens Biograph mCT system equipped with lutetium oxyorthosilicat crystals, PSF and time-of-flight algorithms and on a General Electric Discovery STE system equipped with BGO crystals. Both a EANM double reconstruction method and a dedicated post-reconstruction algorithm (marketed as EQ-filter) were tested to harmonize the quantitative values of the two PET/CT scanners. For phantom measurements we used a NEMA IQ phantom and a Jaszczak cylindrical phantom equipped with small spheres (lesion to background ratios of 8:1 and 4:1). Several different reconstruction settings were tested in order to provide a general methodology. Data obtained by phantom measurements were validated on seven oncologic patients who performed a one-bed extra acquisition on a different scanner. The evaluation regarded 39 small lesions (diameters: 0.3-2.6 cm) and was performed by two experienced nuclear medicine physicians. The SUV recoveries measured with the PSF reconstruction exceeded those obtained by the OSEM reconstruction with deviations ranging from 16% to 150%. These discrepancies resulted below 7% applying the optimized value of the EQ.filter or the double reconstruction methods. For each reconstruction setting the optimal value of the EQ.filter was identified in order to minimize these discrepancies. Patient data, analyzed by Wilcoxon statistical test, confirmed and validated phantom measurements. EQ.filter can harmonize SUV values between different PET/CT scanners using a single reconstruction optimized to maximum lesion detectability. In this way, the second reconstruction proposed by EANM/EARL is avoided. PMID- 30474622 TI - The Adenosine Monophosphate (AMP) Analog, 5-Aminoimidazole-4-Carboxamide Ribonucleotide (AICAR) Inhibits Hepatosteatosis and Liver Tumorigenesis in a High Fat Diet Murine Model Treated with Diethylnitrosamine (DEN). AB - BACKGROUND The development and progression of hepatocellular carcinoma (HCC) are associated with obesity and hepatosteatosis. AMP-activated protein kinase (AMPK) regulates metabolic homeostasis. This study aimed to investigate the effects of treatment with the adenosine monophosphate (AMP) analog, 5-aminoimidazole-4 carboxamide ribonucleotide (AICAR) on hepatosteatosis in a mouse model fed a high fat diet (HFD), and on hepatocellular carcinoma (HCC) induced by diethylnitrosamine (DEN) in the HFD mouse model. MATERIAL AND METHODS Male C57BL/6 male mice from two weeks of age were fed a high-fat diet, resulting in hepatosteatosis. HFD mice (15-20 per group) were treated with AICAR and without AICAR. HFD mice were treated with DEN, with and without AICAR. Mouse liver tissues were examined histologically using lipid histochemical stains, immunohistochemistry, and immunofluorescence. Levels of cytokines, alanine transaminase (ALT), triacylglyceride (TAG), and apoptosis were determined. Western blot was used to detect AMPK, pAMPK, STAT3, and pSTAT3. Real-time polymerase chain reaction (RT-PCR) detected expression of the ACL, FAS, CD36, ATGL, CPT1, and IL6 genes. RESULTS In the HFD mouse model, AICAR treatment inhibited hepatic lipid synthesis and IL-6 expression. In the DEN-treated mice, AICAR treatment reduced tumorigenesis, IL-6 signaling, and STAT3 activation. Short-term AICAR treatment had no significant effect in advanced HCC. CONCLUSIONS In an HFD mouse model, treatment with AICAR reduced the development of hepatosteatosis, and following treatment with the liver carcinogen, DEN, AICAR reduced the development of HCC. These preliminary findings support further studies on the role of AICAR in fatty liver disease and HCC. PMID- 30474623 TI - Severe Burn Injury in a Swine Model for Clinical Dressing Assessment. AB - Wound healing is a dynamic repair process and is the most complex biological process in human life. In response to burn injury, alterations in biological pathways impair the inflammation response, resulting in delayed wound healing. Impaired wound healing frequently occurs in patients with diabetes leading to unfavorable outcomes such as amputation. Hence, dressings having beneficial effect in promoting burn wound repair are needed. However, studies on burn wound treatment are limited due to lack of proper animal models. Our previous study demonstrated wound-healing performance in rat and swine models using a minimally invasive surgical technique. This study aimed to demonstrate a swine model of severe burn injury that eliminates wound contraction and more closely approximates the human processes of re-epithelialization and new tissue formation. This protocol provides a detailed procedure for creating consistent burn wounds and examining the wound-healing performance under the treatment of an experimental dressing in a swine model. Six burn wounds were created symmetrically on the dorsum, which were covered with a clinical dressing composed of four layers: an inner contact layer of experimental materials, an inner intermediate layer of waterproof film, an outer intermediate layer of gauze, and an outer layer of adhesive plaster. Upon the completion of experiments, wound closure, wound area, and Vancouver Scar Scale score were examined. The samples of skin resected from each animal post-sacrifice were histologically prepared and stained using hematoxylin and eosin staining. Antibacterial activity of each dressing in the context of wound healing was also examined. The application of the clinical dressing to the wounds in swine model mimics the biological processes of human wound healing with respect to the processes of epithelialization, cellular proliferation, and angiogenesis. Therefore, this swine model provides an easy-to-learn, cost-effective, and robust method to assess the effect of clinical dressings in severe burn injury. PMID- 30474624 TI - A High-throughput Platform for the Screening of Salmonella spp./Shigella spp. AB - Fecal-oral transmission of acute gastroenteritis occurs from time to time, especially when people who handled food and water are infected by Salmonella spp./Shigella spp. The gold standard method for the detection of Salmonella spp./Shigella spp. is direct culture but this is labor-intensive and time consuming. Here, we describe a high-throughput platform for Salmonella spp./Shigella spp. screening, using real-time polymerase chain reaction (PCR) combined with guided culture. There are two major stages: real-time PCR and the guided culture. For the first stage (real-time PCR), we explain each step of the method: sample collection, pre-enrichment, DNA extraction and real-time PCR. If the real-time PCR result is positive, then the second stage (guided culture) is performed: selective culture, biochemical identification and serological characterization. We also illustrate representative results generated from it. The protocol described here would be a valuable platform for the rapid, specific, sensitive and high-throughput screening of Salmonella spp./Shigella spp. PMID- 30474625 TI - Employing Pressurized Hot Water Extraction (PHWE) to Explore Natural Products Chemistry in the Undergraduate Laboratory. AB - A recently developed pressurized hot water extraction (PHWE) method which utilizes an unmodified household espresso machine to facilitate natural products research has also found applications as an effective teaching tool. Specifically, this technique has been used to introduce second- and third-year undergraduates to aspects of natural products chemistry in the laboratory. In this report, two experiments are presented: the PHWE of eugenol and acetyleugenol from cloves and the PHWE of seselin and (+)-epoxysuberosin from the endemic Australian plant species Correa reflexa. By employing PHWE in these experiments, the crude clove extract, enriched in eugenol and acetyleugenol, was obtained in 4-9% w/w from cloves by second-year undergraduates and seselin and (+)-epoxysuberosin were isolated in yields of up to 1.1% w/w and 0.9% w/w from C. reflexa by third-year students. The former exercise was developed as a replacement for the traditional steam distillation experiment providing an introduction to extraction and separation techniques, while the latter activity featured guided-inquiry teaching methods in an effort to simulate natural products bioprospecting. This primarily derives from the rapid nature of this PHWE technique relative to traditional extraction methods that are often incompatible with the time constraints associated with undergraduate laboratory experiments. This rapid and practical PHWE method can be used to efficiently isolate various classes of organic molecules from a range of plant species. The complementary nature of this technique relative to more traditional methods has also been demonstrated previously. PMID- 30474626 TI - Isolation of Extracellular Vesicles from Murine Bronchoalveolar Lavage Fluid Using an Ultrafiltration Centrifugation Technique. AB - Extracellular vesicles (EVs) are newly discovered subcellular components that play important roles in many biological signaling functions during physiological and pathological states. The isolation of EVs continues to be a major challenge in this field, due to limitations intrinsic to each technique. The differential ultracentrifugation with density gradient centrifugation method is a commonly used approach and is considered to be the gold standard procedure for EV isolation. However, this procedure is time-consuming, labor-intensive, and generally results in low scalability, which may not be suitable for small-volume samples such as bronchoalveolar lavage fluid. We demonstrate that an ultrafiltration centrifugation isolation method is simple and time- and labor efficient yet provides a high recovery yield and purity. We propose that this isolation method could be an alternative approach that is suitable for EV isolation, particularly for small-volume biological specimens. PMID- 30474627 TI - Design and Fabrication of an Optical Fiber Made of Water. AB - In this report, an optical fiber of which the core is made solely of water, while the cladding is air, is designed and manufactured. In contrast with solid cladding devices, capillary oscillations are not restricted, allowing the fiber walls to move and vibrate. The fiber is constructed by a high direct current (DC) voltage of several thousand volts (kV) between two water reservoirs that creates a floating water thread, known as a water bridge. Through the choice of micropipettes, it is possible to control the maximal diameter and length of the fiber. Optical fiber couplers, at both sides of the bridge, activate it as an optical waveguide, allowing researchers to monitor the water fiber capillary body waves through transmission modulation and, therefore, deducing changes in surface tension. Co-confining two important wave types, capillary and electromagnetic, opens a new path of research in the interactions between light and liquid-wall devices. Water-walled microdevices are a million times softer than their solid counterparts, accordingly improving the response to minute forces. PMID- 30474628 TI - Photobleaching Enables Super-resolution Imaging of the FtsZ Ring in the Cyanobacterium Prochlorococcus. AB - Super-resolution microscopy has been widely used to study protein interactions and subcellular structures in many organisms. In photosynthetic organisms, however, the lateral resolution of super-resolution imaging is only ~100 nm. The low resolution is mainly due to the high autofluorescence background of photosynthetic cells caused by high-intensity lasers that are required for super resolution imaging, such as stochastic optical reconstruction microscopy (STORM). Here, we describe a photobleaching-assisted STORM method which was developed recently for imaging the marine picocyanobacterium Prochlorococcus. After photobleaching, the autofluorescence of Prochlorococcus is effectively reduced so that STORM can be performed with a lateral resolution of ~10 nm. Using this method, we acquire the in vivo three-dimensional (3-D) organization of the FtsZ protein and characterize four different FtsZ ring morphologies during the cell cycle of Prochlorococcus. The method we describe here might be adopted for the super-resolution imaging of other photosynthetic organisms. PMID- 30474629 TI - A Micro-CT-based Method for Characterizing Lesions and Locating Electrodes in Small Animal Brains. AB - Lesion and electrode location verification are traditionally done via histological examination of stained brain slices, a time-consuming procedure that requires manual estimation. Here, we describe a simple, straightforward method for quantifying lesions and locating electrodes in the brain that is less laborious and yields more detailed results. Whole brains are stained with osmium tetroxide, embedded in resin, and imaged with a micro-CT scanner. The scans result in 3D digital volumes of the brains with resolutions and virtual section thicknesses dependent on the sample size (12-15 and 5-6 um per voxel for rat and zebra finch brains, respectively). Surface and deep lesions can be characterized, and single tetrodes, tetrode arrays, electrolytic lesions, and silicon probes can also be localized. Free and proprietary software allows experimenters to examine the sample volume from any plane and segment the volume manually or automatically. Because this method generates whole brain volume, lesions and electrodes can be quantified to a much higher degree than in current methods, which will help standardize comparisons within and across studies. PMID- 30474630 TI - Detection of Low Copy Number Integrated Viral DNA Formed by In Vitro Hepatitis B Infection. AB - Hepatitis B Virus (HBV) is a common blood-borne pathogen causing liver cancer and liver cirrhosis resulting from chronic infection. The virus generally replicates through an episomal DNA intermediate; however, integration of HBV DNA fragments into the host genome has been observed, even though this form is not necessary for viral replication. The exact purpose, timing, and mechanism(s) by which HBV DNA integration occurs is not yet clear, but recent data show that it occurs very early after infection. Here, the in vitro generation and detection of HBV DNA integrations are described in detail. Our protocol specifically amplifies single copies of virus-cell DNA integrations and allows both absolute quantification and single-base pair resolution of the junction sequence. This technique has been applied to various HBV-susceptible cell types (including primary human hepatocytes), to various HBV mutants, and in conjunction with various drug exposures. We foresee this technique becoming a key assay to determine the underlying molecular mechanisms of this clinically relevant phenomenon. PMID- 30474631 TI - Detection of Tilapia Lake Virus Using Conventional RT-PCR and SYBR Green RT-qPCR. AB - The aim of this method is to facilitate the fast, sensitive and specific detection of Tilapia Lake Virus (TiLV) in tilapia tissues. This protocol can be used as part of surveillance programs, biosecurity measures and in TiLV basic research laboratories. The gold standard of virus diagnostics typically involves virus isolation followed by complementary techniques such as reverse transcription polymerase chain reaction (RT-PCR) for further verification. This can be cumbersome, time-consuming and typically requires tissue samples heavily infected with virus. The use of RT-quantitative (q)PCR in the detection of viruses is advantageous because of its quantitative nature, high sensitivity, specificity, scalability and its rapid time to result. Here, the entire method of PCR based approaches for TiLV detection is described, from tilapia organ sectioning, total ribonucleic acid (RNA) extraction using a guanidium thiocyanate phenol-chloroform solution, RNA quantification, followed by a two-step PCR protocol entailing, complementary deoxyribonucleic acid (cDNA) synthesis and detection of TiLV by either conventional PCR or quantitative identification via qPCR using SYBR green I dye. Conventional PCR requires post-PCR steps and will simply inform about the presence of the virus. The latter approach will allow for absolute quantification of TiLV down to as little as 2 copies and thus is exceptionally useful for TiLV diagnosis in sub-clinical cases. A detailed description of the two PCR approaches, representative results from two laboratories and a thorough discussion of the critical parameters of both have been included to ensure that researchers and diagnosticians find their most suitable and applicable method of TiLV detection. PMID- 30474632 TI - Semi-quantitative Assessment Using [18F]FDG Tracer in Patients with Severe Brain Injury. AB - Patients with severe traumatic brain injury (sTBI) have difficulty knowing whether they are accurately expressing their thoughts and emotions because of disorders of consciousness, disrupted higher brain function, and verbal disturbances. As a consequence of an insufficient ability to communicate, objective evaluations are needed from family members, medical staff, and caregivers. One such evaluation is the assessment of functioning brain areas. Recently, multimodal brain imaging has been used to explore the function of damaged brain areas. [18F]-fluorodeoxyglucose positron emission tomography computed tomography ([18F]FDG-PET/CT) is a successful tool for examining brain function. However, the assessment of brain glucose metabolism based on [18F]FDG PET/CT is not standardized and depends on several varying parameters, as well as the patient's condition. Here, we describe a series of semiquantitative assessment protocols for a region-of-interest (ROI) image analysis using self produced [18F]FDG tracers in patients with sTBI. The protocol focuses on screening the participants, preparing the [18F]FDG tracer in the hot lab, scheduling the acquisition of [18F]FDG-PET/CT brain images, and measuring glucose metabolism using the ROI analysis from a targeted brain area. PMID- 30474633 TI - Visualizing the Node and Notochordal Plate In Gastrulating Mouse Embryos Using Scanning Electron Microscopy and Whole Mount Immunofluorescence. AB - The post-implantation mouse embryo undergoes major shape changes after the initiation of gastrulation and morphogenesis. A hallmark of morphogenesis is the formation of the transient organizers, the node and notochordal plate, from cells that have passed through the primitive streak. The proper formation of these signaling centers is essential for the development of the body plan and techniques to visualize them are of high interest to mouse developmental biologists. The node and notochordal plate lie on the ventral surface of gastrulating mouse embryos around embryonic day (E) 7.5 of development. The node is a cup-shaped structure whose cells possess a single slender cilium each. The proper subcellular localization and rotation of the cilia in the node pit determines left-right asymmetry. The notochordal plate cells also possess single cilia albeit shorter than those of the node cells. The notochordal plate forms the notochord which acts as an important signaling organizer for somitogenesis and neural patterning. Because the cells of the node and notochordal plate are transiently present on the surface and possess cilia, they can be visualized using scanning electron microscopy (SEM). Among other techniques used to visualize these structures at the cellular level is whole mount immunofluorescence (WMIF) using the antibodies against the proteins that are highly expressed in the node and notochordal plate. In this report, we describe our optimized protocols to perform SEM and WMIF of the node and notochordal plate in developing mouse embryos to help in the assessment of tissue shape and cellular organization in wild-type and gastrulation mutant embryos. PMID- 30474634 TI - High Frequency Ultrasound for the Analysis of Fetal and Placental Development In Vivo. AB - Ultrasound imaging is a widespread method used to detect organ anomalies and tumors in human and animal tissues. The method is non-invasive, harmless, and painless, and the application is easy, fast, and can be done anywhere, even with mobile devices. During pregnancy, ultrasound imaging is standardly used to closely monitor fetal development. The technique is important to assess intrauterine growth restriction (IUGR), a pregnancy complication with short- and long-term health consequences for both the mother and fetus. Understanding the process of IUGR is indispensable for developing effective therapeutic strategies. The ultrasound system used in this manuscript is an ultrasound device produced for the analysis of small animals and can be used in various research fields, including pregnancy research. Here we describe the usage of the system for in vivo analysis of fetuses from natural killer (NK) cell/mast cell (MC)-deficient mothers that give birth to growth-restricted pups. The protocol includes preparation of the system, handling of the mice before and during measurements, and the usage of the B-mode, color doppler mode, and pulse-wave doppler mode. Fetal size, placental size, and blood supply to the fetus were analyzed. We found reduced implantation sizes and smaller placentas in NK/MC-deficient mice from mid gestation onwards. In addition, MC/NK-deficiency was associated with absent and reversed end diastolic flow in the fetal Arteria umbilicalis(UmA) and an elevated resistance index. The methods described in the protocol can easily be used for related and non-related research topics. PMID- 30474635 TI - A Two-interval Forced-choice Task for Multisensory Comparisons. AB - We provide a procedure for a psychophysics experiment in humans based on a previously described paradigm aimed to characterize the perceptual duration of intervals within the range of milliseconds of visual, acoustic, and audiovisual aperiodic trains of six pulses. In this task, each of the trials consists of two consecutive intramodal intervals where the participants press the upward arrow key to report that the second stimulus lasted longer than the reference, or the downward arrow key to indicate otherwise. The analysis of the behavior results in psychometric functions of the probability of estimating the comparison stimulus to be longer than the reference, as a function of the comparison intervals. In conclusion, we advance a way of implementing standard programming software to create visual, acoustic, and audiovisual stimuli, and to generate a two-interval forced-choice (2IFC) task by delivering stimuli through noise-blocking headphones and a computer's monitor. PMID- 30474636 TI - Isolation and Culture of Embryonic Mouse Neural Stem Cells. AB - Neural stem cells (NSCs) are multipotent and can give rise to the three major cell types of the central nervous system (CNS). In vitro culture and expansion of NSCs provide a suitable source of cells for neuroscientists to study the function of neurons and glial cells along with their interactions. There are several reported techniques for the isolation of neural stem cells from adult or embryo mammalian brains. During the microsurgical operation to isolate NSCs from different regions of the embryonic CNS, it is very important to reduce the damage to the brain cells to obtain the highest ratio of live and expandable stem cells. A possible technique for stress reduction during isolation of these cells from the mouse embryo brain is the reduction of surgical time. Here, we demonstrate a developed technique for rapid isolation of these cells from the E13 mouse embryo ganglionic eminence. Surgical procedures include harvesting E13 mouse embryos from the uterus, cutting the frontal fontanelle of the embryo with a bent needle tip, extracting the brain from the skull, microdissection of the isolated brain to harvest the ganglionic eminence, dissociation of the harvested tissue in NSC medium to gain a single cell suspension, and finally plating cells in suspension culture to generate neurospheres. PMID- 30474637 TI - Using the FishSim Animation Toolchain to Investigate Fish Behavior: A Case Study on Mate-Choice Copying In Sailfin Mollies. AB - Over the last decade, employing computer animations for animal behavior research has increased due to its ability to non-invasively manipulate the appearance and behavior of visual stimuli, compared to manipulating live animals. Here, we present the FishSim Animation Toolchain, a software framework developed to provide researchers with an easy-to-use method for implementing 3D computer animations in behavioral experiments with fish. The toolchain offers templates to create virtual 3D stimuli of five different fish species. Stimuli are customizable in both appearance and size, based on photographs taken of live fish. Multiple stimuli can be animated by recording swimming paths in a virtual environment using a video game controller. To increase standardization of the simulated behavior, the prerecorded swimming path may be replayed with different stimuli. Multiple animations can later be organized into playlists and presented on monitors during experiments with live fish. In a case study with sailfin mollies (Poecilia latipinna), we provide a protocol on how to conduct a mate choice copying experiment with FishSim. We utilized this method to create and animate virtual males and virtual model females, and then presented these to live focal females in a binary choice experiment. Our results demonstrate that computer animation may be used to simulate virtual fish in a mate-choice copying experiment to investigate the role of female gravid spots as an indication of quality for a model female in mate-choice copying. Applying this method is not limited to mate-choice copying experiments but can be used in various experimental designs. Still, its usability depends on the visual capabilities of the study species and first needs validation. Overall, computer animations offer a high degree of control and standardization in experiments and bear the potential to 'reduce' and 'replace' live stimulus animals as well as to 'refine' experimental procedures. PMID- 30474638 TI - Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia. AB - Alzheimer's disease (AD) is a progressive neurodegenerative condition in which aggregated tau and amyloid proteins accumulate in the brain causing neuronal dysfunction which eventually leads to cognitive decline. Hyperphosphorylated tau aggregates in the neuron are believed to cause most of the pathology associated with AD. These aggregates are assumed to be released into the extracellular compartment and taken up by adjacent healthy neurons where they induce further tau aggregation. This "prion-like" spreading can be interrupted by antibodies capable of binding and "neutralizing" extracellular tau aggregates as shown in preclinical mouse models of AD. One of the proposed mechanisms by which therapeutic antibodies reduce pathology is antibody-mediated uptake and clearance of pathological aggregated forms of tau by microglia. Here, we describe a quantitative cell-based assay to assess tau uptake by microglia. This assay uses the mouse microglial cell line BV-2, allows for high specificity, low variability and medium throughput. Data generated with this assay can contribute to a better characterization of anti-tau antibody effector functions. PMID- 30474639 TI - Detection of Small GTPase Prenylation and GTP Binding Using Membrane Fractionation and GTPase-linked Immunosorbent Assay. AB - The Rho GTPase family belongs to the Ras superfamily and includes approximately 20 members in humans. Rho GTPases are important in the regulation of diverse cellular functions, including cytoskeletal dynamics, cell motility, cell polarity, axonal guidance, vesicular trafficking, and cell cycle control. Changes in Rho GTPase signaling play an essential regulatory role in many pathological conditions, such as cancer, central nervous system diseases, and immune system dependent diseases. The posttranslational modification of Rho GTPases (i.e., prenylation by mevalonate pathway intermediates) and GTP binding are key factors which affect the activation of this protein. In this paper, two essential and simple methods are provided to detect a broad range of Rho GTPase prenylation and GTP binding activities. Details of the technical procedures that have been used are explained step by step in this manuscript. PMID- 30474640 TI - Fluorescent Paper Strips for the Detection of Diesel Adulteration with Smartphone Read-out. AB - Three fluorescent molecular rotors of 4-dimethylamino-4-nitrostilbene (4-DNS) were investigated for their potential use as viscosity probes to indicate the content of kerosene in diesel/kerosene blends, a wide-spread activity to adulterate fuel. In solvents with low viscosity, the dyes rapidly deactivate via a so-called twisted intramolecular charge transfer state, efficiently quenching the fluorescence. Measurements of diesel/kerosene blends revealed a good linear correlation between the decrease in fluorescence and the increase of the fraction of the less viscous kerosene in diesel/kerosene blends. Immobilization of the hydroxy derivative 4-DNS-OH in cellulose paper yielded test strips that preserve the fluorescent indicator's behavior. Combination of the strips with a reader based on a smartphone and a controlling app allowed to create a simple field test. The method can reliably detect the presence of kerosene in diesel from 7 to 100%, outperforming present standard methods for diesel adulteration. PMID- 30474641 TI - Reproducible dsRNA Microinjection and Oviposition Bioassay in Mosquitoes and House Flies. AB - Synthetic dsRNAs, used to induce RNA interference, may have dose dependent phenotypic effects. These effects are difficult to define if the dsRNAs are delivered using a non-quantitative method. Accurate delivery of known quantities of nucleic acids or other chemicals is critical to measure the efficacy of the compound being tested and to allow reliable comparison between compounds. Here we provide a reproducible, quantitative microinjection protocol that ensures accurate delivery of specific doses of dsRNA, reducing the mortality typically induced by injection injury. These modifications include the addition of Rhodamine B, a graduated injection needle, and an improved recovery method borrowed from Isoe and Collins. This method allows calculation of dose responses and facilitates comparisons between compounds. Versions of this method have been successfully used on three genera of mosquitoes as well as house flies to assess the reduction in fecundity resulting from gene silencing of ribosomal RNA transcripts. This protocol provides strategies to reduce several challenges of small insect microinjection. Together, mechanical delivery of dsRNAs accompanied by visual verification, identification of effective locations for delivery, and inclusion of a post-injection recovery period ensure accurate dosing and low injury mortality. This protocol also describes an oviposition bioassay for uniform determination of effects on fecundity. PMID- 30474642 TI - Microdialysis of Excitatory Amino Acids During EEG Recordings in Freely Moving Rats. AB - Microdialysis is a well-established neuroscience technique that correlates the changes of neurologically active substances diffusing into the brain interstitial space with the behavior and/or with the specific outcome of a pathology (e.g., seizures for epilepsy). When studying epilepsy, the microdialysis technique is often combined with short-term or even long-term video-electroencephalography (EEG) monitoring to assess spontaneous seizure frequency, severity, progression and clustering. The combined microdialysis-EEG is based on the use of several methods and instruments. Here, we performed in vivo microdialysis and continuous video-EEG recording to monitor glutamate and aspartate outflow over time, in different phases of the natural history of epilepsy in a rat model. This combined approach allows the pairing of changes in the neurotransmitter release with specific stages of the disease development and progression. The amino acid concentration in the dialysate was determined by liquid chromatography. Here, we describe the methods and outline the principal precautionary measures one should take during in vivo microdialysis-EEG, with particular attention to the stereotaxic surgery, basal and high potassium stimulation during microdialysis, depth electrode EEG recording and high-performance liquid chromatography analysis of aspartate and glutamate in the dialysate. This approach may be adapted to test a variety of drug or disease induced changes of the physiological concentrations of aspartate and glutamate in the brain. Depending on the availability of an appropriate analytical assay, it may be further used to test different soluble molecules when employing EEG recording at the same time. PMID- 30474643 TI - Using a Knee Arthrometer to Evaluate Tissue-specific Contributions to Knee Flexion Contracture in the Rat. AB - Normal knee range of motion (ROM) is critical to well-being and allows one to perform basic activities such as walking, climbing stairs and sitting. Lost ROM is called a joint contracture and results in increased morbidity. Due to the difficulty of reversing established knee contractures, early detection is important, and hence, knowing risk factors for their development is essential. The rat represents a good model with which the effect of an intervention can be studied due to the similarity of rat knee anatomy to that of humans, the rat's ability to tolerate long durations of knee immobilization in flexion, and because mechanical data can be correlated with histologic and biochemical analysis of knee tissue. Using an automated arthrometer, we demonstrate a validated, precise, reproducible, user-independent method of measuring the extension ROM of the rat knee joint at specific torques. This arthrometer can be used to determine the effects of interventions on knee joint ROM in the rat. PMID- 30474644 TI - Effects of Taste Signaling Protein Abolishment on Gut Inflammation in an Inflammatory Bowel Disease Mouse Model. AB - Inflammatory bowel disease (IBD) is one of the immune-related gastrointestinal disorders, including ulcerative colitis and Crohn's disease, that affects the life quality of millions of people worldwide. IBD symptoms include abdominal pain, diarrhea, and rectal bleeding, which may result from the interactions among gut microbiota, food components, intestinal epithelial cells, and immune cells. It is of particular importance to assess how each key gene expressed in intestinal epithelial and immune cells affects inflammation in the colon. G protein-coupled taste receptors, including G protein subunit alpha-gustducin and other signaling proteins, have been found in the intestines. Here, we use alpha gustducin as a representative and describe a dextran sulfate sodium (DSS)-induced IBD model to evaluate the effect of gustatory gene mutations on gut mucosal immunity and inflammation. This method combines gene knockout technology with the chemically induced IBD model, and thus can be applied to assess the outcome of gustatory gene nullification as well as other genes that may exuberate or dampen the DSS-induced immune response in the colon. Mutant mice are administered with DSS for a certain period during which their body weight, stool, and rectal bleeding are monitored and recorded. At different timepoints during administration, some mice are euthanized, then the sizes and weights of their spleens and colons are measured and gut tissues are collected and processed for histological and gene expression analyses. The data show that the alpha-gustducin knockout results in excessive weight loss, diarrhea, intestinal bleeding, tissue damage, and inflammation vs. wild-type mice. Since the severity of induced inflammation is affected by mouse strains, housing environment, and diet, optimization of DSS concentration and administration duration in a pilot experiment is particularly important. By adjusting these factors, this method can be applied to assess both anti- and pro-inflammatory effects. PMID- 30474645 TI - A Conditioned Place Preference Protocol for Measuring Incubation of Craving in Rats. AB - A major cause of repeated relapses is a craving for the drug. Drug craving increases progressively during the abstinence period, a phenomenon termed incubation of drug craving. Here, we describe a morphine conditioned place preference (CPP) protocol for measuring the incubation of craving in rats. In this protocol, a CPP paradigm mainly employing somatosensory cues is used to establish a long-term reward memory of morphine. A three-chamber CPP box that differs in the texture of the chamber floor is constructed. First, the animals are tested for their baseline preference to the two side chambers for three consecutive days. Then, they are injected intraperitoneally with morphine/saline and put into their non-preferred/preferred chamber for 45 min. After 6 days of conditioning, their preference to the side chambers is tested for 15 min at different time points after the last conditioning session. With this paradigm, the reward memory of morphine could last for at least 18 days. To test whether the above-mentioned protocol can model increased craving, the number of entrances into the two side chambers are counted during the abstinence period. The results show that the entrances increased, suggesting that the CPP paradigm could mimic the incubation of craving. Future studies can employ this model to study neural mechanisms underlying long-term memory and incubation of craving. PMID- 30474646 TI - Construction of a Compact Low-Cost Radiation Shield for Air-Temperature Sensors in Ecological Field Studies. AB - Low cost temperature sensors are increasingly used by ecologists to assess climatic variation and change on ecologically relevant scales. Although cost effective, if not deployed with proper solar radiation shielding, the observations recorded from these sensors will be biased and inaccurate. Manufactured radiation shields are effective at minimizing this bias, but are expensive compared to the cost of these sensors. Here, we provide a detailed methodology for constructing a compact version of a previously described custom fabricated radiation shield, which is more accurate than other published shielding methods that attempt to minimize shield size or construction costs. The method requires very little material: corrugated plastic sheets, aluminum foil duct tape, and cable ties. One 15 cm and two 10 cm squares of corrugated plastic are used for each shield. After cutting, scoring, taping and stapling of the sheets, the 10 cm squares form the bottom two layers of the solar radiation shield, while the 15 cm square forms the top layer. The three sheets are held together with cable ties. This compact solar radiation shield can be suspended, or placed against any flat surface. Care must be taken to ensure that the shield is completely parallel to the ground to prevent direct solar radiation from reaching the sensor, possibly causing increased warm biases in sun-exposed sites in the morning and afternoon relative to the original, larger design. Even so, differences in recorded temperatures between the smaller, compact shield design and the original design were small (mean daytime bias = 0.06 degrees C). Construction costs are less than half of the original shield design, and the new design results in a less conspicuous instrument that may be advantageous in many field ecology settings. PMID- 30474647 TI - One-anastomosis Gastric Bypass (OAGB) in Rats. AB - The goal of this protocol is to set up a preclinical model of bariatric surgery and, more specifically, OAGB in obese rats. Based on this preclinical model, longitudinal studies can be carried out to provide an improved understanding of the mechanisms underlying the outcomes seen after bariatric surgery in humans. For this purpose, rats are operated on through a laparotomy under general anesthesia with isoflurane. First, the surgeon creates a long and tubular gastric pouch: after greater curve and hiatal dissection, the nonglandular stomach is stapled and removed. Then, the remaining stomach is also stapled in order to create a gastric tube and exclude the antrum of the stomach. After that, the surgeon performs a single end-to-side gastrojejunostomy 35 cm from the duodenojejunal angle. This limb length has been chosen in order to reproduce the same ratio between the biliopancreatic limb (BPL) and common limb (CL) length as in human bariatric surgery. The operation ends by aponeurotic and cutaneous closure. The early postoperative management consists of subcutaneous hydration, an intramuscular prophylactic antibiotic injection, a parietal injection of xylocaine, the administration of painkillers, and a progressive reintroduction of diet. PMID- 30474648 TI - Longitudinal assessment of peripheral blood BRAFV600E levels in patients with Langerhans cell histiocytosis. AB - BACKGROUND: Langerhans cell histiocytosis (LCH) is a histiocytic disorder driven by a constitutive activation of the MAPK signaling pathway in myeloid cells. In 50-60% of cases, it is caused by the BRAFV600E mutation. There is evidence that levels of BRAFV600E in the peripheral blood of patients with LCH correlate with disease burden and could be used as marker for disease extent and response to therapy. However, there is currently no consensus on how testing for minimal disseminated disease should be performed. METHODS: Different approaches to determine the mutation load in patients with LCH were assessed and longitudinal evaluation of patient DNA during treatment with chemotherapy and/or the RAF inhibitor vemurafenib was performed. DNA was isolated from whole blood, different leukocyte subsets, and circulating cell-free DNA (ccf-DNA). RESULTS: We show that determining BRAF levels from whole blood is superior to using ccfDNA. Furthermore, it is important to identify the clinically relevant BRAF-mutated cellular subpopulations such as CD14+ monocytes or CD1c DCs, since other blood cells can also harbor the mutation and therefore confound whole blood or ccfDNA measurements. CONCLUSION: Our data support the view that single-agent treatment with an RAF inhibitor reduces disease activity but does not cure LCH. PMID- 30474649 TI - Lessons learned from two decades of BRCA1 and BRCA2 genetic testing: the evolution of data sharing and variant classification. PMID- 30474650 TI - Frequency of de novo variants and parental mosaicism in vascular Ehlers-Danlos syndrome. AB - PURPOSE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare inherited autosomal dominant disorder caused by COL3A1 pathogenic variants. A high percentage of de novo cases has been suggested. Part of it could be due to parental mosaicism, but its frequency is unknown. METHODS: This retrospective study included a large series of COL3A1-confirmed vEDS probands with family information. The frequency of de novo cases was evaluated and the distribution of the type of variants was compared according to the mode of inheritance. The COL3A1 mosaicism was studied by deep targeted next- generation sequencing (NGS) from parental blood DNA. RESULTS: Out of 177 vEDS probands, 90 had a negative family history, suggesting a high rate (50.8%) of de novo pathogenic variants, enriched in the more severe COL3A1 variants (no null variant). Among those, both parental DNA were available in 36 cases and one parental DNA in 18 cases. NGS detected only one mosaicism from maternal blood DNA (allelic ratio 18%), which was confirmed in saliva (allelic ratio 22%). CONCLUSION: vEDS is characterized by a high frequency of de novo pathogenic variants. Parental mosaicism is rare (2-3%), but should be systematically searched with targeted NGS, taking into account its importance in genetic counseling. PMID- 30474652 TI - Wurtzite CoO: a direct band gap oxide suitable for a photovoltaic absorber. AB - A direct band gap of 1.6 eV has been identified in wurtzite CoO thin films, which matches the required value to achieve a theoretically high conversion efficiency solar cell. Its p-type conduction has been determined and an intense sub-gap absorption between 0.7 and 1.1 eV has been observed. PMID- 30474653 TI - A hepatitis B virus-derived human hepatic cell-specific heparin-binding peptide: identification and application to a drug delivery system. AB - Viruses are naturally evolved nanocarriers that can evade host immune systems, attach specifically to the surfaces of target cells, enter the cells through endocytosis, escape from endosomes efficiently, and then transfer their genomes to host cells. Hepatitis B virus (HBV) is a ~42 nm enveloped DNA virus that can specifically infect human hepatic cells. To utilize the HBV-derived early infection machinery in synthetic nanocarriers, the human hepatic cell-binding site (i.e., the sodium taurocholate co-transporting polypeptide (NTCP)-binding site, with myristoylated pre-S1(2-47)) and the low pH-dependent fusogenic domain (pre-S1(9-24)) are indispensable for targeting and endosomal escape, respectively. However, cell-surface NTCP has recently been shown not to be involved in the initial attachment of HBV. In this study, we identified a novel heparin-binding site (pre-S1(30-42)) in the N-terminal half of the pre-S1 region, which presumably interacts with cell-surface heparan sulfate proteoglycan (HSPG) and plays a pivotal role in the initial attachment of HBV to human hepatic cells. The evolutionarily conserved amino acid residues Asp-31, Trp-32, and Asp-33 are indispensable for the heparin-binding activity. Liposomes (LPs) displaying the peptide were endocytosed by human hepatic cells in a cell-surface heparin dependent manner and delivered doxorubicin to human hepatic cells more efficiently than myristoylated pre-S1(2-47)-displaying LPs. These results demonstrated that the pre-S1(30-42) peptide is the most promising HBV-derived targeting peptide for synthetic nanocarriers, and that this peptide exhibits high specificity for human hepatic cells and efficiently induces endocytosis. PMID- 30474651 TI - ELUCIDATING NUCLEAR SIZE CONTROL IN THE XENOPUS MODEL SYSTEM. AB - Background: Nuclear size is a tightly regulated cellular feature. Mechanisms that regulate nuclear size and the functional significance of this regulation are largely unknown. Nuclear size and morphology are often altered in many diseases, such as cancer. Therefore, understanding the mechanisms that regulate nuclear size is crucial to provide insight into the role of nuclear size in disease. Scope and Approach: The goal of this review is to summarize the most recent studies about the mechanisms and functional significance of nuclear size control using the Xenopus model system. First, this review describes how Xenopus egg extracts, embryos, and embryo extracts are prepared and used in scientific research. Next, the review focuses on the mechanisms and functional effects of proper nuclear size control that have been learned using the Xenopus system. Key Findings and Conclusions: Xenopus is an excellent in vivo and in vitro experimental platform to study mechanisms of nuclear size control. Given its close evolutionary relationship with mammals and that most cellular processes and pathways are highly conserved between Xenopus and humans, the Xenopus system has been a valuable tool to advance biomedical research. Some of the mechanisms that regulate nuclear size include components of nuclear import such as importin alpha and NTF2, nuclear lamins, nucleoporins, proteins that regulate the morphology of the endoplasmic reticulum, and cytoskeletal elements. PMID- 30474654 TI - Diastereoselective solid-state crossed photocycloaddition of olefins in a 3D Zn(ii) coordination polymer. AB - 1,2-Bis(4-pyridyl)ethylene undergoes a photoinitiated [2+2] cross-cycloaddition reaction with allyl groups of allylmalonate in pores of a 3D metal-organic framework (MOF) [Zn2(H2O)2(Amal)2(bpe)] to produce a 3D MOF with a new topology. PMID- 30474655 TI - Anti-biofouling therapeutic nanoparticles with removable shell and highly efficient internalization by cancer cells. AB - Cationic gelatin nanoparticles ((+)nGNPs) were prepared by in situ polymerization upon the surfaces of monodispersed gelatin nanoparticles (GNPs) using N-(3 Aminopropyl)methacrylamide (APm) as monomer, which were then decorated with doxorubicin terminated poly(2-methylacryloyloxyethyl phosphorylcholine) (DOX pMPC) via EDC/NHS conjugation to obtain core-shell nanoparticles ((+)nGNPs@DOX pMPC) for cancer therapy. The non-fouling pMPC shell could effectively shield the positively charged surface of inner nanoparticle and prevent non-specific protein adsorption, thus endowing the materials with potential for long-acting cancer treatment. Furthermore, the acyl hydrazone bond connecting DOX and pMPC chain could be easily hydrolyzed in the weakly acidic tumor microenvironment. After decladding of the pMPC shell, electropositive (+)nGNPs carrying the drugs can be effectively internalized by cancer cells to induce apoptosis, avoiding undesirable hindrance caused by the superhydrophilic outer layer. On combining the above properties, this drug delivery system can be a promising candidate for long-acting, low-toxicity and high-efficiency cancer therapy. PMID- 30474656 TI - A copper-catalyzed three component reaction of aryl acetylene, sulfonyl azide and enaminone to form iminolactone via 6pi electrocyclization. AB - We developed a copper-catalyzed three component reaction of aryl acetylene, enaminone and sulfonyl azide to construct iminolactone via a cascade process involving copper-catalyzed alkyne-azide cycloaddition (CuAAC), Michael addition of metalated ketenimine followed by elimination and 6pi electrocyclization. PMID- 30474657 TI - Selectively light-up hydrogen peroxide in hypoxic cancer cells with a novel fluorescent probe. AB - A novel fluorescent turn-on probe (HCyHP) was developed in a simple two-step synthesis for monitoring of exogenous and endogenous H2O2 levels in biological samples and hypoxic cancer diagnosis. PMID- 30474658 TI - [(NHC)CoR2]: pre-catalysts for homogeneous olefin and alkyne hydrogenation. AB - A novel synthesis for dialkyl cobalt compounds [(tmeda)CoR2] is presented. In these complexes tmeda is readily replaced by an NHC or a bidentate phosphine ligand to form 3- and 4-coordinate compounds, respectively. [(ItBu)Co(CH2SiMe3)2] (ItBu = 1,3-di-tert-butylimidazolin-2-ylidene) serves as an efficient, homogeneous olefin hydrogenation pre-catalyst and allows the preparation of the novel cobalt bis(alkyne) complex [(ItBu)Co(eta2-PhCCPh)2]. PMID- 30474659 TI - Palladium-catalyzed intramolecular transfer hydrogenation & cycloaddition of p quinamine-tethered alkylidenecyclopropanes to synthesize perhydroindole scaffolds. AB - A palladium(0)-catalyzed intramolecular transfer hydrogenation and cycloaddition of p-quinamine-tethered alkylidenecyclopropanes (ACPs) to synthesize perhydroindole scaffolds has been reported in this communication. Mechanistic investigations on the basis of deuterium labeling experiments suggest that the reaction proceeded through an oxidative addition of Pd(0) into the distal bond of the ACP moiety to afford a trimethylenemethane (TMM)-Pd intermediate followed by transfer hydrogenation using alcohol. PMID- 30474660 TI - Transition metal-coordinated graphitic carbon nitride dots as a sensitive and facile fluorescent probe for beta-amyloid peptide detection. AB - Herein, we developed a sensitive graphitic carbon nitride quantum dot (gCNQD) based fluorescent strategy for beta-amyloid peptide monomer (Abeta) determination down to the ng mL-1 level for the first time. To realize this goal, the nanostructured gCNQDs were firstly coordinated with four transition metal ions (Cu2+, Cu+, Fe3+, Zn2+). Our findings showed that the fluorescence (FL) intensity of gCNQDs was quenched in the presence of these metal ions possibly due to the effective chelation with the nitrogen element in gCNQDs and subsequent photoinduced electron transfer (PET) of gCNQDs. The degree of fluorescence quenching was found to be the most intense with the addition of Cu2+ and therefore, we selected Cu2+ as the quencher for the following Abeta determination. Through binding to Cu2+, the introduction of Abeta unexpectedly induced a further decline of FL intensity. Importantly, on account of different peptide sequences coexisting in the same cerebral system, including Abeta1-11, Abeta1-16, Abeta1-38, Abeta1-40 and Abeta1-42, their affinities to Cu2+ could be reflected by the distinguished declining extent of FL intensity. The possible mechanism of Abeta sensing by the probe was clarified by TEM characterization. The developed fluorescent biosensor was demonstrated to give a wide linear range from 1 to 700 ng mL-1 and a low detection limit of 0.18 ng mL-1 for Abeta1-42. In the end, the proposed fluorescence approach was successfully applied to monitoring of Abeta1-42 variations in the cortex and hippocampus of AD rats. PMID- 30474661 TI - A field amplification enhanced paper-based analytical device with a robust chemiluminescence detection module. AB - A sensitive detection method combined with an effective on-line concentration may improve the analytical performance of a paper-based analytical device (PAD), and its merits of low cost and portability in POCT are fully demonstrated. Here, a sensitive PAD system with chemiluminescence (CL) detection and electrokinetic preconcentration was introduced, and the performance was demonstrated by the detection of hemin. A commercially available low cost and miniaturized optical detection module was used for the CL detection. Firstly, hemin was stacked on a simple paper fluidic channel based on field amplified stacking (FAS), and then a CL reagent (luminol-H2O2) was loaded on the stacked band to initiate the CL reaction. The photons were directly detected using the detection module. With optimization of the background electrolyte (BGE), voltage and CL reagent, a limit of detection (LOD) of 0.58 nM for hemin was obtained with a linear range of 1 1000 nM (R2 = 0.995). With FAS, the signal intensity was about 13-fold enhanced. This PAD also exhibited satisfactory selectivity over possible interfering components at a 104 times higher concentration. The applicability of the PAD was demonstrated by the detection of hemin from iron supplements and human serum samples. With total manual operation, recovery rates of 84.8-115.6% were obtained with an RSD of less than 14.3%. With the introduction of the optical detection model, and together with FAS, both the LOD and dynamic range of this PAD were effectively improved. PMID- 30474662 TI - Highly conductive PEDOT:PSS threaded HKUST-1 thin films. AB - Highly conductive PEDOT:PSS threaded HKUST-1 thin films with high porosity were prepared. The highest conductivity of these films was 13 S cm-1, nine orders of magnitude greater than that of pristine HKUST-1. A PEDOT:PSS threaded HKUST-1 thin film with 20 wt% PEDOT:PSS exhibits 300 times enhancement of the electrochemical performance of pristine HKUST-1 when applied as an electrode for thin-film-like supercapacitors. PMID- 30474663 TI - Hydrogel bioelectronics. AB - Bioelectronic interfacing with the human body including electrical stimulation and recording of neural activities is the basis of the rapidly growing field of neural science and engineering, diagnostics, therapy, and wearable and implantable devices. Owing to intrinsic dissimilarities between soft, wet, and living biological tissues and rigid, dry, and synthetic electronic systems, the development of more compatible, effective, and stable interfaces between these two different realms has been one of the most daunting challenges in science and technology. Recently, hydrogels have emerged as a promising material candidate for the next-generation bioelectronic interfaces, due to their similarities to biological tissues and versatility in electrical, mechanical, and biofunctional engineering. In this review, we discuss (i) the fundamental mechanisms of tissue electrode interactions, (ii) hydrogels' unique advantages in bioelectrical interfacing with the human body, (iii) the recent progress in hydrogel developments for bioelectronics, and (iv) rational guidelines for the design of future hydrogel bioelectronics. Advances in hydrogel bioelectronics will usher unprecedented opportunities toward ever-close integration of biology and electronics, potentially blurring the boundary between humans and machines. PMID- 30474665 TI - Efficient and stable radiolabeling of polycyclic aromatic hydrocarbon assemblies: in vivo imaging of diesel exhaust particulates in mice. AB - As a robust radioanalytical method for tracking carbonaceous particulates in vivo, polycyclic aromatic hydrocarbons from diesel exhaust were labeled with a radioactive-iodine-tagged pyrene analogue. Single-photon emission computed tomography and biodistribution studies showed high uptake and slow clearance of this matter in the respiratory system, which may underlie its severe toxicity. PMID- 30474670 TI - Cathodoluminescence nanoscopy of open single-crystal aluminum plasmonic nanocavities. AB - Exact understanding of the plasmon response of aluminum (Al) nanostructures in deep subwavelengths is critical for the design of Al based plasmonic applications, such as the emission control of quantum dots and surface-enhanced resonance Raman scattering in the ultraviolet (UV) range. Here, the plasmonic properties of open triangle cavities patterned by a focused ion beam in single crystal bulk Al were explored using cathodoluminescence. The resonant modes were determined by experimental spectra and deep subwavelength real-space mode patterns ranging from the visible to the UV, which agreed well with full-wave electromagnetic simulations. The dispersion relation of the cavity modes was consistent with that at the interface between Al and vacuum, showing strong electromagnetic field confinement in the cavities. Open Al triangle cavities provided room for the interaction between optical emitters and confined electromagnetic fields, paving the way for plasmonic devices for a variety of applications, such as plasmonic light-emitting devices or nanolasers in the UV range. PMID- 30474671 TI - Fluorescent 2D metal-organic framework nanosheets (MONs): design, synthesis and sensing of explosive nitroaromatic compounds (NACs). AB - 2D metal-organic framework nanosheets (MONs) lie at the heart of contemporary research on metal-organic materials. We have rationally designed and synthesized a fluorescent 6-connecting hexaacid linker H6TPA based on the 1,3,5 triphenylbenzene core to access layered MOFs by metal-assisted self-assembly. Treatment of H6TPA with In3+ salt does indeed lead to a layered porous MOF, i.e.In-TPA. It is shown that the ultrasonication-induced liquid phase of exfoliation (UILPE) of the latter in a top-down fashion affords few-layer 2D metal-organic nanosheets (MONs). The delamination of 2D MONs in ethanol occurs with 'turn-on' fluorescence, which is otherwise suppressed in the bulk material. The exfoliated MONs in ethanol exhibit blue fluorescence with a respectable quantum yield of 0.15 and serve as efficient sensory materials for 'turn-off' fluorescence detection of explosive nitroaromatic compounds (NACs). While all nitroaromatics are found to quench the fluorescence of MONs, the most electron deficient trinitrotoluene (TNT) exhibited the highest efficiency; at 2 mM concentration of TNT, the fluorescence of 2D MONs was found to be quenched with an efficiency of 80% (permitting the detection of TNT at ca. 11 ppm level), while that of the unmetallated linker, i.e.H6TPA, was quenched with only 5% efficiency. The unique attributes of MONs, namely the rigidity of the linker upon metallation and porosity that facilitates guest confinement within the pores, for efficient sensing of nitroaromatics are thus demonstrated for the first time. PMID- 30474672 TI - Switchable dissociation of excitons bound at strained CdTe/CdS interfaces. AB - Charge carrier dynamics of semiconductor nano-heterostructures are determined by band alignment and lattice mismatch of the adjacent materials. However, quantum efficiencies for the separation of excited charge carriers at such an interface are hard to predict and cannot yet be easily controlled. In this work we examine nanorods with a severely strained, axial CdTe/CdS interface using femtosecond transient absorption spectroscopy. We show that charge separation is mitigated by equal contributions of valence band distortion and formation of coulomb pairs across the interface. Left undisturbed such localised excitons relax rapidly via non-radiative recombination channels. By adding a competitive hole acceptor that disrupts the coulomb interaction we overcome the synergetic co-localisation of the carriers and realise charge separation. The thus created long-lived state can be exploited for a broad range of applications such as photocatalysis, water splitting, and switchable nanodevices. PMID- 30474673 TI - A general strategy for printing colloidal nanomaterials into one-dimensional micro/nanolines. AB - Though patterned one-dimensional (1D) micro/nanoline arrays are of great importance in the field of integrated circuits and optoelectronics, the fabrication of high-precision micro/nanolines with excellent optical and electrical performance remains a great challenge. Herein, a general strategy for printing 1D micro/nanolines is proposed by manipulating the self-assembly of functional nanoparticles as a multilayer or monolayer stack with a single nanoparticle width. This method is universal for dispersible nanoparticles, and the silver nanoparticle was selected as a model nanoparticle due to its good conductivity, dispersibility and narrow-size distribution. The results indicate that the morphologies of printed micro/nanolines can be precisely regulated by the substrate wettability and the suspension concentration. Specifically, 1D nanoparticle-assembled architectures are printed as a monolayer stack on the substrate with a low contact angle (below 45 degrees ), while a multilayer stack is formed on the substrate with a high contact angle (above 50 degrees ) or a high concentration (more than 0.12%). The controllability of micro/nanoline morphologies can be interpreted through the influence of the three phase contact line slipping motion and the nanoparticle diffusion on diverse substrates at different concentrations. Alteration of the printing template structures enables the intervals of 1D micro/nanolines to span from 16 MUm to 48 MUm. These results provide an efficient methodology for fabricating micro/nano-circuits or optics and strengthening the understanding of the self-assembling process. PMID- 30474675 TI - Beyond the traditional roles of Ag in catalysis: the transmetalating ability of organosilver(i) species in Pd-catalysed reactions. AB - Silver salts are one of the most widely used additives in Pd-catalysed transformations. Apart from acting as a halide scavenger and/or an external oxidant, over the past decade it has been revealed that silver salts can play other roles such as a C-H activation promoter or decarboxylating agent, generating organosilver(i) species. These nucleophiles can promote innovative transformations by reacting with PdII intermediates through a transmetalation step. This review article covers different Pd-catalysed C-C bond-forming reactions where silver complexes have been proposed to act as nucleophilic coupling partners. We will also provide relevant mechanistic features associated with these transformations. PMID- 30474674 TI - Stabilisation of lipid membrane-incorporated porphyrin derivative aqueous solutions and their photodynamic activities. AB - Lipid membrane-incorporated porphyrin derivatives (LMIPors) having three phenyl moieties and one pyridyl or pyridinium moiety at the meso-positions were more stable than LMIPors having phenyl and/or pyridyl moieties. The former two LMIPors showed high photodynamic activity toward cancer cells under photoirradiation at wavelengths over 600 nm, which are the most suitable for photodynamic therapy. The photodynamic activities were greater than that of Photofrin, which is currently the main drug employed clinically as a photosensitiser. The results represent significant progress toward the optimisation of LMIPors as photosensitisers. PMID- 30474676 TI - Facile and environmentally friendly synthesis of six heterometallic dumbbell shaped MLn (M = Co, Ni; Ln = Eu, Gd, Dy) clusters as cryogenic magnetic coolants and molecular magnets. AB - Six analogous dumbbell-shaped 3d-4f complexes MLn were obtained by the reaction of Ln(NO3)3 (Ln = Eu, Gd, Dy) and M(OAc)2 (M = Co, Ni) without any other organic ligands, and M5Gd4 exhibited a large magnetocaloric effect (-DeltaSm = 31.0, 37.3 J kg-1 K-1 for Co5Gd4 and Ni5Gd4 respectively), while M5Dy4 and Co5Eu4 showed single molecule magnet behaviour. To the best of our knowledge, Co5Eu4 is the first Eu-based cluster to display single molecule magnet behaviour (Ueff = 16.4 K). PMID- 30474677 TI - Computationally-inspired discovery of an unsymmetrical porous organic cage. AB - A completely unsymmetrical porous organic cage was synthesised from a C2v symmetrical building block that was identified by a computational screen. The cage was formed through a 12-fold imine condensation of a tritopic C2v symmetric trialdehyde with a ditopic C2 symmetric diamine in a [4 + 6] reaction. The cage was rigid and microporous, as predicted by the simulations, with an apparent Brunauer-Emmett-Teller surface area of 578 m2 g-1. The reduced symmetry of the tritopic building block relative to its topicity meant there were 36 possible structural isomers of the cage. Experimental characterisation suggests a single isomer with 12 unique imine environments, but techniques such as NMR could not conclusively identify the isomer. Computational structural and electronic analysis of the possible isomers was used to identify the most likely candidates, and hence to construct a 3-dimensional model of the amorphous solid. The rational design of unsymmetrical cages using building blocks with reduced symmetry offers new possibilities in controlling the degree of crystallinity, porosity, and solubility, of self-assembled materials. PMID- 30474680 TI - Alpha-terpineol affects synthesis and antitumor activity of triterpenoids from Antrodia cinnamomea mycelia in solid-state culture. AB - To enhance production of Antrodia cinnamomea triterpenoids (ACTs) from mycelia in solid-state culture, alpha-terpineol was added to the medium as an elicitor at an optimal concentration of 0.05 mL L-1. Multi-stage solvent extraction and HPLC analysis were performed, and the compositions of ACTs-E (from culture with elicitor) and ACTs-NE (from culture without elicitor) were found to be quite different. In assays of in vitro antitumor activity, ACTs-E, in comparison with ACTs-NE, produced stronger viability reduction in several tumor cell lines and stronger apoptosis induction in HeLa in a dose-dependent manner. Several related proteins involved in the mitochondrial pathway of apoptosis (p53, Bax, caspase-3) did not show expression upregulation by ACTs-E, suggesting that apoptosis induction occurred through a p53-independent process. Further analysis revealed that ACTs-E strongly inhibited synthesis of topoisomerase I (TOP1) and tyrosyl DNA phosphodiesterase I (TDP1), which are involved in DNA repair, at both transcriptional and protein levels. Our findings suggest that ACTs-E have potential for applications in the pharmaceutical, clinical, and functional food industries, as a novel antitumor agent and a dual TOP1/TDP1 inhibitor. PMID- 30474681 TI - Biomimetic macroscopic mesocrystalline films produced by oriented assembly of nanorods under magnetic field. AB - Millimeter-scale mesocrystals and cross-lamellae mimicking the nanostructure of seashells were produced on a substrate through the three-dimensionally oriented assembly of c-axis-elongated calcite nanorods ~50 nm wide and ~500-1000 nm long by combining arrangement with evaporation-driven capillary force and alignment under an intense magnetic field. PMID- 30474682 TI - Construction of spirothioureas having an amino quaternary stereogenic center via a [3 + 2] annulation of 3-isothiocyanato oxindoles with 2-aminoacrylates. AB - A useful and convenient strategy for the diastereoselective synthesis of spirothioureas having an amino quaternary stereogenic center via a [3 + 2] annulation of 3-isothiocyanato oxindoles with 2-aminoacrylates was established. A diverse set of spirooxindole derivatives were synthesized in good to excellent yields and diastereoselectivities. Good enantioselectivities (up to 96 : 4 er) were obtained in the subsequent asymmetric study. PMID- 30474684 TI - Strategic synthesis of [Cu2], [Cu4] and [Cu5] complexes: inhibition and triggering of ligand arm hydrolysis and self-aggregation by chosen ancillary bridges. AB - The Schiff base ligand HL1 ({2,6-bis(allylimino)methyl}-4-methylphenol) having no coordinating donor arm has been examined for its reaction medium and ancillary bridge dependent reactivity for a hierarchical family of CuII complexes. The ligand showed a unique reactivity pattern toward CuII in solution. The bridging nature of in situ generated HO- ions in the absence and presence of externally added carboxylates (RCOO-; R = CF3, C6H5 and CH3) has been utilized to produce complexes {[Cu2(MU-L2)2(H2O)]2[Cu2(MU-L2)2(H2O)2](ClO4)6} (1) (HL2 = 3 {(allylimino)methyl}-2-hydroxy-5-methylbenzaldehyde), [Cu4(MU4-O)(MU-L1)2(MU1,3 O2CCF3)4] (2), [Cu4(MU4-O)(MU-L1)2(MU1,3-O2CC6H5)4].H2O (3), and [Cu5(MU3-OH)2(MU L1)2(MU1,3-OAc)2(OAc)2(H2O)4][Cu5(MU3-OH)2(MU-L1)2(MU1,3 OAc)2(OAc)3(H2O)](ClO4)3.2C2H5OH (4). The absence of carboxylate anions did not yield HO- ions in situ and triggered single ligand arm hydrolysis. The formation of tetra- and pentanuclear aggregates as well as ligand hydrolyzed dinuclear products has been rationalized to identify the possible roles of carboxylate anions in solution. Detailed characterization of the complexes in the solid state and in solution has been carried out using spectroscopic measurements, X-ray crystallography, variable temperature magnetic measurements and functional behavior. In MeOH solutions at 298 K, the complexes 1-4 showed catalytic oxidation of 3,5-di-tert-butyl catechol (3,5-DTBCH2) saturated with O2 from the air. PMID- 30474685 TI - A Cu-NHC based phosphorescent binuclear iridium(iii)/copper(i) complex with an unpredictable near-linear two-coordination mode. AB - A novel Cu-NHC based phosphorescent binuclear iridium(iii)/copper(i) complex has been prepared. The copper(i) center adopts an unpredictable near-linear two coordination mode with short Cu-N and Cu-C bond lengths and two obvious CH-pi interactions, which support its stability in the solid state. It also shows better optical properties (higher luminescence efficiency and shorter emission lifetime) in both solution and solid states relative to the model binuclear copper(i)/copper(i) complex, and was successfully applied in solution-processed organic light-emitting diodes. PMID- 30474686 TI - Evaporation and morphological patterns of bi-dispersed colloidal droplets on hydrophilic and hydrophobic surfaces. AB - Understanding the formation of different morphological patterns depending on the particle size and surface wettability has great relevance in the separation, mixing and concentration of micro/nano particles and biological entities. We report the evaporation and morphological patterns of evaporating bi-dispersed colloidal droplets on hydrophilic and hydrophobic surfaces. To explain the underlying mechanisms of various particle distribution patterns, we propose a phenomenological model that accounts for the drag force, van der Waals and electrostatic interaction forces, and surface tension force acting on the particles. In the case of the hydrophilic surface (theta ~ 27 degrees ), there is a competition between the frictional force arising due to the van der Waals (~10 8 N) and electrostatic interaction forces (~10-10 N) and the surface tension force (~10-7 N) that depends on the particle size. Consequently, the smaller particles (0.2 and 1.0 MUm in diameter) are found to be pinned and form an outer ring at the contact line whereas the larger particles (3.0 and 6.0 MUm in diameter) move inward, either forming an inner ring or flocculating depending on the particle size. Interestingly, a completely different morphological pattern of the micro/nano particles is observed on a hydrophobic substrate (theta ~ 110 degrees ): contact line pinning is no longer observed and particles form a centralized deposition pattern. The order of the magnitude of the surface tension force is higher as compared to the frictional force (~10-8 N); thus the particles are driven radially inward and accumulate at the center of the droplet. Owing to the mixed mode of evaporation toward the end of evaporation, only a fraction of smaller particles travel radially outward due to the coffee-ring effect. Scanning electron microscopy images reveal that smaller particles are present mostly at the center with a small fraction of smaller particles at the edge of the pattern, whereas larger particles are uniformly distributed throughout. PMID- 30474687 TI - Preclinical alternative model for analysis of porous scaffold biocompatibility in bone tissue engineering. AB - Using scaffolds with appropriate porosity represents a potential approach for repair of critical-size bone defects. Vascularization is essential for bone formation and healing. This study investigates methods for monitoring angiogenesis within porous biopolymer scaffolds on the basis of polyhydroxybutyrate (PHB)/chitosan. We use the chick and quail chorioallantoic membrane (CAM) assay as an in vivo model focused on the formation of new blood vessels inside the implant structure. Chemical properties of the surface in biopolymer scaffold matrix were characterized as well as the tissue reaction of the CAM. Implantation of a piece of polymer scaffold results in vascular reaction, documented visually and by ultrasound biomicroscopy. Histological analysis shows myofibroblast reaction (smooth muscle actin-positive cells) without excessive collagen deposition. Cell invasion is observed inside the implant, and QH1 marker, detecting hemangioblasts and endothelial cells of quail origin, confirms the presence of vascular network. The CAM assay is a rapid and easy way to test biocompatibility and vasculogenic potential of new candidate scaffolds for bone tissue bioengineering with respect to the 3R' s. PMID- 30474688 TI - Effects of stimulus intensity and auditory white noise on human somatosensory cognitive processing: a study using event-related potentials. AB - Exposure to auditory white noise has been shown to facilitate cognitive function. This phenomenon is often called stochastic resonance, and a moderate amount of auditory noise has been suggested to benefit individuals in hypodopaminergic states. Previous studies using psychophysic methods reported that stochastic resonance was sensitive to stimulus intensity; however, the relationship between neural activities elicited by different stimulus intensities and auditory white noise has not yet been clarified Thus, the present study aimed to investigate the effects of stimulus intensity (Experiment 1) and auditory white noise (Experiment 2) on behavioral data (reaction time (RT), the standard deviation of RT, and error rates), and the N140 and P300 components of event-related potentials (ERPs) in somatosensory Go/No-go paradigms. The subjects had to respond to the somatosensory stimuli by pressing a button with their right thumb only after presentation of the Go stimulus. In Experiment 1 with four different stimulus intensity levels, the peak latencies of N140 and P300 became shorter, and the peak amplitudes of N140 and P300 were enhanced with increases in stimulus intensity. In Experiment 2 with weak and mild intensities under auditory white noise and control conditions, the amplitudes of Go-P300 and No-go-P300 were enhanced by white noise, irrespective of weak and mild intensities, during Go/No go paradigms. Auditory white noise did not significantly affect the amplitude of N140 or the latencies of N140 and P300. These results suggest the presence of a characteristic cross-modal stochastic resonance in neural substrates utilizing somatosensory ERPs. PMID- 30474689 TI - Factors that influence neurological deficit and recovery in lumbar disc prolapse a narrative review. AB - Neurodeficit due to lumbar disc herniation (LDH) is a serious complication and can range from sensory hypoesthesia in a single dermatome to a debilitating condition like cauda equina syndrome (CES). Many authors have described variable clinical and radiological risk factors for neurodeficit in LDH. Similarly the prognostic factors influencing recovery have been variable across the studies. This narrative review discusses the pathogenesis, most consistent factors associated with the occurrence of neurodeficit in LDH patients and also the factors which have a prognostic role in recovery. Pathological mechanisms like venous congestion, neuronal ischaemia and multiple root impairment act either individually or in combination to result in neurodeficit in LDH patients. Among the clinical risk factors, diabetes mellitus and acute onset of symptoms have been associated with neurodeficit while pre-existing spinal canal stenosis, non contained discs (sequestrated/migrated) are potential radiological risk factors for developing neurodeficit. When considering prognostic factors for recovery, pre-operative muscle strength is the only significant factor. Knowledge about the causative and prognostic factors in neurodeficit following LDH would help in the successful management of this condition. PMID- 30474690 TI - Comparison of 238U, 210Po and 210Pb Speciation in Six Different Types of Soils. AB - Speciation of 238U, 210Po and 210Pb in six different types of Syrian soil (Entisols, Inceptisol, Aridisol, Mollisols, Vertisols and Rock outcrops) was studied using a four-step sequential extraction procedure. The binding nature of 238U, 210Po and 210Pb was correlated with soil properties including soil particles, pH, EC, OM, sand, silt and clay. The results showed that the exchangeable and carbonate fractions of 238U did not exceed 10%. In addition, the 238U, 210Po and 210Pb fractions bonded to organic matter increased as the soil clay content decreased. The highest 210Po fraction was found to be bonded to soil Fe/Al/Mn-oxides for Entisols soils (56%) and silica for Aridisol soils (53%). Soil clay content showed a linear correlation with 210Po concentrations in soils ranging from 0.34 to 0.91. The results are considered useful in assessing the risks resulting from soils contaminated by naturally occurring radioactive material from the phosphate and oil industry. PMID- 30474691 TI - The association between antidepressant use and deaths from road traffic accidents: a case-crossover study. AB - PURPOSE: Antidepressants are some of the most commonly used psychiatric medications, but little information is available about the effects of antidepressant treatment on the risk of traffic accidents across classes of antidepressants or associated with each substance individually. To investigate the relationship between exposure to antidepressants and risk of fatality in road traffic accidents. METHODS: We used a Korean national road traffic authority database linked with a national health insurance database between January 1, 2010 and December 31, 2014 and applied a case-crossover design. The study subjects were drivers in South Korea who died from traffic accidents and who had prescriptions for antidepressants within 1 year prior to the date of the accident. We compared the status of prescription for antidepressants with the hazard period and four matched control periods using conditional logistic regression, adjusting for other drug use. The trends of antidepressant utilization were described in terms of the number of prescriptions. A case-case time-control design was applied to drugs with an increasing trend in use and a significant case-crossover odds ratio (OR). RESULTS: A total of 1250 antidepressant-using drivers were included, and an increased risk was observed during the 30-day hazard period (adjusted OR 1.30; 95% CI 1.03-1.63). Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) showed significant risks, but tricyclic antidepressants did not. However, the associations of all antidepressants, SSRIs, SNRIs, escitalopram, and duloxetine did not remain significant after adjusting for trends in utilization. Paroxetine and milnacipran were associated with increased risks, with no obvious increase in their utilization, but the possibility of confounding by indication could have affected the results for milnacipran. CONCLUSION: Considering the trends of antidepressant prescription and utilization, the use of paroxetine increased the risk of fatal traffic accidents. PMID- 30474692 TI - Dynamic intraligamentary stabilization for ACL repair: a systematic review. AB - PURPOSE: It was the aim to assess all published original research dealing with dynamic repair of the anterior cruciate ligament (ACL) and to provide a semi quantitative analysis of clinical outcome reports. METHODS: Both OVIS and MEDLINE databases were utilized for allocation of articles. All preclinical and clinical studies related to dynamic intraligamentary stabilization (DIS) were identified. Results were tabulated and semi-quantitative analysis performed. RESULTS: Twenty three articles related to DIS were identified. The predominant level of evidence ranged between II and IV, with only one level I study. Reported failure rates ranged between 4% and 13.6%. Most clinical studies only reported revision rates without referring to failure of restoring stability. Highest success was achieved with proximal ACL ruptures. Both the level of physical activity and patient age have been found to influence the risk of failure. CONCLUSION: There is sufficient evidence to support that DIS repair may be an effective modality for the treatment of acute proximal tears of the ACL. However, comparative studies are lacking. Upcoming studies should compare the technique to ACL reconstruction with failure as an endpoint. Comparison to rigid methods of proximal fixation is also necessary to justify the need for dynamic fixation. Overall, there is evidence to suggest the potential space for ACL repair in the decision tree for individualized treatment planning. The best outcome will be in the hands of the best patient selectors. LEVEL OF EVIDENCE: IV. PMID- 30474693 TI - Triaxial accelerometer can quantify the Lachman test similarly to standard arthrometers. AB - PURPOSE: To assess the relationship between the KiRA triaxial accelerometer and the KT-1000 measurements in the intact, anterior cruciate ligament (ACL) deficient, and ACL reconstructed knee joint for the quantification of the Lachman test. Moreover, the intra- and inter-examiner repeatability of the KiRA device will be determined. It was hypothesized that the side-to-side difference of the anterior tibial translation as measured by the KiRA device would be equivalent to the one measured by the KT-1000 during the Lachman test. METHODS: Sixty patients were divided into three groups and have been prospectively included in the present study. Group_A composed of 20 patients with a diagnosis of an isolated ACL tear. Group_B composed of 20 patients who underwent ACL reconstruction with a Single-Bundle Lateral Plasty (SBLP) technique with at least 20 years of follow up. Group_C was the control group and included 20 patients with no history of ACL lesion. Lachman test has been performed at manual-maximum load on both sides, the involved and the contralateral and analyzed with the two different devices. RESULTS: The KiRA device in terms of side-to-side difference resulted not statistically different from the measurement of the KT-1000 arthrometer for the three study groups (n.s): Group_A: (4 +/- 2 mm KiRA, 4 +/- 2 mm KT1000), Group_B: (4 +/- 2 mm KiRA, 4 +/- 2 mm KT-1000), Group_C: (4 +/- 2 mm KiRA, 4 +/- 2 mm KT 1000), an excellent intra- (ICC = 0.88-0.89) and inter-examiner (ICC = 0.79) agreement was found for KiRA measurements. CONCLUSION: The KiRA (I+, Italy) device offers a valid method to quantify the Lacham test. LEVEL OF EVIDENCE: II. PMID- 30474694 TI - H19X-encoded miR-424(322)/-503 cluster: emerging roles in cell differentiation, proliferation, plasticity and metabolism. AB - miR-424(322)/-503 are mammal-specific members of the extended miR-15/107 microRNA family. They form a co-expression network with the imprinted lncRNA H19 in tetrapods. miR-424(322)/-503 regulate fundamental cellular processes including cell cycle, epithelial-to-mesenchymal transition, hypoxia and other stress response. They control tissue differentiation (cardiomyocyte, skeletal muscle, monocyte) and remodeling (mammary gland involution), and paradoxically participate in tumor initiation and progression. Expression of miR-424(322)/-503 is governed by unique mechanisms involving sex hormones. Here, we summarize current literature and provide a primer for future endeavors. PMID- 30474695 TI - Estimating bone mass in children: can bone health index replace dual energy x-ray absorptiometry? AB - BACKGROUND: Bisphosphonates have been shown to increase metacarpal cortical width. Bone health index is computed from hand radiographs by measuring cortical thickness, width and length of the three middle metacarpals, and may potentially help predict fracture risk in children. OBJECTIVE: To compare bone health index with bone mineral density as measured from dual energy X-ray absorptiometry scans in patients with and without bisphosphonate treatment. MATERIALS AND METHODS: Two hundred ninety-three Caucasian patients (mean age: 11.5+/-3.7 years) were included. We documented absolute values and z-scores for whole-body less head and lumbar spine bone mineral density then correlated these with the bone health index, which were acquired on the same day, in different patient groups, depending on their ethnicity and diagnosis. RESULTS: Bone health index showed moderate to strong correlation with absolute values for whole-body (r=0.52) and lumbar spine (r=0.70) bone mineral density in those not treated with bisphosphonates and moderate correlation absolute values for whole-body (r=0.54) and lumber spine (r=0.51) bone mineral density for those treated with bisphosphonates. There was weak correlation of z-scores, ranging from r=0.11 to r=0.35 in both groups. CONCLUSION: The lack of a strong correlation between dual energy X-ray absorptiometry and bone health index suggests that they may be assessing different parameters. PMID- 30474696 TI - Amitriptyline attenuates bleomycin-induced pulmonary fibrosis: modulation of the expression of NF-kappabeta, iNOS, and Nrf2. AB - Amitriptyline is a tricyclic antidepressant that was suggested to have antifibrotic potential. The current study aimed to investigate the modulatory effects of amitriptyline on bleomycin-induced pulmonary fibrosis in rats. Rats were randomly assigned into 4 groups: normal control, bleomycin control, amitriptyline+bleomycin, and amitriptyline only treated group. Lung injury was evaluated through the histological examination and immunohistochemical detection of alpha-smooth muscle actin (alpha-SMA) in lung tissue, in addition to the biochemical assessment of pulmonary contents of hydroxyproline and transforming growth factor beta-1 (TGF-beta1). In addition, the following parameters were investigated for studying the possible mechanisms of amitriptyline antifibrotic effect: inducible nitric oxide synthase (iNOS), nuclear factor-kappabeta (NF kappabeta), tumor necrosis factor-alpha (TNF-alpha), serpine-1, p53, nuclear factor erythroid 2-related factor 2 (Nrf2), lipid peroxides, and reduced glutathione (GSH). Amitriptyline exhibited potent antifibrotic effect that was reflected upon the histopathological examination and through its ability to suppress all the fibrotic parameters. Amitriptyline successfully suppressed the expression of NF-kappabeta, Nrf2, iNOS, and p53 in lung tissues besides the inhibition of other oxidative stress and inflammatory mediators. Amitriptyline could be a promising treatment to pulmonary fibrosis. Amitriptyline not only prevents the depression and its drawbacks in patients suffering from pulmonary fibrosis but also it can suppress fibrosis through variable mechanisms mainly via inhibition of NF-kappabeta/TNF-alpha/TGF-beta pathway in addition to inhibition of Nrf2 and iNOS expression. PMID- 30474697 TI - Involvement of the two L-lactate dehydrogenase in development and pathogenicity in Fusarium graminearum. AB - Lactate dehydrogenase (LDH) widely exists in organisms, which catalyzes the interconversion of pyruvate into lactate with concomitant interconversion of NADH and NAD+. In this study, two L-type lactate dehydrogenase genes FgLDHL1 and FgLDHL2 were characterized in an ascomycete fungus Fusarium graminearum, a causal agent of wheat head blight. Both the single-gene deletion mutants of FgLDHL1 or FgLDHL2 exhibited phenotypic defects in vegetative growth, sporulation, spore germination, L-lactate biosynthesis and activity. Additionally, the two L-lactate dehydrogenases were involved in the utilization of carbon sources and maintenance of redox homeostasis during spore germination. Pathogenicity assays showed that DeltaFgLDHL1 exhibits reduced virulence on wheat spikelets and on corn stigmas, suggesting that it was indirectly correlated with a reduced level of deoxynivalenol accumulation. These results indicate that FgLDHL1 and FgLDHL2 play multiple roles in the developmental processes and pathogenesis in F. graminearum, and help understand the functional diversity of D-/L-lactate dehydrogenase in phytopathogenic fungi. PMID- 30474698 TI - Alpha-blockers are widely used in medical expulsion therapy for ureteral stones besides management of lower urinary tract symptoms. PMID- 30474699 TI - The side and the location of the primary tumor does not affect the probability of lymph node invasion in patients with renal cell carcinoma. AB - PURPOSE: To evaluate the role of side and location of the primary renal cell carcinoma (RCC) on the risk of lymph node invasion (LNI) and/or nodal progression (NP) during follow-up. MATERIALS AND METHODS: We evaluated 2485 patients with unilateral RCC, surgically treated in a single tertiary care referral center. Outcomes were LNI at surgery and/or NP during follow-up. We studied if RCC side (left vs. right) and location (upper vs. middle vs. hilar vs. lower area vs. more than one area) affected the probability of LNI and/or NP at follow-up. RESULTS: Overall, 43 and 15% of patients underwent lymph node dissection and had LNI at surgery, respectively. During follow-up, 2.2% of patients had NP. Higher rates of LNI and NP were observed for patients with primary tumor located in more than one anatomical kidney area relative to patients with tumor in a single area (upper 11% vs. middle 10% vs. hilar 0%, vs. lower 12% vs. more than one area 26%, p < 0.01). cM1, cN1, pT2/pT3/pT4 disease and Fuhrman grade 3/4 were independent predictors of the study outcome (all p <= 0.01). Neither the RCC side nor the location reached the independent predictor status (all p > 0.1). CONCLUSIONS: Patients with single-side and more than one anatomical kidney area affected by RCC have higher rate of LNI at surgery and/or NP at follow-up. Neither side nor location of primary RCC tumor is related to the risk of harboring LNI at surgery and/or developing NP at follow-up. PMID- 30474700 TI - The effects of two mixed intravenous lipid emulsions on clinical outcomes in infants after gastrointestinal surgery: a prospective, randomized study. AB - BACKGROUND: There are many advantages of a SMOF emulsion (SMOF-lipid), such as liver-protective properties and anti-inflammatory effects. The objective of this study was to compare the clinical outcomes of SMOF-lipid with medium-chain triglycerides (MCT) /long-chain triglycerides (LCT) in infants after intestinal surgery. METHODS: This was a prospective, randomized study. Neonates receiving intravenous nutrient solution, including lipid emulsion after gastrointestinal surgery, were included in this study. The patients were randomly assigned to the SMOF-lipid or MCT/LCT groups. Infants who received intravenous lipid emulsion continuously for > 2 weeks were considered to have completed the study. Differences in weight gain, nutrition indices, alanine transaminase (ALT), aspartate transaminase (AST), and direct bilirubin (DB), and inflammation cytokine markers (interleukin [IL]-6 and tumor necrosis factor [TNF]-alpha) were measured. RESULTS: The final sample included 160 infants. One hundred fourteen infants received intravenous SMOF-lipid (74) or MCT/LCT (86) > 2 weeks and 46 infants received intravenous SMOF-lipid (22) or MCT/LCT (24) > 4 weeks. There were no significant differences in weight gain, nutrition indices, inflammation cytokine markers, and sepsis between the groups at the end of 2 and 4 weeks; however, in the SMOF group, the ALT, AST, and DB levels were significantly lower than the MCT/LCT group at the end of 4 weeks. CONCLUSION: The mixture and balanced emulsion of SMOF-lipid was well-tolerated in infants who have undergone gastrointestinal surgery, and liver-protective properties were demonstrated following long-term venous nutrition, especially > 4 weeks. PMID- 30474701 TI - Mucosal bridges (MB): a 9-year retrospective study of their incidence with a third variant proposed. AB - BACKGROUND: Mucosal bridges (MBs) are rare laryngeal lesions that may cause dysphonia of varying degrees. We propose the existence of a third variant of MB besides thin and thick MBs, and have termed this as an incomplete mucosal bridge (IMB). The concept of an IMB has not been previously discussed in literature. Thin and thick MBs are attached anteriorly and posteriorly on the membranous vocal fold and may cause dysphonia because of their separate vibratory characteristics from the main vocal fold. We propose the presence of an entity named as IMB, which is typically identified by palpation of a slit on the superior surface of the membranous vocal fold. AIM: To propose and describe the existence of IMBs. Furthermore, to study the percentage of various types of MBs found while performing microlaryngeal surgeries (MLS) for benign glottic lesions, over a 9-year period at our Voice Clinic. METHOD: An IMB may be described as a MB that does not open at its medial edge. Thus it appears as an epithelial slit on the surface of the vocal fold. On palpating this slit with a microflap elevator, a flat pocket lying just below and parallel to the vocal fold epithelium is identified. These pockets are always directed medially (never laterally) and just stop short of opening up at the medial edge. These IMBs differ from sulci and focal pit as sulci and focal pits are not covered with a hood of epithelium. Our operative records of all MLS performed for benign glottic lesions were audited from 2009 to 2017 for cases of MBs. RESULTS: A total of 1728 MLS for benign glottic lesions were performed from 2009 to 2017 and 27 MBs were identified in 23 patients, 16 being male. A total of 11 IMBs were identified in 10 patients, with 1 case revealing a bilateral IMB. Other associated lesions were cysts, sulci, and polyps. A total of 14 thin MBs were identified in 11 patients with 3 cases revealing these bilaterally. Two thick MBs were identified in two separate cases, with one case having a bilobed hemorrhagic polyp attached to the thick MB. CONCLUSION: Our study found MBs in 1.33% of patients being operated for benign glottic lesions. The incidence of MBs in this group was 1.56% with IMBs accounting for 0.63%, thin MBs accounting for 0.81% and thick MBs in 0.11%. We recommend all patients undergoing MLS be actively palpated for the presence of mucosal bridges including IMBs especially if a small slit is found on the surface of the vocal fold. This is vital for accurate identification and documentation of all the lesions responsible for the patients voice quality. Ours is an ongoing study and we propose to analyze the vocal outcomes associated with surgical management of these IMBs. PMID- 30474702 TI - Differential incidence and morphology of provoked spasm between intracoronary acetylcholine and ergonovine testing: recommendation of supplementary use. AB - When cardiologists diagnose patients with coronary spastic angina, Japanese Circulation Society (JCS) guidelines recommend the intracoronary injection of acetylcholine (ACh) and ergonovine (ER) as class I. However, the pharmacological difference between ACh and ER is controversial in the clinic. We performed both ACh and ER tests in the same 528 patients during 26 years. We investigated the provoked spasm configuration, spasm site, and clinical characteristics of provoked spasm between ACh and ER, retrospectively. We defined positive spasm as >=90% luminal narrowing. Provoked positive spasm was observed in 161 right coronary arteries (RCA) including 83 ACh just positive, 35 ER just positive, and 43 both positive. In contrast, positive spasm was documented in 172 left coronary arteries (LCA) including 94 ACh just positive, 28 ER just positive, and 50 both positive. ACh provoked spasm more distally and diffusely, while ER induced spasm more proximally and totally or focally in the RCA. In the LCA, ACh provoked spasm more proximally, whereas ER induced spasm more distally. ER testing after the negative ACh tests of RCA and LCA documented new positive spasms in 10.3% (35/340) and 7.4% (28/376), respectively. Coronary artery trees may each have a sensitive receptor on each segment. We recommend the supplementary use of ACh and ER to document coronary artery spasm in the cardiac catheterization laboratory. PMID- 30474703 TI - Prevalence of TPMT, ITPA and NUDT 15 genetic polymorphisms and their relation to 6MP toxicity in north Indian children with acute lymphoblastic leukemia. AB - PURPOSE: Toxicity of 6-Mercaptopurine (6MP) is related to single nucleotide polymorphism (SNP) in genes coding for metabolizing enzymes, with TPMT analysis being recommended prior to maintenance therapy. However, ITPA and NUDT15 polymorphisms appear more important in the Asian population. METHOD: In this study 63 consecutive patients with ALL, entering maintenance phase of therapy, were evaluated for TPMT, ITPA and NUDT15 polymorphisms by PCR RFLP and confirmed by sequencing. Hematological and hepatic toxicities were monitored for 36 weeks. The groups with and without any of the three studied polymorphisms (Risk SNP + and Risk SNP-) were compared. RESULTS: Eighteen (28.6%) patients had major polymorphisms, 17 being heterozygous. ITPA(198CA): 11(17.5%); NUDT (415CT): 6(9.5%) and TPMT*3C: in 2(3.1%). Mean cumulative dose of 6MP was lower: 10927 mg/m2 in group with one of the polymorphisms compared to 12533 mg/m2 in the group without a polymorphism (p = 0.009). The group with Risk SNP + tolerated lesser weeks of full-dose 6MP chemotherapy (20.81 vs 30.40 weeks; p = 0.001). Risk of neutropenia > 3 weeks was pronounced in Risk SNP + group. The individual TPMT, ITPA and NUDT15 polymorphism subgroups had similar cumulative 6MP dose and chemotherapy interruptions. There was no difference in the average cumulative dose of methotrexate in the two groups. No significant hepatotoxicity was noted. CONCLUSION: Polymorphisms in ITPA and NUDT15 have a greater prevalence in the north Indian population. Patients with these SNPs tolerate lower doses of 6MP. PMID- 30474705 TI - Which lateral clavicle fractures can be treated by an arthroscopic-assisted endobutton procedure? An analysis of risk factors. AB - INTRODUCTION: Arthroscopy-assisted treatment of lateral clavicle fractures with coracoclavicular stabilization and an endobutton device have gained popularity over recent years. There is little evidence to support which types of lateral clavicle fractures are suitable for this treatment. The primary aim of this study was to evaluate the clinical und radiological outcomes of this treatment and to identify which fracture types are suitable. The secondary outcome was to evaluate potential risk factors for complications MATERIAL/METHODS: A retrospective single center review of 20 unstable lateral clavicle fractures treated with an arthroscopy-assisted CC stabilization technique and Endobutton device between September 2012 and August 2016. The functional outcome was evaluated using Constant and DASH Scores, VAS and SSV. RESULTS: Between September 2012 and August 2016, 20 patients were treated using this method (average age 45 years; male: female ratio 14:6). The DASH Score was on average 2.0 (0-9.82) and the Constant Score on average 81.8 points (range 68-93) with an average difference between the affected and the unaffected side of 4.1 points (range 0-15). Six patients had nonunion fractures of which two needed revision. CONCLUSIONS: Our study shows that arthroscopy-assisted CC stabilization using an endobutton technique delivers good functional results. Highly lateral unstable clavicle fractures seem to be especially suitable for this surgical technique. There was a high number of delayed unions. Analysis of risk factors showed that early mechanical stress, a lateral clavicular fragment larger than 3 cm and a time delay to surgery could be risk factors for nonunions. PMID- 30474704 TI - Toll-like receptor/interleukin-1 domain innate immune signalling pathway genetic variants are candidate predictors for severe gastrointestinal toxicity risk following 5-fluorouracil-based chemotherapy. AB - PURPOSE: Severe gastrointestinal (GI) toxicity is a common adverse effect following 5-fluorouracil (5-FU)-based chemotherapy treatment. The presence of severe GI toxicity leads to treatment revisions, sub-optimal therapy outcomes, and decreases to patients' quality of life. There are no adequate predictors for 5-FU-induced severe GI toxicity risk. The Toll-like receptor/interleukin-1 (TIR) domain innate immune signalling pathway is known to be a mediating pathway in the development of GI toxicity. Hence, genetic variability in this signalling pathway may alter the pathophysiology of GI toxicity and, therefore, be predictive of risk. However, little research has investigated the effects of TIR domain innate immune signalling pathway single nucleotide polymorphism (SNPs) on the risk and development of severe GI toxicity. METHODS: This critical review surveyed the literature and reported on the in vitro, ex vivo and in vivo effects, as well as the genetic association, of selected TIR domain innate immune signalling pathway SNPs on disease susceptibility and gene functioning. RESULTS: Of the TIR domain innate immune signalling pathway SNPs reviewed, evidence suggests interleukin-1 beta (IL1B) and tumour necrosis factor alpha (TNF) SNPs have the greatest potential as predictors for severe GI toxicity risk. These results warrant further research into the effect of IL1B and TNF SNPs on the risk and development of severe GI toxicity. CONCLUSIONS: SNPs of the TIR domain innate immune signalling pathway have profound effects on disease susceptibility and gene functioning, making them candidate predictors for severe GI toxicity risk. The identification of a predictor for 5-FU-induced severe GI toxicity will allow the personalization of supportive care measures. PMID- 30474706 TI - Outcome and safety of rechallenge [177Lu]Lu-PSMA-617 in patients with metastatic prostate cancer. AB - BACKGROUND: Data are sparse regarding the feasibility of radioligand therapy (RLT) with [177Lu]Lu-PSMA-617 as a retreatment. We aimed to assess the outcome and safety of rechallenge PSMA-RLT in patients with progressive prostatic cancer who previously benefited from this therapy. MATERIALS AND METHODS: Patients who received rechallenge therapy at our department from January 2015 to March 2018 were assessed. Non-haematological and haematological adverse events were evaluated from laboratory data and clinical reports and were graded according to the Common Terminology Criteria for Adverse Events (CTCAE v. 5.0). Time to prostate-specific-antigen (PSA) progression and the overall survival (OS) rate of the study patients were calculated from the date of the first rechallenge cycle. Furthermore, the OS calculated from the first cycle baseline PSMA-RLT was compared with the survival of patients who received only baseline PSMA-RLT. The response data were determined using [68Ga]Ga-PSMA-PET/CT and measurements of the tumour marker PSA. RESULTS: Included in this retrospective study were 30 patients who were initially treated with a median of 3 cycles (range 1-5) of PSMA-RLT and were eventually retreated after a median of 6 months (range 2-26). Each patient received a median of 3 (range 1-6) rechallenge cycles. None of the patients experienced a disabling or life-threatening grade 4 adverse event according to the Common Toxicity Criteria (CTC). Grade 3 toxicity occurred in 8 patients (27%). Serious adverse events included leucopoenia (n = 2), neutropoenia (n = 1), anaemia (n = 4), thrombopenia (n = 4) and elevated renal parameters (n = 1). Irreversible adverse events occurred in 21 patients (70%). The permanent adverse events were mild/moderate (CTC grade 1/2) in 19 patients and serious (CTC grade 3) in two patients, respectively. According to PSA measurements, 75-90% of patients showed a benefit (response/stable) from the first 4 rechallenge cycles. The median OS was 12 months calculated from the first rechallenge cycle and 25 months calculated from the first cycle baseline PSMA-RLT. For comparison, the median OS in patients who received only baseline PSMA-RLT was 9 months. The difference according to the logrank test was significant: p value <0.001. Patients with a PSA decrease after the first cycle of rechallenge PSMA-RLT survived a median of 19 months, while patients with a PSA increase survived only 6 months. CONCLUSION: Rechallenge prostate-specific membrane antigen (PSMA) therapy has an acceptable safety profile. The majority of the retreated patients benefited from the rechallenge therapy. Patients who showed a biochemical response achieved a longer OS compared to patients who did not respond. The median OS was significantly longer in patients after rechallenge PSMA-RLT than in patients who received only baseline PSMA-RLT. PMID- 30474707 TI - Lactobacillus futsaii subsp. chongqingii subsp. nov., Isolated from a Traditional Chinese Pickle. AB - Strain CQ16Z1T was isolated from jamiecosley, a traditional Chinese pickle. The isolate was Gram-positive, non-motile, non-spore-forming, facultatively anaerobic, catalase-negative, and long rod-shaped. The optimal temperature for growth was 37 degrees C and the DNA G + C content was 39.1 mol%. The results of 16S rRNA and rpoA gene sequencing, DNA-DNA hybridization, and peptidoglycan type analyses indicated that strain CQ16Z1T belongs to the recognized species Lactobacillus futsaii. However, the analysis results of pheS gene sequencing, amplified fragment length polymorphism, phenotypic profiles, cellular fatty acid, cell-wall monosaccharide determination, and cell morphology revealed that the novel strain was obviously different from the type strain L. futsaii JCM17355T, and had genetic relationship with Weissella cibaria to a certain degree, suggesting that the novel strain represents a novel subspecies of L. futsaii, for which the following names are proposed: L. futsaii subsp. futsaii subsp. nov. (type strain YM0097T = JCM 17355T = BCRC 80278T) and L. futsaii subsp. chongqingii subsp.nov., with the type strain CQ16Z1T (= CCTCC AB2017187T = KCTC 21089T). PMID- 30474708 TI - Significant Delay in the Detection of Desaturation between Finger Transmittance and Earlobe Reflectance Oximetry Probes during Fiberoptic Bronchoscopy: Analysis of 104 Cases. AB - PURPOSE: There is clinical significance to a delay in response time for detecting desaturation by pulse oximetry. Our aim in this study was to compare the response time of the reflectance and transmittance saturation probes during fiberoptic bronchoscopy (FOB) under monitored anesthesia care. METHODS: A prospective study included 104 patients scheduled for FOB. Patients were monitored with transmittance (finger) and reflectance (ear) oximetry probes. The response time was evaluated during desaturation and resaturation. We also acquired blood tests for arterial oxygen saturation to assess the agreement with the oximetry probes. RESULTS: Ninety patients had a desaturation episode during FOB and were included in the final analysis. Mean time difference between the reflectance ear probe (reference probe) and transmittance finger probe for the detection of desaturation (SpO2 = 90%) was + 36 s (CI 27.0-45.0, P < 0.001). The time difference between probes at end of desaturation episode (SpO2 = 95%) was + 31 s (CI 19.0-43.0; P < 0.001). A significant difference in response time was evident throughout the episode in all saturation values. The reflectance ear probe showed better agreement with arterial blood gases. The bias (and precision) for the earlobe and finger oximeters were of 0.24 (1.04) and 2.31 (3.37), respectively. CONCLUSION: The data displayed by a centrally located reflectance probe are more accurate and allows for earlier identification, treatment, and resolution of desaturation events. In light of these data and the added value of the reflectance probe ability to measure transcutaneous PCO2, we recommend monitoring bronchoscopy by a reflectance oximetry probe. PMID- 30474709 TI - Effect of High Glucose on Human Alveolar Macrophage Phenotype and Phagocytosis of Mycobacteria. AB - PURPOSE: Diabetes mellitus (DBM) reduces immunological activity and increases susceptibility to various infections, including tuberculosis (TB). Human alveolar macrophage (hAM) functions are altered in DBM. METHODS: To mimic hyperglycemic conditions in the lung alveolus, we co-cultured a hAM cell line (Daisy cell line) with human umbilical vein endothelial cells for 48 h in the presence of culture media alone, normal glucose (5 mM), and high glucose (22 mM). Using flow cytometry, immunophenotype characterization included cell surface markers CD 11c, CD14, CD16, CD86, CD163, CD169, CD206, CX3CR-1, CSF-1R, and matrix metalloproteinase-9 (MMP9). Phagocytic function was measured by immunofluorescence microscopy at 24 h after inoculation of cells with GFP expressing Mycobacterium smegmatis. RESULTS: Direct exposure of AMs to high glucose and exposure in the co-culture system yield different results for the same phenotypic markers. MMP9 expression was increased under both conditions. CD169 and CX3CR1 expressions were decreased when AMs were exposed directly to high glucose but increased under co-culture. Immunofluorescence assay revealed that phagocytosis decreased in AMs when directly exposed to increased glucose levels from 2.5 mM to normal glucose (5 mM), yet AMs under co-culture did not show decreased phagocytosis until concentrations were raised to 25 mM. CONCLUSION: Alteration in the expression of certain receptors may contribute to defective sentinel function of AMs, promoting susceptibility to TB in a diabetic host. Variability in cell surface marker expression under direct glucose exposure compared to exposure via co-culture reveals that cell signaling between endothelial cells and AMs may play a crucial role in the phenotypic expression of AMs. PMID- 30474710 TI - Common left carotid bifurcation at C7-Th1 level: a rare anatomical variant. AB - The left common carotid artery usually bifurcates to the internal and external carotids at or near the superior border of thyroid cartilage. In head and neck surgery, the common carotid arteries are important landmarks, defining the plane of dissection during radical neck surgeries. According to the literature, many variations exist regarding the carotid bifurcation. Anatomical knowledge of these variants is important for surgical approaches in the head and neck regions, to avoid devastating complications that may occur, mainly during anterior neck dissections. We report an interesting case of a 75-year-old male patient with low bifurcation of the left common carotid artery, accidentally found during a routine carotid Doppler ultrasonography. Bifurcation was located at the C7-Th1 intervertebral disc height, approximately 4 cm from the aortic arch. PMID- 30474711 TI - Functional magnetic resonance urography in infants: feasibility of a feed-and sleep technique. AB - BACKGROUND: Functional magnetic resonance (MR) urography has been well established in the diagnostic workup of congenital anomalies of kidneys and urinary tract, though long acquisition time requires sedation or general anesthesia in infants. OBJECTIVE: To evaluate the success rate of an optimized functional MR urography protocol in infants carried out in natural sleep. MATERIALS AND METHODS: We retrospectively evaluated all functional MR urographies performed under general anesthesia or during natural sleep in infants younger than 1 year between 2010 and 2017 and rated image quality in both cohorts using a 3-point Likert scale. We tested the analyzability of functional sequences using a free available software. We also calculated examination time. Finally, we compared examinations in natural sleep and those with general anesthesia using independent t-test for continuous data and Mann-Whitney U test for categorical data. RESULTS: Functional MR urography could be performed successfully during natural sleep in 38 of 42 (90%) infants younger than 10 months. Four examinations were aborted before contrast medium was administrated. In the same period, 19 functional MR urographies were performed successfully under general anesthesia. Although image quality was significantly better in this group (P<0.0001), image quality was at least diagnostic in all finished examinations in natural sleep, and the functional analyzability was given in all completed examinations. There was a significant saving in examination time during natural sleep (P<0.001). CONCLUSION: Functional MR urography can be successfully performed in natural sleep in infants younger than 10 months. PMID- 30474712 TI - Placental abruption and long-term cardiovascular morbidity of the offspring. AB - OBJECTIVE: While placental abruption is often associated with short-term adverse pregnancy outcomes, we sought to assess whether placental abruption increases the risk for long-term cardiovascular morbidity of the offspring. METHODS: To study the long-term cardiovascular hospitalizations of offspring of patients with and without placental abruption, cardiovascular morbidity was assessed up to the age of 18 years according to a predefined set of ICD-9 codes associated with hospitalization of the offspring. Our data consist of deliveries which occurred between the years 1991 and 2014 in a tertiary medical center. Pregnancies following fertility treatments, multifetal pregnancies, and pregnancies with offspring with congenital anomalies, lack of prenatal care, and perinatal mortality were excluded from the study. We used Kaplan-Meier curve to compare cumulative morbidity incidence and Cox proportional hazards model to control for confounder. RESULTS: During the study period, we examined 217,910 deliveries, out of which 0.46% (n = 1003) were effected by placental abruption. Compared to normal birth children, children born to mothers with placental abruption did not show a significantly higher cumulative incidence of long-term cardiovascular morbidity (1.0% vs. 0.6%; p = 0.127). Placental abruption was not noted as an independent risk factor for long-term cardiovascular morbidity of offspring in the Cox regression analysis, which adjusted for confounders. CONCLUSION: Our study does not support the association between placental abruption and risk for long-term cardiovascular morbidity of the offspring. PMID- 30474713 TI - Review on current treatment options for lesions of uncertain malignant potential (B3 lesions) of the breast: do B3 papillary lesions need to be removed in any case by open surgery? AB - BACKGROUND: In breast tissue, pre-malignant lesions are classified as BIRADS 3. The treatment of this heterogeneous group varies with expertise and tools available. MATERIALS AND METHODS: With the example of two case reports, the literature is reviewed on current treatment options for BIRADS 3 breast lesions. RESULTS: About 7% of all B-type breast biopsies fall into the B3 category. Approximately 35% of these B3 lesions are due to FEA, 20% to PLs and another 20% to ADH. Due to improvement in diagnostics, the incidence is increasing, while their value as a predictive factor for malignancy has steadily been fallen. CONCLUSION: Depending on the histology of the needle biopsy, a complete resection with vacuum-assisted biopsy may be a treatment alternative to open biopsy. PMID- 30474714 TI - Cerebro-venous hypertension: a frequent cause of so-called "external hydrocephalus" in infants. AB - INTRODUCTION: External hydrocephalus (eHC) is commonly defined as a subtype of infant "hydrocephalus" consisting of macrocepahly associated with enlarged subarachnoid space and no or mild ventriculomegaly. This status is thought to be related to impaired CSF absorption because of arachnoid villi immaturity. However, other factors like the venous system might be involved in the development of the clinical picture. METHODS: All patients diagnosed with eHC received prospectively contrast-enhanced 3D MR phlebography. Venous sis abnormalities were graded depending on the number of affected sinus segments and type. External CSF space volume was quantified planimetrically. RESULTS: Seventeen patients with the typical clinical feature of eHC were included. In 15, venous sinus abnormalities were found. There was a significant correlation between the volume of the widened cortical subarachnoid space (CSAS) and the number of venous sinus segments affected. Conversely, ventricular volume was not correlated. CONCLUSION: These results support the hypothesis that impaired venous outflow plays a major role in external hydrocephalus development. Raised venous pressure increases intracranial pressure accelerating head growth, resulting in an enlargement of the cortical subarachnoid space. Increased venous pressure increases the capillary bed pressure and brain turgor preventing ventricular space to enlarge forcing displacement of ventricular CSF to the subarachnoid space. As a result, ventriculomegaly is rarely found. The descriptive term "external hydrocephalus" implying a primary etiology within the CSF system is misleading and this work supports the notion that venous hypertension is the leading cause of the clinical picture. PMID- 30474715 TI - Radiosurgical treatment of arteriovenous malformations in a retrospective study group of 33 children: the importance of radiobiological scores. AB - PURPOSE: Arteriovenous malformations' (AVMs) obliteration depends on several factors; among the many factors that must be considered to obtain a high rate of obliteration and a low rate of complications, Flickinger-Pollock Score (FPS) seems to have an important role but still have to be validated in the pediatric population while Paddick-Conformity Index (PCI) still has no demonstration of its utility on the outcome and is considered only as a treatment quality marker. METHODS: We retrospectively analyzed 33 consecutive children (2-18 years) with an AVM, treated with stereotactic radiosurgery Gamma Knife (SRS-GK) from 2001 to 2014 in our institution. We assess angiographic (DSA) Obliteration Rate (OR) as well FPS and PCI to draw conclusions. RESULTS: DSA-OR was 60.6% with a rate of hemorrhage of 0%. median target volume (TV) was 3.60 cc (mean 4.32 +/- 3.63; range 0.15-14.2), median PD was 22 Gy (mean 21.4 +/- 2.6; range 16.5-25). Median percentage of coverage was 98% (mean 97 +/- 3; range 84-100). The median modified FPS was 0.78 (mean 0.89 +/- 0.52; range 0.21-2.1) and highly correlate with OR (p = 0.01). The median PCI was 0.65 (mean 0.65 +/- 0.14; range 0.34-0.95) A PCI lower than 0.57 highly correlates with final OR (p = 0.02). CONCLUSION: SRS-GK was safe and gradually effective in children. A prescription dose-like that used in adult population (i.e. > 18 and between 20 and 25 Gy) is essential to achieve obliteration. A PD of 23 Gy and 22 Gy did impact OR, respectively (p = 0.02) and (p = 0.05). FPS and PCI are valuable scores that seem to correlate with the OR also in the pediatric population although further prospective studies are needed to confirm these observations. PMID- 30474716 TI - Probing the effect of a room temperature ionic liquid on phospholipid membranes in multilamellar vesicles. AB - The large number of potential applications of ionic liquids (ILs) requires an understanding of their environmental impacts including their adverse effects on microorganisms living in soil and water. The molecular mechanism of toxic activities of these liquids is yet to be understood in detail. Any foreign molecules, interacting with an organism, have to encounter first the cellular membrane, which is predominantly composed of the lipid bilayer. In this work, multilamellar vesicles (MLV) of phospholipids have been used to shed light on the effect of an IL on the structure of a cellular membrane. The MLVs formed by the zwitterionic lipid, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) are found to shrink as a consequence of interaction with an imidazolium-based IL, 1-decyl-3 methylimidazolium tetrafluoroborate ([DMIM] [BF4]). The absorbed ILs significantly modify the surface charge of the MLVs. While these observations indicate a strong membrane-IL interaction, synchrotron-based small angle X-ray diffraction (SAXD) measurements provide a structural description of the interaction. SAXD and Fourier transform infrared spectroscopy studies clearly reveal a disordering effect of the IL on the conformational organization of the lipid chains. The presence of the negatively charged lipid 1,2-dipalmitoyl-sn glycero-3-phospho-L-serine sodium salt (DPPS) in MLVs plays an important role in disordering the chains in the membrane and inter-bilayer interactions. PMID- 30474717 TI - Effects of ripasudil, a rho kinase inhibitor, on blood flow in the optic nerve head of normal rats. AB - PURPOSE: To evaluate the effect of topically administrated ripasudil, a rho kinase inhibitor, on blood flow in the optic nerve head (ONH) of normal rats. METHODS: Ripasudil (0.4%) or placebo was administered in the right eye of normal Brown Norway rats in a double-blind manner. Laser speckle flowgraphy was measured in the ONH of the right eye 20 or 40 min after a single instillation and before and after 7 or 14 days of twice daily instillation. Mean blur rate was evaluated in the total area (MA), the vessel region (MV), and the tissue region (MT). Intraocular pressure (IOP), blood pressure, ocular perfusion pressure (OPP), and heart rate were also recorded at each time point. RESULTS: After a single instillation, MV was significantly larger at 40 min than 20 min in the ripasudil group (P = 0.044) and was significantly lower in the placebo group (P = 0.023). MA and MV 40 min after instillation were significantly larger in the ripasudil group than in the placebo group (P = 0.022 and P = 0.006, respectively). After continuous instillation, MA and MV in the ripasudil group significantly increased from baseline after 7 and 14 days of treatment (both P < 0.05) and MA, MV, and MT were significantly higher than in the placebo group (MA: 7 and 14 days, P < 0.01; MV: 7 days, P = 0.003, and 14 days, P = 0.012; MT: 7 days, P = 0.046). There were no significant changes in IOP, blood pressure, or OPP after single or continuous instillation. CONCLUSIONS: Topical instillation of ripasudil increased blood flow around the ONH in the eyes of normal rats. PMID- 30474720 TI - Persistence with biological drugs in patients treated in rheumatology practices in Germany. AB - The goal of this study was to investigate the persistence with biological drugs in patients treated in rheumatology practices in Germany. This study included patients diagnosed with rheumatoid arthritis (RA), psoriatic arthritis (PA), or ankylosing spondylitis (AS) who received a first prescription of biological drugs between 2008 and 2016 (index date) in 21 rheumatology practices in Germany (n = 4925; Disease Analyzer database). The main outcome measure was the rate of persistence within 5 years of the index date. Kaplan-Meier analyses were performed to study treatment persistence as a function of diagnosis, gender and age. A Cox proportional hazards regression model was used to estimate the relationship between non-persistence and diagnosis, gender, age, and comorbidities. After 5 years of follow-up, the rate of persistence was 31.8% in patients with RA, 35.2% in those with AS, and 33.2% in those with PA (log-rank p value = 0.028). Furthermore, 33.8% of men and 31.9% of women were persistent (log rank p value = 0.035). The rate of persistence was 20.8%, 27.9%, 33.0%, 36.6%, 35.2%, and 32.0% in people aged <= 30, 31-40, 41-50, 51-60, 61-70, and > 70 years, respectively (log-rank p value = 0.002). The risk of discontinuation was lower in participants diagnosed with AS than in those diagnosed with RA [hazard ratio (HR) = 0.87; 95% confidence interval (CI) 0.79-0.96]. In addition, patients aged <= 30 years were more likely to discontinue their biological therapy than those aged > 70 years (HR = 1.29; 95% CI 1.10-1.52). Persistence with biological drugs was low after 5 years of follow-up in rheumatology practices. PMID- 30474718 TI - Comparison of blast percentage calculated based on bone marrow all nucleated cells and non-erythroid cells in myelodysplastic syndromes with erythroid hyperplasia. AB - It is controversial whether blast percentage based on all nucleated cells (ANC) or non-erythroid cells (NEC) more accurately reflects the prognosis of patients with myelodysplastic syndromes (MDS). We considered that the impact of blast percentage on survival should be similar in MDS with erythroid hyperplasia (MDS E) and MDS with no erythroid hyperplasia (MDS-NE), and from this perspective, we retrospectively analyzed 322 patients, including 44 with MDS-E and 278 with MDS NE. Overall survival was similar between the MDS-E and MDS-NE groups (P = 0.94). In a subgroup of patients with bone marrow (BM) blasts of < 5%, no difference in survival was found between MDS-E and MDS-NE by either calculation method. However, in patients with a blast percentage between 5 and 10%, a significant difference in survival was observed only when the blast percentage in MDS-E was calculated from ANC (P < 0.001 by ANC and P = 0.66 by NEC). A similar result was observed when we analyzed the remaining patients with higher blasts together with those with blasts between 5 and 10%. These results suggest that the calculation of the BM blast percentage based on NEC in MDS-E provides a blast percentage value with a clinical impact consistent with that in MDS-NE. PMID- 30474719 TI - Folate receptor-targeted novel boron compound for boron neutron capture therapy on F98 glioma-bearing rats. AB - Folic acid (FA) has high affinity for the folate receptor (FR), which is limited expressed in normal human tissues, but over-expressed in several tumor cells, including glioblastoma cells. In the present work, a novel pteroyl-closo dodecaborate conjugate (PBC) was developed, in which the pteroyl group interacts with FR, and the efficacy of boron neutron capture therapy (BNCT) using PBC was investigated. Thus, in vitro and in vivo studies were performed using F98 rat glioma cells and F98 glioma-bearing rats. For the in vivo study, boronophenylalanine (BPA) was intravenously administered, while PBC was administered by convection-enhanced delivery (CED)-a method for direct local drug infusion into the brain of rats. Furthermore, a combination of PBC administered by CED and BPA administered by intravenous (i.v.) injection was also investigated. In the biodistribution experiment, PBC administration at 6 h after CED termination showed the highest cellular boron concentrations (64.6 +/- 29.6 ug B/g). Median survival time (MST) of untreated controls was 23.0 days (range 21 24 days). MST of rats administered PBC (CED) followed by neutron irradiation was 31 days (range 26-36 days), which was similar to that of rats administered i.v. BPA (30 days; range 25-37 days). Moreover, the combination group [PBC (CED) and i.v. BPA] showed the longest MST (38 days; range 28-40 days). It is concluded that a significant MST increase was noted in the survival time of the combination group of PBC (CED) and i.v. BPA compared to that in the single-boron agent groups. These findings suggest that the combination use of PBC (CED) has additional effects. PMID- 30474723 TI - Structured reporting of MRI for perianal fistula. AB - OBJECTIVE: The purpose of this article is to review MRI technique, relevant anatomy, and MRI classification systems for the assessment of perianal fistulising disease. We present a stepwise approach to the assessment of perianal fistulas on MRI utilizing a systematic reporting format. CONCLUSION: MRI is invaluable for the assessment of perianal fistulas. A systematic report can help communicate the anatomy of complex fistulising disease to assist with optimal management. PMID- 30474721 TI - How elderly rheumatoid arthritis patients respond at one year of treatment with certolizumab pegol. PMID- 30474722 TI - Association between CT-texture-derived tumor heterogeneity, outcomes, and BRCA mutation status in patients with high-grade serous ovarian cancer. AB - PURPOSE: To assess the associations between inter-site texture heterogeneity parameters derived from computed tomography (CT), survival, and BRCA mutation status in women with high-grade serous ovarian cancer (HGSOC). MATERIALS AND METHODS: Retrospective study of 88 HGSOC patients undergoing CT and BRCA mutation status testing prior to primary cytoreductive surgery. Associations between texture metrics-namely inter-site cluster variance (SCV), inter-site cluster prominence (SCP), inter-site cluster entropy (SE)-and overall survival (OS), progression-free survival (PFS) as well as BRCA mutation status were assessed. RESULTS: Higher inter-site cluster variance (SCV) was associated with lower PFS (p = 0.006) and OS (p = 0.003). Higher inter-site cluster prominence (SCP) was associated with lower PFS (p = 0.02) and higher inter-site cluster entropy (SE) correlated with lower OS (p = 0.01). Higher values of all three metrics were significantly associated with lower complete surgical resection status in BRCA negative patients (SE p = 0.039, SCV p = 0.006, SCP p = 0.02), but not in BRCA positive patients (SE p = 0.7, SCV p = 0.91, SCP p = 0.67). None of the metrics were able to distinguish between BRCA mutation carrier and non-mutation carrier. CONCLUSION: The assessment of tumoral heterogeneity in the era of personalized medicine is important, as increased heterogeneity has been associated with distinct genomic abnormalities and worse patient outcomes. A radiomics approach using standard-of-care CT scans might have a clinical impact by offering a non invasive tool to predict outcome and therefore improving treatment effectiveness. However, it was not able to assess BRCA mutation status in women with HGSOC. PMID- 30474724 TI - Quantification and differentiation of composition of mixed pancreatic duct stones using single-source dual-energy CT: an ex vivo study. AB - PURPOSE: To evaluate the feasibility of using single-source dual-energy CT (SS DECT) to quantify and differentiate calcium carbonate (CA) and non-calcium carbonate (NCA) components of pancreatic duct stones (PDS) with mixed composition. MATERIALS AND METHODS: A total of 12 PDS harvested from general surgery department in our hospital were analyzed with micro-CT as a reference standard for CA and NCA composition. These stones were placed in a TOS water phantom of 35 cm diameter to simulate standard adult body size. High- and low energy image sets were acquired from SS DECT scans with high/low tube potential pairs of 80 kVp/140 kVp. All the image sets were imported into an in-house software for further post-processing. CT number ratio (CTR), defined as the ratio of the CT number at 80 kVp to 140 kVp was calculated for each pixel of the images. Threshold was preset between 1.00 and 1.25 to classify CA and NCA components. Pixels in PDS with CTR higher than the threshold were classified as CA, and those with CTR lower than the threshold were classified as NCA. The percentages of CA and NCA for each stone were determined by calculating the number of CA and NCA pixels. Finally, the minimal, maximal and root-mean-square errors (RMSE) of composition measured by SS DECT under each threshold were calculated by referring to the composition data from micro-CT. The optimal threshold was determined with the minimal RMSE. A paired t test was used to compare the stone composition determined by DECT with micro-CT. RESULTS: The optimal CTR threshold was 1.16, with RMSE of 6.0%. The minimum and maximum absolute errors were 0.22% and 11.35%, respectively. Paired t test showed no significant difference between DECT and micro-CT for characterizing CA and NCA composition (p = 0.414). CONCLUSION: SS DECT is a potential approach for quantifying and differentiating CA and NCA components in PDS with mixed composition. PMID- 30474725 TI - Hydrothermal liquefaction of organic resources in biotechnology: how does it work and what can be achieved? AB - Increasing the overall carbon and energy efficiency by integration of thermal processes with biological ones has gained considerable attention lately, especially within biorefining. A technology that is capable of processing wet feedstock with good energy efficiency is advantageous. Such a technology, exploiting the special properties of hot compressed water is called hydrothermal liquefaction. The reaction traditionally considered to take place at moderate temperatures (200-350 degrees C) and high pressures (10-25 MPa) although recent findings show the benefits of increased pressure at higher temperature regions. Hydrothermal liquefaction is quite robust, and in theory, all wet feedstock, including residues and waste streams, can be processed. The main product is a so called bio-crude or bio-oil, which is then further upgraded to fuels or chemicals. Hydrothermal liquefaction is currently at pilot/demo stage with several lab reactors and a few pilots already available as well as there are a few demonstration plants under construction. The applied conditions are quite severe for the processing equipment and materials, and several challenges remain before the technology is commercial. In this review, a description is given about the influence of the feedstock, relevant for integration with biological processing, as well as the processing conditions on the hydrothermal process and products composition. In addition, the relevant upgrading methods are presented. PMID- 30474726 TI - Combined antioxidant-biofuel production from coffee silverskin. AB - Biorefinery concept asks for an integrated processing approach to exploit all biomass components. The self-sustainability target may be approached if molecules characterized by high added value and fermentable sugars are produced simultaneously. In the present study, sequential (i) mild hydrothermal pretreatment to produce antioxidants and (ii) NaOH pretreatment to produce a fermentable sugar solution were carried out on coffee silverskin. Twenty-minute treatment and biomass to liquid ratio 1:30 (g mL-1) were identified as optimal operating conditions to extract bioactive compounds characterized by antioxidant activity (22.2 mgGAE/gCSS; 13.9 mgTE/gCSS). Twenty-minutes and biomass to liquid ratio of 1:20 (g mL-1) were identified as optimal operating conditions to maximize sugar recovery and ABE production (solvent yield YABE/Sugars and ABE productivity of 0.21 g g-1 and 0.12 g L-1 h-1 were obtained, respectively). The study marks the highly economic potential of the process aimed to exploit the CSS as feesdstock for antioxidant and biofuel production. PMID- 30474727 TI - Diazotrophic microbial community and abundance in acidic subtropical natural and re-vegetated forest soils revealed by high-throughput sequencing of nifH gene. AB - Biological nitrogen fixation (BNF) is an important natural biochemical process converting the inert dinitrogen gas (N2) in the atmosphere to ammonia (NH3) in the N cycle. In this study, the nifH gene was chosen to detect the diazotrophic microorganisms with high-throughput sequencing from five acidic forest soils, including three natural forests and two re-vegetated forests. Soil samples were taken in two seasons (summer and winter) at two depth layers (surface and lower depths). A dataset of 179,600 reads obtained from 20 samples were analyzed to provide the microbial community structure, diversity, abundance, and relationship with physiochemical parameters. Both archaea and bacteria were detected in these samples and diazotrophic bacteria were the dominant members contributing to the biological dinitrogen fixation in the acidic forest soils. Cyanobacteria, Firmicutes, Proteobacteria, Spirocheates, and Verrucomicrobia were observed, especially the Proteobacteria as the most abundant phylum. The core genera were Bradyrhizobium and Methylobacterium from alpha-Proteobacteia, and Desulfovibrio from delta-Proteobacteia in the phylum of Proteobacteia of these samples. The diversity indices and the gene abundances of all samples were higher in the surface layer than the lower layer. Diversity was apparently higher in re vegetated forests than the natural forests. Significant positive correlation to the organic matter and nitrogen-related parameters was observed, but there was no significant seasonal variation on the community structure and diversity in these samples between the summer and winter. The application of high-throughput sequencing method provides a better understanding and more comprehensive information of diazotrophs in acidic forest soils than conventional and PCR-based ones. PMID- 30474728 TI - Methanotrophic contribution to biodegradation of phenoxy acids in cultures enriched from a groundwater-fed rapid sand filter. AB - Drinking water supply is in many parts of the world based on groundwater. Groundwater often contains methane, which can be oxidized by methanotrophs upon aeration. Sand from rapid sand filters fed with methane-rich groundwater can remove some pesticides (Hedegaard and Albrechtsen in Water Res 48:71-81, 2014). We enriched methanotrophs from filter sand and investigated whether they could drive the degradation of various pesticides. To enrich for methanotrophs, we designed and operated four laboratory-scale, continuously methane-fed column reactors, inoculated with filter sand and one control column fed with tap water. When enrichments were obtained, methane was continuously supplied to three reactors, while the fourth was starved for methane for 1 week, and the reactors were spiked with ten pesticides at groundwater-relevant concentrations (2.1-6.6 MUg/L). Removal for most pesticides was not detected at the investigated contact time (1.37 min). However, the degradation of phenoxy acids was observed in the methanotrophic column reactor starved for methane, while it was not detected in the control column indicating the importance of methanotrophs. Phenoxy acid removal, using dichlorprop as a model compound, was further investigated in batch experiments with methanotrophic biomass collected from the enrichment reactors. Phenoxy acid removal (expressed per gram of matrix sand) was substantially improved in the methanotrophic enrichment compared to parent filter sand. The presence of methane did not clearly impact dichlorprop removal but did impact mineralization. We suggest that other heterotrophs are responsible for the first step in dichlorprop degradation, while the subsequent steps including ring hydroxylation are driven by methanotrophs. PMID- 30474729 TI - Bacteriophage production processes. AB - High quantities of bacteriophages are currently used in the food industry and agriculture. However, growing antibiotic resistance of bacteria has recently awakened the interest to use bacteriophages for the treatment of bacterial infections in humans indicating that even higher quantities will be required in the future. High demand combined with a wide range of applications requires also efficient bacteriophage production processes operating at low production costs and with high productivity. To achieve this goal, different approaches were introduced and extensive studies of various parameters affecting bacteriophage formation were investigated. In this mini-review, we provide a short overview about different operation modes of bacteriophage production such as batch, semi continuous and especially continuous with the pros and cons of each. We present factors affecting bacterial physiological state, its effect on phage formation and provide a description of methods for determination of bacteriophage growth parameters, through which bacteriophage formation is obtained. Understanding of described phenomena and inclusion of potential occurrence of mutations and selection in continuous systems enables evaluation of continuous process productivity and its optimization. PMID- 30474730 TI - The Oral Bacterium Fusobacterium nucleatum Binds Staphylococcus aureus and Alters Expression of the Staphylococcal Accessory Regulator sarA. AB - Staphylococcus aureus, an opportunistic pathogen member of the nasal and skin microbiota, can also be found in human oral samples and has been linked to infectious diseases of the oral cavity. As the nasal and oral cavities are anatomically connected, it is currently unclear whether S. aureus can colonize the oral cavity and become part of the oral microbiota, or if its presence in the oral cavity is simply transient. To start addressing this question, we assessed S. aureus ability to directly bind selected members of the oral microbiota as well as its ability to integrate into a human-derived complex oral microbial community in vitro. Our data show that S. aureus forms aggregates with Fusobacterium nucleatum and Porphyromonas gingivalis and that it can incorporate into the human-derived in vitro oral community. Further analysis of the F. nucleatum-S. aureus interaction revealed that the outer-membrane adhesin RadD is partially involved in aggregate formation and that the RadD-mediated interaction leads to an increase in expression of the staphylococcal global regulator gene sarA. Our findings lend support to the notion that S. aureus can become part of the complex microbiota of the human mouth, which could serve as a reservoir for S. aureus. Furthermore, direct interaction with key members of the oral microbiota could affect S. aureus pathogenicity contributing to the development of several S. aureus associated oral infections. PMID- 30474731 TI - Distribution and Variation of Bacterial Endosymbiont and "Candidatus Liberibacter asiaticus" Titer in the Huanglongbing Insect Vector, Diaphorina citri Kuwayama. AB - The Asian citrus psyllid (ACP), Diaphorina citri Kuwayama, is an economic insect pest in most citrus-growing regions and the vector of 'Candidatus Liberibacter asiaticus' (CLas), one of at least three known bacteria associated with Huanglongbing (HLB or citrus greening disease). D. citri harbors bacterial endosymbionts, including Wolbachia pipientis (strain Wolbachia wDi), 'Candidatus Carsonella ruddii,' and 'Candidatus Profftella armatura.' Many important functions of these bacteria can be inferred from their genome sequences, but their interactions with each other, CLas, and their D. citri host are poorly understood. In the present study, the titers of the endosymbionts in different tissues, in each sex, and in insects reared on healthy citrus (referred to as unexposed) and CLas-infected citrus (referred to as CLas-exposed) D. citri were investigated using real-time, quantitative PCR (qPCR) using two different quantitative approaches. Wolbachia and CLas were detected in all insect tissues. The titer of Wolbachia was higher in heads of CLas-exposed males as compared to unexposed males. In males and females, Wolbachia titer was highest in the Malpighian tubules. The highest titer of CLas was observed in the gut. Profftella and Carsonella titers were significantly reduced in the bacteriome of CLas exposed males compared with that of unexposed males, but this effect was not observed in females. In ovaries of CLas-exposed females, the Profftella and Carsonella titers were increased as compared to non-exposed females. CLas appeared to influence the overall levels of the symbionts but did not drastically perturb the overall microbial community structure. In all the assessed tissues, CLas titer in males was significantly higher than that of females using absolute quantification. These data provide a better understanding of multi-trophic interactions regulating symbiont dynamics in the HLB pathosystem. PMID- 30474732 TI - Efficiency of the TOF-CuffTM for the evaluation of rocuronium-induced neuromuscular block and its reversal with sugammadex: a comparative study vs. acceleromyography. AB - PURPOSE: The aim of this study was to compare TOF-CuffTM (TOF-C) and TOF-WatchTM (TOF-W) data following rocuronium-induced neuromuscular block and its reversal with sugammadex. METHODS: Twenty elderly patients aged 68-82 years scheduled for surgery under general anesthesia were enrolled in this study. After induction of anesthesia, neuromuscular block resulting from administration of 0.6 mg/kg rocuronium was concurrently evaluated using TOF-C and TOF-W. The onset of neuromuscular block and duration until the first twitch response following post tetanic count (PTC) and 2 Hz train-of-four (TOF) stimulation reappeared were evaluated. When the response to the TOF stimulus was detected with both monitors, additional doses of rocuronium were administered to maintain the neuromuscular block. After surgery, 2 mg/kg sugammadex was administered when 1-2 TOF twitches were observed with the TOF-W and the time required for facilitated recovery to a TOF ratio of > 0.9 was assessed. RESULTS: Regression analyses revealed no statistically significant differences in the mean [SD] onset of rocuronium induced neuromuscular block [127.8 (27.2) s, 123.5 (30.5) s], time to recovery of the first PTC twitch [23.9 (8.0) min, 25.4 (8.6) min], time to recovery of the first twitch with TOF stimulation [37.2 (8.8) min, 38.9 (11.1) min] and time to adequate reversal with sugammadex [139.2 (30.6) s, 151.8 (31.5) s] between TOF-C and TOF-W, respectively. Bland-Altman analyses also showed acceptable ranges of the biases and limits of agreement between the two methods. CONCLUSIONS: TOF-C may be clinically applicable for the evaluation of both the depth of neuromuscular block and restoration of neuromuscular function. PMID- 30474733 TI - Predicting long-term sickness absence among employees with frequent sickness absence. AB - PURPOSE: Frequent absentees are at risk of long-term sickness absence (SA). The aim of the study is to develop prediction models for long-term SA among frequent absentees. METHODS: Data were obtained from 53,833 workers who participated in occupational health surveys in the period 2010-2013; 4204 of them were frequent absentees (i.e., employees with >= 3 SA spells in the year prior to the survey). The survey data of the frequent absentees were used to develop two prediction models: model 1 including job demands and job resources and model 2 including burnout and work engagement. Discrimination between frequent absentees with and without long-term SA during follow-up was assessed with the area under the receiver operating characteristic curve (AUC); (AUC) >= 0.75 was considered useful for practice. RESULTS: A total of 3563 employees had complete data for analyses and 685 (19%) of them had long-term SA during 1-year follow-up. The final model 1 included age, gender, education, marital status, prior long-term SA, work pace, role clarity and learning opportunities. Discrimination between frequent absentees with and without long-term SA was significant (AUC 0.623; 95% CI 0.601-0.646), but not useful for practice. Model 2 showed comparable discrimination (AUC 0.624; 95% CI 0.596-0.651) with age, gender, education, marital status, prior long-term SA, burnout and work engagement as predictor variables. Differentiating by gender or sickness absence cause did not result in better discrimination. CONCLUSIONS: Both prediction models discriminated significantly between frequent absentees with and without long-term SA during 1 year follow-up, but have to be further developed for use in healthcare practice. PMID- 30474734 TI - Psychological treatments for return to work in individuals on sickness absence due to common mental disorders or musculoskeletal disorders: a systematic review and meta-analysis of randomized-controlled trials. AB - PURPOSE: Common mental disorders (CMDs) and musculoskeletal disorders are highly prevalent in the population and cause significant distress and disability, and high costs to society. The main objective of this systematic review and meta analysis was to examine the outcome and comparative effectiveness of psychological interventions in reducing sickness absence (SA) due to CMDs or musculoskeletal disorders, compared to a waitlist control group, usual care or another clinical intervention. METHODS: We reviewed 3515 abstracts of randomized controlled trials published from 1998 to 2017. Of these, 30 studies were included in the analysis. RESULTS: The psychological interventions were overall more effective than treatment as usual in reducing SA (small effect sizes), but not compared to other clinical interventions. Results were similar for studies on CMDs and musculoskeletal pain. A few significant moderating effects were found for treatment-specific variables. However, these were difficult to interpret as they pointed in different directions. CONCLUSION: There was a small but significant effect of psychological treatments in reducing SA. We identified areas of improvement such as methodological problems among the included studies and failure to specifically address RTW in the interventions that were evaluated. Clinical implications of the findings, and ways of improving methodological rigour of future studies are discussed. PMID- 30474736 TI - Association of emergency department admission and early inpatient palliative care consultation with hospital mortality in a comprehensive cancer center. AB - PURPOSE: Consultation to palliative care (PC) services in hospitalized patients is frequently late after admission to a hospital. The purpose of this study is to examine the association of in-hospital mortality and timing of palliative care consultation in cancer patients admitted through the emergency department (ED) of MD Anderson Cancer Center. METHODS: Institutional databases were queried for unique medical admissions over a period of 1 year. Primary cancer type, ED versus direct admission, length of stay (LOS), presenting symptoms, and in-hospital mortality were reviewed; patient data were analyzed, and risk factors for in hospital mortality were identified. The association of early palliative care consultation (within 3 days of admission) with these outcomes was studied. Descriptive statistics and multivariate logistic regression model were used. RESULTS: Equal numbers of patients were admitted directly versus through the ED (7598 and 7538 respectively). However, of all patients who died in the hospital, 990 (88%) were admitted through the ED, compared with 137 admitted directly (P < 0.001). Patients who died in the hospital had longer median LOS compared with patients who were discharged alive (11 vs. 4 days, respectively, P < 0.001). Early palliative care consultation was associated with decreased mortality, compared with late consultation (P < 0.001). Chief complaints of respiratory problems, neurologic issues, or fatigue/weakness were significantly associated with in-hospital mortality. CONCLUSION: We found an association between ED admission and hospital mortality. Decedent cancer patients had a prolonged LOS, and early palliative care consultation for terminally ill symptomatic patients may prevent in-hospital mortality and improve quality of cancer care. PMID- 30474735 TI - Short- and long-term outcomes of choledochojejunostomy during pancreaticoduodenectomy and total pancreatectomy: interrupted suture versus continuous suture. AB - PURPOSE: Choledochojejunostomy can be performed with either interrupted sutures (IS) or continuous sutures (CS). No reports have compared the short- or long-term patient outcomes resulting from these two methods. METHODS: A total of 228 consecutive patients who underwent pancreaticoduodenectomy or total pancreatectomy were prospectively enrolled in this study. All patients were alternately (by turns) assigned to the IS and CS groups. Among those patients, 161 patients who received regular postoperative follow-up for more than 2 years were eligible for analysis (IS group, n = 81; CS group, n = 80). A comparative analysis was performed between these groups regarding short-term (e.g., anastomotic leakage) and long-term complications (e.g., anastomotic stricture), time required to complete the anastomosis, and cost. RESULTS: The incidence of anastomotic leakage and anastomotic stricture was comparable between the IS and CS groups (1.2% vs. 1.2%, p = 0.993; 8.6% vs. 6.2%, p = 0.563). The groups did not differ regarding the incidence of any short- or long-term complications. The time required to complete the anastomosis in the IS group was 27.0 +/- 6.6 min, compared with 16.2 +/- 5.0 min in the CS group (p < 0.001). The cost was $144.7 +/- 34.6 in the IS group vs. $11.7 in the CS group (p < 0.001). CONCLUSIONS: The IS and CS groups did not differ regarding short- and long-term outcomes. The anastomosis was completed in significantly less time in the CS group. The CS method was also superior in terms of cost. PMID- 30474737 TI - Babesia gibsoni endemic to Wuhan, China: mitochondrial genome sequencing, annotation, and comparison with apicomplexan parasites. AB - Babesia gibsoni (B. gibsoni), an intracellular apicomplexan protozoan, poses great threat to canine health. Currently, little information is available about the B. gibsoni (WH58) endemic to Wuhan, China. Here, the mitochondrial (mt) genome of B. gibsoni (WH58) was amplified by five pairs of primers and sequenced and annotated by alignment with the reported mt genome sequences of Babesia canis (B. canis, KC207822), Babesia orientalis (KF218819), Babesia bovis (AB499088), and Theileria equi (AB499091). The evolutionary relationships were analyzed with the amino acid sequences of cytochrome c oxidase I (cox1) and cytochrome b (cob) genes in apicomplexan parasite species. Additionally, the mt genomes of Babesia, Theileria, and Plasmodium spp. were compared in size, host infection, form, distribution, and direction of the protein-coding genes. The full size of the mt genome of B. gibsoni (WH58) was 5865 bp with a linear form, containing terminal inverted repeats on both ends, six large subunit ribosomal RNA fragments, and three protein-coding genes: cox1, cob, and cytochrome c oxidase III (cox3). Babesia, Theileria, and Plasmodium spp. had a similar mt genome size of about 6000 bp. The mt genomes of parasites that cause canine babesiosis showed a slightly smaller size than the other species. Moreover, Babesia microti (R1 strain) was about 11,100 bp in size, which was twice larger than that of the other species. The mt form was linear for Babesia and Theileria spp. but circular for Plasmodium falciparum and Plasmodium knowlesi. Additionally, all the species contained the three protein-coding genes of cox1, cox3, and cob except Toxoplasma gondii (RH strain) which only contained the cox1 and cob genes. The phylogenetic analysis indicated that B. gibsoni (WH58) was more identical to B. gibsoni (AB499087), B. canis (KC207822), and Babesia rossi (KC207823) and most divergent from Babesia conradae in Babesia spp. Despite the highest similarity to B. gibsoni (AB499087) reported in Japan, B. gibsoni (WH58) showed notable differences in the sequence of nucleotides and amino acids and the property in virulence to host and in vitro cultivation. This study compared the mt genomes of the two B. gibsoni isolates and other parasites in the phylum Apicomplexa and provided new insights into their differences and evolutionary relationships. PMID- 30474738 TI - Validation of the pathological prognostic staging system proposed in the revised eighth edition of the AJCC staging manual in different molecular subtypes of breast cancer. AB - The authors investigated the clinical utility of the revised prognostic staging system proposed in the eighth edition of the American Joint Committee on Cancer (AJCC) staging manual in breast cancer (BC) patients. We retrospectively reviewed the data of 714 BC patients that received surgical treatment and standard adjuvant therapy from January 2005 to December 2007. All patients were restaged for anatomic TNM stage and pathological prognostic (PP) stage as defined in the revised eighth edition of the AJCC manual. Compared with anatomic stage, PP stage was different from anatomic stage in 325 (45.5%) patients, 254 were down-staged and 71 were upstaged. There were significant differences in overall survival (OS) and disease-free survival (DFS) according to different anatomic stages or PP stages (all, p < 0.001). In anatomic stage I patients, OS was significantly different between PP stages IA and IB (p < 0.001), but no significant difference was observed between anatomic stages IA and IB (p = 0.413). PP stages exhibited significant OS differences in anatomic stage IIB (p = 0.011), but survival differences according to PP stages were not observed in anatomic stage IIA, IIIA, or IIIC. PP stages were found to have prognostic value with respect to OS and DFS for luminal (p < 0.001 and p < 0.001), HER2-positive (p = 0.001 and p = 0.013), and triple-negative (p = 0.008 and p = 0.03) subtypes. The prognostic staging system proposed in the eighth edition of the AJCC more accurately predicts the clinical outcomes of BC patients than the traditional anatomic staging system. PMID- 30474739 TI - Flexibility in joint coordination remains unaffected by force and balance demands in young and old adults during simple sit-to-stand tasks. AB - PURPOSE: We examined the possibility that old adults use flexibility in joint coordination as a compensatory mechanism for the age-related decline in muscle strength when performing the sit-to-stand (STS) task repeatedly under high force and balance demands. METHOD: Young (n = 14, 22.4 +/- 2.1) and old (n = 12, 70 +/- 3.2) healthy adults performed repeated STSs under high and low force and balance demands. The balance demand was manipulated by reducing the base of support and the force demand by increasing body weight with a weight vest. Uncontrolled manifold analysis was used to quantify age differences in motor flexibility. RESULTS: While there were age-typical differences in kinematic STS strategies, flexibility in joint coordination was independent of age and task difficulty during repeated STSs. DISCUSSION: That simple manipulations of force and balance demands did not affect flexibility in joint coordination in old and young adults suggests that motor flexibility acts as a compensatory mechanism only at the limits of available muscle strength and balance abilities during STS movements. Intervention studies should identify how changes in specific neuromuscular functions affect flexibility in joint coordination during activities of daily living such as STS. PMID- 30474740 TI - Cardiovascular, muscular, and skeletal adaptations to recreational team handball training: a randomized controlled trial with young adult untrained men. AB - PURPOSE: The prevalence of lifestyle diseases has escalated, and effective exercise training programmes are warranted. This study tested the hypothesis that regular participation in small-sided team handball training could provide beneficial health effects on cardiovascular, skeletal, and muscular parameters in young adult untrained men. METHOD: Twenty-six untrained 20-30-year-old men were randomly allocated to either a team handball training group (HG; n = 14), which completed 1.9 +/- 0.3 training sessions per week over 12 weeks, or an inactive control group (CG; n = 12). Physiological training adaptations were assessed pre- and post interventions by DXA scans, blood samples, muscle biopsies, and physical tests. RESULTS: The average heart rate during training was equivalent to 84 +/- 4% of maximal heart rate. Compared to CG, HG displayed significant increases in VO2max (11 +/- 6%), proximal femur bone mineral density (2 +/- 1%), whole-body bone mineral content (2 +/- 1%), intermittent endurance performance (32 +/- 16%), incremental treadmill test performance (16 +/- 7%) and muscle citrate synthase activity (22 +/- 28%) as well as decreases in total fat mass (7 +/- 7%) and total fat percentage (6 +/- 7%) (all p < 0.05). There were no significant changes in muscle mass, blood pressure, resting heart rate, muscle hydroxyl-acyl dehydrogenase activity, or blood lipids (all p > 0.05). CONCLUSION: Participation in regular recreational team handball training was associated with positive cardiovascular, skeletal, and muscular adaptations, including increased maximal oxygen uptake, increased muscle enzymatic activity, and improved bone mineralization as well as lower fat percentage. These findings suggest that recreational team handball training may be an effective health-promoting activity for young adult men. PMID- 30474741 TI - Treatment for proximal pole scaphoid nonunion with capsular-based vascularized distal radius graft. AB - PURPOSE: We retrospectively reviewed the results of 89 patients with proximal pole scaphoid nonunion, 58 with avascular necrosis, treated with a capsular-based vascularized distal radius graft. METHODS: Seventy-one male and eighteen female patients with symptomatic nonunion at the proximal pole of the scaphoid were included in this study. No patient had a humpback deformity. In all patients, the vascularized bone graft was harvested from the dorsum of the distal radius and was attached to a capsular flap of the dorsal wrist capsule. After fixation of the scaphoid with a small cannulated screw, the graft was inserted press-fit into the scaphoid trough in the nonunion site. Supplementary fixation of the graft with a microsuture anchor into the scaphoid was used in 66 patients. RESULTS: At a mean time of 12.3 weeks (range 6-24) after surgery, solid union was achieved in 76 of 89 patients (49 of 58 with avascular necrosis). Eleven patients had persistent nonunion and two fibrous union as determined by CT scan. Sixty-six of the patients with solid bone union were completely pain free, and ten complained of slight pain with strenuous activities. No donor site morbidity was observed. CONCLUSIONS: The capsular-based vascularized bone graft from the distal radius is a reliable alternative technique for scaphoid nonunions. It is a simple and expedient harvesting technique without the need for a microsurgical anastomoses. The supplemental fixation with a microsuture anchor eliminates the risk of graft displacement. PMID- 30474743 TI - Correction to: Robust Findings From 25 Years of PTSD Genetics Research. AB - The original version of this article contained an error in the title. The correct title should read "Robust Findings From 25 Years of PTSD Genetics Research" as shown above. The original article has been corrected. PMID- 30474744 TI - A study on the role of hydrogeology on the distribution of uranium in alluvial aquifers of northwest India. AB - A study was undertaken to decipher the uranium distribution in relation to a number of hydrogeological factors in groundwater of southwest Punjab. Existing geological information for the region suggests that the shallow alluvial aquifer extends up to 50-70 m below ground level (bgl) and is in turn underlain by a deeper aquifer which extends to a depth of 250 m bgl. The presence of clayey units limits the vertical mixing of groundwater between the shallow and deep aquifers. Water level data (averaged over 5 years period) indicates that the south and southwestern regions of the study area have shallow water levels (3-5 m bgl) while the north and northeast regions have deep water levels (20-28 m bgl). This difference in water levels is found to be increasing with time. Higher concentrations of uranium occur in the central, southern, and southwestern parts of the study area where the water table occurs at shallow depth. Groundwater in the northern and northeastern parts of the study area shows U concentration within permissible levels for potable use (< 30 MUg/L) while the highest concentration of U (341 MUg/L) was found in the central part of the study area. Seasonal variation in dissolved U concentration is found to be statistically significant. The observed increases in U concentrations during the post-monsoon season are due to the addition of bicarbonate from the root zone as well as increased dissolved oxygen, nitrate, and sulphate concentration (oxic condition) in the groundwater while the decrease in U concentration is attributed to quick recharge by precipitation through sand dunes and contribution of surface water. Deeper groundwater does not show much seasonal variation in dissolved U concentration. Correlation between U and other hydrochemical parameters was evaluated. Cluster analysis of the data also indicates the oxidative mobilization of U from the sediments. Based on the lithological, hydrogeological, and dissolved U data, a schematic map is prepared depicting the various factors affecting the U distribution in alluvial aquifers, which can also be applied to other regions of similar hydrogeological setup. Graphical abstract ?. PMID- 30474745 TI - Shift work, sleep duration, and body image dissatisfaction among female workers in southern Brazil. AB - We examined the association between shift work and sleep duration with body image dissatisfaction (BID) among shift-working women in southern Brazil. In this cross sectional study, data of 505 women shift workers, between 18 and 60 years old, were collected between January and April 2011. BID was assessed using the Stunkard Figure Rating Scale. Information on shift work, sleep duration, and other explanatory variables was collected through a questionnaire. An aggregated exposure variable was created and termed "sleep deprivation," with the exposure category being night-shift workers who slept < 7 h/day. The respective prevalence ratio values were estimated using a Poisson regression. The prevalence of BID among shift-working women was 42.4 (95% CIs = 38.0 to 46.7%), and 199 (93.0%) of these women wished they had a smaller body size. Shift work (PR = 1.40; p = 0.006) and sleep duration (PR = 1.32; p = 0.010) were independently associated with BID. Additionally, workers with sleep deprivation exhibited a higher probability of BID than those without sleep deprivation (PR = 1.31; p = 0.012). These results reveal a situation of vulnerability and the need for strategies and actions directed at shift-working women with the aim of reducing the effects of sleep deprivation on mental health, particularly with regard to body image disorders. PMID- 30474746 TI - Reply to Gaertner, K. and Frass, M. PMID- 30474742 TI - Expression, purification, and evaluation of in vivo anti-fibrotic activity for soluble truncated TGF-beta receptor II as a cleavable His-SUMO fusion protein. AB - Excessive production of transforming growth factor-beta1 (TGF-beta1) and its binding to transforming growth factor-beta receptor type II (TGF-betaRII) promotes fibrosis by activation of the TGF-beta1-mediated signaling pathway. Thus, the truncated extracellular domain of TGF-betaRII (tTbetaRII) is a promising anti-fibrotic candidate, as it lacks the signal transduction domain. In this work, the native N-terminal tTbetaRII was prepared as a His-SUMO fusion protein (termed His-SUMO-tTbetaRII) in Escherichia coli strain BL21 (DE3). His SUMO-tTbetaRII was expressed as a soluble protein under optimal conditions (6 h of induction with 0.5 mM IPTG at 37 degrees C). His-SUMO-tTbetaRII was purified by Ni-NTA resin chromatography, and then cleaved with SUMO protease to release native tTbetaRII, which was re-purified using a Ni-NTA column. Approximately 12 mg of native tTbetaRII was obtained from a one liter fermentation culture with no less than 95% purity. In vivo studies demonstrated that tTbetaRII prevented CCl4 induced liver fibrosis, as evidenced by the inhibition of fibrosis-related Col I and alpha-SMA protein expression in C57BL/6 mice. In addition, tTbetaRII downregulated phosphorylation of SMAD2/3, which partly repressed TGF-beta1 mediated signaling. These data indicate that the His-SUMO expression system is an efficient approach for preparing native tTbetaRII that possesses anti-liver fibrotic activity, allowing for the large-scale production of tTbetaRII, which potentially could serve as an anti-fibrotic candidate for treatment of TGF-beta1 related diseases. PMID- 30474748 TI - Self-assessed neurological disturbances after surgical removal of impacted lower third molar: a pragmatic prospective study on 423 surgical extractions in 247 consecutive patients. AB - OBJECTIVES: The aim of this study was to assess the combined role of current radiographic risk indicators and patient age in predicting lower lip sensitivity disturbances after surgical removal of impacted lower third molars. The question was which combinations indicate low or high risk. MATERIALS AND METHODS: A prospective study was implemented involving 247 consecutive outpatients who underwent 423 surgical extractions. The predictor variables were patient age and risk indicators observed on panoramic radiographs. The outcome variable was the incidence of self-assessed lip sensitivity alterations. The extractions were subdivided into four groups according to the predictors. RESULTS: Two hundred forty-five teeth were extracted in patients younger than 25 years and 178 in patients 25 years old or older; radiographic risk indicators were associated with 226 out of 423 teeth (53.43%). No permanent neurological damage was observed. Transient lip sensitivity alterations were observed in five cases (1.18%; 95% confidence interval = 0.4 to 2.7%), all in the older group with radiographic risk indicators. CONCLUSIONS: The data indicate a low overall incidence of transient lip sensitivity impairment that occurred only in the presence of radiographic risk indicators in patients aged >= 25 years. CLINICAL RELEVANCE: Informed consent should include the possibility of inferior alveolar nerve injury in mature patients with radiographic risk indicators. Prophylactic removal of impacted teeth with radiographic signs of risk may be indicated when the patient is not yet aged 25 years. PMID- 30474747 TI - Comparison of axitinib and sunitinib as first-line therapies for metastatic renal cell carcinoma: a real-world multicenter analysis. AB - We aimed to compare oncological outcomes and safety of axitinib and sunitinib in patients with treatment-naive metastatic renal cell carcinoma (mRCC). We retrospectively evaluated 169 patients with mRCC who were treated with axitinib or sunitinib as the first-line therapy in five hospitals between October 2008 and August 2018. Oncological outcomes and safety were compared between axitinib (n = 68) and sunitinib (n = 101) groups. Inverse probability of treatment weighted (IPTW)-adjusted Cox regression analysis was performed to evaluate effects of first-line therapies on progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Patients in the axitinib group were significantly older (66 vs. 72 years) than those in the sunitinib group. Median relative dose intensity was significantly higher in the axitinib group (94 +/- 62%) than in the sunitinib group (65 +/- 20%; P = 0.001). Objective response rate was significantly higher in the axitinib group (21%) than in the sunitinib group (10%; P = 0.042). IPTW-adjusted Cox regression analysis revealed significant differences in CSS and OS but not in PFS between the two groups. Safety in terms of grade >= 3 adverse events was significantly different between the axitinib (34%) and sunitinib (55%) groups (P = 0.006). Compared with sunitinib, axitinib significantly prolonged CSS and OS and showed a safer profile as the first-line therapy for treatment-naive mRCC. PMID- 30474749 TI - First report of a planar and a quasi-planar Al13+ cluster having localized antiaromatic deltas within an aromatic sea: NICS, ELF, AIM, and AdNDP bonding analysis. AB - A perfectly planar Al13+ cluster (CI) and a quasi-planar Al13+ cluster (CII) have been found for the first time. Both clusters have a triangular core surrounded by a set of ten Al atoms in the form of a ring. These cationic clusters have substantial aromatic character. The planar CI cluster has local antiaromatic patches within global aromatic sea. It is doubly aromatic having both sigma and pi aromatic character. The quasi-planar CII cluster is also aromatic but it has more sigma-delocalization. Graphical abstract Planar and quasi-planar Al13+ clusters with triangular core surrounded by a ring of ten atoms. PMID- 30474750 TI - How I do it: operative nuances of multiple burr hole surgery for moyamoya disease and syndrome. AB - BACKGROUND: Burr hole surgery for moyamoya disease and moyamoya syndrome is known to be an effective, versatile, and relatively simple revascularization technique. We will focus on the technical operative aspects of multiple burr hole surgery as we perform it in our center. METHODS: Periosteal flaps are prepared and placed in a burr hole with beveled edge, after opening the dura and arachnoid membrane, in order to facilitate neovascularization into the ischemic cortex. CONCLUSIONS: Burr hole surgery is a versatile treatment modality for moyamoya and moyamoya like disease. Success can be maximized by having a meticulous operative technique. PMID- 30474751 TI - Abnormal neural responses to emotional stimuli in children with primary monosymptomatic nocturnal enuresis. AB - Nocturnal enuresis (NE) is a common disorder in school-aged children that has been reported to affect nearly 10% of 7-year-old children and affects both the children and their families. Previous studies have shown that the risk of psychosocial difficulties in children with enuresis is elevated. Thus, children with NE may experience negative effects on psychosocial health or emotion processing. Therefore, the aim of this study was to investigate the potential disturbance in emotional processing in children with NE using functional magnetic resonance imaging (fMRI). In this work, we used fMRI and an affective picture task to evaluate brain response changes in children with NE. Two groups, one consisting of 22 children with primary monosymptomatic NE and one with 23 healthy controls, were scanned using fMRI. Compared to the healthy subjects, children with NE mainly showed increased activation when viewing negative vs. neutral pictures in the bilateral medial superior frontal gyrus that extended to the anterior cingulate cortex. Our results demonstrated that children with primary monosymptomatic NE showed abnormal neural responses to emotional stimuli and overactivation in the medial prefrontal and anterior cingulate cortices suggested that children with primary monosymptomatic NE may be hypersensitive in their sensory perception of negative pictures. PMID- 30474752 TI - Advances in techniques for identifying small pulmonary nodules. AB - Since the introduction of video-assisted thoracoscopic surgery, the demand for its use in resecting small pulmonary nodules has increased. In parallel, the development of high-resolution computed tomography has led to an increase in the detection of the early lung cancers appearing as nodules with ground-glass opacity. Several techniques to resect these small lesions have been devised, the most familiar of which is the use of a computed tomography-guided percutaneous hook wire. We recently developed virtual-assisted lung mapping to achieve safer and more reliable resection of these lesions. Virtual-assisted lung mapping is carried out using three-dimensional computed tomography, bronchoscopy, and fluoroscopically guided navigation to mark the lung surface with dye. A prospective study showed that this technique was safe and had a high success rate. Multiple marking around the targeted lesion allows for a sufficient surgical margin at resection. We recently introduced an electromagnetic navigation bronchoscopy system to confirm the sites to be marked by virtual assisted lung mapping in the operating room prior to video-assisted thoracoscopic surgery. We are now studying a method to enable minimally invasive, safe, and reliable resection of lesions located deep in the lung parenchyma. PMID- 30474753 TI - Molecular evolutionary and antigenic characteristics of newly isolated H9N2 avian influenza viruses in Guangdong province, China. AB - Four new H9N2 avian influenza viruses (AIVs) were isolated from domestic birds in Guangdong between December 2015 and April 2016. Nucleotide sequence comparisons indicated that most of the internal genes of these four strains were highly similar to those of human H7N9 viruses. Amino acid substitutions and deletions found in the HA and NA proteins indicated that all four of these new isolates may have an enhanced ability to infect humans and other mammals. A cross hemagglutinin-inhibition assay, conducted with two vaccine strains that are broadly used in China, suggested that antisera against vaccine candidates could not provide complete inhibition of the new isolates. PMID- 30474754 TI - Correction to: An estrogen antagonist, cyclofenil, has anti-dengue-virus activity. AB - We would like to correct the information on the antibody used in this study. In Fig. 5 of the article, cellular beta-actin was detected as an internal control using anti-beta-actin antibody (Fujifilm Wako Pure Chemicals, #017-24573). PMID- 30474755 TI - Unravelling the antitumoral potential of novel bis(thiosemicarbazonato) Zn(II) complexes: structural and cellular studies. AB - The development of pharmacologically active compounds based on bis(thiosemicarbazones) (BTSC) and on their coordination to metal centers constitutes a promising field of research. We have recently explored this class of ligands and their Cu(II) complexes for the design of cancer theranostics agents with enhanced uptake by tumoral cells. In the present work, we expand our focus to aliphatic and aromatic BTSC Zn(II) complexes bearing piperidine/morpholine pendant arms. The new complexes ZnL1-ZnL4 were characterized by a variety of analytical techniques, which included single crystal X-ray crystallography for ZnL2 and ZnL3. Taking advantage of the fluorescent properties of the aromatic complexes, we investigated their cellular uptake kinetics and subcellular localization. Furthermore, we tried to elucidate the mechanism of action of the cytotoxic effect observed in human cancer cell line models. The results show that the aliphatic complexes (ZnL1 and ZnL2) have a symmetrical structure, while the aromatic counterparts (ZnL3 and ZnL4) have an asymmetrical nature. The cytotoxic activity was higher for the aromatic BTSC complexes, as well as the cellular uptake, evaluated by measurement of intracellular Zn accumulation. Among the most active complexes, ZnL3 presented the fastest uptake kinetics and lysosomal localization assessed by live-cell microscopy. Detailed studies of its impact on cellular production of reactive oxygen species and impairment of lysosomal membrane integrity reinforced the influence of the pendant piperidine in the biological performance of aromatic BTSC Zn(II) complexes. PMID- 30474756 TI - Histone deacetylase inhibitor ITF2357 (givinostat) reverts transformed phenotype and counteracts stemness in in vitro and in vivo models of human glioblastoma. AB - PURPOSE: Aberrant expression and activity of histone deacetylases (HDACs) sustain glioblastoma (GBM) onset and progression, and, therefore, HDAC inhibitors (HDACi) represent a promising class of anti-tumor agents. Here, we analyzed the effects of ITF2357 (givinostat), a pan-HDACi, in GBM models for its anti-neoplastic potential. METHODS: A set of GBM- and patient-derived GBM stem-cell lines was used and the ITF2357 effects on GBM oncophenotype were investigated in in vitro and in vivo xenograft models. RESULTS: ITF2357 inhibited HDAC activity and affected GBM cellular fate in a dose-dependent manner by inducing G1/S growth arrest (1-2.5 uM) or caspase-mediated cell death (>= 2.5 uM). Chronic treatment with low doses (<= 1 uM) induced autophagy-mediated cell death, neuronal-like phenotype, and the expression of differentiation markers, such as glial fibrillar actin protein (GFAP) and neuron-specific class III beta-tubulin (Tuj-1); this reduces neurosphere formation from patient-derived GBM stem cells. Autophagy inhibition counteracted the ITF2357-induced expression of differentiation markers in p53-expressing GBM cells. Finally, in in vivo experiments, ITF2357 efficiently passed the blood-brain barrier, so rapidly reaching high concentration in the brain tissues, and significantly affected U87MG and U251MG growth in orthotopic xenotransplanted mice. CONCLUSIONS: The present findings provide evidence of the key role played by HDACs in sustaining transformed and stem phenotype of GBM and strongly suggest that ITF2357 may have a clinical potential for the HDACi-based therapeutic strategies against GBM. PMID- 30474757 TI - Should patients with stage IB non-small cell lung cancer receive adjuvant chemotherapy? A comparison of survival between the 8th and 7th editions of the AJCC TNM staging system for stage IB patients. AB - INTRODUCTION: The aims of this study were to compare the efficacy of platinum based adjuvant chemotherapy in resected patients with stage IB NSCLC according to the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) staging manuals on tumor, node, and metastasis (TNM) staging systems, respectively. METHODS: This retrospective analysis included 569 patients who underwent pulmonary resection for primary non-small cell lung cancer. 5-year overall survival (OS) was compared in stage IB disease using the 8th and 7th editions of the TNM classification, respectively. Survival curves were plotted using the Kaplan-Meier method, and log-rank test was used to evaluate differences between subgroups. RESULTS: The 5-year overall survival was 76.9% and 83.5% (p = 0.044) for patients in the observation and adjuvant groups, respectively. The presence of adjuvant chemotherapy, lymphovascular invasion, TNM stage, and performance status (PS) were risk factors for OS in univariate analysis. In multivariate analysis, TNM stage [hazard ratio (HR) 5.403, 95% confidence interval (CI) 3.743 7.801, p < 0.001], PS (HR 4.375, 95% CI 2.856-6.703, p < 0.001) and adjuvant chemotherapy (HR 1.476, 95% CI 1.028-2.119, p = 0.035) were risk factors for OS. Subgroup analysis showed that for patients with 8th edition stage IB NSCLC, 5 year OS was 87.6% in the observation group (n = 265) and 82.4% in the adjuvant group (p = 0.021). For patients with 8th edition stage IIA NSCLC, 5-year OS was 48.1% and 87.7% in the observation group and the adjuvant group (p < 0.001), respectively. For patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0, a better 5-year OS was seen in the adjuvant group (79.3% vs 91.6%, p = 0.001) By contrast, for patients with a PS score of ECOG 1, the 5-year OS was significantly improved in the observation group (58.6% vs 17.2%, p = 0.021). CONCLUSION: The 8th edition of the AJCC staging identified the beneficiary population of platinum-based adjuvant chemotherapy in early-stage NSCLC. Moreover, patients with good PS (ECOG 0) benefited from adjuvant chemotherapy. A large prospective randomized clinical trial is needed to determine the real role of adjuvant chemotherapy in this setting. PMID- 30474758 TI - Patient-derived, three-dimensional spheroid cultures provide a versatile translational model for the study of organ-confined prostate cancer. AB - PURPOSE: To generate and characterize 3D spheroid suspension cultures from radical prostatectomy (RP) specimens as a versatile model system for organ confined prostate cancer (PCa). METHODS: Cancerous tissue samples from RP specimens were excised by a uropathologist. Preparation of 3D spheroids was done by mechanical disintegration and limited enzymatic digestion followed by serial filtration through 100 MUm- and 40 MUm-cell strainers. Thereafter, spheroids were cultured in a modified stem cell medium and characterized by a live/dead assay, whole-spheroid immunohistochemistry (IHC; CK5, CK8, AMACR, PSA, Ki67, AR, alphaSMA, Vimentin, E-Cadherin) and PSA-measurements in culture medium. Furthermore, their response to pharmaceutical treatment with docetaxel, bicalutamide, enzalutamide and abiraterone was tested. RESULTS: 173 RP cases were included. The median preoperative PSA-level was 16.12 ng/ml [range 0.99;345], the median Gleason score was 7b [6;10]. 64 cases were excluded due to low tumor content in frozen sections (43) or to insufficient spheroid formation (21). In the remaining 109 cases, spheroids formed successfully and stayed viable for up to several months. IHC analysis revealed AR-, CK8-, and AMACR-positivity in nearly all cases, while CK5-positive cells were detectable only occasionally as were alpha-SMA and Vimentin. E-Cadherin was positive in most cases. Furthermore, spheroids proved to be amenable to cryopreservation. While abiraterone had no effect and docetaxel only a moderate effect, spheroid viability was markedly reduced upon bicalutamide and enzalutamide treatment. CONCLUSIONS: Multicellular 3D spheroids can be generated from patient-derived RP tissue samples and serve as an innovative in vitro model of organ-confined PCa. PMID- 30474760 TI - Status of the northern muriqui (Brachyteles hypoxanthus) in the time of yellow fever. AB - Understanding the impact of zoonotic diseases on wild primate populations is important for assessing local extinction risks and for evaluating potential mitigating factors. Comparative data on demographic changes in two isolated populations of the northern muriqui (Brachyteles hypoxanthus) during a severe yellow fever outbreak in southeastern Brazil provide unique insights into the potential effects of this disease in this Critically Endangered species. From October 2016 to April 2017, the muriqui population at the Reserva Particular do Patrimonio Natural-Feliciano Miguel Abdala (Caratinga) lost 31 of its 324 members, or nearly 10%, whereas the population at the Reserva Particular do Patrimonio Natural-Mata do Sossego (Sossego) declined from 34 to 25 individuals, or 26%. Greater per-capita risks to muriquis in the Sossego population could be related to ecological and anthropogenic differences, including a wetter climate and an absence of sympatric howler monkeys (Alouatta guariba), which may have directly or indirectly buffered the Caratinga muriquis. Although we lack definitive confirmation that the muriqui population declines were caused by yellow fever, the timing and magnitude of the losses strongly implicate the disease. We highlight the risks of catastrophic population declines in small populations and emphasize the value of long-term demographic monitoring studies. PMID- 30474759 TI - Synthesis, crystal structure, DFT studies and biological activity of (Z)-3-(3 bromophenyl)-1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-hydroxyprop-2-en-1-one. AB - BACKGROUND: Nowadays, is emerging a new generation of highly promising inhibitors bearing the beta-ketoenol functionality. The present work relates to the first synthesis, the structure determination, the DFT studies and the use of a new biomolecule designed with a beta-ketoenol group bounded to a pyrazolic moiety. RESULT: A novel beta-ketoenol-pyrazole has been synthesized, well characterized and its structure was confirmed by single crystal X-ray diffraction. The electron densities and the HOMO-LUMO gap have been calculated using the DFT method with BLYP, PW91, PWC functionals and 6-31G* basis set. An evaluation of the molecule stability is provided by a NBO analysis and the calculated Fukui and Parr functions have been used to locate the reactive electrophile and nucleophile centers in the molecule. The synthesized compound, screened for its in vitro antifungal behavior against the Fusarium oxysporum f.sp. albedinis FAO fungal strains, shows a moderate activity with an inhibition percentage of 46%. The product was also tested against three bacterial strains (Escherichia coli, Bacillus subtilis and Micrococcus luteus), but no significant effect was observed against these organisms. CONCLUSIONS: Density functional calculations are used to evaluate the HOMO-LUMO energy gap, the molecular electrostatic potential and to provide a natural bond orbital analysis. The measured antimicrobial activities encourage us to continue searching for other structures, likely to be good antifungal candidates. PMID- 30474761 TI - A slanted-nanoaperture metal lens: subdiffraction-limited focusing of light in the intermediate field region. AB - Diffraction of light limits the resolution of beam focusing with conventional lenses, as dictated by the Abbe limit, that is, approximately half the wavelength. Numerous techniques have been explored to overcome this limit. One of the most intensively explored approaches is to design a lens that operates in the near-field region, that is, with a focal length on the order of 10 nm, where evanescent fields can carry and project large in-plane wave-vectors (greater than free-space wave-vectors) to a focal plane. From a practical perspective, however, the requirement of such an ultra-short focal length puts too much constraint, since much longer focal length is commonly desired for intermediate or far-field operation. Here we report a method to beat the Abbe limit while operating with focal length greater than wavelength lambda. Our approach is to tailor the radiation patterns of nanoaperture transmission by tilting aperture axes away from the surface of a metal film such that each slanted aperture transmits a highly directed, tilt-oriented beam onto a common focal point carrying maximal in plane wave-vector components. The proposed nanoaperture array lens was fabricated by forming tilted nanoslits in a Ag, Al, or Cr film. We demonstrate minimal spot size of lambda/3 (210-nm or 110-nm full-width half-maximum at lambda = 633 nm or 325 nm, respectively) with 1-4lambda focal length in air, beating the Abbe limit. PMID- 30474762 TI - Usefulness of cell-free and concentrated ascites reinfusion therapy in the therapeutic management of advanced ovarian cancer patients with massive ascites. AB - BACKGROUND: The management of refractory ascites in advanced ovarian cancer (AOC) is vital for patients with abdominal distention, respiratory distress, and anorexia due to massive ascites with cancer peritonitis. We analyzed the benefits of concentrated ascites reinfusion therapy (CART) in the management of AOC. METHODS: We reviewed records of AOC patients who underwent CART between January 2011 and March 2017. We retrospectively analyzed patients' backgrounds and physiological changes, including body weight, abdominal girth, urine volume, blood component values, blood pressure, heart rate, and body temperature before and after CART. We investigated the clinicopathological significance of CART by measuring the mean number of ascites tumor cell (ATC) clusters before CART. RESULTS: A retrospective analysis was performed on 29 cases of AOC with massive ascites involving 47 CART sessions. The patients' mean age was 56.6 +/- 12.8 years, and the mean number of sessions was 1.7 +/- 1.2. The mean volume of the processed ascites was 2,937 +/- 820 mL, which was concentrated to 272 +/- 84 mL containing 85.0 +/- 33.2 g protein on average. Significant reductions in abdominal girth (- 5.30 +/- 0.65 cm; p < 0.0001) and body weight (- 2.97 +/- 0.26 kg; p = 0.0011), increased urine volume (+ 824.29 +/- 145.21 mL; p < 0.0001), and improved serum albumin levels (+ 0.18 +/- 0.34; p < 0.0001) were observed after CART. Analysis of variance revealed significant elevations in body temperature after CART in 11 patients with a small number of ATC clusters. CONCLUSIONS: CART is useful for the therapeutic management of AOC patients with refractory massive ascites. Elevations of body temperature after CART may be avoided by the investigation of patients' peritoneal cytology before CART. PMID- 30474765 TI - ASO Author Reflections: Advanced Imaging Allows Better Detection of Peritoneal Metastases. PMID- 30474763 TI - Role of the acetabular labrum on articular cartilage consolidation patterns. AB - Damage to the acetabular labrum has been associated with cartilage degeneration. Because conventional pressure measurement devices were unable to examine the sealing function of the acetabular labrum on cartilage contact mechanics, we used an image-based computational method to examine how labrectomy affects articular cartilage contact area and strain patterns in porcine hips. Cyclically loaded hip samples were continuously imaged in a CT scanner every 3 min to trace the positions of the femur and acetabulum. Image-based displacement-controlled finite element analysis was used to calculate articular cartilage contact area and nominal strain at different time points. No changes in cartilage contact area were found after labrectomy. Compared to the labrum intact condition, average nominal strain in labrectomized hips was elevated at early time points after load application. The areas of 'high' strain in labrectomized hips were found to be increased by approximately 7% after 30 min of cyclic loading, while the changes in the areas of 'low' strain were minimal. Our result showed that changes in articular cartilage strain following labrectomy were concentrated on locally overloaded areas where the degenerative process of articular cartilage may be initiated. PMID- 30474764 TI - Gastrointestinal stromal tumor with skeinoid fibers: an unusual presentation. PMID- 30474766 TI - ASO Author Reflections: Reducing Axillary Lymph Node Dissections in Node-Positive Breast Cancer Patients. PMID- 30474767 TI - Repeated craniotomies for intracranial tumors: is the risk increased? Pooled analysis of two prospective, institutional registries of complications and outcomes. AB - PURPOSE: Deciding whether to re-operate patients with intracranial tumor recurrence or remnant is challenging, as the data on safety of repeated procedures is limited. This study set out to evaluate the risks for morbidity, mortality, and complications after repeated operations, and to compare those to primary operations. METHODS: Retrospective observational two-center study on consecutive patients undergoing microsurgical tumor resection. The data derived from independent, prospective institutional registries. The primary endpoint was morbidity at 3 months (M3), defined as significant decrease on the Karnofsky Performance Scale (KPS). Secondary endpoints were mortality, rate and severity of complications according to the Clavien-Dindo Grade (CDG). RESULTS: 463/2403 (19.3%) were repeated procedures. Morbidity at M3 occurred in n = 290 patients (12.1%). In univariable analysis, patients undergoing repeated surgery were 98% as likely as patients undergoing primary surgery to experience morbidity (OR 0.98, 95% CI 0.72-1.34, p = 0.889). In multivariable analysis adjusted for age, sex, tumor size, histology and posterior fossa location, the relationship remained stable (aOR 1.25, 95% CI 0.90-1.73, p = 0.186). Mortality was n = 10 (0.4%) at discharge and n = 95 (4.0%) at M3, without group differences. At least one complication occurred in n = 855, and the rate (35.5% vs. 35.9%, p = 0.892) and severity (CDG; p = 0.520) was similar after primary and repeated procedures. Results were reproduced in subgroup analyses for meningiomas, gliomas and cerebral metastases. CONCLUSIONS: Repeated surgery for intracranial tumors does not increase the risk of morbidity. Mortality, and both the rate and severity of complications are comparable to primary operations. This information is of value for patient counseling and the informed consent process. PMID- 30474768 TI - A3 foresight network on natural products. AB - Discovery and development of natural products (NPs) have played important roles in the fields of human medicine and other biotechnology fields for the past several decades. Recent genome-mining approaches for the isolation of novel and cryptic NP biosynthetic gene clusters (BGCs) have led to the growing interest in NP research communities including Asian NP researchers from China, Japan, and Korea. Recently, a three-nation government-sponsored program named 'A3 Foresight Network on Chemical and Synthetic Biology of NPs' has been launched with a goal of establishing an Asian hub for NP research-&-personnel exchange program. This brief commentary describes introduction, main researchers, and future perspective of A3 NP network program. PMID- 30474769 TI - Descriptive analysis of pharmacy services provided after community pharmacy screening. AB - Background Community pharmacies are promising locations for opportunistic screening due to pharmacist accessibility and ability to perform various health and medication management services. Little is known as to the provision of pharmacy services following screening initiatives. Objective To describe provision of pharmacy services for participants following a community pharmacy stroke screening initiative. Setting The Program for the Identification of "Actionable Atrial" Fibrillation Pharmacy initiative took place in 30 pharmacies in Alberta and Ontario, Canada. 1149 participants >= 65 were screened for atrial fibrillation, type 2 diabetes, and hypertension. Method Retrospective, secondary analysis of data using participant case-report forms, pharmacy data, and pharmacy claims to describe pharmacy services received by participants post-screening. Main Outcome Measure Number and types of remunerated pharmacy services received by participants post-screening. Results A total of 535/1149 (46.6%) participants screened at their regular pharmacy were included in this analysis. Of these, 165 (30.8%) participants received 229 pharmacy services within 3 months post screening, including 146 medication reviews, 57 influenza vaccinations, and 21 pharmaceutical opinions. A median (interquartile range, IQR) of 6 (2-11) pharmacy services were delivered, and median (IQR) reimbursement was $187.50 ($67.50 $342.50). Conclusions Approximately one-third of participants received a pharmacy service within 3 months post-screening. Relatively large numbers of annual and follow-up medication reviews were delivered despite low eligibility for annual only reviews and despite many missed opportunities for pharmacy service provision in at-risk patients. In-pharmacy screening may facilitate provision of some services, namely medication reviews, by providing opportunities to identify patients at-risk. PMID- 30474770 TI - Knowledge of cardiovascular disease risk factors and practice of primary prevention of cardiovascular disease by Community Pharmacists in Nigeria: a cross sectional study. AB - Background Studies in international literature have shown that Community Pharmacists can make considerable impact in controlling cardiovascular disease risk factors, especially hypertension. In Nigeria, there are no studies on the knowledge of CVD risk factors by Community Pharmacists and their practice of primary prevention. Objective To assess the knowledge of CVD risk factors and practice of primary prevention of CVD amongst Nigerian community pharmacists. Setting Community Pharmacists in Lagos, Nigeria. Methods This cross-sectional study involved 168 Community Pharmacists. Their knowledge of CVD risk factors was assessed with the Heart Disease Fact Questionnaire. Their opportunistic screening practices for CVD risk factors (primary prevention) were also assessed. Main outcome measures Knowledge of CVD risk factors and practice of primary CVD prevention. Results The mean age of the participating pharmacists was 41.7 (+/- 11.2) years and 87 (51.8%) of them were males. The median number of years of practice was 9.0 (3-15) years. Mean knowledge score was 22.1 (+/- 3.0) with 154 (91.7%) of the subjects scoring above 70%. An average of 95.5% of the participants correctly identified hypertension, smoking, dyslipidaemia, obesity, physical inactivity and diabetes as CVD risk factors. Eighty-one (48.2%) had good practice of primary CVD prevention. Conclusion: This study shows that Community Pharmacists in Nigeria have very good knowledge level of CVD risk factors and almost 50% of them practised primary prevention of CVD. PMID- 30474771 TI - Caryopincaolide M, a rearranged abietane diterpenoid with new skeleton and a new iridoid from Caryopteris incana. AB - Caryopincaolide M (1), a new rearranged abietane diterpenoid with an unusual pent 4-enoic acid group on a 6/6/5 tricyclic ring system, and 7-epi-8 dehydroxypatriscabrol (3), a new iridoid, together with 17 known compounds, have been isolated from the whole plant of Caryopteris incana (Thunb.) Miq. Their structures were elucidated on the basis of 1-D and 2-D NMR, IR, and mass spectroscopic data. Compounds 1-5 were evaluated for their inhibitory activities against enzyme alpha-glucosidase, and the results showed that only 1 has moderate inhibitory activity against enzyme alpha-glucosidase with IC50 at 528.3 +/- 12.37 mg/L. PMID- 30474772 TI - Algae induce siderophore biosynthesis in the freshwater bacterium Cupriavidus necator H16. AB - Cupriachelin is a photoreactive lipopeptide siderophore produced by the freshwater bacterium Cupriavidus necator H16. In the presence of sunlight, the iron-loaded siderophore undergoes photolytic cleavage, thereby releasing solubilized iron into the environment. This iron is not only available to the siderophore producer, but also to the surrounding microbial community. In this study, the cupriachelin-based interaction between C. necator H16 and the freshwater diatom Navicula pelliculosa was investigated. A reporter strain of the bacterium was constructed to study differential expression levels of the cupriachelin biosynthesis gene cucJ in response to varying environmental conditions. Not only iron starvation, but also culture supernatants of N. pelliculosa were found to induce cupriachelin biosynthesis. The transcription factors involved in this differential gene expression were identified using DNA protein pulldown assays. Besides the well-characterized ferric uptake regulator, a two-component system was found to tune the expression of cupriachelin biosynthesis genes in the presence of diatom supernatants. PMID- 30474773 TI - Edaphocola aurantiacus gen. nov., sp. nov., a new member of the family Chitinophagaceae isolated from wetland soil in South Korea. AB - A short rod-shaped, yellow-orange pigmented, strictly aerobic bacterium, designated as strain H2T, was isolated from the wetland soil of Halla Mountain, Jeju-island, South Korea. Growth was observed at temperatures of 10-30 degrees C (optimum at 25-30 degrees C), pH of 6-8 (optimum at pH 7), and salt concentrations of 0-1% (w/v) NaCl (optimum at 0%). The strain H2T was found to be a catalase and oxidase-positive, non-motile, Gram-negative bacterium. On the basis of 16S rRNA gene sequence similarity and phylogenetic analysis, strain H2T was found to be related to the members of the Chitinophagaceae family, being closely related to Taibaiella chishuiensis AY17T (94.3% sequence similarity). The major polar lipids are phosphatidylethanolamine and glycolipid. Strain H2T contained MK-7 as the only menaquinone as well as iso-C15:0, iso-C15:1 G and iso C17:0 3-OH as the major fatty acids (> 15%). The DNA G+C content of strain H2T was determined to be 48.3 mol%. Based on the phylogenetic, phenotypic characteristics and chemotaxonomic analysis data, strain H2T (= KCTC 62115T = JCM 32353T) should be classified as representative of a novel species of a novel genus within the family Chitinophagaceae, for which the name Edaphocola aurantiacus gen. nov., sp. nov., is proposed. PMID- 30474774 TI - The neuroprotective effect of agmatine against amyloid beta-induced apoptosis in primary cultured hippocampal cells involving ERK, Akt/GSK-3beta, and TNF-alpha. AB - beta-Amyloid peptide (Abeta), the major element of senile plaques in Alzheimer's disease (AD), has been found to accumulate in brain regions critical for memory and cognition. Deposits of Abeta trigger neurotoxic events which lead to neural apoptotic death. The present study examined whether agmatine, an endogenous polyamine formed by the decarboxylation of L-arginine, possesses a neuroprotective effect against Abeta-induced toxicity. Primary rat hippocampal cells extracted from the brains of 18-19-day-old embryos were exposed to 10 uM of Abeta (25-35) in the absence or presence of agmatine at 150 or 250 uM. Additionally, the involvement of Akt (Protein Kinae B), GSK-3beta (glycogen synthase kinase 3-beta), ERK (Extracellular Signal-Regulated Kinase) and TNF alpha (Tumor necrosis factor-alpha) in the agmatine protection against Abeta induced neurotoxicity was investigated. Agmatine significantly prevented the effect of Abeta exposure on cell viability and caspase-3 assays. Furthermore, agmatine considerably restored Abeta-induced decline of phospho-Akt and phospho GSK and blocked Abeta-induced increase of phospho-ERK and TNF-alpha. Taken together, these findings might shed light on the protective effect of agmatine as a potential therapeutic agent for AD. PMID- 30474775 TI - Cloning, characterization and paper pulp applications of a newly isolated DyP type peroxidase from Rhodococcus sp. T1. AB - A newly identified ligninolytic Rhodococcus strain (Rhodococcus sp. T1) was isolated from forestry wastes (Trabzon/Turkey). The DyP type peroxidase of Rhodococcus sp. T1 (DyPT1) was cloned, characterized and paper treated for industrial applications. Molecular weight of the protein was about 38 kDa. The kinetic parameters were 0.94 mM and 1417.53 umol/min/mg for Km and Vmax, respectively. The enzyme was active at the temperature range of 25-65 degrees C and optimum temperature was 35 degrees C, enzyme was stable up to 6 days at room temperature. Optimum pH of the DyPT1 was 4.0 and it was stable between pH 4.0-6.0 up to 8 days at room temperature. Effects of some metal ions, Hemin, and some chemical agents on DyPT1 were determined. Hemin has implemented protective effects on the stability and the activity of the enzyme in long time periods when added into growing medium. DyPT1 was applied to eucalyptus kraft pulp for analyzing the bleaching efficiency, physical and optical tests of the manufuctared paper were carried out. Application of lignin peroxidase to kraft pulp caused a decrease of 5.2 units for kappa number and an increase from 52.05 to 64.18% in the delignification rate. PMID- 30474776 TI - Low-grade "benign" birdshot retinochoroiditis: prevalence and characteristics. AB - PURPOSE: To establish the prevalence, morphologic and functional characteristics and evolution of mild birdshot retinochoroiditis (BRC). METHODS: Retrospective review of all BRC cases treated at the Centre for Ophthalmic Specialized Care, Lausanne, Switzerland, with at least 3 years of follow-up since the initial symptoms. Sub-Tenon's injection of triamcinolone was the first line of treatment if visual field changes were unilateral, with no additional treatment if visual field returned to normal. The percentage of patients who did not need systemic therapy was established, and the following parameters were evaluated: demographic characteristics, best-corrected visual acuity (BCVA), fundus photographs, fluorescein angiography (FA) and indocyanine green (ICGA) angiography frames and perimetry evaluation from initial visit to last follow-up. RESULTS: Twenty cases of BRC were included in this study. Three of these patients (15%) received only local periocular therapy and qualified as mild BRC, with a mean follow-up of 9.3 years. The BCVA was 0.89 +/- 0.25 at presentation and 1.0 +/- 0.39 at last follow up. Average visual field mean defect was 5.05 +/- 3.27 at presentation and 1.78 +/- 0.95 at last follow-up. Depigmented fundus lesions remained stable from presentation to last follow-up. Choroidal inflammatory activity monitored by ICGA decreased from 11.66 +/- 3.44 at presentation to 4.25 +/- 2.87 at last follow-up. FA revealed mild retinal vasculitis (2.25 +/- 3.20) which remained stable (2.00 +/- 4.00). CONCLUSIONS: In our setting, 15% of BRC cases had a benign course, controlled with periocular treatment. It is important to identify such cases in order not to overtreat, exposing patients needlessly to potential side effects of aggressive and prolonged immunosuppressive treatment. PMID- 30474777 TI - Prognostic impact and possible pathogenesis of lymph node metastasis in ductal carcinoma in situ of the breast. AB - PURPOSE: Ductal carcinoma in situ (DCIS)-preinvasive breast cancer-with lymph node metastasis can clinically be treated as different stages: occult invasive cancer with true metastasis (T1N1) or pure DCIS with iatrogenic dissemination (TisN0). In this retrospective cohort study, we aimed to elucidate the prognostic impact and possible pathogenesis of nodal metastasis in DCIS to improve clinical management. METHODS: Subjects were comprised of 427 patients with routine postoperative diagnosis of DCIS who underwent sentinel node (SN) biopsy using molecular whole-lymph-node analysis. Clinicopathological characteristics and prognosis were compared between SN-positive and -negative patients. Primary tumour tissues of SN-positive patients were exhaustively step-sectioned to detect occult invasions, and predictive factors for occult invasion were investigated. Median follow-up time was 73.6 months. RESULTS: Of the 427 patients, 19 (4.4%) were SN-positive and 408 (95.6%) were SN-negative. More SN-positive patients received adjuvant systemic therapy than SN-negative patients (84.2% vs. 5.4%). Seven-year distant disease-free survivals were favourable for both cohorts (SN positive, 100%; SN-negative, 99.7%). By examining 1421 slides, occult invasion was identified in 9 (47.4%) of the 19 SN-positive patients. Tumour burdens in SN and incidence of non-SN metastasis were similar between patients with and without occult invasion, and no predictive factor for occult invasion was found. CONCLUSIONS: Node-positive DCIS has favourable prognosis with adjuvant systemic therapy. Half of the cases may be occult invasive cancer with true metastasis. In practical settings, clinicians may have to treat these tumours as node-positive small invasive cancers because it is difficult to predict the pathogenesis without exhaustive primary tumour sectioning. PMID- 30474778 TI - Trends in use of bilateral prophylactic mastectomy vs high-risk surveillance in unaffected carriers of inherited breast cancer syndromes in the Inherited Cancer Registry (ICARE). AB - PURPOSE: Awareness of inherited breast cancer has increased bilateral prophylactic mastectomy (BPM) among unaffected genetic mutation carriers, yet many still choose surveillance. We aimed to identify differences among women electing BPM vs high-risk surveillance. METHODS: Participants from an IRB approved database recruited from 11/2000 to 01/2017 with a deleterious/pathogenic, variant suspected deleterious, or likely pathogenic mutation in >= 1 of 11 genes with increased risk for breast cancer (per 2017 NCCN guidelines) were identified. Participants with breast cancer and males were excluded. Sociodemographic and clinical data were collected. The BPM and high risk surveillance groups were compared using Wilcoxon, Fisher's Exact, and Pearson's Chi-Square analyses. RESULTS: A total of 304 unaffected genetic mutation carriers were identified; 22 men were excluded. 113/282 (40%) underwent BPM. There was no significant difference in age, race, marital status, high school graduates, family history of breast cancer, breast biopsies, chemoprevention use, or understanding implications of genetic mutation carriage. BPM participants were more likely to have a prior pregnancy (p = 0.0005), college education (p = 0.04), income > $50,000/year (p = 0.01), first-degree relative with breast cancer (p = 0.04), higher total number of relatives with breast cancer (p = 0.01), and rate of risk-reducing salpingo-oophorectomy (p = < 0.0001). The high-risk surveillance group was more likely to have a history of ovarian cancer (p = 0.009) and cancer worry (p = < 0.0001). CONCLUSIONS: BPM is a common but not universal choice among unaffected genetic carriers of inherited breast cancer syndromes. Parity, education, income, ovarian cancer history, first degree relatives with breast cancer, and cancer worry play significant roles in these decisions. PMID- 30474779 TI - Connexin 43 is an independent predictor of patient outcome in breast cancer patients. AB - PURPOSE: Gap junctions are specialized membrane structures that form channels between adjacent cells allowing cell communication. Gap junctions and specifically Connexin 43 (Cx43) are down-regulated in cancer; however, there are contrasting reports on how this effects breast cancer patient survival. This paper is the first large-scale tissue microarray analysis of Cx43 expression in breast cancer patients with an associated clinical long-term follow-up. METHODS: Using a validated TMA of 1118 primary breast cancers, coupled to a comprehensive database of clinicopathological variables, the expression levels and subcellular localisation of Cx43 was assessed by immunohistochemistry. Its impact in terms of survival, distant metastasis-free survival, and clinicopathological variables was determined. RESULTS: Patients whose tumors expressed high levels of Cx43 had significantly better survival (p < 0.001) than patients with low levels. High Cx43 expression within tumors was associated with an 18-month survival advantage. Loss of Cx43 expression was associated with markers of poor prognosis, namely large tumor size, high grade, high proliferation status, high pleomorphism, high mitosis, poor Nottingham Prognostic Index (NPI), and triple negative tumors. Cx43 expression was independent of tumor size, grade, stage and ER-status in predicting poor survival on multivariate analysis (p = 0.004). CONCLUSION: Connexin 43 (Cx43) is an independent predictor of breast cancer survival and distant metastasis-free survival. High expression of Cx43 was seen in only 13% of tumors, suggesting that drugs to increase Cx43 expression may result in prolonged patients survival. PMID- 30474780 TI - A new high-quality genome sequence in soybean. PMID- 30474781 TI - New cytosine base editor for plant genome editing. PMID- 30474782 TI - The phosphodiesterase type 4 inhibitor roflumilast suppresses inflammation to improve diabetic bladder dysfunction rats. AB - PURPOSE: To demonstrate that phosphodiesterase type 4 (PDE4) inhibitors could potentially treat diabetic bladder dysfunction (DBD) through modulation of the systemic inflammatory response. METHODS: In this 6-week study, 60 female Sprague Dawley rats were divided into three groups: (i) vehicle-treated control rats; (ii) vehicle-treated streptozocin (STZ)-injected rats; and (iii) roflumilast treated STZ-injected rats. Oral roflumilast (5 mg/kg/day) was administered during the last 4 weeks of STZ injection to induce diabetes in the test group. At 6 weeks, a urodynamic study was performed in each group. The expression of nuclear factor kappa B (NF-kappaB), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-1beta in detrusor smooth muscle (DSM) was analyzed using quantitative reverse transcription-polymerase chain reaction and Western blotting. RESULTS: A significant decrease in bodyweight and significant increases in bladder weight and blood glucose level were observed in the diabetic rats and were not ameliorated by roflumilast treatment. Cystometry showed the increased bladder capacity, voiding volume, residual urine volume, and voiding interval in the diabetic rats and the prevention of these changes by roflumilast. These changes were accompanied by significantly enhanced expression of NF-kappaB, TNF alpha, IL-6, and IL-1beta in DSM tissue from diabetic rats. Furthermore, roflumilast attenuated the expression of inflammatory factors in DSM tissue. CONCLUSIONS: Oral treatment with roflumilast in diabetic rats improves bladder function and inhibits the expression of inflammatory factors in DSM tissue, indicating that PDE4 is a potential therapeutic target for DBD. PMID- 30474783 TI - Feasibility of a novel technique using 3-dimensional modeling and augmented reality for access during percutaneous nephrolithotomy in two different ex-vivo models. AB - PURPOSE: We describe a novel technique that uses mathematical calculation software, 3-dimensional (3D) modeling and augmented reality (AR) technology for access during percutaneous nephrolithotomy (PCNL) and report our first preliminary results in two different ex-vivo models. METHODS: Novel software was created in order to calculate access point and angle by using pre-operative computed tomography (CT) obtained in 50 patients. Two scans, 27 s and 10 min after injection of contrast agent, were taken in prone PCNL position. By using DICOM objects, mathematical and software functions were developed to measure distance of stone from reference electrodes. Vectoral 3D modeling was performed to calculate the access point, direction angle and access angle. With specific programs and AR, 3D modeling was placed virtually onto real object, and the calculated access point and an access needle according to the calculated direction angle and access angle were displayed virtually on the object on the screen of tablet. RESULTS: The system was tested on two different models-a stone placed in a gel cushion, and a stone inserted in a bovine kidney that was placed in a chicken-for twice, and correct access point and angle were achieved at every time. Accuracy of insertion of needle was checked by feeling crepitation on stone surface and observing tip of needle touching stone in a control CT scan. CONCLUSIONS: This novel device, which uses software-based mathematical calculation, 3D modeling and AR, seems to ensure a correct access point and angle for PCNL. Further research is required to test its accuracy and safety in humans. PMID- 30474784 TI - Improved voiding function by deep brain stimulation in traumatic brain-injured animals with bladder dysfunctions. AB - OBJECTIVE: Traumatic brain injury (TBI) is a global scenario with high mortality and disability, which does not have an effectual and approved therapy till now. Bladder dysfunction is a major symptom after TBI, and this study deals with the alleviation of bladder function in TBI rats, with the aid of deep brain stimulations (DBS). METHODS: TBI was induced by weight drop model (WDM) and standardized with the experimental subjects with variable heights for weight dropping. The rats survived after TBI were considered for bladder dysfunction observations. DBS with variable stimulation parameters like cystometric analysis and MRI studies were also performed. RESULTS: After experimental studies, TBI 2-m height crash was determined as suitable parameter due to minimal mortality rate and significant reduction in the voiding efficiency from 67 to 28%, whereas DBS significantly reversed the value of voiding efficiency to 65-84%. MRI studies revealed the severity of TBI impact and DBS localization. CONCLUSION: The results showed profound therapeutic effect of PnO-DBS on voiding functions and bladder control on TBI rats. PMID- 30474785 TI - New records of ticks infesting bats in Brazil, with observations on the first nymphal stage of Ornithodoros hasei. AB - In Brazil, at least 14 species of soft ticks (Argasidae) are associated with bats. While Ornithodoros hasei seems to be abundant among foliage-roosting bats, other groups of ticks are found exclusively inside caves. In this paper, noteworthy records of soft ticks infesting bats are documented in new localities from Bahia, Pernambuco, Piaui, and Rondonia states. Out of 201 bats examined, 25 were infested by 152 ticks belonging to seven taxa: Ornithodoros cavernicolous, O. hasei, Ornithodoros marinkellei, Ornithodoros cf. fonsecai, Ornithodoros cf. clarki, Antricola sp., and Nothoaspis amazoniensis. These findings provide new insights into the geographical distribution and host association of soft ticks occurring in the Neotropical region. Remarkably, morphological and biological observations about O. hasei are inferred based on the examination of on-host collected first stage nymphs. PMID- 30474786 TI - Robotic colectomy with intracorporeal anastomosis is feasible with no operative conversions during the learning curve for an experienced laparoscopic surgeon developing a robotics program. AB - The benefits of performing a colectomy robotically instead of laparoscopically have not conclusively been demonstrated. Evaluation of studies is limited by sample size, retrospective design, heterogeneity of operative techniques, sparse adjustment for learning curve, and mixed results. Consequently, adoption of robotic colectomy by surgeons has been expectedly slow. The objectives of the study were to compare the outcomes of robotic colectomy to laparoscopic colectomy for patients with right-sided tumors undergoing a standardized completely intracorporeal operation and to examine the impact of prior experience with laparoscopic right colectomies on the performance of robotic right colectomies. Retrospective review of outcomes of consecutive patients undergoing a robotic right colectomy (robot) compared to those undergoing laparoscopic colectomy (LAP). LAP patients were further subdivided into a group during the learning curve (LC) and after the learning curve (post-LC). Data collected included operative time (OT), conversion to laparotomy, lymph nodes harvested (LN), length of stay (LOS), 30-day morbidity, and mortality. Comparison of continuous and categorical variables was assessed with the independent samples t test and Chi square test, respectively. Data are expressed as mean +/- SD, and significance defined as p < 0.05. 122 patients underwent robot (n = 21), LAP (n = 101), LC (n = 51), or post-LC (n = 50). OT was decreased for post-LC compared to LC (198 vs. 228 min). There were no conversions in robot and five with LAP. Morbidity was similar for robot (14%) compared to LAP (22%), LC (24%), or post-LC cases (20%). Median LOS was similar for robot vs. LAP (3 vs. 5 days). Robot had greater mean LN yield vs. LAP (19 vs. 14, p = 0.02). The initial outcomes with completely intracorporeal colectomy achieved robotically were equivalent to results during or after LC for laparoscopic resection. Proficiency gained with LAP seems to positively impact the initial results with the robot. PMID- 30474787 TI - Oxidative Damages to Eye Stem Cells, in Response to, Bright and Ultraviolet Light, Their Associated Mechanisms, and Salvage Pathways. AB - The surface of the eye is continuously exposed to the harshness of the external environment. As a homeostatic mechanism for replenishing the worn off cells of the ocular surface, a balance is maintained via the role of ocular stem cells. However, under extreme conditions of harshness like exposure to bright and ultraviolet light, the ocular stem cells are unable to do the repair mechanisms resulting in severe impairment of vision and disturbances in the eye. This work reappraises the recent understandings of mechanisms of oxidative damages caused to the ocular stem cells by UV/bright light and their probable mitigation. PMID- 30474788 TI - The Study on Polymorphism of TrxR and Nrf2/HO-1 Signaling Pathway in Kaschin-Beck Disease. AB - Kaschin-Beck disease (KBD) is an endemic, chronic, and degenerative osteoarthropathy, which seriously impairs the quality of patients' life. We detected the expression of TrxR by ELISA and found that TrxR was lower in KBD than in normal control group significantly (P < 0.001); this result indicated that TrxR must be related to KBD. We retrieved cSNPs in NCBI SNP database and used three bioinformatics programmers, including SIFT, PolyPhen, and SNP3d, to help select the researched nsSNP. Then, we used PCR-RFLP to analyze the relationship between the SNP site rs5746841 in TrxR2 gene and susceptibility of KBD and detected the expression of Nrf2 and HO-1 by western blot. The results showed that the genotype of rs5746841 in 93 normal controls and 103 KBD subjects were C/C totally, but A/A and A/C were not found, which indicated preliminarily that there was no correlation between rs5746841 in TrxR2 gene and susceptibility of KBD. The expression of TrxR was lower in KBD than in normal control group significantly, while the expressions of Nrf2 and HO-1 were higher in KBD than in normal control group. These results indicated that the low expression of selenoprotein TrxR may be a candidate factor of KBD, which related to Nrf2/HO-1 signaling pathway. PMID- 30474789 TI - Is there a role for lumbar puncture in early detection of subarachnoid hemorrhage after negative head CT? AB - To investigate the role of lumbar puncture (LP) after a negative head computed tomography (CT) when ruling out subarachnoid hemorrhage (SAH) within 24 h of symptom onset. In a single-center, retrospective cohort study, we studied a consecutive series of patients from 2011 to 2015. All patients underwent CT or CT following LP to rule out SAH. Patients were categorized into four groups depending on the time of symptom onset to initial head CT: 0-6 h, 6-12 h, 12-24 h, and over 24 h. Experienced radiologists interpreted all CT scans. We investigated the sensitivity, specificity, and negative predictive value (NPV) of noncontrast CT in detecting SAH. Of 539 patients with suspected SAH and negative CT, 280 (51.9%) had their CT performed within 24 h of symptom onset. None of these patients had SAH. Five (1.9%) out of 259 patients with CT performed after 24 h of symptom onset had SAH diagnosed, and two turned out to be aneurysmal. When CT was performed within 24 h of symptom onset it had a sensitivity of 100% (95% CI 95-100%), specificity of 98% (95% CI 96-99.7%), and NPV of 100% (95% CI 98-100%) in detecting SAH. Modern CT scanners seem to have high sensitivity and specificity in the diagnosis of SAH when performed within 24 h of symptom onset. Beyond this point, CT seems to lack sensitivity and further investigation with LP is required. PMID- 30474790 TI - Risk, prevalence, and impact of hospital malnutrition in a Tertiary Care Referral University Hospital: a cross-sectional study. PMID- 30474791 TI - Comparison of Intravenous Ibuprofen and Paracetamol for Postoperative Pain Management after Laparoscopic Sleeve Gastrectomy. A Randomized Controlled Study. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is defined as the first-step bariatric surgery for the treatment of obesity. Opioid analgesics are often preferred for pain management because of their strong analgesic potentials. However, opioids have undesirable adverse effects. OBJECTIVES: The objective of this study is to evaluate and compare the influence of IV forms of ibuprofen and paracetamol on pain management and opioid consumption on patients undergoing LSG surgery. SETTING: This study was conducted at Istanbul Medipol University Hospital. METHODS: Patients were stratified into three groups. Group I (group ibuprofen, n = 30) was administered 800 mg of IV ibuprofen, group P (group paracetamol, n = 30) was administered 1000 mg of IV paracetamol, and group C (control group, n = 30) was given 100 ml of saline solution. We evaluated opioid consumption and VAS scores postoperatively. RESULTS: This study included 90 patients who underwent LSG. The use of rescue medication in group I was statistically lower than the other groups. VAS scores in group I and group P at recovery and at 2, 4, 8, 12, and 24 h were lower than those in group C. In particular, the VAS scores in group I at the first 2 h postoperatively were significantly lower than those in group P (p < 0.05). Opioid consumption in group C was significantly higher than the other groups (p < 0.05). CONCLUSION: Our study suggested that IV ibuprofen resulted in lower pain scores compared to paracetamol by reducing postoperative opioid use in the first 24 h in patients undergoing LSG surgery. PMID- 30474792 TI - Efficacy and Safety of Intra-gastric Balloon Placement in Dialyzed Patients Awaiting Kidney Transplantation. AB - BACKGROUND: The number of obese patients who are candidates for renal transplantation has considerably increased, but obesity can be a barrier to kidney transplantation. Weight loss is often difficult through diet alone. We studied the efficacy and tolerance of the intra-gastric balloon (IGB) procedure in obese patients who were undergoing dialysis and were candidates for a renal transplantation. PATIENTS AND METHODS: Obese patients (BMI > 30 kg/m2) who were candidates for renal transplantation were prospectively included in the study between 2010 and 2012. The balloon was inserted and removed during a gastric endoscopy under general anesthesia. The treatment lasted 6 months. The end point was a decrease in BMI after 6 months. Body impedance spectrometry (BIS) and nutritional statute were evaluated initially and then after IGB removal. RESULTS: Seventeen patients (nine females and eight males) with a mean age of 53.4 years [19.4-69.4] were included. The decrease in body mass index (BMI) during the 6 month placement was 3 kg/m2 (from 37.7 to 34.4 kg/m2). The mean weight loss was 7 kg. The mean percentage of excess weight loss after 6 months was 20.2 (+/- 11.4). The tolerance was good without any complications. Eleven patients underwent kidney transplantation. CONCLUSION: IGB in obese dialyzed patients who are candidates for renal transplantation is safe and effective. However, the amount of weight loss can vary. PMID- 30474794 TI - An exploratory study of experiences with conventional eating disorder treatment and ceremonial ayahuasca for the healing of eating disorders. AB - PURPOSE: Ayahuasca is a traditional Amazonian medicine that is currently being researched for its potential in treating a variety of mental disorders. This article reports on exploratory qualitative research relating to participant experiences with ceremonial ayahuasca drinking and conventional treatment for eating disorders (EDs). It also explores the potential for ayahuasca as an adjunctive ED treatment. METHODS: Thirteen individuals previously diagnosed with an ED participated in a semi-structured interview contrasting their experiences with conventional ED treatment with experiences from ceremonial ayahuasca. The interviews were analyzed using thematic analysis. RESULTS: Participant reports were organized with key themes including that ayahuasca: led to rapid reductions in ED thoughts and symptoms; allowed for the healing of the perceived root of the ED; helped to process painful feelings and memories; supported the internalization of greater self-love and self-acceptance; and catalyzed spiritual elements of healing. CONCLUSIONS: The results suggest that ayahuasca may have potential as a valuable therapeutic tool, and further research-including carefully controlled clinical trials-is warranted. LEVEL OF EVIDENCE: Level V, qualitative descriptive study. PMID- 30474793 TI - Brain Network Reconfiguration During Motor Imagery Revealed by a Large-Scale Network Analysis of Scalp EEG. AB - Mentally imagining rather physically executing the motor behaviors is defined as motor imagery (MI). During MI, the mu rhythmical oscillation of cortical neurons is the event-related desynchronization (ERD) subserving the physiological basis of MI-based brain-computer interface. In our work, we investigated the specific brain network reconfiguration from rest idle to MI task states, and also probed the underlying relationship between the brain network reconfiguration and MI related ERD. Findings revealed that comparing to rest state, the MI showed the enhanced motor area related linkages and the deactivated activity of default mode network. In addition, the reconfigured network index was closely related to the ERDs, i.e., the higher the reconfigured network index was, the more obvious the ERDs were. These findings consistently implied that the reconfiguration from rest to task states underlaid the reallocation of related brain resources, and the efficient brain reconfiguration corresponded to a better MI performance, which provided the new insights into understanding the mechanism of MI as well as the potential biomarker to evaluate the rehabilitation quality for those patients with deficits of motor function. PMID- 30474795 TI - Anorectal Cancer in Crohn's Disease Has a Poor Prognosis Due to its Advanced Stage and Aggressive Histological Features: a Systematic Literature Review of Japanese Patients. AB - BACKGROUND: Patients with Crohn's disease (CD) are generally known to be at an increased risk of cancer. The anorectal area is the most frequent cancer site in Japanese CD patients. However, the risks are not well defined. The aim of this study was to clarify the clinicopathological characteristics of Japanese CD associated anorectal carcinoma patients and to explore screening methods for the detection of cancer at earlier stages. METHODS: A systematic review of case series and reports of Japanese CD-associated anorectal cancer patients published between 1983 and 2016 was conducted. RESULT: There were 144 cases of cancer arising from anorectal lesions of CD. The median duration from the onset of CD to the cancer diagnosis was approximately 17 (0-39) years. The most prevalent histological type of cancer was mucinous carcinoma (49.3%), and 82.1% of patients were over T3 invasion. There were only 15.6% cases with early stage disease. A total of 82% patients had enhanced symptoms, whereas 56.3% of the early cancer cases had no symptomatic changes. Approximately 90% of cases were diagnosed preoperatively, and almost all early cancer patients were diagnosed with colonoscopy. The 5-year overall survival rate was 35.8%. CONCLUSION: CD associated anorectal carcinoma had a poor prognosis due to the advanced stage of the cases and aggressive histological features. As earlier-stage cancer is associated with a better prognosis than advanced stage disease, and it is also typically diagnosed by colonoscopy, surveillance colonoscopy may therefore help to improve the prognosis in cases without any symptomatic changes. PMID- 30474796 TI - In Vitro Wound Healing Activity of Wheat-Derived Nanovesicles. AB - Triticum aestivum plant extracts are often used as a natural healer in traditional medicine but which particles mainly have role in these processes are not scientifically proven. In other words, no attempts have been made to investigate the effects of wheat exosomes in regenerative medicine applications or drug development up to now. The current study was first time performed to demonstrate the activity of wheat exosomes in wound healing process using in vitro approaches. Although its fundamental wound healing process remains a mystery, in the current study, the efficiency of wheat grass juice-derived exosomes on cell viability and migration was examined. Increasing concentrations up to 200 MUg/mL of the wheat exosome have yielded astonishing proliferative and migratory effects on endothelial, epithelial, and dermal fibroblast cells. RT-PCR analysis also showed collagen type I; mRNA levels were approximately twofold higher in expression after treating with 200 MUg/mL wheat exosome. Additionally, Annexin V staining of apoptotic cells accompanied with the cell cycle analysis resulted with the reduction of the apoptotic cell number with no dispersion to the cell cycle analysis while plant exosomes have also increased tube-like structure formation of the endothelial cells. All in all, this research suggests a brand-new opening for skin wound healing therapy strategy by using wheat derived exosomes due to its proliferative and migratory characteristics. Plant exosomes require a further research both clinically and in in vivo for wound healing drug development. Moreover, plant exosome therapy strategies would be safer and economical alternative for clinical wound healing. PMID- 30474797 TI - Early Exposure to a High-Fat Diet Impacts on Hippocampal Plasticity: Implication of Microglia-Derived Exosome-like Extracellular Vesicles. AB - Adolescence is a transitional period from childhood to adulthood characterized by puberty and brain maturation involving behavioral changes and environmental vulnerability. Diet is one of the factors affecting brain health, potentially leading to long-lasting effects. Hence, we studied the impact of early exposure (P21-60) to a high-fat diet (HFD) on mouse hippocampus, analyzing inflammation, adult neurogenesis, dendritic spine plasticity, and spatial memory. Glycemia and seric pro-inflammatory IL1beta were higher in HFD mice without differences on body weight. In the HFD hippocampus, neuroinflammation was evidenced by Iba1+ cells reactivity together with a higher expression of TNFalpha and IL1beta while the neurogenic capability in the dentate gyrus was strongly reduced. We found a predominance of immature Dil-labeled dendritic spines from CA1 neurons along with diminished levels of the scaffold protein Shank2, suggesting a defective connectivity. Moreover, the HFD group exhibited spatial memory alterations. To elucidate whether microglia could be mediating HFD-associated neuronal changes, the lipotoxic context was emulated by incubating primary microglia with palmitate, a saturated fatty acid present in HFD. Palmitate induced a pro inflammatory profile as shown by secreted cytokine levels. The isolated exosome fraction from palmitate-stimulated microglia induced an immature dendritic spine phenotype in primary GFP+ hippocampal neurons, in line with the in vivo findings. These results provide novel data concerning microglia to neuron communication and highlight that fat excess during a short and early period of life could negatively impact on cognition and synaptic plasticity in a neuroinflammatory context, where microglia-derived exosomes could be implicated. Graphical Abstract ?. PMID- 30474798 TI - Periostin concentrations in childhood-onset craniopharyngioma patients. AB - PURPOSE: Periostin is highly expressed in craniopharyngioma (CP)-associated fibroblasts and has been identified as a marker for non-alcoholic fatty liver disease (NAFLD). Half of CP patients with hypothalamic syndrome develop NAFLD. We hypothesized that periostin concentration is elevated in biological fluids of CP and associated with pathological hepatic parameters, indicating increased risk for NAFLD. METHODS: A cross-sectional study on 35 patients with sellar masses (SMP) recruited in the German Childhood Craniopharyngioma Registry (32 CP, 2 xanthogranuloma, 1 pilocytic astrocytoma), three short-statured patients with isolated growth hormone deficiency, five short-statured patients with normal findings in GH-stimulating tests and decreased insulin-like growth factor (IGF)-1 and seven healthy controls. Periostin was measured by Elisa in serum, urine and saliva. RESULTS: Periostin serum, urine and saliva concentrations in CP were similar to concentrations of the other groups. Hypothalamic involvement/hypothalamic lesions, degree of obesity as well as hepatic enzymes were not associated with elevated periostin concentrations. Due to low patient numbers with pathological hepatic parameters, missing imaging data on the degree of steatosis hepatis and the lack of histological proof of NAFLD, no definitive conclusions can be drawn from measured periostin concentrations in serum. Interestingly, the subgroup of patients with decreased IGF-1 levels showed elevated concentrations of serum periostin when compared with other groups. CONCLUSIONS: In CP, periostin concentrations are not associated with known risk factors for NAFLD such as hepatic and metabolic parameters, obesity and hypothalamic lesions. Accordingly, periostin does not seem to be a suitable marker for NAFLD in CP. PMID- 30474801 TI - Assessing the measurement invariance of the RCADS-25 questionnaire across gender and child-parent dyads in the presence of multilevel data. AB - PURPOSE: This study aims to assess the measurement invariance of the short version of the Revised Child Anxiety and Depression Scale (RCADS-25) across male and female adolescents along with child self-reports and parent proxy-reports. METHODS: The sample consisted of 2039 adolescents and their parents from 51 public and private schools in Shiraz (southern Iran). The measurement invariance of the RCADS-25 was investigated by the multilevel multiple-indicators multiple causes model. In addition, the reliability of the questionnaire was examined by Cronbach's alpha coefficient, and its validity was evaluated by exploratory and categorical confirmatory factor analysis. RESULTS: Although the RCADS-25 includes five (20%) non-invariant items across male and female adolescents, their impact is negligible at the scale level. In addition, 10 out of 25 items (40%) were non invariant across self- and proxy-reports, which did not have substantial effect at the scale level. CONCLUSION: Based on our findings, the instrument can be used, albeit with caution, for comparing depression and anxiety scores between male and female adolescents as well as child self-reports and parent proxy reports. PMID- 30474799 TI - Rs7219 Regulates the Expression of GRB2 by Affecting miR-1288-Mediated Inhibition and Contributes to the Risk of Schizophrenia in the Chinese Han Population. AB - In the present study, we examined a potential genetic association between the variant rs7219 within the 3'-UTR of GRB2 and the susceptibility to schizophrenia (SCZ) and bipolar disorder (BD) in the Chinese Han population. A genetic association study, including 548 SCZ patients, 512 BD patients, and 598 normal controls, was conducted in the Chinese Han population. Genotyping was performed through the Sequenom MassARRAY technology platform. The expression of GRB2 was detected using quantitative real-time polymerase chain reaction (qRT-PCR). A dual luciferase reporter assay was performed to determine whether miR-1288 could bind to the 3'-UTR region of GRB2 containing rs7219. We found that rs7219 was significantly associated with the susceptibility to SCZ under different genetic models, including additive [OR (95% CI) = 1.24 (1.02-1.49), P = 0.027], dominant [OR (95% CI) = 1.31 (1.04-1.66), P = 0.025], and allelic models[OR (95% CI) = 1.24 (1.03-1.49), P = 0.027]. However, no significant associations were found between rs7219 and the risk for BD (all P > 0.05). Moreover, we observed that the expression of GRB2 significantly decreased in SCZ patients compared with the controls (P = 0.004). The dual-luciferase reporter assay showed that the minor allele C of rs7219 significantly decreased the luciferase activity by binding miR 1288 (P < 0.001). In summary, we are the first to reveal that rs7219 is significantly associated with the susceptibility to SCZ in the Chinese Han population. Moreover, the minor allele C of rs7219 is identified as a risk allele for SCZ because it generates a binding site for miR-1288, thereby resulting in decreased expression of GRB2 and ultimately increasing the risk of SCZ. PMID- 30474800 TI - Systemic Approach to Prevent Inadvertent Perfusion in Eyes with Extensive Choroidal Detachment, Suprachoroidal Fluid, and Hypotony During Pars Plana Vitrectomy. AB - INTRODUCTION: Rhegmatogenous retinal detachment (RRD) with extensive choroidal detachment (CD), suprachoroidal fluid (SCF), and lower intraocular pressure (IOP) markedly increase the difficulty of pars plana vitrectomy (PPV) because it makes the insertion and placement of the trocar cannulas for PPV time-consuming and technically challenging. In this study, we developed a systemic approach that avoids the risks of sclerotomy or using a longer trocar to help in the safe placement of the trocar cannulas in order to prevent inadvertent fluid/air perfusion during PPV in RRD eyes with extensive CD, SCF, and hypotony. METHODS: This is a prospective case series study. Consecutive patients diagnosed with RRD with extensive CD, SCF, and hypotony were recruited. The main steps included injecting transconjunctival intravitreal fluid to increase IOP and enable the passive egress of SCF into the subconjunctival space, creating and broadening the inner opening for the trocar cannulas, transillumination with an endoillumination light pipe, and indentation of the infusion cannula to create maximum visual exposure of the inner segment and help peripheral shaving around the infusion tip. MAIN OUTCOMES: the success rate of the infusion placement into the vitreous cavity, surgical duration, intra- and postoperative complications, and functional and anatomical outcomes. RESULTS: Thirty-eight patients (38 eyes) were included. The first-time success rate of cannula placement into the vitreous cavity was 100%, with a mean surgical duration of 8.5 +/- 1.8 min. No intra- or postoperative complications related to the approach were observed. Significant vision improvement was noted in 68.4% (26/38) of the patients at the final follow up. The primary and final retinal reattachment rates were 94.7% (36/38) and 100% (38/38), respectively. CONCLUSION: This systemic approach is a feasible option to ensure the safe placement of trocar cannulas and prevent inadvertent perfusion during small-gauge PPV in RRD eyes with extensive CD, SCF, and hypotony, without the need for a draining sclerotomy, a longer trocar, or a sharp clearing of the cannula tip. PMID- 30474802 TI - DAMPs and sterile inflammation in drug hepatotoxicity. AB - Drug hepatotoxicity is the leading cause of acute liver failure (ALF) in the developed countries. The early diagnosis and treatment are still problematic, and one important reason is the lack of reliable mechanistic biomarkers and therapeutic targets; therefore, searching for new biomarkers and therapeutic targets is urgent. Drug hepatotoxicity induces severe liver cells damage and death. Dead and damaged cells release endogenous damage-associated molecular patterns (DAMPs). Increased circulating levels of DAMPs (HMGB1, histones and DNA) can reflect the severity of drug hepatotoxicity. Elevated plasma HMGB1 concentrations can serve as early and sensitive mechanistic biomarker for clinical acetaminophen hepatotoxicity. DAMPS significantly contribute to liver injury and inhibiting the release of DAMPs ameliorates experimental hepatotoxicity. In addition, HMGB1 mediates 80% of gut bacterial translocation (BT) during acetaminophen toxicity. Gut BT triggers systemic inflammation, leading to multiple organ injury and mortality. Moreover, DAMPs can trigger and extend sterile inflammation, which contributes to early phase liver injury but improves liver regeneration at the late phase of acetaminophen overdose, because anti-inflammatory treatment reduces liver injury at early phase but impairs liver regeneration at late phase of acetaminophen toxicity, whereas pro-inflammatory therapy improves late phase liver regeneration. DAMPs are promising mechanistic biomarkers and could also be the potential therapeutic targets for drug hepatotoxicity. DAMPs-triggered sterile inflammation contributes to liver injury at early phase but improves liver regeneration at later phase of acetaminophen hepatotoxicity; therefore, anti-inflammatory therapy would be beneficial at early phase but should be avoided at the late phase of acetaminophen overdose. PMID- 30474803 TI - Future Costs in Cost-Effectiveness Analyses: Past, Present, Future. AB - There has been considerable debate on the extent to which future costs should be included in cost-effectiveness analyses of health technologies. In this article, we summarize the theoretical debates and empirical research in this area and highlight the conclusions that can be drawn for current practice. For future related and future unrelated medical costs, the literature suggests that inclusion is required to obtain optimal outcomes from available resources. This conclusion does not depend on the perspective adopted by the decision maker. Future non-medical costs are only relevant when adopting a societal perspective; these should be included if the benefits of non-medical consumption and production are also included in the evaluation. Whether this is the case currently remains unclear, given that benefits are typically quantified in quality-adjusted life-years and only limited research has been performed on the extent to which these (implicitly) capture benefits beyond health. Empirical research has shown that the impact of including future costs can be large, and that estimation of such costs is feasible. In practice, however, future unrelated medical costs and future unrelated non-medical consumption costs are typically excluded from economic evaluations. This is explicitly prescribed in some pharmacoeconomic guidelines. Further research is warranted on the development and improvement of methods for the estimation of future costs. Standardization of methods is needed to enhance the practical applicability of inclusion for the analyst and the comparability of the outcomes of different studies. For future non-medical costs, further research is also needed on the extent to which benefits related to this spending are captured in the measurement and valuation of health benefits, and how to broaden the scope of the evaluation if they are not sufficiently captured. PMID- 30474804 TI - 4-Hydroxyderricin inhibits osteoclast formation and accelerates osteoblast differentiation. AB - 4-Hydroxyderricin (4-HD) is a major polyphenol of Angelica keiskei (Japanese name Ashitaba), exhibiting anti-allergic, anti-diabetic, anti-oxidant, and antitumor effects. The present study was designed to evaluate the effects of 4-HD on bone formation and maintenance by using cultured osteoclasts and osteoblasts. 4-HD did not affect cell proliferation of stromal ST2 cells and preosteoblast MC3T3-E1 cells at concentrations of 1-10 MUM. This compound inhibited the formation of multinucleated osteoclasts from mouse splenic cells, and we identified a molecular pathway of osteoclast differentiation mediated by 4-HD, which led to inhibition of the expression of receptor activator of nuclear factor-kappaB ligand and macrophage-colony stimulating factor in ST2 cells. By contrast, 4-HD enhanced indices of osteoblast differentiation, such as alkaline phosphatase activity and calcium deposition by osteoblastic MC3T3-E1 cells, at concentrations of 1-10 MUM. Furthermore, we found that 4-HD at 1 MUM attenuated H2O2 levels in MC3T3-E1 cells. Our findings indicate that 4-HD may have critical effects on bone formation and maintenance. PMID- 30474805 TI - Ambivalence over emotional expression and intrusive thoughts as moderators of the link between self-stigma and depressive symptoms among Chinese American breast cancer survivors. AB - Due to successful public health campaigns, breast cancer has successfully transformed from a highly stigmatized illness to a philanthropically supported disease in the United States. However, Chinese American breast cancer survivors continue to experience high levels of self-stigma and associated negative mental health outcomes. In the present study, we examined the relations between self stigma and depressive symptoms, and further tested individual difference variables such as ambivalence over emotional expression and intrusive thoughts that may exacerbate the harmful effects of self-stigma among this population. One hundred and twelve foreign-born Chinese breast cancer survivors living in the United States completed questionnaires measuring self-stigma, depressive symptoms, AEE, and intrusive thoughts. We found significant AEE * self-stigma and intrusive-thought * self-stigma interaction effects in predicting depressive symptoms. Specifically, the relationships between self-stigma and depressive symptoms were exacerbated among individuals with high levels of AEE and intrusive thoughts. Self-stigma represents a significant predictor of depressive symptoms among Chinese breast cancer survivors, and particularly so for individuals with higher levels of AEE and intrusive thoughts. The findings suggest that for interventions designed to reduce the negative mental health outcomes associated with self-stigma, targeting risk factors such as AEE and intrusive thoughts might be promising. PMID- 30474806 TI - Music as a Medicine for the Soul in Bible and Christian Patristic Tradition. PMID- 30474807 TI - The chirality of imazethapyr herbicide selectively affects the bacterial community in soybean field soil. AB - The chiral herbicide imazethapyr (IM) is frequently used to control weeds in soybean fields in northeast China. However, the impact of IM enantiomers on microbial communities in soil is still unknown. Genetic markers (16S rRNA V3-V4 regions) were used to characterize and evaluate the variation of the bacterial communities potentially effected by IM enantiomers. Globally, the bacterial community structure based on the OTU profiles in (-)-R-IM-treated soils was significantly different from those in (+)-S-IM-treated soils, and the differences were enlarged with the treatment dose increasing. Interestingly, the Rhizobiaceae family and several other beneficial bacteria, including Bradyrhizobium, Methylobacterium, and Paenibacillus, were strongly enriched in (-)-R-IM treatment compared to (+)-S-IM treatment. In contrast, the pathogenic bacteria, including Erwinia, Pseudomonas, Burkholderia, Streptomyces, and Agrobacterium, were suppressed in the presence of (-)-R-IM compared to (+)-S-IM. Furthermore, we also observed that the bacterial community structure in (-)-R-IM-treated soils was more quickly restored to its original state compared with those in (+)-S-IM treated soils. These findings unveil a new role of chiral herbicide in the development of soil microbial ecology and provide theoretical support for the application of low-persistence, high-efficiency, and eco-friendly optical rotatory (-)-R-IM. PMID- 30474808 TI - As(III) and Cr(VI) oxyanion removal from water by advanced oxidation/reduction processes-a review. AB - Water pollution by human activities is a global environmental problem that requires innovative solutions. Arsenic and chromium oxyanions are toxic compounds, introduced in the environment by both natural and anthropogenic activities. In this review, the speciation diagrams of arsenic and chromium oxyanions in aqueous solutions and the analytical methods used for their detection and quantification are presented. Current and potential treatment methods for As and Cr removal, such as adsorption, coagulation/flocculation, electrochemical, ion exchange, membrane separation, phyto- and bioremediation, biosorption, biofiltration, and oxidative/reductive processes, are presented with discussion of their advantages, drawbacks, and the main recent achievements. In the last years, advanced oxidation processes (AOPs) have been acquiring high relevance for the treatment of water contaminated with organic compounds. However, these processes are also able to deal with inorganic contaminants, mainly by changing metal/metalloid oxidation state, turning these compounds less toxic or soluble. An overview of advanced oxidation/reduction processes (AO/RPs) used for As and Cr removal was carried out, focusing mainly on H2O2/UVC, iron based and heterogeneous photocatalytic processes. Some aspects related to AO/RP experimental conditions, comparison criteria, redox mechanisms, catalyst immobilization, and process intensification through implementation of innovative reactors designs are also discussed. Nevertheless, further research is needed to assess the effectiveness of those processes in order to improve some existing limitations. On the other hand, the validation of those treatment methods needs to be deepened, namely with the use of real wastewaters for their future full scale application. Graphical abstract ?. PMID- 30474809 TI - Importance of legislation on the treatment of chemical effluents as a way to avoid environmental pollution: the use of numerical technique to simulate the sedimentation of chemical effluents. AB - Environmental pollution analysis should be present in scientific research. The more organized the environmental laws of a particular place, the smaller the risks imputed to the ecosystem. The environmental damages that irregular waste from industrial effluents can cause are notorious. However, Brazil lacks extensive legal regulation, which is an embryonic legal matter. There is no specific law regulating a National Industrial Effluent Policy, dealing with the treatment and final disposal of these chemical compounds. Until a solid legal structure has been formalized on the treatment and final disposal of industrial effluents in Brazil, it is necessary that scientific researches optimize techniques capable of causing lower environmental impacts, so as to avoid possible pollution to the bodies of water. This article defends the argument that it is possible to elaborate legislation on the treatment and final disposal of industrial effluents in Brazil, through the application of engineering techniques, specifically through numerical simulation, by using the discrete elements method or particles method. The present case study is the Camacari Petrochemical Pole, state of Bahia, which is the largest integrated industrial complex in the Southern Hemisphere, composed of more than 90 companies in the chemical and petrochemical areas. All the effluents from this locality are treated by CETREL (Liquid Effluent Treatment Plant). Particle analysis was performed in CETREL tanks to illustrate how numerical simulations can be applied to investigate the treatment of industrial effluents and, consequently, to affirm the importance of developing procedures and norms for this matter. It is believed that this article brings relevant information to support a future law that regulates a Brazilian National Policy of Industrial Effluents. PMID- 30474810 TI - Divergent patterns of soil phosphorus discharge from water-level fluctuation zone after full impoundment of Three Gorges Reservoir, China. AB - Phosphorus (P) discharged from soils in the water-level fluctuation (WLF) zone becomes increasingly important to the water quality control of the Three Gorges Reservoir (TGR) as the decrease in P input from upstream reaches and point-source pollution. To investigate the amount of soil P discharge from the WLF zone since the full impoundment of the TGR in 2010, soil and sediment samples were collected along the altitudinal gradients (140, 150, 160, 170, and 180 m above sea level) in three transects in the middle reaches of the TGR. Soil P composition was determined by a sequential extraction procedure. Different amounts of P discharge from the WLF zone were found among three soil types because of their difference in the initial P content before impoundment, with an order of yellow earth (171.1 g m-2), fluvo-aquic soil (141.7 g m-2), and purple soil (73.8 g m-2). An altitudinal pattern of soil P discharge was observed with the maximum at the 170 m sites. The downward transport of exchangeable P and clay-bound P with runoff was the major path of the soil P discharge at the 170-m sites with a slope gradient > 15 degrees . Considerable P discharge with erosion at the upper section of the WLF zone was facilitated by the longer exposure period compared with that at bottom section (150-m sites) because of the annual anti-seasonal impoundment-exposure cycles of the TGR. The transformation of Al/Fe-P and subsequent release to water was a main mechanism of the soil P discharge during the impoundment period. The altitudinal pattern of P discharge was a result of joint effects of slope gradient, soil P forms, and the anti-seasonal hydrological regime of the TGR. The results highlight the critical role of the upper section (165-175 m) in controlling the P output from the WLF zone into the water of the TGR. PMID- 30474812 TI - Fenton-based electrochemical degradation of metolachlor in aqueous solution by means of BDD and Pt electrodes: influencing factors and reaction pathways. AB - This work explores the role of electrode material and the oxidation ability of electrochemical advanced oxidation processes (EAOPs), such as electro-oxidation (EO) with or without H2O2 production, electro-Fenton (EF), and UVA photoelectron Fenton (PEF), in the degradation of metolachlor. The performance of the EAOPs using Boron-doped diamond (BDD) or Pt as anode has been compared from the analysis of decay kinetics, mineralization profile, and energy consumption using small undivided batch cell. Metolachlor concentration always decays following a pseudo-first-order kinetics. Using the Pt anode, none of the processes reaches 30% mineralization, including PEF. In contrast, the BDD anode showed a higher mineralization rate allowing almost total mineralization in PEF due to the synergetic action of UVA light and oxidant hydroxyl radicals formed in the bulk from Fenton's reaction, as well as in the BDD, which has large reactivity to oxidize the pollutants. The increase in current density and decrease in metolachlor concentration accelerated the mineralization in PEF, although lower current efficiency and higher energy consumption was obtained. The GC-MS and HPLC analysis allowed the identification of up to 17 aromatics intermediates and 7 short-chain carboxylic acids. Finally, a reaction pathway for metolachlor mineralization by EAOPs is proposed. PEF with BDD allowed total removal of the herbicide in real water matrix and a high mineralization (83.82%). PMID- 30474811 TI - Producing more grain yield of rice with less ammonia volatilization and greenhouse gases emission using slow/controlled-release urea. AB - Ammonia (NH3) volatilization and greenhouse gas (GHG) emission from rice (Oryza sativa L.) fields contaminate the atmospheric environment and lead to global warming. Field trials (2013-2015) were conducted to estimate the influences of different types of fertilization practices on grain yield, NH3 volatilization, and methane (CH4) and nitrous oxide (N2O) emissions in a double rice cropping system in Central China. Results showed that grain yields of rice were improved significantly by using slow/controlled-release urea (S/C-RU). Compared with farmers' fertilizer practice (FFP) treatment, average annual grain yield with application of polymer-coated urea (CRU), nitrapyrin-treated urea (CP), and urea with effective microorganism (EM) treatments was increased by 18.0%, 16.2%, and 15.4%, respectively. However, the effects on NH3 volatilization and CH4 and N2O emissions differed in diverse S/C-RU. Compared with that of the FFP treatment, the annual NH3 volatilization, CH4 emission, and N2O emissions of the CRU treatment were decreased by 64.8%, 19.7%, and 35.2%, respectively; the annual CH4 and N2O emissions of the CP treatment were reduced by 33.7% and 40.3%, respectively, while the NH3 volatilization was increased by 18.5%; the annual NH3 and N2O emissions of the EM treatment were reduced by 6.3% and 28.7%, while the CH4 emission was improved by 4.3%. Overall, CP showed the best emission reduction with a decrement of 34.3% in global warming potential (GWP) and 44.4% in the greenhouse gas intensity (GHGI), followed by CRU treatment with a decrement of 21.1% in GWP and 31.7% in GHGI, compared with that of the FFP treatment. Hence, it is suggested that polymer-coated urea can be a feasible way of mitigating NH3 volatilization and CH4 and N2O emission from rice fields while maintaining or increasing the grain yield in Chinese, the double rice cropping system. PMID- 30474813 TI - Spatial variations in trophic-functional patterns of periphytic ciliates and indications to water quality in coastal waters of the Yellow Sea. AB - To evaluate the water quality status using ecological features of the periphytic ciliate communities, a 1-year (Jan. to Dec., 2016) investigation was conducted in coastal waters of the Yellow Sea, northern China. Four trophic-functional groups (TFgrs) were recorded from a total of 141 species-abundance dataset: algivores (A); bacterivores (B); non-selectives (N); and predators (R), comprising of 65, 34, 26, and 16 species, respectively. In terms of species number, TFgr A was predominant in clean areas while TFgrs B and N were dominant in heavy polluted areas and TFgr R was dominant in slightly polluted area. The trophic-functional patterns of the periphytic ciliate communities showed a clear spatial variation within the pollution gradient. Trophic-functional trait diversity measures represented a clear increasing trend from polluted stations to the clean area regarding the pollution gradients. Multivariate correlation and best matching analysis revealed that the spatial pattern of the trophic-functional groupings were significantly shaped by environmental variable nutrients and chemical oxygen demand, alone or in combination with pH, dissolved oxygen, salinity, and transparency. Thus, we suggest that the ecological features based on the trophic functional patterns of periphytic ciliate communities might be used for bioassessment of water quality in marine ecosystems. PMID- 30474814 TI - Effects of temperature on hospitalisation among pre-school children in Hanoi, Vietnam. AB - This study examined the effect of short-term changes in ambient temperature on hospital admissions among children aged less than 5 years old in Hanoi, Vietnam. Data on daily hospital admissions from January 2010 to June 2014 were collected from two hospitals. Daily meteorological data were obtained for the same period. We applied time series analysis to evaluate the risk of hospitalisation related to hot and cold weather by age and causes. We found that a 1 degrees C decrease in minimum temperature during the cold weather months was associated with 2.2% increase in hospital admission for respiratory infection among children 3-5 years old. A 1 degrees C increase in diurnal temperature range (DTR) in cold weather was associated with an increase of 1.9% and 1.7% in hospitalisation for all causes and respiratory infection, respectively, among children < 3 years old and an increase of 1.8% and 3.4% in hospitalisation for all causes and respiratory infection, respectively, among children of 3-5 years old. Negative associations between hot weather and hospital admissions were demonstrated. These findings suggested that low temperature and DTRs in winter are important risk factors for hospital admissions among children aged < 5 years old in Hanoi. Other factors may have modified the effect of high temperature on hospital admissions of children in Hanoi. PMID- 30474815 TI - Impact of energy mix on nitrous oxide emissions: an environmental Kuznets curve approach for APEC countries. AB - There are a limited number of studies on the estimation of environmental Kuznets curve (EKC) hypothesis for nitrous oxide (N2O) emissions, though it is one of the most harmful greenhouse gases (GHGs) present in ambient atmosphere. In the wake of industrialization, it is necessary to understand the impact of energy consumption pattern on N2O emissions and revise the energy policies accordingly. In this study, we have analyzed the impact of renewable and fossil fuel energy consumptions on N2O emissions for APEC countries over the period of 1990-2015, and the analysis has been carried out following the EKC hypothesis framework. The results obtained from the study indicate the efficacy of the renewable energy solutions in having positive impact on environmental quality by helping to reduce the level of N2O emissions. The policy implications derived from the results are designed while keeping the objectives of sustainable development goals (SDGs) in mind, so that the energy policies can bring forth sustainability in the economic systems in these nations. PMID- 30474816 TI - Monitoring the morphological integrity of neotropical anurans. AB - Amphibians are considered to be excellent bioindicators to their morphophysiological characteristics and life cycle. In this context, the present study investigated the morphological integrity of anuran larvae collected in preserved environments in the Emas National Park, in the municipality of Mineiros (Goias state, Brazil), and in environments representative of the agricultural matrix of the Rio Verde region, also in Goias, where there is a long history of the use of agricultural pesticides. Samples of water from temporary ponds, permanent dams, and veredas were analyzed for the presence of pesticides and, especially atrazine (5350 MUg/L), found at significantly higher concentrations in the agricultural matrix. We observed a high percentage (approximately 10%) of morphological malformations including alterations of the fins in Boana albopunctatus and Scinax fuscovarius; alteration in oral structures in B. albopunctatus, Dematonotus muelleri, Physalaemus centralis, Physalaemus cuvieri, and Leptodactylus fuscus mainly in the tadpoles collected in the agricultural environment in comparison with those from the protected area (3.5%; P < 0.0001, chi2 31.75). However, changes in the eyes, mouth, intestines, and nostrils, as well as amelia were observed only in the agricultural environment. The vast majority of the observed malformations were associated with the tail and oral disc, which suggests that these anatomical parameters may be used as sensitive morphological biomarkers. Given these findings, we reinforce that areas of agricultural land may have a deleterious effect on the morphological integrity of the tadpoles and consequently, on their development, and that these features may be used as indicators of environmental quality and health. PMID- 30474817 TI - A Novel 3-Dimensional Co-culture Method Reveals a Partial Mesenchymal to Epithelial Transition in Breast Cancer Cells Induced by Adipocytes. AB - Cancer metastases are accountable for almost 90% of all human cancer related deaths including from breast cancer (BC). Adipocytes can alter the tumor microenvironment, which can promote metastasis by inducing an epithelial-to mesenchymal transition (EMT) in BC cells. However, the role of adipocytes during the mesenchymal-to-epithelial transition (MET), that can be important in metastasis, is not clear. To understand the effect of adipocytes on the BC progression, there is a requirement for a better in vitro 3-dimensional (3D) co culture system that mimics the breast tissue and allows for more accurate analysis of EMT and MET. We developed a co-culture system to analyze the relationship of BC cells grown in a 3D culture with adipocytes. We found that adipocytes and adipocyte-derived conditioned media, but not pre-adipocytes, caused the mesenchymal MDA-MB-231 and Hs578t cells to form significantly more epithelial-like structures when compared to the typical stellate colonies formed in control 3D cultures. SUM159 cells and MCF7 cells had a less dramatic shift as they normally have more epithelial-like structure in 3D culture. Biomarker expression analysis revealed that adipocytes only induced a partial MET with proliferation unaffected. In addition, adipocytes had reduced lipid droplet size when co-cultured with BC cells. Thus, we found that physical interaction with adipocytes and ECM changes the mesenchymal phenotype of BC cells in a manner that could promote secondary tumor formation. PMID- 30474818 TI - Efficacy and Safety of IDegAsp Versus BIAsp 30, Both Twice Daily, in Elderly Patients with Type 2 Diabetes: Post Hoc Analysis of Two Phase 3 Randomized Controlled BOOST Trials. AB - INTRODUCTION: The majority of elderly patients (>= 65 years of age) with type 2 diabetes mellitus (T2DM) will eventually require insulin therapy, but they are particularly vulnerable to hypoglycemia and challenging to treat. Insulin degludec/insulin aspart (IDegAsp) is a novel co-formulation of 70% insulin degludec and 30% insulin aspart administered in a single injection, either once or twice daily with main meals. METHODS: A combined analysis of the phase 3 BOOST INTENSIFY PREMIX I (NCT01009580) and BOOST INTENSIFY ALL (NCT01059812) trials has previously reported lower rates of hypoglycemia during the maintenance period in patients with T2DM treated with IDegAsp twice daily (BID) versus biphasic insulin aspart 30 (BIAsp 30) BID. This post hoc analysis examined the safety and efficacy of IDegAsp versus BIAsp 30 in elderly patients from the global population of these two trials, and also from the Japanese cohort of BOOST INTENSIFY ALL. RESULTS: Change in HbA1c was similar for IDegAsp versus BIAsp 30 (p > 0.5). Compared with BIAsp 30, IDegAsp resulted in significant reductions in fasting plasma glucose (p < 0.0001), numerically lower rates of overall and nocturnal hypoglycemia (global estimated rate ratios: 0.92 [0.67; 1.26]95% confidence interval [CI], p = 0.5980 and 0.67 [0.39; 1.18]95% CI, p = 0.1676, respectively), and a significantly lower total daily insulin dose at end of trial (global estimated treatment difference 0.79 [0.73; 0.87]95% CI, p < 0.0001) in elderly patients. CONCLUSION: The results described here are consistent with those of the overall trial populations, demonstrating that IDegAsp BID is efficacious in elderly patients and suggesting that there is no need for special safety precautions. FUNDING: Novo Nordisk. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT01009580 and NCT01059812. Plain language summary available for this article. PMID- 30474819 TI - Integrative Medicine Intervention for Chronic Disease Management-Cardiovascular Disease. PMID- 30474820 TI - Contribution of the left atrial remodeling to the elevated pulmonary capillary wedge pressure in patients with WHO Group II pulmonary hypertension. AB - BACKGROUND: The contribution of progressive left atrial (LA) enlargement to elevated pulmonary capillary wedge pressure (PCWP) in patients with WHO Group II pulmonary hypertension (PH) has not been well studied. We hypothesized that progressive LA enlargement is associated with increased PCWP. METHODS: A cross sectional retrospective cohort consisted of 166 patients with HF and WHO Group II PH, confirmed by right heart catheterization (RHC). LA anteroposterior dimension and volume were measured on TTE. PCWP and other hemodynamic parameters were measured by RHC. Univariate and multivariate logistic regression models were used for analysis. RESULTS: LA enlargement was associated with advanced age, increased BMI, and LV ejection fraction < 40%. PCWP was progressively increased in patients with dilated LA: 16.9 +/- 7.4 mmHg in normal LA, 17.6 +/- 7.2 mmHg in mildly dilated LA, 22.6 +/- 6.3 mmHg in moderately and 22 +/- 7.6 in severely dilated LA (p < 0.001). In multiple logistic regression, after adjustment for echocardiographic and clinical variables, severe LA enlargement was independently predictive of elevated PCWP (OR 3.468; 95% CI 1.046-11.504; p = 0.042). After excluding significant mitral regurgitation, progressive LA dilatation was associated with higher PCWP V-wave amplitude: from 21.3 +/- 10.4 mmHg in patients with normal LA size, to 30.9 +/- 11.7 mmHg in moderately dilated and 31.0 +/- 11.6 mmHg in severely dilated LA (p < 0.001). CONCLUSIONS: In patients with HF and WHO Group II PH, progressive LA enlargement was independently associated with elevated PCWP. After excluding significant mitral regurgitation, LA enlargement was also associated with increased V-wave amplitude, indicative of decreased atrial compliance. PMID- 30474821 TI - 1H, 15N, 13C resonance assignment of the human CD44 cytoplasmic tail (669-742). AB - CD44 is a universally and abundantly expressed single-pass type I protein that spans the cytoplasmic membrane and is considered the principal receptor for hyaluronan in the extracellular matrix. CD44 exerts a multitude of biological functions, especially in cell adhesion and migration, and its deregulation has several pathological implications, including a putative role in cancer cell dissemination. Here we report the NMR chemical shift assignment of the recombinant intrinsically disordered CD44 cytoplasmic region (669-742). PMID- 30474822 TI - Diabetes in patients with acromegaly treated with pegvisomant: observations from acrostudy. AB - PURPOSE: To explore the effects of pegvisomant (PEGV) on glucose metabolism in patients with acromegaly within ACROSTUDY, an international, observational, prospective safety surveillance study. METHODS: Patients were retrospectively divided into two cohorts, with (DM group) or without diabetes mellitus (no-DM). Parameters of glucose metabolism and IGF-I values were analyzed yearly both cross sectionally for 4 years (yrs) and longitudinally at 1 and 4-5 yrs of PEGV treatment. RESULTS: Among 1762 patients, 510 (28.9%) had DM before PEGV start. At cross-sectional analyses, in the DM group mean blood glucose was 140.0 +/- 58.7 mg/dl at baseline, 116.4 +/- 44.8 mg/dl at year 1 and 120.0 +/- 44.3 mg/dl at yr 4. Mean HbA1c was 6.6 +/- 1.2 % at yr 1 vs. 7.0 +/- 1.4 % at baseline. HbA1c was above 6.5% in 61.9% at baseline and ranged from 45.4 to 53.8% at subsequent yearly time points. At the 4-yr longitudinal analysis, in the DM group (n = 109), mean blood glucose decreased by 20.2 mg/dl at yr 4, mean HbA1c was 7.0 +/- 1.5% at baseline vs. 6.8 +/- 1.4%. Patients achieved IGF-I normalization in 52.1% and 57.4% of cases in the DM and no-DM groups, respectively at 1 year. The mean daily PEGV dose (mg/day) was higher in the DM group (18.2 vs. 15.3) while the absolute change of IGF-I values from baseline was similar in both groups. PEGV was well tolerated in both groups without any unexpected AEs. CONCLUSIONS: Patients with DM had a moderate decrease in mean fasting glucose values during PEGV treatment. PMID- 30474823 TI - Hormonal aggressiveness according to the expression of cellular markers in corticotroph adenomas. AB - PURPOSE: The molecular mechanisms underlying tumor growth in Cushing's disease (CD) still remain a challenge. Moreover, clinical manifestations of CD may vary depending on hormonal activity; however, factors involved in the hormonal aggressiveness of adrenocorticotropic hormone (ACTH)-secreting pituitary tumors have not been fully clarified. We investigated the association between the expression of cellular markers regarding pituitary tumor progression and initial or postoperative hormone levels in patients with CD. METHODS: Tumor tissues from 28 corticotroph adenomas (female 26, male 2, mean age 39.21 +/- 10.39 years) were subject to immunohistochemical study using the following antibodies: pituitary tumor-transforming gene 1 (PTTG1), cyclin D1, p16, p27, brahma related-gene 1 (Brg1), and Ki-67. We then analyzed the relationship between each cellular marker expression and hormone levels, including 24 h urinary free cortisol (UFC), plasma ACTH, and serum cortisol. RESULTS: PTTG1 and Ki-67 were expressed in 100% and 50% of patients, respectively. However, the levels did not reflect initial hormonal activity. The cyclin D1-negative group showed higher serum cortisol levels compared to the cyclin D1-positive group (p = 0.01). The 24 h UFC levels were significantly higher in the p27-negative group than in the p27-positive group (p = 0.04), whereas the Brg1-positive group revealed higher serum cortisol levels than in the Brg1-negative group (p = 0.02). CONCLUSIONS: Although PTTG1 and Ki-67 play an essential role in developing ACTH-secreting tumors, cyclin D1, p27, and Brg1 may be better biomarkers to determine hormonal aggressiveness of the tumor. Further research is needed to understand the influence of cellular markers on hormonal activity in CD. PMID- 30474825 TI - Methimazole-induced acute pancreatitis: a case report. AB - A 76-year-old Japanese woman was diagnosed with Graves' disease and was administered methimazole (MMI) 10 mg and potassium iodide 50 mg. After 19 days of the drug regime, she developed high-grade fever and nausea and was admitted to our hospital. Blood test results showed elevated pancreatic enzymes and C reactive protein levels. Abdominal computed tomography showed swollen pancreas, and she was diagnosed with acute pancreatitis. These abnormalities improved after discontinuation of MMI. Five similar cases have been reported, but this is the first case report without abdominal pain. When acute pancreatitis is observed after the initiation of MMI, drug-induced pancreatitis should be considered as the possible etiology. PMID- 30474824 TI - Validation and comparison of three newly-released Thyroid Imaging Reporting and Data Systems for cancer risk determination. AB - PURPOSE: To validate and compare diagnostic value of three newly-released Thyroid Imaging Reporting and Data Systems (TIRADS) for cancer risk determination. METHODS: Total 2031 patients with 2465 thyroid nodules were recruited for this study. Ultrasound (US) images were categorized based on three TIRADS editions established by Korean Society of Thyroid Radiology (KSThR), European Thyroid Association (ETA) and American College of Radiology (ACR). ROC curves were established to compare diagnostic value. RESULTS: Total 1460 benign and 1005 malignant nodules were enrolled. The malignancy rates of each category in KSThR TIRADS were 2.8%, 5.1%, 33.7% and 79.6%, respectively. For European-TIRADS, 0, 3.1, 22.8, and 73.5% of nodules categorized as 2 to 5 were malignant. Distribution of carcinomas among ACR-TIRADS categories was 0%, 2.3%, 7.5%, 40.1% and 81.4%, respectively. In terms of diagnostic value, KSThR-TIRADS had highest AUC (0.855) and specificity (87.4%), while lowest (71.4%) sensitivity. ACR-TIRADS showed best sensitivity (96.6%) with lowest specificity (52.9%) and the AUC (0.846) was slightly lower than KSThR-TIRADS. Total 56.1, 45.4, and 37.4% fine needle aspiration biopsy (FNAB) were recommended by KSThR, ETA and ACR, revealing 42.8%, 44.5% and 53.6% malignant lesions, respectively. The rate of unnecessary FNAB was lowest with the ACR (17.3%), followed by ETA (25.2%) and KSThR (32.1%). CONCLUSION: All these US models showed great value in predicting thyroid malignancy. Among them, KSThR-TIRADS showed the most effective diagnostic performance in specificity, while ACR-TIRADS yielded best sensitivity. As for FNAB criteria, ACR-TIRADS showed the lowest rate of unnecessary FNAB and highest rate of malignancy in FNAB. PMID- 30474827 TI - Preliminary experience with single fecal microbiota transplant for treatment of recurrent overt hepatic encephalopathy-A case series. AB - Experimental studies demonstrated that fecal microbiota transplant (FMT) may reverse intestinal microbial dysbiosis. In this retrospective case series, we share our experience of treating recurrent overt hepatic encephalopathy (HE) with single FMT treatment. A total of 10 patients, age ranged from 25 to 65 years, were treated with single FMT through colonoscopy using fecal material received from rigorously screened patient-identified donors. There was sustained clinical response with single FMT treatment in 6 patients at post-treatment week 20. Arterial ammonia concentration decreased considerably (96 [87.25-117.75] vs. 74 [70-82]; p = 0.024) at post-treatment week 20. Moreover, there was statistically significant decrease in Child-Turcotte-Pugh (CTP) score (9.5 [9-10.75] vs. 8 [7 8]; p = 0.005) and model for end-stage liver disease (MELD) score (18 [16.25-19] vs. 15 [14-16]; p = 0.008). Four patients experienced six adverse-events. Overt HE and re-hospitalization were observed in 3 and 2 patients, respectively. One patient (who also experienced overt HE) died within 2 months of the index procedure. PMID- 30474828 TI - C1q and TNF related protein 1 regulates expression of inflammatory genes in vascular smooth muscle cells. AB - BACKGROUND: C1q and TNF related protein 1 (C1QTNF1) is known to be associated with coronary artery diseases. However, the molecular function of C1QTNF1 on the vascular smooth muscles remains to be investigated. OBJECTIVE: This study was therefore undertaken to investigate the effect of C1QTNF1 on gene expression of human smooth muscle cells and to reveal potential molecular mechanisms mediated by C1QTNF1. METHODS: Vascular smooth muscle cells were incubated with recombinant C1QTNF1 for 16 h, followed by determining any change in mRNA expressions by Affymetrix genechip. Gene ontology (GO), KEGG pathway, and protein-protein interaction (PPI) network were analyzed in differentially expressed genes. In addition, validation of microarray data was performed using quantitative real time PCR. RESULTS: The mRNA expressions of annotated 74 genes were significantly altered after incubation with recombinant C1QTNF1; 41 genes were up-regulated and 33 down-regulated. The differentially expressed genes were enriched in biological processes and KEGG pathways associated with inflammatory responses. In the PPI network analysis, IL-6, CCL2, and ICAM1 were identified as potential key genes with relatively high degree. The cluster analysis in the PPI network identified a significant module composed of upregulated genes, such as IL-6, CCL2, NFKBIA, SOD2, and ICAM1. The quantitative real-time PCR results of potential key genes were consistent with microarray data. CONCLUSION: The results in the present study provide insights on the effects of C1QTNF1 on gene expression of smooth muscle cells. We believe our findings will help to elucidate the molecular mechanisms regarding the functions of C1QTNF1 on smooth muscle cells in inflammatory diseases. PMID- 30474829 TI - Personality disorders are associated with more severe forms of migraine. AB - To investigate the clinical manifestation, disease course, and prognosis of migraine patients with or without personality disorders. This cross-sectional study evaluated 61 patients with migraine diagnosed according to the criteria of the International Headache Society (IHS). Personality disorders were assessed with the Structured Clinical Interview for DSM-IV (SCID-II). Migraine severity was assessed with the Headache Impact Test-6 (HIT-6). We also used a structured clinical interview to diagnose comorbid mood disorders. Of the 61 patients, 20 (32.8%) had personality disorders. Personality disorders included obsessive compulsive 14/61 (23.0%), avoidant 6/61 (9.8%), borderline 6/61 (9.8%), paranoid 6/61 (9.8%), schizoid 2/61 (3.3%), histrionic 1/61 (1.6%) and dependent 1/61 (1.6%) types. Compared to migraine patients without personality disorders, comorbidity with any personality disorders was associated with an increased frequency of chronic migraine (p < 0.001) and more severe headache as assessed by the HIT-6 (p < 0.001). Comorbidity with personality disorders was associated with more severe forms of migraine symptoms. PMID- 30474830 TI - Assessing ecosystem service trade-offs and synergies: The need for a more mechanistic approach. AB - Positive (synergistic) and negative (trade-off) relationships among ecosystem services are influenced by drivers of change, such as policy interventions and environmental variability, and the mechanisms that link these drivers to ecosystem service outcomes. Failure to account for these drivers and mechanisms can result in poorly informed management decisions and reduced ecosystem service provision. Here, we review the literature to determine the extent to which drivers and mechanisms are considered in assessments of ecosystem service relationships. We show that only 19% of assessments explicitly identify the drivers and mechanisms that lead to ecosystem service relationships. While the proportion of assessments considering drivers has increased over time, most of these studies only implicitly consider the drivers of ecosystem service relationships. We recommend more assessments explicitly identify drivers of trade offs and synergies, which can be achieved through a greater uptake of causal inference and process-based models, to ensure effective management of ecosystem services. PMID- 30474831 TI - Development and application of GIS-based assessment of land-use impacts on water quality: A case study of the Kharaa River Basin. AB - Effective analytical tools, such as geographical information systems (GIS) and multivariate analysis, help to deal with spatial data and complex interactions in watershed management. To investigate the impact of land-use on chemical water quality in the Mongolian Kharaa River Basin, the whole catchment and sub catchments in relation to each sampling point were delineated. Chemical water quality over three seasons was assessed with GIS and RDA in a modeling approach with forward selection of variables and cluster analysis. The most powerful predictors of river water quality were altitude, settlements, forest, cropland, and distance to spring. In particular, this was true when instead of full sub basins riparian buffer zones (max. 3 km) were considered. From a management perspective, this implies that the protection of riparian zones should be a priority in the Kharaa basin and similar river basins in Mongolia and Central Asia. Because of its positive effects on water quality, forest protection should be closely coupled with river basin management. PMID- 30474832 TI - Beekeeper stewardship, colony loss, and Varroa destructor management. AB - Varroa (Varroa destructor) is a leading cause of honey bee mortality worldwide. In a U.S. national survey of beekeepers, 3519 respondents noted what they believe are the advantages and disadvantages of managing for Varroa, what good stewardship means in beekeeping, and whether they treated for Varroa. Dominant attitudes were keeping bees healthy, minimizing disturbance, and monitoring hives. We found a bifurcation in Varroa management beliefs. Decision tree analyses show group distinctions. Treatment Skeptics tend to say that stewardship means bees should not be disturbed or subjected to chemicals, and should be given forage to do their 'normal business.' This group was less likely to treat for Varroa. Treatment Adherents identify themselves as bee stewards and say stewardship means active hive management and keeping bees healthy and alive. Illuminating beekeeper stewardship is essential for a socioecological understanding of how to address challenging Varroa management and complex human environmental production systems that have landscape-level effects. PMID- 30474833 TI - Assessment of immunological profile in ankylosing spondylitis patients following a clinical trial with guluronic acid (G2013), as a new NSAID with immunomodulatory properties. AB - The present research aims to study the effects of guluronic acid (G2013) on gene expression levels of the T-bet, GATA3, RORgammat, AHR, and FOXP3 transcription factors and on gene expression of their related cytokines following oral administration of this drug in ankylosing spondylitis (AS) patients. In this trial (clinical trial identifier: IRCT2016091813739N4), 14 AS patients and 12 age and sex-matched healthy individuals were enrolled. The level of transcription factors' gene expression and expression of their related cytokines were measured by quantitative real-time PCR, before and 3 months after G2013 therapy. Our data indicated that the gene expression levels of the T-bet and IFN-gamma were not significantly reduced during 12 weeks of treatment with G2013 (p > 0.05). The findings showed that the gene expression levels of the GATA3 and IL-4 increased significantly during 12 weeks of treatment with G2013 (p < 0.05). In addition, gene expression levels of the RORgammat, IL-17, AHR, and IL-22 decreased significantly during the 12-week treatment with G2013 (p < 0.05). Moreover, the gene expression level of the FOXP3 increased significantly during 12 weeks of treatment with G2013, but the gene expression level of IL-10 did not increase significantly (p < 0.05, p > 0.05, respectively). The present study showed that oral intake of G2013 was able to modify the severity of articular and inflammatory symptoms of AS through reducing the gene expression levels of the RORgammat, IL-17, AHR, and IL-22 and increasing the gene expression levels of the GATA3, IL-4, and FOXP3. PMID- 30474834 TI - Detecting Cellular Senescence in Reprogramming. AB - Cellular senescence has been suggested to facilitate tissue regeneration via promoting cellular plasticity. Here, we describe multiple systems, both in vitro and in vivo, to detect senescence in the context of cellular reprogramming. PMID- 30474835 TI - DNA Damage In Situ Ligation Followed by Proximity Ligation Assay (DI-PLA). AB - Cells have evolved DNA repair mechanisms to maintain their genetic information unaltered and a DNA damage response pathway that coordinates DNA repair with several cellular events. Despite a clear role for DNA damage in the form of DNA double-strand breaks (DSBs) in several cellular processes, the most commonly used methods to detect DNA lesions are indirect, and rely on antibody-based recognition of DNA damage-associated factors, leaving several important questions unanswered. Differently, here we describe DNA damage In situ ligation followed by Proximity Ligation Assay (DI-PLA), that allows sensitive detection of physical DSBs in fixed cells, through direct labeling of the DSBs with biotinylated oligonucleotides, and subsequent signal amplification by PLA between biotin and a partner protein in the proximity of the DNA break. PMID- 30474836 TI - Reactive Oxygen Species Detection in Senescent Cells. AB - Cumulative evidence suggests that cellular senescence plays a variety of important physiological roles, including tumor suppression, embryonic development and ageing. Senescent cells are characterized by increased production of reactive oxygen species (ROS), mostly produced by dysfunctional mitochondria. Both intracellular and extracellular ROS have been shown to contribute to the induction of senescence. ROS have also been shown to act as signaling molecules during senescence, stabilizing the cell-cycle arrest. In this chapter, we present a detailed description of protocols that allow us to characterize intracellular and extracellular ROS in live senescent cells. PMID- 30474837 TI - Cellular Identification and Quantification of Senescence-Associated beta Galactosidase Activity In Vivo. AB - Senescence-associated beta-galactosidase (hereafter SA-beta-gal) staining has now been employed for more than 20 years to identify the presence of senescent cells (Dimri et al., Proc Natl Acad Sci U S A 92:9363-9367, 1995). These cells, characterized by a permanent cell-cycle arrest (Hayflick and Moorhead, Exp Cell Res 25:585-621, 1961) and the production of a distinct secretory phenotype of cytokines, chemokines, and proteases (Coppe et al., PLoS Biol 6:2853-2868, 2008), have received much attention in recent years for their impacts on diverse biological processes. Here we describe a method to identify and quantify the specific cells that become senescent in vivo using transmission electron microscopy after SA-beta-gal staining that can be used in countless scenarios. PMID- 30474838 TI - Relative Human Telomere Length Quantification by Real-Time PCR. AB - Telomere measurement by quantitative PCR amplification is a well-known simple method to detect telomere length that involves large numbers of samples. The method has been developed by Cawthon in 2002 (Cawthon, Nucleic Acids Res 30:47e 47, 2002) and remains the most frequently used technique either in original or modified version. Telomere length is estimated by comparing the amount of telomere repeat amplification product (T) to a single copy gene (S) product. The T/S ratio correlates with the average telomere length. Cawthon suggested and recommended the use of 36B4 (RPLP0) as a single copy gene. However, Cawthon's suggestion was no longer considered a single copy gene and the gene was not suitable and appropriate for normalization.We thereby introduced a simple method for relative measurement of average human telomere length using quantitative real time PCR. Our protocol was based on Cawthon's initial technique (Cawthon, Nucleic Acids Res 30:47e-47, 2002), modified by single-copy gene (SCG) primers and optimized.This technique is rapid, low cost, not demanding on DNA amount (or live cells), and can be used for a high-throughput screening and time monitoring. PMID- 30474839 TI - Assessing Functional Roles of the Senescence-Associated Secretory Phenotype (SASP). AB - Cellular senescence is linked to many normal biological processes, including tumor suppression, development, and wound healing, but it is also associated with age-related pathologies such as cancer progression. Numerous functions of senescent cells depend on their ability to secrete bioactive molecules, a characteristic termed the senescence-associated secretory phenotype (SASP). Although the SASP is generally described as proinflammatory, its true microenvironmental impact and composition may vary according to cell types (i.e., fibroblasts/epithelial, normal/cancerous) and senescence-triggering stimuli (i.e., replicative senescence, DNA damage-induced senescence, oncogene-induced senescence). The SASP reinforces autocrine cell-autonomous functions such as the senescence-associated proliferation arrest, but also mediates potent paracrine, non-cell-autonomous effects. In a paracrine manner, senescent cells influence the remodeling of surrounding tissues and the biology of adjacent cells, including modulation of proliferation and migration/invasion, reinforcement/induction of peripheral senescence, and immune cell activity or recruitment. Overall, the complexity of the context-dependent SASP composition and varied microenvironmental impact demonstrate the importance of properly assessing SASP functions directly on target cells. In this chapter, we focus on experimental approaches to evaluate the impact of SASP on the proliferation and migration/invasion capacities of target cancer cells. These techniques, with combined supplemental notes, will facilitate the assessment of novel functions of senescent cells on their microenvironment, and can be easily adapted beyond the use of the presented SASP-cancer scenario. PMID- 30474840 TI - Measuring the Inflammasome in Oncogene-Induced Senescence. AB - Inflammasomes are multimeric protein complexes that process IL-1beta by cleaving the translated full-length protein into its active IL-1beta mature fragment. In oncogene-induced senescence, inflammasomes play a crucial role by regulating IL1R signaling and consequently modulating proliferation and the senescence-associated secretory phenotype (SASP). Inflammasome activation requires two steps: (a) priming of the inflammasome by activation of IL1B expression, followed by (b) cleavage and release of mature IL-1beta. In this chapter, we describe methods to detect both stages of inflammasome activation in cellular senescence. PMID- 30474841 TI - Alarmin Detection in Senescent Cells. AB - Senescent cells secrete diverse array of proteins. One group of proteins, damage associated molecular pattern (DAMP) proteins exhibit relocalization from inside to outside the cell. High Mobility Group Box 1 protein (HMGB1) is the founding DAMP member. HMGB1 relocalization from the nucleus provides a molecular signature during senescence. We provide distinct molecular techniques (immunofluorescence, immunohistochemistry, and Western blot assays) to assess HMGB1 relocalization during the initial stages of senescence. PMID- 30474842 TI - IMR90 ER:RAS: A Cell Model of Oncogene-Induced Senescence. AB - Oncogene-induced senescence (OIS) is a cellular response that limits the replication of cells expressing oncogenes. As a result, OIS is a potent tumor suppressor mechanism limiting cancer progression. Here we describe IMR90 ER:RAS, a widely used model to study OIS in cell culture. This model takes advantage of IMR90 human primary fibroblast infected with a 4-hydroxy-tamoxifen (4-OHT) inducible ER:RAS construct. RAS activation upon 4-OHT treatment results in a coordinated induction of senescence, recapitulating different aspects of the phenotype such as the growth arrest and the establishment of a senescence associated secretory phenotype (SASP). PMID- 30474844 TI - A Multiparametric Assay to Evaluate Senescent Cells. AB - Cellular senescence is a permanent growth arrest mechanism triggered by various forms of stress. Senescent cells accumulate in the mammalian organism with age and are present at sites of tissue damage and age related pathologies. However, the characterization of senescence cells in vivo is currently limited and the need for new technologies to detect and monitor the senescence state in vivo has greatly increased. Here we demonstrate the use of the ImageStreamX as a powerful method for detection and quantification of senescent cells at distinct tissues and cell subpopulations. The identification of senescent cells using ImageStreamX enables the use of a combination of several senescence-related markers, together with the commonly used senescence-associated beta-galactosidase assay. These can be combined with the use of other molecular features typical of senescence cells, such as the gammaH2AX foci, indicating the activation of DNA damage response. This novel method offers a feasible solution to quantify senescent cells in vivo, in a comprehensive manner. Such quantification is necessary in order to understand the role of cellular senescence in aging and disease. PMID- 30474843 TI - Genotoxic Stress-Induced Senescence. AB - A cell's genomic integrity is at risk when DNA-damaging stress, evoked by mitogenic oncogenes or genotoxic treatment modalities such as radiation or chemotherapy, apply. If the DNA repair machinery fails to fix the damaged site during a temporary cell-cycle arrest, or if massive genotoxic stress overwhelmed the repair capacity, cellular failsafe programs such as apoptosis or senescence will be triggered to limit aberrant propagation of these damaged and potentially harmful cells. After decades of scientific focusing on apoptosis, cellular senescence is increasingly recognized as an equally important but biologically and fundamentally different type of ultimate cell-cycle exit program, because of its lastingly persistent nature and cell-intrinsic and extrinsic roles within the tissue and tumor microenvironment. We established primary apoptosis-compromised, Bcl2-expressing EMU-myc transgenic mouse lymphomas as a versatile and clinically relevant model system to study therapy-induced senescence (TIS). Given the lack of a single specific senescence-defining marker, we previously exploited co staining of senescence-associated beta-galactosidase (SA-beta-gal) activity with immunohistochemical detection of trimethylated histone H3 lysine 9 (H3K9me3), an established S-phase gene expression-controlling, repressive chromatin mark, and the proliferation marker Ki67. This biomarker panel is instrumental to characterize cells as senescent via their high SA-beta-gal activity, strong nuclear H3K9me3 expression and Ki67-negative profile. In this chapter, we demonstrate the detection of viable senescent cells by novel methods based on a fluorescent version of the SA-beta-gal (fSA-beta-gal) assay, combined with immuno fluoroscence staining of H3K9me3 or Ki67, or analysis of the DNA replication status by incorporating 5-ethynyl-2'-deoxyuridine (EdU) detection into the protocol. Notably, while most senescence markers, irrespective of their specificity and sensitivity, may only be assessed in endpoint assays, we would like to emphasize here the strength of viable fSA-beta-gal to track single-cell fate in senescent populations over time. PMID- 30474845 TI - A Novel Quantitative Method for the Detection of Lipofuscin, the Main By-Product of Cellular Senescence, in Fluids. AB - Lipofuscin accumulation is a hallmark of senescence. This nondegradable material aggregates in the cytoplasm of stressed or damaged cells due to metabolic imbalance associated with aging and age-related diseases. Indications of a soluble state of lipofuscin have also been provided, rendering the perspective of monitoring such processes via lipofuscin quantification in liquids intriguing. Therefore, the development of an accurate and reliable method is of paramount importance. Currently available assays are characterized by inherent pitfalls which demote their credibility. We herein describe a simple, highly specific and sensitive protocol for measuring lipofuscin levels in any type of liquid. The current method represents an evolution of a previously described assay, developed for in vitro and in vivo senescent cell recognition that exploits a newly synthesized Sudan Black-B analog (GL13). Analysis of human clinical samples with the modified protocol provided strong evidence of its usefulness for the exposure and surveillance of age-related conditions. PMID- 30474846 TI - Measurement of Metabolite Changes in Senescent Cells by Mass Spectrometry. AB - Senescent cells display altered metabolic signatures that can either be causal for aspects the senescent phenotype, or act as biomarkers for senescence. Steady state levels of multiple metabolites change with senescence, and can be detected using analytical methods. Here, we describe a liquid chromatography-mass spectrometry (LC-MS) method for detecting altered metabolites from cultured senescent cells. PMID- 30474847 TI - Quantification of Autophagy During Senescence. AB - Autophagy constitutes an evolutionarily conserved catabolic process that contributes to the clearance of damaged cellular components in response to a variety of stress conditions. Additionally, it plays a variety of physiological and pathophysiological roles in maintaining cell homeostasis. Recently, the critical role of autophagy during cellular senescence has been supported by evidences demonstrating the reversal of senescence by the reestablishment of autophagy. As considerable attention has been directed toward understanding the molecular mechanisms underlying senescence and autophagy, a method to accurately quantify autophagy during senescence is critical to understand its role in senescence and senescence-related diseases. In this chapter, we describe the use of CYTO-ID(r) green dye and DQTM Red BSA to monitor the autophagic flux as an accurate method to quantify autophagic activity. This technique relies on the specificity of CYTO-ID(r) green dye in staining autophagosome and the cleavage of the self-quenched DQTM Red BSA protease substrates in an acidic compartment. In particular, herein we describe protocols to quantify autophagy during senescence. PMID- 30474849 TI - Identification of Genomic Alterations Through Multilevel DNA Structural Analysis. AB - Current methods to identify genomic alterations using whole-genome sequencing (WGS) data are often limited to single nucleotide polymorphisms and insertions and deletions that are less than 10 bp in length. These limitations are largely due to challenges in accurately mapping short sequencing reads that significantly diverge from the reference genome. Newer sequencing-based methods have been developed to define and characterize larger DNA structural elements. This is achieved by enriching for and sequencing regions of the genome that contain a specific element, followed by identifying genomic regions with high densities of mapped short reads that designate the location of these elements. This process essentially aggregates short read data into larger structural units for further characterization. Here, we describe protocols for identifying various types of genomic alterations using differential analysis of these structural units. We focus on changes in DNA accessibility, protein-DNA interactions, and chromosomal contacts as measured by ATAC-Seq, ChIP-Seq, and Hi-C respectively. As many protocols have been published describing the generation and processing of these data, we focus on simple methods that can be used to identify mutations in these data, and can be executed by someone with limited computational expertise. PMID- 30474848 TI - Quantification of Aneuploidy in Mammalian Systems. AB - High-throughput next generation sequencing karyotyping has emerged as a powerful tool for the detection of genomic heterogeneity in normal tissues and cancers. Here we describe a single-cell whole genome sequencing (scWGS) platform to assess whole-chromosome aneuploidy, structural aneuploidies involving only chromosome fragments and more local small copy number alterations in individual cells. We provide a detailed protocol for the isolation, library preparation, low coverage sequencing and data analysis of single cells. Since our approach does not involve a whole-genome preamplification step, our method allows for acquisition of reliable high-resolution single-cell copy number profiles. Moreover, the protocol allows multiplexing of 384 single-cell libraries in one sequencing run, thereby significantly reducing sequencing costs and can be completed in 3-4 days starting from single cell isolation to analysis of sequencing data. PMID- 30474850 TI - Mouse Models of Accelerated Cellular Senescence. AB - Senescent cells accumulate in multiple tissues as virtually all vertebrate organisms age. Senescence is a highly conserved response to many forms of cellular stress intended to block the propagation of damaged cells. Senescent cells have been demonstrated to play a causal role in aging via their senescence associated secretory phenotype and by impeding tissue regeneration. Depletion of senescent cells either through genetic or pharmacologic methods has been demonstrated to extend murine lifespan and delay the onset of age-related diseases. Measuring the burden and location of senescent cells in vivo remains challenging, as there is no marker unique to senescent cells. Here, we describe multiple methods to detect the presence and extent of cellular senescence in preclinical models, with a special emphasis on murine models of accelerated aging that exhibit a more rapid onset of cellular senescence. PMID- 30474851 TI - Methods to Quantify the NF-kappaB Pathway During Senescence. AB - Nuclear factor kappaB (NF-kappaB) is a family of transcription factors important for regulating innate and adaptive immunity, cellular proliferation, apoptosis and senescence. The NF-kappaB family is comprised of five subunits, RelA/p65, RelB, C-Rel, p50 (p105/NF-kappaB1), and p52 (p100/NF-kappaB2). NF-kappaB activity goes up with age in multiple tissues. The two subunits RelA/p65 and p50 have been implicated in senescence and aging with genetic deletion of p65 and p50 reducing or increasing senescence respectively. Pharmacologic inhibition of NF-kappaB also extends health span and reduces senescence in mouse models of accelerated aging. In addition, NF-kappaB regulates expression of many of senescence associated secretory phenotype (SASP) factors released by certain types of senescent cells that drives loss of tissue homeostasis and secondary senescence. To measure NF kappaB activity with aging in vivo, multiple methods can and need to be utilized including cellular localization of p65, EMSA analysis of NF-kappaB DNA binding, RNA in situ hybridization, and analysis of expression of NF-kappaB target genes. To colocalize NF-kappaB activation and senescence, p65 localization or transcriptional activity can be measured by immunostaining or RNA in situ hybridization for NF-kappaB regulated genes along with methods such as immunostaining for gammaH2AX or RNA in situ for senescence markers like p16INK4a and p21. These and related methods will be described in this chapter. PMID- 30474852 TI - Does seminal vesicle-sparing robotic radical prostatectomy influence postoperative prostate-specific antigen measured with an ultrasensitive immunoassay? PMID- 30474853 TI - Class 1 HDAC and HDAC6 inhibition inversely regulates CD38 induction in myeloma cells via interferon-alpha and ATRA. PMID- 30474855 TI - Discrimination of dynamically and post-dynamically recrystallized grains based on EBSD data: application to Inconel 718. AB - The importance of angular resolution in EBSD analyses is discussed based on an Inconel 718 sample containing several populations of recrystallized grains, with subtle differences in dislocation contents. Classical EBSD analyses (with angular resolution in the range of 0.5-1 degrees ) do not allow for distinguishing recrystallized grains grown dynamically or post-dynamically. The angular resolution of EBSD orientation and misorientation data can be significantly improved (down to about 0.1-0.2 degrees ) either using more sophisticated Kikuchi pattern indexing methods and/or using the recently proposed LLASS denoising filter (Local Linear Automatic Smoothing Splines). Then the coexistence of both dynamically and post-dynamically recrystallized grains in the sample can be confirmed and quantified. ECCI images unambiguously confirm the conclusions drawn from the analysis of improved angular resolution EBSD data, and furthermore reveal the presence of thermal stress induced dislocations with typical patterns in water quenched Inconel 718 recrystallized grains. LAY DESCRIPTION: EBSD is widely used to study recrystallization phenomena. Conventional EBSD is nevertheless not able to distinguish dynamic recrystallized grains from post dynamic recrystallized grains which differ by subtitle differences in dislocation contents. In this paper, we show that improving the orientation precision of EBSD data by means of different methods allows distinguishing these two recrystallized grains populations. Analyses and discussion are based on an Inconel 718, a famous Nickel-based superalloy in aeronautic. PMID- 30474856 TI - Refining statistics clarifies leukaemic stem cell genomics. PMID- 30474854 TI - Motor function in Rett syndrome: comparing clinical and parental assessments. AB - AIM: To describe a new clinical tool, the Rett Syndrome Motor Evaluation Scale (RESMES) and to assess (loco-)motor function in people with Rett syndrome (RTT). METHOD: Formal assessment provided by physicians was followed by parents' direct observation at home using the RESMES. Sixty females (mean [SD] age 12y 5mo [8y 9mo], range 3-40y) with a clinical diagnosis and genetically determined RTT participated in the study. Spearman's/Pearson's coefficients assessed the correlation between the clinicians' and caregivers' evaluations, as well as the correlation of RESMES scores with other scales, namely the Pain Assessment in Advanced Dementia, the Rett Assessment Rating Scale, the Modified Ashworth Scale, and hand function (assessed with a scale of evaluation of purposeful hand function). Scores provided by parents and clinicians were tested statistically by Mann-Whitney U test. RESULTS: Approximately 88% of patients had moderate to severe RTT symptoms and, on average, moderate motor impairment based on the RESMES. RESMES total scores provided by clinicians and caregivers were highly correlated (r=0.91), as were the subscale scores. Postural transition was a critical area of the RESMES, where parents systematically provided lower scores than clinicians, indicating milder degrees of disability. Severity of scoliosis and mutation type emerged as significant predictors of motor function. INTERPRETATION: The RESMES characterized the (loco-)motor impairments of the patients with RTT well. It also showed a close correlation between the evaluations of clinicians and caregivers, with the possible exception of postural transition tasks, which should be carefully addressed in a clinical setting. The type of mutation and presence of scoliosis should be evaluated, as they predicted the ability to walk. WHAT THIS PAPER ADDS: Caregivers at home can reliably assess motor function in Rett syndrome using the Rett Syndrome Motor Evaluation Scale (RESMES). RESMES scores provided by clinicians and parents were highly correlated. The severity of scoliosis and the genetic mutation predicted standing and walking abilities. PMID- 30474857 TI - Antibody-mediated immunosuppression can result from RBC antigen loss independent of Fcgamma receptors in mice. AB - BACKGROUND: Anti-RhD administration can prevent de novo anti-RhD formation following RhD+ red blood cell (RBC) exposure, termed antibody-mediated immunosuppression (AMIS). Recent studies suggest that AMIS may occur through target antigen alterations, known as antigen modulation. However, studies suggest that AMIS may occur independent of antigen modulation. In particular, AMIS to RBCs that transgenically express the fusion hen egg lysozyme-ovalbumin-Duffy (HOD) antigen have been shown to occur independent of activating Fcgamma receptors (FcgammaRs) thought to be required for antigen modulation. Therefore, we sought to determine the mechanism behind AMIS following HOD RBC exposure. STUDY DESIGN AND METHODS: Following transfer of HOD RBCs into wild-type or FcgammaR-chain knockout recipients in the presence or absence of monoclonal anti hen egg lysozyme (HEL) antibody, individually or in combination, HOD antigen levels and anti-HOD antibody formation were examined. RESULTS: Our results demonstrate that anti-HEL antibodies individually or in combination suppressed anti-HOD IgM, which correlated with the rate of detectable decrease in HEL on HOD RBCs. Furthermore, exposure to anti-HEL antibodies alone or in combination equally suppressed anti-HOD IgG formation. Unexpectedly, combination or individual anti-HEL antibodies induced AMIS and antigen modulation in an FcgammaR independent manner. Pre-exposure of HOD RBCs to anti-HEL antibodies reduced antigen levels and suppressed anti-HOD antibody formation following HOD RBC exposure. CONCLUSION: These results suggest that antibody-mediated antigen modulation may reflect a mechanism of AMIS that can occur independent of activating FcgammaRs and may provide a surrogate to identify antibodies capable of inducing AMIS against different RBC antigens. PMID- 30474859 TI - Carcinocythaemia in an advanced stage of invasive ductal carcinoma of the breast. PMID- 30474858 TI - Frequent blood donations alter susceptibility of red blood cells to storage- and stress-induced hemolysis. AB - BACKGROUND: Frequent whole blood donations increase the prevalence of iron depletion in blood donors, which may subsequently interfere with normal erythropoiesis. The purpose of this study was to evaluate the associations between donation frequency and red blood cell (RBC) storage stability in a racially/ethnically diverse population of blood donors. STUDY DESIGN: Leukoreduced RBC concentrate-derived samples from 13,403 donors were stored for 39 to 42 days (1-6 degrees C) and then evaluated for storage, osmotic, and oxidative hemolysis. Iron status was evaluated by plasma ferritin measurement and self-reported intake of iron supplements. Donation history in the prior 2 years was obtained for each subject. RESULTS: Frequent blood donors enrolled in this study were likely to be white, male, and of older age (56.1 +/- 5.0 years). Prior donation intensity was negatively associated with oxidative hemolysis (p < 0.0001) in multivariate analyses correcting for age, sex, and race/ethnicity. Increased plasma ferritin concentration was associated with increased RBC susceptibility to each of the three measures of hemolysis (p < 0.0001 for all), whereas self-reported iron intake was associated with reduced susceptibility to osmotic and oxidative hemolysis (p < 0.0001 for both). CONCLUSIONS: Frequent blood donations may alter the quality of blood components by modulating RBC predisposition to hemolysis. RBCs collected from frequent donors with low ferritin have altered susceptibility to hemolysis. Thus, frequent donation and associated iron loss may alter the quality of stored RBC components collected from iron-deficient donors. Further investigation is necessary to assess posttransfusion safety and efficacy in patients receiving these RBC products. PMID- 30474860 TI - HDL mimetic peptides affect apolipoprotein E metabolism: equal supplement or functional enhancer?: An Editorial for 'High-density lipoprotein mimetic peptide 4F mitigates amyloid-beta-induced inhibition of apolipoprotein E secretion and lipidation in primary astrocytes and microglia' on doi:10.1111/jnc.14554. AB - epsilon4 allele of ApoE is the strongest genetic risk factor for late onset Alzheimer's disease (AD). Supplementation of ApoE proteins or mimetics has been pursued for drug developments against AD. A very low-density lipoprotein (HDL) mimetic peptide 4F was shown to alleviate AD-related deficits in APP transgenic mice, and this editorial highlights a study by Chernick et al. who use both mouse and human neuroglial cells to explore the mechanism underlying beneficial effects of this peptide. The authors demonstrate that 4F peptide significantly increased the secretion and lipidation of ApoE in the absence and presence of Abeta independent of de novo transcription/translation, but requiring ABCA1 and the integrity of the secretory pathway between ER and Golgi. This study reveals a novel mechanism of HDL mimetic peptide as a functional ApoE enhancer and support further development of ApoA-I 4F peptide as effective ApoE modulating agents against AD. PMID- 30474861 TI - Seroprevalence of Trypanosoma cruzi infection among at-risk blood donors in Japan. AB - BACKGROUND: Chagas disease is caused by Trypanosoma cruzi and is endemic in Latin America. In nonendemic countries, including Japan, Chagas disease is primarily a problem in the context of transfusion transmission. Approximately 250,000 immigrants from Latin America reside in Japan, and many of those individuals serve as active blood donors. This study surveyed the seroprevalence of T. cruzi infection among at-risk blood donors in Japan, defined as those who themselves (or whose mothers) were born (or raised) in Latin America, or those with a travel history to Latin America. STUDY DESIGN AND METHODS: Blood samples were obtained from at-risk donors in two periods, 2004-2012 and 2013-2016. Collected samples were tested for T. cruzi antibodies using both an enzyme-linked immunosorbent assay and a chemiluminescent immunoassay. Samples that tested positive in both assays were additionally tested by polymerase chain reaction, and look-back investigation was conducted when necessary. RESULTS: Of 18,484 samples obtained from 18,076 at-risk donors, 3 (1:6,025, 0.017%) donors showed seroreactivity by enzyme-linked immunosorbent assay and chemiluminescent immunoassay. All antibody positive donors were born in Latin America. One of them also was positive for T. cruzi DNA. Eleven previous donations from this donor were subjected to look-back investigation, and five recipients were tested. All five recipients tested negative for T. cruzi antibodies. CONCLUSION: Seroprevalence of T. cruzi was 0.017% among at-risk donors in Japan. Transfusion-transmitted infection of Chagas disease has not been confirmed to date. Screening for T. cruzi antibodies by targeting at-risk donors is an appropriate strategy for ensuring blood safety in Japan. PMID- 30474862 TI - Mass Spectrometry: A Platform for Biomarker Discovery and Validation for Alzheimer's and Parkinson's Diseases. AB - Accurate, reliable, and objective biomarkers for Alzheimer's disease (AD), Parkinson's disease (PD), and related age-associated neurodegenerative disorders are urgently needed to assist in both diagnosis, particularly at early stages, and monitoring of disease progression. Technological advancements in protein detection platforms over the last few decades have resulted in a plethora of reported molecular biomarker candidates for both AD and PD; however, very few of these candidates are developed beyond the discovery phase of the biomarker discovery pipeline, a reflection of the current bottleneck within the field. In this review, the expanded use of selected reaction monitoring (SRM) targeted mass spectrometry will be discussed in detail as a platform for systematic verification of large panels of protein biomarker candidates prior to costly validation testing. We also advocate for the coupling of discovery-based proteomics with modern targeted-MS based approaches (e.g. SRM) within a single study in future workflows to expedite biomarker development and validation for AD and PD. It is our hope that improving the efficiency within the biomarker development process by use of an SRM pipeline may ultimately hasten the development of biomarkers that both decrease misdiagnosis of AD and PD and ultimately lead to detection at early stages of disease and objective assessment of disease progression. This article is protected by copyright. All rights reserved. PMID- 30474863 TI - Hydrogen peroxide facilitates Arabidopsis seedling establishment by interacting with light signaling pathway in the dark. AB - Light is essential for the plant establishment. Arabidopsis seedlings germinated in the dark cannot grow leaf and only have closed cotyledons. However, exogenous application of H2 O2 can induce leaves (establishment) in the dark. Comparative transcriptomic analysis revealed that light responsive genes were activated by H2 O2 treatment. These genes are functionally correlated with photosynthesis, photorespiration, and components of photosystem, such as antenna proteins and light-harvesting chlorophyll proteins. We further found that application of H2 O2 facilitates cell cycle by accelerating G2-M checkpoint transition in shoot apical meristem. Phytochrome mediated light signaling pathway was also involved in the H2 O2 -facilitated-establishment process. The Constitutive photomorphogenesis 1 (COP1) and phytochrome interacting factor 3 (PIF3) proteins were shown to be downregulated by H2 O2 treatment, and accordingly removed their inhibitory effects on photomorphogenesis in the dark. The crosstalk between oxidation and light signal pathways explains the mechanism that H2 O2 regulates plant dark establishment. The endogenous photorespiratory H2 O2 production was mimicked by overexpression of glycolate oxidase genes and supplement of substrate glycolate. As expected, seedling establishment was also induced by the endogenously produced H2 O2 under dark condition. These findings also suggest that photorespiratory H2 O2 production is at least partially involved in post germination establishment. PMID- 30474864 TI - Parliamentary identity and the management of the far-right: A discursive analysis of Dutch parliamentary debates. AB - In many Western democratic societies, the far-right has considerable popular support and is often perceived as the winner of political debates. This raises the important question of how other politicians try to manage the far-right. We use parliamentary debates to examine how politicians define the identity of Member of Parliament (MP) in response to Geert Wilders, leader of the far-right Party for Freedom in the Netherlands. The analysis shows that politicians made relevant the shared responsibility of MPs to solve societal problems, by using inclusive language, asking for concrete proposals, and emphasizing engagement in debate. These identity-related features question the parliamentary role performance of the far-right. In response, Wilders stressed the MP's responsibility of representing the ordinary people. The politicians used three strategies to challenge this defence: Questioning that the far-right actually fulfils their self-ascribed representative role; challenging the notion that only the far-right would represent the people; moving into a more populist position. Implications for social psychological research on marginal group members are discussed. PMID- 30474866 TI - Addendum To: The Profession of Couple, Marital, and Family Therapy (CMFT): Defining Ourselves and Moving Forward. PMID- 30474865 TI - Treatment of oral manifestations of toxic epidermal necrolysis with low-level laser therapy in a pediatric patient. AB - Drug-induced reactions are complications associated with high mortality and significant morbidity. Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are examples of these conditions, which are characterized by skin and mucous lesions. Here, we report a case of a 9-year-old girl who presented with blisters associated with an extensive vesicular rash and multiple ulcerations on the lips and oral cavity. A drug-induced hypersensitivity reaction to antibiotics was suspected, and a diagnosis of TEN was made. The patient was managed with withdrawal of the suspected causative agent, and the oral lesions were treated with low-level laser therapy (LLLT) and oral hygiene. This case highlights that TEN requires interdisciplinary intervention with dental assistance and follow-up to improve symptoms, nutrition, systemic condition, and quality of life. PMID- 30474867 TI - Gastrointestinal bleeding with severe mucosal involvement in a patient with generalized pustular psoriasis without IL36RN mutation. AB - Generalized pustular psoriasis (GPP) is a systemic inflammatory disease that presents with erythema and sterile pustules, pathologically characterized by Kogoj's spongiform pustules. GPP is sometimes accompanied by mucosal involvement, and the most common lesion is on the tongue. IL36RN mutation was found to contribute to the pathogenesis of GPP especially in patients who develop GPP without a past medical history of psoriasis vulgaris. The association of IL36RN mutation with mucosal involvement in GPP is controversial. We herein report a 60 year-old male GPP patient with no past history of plaque psoriasis presenting with not only severe skin lesions and arthritis but also severe mucosal involvements of pharyngeal and gastrointestinal lesions, which led to gastrointestinal bleeding. Our case did not have any mutation in the IL36RN gene. We should be aware that severe GPP can cause gastrointestinal bleeding. The relevancy of IL36RN mutation with mucosal involvement in GPP remains to be elucidated. PMID- 30474868 TI - Metabolic syndrome and psoriatic arthritis among patients with psoriasis vulgaris: Quality of life and prevalence. AB - Interest has increased in comorbidities associated with psoriasis and their effects on health-related quality of life (HRQoL). This study aimed to evaluate the prevalence of metabolic syndrome (MetS) and psoriatic arthritis (PsA) and to investigate HRQoL and the prevalence of hypertension, type 2 diabetes mellitus (T2DM), obesity and dyslipidemia. In a cross-sectional design, patients diagnosed with plaque psoriasis answered an interview and standardized questionnaires (Dermatology Life Quality Index questionnaire [DLQI], 36-Item Short Form Health Survey [SF-36] and EuroQol Five-Dimension Questionnaire Three-Level version [EQ 5D-3L]). Physical examination and several tests to assess desired outcomes were performed by a dermatologist and a rheumatologist during three visits. The prevalence of MetS and PsA was 50.0% and 41.8%, respectively. Dyslipidemia was the most prevalent (74.5%) secondary comorbidity, followed by hypertension (61.8%), obesity (52.5%) and T2DM (30.9%). The mean (standard deviation) DLQI score was 6.5 (6.9), and mean physical and mental SF-36 measures were 45.2 (10.4) and 45.5 (12.3), respectively, and for EQ-5D-3L, mean utility index and EQ-VAS scores were 0.68 (0.27) and 72.7 (19.7), respectively. PsA and MetS are important comorbidities; a reduced HRQoL is noted among plaque psoriasis patients with these comorbidities, emphasizing the relevance of diagnosis and treatment beyond the care of skin lesions. PMID- 30474869 TI - Electrokinetics over hydrophobic surfaces. AB - Segregation of phases in the vicinity of hydrophobic surfaces may turn out to be immensely consequential towards altering the coupling of electrostatics and hydrodynamics over interfacial scales. Here, we review the fundamental advances towards bringing out the various facets of electrokinetic transport over hydrophobic interfaces. We lay significant emphasis on the developments in understanding the slippery electrohydrodynamics over such interfaces, by appealing to the considerations across various spatio-temporal scales as unveiled by molecular dynamics as well as mesoscopic modelling paradigms (such as phase field and lattice Boltzmann). We envisage that despite significant advancements being achieved towards relating the macroscopic slip-length with the underlying molecular or mesoscopic phenomena, future efforts could be directed towards developing more robust statistically based models that may connect rarefied gas dynamics in the segregated phase with bulk electrokinetic transport and possible giant augmentations in the consequent fluid flow. PMID- 30474870 TI - LncRNA C2dat1 enhances vascular smooth muscle cell proliferation and migration by targeting MiR-34a-5p. AB - Deregulated proliferation of vascular smooth muscle cells (VSMCs) is one common phenomenon of atherosclerosis progression. Long noncoding RNAs (lncRNAs) are one group of noncoding RNAs that play essential roles in many cell biological processes, including cell development, growth, and migration. However, the role of a novel CAMK2D-associated lncRNA, CAMK2D-associated transcript 1 (C2dat1), in VSMCs is still uncovered. In this study, we showed that the expression level of C2dat1 was higher in coronary artery disease (CAD) tissues than in normal arterial tissues and the C2dat1 expression level was upregulated in the proliferating VSMC after being treated with PDGF-bb or TNF-alpha. In addition, we indicated that overexpression of C2dat1 promoted VSMC growth and enhanced PCNA expression in VSMC. Moreover, ectopic expression of C2dat1 increased VSMC migration. Furthermore, we showed that elevated expression of C2dat1 suppressed miR-34a expression and promoted sirtuin 1 (SIRT1) expression, which was a direct target gene of miR-34a. We demonstrated that the expression level of miR-34a was lower in CAD tissues than in normal arterial tissues and the expression of miR 34a was negatively correlated with C2dat1 expression. Restored expression of C2dat1 increased VSMC proliferation and migration through promoting SIRT1 expression. These data suggested that lncRNA C2dat1 might be a potential therapeutic target to promote VSMC growth and migration in CAD. PMID- 30474872 TI - Microplate Assay for Denatured Collagen using Collagen Hybridizing Peptides. AB - The purpose of this study was to develop a microplate assay for quantifying denatured collagen by measuring the fluorescence of carboxyfluorescein bound collagen hybridizing peptides (F-CHP). We have shown that F-CHP binds selectively with denatured collagen, and that mechanical overload of tendon fascicles causes collagen denaturation. Proteinase K was used to homogenize tissue samples after F CHP staining, allowing fluorescence measurement using a microplate reader. We compared our new assay to our previous image analysis method and the trypsin hydroxyproline assay, which is the only other available method to directly quantify denatured collagen. Relative quantification of denatured collagen was performed in rat tail tendon fascicles subjected to incremental tensile overload, and normal and ostoeoarthritic guinea pig cartilage. In addition, the absolute amount of denatured collagen was determined in rat tail tendon by correlating F CHP fluorescence with percent denatured collagen as determined by the trypsin hydroxyproline assay. Rat tail tendon fascicles stretched to low strains (<7.5%) exhibited minimal denature collagen, but values rapidly increased at medium strains (7.5-10.5%) and plateaued at high strains (>=12%). Osteoarthritic cartilage had higher F-CHP fluorescence than healthy cartilage. Both of these outcomes are consistent with previous studies. With the calibration curve, the microplate assay was able to absolutely quantify denatured collagen in mechanically damaged rat tail tendon fascicles as reliably as the trypsin hydroxyproline assay. Further, we achieved these results more efficiently than current methods in a rapid, high-throughput manner, with multiple types of collagenous tissue while maintaining accuracy. PMID- 30474871 TI - Manipulation of molecular pathways and senescence hallmarks by natural compounds in fibroblast cells. AB - Aging contributes to an increased risk of developing a number of neurodegenerative and chronic disorders, predominantly related to oxidative stress (OS) and defects in the antioxidant balance. This study focused on the antisenescence effect of four plant species (Falcaria vulgaris, Ixiolirion tataricum, Ajuga chamaecistus, and Scabiosa flavida) on H2 O2 -induced premature senescence in rat NIH3T3 fibroblasts, which were found to be rich in effective phytochemicals with traditional ethnobotanical backgrounds. Plant materials were collected, identified, and extracted. To determine the viability of NIH3T3 cells, an MTT assay was conducted. The levels of OS markers and the senescence associated beta-galactosidase (SA-beta-GAL) activity were analyzed by the Elisa reader. The cell cycle pattern was evaluated by flow cytometry. The expression of senescence-related inflammatory cytokines and the molecules involved in aging signaling pathways were investigated using the real-time reverse transcription polymerase chain reaction (RT-PCR). H2 O2 treatment decreased cell viability and increased lipid peroxidation (LPO) and the reactive oxygen species (ROS) in NIH3T3s. However, S. flavida exhibited low cytotoxicity, reduced OS and SA-beta GAL activities in NIH3T3 cells compared with the H2 O2 -treated group. I. tataricum was the second best plant, although it was more toxic to NIHT3T cells. S. flavida decreased G0/G1 arrest and facilitated the G2/M transition of NIH3T3s, also downregulated the expression of p38, p53, p16, and the related inflammatory mediators. S. flavida potentially modulated senescence-associated hallmarks in fibroblasts exposed to H2 O2 , thus it may inhibit the aging process via controlling the OS. Therefore it is a promising candidate for future antiaging explorations. PMID- 30474873 TI - Chinese herbal decoction of Wenshen Yangxue formula improved fertility and pregnancy rate in mice through PI3K/Akt signaling. AB - OBJECTIVE: Traditional Chinese medicine (TCM) is an effective management to infertility. The association between TCM-mediated fertility and inhibition of phosphatidylinositol-3-kinase (PI3K) would be investigated. METHODS: Institute of Cancer Research mice were treated with three herbal decoctions, named Wenshen Yangxue formula, Wenshen formula, and Yangxue formula, plus with human gonadotropins. PI3K inhibitor wortmannin was administrated to half of mice. Some index such as body weight, fertility ability would be investigated. The expression of P13K/Akt signaling was detected by using Western blot analysis. RESULTS: No difference was observed in body weight among groups. Mice receiving the administration of human gonadotropins and herbal decoctions showed increased follicle numbers, percentage of fertilization, and promoted embryonic development. The treatment of Wenshen Yangxue formula decoction showed the highest efficiency, significant higher than Wenshen and Yangxue formulas. And increased the expression of p-PI3K and p-Akt proteins. CONCLUSION: These results suggested the herbal decoctions promoted the fertilization of mice, which was related to the charge of PI3K/Akt activation. PMID- 30474874 TI - Virtual screening of National Cancer Institute database for claudin-4 inhibitors: Synthesis, biological evaluation, and molecular dynamics studies. AB - Claudin-4 (CLDN4) is a vital member of tight-junction proteins that is often overexpressed in cancer and other malignancies. The three-dimensional structure of human CLDN4 was constructed based on homology modeling approach. A total of 265 242 molecules from the National Cancer Institute (NCI) database has been utilized as a dataset for this study. In the present work, structure-based virtual screening is performed with the NCI database using Glide. By molecular docking, 10 candidate molecules with high scoring functions, which binds to the active site of CLDN4 were identified. Subsequently, molecular dynamics simulations of membrane protein were used for optimization of the top-three lead compounds (NCI110039, NCI344682, and NCI661251) with CLDN4 in a dynamic system. The lead molecule from NCI database NCI11039 (purpurogallin carboxylic acid) was synthesized and cytotoxic properties were evaluated with A549, MCF7 cell lines. Our docking and dynamics simulations predicted that ARG31, ASN142, ASP146, and ARG158 as critically important residues involved in the CLDN4 activity. Finally, three lead candidates from the NCI database were identified as potent CLDN4 inhibitors. Cytotoxicity assays had proved that purpurogallin carboxylic acid had an inhibitory effect towards breast (MCF7) and lung (A549) cancer cell lines. Computational insights and in vitro (cytotoxicity) studies reported in this study are expected to be helpful for the development of novel anticancer agents. PMID- 30474875 TI - Severe vemurafenib-induced photosensitivity in a 6-year-old boy. AB - Vemurafenib, a selective BRAF kinase inhibitor, has been found to induce several cutaneous adverse effects, ranging from a keratosis pilaris-like reaction to squamous cell carcinoma. While photosensitivity has been well described as one of these manifestations, we report a case of a 6-year-old boy on vemurafenib who developed a severe blistering sunburn after only two 30-minute episodes of sun exposure. A brief review of other common cutaneous adverse effects of vemurafenib is also provided. PMID- 30474877 TI - A Family Affair: Supporting Children with Chronic Illnesses. AB - BACKGROUND: Children living with chronic illnesses may rely on family for social support during hospitalization. Understanding child and parent perspectives about the nature of the sibling and family relationships during hospitalization will provide information about these relationships during a stressful period. METHODS: English speaking children diagnosed with chronic illnesses, siblings, and parents participated. They were residing at a Ronald McDonald House. A qualitative study using interviews with children and parents was completed. RESULTS: Seventeen mothers, eight children with illnesses, and twelve siblings completed interviews. Children with illnesses benefitted from connections with parents. Mothers believed that siblings and the ill child benefitted from being in close contact. Siblings were worried about their brother or sister with an illness, and despite this, the family was coping well. Siblings helped with the medical regimen for a brother or sister with a chronic illness. Trying to help the family function in a routine or "normal" fashion was important to children with illnesses and siblings. CONCLUSIONS: Family connection was critical for children with chronic illnesses during hospitalization. Findings highlighted the importance of sibling support, as a factor promoting child and family resilience when a child is facing medical procedures. PMID- 30474876 TI - The interaction between ANXA2 and lncRNA Fendrr promotes cell apoptosis in caerulein-induced acute pancreatitis. AB - BACKGROUND: Annexin A2 (ANXA2) plays a crucial role in acute pancreatitis (AP). However, its potential mechanism remains unclear. METHODS: In the present study, we used caerulein-treated AR42J rat pancreatic acinar cells as cell model of AP to investigate the potential functions of ANXA2 and its predicted long noncoding RNA (lncRNA) FOXF1 adjacent noncoding developmental regulatory RNA (lncRNA Fendrr). Cell apoptosis was evaluated by flow cytometry using annexinV fluorescein isothiocyanate/propidium iodide staining. The expressions of ANAX2 and lncRNA Fendrr were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Furthermore, Western blot analysis was performed to determine the protein levels of ANXA2, Bcl-2, and Bax. The association between lncRNA Fendrr and ANXA2 was disclosed by RNA pull-down, RNA immunoprecipitation, and electrophoretic mobility shift assays. RESULTS: ANXA2 was elevated in caerulein induced AP model and promoted apoptosis of AR42J cells. LncRNA Fendrr was also upregulated in AP cell model and directly bound ANXA2 protein. Further studies indicated that the interaction between ANXA2 and lncRNA Fendrr contributed to the apoptosis of AR42J cells in AP cell model. CONCLUSION: Our study demonstrated that ANXA2 promoted AP progression via interacting with lncRNA Fendrr in vitro, which will provide a novel insight into the therapeutic target for AP. PMID- 30474878 TI - Dramatic effect of nivolumab against melanoma and immune-related liver toxicity: A detailed histopathological and immunohistochemical analysis of nivolumab induced liver toxicity. PMID- 30474879 TI - Long noncoding RNA POU3F3 promotes cancer cell proliferation in prostate carcinoma by upregulating rho-associated protein kinase 1. AB - Long noncoding RNAs (lncRNAs) POU3F3 is overexpressed in esophageal squamous-cell carcinomas, while its role in other human cancers is unclear. In this study we found that POU3F3 and rho-associated protein kinase 1 (ROCK1) were both increased in tumor tissues than in adjacent healthy tissues of patients with prostate carcinoma. Expression levels of POU3F3 increased with increase in the diameter of tumor but were not significantly affected by lymph node metastasis or distant metastasis. Expression levels of POU3F3 and ROCK1 were positive correlated in tumor tissues but not in adjacent healthy tissues. POU3F3 and ROCK1 overexpression promoted, while ROCK1 knockdown inhibited the proliferation of prostate carcinoma cells. ROCK1 knockdown reduced the enhancing effect of POU3F3 overexpression on cancer cell proliferation. POU3F3 overexpression led to ROCK1 overexpression in prostate carcinoma cells, while ROCK1 overexpression did not significantly affect POU3F3 expression. Therefore, lncRNA POU3F3 may promote cancer cell proliferation in prostate carcinoma by upregulating ROCK1. PMID- 30474880 TI - Identification of NPAC as a novel biomarker and regulator for hepatocellular carcinoma. AB - OBJECTIVE: Hepatocellular carcinoma (HCC) has a high morbidity and mortality around the world, yet the effective therapeutic option for HCC is still limited. NPAC, also known as glyoxylate reductase 1 homolog, is a new nuclear protein recently implicated in tumor biology. However, the role of NPAC in HCC remains unclear. The present study aimed to evaluate the clinical significance and potential role of NPAC in HCC. METHODS: The NPAC expression in HCC tissues and matched adjacent normal tissues was detected by real-time polymerase chain reaction, immunohistochemistry (IHC), and Western blot analysis. The clinical significance of the expression of NPAC in HCC was assessed by the Kaplan-Meier survival curve and the Cox regression model. In addition, we established a doxiline-induced overexpression of the NPAC system. The effects of NPAC on HCC cell proliferation, migration, and apoptosis were checked by CCK-8 proliferation assays, transwell, and flow cytometry, respectively. RESULTS: The NPAC expression was significantly downregulated in HCC tissues and HCC cell lines. NPAC reduction was significantly correlated with poorer survival among patients with HCC, and the multivariate analysis confirmed its independent prognostic value. Furthermore, overexpression of NPAC dramatically suppressed the proliferation of HCC cells and promoted HCC cells apoptosis. Besides, the levels of phosphorylation of janus kinase 2 (JAK2) and signal transduction and activator 3 (STAT3) were significantly reduced after overexpression of NPAC in HCC cell lines. CONCLUSIONS: These results suggest that NPAC may play an important role in the development and progression of HCC, and can act as a novel potential prognostic biomarker and therapeutic target for HCC. PMID- 30474881 TI - Disorders in NADPH generation via pentose phosphate pathway influence the reproductive potential of the Saccharomyces cerevisiae yeast due to changes in redox status. AB - Intermediary metabolites have a crucial impact on basic cell functions. There is a relationship between cellular metabolism and redox balance. To maintain redox homoeostasis, the cooperation of both glutathione and nicotine adenine dinucleotides is necessary. Availability of nicotinamide adenine dinucleotide phosphate (NADPH) as a major electron donor is critical for many intracellular redox reactions. The activity of glucose-6-phosphate dehydrogenase (Zwf1p) and 6 phosphogluconate dehydrogenase (Gnd1p and Gnd2p) is responsible for NADPH formation in a pentose phosphate (PP) pathway. In this study, we examine the impact of redox homoeostasis on cellular physiology and proliferation. We have noted that the Deltazwf1 mutant lacking the rate-limiting enzyme of the PP pathway shows changes in the cellular redox status caused by disorders in NADPH generation. This leads to a decrease in reproductive potential but without affecting the total lifespan of the cell. The results presented in this paper show that nicotine adenine dinucleotides play a central role in cellular physiology. PMID- 30474882 TI - Mechanical properties of a hierarchical electrospun scaffold for ovine anterior cruciate ligament replacement. AB - The anterior cruciate ligament (ACL) acts to stabilize the knee and prevent excessive motion of the tibia relative to the femur. Tears of the ACL are common and can result in pain and damage to surrounding tissues. Thus a torn ACL is often surgically replaced with an autograft or allograft material. Drawbacks to clinically available ACL grafts motivate the development of a tissue engineered ACL replacement. Our group has previously developed a polycaprolactone electrospun scaffold that mimics the hierarchical structure of the ACL. The goal of this study was to investigate the mechanical properties of the electrospun scaffold as an ACL replacement. Scaffold mechanical properties were assessed prior to implantation via stress relaxation and pull to failure testing. Following in vitro characterization, electrospun scaffolds and soft tissue grafts were implanted into ovine cadaver stifle joints as ACL replacements. Stifle joints with ACL replacements were tested via a simulated anterior drawer test as well as in situ stress relaxation and pull to failure tests and compared to stifle joints with the native ACL intact. Prior to implantation the scaffold matched the native ovine ACL well in the range of functional strains as evidenced by stress relaxation measures and the toe region stiffness. After implantation the scaffold was more similar to the native ACL than the soft tissue graft, particularly when it came to reducing joint laxity and matching stress relaxation measures. These results demonstrate that the electrospun scaffold has the potential to be a suitable material for ACL replacement. PMID- 30474883 TI - Predictors of fracture healing in patients with recalcitrant nonunions treated with autologous culture expanded bone marrow-derived mesenchymal stromal cells. AB - The study reports the prospective outcome of treating severe recalcitrant fracture nonunion in patients with autologous bone marrow-derived mesenchymal stromal cells (BMSC) from 2003-2010 and analyse predictors of union. Autologous BMSC were culture expanded and inserted at nonunion site with or without carriers in addition to surgical stabilisation of the fracture. Radiological union was ascertained by musculoskeletal radiologists on plain radiographs and/or CT scans. A logistic regression analysis was performed with cell-expansion parameters (cell numbers, cell doubling time) and known clinical factors (e.g. smoking and diabetes) as independent variables and fracture union as the dependent variable to identify the factors that influence bony healing. An Eq5D index score assessed the effect of treatment on general quality of health. A total of 35 patients (mean age 51 +/ - 13 years) with established nonunion (median 2.9 years,1-33) and, at least one failed nonunion surgery (median 4,1-14) received treatment. Fracture union was achieved in 21 patients (60%; 95% CI 44-75) at 2.6 years. Multiple penalized logistic regression revealed faster cell doubling time (p = 0.07), absence of diabetes (p = 0.003), less previous surgeries (p = 0.008) and lower age at cell implantation (p = 0.02) were significant predictors for fracture union. A significant increase in Eq5D index (p = 0.01) was noted with a mean rise of the score by 0.34 units (95% CI 0.11 to 0.58) at one year following the study. In summary, the study revealed cell doubling time as a novel in vitro parameter in conjunction with age, multiple surgeries and diabetes as being significant predictors of the fracture union. PMID- 30474885 TI - Psychological Inflexibility Predicts Suicidality Over Time in College Students. AB - OBJECTIVE: It is essential to identify modifiable risk factors that can be targeted to reduce suicidal ideation (SI) and behavior in college students. Psychological inflexibility, a pattern of responding to internal experiences in a literal and rigid way, and attempting to control those experiences even when it interferes with valued living, could theoretically lead to SI or increase its intensity. METHOD: Psychological inflexibility and its component processes were tested as a predictor of SI in a longitudinal survey of college students (n = 603, age M = 20.62, 68.9% female, and 94.0% White) in a series of cross-sectional and longitudinal hierarchical regression models, controlling for relevant predictors such as distress and baseline SI. Interactions were also tested between psychological inflexibility and distress, cognitive defusion, values obstruction, and values progress in predicting SI. RESULTS: Psychological inflexibility predicted SI cross-sectionally and longitudinally, controlling for distress and baseline SI. Psychological inflexibility interacted with distress, cognitive fusion, and values progress such that distress, cognitive fusion, and values progress had the strongest association with suicidal ideation among those who were high in psychological inflexibility. CONCLUSIONS: Psychological inflexibility may be a useful mechanism to target for suicide prevention in college students. PMID- 30474884 TI - Biomechanical Evaluation of Tendon Regeneration with Adipose-derived Stem Cell. AB - The use of Adipose-Derived Stem Cells (ADSC) has been presented as a new alternative for tendon reconstruction. Have been admitted that ADSCs are related to better outcomes when used in tendon healing. This research was designed to apply the potential of ADSCs in tendon healing. Flexor digitorum superficialis tendon lesion was performed on both legs of eleven New Zealand rabbits and them, at the same time, treated as follows: suture alone (Group III - Suture, n:10), suture associated with ADSC (Group IV - Suture + ADSC, n:10) or without suture (Group II - SHAN, n:2). At four weeks after the tendon surgery, the animal was euthanized, and the tendon evaluated (biomechanically and macroscopically). We used 5 additional New Zealand rabbits in the control group "Group I - Control, n:10". In the macroscopic evaluation, the group with ADSC presented a more homogeneous gross morphology compared with the group III. Biomechanical testing showed a lower ultimate tensile load, stiffness and a higher cross-sectional area in the group III and IV compared with the control group. The group with ADSC showed a greater ultimate tensile load, a larger cross-sectional area and bigger deformation at the ultimate tensile load when compared to the group without ADSC. " In general terms, the use of ADSCs in tendon healing have biomechanical advantages compared to the non-use of ADSCs at 4 weeks after surgery. PMID- 30474887 TI - Kirpal Singh Chugh (1932-2017). PMID- 30474888 TI - In Vitro Study on the Dynamics of Blood Flow Impelled by an Alternating Current Magnetohydrodynamic Blood Pump. AB - Artificial hearts are effective devices to treat heart failure in clinical practice and can be divided into two categories: artificial hearts and ventricular assist devices. The goal of this work was to investigate the fluidity and biological changes of in vitro sheep blood using a novel alternating current (AC) magnetohydrodynamic blood pump (central magnetic intensity: 0.9 T, alternating current frequency of the electric motor: 0-80 Hz). Blood samples were collected from five sheep and were divided into two groups: the control group (no exposure to an external magnetic field) and the exposed group (3 h of exposure to an alternating magnetic field). The blood cell counts, changes in blood viscosity, and ultrastructural changes of the blood cells under transmission electron microscopy were investigated. This study demonstrated several findings: (i) Continuous sheep blood flow can be achieved; (ii) The blood cell counts remained unchanged after 3 h of exposure to an alternating magnetic field; (iii) Compared with the control group, the high- and low-shear viscosities of the whole blood from the sheep significantly decreased after 3 h of exposure to an alternating magnetic field (P < 0.05 and P < 0.01, respectively). Plasma viscosity was significantly reduced after exposure to high-intensity alternating magnetic fields (P < 0.001); (iv) The cytoplasm of blood cells (especially erythrocytes) became lighter in color in the exposure group compared to the control group, and "beads-on-string" aggregations of black particles appeared. This work provides detailed and reliable scientific research data for the development of this type of blood pump, which may serve as a transition to the clinical artificial heart. PMID- 30474889 TI - Book Presentation Biomedical Membranes and (Bio) Artificial Organs. PMID- 30474890 TI - Unravelling Synthesis and Chemistry of Stable, Acyclic and Double-Deficient 1,3 Butadienes: An endo-selective Diels-Alder Route to Hedgehog Pathway Inhibitors. AB - The first synthetic access to stable and acyclic 1,3-butadienes with two electron withdrawing carbonyl groups and their potential to deliver novel molecular scaffolds via intriguing endo-selective Diels-Alder cycloadditions is presented. The bicyclic scaffolds emanating from cycloaddition chemistry of electron deficient dienes afforded potent hedgehog signaling pathway inhibitors. PMID- 30474891 TI - Hydrostatic Pressure on Toroidal Interaction and Propeller Chirality of Hexaarylbenzenes. Explicit Solvent Effects on Differential Volumes in Methylcyclohexane and Hexane. AB - A unique and effective interaction between the peripheral aromatic blades makes hexaarylbenzenes (HABs) attractive in fundamental research as well as various applications such as molecular wires, sensors, and supramolecular assemblies. The chiroptical responses of HABs are susceptible to environmental factors such as solvent and temperature due to the dynamic conformational transitions between the conformers. In this study, pressure dependence on the propeller chiral HABs in two different solvents was studied in detail. The effective differential volumes for two different equilibria were determined by quantitative analyses of CD spectra, affording very large differential volumes from the propeller to toroidal conformer (DeltaVt-c) of +43 and +42 cm3 mol-1, for H2 and H6, respectively, in methylcyclohexane. The value of H6 was further enhanced to +72 cm3 mol-1 in hexane, the largest value for the typical unimolecular conformational change. Such a response of propeller chirality in HABs is expedient in designing more advanced piezo-sensitive materials. PMID- 30474893 TI - Efficacy of Chinese herb Cistanche Yishen granules in treatment of tinnitus for patients with chronic nephritis. AB - OBJECTIVE: This study aimed to investigate the efficacy of Chinese herb Cistanche Yishen granules (CYG) in the treatment of tinnitus for patients with chronic nephritis. METHODS: A total of 89 adult patients were diagnosed with chronic glomerulonephritis from January 2016 to December 2017. All the patients were randomly divided into two groups, such as the control group and the CYG group. The efficacy of tinnitus was determined using tinnitus handicap inventory (THI), Pittsburgh sleep quality index (PSQI), pure tone audiometry (PTA), speech reception threshold (SRT), and visual analog scale (VAS) for tinnitus loudness and annoyance. RESULTS: In both these two groups of patients, values of THI, PSQI, PTA, SRT, and VAS for tinnitus loudness and annoyance were significantly decreased after the treatment compared with those before treatment. However, all values in CYG group after the treatment were significantly lower than those in the control group. CONCLUSION: CYG could apparently release the tinnitus symptoms in the patients with chronic nephritis. This study might give more clinical evidence for Cistanche in the treatment of tinnitus and give a new treatment method for the patients with tinnitus. PMID- 30474892 TI - Exploring the relationship between polygenic risk for cannabis use, peer cannabis use, and the longitudinal course of cannabis involvement. AB - BACKGROUND AND AIMS: Few studies have explored how polygenic propensity to cannabis use unfolds across development, and no studies have yet examined this question in the context of environmental contributions such as peer cannabis use. Outlining the factors that contribute to progression from cannabis initiation to problem use over time may ultimately provide insights into mechanisms for targeted interventions. We sought to examine the relationships between polygenic liability for cannabis use, cannabis use trajectories across ages 12-30, and perceived peer cannabis use at ages 12-17. DESIGN: Mixed effect logistic and linear regressions were used to examine associations between polygenic risk scores, cannabis use trajectory membership, and perceived peer cannabis use. SETTING: USA PARTICIPANTS: From the Collaborative Study on the Genetics of Alcoholism (COGA) study, a cohort of 1,167 individuals aged 12-26 years at their baseline (i.e., first) interview. MEASUREMENTS: Key measurements included lifetime cannabis use (yes/no), frequency of past 12-month cannabis use, maximum lifetime frequency of cannabis use, cannabis use disorder (using DSM-5 criteria), and perceived peer cannabis use. Polygenic risk scores (PRS) were created using summary statistics from a large (N = 162,082) genome-wide association study (GWAS) of cannabis use. FINDINGS: Three trajectories reflecting no/low (n=844), moderate (n=137) and high (n=186) use were identified. PRS were significantly associated with trajectory membership (p=0.002-0.006, maximum conditional R2 = 0.014, ORs = 1.40-1.49). Individuals who reported that most/all of their best friends used cannabis had significantly higher PRS than those who reported that none of their friends were users (OR = 1.35, 95% C.I. = [1.04, 1.75], p = 0.023). Perceived peer use itself explained up to 11.3% of the variance in trajectory class membership (OR: 1.50-4.65). When peer cannabis use and the cannabis use PRS were entered into the model simultaneously, both the PRS and peer use continued to be significantly associated with class membership (p < 0.01). CONCLUSIONS: Genetic propensity to cannabis use derived from heterogeneous samples appears to correlate with longitudinal increases in cannabis use frequency in young adults. PMID- 30474895 TI - Food insecurity and food preparation equipment in US households: exploratory results from a cross-sectional questionnaire. AB - BACKGROUND: Food insecurity (FI) impacted 15.7% (5.9 million) of US households with children in 2017. These households often experience issues within one or more of the food security pillars: access, availability, utilisation or stability. An underexplored area within the pillar of utilisation that may impact FI risk is the availability of kitchen equipment in households. This exploratory project aimed to quantify household food preparation equipment ownership and use by household FI status. METHODS: An online platform (Qualtrics, Provo, UT, USA) was used to administer a questionnaire to a sample of 135 parents of children aged 11-14 years. The instrument queried sociodemographic characteristics, food preparation items owned and frequency of use of 44 items within a 6-month interval. Household FI was measured using the 18-item US Department of Agriculture, Household Food Security Survey Module with a 12-month reference period. RESULTS: Households experiencing FI (n = 39; 28.9%) owned an average of five fewer items than their food secure counterparts (n = 96, 71.1%, P < 0.001), reporting lower item ownership within each equipment category subgroup (i.e. large appliances, small appliances, food preparation utensils and cooking utensils; all P < 0.01). There were no differences between FI and food secure households in frequency of use (all P > 0.01). CONCLUSIONS: Compared to food secure households, the number of food preparation items owned was lower, although frequency of use was the same, in US households that were FI. Future projects should investigate how food equipment ownership impacts cooking behaviours, and whether households experiencing FI display behaviours to compensate for a differing set of equipment. PMID- 30474894 TI - Luteolin-mediated Kim-1/NF-kB/Nrf2 signaling pathways protects sodium fluoride induced hypertension and cardiovascular complications. AB - The use of sodium fluoride (NaF) as a major ingredient for tooth paste, mouth wash, and mouth rinse has become inevitable in our day-to-day life. However, flavonoids such as Luteolin might be of great value in the prevention of toxicity associated with accidental or inevitable ingestion of NaF. In the study, 40 male Wistar albino rats were randomly divided into four groups with 10 rats in a group. Group A was the control group and received normal saline, Group B was exposed to NaF at 300 ppm (300 mg/L) in drinking water daily for a week, Groups C and D were exposed to 300 ppm (300 mg/L) of NaF and coadministered with Luteolin orally daily at a dosage of 100 mg/kg and 200 mg/kg for the same time point. Our results indicated that NaF caused significant increases in systolic blood pressure, diastolic blood pressure, mean arterial pressure, malondialdehyde, protein carbonyl, myeloperoxidase, advanced oxidative protein products, together with significant reductions in glutathione peroxidase, superoxide dismutase, catalase, glutathione reductase, reduced glutathione, and nitric oxide (NO) bioavailability. The electrocardiogram results showed that NaF alone caused significant prolongation of QT and QTc intervals. Immunohistochemistry revealed that NaF caused increase expressions of Kidney injury marker 1 (Kim-1), nuclear factor kappa bet (NF-kappaB), nuclear factor erythroid 2-related factors 2 (Nrf2), and cardiac troponin I (CTnI). Together, Luteolin coadministration with NaF improved NO bioavailability, reduced high blood pressure, markers of oxidative stress, reversed prolongation of QT and QTc intervals, and lowered the expressions of Kim-1, NF-kappaB, and CTnI. (c) 2018 BioFactors, 2018. PMID- 30474896 TI - Exercise training in patients with ventricular assist devices: a review of the evidence and practical advice. A position paper from the Committee on Exercise Physiology and Training and the Committee of Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology. AB - Exercise training (ET) and secondary prevention measures in cardiovascular disease aim to stimulate early physical activity and to facilitate recovery and improve health behaviours. ET has also been proposed for heart failure patients with a ventricular assist device (VAD), to help recovery in the patient's functional capacity. However, the existing evidence in support of ET in these patients remains limited. After a review of current knowledge on the causes of the persistence of limitation in exercise capacity in VAD recipients, and concerning the benefit of ET in VAD patients, the Heart Failure Association of the European Society of Cardiology has developed the present document to provide practical advice on implementing ET. This includes appropriate screening to avoid complications and then starting with early mobilisation, ET prescription is individualised to meet the patient's needs. Finally, gaps in our knowledge are discussed. PMID- 30474897 TI - Oxidation-Responsive Materials: Biological Rationale, State of the Art, Multiple Responsiveness, and Open Issues. AB - In this review, a general introduction to biological oxidants (focusing on reactive oxygen species, ROS) and the biomedical rationale behind the development of materials capable of responding to ROS is provided. The state of the art for preparative aspects and mechanistic responses of the most commonly used macromolecular ROS-responsive systems, including polysulfides, polyselenides, polythioketals, polyoxalates, and also oligoproline- and catechol-based materials, is subsequently given. The endowment of multiple responsiveness, with specific emphasis on the cases where a molecular logic gate behavior can be obtained, is focused on. Finally, fundamental open issues, which include implications of the "drug"-like character of ROS-responsive materials (inherent anti-inflammatory behavior) and the poor quantitative understanding of ROS roles in biology, are discussed. PMID- 30474898 TI - The unusual fusion of alpha-fluorinated benzophenones under McMurry reaction conditions. AB - By exposing of alpha-fluorinated benzophenones to McMurry reaction conditions, we have observed remarkable formation of 9,10-diphenylanthracene's derivatives. This unexpected transformation necessitates the cleavage of the exceptionally stable aromatic C-F bond under mild McMurry conditions. In this work we have investigated the condensation of several related fluorinated benzo- and acetophenones, which allow us to propose the domino-like fusion mechanism for this unusual transformation. The scope and limitation of the fluorine-promoted benzophenone fusion is discussed. PMID- 30474899 TI - How to Install TEMPO in Dielectric Polymers-Their Rational Design toward Energy Storable Materials. AB - Polar groups and the charge-transport capability play significant roles in the dielectric properties of organic polymers, and thus influence the electric energy density upon application as a capacitor material. Here, the dielectric properties and electric conductivity of a series of polymers containing 2,2,6,6 tetramethylpiperidine-1-oxyl (TEMPO) radicals are investigated. The neat radical polymer poly(TEMPO methacrylate) (PTMA) has a high dielectric constant but poor breakdown strength. Poly(methyl methacrylate) (PMMA) is introduced as an insulating polymer with high resistivity on breakdown, along with molecular design of PTMA. Copolymers of TEMPO methacrylate and methyl methacrylate, P(TMA-r MMA), exhibit high breakdown strengths but low dielectric constants. PMMA blended with TEMPO exhibits the highest electric energy density of 7.4 J cm-3 (that of PTMA is 0.48 J cm-3 as a control), with both a high dielectric constant (~6.8) and a high breakdown strength (~500 MV m-1 ). It benefits from long-range but not bulk charge transport in the blends, which is different from the bulk charge transport in PTMA and the short-range charge transport in P(TMA-r-MMA). These results indicate that the TEMPO moiety located in the high breakdown matrix leads to a high energy-storage density in the capacitor. PMID- 30474900 TI - Brain size predicts behavioural plasticity in guppies (Poecilia reticulata): an experiment. AB - Understanding how animal personality (consistent between-individual behavioural differences) arises has become a central topic in behavioural sciences. This endeavour is complicated by the fact that not only the mean behaviour of individuals (behavioural type), but also the strength of their reaction to environmental change (behavioural plasticity) varies consistently. Personality and cognitive abilities are linked and we suggest that behavioural plasticity could also be explained by differences in brain size (a proxy for cognitive abilities), since accurate decisions are likely essential to make behavioural plasticity beneficial. We test this idea in guppies (Poecilia reticulata), artificially selected for large and small brain size, which show clear cognitive differences between selection lines. To test whether those lines differed in behavioural plasticity, we reared them in groups in structurally enriched environments, and then placed adults individually into empty tanks, where we presented them daily with visual predator cues and monitored their behaviour for 20 days with video-aided motion tracking. We found that individuals differed consistently in activity and risk-taking, as well as in behavioural plasticity. In activity, only the large-brained lines demonstrated habituation (increased activity) to the new environment, while in risk-taking, we found sensitization (decreased risk-taking) in both brain size lines. We conclude that brain size, potentially via increasing cognitive abilities, may increase behavioural plasticity, which in turn can improve habituation to novel environments. However, the effects seem to be behaviour-specific. Our results suggest that brain size likely explain some of the variation in behavioural plasticity found at the intra species level. This article is protected by copyright. All rights reserved. PMID- 30474901 TI - Predicting clinical course in major depressive disorder: The association between DM-TRD score and symptom severity over time in 1115 outpatients. AB - BACKGROUND: The Dutch Measure for Quantification of Treatment Resistance in Depression (DM-TRD) is a promising prediction tool for major depressive disorder (MDD) based on variables associated with treatment outcome. The objective of our study was to examine the association between the DM-TRD and clinical course in a large cohort of MDD outpatients receiving treatment as usual. Furthermore, we examined whether the addition of an item measuring the presence of childhood adversity improved this association. METHODS: We included 1115 subjects with MDD (according to the DSM-IV) who were naturalistically treated at seven outpatient departments of a secondary mental healthcare center in the Netherlands. Data on subjects who had a diagnostic work-up between June 2014 and June 2016 were analyzed. Multilevel analyses were performed to examine the association between the DM-TRD score at baseline and clinical course, defined by symptom severity according to scores on the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) over time. We also investigated whether an extra item measuring childhood adversity improved the model. RESULTS: The model including the DM-TRD and its interaction with time was superior to previous models. The addition of childhood adversity and its interaction with time did not improve the model. CONCLUSIONS: In depressed outpatients receiving treatment as usual, the solid longer-term association between higher DM-TRD scores and worse clinical course supports its usefulness in clinical practice. Childhood adversity did not improve the model value indicating that-counterintuitively-this parameter offers no additional predictive power to the variables included. PMID- 30474902 TI - Impact of big data on oral health outcomes. AB - Biomedical big data amasses from different sources such as electronic health records, health research, wearable devices and social media. Recent advances in data capturing, storage and analysis techniques have facilitated conversion of a wealth of knowledge in biomedical big data into evidence-based actionable plans to enhance population health and wellbeing. The delay in reaping the benefits of biomedical big data in dentistry is mainly due to the slow adoption of electronic health record systems, unstructured clinical records, tattered communication between data silos and perceiving oral health as a separate entity from general health. Recent recognition of the complex interplay between oral and general health has acknowledged the power of oral health big data to glean new insights on disease prevention and management. This review paper summarizes recent advances, limitations and challenges in biomedical big data in health care with emphasis on oral health and discusses the potential future applications of oral health big data to improve the quality and efficiency of personalized health care. This article is protected by copyright. All rights reserved. PMID- 30474903 TI - Track density imaging in progressive supranuclear palsy: A pilot study. AB - Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by white matter (WM) changes in different supra- and infratentorial brain structures. We used track density imaging (TDI) to characterize WM microstructural alterations in patients with PSP-Richardson's Syndrome (PSP-RS). Moreover, we investigated the diagnostic utility of TDI in distinguishing patients with PSP-RS from those with Parkinson's disease and healthy controls (HC). Twenty PSP-RS patients, 21 PD patients, and 23 HC underwent a 3 T MRI diffusion-weighted (DW) imaging. Then, we combined constrained spherical deconvolution and WM probabilistic tractography to reconstruct track density maps by calculating the number of WM streamlines traversing each voxel. Voxel-wise analysis was performed to assess group differences in track density maps. A support vector machine (SVM) approach was also used to evaluate the performance of TDI for discriminating between groups. Relative to PD patients, decreases in track density in PSP-RS patients were found in brainstem, cerebellum, thalamus, corpus callosum, and corticospinal tract. Similar findings were obtained between PSP-RS patients and HC. No differences in TDI were observed between PD and HC. SVM approach based on whole-brain analysis differentiated PD patients from PSP-RS with an area under the curve (AUC) of 0.82. The AUC reached a value of 0.98 considering only the voxels belonging to the superior cerebellar peduncle. This study shows that TDI may represent a useful approach for characterizing WM alterations in PSP-RS patients. Moreover, track density decrease in PSP could be considered a new feature for the differentiation of patients with PSP-RS from those with PD. PMID- 30474905 TI - Synthesis of gamma-Boryl-Substituted Homoallylic Alcohols with Anti Stereochemistry Based on a Double-Bond Transposition Protocol. AB - The stereoselective synthesis of anti-isomers of gamma-boryl-substituted homoallylic alcohols is disclosed. (E)-1,2-Di(boryl)alk-1-enes undergo Ru catalyzed double-bond transposition with control of the geometry. The in situ generated (E)-1,2-di(boryl)alk-2-enes add to aldehydes in a stereospecific manner. The alkenylboron group within the product is amenable to a variety of synthetic derivatizations. PMID- 30474904 TI - Effects of equibiaxial mechanical stretch on extracellular matrix-related gene expression in human calvarial osteoblasts. AB - Mechanical stretch commonly promotes craniofacial suture remodeling during interceptive orthodontics. The mechanical responses of osteoblasts in craniofacial sutures play a role in suture remodeling. Moreover, the extracellular matrix (ECM) produced by osteoblasts is crucial for the transduction of mechanical signals that promote cell differentiation. Therefore, we aimed to investigate the effect of mechanical stretch on cell viability and ECM-related gene-expression changes in human osteoblasts. Human calvarial osteoblasts (HCObs) were subjected to 2% deformation. Caspase activity, MTT, and cell viability assays were used to estimate osteoblast apoptosis, proliferation, and viability, respectively. Real-time RT-PCR (RT2 -PCR) arrays were used to assess expression of cytoskeletal-, apoptosis-, osteogenesis-, and ECM-related genes. We found that mechanical stretch significantly increased osteoblast viability and cell proliferation, and decreased the activities of caspases 3 and 7. Moreover, the expression of 18 genes related to osteoblast differentiation, apoptosis, and ECM remodeling changed by more than two-fold in a time-dependent manner. Therefore, mechanical stretch promotes HCOb viability and alters expression of genes that are closely related to suture remodeling under mechanical stretch. PMID- 30474906 TI - Hepatic and renal toxicity and associated factors among HIV-infected children on antiretroviral therapy: a prospective cohort study. AB - OBJECTIVES: The aim of the study was to investigate the prevalence of renal function and liver enzyme abnormalities among HIV-infected children, changes in prevalence with time on combination antiretroviral therapy (cART), and the factors associated with these abnormalities. METHODS: A prospective cohort study was conducted among HIV-infected children < 18 years old (n = 705) who were on first-line cART. Liver enzymes, renal function, haematology, immunology and virological response were assessed at enrolment and followed bi-annually for 18 months. Liver fibrosis and cirrhosis were assessed using noninvasive markers including the aspartate aminotransferase (AST) to platelet ratio index (APRI) and fibrosis score (FIB-4). RESULTS: The median age was 12 [interquartile range (IQR) 8-14] years; 53.3% of patients were male. At enrolment, the median cART duration was 3.3 (IQR 1.1-6.1) years; 177 (25.1%) and 83 (11.8%) patients had elevated AST and alanine aminotransferase (ALT), respectively. A tenth of the children had an APRI score > 0.5, suggesting liver fibrosis. Being on a zidovudine (ZDV)- or nevirapine (NVP)-based regimen and having a viral load > 1000 HIV-1 RNA copies/mL were significantly associated with elevated ALT. Twenty-four (3.4%) and 84 (12.1%) patients had elevated creatinine and blood urea nitrogen (BUN), respectively. As cART duration increased by 6 months, median BUN increased by 1.6 [95% confidence interval (CI) 0.4-2.7] mg/dL (P = 0.01); the glomerular filtration rate (GFR) decreased by 35.6 (95% CI 17.7-53.4) mL/min/1.73 m2 (P < 0.0001); and AST and ALT decreased by 1.4 (95% CI 0.4-2.5) IU/L (P = 0.01) and 1.4 (95% CI 0.2-2.6) IU/L (P = 0.01), respectively. CONCLUSIONS: A high prevalence of liver enzyme and renal function abnormalities was observed at enrolment. Decreasing liver enzyme levels during follow-up are possibly reassuring, while the progressive reduction in GFR and the increase in BUN are worrisome and require further study. PMID- 30474907 TI - A Halogen Substitution in Isoquinoline Scaffold Switches the Selectivity of Inhibition between USP2 and USP7. AB - Deubiquitinases are important components of the protein regulatory network and hence constitute a tempting drug target. We report herein the structure-activity relationship studies to develop halogen substituted isoquionoline-1,3-dione-based inhibitor of the deubiquitinase USP2. In contrast to our previous reports, the best compound discovered here acts through a reactive oxygen species-independent uncompetitive mechanism with an IC50 of 250 nM. We show a crucial role of the halogens in the common scaffold to provide potency and selectivity of our compound, where the introduction of the fluorine atom completely switches the selectivity of the inhibitor between USP2 and USP7. Our cellular studies highlight the potential applicability of the reported compound for the in vivo experiments. The discovery of isoquinoline-1,3-dione core and the obtained knowledge of halogen substitutions provide a platform towards understanding the USP2 inhibition and development of highly selective next-generation DUB inhibitors. PMID- 30474908 TI - Lost but not forgotten: A population-based study of mortality and care trajectories among people living with HIV who are lost to follow-up in Ontario, Canada. AB - OBJECTIVES: Selection as a consequence of volunteer participation in, and loss to follow-up from, cohort studies may bias estimates of mortality and other health outcomes. To quantify this potential, we estimated mortality and health service use among people living with HIV (PLWH) who were lost to cohort follow-up (LTCFU) from a volunteer clinical HIV-infected cohort, and compared these to mortality and health service use in active cohort participants and non-cohort-participants living with HIV in Ontario, Canada. METHODS: We analysed population-based provincial health databases from 1995 to 2014, identifying PLWH >= 18 years old; these included data from participants in the Ontario HIV Treatment Network Cohort Study (OCS), a volunteer, multi-site clinical HIV-infected cohort. We calculated all-cause mortality, hospitalization and emergency department (ED) visit rates per 100 person-years (PY) and estimated hazard ratios (HRs) of mortality, adjusting for age, sex, income, rurality, and immigration status. RESULTS: Among 23 043 PLWH, 5568 were OCS participants. Compared with nonparticipants, participants were younger and less likely to be female, to be an immigrant and to reside in a major urban centre, and had lower comorbidity. Mortality among active participants, participants LTCFU and nonparticipants was 2.52, 3.30 and 2.20 per 100 PY, respectively. After adjustment for covariates, mortality risk was elevated among participants LTCFU compared with active participants (HR 2.26; 95% confidence interval 1.91, 2.68). Age-adjusted hospitalization rates and ED visit rates were highest among participants LTCFU. CONCLUSIONS: Mortality risk and use of health care resources were lower among active cohort participants. Our findings may inform health outcome estimates based on volunteer cohorts, as well as quantitative bias adjustment to correct for such biases. PMID- 30474909 TI - Diagnosing hypertension in Indigenous Canadians (DREAM-GLOBAL): A randomized controlled trial to compare the effectiveness of short message service messaging for management of hypertension: Main results. AB - Hypertension, the leading cause of cardiovascular morbidity and mortality, affects more than 1 billion people globally. The rise in mobile health in particular the use of mobile phones and short message service (SMS) to support disease management provides an opportunity to improve hypertension awareness, treatment, and control, in remote and vulnerable patient populations. The primary objective of this randomized controlled study was to assess the effect of active (with hypertension specific management SMS) or passive (health behaviors SMS alone) on the difference in blood pressure (BP) reduction between the active and passive SMS groups in hypertensive Canadian First Nations people from six rural and remote communities. Pragmatic features of the study included shifting of BP measures to non-medical health workers. Despite an overall reduction in BP over the study, there was no difference in the BP change between groups from baseline to final for systolic 0.8 (95% CI -4.2 to 5.8 mm Hg) or diastolic -1.0 (95% CI 3.7 to 1.8 mm Hg, P = 0.5) BP. Achieved BP control was 37.5% (25.6%-49.4%, 95% CI) in the active group and 32.8% (20.6%-44.8%, 95% CI) in the passive group (difference in proportions -4.74% (-21.7% to 12.2%, 95% CI, P = 0.6). The study looked at changes in health services delivery, mobile health technologies, and patient engagement to support better management of hypertension in Canadian First Nations communities. The active hypertension specific SMS did not lead to improvements in BP control. PMID- 30474911 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 49/2018. PMID- 30474910 TI - Time since first cannabis use and 12-month prevalence of cannabis use disorder among youth and emerging adults in the United States. AB - AIM: This study estimated whether and how the 12-month prevalence of cannabis use disorder among U.S. youth aged 12-17 and emerging adults aged 18-25 varied by time since first cannabis use. DESIGN: Repeated cross-sectional survey data from the 2015-2017 National Surveys on Drug Use and Health (NSDUH). SETTING: United States. PARTICIPANTS: 101,000 NSDUH participants aged 12-25. MEASUREMENTS: Past 12-month cannabis use disorder was assessed using DSM-IV criteria. FINDINGS: Among youth, the lifetime prevalence of cannabis use was 15.3% (95% CI=14.86% 15.65%). Among emerging adults, the lifetime prevalence of cannabis use was 52.4% (95% CI=51.77%-53.01%). The adjusted 12-month prevalence of cannabis use disorder among youth with lifetime cannabis use was 10.9% (95% CI=9.24%-12.75%) in the first year after starting cannabis use, 15.3% (95% CI=13.68%-17.12%) in the second year, 17.7% (95% CI=15.55%-19.97%) in the third year, and 20.6% (95% CI=18.23%-23.17%) in the fourth year and beyond, which was consistently higher after the first year (linear trend only: p<0.0001). The adjusted 12-month prevalence of cannabis use disorder among emerging adults with lifetime use ranged from 5.6% (95% CI=4.26%-7.23%) in the first year after starting cannabis use, 7.7% (95% CI=6.45%-9.17%) in the second year, 9.1% (95% CI=7.81%-10.57%) in the third year, to 10.5% (95% CI=9.87%-11.12%) in the fourth year and beyond, which was consistently higher after the first year (linear trend only: p<0.0001). Within each timeframe since first cannabis use, the adjusted 12-month prevalence of cannabis use disorder was higher among youth lifetime users than their emerging adult counterparts. CONCLUSIONS: Among youth and emerging adults in the US, prevalence of cannabis use disorder appears to increase with time since initiation of use. This increase appears to be steeper for youth than emerging adults. PMID- 30474912 TI - A Comprehensive Multimodality Heart Motion Prediction Algorithm for Robotic Assisted Beating Heart Surgery. AB - BACKGROUND: An essential requirement for performing robotic assisted surgery on a freely beating heart is a prediction algorithm which can estimate the future heart trajectory. METHOD: Heart motion, respiratory volume (RV) and electrocardiogram (ECG) signal were measured from two dogs during thoracotomy surgery. A comprehensive multimodality prediction algorithm was developed, based on the multivariate autoregressive model, to incorporate the heart trajectory and cardiorespiratory data, with multiple inherent measurement rates, explicitly. RESULTS: Experimental results indicated strong relationships between the dominant frequencies of heart motion with RV and ECG. The prediction algorithm revealed a high steady state accuracy, with the RMS errors in the range of 82 to 162 MUm for a 300 sec interval, less than half of that of the best competitor. CONCLUSION: The proposed multimodality prediction algorithm is promising for practical use in robotic assisted beating heart surgery, considering its capability of providing highly accurate predictions in long horizons. PMID- 30474913 TI - Gene expression in the phenotypically plastic Arctic charr (Salvelinus alpinus): A focus on growth and ossification at early stages of development. AB - Gene expression during development shapes the phenotypes of individuals. Although embryonic gene expression can have lasting effects on developmental trajectories, few studies consider the role of maternal effects, such as egg size, on gene expression. Using qPCR, we characterize relative expression of 14 growth and/or skeletal promoting genes across embryonic development in Arctic charr (Salvelinus alpinus). We test to what extent their relative expression is correlated with egg size and size at early life-stages within the study population. We predict smaller individuals to have higher expression of growth and skeletal promoting genes, due to less maternal resources (i.e., yolk) and prioritization of energy toward ossification. We found expression levels to vary across developmental stages and only three genes (Mmp9, Star, and Sgk1) correlated with individual size at a given developmental stage. Contrary to our hypothesis, expression of Mmp9 and Star showed a non-linear relationship with size (at post fertilization and hatching, respectively), whilst Sgk1 was higher in larger embryos at hatching. Interestingly, these genes are also associated with craniofacial divergence of Arctic charr morphs. Our results indicate that early life-stage variation in gene expression, concomitant to maternal effects, can influence developmental plasticity and potentially the evolution of resource polymorphism in fishes. PMID- 30474915 TI - Pelagiphages in the Podoviridae family integrate into host genomes. AB - The Pelagibacterales order (SAR11) in the Alphaproteobacteria dominates marine surface bacterioplankton communities, where it plays a key role in carbon and nutrient cycling. SAR11 phages, known as pelagiphages, are among the most abundant phages in the ocean. Four pelagiphages that infect Pelagibacter HTCC1062 have been reported. Here we report 11 new pelagiphages in the Podoviridae family. Comparative genomics classified these pelagiphages into the HTVC019Pvirus genus, which includes the previously reported pelagiphages HTVC011P and HTVC019P. Phylogenomic analysis clustered HTVC019Pvirus pelagiphages into three subgroups. Integrases were identified in all but one HTVC019Pvirus genome. Site-specific integration of HTVC019Pvirus pelagiphages into host tRNA genes was verified experimentally, demonstrating the capacity of these pelagiphages to propagate by both lytic and lysogenic infection. Evidence of pelagiphage integration was also retrieved from the Global Ocean Survey database, showing that HTVC019Pvirus pelagiphage integrate natural SAR11 populations. HTVC019Pvirus pelagiphages could impact SAR11 populations by a variety of mechanisms, including mortality, genetic transduction, and prophage-induced viral immunity. HTVC019Pvirus pelagiphages are a rare example of cultured lysogenic phage that can be implicated in ecological processes on broad scales. These pelagiphages have the potential to become a useful model for investigating the strategies of host infection and phage dependent horizontal gene transfer. This article is protected by copyright. All rights reserved. PMID- 30474914 TI - Proteomic profiling of LPS-induced macrophage derived exosomes indicates their involvement in acute liver injury. AB - Exosomes are typically involved in cellular communication and signaling. Macrophages played key role in lipopolysaccharide (LPS) induced sepsis. However, the molecular comparison of exosomes derived from LPS induced macrophage has not been well analyzed. We validated the macrophage-exosomes and investigated the protein composition of those exosomes by iTRAQ mass spectrometry. 5056 proteins were identified in macrophage-exosomes. 341 increased proteins and 363 reduced proteins were discovered in LPS treated macrophages-exosomes compared with control-exosomes. In addition, gene ontology analysis demonstrated that macrophage-exosomes proteins were mostly linked to cell, organelle, extracellular region and membrane. The bioinformatics analysis also indicated that these proteins were mainly involved in cellular process, single-organism process, metabolic process, and biological regulation. Among these 341 up-regulated proteins, KEGG analysis revealed that 22 proteins were involved in the NOD-like receptor signaling pathway. Finally, hepatocytes could uptake macrophages exosomes and subsequently NLRP3 inflammasome was activated in vitro and in vivo. These data emphasize the fundamental importance of macrophages-exosomes in sepsis induced liver injury. Therefore, the iTRAQ proteomic strategy brought new insights into macrophages derived exosomes. It may improve our understanding of macrophages-exosomes' functions and their possible use as therapeutic targets for sepsis. This article is protected by copyright. All rights reserved. PMID- 30474916 TI - Cardiovascular disease and diabetes in HIV-positive and HIV-negative gay and bisexual men over the age of 55 years in Australia: insights from the Australian Positive & Peers Longevity Evaluation Study. AB - OBJECTIVES: As HIV-positive people age, diagnosis and management of comorbidities associated with ageing are of increasing concern. In this study, we aimed to compare the self-reported prevalences of heart disease, stroke, thrombosis and diabetes in older Australian HIV-positive and HIV-negative gay and bisexual men (GBM). METHODS: We analysed data from the Australian Positive & Peers Longevity Evaluation Study (APPLES), a study of a prospectively recruited cross-sectional sample of 228 (51.1%) HIV-positive and 218 (48.9%) HIV-negative GBM, aged >= 55 years. Regression methods were used to assess the association of HIV status with self-reported comorbidities. RESULTS: Of 446 patients, 389 [200 (51.4%) HIV positive] reported their disease history. The reported prevalence of comorbidities was higher in the HIV-positive group than in the HIV-negative group: heart disease, 19.5 versus 12.2%; stroke, 7.5 versus 4.2%; thrombosis, 10.5 versus 4.2%; and diabetes, 15.0 versus 9.0%, respectively. In adjusted analyses, HIV-positive GBM had significantly increased odds of reporting heart disease [adjusted odds ratio (aOR) 1.99; P = 0.03] and thrombosis (aOR 2.87; P = 0.01). In our analysis, HIV status was not significantly associated with either age at diagnosis of heart disease (median 53 years for HIV-positive GBM versus 55 years for HIV-negative GBM; P = 0.64) or 5-year cardiovascular disease (CVD) risk estimated using the Framingham risk score. CONCLUSIONS: HIV-positive GBM more commonly reported heart disease and thrombosis compared with their HIV-negative peers. These results further highlight the need to understand the impact of HIV on age-related comorbidities in GBM, to guide optimal screening and treatment strategies to reduce the risk of these comorbidities among the HIV-positive population. PMID- 30474917 TI - Nanostructured Metal Catalysts for Selective Hydrogenation and Oxidation of Cellulosic Biomass to Chemicals. AB - Conversion of biomass to chemicals provides essential products to human society from renewable resources. In this context, achieving atom-economical and energy efficient conversion with high selectivity towards target products remains a key challenge. Recent developments in nanostructured catalysts address this challenge reporting remarkable performances in shape and morphology dependent catalysis by metals on nano scale in energy and environmental applications. In this review, most recent advances in synthesis of heterogeneous nanomaterials, surface characterization and catalytic performances for hydrogenation and oxidation for biorenewables with plausible mechanism have been discussed. The perspectives obtained from this review paper will provide insights into rational design of active, selective and stable catalytic materials for sustainable production of value-added chemicals from biomass resources. PMID- 30474918 TI - Dynamic polyphosphate metabolism in cyanobacteria responding to phosphorus availability. AB - Despite the crucial role of polyphosphate (polyP) in aquatic environments, its metabolism in cyanobacteria responding to nutrients is poorly understood. We investigate polyP in three cyanobacteria species, specifically unicellular picocyanobacteria, under various nutritional conditions. Our experiments show that the accumulation of polyP in cyanobacteria is strongly dynamic, depending on phosphate levels and growth stages. "Overplus" uptake of phosphorus (P) during the lag phase leads to the rapid accumulation of polyP, followed by lower polyP quotas during the exponential growth stage as a result of competing "luxury" P uptake and polyP utilization to support rapid cell division. Cyanobacteria are capable of P deficiency responses that preferentially maintain polyP. However, preferential utilization of polyP occurs under severe P stress, suggesting the crucial role of polyP as P reserve to support cellular survival. Strong variability was observed among different species of cyanobacteria in their ability to accumulate polyP, and likely in the threshold P levels at which preferential polyP degradation occurs. This suggests that some cyanobacteria may be more adaptive to P-stressed or P-fluctuating conditions. Our results explain and provide important insights into the variability of polyP observed in aquatic environments where picocyanobacteria are the dominant primary producers. This article is protected by copyright. All rights reserved. PMID- 30474919 TI - Unveiling the Genetic Architecture of Human Disease for Precision Medicine. PMID- 30474920 TI - Next-generation experiments linking community structure and ecosystem functioning. PMID- 30474921 TI - Electrochemical Dimerization of Phenylpropenoids and the Surprising Antioxidant Activity of the Resultant Quinone Methide Dimers. AB - A simple method for the dimerization of phenylpropenoid derivatives is reported. It leverages electrochemical oxidation of p-unsaturated phenols to access the dimeric materials in a biomimetic fashion. The mild nature of the transformation provides excellent functional group tolerance, resulting in a unified approach for the synthesis of a range of natural products and related analogues with excellent regiocontrol. The operational simplicity of the method allows for greater efficiency in the synthesis of complex natural products. Interestingly, the quinone methide dimer intermediates are potent radical-trapping antioxidants; more so than the phenols from which they are derived-or transformed to-despite the fact that they do not possess a labile H-atom for transfer to the peroxyl radicals that propagate autoxidation. PMID- 30474922 TI - CD44v9 is associated with epithelial-mesenchymal transition and poor outcomes in esophageal squamous cell carcinoma. AB - CD44 serves as a marker of cancer stem cells. Alternative splicing generates the CD44v9 isoform. Cancer stem cells are associated with the epithelial-mesenchymal transition in cancers, although little is known about their role in esophageal squamous cell carcinoma. Here, we aimed to clarify the relationship between CD44v9 expression, the epithelial-mesenchymal transition, and clinicopathological features of patients with esophageal squamous cell carcinoma. CD44v9 levels were higher at the tumor invasive front compared with the center of the tumor and higher in metastatic lymph nodes compared with primary tumors. High levels of CD44v9 at the tumor invasive front were significantly associated with deeper tumor invasion and shorter overall survival and recurrence-free survival. The expression of CD44v9 was increased by treatment with transforming growth factor beta, which induced esophageal squamous cell carcinoma cells to undergo the epithelial-mesenchymal transition. Moreover, inhibition of CD44v9 expression decreased the migration and invasiveness of esophageal squamous cell carcinoma cells. These results indicate that the expression of CD44v9 at the tumor invasive front induced by stemness was strongly associated with the epithelial-mesenchymal transition and poor prognosis of patients with esophageal squamous cell carcinoma. CD44v9 may therefore serve as a novel prognostic biomarker and a potential therapeutic target for esophageal squamous cell carcinoma. PMID- 30474923 TI - The prevalence and factors associated with bone erosion in patients with gout. AB - OBJECTIVE: The aim of this study was to determine the prevalence, distribution and factors associated with bone erosion detectable by ultrasound in patients with gout. METHODS: Ultrasound scans were performed in 980 gout patients, and bone erosion was detected. The prevalence and distribution of bone erosion in gout patients were calculated. Both clinical variables and ultrasound signs were entered into a multivariate logistic regression analysis to clarify the factors associated with bone erosion in gout patients. RESULTS: Bone erosion was found in 431 (44.0%) of the 980 patients with gout, and in 338 (78.4%) it was found in the first metatarsophalangeal (MTP) joint. A multivariable logistic regression analysis showed that age, duration of gout, the existence of tophi, ultrasound detected synovial hypertrophy and joint effusion were independently associated with bone erosion. A tophus was the most powerful factor associated with bone erosion, with an odds ratio (OR) of 4.218 (95% confidence interval 3.092, 5.731). The risk for bone erosion also increased as the number of tophi increased (p < 0.001). However, after stratifying the size of tophi, the ORs did not increase significantly (p = 0.206). CONCLUSION: A high percentage of gout patients had bone erosions; the first MTP joint was the most frequently involved site. Age, duration of gout, tophi and synovial hypertrophy were factors associated with bone erosion in gout patients. The number of tophi, but not their size, was strongly associated with bone erosion in patients with gout. This article is protected by copyright. All rights reserved. PMID- 30474924 TI - Hip involvement in patients with calcium pyrophosphate deposition disease: potential and limits of musculoskeletal ultrasound. AB - OBJECTIVES: To preliminarily explore the diagnostic potential of ultrasound (US) in detecting calcium pyrophosphate crystal (CPP) deposits at the hip joint in a cohort of patients with calcium pyrophosphate deposition disease (CPPD) which were previously evaluated by conventional radiography (CR); to assess the sensitivity and specificity as well as the agreement between US and CR in the evaluation of hip CPP crystal deposits. DESIGN: Fifty consecutive patients with "definite" CPPD and 40 age/sex/body mass index-matched disease controls who had undergone hip CR within the previous six months were enrolled. Bilateral hip US examination was carried out by one of the authors (A.D.M) to assess the presence of CCP crystal deposits at the acetabular labrum fibrocartilage and at femoral head's hyaline cartilage. Two independent radiologists evaluated the presence of hip CPP crystal deposits on CR in both groups. RESULTS: US findings indicative of CPP crystal deposits were found in at least one hip in 45 out of 50 (90.0%) patients with CPPD, in 73 out of 100 (73.0%) hips. CPP crystal deposits were more frequently found at the acetabular labrum fibrocartilage than at femoral head's hyaline cartilage (72% and 17% of the hips in CPPD patients, respectively). US and CR sensitivity was 90% and 86% whereas US and CR specificity was 85% and 90%, respectively. Total agreement between the US and CR findings was 77.8%. CONCLUSIONS: Our results provide new evidence supporting US as a first-line, sensitive, safe and reliable imaging technique in detecting CPP crystal deposits at hip level. This article is protected by copyright. All rights reserved. PMID- 30474925 TI - QSP and empirical models; friends or foes? AB - Recently, it has been proposed that more complex models should routinely be compared to empirical or simpler models; often simple models can predict specific emergent properties of complex systems as well as more complex models, hence questioning the added value of the latter. This perspective discusses this important point in the context of the purpose of modelling. This article is protected by copyright. All rights reserved. PMID- 30474926 TI - Pretreatment values of bilirubin and albumin are not prognostic predictors in patients with advanced pancreatic cancer. AB - PURPOSE: To identify the pretreatment values of bilirubin and albumin and other serum biomarkers in predicting the prognosis for advanced pancreatic cancer. METHODS: A total of 201 consecutive patients pathologically diagnosed as advanced pancreatic cancer were retrospectively reviewed. Tumor location, TNM classification, the level of baseline total bilirubin (TBIT), direct bilirubin (DBIT), albumin (ALB), globulin (GLOB), total protein (TP), ALB to GLOB ratio (AGR), CA19-9, CA242, and CA50 were collected. The values of CA19-9, CA242, and CA50 were divided into two groups according to the upper limit value which were 1000 U/mL, 150 IU/mL, and 500 IU/mL, respectively. The values of TBIL, DBIL, IBIL, ALB, GLOB, TP, ALB, and GLOB were divided into low and high groups according to the median. To investigate if the median was an effective discriminator in dividing these markers, the patients were divided into a test set (n = 100) and a validation set (n = 101). Kaplan-Meier (K-M) survival analysis and Cox regression analysis were performed to explore the potential relationship between them and overall survival (OS). RESULTS: A K-M survival analysis revealed that the investigated markers in test set, including TBIL, DBIL, IBIL, ALB, GLOB, TP, ALB, and GLOB, were not associated with the OS. The findings from the validation set were consistent with those in the test set. Factors with P value smaller than 0.1 in the univariate analysis along with the tumor location, CA19-9, CA242, CA50, were entered into the multivariate analysis. A Cox regression analysis suggested that the cancerization at head of pancreas (P = 0.01) and a high level of CA19-9 (P = 0.02) were independent prognostic indicators for poor OS of pancreatic cancer. CONCLUSIONS: Baseline bilirubin and serum proteins were not associated with the prognosis of advanced pancreatic cancer. Tumor location and level of CA19-9 may serve as significant indicators for poor prognosis in those patients. PMID- 30474927 TI - Designing interventions for blood pressure control in challenging settings: Active not passive intervention is needed. PMID- 30474928 TI - Ten years of interventional research in systemic sclerosis: a systematic mapping of trial registries. AB - OBJECTIVE: To provide a comprehensive overview of interventional clinical trials registered in international databases planned and conducted within the last 10 years in patients with systemic sclerosis (SSc). METHODS: We searched the International Clinical Trials Registry Platform (ICTRP) all records on interventional clinical trials targeting patients with SSc performed since September 2007. Two reviewers selected studies according to the pre-specified eligibility criteria. Information on start date, country of origin, funding sources, phase of development, study design, (planned) sample size, enrollment status, outcomes, disease complication and treatments investigated, were retrieved and summarized. RESULTS: Among the 198 eligible studies identified (122 [62%)] randomized controlled trials, RCTs), 87 (30%) were conducted in Europe, 165 (83%) in a single country, and 81 (41%) were industry-funded. The majority of trials investigated pharmacologic treatments (75%), mostly non-biotherapies (57%). RCTs were mostly 2-arms (82%) placebo-controlled (71%) studies with a median number of patients enrolled or planned to be enrolled of 40 (IQR 24,75-77, range 10-586). Twenty-one RCTs (17%) planned to enroll or enrolled more than 100 patients. Time to assess primary outcome was found to be adequate in 29 to 50% of RCTs retrieved. Patients older than 65 years were excluded in 14% of studies. SSc complications more frequently investigated in overall studies were skin thickness (26%), Raynaud's phenomenon/digital ulcers (24%), and interstitial lung disease (14%). CONCLUSIONS: The SSc research landscape is dominated by small, short and mainly placebo-controlled trials, investigating especially pharmacologic treatments. Some patient's needs remain still neglected. This article is protected by copyright. All rights reserved. PMID- 30474929 TI - Physical Fitness in Patients with Oligo- and Polyarticular Juvenile Idiopathic Arthritis Diagnosed in the Era of Biologics - A Controlled Cross-Sectional Study. AB - OBJECTIVE: To perform a comprehensive evaluation of and identify correlates for physical fitness in consecutive patients with juvenile idiopathic arthritis (JIA) diagnosed in the era of biologics; also to compare the results with those obtained in healthy controls. METHODS: The study cohort included 60 JIA patients (50 girls) aged 10-16 years and 60 age- and sex-matched controls. The JIA group included 30 patients with persistent oligo JIA and 30 patients with extended oligo- or poly-articular disease. Measures of physical fitness included (i) cardiorespiratory fitness (CRF) by peak oxygen uptake (VO2peak ) during a continuous graded treadmill exercise test, (ii) muscle strength by isokinetic and isometric knee and hand grip evaluations, (iii) bone mineral density (BMD) and body composition by Dual Energy X-ray Absorptiometry. Physical activity was assessed by accelerometry. RESULTS: Forty-two % of the patients were on biological drugs. JIA patients demonstrated lower muscle strength and total body BMD compared to controls, but there were no differences in CRF and body composition. Physical fitness was comparable between the persistent oligo- and extended oligo/poly-JIA groups. In JIA patients, we identified associations between higher vigorous physical activity and higher CRF and muscle strength, but did not find any association between physical fitness and disease variables. CONCLUSION: In this JIA cohort, we found suboptimal muscle strength and BMD compared to controls, but no differences in CRF and body composition. Vigorous physical activities appeared important for optimizing muscle strength and CRF in JIA; the importance of such activities should be highlighted in patient education. This article is protected by copyright. All rights reserved. PMID- 30474930 TI - Comprehensive longitudinal surveillance of the IgG autoantibody repertoire in established systemic lupus erythematosus. AB - OBJECTIVE: to appraise the role of epitope spreading in established human systemic lupus erythematosus (SLE). METHODS: IgG-autoantibody reactivity to 398 distinct recombinant proteins was measured in 69 SLE patients over 6 years and compared to 45 controls. Changes in mean fluorescence intensity (MFI), number of autoantibodies to distinct antigens, and reactivity to distinct clones of selected established antigenic targets U1-RNP, Sm, and ribosomal P representing epitope fine mapping were assessed. Linear mixed modelling adjusted for age and sex with Bonferroni correction was applied. RESULTS: The total number of autoantibodies, mean MFI, and number of autoantibodies in epitope fine mapping were higher in SLE compared to controls (p<0.0001). The total number of antibodies to distinct autoantigens remained stable, while the mean MFI decreased over time in SLE (p<0.021). SLE patients showed variable recognition of epitopes in fine mapping over time. In particular, SLE patients recognized more clones of the U1-RNP complex at the time of new organ involvement (+0.65, p =0.007). Patients with lupus nephritis had a higher mean MFI (p=0.047). Time-averaged MFI of 22 individual autoantibodies were higher in SLE after Bonferroni correction including dsDNA (p<0.0001). DsDNA and histone cluster 2 H3c MFIs were associated to the SLAM (p<0.0001). CONCLUSION: Longitudinal surveillance of the IgG autoantibody repertoire in established SLE reveals evidence for sustained breadth of autoantibody repertoire without significant expansion. Associations of disease activity are confirmed for dsDNA and histone H3 autoantibodies. This article is protected by copyright. All rights reserved. PMID- 30474931 TI - A novel lncRNA-miRNA-mRNA network analysis identified the hub lncRNA RP11 159F24.1 in the pathogenesis of papillary thyroid cancer. AB - Papillary thyroid cancer (PTC) is one of the most common cancers worldwide, and its carcinogenesis is influenced by a complex network of gene interactions. In this study, the microarray expression profile was re-annotated into a lncRNA-mRNA biphasic profile. LncRNA-mRNA interactions were confirmed by established miRNA RNA data and hypergeometric test. Then, a PTC-related lncRNA-miRNA-mRNA network (PTCRN) was constructed by integrating differentially expressed genes with the RNA-RNA networks. The new network consisted of 21 lncRNAs, 241 mRNAs and 803 edges. To prioritize PTC-related genes, we performed topological analysis and random walk with restart (PWR) algorithm analysis of PTCRN. Both analyses identified lncRNA RP11-159F24.1 as a hub node in the network, which could interact with 47 mRNAs by sponging miR-485. In functional enrichment analysis, these interacting mRNAs were associated with the pathways in cancer. In validation, RP11-159F24.1 (up-regulated; P = 0.0013) showed an opposite expression pattern with its target miR-485 (down-regulated; P = 0.0013) in PTC, indicating that the RP11-159F24.1/miR-485/mRNAs axis might play an important role in the development of PTC. In conclusion, this study has constructed a PTC related lncRNA-miRNA-mRNA network and identified the hub lncRNA RP11-159F24.1 in the tumorigenesis, which provided novel insights to explore the underlying mechanism of PTC. PMID- 30474932 TI - Tender joint count may not reflect inflammatory activity in established rheumatoid arthritis patients - results from a longitudinal study. AB - OBJECTIVE: Tender joint count (TJC) is included in Composite Disease Activity Scores (CDAS) (DAS28/CDAI/SDAI). The impact of having predominantly tender joints was explored by use of the Tender-Swollen Joint count Difference (TSJD). Ultrasound (US) provides a measure of joint inflammation. The present study aimed to explore the cross-sectional and longitudinal associations between TSJD and a spectrum of outcome measures including US scores in patients with established rheumatoid arthritis (RA) during follow-up on bDMARD treatment. METHODS: This is an observational study of 209 patients with established RA consecutively included when initiating bDMARD and followed with clinical, laboratory and comprehensive US examinations at 0, 1, 2, 3, 6 and 12 months. Patients were categorized into two groups - with predominantly tender (TSJD>0) or predominantly swollen (TSJD<=0) joints. Statistical analyses included Pearson's correlation, independent samples T-test and regression analyses. RESULTS: TJC had high correlations only with patient reported outcomes (PROMs)(p<0.001). Levels of CDAS and PROMs were significantly higher (p<0.001) at all visits in patients with TSJD>0 compared to TSJD<0, laboratory markers and assessor's global were similar, and US sum scores were significantly lower (p<0.001-0.03). Baseline TSJD positively predicted levels of all CDAS at 6 months (p<0.001-0.019) but was a negative predictor of US sum scores (grey scale and power Doppler) at 6 and 12 months (p<0.001). CONCLUSIONS: Patients with predominantly tender joints had higher CDAS but lower levels of inflammation defined by US. These findings indicate that inclusion of TJC in CDAS may contribute to misleading information about inflammatory activity. This article is protected by copyright. All rights reserved. PMID- 30474933 TI - Chronic Opioid Use in Rheumatoid Arthritis: Prevalence and Predictors. AB - OBJECTIVES: The opioid epidemic is a major public health concern. However, little is known about opioid use among rheumatoid arthritis (RA) patients. We examined trends in chronic opioid use in RA patients from 2002-2015 and identified clinical predictors. METHODS: RA patients were identified from the Corrona registry. Opioid use was ascertained from surveys obtained at clinical visits, as often as every 3 months. Chronic opioid use was defined as any opioid use reported during >=2 consecutive study visits. Annual prevalence of chronic opioid use was calculated among 33,739 RA patients with data on opioid use from >=2 visits. Among the 26,288 individuals who were not taking opioids at baseline, Cox proportional hazards models identified associations between patient characteristics and incident chronic opioid use. RESULTS: Chronic opioid use increased from 7.4% in 2002 to 16.9% in 2015. Severe pain (HR 2.53, 95% CI 2.19 2.92) and antidepressant use (HR 1.79, 95% CI 1.64-1.92) were associated with increased risk for chronic opioid use. High disease activity (HR 1.55, 95% CI 1.30-1.84) and high disability (HR 1.45, 95% CI 1.27-1.65) were also associated with chronic opioid use, whereas Asian race (HR 0.49, 95% CI 0.36-0.68) was associated with decreased risk for chronic opioid use. CONCLUSION: Among RA patients, chronic opioid use doubled from 2002 to 2015. Pain and antidepressant use were the strongest predictors of chronic opioid use. To curb the rise in chronic opioid use, strategies for stringent control of RA disease activity and management of pain and depression should be research priorities. This article is protected by copyright. All rights reserved. PMID- 30474934 TI - Ibudilast inhibits chemokine expression in rheumatoid synovial fibroblasts and exhibits immunomodulatory activity in experimental arthritis. AB - OBJECTIVE: Ibudilast is a well-tolerated, orally available type 4 phosphodiesterase (PDE4) inhibitor used to treat asthma and stroke. As PDE4 inhibition suppresses inflammatory mediator production and cell proliferation in leukocytes, ibudilast may be a valuable therapy for the treatment of inflammatory auto-immune diseases such as rheumatoid arthritis (RA). We assessed the therapeutic potential of ibudilast by measuring its capacity to modulate inflammation in human leukocytes, RA synovial fibroblasts (RASF) and in experimental arthritis. METHODS: Using standard curve-qPCR, the effect of ibudilast on gene expression in activated human leukocytes and RASF was measured. Ibudilast was used to treat DBA/1 mice with collagen-induced arthritis and an adoptive transfer model was used to assess its tolerogenic capacity. RESULTS: Ibudilast inhibited the expression of TNF, IL12A and IL12B, the secretion of TNFalpha and IL12/23p40 from leukocytes and reduced the expression of CCL5 and CCL3 in activated RASF. Treatment of experimental arthritis with ibudilast resulted in a reduction in IL-17-producing cells and inhibition of disease progression. When combined with a TNF-inhibitor, ibudilast caused marked suppression of active disease. Exposure of leukocytes from type II collagen immunised DBA/1 mice to ibudilast in vitro attenuated their ability to adoptively transfer arthritis to DBA/1J-PrkdcSCID mice, providing evidence of an immunomodulatory effect. CONCLUSION: Ibudilast reduced the expression and/or secretion of inflammatory mediators from activated human leukocytes and RASF, inhibited Th17 responses in vivo and improved established arthritis. Given the established safety profile of ibudilast in man, its clinical evaluation in RA, either alone or in combination with a TNF inhibitor, should be considered. This article is protected by copyright. All rights reserved. PMID- 30474935 TI - Outpatient initiation of non-invasive ventilation in children. PMID- 30474936 TI - Association between lung ultrasound findings and invasive exercise haemodynamics in patients with undifferentiated dyspnoea. AB - AIMS: Dyspnoea is common in heart failure (HF) but non-specific. Lung ultrasound (LUS) could represent a non-invasive tool to detect subclinical pulmonary congestion in patients with undifferentiated dyspnoea. METHODS AND RESULTS: We assessed the feasibility of an abbreviated LUS protocol (eight and two zones) in a prospective pilot study of 25 ambulatory patients with undifferentiated dyspnoea undergoing clinically indicated invasive cardiopulmonary exercise testing (iCPET) at rest (LUS 1) and after peak exercise (LUS 2). We also related LUS findings (B-lines) to invasive haemodynamics stratified by supine pulmonary capillary wedge pressure (PCWP) (Congestion, >15 mmHg; Control, <=15 mmHg). All enrolled patients (median age 68, 60% women, 32% prior HF, median ejection fraction 59%) had interpretable LUS 1 images in eight zones, and 20 (80%) had adequate LUS 2 images. LUS images were adequate in two posterior zones in 24 patients (96%) for LUS 1 and 18 (72%) for LUS 2. Although B-line number was numerically higher in the Congestion group at rest and after peak exercise, this difference did not reach statistical significance. In the entire cohort, there was an association between B-lines and rest systolic pulmonary artery pressure (r = 0.46, P = 0.02) and PCWP (r = 0.54, P = 0.005). There was an inverse relationship between B-lines and peak VO2 (r = -0.65, P = 0.002). CONCLUSIONS: Among ambulatory patients with undifferentiated dyspnoea, an abbreviated LUS protocol before and after iCPET is feasible in the majority of patients. B-line number at rest was associated with invasively measured markers of haemodynamic congestion and was inversely related with peak VO2 . PMID- 30474938 TI - Depression, Cognitive Functions, and Impaired Functioning in Middle-Aged Adults From the CONSTANCES Cohort. AB - OBJECTIVE: This large-scale population-based prospective study examined the association between depressive symptoms and cognitive performance at baseline with later functioning in middle-aged adults. METHODS: The Center for Epidemiologic Studies Depression Scale, the Digit Symbol Substitution Test (DSST), the Trail Making Test B (TMT-B), and the Semantic Verbal Fluency test (SVF) were completed at baseline by 7,426 participants aged >= 45 years from February 2012 to December 2013. Role limitations and social functioning were later assessed with the second version of the 12-Item Short Form Health Survey. The association between depressive symptoms and cognitive performance at baseline with functioning at follow-up was examined using general linear models and mediation analyses including sex, age, education, alcohol intake, and cannabis use as covariates. RESULTS: Altered functioning at follow-up was predicted by depressive symptoms (beta per standard deviation [95% confidence intervals]: 1.10 [-1.16 to -1.03] and -1.02 [-1.08, -0.96] for role limitations and social functioning, respectively) and DSST, TMT-B, and SVF performance (for role limitations: 0.11 [0.09 to 0.14], -0.11 [-0.13 to -0.08], and 0.03 [0.01 to 0.06], respectively; for social functioning: 0.10 [0.07 to 0.12], -0.08 [-0.11 to -0.06], and 0.04 [0.01 to 0.05], respectively) at baseline. Depressive symptoms were associated with poorer cognitive performance at baseline (-0.19 [-0.25 to 0.13], 0.15 [0.08 to 0.21], and -0.11 [-0.17 to -0.04], respectively). Cognitive performance accounted for only 0.3%-1.4% of the relationship between depressive symptoms and functioning. In contrast, depressive symptoms accounted for 19.5% 43.7% of the association between cognitive performance and functioning. CONCLUSIONS: In middle-aged adults from the general population, cognitive impairment is unlikely to substantially explain the association between depressive symptoms and later role limitations and social functioning. PMID- 30474937 TI - Role of CXCR2 in the Ac-PGP-Induced Mobilization of Circulating Angiogenic Cells and its Therapeutic Implications. AB - Circulating angiogenic cells (CACs) have been implicated in the repair of ischemic tissues, and their mobilization from bone marrow is known to be regulated by the activations of chemokine receptors, including CXCR2 and CXCR4. This study was conducted to investigate the role of N-acetylated proline-glycine proline (Ac-PGP; a collagen-derived chemotactic tripeptide) on CAC mobilization and its therapeutic potential for the treatment of peripheral artery diseases. Ac PGP was administered daily to a murine hind limb ischemia model, and the effects of Ac-PGP on blood perfusion and CAC mobilization (Sca1+ Flk1+ cells) into peripheral blood were assessed. Intramuscular administration of Ac-PGP significantly improved ischemic limb perfusion and increased limb salvage rate by increasing blood vessel formation, whereas Ac-PGP-induced blood perfusion and angiogenesis in ischemic limbs were not observed in CXCR2-knockout mice. In addition, Ac-PGP-induced CAC mobilization was found to occur in wild-type mice but not in CXCR2-knockout mice. Transplantation of bone marrow from green fluorescent protein (GFP) transgenic mice to wild-type mice showed bone marrow derived cells homed to ischemic limbs after Ac-PGP administration and that GFP positive cells contributed to the formation of ILB4-positive capillaries and alpha-smooth muscle actin-positive arteries. These results suggest CXCR2 activation in bone marrow after Ac-PGP administration improves blood perfusion and reduces tissue necrosis by inducing CAC mobilization. These findings suggest a new pharmaceutical basis for the treatment of critical limb ischemia. Stem Cells Translational Medicine 2018. PMID- 30474939 TI - Physical Frailty Correlates With Behavioral and Psychological Symptoms of Dementia and Caregiver Burden in Alzheimer's Disease. AB - OBJECTIVE: The aim of this study was to clarify the association of physical frailty with behavioral and psychological symptoms of dementia (BPSD) and caregiver burden in patients with Alzheimer's disease (AD). METHODS: The subjects were 1,193 AD patients who presented to the Memory Clinic at the National Center for Geriatrics and Gerontology of Japan during the period from October 2010 to February 2015 (mean +/- SD age = 78.8 +/- 6.3 years; female, 68.6%). AD was diagnosed based on the criteria of the National Institute on Aging and Alzheimer's Association workgroups. The Frailty Index (FI) was calculated as the ratio of actual to 38 potential deficits. BPSD and caregiver burden were assessed by using the Dementia Behavior Disturbance Scale (DBD) and the Japanese version of Zarit Burden Interview (J-ZBI). Multiple linear regression analyses and structural equation modeling (SEM) were performed to examine the relationship between the FI, DBD, and J-ZBI. RESULTS: The subjects' mean FI score was 0.16 +/- 0.10, with 663 (55.6%) and 198 (16.6%) subjects shown to be pre-frail (0.08 <= FI < 0.25) and frail (FI >= 0.25), respectively. Multiple linear regression analyses and SEM showed that the FI was independently associated with both DBD (beta = 0.30, P < .001) and J-ZBI (beta = 0.13, P < .001). Moreover, when the FI was considered as a categorical variable, even pre-frailty was associated with increased DBD score (beta = 0.16, P < .001) and J-ZBI score (beta = 0.09, P = .003). CONCLUSIONS: The presence of not only physical frailty but also pre frailty, as determined by the FI, could increase BPSD and caregiver burden in patients with AD. PMID- 30474940 TI - Outcomes of Cardiac Screening in Adolescent Soccer Players. PMID- 30474941 TI - Outcomes of Cardiac Screening in Adolescent Soccer Players. PMID- 30474942 TI - Outcomes of Cardiac Screening in Adolescent Soccer Players. PMID- 30474944 TI - Targeted therapy of polycytemia vera patients. AB - The discovery of the JAK2V617F mutation was the beginning of a new era in the study of myeloproliferative neoplasms (MPN). In addition to contributing to the understanding of the pathophysiology of Ph-negative MPN, JAK2 mutation has become a new therapeutic target in their treatment. In treatment of PV a new era began the era of targeted therapy, which gave a hope for better treatment outcomes and improved quality of life for patients who are resistant to standard therapy. This work presents literature data on molecular-genetic features of the pathogenesis of polycythemia vera (PV) and new possibilities in the treatment of this disease, literature review about JAKinhibitors, targeted therapy of PV. There are reviewed issues on resistance and intolerance of hydroxycarbamide and interferon (IFN-a) and the definition of the indications for administration of JAK-inhibitors. There are presented data on the efficacy and safety of ruxolitinib, which were proven within the clinical trial RESPONSE. PMID- 30474943 TI - Possibilities of liquid biopsy in gastric cancer. AB - The increasing popularity of the concept of liquid biopsy, which involves the definition of circulating tumor cells and circulating nucleic acids in the blood can significantly improve long-term results of treatment for gastric cancer due to the high sensitivity of techniques. It needs further study in relation to gastric cancer, the search for universal markers and methods. PMID- 30474945 TI - Tumor-associated eosinophilia. AB - The review provides information on current literature on structural and functional features of eosinophilic granulocytes and their role in the pathogenesis of cancer. There are examined data of clinical and experimental studies about an influence of hemic and tissue eosinophilia on the course and prognosis of malignant tumors. Molecular mechanisms of action of eosinophils in tumor pathology are discussed. PMID- 30474946 TI - Radionuclide therapy for bone metastases by drugs based on Re-188. AB - The systemic radionuclide therapy with bone affinity substances is an effective therapy in bone palliative treatment. Studies with radiolabeled Bisphosphonate or strontium-89 show reduction of pain in 70-80% and about 20% of treated patients are pain-free. The generator product rhenium-188 represents an interesting radionuclide for bone pain palliation. It is readily available and with appropriate patient numbers is very cost-effective. Radiopharmaceuticals with Re 188 show a comparable effectiveness in bone pain palliation and bone marrow toxicity as the other known radioactive Bisphosphonate. Repeat courses of treatment with rhenium-188 HEDP even a slightly increased survival could be observed. Using therapy with alpha emitters Radium-223 in prostate cancer patients with bone metastases there was observed a prolongation of survival by 3,6 months compared with placebo. Two drugs are created in Russia on the basis of Re-188. Phosphoren is an analog of Re-188-HEDP. It showed properties similar to them in clinical studies. Complex Re-188-zoledronic acid (Zoleren) is a unique development that combines the therapeutic effect of zoledronic acid and Re-188. PMID- 30474947 TI - STATISTICAL FEATURES OF BREAST CANCER INCIDENCE IN THE OMSK REGION. AB - Statistical patterns of breast cancer were studied in the Omsk Region in order to optimize early diagnosis and improve the effectiveness of treatment. It was found that the proportion of breast cancer patients in stage I in all age groups was 22. 9%, which was identical with that in the majority of regions of Russia (15 26%) and was close to the average population indices (18. 3%). For patients with disease of stage IV it should be marked the most significant differences in the smaller side compared with average indices for Russia for patients of older age group (17. 4% vs. 40. 6%). It was noted that in the age group up to 40 years there were revealed later stages of breast cancer, so necessary adjustments to screening program based on young patients were required. Due to limitations of mammographic examination of young patients the developments of alternative screening programs for this age group are actual. PMID- 30474948 TI - Manipulating the Ferroelectric Domain States and Structural Distortion in Epitaxial BiFeO3 Ultrathin Films via Bi Nonstoichiometry. AB - Exploring and manipulating the domain configurations in ferroelectric thin films are of critical importance for the design and fabrication of ferroelectric heterostructures with novel functional performance. In this study, BiFeO3 (BFO) ultrathin films with various Bi/Fe ratios from Bi-excess to Bi-deficient have been grown on (La0.7Sr0.3)MnO3 (LSMO) covered SrTiO3 substrates by laser molecular beam epitaxy system. Atomic force microscopy and piezoresponse force microscopy measurements show that both the surface morphology and ferroelectric polarization of the films are relevant to the Bi nonstoichiometry. More significantly, the Bi-excess thin films show upward (from substrate to film surface) uniform ferroelectric polarization, while a Bi-deficient thin film exhibits downward uniform polarization, which means the as-grown polarization of the BFO thin films can be controlled by changing Bi contents. Atomic-scale structural and chemical characterizations and second harmonic generation measurements reveal that two different kinds of structural distortion and interface atomic configuration in the BFO/LSMO heterostructures can be induced by the change of Bi nonstoichiometry, leading to the two opposite as-grown ferroelectric polarizations. It has also been revealed that the band gap of the BFO thin films can be modulated via Bi nonstoichiometry. These results demonstrate that Bi nonstoichiometry plays a key role on the ferroelectric domain states and physical properties of BFO thin films, and also open a new avenue to manipulate the structure and ferroelectric domain states in BFO thin films. PMID- 30474949 TI - Understanding the thermal treatment effect of two dimensional siloxene sheets and the origin of superior electrochemical energy storage performances. AB - Two dimensional siloxene sheets are an emerging class of materials with eclectic range of potential applications including electrochemical energy conversion and storage sectors. Here we have demonstrated the dehydrogenation/dehydroxylation of siloxene sheets by thermal annealing at high temperature (HT) and investigated their supercapacitive performances using ionic liquid electrolyte. The X-ray diffraction analysis, spectroscopic (FT-IR, laser Raman, and XPS) studies and morphological analysis of HT-siloxene revealed the removal of functional groups at the edges/basal planes of siloxene, and preservation of oxygen interconnected Si6 rings with sheet-like structures. The HT-siloxene symmetric supercapacitor (SSC) operates over a wide potential window (0 to 3.0 V), delivers a high specific capacitance (3.45 mF cm-2), high energy density of about 15.53 mJ cm-2 (almost two-fold higher than as-prepared siloxene SSC), low equivalent series resistance (compared to reported silicon based SSCs) with excellent rate capability and long cycle life over 10,000 cycles. PMID- 30474950 TI - Bioinspired Concentric-cylindrical Multilayered Scaffolds with Controllable Architectures: Facile Preparation and Biological Applications. AB - Multilayered objects in nature show interesting structures exhibiting multiple functionalities. Inspired by the excellent structural-functional characteristics of nature creatures, concentric-cylindrical multilayered scaffolds were prepared by a combination of melt extrusion and leaching, in which well-defined alternating microlayer/gap is assembled. Furthermore, the macroscopic shape, internal structure and surface topography of such multilayered scaffold can be elaborately prepared by simple physical process. The whole process is low-cost, efficient and environmentally friendly. Furthermore, such multilayered scaffolds show some interesting applications, e.g., lipophilic/hydrophilic drugs delivery and cell self-seeding. Considering the facile preparation process and versatile applications, this study will open up a new pathway to fabricate scaffolds with controllable architectures and expand biodegradable polymer applications. PMID- 30474951 TI - Stretchable Triboelectric Textile Composed of Wavy Conductive-Cloth-PET and Patterned Stretchable Electrode for Harvesting Multi-variant Human Motion Energy. AB - Triboelectric textile with wearable property and feasibility of large area preparation has presented great prospect in effectively collecting energy from human body motion to provide power supply for diversified wearable electronics. Here, we report a stretchable triboelectric textile (STET) composed of wavy conductive-cloth-PET and patterned stretchable electrode as basic knitting units, which can achieve multi-variant energy harvesting with low cost and well comfort. The STET display excellent output performances due to diversified working principles containing contact-separation and contact-sliding modes. Interaction between the knitting units can generate open-circuit voltage with a peak-to-peak value of 350 V and instantaneous peak power of 1 mW, the stretched-released STET produces peak voltage of 32 V, while tapping the STET with cotton twice contact separation movements generate improved peak voltage and current. To prove the potential application, the STET is fixed onto different positions of human body to effectively harvest multi-variant human body motion energy. Therefore this work provides a new approach applying stretchable triboelectric textile for power supply of wearable devices. PMID- 30474952 TI - Ultrathin scale tailoring of anisotropic magnetic coupling and anomalous magneto resistance in SrRuO3/PrMnO3 superlattices. AB - A strong perpendicular magneto-crystalline anisotropy (PMA) in antiferromagnetically coupled SrRuO_3 (17 u.c.(unit cell))/PrMnO_3 (n u.c.) superlattices effectively reconstructs the interfacial spin ordering. The occurrence of significant anisotropic interfacial antiferromagnetic coupling between the Ru and Mn ions is systematically tuned by varying the PrMnO_3 layer thickness in ultrathin scale from 3 to 12 u.c., which is associated with a rise in PMA energy from 0.28*?10?^(6 ) erg/?cm?^3 to 1.60*?10?^(6 ) erg/?cm?^3. The analysis using the Stoner-Wohlfarth model and density functional theory confirm that the exchange anisotropy is the major contribution to the PMA. The superlattices with PrMnO_3 layer thickness > 6 u.c. exhibit the tunneling like transport of Ru 4d electrons, which is rather expected in the stronger antiferromagnetically coupled superlattices with thinner PrMnO_3 layer. Tunneling like transport at thicker spacer layer in the SrRuO_3-PrMnO_3 superlattice system is an unique feature of two ferromagnet based superlattices. Our investigations show that the technologically important interfacial magnetic coupling, PMA, and tunneling magnetoresistance could be achieved in a periodically stacked bilayer and can be precisely manipulated by the size effect in ultrathin scale. PMID- 30474953 TI - Tungsten trioxide doped with CdSe quantum dots for smart windows. AB - Nanocrystal quantum dots (QDs) provide tunable optoelectronic properties based on their dimension. CdSe QDs, which are size-dependent colloidal nanocrystals, are used for efficient electrochromic devices owing to their unique properties in modulating quantum confinement, resulting in enhanced electron insertion during the electrochromic process. Incorporating a well-known metal oxide electrochromic material such as WO3 into CdSe QDs enhances the redox process. Herein, we propose a facile method for producing and optimizing CdSe QDs doped in WO3. The fabrication of the electrochromic film involves a solution and annealing process. Moreover, the effect of the QD size to optimize the electrochromic layer is studied. As a result, the coloration efficiency of WO3 and optimized CdSe QDs-WO3 are obtained as 68.6 and 112.3 cm2/C, respectively. Thus, size-tunable nanocrystal QDs combined with a metal oxide yield high-performance electrochromic devices and are promising candidates for producing smart windows. PMID- 30474954 TI - Cryoprotectant-Free Freezing of Cells Using Liquid Marbles Filled with Hydrogel. AB - Cryopreservation without cryoprotectant remains a significant challenge for the reestablishment of cell culture after freeze-thaw. Thus, finding an alternative and simple cryopreservation method is necessary. Liquid marble (LM) based digital microfluidics is a promising approach for cryoprotectant-free cryopreservation. However, the use of this platform to efficiently preserve samples with low cell density and well controlled serum concentrations has not been investigated. We addressed this issue by embedding an agarose-containing fetal bovine serum (FBS) inside the LM. A low density of 500 cells/uL of murine 3T3 cells was selected for evaluating the post-cryogenic survivability. The effects on the post-thaw cell viability of the concentration of agarose, the amount of FBS inside the agarose and the volume of the LM were investigated systematically. This paper also presents an analysis on the changes in shape and crack size of post-thawed agarose. The results revealed that the embedded agarose gel serve as a controlled release mechanism of FBS and significantly improves cell viability. Post-thaw recovery sustains major cellular features such as viability, cell adhesion, and morphology. The platform technology reported here open up new possibilities to cryopreserve rare biological samples without the toxicity risk of cryoprotectants. PMID- 30474955 TI - Analgesic effects of the GIRK Activator, VU0466551, alone and in combination with morphine in acute and persistent pain models. AB - G protein-gated inwardly-rectifying potassium (GIRK) channels are potassium selective ion channels. As their name suggests, GIRK channels are effectors of Gi/o G protein-couple receptors whereby activation of these GPCRs leads to increased GIRK channel activity resulting in decreased cellular excitability. In this way, GIRK channels play diverse roles in physiology as effectors of Gi/o coupled GPCRs: peacemaking in the heart rate, modulation of hormone secretion in endocrine tissues, as well as numerous CNS functions including learning, memory and addiction/reward. Notably, GIRK channels are widely expressed along the spinothalamic tract and are positioned to play roles in both ascending and descending pain pathways. More notably, GIRK channel knockout and knock-down studies have found that GIRK channels play a major role in the action of opioid analgesics which act predominantly through Gi/o-coupled, opioid-activated GPCRs (e.g. MU-opioid receptors). Recent advances in GIRK channel pharmacology have led to the development of small molecules that directly and selectively activate GIRK channels. Based on research implicating the involvement of GIRK channels in pain pathways and as effectors of opioid analgesics, we conducted a study to determine whether direct pharmacological activation of GIRK channels could produce analgesic efficacy and/or augment the analgesic efficacy morphine, an opioid receptor agonist capable of activating MU-opioid receptors as well as other opioid receptor subtypes. In the present study, we demonstrate that the small molecule GIRK activator, VU0466551, has analgesic effects when dosed alone or in combination with sub-maximally effective doses of morphine. PMID- 30474956 TI - A Novel Fluorescence Switch for MicroRNA Imaging in Living Cells based on DNAzyme Amplification Strategy. AB - MicroRNAs (miRNAs) play important roles in the regulation of target gene expression and cell development. Therefore, developing of accurate and visual detection methods for miRNAs is important for early diagnosis of cancer. In this study, we established a visual detection method for miRNA 155 based on DNAzyme amplification strategy in living cells. MnO2 nanosheets were employed to deliver Locked DNAzyme and Substrate DNA into cells. AuNPs-Probe were taken up by cells autonomously. Then, MnO2 nanosheets were reduced to Mn2+ by glutathione (GSH) in cells and DNA modules were released. MiRNA 155 took away Locker DNA by strand displacement reaction to activate the DNAzyme. Then the DNAzyme cleaved substrate DNA and released single-stranded DNA named Key DNA. Key DNA opened the hairpin DNA that modified on gold nanoparticles (AuNPs) and turn on the fluorescence of cy5. One target miRNA led to plenty of released Key DNA when lots of substrate DNA were added. Thus, the visual detection of miRNA 155 in living cells would be initiated. Under confocal laser microscopy, the fluorescence was obviously observed in tumor cells but not in normal cells. The method has a linear range from 0.1 nM to 10 nM and a low detection limit of 44 pM in vitro detection. PMID- 30474957 TI - A sulfonated thiophene derivative stabilized aqueous P3HT:PCBM nanoparticle dispersion for organic solar cell applications. AB - Aqueous nanoparticle (NP) dispersion made from P3HT:PCBM blend have been fabricated using a thiophene-based surfactant 2-(3-thienyl)ethyloxybutylsulfonate sodium salt (TEBS) for the first time via the miniemulsion process. The use of TEBS resulted in a stable dispersion of P3HT:PCBM NPs, of which the effect of various fabrication parameters was investigated. The generated NPs were characterized by dynamic light scattering, scanning electron microscopy, contrast variation small/ultra-small angle neutron scattering and cyclic voltammetry. The TEBS-stabilized P3HT:PCBM NPs were compared to that of sodium dodecyl sulfate (SDS)-stabilized core-shell NPs at the same concentrations. Contrast-variation small angle neutron scattering and electrochemical test results showed a more homogeneous distribution of de-mixed P3HT and PCBM small domains in the internal structure of TEBS-stabilized P3HT:PCBM NPs, reminiscent of cast film. Electron microscopy images show evidence of particles fusion upon drying (without annealing), which indicates that the thiophene-containing TEBS may improve compatibility and film-forming properties of these NPs and thus be more suited for conventional film processing methods. PMID- 30474958 TI - Implications of successfully symptomatic treatment in Parkinson's disease for therapeutic strategies of Alzheimer's disease. AB - Alzheimer's disease (AD) has been a devastating neurodegenerative disorder and lacks effective treatment to improve the prognosis of the patients. Symptomatic treatment for AD mainly includes two categories: Acetylcholinesterase inhibitors and the N-methyl-D-aspartate (NMDA) receptor antagonist (memantine). They can't significantly improve the quality of life and extend survival time for AD patients. In a worse case, almost all clinical trials for disease-modifying drugs had failed and the reduction of brain beta-amyloid (Abeta) deposition by multiple approaches, including inhibitors of beta or gamma-secretase, vaccines and antibodies against Abeta deposition, was found to have little effect on AD progression. New therapeutic strategy for AD is urgently needed. Parkinson's disease also is a neurodegenerative disease having no effective treatment for modifying the disease. Nevertheless, the successfully symptomatic treatment using the combined therapies of L-dopa supplement and the modulators of L-dopa metabolism greatly improves the prognosis of PD patients, which the average survival time of the patient has been extended from 3-4 years to 10-15 years although dopaminergic neurons are still progressively decreasing. It provides useful implications for AD therapeutic strategies. AD patients manifest global cognitive decline, prominently represented by memory deficit, especially at the early stage of the disease. Further, the degree of decreased cognitive abilities correlates with cholinergic dysfunction and the hypometabolism of glucose, the dominant energy fuel for brain. Thus, the amelioration of brain cholinergic function and brain energy metabolism may be effective treatment to improve cognitive abilities of AD patients. Here, we highlighted the explorations of symptomatic therapeutics through modulating brain cholinergic function and energy metabolism in AD. PMID- 30474959 TI - Nanoliter-Sized Microchamber/Microarray Microfluidic Platform for Antibiotic Susceptibility Testing. AB - The rise of antimicrobial resistance is challenging for physicians in clinical practice to prescribe antibiotics that are effective against bacterial infections. Conventional antibiotic susceptibility testing (AST) is labor intensive and time-consuming (18-24 h). Newly emerging technologies such as microfluidics may enable more rapid AST assay time. In this study, we utilize a nanoliter-sized microchamber/microarray-based microfluidic (N-3M) platform to reduce the AST assay time and rapidly determine the minimum inhibitory concentrations of different antibiotics. Bacterial suspensions, with or without antibiotics, are loaded into small nanoliter-sized chambers, and the change in fluorescent intensity emitted from resazurin reduction, which correlated with bacterial growth, is measured. We demonstrate the reproducibility, functionality, and efficiency of our N-3M platform for numerous wild-type clinical bacterial isolates including Escherichia coli, Klebsiella pneumoniae, and Enterococcus faecalis. The time-to-result of our N-3M platform varies between ~1-3 h, depending on growth rates of different bacterial species. We believe that our proposed N-3M platform is robust, is easy-to-implement, has a short time-to result, and can be applicable for microbial AST in clinical applications. PMID- 30474960 TI - Dynamic Single Molecular Rulers: Toward Quantitative Detection of MicroRNA-21 in Living Cells. AB - Innovative techniques to measure microRNA (miRNA) in vivo could greatly improve the fundamental understanding of complex cellular processes. Herein, we report a novel method for real-time, quantitative miRNA detection inside living cells based on core-satellite plasmon rulers (PRs). This approach allows for the statistical analysis of single hybridization event caused by target miR-NA. We investigated hundreds of satellite leaving events and found that the distribution of the time range for one strand dis-placement event is miRNA concentration dependent, which obeyed Poisson statistics. Probing several such PRs under dark field microscopy would provide precise determination of miRNA in vitro and in living cells, without photobleaching or blinking of the fluorophores. We believe the simple and practical approach on the basis of dynamic PRs with single molecule sensitivity combined with statistical analysis hold promising potential to visualize native nucleic acids with short sequence and low-abundance. PMID- 30474961 TI - Highly Stable Silica-Wrapped Mn-Doped CsPbCl3 Quantum Dots for Bright White Light Emitting Devices. AB - As an outstanding less-Pb candidate, doping Mn2+ ions into perovskite quantum dots has received significant interest in the application of light-emitting diodes (LED). However, their further applications are impeded by the poor chemical instability. Here, the silica wrapped Mn-doped CsPbCl3 QDs is fabricated via hydrolyzing (3-aminopropyl) triethoxysilane (APTES) with improved the operational stability. And the PL quantum yields (PLQY) as high as 55.4% for the CsPbMnCl3@SiO2 composite is achieved. Silica wrapping can protect the perovskite QDs from damaged by temperature and humidity as well as anion exchange. Furthermore, white LED devices are prepared by employing the mixture of the green CsPbBr3 QDs and the orange-red CsPbMnCl3@SiO2 composite. The as-obtained white LED device operated at a forward current of 20 mA shines bright natural light with a high luminous efficiency of 77.59 lm/W, and the corresponding color rendering index (CRI) of 82 and color temperature (CCT) of 3950 K are obtained. Additionally, the electroluminescence (EL) spectrum shows nearly no variation after 24 hours operation. This work will promote the Mn-doped CsPbCl3 QDs material to the practical application in solid-state LED. PMID- 30474962 TI - Atomic Substitution Enabled Synthesis of Vacancy-Rich Two-Dimensional Black TiO2- x Nanoflakes for High-Performance Rechargeable Magnesium Batteries. AB - Rechargeable magnesium (Mg) batteries assembled with dendrite-free, safe, and earth-abundant metal Mg anodes potentially have the advantages of high theoretical specific capacity and energy density. Nevertheless, owing to the large polarity of divalent Mg2+ ions, the insertion of Mg2+ into electrode materials suffers from sluggish kinetics, which seriously limit the performance of Mg batteries. Herein, we demonstrate an atomic substitution strategy for the controlled preparation of ultrathin black TiO2- x (B-TiO2- x) nanoflakes with rich oxygen vacancies (OVs) and porosity by utilizing ultrathin 2D TiS2 nanoflakes as precursors. We find out that the presence of OVs in B-TiO2- x electrode material can greatly improve the electrochemical performances of rechargeable Mg batteries. Both experimental results and density functional theory simulations confirm that the introduction of OVs can remarkably enhance the electrical conductivity and increase the number of active sites for Mg2+ ion storage. The vacancy-rich B-TiO2- x nanoflakes exhibit high reversible capacity and good capacity retention after long-term cycling at large current densities. It is hoped that this work can provide valuable insights and inspirations on the defect engineering of electrode materials for rechargeable magnesium batteries. PMID- 30474963 TI - Ultrahigh Selective Colorimetric Quantification of Chromium (VI) Ions based on Gold Amalgam Catalyst Oxidoreductase-like Activity in Water. AB - Hexavalent chromium ion (Cr6+) is one of the most toxic substances for plants, animals and a confirmed human respiratory carcinogen. However, so far, there are few independent and efficient colorimetric methods to detection of Cr6+. Here, we introduce a convenient, label-free, catalysis-based, and efficient strategy to quantification of Cr6+ by using a colorimetric sensing probe 3,3',5,5' tetramethylbenzidine (TMB). In the presence of trace amount of gold amalgam nanocomposites (Au@Hg) and Cr6+, TMB can be oxidized to oxTMB and the color changed to an intense blue that was observed by naked-eye and absorption spectroscopic method. In addition, the colorimetric method shows the high selectivity against 34 other interfering substances and it can be performed at room temperature, in water, and requires only ~5 min. Thus, the catalysis-based colorimetric assay for accurate and ultrahigh selective identification of Cr6+ will be found widespread use in real world. PMID- 30474964 TI - Real-time functional bioimaging of neuron-specific microRNA dynamics during neuronal differentiation using a dual luciferase reporter. AB - The capability of monitoring the neuronal differentiation process in living cells is crucial to the understanding of neuronal development and the practical application of cell therapy for the treatment of neurodegenerative disorders. Current research methods, including northern blot and real-time PCR analysis, have been extensively employed to quantify miRNA expression during cellular processes. However, these methods require the cell destruction and could not provide dynamic information of miRNA expression and function in living organisms. In the present study, we developed a dual luciferase reporter to monitor the expression pattern of neuron-specific miRNA-9 and miRNA-124a during neuronal differentiation in vitro and in vivo. The miRNA-responsive reporter was designed to encode a firefly luciferase (Fluc) gene containing miRNA target sequences and a Renilla luciferase (Rluc) gene for normalization. These two genes were independent modules and transcribed by two different promoters, which enables precise sensing miRNA activity without mutual transcription interference. We demonstrated that the functional activation of miRNA-9 and miRNA-124a during neurogenesis was visualized by the reduction of Fluc bioluminescence signal in P19 cells and nude mice without Rluc signal change, suggesting that miRNA-9 and miRNA-124a specifically downregulated their targets in accordance with their expression. Our dual luciferase-based miRNA imaging system provides a useful tool to quantitatively and continuously monitor miRNA activity during various biological processes. PMID- 30474965 TI - Nanostructured Thermo-responsive Surfaces Engineered via Stable Immobilization of Smart Nanogels with Assistance of Polydopamine. AB - Thermo-responsive surfaces featured with nanostructures have found wide potential applications in biological and chemical fields. Herein, we report nanostructured thermo-responsive surfaces engi-neered via stable immobilization of thermo responsive nanogels with assistance of polydopamine. The results show that the thin layer of polydopamine on the poly(N-isopropylacrylamide) (PNIPAM) nanogels nearly does not affect the thermo-responsive property of the nanogels. The stability of thermo-responsive nanogels on the substrate surfaces immobilized under different pH conditions of dopamine solutions are quatitively studied by fluid shearing experiments inside capil-laries, and the characterization results show that the strong interaction forces between the polydo-pamine layer on the substrate surfaces and the thermo-responsive nanogels are heavily depended on the oxidation state of dopamine molecules. With the proposed strategy, thermo responsive nanostructured surfaces immobilized with PNIPAM nanogels on two dimensional and three-dimensional substrate surfaces are generated to respectively achieve smart cell culture plates and smart gating membranes, which demonstrate versatile applications of the nanostructured thermo-responsive surfaces. PMID- 30474966 TI - Amorphous-MgGaO Film Combined with Graphene for Vacuum-Ultraviolet Photovoltaic Detector. AB - Vacuum-ultraviolet (VUV) detector equipped on satellites has extensive application in space exploration and cosmic science. For VUV detector, a semiconductor material with sufficiently wide band gap is eagerly desired. In this work, a wide-band-gap amorphous-MgGaO (a-MGO) film was epitaxially grown on n-type GaN substrate by atomic layer deposition and a p-i-n type heterojunction device for VUV detection was constructed with a-MGO film as photosensitive layer and p-type graphene as transparent conductive layer. The device exhibits a good spectral selectivity of VUV with photovoltaic response, a high responsivity (2 mA*W-1) under zero bias and an ultrafast response speed (rise time of 4.98 MUs and decay time of 1 ms) under nanosecond VUV pulse irradiation. This newly developed device shows great potential in VUV detection for space exploration. PMID- 30474968 TI - Ion Permeation Through a Phospholipid Membrane: Transition State, Path Splitting, and Calculation of Permeability. AB - We investigate the thermodynamics and kinetics of the permeation of a potassium ion through a phospholipid membrane. We illustrate that the conventional reaction coordinate (the position of the ion along the normal to the membrane plane) is insufficient to capture essential elements of the process. It is necessary to add coarse variables that measure membrane distortion. New coarse variables are suggested and a two-dimensional coarse-space is proposed to describe the permeation. We illustrate path splitting and two transition states of comparable barrier heights. The alternative pathways differ by the extent of water solvation of the ion-phosphate pairs. The permeation process cannot be described by a local one-dimensional reaction coordinate and a network formulation is more appropriate. We use Milestoning with Voronoi tessellation in two dimensions to quantify the equilibrium and rate of the permeation of the positively charged ion. The permeation coefficient is computed and compared favorably to experiment. PMID- 30474967 TI - Direct Three-Dimensional Observation of Core/Shell-Structured Quantum Dots with a Composition-Competitive Gradient. AB - Synthesizing semiconductor nanoparticles through core/shell structuring is an effective strategy to promote the functional, physical, and kinetic performance of optoelectronic materials. However, elucidating the internal structure and related atomic distribution of core/shell structured quantum dots (QDs) in three dimensions, particularly at heterostructure interfaces, has been an overarching challenge. Herein, by applying complementary analytical techniques of electron microscopy and atom probe tomography, the dimensional, structural, topological, and compositional information on commercially available 11.8 nm-sized CdSSe/ZnS QDs were obtained. Systematic experiments at high resolution reveal the presence of a 1.8 nm-thick Cd xZn1 - xS inner shell with a composition gradient between the CdSe core and the ZnS outermost shell. More strikingly, the inner shell shows compositional variation because of competitive atomic configuration between Cd and ZnS, but it structurally retains a zinc-blende crystal structure with the core. The inner shell may grow through the decreased reactivity of S with Cd, followed by atomic diffusion-related processes. The composition-competitive gradient inner shell alleviates lattice misfit strain at heterostructure interfaces, thereby enhancing the quantum yield and photostabilty to a greater extent than those of other single-shell structures. Thus, this precise measurement approach could offer a potential pathway to develop a wide variety of three-dimensional core/shell-structured materials. PMID- 30474969 TI - Unprecedented increases in total and methyl mercury concentrations downstream of retrogressive thaw slumps in the western Canadian Arctic. AB - Retrogressive thaw slumps (RTSs) are thermokarst features created by rapid thaw of ice-rich permafrost, and can mobilize vast quantities of sediments and solutes downstream. However, the effect of slumping on downstream concentrations and yields of total mercury (THg) and methylmercury (MeHg) is unknown. Fluvial concentrations of THg and MeHg downstream of RTSs on the Peel Plateau (Northwest Territories, Canada) were up to two orders of magnitude higher than upstream, reaching concentrations of 1,200 ng L-1 and 7 ng L-1, respectively, the highest ever measured in uncontaminated sites in Canada. MeHg concentrations were particularly elevated at sites downstream of RTSs where debris tongues dammed streams to form reservoirs where microbial Hg methylation was likely enhanced. However, >95% of the Hg downstream was typically particle-bound and potentially not readily bioavailable. Mean open-water season yields of THg (610 mg km-2 d-1) and MeHg (2.61 mg km-2 d-1) downstream of RTSs were up to an order of magnitude higher than those on the nearby large Yukon, Mackenzie and Peel rivers. We estimate that ~5% of the Hg stored for centuries or millennia in northern permafrost soils (88 Gg) is susceptible to release into modern-day Hg biogeochemical cycling from further climate changes and thermokarst formation. PMID- 30474970 TI - Carbohydrate background removal in metabolomics samples. AB - NMR-based metabolomics is a powerful tool to comprehensively monitor chemical processes in biological systems. Key to its success is the accurate and complete metabolite identification and quantification. Due to the inherent complexity of most metabolic mixtures, NMR peak overlap can make data analysis of 1D or even 2D NMR spectra challenging, especially for the 1H spectral region from 3.2-4.5 ppm that is dominated by carbohydrates and their derivatives. To address this problem, we present an effective method for carbohydrate signal removal in complex metabolomics samples by oxidation via the addition of sodium periodate (NaIO4). In an optional step, reaction products can be removed with hydrazide beads. The treated samples show substantially simplified 1D and 2D NMR spectra with their carbohydrate peaks removed, whereas non-carbohydrate peaks remain mostly unaf-fected. This allows the unrestricted detection of those metabolites that are otherwise obscured by carbohydrate signals. The method was first tested for metabolite model mixtures and then applied to urine and serum samples. It revealed a significant number of non-carbohydrates that were made unambiguously observable and identifiable by this method. The proposed protocol is simple and it is suitable for high-throughput sample treatment for the comprehensive metabolite identification in a broad range of samples. PMID- 30474971 TI - Visualizing Endogenous Sulfur Dioxide Derivatives in Febrile Seizure-Induced Hippocampal Damage by a Two-Photon Energy Transfer Cassette. AB - Febrile seizure (FS), a frequently encountered seizure disorder in pediatric populations, can cause hippocampus damage. It has been elucidated that sulfur dioxide (SO2) content is overproduced during the development of FS and related brain injury. Thus, in situ monitoring the level of endogenous SO2 in FS-related models is helpful to estimate the pathogenesis of FS-induced brain injury, but effect detection method remains to be explored. Herein, we developed a two-photon energy transfer cassette based on acedan-anthocyanidin scaffold, TP-Ratio-SO2, enabling to achieve this purpose. TP-Ratio-SO2 specifically responds to SO2 derivatives (HSO3-/SO32-) in ultrafast fashion (less than 3s), and HSO3-/SO32- can be sensitively determined with a detection limit of 26 nM. Moreover, it exhibits significant changes in two well-resolved fluorescence emission (?lambda = 140 nm) by reacting with HSO3-/SO32-, behaving as a ratiometric fluorescent sensor. Importantly, ratiometric imaging of endogenous SO2 derivatives generation in hyperpyretic U251 cells and as well as in rat model of FS-treated hippocampus damage were successfully carried out by TP-Ratio-SO2, demonstrating that it may be a promising tool for studying the role of SO2 in FS-associated neurological diseases. PMID- 30474973 TI - A combinatorial approach to study cytochrome P450 enzymes for de novo production of steviol glucosides in baker's yeast. AB - Biosynthesis of steviol glycosides in planta proceeds via two cytochrome P450 enzymes (CYPs): kaurene oxidase (KO) and kaurenoic acid hydroxylase (KAH). KO and KAH function in succession with the support of a NADPH-dependent cytochrome P450 reductase (CPR) to convert kaurene to steviol. This work describes a platform for recombinant production of steviol glucosides (SGs) in Saccharomyces cerevisiae, demonstrating the full reconstituted pathway from the simple sugar glucose to the SG precursor steviol. With a focus on optimization of the KO-KAH activities, combinations of functional homologs were tested in batch growth. Among the CYPs, novel KO75 (CYP701) and novel KAH82 (CYP72) outperformed their respective functional homologs from Stevia rebaudiana, SrKO (CYP701A5) and SrKAH (CYP81), in assays where substrate was supplemented to culture broth. With kaurene produced from glucose in the cell, SrCPR1 from S. rebaudiana supported highest turnover for KO-KAH combinations, besting two other CPRs isolated from S. rebaudiana, the Arabidopsis thaliana ATR2, and a new class I CPR12. Some co-expressions of ATR2 with a second CPR were found to diminish KAH activity, showing that co-expression of CPRs can lead to competition for CYPs with possibly adverse effects on catalysis. PMID- 30474972 TI - Stationary Phase EPR Spectroscopy for Monitoring Membrane Protein Refolding by Conformational Response. AB - Protein production remains a major bottleneck in membrane protein structural biology. In many cases, largescale recombinant protein expression is either unfeasible or impossible, driving structural biologists to explore new production avenues. Several membrane proteins have been successfully refolded from solubilized E. coli inclusion bodies. In recent years, a structure of the G protein-coupled receptor CXCR1 was obtained using refolded material from E. coli inclusion bodies. However, aggregation during the refolding process is a common difficulty, which is often addressed by immobilization of the protein onto a solid support. Most spectroscopic methods are incompatible with these light scattering matrices, which renders automated buffer exchange to screen refolding conditions impossible. This work explores a potential approach to overcome this problem by utilizing site-directed spin labelling and electron paramagnetic resonance (EPR) spectroscopy of protein bound to standard, commercially available Ni-NTA agarose resin. With this approach, the correct protein fold is determined by activity, which is inferred from a protein conformational response to a known stimulant. EPR spectra at each state of the refolding workflow of spin-labelled Haloarcula marismortui bacteriorhodopsin-I (HmbRI) are obtained and refolded fractions of HmbRI with this platform are quantitated using both protein from inclusion bodies and denatured recombinant protein from E. coli membranes. The stimulant used for HmbRI is visible light. The solid support allows for multiple refolding trials through buffer exchanges, and the EPR spectra are collected on the order of seconds under ambient conditions. PMID- 30474974 TI - MD Simulations on the Transport Behaviors of Mixed Na+ and Li+ in a Transmembrane Cyclic Peptide Nanotube under an Electric Field. AB - .Due to its inherently stronger hydration, Li+ faces a higher dehydration energy than Na+at the entrance of the 8x(WL)4/POPE-CPNT. Present MD simulations show that it can enter the channel from a NaCl/LiCl solution only under an electric field stronger than 0.3 V nm-1, while Na+ is easier to move into the channel, which is well elucidated by two cations' PMF profiles. The cation-Ow radial distribution functions, the electrostatic interactions with water and the orientations of neighboring water all refer to a more compact solvation structure and stronger hydration of Li+. Regardless of whether there is an external electric field, Na+ mainly appears in an alpha-plane zone, while Li+ does so in a midplane region. The increase of the electric field strength significantly accelerates the cations' axial diffusions, shortening the residence times of two cations in the channel. Furthermore, it makes channel water tend to take positive dipole states. PMID- 30474975 TI - Nickel-Catalyzed Synthesis of N-substituted Pyrroles using Diols with Aryl and Alkyl Amines. AB - Herein, nickel-catalyzed sustainable strategy for the synthesis of N-substituted pyrroles using butene-1,4-diols and butyne-1,4-diols with a series of aryl, alkyl, and heteroaryl amines is reported. The catalytic protocol is tolerant to free alcohol, halides, alkyl, alkoxy, oxygen heterocycles, activated benzyl, and the pyridine moiety and resulted in up to 90% yield. Initial mechanistic studies involving defined nickel-catalyst, determination of rate and order of reaction including deuterium-labeling experiments were performed for pyrrole synthesis. PMID- 30474977 TI - Atomic Charges. AB - The problem of deriving atomic charges from the results of ab Initio MO calculations has been studied by the use of several reported methods: Mulliken population analysis, the Minimal Basis Set (MBS) procedure, the Natural population analysis (NPA), two electrostatic potential fitting methods, M-K and ChelpG, the Hirshfeld population analysis and CM5 (charge model 5) that is related to the Hirshfeld method. The first set of studies were concerned with hydrogen charges using data for 20 compounds, giving 43 data points. It was found that the MBS charges were linearly related to the Hirshfeld charges. The electrostatic potential derived methods gave a modest linear dependence between them, but not with the other methods. The Hirshfeld, CM5 and MBS methods, but not the others, provided an excellent correlation for H atomic charge with bond angle, which is a proxy for hybridization, and with calculated gas-phase acidity. The two methods that were linearly related and gave hydrogen charges in agreement with an experimental study of partially deuterated methanes are MBS and Hirshfeld. In order to see which of the two methods is the more satisfactory, the MP2/aug-cc-pVTZ structure of a methanol dimer was obtained via geometry optimization. The calculated H bond energy was 6.2 kcal/mol in good agreement with studies of hydrogen bonds. The Coulombic interaction for the O...H bond was estimated using the MBS and Hirshfeld charges. The latter gave a calculated energy of 3-6 kcal/mol, whereas MBS gave an energy of ~35 kcal/mol. Clearly, the Hirshfeld method is more satisfactory and should be the method of choice. Some examples of the use of these charges are given. In the second part, we studied a wider range of compounds with the charges at the hydrogens included with the attached atoms. Again, the Hirshfeld charges were found to be the more satisfactory. PMID- 30474976 TI - Application of the ChIMES Force Field to Non-Reactive Molecular Systems: Water at Ambient Conditions. AB - We demonstrate development of the Chebyshev Interaction Model for Efficient Simulation (ChIMES) for molecular systems through application to water under ambient conditions (298 K, 1 g/cm3). These models, which are comprised of linear combinations of Chebyshev polynomials explicitly describing two- and three-body interactions, are largely fit by force matching to Kohn-Sham Density Functional Theory (DFT). Protocols for selecting user-specified parameters and inclusion of stress tensor data are investigated, and structural and dynamical property prediction for resulting models is benchmarked against DFT. We show that the present ChIMES force fields yield excellent agreement with DFT without the need for additional terms such as those for Coulomb interactions. Overall, we show that tractable parameterization and subsequent accuracy of the present models make ChIMES an ideal candidate for extension of DFT dynamics to larger system sizes and longer time scales. PMID- 30474978 TI - Structure-activity Relationship Analysis on Antioxidant and Anticancer Actions of Theaflavins on Human Colon Cancer Cells. AB - The roles of natural products as effective cancer prevention and therapeutic agents have been documented by various studies in recent years, but the action mechanisms and structure-activity relationship need more elucidation. The present study showed that theaflavins (theaflavin and its derivatives, TFs) from black tea caused an inhibitory effect on the proliferation of human colon adenocarcinoma cancer SW480 cells and human colon cancer SW620 cells (IC50 < 32.0 MUM) by the induction of cell cycle arrest, but exerted lower toxicity against normal cells with high safety index (1.89 - 6.26). Moreover, TFs triggered a decrease in reactive oxygen species (ROS) in SW480 cells due to their excellent radical-scavenging ability (e.g., IC50 value of TF4 to ABTS*+ was 1.91 +/- 0.21 MUM). More importantly, the structure-activity relationship analysis of TFs exhibited that the galloyl group was important factor to affect these activities. Taken together, we revealed that the TFs could act as substitutes for natural antioxidants and promising anticancer agents with beneficial influence on human health, and then anticipated that this study may provide useful information on the development of therapeutic natural products. PMID- 30474979 TI - Selective Photocatalytic C-F Borylation of Polyfluoroarenes by Rh/Ni Dual Catalysis Providing Valuable Fluorinated Arylboronate Esters. AB - A highly selective and general photocatalytic C-F borylation protocol that employs a rhodium biphenyl complex as a triplet sensitizer and the nickel catalyst [Ni(IMes)2] (IMes = 1,3-dimesitylimidazolin-2-ylidene) for the C-F bond activation and defluoroborylation process is reported. This tandem catalyst system operates with visible (blue, 400 nm) light and achieves borylation of a wide range of fluoroarenes with B2pin2 at room temperature in excellent yields and with high selectivity. Direct irradiation of the intermediary C-F bond oxidative addition product trans-[NiF(ArF)(IMes)2] leads to very fast decomposition when B2pin2 is present. This destructive pathway can be bypassed by indirect excitation of the triplet states of the nickel(II) complex via the photoexcited rhodium biphenyl complex. Mechanistic studies suggest that the exceptionally long-lived triplet excited state of the Rh biphenyl complex used as the photosensitizer allows for efficient triplet energy transfer to trans [NiF(ArF)(IMes)2], which leads to dissociation of one of the NHC ligands. This contrasts with the majority of current photocatalytic transformations, which employ transition metals as excited state single electron transfer agents. We have previously reported that C(arene)-F bond activation with [Ni(IMes)2] is facile at room temperature, but that the transmetalation step with B2pin2 is associated with a high energy barrier. Thus, this triplet energy transfer ultimately leads to a greatly enhanced rate constant for the transmetalation step and thus for the whole borylation process. While addition of a fluoride source such as CsF enhances the yield, it is not absolutely required. We attribute this yield-enhancing effect to (i) formation of an anionic adduct of B2pin2, i.e. FB2pin2-, as an efficient, much more nucleophilic {Bpin-} transfer reagent for the borylation/transmetalation process, and/or (ii) trapping of the Lewis acidic side product FBpin by formation of [F2Bpin]- to avoid the formation of a significant amount of NHC-FBpin and consequently of decomposition of {Ni(NHC)2} species in the reaction mixture. PMID- 30474980 TI - Ferrihydrite Particle Encapsulated within a Molecular Organic Cage. AB - Metal oxides with sizes of a few nm show variable crystal and electronic structures depending on their dimensions, and the synthesis of metal oxide particles with a desired size is a key technology in materials science. Although discrete metal oxide particles with the average diameter (d) smaller than 2 nm are expected to show size-specific properties, such ultrasmall metal oxide particles are significantly limited in number. In nature, on the other hand, nano sized ferrihydrite (Fh), which is ferric oxyhydroxide, occurs as a result of biomineralization in ferritin, an iron storage protein cage. Here we describe the synthesis of Fh particle using a covalent molecular organic cage (MOC) derived from 8+12 cyclocondensation of triaminocyclohexane with a diformylphenol derivative. At the initial reaction stage, eight iron ions accumulated at the metal binding sites in the cage cavity, and Fh particles (d = 1.9 +/- 0.3 nm) encapsulated within the cage (Fh@MOC) formed with quite a narrow size distribution. The formation process of the Fh particle in the organic cage resembles the biomineralization process in the natural iron storage protein, and the present method could be applicable to the synthesis of other metal oxide particles. Fh@MOC is soluble in common organic solvents and shows substantial redox activity in MeCN. PMID- 30474981 TI - Iron Acquisition in Mycobacterium tuberculosis. AB - The highly contagious disease tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis (Mtb), which has been evolving drug resistance at an alarming rate. Like all human pathogens, Mtb requires iron for growth and virulence. Consequently, Mtb iron transport is an emerging drug target. However, the development of anti-TB drugs aimed at these metabolic pathways has been restricted by the dearth of information on Mtb iron acquisition. In this Review, we describe the multiple strategies utilized by Mtb to acquire ferric iron and heme iron. Mtb iron uptake is a complex process, requiring biosynthesis and subsequent export of Mtb siderophores, followed by ferric iron scavenging and ferric-siderophore import into Mtb. Additionally, Mtb possesses two possible heme uptake pathways and an Mtb-specific mechanism of heme degradation that yields iron and novel heme-degradation products. We conclude with perspectives for potential therapeutics that could directly target Mtb heme and iron uptake machineries. We also highlight how hijacking Mtb heme and iron acquisition pathways for drug import may facilitate drug transport through the notoriously impregnable Mtb cell wall. PMID- 30474983 TI - Protein inference using PIA workflows and PSI standard file formats. AB - Proteomics using LC-MS/MS has become one of the main methods to analyze the proteins in biological samples in high-throughput. But the existing mass spectrometry instruments are still limited with respect to resolution and measurable mass ranges, which is one of the main reasons why shotgun proteomics is the major approach. Here, proteins are digested, which leads to the identification and quantification of peptides instead. While often neglected, the important step of protein inference needs to be conducted to infer from the identified peptides to the actual proteins in the original sample. In this work, we highlight some of the previously published and newly added features of the tool PIA - Protein Inference Algorithms, which helps the user with the protein inference of measured samples. We also highlight the importance of the usage of PSI standard file formats, as PIA is the only current software supporting all available standards used for spectrum identification and protein inference. Additionally, we briefly describe the benefits of working with workflow environments for proteomics analyses and show the new features of the PIA nodes for the KNIME Analytics Platform. Finally, we benchmark PIA against a recently published dataset for isoform detection. PIA is open source and available for download on GitHub (https://github.com/mpc-bioinformatics/pia) or directly via the community extensions inside the KNIME analytics platform. PMID- 30474982 TI - Studies toward the Total Synthesis of the Marine Macrolide Salarin C. AB - A convergent strategy for the synthesis of dideoxysalarin C (3) as a potential intermediate for the total synthesis of the marine macrolide salarin C (1) is described. The macrolactone core of 3 was assembled by Suzuki coupling between alkyl iodide 9 and vinyl iodide 8 and Shiina macrolactonization as key transformations. All macrocyclic intermediates were found to be of low stability. PMID- 30474984 TI - Genome Mining for Mycemycin: Discovery and Elucidation of Related Methylation and Chlorination Biosynthetic Chemistries. AB - A silent dibenzoxazepinone (DBP) biosynthetic gene cluster ( myc) was mutagenically activated in Streptomyces olivaceus SCSIO T05, enabling the discovery of mycemycin C (4) and three new analogues [mycemycins F-H (1-3)]. Gene disruption, complementation experiments, and enzymatic assays unveiled salicylic acid and 5-Cl-kynurenine as biosynthetic precursors and shed significant functional insights into MycO, MycB, MycR, and MycJ, enzymes responsible for fine tuning of the DBP scaffold. PMID- 30474985 TI - Single-Chain Atomic Crystals as Extracellular Matrix-Mimicking Material with Exceptional Biocompatibility and Bioactivity. AB - In this study, Mo3Se3- single-chain atomic crystals (SCACs) with atomically small chain diameters of ~0.6 nm, large surface areas, and mechanical flexibility were synthesized and investigated as an extracellular matrix (ECM)-mimicking scaffold material for tissue engineering applications. The proliferation of L-929 and MC3T3-E1 cell lines increased up to 268.4 +/- 24.4% and 396.2 +/- 8.1%, respectively, after 48 h of culturing with Mo3Se3- SCACs. More importantly, this extremely high proliferation was observed when the cells were treated with 200 MUg mL-1 of Mo3Se3- SCACs, which is above the cytotoxic concentration of most nanomaterials reported earlier. An ECM-mimicking scaffold film prepared by coating Mo3Se3- SCACs on a glass substrate enabled the cells to adhere to the surface in a highly stretched manner at the initial stage of cell adhesion. Most cells cultured on the ECM-mimicking scaffold film remained alive; in contrast, a substantial number of cells cultured on glass substrates without the Mo3Se3- SCAC coating did not survive. This work not only proves the exceptional biocompatible and bioactive characteristics of the Mo3Se3- SCACs but also suggests that, as an ECM-mimicking scaffold material, Mo3Se3- SCACs can overcome several critical limitations of most other nanomaterials. PMID- 30474986 TI - Strain-Engineering of Twist-Angle in Graphene/hBN Superlattice Devices. AB - The observation of novel physical phenomena such as Hofstadter's butterfly, topological currents, and unconventional superconductivity in graphene has been enabled by the replacement of SiO2 with hexagonal boron nitride (hBN) as a substrate and by the ability to form superlattices in graphene/hBN heterostructures. These devices are commonly made by etching the graphene into a Hall-bar shape with metal contacts. The deposition of metal electrodes, the design, and specific configuration of contacts can have profound effects on the electronic properties of the devices possibly even affecting the alignment of graphene/hBN superlattices. In this work, we probe the strain configuration of graphene on hBN in contact with two types of metal contacts, two-dimensional (2D) top-contacts and one-dimensional edge-contacts. We show that top-contacts induce strain in the graphene layer along two opposing leads, leading to a complex strain pattern across the device channel. Edge-contacts, on the contrary, do not show such strain pattern. A finite-elements modeling simulation is used to confirm that the observed strain pattern is generated by the mechanical action of the metal contacts clamped to the graphene. Thermal annealing is shown to reduce the overall doping while increasing the overall strain, indicating an increased interaction between graphene and hBN. Surprisingly, we find that the two contact configurations lead to different twist-angles in graphene/hBN superlattices, which converge to the same value after thermal annealing. This observation confirms the self-locking mechanism of graphene/hBN superlattices also in the presence of strain gradients. Our experiments may have profound implications in the development of future electronic devices based on heterostructures and provide a new mechanism to induce complex strain patterns in 2D materials. PMID- 30474987 TI - Strain-Tunable Quantum Integrated Photonics. AB - Semiconductor quantum dots are crucial parts of the photonic quantum technology toolbox because they show excellent single-photon emission properties in addition to their potential as solid-state qubits. Recently, there has been an increasing effort to deterministically integrate single semiconductor quantum dots into complex photonic circuits. Despite rapid progress in the field, it remains challenging to manipulate the optical properties of waveguide-integrated quantum emitters in a deterministic, reversible, and nonintrusive manner. Here we demonstrate a new class of hybrid quantum photonic circuits combining III-V semiconductors, silicon nitride, and piezoelectric crystals. Using a combination of bottom-up, top-down, and nanomanipulation techniques, we realize strain tuning of a selected, waveguide-integrated, quantum emitter and a planar integrated optical resonator. Our findings are an important step toward realizing reconfigurable quantum-integrated photonics, with full control over the quantum sources and the photonic circuit. PMID- 30474988 TI - Thickness-Encoded Micropatterns in One-Component Thermoresponsive Polymer Brushes for Culture and Triggered Release of Pancreatic Tumor Cell Monolayers and Spheroids. AB - Fabrication, characterization, and application of micropatterned one-component poly(di(ethylene glycol)methyl ether methacrylate) (PDEGMA) brushes for monolayer cell and spheroid culture and temperature-triggered release are reported. Micropatterns of various shapes and sizes were designed to possess a unique functionality imparted by thermoresponsive thin PDEGMA patches, which are cell adhesive at 37 degrees C, embedded in a much thicker cell-resistant PDEGMA matrix that does not exhibit measurable thermoresponsive properties. Depending on the cell seeding density, PaTu 8988t human pancreatic tumor cells or spheroids were cultured area-selectively, confined by the 40 +/- 4 nm thick passivating PDEGMA matrix, and could be released on demand by a mild thermally triggered brush swelling in the 5 +/- 1 nm thin regions. As shown by surface plasmon resonance (SPR) measurements, in contrast to the thinner brushes, the thicker brushes exhibited virtually no fibronectin adhesive properties at 37 degrees C, whereas at 25 degrees C, both areas showed similar protein resistant behavior. The quasi-2D thickness-encoded micropatterns were shown to be useful templates for the growth of 3D multicellular aggregates. Thermally induced release after 5 days of incubation afforded 3D cell spheroids comprising up to 99% viable cells demonstrating that the system can be used as a 3D spheroid in vitro model for basic tumor research and anticancer drug screenings. PMID- 30474989 TI - Does purpose in life or ethnic identity moderate the association for racial discrimination and suicide ideation in racial/ethnic minority emerging adults? AB - OBJECTIVE: To examine purpose in life (PIL) and ethnic identity (EI) as buffers to suicide ideation for Asian American, Hispanic, and Black emerging adults who perceive racial discrimination. METHOD: Two-hundred eighty-nine undergraduate students enrolled at a large university in the southwestern region of the United States (40.8% Asian American, 32.5% Hispanic, 26.6% Black; 61.2% women; mean age = 20.47, SD = 1.83) reported on experiences of racial discrimination, PIL, EI, and suicidal thoughts. Covariates were intrinsic religiosity, gender, and age. RESULTS: Regression analysis showed that EI was not a significant moderator for the association between perceived racial discrimination (PRD) and suicidal ideation (beta = -.08, p = .13; 95% confidence interval (CI) [-.19, .03]). However, PIL was a significant moderator (beta = -.11, p = .025; CI [-.20, .01]). A hierarchical regression showed that PIL as a moderator explained additional variance (DeltaR2 = 0.11, p < .001) in suicide ideation above and beyond EI. CONCLUSIONS: These findings provide some insight into how life purpose might ameliorate the impact of social stressors above and beyond a positive cultural identity for young racial/ethnic minority adults. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30474990 TI - Increasing bystander behavior to prevent adolescent relationship violence: A randomized controlled trial. AB - OBJECTIVE: The present research reports a randomized controlled trial evaluating TakeCARE, a video bystander program designed to help prevent relationship and sexual violence among high school students. METHOD: High school students (n = 165) were randomly assigned to view TakeCARE or a control video. Students completed self-report measures of bystander behavior and bystander self-efficacy before viewing the videos. One week later, students completed the self-efficacy measure and were observed in virtual reality simulations of situations that offered opportunities to engage in bystander behavior. Measures were readministered at a 6-month follow-up. RESULTS: Compared to students who viewed the control video, students who viewed TakeCARE self-reported more bystander behavior at the 6-month follow-up. They were also observed to engage in greater levels of bystander behavior in the virtual reality simulations at postintervention and 6-month follow-up. Self-efficacy partially mediated this effect on observed bystander behavior. CONCLUSION: Video bystander programs like TakeCARE might be an effective addition to high school efforts to prevent relationship and sexual violence. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30474991 TI - Therapists' empathic accuracy toward their clients' emotions. AB - OBJECTIVE: Therapists' empathic accuracy (EA) toward their clients' fluctuating emotions is a crucial clinical skill that underlies many therapeutic interventions. In contrast to the subjective components of empathy, limited empirical work has addressed EA or its effect on the outcomes of psychotherapy. Here, we differentiate between the components of EA (tracking accuracy, directional discrepancy) as well as the valence of the target emotions (positive vs. negative). We also investigated the relative contribution of cognitive and emotional processes to therapists' EA and examined the associations between EA and treatment outcomes. METHOD: The sample comprised 93 clients treated by 62 therapists in a university setting. Prior to each session, clients self-reported their symptoms. Following each session, clients rated their positive (PE) and negative (NE) emotions during the session and therapists rated their own emotions, as well as their assessment of their clients' emotions. RESULTS: Therapists accurately tracked their clients' PE and NE and were more accurate for NE. Therapists tended to overestimate their clients' NE and underestimate their clients' PE. Therapists' emotions were associated with their clients' emotions (real similarity). Therapists' emotions were also associated with their assessments of their clients' emotions (assumed similarity). Therapists' own emotions partially mediated the association between clients' emotions and therapists' assessments. Therapists' inaccuracy in assessing their clients' PE was associated with higher reported symptoms in the next session. CONCLUSION: These findings help provide a better understanding of the specific characteristics associated with more EA and underscore the importance of EA in facilitating clients' emotional well-being. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30474992 TI - Relations among academic achievement, self-esteem, and subjective well-being in school among elementary school students: A longitudinal mediation model. AB - Situated within a positive psychology perspective, the current study examined the relations among academic achievement, self-esteem, and subjective well-being (SWB) in school among Chinese elementary school students using a longitudinal mediation model. A total of 807 elementary school students (Mage = 9.43 years; 52.9% male) completed a multimeasure questionnaire that tapped the targeted variables at 3 time points, across 18 months. After controlling for gender, age, and family socioeconomic status, the results revealed that (a) academic achievement positively predicted later SWB in school; (b) self-esteem at Time 2 completely mediated the relation between academic achievement at Time 1 and SWB in school at Time 3; and (c) significant bidirectional relations were observed between self-esteem and SWB in school. Limitations and practical applications related to the cultural context of China were discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30474993 TI - Multilevel confirmatory factor analysis of the Effective Behavior Support Self Assessment Survey. AB - One evaluation measure available through the Positive Behavioral Interventions and Supports framework is the Effective Behavior Support Self-Assessment Survey (SAS). Evaluations of the SAS have supported its factor structure. However, the SAS is designed to be completed by school personnel who are nested within other levels of analysis (e.g., schools, grade level, district). There have been no studies examining the SAS from a multilevel perspective. The current study addressed this gap by evaluating the SAS using data from 1,726 respondents across 36 public schools in 3 school districts. Another purpose of this study was to evaluate whether the SAS can be shortened yet remain psychometrically sound to encourage completion of the survey by busy school staff members. Intraclass correlation coefficients indicated substantial dependence in item responses. Factor correlations were substantial across all models tested. Compared with a 2nd-order, hierarchical model and the basic 4-factor model based on the original hypothesized structure of the SAS, the best combination of fit and parsimony was obtained from a reduced set of 24 of the original 46 items organized within a multilevel bifactor structure (e.g., comparative fit index = .979, root-mean square error of approximation = .019), suggesting that the SAS may be shortened. The bifactor model partitioned item variances to a general implementation fidelity factor and to 1 of the 4 hypothesized factors. These results suggest that the SAS items aim to describe dimensions for measuring implementation status that may be as relevant at the school level as they are at the individual level. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30474994 TI - Assessment of teaching to predict gains in student achievement in urban schools. AB - We examined the degree to which assessment of teachers' instructional and behavior management practices, as measured by the Classroom Strategies Assessment System (CSAS; Reddy & Dudek, 2014), relates to gains in student achievement as measured by the Measures of Academic Progress (Northwest Evaluation Association [NWEA], 2011). Two-level hierarchical linear modeling was applied to achievement scores from 2,771 students in 130 kindergarten through 8th-grade classrooms in 13 urban schools serving students in communities with high concentrations of poverty. Results suggest that teachers' use of evidence-based instructional and behavior management strategies, as measured by the CSAS, were associated with reading and mathematics gains. In general, students in classrooms with higher quality use of evidence-based teaching strategies exhibited greater gains, whereas students in classrooms with lower quality use of effective strategies exhibited lesser gains. Implications of these findings for research and educational practice are presented. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30474995 TI - Lifetime discrimination burden, racial discrimination, and subclinical cerebrovascular disease among African Americans. AB - OBJECTIVE: Explore interactive relations of lifetime discrimination burden and racial discrimination-chronic stressors among African Americans (AAs)-and age with MRI-assessed white matter lesion volume (WMLV), a prognostic indicator of poor clinical brain health outcomes. METHOD: AAs (N = 71; 60.6% female, mean age = 50) participating in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) SCAN study underwent quantitative magnetic resonance imaging coded for WMLV. Participants self-reported lifetime discrimination burden and racial discrimination approximately 5 years earlier. Multivariable regression models assessed interactions of linear and quadratic effects of discrimination and age with WMLV adjusted for sex and socioeconomic status. RESULTS: Findings revealed significant interactive relations of age and (a) quadratic, lifetime discrimination burden, B = .05, p = .014, etapartial2 = .092, and (b) quadratic, racial discrimination, B = .03, p = .001, etapartial2 = .155, with WMLV. Among older AA, increases in lifetime discrimination burden and racial discrimination were associated with increases in WMLV (ps < .03); in younger AA, decreasing levels of racial discrimination were related to increases in WMLV (p = .006). CONCLUSIONS: Among older AA, as lifetime discrimination burden and racial discrimination increased, so did WMLV. However, in younger AA, decreases in racial discrimination were associated with increased WMLV. Elucidation of complex mechanistic underpinnings, including potentially differential impacts of the acknowledgment versus suppression or underreporting of discriminatory experiences, among AA of different age cohorts, is critical to understanding the present pattern of findings. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30474996 TI - Does delay discounting predict maladaptive health and financial behaviors in smokers? AB - OBJECTIVE: Excessive delay discounting, the rapid devaluation of future rewards, is often demonstrated by individuals suffering from substance use disorders, including chronic cigarette smokers. This constricted temporal window not only produces increased valuation of immediate unhealthy rewards (e.g., cigarettes) but also a decreased valuation of both future healthy rewards (e.g., increased energy) and future consequences (e.g., lung cancer). Moreover, in addition to cigarettes, smokers tend to engage in other behaviors that elicit immediate rewards and negative future consequences such as overconsuming alcohol, unhealthy eating, physical inactivity, and/or irresponsible spending. The present study sought to determine whether smokers' discounting rate would predict the frequency of engagement in other poor health and financial behaviors, independent of cigarette smoking. METHOD: A total of 303 daily smokers were asked to complete a delay discounting task and then answer how frequently they typically engaged in health and finance related behaviors. RESULTS: A structural equation model was used to group the questions into highly significantly latent factors of "Drug Use," "Finances," "Fitness," "Food," "Health," "Household Savings," "Personal Development," and "Safe Driving." When regressed on the model, delay discounting significantly predicted engagement all of the factors, except "Safe Driving," independent of smoking status. CONCLUSION: In sum, these findings highlight delay discounting as a useful metric for predicting whether individuals' engagement in variety of healthy physical and financial behaviors, as a function of their temporal window. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30474997 TI - Lying, negligence, or lack of knowledge? Children's intention-based moral reasoning about resource claims. AB - In a hidden inequality context, resource allocators and resource recipients are unaware that an unknowingly advantaged recipient possesses resources. The present study presented children aged 3-13 years (N = 121) with a hidden inequality vignette involving an accidental transgression in which one resource claimant, who unknowingly possessed more resources than another claimant, made an "unintentional false claim" to resources. This unintentional false claim resulted in depriving another recipient of needed resources. Results revealed that children's ability to accurately identify the claimant's intentions was related to how they evaluated and reasoned about resource claims, a previously understudied aspect of resource allocation contexts. Children's attributions of intentions to the accidental transgressor mediated the relationship between age and evaluations of the accidental transgression and the relationship between age and assignment of punishment to the accidental transgressor. With age, children who negatively evaluated the unintentional false claim shifted from reasoning about lying to a focus on negligence on the part of the unintentional false claimant. This shift reflects an increasing understanding of the accidental transgressor's benign intentions. These findings highlight how mental state knowledge and moral reasoning inform children's comprehension of resource allocation contexts. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30474998 TI - All in the family: Within-family differences in parental monitoring and adolescent information management. AB - This article used a sample of 2 adolescents per family to (a) examine the extent to which parental monitoring and adolescent information management are characteristics of families or of dyads and (b) replicate past research on parental monitoring and adolescent information management using models that distinguish differences between families from differences within them. Within- and between-family differences were examined as a function of parents (positive and negative parenting, immigration status), individual and peer-reported problem behavior, and adolescent characteristics (age, gender) in a sample of 300 Swedish families with 2 siblings each (aged 10 to 19). Parents' self-reports of their monitoring of siblings and of their adolescents' information management were consistently more similar than adolescents' self-reports or reports on parents. Siblings' reports of parental monitoring and self-reports of routine and personal information management were modestly related to one another. Reports of secrecy, however, were statistically independent. Results predicting between-sibling differences are consistent with those obtained from longitudinal studies of one sibling per family: adolescents who engage in problem behavior are more secretive and disclose less information to parents. Their parents report them to be more secretive. Siblings who engage in delinquency report lower parent solicitation and control. Siblings' reports of both positive and negative parenting were associated with within-family differences in parental monitoring and their own information management. The results reinforce previous findings on the important role adolescents play in their own socialization. Differences between adolescent and parent reports highlight important methodological biases that may obscure key processes in family communication. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30474999 TI - Give and take: An episodic perspective on leader-member exchange. AB - Research on leader-member exchange (LMX) has predominantly taken a dyadic relationship perspective to understand the differences in overall exchanges across leader-member dyads, while neglecting the within-dyad exchange dynamics across a series of episodic resource transactions. Drawing from the literature on equity and reciprocity principles of social exchange, we develop and test a model of leader-member episodic resource transactions that delineates the momentary psychological mechanism and the boundary condition under which episodic resource contribution surplus generates member subsequent reciprocations. Multilevel polynomial regression analyses of 600 episodic exchange responses from 73 employees show that resource contribution surplus in an exchange episode increased state work engagement immediately following the episode and member resource contribution in the next episode by evoking member momentary sense of obligation to reciprocate. Additionally, the between-dyad LMX relationship quality attenuated these effects by reducing the likelihood to feel obligated to reciprocate due to episodic resource contribution surplus. Our research highlights the microdynamic transaction nature of the exchanges between leaders and members and provides insight into how leader-member dyads exchange resources in episodic interactions. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475001 TI - A formal model of leadership goal striving: Development of core process mechanisms and extensions to action team context. AB - This research develops and tests a formal process-oriented theory of leader goal striving. Drawing on self-regulation theory, we developed a computational model that explicates the core process mechanisms involved in a leader-subordinate dyadic goal pursuit system. We then extended this core model to incorporate action team features (i.e., negative external disturbances, deadlines, and task interdependence) to account for leadership behavior in action team context. We simulated our proposed model to generate predictions about trajectories of a critical leadership function (i.e., leader engaging in team task-specific actions) under different conditions of disturbances, deadlines, task interdependence, and leader attributes. The predicted relationships were then tested in a laboratory experiment. As predicted by the model, time-related factors, including disturbances and deadlines, had significant effects on trajectories of leader actions. Over time within a given task, leaders were more likely to take actions when further than closer to the deadline. Leaders were also more likely to take actions when external disturbances set task states back. In addition, leaders' time allocation was less evenly distributed across subordinates when the deadline was short (vs. long). We discussed the implications of the model and how future research can extend our model to account for more complicated goal pursuit and team processes. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475000 TI - Lay theories of effortful honesty: Does the honesty-effort association justify making a dishonest decision? AB - Are our moral decisions and actions influenced by our beliefs about how much effort it takes to do the right thing? We hypothesized that the belief that honesty is effortful predicts subsequent dishonest behavior because it facilitates one's ability to justify such actions. In Study 1 (N = 210), we developed an implicit measure of people's beliefs about whether honesty is effortful, and we found that this lay theory predicts dishonesty. In Study 2 (N = 339), we experimentally manipulated individuals' lay theories about honesty and effort and found that an individual's lay theory that honesty is effortful increased subsequent dishonesty. In Study 3, we manipulated (Study 3a; N = 294) and measured (Study 3b; N = 153) lay theories, and then manipulated the strength of situational force that encourages dishonesty, and found that an individual's lay theory influences subsequent dishonesty only in a weak situation, where individuals have more agency to interpret the situation. This research provides novel insights into how our lay theories linking honesty and effort can help us rationalize our dishonesty, independent of whether a particular moral decision requires effort or not. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475002 TI - Learning helplessness in the family: Maternal agency and the intergenerational transmission of depressive symptoms. AB - Children of mothers with elevated depressive symptoms may observe and learn a maladaptive cognitive style, including low perceptions of agency, that is, low perceived control over their emotions and circumstances. In turn, children may face increased cognitive vulnerability to depressive symptoms; however, this mediational model has yet to be tested. Using a longitudinal design and testing our hypotheses within a community sample, we investigated the mediating role of maternal agency in the associations between maternal depressive symptoms and child behavioral helplessness and depressive symptoms one and a half years later (M = 18.58 months, SD = 6.91 months). A diverse sample of school-age children (N = 137, 57.4% female, Mage = 9.74 years, SDage = 1.51 years) and their mothers (N = 122) reported on their depressive symptoms at Time 1. A subsample of children and mothers returned to report on depressive symptoms at Time 2 (N = 68 dyads; 49 with complete data prior to multiple imputation). Maternal agency was coded from narrative responses to the Parent Development Interview-Revised for Parents of School-aged Children (Slade et al., 2009), completed at Time 1. Child behavioral helplessness was indicated by low strategy use at the end of a challenging puzzle task at Time 2. Results revealed that lower maternal agency predicted higher child depressive symptoms at Time 2 and mediated the associations between higher maternal depressive symptoms at Time 1 and higher child behavioral helplessness and depressive symptoms at Time 2. Implications for clinical intervention and future investigations are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475003 TI - The longitudinal association between maternal parenting stress and spousal supportiveness. AB - Parenting stress can negatively impact mothers and the family unit. Previous research has identified spousal supportiveness as a critical resource in helping reduce maternal parenting stress, whereas other research demonstrates that parenting stress may reduce supportive behaviors over time. However, it is unclear whether the association between spousal supportiveness and maternal parenting stress is robust over an extended period of children's development, or whether economic hardship impacts change in both constructs. Using 4 waves of data from 612 mothers in the Fragile Family and Child Wellbeing study, we explored whether maternal parenting stress was associated with change in spousal supportiveness and whether spousal supportiveness simultaneously was associated with change in maternal parenting stress. We examined these bidirectional associations while accounting for economic hardship. We found parenting stress and perceptions of spousal supportiveness changed at varying rates throughout the 8 years of the study. We also found that when the focal child was 1 year old, perceptions of spousal supportiveness were associated with increases in mothers' parenting stress, whereas when the child was 3 and 5 years old, perceptions of spousal supportiveness were associated with a faster decrease in mothers' parenting stress. Maternal parenting stress was not associated with perceptions of spousal supportiveness over time. We also found that mothers with greater economic hardship showed a slower decline in perceptions of spousal supportiveness compared with the decline in perceptions of spousal supportiveness observed without economic hardship in the model. We conclude by providing both developmental and practical implications for helping mothers. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475004 TI - Parent-adolescent conflict and young adult romantic relationship negativity: Genetic and environmental influences. AB - Prior work indicates that aspects of interpersonal relationships are heritable, including negativity within parent-adolescent relationships as well as romantic relationships during adulthood. There have not, however, been systematic studies to disentangle genetic and environmental influences on relationship dynamics with parents as they relate to romantic partner relationship dynamics. Thus, the present study examined genetic and environmental influences on associations between parent-adolescent conflict and young adult reports of negativity with a romantic partner using a longitudinal twin/sibling design. We found that genetic, shared, and nonshared environmental factors contributed to conflict in parent adolescent relationships and that genetic and nonshared environmental factors uniquely contributed to negativity in the romantic partnership during young adulthood. The longitudinal association between parent-adolescent conflict and romantic relationship conflict was explained entirely by genetic influences shared by the 2 constructs. These findings have implications for understanding interpersonal functioning across different relationship types, spanning multiple developmental periods. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475005 TI - Intentions and actions. AB - Manipulable objects have the potential to evoke mental representations of hand actions. Behavioural evidence favouring the view that this process happens automatically while passively viewing objects is critically examined. A case is made for the alternative proposal that objects may evoke action representations when observers concurrently operate with an intention to engage in a reach-and grasp action. In addition, the nature of hand action representations was examined by considering two components of actions, hand selection and wrist orientation, and it is shown that the relationship between these dimensions is modulated by task context. When an action representation is evoked by a task-irrelevant object, these two dimensions are to a large extent independent of one another, but when an observer prepares an action for immediate production, these two action features are hierarchically integrated, with hand selection dominating the hierarchy. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475006 TI - Perspectives on a contingency management intervention for alcohol use among consumers with serious mental illness. AB - OBJECTIVE: This study describes the perspectives of outpatients with serious mental illness (SMI) and alcohol dependence on their participation in a contingency management (CM) intervention for alcohol use. METHODS: Thirty-five adults with SMI and alcohol dependence participated in a randomized trial of CM for alcohol use, where they were rewarded with prizes contingent on abstinence from alcohol. All participants were interviewed regarding their participation in CM with a consistent structure that included nine open-ended questions. Favored and disliked aspects of CM, perception of alcohol biomarker accuracy, and interest in participating in similar CM interventions provided by treatment centers, rather than researchers, were explored. RESULTS: Participants spoke enthusiastically about receiving prizes, as well as how CM increased their awareness of drinking and helped support their abstinence from alcohol. Most participants felt the ethyl glucuronide biomarker urine tests used to measure alcohol use were accurate, and they were interested in enrolling in CM if it was offered as a clinical program. Research staff who implemented the intervention were well regarded by participants, and interactions with research staff were perceived positively. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Adults with SMI and alcohol dependence participating in a trial of CM for alcohol use reported overall positive perceptions of and experiences with CM. Receiving small tangible prizes and having positive interpersonal interactions with study staff were reported as especially impactful. These findings indicate that CM is well received by consumers, in addition to its empirical and practical benefits as an evidence-based, low-cost intervention. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475007 TI - An interdependence account of sexism and power: Men's hostile sexism, biased perceptions of low power, and relationship aggression. AB - Protecting men's power is fundamental to understanding the origin, expression, and targets of hostile sexism, yet no prior theoretical or empirical work has specified how hostile sexism is related to experiences of power. In the current studies, we propose that the interdependence inherent in heterosexual relationships will lead men who more strongly endorse hostile sexism to perceive they have lower power in their relationship, and that these perceptions will be biased. We also predicted that lower perceptions of power would in turn promote aggression toward intimate partners. Across 4 studies, men who more strongly endorsed hostile sexism perceived lower power in their relationships. Comparisons across partners supported that these lower perceptions of power were biased; men who more strongly endorsed hostile sexism underestimated the power they had compared with their partners' reports of that power (Studies 1 and 2). These lower perceptions of power, in turn, predicted greater aggression toward female partners during couples' daily interactions (Study 1), observed during couples' video-recorded conflict discussions (Study 2), and reported over the last year (Studies 3 and 4). Moreover, the associations between hostile sexism, power, and aggression were specific to men perceiving lower relationship power rather than desiring greater power in their relationships (Studies 3 and 4), and they were not the result of generally being more dominant and aggressive (Studies 3 and 4), or more negative relationship evaluations from either partner (Studies 1-4). The findings demonstrate the importance of an interdependence perspective in understanding the experiences, aggressive expressions, and broader consequences associated with hostile sexism. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475008 TI - Norm talk and human cooperation: Can we talk ourselves into cooperation? AB - Norm talk is verbal communication that explicitly states or implicitly implies a social norm. To investigate its ability to shape cultural dynamics, 2 types of norm talk were examined: injunction, which explicitly states what should be done, and gossip, which implies a norm by stating an action approved or disapproved of by the communicator. In 2 experiments, participants engaged in norm talk in repeated public goods games. Norm talk was found to help sustain cooperation relative to the control condition; immediately after every norm talk opportunity, cooperation spiked, followed by a gradual decline. Despite the macrolevel uniformity in their effects on cooperation, evidence suggests different microlevel mechanisms for the cooperation-enhancing effects of injunction and gossip. A 3rd study confirmed that both injunction and gossip sustain cooperation by making salient the norm of cooperation, but injunction also effects mutual verification of the communicated norm, whereas gossip emphasizes its reputational implications by linking cooperation to status conferral and noncooperation to reputational damage. A 4th experiment provided additional evidence that norm talk was superior to the promise of conditional cooperation in sustaining cooperation. Implications of the findings for cultural dynamics are discussed in terms of how feelings of shared morality, language-based interpersonal communication, and ritualization of norm communication contribute to social regulation. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475009 TI - Comparability of the WCST and WCST-64 in the assessment of first-episode psychosis. AB - The Wisconsin Card Sorting Test (WCST) was designed as a measure of executive functioning and is commonly used in the assessment of psychiatric disorders. The original WCST, consisting of 128 cards, has been criticized as being too lengthy for patients experiencing significant distress. Consequently, a shortened version consisting of a single 64-card deck (WCST-64) was created. The purpose of this study was to examine the comparability of the WCST and WCST-64 in 99 patients with first-episode psychosis. Findings showed the WCST-64 yielded a mean T score for perseverative responses (PR) that was 4.08 points lower than the corresponding variable from the WCST, and the correlation between the variables was r = .65. The mean discrepancy was only 2.34 for nonperseverative error (NPE) T scores and the correlation was also stronger, r = .82. Nearly half the sample (44%) had a T score discrepancy between the respective PR indexes that was greater than 1 SD, whereas this discrepancy was observed in only 4% of the sample for NPE. Based on a cut point of < 40T to define impaired versus normal performance for PR, 80% of the sample received the same classification. These findings suggest that NPE scores may be comparable across both tests. Conversely, whereas the PR score from the WCST-64 and WCST can be used as a gross measure of impairment, this score should not be used interchangeably to characterize the severity of perseverative tendencies in first-episode patients on a case-by-case basis. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475010 TI - Slow and steady: Training induced improvements to response time consistency are due to overall slowing and minimized extremely slow responses. AB - Previous studies on response time intraindividual variability (RT IIV) have focused on differences between groups, ignoring the potential for modification. The current study provides a detailed analysis of RT IIV training effects across three age groups. Healthy adults (40 young [aged 18-30], 40 young-old [aged 65 74], and 41 old-old [aged 75-85]) were assigned to feedback or no feedback (standard) conditions during a touch-screen feature integration task. In the feedback condition, participants were shown their performance on the previous block of trials and encouraged to improve going forward. Transfer was assessed by comparing pre- and posttraining performance on a 4-choice RT task. Data were analyzed with respect to RT IIV, ex-Gaussian distribution fitting, and the diffusion model of RT decision making. Significant feedback-related reductions were observed in Target RT IIV and the ex-Gaussian parameter tau, accompanied by an increase in MU. There was no significant change in sigma, and no evidence of transfer to the 4-choice RT task. The diffusion model analysis indicated that feedback training promoted a reduction in response threshold for the young and young-old groups, as well as a modulation of drift rate throughout training in the young group. The findings indicate that training to improve consistency induces overall slowing, but also reduces the frequency of extremely slow responses that have been linked to brief attention lapses. The results provide evidence that RT consistency is malleable, but improvements are not necessarily transferable. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475011 TI - Can working memory capacity be expanded by boosting working memory updating efficiency in older adults? AB - Working memory updating (updating) and working memory capacity (WMC) have been assumed to share a common mechanism. However, it is unclear whether WMC can be expanded by boosting the efficiency of updating, particularly during late adulthood. In this randomized controlled study, 33 older adults (aged 60 years and above, M = 69.53, SD = 5.21) were assigned to updating training (n = 17) and contact control (n = 16) groups. In the training group, updating was targeted by a running memory task and a chess game in each training session; whereas in the control group, motivational effects were estimated by their attendance to a series of mental health-related lectures. The boosted updating efficiency was demonstrated by direct training gains over sessions on updating criterion/training tasks, and significant frontocentral inflation at the N2 time range. Near transfer effects were revealed on untrained similar measures immediately after training and partly maintained at a 3-month follow-up. Far transfer effects to WMC were revealed by a significant increase in contralateral delay activity (CDA) ERP measures, although these effects did not manifest on WMC span tasks and other far transfer measures. Note that increased CDA was significantly correlated with the extent of direct gains in updating training. Our findings suggest that updating efficiency can be boosted in older adults; although it has not yet brought about an explicit expansion of WMC in our behavioral measures (i.e., on span tasks), capacity-related neural changes (i.e., on CDA) have nevertheless, started to show up in our short-term updating training program. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475012 TI - Elevated cannabis demand is associated with driving after cannabis use in a crowd sourced sample of adults. AB - Epidemiological and roadside studies suggest that driving after cannabis use (DACU) is prevalent in the United States, and rates have increased following legalization or decriminalization of cannabis in some U.S. states. Reinforcing value of addictive substances (as measured by behavioral economic demand tasks), is an emerging risk factor for driving under the influence. This study sought to expand upon the previously documented link between alcohol demand and driving after drinking by examining whether similar associations exist between cannabis demand and DACU. A large diverse sample of adults (N = 733) recruited via an online crowd-sourcing platform (Amazon Mechanical Turk) competed a validated marijuana purchase task assessing cannabis consumption across a range of prices and validated assessments of DACU, cannabis misuse, and demographics. In analyses of covariance controlling for age, sex, income, and level of cannabis misuse, individuals who endorsed DACU showed elevated cannabis demand across all demand indices examined (ps < .05). Logistic regression indicated that increased intensity of demand was uniquely associated with a greater likelihood of DACU (odds ratio [OR] = 1.61-2.02, ps < .03). Breakpoint, maximum expenditure, and price point corresponding to maximum expenditure uniquely predicted DACU in separate models (OR = 1.41-1.68, ps < .03) but not in a combined model (ORs < 1.36, ps > .47). These results provide initial evidence that elevated cannabis demand may be a distal risk factor for DACU, but future research is needed to clarify the specific relationship between cannabis demand and DACU. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475013 TI - Failed attempts to improve the reliability of the alcohol visual probe task following empirical recommendations. AB - The visual probe task (VPT) is a computerized task used to measure attentional bias to substance-related stimuli. Little research has examined the psychometric properties of the VPT, despite concerns it demonstrates poor test-retest reliability and internal consistency. These issues can reduce confidence in inferences based on VPT performance. As such, we attempted to identify parameters under which the reliability of the alcohol VPT might be improved by applying recent empirical recommendations for outlier handling, bias calculation, and task design from the anxiety literature. We reanalyzed data from 3 previously published studies in our laboratory and 2 newly collected data sets. We compared tasks which presented images on the left/right of the screen to above/below, whether participants responded to the location or content of the probe, and whether general alcohol-related images or images personalized to the individual were used. In each VPT we also applied a priori outlier removal (2 and 3 standard deviations and median absolute difference) and data-driven outlier removal (winsorizing), in addition to calculating trial-level bias scores. Across all studies and tasks internal consistency and test-retest reliability of attentional bias measures were inadequate. There was no consistent improvement in internal consistency or test-retest reliability as a function of outlier removal methods. We were unable to demonstrate adequate reliability of the alcohol VPT, which further supports observations that these tasks may not yield reliable measures. Future research should focus on improving the reliability of these tasks or abandoning them in favor of more reliable alternatives. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475014 TI - Randomized trial of working memory training as an adjunct to inpatient substance use disorder treatment. AB - Despite interest in computerized working memory training as a transdiagnostic intervention, little is known about its feasibility and efficacy in addiction treatment settings. This double-blind, randomized controlled trial examined the efficacy of working memory training for improving performance on standardized measures of executive function during inpatient substance use disorder treatment. Secondary outcomes included delay discounting, adherence to cognitive training, and posttreatment relapse. Adults (N = 110) entering inpatient alcohol or drug treatment were randomized to active (adaptive) or control (nonadaptive) training conditions, with up to 25 training sessions spanning inpatient and postdischarge phases. In generalized estimating equation (GEE) analyses, the experimental group showed relatively greater improvements on the primary outcome (digit span performance) based on Time * Treatment interactions in per-protocol (p < .05) and intent-to-treat (p = .07) models. Similar results were observed for one secondary outcome. Lower working memory performance at baseline predicted significantly greater delay discounting; however, no time or treatment effects on discounting were observed. Adherence to cognitive training was generally good during inpatient treatment, but suboptimal overall. These results suggest that implementing cognitive training is feasible in inpatient settings, and that adaptive working memory training can potentially lead to near-transfer effects for select cognitive outcomes. However, further work is necessary to establish training effects on clinical outcomes and to improve adherence in outpatient contexts. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475015 TI - Slot machine gambling and testosterone: Evidence for a "winner-loser" effect? AB - The "winner-loser effect" refers to a phenomenon in testosterone research where the outcome of a social competition induces increases (wins) and/or decreases (losses) in testosterone levels. Here, we sought to test to what extent changes in testosterone occur in response to gambling behavior. More specifically, we hypothesized that the winner-loser effect would extend to slot machine gambling as a solitary (noncompetitive) gambling activity in players who "anthropomorphized" the slot machine, thus treating the machine as a human opponent. Male participants (n = 113) were recruited into a quasi-experimental design involving 15 min of authentic slot machine gambling, incentivized by a $10 cash bonus for participants who finished in profit. In addition to salivary measures of testosterone, salivary cortisol and self-reported anthropomorphization of the slot machine were tested as potential moderators. Contrary to predictions, winning and losing slot machine sessions did not exert significant differential effects on testosterone, and this pattern was not moderated by cortisol levels or slot machine anthropomorphization. Exploratory analyses tested relationships between subjective gambling experiences in the sessions and testosterone change. Higher positive affect and flow predicted greater testosterone declines from pre- to postgambling. The testosterone results add to a growing literature on the boundary conditions of the winner-loser effect and inform future studies on testosterone reactivity in relation to gambling and disordered gambling. The tendency to anthropomorphize slot machines is a neglected cognitive distortion in gambling that merits further study. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475016 TI - Quasi-experimental evidence on short- and long-term consequences of bullying victimization: A meta-analysis. AB - Exposure to bullying victimization is associated with a wide-range of short and long-term adverse outcomes. However, the extent to which these associations reflect a causal influence of bullying victimization remains disputed. Here, we aimed to provide the most stringent evidence regarding the consequences of bullying victimization by meta-analyzing all relevant quasi-experimental (QE) studies. Multilevel random effects models and metaregression were employed to (a) estimate the pooled QE-adjusted effect size (Cohen d) for bullying victimization on outcomes and to (b) evaluate potential sources of heterogeneity. A total of 16 studies were included. We derived 101 QE-estimates from three different methods (twin design, fixed effects analysis, and propensity score matching) for three pools of outcomes (internalizing symptoms, externalizing symptoms, academic difficulties). QE-adjusted effects were small for internalizing symptoms (dadjusted = 0.27, 95% CI [0.05, 0.49]), and smaller for externalizing symptoms (dadjusted = 0.15, 95% CI [0.10, 0.21]) and academic difficulties (dadjusted = 0.10, 95% CI [0.06, 0.13]). Accounting for a shared rater effect between the exposure and the outcome further reduced the effect for internalizing (dnonshared rater = 0.14, 95% CI [0.05, 0.23]) and externalizing symptoms (dnonshared rater = 0.06, 95% CI [0.01, 0.11]). Finally, the adverse effects declined in the long term, most markedly for internalizing symptoms (dlong-term = 0.06, 95% CI [-0.01, 0.13]). Based on the most stringent evidence available to date, findings indicate that bullying victimization may causally impact children's wellbeing in the short term, especially anxiety and depression levels. The reduction of adverse effects over time highlights the potential for resilience in individuals who have experienced bullying. Secondary preventive interventions in bullied children should therefore focus on resilience and address children's preexisting vulnerabilities. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475017 TI - "The case against specialized visual-spatial short-term memory": Correction to Morey (2018). AB - Reports an error in "The case against specialized visual-spatial short-term memory" by Candice C. Morey (Psychological Bulletin, 2018[Aug], Vol 144[8], 849 883). In the article, the text describing the case reports of patient E. L. D. (Hanley, Pearson, & Young, 1990, Hanley, Young, & Pearson, 1991) the text should read that E. L. D. had difficulties compared to a control sample choosing which of 20 faces (rather than 12 faces) she had recently seen. Later in the same section, the text should read "she had little difficulty recognizing which of two familiar faces she had encountered in a recent experimental session . . . .", rather than unfamiliar. Discussion with the original authors of the case reports describing E. L. D. also clarified a methodological point in their original report (Hanley, et al., 1990). The original report says that E. L. D. was given a recognition test for which particular view of an object she observed a month later. This in fact meant that E. L. D. undertook the entire task a month later than the other tasks in the set, not that she received the recognition test a month after exposure. None of these errors impact Morey's (2018) conclusions, including the conclusion that E. L. D.'s case does not meet the criteria for an unambiguous, selective visual-spatial short-term memory deficit. (The following abstract of the original article appeared in record 2018-24700-001.) The dominant paradigm for understanding working memory, or the combination of the perceptual, attentional, and mnemonic processes needed for thinking, subdivides short-term memory (STM) according to whether memoranda are encoded in aural-verbal or visual formats. This traditional dissociation has been supported by examples of neuropsychological patients who seem to selectively lack STM for either aural verbal, visual, or spatial memoranda, and by experimental research using dual task methods. Though this evidence is the foundation of assumptions of modular STM systems, the case it makes for a specialized visual STM system is surprisingly weak. I identify the key evidence supporting a distinct verbal STM system-patients with apparent selective damage to verbal STM and the resilience of verbal short-term memories to general dual-task interference-and apply these benchmarks to neuropsychological and experimental investigations of visual spatial STM. Contrary to the evidence on verbal STM, patients with apparent visual or spatial STM deficits tend to experience a wide range of additional deficits, making it difficult to conclude that a distinct short-term store was damaged. Consistently with this, a meta-analysis of dual-task visual-spatial STM research shows that robust dual-task costs are consistently observed regardless of the domain or sensory code of the secondary task. Together, this evidence suggests that positing a specialized visual STM system is not necessary. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475018 TI - What have we learned from offender profiling? A systematic review and meta analysis of 40 years of research. AB - In the 4 decades since offender profiling (OP) was established, hundreds of journal articles, books, book chapters, reports, and magazine articles have been published on the topic, and the technique has been used by countless law enforcement agencies around the globe. However, despite the popularity and extensive literature published on OP, very little is known about its evolution, current state, or findings of the field to date. Therefore, this study presents a systematic review and meta-analysis of 426 publications on OP from 1976 through 2016. Results of this systematic review suggest that there have been considerable improvements in the scientific rigor and self-assessment being conducted in the discipline, although in total, few studies have used a strong empirical approach to develop new profiles. Even fewer evaluations of the effectiveness of OP have been conducted. The first summary of offender profiles proposed for major crimes in OP literature is also presented, with results indicating some recurrent themes in profiles, but wide variations in the number, name, and description of the profiles often found. A meta-analysis of case linkage analysis research indicates that this area is statistically sophisticated, and has yielded moderate to strong accuracy rates for linking crimes to a single offender. Finally, the first analysis of the most prolific authors, researchers, departments, and outlets for OP research, and the methods, approach, and most cited publications in OP are identified. Suggestions for future research on OP and the potential impact that this may have on policy and practice are also discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475019 TI - Parental alienating behaviors: An unacknowledged form of family violence. AB - Despite affecting millions of families around the world, parental alienation has been largely unacknowledged or denied by legal and health professionals as a form of family violence. This complex form of aggression entails a parental figure engaging in the long-term use of a variety of aggressive behaviors to harm the relationship between their child and another parental figure, and/or to hurt the other parental figure directly because of their relationship with their child. Like other forms of family violence, parental alienation has serious and negative consequences for family members, yet victims are often blamed for their experience. In order to be recognized as a form of family violence and to secure protection for victims under law and social policies, a formal review and comparison of parental alienating behaviors and outcomes to child abuse and intimate partner violence has been sorely needed. The result of this review highlights how the societal denial of parental alienation has been like the historical social and political denial or other forms of abuse in many parts of the world (e.g., child abuse a century ago). Reframing parental alienating behaviors as a form of family violence also serves as a desperate call to action for social scientists to focus more theoretical and empirical attention to this topic. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475020 TI - The role of rearrests in juvenile offenders' and their mothers' attitudes toward police. AB - Both personal experience and parental attitudes shape youths' attitudes toward the justice system. The present study tested the influence of (a) youth rearrests and (b) parents' attitudes toward police on trajectories of youthful offenders' attitudes toward police over 3 years. Among a sample of 317 first-time male juvenile offenders and their mothers, group-based trajectory modeling identified 4 trajectories of youths' attitudes toward police over the 3 years since the youths' first arrests. Mothers with more positive initial attitudes toward the police were more likely to have sons who were part of 1 of the 2 positive attitude trajectory groups than the 2 negative attitude trajectory groups. In contrast, youth rearrests were rarely associated with trajectory group membership, suggesting that a mother's attitude toward the police may outweigh a youth's own experience (via arrests) with the justice system in determining trajectories of his attitudes toward the police. Additionally, the present study tests whether parents' own attitudes toward police are predicted by their children's rearrests. We found that mothers whose sons were rearrested during the study period had more negative attitudes toward the police. The results add a novel component to our understanding of family attitude dynamics as related to perceptions of law enforcement and juvenile arrests. Overall, a family level perspective is necessary when considering the effects of rearrests on youths'-and their parents'-attitudes toward the police. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475021 TI - Negative evidence and inductive reasoning in generalization of associative learning. AB - When generalizing properties from known to novel instances, both positive evidence (instances known to possess a property) and negative evidence (instances known not to possess a property) must be integrated. The current study compared generalization based on positive evidence alone against a mixture of positive evidence and perceptually dissimilar negative evidence in an interdimensional discrimination procedure. In 2 experiments, we compared generalization following training with a single positive stimulus (that predicted shock) against groups where an additional negative stimulus (that did not predict shock) was presented in a causal judgment (Experiment 1) and a fear conditioning (Experiment 2) procedure. In contrast to animal conditioning studies, we found that adding a "distant" negative stimulus resulted in an overall increase in generalization to stimuli varying on the dimension of the positive stimulus, consistent with the inductive reasoning literature. We show that this key qualitative result can be simulated by a Bayesian model that incorporates helpful sampling assumptions. Our results suggest that similar processes underlie generalization in inductive reasoning and associative learning tasks. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475022 TI - Capacity limitations of dishonesty. AB - Cognitive theories of dishonesty revolve around an automatic activation of honest response tendencies, which is assumed to impair response selection for the intended dishonest response. Clear-cut evidence for the claim is still limited, however. We therefore present a novel approach to dishonest responding that takes advantage of psychological refractory period methodology. Four experiments yielded evidence supporting the assumption of prolonged response selection during dishonest responding. Moreover, they also showed differences in early response activation and they revealed additional downstream consequences of this behavior that are currently not sufficiently covered by common theoretical models. Notably, these downstream consequences included increased monitoring relative to honest behavior. Our results thus provide an extensive coverage of the cognitive architecture of dishonest responses, informing current theorizing while simultaneously grounding the assumed processes in the framework of sensorimotor stage models of information processing. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475023 TI - Helping consumers to evaluate annual percentage rates (APR) on credit cards. AB - To help consumers make informed decisions, regulators often impose disclosure requirements on financial institutions. However, disclosures may not be informative for consumers if they contain difficult-to-evaluate attributes, such as annual percentage rates (APRs). To improve a consumer's ability to evaluate the relative attractiveness of products with difficult-to-evaluate attributes, evaluability theory suggests providing consumers with distributional information. Here, we tested whether credit card disclosures containing graphs of the distribution of APRs in the credit card market help consumers estimate the relative costs of credit and evaluate credit cards. In two studies, we found that consumers using standard credit card disclosures (without distributional information) underestimated the costs of credit card APRs relative to the market. We then built on the graph design literature to design different graphs for presenting distributional APR information. A comparison of the graphs we designed showed that a histogram was most successful at improving consumers' estimates of APR costs relative to the market and modifying consumers' evaluations of an expensive credit card. We discuss the implications of our findings for evaluability theory, graph design, and communication efforts that aim to provide consumers with meaningful financial disclosures. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475024 TI - Perceiving faces: Too much, too fast?-face specificity in response caution. AB - Faces are a major source of information in social interaction. The ability to perceive and interpret faces thus carries paramount importance in people's social lives. However, this crucial ability is not yet fully understood. Individual differences studies show that the speed and accuracy of face cognition (including perception and memory/recognition), the two facets targeted when measuring cognitive performance, are relatively independent traits. Unlike accuracy data, individual differences in reaction times (RTs) measured in perceptual decision tasks with or without memory load using faces and objects, do not show face specific variance. Here, we applied the diffusion model to RT and accuracy data captured by simple perceptual decision tasks to improve understanding of the lack of face specificity. If performance speed in face cognition tasks is truly a global, nonspecific individual ability, no parameter of the diffusion model should hold face specificity. In a study on adults (N = 217), we administered two tasks of face and object perception. We used individually estimated diffusion model parameters as manifest variables to study face specificity in drift rate (nu), boundary separation (a), and nondecision time (Ter) using structural equation modeling. Furthermore, to study differential relationships between diffusion model parameters and measures of cognitive abilities, we regressed factors of face and object cognition accuracy on factors of diffusion model parameters. The results revealed face specificity only in boundary separation. This suggests face-specific adjustment in the cautiousness of information processing. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475025 TI - Stimulus-based and task-based attention modulate auditory stream segregation context effects. AB - Previous studies have shown that perceptual segregation increases after listening to longer tone sequences, an effect known as buildup. More recently, an effect of prior frequency separation (Deltaf) has been discovered: presenting tone sequences with a small Deltaf biases following sequences with an intermediate Deltaf to be segregated into two separate streams, whereas presenting context sequences with a large Deltaf biases following sequences to be integrated into one stream. Here we investigated how attention and task demands influenced these effects of prior stimuli by having participants perform one of three tasks during the context: making streaming judgments on the tone sequences, detecting amplitude modulation in the tones, and performing a visual task while ignoring the tones. Results from two experiments showed that although the effect of prior Deltaf was present across all conditions, the effect was reduced whenever streaming judgments were not made during the context. Experiment 2 showed that streaming was reduced during the beginning of a test sequence only when participants performed the visual task during the context. These experiments suggest that task-based and stimulus-based attention differentially affect distinct influences of prior stimuli, and are consistent with the contribution of distinct levels of processing that affect auditory segregation. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475027 TI - Cultural differences in the age-related positivity effect: Distinguishing between preference and effectiveness. AB - Prior studies have found mixed results regarding whether there are cultural differences in the age-related positivity effect, defined as older adults' showing a greater bias in cognitive processing for positively over negatively and neutrally valenced information relative to younger adults. This study attempted to address this controversy by examining visual attention toward culturally relevant versus irrelevant pictures that differed in valence among younger and older U.S. Americans and Hong Kong Chinese. Preferences (attentional biases toward particular valence) and effectiveness (whether the attentional biases are associated with better mood) were also distinguished. Findings revealed that regardless of cultural relevance of the pictures, older U.S. Americans showed more gaze preference for positive over negative pictures compared to their younger counterparts; this age difference was not found among Hong Kong Chinese. In contrast, older Hong Kong Chinese showed better mood as a function of more gaze preference for positive over negative pictures. Younger Hong Kong Chinese and younger and older U.S. Americans did not show this association. The results suggest that an age-related positivity effect exists at the preference level for U.S. Americans but at the effectiveness level for Chinese. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475026 TI - Context facilitates performance on a classic cross-cultural emotion perception task. AB - The majority of studies designed to assess cross-cultural emotion perception use a choice-from-array task in which participants are presented with brief emotion stories and asked to choose between target and foil cues. This task has been widely criticized, evoking a lively and prolonged debate about whether it inadvertently helps participants to perform better than they otherwise would, resulting in the appearance of universality. In 3 studies, we provide a strong test of the hypothesis that the classic choice-from-array task constitutes a potent source of context that shapes performance. Participants from a remote small-scale (the Hadza hunter-gatherers of Tanzania) and 2 urban industrialized (China and the United States) cultural samples selected target vocalizations that were contrived for 6 non-English, nonuniversal emotion categories at levels significantly above chance. In studies of anger, disgust, fear, happiness, sadness, and surprise, above chance performance is interpreted as evidence of universality. These studies support the hypothesis that choice-from-array tasks encourage evidence for cross-cultural emotion perception. We discuss these findings with reference to the history of cross-cultural emotion perception studies, and suggest several processes that may, together, give rise to the appearance of universal emotions. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475028 TI - Are emotion recognition abilities intact in pediatric ADHD? AB - Extant studies suggest that children with attention-deficit/hyperactivity disorder (ADHD) may make more errors and respond more slowly on tasks that require them to identify emotions based on facial affect. It is unclear, however, whether these findings reflect a unique deficit in emotion recognition, or more general difficulty with choice-response tasks (i.e., tasks that require participants to select among a set of competing options). In addition, ADHD is associated with executive dysfunction, but there is inconsistent evidence regarding the extent to which top-down cognitive control is involved in emotion recognition. The current study used a series of four counterbalanced tasks to systematically manipulate emotional content and working memory demands to determine (a) whether children with ADHD exhibit a unique facial affect recognition deficit and (b) the extent to which facial affect recognition is an automatic versus controlled process that depends in part on working memory. Bayesian results from a carefully phenotyped sample of 64 children ages 8 to 13 (M = 10.42, SD = 1.56; 26 girls; 67% Caucasian/non-Hispanic) with ADHD (n = 35) and without ADHD (n = 29) indicated that working memory is involved in children's ability to efficiently infer emotional state from facial affect (BF10= 4.59 * 1014). Importantly, there was significant evidence against deficits in emotion recognition for children with ADHD. The ADHD/non-ADHD groups were statistically equivalent in terms of recognition accuracy (BF01 = 1.32 * 1054, d = -0.18), and the ADHD group's slower recognition speed was parsimoniously explained by difficulty with choice-response tasks rather than unique to emotional stimuli (BF10 = 3.23, d = 0.31). These findings suggest that emotion recognition abilities are intact in children with ADHD, and highlight the need to control for impaired bottom-up (choice-response) and top-down abilities (working memory) when investigating emotional functioning in ADHD. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475029 TI - Functional divergence of two threat-induced emotions: Fear-based versus anxiety based cybersecurity preferences. AB - Two threat-induced emotions and their respective ability to sway cybersecurity preferences were investigated after a cyberattack on financial institutions. Our theoretical aim was to advance the functionalist claim and differentiate between fear and anxiety by their action tendencies. The emotions were expected to have unique motivation power and thus show mutually exclusive ties to the three types of safety behaviors emerged in our study. Avoidance would be uniquely embraced by fearful participants, whereas surveillance and vigilance would uniquely appeal to anxious participants. Study 1 (N = 199) used a cross-sectional design and found full support for the hypothesis regarding anxiety but only partial support for the hypothesis regarding fear. Study 2 (N = 304), an experiment of fearful, anxious, and relaxed groups, did not yield significant results but did offer methodological recommendations. The quasi-experiments in Study 3 (N = 120) and Study 4 (N = 156) supported the hypotheses on fear and anxiety. Our results in the novel domain of cyber threat brought new evidence to bear on the mixed literature on fear and anxiety. A discussion is offered on the methodological challenges of differentiating two closely related emotions as well as implications for the emerging debate of cybersecurity solutions. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475030 TI - Not in front of the kids: Effects of parental suppression on socialization behaviors during cooperative parent-child interactions. AB - Parents often try to hide their negative emotions from their kids, hoping to protect them from experiencing adverse responses. However, suppression has been linked with poor social interactions. Suppression may be particularly damaging in the context of parent-child relationships because it may hinder parents' ability to support children's emotion regulation. Immediately after completing a stressful task, 109 parents of 7 to 11 year olds were randomly assigned to a suppression condition or a control condition during an interaction with their child. Children were given a set of instructions with pictures to build a Lego house and told to verbally instruct their parent without touching the Legos themselves. Trained research assistants coded parents' and children's positive and negative mood, responsiveness, warmth, parents' guidance, and the quality of the interaction. We found that suppression decreased parents' observed positive mood, responsiveness, warmth, and guidance, as well as children's observed positive mood, responsiveness, and warmth, and decreased the overall dyadic interaction quality. However, parent sex played a significant role in moderating these effects. Fathers in the suppression condition were less responsive and warm than control fathers, though children interacting with their fathers did not exhibit decrements in responsiveness or warmth. In contrast, children of suppressing mothers appeared less warm than children of mothers in the control condition, though suppressing mothers did not exhibit decrements in their observed warmth or responsiveness relative to control mothers. Taken together, these findings suggest that the desire to hide one's feelings from one's children may have unwanted negative consequences but may differ for fathers versus mothers. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475031 TI - A brief behavioral measure of frustration tolerance predicts academic achievement immediately and two years later. AB - Achieving important goals is widely assumed to require confronting obstacles, failing repeatedly, and persisting in the face of frustration. Yet empirical evidence linking achievement and frustration tolerance is lacking. To facilitate work on this important topic, we developed and validated a novel behavioral measure of frustration tolerance: the Mirror Tracing Frustration Task (MTFT). In this 5-min task, participants allocate time between a difficult tracing task and entertaining games and videos. In two studies of young adults (Study 1: N = 148, Study 2: N = 283), we demonstrated that the MTFT increased frustration more than 18 other emotions, and that MTFT scores were related to self-reported frustration tolerance. Next, we assessed whether frustration tolerance correlated with similar constructs, including self-control and grit, as well as objective measures of real-world achievement. In a prospective longitudinal study of high school seniors (N = 391), MTFT scores predicted grade-point average and standardized achievement test scores, and-more than 2 years after completing the MTFT-progress toward a college degree. Though small in size (i.e., rs ranging from .10 to .24), frustration tolerance predicted outcomes over and above a rich set of covariates, including IQ, sociodemographics, self-control, and grit. These findings demonstrate the validity of the MTFT and highlight the importance of frustration tolerance for achieving valued goals. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475032 TI - Sex moderates the relationship between resting heart rate variability and self reported difficulties in emotion regulation. AB - Lower resting vagally mediated heart rate variability (HRV) is thought to reflect poorer function of the neurophysiological pathways underlying emotion regulation (ER) and thus, poorer ER abilities. Sex differences in resting HRV exists such that women typically exhibit higher resting HRV than men. It is proposed that greater HRV in women reflects compensation for greater negative affect such as anxiety and depression. However, research has not yet investigated how the association between resting HRV and every day perceived difficulties in ER may be moderated by sex. The current study sought to test this in a sample of 362 young participants (207 females, mean age of 19). Resting HRV was assessed during a 5 min baseline period using an electrocardiogram. Participants then completed the 36-item Difficulties in Emotion Regulation Scale (DERS) designed to evaluate participant's daily difficulties in ER. Controlling for several covariates, sex significantly moderated the relationship between resting HRV and ER difficulties, such that women showed a much stronger relationship compared with men. Specifically, women with lower HRV reported greater difficulties in ER compared with men with lower HRV, whereas women with higher HRV reported slightly lesser difficulties in ER compared with all men. Overall, this study supports a deeper understanding of how neurophysiological differences in ER between men and women as indexed by resting HRV-may contribute to how effectively individuals regulate their emotions on a day-to-day basis, with implications for well-being. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475033 TI - Capturing naturally occurring emotional suppression as it unfolds in couple interactions. AB - Most research examining the consequences of suppressing emotional expression has focused on either experimentally manipulated and conscious suppression, or self reported suppression behavior. This study examined suppression as it naturally occurred in couple (n = 105) discussions regarding a challenging topic. A Suppression Index (SI) was created by calculating the difference between continuous self-reports of emotional experience, obtained using cued video recall, and coders' continuous ratings of expressed emotion. Suppression was common for both men and women, though there was also substantial individual variation. Autocorrelations of the SI were used to tap suppressive rigidity (Srig), or the tendency to inflexibly use suppression throughout the discussions. Srig scores were consistent within individuals across repeated conversations and varied across individuals, suggesting that Srig captures stable individual differences. Women's greater suppression of negative emotions combined with more rigid use of suppression was associated with their own lower relationship satisfaction but not their partners'. These findings indicate that suppressive behavior may be linked to relationship quality, and that it is not just the use of suppression that may matter but how rigidly one applies this regulatory approach. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475034 TI - 2:0 for the good guys: Character information influences emotion perception. AB - Previous research has demonstrated that facial social category cues influence emotion perception such that happy expressions are categorized faster than negative expressions on faces belonging to positively evaluated social groups. We examined whether character information that is experimentally manipulated can also influence emotion perception. Across two experiments, participants learned to associate individuals posing neutral expressions with positive or negative acts. In a subsequent task, participants categorized happy and angry expressions of these same individuals as quickly and accurately as possible. As predicted, a larger happy face advantage emerged for individuals associated with positive character information than for individuals associated with negative character information. These results demonstrate that experimentally manipulated evaluations of an individual's character are available quickly and affect early stages of face processing. Emotion perception is not only influenced by preexisting attitudes based on facial attributes, but also by information about a person that has been recently acquired. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475035 TI - Does priming negative emotions really contribute to more positive aesthetic judgments? A comparative study of emotion priming paradigms using emotional faces versus emotional scenes and multiple negative emotions with fEMG. AB - An outstanding question in empirical aesthetics concerns whether negative emotions (e.g., fear, disgust) can improve aesthetic judgments of liking. Although negative emotions are sometimes linked with enjoyment in music or visual design/art, emotion priming studies have shown conflicting results, reporting both more negative and more positive assessments. These divergences may be driven by key differences in priming procedures. Specifically, past studies' use of either emotional faces or emotional scenes as primes as well as differing negative emotion content (fear, disgust) may involve differing processes leading to opposing effects, particularly in aesthetic judgments. To differentiate among these, we presented emotion primes (20 ms) consisting of either emotional faces or scenes, further subdivided in disgusting, fearful, neutral, or positive emotional content and tested how liking, valence, and arousal ratings of abstract patterns were affected. Additionally, facial electromyography (fEMG) over M. frontalis (indicator of fear), M. levator labii (disgust), and M. zygomaticus (positive) muscles was recorded, to see whether primes would elicit prime-emotion congruent changes. However, fEMG activations indicated no prime congruent changes. Critically, primes influenced ratings in an emotion congruent manner in both faces and emotional scenes. Stimuli were rated as more liked and positively valenced after positive primes and less liked/more negatively valenced after fear or disgust primes. The similarity of priming effects in both prime types in absence of congruent fEMG changes may suggest that priming exerts its influence via a cognitive rather than a more immediate emotional route. Overall-at least in emotional priming-negative emotions seem to be incompatible with higher liking. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475036 TI - A multi-semester classroom demonstration yields evidence in support of the facial feedback effect. AB - The facial feedback effect refers to the influence of unobtrusive manipulations of facial behavior on emotional outcomes. That manipulations inducing or inhibiting smiling can shape positive affect and evaluations is a staple of undergraduate psychology curricula and supports theories of embodied emotion. Thus, the results of a Registered Replication Report indicating minimal evidence to support the facial feedback effect were widely viewed as cause for concern regarding the reliability of this effect. However, it has been suggested that features of the design of the replication studies may have influenced the study results. Relevant to these concerns are experimental facial feedback data collected from over 400 undergraduates over the course of 9 semesters. Circumstances of data collection met several criteria broadly recommended for testing the effect, including limited prior exposure to the facial feedback hypothesis, conditions minimally likely to induce self-focused attention, and the use of moderately funny contemporary cartoons as stimuli. Results yielded robust evidence in favor of the facial feedback hypothesis. Cartoons that participants evaluated while holding a pen or pencil in their teeth (smiling induction) were rated as funnier than cartoons they evaluated while holding a pen or pencil in their lips (smiling inhibition). The magnitude of the effect overlapped with original reports. Findings demonstrate that the facial feedback effect can be successfully replicated in a classroom setting and are in line with theories of emotional embodiment, according to which internal emotional states and relevant external emotional behaviors exert mutual influence on one another. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475037 TI - Perceptions of the competent but depressed. AB - Accurately recognizing and remembering the depressive symptoms of other people can be crucial in helping those suffering from depression. Yet, lay theories about depression might interfere with accurate perception or recollection of depression in others. The current study examined whether laypersons would misremember depressive symptoms in highly competent people as being less severe than they actually are. Participants first read a target vignette about a character displaying depressive symptoms, whereas the level of competency of the target character varied across different conditions. Then, participants read a foil vignette describing a character with similar depressive symptoms, which was intended to elicit memory errors for the target vignette. When the foil vignette described that the depressive symptoms were eventually overcome, participants were more likely to false-alarm the recovery as the competent character's than as the less competent character's (Experiment 1a). Conversely, when the foil vignette's depressive symptoms were described to be highly severe, participants were less likely to false-alarm them as the competent character's symptoms than as the less competent character's symptoms (Experiment 2a). This phenomenon appears to be unique to laypeople's perception of depression, as the same pattern of results was not obtained when the participants were mental health clinicians (Experiments 1b and 2b) or when laypeople participants read about symptoms of physical disorders or other mental disorders (Experiment 3). Taken together, the current study presents novel findings suggesting that competent people's depression is underdetected by laypeople. The implications and the limitations of the study are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475038 TI - Expectancies influence attention to neutral but not necessarily to threatening stimuli: An fMRI study. AB - Recent behavioral observations suggest an influence of prior expectancies on attention to neutral targets, whereas the detection of threatening targets remains comparably immune to these expectancies. The origin of this asymmetry, however, remains unclear. Here, therefore, we investigated its neural basis by using fMRI. Specifically, we tested whether, in accordance with the idea of a resetting attentional system during phylogenetic threat detection, neural responses for threatening compared with neutral targets would remain largely unaffected by prior expectancies. Alternatively, neural responses could reflect equally strong expectancy influences on both types of targets, with the respective patterns differing, thereby producing the asymmetric effect observed in behavior. Predictive cues in our study evoked specific behavioral and neural expectancy states and effectively modulated response latencies to detect neutral (bird) targets in a 3 * 3 visual search matrix: When threat-related (spider) rather than neutral targets were expected, bird detection was considerably slowed, and the neural response to expected birds differed from that to unexpected birds. Conversely, and in line with the hypothesis of a resetting attentional system for phylogenetic threat, expectancy cues had no impact on RTs or neural responses for spider targets-either in spider phobic participants or in non-spider-fearful control participants. Our data support the idea of bottom-up enhancement of threat-related information through processing pathways unaffected by top-down modulatory influences such as expectancy. These pathways may subserve rapid and comparably automatic responding to threat stimuli by safeguarding independence from more controlled and explicit expectancies, consequently promoting adaptive behavior and survival. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475039 TI - Actions speak louder than outcomes in judgments of prosocial behavior. AB - Recently proposed models of moral cognition suggest that people's judgments of harmful acts are influenced by their consideration both of those acts' consequences ("outcome value"), and of the feeling associated with their enactment ("action value"). Here we apply this framework to judgments of prosocial behavior, suggesting that people's judgments of the praiseworthiness of good deeds are determined both by the benefit those deeds confer to others and by how good they feel to perform. Three experiments confirm this prediction. After developing a new measure to assess the extent to which praiseworthiness is influenced by action and outcome values, we show how these factors make significant and independent contributions to praiseworthiness. We also find that people are consistently more sensitive to action than to outcome value in judging the praiseworthiness of good deeds, but not harmful deeds. This observation echoes the finding that people are often insensitive to outcomes in their giving behavior. Overall, this research tests and validates a novel framework for understanding moral judgment, with implications for the motivations that underlie human altruism. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475040 TI - Treatment choice among veterans with PTSD symptoms and substance-related problems: Examining the role of preparatory treatments in trauma-focused therapy. AB - Although common practice in Veterans Affairs (VA) PTSD clinics, it is unclear whether preparatory treatment improves trauma-focused treatment (TFT) completion and outcomes. Furthermore, little is known about whether treatment-seeking veterans in naturalistic settings would chose to prioritize preparatory treatment if given the option of a phase-based approach or direct access to TFT, and how substance-related problems (SRPs) influence this treatment choice. The first aim of this study was to explore how co-occurring SRPs (ranging from none to moderate/severe) influence PTSD treatment choices in a naturalistic setting where veterans were offered a choice between a phase-based approach (i.e., preparatory treatment) or direct access to TFT. The study also examined whether initial treatment choice and severity of co-occurring SRPs influenced TFT completion and outcomes. The second aim was to investigate whether preparatory treatment led to superior TFT completion or outcomes, irrespective of co-occurring SRPs. Analyses were conducted using archival data from 737 United States veterans referred for outpatient VA PTSD treatment. SRPs did not predict initial treatment choice or the length of preparatory group participation. Neither SRPs nor preparatory group participation predicted TFT completion or outcomes (measured as change in PTSD and depression symptoms from pre- to post-TFT). Preparatory group participation did not predict improved TFT completion or outcomes, irrespective of co-occurring SRPs. These findings suggest that veterans with PTSD symptoms and co-occurring SRPs may make similar treatment choices and benefit from either a phase-based approach or direct TFT initiation, and preparatory treatments may not increase patient readiness for veterans seeking TFT. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475041 TI - "It didn't fit for me:" A qualitative examination of dropout from prolonged exposure and cognitive processing therapy in veterans. AB - Trauma-focused psychotherapies, such as prolonged exposure and cognitive processing therapy, are the most effective forms of treatment for posttraumatic stress disorder. These treatments are commonly delivered in the Veterans Health Administration; however, dropout means that some veterans fail to benefit. Ending treatment prematurely is a common problem across psychotherapies, with on average, 20% to 25% of patients dropping out. The purpose of this study was to examine veterans' self-reported reasons for dropping out of prolonged exposure or cognitive processing therapy. Veterans who dropped out from prolonged exposure or cognitive processing therapy (N = 28) completed qualitative interviews about their experiences. Interviews were coded by 2 coders using grounded theory. Therapy-related barriers were the largest category reported, and included lack of buy-in to the rationale or specific therapy tasks, believing that treatment was not working, alliance issues, or switching to a different treatment. Practical barriers and finding treatment "too stressful" were also common reasons for dropout. This research provides information that can shape how PTSD treatments are delivered in health care settings. Therapy-related barriers were the largest group, suggesting that providers may need to find more effective ways to communicate the rationale for these therapies or to tailor them to individual patients' needs. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475042 TI - Factor structure and validity of the SIQ-JR in a southwest American Indian tribe. AB - Previous literature is severely limited in evaluation of psychometric properties of suicide screening methods in American Indian (AI) populations, despite the disproportionate burden of suicide faced within AI communities. The purpose of the current study was to examine the psychometric properties of the Suicidal Ideation Questionnaire-Junior (SIQ-JR) for AI youth using 2 community samples of AI adolescents from a Southwestern tribe. The present study sample was comprised of 114 participants (n = 91 and n = 23), ages 10-19 years of age, from 2 studies, both of which were administered the SIQ-JR within 90 days of an index suicide attempt. Findings indicated that a two-factor model resulted in appropriate fit indices with AI youth, a general ideation index and an active ideation index. Scores on the active ideation and general ideation indices were also related to cumulative stress, self-reported suicidal ideation and previous suicide attempt, providing a measure of convergent validity. Finally, use of cutpoint of 20, rather than published cutpoint of 31, evidenced marginally better positive and negative predictive values, with sensitivity within acceptable ranges. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475043 TI - A pilot randomized controlled trial evaluating a web-based training program on pediatric medical traumatic stress and trauma-informed care for emergency department staff. AB - This pilot parallel group superiority randomized controlled trial investigated the efficacy and acceptability of a web-based training program on pediatric medical traumatic stress and trauma-informed care (Australian and New Zealand Clinical Trials Registry number: ACTRN12617001148369). Eligibility criteria for this study included being a nurse or physician working in an ED in Australia or New Zealand, being fluent in English and having Internet access. Emergency department (ED) staff (N = 71) were randomly assigned into the training (n = 32) or control group n = 39). We hypothesized that compared to the control group, ED staff in the training group would show a greater improvement in knowledge of pediatric medical traumatic stress 1-week post training and that improvement would be maintained at 1-month post training. At baseline participants completed a brief questionnaire assessing knowledge of pediatric medical traumatic stress. The training group then completed the 15-min online training program. The knowledge questionnaire was readministered to all participants' 1 week and 1 month posttraining, after which the control group gained access to the training. Acceptability was based on a program evaluation measure utilizing quantitative and qualitative items. The training group had significantly greater knowledge following training and at follow-up than the control group (p > .001, f = .42) and reported high rates of satisfaction. The results demonstrated an improvement in ED staff knowledge as a result of the training and provide preliminary support for the efficacy and acceptability of brief online training to improve the knowledge of ED staff interested in pediatric medical traumatic stress and trauma informed care. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475044 TI - Empirically-guided assessment of complex trauma for children in foster care: A focus on appropriate diagnosis of attachment concerns. AB - Complex trauma is defined as repeated or prolonged exposure to traumatic events perpetrated within the caregiving relationship during early childhood. Diagnostic decision making is challenging for this vulnerable population, given the widespread impact of these experiences across domains of developmental, social, emotional, and behavioral functioning. One domain, attachment, receives considerable attention for youth within the child welfare system, leading to frequent diagnosis of attachment disorders (i.e., reactive attachment disorder and disinhibited social engagement disorder). This is concerning, given the rarity, level of misunderstanding, associated stigma, and lack of psychometrically sound measures to assess attachment disorders. This article provides an overview of complex trauma and its effects, with a focus on attachment concerns. It subsequently describes one statewide assessment program for youth in the child welfare system with a history of experiencing complex trauma, elaborating on strengths and areas of future growth. A case study demonstrates the program's adherence to established guidelines and the resulting diagnoses and recommendations. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475045 TI - Trauma-informed care in a patient-centered medical home for adolescent mothers and their children. AB - Adolescent mothers experience higher rates of trauma and abuse, as well as increased risks for mental health disorders, compared to adolescent girls who are not mothers, making them a particularly vulnerable population and contributing to them feeling less supported by or allied with their medical provider. Women with a history of childhood abuse face increased rates of obstetric complications; their infants are at increased risk for low birthweight, developmental and intellectual delays, and behavioral problems. Trauma-informed care has become widespread in mental health settings; however, this model has not been as commonly applied to other settings, such as patient-centered medical homes (PCMHs). The Colorado Adolescent Maternity Program (CAMP) is an obstetric and pediatric medical home for pregnant and parenting adolescent girls through age 22 and their children located within Children's Hospital Colorado. With the integration of behavioral health into CAMP, and given the prevalence of trauma histories among adolescent mothers reported in the literature, programmatic and operational changes to clinical care were made using the Substance Abuse and Mental Health Services Administration's six key principles of a trauma-informed approach. Data showed that nearly 30% of participants reported a history of trauma. Following the inclusion of trauma-informed principles, patients had significantly higher rates of attendance at prenatal appointments (p < .001) and significantly lower rates of low birthweight babies (p = .02). Future programmatic changes and long-term assessment outcomes of this trauma-informed approach in a PCMH are also discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475046 TI - Implementation of a standardized screening program for risk of posttraumatic stress disorder among youth hospitalized with injury. AB - Children with pediatric injury and their parents are at risk for developing posttraumatic stress disorder (PTSD). Although challenging to implement, standardized screening for risk of developing PTSD can identify families most at risk. The current retrospective, chart review study evaluated the implementation of a clinical program that integrated screening for risk of PTSD into standard care for youth admitted to a Level I pediatric trauma center due to injury. Advanced practice nurses administered the Screening Tool for Early Predictors of PTSD (STEPP), a brief screen that evaluates risk of developing PTSD for injured children (ages 8-17 years) and their parents. Positive parent or child STEPPs prompted a referral to psychology for an inpatient consultation. Data were collected via review of electronic medical records and trauma program registry, including demographic, injury, and admission information, completion of and result on the STEPP, and completion of a psychology consultation. During the 2.5 year study period, 1,153 youth (birth-17 years) were admitted due to injury. Among those eligible for the STEPP (i.e., >=8 years; N = 562), 67% completed the STEPP. Among those who completed the STEPP, 25% had positive parent or child screens and 68% of these completed an inpatient psychology consultation. Standardized screening was related to significantly higher use of inpatient psychology services compared with a control sample not eligible for screening (i.e., <8 years). STEPP scores varied by demographic, admission and injury factors. Results suggest standardized screening is feasible and improves reach of trauma-informed care. Barriers and facilitators of this screening program are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475048 TI - Contributions of olfactory and neuropsychological assessment to the diagnosis of first-episode schizophrenia. AB - OBJECTIVE: First-episode schizophrenia and schizoaffective patients (SZ+) show olfactory impairments, but how these relate to cognitive dysfunction remains unclear. We examined the relationship between cognitive and olfactory dysfunction in SZ+ and the clinical utility of these measures in the assessment of SZ+ patients. METHOD: First-episode SZ+ patients (n = 63) and controls (n = 63) were administered tests of odor identification and discrimination in addition to measures of manual dexterity, processing speed, attention and working memory, executive functioning, ideational fluency, and memory. We analyzed the relationships between olfactory and cognitive variables and conducted stepwise multiple regressions to identify which cognitive indices best predicted olfactory performance within the SZ+ group. Linear discriminant analysis was used to identify which measures best distinguished cases from controls. RESULTS: Among patients, odor discrimination correlated with perseverative errors and odor identification correlated with bilateral manual dexterity. Odor discrimination performance was best predicted by perseverative errors and letter fluency, whereas odor identification ability was best predicted by manual dexterity. Stepwise linear discriminant analysis revealed that manual dexterity, letter guided word fluency, and odor discrimination best distinguished SZ+ from healthy adults. CONCLUSIONS: These findings indicate that manual dexterity, letter-guided word fluency, and odor discrimination may provide incremental information that strengthens a diagnosis of SZ+. Although odor discrimination tasks have received limited attention in schizophrenia studies, the extant data along with the present results indicate that odor discrimination tasks may have utility over odor identification measures as a neurodevelopmental risk marker. Additional studies examining odor discrimination as a predictor of SZ spectrum illness are warranted. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475047 TI - Information processing deficit in older adults with HIV infection: A comparison with Parkinson's disease. AB - OBJECTIVE: Individuals with HIV treated with antiretroviral therapy can expect to reach average life span, making them susceptible to combined disease and aging effects on cognitive and motor functions. Slowed processing speed in HIV is a concern for cognitive and everyday functioning and is sensitive to declines in aging. We hypothesized that information processing (IP) deficits, over and above that expected with normal aging, would occur in older HIV patients similar to those observed in Parkinson's disease (PD) patients, with both conditions affecting frontostriatal pathways. METHOD: Groups comprised 26 individuals with HIV infection, 29 with mild-to-moderate PD, and 21 healthy controls (C). Speed of IP was assessed with the oral version of the Symbol Digit Modalities Test and the color naming condition of the Golden Stroop Task. RESULTS: The HIV group was impaired on speed of IP tasks compared with both the C and PD groups. Even after controlling for normal aging effects, older age in the HIV group correlated with IP slowing. Slower IP speed was associated with poorer general cognitive ability and more extrapyramidal motor signs in older HIV-infected individuals. CONCLUSIONS: The notable effects of impaired IP speed, over and above neurotypical age-related declines, indicate that older HIV-infected individuals may have an enhanced vulnerability for developing nonmotor and motor symptoms despite antiretroviral therapy. Assessing for oral IP speed may provide the unique opportunity to identify early signs of progressive clinical declines in HIV. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475049 TI - Lesion symptom mapping at the regional level in patients with a meningioma. AB - OBJECTIVE: The majority of meningioma patients suffer from presurgical cognitive deficits. Since meningiomas do not directly damage the brain, this is presumably caused by a functional integrity reduction of the surrounding brain tissue through perilesional edema and/or mass effect of the tumor. Tumor location is a key feature in determining neurological symptoms in brain tumor patients, but the relationship between meningioma location and cognitive performance remains unclear. This study aimed to identify brain areas where the presence of a meningioma forms a potential risk factor for worse cognitive performance as compared to meningiomas at other locations. METHOD: Neuropsychological data (CNS Vital Signs) and MRI were collected in 224 meningioma patients one day before surgery. Sociodemographically corrected scores were calculated for 7 cognitive domains. Tumors were semiautomatically segmented and mapped into MNI-space for use in Statistical Region of Interest analyses. For each cognitive domain, we tested whether larger proportions of tumor overlap with each of the 150 defined regions were associated with worse performance. RESULTS: After multiple comparison (Bonferroni) and lesion volume correction, larger proportions of tumor overlap with both the left middle and superior frontal gyrus were associated with worse complex attention scores. Larger proportions of tumor overlap with the left middle frontal gyrus were associated with worse cognitive flexibility scores. For the other domains, no association between tumor overlap with a region and cognitive performance was found. CONCLUSIONS: The current results suggest that, compared to patients with a meningioma at other locations, patients with a meningioma at the left middle frontal gyrus are at potential risk for worse performance on cognitive flexibility and complex attention whereas patients with a meningioma at the left superior frontal gyrus are at potential risk for worse performance on complex attention. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475050 TI - Training mental health activists increases the well-being of participants with high baseline levels of self-stigma: Results of the Obertament training evaluation. AB - There is a strong interest in improving the quality of anti-stigma contact-based interventions. Hence, some mental health anti-stigma campaigns offer prior training to their activists with lived experience of mental disorders. Additionally, collective mobilization seems to impact the identity and well-being of its participants. The main objective of this work was to understand the impact that activism training activities have on the internalized/self-stigma and well being of activists being trained by the Obertament alliance against stigma in mental health. The Internalized Stigma of Mental Illness Inventory and the Pemberton Happiness Index were used to measure internalized stigma and well being, respectively, at the beginning and the end of anti-stigma training courses. Sixty-eight activists receiving training were enrolled within a pretest, posttest, 1-group design. A total of 39 participants were included in repeated measures calculations. Twenty-seven participants did not complete the total training schedule and two more did not complete baseline assessment. Our results show generalized increases in well-being and decreases in the internalized stigma of participants. Additionally, a covariation between these changes was found. To further illustrate this covariation, separate groups were created using the baseline median. Hence, greater increases in well-being were for those participants with higher levels of baseline self-stigma and vice versa. This article shows the importance of addressing internalized stigma among mental health activists, thus boosting their recovery process. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475051 TI - Investigating word length effects in Chinese reading. AB - A word's length in English is fundamental in determining whether readers fixate it, and how long they spend processing it during reading. Chinese is unspaced, and most words are two characters long: Is word length an important cue to eye guidance in Chinese reading? Eye movements were recorded as participants read sentences containing a one-, two-, or three-character word matched for frequency. Results showed that longer words took longer to process (primarily driven by refixations). Furthermore, skips were fewer, incoming saccades longer, and landing positions further to the right of long than short words. Additional analyses of a three-character region (matched stroke number) showed an incremental processing cost when character(s) belonged to different, rather than the same, word. These results demonstrate that word length affects both lexical identification and saccade target selection in Chinese reading. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475052 TI - Uncertainty information that is irrelevant for report impacts confidence judgments. AB - Humans intuitively evaluate their decisions with different levels of confidence. Although confidence and sensitivity are highly correlated, recent evidence has shown that confidence is disproportionately impacted by signal variability (e.g., de Gardelle & Mamassian, 2015; Spence, Dux, & Arnold, 2016; Zylberberg, Roelfsema, & Sigman, 2014). Previous studies investigating this issue have involved manipulations of variability in the components of the decision stimulus itself. Here, in 3 experiments, we investigated whether discrete variability, from a visual stimulus that does not require a response, can affect confidence in a secondary visual task. Participants made brightness or direction judgments about the dots in motion kinematograms with different ranges of motion around the global direction. Specifically, after viewing pairs of dot-motion displays, participants received a postcue at the end of each trial asking them to report either the relative brightness or the direction of the second display relative to the first. Importantly, the range of motion directions was irrelevant to the task when individuals were required to judge the brightness of the dots. We found that a larger range of motion directions reduced participants' confidence in their brightness judgments but with no corresponding change in performance. These findings suggest that confidence is impacted not only by variability directly relevant to the decision stimulus itself but also by variability in the context in which the decision evidence was encoded. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475053 TI - Beep, be-, or -ep: The impact of auditory transients on perceived bouncing/streaming. AB - Establishing object correspondence over time ("Which object went where?") is important for productively interacting with the surrounding environment. Here, we study auditory contributions to this process using the ambiguous bouncing/streaming display. Typically, a brief coinciding tone alters this dynamic event toward the perception of 2 disks bouncing off each other rather than streaming past each other. In 4 experiments, we tested the hypothesis that this crossmodal interaction is primarily driven by additive contributions of sensory transients rather than by the high-level processing of sound category. We orthogonally manipulated the number and semantic category of auditory transients. Specifically, different combinations of auditory transients generate qualitatively different events with distinct meanings; a single auditory transient can be a tone onset or offset, and a pair of transients can be a brief tone (onset + offset) or a brief gap (offset + onset). The proportion of seeing bouncing was larger for 2 transients than 1 transient and larger for 1 transient than no transients regardless of the sound's semantic category. A tone onset and a tone offset were equally effective (relative to no transients), and a brief tone (onset + offset) and a brief gap (offset + onset) were equivalently more effective. We identified a critical window of +/-200 ms around the visual overlap; a longer tone whose offset occurred outside the window was only as effective as a single onset. These results suggest that a simple addition of auditory transients within the critical time window primarily contributes to the auditory biasing of visual bouncing percepts. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475054 TI - Evaluating transdiagnostic, evidence-based mental health care in a safety-net setting serving homeless individuals. AB - Homeless individuals experience higher rates of mental illness than the general population, though this group is less likely to receive evidence-based psychological treatment for these difficulties. One explanation for this science to-service gap may be that most empirically supported interventions are designed to address a single disorder, which may not map on to the substantial comorbidity present in safety-net samples, and create a high training burden for often underresourced clinicians who must learn multiple protocols to address the needs of their patients. One solution may be to prioritize the dissemination of transdiagnostic interventions that can reduce therapist burden and simultaneously address comorbid conditions. The purpose of the present article is to describe the process of conducting a pilot study administering the Unified Protocol (UP), a transdiagnostic treatment for the range of emotional disorders, at a community based organization that provides health care and other services to homeless individuals and families in Boston, Massachusetts. Therapists on a specialized behavioral health unit received didactic training in the intervention, followed by weekly consultation while they provided the UP to patients on their caseload. Qualitative and quantitative data were collected from both patients and therapists. Barriers to use of the UP by therapists, as well as to conducting research in this setting, will be discussed, along with the solutions that were used. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475055 TI - Silence is golden: A mixed methods investigation of silence in one case of psychodynamic psychotherapy. AB - We investigated the antecedents, occurrences, and consequences of 183 silence events in the first 5 and last 5 sessions of a 73-session case of successful psychodynamic psychotherapy. Silences generally occurred within client speaking turns, such that the client often paused to reflect while speaking. In the last 5 sessions, as compared with the first 5 sessions, the client was more collaborative before and after silences, silences were shorter, the therapist was more connectional during silences (e.g., shared emotion and meaning with client), and the client was more emotional after silences. Antecedent client collaboration, duration of the silence, therapist behavior during silence events, client behavior during silence events, and who broke the silence all related to change in collaboration from before to after the silence events. We concluded that silence was helpful in this case because of client factors (the client naturally paused a lot during discussion, the client was quite reflective and insightful), therapist factors (the therapist was comfortable with and believed in silence), and relationship factors (there was a strong therapeutic relationship). (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475056 TI - Assessing and investigating clinicians' research interests: Lessons on expanding practices and data collection in a large practice research network. AB - Conducted in naturalistic settings, practice-oriented research (POR) is aimed at building stronger connections between the science and practice of psychotherapy. Promoting the principles of POR, this article has 2 aims: (a) presenting the results of a survey assessing the interests of members of a large practice research network in topics that could guide future research conducted as part of clinical routine, and (b) describing difficulties in implementing a study in line with such interests. Despite the significant interest in and perceived clinical significance of two relationship constructs (alliance and countertransference), there were unique obstacles faced in their empirical investigation within an already operationally functional practice research network. Challenges in this process included resource-related difficulties (such as changes in staff and the time required to set up the study and administer the measures), logistics-related issues, and effectively incorporating the assessment procedure into an existing clinical system. The article also describes strategies to address these obstacles, with differing degrees of success, including the role of a "local champion" at each site, the importance of a personal/professional relationship between the researcher and participating centers, as well as the pragmatic assistance to sites during the preparation, coordination, and implementation process (e.g., providing templates and feedback on institutional review board applications, and technological assistance on how to incorporate the measures into existing center software). The article concludes with general recommendations and future directions for POR. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475057 TI - Practical solutions for sustaining long-term academic-community partnerships. AB - The science-practice gap in the treatment of mental health is most pronounced in community settings, where clients with the highest needs often receive their care. Implementation science and community-based participatory research strategies aim to effectively address this gap by establishing partnerships that focus on scientifically rigorous, as well as clinically and socially relevant, research. Despite significant benefits, the community-based participatory research implementation framework has a unique set of challenges. The current article describes evidence-supported implementation strategies that were deployed to address various barriers to the implementation and long-term sustainability of an innovative cognitive-behavioral theory (CBT) life skills program identified during a feasibility trial. Through the committed work of an established partnership between a community-based nonprofit organization and researchers, barriers and the strategies for mitigating these obstacles were jointly identified. Specific challenges included fidelity (variability in staff's CBT competency and delivery), sustainability, and the cost of guideline implementation (data collection, time, and resources) of the CBT curriculum. We also provide details on the partnership's solutions to these major obstacles, including the development of an intensive 3-month training and coaching phase. The results of this rigorous training suggest improvement in staff's overall CBT competency and fidelity, increased participant engagement in the CBT curriculum, and enhanced data-collection procedures; yet, sustainability difficulties remained. General recommendations for long-term community research partnerships include early organizational buy-in; comprehensive needs assessments, including the organization's research building capacity; and sustained training and coaching models. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475058 TI - A further investigation of the good-enough level model across outcome domains and termination status. AB - Accurate estimations of progress in psychotherapy are necessary for therapists to identify clients at risk of deterioration and potentially reduce premature terminations. This need has resulted in a large body of literature examining the rate and trajectory of change in psychotherapy; however, few studies have tested these dose-response relationships outside of global measures of mental health. Moreover, there is a paucity of research examining the relationship between progress in treatment, treatment length, and premature termination. In this study, we conducted multivariate multilevel analyses to test the good-enough level model across the three domains of the phase model of psychotherapy: psychological symptoms, life functioning, and well-being. In addition, we tested changes in well-being, psychological symptoms, and life functioning, treatment length, and an interaction between treatment progress and treatment length as predictors of premature termination. Data for this study consisted of 438 clients who were treated by 57 therapists within a brief therapy model. Results failed to support the good-enough level model for changes in well-being, psychological symptoms, and life functioning, such that the rate of change across all three scales did not significantly vary as a function of treatment length. However, exploratory analyses revealed a significant interaction effect between changes in well-being, treatment length, and premature termination, indicating that clients who experienced high rates of change in well-being early in treatment were more likely to prematurely terminate treatment. Clinical implications and future research are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30475060 TI - Butyrate-Induced In Vitro Colonocyte Differentiation Network Model Identifies ITGB1, SYK, CDKN2A, CHAF1A, and LRP1 as the Prognostic Markers for Colorectal Cancer Recurrence. AB - Numerous mechanisms are believed to contribute to the role of dietary fiber derived butyrate in the protection against the development of colorectal cancers (CRCs). To identify the most crucial butyrate-regulated genes, we exploited whole genome microarray of HT-29 cells differentiated in vitro by butyrate treatment. Butyrate differentiates HT-29 cells by relaxing the perturbation, caused by mutations of Adenomatous polyposis coli (APC) and TP53 genes, the most frequent mutations observed in CRC. We constructed protein-protein interaction network (PPIN) with the differentially expressed genes after butyrate treatment and extracted the hub genes from the PPIN, which also participated in the APC-TP53 network. The idea behind this approach was that the expression of these hub genes also regulated cell differentiation, and subsequently CRC prognosis by evading the APC-TP53 mutational effect. We used mRNA expression profile of these critical hub genes from seven large CRC cohorts. Logistic Regression showed strong evidence for association of these common hubs with CRC recurrence. In this study, we exploited PPIN to reduce the dimension of microarray biologically and identified five prognostic markers for the CRC recurrence, which were validated across different datasets. Moreover, these five biomarkers we identified increase the predictive value of the TNM staging for CRC recurrence. PMID- 30475059 TI - Effects of folic acid on growth performance, ruminal fermentation, nutrient digestibility and urinary excretion of purine derivatives in post-weaned dairy calves. AB - This study evaluated the effects of folic acid (FA) supplementation on growth performance, ruminal fermentation, nutrient digestibility and urinary purine derivatives (PD) excretion in dairy calves. Forty-eight Chinese Holstein male dairy calves at 60 +/- 3.2 d of age and 89 +/- 5.9 kg body weight (mean +/- standard error) were assigned to one of four groups in a randomised block design. Calves in control group were fed basal diet, calves in low FA, medium FA and high FA groups with 3.6, 7.2 and 10.8 mg FA per kg basal diet, respectively. The dietary corn silage to concentrate ratio was 50:50 (dry matter [DM] basis). DM intake and average daily gain (ADG) quadratically increased, and feed conversion ratio quadratically decreased with increasing FA supplementation. Ruminal pH linearly decreased, whereas total volatile fatty acids quadratically increased. The unchanged acetate-to-propionate ratio was due to the similar change in acetate and propionate concentration. Ammonia N content quadratically decreased. Digestibility of DM, organic matter, crude protein, ether extract, neutral detergent fibre and acid detergent fibre linearly increased. Activities of carboxymethyl cellulase, cellobiase, xylanase and pectinase linearly increased, but alpha-amylase and protease quadratically increased. Abundance of Ruminococcus albus, Ruminococcus flavefaciens and Fibrobacter succinogenes linearly increased, but Butyrivibrio fibrisolvens and Prevotella ruminicola quadratically increased. Urinary total PD excretion quadratically increased. The results indicated that FA supplementation increased ADG, ruminal fermentation and nutrient digestibility with promoted ruminal microbial growth and enzyme activity, and the optimum dose was 7.2 mg FA per kg basal diet for calves. PMID- 30475061 TI - The importance of evaluating the chemical structures and strategies to avoid pitfalls in quantitative bioanalysis. AB - Quantitative bioanalytical data are crucial in pharmaceutical research and development, allowing project teams to make informed scientific decisions on the progression of candidate molecules to medicines. Many challenges are often encountered during the bioanalysis of drugs in biological matrices which require resolution in a timely manner. In this publication, guidance is provided to bioanalytical scientists on how to identify potential problems before they become an obstacle for the drug development and to share our experiences dealing some of most common problems encountered in the bioanalytical laboratory. Relevant topics in bioanalysis such as stabilization approaches for glucuronides (Acyl and N-); prodrugs (phosphate and esters), amides, amines, N-oxides; bioanalysis of light sensitive molecules, halogenated drugs and lactones are discussed in this publication. PMID- 30475063 TI - The Contribution of Genetic Variants of the Peroxisome Proliferator-Activated Receptor-Alpha Gene to High-Altitude Hypoxia Adaptation in Sherpa Highlanders. AB - Kinota, Fumiya, Yunden Droma, Nobumitsu Kobayashi, Toshimichi Horiuchi, Yoshiaki Kitaguchi, Masanori Yasuo, Masao Ota, and Masayuki Hanaoka. The contribution of genetic variants of the gene encoding peroxisome proliferator-activated receptor alpha gene (PPARA) to high-altitude hypoxia adaptation in Sherpa highlanders. High Alt Med Biol. 16:000-000, 2018.-Sherpa highlanders, who play invaluable roles in the exploration of Mount Everest, have exceptional tolerance to hypobaric hypoxia. Sherpa people are well known to possess the traits determined by genetic background for high-altitude adaptation. The metabolic adaptation mechanism is one of the biological ways for Sherpa highlanders in protecting them from hypoxia stress at high altitude. Studies have suggested that the gene encoding PPARA is associated with metabolic adaptation in the Himalayan population of Tibetans. This study attempts to investigate the genetic variants of the PPARA in Sherpa highlanders and the association with high-altitude hypoxia adaptation. Seven single-nucleotide polymorphisms (SNPs; rs135547, rs5769178, rs881740, rs4253712, rs5766741, and rs5767700 in introns and rs1800234 in exon 6) in the PPARA were genotyped in 105 Sherpa highlanders who lived in the Khumbu region (3440 m above sea level) and 111 non-Sherpa lowlanders who resided in Kathmandu (1300 m) in Nepal. By means of analyses of genetic distances, genotype distributions, allele frequencies, linkage disequilibrium, and haplotype constructions of the seven SNPs in the Sherpa highlanders versus the non-Sherpa lowlanders, it was revealed that the frequencies of minor alleles of rs4253712, rs5766741, rs5767700, and rs1800234 SNPs, as well as the frequency of haplotype constructed by the minor alleles of rs5766741-rs5767700-rs1800234, were significantly overrepresented in the Sherpa highlanders in comparison with the non-Sherpa lowlanders. The results strongly suggest that the genetic variants of the PPARA are likely to contribute to the high-altitude adaptation in Sherpa highlanders. PMID- 30475062 TI - Prolonged intake of desloratadine: mesenteric lymphatic vessel dysfunction and development of obesity/metabolic syndrome. AB - This study aimed to establish mechanistic links between the prolonged intake of desloratadine, a common H1 receptor blocker (i.e. antihistamine), and development of obesity and metabolic syndrome. Male Sprague-Dawley rats were treated orally for 16 weeks with desloratadine. We analyzed the dynamics of body weight gain; tissue fat accumulation/density; contractility of isolated mesenteric lymphatic vessels; levels of blood lipids, glucose and insulin; together with parameters of liver function. Prolonged intake of desloratadine induced development of an obesity-like phenotype and signs of metabolic syndrome. These alterations in the body included excessive weight gain, increased density of abdominal subcutaneous fat and intracapsular brown fat, high blood triglycerides with an indication of their re-routing towards portal blood, high HDL, high fasting blood glucose with normal fasting and non-fasting insulin levels (insulin resistance), high liver/body weight ratio, and liver steatosis (fatty liver). These changes were associated with dysfunction of mesenteric lymphatic vessels, specifically high lymphatic tone and resistance to flow together with diminished tonic and abolished phasic responses to increases in flow, (i.e. greatly diminished adaptive reserves to respond to postprandial increases in lymph flow). The role of nitric oxide in this flow-dependent adaptation was abolished, with remnants of these responses controlled by lymphatic vessel-derived histamine. Our current data, considered together with reports in the literature, support the notion that millions of the United States population are highly likely affected by under evaluated, lymphatic-related side effects of antihistamines, and may develop obesity and metabolic syndrome due to the prolonged intake of this medication. PMID- 30475064 TI - A novel HPLC-DAD method for simultaneous determination of febuxostat and diclofenac in biological samples: pharmacokinetic outcomes. AB - AIM: To develop a simple HPLC-DAD method for simultaneous determination of febuxostat (FEB) and diclofenac (DIC) in biological samples to assess pharmacokinetic outcomes of their coadministration. Methodology & results: Sample preparation was performed by liquid-liquid extraction. Drugs analysis was done on C18 column using methanol-formic acid pH 2.1 (76:24, v/v) as mobile phase and time-programmed UV detection. Lower limits of quantitation for FEB and DIC were 10 and 20 ng/ml, respectively. Baseline pharmacokinetics were similar to published data on either drug alone. Coadministration led to more than twofold increase in FEB Cmax and AUC together with a reduced hepatic uptake in rats. CONCLUSION: DIC interfered with initial distribution and terminal clearance of FEB potentially due to reduced FEB hepatic uptake. PMID- 30475065 TI - Food knowledge, loss aversion, and complementary feeding. PMID- 30475066 TI - Anthrozoology in Action: Performing Cognitive Training Paths in a Garden Shelter to Make Dogs More Suitable as Pets. AB - The overpopulation of shelters and the increase of homeless dogs have become serious problems in many countries. One contributor to the number of both sheltered and homeless dogs is the abandonment and relinquishment of pet dogs by their owners for different reasons - in many cases depending on dogs' undesirable or problematic behaviors. Luckily, the behavioral characteristics of a dog are, to some extent, modifiable parameters. The aim of this study was to train the dogs housed in a garden shelter in Italy to become suitable as pets by becoming familiar to different tools and situations that they could encounter in a domestic setting through a customized educational path based on social and environmental enrichment. Shelters can hardly afford the expenses for administering training to dogs. The problem could be overcome by engaging the best graduating students attending referenced training schools, whose mission is to train professionals with high theoretical and practical skills. Shelters' administrators should choose referenced schools only, that teach positive training methods respectful of animals and that support the human-animal bond. PMID- 30475067 TI - Technology makes older adults feel older. AB - The current study aims to examine the effect of technology use on the assessment of subjective age across the adult lifespan, with the assumption that using technology might make older people feel older. One-hundred and fifty-one participants (ages 18-83) assessed their subjective age before and after using familiar and unfamiliar applications on a touchscreen tablet. Subjective age was assessed either by line marking or by numerical response. The oldest participants felt older after the manipulation relative to their pre-manipulation baseline, unlike the youngest participants in the sample. This effect was stronger for the unfamiliar application than for the familiar application. We suggest that using technology evokes stereotype threat. Although this threat does not impair performance, it still changes self perception. These findings could have far reaching implications for the well-being of older adults in an ever more technological world. PMID- 30475068 TI - European Bioanalysis Forum recommendation on the best practices to demonstrate processed sample stability. AB - The European Bioanalysis Forum is providing a proposal on experiments to be conducted if processed samples are to be stored for a period of time, either after an initial injection or if processed samples are to be stored for a period of time prior to their first injection. Using survey information and extensive discussion an insight was gained as to whether the current practices employed during method validation were conducted to scientifically validate actual sample handling conditions or to simply meet a perceived regulatory expectation. The goal of this report is to recommend the adoption of scientifically justified validation experiments that exactly reproduce and processed test sample handling and storage procedures and to introduce some uniformity across the industry. PMID- 30475069 TI - Pituitary apoplexy secondary to metastatic breast carcinoma into a gonadotroph cell adenoma of the pituitary. AB - A 65 year-old lady with metastatic breast cancer presented with pituitary apoplexy. Following surgery, histopathology confirmed metastatic breast carcinoma into a gonadotroph cell adenoma of the pituitary. Tumours that metastasise to a normal pituitary gland are unusual. More so, such neoplasm-to-neoplasm metastasis is extremely rare. This is, as far as we are aware, the first description of a metastasis into a gonadotroph cell pituitary adenoma presenting as apoplexy. PMID- 30475070 TI - On-line monitoring human breath acetone during exercise and diet by proton transfer reaction mass spectrometry. AB - AIM: This study aims to develop a method for monitoring fat loss by detection of breath acetone. METHODS: A new method combining direct breath sampling system and proton transfer reaction MS (PTR-MS) was developed for on-line detection of breath acetone. The breath acetone of 272 volunteers was detected respectively when exercise or diet. RESULTS: Exercises perennially can make the breath acetone increase by 40-130%. Dinner fasting for 1 week can make it increase by 140%. CONCLUSION: Exercise and diet are two useful methods to lose fat. Determination of breath acetone concentration using the direct breath sampling system-proton transfer reaction MS can help design scheme of exercise and diet for losing weight. PMID- 30475071 TI - Eating Experiences, Sweet Preference, and Weight Gain in Women During Chemotherapy for Breast Cancer: A Mixed Methods Study. AB - Weight gain during breast cancer treatment has not been explained yet. This study aimed to explore eating experience and its relationship with weight gain and sweet preference and intake in women in chemotherapy treatment for breast cancer. Thirty-one patients indicated for adjuvant (n = 16) or neoadjuvant (n = 15) chemotherapy containing anthracyclines were evaluated. Weight, sweet preference in cashew juice (weight/volume, 3, 6, 12, 24, and 36%), and sweet food intake frequency ["healthy sweets" (HS) for fruits and natural juices and "nonhealthy sweets" (NHS) for other sweets] were assessed prior to initiating (T0) and after the fourth chemotherapy cycle (T1). A semistructured interview was applied at T1. At baseline, patients were 46.7 +/- 11.6 years old and the mean body mass index (BMI) was 29.3 +/- 7.1 kg/m2. The patients' weight and BMI increased, as did the HS intake, with positive correlation between HS intake and weight change (r = 0.38; P = 0.039). Baseline sweet preference is correlated to NHS intake at T0 (r = 0.51; P = 0.004) and influences NHS intake change. The interview analysis showed opposite food behaviors: at times driven by self-care and, at other times, driven by the emotional vulnerability, which may contribute to the weight gain observed. PMID- 30475073 TI - Analytical techniques for characterization of biological molecules - proteins and aptamers/oligonucleotides. AB - With the advent of the high-throughput technologies and exciting times for biology, the discipline of analytical methodology is experiencing a surge in the growth and the scope. Over the years, multitude of analytical techniques have evolved from a work-intensive, low sensitivity and high volume of reagent and sample consumption endeavor to automated, better selectivity, lower limit of quantification and cost-effective techniques for biological research. In this review, we give an overview of the currently available wide range of cell-based and noncell based and structural based analytical techniques, their principle and biological applications. The analytical techniques discussed in this paper includes surface plasmon resonance, electrophoresis, enzyme linked immunosorbent assay, Western blotting, flow cytometry, fluorescence activated cell sorting, mass spectrometry, nuclear magnetic resonance and x-ray crystallography. PMID- 30475072 TI - Biomarker assay validation for clinical trials: a questionnaire survey to pharmaceutical companies in Japan. PMID- 30475074 TI - 'Feeling younger, remembering better': the effect of experimentally induced subjective age on memory performance among Chinese older adults. AB - OBJECTIVES: This study aimed to explore whether experimentally induced younger subjective age can lead to better memory performance among Chinese older adults. METHOD: A total of 203 participants aged 60-84 years were randomly assigned to three groups. In the positive and neutral feedback groups, participants were told that their memory performance was better than and equivalent to the same-aged peers after an initial memory task, respectively, in contrast to no feedback in the control group. Participants then completed a second memory measure. RESULTS: The results revealed that participants in the positive feedback group felt younger and showed a significant increase in memory performance, whereas participants in the neutral feedback group felt older but also showed a significant increase in memory performance. For participants in the control group, no significant changes in memory performance were observed. CONCLUSION: It seems that experimentally induced younger subjective age can lead to better memory performance among older adults, providing a promising strategy to maintain memory functioning in old age. PMID- 30475075 TI - Detection and Analysis of Endogenous Polar Volatile Organic Compounds (PVOCs) in Urine for Human Exposome Research. AB - BACKGROUND: The human exposome, defined as "...everything that is not the genome", comprises all chemicals in the body interacting with life processes. The exposome drives genes x environment (GxE) interactions that can cause long-term latency and chronic diseases. The exposome constantly changes in response to external exposures and internal metabolism. Different types of compounds are found in different biological media. OBJECTIVE: Measure polar volatile organic compounds (PVOCs) excreted in urine to document endogenous metabolites and exogenous compounds from environmental exposures. METHODS: Use headspace collection and sorbent tube thermal desorption coupled with bench-top gas chromatography - mass spectrometry (GC-MS) for targeted and non-targeted approaches. Identify and categorize PVOCs that may distinguish among healthy and affected individuals. RESULTS: Method is successfully demonstrated to tabulate a series of 28 PVOCs detected in human urine across 120 samples from 28 human subjects. Median concentrations range from below detect to 165 ng/ml. Certain PVOCs have potential health implications. CONCLUSIONS: Headspace collection with sorbent tubes is an effective method for documenting PVOCs in urine that are otherwise difficult to measure. This methodology can provide probative information regarding biochemical processes and adverse outcome pathways (AOPs) for toxicity testing. PMID- 30475076 TI - Transdermal sampling of vitamin D3 and 25-hydroxyvitamin D3. AB - AIM: Transdermal analysis is proposed for vitamin D3 and its hydroxylated metabolite to overcome problems associated with blood analysis. METHODS: Vitamin D3 was extracted directly from skin with solid patches and liquid phases. Deuterium-labeled vitamin D3 was added to the extraction solutions to compensate for variability and accurately determine the rate of transdermal transfer. Of the different extraction solvents tested, 50:50 octanol:isopropanol showed the best results, with an accuracy of 115% and reproducibility better than 30%. CONCLUSION: The research shows that transdermal route can be used for analysis of vitamin D3 in porcine skin. When microneedles are used, accurate measurements were obtained in 1 h. With intact skin, the highest accuracy was obtained when extraction was done for 2 h. PMID- 30475077 TI - A low cost dural closure simulation model for tomorrow's spinal neurosurgeons. AB - INTRODUCTION: We present a low cost model that can be used to improve a trainee's skills in spinal dural closure. Development of microsurgical skills in a simulated environment provides a safe environment in which patients are protected. We argue that this is likely to improve the quality of dural closure, especially for surgeons early in their training and may lead to a commensurate reduction in post-operative CSF leak. METHOD: In our model, two consultant spine surgeons assessed the ability of participants to close the spinal dura. Participants were scored both quantitatively (time taken to complete the task) and qualitatively under the category of "surgical performance"- assessed by video and inspection of the closed dural substitute. RESULTS: The cohort under assessment included senior and newly appointed consultants, clinical fellows and thirteen specialty trainees. 10 trainees were assessed a second time and a significant majority improved on both domains: 8 (80%) were faster on their second attempt; surgical performance scores also improved in the majority of trainees (90%). CONCLUSION: Our results, albeit with small numbers, show that a large proportion of trainees improve with practice with a reduction in overall task time and an improvement in surgical performance. Our model is cost-effective and easy to reproduce: simulation need not be an expensive exercise. This study further validates the use of simulation in modern neurosurgical training. PMID- 30475078 TI - Are We Making Progress on Communication with People Who Are Near the End of Life in the Australian Health System? A Thematic Analysis. AB - Initiating end-of-life (EoL) discussions with patients is often delayed or avoided altogether by healthcare practitioners even in light of imminent death. This continues despite the availability of guidelines and conceptual frameworks on how to communicate prognoses at EoL. We surveyed healthcare practitioners to elicit their exposure to and confidence in EoL discussions and to better understand factors that enable or challenge the initiation of discussions in Australian healthcare settings. Thematic analysis identified that EoL discussions could be emotionally burdensome for healthcare practitioners but were regarded as valuable. Effective communications were challenged by conflict with families and between healthcare practitioners as to appropriate care goal transition, and by prognostic uncertainty. Communication skills appeared to be developed more from experience, and beneficial strategies such as role play and mentoring particularly for younger nurses and doctors were identified. Specific training in EoL communications should target undergraduates and new healthcare practitioners. PMID- 30475079 TI - Effect of different operationalizations of sedentary behavior in people with chronic stroke. AB - PURPOSE: Sedentary behavior is common in people with stroke and has devastating impact on their health. Quantifying it is important to provide people with stroke with adequate physical behavior recommendations. Sedentary behavior can be quantified in terms of posture (sitting) or intensity (low energy expenditure). We compared the effect of different operationalizations of sedentary behavior on sedentary behavior outcomes (total time; way of accumulation) in people with stroke. METHODS: Sedentary behavior was analyzed in 44 people with chronic stroke with an activity monitor that measured both body postures and movement intensity. It was operationalized as: (1) combining postural and intensity data; (2) using only postural data; (3) using only intensity data. For each operationalization, we quantified a set of outcomes. Repeated measures ANOVA and Bland-Altman plots were used to compare the operationalizations. RESULTS: All sedentary behavior outcomes differed significantly between all operationalizations (p < 0.01). Bland Altman plots showed large limits of agreement for all outcomes, showing large individual differences between operationalizations. CONCLUSIONS: Although it was neither possible nor our aim to investigate the validity of the two-component definition of sedentary behavior, our study shows that the type of operationalization of sedentary behavior significantly influences sedentary behavior outcomes in people with stroke. Implications for Rehabilitation Reliable assessment of sedentary behavior after stroke is important in order to provide adequate physical behavior recommendations for people with stroke. Sedentary behavior can be operationalized in terms of body posture (sitting time) or in terms of movement intensity (time <1.5 MET) or as a combination of both criteria; this study reveals that the type of operationalization affects the different outcome measures used to quantify sedentary behavior. Comparing sedentary behavior outcomes requires caution and should only be done when sedentary behavior is operationalized in the same way. PMID- 30475080 TI - Current opinions on autophagy in pathogenicity of fungi. AB - The interaction between pathogens and their host plants is a ubiquitous process. Some plant fungal pathogens can form a specific infection structure, such as an appressorium, which is formed by the accumulation of a large amount of glycerin and thereby the creation of an extremely high intracellular turgor pressure, which allows the penetration peg of the appressorium to puncture the leaf cuticle of the host. Previous studies have shown that autophagy energizes the accumulation of pressure by appressoria, which induces its pathogenesis. Similar to other eukaryotic organisms, autophagy processes are highly conserved pathways that play important roles in filamentous fungal pathogenicity. This review aims to demonstrate how the autophagy process affects the pathogenicity of plant pathogens. PMID- 30475081 TI - The effect of microRNA-129 on the migration and invasion in NSCLC cells and its mechanism. AB - PURPOSE: To investigate the effect of microRNA-129 on the migration and invasion in (Non small cell lung cancer) NSCLC cells and involved mechanism. MATERIALS AND METHODS: A549 cells were cultured and transfected with microRNA-129 (miR-129) mimic. Wound-healing assay and transwell assay were used to analyses the migration and invasion of A549 cells, respectively. The SOX4 expression changes were detected by qRT-PCR and Western blot. Dual-luciferase reporter assay was used to determine the binding site between miR-129 and the 3'-UTR of SOX4. A549 cells, miR-129 up-regulated A549 cells and miR-129 + SOX4 up-regulated A549 cells were treated with TGF-beta in order to induce the epithelial-mesenchymal transition (EMT). The miR-129 and SOX4 after TGF-beta treatment were measured. The EMT markers level changes were detected by western blot. RESULTS: Up regulation of miR-129 significantly inhibited the migration and invasion of A549 cells. miR-129 mimic transfection could reduce the mRNA and protein level of SOX4. Dual-luciferase reporter assay showed that miR-129 could bind to the 3'-UTR of SOX4. TGF-beta induced EMT accompanied by the reduction of miR-129 and elevating of SOX4. Up-regulation of miR-129 could reverse the EMT marker changes caused by TGF-beta, however, the SOX4 overexpression antagonized this effect of miR-129. CONCLUSIONS: miR-129 could suppress the migration and invasion of A549 cells. The potential mechanism may be that miR-129 inhibit EMT via targeting SOX4. PMID- 30475082 TI - Spinal cord lesions and atrophy in NMOSD with AQP4-IgG and MOG-IgG associated autoimmunity. AB - BACKGROUND:: Spinal cord (SC) affection is a hallmark symptom of neuromyelitis optica spectrum disorders (NMOSD). Patients with aquaporin-4 (AQP4-IgG+) or myelin oligodendrocyte glycoprotein (MOG-IgG+) antibody seropositivity show this overlapping clinical phenotype. OBJECTIVE:: Quantitative comparison of SC lesions and atrophy in AQP4-IgG+ and MOG-IgG+ NMOSD. METHODS:: AQP4-IgG+ ( n = 38), MOG IgG+ ( n = 15) NMOSD patients and healthy controls (HC, n = 24) were analysed for SC lesion (prevalence, length, location), atrophy as mean upper cervical cord area (MUCCA), Expanded Disability Status Scale (EDSS), timed 25-foot walk speed (T25FWS) and 9-hole peg test (9HPT) measures. RESULTS:: In total, 92% (35/38) of AQP4-IgG+ and 53% (8/15) of MOG-IgG+ patients had myelitis attacks (chi2 = 6.47, p = 0.011). 65.8%/26.7% of AQP4-/MOG-IgG+ patients had chronic SC lesions (chi2 = 5.16, p = 0.023), with similar proportions in cervical, upper thoracic and lower thoracic cord, and no length differences. MUCCA was decreased in AQP4-IgG+ ( t = 2.27, p = 0.028), but not MOG-IgG+ patients ( t = 0.58, p = 0.57) compared to HC. MUCCA associated with myelitis attacks (rho = -0.33, p = 0.016), EDSS (rho = 0.31, p = 0.030), pyramidal functional score (rho = -0.42, p = 0.003), T25FWS ( r = 0.43, p = 0.010) and 9HPT Z-score ( r = 0.32, p = 0.037), regardless of antibody status. CONCLUSION:: AQP4-IgG+ patients had more myelitis attacks, SC lesions and SC atrophy was more pronounced than in MOG-IgG+ patients. MUCCA is associated with clinical myelitis attacks and disability in all NMOSD patients. PMID- 30475083 TI - An elderly patient with Alzheimer's Disease, Normal Pressure Hydrocephalus and Traumatic Brain Injury: presented with behavioral symptoms similar to behavioral variant Frontotemporal Dementia. AB - Traumatic brain injury (TBI) is nondegenerative insult to brain from external mechanical forces. It may cause cognitive impairment, psychological problems in the long period. Besides traumatic brain injury also induces neuroinflammation and neurodegeneration process, and increases risk of dementia. It may cause various psychiatric complications such as depression, posttraumatic stress disorder, generalized anxiety disorder, and other cognitive and behavioral sequela according to site of involvement in the brain. We report a patient who has behavioral symptoms, amnesia and gait apraxy after TBI. Although patient's symptoms were similar to behavioral variant Frontotemporal Dementia (bv FTD), after detailed neurocognitive and radiologic evaluation he was diagnosed with Normal Pressure Hydrocephalus (NPH), and Alzheimer's Disease (AD) following TBI. Therefore, comprehensive geriatric assessment, including detailed radiological examinations, if it is necessary, is recommended for the optimum management of elderly patients with cognitive and psychosocial problems in order to avoid misdiagnosis and inappropriate treatment. PMID- 30475084 TI - The effect of transferrin-targeted, resveratrol-loaded liposomes on neurosphere cultures of glioblastoma: Implications for targeting tumor-initiating cells. AB - Glioblastomas (GBMs) are known to harbor subsets of cells known as tumor initiating cells (TICs), which are responsible for the maintenance, invasiveness and recurrence of GBMs. Conventional chemotherapeutics act on rapidly dividing cells, sparing the TICs and result in tumor relapse. Resveratrol, (RES) has shown chemopreventive effects in all the major stages of cancer including initiation, promotion and progression, but poor physico-chemical and pharmacokinetic properties limit its use as a free drug. Hence we developed a liposomal formulation of RES (RES-L) to eradicate both the bulk tumor cells and TICs in GBMs. Since both these sub-populations of cells are known to over-express transferrin receptors, we developed transferrin-targeted RES-L (Tf-RES-L) to enhance tumor-specific delivery. We studied the effects of RES on neurospheres (NS) used as an in vitro model to study TICs derived from GBM cell lines. Free RES and RES-formulations inhibited the anchorage-independent growth of GBM neurospheres. The NS-derived cells expressed TfRs and the Tf-targeted liposomes showed a significantly higher association with NS versus the non-targeted liposomes. Finally an increased activation of caspases 3/7 was seen when NS were treated with RES formulations. Together, these studies advocate for further investigations with RES-L and the use Tf to target the TIC populations. PMID- 30475085 TI - Evolutionary changes of the novel Influenza D virus hemagglutinin-esterase fusion gene revealed by the codon usage pattern. AB - The codon usage pattern can reveal the adaptive changes that allow virus survival and fitness adaptation to their particular host, as well as the external environment. Although still considered a novel influenza virus, there is an increasing number of influenza D viruses (IDV) reported. Considering the vital role of the hemagglutinin-esterase fusion (HEF) gene in in receptor binding, receptor degradation, and membrane fusion, we investigated the codon usage pattern of the IDV HEF gene to better understand its adaptive changes during evolution. Based on the HEF gene, three groups including, D/OK, D/660, and D/Japan were identified. We found a low codon usage bias, which allowed IDV to replicate in the corresponding hosts by reducing competition during evolution, that was mainly driven by natural selection and mutation pressure, with a profound role of natural selection. Furthermore, the interaction between the codon adaption index (CAI) and the relative codon deoptimization index (RCDI) revealed the adaption of IDV to multiple hosts, especially cattle which is currently considered its reservoir. Additionally, similarity index (SiD) analysis revealed that the swine exerted a stronger evolutionary pressure on IDV than cattle, though cattle is considered the primary reservoir. In addition, the conserved PB1 gene showed a similar pattern of codon usage compared to HEF. Therefore, we hypothesized that IDV has a preference to maintain infection in multiple hosts. The study aids the understanding of the evolutionary changes of IDV, which could assist this novel virus prevention and control. PMID- 30475086 TI - Cystic Hygroma: A Preliminary Genetic Study and a Short Review from the Literature. AB - BACKGROUND: The objective of this study is to examine the hypothesis that cystic hygroma (CH) with normal karyotype can manifest as a Mendelian inherited trait, and that a genetic similitude with hereditary lymphedema exists. To reach this goal, we investigated the prevalence of genetic variants in angiogenesis and lymphangiogenesis genes in a cohort of euploid fetuses with CH that almost resolved before delivery. A short review of cases from literature is also reported. METHODS AND RESULTS: Five fetuses were screened using a next-generation sequencing approach by targeting 33 genes known to be associated with vascular and lymphatic malformations. The genetic evaluation revealed two novel variants in KDR and KRIT1 genes. CONCLUSION: A review of the literature to date revealed that an association exists between CH and hereditary lymphedema and, similar to lymphedema, CH can be inherited in autosomal recessive and autosomal dominant manner, with the latter most likely associated with a better prognosis. About KDR and KRIT1 genes, no other similar associations are reported in the literature and caution is needed in their interpretation. In conclusion, we thought that a genetic test for the outcome of familial CH could be of enormous prognostic value. PMID- 30475087 TI - The Intertwined Life Cycles of Enterovirus and Autophagy. AB - Enteroviruses (EVs) are the most common human pathogens worldwide. Recent international outbreaks in North America and South East Asia have emphasized the need for more effective anti-viral therapies. As obligate parasites, EVs rely on the host cellular machinery for effective viral propagation. Accumulating evidence has indicated that EVs subvert and disrupt the cellular autophagy pathway to facilitate productive infection, and consequently leading to host pathogenesis. Given that defective autophagy is a common factor in various human diseases, including neurodegeneration, cardiomyopathy, and metabolic disorders, a clear understanding of the relationship between EV infection and autophagy is warranted. In this review, we highlight recent advances in understanding the molecular mechanisms by which EVs exploit the autophagy pathway during different steps of viral life cycle, from entry, replication, and maturation to release. We also provide an overview of recent progress in EV subversion of the autophagy for immune evasion. PMID- 30475088 TI - Time to restrict the use of p-values in Acta Orthopaedica. PMID- 30475089 TI - The differential similarity of positive and negative information - an affect induced processing outcome? AB - People judge positive information to be more alike than negative information. This good-bad asymmetry in similarity was argued to constitute a true property of the information ecology (Alves, H., Koch, A., & Unkelbach, C. (2017). Why good is more alike than bad: Processing implications. Trends in Cognitive Sciences, 21, 69-79). Alternatively, the asymmetry may constitute a processing outcome itself, namely an influence of phasic affect on information processing. Because no research has yet tested whether phasic affect influences perceived similarity among stimuli, we conducted 5 Experiments that also tested whether phasic affect can account for the higher judged similarity among positive compared to negative stimuli. In three experiments, we affectively charged pictures of different Pokemon by pairing them with monetary gains and losses (Exp. 1a, 1b) as well as positive and negative trait words (Exp. 2); yet, the evaluative charge did not differentially influence perceived similarity among the Pokemon. Experiment 3 replicated the basic similarity asymmetry among positive and negative words, and found that it was unaffected by externally induced phasic affect. Experiment 4 showed that phasic affect had no influence on perceived similarity of non evaluative words either. We conclude that albeit a weak influence of phasic affect on perceived similarity of stimuli cannot be ruled out entirely, it can most likely not account for the typically medium to large sized asymmetry in similarity among positive and negative stimuli. PMID- 30475090 TI - Advances in orally administered pharmacotherapy for the treatment of migraine. AB - INTRODUCTION: Migraine is a common and highly disabling neurological disorder whose acute treatment remains problematic and unsatisfactory in a high percentage of cases. Consequently, there remains a need for new symptomatic therapies that can be easily handled by patients (i.e. by oral administration). Area covered: This review reports on compounds currently under development for the oral treatment of acute migraine attacks, focusing on Calcitonin-Gene-Related-Peptide receptor antagonists, specifically ubrogepant and rimegepant. This article is based on literature obtained from PubMed and publicly available clinical trial data. Expert opinion: Both reviewed compounds meet the need for rapid and effective pain control, combined with the control of associated bothersome symptoms while also lacking significant adverse events and safety concerns. Though further studies should assess the profile of these compounds comparatively with existing and available treatments (namely triptans), the currently available data points to these new therapies as being very promising new symptomatic oral treatments of migraines. PMID- 30475091 TI - Evaluation of vilazodone for the treatment of depressive and anxiety disorders. AB - INTRODUCTION: Major Depressive Disorder (MDD) and General Anxiety Disorder (GAD) significantly contribute to the global burden of disease. Vilazodone, a combined serotonin reuptake inhibitor and 5-HT1A partial agonist, is an approved therapy for the treatment of MDD and which has been further investigated for GAD. Areas covered: This article covers the pharmacokinetics and pharmacodynamics of vilazodone and provides an evaluation of the clinical usefulness of vilazodone for the treatment of MDD and anxiety disorders. A literature search was performed using PubMed/MEDLINE, Web of Science and the Cochrane Library. Expert opinion: Studies have shown that vilazodone is significantly superior to placebo. However, vilazodone cannot as yet be recommended as a first-line treatment option for MDD as it is unclear whether the drug's dual mechanism of action provides greater efficacy than prevailing treatment options. Moreover, more phase IV studies are needed to establish its efficacy and long-term safety in larger and more diverse populations. Although vilazodone may have an additional advantage for the treatment of anxiety symptoms in MDD, here also additional studies are required to confirm its efficacy over and above SSRI alternatives and other antidepressant treatments. Therefore, presently, vilazodone should be considered as a second- or third-line treatment option for MDD and GAD. PMID- 30475092 TI - Morphological consequences of acoustic trauma on cochlear hair cells and the auditory nerve. AB - Hearing loss is the most common form of sensory impairment in humans. Noise exposure is responsible for around 10% of hearing loss in adults. Short impulses of a high intensity noise, such as a gunshot or explosion, can trigger sudden hearing loss, which is generally irreversible and associated with structural tissue damage of the cochlea and auditory nerve. It is well established that myelination is essential for the rapid propagation of action potentials along axons in both the central and peripheral nervous systems, and that Schwann cells are responsible for myelin sheath production in the peripheral nervous system. In the cochlea, sensory hair cells and neurons are in close proximity with several types of glial cells. Hair cells are surrounded by supporting cells, whereas spiral ganglion neuron axons are myelinated by Schwann cells. This myelin contributes to axonal protection and allows for efficient action potential transmission along the auditory nerve. For this reason, here we study the morphological changes on cochlear hair cells and myelin sheaths of the auditory nerve directly linked to hearing impairment induced by acoustic trauma in rats. PMID- 30475093 TI - Phenotypic features and predictors of the clinical severity of keratoconjunctivitis sicca and salivary gland dysfunction in patients with Sjogren's syndrome: a longitudinal analysis of the Korean Initiative of primary Sjogren's Syndrome (KISS) cohort. AB - OBJECTIVE: The aim was to investigate prevalence and degree of ocular and oral involvement in patients with primary Sjogren's syndrome (PSS). METHOD: We analysed 134 participants from the Korean Initiative of PSS cohort who completed a 2 year follow-up oral and ocular sign test. The severity of keratoconjunctivitis sicca (KCS) was determined with the Schirmer I test value (STV) [abnormal (AB) <= 5 mm/5 min; normal (N) > 5 mm/5 min]. Salivary gland dysfunction (SGD) was determined by unstimulated whole salivary (UWS) flow rate [moderate to severe (MS) < 0.1 mL/min; mild (Mi) >= 0.1 mL/min]. Subgroups were divided into three groups according to STV and severity of SGD: AB-STV/MS-SGD, AB STV/Mi-SGD, and N-STV/MS-SGD groups. We analysed the changes in STV and SGD during the follow-up period. RESULTS: Among the 134 participants enrolled in this study, 105 (78%) were placed in the AB-STV/MS-SGD group, 16 (12%) in the AB STV/Mi-SGD, and 13 (10%) in the N-STV/MS-SGD at the 2 year follow-up. The AB STV/Mi-SGD group was younger than the other two groups, and had a lower Xerostomia Inventory score and lower level of beta2-microglobulin. Participants in the N-STV/MS-SGD group had less hyperimmunoglobulinaemia, rheumatoid factor (RF), and antinuclear antibodies (ANAs). Patients and those with positive RF or ANA >= 1:320 at baseline were more likely to have abnormal STV at the 2 year follow-up. CONCLUSIONS: Patients with PSS and positive RF or ANA >= 1:320 at baseline may benefit from regular ophthalmology examinations, even if they do not have KCS at baseline or dry eye symptoms. PMID- 30475094 TI - The role of DNA methylation in human trophoblast differentiation. AB - The placenta is a vital fetal exchange organ connecting mother and baby. Specialised placental epithelial cells, called trophoblasts, are essential for adequate placental function. Trophoblasts transform the maternal vasculature to allow efficient blood flow to the placenta and facilitate adequate nutrient uptake. Placental development is in part regulated by epigenetic mechanisms. However, our understanding of how DNA methylation contributes to human trophoblast differentiation is limited. To better understand how genome-wide methylation differences affect trophoblast differentiation, reduced representation bisulfite sequencing (RRBS) was conducted on four matched sets of trophoblasts (a candidate human trophoblast stem cell population), cytotrophoblasts (an intermediate progenitor population) and extravillous trophoblasts (EVT, a terminally differentiated population) each isolated from the same first trimester placenta. Each trophoblast population had a distinct methylome. In line with their close differentiation relationship, the methylation profile of side-population trophoblasts was most similar to cytotrophoblasts, whilst EVT had the most distinct methylome. In comparison to mature trophoblast populations, side-population trophoblasts exhibited differential methylation of genes and miRNAs involved in cell cycle regulation, differentiation, and regulation of pluripotency. A combined methylomic and transcriptomic approach was taken to better understand cytotrophoblast differentiation to EVT. This revealed methylation of 41 genes involved in epithelial to mesenchymal transition and metastatic cancer pathways, which likely contributes to the acquisition of an invasive EVT phenotype. However, the methylation status of a gene did not always predict gene expression. Therefore, while CpG methylation plays a role in trophoblast differentiation, it is likely not the only regulatory mechanism involved in this process. PMID- 30475095 TI - Cognitive impairment does not cause invalid performance: analyzing performance patterns among cognitively unimpaired, impaired, and noncredible participants across six performance validity tests. AB - OBJECTIVE: Performance validity tests (PVTs) are essential in neuropsychological evaluations; however, it has been questioned how PVTs function in the context of cognitive impairment, and whether cognitive impairment alone is sufficient to cause PVT failure. Further, there is concern that some clinicians will disregard failed PVTs due to their perception that failures represent false-positive errors secondary to cognitive impairment. This study examined patterns associated with cognitively impaired versus noncredible performance across a battery of PVTs and neuropsychological tests. Additionally, the impact of VA service-connection and disability-seeking status on test validity was investigated. METHOD: A mixed clinical sample of 103 veterans were administered six PVTs and neuropsychological tests. Performance was compared across three groups: valid-cognitively unimpaired, valid-cognitively impaired, and noncredible. RESULTS: Significant PVT score differences and failure rates emerged across the three groups, with nonsignificant to small differences between valid-unimpaired and valid-impaired groups, and large differences between impaired and noncredible groups. In contrast, there were nonsignificant to small differences on neuropsychological tests between the valid-impaired and noncredible groups, indicating that impaired participants performed significantly better on PVTs despite comparable neurocognitive test scores. Service-connection rating itself was not associated with PVT failure, but an active disability claim to increase and/or establish service connection was associated with worse PVT performance. CONCLUSION: This study supports the use of multiple PVTs during evaluations of patients with varied cognitive abilities. Results indicated increased risk of PVT failure in patients who were seeking initiation/increase in service-connected payments, and shows that cognitive impairment does not cause PVT failure. PMID- 30475096 TI - Adult Convulsive status epileptic us: clinical, etiological and predictors of outcome study from rural population of North India. AB - AIM: To determine the clinical profile, aetiologies and predictors of mortality in patients with convulsive status epilepticus (CSE) among rural population of North India in view of limited published data on epidemiology and aetiology of status epilepticus (SE) from developing countries. METHODS: 162 consecutive adult patients with CSE were evaluated from 2016 to 2018 for demographic profile, aetiologies and predictors of poor outcome. RESULTS: The mean age was 41.71 +/- 19.72 years. Most of the CSE cases were acute symptomatic (48.8%) type with central nervous system (CNS) infections (24.1%) being the predominant precipitating factor. Antiepileptic drugs (AEDs) noncompliance accounted for 34.9% of the cases with pre-existing epilepsy. The median duration of CSE was 5.5 h (IQR-3-10h). 82.1% cases responded to the first line drugs and their response was related with duration of CSE (p = 0.0045). Case fatality was 16.0% and the predictors of the mortality were; low Glasgow Coma Scale (GCS) (OR =9.64, 95% CI= 2.064-45.02; p = 0.0001), lack of response to first line drugs (OR =0.019, 95% CI= 0.003-0.11; p = 0.0001) and absence of past history of epilepsy (OR =0.525, 95%CI =0.104-2.66; p = 0.004). CONCLUSIONS: CNS infection and AEDs non compliance were identified to be the major cause of CSE which can be potentially preventable. Present study signifies that prompt and successful control of infections appears to be the most efficient preventive approach. Level of consciousness as a potential predictor of poor outcome can be quickly accessible to the treating clinician in optimizing treatment strategies. PMID- 30475097 TI - Structure elucidation of ostreocin-A and ostreocin-E1, novel palytoxin analogs produced by the dinoflagellate Ostreopsis siamensis, using LC/Q-TOF MS. AB - Palytoxin analogs are marine toxins with large complex polyol structures. A benthic dinoflagellate Ostreopsis siamensis produces more than ten palytoxins (ostreocins, OSTs). The limited sample availability of minor OSTs restricts the definition of their chemical structures. The present investigation characterizes structures of two minor OSTs, i.e., ostreocin-A (OSTA) and ostreocin-E1 (OSTE1), using ostreocin-D (OSTD) as a reference compound, by liquid chromatography/quadrupole-time-of-flight mass spectrometry. The molecular formulas of OSTA and OSTE1 were C127H219N3O54 and C127H217N3O52, respectively. Compared to OSTD, OSTA has an extra oxygen atom whereas OSTE1 lacks one oxygen atom and two hydrogen atoms. The MS/MS experiments (precursor ions: [M + H]+ and [M-H]-) suggested a hydroxyl substitution at C82 in OSTA and alteration(s) between C53 and C100 in OSTE1. Further analysis of structural details in OSTE1 was performed through a pseudo-MS3 experiment (precursor ion: m/z 1432.748). Accordingly, the planar structures of OSTA and OSTE1 were assigned to 42,82 dihydroxy-3,26-didemethyl-19,44-dideoxypalytoxin and 42-hydroxy-3,26-didemethyl 19,44,73-trideoxypalytoxin-72-ene, respectively. Abbreviations:CID: collision induced dissociation; HR-LC/MS/MS: high-resolution liquid chromatography/tandem mass spectrometry; LC/ESI/Q-TOF MS: liquid chromatography/quadrupole time-of flight mass spectrometry equipped with an electrospray ionization source; NMR: nuclear magnetic resonance; OSTs: ostreocins; OSTA: ostreocin-A; OSTB: ostreocin B; OSTD: ostreocin-D; OSTE1: ostreocin-E1; OVTX-a: ovatoxin-a; OVTXs: ovatoxins; PLTX: palytoxin. PMID- 30475099 TI - Paul Allen. PMID- 30475100 TI - Cell biology of stem cells: studying stem cells at the level of cell biology and studying cell biology using stem cells. PMID- 30475098 TI - Stem cell models of human synapse development and degeneration. AB - Many brain disorders exhibit altered synapse formation in development or synapse loss with age. To understand the complexities of human synapse development and degeneration, scientists now engineer neurons and brain organoids from human induced pluripotent stem cells (hIPSC). These hIPSC-derived brain models develop both excitatory and inhibitory synapses and functional synaptic activity. In this review, we address the ability of hIPSC-derived brain models to recapitulate synapse development and insights gained into the molecular mechanisms underlying synaptic alterations in neuronal disorders. We also discuss the potential for more accurate human brain models to advance our understanding of synapse development, degeneration, and therapeutic responses. PMID- 30475101 TI - Results from Zimbabwe's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475102 TI - The Results from Estonia's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475103 TI - Results From China's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475105 TI - Results From England's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475104 TI - Results from Canada's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475106 TI - Results From Ecuador's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475107 TI - Results from Ghana's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475108 TI - Results from Flanders' 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475109 TI - Results from Ethiopia's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475111 TI - Results from the Bailiwick of Guernsey's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475110 TI - Results from Bangladesh's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475112 TI - Results from Australia's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475113 TI - Results from Germany's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475114 TI - Results from New Zealand's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475115 TI - Results from Poland's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475116 TI - Results from Mexico's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475118 TI - Results From Japan's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475117 TI - Results from Lebanon's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475119 TI - Results from Venezuela's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475120 TI - Results From Wales' 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475121 TI - Results From Bulgaria's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475122 TI - Results From Uruguay's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475123 TI - Results From the United Arab Emirates' 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475124 TI - Results from Slovenia's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475125 TI - Results from Thailand's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475126 TI - Results From Brazil's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475128 TI - Results From Spain's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475127 TI - Results From Portugal's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475129 TI - Results from Botswana's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475130 TI - Results from Qatar's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475131 TI - Results from Hong Kong's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475132 TI - Results from the Czech Republic's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475133 TI - Results from Colombia's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475134 TI - Results from Lithuania's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475135 TI - Results from Denmark's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475136 TI - Report Card Grades on the Physical Activity of Children and Youth From 10 Countries With High Human Development Index: Global Matrix 3.0. AB - BACKGROUND: The Global Matrix 3.0 brings together the Report Card grades for 10 physical activity indicators for children and youth from 49 countries. This study describes and compares the Global Matrix 3.0 findings among 10 countries with high Human Development Index. METHODS: Report Cards on physical activity indicators were developed by each country following a harmonized process. Countries informed their Report Cards with the best and most recent evidence available. Indicators were graded using a common grading rubric and benchmarks established by the Active Healthy Kids Global Alliance. A database of grades from the countries was compiled, and letter grades were converted to numerical equivalents. Descriptive statistics and scores for groups of indicators were calculated, and correlation analyses were conducted. RESULTS: Grades for the 10 countries clustered around "D" ranging from "F" to "B+." Active Transportation had the highest average grade ("C"), whereas Overall Physical Activity had the lowest average grade ("D-"). Low grades were observed for both behavioral and sources of influence indicators. CONCLUSIONS: In the context of social and economical changes of high- Human Development Index countries, urgent actions to increase physical activity among children and youth are required. Surveillance and monitoring efforts are required to fill research gaps. PMID- 30475138 TI - Results from Chinese Taipei (Taiwan)'s 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475139 TI - Results from France's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475137 TI - Global Matrix 3.0 Physical Activity Report Card Grades for Children and Youth: Results and Analysis From 49 Countries. AB - BACKGROUND: Accumulating sufficient moderate to vigorous physical activity is recognized as a key determinant of physical, physiological, developmental, mental, cognitive, and social health among children and youth (aged 5-17 y). The Global Matrix 3.0 of Report Card grades on physical activity was developed to achieve a better understanding of the global variation in child and youth physical activity and associated supports. METHODS: Work groups from 49 countries followed harmonized procedures to develop their Report Cards by grading 10 common indicators using the best available data. The participating countries were divided into 3 categories using the United Nations' human development index (HDI) classification (low or medium, high, and very high HDI). RESULTS: A total of 490 grades, including 369 letter grades and 121 incomplete grades, were assigned by the 49 work groups. Overall, an average grade of "C-," "D+," and "C-" was obtained for the low and medium HDI countries, high HDI countries, and very high HDI countries, respectively. CONCLUSIONS: The present study provides rich new evidence showing that the situation regarding the physical activity of children and youth is a concern worldwide. Strategic public investments to implement effective interventions to increase physical activity opportunities are needed. PMID- 30475140 TI - Results from Jersey's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475141 TI - Results from Finland's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475142 TI - Results from Chile's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475143 TI - Results from the United States 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475145 TI - Results from India's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475144 TI - Report Card Grades on the Physical Activity of Children and Youth Comparing 30 Very High Human Development Index Countries. AB - BACKGROUND: To better understand the childhood physical inactivity crisis, Report Cards on physical activity of children and youth were prepared concurrently in 30 very high Human Development Index countries. The aim of this article was to present, describe, and compare the findings from these Report Cards. METHODS: The Report Cards were developed using a harmonized process for data gathering, assessing, and assigning grades to 10 common physical activity indicators. Descriptive statistics were calculated after converting letter grades to interval variables, and correlational analyses between the 10 common indicators were performed using Spearman's rank correlation coefficients. RESULTS: A matrix of 300 grades was obtained with substantial variations within and between countries. Low grades were observed for behavioral indicators, and higher grades were observed for sources of influence indicators, indicating a disconnect between supports and desired behaviors. CONCLUSION: This analysis summarizes the level and context of the physical activity of children and youth among very high Human Development Index countries, and provides additional evidence that the situation regarding physical activity in children and youth is very concerning. Unless a major shift to a more active lifestyle happens soon, a high rate of noncommunicable diseases can be anticipated when this generation of children reaches adulthood. PMID- 30475146 TI - Results from Nigeria's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475147 TI - Results From the Netherlands' 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475148 TI - Results from Nepal's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475149 TI - Results from Sweden's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475151 TI - Results from South Africa's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475150 TI - Results from South Korea's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475152 TI - Results from Scotland's 2018 Report Card on Physical Activity for Children and Youth. PMID- 30475153 TI - Pantothenate auxotrophy of Methylobacterium spp. isolated from living plants. AB - A number of pink-pigmented facultative methylotrophs (PPFMs) belonging to Methylobacterium spp. isolated from living plant samples were found to require B vitamins for their growth in minimal medium, and most B vitamin-auxotrophic PPFMs required pantothenate (vitamin B5). Further investigation of pantothenate auxotrophy using the representative strain Methylobacterium sp. OR01 demonstrated that this strain cannot synthesize beta-alanine, one of the precursors of pantothenate. beta-alanine and several precursors of pantothenate restored the growth of Methylobacterium sp. OR01 in minimal medium. Furthermore, this strain could colonize leaves of Arabidopsis thaliana cultivated in medium without pantothenate or its precursors. Pantothenate, beta-alanine and several precursors were detected in the suspension of A. thaliana leaves. These results suggest that pantothenate-auxotrophic PPFMs can symbiotically colonize the surface of plant leaves by acquiring beta-alanine and other precursors, in addition to pantothenate. Finally, the fitness advantage of B vitamin auxotrophy of PPFMs in the phyllosphere environment is discussed. PMID- 30475154 TI - Drp1-dependent mitochondrial fission regulates p62-mediated autophagy in LPS induced activated microglial cells. AB - Microglial activation is known to be an important event during innate immunity, but microglial inflammation is also thought to play a role in the etiology of neurodegenerative diseases. Recently, it was reported that autophagy could influence inflammation and activation of microglia. However, little is known about the regulation of autophagy during microglial activation. In this study, we demonstrated that mitochondrial fission-induced ROS can promote autophagy in microglia. Following LPS-induced autophagy, GFP-LC3 puncta were increased, and this was suppressed by inhibiting mitochondrial fission and mitochondrial ROS. Interestingly, inhibition of mitochondrial fission and mitochondrial ROS also resulted in decreased p62 expression, but Beclin1 and LC3B were unaffected. Taken together, these results indicate that ROS induction due to increased LPS stimulated mitochondrial fission triggers p62 mediated autophagy in microglial cells. Our findings provide the first important clues towards understanding the correlation between mitochondrial ROS and autophagy. Abbreviations: Drp1; Dynamin related protein 1, LPS; Lipopolysaccharide, ROS; Reactive Oxygen Species, GFP; Green Fluorescent Protein, CNS; Central Nervous System, AD; Alzheimer's Disease, PD; Parkinson's Disease, ALIS; Aggresome-like induced structures, iNOS; inducible nitric oxide synthase, Cox-2; Cyclooxygenase-2, MAPK; Mitogen-activated protein kinase; SODs; Superoxide dismutase, GPXs; Glutathione Peroxidase, Prxs; Peroxiredoxins. PMID- 30475155 TI - Spine duplication or split notochord syndrome - case report and literature review. AB - CONTEXT: Spine duplication is a rare condition, with various extents and severe additional anomalies. The goal of this study was to describe a unique case of a boy with split notochord syndrome who was followed up from birth until maturity. FINDINGS: Physical examination at birth showed defects of the abdominal wall and cloacal exstrophy with visible urether outlets. A transposed anus was present in the perineal region. Split bony elements of the spine with nonpalpable sacral bone were noted. A soft, skin-covered lump, with the consistency of a lipoma, was present in the sacral area. There was asymmetry of the lower limbs: the left was hypoplastic, with a deformed foot and hip. Computed tomography revealed a normal shape of the Th12 and L1 vertebrae, whereas the L2 was split. Downward from L3, there were two vertebrae at each level, with two spinal canals. The spinal cord divided into two "semicords" at the level of L1. Neurologic status and the shape of the spine remained unchanged during puberty. The last follow-up was performed at the age of 18 years. He managed to walk independently in prosthesis with visible limping. CONCLUSION: Spine deformities are always suspected in neonates with lipoma in the sacral region, which may sometimes be serious. Walking ability and quality of life depend on neurologic deficits; even with long duplication and double sacrum, walking can be a feasible option. PMID- 30475156 TI - Validity and reliability of fatigue severity scale in stroke. AB - BACKGROUND: Fatigue is a frequent complaint after stroke and may be associated with dependence in activities of daily living, decreased quality of life, increased institutionalization and mortality. Although fatigue severity scale (FSS) is the most frequently used scale in stroke, validation studies are scarce. OBJECTIVES: This study aimed to examine the psychometric properties of FSS in subjects with stroke. METHODS: A total of 46 subjects with stroke who were admitted for rehabilitation and 52 control subjects who were admitted for local musculoskeletal problems were included. A comprehensive assessment including functional independence measure, Folstein Mini-Mental State Examination, Hospital Anxiety and Depression Scale (HADS), visual analog scale for fatigue (VAS), FSS, and vitality subscale of 36-item Medical Outcomes Study Short-Form Health Survey (SF-36v) was conducted. FSS, VAS and SF-36v were repeated 7 days later. RESULTS: FSS demonstrated excellent internal consistency in subjects with stroke (Cronbach's alpha: 0.928). There was a moderate correlation between FSS and SF 36v (r = -0.498, p < 0.001). FSS was weakly correlated with HADS anxiety (r = 0.310, p = 0.041) and HADS depression (r = 0.334, p = 0.027). Test-retest reliability of SF-36v (ICC: 0. 746, CI: 0.518-0.866), VAS (ICC: 0.829, CI: 0.671 0.911) and FSS (ICC: 0.742, CI: 0.512-0.863, p < 0.001) was good. ICC values for individual items of FSS were good except for item 6. CONCLUSIONS: FSS is a valid and reliable scale to measure fatigue in stroke. FSS is not sensitive to differentiate fatigue in stroke from the control subjects with orthopedic problems with similar age and gender. PMID- 30475158 TI - Measuring LGBTQ Microaggressions: The Sexual Orientation Microaggressions Scale (SOMS) and the Gender Identity Microaggressions Scale (GIMS). AB - Microaggressions are brief and commonplace daily verbal, behavioral, or environmental indignities, intentional or unintentional, that demonstrate bias toward members of historically marginalized groups. While numerous quantitative studies on racial microaggressions have emerged in recent years, studies on sexual orientation and gender identity microaggressions have been mostly qualitative-likely due to limited measures of anti-LGBTQ microaggressions. In this three-part study, the Sexual Orientation Microaggressions Scale (SOMS) and the Gender Identity Microaggressions Scale (GIMS) are introduced to empirically explore the multifaceted experiences of microaggressions toward lesbian, gay, bisexual, and queer (LGBQ) people and transgender and gender nonconforming (TGNC) people. In Study 1 (N = 260), a principal components analysis yielded a five factor structure of sexual orientation microaggressions; in Study 2, a new sample (N = 140) is used to confirm the utility of the SOMS. In Study 3, the GIMS is piloted with a sample of TGNC participants (N = 160). Implications for future studies are discussed. PMID- 30475157 TI - Hearing "That's So Gay" and "No Homo" on Campus and Substance Use Among Sexual Minority College Students. AB - Sexual orientation microaggressions are common on college campuses and can contribute to negative outcomes; yet little is known about their relationship with substance use outcomes. Among a convenience sample of cisgender sexual minority college students (n= 574; 57.0% female, 24.9% people of color, 50.7% gay/lesbian; 72.4% public school) from 37 states (67.8% Midwest), this analysis investigates the association between hearing "that's so gay" and "no homo" on campus and hazardous alcohol use and the frequency of illicit drug use. Using multivariable regression analyses, the commonly heard phrases "that's so gay" and "no homo" were each found to significantly increase the risk for hazardous drinking and the frequency of drug use among students. Efforts should be made to create more welcoming campus climates for sexual minority students by reducing the use of these microaggressions and, in the meantime, offering supports to mitigate their harmful effects. PMID- 30475159 TI - Therapeutic Hypothermia and Targeted Temperature Management for Traumatic Arrest and Surgical Patients. AB - Therapeutic hypothermia (TH) and targeted temperature management (TTM) have been shown to improve outcomes in survivors of cardiac arrest, but prior research has excluded trauma and postoperative patients. We sought to determine whether TH/TTM is safe in trauma and surgical patients. A retrospective cohort study was conducted at a single level I trauma center reviewing adults presenting as a traumatic arrest or cardiac arrest in the postoperative period with a Glasgow Coma Scale <8 after return of circulation who were treated with either TH or TTM. Neurological recovery is considered favorable if a patient was discharged following commands. A total of 32 cardiac arrest patients were included in the study, 14 of whom were treated with TH and 18 with TTM protocols, with goal temperatures of 33 degrees C and 36 degrees C, respectively. Mean age of the cohort was 60 +/- 13, with 26 (81%) men. There were 18 trauma patients and 14 postoperative patients. Complications included pneumonia (13%), sepsis (6%), bleeding requiring transfusion (22%), arrhythmias (6%), and seizures (9%), which are similar to prior published series. Overall survival to discharge was 41% (n = 13), and all survivors had favorable neurological recovery. Traumatic arrest and perioperative cardiac arrest patients previously excluded from TH/TTM studies appear to have an acceptable incidence of complications compared with standard TH/TTM patients. PMID- 30475160 TI - The history of universal access to emergency contraception in Peru: a case of politics deepening inequalities. PMID- 30475161 TI - Cross-validity of one maximum repetition predictive equation for men with spinal cord injury. AB - OBJECTIVES: The study aimed to test the cross-validation of a specific one maximum repetition (1RM) predictive equation based on the 4- to 12-maximum repetition test (4-12RM) for men with spinal cord injury (SCI). STUDY DESIGN: Cross-sectional study. SETTING: Rehabilitation Hospital Network. PARTICIPANTS: Fifty-eight men aged 31.9 (20.0-38.0) years (median and quartile) with SCI were enrolled in the study. INTERVENTIONS: None. OUTCOMES MEASURES: Volunteers were tested in 1RM test or 4-12RM of the bench press exercise with 2-3 interval days in a random order. The intraclass correlation coefficient (ICC) with Bland Altman plot was used to compare a specific predictive equation (SPE) and six current predictive equations (CPE) based on the 4- to 12-maximum repetition with the 1RM test. RESULTS: The SPE showed the highest intraclass correlation coefficient (ICC = 0.91; 95%CI 0.85-0.95), the smallest range of the interval around the differences (Delta = 36.6) and the second lowest mean difference between 1RM test and 1RM predictive equation (-2.4 kg). The CPE3 presented the lowest mean difference (-1.6 kg). All intraclass correlations' predictive equations were classified as excellent. CONCLUSION: The SPE presented a suitable and satisfactory validity to assess men with SCI at the bench press exercise. Thus, the equation is an accurate method to predict 1RM in SCI. PMID- 30475163 TI - "A Whole Bunch of Love the Sinner Hate the Sin": LGBTQ Microaggressions Experienced in Religious and Spiritual Context. AB - Research on microaggressions experienced by LGBTQ people has focused largely on a general understanding of this concept; however, no research exists that focuses exclusively on microaggressions that LGBTQ people face across religious and spiritual communities. The present study addressed this gap in the literature by using a qualitative method to allow LGBTQ people (N= 90) to directly report microaggressions that they have experienced within their religious and spiritual communities. Thematic analysis revealed three predominant themes: (1) LGBTQ identities as inauthentic; (2) religious/spiritual tolerance of LGBTQ Identities, and (3) LGBTQ and religious/spiritual identities as incompatible. Implications and future directions discussed. PMID- 30475164 TI - Community exercise programing and its potential influence on quality of life and functional reach for individuals with spinal cord injury. AB - CONTEXT/OBJECTIVE: After an individual with a Spinal Cord Injury (SCI) participates in the initial rehabilitation process, they often experience limited access to physical therapy services and other fitness activities. The purpose of this study was to examine previously collected data for changes in quality of life (QoL) and functional reach in individuals with SCI following an 8-week community exercise program. DESIGN: Secondary analysis of previously collected data. SETTING: Community-based exercise program. PARTICIPANTS: Twenty-two participants with an average of 9 years post-SCI, both complete and incomplete injuries, and injury levels ranging from C2 to L5. INTERVENTIONS: Participants completed an 8-week program, once per week for 4 hours that included a four station circuit of resistance training, aerobic exercise, trunk stability, and education. OUTCOME MEASURES: Physical function was measured using the modified Functional Reach Test (mFRT). QoL was measured with the Life Satisfaction Questionnaire-9 (LiSAT-9). RESULTS: The mFRT improved by 2 inches (+/-7.04) P < 0.001 and QoL improved as well, P < 0.001. CONCLUSION: The findings of this study are consistent with the hypothesis that a supervised post-rehabilitation community exercise program, like Spinal Mobility, may positively impact the QoL and functional reach in individuals with SCI. PMID- 30475162 TI - Development and evaluation of a pilot overdose education and naloxone distribution program for hospitalized general medical patients. AB - BACKGROUND: Overdose education and naloxone distribution (OEND) to people at risk of witnessing or experiencing an opioid overdose has traditionally been provided through harm reduction agencies. Expanding OEND to inpatient general medical settings may reach at-risk individuals who do not access harm reduction services and have not been trained. An OEND program targeting inpatients was developed, piloted, and evaluated on 2 general medicine floors at Montefiore Medical Center, a large urban academic medical center in Bronx, New York. METHODS: The planning committee consisted of 10 resident physicians and 2 faculty mentors. A consult service model was piloted, whereby the primary inpatient care team paged the consult team (consisting of rotating members from the planning committee) for any newly admitted patient who had used any opioid in the year prior to admission. Consult team members assessed patients for eligibility and provided OEND to eligible patients through a short video training. Upon completion, patients received a take-home naloxone kit. To evaluate the program, a retrospective chart review over the first year (April 2016 to March 2017) of the pilot was conducted. RESULTS: Overall, consults on 80 patients were received. Of these, 74 were eligible and the consult team successfully trained 50 (68%). Current opioid analgesic use of >=50 morphine milligram equivalents daily was the most common eligibility criterion met (38%). Twenty-four percent of patients were admitted for an opioid-related adverse event, the most common being opioid overdose (9%), then opioid withdrawal (8%), skin complication related to injecting (5%), and opioid intoxication (2%). Twenty-five percent had experienced an overdose, 35% had witnessed an overdose in their lifetime, and 83% had never received OEND previously. CONCLUSIONS: Integrating OEND into general inpatient medical care is possible and can reach high-risk patients who have not received OEND previously. Future research should identify the optimal way of implementing this service. PMID- 30475165 TI - Baseline characteristics of the 1149 patients recruited into the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2) randomized controlled trial. AB - BACKGROUND: High blood pressure is common in acute stroke and associated with a worse functional outcome. Glyceryl trinitrate, a nitric oxide donor, lowers blood pressure in acute stroke and may improve outcome. AIMS: Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2) tested the feasibility of performing a UK multicenter ambulance-based stroke trial, and the safety and efficacy of glyceryl trinitrate when administered by paramedics before hospital admission. METHODS: Paramedic-led ambulance-based multicenter prospective randomized single-blind blinded-endpoint parallel-group controlled trial of transdermal glyceryl trinitrate (given for four days) versus sham in patients with ultra-acute (<4 h) presumed stroke. Data are number (%), median (interquartile range) or mean (standard deviation). RESULTS: Recruitment ran from October 2015 to 31 May 2018. A total 1149 patients were recruited from eight UK ambulance services and taken to 54 acute hospitals. Baseline characteristics include: mean age 73 (15) years; female 555 (48%); median time from stroke to randomization 70 (45, 115) min; face-arm-speech scale score 2.6 (0.5); and blood pressure 162 (25)/92 (18) mmHg. The final diagnosis was ischemic stroke 52%, hemorrhagic stroke 13%, Transient Ischemic Attack (TIA) 9%, and mimic 25%. The main trial results will be presented in quarter 4 2018. The results will also be included in updated Cochrane systematic reviews, and individual patient data meta analyses of all relevant randomized controlled trials. CONCLUSION: It was feasible to perform a multicenter ambulance-based ultra-acute stroke trial in the UK and to treat with glyceryl trinitrate versus sham. The relatively unselected cohort of stroke patients is broadly representative of those admitted to hospital in the UK. TRIAL REGISTRATION: ISRCTN26986053. PMID- 30475166 TI - A mobile hemangioblastoma of the cauda equina: Case report and review of the literature. AB - CONTEXT: Cases of migratory spinal tumors have been reported since 1963. Most involve spinal schwannomas, which are benign tumors of the lining of nerve cells. We report a rare case of a mobile spinal hemangioblastoma, which is a type of benign vascular tumor. FINDINGS: A 50-year-old man visited the hospital for painful swelling in his lower back. An MRI scan indicated that a lesion was at the L5 vertebral level. Two weeks later, however, an enhanced MRI showed that the lesion had migrated to the L4 vertebral level. During surgery, the location of the lesion remained consistent with the enhanced MRI reviewed. The histopathological diagnosis was hemangioblastoma. CONCLUSION: This is the first known report of a mobile spinal hemangioblastoma. Mobile spinal hemangioblastoma requires careful preoperative and intraoperative evaluation of its real-time location to avoid performing surgery at the wrong vertebral level. PMID- 30475167 TI - Navigating stigma, survival, and sex in contexts of social inequity among young transgender women and sexually diverse men in Kingston, Jamaica. AB - Social inequities, including stigma, criminalisation of same-sex practices, and poverty, elevate HIV exposure among young transgender women and sexually diverse men in Jamaica. Yet the ways transgender women and sexually diverse men in Jamaica navigate sex and HIV in contexts of social inequity are underexplored. The study objective was to explore experiences and perceptions of sexual decision making and HIV risk among young (aged 18-30) sexually diverse men and transgender women in Kingston, Jamaica. We conducted a community-based qualitative study in Kingston that involved in-depth individual interviews (transgender women: n = 20; sexually diverse men: n = 20), 2 focus groups (transgender women: n = 8; sexually diverse men: n = 10) and 13 key informant interviews. Focus groups and interviews were digitally recorded, transcribed verbatim, and analysed with a thematic approach. Findings suggest that transgender women and sexually diverse men in Kingston are aware of, and managing survival challenges and HIV risks in contexts of social inequity. Daily survival challenges include stigma and a lack of human rights protections that contributed to barriers to employment, housing, healthcare, education, and exposure to violence. Challenges maintaining sexual relationships included the need to hide for safety, often resulting in difficulties forming lasting relationships. These survival and relationship challenges converged to lower self-esteem and self-acceptance. In the face of these challenges, participants navigated sexual risk and pleasure. Findings provide insight into agency and sexual decision-making processes in contexts of social inequities. Findings can inform multi-level strategies to promote social equity, sexual health, and HIV prevention with young transgender women and sexually diverse men in Jamaica. PMID- 30475168 TI - College degree attainment by age of first marijuana use and parental education. AB - BACKGROUND: Age of first marijuana use is a key predictor of later educational outcomes, but limited work has identified demographic factors that impact this association across continuous ages of first use. The purpose of this study was threefold: (1) to identify the age-varying prevalence of later college degree attainment as a function of age of first marijuana use; (2) to examine the age varying association of gender and college degree attainment as a function of age of first use; and (3) to examine the age-varying association of parent education and college degree attainment as a function of age of first use. METHODS: Data were from the panel portion of the Monitoring the Future (MTF) study, an ongoing longitudinal study of adolescents and young adults. Those who used marijuana by age 22 were included in analyses. Among these participants (N = 2134), 47.0% were male, 67.5% were white, 53.2% reported having at least one parent with a bachelor's degree or higher, and 44.1% attained a bachelor's degree or higher by age 25/26. RESULTS: Intercept-only and logistic time-varying effect models (TVEMs) modeled prevalences and associations as functions of age of first marijuana use. Prevalence of college degree completion was relatively linear across age of first use; such that college degree attainment increased as age of first use increased. Results indicated that college degree attainment varied across age of first use similarly for men and women. Degree attainment differences existed based on parent education. Parental education and degree attainment were most strongly linked at an age of first use between 16 and 19 years. CONCLUSIONS: Findings suggest that age of first marijuana use has an association with academic achievement such that earlier ages of first use are associated with lower academic achievement later in adulthood. Parental education serves as a protective factor against college degree attainment in late adolescence. PMID- 30475169 TI - Association of Single Nucleotide Polymorphisms in TNFA and IL10 Genes with Disease Severity in Influenza A/H1N1pdm09 Virus Infections: A Study from Western India. AB - Susceptibility to severe influenza A/H1N1pdm09 virus is multifactorial. The present study was carried out in 246 patients infected with A/H1N1pdm09 virus to find out whether single nucleotide polymorphisms (SNPs) in the genes coding for proinflammatory and anti-inflammatory cytokines are associated with disease severity. Among the cases, 129 had mild disease, whereas 117 had severe disease. There were 27 fatal cases. TNFA rs1800629, IFNG rs2430561, IL10 rs1800872, IL10 rs1800896, and CCL2 rs1024611 SNPs were genotyped by polymerase chain reaction based methods. A significantly higher frequency of TNFA rs1800629 "G/A" genotype was observed in severe and fatal cases compared with mild and survived cases, respectively. In a dominant mode, IL10 rs1800896 "G" allele was significantly negatively associated with disease severity. IL10 rs1800896 "C/A" genotype was significantly associated with fatality in influenza A/H1N1pdm09 infections. The results suggest that SNPs in the IL10 and TNFA genes might be associated with disease severity in influenza A/H1N1pdm09-infected patients. PMID- 30475170 TI - Assessing Experiences With LGBT Microaggressions in the Workplace: Development and Validation of the Microaggression Experiences at Work Scale. AB - LGBT people experience microaggressions in the workplace; however, limited research exists in this area partly due to a lack of psychometrically sound instruments measuring the prevalence of LGBT microaggressions in the workplace. To address this gap, an empirical study was conducted and the LGBT-MEWS was created and tested. The LGBT-MEWS is a 27-item self-report scale comprising three subscales. Each subscale conceptually represents a different domain through which microaggressions impact LGBT employees: (1) workplace values, (2) heteronormative assumptions, and (3) cisnormative culture. The results of testing indicated that the subscales demonstrate strong reliability and validity. PMID- 30475171 TI - Both thapsigargin- and tunicamycin-induced endoplasmic reticulum stress increases expression of Hrd1 in IRE1-dependent fashion. AB - OBJECTIVES: We have investigated the impact of endoplasmic reticulum (ER) stress, which is often implicated in neurodegenerative diseases, on the expression of Hrd1, an E3 ubiquitin ligase that plays a central role in the process of ER associated degradation (ERAD). METHODS: SH-SY5Y neuroblastoma cells, a frequently used model for studying neurotoxicity in dopaminergic neurons and the mechanisms of neurodegeneration associated with Parkinson's disease, and parental SK-N-SH cells were studied. RESULTS: We demonstrate that ER stress, induced by thapsigargin or tunicamycin, correlates with the increased expression of Hrd1 in both SH-SY5Y and SK-N-SH cells. Inhibition of PERK does not significantly suppress the thapsigargin- or tunicamycin-induced expression of Hrd1. Nevertheless, PERK inhibition has a positive effect on the survival of SH-SY5Y cells treated with thapsigargin but not on those treated with tunicamycin. Inhibition of IRE1 associated with the inhibition of XBP1 splicing does not affect the survival of SH-SY5Y cells treated with either thapsigargin or tunicamycin but results in the complete suppression of both the thapsigargin- and tunicamycin-induced expression of Hrd1. DISCUSSION: Thus, the ER-stress-induced expression of Hrd1 in SH-SY5Y depends on Hrd1 transcription activation, which is a consequence of IRE1 but not of PERK activation. PMID- 30475172 TI - Bone changes in the lower limbs from participation in an FES rowing exercise program implemented within two years after traumatic spinal cord injury. AB - OBJECTIVE: To determine the effect of a functional electrical stimulation (FES) rowing program on bone mineral density (BMD) when implemented within two years after SCI. DESIGN: Prospective. SETTING: Health Care Facility. PARTICIPANTS: Convenience sample; four adults with recent (<2 years) traumatic, motor complete SCI (C7-T12 AIS A-B). INTERVENTION: A 90-session FES rowing exercise program; participants attended 30-minute FES training sessions approximately three times each week for the duration of their participation. OUTCOME MEASURES: BMD in the distal femur and tibia were measured using peripheral Quantitative Computed Tomography (pQCT) at enrollment (T0) and after 30 (T1), 60 (T2), and 90 (T3) sessions. Bone stimulus was calculated for each rower at each time point using the average number of weekly loading cycles, peak foot reaction force, and bone mineral content from the previous time point. A regression analysis was used to determine the relationship between calculated bone stimulus and change in femoral trabecular BMD between time points. RESULTS: Trabecular BMD in the femur and tibia decreased for all participants in T0-1, but the rate of loss slowed or reversed between T1-2, with little-to-no bone loss for most participants during T2-3. The calculated bone stimulus was significantly correlated with change in femoral trabecular BMD (P = 0.016; R2 = 0.458). CONCLUSION: Consistent participation in an FES rowing program provides sufficient forces and loading cycles to reduce or reverse expected bone loss at the distal femur and tibia, at least temporarily, in some individuals within two years after SCI. TRIAL REGISTRATION: NCT02008149. PMID- 30475173 TI - Early microalbuminuria as a clinical marker for acute cerebral small vessel infarction. AB - BACKGROUND: Previous studies have shown the potential interactions between cerebrovascular diseases and microalbuminuria. However, the relationship between urine microalbumin and acute lacunar infarction caused by cerebral small vessel disease (CSVD) remains unknown. METHODS: The clinical data of 148 patients with acute lacunar infarction admitted to the Department of Neurology, Shengjing Hospital of China Medical University between April 2016 and April 2017 were analyzed. They were divided into either a CSVD group (n = 70) or a cerebral large vessel disease (CLVD) group (n = 78) according to their carotid artery B-mode ultrasonography and head magnetic resonance angiography (MRA) findings. The concentration of urinary microalbumin in both groups was determined. Statistic analysis was conducted using SAS 9.1 software (North Carolina state university, USA). A Logistic regression analysis was used to determine the independent risk factors for acute lacunar infarction caused by CSVD. RESULTS: The concentration of urine microalbumin in the CSVD group (23 +/- 12 mg/L) was significantly lower than that in the CLVD group (29 +/- 15 mg/L) (p < 0. 01). However, there was an increasing trend for the proportion of patients with urine microalbumin concentration 10- < 30 mg/L (34.3%) in the CSVD group compared with the CLVD group (19.2%). Logistic regression analysis showed that microalbuminuria (10- < 30 mg/L) was independently associated with acute lacunar infarction caused by CSVD (OR = 3.582; 95% CI 1.347~6.274; p < 0.01). CONCLUSIONS: These findings demonstrate that in patients with acute lacunar infarction, slightly increased microalbuminuria seems to be a potential clinical marker for CSVD. The presence of microalbuminuria early may help to differentiate CSVD from stroke subtypes. PMID- 30475174 TI - Just Policy? An Ethical Analysis of Early Intervention Policy Guidance. AB - Early intervention (EI) aims to identify children or families at risk of poor health, and take preventative measures at an early stage, when intervention is more likely to succeed. EI is concerned with the just distribution of "life chances," so that all children are given fair opportunity to realize their potential and lead a good life; EI policy design, therefore, invokes ethical questions about the balance of responsibilities between the state, society, and individuals in addressing inequalities. We analyze a corpus of EI policy guidance to investigate explicit and implicit ethical arguments about who should be held morally responsible for safeguarding child health and well-being. We examine the implications of these claims and explore what it would mean to put the proposed policies into practice. We conclude with some remarks about the useful role that philosophical analysis can play in EI policy development. PMID- 30475175 TI - The Epigenetic Imperative: Responsibility for Early Intervention at the Time of Biological Plasticity. PMID- 30475176 TI - Health Research Priority Setting: The Duties of Individual Funders. AB - The vast majority of health research resources are used to study conditions that affect a small, advantaged portion of the global population. This distribution has been widely criticized as inequitable and threatens to exacerbate health disparities. However, there has been little systematic work on what individual health research funders ought to do in response. In this article, we analyze the general and special duties of research funders to the different populations that might benefit from health research. We assess how these duties apply to governmental, multilateral, nonprofit, and for-profit organizations. We thereby derive a framework for how different types of funders should take the beneficiaries of research into account when they allocate scarce research resources. PMID- 30475177 TI - Beyond Parenting: The Responsibility of Multidisciplinary Health Care Providers in Early Intervention Policy Guidance. PMID- 30475178 TI - Public Health Disaster-Related Research: A Solidaristic Ethical Prism for Understanding Funders' Duties. PMID- 30475179 TI - Acquired Duties for Ethical Research With American Indian/Alaska Native Populations: An Application of Pierson and Millum's Framework. PMID- 30475180 TI - Conceptual, Structural, and Practical Challenges to Ethical Allocation of Research Funds. PMID- 30475181 TI - Is There a Business Case for Constitutive Duties of For-Profit Research Funders? PMID- 30475182 TI - Distinguishing Primary and Secondary Early Intervention Programs: Implications for Families, Clinicians, and Policymakers. PMID- 30475183 TI - Just Ethics? Bioethical Prescriptions for Policymakers Should Remain Communal. PMID- 30475184 TI - One Health, Bioethics, and Nonhuman Ethics. PMID- 30475185 TI - Universal Funder Responsibilities That Advance Social Value. PMID- 30475186 TI - Aligning Research Priorities to Improve Equity: A Challenge for Health Funders. PMID- 30475187 TI - Priority Setting Is More Than Resource Allocation: Reflecting on the Content of Funders' Duties and Their Implications for Current Practice. PMID- 30475188 TI - Health Research Priority Setting: A Duty to Maximize Social Value? PMID- 30475189 TI - Asymmetrical Intuitions. PMID- 30475190 TI - Response to Commentaries on "Shrinking Poor White Life Spans". PMID- 30475191 TI - Family Ethics and Public Policy: Beyond the Medical Model. PMID- 30475192 TI - Response from UK Society of Behaviour Analysis - Positive Behaviour Support Special Interest Group. PMID- 30475194 TI - Complex personality disorders. PMID- 30475193 TI - Child maltreatment and mental health problems in adulthood: birth cohort study. AB - BACKGROUND: Retrospective studies have shown a high association between child abuse and subsequent psychiatric morbidity. Prospective studies are rarer.AimsTo examine, using a prospective record-linkage analysis, whether substantiated child maltreatment is associated with adverse psychological outcomes in early adulthood. METHOD: The participants were 3778 mother and child pairs enrolled in a population-based birth cohort study in Brisbane, Australia. Exposure to suspected child maltreatment was measured by linkage with state child protection agency data. The primary outcomes were the internalising and externalising scales of the Youth Self-Report and the Centre for Epidemiological Studies-Depression scales (CES-D) at approximately 21 years of age. A subset completed the Composite International Diagnostic Interview-Auto version (CIDI-Auto). RESULTS: In total, 171 (4.5%) participants had a history of substantiated child maltreatment, most commonly emotional abuse (n = 91), followed by physical abuse (n = 78), neglect (n = 73) and sexual abuse (n = 54). After adjustment for potential confounders, depressive symptoms on the CES-D, as well as internalising and externalising behaviours were strongly associated with substantiated abuse in all forms, except sexual abuse. The results for the subset of the sample who completed the CIDI Auto were less clear. Anxiety, especially post-traumatic stress disorder, showed the strongest association whereas the findings for depressive disorder were equivocal. However, across all diagnostic categories, emotional abuse and neglect, as well as multiple forms of abuse, showed a consistent association. CONCLUSIONS: Child maltreatment, particularly neglect and emotional abuse, has serious adverse effects on early adult mental health. These two warrant the attention given to other forms of child maltreatment. Children experiencing more than one type of maltreatment are at particular risk.Declaration of interestNone. PMID- 30475195 TI - Unleashing talent in mental health sciences: gender equality at the top. AB - SummarySociety is undergoing a shift in gender politics. Science and medicine are part of this conversation, not least as women's representation and pay continue to drop as one progresses through more senior academic and clinical levels. Naming and redressing these inequalities needs to be a priority for us all.Declaration of interestNone. PMID- 30475196 TI - Gender discrimination, victimisation and women's mental health. AB - SummaryGender inequality and discrimination, as well as violence and victimisation towards women, have recently hit the headlines creating a media furore. We provide a timely discussion surrounding the impact of these issues on women's mental health and a discussion of the role of psychiatry in this context.Declaration of interestK.B. is the editor for the British Journal of Psychiatry but has not played a role in the decision to accept this editorial for publication in this journal. G.H. has no conflict of interest to declare. PMID- 30475197 TI - Kaleidoscope. PMID- 30475199 TI - Social aspects of dementia and dementia practice. AB - Social aspects of dementia are becoming increasingly important as part of a wider shift in emphasis from cure to care. This is partly because approaches based on finding a cure have proved far more difficult and complex than originally imagined (WHO, 2016). New evidence on the effectiveness of public health measures, that while incidence is growing as the proportion of older people in society increases its prevalence amongst older adults is actually falling, has also lead to increased interest in social dimensions of prevention, lifestyle change, and practical intervention in community settings (Prince et al., 2016; Kivipelto et al., 2017). This, in turn, has led to a rediscovery of the role of supports to people living with dementia in their daily lives, the needs of informal carers, and professional activities that can maintain the social engagement of each party (Winblad et al., 2016). The expansion of practice around person-centered care, beyond traditional institutional settings, has also contributed to a socialized view of how interactions in dementia care are thought about (Bartlett et al., 2017), as has an increased awareness of the effects of the social construction of dementia in the public mind (Biggs, 2018). Most recently, people living with dementia, and particularly with respect to younger onset dementia, have begun to find a voice and to make connections to the wider disability movement (Dementia Alliance International, 2017). Each of these developments, in their different ways, have led to a re-emphasis on psycho-social elements of dementia, its experience, and how that might translate into clinical practice and service delivery. PMID- 30475198 TI - Where are we at with model-based economic evaluations of interventions for dementia? a systematic review and quality assessment. AB - : ABSTRACTObjective:To identify, review, and critically appraise model-based economic evaluations of all types of interventions for people with dementia and their carers. DESIGN: A systematic literature search was undertaken to identify model-based evaluations of dementia interventions. A critical appraisal of included studies was carried out using guidance on good practice methods for decision-analytic models in health technology assessment, with a focus on model structure, data, and model consistency. SETTING: Interventions for people with dementia and their carers, across prevention, diagnostic, treatment, and disease management. RESULTS: We identified 67 studies, with 43 evaluating pharmacological products, 19 covering prevention or diagnostic strategies, and 5 studies reporting non-pharmacological interventions. The majority of studies use Markov models with a simple structure to represent dementia symptoms and disease progression. Half of all studies reported taking a societal perspective, with the other half adopting a third-party payer perspective. Most studies follow good practices in modeling, particularly related to the decision problem description, perspective, model structure, and data inputs. Many studies perform poorly in areas related to the reporting of pre-modeling analyses, justifying data inputs, evaluating data quality, considering alternative modeling options, validating models, and assessing uncertainty. CONCLUSIONS: There is a growing literature on the model-based evaluations of interventions for dementia. The literature predominantly reports on pharmaceutical interventions for Alzheimer's disease, but there is a growing literature for dementia prevention and non-pharmacological interventions. Our findings demonstrate that decision-makers need to critically appraise and understand the model-based evaluations and their limitations to ensure they are used, interpreted, and applied appropriately. PMID- 30475200 TI - Characterization of a colistin-resistant Avian Pathogenic Escherichia coli ST69 isolate recovered from a broiler chicken in Germany. AB - In recent years, several plasmids harbouring genes encoding phosphoethanolamine transferases conferring colistin resistance have been described in multiple Enterobacteriaceae species. Avian Pathogenic E. coli (APEC) causes colibacillosis and is responsible for a considerable proportion of the disease burden in commercial poultry flocks, and may be linked to zoonotic infections in humans. Here, we describe the genotypic and phenotypic characteristics of a multidrug resistant APEC ST69 isolate (APECA2), recovered in 2016 from a diseased broiler at post-mortem examination in Germany. The isolate was resistant to several antibiotics of human and veterinary importance, including colistin. The mcr-1 gene was detected on a mobile genetic element located on an IncHI2/ST4 plasmid, which was characterized using long-read Nanopore and short-read Illumina sequencing of purified plasmid. Isolate APECA2 displayed resistance to chicken serum and harbours numerous virulence genes. This study highlights the public health importance of enhanced antimicrobial resistance surveillance and strict antimicrobial stewardship in human and veterinary healthcare. PMID- 30475201 TI - Regulation of cid and lrg expression by CcpA in Streptococcus mutans. AB - The Streptococcus mutans Cid/Lrg system represents an ideal model for studying this organism's ability to withstand various stressors encountered in the oral cavity. The lrg and cid operons display distinct and opposite patterns of expression in response to growth phase and glucose levels, suggesting that the activity and regulation of these proteins must be tightly coordinated in the cell and closely associated with metabolic pathways of the organism. Here, we demonstrate that expression of the cid and lrg operons is directly mediated by a global transcriptional regulator CcpA in response to glucose levels. Comparison of the cid and lrg promoter regions with the conserved CcpA binding motif revealed the presence of two potential cre sites (for CcpA binding) in the cid promoter (designated cid-cre1 and cid-cre2), which were arranged in a similar manner to those previously identified in the lrg promoter region (designated lrg cre1 and lrg-cre2). We demonstrated that CcpA binds to both the cid and lrg promoters with a high affinity, but has an opposing glucose-dependent effect on the regulation of cid (positive) and lrg (negative) expression. DNase I footprinting analyses revealed potential binding sequences for CcpA in both cid and lrg promoter regions. Collectively, these data suggest that CcpA is a direct regulator of cid and lrg expression, and are suggestive of a potential mechanism by which Cid/Lrg-mediated virulence and cellular homeostasis is integrated with signals associated with both the environment and cellular metabolic status. PMID- 30475202 TI - Capsulimonas corticalis gen. nov., sp. nov., an aerobic capsulated bacterium, of a novel bacterial order, Capsulimonadales ord. nov., of the class Armatimonadia of the phylum Armatimonadetes. AB - An aerobic bacterial strain designated AX-7T was isolated from the trunk surface of a Japanese beech (Fagus crenata). Cells of strain AX-7T were Gram-stain negative, non-spore-forming, non-motile rods (1.0-1.2 um in width and 1.2-3.0 um in length) with peritrichous fimbriae. Cells were capsulated, and a number of them were surrounded by a thick slime layer. During growth, large aggregates formed, and the culture medium became viscous probably owing to exopolysaccharide release from the slime layer. The temperature range for growth was 10-37 degrees C, with an optimum at 30 degrees C. The pH range for growth was 5.0-7.0, with an optimum at pH 6.0. Strain AX-7T used various sugars, including polysaccharides, and yeast extract as growth substrates. Strain AX-7T contained menaquinones MK-9 and MK-10 as the respiratory quinones, and C16 : 1omega5c, C16 : 1omega11c, C16 : 0 and C14 : 0 as the major cellular fatty acids. Four unidentified phospholipids and 11 unidentified polar lipids constituted the polar lipids. The DNA G+C content was 61.0 mol%. The cell-wall peptidoglycan contained ll-diaminopimelic acid. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain AX-7T belonged to the class Armatimonadia, its closest relative being Armatimonas rosea YO-36T, with sequence similarity of 88.1%. Based on data from this polyphasic study, we propose that strain AX-7T represents a new genus of a novel species within the novel order Capsulimonadales ord. nov. of the class Armatimonadia, for which the name Capsulimonas corticalis gen. nov., sp. nov. is proposed. The type strain of C. corticalis is AX-7T (=DSM 105890T=NBRC 113044T). PMID- 30475203 TI - The shape of the ribosome exit tunnel affects cotranslational protein folding. AB - The E.coli ribosome exit tunnel can accommodate small folded proteins, while larger ones fold outside. It remains unclear, however, to what extent the geometry of the tunnel influences protein folding. Here, using E. coli ribosomes with deletions in loops in proteins uL23 and uL24 that protrude into the tunnel, we investigate how tunnel geometry determines where proteins of different sizes fold. We find that a 29-residue zinc-finger domain normally folding close to the uL23 loop folds deeper in the tunnel in uL23 Dloop ribosomes, while two ~100 residue protein normally folding close to the uL24 loop near the tunnel exit port fold at deeper locations in uL24 Dloop ribosomes, in good agreement with results obtained by coarse-grained molecular dynamics simulations. This supports the idea that cotranslational folding commences once a protein domain reaches a location in the exit tunnel where there is sufficient space to house the folded structure. PMID- 30475204 TI - Hyperactivation of ERK by multiple mechanisms is toxic to RTK-RAS mutation-driven lung adenocarcinoma cells. AB - Synthetic lethality results when mutant KRAS and EGFR proteins are co-expressed in human lung adenocarcinoma (LUAD) cells, revealing the biological basis for mutual exclusivity of KRAS and EGFR mutations. We have now defined the biochemical events responsible for the toxic effects by combining pharmacological and genetic approaches and to show that signaling through extracellular signal regulated kinases (ERK1/2) mediates the toxicity. These findings imply that tumors with mutant oncogenes in the RAS pathway must restrain the activity of ERK1/2 to avoid toxicities and enable tumor growth. A dual specificity phosphatase, DUSP6, that negatively regulates phosphorylation of (P)-ERK is up regulated in EGFR- or KRAS-mutant LUAD, potentially protecting cells with mutations in the RAS signaling pathway, a proposal supported by experiments with DUSP6-specific siRNA and an inhibitory drug. Targeting DUSP6 or other negative regulators might offer a treatment strategy for certain cancers by inducing the toxic effects of RAS-mediated signaling. PMID- 30475205 TI - Mechanical force regulates tendon extracellular matrix organization and tenocyte morphogenesis through TGFbeta signaling. AB - Mechanical forces between cells and extracellular matrix (ECM) influence cell shape and function. Tendons are ECM-rich tissues connecting muscles with bones that bear extreme tensional force. Analysis of transgenic zebrafish expressing mCherry driven by the tendon determinant scleraxis reveals that tendon fibroblasts (tenocytes) extend arrays of microtubule-rich projections at the onset of muscle contraction. In the trunk, these form a dense curtain along the myotendinous junctions at somite boundaries, perpendicular to myofibers, suggesting a role as force sensors to control ECM production and tendon strength. Paralysis or destabilization of microtubules reduces projection length and surrounding ECM, both of which are rescued by muscle stimulation. Paralysis also reduces SMAD3 phosphorylation in tenocytes and chemical inhibition of TGFbeta signaling shortens tenocyte projections. These results suggest that TGFbeta, released in response to force, acts on tenocytes to alter their morphology and ECM production, revealing a feedback mechanism by which tendons adapt to tension. PMID- 30475206 TI - Splicing factors Sf3A2 and Prp31 have direct roles in mitotic chromosome segregation. AB - Several studies have shown that RNAi-mediated depletion of splicing factors (SFs) results in mitotic abnormalities. However, it is currently unclear whether these abnormalities reflect defective splicing of specific pre-mRNAs or a direct role of the SFs in mitosis. Here we show that two highly conserved SFs, Sf3A2 and Prp31, are required for chromosome segregation in both Drosophila and human cells. Injections of anti-Sf3A2 and anti-Prp31 antibodies into Drosophila embryos disrupt mitotic division within 1 minute, arguing strongly against a splicing related mitotic function of these factors. We demonstrate that both SFs bind spindle microtubules (MTs) and the Ndc80 complex, which in Sf3A2- and Prp31 depleted cells is not tightly associated with the kinetochores; in HeLa cells the Ndc80/HEC1-SF interaction is restricted to the M phase. These results indicate that Sf3A2 and Prp31 directly regulate interactions among kinetochores, spindle microtubules and the Ndc80 complex in both Drosophila and human cells. PMID- 30475207 TI - FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer. AB - Changes in cancer cell identity can alter malignant potential and therapeutic response. Loss of the pulmonary lineage specifier NKX2-1 augments the growth of KRAS-driven lung adenocarcinoma and causes pulmonary to gastric transdifferentiation. Here we show that the transcription factors FoxA1 and FoxA2 are required for initiation of mucinous NKX2-1-negative lung adenocarcinomas in the mouse and for activation of their gastric differentiation program. Foxa1/2 deletion severely impairs tumor initiation and causes a proximal shift in cellular identity, yielding tumors expressing markers of the squamocolumnar junction of the gastrointestinal tract. In contrast, we observe downregulation of FoxA1/2 expression in the squamous component of both murine and human lung adenosquamous carcinoma. Using sequential in vivo recombination, we find that FoxA1/2 loss in established KRAS-driven neoplasia originating from SPC-positive alveolar cells induces keratinizing squamous cell carcinomas. Thus, NKX2-1, FoxA1 and FoxA2 coordinately regulate the growth and identity of lung cancer in a context-specific manner. PMID- 30475210 TI - Response to short-term deprivation of the human adult visual cortex measured with 7T BOLD. AB - Sensory deprivation during the post-natal 'critical period' leads to structural reorganization of the developing visual cortex. In adulthood, the visual cortex retains some flexibility and adapts to sensory deprivation. Here we show that short-term (2h) monocular deprivation in adult humans boosts the BOLD response to the deprived eye, changing ocular dominance of V1 vertices, consistent with homeostatic plasticity. The boost is strongest in V1, present in V2, V3 and V4 but absent in V3a and hMT+. Assessment of spatial frequency tuning in V1 by a population Receptive-Field technique shows that deprivation primarily boosts high spatial frequencies, consistent with a primary involvement of the parvocellular pathway. Crucially, the V1 deprivation effect correlates across participants with the perceptual increase of the deprived eye dominance assessed with binocular rivalry, suggesting a common origin. Our results demonstrate that visual cortex, particularly the ventral pathway, retains a high potential for homeostatic plasticity in the human adult. PMID- 30475208 TI - ppargc1a controls nephron segmentation during zebrafish embryonic kidney ontogeny. AB - Nephron segmentation involves a concert of genetic and molecular signals that are not fully understood. Through a chemical screen, we discovered that alteration of peroxisome proliferator-activated receptor (PPAR) signaling disrupts nephron segmentation in the zebrafish embryonic kidney (Poureetezadi et al., 2016). Here, we show that the PPAR co-activator ppargc1a directs renal progenitor fate. ppargc1a mutants form a small distal late (DL) segment and an expanded proximal straight tubule (PST) segment. ppargc1a promotes DL fate by regulating the transcription factor tbx2b, and restricts expression of the transcription factor sim1a to inhibit PST fate. Interestingly, sim1a restricts ppargc1a expression to promote the PST, and PST development is fully restored in ppargc1a/sim1a deficient embryos, suggesting Ppargc1a and Sim1a counterbalance each other in an antagonistic fashion to delineate the PST segment boundary during nephrogenesis. Taken together, our data reveal new roles for Ppargc1a during development, which have implications for understanding renal birth defects. PMID- 30475209 TI - Endocytosis at the Drosophila blood-brain barrier as a function for sleep. AB - Glia are important modulators of neural activity, yet few studies link glia to sleep regulation. We find that blocking activity of the endocytosis protein, dynamin, in adult Drosophila glia increases sleep and enhances sleep need, manifest as resistance to sleep deprivation. Surface glia comprising the fly equivalent of the blood-brain barrier (BBB) mediate the effect of dynamin on sleep. Blocking dynamin in the surface glia causes ultrastructural changes, albeit without compromising the integrity of the barrier. Supporting a role for endocytic trafficking in sleep, a screen of Rab GTPases identifies sleep modulating effects of the recycling endosome Rab11 in surface glia. We also find that endocytosis is increased in BBB glia during sleep and reflects sleep need. We propose that endocytic trafficking through the BBB represents a function of sleep. PMID- 30475211 TI - Translational initiation factor eIF5 replaces eIF1 on the 40S ribosomal subunit to promote start-codon recognition. AB - In eukaryotic translation initiation AUG recognition of the mRNA requires accommodation of Met-tRNAi in a 'PIN' state, which is antagonized by the factor eIF1. eIF5 is a GTPase activating protein (GAP) of eIF2 that additionally promotes stringent AUG selection, but the molecular basis of its dual function was unknown. We present a cryo-electron microscopy (cryo-EM) reconstruction of a yeast 48S pre-initiation complex (PIC), at an overall resolution of 3.0 A, featuring the N-terminal domain (NTD) of eIF5 bound to the 40S subunit at the location vacated by eIF1. eIF5 interacts with and allows a more accommodated orientation of Met-tRNAi. Substitutions of eIF5 residues involved in the eIF5 NTD/tRNAi interaction influenced initiation at near-cognate UUG codons in vivo, and the closed/open PIC conformation in vitro, consistent with direct stabilization of the codon:anticodon duplex by the wild-type eIF5-NTD. The present structure reveals the basis for a key role of eIF5 in start-codon selection. PMID- 30475212 TI - Lamivudine's efficacy and safety in preventing mother-to-child transmission of hepatitis B: A meta-analysis. AB - BACKGROUND/AIMS: Mother-to-child transmission (MTCT) is a common transmission mode of hepatitis B virus (HBV). It has been shown that the infection may occur in some infants despite the use of immunoprophylaxis, and many studies have demonstrated the efficacy of antivirals such as lamivudine to reduce such events. MATERIALS AND METHODS: A meta-analysis was conducted concerning the efficacy and safety of lamivudine during pregnancy, in the prevention of vertical transmission of HBV infection. Studies were identified by searching various databases up to January 2016 for variations of the following phrase: "lamivudine AND (pregnancy or pregnant) AND (HBV or hepatitis)." Subjects who had received lamivudine were included in the case group, and those who had not were included in the control group. RESULTS: Our search identified a total number of 881 citations, of which 25 studies (with a total number of 2,667 pregnant women) were included in the meta-analysis. The analysis showed a significant difference between the seropositive HBsAg infants from the case and control groups (RR= 16.97, 95% confidence interval 8.36-34.45), which is the most critical factor in determining the MTCT of HBV. No significant difference was reported between the prevalence of side effects in the case and control groups. CONCLUSION: This meta-analysis strongly suggests the use of lamivudine in the prevention of HBV vertical transmission in carrier pregnant women with the HBV DNA levels greater than 106 copies/mL. And for women with the HBV viral loads lower than 106 copies/mL, we suggest clinicians to examine the use of lamivudine on a case-to-case basis, noting that lamivudine seems to be a safe drug for the mother and the fetus. PMID- 30475213 TI - Prevalence of Induced Abortion in Iran: A Comparison of Two Indirect Estimation Techniques. AB - CONTEXT: Surveys that use direct questions to ascertain women's history of induced abortion tend to underestimate abortion prevalence, especially in such contexts as Iran where the procedure is legally restricted and highly stigmatized. No previous study has compared two indirect techniques for estimating abortion prevalence. METHODS: A sample of 708 married women were recruited from one public hospital in Tehran between August and December 2013. Participants completed a survey, which included induced abortion estimation using the randomized response technique (RRT) and the unmatched count technique (UCT), as well as questions about demographic characteristics, trust in direct questions about abortion, and comprehensibility of and trust in RRT and UCT. Prevalence of induced abortion was calculated for each technique. Spearman correlation was used to evaluate whether comprehensibility of and trust in estimation methods were associated with women's age and education. RESULTS: The prevalence of induced abortion was estimated to be 14% using RRT and 12% using UCT; the estimates were not significantly different. Ninety-one percent of women reported that UCT was very easy to comprehend; the proportion for RRT was 78%. Sixty-three percent of women reported completely trusting in the confidentiality of UCT; the proportion for RRT was 50%. Age was inversely associated with comprehensibility for UCT (correlation coefficient, -0.13), and with trust for both RRT and UCT (-0.12 and 0.08, respectively); education was directly associated with trust for both methods (0.24 and 0.22). CONCLUSIONS: Of the two indirect methods, UCT may be simpler and more dependable for the estimation of induced abortion prevalence in low-literacy, abortion-restricted settings. PMID- 30475214 TI - Dibenzoylmethane ameliorates lipid-induced inflammation and oxidative injury in diabetic nephropathy. AB - Dibenzoylmethane (DBM) is a beta-diketone analog of curcumin. Numerous studies have shown the beneficial effects of curcumin on diabetes, obesity and diabetic complications including diabetic nephropathy. Recently, we investigated the beneficial metabolic effects of DBM on high-fat diet-induced obesity. However, the effects and mechanisms of action of DBM in the kidney are currently unknown. To investigate the renoprotective effects of DBM in type 2 diabetes, we administered DBM (100 mg/kg) orally for 12 weeks to high-fat diet-induced diabetic model mice. We used mouse renal mesangial (MES13) and macrophage (RAW 264.7) cells to examine the mechanism of action of DBM (20 MUM). After DBM treatment, the albumin-to-creatinine ratio was significantly decreased compared to that of the high-fat-diet group. Moreover, damaged renal ultra-structures and functions including increased glomerular volume, glomerular basement membrane thickness and inflammatory signals were ameliorated after DBM treatment. Stimulation of MES13 and RAW264.7 cells by palmitate or high-dose glucose with lipopolysaccharides increased inflammatory signals and macrophage migration. However, these changes were reversed by DBM treatment. In addition, DBM inhibited NADPH oxidase 2 and 4 expression and oxidative DNA damage. Collectively, these data suggested that DBM prevented diabetes-induced renal injury through its anti inflammatory and antioxidant effects. PMID- 30475215 TI - Molecular genetic insights into sporadic primary hyperparathyroidism. AB - Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by dysregulation of parathyroid hormone release. The large majority of PHPT cases are attributable to sporadic, single-gland parathyroid adenoma, in which MEN1 and CCND1/cyclin D1 are the most well-established drivers of tumorigenesis. Sporadic parathyroid carcinoma, which appears to mostly arise through molecular pathways distinct from those causing benign parathyroid tumors, is rare and is most frequently driven by mutational inactivation of the CDC73 (HRPT2) tumor suppressor gene. Targeted investigation of suspected tumor driver genes, as well as unbiased whole-genome or exome sequencing of small cohorts, have revealed additional novel candidate tumor genes in sporadic parathyroid neoplasia, generally at modest or low mutational frequencies consistent with marked molecular genetic heterogeneity from tumor to tumor. The ability of these additional candidates to participate in the pathogenic process of driving parathyroid tumorigenesis in vivo largely remains to be demonstrated experimentally. This review will summarize the molecular genetic abnormalities identified to date in sporadic PHPT and discuss the strength of evidence for their proposed roles in parathyroid tumor formation. PMID- 30475216 TI - Honey dressing on a leg ulcer with tendon exposure in a patient with type 2 diabetes. AB - Honey has been used as a wound dressing for hundreds of years by ancient civilizations, but only recently it has acquired scientific interest because of its relevant biological properties. In the last decade, indeed, several trials and observational studies have reported that, compared to conventional treatment (e.g. antiseptics, polyurethane film, paraffin gauze, soframycin-impregnated gauze), honey dressings seem to be better in healing time of different types of wounds, including diabetic foot ulcers. However, to date, information about a potential favorable biological effect of honey dressings on diabetic ulcers with exposed tendon are still scarce. Notably, foot or leg ulcers with exposed tendon are serious complications in patients with type 2 diabetes, as they are associated with an increased risk of adverse outcome. Therefore, the use of effective and safe treatments to bring these lesions to timely healing is very important in clinical practice. We herein report the case of a Caucasian adult patient with type 2 diabetes presenting a chronic right posterior lower limb ulcer (Texas University Classification (TUC) 2D) with tendon exposure that was successfully treated with honey dressings (glucose oxidase (GOX) positive with peroxide activity) in addition to systemic antibiotic therapy, surgical toilette and skin graft. In our case, the use of honey dressing for treating exposed tendon tissue probably allowed the timely wound healing. Although further studies are required, such treatment may constitute part of the comprehensive management of diabetic wounds, including those with tendon exposure, and should be considered by clinicians in clinical practice. Learning points: Honey has been used as a wound dressing for hundreds of years, but only recently it has acquired scientific interest for its biological properties. Several studies have documented that, compared to conventional dressings, honey seems to be better in healing time of different types of wounds, including diabetic foot ulcers. Our case report is the first to highlight the importance to use honey dressings also for the treatment of ulcers with tendon exposure in patients with type 2 diabetes, suggesting that this kind of dressing should be considered by clinicians in clinical practice. PMID- 30475217 TI - Somatic mutations in adrenocortical carcinoma with hyperaldosteronism. AB - Several somatic mutations specific to aldosterone-producing adenomas (APA) have been described. A small proportion of adrenocortical carcinomas (ACC) are associated with hyperaldosteronism, either primary aldosteronism or hyperreninemic hyperaldosteronism. However, it is unknown, whether they harbor mutations of the same spectrum as APAs. The objective of this study is to describe the clinical phenotype and molecular genotype of ACCs with hyperaldosteronism, particularly the analysis for common APA-associated genetic changes. Patients were identified by retrospective chart review at a specialized referral center and by positive staining for CYP11B2 of tissue microarrays. 25 patients with ACC and hyperaldosteronism were initially identified by retrospective chart review and tissue for further analysis was available on 13 tumors. Seven patients were identified by positive staining for CYP11B2 in a tissue microarray, of which 2 were already identified in the initial chart review. Therefore, a total number of 18 patients with a diagnosis of ACC and features of either primary aldosteronism or hyperreninemic hyperaldosteronism were therefore included in the final study. Mutational status for a select list of oncogenes, tumor suppressor genes, and genes known to carry mutations in APAs were analyzed by next generation sequencing. Review of clinical data suggested autonomous aldosterone production in the majority of cases, while for some cases hyperreninemic hyperaldosteronism was the more likely mechanism. The mutational landscape of ACCs associated with hyperaldosteronism was not different from ACCs with a different hormonal phenotype. None of the ACCs harbored mutations of known APA-associated genes, suggesting an alternative mechanism conferring aldosterone production. PMID- 30475218 TI - Cancer risk in Chinese diabetes patients: a retrospective cohort study based on management data. AB - The excess risk of cancer observed in patients with type 2 diabetes (T2DM) may have been influenced by detection bias. The aim of this study was to examine the real association by evaluating time-varying site-specific cancer risks in newly diagnosed T2DM patients. A total of 51,324 registered cancer-free individuals newly-diagnosed with T2DM between 2004 and 2014 were linked with the Shanghai Cancer Registry and the Vital Statistics through September 2015. A total of 2,920 primary, invasive cancer cases were identified during 325,354 person-years period. Within 1 year following diabetes onset, participants with T2DM had higher risks of total, lung and rectal cancer in men and total, liver, pancreas, thyroid, breast and uteri cancer in women. Thereafter the incidence for overall cancer decreased and then increased along with follow-up time, with the upward trend varying by cancer, suggesting potential detection bias. After the initial 1 year period, Standardized incidence ratios (SIR) and 95% confidence intervals (CIs) for overall cancer were 0.80 (95% CI 0.76-0.85) in men and 0.93 (95% CI 0.88-0.99) in women, but a higher risk of breast and thyroid cancers were observed in women, with SIR and 95%CI being 1.13(1.01, 1.28) and 1.37(1.11, 1.63), respectively. Our results suggest that T2DM patients are at higher risk of certain cancers; this risk particularly increases shortly after diabetes diagnosis, which is likely to be due to detection bias caused by increased ascertainment. Prevention of female breast and thyroid cancers should be paid attention in Chinese individuals with T2DM. PMID- 30475219 TI - The impact of anorexigenic peptides in experimental models of Alzheimer's disease pathology. AB - Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the elderly population. Numerous epidemiological and experimental studies have demonstrated that patients who suffer from obesity or type 2 diabetes mellitus have a higher risk of cognitive dysfunction and of AD. Several recent studies demonstrated that food intake-lowering (anorexigenic) peptides have the potential to improve metabolic disorders and that they may also potentially be useful in the treatment of neurodegenerative diseases. In this review, the neuroprotective effects of anorexigenic peptides of both peripheral and central origins are discussed. Moreover, the role of leptin as a key modulator of energy homeostasis is discussed in relation to its interaction with anorexigenic peptides and their analogs in AD-like pathology. Although there is no perfect experimental model of human AD pathology, animal studies have already proven that anorexigenic peptides exhibit neuroprotective properties. This phenomenon is extremely important for the potential development of new drugs in view of the aging of the human population and of the significantly increasing incidence of AD. PMID- 30475220 TI - MANAGEMENT OF ENDOCRINE DISEASE: The role of confirmatory tests in the diagnosis of primary aldosteronism. AB - The strategy for diagnosis of primary aldosteronism (PA) in the hypertensive population includes firstly a screening step, based on the measurement of plasma aldosterone-to-renin ratio (ARR), a test which must have high sensitivity, and secondly a confirmatory step based on the demonstration of excessive aldosterone production independent of the renin-angiotensin-aldosterone system (RAAS) activity. The high proportion of false positive ARR results and conversely of actual PA without a persistent elevation in baseline plasma aldosterone concentration necessitates the addition of a confirmatory step in the work-up of PA diagnosis. The present review focuses on the description of the different dynamic tests available for demonstrating autonomy of aldosterone secretion, on the performance and limitations of confirmatory tests, and on possible strategies for PA diagnosis which may either include or avoid the confirmatory step for PA diagnosis. Large prospective studies comparing different strategies with and without dynamic testing are mandatory to delineate clearly the role and limits of confirmatory tests in the workup of PA. t. PMID- 30475221 TI - Geoffrey Harris Prize 2018: Novel pathways regulating neuroendocrine function, energy homeostasis and metabolism in humans. AB - The discovery of leptin, an adipocyte secreted hormone, set the stage for unraveling the mechanisms dictating energy homeostasis, revealing adipose tissue as an endocrine system that regulates appetite and body weight. Fluctuating leptin levels provide molecular signals to the brain regarding available energy reserves modulating energy homeostasis and neuroendocrine response in states of leptin deficiency and to a lesser extent in hyperleptinemic states. While leptin replacement therapy fails to provide substantial benefit in common obesity, it is effective treatment for congenital leptin deficiency and states of acquired leptin deficiency such as lipodystrophy. Current evidence suggests that regulation of eating behavior in humans is not limited to homeostatic mechanisms and that the reward, attention, memory and emotion systems are involved, participating in a complex central nervous system network. It is critical to study these systems for the treatment of typical obesity. Although progress has been made, further studies are required to unravel the physiology, pathophysiology and neurobehavioral mechanisms underlying potential treatments for weight-related problems in humans. PMID- 30475222 TI - Moderate increases in daily step count are associated with reduced IL-6 and CRP in women with PCOS. AB - AIMS: Physical activity has been proposed to be an effective non-pharmacological method of reducing systemic inflammation and therefore may prove particularly efficacious for women with polycystic ovary syndrome (PCOS) who have been shown to have high levels of inflammation and an increased risk of type 2 diabetes (T2DM) and cardiovascular disease (CVD). Therefore the aim of the present study was to assess whether modest changes daily step count could significantly reduce levels of inflammatory markers in women with PCOS. SUBJECTS AND METHODS: Sixty five women with PCOS were assessed at baseline and again at 6 months. All had been provided with an accelerometer and encouraged to increase activity levels. Multivariate linear regression analyses (adjusted for age, ethnicity, baseline step count, change in BMI and change in accelerometer wear-time) were used to assess changes in daily step count against clinical and research biomarkers of inflammation, CVD and T2DM. RESULTS: Mean step count/day at baseline was 6337 (+/ 270). An increase in step count (by 1000 steps) was associated with a 13% reduction in IL-6 (beta: -0.81ng/L; 95% CI, -1.37, -0.25, p=0.005) and a 13% reduction in CRP (beta: -0.68mg/L; 95% CI, -1.30, -0.06, p=0.033). Additionally, there was a modest decrease in BMI (beta: 0.20 kg/m2; 95% CI, -0.38, -0.01, p=0.038). Clinical markers of T2DM and CVD were not affected by increased step count. CONCLUSIONS: Modest increases in step count/day can reduce levels of inflammatory markers in women with PCOS which may reduce the future risk of T2DM and CVD. PMID- 30475223 TI - Management of precocious puberty in girls with McCune-Albright syndrome using letrozole. AB - OBJECTIVE: To evaluate the safety and efficacy of letrozole in girls with progressive precocious puberty (PP) associated with McCune-Albright syndrome (MAS). DESIGN: Monocentric retrospective cross-sectional and longitudinal study of consecutive patients. PATIENTS: Ten MAS patients treated at Peking Union Medical College Hospital between September 1999 and December 2017 were retrospectively reviewed; those with complications due to PP were followed. RESULTS: The mean age at letrozole initiation was 4.45+/-2.56 years, while the mean duration of treatment was 3.31+/-2.35 years. Letrozole was highly effective at decreasing the rate of skeletal maturation, with a significant decrease in the bone age-to-chronological age (BA/CA) ratio from 1.93 +/-1.12 pre-treatment to 1.51+/-1.23 on letrozole treatment (P = 0.016). Moreover, growth velocity Z scores declined from 0.41+/-0.50 to -0.20+/-0.31 with treatment (P < 0.001). Predicted adult height Z-scores increased significantly from -2.03+/-2.33at baseline to 1.13+/-0.84 following treatment initiation (P = 0.029). Moreover, vaginal bleeding declined significantly on letrozole. CONCLUSIONS: Our findings suggest that letrozole may be an effective therapy in some girls with MAS, as treatment results in improved BA/CA ratio, growth velocity, and predicted adult height. Possible adverse effects include nettle-rash. PMID- 30475224 TI - IGFBP-2 And Aging; A 20 Year Longitudinal Study on IGFBP-2, IGF-I, BMI, Insulin Sensitivity and Mortality in an Aging Population. AB - OBJECTIVE: Insulin-like growth factor binding protein-2 (IGFBP-2) concentrations are low in subjects with metabolic syndrome and type 2 diabetes. Intriguingly, recent studies have demonstrated an association between high IGFBP-2 concentrations and increased mortality in populations with certain types of cancer, but also in relatively healthy populations. We evaluated the role of IGFBP-2 in relation to BMI and mortality. DESIGN AND PARTICIPANTS: BMI, insulin sensitivity, IGF-I and IGFBP-2 were assessed repeatedly in 539 participants of the Baltimore Longitudinal Study of Aging around the age of 55, 65 and 75. RESULTS: IGFBP-2 concentrations positively correlated with insulin-sensitivity and inversely with BMI, both at baseline and follow-up. Independent of IGF-I, sex, BMI and insulin-sensitivity, circulating IGFBP-2 levels positively correlated with age (P<0.001). Changes over time in BMI were associated with an inverse correlation in IGFBP-2 concentrations. Furthermore, we found indications of a relationship between low baseline IGFBP-2 levels and mortality. Remarkably, after adjustment for insulin-sensitivity, the opposite association was found, as a unit increase of log(IGFBP2) was associated with an increase in the log hazard by 1.43(95%CI 0.3;2.6). This accounted for both baseline as well as serial measurements of IGFBP2 measurements. Finally, in this longitudinal study we found that IGF-I concentrations increased with age (0.82+/-0.2(ug/L)/yr,P<0.001). CONCLUSION: This is the first study investigating the relationship between IGFBP 2 levels and age in a longitudinal setting. Serum IGFBP-2 levels increase with age after the age of fifty and evolve in parallel with insulin sensitivity. IGFBP 2 may therefore be a potential marker for insulin sensitivity. We further show that IGFBP-2 levels can predict mortality in this aging population. However, its predictive value for mortality can only be interpreted in relation to insulin sensitivity. After adjustment for insulin sensitivity, high IGFBP-2 levels are predictive of an increased mortality. PMID- 30475226 TI - Mouse models in endocrine tumors. AB - Endocrine and neuroendocrine tumors comprise a highly heterogeneous group of neoplasms that can arise from (neuro)endocrine cells, either from endocrine glands or from the widespread diffuse neuroendocrine system, and, consequently, are widely distributed throughout the body. Due to their diversity, heterogeneity and limited incidence, studying in detail the molecular and genetic alterations that underlie their development and progression is still a highly elusive task. This, in turn, hinders the discovery of novel therapeutic options for these tumors. To circumvent these limitations, numerous mouse models of endocrine and neuroendocrine tumors have been developed, characterized and used in pre clinical, co-clinical (implemented in mouse models and patients simultaneously) and post-clinical studies, for they represent powerful and necessary tools in basic and translational tumor biology research. Indeed, different in vivo mouse models, including cell line-based xenografts (CDXs), patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMs), have been used to delineate the development, progression and behavior of human tumors. Results gained with these in vivo models have facilitated the clinical application in patients of diverse breakthrough discoveries made in this field. Herein, we review the generation, characterization and translatability of the most prominent mouse models of endocrine and neuroendocrine tumors reported to date, as well as the most relevant clinical implications obtained for each endocrine and neuroendocrine tumor type. PMID- 30475225 TI - The SLC16A11 risk haplotype is associated with decreased insulin action, higher transaminases and large-sized adipocytes. AB - OBJECTIVE: A haplotype at chromosome 17p13 that reduces expression and function of the solute carrier transporter SLC16A11 is associated with increased risk for type 2 diabetes in Mexicans. We aim to investigate the detailed metabolic profile of SLC16A11 risk haplotype carriers to identify potential physiological mechanisms explaining the increased type 2 diabetes risk. DESIGN: Cross-sectional study. METHODS: We evaluated carriers (n=72) and non-carriers (n=75) of the SLC16A11 risk haplotype, with or without type 2 diabetes. An independent sample of 1,069 subjects was used to replicate biochemical findings. The evaluation included euglycemic-hyperinsulinemic clamp, frequently sampled intravenous glucose tolerance test (FSIVGTT), dual-energy X-ray absorptiometry (DXA), magnetic resonance imaging (MRI) and spectroscopy and subcutaneous abdominal adipose tissue biopsies. RESULTS: Fat-free mass (FFM) adjusted M value was lower in carriers of the SLC16A11 risk haplotype after adjusting for age and type 2 diabetes status (beta= -0.164, p=0.04). Subjects with type 2 diabetes and the risk haplotype demonstrated an increase of 8.76 U/L in alanine aminotransferase (ALT) (p=0.02) and of 7.34 U/L in gamma- glutamyltransferase (GGT) (p=0.05) compared with non-carriers and after adjusting for gender, age, and ancestry. Among women with the risk haplotype and normal BMI, the adipocyte size was higher (p<0.001). CONCLUSIONS: Individuals carrying the SLC16A11 risk haplotype exhibited decreased insulin action. Higher serum ALT and GGT levels were found in carriers with type 2 diabetes, and larger adipocytes in subcutaneous fat in the size distribution in carrier women with normal weight. PMID- 30475227 TI - Organoids from pituitary as a novel research model toward pituitary stem cell exploration. AB - The pituitary is the master endocrine gland, harboring stem cells of which the phenotype and role remain poorly characterized. Here, we established organoids from mouse pituitary with the aim to generate a novel research model to study pituitary stem cell biology. The organoids originated from the pituitary cells expressing the stem cell marker SOX2, were long-term expandable, displayed a stemness phenotype during expansive culture and showed specific hormonal differentiation ability, although limited, after subrenal transplantation. Application of the protocol to transgenically injured pituitary harboring an activated stem cell population, resulted in more numerous organoids. Intriguingly, these organoids presented with a cystic morphology whereas the organoids from undamaged gland were predominantly dense, and appeared more limited in expandability. Transcriptomic analysis revealed distinct epithelial phenotypes and showed that cystic organoids more resembled the pituitary phenotype, at least to an immature state, and displayed in vitro differentiation, although yet moderate. Organoid characterization further exposed facets of regulatory pathways of the putative stem cells of the pituitary and advanced new injury-activated markers. Taken together, we established a novel organoid research model revealing new insights into the identity and regulation of the putative pituitary stem cells. This organoid model may eventually lead to an interesting tool to decipher pituitary stem cell biology in both healthy and diseased gland. PMID- 30475229 TI - Rejuvenation of beta cells by epigenetic editing. AB - Insulin-secreting beta cell loss or dysfunction is a feature of both type 1 and type 2 diabetes. Strategies to restore beta cell mass are limited, as sources of healthy islets are scarce and mature beta cells are not readily expanded in vitro. In this issue of the JCI, Ou et al. report that mature beta cell expansion can be induced in situ through epigenetic editing of regulatory elements in pancreatic tissue. Specifically, hypomethylation at imprinting control region 2 (ICR2) in human islets promoted beta cell expansion. Importantly, transplantation of these epigenetically edited islets into diabetic mice reduced blood glucose levels. Together, these results support further evaluation of this strategy for restoring beta cell mass in patients with diabetes. PMID- 30475228 TI - Compound haploinsufficiency of Dok2 and Dusp4 promotes lung tumorigenesis. AB - Recurrent broad-scale heterozygous deletions are frequently observed in human cancer. Here we tested the hypothesis that compound haploinsufficiency of neighboring genes at chromosome 8p promotes tumorigenesis. By targeting the mouse orthologs of human DOK2 and DUSP4 genes, which were co-deleted in approximately half of human lung adenocarcinomas, we found that compound-heterozygous deletion of Dok2 and Dusp4 in mice resulted in lung tumorigenesis with short latency and high incidence, and that their co-deletion synergistically activated MAPK signaling and promoted cell proliferation. Conversely, restoration of DOK2 and DUSP4 in lung cancer cells suppressed MAPK activation and cell proliferation. Importantly, in contrast to downregulation of DOK2 or DUSP4 alone, concomitant downregulation of DOK2 and DUSP4 was associated with poor survival in human lung adenocarcinoma. Therefore, our findings lend in vivo experimental support to the notion that compound haploinsufficiency, due to broad-scale chromosome deletions, constitutes a driving force in tumorigenesis. PMID- 30475230 TI - Fc-dependent functions are redundant to efficacy of anti-HIV antibody PGT121 in macaques. AB - A considerable body of evidence suggests that Fc-dependent functions improve the capacity of broadly neutralizing antibodies (BnAbs) to protect against and control HIV-1 infection. This phenomenon, however, has not been formally tested in robust cell-associated macaque simian-human immunodeficiency virus (SHIV) models with newer-generation BnAbs. We studied both the WT BnAb PGT121 and a LALA mutant of PGT121 (which has impaired Fc-dependent functions) for their ability to protect pigtail macaques from an i.v. high-dose cell-associated SHIVSF162P3 challenge. We found that both WT and LALA PGT121 completely protected all 12 macaques studied. Further, partial depletion of NK cells, key mediators of Fc dependent functions, did not abrogate the protective efficacy of PGT121 in 6 macaques. Additionally, in animals with established SHIVSF162P3 infection, SHIV viremia levels were equally rapidly reduced by LALA and WT PGT121. Our studies suggest that the potent neutralizing capacity of PGT121 renders the Fc-dependent functions of the Ab at least partially redundant. These findings have implications for Ab-mediated protection from and control of HIV-1 infection. PMID- 30475231 TI - Blocking HIV-1 replication: are Fc-Fcgamma receptor interactions required? AB - Interactions between IgG Fc and its receptors (FcgammaRs) have been shown to augment broadly neutralizing Ab-mediated (BnAb-mediated) protection from simian human immunodeficiency virus (SHIV) challenge. In the current issue of the JCI, Parsons and collaborators compared the BnAb PGT121 with a version engineered to have impaired FcgammaR binding for their ability to protect macaques from an intravenous challenge with SHIV-infected cells as well as to treat already infected animals. Unexpectedly, and in contrast to previous studies, both versions of the Ab were equally able to prevent infection and decrease viral loads in infected animals. Thus, FcgammaR engagement does not always improve the in vivo antiviral activity of BnAbs. PMID- 30475233 TI - Three-Dimensional Printing Technology Combined With Postmortem Computed Tomography Angiography as New Form of Forensic Evidence: A Case Report. AB - Postmortem computed tomography (PMCT) and PMCT angiography are increasingly used in forensic practice. However, their application in court is still limited because they need professional equipment or software to be displayed. In this article, the authors introduce 3-dimensional (3D) printing technology as a new approach to provide evidence in court. A 67-year-old woman suffered from severe sick sinus syndrome, and she was fitted with a ventricular demand inhibited pacemaker. The operation failed as the doctor accidentally perforated her heart with an electrode wire. Her heart stopped beating, and she died after the operation. Targeted PMCT with pulmonary artery angiography was performed after the body was dissected, and a model of the heart was reconstructed using 3D printing technology, with different colored materials. The results confirmed by the autopsy suggested that the victim had died of cardiac rupture. The apex close to the right margin of the heart showed a tiny cleft where the contrast agent was flowing out. The heart model was an effective way to interpret this medical injury. This 3D printing technology, combined with PMCT angiography, provides a convenient, efficient tool for identifying the cause of death. It could become a powerful form of court evidence in the future. PMID- 30475232 TI - Amisulpride for the Rescue Treatment of Postoperative Nausea or Vomiting in Patients Failing Prophylaxis: A Randomized, Placebo-controlled Phase III Trial. AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Although antiemetics are commonly used to prevent postoperative nausea or vomiting, the failure rate is appreciable and there is currently no generally accepted standard for rescue treatment of postoperative nausea or vomiting after failed prophylaxis. This prospective, randomized, double-blind, parallel-group, placebo-controlled, multicenter study was designed to test the hypothesis that intravenous amisulpride, a dopamine D2/D3-antagonist, is superior to placebo at treating established postoperative nausea or vomiting after failed prophylaxis. METHODS: A total of 2,285 adult patients undergoing surgery under general inhalational anesthesia and receiving standard antiemetic prophylaxis were enrolled at 23 sites in Canada, France, Germany, and the United States. Of these, 702 patients experienced postoperative nausea or vomiting in the 24-h period after surgery and were randomized to receive a single dose of 5 or 10 mg intravenous amisulpride or matching placebo. The primary endpoint was complete response, defined as no emesis or rescue antiemetic use for 24 h after study drug administration, excluding emesis in the first 30 min. Secondary endpoints included incidence of emesis and rescue medication use, nausea burden, time to treatment failure, and length of stay in postanesthesia care unit and hospital. RESULTS: Complete response occurred in significantly more patients receiving 10 mg amisulpride (96 of 230, 41.7%) than placebo (67 of 235, 28.5%), a 13.2% difference (95% CI, 4.6 to 21.8; odds ratio, 1.80; P = 0.006). A 5-mg dose of amisulpride did not show a significant benefit (80 of 237, 33.8%); the difference from placebo was 5.2% (95% CI, 3.1 to 13.6; odds ratio, 1.24; P = 0.109). The total number of adverse events recorded and proportion of patients with at least one adverse event were comparable between the placebo and amisulpride groups. No clinically relevant toxicities were observed. CONCLUSIONS: A single 10-mg dose of intravenous amisulpride was safe and more effective than placebo at treating established postoperative nausea or vomiting in patients failing postoperative nausea or vomiting prophylaxis. PMID- 30475234 TI - Neisseria meningitidis Isolated in Vitreous Humor in a 5-Month-Old Infant Death From Meningococcal Sepsis. AB - Diagnosing sepsis at postmortem is challenging. With respect to meningococcal sepsis, the postmortem microbiological identification of Neisseria meningitidis is nearly always due to true infection, including in cases of decomposition. Previous case series and case reports were able to isolate N. meningitidis in vitreous humor in adult deaths from meningococcal sepsis when blood and/or cerebrospinal fluid was unavailable. It was suggested that vitreous humor polymerase chain reaction (PCR) may be useful in the diagnosis of meningococcal sepsis. We describe a fatal case of meningococcal sepsis in a 5-month-old infant where N. meningitidis was detected in vitreous humor, cerebrospinal fluid, and blood through PCR. The presented case report gives further evidence in the potential use of vitreous PCR analysis in suspected meningococcal sepsis, particularly in the pediatric population. PMID- 30475235 TI - Biochemical Differences Between Vitreous Humor and Cerebral Spinal Fluid in a Death From Diabetic Ketoacidosis. AB - Biochemical analysis of cerebrospinal fluid (CSF) and vitreous humor (VH) forms an important diagnostic ancillary test at autopsy. Cerebrospinal fluid can be sampled from the ventricular system (VA) and from lumbar puncture (LP), whereas VH can be sampled from the orbits. Biochemical electrolytes seem to vary between VH and CSF collected from different sites, but whether there is any difference in glucose and beta-hydroxybutyrate is unclear. We present a case report of a 21 year-old man who died of diabetic ketoacidosis confirmed at autopsy. Ventricular system, LP, and VH were biochemically analyzed and showed that glucose was highest in VH (41 mmol/L) and was 6 and 8 mmol/L higher than CSF in the LP and VA, respectively. beta-Hydroxybutyrate was also highest in VH (20 mmol/L) and was 5 and 6 mmol/L higher than LP and VA, respectively. Our findings suggest that postmortem CSF glucose and beta-hydroxybutyrate may not truly reflect that of VH and vary between CSF sampling sites. PMID- 30475236 TI - Selecting the Appropriate Patient for Opioid Therapy: Risk Assessment and Treatment Strategies for Gynecologic Pain. AB - Chronic pelvic pain is a commonly encountered clinical entity, and many women with this chronic pain condition will be treated at some point in time with opioids for management of their pain. Clinicians in women's health are frequently asked and expected to participate in the care of women with chronic pelvic pain, as well as other gynecologic pain conditions, and should be familiar with the role of opioid therapy for these conditions. The goal of this article is to help determine which patients may be appropriate candidates for the initiation or continuation of opioid therapy for gynecologic pain. In addition, this article will help the clinician to establish treatment goals, select appropriate medications, monitor the efficacy of treatment, and to determine when discontinuation of medications is appropriate. PMID- 30475237 TI - Integrating Symptoms Into the Middle-Range Theory of Self-Care of Chronic Illness. AB - The Middle-Range Theory of Self-Care of Chronic Illness has been used widely since it was first published in 2012. With the goal of theoretical refinement in mind, we evaluated the theory to identify areas where the theory lacked clarity and could be improved. The concept of self-care monitoring was determined to be underdeveloped. We do not yet know how the process of symptom monitoring influences the symptom appraisal process. Also, the manner in which self-care monitoring and self-care management are associated was thought to need refinement. As both of these issues relate to symptoms, we decided to enrich the Middle-Range Theory with knowledge from theories about symptoms. Here, we propose a revision to the Middle-Range Theory of Self-Care of Chronic Illness where symptoms are clearly integrated with the self-care behaviors of self-care maintenance, monitoring, and management.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30475238 TI - Bilateral Erector Spinae Plane Block for Surgery on the Posterior Aspect of the Neck: A Case Report. AB - The erector spinae plane block is an interfascial plane block whereby local anesthetic is injected within the plane deep to the erector spinae muscle and superficial to the transverse process. To date, it has been used to provide analgesia in thoracic, abdominal, and lumbar regions. We present the first reported case of bilateral erector spinae plane block being used to provide surgical anesthesia in the cervical region. PMID- 30475239 TI - Apneic Oxygenation With High-Flow Nasal Cannula and Transcutaneous Carbon Dioxide Monitoring During Airway Surgery: A Case Series. AB - Three patients underwent laryngeal and tracheal surgeries under apneic conditions using transnasal humidified rapid-insufflation ventilatory exchange. Transcutaneous carbon dioxide (CO2) levels were recorded throughout the apneic period to detect rates of CO2 rise. Conventional airway management was initiated after 15 minutes of apnea with either tracheal intubation or jet ventilation. No patient experienced oxygen desaturation <97%. The average rate of transcutaneous CO2 rise (1.7 mm Hg/min) was higher than previously reported using this technique. This suggests a need for further investigation into the utility of transnasal humidified rapid-insufflation ventilatory exchange for airway surgery and adequate ventilation during apnea. PMID- 30475240 TI - Clinical Impact of Ossification of the Posterior Longitudinal Ligament Progression After Cervical Laminoplasty. AB - STUDY DESIGN: This is a retrospective study. OBJECTIVES: (1) To analyze the incidence of second surgery after initial laminoplasty for ossification of the posterior longitudinal ligament (OPLL) due to disease progression, (2) to examine factors associated with poor surgical outcome. SUMMARY OF BACKGROUND DATA: Neurological deterioration after laminoplasty is frequently encountered due to OPLL progression. PATIENTS AND METHODS: Of 201 OPLL patients treated by laminoplasty at a single-institution, the 153 monitored for >3 years postsurgery were included in this analysis. Neurological findings were graded by the Japanese Orthopaedic Association (JOA) score. We retrospectively examined the incidence of second surgery due to OPLL progression. We also evaluated the clinical characteristics and the surgical outcomes after second operation to identify potential risk factors for poor outcome. RESULTS: Eight patients required a second surgery due to OPLL progression. Neurological recovery was achieved in 5 of these patients, whereas 3 exhibited continued dysfunction. Patients with poor recovery showed kyphotic changes of spinal alignment and high-intensity regions in the spinal cord on T2-weighted magnetic resonance images (T2-MRI). CONCLUSIONS: Only a small fraction of OPLL patients required a second surgery due to OPLL progression. Recovery was poor in those with clear high-intensity T2-MRI signals in the spinal cord. PMID- 30475241 TI - Safety of 2-level Anterior Cervical Discectomy and Fusion (ACDF) Performed in an Ambulatory Surgery Setting With Same-day Discharge. AB - STUDY DESIGN: This was a retrospective review of prospectively collected data. OBJECTIVE: To evaluate differences in patient factors, procedural factors, outcomes and safety in 2-level anterior cervical discectomy and fusion (ACDF) performed in ambulatory surgery centers (ASCs) versus the hospital setting. BACKGROUND: Emphasis on reducing health care costs has led to numerous surgeries across specialties being performed in ASCs. Because of short operative times and moderate postoperative pain, 1-level ACDF is one of the most common spine surgeries successfully performed in ASCs. Despite the success of single-level ACDF, concerns over postoperative complications, including respiratory compromise have curtailed the performance of 2-level ACDF in ASCs. MATERIALS AND METHODS: Patient demographics, operative factors and outcomes [blood loss, operative time, length of stay, complications and patient-reported outcomes (PROs)] of patients undergoing 2-level ACDF in an ASC and a hospital were compared using the Fisher exact test for categorical and the Student t test for continuous variables. RESULTS: Of the 83 patients included, 25 underwent 2-level ACDF in an ASC, and 58 in a hospital. Mean age for the ASC group was 51.7+/-7.6 and 53.2+/-7.9 years for the hospital group (P=0.44). Body mass index was lower in the ASC group, at 27.3 kg/m versus 30.4 in the hospital group (P=0.03). Likewise, the ASC group had a lower ASA grade, favoring ASA 1 and 2 (P<0.001). There were no differences in blood loss (P=0.72) or complication rates, (P=0.16) with urinary retention being most common, and only 1 patient in the hospital setting requiring reintubation. In addition, no patients in the ASC setting required hospitalization. There were no differences in preoperative, 6-week and 6-month PROs. CONCLUSIONS: The results of our study suggest that 2-level ACDF can be performed safely in the ASC setting without increased risk of complications compared with the hospital setting in an appropriately selected patient. Specifically, body mass index, and ASA class should be taken into consideration. Importantly, the setting of the surgery does not impact early PROs. LEVEL OF EVIDENCE: Level 3. PMID- 30475242 TI - Decompression With or Without Fusion for Adjacent Segment Disease Without Instability. PMID- 30475243 TI - Surgical Treatment of Periimplantitis With Non-Augmentative Techniques. AB - OBJECTIVES: The aim of this review was to systematically screen the literature on surgical non-regenerative treatments of periimplantitis, especially for radiologic and clinical outcomes, and to determine predictable therapeutic options for the clinical management of periimplantitis lesions. MATERIAL AND METHODS: The potentially relevant literature was assessed independently by 2 reviewers to identify clinical studies, trials, and case series in humans describing the surgical non-regenerative treatment outcomes of periimplantitis with a follow-up of at least 6 months. MEDLINE, EMBASE, and the Cochrane Library were searched for studies reporting changes in probing depth (PD) and/or bleeding on probing (BOP) and/or radiologic marginal bone-level changes. RESULTS: A total of 10 publications were included: 6 prospective randomized controlled trials, 1 prospective cohort study, 2 retrospective controlled studies, and 1 case series. Clinical parameters can be reduced by surgical non-regenerative treatments. Concerning 3 year follow-ups, BOP and PD values decreased more efficiently after implantoplasty than using systematic administration of antibacterials. Adjunctive local chemical irrigations or diode laser have no long-term effects. The non regenerative surgical approach in combination with implantoplasty also shows improved radiographic parameters. CONCLUSIONS: Surgical non-regenerative treatment of periimplantitis can reduce the amount of inflammation in the short term follow-up. Using implantoplasty may result in the improvement of clinical and radiographic parameters. Because of limited evidence and heterogeneity in study design, there is a need for randomized controlled studies with proper design and powerful sample size in the future. PMID- 30475244 TI - Maxillary Sinus Floor Augmentation With Autogenous Bone Graft From the Ascending Mandibular Ramus. AB - PURPOSE: The objective of the present study was to assess patient satisfaction and esthetic implant outcome 10 years after maxillary sinus floor augmentation with autogenous bone graft from the mandibular ramus. MATERIALS AND METHODS: Maxillary sinus floor augmentation with autogenous bone graft from the mandibular ramus was conducted in 48 consecutive patients from 2002 to 2006. Records and radiographs were retrospectively analyzed. Twenty-four patients including 34 sinus augmentation procedures and 37 implants were evaluated after 10 years. Subjective and professional evaluations of the final periimplant soft tissue, implant crown, and total implant treatment were conducted. RESULTS: The 10-year survival of suprastructures and implants was 84% and 100%, respectively. The patients were highly satisfied with the esthetic and implant treatment outcome expressed by scores >90 on the visual analog scale. Most implants were characterized by scores of 1 or 2, resulting in a mean pink esthetic score of 9 (maximum 14) and a white esthetic score of 8 (maximum 10). CONCLUSION: Maxillary sinus floor augmentation with autogenous bone graft is characterized by high long term implant survival rate and patient satisfaction. PMID- 30475245 TI - What Do Parents Need to Know About Concussion? Developing Consensus Using the Delphi Method. AB - OBJECTIVE: Many schools and sports leagues provide preseason concussion education to parents/guardians, and in some jurisdictions, it is required for interscholastic sports participation. However, directives about content are absent or vague. The purpose of this study was to obtain expert consensus about what parents/guardians need to know to about concussion. DESIGN: A modified Delphi process with nationally recognized expert panel members was used to obtain consensus about parent/guardian behaviors relevant to concussion prevention, identification, and management and knowledge domains relevant to performance of those behaviors. RESULTS: Sixteen parent/guardian behaviors and 24 knowledge domains were identified. However, consensus was not achieved regarding whether it is realistic to expect parents/guardians to perform approximately one-third of the behaviors that experts agreed mattered. This variability may reflect underlying uncertainty about the capacities of some parents/guardians to put knowledge into action or the belief that there are other barriers to action. Furthermore, for most knowledge domains, there was a lack of agreement about whether or not there could be a "correct" answer on the basis of current scientific knowledge. CONCLUSIONS: These findings raise practical and ethical questions: how can we expect parents/guardians to help prevent, identify, or manage concussion if they cannot have all the information required to engage in these behaviors due to lack of scientific consensus? This issue is not unique to concussion. Best practices for risk communication and shared decision-making can inform how we think about educating parents/guardians about concussion inside and outside of the health care setting. PMID- 30475246 TI - Heart Failure Care Dyadic Typology: Initial Conceptualization, Advances in Thinking, and Future Directions of a Clinically Relevant Classification System. AB - BACKGROUND: Heart failure (HF) dyadic self-care science is advancing rapidly, as evidenced by recent theoretical work, literature reviews, and multiple empiric studies. Typologies, once considered archaic, are now viewed as person-oriented classification systems that allow a whole-system view of information patterns. This whole-system view is particularly needed to understand complex tasks like dyadic HF self-care. PURPOSE: The purpose of this article is to review the initial conceptualization of an HF care dyadic typology and the present advances in our thinking and suggest future directions for this clinically relevant classification system. CONCLUSIONS: Development and testing of the typology across 5 studies resulted in a well-characterized, pragmatic and parsimonious, person-oriented classification system for understanding how patients and informal caregivers conduct patients' HF self-care at home. The 4 types are characterized as 2 individually oriented types-type I, patient oriented; type II, caregiver oriented; and 2 relationally oriented types-type III, collaboratively oriented; and type IV, incongruently oriented. We have devised a single-item measure of typology group that can be assessed in the clinical setting. Once this information is ascertained, the clinician can personalize the plan of care to the realities of the dyad. IMPLICATIONS: Dyads that disagree on who is responsible for self-care may forego or delay action, resulting in self-care failures with subsequent HF advancement, hospitalization, and mortality. As the HF dyadic self care science has advanced, we have come to appreciate the complexity that arises when 2 individuals work together on 1 complex task-HF self-care. PMID- 30475247 TI - Preoperative Parathyroid Imaging: Trends in Utilization and Comparative Accuracy of Sonography, Scintigraphy, and 4-Dimensional Computed Tomography. AB - OBJECTIVE: The purposes of this study were to describe trends in parathyroid imaging utilization and to compare the sensitivities of sonography, scintigraphy, and 4-dimensional computed tomography (4DCT) in different imaging algorithms. METHODS: A retrospective review of consecutive patients who underwent parathyroid surgery from 2009 to 2014 was performed. Utilization and accuracy were compared for sonography, scintigraphy, and 4DCT. RESULTS: The study population was composed of 604 patients with 850 adenomas or hyperplastic glands. Sonography was the most common imaging modality, performed in 91.2% (551/604) of patients. The utilization of 4DCT increased in the study period from 1.5% (2/133) in 2009-2010 to 75.8% (72/95) in 2013-2014 (P < 0.01). The overall sensitivities of sonography, scintigraphy, and 4DCT, regardless of order of imaging or imaging algorithm, were 58.6% (456/778), 49.1% (317/645), and 82.3% (121/147), respectively (P < 0.01). CONCLUSIONS: Four-dimensional CT has the highest sensitivity for localization of parathyroid adenomas regardless of order of imaging or imaging algorithm. PMID- 30475248 TI - Impact Analysis of the Routine Use of Dual-Energy Computed Tomography for Characterization of Incidental Renal Lesions. AB - OBJECTIVE: The aim of this study was to quantify the prevalence of incidental, indeterminate renal lesions on routine contrast-enhanced abdominal computed tomography (CT) and the proportion of such lesions that could be exonerated by dual-energy CT (DECT) postprocessing as benign hyperdense cysts. METHODS: The reports for 2729 consecutive contrast-enhanced DECT scans in the emergency department setting were reviewed for the mention of any renal lesion. For scans with a reported lesion, images were reviewed to assess for the presence of an indeterminate lesion that could not be definitively characterized as benign. All indeterminate lesions were reviewed with DECT postprocessing by 2 radiologists to assess for enhancement and other imaging characteristics and characterized by readers as benign or not definitively benign. Agreement between readers was assessed statistically, and disagreement was resolved by consensus. RESULTS: Two thousand seven hundred twenty-nine scans were performed in 2406 unique patients; a renal lesion was reported in 805 unique patient scans (33.4%). Review of these 805 scans led to discovery of 137 indeterminate lesions in 125 scans (5.2% of patients). Of the 137 lesions, 70 (51.1%) were classified as benign hyperdense cysts by readers, with the remaining 67 lesions classified as not definitively benign (43 solid masses, 9 Bosniak IIF cysts, 8 Bosniak III cysts, 7 Bosniak IV cysts). CONCLUSIONS: Incidental indeterminate renal lesions are common on routine contrast-enhanced CT. More than half of these lesions could potentially be exonerated with DECT as benign Bosniak II cysts, which could avert the need for further workup in 2.8% of patients undergoing routine abdominal CT. PMID- 30475249 TI - Differentiating Transition Zone Cancers From Benign Prostatic Hyperplasia by Histogram Analysis of Apparent Diffusion Coefficient Maps With Standard and Ultrahigh b-value Diffusion-weighted MR Imaging. AB - OBJECTIVE: To compare the diagnostic performance of standard and ultrahigh b value Diffusion-weighted Imaging (DWI) using volumetric histogram analysis in differentiating transition zone (TZ) cancer from benign prostatic hyperplasia (BPH). METHODS: 57 TZ cancer and 61 BPH patients received standard (1000 s/mm) and ultrahigh b-value (2000 s/mm) DWI. The diagnostic ability of ADC histogram parameters derived from two DWI for differentiating TZ cancer from BPH was determined by receiver operating characteristic curve. RESULTS: Median, minimum, the 10th, 25th percentile ADC in both ADC1000 and ADC2000 and skewness in ADC2000 had significant differences between TZ cancer and BPH (for all, P < 0.05).The 10th percentile ADC showed highest area under the ROC curve (AUC) in both ADC1000 and ADC2000.The 10th percentile ADC of ADC2000 showed significantly higher AUC than did ADC1000 (P = 0.0385). CONCLUSIONS: The 10th percentile ADC obtained from ultrahigh b-value DWI performed better for differentiating TZ cancer from BPH. PMID- 30475250 TI - Positive precepting: Identifying NP student learning levels and needs. AB - BACKGROUND AND PURPOSE: Clinical preceptors are vital partners in the education of nurse practitioner (NP) students. This article describes NP student learning stages and proposes strategies preceptors can use to facilitate precepting NP students who enter clinical rotations at varied learner levels. METHODS: Searches were conducted in the Cumulative Index to Nursing and Allied Health Literature and PubMed and EBSCOhost interfaces to MEDLINE using terms related to NPs, students, higher education, and preceptorship. Because only 10 publications met the inclusion criteria focusing on precepting NP students at different levels, literature from related health fields are included in the discussion. CONCLUSIONS: Benner's Novice to Expert Model is applied to NP education in primary care settings to describe the clinical levels of learning. Clinical teaching methods that focus on either preceptor- or student-led communication are described, followed by a discussion of the association between methods and levels of learners. IMPLICATIONS FOR PRACTICE: Nurse practitioners who precept NP students at various levels of their clinical learning can apply specific teaching methods that are delineated in this article. By recognizing the unique needs of NP students at different levels, preceptors can help facilitate their experiential learning. PMID- 30475251 TI - An exploration of the deleterious effects of hyperoxemia on the morbidity and mortality of hospitalized adult patients. AB - BACKGROUND AND PURPOSE: To explore the deleterious effects of hyperoxia due to liberal oxygen use and clarify the significance of overuse and effects on morbidity and mortality in adult hospitalized patients. This literature review is also intended to bring awareness to nurse practitioners regarding the iatrogenic harm caused by excessive oxygenation and promote individualized patient care. METHODS: A review of existing literature was conducted using PubMed and CINAHL databases. The keywords "hyperoxia", "hyperoxemia", "oxygen toxicity" and "excessive oxygenation" were used to yield articles for consideration. RESULTS: Of the six studies compared for this review, five identified positive correlations between hyperoxia and adverse outcomes. The sixth study found no significant differences in morbidity or mortality with the use of liberal oxygenation versus a more conventional approach. CONCLUSIONS: Overwhelming evidence suggests that states of hyperoxemia lead to increased mortality and morbidity. However, there is considerable variability on the threshold at which hyperoxia occurs. Further research is required to define levels of hyperoxia to better protect patients from iatrogenic harm. IMPLICATIONS FOR PRACTICE: Nurse practitioners in all specialties can increase awareness of the dangers of excessive oxygenation and effect a change in practice through education. PMID- 30475252 TI - Review of evidence for bosentan therapy for treatment of Eisenmenger syndrome. AB - BACKGROUND AND PURPOSE: Eisenmenger syndrome (ES) is a rare condition caused by a right-to-left cyanotic shunt. To date, only heart-lung transplant has been shown to be curative. Bosentan is the only medication studied with a double-blind placebo-controlled randomized trial for management of this condition. The intent of this article is to explore the literature surrounding bosentan in ES and assess its efficacy. METHODS: A literature review was conducted with no limitation on date. Titles were scanned for applicability, and abstracts of those articles found to be pertinent were reviewed. Those articles considered relevant based on the abstract were read in entirety. CONCLUSIONS: Eisenmenger syndrome remains incurable except through heart-lung transplant. Although no specific medical treatment or algorithm exists, three pharmacological classes show promise in disease management: endothelin receptor antagonists, phosphodiesterase inhibitors, and prostacyclins. Combined therapy with these agents may improve cardiopulmonary function. Bosentan has not been proven as a monotherapy for ES and is not appropriate in all patients as side effects are commonly reported. IMPLICATIONS FOR PRACTICE: Further study is required to assess efficacy of combination therapy and utilization as a bridge to transplant or surgical correction of the underlying defect. PMID- 30475253 TI - Patterns of Urachal Remnant Involvement by Urothelial Carcinoma: Intraluminal Noninvasive Spread can Mimic a Deep-seated Bladder Invasion. AB - Benign urachal remnants can be encountered in the adult urinary bladder and it is recognized that these can uncommonly give rise to urachal urothelial carcinoma. However, urachal remnants containing urothelial carcinoma incidentally encountered in cystectomies for bladder cancer has not been previously described. Herein, we present 8 adult bladder cancer cystectomies with incidental urachal remnants containing urothelial carcinoma. All 8 incidental urachal remnants with tumor were located at the dome that varied from small tubular to tubulocystic structures and contained urothelial carcinoma in situ (CIS) (6), noninvasive high grade papillary urothelial carcinoma (PUC) (1), and coexistent noninvasive high grade PUC and urothelial CIS (1). Six of the 8 urachal remnants with tumor also showed benign urothelial cells (2), mixed urothelial and glandular cells (2), and cuboidal cells (2). The bladder mucosa directly above the remnant showed urothelial CIS (4), PUC (1), concomitant PUC and urothelial CIS (1), invasive urothelial carcinoma (1), and benign urothelium (1); only 1 remnant intermingled with invasive urothelial carcinoma nests. Two remnants with tumor were at a region away from the main bladder tumor including the one overlaid by benign urothelium. The remnant with tumor extended into the upper half (5) or lower half (3) of muscularis propria (MP) and if misinterpreted as MP invasion, 5 of 8 bladder tumors will be overstaged. In conclusion, urachal remnant can have an early involvement by urothelial CIS or PUC similar in the bladder proper lumen. Urothelial carcinoma involving the urachus can be divided into a: (a) contiguous spread from a bladder urothelial carcinoma, (b) separate (noncontiguous) focus concomitant to bladder urothelial carcinoma, and (c) primary urachal urothelial carcinoma. Caution is warranted not to over interpret urachal remnant involvement by noninvasive urothelial carcinoma as an invasive tumor focus which could lead to overstaging. PMID- 30475254 TI - Tumor Budding and Cell Nest Size are Highly Prognostic in Laryngeal and Hypopharyngeal Squamous Cell Carcinoma: Further Evidence for a Unified Histopathologic Grading System for Squamous Cell Carcinomas of the Upper Aerodigestive Tract. AB - Squamous cell carcinoma (SCC) is the most common cancer of the head and neck region including-among others-laryngeal (LSCC) and hypopharyngeal (HSCC) subsites. LSCC/HSCC are heterogenous diseases with respect to patient outcome. Currently, tumor stage-based patient stratification is essential to predict prognosis and thus selection of the appropriate treatment modalities. In contrast, the prognostic impact of the current HSCC/LSCC grading system according to the WHO classification is limited. Recently, a novel grading system based on tumor budding activity (BA) and cell nest size (CNS) has been introduced for SCC in different anatomic regions of the upper aerodigestive tract. To test and transvalidate this grading scheme in LSCC and HSCC, we retrospectively correlated BA, CNS, and additional histomorphologic parameters with clinicopathologic data of 157 treatment-naive patients. In doing so, we demonstrate that a 3-tiered novel grading system (well-differentiated [nG1], intermediately [nG2], and poorly differentiated [nG3]) based on a sum score for BA and CNS is highly and independently prognostic for patient survival in LSCC/HSCC, strongly outperforming the current WHO grading scheme with a hazard ratio for disease specific survival of 6.6 for nG2 and 13.4 for nG3 cases (P<0.001). This finding contributes to a growing body of evidence that a CNS and BA-based pan-entity grading system in SCC might be useful and seems to capture differences in underlying SCC biology crucial for survival. PMID- 30475255 TI - Distinct Genomic Patterns in Pigmented Epithelioid Melanocytoma: A Molecular and Histologic Analysis of 16 Cases. AB - Pigmented epithelioid melanocytoma (PEM) is considered an intermediate grade melanocytic lesion that is histologically indistinguishable from epithelioid blue nevi associated with Carney complex. PEM are characterized by an intradermal population of heavily pigmented epithelioid-shaped melanocytes along with some spindled and dendritic melanocytes with frequent melanophages. These melanocytic tumors occasionally involve regional lymph nodes but only rarely result in distant metastases. Recent studies have demonstrated a variable but limited number of specific genomic aberrations including protein kinase A regulatory subunit alpha (PRKAR1A), BRAF, GNAQ, and MAP2K1 mutations as well as protein kinase C alpha isoform (PRKCA) fusions. We performed an 8-year retrospective review of our database and identified 16 cases of PEM. Using targeted DNA sequencing and RNA-seq to assess 1714 cancer-related genes, we detected gene fusions involving PRKCA in 31% of cases (5/16) with 5' partners SCARB1(12q24) in 2 cases, CD63 (12q13) in 1 case, ATP2B4 (1q32) in 1 case, and MAP3K3 (17q23) in 1 case. Additional fusions were identified in TPR-NTRK1 (1/16), ALK (1/16), and MYO5A-NTRK3 (1/16). PRKCA fusion lesions tended to occur in younger-aged patients and histologic examination demonstrated sheets of monomorphic epithelioid-shaped melanocytes, moderate to high-grade nuclear atypia, and higher mitotic activity (P=0.037). Our gene panel also identified previously described mutations in PRKAR1A, GNAQ, MAP2K1, BRAF, NF1. To our knowledge, this is the largest and most comprehensive study of PEM integrating molecular data with histologic features that can be utilized in future studies for improved subclassification and prognostication of heavily pigmented melanocytic neoplasms. PMID- 30475257 TI - Changes in Healthcare Encounter Rates Possibly Related to Cannabis or Alcohol following Legalization of Recreational Marijuana in a Safety-Net Hospital: An Interrupted Time Series Analysis. AB - OBJECTIVES: Liberalization of marijuana laws in Colorado contributed to increases in cannabis-related adverse events over time. We examined characteristics of patients with healthcare encounters possibly related to cannabis and assessed the temporal association between legalization of recreational marijuana and healthcare encounters possibly attributed to cannabis. METHODS: Annual encounter rates possibly related to cannabis and alcohol were compared using negative binomial regression. Two-time intervals, pre/post-recreational marijuana legalization (January 2009 to December 2013 and January 2014 to December 2015, respectively) were used to examine changes in monthly rates of emergency encounters and hospitalizations possibly related to cannabis. Level and trend changes on encounter rates by legalization period were assessed using interrupted time series analyses. Encounters possibly related to alcohol were used as a comparator group. RESULTS: Most encounters identified during the study period had alcohol-related International Classification of Diseases Diagnosis and Procedural Codes (ICD-9/10-CM) codes (94.8% vs 5.2% for cannabis). Patients with encounters possibly related to cannabis were younger, more likely to be hospitalized and more likely to be admitted to the psychiatric unit than patients with encounters possibly related to alcohol. Initial and sustained effects of encounter rates possibly related to cannabis demonstrated an increased trend in slope before and after recreational marijuana legalization. The slope became more abrupt following legalization with a significant increase in trend during the post-legalization period (beta = 2.7, standard error = 0.3, rho < 0.0001). No significant change was noted for encounters possibly related to alcohol. CONCLUSIONS: Additional research should identify patients at highest risk of an adverse health event related to cannabis and quantify costs associated with cannabis-related healthcare delivery. PMID- 30475256 TI - Displaced Cartilage Within Lymph Node Parenchyma is a Novel Biopsy Site Change in Resected Mediastinal Lymph Nodes Following EBUS-TBNA. AB - Biopsy site changes in mediastinal lymph nodes (LNs) attributable to prior endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) have not been studied in a systematic manner. Twenty-four contributors from 14 institutions in 5 countries collaborated via social media (Twitter) to retrospectively review consecutive cases of resected mediastinal LNs from patients with prior EBUS-TBNA. Resected LNs were reexamined by submitting pathologists for changes attributable to EBUS-TBNA. Patients who received neoadjuvant therapy were excluded. Cases with suspected biopsy site changes underwent central review by 5 pathologists. A total of 297 mediastinal LN resection specimens from 297 patients (183 male/114 female, mean age: 65 y, range: 23 to 87) were reviewed. Biopsy site changes were most common in station 7 (10 cases) followed by 11R, 4R, and 10R, and were found in 34/297 (11.4%) cases, including displacement of tiny cartilage fragments into LN parenchyma in 26, intranodal or perinodal scars in 7, and hemosiderin in 1. Cartilage fragments ranged from 0.26 to 1.03 mm in length and 0.18 to 0.62 mm in width. The mean interval between EBUS-TBNA and LN resection was 38 days (range: 10 to 112) in cases with biopsy site changes. A control group of 40 cases without prior EBUS TBNA, including 193 mediastinal LN stations, showed no evidence of biopsy site changes. Biopsy site changes are identified in a subset of resected mediastinal LNs previously sampled by EBUS-TBNA. The location of the abnormalities, temporal association with prior EBUS-TBNA, and the absence of such findings in cases without prior EBUS-TBNA support the contention that they are caused by EBUS-TBNA. PMID- 30475258 TI - A taxonomy of hospitals based on partnerships for population health management. AB - BACKGROUND: Hospitals face growing pressures and opportunities to engage with partner organizations in efforts to improve population health at the community level. Variation has been observed in the degree to which hospitals develop such partnerships. PURPOSE: The aim of this study was to generate a taxonomy of hospitals based on their partnerships with external organizations, employing the theoretical notion of organizations' focus on exploration versus exploitation. METHODOLOGY: With 1,238 valid cases from the 2015 American Hospital Association Population Health Survey, our study uses items asking about the level of partnership strength for 36 named partner types. Excluding three variables with low reliability, 33 variables are classified into six partner groups by factor analysis. Then, cluster analysis is conducted to generate a taxonomy of hospitals based on their partnerships with the six partner groups. FINDINGS: Of 1,238 hospitals, 26.1% are classified as exploratory hospitals that develop more collaborative relationships with partners outside the medical sector. Exploitative hospitals (18.3%) focus on relationships with traditional medical sector partners. Ambidextrous hospitals (27.0%) develop partnerships both in and outside the medical sector. Finally, independent hospitals (28.6%) do not establish strong partnerships. Larger hospitals, not-for-profit hospitals, and teaching hospitals are more likely to be classified as exploratory. PRACTICE IMPLICATIONS: The four-cluster taxonomy can provide hospital and health system leaders and managers with a better understanding of the wide variation in partnerships that hospitals establish and insights into their different strategic options with regard to partnership development.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30475259 TI - Examining the role of value congruence, professional identity, and managerial job engagement in the budgetary participation-performance link. AB - BACKGROUND: In health care, important phenomena of perceived incompatibility between professional and managerial values have emerged as consequences of New Public Management reforms. Although there is a growing evidence on the variation in the enactment of hybrid roles by medical managers, existing research in health care management is mostly descriptive with little emphasis on the conditions under which hybrid roles are enacted and, importantly, on the effects of this variation on performance. PURPOSE: In this article, we seek to fill this research gap by empirically examining (a) whether budgetary participation aligns professional and organizational values, (b) the impact of this alignment on employees' work-related feelings and managerial performance, and (c) the effect of professional identity on value congruence. METHODOLOGY: Data were collected by a survey conducted in an Italian hospital, and partial least square was used to test the relationships among variables. RESULTS: Overall, results show that (a) high involvement in budgeting is instrumental in facilitating medical managers' value congruence, and this, in turn, positively effects managerial job engagement; (b) the effect of budgetary participation on value congruence depends on the extent of professional identity; and (c) as a result of enhanced value congruence and managerial job engagement, employees tend to deliver superior role performance. PRACTICE IMPLICATION: Findings of this study provide some guidance for managers on how organizations can take steps to guarantee effective support to hybrid professionals. PMID- 30475260 TI - Dexmedetomidine as an Adjuvant to Local Anesthetics in Transversus Abdominis Plane Block: A Systematic Review and Meta-analysis. AB - OBJECTIVES: The objective of this meta-analysis was to evaluate the analgesic effects of dexmedetomidine (DEX) in transversus abdominis plane (TAP) blocks for abdominal surgery. METHODS: Electronic databases, including PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI), Wan Fang, and the Cochrane Library , were conducted to collect the randomized controlled trials (RCTs) from inception to March 2018. RCTs investigating the impact of adding DEX to local anesthetics for TAP blocks were included in this analysis. Pain scores (at rest and movement), opioid consumption, the duration of the TAP block and the common adverse effects were analyzed. RESULTS: Twenty published trials including 1212 patients met the inclusion criteria. The addition of DEX significantly reduced pain scores 8 hours postoperatively at rest (WMD -0.78, 95% CI -1.27 to -0.30, P=0.001), 4 hours postoperatively on movement (WMD -1.13, 95% CI -1.65 to -0.60, P<0.001) and opioid consumption (WMD -146.34, 95% CI -188.89 to -103.78, P<0.001) when compared with control group. Furthermore, perineural DEX prolonged the duration of the TAP block (WMD 3.33, 95% CI 2.85 to 3.82, P<0.001). Meanwhile, it did not affect the incidence of postoperative nausea and vomiting, hypotension, bradycardia, somnolence, or pruritus. CONCLUSION: DEX is a potential anesthetic adjuvant that can facilitate better postoperative analgesia, reduce postoperative analgesic requirements and prolong the local anesthetic effect when administered in TAP blocks.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc nd/4.0/. PMID- 30475261 TI - Economy, migrant labour and sex work: interplay of HIV epidemic drivers in Zimbabwe over three decades. AB - BACKGROUND: HIV took off rapidly in Zimbabwe during the 1980s. Yet, between 1998 and 2003, as the economy faltered, HIV prevalence declined abruptly and without clear explanation. METHODS: We reviewed epidemiological, behavioural, and economic data over three decades to understand changes in economic conditions, migrant labour and sex work that may account for observed fluctuations in Zimbabwe's HIV epidemic. Potential biases related to changing epidemic paradigms and data sources were examined. RESULTS: Early studies describe rural poverty, male migrant labour and sex work as conditions facilitating HIV/sexually transmitted infection (STI) transmission. By the mid-1990s, as Zimbabwe's epidemic became more generalized, research focus shifted to general population household surveys. Yet, less than half as many men than women were found at home during surveys in the 1990s, increasing to 80% during the years of economic decline. Other studies suggest that male demand for sex work fell abruptly as migrant workers were laid off, picking up again when the economy rebounded after 2009. Numbers of clients reported by sex workers, and their STI rates, followed similar patterns reaching a nadir in the early 2000s. Studies from 2009 describe a return to more active sex work, linked to increasing client demand, as well as a revitalized programme reaching sex workers. CONCLUSION: The importance of the downturn in migrant labour and resultant changes in sex work may be underestimated as drivers of Zimbabwe's rapid HIV incidence and prevalence declines. Household surveys underrepresent populations at the highest risk of HIV/STI acquisition and transmission, and these biases vary with changing economic conditions. PMID- 30475262 TI - Eliminating perinatal HIV in the United States: mission possible? AB - In 2015, only 53 infants born in the United States acquired HIV, the lowest recorded number of perinatal HIV infections. Recognizing this significant achievement, we must acknowledge that the United States has not yet reached the goal of eliminating perinatal HIV transmission. This manuscript describes different approaches to perinatal HIV preventive services among five states and the District of Columbia as case studies. Continuous focus on improving identification, surveillance and prevention of HIV infection in pregnant women and their infants is necessary to reach the goal of eliminating perinatal HIV transmission in the United States. PMID- 30475264 TI - Strain-specific effect on biphasic DNA binding by HIV-1 integrase. AB - The oligomerization of HIV-1 integrase onto DNA is not well understood. Here we show that HIV-1 integrase binds the DNA in a biphasic (high- and low-affinity) modes. For HIV-1 subtype B, the high-affinity mode is ~100-fold greater than low affinity mode (Kd.DNA = 37 and 3400 nM, respectively). The Kd.DNA values of patient-derived integrases containing subtype-specific polymorphisms were affected 2-4-fold, suggesting that polymorphisms may influence on effective concentrations of inhibitors, since these inhibitors preferably bind to integrase DNA complex. PMID- 30475263 TI - GlycA, a novel inflammatory marker, is associated with subclinical coronary disease in the multicenter AIDS cohort study. AB - OBJECTIVE: GlycA, a novel NMR biomarker of inflammation, has been associated with incident cardiovascular disease (CVD) in the general population, but its association with CVD among HIV-infected individuals is unknown. We examined the associations between GlycA and subclinical coronary plaque among HIV-infected and HIV-uninfected men participating in MACS. DESIGN: Cross-sectional analysis of 935 men with plasma measurement of GlycA and noncontrast cardiac computed tomography (CT) and/or coronary CT angiography. METHODS: We used multivariable Poisson and linear regression to assess associations of GlycA with prevalent coronary atherosclerosis and plaque extent, respectively. RESULTS: Mean +/- SD age was 54 +/- 7 years; 31% were black; 63% HIV-infected. GlycA levels were higher in HIV infected compared with HIV-uninfected men (397 +/- 68 vs. 380 +/- 60 MUmol/l, P = 0.0001), and higher for men with detectable viral load vs. undetectable (413 +/- 79 vs. 393 +/- 65 MUmol/l, P = 0.004). After adjusting for HIV serostatus, demographic and CVD risk factors, every 1SD increment in GlycA level was associated with a higher prevalence of coronary artery calcium (CAC >0) [prevalence ratio 1.09 (95% CI 1.03-1.15)] and coronary stenosis at least 50% [1.20 (1.02-1.41)]. These associations did not significantly differ after adjusting for traditional inflammatory biomarkers or by HIV serostatus. Among men with plaque, GlycA was positively associated with the extent of CAC and total plaque. CONCLUSION: HIV infection was associated with higher GlycA levels. In both HIV-infected and HIV-uninfected individuals, GlycA was significantly associated with several measures of subclinical coronary atherosclerosis, independent of other CVD risk factors and inflammatory biomarkers. These findings suggest the potential role of GlycA in CVD risk stratification among HIV patients. PMID- 30475265 TI - Success and failure of initial antiretroviral therapy in adults: an updated systematic review of 77,999 subjects from 1994 to 2017. AB - BACKGROUND: We updated a prior systematic review of initial ART efficacy through Week 144. MATERIALS AND METHODS: Studies (1994-July 2017) were drawn from PubMed, ClinicalTrials.gov, Cochrane Library, and major conferences; design, eligibility, subject and ART data were abstracted. Outcomes are expressed as group size weighted means. Mixed-effects meta-regression was used to identify sources of efficacy heterogeneity. RESULTS: Within 354 groups (181 studies, 77,999 subjects), principal backbones were tenofovir-emtricitabine (TDF/TAF-FTC) (44.2%), thymidine-based (27.7%), and abacavir-lamivudine (9.7%). Principal anchors were non-nucleoside analogue (49.7%), boosted protease inhibitor (28.1%) and integrase inhibitor (INSTI; 11.5%). Mean intention-to-treat efficacy (RNA<50 copies/mL) was 71.3%, 63.5% (145 groups) and 61.8% (48 groups) at Weeks 48, 96, and 144, respectively (for post-2010 studies, 83.8%, 79.9% and 77.1%). TDF/TAF FTC and INSTI were independent predictors of greater efficacy at Weeks 48, 96 and 144. Additional independent predictors at Week 48 were pre-ART resistance genotyping, higher baseline CD4 count and once-daily ART. Fewer pills per day predicted greater efficacy at Weeks 96 and 144. Phase-4 studies yielded progressively inferior efficacy than phase-3 studies (difference 5.1% at Week 48, 15.8% at Week 144). Cessation through Week 144 overall (29.4%) and for adverse events (8.9%) declined over time, but cessation for virological failure (5.2%) did not. CONCLUSIONS: Initial ART efficacy continues to improve, but >20% of post 2010 subjects failed over 3 years. Real-world efficacy is lower than in phase-3 trials. Guidelines should list non-INSTI-based initial ART as non-preferred. Strategies are needed to improve access to pre-ART genotyping and to increase early initiation of once-daily ART. PMID- 30475266 TI - HIV brain latency as measured by CSF BcL11b relates to disrupted brain cellular energy in virally suppressed HIV infection. AB - OBJECTIVE: We investigated whether HIV brain latency was associated with brain injury in virally suppressed HIV infection. DESIGN: observational cross-sectional and longitudinal study. METHODS: The study included 26 virally-suppressed HIV+ men (61.5% with HAND) who undertook cerebrospinal fluid (CSF) analyses at baseline. They also completed a proton MR Spectroscopy (H MRS) and neuropsychological assessments at baseline and 18-months. To quantify whether there was residual brain HIV transcription, we measured CSF HIV-tat. As an HIV brain latency biomarker, we used concentrations of CSF BcL11b, a microglia transcription factor that inhibits HIV transcription. Concurrently we assessed neuroinflammation with CSF neopterin, neuronal injury with CSF Neurofilament Light-Chain (NFL), and in vivo neurochemistry with H MRS of N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), myo-inositol (MI), glutamine/glutamate (Glx) in the frontal white matter (FWM), posterior cingulate cortex (PCC), and caudate nucleus area (CA). RESULTS: Baseline adjusted regression models for neopterin, NFL and tat showed that a higher CSF BcL11b was consistently associated with lower FWM Cr (when adjusted for neopterin: beta=-.30; p = .15; when adjusted for NFL: beta=-.47; p = .04; and when adjusted for tat: beta=-.47; p = .02). In longitudinal analyses, we found no time effect, but a consistent BcL11b altering effect on FW M Cr. The effect reached a significant moderate effect size range when corrected for CSF NFL (beta=-.36, p = .02) and CSF tat (beta=-.34, p = .02). CONCLUSIONS: Reduced frontal white matter total creatine may indicate subclinical HIV brain latency-related injury. H MRS may offer a non-invasive option to measure HIV brain latency. PMID- 30475267 TI - Extremely Low Hepatitis C prevalence among HIV co-infected individuals in 4 countries in sub-Saharan Africa. AB - : A multicentric, retrospective case-series analysis (facility-based) in five sites across Kenya, Malawi, Mozambique, and Uganda screened HIV-positive adults for hepatitis C virus (HCV) antibodies using Oraquick rapid testing and viral confirmation (in three sites). Results found substantially lower prevalence than previously reported for these countries compared with previous reports, suggesting that targeted integration of HCV screening in African HIV programs may be more impactful than routine screening.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0. PMID- 30475268 TI - Turning Away From Industrial Health Care Toward Careful and Kind Care. AB - The health care industry is increasingly driven by the pursuit of value. The author of this Invited Commentary believes this value is nothing more than a business rebranding of efficiency with little connection to care. Overclocked clinicians, increasingly impaired by symptoms of burnout and too focused on documenting, cannot see patients in high definition. The author shows that treatment which is blind to patients' contexts often overwhelms patients with medical errands, a topic absent from medical curricula. Care must not be the means by which health care satisfies its industrial mission, but rather the end for which it mobilizes its means. In unhurried consultations, clinicians must appreciate and respond sensibly to patients' problematic situation, and care for and about them. Medical training must cultivate future clinicians who value caring over caring for value. Medical educators and trainees at all levels must turn away from industrial health care, toward careful and kind care for all. PMID- 30475269 TI - Crossing the Gap: Using Competency-Based Assessment to Determine Whether Learners Are Ready for the Undergraduate-to-Graduate Transition. AB - In 2011, the Education in Pediatrics Across the Continuum (EPAC) Study Group recruited four medical schools (University of California, San Francisco, University of Colorado, University of Minnesota, and University of Utah) and their associated pediatrics clerkship and residency programs directors to be part of a consortium to pilot a model designed to advance learners from undergraduate medical education (UME) to graduate medical education (GME) and then to fellowship or practice based on competence rather than time spent in training. The central design features of this pilot included predetermined expectations of performance and transition criteria to ensure readiness to progress from UME to GME, using the Core Entrustable Professional Activities for Entering Residency (Core EPAs) as a common assessment framework. Using this framework, each site team (which included, but was not limited to, the EPAC course, pediatric clerkship, and pediatric residency program directors) monitored learners' progress, with the site's clinical competency committee marking the point of readiness to transition from UME to GME (i.e., the attainment of supervision level 3a). Two of the sites implemented time-variable transition from UME to GME, based on when a learner met the performance expectations and transition criteria. In this Article, the authors describe each of the four sites' implementation of Core EPA assessment and their approach to gathering the data necessary to determine readiness for transition. They conclude by offering recommendations and lessons learned from the pilot's first 7 years of development, adaptation, and implementation of assessment strategies across the sites, and discussing next steps. PMID- 30475270 TI - Technologies of Exposure: Videoconferenced Distributed Medical Education as a Sociomaterial Practice. AB - PURPOSE: Videoconferencing-a network of buttons, screens, microphones, cameras, and speakers-is one way to ensure that undergraduate medical curricula are comparably delivered across distributed medical education (DME) sites, a common requirement for professional accreditation. However, few researchers have critically explored the role of videoconference technologies in day-to-day DME. The authors, therefore, conducted a three-year ethnographic study of a Canadian undergraduate DME program. METHOD: Drawing on 108 hours of observations, 33 interviews, and analysis of 65 documents-all collected at two campuses between January 2013 and February 2015-the authors explored the question, "What is revealed when we consider videoconferencing for DME as a sociomaterial practice?" RESULTS: The authors describe three interconnected ways that videoconference systems operate as unintended "technologies of exposure": visual, curricular, and auditory. Videoconferencing inadvertently exposes both mundane and extraordinary images and sounds, offering access to the informal, unintended, and even disavowed curriculum of everyday medical education. The authors conceptualize these exposures as sociomaterial practices, which add an additional layer of complexity for members of medical school communities. CONCLUSIONS: This analysis challenges the assumption that videoconferencing merely extends the bricks-and mortar classroom. The authors discuss practical implications and recommend more critical consideration of the ways videoconferencing shifts the terrain of medical education. These findings point to a need for more critically oriented research exploring the ways DME technologies transform medical education, in both intended and unintended ways. PMID- 30475271 TI - Our Senior Editorial Reviewers: A Centerpiece. PMID- 30475272 TI - Periimplantitis and Implant Body Roughness: A Systematic Review of Literature. AB - PURPOSE: The aim of this systematic review was to evaluate whether implant roughness is associated with periimplantitis in humans. MATERIALS AND METHODS: An electronic search of 3 databases (MEDLINE, Web of Knowledge, and the Cochrane Library) was undertaken until October 2017 and was supplemented by manual searching. Prospective studies were included if they met the following criteria: (1) give a clear definition of periimplantitis and (2) contain outcome data (clinical and radiological data) considering the periimplantitis rate. A systematic review was carried out to evaluate the impact of roughness on the periimplantitis rate. RESULTS: Of 4690 potentially eligible articles, 22 were included in the qualitative analysis and quantitative synthesis. CONCLUSIONS: This systematic review suggests that roughness and surface treatment of dental implants are important factors associated with periimplantitis. PMID- 30475273 TI - The "Line Sign" Is a Rapid and Efficient Diagnostic "Test" for Morphea: Clinicopathological Study of 73 Cases. AB - Histologic clues that facilitate rapid diagnosis of morphea at scanning magnification have been described but not well studied. We examined 73 cases of morphea and 42 control cases to determine the sensitivity and specificity of a novel histopathological feature-"the line sign (LS)"-a prominent, straight interface between subcutis and adjacent collagen. The sensitivity of LS was shown to be the most sensitive feature among 4 other existing histopathological features. Its specificity, however, was not the highest among the other features and needs to be evaluated further in future studies to confirm the usefulness of LS as a diagnostic tool for morphea. PMID- 30475274 TI - Facial Plaque in a Woman With Sjogren Syndrome: Answer. PMID- 30475276 TI - Verrucous Intertriginous Plaques: Answer. PMID- 30475275 TI - Pruritic Linear Eruption in a 53-Year-Old Woman: Answer. PMID- 30475277 TI - Microinstability of the Hip-Gaining Acceptance. AB - The hip has generally been considered an inherently stable joint. However, the femoral head moves relative to the acetabulum. Although the bones are primarily important in hip stability, the importance of the soft tissues has recently been demonstrated. Symptomatic microinstability of the hip is defined as extraphysiologic hip motion that causes pain with or without symptoms of hip joint unsteadiness and may be the result of bony deficiency and/or soft-tissue damage or loss. Recent work has helped improve the ability to identify microinstability patients preoperatively. Initial management begins with activity modification and strengthening of the periarticular musculature. Failing nonsurgical management, surgical intervention can be beneficial, focusing on treatment of the underlying cause of microinstability, as well as associated intra-articular pathology. Bony deficiency may be treated with a redirectional osteotomy, whereas those with adequate bony coverage may be treated with capsular plication, capsular reconstruction, and/or labral reconstruction. PMID- 30475278 TI - Preoperative Opioid Use Among Patients Undergoing Shoulder Arthroplasty Predicts Prolonged Postoperative Opioid Use. AB - INTRODUCTION: This study determines the incidence of opioid use before shoulder arthroplasty and analyzes its influence on postoperative use. METHODS: A retrospective analysis of patients undergoing shoulder arthroplasty with at least 2-year follow-up was performed. Then, at pre- and postoperative appointments, the patients were asked "Do you take narcotic pain medication (codeine or stronger)?" RESULTS: Among 490 patients included in the study, 35.5% reported preoperative opioid use. These patients had higher incidence of opioid use at 1-year follow-up (29.1% versus 4.9%; odds ratio, 8.320; P < 0.001) and at final follow-up (35.1% versus 7.3%; odds ratio, 6.877; P < 0.001). Opioid usage did not change markedly from 1 year follow-up to final follow-up (P > 0.18). DISCUSSION: Approximately one-third of patients used opioids preoperatively and were seven times more likely to continue opioid use postoperatively. Opioid usage did not change from 1 year follow-up to final follow-up, suggesting that patients still using opioids at their 1-year appointment were likely to continue opioid use. LEVEL OF EVIDENCE: Level III. PMID- 30475279 TI - Deltoid Ligament Rupture in Ankle Fracture: Diagnosis and Management. AB - The last stage of a supination-external rotation ankle fracture involves either transverse fracture of the medial malleolus or rupture of the deltoid ligament. When the deltoid ligament ruptures, a "bimalleolar equivalent" ankle fracture occurs, and the surgeon is presented with several diagnostic and therapeutic challenges. In the native ankle, the deltoid ligament provides restraint to eversion and external rotation of the talus on the tibia. In bimalleolar equivalent ankle fractures, there is often gross medial instability even after fibular reduction. Retraction of the deltoid with subsequent healing in a nonanatomic position theoretically may cause instability, persistent medial gutter pain, and loss of function with risk of early arthritis. In mild cases, deltoid injury may not be obvious, and potential diagnostic techniques include preoperative and intraoperative stress radiography, MRI, and ultrasonography. The most common injury pattern is avulsion from the medial malleolus, and most current repair techniques involve direct repair of the capsular and deltoid injuries involving suture anchors in the medial malleolus and imbrication of the superficial and deep deltoid fibers. To date, there is limited evidence of superior clinical outcomes with the addition of deltoid repair compared with open reduction and internal fixation of the fibula alone. PMID- 30475281 TI - Change. PMID- 30475280 TI - Etiology, Evaluation, and Management Options for the Stiff Digit. AB - The stiff digit may be a consequence of trauma or surgery to the hand and fingers and can markedly affect a patient's level of function and quality of life. Stiffness and contractures may be caused by one or a combination of factors including joint, intrinsic, extensor, and flexor tendon pathology, and the patient's individual biology. A thorough understanding of the anatomy, function, and relationship of these structures on finger joint range of motion is crucial for interpreting physical examination findings and preoperative planning. For most cases, nonsurgical management is the initial step and consists of hand therapy, static and dynamic splinting, and/or serial casting, whereas surgical management is considered for those with more extensive contractures or for those that fail to improve with conservative management. Assuming no bony block to motion, surgery consists of open joint release, tenolysis of flexor and/or extensor tendons, and external fixation devices. Outcomes after treatment vary depending on the joint involved along with the severity of contracture and the patient's compliance with formal hand therapy and a home exercise program. PMID- 30475282 TI - Great News about the Local Coverage Determination Process. PMID- 30475283 TI - Diagnosis and Management of Atopic Dermatitis: A Review. AB - GENERAL PURPOSE: The purpose of this learning activity is to provide information about the diagnosis and management of atopic dermatitis (AD). TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After completing this continuing education activity, you should be able to:1. Recall the diagnostic process of AD.2. Identify nonpharmacologic therapies for skin care in patients with AD.3. Explain the pharmacologic management of AD. ABSTRACT: Atopic dermatitis is a chronic, relapsing, intensely pruritic inflammatory skin disease that affects both children and adults. This article provides an overview of the epidemiology, clinical features, pathophysiology, complications, and specific investigations of atopic dermatitis. The current and novel therapies for the treatment of atopic dermatitis will be discussed. PMID- 30475284 TI - Perioperative Pressure Injuries: A Systematic Literature Review. AB - OBJECTIVE: To conduct a systematic review to investigate risk factors, incidence, and preventive strategies for perioperative pressure injuries (PIs). METHODS: The authors reviewed four databases for literature published from January 2001 to December 2017. Selected articles included primary quantitative studies with prospective, descriptive, and longitudinal design or randomized controlled trials that evaluated risk factors, incidence, and preventive strategies for perioperative PIs. The studies included were evaluated for methodological quality using the Edwards Method Score. The authors used a standardized extraction form to extract inclusion and exclusion criteria, participant demographics, methodology, PI risk instrument and classification systems, type of surgery and anesthesia, PI risk factors, incidence, preventive strategies, and outcomes evaluation. MAIN RESULTS: Of the 115 publications identified, 11 met the inclusion criteria. The risk assessment and PI classification instruments used differed in every study. Incidence of PI varied throughout the studies and was reduced by warming therapy and by a skin care intervention program. CONCLUSIONS: Further studies are necessary to develop a standard risk assessment instrument and preventive strategies and to clarify some contradictions evident in the literature. PMID- 30475285 TI - Silk-Based Biomaterials in Cutaneous Wound Healing: A Systematic Review. AB - OBJECTIVE: Effective wound dressings should promote healing through cellular migration, neovascularization, and re-epithelialization. Silk fibroin (SF) and silk sericin (SS) are reported to have very good biocompatibility, excellent mechanical properties, and controlled biodegradability. This review investigates the use and performance of silk-based biomaterials in cutaneous wounds within in vitro, in vivo, and randomized controlled studies. METHODS: Study authors conducted a comprehensive literature search on the use of silk-based dressings in cutaneous wound healing and investigated reports of the advantages and disadvantages of SF and SS along with these materials' methods of characterization, cell migration, neovascularization, wound closure, and cytotoxicity. RESULTS: In vitro and in vivo animal models have shown SF-based biomaterials promote good cellular adhesion and fibroblast proliferation in cutaneous wounds. The porosity and silk concentration of silk-based scaffolds are key determinants of biodegradation and plasmatic imbibition capabilities and can help promote wound healing. In reviewed studies, SF biomaterials promoted neovascularization as early as 7 days and better than common dressings, demonstrating low cytotoxicity and immunogenicity. That said, a concern with the use of SS is the tendency to cause a hypersensitivity reaction. CONCLUSIONS: The benefits of silk-based biomaterials seem evident based on promising preclinical studies. Both SF and SS have been shown to have excellent wound healing properties by promoting cell attachment, migration, and collagen deposition. The authors encourage the use of SF and SS in more trials for wound healing. PMID- 30475287 TI - Diagnosis and Management of Atopic Dermatitis: A Review. PMID- 30475286 TI - Review, Reconcile, and Optimize Your Workflows. PMID- 30475289 TI - RIDGE-SHAPED MACULA IN YOUNG MYOPIC PATIENTS AND ITS DIFFERENTIATION FROM TYPICAL DOME-SHAPED MACULA IN ELDERLY MYOPIC PATIENTS. AB - PURPOSE: To assess and compare clinical features of a ridge-shaped macula (defined as macular elevation only in one meridian across the fovea) in individuals younger than 20 years with those of a dome-shaped macula (DSM) in patients aged 20+ years. METHODS: The retrospective observational case series study included 185 highly myopic eyes of 100 consecutive patients younger than 20 years, who were compared with highly myopic patients with DSMs, aged 20+ years and examined in previous studies. RESULTS: Seventeen (9.2%) eyes of the highly myopic young patients showed macular elevations all of which ran only in the horizontal direction across the vertical optical coherence tomographic section fulfilled the definition of a ridge and did not show any staphylomas or any macular Bruch membrane defects. By contrast, in the older patients with DSMs, the DSMs were significantly higher and had a narrower base than the ridges in the young patients, and showed macular Bruch membrane defects in their vicinity, with the axial length being significantly longer, the myopic maculopathy more severe, and the subfoveal choroid thinner. CONCLUSION: Macular elevations detected in children and adolescents are usually ridge-shaped maculas and do not have the characteristics of DSMs. In comparison with DSMs, ridge-shaped maculas do not show a spatial association with macular Bruch membrane defects or posterior staphylomas and have a wider basis and smoother elevation slope. As a hypothesis, ridge-shaped maculas may be due to a folding of Bruch membrane at the posterior pole, potentially caused by an asymmetrical enlargement of Bruch membrane in the equatorial region. PMID- 30475290 TI - Predictive Factors for Hypotension Associated With Supine-to-Prone Positional Change in Patients Undergoing Spine Surgery. AB - BACKGROUND: Positional change during general anesthesia can cause hypotension. The objective of this retrospective study was to determine predictive factors for hypotension associated with supine-to-prone positional change in spinal surgery patients. MATERIALS AND METHODS: Data on demographics, current medications, comorbidity, intraoperative mean arterial pressure (MAP), heart rate, pulse pressure variation, tidal volume, peak inspiratory pressure, and propofol and remifentanil effect-site concentrations were collected from 179 patients undergoing elective spine surgery. Hypotension associated with supine-to-prone positional change was defined as >20% reduction in MAP during positional change. RESULTS: Hypotension associated with supine-to-prone positional change was observed in 16 (8.9%) patients. The median (interquartile range) effect-site concentration of remifentanil (5.3 [4.0 to 8.5] vs. 4.0 [3.1 to 4.0] ng/mL, P<0.001), MAP (95.0 [86.0 to 103.5] vs. 80.0 [70.0 to 94.0] mm Hg, P=0.014), peak inspiratory pressure (16.5 [15.0 to 18.5] vs. 15.0 [14.0 to 17.0] hPa, P=0.040) in the supine position, and pulse pressure variation in the prone position (12.0 [9.0 to 16.4] vs. 9.0 [7.0 to 12.0]%, P=0.019) were significantly higher in the hypotension group. In multivariate logistic regression analysis, the effect-site concentration of remifentanil (odd ratio [95% confidence interval], 2.12 [1.51 2.96], P<0.001), preoperative use of beta-blocker (7.64 [1.21-48.36], P=0.031), and MAP in the supine position (1.04 [1.00-1.07], P=0.033) were independent predictive factors for hypotension associated with supine-to-prone positional change. CONCLUSIONS: Increased effect-site concentration of remifentanil, preoperative use of beta-blocker, and high MAP in the supine position were predictive factors for hypotension associated with supine-to-prone positional change in spinal surgery patients. PMID- 30475288 TI - ADVERSE EVENTS OF THE ARGUS II RETINAL PROSTHESIS: Incidence, Causes, and Best Practices for Managing and Preventing Conjunctival Erosion. AB - PURPOSE: To analyze and provide an overview of the incidence, management, and prevention of conjunctival erosion in Argus II clinical trial subjects and postapproval patients. METHODS: This retrospective analysis followed the results of 274 patients treated with the Argus II Retinal Prosthesis System between June 2007 and November 2017, including 30 subjects from the US and European clinical trials, and 244 patients in the postapproval phase. Results were gathered for incidence of a serious adverse event, incidence of conjunctival erosion, occurrence sites, rates of erosion, and erosion timing. RESULTS: Overall, 60% of subjects in the clinical trial subjects versus 83% of patients in the postapproval phase did not experience device- or surgery-related serious adverse events. In the postapproval phase, conjunctival erosion had an incidence rate of 6.2% over 5 years and 11 months. In 55% of conjunctival erosion cases, erosion occurred in the inferotemporal quadrant, 25% in the superotemporal quadrant, and 20% in both. Sixty percent of the erosion events occurred in the first 15 months after implantation, and 85% within the first 2.5 years. CONCLUSION: Reducing occurrence of conjunctival erosion in patients with the Argus II Retinal Prosthesis requires identification and minimization of risk factors before and during implantation. Implementing inverted sutures at the implant tabs, use of graft material at these locations as well as Mersilene rather than nylon sutures, and accurate Tenon's and conjunctiva closure are recommended for consideration in all patients. PMID- 30475291 TI - Prognostic Value of Tissue Oxygen Monitoring and Regional Cerebral Oxygen Saturation Monitoring and Their Correlation in Neurological Patients With Sepsis: A Preliminary, Prospective, Observational Study. AB - BACKGROUND: There is paucity of literature on the prognostic value of tissue oxygen saturation (StO2) and regional cerebral oxygen saturation (rSO2) in neurological patients with sepsis. In this preliminary study, we investigated the prognostic value of StO2 and rSO2 in a group of neurological patients and correlated StO2 and rSO2 with hemodynamic and metabolic parameters. MATERIALS AND METHODS: This preliminary, prospective observational study was conducted in 45 adult neurological patients admitted to intensive care unit. Once a diagnosis of sepsis or septic shock was established, parameters of oxygenation (StO2, rSO2, central venous oxygen saturation [ScvO2]), serum lactate, illness severity scores (Acute Physiology and Chronic Health Evaluation score, Sequential Organ Failure Assessment score, Glasgow Coma Scale) were recorded at 0, 6, 12, 24, 36, and 48 hours, and once daily thereafter. Outcomes were in-hospital mortality attributable to sepsis and the Glasgow outcome score at hospital discharge. RESULTS: There was a moderately positive correlation between StO2 and rSO2 at baseline (r=0.599; P=0.001). StO2, illness severity scores and serum lactate, but not rSO2, were significantly different between survivors (n=29) and nonsurvivors (n=16) at baseline and during the first 48 hours. An rSO2 of 62.5% had a sensitivity of 83% and specificity of 67% to differentiate survivors and nonsurvivors of septic shock at 48 hours. StO2 had a higher correlation with ScvO2 and serum lactate than rSO2. CONCLUSIONS: StO2 prognosticates survival and favorable/unfavorable outcomes in neurological patients with sepsis. The role of rSO2 in predicting survival in milder form of sepsis is doubtful. PMID- 30475292 TI - Costochondral Grafting for Nasal Airway Reconstruction in an Infant With Frontonasal Dysplasia. AB - Frontonasal dysplasia (FND) is a congenital malformation of the central portion of the face, including the eyes, nose, and forehead. Owing to its rarity and wide spectrum of phenotypes, the optimal timing and technique of surgery remain controversial. Here, we report a case of a patient with FND, who presented with respiratory distress. The deformed nostrils were so small that the patient could not normally breathe through the nose immediately after birth. Rhinoplasty using a costochondral graft was performed at 16 months of age. After surgery, the nostrils enlarged and the appearance of the nose improved. Although congenital nasal deformity is frequently corrected during adolescence, surgery at an early stage can be considered when important issues are noted, such as inability to breathe through the nose. PMID- 30475293 TI - Foreign-Body Reaction to Bioabsorbable Plate and Screw in Craniofacial Surgery. AB - Hydroxyapatite and poly-L-lactide plates are often used for maxillofacial surgery. These plates take 3 to 4 years to resorb completely, leading to the possibility of a foreign-body reaction. A 20-year-old woman who developed a foreign-body reaction to the plates was reported. Based on review of the relevant literature, foreign-body reactions have often been reported with this plate. Long term follow-up is warranted to evaluate patients using this plate in maxillofacial surgery. PMID- 30475294 TI - Endoscope-Assisted Resection of Intramuscular Cavernous Hemangioma Within the Temporal Muscle. AB - Hemangiomas are benign vascular soft tissue tumors, which most frequently occur in the skin or subcutaneous tissue. Intramuscular hemangiomas typically occur in the trunk and extremities and less frequently in the head and neck. Among these, those occurring in the temporalis muscle are extremely rare. The authors report the case of a 43-year-old Japanese male with a mass in his left temporal fossa. Computed tomography images showed no erosion of the zygomatic bone, and magnetic resonance imaging revealed an ovoid well-marginated mass within the temporal muscle. The lesion was surgically excised with an endoscopy procedure used for minimally invasive lesions and complete removal. Histopathological examination confirmed the diagnosis of intramuscular cavernous hemangioma. The postoperative clinical course was good, with no indications of temporary nerve paralysis. No signs of local recurrence were observed postoperatively. Therefore, a cavernous hemangioma should be suspected when a mass occurs in the temporal region with accompanying radiologic findings suggesting vascular origin. In surgical treatment, the endoscopy-assisted technique is very useful to achieve complete tumor resection and prevent relapse while avoiding serious complications due to surgical procedures. PMID- 30475295 TI - Recurrent Pott's Puffy Tumor Treated With Anterior Skull Base Resection With Reconstruction of the Anterolateral Thigh Flap. AB - Pott's puffy tumor (PPT) is a rare, life-threatening complication of frontal sinusitis that is treated with a combination of appropriate antibiotics and surgery for the removal of infected tissue. A 56-year-old man with recurrent forehead swelling was admitted and diagnosed with recurrent PPT. He had undergone endoscopic sinus surgery and pericranial abscess drainage. We planned to remove the infected tissue and bones and perform reconstruction with an anterolateral thigh (ALT) flap. Eight weeks after surgery, the patient showed no inflammation, and the antibiotics were discontinued. No recurrence was observed at 1 year and 7 months after surgery. Combined surgical and antibiotic treatment is effective for PPT. Reconstructive treatment can be chosen for refractory recurrent cases with intracranial complications. To our knowledge, this is the first report of PPT treated by anterior skull base resection with reconstruction using an ALT flap in an immunocompromised patient. PMID- 30475297 TI - Oral Complications in Children Undergoing Chemotherapy: The COMEDY (Clenching, Oral Mucositis, Eyes, DYsphagia) Pattern. PMID- 30475298 TI - Cognitive Behavior Therapy for Persistent Severe Fatigue in Childhood Cancer Survivors: A Pilot Study. AB - OBJECTIVES: Fatigue is a common and disabling late effect in childhood cancer survivors (CCS). In this pilot study, the effectiveness of cognitive behavior therapy (CBT) in CCS with persistent and severe fatigue was retrospectively evaluated. MATERIALS AND METHODS: In total, 33 consecutively referred CCS with persistent severe fatigue were offered CBT. The primary outcome was fatigue severity (Checklist Individual Strength, Fatigue Severity Subscale). Secondary outcomes were functional impairment, psychological distress, and quality of life (QoL). RESULTS: In total, 25 CCS completed CBT (76%). The mean age of CCS was 23.1 years (range, 11 to 42 y), mean age at primary cancer diagnosis was 9.7 years (range, 0 to 17 y), and mean time since primary cancer diagnosis was 13 years (range, 5 to 34 y). Fatigue severity ([INCREMENT] 17.4; confidence interval (CI)=12.7-22.1; P<0.001), functional impairment (SIP8 [INCREMENT] 470.3; CI=312.3 628.4; P<0.001/SF36 [INCREMENT] 11.7; CI=17.2-6.3; P<0.001), and psychological distress ([INCREMENT] 26.4; CI=15.6-34.9; P<0.001) were significantly decreased at second assessment. QoL ([INCREMENT] 13.5; CI=22.0-4.3; P=0.005) was significantly improved. A total of 23 CCS of the 33 CCS (70%) met the criteria for clinically significant improvement of fatigue. CONCLUSIONS: In this pilot study, the majority of severely fatigued CCS showed a clinically significant reduction in fatigue following CBT. Moreover, daily function and QoL improved, and psychological distress decreased. PMID- 30475296 TI - Management of penetrating intra-peritoneal colon injuries: A meta-analysis and practice management guideline from the Eastern Association for the Surgery of Trauma. AB - BACKGROUND: The management of penetrating colon injuries in civilians has evolved over the last four decades. The objectives of this meta-analysis are to evaluate the current treatment regimens available for penetrating colon injuries and assess the role of anastomosis in damage control surgery to develop a practice management guideline for surgeons. METHODS: Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, a subcommittee of the Practice Management Guidelines section of EAST conducted a systematic review using MEDLINE and EMBASE articles from 1980 through 2017. We developed three relevant problem, intervention, comparison, and outcome (PICO) questions regarding penetrating colon injuries. Outcomes of interest included mortality and infectious abdominal complications. RESULTS: Thirty-seven studies were identified for analysis, of which 16 met criteria for quantitative meta-analysis and included 705 patients considered low-risk in six prospective randomized studies. Seven hundred thirty-eight patients in 10 studies undergoing damage control laparotomy (DCL) and repair or resection and anastomosis (R&A) were included in a separate meta-analysis. Meta-analysis of high-risk patients undergoing repair or R&A was not feasible due to inadequate data. CONCLUSIONS: In adult civilian patients sustaining penetrating colon injury without signs of shock, significant hemorrhage, severe contamination, or delay to surgical intervention, we recommend that colon repair or R&A be performed rather than routine colostomy. In adult high-risk civilian trauma patients sustaining penetrating colon injury, we conditionally recommend that colon repair or R&A be performed rather than routine colostomy. In adult civilian trauma patients sustaining penetrating colon injury who had DCL, we conditionally recommend that routine colostomy not be performed; instead, definitive repair or delayed R&A or anastomosis at initial operation should be performed rather than routine colostomy. LEVEL OF EVIDENCE: Systematic review/meta-analysis, Level III. PMID- 30475299 TI - Macropolycyte in Pediatrics. AB - Macropolycytes are tetraploid neutrophils produced during accelerated myelopoiesis. They have been reported in adults with pernicious anemia, sepsis, and after cytotoxic chemotherapy. Two pediatric cases are reported, one after granulocyte colony-stimulating factor treatment and the other following Kawasaki disease, respectively. PMID- 30475300 TI - Prevalence and Risk Factors for Arterial Hypertension Development in Childhood Acute Lymphoblastic Leukemia Survivors. AB - BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) survivors are at an increased risk of cardiovascular disease including arterial hypertension (AH). The objectives of this study were to assess the prevalence of AH using 24-hour ambulatory blood pressure monitoring, explore characteristics of AH, and define risk factors for the development of AH in childhood ALL survivors. PATIENTS AND METHODS: The study comprised 81 childhood ALL survivors (aged, 5 to 25 y) after a median follow-up time of 5 years. The control group consisted of 52 healthy children (aged, 5 to 17 y) without any known severe or chronic medical condition. Ambulatory blood pressure monitoring was performed in all patients and controls. Serum lipids were measured in all patients and controls. RESULTS: ALL survivors were more likely to have AH than controls (odds ratio, 2.47; 95% confidence interval, 1.08-5.63; P=0.0315). The mean time from ALL diagnosis until diagnosis of AH was 5.1+/-2.97 years. Day-time diastolic SDS and day-time mean arterial pressure SDS were significantly higher in ALL cohort compared with the controls ( 0.3+/-1.43 vs. -0.76+/-0.95; P=0.04 and 1.44+/-1.64 vs. 0.92+/-1.03; P=0.047). Childhood ALL survivors with AH were more likely to be systolic extreme dippers and reverse systolic/diastolic dippers compared with those with normal blood pressure (P<0.05). There was no association of AH with leukemia subtype, leukemia risk group, sex, central nervous system irradiation, and obesity. CONCLUSIONS: The prevalence of AH in childhood ALL survivors may be as high as 37%. We recommend regular monitoring of blood pressure in childhood ALL survivors early in the follow-up. PMID- 30475301 TI - Assessment of Nutritional Status and Malnutrition Risk at Diagnosis and Over a 6 Month Treatment Period in Pediatric Oncology Patients With Hematologic Malignancies and Solid Tumors. AB - In total, 74 pediatric oncology patients with hematologic malignancies (n=56) or solid tumors (n=18) and a median age of 78.5 months were included in this prospective study. The aims were to assess malnutrition risks and nutritional status over a 6-month treatment period measured at regular intervals. The rate of patients with high risk for malnutrition at diagnosis was 28.4% by Screening Tool for Risk of Impaired Nutritional Status and Growth tool and 36.5% by Pediatric Yorkhill Malnutrition Score. Body mass index (BMI) z-scores at diagnosis showed 12.3% undernutrition (<-2 SD) and 6.8% overnutrition (>2 SD), which changed to 6.7% and 11.1% at the sixth month, respectively. Malnutrition (BMI<5th age percentile) was detected in 13.7% at diagnosis. Despite an initial deterioration noted in BMI, BMI for age percentile, and z-scores at month 1 in all malignancy subgroups (at month 3 for acute lymphoblastic leukemia), the scores improved later on. There was an increase in weight from baseline in 88.2% of patients over 6 months. This study revealed a decrease in the prevalence of undernutrition and malnutrition over a 6-month treatment period with improved anthropometrics despite an initial deterioration in all malignancy subgroups and even in patients with high risk for malnutrition at baseline screening. Solid tumors and acute lymphoblastic leukemia seem to be associated with higher likelihood of undernutrition and overnutrition, respectively, during treatment. PMID- 30475302 TI - Successful Management of Unusual Multiple Gut Colonization With Extremely Drug resistant Bacteria in an Infant Undergoing Hematopoietic Cell Transplantation. AB - Enterobacterales represent a serious threat to transplant patients due to their increase frequency of carbapenem resistance and wide spreading. We present a case of an infant with acute lymphoblastic leukemia undergoing hematopoietic stem cell transplantation. Before transplantation an unusual double colonization of the gastrointestinal tract with extremely resistant Escherichia coli and Klebsiella pneumoniae strains producing metallo-beta-lactamase was diagnosed. Respective epidemiological management was implemented, based on the strict reverse isolation in patient-protective environment, and intensified antimicrobial surveillance. After granulocyte recovery, no extremely drug-resistant strains were found, and no case of isolation and/or transmission of carbapenem-resistant bacteria has been identified in the transplant center during the following 6 months. PMID- 30475303 TI - Oral Methods of Urinary Alkalinization for High-dose Methotrexate Administration: Alternatives to Intravenous Sodium Bicarbonate During a Critical Drug Shortage. AB - A nationwide shortage of intravenous (IV) sodium bicarbonate required institutions to explore alternative options for urinary alkalinization for high dose methotrexate (HDMTX). Children's Hospital Colorado implemented a protocol utilizing oral alkalinizing agents as alternatives to intravenous sodium bicarbonate during the shortage. The purpose of this study was to determine the safety and efficacy of oral alkalinization strategies for HDMTX administration. This retrospective study was conducted at a pediatric institution and evaluated cycles of HDMTX administered with at least one dose of oral sodium bicarbonate tablets or sodium citrate-citric acid oral solution. The time to achieve urine pH of >=7 was 3.48 hours from the start of alkalinization. A median dose of 66.4 mEq/m/day of oral sodium bicarbonate was administered to maintain a urine pH of >=7 until methotrexate was cleared. Gastrointestinal side effects occurred with 43% of HDMTX cycles and patients switched to IV sodium acetate in 25.5% of HDMTX cycles, primarily due to inadequate alkalinization or intolerance. During a shortage of IV sodium bicarbonate, oral alkalinization is an effective strategy for most patients to allow for administration of HDMTX. PMID- 30475304 TI - Hand Mirror Cells and Hypercalcemia: A Rare Presentation of Pediatric Acute Lymphoblastic Leukemia. AB - Hand mirror cell (HMC) leukemia is a variant of acute lymphoblastic leukemia previously described in the adult population where lymphoblasts manifest distinctive hand mirror morphologic features. HMC has been previously identified in 23% of childhood acute lymphoblastic leukemia patients, but its prognostic significance in children is not well understood. Hypercalcemia is also uncommon in childhood leukemias. Hypercalcemia associated with HMC leukemia has not been previously reported. We report a 5-year-old boy with HMC B-lymphoblastic leukemia who presented with hypercalcemia. PMID- 30475305 TI - Work-Relatedness. PMID- 30475306 TI - Cardiovascular Risk Factor Reduction in First Responders Resulting From an Individualized Lifestyle and Blood Test Program: A Randomized Controlled Trial. AB - OBJECTIVE: We tested the hypothesis that a lifestyle program would improve risk factors linked to cardiovascular disease (CVD) in first responders. METHODS: A 1 year cluster-randomized controlled clinical trial in 10 cities. Participants were 175 first responders, with increased waist circumference and/or low levels of large (alpha1) high-density lipoprotein (HDL) particles. The intervention group received personalized online tools and access to telephonic coaching sessions. RESULTS: At 1 year the intervention significantly reduced body weight (P = 0.004) and waist circumference (P = 0.002), increased alpha1 HDL (P = 0.01), and decreased triglyceride (P = 0.005) and insulin concentrations (P = 0.03). Program adherence was associated with weight loss (P = 0.0005) and increases in alpha1 HDL (P = 0.03). CONCLUSIONS: In first responders, a personalized lifestyle intervention significantly improved CVD risk factors in proportion to program adherence. Changes in large HDL particles were more sensitive indicators of lifestyle changes than HDL-cholesterol measurement. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT03322046This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0. PMID- 30475307 TI - An Introduction to Occupational Medicine Using a Team-Based Learning Methodology. AB - OBJECTIVE: To explore the experiences of three cohorts of medical students where Team Based Learning (TBL) methodology was used to facilitate the achievement of Occupational Medicine learning objectives. METHODS: The TBL Occupational Medicine sessions involved five components, pre-class preparation, readiness quizzes, application activities, full-group discussion, debriefing and feedback surveys. RESULTS: Learning objectives were met. Students gained a good introduction to return-to-work issues that they will likely face in a clinical setting, and commented that the process generated effective discussion related to realistic cases. Through authentic teamwork, students applied their collective knowledge and critical thinking skills to complex problems related to workplace health and safety. CONCLUSIONS: Traditional case based learning activities could be modified to incorporate aspects of TBL, including readiness quiz, team activities with realistic cases and debriefing. TBL requires role and attitudinal changes from both faculty and students. PMID- 30475309 TI - Health and Safety of Limited English Speaking Asian Homecare Aides in Chicago: A Pilot Study. AB - OBJECTIVES: To identify health and safety hazards and needs among limited English speaking Asian home care aides, and characterize their acculturation status and how it affects their health and safety. METHODS: Surveyed 60 home care aides and interviewed 6 home care service providers to assess health and safety hazards and needs of the study population. RESULTS: The majority of the study participants were older and did not speak English or did not speak English well. They communicated with senior clients in their native language only or most of the time. Many experienced work related injuries and musculoskeletal pain. DISCUSSION: The Asian homecare aides met the critical needs of an aging community. They experienced many challenges working as a home care aide and as a result of cultural barriers. PMID- 30475308 TI - Vascular Aging is Accelerated in Flight Attendants with Occupational Secondhand Smoke Exposure. AB - OBJECTIVE: To determine whether early vascular aging may be present in flight attendants with remote in-cabin secondhand smoke (SHS) exposure. METHODS: Twenty six flight attendants with a history of in-cabin SHS exposure prior to the airline smoking bans were recruited. Pulse wave analysis, peripheral arterial tonometry, and brachial artery reactivity testing evaluated their arterial compliance and endothelial function. RESULTS: Flight attendants with remote in cabin SHS exposure have normal blood pressure, pulse wave velocity, and reactive hyperemia index, but abnormal pulse pressure, augmentation index, flow-mediated dilation, and hyperemic mean flow ratio. CONCLUSION: These preliminary findings suggest that flight attendants with remote in-cabin SHS exposure have pre clinical signs of accelerated vascular aging and raise new questions about the relationship between remote SHS exposure and vascular health. PMID- 30475310 TI - Trait Mindfulness Helps Explain the Relationships Between Job Stress, Physiological Reactivity and Self-perceived Health. AB - OBJECTIVE: To assess, for the first time, the associations among work stress as measured by the job-demands resources (JD-R) model, trait mindfulness and indices of the physiological stress response. METHOD: Dairy farmers (N = 79) completed job stress (using the JD-R model), trait mindfulness, burnout, and self-reported health questionnaires and provided physiological indices of the stress response. RESULTS: Our findings suggest that those reporting higher mindfulness have better physical and mental health, and that being more mindful may buffer the effects of a large cortisol awakening response on poor physical health. CONCLUSION: While assessments of both psychological and physiological indicators of stress and ill health will inform the underlying mechanisms of the associations between work stress and disease, assessing the role of trait mindfulness in this relationship may prove useful. PMID- 30475311 TI - Evaluation of the Quebec Healthy Enterprise Standard Effect on Adverse Physical and Psychosocial Work Factors and Work-Related Musculoskeletal Problems. AB - OBJECTIVE: Evaluate the effect of the Quebec Healthy Enterprise Standard (QHES) on adverse physical and psychosocial work factors and work-related musculoskeletal problems (WMSP). METHODS: Workers of ten organizations completed questionnaires before (n = 2849) and 2-3 years following (n = 2560) QHES implementation. Outcomes were assessed using validated instruments. RESULTS: Workers exposed to adverse physical and psychosocial work factors had a higher prevalence of WMSP. After interventions, the prevalences of one adverse physical and three adverse psychosocial work factors were lower among workers exposed to interventions. Among men exposed to physical and psychosocial interventions, the lower prevalence of neck WMSP is compatible with a beneficial intervention effect. Other results generally showed few effects on WMSP. CONCLUSIONS: Results suggest that QHES implementation lead to a decrease in some adverse physical and psychosocial factors. Few effects were observed on WMSP. PMID- 30475312 TI - Temperament and Early Intentions to Retire: A Northern Finland Birth Cohort 1966 Study. AB - OBJECTIVE: To examine associations between temperament traits and early retirement intentions. METHODS: In the Northern Finland Birth Cohort 1966, we analyzed early retirement intentions at the age 46 according to Cloninger's temperament traits at the age 46 (n = 4409) and at the age 31 (n = 3226). Ordinal logistic regression analyses were used. Adjustments were made for marital status, education, work type, job satisfaction, perceived health and mental health problems. RESULTS: 11% of men and 9% of women had strong retirement intentions. Especially higher harm avoidance was associated with higher early retirement intentions in both genders at the age of 46. A similar pattern of results, although with weaker associations, was found for temperament assessed at the age of 31. CONCLUSIONS: Temperament and especially harm avoidance is related to early retirement intentions. PMID- 30475313 TI - Air Quality and Chronic Stress: A Representative Study of Air Pollution (PM2.5, PM10) in Germany. AB - OBJECTIVE: With rising attention on climate change and the aftermath of burning fossil fuels, there is much concern regarding the effects of air pollution on physical and psychologic health. However, the relationship between chronic stress and air pollution is relatively unexplored in humans. METHODS: By combining German representative data with national pollution data and using step-wise regression analyses, this study investigates how air pollution (PM2.5 and PM10) impacts ones' chronic stress levels (TICS). RESULTS: Results show PM2.5 fine-dust particles significantly affect chronic stress, while PM10 has no such effect. Air pollution (PM2.5), age and income together explain 3% of variation in chronic stress in a nationally representative sample. CONCLUSIONS: Further studies must test pollutants such as NO2 and O3 as well as investigate the potential accumulated effect of pollution and stress combined on human health. PMID- 30475314 TI - Telomere Length in workers was effected by Omethoate exposure, GSTM1 deletion, Interaction between Smoking and GSTP1 Polymorphisms. AB - OBJECTIVE: The aim of this study was to explore the association between telomere length and metabolizing enzyme gene polymorphisms and environmental factors in omethoate-exposed workers. METHODS: The gene-environment interactions were analyzed with generalized linear model method. RESULTS: The relative telomere lengths in the individuals with GSTM1-deletion were longer than that in non deletion genotype in the control group (P = 0.011); the relative telomere lengths with GG+AG genotypes in GSTP1 rs1695 were longer than that of AA genotype in the exposure group (P = 0.039). The interaction between the GG+AG genotypes in GSTP1 rs1695 and smoking exposure had significant effect on telomere length (P < 0.05). CONCLUSIONS: The prolongation of relative telomere length in omethoate exposed workers was associated with GSTM1-deletion, GG+AG genotypes, and interactions of GG+AG genotypes and smoking factor. PMID- 30475315 TI - Medical Surveillance Programs for Workers Exposed to Hazardous Medications: A Survey of Current Practices in Health Care Institutions. AB - OBJECTIVE: To assess current medical surveillance monitoring practices for health care workers who prepare, handle, or administer hazardous medications. METHODS: A cross-sectional survey was distributed to members of the American College of Occupational and Environmental Medicine and the National Comprehensive Cancer Network. RESULTS: Forty-six of the 91 survey respondents indicated that their institution had a hazardous medication surveillance program. We identified the most frequent laboratory (complete blood count) and physical (skin) examination components. A health history was frequently used. Statistical analysis did not suggest an association between institutions with greater resources and presence of a surveillance program. CONCLUSIONS: A consensus standard for medical monitoring was not reported by the respondents. We recommend using a standardized surveillance questionnaire and applying uniform laboratory testing across institutions, in addition to establishing a national repository for surveillance data. PMID- 30475316 TI - Messes with Meds. PMID- 30475319 TI - Use of Magnetic Spinal Growth Rods (MCGR) With and Without Preoperative Halo gravity Traction (HGT) for the Treatment of Severe Early-onset Scoliosis (EOS). AB - BACKGROUND: Correction of severe scoliosis through distraction-based techniques poses a challenge. Magnetically controlled growing rod (MCGR) hardware complications are common with a 27.8% to 46.7% revision rate in under 2 years. Loss of correction and diminishing returns are the norm. Treatment of severe scoliosis with halo-gravity traction (HGT) before MCGR has not been previously reported. The purpose of this study was to assess initial correction, maintenance of correction, and complication rate in patients with severe scoliosis treated with and without HGT before MCGR. METHODS: IRB-approved retrospective single site cohort study of a prospectively collected database. Forty-two patients underwent MCGR between 2014 and 2017 at a single site, 12 with prior growing constructs were excluded, 30 patients were included, 12 patients underwent preoperative HGT. Charts were reviewed for demographic, clinical, and radiographic information. RESULTS: The HGT group had larger major curves averaging 90 (69 to 114) degrees versus 77 (56 to 113) degrees in the non-HGT group P=0.018. Percent correction on preoperative flexibility films were 17% versus 40% for those in the HGT versus non-HGT group, P=0.000. An additional 22% correction of the curve magnitude occurred between the flexibility and in-traction films representing 43% of the total correction achieved, P=0.000, was achieved. EBL, and postoperative major curve and major curve correction were not significant. Thirteen percent of patients experienced complications. Average follow-up was 712 versus 561 days in the HGT versus non-HGT groups. CONCLUSIONS: Large, rigid curves can achieve equivalent correction to flexible curves with HGT. Forty-three percent of the total correction achieved occurred during traction. Thirty percent of the total correction occurred at implantation of the MCGR in the HGT group versus 28% in the non-HGT group. At most recent follow-up HGT patients had statistically maintained their major curve correction better than non-HGT patients. LEVEL OF EVIDENCE: Level III-therapeutic study. PMID- 30475320 TI - Bilateral Developmental Dysplasia of the Hip: Does Closed Reduction Have a Role in Management? Outcome of Closed and Open Reduction in 92 Hips. AB - BACKGROUND: Bilateral developmental dysplasia of the hip (DDH) is believed to have a worse outcome than unilateral DDH with the optimal treatment unclear. To define indications for treatment we report a retrospective series of 92 hips (46 patients) who underwent closed reduction (CR) and/or open reduction (OR). METHODS: A total of 58 hips in 29 patients underwent attempted CR using our standardized protocol. In the same 12 year time period, 54 hips in 27 patients underwent an OR. Outcome measures included resolution of acetabular dysplasia, need for further surgery, development of osteonecrosis (ON), and modified Severin Grade. RESULTS: CR was successful in 57% of hips; in this group secondary surgery was required in 15% and ON was seen in 12%. In the OR group, 11% failed to stabilize and required further early surgery: ON rate was 15% overall, and secondary surgery was required in 5%. In Tonnis 2/3 hips younger than 2 years, Severin grading was comparable following CR and OR, with 92% and 90% graded as Severin 1, respectively. The rate of significant ON was higher after CR in Tonnis 2/3 hips (12%) than after OR (0%). Overall, Tonnis 4 hips did badly: 94% failed CR and following OR, further surgery for redislocation/residual dysplasia was required in 21%. CONCLUSIONS: CR can be successful in Tonnis 2/3 bilateral hips, with acceptable rates of secondary surgery, ON, and Severin grading, the latter equivalent to open reduction. Importantly, persisting with casting of a unilateral dislocation, to allow the contra-lateral hip to stabilize, does not have an adverse effect. CR is not advised in Tonnis 4 bilateral hips. Parents should be counseled that the outcome of surgery for bilateral hips is not as good as for unilateral DDH, particularly for Tonnis 4 hips which are more difficult to stabilize and more likely to require supplementary surgery even after open reduction. LEVEL OF EVIDENCE: Level IV-Therapeutic Study. PMID- 30475321 TI - Nurses and Patients: Natural Partners to Advance Patient Safety. PMID- 30475322 TI - Advanced Practice Registered Nurses' Quality Improvement Efforts to Reduce Antipsychotic Use in Nursing Homes. PMID- 30475323 TI - Perceptions of Missed Care Across Oncology Nursing Specialty Units. AB - BACKGROUND: An opportunity was identified to compare perceptions of the occurrence and types of missed care at a comprehensive cancer center. PURPOSE: The purpose was to evaluate the difference in perceived occurrence and types of missed care between medical, surgical, and hematologic oncology units in the context of a newly implemented patient care delivery system, Primary Team Nursing (PTN). METHODS: A descriptive, repeated-measures design was used. The MISSCARE survey was distributed electronically to 580 staff members across 6 inpatient units. RESULTS: Frequently perceived elements of missed nursing care were ambulation, turning every 2 hours, and care conference attendance. At the time of study implementation, surgical units reported 0.24 higher scores than medical units (P = .017); hematology units reported 0.26 lower scores than surgical units (P = .005). PTN status did not affect MISSCARE scores (P = .525). CONCLUSIONS: Study findings suggest that perceived missed care in a comprehensive cancer center is similar to that in other hospital settings. PMID- 30475324 TI - Using Lean to Enhance Heart Failure Patient Identification Processes and Increase Core Measure Scores. PMID- 30475325 TI - The Response to the Letter to the Editor Titled: "Is Triple Self-plagiarism "ok" if Only Made Transparent?" by Volker R Jacobs, MD, MBA. PMID- 30475326 TI - Is Triple Self-Plagiarism "OK" If Only Made Transparent? PMID- 30475327 TI - Comment from the Editorial Office on "Is Triple Self-Plagiarism "ok" If Only Made Transparent?" PMID- 30475328 TI - Dexmedetomidine Attenuates Acute Lung Injury Induced by Heatstroke and Improve Outcome. AB - INTRODUCTION: Dexmedetomidine (DEX) has been demonstrated to inhibit inflammatory response and protect against multiorgan injury in various scenarios. The objectives of the present study was to ascertain whether DEX is able to attenuate acute lung injury (ALI) under heatstroke (HS), and to explore the underlying mechanism. METHODS: Male C57BL/6 mice were exposed to ambient temperature of 39.5 +/- 0.2 degrees C until core temperature (Tc) reach 43 degrees C. DEX or 0.9% saline was injected intraperitoneally immediately. At the end of the experiment, Bronchoalveolar lavage fluid (BALF) and lung tissue was harvested. RESULTS: HS induce acute lung injury and pulmonary dysfunction, while DEX treatment could significantly inhibit lung injury and improve respiratory dysfunction under HS. The overall effect was beneficial and improved the 72 h cumulative survival rate of mice with HS. Furthermore, HS significantly elevated the levels of cytokines in bronchoalveolar lavage fluid (BALF), as well as increased the activity of Toll like receptor 4 (TLR4)/MyD88/nuclear factor-kappaB (NFkappaB) signaling pathway in lung tissue, while DEX treatment could inhibit such effects. Finally, DEX could upregulate the expression of caveolin 1 downregulated by HS, which may contribute to the inhibition of TLR4/MyD88/NFkappaB signaling pathway. DISCUSSION: In conclusion, the present results indicated that DEX may protect against lung inflammatory response and injury under HS via TLR4/MyD88/NFkappaB signaling pathway, and caveolin-1 may participate in the effects. PMID- 30475329 TI - Hemorrhage Attenuates Neutrophil Recruitment in Response to Secondary Respiratory Infection by Pseudomonas Aeruginosa. AB - Neutrophil recruitment into the lung airspaces plays an important role in the containment and clearance of bacteria. Hemorrhagic shock, a complication of traumatic injury, induces immune dysfunction that compromises host defense and frequently leads to secondary infection. The objective of the current study was to determine whether prior hemorrhage impacts neutrophil recruitment in response to secondary Pseudomonas aeruginosa. Experiments were performed using a mouse model (C57BL/6) of respiratory infection by P. aeruginosa (strain PA103, 3 x 10 colony-forming units [CFUs]) that is delivered by intratracheal inhalation 24 hours after hypovolemic hemorrhagic shock (fixed mean arterial blood pressure at 35 mmHg for 90 minutes, Ringer's lactate infused as fluid resuscitation). By post mortem flow cytometry analyses of bronchoalveolar lavage fluid, we observe that prior hemorrhage attenuates the entry of neutrophils into the lung airspaces in response to P. aeruginosa. The reduction in neutrophil recruitment occurs in an amplified inflammatory environment, with elevated lung tissue levels of interleukin 6 and C-X-C motif ligand 1 (CXCL1) in mice receiving hemorrhage prior to infection. As compared to either insult alone, outcome to sequential hemorrhage and respiratory infection includes enhanced mortality compared to either insult alone. The effect of prior hemorrhage on clearance of P. aeruginosa, as determined by quantifying bacterial CFUs in lung tissue, was not statistically significant at 24 hours post-infection, but our data suggest that further inquiry may be needed to fully understand the potential impact of hemorrhagic shock on this process. These results suggest that changes in neutrophil recruitment may contribute to the immune dysfunction following hemorrhagic shock that renders the host susceptible to severe respiratory infection. PMID- 30475330 TI - What's New in Shock, March 2019? PMID- 30475331 TI - "Trans-Esophageal Doppler Assessment of Acute Hemodynamic Changes Due to Prone Positioning in Acute Respiratory Distress Syndrome Patients". AB - BACKGROUND: Effect of prone positioning on acute hemodynamic changes (within 10 minutes) in acute respiratory distress syndrome (ARDS) has not been studied. METHODS: In this prospective observational study, hemodynamic assessment by trans esophageal Doppler (TED) was done with the primary aim to measure early changes in cardiac index (CI), if any, after prone positioning in moderate to severe ARDS patients. A subgroup analysis was also done based on the response to passive leg raise (PLR). RESULTS: The baseline hemodynamic variables of 26 included patients were: CI 3.5 (3.1-4.3) L/min/m, peak velocity (PV) 83.2 (60.9-99.3) cm/sec, flow time corrected (FTc) 341 (283-377) ms, mean acceleration (MA) 9.0 (7.04-11.7) m/sec. After prone position, there were no statistically significant changes in CI, 3.5 (p=0.83), 3.75 (p = 0.96), 3.7 (p = 0.34), and 3.9 (p = 0.95) at 5, 10, 20 and 30 min respectively. FTc, mainly indicator of preload, showed decreasing trend to 315 (275-367) ms at 30 min post prone (p = 0.06). On the basis of PLR test also, CI did not changed significantly in both PLR+ and PLR- groups. In PLR+ group, PV increased from 72.4 to 83 (p = 0.01), 74.9 (p = 0.03), 82 (p = 0.02) and 82 (p = 0.03) cm/sec; while in PLR- group, MA increased from 8.8 to 9.7 (p = 0.03), 10.1 (p = 0.03), 9.3 (p = 0.04) and 10.6 (p = 0.01) m/sec at 5, 10, 20 and 30 min respectively. CONCLUSIONS: In moderate to severe ARDS patients, there were no significant changes in CI during first 30 min after prone positioning, even in the subgroups on the basis of PLR response. PMID- 30475332 TI - Genetic Predisposition to Symptomatic Lumbar Disk Herniation in Pediatric and Young Adult Patients. AB - STUDY DESIGN: Case-control whole genome sequencing analysis of a highly selected, young cohort with symptomatic lumbar disk herniation (LDH) compared to the standard variation in a large reference population. OBJECTIVE: To assess genetic influences predisposing pediatric and young adult patients to symptomatic LDH. SUMMARY OF BACKGROUND DATA: LDH has traditionally been attributed to natural weakening or mechanical insult, but recent literature supports a potential genetic influence. METHODS: Young patients with symptomatic, clinically confirmed LDH who underwent surgical treatment were included. Patients were younger than the average age of presentation, limiting the influence of environmental risks. DNA collected from these patients was compared to a reference genome (1000 Genomes Project). A genome-wide association study using whole genome sequencing was used to characterize genetic mutations potentially associated with LDH. RESULTS: Among the 61 candidate genes flagged, 20 had missense mutations in 2 or more LDH cases. Missense mutations in collagen-encoding genes were observed in 12 of 15 patients (80%). A potential association with clinical presentation was indicated by odds ratios (ORs) of key single-nucleotide polymorphism (SNP) variants in genes that encode collagen. Relative to the reference population, the LDH cohort demonstrated 2 statistically significant SNP variants in the gene encoding for aggrecan, a protein that facilitates load-bearing properties in the cartilaginous end plate. Aggrecan gene SNPs rs3817428 and rs11638262 were significantly associated with decreased odds of symptomatic LDH: OR 0.05 (0.02 - 0.11) and 0.04 (0 - 0.26), respectively (P < 1 * 10 for both). CONCLUSIONS: These results suggest that collagen-encoding variants may be a genetic risk factor for LDH. They also shed new light on the role of variants that impact aggrecan, which sustains the cartilaginous end plate. Genetic predisposition to LDH may therefore be related to a multimodal combination of mutations that affect the nucleus pulposus, annulus fibrosus, and the cartilaginous end plates. LEVEL OF EVIDENCE: 4. PMID- 30475333 TI - The Anatomic Characteristics of the Retroperitoneal Oblique Corridor to the L1-S1 Intervertebral Disc Spaces. AB - STUDY DESIGN: This is a cross-sectional study. OBJECTIVE: To investigate the oblique corridor to the L1-S1 intervertebral disc space between the psoas muscle and the great vessels in cadaveric specimens bilaterally and the location of genitofemoral nerve and the diaphragmatic crura relative to the oblique corridor. SUMMARY OF BACKGROUND DATA: Although use of oblique lumbar interbody fusion(OLIF) is rapidly expanding, the morphometric data related to the procedure are limited. METHODS: Twelve fresh-frozen full-torso cadaveric specimens were dissected to exam the oblique corridor to access the L1-S1 space in a static state and with mild retraction of the psoas. The level at which the genitofemoral nerve pierces from the psoas major and the diaphragmatic crura originate from the lumbar vertebral body was also investigated. RESULTS: The mean width of oblique corridor in the static state and with mild psoas retraction, respectively, were as follows: on the right side: (L1-2) 13.33 and 16.75 mm; (L2-3) 15.42 and 21.42 mm; (L3-4) 16.58 and 22.67 mm; (L4-5) 12.75 and 21.17 mm; (L5-S1) 5.92 and 12.00 mm; on the left side: (L1-2) 16.75 and 19.67 mm; (L2-3) 18.50 and 25.33 mm; (L3-4) 20.58 mm and 28.00 mm; (L4-5) 18.17 and 26.08 mm; (L5-S1) 5.83 and 12.00 mm. The level at which the genitofemoral nerve pierces from the psoas major was between L2 to L4. The diaphragmatic crura originates from L1 to L3. CONCLUSIONS: The oblique corridor allows access to the L1-L5 discs from both sides, but it is larger on the left side. The corridor between the iliac vessels and the psoas for L5-S1 is difficult to be applied clinically. Mild psoas retraction can moderately enlarge the oblique corridor. The genitofemoral nerve and diaphragmatic crura may be encountered in this approach and should be carefully observed. LEVEL OF EVIDENCE: 5. PMID- 30475335 TI - The Association Between Pre-operative MRI Findings and Surgical Revision Within Three Years After Surgery for Lumbar Disc Herniation. AB - STUDY DESIGN: This cohort study was an analysis of prospectively collected data in the DaneSpine Database. OBJECTIVE: The objective was to determine whether pre operative magnetic resonance imaging (MRI) findings were associated with the frequency of surgical revision due to recurrent lumbar disc herniation (LDH) within three years after first-time, single-level, simple lumbar discectomy. SUMMARY OF BACKGROUND DATA: Because of a risk of poorer outcome in patients receiving revision surgery compared to first-time discectomy, there is a need to identify patients with LDH in risk of surgical revision prior to the primary discectomy. The association between pre-operative MRI findings and revision surgery in patients with LDH has not been thoroughly studied. METHODS: Following an inter-observer reliability study pre-operative MRIs were evaluated. Potential predictive variables for surgical revision were evaluated using univariate and multivariate logistic regression analysis. Also, a sum-score of the number of MRI findings at the involved level was assessed. RESULTS: In a study population of 451 operated patients, those who had surgical revision were significantly younger and were significantly less likely to have vertebral endplate signal changes Type 2 (OR 0.36 (95% CI 0.15-0.88)) or more than five MRI findings (OR 0.45 (95% CI 0.21-0.95)) at the involved level than the patients not undergoing surgical revision. Surgical revision was not significantly associated with any other MRI findings. CONCLUSIONS: In general, pre-operative MRI findings have a limited explanatory value in predicting surgical revision within three years after first time, single-level, simple lumbar discectomy. Both the single variable VESC Type 2 and a sum-score > 5 MRI findings at the operated level was found to be negatively associated with patients undergoing surgical revision. LEVEL OF EVIDENCE: 3. PMID- 30475336 TI - Comparison of Single Level vs Multi-level Vertebral Column Resection Surgery for Pediatric Patients with Severe Spinal Deformities. AB - STUDY DESIGN: Retrospective cohort of pediatric patients (= 14), moderate (9 to 13), or severe (< 9) categories on the mJOA scores. A McNemar-Bowker test was used to assess whether a significant proportion of patients changed mJOA category between preoperative and 12 months postoperative. A multivariable proportional odds ordinal logistic regression model was fitted with 12-month satisfaction as the outcome of interest. RESULTS: We identified 1963 patients who underwent elective surgery for DCM and completed 12-months follow-ups. Comparing mJOA severity level preoperatively and at 12 months revealed that 55% remained in the same category, 37% improved, and 7% moved to a worse category. After adjusting for baseline and surgery-specific variables, the 12-month mJOA category had the highest impact on patient satisfaction (p < .001). CONCLUSION: Patient satisfaction is an indispensable tool for measuring quality of care following spine surgery. In this sample, 12-month mJOA category, regardless of preop mJOA, was significantly correlated with satisfaction. Given these findings, it is important to advise patients of the probability that surgery will change their mJOA severity classification and the changes required to achieve post-operative satisfaction. LEVEL OF EVIDENCE: 3. PMID- 30475337 TI - An Evaluation of PROMIS in Patients with Primary or Metastatic Spine Tumors. AB - STUDY DESIGN: Retrospective evaluation of prospectively collected data OBJECTIVE.: In spine tumor patients: 1) To assess the correlation of PROMIS Physical Function (PF), Pain Interference (PI) and Depression scores with Oswestry Disability Index (ODI) and Neck Disability Index (NDI) scores; 2) To assess ceiling and floor effects of PROMIS PF, PI and Depression domains and the ODI/NDI. SUMMARY OF BACKGROUND DATA: There remains no widely used PRO instrument for spine tumor patients. PROMIS, a universal PRO tool, may add notable value to patient care. A paucity of work exists comparing PROMIS to legacy PRO tools in primary and metastatic spine tumor patients. METHODS: Patients confirmed to have a primary or metastatic spine tumor were asked to complete PROMIS PF, PI and Depression domains and either an ODI or NDI questionnaire between May 2015 and December 2017. Pearson correlation coefficients (r) were calculated. Ceiling and floor effects were determined. p < 0.05 was significant. RESULTS: Eighty unique visits from 51 patients with spine tumors (44 metastatic/67 visits; 7 primary/13 visits) met our inclusion criteria. A strong correlation existed between PROMIS PI and the ODI/NDI in both primary and metastatic tumor patient subgroups (range, r = 0.75 - 0.86, p < 0.05). PROMIS PF and the ODI/NDI demonstrated a strong correlation among all patients (r = -0.75, p < 0.05) and in the metastatic disease subgroup (r = -0.78, p < 0.05). A strong correlation existed between PROMIS Depression and the ODI/NDI in the primary tumor subgroup (r = 0.79, p < 0.05). PROMIS Depression demonstrated the largest floor effect (13.6%); there were similar ceiling effects. CONCLUSIONS: PROMIS PF and PI domains correlate well with the ODI/NDI in spine tumor patients and have a similar ceiling effect but decreased floor effect. PROMIS Depression was not as well captured, except in the primary tumor subgroup. LEVEL OF EVIDENCE: 2. PMID- 30475338 TI - Urinary N-Telopeptide Can Predict Pseudarthrosis after Anterior Cervical Decompression and Fusion (ACDF): A Prospective Study. AB - STUDY DESIGN: Prospective Cohort Study OBJECTIVE.: To examine preoperative urinary cross-linked n-telopeptide (uNTx) and assess for association with fusion rates in patients undergoing single and multi-level ACDF SUMMARY OF BACKGROUND DATA.: Although high rates of fusion have been reported for ACDF, the risk of pseudarthrosis remains substantial. An established marker of bone turnover, uNTx may prove useful as a predictor of fusion. METHODS: Patients undergoing primary ACDF with allograft/plating technique from 2015-2017 by a single surgeon were consecutively enrolled and preoperative uNTx was collected. Patients undergoing revision, with creatinine>1.2, and with improperly-collected uNTx were excluded. Demographics, laboratory values, and fusion status were assessed at 6 months, 1 year and 2 years postoperatively. RESULTS: Of the 97 patients enrolled, 69 met inclusion criteria. Of included cases, 41%, 33%, 18% and 8% underwent 1, 2, 3, and 4-level ACDF, respectively. Overall, fusion rates were 37.3%, 70.9%, and 95.3% at 6 months, 1 year, and 2 years, respectively. UNTx was higher in the fusion group (31.1 vs. 22.2, p = 0.001) at 6 months and 1 year (30.0 vs. 21.0, p = 0.006), with no difference at 2 years. No differences were identified in the proportion of smokers, immunomodulatory agents, corpectomies, or fusion levels between groups. Multivariate regression analysis demonstrated that uNTx is an independent predictor of fusion (OR 1.124, p = 0.003). Both groups experienced improvements in NDI and VAS neck pain at 6 months with no significant differences noted between groups. Of 16 patients with pseudarthrosis at 1 year, 2 underwent posterior cervical fusion for symptoms. CONCLUSIONS: Preoperative uNTx was greater in patients with successful ACDF fusion compared to patients with pseudarthrosis at 6 months and 1 year. A negative correlation was found between preoperative uNTx and motion on dynamic imaging. These results suggest that uNTx could serve to identify patients at risk for pseudarthrosis after ACDF. LEVEL OF EVIDENCE: 3. PMID- 30475339 TI - 30- and 90-day Unplanned Readmission Rates, Causes, and Risk Factors after Cervical Fusion: A Single Institution Analysis. AB - STUDY DESIGN: Retrospective cohort study OBJECTIVE.: To study 30- and 90-day readmission rates, causes, and risk factors after anterior cervical discectomy and fusion (ACDF) and posterior cervical fusion (PCF). SUMMARY OF BACKGROUND DATA: Existing data on readmission after cervical fusion is majorly derived from national databases. Given their inherent limitations in accuracy, follow-up available and missing data, we intend to add to literature from our institutional analysis. METHODS: Patients who underwent ACDF and PCF for degenerative cervical pathology in 2013 and 2014 were identified for the study. Comprehensive chart review was performed to record demographics and clinical patient profile. Hospital readmission within 30- and 90-days was identified, and the causes and management were recorded. Binary logistic regression analysis was done to study risk factors for readmission. ACDF and PCF were studied separately. RESULTS: Our analysis included a total of 549 patients, stratified as 389 ACDFs and 160 PCFs. The 30- and 90-day unplanned readmission rate was 5.1% and 7.7% after ACDF. These rates were 11.2% and 16.9% after PCF. The most common cause of readmission was systemic infection and sepsis after ACDF and PCF (31.4% and 25.8% of readmitted, respectively), followed by pulmonary complications after ACDF (14.3% of readmitted) and wound complications after PCF (19.4% of readmitted). Predictors of readmission after ACDF included heart failure, history of malignancy, history of deep vein thrombosis/pulmonary embolism and any intraoperative complication. In the PCF cohort, history of ischemic heart disease, increasing number of fusion levels and longer length of stay were independently predictive. CONCLUSIONS: The rates, causes and risk factors of readmission after ACDF and PCF have been identified. There is variation in published data regarding the incidence and risk factors for readmission after cervical fusion, however majority of readmissions occur due to medical complications and systemic infection. LEVEL OF EVIDENCE: 3. PMID- 30475340 TI - Does Decreased Surgical Stress Really Improve the Psychosocial Health of Early Onset Scoliosis Patients? A Comparison of Traditional Growing Rods and Magnetically-Controlled Growing Rods Patients Reveals Disappointing Results. AB - STUDY DESIGN: Cross-sectional case-control study. OBJECTIVE: Compare psychosocial profile of magnetically-controlled growing rod (MCGR) patients to traditional growing rod (TGR) with an array of psychiatric tools, expecting improvement in MCGR due to decreased number of surgical procedures. SUMMARY OF BACKGROUND DATA: TGR treatment has had positive clinical and radiographic results; however, upwards of 10 surgical sessions and high complication rates have called into question the quality of life of these children. Improvement with the introduction of the MCGR is expected. METHODS: GR patients with minimum of 2-years follow-up were recruited. None had neurological conditions. All underwent testing with the Wechsler Intelligence Scale for Children-Revised, and only those in the normal range were included. Patients filled out questionnaires with mental health professionals to measure psychosocial status. MCGR patients' results were compared to TGR patients. RESULTS: Twenty-seven patients met criteria(10 MCGR, 17 TGR): average age at enrollment 11.8 years(range 5.9-17). MCGR group was significantly younger(9.1 vs. 13.3 years) and had significantly shorter follow up(45.6 vs. 82.8 months)(p < 0.05). TGR patients underwent an average of 16 surgical procedures, MCGR an average of 1.5(including complications, p < 0.05). Age at index surgery(6 years), preoperative and postoperative major curve magnitudes(60 degrees ,40 degrees respectively) were statistically similar.There was no difference in current psychiatric diagnoses between the groups. MCGR patients scored worse than TGR patients in general functionality domains. TGR patients showed increased functionality and prosocial scores with increased number of procedures. This effect was not observed in MCGR. CONCLUSIONS: The expected improvement in psychosocial status with the MCGR was not observed at a 31.6-month-follow-up. It appears that provided the patient spends enough time in the treatment process to notice benefit and does not experience major complications, non-invasiveness of lengthening procedures does not show up as an advantage with the psychosocial tools utilized in this study. LEVEL OF EVIDENCE: 3. PMID- 30475341 TI - Cost-Utility Analysis of Operative vs. Nonoperative Treatment of Thoracic AIS. AB - STUDY DESIGN: Cost utility analysis OBJECTIVE.: To compare the cost utility of operative vs. nonoperative treatment of adolescent idiopathic scoliosis (AIS) and identity factors that influence cost-utility estimates. SUMMARY OF BACKGROUND DATA: AIS affects 1%-3% of children aged 10-16 years. When the major coronal curve reaches 50 degrees , operative treatment may be considered. The cost utility of operative treatment of AIS is unknown. METHODS: A decision-analysis model comparing operative vs. nonoperative treatment was developed for a hypothetical 15-year-old skeletally mature girl with a 55 degrees right thoracic (Lenke 1) curve. The AIS literature was reviewed to estimate the probability, health utility, and quality-adjusted life years (QALYs) for each event. For the conservative model, we assumed that operative treatment did not result directly in any QALYs gained, and the health utility in AIS patients was the same as the age-matched US population mean. Costs were inflation-adjusted at 3.22% per year to 2015 US dollars. Costs and benefits were discounted at 3%. Probabilistic sensitivity analysis was performed using mixed first-order and second-order Monte Carlo simulations. Incremental cost utility ratio (ICUR) and incremental net monetary benefit (INMB) were calculated. One-way sensitivity analyses were performed by varying cost, probability, and QALY estimates. RESULTS: Operative treatment was favored in 98.5% of simulations, with a median ICUR of $20,600/QALY (95% confidence interval [CI], $20,500-$21,900) below the societal willingness-to pay threshold of $50,000/QALY. The median INMB associated with operative treatment was $15,100 (95% CI, $14,800-$15,700). Operative treatment produced net monetary benefit across various willingness-to-pay thresholds. Factors that most affected the ICUR were net costs associated with uncomplicated operative treatment, undergoing surgery during adulthood, and development of pulmonary complications. CONCLUSIONS: Cost-utility analysis suggests that operative treatment of AIS is favored over nonoperative treatment and falls below the $50,000/QALY willingness-to-pay threshold for patients with Lenke 1 curves. LEVEL OF EVIDENCE: 2. PMID- 30475342 TI - Differential Psychometric Properties of EuroQoL 5-Dimension 5-Level and Short Form 6-Dimension Utility Measures in Low Back Pain. AB - STUDY DESIGN: Prospective study. OBJECTIVE: To examine the acceptability, validity, and reliability of EuroQoL 5-dimension 5-level (EQ-5D-5L) and Short Form 6-Dimension (SF-6D) health utility measures in patients with low back pain (LBP). SUMMARY OF BACKGROUND DATA: LBP requires multiple diagnostic tests and treatment that can incur high medical costs. It is thus desirable to have an appropriate measure for cost-utility analysis of various LBP-related interventions. METHODS: Health-related quality of life (HRQoL) questionnaires including generic 12-item Short Form Health Survey (SF-12), EQ-5D-5L, and low back/back-related questionnaires were administered at a specialty clinic. SF-12 items responses were transformed to SF-6D utility scores using the Hong Kong population scoring algorithm whereas EQ-5D-5L responses were mapped onto EQ-5D-3L response, then converted to EQ-5D-5L utility scores using the Chinese-specific value set. Construct validity was determined by evaluating Spearman correlation between SF-12 and EQ-5D-5L scores. Correlation between back-specific questionnaires and HRQoL scores were assessed. RESULTS: A total of 100 patients were recruited. No significant (>15%) floor and ceiling effects were observed for EQ-5D-5L and SF-6D scores. Detailed proportion of respondents for each EQ-5D-5L domain indicated that Pain/Discomfort domain was the most prevalent problem. SF 6D utility score and EQ-5D-5L had respective strong (0.600-0.855) and moderate-to strong (0.455-0.700) correlations with SF-12 domain and summary scores. EQ-5D-5L and SF-6D scores were correlated (0.625), with adequate construct validity as both utility scores conceptually measure the similar construct. Patients with no previous spine surgery nor disc degeneration had significantly higher EQ-5D-5L scores. Both EQ-5D-5L and SF-6D significantly correlated with back-specific questionnaires. CONCLUSION: Both EQ-5D-5L and SF-6D appeared as applicable and valid measures in assessing HRQoL of LBP patients. Being the first study examining the differential psychometric properties and validation of the use of EQ-5D-5L and SF-6D in Chinese LBP population, this allows future exploration of the impact of utility score selection on assessing effectiveness of clinical intervention for LBP. LEVEL OF EVIDENCE: 2. PMID- 30475344 TI - Comment on "retropharyngeal Steroids and Dysphagia Following Multilevel Anterior Cervical Surgery". PMID- 30475343 TI - Does symmetric thoracic fusion make a difference in Lenke 1 A/B AIS Patients? AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To compare the long-term outcomes of correction surgery for Lenke 1 A/B scoliosis among those with symmetric fusion (SF), upper-dominant fusion (UF) and lower-dominant fusion (LF) in adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Symmetric fusion, defined as equal number of vertebral levels included in instrumented fusion above and below the apical vertebra or disc of the primary curve, was a new concept raised in AIS selective fusion. Former study showed that similar correction the effect on clinical outcomes of this fusion style. METHODS: Preoperative, postoperative, and last follow-up radiographs of 117 consecutive patients with Lenke type 1A/B curves who underwent posterior selective thoracic instrumentation surgery were analyzed. Patients were divided into two groups (SF and NSF). Patients in NSF was further divided into two groups UF (more vertebrate was fused above the apex) and LF (more vertebrate was fused below the apex). Clinical outcomes and coronal decompensation including adding-on and trunk shift were analyzed and compared among three groups. RESULTS: There was no significant difference between SF and NSF in magnitude of preoperative main thoracic curve (P = 0.69) and correction rate (P = 0.50). Distal adding-on was observed in 21 patients (17.9%), coronal decompensation was observed in 8 patients (6.8%) in all at final follow up. No significant differences were found between the two groups regarding adding-on phenomenon (P = 0.64) and coronal imbalance (P = 0.72). Significant higher rate of adding-on were found in UF compared to SF and LF (p < 0.001). Subgroup analysis between UF and LF in NSF patients, significant differences were found between two subgroups in the rate of trunk shift (P = 0.038). No significant differences in SRS-22 scores were observed among three groups. CONCLUSIONS: In Lenke 1A/B AIS with posterior selective fusion, SF provides no significant differences from NSF. However, in NSF, UF was found to be high risky of adding-on phenomenon. LEVEL OF EVIDENCE: 3. PMID- 30475345 TI - Timing of Prophylactic Anticoagulation and Its Effect on Thromboembolic Events after Surgery for Metastatic Tumors of The Spine. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To investigate the effect of timing of initiation of prophylactic anticoagulation (AC) on the incidence of venous thromboembolism (VTE) after surgery for metastatic tumors of the spine. SUMMARY OF BACKGROUND DATA: VTE is a known complication in patients undergoing surgery for metastatic spine disease. However, there is limited data on the use of prophylactic AC in this population and its impact on the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as the risk of epidural hematoma. METHODS: A retrospective review of our institutional neurosurgical spine database for the years 2012 through 2018 was performed. Patients who underwent surgery for metastatic tumors were identified. The development of VTE within 30 days was examined, as well as the occurrence of epidural hematoma. The incidence of VTE was compared between patients receiving "early" (within postoperative days 1-3) and "delayed" prophylactic AC (on or after postoperative day 4). RESULTS: Sixty-five consecutive patients were identified (mean age 57, 62% male). The overall rate of VTE was 16.9% - all of whom had DVTs with a 3.1% rate of non-fatal PE (two patients also developed PE). From the overall cohort, 36/65 (56%) received prophylactic AC in addition to mechanical prophylaxis - 22 in the early group (61.1%) and 14 in the delayed group (38.9%). The risk of VTE was 9.1% in the early group and 35.7% in the delayed group (26.6% absolute risk reduction; p = 0.049); there was one case of epidural hematoma (1.5%). On multivariate analysis, delayed prophylactic AC was found to significantly increase the odds of VTE development (OR 6.43; 95% CI, 1.01 - 41.2; p = 0.049). CONCLUSION: The findings of this study suggest that administration of prophylactic AC between day 1-3 after surgery for metastatic tumors of the spine may significantly reduce the risk of postoperative thromboembolic events. LEVEL OF EVIDENCE: 4. PMID- 30475346 TI - Does the Severity of the Curve in Lenke 1 and 2 Adolescent Idiopathic Scoliosis Patients Affect the Distance and Position of the Aorta from Vertebra? AB - STUDY DESIGN: Retrospective study of a prospectively-collected data. OBJECTIVE: To determine whether the severity of the curve magnitude in Lenke 1 and 2 adolescent idiopathic scoliosis (AIS) patients affects the distance and position of the aorta from the vertebra. SUMMARY OF BACKGROUND DATA: There were studies that looked into the position of the aorta in scoliotic patients but none of them documented the change in distance of the aorta to the vertebra in relation to the magnitude of the scoliosis. METHODS: Patients with Lenke 1 and 2 AIS who underwent posterior spinal fusion using pedicle screw construct and had a preoperative computed tomography (CT) scan performed were recruited. The radiological parameters measured on preoperative CT scan were: Aortic-Vertebral Distance (AVD), Entry-Aortic Distance (EAD), Aortic-Vertebral angle (AVA), Pedicle Aorta angle/Aortic Alpha angle (alpha angle), and Aortic Beta angle (beta angle). RESULTS: 39 patients were recruited. Significant moderate to strong positive correlation was found between AVD and Cobb angle from T8 to T12 vertebrae (r = 0.360 to 0.666). The EAD were generally small in the thoracic region (T4 to T10) with mean EAD of less than 30 mm. Among all apical vertebrae, the mean AVD was 5.9 +/- 2.2 mm with significant moderate-strong positive correlation to Cobb angle (r = 0.580). The mean alpha angle was 37.7 +/- 8.7 degrees with significant weak positive correlation with Cobb angle (r = 0.325). CONCLUSION: The larger the scoliotic curve, the further away the aorta from the apical vertebral wall. The aorta has less risk of injury from a minor left lateral pedicle screw breach (grade 1 or 2) in larger scoliotic curve at the apical region. The distance from the pedicle screw entry point to the wall of the aorta were generally small (less than 30 mm) in the thoracic region (T4 to T10). LEVEL OF EVIDENCE: 4. PMID- 30475347 TI - Cervical and Cervicothoracic Sagittal Alignment According to Roussouly's Thoracolumbar Subtypes. AB - STUDY DESIGN: Cross-sectional cohort. OBJECTIVE: To determine normative radiographic sagittal cervical alignment in asymptomatic volunteers based on Roussouly's thoracolumbar sagittal alignment subtypes. SUMMARY OF BACKGROUND DATA: Comprehension of differences in cervicothoracic alignment with respect to variations in thoracolumbar alignment is limited. METHODS: Asymptomatic adults were recruited and the following parameters measured: PI, PT, SS, LL, orbital tilt, orbital slope, occipital slope and incidence, occiput-C2 lordosis, C2-7 lordosis, occiput-C7 lordosis, CBVA, T1 slope, cervicothoracic alignment, T2-5 kyphosis, and C2-C7 sagittal vertebral alignment (SVA). Each was classified into one of Roussouly's four thoracolumbar subtypes and cervical alignment parameters were compared between groups. RESULTS: Eighty-seven individuals [male-23; female 64; average age 49 +/- 16 years (22-77 years)] were included for analysis. The four groups were not different by age, gender, and body mass index (BMI). Lumbopelvic parameters (PI, SS, PT, LL) were different between Roussouly types. Average values for all patients included: CBVA (-1 +/- 9), occiput-C2 lordosis (28 +/- 9), occiput-C7 lordosis (39 +/- 14), C2-7 lordosis (11 +/- 14), C2-7 SVA (21 +/- 9 mm), T1 slope (25 +/- 9), C6-T4 angle (5 +/- 8), T2-5 angle (16 +/- 7), thoracic kyphosis (47 +/- 13). No sagittal radiographic alignment measurements of the cervical spine and cervicothoracic junction were different between groups, except for the global cervical lordosis (occiput-C7 Cobb), which was found to be lowest for Roussouly type 2 (35 +/- 14) and highest for type 4 (48 +/- 14) (p = 0.01). Mean C2-C7 sagittal Cobb, T2-T5 sagittal Cobb, and T1 slope were not different between groups. CONCLUSIONS: In asymptomatic volunteers, normative sagittal alignment parameters of the cervical spine, cervicothoracic junction, and thoracic spine based on variations in thoracolumbar sagittal alignment, as proposed by Roussouly, are established. These data may guide surgical correction of cervicothoracic deformities to ensure appropriate restoration of normal cervicothoracic parameters in order to maintain good horizontal gaze and overall sagittal plane alignment. LEVEL OF EVIDENCE: 3. PMID- 30475348 TI - The Influence of Body Mass Index on Functional Outcomes, Satisfaction and Return To Work After Single-Level Minimally-Invasive Transforaminal Lumbar Interbody Fusion: A Five-Year Follow-Up Study. AB - STUDY DESIGN: Retrospective study using prospectively collected registry data. OBJECTIVES: To evaluate the effect of obesity on patient-reported outcome measures of pain, disability, quality of life, satisfaction and return to work after single-level minimally invasive transforaminal lumbar interbody fusion (MIS TLIF). SUMMARY OF BACKGROUND DATA: MIS-TLIF is an appealing alternative for obese patients with potentially lower complication risk. However, there is limited data investigating the influence of obesity on outcomes 5 years after MIS-TLIF. METHODS: Prospectively collected registry data of 296 patients who underwent single-level MIS-TLIF at a single institution were reviewed. Patients had complete 2- and 5-year follow-up data. Patients were stratified into control (<25.0 kg/m), overweight (25.0-29.9 kg/m) and obese (>=30.0 kg/m) groups. Outcomes assessed were visual analogue scale for back pain, leg pain, Oswestry Disability Index, Short-form 36, North American Spine Society score for neurogenic symptoms, return to work (RTW), return to function (RTF), satisfaction and expectation fulfilment. Length of operation, length of stay and comorbidities were recorded. RESULTS: Among the patients, 156 (52.7%) had normal weight, 108 (36.5%) were overweight and 32 (10.8%) were obese. There was no difference in length of operation or hospitalization (p > 0.05). All three groups had comparable preoperative scores at baseline (p > 0.05). At 5 years, the control group had significantly higher PCS compared to the overweight (p = 0.043) and obese groups (p = 0.007), although the change in scores was similar (p > 0.05). The rate of MCID attainment, RTW, RTF, expectation fulfilment and satisfaction was comparable. CONCLUSION: Non-obese patients had better physical well-being in the mid-term, although obese patients experienced a comparable improvement in clinical scores. Obesity had no impact on patients' ability to RTW or RTF. Equivalent proportions of patients were satisfied and had their expectations fulfilled up to 5 years after MIS-TLIF. LEVEL OF EVIDENCE: 3. PMID- 30475349 TI - An oncolytic herpesvirus expressing E-cadherin improves survival in mouse models of glioblastoma. AB - The efficacy of oncolytic herpes simplex virus (oHSV) is limited by rapid viral clearance by innate immune effector cells and poor intratumoral viral spread. We combine two approaches to overcome these barriers: inhibition of natural killer (NK) cells and enhancement of intratumoral viral spread. We engineered an oHSV to express CDH1, encoding E-cadherin, an adherent molecule and a ligand for KLRG1, an inhibitory receptor expressed on NK cells. In vitro, infection with this engineered virus, named OV-CDH1, induced high surface E-cadherin expression on infected glioblastoma (GBM) cells, which typically lack endogenous E-cadherin. Ectopically expressed E-cadherin enhanced the spread of OV-CDH1 by facilitating cell-to-cell infection and viral entry and reduced viral clearance by selectively protecting OV-CDH1-infected cells from KLRG1+ NK cell killing. In vivo, OV-CDH1 treatment substantially prolonged the survival in GBM-bearing mouse models, primarily because of improved viral spread rather than inhibition of NK cell activity. Thus, virus-induced overexpression of E-cadherin may be a generalizable strategy for improving cancer virotherapy. PMID- 30475350 TI - Correction to: 'Anastasis: recovery from the brink of cell death'. AB - [This corrects the article DOI: 10.1098/rsos.180442.]. PMID- 30475351 TI - Designing surface-enhanced Raman scattering (SERS) platforms beyond hotspot engineering: emerging opportunities in analyte manipulations and hybrid materials. AB - Surface-enhanced Raman scattering (SERS) is a molecule-specific spectroscopic technique with diverse applications in (bio)chemistry, clinical diagnosis and toxin sensing. While hotspot engineering has expedited SERS development, it is still challenging to detect molecules with no specific affinity to plasmonic surfaces. With the aim of improving detection performances, we venture beyond hotspot engineering in this tutorial review and focus on emerging material design strategies to capture and confine analytes near SERS-active surfaces as well as various promising hybrid SERS platforms. We outline five major approaches to enhance SERS performance: (1) enlarging Raman scattering cross-sections of non resonant molecules via chemical coupling reactions; (2) targeted chemical capturing of analytes through surface-grafted agents to localize them on plasmonic surfaces; (3) physically confining liquid analytes on non-wetting SERS active surfaces and (4) confining gaseous analytes using porous materials over SERS hotspots; (5) synergizing conventional metal-based SERS platforms with functional materials such as graphene, semiconducting materials, and piezoelectric polymers. These approaches can be integrated with engineered hotspots as a multifaceted strategy to further boost SERS sensitivities that are unachievable using hotspot engineering alone. Finally, we highlight current challenges in this research area and suggest new research directions towards efficient SERS designs critical for real-world applications. PMID- 30475352 TI - A facile and general approach for the preparation of boronic acid-functionalized magnetic nanoparticles for the selective enrichment of glycoproteins. AB - Biomedical applications and biomarkers for early clinical diagnostics and the treatment of diseases demand efficient and selective enrichment platforms for glycoproteins. Thus, we herein report a facile and general approach for the preparation of boronic acid-functionalized magnetic nanoparticles for the selective enrichment of glycoproteins. More specifically, Fe3O4 magnetic nanoparticles were initially prepared via a solvothermal reaction, and core-shell structured Fe3O4@SiO2 nanoparticles were obtained according to a sol-gel process. Subsequently, the Fe3O4@SiO2 surfaces were modified using 4-formylphenylboronic acid to allow the formation of strong yet reversible covalent bonds between boronic acid (BA) and the cis-1,2-diol groups of glycoproteins. The morphology and structure of the Fe3O4, Fe3O4@SiO2, and Fe3O4@SiO2-BA nanoparticles were characterized by scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and vibrating sample magnetometry, thereby confirming their successful preparation. The obtained BA-modified Fe3O4@SiO2 magnetic nanoparticles were applied in the attempted enrichment of two glycoproteins (ovalbumin (OVA) and transferrin (TRF)) and two non-glycoproteins (bovine serum albumin (BSA) and cytochrome c (Cyt C)). The results confirmed a significant difference in affinity between glycoproteins and non-glycoproteins. In addition, the recognition capability of the Fe3O4@SiO2 BA nanoparticles was demonstrated by the selective enrichment of glycoproteins from a complex system containing both glycoproteins (i.e., TRF) and non glycoproteins (i.e., Cyt C). PMID- 30475353 TI - Aqueous-phase synthesis of layered double hydroxide nanoplates as catalysts for the oxygen evolution reaction. AB - Transition metal layered double hydroxide (LDH) nanomaterials have been considered as good catalytic materials for various applications; however, there has been a limit in the economic efficiency and convenience of the synthetic method. In this work, we report a facile aqueous-phase route to the synthesis of transition metal LDH nanoplates including Mn-Ni and Zn-Ni. Electrochemical characterization of the synthesized Mn-Ni LDHs with different intercalated halogen anions was carried out for the oxygen evolution reaction (OER) and a Tafel slope of about 80 mV per decade was obtained which is comparable to those of the previously reported LDH nanoplates. PMID- 30475354 TI - Synthesis, purification, properties and characterization of sorted single-walled carbon nanotubes. AB - Single-walled carbon nanotubes (SWCNTs) have attracted significant attention due to their outstanding mechanical, chemical and optoelectronic properties, which makes them promising candidates for use in a wide range of applications. However, as-produced SWCNTs have a wide distribution of various chiral species with different properties (i.e. electronic structures). In order to take full advantage of SWCNT properties, highly purified and well-separated SWCNTs are of great importance. Recent advances have focused on developing new strategies to effectively separate nanotubes into single-chirality and/or semiconducting/metallic species and integrating them into different applications. This review highlights recent progress in this cutting-edge research area alongside the enormous development of their identification and structural characterization techniques. A comprehensive review of advances in both controlled synthesis and post-synthesis separation methods of SWCNTs are presented. The relationship between the unique structure of SWCNTs and their intrinsic properties is also discussed. Finally, important future directions for the development of sorting and purification protocols for SWCNTs are provided. PMID- 30475355 TI - Prospective on using fibre mid-infrared supercontinuum laser sources for in vivo spectral discrimination of disease. AB - Mid-infrared (MIR) fibre-optics may play a future role in in vivo diagnosis of disease, including cancer. Recently, we reported for the first time an optical fibre based broadband supercontinuum (SC) laser source spanning 1.3 to 13.4 MUm wavelength to cover the spectral 'fingerprint region' of biological tissue. This work has catalysed the new field of fibre MIR-SC and now very bright sources equivalent to a 'few synchrotrons' have been demonstrated in fibre. In addition, we have made record transparency MIR fibre for routeing the MIR light and reported first-time MIR photoluminescence (with long lifetime) in small-core, rare earth ion doped, MIR fibre - an important step towards MIR fibre lasing at >4 MUm wavelength for pumping fibre MIR-SC. First time fibre MIR-SC spectroscopic imaging of colon tissue is described at wavelengths in the 'fingerprint region'. PMID- 30475356 TI - Electrical switching properties and structural characteristics of GeSe-GeTe films. AB - Germanium chalcogenides, especially GeSe and GeTe alloys, have recently gained popularity because of their Ovonic threshold (volatile) and memory (non-volatile) switching properties, with great potential for electric storage applications. Materials designed in a pseudo-binary way may possess superior properties in their phase transition, e.g. GeTe-Sb2Te3 materials, and bring about revolutionary advances in optical storage. However, to date, the electrical switching behaviors of films of pseudo-binary GeSe-GeTe have not yet been studied, and neither have the structural characteristics. Herein, we present both the thermally and electrically induced switching behaviors of GeSe-GeTe film, as well as the structural evolution due to composition tuning. The crystallization temperature of GeSe-GeTe films increases with GeSe content quite sensitively. An atom resolved picture of the GeSe-GeTe alloy with a state-of-the-art atomic mapping technology has been presented, where a randomly mixed arrangement of Se and Te atoms is determined unambiguously in Ge50Se13Te34 with a GeTe-like rhombohedral structure. The local structural motifs in GeSe-GeTe, more specifically, sixfold coordinated octahedra with a distinguished degree of Peierls distortion and geometric variety, are essential to understand its electric properties. GeSe-GeTe alloy, Ge50Se13Te34, based memory cells have been fabricated, showing a fast memory switching behavior and excellent retention of 10 years at 208 degrees C. PMID- 30475357 TI - Thermal dehydrochlorination in the 4-fluoroaniline-trichloroborane system: identification of reactive intermediates involved in the formation of B,B',B'' trichloro-N,N',N''-tri((4-fluoro)phenyl)borazine. AB - Borazines are used in chemical vapor deposition processes to produce hybrid graphene-boron nitride nanostructures. As the knowledge on the mechanism of borazine formation is scarce, we studied the mechanism of formation of B,B',B'' trichloro-N,N',N''-tri(p-fluorophenyl)borazine (3a) from p-fluoroaniline and boron trichloride employing NMR spectroscopy, X-ray single crystal structure analysis, trapping experiments, and computational chemistry methods up to the coupled cluster CCSD(T) level of theory. These studies suggest the initial formation of the 1 : 1 adduct 1a (ArNH2BCl3, Ar = 4-fluorophenyl) with a dative B N bond that could be fully characterized including single crystal X-ray diffraction. Adduct 1a undergoes unimolecular hydrogen chloride elimination with a first-order rate constant of k1 = 3.03(7) * 10-2 min-1 in toluene at 100 degrees C. This rate constant is in very good agreement with the one derived (k1 = 3.18 * 10-2 min-1) from computed activation parameters (DeltaH?373.15 = 28.1 kcal mol-1, DeltaS?373.15 = 1.56 eu, DeltaG?373.15 = 27.6 kcal mol-1). The product of the first hydrogen chloride evolution is anilinodichloroborane ArNHBCl2 (2a). Compound 2a cannot be isolated in a pure form due to instability, but its presence as a transient reactive intermediate can be derived from NMR spectroscopy. Reactive intermediates other than anilinodichloroborane cannot be assigned by NMR spectroscopy. We propose that the mechanism of formation of borazine 3a involves the reaction of 2a with 4-fluoroaniline as the rate determining step. PMID- 30475358 TI - Low temperature solution synthesis of reduced two dimensional Ti3C2 MXenes with paramagnetic behaviour. AB - MXenes - two dimensional, 2D, early transition metal, M, carbides and nitrides, X - are the latest addition to the 2D materials' world. Herein, we report on a facile low temperature solution chemical synthesis method to reduce Ti3C2Tx multilayered, ML, MXenes. Using X-ray photoelectron spectroscopy, electron spin resonance, magnetization measurements and other techniques, we concluded that immersing Ti3C2Tx MLs in the reducing agent Li-ethylenediamine (Li-EDA) - held at temperatures varying from room to 120 degrees C - reduces the 2D layers creating Ti3+ ions and oxygen vacancies. Above a temperature (T) of ~10 K, the magnetic susceptibilities, chi, are temperature independent, implying that the resulting powders are Pauli paramagnetic. The loss of the magnetic signal upon intercalation of Li+ or EDA, together with a Curie-like increase in chi at T < 10 K, is consistent with that of a disordered metal that is close to a metallic to insulator transition and proves that the magnetism is associated with the 2D flakes. This result is the first evidence of any magnetism of any MXene. PMID- 30475359 TI - A synergetic stabilization and strengthening strategy for two-dimensional ordered hybrid transition metal carbides. AB - Two-dimensional (2D) transition metal carbides (MXenes) exhibit excellent thermodynamic stability and remarkable mechanical strength and flexibility, as well as rich functionality, which attract considerable interest due to their potential application for high-performance flexible and stretchable devices. However, premature phonon instability of some non-hybrid MXenes was recently found to intrinsically limit their strength and flexibility, evoking passionate curiosity in pursuing an effective solution for more impressive mechanical properties. In this work, on the basis of an alloying strengthening mechanism, a combinational strategy is proposed to build ordered hybrid M2''M'C2O2 (M'' = Mo, W; M' = Ti, Zr, Hf) with remarkable dynamic stability and superior mechanical properties by hindering the premature phonon instability originating from the outer transition metals. By means of comprehensive screening, symmetrical Mo2TiC2O2 is interestingly found to possess excellent stability at equilibrium and outstanding tolerance to phonon instability during straining compared to its Ti counterpart, being attributed to the character of the robust Mo-dz2 and O-pz hybridization. Although similar optical phonon soft modes appear in Ti3C2O2 and Mo2TiC2O2 under multiple loadings, the latter is much stiffer during straining. An in-depth analysis of deformed electronic structures reveals that a strain induced increasing density of states in the vicinity of the Fermi level mainly composed of Mo-dz2 states facilitates the fatal phonon softening in Mo2TiC2O2 under biaxial tension, while differing from the mechanical instability in Ti3C2O2 triggered by a Peierls transition. Our findings provide a novel stabilization and strengthening strategy for 2D materials, and pave a new way for searching for 2D material candidates in designing flexible devices. PMID- 30475361 TI - Collective dynamics of red blood cells on an in vitro microfluidic platform. AB - Understanding the dynamics of blood flow in physiologically relevant confinements turns out to be an outstanding proposition in biomedical research. Despite the large number of studies being reported to theoretically elucidate the dynamics of red blood cells (RBCs) in confined geometries, in vitro experimental studies unveiling the implications of the collective dynamics of red blood cells in physiologically relevant bio-mimetic microfluidic channels remain elusive. Here, we investigate the implications of complex dynamvic interactions between the whole blood and a deformable channel wall fabricated using a hydrogel matrix. For a range of flow rates, we map the trajectories of the RBCs for varying levels of softness of the microchannel wall. We compare these scenarios with the reference cases of rigid polydimethylsiloxane (PDMS) channels. Our results reveal that the smallest channels investigated herein exhibit the most intricate interactions between the collective dynamics of the RBC and the wall flexibility, attributable to confinement-induced hydrodynamic interactions in the presence of spatially varying shear rates. These results may open up new paradigms in conceptual understanding of in vivo dynamics of blood flow through simple in vitro experiments on a simple microfluidic platform. PMID- 30475360 TI - Tunable band offsets in the BP/P4O10 van der Waals heterostructure: first principles calculations. AB - The structural and electronic properties of the black phosphorus/phosphorus pentoxide (BP/P4O10) van der Waals (vdW) heterostructure are investigated theoretically by first-principles calculations. The BP/P4O10 vdW heterostructure is a direct bandgap semiconductor with intrinsic type-II band alignment thus facilitating separation of photoexcited charge carriers. A transition from semiconducting to metallic is predicted under a positive electric field and the transition of type-II to type-I band alignment occurs under a negative electric field in the BP/P4O10 vdW heterostructure. Moreover, the bandgap can be modulated by adjusting the interlayer distance. The results indicate that the band offsets of the BP/P4O10 vdW heterostructure are tunable, consequently boding well for application to nanoelectronics and optoelectronics. PMID- 30475362 TI - Large tunability in the mechanical and thermal properties of carbon nanotube fullerene hierarchical monoliths. AB - Carbon based materials have attracted much attention as building blocks in technologically relevant nanocomposites due to their unique chemical and physical properties. Here, we propose a new class of hierarchical carbon based nano-truss structures consisting of fullerene joints attached with carbon nanotubes as the truss forming a three-dimensional network. Atomistic molecular dynamics simulations allow us to systematically demonstrate the ability to simultaneously control the mechanical and thermal properties of these structures, elucidating their unique physical properties. Specifically, we perform uniaxial tensile and compressive loading to show that by controlling the length of the carbon nanotube trusses, the mechanical properties can be tuned over a large range. Furthermore, we utilize the Green-Kubo method under the equilibrium molecular dynamics simulations framework to show that the thermal conductivities of these structures can be manipulated by varying the densities of the overall structures. This work provides a computational framework guiding future research on the manipulation of the fundamental physical properties in these organic-based hierarchical structures composed of carbon nanotubes and fullerenes as building blocks. PMID- 30475363 TI - The influence of roughness on stem cell differentiation using 3D printed polylactic acid scaffolds. AB - With the increase in popularity of 3D printing, an important question arises as to the equivalence between devices manufactured by standard methods vs. those presenting with identical bulk specifications, but manufactured via fused deposition modeling (FDM) printing. Using thermal imaging in conjunction with electron and atomic force microscopy, we demonstrate that large thermal gradients, whose distribution is difficult to predict, are associated with FDM printing and result in incomplete fusion and sharkskin of the printing filament. Even though these features are micro or submicron scale, and hence may not interfere with the intended function of the device, they can have a profound influence if the device comes in contact with living tissue. Dental pulp stem cells were cultured on substrates of identical dimensions, which were either printed or molded from the same PLA stock material. The cultures exhibited significant differences in plating efficiency, migration trajectory, and morphology at early times stemming from attempts by the cells to minimize cytoplasm deformation as they attempt to adhere on the printed surfaces. Even though biomineralization without dexamethasone induction was observed in all cultures at later times, different gene expression patterns were observed on the two surfaces. (Osteogenic markers were upregulated on molded substrates, while odontogenic markers were upregulated on the FDM printed surfaces.) Our results clearly indicate that the method of manufacturing is an important consideration in comparing devices, which come in contact with living tissues. PMID- 30475364 TI - Silyl radical initiated radical cascade addition/cyclization: synthesis of silyl functionalized 4H-pyrido[4,3,2-gh]phenanthridin-5(6H)-ones. AB - A cyclization cascade initiated by the addition of a silyl radical to an electron deficient carbon-carbon double bond of N-arylacrylamides, followed by intramolecular cyano group insertion and homolytic aromatic substitution has been reported. In the presence of di-lauroyl peroxide (LPO), under metal-free conditions, several readily available hydrosilanes were successfully used as the source of silyl radicals and a series of silyl functionalized 4H-pyrido[4,3,2 gh]phenanthridin-5(6H)-ones were obtained in moderate to good yields. PMID- 30475365 TI - Copper-catalyzed diastereoselective synthesis of beta-boryl-alpha-quaternary carbon carboxylic esters. AB - Cu(i)-Catalyzed diastereoselective carboboration of alpha-alkyl-substituted alpha,beta-unsaturated carboxylic esters to produce beta-boryl-alpha-quaternary carbon esters was developed. The carbon skeletons of dialkyl sulfates, primary allyl halides, and benzyl bromides were transferred to the alpha-position of the substrates to provide products in moderate to good yields with a diastereoselectivity of >95% in most cases. Substrates bearing a beta (hetero)aryl substituent gave higher diastereoselectivities than those bearing a linear beta-alkyl substituent. The crystal structure of the potassium trifluoroborate derivative shows that the reactions probably go through a copper(i) enolate intermediate and the diastereoselectivity arises from the electrophilic attack of electrophiles to the less hindered side of the enolates. PMID- 30475366 TI - Adhesion of a polymer-grafted nanoparticle to cells explored using generalized Langevin dynamics. AB - We model a polymer-grafted stealth nanoparticle (SNP) as a composite system consisting of a spherical core coated with a porous polymeric brush with end ligands. Adjacent to target cells, the near-wall hydrodynamics, thermal fluctuations, and thermodynamic adhesive interactions simultaneously impact the transient motion of the SNP. Employing both the Langevin framework for the effective hard sphere dynamics and the coupled generalized Langevin framework for the nanoparticle-polymer dynamics, we comprehensively investigate the velocity and position temporal relaxations of the SNP in the absence and presence of end to-end distance fluctuations for the tethered polymer. We demonstrate that polymer structural relaxations substantially impact the SNP adhesive dynamics, especially when the grafted polymer is more flexible. Moreover, a long-time tail with t-3/2 scaling due to polymer chain-length fluctuations is observed in the velocity autocorrelation for a bound SNP. Finally, the thermodynamic effects of membrane morphology on SNP adhesion are explored by modifying the membrane mediated binding potential of mean force. PMID- 30475367 TI - Increasing the functionalities of 3D printed microchemical devices by single material, multimaterial, and print-pause-print 3D printing. AB - 3D printing has emerged as a valuable approach for the fabrication of fluidic devices and may replace soft-lithography as the method of choice for rapid prototyping. The potential of this disruptive technology is much greater than this - it allows for functional integration in a single, highly automated manufacturing step in a cost and time effective manner. Integration of functionality with a 3D printer can be done through spatial configuration of a single material, inserting pre-made components mid-print in a print-pause-print approach, and/or through the precise spatial deposition of different materials with a multimaterial printer. This review provides an overview on the ways in which 3D printing has been exploited to create and use fluidic devices with different functionality, which provides a basis for critical reflection on the current deficiencies and future opportunities for integration by 3D printing. PMID- 30475368 TI - Two dimensional allotropes of arsenene with a wide range of high and anisotropic carrier mobility. AB - Considering the rapid development of experimental techniques for fabricating 2D materials in recent years, various monolayers are expected to be experimentally realized in the near future. Motivated by the recent research activities focused on the honeycomb arsenene monolayers, the stability and carrier mobility of non honeycomb and porous allotropic arsenene are determined using first principles calculations. In addition to five honeycomb structures of arsenene, a total of eight other structures are considered in this study. An extensive analysis comprising energetics, phonon spectra and mechanical properties confirms that these structures are energetically and dynamically stable. All these structures are semiconductors with a broad range of band gaps varying from ~1 eV to ~2.5 eV. Significantly, these monolayer allotropes possess anisotropic carrier mobilities as high as several hundred cm2 V-1 s-1 which is comparable with well-known 2D materials such as black phosphorene and monolayer MoS2. Combining such broad band gaps and superior carrier mobilities, these monolayer allotropes can be promising candidates for the superior performance of the next generation nanoscale devices. We further explore these monolayer allotropes for photocatalytic water splitting and find that arsenene monolayers have potential for usage in visible light driven photocatalytic water splitting. PMID- 30475369 TI - A meal with mixed soy/whey proteins is as efficient as a whey meal in counteracting the age-related muscle anabolic resistance only if the protein content and leucine levels are increased. AB - With aging, skeletal muscle becomes resistant to the anabolic effect of dietary proteins and sarcopenia develops. Animal proteins, which are rich in leucine, are recommended for the elderly, but it is not known whether their replacement by plant proteins would maintain the health and physical independence of this population. Aged rats were fed with animal proteins (casein and whey proteins) with different leucine contents and compared to rats fed with diets in which whey was substituted with soy proteins and by increasing the total protein content or not. Our results clearly showed that the meal with mixed soy/whey proteins allowed the anabolic response of skeletal muscle during aging only if the protein content was increased by 25%. Indeed, if the protein content of the soy/whey diet was decreased to a similar protein content such as a whey diet, i.e. 13%, the anabolic effect decreased. The same observation was recorded if the whey proteins were totally substituted with soy proteins. PMID- 30475370 TI - Synergy of light harvesting and energy transfer as well as short-range charge shift reactions in multicomponent conjugates. AB - We report herein on the design, the synthesis, and the characterization of a panchromatic, charge stabilizing electron donor-acceptor conjugate: (BBPA)3-ZnPor ZnPc-SubPc 1. Each component, that is, bis(biphenyl)phenylamine (BBPA), Zn(ii) porphyrin (ZnPor), Zn(ii) phthalocyanine ZnPc, and subphthalocyanine (SubPc), has been carefully chosen and modified to enable a cascade of energy and charge transfer processes. On one hand, ZnPor, has been functionalized with three electron-donating BBPA as primary and secondary electron donors and to stabilize the final charge-separated state, and, on the other hand, a perfluorinated SubPc has been selected as ultimate electron acceptor. In addition, the ZnPc unit contains several trifluoromethylphenyl moieties to match its energy levels to those of the other components. In fact, irradiation of the heteroarray 1 triggers a cascade of light harvesting across the entire visible range, unidirectional energy transfer, exergonic charge separating, and short-range charge shifting to afford in 14% quantum yield a (BBPA)3+-ZnPor-ZnPc-SubPc- charge-separated state. The lifetime of the latter reaches well into the range of tens of nanoseconds. PMID- 30475371 TI - Monitoring the electric field in CdSe quantum dots under ultrafast interfacial electron transfer via coherent phonon dynamics. AB - Coherent phonon dynamics in CdSe quantum dots (QD) under an ultrafast electron transfer (ET) reaction of the (1Se-1S3/2) exciton quenched by methyl viologen (MV2+) adsorbed onto the QD surface was studied by ultrafast pump-probe spectroscopy. Frequency and amplitude modulations (FM, AM) of the transient absorption DeltaA(omegaprobe,t) in the pure CdSe and coupled CdSe/MV2+ QDs were identified in the bleach band dynamics of the red-edge exciton. The fast Fourier transform (FFT) and continuous wavelet transform analysis of the FM and AM oscillations revealed peaks at 0.51-0.58 THz (17-19 cm-1) and 6.06-6.27 THz (202 209 cm-1) attributed to the longitudinal acoustic (LA) and longitudinal optical (LO) phonons, respectively. The electron transfer to MV2+ proceeded non exponentially with effective time constants of 164 fs (~30%) and 540 fs (~70%). The quantum yield of MV+ radical formation was 40 +/- 5%. It implies a fast route for the electron-hole pair [h+...MV+] recombination that can be rationalized in accordance with the adiabatic ET mechanism at the semiconductor surface. In the coupled CdSe/MV2+ QDs, the amplitude of the FM oscillations rose considerably with time despite the natural attenuation of the phonon amplitude due to decoherence processes. A kinetic model explaining the increase of FM oscillations is proposed. The surprising growth of FM oscillations is elucidated by the kinetic model taking into account the relatively slow damping of LO phonon oscillations (~1.5 ps), the ultrafast ET to MV2+, and the quantum yield of charge separation [h+...MV+] (~40%). The fast formation of the charge-separated pair [h+...MV+] suggests the appearance of an electric field F with a strength of ~3 * 106 V cm-1. The MV2+ reduction substantially increased the magnitude of LA phonon oscillations. Since the ET time is shorter than the period of LA phonon oscillations (~1.8 ps), the MV2+ reduction substantially increased the magnitude of LA phonon oscillations due to the inverse piezoelectric effect. The CdSe nanocrystals exposed to the electric field F exhibit the quantum-confined Stark and Franz-Keldysh electro-absorption effects. The proposed kinetic model gives consideration to the dynamic Stark shift of the red-edge exciton and to the increased amplitude of LO phonon oscillations in the bleach band dynamics. PMID- 30475372 TI - Distribution of superparamagnetic Au/Fe nanoparticles in an isolated guinea pig brain with an intact blood brain barrier. AB - Diagnosis and treatment of brain disorders, such as epilepsy, neurodegenerative diseases and tumors, would benefit from innovative approaches to deliver therapeutic or diagnostic compounds into the brain parenchyma, with either a homogeneous or a targeted localized distribution pattern. To assess the mechanistic aspect of penetration of nanoparticles (NPs) into the brain parenchyma, a complex, yet controlled and facilitated environment was used: the isolated guinea pig brain maintained in vitro by arterial perfusion. In this unique preparation the blood-brain barrier and the interactions between vascular and neuronal compartments are morphologically and functionally preserved. In this study, superparamagnetic Au/Fe nanoparticles (MUS:OT Au/Fe NPs), recently studied as a promising magnetic resonance T2 contrast agent with high cellular penetration, were arterially perfused into the in vitro isolated brain and showed high and homogeneous penetration through transcytosis into the brain parenchyma. Ultramicroscopy investigation of the in vitro isolated brain sections by TEM analysis of the electron-dense core of the MUS:OT Au/Fe NPs was conducted to understand NPs' brain penetration through the BBB after in vitro arterial perfusion and their distribution in the parenchyma. Our data suggest that MUS:OT Au/Fe NPs enter the brain utilizing a physiological route and therefore can be exploited as brain penetrating nanomaterials with potential contrast agent and theranostics capabilities. PMID- 30475373 TI - Self-assembling peptides cross-linked with genipin: resilient hydrogels and self standing electrospun scaffolds for tissue engineering applications. AB - Self-assembling peptides (SAPs) are synthetic bioinspired biomaterials that can be feasibly multi-functionalized for applications in surgery, drug delivery, optics and tissue engineering (TE). Despite their promising biocompatibility and biomimetic properties, they have never been considered real competitors of polymers and/or cross-linked extracellular matrix (ECM) natural proteins. Indeed, synthetic SAP-made hydrogels usually feature modest mechanical properties, limiting their potential applications, due to the transient non-covalent interactions involved in the self-assembling phenomenon. Cross-linked SAP hydrogels have been recently introduced to bridge this gap, but several questions remain open. New strategies leading to stiffer gels of SAPs may allow for a full exploitation of the SAP technology in TE and beyond. We have developed and characterized a genipin cross-linking strategy significantly increasing the stiffness and resiliency of FAQ(LDLK)3, a functionalized SAP already used for nervous cell cultures. We characterized different protocols of cross-linking, analyzing their dose and time-dependent efficiency, influencing stiffness, bioabsorption time and molecular arrangements. We choose the best developed protocol to electrospin into nanofibers, for the first time, self-standing, water stable and flexible fibrous mats and micro-channels entirely made of SAPs. This work may open the door to the development and tailoring of bioprostheses entirely made of SAPs for different TE applications. PMID- 30475374 TI - Tracking down the origin of peculiar vibrational spectra of aromatic self assembled thiolate monolayers. AB - Several studies have previously observed surprisingly low frequencies for the C-H stretching modes of self-assembled monolayers (SAMs) prepared from aromatic thiols. The reason for this property has so far remained elusive. Therefore, we report a novel study of the vibrational spectra of SAMs prepared on Au from two different aromatic thiols, namely, 4'-nitro-1,1'-biphenyl-4-thiol (NBPT) and 4 aminothiophenol (ATP). The SAMs were prepared by vapor deposition (VD) in ultrahigh vacuum (UHV) as well as by the solution method (SM) and their quality was controlled by X-ray photoelectron spectroscopy (XPS). In addition, amino terminated SAMs were also obtained by electron irradiation and by chemical reduction of NBPT SAMs. Beside infrared reflection absorption spectroscopy (IRRAS), we have employed high resolution electron energy loss spectroscopy (HREELS), by which VD SAMs can be studied in situ, i.e. without exposing them to air. Hence, we can exclude possible contributions of solvent molecules to the vibrational spectra. Nonetheless, HREELS in fact reveals the same large red shift of the C-H stretching modes in the SAMs as also observed in ex situ IRRAS experiments. In contrast, HREELS for physisorbed ATP and ATP in a KBr pellet measured by transmission infrared spectroscopy exhibit the expected aromatic bands. Using a computational approach, we can exclude molecular packing effects as origin of this shift. Therefore, we propose chemical changes in the aromatic rings during SAM formation as an alternative explanation for the observed frequency shift. As another striking effect, the N-H stretching vibrational modes of the amino-terminated SAMs are extremely weak in both IRRAS and HREELS despite the fact that XPS confirms the presence of amino groups. A very weak signal is observed only in the case of an electron irradiated NBPT SAM. In contrast, an energy loss ascribed to the N-H stretching vibrations is clearly observed in HREELS of ATP physisorbed on an ATP SAM and on graphite as well as in the transmission infrared spectrum of ATP in KBr. The extremely low intensity of these vibrations in the SAM is traced back to the inherently low transition dipole moment for the excitation of N-H stretching modes in free N-H groups. Furthermore, the calculations suggest that the much stronger signals of N-H stretching modes involved in hydrogen-bonding with adjacent amino groups are suppressed because these vibrations are oriented parallel to the surface. PMID- 30475375 TI - Ionic conductivity and structure of M1-xPbxF2 (M = Ca, Sr, Ba) solid solutions prepared by ball milling. AB - Nanocrystalline M1-xPbxF2 (M = Ca, Sr, Ba) solid solutions were prepared by ball milling mixtures of binary parent materials. The structure of the obtained materials was investigated by 19F MAS NMR spectroscopy and XRPD, and their ionic conductivity by impedance spectroscopy. It was found that fluorite-structured solid solutions over the whole range of compositions can be prepared by ball milling for all three systems, closing the broad miscibility gap of the CaF2-PbF2 system. The fluoride ion conductivity increased with increasing Pb content of the solid solutions, with Ba0.10Pb0.90F2 showing the highest conductivity of all samples prepared, being 1.5 orders of magnitude smaller than the one of PbSnF4. Ca1-xPbxF2 showed a fluoride ion conductivity increase which can be assigned to geometric frustration induced disorder. Ball milling of pure PbF2 revealed an increase of the fluoride ion conductivity by 2.5 orders of magnitude in the case of PbF2 containing a large amount of beta-PbF2 compared to microcrystalline beta PbF2. Its fluoride ion conductivity is also 2.5 orders of magnitude larger than the fluoride ion conductivity of ball milled PbF2 consisting of a small amount of beta-PbF2 but a large amount of alpha-PbF2 pointing to differently conducting and structured grain boundaries of alpha-PbF2 and beta-PbF2. PMID- 30475376 TI - Changes to the tropomyosin structure alter the angiotensin-converting enzyme inhibitory activity and texture profiles of eel balls under high hydrostatic pressure. AB - Changes in the structure of tropomyosin (TM) altered the texture profiles of eel balls and the inhibitory activity of the angiotensin-converting enzyme (ACE). The secondary and tertiary structure of TM was determined after high hydrostatic pressure (HHP) treatment. The correlation between the spatial structure of TM and the texture profiles of eel balls was developed and discussed. The beta-sheet was converted to a beta-turn and a random coil when treated at HHP (200-400 MPa), meanwhile the alpha-helix unfolded and was converted into a beta-sheet, beta-turn and a random coil with treatment at 500 and 600 MPa. The surface hydrophobicity (H0) was increased and the sulfhydryl (SH) content decreased with an increase in the pressure. The results indicated that the texture profiles of eel balls showed a negative relationship with the alpha-helix, beta-sheet and SH content. The texture profiles of eel balls were greatly enhanced after treatment at 500 and 600 MPa, leading to the improved surface network of the eel ball products. The ACE inhibitory activity of TM after HHP treatment exhibited a positive relationship with the beta-sheet content in the protein. The ACE inhibitory activity was preserved under 600 MPa. PMID- 30475377 TI - Reorientational dynamics of organic cations in perovskite-like coordination polymers. AB - Here we report the dynamics of organic cations as guest molecules in a perovskite host-framework. The molecular motion of CH3NH3+ (MAFe), (CH3)2NH2+ (DMAFe) and (CH3)3NH+ (TrMAFe) in the cage formed by KFe(CN)63- units was studied using a combination of experimental methods: (i) thermal analysis, (ii) dielectric and electric studies, (iii) optical observations, (iv) EPR and 1H NMR spectroscopy and (v) quasielastic neutron scattering (QENS). In the case of MAFe and TrMAFe, the thermal analysis reveals one solid-to-solid phase transition (PT) and two PTs for the DMAFe crystal. A markedly temperature-dependent dielectric constant indicates the tunable and switchable properties of the complexes. Also, their semiconducting properties are confirmed by a dc conductivity measurement. The broadband dielectric relaxation is analyzed for the TrMAFe sample in the frequency range of 100 Hz-1 GHz. QENS shows that we deal rather with the localized motion of the cation than a diffusive one. Three models, which concern the simultaneous rotation of the CH3 and/or NH3 group, pi-flips and free rotations of the organic cation, are used to fit the elastic incoherent structure factor. The 1H NMR spin-lattice relaxation time for all compounds under study, as well as the second moments, has been measured in a wide temperature range. In all studied samples, the temperature dependence of the second moment of the proton NMR line indicated the gradual evolution of the molecular movements from the rigid state up to a highly disordered one. PMID- 30475378 TI - Na3Ca4(TeO3)(PO4)3: a new noncentrosymmetric tellurite phosphate with fascinating multimember-ring architectures and intriguing nonlinear optical performance. AB - A new functional compound Na3Ca4(TeO3)(PO4)3 has been successfully synthesized and fully characterized. It is the first example of a tellurite phosphate that exhibits a fascinating multimember-ring configuration. Moreover, a careful theoretical and experimental study also reveals the intriguing nonlinear optical performance of Na3Ca4(TeO3)(PO4)3. PMID- 30475379 TI - Temperature-dependent studies of a new two-dimensional cadmium dicyanamide framework exhibiting an unusual temperature-induced irreversible phase transition into a three-dimensional perovskite-like framework. AB - We report the synthesis, crystal structure, and thermal, dielectric, optical and phonon properties of a new two-dimensional (2D) cadmium(ii) complex [(C3H7)4N][Cd(N(CN)2)3]. Our results show that this compound crystallizes in a two-dimensional monoclinic structure, with the space group P2/n, with ordered tetrapropylammonium cations and disorder of some dicyanamide linkers. It undergoes a structural phase transition at 245 K into another low-temperature (LT) monoclinic structure, with the space group P21/n. X-ray diffraction, dielectric, IR and Raman studies show that freezing of the dca motions stands at the origin of the phase transition. Optical studies indicate that this material has an energy band gap of 4.83 eV and exhibits intense bluish-white emission under 266 nm excitation. Upon heating, this compound undergoes an irreversible phase transition near 390 K associated with significant bond rearrangement. The high-temperature (HT) phase has a three-dimensinal (3D) perovskite-like structure. [(C3H7)4N][Cd(N(CN)2)3] is, therefore, the first example of a hybrid organic-inorganic dicyanamide exhibiting a temperature-induced reconstructive transition from a 2D (layered) structure to a 3D (perovskite-like) structure. PMID- 30475380 TI - Synthesis of bimetallic complexes bridged by 2,6-bis(benzimidazol-2-yl) pyridine derivatives and their catalytic properties in transfer hydrogenation. AB - A series of binuclear rhodium(i) and iridium(i) complexes with 2,6 bis(benzimidazol-2-yl) pyridine (bzimpy) derivatives were synthesized and characterized by elemental analysis and spectroscopic methods. The molecular and crystal structures of complex 3d were determined by the single crystal X-ray diffraction technique. Their monometallic analogues were prepared to compare the catalytic properties of the bimetallic complexes. To determine the catalyst properties that result in a cooperative, bimetallic enhancement of the reaction rate, the systematic variation of the intermetallic distance and the ligand donor properties of the bimetallic complexes were explored based on the transfer hydrogenation reactions of ketones. PMID- 30475381 TI - Robust polyimide nanofibrous membrane with porous-layer-coated morphology by in situ self-bonding and micro-crosslinking for lithium-ion battery separator. AB - Herein, we demonstrate a strategy to improve the tensile strength, thermal safety issues, and electrochemical performance of an as-synthesized polyimide separator. By spraying the solution of a specific chemical constituent on both sides of a poly(amic acid) non-woven membrane followed by thermal treatment, a novel polyimide nanofibrous membrane with porous-layer-coated morphology was successfully fabricated by in situ self-bonding and micro-crosslinking technique. The self-bonding and micro-crosslinking techniques improve the tensile strength of the nanofiber membranes from 5 MPa to 28 MPa by forming a crosslinked network structure, thereby reducing the risk of nanofiber disassembly during long-term operation. The rigid structure and aromatic groups in the polyimide chain enable the separator to have outstanding thermal dimensional stability at temperatures as high as 300 degrees C and thermal stability (5% weight loss at about 528 degrees C). Additionally, the unique flame retarding capability of polyimide ensures high security of the battery as well. Notably, the lithium-ion battery using porous-layer-coated polyimide separator exhibits a much higher capability (129.9 mA h g-1, 5C) than that using a Celgard-2400 separator (95.2 mA h g-1, 5C) and could work steadily at 120 degrees C, thus implying promising application in next generation high-safety and high-performance lithium-ion batteries. PMID- 30475382 TI - STIM promotes the epithelial-mesenchymal transition of podocytes through regulation of FcgammaRII activity in diabetic nephropathy. AB - BACKGROUND: Diabetic nephropathy (DN) is a serious complication in diabetic patients and has been considered as the main cause of end-stage renal disease. However, there are no studies on the role of stromal interaction molecule (STIM) and its two subtypes, STIM1 and STIM2, in the epithelial-to-mesenchymal transition (EMT) of podocytes induced by diabetic kidney disease (DKD). The present study suggests for the first time that STIM inhibition decreases DKD induced EMT. METHODS: All DKD patients were diagnosed based on renal biopsies carried out at the Department of Nephrology, Zhejiang Provincial People's Hospital and selected using the Mayo Clinic/Renal Pathology Society Consensus Report on Pathologic Classification, Diagnosis, and Reporting of GN. Images were taken and the number of positive puncta in cells was analyzed using software equipped for immunofluorescence microscopy. STIM1, STIM2, FcgammaRIIa, FcgammaRIIb, Nephrin, CTGF, and alpha-SMA protein levels were detected by Western blotting analysis using the corresponding antibodies. The viability of cells was measured using CCK-8 assays. Absorbance at 450 nm was measured with a Multiskan FC Microplate Reader (Thermo Scientific, USA) and the results were normalized to those of untreated cells. All statistical analyses were performed using SPSS 19.0 software (Stanford University, Stanford, CA, USA). RESULTS: A total of 30 DKD patients and 30 control patients were enrolled in the study. We found that the level of urine protein in patients and db/db diabetic mice is higher than control group and the levels of STIM1 and 2 significantly increased in DKD groups. We also demonstrated that STIM is upregulated during DKD injury. Next, we discovered that DKD-induced podocyte EMT is related to STIM overexpression in vivo and in vitro. Further research demonstrated that STIM siRNA reverses podocytes from DKD induced injury and EMT and reverses FcgammaRII activity in HG-treated podocytes. CONCLUSION: Our study suggests that STIM and FcgammaRII play an essential role in the regulation of DKD-induced podocyte EMT. STIM is an essential component of FcgammaR activation and inhibition of STIM-mediated signaling pathway might be a new strategy to treat IgG-dependent renal diseases. PMID- 30475383 TI - Extended differentiation of veins and stomata is essential for the expansion of large leaves in Rheum rhabarbarum. AB - PREMISE OF THE STUDY: The densities of veins and stomata govern leaf water supply and gas exchange. They are coordinated to avoid overproduction of either veins or stomata. In many species, where leaf area is greater at low light, this coordination is primarily achieved through differential cell expansion, resulting in lower stomatal and vein density in larger leaves. This mechanism would, however, create highly inefficient leaves in species in which leaf area is greater at high light. Here we investigate the role of cell expansion and differentiation as regulators of vein and stomatal density in Rheum rhabarbarum, which produces large leaves under high light. METHODS: Rheum rhabarbarum plants were grown under full sunlight and 7% of full sunlight. Leaf area, stomatal density, and vein density were measured from leaves harvested at different intervals. KEY RESULTS: Leaves of R. rhabarbarum expanded at high light were six times larger than leaves expanded at low light, yet vein and stomatal densities were similar. In high light-expanded leaves, minor veins were continuously initiated as the leaves expanded, while an extended period of stomatal initiation, compared to leaves expanded at low light, occurred early in leaf development. CONCLUSIONS: We demonstrate that R. rhabarbarum adjusts the initiation of stomata and minor veins at high light, allowing for the production of larger leaves uncoupled from lower vein and stomatal densities. We also present evidence for an independent control of vein and stomatal initiation, suggesting that this adjustment must involve some unknown developmental mechanism. PMID- 30475384 TI - Cervical human papillomavirus among 19,753 women attending gynecological department of a major comprehensive hospital in north Anhui China 2013-2016: implication for cervical cancer screening and prevention. AB - Our study aimed to assess the prevalent, incident and persistent infection and clearance of HPV among 19,753 individual women attending the gynecological department at a major comprehensive hospital. HPV16, 52 and 58 ranked top 3 types with the highest prevalence and incidence. The prevalence of high-risk (HR) HPV peaked among women aged 15-19 years, then sharply decreased with age, stabilized among women aged 25-44 years and then surged again among women aged 45 years and older. HR HPV infection were more likely to be prevalent (15.9% vs 1.3%, p<0.001), incident (17.3 vs 2.0 per 1000 person-months, p<0.001) and persistent (33.0% vs 24.2%, p=0.033), and less likely to clear (88 vs 115 per 1000 person months, p=0.040) compared to LR HPV types. The majority of women detected with HR HPV types did not retest within 12 months. Clinical guidelines on HPV DNA testing are needed and education, and counseling about HPV infection and its implications for women detected with HPV at clinical settings, are warranted. This article is protected by copyright. All rights reserved. PMID- 30475385 TI - RNA is taking its Toll - Impact of RNA-specific Toll-like receptors on health and disease. AB - RNA-sensing Toll-like receptors (TLRs) are often described as anti-viral receptors of the innate immune system. However, the past decade has shown that the function and importance of these receptors is far more complex. These receptors were found to be relevant for the detection of various bacterial, archaeal, and eukaryotic microorganisms and facilitate the discrimination between dead and living microbes. The cytokine and interferon response profile that is triggered has the potential to improve the efficacy of next-generation vaccines and may prevent the development of asthma and allergy. Nevertheless, the ability to recognize foreign RNA comes with a cost as also damaged host cells can release nucleic acids that might induce an inappropriate immune response. Thus, it is not surprising that RNA-sensing TLRs play a key role in various autoimmune diseases. However, promising new inhibitors and antagonists are on the horizon to improve their treatment. This article is protected by copyright. All rights reserved. PMID- 30475386 TI - Three-Dimensional Printing Biotechnology for the Regeneration of the Tooth and Tooth-supporting Tissues. AB - The tooth and its supporting tissues are organized with complex three-dimensional (3D) architecture, including the dental pulp with a blood supply and nerve tissues, complex multilayer periodontium, and highly aligned periodontal ligament (PDL). Mimicking such 3D complexity and the multicellular interactions naturally existing in dental structures represents great challenges in dental regeneration. Attempts to construct the complex system of the tooth and tooth-supporting apparatus (i.e., the periodontal ligament, alveolar bone and cementum) have made certain progress owing to 3D printing biotechnology. Recent advances have enabled the 3D printing of biocompatible materials, seed cells and supporting components into complex 3D functional living tissue. Furthermore, 3D bioprinting is driving major innovations in regenerative medicine, giving the field of regenerative dentistry a boost. The fabrication of scaffolds via 3D printing is already being performed extensively at the laboratory bench and in clinical trials; however, printing living cells and matrix materials together to produce tissue constructs by 3D bioprinting remains limited to the regeneration of dental pulp and the tooth germ. This review summarizes the application of scaffolds for cell seeding and biofabricated tissues via 3D printing and bioprinting, respectively, in the tooth and its supporting tissues. Additionally, the key advantages and prospects of 3D bioprinting in regenerative dentistry are highlighted, providing new ideas for dental regeneration. This article is protected by copyright. All rights reserved. PMID- 30475387 TI - Surgery remains the best solution for patients with soft-tissue sarcomas. PMID- 30475388 TI - CCR10+ ILC2s with ILC1-like properties exhibit a protective function in severe allergic asthma. AB - BACKGROUND: We previously showed that patients with severe allergic asthma have high numbers of circulating ILC2s expressing CCR10. METHOD: Herein, CCR10+ ILC2s were further analyzed in the blood of healthy individuals or patients with allergic and non-allergic asthma. Characteristics of human CCR10+ and CCR10- ILC2s were assessed by flow cytometry as well as single-cell multiplex RT-qPCR. The role of CCR10+ ILC2s in asthma pathophysiology was studied in allergen treated mice. RESULTS: When compared to healthy controls, CCR10+ ILC2s are enriched in the blood of both allergic and non-allergic severe asthmatic patients, and these cells are recruited to the lungs. Plasma concentrations of the CCR10 ligand CCL27 are significantly increased in severe asthmatics when compared to non-asthmatic patients. CCR10+ ILC2s secrete little TH 2 cytokines, but exhibit ILC1-like properties, including a capacity to produce IFN-gamma. Also, single cell analysis reveals that the CCR10+ ILC2 subset is enriched in cells expressing Amphiregulin. CCR10+ ILC2s depletion, as well as blocking of IFN gamma activity, exacerbates airway hyperreactivity in allergen-challenged mice, providing evidence for a protective role of these cells in allergic inflammation. CONCLUSIONS: Frequencies of circulating CCR10+ ILC2s and CCL27 plasma concentrations represent candidate markers of asthma severity. The characterization of CCR10+ ILC2s in human samples and in mouse asthma models suggests that these cells downregulate allergic inflammation through IFN-gamma production. This article is protected by copyright. All rights reserved. PMID- 30475389 TI - Penalized likelihood and multiple testing. AB - The classical multiple testing model remains an important practical area of statistics with new approaches still being developed. In this paper we develop a new multiple testing procedure inspired by a method sometimes used in a problem with a different focus. Namely, the inference after model selection problem. We note that solutions to that problem are often accomplished by making use of a penalized likelihood function. A classic example is the Bayesian information criterion (BIC) method. In this paper we construct a generalized BIC method and evaluate its properties as a multiple testing procedure. The procedure is applicable to a wide variety of statistical models including regression, contrasts, treatment versus control, change point, and others. Numerical work indicates that, in particular, for sparse models the new generalized BIC would be preferred over existing multiple testing procedures. PMID- 30475390 TI - Detection of recombinant and endogenous mouse melatonin receptors by monoclonal antibodies targeting the C-terminal domain. AB - Melatonin receptors play important roles in the regulation of circadian and seasonal rhythms, sleep, retinal functions, the immune system, depression and type 2 diabetes development. Melatonin receptors are approved drug targets for insomnia, non-24h sleep-wake disorders and major depressive disorders. In mammals, two melatonin receptors (MTRs) exist, MT1 and MT2 , belonging to the G protein-coupled receptor (GPCR) super-family. Similar to most other GPCRs, reliable antibodies recognizing melatonin receptors prooved to be difficult to obtain. Here we describe the development of the first monoclonal antibodies (mABs) for mouse MT1 and MT2 . Purified antibodies were extensively characterized for specific reactivity with mouse, rat and human MT1 and MT2 by western blot, immunoprecipitation, immunofluorescence and proximity ligation assay. Several mABs were specific for either mouse MT1 or MT2 . None of the mABs cross-reacted with rat MTRs, and some were able to react with human MTRs. The specificity of the selected mABs was validated by immunofluorescence microscopy in three established locations (retina, suprachiasmatic nuclei, pituitary gland) for MTR expression in mice using MTR KO mice as control. MT2 expression was not detected instead in mouse insulinoma MIN6 cells or pancreatic beta-cells. Collectively, we report the first monoclonal antibodies recognizing recombinant and native mouse melatonin receptors that will be valuable tools for future studies. This article is protected by copyright. All rights reserved. PMID- 30475391 TI - Characterizing modes of action and interaction for multicomponent osmolyte solutions on Jurkat cells. AB - This study examined the post-thaw recovery of Jurkat cells cryopreserved in three combinations of five osmolytes including trehalose, sucrose, glycerol, mannitol and creatine. Cellular response was characterized using low temperature Raman spectroscopy and variation of post-thaw recovery was analyzed using statistical modeling. Combinations of osmolytes displayed distinct trends of post-thaw recovery and a non-linear relationship between compositions and post-thaw recovery was observed, suggesting interactions not only between different solutes but also between solutes and cells. The post-thaw recovery for optimized cryoprotectants in different combinations of osmolytes at a cooling rate of 1 degrees C/min was comparable to that measured with 10 % dimethyl sulfoxide. Statistical modeling was used to understand the importance of individual osmolytes as well as interactions between osmolytes on post thaw recovery. Both higher concentrations of glycerol and certain interactions between sugars and glycerol were found to typically increase post-thaw recovery. Raman images showed the influence of osmolytes and combinations of osmolytes on ice crystal shape, which reflected the interactions between osmolytes and water. Differences in composition also influenced the presence or absence of intracellular ice formation, which could also be detected by Raman. These studies help us understand modes of action for cryoprotective agents in these osmolyte solutions. This article is protected by copyright. All rights reserved. PMID- 30475392 TI - Monkey business: Collaborating to grow an ecological physiology of primates. AB - The lab and field provide differing approaches to studying primate biology. We outline the challenges and benefits of these approaches and demonstrate how collaboration can help bridge these perspectives to provide complementary insight into primate adaptive pathways. With this aim, our collaboration has made tangible insights into the ecological physiology of several primate species, and also yielded more subtle, intangible professional benefits. PMID- 30475393 TI - All items of the Food Allergy Quality of Life Questionnaires are relevant for peanut-allergic patients. PMID- 30475394 TI - Poly(2-oxazoline)s Terminated with 2,2'-Imino diacetic acid Form Non-covalent Polymer Enzyme Conjugates that are Highly Active in Organic Solvents. AB - A great limitation for the usability of free enzymes in organic solvents is their insolubility in these media. Some surfactants are capable of solubilizing enzymes in such media, but they are hard to remove. Covalent modification of enzymes with polymers has led to polymer enzyme conjugates (PECs) that are soluble in organic solvents, but the process is quite elaborate. Poly(2-oxazoline)s (POx) with the end group 2,2'-imino diacetic acid (IDA) were shown to form reversible, nano sized non-covalent aggregates with enzymes. These PECs give clear solutions in organic solvents. The enzymes Lysozyme, Horse Radish Peroxidase (HRP), Laccase, alpha-Chymotrypsin (CT), Catalase, and Alcohol Dehydrogenase could be solubilized in chloroform and toluene at concentrations of up to 2 mg protein per mL. Laccase, HRP, and CT were shown to survive the transfer into the organic medium and back to water in their active form. The distribution coefficient of the proteins between water and organic solvent was shown to be dependent on the nature of the POx backbone. All three biocatalysts exhibit greatly enhanced activity in the respective organic solvent. This article is protected by copyright. All rights reserved. PMID- 30475395 TI - Preface to ToScA 2017 special issue. PMID- 30475396 TI - The Journal of Microscopy would like to thank all those referees who reviewed papers for the Journal during 2018. Your assistance and contribution to the Journal is greatly appreciated. PMID- 30475397 TI - Role of the Signal Sequence in Proteorhodopsin Biogenesis in E. coli. AB - Blue-absorbing proteorhodopsin (BPR) from marine bacteria is a retinal-bound, light-activated, outwards proton transporter containing seven alpha-helical transmembrane segments (TMS). It is synthesized as a precursor species (pre-BPR) with a predicted N-terminal signal sequence that is cleaved to yield the mature protein. While optimizing the production of BPR in E coli to facilitate the construction of bioprotonic devices, we observed significant pre-BPR accumulation in the inner membrane and explored signal sequence requirements and export pathway. We report here that BPR does not rely on the Sec pathway for inner membrane integration, and that although it greatly enhances yields, its signal sequence is not necessary to obtain a functional product. We further show that an unprocessable version of pre-BPR obtained by mutagenesis of the signal peptidase I site exhibits all functional attributes of the wild type protein and that is has the advantage of being produced at higher levels. Our results are consistent with the BPR signal sequence being recognized by the signal recognition particle (SRP; a protein that orchestrates the cotranslational biogenesis of inner membrane proteins) and serving as a beneficial "pro" domain rather than a traditional secretory peptide. This article is protected by copyright. All rights reserved. PMID- 30475398 TI - First Person: Hyman Muss, MD: Geriatric oncology pioneer continues leading efforts to help older patients with cancer. PMID- 30475399 TI - Cancer centers issue call to action regarding the human papillomavirus vaccine. PMID- 30475401 TI - STAR act expected to improve care for pediatric patients with cancer. PMID- 30475400 TI - Costs of cancer along the care continuum: What we can expect based on recent literature. AB - BACKGROUND: Cancer costs should be discussed by patients and providers, but information is not readily available. Results from recently published studies (in the last 5 years) on direct and indirect cancer costs may help guide these discussions. METHODS: The authors reviewed studies published between 2013 and 2017 that reported direct health care costs and indirect (productivity losses) costs. The annual mean total and net costs of cancer were summarized for all payers and for survivors only by age (ages 18-64 and >=65 years), by phase of care (initial [ie, 12 months from diagnosis], continuing, and end-of-life [ie, 12 months before death]), or for recently diagnosed (within 1-2 years of diagnosis) and longer term survivors. RESULTS: For all payers combined, costs for cancers like breast, prostate, colorectal, and lung cancers were $20,000 to $100,000 in the initial phase, $1000 to $30,000 annually in the continuing phase, and >=$60,000 in the end-of-life phase. Annual out-of-pocket costs to recently diagnosed survivors were >$1000 for medical care and time costs, approximately $2000 for productivity losses, and from $2500 to >$4000 for employment disability, depending on age. For longer term survivors, the cost of medical care was approximately $1500 for older survivors and $747 for younger survivors, time costs were $831 to $955 for older survivors and $459 to $630 for younger survivors, and productivity losses were approximately $800. Disability among long term survivors was similar to that among short-term survivors. Limitations of the reviewed studies included older data and under-representation of higher cost cancers. CONCLUSIONS: Frequently updated cost information for all cancer types is needed to guide discussions of anticipated short-term and long-term cancer related costs with survivors. Cancer 2018;000:000-000. (c) 2018 American Cancer Society. PMID- 30475402 TI - RNA-dependent chaperone (Chaperna) as an engineered pro-region for the folding of recombinant microbial transglutaminase. AB - Transglutaminase (TGase) induces the cross-linking of proteins by catalyzing an acyl transfer reaction. TGase is a zymogen, activated by the removal of its pro region. Since the pro-region is crucial for folding and inhibition of TGase activity, the recombinant expression of the mature TGase (mTGase) without the pro region, usually results in inactive inclusion bodies or low protein yield. Here, Streptomyces netropsis TGase was fused with E. coli lysyl tRNA synthetase (LysRS), as a module with chaperoning activity in an RNA dependent manner (chaperna). The TGase activity from purified fusion protein induced via removal of LysRS by tev protease in vitro. Moreover, active mTGase was produced in E. coli via an intracellular cleavage system, wherein LysRS-mTGase was cleaved by the co-expressed tev protease in vivo. The results suggest that LysRS essentially mimics pro-region, which exerts a dual function-folding of TGase into active conformation and keeping it as dormant state-in an RNA-dependent manner. Thus, trans-acting RNAs, prompt the cis-acting chaperone function of LysRS, while being mechanistically similar to the intra-molecular chaperone function of the pro region. These results could be implemented and extended for the folding of "difficult-to-express" recombinant proteins, by harnessing chaperna function. This article is protected by copyright. All rights reserved. PMID- 30475403 TI - A single preoperative blood test predicts postoperative sepsis and pneumonia after coronary bypass or open aneurysm surgery. AB - BACKGROUND: Major surgery comes with a high risk for postoperative inflammatory complications. Preoperative risk scores predict mortality risk but fail to identify patients at risk for complications following cardiovascular surgery. We therefore assessed the value of preoperative red cell distribution width (RDW) as a predictor for pneumonia and sepsis after cardiovascular surgery and studied the relation of RDW with hematopoietic tissue activity. METHODS: RDW is an easily accessible, yet seldomly used parameter from routine hematology measurements. RDW was extracted from the Utrecht Patient Orientated Database (UPOD) for preoperative measurements in patients undergoing open abdominal-aortic-aneurysm repair (AAA)(N=136) or coronary artery bypass grafting (CABG)(N=2193). The cohorts were stratified in tertiles to assess effects over the different groups. Generalized Linear Models were used to determine associations between RDW and postoperative inflammatory complications. Hematopoietic tissue activity was scored using fluor-18-(18 F)-deoxyglucose positron-emission-tomography and associated with RDW using linear regression models. RESULTS: In total, 43(31.6%) and 73 patients(3.3%) suffered from inflammatory complications after AAA-repair or CABG, respectively; the majority being pneumonia in both cohorts. Postoperative inflammatory outcome incidence increased from 19.6% in the lowest to 48.9% in the highest RDW-tertile with a corresponding risk ratio (RR) of 2.35 ((95%CI:1.08-5.14)p=0.032) in AAA-patients. In the CABG-cohort, the incidence of postoperative inflammatory outcomes increased from 1.8% to 5.3% with an adjusted RR of 1.95 (95%CI:1.02-3.75)p=0.044) for the highest RDW-tertile compared with the lowest RDW-tertile. FDG-PET scans showed associations of RDW with tissue activity in the spleen (B=0.517 (p=0.001)) and the lumbar bone marrow (B=0.480 (p=0.004)). CONCLUSION: Elevated RDW associates with increased risk for postoperative inflammatory complications and hematopoietic tissue activity. RDW likely reflects chronic low-grade inflammation and should be considered to identify patients at risk for postoperative inflammatory complications following cardiovascular surgery. This article is protected by copyright. All rights reserved. PMID- 30475404 TI - Review of advanced physical and data-driven models for dynamic bioprocess simulation: Case study of algae-bacteria consortium wastewater treatment. AB - Microorganism production and remediation processes are of critical importance to the next generation of sustainable industries. Undertaking mathematical treatment of dynamic biosystems operating at any spatial or temporal scale is essential to guarantee their performance and safety. However, constructing physical models remains a challenge due to the extreme complexity of process biological mechanisms. Data-driven models also encounter severe limitations because datasets from large-scale bioprocesses are often scarce without complete information and on a restricted operational space. To fill this gap, the current research compares the performance of advanced physical and data-driven models for dynamic bioprocess simulations subject to incomplete and scarce datasets, which to the best of our knowledge has never been addressed before. In specific, kinetic models were constructed by integrating different classic models, and state-of-the art hyperparameter selection frameworks were developed to design artificial neural networks and Gaussian process regression models. An algae-bacteria consortium wastewater treatment process was selected to test the accuracy of these modelling strategies, as it is one of the most sophisticated biosystems due to the intricate mutualistic and competitive interactions. Based on the current results and available data, a heuristic model selection procedure is provided. This research paves the way to facilitate future bioprocess modelling. This article is protected by copyright. All rights reserved. PMID- 30475405 TI - Perioperative management may lead to less pain after breast cancer surgery. PMID- 30475406 TI - Hydrogen bonding networks in gabapentin protic pharmaceutical salts: NMR and in silico studies. AB - Hydrogen Bonds (HB) play a key role in the supramolecular arrangement of crystalline solids and, although they have been extensively studied, the influence of their strength and geometry on crystal packing remains poorly understood. Here we describe the crystal structures of two novel protic gabapentin (GBP) pharmaceutical salts prepared with the co-formers methanesulfonic acid (GBP:METHA) and ethanesulfonic acid (GBP:ETHA). This study encompasses experimental and computational electronic structure analyses of 1 H NMR chemical shifts (CS), upon in silico HB cleavage. GBP:METHA and GBP:ETHA crystal packing comprise two main structural domains: an ionic layer (characterized by the presence of charge-assisted + NHGBP ?O- METHA/ETHA HB interactions) and a neutral layer generated in a different way for each salt, mainly due to the presence of bifurcated HB interactions. A comprehensive study of HB networks is presented for GBP:METHA, by isolating molecular fragments involved in distinct HB types (NH?O, OH?O and CH?O) obtained from in silico disassembling of an optimized three-dimensional packing structure. Formation of HB leads to calculated 1 H NMR CS changes from 0.4 to ~ 5.8 ppm. This study further attempts to assess how 1 H NMR CS of protons engaged in certain HB are affected when other nearby HB, involving bifurcated or geminal/vicinal hydrogen atoms, are removed. PMID- 30475408 TI - Excisionase in Pf Filamentous Prophage Controls Lysis-Lysogeny Decision-Making in Pseudomonas aeruginosa. AB - Pf filamentous prophages are prevalent among clinical and environmental Pseudomonas aeruginosa isolates. Pf4 and Pf5 prophages are integrated into the host genomes of PAO1 and PA14, respectively, and play an important role in biofilm development. However, the genetic factors that directly control the lysis lysogeny switch in Pf prophages remain unclear. Here, we identified and characterized the excisionase genes in Pf4 and Pf5 (named xisF4 and xisF5, respectively). XisF4 and XisF5 represent two major subfamilies of functional excisionases and are commonly found in Pf prophages. While both of them can significantly promote prophage excision, only XisF5 is essential for Pf5 excision. XisF4 activates Pf4 phage replication by upregulating the phage initiator gene (PA0727). In addition, xisF4 and the neighboring phage repressor c gene pf4r are transcribed divergently and their 5'-untranslated regions overlap. XisF4 and Pf4r not only auto-activate their own expression but also repress each other. Furthermore, two H-NS family proteins, MvaT and MvaU, coordinately repress Pf4 production by directly repressing xisF4. Collectively, we reveal that Pf prophage excisionases cooperate in controlling lysogeny and phage production. This article is protected by copyright. All rights reserved. PMID- 30475407 TI - Postoperative radiotherapy for T1/2N0M0 mucoepidermoid carcinoma positive for CRTC1/3-MAML2 fusions. AB - BACKGROUND: The National Comprehensive Cancer Network (NCCN) guidelines recommend considering postoperative radiotherapy (PORT) for completely resected T1/2N0M0 salivary mucoepidermoid carcinomas when they show tumor spillage, perineural invasion, or intermediate/high-grade histology. CRTC1/3-MAML2 fusions have been associated with a favorable clinical outcome. METHODS: Forty-seven T1/2N0M0 mucoepidermoid carcinoma cases positive for CRTC1/3-MAML2 fusions were completely resected and were not treated with PORT. RESULTS: Pathologically, none of the cases showed tumor spillage or perineural invasion. Cases with intermediate/high grade histology numbered 9 (19%) to 26 (55%) with the currently used 3 different grading systems. During the follow-up (median 60 months), locoregional tumor recurrence occurred in 4 cases, which were treated with surgery alone. At the last follow-up (median 60 months; 7-160), all patients were alive with no evidence of disease. CONCLUSION: An excellent prognosis may be achieved without PORT in T1/2N0M0 mucoepidermoid carcinoma patients positive for CRTC1/3-MAML2 fusions when the tumors are completely resected without tumor spillage. PMID- 30475409 TI - Risks, benefits, and ethical questions associated with transplanting kidneys from hepatitis C virus-infected donors into hepatitis C virus-negative patients. AB - Utilization of kidneys from hepatitis C virus (HCV)-infected deceased donors has the potential to increase the number of kidney transplants by 500-1000 (or more) each year. This increase in the number of kidney transplants offers major opportunities to extend survival and improve quality of life for patients infected with HCV, as well as uninfected recipients. However, due to a lack of prospective safety and efficacy data on a sufficient number of HCV-negative recipients who received a kidney from a HCV-infected donor, as well as key logistical barriers, the practice of transplanting HCV-infected organs into uninfected recipients is not yet ready to be considered as standard of care. Ongoing research coupled with a collaboration between insurers and transplant centers might bring positive-into-negative transplant into the realm of standard of care in well-informed transplant candidates, regardless of HCV status. PMID- 30475410 TI - Nonclassical mechanism in the cyclodehydration of diols catalyzed by a bifunctional iridium complex. AB - 1,4- and 1,5-Diols undergo cyclodehydration upon treatment with cationic N heterocyclic carbene (NHC) Ir(III) complexes to give tetrahydrofurans and tetrahydropyrans, respectively. The mechanism was investigated, and a metal hydride-driven pathway is proposed for all substrates, with the exception of very electron rich ones, which contrasts with the well-established classical pathways involving nucleophilic substitutions. PMID- 30475411 TI - Heterogeneous metal-organic frameworks-based biohybrid catalysts for cascade reaction in organic solvent. AB - In cooperative catalysis, the combination of chemo- and biocatalysts to perform one-pot synthetic route is a powerful tool for the improvement of chemical synthesis. Herein, UiO-66-NH2 was employed to stepwise immobilize Pd nanoparticles (NPs) and Candida antarctica lipase B (CalB) for the fabrication of biohybrid catalysts for cascade reaction. Distinct from traditional materials, UiO-66-NH2 has a robust but tunable structure which can be utilized with a ligand exchange approach to adjust its hydrophobicity, resulting in excellent catalyst dispersity in diverse reaction media. These attractive properties eventually contribute the MOF-based biohybrid catalysts with high activity and selectivity in the synthesis of benzyl hexanoate from benzaldehyde and ethyl hexanoate. With this proof-of-concept, we reasonably expect that future tailor-made MOFs can combine more other catalysts, ranging from chemical to biological catalysts for perspective applications in industry. PMID- 30475412 TI - Community structure dynamics and carbon stock change of rehabilitated mangrove forests in Sulawesi, Indonesia. AB - To date, discourse associated with the potential application of "blue carbon" within real-world carbon markets has focused on blue carbon as a mitigation strategy in the context of avoided deforestation (e.g., REDD+). Here, we report structural dynamics and carbon storage gains from mangrove sites that have undergone rehabilitation to ascertain whether reforestation can complement conservation activities and warrant project investment. Replicated sites at two locations with contrasting geomorphic conditions were selected, Tiwoho and Tanakeke on the island of Sulawesi, Indonesia. These locations are representative of high (Tiwoho, deep muds and silty substrates) and low (Tanakeke, shallow, coralline sands) productivity mangrove ecosystems. They share a similar management history of clearing and conversion for aquaculture before restorative activities were undertaken using the practice of Ecological Mangrove Rehabilitation (EMR). Species diversity and mean biomass carbon storage gains after 10 yr of regrowth from the high productivity sites of Tiwoho (49.2 +/- 9.1 Mg C.ha-1 .yr-1 ) are already almost of one-third of mean biomass stocks exhibited by mature forests (167.8 +/- 30.3 Mg C.ha-1 .yr-1 ). Tiwoho's EMR sites, on average, will have offset all biomass C that was initially lost through conversion within the next 11 yr, a finding in marked contrast to the minimal carbon gains observed on the low productivity, low diversity, coral atoll EMR sites of Tanakeke (1.1 +/- 0.4 Mg C.ha-1 .yr-1 ). These findings highlight the importance of geomorphic and biophysical site selection if the primary purpose of EMR is intended to maximize carbon sequestration gains. PMID- 30475413 TI - Cervico-vaginal secretion cytokine profile: A non-invasive approach to study the endometrial receptivity in IVF cycles. AB - PROBLEM: Cytokines have a significant role in the process of embryo implantation, trophoblast growth, and differentiation by modulating the immune and endocrine system. The aim of this study was to investigate the profile of a large set of cytokines in the cervico-vaginal washing of women undergoing IVF, to explore the association of these proteins with a good receptive endometrium. METHOD OF STUDY: A cohort of 155 women scheduled for IVF cycle was recruited. All patients were asymptomatic for genitourinary infections and had been screened for chlamydia, mycoplasma, and other bacterial infections. All IVF subjects were treated according to standard clinical and laboratory protocols. A panel of 48 immune factors was analyzed on cervico-vaginal washing, using magnetic bead-based multiplex immunoassays (Bio-Plex, BIO-RAD Laboratories, Milano, Italy). RESULTS: A total of 99 patients reached embryo transfer, of which 31 had a clinical pregnancy. A pattern of four pro-inflammatory immune molecules, IL-12p40, IFN-a, MIF, and MCP3 (P < 0.001), was found significantly up-regulated in the cervico vaginal fluid of women with clinical pregnancy. A significantly increased expression of IL-9, Groalpha , and SDF-1alpha (P < 0.05) was observed in the presence of endometriosis, while high levels of IL-13 and L-15 were associated with ovulatory infertility factor (P < 0.05). CONCLUSION: In this pilot study, we demonstrated that the expression of specific cytokines in the cervico-vaginal washing on the day of oocyte retrieval might have a positive correlation with the potential clinical pregnancy. Therefore, cervico-vaginal secretion cytokine profiling might be a new, non-invasive approach to study the endometrial receptivity in IVF management. PMID- 30475414 TI - Massive aneurysmal bone cyst of the skull base treated with denosumab. AB - BACKGROUND: Aneurysmal bone cysts are rare, benign expansile tumors most commonly involving long bones and vertebrae in patients younger than age 20. Skull base involvement is rare. Aneurysmal bone cysts shares radiological and histological features with other bone tumors, posing a diagnostic challenge. METHODS/RESULTS: We report the case of a 32-year-old man who presented with facial pain, epistaxis, and cranial neuropathies secondary to a massive tumor of the maxillary sinus and anterior skull base. The tumor was originally misdiagnosed as osteosarcoma. However, genomic analysis revealed a rearrangement in the USP6 gene, elucidating a diagnosis of primary aneurysmal bone cysts. The patient was treated with denosumab. Within 5 months, the patient was asymptomatic with CT showing ossification of the tumor. CONCLUSIONS: This case highlights (1) the utility of genomic analysis in aggressive bone tumors when the diagnosis is unclear and (2) the effectiveness of denosumab as a treatment for aneurysmal bone cysts when surgical resection is unfavorable. PMID- 30475415 TI - Treating hepatitis C virus in dialysis patients: How, when, and why? AB - The identification of hepatitis C virus (HCV) occurred in 1989, and soon thereafter, it was recognized that there was a higher prevalence of anti-HCV seropositivity in patients with end-stage renal disease (ESRD) when compared to the general population. Multiple extrahepatic manifestations have been associated with HCV infection in patients with ESRD; these include an increased prevalence and risk of cardiovascular complications, insulin resistance, diabetes mellitus, and lymphoproliferative disorders. Infection with HCV has also been associated with an increased relative risk of mortality in the ESRD patient when contrasted to those patients without infection. The availability of second-generation direct acting antiviral agents has revolutionized the treatment of HCV in both the general population as well as those patients with advanced chronic kidney disease and receiving dialysis. These new treatment protocols are very well tolerated with limited side effects and manageable drug-drug interactions while achieving remarkable sustained viral response rates. It is important that nephrologists become familiar with the differing strategies available for HCV-infected ESRD patients so that the appropriate decision of when and who to treat can be made for each patient. PMID- 30475416 TI - Operative technique: Lateral neck dissection. PMID- 30475417 TI - H2 activation in [FeFe]-hydrogenases cofactor vs diiron dithiolate models: factors underlying the catalytic success of Nature and implications for an improved biomimicry. AB - Catalytic H2 oxidation has been dissected by DFT in the key steps common both to the Fe2 unit of the [FeFe]-hydrogenase cofactor and to selected biomimicry. The aim was to elucidate molecular details underlying the very different performances of the two systems. We found out that the higher enzyme performance is based on a single Fe atom that is maintained electron-poor, favoring H2 binding, although embedded within a highly electron rich cofactor, ensuring a facile oxidation of the Fe2-H2 adduct. That is due to: i) CN- that coordinate both Fe's, due to their amphipathic Lewis acid-base properties and ii) the 4Fe4S subunit further withdrawing electrons from the Fe2 core. Preserving a moderate electron deficiency at a single Fe also helps cofactor preserve hydride affinity, that favors the H2 cleavage. Such valuable characteristics allow the bio-catalyst to turnover close to equilibrium conditions. All previous biomimicry show, in contrast, the impossibility to properly balance the two apparently contrasting aforementioned requisites, although evident progresses have been made by H2-ase community. Disclosure of the differences identified could inspire the design of novel biomimicry, for instance reconsidering the use of CN- in the catalyst architecture. Indeed, in the presence of bases normally employed in oxidative catalysis, undesired stable protonation at coordinated CN-, which affects the opposite process (proton reduction), could be overcome. PMID- 30475418 TI - Mapping discourse coalitions in the Minimum Unit Pricing for alcohol debate: A discourse network analysis of UK newspaper coverage. AB - BACKGROUND AND AIM: Minimum Unit Pricing (MUP) for alcohol was introduced in Scotland on 1 May 2018 and is now on the policy agenda in other devolved administrations and at Westminster. Previous research has explored the arguments deployed for and against MUP, but the congruence between actors in the MUP debate has not been sufficiently examined. This study identified and mapped the discourse coalitions that emerged in the UK MUP debate through an analysis of actors' use of arguments in media coverage of the policy debates. DESIGN: A sample of print media coverage of MUP was obtained from the LexisNexis newspaper database. The resulting sample was imported into discourse network analysis (DNA) software for coding and subsequent visualisation of actor networks. SETTING: United Kingdom. OBSERVATIONS: 348 articles from eight UK-wide and three Scottish newspapers from an 18-month period, ending in November 2012, were analysed. MEASUREMENTS: Actors' arguments were coded to generate structured data for conversion into a weighted actor network where ties represent similarities among actors in terms of arguments in support of or opposition to MUP. FINDINGS: Two polarised discourse coalitions, Opponents and Proponents of MUP, emerged in media coverage. The Proponents coalition consisted mainly of health advocacy groups, charities, political parties and academic institutions. In the Opponents coalition, the networks were formed of key alcohol manufacturers and economic think-tanks. Whilst producer organisations were central to the Opponents coalition, some commercial actors were more favourable to MUP highlighting divisions within the industry overall. CONCLUSIONS: Media coverage of Minimum Unit Pricing (MUP) in Scotland from June 2011 to November 2012 showed alignment between the policy positions of 1) alcohol producers and think-tanks opposed to MUP; and 2) public health advocates and health charities in favour of the policy. Some alcohol industry actors were supportive of MUP indicating divisions amongst the industry. Discourse network analysis may be usefully applied to study other highly contested policy issues in health and beyond. PMID- 30475419 TI - Parental views on the principles for cluster randomised trials involving neonates and infants. AB - The European Foundation for the Care of Newborn Infants (EFCNI) is the first pan European organisation and network to represent the interests of preterm and newborn infants and their families. The Foundation brings together parents, healthcare experts from different disciplines and scientists with the common goal of improving the long-term health of preterm and newborn infants. It does this by ensuring that infants receive the best possible prevention, treatment, care and support, based on the best available evidence, which has ideally been proven in high-quality randomised, controlled clinical trials (1). This article is protected by copyright. All rights reserved. PMID- 30475421 TI - Direct acting anti-viral medications for hepatitis C: Clinical trials in patients with advanced chronic kidney disease. AB - Hepatitis C is a global health concern, with important implications in chronic kidney disease (CKD) due to its increased prevalence in this population. Patients with advanced CKD have until recently been excluded from the pivotal direct acting anti-viral (DAA) trials, which have demonstrated high virological cure numbers. Sofosbuvir-free DAAs dasabuvir, ombitasvir/paritaprevir/ritonavir with or without ribavirin, and elbasvir/grazoprevir are well-tolerated in patients with genotype 1 and 4 CHC with CKD 4 or 5 (including HD), with virologic cure rates of above 90%, in both single-arm and placebo-controlled studies. More recently a pangenotypic approach using glecaprevir and pibrentasvir has also been shown to be highly effective in CKD 4-5. With increasingly successful treatment options with minimal side-effects most hepatitis C virus (HCV)-infected patients with CKD and ESRD can be cured. Outstanding issues to be considered is how to raise the awareness of the availability of safe DAAs and excellent outcomes in CKD, and moreover to define optimal timing of treatment and address the question of HCV eradication in all stages of CKD including the dialysis population. PMID- 30475420 TI - Comparison of Three Different Stents for EUS-guided Drainage of Pancreatic Fluid Collection: A Large Retrospective Study. AB - BACKGROUND AND OBJECTIVE: Endoscopic transmural drainage has been recognized as the first-line treatment for pancreatic fluid collection (PFC). Currently, three different types of stents have been extensively applied, including double pigtail plastic stent (PS), fully covered self-expanding metal stent (FCSEMS) and novel lumen-apposing metal stent (LAMS). Nonetheless, limited data are available about the comparison among them in terms of their clinical outcomes and safety for endoscopic ultrasound (EUS)-guided drainage of PFC. METHODS: The current retrospective study was carried on 160 PFC patients undergoing EUS-guided drainage from 2010 to 2018 at a single tertiary care center. Patients were divided into 3 groups based on different drainage ways: drainage using PS, FCSEMS or LAMS. RESULTS: A total of 160 PFC patients (104 male, 56 female) were analyzed in this retrospective study, including 62 patients drained with PS, 28 with FCSEMS and 70 with LAMS. Typically, the technical success (93.5% vs 96.4% vs94.3%, P=1.000) and treatment success rates (84.6%vs 85.2% vs 89.2%, P=0.763) were similar between PS, FCSEMS and LAMS. With regard to major AEs, 4 patients (FCSEMS: n=2, and LAMS: n=2) with pseudoaneurysms developed severe bleeding, among them, 75%(3/4) patients were observed within 2 weeks after intervention and 2 patients in LAMS group died. CONCLUSIONS: There are no significant differences in the clinical outcomes of PFC patients treated with PS, FCSEMS or LAMS. Nonetheless, severe (or even fatal) bleeding may occur at the early stage after metal stent placement, which should be paid particular attention to. PMID- 30475422 TI - Competitive metal-coordination of hexaaminotriphenylene on Cu(111) by intrinsic copper versus extrinsic nickel adatoms. AB - The interplay between self-assembly and surface chemistry of 2,3,6,7,10,11 hexaminotriphenylene (HATP) on Cu(111) was complementarily studied by high resolution Scanning-Tunneling-Microscopy (STM) and X-ray Photoelectron Spectroscopy (XPS) under ultra-high vacuum conditions. To shed light on competitive metal-coordination, comparative experiments were carried out on pristine and nickel-covered Cu(111). Directly after room temperature deposition of HATP onto pristine Cu(111) self-assembled aggregates were observed by STM, while XPS indicated non-deprotonated amino groups. Annealing up to 200 degrees C activated the progressive single deprotonation of all amino groups as indicated by chemical shifts of both N 1s and C 1s core levels in the XP spectra. This enabled the formation of topologically versatile pi-d conjugated coordination networks with intrinsic copper adatoms. The basic motif of these networks was a metal-organic trimer, where three HATP molecules were coordinated by Cu3 clusters, as corroborated by accompanying Density Functional Theory (DFT) simulations. Additional deposition of more reactive nickel atoms resulted in both chemical and structural changes with deprotonation and formation of bis(diimino) Ni bonded networks already at room temperature. Even though fused hexagonal pores were observed, extended honeycomb networks remained elusive, as tentatively explained by a restricted reversibility of these metal-organic bonds. PMID- 30475423 TI - Weakly Coordinating Ketone-Directed Cp*Co(III)- and Cp*Rh(III)-Catalyzed C-H Amidation of Arenes: A Route to Acridone Alkaloids. AB - Weakly coordinating, ketone-directed, regioselective mono-amidation of aromatic ketones, chalcone, carbazole, and benzophenones are achieved employing high valent cobalt- and rhodium-catalysis to access numerous biologically important molecular building blocks. This amidation proceeds smoothly with varieties of ketones as well as with several amidating partners. The application of the products to the syntheses of heterocycles acridones, indoles, quinoline, quinolones, quinolinones, and quinazolines is also described. The total syntheses of acridone based alkaloids, namely toddaliopsin A, toddaliopsin D, arborinine, and formal syntheses of acronycine and noracronycin have also been accomplished applying this method. The mechanistic study reveals this amidation reaction follows a base assisted intermolecular electrophilic substitution (BIES) pathway. PMID- 30475424 TI - Non-failure blood flow restricted exercise induces similar muscle adaptations and less discomfort than failure protocols. AB - Low-load blood flow restricted resistance exercise (BFRE) performed to volitional failure is suggested to constitute an effective method for producing increases in muscle size and function. However, failure BFRE may entail high levels of perceived exertion, discomfort and/or delayed onset of muscle soreness (DOMS). The aim of the study was to compare BFRE performed to volitional failure (F-BFRE) vs non-failure BFRE (NF-BFRE) on changes in muscle size, function and perceptual responses. Fourteen young untrained males had one leg randomized to knee extension F-BFRE while the contralateral leg performed NF-BFRE. The training consisted of 22 training bouts over an 8-week period. Whole-muscle cross sectional area (CSA) of quadriceps components, muscle function, and DOMS were assessed before and after the training period. Perceived exertion and discomfort were registered during each training bout. Both F-BFRE and NF-BFRE produced regional increases in muscle CSA in the range of; quadriceps (2.5-3.8%), vastus lateralis (8.1-8.5%), and rectus femoris (7.9-25.0%). All without differences between leg. Muscle strength (6.8-11.5%) and strength-endurance capacity (13.9 18.6%) also increased to a similar degree in both legs. Less perceived exertion, discomfort and DOMS were reported with NF-BFRE compared to F-BFRE. In conclusion, non-failure BFRE enable increases in muscle size and muscle function, while involving reduced perceptions of exertion, discomfort and DOMS. Non-failure BFRE may be a more feasible approach in clinical settings. This article is protected by copyright. All rights reserved. PMID- 30475425 TI - ESRD patients coinfected with human immunodeficiency virus and Hepatitis C: Outcomes and management challenges. AB - HIV infection is a major public health problem worldwide. Due to shared modes of acquisition, many HIV+ patients are coinfected with Hepatitis C. HIV/HCV coinfected patients have an increased burden of chronic kidney disease and are more likely to progress to end-stage renal disease. Dialysis survival is diminished in the coinfected population, even in the contemporary era. Kidney transplantation offers a survival benefit over remaining on dialysis; however, posttransplant outcomes are inferior compared to patients with HIV infection alone. Direct acting antiviral agents may offer an opportunity to improve patient survival, but there are significant drug-drug interactions involving the direct acting antiviral agents, antiretroviral therapy, and immunosuppression that the clinician should be aware of. PMID- 30475426 TI - ERRATUM. PMID- 30475427 TI - Relative reactivity to egg white and yolk or change upon heating as markers for baked egg tolerance. AB - BACKGROUND: Hen's egg food allergy is frequent in childhood and phenotypically heterogeneous. Some children can tolerate extensively heated egg. We investigated whether individual relative responses could differentiate children who tolerate baked egg. METHODS: Reactivities to raw, pasteurized or hard-boiled egg (E), egg white (EW) and egg yolk (EY) fractions were tested by skin prick test (SPT) in 54 egg-allergic children. IgE-sensitization to EW and EY was determined by ImmunoCAP and IgE-binding to EW and 8 EW proteins and to EY and 4 EY sub-fractions by ELISA. Population heterogeneity was assessed by hierarchical ascending classification upon individual variations of reactivity and links between classifications and clinical features by analyzing the contingency tables. RESULTS: All children had positive SPT to raw E and raw EW and 72% to raw EY. Heating decreased SPT reactivity for some children, pasteurization being less effective than hard-boiling. Children were classed into three classes from relative SPT-reactivity to raw fractions, two from variations of SPT-reactivity with each thermal processing or EW/EY ratio of sensitization and four from their sensitization pattern. Classifications according to heating were found independent of each other. SPT variations with hard-boiling, IgE-sensitization (ratio or pattern) were linked to allowance by the physicians of egg in baked products. CONCLUSIONS: Egg-allergic children were often both sensitized to EY and EW and heterogeneous patterns of relative responses were evidenced. Irrespective of age and level of sensitization, a low EW/EY ratio or SPT getting null with hard-boiling were found in children allowed to eat baked egg. This article is protected by copyright. All rights reserved. PMID- 30475428 TI - Pharmacokinetics of plasma infusion in congenital thrombotic thrombocytopenic purpura. AB - BACKGROUND: Congenital thrombotic thrombocytopenic purpura (TTP) is defined by persistent severe deficiency of ADAMTS-13 in the absence of anti-ADAMTS-13 inhibitory antibodies, confirmed by mutational analysis. Replacement of the missing protease prevents disease relapse, primarily using plasma infusion (PI). OBJECTIVES, PATIENTS AND METHODS: There is scant evidence regarding optimal dose and frequency of treatment, tending to be empirically guided. We present a pharmacokinetic analysis of ADAMTS-13 in 6 patients with congenital TTP on established regimes following PI. RESULTS: We found a median clearance of 25.41ml/h and half-life of 130 hours, ranging between 82.6 and 189.5 hours (3.4 to 7.9 days respectively). All patients reached baseline ADAMTS-13 level within 7 10 days post plasma. Median ADAMTS-13 activity peak post PI was 24.05IU/dL. Variation was related to elimination rate, in turn affected by weight and metabolism, but not to von Willebrand factor antigen or activity levels. Using the pharmacokinetic parameters, we simulated individualised protocols based on PI dose or frequency to target hypothetical optimal plasma levels of ADAMTS-13 of 10 and 50IU/dL respectively. Results suggest a target trough ADAMTS-13 of 10IU/dL is feasible but 50IU/dL would not be achievable taking into account volume required. CONCLUSIONS: Further work is needed to compare treatment of congenital TTP with PI versus recombinant ADAMTS-13. PI may provide longer duration of ADAMTS-13 effect, but is limited by plasma volume required, whereas recombinant therapy can provide a higher ADAMTS-13 peak. We propose that investigation of interindividual clearance of ADAMTS-13 is necessary to optimise treatment, to enable rationale for dose and frequency of prophylaxis. This article is protected by copyright. All rights reserved. PMID- 30475429 TI - What is early intervention in bipolar disorder? - Recommendation of a pragmatic way focusing on early intervention in patients with newly diagnosed bipolar disorder. Commentary on the Debate around Malhi et al.'s paper "Is "early intervention" in bipolar disorder what it claims to be?" AB - Malhi etal. in their review discuss that, while early intervention in bipolar disorder is a desirable objective, at present important gaps in our knowledge make this difficult to implement. Accordingly, Duffy and Grof in a commentary conclude that given the state of evidence for emerging bipolar disorder, recommending early intervention in general is premature as the target population of individuals at high risk and the interventions are not well-defined. Consequently, the need for research within high-risk populations is highlighted and, in the meantime, caution is recommended. This article is protected by copyright. All rights reserved. PMID- 30475431 TI - Influence of restorative margins position on one-stage laser-microgrooved implants-supported single screwed crowns: A clinical, biochemical, and microbiological analysis. AB - AIM: To clinically, biochemically, and microbiologically evaluate the influence of crown margins position on one-stage laser-microgrooved implants. MATERIALS AND METHODS: Twenty-one-stage titanium implants with a laser-microgrooved collar surface, supporting screwed, single crown restorations, were placed in 20 partially edentulous patients and evaluated. Clinical parameters included modified plaque index, modified gingival index, peri-implant probing pocket depth, bleeding on probing, and distance between implant shoulder and mucosal margin. The parameters were recorded at baseline (crowns delivery) and at every 6 month recall visit, until the end of the 3 years follow-up period. At the same time intervals, radiographic marginal bone levels were assessed at the mesial and distal aspect of the implant sites. For biochemical analysis, the volume of the peri-implant sulcus fluid, and its levels of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and of tumor necrosis factor-alpha, were utilized to evaluate the peri-implant health conditions at the end of the 3-year follow-up period. At the same time, microbiological analysis, including the concentration of five putative periodontal pathogens (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Treponema denticola, and Tannerella forsythensis), were assessed. The crown margins positions were classified into four groups (A = intracrevicular position >2 mm, B = intracrevicular position <=2 mm/<1 mm, C = intracrevicular position <=1 mm/<0 mm, and D = extracrevicular position), and the biochemical, and microbiological parameters were evaluated at 3 years. RESULTS: No statistical differences of clinical and biochemical parameters were found between the four groups. In group A, compared to groups B, C, and D, a statistically significant higher concentration of putative periodontal pathogens was found. CONCLUSIONS: Results showed that the intracrevicular deeper position of the restoration margin does not influence the clinical and biochemical peri-implant parameters. The deeper position of the crown margin is associated with a greater amount of putative periodontal pathogenic microflora colonization. PMID- 30475430 TI - Differences between unipolar mania and bipolar-I disorder: Evidence from nine epidemiological studies. AB - OBJECTIVES: Although clinical evidence suggests important differences between unipolar mania and bipolar-I disorder (BP-I), epidemiological data are limited. Combining data from 9 population-based studies, we compared subjects with mania (M) or mania with mild depression (Md) to those with BP-I with both manic and depressive episodes with respect to demographic and clinical characteristics in order to highlight differences. METHODS: Participants were compared for gender, age, age at onset of mania, psychiatric comorbidity, temperament and family history of mental disorders. Generalized Linear Mixed Models with adjustment for sex and age as well as for each study source were applied. Analyses were performed for the pooled adult and adolescent samples, separately. RESULTS: Within the included cohorts, 109 adults and 195 adolescents were diagnosed with M/Md and 323 adults and 182 adolescents with BP-I. In both adult and adolescent samples, there was a male preponderance in M/Md, whereas lifetime generalized anxiety and/panic disorders and suicide attempts were less common in M/Md than in BP-I. Furthermore, adults with mania revealed bulimia/binge eating and drug use disorders less frequently than those with BP-I. CONCLUSIONS: The significant differences found in gender and comorbidity between mania and BP-I suggest that unipolar mania, despite its low prevalence, should be established as a separate diagnosis both for clinical and research purposes. In clinical settings, the rarer occurrence of suicide attempts, anxiety and drug use disorders among individuals with unipolar mania may facilitate successful treatment of the disorder and lead to a more favorable course than that of BP-I disorder. This article is protected by copyright. All rights reserved. PMID- 30475432 TI - A practical guide to developing virtual and augmented reality exercises for teaching structural biology. AB - Although virtual and augmented reality (VR and AR) techniques have been used extensively in specialized laboratories, only recently did they become affordable, reaching wider consumer markets. With increased availability, it is timely to examine the roles that VR and AR may play in teaching structural biology and in experiencing complex data sets such as macromolecular structures. This guide is suitable for those teachers of structural biology who do not have a deep knowledge of information technologies. This study focuses on three questions: 1) How can teachers of structural biology produce and disseminate VR/AR-ready educational material with established and user-friendly software tools?; 2) What are the positive and negative experiences reported by test participants when performing identical learning tasks in the VR and AR environments?; and 3) How do the test participants perceive prerecorded narration during VR/AR exploration? (c) 2018 International Union of Biochemistry and Molecular Biology, 1-9, 2018. PMID- 30475433 TI - Teaching metabolism with scientific articles: A new approach. AB - Scientific articles have been explored as a didactic resource in the teaching of Biochemistry, as well as in other areas of science. This teaching strategy contributes to the learning and understanding of specific concepts, and development of the skills, necessary for the research training of students. The present study investigated the use of scientific articles in the Topics in Metabolism course, which was offered to Biochemistry graduate students, at the University of Sao Paulo. Instead of lectures and seminars, two main activities were used: directed study (DS) and discussion groups (DG). Both utilized and explored high impact publications with a recognized quality of intellectual production. In this active learning environment, the objective was to evaluate the perception of the students regarding the teaching strategy, and the level of effort each student expended to understand the course material. Data collection involved using the responses to open and closed questions, from two questionnaires. Then the Pirouette software was employed to perform the Hierarchical Cluster Analysis (HCA). The results indicated that 78% of the students had a positive perception of the teaching strategy and struggled less to understand the course material. On the other hand, 22% of the students had a less positive perception of the strategy and displayed a less intense course engagement. Ultimately, the results presented in the present study indicate that the adoption of this teaching strategy can help graduate students to develop the ability to read critically and thoroughly understand scientific materials, which are fundamental skills for future researchers. (c) 2018 International Union of Biochemistry and Molecular Biology, 1-7, 2018. PMID- 30475434 TI - Bone marrow lesions of the distal condyles of the third metacarpal bone are common and not always related to lameness in sports and pleasure horses. AB - The metacarpophalangeal joint is a common site of pain in horses. Little information is available about bone marrow lesions in the distal condyles of the third metacarpal bone in sports and pleasure horses. Aims of this prospective, retrospective, observational study were to evaluate the prevalence of bone marrow lesions in the distal condyles of the third metacarpal bone, to describe their anatomic distribution and to correlate lesions with the presence of lameness and the level and type of activity. All sports and pleasure horses undergoing standing low-field MRI of the front fetlock region between 2009 and 2016 were included and divided into three lameness groups according to the results of diagnostic analgesia. Bone marrow lesions were analyzed and graded by one reader. Grades were compared between anatomical locations and between lameness groups. A total of 166 horses were sampled. The prevalence of bone marrow lesions was 76.5% (127/166). The dorsal aspects of the medial condyle (31%, 39/127) and of the sagittal ridge (28%, 36/127) were the most commonly affected locations. There was no significant difference between both forelimbs (lame limb and non-lame limb) of the same horse. Lesion severity was neither significantly associated with the lameness group nor with the type or level of activity. The prevalence of bone marrow lesions in the distal condyles of the third metacarpal bone is high in this population and the clinical significance is not always clear. Further studies are required to elucidate the clinical significance of this finding in sports and pleasure horses. PMID- 30475435 TI - Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities. AB - Polyamines serve a number of vital functions in humans, including regulation of cellular proliferation, intracellular signaling, and modulation of ion channels. Ornithine decarboxylase 1 (ODC1) is the rate-limiting enzyme in endogenous polyamine synthesis. In this report, we present four patients with a distinct neurometabolic disorder associated with de novo heterozygous, gain-of-function variants in the ODC1 gene. This disorder presents with global developmental delay, ectodermal abnormalities including alopecia, absolute or relative macrocephaly, and characteristic facial dysmorphisms. Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow-Robin spaces, periventricular cysts, and abnormalities of the corpus callosum. Plasma clinical metabolomics analysis demonstrates elevation of N-acetylputrescine, the acetylated form of putrescine, with otherwise normal polyamine levels. Therapies aimed at reducing putrescine levels, including ODC1 inhibitors, dietary interventions, and antibiotics to reduce polyamine production by gastrointestinal flora could be considered as disease-modifying therapies. As the ODC1 gene has been implicated in neoplasia, cancer surveillance may be important in this disorder. PMID- 30475436 TI - Structural imaging biomarkers for bipolar disorder: Meta-analyses of whole-brain voxel-based morphometry studies. AB - BACKGROUND: Bipolar disorder (BD) is a common and destructive psychiatric illness worldwide. Although it is known that BD is associated with morphological abnormalities of the brain, the regions implicated in BD remain unclear. Therefore, we aimed to update current knowledge on potential structural imaging biomarkers of BD. METHODS: Studies published up to January 31, 2018, were identified by a comprehensive literature search of PubMed, EBSCO, and BrainMap voxel-based morphometry (VBM) database. Whole-brain VBM studies that examined gray matter (GM) abnormalities of group comparisons between BD and healthy controls (HC) and reported results as coordinates in a standard reference space were included. Different meta-analyses were performed by activation likelihood estimation (ALE) algorithm. RESULTS: A total of 46 studies with 56 experiments, including 1720 subjects and 268 foci were included. Seven different meta-analyses were calculated separately across experiments reporting decreased or increased GM volume among BD, BDIota, BD-adults, and BD-youths groups. Fifteen regions of significantly different GM volume between four groups and HC were identified. There were extensive GM deficits in the prefrontal and temporal cortex, and enlargements in the putamen, cingulate cortex, and precuneus. CONCLUSIONS: The results revealed that the thinning of prefrontal cortex was a key region in the pathophysiology of BD. The enlargement of the cingulate cortex may be implicated in a compensatory mechanism. It underscored important differences between BD adults and BD-youths and specific biomarkers of three subgroups. PMID- 30475438 TI - Multimodality fMRI with perfusion, diffusion-weighted MRI and 1 H-MRS in the diagnosis of lympho-associated benign and malignant lesions of the parotid gland. AB - BACKGROUND: Differential diagnosis of the mucosa-associated lymphoid tissue lymphoma (MALToma) and tumor-like benign lymphoepithelial lesion (BLEL) in the parotid gland is difficult. PURPOSE: To distinguish MALToma and BLEL with multimodality MRI including hydrogenproton magnetic resonance spectroscopy (1 H MRS), diffusion-weighted imaging (DWI-MR), and dynamic contrast-enhanced (DCE MR), and evaluate each sequence. STUDY TYPE: Retrospective. POPULATION: Twenty five patients with parotid tumor-like BLEL and 20 with parotid MALToma. FIELD STRENGTH/SEQUENCE: 1.5-T/T1 WI, T2 WI, single-voxel 1 H-MRS, DWI-MR, and DCE-MR. ASSESSMENT: All MR images were interpreted and agreed upon by two radiologists who were blinded to clinical information and histopathologic results. The imaging diagnoses were then compared to the histopathologic results. STATISTICAL TESTS: Youden index was used to determine the optimized threshold value. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic efficiency of different functional (f)MRI methods. RESULTS: Fisher's exact test indicated a significant difference between the 1 H-MRS images of the two lesions (P < 0.001). The sensitivity, specificity, and accuracy of positive choline (Cho) peak in 1 H-MRS of parotid MALToma were 80%, 76%, and 77.7%, respectively. The mean apparent diffusion coefficient (ADC) was 0.992 * 10-3 mm2 /s in patients with parotid tumor-like BLEL and 0.634 * 10-3 mm2 /s in patients with parotid MALToma, and the difference was statistically significant (t-test, P < 0.001). Choosing the Youden index as 0.669 * 10-3 mm2 /s, the sensitivity, specificity, and accuracy of the assay were 78.9%, 95.8%, and 88.4%, respectively. Assuming that time-intensity curve (TIC) type I indicated parotid MALToma (positive), and type II and type III indicated parotid tumor-like BLEL (negative), the sensitivity, specificity, and accuracy of time-to-peak (TTP) and initial slope of increase (ISI) in diagnosing MALToma were 94.1%, 95.2%, and 94.7%, respectively. Combining methods of TTP, ADC, and Cho peak reached the highest AUC (1.000). DATA CONCLUSION: Combined use 1 H-MRS, DWI-MR, and DCE-MR increased the accuracy of the differential diagnosis between these lesions to 100%. Cho peak in 1 H-MRS, ADC less than 0.669 * 10-3 mm2 /s, TIC type I together indicated parotid MALToma. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30475437 TI - Catalytic Enantioselective Intramolecular C(sp3)-H Amination of 2 Azidoacetamides. AB - An enantioselective ring-closing C(sp3)-H amination of 2-azidoacetamides is catalyzed by a chiral-at-metal ruthenium complex and provides chiral imidazolidin 4-ones in 31-95% yield, with enantioselectivities up to 95% ee, and catalyst loadings down to 0.1 mol% (740 TON). To our knowledge, this is the first example of a highly enantioselective C(sp3)-H amination with aliphatic azides. Mechanistic experiments reveal the importance of the amide group presumably by enabling an initial bidentate coordination of the 2-azido acetamides to the catalyst. DFT calculations show that the transition state leading to the major enantiomer features a better steric fit and favorable pi-pi stacking between the substrate and the catalyst framework. PMID- 30475439 TI - Contrast-enhanced ultrasonography characteristics of intrathoracic mass lesions in 36 dogs and 24 cats. AB - Contrast-enhanced ultrasonography (CEUS) is increasingly available for veterinary patients, however limited studies describe the use of this method for characterizing intrathoracic mass lesions. The aim of this prospective, observational study was to describe CEUS enhancement patterns for intrathoracic mass lesions in a sample of cats and dogs. Sixty patients (36 dogs, 24 cats) were included. Standardized CEUS examinations were performed for 41 pulmonary masses (68%) and 19 mediastinal masses (32%). Final diagnosis was based on cytology and/or histopathology. Absolute time to enhancement (TTE) values were recorded for the intrathoracic mass lesions and spleen. The spleen was used as a reference parenchymal organ to calculate relative TTE (rTTE) values. Absolute TTE of the spleen and intrathoracic mass lesions differed for dogs and cats (P = 0.001). The rTTE values significantly differed between lesions of neoplastic versus non neoplastic origin (P = 0.004). The majority of neoplastic pulmonary masses were supplied by bronchial arteries (63%), while most nonneoplastic pulmonary masses were supplied by pulmonary arteries (78%). The sensitivity and specificity for detecting pulmonary neoplastic masses with rTTE were 63% and 78%, respectively. Enhancement patterns for mediastinal thymomas and lymphomas significantly differed (P = 0.002). Thymomas enhanced heterogeneously in a centripetal pattern (86%), whereas lymphomas typically enhanced uniformly in a centrifugal pattern (75%). Findings indicated that CEUS is a feasible method for characterizing intrathoracic mass lesions in dogs and cats, however, the diagnostic sensitivity for detecting neoplastic pulmonary masses was low. PMID- 30475440 TI - Combined liver-kidney transplantation for primary hyperoxaluria type I in children: Single Center Experience. AB - Primary hyperoxalurias are rare inborn errors of metabolism with deficiency of hepatic enzymes that lead to excessive urinary oxalate excretion and overproduction of oxalate which is deposited in various organs. Hyperoxaluria results in serious morbid-ity, end stage kidney disease (ESKD), and mortality if left untreated. Combined liver kidney transplantation (CLKT) is recognized as a management of ESKD for children with hyperoxaluria type 1 (PH1). This study aimed to report outcome of CLKT in a pediatric cohort of PH1 patients, through retrospective analysis of data of 8 children (2 girls and 6 boys) who presented by PH1 to Wadi El Nil Pediatric Living Related Liver Transplant Unit during 2001 2017. Mean age at transplant was 8.2 +/- 4 years. Only three of the children underwent confirmatory genotyping. Three patients died prior to surgery on waiting list. The first attempt at CLKT was consecutive, and despite initial successful liver transplant, the girl died of biliary peritonitis prior to scheduled renal transplant. Of the four who underwent simultaneous CLKT, only two survived and are well, one with insignificant complications, and other suffered from abdominal Burkitt lymphoma managed by excision and resection anastomosis, four cycles of rituximab, cyclophosphamide, vincristine, and prednisone. The other two died, one due to uncontrollable bleeding within 36 hours of procedure, while the other died awaiting renal transplant after loss of renal graft to recurrent renal oxalosis 6 months post-transplant. PH1 with ESKD is a rare disease; simultaneous CLKT offers good quality of life for afflicted children. Graft shortage and renal graft loss to oxalosis challenge the outcome. PMID- 30475442 TI - Potential risk factors for maxillary sinus membrane perforation and treatment outcome analysis. AB - BACKGROUND: Most common complication of sinus floor elevation (SFE) is sinus membrane perforation (SMP). PURPOSE: To investigate the correlation between SMP and potential risk factors and to evaluate SMP treatment outcomes. MATERIALS AND METHODS: This study included patients who had undergone a SFE at Division of Oral Surgery and Orthodontics, Medical University of Graz from 2013 to 2017. Analysis of patients' records and CBCT focused on patient-related risk factors (sinus contours, thickness of membrane and lateral sinus wall, interfering septa, crossing vessels, former oroantral communication) and intervention-related risk factors (surgical approach, sides, number of tooth units, and sites). The outcome of SMP treatment was analyzed in the recalls. RESULTS: In all, 121 patients underwent 137 SFE. There were 19 cases of SMP (13.9%). Two significant factors were identified: maxillary sinus contours (P = .001) and thickness of the sinus membrane (P = .005). The sinus membrane perforation rate was highest in narrow tapered sinus contours and when the sinus membrane was thinner than 1 mm. Among 19 cases with SMP, no complications were seen upon recall. CONCLUSIONS: Maxillary sinus contours and sinus membrane thickness seem to be relevant factors for SMP. Sinus membrane perforations were successfully treated by coverage with collagen membrane. PMID- 30475441 TI - Electrocardiography-gated cardiac CT angiography can differentiate brachycephalic dogs with and without pulmonary valve stenosis and findings differ from transthoracic echocardiography. AB - Pulmonary valve stenosis (PS) is one of the most commonly diagnosed congenital heart defects in dogs. Currently, transthoracic echocardiography (TTE) is the standard modality used to evaluate PS. Image acquisition by TTE can be challenging in some brachycephalic breeds of dogs. The use of echocardiographic gated CT angiography (ECG-gated CTA) in veterinary medicine is limited. This retrospective method comparison study investigated right and left ventricular outflow diameters by sedated ECG-gated CTA and unsedated TTE in 14 brachycephalic dogs with PS and 12 brachycephalic dogs without PS. Measurements of ventricular outflow structures were made in early systole and end diastole for both modalities and then compared for significance between systolic and diastolic phases, as well as between the two modalities. Ratios of the pulmonary trunk diameter to the aorta at different locations (aortic valve, aortic annulus, and ascending aorta) and in different planes (transverse, sagittal) were compared between dogs with PS and without PS, as well as within dogs, by both TTE and ECG gated CTA. Transthoracic echocardiography and ECG-gated CTA both detected significantly greater pulmonary trunk to aorta ratios in dogs with PS at all aortic locations (P < 0.05). Pulmonary valve to aortic valve ratios were significantly smaller in dogs with PS (P < 0.05). Pulmonary trunk to aorta and pulmonary valve to aorta ratios were achieved with good anatomic detail using ECG gated CTA. Ratios of the pulmonary trunk and pulmonary valve relative to the aorta may be useful to evaluate for PS using a modality that is underutilized for cardiac assessment. PMID- 30475443 TI - The accuracy of computer-based diagnostic tools for the identification of concurrent genetic disorders. AB - The increasing use of next-generation sequencing, especially clinical exome sequencing, has revealed that individuals having two coexisting genetic conditions are not uncommon occurrences. This pilot study evaluates the efficacy of two methodologically distinct computational differential diagnosis generating tools-FindZebra and SimulConsult-in identifying multiple genetic conditions in a single patient. Clinical query terms were generated for each of 15 monogenic disorders that were effective in resulting in the top 10 list of differential diagnoses for each of the 15 monogenic conditions when entered into these bioinformatics tools. Then, the terms of over 125 pairings of these conditions were entered using each tool and the resulting list of diagnoses evaluated to determine how often both diagnoses of a pair were represented in that list. Neither tool was successful in identifying both members of a pair of conditions in greater than 40% of test cases. Disorder detection sensitivity was not homogeneous within a tool, with each tool favoring the identification of a subset of genetic conditions. In view of recent exome sequencing data showing an unexpectedly high prevalence of coexistent monogenic conditions, the results from this pilot study highlight a need for the development of computational tools designed to effectively generate differential diagnoses with consideration of the possibility of coexisting conditions. PMID- 30475444 TI - Bottom-up Construction and Reversible Structural Transformation of Supramolecular Isomers based on Large Truncated Tetrahedra. AB - Controllable assembly and structural transformation of supramolecular isomers remains an inherent challenge in crystal engineering. Here, we develop a rational synthetic strategy to construct two supramolecular isomers based on polyoxovanadate organic polyhedra with tetrahedral symmetries. VMOP-alpha, a product of low-temperature, has an extremely large cell volume (466142 A3), which is one of the top three for well-defined MOPs. The "corner-to-corner" packing of tetrahedra leads to a pretty low density of 0.176 g/cm3 with 1D channels about 5.4 nm. The effective pore volume is up to 93.9% of cell volume, nearly the largest ever found in MOPs. While for the high-temperature outcome VMOP-beta, the cell volume is only 15513 A3. The packing mode of tetrahedra is "corner-to-face", giving rise to a high-density architecture (1.324 g/cm3 and the channel is 0.8 nm). Most strikingly, supramolecular structural transformation between VMOP-alpha and VMOP-beta can be reversibly achieved by temperature-induced solvent-mediated transformation. These findings give a good opportunity for understanding the 3D supramolecular aggregation and crystal growth based on large molecular tectonics. PMID- 30475445 TI - A Systematic Review and Narrative Synthesis on the histological and neurobehavioral long term effects of dexmedetomidine. AB - BACKGROUND: Recent experimental studies suggest that currently used anesthetics have neurotoxic effects on young animals. Clinical studies are increasingly published about the effects of anesthesia on the long term outcome, providing contradictory results. The selective alpha-2 adrenergic receptor agonist dexmedetomidine has been suggested as an alternative non-toxic sedative agent. AIM: The aim of this systematic review is to assess the potential neuroprotective and neurobehavioral effects of dexmedetomidine in young animals and children. METHODS: Systematic searches separately for preclinical and clinical studies were performed in Medline Ovid and Embase on February 14th 2018. RESULTS: The initial search found preclinical (n=661) and clinical (n=240) studies. A total of 20 preclinical studies were included. None of the clinical studies met the predefined eligibility criteria. Histologic injury by dexmedetomidine was evaluated in 11 studies, and was confirmed in three of these studies (caspase-3 activation or apoptosis). Decrease of injury caused by another anesthetic was evaluated in 16 studies and confirmed in 13 of these. Neurobehavioral tests were performed in 7 out of the 20 studies. Of these 7 rodent studies, 3 studies tested the effects of dexmedetomidine alone on neurobehavioral outcome in animals (younger than P21). All 3 studies found no negative effect of dexmedetomidine on the outcome. In 6 studies outcome was evaluated when dexmedetomidine was administered following another anesthetic. Dexmedetomidine was found to lessen the negative effects of the anesthetic. CONCLUSION: In animals, dexmedetomidine was found not to induce histologic injury and to show a beneficial effect when administered with another anesthetic. No clinical results on the long term effects in children have been identified yet. This article is protected by copyright. All rights reserved. PMID- 30475446 TI - Extract of the Microalga Nitzschia laevis Prevents High-Fat-Diet Induced Obesity in Mice by Modulating the Composition of Gut Microbiota. AB - SCOPE: The aim of the present study is to investigate the efficacy of Nitzschia laevis extract (NLE) in preventing obesity in mice fed with a high-fat diet (HFD), and the potential underlying mechanisms focusing on modulation of the gut microbiota profile. METHODS AND RESULTS: Physiological, histological, and biochemical parameters and gut microbiota compositions are compared among four experimental groups fed respectively with the following diets for 8 weeks: Normal chow diet, HFD, HFD + low concentration of NLE, and HFD + high concentration of NLE. The results demonstrate that NLE supplementation significantly reduces body weight gain and effectively prevents lipid accumulation in the white adipose tissue and liver of the mice. Mechanistic analysis reveals that NLE promotes the expression of uncoupling protein 1 and peroxisome proliferators-activated receptor-gamma coactivator-1 mRNA in brown adipose tissue. Furthermore, NLE protects the gut epithelium and positively reshapes the gut microbiota composition against the damaging effect of HFD. CONCLUSIONS: NLE supplementation demonstrates a protective effect against HFD-induced obesity in mice, which is associated with reshaping the profile of gut microbiota. To the best of our knowledge, this has been the first report on the potential of microalgal extract to prevent obesity by modulating gut microbiota. PMID- 30475447 TI - HPV-associated neuroendocrine carcinomas of the head and neck in FNA biopsies: Clinicopathologic features of a rare entity. AB - BACKGROUND: The majority of human papillomavirus (HPV)-associated oropharyngeal carcinomas are squamous cell carcinomas; however, there are rare reports of HPV associated neuroendocrine carcinomas (HPV-NECs) in the upper aerodigestive tract. The aim of this study was to characterize the diagnostic features of fine-needle aspiration (FNA) cases of head and neck HPV-NEC. METHODS: Cytology cases of HPV NEC were identified over a 3-year period from 2 institutions. Clinical, cytomorphologic, and ancillary test results were evaluated. RESULTS: Five FNA cases of HPV-NEC were identified from 4 patients with cervical lymph node metastases with primaries in the oropharynx (n = 2), nasopharynx (n = 1), and larynx (n = 1). Three cases showed mixed small cell and large cell neuroendocrine morphologies; 1 case was a small cell carcinoma, and the last case appeared as a large cell neuroendocrine carcinoma. All tumors were strongly positive for synaptophysin and p16 and negative for p63/p40. Two cases tested for INSM1 showed diffuse nuclear staining. HPV was confirmed by in situ hybridization in 4 cases, and HPV-18 was detected by polymerase chain reaction in the fifth case. Retinoblastoma (Rb) staining was moderate to weak (5/5), and p53 was weakly positive (5/5). CONCLUSIONS: Head and neck HPV-NEC is a rare, aggressive entity that can show mixed small and large cell features and p16 upregulation; p53 and Rb are variable with limited diagnostic utility. Because p16 positivity can be nonspecific, confirmatory HPV testing is required and may be helpful in determining the primary site for neuroendocrine carcinoma of an unknown primary. The accurate diagnosis of HPV-NEC is also important because of its worse prognosis in comparison with HPV-associated squamous cell carcinoma. PMID- 30475448 TI - Infections in children with autism spectrum disorder: Study to Explore Early Development (SEED). AB - Immune system abnormalities have been widely reported among children with autism spectrum disorder (ASD), which may increase the risk of childhood infections. The Study to Explore Early Development (SEED) is a multisite case-control study of children aged 30-69 months, born in 2003-2006. Cases are children previously diagnosed and newly identified with ASD enrolled from education and clinical settings. Children with a previously diagnosed non-ASD developmental condition were included in the developmental delay/disorder (DD) control group. The population (POP) control group included children randomly sampled from birth certificates. Clinical illness from infection during the first 28 days ("neonatal," from medical records) and first three years of life (caregiver report) in cases was compared to DD and POP controls; and between cases with and without regression. Children with ASD had greater odds of neonatal (OR = 1.8; 95%CI: 1.1, 2.9) and early childhood infection (OR = 1.7; 95%CI: 1.5, 1.9) compared to POP children, and greater odds of neonatal infection (OR = 1.5; 95%CI: 1.1, 2.0) compared to DD children. Cases with regression had 1.6 times the odds (95%CI: 1.1, 2.3) of caregiver-reported infection during the first year of life compared to cases without regression, but neonatal infection risk and overall early childhood infection risk did not differ. Our results support the hypothesis that children with ASD are more likely to have infection early in life compared to the general population and to children with other developmental conditions. Future studies should examine the contributions of different causes, timing, frequency, and severity of infection to ASD risk. Autism Res 2018. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We looked at infections during early childhood in relation to autism spectrum disorder (ASD). We found that children with ASD were more likely to have an infection in the first 28 days of life and before age three compared to children with typical development. Children with ASD were also more likely than children with other developmental delays or disorders to have an infection in the first 28 days of life. PMID- 30475449 TI - Regression in autism spectrum disorder: Reconciling findings from retrospective and prospective research. AB - The way in which the behavioral manifestations of autism spectrum disorder (ASD) emerge in infancy is variable. Regression-loss of previously acquired skills occurs in a subset of children. However, the etiology and significance of regression remains unclear. Until recently, investigation of regression relied on retrospective report by parents or examination of home videos from early in life. However, home videos and retrospective report of the nature and timing of regression, and association with factors such as illness or immunization, is potentially subject to bias. The advent of prospective studies of infant siblings at familial high-risk of ASD has the potential to document regression as it occurs. Recent research has suggested that subtle loss of skills occurs in a larger proportion of children with ASD than previously assumed; however, there are few reports of clear-cut regressions, such as that involving dramatic loss of language and other established skills, in the prospective literature. This could be because of the following: clear-cut regression occurs less commonly than parent report suggests, study design limits the potential to detect regression, or there are differences between multiplex and simplex families in the rate of de novo genetic mutations and therefore regression risk. This review will bring together literature from retrospective and prospective research and attempt to reconcile diverging findings, with a specific focus on methodological issues. Changing conceptualizations of regression will be discussed, as well as etiological factors that may be associated with regression. The main challenges that need to be addressed to measure regression in prospective studies will be set out. Autism Research 2018, 11: 1602-1620. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Regression-a loss of previously established skills-occurs in a subset of children with ASD. Parental recall is not always accurate but studying younger siblings of children with ASD, 10-20% of whom will develop ASD, should make it possible to measure regression as it occurs. Clear-cut regression, like loss of language, has not often been reported in infant sibling studies, but recent research suggests that gradual loss of social engagement might be more common. This review looks at the evidence for regression from infant sibling studies and asks how study design affects the likelihood of capturing regression. PMID- 30475450 TI - Auditory-visual misalignment: A theoretical perspective on vocabulary delays in children with ASD. AB - In this commentary, we describe a novel theoretical perspective on vocabulary delays in children with autism spectrum disorder (ASD)-a perspective we refer to as auditory-visual misalignment. We synthesize empirical evidence that: (a) as a result of differences in both social and nonsocial visual attention, the auditory visual statistics available to children with ASD for early word learning are misaligned; (b) this auditory-visual misalignment disrupts word learning and contributes to the vocabulary delays shown by children with ASD; and (c) adopting a perspective of auditory-visual misalignment has important theoretical and clinical implications for understanding and supporting vocabulary development in children with ASD. Theoretically, the auditory-visual misalignment perspective advances our understanding of how attentional differences impact vocabulary development in children with ASD in several ways. By adopting the point of view of the child, we provide a framework that brings together research on social and domain-general visual attention differences in children with ASD. In addition, the auditory-visual misalignment perspective moves current thinking beyond how misalignment disrupts vocabulary development in the moment, and considers the likely consequences of misalignment over developmental time. Finally, considering auditory-visual misalignment may assist in identifying active ingredients of existing language interventions or in developing new interventions that deliver high quality, aligned input. Future research is needed to determine how manipulating auditory-visual alignment changes word learning in ASD and whether the effects of auditory-visual misalignment are unique to ASD or shared with other neurodevelopmental disorders or sources of language impairment. Autism Research 2018, 11: 1621-1628. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This article describes a new way of thinking about vocabulary delays in children with autism spectrum disorder (ASD). We suggest that children with ASD may have difficulty learning words because their attention is not tuned in to what is most important for learning, creating a mismatch between what they see and what they hear. This perspective brings together research on different types of attentional differences in people with ASD. It may also help us to understand how language interventions work. PMID- 30475451 TI - Social difficulties in youth with autism with and without anxiety and ADHD symptoms. AB - Social difficulties inherent to autism spectrum disorder are often linked with co occurring symptoms of anxiety and attention deficit hyperactivity disorder (ADHD). The present study sought to examine the relation between such co occurring symptoms and social challenges. Parents of adolescents with autism (N = 113) reported upon social challenges via the social responsiveness scale (SRS) and anxiety and ADHD symptomatology via the Child Behavior Checklist. Results revealed differences in SRS scores across co-occurring symptom subgroups (Anxiety, ADHD, Both, Neither)-namely, adolescents with autism and anxiety as well as those with autism, anxiety, and ADHD showed greater scores on the SRS than the other groups. Implications for research and clinical practice are discussed and recommendations are offered. Autism Research 2018, 11: 1679-1689. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Anxiety and attention deficit hyperactivity disorder (ADHD) symptoms are related to greater social challenges for adolescents with autism spectrum disorder. The present study found that autism with anxiety and autism with anxiety and ADHD, was related to greater social difficulties than autism alone. Findings provide further support for the intertwined nature of anxiety and ADHD symptoms in autism. What this may mean for research and clinical practice is considered and recommendations are suggested. PMID- 30475452 TI - An ultrasound-responsive dual-modal US/T1 -MRI contrast agent for potential diagnosis of prostate cancer. AB - BACKGROUND: Interest in an ultrasound-mediated delivery system for effective T1 MRI of prostate cancer without adverse effects has steadily increased. PURPOSE: To develop an ultrasound-responsive dual-modal ultrasound (US)/T1 -MRI contrast agent for efficient diagnosis of prostate cancer cells overexpressing prostate specific membrane antigen (PSMA) and assess their potential. STUDY TYPE: In vitro. SUBJECTS: Two prostate cancer cell lines. FIELD STRENGTH/SEQUENCE: Each study group underwent 3.0T MRI under a TR 400 msec, TE 10 msec, a 240 * 240 matrix, a flip angle 90 degrees , a slice thickness 3 mm, NSA with 4, bandwidth 115 Hz/pixel, and an FOV of 120 * 120 mm. ASSESSMENT: Microscopes, quantitative and qualitative analyzing instruments, and clinical devices were used for assessing this novel contrast agent and its diagnosis effects. STATISTICAL TESTS: We used linear regression analyses to determine the longitudinal relaxivity (r1 ) values of our US/T1 -MRI contrast agent and gadobutrol. RESULTS: Microbubble+Fe3+ melanin nanoparticle+peptides (MB+Fe3+ MNPPs) had a good US contrast effect, like a commercial US agent. The differences of US intensities between them was below 5%. The r1 values of MB+Fe3+ MNPPs and gadobutrol were 4.5 and 3.7 s-1 /mM, respectively. More than hundreds of Fe3+ MNPPs were located in prostate cancer cells treated with MB+Fe3+ MNPPs and US stimulus, but the number of Fe3+ MNPPs was below dozens in the other prostate cancer cells expressing less PSMA. The former cells with MB+Fe3+ MNPPs and US stimulus only showed the highest T1 -MRI signal because of synergy effects of the peptides targeting the cells and US stimulus for delivery of Fe3+ MNPPs to the cells. No cytotoxicity of MB+Fe3+ MNPPs was confirmed by using a WST assay. Viability of the cells with the complexes was above 90%. DATA CONCLUSION: We synthesized MB+Fe3+ MNPPs as a potential US/T1 -MRI contrast agent. This complex was applicable for diagnosing desired prostate cancer cells. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1610-1616. PMID- 30475454 TI - A pilot community-based randomized comparison of speech generating devices and the picture exchange communication system for children diagnosed with autism spectrum disorder. AB - A pilot community-based randomized controlled trial was conducted to compare the effects of the Picture Exchange Communication System (PECS) to a teaching sequence using a high-tech Speech Generating Device (SGD) to teach social communication behaviors. The two approaches were compared to evaluate the effectiveness of the newer, more high-tech intervention using technology to improve social and communicative behavior of children diagnosed with Autism Spectrum Disorder. A total of 35 school-age children were randomized to either a high-tech (SGD device) or low-tech (PECS cards) form of Augmentative and Alternative Communication (AAC). Study participants received 4 months of communication training delivered in their classrooms, and the primary outcome measures of the trial were several functional communication skills emphasized in the PECS teaching sequence. Results indicated that both high-tech and low-tech AAC approaches resulted in significant improvements in communication, and that these improvements did not differ significantly between the two approaches. These findings support the use of high-tech AAC, and highlight the need for evidence based guidelines for its use as well as evaluation with individuals with a range impairments and disabilities. Autism Research 2018, 11: 1701-1711. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study compared the effectiveness of a free and open-source app for teaching social and communicative behavior to children with autism spectrum disorder (ASD) to traditional picture card approaches. Thirty-five children with ASD were randomized to a picture card or app-based intervention and both treatment approaches resulted in significant improvements in social and communicative behavior. These data indicated that both "high-tech" and "low-tech" interventions were effective for improving behavior and that there was not a significant difference between the two approaches. PMID- 30475453 TI - Aberrant functional connectivity of neural circuits associated with social and sensorimotor deficits in young children with autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by atypical functional integration of brain regions. The vast majority of neuroimaging studies of ASD have focused on older children, adolescents, and adults with the disorder. Very little work has explored whole-brain functional connectivity of young children with ASD. Here, we collected resting-state functional magnetic resonance imaging data from 58 young children (mean age 4.98 years; 29 with ASD; 29 matched healthy controls [HC]). All children were under sedation during scanning. A functional "connectedness" method was first used to seek for brain regions showing atypical functional connectivity (FC) in children with ASD. Then, a recurrent-seek strategy was applied to reveal atypical FC circuits in ASD children. FC matrices between regions-of-interest (ROIs) were compared between ASD and HC. Finally, a support vector regression (SVR) method was used to assess the relationship between the FC circuits and ASD symptom severity. Two atypical FC circuits comprising 23 ROIs in ASD were revealed: one predominantly comprised brain regions involved with social cognition showing under-connectivity in ASD; the other predominantly comprised sensory-motor and visual brain regions showing over-connectivity in ASD. The SVR analysis showed that the two FC circuits were separately related to social deficits and restricted behavior scores. These findings indicate disrupted FC of neural circuits involved in the social and sensorimotor processes in young children with ASD. The finding of the atypical FC patterns in young children with ASD underscores the utility of studying younger children with the disorder, and highlights nuanced patterns of brain connectivity underlying behavior closer to disorder onset. Autism Research 2018, 11: 1643-1652. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder. Understanding brain functional alterations at early ages is important for understanding biological mechanisms of ASD. Here, we found two atypical brain functional circuits in young children with ASD that were related to social and sensorimotor function. These results show how atypical patterns of brain functional connectivity in young children with of ASD may underlie core symptoms of the disorder. PMID- 30475455 TI - PD-L1 expression in ROS1-rearranged non-small cell lung cancer: A study using simultaneous genotypic screening of EGFR, ALK, and ROS1. AB - BACKGROUND: The aim of the current study was to investigate the prevalence and clinicopathologic characteristics of ROS1-rearranged non-small cell lung cancer (NSCLC) in routine genotypic screening in conjunction with the study of PD-L1 expression, a biomarker for first-line treatment decisions. METHODS: Reflex simultaneous genotypic screening for EGFR by peptide nucleic acid clamping, and ALK and ROS1 by fluorescence in situ hybridization (FISH) was performed on consecutive NSCLC cases at the time of initial pathologic diagnosis. We evaluated genetic aberrations, clinicopathologic characteristics, and PD-L1 tumor proportion score (TPS) using a PD-L1 22C3 assay kit. RESULTS: In 407 consecutive NSCLC patients, simultaneous genotyping identified 14 (3.4%) ROS1 and 19 (4.7%) ALK rearrangements, as well as 106 (26%) EGFR mutations. These mutations were mutually exclusive and were found in patients with similar clinical features, including younger age, a prevalence in women, adenocarcinoma, and advanced stage. The PD-L1 assay was performed on 130 consecutive NSCLC samples. High PD-L1 expression (TPS >= 50%) was observed in 29 (22.3%) tumors. PD-L1 expression (TPS >= 1%) was significantly associated with wild type EGFR, while ROS1 rearrangement was associated with high PD-L1 expression. Of the 14 cases with ROS1 rearrangement, 12 (85.7%) showed PD-L1 expression and 5 (35.7%) showed high PD-L1 expression. CONCLUSION: In the largest consecutive routine Asian NSCLC cohort analyzed to date, we found that high PD-L1 expression frequently overlapped with ROS1 rearrangement, while it negatively correlated with EGFR mutations. PMID- 30475456 TI - The diagnosis conundrum: Comparison of crowdsourced and expert assessments of toddlers with high and low risk of autism spectrum disorder. AB - As the diagnosis and treatment of Autism Spectrum Disorder (ASD) becomes a greater public health concern, access to professionals and expert assessment becomes increasingly more challenging. Novel techniques to improve efficiency of assessment of young children with social communication concerns are desperately needed to address significant barriers to accessing diagnostic evaluations. Utilizing crowdsourcing technology, we compared ratings by experts and crowdworkers of social communication behaviors in videos of 18-month-old children. Of note, 563 crowdworkers and 24 expert responses were collected in approximately 7 hr and 57 days, respectively. Summed scores of social communication behaviors observed by crowdworkers showed high correlation to those of experts. These data introduce a novel and perhaps efficient way in which to examine of social communication impairments in toddlers. Autism Research 2018, 11: 1629-1634. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This research compared crowdsourced assessments of social communication behaviors to assessments by experts, for toddlers whose behaviors ranged in severity from typical to atypical. Results showed that crowdsourced rankings of social communication behavior significantly correlate with those of experts. PMID- 30475458 TI - Molecular radical chain initiators for ambient to low temperature applications. AB - An overview is given of methods for the initiation of radical chain reactions by specific initiator compounds that generate radicals. These can be utilized to initiate any kind of radical chain reaction by transforming substrates into the desired radical intermediates. Azo initiators, peroxides, nitroxides, trialkylboranes, dialkyl zinc compounds and type I photoinitiators are discussed, as well as methods of redox- and sonochemical initiation. Not included are methods of direct radical formation from the substrates like photoredox catalysis or high-energy irradiation. The focus of this review lies on rather "low" temperatures in the range of 50 degrees C down to -78 degrees C, which can be useful to achieve more selective reactions. Illustrative applications of such radical chain initiators in a variety of reactions are discussed, including stereoselective ones and polymerizations. PMID- 30475457 TI - Behavioral inhibition and activation as a modifier process in autism spectrum disorder: Examination of self-reported BIS/BAS and alpha EEG asymmetry. AB - The Modifier Model of autism spectrum disorder (ASD) suggests that phenotypic variability within ASD is rooted in modifier processes, such as the behavioral inhibition system (BIS) and behavioral activation system (BAS). Among a sample of 53 adolescents with ASD, this study examined associations between (a) self reported BIS/BAS and frontal and parietal alpha electroencephalogram asymmetry and whether these indices related to (b) ASD severity (via the Autism Quotient), and/or (c) co-occurring anxiety and attention-deficit hyperactivity disorder (via Youth Self Report and Child Behavior Checklist). Findings showed that alpha asymmetry was associated with self-reported BAS scores, such that greater BAS was related to greater right-frontal hemisphere activation and relatively greater left-parietal hemisphere activation. Additionally, associations emerged between ASD severity and self-reported BAS and alpha asymmetry, and between anxiety symptoms and self-reported BIS and alpha asymmetry. Furthermore, mediation analyses revealed that BAS mediated the association between asymmetry and autism severity. Therefore, alpha asymmetry and BIS/BAS activity may provide insight into how ASD presents in adolescence as well as who might be at greater risk for developing co-occurring psychopathologies. This study highlights the importance of considering motivational systems to elucidate individual differences among youth with ASD and working toward the longer term goal of better understanding differential responses to treatment. Autism Research 2018, 11: 1653-1666. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Differences in the likelihood to avoid (behavioral inhibition system; BIS) or approach (behavioral activation system; BAS) situations are thought to relate to patterns of brain activity (via electroencephalogram asymmetry asymmetry). This study revealed that these tendencies may influence the presentation of autism spectrum disorder (ASD) and symptoms of anxiety in adolescents with ASD. PMID- 30475459 TI - Construction of Soft Base Tongs on Separator to Grasp Polysulfides from Shuttling in Lithium-Sulfur Batteries. AB - Rechargeable lithium-sulfur batteries, which use sulfur as the cathode material, promise great potentials to be the next-generation high-energy system. However, higher-order lithium polysulfides, Li2 Sx (x = 4, 6, and 8), regardless of in charge or in discharge, always form first, dissolve subsequently in the electrolyte, and shuttle to the cathode and the anode, which is called "shuttle effect." The polysulfides shuttle effect leads to heavy loss of the active-sulfur materials. Literature works mostly "cover or fill" the pores to block polysulfides from shuttling, which also hinder the lithium ion transfer. Here a protocol is invented to grasp polysulfides based on the "soft and hard acid-base" theory. Tertiary amine layer (TAL) polymerized on a polypropylene separator selectively coordinates with the dissolved high-order Li2 Sx in the cathode. Meanwhile, the transportation of lithium cations is not interrupted because of enough pores left for their transportation. After 400 cycles of charge/discharge at 0.5C, the TAL modified separator battery still possesses a capacity of 865 mAh g-1 , which is among the best of the state-of-the-art performances of lithium sulfur batteries. The flexible "polysulfides tongs" construction method paves a new way for Li-S batteries to reach desired performances with less worry about polysulfides shuttle. PMID- 30475460 TI - Hot streak continues for bond market. PMID- 30475461 TI - Consumers can skip HealthCare.gov for 2018 insurance coverage. PMID- 30475462 TI - Nursing homes and hospice providers face looming emergency preparedness deadline. PMID- 30475463 TI - Senate eyes changes to Medicare Advantage, expanding telemedicine. PMID- 30475464 TI - Recognizing the top workplaces in healthcare. PMID- 30475466 TI - Foreign ventures help academic systems boost brand, revenue. PMID- 30475465 TI - CEOs weigh the risks and rewards of payment reform. PMID- 30475468 TI - Let's look to innovation, not slashing programs, to make healthcare more effective, affordable. AB - As the national healthcare debate continues, what if instead of cutting Medicaid eligibility and capping spending, as the legislation approved by the House of Representatives would do, we were discussing innovations that would make the healthcare system more effective and affordable? PMID- 30475467 TI - A false start in the fight against opioid addiction. AB - As with so much else, the Trump administration has stumbled in its initial efforts to combat opioid addiction. Given the magnitude of the crisis, healthcare professionals have an obligation to speak out against ill-considered policies. PMID- 30475469 TI - Decreasing pediatric antibiotic use through collaboration. PMID- 30475470 TI - 'We needed to think of ourselves a little bit differently'. AB - In Chicago's uber-competitive healthcare landscape, academic medical centers have been forging new alliances at a staggering rate, especially as they eye growth in the surrounding suburbs. In March, Rush University Medical Center, situated in Chicago's predominately low-income near West Side, and suburban Rush-Copley Medical Center formalized a 30-year affiliation by joining together under a new banner: Rush. Michael Dandorph, president of Rush University Medical Center, will take the helm as president of the newly formed system. He recently spoke with Modern Healthcare reporter Maria Castellucci about Rush's expansion plans, efforts to improve care coordination and its role in addressing population health issues. The following is an edited transcript. PMID- 30475471 TI - CMS to make MACRA less painful with'pick your pace'options. PMID- 30475473 TI - Employers hate the Cadillac tax. Why? PMID- 30475472 TI - What Paul Ryan's healthcare proposals look like from Janesville. PMID- 30475475 TI - The coming transformation. AB - No matter what the outcome of the election or its impact on the Affordable Care Act, there's one thing neither party disputes. PMID- 30475474 TI - Medical tech's starring role in hospital marketing campaigns. PMID- 30475476 TI - CMS must protect vulnerable populations in new rules for third-party premium support. AB - Insurers claim they are losing money in the health insurance marketplace under the Affordable Care Act because some high-cost patients receive charitable help to pay their premiums, threatening the risk pool. PMID- 30475478 TI - 'There's a culture of physician engagement and transparency'. AB - Carl Armato, president and CEO of 14-hospital Novant Health, has worked with the system's employed and affiliated physicians to put them at the center of decisionmaking, a model he says has facilitated a systemwide embrace of electronic health records. Armato, who joined the Winston-Salem, N.C.-based health system Novant in 1998 and has been the top exec since 2012, recently spoke with Modern Healthcare Southern Bureau Chief Dave Barkholz about that physician administrative partnership, Novant's effort to improve its hospital operations and North Carolina's efforts to provide price transparency for healthcare consumers. This is an edited transcript. PMID- 30475477 TI - Making death from postpartum hemorrhaging a 'never event'. PMID- 30475479 TI - Largest revenue-cycle management firms: Ranked by total number of healthcare revenue-cycle contracts, 2015. PMID- 30475480 TI - As IT's importance grows, CIO role grows with technology's reach. AB - As technology becomes more integral to all aspects of running hospitals, CEOs and board members are handing CIOs more authority. And they want data and results in return. PMID- 30475481 TI - After nod to Sanders, Clinton may go her own way on health policy. AB - Clinton's focus is on strengthening the ACA markets to make premiums, out-of pocket costs and prescription drugs more affordable. PMID- 30475482 TI - Physician Competition: Competition for new docs pushing pay higher. PMID- 30475483 TI - The education of a safety specialist. PMID- 30475484 TI - Why assume failure for cost control? AB - Last week, two well-respected groups of government economists predicted the end is nigh for the era of restrained growth in healthcare spending. Ignore them. They've been wrong before. They will be proven wrong again. PMID- 30475485 TI - Hospitals, systems play critical leadership role in boosting our national health security. AB - America's hospitals and health systems must be prepared for anything, but as the range of threats to health in our communities becomes broader and the threats hit more quickly and frequently- whether it's the devastation of natural disasters or emerging threats such as the Zika virus-provider organizations will need to play bigger roles in heading off problems before they spiral into crises. PMID- 30475486 TI - Opioid crisis renews interest in osteopathic manipulation. AB - Toolbox of solutions: Chronic Pain management begins with counseling patients on achieving realistic pain relief goals. Engage patients in the management and treatment of their pain. Be open to multidisciplinary approaches. Goals should focus on reducing pain severity, improving functionality and gaining a better quality of life--not the immediate elimination of all pain. PMID- 30475487 TI - 'We need a healthcare policy in this country. We don't have one. We have a healthcare financing policy'. AB - Ascension, the nation's largest Catholic healthcare system with 125 hospitals, 7,000 employed physicians and multiple health-related enterprises, has in recent years taken a number of steps to reduce the financial burden for low-income people when they access the healthcare system. Modern Healthcare editor Merrill Goozner recently asked CEO Anthony Tersigni about some of those moves and other major issues affecting the sprawling system's operations. This is an edited transcript. PMID- 30475488 TI - Largest allopathic medical schools Ranked by total active enrollment for the 2015 16 school year. Largest osteopathic medical schools Ranked by total active enrollment for the 2015-16 school year. PMID- 30475489 TI - CARE IN THE SHADOWS: THE CHALLENGES FOR UNDOCUMENTED IMMIGRANTS. PMID- 30475490 TI - A Look at MACRA: What to Expect in 2017. AB - The Medicare Access and Children's Health Insurance Program (CHIP) Reauthorization Act of 2015 fundamentally changes how physicians who care for Medicare patients will be paid. Although physicians won't see changes in their payments in 2017, they need to understand that their performance in 2017 will be the basis for the payments made to them starting in 2019. This article summarizes the two paths for determining future Medicare payments established by the law: the merit-based incentive payment system and advanced alternative payment models. PMID- 30475491 TI - Raising the Minimum Legal Sale Age for Tobacco to 21: The Estimated Effect for Minnesota. AB - A campaign to raise the minimum legal sale age for tobacco products from 18 to 21 years known as Tobacco 21 is having a nationwide impact, with at least 200 localities in 14 states having already implemented a Tobacco 21 policy. A 2015 report from the Institute of Medicine (IOM) estimated the effects of such policy on cigarette use at the national level; however, little is known about the expected effects for individual states. The purpose of this study was to consider the effect on smoking initiation in Minnesota if the minimum sale age were 21 in 2015. Estimates from the Minnesota Adolescent Community Cohort and Minnesota Adult Tobacco Survey were used to calculate the uptake of smoking in a hypothetical cohort of Minnesota adolescents 15 to 20 years of age. Expected reductions in initiation in the IOM report were used to calculate the effects of Tobacco 21 policy on smoking uptake in this cohort. Results revealed that raising the sale age to 21 in 2015 would prevent 3,355 young Minnesotans from starting to smoke. PMID- 30475492 TI - THE BURDEN ON DEMENTIA CAREGIVERS: How Can Communities and Health Care Organizations Help? AB - Family members are integral to the care, safety and overall well-being of persons with Alzheimer's disease and related dementias. Being a caregiver is often associated with significant isolation as well as emotional, psychosocial and financial burden. In recognition of the toughness of this job and the increasing prevalence of dementia, there has been growing momentum among public policy makers and within communities and the health care system to address the challenges caregivers face. This article describes efforts in Minnesota communities to do so. The authors make recommendations for communities and health care systems. PMID- 30475493 TI - Constituents of Melittis melissophyllum subsp. albida. AB - In this paper, for the first time, we have reported the analysis of the polar fraction of Melittis melissophyllum subsp. albida, a species with ecological relevance which is also used in traditional medicine of Central-Southern Italy. Iridoid glucosides were mainly identified, together with verbascoside, an ubiquitous phenyl-ethanoid glycoside, with chemotaxonomic implications in Lamiales order. The majority of the isolated compounds is endowed with interesting bio- activities and may justify the traditional uses of this plant also from a chemical point of view. Several peculiarities were also recorded in the metabolic pattern of this subspecies, i.e. the presence of virginioside and geniposidic acid, two rare compounds in the Lamiaceae family. The presence of free cinnamic acid was an additional characteristic of this subspecies which showed a specific secondary metabolites content. These phytochemical peculiarities, together with the morphological differences showed by the subsp. albida in respect to the nominal species, may be a base for a reconsideration of the systematic of Melittis melissophyllum subsp. albida. PMID- 30475494 TI - Synthesis of Ester-linked Docetaxel-glycoside Conjugate and Its Application to Drug Delivery System using Immunoliposome Targeted with Trastuzumab. AB - Chemo-enzymatic synthesis of the ester-linked monosaccharide conjugate of docetaxel, 7-glycolyldocetaxel 2"-O-beta-D-galactopyranoside, was achieved by using lactase as a biocatalyst. The water-solubility and, EE and LE values for the liposome of 7-glycolyldocetaxel 2"-O-beta-D-galactopyranoside were much higher than those of docetaxel. The immunoliposome containing 7-glycolyldocetaxel 2"-O-beta-D-galactopyranoside showed effective suppression of tumor growth. PMID- 30475495 TI - A New Ursane-type Triterpenoid and Other Constituents from the Leaves of Crataegus azarolus var. aronia. AB - A new ursane-type triterpene acid, named azarolic acid (1), along with four known phenolic compounds and four known triterpene acids, was isolated from the crude EtOAc extract of the leaves of Crataegus azarolus var. aronia L. The structure of 1 was determined from 1D and 2D NMR spectroscopic data. Euscaphic acid showed high anti-vasoconstriction effects on aortic rings, supporting the use of this medicinal plant in cardiovascular disease. PMID- 30475496 TI - Aggregation Behavior of 6-Isocassine and N-Methyl-6-Isocassine: Insights into the Biological Mode of Action of Lipid Alkaloids. AB - The aggregation behavior of 6-isocassine and N-methyl-6-isocassine, two piperidin 3-ol alkaloids isolated respectively from the barks of Prosopis nigra and P. affinis, was investigated using a combination of NOE experiments and diffusion measurements in solvents of varying polarity and hydrogen bonding capacity. While the NOE enhancements for N-methyl-6-isocassine are positive, regardless of the solvent, those for 6-isocassine shift from negative to positive when going from chloroform-d to methanol-d(4) solution. In addition, despite the self-diffusion coefficients of both compounds being virtually identical in methanol-d4, N-methyl 6-isocassine diffuses nearly twice as fast as the non-methylated alkaloid in chloroform-d. The changes in rotational and translational dynamics observed between solvents for 6-isocassine suggest that the molecule forms dimeric head-to head aggregates in non-polar aprotic environments, a behavior that could help explain the biological mode of action that has been proposed for this type of alkaloids. PMID- 30475497 TI - Antimicrobial and Cytotoxic Evaluation of New Quinazoline Derivatives. AB - The synthesis of nine new quinazoline derivatives (2a-2i) and evaluation of their antimicrobial and cytotoxic activities were aims of the present work. For the synthesis of the compounds, 2-chloro-6,7-dimethoxyquinazolin-4-amine was used as the initial starting material. The intermediate product, 2-hydrazinyl-6,7- dimethoxyquinazolin-4-amine, was reacted with appropriate aromatic aldehydes to obtain 2-(2-benzylidenehydrazinyl)-6,7-dimethoxyquinazolin-4-amine derivatives as final compounds. The structures of the compounds were elucidated by (1)H- and (13)C-NMR, IR, and-MS analyses. The new pure compounds were evaluated for their potential antimicrobial and cytotoxic activities using in vitro microdilution and cell culture techniques, respectively. The compounds 2e and 2f may be promising candidates for the treatment of fungal infections with their activity and cytotoxicity. PMID- 30475498 TI - Synthetic Anthocyanidins from Natural Benzopyrans. AB - A hydride abstraction strategy can be used to make anthocyanidins and isoflavylium salts from benzopyrans in good yields. PMID- 30475499 TI - Anti-inflammatory Effects of Compounds from Polygonum odoratum. AB - Polygonum odoratum is an edible plant traditionally used as an antidiabetic, antimicrobial, anti-inflammatory, and antitumor agent in Asia. The aim of the study was to evaluate the anti-inflammatory effect of P. odoratum and the isolation and characterization of its main fractions. Extracts of the aerial parts were tested for anti-inflammatory activity as indicated by a change in the cytokine secretion in lipopolysaccharide-stimulated macrophages. After separation of the extract by reversed-phase high-performance liquid chromatography, the anti inflammatory activity of the fractions was determined. Furthermore, the two main fractions were identified by nuclear magnetic resonance spectroscopy ((1)H- and (13)C-NMR). The ethanolic extract significantly reduced IL-6 secretion (IC50 25 pg/mL). The two main fractions (5 and 7) significantly decreased IL-6 production with an IC(50) of 102 MUM (5) and 77 MUM (7), respectively, and were identified as scutellarein-7-glucoside (5) and quercitrin (7). Since inflammation plays a major role in various diseases with high prevalence globally, it may be of importance that P. odoratum and its main constituents scutellarein-7-glucoside and quercitrin can be used as either an alternative or complementary treatment. Additionally, both are glycosides and their activity may be enhanced tremendously by deglycosylation by the gut microbiota. PMID- 30475500 TI - The LC/ESI-MSMS Profiles and Biological Potentials of Vitex agnus castus Extracts. AB - The chemical profile, cytotoxic and apoptotic effect, and antioxidant activity were determined of ethanolic extracts of Vitex agnus-castus L. (chaste tree). Ripened fruits and fruitless aerial parts were extracted with ethanol, and the chemical characterization of the extracts was determined by LC/ESI-MS-MS. Twelve compounds were tentatively identified in the extracts. The dose-dependent cytotoxic effects of the extracts were tested on C6, A549 and MCF-7 cells by using MT7 assay; inhibition of DNA synthesis, and apoptotic and caspase-3 activation effects of the extracts were determined. The potential antioxidant activities of the extracts were evaluated by in vitro methods such as DPPH and ABTS scavenging activity, reducing power and 3-carotene bleaching assays. The fruit extract showed noticeable cytotoxic activity against MCF-7 cells with an IC(50) value of 88 MUg/mL. Both extracts showed similar DPPH scavenging activity comparably with that of the standard. PMID- 30475501 TI - Chemical Constituents of the Leaves of Tussilago farfara and their Aldose Reductase Inhibitory Activity. AB - The inhibitory activity of 37 medicinal plant extracts against aldose reductase (AR) activity was evaluated. The most potent AR inhibitory activity was found in the MeOH extract of the leaves of Tussilagofarfara (Compositae). Enzyme assay guided fractionation of the extract led to the isolation of a new flavonoid glycoside, kaempferol 3-0-[3,4-0-(isopropylidene)-alpha-L-arabinopyranoside] (1), along with 15 known compounds (2-16), of which 3, 5, 13, 15, and 16 were isolated from T. faifara for the first time. The structures of 1-16 were elucidated based on MS and NMR data. Dicaffeoylquinic acid derivatives (7-12) showed potent AR inhibitory activity with IC(50)values ranging from 0.58 to 5.38 MUM, whereas flavonoid glycosides 1, 3, 5, and 6 showed weak inhibitory activity with IC(50) values of 13.9, 15.1, 13.3, and 14.1 MUM, respectively. PMID- 30475502 TI - Quantitative Determination by HPLC-DAD of Icariin, Epimedin A, Epimedin B, and Epimedin C in Epimedium (Berberidaceae) Species Growing in Turkey. AB - The genus Epimedium is rich in terms of flavonoids, of which icariin, epimedin A, epimedin B and epimedin C are known especially to be biologically active. Therefore, it is important to quantify these compounds. In this study, a HPLC method coupled with DAD detection was developed and validated for the determination of icariin, epimedin A, epimedin B and epimedin C in Epimedium species growing in Turkey. The chromatographic separation was performed using a gradient system with a mobile phase of 0.1% formic acid (A) and acetonitrile (B) applied at a flow rate of 1 mL/min using.a diode array detector. The highest values were, respectively, icariin 0.65%, epimedin A 0.13%, epimedin B 0.11%, epimedin C 0.06%. The highest values were obtained from the materials collected in Uzungol (Trabzon-Turkey). PMID- 30475503 TI - Simultaneous Determination of the Five Marker Compounds in Melandriumfirmum using High-Performance Liquid Chromatography with Photodiode-Array Detection. AB - In Korean folk medicine, Melandrium firmum Rohrbach (Caryophyllaceae) has been used to treat various diseases, including anuria, breast cancer, and gonorrhea. In this study, a high-performance liquid chromatography method with photodiode array UV detection (HPLC-PDA) was established and then validated for the simultaneous determination of five flavonoids in M firnum: schaftoside, homoorientin, cytisoside, vitexin, and isovitexin. Separation of the five compounds was performed on a Gemini C18 column at 40'C by gradient elution of two mobile phases. The flow rate and injection volume were 1.0 m/min and 10 pL, respectively. The HPLC-PDA method showed excellent linear regression with r2 values of 0.9999 within the test ranges. The limits of -detection and quantification of all components were 0.01-0.11 and 0.04-0.34 pg/mL, respectively. The extraction recovery of the five analytes was 97.6-- 105.6% and the RSD values were < 2.0%. The relative standard deviation values of intra- and interday precision for all analytes were < 1.71 and < 1.46%,. respectively. As determined using the established and validated HPLC-PDA method described here, the amounts of the five marker compounds in M firmuin .were 0.02-2.54 mg/g. PMID- 30475504 TI - Inhibitory Activities of Sesame Seed Extract and its Constituents against beta Secretase. AB - The need for a preventive agent against dementia led us to screen natural plant resources. Among the herbs and spices tested, sesame seed prepared from Sesamum indicum seeds showed potent beta-secretase inhibitory activity. The active principles were determined to be sesamin and sesamolin, typical lignans in S. indicum. The IC(50) values of sesamin and sesamolin were 257 and 140 MUM, respectively. These compounds were investigated in a preliminary absorption experiment. After oral administration, these compounds were detected in an intact form in the brain and serum. These results suggest that consumption of sesame seeds may prevent dementia by sesamin and sesamolin, the constituents in sesame seeds. PMID- 30475505 TI - Toxicity of Compounds Isolated from White Snakeroot (Ageratina altissima) to Adult and Larval Yellow Fever Mosquitoes (Aedes aegypti). AB - Botanicals have been the source for several classes of pesticides for mosquitoes. However, increasing resistance to these products and reduced numbers of choices necessitate the search for new active ingredients. Ageratina altissima (L.) King & H. Rob. or white snakeroot, is found throughout the eastern United States and contains known toxic compounds. We examine chromenes (benzopyrans) and benzofurans isolated fiom this plant for larvicidal and adulticidal activity against the dengue vector Aedes aegypti L. Initial activity identified several compounds that were effective against either larvae or adults. Interestingly, only two compounds were effective against both larva and adults. Dose curves were constructed from further testing of these active compounds to allow. comparative ranking of efficacy. We identified dehydrotremetone as the most effective larvicide (0.03 +/- 0.001 ng/MUL) and 6-acetyl-7-methoxy-2,2- dimethylchromene as the most effective adulticide (1.17 +/- 0.31 MUg/org) although other compounds were also active. This study provides additional useful data for evaluation of chromenes and benzofurans as possible mosquiticidal agents. PMID- 30475506 TI - Compounds from Terminalli brownii Extracts with Toxicity against the Fish Pathogenic Bacterium Flavobacterium columnare. AB - The pond-raised channel catfish (Ictaluruspunctatus) industry in the United States of America can incur losses of over a $100 million annually due to bacterial diseases including columnaris disease caused by Flavobacterium columnare. One management approach available to catfish producers is the use of medicated- feed containing antibiotics. However, the negative attributes of antibiotic use in agriculture include public concerns and the potential development of antibiotic-resistant bacteria. Therefore, the discovery of environmentally-safe natural compounds for use as therapeutic agents would greatly benefit the catfish industry. In this study, a rapid bioassay was used to evaluate crude plant extracts as the first step in the discovery of natural therapeutants. Plant extracts from Terminalia brownii were found to be inhibitory towards F. columnare. The minimum inhibitory concentration (MIC) of the 5% water methanol extract ofT. brownii (stem bark) was 10 MUg/mL and the 24 h 50% inhibition concentration (IC(50)) was 40 pg/mL. Subsequent bioassay-guided fractionation of the T. brownR ethanol extract using reverse phase C-4 chromatography revealed the highest level of activity in the aqueous:methanol (50:50) fraction. HPLC analysis and subsequent purification of this fraction provided two compounds identified as ellagic acid (1) and 4-O-(3",4"-di-O-galloyl a-L-rhamnopyrahosyl)ellagic acid (2). Compound 2 was the most active isolated compound, with a minimum inhibitory concentration (MIC) of 10+/-0 MUg/mL and 24 h IC(50) of 31+/-1 MUg/mL. Although 1 was more active according to a MIC of 6+/-5 MUg/mL, its 24 h IC(50) was >100 MUg/mL, and, therefore, it was less active overall of the two most active isolated compounds. PMID- 30475507 TI - Substrate Specificity of Aglaia loheri Active Isolate towards P-glycoprotein in Multidrug-Resistant Cancer Cells. AB - Multidrug resistance (MDR) is a major contributory factor in the failure of chemotherapy. Concrete interpretation of P-glycoprotein (P-gp) substrate specificity, whether a substance is a substrate or an inhibitor, represents an important feature of a compound's pharmaceutical profiling in drug design and development. In this work, the P-gp substrate specificity of Maldi 531.2[M+H](+), a phenol ester from Aglaia loheri Blanco leaves was investigated. This study focuses on the effect of Maldi 531.2[M+H](+) on P-gp ATPase activity, which was examined by measuring the amount of inorganic phosphates (Pi) released as a result of ATP hydrolysis. To test the effects of Maldi 531.2[M+H](+) on MDR activity, an attempt to combine Maldi 531.2[M+H](+) with a potent P-gp substrate such as verapamil was performed. As a result of this combination treatment, two distinct patterns of interaction with P-gp activity were determined by a calcein acetoxymethyl ester (AM) assay. Depending on the concentratgion, both stimulation and inhibition of MDR activity were observed at certain drug concentrations suggesting biphasic reactions, which can be understood as cooperative stimulation and competitive inhibition, respectively. Verapamil is a strong substrate to P gp. Substrate specificity of Maldi 531.2[M+H](+) may be less than the substrate specificity of verapamil, but it acts additively together with low concentrations of verapamil in stimulating ATPase activity. On the one hand, verapamil and Maldi 531.2[M+H](+) exerted cooperative stimulation on P-gp. On the other hand, Maldi 531.2[M+H](+) acts as competitive inhibitor at higher concentrations. PMID- 30475508 TI - Quantitative Determination of Betaine, Choline, Acetylcholine, and 20 Hydroxyecdysone Simultaneously from Atriplex Species by UHPLC-UV-MS. AB - A simple, rapid, and sensitive UHPLC-UV-MS method was developed for the quantitative determination of betaine (1), choline (2), acetylcholine (3), and 20 hydroxyecdysone (4) from various species of Atriplex. The baseline separation of the four analytes was achieved on a reversed phase C 18 column within nine minutes. The mobile phase was composed of 50 mM ammonium formate in 2% methanol water containing 5 mM sodium dodecyl sulfate (pH = 8.2) and methanol with 0.01% ammonium hydroxide. The analytical method was validated for recovery, precision, limits of detection (LOD), and limits of quantification (LOQ). The developed method was applied for the characterization and quantitation of analytes from plant parts of different Atriplex species, including A. canescens, A. fruticulosa, A. fasciculata, A. semibaccata, and A. lentiformis. Compounds 1-4 were found in a range of 0.53-1.61%, detection under limit of quantification (DUL)-0.74, DUL-0.0038, and 0-0.10% (w/w, mg in 100 mg plant material), respectively, in test samples. In leaf and fruit of A. canescens, a high content of 1, 2, and 4 were identified. The content of 1, 2, and 4 in A. canescens explains the potential implications of this native US plant for human health and nutrition. The result of this study provides a new method to analyze these phytoconstituents simultaneously in a mixture. PMID- 30475509 TI - Phytochemical Content, Antioxidant and Cytotoxic Activities of Sedum spurium. AB - Sedum L. species are used for their hemostatic, antidiarrheal, antifungal, diuretic and wound healing properties, and there is growing interest in these species because of their usage in folk medicine. DPPH, SO, NO, and ABTS radical scavenging activities and protective effects against H(2)(02) induced cytotoxicity, as well as cytotoxic activities against the Hep-2 cell line of various extracts from Sedum spurium Bieb. were investigated. Besides, the total phenol, flavonoid, and flavonol contents of the extracts were determined to clarify their biological and phytochemical properties. Chromatographic studies on the most active extract led to the isolation of the major compound, identified as 2-methyl-erythritol by (1)H and (13)C NMR techniques. The EtOAc extract is found to be the most active extract in all tests. However, major compound of EtOAc extract did not possess tested activities. The EtOAC extract of S. spurium could be effective to improve antihemolytic defences of erythrocytes, and radical scavenging potential of the antioxidant mechanism. The extracts should be investigated in detail for their cytotoxic activities because of their possible pro-oxidant effects at high concentrations. PMID- 30475510 TI - Fatty Acid Methyl Ester Composition of Some Turkish Apiaceae Seed Oils: New Sources for Petroselinic Acid. AB - The seed oils of twenty-six species of Apiaceae belonging to the genera Bunium, Cnidium, Ferula, Ferulago, Heracleum, Hippomarathrum, Malabaila, Myrrhoides, Olymposciadium, Pimpinella, Prangos, Szovitsia, Trigonasciadium, Trinia and Zosima, collected in Turkey, were investigated for their oil content, and amount of petroselinic acid (PA), as well as for the composition of their fatty acid methyl esters (FAMEs) by GC-MS. Seed oil content ranged from 7.1% in Szovitsia callicarpa to 29.3% in Ferda haussknechtii. The results showed that the seed oils of the studied species contained high amounts of PA (1.2-72.2%), followed by significant amounts of linoleic (LA, 13.8-50.8%) and oleic (OA, 4.2-61.6%) acids. PA was found in all the analyzed species, except for Olymposciadium caespitosum, which belongs to a monotypic endemic genus of the family. According to data from our study, PA was found to be predominantly in the seed oils of Hippomarathrum cristatum (72.2%), Trinia glauca (64.9%) and Bunium microcarpum (59.7%) and, therefore these species might be considered as new sources of PA, and represent a potential oleochemical raw material. This is the first extensive study of the composition ofTurkish Apiaceae species. The high amounts of PA may also have chemotaxonomic significance. PMID- 30475511 TI - Chemical Composition of Vietnamese Essential Oils of Cinnamomum rigidifolium, Dasymaschalon longiusculum, Fissistigma maclurei and Goniothalamus albiflorus. AB - Cinnamomum rigidifolium, Dasymaschalon longiusculum, Fissistigma maclurei and Goniothalamus albiflorus were collected from different landscapes in Vietnam and hydro distilled to produce essential oils with yields from 0.15 - 0.35%. The oils were analyzed by GC-MS-FID and rechecked by measurements on two different instrumentation configurations. The main components of the studied essential oils were for Cinnamomum rigidifolium linalool (19.4%), alpha-pinene (13.8%), verbenone (9.9%) and cis-verbenol (8.9%), total identified 90.5%; for Dasymaschalon longiusculum spathulenol (21.4%), caryophyllene oxide (17.6%), a pinene (5.5%) and beta-pinene (5.2%), total identified 70.1%; for Fissistigma maclurei spathulenol (17.8%), guaia-6,10(14)-diene-40-ol (10.3%), (E)-beta caryophyllene (7.3%) and caryophyllene oxide (7.0%), total identified 75.3% and for Goniothalamus albiflorus 1,8-cineole (13.2%), alpha-pinene (10.6%), ledol (7.5%) and caryophyllene oxide (7.3%), total identified 78.0%. PMID- 30475512 TI - Detection and Identification of Antibacterial and Antioxidant Components of Essential Oils by TLC-Biodetection and GC-MS. AB - Components of cinnamon bark, rosemary, clove and thyme essential oils were screened for antioxidant and antibacterial activity utilizing thin-layer chromatography (TLC) coupled with the DPPH(.) test and direct bioautography using Bacillus subtilis cells. The compounds in the active chromatographic zones were identified by solid-phase microextraction-gas chromatography-mass spectrometry (SPME-GC-MS) after their elution. Seven antibacterial components were found: cinnamaldehyde and eugenol in cinnamon bark oil, 1,8-cineole, camphor, borneol and alpha-terpineol in rosemary oil, eugenol in clove oil and thymol in thyme oil. Only two of them, thymol and eugenol displayed a free radical scavenging effect. PMID- 30475513 TI - Essential Oils and Their Vapors as Potential Antibacterial Agents against Respiratory Tract Pathogens. AB - Increasing appearance of antibiotic-resistant pathogens, which could be one of the major causes of respiratory tract infections, has again drawn attention to natural substances and alternative treatments. Therefore, the aim of the present study was the antibacterial evaluation of cinnamon bark, clove, thyme, citronella, peppermint, Scots pine, and eucalyptus essential oils (EOs) against respiratory tract pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa with in vitro vapor phase (VP) and tube dilution (TD) techniques. The chemical and percentage compositions of the EOs were determined by GC-FID and GC-MS analysis. Among the EOs, cinnamon bark was the most effective against all the investigated pathogens (MIC: 31.25-125 MUL/L) in the VP assay, but clove oil presented the best inhibition against MRSA in liquid medium (MIC: 0.1 mg/mL). Thyme oil also showed antibacterial activity against MRSA and the antibiotic-sensitive strain of P. aeruginosa in both methods. In higher concentration, we found that peppermint oil was effective only in vapor form; contrarily, eucalyptus oil was more efficient in liquid medium. Surprisingly, Scots pine did not show any activity in our test systems. These results suggest that EOs could be promising solutions for the problem of antibiotic resistance due to their multiple composition and complex mode of action. However, more in vivo studies are necessary to calculate the effective dose of EOs in patients and determine their possible side effects and toxicity. PMID- 30475514 TI - Lantana montevidensis Essential Oil: Chemical Composition and Mosquito Repellent Activity against Aedes aegypti. AB - The essential oil (EO) of Lantana montevidensis (Spreng.) Briq. (L. sellowiana Link & Otto) was investigated for its chemical composition and mosquito repellent activity. The essential oil obtained by hydrodistillation of aerial plant parts was analyzed by GC-FID and GC-MS. The major constituents were p-elemene (22.0%), beta-caryophyllene (20.1%), and germacrene D (9.4%). Sesquiterpene hydrocarbons were present.in considerable quantities (78.9%) in the L. montevidensis EO, followed by oxygenated sesquiterpenes (8.9%), monoterpene hydrocarbons (7.7%), oxygenated monoterpenes (1.9%), diterpenes (1.2%) and other compounds (0.2%). The oil of L. montevidensis was repellent with a minimum effective dosage (MED) of 0.021 +/- 0.013 mg/cm(2) as compared with that of the positive control N,N diethyl-3-methylbenzamide (DEET) with a MED of 0.006 : 0.001 mg/cm(2)) against Aedes aegypti L. The major compound beta-elemene was tested individually for its repellency and had a MED value of 0.23 ? 0.14 mg/cm2 (DEET was 0.008 ? 0.001 mg/cm2). This is the first report on the repellent activity of L. montevidensis EO and P-elemene using human-based in vivo assays against Ae. aegypti. PMID- 30475515 TI - Chemical Composition, Antioxidant, Antimicrobial and Insecticidal Activities of Essential Oil from a Moroccan Endemic Plant: Bubonium imbricatum. AB - The chemical composition, antioxidant, antimicrobial and insecticidal properties of essential oil obtained by hydro-distillation from Bubonium imbricatum Cav. have been investigated. The essential oil of aerial parts was analyzed by GC-FID and GC-MS. A total of 63 compounds were identified representing more than 82% of the oil. The major components were cis-chrysanthenyl acetate (31.2%) and thymol isobutyrate (3.4%). The antioxidant activity was evaluated by the DPPH and reducing power test. The data showed moderate activity compared with the reference compounds. Our results showed strong activity of the investigated oil against all tested microorganisms. The highest antibacterial activity was observed against Bacillus subtilis (inhibition zone= 18 +/- 0.21, MIC= 0.18 mg/mL). In general, Gram-positive bacteria were more susceptible than Gram negative ones. Candida parapsilosis was the most sensitive among the Candida strains tested. LD50 and LD90 values were 33.1 and 53.1 ppm against 1-d-old larvae of Aedes aegypti L. PMID- 30475516 TI - Phytotoxic and Antibacterial Activity of Essential Oil of New Peppermint Cultivar. AB - A new menthol cultivar of Mentha x piperita L. bred in East Slovakia was evaluated for the biological activity of its essential oils (EOs). The content and composition of the EO components changed during plant development and the different effects of samples collected each month (April - September) within the growing season were noted. EOs are considered to be an important source of potential allelochemicals. Changes in EO composition influenced phytotoxic activity. Stimulation and inhibition of seed germination and root elongation occurred with different EO concentrations. The four tested bacterial strains: presented different resistance to the samples collected in different growing periods. PMID- 30475517 TI - Mint Flavorings from Candies Inhibit the Infectivity of Chlamydia pneumoniae. AB - The impact of solvent extracts from the distillation water (flavoring extracts) isolated from mint flavored candies on the infectivity of the intracellular bacterium Chlamydia pneumoniae was evaluated by an in vitro model of epithelial cell infections., The mint flavoring extracts were isolated from the candies by simultaneous hydrodistillation and their chemical composition, established by GC MS, demonstrated menthol and limonene as the most abundant components. Results obtained by treating C. pneumoniae elementary bodies (EBs) with the flavoring extracts or pure reference compounds showed a significant decrease in EB infectivity, achieved with most of the extracts. This antichlamydial activity could be related to the relatively high menthol content of the extracts. Overall, the obtained data indicates that the flavorings present in the candies are able to target the metabolically quiet, non-replicating form of the bacterium and to suppress the spread of this respiratory pathogen from one cell to another. PMID- 30475518 TI - The Use of the Comins-Meyers Amide in Synthetic Chemistry: an Overview. AB - Formylation reactions are fundamental operations in synthetic chemistry allowing the incorporation into a given structure formyl groups amenable to further deiivatization. Conceptually, the introduction of such groups through the reaction between an electrophilic donor and a nucleophilic acceptor (i.e. organometallic reagent) constitutes a reliable technique with widespread applications. In this Highlight, we summarize the effectiveness of the so called Comnins-Meyers amide - [2-(N-methyl-N-formylamino]pyridine - in such a chemistry with vistas to the synthesis of natural products and biologically active substrates. PMID- 30475519 TI - Multidimensional Effects of Soy Isoflavone by Food or Supplements in Menopause Women: a Systematic Review and Bibliometric Analysis. AB - Isoflavones can exert their action on various levels: on cardiovascular system, bone and muscle health, on cancer, on menopausal symptoms, on obesity, on thyroid and on cognitive function. The aim of this systematic review is to evaluate the multidimensional effects of phytoestrogens in postmenopausal woman, and specifically to explore the impact on scientific literature. A research strategy was planned on PubMed and Scopus by defining the following key words:: menopause, climacteric, soy, isoflavone, phytoestrogens, cardiovascular system, bone mineral density, muscle mass, cancer, thyroid, obesity, cognitive. A total of 43 studies (in humans) were retrieved. The majority (12) describe the applications of soy isoflavones on cardiovascular disease, followed by effects on bone and muscle health (9), and studies concerning their action on menopausal symptoms (7), on cancer (6), on obesity (4), on cognitive function (3) and on thyroid function (2). The citation analysis revealed a growing interest for this topic and the papers on thyroid function are the most cited. Citation trends ofthe articles regarding the action on cardiovascular disease and on obesity are growing in the last years. Concerning the research areas, this review has assessed the effectiveness of various activities of isoflavones on welfare of menopausal women. In particular, literature show that a specific dosage of isoflavdnes reduces cardiovascular disease (from 20 to 100 mg/die), may be protective in osteoporosis and muscular fatigue (from 20 to 80 mg/die), may be useful for cancer prevention on endometrium, mammary glands and liver (from 50 to 100 mg/die), might improve menopausal symptoms, particularly in reducing the frequency of hot flashes (from 50 to 120 mg/die), can reduce abdominal fat and circulating inflammatory markers (from 80 to 160 mg/die), may ameliorate the pdssible interaction between endogenous estrogen and thyroid function (75 mg/die) and improve visual memory (from 50 to 100 mg/die). PMID- 30475520 TI - Antinociceptive Properties of St. John's Wort (Hypericum perforatum) and Other Hypericum Species. AB - This review aims at a coherent summary of the results obtained from various studies that concern analgesic-like activity of the extracts of H. preforatum L and thirteen other Hypericum L. species (Hypericaceae). Botanical origin, plant organs and extraction modes of the plant material, experimental models, routes of administration and doses used for animal treatment are summarized. Mechanisms of action and substances (and even the synergy thereof) proposed so far to be responsible for the observed activity have also been discussed. Even though St. John's wort (H. perforatum) is the most renowned plant species of this genus, it is neither the only nor the most potent one in inducing pain relief. PMID- 30475521 TI - Zuccagnia punctata: A Review of its Traditional Uses; Phytochemistry, Pharmacology and Toxicology. AB - Zuccagnia punctata Cav. (Fabaceae, Caesalpiniaceae) is a plant with a long history of use in Argentine traditional medicines; it belongs to a monotypic genus, and is an endemic species of Argentina. This review provides a comprehensive overview of the traditional uses, phytochemistry, pharmacological activity and toxicology of Z. punctata. A wide range of traditional uses are cited in the literature such as antibacterial, antifungal, anti-inflammatory, and antitumor, among - others. Pharmacological studies to date have demonstrated significant activities that support the traditional uses of this plant. No human clinical trials had been - completed up to the time of this review and no toxic effect had been detected in animals. Compounds from different chemical groups have been isolated such las phenolic compounds and essential oils. Plant extracts and phytochemicals isolated exhibit a broad range of activities, anti inflamnatory, antibacterial, antifungal, antigenotoxic, antioxidant, antiulcer, and nematicidal. The main bioactive phytochemicals in the aerial parts (leaf, stem and flower) were identified as 2', 4'-dihydroxy-3'-methoxychalcone and 2', 4'-dihydroxychalcone and were proposed as chemical markers. Consequently, standardized dry extracts of aerial parts of Z. puntacta could be used in herbal medicinal products. Also, they could be included in phytotherapeutic preparations such as capsules, creams, and gels, and for microencapsulation. PMID- 30475522 TI - Leonurine, a Potential Agent of Traditional Chinese Medicine: Recent Updates and Future Perspectives. AB - Herba Leonuri, also named Chinese Motherwort, has been extensively investigated as an effective agent on the uterus system. Our group has been studying the natural products of Herba Leonuri for several years, and during this period, many biological activities of the drug were recognized. Leonurine (4-guanidino-N- butyl-syringate) is an alkaloid present in Herba Leonuri. Recently, growing evidence has highlighted the therapeutic potential of leonurine in multiple diseases, especially cardiovascular. In this review, we discuss the biological activities of leonurine, as well as recent advances involving this alkaloid. PMID- 30475523 TI - A Guidance Manual for the Toxicity Assessment of Traditional Herbal Medicines. AB - Herbal remedies have been used for thousands of years in worldwide traditional medicines for their potential health benefits. Although they are generally presumed safe unless a significant risk has been identified in humans, increasing number of case reports notify acute or chronic intoxications resulting from their use. This study aims to produce a scientific guide for the evaluation of traditional herbal medicines (THMs) in terms of their toxicity risks based on the published regulatory documents. For this purpose recommended in vitro and in vivo toxicity tests on medicinal products for human use issued by the international regulatory bodies are overviewed and they are then adopted to be used for the toxicity assessment of THMs. Accordingly, based on compilation of these issued regulations, the following tests are recommended for the toxicity assessment of THMs; in vitrocytotoxicity, genotoxicity, acute and repeated dose toxicity, carcinogenicity, reproductive and developmental toxicity, local tolerance tests, toxicokinetic studies, and additional toxicity tests including safety pharmacology, immunotoxicity and antigenicity, endocrine system toxicity, gastro intestinal toxicity, renal and hepatotoxicity, and drug interaction studies. This study describes and discusses the applicability of these tests for the risk assessment in THMs. PMID- 30475524 TI - Dynamics of morbidity of patients with malignant tumors of the tongue with regard to the stage of disease and histological structure of tumors (population-based study). AB - Introduction: Malignant tumors of the tongue (C-01. 02) are relatively rare visual tumor sites. Incidence rate in men is usually 4-5 times higher than in women. To estimate a complex of analytical rates with respect to malignant tumors of the tongue (morphological level of verification, the distribution of patients by the stage of disease, to evaluate one-year and relative survival, etc. ) in accordance with the state report (F. No35) is impossible since malignant tumors of the tongue are not considered separately. Such research can be performed only on the basis of data of the population-based cancer registry. Purpose of the study: To study the prevalence, the detailed structure of morbidity, to estimate a number of analytical rates characterizing malignant tumors of the tongue. Materials and methods: On the basis of materials of the International Agency for Research on Cancer (IARC), Statistical Handbooks of the P. A. Herzen Moscow Research Oncological Institute and database of the Population-based Cancer Registry of St. Petersburg there were studied all the aspects put in the purpose of the study, using a range of instructional techniques recommended by the International Association of Cancer Registries, which member we are at number 221. Results: This study showed that from 1970 to 2005 in various countries of the world the incidence rate (standardized rate the world standard) of malignant tumors of the tongue increased a little or maintained its level. In Russia it is possible to carry out such assessment only from 1989 to 2013. During this period the incidence rate of malignant tumors of the tongue has increased from 2,20/0000 till 2,30/0000 in men, and from 0,40/0000 and 0 ,50/0000 in women. In St. Petersburg-Leningrad since 1980 standardized rate of malignant tumors of the tongue has increased from 2,1 till 3,5 0/0000 in men or by 66. 6% and from 0,5 till 1,50/0000 in women three times more. Positive dynamics of survival rates of patients with malignant tumors of the tongue but a significant backlog from the European average retains. PMID- 30475525 TI - Diagnostic transcranial magnetic stimulation as a method of objective evaluation of motor pathways in patients with neoplastic and infectious brain damage. AB - The aim of our study was to evaluate validity of transcranial magnetic stimulation as evaluation tool of motor pathways condition dynamics in patients with gliomas and meningitis. There were included 91 patients: 40 children with aseptic meningitis, 26 matching age controls, 10 adults with gliomas and 16 matching controls. All patients underwent transcranial magnetic stimulation (TMS) before and after the treatment. TMS showed good tolerability in all groups. Significant improvement of central motor pathways conductivity (MEPs amplitudes) was seen in both groups. In meningitis group significant rising of functional state of motoneurons was seen as well. We propose that TMS proved to be effective evaluation tool of motor pathways condition dynamic in patients with gliomas and meningitis. PMID- 30475526 TI - Role of molecular-genetic abnormalities in pathogenesis and risk stratification of multiple myeloma. AB - Over the past decades the studies have greatly improved our understanding of the molecular basis of multiple myeloma (MM) and mechanisms of disease progression. The majority of the most widespread chromosomal aberrations, revealing in MM, has independent predictive value and influence on a choice of optimal treatment. There were observed 190 MM patients in hematologic hospitals of St. Petersburg. Genetic anomalies (GA) were detected at 3l,3% of patients and did not depend on their age. Patients with ISS III had a detectability of GA higher than with ISS II and ISS I (48, degrees % (24/5 degrees ), 2l,2% (7/33) and 27,6% (8/29)). Translocation t(ll;l4) was found in 23,3% (3O/129) patients; dell3q - 20,8% (27/13 degrees ); dell7p - at 8,4% (7/83); t(4;l4) - at 6,9% (9/13O), that allowed to stratify patients in groups of risk according to mSMART version l. O and 2. O. Median overall survival (OS) modified mSMART l. O in group of standard risk was 7 degrees months, high risk - 47,l months. Median OS mSMART 2. O in group of standard risk was 7 degrees months, intermediate risk - 47 months, high risk - 45 months. OS did not depend on age, clinical manifestations, treatment and other factors. PMID- 30475527 TI - Leiomyosarcoma of soft tissues. Clinical characteristic and results of treatment. AB - Clinical characteristics of leiomyosarcoma of soft tissues and results of treatment of patients with this pathology are presented. It was revealed that the peak of incidence was in the age group 5O-69 years. There was showed the priority of surgery, as the only method of treatment, and in the combined regimen with the overall five-year survival of 43,2% and 33,3% respectively. PMID- 30475528 TI - Kidney cancer with brain metastases. Prognostic factors and treatment outcome. AB - The aim of this study was to study the effectiveness of stereotactic radiosurgery by Gamma Knife in kidney cancer with brain metastases. There were analyzed results in 112 patients with such spread of the disease who received treatment in the Gamma Knife Center, Moscow. The median age of patients was 58 years (range, 33-77 years). Total number of metastatic lesions was 444, and the average number of brain metastases in one patient 4 (from 1 to 30). A single brain metastasis had 28 patients (25 %). Median of total volume of brain metastasis for each patient was 5. 9 cm3 (from 0. 1 to 29,1sm3). Mean marginal dose for metastatic lesion was 22 Gy (from 12 Gy to 26 Gy) and the average value of isodose, on which planning was performed - 64% (from 39% to 99%). The overall survival after radiosurgery was 37,7%, 16,4% and 9,3% for 12, 24 and 36 months, respectively, with a median overall survival of 9,1 months (95% CI = 7,1-11,8). New brain metastases after radiosurgical treatment occurred in 44 (54,3%) patients with a median of 10,1 months. (95% CI = 7-18). Local recurrences after radiosurgical treatment were detected in 19 (17%) patients with a median of 6,6 months (95% CI = 4,0-9,6). The Karnovsky index was >80. Local control was achieved in 96% of metastatic lesions in 87% of patients. Side effects of radiosurgical treatment occurred in 33. 8% of patients (6% radionecrosis and 23. 8% an increase of perifocal edema). Thus stereotactic radiosurgery by Gamma Knife is an effective treatment option for brain metastases in kidney cancer providing a high level of local control of metastatic lesions with minimal neurotoxicity. In a case of distant recurrence reuse of such treatment provides good local control and improves overall survival compared with other methods of treatment. PMID- 30475529 TI - Chemotherapy and intraoperative radiation therapy for operable stage III non small cell lung cancer. AB - The study was undertaken to evaluate results of combined modality treatment including intraoperative radiation therapy (IORT) in 202 patients with stage III non-small cell lung cancer. The 5-year disease-free and overall survival rates in patients who underwent 15 Gy IORT were 18. 7% and 29. 2%, respectively. The overall response rate to preoperative chemotherapy with paclitaxel/carboplatin was 43. 7%, treatment was well tolerated. Preoperative chemotherapy with paclitaxel/ carboplatin in combination with 15 Gy IORT led to a significant increase in the 5-year disease-free and overall survival rates to 31. 4% and 39. 2%, respectively (p<0. 05). The 5-year disease-free and overall survival rates were respectively 32. 6% and 40. 8% in patients who received additional administration of cisplatin combined with 10 Gy IORT. Radiosensibilization with cisplatin in patients treated with 15 Gy IORT increased the 5-year disease-free and overall survival rates to 41. 7% and 47. 9%, respectively (p<0. 05). PMID- 30475530 TI - Childbirth after treatment for breast cancer: experience of the P. A. Herzen Moscow Research oncology Institute. AB - The article presents an analysis of births after treatment for breast cancer in women of reproductive age. In details there is described this group of patients based on a retrospective analysis of case histories. Eight patients, included in this study, received anti-cancer treatment between 2000 and 2009. All pregnancies appeared on their own without the use of supporting reproductive technologies. There are presented oncological and reproductive outcomes. The discussion includes data of literature on the possibility of pregnancy after breast cancer treatment. PMID- 30475531 TI - Blood DNA radiosentivity as a predictive bindex of radiochemical treatment efficacy in cervical cancer patients. AB - Study of cervical cancer patients with I-III stage was performed with biomarker determination of the blood DNA radiosensitivity ex vivo. The biochemical index was measured before treatment start during 4 hours by use fluorescent dye. The relationship between changes of these index levels and volume tumor reductions after radiochemical treatment evidenced that blood DNA radiosensitivity was enabled to predict an outcome of the cervical cancer patient treatment earlier than the assessment of therapy efficacy by help of ultrasound measurements. PMID- 30475532 TI - Genetic disorders in primary brain glioblastomas. AB - Glioblastomas are characterized by a variety of genetic and epigenetic disorders, identification of which allows constantly expanding a list of genes directly involved in carcinogenesis, thus increasing molecular diagnostics, monitoring and predicting disease. Molecular-genetic studies of patients with glioblastomas allowed revealing changes relevant to this disease and determining their prognostic significance. In the future molecular-biological markers along with clinical and therapeutic factors may play a role of separate and independent factors of prognosis in patients with malignant brain lesions. PMID- 30475533 TI - Clinical significance of mammoscintigraphy results in breast cancer patients receiving neoadjuvant polychemotherapy. PMID- 30475534 TI - Molecular-biological properties of edematous-infiltrative form of breast cancer. AB - There was conducted a study of edematous-infiltrative form of breast cancer in comparison with other forms of locally advanced breast cancer in various molecular-biological parameters. It was provided an evaluation of expression of receptors of steroid hormones, mutational status of HER2/neu gene, mutation status of ALK gene (a number of copies of a gene, translocation of EML4-ALK, point mutations in exons 22-25). There were studied mutational changes of genes of signaling pathway PIK3-AKT-mTOR (point mutations in exons 9 and 2 degrees of PIK3CA gene and 4 in exon of AKT gene), mutations in exons 5-8 of p53 gene. It was found that in edematous breast cancer significantly more frequently there were met tumors with negative receptor status (p = 0.006) and a positive HER2/neu status (p<0,001). In 5% of patients with edematous-infiltrative breast cancer there was detected translocation of EML4-ALK (p = 0.045), while it was not found a single case of ALK gene amplification. In the analysis of PIK3CA gene it was revealed that significantly frequently mutations localized in exon 9 (p = 0.038). There were no statistically substantial differences in the number of point mutations of p53 gene between a grou of edematous-infiltrative breast cancer and a control group. PMID- 30475535 TI - Comparative results of preoperative chemoradiotherapy and thermochemoradiotherapy for locally advanced laryngeal cancer. AB - The study is based on the results of treatment of 60 patients with locally advanced laryngeal cancer (T3-4N0-3M0) exposed to combined treatment: 31 with preoperative chemoradiothera-py, 29 thermochemoradiotherapy. Radiotherapy was performed in the hyperfractionated mode: "1 Gy +1 Gy" (every 4-5 hours) 5 times a week to 30-40 Gy in total. Local hyperthermia was performed 2 times a week before the second fraction of radiotherapy in 3-4 sessions. Eight-day courses of chemotherapy were administered in the beginning of radiotherapy by scheme: vincristine (1. 4 mg/m2 per 1day), cisplatin (20 mg/m2 2, 3, 4 days), bleomycetin (10 mg/m2 5, 6 days), cyclophosphamide (200 mg/m2 7, 8 days). Surgical treatment was performed through 2,5 3 weeks after completion of radiotherapy. Local hyperthermia intensified the course of radiation reaction on the mucous of the larynx but not significant influenced on healing of surgical wounds. Thermochemoradiotherapy compared with chemoradiotherapy raised local relapse-free survival from 75 to 93% (p = 0. 07), regional, for a group of patients with stage N1-3 from 33 to 70%, N1-2 from 40 to 78% (p = 0. 1), loco -regional from 67 to 87% (p = 0. 04). Our findings suggest the necessity for further research on the use of thermochemoradiotherapy in combined treatment of patients with locally advanced laryngeal cancer. PMID- 30475536 TI - EPIDEMIOLOGICAL FEATURES OF BREAST CANCER IN THE REPUBLIC OF UZBEKISTAN. AB - There were analyzed epidemiological risk factors in 505 breast cancer patients receiving treatment in the Tashkent City Oncology Dispensary. The tumor was studied by the hormone-receptor status, the level of Her2/neu protein hyperexpression and proliferation index in tumor cells Ki 67. The risk of developing breast cancer was higher in women aged 40 to 60 years with the most adverse prognostic biological subtypes of breast cancer. The high incidence of hypothyroidism along with established epidemiological risk factor for breast cancer, such as obesity, was investigated. PMID- 30475537 TI - Prediction of the effect of neoadjuvant chemotherapy in patients with non-small cell lung cancer of stage III at phases of combined treatment. AB - We examined 100 patients with non-small cell lung cancer (NSCLC). In addition to surgery there was performed neoadjuvant chemotherapy (2-3 cycles) EP (cisplatin at a dose of 80 mg/m2 on first day + etoposide at a dose of 120 mg/ m2 on days 1,3,5). There were studied the levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) as prognostic factors in the use of neoadjuvant chemotherapy in patients with NSCLC. The control group consisted of 30 healthy volunteers. The baseline level of bFGF was necessary for the prediction of combined treatment in patients with NSCLC stage III. The threshold value bFGF>10,2 ng/ml allowed predicting a good effect from chemotherapy with a sensitivity of 71,4% and specificity of 80,6%, while the sensitivity of VEGF in terms of forecasting bicycles reached 42,9 %. The resulting algorithm for predicting of the effect of neoadjuvant chemotherapy of patients with NSCLC provided perspectives to improve the outcomes of such patients. PMID- 30475538 TI - Changes of infection of the prostate tissue by Herpesviridae family viruses and HPV in prostate cancer patients depending on the stage of the pathological process. AB - The role of infection in the beginning and progression of prostate cancer is not known to the end at the moment. Experimental data, presented in the article, are obtained by hybridization in situ and demonstrate high degree of infection of the prostate tissue by viruses with the oncogenic and oncomodulation properties HCMV, EBV, HHV8 and HPV. The authors revealed that in patients at different substages of T2 stage infection of the prostate tissue increased from T2a to T2c. The importance of these findings is discussed. PMID- 30475539 TI - Cancer of the vulva: modern methods of diagnostics and surgical treatment. AB - Over the last 15 years in the Novgorod Region the incidence of cancer of the vulva, with some fluctuations, increased almost 3 times and had a definite tendency to increase including HRV positive variants in younger persons. It was found that the use of new technologies in particular cryoapplication and expanded surgery with subsequent reconstructive plastic for cancer of the vulva, allowed reducing blood loss and the death rate to 0.58 per lOO thousand of female population. PMID- 30475540 TI - NON-INVASIVE MONITORING OF EGFR MUTATIONS IN NONSMALL CELL LUNG CANCER (NSCLC) DURING TARGETED THERAPY: STATE OF THE ART AND OUR EXPERIENCE. AB - Liquid biopsy is a promising approach to molecular tumor testing in the context of targeted therapy. During this pilot study we applied a high-sensitivity protocol for detection of tumor-derived mutations in circulating plasma DNA of EGFR-positive non-small cell lung cancer (NSCLC) patients during EGFR-TKI therapy. We showed that this protocol was well suited for dynamic monitoring during targeted therapy as well as for detection of acquired resistance mutations. PMID- 30475541 TI - Phenotypic and functional characteristics of dendritic cells and contents of suppressor cell populations in peripheral blood of breast cancer patients. AB - The progression or the appearance of distant metastases in breast cancer (BC) is influenced by a variety of antitumor immune response suppression mechanisms. In this paper we study circulating dendritic cells (DC) and the suppressor cell populations in peripheral blood of breast cancer patients. The study of phenotypic and functional properties of DCs was performed in the samples of intact and TLR-stimulated whole blood from breast cancer patients and healthy women by multicolor flow cytometry. To determine the suppressor cell population among lymphocytes multicolor panel comprising markers CD 4, CD 25, CD 127, FoxP3 was used. It is showed that the formation of secondary foci of tumor growth in patients was accompanied by disturbances of the functional activity plasmocytoid DC and accumulation of cells with immunosuppressive functions. PMID- 30475542 TI - TREATMENT OF LOCAL RADIATION LESIONS IN BREAST CANCER PATIENTS. AB - The purpose of this paper is the demonstration and analysis of the effectiveness of spinal cord stimulation in treatment of chronic drug-resistant neuropathy pain in a patient with radiation-induced plexopathy. She underwent radiation therapy for cancer of the right breast in 2000. Ten years later she complained with pain and weakness her right arm. After physical examination and investigation right side brachial plexopathy was diagnosed. Antidepressant and anticonvulsant had positive effect during one year but then pain appeared again. That is why the patient has been implanted the system of epidural electrostimulation of thickening of the cervical spinal cord. During the post-operative period significant improvement of pain relief was noted. The doses of analgesics were decreased. Spinal cord stimulation efficacy for treatment of chronic pain was repeatedly proved in clinical investigation and meta-analyses. Nevertheless spinal cord stimulation effects on radiation-induced neurological disorders and possible pathophysiological mechanisms are not enough examined. All these facts require further investigation. PMID- 30475550 TI - Pain in cancer and psychological methods of its correction. AB - Physical pain can be a major component of cancer patient's suffering but suffering itself covers much more different sides of a human being than physical manifestations and often happens in the absence of physical pain. Suffering or total pain include physical pain, social pain, psychological pain and spiritual pain, which have a mutual influence on each other. The efficacy of treatment of total pain in cancer patients may be increased by additional use of psychological methods of its correction. PMID- 30475569 TI - Sudden death in cancer pathology forensic-medical characteristics. AB - The article presents a review of references on causes of sudden death of persons suffering from oncological diseases. The paper describes the main mechanisms of sudden death of persons with cancer who are subjected to forensic-medical research. Data on the structure of sudden death for the last 10 years are demonstrated. The authors have identified the increase of a number of sudden deaths in the group with oncological pathology 2. 2 times more in comparison with 2005. There are showed peculiarities of forensic-medical diagnostics of reasons of sudden death in cancer. PMID- 30475570 TI - Contribution of Academician L. M. Shabad in the theory and practice of preventing cancer from exposure to carcinogenic agents (Leningrad period). AB - The article is devoted to the Leningrad period of activity of Academician Leon Manusovich Shabad, his contribution to the theory and practice of preventing cancer from exposure to carcinogenic agents. PMID- 30475571 TI - Hard@Soft Integrated Morning Glory-like Porous Carbon as Cathode for High Energy Lithium-ion Capacitor. AB - Lithium-ion capacitor (LIC) is a hybrid energy storage device that combines the energy storage mechanism of lithium-ion batteries and supercapacitors and presents the complementary features of them. However, imbalances of the capacity and kinetics between cathode and anode are still remained challenges. Herein, to address the issue of low capacity in cathode, we constructed a morning glory-like porous material crimped from an opening sandwich structure consisting of hard carbon inner layer and soft carbon outer layer, by coating graphene oxide containing flaky phenolic resin with coal tar pitch followed with carbonization and activation. Both the hard@soft carbon integrated design and the reduced graphene oxide network co-contributed to a favorable electrical conductivity and a developed microporosity. To against the sluggish kinetics limitation in anode, a structure-optimized MnO@C electrode prepared by pore-creating of CO2 from the MnCO3@polydopamine precursor was chosen due to its excellent rate performance. The LIC with this configuration can deliver a maximum energy density of 117.6 Wh kg-1 and an favorable cyclability of 76% capacity retain after 3000 cycles at 2050 W kg-1. Furthermore, the energy density of 27.8 Wh kg-1 can still be delivered even at a high power density of 10,250 W kg-1. In general, this well designed hybrid capacitor has a potential to make up the gap between lithium-ion batteries and supercapacitors. PMID- 30475572 TI - Tailored Polyimide-Graphene Nanocomposite as Negative Electrode and Reduced Graphene Oxide as Positive Electrode for Flexible Hybrid Sodium-ion Capacitors. AB - Redox-active polyimide materials hold a great promise for electrochemical energy storage applications, especially for flexible energy storage devices. However, the low utilisation efficiency due to poor electrical conductivity of the materials remains one of the greatest challenges. In this work, we designed and prepared polyimide-graphene composite materials and tested their electrochemical properties in sodium-ion capacitors. By manipulating the interfacial chemistry and interactions between the polyimide and graphene, composite electrode materials with different polyimide particle sizes and morphologies were obtained. Sodium-ion storage capacity was significantly improved, from ~ 50 mAh g-1 for pure polyimide to 225 mAh g-1 for a polyimide-graphene composite. A hybrid sodium ion capacitor fabricated with freestanding polyimide-graphene composite as the negative electrode and reduced graphene oxide as the positive electrode delivered energy densities of 55.5 Wh kg-1 and 21.5 Wh kg-1 at power densities of 395 W kg 1 and 3400 W kg-1, respectively. A flexible sodium-ion capacitor with outstanding mechanical properties was also demonstrated. PMID- 30475573 TI - Bioactive Nanofibers Induce Neural Transdifferentiation of Human Bone Marrow Mesenchymal Stem Cells. AB - The combination of biomaterials with stem cells is a promising therapeutic strategy to repair traumatic injuries in the central nervous system, and human bone marrow mesenchymal stem cells (BMSCs) offer a clinically translatable option among other possible sources of stem cells. We report here on the use of a supramolecular bioactive material based on a peptide amphiphile (PA), displaying a laminin-mimetic IKVAV sequence to drive neural transdifferentiation of human BMSCs. The IKVAV-PA self-assembles into supramolecular nanofibers that induce neuroectodermal lineage commitment after 1 week, as evidenced by the upregulation of the neural progenitor gene nestin ( NES) and glial fibrillary acidic protein ( GFAP). After 2 weeks, the bioactive IKVAV-PA nanofibers induce significantly higher expression of neuronal markers beta-III tubulin (TUJ-1), microtubule associated protein-2 (MAP-2), and neuronal nuclei (NEUN), as well as the extracellular matrix laminin (LMN). Furthermore, the human BMSCs exposed to the biomaterial reveal a polarized cytoskeletal architecture and a decrease in cellular size, resembling neuron-like cells. We conclude that the investigated supramolecular biomaterial opens the opportunity to transdifferentiate adult human BMSCs into neuronal lineage. PMID- 30475574 TI - Highly energetic materials-hosted 3D inverse opal-like porous carbon: stabilization/desensitization of explosives. AB - The precise control of sensitivity to external stimuli, e.g., impact, friction, and thermal energy, has been emphasized for highly energetic materials, including RDX and HMX. Such sensitivities could be controlled by adjusting the surface area or (in)organic additives however, increased stability leads to a decrease in the explosives' performance. Here, high-energy-density molecules hosted in inverse opal-like porous carbon (IOC) nanocomposites demonstrate the mechanical stabilization and desensitization of RDX and HMX inside the carbon nanostructure using host-guest chemistry techniques. For this strategy, the uniform, vacant voids of the IOC were used to provide internal crystallization for the impact/frictional stabilization of explosives, and also to enhance the thermal reactivity by the high heat conductivity of IOC initiating detonation by thermally induced hotspot. The weight percentage of high explosives hosted by recrystallization at high temperatures and in vacuum reached ~70%. After high explosives were embedded inside the IOC, the impact, friction and electrostatic stability was greatly increased (2~2.15 fold, 1.86~1.92 fold and 1.25~2, respectively) compared with free RDX and HMX. Also, addition of PVP as a binder controlled the effectiveness and efficiency of the carbon template, enabling control of the impact and friction sensitivity from 14.72 J to >79.43 J and from 295.81 N to 352.80 N, respectively. PMID- 30475575 TI - Core-Shell Electrospun Polycrystalline ZnO Nanofibres for Ultra-Sensitive NO2 Gas Sensing. AB - This paper discusses the growth of polycrystalline, self-supporting ZnO nanofibres which can detect nitrogen dioxide (NO2) gas down to 1 part per billion (ppb), one of the smallest detection limits reported for NO2 using ZnO. A new and innovative method has been developed for growing polycrystalline ZnO nanofibres. These nanofibres have been created using core-shell electrospinning of inorganic metal precursor zinc neodecanoate, where growth occurs at the core of the nanofibres. This process produces contamination-free, self-supporting, polycrystalline ZnO nanofibres of an average diameter and grain size 50 nm and 8 nm respectively, which are ideal for gas sensing applications. This process opens up an exciting opportunity for creating nanofibres from a variety of metal oxides, facilitating many new applications especially in the areas of sensors and wearable technologies. PMID- 30475576 TI - Collagen Functionalized With Graphene Oxide Enhanced Biomimetic Mineralization and In Situ Bone Defect Repair. AB - Biomimetic mineralization using simulated body fluid (SBF) can form a bone-like apatite (Ap) on the natural polymers and enhance osteoconductivity, biocompatibility and reduce immunological rejection. Nevertheless, the coating efficiency of bone-like apatite layer on natural polymers is still needed to be improved. Graphene oxide (GO) is rich in functional groups, such as carbonyls ( COOH) and hydroxyls (-OH), which can provide more active sites for biomimetic mineralization and improve the proliferation of the rat bone marrow stromal cells (r-BMSCs). In this study, we introduced 0% W/V, 0.05% W/V, 0.1% W/V and 0.2% W/V concentrations of GO into collagen (Col) scaffolds and immersed the fabricated scaffolds into SBF for 1, 7 and 14 days. In vitro environment scanning electron microscopy (ESEM), energy dispersive spectrometer (EDS), thermogravimetric analysis (TGA), micro CT, calcium quantitative analysis and cellular analysis were used to evaluate the formation of bone-like apatite on the scaffolds. In vivo implantation of the scaffolds into the rat cranial defect was used to analyse the bone regeneration ability. The resulting GO-Col-Ap scaffolds exhibited a porous and interconnected structure coated with a homogeneous distribution of bone-like apatite on their surfaces. Ca/P ratio of 0.1% GO-Col-Ap group was equal to that of natural bone tissue based on EDS analysis. More apatites were observed in 0.1% GO-Col-Ap group through TGA analysis, micro CT evaluation, and calcium quantitative analysis. Furthermore, the 0.1% GO-Col-Ap group showed significantly higher r-BMSCs adhesion and proliferation in vitro and more than two-fold higher bone formation than Col-Ap group in vivo. Our study provides a new approach of introducing graphene oxide into bone tissue engineering scaffolds to enhance biomimetic mineralization. PMID- 30475577 TI - 3D conductive scaffolds as Neural Prostheses based on Carbon Nanotubes and Polypyrrole. AB - Three-dimensional scaffolds for cellular organization need to enjoy a series of specific properties. On the one hand, the morphology, shape and porosity are critical parameters, and eventually re-lated with the mechanical properties. On the other hand, electrical conductivity is an important asset when dealing with electroactive cells, so it is a desirable property even if the conductivity values are not particularly high. Here, we construct 3D porous and conductive composites, where C8-D1A astrocytic cells were incubated to study their biocompatibility. The manufactured scaf-folds are composed exclusively of Carbon Nanotubes (CNTs), a most promising material to inter-face with neuronal tissue, and polypyrrole (PPy), a conjugated polymer demonstrated to reduce gliosis, improve adaptability and increase charge-transfer efficiency in brain-machine interfaces. We developed a new and easy strategy, based on the Vapor Phase Polymerization (VPP) tech-nique, where the monomer vapor is polymerized inside a sucrose sacrificial template containing CNT and an oxidant agent. After removing the sucrose template, a 3D porous scaffold was ob-tained whose physical, chemical and electrical properties were evaluated. The obtained scaffold showed very low density, high and homogeneous porosity, electrical conductivity and Young Modulus similar to the in vivo tissue. Its high biocompatibility was demonstrated even after 6 days of incubation, thus paving the way for the development of new conductive 3D scaffolds potentially useful in the field of electroactive tissues. PMID- 30475578 TI - The inhibition of guanfu base A on the neuropathic pain mediated by P2Y12 receptor in dorsal root ganglia. AB - Activation of satellite glial cells (SGCs) in the dorsal root ganglia (DRG) is involved in mechanical and thermal hyperalgesia. The upregulated P2Y12 receptor expressed in SGCs of the DRG participates the nociceptive transmission of neuropathic pain. Guanfu base A (GFA) has been reported to exhibit anti-arrhythmi and anti-inflammatory effects. In this study, we explored the effects of GFA on the P2Y12 receptor-mediated mechanical and thermal hyperalgesia in chronic constriction injury(CCI) rats. Sprague-Dawley rats were randomly divided into, sham operation group(Sham), CCI operation group(CCI), CCI rats treated with guanfu base A group(CCI+GFA) and control rats plus GFA group (Ctrl+GFA). Mechanical withdrawal threshold and thermal withdrawal latency were measured. P2Y12 expression in L4-L6 dorsal root ganglion (DRG) was detected by Quantitative real-time PCR and Western blot. Ater CCI treatment, mechanical and thermal hyperalgesia and the expression values of P2Y12 receptor mRNA and protein in DRG were increased. Dual-labeling immunofluorescence showed that the coexpression of P2Y12 receptor and glial fibrillary acidic protein (GFAP) in the DRG of CCI rats was increased compared to sham rats. GFA relieved mechanical and thermal hyperalgesia in the CCI rats, decreased the expression of P2Y12 mRNA and protein and phosphorylation of p38 MAPK in the DRG, and increased the ADP-downregulated cAMP concentrations in HEK293 cells transfected with P2Y12 plasmid. After CCI rats were treated with GFA, the coexpression of P2Y12 receptor and GFAP in the DRG was significantly decreased compared to the untreated CCI group. Thus, downregulating the P2Y12 receptor relieved mechanical and thermal hyperalgesia in the CCI rats. PMID- 30475579 TI - Modulation of proton-gated channels by antidepressants. AB - The chemical structures of some antidepressants are similar to those of recently described amine-containing ligands of acid-sensing ion channels (ASICs). ASICs are expressed in brain neurons and participate in numerous CNS functions. As such, they can be related to antidepressants action or side effects. We therefore studied the actions of a series of antidepressants on recombinant ASIC1a and ASIC2a, and on native ASICs in rat brain neurons. Most of the tested compounds prevented steady-state ASIC1a desensitization evoked by conditioning acidification to pH = 7.1. Amitriptyline also potentiated ASIC1a responses evoked by pH drops from 7.4 to 6.5. We conclude that amitriptyline has a twofold effect: it shifts activation to less acidic values while also shifting steady-state desensitization to more acidic values. Chlorpromazine, desipramine, amitriptyline, fluoxetine and atomoxetine potentiated ASIC2a response. Tianeptine caused strong inhibition of ASIC2a. Both potentiation and inhibition of ASIC2a were accompanied by the slowdown of desensitization suggesting distinct mechanisms of action on activation and desensitization. In experiments on native heteromeric ASICs, tianeptine and amitriptyline demonstrated the same modes of action as on ASIC2a although with reduced potency. PMID- 30475580 TI - Impact on Glioblastoma U87 Cell Gene Expression of a Carborane Cluster-bearing Amino Acid: Implications for Carborane Toxicity in Mammalian Cells. AB - Carboranes have been extensively investigated as potential drugs for the treatment of malignant human brain tumors by boron neutron capture therapy (BNCT). This non-invasive treatment modality utilizes compounds containing the non-radioactive isotope 10B which has a high propensity to capture slow neutrons. In response, it emits high energy alpha-particles that kill the cell. We have successfully synthesized a boron delivery agent by installing a boron-rich m carborane within the amino acid cysteine. Rapid uptake of this compound into U87 glioblastoma cells within 5 min of exposure was observed, and fluorescence microscopy studies showed that it was retained intracellularly after 48 h. In the absence of thermal neutrons, a cytostatic effect in U87 cells was observed at exposures ranging from 1 MUM to 1000 MUM relative to the control, while no change was observed at 1 MUM to 0.01 MUM. Microarray studies unveiled a wide range of unique changes in the gene expression profile of the U87 cells, particularly for the genes associated with cell cycle, which were observed to be greatly suppressed after treatment with the compound These results were validated by qPCR studies. Although the compound was designed for BNCT, its distinctive impacts on gene regulation reveal that it and other carborane-containing cluster molecules may exert unique heretofore unknown effects on the transcriptome, even in the absence of applied radiation. PMID- 30475581 TI - Tuning the Reactivity of Small Metal Clusters by Heteroatom Doping. AB - The reactivity of small metallic clusters, nanoparticles composed of a countable number of atoms (typically up to ~100 atoms), has attracted much attention due to the fascinating properties these objects possess toward a variety of molecules. Cluster reactivity often is significantly different from the homologous bulk, with gold as prototypical example. Bulk gold is the noblest of all metals, whereas small gold clusters react with carbon monoxide, molecular oxygen, and hydrocarbons, among others. Furthermore, cluster reactivity is strongly size and composition dependent, allowing a wide range of tuning possibilities. The study of cluster reactivity usually follows two routes of investigation. In the first, research aims for fundamental understanding of mechanisms, mainly driven by curiosity. One consequence of the inherent small size of a cluster is that atoms can arrange themselves very differently from the crystallographic structure of the homologous bulk. In addition, quantum confinement effects dominate the electronic structure of a cluster with atom-like electronic shells instead of the electronic bands in bulk. These features result in a very rich and size-dependent interaction of a cluster with small molecules, governed by a fine interplay between the geometry and the electronic structure of the system. An alternative research approach uses the investigation of chemical reactions of isolated small clusters in the gas phase as model systems for the reactions taking place in more complex systems. This offers several advantages compared to more conventional methods and techniques used to study such complex systems. First, clusters can be produced under well-defined conditions, with control over size, composition, and charge state. Second, clusters in the gas phase solely interact with the molecule(s) chosen by the researcher, since contaminations are limited by the high vacuum conditions of the experiments. Third, due to the small number of atoms involved, detailed quantum chemical calculations can be performed on the systems under investigation. Thus, even though gas phase clusters differ significantly in size and in environmental conditions from those encountered, for example, in industrial catalysis, they can be used to unravel the complicated nature of a metal-molecule chemical bonding process. In this Account, both routes of investigation are discussed. The nature of the interaction between small gas phase clusters with diverse molecules is described, stressing the broader relevance of these studies. Particular emphasis is given to the effect of heteroatom doping. By adding a different element to a cluster, its geometric and electronic structure is modified, thereby altering its reactivity. Specifically, the effect of varying size and composition of doped gold, platinum, and aluminum clusters on their reactivity toward diverse molecules, relevant for catalytic applications, is discussed. Most studies presented here combine experiments based on mass spectrometric techniques with density functional theory calculations, allowing a deep understanding of the reaction mechanisms at a molecular level. PMID- 30475582 TI - Bioinspired Macroscopic Ribbon Fibers with a Nacre-Mimetic Architecture Based on Highly Ordered Alignment of Ultralong Hydroxyapatite Nanowires. AB - A variety of biological materials in natural organisms supply a rich source of structural design guidelines and inspirations for the construction of advanced structural materials with excellent mechanical properties. In this work, inspired by the natural nacre and human bone, a kind of flexible macroscopic ribbon fiber made from highly ordered alignment of ultralong hydroxyapatite (HAP) nanowires and sodium polyacrylate (PAAS) with a "brick-and-mortar" layered structure has been developed by a scalable and convenient wet-spinning method. The quasi-long range orderly liquid crystal of one-dimensional ultralong hydroxyapatite nanowires is employed and spun into the continuous flexible macroscopic ribbon fiber. In this work, highly ordered ultralong HAP nanowires act as the hard "brick" and PAAS acts as the soft "mortar", and the nacre-mimetic layered architecture is obtained. The as-prepared flexible macroscopic HAP/PAAS ribbon fiber exhibits superior mechanical properties, and the maximum tensile strength and Young's modulus are as high as 203.58 +/- 45.38 MPa and 24.56 +/- 5.35 GPa, respectively. In addition, benefiting from the excellent flexibility and good knittability, the as-prepared macroscopic HAP/PAAS ribbon fiber can be woven into various flexible macroscopic architectures. Additionally, the as-prepared flexible macroscopic HAP/PAAS ribbon fiber can be further functionalized by incorporation of various functional components, such as magnetic and photoluminescent constituents. The as-prepared flexible macroscopic HAP/PAAS ribbon fiber has potential applications in various fields such as smart wearable devices, optical devices, magnetic devices, and biomedical engineering. PMID- 30475583 TI - Observable Two-Step Nucleation Mechanism in Solid-State Formation of Tungsten Carbide. AB - The nucleation of crystals from ubiquitous solid-state reactions impacts a wide range of natural and synthetic processes and is fundamental to physical and chemical synthesis. However, the microscopic organization mechanism of amorphous precursors to nanoscale clusters of ordered atoms (nucleus) in an all-solid environment is inaccessible by common experimental probes. Here, by using in situ transmission electron microscopy in combination with theoretical simulations, we show in the reactive formation of a metal carbide that nucleation actually occurs via a two-step mechanism, in which a spinodal-structured amorphous intermediate reorganizes from an amorphous precursor and precedes the emergence of a crystalline nucleus, rather than direct one-step nucleation from classical consideration. We further isolated a series of sophisticated dynamics during formation and development of the nucleus in real-space and interpreted them by thermodynamic favorability. We anticipate that such an indirect organization mechanism which contains a metastable intermedium among the free energy gap between precursors and nanocrystals has its chance in underlying most solid-state crystallizations, whereas the as-established experimental method represents a step forward in exploring fundamentals in chemical reaction, material engineering, etc. PMID- 30475585 TI - Signatures of Topological Superconductivity in Bulk Insulating Topological Insulator BiSbTe1.25Se1.75 in Proximity with Superconducting NbSe2. AB - The combination of superconductivity and spin-momentum locking at the interface between an s-wave superconductor and a three-dimensional topological insulator (3D-TI) is predicted to generate exotic p-wave topological superconducting phases that can host Majorana fermions. However, large bulk conductivities of previously investigated 3D-TI samples and Fermi level mismatches between 3D bulk superconductors and 2D topological surface states have thwarted significant progress. Here we employ bulk insulating topological insulators in proximity with two-dimensional superconductor NbSe2 assembled via Van der Waals epitaxy. Experimentally measured differential conductance yields unusual features including a double-gap spectrum, an intrinsic asymmetry that vanishes with small in-plane magnetic fields and differential conductance ripples at biases significantly larger than the superconducting gap. We explain our results on the basis of proximity induced superconductivity of topological surface states, while also considering possibilities of topologically trivial superconductivity arising from Rashba-type surface states. Our work demonstrates the possibility of obtaining p-wave superconductors by proximity effects on bulk insulating TIs. PMID- 30475584 TI - Scalable Preparation of Superamphiphobic Coatings with Ultralow Sliding Angles and High Liquid Impact Resistance. AB - In spite of great progress, preparation of superamphiphobic coatings with excellent static and dynamic superamphiphobicity remains challenging. Here, we report superamphiphobic coatings with ultralow sliding angles and high liquid impact resistance. The coatings were prepared by spray-coating the polysiloxane/silica stock suspensions, synthesized by hydrolytic condensation of silanes with silica nanoparticles. The superamphiphobicity relies on microstructure of the coatings, controllable by the diameter of silica nanoparticles. The coatings feature excellent static and dynamic superamphiphobicity for various liquids with surface tension as low as 23.8 mN m 1. Furthermore, we achieved large-scale preparation of the coatings, which paved the way for their applications. PMID- 30475586 TI - A Novel Inorganic Ni-La2O3 Composite with Superfast and Versatile Water Purification Behavior. AB - Water-purifying materials are of vital importance for providing sanitary water, especially in epidemic and disaster areas and for wilderness survival. Here, we report a novel inorganic composite with a fast, reusable and pleiotropic water purification ability. The composite of heterogeneous Ni-La2O3 nanofibers was developed using an easy, low-cost and large-scale production process, i.e., an electrospinning technique. Due to the unique heterostructure formed by introducing nickel nanoparticles into the La2O3 host, the nanocomposite fibers can rapidly remove various detrimental micropollutants with absorption rate constants hundreds of times greater than those of inorganic materials and activated carbons. In addition, the nanocomposite can be recycled by a soft washing procedure at ambient temperature and demonstrates a much more stable performance than the state-of-the-art activated carbon materials. Furthermore, the nanofibers have an excellent germicidal effect against the high-risk human pathogen Escherichia coli. Our work introduces a promising inorganic absorbent suitable for purifying life-sustaining water supplies in emergency situations and alleviating worldwide water shortages. PMID- 30475587 TI - Gold Nanoparticle-Stabilized, Tyrosine-Rich Peptide Self-Assemblies and Their Catalytic Activities in the Reduction of 4-Nitrophenol. AB - Peptides are suitable candidates for templates in the fabrication of various metal nanoparticles (NPs) because of their metal-binding ability and templating effect, which impart physicochemical properties to the produced nanoparticles. Peptide-binding gold nanoparticles (AuNPs) show high catalytic activity that permits their application in oxidation or reduction reactions. Herein, we prepared morphology-controllable AuNPs stabilized by self-assembled tyrosine-rich peptides (YC7) by varying the pH and YC7 peptide/Au3+ concentration ratio in 2-( N-morpholino)ethanesulfonic acid (MES) buffer solution. The catalytic activities of the YC7 peptide-stabilized AuNPs (YC7@AuNPs) were tested for 4-nitrophenol (4 NP) reduction, and kinetic analysis was performed to calculate the apparent rate constants and activation energies. The relatively low activation energy of the YC7@AuNPs could be explained by the hypothesis that the tyrosine-moiety of YC7 enriches the electron density of Au metal. PMID- 30475588 TI - NADPH-auxotrophic E. coli: a sensor strain for testing in vivo regeneration of NADPH. AB - Insufficient rate of NADPH regeneration often limits the activity of biosynthetic pathways. Expression of NADPH-regenerating enzymes is commonly used to address this problem and increase cofactor availability. Here, we construct an Escherichia coli NADPH-auxotroph strain, which is deleted in all reactions that produce NADPH with the exception of 6-phosphogluconate dehydrogenase. This strain grows on a minimal medium only if gluconate is added as NADPH source. When gluconate is omitted, the strain serves as a 'biosensor' for the capability of enzymes to regenerate NADPH in vivo. We show that the NADPH-auxotroph strain can be used to quantitatively assess different NADPH-regenerating enzymes and provide essential information on expression levels and/or concentrations of reduced substrates required to support optimal NADPH production rate. The NADPH-auxotroph strain thus provides a fast and effective metabolic platform for evaluating NADPH regeneration within the cellular context. PMID- 30475589 TI - Ultrasensitive Refractometry via Supercritical Angle Fluorescence. AB - Refractometry, namely, the measurement of refractive index (RI), provides information about various sample properties such as concentrations and molecular structure. One physical phenomenon which enables precise determination of a sample's RI in a microscope is the supercritical-angle fluorescence. This effect is observed when the fluorescence from an emitter near a glass-medium interface is captured by an objective lens with a high numerical aperture. The materials' index mismatch creates a distinguishable transition in the intensity pattern at the back focal plane of the objective that changes proportionally to the RI of the media. Here, we present a refractometry approach in which the fluorophores are preattached to the bottom surface of a microfluidic channel, enabling highly sensitive determination of the RI using tiny amounts of liquid (picoliters). With this method, we attained a standard deviation of 3.1 * 10-5 and a repeatability of 2.7 * 10-5 RI units. We first determine the capabilities of the device for glycerol-water solutions and then demonstrate the relevance of our system for monitoring changes in biological systems. As a model system, we show that we can detect single bacteria ( Escherichia coli) and measure population growth. PMID- 30475590 TI - Physicochemical Properties can be Key Determinants of Mesoporous Silica Nanoparticle Potency In Vitro. AB - Nanoforms of mesoporous silica (mSiNPs) are increasingly applied in medicine, imaging, energy storage, catalysis, biosensors and bioremediation. The impact of their physicochemical properties on health and the environment remain to be elucidated. In this work, newly synthesized mesoporous silica (sizes: 25, 70, 100, 170 and 600 nm; surface functionalization: pristine, C3- and C11-COOH moieties) were assessed for cytotoxicity and induction of inflammatory responses in vitro (A549, THP-1, J774A.1 cells). All toxicity endpoints were integrated to obtain simple descriptors of biological potencies of these mSiNPs. The findings indicate that mSiNPs are less bioactive than the nonporous reference SiNP used in this study. The C3-COOH modified mSiNPs were generally less cytotoxic than their pristine and C11-modified counterparts in the nano-range (<=100 nm). Carboxyl modified mSiNPs affected inflammatory marker release across all sizes with cell type specificity, suggesting a potential for immunomodulatory effects. Surface area, size, extent of agglomeration, zeta potential and surface modification appeared to be important determinants of cytotoxicity of mSiNPs based on association tests. Pathway analysis identified particle and cell type-specific alteration of cellular pathways and functions by mSiNPs. The integration of exposure-related biological responses in multiple cell lines to mSINPs allowed for a comprehensive evaluation of the impact of physicochemical factors on their toxicity characteristics. The integrated multi-level toxicity assessment approach can be valuable as a hazard screening tool for safety evaluations of emerging nanomaterials for regulatory purpose. PMID- 30475591 TI - Activatable Near-Infrared Fluorescence Imaging Using PEGylated Bacteriochlorin Based Chlorin and BODIPY-Dyads as Probes for Detecting Cancer. AB - Near infrared (NIR) fluorescent probes are attractive tools for biomedical in vivo imaging due to the relatively deeper tissue penetration and lower background autofluorescence. Activatable probes are turned on only after binding to their target, further improving target to background ratios. However, the number of available activatable NIR probes is limited. In this study, we introduce two types of activatable NIR fluorophores derived from bacteriochlorin; chlorin bacteriochlorin energy-transfer dyads and boron-dipyrromethene (BODIPY) bacteriochlorin energy-transfer dyads. These fluorophores are characterized by multiple narrow excitation bands with relatively strong emission in the NIR. Targeted bacteriochlorin-based antibody or peptide probes have been previously limited by aggregation after conjugation. Polyethylene glycol (PEG) chains were added to improve the hydrophilicity without altering pharmacokinetics of the targeting moieties. These PEGylated bacteriochlorin-based activatable fluorophores have potential as targeted activatable, multi-color NIR fluorescent probes for in vivo applications. PMID- 30475592 TI - Construction of Enzyme-Cofactor/Mediator Conjugates for Enhanced in Vitro Bioelectricity Generation. AB - Cofactor-dependent oxidoreduction and electron transfer play an important role in in vitro bioelectricity generation and many other enzyme biocatalysis reactions. To facilitate such electron generation and transfer, several approaches based on the coimmobilization of cofactors and oxidoreductases have been demonstrated. Herein, a convenient and immobilization-free approach of constructing enzyme cofactor and enzyme-mediator conjugates was developed. The in vitro bioelectricity generation reactions via enzymatic fuel cells were evaluated. The cells equipped by the conjugates exhibited significantly improved power output and stability in contrast to those mediated by unconjugated enzymes. These results may bring a new avenue in constructing efficient in vitro electron transfer chains for various biocatalysis applications. PMID- 30475593 TI - Influence of Library Composition on SourceTracker Predictions for Community-Based Microbial Source Tracking. AB - Community-based microbial source tracking (MST) utilizes high-throughput DNA sequencing to profile and compare the microbial communities in different fecal sources and environmental samples. SourceTracker, a program that compares a library of OTUs from fecal sources (i.e., sources) to those in environmental samples (i.e., sinks) in order to determine sources of fecal contamination, is an emerging tool for community-based MST studies. In this study, we investigated the ability of SourceTracker to determine sources of known fecal contamination in spiked, in situ mesocosms containing different source contributors. We also evaluated how SourceTracker results were impacted by accounting for autochthonous taxa present in the sink environment. While SourceTracker was able to predict most sources present in the in situ mesocosms, fecal source library composition substantially influenced the program's ability to predict source contributions. Moreover, prediction results were most reliable when the library contained only known sources, autochthonous taxa were accounted for and when source profiles had low intra-group variability. Although SourceTracker struggled to differentiate between sources with similar bacterial community structures, it was able to consistently identify abundant and expected sources, suggesting that the SourceTracker program can be a useful tool for community-based MST studies. PMID- 30475594 TI - A hollow core photonics crystal fiber based miniaturized sensor for detection of aggregation-induced emission molecules. AB - A miniature sensor for detection of aggregation-induced emission (AIE) molecule is proposed in this work. The sensing head is fabricated by use of hollow core photonic crystal fiber with a core diameter of about 4.8 MUm. The cladding holes are sealed by fusion splicing technique while the central hole remains open to allow the filtration of solution with AIE molecules. When the solution is excited by ultraviolet lamp, the fluorescence light is received by a fiber optic spectrometer. The fluorescence intensity is associated with the concentration of AIE molecules and the infiltrated core length. In the whole process of the experiments, the output peak wavelength is stable which indicates that the existing forms of AIE particles are stable and the fluorescence reabsorption can be neglected. The experimental results obtained are in accordance with the traditional microplate spectrophotometer methods. The most exciting result is the amount of sample measured can be as low as 0.36 nL, which allows detection of AIE molecules at only 0.02 pmol. In addition, the miniature sensor was successfully applied to detect an AIE-based bio-probe for evaluating the activity of DPP-4 inhibitor sitagliptin with IC50 of 69.32 nM. The advantage of small device size and nanoliter scale sample volume suggested the proposed sensor is promising in many biosensing applications. PMID- 30475595 TI - Capacity Degradation Mechanism and Cycling Stability Enhancement of AlF3 coated Nano-Rod Gradient Na[Ni0.65Co0.08Mn0.27]O2 Cathode for Sodium-Ion Batteries. AB - O3-type Na[NixCoyMnz]O2 materials are attractive cathodes for sodium-ion batteries because of their full-cell fabrication practicality, high energy density, and relatively easy technology transfer arising from their similarity to Li[NixCoyMnz]O2 materials, yet their performance viability with Ni-rich composition (x ? 0.6) is still doubtful. More importantly, their capacity degradation mechanism remains to be established. In this paper, we introduce an O3-type Ni-rich AlF3 coated nano-rod gradient Na[Ni0.65Co0.08Mn0.27]O2 cathode with enhanced electrochemical performance in both half-cells and full-cells. AlF3 coated nano-rod gradient Na[Ni0.65Co0.08Mn0.27]O2 particles were synthesized through a combination of dry ball-mill coating and columnar composition gradient design and deliver a discharge capacity of 168 mAh g-1 with 90 % capacity retention in half-cells (50 cycles) and 132 mAh g-1 with 90 % capacity retention in full-cells (200 cycles) at 75 mA g-1 (0.5C, 1.5 - 4.1 V). Through analysis of the cycled electrodes, the capacity degradation mechanism was unraveled in O3 type Ni-rich Na[NixCoyMnz]O2 from a structural perspective with emphasis on high resolution TEM, providing valuable information on improving O3-type Na[NixCoyMnz]O2 cathode performance. PMID- 30475597 TI - Validation and Applications of Protein-Ligand Docking Approaches Improved for Metalloligands with Multiple Vacant Sites. AB - Decoding the interaction between coordination compounds and proteins is of fundamental importance in biology, pharmacy, and medicine. In this context, protein- ligand docking represents a particularly interesting asset to predict how small compounds could interact with biomolecules, but to date, very little information is available to adapt these methodologies to metal-containing ligands. Here, we assessed the predictive capability of a metal-compatible parameter set for the docking program GOLD for metallo ligands with multiple vacant sites and different geometries. The study first presents a benchmark of 25 well-characterized X-ray metallo ligand-protein adducts. In 100% of the cases, the docking solutions are superimposable to the X-ray determination, and in 92% the value of the root-mean-square deviation between the experimental and calculated structures is lower than 1.5 A. After the validation step, we applied these methods to five case studies for the prediction of the binding of pharmacological active metal species to proteins: (i) the anticancer copper(II) complex [CuII(Br)(2-hydroxy-1-naphthaldehyde benzoyl hydrazine)(indazole)] to human serum albumin (HSA); (ii) one of the active species of antidiabetic and antitumor vanadium compounds, VIVO2+ ion, to carboxypeptidase; (iii) the antiarthritic species [AuI(PEt3)]+ to HSA; (iv) the antitumor oxaliplatin to ubiquitin; (v) the antitumor ruthenium(II) compound RAPTA-PentaOH to cathepsin B. The calculations suggested that the binding modes are in good agreement with the partial information retrieved from spectroscopic and spectrometric analysis and allowed us, in certain cases, to propose additional hypotheses. This method is an important update in protein-metallo ligand docking, which could have a wide field of application, from biology and inorganic biochemistry to medicinal chemistry and pharmacology. PMID- 30475596 TI - Design and Comparative Studies of Z-Scheme and Type II Based Heterostructures of NaNbO3/CuInS2/In2S3 for Efficient Photoelectrochemical Applications. AB - Here, we report the fabrication of a new Z-scheme based core/shell/shell heterostructure of NaNbO3/CuInS2/In2S3 (core/shell/shell) for photoelectrochemical (PEC) water splitting and also for degradation of organic pollutants. We have also performed a comparative study with a modified heterostructure of NaNbO3/In2S3/CuInS2 having Type II band alignment. The PEC measurements under visible light irradiation show increased photocatalytic performance for the NaNbO3/CuInS2/In2S3 heterostructures as revealed by a high current density of ~6.72 mA/cm2 at -1.0 V versus Ag/AgCl and low photocurrent onset potential of ~ -110 mV in comparison to the Type II system (~1.63 mA/cm2 and -180 mV vs Ag/AgCl). Mott-Schottky plots confirmed the n-p-n type heterojunction formation in the NaNbO3/CuInS2/In2S3 heterostructure which reduces the charge carrier recombination (revealed by PL intensity and short lifetime). The Z-scheme based system also exhibits excellent degradation efficiency (~99.6%) of organic pollutants. This work shows that the Z-scheme charge separation mechanism in NaNbO3/CuInS2/In2S3 nanostructures is more efficient than the Type II based on NaNbO3/In2S3/CuInS2. PMID- 30475598 TI - The Impact of Branching on the Solution Behavior and Serum Stability of Star-like Block Copolymers. AB - The size control of nanomedicines for tumor diagnosis and therapy is of high importance, since it enables or disables deep and sufficient tumor penetration. Amphiphilic star shaped block copolypept(o)ides offer substantial promise to precisely adjust the hydrophobic core and the hydrophilic corona, independent of each other, and therefore, simultaneously control the size dimension in the interesting size range from 10 - 30 nm. To gain access to core-shell structures of such sizes, 3-arm and 6-arm PeptoStars, based on poly(gamma-t-butyloxycarbonyl L-glutamate)-b-polysarcosine (pGlu(OtBu)-b-pSar), were prepared via controlled living ring-opening polymerization (ROP) of the corresponding N carboxyanhydrides. Moreover, size exclusion chromatography (SEC) proves the presence of well-defined star shaped polymers with molecular weights from 38 to 88 kg/mol with low polymer dispersities of 1.16 to 1.23. By varying the alpha helical peptide core and maintain a constant polysarcosine corona, hydrodynamic size analyses revealed the importance of using a sufficiently large and dense hydrophilic shielding corona to prevent aggregation of the hydrophobic core and obtain uniform-sized spherical-shaped particles with hydrodynamic diameters below 24 nm. Fluorescence correlation spectroscopy (FCS) additionally demonstrates the absence of protein adsorption in human plasma for 6-arm polypept(o)ide stars and thus, confirms polysarcosine as stealth-like material. PMID- 30475599 TI - New Acridine-Based Tridentate Ligand for Ruthenium(II): Coordination with a Twist. AB - A new tridentate ligand based on acridine has been synthetized. The central acridine heterocycle bears two pyridine coordinating units at positions 4 and 5. The terdentate 2,7-di- tert-butyl-4,5-di(pyridin-2-yl)acridine (dtdpa) was then coordinated to a ruthenium(II) cation. The corresponding homoleptic complex could only be obtained where both ligands coordinate to the ruthenium in a fac fashion. Thus, a heteroleptic compound (2) was constructed in combination with a terpyridine ligand in order to constrain the ligand to adopt a mer geometry. Such a coordination imposes a dramatic twist on the acridine heterocycle, resulting in an unexpected photophysical behavior. The electrochemical and photophysical properties of both complexes were studied, and the molecular structure of 2 was determined by X-ray diffraction. The two compounds absorb at low energy wavelengths, and a very weak luminescence is detected only for complex 2 in the near-infrared region. PMID- 30475600 TI - Solvent-Dependent Sensitization of Ytterbium and Neodymium via an Intramolecular Excimer. AB - We report the synthesis of a di(1-pyrenyl)phosphoryl acetophenone ligand containing two pyrenyl moieties linked by a single phosphorus atom. The ligand exhibits solvent-dependent emission: in nonpolar solvents, typical monomeric pyrene emission is observed, whereas in polar solvents, an additional broad and structureless emission appears. The emission in polar solvents is concentration independent and is attributed to the emission of an intramolecular excimer. The coordination of the di(1-pyrenyl)phosphoryl acetophenone ligand as well as the corresponding deprotonated anionic di(1-pyrenyl)phosphoryl acetophenonate ligand was studied with the near-infrared emitting lanthanides, neodymium and ytterbium. Solvent-dependent sensitization of both lanthanides was observed and correlates with the presence of the excimer emission. Sensitization of ytterbium is more efficient than neodymium, and the overall quantum yields were found to be 12.8 and 1.9% for ytterbium and neodymium, respectively. PMID- 30475601 TI - Effects of Conformational Changes in Peptide-CRM197 Vaccines. AB - Conjugate vaccines prepared with the cross-reactive material 197 (CRM197) carrier protein have been successful in the clinic and are of great interest in the field of immunotherapy. One route to preparing peptide-CRM197 conjugate vaccines involves an activation-conjugation strategy, effectively coupling lysine residues on the protein to cysteine thiolate groups on the peptide of interest using a heterobifunctional linker as an activation agent. This method has been found to result in two distinct populations of conjugates, believed to be the result of a conformational change of CRM197 during preparation. This report explores the factors that lead to this conformational change, pointing to a model in which the unintentional alkylation of histidine-21 by the activating agent promotes the "opening" of the monomeric protein. This exposes a new set of lysine residues that are modified by additional activation agents. Subsequent peptide ligation to these sites results the two conformers. This is the first time that a specific chemical modification is demonstrated to induce a defined conformational change for this carrier protein. Importantly, alternative conditions and reagents have been found to minimize this effect, improving the conformational homogeneity of peptide-CRM197 conjugates. PMID- 30475602 TI - A Novel Near-infrared Fluorescent Probe TMTP1-PEG4-ICG for in vivo Tumor Imaging. AB - Molecular imaging agents are considered to be promising tracers for tumor imaging and guided therapy. TMTP1 was screened through the FliTrx bacterial peptide display system in our laboratory previously and shown to specifically target to primary tumors and metastatic foci. In this study, Small peptide TMTP1 was designed to conjugate to a near-infrared fluorescent agent ICG derivative ICG-OSu through PEG4, forming the novel probe TMTP1-PEG4-ICG. It was successfully synthesized and certificated. CCK-8 assay showed it was nontoxic to normal cells and cancerous cells. Dynamics study indicated the probe was cleared through liver intestine and kidney-bladder pathway. Tumor targeting capability of this probe in vitro was evaluated on 4T1, SiHa, HeLa, S12 and HaCaT cells by flow cytometry. In vivo imaging of 4T1 and Hela tumor-bearing mice further identified the tumor homing ability. As we had expected, the probe showed excellent affinity to cancer cells not only in vitro but also in vivo, no matter in murine tumor or humanized tumor. In conclusion, TMTP1-PEG4-ICG demonstrated ideal imaging effect on tumor bearing mice model, providing new opportunities for tumor diagnostic or guiding resection. PMID- 30475603 TI - Solubility and Complexation of the Bismuthate Ion in Nitric Acid Systems. AB - The dissolution rate and solubility of NaBiO3 have been investigated in nitric acid systems ranging from 4 to 6 M HNO3 and were found to be 58-76 MUg/cm2.d and 490-830 mM, respectively. The presence of 50 mM U(VI) drastically increased the solubility to 540-1200 mM, while rates of dissolution were relatively unchanged. The solubility of NaBiO3 increased with an increase in U(VI) concentrations at 4 M HNO3, with log-log analysis indicating a one-to-one complex between Bi and U and infrared spectroscopic evidence monitoring uranyl stretching, suggesting complex formation. Absorbance spectra were obtained experimentally and computationally with an absorbance band in the range of 450-600 nm that has been attributed to Bi(V). The ingrowth and decay of Bi(V) in solution was also studied as a function of mass of solid NaBiO3 present, acidity, and temperature. The activation energies of dissolution and decomposition were calculated to be 39 +/- 4 and 61 +/- 6 kJ/mol, respectively. These results indicate that dissolution of NaBiO3 into the respective Na+ and BiO3-occurs prior to undergoing reduction, a process which conventionally has been believed to occur in the reverse order. PMID- 30475604 TI - Synthesis of Ultrathin Few-Layer 2D Nanoplates of Halide Perovskite Cs3Bi2I9 and Single-Nanoplate Super-Resolved Fluorescence Microscopy. AB - The discovery of new two-dimensional (2D) perovskite halides has created sensation recently because of their structural diversity and intriguing optical properties. The toxicity of Pb-based perovskite halides led to the development of Pb-free halides. Herein, we have demonstrated a one-pot solution-based synthesis of 2D ultrathin (~1.78 nm) few-layer (2-4 layers) nanoplates (300-600 nm lateral dimension), nanosheets (0.6-1.5 MUm), and nanocrystals of layered Cs3Bi2I9 by varying the reaction temperature from 110 to 180 degrees C. We have established a mechanistic pathway for the variation of morphology of Cs3Bi2I9 with temperature in the presence of organic capping ligands. Further, we have synthesized the bulk powder of Cs3Bi2I9 by mechanochemical synthesis and liquid assisted grinding and crystalline ingot by vacuum-sealed tube melting. 2D nanoplates and bulk Cs3Bi2I9 demonstrate optical absorption edge along with excitonic transition. Photoluminescence properties of individual nanoplates were studied by super-resolution fluorescence imaging, which indicated the blinking behavior down to the level of an individual Cs3Bi2I9 nanoplate along with its emission at the far-red region and high photostability. PMID- 30475605 TI - Insight into the Crystalline Structure of ThF4 with the Combined Use of Neutron Diffraction, 19F Magic-Angle Spinning-NMR, and Density Functional Theory Calculations. AB - Because of its sensitivity to the atomic scale environment, solid-state NMR offers new perspectives in terms of structural characterization, especially when applied jointly with first-principles calculations. Particularly, challenging is the study of actinide-based materials because of the electronic complexity of the actinide cations and to the hazards due to their radioactivity. Consequently, very few studies have been published in this subfield. In the present paper, we report a joint experimental-theoretical analysis of thorium tetrafluoride, ThF4, containing a closed-shell actinide (5f0) cation. Its crystalline structure has been revisited in the present work using powder neutron diffraction experiments. The 19F NMR parameters of the seven F crystallographic sites have been modeled using an empirical superposition model, periodic first-principles calculations, and a cluster-based all-electron approach. On the basis of the atomic position optimized structure, a complete and unambiguous assignment of the 19F NMR resonances to the F sites has been obtained. PMID- 30475606 TI - Long-range hierarchical nanocrystal assembly driven by molecular structural transformation. AB - The hierarchical control in biogenic minerals, from precise nanomorphology control to subsequent macroscopic assembly, remains a formidable challenge in artificial synthesis. Studies in biomineralization, however, are largely limited to atomic/molecular scale crystallization, devoting little attention to biomolecular higher order structures (HOSs) which impact critically on long-range assembly of biominerals. Here we demonstrate a biomimetic route that explores peptide HOSs on guiding nanocrystal formation and anisotropic assembly into hierarchical structures. It is found that Pt{100} specific peptide T7 (Ac-TLTTLTN CONH2) adopts ST-turn, promoting cubic Pt nanocrystal formation at low concentration, and spontaneously transforms into beta-sheet with increased concentration. The beta-sheet T7-Pt{100} specificity drives cubic Pt nanocrystals to self-assemble into large-area, long-range, [100] linear assemblies. This study provides a robust demonstration for bio/non-biogenic material specificity, nanoscale synthesis, and long-range self-organization with biomolecular HOSs, and opens vast opportunities for multiscale programmable structures. PMID- 30475607 TI - Monitoring of glycoprotein quality control system with a series of chemically synthesized homogeneous native and misfolded glycoproteins. AB - The glycoprotein quality control (GQC) system in the endoplasmic reticulum (ER) effectively uses chaperone-type enzymes and lectins such as UDP glucose:glycoprotein glucosyltransferase (UGGT), calnexin (CNX), calreticulin (CRT), protein di-sulfide bond isomerases (ERp57 or PDIs), and glucosidases to generate native-folded glycoproteins from nascent glycopoly-peptides. However, the individual processes of the GQC system at the molecular level are still unclear. We chemically syn-thesized a series of several homogeneous glycoproteins bearing M9-high-mannose type oligosaccharides (M9-glycan), such as erythropoietin (EPO), interferon-? (IFN-?), and interleukin 8 (IL8) and their misfolded counterparts, and used these glycopro-tein probes to better understand the GQC process. The analyses by high performance liquid chromatography and mass spec trometer clearly showed refolding processes from synthetic misfolded glycoproteins to native form through folding interme-diates, allowing for the relationship between the amount of glucosylation and the refolding of the glycoprotein to be estimat-ed. The experiment using these probes demonstrated that GQC system isolated from rat liver acts in a catalytic cycle regulat-ed by the fast crosstalk of glucosylation/deglucosylation in order to accelerate refolding of misfolded glycoproteins. PMID- 30475608 TI - A Dynamic Tetracationic Macrocycle Exhibiting Photoswitchable Molecular Encapsulation. AB - Designing macrocycles with appropriate molecular recognition features that allow for the integration of suitable external stimuli to control host-guest processes is a challenging endeavor which enables molecular containers to solubilize, stabilize and separate chemical entities in an externally controlled manner. Herein, we introduce photo- and thermal-responsive elements into a semi-rigid tetracationic cyclophane, OPVEx2Box4+, that is composed of oligo(p phenylenevinylene) pyridinium units and the biphenylene-bridged 4,4-bipyridinium extended viologens, and adopts a rectangle-like geometry. It transpires that the reversibility of the photoactive oligo(p-phenylenevinylene) pyridinium unit is dramatically improved when incorporated in a macrocyclic scaffold, and the configurations of the cyclophane can go back and forth between (EE)- and (EZ) isomers upon alternating blue light irradiation and heat. When the macrocycle is found in its (EE)-configuration, it is capable of binding various pi-electron rich guests?e.g., anthracene and perylene?as well as pi-electron-deficient guests?e.g., 9,10-anthraquinone and 5,12-tetracenequinone?through charge transfer and van der Waals interactions. When irradiated with blue light, the (EE)-isomer of the cyclophane can be transformed successfully to the (EZ)-isomer, resulting in the switching off of the binding affinity for guest molecules, which are bound once again upon heating. The use of light and heat as external stimuli to control host-guest interaction involving a multi-responsive host and various guests provides us with a new opportunity to design and construct more advanced molecular switches and machines. PMID- 30475609 TI - Direct Asymmetric Hydrogenation of N-Methyl and N-Alkyl Imines with an Ir(III)H Catalyst. AB - A novel cationic [IrH(THF)(P,N)(imine)] [BArF] catalyst containing a P stereogenic MaxPHOX ligand is described for the direct asymmetric hydrogenation of N-methyl and N-alkyl imines. This is the first catalytic system to attain high enantioselectivity (up to 94% ee) in this type of transformation. The labile tetrahydrofuran ligand allows for effective activation and reactivity, even at low temperatures. Density functional theory calculations allowed the rationalization of the stereochemical course of the reaction. PMID- 30475610 TI - Stereoretentive C( sp3)-S Cross-Coupling. AB - We report a stereoretentive cross-coupling reaction of configurationally stable nucleophiles with disulfide and N-sulfenylsuccinimide donors promoted by Cu(I). We demonstrate the utility of this method in the synthesis of thioglycosides derived from simple alkyl and aryl thiols, thioglycosides, and in the glycodiversification of cysteine residues in peptides. These reactions operate well with carbohydrate substrates containing common protective groups and reagents with free hy-droxyl and secondary amide functionalities under standardized conditions. Competition experiments in combination with computational DFT studies established that the putative anomeric intermediate is an organocopper species that is configura-tionally stable and resistant to epimerization due to its short lifetime. The subsequent reductive elimination from the Cu(III) intermediate is rapid and stereoretentive. Taken together, the glycosyl cross-coupling is ideally suited for late stage glycodi-versification and bioconjugation under highly controlled installation of the aliphatic carbon sulfur bonds. PMID- 30475611 TI - Enzyme Architecture: Breaking Down the Catalytic Cage that Activates Orotidine 5' Monophosphate Decarboxylase for Catalysis. AB - We report the results of a study of the catalytic role of a network of four interacting amino acid side chains at yeast orotidine 5'-monophosphate decarboxylase (ScOMPDC), by the stepwise replacement of all four side chains. The H-bond, which links the -CH2OH side chain of S154 from the pyrimidine umbrella loop of ScOMPDC to the amide side chain of Q215 in the phosphodianion gripper loop, creates a protein cage for the substrate OMP. The role of this interaction in optimizing transition state stabilization from the dianion gripper side chains Q215, Y217 and R235 was probed by determining the kinetic parameter kcat/Km for 16 enzyme variants, which include all combinations of single, double, triple and quadruple mutations of S154A Q215A, Y217F and R235A. The effects of consecutive Q215A, Y217F and R235A mutations on DeltaG? for wildtype enzyme-catalyzed decarboxylation sum to 11.6 kcal/mol, but to only 7.6 kcal/mol, when starting from S154A mutant. This shows that the S154A mutation results in a (11.6 - 7.6) = 4.0 kcal/mol decrease in transition state stabilization from interactions with Q215, Y217 and R235. Mutant cycles show that ca 2 kcal/mol of this stabilization at wildtype ScOMPDC is from the direct interaction of the Q215 side chain and that ca. 2 kcal/mol is from a tightening in the interactions with Y217 and R235. The sum of the effects of single S154, Q215, Y217 and R235 substitutions at the quadruple mutant of ScOMPDC on DeltaG? , 5.4 kcal/mol, is much smaller than 16.0 kcal/mol, the sum of the effects of the related four substitutions at wildtype ScOMPDC to give the respective single mutants. The former small effects are consistent with a large entropic cost to holding the flexible loops of ScOMPDC in the active closed conformation. PMID- 30475612 TI - Quasi-Chemical Theory with Cluster Sampling from Ab Initio Molecular Dynamics: Fluoride (F-) Anion Hydration. AB - Accurate predictions of the hydration free energy for anions typically has been more challenging than for cations. Hydrogen bond donation to the anion in hydrated clusters such as F(H2O)n- can lead to delicate structures. Consequently, the energy landscape contains many local minima, even for small clusters, and these minima present a challenge for computational optimization. Utilization of cluster experimental results for the free energies of gas phase clusters shows that, even though anharmonic effects are interesting, they need not be of troublesome magnitudes for careful applications of quasi-chemical theory to ion hydration. Energy-optimized cluster structures for anions can leave the central ion highly exposed and application of implicit solvation models to these structures can incur more serious errors than for metal cations. Utilizing cluster structures sampled from ab initio molecular dynamics simulations substantially fixes those issues. PMID- 30475613 TI - A Simple and Effective Binomial Block Based Pulse Sequence Capable of Suppressing Multiple NMR Signals. AB - A binomial-like block based multiple suppression NMR pulse sequence, termed MULTI GATE-FSB, that is simple to implement with outstanding suppression performance for multiple solvent signals (or multiple resonances) is investigated. The sequence was tested on two water-alcohol solvent systems, and a standard lysozyme sample, and with suppression of three or four regions (though it is extendable to any number of regions). The suppression of all solvent signals was possible in the alcohol-water systems tested with both long and short recycle delays, and without the requirement for lengthy pre-saturation pulses. Such a sequence holds promise not only for LC-NMR applications and solvent suppression but for multiple suppression applications in general (e.g., analysis of impurities/components). PMID- 30475614 TI - Enantioselective Allylic Alkylation with 4-Alkyl-1,4-dihydro-pyridines Enabled by Photoredox/Palladium Cocatalysis. AB - Highly regio- and enantioselective allylic alkylation has been achieved enabled by the merger of photoredox and palladium catalysis. In this dual catalytic process, alkyl radicals generated from 4-alkyl-1,4-dihydropyridines act as the coupling partners of the pi-allyl palladium complexes. The generality of this method has been illustrated through the reaction of a variety of allyl esters with 4-alkyl-1,4-dihydropyridines. This mechanistically novel strategy expands the scope of the traditional Pd-catalyzed asymmetric allylic alkylation reaction and serves as its alternative and potential complement. PMID- 30475615 TI - Identifying Single Viruses Using Biorecognition Solid-State Nanopores. AB - Immunosensing is a bioanalytical technique capable of selective detections of pathogens by utilizing highly specific and strong intermolecular interactions between recognition probes and antigens. Here, we exploited the molecular mechanism in artificial nanopores for selective single-virus identifications. We designed hemagglutinin antibody mimicking oligopeptides with a weak affinity to influenza A virus. By functionalizing the pore wall surface with the synthetic peptides, we rendered specificity to virion-nanopore interactions. The ligand binding thereof was found to perturb translocation dynamics of specific viruses in the nanochannel, which facilitated digital typing of influenza by the resistive pulse bluntness. As amino acid sequence degrees of freedom can potentially offer variety of recognition ability to the molecular probes, this peptide nanopore approach can be used as a versatile immunosensor with single particle sensitivity that promises wide applications in bioanalysis including bacterial and viral screening to infectious disease diagnosis. PMID- 30475616 TI - Highly Diastereoselective Synthesis of A HCV NS5B Nucleoside Polymerase Inhibitor. AB - An asymmetric synthesis of HCV NS5B nucleoside polymerase inhibitor (1) is described. This novel route features several remarkably diastereoselective and high yielding transformations, including construction of the all carbon quaternary stereogenic center at C-2 via a thermodynamic aldol reaction. Subsequent glycosylation reaction with activated uracil via C-1 phosphate, and installation of the cyclic phosphate group using an achiral phosphorous (III) reagent followed by oxidation provides 1. PMID- 30475617 TI - Dynamic Nuclear Polarization Using Photo-Excited Triplet Electron Spins in Eutectic Mixtures. AB - Dynamic nuclear polarization using photo-excited triplet electrons (Triplet-DNP) is a method to significantly enhance nuclear spin polarization even in a low magnetic field and at room temperature. Pentacene has been practically used as an efficient polarizing agent for Triplet-DNP. In this study, we demonstrate room temperature 1H and 13C hyperpolarization of eutectic mixtures of deuterated benzoic acid doped with pentacene and a target molecule such as salicylic acid, nicotinic acid, or 2-naphthoic acid. These molecules are otherwise difficult to hyperpolarize by Triplet-DNP due to the low pentacene-dopabilities of these molecules. The highest 1H polarization of 1.2% has been obtained for the eutectic mixture of salicylic acid in 0.39 T. The present sample preparation is a crucial method to widen the range of applications of Triplet-DNP to chemical and biomedical analyses. PMID- 30475618 TI - Quantitative Assessment of Thermodynamic Theory in Elucidating Behavior of Water under Hydrophobic Confinement. AB - A macroscopic thermodynamics-based theory that can quantitatively describe the behavior of water confined between hydrophobic solutes has so far remained elusive. In this work, we progress towards this goal by comparing the predictions of macroscopic theory with the results from computer simulations. We have determined free energy profiles of water confined between two nanometer-sized surfaces of varying hydrophobicity using molecular simulations, and have estimated thermodynamic properties such as contact angle, line tension and size of the critical vapor tube from independent simulations. We show that the scaling of free energy barrier to evaporation is fairly-well captured by the factor (D/2+lambda/gammaLV)2, where D is the confinement gap and lambda/gammaLV is the ratio of line-tension and liquid-vapor surface tension. The radius of the critical vapor tube necessary for nucleating evaporation scales by the factor (D/2+lambda/gammaLV). Exclusion of the line-tension term leads to a qualitative disagreement between theoretical predictions and results from molecular simulations. We also demonstrate that macroscopic theory that includes the line tension term is able to quantitatively match the entire free energy profile associated with the formation of a vapor-tube inside the confined region for conditions when the vapor state is the most stable state. The match is however only qualitatively correct for the conditions when the liquid state is more stable. Overall, the conclusion is that the inclusion of line-tension in macroscopic theory is necessary to describe the behavior of water under nanoscale confinement between two hydrophobic solutes. PMID- 30475619 TI - Exciton Dynamics of Photoexcited Pendant Porphyrin Polymers in Solution and in Thin Films. AB - Several new polymers with rotatable zinc porphyrin pendants have been synthesized and their optical spectroscopic and photophysical properties, including upconversion efficiencies, determined in both fluid solution and thin films. Comparisons made with the ?-substituted zinc tetraphenylporphyrin monomers and ZnTPP itself reveal that the yield of triplets resulting from either Q-band or Soret-band excitation of the polymers is surprisingly small. A detailed kinetic analysis of the fluorescence decays and transient triplet absorptions of the substituted monomers and their corresponding polymers reveals that this phenomenon is due to two parallel internal singlet quenching processes assigned to transient intrachain excimer formation. Consequently, the yields of upconverted S2 fluorescence resulting from Q-band excitation in the degassed polymers are significantly diminished in both fluid solution and thin films. Implications of these results for the design of polymer upconverting systems are discussed. PMID- 30475620 TI - Molecular Self-assembly Strategy for Encapsulation of an Amphipathic alpha Helical Antimicrobial Peptide into the Different Polymeric and Copolymeric Nanoparticles. AB - Encapsulation of peptide and protein-based drugs in polymeric nanoparticles is one of the fundamental fields in controlled-release drug delivery systems. The molecular mechanisms of absorption of peptides to the polymeric nanoparticles are still unknown and there is no precise molecular data on the encapsulation process of peptide and protein-based drugs. Herein, the self-assembly of different polymers and block copolymers with combinations of the various molecular weight of blocks and the effects of resultant polymer and copolymer nano-micelles on the stability of magainin2, an alpha-helical antimicrobial peptide, were investigated by means of all-atom molecular dynamics (MD) simulation. The micelle forming, morphology of micellar aggregations and changes in the first hydration shell of the micelles during micelles formation were explored, as well. The results showed that the peptide binds to the polymer and copolymer micelles and never detaches during the MD simulation time. In general, all polymers and copolymers simultaneously encapsulated the peptide during micelles formation and had the ability to maintain the helical structure of the peptide, whereas the first hydration shell of the peptide remains unchanged. Among the micelles, the polyethylene glycol (PEG) micelles completely encapsulated magainin2 and, surprisingly, the NMR structure of the peptide was perfectly kept during the encapsulation process. The MD results also indicated that the aromatic and basic residues of the peptide strongly interact with polymers/copolymers and play important roles in the encapsulation mechanism. This research will provide a good opportunity in the design of polymer surfaces for drug delivery applications such as controlled-release peptide delivery systems. PMID- 30475621 TI - Structural and functional assessment of mBjAMP1, an antimicrobial peptide from Branchiostoma japonicum, revealed a novel alpha-hairpinin-like scaffold with membrane permeable and DNA binding activity. AB - Here we describe the three-dimensional structure and antimicrobial mechanism of mBjAMP1, an antimicrobial peptide (AMP) isolated from Branchiostoma japonicum. The structure of mBjAMP1 was determined by 2D solution NMR spectroscopy and revealed a novel alpha-hairpinin-like scaffold stabilized by an intramolecular disulfide bond. mBjAMP1 showed effective growth inhibition and bactericidal activities against pathogenic bacteria but was not cytotoxic to mammalian cells. Antimicrobial mechanism studies using fluorescence-based experiments demonstrated that mBjAMP1 did not disrupt membrane integrity. Laser-scanning confocal microscopy indicated that mBjAMP1 is able to penetrate the bacterial cell membrane without causing membrane disruption. Moreover, gel retardation assay suggested that mBjAMP1 directly binds to bacterial DNA as an intracellular target. Collectively, mBjAMP1 may inhibit cellular functions by binding to DNA or RNA after penetrating the bacterial cell membrane, thereby causing cell death. These results suggest that mBjAMP1 may present a promising template for the development of peptide-based antibiotics. PMID- 30475622 TI - Water Clathrates in Nanostructural Organization of Hydrated Ionic Liquids Manifest in Peculiar Density Trend. AB - Ionic liquid-water binary solutions have significantly expanded the applications of ionic liquids (ILs) in chemical and biological research. Therefore, considerable research has focused on measuring the thermophysical properties of these binary mixtures. From low-to-moderate concentrations of water, several IL/water mixtures exhibit deviations from expected trends in thermophysical behavior. One such example is a unique density trend observed for certain IL classes, which exhibit a characteristic increase in density with the addition of small amounts of water. Since water primarily interacts with the IL anion, such deviations have always been explained in the context of anion-water associations. Surprisingly, however, IL/water mixtures containing different cations but a common Lactate anion exhibit similar peculiarities in density trends. Using atomistic level molecular dynamics simulations, we show that diverse density trends are caused by cation-mediated modulations in the IL nanostructure. Depending on its nature, the IL cation can play a dual role in modulating the IL nanostructure - (i) resist water-mediated breakdown of the nanostructure by interacting with the anion very strongly, (ii) further strengthen the nanostructure by incorporating water in the IL framework. The [emim] cation fails to play both roles resulting in the density decrease, while the [tmg] cation fulfills both roles leading to a density rise. The choline cation resists the density fall by inducing the formation of 'water-clathrates' in the solution. Such occurrence of clathrates in IL/water binary mixtures, reported for the first time in this study, further emphasizes that the properties of ILs and its mixtures are not merely determined by the chemical nature of the component ions, but also by their unique nanostructural organizations. This unique nanostructural organizations also manifest in their unusual dynamics. PMID- 30475623 TI - Resonant Inelastic X-Ray Scattering and Non-Resonant X-ray Emission Spectra from Coupled-Cluster (Damped) Response Theory. AB - A coupled cluster protocol rooted in damped response theory is presented for computing Resonant Inelastic X-Ray Scattering spectra of molecules in gas-phase. Working equations are reported for both linear (i.e., equation-of-motion) and non linear parametrizations of the coupled-cluster wavefunction response. A simple scheme to compute non-resonant X-ray emission spectra is also proposed. Illustrative results are presented for water. PMID- 30475624 TI - Numerical study of soft colloidal nanoparticles interaction in shear flow. AB - The mechanical behavior of nanoparticle assemblies depends on complex particle interactions that are difficult to study experimentally. Depending on the nanoparticle morphology, these interactions could lead to adhesive and elastic plastic behavior during contact deformation. The aim of this research is to study the effect of contact interactions between polymer nanoparticles and their impact on the macroscopic properties of formed aggregates. For this purpose, Discrete Element Method (DEM) was used to develop an interaction model combining elastic plastic deformation and adhesion to study the behavior of spherical polymeric nanoparticles. Initially, a pair of particles interacting in the normal direction was simulated to evaluate the effect of adhesion and plastic deformation in the pull off force of the contact. Based on these results, the simulations were extended to a dispersed system of nanoparticles, in which multi-body interactions become dominant. Considering the aggregation between the nanoparticles induced by a shear flow, we performed an analysis of the number of aggregates and aggregates size in time in order to characterize the strength of clusters formed during the process. The simulation results showed that the interaction strength upon breakage of the clusters, correlating with the aggregates size, depends on the nanoparticle softness. In this way, we verified that the type of contact interaction directly influences the macroscopic mechanical response of nanoparticle assemblies. Therefore, our model represents a new way of predicting the mechanical behavior of polymer nanoparticle systems and of optimizing it by adjusting primary particle properties. PMID- 30475625 TI - Colonic Proteome Signature in Immunoproteasome-Deficient Stressed Mice and Its Relevance for Irritable Bowel Syndrome. AB - A role for immunoproteasome in the regulation of intestinal permeability has been previously suggested both in mice during water avoidance stress (WAS) and in patients with irritable bowel syndrome (IBS). Here, we provide evidence that the ubiquitin-proteasome system (UPS) contributes to the pathophysiology of IBS. Indeed, we report that colonic proteome is altered in WAS mice and that beta2i subunit deficiency modifies the proteome response that is associated with a limitation of colonic hyperpermeability. Interestingly, we show specific alterations of proteins involved in UPS, mitochondrial, and energy metabolism. We also report changes in the pattern of colonic ubiquitome in diarrhea-predominant IBS (IBS-D) patients and particularly a reduced expression of ubiquitinated proteins involved in the nuclear factor-kappa B (NF-kappaB) inflammatory signaling pathway. All these data suggest that immunoproteasome targeting may represent a new therapeutic strategy for the treatment of IBS patients with increased intestinal permeability. PMID- 30475626 TI - Blue-Emitting CsPbCl3 Nanocrystals: Impact of Surface Passivation for Unprecedented Enhancement and Loss of Optical Emission. AB - High-energy-emitting CsPbCl3 nanocrystals have shown significant loss and enhancement of their emission intensity (~40-50 folds) during purification and surface treatments, respectively. This confirms that the surfaces of these nanocrystals are very sensitive. In this Letter, physical insights of the interface bindings on the surface of these blue-emitting CsPbCl3 nanocrystals with different passivating agents and their consequential impact on purification are investigated. Using various metal chlorides irrespective of the charge and size of the metal ions, metal acetates, and nonmetal chloride, the predominant influence of chloride ions in helping retrieve/intensify the blue emission is established. The purification processes are observed to be very delicate, and successive purifications with introduction of polar nonsolvents led to the transformation of an emitting cubic CsPbCl3 phase to nonemitting tetragonal CsPb2Cl5 phase nanocrystals irreversibly. The impact of various salt additions only temporarily helped in enhancing the emission, but the phase change remained inevitable upon successive purification. However, as a remedy, by in situ use of alkylammonium chloride salt in high-temperature reactions, the surface binding was improved, and significant emission as well as the phase could be retained with successive purifications. PMID- 30475627 TI - Ag-Catalyzed Thiocyanofunctionalization of Terminal Alkynes To Access Alkynylthiocyanates and alpha-Thiocyanoketones. AB - Unprecedented one-pot thiocyanofunctionalizations of terminal alkynes to deliver alkynylthiocyanates and alpha-thiocyanoketones using a silver-catalyzed procedure or under silver/gold relay catalysis is reported. These synthetically valuable organothiocyanates are accessed in high efficiency, and their derivatization into a variety of valuable sulfur-containing heterocycles and sulfides has also been demonstrated. PMID- 30475628 TI - Molecular Simulations Shed Light on Potential Uses of Ultrasound in Nitrogen Adsorption Experiments. AB - Nitrogen adsorption is one of the main characterization techniques for nanoporous materials. The experimental adsorption isotherm provides information on the surface area and pore size distribution (PSD) for a sample. In this work we show that additional insight into PSD can be gained when the speed of sound propagation through a sample is measured during nitrogen adsorption experiment. We analyzed published experimental data on ultrasound propagation through a nanoporous Vycor glass sample during nitrogen adsorption experiment. We calculated the change of the longitudinal and shear moduli of the sample as a function of relative vapor pressure. We show that the shear modulus of the sample does not change upon filling the pores, evidencing that adsorbed nitrogen at 77K has zero shear modulus, similarly to a bulk liquid. The longitudinal modulus of the sample behaves differently: it changes abruptly at the capillary condensation and keeps gradually increasing thereafter. We carried out Monte Carlo molecular simulations to predict the compressibility of adsorbed nitrogen and then calculated the longitudinal modulus of the nitrogen-saturated Vycor using Gassmann equation. Our theoretical predictions nicely matched the longitudinal modulus derived from the experimental data. Additionally, we performed molecular simulations to model nitrogen adsorbed in silica pores of sizes ranging from 2 to 8 nm. We found that the isothermal elastic modulus of adsorbed nitrogen depends linearly on the inverse pore size. This dependence, along with the proposed recipe for probing the modulus of adsorbed nitrogen, sets up the grounds for extracting additional information on the porous samples, when the nitrogen adsorption is combined with ultrasonic experiments. PMID- 30475630 TI - C-H Functionalization of N-Methylated Amino Acids and Peptides as Tool in Natural Product Synthesis: Synthesis of Abyssenine A and Mucronine E. AB - N-Methylated amino acids and peptides with an 8-aminoquinoline (AQ) directing group can be subjected to stereoselective Pd-catalyzed beta-functionalizations. The best results are obtained with aryl iodides, but alkyl and alkenyl side chains can also be introduced. The AQ protecting group can easily be removed, providing the free carboxylic acid, which can be used directly in peptide couplings. This protocol was used successfully as a key step in the synthesis of the cyclopeptide alkaloids abyssenine A and mucronine E. PMID- 30475629 TI - High Efficiency Non-Fullerene Organic Tandem Photovoltaics Based on Ternary Blend Sub-Cells. AB - The application of tandem structure that integrates multiple sub-cells into one device is a promising way to realize high efficiency organic solar cells. However, current-matching among different sub-cells remains as the main challenge for organic tandem photovoltaics. Here, we provide a facile approach to achieve a good current matching via engineering the chemical composition of non-fullerene ternary blend sub-cells. For the front sub-cell, a ternary blend of PDBT-T1:TPH Se:ITIC is selected due to its good thermal stability. The amorphous nature of TPH-Se can sufficiently suppress the unfavorable phase separation of blends during the heat treatment, enabling a sintering in the fabrication of high quality interconnecting layer. A double-junction tandem device is fabricated with a rear sub-cell consisting of PBDB-T:ITIC. After the optimization of the chemical composition of the front sub-cell, power conversion efficiency (PCE) of double junction tandem device increased from 10.6% using PDBT-T1:TPH-Se binary front sub cell to 11.5% using PDBT-T1:TPH-Se:ITIC (1:0.9:0.1) ternary front sub-cell due to better current matching. In order to further enhance the light absorption in the near-infrared region, a third junction PBDTTT-EFT:IEICO-4F is introduced. The champion cell of triple-junction non-fullerene tandem solar cell achieves a PCE of 13.0% with a high open circuit voltage of 2.52 V. PMID- 30475631 TI - Tunneling into the Vortex State of NbSe2 with van der Waals Junctions. AB - We have performed device-based tunneling spectroscopy of NbSe2 in the vortex state with a magnetic field applied both parallel and perpendicular to the a- b plane. Our devices consist of layered semiconductors placed on top of exfoliated NbSe2 using the van der Waals transfer technique. At zero field, the spectrum exhibits a hard gap, and the quasiparticle peak is split into low- and high energy features. The two features, associated with the effective two-band nature of superconductivity in NbSe2, exhibit markedly distinct responses to the application of magnetic field, suggesting an order-of-magnitude difference in the spatial extent of the vortex cores of the two bands. At energies below the superconducting gap, the hard gap gives way to vortex-bound Caroli-de Gennes Matricon states, allowing the detection of individual vortices as they enter and exit the junction. Analysis of the subgap spectra upon application of parallel magnetic field allows us to track the process of vortex surface formation and spatial rearrangement in the bulk. PMID- 30475632 TI - Reversible Solubilization of Pyrene by a Gas Switchable Surfactant Investigated by Molecular Dynamics Simulation. AB - The reversible solubilization behavior of pyrene by a CO2/N2 switchable surfactant (named N'-dodecyl-N, N-dimethylacetamidinium bicarbonate (DDAB)) was investigated with molecular dynamics (MD) simulations. We first individually simulated the aggregation of the inactive surfactant N'-dodecyl-N, N dimethylacetamidines (DDA) and effective surfactant DDAB in water. Detailed structural properties analysis showed that DDAB molecules aggregated into a micelle, while the aggregation of DDA molecules was considered to be an oil droplet that was separated from the water phase. MD simulations revealed that pyrene molecule was solubilized in the interior hydrophobic region of the micelle as expected. Pyrene was adsorbed on the surface of the oil droplet which is due to the dense packing of DDA molecules inside the oil droplet. The simulated release process showed that the solubilized pyrene in the interior was squeezed out when the micelle was changed to an oil droplet. Reduced density gradient (RDG) function was used to study the weak interactions and explore the molecular driving force behind the reversible solubilization. The results demonstrated that repulsion effects of water molecules on the DDA headgroups play an important role on the pyrene release. Due to the persistent molecular motion of DDA molecules into the droplet center, pyrene was finally repelled out of the oil droplet. Our study provided a molecular mechanism into the reversible solubilization of a gas controlled switchable surfactant. This is expected to be useful for surfactant enhanced remediation (SER) experiments. PMID- 30475633 TI - A three-level hepatotoxicity prediction system based on adverse hepatic effects. AB - Hepatotoxicity is a major cause of drug withdrawal from the market. To reduce the drug attrition induced by hepatotoxicity, an accurate and efficient hepatotoxicity prediction system must be constructed. In the present study, we constructed a three-level hepatotoxicity prediction system based on different levels of adverse hepatic effects (AHEs) combined with machine learning, using: 1, an endpoint: hepatotoxicity; 2, four hepatotoxicity severity degrees and 3, specific AHEs. After collecting and curing 15,873 compound-AHE pairs associated with 2017 compounds and 403 AHEs, we constructed 27 models with three endpoint levels with the random forest algorithm, and obtained accuracies ranging from 67.0% to 78.2% and the area under receiver operating characteristic curves (AUCs) of 0.715-0.875. The 27 models were fully integrated into a tiered hepatotoxicity prediction system. The existence of hepatotoxicity existence, severity degree and potential AHEs for a given compound could be inferred simultaneously and systematically. Thus, the tiered hepatotoxicity prediction system allows researchers to have significant confidence in confirming compound hepatotoxicity, analyze hepatotoxicity from multiple perspectives, obtain warnings for the potential hepatotoxicity severity and even rapidly select the proper in vitro experiments for hepatotoxicity verification. We also applied three external sets (11 drugs or candidates that failed in clinical trials or were withdrawn from the market, the PharmGKB (offsides) database and an herbal hepatotoxicity dataset) to test and validate the prediction ability of our system. Furthermore, the hepatotoxicity prediction system was adapted into a flow framework based on Konstanz Information Miner (KNIME), which was made available for researchers. PMID- 30475634 TI - Reactive molecular dynamics simulations of thermal film growth from di-tert-butyl disulfide on an Fe(100) surface. AB - Iron sulfide films are present in many applications, including lubricated interfaces, where protective films form through the reactions of lubricant additive molecules with steel surfaces during operation. Such films are critical to the efficiency and useful lifetime of moving components. However, the mechanisms by which films form are still poorly understood because the reactions occur between two surfaces and so cannot be directly probed experimentally. To address this, we explore the thermal contribution to film formation of di-tert butyl disulfide - an important extreme pressure additive - on an Fe(100) surface using reactive molecular dynamics simulations, where the reactive potential parameters are validated by comparison to ab-initio calculations. The reaction pathway leading to the formation of iron sulfide surfaces is characterized using the reactive simulations. Then, the film formation process is mimicked by simulations where di-tert-butyl disulfide molecules are cyclically added to the surface and subjected to temperatures comparable to that expected due to frictional heating. The use of an empirical reactive potential is a novel approach to modeling the iterative nature of thermal film growth with realistic lubricant additive molecules. PMID- 30475635 TI - Editorial: Malaria in the Korean peninsula: Risk factors, latent infections, and the possible role of tafenoquine, a new antimalarial weapon. PMID- 30475636 TI - Cluster of vivax malaria in U.S. soldiers training near the demilitarized zone, Republic of Korea during 2015. AB - This report describes a cluster of 11 soldiers with vivax malaria among U.S. military personnel who trained at Dagmar North training area, near the demilitarized zone (DMZ), in the Republic of Korea (ROK) in 2015. Two cases were diagnosed in the ROK in 2015, one of whom subsequently experienced a relapse, and nine other cases were diagnosed in 2016, 8-11 months after the soldiers had returned to the U.S. Vivax malaria poses a health threat to U.S. Forces Korea operating near the DMZ in the ROK. Continuing and enhanced focus on force health protection measures in endemic zones is warranted. PMID- 30475637 TI - Update: Cold weather injuries, active and reserve components, U.S. Armed Forces, July 2013-June 2018. AB - From July 2017 through June 2018, a total of 478 members of the active (n=402) and reserve (n=76) components had at least one medical encounter with a primary diagnosis of cold injury. The crude overall incidence rate of cold injury for all active component service members in 2017-2018 was 19.6% higher than the rate for the 2016-2017 cold season and was the highest rate since the 2013-2014 season. Frostbite was the most common type of cold injury among active component service members in 2017-2018. Among active component members during the 2013-2018 cold seasons, overall rates of cold injuries were generally highest among males, non Hispanic black service members, the youngest (less than 20 years old), and those who were enlisted. As noted in prior MSMR updates, the rate of all cold injuries among active component Army members was considerably higher in females than in males due to a much higher rate of frostbite among female soldiers. The numbers of cold injuries associated with overseas deployments have fallen precipitously in the past three cold seasons and included 17 cases in the most recent year. PMID- 30475638 TI - Brief report: Increased number of possible rabies exposures among U.S. healthcare beneficiaries treated in military clinics in southern Germany in 2016. PMID- 30475639 TI - Suture Button Versus Syndesmotic Screw for Syndesmosis Injuries: A Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND:: Operative treatment is indicated for unstable syndesmosis injuries, and approximately 20% of all ankle fractures require operative fixation for syndesmosis injuries. PURPOSE:: To perform a meta-analysis of randomized controlled trials evaluating clinical outcomes between suture button (SB) and syndesmotic screw (SS) fixation techniques for syndesmosis injuries of the ankle. STUDY DESIGN:: Meta-analysis. METHODS:: A literature search was performed according to the PRISMA guidelines to identify randomized controlled trials comparing the SB and SS techniques for syndesmosis injuries. Level of evidence was assessed per the criteria of the Oxford Centre for Evidence-Based Medicine. Statistical analysis was performed with RevMan, and a P value <=.05 was considered statistically significant. RESULTS:: Five clinical studies were identified, allowing comparison of 143 patients in the SB group with 142 patients in the SS group. Patients treated with the SB technique had a higher postoperative American Orthopaedic Foot & Ankle Society score at a mean 20.8 months (95.3 vs 86.7, P < .001). The SB group resulted in a lower rate of broken implants (0.0% vs 25.4%, P < .001), implant removal (6.0% vs 22.4%, P = .01), and joint malreduction (0.8% vs 11.5%, P = .05) as compared with the SS group. CONCLUSION:: The SB technique results in improved functional outcomes as well as lower rates of broken implant and joint malreduction. Based on the findings of this meta-analysis, the SB technique warrants a grade A recommendation by comparison with the SS technique for the treatment of syndesmosis injuries. PMID- 30475640 TI - Newly qualified chiropractors' perceptions of preparedness for practice: A cross sectional study of graduates from European training programs. AB - OBJECTIVE: The purpose of this pilot study was to explore chiropractic graduates' perceived preparedness for practice in the 7 key competencies of the Canadian Medical Education Directives for Specialists. METHODS: An anonymous 5-point Likert scale electronic questionnaire was distributed to graduates from the 2014 2016 cohorts of 9 European chiropractic colleges accredited by the European Council of Chiropractic Education. For each group under 1 competency role, the mean overall score was calculated. Statistical differences were analyzed using a t test and analysis of variance. Cronbach's alpha was calculated for internal consistency. RESULTS: Results of 7 chiropractic colleges were analyzed ( n = 121). Differences were found among colleges, competencies, and items. Overall, the graduates who responded scored the lowest in collaborator (3.76) and scholar (3.78) competencies. They scored the highest in professional (4.39) and chiropractic expert (4.13) competencies. In all colleges, a lower level of perceived preparedness was found in collaborator, scholar, and manager competencies. Statistical differences were found that compared the type of employment and cohorts. CONCLUSION: Our results show there may be a gap between education and professional practice regarding perceived preparedness, and graduates perceived themselves to be unprepared in some competencies. The preliminary results of this study could be used to improve curricula of chiropractic education. PMID- 30475641 TI - Centrosomal protein FOR20 is essential for cilia-dependent development in zebrafish embryos. AB - Centrosomal proteins play critical roles in ciliogenesis. Mutations in many centrosomal proteins have been documented to contribute to developmental defects and cilia-related diseases. Centrosomal protein fibroblast growth factor receptor 1 oncogene partner-related protein of 20 kDa (FOR20) is crucial for ciliogenesis in mammalian cells and the unicellular eukaryote Paramecium; however, the biologic significance of FOR20 in vertebrate development remains unclear. We cloned the zebrafish homolog of the for20 gene and found that for20 mRNA is enriched in ciliated tissues during early zebrafish development. Knockdown of for20 by morpholino oligonucleotides in zebrafish results in multiple ciliary phenotypes, including curved body, hydrocephaly, pericardial edema, kidney cysts, and left-right asymmetry defects. for20 morphants show reduced number and length of cilia in Kupffer's vesicle and pronephric ducts. High-speed video microscopy reveals that cilia in most for20 morphants are consistently paralyzed or beat arrhythmically. To confirm the ciliary phenotypes of for20 morphants, we used the CRISPR/Cas9 system to disrupt for20 gene in zebrafish. for20 mutants exhibit multiple ciliary phenotypes resembling the defects in for20 morphants. All of these phenotypes in for20 morphants and mutants are significantly reversed by exogenous expression of for20 mRNA. Taken together, these data suggest that FOR20 is required for cilia-mediated processes during zebrafish embryogenesis.-Xie, S., Jin, J., Xu, Z., Huang, Y., Zhang, W., Zhao, L., Lo, L. J., Peng, J., Liu, W., Wang, F., Shu, Q., Zhou, T. Centrosomal protein FOR20 is essential for cilia dependent development in zebrafish embryos. PMID- 30475642 TI - Of platelets and aggregometers: personal reminiscences of Gus Born (1921-2018). AB - This paper recounts the author's personal reminiscences of the late Gustav Born and details some of his major influences on the field of platelet biology and mechanisms of hemostasis. In particular, it focuses on his development of the 'Born aggregometer' and the differences that are seen in the aggregation response to certain stimuli when aggregation is recorded using other techniques such as the impedance method. PMID- 30475643 TI - Shikonin exerts antitumor activity by causing mitochondrial dysfunction in hepatocellular carcinoma through PKM2-AMPK-PGC1alpha signaling pathway. AB - Shikonin, a naphthoquinone derivative isolated from the root of Lithospermum erythrorhizon exhibited broad-spectrum antitumor activity via different molecular mechanisms. In the present study, we investigated the effect of shikonin on the mitochondrial dysfunction in hepatocellular carcinoma (HCC). Our results showed that shikonin inhibited the proliferation, migration, and invasion of HCCLM3 cells, and meanwhile, promoted cell apoptosis in a dose-dependent manner. More importantly, shikonin affected mitochondrial function by disrupting mitochondrial membrane potential and oxidative stress (OS) status. Furthermore, shikonin decreased oxygen consumption rate of HCCLM3 cells, as well as the levels of ATP and metabolites involved in tricarboxylic acid cycle (TCA cycle). We also investigated the molecular mechanism underlying the regulation of mitochondrial function by shikonin as an inhibitor of PKM2. Shikonin decreased the expression of PKM2 in the mitochondria and affected other metabolic pathways (AMPK and PGC1alpha pathways), which aggravated the oxidative stress and nutrient deficiency. Our results indicate a novel role of shikonin in triggering mitochondria dysfunction via the PKM2-AMPK-PGC1alpha signaling pathway and provide a promising therapeutic approach for the treatment of HCC. PMID- 30475644 TI - Role of TLR4-MAP4K4 signaling pathway in models of oxygen-induced retinopathy. AB - Retinopathy of prematurity is a vision-threatening condition, and therapies based on antagonizing VEGF may elicit serious side effects in premature infants. Mechanisms of retinal angiogenesis, particularly the signaling pathways independent of VEGF, remain elusive. The goals of our study were to explore TLR4 mediated signaling pathways in human retinal microvascular endothelial cells (HRMECs) and to examine the effects of TLR4 antagonists in models of oxygen induced retinopathy (OIR). Our results show that intravitreal injection of the TLR4 antagonist TAK-242 reduced areas of nonperfusion, inhibited aberrant angiogenesis, and improved vascular density in the retina of OIR mice. The effects were further potentiated by the anti-VEGF antibody ranibizumab. In cultured HRMECs, the TLR4 agonist LPS up-regulated TLR4/MAPKK kinase kinase 4 (MAP4K4) signaling, and promoted cell proliferation and migration, and reduced barrier functions of the cells. Down-regulation of MAP4K4 in HRMECs abolished the proangiogenic effects by LPS. Our data suggest that the TLR4-MAP4K4 pathway can regulate retinal neovascularization via mechanisms independent of VEGF.-Chen, W., Zhang, J., Zhang, P., Hu, F., Jiang, T., Gu, J., Chang, Q. Role of TLR4-MAP4K4 signaling pathway in models of oxygen-induced retinopathy. PMID- 30475645 TI - Monitoring Antioxidant Enzyme Activity during Exacerbations of Chronic Obstructive Pulmonary Disease. AB - Superoxide dismutases (SODs) and catalase (CAT) have been implicated as major antioxidant enzymes of the human lungs. In this study, we investigated whether activities of these enzymes are altered in the airways of patients hospitalized with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). SOD and CAT activities were measured in the sputum, exhaled breath condensate, and serum of 36 COPD patients experiencing a severe exacerbation. Measurements were performed using colorimetric assays in samples collected at the time of hospital admission and at the time of hospital discharge following treatment of AECOPD. For comparison, antioxidants were also assessed in 24 stable COPD patients and 23 healthy control subjects. SOD and CAT activities in sputum were significantly increased in patients with AECOPD compared to those with stable disease (SOD: 0.142 [0.053-0.81] vs. 0.038 [0.002-0.146] U/mL, p < 0.01; CAT: 48.7 [18.7-72.6] vs. 10.2 [2.9-40.6] nmol/min/mL, p < 0.05), while treatment of exacerbation led to a decrease in enzyme activities (SOD: 0.094 [0.046-0.45] U/mL, p < 0.05; CAT: 28.0 [7.3-60.4] nmol/min/mL, p < 0.005). No changes were observed in the serum (p > 0.05). Both SOD and CAT activities significantly correlated with sputum neutrophil and lymphocyte cell counts in patients with AECOPD. Moreover, SOD and CAT values correlated with each other and also with sputum malondialdehyde, an established marker for oxidative stress. Our data demonstrate that sputum antioxidant activity is elevated during COPD exacerbation and suggest that activation of SODs and CAT is an integral part of the human defense mechanism against the increased oxidant production associated with AECOPD. PMID- 30475646 TI - Anti-inflammatory and anticancer activities of erythrodiol-3-acetate and 2,4-di tert-butylphenol isolated from Humboldtia unijuga. AB - Humboldtia unijuga Bedd., endemic to Agasthyamala in Western Ghats in India, is traditionally used by local Kani tribes for chicken pox, head ache and snake bite. This study reports the isolation of erythrodiol-3-acetate (HU-1) and 2,4-di tert-butylphenol (HU-2) from H. unijuga roots and their anti-inflammatory and anticancer activities in macrophage, skin and breast cancer cell lines. Effects of HU-1 and HU-2 treatments (50, 100 ug/mL) on gene expression profiles of pro inflammatory cytokines TNFalpha, IL-6 and IL-1beta, and apoptosis genes p53 and caspase 7 were studied. HU-2 exerted a significantly superior anti-inflammatory effect compared to HU-1 in all three pro-inflammatory genes. HU-2 showed a superior dose dependent anticancer effect through activation of p53 gene over HU 1 in MCF-7 cells. HU-1 exhibited a dose dependent effect on caspase 7 gene in both cell lines while HU-2 was more effective in A431. HU-2 has potential for development as a novel anti-inflammatory and anticancer agent. PMID- 30475647 TI - Comparison of anterior retraction and anchorage control between en masse retraction and two-step retraction: A randomized prospective clinical trial. AB - OBJECTIVES:: The purpose of this two-arm parallel trial was to compare en masse (ER) and two-step retraction (TSR) during space closure. MATERIALS AND METHODS:: Forty-eight adult patients with bimaxillary protrusion who were planned for treatment with extraction of four first premolars were enrolled. All patients were randomly allocated in a 1:1 ratio to either the ER (n = 24) group or the TSR (n = 24) group. The main outcome was the amount of posterior anchorage loss in the molars and the retraction of the incisors between ER and TSR; the difference in incisor and molar inclination was a secondary outcome. Lateral cephalometric radiographs and oblique cephalometric radiographs at 45 degrees were taken before retraction (T1) and after space closure (T2). Cephalograms were digitized and superimposed on the anatomic best fit of the maxilla and mandible by one operator who was blinded to the treatment group. RESULTS:: Neither incisor nor molar crown movements showed any significant differences between the ER and TSR. There were no significant differences in the tipping of incisors and molars between the two groups. CONCLUSIONS:: No significant differences existed in the amount of retraction of incisors and anchorage loss of molars between ER and TSR. Changes in incisor and molar tipping were similar, with the crowns showing more movement than the apex. PMID- 30475648 TI - Comparison of condylar size among different anteroposterior and vertical skeletal patterns using cone-beam computed tomography. AB - OBJECTIVES:: To compare condylar size among different anteroposterior and vertical skeletal patterns using cone-beam computed tomography (CBCT). MATERIALS AND METHODS:: The study included 166 subjects (61 men, mean age: 27.2 +/- 7.6 years; 105 women, mean age: 27.4 +/- 9.2 years). The anteroposterior skeletal patterns of the subjects were classified into Classes I (-1 degrees <= A point nasion-B point angle [ANB] < 4 degrees ), II (ANB >= 4 degrees ), and III (ANB < 1 degrees ). The vertical skeletal patterns were classified into hypodivergent (mandibular plane [MP] <= 23 degrees ), normodivergent (23 degrees < MP < 30 degrees ), and hyperdivergent (MP >= 30 degrees ) groups. The condylar length, height, and width were examined using CBCT images. Analysis of covariance was used to compare three condylar size measurements among the three anteroposterior groups and the three vertical groups using sex as a covariate. Both left and right sides were examined. Nine groups were further divided according to the anteroposterior and vertical groups, and two-way analysis of covariance (ANCOVA) was applied to estimate the composite effect of skeletal patterns in both directions. RESULTS:: Sex as a covariate showed statistical significance in most examinations. The condylar height on both sides had statistically different anteroposterior skeletal patterns ( P < .001). The condylar width on both sides also had statistically different vertical skeletal patterns ( P < .001). After adjusting for sex, the condylar height and width on both sides increased from Class II, Class I, and Class III. The condylar width on both sides increased from the hypodivergent group, the normodivergent group, and the hyperdivergent group. No composite effect of skeletal patterns in both directions was observed. CONCLUSIONS:: Condylar height and width considerably differed among subjects with different anteroposterior or vertical skeletal patterns. The anteroposterior or vertical skeletal patterns independently affected the condylar size. PMID- 30475649 TI - In vitro evaluation of Cuscuta reflexa Roxb. for thrombolytic, antioxidant, membrane stabilizing and antimicrobial activities. AB - The key purpose of this experiment was to evaluate the thrombolytic, antioxidant, membrane stabilizing and antimicrobial potentials of crude ethanol extracts (CEE) of whole plant, organic and aqueous soluble fractions (OF & AQSF). CEE showed the highest (44.63%) clot lysis activity compared to streptokinase (64.35%). In DPPH study, petroleum ether soluble fraction (PSF) has exhibited IC50 of 18.83 MUg/mL while the standard ascorbic acid was 2.48 ug/mL. AQSF profoundly inhibited the lysis of erythrocytes (66.20%) which was insignificantly different (p > 0.05) to acetylsalicylic acid (71.98%), the reference. However, AQSF showed a significantly stronger level of protection against heat-induced hemolysis (64.80%) as compared with the acetylsalicylic acid (78.90%). CEE, OF and AQSF have displayed reasonable growth of inhibition of tested bacteria compared to negative control and standard drug (77.50 mg of GAE/g). PMID- 30475650 TI - Ginsenoside metabolite compound K induces apoptosis and autophagy in non-small cell lung cancer cells via AMPK/mTOR and JNK pathways. AB - Compound K (C-K, 20-O-(beta-D-glucopyranosyl)-20(S)-protopanaxadiol), as a metabolite of ginsenoside, has been verified to have antitumor effects in various cancers, including non-small cell lung cancer (NSCLC). However, the detailed mechanisms of C-K in NSCLC remain largely unknown. In this study, we aimed to evaluate the effect of C-K on apoptosis and autophagy in NSCLC cells as well as its related mechanisms. According to the results, C-K suppressed the proliferation, led to G1 phase arrest and apoptosis in A549 and H1975 cells. Subsequently, C-K promoted autophagy as confirmed by enhanced rate of positive acridine orange staining cells, increased LC3II and Beclin-1 levels, while decreased p62 level in A549 and H1975 cells. Moreover, 3-Methyladenine (3-MA, an inhibitor of autophagy) effectively suppressed proliferation inhibition and apoptosis induced by C-K. Finally, C-K treatment promoted the activation of AMPK/mTOR and JNK signaling pathways. Treatment with compound C (AMPK inhibitor) or SP600125 (JNK inhibitor) significantly restrained C-K-induced proliferation inhibition, apoptosis and autophagy in A549 and H1975 cells. In conclusion, this study demonstrates that C-K promotes autophagy-mediated apoptosis in NSCLC via AMPK/mTOR and JNK signaling pathways. PMID- 30475652 TI - Morphological and functional impairment in the gut in a partial body irradiation minipig model of GI-ARS. AB - PURPOSE: Gottingen minipig (G-MP) displays classic gastrointestinal acute radiation syndrome (GI-ARS) following total body irradiation (TBI) at GI doses which are lethal by 10-14 days. In collaboration with BARDA, we are developing a hemi-body/partial body irradiation (PBI) model by exposing only the abdomen and lower extremities to study GI structure/function impairment, natural history of injury and recovery, as well as correlative biomarkers out to 30 days. MATERIALS AND METHODS: Twenty-four G-MP were exposed to either 12 or 16 Gy (LINAC Elekta); head, forelimbs, and thorax were outside the irradiation field, sparing ~50% of the bone marrow. Animals were followed for 30 days with euthanasia scheduled at pre-set intervals to study the time course of GI injury and recovery. Hematological profiles, clinical symptoms, gross- and histo-pathology including markers of proliferation and apoptosis in the small intestines, gut function parameters (food tolerance, digestion, absorption, citrulline production), and levels of two biomarkers, CRP and IGF-1, were evaluated. RESULTS: PBI at 16 Gy yielded higher lethality than 12 Gy. Unlike TBI, PBI did not cause severe pancytopenia or external hemorrhage, as expected, and allowed to focus the injury on GI organs while sparing the radiation sensitive heart and lung. Compromised animals showed inactivity, anorexia, vomiting, diarrhea, and weight loss. Histology revealed that in 12 Gy irradiated animals, lesions recovered overtime. In 16 Gy irradiated animals, lesions were more pronounced and persistent. BrdU and Ki67 labelling demonstrated dose-dependent loss of crypts and subsequent mucosal ulceration which recovered over time. Minimal apoptosis was observed at both doses. Reductions in food tolerance, digestion, absorption, and citrulline production were time and dose-dependent. Loss of citrulline reached a nadir between 6-12 days and then recovered partially. CRP and IGF-1 were upregulated following PBI at GI doses. CONCLUSIONS: This lower hemi-body irradiation model allowed for extended survival at GI-specific ARS doses and development of a well controlled GI syndrome with minimal hematopoietic injury or confounding mortality from cardiopulmonary damage. A dose-dependent impairment in the intestinal structure resulted in overall decreased gut functionality followed by a partial recovery. However, while the structure appeared to be recovered, not all functionality was attained. PBI induced systemic inflammation and altered the IGF 1 hormone indicating that these can be used as biomarkers in the minipig even under partial body conditions. This PBI model aligns with other minipig models under BARDA's large animal consortium to test medical countermeasure efficacy against a less complex GI-specific ARS injury. PMID- 30475651 TI - Cancer Survivors' Beliefs About the Causes of Their Insomnia: Associations of Causal Attributions With Survivor Characteristics. AB - OBJECTIVES: Insomnia is common among cancer survivors, yet survivors' beliefs about their insomnia following cancer are largely unknown. This study describes cancer survivors' causal attributions of insomnia and whether these beliefs differ by sociodemographic characteristics. PARTICIPANTS: 160 cancer survivors meeting diagnostic criteria for insomnia disorder. METHODS: Survivors endorsed how likely they believed 12 different factors were causally related to their insomnia and self-reported sociodemographics. Multinomial logistic regression tested associations between attribution endorsement and sociodemographics. Latent class analysis (LCA) examined patterns of attribution endorsement and whether sociodemographics were associated. RESULTS: One hundred fifty-four survivors (96%) endorsed that at least 1 causal attribution was likely related to their insomnia. Most survivors endorsed that emotions (77%), thinking patterns (76%), sleep-related emotions (65%), and sleep-related thoughts (57%) were related to their insomnia, similar to data previously published among healthy persons with insomnia. Younger participants were more likely to endorse that biochemical factors related to their insomnia (ps < .02); females were more likely to endorse that hormonal factors related to their insomnia (ps < .001). LCA identified three classes (AIC = 3209.50, BIC = 3485.13). Approximately 40% of survivors endorsed most of the causal attributions were likely related to their insomnia; 13% frequently endorsed attributions were neither likely nor unlikely to be related. Older survivors were more likely to belong to the 47% who reported most attributions were unlikely related to their insomnia (p = .03). CONCLUSIONS: Cancer survivors with insomnia commonly endorsed that thoughts and emotions contributed to their sleep disturbance. Survivors' sociodemographic characteristics did not meaningfully explain individual differences for most causal attribution beliefs. PMID- 30475653 TI - Individual variations in steps per day for meeting physical activity guidelines in young adult women. AB - Cross-sectional studies have found a correlation between the duration or volume of moderate-to-vigorous physical activity (MVPA) and steps per day (STEP), but there is little information on why this relationship varies among individuals. No previous research has established whether STEP can be used to estimate the duration of PA at or above lactate threshold (>=LT), such as for maintaining cardiorespiratory fitness. This study explored the association among STEP, MVPA indices and >=LT under free-living conditions. Seventy young adult women measured their PA for 7 days using a validated accelerometer. The mean LT measured by an exercise test was 5.8+/-1.0 METs. STEP, MVPA, METs*h and >=LT were 9324+/-2677 steps/d, 231.9+/-101.5 min/w, 16.6+/-7.4 METs*h/w and 24.0+/-22.2 min/w, respectively. Significant correlations were found between STEP and MVPA duration and between STEP and METs*h/w (r = 0.81 and r = 0.81); however, approximately 1600 steps/d of the standard error of estimates in the regression equations were found. Multiple stepwise regression analysis revealed that the percentage of total time spent at light-intensity PA (LPA) and MVPA were significant determinants of the percent deviation of STEP from the linear relationships between STEP and MVPA indices. No significant relationship was observed between >=LT and STEP. The association between STEP and MVPA fluctuated depending on individual daily LPA and MVPA. Thus, consideration of both STEP and the PA at specific intensities are necessary to ensure the PA guidelines are met and the health benefits gained. STEP alone would be not a sufficient indicator for assessing the >=LT. PMID- 30475654 TI - Pattern of Cardiovascular Comorbidity in COPD in a Country with Low-smoking Prevalence: Results from Two-population-based Cohorts from Sweden. AB - Cardiovascular diseases are the most common comorbidities in COPD, due to common risk factors such as smoking. The prevalence of current smokers in Sweden has decreased over four decades to around 10%. The aim of the present study was to investigate the prevalence, distribution and associations of cardiovascular comorbidities in COPD by disease severity in two large areas of Sweden, both with low-smoking prevalence. Data from clinical examinations in 2009-2012, including spirometry and structured interview, from two large-scale population studies, the West Sweden Asthma Study (WSAS) and the OLIN Studies in Northern Sweden, were pooled. COPD was defined using post-bronchodilator spirometry according to the fixed ratio FEV1/FVC <0.70 and the lower limit of normal (LLN5th percentile) of the ratio of FEV1/FVC. Of the 1839 subjects included, 8.7% and 5.7% had COPD according to the fixed ratio and the LLN criterion. Medication for heart disease or hypertension among those with moderate-to-severe COPD was more common than among those without COPD (fixed ratio definition of COPD: 51% vs. 23%, p < 0.001; LLN definition: 42% vs. 24%, p = 0.002). After adjusting for known risk factors for COPD, including smoking, age, socio-economic status, and occupational exposure for gas, dust and fumes, only heart failure remained significantly, and independently, associated with COPD, irrespective of the definitions of COPD. Though a major decrease in smoking prevalence, the pattern of cardiovascular comorbidities in COPD still remains similar with previously performed studies in Sweden and in other Westernized countries as well. PMID- 30475655 TI - Twelve tips for providing feedback to peers about their teaching. AB - When healthcare professionals provide feedback to peers after a teaching observation, there are benefits for both parties. In this article, we outline strategies to use before, during, and after teaching observations to engage in mutually-beneficial conversations that highlight best practices, identify solutions for teaching dilemmas, and initiate teaching relationships. We discuss the importance of choosing words wisely; giving feedback about teaching skills, not the teacher as a person; recognizing how colleagues view their teaching identities; and ensuring peers are emotionally ready for a post-observation conversation. We also explain how to use pronouns, questions, and active listening during feedback conversations. Finally, we explore the impact of biases on observations, how to establish peer observer credibility, and how to make the teaching observation process and feedback discussion valuable experiences for both parties so that it leads to long-lasting partnerships in the quest to improve educational quality. PMID- 30475656 TI - Wound Healing: A Cellular Perspective. AB - Wound healing is one of the most complex processes in the human body. It involves the spatial and temporal synchronization of a variety of cell types with distinct roles in the phases of hemostasis, inflammation, growth, re-epithelialization, and remodeling. With the evolution of single cell technologies, it has been possible to uncover phenotypic and functional heterogeneity within several of these cell types. There have also been discoveries of rare, stem cell subsets within the skin, which are unipotent in the uninjured state, but become multipotent following skin injury. Unraveling the roles of each of these cell types and their interactions with each other is important in understanding the mechanisms of normal wound closure. Changes in the microenvironment including alterations in mechanical forces, oxygen levels, chemokines, extracellular matrix and growth factor synthesis directly impact cellular recruitment and activation, leading to impaired states of wound healing. Single cell technologies can be used to decipher these cellular alterations in diseased states such as in chronic wounds and hypertrophic scarring so that effective therapeutic solutions for healing wounds can be developed. PMID- 30475657 TI - The Functional and Neurobiological Properties of Bad Taste. AB - The gustatory system serves as a critical line of defense against ingesting harmful substances. Technological advances have fostered the characterization of peripheral receptors and have created opportunities for more selective manipulations of the nervous system, yet the neurobiological mechanisms underlying taste-based avoidance and aversion remain poorly understood. One conceptual obstacle stems from a lack of recognition that taste signals subserve several behavioral and physiological functions which likely engage partially segregated neural circuits. Moreover, although the gustatory system evolved to respond expediently to broad classes of biologically relevant chemicals, innate repertoires are often not in register with the actual consequences of a food. The mammalian brain exhibits tremendous flexibility; responses to taste can be modified in a specific manner according to bodily needs and the learned consequences of ingestion. Therefore, experimental strategies that distinguish between the functional properties of various taste-guided behaviors and link them to specific neural circuits need to be applied. Given the close relationship between the gustatory and visceroceptive systems, a full reckoning of the neural architecture of bad taste requires an understanding of how these respective sensory signals are integrated in the brain. PMID- 30475658 TI - HISTOPATHOLOGIC FINDINGS IN FREE-RANGING CALIFORNIA HUMMINGBIRDS, 1996-2017. AB - A histopathologic study of free-ranging hummingbirds in California was performed to identify mortality trends. Tissues from 61 wild hummingbirds representing five native California species collected by the San Diego Zoo from 1996 to 2016 or the Lindsay Wildlife Experience from 2015 to 2017 were histologically examined. Birds were either found dead or moribund at the time of submission or were euthanized due to unresolvable health issues. Long-term rehabilitated birds were excluded from this study. Lesions were sorted by organ, etiology, and gender. The most commonly affected organs were the lung (68%, 40/59), followed by the ingluvies (67%, 34/51) and the liver (54%, 33/61). While some birds had minimal or nonspecific lesions, 23% (14/61) had lesions primarily attributable to trauma, 16% (10/61) had lesions associated with bacteria, fungi, or viruses, 11% (7/61) had parasitic lesions, and 13% (8/61) had multifactorial concurrent processes. Infectious disease lesions included those associated with avian poxvirus, intestinal adenovirus, disseminated aspergillosis, bacterial septicemia, malaria ( Haemoproteus spp.), and mycobacteriosis. The most commonly identified parasitic infection was intestinal cestodiasis, for which there was no significant associated intestinal damage, although the large size of these cestodes may have affected digestion. The incidence of traumatic lesions did not vary significantly by sex, age, species, or sampling location. Other significant findings not related to disease or trauma, but not previously documented, were histologic evidence of a gallbladder and the presence of aortic ossification. Our study reported mortality trends at a population level for free-ranging hummingbirds in California and identified the presence of intestinal adenovirus and two anatomic structures not previously described. PMID- 30475659 TI - Occurrence of the Parasitic Fly Philornis torquans on Fledglings of the Rufous throated Thornbird ( Phacellodomus rufifrons) in Southeast Brazil. AB - Philornis is a neotropical genus of muscid fly that interacts with birds and may affect the development and survival of the birds' offspring. Although Philornis is a relatively common parasite, there is a lack of information about Philornis hosts in several parts of the Americas. In this study, two nests of the Rufous fronted Thornbird ( Phacellodomus rufifrons) were collected in Pedro Leopoldo, southeast Brazil. The first contained four nestlings of advanced age (about 20 d old) and a recently emerged Philornis torquans female adult fly. The second nest contained three nestlings (less than 7 d old) and several Philornis torquans subcutaneous larvae. One of the nestlings was infested by 53 larvae, which had attacked several parts of its body and caused individual wounds containing 1 to more than 15 larvae. The length of the larvae ranged from 3 to 18 mm and only one was a second instar; the remaining 69 were third instars. The pupal period lasted 9-13 d. In total, 71 larvae were collected from the nest, with nestling parasitism varying from 7 to 53 larvae (mean=23.7+/-25.5 larvae/nestling). PMID- 30475660 TI - Blood Flow-Restricted Training for Lower Extremity Muscle Weakness due to Knee Pathology: A Systematic Review. AB - CONTEXT:: Blood flow-restricted training (BFRT) has been suggested to treat lower extremity muscle weakness. The efficacy of BFRT for muscle problems related to knee pathology is unclear. OBJECTIVE:: To determine whether BFRT (1) improves muscle strength and cross-sectional area (CSA) for chronic knee-related lower extremity atrophy and (2) prevents muscle atrophy after knee surgery. DATA SOURCES:: A systematic review of the literature from 1974 to 2017 was conducted using the PubMed and Cochrane databases. STUDY SELECTION:: Controlled trials that used BFRT to treat chronic knee-related lower extremity muscle atrophy or to prevent muscle atrophy after knee surgery that measured the effects on quadriceps or hamstrings muscle strength or CSA were included. STUDY DESIGN:: Systematic review. LEVEL OF EVIDENCE:: Level 2. DATA EXTRACTION:: Data were extracted as available from 9 studies (8 level 1, 1 level 2). Assessment of study quality was rated using the Physiotherapy Evidence Database or Methodological Index for Non Randomized Studies instruments. RESULTS:: BFRT was used after anterior cruciate ligament reconstruction and routine knee arthroscopy and in patients with knee osteoarthritis or patellofemoral pain. There were a total of 165 patients and 170 controls. Vascular occlusion and exercise protocols varied; all studies except 1 incorporated exercises during occlusion, most of which focused on the quadriceps. Six of 7 studies that measured quadriceps strength reported statistically significant improvements after training. Few benefits in quadriceps CSA were reported. Hamstrings strength was only measured in 2 studies. There were no complications related to training. CONCLUSION:: Published limited data show BFRT to be safe and potentially effective in improving quadriceps muscle strength in patients with weakness and atrophy related to knee pathology. The use of short duration vascular occlusion and light-load resistance exercises appears safe after knee surgery or in arthritic knees. This treatment option requires further investigation to refine protocols related to cuff pressure and exercise dosage and duration. PMID- 30475661 TI - A historical review of investigations on laterality of emotions in the human brain. AB - Different models of emotional lateralization, advanced since the first clinical observations raised this issue, will be reviewed following their historical progression. The clinical investigations that have suggested a general dominance of the right hemisphere for all kinds of emotions and the experimental studies that have proposed a different hemispheric specialization for positive vs. negative emotions (valence hypothesis) or for approach vs. withdrawal tendencies (motivational hypothesis) will be reviewed first and extensively. This historical review will be followed by a short discussion of recent anatomo-clinical and activation studies that have investigated (a) emotional and behavioral disorders of patients with asymmetrical forms of fronto-temporal degeneration and (b) laterality effects in specific brain structures (amygdala, ventro-medial prefrontal cortex, and anterior insula) playing a critical role in different components of emotions. Overall, these studies support the hypothesis of a right hemisphere dominance for all components of the emotional system. PMID- 30475663 TI - DNA binding, prominent photonuclease activity and antibacterial PDT of cobalt(II) complexes of phenanthroline based photosensitizers. AB - The chemistry of Co(II) complexes showing efficient light induced DNA cleavage activity, binding propensity to calf thymus DNA and antibacterial PDT is summarized in this article. Complexes of formulation [Co(mqt)(B)2]ClO4 1-3 where mqt is 4-methylquinoline-2-thiol and B is N,N-donor heterocyclic base, viz. 1,10 phenanthroline (phen 1), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq 2) and dipyrido[3,2-a:2',3'-c]phenazine (dppz 3) have been prepared and characterized. The DNA-binding behaviors of these three complexes were explored by absorption spectra, viscosity measurements and thermal denaturation studies. The DNA binding constants for complexes 1, 2 and 3 were determined to be 1.6 * 103 M-1, 1.1 * 104 M-1 and 6.4 * 104 M-1 respectively. The experimental results suggest that these complexes interact with DNA through groove binding mode. The complexes show significant photocleavage of supercoiled (SC) DNA proceeds via a type-II process forming singlet oxygen as the reactive species. Antimicrobial photodynamic therapy was studied using photodynamic antimicrobial chemotherapy (PACT) assay against E. coli and all complexes exhibited significant reduction in bacterial growth on photoirradiation. PMID- 30475662 TI - Constituent analysis and proteomic evaluation of ovular secretions in Ginkgo biloba: not just a pollination medium. AB - Pollination drop (PD) is a characteristic feature of major wind-pollinated gymnosperms and plays a vital role during the course of pollination, however, the composition and proteomic profile of PDs in Ginkgo biloba remain unclear. Through inductively coupled plasma mass spectrometry, we detected mineral elements in PDs, including calcium (Ca), sulfur (S), magnesium, boron, and potassium (K), among which S, Ca, and K were found at high levels. The total sugar concentration was approximately 5.908 mg/mL, which accounted for approximately 5.9% (mass ratio) of the PD. The sugars primarily consisted of fructose, glucose, and sucrose, of which the glucose level was highest, accounting for 57.6%, followed by fructose (37.1%) and sucrose (5.3%). We also used FTIR to validate the presence of sugars and proteins in PDs. Further proteomic analysis revealed that the PD contained calmodulin, alpha-L-arabinofuranosidase, beta-D-xylosidase, superoxide dismutase, alpha-L-arabinosidase, glutathione S-transferase, histones, glycine-rich family protein, methionine synthase, and arabinogalactan, suggesting that proteins present in PDs of G. biloba play a critical role in the defense against external bacteria and facilitate germination and growth of the pollen tube. Our results suggest that PDs are not merely a medium to receive and transport pollen but may also play a more complex biological role in pollination and fertilization. PMID- 30475664 TI - ABO antigen levels on platelets of normal and variant ABO blood group individuals. AB - Although differential expression of ABO antigens on platelets is related to recipients' platelet recovery and neonatal alloimmune thrombocytopenia in ABO incompatible transfusion and pregnancy, the expression of ABO antigens on platelets in normal and variant ABO blood group individuals is rarely reported. Here, we analyzed the expression of ABO antigens on platelets in a cohort of 515 individuals with normal and variant ABO. The variants were also genotyped for ABO and/or FUT1 loci to distinguish inherited or acquired ABO variants. The results showed that ABO antigens expression on individual platelets was relatively stable during the storage period in vitro. The frequency of low-, moderate-, and high expression phenotype in normal individual was 59.6%, 35.5%, and 4.9%, respectively. The platelets from para-Bombay and most inherited ABO subgroups express very low levels of ABO antigens, but the acquired ABO variants and the B3 subgroup express normal or abnormally high levels of ABO antigens on platelets. The data extend the information of antigens expression on platelets, which may help to improve the strategy of platelets transfusion. PMID- 30475665 TI - Role of OCT Angiography in the Detection of Retinal Vascular and Macular Abnormalities in Subjects with Asteroid Hyalosis. AB - PURPOSE: To study the role of Optical coherence tomography (OCT) Angiography (OCTA) in detecting retinal vascular and macular abnormalities as compared to Fundus Fluorescein Angiography (FFA) in subjects with Asteroid hyalosis (AH). METHODS: In a prospective study, patients with AH underwent OCTA and FFA. AH graded as Grade 1 in 8 (optic disc, second order vessels visible), Grade 2 in 4 (optic disc, first-order vessels visible), Grade 3 in 11 (hazy view of optic disc) and Grade 4 (no view of fundus) in 2 eyes. RESULTS: A total of 20 patients (25 eyes) with AH were included. In comparison to FFA, OCTA was able to similarly detect Diabetic Retinopathy changes such as Neovascularization, microaneurysms, capillary dropout, and foveal avascular zone extent in vascular occlusion in all grades of AH. CONCLUSION: OCTA, a noninvasive imaging tool, could detect various retinal vascular and macular abnormalities in patients with all grades of AH in comparison to FFA. PMID- 30475666 TI - Further Examining the TROG 99.03 Trial in Early-Stage Follicular Lymphoma: Cure Rate and the Role of Positron Emission Tomography. PMID- 30475667 TI - Reply to Z. Li et al. PMID- 30475669 TI - Reply to M. Sorigue et al. PMID- 30475668 TI - Adjuvant Letrozole and Tamoxifen Alone or Sequentially for Postmenopausal Women With Hormone Receptor-Positive Breast Cancer: Long-Term Follow-Up of the BIG 1-98 Trial. AB - PURPOSE: Luminal breast cancer has a long natural history, with recurrences continuing beyond 10 years after diagnosis. We analyzed long-term follow-up (LTFU) of efficacy outcomes and adverse events in the Breast International Group (BIG) 1-98 study reported after a median follow-up of 12.6 years. PATIENTS AND METHODS: BIG 1-98 is a four-arm, phase III, double-blind, randomized trial comparing adjuvant letrozole versus tamoxifen (either treatment received for 5 years) and their sequences (2 years of one treatment plus 3 years of the other) for postmenopausal women with endocrine-responsive early breast cancer. When pharmaceutical company sponsorship ended at 8.4 years of median follow-up, academic partners initiated an observational, LTFU extension collecting annual data on survival, disease status, and adverse events. Information from Denmark was from the Danish Breast Cancer Cooperative Group Registry. Intention-to-treat analyses are reported. RESULTS: Of 8,010 enrolled patients, 4,433 were alive and not withdrawn at an LTFU participating center, and 3,833 (86%) had at least one LTFU report. For the monotherapy comparison of letrozole versus tamoxifen, we found a 9% relative reduction in the hazard of a disease-free survival event with letrozole (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.01). HRs for other efficacy end points were similar to those for disease-free survival. Efficacy of letrozole versus tamoxifen for contralateral breast cancer varied significantly over time (0- to 5-, 5- to 10-, and > 10-year HRs, 0.62, 0.47, and 1.35, respectively; treatment-by-time interaction P = .005), perhaps reflecting a longer carryover effect of tamoxifen. Reporting of specific long-term adverse events seemed more effective with national registry than with case-record reporting of clinical follow-up. CONCLUSION: Efficacy end points continued to show trends favoring letrozole. Letrozole reduced contralateral breast cancer frequency in the first 10 years, but this reversed beyond 10 years. This study illustrates the value of extended follow-up in trials of luminal breast cancer. PMID- 30475670 TI - PHOENIX-GC Trial: Underpowered for Significant Results? PMID- 30475671 TI - Latin Hypercube Designs with Branching and Nested Factors for Initialization of Automatic Algorithm Configuration. AB - The configuration of algorithms is a laborious and difficult process. Thus, it is advisable to automate this task by using appropriate automatic configuration methods. The irace method is among the most widely used in the literature. By default, irace initializes its search process via uniform sampling of algorithm configurations. Although better initialization methods exist in the literature, the mixed-variable (numerical and categorical) nature of typical parameter spaces and the presence of conditional parameters make most of the methods not applicable in practice. Here, we present an improved initialization method that overcomes these limitations by employing concepts from the design and analysis of computer experiments with branching and nested factors. Our results show that this initialization method is not only better, in some scenarios, than the uniform sampling used by the current version of irace, but also better than other initialization methods present in other automatic configuration methods. PMID- 30475672 TI - Automated Algorithm Selection: Survey and Perspectives. AB - It has long been observed that for practically any computational problem that has been intensely studied, different instances are best solved using different algorithms. This is particularly pronounced for computationally hard problems, where in most cases, no single algorithm defines the state of the art; instead, there is a set of algorithms with complementary strengths. This performance complementarity can be exploited in various ways, one of which is based on the idea of selecting, from a set of given algorithms, for each problem instance to be solved the one expected to perform best. The task of automatically selecting an algorithm from a given set is known as the per-instance algorithm selection problem and has been intensely studied over the past 15 years, leading to major improvements in the state of the art in solving a growing number of discrete combinatorial problems, including propositional satisfiability and AI planning. Perinstance algorithm selection also shows much promise for boosting performance in solving continuous and mixed discrete/continuous optimisation problems. This survey provides an overview of research in automated algorithm selection, ranging from early and seminal works to recent and promising application areas. Different from earlier work, it covers applications to discrete and continuous problems, and discusses algorithm selection in context with conceptually related approaches, such as algorithm configuration, scheduling or portfolio selection. Since informative and cheaply computable problem instance features provide the basis for effective perinstance algorithm selection systems, we also provide an overview of such features for discrete and continuous problems. Finally, we provide perspectives on future work in the area and discuss a number of open research challenges. PMID- 30475673 TI - A Meta-Objective Approach for Many-Objective Evolutionary Optimization. AB - Pareto-based multi-objective evolutionary algorithms experience grand challenges in solving many-objective optimization problems due to their inability of maintaining both convergence and diversity in a high-dimensional objective space. Exiting approaches usually modify the selection criteria to overcome this issue. Different from them, we propose a novel meta-objective (MeO) approach that transforms the manyobjective optimization problems in which the new optimization problems become easier to solve by the Pareto-based algorithms. MeO converts a given many-objective optimization problem into a new one, which has the same Pareto optimal solutions and the number of objectives with the original one. Each meta-objective in the new problem consists of two components which measure the convergence and diversity performances of a solution, respectively. Since MeO only converts the problem formulation, it can be readily incorporated within any multi-objective evolutionary algorithms, including those non Pareto-based ones. Particularly, it can boost the Pareto-based algorithms' ability to solve many objective optimization problems. Due to separately evaluating the convergence and diversity performances of a solution, the traditional density-based selection criteria, e.g., crowding distance, will no longer mistake a solution with poor convergence performance for a solution with low density value. By penalizing a solution in term of its convergence performance in the meta-objective space, the Pareto dominance becomes much more effective for a many-objective optimization problem. Comparative study validates the competitive performance of the proposed meta-objective approach in solving many-objective optimization problems. PMID- 30475674 TI - Attributions of Blame among Victims of Child Sexual Abuse: Findings from a Community Sample. AB - According to the attribution theory, negative outcomes of child sexual abuse (CSA) are thought to vary depending on whether CSA victims attribute the abuse to internal or external factors, respectively, self-blame and perpetrator-blame. Therefore, the purpose of this study was to identify abuse characteristics and attitudes that influence blame attributions among CSA victims from a community sample. Data from respondents with a history of CSA (N = 1,496) have been used in predicting blame attributions; perpetrator-blame, self-blame, or both. Results from a multinomial logistic regression analysis showed that attitudes toward gender roles had a significant effect on blame: victims were more likely to blame themselves when they endorsed more conservative gender attitudes than victims with more liberal attitudes. Implications for this finding are discussed. PMID- 30475675 TI - The effect of body image on sexual quality of life in obese married women. AB - In this descriptive and comparative study, our aim was to determine the effect of body image on sexual quality of life in obese married women. The sample of the study consisted of 583 women over the age of 18 (38.9% normal weight, 28.5% overweight, and 32.6% obese). Data were collected using The Body Image Scale and The Sexual Quality of Life Scale-Women's Form. The body image satisfaction and sexual quality of life levels of obese women were found to be low. Additionally, as the positive body image increased in normal weight, overweight and obese women, sexual quality of life increased. PMID- 30475676 TI - Evaluation of parabens and their metabolites in fish and fish products: a comprehensive analytical approach using LC-HRMS. AB - Parabens (PBs) are preservatives frequently used in cosmetics and personal care products as well as in the pharmaceutical and food industries due to their extensive defence mechanisms against multiple categories of microorganisms. Although they are considered safe when used within defined concentration limits, concern about their potential toxicity is still particularly active. Revealed as emerging pollutants, their incidence and behaviour in the aquatic environment have been studied, but there is only sporadic information when it comes to their extent and distribution in seafood. This study explores the presence of methyl- (MeP), ethyl-, propyl-, butyl-, and benzylparaben and their main degradation product 4-hydroxybenzoic acid (pHBA) in several fish species and bivalve samples with the aim to evaluate these food matrices as potentially important contamination sources of PB. Additionally, infant food containing fish was also enrolled in this survey: firstly, due to the absence of any information regarding this exceptionally important food item, and secondly, because of the necessity to estimate the PB content in the processed food. For this purpose, a fast, reliable and robust method was developed based on a simple liquid-liquid extraction followed by high-performance LC, coupled with a benchtop Q-Exactive Orbitrap high resolution MS. The Q-Exactive parameters were carefully scheduled to achieve a balance between the optimal scan speed and selectivity, considering the limitations that are associated with generic sample preparation methodology. The method was validated through specificity, linearity, recovery, intra- and inter day repeatability, LOD and LOQ. LOD and LOQ reached the ranges 0.65-3.5 and 2.15 11.7 ng g-1, respectively, while overall recovery ranged from 77% to 118%. The PBs were more frequently present in bivalves than in fish samples with MeP as the main PB detected. No PBs were found in infant food, but pHBA was observed in all samples. PMID- 30475677 TI - Identification of Mycobacterium genavense natural infection in a domestic ferret. AB - A 6-y-old neutered male ferret ( Mustela putorius furo) was presented because of a 1-mo history of progressive weight loss, chronic cough, and hair loss. On clinical examination, the animal was coughing, slightly depressed, moderately hypothermic, and had bilateral epiphora. Thoracic radiography was suggestive of severe multinodular interstitial pneumonia. Abdominal ultrasound examination revealed hepatosplenomegaly and mesenteric and pancreaticoduodenal lymphadenopathy. Fine-needle aspiration of the pancreaticoduodenal lymph node, followed by routine Romanowsky and Ziehl-Neelsen stains, revealed numerous macrophages containing myriad acid-fast bacilli, leading to identification of mycobacteriosis. Autopsy and histologic examination confirmed the presence of disseminated, poorly defined, acid-fast, bacilli-rich granulomas in the pancreaticoduodenal and mesenteric lymph nodes, intestines, and lungs. Destaining of May-Grunwald/Giemsa-stained slides with alcohol, and then restaining with Ziehl-Neelsen, revealed acid-fast rods and avoided repeat tissue sampling without affecting the Ziehl-Neelsen stain quality and cytologic features. Tissue samples were submitted for a PCR assay targeting the heat shock protein gene ( hsp65) and revealed 100% homology with Mycobacterium genavense. We emphasize the use of special stains and PCR for identification of this potential zoonotic agent. PMID- 30475678 TI - Sexual and reproductive health and rights matters: a new age. PMID- 30475679 TI - Identification and quantification of cereulide in cow's milk using liquid chromatography-tandem mass spectrometry. AB - In this study, the presence of cereulide in cow's milk was identified and quantified using our validated method with liquid chromatography-tandem mass spectrometry. Cereulide was concentrated using protein acid-precipitation and extracted from the precipitate by using acetonitrile twice. The combination of protein acid-precipitation and extraction sufficiently eliminated the matrix compounds from the milk and a further clean-up step utilising solid-phase extraction could be omitted. For robustly measuring the samples and keeping the MS devices clean, the extraction solution was diluted 10-fold using methanol. Owing to the minimisation of the interferences caused by fragmentation patterns, multiple reaction monitoring information-dependent acquisition-enhanced product ion spectra enabled the characterisation and identification of cereulide. Besides the matrix effect (-4%), an external solvent calibration curve was adapted for accurate quantification. The method was validated using fortified recovery tests, at two concentrations (10 and 50 ug kg-1), using three samples daily on five different days based on the Japanese guidelines. This new method exhibited good accuracy ranging from 91% to 94%. The relative standard deviations of repeatability ranged from 2% to 5%, and the relative standard deviation of within laboratory reproducibility ranged from 5% to 6%. These standard deviations satisfied the criteria for the Japanese validation guidelines. The limit of quantification (LOQ) was estimated to be 2 MUg kg-1. On the product ion spectra at the LOQ level, the library match was satisfactory with a purity fit value of >70%. The method was applied to 14 raw milk and three milk samples pasteurised using the low-temperature, long-time process and collected in Tokyo. None of the samples was found to contain the target toxin. PMID- 30475680 TI - Fatal bronchopneumonia caused by skunk adenovirus 1 in an African pygmy hedgehog. AB - Eleven adult African pygmy hedgehogs ( Atelerix albiventris) were added to a group of 35 animals, and within 10 d, respiratory distress affected 8 of 35 resident animals in the group, but none of the introduced animals. Three animals died following onset of clinical signs. Tissues from one animal were collected and submitted for histopathology, which revealed acute necrotizing bronchopneumonia and tracheitis with intraepithelial intranuclear inclusion bodies. Electron microscopy identified 75-90 nm diameter encapsulated icosahedral virions. Degenerate nested PCR analysis identified adenovirus within the affected lung tissue. Deep sequencing showed 100% homology to skunk adenovirus 1 (SkAdV 1). Adenoviruses are usually species-adapted and -specific, but our case supports the single previous report of non-skunk infection with SkAdV-1, indicating that this virus can infect other species, and further shows that it can cause fatal disease. PMID- 30475681 TI - Enhancing use of emergency contraceptive pills: A systematic review of women's attitudes, beliefs, knowledge, and experiences in Australia. AB - Over a decade after emergency contraceptive pills (ECPs) became available without a prescription, the rate of unintended pregnancies remains high in many settings. Understanding women's experiences and perceptions of ECPs may provide insights into this underutilization. We systematically searched databases to identify qualitative and quantitative primary studies about women's beliefs, knowledge, and experiences of ECPs in Australia. Findings demonstrate persistent misunderstandings around access, how ECPs work, and a moral discourse around acceptable versus unacceptable use. Addressing knowledge and the stigma around ECPs use is fundamental to increasing the use of this medically safe and effective strategy. PMID- 30475682 TI - Spilling the T on Trans-Misogyny and Microaggressions: An Intersectional Oppression and Social Process Among Trans Women. AB - Minority stress frameworks seek to explain how stress impacts the health of minorities. Examining the social location of trans women in society is critical to understand the unique forms of oppression that engender stress and microaggression for trans women. This article uses intersectionality to examine the lived experiences of young trans women and develop new theoretical concepts to understand the social process of trans-misogyny. We use grounded theory to analyze semistructured, in-depth interviews conducted with 38 young trans women ages 16-24 in Los Angeles and Chicago. Our findings describe key concepts: trans misogyny, cis-sexism, the passing complex, and transition work. We describe how trans-misogyny acts as an intersectional, interlocking structure of oppression, fueling the passing complex, and, as a result, how trans women experience overt and covert forms of discrimination. PMID- 30475683 TI - Influence of microwave, the combined microwave/hot air and only hot air roasting on the formation of heat-induced contaminants of carob powders. AB - This study aims to investigate the effects of microwave, combined microwave/hot air treatment and hot air-only roasting on the formation of heat-induced contaminants of carob powders. Moisture content, water activity and pH values of the product decreased with the increasing roasting time and microwave power, while browning index (BI) and ultraviolet absorbance (UV-A) values were increased. While L and b values of carob powders decreased with increasing the roasting time and microwave power, a and DeltaE values were increased. Varying roasting conditions also significantly affected the content of Maillard reaction products (MRPs): 5-hydroxymethylfurfural (HMF) (0.69-28.32 mg/kg dry matter), furfural (=30% total body surface area. Of the 224 patients, 81.7% were males, and 18.4% were females. In the mortality group, 41.3% were males, and 58.5% were females. Gender (female, p<0.041), age (p<0.001), age group (0-14/15-59/>60 years, p<0.001), total body surface area (p<0.001), type of burn (flame, p<0.002), presence of inhalation injury (p<0.001), process of the burn (p<0.002), time spent between the event and admission to the hospital (p<0.001), length of hospitalization (p<0.001), presence of comorbidity (p<0.038), diabetes mellitus (p<0.05), ventilation support (p<0.001), lactate dehydrogenase values (lactate dehydrogenaseadmission, p<0.001; lactate dehydrogenasemiddle, p<0.015; lactate dehydrogenaselast, p<0.001), white blood cell count (p<0.001), and platelet count (p<0.043) were found to be significant for univariate analyses. These parameters were further evaluated using multivariate analyses. lactate dehydrogenaselast level (p<0.001), age (p<0.001), length of hospitalization (negative odds ratio), p<0.001), presence of inhalation injury (p<0.029), total body surface area burned (p<0.029), and leukocytosis (p<0.006) were found to be significantly associated with mortality; however, leukocytosis and length of hospitalization did not pose risk for mortality with regard to odds ratios. CONCLUSION: Early realization of the factors affecting morbidity and mortality in patients and taking preventive measures, in addition to earlier detection and prevention of complications in long-time intensive care unit patients, could reduce complication and mortality rates in major burn trauma patients. Parameters for the indication of severity and mortality are important; however, lactate dehydrogenase is an easily studied parameter and is found to have a predictive value on prognosis. PMID- 30475697 TI - Intraoperative nerve monitoring is useful for surgical training in thyroid surgery. AB - OBJECTIVE: Parathyroid glands and recurrent laryngeal nerves (RLNs) are at risk during thyroid surgery. However, the identification of the nerves reduced these risks. Intraoperative nerve monitoring (IONM) during thyroid surgery has gained widespread acceptance as an aid to the gold standard of visually identifying the RLN. The aim of the present study was to evaluate the effect of the identification of the RLN during thyroidectomy by using IONM. MATERIAL AND METHODS: Seven hundred forty-eight patients were included in our prospectively designed study. Of these 748 patients, 1496 nerves at risk were studied. Group 1 consisted of 736 nerves that were identified using IONM, whereas Group 2 consisted of 760 visually identified nerves. RESULTS: In the non-IONM group, the rate of temporary nerve palsy was lower in patients who were operated by experienced surgeons than in patients who were operated by residents (p=0.001). In the IONM group, RLN injury rates were similar between experienced surgeons and residents. CONCLUSION: In spite of the fact that the duration of the operation was lower with IONM, the abbreviated duration may not appear to have clinical significance. The main advantage is for less experienced surgeons. IONM significantly decreases RLN palsy rates of surgeons with limited experience in thyroid surgery. PMID- 30475698 TI - Gasless robotic perineal radical prostatectomy: An initial experience. AB - Radical prostatectomy (RP) is the gold standard treatment method of localized prostate cancer. Today, this surgery is performed with open or minimally invasive methods. The history of open perineal RP (RPP) is very old, but it is not often preferred by urologists. The use of robot-assisted laparoscopic RP (RALP) is very frequently applied today. Robotic perineal RP (r-RPP) by using a Gel-Point and insufflating CO2 into the perineal region was first described in 2014. In this case report, we report a 68-year-old patient with localized prostate cancer in whom we successfully performed gasless r-RPP, and according to our knowledge, this is the first case of gasless r-RPP to be reported. PMID- 30475699 TI - Safety and efficacy of Intravesical hyaluronic acid/chondroitin sulfate in the treatment of refractory painful bladder syndrome. AB - OBJECTIVE: To evaluate the safety and efficacy of intravesical instillation of hyaluronic acid/chondroitin sulfate in the treatment of refractory painful bladder syndrome. MATERIAL AND METHODS: Forty patients were subjected to intravesical instillations of hyaluronic acid/chondroitin sulfate weekly for 4 weeks and at 6., 8., 12. and 16. weeks, afterwards. Then we evaluated the efficacy of this treatment modality by determining the mean changes in visual analogue scale (VAS) pain score, the pelvic pain and urgency/frequency questionnaire, the O'Leary-Sant interstitial cystitis symptoms index/problems index and 3 day-voiding diary results including daily number of voids and mean voided volume at 2 weeks, 3, and 9 months after the last dose (4th month) and urodynamic studies including cystometric capacity, 1st sensation of urination, and Q-max at 9 months after the last dose. RESULTS: Thirty-seven patients (6 males 16.2%, 31 females 83.8%) completed the entire follow-up protocol of this study. Age of the patients ranged from 22 to 37 years (mean, 30.7+/-4.18 years) and their body mass indexes (BMIs) ranged between 29 and 37 kg/m2 (mean, 33.5+/ 2.58 kg/m2). An initial response to treatment in all parameters at variable degrees was noticed at 2 weeks after the last instillation when compared to the baseline, and these changes were statistically significant (p <0.001). Progressive improvement in all test parameters was noticed at 3 months after treatment, and this improvement was statistically significant compared with baseline and 2 weeks after treatment, respectively (p <0.001). CONCLUSION: Intravesical instillation with both hyaluronic acid/chondroitin sulfate in the treatment of refractory painful bladder syndrome is safe, effective and well tolerated by all patients with no recorded side effects. PMID- 30475700 TI - Outcome of patients with failed pelvic fracture-associated urethral injury repair: A single centre 10-year experience. AB - OBJECTIVE: The management of recurrent posterior urethral strictures developing after pelvic fracture urethral injury (PFUI) is a challenging task. Despite availability of many surgical approaches, there is no consensus regarding the optimal approach. The objective of this study was to present our 10-year experience in the management of recurrent urethral strictures due to PFUI. MATERIAL AND METHODS: We did a retrospective single-institution review of patients who underwent surgical management for recurrent posterior urethral strictures from January 2006 to December 2016 using descriptive statistics. We included only those patients with PFUI who underwent some definitive surgical procedure for their previous failed repair(s). RESULTS: The final analysis included data of 50 male patients (10 adolescents and 40 adults). Mean age of the patients was 29.92+/-10.62 years. The average length of stricture was 3.02+/-1.47 cm. Progressive perineal urethroplasty (PPU) was done in 40 cases. Two patients with concomitant rectourethral fistula/false passage underwent transpubic urethroplasty (TPU). Three patients with complete bulbar necrosis were managed with single stage/staged preputial tube reconstruction. One patient underwent microsurgical urethroplasty using radial free forearm flap while in two patients each Mitrofanoff appendicovesicostomy and perineal urethrostomy was done. Majority of complications were minor (Clavien Grade 1 and 2). Overall success rate of PPU was 75%. Mean follow-up period was 29.46+/-10.68 months (range: 13-60 months). CONCLUSION: Most cases of recurrent posterior urethral strictures of <3 cm in length can be operated by PPU with reasonable success rates. Complex and long-segment (higher than 3 cm) strictures require use of ancillary procedures like TPU, substitution urethroplasty and Mitrofanoff appendicovescostomy. PMID- 30475701 TI - Rare cases of ectopic ureter: Analysis from a single centre with review of the literature. AB - OBJECTIVE: Purpose of our study was to aggregate and analyse rare cases of Ectopic Ureter (EU), their association with other anomalies, clinical features, diagnosis and management. MATERIAL AND METHODS: A total of nine patients with rare presentation of EU were evaluated. Combination of endoscopic and imaging modalities was used as required to define the anatomy and devise the best surgical approach in these cases. RESULTS: Among six females and three males with EU, four cases had bilateral EU, four unilateral EU and one case had EU of a solitary kidney. Urinary incontinence was encountered in five cases including one male patient whilst other cases presented with varied clinical features and associated anomalies. Two patients had anorectal malformations, and two had uterine anomalies in the form of bicornuate uterus. Other patients had multiple rare associations such as triplication of ureter, bilateral absence of seminal vesicles with infertility, multicystic dysplastic kidney, ureter draining in uterus, renal failure, absence of bladder trigone, and hypospadias etc. Ureteric reimplantation was performed in four cases, two required ureteroureterostomy, another two had undergone upper pole nephrectomy and in one case renal transplant had been carried out owing to chronic renal failure. CONCLUSION: EU is among group of those congenital entities which remain shrouded until adulthood, when symptoms become distressing. Fortunately, prognosis is favourable after surgical correction, in spite of its rarity. Complexity arises when other associated anomalies are identified. PMID- 30475703 TI - Intraoperative Thermography of the Electrical Stimulation Mapping: A Safety Control Study. AB - A standard procedure for continuous intraoperative monitoring of the integrity of the corticospinal tracts by eliciting muscle responses is the electric stimulation mapping (ESM). However, standard ESM protocols are ineffective in 20% of young children. We have developed a novel, highly efficient paradigm consisting of short-time burst (30 ms) of high frequency (500 Hz) and high peak current (<=100 mA), which may cause local tissue overheating. The presented safety control study was therefore designed. The infrared thermography camera captured to-be-resected cortex of 13 patients in vivo during ESM. Thermograms were image processed to reveal discrete ESM thermal effect of currents from 10 to 100 mA. Peak 100 mA currents induced a maximal increase in temperature of 3.1 degrees C, 1.23+/-0.72 degrees C in average. The warming correlated with stimulating electrode resistance ( ). The measurement uncertainty was estimated +/- 1.01 oC for the most skeptical conditions. The histopathological evaluation of stimulated tissue (performed in all cases) did not show any destructive changes. Our study demonstrates the ability of the thermographic camera to measure the discrete thermal effect of the ESM. The results provide evidence for the safety of the proposed protocol for full range currents with minimal risk of brain tissue damage. PMID- 30475702 TI - The prevalence of Burnout Syndrome among Turkish Urologists: Results of a Nationwide Survey. AB - OBJECTIVE: To investigate the prevalence of Burnout syndrome (BS) with its emotional exhausting (EE), depersonalization (DP), and personal accomplishment (PA) dimensions among Turkish urologists. MATERIAL AND METHODS: A total of 2,259 certified Turkish urologists were invited by e-mail to participate in this cross sectional survey-based study. An online survey was conducted to evaluate three dimensions of BS ie: -EE, DP and PA-and their association with socio-demographic variables of Turkish urologists using the Maslach Burnout Inventory (MBI). RESULTS: Of the 2259 urologists contacted, 362 (with a mean age of 44+/-9.9 years) completed the survey. The mean EE, DP and PA scores were 16.8+/-8.7, 6.6+/ 4.6 and 8.2+/-5.6, respectively. Cronbach's alpha reliability coefficiencies were 0.920 for EE, 0.819 for DP and 0.803 for PA. Antidepressant drug usage was quite prevalent among participants (21.9%), and the most common comorbidity was hypertension (13%). The academic title, age, smoking status, monthly income and relationships between colleagues and employers were associated with BS (p<0.05). CONCLUSION: The prevalence of BS among Turkish urologists is quite prevalent in terms of EE and DP subscales and may negatively affect the psychosocial status and well-being of the urologists. In this study, a high prevalence of BS has been reported among Turkish urologists. In conclusion the BS could become an important occupational and health problem, if it is not properly managed. PMID- 30475704 TI - Functional Selectivity of Lumbosacral Stimulation: Methodological Approach and Pilot Study to Assess Visceral Function in Pigs. AB - Nearly all spinal cord injured (SCI) individuals lose bladder control and are prone to kidney complications if intermittent catheterization is not applied. Electrical stimulation of the sacral anterior roots with an implantable neuroprosthesis is one means to restore continence and control micturition. However, only a small percentage of the SCI population benefits from this solution because of its drawbacks, e.g., section of sacral posterior roots with loss of spared sensitivity. There has been renewed interest in spinal cord stimulation in recent years, but most studies have focused on locomotion and only few have reported the impact on visceral functions. Moreover, even though the lumbosacral spinal cord is the location of many pre-cabled neural networks (involved in locomotion, bladder, and bowel management), the functional selectivity of spinal stimulations has never been investigated in detail. Here, we present: 1) a methodology designed to study lumbosacral epispinal-intradural stimulation selectivity; 2) preliminary results assessing the impact of epispinal stimulation on bladder and bowel functions in two domestic pigs; and 3) a comparison of these visceral responses with abdominal and lower limb activities. Our experiments resulted in selective bladder and rectal responses, i.e., without hind paw responses, thus reaffirming the rehabilitation potential of spinal cord stimulation. PMID- 30475705 TI - Automatic Assessment of Full Left Ventricular Coverage in Cardiac Cine Magnetic Resonance Imaging with Fisher Discriminative 3D CNN. AB - Cardiac magnetic resonance (CMR) images play a growing role in the diagnostic imaging of cardiovascular diseases. Full coverage of the left ventricle (LV), from base to apex, is a basic criterion for CMR image quality and necessary for accurate measurement of cardiac volume and functional assessment. Incomplete coverage of the LV is identified through visual inspection, which is time consuming and usually done retrospectively in the assessment of large imaging cohorts. This paper proposes a novel automatic method for determining LV coverage from CMR images by using Fisher-discriminative three-dimensional (FD3D) convolutional neural networks (CNNs). In contrast to our previous method employing 2D CNNs, this approach utilizes spatial contextual information in CMR volumes, extracts more representative high-level features and enhances the discriminative capacity of the baseline 2D CNN learning framework, thus achieving superior detection accuracy. A two-stage framework is proposed to identify missing basal and apical slices in measurements of CMR volume. First, the FD3D CNN extracts high-level features from the CMR stacks. These image representations are then used to detect the missing basal and apical slices. Compared to the traditional 3D CNN strategy, the proposed FD3D CNN minimizes within-class scatter and maximizes between-class scatter. We performed extensive experiments to validate the proposed method on more than 5,000 independent volumetric CMR scans from the UK Biobank study, achieving low error rates for missing basal/apical slice detection (4.9%/4.6%). The proposed method can also be adopted for assessing LV coverage for other types of CMR image data. PMID- 30475706 TI - Closed Loop Spatial and Temporal Control of Cavitation Activity with Passive Acoustic Mapping. AB - Ultrasonically actuated microbubble oscillations hold great promise for minimally invasive therapeutic interventions. While several preclinical studies have demonstrated the potential of this technology, real-time methods to control the amplitude and type of microbubble oscillations (stable vs inertial acoustic cavitation) and ensure that cavitation occurs within the targeted region are needed for their successful translation to the clinic. In this paper, we propose a real-time nonlinear state controller that uses specific frequency bands of the microbubble acoustic emissions (harmonic, ultra-harmonic, etc.) to control cavitation activity (observer states). To attain both spatial and temporal control of cavitation activity with high signal to noise ratio, we implement a controller using fast frequency-selective passive acoustic mapping (PAM) based on the angular spectrum approach. The controller includes safety states based on the recorded broadband signal level and is able to reduce sensing inaccuracies with the inclusion of multiple frequency bands. In its simplest implementation the controller uses the peak intensity of the passive acoustic maps, reconstructed using the 3rd harmonic (4.896 * 0.019 MHz) of the excitation frequency. Our results show that the proposed real-time nonlinear state controller based on PAM is able to reach the targeted level of observer state (harmonic emissions) in less than 6 seconds and remain within 10 % of tolerance for the duration of the experiment (45 seconds). Similar response was observed using the acoustic emissions from single element passive cavitation detection, albeit with higher susceptibility to background noise and lack of spatial information. Importantly, the proposed PAM-based controller was able to control cavitation activity with spatial selectivity when cavitation existed simultaneously in multiple regions. The robustness of the controller is demonstrated using a range of controller parameters, multiple observer states concurrently (harmonic, ultra-harmonic, and broadband), noise levels ( degrees 6 to 12 dB SNR), and bubble concentrations (0.3 to 180 * 103 bubbles per microliter). More research in this direction under preclinical and clinical conditions is warranted. PMID- 30475707 TI - Single Element Remote-PPG. AB - Camera-based remote photoplethysmography technology (remote-PPG) has shown great potential for contactless pulse-rate monitoring. However, remote-PPG systems typically analyze face images, which may restrict applications in view of privacy preserving regulations such as the recently announced General Data Protection Regulation in the European Union. In this paper, we investigate the case of using single-element sensing as an input for remote-PPG extraction, which prohibits facial analysis and thus evades privacy issues. It also improves the efficiency of data storage and transmission. In contrast to known remote-PPG solutions using skin-selection techniques, the input signals in a single-element setup will contain a non-negligible degree of signal components associated with non-skin areas. Current remote-PPG extraction methods based on physiological and optical properties of skin reflections are therefore no longer valid. A new remote-PPG method, named Soft Signature based extraction (SoftSig), is proposed to deal with this situation by softening the dependence of pulse extraction on prior knowledge. A large scale experiment validates the concept of single-element remote-PPG monitoring and shows the improvement of SoftSig over general purpose solutions. PMID- 30475708 TI - Encapsulation Approaches for In-Stent Wireless Magnetoelastic Sensors. AB - Wireless magnetoelastic sensors offer significant potential for measuring the accumulation of biomass within stents - enabling early detection prior to stent occlusion - but the encapsulation of these sensors remains a critical challenge. The encapsulation must allow the sensors to navigate the curvature and accommodate the contact forces imparted during and after the implantation procedure, while also leaving the sensor open to mechanical interaction with the biomass during the extended period of deployment. This paper is focused on the encapsulation of ribbon-like magnetoelastic sensors (12.5 mm x 1 mm x 60 MUm) within plastic biliary stents (inner diameter of 2.54 mm). The compromise between two polymer-based package designs - one mechanically flexible (Type F) and one mechanically stiff (Type S) - is evaluated. The primary advantage of the Type F package is the flexibility during the delivery process while that of the Type S package is in maintaining a strong signal even when the stent is in a curved bile duct. The maximum thicknesses of the Type F and S packages are 0.53 mm and 0.74 mm, respectively. Mechanical tests show that both types protect the sensors from forces imparted by a standard introducer, and allow the encapsulated sensors to accommodate bending with a radius of curvature as small as 3 cm. The Type F package has also been tested in situ, in the bile duct of a porcine carcass. The signal is measurable with a wireless range of 10 cm, at a resonant frequency of 159 kHz and a quality factor of 397. PMID- 30475709 TI - Predicting Invasive Disease-Free Survival for Early-stage Breast Cancer Patients Using Follow-up Clinical Data. AB - OBJECTIVE: Chinese women are seriously threatened by breast cancer with high morbidity and mortality. The lack of robust prognosis models results in difficulty for doctors to prepare an appropriate treatment plan that may prolong patient survival time. An alternative prognosis model framework to predict Invasive Disease-Free Survival (iDFS) for early-stage breast cancer patients, called MP4Ei, is proposed. MP4Ei framework gives an excellent performance to predict the relapse or metastasis breast cancer of Chinese patients in 5 years. METHODS: MP4Ei is built based on statistical theory and gradient boosting decision tree framework. 5246 patients, derived from the Clinical Research Center for Breast (CRCB) in West China Hospital of Sichuan University, with early-stage (stage I-III) breast cancer are eligible for inclusion. Stratified feature selection, including statistical and ensemble methods, is adopted to select 23 out of the 89 patient features about the patient' demographics, diagnosis, pathology and therapy. Then 23 selected features as the input variables are imported into the XGBoost algorithm, with Bayesian parameter tuning and cross validation, to find out the optimum simplified model for 5-year iDFS prediction. RESULTS: For eligible data, with 4196 patients (80%) for training, and with 1050 patients (20%) for testing, MP4Ei achieves comparable accuracy with AUC 0.8451, which has a significant advantage (p < 0.05). CONCLUSION: This work demonstrates the complete iDFS prognosis model with very competitive performance. SIGNIFICANCE: The proposed method in this paper could be used in clinical practice to predict patients' prognosis and future surviving state, which may help doctors make treatment plan. PMID- 30475710 TI - Single Image Dehazing Using Haze-Lines. AB - Haze often limits visibility and reduces contrast in outdoor images. The degradation varies spatially since it depends on the objects' distances from the camera. This dependency is expressed in the transmission coefficients, which control the attenuation. Restoring the scene radiance from a single image is a highly ill-posed problem, and thus requires using an image prior. Contrary to methods that use patch-based image priors, we propose an algorithm based on a non local prior. The algorithm relies on the assumption that colors of a haze-free image are well approximated by a few hundred distinct colors, which form tight clusters in RGB space. Our key observation is that pixels in a given cluster are often non-local, i.e., spread over the entire image plane and located at different distances from the camera. In the presence of haze these varying distances translate to different transmission coefficients. Therefore, each color cluster in the clear image becomes a line in RGB space, that we term a haze-line. Using these haze-lines, our algorithm recovers the air-light, the distance map and the haze-free image. The algorithm has linear complexity, requires no training, and performs well on a wide variety of images compared to other state of-the-art methods. PMID- 30475711 TI - Adversarial Action Prediction Networks. AB - Different from after-the-fact action recognition, action prediction task requires action labels to be predicted from partially observed videos containing incomplete action executions. It is challenging because these partial videos have insufficient discriminative information, and their temporal structure is damaged. We study this problem in this paper, and propose an efficient and powerful deep network for learning representative and discriminative features for action prediction. Our approach exploits abundant sequential context information in full videos to enrich the feature representations of partial videos. This information is encoded in latent representations using a variational autoencoder (VAE), which are encouraged to be progress-invariant. Decoding such latent representations using another VAE, we can reconstruct missing information in the features extracted from partial videos. An adversarial learning scheme is adopted to differentiate the reconstructed features from the features directly extracted from full videos in order to well align their distributions. A multi-class classifier is also used to encourage the features to be discriminative. Our network jointly learns features and classifiers, and generates the features particularly optimized for action prediction. Extensive experimental results on UCF101, Sports-1M and BIT datasets demonstrate that our approach remarkably outperforms state-of-the-art methods, and shows significant speedup over these methods. Results also show that actions differ in their prediction characteristics; some actions can be correctly predicted even though only the beginning 10% portion of videos is observed. PMID- 30475712 TI - Deep Variational and Structural Hashing. AB - In this paper, we propose a deep variational and structural hashing (DVStH) method to learn compact binary codes for multimedia retrieval. Unlike most existing deep hashing methods which use a series of convolution and fully connected layers to learn binary features, we develop a probabilistic framework to infer latent feature representations inside the network. Then, we design a struct layer, instead of a bottleneck hash layer, to obtain the binary codes through a simple encoding procedure. By doing these, we are able to obtain binary codes discriminatively and generatively. To make it applicable to cross-modal multimedia retrieval, we extend our method to a cross-modal deep variational and structural hashing (CM-DVStH). We design a deep fusion network with a struct layer to maximize the correlation between image-text input pairs during the training so that a unified binary code can be obtained. We then design modality specific hashing networks suitable for the out-of-sample extension. Here, we train a network for each modality which outputs a latent representation that is as close as possible to the binary codes inferred from the fusion network. Experimental results on five benchmark datasets are presented to show the efficacy of the proposed approach. PMID- 30475713 TI - Reconstruction-Aware Imaging System Ranking by use of a Sparsity-Driven Numerical Observer Enabled by Variational Bayesian Inference. AB - It is widely accepted that optimization of imaging system performance should be guided by task-based measures of image quality (IQ). It has been advocated that imaging hardware or data-acquisition designs should be optimized by use of an ideal observer (IO) that exploits full statistical knowledge of the measurement noise and class of objects to be imaged, without consideration of the reconstruction method. In practice, accurate and tractable models of the complete object statistics are often difficult to determine. Moreover, in imaging systems that employ compressive sensing concepts, imaging hardware and sparse image reconstruction are innately coupled technologies. In this work, a sparsity-driven observer (SDO) that can be employed to optimize hardware by use of a stochastic object model describing object sparsity is described and investigated. The SDO and sparse reconstruction method can therefore be "matched" in the sense that they both utilize the same statistical information regarding the class of objects to be imaged. To efficiently compute the SDO test statistic, computational tools developed recently for variational Bayesian inference with sparse linear models are adopted. The use of the SDO to rank data-acquisition designs in a stylized example as motivated by magnetic resonance imaging (MRI) is demonstrated. This study reveals that the SDO can produce rankings that are consistent with visual assessments of the reconstructed images but different from those produced by use of the traditionally employed Hotelling observer (HO). PMID- 30475714 TI - Novel Effective Connectivity Inference Using Ultra-Group Constrained Orthogonal Forward Regression and Elastic Multilayer Perceptron Classifier for MCI Identification. AB - Mild cognitive impairment (MCI) detection is important such that appropriate interventions can be imposed to delay or prevent its progression to severe stages including Alzheimer's disease (AD). Brain connectivity network inferred from fMRI data has been prevalently used to identify the individuals with MCI/AD from the normal controls (NCs). The capability to detect the causal or effective connectivity is highly desirable for understanding directed functional interactions between brain regions and further helping detection of MCI. In this paper, we proposed a novel sparse constrained effective connectivity inference method and an elastic multilayer perceptron classifier for MCI identification. Specifically, a ultra-group constrained structure detection algorithm is first designed to identify the parsimonious topology of the effective connectivity network, in which the weak derivatives of the observable data are considered. Second, based on the identified topology structure, an effective connectivity network is then constructed by using an ultra-orthogonal forward regression (UOFR) algorithm to minimize the shrinking effect of the group constraint-based method. Finally, the effective connectivity network is validated in MCI identification using an elastic multilayer perceptron classifier which extracts lower to higher level information from initial input features and hence improves the classification performance. Relatively high classification accuracy is achieved by the proposed method when compared to the state-of-the-art classification methods. Furthermore, the network analysis results demonstrate that MCI patients suffer a rich club effect loss and have decreased connectivity among several brain regions. These findings suggest that the proposed method not only improves the classification performance but also successfully discovers critical disease-related neuroimaging biomarkers. PMID- 30475715 TI - Highly and Adaptively Undersampling Pattern for Pulmonary Hyperpolarized 129Xe Dynamic MRI. AB - Hyperpolarized (HP) gas (e.g. 3He or 129Xe) dynamic MRI could visualize the lung ventilation process, which provides characteristics regarding lung physiology and pathophysiology. Compressed sensing (CS) is generally used to increase the temporal resolution of such dynamic MRI. Nevertheless, the acceleration factor of CS is constant, which results in difficulties in precisely observing and/or measuring dynamic ventilation process due to bifurcating network structure of the lung. Here, an adaptive strategy is proposed to highly undersample pulmonary HP dynamic k-space data, according to the characteristics of both lung structure and gas motion. After that, a valid reconstruction algorithm is developed to reconstruct dynamic MR images, considering the low-rank, global sparsity, gas inflow effects, and joint sparsity. Both simulation and in vivo results verify that the proposed approach outperforms state-of-the-art methods both in qualitative and quantitative comparisons. In particular, the proposed method acquires 33 frames within 6.67 seconds (more than double the temporal resolution of the recently proposed strategy), and achieves high image quality [The improvements are 29.63%, 3.19%, 2.08%, and 13.03% regarding the mean absolute error (MAE), structural similarity index (SSIM), quality index based on local variance (QILV), and contrast-to-noise ratio (CNR) comparisons]. This provides accurate structural and functional information for early detection of obstructive lung diseases. PMID- 30475716 TI - Optimal Dual-VENC (ODV) Unwrapping in Phase-Contrast MRI. AB - Dual-VENC strategies have been proposed to improve the velocity-to-noise ratio in Phase-Contrast MRI. However, they are based on aliasing-free high-VENC data. The aim of this work is hence to propose a dual-VENC velocity estimation method allowing high-VENC aliased data. For this purpose, we reformulate the phase contrast velocity as a least squares estimator, providing a natural framework for including multiple encoding gradient measurements. By analyzing the mathematical properties of both single- and dual-VENC problems, we can justify theoretically high/low-VENC ratios such that the aliasing velocity can be minimized. The resulting reconstruction algorithm was assessed using three types of data: numerical, experimental and volunteers. In clinical practice, this method would allow shorter examination times by avoiding tedious adaptation of VENC values by repeated scans. PMID- 30475717 TI - Ultra Low Phase Noise 10MHz Crystal Oscillators. AB - This paper describes the design and implementation of low phase noise 10MHz Crystal Oscillators (using SC cut crystal resonators) which are being used as part of the chain of a local oscillator for use in compact atomic clocks. The design considerations and phase noise measurements are presented. The design includes a low noise transformer coupled differential amplifier, spurious resonance rejection filter and electronically tuned phase shifter. Phase noise measurements demonstrate a performance of -122dBc to -123dBc/Hz at 1Hz and 148dBc/Hz at 10Hz offsets. The phase noise at 1Hz offset is very similar to the phase noise produced by the low noise version of a doubled 5MHz BVA resonator based oscillators (Model number 8607) previously produced by Oscilloquartz. The noise floor of the oscillators presented in this paper is around - 161dBc/Hz. These designs can be used as the reference oscillator to control the timing of many modern electronics systems. PMID- 30475718 TI - One-for-All: Grouped Variation Network Based Fractional Interpolation in Video Coding. AB - Fractional interpolation is used to provide sub-pixel level references for motion compensation in the inter prediction of video coding, which attempts to remove temporal redundancy in video sequences. Traditional handcrafted fractional interpolation filters face the challenge of modeling discontinuous regions in videos, while existing deep learning based methods are either designed for a single quantization parameter (QP), only generate half-pixel samples, or need to train a model for each subpixel position. In this paper, we present a one-for-all fractional interpolation method based on grouped variation convolutional neural network (GVCNN). Our method can deal with video frames coded using different QPs and is capable of generating all sub-pixel positions at one sub-pixel level. Also, by predicting variations between integer-position pixels and sub-pixels, our network offers more expressive power. Moreover, we perform specific measurements in training data generation to simulate practical situations in video coding, including blurring the downsampled sub-pixel samples to avoid aliasing effects and coding integer pixels to simulate reconstruction errors. In addition, we analyze the impact of the size of blur kernels theoretically. Experimental results verify the efficiency of GVCNN. Compared with HEVC, our method achieves 2.2% in bit saving on average and up to 5.2% under low-delay P configuration. PMID- 30475719 TI - Joint Learning of Fuzzy K-Means and Nonnegative Spectral Clustering with Side Information. AB - As one of the most widely used clustering techniques, the fuzzy K-Means (also known as FKM) assigns every data point to each cluster with a certain degree of membership. However, conventional FKM approach relies on the square data fitting term, which is sensitive to the outliers with ignoring the prior information. In this paper, we develop a novel and robust fuzzy K-Means clustering algorithm, namely, Joint Learning of Fuzzy K-Means and Nonnegative Spectral Clustering with Side Information. The proposed method combines fuzzy K-Means and nonnegative spectral clustering into a unified model, which can further exploit the prior knowledge of data pairs such that both the quality of affinity graph and the clustering performance can be improved. In addition, for the purpose of enhancing the robustness, the adaptive loss function is adopted in the objective function, since it smoothly interpolates between l1-norm and l2-norm. Finally, experimental results on benchmark datasets verify the effectiveness and the superiority of our clustering method. PMID- 30475720 TI - Moving Object Detection in Video via Hierarchical Modeling and Alternating Optimization. AB - In conventional wisdom of video modeling, background is often treated as the primary target and foreground is derived using the technique of background subtraction. Based on the observation that foreground and background are two sides of the same coin, we propose to treat them as peer unknown variables and formulate a joint estimation problem, called Hierarchical modeling and Alternating Optimization (HMAO). The motivation behind our hierarchical extensions of background and foreground models is to better incorporate a priori knowledge about the disparity between background and foreground. For background, we decompose it into temporally low-frequency and high-frequency components for the purpose of better characterizing the class of video with dynamic background; for foreground, we construct a Markov random field prior at a spatially low resolution as the pivot to facilitate noise-resilient refinement at higher resolutions. Built on hierarchical extensions of both models, we show how to successively refine their joint estimates under a unified framework known as alternating direction multipliers method. Experimental results have shown that our approach produces more discriminative background and demonstrates better robustness to noise than other competing methods. When compared against current state-of-the-art techniques, HMAO achieves at least comparable and often superior performance in terms of F-measure scores especially for video containing dynamic and complex background. PMID- 30475721 TI - Semantics-Space-Time Cube. A Conceptual Framework for Systematic Analysis of Texts in Space and Time. AB - We propose an approach to analyzing data in which texts are associated with spatial and temporal references with the aim to understand how the text semantics vary over space and time. To represent the semantics, we apply probabilistic topic modeling. After extracting a set of topics and representing the texts by vectors of topic weights, we aggregate the data into a data cube with the dimensions corresponding to the set of topics, the set of spatial locations (e.g., regions), and the time divided into suitable intervals according to the scale of the planned analysis. Each cube cell corresponds to a combination (topic, location, time interval) and contains aggregate measures characterizing the subset of the texts concerning this topic and having the spatial and temporal references within these location and interval. Based on this structure, we systematically describe the space of analysis tasks on exploring the interrelationships among the three heterogeneous information facets, semantics, space, and time. We introduce the operations of projecting and slicing the cube, which are used to decompose complex tasks into simpler subtasks. We then present a design of a visual analytics system intended to support these subtasks. To reduce the complexity of the user interface, we apply the principles of structural, visual, and operational uniformity while respecting the specific properties of each facet. The aggregated data are represented in three parallel views corresponding to the three facets and providing different complementary perspectives on the data. The views have similar look-and-feel to the extent allowed by the facet specifics. Uniform interactive operations applicable to any view support establishing links between the facets. The uniformity principle is also applied in supporting the projecting and slicing operations on the data cube. We evaluate the feasibility and utility of the approach by applying it in two analysis scenarios using geolocated social media data for studying people's reactions to social and natural events of different spatial and temporal scales. PMID- 30475722 TI - "Remind-to-Move" for promoting upper extremity recovery using wearable devices in subacute stroke: a multi-center randomized controlled study. AB - This study examined the effects of "Remind-to-Move" (RTM) via vibration cueing using wearable devices to increase the use of the affected upper limb and integrate upper limb activities undertaken at home in patients with subacute stroke after inpatient discharge. In a multi-centered randomized controlled trial, 84 eligible patients from four general hospitals who had had a first stroke in the last six months were randomly allocated to either an experimental, sham, or control group, stratified by arm function levels. Patients in the experimental group were treated by RTM, using wearable devices for three consecutive hours daily, over four weeks. The sham group used sham devices and the control group received usual care alone. A masked assessor evaluated the patients at 0, 4th, 8th and 12th weeks using outcome measures included arm function tests, motor activity log, and movement recorded by the devices. Results showed that there was a significant group by time interaction, and the average movement amount and Action Research Arm Test score in the experimental group was significantly higher than in the sham group. This study demonstrates that RTM via wearable devices used for the hemiplegic upper extremities could promote more arm recovery than the sham or control, and hence, produce an optimal functional improvement for subacute stroke patients. PMID- 30475723 TI - Automatic Multichannel Intramuscular Electromyogram Decomposition: Progressive FastICA Peel-off and Performance Validation. AB - The progressive FastICA peel-off (PFP) is a recently developed blind source separation approach for high-density surface EMG decomposition. This study explores a novel application of PFP for automatic decomposition of multi-channel intramuscular electromyogram signals. The automatic PFP (APFP) was used to decompose an open access multichannel intramuscular EMG dataset, simultaneously collected from the brachioradialis muscle using 6 to 8 fine wire or needle electrodes. Given usually limited number of intramuscular electrodes compared with high-density surface EMG recording, a modification was made to the original APFP framework to dramatically increase the decomposition yield. A total of 131 motor units were automatically decomposed by the APFP framework from 10 multichannel intramuscular EMG signals, among which 128 motor units were also manually identified from the expert interactive EMGLAB decomposition. The average matching rate of discharge instants for all the common motor units was (98.71+/ 1.73) %. The outcomes of this study indicate that the APFP framework can also be used to automatically decompose multichannel intramuscular EMG with high accuracies, even though the number of recording channels is relatively small compared with high-density surface EMG. PMID- 30475724 TI - Molecular Communications in the Context of "Synthetic Cells" Research. AB - The recent progresses in bottom-up synthetic biology allow the construction of cell-like systems (shortly called "synthetic cells") based on the encapsulation of chemicals and biological macromolecules inside lipid vesicles. Synthetic cells are far from being alive, but can be designed in order to imitate biological cells with respect to specific functions. The exchange of chemical signals is one of the most fascinating ones. Experimental papers have shown that synthetic cells can be designed to send and receive molecular signals, inaugurating a new research avenue that can be highly relevant not only for nano-medicine and nano biotechnology, but also for basic understanding of minimal cognitive systems. Here we shortly present the synthetic cell technology and illustrate how to implement the concept of molecular communication in this field. PMID- 30475725 TI - Identifying TF Binding Motifs from Partial Set of Target Genes and its Application to Regulatory Network Inference. AB - Motif identification has been one of the most widely studied problems in bioinformatics. Many methods have been developed to discover binding motifs from a large set of genes. But when the given genes are only a partial set of target genes, the statistical significance usually contains a bias towards the input. If we can identify the TF binding motif from a partial set of target genes, we can save the labor costs and resources of doing many experiments. In this paper, we propose a method MISA (Motif Identification through Segments Assembly) to identify binding motifs from a subset of target genes. By ranking and assembling the segments, MISA discovers a set of binding motifs with the best length to fit our proposed objective function. We also predict the additional target genes as an application of regulatory network inference. We compare our approach with two widely used methods MEME and AlignACE by analyzing both the quality of the binding motif and network inference. Using two model organisms S. cerevisiae and E. coli, we show that with 20?% of the target genes(minimum size of genes is 20), we can achieve a motif similarity of 82?% with the known motifs. PMID- 30475726 TI - An Efficient Ensemble Learning Approach for Predicting Protein-Protein Interactions by Integrating Protein Primary Sequence and Evolutionary Information. AB - Protein-protein interactions (PPIs) perform a very important function in many cellular processes, including signal transduction, post-translational modifications, apoptosis, and cell growth. Deregulation of PPIs results in many diseases, including cancer and pernicious anemia. Although many high-throughput methods have been applied to generate a large amount of PPIs data, they are generally expensive, inefficient and labor-intensive. Hence, there is an urgent need for developing a computational method to accurately and rapidly detect PPIs. In this article, we proposed a highly efficient approach to predict PPIs by integrating a new protein sequence substitution matrix feature representation and ensemble weighted sparse representation model classifier. The proposed method is demonstrated on Saccharomyces cerevisiae dataset and achieved 99.26% prediction accuracy with 98.53% sensitivity at precision of 100%, which is shown to have much higher predictive accuracy than current state-of-the-art algorithms. Extensive experiments are performed with the benchmark data set from Human and Helicobacter pylori that the proposed method achieves outstanding better success rates than other existing approaches in this problem. Experiment results illustrate that our proposed method presents an economical approach for computational building of PPI networks, which can be a helpful supplementary method for future proteomics researches. PMID- 30475727 TI - Deleterious Non-Synonymous Single Nucleotide Polymorphism Predictions on Human Transcription Factors. AB - Transcription factors are the major components of human gene regulation. In particular, they bind onto specific DNA sequences and regulate neighborhood genes in different tissues at different developmental stages. Non-synonymous single nucleotide polymorphisms on its protein-coding sequences could result in undesired consequences in human. Therefore, it is necessary to develop methods for predicting any abnormality among those non-synonymous single nucleotide polymorphisms. PMID- 30475728 TI - A 65-nm CMOS Fully-Integrated Analysis Platform Using an On-Chip Vector Network Analyzer and a Transmission-Line-Based Detection Window for Analyzing Circulating Tumor Cell and Exosome. AB - A fully-integrated CMOS circuit based on a vector network analyzer (VNA) and a transmission-line-based detection window for circulating tumor cell (CTC) and exosome analysis is presented for the first time. We have introduced a fully integrated architecture, which eliminates the undesired parasitic components and enables high-sensitivity, to analyze extremely low concentration CTC in blood. The detection window was designed on the high-sensitive coplanar waveguide (CPW) line. To validate the operation of the proposed system, a test chip was fabricated using 65-nm CMOS technology. Measurements were performed after adding a tiny lump of silicone or a droplet of water on its detection window. The measured results show |S_21| degradation of -1.96 dB and -6.04 dB for the silicone and the droplet, respectively, at 1.4 GHz. In addition, in another measurement using magnetic beads, it is confirmed that the proposed circuit can analyze even low concentrations of 20 beads/L. As well as microbeads, measurement with CTCs was successfully demonstrated. PMID- 30475729 TI - Eyelid Drive System: An Assistive Technology Employing Inductive Sensing of Eyelid Movement. AB - This paper presents the design, development, and validation of the Eyelid Drive System (EDS), an assistive technology comprising a specialized pair of glasses and millimeter-sized passive resonators, attached to the wearer's eyelids, that transduce eyelid movement (blinking and winking) through inductive sensing. The theory of operation and design optimization with simulations are presented. A proof-of-concept prototype EDS was constructed using a pair of non-prescription glasses and commercial-off-the-shelf components. In benchtop tests with model eyelids, the EDS demonstrated basic functionality. Initial trials were performed involving six human subjects interacting with custom designed graphical user interfaces (GUIs) on a computer. A group mean accuracy of 96.3% was achieved using a set of four different commands at a response rate of 3 s. A mean information transfer rate (ITR) of 56.1 bits/min over all subjects was achieved with a set of six different commands at a response rate of 1.5 s. The wearable portion of this proof-of-concept system consumes 51.6 mW from a 3-V battery. The EDS compares favorably with related eye-interfacing assistive technologies and provides a unique combination of advantages, including high accuracy and ITR, wearability, insensitivity to lighting and noise conditions, aesthetic acceptability, and use of non-exaggerated gestures. PMID- 30475730 TI - Low-voltage OTA-C Filter with an Area- and Power-efficient OTA for Biosignal Sensor Applications. AB - This paper presents a systematic method for decreasing the amount of transconductors used by an operational transconductance amplifier-capacitor (OTA C) filter to decrease the power consumption and the active area. An OTA with a local-feedback linearized technique and a transconductance booster is proposed based on the presented method. The proposed OTA combines current division with source degeneration to enhance linearity and implement low transconductance. This topology enables the proposed OTA to drive multiple integration capacitors without an additional output stage. The OTA-based circuit realizes low power consumption by operating under a weak inversion at a supply voltage of 1 V. Thus, a fifth-order ladder-type low-pass Butterworth OTA-C filter is implemented for the acquisition of electrocardiograph (ECG) signals. The proposed method is validated using a prototype fabricated through a 1P6M 0.18-MUm CMOS process. Results show that in ECG signal acquisition, the proposed filter has a signal bandwidth located within 250 Hz, a dynamic range of 61.2 dB, and a power consumption of 41 nW to achieve a figure-of-merit of 5.4 * 10. The active area of the filter is 0.24 mm. PMID- 30475731 TI - Increasing Impact by Mechanical Resonance for Teleoperated Hammering. AB - Series elastic actuators (SEAs) are interesting for usage in harsh environments as they are more robust than rigid actuators. This paper shows how SEAs can be used in teleoperation to increase output velocity in dynamic tasks. A first experiment is presented that tested human ability to achieve higher hammerhead velocities with a flexible hammer than with a rigid hammer, and to evaluate the influence of the resonance frequency. In this experiment, 13 participants executed a hammering task in direct manipulation using flexible hammers in four conditions with resonance frequencies of 3.0 Hz to 9.9 Hz and one condition with a rigid hammer. Then, a second experiment is presented that tested the ability of 32 participants to reproduce the findings of the first experiment in teleoperated manipulation with different feedback conditions: with visual and force feedback, without visual feedback, without force feedback, and with a communication delay of 40 ms. The results indicate that humans can exploit the mechanical resonance of a flexible system to at least double the output velocity without combined force and vision feedback. This is an unexpected result, allowing the design of simpler and more robust teleoperators for dynamic tasks. PMID- 30475732 TI - Fast and Accurate Sparse Coding of Visual Stimuli With a Simple, Ultralow-Energy Spiking Architecture. AB - Memristive crossbars have become a popular means for realizing unsupervised and supervised learning techniques. In previous neuromorphic architectures with leaky integrate-and-fire neurons, the crossbar itself has been separated from the neuron capacitors to preserve mathematical rigor. In this paper, we sought to design a simplified sparse coding circuit without this restriction, resulting in a fast circuit that approximated a sparse coding operation at a minimal loss in accuracy. We showed that connecting the neurons directly to the crossbar resulted in a more energy-efficient sparse coding architecture and alleviated the need to prenormalize receptive fields. This paper provides derivations for the design of such a network, named the simple spiking locally competitive algorithm, as well as CMOS designs and results on the CIFAR and MNIST data sets. Compared to a nonspiking, nonapproximate model which scored 33% on CIFAR-10 with a single-layer classifier, this hardware scored 32% accuracy. When used with a state-of-the-art deep learning classifier, the nonspiking model achieved 82% and our simplified, spiking model achieved 80% while compressing the input data by 92%. Compared to a previously proposed spiking model, our proposed hardware consumed 99% less energy to do the same work at 21x the throughput. Accuracy held out with online learning to a write variance of 3%, suitable for the often reported 4-bit resolution required for neuromorphic algorithms, with offline learning to a write variance of 27%, and with read variance to 40%. The proposed architecture's excellent accuracy, throughput, and significantly lower energy usage demonstrate the utility of our innovations. PMID- 30475733 TI - Biased Random Forest For Dealing With the Class Imbalance Problem. AB - The class imbalance issue has been a persistent problem in machine learning that hinders the accurate predictive analysis of data in many real-world applications. The class imbalance problem exists when the number of instances present in a class (or classes) is significantly fewer than the number of instances belonging to another class (or classes). Sufficiently recognizing the minority class during classification is a problem as most algorithms employed to learn from data input are biased toward the majority class. The underlying issue is made more complex with the presence of data difficult factors embedded in such data input. This paper presents a novel and effective ensemble-based method for dealing with the class imbalance problem. This paper is motivated by the idea of moving the oversampling from the data level to the algorithm level, instead of increasing the minority instances in the data sets, the algorithms in this paper aims to ''oversample the classification ensemble'' by increasing the number of classifiers that represent the minority class in the ensemble, i.e., random forest. The proposed biased random forest algorithm employs the nearest neighbor algorithm to identify the critical areas in a given data set. The standard random forest is then fed with more random trees generated based on the critical areas. The results show that the proposed algorithm is very effective in dealing with the class imbalance problem. PMID- 30475734 TI - Hippocampus Analysis by Combination of 3D DenseNet and Shapes for Alzheimer's Disease Diagnosis. AB - Hippocampus is one of the first involved regions in Alzheimer's disease (AD) and mild cognitive impairment (MCI), a prodromal stage of AD. Hippocampal atrophy is a validated, easily accessible and widely used biomarker for AD diagnosis. Most of existing methods on hippocampus analysis are based on the hippocampal shape and volume features using structural magnetic resonance images (MRI). However, the regions adjacent to hippocampus may be relevant to AD, and the visual features of hippocampal region are also important for disease diagnosis. In this paper, we have proposed a new hippocampus analysis method to combine the global and local features of hippocampus based on 3D Densely Connected Convolutional Networks (3D DenseNet) and shape analysis for AD diagnosis. The proposed method can make full use of both the local visual and global shape features for hippocampus analysis to enhance the classification. Tissue segmentation and nonlinear registration are not required in the proposed method. Our method is evaluated with the T1-weighted structural MRIs from 811 subjects including 192 AD, 396 MCI (231 stable MCI and 165 progressive MCI), 223 Normal Control (NC) in Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Experimental results show the proposed method achieves a classification accuracy of 92.29% and AUC (Area Under the ROC Curve) of 96.95% for AD classification. Results comparison demonstrates the proposed method performs better than other methods. PMID- 30475735 TI - Adversarial MACE Prediction after Acute Coronary Syndrome using Electronic Health Records. AB - Acute coronary syndrome (ACS), as an emergent and severe syndrome due to decreased blood flow in the coronary arteries, is a leading cause of death and serious long-term disability globally. ACS is usually caused by one of three problems: ST elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI), or unstable angina (UA). Major adverse cardiac event (MACE) prediction, as a critical tool to estimate the likelihood an individual is at risk of ACS, has been widely adopted in the early prevention and intervention of ACS. Although valuable, existing MACE prediction models are designed to predict the overall probability of MACE occurrence for ACS patients, and lack the ability to look for insight into the disease to distinguish the different subtypes of ACS in a fine-grained manner. It is interesting to exploit the different subtypes of ACS and mine their private and shared underlying knowledge to improve the performance of MACE prediction. In this study, we propose utilizing a large volume of heterogeneous electronic health records for the application of MACE prediction. In detail, we address the multi-subtype-oriented MACE prediction for ACS as a multi-task learning (MTL) problem, present a MTL-based model to predict MACE of ACS patients with the different subtypes, and incorporate adversarial learning into the model to alleviate both the shared and private latent feature spaces of each subtype of ACS from interfering with each other. A real-world clinical dataset containing 2,863 ACS patient samples is collected from a Chinese hospital to validate the proposed model. Experimental results demonstrate that the prediction performance of our proposed model obtains a significant improvement, compared to single-subtype-oriented MACE prediction models. PMID- 30475736 TI - Non-Invasive Detection of Mechanical Alternans Utilizing Photoplethysmography. AB - BACKGROUND AND SIGNIFICANCE: Mechanical alternans (MA) is a biomarker associated with mortality and life-threatening arrhythmias in heart failure patients. Despite showing prognostic value, its use is limited by the requirement of measuring continuous blood pressure (BP), which is costly and impractical. OBJECTIVE: To develop and test, for the first time, non-invasive MA surrogates based on photoplethysmography (PPG). METHODS: Continuous BP and PPG were recorded during clinical procedures and tests in 35 patients. MA was induced either by ventricular pacing (Group A, N=19) or exercise (Group B, N=16). MA was categorized as sustained or intermittent if MA episodes were observed in at least 20 or between 12 to 20 consecutive beats, respectively. Eight features characterizing pulse morphology were derived from the PPG and MA surrogates were evaluated. RESULTS: Sustained alternans was observed in 9 patients (47%) from Group A, whereas intermittent alternans was observed in 13 patients (68%) from Group A and in 10 patients (63%) from Group B. The PPG-based MA surrogate showing the highest accuracy, V'M, was based on the maximum of the first derivative of the PPG pulse. It detected both sustained and intermittent MA with 100% sensitivity and 100% specificity in Group A and intermittent MA with 100% sensitivity and 83% specificity in Group B. Furthermore, the magnitudes of MA and its PPG-based surrogate were linearly correlated (R=0.83, p<0.001). CONCLUSION: MA can be accurately identified non-invasively through PPG analysis. This may have important clinical implications for risk stratification and remote monitoring. PMID- 30475737 TI - Densely-Connected Multi-Magnification Hashing for Histopathological Image Retrieval. AB - Content-based Medical Image Retrieval (CBMIR) is an important computer-aided diagnosis technique providing the clinicians with interpretative guidance based on visual similarity. In this paper, we focus on the tasks of histopathological image retrieval for breast cancer diagnosis. The Densely-Connected Multi Magnification (DCMMH) framework is proposed that learns the discriminative binary codes by exploiting the histopathological images with multiple magnification factors. The low-magnification images are boosted by the accumulated similarity based on local patches which also regularize the feature learning of high magnification images. In order to fully utilize the information over all magnification levels, a densely-connected architecture is finally deployed for low-high magnification pairs of datasets. The experiments on BreakHis dataset demonstrate that DCMMH outperforms the previous hashing methods on histopathological image retrieval. PMID- 30475738 TI - Improving Health Care Management Through Persistent Homology of Time-Varying Variability of Emergency Department Patient Flow. AB - Excessive admissions at the Emergency Department (ED) is a phenomenon very closely linked to the propagation of viruses. It is a cause of overcrowding for EDs and a public health problem. The aim of this work is to give EDs' leaders more time for decision making during this period. Based on the admissions time series associated with specific clinical diagnoses, we will first perform a Detrended Fluctuation Analysis (DFA) to obtain the corresponding variability time series. Next, we will embed this time series on a manifold to obtain a point cloud representation and use Topological Data Analysis (TDA) through persistent homology technic to propose two early real-time indicators. One is the early indicator of abnormal arrivals at the ED whereas the second gives the information on the time index of the maximum number of arrivals. The performance of the detectors is parameter dependent and it can evolve each year. That is why we also propose to solve a bi-objective optimization problem to track the variations of this parameter. PMID- 30475739 TI - Identifying Brain Networks at Multiple Time Scales via Deep Recurrent Neural Network. AB - For decades, task-based functional magnetic resonance imaging (tfMRI) has been a powerful noninvasive tool to explore the organizational architecture of human brain function. Researchers have developed a variety of brain network analysis methods for tfMRI data, including the general linear model (GLM), independent component analysis (ICA) and sparse representation methods. However, these shallow models are limited in faithful reconstruction and modeling of the hierarchical and temporal structures of brain networks, as demonstrated in more and more studies. Recently, recurrent neural networks (RNNs) exhibit great ability of modeling hierarchical and temporal dependency features in the machine learning field, which might be suitable for tfMRI data modeling. To explore such possible advantages of RNNs for tfMRI data, we propose a novel framework of deep recurrent neural network (DRNN) to model the functional brain networks from tfMRI data. Experimental results on the motor task tfMRI data of Human Connectome Project 900 subjects release demonstrated that the proposed DRNN can not only faithfully reconstruct functional brain networks, but also identify more meaningful brain networks with multiple time scales which are overlooked by traditional shallow models. In general, this work provides an effective and powerful approach to identifying functional brain networks of multiple time scales from fMRI data. PMID- 30475740 TI - Robot-Assisted Pedestrian Regulation Based on Deep Reinforcement Learning. AB - Pedestrian regulation can prevent crowd accidents and improve crowd safety in densely populated areas. Recent studies use mobile robots to regulate pedestrian flows for desired collective motion through the effect of passive human-robot interaction (HRI). This paper formulates a robot motion planning problem for the optimization of two merging pedestrian flows moving through a bottleneck exit. To address the challenge of feature representation of complex human motion dynamics under the effect of HRI, we propose using a deep neural network to model the mapping from the image input of pedestrian environments to the output of robot motion decisions. The robot motion planner is trained end-to-end using a deep reinforcement learning algorithm, which avoids hand-crafted feature detection and extraction, thus improving the learning capability for complex dynamic problems. Our proposed approach is validated in simulated experiments, and its performance is evaluated. The results demonstrate that the robot is able to find optimal motion decisions that maximize the pedestrian outflow in different flow conditions, and the pedestrian-accumulated outflow increases significantly compared to cases without robot regulation and with random robot motion. PMID- 30475741 TI - The effect of fractal-like mechanical ventilation on vital signs in a rat model of acute-on-chronic liver failure. AB - OBJECTIVE: The network of interactions between different organs is impaired in liver cirrhosis. Liver cirrhosis is associated with multi-system involvement, which eventually leads to multiple organ failure. This process is accelerated by a precipitating factor such as bacterial infection, which leads to respiratory distress, circulatory shock, neural dysfunction and very high mortality. Cirrhotic patients often have blunted respiratory sinus arrhythmia and impaired cardio-respiratory variability. Fractal-like mechanical ventilation is reported to enhance respiratory sinus arrhythmia and attenuate respiratory distress in experimental models. In the present study we hypothesise that fractal-like mechanical ventilation may improve the outcome of cirrhotic rats with multiple organ failure. APPROACH: Cirrhosis was induced by chronic biliary obstruction in rats. Acute multiple organ failure was induced by intraperitoneal injection of bacterial endotoxin in cirrhotic rats. The effect of conventional mechanical ventilation (with constant tidal volume and respiratory rate) or fractal-like ventilation (with the same average but variable tidal volume and respiratory rate) were assessed on vital signs, oxygen saturation and plasma alanine aminotransferase in anaesthetised cirrhotic rats. MAIN RESULTS: We demonstrated that fractal-like mechanical ventilation was accompanied by improved oxygen saturation, reduced heart rate and decreased liver injury following injection of bacterial endotoxin. Moreover, variable mechanical ventilation in cirrhotic rats reduced mortality and prevented a fall in short-term heart rate variability following endotoxin challenge in comparison with rats with constant mechanical ventilation. SIGNIFICANCE: We suggest further investigations into the beneficial effects of fractal-like ventilation strategy in critically ill patients with liver failure requiring organ support and mechanical ventilation. PMID- 30475742 TI - Myotonometry as a measure to detect myofascial trigger points: an inter-rater reliability study. AB - OBJECTIVE: Several diagnostic methods have been used in the identification of mechanical properties of skeletal muscle, including myofascial trigger points (MTrPs), however, they are not suitable for daily clinical use. Myotonometry offers an easy noninvasive alternative to assess these muscle properties. Nevertheless, previous research has not yet studied the mechanical properties of MTrPs by myotonometry. The purposes of this study were (1) to analyze the differences in the mechanical properties between latent MTrPs and their taut bands by myotonometry, (2) to investigate the inter-rater reproducibility of myotonometric measurements, and (3) to examine the association between myotonometry and passive isokinetic dynamometry. APPROACH: Fifty individuals (58% male; age 24.6 +/- 7.9 years) with a latent medial MTrP of the right soleus muscle participated. The mechanical properties of this MTrP area of soleus muscle and its taut band area were measured using a myotonometer (MyotonPRO). Additionally, passive resistive torque and extensibility of triceps surae muscle were assessed using a Kin-Com dynamometer. MAIN RESULTS: Statistical analysis indicated higher values for the stiffness parameter in the taut band with respect to the MTrP (P < 0.05). The inter-rater reliability of the myotonometric measurements was good for all variables (ICC3,1 > 0.75). The standard error of measurement (SEM) and minimal detectable difference (MDD) indicated a small measurement error for frequency and stiffness variables (SEM% < 10%; MDD95% < 20%). Significant fair correlations between myotonometric parameters and passive isokinetic parameters ranged from -0.29 to 0.48 (P < 0.05). SIGNIFICANCE: The myotonometer was demonstrated to be a reliable tool and was able to quantify differences in the mechanical properties of myofascial tissues. The potential of this method for the assessment of myofascial pain syndromes requires further investigation. PMID- 30475743 TI - Efficient sleep classification based on entropy features and a support vector machine classifier. AB - OBJECTIVE: Sleep quality helps to reflect on the physical and mental condition, and efficient sleep stage scoring promises considerable advantages to health care. The aim of this study is to propose a simple and efficient sleep classification method based on entropy features and a support vector machine classifier, named SC-En&SVM. APPROACH: Entropy features, including fuzzy measure entropy (FuzzMEn), fuzzy entropy, and sample entropy are applied for the analysis and classification of sleep stages. FuzzyMEn has been used for heart rate variability analysis since it was proposed, while this is the first time it has been used for sleep scoring. The three features are extracted from 6 376 730 s epochs from Fpz-Cz electroencephalogram (EEG), Pz-Oz EEG and horizontal electrooculogram (EOG) signals in the sleep-EDF database. The independent samples t-test shows that the entropy values have significant differences among six sleep stages. The multi-class support vector machine (SVM) with a one-against-all class approach is utilized in this specific application for the first time. We perform 10-fold cross-validation as well as leave-one-subject-out cross-validation for 61 subjects to test the effectiveness and reliability of SC-En&SVM. MAIN RESULTS: The 10-fold cross-validation shows an effective performance with high stability of SC-En&SVM. The average accuracy and standard deviation for 2-6 states are 97.02 +/- 0.58, 92.74 +/- 1.32, 89.08 +/- 0.90, 86.02 +/- 1.06 and 83.94 +/- 1.61, respectively. While for a more practical evaluation, the independent scheme is further performed, and the results show that our method achieved similar or slightly better average accuracies for 2-6 states of 94.15%, 85.06%, 80.96%, 78.68% and 75.98% compared with state-of-the-art methods. The corresponding kappa coefficients (0.81, 0.74, 0.72, 0.71, 0.67) guarantee substantial agreement of the classification. SIGNIFICANCE: We propose a novel sleep stage scoring method, SC-En&SVM, with easily accessible features and a simple classification algorithm, without reducing the classification performance compared with other approaches. PMID- 30475744 TI - Highlights of articles in this issue. AB - Highlights of the articles in this issue are given in the PDF file. PMID- 30475745 TI - A method for determining local pulse wave velocity in human ascending aorta from sequential ultrasound measurements of diameter and velocity. AB - BACKGROUND: Pulse wave velocity (PWV) is an indicator of arterial stiffness, and predicts cardiovascular events independently of blood pressure. Currently, PWV is commonly measured by the foot-to-foot technique thus giving a global estimate of large arterial stiffness. However, and despite its importance, methods to measure the stiffness of the ascending aorta are limited. OBJECTIVE: To introduce a method for calculating local PWV in the human ascending aorta using non-invasive ultrasound measurements of its diameter (D) and flow velocity (U). APPROACH: Ten participants (four females) were recruited from Brunel University students. Ascending aortic diameter and velocity were recorded with a GE Vivid E95 equipped with a 1.5-4.5 MHz phased array transducer using M-mode in the parasternal long axis view and pulse wave Doppler in the apical five chamber view respectively. Groups of six consecutive heartbeats were selected from each 20 s run based on the most similar cycle length resulting in three groups for D and three for U each with six waveforms. Each D waveform was paired with each U waveform to calculate PWV using ln(D)U-loop method. MAIN RESULTS: The diastolic portions of the diameters or velocities waveforms were truncated to allow the pairs to have equal length and were used to construct ln(D)U-loops. The trimmed average, excluding 10% of extreme values, resulting from the 324 loops was considered representative for each participant. Overall mean local PWV for all participants was 4.1(SD = 0.9) m s-1. SIGNIFICANCE: Local PWV can be measured non-invasively in the ascending aorta using ultrasound measurements of diameter and flow velocity This should facilitate more widespread assessment of ascending aortic stiffness in larger studies. PMID- 30475746 TI - The effect of cranial electrotherapy stimulation on sleep in healthy women. AB - OBJECTIVE: Cranial electrotherapy stimulation (CES) is considered to be a potential treatment for insomnia. Women are more likely to suffer from insomnia than men. Therefore we studied the effect of CES on sleep efficiency in young healthy women. METHODS: A randomized, controlled clinical study was conducted on 40 women (age 18-35 years) without sleep disorders. Each subject underwent two nights of polysomnography in a sleep center. During the second night, we applied CES with a commercial device (Alpha-Stim 100) using either active or sham stimulation (double-blinded). Sleep was evaluated with respect to differences between the active and sham modes. Sleep electroencephalogram (EEG) analysis was applied to determine frequency changes. RESULTS: In our study we found no evidence of any direct influence of the Alpha-Stim 100 on sleep. After application of CES, we determined no significant differences between the active group and the control group (sham). Using EEG spectral analysis there was evidence of a frequency-lowering influence on the low-alpha frequency band (8-10 Hz). CONCLUSIONS: At most we may assume a reproducible effect on the alpha frequency measured in the EEG for application of CES with current levels >100 uA and presumably also with frequencies >0.5 Hz, with application directly at the cranium. We found no influence on sleep parameters. The effect on the low-alpha band evidenced in quantitative EEG analysis would require further investigation in a study with sufficient effect size. SIGNIFICANCE: This is the first study to investigate the effects of CES with polysomnography during and after therapy. Our study contributes to the few controlled trials that have been conducted to study CES and its effects on the EEG alpha band. Highlights * This is the first study to investigate the effects of the Alpha-Stim in polysomnography during and subsequent to therapy. * In a quantitative electroencephalogram analysis we studied the data obtained for systematic changes. * To minimize placebo effects in patients with sleep disorders, we conducted the tests on subjects without such disorders. PMID- 30475747 TI - A novel wavelet-based filtering strategy to remove powerline interference from electrocardiograms with atrial fibrillation. AB - OBJECTIVE: The electrocardiogram (ECG) is currently the most widely used recording to diagnose cardiac disorders, including the most common supraventricular arrhythmia, such as atrial fibrillation (AF). However, different types of electrical disturbances, in which power-line interference (PLI) is a major problem, can mask and distort the original ECG morphology. This is a significant issue in the context of AF, because accurate characterization of fibrillatory waves (f-waves) is unavoidably required to improve current knowledge about its mechanisms. This work introduces a new algorithm able to reduce high levels of PLI and preserve, simultaneously, the original ECG morphology. APPROACH: The method is based on stationary wavelet transform shrinking and makes use of a new thresholding function designed to work successfully in a wide variety of scenarios. In fact, it has been validated in a general context with 48 ECG recordings obtained from pathological and non-pathological conditions, as well as in the particular context of AF, where 380 synthesized and 20 long-term real ECG recordings were analyzed. MAIN RESULTS: In both situations, the algorithm has reported a notably better performance than common methods designed for the same purpose. Moreover, its effectiveness has proven to be optimal for dealing with ECG recordings affected by AF, since f-waves remained almost intact after removing very high levels of noise. SIGNIFICANCE: The proposed algorithm may facilitate a reliable characterization of the f-waves, preventing them from not being masked by the PLI nor distorted by an unsuitable filtering applied to ECG recordings with AF. PMID- 30475748 TI - Sinus or not: a new beat detection algorithm based on a pulse morphology quality index to extract normal sinus rhythm beats from wrist-worn photoplethysmography recordings. AB - OBJECTIVE: Wrist-worn photoplethysmography (PPG) can enable free-living physiological monitoring of people during diverse activities, ranging from sleep to physical exercise. In many applications, it is important to remove the pulses not related to sinus rhythm beats from the PPG signal before using it as a cardiovascular descriptor. In this manuscript, we propose an algorithm to assess the morphology of the PPG signal in order to reject non-sinus rhythm pulses, such as artefacts or pulses related to arrhythmic beats. APPROACH: The algorithm segments the PPG signal into individual pulses and dynamically evaluates their morphological likelihood of being normal sinus rhythm pulses via a template matching approach that accounts for the physiological variability of the signal. The normal sinus rhythm likelihood of each pulse is expressed as a quality index that can be employed to reject artefacts and pulses related to arrhythmic beats. MAIN RESULTS: Thresholding the pulse quality index enables near-perfect detection of normal sinus rhythm beats by rejecting most of the non-sinus rhythm pulses (positive predictive value 98%-99%), both in healthy subjects and arrhythmic patients. The rejection of arrhythmic beats is almost complete (sensitivity to arrhythmic beats 7%-3%), while the sensitivity to sinus rhythm beats is not compromised (96%-91%). SIGNIFICANCE: The developed algorithm consistently detects normal sinus rhythm beats in a PPG signal by rejecting artefacts and, as a first of its kind, arrhythmic beats. This increases the reliability in the extraction of features which are adversely influenced by the presence of non-sinus pulses, whether related to inter-beat intervals or to pulse morphology, from wrist-worn PPG signals recorded in free-living conditions. PMID- 30475750 TI - Are improvements in symptoms associated with changes in lumbopelvic posture in patients with posterior derangement using Mechanical Diagnosis and Therapy? AB - BACKGROUND: Mechanical Diagnosis and Therapy (MDT) manages low back pain (LBP) with subgroup classifications. For a subgroup of the posterior derangement syndrome, postural education limiting lumbar flexion is included. However, it is not known if habitual posture in this subgroup actually changes through MDT management because of technical difficulties in monitoring habitual lumbopelvic posture. However, a wearable device, "LUMOback", which can evaluate the proportion of time with a neutral lumbopelvic posture (posture score), has now become available. OBJECTIVE: To preliminarily investigate whether the posture score changes through the course of MDT management. METHODS: Primary inclusion criterion was LBP with the posterior derangement syndrome. Primary outcome measure was the posture score during one week. The posture score was assessed one week before and six weeks after the initial MDT management, which included extension exercises and postural education. RESULTS: All participants (n= 8) reported a successful treatment effect after the 6-week MDT intervention; however, there was no specific trend in the posture score (Friedman test: p= 0.277). CONCLUSIONS: This study found evidence that the proportion of time with a neutral lumbopelvic posture during daily living, the posture score, which was measured with the LUMOback, did not systematically change with MDT management. PMID- 30475749 TI - Is there a relation between rotator cuff injury and core stability? AB - BACKGROUND: Strong core stabilization not only minimizes the load on the vertebral column, but also improves strength and endurance of peripheral joints, and enables the energy transfer to distal segments. Despite the current interest surrounding core stability, none of the studies investigated the effect of core stability on the formation of rotator cuff tear or healing after repair. OBJECTIVE: To determine the relationship between core stability and upper extremity functional performance in patients who underwent rotator cuff repair surgery and to compare those with healthy subjects of similar age. METHODS: Patients who underwent rotator cuff repair (RC repair group, n= 58 patient) and healthy subjects of the similar age group (control group, n= 114) were included in the study. The mean age was 55.03 +/- 9.84 years in the RC repair group and 52.71 +/- 6.31 years in the control group. The RC repair group took standardized rehabilitation. The rehabilitation program did not include core strength and stability exercise. Core endurance was assessed with Flexor Endurance, Prone Bridge and Supine bridge test. Disabilities of the Arm, Shoulder and Hand (DASH), Short Form-36 (SF-36) and the Close Kinetic Chain Upper Extremity Stability (CKCUES) test were used to evaluate the upper extremity functional performance. RESULTS: The core endurance (prone and supine bridge test) of the control group was statistically significantly better than the RC repair group (p? 0.005). The DASH-T, SF-36 and CKCUES scores of the control group were also statistically significantly better. CONCLUSION: The neuromuscular system should be considered as a whole, and addition of the core stabilization exercises to an effective rehabilitation program after RC repair surgery may be beneficial. PMID- 30475751 TI - Effectiveness of the muscle energy technique on respiratory muscle strength and endurance in patients with fibromyalgia. AB - BACKGROUND: Fibromyalgia is characterized by a chronic and common musculoskeletal system pain that affects cervical mobility and inspiration. This may cause changes in thoracic mechanics. OBJECTIVE: To investigate the effectiveness of the muscle energy technique applied to cervical accessory respiratory muscles on respiratory muscle strength and endurance in patients with fibromyalgia. METHODS: The participants were 37 women diagnosed with fibromyalgia. They were assessed for their respiratory muscle strength, respiratory muscle endurance, pain and fatigue severity, flexibility and disability. The muscle energy technique was applied to the scalene, upper trapezius, and sternocleidomastoid muscles after a superficial heat application. The treatment was continued for 3 weeks with 3 sessions per week. RESULTS: After the treatment, expiratory muscle strength and respiratory muscle endurance increased significantly. Severity of pain and fatigue and disability were reduced, cervical flexibility increased significantly (p< 0.05). The effect size was r? 0.4 for all the variables. CONCLUSION: The muscle energy technique applied to cervical accessory respiratory muscles in patients with fibromyalgia who had complaints in the neck and back region positively increased respiratory muscle strength and endurance, cervical flexibility, and decrease pain intensity, fatigue and disability. It is recommended that subsequent randomized studies are carried out with a placebo control group. PMID- 30475752 TI - Efficiency examination of a 6-month trunk prevention program among recruitment kayak-canoe athletes: A randomized control trial. AB - BACKGROUND: Trunk prevention training, which provides the basis of several conditioning training programs, is used in sports at professional and amateur levels, taking the specifications of the given sport and the age-related characteristics of the athletes into consideration. OBJECTIVE: Our aim was to examine the strength and flexibility of muscles responsible for correct posture, the lumbar motor control ability and the posture of recruitment kayak-canoe athletes. METHODS: Controlled, randomized examination with 103 persons (age: 15.1 +/- 3.5 years), who were divided into two groups. Fifty were in the intervention group, who took part in the 6-month trunk prevention training program (height: 162.30 cm, body weight: 49.70 +/- 10.32 kg), 53 in the control group (not performing trunk prevention training) (height: 158.24 cm, body weight: 51.45 +/- 11.71 kg). The strength of core muscles was measured with Kraus-Weber test, muscle flexibility with Kempf-test, lumbar motor control ability with Sitting Forward Lean and Leg Lowering test and posture with photogrammetry test before and after the program. RESULTS: Static strength of abdominal muscles (p< 0.001), superficial and deep dorsal muscles (p< 0.001), flexibility of knee extensors (p< 0.001), chest muscles (p< 0.001), the lumbar motor control ability (p< 0.001) and habitual posture (p< 0.001) significantly improved in the intervention group. The post-measurements in the intervention group were significantly (p< 0.001) better than in the control group. CONCLUSIONS: As a result of the trunk prevention training the strength of core stabilization muscles, the lumbar motor control ability and the posture also improved in case of recruitment athletes. PMID- 30475753 TI - Comparison of kinesio taping and occlusal splint in the management of myofascial pain in patients with sleep bruxism. AB - OBJECTIVES: To evaluate the efficacy of Kinesio taping (KT) in patients with sleep bruxism (SB) and to determine whether KT may be an alternative for occlusal splint (OS) for the treatment of SB. MATERIALS AND METHODS: Sixteen patients with SB were treated with KT (kinesio group) and 18 patients were treated with OS (splint group). Masseter and temporal muscle pressure pain thresholds (MPPT and TPPT), visual analogue scale (VAS) values and mouth opening measurements of patients were compared before treatment, and at the 1st and 5th weeks of treatment. RESULTS: Both KT and OS treatments significantly reduced muscle pain, decreased VAS values, and increased mouth opening measurements. No statistically significant difference was found between the kinesio and splint groups in terms of MPPT, TPPT, VAS and mouth opening values before treatment and at the 1st and 5th weeks of treatment except for TPPT values at 1st week of treatment where the TPPT values of the kinesio group were significantly higher than the splint group (p< 0.05). CONCLUSIONS: KT was identified as an easy-to-use treatment method for bruxism and was found to reduce muscle pain and increase mouth opening. KT is at least as effective as OS for the treatment of SB. PMID- 30475754 TI - Plasma microRNA expression signature involving miR-548q, miR-630 and miR-940 as biomarkers for nasopharyngeal carcinoma detection. AB - BACKGROUND: Increasing studies have identified a series of circulating mircoRNAs (miRNAs) as biomarkers for disease detection due to their stability in the blood. The aim of the present study was to identify specific plasma miRNAs as potential biomarkers for nasopharyngeal carcinoma (NPC) detection. MATERIALS AND METHODS: Relative public microarray data were obtained and analyzed for screening of the plasma differentially expressed miRNAs (DEMs) between NPC patients and controls. This study contained two phases: a screening phase and a validation one. Logistic regression and receiver operating characteristics curve (ROC) analyses were used to identify DEM signatures. Moreover, targeted genes of the selected DEMs were predicted and their functions were annotated by using bioinformatic analysis. RESULTS: Both the screening and the validation phases showed that three miRNAs (miR-548q, miR-630 and miR-940) in the plasma of NPC patients were up-regulated compared to those of controls. They can be used as biomarkers for discriminating NPC patients from non-cancerous controls. Moreover, we found a classifier including only two miRNAs (miR-548q and miR-940) that can be used as a diagnostic signature for NPC, achieving an area under curve (AUC) of 0.972, a sensitivity of 0.94, and a specificity of 0.925. CONCLUSIONS: The present study demonstrated that three miRNAs (miR-548q, miR-630 and miR940) might be novel and useful biomarkers for NPC detection. A two-miRNA signature (miR-548q and miR940) may be considered as a better biomarker for NPC detection with relatively high sensitivity and specificity. Future studies with large sample sizes are needed for further validation. PMID- 30475755 TI - Knockdown of lncRNA GHET1 inhibits osteosarcoma cells proliferation, invasion, migration and EMT in vitro and in vivo. AB - OBJECTIVE: Osteosarcoma is the most common primary malignant skeleton tumor that derives from mesenchymal cells. Emerging evidences have identified the vital role of long non-coding RNAs (lncRNAs) in the development of osteosarcoma. In this study, we aimed to investigate the role of lncRNA gastric carcinoma highly expressed transcript 1 (GHET1) in osteosarcoma progression. METHODS: The expression levels of relevant genes in clinical samples and cell lines were determined by quantitative real-time PCR. Cell proliferation was determined by CCK8 and cell colony formation assays. Transwell assay was used to detect the invasion and migration of osteosarcoma cells. Cell apoptosis and cell cycle were detected by flow cytometry. Protein levels were detected by western blot. In vivo tumor growth was investigated in the xenograft nude mice model. To determine whether growth inhibition and apoptosis are responsible for antitumor activity of silencing GHET1, immunohistochemistry for proliferation and TUNEL assay was performed in xenograft tissues. In vivo lung metastasis was performed to detect the effect of GHET1 on cell metastasis ability. RESULTS: Our results revealed that GHET1 was up-regulated in osteosarcoma tissues compared to normal tissues. GHET1 was also increased in osteosarcoma cell lines compared to normal osteoplastic cell line. The up-regulation of GHET1 was significantly associated with TNM stage, distant metastasis and lymph node metastasis in patients with osteosarcoma. In vitro studies showed that silencing GHET1 in MG-63 and U2OS cells inhibited cell proliferation, cell invasion and migration and epithelial-to mesenchymal transition (EMT), promoted cell apoptotic rate, and also caused an increase in cell population at G0/G1 phase with a decrease in cell population at S phase. Overexpression of GHET1 promoted the proliferation, invasion and migration of osteosarcoma cells. Importantly, silencing GHET1 inhibited tumor growth and tumor metastasis in mice MG-63-xenograft model in association with changes of EMT-related genes, reduced expression of Ki-67 and promotion of apoptosis. CONCLUSION: GHET1 was up-regulated in osteosarcoma tissues and cell lines, inhibited cell apoptosis, promoted cell proliferation, invasion and migration by affecting EMT in vitro, and was correlated with the tumor growth and metastasis in vivo. GHET1 may be a potential therapeutic target of osteosarcoma treatment. PMID- 30475756 TI - TROY expression is associated with pathological stage and poor prognosis in patients treated with radical cystectomy. AB - BACKGROUND: New biomarkers may help us provide individualized prognosis and allow risk-stratified clinical decision making about radical treatment. OBJECTIVES: This study aimed to determine the tumor necrosis factor of receptor superfamily 19 (TROY) expression in urothelial carcinoma and its relationship to clinicopathological findings. METHODS: Immunohistochemical staining for TROY was carried out in 136 archival radical cystectomy specimens with immunoreactivity being stratified on a 0-9 scale. Expression scores for TROY were further stratified into negative (score 0) and positive (score 1 or greater). Median age was 65 years, and the median follow-up period was 50.7 months. RESULTS: Expression of TROY was significantly associated with the pathological stage (p= 0.019) and expression of nestin (p= 0.013). Log-rank tests indicated that expression of TROY was significantly associated with disease progression and cancer-specific mortality (p= 0.044 and 0.008, respectively). In multivariate Cox regression analysis, lymph node status was the only independent prognostic factor for disease progression and cancer-specific survival. Expression of TROY was a marginal prognostic factor for cancer-specific survival. CONCLUSIONS: TROY may therefore be a new molecular marker to aid in identifying and selecting patients undergoing radical cystectomy who could potentially benefit from multimodal treatment. PMID- 30475757 TI - alpha2delta1 may be a potential marker for tumor stem cell in laryngeal squamous cell carcinoma. AB - Cancer stem cells (CSCs) have the ability to dictate tumor initiation, recurrence, and metastasis. Here, we examined the expression of aalpha2delta1+ in laryngeal cancer tissues and further determined the effect of alpha2delta1 on the migratory ability and tumorigenicity of laryngeal cancer cells. Immunofluorescence staining revealed that alpha2delta1 was positive in 13 (13/16, 81.25%) cases in laryngeal squamous cell carcinoma (LSCC) tissues, 7 (7/16, 43.75%) cases in paracancerous tissues and only 2 (2/16, 12.5%) cases in normal tumor tissues. Our quantitative RT-PCR assays further showed that alpha2delta1+ LSCC cells expressed significantly higher levels of stem cell-associated genes and drug efflux and resistance genes versusalpha2delta1- cells. Sphere-forming assays demonstrated higher sphere-forming efficiency in the alpha2delta1+versusalpha2delta1- subpopulation. Our Matrigel assays showed that alpha2delta1+ cells exhibited significantly greater invasive and migratory ability than alpha2delta1- cells. Furthermore, the percentage of purified alpha2delta1+ in TU686 and TU212 cells treated cisplatin or paclitaxel was significantly higher than that of the control group. Tumor xenograft assays revealed that the tumorigenicity of alpha2delta1+ cells was much higher than alpha2delta1- cells. In conclusion, a alpha2delta1+ subpopulation with CSC-like property was present in laryngeal cancer and possessed high self-renewal activity and was sufficient for tumor growth, differentiation, migration, invasion, and chemotherapeutic resistance. They could represent a promising therapeutic target for LSCC. PMID- 30475758 TI - Targeted regulation by ROCK2 on bladder carcinoma via Wnt signaling under hypoxia. AB - Bladder cancer is frequently occurred in urinary system and has complicated pathogenesis factors including both genetics and environmental factors that have not been fully illustrated. Hypoxia can further induce tumor progression. ROCK2 has abnormal expression in various tumors but its expression or functional role in bladder cancer have not been illustrated. In vitro cultured bladder cancer cell line T24 was randomly assigned into control group, hypoxia group (prepared under hypoxic culture), and ROCK2 siRNA group (transfected with ROCK2 siRNA after hypoxia treatment). Real-time PCR and Western bot measured ROCK2 expression. MTT assay tested cell proliferation, and cell migration was quantified. Cell apoptosis was measured by caspase3 activity assay kit and Transwell chamber measured cell migration. Western blot quantified expressional change of HIF 1alpha and E-cadherin, and Wnt signal pathway proteins including Wnt4, and beta catenin. ROCK2 is up-regulated in bladder cancer T24 cells under hypoxia, and can facilitate cell proliferation, migration and invasion, inhibited Caspase3 activity, enhanced HIF-1alpha expression, decreased E-cadherin expression, and up regulated Wnt4 and beta-catenin (p< 0.05 comparing to hypoxia group). Under hypoxia conditions, ROCK2 can facilitate apoptosis of bladder cancer cells via modulating Wnt signal pathway, inhibit cell proliferation, migration, invasion or formation of epithelial mesenchymal transition (EMT). PMID- 30475759 TI - Association between genetic polymorphisms in long non-coding RNAs and pancreatic cancer risk. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) are emerging as candidate biomarkers of cancer, having regulatory functions in both oncogenic and tumor-suppressive pathways. Concerning pancreatic cancer (PC), deregulation of lncRNAs involved in tumor initiation, invasion, and metastasis seem to play a key role. However, data is scarce about regulatory mechanism of lncRNA expression. OBJECTIVE: The aim of our study was to investigate the contribution of two lncRNAs polymorphisms (rs1561927 and rs4759313 of PVT1 and HOTAIR, respectively) in PC susceptibility. METHODS: A case-control study was conducted analysing rs1561927 and rs4759313 polymorphisms using DNA collected in a population-based case-control study of pancreatic cancer (111 pancreatic ductal adenocarcinoma cases (PDAC), 56 pancreatic neuroendocrine tumor (PNET), and 125 healthy controls). RESULTS: Regarding the PVT1 rs1561927 polymorphism the G allele was significantly overrepresented in both PDAC and PNET patients compared to the controls, while the presence of the HOTAIR rs4759314 G allele was found to be overrepresented in the PNET patients only compared to the controls. The PVT1 rs1561927 AG/GG genotypes were associated with poor overall survival in PDAC patients. CONCLUSIONS: Our results suggested that polymorphisms of these two lncRNA polymorphisms implicated in pancreatic carcinogenesis. Further large-scale and functional studies are needed to confirm our results. PMID- 30475760 TI - Targeted Assessment of Enlargement of the Perivascular Space in Alzheimer's Disease and Vascular Dementia Subtypes Implicates Astroglial Involvement Specific to Alzheimer's Disease. AB - Waste clearance from the brain parenchyma occurs along perivascular pathways. Enlargement of the perivascular space (ePVS) is associated with pathologic features of Alzheimer's disease (AD), although the mechanisms and implications of this dilation are unclear. Fluid exchange along the cerebral vasculature is dependent on the perivascular astrocytic water channel aquaporin-4 (AQP4) and loss of perivascular AQP4 localization is found in AD. We directly measured ePVS in postmortem samples of pathologically characterized tissue from participants who were cognitively intact or had AD or mixed dementia (vascular lesions with AD). We found that both AD and mixed dementia groups had significantly increased ePVS compared to cognitively intact subjects. In addition, we found increased global AQP4 expression of the AD group over both control and mixed dementia groups and a qualitative reduction in perivascular localization of AQP4 in the AD group. Among these cases, increasing ePVS burden was associated with the presence of tau and amyloid-beta pathology. These findings are consistent with the existing evidence of ePVS in AD and provide novel information regarding differences in AD and vascular dementia and the potential role of astroglial pathology in ePVS. PMID- 30475761 TI - Bioactive Food Abates Metabolic and Synaptic Alterations by Modulation of Gut Microbiota in a Mouse Model of Alzheimer's Disease. AB - Recent investigations have demonstrated an important role of gut microbiota (GM) in the pathogenesis of Alzheimer's disease (AD). GM modulates a host's health and disease by production of several substances, including lipopolysaccharides (LPS) and short-chain fatty acids (SCFAs), among others. Diet can modify the composition and diversity of GM, and ingestion of a healthy diet has been suggested to lower the risk to develop AD. We have previously shown that bioactive food (BF) ingestion can abate neuroinflammation and oxidative stress and improve cognition in obese rats, effects associated with GM composition. Therefore, BF can impact the gut-brain axis and improved behavior. In this study, we aim to explore if inclusion of BF in the diet may impact central pathological markers of AD by modulation of the GM. Triple transgenic 3xTg-AD (TG) female mice were fed a combination of dried nopal, soy, chia oil, and turmeric for 7 months. We found that BF ingestion improved cognition and reduced Abeta aggregates and tau hyperphosphorylation. In addition, BF decreased MDA levels, astrocyte and microglial activation, PSD-95, synaptophysin, GluR1 and ARC protein levels in TG mice. Furthermore, TG mice fed BF showed increased levels of pGSK-3beta. GM analysis revealed that pro-inflammatory bacteria were more abundant in TG mice compared to wild-type, while BF ingestion was able to restore the GM's composition, LPS, and propionate levels to control values. Therefore, the neuroprotective effects of BF may be mediated, in part, by modulation of GM and the release of neurotoxic substances that alter brain function. PMID- 30475764 TI - Systematic Multi-Domain Alzheimer's Risk Reduction Trial (SMARRT): Study Protocol. AB - This article describes the protocol for the Systematic Multi-domain Alzheimer's Risk Reduction Trial (SMARRT), a single-blind randomized pilot trial to test a personalized, pragmatic, multi-domain Alzheimer's disease (AD) risk reduction intervention in a US integrated healthcare delivery system. Study participants will be 200 higher-risk older adults (age 70-89 years with subjective cognitive complaints, low normal performance on cognitive screen, and >= two modifiable risk factors targeted by our intervention) who will be recruited from selected primary care clinics of Kaiser Permanente Washington, oversampling people with non-white race or Hispanic ethnicity. Study participants will be randomly assigned to a two-year Alzheimer's risk reduction intervention (SMARRT) or a Health Education (HE) control. Randomization will be stratified by clinic, race/ethnicity (non-Hispanic white versus non-white or Hispanic), and age (70-79, 80-89). Participants randomized to the SMARRT group will work with a behavioral coach and nurse to develop a personalized plan related to their risk factors (poorly controlled hypertension, diabetes with evidence of hyper or hypoglycemia, depressive symptoms, poor sleep quality, contraindicated medications, physical inactivity, low cognitive stimulation, social isolation, poor diet, smoking). Participants in the HE control group will be mailed general health education information about these risk factors for AD. The primary outcome is two-year cognitive change on a cognitive test composite score. Secondary outcomes include: 1) improvement in targeted risk factors, 2) individual cognitive domain composite scores, 3) physical performance, 4) functional ability, 5) quality of life, and 6) incidence of mild cognitive impairment, AD, and dementia. Primary and secondary outcomes will be assessed in both groups at baseline and 6, 12, 18, and 24 months. PMID- 30475762 TI - Maintain Your Brain: Protocol of a 3-Year Randomized Controlled Trial of a Personalized Multi-Modal Digital Health Intervention to Prevent Cognitive Decline Among Community Dwelling 55 to 77 Year Olds. AB - BACKGROUND: Maintain Your Brain (MYB) is a randomized controlled trial of an online multi-modal lifestyle intervention targeting modifiable dementia risk factors with its primary aim being to reduce cognitive decline in an older age cohort. METHODS: MYB aims to recruit 8,500 non-demented community dwelling 55 to 77 year olds from the Sax Institute's 45 and Up Study in New South Wales, Australia. Participants will be screened for risk factors related to four modules that comprise the MYB intervention: physical activity, nutrition, mental health, and cognitive training. Targeting risk factors will enable interventions to be personalized so that participants receive the most appropriate modules. MYB will run for three years and up to four modules will be delivered sequentially each quarter during year one. Upon completing a module, participants will continue to receive less frequent booster activities for their eligible modules (except for the mental health module) until the end of the trial. DISCUSSION: MYB will be the largest trial to attempt to prevent cognitive decline and potentially dementia. If successful, MYB will provide a model for not just effective intervention among older adults, but an intervention that is scalable for broad use. PMID- 30475763 TI - Peripheral GRN mRNA and Serum Progranulin Levels as a Potential Indicator for Both the Presence of Splice Site Mutations and Individuals at Risk for Frontotemporal Dementia. AB - Progranulin (GRN) gene mutations are a major cause of frontotemporal dementia (FTD). Most mutations identified to date are null mutations, which are predicted to cause the pathology via haploinsufficiency. Decreased peripheral progranulin protein (PGRN) levels are associated with the presence of GRN null mutations and are accepted as reliable biomarkers. In this study, our aim was to test whether the presence of specific GRN splice site mutations (c.- 8+2T>G and c.708+6_9del), could be predicted by peripheral mRNA or protein GRN levels, by studying affected and asymptomatic individuals from FTD families. We also tested four missense GRN variants to assess if altered GRN levels depended on the type of mutation.Our results confirmed a reduction in both mRNA and protein PGRN levels in the splice site mutation carriers, which is consistent with previous reports for null mutations. Our results also suggested that both decreased peripheral GRN mRNA and serum PGRN levels indicate the presence of pathogenic mutations in affected individuals, and identify the asymptomatic individuals at risk, without previous knowledge of genetic status. Both inferences suggest a potential use of peripheral GRN mRNA or serum PGRN levels as biomarkers for families with FTD. PMID- 30475765 TI - Astrocyte-and Microglia-Specific Mitochondrial DNA Deletions Levels in Sporadic Alzheimer's Disease. AB - Oxidative stress is implicated in the pathogenesis of neurodegenerative diseases, including sporadic Alzheimer's disease (AD). Mitochondrial DNA (mtDNA) deletions are markers of oxidative damage with an age-dependent accumulation. In a previous study, we analyzed mtDNA levels in diverse neuronal cell types in order to unravel the impact of oxidative stress in brains of AD patients. The aim of this study was to identify possible correlations between mtDNA deletion levels of selected astrocytes and microglia from three brain regions with different vulnerability to AD pathology and different stages of disease compared to controls. Our results reflect a higher vulnerability of hippocampal astrocytes and microglia to oxidative stress compared to other brain regions, such as cerebellum and brain stem. PMID- 30475766 TI - Utility of Amyloid PET Scans in the Evaluation of Patients Presenting with Diverse Cognitive Complaints. AB - BACKGROUND: The impact of amyloid positron emission tomography (Abeta-PET) in a "real-world" memory disorders clinic remains poorly studied. OBJECTIVE: we studied the impact of Abeta-PET in diagnosis and management in the memory clinic and factors making the most impact in diagnosis and management. METHODS: We studied 102 patients who had presented at a memory disorders clinic (the Wien Center for Alzheimer's Disease and Memory Disorders, Miami Beach, FL) and had a diagnostic work-up for cognitive complaints, including Abeta-PET scans. RESULTS: Following Abeta-PET, changes were made in diagnosis (37.3%), in specific treatments for Alzheimer's disease (26.5%) and in psychiatric treatments (25.5%). The agreement between diagnosis pre-Abeta-PET versus post-Abeta-PET diagnosis was only fair, with a Cohen's kappa of 0.23 (95% CI 0-0.42). Patients with MRI findings suggestive of AD (medial temporal and/or parietal atrophy) were more frequently amyloid positive than amyloid negative (66.2% versus 33.8%, p = 0.04). Among patients with atypical clinical features for AD, but with MRI findings suggestive of AD, an amyloid negative PET scan had a greater impact than an amyloid positive PET scan on diagnosis (84.2% versus 17.1%, p < 0.001), management (84.2% versus 40%, p < 0.01) and discussion of results and advice on lifestyles (73.7% versus 22.9%, p < 0.001). CONCLUSIONS: We conclude that MRI features suggestive of AD predict a positive amyloid PET scan. However, among those with MRI features suggestive of AD but with atypical clinical features of AD, the clinical impact on diagnosis and management is greater for an amyloid negative than an amyloid positive Abeta-PET scans. PMID- 30475767 TI - Loss of Swallow Tail Sign on Susceptibility-Weighted Imaging in Dementia with Lewy Bodies. AB - We assessed nigral dorsolateral hyperintensity (swallow tail sign) at susceptibility-weighted imaging using 3T-MRI in 15 dementia with Lewy bodies (DLB), 11 Alzheimer's disease (AD), and 8 frontotemporal dementia (FTD) patients and 10 subjects with subjective memory complaint (SMC). More DLB patients lacked nigral hyperintesity (p < 0.05). Sensitivity, specificity, and accuracy of DLB diagnosis were, respectively: 80%, 64%, and 73% versus AD; 80%, 75%, and 78% versus FTD; and 80%, 90%, and 84% versus SMC. Considering bilateral loss, sensitivity decreased (53% ) but specificity increased (82-100% ). Swallow tail sign loss, especially if bilateral, can be useful for DLB diagnosis. PMID- 30475768 TI - Blood Glucose Levels May Exacerbate Executive Function Deficits in Older Adults with Cognitive Impairment. AB - BACKGROUND: Identifying protective factors that promote healthy cognitive aging is of importance due to the growing older adult population. Preventing chronic hyperglycemia may be one such way to preserve cognitive abilities, as high blood glucose levels have been associated with cognitive impairment and decline. OBJECTIVE: To evaluate the influence of blood glucose levels on cognition among older adults using common neuropsychological tests and a spatial navigation task. METHODS: The association between cognitive performance and blood glucose levels was assessed among 117 older adults classified as cognitively healthy, subjective cognitive decline, amnestic mild cognitive impairment, or Alzheimer's disease dementia from the Czech Brain Aging Study. Cognitive abilities were measured by tests of verbal memory, nonverbal memory, working memory, visuospatial skills, and executive function. A test of spatial navigation known as the Hidden Goal Task was also used. Blood glucose levels were measured by glycosylated hemoglobin A1c (HbA1c). Analyses were performed using multiple linear regression controlling for age, gender, education, depressive symptoms, diabetes, and cognitive status. RESULTS: A significant relationship was observed for HbA1c and executive function performance (beta = -2.46, SE = 0.92, p = 0.008). Following moderation analysis, this relationship was significant only among those with cognitive impairment (beta = -4.37, SE = 1.28, p = 0.001, 95% CI [-6.91, -1.83]). Associations between HbA1c and other cognitive domains were not significant (ps > 0.05). CONCLUSIONS: Higher HbA1c was associated with poorer executive function among persons with cognitive impairment, but not with performance on other cognitive domains. Maintaining proper glucoregulation may help preserve executive function performance among cognitively impaired older adults. PMID- 30475769 TI - Contribution of Bilingualism to Cognitive Reserve of an Italian Literature Professor at High Risk for Alzheimer's Disease. AB - Bilingualism is an independent component of cognitive reserve that permits to delay dementia onset up to 5 years. We describe a case of a bilingual Italian man affected by mild cognitive impairment with high cognitive reserve that, despite the presence of multiple risk factors (ApoE E4/E4 genotype, older age, untreated Obstructive Sleep Apnea Syndrome, AD-like biomarker alterations) did not convert to Alzheimer's disease up to 5 years follow-up. The present case confirms the role of bilingualism as a strong protective factor for dementia, even in the occurrence of multiple risk factors. PMID- 30475770 TI - A Comparison of Partial Volume Correction Techniques for Measuring Change in Serial Amyloid PET SUVR. AB - Longitudinal PET studies in aging and Alzheimer's disease populations rely on accurate and precise measurements of change over time from serial PET scans. Various methods for partial volume correction (PVC) are commonly applied to such studies, but existing comparisons and validations of these PVC methods have focused on cross-sectional measurements. Rate of change measurements inherently have smaller magnitudes than cross-sectional measurements, so levels of noise amplification due to PVC must be smaller, and it is necessary to re-evaluate methods in this context. Here we compare the relative precision in longitudinal measurements from serial amyloid PET scans when using geometric transfer matrix (GTM) PVC versus the traditional two-compartment (Meltzer-style), three compartment (Muller-Gartner-style), and no-PVC approaches. We used two independent implementations of standardized uptake value ratio (SUVR) measurement and PVC (one in-house pipeline based on SPM12 and ANTs, and one using FreeSurfer 6.0). For each approach, we also tested longitudinal-specific variants. Overall, we found that measurements using GTM PVC had significantly worse relative precision (unexplained within-subject variability ~4-8%) than those using two compartment, three-compartment, or no PVC (~2-4%). Longitudinally-stabilized approaches did not improve these properties. This data suggests that GTM PVC methods may be less suitable than traditional approaches when measuring within person change over time in longitudinal amyloid PET. PMID- 30475771 TI - Interactive Effect of Depression and Cognitive Impairment on Olfactory Identification in Elderly People. AB - Olfactory identification (OI) deficits have been regarded as an indicator of cognitive impairment in the elderly, but few studies have analyzed the mixed effect of depression on OI. Since depression is common in the elderly and strongly associated with OI, we aimed to explore whether the comorbidity of depression and cognitive impairment may be associated with worse outcomes. In total, 153 elderly patients with depression and 154 normal elderly were recruited. Subjects underwent assessments of depression, cognitive function, and OI. Information on the factors that may affect OI performance was collected (age, sex, smoking history, diabetes, etc.). Correlation analysis showed that several factors had a significant influence on OI performance in the elderly, including severity of depression, cognitive scores, age, sex, and years of education (p < 0.05). Among the different cognitive domains, OI was positively associated with global cognition, memory, language, executive function, and attention performance (p < 0.05). The multiple linear regression analysis indicated that memory scores, age, HAMD scores, and sex were the most relevant factors to OI scores across all elderly participants. The factorial analysis suggested that elderly with comorbidity of depression and cognitive impairment (memory deficits or language deficits) had worse OI impairment, and there was an interactive effect of depression and memory deficits on OI in elderly people. The present study suggested that the coexistence of depressive symptoms and cognitive impairment was associated with worse OI in the elderly. Studies exploring the association between OI and cognitive function should include an assessment of depression and adjust the interactive effects of depression. PMID- 30475772 TI - Formyl Peptide Receptor 2 Deficiency Improves Cognition and Attenuates Tau Hyperphosphorylation and Astrogliosis in a Mouse Model of Alzheimer's Disease. AB - Alzheimer's disease (AD) is characterized by progressive loss of memory and other cognitive functions. Accumulation of amyloid-beta (Abeta) and hyperphosphorylated tau are two major neuropathological features of AD. Formyl peptide receptor 2 (FPR2), contributing to innate immunity and inflammation, has been implicated in the uptake and clearance of Abeta. It remains unclear whether FPR2 affects cognition and tau phosphorylation. The effects of FPR2 in cognition and tau phosphorylation were examined using FPR2 knock-out (Fpr2-/-) mice receiving intracerebroventricular (ICV) injection of streptozotocin (STZ). The general behaviors and cognitive functions were evaluated using rotarod, open field test, and Morris water maze test. The alteration in tau hyperphosphorylation and activation of astrocytes were determined by using western blotting and/or immunofluorescence staining. ICV injection of STZ impaired spatial learning and memory of mice in Morris water maze. FPR2 deficiency improved spatial learning and memory of ICV-STZ mice. In the hippocampus and cortex of ICV-STZ mice, a marked increase was observed in tau phosphorylation at Ser199, Thr205, and Ser396 compared with ICV-saline control mice. However, FPR2 deficiency attenuated the hyperphosphorylation of tau at Ser199 and Ser396. In addition, the expression of GFAP was significantly increased in hippocampus and cortex of ICV-STZ mice. FPR2 deletion reduced the increase of GFAP expression induced by ICV injection of STZ. These results indicate that FPR2 deficiency is associate with improved cognition, reduced tau hyperphosphorylation, and activation of astrocytes in the mouse AD model tested. FPR2 may be a potential target in AD prevention and therapy. PMID- 30475773 TI - Ethical Issues in the Treatment of Late-Stage Alzheimer's Disease. AB - There is hope that the continuing efforts of researchers will yield a disease modifying drug for Alzheimer's disease. Such a drug is likely to be capable of halting, or significantly slowing, the underlying pathological processes driving cognitive decline; however, it is unlikely to be capable of restoring brain function already lost through the pathological process. A therapy capable of halting Alzheimer's disease, while not providing restoration of function, may prompt serious ethical questions. For example, is there a stage in the disease process when it becomes too late for therapeutic intervention to commence? And who bears the responsibility of making such a decision? Conversations regarding the ethics of treating neurodegenerative conditions with non-restorative drugs have been largely absent within both clinical and research communities. Such discussions are urgently required to ensure that patients' rights and well-being are protected when such therapeutic options become available. PMID- 30475774 TI - Rbfox3/NeuN Regulates Alternative Splicing of Tau Exon 10. AB - Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule-binding repeats, 3R-tau or 4R-tau, which are under developmental regulation. Dysregulation of tau exon 10 splicing is sufficient to cause neurodegenerative disorders. The RNA-binding Fox3 (Rbfox3), identified as NeuN, regulates RNA processing. However, whether Rbfox3/NeuN regulates tau exon 10 splicing is unknown. In the present study, we found that the developmental expression of 4R-tau coincided with the expression of Rbfox3 in rat brains. Rbfox3 enhanced tau exon 10 inclusion. Tau intron 10 contains UGCAUG, the conservative binding sequence of Rbfox3. Intron 10 of tau pre-mRNA was co immunoprecipitated by Rbfox3/NeuN. Deletion mutants of the RNA recognition motif (RRM) or three RNA-binding sites of the RRM in Rbfox3/NeuN failed to enhance tau exon 10 inclusion. Rbfox3, specifically expressed in the fetal brain, did not affect tau exon 10 splicing. The level of Rbfox3/NeuN was reduced and was associated with the ratio of 4R-tau/3R-tau in the excitotoxic mouse brains induced by kainic acid. These findings suggest that Rbfox3/NeuN regulates the alternative splicing of tau exon 10 and that decreased Rbfox3/NeuN may lower the ratio of 4R-tau/3R-tau. PMID- 30475775 TI - A Systematic Review and Case Series of Ziprasidone for Psychosis in Parkinson's Disease. AB - The atypical antipsychotic ziprasidone has been considered inappropriate for use in patients with Parkinson's disease (PD), as most atypical antipsychotics worsen parkinsonism. However, the current evidence for safety and efficacy of ziprasidone in PDP has not been evaluated in a systematic fashion. We review published experience with ziprasidone for treating psychosis in PD via systematic search of MEDLINE, Embase, Cochrane CENTRAL, and Clinicaltrials.gov with terms related to "ziprasidone" and "Parkinson's disease", inclusive of case reports and prospective studies. We also add seven cases of ziprasidone exposure in patients in our center with idiopathic PD or Lewy body dementia (DLB), selected by retrospective query of all clinical data since 1996. In our review, two prospective trials and 11 case reports or series were found, with ziprasidone found to be generally effective for treatment of psychosis and with few adverse events reported. Our case series did not support efficacy of ziprasidone; it was generally safe in PD, but two patients with DLB had adverse motor events. We conclude that, although ziprasidone occasionally can produce substantial worsening of motor signs, it usually is well tolerated, and may provide in some cases a useful alternative to quetiapine, clozapine and pimavanserin, particularly in the acute care setting. Further randomized controlled studies are needed. PMID- 30475776 TI - Computerized hybrid decision-making system for hormone replacement therapy in menopausal women. AB - BACKGROUND: OBJECTIVE: To develop an intelligent decision-making system for hormone replacement treatment (HRT) in menopausal women in order to assist physicians. METHODS: This study consisted of 179 peri- and post-menopausal patients who were admitted to Hacettepe University Hospital (between 1996 and 2001) with various menopausal complaints. Database variables used in this study were age, height, weight, menopause duration, clinical condition, HRT duration, and the laboratory test results. Our newly developed multiple-centered fuzzy clustering (MCFC) algorithm was applied to the medical data set to differentiate patient groups. Finally, a hybrid intelligent decision-making system was developed by combining knowledge-based algorithms and the MCFC algorithm results. RESULTS: We have used Fuzzy C-means, K-means, Hard C-means, similarity based clustering, and MCFC algorithms on the medical data set and have determined that the MCFC algorithm is the most appropriate algorithm for our medical model. We have defined 5 clusters and 16 cluster centers. A diagnostic phrase was assigned to each cluster center by the physician and these clusters together with knowledge-based algorithms were used for the decision-making system. CONCLUSIONS: We have developed a computerized hybrid decision-making system recommending HRT to peri- and post-menopausal women in order to assist and protect physicians. PMID- 30475777 TI - A clinical study on mechanical ventilation PEEP setting for traumatic ARDS patients guided by esophageal pressure. AB - OBJECTIVE: This study aims to explore whether positive end-expiratory pressure (PEEP) guided by esophageal pressure is better than the acute respiratory distress syndrome network (ARDSNet) during the treatment of traumatic acute respiratory distress syndrome (ARDS) patients. SUGGESTIONS: The use of the oxygenation method of inhaled oxygen concentration titration PEEP is suggested. METHODS: This study takes traumatic ARDS patients as the research object. The data of 23 patients were included in this study. The patients were randomly divided into two groups: the esophageal pressure titration PEEP group (n= 12), and the ARDSNet (PEEP-FiO2 table) titration PEEP group (n= 11). All patients were given mechanical ventilation, and changes in oxygenation index, respiratory mechanics, hemodynamics and inflammatory reaction index were recorded when titrating the best PEEP with the two methods on the current day of grouping and after grouping for 24, 48 and 72 hours. RESULTS: The PEEP titration value in the esophageal pressure group was 12 +/- 4 cm H2O, and this value was significantly higher than the PEEP titration value in the ARDSNet group (8 +/- 3 cm H2O) (P< 0.05). The end-expiratory transpulmonary pressure of titrating the best PEEP with the esophageal pressure method and ARDSNet method is 0.5 +/- 0.7 cm H2O vs.-1.1 +/- 3.3 cm H2O (P< 0.05). When titrating the best PEEP with the esophageal pressure method, lung tissue compliance, end-expiratory transpulmonary pressure and the oxygenation index are higher than those obtained through the ARDSNet method (P< 0.05). (2) In the esophageal pressure group, with the extension of treatment time, high-sensitivity C reactive protein (hs-CRP) and procalcitonin (PCT) exhibited a trend of significant decrease (P< 0.05). In the ARDSNet group, with the extension of treatment time, PCT also exhibited a significant decrease (P< 0.05), while the decrease in hs-CRP was not significant (P> 0.05). After comparing these two treatment groups at each monitoring time point, we found that the difference in hs-CRP and PCT was not statistically significant (P> 0.05). During the 72-hour treatment of interleukin-6 (IL-6) and interleukin-8 (IL-8), we found that these two were significantly lower in the esophageal pressure group than in the ARDSNet group (P< 0.05). CONCLUSIONS: The PEEP selection of mechanical ventilation of patients with traumatic ARDS guided by transpulmonary pressure and calculated by measuring intrapleural pressure can realize the individual adjustment of PEEP, identify ARDS patients benefiting from high PEEP, and provide a PEEP setting that can better meet the needs of traumatic patients. PMID- 30475778 TI - The role of biopsychosocial factors in the rehabilitation process of individuals with a stroke. AB - BACKGROUND: A large proportion of individuals with a stroke are unable to return to work, although figures vary greatly. Due to the very high cost of post-stroke care, both tangible and intangible, in the form of long-term social consequences, it seems extremely important to search for factors responsible for the low efficiency of the rehabilitation and recovery process, because this fact has direct influence on future employment. Such knowledge would enable physiotherapists to quickly identify those patients who are at risk of rehabilitation breakdown, in order to provide them with special care and include them in intensive therapeutic treatments. OBJECTIVE: The aim of the study was to assess the efficacy of post-stroke rehabilitation, evaluated within the biopsychosocial aspect. METHODS: The study consisted of 120 patients after first stroke, including 48 women and 72 men aged 58.0 (+/-8.6). The measure of the effects of physiotherapy in the present study was not only the improvement of the functional state (simple and complex activities of daily life, locomotive activities), but also the improvement of the mental state (mood and the sense of well-being, level of acceptance of illness, perceived self-efficacy) and the reduction of pain. The Mini-Mental State Examination, the Geriatric Depression Scale, the Generalized Self-Efficacy Scale, the Acceptance of Illness Scale, the Visual Analogue Scale, the Barthel Index, the Instrumental Activity of Daily Living and the Rivermead Mobility Index were used. All parameters were measured twice: on admission to the ward and after three weeks of physiotherapy. The characteristics of the study group were presented using descriptive statistics. The analysis of interdependence of the efficacy of physiotherapy used two non parametric tests: the Mann-Whitney U test to compare two groups, and the Kruskal Wallis ANOVA test to compare a greater number of groups. Correlations between characteristics with continuous distributions were assessed using Spearman's rank correlation coefficient (rho), and in case of categorical variables, Pearson's chi-squared (chi2) correlation coefficient. Linear regression was used to determine the hierarchy of the influence of particular characteristics on the efficacy of physiotherapy. RESULTS: Statistical analyzes show that patient's age, time since stroke, number of comorbidities, family care capacity, marital status of the patient and also a low level of acceptance of illness, depression symptoms and lack of a sense of self-efficacy were related with low efficacy of post stroke rehabilitationCONCLUSIONS:Comprehensive neurological rehabilitation, taking into account mental challenges and socio-economic circumstances of individuals with a stroke is essential in order to achieve high efficacy of physiotherapy. Important external factors may play a pivotal role in returning to work as well and should be taken into account during rehabilitation. Of interest should be to assess more biopsychological factors, such as acceptance of illness and a sense of self-efficacy referred to as barriers to return to work. PMID- 30475779 TI - The office changes leading to sit to stand ergonomics. AB - The office ergonomic design from the late 1980's to the present has undergone significant changes during the transition from typewriters to the various human computer interfaces that evolved to the present day. Designs to accommodate various sized monitors and pointing devices have posed a challenge for ergonomist and designers of office workstations. Recent research suggesting adverse health effects associated with sedentary work environments have put additional pressure to incorporate the option to stand while working. This article reviews the current available options and suggests approaches to workplace design to meet the desire for employees to vary their work environment and the concern by management for worker health. PMID- 30475780 TI - Navigating the progressive intensity of lifelong learning from medical student to attending physician. PMID- 30475781 TI - An ergonomic intervention to relieve musculoskeletal symptoms of assembly line workers at an electronic parts manufacturer in Iran. AB - BACKGROUND: Prolonged, awkward postures among assembly line workers can lead to work-related musculoskeletal disorders (WMSDs). OBJECTIVE: This study determined the prevalence of WMSDs and ergonomic risk factors among assembly line workers at an electronic parts manufacturer, and introduced a low-cost ergonomic intervention. METHODS: Data were gathered by means of a questionnaire. The Rapid Upper Limb Assessment (RULA) technique was used to determine ergonomic risk factors. A low-cost intervention, designed to improve working postures was introduced. RESULTS: Most musculoskeletal symptoms were associated with the lower back (73.6%), wrist/ hands (71.7%), and neck (67.9%). Most (80%) of the working postures analyzed using the RULA were at action levels 3 or 4. CONCLUSIONS: The ergonomic intervention resulted in a significant reduction in posture scores for the neck and trunk. This indicated that the intervention helped to improve workplace ergonomics. PMID- 30475782 TI - The experiences of workers who do not successfully return to work following a work-related injury. AB - BACKGROUND: A minority of workers with work-related injuries experience challenges returning to work. While factors that hinder return-to-work (RTW) are well-documented, the consequences of failing to successfully return to work on the lives of workers who have experienced a workplace injury remain poorly understood. OBJECTIVE: The purpose of this study is to explore the experiences of workers who do not successfully return to work following a work-related injury. METHODS: Using an interpretive approach to qualitative research and maximal variability sampling, 11 workers who have sustained work-related injuries without a successful RTW and four service providers were recruited through community organizations. Participants were interviewed using a semi-structured interview guide. A constant comparative approach was used to identify key themes across the worker and service provider experiences. RESULTS: The findings that emerged from the analysis capture the challenging RTW experiences of workers and describe wide ranging impacts on their lives when their workers' compensation claims are denied or discontinued, including ongoing financial strain, family tensions, subsequent health concerns, and negative employment experiences. The findings also highlight the negative consequences of existing cost-cutting frameworks that can restrict entitlement and benefits for many people with disabilities. CONCLUSIONS: The findings from this study highlight the experiences of workers who might need additional supports throughout the RTW process, and begin to shed light on the impact on their lives when RTW is not successful. [Word count -228]. PMID- 30475783 TI - Work-related determinants of psychosocial risk factors among employees in the hospital setting. AB - BACKGROUND: Understanding which factors influence occupational safety and health risks is crucial to promote psychosocial risk management. OBJECTIVE: To assess the main work-related determinants of high exposure to psychosocial risk factors among Portuguese employees in the hospital setting. METHODS: Between May and July 2014, 399 employees of a public hospital completed a structured questionnaire. Psychosocial factors were assessed by the Portuguese medium length version of the Copenhagen Psychosocial Questionnaire. Age and gender adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were computed by logistic regression models. RESULTS: The highest psychosocial risks emerged in the p ersonality (53.8%), workplace demands (28.1%), and social relationships and leadership (24.4%) categories. Professionals with non-health care roles presented a higher risk in the worker-work interface (OR = 2.60;95% CI:1.02-6.62), that evaluated work insecurity, satisfaction and the work-family interface. Shift workers were exposed to a higher psychosocial risk in workplace demands (OR = 1.79;95% CI:1.10 2.91), personality (OR = 2.45;95% CI:1.36-4.41), and health and well-being (OR = 3.18; 95% CI:1.72-5.66). Non-government employees had a higher risk exposure in personality (OR = 2.20;95% CI:1.15-4.21), and those who were absent from work in personality (OR = 2.62;95% CI:1.41-4.86), and health and wellbeing (OR = 2.34;95% CI:1.27-4.31). CONCLUSIONS: Employees working in the hospital setting are vulnerable to psychosocial risk factors. Identifying those risks contributes to optimize workers' psychosocial health, increasing the effectiveness of the organization. PMID- 30475784 TI - Understanding salutogenic approaches to managing intensive work: Experiences from three Swedish companies. AB - BACKGROUND: Recent research has highlighted the risks involved in work intensification; i.e. the risk of human resources being consumed, incurring higher risks of emotional ill health such as burnout among employees. At the same time, there are some indications that individual employees are being left to themselves to manage work tasks in intensive work environments. OBJECTIVE: This article explores how strongly engaged people master intensive work through coping and job crafting in a salutogenic way. METHODS: The article is based on 34 intdepth interviews of persons in various professions within research and development departments in three Swedish companies. RESULTS: The interviews indicated that employees generally experienced work as almost constantly intense. We identified two strategies for mastering intensive work; i.e. an active strategy and a cognitive strategy, involving elements of both coping and job crafting. The specific elements of these strategies determine whether salutogenic processes are present. CONCLUSIONS: The results suggest that it is the specific elements of the coping and job-crafting strategies that determine whether or not salutogenic processes occur, and that organisational support is an important supplement to the individual processes for mastering intensive work. PMID- 30475785 TI - Pressure distributions on the chair seat and backrest correlate with handwriting outcomes of school children. AB - BACKGROUND: Postures while sitting are believed to have an important influence on the process of writing and quality of handwriting, but data in this field are sparse. OBJECTIVES: The current study was undertaken to investigate correlations between 'ordinary' children's handwriting skills and their posture and stability while sitting. METHODS: Twenty-nine children with typical development (age 9.2+/ 0.8 years) underwent the Hebrew Handwriting Evaluation, while the pressure distributions on their seats and backrests were recorded using a pressure mapping system. RESULTS: There was an increase in the odds of erasing and overwriting letters in dictation tasks when body displacements of the buttocks increased [Odds Ratio (OR) = 1.01, 95% CI 1.000-1.02, p = 0.050]. Children who did not lean on the backrest were more likely to have legible handwriting in copying tasks (OR = 0.136, 95% CI 0.026-0.723, p = 0.019). CONCLUSIONS: The awareness and involvement of health practitioners in sitting postures of children at school might promote activities such as writing. Further investigation of movement patterns while writing and of the correlations of these patterns with handwriting outcomes is recommended. More research regarding adjustments at the school environment for children with developmental disorders is also warranted. PMID- 30475786 TI - The work activity as an interface among different logics: The case of distributing food in a university restaurant. AB - BACKGROUND: Work activity integrates the tasks to be performed, the means of work available, the instructions, the rules to be observed, the particular factors related to the individuals (skills, inner state), and the effects both on the task and on the operator. By analyzing the activity, the different logics and conflicts in the design of production systems are revealed. OBJECTIVE: To show how the work activity can support the transformation of the working conditions, when revealed by an ergonomic intervention, by integrating the different design standpoints, which are always present in the project's work situations. METHODS: For this case study, the Ergonomic Work Analysis (EWA) was used on the staff that serves meals at a new university restaurant in Rio de Janeiro (Brazil) with a focus on the portioning of the transported ready-cooked meals and the variability related thereto. The results of observations, verbalizations, self-confrontations and strategy analysis, collected through field notes and audio and photographic records, became a final report submitted to the directors of the university restaurant. RESULTS: This research showed that the work activity of the serving maids helped to reveal the different logics of the heterogeneous actors in the design of the work situation under analysis. The work activity, when revealed by an ergonomic intervention, can be an interface during the design process to articulate these different logics and to support the dialog among different design standpoints. Thus, the concept of fixed portioning became a concept of flexible portioning, which provided the serving maids with an increased autonomy level at the counter, thus improving both the quality of services and the working conditions of those involved therewith. CONCLUSIONS: The activity-focused design can be understood as an ongoing, multiple logical process whereby workers bring the design into their workplaces, which reveals aspects of their own activity, thus helping to change the initial concepts. The ergonomic intervention, based on the revealed activity, helps to highlight the existence of different logics and also to support the actors in articulating their own logics during the design process. PMID- 30475787 TI - CHANGES IN VISUAL ACUITY AND PHOTORECEPTOR DENSITY USING ADAPTIVE OPTICS AFTER RETINAL DETACHMENT REPAIR. AB - PURPOSE: To quantify changes in photoreceptor density using adaptive optics fundus camera in patients after retinal detachment (RD) and to correlate them with macular involvement and best-corrected visual acuity. METHODS: At 1 and 3 months (M1 and M3) after vitrectomy, 194 patients underwent adaptive optics imagery in both eyes, at 5 locations, that we matched between time points using anatomical landmarks. Twenty-two patients (10 fovea-OFF [OFF] and 12 fovea-ON [ON]) had matched and analyzable adaptive optics images. We used analysis of variance for repeated measures. RESULTS: Best-corrected visual acuity (logarithm of the minimum angle of resolution and Snellen equivalent [SE]) was significantly different between OFF and ON RDs at baseline: 2.0 (2.3-0.95) (SE: 20/2000) versus 0 (0.1-0) (SE: 20/20); at M1: 0.35 (0.5-0.1) (SE: 20/40) versus 0.05 (0-0.1) (SE: 20/25); and at M3: 0.25 (0.3-0.1) (SE: 20/32) versus 0 (0-0) (SE: 20/20). We observed that cone density was stable in fellow eyes between M1 and M3 (P = 0.67); decreased in treated eyes than in fellow eyes (P < 0.05); and increased postoperatively in the ON group (P = 0.02) but not in the OFF group (P = 0.97). Visual acuity and RD type were independently correlated with cone density (P = 0.004, P = 0.000). CONCLUSION: Postoperative cone density was reduced in OFF RD, but also in the ON group, although the drop recovered during the 3-month follow up. Cone density was significantly correlated with both visual acuity and type of RD at both time points.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30475788 TI - THE OCCURRENCE, CHARACTERISTICS, MANAGEMENT, AND PROGNOSIS OF RETINAL PIGMENT EPITHELIUM TEARS IN PATIENTS WITH POLYPOIDAL CHOROIDAL VASCULOPATHY: A Retrospective Study of 397 Patients. AB - PURPOSE: To investigate retinal pigment epithelium (RPE) tears in patients with polypoidal choroidal vasculopathy. METHOD: A retrospective review of polypoidal choroidal vasculopathy cases with confirmed RPE tears was conducted. Patients' comprehensive clinical data were collected and analyzed. The treatment strategy was a loading dose of one intravitreal antivascular endothelial growth factor injection, combined with additional injections if exudative activities or visual deterioration were detected. RESULTS: Among 397 polypoidal choroidal vasculopathy patients, 33 patients with RPE tears (8.3%) were included. 42.4% of them happened spontaneously. Pigment epithelial detachment (PED) occurred more frequently in RPE tear patients and most of them had serous vascularized or hemorrhagic PED. The height and greatest linear diameter of PED, and the subfoveal choroidal thickness of these cases were significantly larger, whereas the central foveal thickness was significantly smaller. Most of the RPE tears occurred at the edge of the PED. After our treatment strategy, patients' best-corrected visual acuity improved significantly from 2.13 +/- 1.24 (median 20/52) to 1.32 +/- 1.31 (median 20/166). Large subretinal hemorrhage may increase the risk of the formation of subretinal fibrosis (P < 0.05). CONCLUSION: Retinal pigment epithelium tears in polypoidal choroidal vasculopathy are associated with high subRPE hydrostatic pressure, produced by a large PED or hemorrhage. After our intervention strategy, this condition may not necessarily result in poor prognosis. PMID- 30475789 TI - OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FEATURES OF SUBRETINAL FIBROSIS AFTER MYOPIC NEOVASCULARIZATION. AB - PURPOSE: To describe the optical coherence tomography (OCT) angiography features of subretinal fibrosis in eyes with myopic choroidal neovascularization after natural evolution or secondary to intravitreal anti-vascular endothelial growth factor therapy. METHODS: Retrospective observational case series. All eyes underwent a multimodal imaging examination including fluorescein angiography, spectral domain OCT, OCT angiography, and en face OCT. RESULTS: Twenty-five eyes of 25 patients with mean age of 56.4 +/- 14.9 were included in the study. Subretinal fibrosis was diagnosed at mean 30 (range 6-116) months before inclusion. Within the subretinal fibrosis, an abnormal vascular network was observed in 20/25 (80%) eyes, located typically in the outer retina (18/20, 90%) or the choriocapillaris (14/20, 70%) segmentation. The most prevalent patterns were "round tangle" and "tapered tangle." On en face OCT, the subretinal fibrosis was evidenced in 24/25 (96%) eyes, most prevalently in the outer retina (21/25, 84%) and in the choriocapillaris (18/25, 72%), where main feature was white hyperreflective (20/21, 95%) and dark-hyporeflective (17/18, 94%) appearance, respectively. The presence of subretinal fibrosis on en face OCT was positively correlated with the presence of abnormal vascular network on OCT angiography in 61% of the cases (P = 0.005). CONCLUSION: Subretinal fibrosis secondary to myopic choroidal neovascularization frequently contains blood flow within a persistent abnormal vascular network as assessed by OCT angiography. PMID- 30475790 TI - SURGICAL MANAGEMENT OF TRAUMATIC MACULAR HOLE: Optical Coherence Tomography Features and Outcomes. AB - PURPOSE: To report the outcomes of eyes receiving surgical management for traumatic macular holes. To describe the preoperative and postoperative optical coherence tomography features of traumatic macular holes and to explore associations between preoperative clinical and optical coherence tomography features, and visual outcome. METHODS: Retrospective study of patients undergoing vitrectomy for traumatic macular hole and entered into the Australian and New Zealand Society of Retinal Specialists surgical registry. Preoperative clinical data, surgical details, and 3-month postoperative outcomes were recorded prospectively. Longer-term outcomes at 12 months were requested retrospectively, as were preoperative and postoperative optical coherence tomography scans. RESULTS: Hole closure was achieved in 91% (21/23) of patients with a single procedure. The average preoperative visual acuity was 20/120. At 3 months postoperatively, the mean visual acuity had improved to 20/70 (P < 0.001), 11/23 (48%) of eyes improved >=15 letters, and the number of eyes with 20/40 acuity or better increased from 1/23 to 7/23. Eyes with worse visual outcomes (visual acuity < 20/80) had larger holes, worse preoperative acuity, and a greater extent of preoperative ellipsoid band attenuation than those with better postoperative visual acuity. CONCLUSION: Eyes receiving surgical management for traumatic macular hole achieved good anatomical results and approximately half had a substantial improvement in acuity. Ellipsoid band attenuation on preoperative optical coherence tomography and worse preoperative acuity were associated with poorer visual outcomes. PMID- 30475791 TI - Correspondence. PMID- 30475792 TI - Risk Factors for Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis: Evidence from 1786 Cases. AB - BACKGROUND Postoperative pancreatitis is one of the most serious complications in endoscopic retrograde cholangiopancreatography (ERCP). To detect potential risk factors for post-ERCP hyperamylasemia and pancreatitis. MATERIAL AND METHODS We reviewed 1786 ERCP procedures in Zhongnan Hospital of Wuhan University from January 2015 to April 2018. Clinical data were extracted, and the complications after ERCP procedures were re-evaluated. Single- and multiple-variable analyses were conducted to detect the potential risk factors. RESULTS We found that 1786 procedures were applied on 1707 patients; 64 patients (3.58%) developed pancreatitis, while asymptomatic hyperamylasemia occurred in 263 cases (14.73%). In multivariate analysis, pancreatic deep wire pass (odds ratio [OR]: 2.280, 95% CI [confidence interval]: 1.129-4.605, P=0.022), endoscopic metal biliary endoprosthesis (OR: 2.399, 95% CI: 1.120-5.138, P=0.024), operation after liver transplantation (OR: 3.057, 95% CI: 1.110-8.422, P=0.031), and fistulotomy (OR: 3.148, 95% CI: 1.036-9.561, P=0.043) were identified as independent risk factors for post-ERCP pancreatitis. Pancreatic deep wire pass (OR: 1.678, 95% CI: 1.136 2.478, P=0.009), fistulotomy (OR: 2.553, 95% CI: 1.096-5.948, P=0.030), and younger age (OR: 0.990, 95% CI: 0.980-0.999, P=0.037) were identified as independent risk factors for hyperamylasemia. CONCLUSIONS To prevent post-ERCP pancreatitis, it is important to avoid high-risk procedures such as fistulotomy and pancreatic deep wire pass, especially in high-risk patients with liver transplantation. For patients with endoscopic metal biliary endoprosthesis, clinicians should pay more attention to the occurrence of post-ERCP pancreatitis. PMID- 30475793 TI - Similarities and differences in the regulation of HoxD genes during chick and mouse limb development. AB - In all tetrapods examined thus far, the development and patterning of limbs require the activation of gene members of the HoxD cluster. In mammals, they are regulated by a complex bimodal process that controls first the proximal patterning and then the distal structure. During the shift from the former to the latter regulation, this bimodal regulatory mechanism allows the production of a domain with low Hoxd gene expression, at which both telomeric (T-DOM) and centromeric regulatory domains (C-DOM) are silent. These cells generate the future wrist and ankle articulations. We analyzed the implementation of this regulatory mechanism in chicken, i.e., in an animal for which large morphological differences exist between fore- and hindlimbs. We report that although this bimodal regulation is globally conserved between the mouse and the chick, some important modifications evolved at least between these two model systems, in particular regarding the activity of specific enhancers, the width of the TAD boundary separating the two regulations, and the comparison between the forelimb versus hindlimb regulatory controls. At least one aspect of these regulations seems to be more conserved between chick and bats than with mouse, which may relate to the extent to which forelimbs and hindlimbs of these various animals differ in their morphologies. PMID- 30475794 TI - The NIH BRAIN Initiative: Advancing neurotechnologies, integrating disciplines. AB - In 2014, the National Institutes of Health (NIH) began funding an ambitious research program, the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, with the singular focus of advancing our understanding of brain circuits though development and application of breakthrough neurotechnologies. As we approach the halfway mark of this 10-year effort aimed at revolutionizing our understanding of information processing in the human brain, it is timely to review the progress and the future trajectory of BRAIN Initiative research. PMID- 30475795 TI - Interactions between the mRNA and Rps3/uS3 at the entry tunnel of the ribosomal small subunit are important for no-go decay. AB - No-go Decay (NGD) is a process that has evolved to deal with stalled ribosomes resulting from structural blocks or aberrant mRNAs. The process is distinguished by an endonucleolytic cleavage prior to degradation of the transcript. While many of the details of the pathway have been described, the identity of the endonuclease remains unknown. Here we identify residues of the small subunit ribosomal protein Rps3 that are important for NGD by affecting the cleavage reaction. Mutation of residues within the ribosomal entry tunnel that contact the incoming mRNA leads to significantly reduced accumulation of cleavage products, independent of the type of stall sequence, and renders cells sensitive to damaging agents thought to trigger NGD. These phenotypes are distinct from those seen in combination with other NGD factors, suggesting a separate role for Rps3 in NGD. Conversely, ribosomal proteins ubiquitination is not affected by rps3 mutations, indicating that upstream ribosome quality control (RQC) events are not dependent on these residues. Together, these results suggest that Rps3 is important for quality control on the ribosome and strongly supports the notion that the ribosome itself plays a central role in the endonucleolytic cleavage reaction during NGD. PMID- 30475796 TI - Binding of the general anesthetic sevoflurane to ion channels. AB - The direct-site hypothesis assumes general anesthetics bind ion channels to impact protein equilibrium and function, inducing anesthesia. Despite advancements in the field, a first principle all-atom demonstration of this structure-function premise is still missing. We focus on the clinically used sevoflurane interaction to anesthetic-sensitive Kv1.2 mammalian channel to resolve if sevoflurane binds protein's well-characterized open and closed structures in a conformation-dependent manner to shift channel equilibrium. We employ an innovative approach relying on extensive docking calculations and free energy perturbation of all potential binding sites revealed by the latter, and find sevoflurane binds open and closed structures at multiple sites under complex saturation and concentration effects. Results point to a non-trivial interplay of site and conformation-dependent modes of action involving distinct binding sites that increase channel open-probability at diluted ligand concentrations. Given the challenge in exploring more complex processes potentially impacting channel anesthetic interaction, the result is revealing as it demonstrates the process of multiple anesthetic binding events alone may account for open-probability shifts recorded in measurements. PMID- 30475797 TI - Mutations in Kinesin family member 6 reveal specific role in ependymal cell ciliogenesis and human neurological development. AB - Cerebrospinal fluid flow is crucial for neurodevelopment and homeostasis of the ventricular system of the brain, with localized flow being established by the polarized beating of the ependymal cell (EC) cilia. Here, we report a homozygous one base-pair deletion, c.1193delT (p.Leu398Glnfs*2), in the Kinesin Family Member 6 (KIF6) gene in a child displaying neurodevelopmental defects and intellectual disability. To test the pathogenicity of this novel human KIF6 mutation we engineered an analogous C-terminal truncating mutation in mouse. These mutant mice display severe, postnatal-onset hydrocephalus. We generated a Kif6-LacZ transgenic mouse strain and report expression specifically and uniquely within the ependymal cells (ECs) of the brain, without labeling other multiciliated mouse tissues. Analysis of Kif6 mutant mice with scanning electron microscopy (SEM) and immunofluorescence (IF) revealed specific defects in the formation of EC cilia, without obvious effect of cilia of other multiciliated tissues. Dilation of the ventricular system and defects in the formation of EC cilia were also observed in adult kif6 mutant zebrafish. Finally, we report Kif6 GFP localization at the axoneme and basal bodies of multi-ciliated cells (MCCs) of the mucociliary Xenopus epidermis. Overall, this work describes the first clinically-defined KIF6 homozygous null mutation in human and defines KIF6 as a conserved mediator of neurological development with a specific role for EC ciliogenesis in vertebrates. PMID- 30475799 TI - Anisotropic Crb accumulation, modulated by Src42A, is coupled to polarised epithelial tube growth in Drosophila. AB - The control of the size of internal tubular organs, such as the lungs or vascular system, is critical for proper physiological activity and to prevent disease or malformations. This control incorporates the intrinsic physical anisotropy of tubes to generate proportionate organs that match their function. The exact mechanisms underlying tube size control and how tubular anisotropy is translated at the cellular level are still not fully understood. Here we investigate these mechanisms using the Drosophila tracheal system. We show that the apical polarity protein Crumbs transiently accumulates anisotropically at longitudinal cell junctions during tube elongation. We provide evidence indicating that the accumulation of Crumbs in specific apical domains correlates with apical surface expansion, suggesting a link between the anisotropic accumulation of Crumbs at the cellular level and membrane expansion. We find that Src42A is required for the anisotropic accumulation of Crumbs, thereby identifying the first polarised cell behaviour downstream of Src42A. Our results indicate that Src42A regulates a mechanism that increases the fraction of Crb protein at longitudinal junctions, and genetic interaction experiments are consistent with Crb acting downstream of Src42A in controlling tube size. Collectively, our results suggest a model in which Src42A would sense the inherent anisotropic mechanical tension of the tube and translate it into a polarised Crumbs accumulation, which may promote a bias towards longitudinal membrane expansion, orienting cell elongation and, as a consequence, longitudinal growth at the tissue level. This work provides new insights into the key question of how organ growth is controlled and polarised and unveils the function of two conserved proteins, Crumbs and Src42A, with important roles in development and homeostasis as well as in disease, in this biological process. PMID- 30475800 TI - Anilinoquinoline based inhibitors of trypanosomatid proliferation. AB - We recently reported the medicinal chemistry re-optimization of a series of compounds derived from the human tyrosine kinase inhibitor, lapatinib, for activity against Plasmodium falciparum. From this same library of compounds, we now report potent compounds against Trypanosoma brucei brucei (which causes human African trypanosomiasis), T. cruzi (the pathogen that causes Chagas disease), and Leishmania spp. (which cause leishmaniasis). In addition, sub-micromolar compounds were identified that inhibit proliferation of the parasites that cause African animal trypanosomiasis, T. congolense and T. vivax. We have found that this set of compounds display acceptable physicochemical properties and represent progress towards identification of lead compounds to combat several neglected tropical diseases. PMID- 30475801 TI - Determinants of early afterdepolarization properties in ventricular myocyte models. AB - Early afterdepolarizations (EADs) are spontaneous depolarizations during the repolarization phase of an action potential in cardiac myocytes. It is widely known that EADs are promoted by increasing inward currents and/or decreasing outward currents, a condition called reduced repolarization reserve. Recent studies based on bifurcation theories show that EADs are caused by a dual Hopf homoclinic bifurcation, bringing in further mechanistic insights into the genesis and dynamics of EADs. In this study, we investigated the EAD properties, such as the EAD amplitude, the inter-EAD interval, and the latency of the first EAD, and their major determinants. We first made predictions based on the bifurcation theory and then validated them in physiologically more detailed action potential models. These properties were investigated by varying one parameter at a time or using parameter sets randomly drawn from assigned intervals. The theoretical and simulation results were compared with experimental data from the literature. Our major findings are that the EAD amplitude and takeoff potential exhibit a negative linear correlation; the inter-EAD interval is insensitive to the maximum ionic current conductance but mainly determined by the kinetics of ICa,L and the dual Hopf-homoclinic bifurcation; and both inter-EAD interval and latency vary largely from model to model. Most of the model results generally agree with experimental observations in isolated ventricular myocytes. However, a major discrepancy between modeling results and experimental observations is that the inter-EAD intervals observed in experiments are mainly between 200 and 500 ms, irrespective of species, while those of the mathematical models exhibit a much wider range with some models exhibiting inter-EAD intervals less than 100 ms. Our simulations show that the cause of this discrepancy is likely due to the difference in ICa,L recovery properties in different mathematical models, which needs to be addressed in future action potential model development. PMID- 30475798 TI - Comprehensive computational modelling of the development of mammalian cortical connectivity underlying an architectonic type principle. AB - The architectonic type principle relates patterns of cortico-cortical connectivity to the relative architectonic differentiation of cortical regions. One mechanism through which the observed close relation between cortical architecture and connectivity may be established is the joint development of cortical areas and their connections in developmental time windows. Here, we describe a theoretical exploration of the possible mechanistic underpinnings of the architectonic type principle, by performing systematic computational simulations of cortical development. The main component of our in silico model was a developing two-dimensional cortical sheet, which was gradually populated by neurons that formed cortico-cortical connections. To assess different explanatory mechanisms, we varied the spatiotemporal trajectory of the simulated neurogenesis. By keeping the rules governing axon outgrowth and connection formation constant across all variants of simulated development, we were able to create model variants which differed exclusively by the specifics of when and where neurons were generated. Thus, all differences in the resulting connectivity were due to the variations in spatiotemporal growth trajectories. Our results demonstrated that a prescribed targeting of interareal connection sites was not necessary for obtaining a realistic replication of the experimentally observed relation between connection patterns and architectonic differentiation. Instead, we found that spatiotemporal interactions within the forming cortical sheet were sufficient if a small number of empirically well-grounded assumptions were met, namely planar, expansive growth of the cortical sheet around two points of origin as neurogenesis progressed, stronger architectonic differentiation of cortical areas for later neurogenetic time windows, and stochastic connection formation. Thus, our study highlights a potential mechanism of how relative architectonic differentiation and cortical connectivity become linked during development. We successfully predicted connectivity in two species, cat and macaque, from simulated cortico-cortical connection networks, which further underscored the general applicability of mechanisms through which the architectonic type principle can explain cortical connectivity in terms of the relative architectonic differentiation of cortical regions. PMID- 30475802 TI - Reaching key populations through key venues: Insights from the Jamaica HIV Prevention Program. AB - INTRODUCTION: HIV prevention strategies often include outreach to female sex workers at social venues identified as places where people meet new sexual partners. Patrons and staff at these venues may include female sex workers, their clients, as well as others who have high rates of new sexual partnerships. Few studies have compared HIV/STI among venue-based and general populations, across types of venues, or by sub-group of the venue population. Program planners often assume that the prevalence of infection is highest among female sex workers and considerably lower among other people at these venues, but there are few empiric studies assessing the prevalence of infection by sex worker status and type of venue. METHODS: In 2011, we used the PLACE method to identify public venues where people meet new sexual partners across Jamaica. The study team visited all venues with reported sex work as well as a 10% random sample of other venues and subsequently interviewed and tested a probability sample of 991 venue patrons and workers for HIV and other STI. RESULTS: Community informants identified 1207 venues. All venues where sex work was reported (735 venues) and a random sample of the remainder (134 of 472) were selected for onsite visits. Of these, 585 were found and operational. At a stratified random sample of venues, survey teams interviewed and tested 717 women and 274 men. 394 women reported recent sex work and 211 of these women reported soliciting clients on the street. Women exchanging sex for money were more likely to be infected with HIV (5.4% vs 1.0%; OR = 5.6, 95% CI = 1.8,17.3) or syphilis (11.7% vs. 5.8%, OR = 2.2, 95% CI = 1.7,4,0) than other women, but not significantly more likely to be infected with gonorrhea (8.4% vs 7.8%; OR = 1.1,95% CI = 0.6,1.9), chlamydia (16.2% vs 21.6%;OR = 0.7,95% CI = 0.5,1.0) or trichomoniasis (23.0% vs 17.0%, OR = 1.5,95% CI = 0.9,2.2). Women at venues were more likely to report sex work and multiple partners than women interviewed in a 2008 national population-based household survey commissioned by the Ministry of Health. CONCLUSIONS: In Jamaica, although the highest HIV prevalence was among street-based sex workers, the risk of HIV and STI extends to men and women at high risk venues, even those who do not self identify as sex workers. Findings confirm the appropriateness of outreach to all men and women at these venues. PMID- 30475803 TI - Monitoring of language selection errors in switching: Not all about conflict. AB - Although bilingual speakers are very good at selectively using one language rather than another, sometimes language selection errors occur. To investigate how bilinguals monitor their speech errors and control their languages in use, we recorded event-related potentials (ERPs) in unbalanced Dutch-English bilingual speakers in a cued language-switching task. We tested the conflict-based monitoring model of Nozari and colleagues by investigating the error-related negativity (ERN) and comparing the effects of the two switching directions (i.e., to the first language, L1 vs. to the second language, L2). Results show that the speakers made more language selection errors when switching from their L2 to the L1 than vice versa. In the EEG, we observed a robust ERN effect following language selection errors compared to correct responses, reflecting monitoring of speech errors. Most interestingly, the ERN effect was enlarged when the speakers were switching to their L2 (less conflict) compared to switching to the L1 (more conflict). Our findings do not support the conflict-based monitoring model. We discuss an alternative account in terms of error prediction and reinforcement learning. PMID- 30475804 TI - Non-significant p-values? Strategies to understand and better determine the importance of effects and interactions in logistic regression. AB - In the context of generalized linear models (GLMs), interactions are automatically induced on the natural scale of the data. The conventional approach to measuring effects in GLMs based on significance testing (e.g. the Wald test or using deviance to assess model fit) is not always appropriate. The objective of this paper is to demonstrate the limitations of these conventional approaches and to explore alternative strategies for determining the importance of effects. The paper compares four approaches to determining the importance of effects in the GLM using 1) the Wald statistic, 2) change in deviance (model fitting criteria), 3) Bayesian GLM using vaguely informative priors and 4) Bayesian Model Averaging analysis. The main points in this paper are illustrated using an example study, which examines the risk factors for cyber abuse victimization, and are further examined using a simulation study. Analysis of our example dataset shows that, in terms of a logistic GLM, the conventional methods using the Wald test and the change in deviance can produce results that are difficult to interpret; Bayesian analysis of GLM is a suitable alternative, which is enhanced with prior knowledge about the direction of the effects; and Bayesian Model Averaging (BMA) is especially suited for new areas of research, particularly in the absence of theory. We recommend that social scientists consider including BMA in their standard toolbox for analysis of GLMs. PMID- 30475806 TI - Insights into antitrypanosomal drug mode-of-action from cytology-based profiling. AB - Chemotherapy continues to have a major impact on reducing the burden of disease caused by trypanosomatids. Unfortunately though, the mode-of-action (MoA) of antitrypanosomal drugs typically remains unclear or only partially characterised. This is the case for four of five current drugs used to treat Human African Trypanosomiasis (HAT); eflornithine is a specific inhibitor of ornithine decarboxylase. Here, we used a panel of T. brucei cellular assays to probe the MoA of the current HAT drugs. The assays included DNA-staining followed by microscopy and quantitative image analysis, or flow cytometry; terminal dUTP nick end labelling to monitor mitochondrial (kinetoplast) DNA replication; antibody based detection of sites of nuclear DNA damage; and fluorescent dye-staining of mitochondria or lysosomes. We found that melarsoprol inhibited mitosis; nifurtimox reduced mitochondrial protein abundance; pentamidine triggered progressive loss of kinetoplast DNA and disruption of mitochondrial membrane potential; and suramin inhibited cytokinesis. Thus, current antitrypanosomal drugs perturb distinct and specific cellular compartments, structures or cell cycle phases. Further exploiting the findings, we show that putative mitogen activated protein-kinases contribute to the melarsoprol-induced mitotic defect, reminiscent of the mitotic arrest associated signalling cascade triggered by arsenicals in mammalian cells, used to treat leukaemia. Thus, cytology-based profiling can rapidly yield novel insight into antitrypanosomal drug MoA. PMID- 30475805 TI - Spatiotemporal dynamics of reward and punishment effects induced by associative learning. AB - While reward associative learning has been studied extensively across different species, punishment avoidance learning has received far less attention. Of particular interest is how the two types of learning change perceptual processing of the learned stimuli. We designed a task that required participants to learn the association of emotionally neutral images with reward, punishment, and no incentive value outcomes through trial-and-error. During learning, participants received monetary reward, neutral outcomes or avoided punishment by correctly identifying corresponding images. Results showed an early bias in favor of learning reward associations, in the form of higher accuracy and fewer trials needed to reach learning criterion. We subsequently assessed electrophysiological learning effects with a task in which participants viewed the stimuli with no feedback or reinforcement. Critically, we found modulation of two early event related potential components for reward images: the frontocentral P2 (170-230 ms) and the anterior N2/Early Anterior Positivity (N2/EAP; 210-310 ms). We suggest that reward associations may change stimuli detection and incentive salience as indexed by P2 and N2/EAP. We also reported, on an exploratory basis, a late negativity with frontopolar distribution enhanced by punishment images. PMID- 30475807 TI - Estimating the local false discovery rate via a bootstrap solution to the reference class problem. AB - Methods of estimating the local false discovery rate (LFDR) have been applied to different types of datasets such as high-throughput biological data, diffusion tensor imaging (DTI), and genome-wide association (GWA) studies. We present a model for LFDR estimation that incorporates a covariate into each test. Incorporating the covariates may improve the performance of testing procedures, because it contains additional information based on the biological context of the corresponding test. This method provides different estimates depending on a tuning parameter. We estimate the optimal value of that parameter by choosing the one that minimizes the estimated LFDR resulting from the bias and variance in a bootstrap approach. This estimation method is called an adaptive reference class (ARC) method. In this study, we consider the performance of ARC method under certain assumptions on the prior probability of each hypothesis test as a function of the covariate. We prove that, under these assumptions, the ARC method has a mean squared error asymptotically no greater than that of the other method where the entire set of hypotheses is used and assuming a large covariate effect. In addition, we conduct a simulation study to evaluate the performance of estimator associated with the ARC method for a finite number of hypotheses. Here, we apply the proposed method to coronary artery disease (CAD) data taken from a GWA study and diffusion tensor imaging (DTI) data. PMID- 30475808 TI - Variation in the quality and out-of-pocket cost of treatment for childhood malaria, diarrhoea, and pneumonia: Community and facility based care in rural Uganda. AB - BACKGROUND: A key barrier to appropriate treatment for malaria, diarrhoea, and pneumonia (MDP) in children under 5 years of age in low income rural settings is the lack of access to quality health care. The WHO and UNICEF have therefore called for the scale-up of integrated community case management (iCCM) using community health workers (CHWs). The current study assessed access to treatment, out-of-pocket expenditure and the quality of treatment provided in the public and private sectors compared to national guidelines, using data collected in a large representative survey of caregivers of children in 205 villages with iCCM-trained CHWs in mid-Western Uganda. RESULTS: The prevalence of suspected malaria, diarrhoea and suspected pneumonia in the preceding two weeks in 6501 children in the study sample were 45%, 11% and 24% respectively. Twenty percent of children were first taken to a CHW, 56% to a health facility, 14% to other providers and no care was sought for 11%. The CHW was more likely to provide appropriate treatment compared to any other provider or to those not seeking care for children with MDP (RR 1.51, 95% CI 1.42-1.61, p<0.001). Seeking care from a CHW had the lowest cost outlay (median $0.00, IQR $0.00-$1.80), whilst seeking care to a private doctor or clinic the highest (median $2.80, IQR $1.20-$6.00). We modelled the expected increase in overall treatment coverage if children currently treated in the private sector or not seeking care were taken to the CHW instead. In this scenario, coverage of appropriate treatment for MDP could increase in total from the current rate of 47% up to 64%. CONCLUSION: Scale-up of iCCM-trained CHW programmes is key to the provision of affordable, high quality treatment for sick children, and can thus significantly contribute to closing the gap in coverage of appropriate treatment. PMID- 30475810 TI - Estimation accuracy in the psychological sciences. AB - Sample means comparisons are a fundamental and ubiquitous approach to interpreting experimental psychological data. Yet, we argue that the sample and effect sizes in published psychological research are frequently so small that sample means are insufficiently accurate to determine whether treatment effects have occurred. Generally, an estimator should be more accurate than any benchmark that systematically ignores information about the relations among experimental conditions. We consider two such benchmark estimators: one that randomizes the relations among conditions and another that always assumes no treatment effects. We show conditions under which these benchmark estimators estimate the true parameters more accurately than sample means. This perverse situation can occur even when effects are statistically significant at traditional levels. Our argument motivates the need for regularized estimates, such as those used in lasso, ridge, and hierarchical Bayes techniques. PMID- 30475809 TI - A study on endonuclease BspD6I and its stimulus-responsive switching by modified oligonucleotides. AB - Nicking endonucleases (NEases) selectively cleave single DNA strands in double stranded DNAs at a specific site. They are widely used in bioanalytical applications and in genome editing; however, the peculiarities of DNA-protein interactions for most of them are still poorly studied. Previously, it has been shown that the large subunit of heterodimeric restriction endonuclease BspD6I (Nt.BstD6I) acts as a NEase. Here we present a study of interaction of restriction endonuclease BspD6I with modified DNA containing single non nucleotide insertion with an azobenzene moiety in the enzyme cleavage sites or in positions of sugar-phosphate backbone nearby. According to these data, we designed a number of effective stimulus-responsive oligonucleotide inhibitors bearing azobenzene or triethylene glycol residues. These modified oligonucleotides modulated the functional activity of Nt.BspD6I after cooling or heating. We were able to block the cleavage of T7 phage DNA by this enzyme in the presence of such inhibitors at 20-25 degrees C, whereas the Nt.BspD6I ability to hydrolyze DNA was completely restored after heating to 45 degrees C. The observed effects can serve as a basis for the development of a platform for regulation of NEase activity in vitro or in vivo by external signals. PMID- 30475811 TI - Identification and binding mode of a novel Leishmania Trypanothione reductase inhibitor from high throughput screening. AB - Trypanothione reductase (TR) is considered to be one of the best targets to find new drugs against Leishmaniasis. This enzyme is fundamental for parasite survival in the host since it reduces trypanothione, a molecule used by the tryparedoxin/tryparedoxin peroxidase system of Leishmania to neutralize hydrogen peroxide produced by host macrophages during infection. In order to identify new lead compounds against Leishmania we developed and validated a new luminescence based high-throughput screening (HTS) assay that allowed us to screen a library of 120,000 compounds. We identified a novel chemical class of TR inhibitors, able to kill parasites with an IC50 in the low micromolar range. The X-ray crystal structure of TR in complex with a compound from this class (compound 3) allowed the identification of its binding site in a pocket at the entrance of the NADPH binding site. Since the binding site of compound 3 identified by the X-ray structure is unique, and is not present in human homologs such as glutathione reductase (hGR), it represents a new target for drug discovery efforts. PMID- 30475812 TI - Individual differences in rate of acquiring stable neural representations of tasks in fMRI. AB - Task-related functional magnetic resonance imaging (fMRI) is a widely-used tool for studying the neural processing correlates of human behavior in both healthy and clinical populations. There is growing interest in mapping individual differences in fMRI task behavior and neural responses. By utilizing neuroadaptive task designs accounting for such individual differences, task durations can be personalized to potentially optimize neuroimaging study outcomes (e.g., classification of task-related brain states). To test this hypothesis, we first retrospectively tracked the volume-by-volume changes of beta weights generated from general linear models (GLM) for 67 adult subjects performing a stop-signal task (SST). We then modeled the convergence of the volume-by-volume changes of beta weights according to their exponential decay (ED) in units of half-life. Our results showed significant differences in beta weight convergence estimates of optimal stopping times (OSTs) between go following successful stop trials and failed stop trials for both cocaine dependent (CD) and control group (Con), and between go following successful stop trials and go following failed stop trials for Con group. Further, we implemented support vector machine (SVM) classification for 67 CD/Con labeled subjects and compared the classification accuracies of fMRI-based features derived from (1) the full fMRI task versus (2) the fMRI task truncated to multiples of the unit of half-life. Among the computed binary classification accuracies, two types of task durations based on 2 half lives significantly outperformed the accuracies using fully acquired trials, supporting this length as the OST for the SST. In conclusion, we demonstrate the potential of a neuroadaptive task design that can be widely applied to personalizing other task-based fMRI experiments in either dynamic real-time fMRI applications or within fMRI preprocessing pipelines. PMID- 30475813 TI - Grading system for periodontitis by analyzing levels of periodontal pathogens in saliva. AB - Periodontitis is an infectious disease that is associated with microorganisms that colonize the tooth surface. Clinically, periodontal condition stability reflects dynamic equilibrium between bacterial challenge and host response. Therefore, periodontal pathogen assessment can assist in the early detection of periodontitis. Here we developed a grading system called the periodontal pathogen index (PPI) by analyzing the copy numbers of multiple pathogens both in healthy and chronic periodontitis patients. We collected 170 mouthwash samples (64 periodontally healthy controls and 106 chronic periodontitis patients) and analyzed the salivary 16S rRNA levels of nine pathogens using multiplex, quantitative real-time polymerase chain reaction. Except for Aggregatibacter actinomycetemcomitans, copy numbers of all pathogens were significantly higher in chronic periodontitis patients. We classified the samples based on optimal cut off values with maximum sensitivity and specificity from receiver operating characteristic curve analyses (AUC = 0.91, 95% CI: 0.87-0.96) into four categories of PPI: Healthy (1-40), Moderate (41-60), At Risk (61-80), and Severe (81-100). PPI scores were significantly higher in all chronic periodontitis patients than in the controls (odds ratio: 31.7, 95% CI: 13.41-61.61) and were associated with age, scaling as well as clinical characteristics including clinical attachment level and plaque index. Our PPI grading system can be clinically useful for the early assessment of pathogenic bacterial burden and follow-up monitoring after periodontitis treatment. PMID- 30475814 TI - Electrophysiological approaches in the study of cognitive development outside the lab. AB - The use of human neuroimaging technology provides knowledge about several emotional and cognitive processes at the neural level of organization. In particular, electroencephalographic (EEG) techniques allow researchers to explore high-temporal resolution of the neural activity that underlie the dynamics of cognitive processes. Although EEG research has been mostly applied in laboratory settings, recently a low-cost, portable EEG apparatus was released, which allows exploration of different emotional and cognitive processes during every-day activities. We compared a wide range of EEG measures using both a low-cost portable and a high-quality laboratory system. EEG recordings were done with both systems while participants performed an active task (Go/NoGo) and during their resting-state. Results showed similar waveforms in terms of morphology and amplitude of the ERPs, and comparable effects between conditions of the applied Go/NoGo paradigm. In addition, the contribution of each frequency to the entire EEG was not significantly different during resting-state, and fluctuations in amplitude of oscillations showed long-range temporal correlations. These results showed that low-cost, portable EEG technology can provide an alternative of enough quality for measuring brain activity outside a laboratory setting, which could contribute to the study of different populations in more ecological contexts. PMID- 30475815 TI - Evolutionary regime transitions in structured populations. AB - The evolutionary dynamics of a finite population where resident individuals are replaced by mutant ones depends on its spatial structure. Usually, the population adopts the form of an undirected graph where the place occupied by each individual is represented by a vertex and it is bidirectionally linked to the places that can be occupied by its offspring. There are undirected graph structures that act as amplifiers of selection increasing the probability that the offspring of an advantageous mutant spreads through the graph reaching any vertex. But there also are undirected graph structures acting as suppressors of selection where this probability is less than that of the same individual placed in a homogeneous population. Here, firstly, we present the distribution of these evolutionary regimes for all undirected graphs with N <= 10 vertices. Some of them exhibit transitions between different regimes when the mutant fitness increases. In particular, as it has been already observed for small-order random graphs, we show that most graphs of order N <= 10 are amplifiers of selection. Secondly, we describe examples of amplifiers of order 7 that become suppressors from some critical value. In fact, for graphs of order N <= 7, we apply computer aided techniques to symbolically compute their fixation probability and then their evolutionary regime, as well as the critical values for which they change their regime. Thirdly, the same technique is applied to some families of highly symmetrical graphs as a mean to explore methods of suppressing selection. The existence of suppression mechanisms that reverse an amplification regime when fitness increases could have a great interest in biology and network science. Finally, the analysis of all graphs from order 8 to order 10 reveals a complex and rich evolutionary dynamics, with multiple transitions between different regimes, which have not been examined in detail until now. PMID- 30475816 TI - Deployment of small cells and a transport infrastructure concurrently for next generation mobile access networks. AB - The exponential growth of mobile traffic means that operators must upgrade their mobile networks to provide higher capacity to final users. A promising alternative is to deploy heterogeneous networks (HetNets) that combine macro Base Stations (BSs) and SmallCells (SCs), although this increases the complexity and cost of the transport (SCs to Fiber Access Point-FAP). Most of the planning strategies outlined in the literature are aimed at reducing the number of SCs and ignore the impact that the transport segment might have on the total cost of network deployment. In this paper, heuristics are used for the joint planning of radio (i.e., SCs) and transport resources (i.e., point-to-point fiber links). These were compared and examined to determine the advantages and disadvantages of each approach, and in some cases, this led to a 50% reduction in total costs, while still creating a non-scalable network. PMID- 30475818 TI - Investigating risk factors for under-five mortality in an HIV hyper-endemic area of rural South Africa, from 2000-2014. AB - INTRODUCTION: Despite global progress, there remains a disproportionate burden of under-five year old deaths in sub-Saharan Africa (SSA), where four out of five child deaths occur. Substantial progress has been made in improving sanitation, controlling communicable diseases and the spread of HIV in most parts of the world. However, significant strides to address some key risk factors related to under-five mortality are still needed in rural SSA if they are to attain relevant 2030 SDG targets. The aim of this study is to investigate the risk factors for under-five mortality in an HIV hyper-endemic area of rural South Africa, from 2000-2014. Some of the key risk factors investigated are, for example: household wealth, source of drinking water, distance to the national road and birth order. METHODS: We conducted a statistical analysis of 759 births from a population based cohort in rural KwaZulu-Natal Province, South Africa, from 2000 to 2014. A Cox Proportional Hazards model was used to identify the risk factors and key socio-demographic correlates of under-five mortality leveraging the longitudinal structure of the population cohort. RESULTS: Child mortality rates declined by 80 per cent from 2000 to 2014, from >140 per 1,000 persons in years 2001-2003 to 20 per 1,000 persons in the year 2014. The highest under-five mortality rate was recorded in 2002/2003, which decreased following the start of antiretroviral therapy rollout in 2003/4. The results indicated that under-five and infant mortality are significantly associated with a low wealth index of 1.49 (1.007 2.48) for under-fives and 3.03 (1.72-5.34) for infants. Children and infants with a lower wealth index had a significantly increased risk of mortality as compared to those with a high wealth index. Other significant factors included: source of household drinking water (borehole) 3.03 (1.72-5.34) for under-fives and 2.98 (1.62-5.49) for infants; having an HIV positive mother 4.22 (2.68-6.65) for under fives and 3.26 (1.93-5.51) for infants, and period of death 9.13 (5.70-14.6) for under-fives and 1.28 (0.75-2.20) for infants. Wealth index had the largest population attributable fraction of 25.4 per cent. CONCLUSIONS: The research findings show a substantial overall reduction in under-five mortality since 2003. Unsafe household water sources and having an HIV-positive mother were associated with an increased risk of under-five mortality in this rural setting. The significant risk factors identified align well with the SDG 2030 targets for reducing child mortality, which include improved nutrition, sanitation, hygiene and reduced HIV infections. Current trajectories suggest that there is some hope for meeting the 2030 SGD targets in rural South Africa and the region if the identified significant risk factors are adequately addressed. PMID- 30475819 TI - Characterization of a heat responsive UDP: Flavonoid glucosyltransferase gene in tea plant (Camellia sinensis). AB - Tea plant (Camellia sinensis) accumulates abundant flavonoid glycosides that are the major bioactive ingredients in tea. Biosynthesis of flavonoid glycosides are catalyzed by UDP-glucosyltransferases (UGTs) that are widely present in plants. Among one hundred and seventy-eight UGTs genes that we have previously identified in tea plant, few of them have been functionally characterized. In the present study, we further identified UGT73A17 gene that is responsible for the biosynthesis of a broad range of flavonoid glycosides. Sequence analysis revealed that the deduced UGT73A17 protein showed high identity with 7-O glycosyltransferases at amino acid level and it was clustered into the clade containing several 7-O-glycosyltransferases from other plant species. Enzymatic assays revealed that the recombinant UGT73A17 protein (rUGT73A17) exhibited activity toward flavonols (kaempferol, quercetin, and myricetin), flavones (apigenin, luteolin, and tricetin), flavanone (naringenin), isoflavones (genistein) and epicatechin gallate, yielding 7-O-glucosides as the major in vitro products. In particular, rUGT73A17 displayed higher activity at high temperatures (eg. 50 degrees C) than at low temperatures, which was consistent with its relatively high expression level at high temperatures. Two amino acid substitutions at I296L and V466A improved the enzymatic activity of rUGT73A17. Our study demonstrated that UGT73A17 is responsible for the biosynthesis of a broad range of flavonoid glucosides, which is also involved in heat response and quality of tea plant. PMID- 30475820 TI - Phylogenetic analysis of West Nile Virus in Maricopa County, Arizona: Evidence for dynamic behavior of strains in two major lineages in the American Southwest. AB - West Nile Virus (WNV) has been detected annually in Maricopa County, Arizona, since 2003. With this in mind, we sought to determine if contemporary strains are endemic to the county or are annually imported. As part of this effort, we developed a new protocol for tiled amplicon sequencing of WNV to efficiently attain greater than 99% coverage of 14 WNV genomes collected directly from positive mosquito pools distributed throughout Maricopa County between 2014 and 2017. Bayesian phylogenetic analyses revealed that contemporary genomes fall within two major lineages; NA/WN02 and SW/WN03. We found that all of the Arizona strains possessed an amino acid substitution known to be under positive selection, which has arisen independently at least four times in Arizona. The SW/WN03 strains exhibited transient behavior, with at least 10 separate introductions into Arizona when considering both historical and contemporary strains. However, NA/WN02 strains are geographically differentiated and appear to be endemic in Arizona, with two clades that have been circulating for four and seven years. This establishment in Maricopa County provides the first evidence of local overwintering by a WNV strain over the course of several years in Arizona. Within a national context, the placement of eleven contemporary Arizona strains in the NA/WN02 lineage indicates while WNV first entered the northeastern United States in 1999, the most ancestral extant strains of WNV are now circulating in the American southwest. PMID- 30475817 TI - Temporal patterns of circulating cell-free DNA (cfDNA) in a newborn piglet model of perinatal asphyxia. AB - Perinatal asphyxia is a severe medical condition resulting from oxygen deficiency (hypoxia) at the time of birth, causing worldwide approximately 680,000 newborn deaths every year. Better prediction of severity of damages including early biomarkers is highly demanded. Elevated levels of circulating cell-free DNA (cfDNA) in blood have been reported for a range of different diseases and conditions, including cancer and prematurity. The objective of this study was to validate methods for assessing cfDNA in blood and cerebrospinal fluid (CSF) and to explore temporal variations in a piglet model of neonatal hypoxia reoxygenation. Different cfDNA extraction methods in combination with cfDNA detection systems were tested, including a fluorescent assay using SYBR Gold and a qRT-PCR-based technique. Newborn piglets (n = 55) were exposed to hypoxia reoxygenation, hypoxia-reoxygenation and hypothermia, or were part of the sham operated control group. Blood was sampled at baseline and at post-intervention, further at 30, 270, and 570 minutes after the end of hypoxia. Applying the fluorescent method, cfDNA concentration in piglets exposed to hypoxia (n = 32) increased from 36.8+/-27.6 ng/ml prior to hypoxia to a peak level of 61.5+/-54.9 ng/ml after the intervention and deceased to 32.3+/-19.1 ng/ml at 570 minutes of reoxygenation, whereas the group of sham-operated control animals (n = 11) revealed a balanced cfDNA profile. Animals exposed to hypoxia and additionally treated with hypothermia (n = 12) expressed a cfDNA concentration of 54.4+/-16.9 ng/ml at baseline, 39.2+/-26.9 ng/ml at the end of hypoxia, and of 41.1+/-34.2 ng/ml at 570 minutes post-intervention. Concentrations of cfDNA in the CSF of piglets exposed to hypoxia revealed at post-intervention higher levels in comparison to the controls. However, these observations were only tendencies and not significant. In a first methodological proof-of-principle study exploring cfDNA using a piglet model of hypoxia-reoxygenation variations in the temporal patterns suggest that cfDNA might be an early indicator for damages caused by perinatal asphyxia. PMID- 30475821 TI - Identification and validation of potential prognostic and predictive miRNAs of epithelial ovarian cancer. AB - BACKGROUND: Ovarian cancer is the leading cause of death by gynecologic cancers in the Western world. The aim of the study was to identify microRNAs (miRNAs) associated with prognosis and/or resistance to chemotherapy among patients with epithelial ovarian cancer. METHODS: Using information from the Pelvic Mass Study we identified a cohort of women with epithelial ovarian cancer. Tumor tissues were then collected and analyzed by global miRNA microarrays. MiRNA profiling was then linked to survival and time to progression using Cox proportional-hazards regression models. Logistic regression models were used for the analysis of resistance to chemotherapy. Our results were validated using external datasets retrieved from the NCBI Gene Expression Omnibus database. RESULTS: A total of 197 patients with epithelial ovarian cancer were included for miRNA microarray analysis. In multivariate analyses we identified a number of miRNAs significantly correlated with overall survival (miR-1183 (HR: 1.42, 95% CI:1.17-1.74, p = 0.0005), miR-126-3p (HR: 1.38, 95% CI:1.11-1.71, p = 0.0036), time to progression (miR-139-3p (HR: 1.48, 95% CI: 1.13-1.94, p = 0.0047), miR-802 (HR: 0.48, 95% CI: 0.29-0.78, p = 0.0035)), progression free survival (miR-23a-5p (HR:1.32, 95% CI:1.09-1.61, p = 0.004), miR-23a-3p (HR:1.70, 95% CI:1.15-2.51, p = 0.0074), miR 802 (HR: 0.48, 95% CI: 0.29-0.80, p = 0.0048)), and resistance to chemotherapy (miR-1234 (HR: 0.26, 95% CI: 0.11-0.64, p = 0.003)). A few miRNAs identified in our training cohort, were validated in external cohorts with similar results. CONCLUSION: Eight miRNAs were identified as significant predictors of overall survival, progression free survival, time to progression, and chemotherapy resistance. A number of these miRNAs were significantly validated using external datasets. Inter-platform and inter-laboratory variations may have influence on the ability to compare and reproduce miRNA results. The use of miRNAs as potential markers of relapse and survival in ovarian cancer warrants further investigation. PMID- 30475822 TI - Clinical and neonatal outcomes of patients of different ages following transfer of thawed cleavage embryos and blastocysts cultured from thawed cleavage-stage embryos. AB - BACKGROUND: Frozen-thawed embryo transfer (FET) has become a routine procedure in assisted reproductive technology (ART). In FET, although blastocysts cultured from thawed cleavage-stage embryos are associated with better perinatal outcomes. it may increase cycle cancellation due to no suitable embryo to transfer. The overall clinical outcomes following transfer of thawed cleavage-stage FET and blastocysts cultured from thawed cleavage-stage embryos in young and advanced age patients remains unclear. Therefore, we aimed to identify the optimal FET strategy in young and advanced age women who undergo FET. METHODS: This retrospective study included 16,387 thaw cycles. We retrospectively analyzed data of couples who had completed the first FET cycle. Two FET strategies were studied: transfer of thawed cleavage-stage embryos (strategy A) or blastocysts cultured from thawed cleavage-stage embryos (strategy B). The clinical and neonatal outcomes of two FET strategies were compared in young (<35 years) and advanced (>=35 years) age women. RESULTS: In young women, the clinical outcomes per transfer cycle were better in strategy B than strategy A. While the clinical pregnancy (59.29%, 52.60%) and live birth rates (49.37%, 43.88%) per thaw cycle were significantly higher in strategy A than in B. In women of advanced age, the clinical outcomes per transfer cycle were still better in strategy B than in A, and the clinical pregnancy (36.44%, 39.66%) and live birth rates (25.70%, 30.00%) per thaw cycle were significantly higher in strategy B than in A. CONCLUSIONS: FET of blastocysts cultured from cleavage-stage embryos showed higher efficiency for per transfer cycle whether in younger or advanced age women. Whereas, when cycle cancellations due to no suitable embryo to transfer were considered, cleavage-stage FET was found to be more suitable for younger women, while FET of blastocysts cultured from cleavage-stage embryos was better suited for women of advanced age. PMID- 30475824 TI - Experimental evidence that the perennial grass persistence pathway is linked to plant growth strategy. AB - Grass species can be classified into different functional types based on their growth strategies, and contrasting persistence strategies are observed in different grass species. Excluding seedling recruitments, changes in populations of grasses are basically a trade-off between natality and mortality of tillers. We hypothesised that the persistence pathway of perennial grasses is linked to their growth strategy, regardless whether they are growing as monoculture or as a mixture. Species with contrasting growth strategies (Arrhenatherum elatius L., Dactylis glomerata L., and Festuca arundinacea Schreb.) were cultivated as monocultures and as a mixture and their tiller natality and mortality were evaluated for two years after swards establishment. All pastures maintained their population size during the experimental period, although decreases in tiller densities occurred during the warmer season. Arrhenatherum elatius had the highest tiller mortality and natality whereas the F. arundinacea had the lowest ones. Arrhenatherum elatius had many tillers appearing in all seasons but their tillers were short-lived. Conversely, F. arundinacea and D. glomerata developed numerous tillers during autumn and winter and their tillers survived, on average, almost six and three times longer than those of A. elatius, respectively. There were no differences in tillering dynamics among populations grown in monocultures or in the mixture. Regardless of whether they were cultivated in monocultures or as a mixture, the persistence pathway of perennial grasses is linked with their growth strategies with exploitative species presenting a high tiller turnover throughout the year whereas the persistence of more conservative species is based on a high tiller survival. PMID- 30475823 TI - Using item response theory with health system data to identify latent groups of patients with multiple health conditions. AB - A critical step toward tailoring effective interventions for heterogeneous and medically complex patients is to identify clinically meaningful subgroups on the basis of their comorbid conditions. We applied Item Response Theory (IRT), a potentially useful tool to identify clinically meaningful subgroups, to characterize phenotypes within a cohort of high-risk patients. This was a retrospective cohort study using 68,400 high-risk Veteran's Health Administration (VHA) patients. Thirty-one physical and mental health diagnosis indicators based on ICD-9 codes from patients' inpatient, outpatient VHA and VA-paid community care claims. Results revealed 6 distinct subgroups of high-risk patients were identified: substance use, complex mental health, complex diabetes, liver disease, cancer with cardiovascular disease, and cancer with mental health. Multinomial analyses showed that subgroups significantly differed on demographic and utilization variables which underscored the uniqueness of the groups. Using IRT models with clinical diagnoses from electronic health records permitted identification of diagnostic constellations among otherwise undifferentiated high risk patients. Recognizing distinct patient profiles provides a framework from which insights into medical complexity of high-risk patients can be explored and effective interventions can be tailored. PMID- 30475825 TI - The prevalence of cardiovascular autonomic neuropathy and its influence on post induction hemodynamic variables in patients with and without diabetes; A prospective cohort study. AB - BACKGROUND: Cardiovascular autonomic neuropathy (CAN) is a known complication of diabetes, but is also diagnosed in patients without diabetes. CAN may be related to perioperative hemodynamic instability. Our objective was to investigate if patients with diabetes would have a higher prevalence of CAN compared to patients without diabetes undergoing surgery. We further studied its relation to changes in post-induction hemodynamic variables. METHODS: We prospectively included 82 adult patients, 55 with DM, 27 without DM, scheduled for major abdominal or cardiac surgery. Patients performed four autonomic function tests on the day before surgery. Primary outcomes were the prevalence of CAN and the relation between CAN and severe post-induction hypotension, defined as mean arterial pressure (MAP) < 50 mmHg or >= 50% decrease from baseline. Secondary outcomes were the relation between CAN, intraoperative hypotension, MAP < 65 mmHg for more than 13 minutes, and the use of vasopressor therapy. RESULTS: The prevalence of CAN in patients with or without DM was 71% versus 63%, (p = 0.437). CAN was not associated with severe post induction hypotension (CAN+ vs. CAN-: 21% vs. 19.2%, p = 0.819) nor with intraoperative hypotension (16% vs. 15%, p = 0.937). Patients with definite CAN received more norepinephrine in the perioperative period compared to patients with mild CAN or no CAN (0.07 mcg kg-1 min-1 (0.05-0.08) vs. 0.03 (0.01-0.07) vs. 0.02 (0.01-0.06) respectively, p = 0.001). CONCLUSIONS: The majority of patients studied had mild to moderate CAN, regardless of the presence of DM. Assessing CAN before surgery did not identify patients at risk for post induction and intraoperative hypotension in our cohort. TRIAL REGISTRATION: Dutch Trial Registry (www.trialregister.nl) NTR4976. PMID- 30475827 TI - A multi-event combination maintenance model based on event correlation. AB - Due to the complexity of large production systems, maintenance events are diverse, simultaneous and dynamic. Appropriate maintenance management of complex large production systems can guarantee high availability and save maintenance costs. However, current maintenance decision-making methods mainly focus on the maintenance events of single-components and series connection multi-components; little research pays attention to the combination maintenance of different maintenance events. Therefore, this paper proposes a multi-event combination maintenance model based on event correlation. First, the maintenance downtime and cost of three types of maintenance events under different maintenance beginning times and degrees are analysed. Then, shared maintenance downtime and cost models are established by maintenance event correlations. In addition, a multi-event combination maintenance model is constructed to achieve the goal of the highest availability and the lowest cost rate in both the decision-making cycle and the remaining life. Moreover, a particle swarm optimization algorithm based on interval segmentation for model solving is designed. Finally, a numerical example is presented to illustrate the model. PMID- 30475826 TI - Utility of the amplitude of RV1+SV5/6 in assessment of pulmonary hypertension. AB - Electrocardiogram (ECG) has been widely used for assessment of right ventricular (RV) hypertrophy (RVH) in patients with pulmonary hypertension (PH). However, it still remains unclear which ECG criteria of RVH are useful to predict for the severity of PH. The aim of our study was to examine the utility of ECG findings of RVH in assessment of PH. A total of 53 patients (42 women, mean age; 57.6 +/- 16.4 years) with pre-capillary PH, who were diagnosed by right heart catheterization, underwent blood sampling, ECG, and cardiac magnetic resonance within a week before the right heart catheterization. We assessed the traditional ECG criteria of RVH in PH patients, and compared to age- and gender-matched control subjects without PH confirmed by 2-dimensional echocardiography (n = 42, mean age 55.3 +/- 15.9 years). We also analyzed the clinical variables associated with ECG findings in patients with PH. Mean pulmonary arterial pressure (mPAP), cardiac index, and pulmonary vascular resistance (PVR) in PH patients were 35.3 +/- 11.9 mmHg, 2.82 (2.09-3.45) L/min/m2, and 576 +/- 376 dyne.sec.cm-5, respectively. The prevalence of right axis deviation (43.4%), R:S ratio V1 > 1 (32.1%), and RV1+SV5/6 > 10.5 mm (69.8%) in PH patients was greater than those in control subjects (p < 0.001). In univariate analysis, mPAP, PVR, RV wall thickness, RV mass index, RV volume, and RV ejection fraction (EF) (inversely) were significantly correlated with the amplitude of RV1+SV5/6. Multiple regression analysis revealed that mPAP and RVEF (inversely) were independently associated with the amplitude of RV1+SV5/6 (R2 = 0.282). Also, we performed the survival analysis among pre-capillary PH patients. During a mean follow-up of 3.7 years, patients with >= 16.4 mm of RV1+SV5/6 had worse prognosis than those with < 16.4 mm (Log rank p = 0.015). In conclusion, the amplitude of SV1+RV5/6 could be the most useful factor reflected for RV remodeling, hemodynamics and survival in patients with pre-capillary PH. PMID- 30475828 TI - Compensatory regrowth of the mouse bladder after partial cystectomy. AB - Cystectomy is the removal of all or part of the urinary bladder. It has been observed that there is significant regrowth of the bladder after partial cystectomy and this has been proposed to be through regeneration of the organ. Regrowth of tissue in mammals has been proposed to involve compensatory mechanisms that share many characteristics of true regeneration, like the growth of specialized structures such as blood vessels or nerves. However, the overall structure of the normal organ is not achieved. Here we tested if bladder growth after subtotal cystectomy (STC, removal of 50% of the bladder) was compensatory or regenerative. To do this we subjected adult female mouse bladders to STC and assessed regrowth using several established cellular parameters including histological, gene expression, cytokine accumulation and cell proliferation studies. Bladder function was analyzed using cystometry and the voiding stain on paper (VSOP) technique. We found that STC bladders were able to increase their ability to hold urine with the majority of volume restoration occurring within the first two weeks. Regenerating bladders had thinner walls with less mean muscle thickness, and they showed increased collagen deposition at the incision as well as throughout the bladder wall suggesting that fibrosis was occurring. Cell populations differed in their response to injury with urothelial regeneration complete by day 7, but stromal and detrusor muscle still incomplete after 8wks. Cells incorporated EdU when administered at the time of surgery and tracing of EdU positive cells over time indicated that many newborn cells originate at the incision and move mediolaterally. Basal urothelial cells and bladder mesenchymal stem cells but not smooth muscle cells significantly incorporated EdU after STC. Since anti-inflammatory cytokines play a role in regeneration, we analyzed expressed cytokines and found that no anti-inflammatory cytokines were present in the bladder 1wk after STC. Our findings suggest that bladder regrowth after cystectomy is compensatory and functions to increase the volume that the bladder can hold. This finding sets the stage for understanding how the bladder responds to cystectomy and how this can be improved in patients after suffering bladder injury. PMID- 30475829 TI - Cost-efficient strategy for reducing PM 2.5 levels in the Tokyo metropolitan area: An integrated approach with air quality and economic models. AB - To attain cleaner air, it is important that authorities make informed decisions when selecting a strategy. Concentrations of particulate matter with an aerodynamic diameter of less than or equal to 2.5 MUm (PM 2.5) are high in the Tokyo metropolitan area, even though concentrations of particulate matter with an aerodynamic diameter of less than or equal to 10 MUm (PM10) have dropped dramatically since the implementation of the NOx-PM Act. Currently, monitored concentration levels continue to exceed the designated ambient air quality standard set by the Japanese Ministry of the Environment. To our knowledge, no study has investigated a cost-efficient strategy for reducing PM 2.5 concentration levels in the Tokyo metropolitan area. This is the first study to examine a proper control strategy for Japan by developing an integrated model that includes both aerosol and economic models. The simulation results show that prefectures in the Tokyo metropolitan area cannot achieve the standards by relying on their own efforts to reduce PM 2.5. That is, prefectural governments in the Tokyo metropolitan areas need to cooperate with prefectures outside of the area to improve their PM 2.5 concentration levels. Thus, we simulated policies under the assumption that emissions from other sources are reduced to levels such that the PM 2.5 concentration declines by approximately 18 MUg/m3. We first simulated an efficient policy, i.e., the implementation of a pollution tax. We found that the total abatement cost to meet the air quality standard using the cost-efficient strategy is approximately 142.7 billion yen. PMID- 30475830 TI - A new Seasonal Difference Space-Time Autoregressive Integrated Moving Average (SD STARIMA) model and spatiotemporal trend prediction analysis for Hemorrhagic Fever with Renal Syndrome (HFRS). AB - Hemorrhagic fever with renal syndrome (HFRS) is a naturally-occurring, fecally transmitted disease caused by a Hantavirus (HV). It is extremely damaging to human health and results in many deaths annually, especially in Hubei Province, China. One of the primary characteristics of HFRS is the spatiotemporal heterogeneity of its occurrence, with notable seasonal differences. In view of this heterogeneity, the present study suggests that there is a need to focus on trend simulation and the spatiotemporal prediction of HFRS outbreaks. To facilitate this, we constructed a new Seasonal Difference Space-Time Autoregressive Integrated Moving Average (SD-STARIMA) model. The SD-STARIMA model is based on the spatial and temporal characteristics of the Space-Time Autoregressive Integrated Moving Average (STARMA) model first developed by Cliff and Ord in 1974, which has proven useful in modelling the temporal aspects of spatially located data. This model can simulate the trends in HFRS epidemics, taking into consideration both spatial and temporal variations. The SD-STARIMA model is also able to make seasonal difference calculations to eliminate temporally non-stationary problems that are present in the HFRS data. Experiments have demonstrated that the proposed SD-STARIMA model offers notably better prediction accuracy, especially for spatiotemporal series data with seasonal distribution characteristics. PMID- 30475831 TI - Investigating speech and language impairments in delirium: A preliminary case control study. AB - INTRODUCTION: Language impairment is recognized as as part of the delirium syndrome, yet there is little neuropsychological research on the nature of this dysfunction. Here we hypothesized that patients with delirium show impairments in language formation, coherence and comprehension. METHODS: This was a case-control study in 45 hospitalized patients (aged 65-97 years) with delirium, dementia without delirium, or no cognitive impairment (N = 15 per group). DSM-5 criteria were used for delirium. Speech was elicited during (1) structured conversational questioning, and (2) the "Cookie Theft" picture description task. Language comprehension was assessed through standardized verbal and written commands. Interviews were audio-recorded and transcribed. RESULTS: Delirium and dementia groups scored lower on the conversational assessment than the control group (p<0.01, moderate effect sizes (r) of 0.48 and 0.51, resp.). In the Cookie Theft task, the average length of utterances (i.e. unit of speech), indicating language productivity and fluency, distinguished patients with delirium from those with dementia (p<0.01, r = 0.50) and no cognitive impairment (p<0.01, r = 0.55). Patients with delirium performed worse on written comprehension tests compared to cognitively unimpaired patients (p<0.01, r = 0.63), but not compared to the dementia group. CONCLUSIONS: Production of spontaneous speech, word quantity, speech content and verbal and written language comprehension are impaired in delirious patients compared to cognitively unimpaired patients. Additionally, patients with delirium produced significantly less fluent speech than those with dementia. These findings have implications for how speech and language are evaluated in delirium assessments, and also for communication with patients with delirium. A study limitation was that the delirium group included patients with co-morbid dementia, which precludes drawing conclusions about the specific language profile of delirium. PMID- 30475832 TI - Comparison of chemical and microbiological changes during the aerobic composting and vermicomposting of green waste. AB - This research was conducted to compare chemical and microbiological properties during aerobic composting (AC) and vermicomposting (VC) of green waste. Relative to AC, VC significantly decreased the pH and lignin and cellulose contents, and significantly increased the electrical conductivity and total N and available P contents. For AC, BIrii41_norank (order Myxococcales) was the major bacterial genus at 30 d and again became dominant genus from 90-150 d, with relative abundances of 2.88% and 4.77-5.19%, respectively; at 45 d and 60 d, the dominant bacterial genus was Nitrosomonadaceae_uncultured (order Nitrosomonadales) with relative abundances of 2.83-7.17%. For VC, the dominant bacterial genus was BIrii41_norank (except at 45 d), which accounted for 2.11-7.96% of the total reads. The dominant fungal class was Sordariomycetes in AC (relative abundances 39.2-80.6%) and VC (relative abundances 42.1-69.5%). The abundances of microbial taxa and therefore the bacterial and fungal community structures differed between VC and AC. The quality of the green waste compost product was higher with VC than with AC. These results will also help to achieve further composting technology breakthroughs in reducing the composting time and improving compost quality. PMID- 30475833 TI - Can the use of digital algorithms improve quality care? An example from Afghanistan. AB - BACKGROUND: Quality of care is a difficult parameter to measure. With the introduction of digital algorithms based on the Integrated Management of Childhood Illness (IMCI), we are interested to understand if the adherence to the guidelines improved for a better quality of care for children under 5 years old. METHODS: More than one year after the introduction of digital algorithms, we carried out two cross sectional studies to assess the improvements in comparison with the situation prior to the implementation of the project, in two Basic Health Centres in Kabul province. One survey was carried out inside the consultation room and was based on the direct observation of 181 consultations of children aged 2 months to 5 years old, using a checklist completed by a senior physicians. The second survey queried 181 caretakers of children outside the health facility for their opinion about the consultation carried out through the tablet and prescriptions and medications given. RESULTS: We measured the quality of care as adherence to the IMCI's guidelines. The study evaluated the quality of the physical examination and the therapies prescribed with a special attention to antibiotic prescription. We noticed a dramatic improvement (p<0.05) of several indicators following the introduction of digital algorithms. The baseline physical examination was appropriate only for 23.8% [IC% 19.9-28.1] of the patients, 34.5% [IC% 30.0-39.2] received a correct treatment and 86.1% [IC% 82.4 89.2] received at least one antibiotic. With the introduction of digital algorithms, these indicators statistically improved respectively to 84.0% [IC% 77.9-88.6], >85% and less than 30%. CONCLUSIONS: Our findings suggest that digital algorithms improve quality of care by applying the guidelines more effectively. Our experience should encourage to test this tool in different settings and to scale up its use at province/state level. PMID- 30475834 TI - Transgenic zebrafish models reveal distinct molecular mechanisms for cataract linked alphaA-crystallin mutants. AB - Mutations in the small heat shock proteins alpha-crystallins have been linked to autosomal dominant cataracts in humans. Extensive studies in vitro have revealed a spectrum of alterations to the structure and function of these proteins including shifts in the size of the oligomer, modulation of subunit exchange and modification of their affinity to client proteins. Although mouse models of these mutants were instrumental in identifying changes in cellular proliferation and lens development, a direct comparative analysis of their effects on lens proteostasis has not been performed. Here, we have transgenically expressed cataract-linked mutants of alphaA- and alphaB-crystallin in the zebrafish lens to dissect the underlying molecular changes that contribute to the loss of lens optical properties. Zebrafish lines expressing these mutants displayed a range of morphological lens defects. Phenotype penetrance and severity were dependent on the mutation even in fish lines lacking endogenous alpha-crystallin. The mechanistic origins of these differences were investigated by the transgenic co expression of a destabilized human gammaD-crystallin mutant. We found that the R49C but not the R116C mutant of alphaA-crystallin drove aggregation of gammaD crystallin, although both mutants have similar affinity to client proteins in vitro. Our working model attributes these differences to the propensity of R49C, located in the buried N-terminal domain of alphaA-crystallin, to disulfide crosslinking as previously demonstrated in vitro. Our findings complement and extend previous work in mouse models and emphasize the need of investigating chaperone/client protein interactions in appropriate cellular context. PMID- 30475835 TI - Second line molecular diagnosis for bovine tuberculosis to improve diagnostic schemes. AB - Surveillance of bovine tuberculosis (bTB) is partly based on the sanitary inspection of carcasses at the abattoir to detect bTB-like lesions which, in compliance with EU recommendations, are analysed by bacteriology and histopathology to disclose Mycobacterium bovis (or M. caprae) infection. Moreover, since 2012, a PCR method with similar sensitivity and specificity values of histopathology and bacteriology respectively is additionally employed in France, partially compensating for the weaknesses of classical diagnostic methods. We analysed a collection of bTB-like lesions from cattle presenting positive histological results albeit with negative PCR results. We present here the results of these samples, recovered from 292 animals culled between 2013 and 2016, analysed with a second line molecular diagnosis approach that consists in a combination of PCRs targeting the M. tuberculosis-M. avium complexes as well as the Mycobacterium genus and sequencing of hsp65 gene. These molecular analyses disclosed to identify the presence of non-tuberculous bacteria which could be responsible for most of these non-specific TB lesions: non tuberculous mycobacteria (24%) or Actinomycetales (56%) such as Rhodococcus equi (53%); 24% of the samples were negative. M. bovis -or any other MTBC members- was neither detected by molecular methods nor isolated in any of them at the end of the 3 months of culture. In conclusion, these results highlight the lack of specificity of histopathology and the usefulness of a first line PCR with a second line molecular diagnostic test to circumvent it. This diagnostic strategy makes it possible to reduce the number of suspect bTB cases raised at the abattoir or shortening their lock-up periods. By simplifying diagnostic schemes, the use of this tool could improve bTB surveillance and make eradication programs more efficient in the future. PMID- 30475836 TI - Seasonal patterns of tuberculosis case notification in the tropics of Africa: A six-year trend analysis in Ethiopia. AB - OBJECTIVE: Seasonal variations affect the health system's functioning, including tuberculosis (TB) services, but there is little evidence about seasonal variations in TB case notification in tropical countries, including Ethiopia. This study sought to fill this gap in knowledge using TB data reported from 10 zones, 5 each from Amhara and Oromia regions. METHODS: Notified TB cases for 2010 2016 were analyzed using SPSS version 20. We calculated the quarterly and annual average TB case notification rates and the proportion of seasonal amplitudes. We applied Winters' multiplicative method of exponential smoothing to break down the original time series into seasonal, trend, and irregular components and to build a suitable model for forecasting. RESULTS: A total of 205,575 TB cases were identified (47.8% from Amhara, 52.2% from Oromia), with a male-to-female ratio of 1.2:1. The means of 8,200 (24%), 7,992 (23%), 8,849 (26%), and 9,222 (27%) TB cases were reported during July-September, October-December, January-March, and April-June, respectively. The seasonal component of our model indicated a peak in April-June and a trough in October-December. The seasonal amplitude in Amhara region is 10% greater than that of Oromia (p < 0.05). CONCLUSIONS: TB is shown to be a seasonal disease in Ethiopia, with a peak in quarter four and a low in quarter two of the fiscal year. The peak TB case notification rate corresponds with the end of the dry season in the two agrarian regions of Ethiopia. TB prevention and control interventions, such as efforts to increase community TB awareness about TB transmission and contact tracing, should consider seasonal variation. Regional variations in TB seasonality may require consideration of geographic-specific TB case-finding strategies. The mechanisms underlying the seasonal variation of TB are complex, and further study is needed. PMID- 30475837 TI - The high prevalence of myopia in Korean children with influence of parental refractive errors: The 2008-2012 Korean National Health and Nutrition Examination Survey. AB - The present study was conducted to investigate the effect of parental refractive errors on myopic children in Korean families using a nationally representative survey. We used the ophthalmologic examination dataset of the Korean National Health and Nutrition Examination Surveys IV and V, a nationwide population-based cross-sectional study using a complex, stratified, multistage, probability cluster survey, which were performed from 2008-2012. We included 3,862 children from 5-18 years of age from 2,344 families without any ocular trauma, surgical history, or cataract affecting refractive errors. The generalized estimating equation was conducted to assess the association of refractive errors among children and their parents. Among 3,862 children, 2,495 had myopia, which was 64.6% prevalence. There were 208 children with high myopia (5.4%). The prevalence rate ratio (PRR) for pediatric myopia and high myopia with myopic parents was 1.34 (95% confidence intervals [CI] 1.24-1.45) and 3.11 (95% CI 1.93-5.01), respectively. The PRR of myopia and high myopia in children significantly increased to 1.37 (95% CI 1.04-1.81) and 11.41 (95% CI 6.24-20.88), as the degree of parental myopia increased (P < 0.001, respectively). Children with two myopic parents were more myopic than those with only one myopic parent (P < 0.001, respectively). In addition to parental myopia, the age of the child and household income were also significant risk factors for all degrees of pediatric myopia in a family (P <= 0.005, respectively). In conclusion, Korean children showed high prevalence of myopia. Children with myopic parents showed a significantly greater risk for myopia and high myopia. PMID- 30475838 TI - Glucocorticoid receptor-regulated TcLEC2 expression triggers somatic embryogenesis in Theobroma cacao leaf tissue. AB - Theobroma cacao, the source of cocoa, is a crop of particular importance in many developing countries. Availability of elite planting material is a limiting factor for increasing productivity of Theobroma cacao; therefore, the development of new strategies for clonal propagation is essential to improve farmers' incomes and to meet increasing global demand for cocoa. To develop a more efficient embryogenesis system for cacao, tissue was transformed with a transgene encoding a fusion of Leafy Cotyledon 2 (TcLEC2) to a glucocorticoid receptor domain (GR) to control nuclear localization of the protein. Upon application of the glucocorticoid dexamethasone (dex), downstream targets of LEC2 involved in seed development were up-regulated and somatic embryos (SEs) were successfully regenerated from TcLEC2-GR transgenic flower and leaf tissue in large numbers. Immature SEs regenerated from TcLEC2-GR leaves were smaller in size than immature SEs from floral tissue, suggesting a different ontogenetic origin. Additionally, exposure of TcLEC2-GR floral explants to dex increased the number of SEs compared to floral explants from control, non-transgenic trees or from TcLEC2-GR floral explants not treated with dex. Testing different durations of exposure to dex indicated that a three-day treatment produced optimal embryo regeneration. Leaf derived SEs were successfully grown to maturity, converted into plants, and established in the greenhouse, demonstrating that these embryos are fully developmentally competent. In summary, we demonstrate that regulating TcLEC2 activity offers a powerful new strategy for optimizing somatic embryogenesis pipelines for cacao. PMID- 30475839 TI - Uncovered variability in olive moth (Prays oleae) questions species monophyly. AB - The olive moth -Prays oleae Bern.- remains a significant pest of olive trees showing situation dependent changes in population densities and in severity of damages. The genetic variability of olive moth was assessed on three main olive orchards regions in Portugal by three different markers (COI, nad5 and RpS5), suggesting high species diversity albeit with no obvious relation with a regional pattern nor to an identified ecological niche. Selected COI sequences obtained in this study were combined with those available in the databases for Prays genus to generate a global dataset. The reconstruction of the Prays phylogeny based on this marker revealed the need to revise Prays oleae to confirm its status of single species: COI data suggests the co-existence of two sympatric evolutionary lineages of morphologically cryptic olive moth. We show, however, that the distinct mitochondrial subdivision observed in the partial COI gene fragment is not corroborated by the other DNA sequences. There is the need of understanding this paradigm and the extent of Prays variability, as the disclosure of lineage specific differences in biological traits between the identified lineages is fundamental for the development of appropriate pest management practices. PMID- 30475841 TI - Perceptions of HIV transmission and pre-exposure prophylaxis among health care workers and community members in Rwanda. AB - There are too many new HIV infections globally with 1.8 million persons infected in 2016 alone. Pre-exposure prophylaxis (PrEP) holds potential to decrease new infections and is synergistic with efforts currently in place to achieve an end to the AIDS epidemic in Sub-Saharan African, but uptake is limited. Given its novelty, assessing the beliefs and attitudes of healthcare professionals and members of the community towards HIV transmission and PrEP will be helpful to inform implementation efforts. Study was a random survey of 201 community members and 51 healthcare providers, carried out at multiple community sites in Huye district, Southern Province, Rwanda and at Kigali University Teaching Hospital (KUTH). The study findings are that there are still misconceptions about HIV in the community with some respondents believing that HIV is due to punishment from God (5.4%), poverty (3.0%), smoking cigarettes (1.0%), drinking alcohol (2.0%), punishment from ancestors (1.0%) and witchcraft (1.5%), and that its transmission is by mosquito bites (10.9%), sharing food or drinks with a HIV infected person (6.5%) or as a result of carelessness (47.8%). More than 50% of respondents from both groups had insufficient knowledge regarding PrEP, but expressed some interest in PrEP (82.6% of the respondents from the community and 86.5% of the health workers). However, some healthcare workers felt that promotion of safe sex practices (74.5%), HIV testing and treating HIV infected patients (60.8%) would work better than PrEP to decrease new HIV infections. Barriers to PrEP implementation included perceived stigma, delayed access to prevention services at the health facilities while personal-level concerns included lack of family support, reluctance to take a medication daily and fear of being perceived as having HIV. This study showed that health care workers and community members are willing to utilize PrEP in Rwanda, but many challenges exist including limited knowledge about PrEP, stigma, provider and system level service delivery barriers at health facilities among others. More studies are needed to assess ways of addressing and /or eliminating these barriers. PMID- 30475840 TI - Warmth and competence predict overoptimistic beliefs for out-group but not in group members. AB - People can be overly optimistic not only about their own future but also for the people with whom they identify. Furthermore, interpersonal perception generally forms along two universal dimensions, i.e. warmth and competence. In this study, we created four fictional characters that would map onto each quadrant of the two dimensional space of warmth and competence, i.e. one in-group member (high on both warmth and competence) and three out-group members (high warmth, low competence; high competence, low warmth; low on both warmth and competence). We then asked respondents to assess the likelihood of each character experiencing a series of identical desirable and undesirable events in order to uncover potential optimistic biases. Our study had two goals. First, we wanted to balance the target desirable and undesirable events on four key characteristics, i.e. event frequency, controllability, emotional intensity and personal experience with the event. Second, we wanted to investigate whether stereotypes of warmth and competence could influence the respondents' likelihood estimates for each character. We show that respondents manifested a strong desirability bias, expecting more desirable than undesirable events for the in-group member and the reverse pattern for the extreme out-group member. More important, we show that, within desirable and undesirable events, respondents anchored their judgments for the in-group member on their personal experience with the target events, further revealing an egocentric bias, but turned to stereotypical knowledge in the form of warmth and competence to judge out-group members. Implications for both social perception and optimism research are discussed. PMID- 30475842 TI - The structure and morphologic changes of antennae of Cyrtorhinus lividipennis (Hemiptera: Miridae: Orthotylinae) in different instars. AB - Cyrtorhinus lividipennis Reuter (Hemiptera: Miridae: Orthotylinae), including nymphs and adults, are one of the dominant predators and have a significant role in the biological control of leafhoppers and planthoppers in irrigated rice. In this study, we investigated the antennal morphology, structure and sensilla distribution of C. lividipennis in different instars using scanning electron microscopy. The antennae of both five different nymphal stages and adults were filiform in shape, which consisted of the scape, pedicel and flagellum with two flagellomeres. There were significant differences found in the types of antennal sensilla between nymphs and adults. The multiporous placodea sensilla (MPLA), basiconica sensilla II (BAS II), and sensory pits (SP) only occurred on the antennae of adult C. lividipennis of both sexes. Moreover, there was chaetica sensilla III (CHA III) only observed in males. Sixteen types of antennal sensilla were recorded altogether. They were microtrichia sensilla (MIC), three types of trichoidea sensilla (TRI I-III), three types of chaetica sensilla (CHA I-III), three types of basiconica sensilla (BAS I-III), two types of coeloconica sensilla (COE I and COE II), placodea sensilla (PLA), campaniform sensilla (CAM), MPLA, and SP. In the five different nymphal stages of C. lividipennis, the length of their antennae was significantly increased with the increase of the instar, as well as the number of the TRI II and TRI III. Moreover, sexual dimorphism usually occurred not only in the distribution (CHA III and SP) and the number of antennal sensilla (MIC, BAS II, TRI II, TRI III and MPLA), but also in the length of flagellum (F1 and F2). The possible functions of antennal sensilla are discussed. Those observations could contribute to a better understanding of the development of the olfactory system, and facilitate future studies on the antennal functions in C. lividipennis. PMID- 30475843 TI - Three-dimensional non-parametric method for limbus detection. AB - PURPOSE: To present a novel non-parametric algorithm for detecting the position of the human eye limbus in three dimensions and a new dynamic method for measuring the full 360 degrees visible iris boundary known as white-to-white distance along the eye horizontal line. METHODS: The study included 88 participants aged 23 to 65 years (37.7+/-9.7), 47 females and 41 males. Clinical characteristics, height data and the apex coordinates and 1024*1280 pixel digital images of the eyes were taken by an Eye Surface Profiler and processed by custom built MATLAB codes. A dynamic light intensity frequency based white-to-white detection process and a novel three-dimensional method for limbus detection is presented. RESULTS: Evidence of significant differences (p<0.001) between nasal temporal and superior-inferior white-to-white distances in both right and left eyes were found (nasal-temporal direction; 11.74+/-0.42 mm in right eyes and 11.82+/-0.47 mm in left eyes & superior-inferior direction; 11.52+/-0.45 mm in right eyes and 11.55+/-0.46 mm in left eyes). Average limbus nasal-temporal diameters were 13.64+/-0.55 mm for right eyes, and 13.74+/-0.40 mm for left eyes, however the superior-inferior diameters were 13.65+/-0.54 mm, 13.75+/-0.38 mm for right and left eyes, respectively. No significant difference in limbus contours has been observed either between the nasal-temporal direction (p = 0.91) and the superior-inferior direction (p = 0.83) or between the right (p = 0.18) and left eyes (p = 0.16). Evidence of tilt towards the nasal-temporal side in the three dimensional shape of the limbus was found. The right eyes mean limbus contour tilt around the X-axis was -0.3+/-1.35 degrees however, their mean limbus contour tilt around the Y-axis was 1.76+/-0.9 degrees . Likewise, the left eyes mean limbus contour tilt around the X-axis was 0.77+/-1.25 degrees and the mean limbus contour tilt around the Y-axis was -1.54+/-0.89 degrees . CONCLUSIONS: The white-to-white distance in the human eye is significantly larger in the nasal temporal direction than in the superior-inferior direction. The human limbus diameter was found not to vary significantly in these directions. The 3D measures show that the limbus contour does not lay in one plane and tends to be higher on the nasal-inferior side of the eye. PMID- 30475844 TI - The effect of emotion on morphosyntactic learning in foreign language learners. AB - Emotions have crucial influence on vocabulary learning and text comprehension. However, whether morphosyntactic learning is influenced by emotional conditions has remained largely unclear. In this study, we investigated how induced positive and negative emotions affect the learning of morphosyntactic rules in a foreign language. It was found that negative emotion increased the accuracy and efficiency of syntactic learning, but had no significant effect on the learning of morphological marking rules. Positive emotion was not found to be significantly associated with learning outcomes. The findings shed light on the effects of affective states on the structural aspects of foreign language learning. PMID- 30475845 TI - Optimal duration of DAPT after second-generation drug-eluting stent in acute coronary syndrome. AB - BACKGROUND: We evaluated optimal duration of dual antiplatelet therapy (DAPT) after second-generation drug-eluting stent (DES) implantation in acute coronary syndrome (ACS). MATERIAL AND METHODS: From pooled analysis of three randomized clinical trials (EXCELLENT, IVUS-XPL, RESET), a total of 2,216 patient with ACS undergoing second-generation DES implantation were selected. Each study randomized patients to a short-duration DAPT arm (n = 1119; <=6 months) or a standard-duration DAPT arm (n = 1097; >=12 months). Two-thirds of patients were male, and their mean age was 63 years. Mean DAPT durations were 164 +/-76 and 359 +/-68 days, respectively. The primary endpoint was composite of cardiac death, myocardial infarction, stent thrombosis, stroke or major bleeding during the first 12 months after implantation, analyzed according to the intention-to-treat population. RESULTS: Demographic characteristics were balanced between groups. Mean DAPT duration was 164 and 359 days, respectively. Primary endpoint occurred in 22 patients with short-DAPT and 21 patients with standard-DAPT (2.0% versus 1.9%; hazard ratio [HR] 1.03; 95% confidence interval [CI] 0.56-1.86; p = 0.94). Landmark analysis after six-months, no significant difference in primary endpoint between short and standard duration DAPT (1.0% versus 0.8%; HR 1.22; 95% CI 0.51 2.95; p = 0.66). CONCLUSIONS: Short-duration DAPT (<=6 months) demonstrated a similar incidence of net adverse cardiovascular and clinical events at 12 months after second-generation DES in ACS compared with standard duration DAPT (>=12 months). CLINICAL TRIAL REGISTRATION: EXCELLENT (ClinicalTrials.gov, NCT00698607), RESET (ClinicalTrials.gov, NCT01145079), IVUS-XPL (ClinicalTrials.gov, NCT01308281). PMID- 30475846 TI - Daily rhythms influence the ability of lung-derived extracellular vesicles to modulate bone marrow cell phenotype. AB - Extracellular vesicles (EVs) are important mediators of intercellular communication and have been implicated in myriad physiologic and pathologic processes within the hematopoietic system. Numerous factors influence the ability of EVs to communicate with target marrow cells, but little is known about how circadian oscillations alter EV function. In order to explore the effects of daily rhythms on EV-mediated intercellular communication, we used a well established model of lung-derived EV modulation of the marrow cell transcriptome. In this model, co-culture of whole bone marrow cells (WBM) with lung-derived EVs induces expression of pulmonary specific mRNAs in the target WBM. To determine if daily rhythms play a role in this phenotype modulation, C57BL/6 mice were entrained in 12-hour light/12-hour dark boxes. Lungs harvested at discrete time points throughout the 24-hour cycle were co-cultured across a cell-impermeable membrane with murine WBM. Alternatively, WBM harvested at discrete time-points was co-cultured with lung-derived EVs. Target WBM was collected 24hrs after co culture and analyzed for the presence of pulmonary specific mRNA levels by RT PCR. In both cases, there were clear time-dependent variations in the patterns of pulmonary specific mRNA levels when either the daily time-point of the lung donor or the daily time-point of the recipient marrow cells was altered. In general, WBM had peak pulmonary-specific mRNA levels when exposed to lung harvested at Zeitgeber time (ZT) 4 and ZT 16 (ZT 0 defined as the time of lights on, ZT 12 defined as the time of lights off), and was most susceptible to lung-derived EV modulation when target marrow itself was harvested at ZT 8- ZT 12. We found increased uptake of EVs when the time-point of the receptor WBM was between ZT 20 -ZT 24, suggesting that the time of day-dependent changes in transcriptome modulation by the EVs were not due simply to differential EV uptake. Based on these data, we conclude that circadian rhythms can modulate EV-mediated intercellular communication. PMID- 30475847 TI - eDRAM: Effective early disease risk assessment with matrix factorization on a large-scale medical database: A case study on rheumatoid arthritis. AB - Recently, a number of analytical approaches for probing medical databases have been developed to assist in disease risk assessment and to determine the association of a clinical condition with others, so that better and intelligent healthcare can be provided. The early assessment of disease risk is an emerging topic in medical informatics. If diseases are detected at an early stage, prognosis can be improved and medical resources can be used more efficiently. For example, if rheumatoid arthritis (RA) is detected at an early stage, appropriate medications can be used to prevent bone deterioration. In early disease risk assessment, finding important risk factors from large-scale medical databases and performing individual disease risk assessment have been challenging tasks. A number of recent studies have considered risk factor analysis approaches, such as association rule mining, sequential rule mining, regression, and expert advice. In this study, to improve disease risk assessment, machine learning and matrix factorization techniques were integrated to discover important and implicit risk factors. A novel framework is proposed that can effectively assess early disease risks, and RA is used as a case study. This framework comprises three main stages: data preprocessing, risk factor optimization, and early disease risk assessment. This is the first study integrating matrix factorization and machine learning for disease risk assessment that is applied to a nation-wide and longitudinal medical diagnostic database. In the experimental evaluations, a cohort established from a large-scale medical database was used that included 1007 RA-diagnosed patients and 921,192 control patients examined over a nine-year follow-up period (2000-2008). The evaluation results demonstrate that the proposed approach is more efficient and stable for disease risk assessment than state-of-the-art methods. PMID- 30475849 TI - Spore morphology and its systematic implication in Pteris (Pteridaceae). AB - Pteris (Pteridaceae) spores are usually trilete and can be distinguished by the perine ornamentation. The systematic value of spore morphology in Pteris is unclear, especially based on the renewed infrageneric classification of Pteris. In the present study, we used scanning electron microscopy (SEM) to understand spore characters in 57 Pteris species, one Onychium species, and two Astrolepis species; 40 species are reported here for the first time. The observed spore characters combined with published spore data, totaling 100 species from 16 sections of Pteris, were mapped onto a reconstructed phylogenetic tree. Seven characters (five proposed in previous studies), including an equatorial flange, laesural ridges, proximal ridges, distal ridges, tubercula on distal faces, coarse reticula on distal faces, and a row of extervermiculi between the distal face and equatorial flange, were analyzed to investigate spore morphology evolution in Pteris. However, the results showed no synapomorphies with other genera in Pteridaceae. Most of the characters were found to have arisen independently several times in different lineages or were even frequently reversed. Equatorial flanges and tubercula on distal faces are plesiomorphies and present in most Pteris species. Overall, the application of spore morphology in section circumscription is limited. Thus, we suggest combining spore morphology with leaf characters for Pteris infrageneric classification. PMID- 30475848 TI - Non-Markovian intracellular transport with sub-diffusion and run-length dependent detachment rate. AB - Intracellular transport of organelles is fundamental to cell function and health. The mounting evidence suggests that this transport is in fact anomalous. However, the reasons for the anomaly is still under debate. We examined experimental trajectories of organelles inside a living cell and propose a mathematical model that describes the previously reported transition from sub-diffusive to super diffusive motion. In order to explain super-diffusive behaviour at long times, we introduce non-Markovian detachment kinetics of the cargo: the rate of detachment is inversely proportional to the time since the last attachment. Recently, we observed the non-Markovian detachment rate experimentally in eukaryotic cells. Here we further discuss different scenarios of how this effective non-Markovian detachment rate could arise. The non-Markovian model is successful in simultaneously describing the time averaged variance (the time averaged mean squared displacement corrected for directed motion), the mean first passage time of trajectories and the multiple peaks observed in the distributions of cargo velocities. We argue that non-Markovian kinetics could be biologically beneficial compared to the Markovian kinetics commonly used for modelling, by increasing the average distance the cargoes travel when a microtubule is blocked by other filaments. In turn, sub-diffusion allows cargoes to reach neighbouring filaments with higher probability, which promotes active motion along the microtubules. PMID- 30475850 TI - Three months of slackline training elicit only task-specific improvements in balance performance. AB - Slackline training is a challenging and motivating type of balance training, with potential usefulness for fall prevention and balance rehabilitation. However, short-term slackline training seems to elicit mostly task-specific performance improvements, reducing its potential for general fall prevention programs. It was tested whether a longer duration slackline training (three months, 2 sessions per week) would induce a transfer to untrained tasks. Balance performance was tested pre and post slackline training on the slackline used during the training, on a slackline with different slack, and in 5 different non-trained static and dynamic balance tasks (N training = 12, N control = 14). After the training, the training group increased their performance more than the control group in both of the slackline tasks, i.e. walking on the slackline (time * group interaction with p < 0.001 for both tasks). However, no differences between groups were found for the 5 non-trained balance tasks, only a main effect of time for four of them. The long-term slackline training elicited large task-specific performance improvements but no transfer to other non-trained balance tasks. The extensive slackline training that clearly enhanced slackline performance did not improve the capability to keep balance in other tasks and thus cannot be recommended as a general fall prevention program. The significant test-retest effect seen in most of the tested tasks emphasizes the need of a control group to adequately interpret changes in performance following balance training. PMID- 30475851 TI - Men's perspectives on the impact of female-directed cash transfers on gender relations: Findings from the HPTN 068 qualitative study. AB - BACKGROUND: HIV is an inherently gendered disease in eastern and southern Africa, not only because more women than men are infected, but also because socially constructed gender norms work to increase women's HIV-infection risk. The provision of cash transfers to young women alone in such a context adds another dimension to already existing complex social relations where patriarchal values are entrenched, gender inequality is the norm, and violence against women and girls is pervasive. It raises concerns about complicating young women's relationships with their male partners or possibly even setting them up for more violence. In our attempt to understand how cash transfers influence social relations in the context of a trial among young women in South Africa, we used qualitative data collected during the trial to explore men's perceptions of the impact of cash transfers on male-female relationships, both intimate and platonic, peer relationships. METHOD: Between April 2012 and August 2015, we conducted focus group discussions (n = 12) and interviews (n = 20) with the male peers and intimate partners of young women aged 13-20 years, who were participating in a phase III randomised controlled trial of CTs for HIV prevention in Mpumalanga, South Africa. A thematic content analysis approach was used to analyse the data. The codebook was developed on the basis of the topic guides, with additional codes added inductively as they emerged from the data. RESULTS: Intimate partners were older (range 20-32 years) and more likely to be working than the male peers. Both intimate partners and male peers were supportive of the CT trial targeting young women; younger peers however expressed some concerns that the money might diminish their power and status in relationships. HIV testing requirements associated with the trial appeared to have improved communication about sex and HIV in intimate relationships, with some women even encouraging their partners to go for an HIV test. CONCLUSION: CTs provide AGYW with a measure of autonomy and power to contribute in their gendered relationships, albeit in limited ways. However, there is potential for CTs to have a negative impact on male-female relationships if the cash received by AGYW is equal to or greater than the income earned by their male counterparts or sexual partners. PMID- 30475853 TI - The influence of depth and a subsea pipeline on fish assemblages and commercially fished species. AB - Knowledge of marine ecosystems that grow and reside on and around subsea oil and gas infrastructure is required to understand impacts of this offshore industry on the marine environment and inform decommissioning decisions. This study used baited remote underwater stereo-video systems (stereo-BRUVs) to compare species richness, fish abundance and size along 42.3 km of subsea pipeline and in adjacent areas of varying habitats. The pipeline is laid in an onshore-offshore direction enabling surveys to encompass a range of depths from 9 m nearshore out to 140 m depth offshore. Surveys off the pipeline were performed across this depth range and in an array of natural habitats (sand, macroalgae, coral reef) between 1 km and 40 km distance from the pipeline. A total of 14,953 fish were observed comprising 240 species (131 on the pipeline and 225 off-pipeline) and 59 families (39 on the pipeline and 56 off-pipeline) and the length of 8,610 fish were measured. The fish assemblage on and off the pipeline was similar in depths of <80 m. In depths beyond 80 m, the predominant habitat off-pipeline was sand and differences between fish assemblages on and off-pipeline were more pronounced. The pipeline was characterised by higher biomass and abundances of larger-bodied, commercially important species such as: Pristipomoides multidens (goldband snapper), Lutjanus malabaricus (saddletail snapper) and Lutjanus russellii (Moses' snapper) among others, and possessed a catch value 2-3 times higher per stereo-BRUV deployment than that of fish observed off-pipeline. Adjacent natural seabed habitats possessed higher abundances of Atule mate (yellowtail scad), Nemipterus spp. (threadfin bream) and Terapon jarbua (crescent grunter), species of no or low commercial value. This is the first published study to use stereo-BRUVs to report on the importance of subsea infrastructure to commercially important fishes over a depth gradient and increases our knowledge of the fish assemblage associated with subsea infrastructure off north-west Australia. These results provide a greater understanding of ecological and fisheries implications of decommissioning subsea infrastructure on the north-west shelf, and will help better inform decision-making on the fate of infrastructure at different depths. PMID- 30475852 TI - Interleukin-27 as a candidate diagnostic biomarker for bacterial infection in immunocompromised pediatric patients. AB - BACKGROUND: Immunocompromised pediatric patients constitute a growing population that is particularly vulnerable to bacterial infection, necessitating prompt recognition and treatment. This study assessed the utility of interleukin-27 (IL 27) and procalcitonin (PCT) as biomarkers of bacterial infection among immunocompromised pediatric subjects. METHODS: This is a single-center prospective cohort study conducted from July 2016 through September 2017, drawing subjects from the inpatient units at Cincinnati Children's Hospital Medical Center (CCHMC), a large, tertiary care children's hospital. Patients were included if they fit the definition of immunocompromised and were under clinical suspicion for infection, defined by the acquisition of a blood culture at any point during the admission. The primary analysis assessed the accuracy of IL-27 to diagnose bacterial infection in immunocompromised pediatric patients, using PCT as a comparator. RESULTS: 293 patients were recruited, representing 400 episodes of suspected bacterial infection. The median age was 7.8 years (IQR 3.1 13.8 years). Fifty-three percent (n = 213) of the population had a primary oncologic diagnosis, 24% (n = 95) had received a bone marrow transplant, and 21% (n = 85) had received a solid organ transplant. The overall infection rate was 37%, with 70% of those patients having some form of culture positivity. Twenty eight-day mortality was 5%, 60-day mortality was 9%, with 87% of patients surviving to hospital discharge. The AUC's of the ROC curve to diagnose bacterial infection were 0.62 (0.5-0.68) for IL-27 and 0.65 (0.6-0.73) for PCT. Using the previously determined cutoff of 5.0 ng/mL, the specificity of IL-27 to diagnose bacterial infection reached 94%, with a negative predictive value of 64%. CONCLUSIONS: Despite prior work demonstrating IL-27 and PCT as possible biomarkers of bacterial infection in immunocompromised pediatric patients, we were unable to validate these findings. This illustrates the challenges associated with developing reliable biomarkers of bacterial infection in this vulnerable population. PMID- 30475855 TI - Molecular modelling and simulation studies of the Mycobacterium tuberculosis multidrug efflux pump protein Rv1258c. AB - Mycobacterial efflux pumps play a major role in the emergence of antimycobacterial drug resistance. Of particular interest is the proteinaceous multi-drug efflux pump protein Rv1258c that encodes a tetracycline/aminoglycoside resistance (TAP-2)-like efflux pump which is active in susceptible and drug resistant Mycobacterium tuberculosis. Rv1258c is implicated in drug resistance to numerous antimycobacterials including first line drugs rifampicin and isoniazid as well as fluoroquinolone and aminoglycoside antibiotic classes. To date, compounds like verapamil and piperine have been shown to inhibit Rv1258c but no direct evidence for binding or mode of action exist. Therefore in the present study we generated an accurate 3D model of Rv1258c using MODELLER and validated its structure using molecular dynamic simulation studies with GROMACS software. The 3D-structures of Rv1258c and the homologous template 1pw4 were simulated within a POPE/POPG lipid bilayer and found to behave similar. Another important finding was the identification of one local energy minima state of the apo protein, which speaks to the flexibility of the protein and will be investigated further. Extraction of one of the open channel conformations of Rv1258c and blind docking of various structurally diverse putative inhibitors and substrates, allowed for the identification of a probable binding site. Spectinamide was found to bind to a different location on the outside surface of the protein suggesting its ability to avoid the efflux channel. We further identified 246 putative compounds that showed higher binding affinity values to Rv1258c compared to piperine and verapamil. Interaction analysis of the top 20 purchasable compounds identified crucial hydrogen bond interactions with Ser26, Ser45 and Glu243 as well as a pi-pi stacking interaction with Trp32 that accounted for the strong affinity of these compounds for Rv1258c. Future studies will entail purchasing a number of compounds for in vitro activity testing against Mycobacterium tuberculosis. PMID- 30475854 TI - CSF macrophage migration inhibitory factor levels did not predict steroid treatment response after optic neuritis in patients with multiple sclerosis. AB - Glucocorticoid (GC) refractory relapses in patients with multiple sclerosis (MS) or clinically isolated syndrome (CIS), who are in potential need of treatment escalation, are a key challenge in routine clinical practice. The pro inflammatory cytokine macrophage migration inhibitory factor (MIF) has been shown to be an endogenous counter-regulator of GC, and potentiates autoimmune-mediated neuroinflammation. In order to evaluate whether MIF levels are elevated in the cerebrospinal fluid (CSF) of MS patients (CSF-MIF), and whether they are higher still during a GC refractory relapse, we compared CSF-MIF concentrations of CIS/MS patients with acute optic neuritis as their first inflammatory episode (ON, n = 20), CIS/MS patients with a stable disease progression/without relapse (CIS/MS w/o, n = 18), and healthy controls (HC, n = 20) using ANOVA. Mean CSF-MIF concentrations in CIS/MS w/o patients were significantly higher than in ON patients and HCs, whereas ON patients and HCs did not differ. A subgroup analysis of the ON group revealed 10 patients to be responsive to GC-treatment (GC-ON) and 10 patients refractory under GC-treatment (rGC-ON). However, mean CSF-MIF concentrations did not differ between GC-ON and rGC-ON cases. We therefore conclude that MIF is not suitable for distinguishing GC responders from non responders in a group of patients with acute optic neuritis, but it rather mirrors the ongoing inflammation in long-term MS disease progression. PMID- 30475856 TI - The effect of inactin on kidney mitochondrial function and production of reactive oxygen species. AB - Inactin is a long lasting anesthetic agent commonly used in rat studies, but is also shown to exert physiological effects such as reducing renal blood flow, glomerular filtration rate and depressing tubular transport capacity. The effect of inactin on isolated kidney mitochondria is unknown and may be important when studying related topics in anaesthetized animals. The aim of this study was to determine whether inactin exerts effects on mitochondrial function and production of reactive oxygen species. Kidney mitochondrial function and production of reactive oxygen after acutely (5 min) or longer (1.5 hour) anesthetizing rats with inactin was evaluated using high-resolution respirometry. The results demonstrate that inactin significantly improves respiratory control ratio, inhibits complex I in the mitochondrial respiratory chain, reduce both unregulated proton leak and time dependently reduce the regulated proton leak via uncoupling protein-2 and adenine nucleotide translocase. Inactin also contributes to increased mitochondrial hydrogen peroxide production. In conclusion, inactin exerts persistent effects on mitochondrial function and these profound effects on mitochondrial function should to be considered when studying mitochondria isolated from animals anesthesized with inactin. PMID- 30475857 TI - From skepticism to assurance and control; Implementation of a patient safety system at a pediatric hospital in Sweden. AB - BACKGROUND: The use of evidence-based practice among healthcare professionals directly correlates to better outcomes for patients and higher professional satisfaction. Translating knowledge in practice and mobilizing evidence-based clinical care remains a continuing challenge in healthcare systems across the world. PURPOSE: To describe experiences from the implementation of an Early Detection and Treatment Program for Children (EDT-C) among health care professionals at a pediatric hospital in Sweden. DESIGN AND METHODS: Sixteen individual interviews were conducted with physicians, nurses and nurse assistants, which of five were instructors. Data were analyzed with qualitative content analysis. RESULTS: An overarching theme was created: From uncertainty and skepticism towards assurance and control. The theme was based on the content of eight categories: An innovation suitable for clinical practice, Differing conditions for change, Lack of organizational slack, Complex situations, A pragmatic implementation strategy, Delegated responsibility, Experiences of control and Successful implementation. CONCLUSIONS: Successful implementation was achieved when initial skepticism among staff was changed into acceptance and using EDT-C had become routine in their daily work. Inter-professional education including material from authentic patient cases promotes knowledge about different professions and can strengthen teamwork. EDT-C with evidenced-based material adapted to the context can give healthcare professionals a structured and objective tool with which to assess and treat patients, giving them a sense of control and assurance. PMID- 30475858 TI - Thought leader perspectives on benefits and harms in precision medicine research. AB - Precision medicine research is underway to identify targeted approaches to improving health and preventing disease. However, such endeavors raise significant privacy and confidentiality concerns. The objective of this study was to elucidate the potential benefits and harms associated with precision medicine research through in-depth interviews with a diverse group of thought leaders, including primarily U.S.-based experts and scholars in the areas of ethics, genome research, health law, historically-disadvantaged populations, informatics, and participant-centric perspectives, as well as government officials and human subjects protections leaders. The results suggest the prospect of an array of individual and societal benefits, as well as physical, dignitary, group, economic, psychological, and legal harms. Relative to the way risks and harms are commonly described in consent forms for precision medicine research, the thought leaders we interviewed arguably emphasized a somewhat different set of issues. The return of individual research results, harm to socially-identifiable groups, the value-dependent nature of many benefits and harms, and the risks to the research enterprise itself emerged as important cross-cutting themes. Our findings highlight specific challenges that warrant concentrated care during the design, conduct, dissemination, and translation of precision medicine research and in the development of consent materials and processes. PMID- 30475859 TI - MRI-related anxiety in healthy individuals, intrinsic BOLD oscillations at 0.1 Hz in precentral gyrus and insula, and heart rate variability in low frequency bands. AB - Participation in magnetic resonance imaging (MRI) scanning is associated with increased anxiety, thus possibly impacting baseline recording for functional MRI studies. The goal of the paper is to elucidate the significant hemispheric asymmetry between blood-oxygenation-level-dependent (BOLD) signals from precentral gyrus (PCG) and insula in 23 healthy individuals without any former MRI experience recently published in a PLOSONE paper. In addition to BOLD signals state anxiety and heart rate variability (HRV) were analyzed in two resting state sessions (R1, R2). Phase-locking and time delays from BOLD signals were computed in the frequency band 0.07-0.13 Hz. Positive (pTD) and negative time delays (nTD) were found. The pTD characterize descending neural BOLD oscillations spreading from PCG to insula and nTD characterize ascending vascular BOLD oscillations related to blood flow in the middle cerebral artery. HRV power in two low frequency bands 0.06-0.1 Hz and 0.1-0.14 Hz was computed. Based on the anxiety change from R1 to R2, two groups were separated: one with a strong anxiety decline (large change group) and one with a moderate decline or even anxiety increase (small change group). A significant correlation was found only between the left-hemispheric time delay (pTD, nTD) and anxiety change, with a dominance of nTD in the large change group. The analysis of within-scanner HRV revealed a pronounced increase of low frequency power between both resting states, dominant in the band 0.06-0.1 Hz in the large change group and in the band 0.1-0.14 Hz in the small change group. These results suggest different mechanisms related to anxiety processing in healthy individuals. One mechanism (large anxiety change) could embrace an increase of blood circulation in the territory of the left middle cerebral artery (vascular BOLD) and another (small anxiety change) translates to rhythmic central commands (neural BOLD) in the frequency band 0.1 0.14 Hz. PMID- 30475862 TI - Two-point-based binary search trees for accelerating big data classification using KNN. AB - Big data classification is very slow when using traditional machine learning classifiers, particularly when using a lazy and slow-by-nature classifier such as the k-nearest neighbors algorithm (KNN). This paper proposes a new approach which is based on sorting the feature vectors of training data in a binary search tree to accelerate big data classification using the KNN approach. This is done using two methods, both of which utilize two local points to sort the examples based on their similarity to these local points. The first method chooses the local points based on their similarity to the global extreme points, while the second method chooses the local points randomly. The results of various experiments conducted on different big datasets show reasonable accuracy rates compared to state-of-the art methods and the KNN classifier itself. More importantly, they show the high classification speed of both methods. This strong trait can be used to further improve the accuracy of the proposed methods. PMID- 30475860 TI - Parameters of visual processing abnormalities in adults with body image concerns. AB - Body dysmorphic disorder (BDD), at the extreme end of the body image concern (BIC) spectrum, is thought to be associated with a local (detail-focussed) visual processing bias. Given that the inversion of a stimulus disrupts holistic processing and demands detail-specific attention, this perceptual bias is characterised by superior processing of such inverted stimuli. This study examined the processing bias, via a body-inversion discrimination task, of 26 participants with non-clinical, high-BIC (Dysmophic Concern Questionnaire (DCQ) scores between 11-19) and 26 participants with low-BIC (DCQ scores between 0-4). This study also explored the impact of varying stimuli presentation durations and discrimination difficulties during the inversion task on visual processing. As hypothesised, compared to those with low-BIC, participants with high-BIC demonstrated superior accuracy when discriminating between images of inverted bodies, indicating a local processing bias. Also as hypothesised, this local processing bias selectively manifested only when stimuli were presented for longer durations and at higher discrimination difficulties, revealing the parameters of this, potentially conscious, processing tendency. Consistent with previous research, this study identified a local processing bias in those with high BIC, which may be a predisposing factor for developing BDD. In turn, identifying the parameters (stimulus exposure and stimulus complexity) in which the local bias manifests has implications for future interventions aiming to reverse this perceptual abnormality. PMID- 30475861 TI - Respiratory pathogens and their association with population performance in Montana and Wyoming bighorn sheep populations. AB - Respiratory disease caused by Mycoplasma ovipneumoniae and Pasteurellaceae poses a formidable challenge for bighorn sheep (Ovis canadensis) conservation. All-age epizootics can cause 10-90% mortality and are typically followed by multiple years of enzootic disease in lambs that hinders post-epizootic recovery of populations. The relative frequencies at which these epizootics are caused by the introduction of novel pathogens or expression of historic pathogens that have become resident in the populations is unknown. Our primary objectives were to determine how commonly the pathogens associated with respiratory disease are hosted by bighorn sheep populations and assess demographic characteristics of populations with respect to the presence of different pathogens. We sampled 22 bighorn sheep populations across Montana and Wyoming, USA for Mycoplasma ovipneumoniae and Pasteurellaceae and used data from management agencies to characterize the disease history and demographics of these populations. We tested for associations between lamb:ewe ratios and the presence of different respiratory pathogen species. All study populations hosted Pasteurellaceae and 17 (77%) hosted Mycoplasma ovipneumoniae. Average lamb:ewe ratios for individual populations where both Mycoplasma ovipneumoniae and Pasteurellaceae were detected ranged from 0.14 to 0.40. However, average lamb:ewe ratios were higher in populations where Mycoplasma ovipneumoniae was not detected (0.37, 95% CI: 0.27 0.51) than in populations where it was detected (0.25, 95% CI: 0.21-0.30). These findings suggest that respiratory pathogens are commonly hosted by bighorn sheep populations and often reduce recruitment rates; however ecological factors may interact with the pathogens to determine population-level effects. Elucidation of such factors could provide insights for management approaches that alleviate the effects of respiratory pathogens in bighorn sheep. Nevertheless, minimizing the introduction of novel pathogens from domestic sheep and goats remains imperative to bighorn sheep conservation. PMID- 30475863 TI - PPE17 (Rv1168c) protein of Mycobacterium tuberculosis detects individuals with latent TB infection. AB - Latent tuberculosis infection (LTBI) is a clinically distinct category of Mycobacterium tuberculosis (Mtb) infection that needs to be diagnosed at the initial stage. We have reported earlier that one of the Mtb proline-proline glutamic acid (PPE) proteins, PPE17 (Rv1168c) is associated with stronger B-cell and T-cell responses and could be used to diagnose different clinical categories of active TB patients with higher specificity and sensitivity than PPD and ESAT 6. Based on these observations we further tested the potential of PPE17 for the diagnosis of LTBI. We tested 198 sera samples collected from LTBI individuals (n = 61), QFT-negative (n = 58) and active TB patients (n = 79). Individuals were defined as LTBI by QuantiFERON-TB Gold In-Tube test (QFT-GIT) positive results, while active TB patients were confirmed based on the guidelines of the Revised National TB Control Programme of India. The antibody responses against PPE17, ESAT-6:CFP-10 and PPD were compared in these subjects by enzyme-linked immunosorbent assay. We observed that LTBI individuals show a higher sero reactivity to PPE17 as compared to currently used latent TB diagnostic antigens like ESAT-6, CFP-10 and PPD. The LTBI and active TB patients display almost similar sensitivity. Interestingly, PPE17 could discriminate LTBI positive subjects from the QFT-negative subjects (P < 0.001). Our study hints that PPE17 may be used as a novel serodiagnostic marker to screen the latently infected subjects and may also be used as a complimentary tool to the QFT-GIT. PMID- 30475864 TI - Accounting for environmental and observer effects in estimating abundance of southern bluefin tuna from aerial survey data. AB - Southern bluefin tuna (SBT) is a valuable species that has been subject to high exploitation rates since the 1950s. In 2011, the spawning stock biomass was estimated to be at a historically low level, at only 5% of pre-fished biomass. A key component for managing and rebuilding the stock is having reliable, fishery independent estimates of juvenile abundance. This paper describes how such estimates have been constructed from aerial surveys of juvenile (age 2-4) SBT conducted annually in the Great Australian Bight from 1993-2000 and 2005-2009. During these surveys, observers flew along pre-set transect lines searching for surface schools of SBT. Data were collected on the location and biomass of SBT sightings, and on the environmental conditions present during the survey. Sea surface temperature (SST) was found to correlate with the size (biomass) of schools, and several environmental variables, SST and wind speed in particular, were found to correlate with the number of sightings (presumably by affecting the ability of observers to see surface schools as well as whether fish were present at the surface). In addition, observers changed over time and differed in their aptitude for spotting tuna. Thus, generalized linear mixed models (GLMMs) were used to standardize the sightings and biomass data to a common set of observers and environmental conditions in order to produce an annual time series of relative abundance estimates. These estimates, which form one of two key inputs to the management procedure used by the international Commission for the Conservation of Southern Bluefin Tuna to set the global catch quota, suggest juvenile abundance was highest in the first years of the survey (1993-1996), after which it declined and fluctuated around a level about four times lower. PMID- 30475865 TI - Impact of "test and treat" recommendations on eligibility for antiretroviral treatment: Cross sectional population survey data from three high HIV prevalence countries. AB - BACKGROUND: Latest WHO guidelines recommend starting HIV-positive individuals on antiretroviral therapy treatment (ART) regardless of CD4 count. We assessed additional impact of adopting new WHO guidelines. METHODS: We used data of individuals aged 15-59 years from three HIV population surveys conducted in 2012 (Kenya) and 2013 (Malawi and South Africa). Individuals were interviewed at home followed by rapid HIV and CD4 testing if tested HIV-positive. HIV-positive individuals were classified as "eligible for ART" if (i) had ever been initiated on ART or (ii) were not yet on ART but met the criteria for starting ART based on country's guidelines at the time of the survey (Kenya-CD4< = 350 cells/MUl and WHO Stage 3 or 4 disease, Malawi as for Kenya plus lifelong ART for all pregnant and breastfeeding women, South Africa as for Kenya plus ART for pregnant and breastfeeding women until cessation of breastfeeding). FINDINGS: Of 18,991 individuals who tested, 4,113 (21.7%) were HIV-positive. Using country's ART eligibility guidelines at the time of the survey, the proportion of HIV-infected individuals eligible for ART was 60.0% (95% CI: 57.2-62.7) (Kenya), 73.4% (70.8 75.8) (South Africa) and 80.1% (77.3-82.6) (Malawi). Applying WHO 2013 guidelines (eligibility at CD4< = 500 and Option B+ for pregnant and breastfeeding women), the proportions eligible were 82.0% (79.8-84.1) (Kenya), 83.7% (81.5-85.6) (South Africa) and 87.6% (85.0-89.8) (Malawi). Adopting "test and treat" would mean a further 18.0% HIV-positive individuals (Kenya), 16.3% (South Africa) and 12.4% (Malawi) would become eligible. In all countries, about 20% of adolescents (aged 15-19 years), became eligible for ART moving from WHO 2013 to "test and treat" while no differences by sex were observed. CONCLUSION: Countries that have already implemented 2013 WHO recommendations, the burden of implementing "test and treat" would be small. Youth friendly programmes to help adolescents access and adhere to treatment will be needed. PMID- 30475866 TI - Patterns of salinity regime in coastal lakes based on structure of benthic invertebrates. AB - The macrozoobenthic diversity patterns along a brackish-freshwater salinity gradient have been identified, considering effects of differences in the level of hydrological connection of coastal lakes with the sea on the structure of benthic invertebrate communities. The study is based on samples from six coastal lakes located along the southern coast of the Baltic Sea in Poland. The analysis of environmental and biological data confirmed the existence of stable phases (brackish water vs. freshwater), but as a result of periodical intrusion of seawater, adaptation of animal communities takes place, which was reflected in low values of the predictors describing them (number of taxa, density and diversity). Redundancy analysis indicates that values of conductivity and salinity are the major factors that determine the abundance of dominant groups of benthic fauna. The gradient of hydrological connection of the lakes with the sea accounted for 50% of the variance in biological data, physico-chemical variables for 25%, trophic variables for 15%, and only 9% of the variance was unexplained. The major implication of our results is that coastal lakes that differ only slightly in salinity can have alternative, regional patterns of diversity of structure of benthic fauna. Periodical inflow of brackish waters initiates adaptive cycles of benthic fauna, and their frequency is strongly linked with the hydrological regime. The rhythm of the inflow of seawater is variable, so that management and protection of coastal lakes are extremely complicated. PMID- 30475868 TI - The UK Research Excellence Framework and the Matthew effect: Insights from machine learning. AB - With the high cost of the research assessment exercises in the UK, many have called for simpler and less time-consuming alternatives. In this work, we gathered publicly available REF data, combined them with library-subscribed data, and used machine learning to examine whether the overall result of the Research Excellence Framework 2014 could be replicated. A Bayesian additive regression tree model predicting university grade point average (GPA) from an initial set of 18 candidate explanatory variables was developed. One hundred and nine universities were randomly divided into a training set (n = 79) and test set (n = 30). The model "learned" associations between GPA and the other variables in the training set and was made to predict the GPA of universities in the test set. GPA could be predicted from just three variables: the number of Web of Science documents, entry tariff, and percentage of students coming from state schools (r squared = .88). Implications of this finding are discussed and proposals are given. PMID- 30475867 TI - Bioactive nanoparticle-based formulations increase survival area of perforator flaps in a rat model. AB - BACKGROUND: Distal flap necrosis is a frequent complication of perforator flaps. Advances in nanotechnology offer exciting new therapeutic approaches. Anti inflammatory and neo-angiogenic properties of certain metal oxides within the nanoparticles, including bioglass and ceria, may promote flap survival. Here, we explore the ability of various nanoparticle formulations to increase flap survival in a rat model. MATERIALS AND METHODS: A 9 x 3 cm dorsal flap based on the posterior thigh perforator was raised in 32 Lewis rats. They were divided in 4 groups and treated with different nanoparticle suspensions: I-saline (control), II-Bioglass, III-Bioglass/ceria and IV-Zinc-doped strontium-substituted bioglass/ceria. On post-operative day 7, planimetry and laser Doppler analysis were performed to assess flap survival and various samples were collected to investigate angiogenesis, inflammation and toxicity. RESULTS: All nanoparticle treated groups showed a larger flap survival area as compared to the control group (69.9%), with groups IV (77,3%) and II (76%) achieving statistical significance. Blood flow measurements by laser Doppler analysis showed higher perfusion in the nanoparticle-treated flaps. Tissue analysis revealed higher number of blood vessels and increased VEGF expression in groups II and III. The cytokines CD31 and MCP-1 were decreased in groups II and IV. CONCLUSIONS: Bioglass-based nanoparticles exert local anti-inflammatory and neo-angiogenic effects on the distal part of a perforator flap, increasing therefore its survival. Substitutions in the bioglass matrix and trace metal doping allow for further tuning of regenerative activity. These results showcase the potential utility of these nanoparticles in the clinical setting. PMID- 30475869 TI - Importance of neuropsychological screening in physicians referred for performance concerns. AB - INTRODUCTION: The literature suggests that 6-12% of practicing physicians are dyscompetent. Dyscompetence can manifest as failures in direct provision of care, but also issues with interpersonal and communications skills and professionalism. There is a growing literature suggesting the value of neurocognitive screening in physicians with clinical competency issues. The contribution of such screening in physicians with workplace behavioral issues is not as established. The aim of this exploratory study was to examine patterns of performance on a commonly used neuropsychological screening instrument. Performances differences, if present, could have implications for remediation and/or monitoring. METHODS: Published data on a computerized neurocognitive screening instrument (MicroCog) for normative physician samples, published data on physicians referred for clinical competency issues, and newly collected data on physicians with workplace behavioral issues were analyzed. A two-way analysis of variance (Sample X Index) and post-hoc paired comparisons were conducted. A second analysis was performed employing an aggregated estimate of normative physician performance. RESULTS: Results revealed a significant main effect for Sample and Index and a significant interaction effect. The second analysis of variance employing the pooled samples (Sample X Index) was conducted. The workplace behavior issues sample differed significantly from each of the samples. The Sample by Index interaction was significant. DISCUSSION: Significant differences in performance on a neurocognitive screening instrument were found between non-referred physicians and physicians with behavioral or medical/technical competency concerns. Those with workplace behavioral issues performed significantly better than those with medical/technical issues, but significantly worse than non-referred physicians. Using these findings, 2.0% of the normal sample versus 35.1% of the medical/technical sample, and 10.9% of the behavioral sample would fail the screen using typical, conservative cutoffs. Further study of the potential role of neurocognitive factors in physicians referred for behavioral comportment issues is warranted. PMID- 30475870 TI - Quantifying the complexity of black-and-white images. AB - We propose a complexity measure for black-and-white (B/W) digital images, based on the detection of typical length scales in the depicted motifs. Complexity is associated with diversity in those length scales. In this sense, the proposed measure penalizes images where typical scales are limited to small lengths, of a few pixels -as in an image where gray levels are distributed at random- or to lengths similar to the image size -as when gray levels are ordered into a simple, broad pattern. We introduce a complexity index which captures the structural richness of images with a wide range of typical scales, and compare several images with each other on the basis of this index. Since the index provides an objective quantification of image complexity, it could be used as the counterpart of subjective visual complexity in experimental perception research. As an application of the complexity index, we build a "complexity map" for South American topography, by analyzing a large B/W image that represents terrain elevation data in the continent. Results show that the complexity index is able to clearly reveal regions with intricate topographical features such as river drainage networks and fjord-like coasts. Although, for the sake of concreteness, our complexity measure is introduced for B/W images, the definition can be straightforwardly extended to any object that admits a mathematical representation as a function of one or more variables. Thus, the quantification of structural richness can be adapted to time signals and distributions of various kinds. PMID- 30475871 TI - Psychotropic use patterns: Are there differences between men and women? AB - This study analyzed differences between men and women regarding the use of psychotropic drugs and associated factors in a population of adults and seniors in the city of Campinas, Brazil. A population-based, cross-sectional study was conducted using data from the ISACamp 2014/2015 health survey in the city of Campinas. The sample was composed of 1999 individuals aged 20 years or older. For each sex, prevalence rates and prevalence ratios were estimated for the use of psychotropic drugs according to demographic characteristics, socioeconomic characteristics, health problems, degree of limitation and type of emotional/mental problem. The most used classes of medications were also determined. The prevalence of the use of psychotropic drugs was 11.7% (7.3% among men and 15.8% among women). The most common therapeutic classes were antidepressants (38.2%) and benzodiazepines (24.0%). The frequency of antidepressant use was higher among women (44.3%) than men (25.5%). Regarding associated factors, reports of emotional/mental problems were associated with the greater use of this type of drug in both sexes. Among the men, white skin color, a lack of an occupational activity, a greater number of complaints of health problems and the occurrence of insomnia were associated with the use psychotropic drugs. Among the women, a significant increase in the use of these drugs was found with the increase in age and higher prevalence rates were found among those with a higher level of schooling, those with a greater number of diagnosed chronic diseases and those with a common mental disorder. The present results confirm the greater use of psychotropic agents, especially antidepressants, in the female sex and reveal that the pattern of associated factors differs between sexes. It is therefore necessary to understand the peculiarities of each sex that exert an influence on the perception of health problems and the desire to seek care, which, in turn, affect the use of psychotropic agents. PMID- 30475872 TI - Animacy cues facilitate 10-month-olds' categorization of novel objects with similar insides. AB - In this experiment, we examined whether sensitivity to the relevance of object insides for the categorization of animate objects is in place around 10 months of age. Using an object examining paradigm, 10-month-old infants' (N = 58) were familiarized to novel objects with varying outward appearances but shared insides in one of three groups: No cues, Eyes, and Cue control. During test trials, infants were presented with a novel in-category test object followed by an out-of category test object. When objects were presented with animacy cues (i.e., Eyes), infants categorized the objects together. In contrast, when objects were presented without any added cues or when they were presented with a shared perceptual marker (Cue control, i.e., plastic spoons placed on top of the objects), infants showed no evidence of categorization. These results indicate that by 10 months of age, eyes signal to infants that objects share some kind of uniting commonality that may not be obvious or readily perceptually available. PMID- 30475873 TI - AMP-activated protein kinase regulates the expression of human telomerase reverse transcriptase. AB - The expression of hTERT in tumor cells contributes to oncogenic transformation by promoting immortalization. For this reason, hTERT is one of the major targets for cancer therapy, and an efficient method to downregulate hTERT expression is required for treatment of hTERT-positive cancer. In this report, we demonstrated that inhibition of AMP-activated protein kinase (AMPK) downregulates the expression of hTERT. We screened cell signaling pathways in AMPK alpha1 knockout cells and found that AMPKalpha1 is required for activity of the hTERT promoter. AMPKalpha1 knockout cells showed decreased expression of hTERT mRNA and protein. We also demonstrated that compound C, a reversible AMPK inhibitor, suppressed the expression of hTERT. However, AMPK activators, including AICAR and metformin, did not increase the level of hTERT protein. Finally, we showed that tumor cells stably expressing hTERT are resistant to compound C treatment. These results indicate that AMPK activity is required for tumor progression. PMID- 30475874 TI - The longitudinal trajectory of body mass index in the Chinese population: A latent growth curve analysis. AB - AIMS: The objective of this study was to investigate the longitudinal trajectory of BMI in the Chinese population, and to assess whether the gender or other personal characteristics were related to BMI, and whether there was a change in trajectory over time. METHODS: Data were obtained from 3,574 Chinese (5 to 89 years of age) who participated in the 2000-2011 of the China Health and Nutrition Survey. Latent growth curve models were used to investigate the longitudinal trajectory of BMI, and to examine the effect of some personal characteristics on BMI trajectory. RESULTS: The linear model resulted in a mean initial BMI value of 22.90 and a significant mean slope (Ms = 0.19, t = 10.73, p<0.001), suggesting a steady increase in BMI over time for the whole sample. For covariates, the educational level, alcohol and physical activity had differences on initial scores for BMI (beta = 0.05, p<0.001; beta = -0.12, p<0.05; beta = -0.08, p<0.05; respectively.), and the age had differences on both the initial scores and slope for BMI (beta = 0.01, p = <0.05; beta = -0.03, p<0.01; respectively.). Baseline measures revealed gender-associated differences on initial scores for BMI, and the slope for male was significantly steeper than that for female (beta = -0.11, p<0.05). The initial BMI status of Chinese living in the rural areas was significantly higher than that of Chinese living in the urban areas, and the slope for rural status was significantly steeper than that for urban status (beta = 0.21, p<0.001). CONCLUSIONS: Results indicated a linear trajectory of BMI in the Chinese population over a 12-year period. The longitudinal trajectories differed by age, gender and urban-rural status, suggesting different interventions should be adopted for different groups. PMID- 30475875 TI - Risk factors for diarrhoea and malnutrition among children under the age of 5 years in the Tigray Region of Northern Ethiopia. AB - BACKGROUND: Diarrhoea and malnutrition are the leading cause of morbidity and mortality among children in areas with poor access to clean water, improved sanitation, and with low socioeconomic status. This study was designed to determine the prevalence of diarrhoea, malnutrition and risk factors among children aged 6-59 months in the Tigray Region of Northern Ethiopia. METHODS: A community based cross-sectional study design was conducted from June to August 2017 to assess the magnitude and factors associated with diarrhoea and malnutrition among children. A standardized questionnaire was used to collect data on diarrhoea, environmental, demographic and behavioural factors from 610 mother-child pairs. Anthropometric measurements were collected from the children. SPSS ver.21 statistical software was used for analysis. Factors associated with diarrhoea and nutritional status were identified using bivariate and multivariate logistic regression. A p-value <= 0.05 was considered statistically significant. RESULTS: Of the 610 children monitored in this study, the incidence of diarrhoea among 6-59 month-old children in the two weeks preceding the day of the interview day was 27.2% (95% CI: 23.6-31%). Specifically, 35.9%, 9.7%, and 1.8% had 1-2, 3 4 and 5-6 times of diarrhoea episodes in a one year of time, respectively. The prevalence of stunting, underweight, wasting, and acute under-nutrition were 36.1% (95% CI: 31-38.6%), 37% (95% CI: 32-39.6%), 7.9% (95% CI: 5.5-9.7%), and 5.4% (95% CI: 3.8-7.4%), respectively. In a multivariate logistic regression analysis, type of drinking water source [AOR = 3.69; 95% CI: 2.03-6.71], mothers not hand washing at critical times [AOR = 15.42; 95% CI: 2.02-117.78], improper solid waste disposal [AOR = 12.81; 95% CI: 2.50-65.62], and child age (36-47 months) [AOR = 2.57; 95% CI: 1.45-4.55] were found to be predictors of diarrhoea. Being within the age range of 12-23 months was a predictor for wasting [AOR = 4.38; 95% CI: 1.61-11.90] and being underweight [AOR = 4.4; 95% CI: 1.7-11.2]. Similarly, the age range of 36-47 months was associated with wasting [AOR = 2.3; 95% CI: 1.45-3.85] and stunting [AOR = 1.7; 95% CI: 1.03-2.67]. Family size (less than 4) [AOR = 0.56; 95% CI: 0.368-0.959] was inversely associated for wasting. CONCLUSIONS: Our study revealed that the problem of diarrhoea and malnutrition amongst 6-59 months children in the study area was significant. Access to clean water was the main problem in the study area. Hence, improving access to clean water and providing health education to mothers on personal and environmental hygiene, and proper waste disposal could improve diarrhoea in the study area. Intervention on children's nutrition should also be implemented to minimize the problem of malnutrition. PMID- 30475877 TI - Repeated elevated plus maze trials as a measure for tracking within-subjects behavioral performance in rats (Rattus norvegicus). AB - The elevated plus maze (EPM) is routinely used in neuroscience research to evaluate emotional behavior in rodents by measuring general exploratory performance and avoidance of the aversive open arms of the maze. According to standard practice, behavior on the EPM is evaluated during a single trial to avoid the possibility of habituation to the apparatus that would result in lost sensitivity of key outcome measures. However, this possibility has not been systematically evaluated across repeated trials or across different environmental conditions. In the current study, we assessed within-subject behavior on the EPM in adult male rats over thirteen trials (tested twice weekly) repeated under identical conditions. We also assessed within-subject behavior on the EPM in adult male rats under dim (1 lux in the closed arm) and lit (246 lux in the closed arm) environmental conditions. We found that measures of general performance (basic movements and total distanced travelled throughout the maze) were stable across repeated trials and environmental conditions. We found that measures of open arm avoidance (distance travelled in, time spent in and entries in to the open arm) varied across trials and environmental conditions and were sensitive to the lighting conditions of the initial test. Though measures of open arm avoidance did show a linear trend indicative of habituation across repeated trials, this effect was variable across trials. Notably, preference for the open arm over the closed arm (measured as % of time spent in the open arm) assessed among individual animals occurred rarely and was never observed on the group level across the thirteen repeated trials. Together, these data demonstrate that measures of general performance such as basic movements and total distance traveled are robust to repeated testing and changing environmental lighting conditions. In contrast, measures of open arm avoidance show habituation with repeated testing and are sensitive to changing environmental lighting conditions. Based on these results, we suggest that within-subjects repeated testing on the EPM is valid in well-controlled studies that include an untreated control group to account for inter-trial variability and habituation. PMID- 30475876 TI - Population-based e-records to evaluate HPV triage of screen-detected atypical squamous cervical lesions in Catalonia, Spain, 2010-15. AB - Equivocal lesions (ASC-US) are common abnormalities in cervical cancer screening exams. HPV testing helps to stratify the risk of progression to high-grade squamous intraepithelial lesions or more (HSIL+). Population-based medical electronic data can be used to evaluate screening recommendations. The study uses routine electronic data from primary health centers to estimate the impact of HPV testing in a 3- and a 5-year risk of HSIL+ after an ASC-US. The study includes data derived from medical electronic information from 85,775 women who first attended a cervical cancer screening visit at the National Health System facilities of Catalonia, Spain, during 2010-11 and followed up to 2015. Included women were aged between 25-65 years old, having at least one follow-up visit, and a cervical cytology of ASC-US (N = 1,647). Women with a first result of low-grade squamous intraepithelial lesions (LSIL) (N = 945) or those with negative cytology (N = 83,183) were included for comparison. Those with a baseline HSIL+ were excluded. Incident HSIL+ was evaluated by means of Kaplan-Meier curves and multivariate regression models. HPV test results were available for 63.4% of women with a baseline ASC-US. Among all ASC-US, 70 incident HSIL+ were identified at 5 years. ASC-US HPV positive women had a high risk of HSIL+ compared to women with negative cytology (adjusted HR = 32.7; 95% CI: 23.6-45.2) and a similar risk to women with baseline LSIL (HR = 29.3; 95% CI: 22.4-38.2), whereas ASC-US HPV negative women had no differential risk to that observed in baseline negative cytology. Women with ASC-US and no HPV test had an average HSIL+ risk (HR = 14.8; 95% CI: 9.7-22.5). Population-based e-medical records derived from primary health care centers allowed monitoring of screening recommendations, providing robust estimates for the study outcomes. This analysis confirms that HPV testing improved risk stratification of ASC-US lesions. The information can be used to improve diagnosis and management of screen detected lesions. PMID- 30475878 TI - Product authenticity versus globalisation-The Tulsi case. AB - Using the Indian medicinal plant Tulsi (Holy Basil) as a case study, we have tested to what extent the discrepancy between vernacular and scientific nomenclature can be resolved, whether the presumed chemical diversity underlying the medicinal use of Tulsi has a genetic component, and whether it is possible to detect this genetic component using genetic barcoding markers. Based on four plastidic markers, we can define several haplotypes within Ocimum that are consistent across these markers. Haplotype II is congruent with O. tenuiflorum, while haplotype I extends over several members of the genus and cannot be resolved into genetically separate subclades. The vernacular subdivision of Tulsi into three types (Rama, Krishna, Vana) can only be partially linked with genetic differences-whereby Rama and Krishna Tulsi can be assigned to O. tenuiflorum, while Vana Tulsi belongs to haplotype I. This genetic difference is mirrored by differences in the profiles of secondary compounds. While developmental state and light quality modulate the amplitude to which the chemical profile is expressed, the profile itself seems to be linked with genetic differences. We finally develop an authentication assay that makes use of a characteristic single nucleotide polymorphism in one of the barcoding markers, establishing a differential restriction pattern that can be used to discriminate Vana Tulsi. PMID- 30475880 TI - Low handgrip strength is closely associated with chronic low back pain among women aged 50 years or older: A cross-sectional study using a national health survey. AB - OBJECT: This study aimed to analyze the association between low handgrip strength (HGS) and low back pain (LBP) according to physical activity (PA) in the general population aged over 50 years. METHODS: Nationwide health surveys and examinations were performed in a cross-sectional representative of the Korean general population (n = 7,550 in 2014, n = 7,380 in 2015). Chronic LBP status was determined by self-reported survey responses with respect to the occurrence of LBP for more than 30 days during the previous 3 months. Maximal HGS was determined as the maximal strength of the dominant hand, and low HGS was defined as measurement in the lower 20th percentile of HGS measurements for the general population. High PA was defined as muscle-strengthening exercise for at least 3 days within 1 week. Demographics, medical history, and other variables were used to analyze adjusted weighted logistic regression models with propensity score matching. After propensity score matching, 429 participants were included in each group. RESULTS: Analysis was confined to those aged 50-89 years who responded to the chronic LBP survey and had no missing data on HGS. Low HGS and LBP showed significant association in the crude logistic regression model. In the multiple logistic regression model, after adjusting for confounding factors, low HGS was significantly associated with LBP in women with low PA (adjusted odds ratio [aOR]: 1.75, p = 0.047). In the logistic regression model after propensity score matching, low HGS was also significantly related to LBP in women with low PA (aOR: 3.12, p = 0.004). CONCLUSIONS: Our study showed the relationship between low HGS and LBP using a cross-sectional Korean population-based health survey. Low HGS in women aged over 50 years with low PA was significantly associated with the presence of LBP. PMID- 30475879 TI - Antibiotic-resistant indicator bacteria in irrigation water: High prevalence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. AB - Irrigation water is a major source of fresh produce contamination with undesired microorganisms including antibiotic-resistant bacteria (ARB), and contaminated fresh produce can transfer ARB to the consumer especially when consumed raw. Nevertheless, no legal guidelines exist so far regulating quality of irrigation water with respect to ARB. We therefore examined irrigation water from major vegetable growing areas for occurrence of antibiotic-resistant indicator bacteria Escherichia coli and Enterococcus spp., including extended-spectrum beta lactamase (ESBL)-producing E. coli and vancomycin-resistant Enterococcus spp. Occurrence of ARB strains was compared to total numbers of the respective species. We categorized water samples according to total numbers and found that categories with higher total E. coli or Enterococcus spp. numbers generally had an increased proportion of respective ARB-positive samples. We further detected high prevalence of ESBL-producing E. coli with eight positive samples of thirty six (22%), while two presumptive vancomycin-resistant Enterococcus spp. were vancomycin-susceptible in confirmatory tests. In disk diffusion assays all ESBL producing E. coli were multidrug-resistant (n = 21) and whole-genome sequencing of selected strains revealed a multitude of transmissible resistance genes (ARG), with blaCTX-M-1 (4 of 11) and blaCTX-M-15 (3 of 11) as the most frequent ESBL genes. Overall, the increased occurrence of indicator ARB with increased total indicator bacteria suggests that the latter might be a suitable estimate for presence of respective ARB strains. Finally, the high prevalence of ESBL producing E. coli with transmissible ARG emphasizes the need to establish legal critical values and monitoring guidelines for ARB in irrigation water. PMID- 30475881 TI - Patterns of weight change associated with disease diagnosis in a national sample. AB - BACKGROUND: The incidence and/or diagnosis of a major disease may activate weight change. Patterns of weight change associated with diagnoses have not been systematically documented. METHODS: We use data on adults ages 30+ in the National Health and Nutrition Examination Survey (NHANES) from 1999-2014. Self reported current weight and weight one year prior are used to estimate percent weight change in the last year. We use self-reported data on arthritis, diabetes, cancer, cardiovascular disease, liver conditions, and respiratory disease diagnoses to compare weight change among individuals never diagnosed with these conditions, individuals diagnosed 0-1 years ago, and individuals diagnosed 2+ years ago. Multinomial logistic regressions adjust for the presence of multiple conditions. RESULTS: 17.7% of the adult population experienced weight loss of 5.0% or more in the year prior to survey. Individuals diagnosed with any of the conditions were less likely to maintain their weight than those without a diagnosis. Arthritis, diabetes, cancer, cardiovascular disease, and liver conditions were associated with net weight loss, whereas respiratory diseases were associated with higher probabilities of both losing and gaining weight. Among those losing 10% or more, 56.7% had been diagnosed with one of the conditions. Cancer was associated with the highest probability of unintentional weight loss and diabetes with the highest probability of intentional weight loss. CONCLUSIONS: Disease-associated weight changes leave a distinct imprint on patterns of weight change in the population. Individuals losing at least 10% of their weight in the last year have likely been diagnosed with one of the six conditions. PMID- 30475884 TI - Resistance to an eriophyid mite in an interspecific hybrid pedigree of Populus. AB - Schizoempodium mesophyllincola is an eriophyid mite that feeds in leaves of Populus trichocarpa in the central part of this cottonwood tree's range (i.e., coastal British Columbia, Washington and Oregon) in the Pacific Northwest (PNW) of North America, and on some interspecific hybrids planted in short-rotation, intensive forestry in the region. The mite, a leaf vagrant, sucks the contents of spongy mesophyll cells, causing leaf discoloration, or "bronzing." Here, we investigate the inheritance pattern of resistance to leaf bronzing using a three generation Populus trichocarpa x P. deltoides hybrid pedigree. We found that resistance to the mite is an exaptation in that its source in two related F2 families of the TxD hybrid pedigree was the non-native host, P. deltoides. Two grandparental genotypes of the latter, 'ILL-5' and 'ILL-129', were completely free of the bronzing symptom and that phenotype was inherited in a Mendelian manner in the F1 and F2. Resistance to S. mesophyllincola is similar to resistance to many other regional pathogens of P. trichocarpa (e.g., Melampsora occidentalis, Venturia inopina, Sphaerulina populicola, and Taphrina sp.) in that it is inherited from the non-native grandparent (e.g., P. deltoides, P. nigra, or P. maximowiczii) in three-generation, hybrid pedigrees. In addition to finding evidence for Mendelian inheritance, we found two QTLs with LOD scores 5.03 and 3.12 mapped on linkage groups (LG) III and I, and they explained 6.7 and 4.2% of the phenotypic variance, respectively. The LG I QTL is close to, or synonymous with, one for resistance to sap-feeding arthropods and leaf developmental traits as expressed in a British study utilizing the same pedigree. PMID- 30475882 TI - Epidemiological analysis of maternal deaths in Hunan province in China between 2009 and 2014. AB - BACKGROUND: The control of maternal deaths continues to be a significant public health issue and commands an enormous amount of attention, especially under the future family planning policy. Here, we describe the epidemiology and trends of maternal deaths in Hunan province, and give several policy implications. METHODS: Maternal deaths in Hunan province between 2009 and 2014 were retrospectively reviewed and analyzed. Cochran-Armitage trend test was used to assess the time trends of maternal mortality rates. Binary logistic regression analyses were undertaken to identify the factors that were associated with unavoidable maternal deaths. RESULTS: In total, there were 987 maternal deaths, with the overall MMR declining by 45.24%. The most common causes of maternal death during this period were pregnancy complications (28.37%), obstetric hemorrhage (25.33%), and amniotic fluid embolism (15.70%). Obstetric hemorrhage (28.14%) was higher in rural areas, while pregnancy complications were higher (29.27%) in urban areas. In all, 627 (63.5%) deaths were avoidable. The risk factors associated with unavoidable maternal deaths was above 35 years (aOR = 1.80 95%CI: 1.27-2.55), without prenatal examination (aOR = 8.97 95%CI: 1.11-7.78), low household incomes (aOR = 1.15 95%CI: 1.02-1.29), without adopting the new way to deliver (aOR = 5.15 95%CI: 3.20-8.31), and death location (aOR = 1.09 95%CI: 1.02-1.18). The most frequent and important factors associated with avoidable deaths was improper knowledge and skills of the county medical institutions. CONCLUSIONS: Moderate progress was made in reducing the MMR in Hunan province. The government should aim to improve the basic midwifery skills in rural areas and the obstetric emergency rescue service for critically ill pregnant women in urban areas, and strengthen training to improve knowledge and skills in medical institutions in counties. PMID- 30475883 TI - Dexamethasone protects retinal ganglion cells but not Muller glia against hyperglycemia in vitro. AB - Diabetic retinopathy (DR) is a common complication of diabetes, for which hyperglycemia is a major etiological factor. It is known that retinal glia (Muller cells) and retinal ganglion cells (RGCs) are affected by diabetes, and there is evidence that DR is associated with neural degeneration. Dexamethasone is a glucocorticoid used to treat many inflammatory and autoimmune conditions, including several eye diseases like DR. Thus, our goal was to study the effect of dexamethasone on the survival of RGCs and Muller glial cells isolated from rat retinas and maintained in vitro under hyperglycemic conditions. The behavior of primary RGC cell cultures, and of mixed RGC and Muller cell co-cultures, was studied in hyperglycemic conditions (30 mM glucose), both in the presence and absence of Dexamethasone (1 MUM). RGC and Muller cell survival was evaluated, and the conditioned media of these cultures was collected to quantify the inflammatory cytokines secreted by these cells using a multiplex assay. The role of IL-1beta, IL-6 and TNFalpha in RGC death was also evaluated by adding these cytokines to the co-cultures. RGC survival decreased significantly when these cells were grown in high glucose conditions, reaching 54% survival when they were grown alone and only 33% when co-cultured with Muller glia. The analysis of the cytokines in the conditioned media revealed an increase in IL-1beta, IL-6 and TNFalpha under hyperglycemic conditions, which reverted to the basal concentration in co-cultures maintained in the presence of dexamethasone. Finally, when these cytokines were added to co-cultures they appeared to have a direct effect on RGC survival. Hence, these cytokines could be implicated in the death of RGCs when glucose concentrations increase and dexamethasone might protect RGCs from the cell death induced in these conditions. PMID- 30475885 TI - Validity of ultrasonography to assess hepatic steatosis compared to magnetic resonance spectroscopy as a criterion method in older adults. AB - BACKGROUND: The rising prevalence of obesity has made hepatic steatosis an increasingly common issue. Ultrasound is generally used in clinical practice to assess steatosis, but its accuracy has been inconsistent across studies. We aimed to determine the validity of ultrasound to diagnose hepatic steatosis when compared to the criterion method proton magnetic resonance spectroscopy (MRS) in older individuals. METHODS: A total of 72 healthy white European individuals (n = 42 men; n = 30 women aged 67-76 years) participating in the Hertfordshire Birth Cohort Physical Activity trial had hepatic steatosis assessed by ultrasound and MRS. The ultrasound scans were graded as normal, mild, moderate and severe steatosis, while hepatic fat content above 5.5% by MRS was used as a cut-off for steatosis. RESULTS: 18 participants (25%) had a level of hepatic fat measured by MRS consistent with diagnosis of steatosis. The sensitivity and specificity of ultrasound in diagnosing hepatic steatosis (mild/moderate/severe vs normal) were 96% (95% CI: 87-99.6%) and 94% (95% CI: 73-100%) respectively, although overlap in MRS hepatic fat content was observed between the ultrasound categories. CONCLUSIONS: Ultrasound is a valid method for detecting the presence or absence of hepatic steatosis in older adults and can be used as an alternative tool in both clinical investigations and epidemiological studies, when other imaging techniques are not feasible. PMID- 30475886 TI - Frailty Index associates with GRIN2B in two representative samples from the United States and the United Kingdom. AB - The concept of frailty has been used in the clinical and research field for more than two decades. It is usually described as a clinical state of heightened vulnerability to poor resolution of homeostasis after a stressor event, which thereby increases the risk of adverse outcomes, including falls, delirium, disability and mortality. Here we report the results of the first genome-wide association scan and comparative gene ontology analyses where we aimed to identify genes and pathways associated with the deficit model of frailty. We used a discovery-replication design with two independent, nationally representative samples of older adults. The square-root transformed Frailty Index (FI) was the outcome variable, and age and sex were included as covariates. We report one hit exceeding genome-wide significance: the rs6765037 A allele was significantly associated with a decrease in the square-root transformed FI score in the Discovery sample (beta = -0.01958, p = 2.14E-08), without confirmation in the Replication sample. We also report a nominal replication: the rs7134291 A allele was significantly associated with a decrease in the square-root transformed FI score (Discovery sample: beta = -0.01021, p = 1.85E-06, Replication sample: beta = -0.005013, p = 0.03433). These hits represent the KBTBD12 and the GRIN2B genes, respectively. Comparative gene ontology analysis identified the pathways 'Neuropathic pain signalling in dorsal horn neurons' and the 'GPCR-Mediated Nutrient Sensing in Enteroendocrine Cells', exceeding the p = 0.01 significance in both samples, although this result does not survive correction for multiple testing. Considering the crucial role of GRIN2B in brain development, synaptic plasticity and cognition, this gene appears to be a potential candidate to play a role in frailty. In conclusion, we conducted genome-wide association scan and pathway analyses and have identified genes and pathways with potential roles in frailty. However, frailty is a complex condition. Therefore, further research is required to confirm our results and more thoroughly identify relevant biological mechanisms. PMID- 30475887 TI - Detectability of radiation-induced changes in magnetic resonance biomarkers following stereotactic radiosurgery: A pilot study. AB - Our objective was to investigate direct voxel-wise relationship between dose and early MR biomarker changes both within and in the high-dose region surrounding brain metastases following stereotactic radiosurgery (SRS). Specifically, we examined the apparent diffusion coefficient (ADC) from diffusion-weighted imaging and the contrast transfer coefficient (Ktrans) and volume of extracellular extravascular space (ve) derived from dynamic contrast-enhanced (DCE) MRI data. We investigated 29 brain metastases in 18 patients using 3 T MRI to collect imaging data at day 0, day 3 and day 20 following SRS. The ADC maps were generated by the scanner and Ktrans and ve maps were generated using in-house software for dynamic tracer-kinetic analysis. To enable spatially-correlated voxel-wise analysis, we developed a registration pipeline to register all ADC, Ktrans and ve maps to the planning MRI scan. To interrogate longitudinal changes, we computed absolute DeltaADC, DeltaKtrans and Deltave for day 3 and 20 post-SRS relative to day 0. We performed a Kruskall-Wallice test on each biomarker between time points and investigated dose correlations within the gross tumour volume (GTV) and surrounding high dose region > 12 Gy via Spearman's rho. Only ve exhibited significant differences between day 0 and 20 (p < 0.005) and day 3 and 20 (p < 0.05) within the GTV following SRS. Strongest dose correlations were observed for ADC within the GTV (rho = 0.17 to 0.20) and weak correlations were observed for ADC and Ktrans in the surrounding > 12 Gy region. Both DeltaKtrans and Deltave showed a trend with dose at day 20 within the GTV and > 12 Gy region (rho = -0.04 to -0.16). Weak dose-related decreases in Ktrans and ve within the GTV and high dose region at day 20 most likely reflect underlying vascular responses to radiation. Our study also provides a voxel-wise analysis schema for future MR biomarker studies with the goal of elucidating surrogates for radionecrosis. PMID- 30475888 TI - Metformin induces significant reduction of body weight, total cholesterol and LDL levels in the elderly - A meta-analysis. AB - BACKGROUND: Metformin is the first-choice drug for patients with Type 2 diabetes, and this therapy is characterized by being weight neutral. However, in the elderly an additional unintentional weight loss could be considered as an adverse effect of the treatment. OBJECTIVES: We aimed to perform a meta-analysis of placebo-controlled studies investigating the body weight changes upon metformin treatment in participants older than 60 years. MATERIALS AND METHODS: PubMed, EMBASE and the Cochrane Library were searched. We included at least 12 week-long studies with placebo control where the mean age of the metformin-treated patients was 60 years or older and the body weight changes of the patients were reported. We registered our protocol on PROSPERO (CRD42017055287). RESULTS: From the 971 articles identified by the search, 6 randomized placebo-controlled studies (RCTs) were included in the meta-analysis (n = 1541 participants). A raw difference of 2.23 kg (95% CI: -2.84 --1.62 kg) body weight change was detected in the metformin-treated groups as compared with that of the placebo groups (p<0.001). Both total cholesterol (-0.184 mmol/L, p<0.001) and LDL cholesterol levels ( 0.182 mmol/L, p<0.001) decreased upon metformin-treatment. CONCLUSIONS: Our meta analysis of RCTs showed a small reduction of body weight together with slight improvement of the blood lipid profile in patients over 60 years. With regard to the risk of unintentional weight loss, metformin seems to be a safe agent in the population of over 60 years. Our results also suggest that metformin treatment may reduce the risk of major coronary events (-4-5%) and all-cause mortality ( 2%) in elderly diabetic populations. PMID- 30475889 TI - Development of a rapid and visual detection method for Rickettsia rickettsii combining recombinase polymerase assay with lateral flow test. AB - OBJECTIVES: Rickettsia rickettsii is the causative agent of Rocky Mountain spotted fever, which is the most severe spotted fever group (SFG) rickettsiosis. Developing a simple and reliable detection method is required. METHODS: A detection method for R. rickettsii was established based on a recombinase polymerase amplification (RPA) assay and the lateral flow (LF) test. A specific target sequence was screened, and corresponding primers and probes were designed, synthesized, and screened for establishing an RPA assay with high amplification efficiency. Reagent concentrations, amplification time, and loading volume for strip development were optimized. The detection limit, analytic sensitivity and specificity were evaluated. RESULTS: A rapid, visual, sensitive and specific method for the detection of R. rickettsii based on RPA and the LF test was successfully established. The novel method had a limit of detection of 10 to 50 copies/reaction without recognizing other organisms. Analytical sensitivity and specificity were >=90% and 100%, respectively, as evaluated by animal and simulative human samples. CONCLUSIONS: Using the established method, detection could be completed in 30 min with visually detectable results by the naked eye, without requirement of any instrument except a constant temperature equipment. The technique shows superior detection performance and is promising for wide use in the field as well as resource-limited areas for R. rickettsii detection. PMID- 30475890 TI - Global treatment costs of breast cancer by stage: A systematic review. AB - BACKGROUND: Published evidence on treatment costs of breast cancer varies widely in methodology and a global systematic review is lacking. OBJECTIVES: This study aimed to conduct a systematic review to compare treatment costs of breast cancer by stage at diagnosis across countries at different levels of socio-economic development, and to identify key methodological differences in costing approaches. DATA SOURCES: MEDLINE, EMBASE, and NHS Economic Evaluation Database (NHS EED) before April 2018. ELIGIBILITY CRITERIA: Studies were eligible if they reported treatment costs of breast cancer by stage at diagnosis using patient level data, in any language. STUDY APPRAISAL AND SYNTHESIS METHODS: Study characteristics and treatment costs by stage were summarised. Study quality was assessed using the Drummond Checklist, and detailed methodological differences were further compared. RESULTS: Twenty studies were included, 15 from high-income countries and five from low- and middle-income countries. Eleven studies used the FIGO staging system, and the mean treatment costs of breast cancer at Stage II, III and IV were 32%, 95%, and 109% higher than Stage I. Five studies categorised stage as in situ, local, regional and distant. The mean treatment costs of regional and distant breast cancer were 41% and 165% higher than local breast cancer. Overall, the quality of studies ranged from 50% (lowest quality) to 84% (highest). Most studies used regression frameworks but the choice of regression model was rarely justified. Few studies described key methodological issues including skewness, zero values, censored data, missing data, and the inclusion of control groups to estimate disease-attributable costs. CONCLUSIONS: Treatment costs of breast cancer generally increased with the advancement of the disease stage at diagnosis. Methodological issues should be better handled and properly described in future costing studies. PMID- 30475893 TI - Chronic kidney disease, health-related quality of life and their associated economic burden among a nationally representative sample of community dwelling adults in England. AB - Chronic kidney disease (CKD) affects up to 15% of the adult population and is strongly associated with other non-communicable chronic diseases including diabetes. However, there is limited information on a population basis of the relationship between CKD and health-related quality of life (HRQoL) and the consequent economic cost. We investigated this relationship in a representative sample in England using the 2010 Health Survey for England. Multivariable Tobit models were used to examine the relationship between HRQoL and CKD severity. HRQoL was converted to quality adjusted life year (QALY) measures by combining decrements in quality of life with reductions in life expectancy associated with increased disease severity. QALYs were adjusted for discounting and monetised using the UK threshold for reimbursement of L30,000. The QALYs were then used in conjunction with forecasted prevalence to estimate the HRQoL burden associated with CKD among individuals with diabetes up to 2025. Individuals with more severe CKD had lower HRQoL compared to those with better kidney function. Compared to those with normal/low normal kidney function and stage 1 CKD, those with stage 2, stage 3 with albuminuria and stage 4/5 CKD experienced a decrement of 0.11, 0.18 and 0.28 in their utility index, respectively. Applying the UK reimbursement threshold for a QALY, the monetised lifetime burden of reduced HRQoL due to stage 2, stage 3 with albuminuria and stage 4/5 CKD were L103,734; L83,399; L125,335 in males and L143,582; L70,288; L203,804 in females, respectively. Utilizing the predicted prevalence of CKD among individuals with diabetes mellitus, the economic burden of CKD per million of individuals with diabetes is forecasted at approximately L11.4 billion in 2025. In conclusion, CKD has a strong adverse impact on HRQoL in multiple domains. The estimated economic burden of CKD among individuals with diabetes mellitus in the UK is projected to rise markedly over time. PMID- 30475892 TI - Analysis of the bond interface between self-adhesive resin cement to eroded dentin in vitro. AB - The purpose of this study was to evaluate the bonding interface between a self adhesive resin cement to in vitro eroded dentin. Seventy-two third molars were used and divided into two groups: sound dentin and in vitro eroded dentin. The in vitro erosion was performed following a demineralization protocol, in which the specimens were immersed in a demineralizing solution for 2 minutes per cycle and remineralizing solution for 10 minutes per cycle for 9 days. Both groups were submitted to four dentin surface treatments: control group (without any treatment), 2% chlorhexidine, 20% polyacrylic acid, and 0.1 M EDTA (n = 9). Blocks of resin-based composite were bonded with RelyX U200 self-adhesive resin cement applied on the pretreated dentin surfaces. The teeth were sectioned into beams (1mm2) and submitted to microtensile bond strength testing to evaluate the bond strength of self-adhesive resin cement to dentin after 24 hours and 8 months of immersion in artificial saliva. Three specimens of each group were longitudinally cut and evaluated using confocal laser scanning microscopy to analyze the dentin/cement interface. Eroded dentin showed higher bond strength values when compared to sound dentin for the 2% chlorhexidine group (p = 0.03), 24 hours after adhesion. When considering eroded dentin, the 0.1M EDTA group showed higher bond strength values with a statistically significant difference only for the control group (p = 0.002). After 8 months of storage, the present results showed that there was no statistically significant difference between the two substrates for all experimental groups (p>0.05). Analysis of the microscopy confocal showed different types of treatments performed on dentin generally increased tags formation when compared to the control group. The eroded dentin showed a significant increase in density and depth of resinous tags when compared to sound dentin. The storage of samples for 8 months seems to have not caused significant degradation of the adhesive interface. PMID- 30475891 TI - Distinct characteristics of Tregs of newborns of healthy and allergic mothers. AB - Allergic diseases represent a major issue in clinical and experimental immunology due to their high and increasing incidence worldwide. Allergy status of the mother remains the best predictor of an individual's increased risk of allergy development. Dysregulation of the balance between different branches of immune response, chiefly excessive polarization towards Th2, is the underlying cause of allergic diseases. Regulatory T cells (Tregs) play a pivotal role in the timely establishment of physiological immune polarization and are crucial for control of allergy. In our study we used flow cytometry to assess Tregs in cord blood of newborns of healthy (n = 121) and allergic (n = 108) mothers. We observed a higher percentage of Tregs (CD4+CD25+CD127lowFoxP3+) in cord blood of children of allergic mothers. However, the percentage of cells expressing extracellular (PD 1, CTLA-4, GITR) and intracellular (IL-10, TGF-beta) markers of function was lower (significantly for PD-1 and IL-10) within Tregs of these children. Furthermore, Helios- induced Tregs in the cord blood of children of allergic mothers were decreased. These results were supported by a decrease in plasma levels of IL-10 and TGF-beta in cord blood of newborns of allergic mothers, implying lower tolerogenic capacity on the systemic level. Taken together, these findings reflect deficient function of Tregs in the group with higher risk of allergy development. This may be caused by a lower maturation status of the immune system, specifically Tregs, at birth. Such immaturity may represent an important mechanism involved in the increased risk of allergy in children of allergic mothers. PMID- 30475894 TI - Prediction of dysnatremias in critically ill patients based on the law of conservation of mass. Comparison of existing formulae. AB - BACKGROUND: We aimed to examine the predictive value of a novel mathematical formula based on the law of conservation of mass in calculating sodium changes in intensive care unit patients and compare its performance with previously published formulae. METHODS: 178 patients were enrolled from 01/2010 to 10/2013. Plasma and urine were collected in two consecutive 8-hour intervals and the sodium was measured. The predicted sodium concentration was calculated based on previous equations and our formula. The two 8-hour period (epoch 1 and 2) results were compared. Variability of predicted values among the measured range of serum sodium levels were provided by Bland-Altman plots with bias and precision statistics. Comparison of the results was performed with the statistical model of the Percentage Similarity. RESULTS: 47.19% patients had dysnatremias. The bias +/ SD with 95% limits of agreement for sodium levels were -1.395+/-3.491 for epoch 1 and -1.623 +/-11.1 for epoch 2 period. Bland-Altman analysis for the epoch 1 study period had the following results: -0.8079+/-3.447 for Adrogue-Madias, 0.56+/-9.687 for Barsoum-Levine, 0.1412+/-3.824 for EFWC and 0.294+/-4.789 for Kurtz-Nguyen formula. The mean similarity, SD and coefficient variation for the methods compared with the measured sodium are: 99.56%, 3.873, 3.89% epoch 1, 99.56%, 1.255, 1.26% for epoch 2, 99.77%, 1.245, 1.26% for Adrogue-Madias, 100.1%, 1.337, 1.34% for Barsoum-Levine, 100.1%, 1.704, 1.7% for Nguyen, 100.1%, 1.370, 1.37% for ECFW formula. CONCLUSIONS: The law of conservation of mass can be successfully applied for the prediction of sodium changes in critically ill patients. PMID- 30475895 TI - Correction: Topical Application of Ochratoxin A Causes DNA Damage and Tumor Initiation in Mouse Skin. AB - [This corrects the article DOI: 10.1371/journal.pone.0047280.]. PMID- 30475896 TI - Relationship of resilience, anxiety and injuries in footballers: Structural equations analysis. AB - Resilience is a psychological characteristic which enhances personal assets and protects individuals from potential negative effects of various stressors. While this topic has been considered in the separate context of sports injuries and anxiety states, these issues have rarely been considered together. The objective of this study is to analyse the association between motivation to overcome injuries in football and the state of anxiety caused by those injuries. One hundred and eighty-five footballers from Spain were analysed by way of the Connor Davidson Resilience Scale, the State-Trait Anxiety Inventory questionnaires, and an injury self-registration sheet. Statistical analyses were performed using structural equations. Results showed a direct and positive relationship between the capacity to face up to injuries or potential injuries and to adapt successfully to them for injured footballers, especially when anxiety was considered as a transitory emotional state. In addition, this relationship was stronger in non-injured sportspersons because their resilience capacity was not being impaired by the experience of an injury. PMID- 30475897 TI - Correction: Metformin reveals a mitochondrial copper addiction of mesenchymal cancer cells. AB - [This corrects the article DOI: 10.1371/journal.pone.0206764.]. PMID- 30475898 TI - Changes in the basic birth beliefs following the first birth experience: Self fulfilling prophecies? AB - Women's basic beliefs about birth as a natural and as a medical process are associated with childbirth choices and experience. These beliefs have only recently been quantified and not much is known about their development. In the current study, we assessed the differential effects of the objective and the subjective birth experience on changes in these beliefs. Using self-report questionnaires, we evaluated prenatal to postpartum changes among 342 Israeli first-time mothers. Participants were recruited during pregnancy, between February 2016 and January 2017, mostly in clinical settings, and followed-up two months postpartum. On average, women's beliefs about birth being natural weakened following childbirth and their belief about birth being medical strengthened. In regression models, it was either the objective or the subjective experience that was related to change in the basic birth beliefs: A more medicalized birth was associated with strengthening of the medical belief while greater birth satisfaction was related to strengthening of the natural belief. A mediation effect was observed, which indicated that the beliefs are strengthened when the lived experience fulfilled women's expectation about birth being satisfying, natural or medical. This study adds to the growing body of knowledge regarding the development and evolution of the birth beliefs. It highlights the need to view the beliefs separately and to distinctively assess the objective and subjective birth experience. It supports the need to empower mothers, especially those who had more medicalized births or unsatisfactory ones, which would help conserve their belief in their body and in the normal physiological course of birth. PMID- 30475899 TI - Nuclear-cytoplasmic compartmentalization of the herpes simplex virus 1 infected cell transcriptome is co-ordinated by the viral endoribonuclease vhs and cofactors to facilitate the translation of late proteins. AB - HSV1 encodes an endoribonuclease termed virion host shutoff (vhs) that is produced late in infection and packaged into virions. Paradoxically, vhs is active against not only host but also virus transcripts, and is involved in host shutoff and the temporal expression of the virus transcriptome. Two other virus proteins-VP22 and VP16 -are proposed to regulate vhs to prevent uncontrolled and lethal mRNA degradation but their mechanism of action is unknown. We have performed dual transcriptomic analysis and single-cell mRNA FISH of human fibroblasts, a cell type where in the absence of VP22, HSV1 infection results in extreme translational shutoff. In Wt infection, host mRNAs exhibited a wide range of susceptibility to vhs ranging from resistance to 1000-fold reduction, a variation that was independent of their relative abundance or transcription rate. However, vhs endoribonuclease activity was not found to be overactive against any of the cell transcriptome in Delta22-infected cells but rather was delayed, while its activity against the virus transcriptome and in particular late mRNA was minimally enhanced. Intriguingly, immediate-early and early transcripts exhibited vhs-dependent nuclear retention later in Wt infection but late transcripts were cytoplasmic. However, in the absence of VP22, not only early but also late transcripts were retained in the nucleus by a vhs-dependent mechanism, a characteristic that extended to cellular transcripts that were not efficiently degraded by vhs. Moreover, the ability of VP22 to bind VP16 enhanced but was not fundamental to the rescue of vhs-induced nuclear retention of late transcripts. Hence, translational shutoff in HSV1 infection is primarily a result of vhs induced nuclear retention and not degradation of infected cell mRNA. We have therefore revealed a new mechanism whereby vhs and its co-factors including VP22 elicit a temporal and spatial regulation of the infected cell transcriptome, thus co-ordinating efficient late protein production. PMID- 30475900 TI - The RNA helicase DDX3X is an essential mediator of innate antimicrobial immunity. AB - DExD/H box RNA helicases, such as the RIG-I-like receptors (RLR), are important components of the innate immune system. Here we demonstrate a pivotal and sex specific role for the heterosomal isoforms of the DEAD box RNA helicase DDX3 in the immune system. Mice lacking DDX3X during hematopoiesis showed an altered leukocyte composition in bone marrow and spleen and a striking inability to combat infection with Listeria monocytogenes. Alterations in innate immune responses resulted from decreased effector cell availability and function as well as a sex-dependent impairment of cytokine synthesis. Thus, our data provide further in vivo evidence for an essential contribution of a non-RLR DExD/H RNA helicase to innate immunity and suggest it may contribute to sex-related differences in resistance to microbes and resilience to inflammatory disease. PMID- 30475901 TI - Correction: Simplified procedure for efficient and unbiased population size estimation. AB - [This corrects the article DOI: 10.1371/journal.pone.0206091.]. PMID- 30475902 TI - Procyanidin trimer C1 reactivates latent HIV as a triple combination therapy with kansui and JQ1. AB - Although anti-retroviral therapies have greatly extended the lives of HIV infected individuals, current treatments are unable to completely eliminate virally infected cells. A number of latency reversing agents have been proposed for use in a "shock and kill" strategy to reactivate latent HIV, thus making it vulnerable to killing mechanisms. Procyanidin trimer C1 (PC1) is a flavonoid found in multiple plant sources including grape, apple, and cacao, which has antioxidant and anti-inflammatory properties. We determined that PC1 reactivates latent HIV in cell line and primary cell models of HIV, through activation of the MAPK pathway. Notably, PC1 reactivates latent HIV without increasing surface markers of T cell activation. Combining several therapeutics, which activate HIV transcription through different mechanisms, is the most efficient approach to clinically reactivate latent reservoirs. We utilized PC1 (MAPK agonist), kansui (PKC agonist), and JQ1 (BET bromodomain inhibitor) in a triple combination approach to reactivate latent HIV in cell line and primary cell models of HIV latency. When used in combination, low concentrations which fail to reactivate HIV as single treatments, are effective. Thus, several mechanisms, using distinct activation pathways, act together to reactivate latent HIV. PMID- 30475903 TI - Correction: Differential changes in the onset of spring across US National Wildlife Refuges and North American migratory bird flyways. AB - [This corrects the article DOI: 10.1371/journal.pone.0202495.]. PMID- 30475904 TI - Cost analysis of outbreaks with Methicillin-resistant Staphylococcus aureus (MRSA) in Dutch long-term care facilities (LTCF). AB - OBJECTIVES: Highly resistant microorganisms (HRMOs) are of high concern worldwide and are becoming increasingly less susceptible for antibiotics. To study the cost effectiveness of infection prevention measures in long-term care, it is essential to first fully understand the impact of HRMOs. The objective of this study is to identify the costs associated with outbreaks caused by Methicillin-resistant Staphylococcus aureus (MRSA) in Dutch long-term care facilities (LTCF). METHODS: After an outbreak of MRSA, Dutch LTCF can submit a reimbursement form to the Dutch Healthcare Authority ("Nederlandse Zorgautoriteit"; NZa) to get a part of the total costs reimbursed. In this study, we requested NZa forms for financial impact analysis. Details regarding the costs of the outbreak have been extracted from these forms and additionally specific LTCF have been visited in person to validate the data. RESULTS: 34 complete reimbursement forms from the period between 2011 and 2016 were received from the NZa and have been included. The median cost per patient per day was estimated at ?83.80, varying between ?16.89 and ?1,820.09. We validated five reimbursement forms by visiting the facility and recalculating the costs. We found a non-significant positive difference of ?26.07 compared with the original data (p = 0.068). CONCLUSIONS: This study is to our knowledge the first to give a national overview of total costs associated with an MRSA outbreak in LTCF in the Netherlands. Overall, costs per patient per day seem lower than in a hospital setting, although total costs are much higher due to the long term of care. PMID- 30475905 TI - Correction: Features of urinary Escherichia coli isolated from children with complicated and uncomplicated urinary tract infections in Mexico. AB - [This corrects the article DOI: 10.1371/journal.pone.0204934.]. PMID- 30475906 TI - Correction: Cognitive Performance and Long-Term Social Functioning in Psychotic Disorder: A Three-Year Follow-Up Study. AB - [This corrects the article DOI: 10.1371/journal.pone.0151299.]. PMID- 30475907 TI - Quantitative image analysis using chest computed tomography in the evaluation of lymph node involvement in pulmonary sarcoidosis and tuberculosis. AB - PURPOSE: To evaluate the feasibility of quantitative analysis of chest computed tomography (CT) scans for the assessment of lymph node (LN) involvement in patients with pulmonary tuberculosis and sarcoidosis. METHODS: In 47 patients with tuberculosis (n = 26) or sarcoidosis (n = 21), 115 lymph nodes (tuberculous, 55; sarcoid, 60) were visually analyzed on chest CT scans according to their size, location, attenuation and shape. Each node was manually segmented using image analysis tool, which was quantitatively analyzed using the following variables: Feret's diameter, perimeter, area, circularity, mean grey value (Mean), standard deviation (SD) of grey value, minimum grey value (Min), maximum grey value (Max), median grey value (Median), skewness, kurtosis, and net enhancement. We statistically analyzed the visual and quantitative CT features of tuberculous and sarcoid LNs. RESULTS: In visual CT analysis, the mean node size in sarcoidosis was significantly greater than that in tuberculosis. There were no statistical differences between tuberculous and sarcoid LNs in terms of location and shape. Central low attenuation and peripheral rim enhancement were more frequently observed in tuberculous LNs than in the sarcoid ones. In quantitative CT analysis, there were significant differences in the values of the Feret's diameter, perimeter, area, circularity, mean grey value, SD, median, skewness, and kurtosis between tuberculous and sarcoid LNs. CONCLUSIONS: Quantitative CT analysis using CT parameters with pixel-by-pixel measurements can help to differentiate of tuberculous and sarcoid LNs. PMID- 30475908 TI - A new method based on quiet stance baseline is more effective in identifying freezing in Parkinson's disease. AB - Freezing, an episodic movement breakdown that goes from disrupted gait patterns to complete arrest, is a disabling symptom in Parkinson's disease. Several efforts have been made to objectively identify freezing episodes (FEs), although a standardized methodology to discriminate freezing from normal movement is lacking. Novel mathematical approaches that provide information in the temporal and frequency domains, such as the continuous wavelet transform, have demonstrated promising results detecting freezing, although still with limited effectiveness. We aimed to determine whether a computerized algorithm using the continuous wavelet transform based on baseline (i.e. no movement) rather than on amplitude decrease is more effective detecting freezing. Twenty-six individuals with Parkinson's disease performed two trials of a repetitive stepping-in-place task while they were filmed by a video camera and tracked by a motion capture system. The number of FEs and their total duration were determined from a visual inspection of the videos and from three different computed algorithms. Differences in the number and total duration of the FEs between the video inspection and each of the three methods were obtained. The accuracy to identify the time of occurrence of a FE by each method was also calculated. A significant effect of Method was found for the number (p = 0.016) and total duration (p = 0.013) of the FEs, with the method based on baseline being the closest one to the values reported from the videos. Moreover, the same method was the most accurate in detecting the time of occurrence, and the one reaching the highest sensitivity (88.2%). Findings suggest that threshold detection methods based on baseline and movement amplitude decreases capture different characteristics of Parkinsonian gait, with the first one being more effective at detecting FEs. Moreover, robust approaches that consider both time and frequency characteristics are more sensitive in identifying freezing. PMID- 30475909 TI - Correction: Cholesterol-lowering effect of Lactobacillus rhamnosus BFE5264 and its influence on the gut microbiome and propionate level in a murine model. AB - [This corrects the article DOI: 10.1371/journal.pone.0203150.]. PMID- 30475910 TI - Cluster sets vs. traditional sets: Levelling out the playing field using a power based threshold. AB - Cluster sets allow for velocity and power output maintenance, but the literature routinely uses highly fatiguing traditional set protocols. Although such studies have merit, others suggest fatigue should be avoided when training to improve power output, making those cluster set studies less practical. Therefore, the purpose of this study was to compare these set structures when truncating sets using a power-based threshold. Nine males (23.4 +/- 0.6 yr) with various sport backgrounds performed 6 sets of back squats with individualized loads that elicited the greatest mean power (MPmax) output (112.7 +/- 12.1% of body mass). Each set during the traditional set (TS) protocol included as many repetitions as possible until two consecutive repetitions dropped below 90% MPmax, which was followed by 120 s inter-set rest. The design was identical for cluster sets (CS) but with an additional 20 s intra-set rest after every 2 repetitions. The number of repetitions performed, mean velocity, and mean power output, were analyzed using 2(protocol)*6(set) repeated measures ANOVA. The number of repetitions during CS (51.8 +/- 14.4) was greater than TS (31.9 +/- 3.7) (p = 0.001), but the average velocity (CS = 0.711 +/- 0.069, TS = 0.716 +/- 0.081 m.s-1; p = 0.732) and power output (CS = 630.3 +/- 59.8, TS = 636.0 +/- 84.3 W; p = 0.629) of those repetitions were similar. These data indicate that CS are a viable option for increasing training volume during contemporary training where sets are ended when repetitions drop below velocity or power thresholds. PMID- 30475911 TI - Propeptide genesis by Kex2-dependent cleavage of yeast wall protein 1 (Ywp1) of Candida albicans. AB - Candida albicans is a prevalent fungal resident and opportunistic pathogen of humans, exhibiting a variety of ovoid and filamentous morphologies. Anchored within the cell wall of the ovoid yeast form of C. albicans is an abundant glycoprotein termed yeast wall protein 1 (Ywp1). Ywp1 has an antiadhesive effect that may facilitate yeast cell dispersal; it also contributes to the masking of the glucan matrix of the yeast cell wall, potentially providing shielding from recognition by the human immune system. Mature Ywp1 consists of an O-glycosylated core of 378 amino acids associated with an N-glycosylated propeptide that originates from an N-terminal segment of Ywp1. A tribasic (-RRR-) sequence in the immature Ywp1 polypeptide is separated by 8 amino acids from a dibasic (-KR-) sequence that is a canonical site for cleavage by the intracellular endopeptidase Kex2, and cleavage occurs at both of these sites to generate an 11 kilodalton (kDa) propeptide that remains strongly associated with the mature core of Ywp1. Previous studies demonstrated an absence of the 11 kDa propeptide in strains lacking Kex2, but the presence of lesser amounts of a 12 kDa propeptide ostensibly (and paradoxically) arising from cleavage at the dibasic site. Subsequent studies of wild type strains, however, suggested that post-secretion cleavages were carried out in vitro by acid proteases in unbuffered cultures to generate the 12 kDa propeptide. Here, intact and Gfp-tagged Ywp1 are utilized to show that neither of the two multibasic sites is normally cleaved in the absence of Kex2, but that uncleaved Ywp1 is still N-glycosylated and subsequently anchored to the cell wall. This furthers our understanding of the multistep cleavage of this highly conserved sequence, as well as the possible contributions of the cleaved propeptide to the maturation and functioning of Ywp1. PMID- 30475913 TI - Correction: From Glacier to Sauna: RNA-Seq of the Human Pathogen Black Fungus Exophiala dermatitidis under Varying Temperature Conditions Exhibits Common and Novel Fungal Response. AB - [This corrects the article DOI: 10.1371/journal.pone.0127103.]. PMID- 30475912 TI - Central adjudication of serious adverse events did not affect trial's safety results: Data from the Efficacy of Nitric Oxide in Stroke (ENOS) trial. AB - BACKGROUND AND PURPOSE: Central adjudication of serious adverse events (SAEs) can be undertaken in clinical trials, especially for open-label studies where outcome assessment may be at risk of bias. This study explored the effect of central adjudication of SAEs on the safety results of the Efficacy of Nitric Oxide in Stroke (ENOS) Trial. METHODS: ENOS assigned patients with acute stroke at random to receive either transdermal glyceryl trinitrate (GTN) or no GTN and to Stop or Continue previous antihypertensive treatment. SAEs were reported by local investigators who were not blinded to treatment allocation. Central adjudicators, blinded to treatment allocation, reviewed the investigators reports and used evidence available to confirm or re-categorise the classification of event, likely causality, diagnosis and expectedness of event. RESULTS: Of 4011 patients enrolled in ENOS, 1473 SAEs were reported by local investigators; this was reduced to 1444 after the review by adjudicators, with 29 re-classified as not an SAE. There was fair agreement between investigators and adjudicators regarding likely causality, with 808 agreements and 644 disagreements (56% crude agreement, weighted kappa, kappa = 0.31). Agreement increased upon dichotomisation of the causality categories, with 1432 agreements and 20 disagreements (99% crude agreement, kappa = 0.54). Repeating the main trial safety analysis with investigator reported events showed that adjudication had no effect on the main trial safety conclusions. CONCLUSIONS: In a large trial, with many SAEs reported, central adjudication of these events did not affect trial conclusions. This suggests that adjudication of SAEs in a clinical trial where the intervention already has a well-established safety profile may not be necessary. Potential efficiency savings (financial, logistical) can be made through not adjudicating SAEs. PMID- 30475914 TI - Correction: Evaluation of porogen factors for the preparation of ion imprinted polymer monoliths used in mercury removal. AB - [This corrects the article DOI: 10.1371/journal.pone.0195546.]. PMID- 30475915 TI - Should I stay, or should I go: Modeling optimal flight initiation distance in nesting birds. AB - Flight initiation distance (FID)-the distance at which an individual leaves in response to the approach of a perceived threat-provides a measurement of risk taking behavior. If individuals optimize their FID, this distance should reflect the point at which the fitness resulting from leaving exceeds the fitness resulting from all other possible decisions. Previous theory of FID has often been aimed at explaining this behavior in foraging individuals. Yet flight initiation in response to approaching threats occurs in a range of contexts that might influence optimal behavior. In breeding individuals, risk-taking decisions that are made at a location of offspring care (e.g., a nest or den) can have significant effects on fitness. Here, we develop a theoretical model of distances at which a parent bird flushes from a nest in response to an approaching threat. We estimate parent fitness with regards to characteristics of the parent (reproductive values, detection distance, and cost of lost parental care cost), the nest (concealment and accessibility), and the approaching predator (detection capability and predation success), developing a dichotomous scenario between staying at the nest or leaving at varying distances. Using a generalized comparison of the benefits of leaving versus staying, we find that increasing costs of lost parental care, probability of predation of the parent due to fleeing, or current reproductive value lead to more instances of staying at the nest. In a complementary approach with specified parameters based on biologically informed factors that likely influence a predator-prey encounter, we find that increasing the current reproductive value, concealment of the nest, or costs of lost parental care decrease optimal FID and can lead to the parent staying at the nest. Other factors, such as increasing residual reproductive value, predation success, and predator capability of detecting the nest, increase optimal FID with some instances of costs of fleeing being so great that staying becomes an optimal strategy. Our theory provides a framework to explain variation in FID among nesting species and individuals and could provide a foundation for future empirical investigations of risk-taking behavior. PMID- 30475917 TI - Correction: A novel encryption scheme for high-contrast image data in the Fresnelet domain. AB - [This corrects the article DOI: 10.1371/journal.pone.0194343.]. PMID- 30475916 TI - Effects of emergency cerclage on the neonatal outcomes of preterm twin pregnancies compared to preterm singleton pregnancies: A neonatal focus. AB - OBJECTIVE: To evaluate the efficacy and safety of emergency cerclage (EC) in preterm twins by comparing neonatal outcomes of preterm twins with those of preterm singletons. STUDY DESIGN: This is a single-institution retrospective study of preterm infants born to women who underwent EC from 2008 to 2014. We compared various maternal and neonatal factors. The primary and secondary goals were to compare the maternal and neonatal morbidities and neonatal mortality, respectively. RESULTS: One hundred fifty-three infants were included comprising 32(21%) twins and 121(79%) singletons. The mean gestational age (GA) at the time of EC and the number of days from EC to delivery were not significantly different (47.9+/-27.5 vs. 48.3+/-35.5). The rate of preterm delivery at <=32 weeks GA (69% vs. 79%) and <=28 weeks GA (50% vs. 55%), and other prematurity-associated morbidities were not significantly different. The survival rate during hospitalization was 75% (24/32) in twins and 88% (107/121) in singletons (P = 0.054). Death within 7 days after birth occurred in 8 twins (25%) and 7 singletons (6%) (P = 0.001). All of the infants were <1,000 g with a GA of <=27 weeks. CONCLUSION: Compared to EC in singleton pregnancies, EC in twin pregnancies resulted in a higher mortality rate for preterm babies. EC might be considered a salvage procedure for selective twin pregnancies with cervical insufficiency. PMID- 30475918 TI - Linguistic analysis of the autobiographical memories of individuals with major depressive disorder. AB - BACKGROUND: Major depressive disorder (MDD) is characterized by biases in memory, attention, and cognition. The present study utilized the Linguistic Inquiry and Word Count (LIWC) to examine the content of specific autobiographical memories (AMs) recalled by individuals with MDD during an autobiographical memory task. METHODS: We examined various features of the text (including use of affective, cognitive, and self-referential terms), as well as their associations with clinical and cognitive features of MDD (depression severity, autobiographical memory specificity, amygdala activity), in 45 unmedicated adults with MDD compared to 61 healthy controls. RESULTS: When recalling positive memories MDD individuals used the word "I" less, fewer positive words, more words indicating present focus (present tense verbs), and fewer words overall to describe memories compared to controls. When recalling negative memories, MDD individuals used "I" more, more words indicating present focus, and more words overall to describe memories relative to controls. Depression severity was correlated with word count, the use of "I", and words indicating present focus in negative memories and inversely correlated with word count and the use of "I" in positive memories. Autobiographical memory specificity was correlated with word count, the use of "I", and words indicating present focus for positive memories and inversely correlated with the use of "I" and words indicating present focus for negative memories. LIMITATIONS: Due to the nature of AM recall, we could not control for the number of memories which participants recalled in each mnemonic category. CONCLUSIONS: Results align with literature implicating rumination and intensive self-focus in depression and suggest that interventions targeting specific word use may be therapeutically beneficial in the treatment of MDD. PMID- 30475920 TI - Differentiation of mucosal lesions in mucocutaneous leishmaniasis and paracoccidioidomycosis. AB - Mucocutaneous leishmaniasis and paracoccidioidomycosis are infectious diseases with similar epidemiological and clinical aspects. Cases of both diseases may manifest similar lesions in the mucosa. Therefore, the determination of distinguishing characteristics for the purpose of differential diagnosis is critical for better management of the diseases. The present study evaluated factors that assist in the differentiation of mucosal lesions between these diseases. This cross-sectional study included data from medical records of 122 cases of mucocutaneous leishmaniasis and 83 cases of paracoccidioidomycosis attended at the university hospital Cassiano Antonio Moraes, located in Vitoria, Espirito Santo State, Brazil. Comparison between the diseases included the following variables: sex, age, time of disease evolution, location of the lesion and symptoms. Adults and males were affected by both diseases at higher rates. Lesions in the nasal region (95.1%; p-value = 0.000) and the pharynx (20.5%; p value = 0.009) and nasal obstruction (34.4%; p-value = 0.000) were associated with leishmaniasis. Paracoccidioidomycosis was associated with lesions in the oral region (90.4%; p-value = 0.000), oral pain (16.9%; p-value = 0.000), and hoarseness (14.5%; p-value = 0.008). In leishmaniasis, lesions in oral regions were not associated with oral pain and were frequently located close to the nasal area. The manifestations cited above could improve the differential diagnosis of leishmaniasis and paracoccidioidomycosis, and thereby potentially aid in the choice of appropriate confirmatory diagnostic testing. PMID- 30475921 TI - A suppressor of a wtf poison-antidote meiotic driver acts via mimicry of the driver's antidote. AB - Meiotic drivers are selfish alleles that subvert gametogenesis to increase their transmission into progeny. Drivers impose a fitness cost, putting pressure on the genome to evolve suppressors. Here we investigate the wtf gene family from Schizosaccharomyces pombe, previously shown to contain meiotic drivers in wild isolates. We discovered that wtf13 found in lab stocks is a meiotic driver. wtf13 kills spores that do not inherit it by generating both a diffusible poison and a spore-specific antidote. Additionally, we demonstrate that wtf13 is suppressed by another wtf gene, wtf18-2, that arose spontaneously in the lab and makes only an antidote. Wtf18-2 does not act indiscriminately to prevent spore destruction. Instead, it rescues only the spores that inherit wtf18-2. In this way, wtf18-2 selfishly gains a transmission advantage of its own while dampening the drive of wtf13. This establishes a novel paradigm for meiotic drive suppressors and provides insight into the mechanisms and evolution of drive systems. PMID- 30475919 TI - Global emergence and population dynamics of divergent serotype 3 CC180 pneumococci. AB - Streptococcus pneumoniae serotype 3 remains a significant cause of morbidity and mortality worldwide, despite inclusion in the 13-valent pneumococcal conjugate vaccine (PCV13). Serotype 3 increased in carriage since the implementation of PCV13 in the USA, while invasive disease rates remain unchanged. We investigated the persistence of serotype 3 in carriage and disease, through genomic analyses of a global sample of 301 serotype 3 isolates of the Netherlands3-31 (PMEN31) clone CC180, combined with associated patient data and PCV utilization among countries of isolate collection. We assessed phenotypic variation between dominant clades in capsule charge (zeta potential), capsular polysaccharide shedding, and susceptibility to opsonophagocytic killing, which have previously been associated with carriage duration, invasiveness, and vaccine escape. We identified a recent shift in the CC180 population attributed to a lineage termed Clade II, which was estimated by Bayesian coalescent analysis to have first appeared in 1968 [95% HPD: 1939-1989] and increased in prevalence and effective population size thereafter. Clade II isolates are divergent from the pre-PCV13 serotype 3 population in non-capsular antigenic composition, competence, and antibiotic susceptibility, the last of which resulting from the acquisition of a Tn916-like conjugative transposon. Differences in recombination rates among clades correlated with variations in the ATP-binding subunit of Clp protease, as well as amino acid substitutions in the comCDE operon. Opsonophagocytic killing assays elucidated the low observed efficacy of PCV13 against serotype 3. Variation in PCV13 use among sampled countries was not independently correlated with the CC180 population shift; therefore, genotypic and phenotypic differences in protein antigens and, in particular, antibiotic resistance may have contributed to the increase of Clade II. Our analysis emphasizes the need for routine, representative sampling of isolates from disperse geographic regions, including historically under-sampled areas. We also highlight the value of genomics in resolving antigenic and epidemiological variations within a serotype, which may have implications for future vaccine development. PMID- 30475922 TI - Use of next generation sequencing to investigate the microbiota of experimentally induced wounds and the effect of bandaging in horses. AB - OBJECTIVES: To use next generation sequencing to characterize the microbiota of horses during healing of skin wounds in two anatomical locations (body and limb) known to present different healing patterns; and to investigate the impact of bandaging on bacterial communities of skin wounds located on the limbs of horses. METHODS: Full-thickness skin wounds were created on the distal extremity of both thoracic limbs and on one lateral mid-thoracic wall of four healthy horses. Limb wounds were randomly assigned to bandaging or not. A full-thickness sample was collected with a biopsy punch from intact thorax and limb skin (T0) and from the margin of one wound per site (thorax, unbandaged limb, bandaged limb) 1 week (T1) and 2 weeks (T2) postoperatively, and at full healing (T3). Thoracic skin samples obtained from three healthy horses were included in the analysis as controls. RESULTS: Anatomic location (thorax vs. limb) significantly influenced bacterial composition of equine skin and healing wounds. Fusobacterium and Actinobacillus were strongly associated with limb wounds during the initial phases of healing. Bandaging had a significant impact on the microbiota during the healing process. The skin microbiota after healing was more similar to samples from controls, demonstrating the resilience and stability of the environment. CONCLUSIONS: Equine skin microbiota is a rich and stable environment that is disturbed by wounding, but returns to its previous stage after full healing. Anatomic location significantly influences bacterial composition of the equine skin during wound healing. Bandaging has a significant impact on the skin microbiota of horses during the healing process. Results of this study provide new insight for a better understanding of the contribution of bacteria to wound healing in horses and may facilitate the future development of therapeutic strategies using commensal bacteria. PMID- 30475923 TI - The lucky ones get cured: Health care seeking among women with pelvic organ prolapse in Amhara Region, Ethiopia. AB - BACKGROUND: The majority of women suffering from maternal morbidities live in resource-constrained settings with diverse barriers preventing access to quality biomedical health care services. This study aims to highlight the dynamics between the public health system and alternative healing through an exploration of the experiences of health care seeking among women living with severe symptomatic pelvic organ prolapse in an impoverished setting. METHODS: The data were collected through ethnographic fieldwork at the hospital and community levels in the Amhara region of Ethiopia. The fieldwork included participant observation, 42 semi-structured interviews and two focus group discussions over a period of one year. A group of 24 women with severe symptomatic pelvic organ prolapse served as the study's main informants. Other central groups of informants included health care providers, local healers and actors from the health authorities and non-governmental organisations. RESULTS: Three case stories were chosen to illustrate the key findings related to health care seeking among the informants. The women strove to find remedies for their aggravating ailment, and many navigated between and combined various available healing options both within and beyond the health care sector. Their choices were strongly influenced by poverty, by lack of knowledge about the condition, by their religious and spiritual beliefs and by the shame and embarrassment related to the condition. An ongoing health campaign in the study area providing free surgical treatment for pelvic organ prolapse enabled a study of the experiences related to the introduction of free health services targeting maternal morbidity. CONCLUSIONS: This study highlights how structural barriers prevent women living in a resource-constrained setting from receiving health care for a highly prevalent and readily treatable maternal morbidity such as pelvic organ prolapse. Our results illustrate that the provision of free quality services may dramatically alter both health-and illness-related perceptions and conduct in an extremely vulnerable population. PMID- 30475924 TI - Etiologic and clinical characterization of community acquired gastroenteritis in adult patients in a Chilean emergency room by the FilmArray GI panel. AB - : Infectious diarrhea can be caused by a large number of microorganisms including bacteria virus and parasites. The clinical syndromic approach has been traditionally used to guide therapy. The aim of this study was to characterize the etiology of acute diarrhea by the FilmArray GI panel and to correlate it with its clinical presentation in an adult population presenting to the emergency room in a developing country. MATERIAL AND METHODS: Adult patients attending the ER due to acute diarrhea were selected. All patients included had a FilmArray GI panel performed and the clinical characteristics were recorded. RESULTS: One hundred and ninety-nine patients were included. One hundred and eighteen (59.3%) were females. The mean age was 43 years old. Thirty three percent of the patients presented dysentery, 36.7% fever, 54.8% referred nauseas and 35.7% vomiting. Sixty three percent of the patients presented some degree of dehydration. In total, 221 microorganisms were detected of which 71.5% corresponded to bacteria (158/221), 19.9% to virus (44/221) and 8.6% to parasites (19/221). In 133 (67.0%) of 199 patients at least one microorganism was identified. Infections with more than one microorganism were detected in 27.1% of the patients. Polimicrobial infections were associated with a higher frequency of nausea (50.0% vs 32.0%, p 0.046), abdominal pain (87.0% vs 44.0%, p<0.0001) and travel history (20.0% vs 5.0%, p 0.0102). Bacterial infections occurred without a seasonal distribution with the exception of Salmonella sp whereas viral infections predominated during the autumn-winter months. Diarreicogenic E. coli were present in the context of a co-infection in more than 80.0% of the cases. DISCUSSION: The use of multiplex panels has given us invaluable information regarding the epidemiology of acute diarrhea in adult. It highlighted the importance of polimicrobial infections and the frequency of diarreicogenic E. coli infections. Nevertheless, the lack of severity compared to monomicrobial infections and the usual association with other microorganisms in the latter make their clinical importance debatable. PMID- 30475925 TI - Correction: On the internal reaction forces, energy absorption, and fracture in the hip during simulated sideways fall impact. AB - [This corrects the article DOI: 10.1371/journal.pone.0200952.]. PMID- 30475926 TI - Device-based treatment for vaginal wellness. AB - Genitourinary syndrome of menopause (GSM), encompassing the disorders of atrophic vaginitis, urinary incontinence, and pelvic prolapse, affects the majority of postmenopausal women, as well as patients who are undergoing breast cancer treatement, post-ovarectomy, post-radiation, and breast-feeding. There is a need for better treatment options for these common conditions that adversely affect physical function and quality of life and that are often underserved by existing options. Lasers have been used to treat genitourinary tissue for over 40 years, and over the past decade, several lasers and radiofrequency devices have been developed and clinically tested for the treatment of GSM, with an accumulating body of evidence demonstrating their safety and efficacy. Fractional lasers, including carbon dioxide, erbium: YAG and hybrid technologies, as well as monopolar radiofrequency devices, work by resurfacing and/or stimulating via heat the vaginal lining resulting in a re-epithelialization, neovascularization, and remodeling of the vaginal tissue from an atrophic postmenopausal state to a thickened, glycogen-rich and well-vascularized state similar to premenopausal vaginal lining. These changes are correlated clinically with improved function on a variety of validated vaginal health scales and urinary incontinence tests. Currently cleared for general application to genitourinary tissue, clinical trials are underway for FDA clearance or approval for specific GSM indications. PMID- 30475927 TI - Common allergens present in personal care products: identification, diagnosis, and management. AB - The incidence of allergic contact dermatitis (ACD) reactions to personal care products has progressively increased, affecting women more so than men. Fragrances and preservatives are the major sensitizers behind cosmetic-induced ACD, due to their ubiquitous presence in these products, though emulsifiers, ultraviolet filters, and botanical allergens have been implicated as well. While patch testing is the standard for diagnosing ACD, many cosmetic-specific antigens are not currently included within the commercially available kits. Therefore, patch testing for potential cosmetic-induced ACD should be supplemented with additional compounds commonly found in personal use products. Effective treatment of ACD must involve accurate identification and removal of the offending agent. PMID- 30475928 TI - Treatment of female pattern hair loss with combination therapy. AB - Female pattern hair loss (FPHL) is a common nonscarring alopecia characterized by progressive loss of terminal hairs. FPHL is a major concern for women and has a high impact on quality of life. Therapeutic regimen is often challenging and requires multiple combinations of topical, systemic, and interventional therapies to control hair loss and produce satisfactory hair regrowth. This article reviews common treatments of FPHL and their efficacy. PMID- 30475929 TI - Aesthetic considerations in female skin of color: what you need to know. AB - The world is flat when it comes to aesthetic treatments, meaning women and men from all walks of life, regardless of culture and ethnicity or even socioeconomic status, are seeking ways to improve their appearance, prevent aging, and rejuvenate their skin. Year after year, statistics show a steady increase in people of color undergoing aesthetic treatments, with neurotoxins, fillers, laser resurfacing, and body contouring being the most sought-after procedures. When treating this cohort of patients, however, dermatologists need to be sensitized to how a patient's ethnicity affects facial structure, the tissue reaction to treatments, and patient's specific expectations for recommended therapies. A balance between tolerability and efficacy needs to be struck to minimize risk for adverse effects such as postinflammatory hyperpigmentation, which can negatively impact a patient's experience and quality of life. PMID- 30475931 TI - Aesthetic Consideration in Women's Health, Introduction. PMID- 30475930 TI - Updates on the understanding and treatment of cellulite. AB - Cellulite is a common dermatologic condition and frequent cause of cosmetic concern among women. This paper aims to update what is known about the pathogenesis of cellulite and reviews targeted treatment modalities that address its underlying components of microvascular dysfunction, endocrine-mediated inflammation, and connective tissue fibrosclerosis. PMID- 30475932 TI - Vaginal wellness: whose turf is it? AB - Dermatologists were the pioneers in the development of laser technology and have the most experience using these lasers to treat the external genitalia for many cutaneous disorders. Dermatologists who have experience and expertise using lasers and devices, are already using them to treat the external genitalia, and are comfortable performing female gynecologic exams may want to explore the wide range of options that are available to treat the functional and aesthetic needs of the female population. Dermatologists should work with obstetricians and gynecologists to ensure that patients are proper candidates for the procedures. PMID- 30475933 TI - The vaginal wellness consultation for treatment with energy-based devices. PMID- 30475934 TI - Vaginal rejuvenation: whose turf? AB - Many medical conditions can cross over the territories of various specialties. These conditions may benefit from, or even require, a multidisciplinary approach. While ideally this leads to a collaborative and coveted patient-centered care model, it can also give rise to competitive turf wars. A popular topic that has entered the turf wars is vaginal rejuvenation. Vaginal rejuvenation through light and energy-based devices is a rapidly expanding field, quickly gaining the attention of dermatologists and gynecologists alike. Dermatology has the most experience and expertise with lasers and energy-based devices for rejuvenation, whereas gynecology has the advanced knowledge of the vaginal anatomy, tissue structure, and function. We herein argue that a collaborative effort between dermatology and gynecology is most appropriate for proper care of our patients and for the advancement of this growing niche. PMID- 30475935 TI - Melasma: update on management. AB - Melasma is a common, acquired, chronic cutaneous pigment disorder that is often difficult to treat and has a high recurrence rate. The goal of a melasma treatment regimen is to decrease pigment production and increase elimination. Topical tyrosinase inhibitors block melanin synthesis and thereby reduce pigment production. Peels and laserand light-based devices increase melanin elimination. A multimodality treatment approach targeting both pigment production and elimination is necessary to achieve equilibrium and disease remission. Maintenance treatments are often necessary due to the high recurrence rate. Strict photoprotection is critical to prevent melanogenesis and rebound. Targeting the vasculature via pulsed dye laser or tranexamic acid is another approach to treatment. PMID- 30475936 TI - Wheeze and Food Allergies in Children Born via Cesarean Section - The Upstate KIDS Study. AB - We examined whether cesarean delivery (CD) increased the risk of wheeze or food allergy in early childhood compared to vaginal delivery and whether these associations were mediated by breastfeeding. The study population was the Upstate KIDS cohort (2008-2010) of mothers and infants from New York State (excluding New York City). Infant's wheeze was reported by questionnaire every 4-6 months until 3 years as was food allergies beginning at 8 months. Modified Poisson regression was used to compare risks of the outcomes by mode of delivery (MOD). Potential confounders were identified a priori using directed acyclic graphs.Emergency CD (n=1,356) was associated with elevated risk of wheeze, adjusting for pregnancy complications, maternal atopy, gestational age, birthweight and pregnancy smoking (Risk Ratio [RR] 2.47, 95% confidence interval [CI]:1.31, 4.66); and an increased risk of food allergy, adjusting for maternal atopy, pre-pregnancy body mass index, pregnancy smoking and parity (RR 3.02, 95% CI:1.26, 7.25). Neither outcome was significantly associated with planned CD (n=1,565 infants). Breastfeeding mediated the association between MOD and wheeze but not food allergy. Other factors not associated with early-life microbial transfer, but relating to the development of the outcomes, may contribute to the association between MOD and wheezing/food allergy. PMID- 30475937 TI - Corrigendum to: The role of RIP3 in cardiomyocyte necrosis induced by mitochondrial damage of myocardial ischemia reperfusion. PMID- 30475938 TI - Relative impacts of mild and major neurocognitive disorder on rate of verbal learning acquisition. AB - Objective: The California Verbal Learning Test-second edition (CVLT-II) learning slope index may signal the presence of cognitive impairment, though the relative impacts of mild (MiND) and major (MaND) neurocognitive disorders on the rate of verbal learning acquisition remain unknown. Methods: Latent intercept-only, linear, quadratic, and exponential models were fit to raw scores for the five CVLT-II learning trials of 197 veterans. Dummy-coded variables reflecting MiND and MaND predicted the growth factors. Results: Quadratic growth best fit the data. MiND and MaND predicted reduced recall on each trial. MaND predicted reduced rate of learning acquisition (i.e., word gains per trial) over-and-above MiND, even after controlling for age, sex, education, race/ethnicity, and mono/bilingualism. Conclusions: Nonlinear growth-with continuous but diminishing gains over trials-best characterized verbal learning acquisition. Reduced word recall each trial may help differentiate MiND from no neurocognitive disorder, while reduced rate of verbal learning acquisition may help differentiate MaND from MiND. PMID- 30475939 TI - Lycopene and Metabolic Syndrome: A Systematic Review of the Literature. AB - Cardiometabolic risk factors increase the likelihood of cardiovascular disease development by 2-fold. Lycopene, a potent lipophilic antioxidant, may be able to mediate oxidative stress, a mechanism underpinning metabolic syndrome (MetS) and its risk factors. This is, to our knowledge, the first systematic review of the literature with the purpose of investigating the relation between circulating lycopene or dietary intake of lycopene and MetS as well as its risk factors. The review was conducted using PubMed and EBSCOhost databases with the search terms "lycopene" and "metabolic syndrome." Inclusion criteria included human studies published in English in a scholarly, peer-reviewed journal and evaluation of lycopene in relation to >=3 of the 5 MetS risk factors as defined by the National Cholesterol Education Program's Adult Treatment Panel III (ATP III) report. The process identified 11 studies, including 8 cross-sectional and 3 intervention studies. Cross-sectional studies were grouped into 3 categories, with several studies falling into >1 category, based on results reporting associations of lycopene with the prevalence and outcomes of MetS (5 studies), presence of ATP III risk factors (4 studies), and variables mediating lycopene's influence on MetS risk (3 studies). All studies in each category reported significant protective associations. Of the 3 intervention studies, all reported significant protective effects from a lycopene-rich beverage, despite varying doses and durations of intake. Although a protective relation between lycopene and MetS was generally supported, different MetS components appeared to be influenced by lycopene rather than demonstrating consistent improvement in a single component. Thus, additional research is needed to elucidate the mechanistic effects of lycopene on MetS, as well as to determine evidence-based recommendations concerning dose-durational effects of lycopene and MetS risk reduction. In conclusion, the evidence of lycopene's benefit exists such that lycopene status or lycopene consumption may be associated with favorable alterations to the components of MetS. PMID- 30475940 TI - Corrigendum. PMID- 30475941 TI - Comment on the paper "Boffetta et al. Validation of the diagnosis of mesothelioma and BAP1 protein expression in a cohort of asbestos textile workers from Northern Italy. Ann Oncol 2018; 29(2): 484-489". PMID- 30475942 TI - Prophylactic Irradiation to the Contralateral Breast for BRCA Mutation Carriers with Early Stage Breast Cancer. AB - Background: Women who carry germ line mutations in BRCA1/2 are at very high risk of developing breast and ovarian cancer. Breast conserving therapy is associated with a similar risk of ipsilateral cancer recurrence in BRCA carriers compared to non-carriers. However, the risk of subsequent contralateral breast cancer in carriers is markedly increased. Therefore, mastectomy of the diseased breast along with risk reducing mastectomy of the contralateral breast is often advocated for BRCA carriers who are treated for early breast cancer. Yet, many BRCA carriers forgo this option for fear of harmful effects and choose breast conserving treatment and observation instead. In Israel, BRCA associated breast cancer is relatively common. Accordingly, a national protocol was devised for this enriched population. Patients and Methods: In this IRB-approved phase II trial, the option of prophylactic irradiation to the contralateral breast, in addition to standard loco-regional treatment, was offered to BRCA carrier patients treated for early breast cancer who declined contralateral mastectomy. The primary end point was contralateral breast cancer. Results: Between May 2007 and October 2017, 162 patients were enrolled. Eighty-one patients opted for standard loco-regional treatment including surgery and radiation to the involved side (control arm) and 81 patients chose additional contralateral breast irradiation (intervention arm). At a median follow-up of 58 months, 10 patients developed contralateral breast cancer in the control arm at a median of 32 months, as compared to 2 patients in the intervention arm who developed contralateral breast cancer 80 and 105 months after bilateral breast irradiation (log-rank P = 0.011). Conclusions: Among BRCA carrier patients treated for early breast cancer, the addition of contralateral breast irradiation was associated with a significant reduction of subsequent contralateral breast cancers and a delay in their onset. PMID- 30475944 TI - Erratum. PMID- 30475945 TI - Ecophysiological strategy switch through development in heteroblastic species of mediterranean ecosystems - an example in the African Restionaceae. AB - Background and Aims: Heteroblasty is a non-reversible morphological change associated with life stage change and has been linked to predictable environmental variation. It is present in several clades from mediterranean-type climates, such as African Restionaceae (restios). These have heteroblastic shoots: juvenile shoots are thin, branched and sterile (sterile shoots); adult shoots are thicker and less branched, and bear inflorescences (reproductive shoots). Ten per cent of the restios retain juvenile-like, sterile shoots as adults (neoteny). We hypothesize (1) that the two shoot types differ in ecophysiological attributes, and (2) that these shoot types (and the neoteny) are associated with different environments. Methods: We measured shoot area per biomass (SMA), maximum photosynthetic capacity per biomass (Amass) and chlorenchyma to ground tissue ratio (CGR) of both shoot types in 14 restio species. We also calculated environmental niche overlap between neotenous and non neotenous species using an improved multidimensional overlap function based on occurrence data, and linked shoot types with environments using a phylogenetic generalized linear model. Key Results: Sterile shoots showed higher Amass, lower SMA and higher CGR than reproductive shoots. Neotenous and non-neotenous species overlapped ecologically less than expected by chance: neotenous species favoured more mesic, non-seasonal conditions. Conclusions: We associate sterile shoot morphology with acquisitive ecophysiological strategies and reproductive shoots with conservative strategies. The heteroblastic switch optimizes carbon efficiency in the juvenile phase (by sterile shoots) in the mesic post-fire conditions. The adult shoots present a compromise between a more conservative strategy favourable under harsher conditions and reproductive success. Heteroblasty in seasonally arid, oligotrophic ecosystems with predictable, fire driven shifts in water and nutrient availability might play a role in the success of restios and other species-rich lineages in mediterranean-type ecosystems. It may represent a previously unrecognized adaptation in mediterranean clades sharing similar conditions, contributing to their ecological and taxonomic dominance. PMID- 30475943 TI - Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic oesophageal cancer; a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS. AB - The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of oesophageal cancer was published in 2016, and covered the management and treatment of local/locoregional disease, limited disease, locally advanced disease and the management of advanced/metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic oesophageal cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic oesophageal cancer representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries. PMID- 30475946 TI - Widespread Incorrect Implementation of the Hoffmann Method, the Correct Approach, and Modern Alternatives. AB - Objectives: The Hoffmann method is a procedure for reference interval estimation using routine clinical results. Many authors incorrectly prepare Hoffmann plots on a linear rather than normal probability scale. We explore the consequences. Methods: This was investigated algebraically, by random number simulations (45 simulations, n = 100,000 each) and using clinical data sets. Strategies compared were: Hoffmann's method as originally and incorrectly implemented, Bhattacharya's method, and maximum likelihood (ML). All R source code and data sets are provided. Results: As the proportion of healthy individuals approaches 1, the incorrect approach generates reference interval estimates of approximately MUH +/ 1.19 sigmaH delineating the central 77% of the healthy subpopulation, not the central 95%. Inappropriately narrow reference interval estimates were seen on random simulations and clinical data sets. ML methods performed best. Conclusions: The erroneous variant Hoffmann method should not be used. ML methods outperform others and are not restricted by Gaussian assumptions. PMID- 30475947 TI - Title: Pembrolizumab Monotherapy for Previously Untreated, PD-L1-Positive, Metastatic Triple-Negative Breast Cancer: Cohort B of the Phase 2 KEYNOTE-086 Study. AB - Background: Standard first-line treatment for metastatic triple-negative breast cancer (mTNBC) is chemotherapy. However, outcomes are poor, and new treatment options are needed. In cohort B of the phase 2 KEYNOTE-086 study, we evaluated pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC. Patients and methods: Eligible patients had centrally confirmed mTNBC, no prior systemic anticancer therapy for metastatic disease, measurable disease at baseline per RECIST v1.1 by central review, no radiographic evidence of central nervous system metastases, and a tumor PD-L1 combined positive score >=1. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. The primary endpoint was safety. Secondary end points included objective response rate (ORR), disease control rate (DCR; percentage of patients with complete or partial response or stable disease for >=24 weeks), duration of response, progression-free survival (PFS) and overall survival (OS). Results: All 84 patients enrolled were women, and 73 (86.9%) received prior (neo)adjuvant therapy. Fifty-three (63.1%) patients had treatment-related adverse events (AEs), including 8 patients (9.5%) with grade 3 severity; no patients experienced grade 4 AEs or died because of treatment-related AEs. Four patients had a complete response and 14 had a partial response, for an ORR of 21.4% (95% CI, 13.9-31.4). Of the 13 patients with stable disease, 2 had stable disease lasting >=24 weeks, for a DCR of 23.8% (95% CI, 15.9-34.0). At data cutoff, 8 of 18 (44.4%) responses were ongoing, and median duration of response was 10.4 months (range, 4.2-19.2+). Median PFS was 2.1 months (95% CI, 2.0-2.2) and median OS was 18.0 months (95% CI, 12.9-23.0). Conclusions: Pembrolizumab monotherapy had a manageable safety profile and showed durable antitumor activity as first-line therapy for patients with PD-L1-positive mTNBC. Clinical trial registration: ClinicalTrials.gov, NCT02447003. PMID- 30475948 TI - Biological background of the genomic variations of cf-DNA in healthy individuals. AB - Background: Cell-free DNA-based liquid biopsy is emerging as a revolutionary new method in individualized cancer treatment and prognosis monitoring, although detecting early-stage cancers using cell-free DNA remains challenging, partially because of the undefined biological background of cell-free DNA. Materials and methods: We investigated somatic mutations in the cell-free DNA of 259 cancer free individuals with a median age of 47 years using an endogenous barcoding duplex method with an ultralow base error rate (2 * 10-7) and compared the variant allele frequencies of these mutations between the cell-free DNA and the corresponding blood cell DNA. Results: Sixty percent (155/259) of the samples showed at least one nonsynonymous mutation on either of two similar target panels covering 508 and 559 cancer-related genes. For individuals older than 50 years of age, the positive rate increased to 76%. Most cell-free DNA mutations were also present at similar variant allele frequencies in the paired blood cell DNA. The most frequently mutated genes were driver genes of hematologic malignancies, including DNMT3A, TET2, AXSL1, and JAK2. However, the other 58.4% (192/329) of the mutations were likely "passenger mutations" of clonal hematopoiesis, including mutations in NOTCH2, FAT3, EXT2, ERBB4, and ARID2, which are driver genes of solid tumors. Conclusion: Hematopoietic clone-derived mutations, including "driver mutations" and "passenger mutations", are prevalent in the cell free DNA of both healthy individuals and cancer patients and may be a potential source of false positives in the liquid biopsy. Our results also suggest the ineffectiveness for distinguishing clonal hematopoietic mutations of low variant allele frequency (<=0.1%) from tumor-derived mutations using conventional next generation sequencing of blood cell DNA. However, an error correction model with an ultralow error rate and high coverage depth is required for blood cell DNA sequencing, which is difficult and costly to achieve with current technologies. PMID- 30475949 TI - Risk Set Matching to Assess the Impact of Hospital-Acquired Bloodstream Infections. AB - Hospital-acquired bloodstream infections certainly have an impact on patient encounters and cause increased length of stay, costs, and mortality. However, methods for estimating these effects are potentially biased, especially if the time of infection is not incorporated into the estimation strategy. We focus on matching patient encounters in which a hospital-acquired infection occurs to comparable encounters in which an infection did not occur. This matching strategy is susceptible to a selection bias because inpatients that stay longer in the hospital are more likely to acquire an infection and thus also are more likely to have longer and more costly stays. Instead, we propose risk set matching, which matches infected encounters to similar encounters still at risk for infection at the corresponding time of infection. Matching on the one dimensional propensity score can create comparable pairs for a large number of characteristics; an analogous propensity score is described for risk set matching. We present dramatically different estimates using these two approaches on a pediatric cohort from the Premier Healthcare Database, 2009-2016. The results suggest that estimates that do not incorporate time of infection exaggerate the impact of hospital-acquired infections in regards to attributed length of stay and costs. PMID- 30475950 TI - Pembrolizumab Monotherapy for Previously Treated Metastatic Triple-Negative Breast Cancer: Cohort A of the Phase 2 KEYNOTE-086 Study. AB - Background: Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase 2 KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC. Patients and methods: Eligible patients had centrally confirmed mTNBC, >=1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Primary endpoints were objective response rate (ORR) in the total and PD-L1-positive populations, and safety. Secondary endpoints included duration of response, disease control rate (DCR; percentage of patients with complete or partial response or stable disease for >=24 weeks), progression-free survival (PFS), and overall survival (OS). Results: All enrolled patients (N=170) were women, 61.8% had PD-L1-positive tumors, and 43.5% had received >=3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7-9.9) in the total and 5.7% (2.4-12.2) in the PD-L1-positive populations. DCR (95% CI) was 7.6% (4.4 12.7) and 9.5% (5.1-16.8), respectively. Median duration of response was not reached in the total (range, 1.2+-21.5+) and in the PD-L1-positive (range, 6.3 21.5+) populations. Median PFS was 2.0 months (95% CI, 1.9-2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.7-11.2), and the 6-month rate was 69.1%. Treatment-related adverse events (AEs) occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs. Conclusions: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile. Clinical trial registration: ClinicalTrials.gov, NCT02447003. PMID- 30475951 TI - Exaggeration of PFS by blinded, independent, central review (BICR). AB - Background: Recent published studies have shown meaningful discrepancies between local investigator and blinded, independent, central review (BICR) assessed median progression-free survival (PFS). When the local review but not BICR shows progression, generally, no further assessments are performed and patients are censored in the BICR analysis, leading to violation of the statistical assumptions of independence between censoring and outcome used in survival analysis methods. Methods: We performed a simulation study to assess methodological reasons behind these discrepancies and corroborated our findings in a case study of three BRCA-mutated ovarian cancer trials. We briefly outline possible methodological solutions that may lead to improved estimation of the BICR medians. Results: The Kaplan-Meier curve for the BICR PFS can often be exaggerated. The degree of bias is largest when there is reasonably strong correlation between BICR and local PFS, especially when PFS is long compared to assessment frequency. This can result in an exaggeration of the medians and their difference; however, the hazard ratio (HR) is much less susceptible to bias. Our simulation shows that when the true BICR median PFS was 19 months, and patients assessed every 12 weeks, the estimated Kaplan-Meier curves were materially biased whenever the correlation between BICR and local PFS was 0.4 or greater. This was corroborated by case studies where, in the active arm, the BICR median PFS was between 6 and 11 months greater than the local median PFS. Further research is required to find improved methods for estimating BICR survival curves. Conclusions: In general, when there is a difference between local and BICR medians, the true BICR Kaplan-Meier curve is likely to be exaggerated and its true median will probably lie somewhere between the observed local and BICR medians. Presentation of data should always include both BICR and local results whenever a BICR is performed. PMID- 30475952 TI - Discordant Partial Thromboplastin Time (PTT) vs Anti-Xa Heparin Activity: Using the Baseline PTT to Improve Concordance. AB - Objectives: To determine the relationship between baseline variations in the partial thromboplastin time (PTT) and the discordance between the PTT and anti-Xa heparin activity (anti-Xa) during heparin therapy. Methods: The baseline PTT on heparin was determined using automated heparin neutralization with protamine (prPTT). The prPTT was used to calculate a baseline-corrected PTT on heparin to reduce discordance with anti-Xa measurements. Results: The prPTT removed up to 1 U/mL of heparin, returning baseline values for normal, factor-deficient, and lupus inhibitor plasmas. A prolonged prPTT was seen in 97 (53%) of 182 samples from heparinized patients. The heparinized PTT was discordant compared with anti Xa in 64 (35%) of 182 samples and 43 (67%) of 64 discordant samples, and 46% of concordant samples showed a prolonged prPTT. A baseline-corrected PTT reduced discordance with anti-Xa measurements by 64%. Conclusions: PTT/anti-Xa discordance due to baseline PTT prolongation could be reduced using a baseline corrected PTT. PMID- 30475953 TI - Maternal hypertensive disorders of pregnancy and offspring risk of hypertension: a population-based cohort and sibling study. AB - BACKGROUND: Women with a history of hypertensive disorders of pregnancy (HDP) are at increased risk of hypertension, cardiovascular disease, and type 2 diabetes. Offspring from pregnancies complicated by HDP also have worse cardiometabolic status in childhood and young adulthood, but the offspring risk of clinical hypertension in adulthood is largely unknown. METHODS: We studied 13,893 first born adult offspring (49.4% female) who attended a structured population-based primary care visit (The Vasterbotten Health Survey) at age 40 years in Sweden between 1994 and 2013. Data on maternal HDP were collected from a population based birth register. We investigated the association between maternal HDP and the risk of adult offspring hypertension and worse cardiometabolic risk factor status utilizing multivariable log binomial and linear regression models. We also conducted a sibling comparison, which inherently accounted for familial factors shared by siblings (N=135). RESULTS: Offspring participants of women with HDP (N=383, 2.8%) had increased relative risk of hypertension (1.67, 95% confidence interval: 1.38, 2.01) and also higher mean body mass index, systolic blood pressure, diastolic blood pressure, and worse 2h 75g oral glucose tolerance test result at age 40 years. No difference was observed for serum cholesterol. Point estimates for the cardiometabolic risk factors were attenuated in the sibling analyses. CONCLUSION: Offspring born to mothers with a history of HDP are on an adverse cardiometabolic trajectory, and should be considered as concomitant targets for primordial prevention of hypertension in the maternal post-pregnancy period. PMID- 30475954 TI - Reply to the letter to the editor on "Response to The effect of PD-L1 testing on the costeffectiveness of immune checkpoint inhibitors" by S. Ogale. PMID- 30475955 TI - Commentary on: Nonsurgical Management of Facial Masculinization and Feminization. PMID- 30475956 TI - Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic gastric cancer; a JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS. AB - The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of gastric cancer was published in 2016, and covered the management and treatment of local, locoregional, locally advanced and metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and The Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic gastric cancer (mGC) in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with mGC representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries. PMID- 30475957 TI - Effects of intermittent and continuous calorie restriction on body weight and metabolism over 50 wk: a randomized controlled trial. AB - Background: Although preliminary evidence suggests that intermittent calorie restriction (ICR) exerts stronger effects on metabolic parameters, which may link obesity and major chronic diseases, compared with continuous calorie restriction (CCR), there is a lack of well-powered intervention studies. Objective: We conducted a randomized controlled trial to test whether ICR, operationalized as the "5:2 diet," has stronger effects on adipose tissue gene expression, anthropometric and body composition measures, and circulating metabolic biomarkers than CCR and a control regimen. Design: One hundred and fifty overweight and obese nonsmokers [body mass index (kg/m2) >=25 to <40, 50% women], aged 35-65 y, were randomly assigned to an ICR group (5 d without energy restriction and 2 d with 75% energy deficit, net weekly energy deficit ~20%), a CCR group (daily energy deficit ~20%), or a control group (no advice to restrict energy) and participated in a 12-wk intervention phase, a 12-wk maintenance phase, and a 26-wk follow-up phase. Results: Loge relative weight change over the intervention phase was -7.1% +/- 0.7% (mean +/- SEM) with ICR, -5.2% +/- 0.6% with CCR, and -3.3% +/- 0.6% with the control regimen (Poverall < 0.001, PICR vs. CCR = 0.053). Despite slightly greater weight loss with ICR than with CCR, there were no significant differences between the groups in the expression of 82 preselected genes in adipose tissue implicated in pathways linking obesity to chronic diseases. At the final follow-up assessment (week 50), weight loss was 5.2% +/- 1.2% with ICR, -4.9% +/- 1.1% with CCR, and -1.7% +/- 0.8% with the control regimen (Poverall = 0.01, PICR vs. CCR = 0.89). These effects were paralleled by proportional changes in visceral and subcutaneous adipose tissue volumes. There were no significant differences between ICR and CCR regarding various circulating metabolic biomarkers. Conclusion: Our results on the effects of the "5:2 diet" indicate that ICR may be equivalent but not superior to CCR for weight reduction and prevention of metabolic diseases. This trial was registered at clinicaltrials.gov as NCT02449148. PMID- 30475958 TI - The association of fatty acid desaturase gene polymorphisms on long-chain polyunsaturated fatty acid composition in Indonesian infants. AB - Background: Adequate availability of long-chain polyunsaturated fatty acids (LC PUFAs) is important for human health from pregnancy to adulthood. Previous studies on fatty acid desaturase (FADS) gene single-nucleotide polymorphisms (SNPs) have been performed predominantly in Western populations and showed that FADS SNPs had a marked impact on LC-PUFA composition in blood and tissues. Objectives: We aimed to investigate the influence of fetal FADS genotypes on LC PUFA composition in umbilical artery plasma lipids in Indonesian infants. Design: We performed a cross-sectional study to assess for these associations. Results: A total of 12 cord plasma n-6 (omega-6) and n-3 (omega-3) fatty acids were analyzed for associations with 18 FADS gene cluster SNPs from 390 women with single parturition from the Indonesian Prospective Study of Atopic Dermatitis in Infants (ISADI). Fetal FADS genotypes influenced cord plasma LC-PUFA composition, but, in contrast to previous studies from Western populations, the quantitatively predominant SNPs were associated with lower LC-PUFA content. Conclusion: To our knowledge, this study was the first in South East Asia on FADS genotypes and arterial cord blood fatty acids to show an association between fetal LC-PUFA composition and fetal FADS SNPs. The FADS genotype distribution differs markedly between different geographical populations. This trial was registered at clinicaltrials.gov as NCT02401178. PMID- 30475959 TI - Association of protein intake with the outcomes of critically ill patients: a post hoc analysis of the PermiT trial. AB - Background: The optimal amount of protein intake in critically ill patients is uncertain. Objective: In this post hoc analysis of the PermiT (Permissive Underfeeding vs. Target Enteral Feeding in Adult Critically Ill Patients) trial, we tested the hypothesis that higher total protein intake was associated with lower 90-d mortality and improved protein biomarkers in critically ill patients. Design: In this post hoc analysis of the PermiT trial, we included patients who received enteral feeding for >=3 consecutive days. Using the median protein intake of the cohort as a cutoff, patients were categorized into 2 groups: a higher-protein group (>0.80 g . kg-1 . d-1) and a lower-protein group (<=0.80 g . kg-1 . d-1). We developed a propensity score for receiving higher protein. Primary outcome was 90-d mortality. We also compared serial values of prealbumin, transferrin, 24-h urinary nitrogen, and 24-h nitrogen balance on days 1, 7, and 14. Results: Among the 729 patients included in this analysis, the average protein intake was 0.8 +/- 0.3 g . kg-1 . d-1 [1.0 +/- 0.2 g . kg-1 . d-1 in the higher-protein group (n = 365) and 0.6 +/- 0.2 g . kg-1 . d-1 in the lower protein group (n = 364); P < 0.0001]. There was no difference in 90-d mortality between the 2 groups [88/364 (24.2%) compared with 94/363 (25.9%), propensity score-adjusted OR: 0.80; 95% CI: 0.56, 1.16; P = 0.24]. Higher protein intake was associated with an increase in 24-h urea nitrogen excretion compared with lower protein intake, but without a significant change in prealbumin, transferrin, or 24-h nitrogen balance. Conclusions: In the PermiT trial, a moderate difference in protein intake was not associated with lower mortality. Higher protein intake was associated with increased nitrogen excretion in the urine without a corresponding change in prealbumin, transferrin, or nitrogen balance. Protein intake needs to be tested in adequately powered randomized controlled trials targeting larger differences in protein intake in high-risk populations. PMID- 30475960 TI - Lack of acute or chronic effects of epicatechin-rich and procyanidin-rich apple extracts on blood pressure and cardiometabolic biomarkers in adults with moderately elevated blood pressure: a randomized, placebo-controlled crossover trial. AB - Background: The reported effects of flavanol-rich foods such as cocoa, dark chocolate, and apples on blood pressure and endothelial function may be due to the monomeric flavanols [mainly (-)-epicatechin (EC)], the oligomeric flavanols [procyanidins (PCs)], or other components. Reports of well-controlled intervention studies that test the effects of isolated oligomeric flavanols on biomarkers of cardiovascular health are lacking. Objective: We studied the acute and chronic effects of an EC-rich apple flavanol extract and isolated apple PCs on systolic blood pressure (BP) and other cardiometabolic biomarkers. Design: Forty-two healthy men and women with moderately elevated BP completed this randomized, double-blind, placebo-controlled, 4-arm crossover trial. Participants ingested a single dose of an apple flavanol extract (70 mg monomeric flavanols, 65 mg PCs), a double dose of this extract (140 mg monomeric flavanols, 130 mg PCs), an apple PC extract (130 mg PCs, 6.5 mg monomeric flavanols), or placebo capsules once daily for 4 wk, in random order. Biomarkers of cardiovascular disease risk and vascular function were measured before and 2 h after ingestion of the first dose and after the 4-wk intervention. Results: Compared with placebo, none of the isolated flavanol treatments significantly (P < 0.05) changed systolic or diastolic BP (peripheral and aortic), plasma nitric oxide (NO) reaction products, or measures of arterial stiffness (carotid femoral pulse wave velocity, brachial-ankle pulse-wave velocity, or Augmentation Index) after 2 h or 4 wk of the intervention. There were no changes in plasma endogenous metabolite profiles or circulating NO; endothelin 1; total, HDL, or LDL cholesterol; triglycerides; fasting glucose; fructosamine; or insulin after 4 wk of the intervention. Conclusions: Our data suggest that, in isolation, neither monomeric flavanols nor PCs affect BP, blood lipid profiles, endothelial function, or glucose control in individuals with moderately elevated BP. The reported benefits of consuming flavanol-rich cocoa, chocolate, and apple products appear to be dependent on other components, which may work in combination with monomeric flavanols and PCs. This trial was registered at www.clinicaltrials.gov as NCT02013856. PMID- 30475961 TI - Genetically determined vitamin D levels and change in bone density during a weight-loss diet intervention: the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) Trial. AB - Background: Obesity is closely associated with bone health. Although diet and weight loss produce many metabolic benefits, studies of weight loss diets on bone health are conflicting. Genetic variations, such as vitamin D levels, may partly account for these conflicting observations by regulating bone metabolism. Objective: We investigated whether the genetic variation associated with vitamin D concentration affected changes in bone mineral density (BMD) in response to a weight-loss diet intervention. Design: In the 2-y Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial, BMD was measured for 424 participants who were randomly assigned to 1 of 4 diets varying in macronutrient intakes. A genetic risk score (GRS) was calculated based on 3 genetic variants [i.e., 7-dehydrocholesterol reductase (DHCR7) rs12785878, cytochrome P450 2R1 (CYP2R1) rs10741657 and group-specific component globulin (GC) rs2282679] related to circulating vitamin D levels. A dual-energy X-ray absorptiometry scan was performed to assess changes in whole-body BMD over 2 y. The final analysis included 370 participants at baseline. Results: We found a significant interaction between dietary fat intake and vitamin D GRS on 2-y changes in whole body BMD (P-interaction = 0.02). In the high-fat diet group, participants with higher GRS showed significantly less reduction in whole-body BMD than those with lower GRS, whereas the genetic associations were not significant in the low-fat diet group. We also found a significant interaction between dietary fat intake and the GRS on 6-mo change in femur neck BMD (P-interaction = 0.02); however, the interaction became nonsignificant at 2 y. Conclusion: Our data indicate that dietary fat intake may modify the effect of vitamin D-related genetic variation on changes in BMD. Overweight or obese patients predisposed to sufficient vitamin D may benefit more in maintaining BMD along with weight loss by eating a low-fat diet. This trial was registered at clinicaltrials.gov as NCT03258203. PMID- 30475963 TI - Effects of protein supplementation on lean body mass, muscle strength, and physical performance in nonfrail community-dwelling older adults: a systematic review and meta-analysis. AB - Background: Increasing protein intake has been suggested as an effective strategy to ameliorate age-related loss of muscle mass and strength. Current reviews assessing the effect of protein supplementation are strongly influenced by the inclusion of studies with frail older adults. Objectives: We assessed the effect of protein supplementation on lean body mass, muscle strength, and physical performance in exclusively nonfrail community-dwelling older adults. Moreover, we assessed the superior effects of protein supplementation during concomitant resistance exercise training on muscle characteristics. Design: A systematic literature search was conducted on PubMed, Embase, and Web of Science up to 15 May 2018. We included randomized controlled trials that assessed the effect of protein supplementation on lean body mass, muscle thigh cross-sectional area, muscle strength, gait speed, and chair-rise ability and performed random-effects meta-analyses. Results: Data from 36 studies with 1682 participants showed no significant effects of protein supplementation on changes in lean body mass [standardized mean difference (SMD): 0.11; 95% CI: -0.06, 0.28], handgrip strength (SMD: 0.58; 95% CI: -0.08, 1.24), lower extremity muscle strength (SMD: 0.03; 95% CI: -0.20, 0.27), gait speed (SMD: 0.41; 95% CI: -0.04, 0.85), or chair rise ability (SMD: 0.10; 95%: CI -0.08, 0.28) compared with a control condition in nonfrail community-dwelling older adults. Moreover, no superior effects of protein supplementation were found during concomitant resistance exercise training on muscle characteristics. Conclusions: Protein supplementation in nonfrail community-dwelling older adults does not lead to increases in lean body mass, muscle cross-sectional area, muscle strength, or physical performance compared with control conditions; nor does it exert superior effects when added to resistance exercise training. Habitual protein intakes of most study participants were already sufficient, and protein interventions differed in terms of type of protein, amount, and timing. Future research should clarify what specific protein supplementation protocol is beneficial for nonfrail community dwelling older adults with low habitual protein intake. PMID- 30475964 TI - Coffee consumption and total mortality in a Mediterranean prospective cohort. AB - Background: The relation of coffee consumption with total mortality is controversial, because the available evidence is still inconsistent. Objective: This study aimed to assess this association in a highly educated, middle-aged Mediterranean cohort. Design: We analyzed data from 201,055 person-years of follow-up arising from 19,888 participants. Coffee consumption was obtained at baseline with the use of a previously validated semiquantitative food-frequency questionnaire. Information on mortality was ascertained by permanent contact with the "Seguimiento Universidad de Navarra" (SUN) participants and their families, postal authorities, and consultation of the National Death Index. We used Cox regression models to estimate HRs and 95% CIs for mortality according to baseline total coffee consumption adjusted for potential confounders. Sex, age, and baseline adherence to the Mediterranean diet were considered as potential effect modifiers. Results: Among the 19,888 participants, 337 died. Overall, in the multivariable adjusted analysis, we found a 22% lower risk of all-cause mortality for each 2 additional cups of total coffee per day (HR: 0.78; 95% CI: 0.66, 0.93). This association was stronger for participants aged >=55 y (HR: 0.67; 95% CI: 0.52, 0.86) than for younger participants, who showed no significant association (P-interaction = 0.002). Conclusion: In a Mediterranean cohort, we found an inverse linear association between total coffee consumption and the risk of all-cause mortality that was strongest among participants older than 54 y. PMID- 30475965 TI - Is abdominal obesity at baseline influencing weight changes in observational studies and during weight loss interventions? AB - Background: Body fat distribution is a marker of metabolic health independent of body size. Visceral fat accumulation has been suggested to result from a decreased expandability of the subcutaneous fat depots. Furthermore, the visceral fat may be easier to mobilize than the peripheral fat. We examined whether differences in abdominal obesity at baseline influenced prospective body-weight changes. Objective: In this study we examined whether body-fat distribution at baseline was associated with long-term and short-term weight changes. Design: We included 3 observational studies (ntotal = 7271) with mean follow-up times of 5-9 y and two 8-10-wk weight loss intervention studies (ntotal = 1091). We examined the association between baseline waist circumference and weight changes in a substitution regression model, where body weight, height, and fat-free mass were fixed so that a difference in waist circumference would reflect a difference in body fat distribution alone. The results were summarized in meta-analyses. Results: In the observational studies, we found no associations between baseline waist circumference and subsequent weight change in men (beta: 0.03 kg; 95% CI: 0.01, 0.08 kg; P = 0.19), but a negligible inverse association in women (beta: 0.05 kg; 95% CI: -0.08, -0.01 kg; P = 0.01). There was no association between baseline waist circumference and weight loss in the intervention studies (men: beta: -0.05 kg; 95% CI: -0.13, 0.03 kg; P = 0.25; women: beta: -0.00 kg; 95% CI: 0.03, 0.03 kg; P = 0.84). However, in all studies, the SDs of the weight change residuals were greater, the greater the waist circumference at baseline. This trend was statistically significant in women in most studies as well as in men in 1 of the studies. Conclusions: With narrow CIs in 3 observational studies and 2 weight loss interventions, we did not find any clinically or epidemiologically relevant association between baseline abdominal obesity and weight change. However, the present study suggests that a greater baseline abdominal obesity is a marker for greater weight fluctuations. The CCHS trial was registered at www.clinicaltrials.gov as NCT02993172. The Health2006 trial was registered at www.clinicaltrials.gov as NCT00316667. The ORG study was conducted before trial registration was required. The NUGENOB trial was registered at www.isrctn.com as ISRCTN25867281. The DiOGenes trial was registered atwww.clinicaltrials.gov as NCT00390637. PMID- 30475966 TI - Intermittent calorie restriction-a more effective approach to weight loss? PMID- 30475962 TI - Dietary intake and blood concentrations of antioxidants and the risk of cardiovascular disease, total cancer, and all-cause mortality: a systematic review and dose-response meta-analysis of prospective studies. AB - Background: High dietary intake or blood concentrations (as biomarkers of dietary intake) of vitamin C, carotenoids, and vitamin E have been associated with reduced risk of cardiovascular disease, cancer, and mortality, but these associations have not been systematically assessed. Objective: We conducted a systematic review and meta-analysis of prospective studies of dietary intake and blood concentrations of vitamin C, carotenoids, and vitamin E in relation to these outcomes. Design: We searched PubMed and Embase up to 14 February 2018. Summary RRs and 95% CIs were calculated with the use of random-effects models. Results: Sixty-nine prospective studies (99 publications) were included. The summary RR per 100-mg/d increment of dietary vitamin C intake was 0.88 (95% CI: 0.79, 0.98, I2 = 65%, n = 11) for coronary heart disease, 0.92 (95% CI: 0.87, 0.98, I2 = 68%, n = 12) for stroke, 0.89 (95% CI: 0.85, 0.94, I2 = 27%, n = 10) for cardiovascular disease, 0.93 (95% CI: 0.87, 0.99, I2 = 46%, n = 8) for total cancer, and 0.89 (95% CI: 0.85, 0.94, I2 = 80%, n = 14) for all-cause mortality. Corresponding RRs per 50-MUmol/L increase in blood concentrations of vitamin C were 0.74 (95% CI: 0.65, 0.83, I2 = 0%, n = 4), 0.70 (95% CI: 0.61, 0.81, I2 = 0%, n = 4), 0.76 (95% CI: 0.65, 0.87, I2 = 56%, n = 6), 0.74 (95% CI: 0.66, 0.82, I2 = 0%, n = 5), and 0.72 (95% CI: 0.66, 0.79, I2 = 0%, n = 8). Dietary intake and/or blood concentrations of carotenoids (total, beta-carotene, alpha-carotene, beta-cryptoxanthin, lycopene) and alpha-tocopherol, but not dietary vitamin E, were similarly inversely associated with coronary heart disease, stroke, cardiovascular disease, cancer, and/or all-cause mortality. Conclusions: Higher dietary intake and/or blood concentrations of vitamin C, carotenoids, and alpha tocopherol (as markers of fruit and vegetable intake) were associated with reduced risk of cardiovascular disease, total cancer, and all-cause mortality. These results support recommendations to increase fruit and vegetable intake, but not antioxidant supplement use, for chronic disease prevention. PMID- 30475967 TI - Effect of nut consumption on semen quality and functionality in healthy men consuming a Western-style diet: a randomized controlled trial. AB - Background: Human semen quality has declined in industrialized countries. Pollution, smoking, and the consumption of a Western-style diet are all hypothesized as potential causes. Objective: We evaluated the effect of chronic consumption of nuts on changes in conventional semen parameters and the potential mechanisms implicated. Design: The FERTINUTS study was a 14-wk randomized, controlled, parallel trial. A total of 119 healthy men, aged 18-35 y, were allocated to 1 of 2 intervention groups: one group was fed the usual Western style diet enriched with 60 g of a mixture of nuts/d (nut group), and the other was fed the usual Western-style diet avoiding nuts (control group). Semen and blood samples were collected at baseline and at the end of the intervention. Dietary information was recorded throughout the trial. Changes in conventional semen parameters (pH, volume, sperm count and concentration, motility, and morphology) were determined as primary outcomes. The effect of nut consumption on sperm DNA fragmentation (SDF), reactive oxygen species (ROS) production, chromosome anomalies (X, Y, and 18), total DNA methylation, and microRNA expression were measured in sperm samples as potential causes of the changes in the seminogram. Results: Compared with the control group, improvements in total sperm count (P = 0.002) and vitality (P = 0.003), total motility (P = 0.006), progressive motility (P = 0.036), and morphology of sperm (P = 0.008) were observed in the nut group. Participants in the nut group showed an increase in the consumption of total fat, monounsaturated fatty acids, polyunsaturated fatty acids, magnesium, vitamin E, alpha-linolenic acid, total omega-3 (n-3) and omega 3:omega-6 ratio intake during the intervention. Participants in the nut group showed a significant reduction in SDF (P < 0.001) and in the expression of hsa miR-34b-3p (P = 0.036). No significant changes in ROS, sperm chromosome anomalies, or DNA methylation were observed between groups. Conclusions: The inclusion of nuts in a Western-style diet significantly improves the total sperm count and the vitality, motility, and morphology of the sperm. These findings could be partly explained by a reduction in the sperm DNA fragmentation. This trial was registered at ISRCTN as ISRCTN12857940. PMID- 30475969 TI - Protein supplementation improves muscle mass and physical performance in undernourished prefrail and frail elderly subjects: a randomized, double-blind, placebo-controlled trial. AB - Background: Age-related loss of muscle mass and function is a major component of frailty. Nutrition supplementation with exercise is an effective strategy to decrease frailty by preventing sarcopenia, but the effect of protein alone is controversial. Objective: The present study was performed to investigate a dose dependent effect of protein supplementation on muscle mass and frailty in prefrail or frail malnourished elderly people. Design: A 12-wk double-blind randomized controlled trial was conducted in elderly subjects aged 70-85 y with >=1 of the Cardiovascular Health Study frailty criteria and a Mini Nutritional Assessment score <=23.5 (n = 120). Participants were randomly assigned to 1 of 3 groups: 0.8, 1.2, or 1.5 g protein . kg-1 . d-1, with concealed allocation and intention-to-treat analysis. Primary outcomes were appendicular skeletal muscle mass (ASM) and skeletal muscle mass index (SMI) measured by dual-energy X-ray absorptiometry. Results: After the 12-wk intervention, the 1.5-g protein . kg-1 . d-1 group had higher ASM (mean +/- SD: 0.52 +/- 0.64 compared with 0.08 +/- 0.68 kg, P = 0.036) and SMI (ASM/weight: 0.87% +/- 0.69% compared with 0.15% +/- 0.89%, P = 0.039; ASM/BMI: 0.02 +/- 0.03 compared with 0.00 +/- 0.04, P = 0.033; ASM:fat ratio: 0.04 +/- 0.11 compared with -0.02 +/- 0.10, P = 0.025) than the 0.8-g protein . kg-1 . d-1 group. In addition, gait speed was improved in the 1.5 g protein . kg-1 . d-1 group compared with the 0.8-g protein . kg-1 . d-1 group (0.09 +/- 0.07 compared with 0.04 +/- 0.07 m/s, P = 0.039). There were no significant differences between the 1.2- and 0.8-g protein . kg-1 . d-1 groups in muscle mass and physical performance. No harmful adverse effects were observed. Conclusions: The present study indicates that protein intake of 1.5 g . kg-1 . d 1 has the most beneficial effects in regard to preventing sarcopenia and frailty compared with protein intakes of 0.8 and 1.2 g . kg-1 . d-1 in prefrail or frail elderly subjects at risk of malnutrition. This trial was registered at cris.nih.go.kr as KCT0001923. PMID- 30475968 TI - Long-term consumption of a Mediterranean diet improves postprandial lipemia in patients with type 2 diabetes: the Cordioprev randomized trial. AB - Background: Patients with type 2 diabetes (T2D) have an elevated postprandial lipemia (PPL) that has been associated with increased cardiovascular risk. Objective: We aimed to analyze whether the long-term consumption of 2 healthy dietary patterns is associated with an improvement in PPL and remnant cholesterol (RC) concentrations in patients with T2D. Design: We selected patients from the Cordioprev study who underwent oral fat load tests (FLTs) at baseline and the 3-y follow-up (241 patients with and 316 patients without T2D). Subjects were randomly assigned to receive either a Mediterranean diet rich in olive oil (MedDiet; 35% of calories from fat [22% monounsaturated fatty acids (MUFAs)] and 50% from carbohydrates) or a low-fat (LF) diet [<30% fat (12-14% MUFAs) and 55% of calories from carbohydrates]. Lipids were measured in serial bloods drawn at 0, 1, 2, 3, and 4 h after the FLT. Results: After 3 y of dietary intervention, patients with T2D showed an improvement in their PPL measured as postprandial triglycerides (TGs) (P < 0.0001), TG area under the curve (AUC) (P = 0.001), and TG-rich lipoproteins (TRLs-TG; P = 0.001) compared with baseline. Subgroup analysis, based on the type of dietary intervention, showed that those T2D patients randomly assigned to the MedDiet presented a reduction in the TG AUC of 17.3% compared with baseline (P = 0.003). However, there were no differences for T2D patients randomly assigned to the LF diet (P > 0.05) or in patients without T2D (P > 0.05) regardless of the dietary intervention. In addition, the MedDiet induced a significant improvement in the RC AUC in patients with T2D (P = 0.04). However, there was no significant improvement in those following the LF diet. Conclusions: Our findings show that the long-term consumption of a MedDiet rich in olive oil improves PPL and RC concentrations mainly in patients with T2D. This trial was registered at clinicaltrials.gov as NCT00924937. PMID- 30475970 TI - Serum retinyl esters are positively correlated with analyzed total liver vitamin A reserves collected from US adults at time of death. AB - Background: Minimal human data exist on liver vitamin A (VA) compared with serum biomarkers. Cutoffs of 5% and 10% total serum VA as retinyl esters (REs) suggest a VA intoxication diagnosis. Objectives: We compared total liver VA reserves (TLRs) with the percentage of total serum VA as REs to evaluate hypervitaminosis with the use of US adult autopsy samples. Secondary objectives evaluated serum retinol sensitivity, TLRs among lobes, and hepatic alpha-retinol concentrations, an alpha-carotene cleavage product. Design: Matched serum and liver samples were procured from cadavers (n = 27; mean +/- SD age: 70.7 +/- 14.9 y; range: 49-101 y). TLRs and alpha-REs were quantified by ultra-performance liquid chromatography. Pearson correlations showed liver and serum associations. Sensitivity and specificity were calculated for >5%, 7.5%, and 10% total serum VA as REs to predict TLRs and for serum retinol <0.7 and 1 MUmol/L to predict deficiency. Results: Serum RE concentrations were correlated with TLRs (r = 0.497, P < 0.001). Nine subjects (33%) had hypervitaminosis A (>=1.0 MUmol VA/g liver), 2 of whom had >7.5% total serum VA as REs; histologic indicators corroborated toxicity at 3 MUmol/g liver. No subject had >10% total serum VA as REs. Serum retinol sensitivity to determine deficiency (TLRs <0.1 MUmol VA/g) was 83% at 0.7 and 1 MUmol/L. Hepatic alpha-retinol was positively correlated with age (P = 0.047), but removing an outlier nullified significance. Conclusions: This study evaluated serum REs as a biomarker of VA status against TLRs (gold standard), and abnormal histology suggested that 7.5% total serum VA as REs is diagnostic for toxicity at the individual level in adults. The long-term impact of VA supplements and fortificants on VA status is currently unknown. Considering the high prevalence of hypervitaminotic TLRs in this cohort, and given that many countries are adding preformed VA to processed products, population biomarkers diagnosing hypervitaminosis before toxicity are urgently needed. This trial was registered at clinicaltrials.govas NCT03305042. PMID- 30475971 TI - Can protein supplementation lead to clinically meaningful improvements in muscle mass and function in undernourished (pre)frail elderly? PMID- 30475972 TI - Intake of protein-rich foods in relation to outcomes of infertility treatment with assisted reproductive technologies. AB - Background: Some dietary factors have been linked to outcomes of infertility treatment with assisted reproductive technology (ART), but the role of intake of meats and other protein-rich foods remains unclear. Objective: The aim of this manuscript was to study the relation between preconception intake of meat and other protein-rich foods and outcomes of infertility treatment with ART. Design: A total of 351 women enrolled in a prospective cohort at the Massachusetts General Hospital Fertility Center and underwent 598 ART cycles for infertility treatment. Meat intake was assessed with a validated food-frequency questionnaire, and ART outcomes were abstracted from electronic medical records. We estimated the associations between intake of protein-rich foods (meats, eggs, beans, nuts, and soy) and the outcome of live birth per initiated cycle using generalized linear mixed models. Results: The average total meat intake was 1.2 servings/d, with most coming from poultry (35%), fish (25%), processed meat (22%), and red meat (17%). Fish intake was positively related to the proportion of cycles resulting in live birth. The multivariable-adjusted probabilities of live birth for women in increasing quartiles of fish intake were 34.2% (95% CI: 26.5%, 42.9%), 38.4% (95% CI: 30.3%, 47.3%), 44.7% (95% CI: 36.3%, 53.4%), and 47.7% (95% CI: 38.3%, 57.3%), respectively (P-trend = 0.04). In the estimated substitution analyses, the ORs of live birth associated with increasing fish intake by 2 servings/wk were 1.54 (95% CI: 1.14, 2.07) when fish replaced any other meat, 1.50 (95% CI: 1.13, 1.98) when fish replaced any other protein-rich food, and 1.64 (95% CI: 1.14, 2.35) when fish replaced processed meat. Conclusions: Fish consumption is related to a higher probability of live birth following infertility treatment with ART. This trial was registered at clinicaltrials.gov as NCT00011713. PMID- 30475973 TI - Sedentary time, physical activity, and adiposity in a longitudinal cohort of nonobese young adults. AB - Background: Young adulthood is a critical period for excessive weight gain. The extent to which young adults' sedentary time (ST) and moderate-to-vigorous physical activity (MVPA) relate to adiposity and weight gain remains unclear. Objective: The purpose of this study was to examine the relation of ST and MVPA with adiposity and change in adiposity in healthy, nonobese young adults over a 2 y period. Design: Participants were 71 adults aged 20-35 y. Measurements included ST and MVPA by accelerometry and reported energy intake at baseline, and anthropometry (%FM) and fat mass (FM) by dual-energy X-ray absorptiometry at baseline, year 1, and year 2. Associations of baseline ST and MVPA with adiposity were examined with the use of repeated-measures linear regression models, controlling for age, sex, and reported energy intake. The Benjamini-Hochberg procedure was used to adjust for multiple comparisons. Results: Participants [mean +/- SD body mass index (BMI; kg/m2): 22.6 +/- 2.4] engaged in 8.5 +/- 1.5 h ST/d and 0.4 +/- 0.3 h MVPA/d. At baseline, adults who engaged in ST for >=8 h/d had higher FM, %FM, and lower MVPA, whereas those who engaged in MVPA for >=30 min/d had lower FM and %FM. In fully adjusted models, ST was significantly associated with baseline body weight, hip circumference, BMI, FM, and %FM and with year-1 body weight, waist and hip circumference, FM, and %FM, but not with any year-2 adiposity indicators. MVPA was not significantly associated with any adiposity indicators at baseline, year 1, or year 2 in fully adjusted models. Over 2 y, participants significantly increased waist circumference, BMI, FM, and %FM (all P-values <0.05), but there were no associations among baseline ST and MVPA with change in adiposity. Conclusions: Among nonobese young adults, high ST and low MVPA were related to elevated adiposity but did not predict change in adiposity over time. This trial was registered at clinicaltrials.gov as NCT00945633. PMID- 30475974 TI - Failure is not final: ctDNA-guided rechallenge therapy in colorectal cancer. PMID- 30475975 TI - Wound Closure Under Tension: It Takes Brains, Not Brawn. PMID- 30475976 TI - A Case Report of a Breast Implant-Associated Plasmacytoma and Literature Review of Non-ALCL Breast Implant-Associated Neoplasms. AB - Lymphomas associated with breast implants are rare, with the most common being anaplastic large cell lymphoma (ALCL). Non-ALCL breast implant-associated lymphomas are even more rare, with only a small handful of such neoplasms reported to date. Given the need to better understand these pathologies as well as the increasing clinical and media attention to these diseases, we review the available literature of hematolymphoid neoplasms other than ALCL associated with breast implants and describe the first case of a patient diagnosed with a primary breast implant-associated plasmacytoma. PMID- 30475978 TI - Do Female and Male Authors Share Promotion of Their Work on Social Media With Equal Frequency? PMID- 30475977 TI - Shift Work and Respiratory Infections in Healthcare Workers. AB - Recently, there has been interest in whether shift work may enhance infection susceptibility. Our aim was to determine whether shift workers in healthcare have a higher incidence, duration, and severity of influenza-like illness (ILI) and acute respiratory illness (ARI) than non-shift workers. From September 2016-June 2017, 501 rotating and/or night shift workers and 88 non-shift workers from the Klokwerk+ study (2016-2017) daily registered occurrence of ILI/ARI symptoms using a smartphone application. Incidence rate of ILI/ARI episodes (defined as >=2 symptoms on the same day/>=1 symptom during two consecutive days), mean duration per episode, and incidence rate of severe episodes were compared between shift and non-shift workers using negative binomial regression and linear mixed model analysis. In total, participants completed 110,347 diaries. Shift workers' incidence rate of ILI/ARI episodes was 1.20 (95%-CI:1.01, 1.43) times higher, and for severe ILI/ARI episodes 1.22 (95%-CI:1.01, 1.49) times higher, compared to non-shift workers. Mean duration per ILI/ARI episode did not differ (ratio between means=1.02 (95%-CI:0.87, 1.19)). In conclusion, shift workers in healthcare had more and more severe ILI/ARI episodes than non-shift workers, but with a similar duration. Insight into underlying mechanisms connecting shift work and infection susceptibility will contribute to the design of preventive initiatives. PMID- 30475979 TI - Commentary on: Endocrine-Metabolic Response in Patients Undergoing Multiple Body Contouring Surgeries After Massive Weight Loss. PMID- 30475981 TI - Impact of hypertension on hospitalizations for cardiovascular diseases in a worksite population -an epidemiologic study using claims data for workers. AB - BACKGROUND: Few of studies investigated the effect of antihypertensives among working population. We aimed to describe the impact of hypertension with and without antihypertensives on hospitalizations due to cardiovascular diseases (CVDs) in the Japanese working population. METHODS: This retrospective study included adults aged 40-64years whose systolic and diastolic blood pressure (BP) readings taken between 2008 and 2015 were available in the Japanese claims database. Individuals were categorized as treated (T) or untreated (UT) depending on their hypertension treatment history. Time to first CVD-related hospitalization was compared among individuals with different BP levels using Cox models which included baseline characteristics with either baseline BP level or a time-dependent variable reflecting BP changes over time. RESULTS: Of 740,784 UT individuals (male: 61.9%, mean age: 47.9years), 2,121 individuals were hospitalized due to a CVD over a 957.3-day average follow-up. Among 72,828 T individuals (male: 74.3%, mean age: 53.7years), the corresponding figure was 470 individuals over an 813.4-day average follow-up. The risk of hospitalization increased with baseline hypertension severity among UT (hazard ratios [HRs]=1.93, 2.82 and 6.32 for grade1, grade2 and grade3, respectively; p<0.0001, reference: optimal) but not among T individuals. UT individuals with hypertension at any given time had a significantly higher probability of hospitalization compared to non-hypertensive individuals (HR=1.74, p<0.0001). CONCLUSION: This study adds quantitative evidence on the impact of hypertension on the risk of CVD-related hospitalization in the Japanese working population. It suggests that antihypertensive treatment had beneficial effects in this relatively young, working population aged 40 to 64 years old. PMID- 30475980 TI - RT States: systematic annotation of the human genome using cell type-specific replication timing programs. AB - Motivation: The replication timing (RT) program has been linked to many key biological processes including cell fate commitment, 3D chromatin organization and transcription regulation. Significant technology progress now allows to characterize the RT program in the entire human genome in a high-throughput and high-resolution fashion. These experiments suggest that RT changes dynamically during development in coordination with gene activity. Since RT is such a fundamental biological process, we believe that an effective quantitative profile of the local RT program from a diverse set of cell types in various developmental stages and lineages can provide crucial biological insights for a genomic locus. Results: In the present study, we explored recurrent and spatially coherent combinatorial profiles from 42 RT programs collected from multiple lineages at diverse differentiation states. We found that a Hidden Markov Model with 15 hidden states provide a good model to describe these genome-wide RT profiling data. Each of the hidden state represents a unique combination of RT profiles across different cell types which we refer to as "RT states". To understand the biological properties of these RT states, we inspected their relationship with chromatin states, gene expression, functional annotation and 3D chromosomal organization. We found that the newly defined RT states possess interesting genome-wide functional properties that add complementary information to the existing annotation of the human genome. Supplementary information: R scripts for inferring HMM models and Perl scripts for further analysis are available https://github.com/PouletAxel/script_HMM_Replication_timing. Supplementary data are available at Bioinformatics online. PMID- 30475983 TI - SGTK: a toolkit for visualization and assessment of scaffold graphs. AB - Summary: Scaffolding is an important step in every genome assembly pipeline, which allows to order contigs into longer sequences using various types of linkage information, such as mate-pair libraries and long reads. In this work we operate with a notion of a scaffold graph - a graph, vertices of which correspond to the assembled contigs, and edges represent connections between them. We present a software package called Scaffold Graph ToolKit (SGTK) that allows to construct and visualize scaffold graphs using different kinds of sequencing data. We show that the scaffold graph appears to be useful for analyzing and assessing genome assemblies, and demonstrate several use cases that can be helpful for both assembly software developers and their users. Availability and implementation: SGTK is implemented in C++, Python and JavaScript and is freely available at https://github.com/olga24912/SGTK. Supplementary material: To be posted on-line. PMID- 30475982 TI - Opioidergic Regulation of Emotional Arousal: A Combined PET-fMRI Study. AB - Emotions can be characterized by dimensions of arousal and valence (pleasantness). While the functional brain bases of emotional arousal and valence have been actively investigated, the neuromolecular underpinnings remain poorly understood. We tested whether the opioid and dopamine systems involved in reward and motivational processes would be associated with emotional arousal and valence. We used in vivo positron emission tomography to quantify MU-opioid receptor and type 2 dopamine receptor (MOR and D2R, respectively) availability in brains of 35 healthy adult females. During subsequent functional magnetic resonance imaging carried out to monitor hemodynamic activity, the subjects viewed movie scenes of varying emotional content. Arousal and valence were associated with hemodynamic activity in brain regions involved in emotional processing, including amygdala, thalamus, and superior temporal sulcus. Cerebral MOR availability correlated negatively with the hemodynamic responses to arousing scenes in amygdala, hippocampus, thalamus, and hypothalamus, whereas no positive correlations were observed in any brain region. D2R availability-here reliably quantified only in striatum-was not associated with either arousal or valence. These results suggest that emotional arousal is regulated by the MOR system, and that cerebral MOR availability influences brain activity elicited by arousing stimuli. PMID- 30475984 TI - A plugin for the Ensembl Variant Effect Predictor that uses MaxEntScan to predict variant spliceogenicity. AB - Summary: Assessing the pathogenicity of genetic variants can be a complex and challenging task. Spliceogenic variants, which alter mRNA splicing, may yield mature transcripts that encode non-functional protein products, an important predictor of Mendelian disease risk. However, most variant annotation tools do not adequately assess spliceogenicity outside the native splice site and thus the disease-causing potential of variants in other intronic and exonic regions is often overlooked. Here, we present a plugin for the Ensembl Variant Effect Predictor that packages MaxEntScan and extends its functionality to provide splice site predictions using a maximum entropy model. The plugin incorporates a sliding window algorithm to predict splice site loss or gain for any variant that overlaps a transcript feature. We also demonstrate the utility of the plugin by comparing our predictions to two mRNA splicing datasets containing several cancer susceptibility genes. Availability: Source code is freely available under the Apache License, Version 2.0: https://github.com/Ensembl/VEP_plugins. Supplementary information: Supplementary data are available online at Bioinformatics. PMID- 30475985 TI - Exposure of the Extracellular Matrix and Colonization of the Ovary in Metastasis of Fallopian Tube Derived Cancer. AB - High-grade serous ovarian cancer (HGSOC) can originate in the fallopian tube epithelium (FTE), but the role of the ovary in these tumors is unclear. Tumorigenic murine oviductal epithelial (MOE) cells allografted in the ovarian bursa resulted in aggressive tumors that spread throughout the peritoneum, while intraperitoneal xenografting the same number of cells did not form tumors, indicating that colonization of the ovary may play a role in metastasis. Physical tearing of the ovarian surface to mimic rupture of the ovary during ovulation (independent of hormonal changes) resulted in more MOE and HGSOC cells adhering to the ovary compared to intact ovaries. More MOE cells also adhered to three dimensional (3D) collagen and primary ovarian stromal cells than to ovarian surface epithelia, indicating that FTE cells adhered to the extracellular matrix (ECM) exposed during ovulation. However, plating cells on 3D collagen reduced the viability of normal FTE but not cancer cells. Mutation of p53 (R273H or R248W) and activation of KRAS (G12V) did not increase the viability of MOE cells on 3D collagen. In contrast, loss of PTEN allowed MOE cells to retain normal viability on 3D collagen. Loss of PTEN activated AKT and RAC1/JNK signaling that each contributed to the increased viability, invasion, and attachment in the collagen rich ovarian microenvironment. These results show that loss of PTEN activates multiple pathways that together enhance colonization of the ovary due to access to 3D collagen, which is a critical organ in the colonization of FTE-derived HGSOC. PMID- 30475986 TI - TGF-beta-SMAD-miR-520e axis regulates NSCLC metastasis through a TGFBR2-mediated negative feedback loop. AB - Transforming growth factor-beta (TGF-beta) pathway plays crucial roles during the carcinogenesis and metastasis. Transforming growth factor-beta receptor 2 (TGFBR2) is a key molecule for the regulation of TGF-beta pathway and frequently downregulated or lost in several cancer types including non-small cell lung cancer (NSCLC) and TGF-beta pathway is often regulated by negative feedback mechanisms but little is known about the mechanism of TGFBR2 downregulation in NSCLC. Here, we found that the expression of miR-520e is upregulated in metastatic tumor tissues compared to non-metastatic ones and its expression is inversely correlated with that of TGFBR2 in clinical samples. We also discovered that TGF-beta dramatically increased the expression of miR-520e, which targeted and downregulated TGFBR2, and the suppression of miR-520e significantly impaired TGF-beta-induced TGFBR2 downregulation. ChIP-PCR experiments further showed that miR-520e is transcriptionally induced by SMAD2/3 in response to TGF-beta. Our findings reveal a novel negative feedback mechanism in TGF-beta signaling and the expression level of miR-520e could be a predictive biomarker for NSCLC metastasis. PMID- 30475987 TI - Seroprevalence of human papillomavirus 6/11/16/18 among self-identified gay/bisexual men who have sex with men, men who have sex with women, and females, United States, 2003-2010. AB - Background: Differences in human papillomavirus (HPV) seroprevalence by sex have been observed, likely due to differences in the anatomic site of HPV exposure. Seroconversion may be more likely after exposure at non-keratinized (mucosal) compared to keratinized epithelium. We compared seroprevalence among self identified gay/bisexual men who have sex with men (MSM) and females, two groups more likely exposed at mucosal epithelium, and men who only have sex with women (MSW), a group likely exposed primarily at keratinized epithelium, using data from the National Health and Nutrition Examination Survey from 2003-2010. Methods: HPV 6/11/16/18 serum antibody was detected using a multiplexed, competitive luminex immunoassay. Weighted seroprevalence was estimated among unvaccinated, sexually experienced 18-59 year-old MSM, MSW, and females, overall and by demographic and sexual behavior characteristics. Seroprevalences were compared using prevalence ratios adjusted for sexual behavior (aPRs). Results: Overall, seroprevalence in MSM, MSW, and females was 42.6%, 13.2%, and 37.1%, respectively. Seroprevalence in MSM was comparable to females (aPR: 0.85, 95% CI: 0.68-1.08) and higher than MSW (aPR: 2.72, 95% CI: 2.19-3.38). MSW had a significantly lower seroprevalence than females (aPR: 0.31, 95% CI: 0.28-0.34). Similar associations were seen in all sociodemographic subgroups. Seroprevalence increased with number of lifetime sex partners in all groups. Conclusions: In this population-based survey, HPV seroprevalence among groups likely exposed at mucosal epithelium (MSM, females) was comparable; seroprevalence in both groups was higher than in MSW. Future research could explore whether differences in seropositivity following infection results in differential protection from future infection. PMID- 30475988 TI - The Safety of Influenza and Pertussis Vaccination in Pregnancy in a Cohort of Australian Mother-Infant Pairs, 2012-2015: The FluMum Study. AB - Background: Inactivated influenza vaccine (IIV) and pertussis vaccination are recommended in pregnancy. Limited safety data exist for women who received IIV vaccine during the first trimester of pregnancy or received both vaccines in pregnancy. We assessed adverse birth outcomes between vaccinated and unvaccinated pregnancies. Methods: Among prospectively enrolled Australian "FluMum" participants (2012-2015), primary exposure was receipt and timing of IIV during pregnancy. Primary outcomes included preterm birth, low birthweight at term (LBWT), and small for gestational age (SGA). We compared birth outcomes for IIV in pregnancy with women unvaccinated in pregnancy using Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs). Adjusted HRs (aHRs) controlled for potential confounding variables. Sensitivity analyses were conducted in a subgroup of women who received pertussis vaccination during pregnancy to assess whether associations between IIV and adverse outcomes were maintained after adjusting for pertussis vaccination. Results: Among 8827 participants in our study, women who received IIV in pregnancy did not have an elevated risk of an adverse birth outcome compared with unvaccinated pregnant women: preterm births (HR, 1.10 [95% CI, .92-1.31]; P = .28); LBWT (HR, 1.05 [95% CI, .76-1.44]; P = .77); or SGA (HR, 0.99 [95% CI, .86-1.15]; P = .94). Adjustment for pertussis vaccination during pregnancy yielded similar results: preterm births (aHR, 1.05 [95% CI, .82-1.34]; P = .69); LBWT (aHR, 0.81 [95% CI, .50-1.29]; P = .37); SGA (aHR, 0.92 [95% CI, .74-1.14]; P = .43). There was no evidence of elevated risk by trimester of IIV. Conclusions: No significant associations were found between maternal IIV or pertussis vaccination in pregnancy and adverse birth outcomes, regardless of the trimester of pregnancy a vaccination was given compared to unvaccinated pregnancies. PMID- 30475989 TI - Control of Carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa in Healthcare Facilities: A Systematic Review and Reanalysis of Quasi-experimental Studies. AB - Carbapenem-resistant Enterobacteriaceae (CRE), Acinetobacter baumannii (CRAB), and Pseudomonas aeruginosa (CRPsA) are a serious cause of healthcare-associated infections, although the evidence for their control remains uncertain. We conducted a systematic review and reanalysis to assess infection prevention and control (IPC) interventions on CRE-CRAB-CRPsA in inpatient healthcare facilities to inform World Health Organization guidelines. Six major databases and conference abstracts were searched. Before-and-after studies were reanalyzed as interrupted time series if possible. Effective practice and organization of care (EPOC) quality criteria were used. Seventy-six studies were identified, of which 17 (22%) were EPOC-compatible and interrupted time series analyses, assessing CRE (n = 11; 65%), CRAB (n = 5; 29%) and CRPsA (n = 3; 18%). IPC measures were often implemented using a multimodal approach (CRE: 10/11; CRAB: 4/5; CRPsA: 3/3). Among all CRE-CRAB-CRPsA EPOC studies, the most frequent intervention components included contact precautions (90%), active surveillance cultures (80%), monitoring, audit and feedback of measures (80%), patient isolation or cohorting (70%), hand hygiene (50%), and environmental cleaning (40%); nearly all studies with these interventions reported a significant reduction in slope and/or level. The quality of EPOC studies was very low to low. PMID- 30475990 TI - Novel Therapies Hijack the Blood Brain Barrier to Eradicate Glioblastoma Cancer Stem Cells. AB - Glioblastoma (GBM) is among the most aggressive brain tumors with a dismal prognosis. Despite significant advances in the current multimodality therapy including surgery, postoperative radiotherapy (RT) and temozolomide (TMZ) based concomitant and adjuvant chemotherapy (CT), tumor recurrence is nearly universal with poor patient outcome. These limitations are in part due to poor drug penetration through the blood brain barrier (BBB) and resistance to CT and RT by a small population of cancer cells recognized as tumor-initiating cells or cancer stem cells (CSCs). Though CT and RT kill the bulk of the tumor cells, they fail to effect CSCs, resulting in their enrichment and their development into more refractory tumors. Therefore, identifying the mechanisms of resistance and developing therapies that specifically target CSCs can improve response, prevent the development of refractory tumors and increase overall survival of GBM patients. Small molecule inhibitors that can breach the BBB and selectively target CSCs are emerging. In this review, we have summarized the recent advancements in understanding the GBM CSC-specific signaling pathways, the CSC - tumor microenvironment niche that contributes to CT and RT resistance, and the use of novel combinatorial therapies of small molecule inhibitors that may be used in conjunction with TMZ based chemoradiation for effective management of GBM. PMID- 30475991 TI - Dietary N-nitroso compounds and risk of pancreatic cancer: results from a large case-control study. AB - N-nitroso compounds (NOCs) are among the most potent dietary and pancreatic carcinogens. N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA) are the most prevalent NOCs identified in foods. Using a validated and comprehensive N-nitroso database developed to estimate total NOCs and important individual NOCs from food intake, we investigated dietary exposure to NOCs in relation to pancreatic cancer in a large matched case-control study. Self-administered food frequency questionnaires (FFQ) were collected from 957 pathologically confirmed pancreatic ductal adenocarcinoma cases and 938 frequency-matched controls. For each food item, frequency of intake and portion size in grams was multiplied by the estimated NOC concentration from the N-nitroso database. Multiple unconditional logistic regression models were used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for pancreatic cancer risk by quartiles of NOCs and major food group contributors to NOCs, with the lowest quartile as referent. Following adjustment for confounders, we observed significant positive associations for NDEA (ORQ4 vs Q1=2.28, 95% CI=1.71-3.04, Ptrend<0.0001) and NDMA from plant sources (ORQ4 vs Q1=1.93, 95% CI=1.42-2.61, Ptrend <0.0001) with pancreatic cancer. The major food groups related to NDEA and NDMA intakes in this population were fermented cheese, pizza, grains, seafood, and beer. No associations of intake of nitrate or total NOCs were observed; nitrite was inversely associated with pancreatic cancer. While some of our findings likely reflect reverse causation bias due to lower meat intake in cases with latent disease, biologically plausible findings for pancreatic carcinogens, NDEA and NDMA, warrant further prospective investigation. PMID- 30475992 TI - Prevalence and epidemiological characteristics of asymptomatic malaria based on ultrasensitive diagnostics: A cross-sectional study. AB - Background: As the global public health objectives for malaria evolve from malaria control towards malaria elimination, there is increasing interest in the significance of asymptomatic infections and the optimal diagnostic test to identify them. Method: We conducted a cross-sectional study of asymptomatic individuals (n=562) to determine epidemiological characteristics associated with asymptomatic malaria. Participants were tested by RDTs (CareStart TM, SD Bioline, and Alere uRDT), LAMP, and quantitative reverse transcription (RT)-PCR to determine malaria positivity. Hemoglobin values were recorded, and anemia was defined as a binary variable according to WHO guidelines. Prevalence ratios were calculated univariately using 2X2 tables and binomial regressions with a log link. Results: Compared to reference qRT-PCR, LAMP had the highest sensitivity: 92.6% (95% CI: 86.4 - 96.5) followed by uRDT AlereTM Malaria: 33.9% (95% CI: 25.5 - 43.1), CareStartTM Malaria: 14.1% (95% CI: 8.4 - 21.5), microscopy: 7.3% (95% CI: 2.7- 15.3) and SD Bioline: 5.0% (1.8 - 10.5). For P. falciparum specimens only, the sensitivity for uRDT AlereTM Malaria was 50.0% (95% CI: 38.8 - 61.3) and SD Bioline was 7.3% (95% CI: 2.7 - 15.3), respectively. Based on multivariate regression analysis with qRT-PCR as the gold standard, for every 3.2% increase in the prevalence of asymptomatic malaria, hemoglobin decreased by one gram per deciliter [PR 0.968 (0.940 - 0.997); p=0.032]. Deletions (4.8%) in hrp2 were noted. Conclusions: uRDT AlereTM Malaria has superior sensitivity to rapid diagnostic tests and microscopy in detecting asymptomatic malaria, with LAMP superior still. Ultrasensitive diagnostics provide accurate prevalence estimates of asymptomatic malaria required for elimination. PMID- 30475993 TI - GUV-AP: multifunctional FIJI-based tool for quantitative image analysis of Giant Unilamellar Vesicles. AB - Motivation: Giant Unilamellar Vesicles (GUVs) are widely used synthetic membrane systems that mimic native membranes and cellular processes. Various fluorescence imaging techniques can be employed for their characterization. In order to guarantee a fast and unbiased analysis of imaging data, the development of automated recognition and processing steps is required. Results: We developed a fast and versatile Fiji-based macro for the analysis of digital microscopy images of GUVs. This macro was designed to investigate membrane dye incorporation and protein binding to membranes. Moreover, we propose a fluorescence intensity-based method to quantitatively assess protein binding. Availability: The ImageJ distribution package FIJI is freely available online: https://imagej.net/Fiji. The macro file GUV-AP.ijm is available at https://github.com/AG-Roemer/GUV-AP. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30475995 TI - GenCoF: A graphical user interface to rapidly remove human genome contaminants from metagenomic datasets. AB - Summary: The removal of human genomic reads from shotgun metagenomic sequencing is a critical step in protecting subject privacy. Freely available tools addressing this issue require advanced programming knowledge or are limited by analytical time and data load due to their server-based nature. Here, we compared the most cited tools for host-DNA removal using synthetic and real metagenomic datasets. Then, we integrated the most efficient pipeline in a graphical user interface to make these tools available without command line use. This interface, GenCoF, rapidly removes human genome contaminants from metagenomic datasets. Additionally, the tool offers quality-filtering, data reduction and interactive modification of any parameter in order to customize the analysis. GenCoF offers both quality and host-associated filtering in a non-commercial, freely available tool in a local, interactive and easy-to-use interface. Availability and Implementation: GenCoF is freely available (under a GPL license) for Mac OS and Linux at https://github.com/MattCzajkowski/GenCoF. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30475994 TI - Alterations in Schizophrenia-Associated Genes Can Lead to Increased Power in Delta Oscillations. AB - Genome-wide association studies have implicated many ion channels in schizophrenia pathophysiology. Although the functions of these channels are relatively well characterized by single-cell studies, the contributions of common variation in these channels to neurophysiological biomarkers and symptoms of schizophrenia remain elusive. Here, using computational modeling, we show that a common biomarker of schizophrenia, namely, an increase in delta-oscillation power, may be a direct consequence of altered expression or kinetics of voltage gated ion channels or calcium transporters. Our model of a circuit of layer V pyramidal cells highlights multiple types of schizophrenia-related variants that contribute to altered dynamics in the delta-frequency band. Moreover, our model predicts that the same membrane mechanisms that increase the layer V pyramidal cell network gain and response to delta-frequency oscillations may also cause a deficit in a single-cell correlate of the prepulse inhibition, which is a behavioral biomarker highly associated with schizophrenia. PMID- 30475997 TI - Corrigendum to: Heart failure with preserved ejection fraction: from mechanisms to therapies. PMID- 30475996 TI - Potential mechanisms underlying the cardiovascular benefits of sodium glucose cotransporter 2 inhibitors: a systematic review of data from preclinical studies. AB - There is growing evidence from phase III randomised clinical trials of the cardiovascular benefits of sodium glucose cotransporter 2 (SGLT2) inhibitors in patients with diabetes mellitus. It is hypothesised that these benefits are mediated by mechanisms other than glucose control. To address this, we performed a systematic review of data from preclinical studies examining the direct cardioprotective effects of SGLT2 inhibitors. Medline, EMBASE, CINAHL and International Pharmaceutical Abstracts databases were searched for preclinical studies that examined the potential cardioprotective effects of SGLT2 inhibitors. Submission documents to the US Food and Drug Administration, European Medicines Agency and Japanese Pharmaceutical and Medical Devices Agency for the registration of SGLT2 inhibitors were also reviewed. A total of 36 reports were included in the final analysis. The potential direct cardiovascular benefits of SGLT2 inhibitors include: augmentation of signal transducer and activator of transcription 3 (STAT3); inhibition of sodium hydrogen exchange (NHE); reduction of atherosclerosis; modulation of natriuretic peptides; vasodilation; modulation of sympathetic tone; and reduction of inflammation, oxidative stress, endoplasmic reticulum stress and cardiac glucose uptake via downregulation of SGLT1 expression. There are a number of mechanisms by which SGLT2 inhibitors may exert cardiovascular benefits beyond glycaemic control. PMID- 30475998 TI - Do We Need Another Study to Control Carbapenem-resistant Organisms, or Do We Just Need to Get Better at the Basics? PMID- 30475999 TI - Cancer-specific expression quantitative loci are affected by expression dysregulation. AB - Expression quantitative trait loci (eQTLs) have been touted as the missing piece that can bridge the gap between genetic variants and phenotypes. Over the past decade, we have witnessed a sharp rise of effort in the identification and application of eQTLs. The successful application of eQTLs relies heavily on their reproducibility. The current eQTL databases such as Genotype-Tissue Expression (GTEx) were populated primarily with eQTLs deriving from germline single nucleotide polymorphisms and normal tissue gene expression. The novel scenarios that employ eQTL models for prediction purposes often involve disease phenotypes characterized by altered gene expressions. To evaluate eQTL reproducibility across diverse data sources and the effect of disease-specific gene expression alteration on eQTL identification, we conducted an eQTL study using 5178 samples from The Cancer Genome Atlas (TCGA). We found that the reproducibility of eQTLs between normal and tumor tissues was low in terms of the number of shared eQTLs. However, among the shared eQTLs, the effect directions were generally concordant. This suggests that the source of the gene expression (normal or tumor tissue) has a strong effect on the detectable eQTLs and the effect direction of the eQTLs. Additional analyses demonstrated good directional concordance of eQTLs between GTEx and TCGA. Furthermore, we found that multi-tissue eQTLs may exert opposite effects across multiple tissue types. In summary, our results suggest that eQTL prediction models need to carefully address tissue and disease dependency of eQTLs. Tissue-disease-specific eQTL databases can afford more accurate prediction models for future studies. PMID- 30476000 TI - Integrate multiple traits to detect novel trait-gene association using GWAS summary data with an adaptive test approach. AB - Motivation: Genetics hold great promise to precision medicine by tailoring treatment to the individual patient based on their genetic profiles. Toward this goal, many large-scale genome-wide association studies (GWAS) have been performed in the last decade to identify genetic variants associated with various traits and diseases. They have successfully identified tens of thousands of disease related variants. However they have explained only a small proportion of the overall trait heritability for most traits and are of very limited clinical use. This is partly owing to the small effect sizes of most genetic variants, and the common practice of "testing association between one trait and one genetic variant at a time" in most GWAS, even when multiple related traits are often measured for each individual. Increasing evidence suggests that many genetic variants can influence multiple traits simultaneously, and we can gain more power by testing association of multiple traits simultaneously. It is appealing to develop novel multi-trait association test methods that need only GWAS summary data, since it is generally very hard to access the individual-level GWAS phenotype and genotype data. Results: Many existing GWAS summary data based association test methods have relied on ad hoc approach or crude Monte Carlo approximation. In this paper we develop rigorous statistical methods for efficient and powerful multi-trait association test. We develop robust and efficient methods to accurately estimate the marginal trait correlation matrix using only GWAS summary data. We construct the principal component (PC) based association test from the summary statistics. PC based test has optimal power when the underlying multi-trait signal can be captured by the first PC, and otherwise it will have suboptimal performance. We develop an adaptive test by optimally weighting the PC based test and the omnibus chi-square test to achieve robust performance under various scenarios. We develop efficient numerical algorithms to compute the analytical p-values for all the proposed tests without the need of Monte Carlo sampling. We illustrate the utility of proposed methods through application to the GWAS meta-analysis summary data for multiple lipids and glycemic traits. We identify multiple novel loci that were missed by individual trait based association test. Availability: All the proposed methods are implemented in an R package available at http://www.github.com/baolinwu/MTAR. The developed R programs are extremely efficient: it takes less than two minutes to compute the list of genome-wide significant SNPs for all proposed multi-trait tests for the lipids GWAS summary data with 2.5 million SNPs on a single Linux desktop. Supplementary information: Supplementary materials are available at Bioinformatics online. PMID- 30476001 TI - Noninfectious Comorbidity in the African Cohort Study (AFRICOS). AB - Background: Noninfectious comorbid diseases (NCDs) contribute to morbidity and mortality in HIV-infected populations in resource-rich countries. With antiretroviral therapy (ART) scale-up in Africa, understanding the burden of NCDs informs public health strategy. We describe NCDs across four countries in The African Cohort Study (AFRICOS). Methods: At enrollment, participants at eleven HIV clinics in Kenya, Uganda, Tanzania and Nigeria underwent medical history, physical, laboratory and neuropsychological assessments to identify elevated blood pressure, hypercholesterolemia, dysglycemia, renal insufficiency, and cognitive impairment. Poisson regression models estimated adjusted relative risks (ARRs) and 95% confidence intervals (CIs) for number of NCDs associated with demographic and clinical factors of interest. Logistic regression was used to evaluate each NCD separately among HIV-infected participants. Results: Among 2720 participants with complete NCD data, 2159 (79.4%) were HIV-infected. Of those, 1426 (66.0%) were taking ART and 813 (37.7%) had at least one NCD. HIV infection was associated with more NCDs, especially with ART (ARR 1.42, CI 1.22-1.66). In addition to age, BMI and program site, ART usage was associated with more NCDs (ARR 1.50, C.I. 1.27-1.78 for virologically suppressed, ARR 1.38, C.I. 1.13-1.68 for viremic) among HIV-infected participants. In participants taking ART, CD4 nadir below 200 cells/mm 3 was associated with more NCDs (ARR 1.43, CI 1.06 1.93). ART use was independently associated with hypercholesterolemia and dysglycemia. Program site was significantly associated with all comorbidities except renal insufficiency. Conclusions: HIV infection was a risk for NCDs, which were common in HIV-infected participants, geographically variable, and largely consistent with metabolic complications of first-line ART. PMID- 30476003 TI - Incidence and Outcomes of Staphylococcus aureus Bacteriuria: A Population-based Study. AB - Background: Staphylococcus aureus bacteriuria (SABU) may represent multiple processes ranging from asymptomatic colonization to a marker of S. aureus bacteremia (SAB). Our objective was to describe SABU at a population-based level and determine patient characteristics associated with SAB. Methods: A retrospective study was performed using electronic databases. All urine cultures positive for S. aureus between 2010-2013 within the Calgary Health Zone were included. Patient characteristics were compared among patients with and without SAB and risk factors identified using multiple logistic regression modelling. Results: A total of 2540 urine cultures positive for S. aureus from 2054 patients were analyzed. The incidence of SABU was greatest amongst geriatric males with multiple comorbidities. 175 (6.9%) of the cohort had SAB. Those with concurrent SAB were more likely to be hospitalized, male, have a recent urinary procedure, have pure S. aureus culture in urine and have laboratory findings suggesting systemic infection. Patients with isolated SABU were more likely to be >=65 years, have dementia and have an abnormal urinalyses with pyuria and urine nitrites. In-hospital mortality in patients with SABU and SABU+SAB was 9.2% and 17.5%, respectively. Patients with SABU detected >=48 hours before SAB had the highest risk of death. Conclusions: Less than 7% of patients with SABU have or will develop SAB. Characteristics associated with SABU were identified that established higher risk for systemic infection. Investigating SABU patients with these characteristics for systemic infection is warranted since a delay in diagnosis is associated with increased mortality. PMID- 30476004 TI - Long-term Endocrine and Metabolic consequences of Cancer Treatment: A Systematic Review. AB - The number of patients surviving five or more years after initial cancer diagnosis has significantly increased over the last decades due to considerable improvements in the treatment of many cancer entities. A negative consequence of this is the emergence of long-term sequelae and endocrine disorders account for a high proportion of these. These late effects can occur decades after cancer treatment and affect up to 50% of childhood cancer survivors. Multiple predisposing factors for endocrine late effects have been identified; including radiation, gender and age at the time of diagnosis.A systematic literature search has been conducted using the PubMed database to offer a detailed overview over the spectrum of late endocrine disorders following oncological treatment. The majority of data are based on late effects of treatment in former childhood cancer patients for whom specific guidelines and recommendations already exist, whereas current knowledge concerning late effects in adult onset cancer survivors is much less clear.Endocrine sequelae of cancer therapy include functional alterations in the hypothalamic/pituitary, thyroid, parathyroid, adrenal and gonadal regulation as well as bone and metabolic complications. Surgery, radio-, chemo- and immunotherapy all contribute. Following irradiation endocrine organs such as the thyroid are also at risk for subsequent malignancies. Although diagnosis and management of functional and neoplastic long-term consequences of cancer therapy are comparable to other causes of endocrine disorders, cancer survivors need individually structured follow-up care in specialized surveillance centers to improve care for this rapidly growing group of patients. PMID- 30476002 TI - Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex. AB - Hereditary spastic paraplegias (HSPs) are rare neurological disorders caused by progressive distal degeneration of the corticospinal tracts. Among the 79 loci and 65 spastic paraplegia genes (SPGs) involved in HSPs, mutations in SPAST, which encodes spastin, responsible for SPG4, are the most frequent cause of both familial and sporadic HSP. SPG4 is characterized by a clinically pure phenotype associated with restricted involvement of the corticospinal tracts and posterior columns of the spinal cord. It is rarely associated with additional neurological signs. However, both age of onset and severity of the disorder are extremely variable. Such variability is both intra- and inter-familial and may suggest incomplete penetrance, with some patients carrying mutations remaining asymptomatic for their entire life. We analysed a cohort of 842 patients with SPG4-HSP to assess genotype-phenotype correlations. Most patients were French (89%) and had a family history of SPG4-HSP (75%). Age at onset was characterized by a bimodal distribution, with high inter-familial and intra-familial variability, especially concerning first-degree relatives. Penetrance of the disorder was 0.9, complete after 70 years of age. Penetrance was lower in females (0.88 versus 0.94 in males, P = 0.01), despite a more diffuse phenotype with more frequent upper limb involvement. Seventy-seven per cent of pathogenic mutations (missense, frameshift, splice site, nonsense, and deletions) were located in the AAA cassette of spastin, impairing its microtubule-severing activity. A comparison of the missense and truncating mutations revealed a significantly lower age at onset for patients carrying missense mutations than those carrying truncating mutations, explaining the bimodal distribution of the age at onset. The age at onset for patients carrying missense mutations was often before 10 years, sometimes associated with intellectual deficiency. Neuropathological examination of a single case showed degeneration of the spinocerebellar and spinocortical tracts, as well as the posterior columns. However, there were numerous small-diameter processes among unusually large myelinated fibres in the corticospinal tract, suggesting marked regeneration. In conclusion, this large cohort of 842 individuals allowed us to identify a significantly younger age at onset in missense mutation carriers and lower penetrance in females, despite a more severe disorder. Neuropathology in one case showed numerous small fibres suggesting regeneration. PMID- 30476005 TI - Alterations in oocyte mitochondrial number and function are related to spindle defects and occur with maternal aging in mice and humans. AB - The objective of this work was to determine the role of mitochondria in the loss of oocyte quality with maternal aging. Our results show that mitochondrial DNA (mtDNA) copy number and function are reduced in eggs from aged mice after both in vivo and in vitro maturation. Higher incidences of spindle abnormalities were observed in old eggs. However, no correlation with egg ATP content was found. In vitro matured eggs from aged mice did not have a normal cortical distribution of active mitochondria and were subject to increased oxidative stress due to higher levels of reactive oxygen species and lower expression of glutamate-cysteine ligase, catalytic subunit (Gclc). Supplementation of antioxidants during in vitro maturation of old eggs mitigated this affect, resulting in increased mtDNA copy number and mitochondrial function, a mitochondria distribution pattern similar to young eggs, and improved chromosomal alignment. Eggs from women of advanced maternal age (AMA) had lower mitochondrial function than eggs from young women, although both age groups displayed a cortical distribution pattern of active mitochondria. In contrast to the mouse, human eggs from AMA women had higher mtDNA copy number than eggs from young women following in vitro maturation. In summary, oocytes of older females are more susceptible to perturbations in mitochondrial number and function, which are associated with increased spindle abnormalities and oxidative stress during in vitro maturation. These results demonstrate that oocyte mitochondria play a critical role in age-related infertility. PMID- 30476006 TI - Valosin-containing protein is associated with maintenance of meiotic arrest in mouse oocytes. AB - Valosin-containing protein (VCP) is a member of the highly conserved AAA (ATPase associated with a variety of cellular activities) superfamily. A previous study has shown that targeted deletion of Vcp in mice results in early embryonic lethality. The aim of the present study was to analyze the expression and localization of VCP and its function in meiotic arrest of mouse oocytes. Vcp mRNA and protein were expressed in multiple mouse tissues. In the ovary, VCP protein was mainly expressed in oocytes and granulosa cells. After ovulation and fertilization, Vcp mRNA and protein were detected in oocytes and preimplantation embryos. Furthermore, VCP protein was localized in both the cytoplasm and nucleus of germinal vesicle (GV) stage oocytes and preimplantation embryos. Moreover, knockdown of Vcp in GV stage oocytes led to a significantly increased rate of germinal vesicle breakdown (GVBD). In addition, inhibition of VCP protein improved the GVBD rate in mouse GV stage oocytes. When VCP inhibition was reversed, the final GVBD rate returned to normal. These results provide the first evidence for a novel function of VCP in meiotic arrest of mouse oocytes. PMID- 30476008 TI - Novel Roles of mTOR Signaling in Regulating Fetal Growth. AB - Mechanistic target of rapamycin (mTOR) signaling functions as a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. mTOR is therefore critical for the growth of most fetal organs and global mTOR deletion is embryonic lethal. This review discusses emerging evidence suggesting that mTOR signaling also has a role as a critical hub in the overall, homeostatic control of fetal growth, adjusting the fetal growth trajectory according to the ability of the maternal supply line to support fetal growth. In the fetus, liver mTOR governs the secretion and phosphorylation of insuIin-like growth factor binding protein 1 (IGFBP-1) thereby controlling the bioavailability of insulin-like growth factors (IGF-I and IGF II), which function as important growth hormones during fetal life. In the placenta, mTOR responds to a large number of growth-related signals, including amino acids, glucose, oxygen, folate and growth factors, to regulate trophoblast mitochondrial respiration, nutrient transport and protein synthesis, thereby influencing fetal growth. In the maternal compartment, mTOR is an integral part of a decidual nutrient sensor which links oxygen and nutrient availability to the phosphorylation of IGFBP-1 with preferential effects on the bioavailability of IGF-I in the maternal-fetal interface and in the maternal circulation. These new roles of mTOR signaling in the regulation fetal growth will help us better understand the molecular underpinnings of abnormal fetal growth, such as intrauterine growth restriction and fetal overgrowth, and may represent novel avenues for diagnostics and intervention in important pregnancy complications. PMID- 30476007 TI - HIV-1 transmission among persons with acute HIV-1 infection in Malawi: demographic, behavioral and phylogenetic relationships. AB - Background: Understanding of sexual networks involving acute HIV-1 infections (AHI) may lead to prevention opportunities to mitigate high rates of onward transmission. We evaluated HIV-1 phylogenetic and behavioral characteristics among persons with AHI and their referred partners. Methods: Between 2012 and 2014, 46 persons with AHI in Malawi participated in a combined behavioral and biomedical intervention. Participants referred sexual partners for HIV-1 testing by passive referral. Demographics and sexual behaviors were collected through interviews. We used maximum-likelihood phylogenetic analyses of HIV-1 pol sequences to assess genetic relationships. Results: Among 45 AHI participants with HIV-1 sequences, none was phylogenetically-linked with another AHI index. Nineteen (42%) AHI participants referred a single partner who returned for testing. Most referred partners (n=17) were or became HIV-infected with 15 (88%) presenting with established infection. Fourteen index-partner pairs had sequences available; 13 (93%) pairs were phylogenetically-linked dyads. The AHI index was female in 7/13 (54%) dyads. Age-disparate relationships among dyads were common (>=5-year age difference in 67% of dyads), including 3/6 dyads involving a male AHI index and a younger woman. Index participants with a referred partner were more likely to report no casual partners and to be living with their current partner than participants not in observed dyads. Conclusions: Passive partner referral successfully identified partners with genetically similar HIV-infection the likely source of infection - but only 40% of index cases referred partners who presented for HIV-1 testing. Future work evaluating assisted partner notification may help reach susceptible partners or more people with untreated HIV-1 infection connected to acute transmission. PMID- 30476009 TI - Southern Pine Beetle (Coleoptera: Curculionidae: Scolytinae) Pheromone Component trans-Verbenol: Enantiomeric Specificity and Potential as a Lure Adjuvant. AB - The southern pine beetle, Dendroctonus frontalis Zimmermann (Coleoptera: Curculionidae: Scolytinae) utilizes a multi-component aggregation pheromone to mediate mass-attacks and thereby colonize otherwise unsusceptible trees. Females produce the attractant frontalin and a synergist, trans-verbenol. We investigated trans-verbenol to determine whether enantiomeric composition, airborne concentration, and possibly other factors might affect its biological activity. Newly-emerged females from Mississippi populations produced 54-87% of the (-) enantiomer; females initiating galleries in logs produced lower amounts and a wider range of enantiomeric ratios [12-92% (-)]. Coupled gas chromatography electroantennographic detection (GC-EAD) studies did not suggest large differences in the concentration threshold of olfaction for the two enantiomers. We examined the effect of adding trans-verbenol to traps located outside infested areas and baited with components of the aggregation attractant. Male attraction was similarly increased by lures with 3, 81, or 98% of the (-)-enantiomer of trans-verbenol, whereas females preferred 81 over 3%. When release rate of 81% ( )-trans-verbenol in traps was varied across three orders of magnitude (0.3, 3, and 30 mg/d), the data suggested a positive dose-response trend. A high release (i.e., 2-5 g/d) device of host-odor alpha-pinene had a much stronger enhancing effect on trap catches than a trans-verbenol device (~30 mg/d), and trans verbenol did not further enhance attraction when alpha-pinene was present. Our results suggest that the weak attraction-enhancing activity of trans-verbenol reported previously cannot be improved by adjusting the enantiomeric composition or release rate of lures, and furthermore there are no anticipated benefits of adding trans-verbenol to the D. frontalis monitoring lure. PMID- 30476011 TI - Redefining successful primary PCI. PMID- 30476012 TI - Intermittent Fasting Improves Glucose Tolerance and Promotes Adipose Tissue Remodeling in Male Mice Fed a High Fat Diet. AB - Obesity is associated with increased macrophage and extracellular matrix accumulation in adipose tissue, which can be partially reversed following weight loss by daily caloric restriction. This study examined the effects of 8 weeks of intermittent fasting (IF, 24-hours fast on 3 non-consecutive days per week) in mice fed a chow or high-fat diet (HFD, 43% fat), on markers of adipose tissue inflammation and fibrosis. We found that IF decreased energy intake, body weight and fat cell size in HFD fed mice, and decreased fat mass and improved glucose tolerance in chow and HFD fed mice. IF decreased mRNA levels of macrophage markers (Lgals3, Itgax, Ccl2 and Ccl3) in inguinal and gonadal fat, and adipose tissue macrophages numbers in HFD fed mice only, and altered NLRP3-inflammasome pathway in both diet groups. IF increased mRNA levels of matrix metallopeptidase 9, which is involved in extracellular matrix degradation, and reduced mRNA levels of collagen 6 alpha-1 and tissue inhibitor of matrix metallopeptidase 1, and fibrosis in gonadal fat in HFD fed mice. In summary, our results show that intermittent fasting improved glucose tolerance in chow and high-fat diet fed mice, and ameliorated adipose tissue inflammation and fibrosis in high-fat diet fed mice. PMID- 30476010 TI - Development and validation of the Charcot-Marie-Tooth Disease Infant Scale. AB - Many genetic subtypes of Charcot-Marie-Tooth disease (CMT) show signs of symptomatic disease during the earliest years of life. This might be the ideal time to intervene before progression of clinical sequelae due to demyelination and axonal loss. In the absence of disease-specific clinical trial outcome measures for CMT during infancy and early childhood the aim of this study was to develop and validate a functional measure of disease severity, known as the Charcot-Marie-Tooth disease Infant Scale (CMTInfS). Development projects involved identification of a preliminary pool of 31 items representing the range of disability in affected patients aged 0-4 years from a systematic review of the literature, peer review by 12 expert clinicians and researchers in the field, design of a scoring algorithm and pilot testing in 22 participants. Subsequently, a series of validation projects were conducted based on 128 assessments of: 26 confirmed cases of inherited neuropathy (17 CMT1A, one CMT1B, one CMT1D, one CMT2C, one CMT2S, two CMT4C, one CMTX3, one Riboflavin Transporter Deficiency Type 2, and one unidentified mutation); seven 'at risk' cases and 95 unaffected healthy controls recruited through the NIH-funded Inherited Neuropathies Consortium. Validation projects included: Item, Factor and Rasch analysis, intra- and inter-rater reliability, discriminant ability and convergent validity with the CMT Pediatric Scale (CMTPedS) for children aged 3-4 years. Development and validation projects produced a psychometrically robust 15-item scale. Rasch analysis supported the viability of the CMTInfS as a unidimensional measure of disease severity and showed good overall model fit, no evidence of misfitting items or persons and was well targeted for affected children. The CMTInfS demonstrated high intra-rater reliability [intraclass correlation coefficient (ICC)3,1 0.999, 95% confidence interval 0.996-1.000) and inter-rater reliability (ICC2,1 0.997, 95% confidence interval 0.992-0.999). The CMTInfS was able to discriminate between the CMT group and controls (P = 0.006), and convergent validity demonstrated good agreement between CMTInfS and CMTPedS scores (r = 0.76, P = 0.01). The final version of the CMTInfS requires 20 min to administer and is a reliable and sensitive functional outcome measure for early onset CMT and related neuropathies.10.1093/brain/awy280_video1awy280media15970672819001. PMID- 30476013 TI - The controversial role of dairy products in cardiovascular health: time to pass from epidemiology to basic research. PMID- 30476014 TI - New heights and hot topics in Cardiovascular Research. PMID- 30476015 TI - Ryanodine receptor dysfunction and the resolution revolution: how Nobel Prize winning techniques transform cardiovascular research. PMID- 30476016 TI - Scientists on the Spot: Esther Lutgens on the immune system and atherosclerosis. PMID- 30476017 TI - Is 're-calibration' of standard cardiovascular disease (CVD) risk algorithms the panacea to improved CVD risk prediction and prevention? PMID- 30476018 TI - Diverticulum of the aortic fibrous interleaflet triangle: multimodality imaging and pathological correlation. PMID- 30476019 TI - Class II PI3K alpha and beta are required for Rho-dependent uterine smooth muscle contraction and parturition in mice. AB - Class II phosphoinositide 3-kinases (PI3K), PI3K-C2alpha and PI3K-C2beta, are highly homologous and distinct from class I and III PI3K in the catalytic products and domain structures. In contrast to class I and class III PI3Ks, physiological roles of PI3K-C2alpha and PI3K-C2beta are not fully understood. Because we previously demonstrated that PI3K-C2alpha is involved in vascular smooth muscle contraction, we studied the phenotypes of smooth muscle-specific knockout (KO) mice of PI3K-C2alpha and PI3K-C2beta. The pup numbers born from single PI3K-C2alpha-KO and single PI3K-C2beta-KO mothers were similar to those of control mothers, but that from double KO (DKO) mother was smaller compared with control mice. However, the number of intrauterine fetuses in pregnant DKO mothers was similar to that in control mice. Both spontaneous and oxytocin-induced contraction of isolated uterine smooth muscle (USM) strips was diminished in DKO mice but not either of the single KO mice, compared with control mice. Furthermore, contraction of USM of DKO mice was less sensitive to a Rho kinase inhibitor. Mechanistically, the extent of oxytocin-induced myosin light chain phosphorylation was greatly reduced in USM from DKO mice compared with control mice. Oxytocin-induced rise in the intracellular Ca2+ concentration in USM was similar in DKO and control mice. However, Rho activation in the intracellular compartment was substantially attenuated in DKO mice compared with control mice, as evaluated by fluorescence resonance energy transfer imaging technique. These data indicate that both PI3K-C2alpha and PI3K-C2beta are required for normal USM contraction and parturition mainly through their involvement in Rho activation. PMID- 30476020 TI - Cardiac tamponade after pulmonary endarterectomy: mind the left side.... PMID- 30476021 TI - Corrigendum to: Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF. PMID- 30476022 TI - Health and socioeconomic circumstances over three generations as predictors of youth unemployment trajectories. AB - Background: Youth unemployment is a critical life event, which may trigger other labour market-related disadvantages and detrimental health implications. To better understand the processes causing unemployment, we study how socioeconomic circumstances of successive generations and familial and health factors in adolescence predict youth unemployment trajectories between ages 16 and 28 in Finland from 2000 to 2009. Methods: We used survey data from 1979 to 1997 on 12- to 18-year-old Finns (n = 43 238) linked with 1970-2009 registry-based data of their grandparents, parents and themselves. Growth mixture modelling and multivariate logistic regression analyses were used. Results: Three latent youth unemployment trajectories emerged; low (46%), decreasing (38%) and high (16%) risk groups. Of adolescent factors, low school achievement was the most important predictor of youth unemployment followed by smoking, stress symptoms and poor self-rated health. Grandparents' education predicted their grandchildren's unemployment but the effects of other grandparental socioeconomic circumstances mediated through parents' socioeconomic status (SES). Parents' low SES and education, and long-term unemployment increased the risk of the child's unemployment. Youth unemployment was related to low education at the age of 29. Conclusion: Grandparents' education, family socioeconomic circumstances and adolescents' health and school achievement predict the developmental trajectory of youth unemployment. Youth unemployment is also related to low education in early adulthood. Our findings suggest that the health selection of unemployment works already in adolescence. PMID- 30476023 TI - Where's the bleed? A response to Piccini et al.'s: Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. PMID- 30476024 TI - Mitogenomics reveals a novel genetic code in Hemichordata. AB - The diverse array of codon reassignments has demonstrated that the genetic code is not universal in nature. Exploring mechanisms underlying codon reassignment is critical for understanding the evolution of the genetic code during translation. Hemichordata, comprising worm-like Enteropneusta and colonial filter-feeding Pterobranchia, is the sister taxon of echinoderms and is more distantly related to chordates. However, only a few hemichordate mitochondrial genomes have been sequenced hindering our understanding of mitochondrial genome evolution within Deuterostomia. In this study, we sequenced four mitochondrial genomes and two transcriptomes, including representatives of both major hemichordate lineages and analysed together with public available data. Contrary to the current understanding of the mitochondrial genetic code in hemichordates, our comparative analyses suggest that UAA encodes Tyr instead of a "Stop" codon in the pterobranch lineage Cephalodiscidae. We also predict that AAA encodes Lys in pterobranch and enteropneust mitochondrial genomes, contradicting the previous assumption that hemichordates share the same genetic code with echinoderms for which AAA encodes Asn. Thus, we propose a new mitochondrial genetic code for Cephalodiscus and a revised code for enteropneusts. Moreover, our phylogenetic analyses are largely consistent with previous phylogenomic studies. The only exception isthe phylogenetic position of the enteropneust Stereobalanus, whose placement has been unstable in previous studies, as sister to all other described enteropneusts. With broader taxonomic sampling, we provide evidence that evolution of mitochondrial gene order and genetic codes in Hemichordata are more dynamic than previously thought and these finding provide insights into mitochondrial genome evolution within this clade. PMID- 30476025 TI - Chylothorax and chylopericardium as unusual manifestation of pacing lead related complication. PMID- 30476026 TI - Echo-derived peak cardiac power output-to-left ventricular mass with cardiopulmonary exercise testing predicts outcome in patients with heart failure and depressed systolic function. AB - Aims: Peak cardiac power output-to-mass (CPOM) represents a measure of the rate at which cardiac work is delivered respect to the potential energy stored in left ventricular (LV) mass. We studied the value of CPOM and cardiopulmonary exercise test (CPET) in risk stratification of patients with heart failure (HF). Materials and results: We studied 159 patients with chronic HF (mean rest LV ejection fraction 30%) undergoing CPET and exercise stress echocardiography. CPOM was calculated as the product of a constant (K = 2.22 * 10-1) with cardiac output (CO) and the mean blood pressure (MBP), divided by LV mass (M), and expressed in the unit of W/100 g: CPOM = [K * CO (L/min) * MBP (mmHg)]/LVM(g). Patients were followed-up for the primary endpoint, including all-cause death, ventricular assist device implantation, and heart transplantation, and the secondary endpoint that comprised hospitalization for HF. In multivariate Cox regression analyses, peak CPOM was selected as the most powerful independent predictor of both primary and secondary endpoint [hazard ratio (HR) 0.004, 95% confidence interval (CI) 0.004-0.3; P = 0.002 and HR 0.09, 95% CI 0.02-0.55; P = 0.009]. Sixty-month survival free from the combined endpoint was 85% in those exhibiting oxygen consumption (VO2) > 14 mL/min/kg and peak CPOM > 0.6 W/100 g. Peak VO2 <= 14 mL/min/kg provided incremental prognostic value over demographic and clinical variables, brain natriuretic peptide, and resting echocardiographic parameters (chi2 from 58 to 64; P = 0.04), that was further increased by peak CPOM <= 0.6 W/100 g (chi2 77; P < 0.001). Conclusion: Peak CPOM and peak VO2 showed independent and incremental prognostic values in patients with chronic HF. PMID- 30476027 TI - Gastrointestinal Malabsorption of Thyroxine. AB - Levothyroxine, a largely prescribed drug with a narrow therapeutic index, is often a lifelong treatment. The therapeutic efficacy of thyroxine may be marred by behavioral, pharmacologic and pathologic issues acting as interfering factors. Despite a continuous search for an optimal thyroxine treatment, a significant number of patients fail to show a complete chemical and/or clinical response to this reference dose of thyroxine. Gastrointestinal malabsorption of oral thyroxine represents an emerging cause of refractory hypothyroidism and may be more frequent than previously reputed.In this review article we aimed at examining the pharmacologic features of thyroxine preparations and their linkage with the intestinal absorption of the hormone. We have stressed the major biochemical and pharmacologic characteristics of thyroxine and its interaction with the putative transporter at the intestinal level. We have examined the interfering role of nutrients, foods, and drugs on thyroxine absorption at gastric and intestinal level. The impact of gastrointestinal disorders on thyroxine treatment efficacy has been also analyzed, in keeping with the site of action and the interfering mechanisms. Based on the evidence obtained from the literature, we also propose a schematic diagnostic workup for the most frequent and, often hidden, gastrointestinal diseases impairing thyroxine absorption. PMID- 30476028 TI - The role of accelerated dental development on the occurrence of aberrant dental traits that indicate malocclusion. AB - Background: Timing of dental development might help orthodontists to optimize initiation of treatment and to prevent and intercept dental misalignment. This study examines the association between timing of dental development and aberrant dental traits such as crowding, impaction, and hypodontia. Methods: This study was performed using 4446 ten-year-old children from a multiethnic birth cohort, the Generation R Study. Dental development was defined using the Demirjian method. Crowding, impaction, and hypodontia were ascertained from 2D and 3D pictures and radiographs. We built three series of logistic regression models to test the associations of dental age with crowding, impaction, and hypodontia. Similar models were built to investigate the associations of the developmental stages of each left mandibular tooth with crowding, impaction, and hypodontia. Results: Inverse associations were found between every 1-year increase in dental age and the presence of crowding [odds ratio (OR) = 0.84, 95% confidence interval (CI): 0.79, 0.89], impaction of teeth (OR = 0.66, 95% CI: 0.52, 0.84), and hypodontia (OR = 0.52, 95% CI: 0.47, 0.56). Lower developmental stages of the second premolar were associated with the presence of crowding (OR = 0.90, 95% CI: 0.83, 0.98). Lower developmental stages of the second premolar (OR = 0.88, 95% CI: 0.79, 0.98), first molar (OR = 0.76, 95% CI: 0.65, 0.90), and the second molar (OR = 0.83, 95% CI: 0.73, 0.94) were associated with the presence of tooth impaction. Lower developmental stages of all mandibular teeth except the central incisor were associated with hypodontia (P < 0.05). Conclusion: Accelerated dental development is associated with lower occurrence of crowding, impaction, and hypodontia. PMID- 30476029 TI - The jury is still out on the use of bilateral internal thoracic arteries in coronary surgery. PMID- 30476030 TI - Is statistician involvement as co-author associated with reduced time to publication of quantitative research in general medical journals? A bibliometric study. AB - Objective: We aimed to compare the number of submissions until acceptance and the time to publication between articles co-authored and articles not co-authored by statisticians. Methods: We randomly selected 781 articles published in 2016 in 18 high impact factor journals of general internal medicine and primary care. For each article, we retrieved its date of submission to the journal and its first publication; we also contacted its corresponding author and asked about the number of submissions necessary from the first submission to a journal until acceptance and whether the article was co-authored by a statistician. After having excluded qualitative studies, we compared the articles co-authored with those not co-authored by statisticians in terms of number of submissions and submission-to-publication time, using negative binomial and Cox regressions, adjusted for intracluster correlations. Results: One hundred fifty-eight authors completed the questionnaire (20%); 136 articles with quantitative design were included in the study. Overall, 63 articles (46%) were co-authored by statisticians. There was no statistically significant difference in the number of submissions (statistician group: mean 2.1 (SD 1.1) versus 2.2 (SD 1.2), P value 0.87). By contrast, we found a statistically significant difference in the submission-to-publication time (statistician group: median 211 days [interquartile range (IQR) 171] versus 260 (IQR 144); hazard ratio 1.44 (95% CI 1.01-2.03), adjusted P value 0.04). Conclusions: Papers co-authored by statisticians have a shorter time to publication. We encourage researchers to closely involve statisticians in the design, conduct and statistical analysis of research, not only to ensure high standards of quality but also to speed up its publication. PMID- 30476031 TI - Adaption and validation of the Working Alliance Inventory for General Practice: qualitative review and cross-sectional surveys. AB - Background: Relational aspects of primary care are important, but we have no standard measure for assessment. The 'working alliance' incorporates elements of the therapeutic relationship, shared decision-making, goal setting and communication skills. The Working Alliance Inventory (short form) (WAI-SF) has been used in adult psychology, and a high score on the survey is associated with improved outcomes for clients. Objective: To adapt the WAI-SF for use between GPs and patients and to test its concurrent validity with measures of shared decision making and the doctor-patient relationship and discriminant validity with measures of social desirability. Methods: Two rounds of online survey feedback from 55 GPs and 47 patients were used to adapt the WAI-SF-the WAI-GP. The tool was then completed by 142 patients in waiting rooms after seeing their GP and by 16 GPs at the end of their session. Concurrent validity with measures of shared decision-making and patient-doctor depth of relationship was determined using Spearman Rho correlations. Patients also completed two social desirability surveys, and discriminant validity with WAI-GP was assessed. Results: Following feedback, the survey was re-worded to remove phrases that were perceived as judgmental or irrelevant. The patient measure of the WAI-GP was strongly correlated with Dyadic OPTION (rho = 0.705, P = 0.0001) and Patient-Doctor Depth of Relationship scale (rho = 0.591, P = 0.0001) and not with measures of social desirability. Conclusion: The psychometric properties of the WAI-GP support its use for measuring GP-patient alliance. Possibilities for use include assessing the influence of therapeutic alliance on the effectiveness of interventions. PMID- 30476032 TI - The morphology and metabolic potential of the Chloroflexi in full-scale activated sludge wastewater treatment plants. AB - Filamentous bacteria belonging to the phylum Chloroflexi have received considerable attention in wastewater treatment systems for their suggested role in the operational problem of impaired sludge settleability known as bulking. Their consistently high abundance in full-scale systems, even in the absence of bulking, indicates that they make a substantial contribution to the nutrient transformations during wastewater treatment. In this study, extensive 16S rRNA amplicon surveys of Danish wastewater treatment plants (WWTPs) with nutrient removal were screened to identify numerically important Chloroflexi genera. Fluorescence in situ hybridization probes were designed for their in situ characterization. All abundant Chloroflexi phylotypes were putatively identified as facultative anaerobic chemoorganotrophs involved in sugar fermentation. They were all filamentous but differed in their morphology and spatial arrangement. 'Candidatus Villigracilis' was predominantly located within the activated sludge flocs, where they possibly have structural importance, and their abundance was relatively stable. Conversely, the abundance of 'Candidatus Amarolinea' was highly dynamic, relative to other genera, sometimes reaching abundances in excess of 30% of the biovolume, suggesting their likely role in bulking episodes. This study gives an important insight into the role of Chloroflexi in WWTPs, thus contributing to the broader goal of understanding the ecology of these biotechnologically important systems. PMID- 30476033 TI - Survival and prognostic factors after pulmonary metastasectomy of head and neck cancer: what are the clinically informative prognostic indicators? AB - OBJECTIVES: The purpose of this study was to elucidate the surgical outcomes and identify the prognostic factors after pulmonary metastasectomy for head and neck cancer (HNC) using a recent, large, single-institutional cohort. METHODS: We retrospectively reviewed the clinicopathological profiles of 77 consecutive patients who underwent metastasectomy for pulmonary metastases (PMs) arising due to HNC from 1992 to 2013. The prognostic factors associated with overall survival (OS) after pulmonary metastasectomy were evaluated using the univariable and multivariable Cox proportional hazard models. The cut-off value of continuous variables was determined by a receiver operating characteristic analysis. RESULTS: The most predominant histology was squamous cell carcinoma (75%). The median disease-free interval between the treatment of primary HNC and the diagnosis of PMs was 17 months. Recurrence before lung metastasectomy was observed in 32% of patients. The median size of the PM was 2.2 cm. The median survival time after lung metastasectomy was 66 months, and the 5-year OS was 54%. In the multivariable analysis, squamous cell histology [hazard ratio (HR) 2.92, 95% confidence interval (CI) 1.00-8.57], disease-free interval (<18 months, HR 3.23, 95% CI 1.49-7.02), recurrence before lung metastasis (HR 2.39, 95% CI 1.19 4.80) and size of the PM (>2.5 cm, HR 2.75, 95% CI 1.33-5.69) were independent predictors of a poor prognosis. The OS of patients with 3 or more factors was significantly worse than that of patients with 2 or less factors (3-year OS 20% vs 83%, P < 0.01). CONCLUSIONS: Surgical resection of PMs from HNC can achieve favourable survival in a selected population. The number of prognostic factors may be useful information for determining the surgical indications and for predicting survival for PMs from HNC. PMID- 30476034 TI - Deletion of GLX3 in Candida albicans affects temperature tolerance, biofilm formation, and virulence. AB - Candida albicans is a predominant cause of fungal infections in mucosal tissues as well as life-threatening bloodstream infections in immunocompromised patients. Within the human body, C. albicans is mostly embedded in biofilms, which provides increased resistance to antifungal drugs. The glyoxalase Glx3 is an abundant proteomic component of the biofilm extracellular matrix. Here, we document phenotypic studies of a glx3Delta null mutant concerning its role in biofilm formation, filamentation, antifungal drug resistance, cell wall integrity, and virulence. First, consistent with its function as glyoxalase, the glx3 null mutant showed impaired growth on media containing glycerol as the carbon source and in the presence of low concentrations of hydrogen peroxide. Importantly, the glx3Delta mutant showed decreased fitness at 37 degrees C and formed less biofilm as compared to WT and a reintegrant strain. At the permissive temperature of 28 degrees C, the glx3Delta mutant showed impaired filamentation as well as increased sensitivity to Calcofluor white, Congo red, SDS, and zymolyase, indicating subtle alterations in wall architecture even though gross quantitative compositional changes were not detected. Interestingly, and consistent with its impaired filamentation, biofilm formation and growth at 37 degrees C, the glx3Delta mutant is avirulent. Our results underline the role of Glx3 in fungal pathogenesis and the involvement of the fungal wall in this process. PMID- 30476035 TI - Mitral valve-in-valve, valve-in-ring, and valve-in-MAC: the Good, the Bad, and the Ugly. PMID- 30476036 TI - Long-term performance of pulmonary homografts after the Ross procedure: experience up to 25 years. AB - OBJECTIVES: The aim of this study was to evaluate the long-term durability and function of pulmonary homografts used for right ventricular outflow tract reconstruction in the Ross procedure at a single centre with 25 years of experience. METHODS: The study included 274 patients (212 male patients and 62 female patients; age 3-59 years), who underwent the Ross procedure between 1991 and 2014. Homograft-related complications and reinterventions were assessed. Homograft haemodynamic function was determined using transthoracic echocardiography undertaken by a single cardiologist. RESULTS: The all-cause 30 day mortality was 1.1% (3 patients), and there were 17 late deaths. One death was associated with a homograft-related complication. During the observation period (median 13.3 years; 3327.5 cumulative patient-years), 21 patients (7.7%) underwent at least 1 right ventricular outflow tract reintervention. Freedom from homograft reintervention was 95.6%, 90.4% and 87.5% at 10, 15 and 20 years, respectively. Paediatric patients had a significant lower rate of freedom from reintervention (log-rank P < 0.001). Remarkably, all patients who underwent reintervention were male (log-rank P = 0.009). Female patients received homografts with a significantly higher (P < 0.001) indexed diameter than male patients, which might be causally related to absent reinterventions in women. The linearized rate of homograft endocarditis was 0.2% per patient-year. At the latest echocardiography (median follow-up time 14.7 years; 164 patients), the peak transhomograft pressure gradient was <40 mmHg in 150 patients (91.5%), and homograft incompetence was none or trivial in 111 patients (67.7%), mild in 49 patients (29.9%) and moderate in 3 patients (1.8%). In 1 patient (0.6%), it was not possible to determine the degree of incompetence. Younger patient age (P < 0.001), a smaller homograft diameter (P = 0.014) and an increase in the body surface area during the follow-up time (P = 0.006) were significantly correlated with a higher peak transhomograft pressure gradient. Men had a significantly higher peak transhomograft pressure gradient than women (P = 0.018). CONCLUSIONS: Pulmonary homografts provide very satisfying long-term results after the Ross procedure. Differences in long-term performance are related to undersizing and young age. PMID- 30476037 TI - Evolution of copy number at the MHC varies across the avian tree of life. AB - The evolution of the Major Histocompatibility Complex (MHC) is shaped by frequent gene duplications and deletions, which generate extensive variation in the number of loci (gene copies) between different taxa. Here, we collected estimates of copy number at the MHC for over 250 bird species from 68 families. We found contrasting patterns of copy number evolution between MHC class I and class IIB, which encode receptors for intra- and extra-cellular pathogens, respectively. Across the avian evolutionary tree, there was evidence of accelerated evolution and stabilizing selection acting on copy number at class I, while copy number at class IIB was primarily influenced by fluctuating selection and drift. Reconstruction of MHC copy number variation showed ancestrally low numbers of MHC loci in non-passerines and evolution towards larger numbers of loci in passerines. Different passerine lineages had the highest duplication rates for MHC class I (Sylvioidea) and class IIB (Muscicapoidea and Passeroidea). We also found support for the correlated evolution of MHC copy number and life-history traits such as lifespan and migratory behavior. These results suggest that MHC copy number evolution in birds has been driven by life histories and differences in exposure to intra- and extra-cellular pathogens. PMID- 30476038 TI - Genomic insights into the metabolism of 'Candidatus Defluviicoccus seviourii', a member of Defluviicoccus cluster III abundant in industrial activated sludge. AB - Filamentous cluster III Defluviicoccus (DF3) are known to proliferate and cause bulking issues in industrial wastewater treatment plants. Members of the genus Defluviicoccus are also known to exhibit the glycogen accumulating organism (GAO) phenotype, which is suggested to be detrimental to enhanced biological phosphorus removal (EBPR). Despite the reported negative impact members of the DF3 have on activated sludge wastewater treatment systems, limited research has focused on understanding the physiological traits that allow them to compete in these environments. In this study, a near complete genome of an abundant filamentous DF3 named 'Candidatus Defluviicoccus seviourii' was obtained from a full-scale sequencing batch reactor (SBR) treating winery wastewater. Annotation of the 'Ca. D. seviourii' genome revealed interesting metabolic features that help to understand the abundance of this microorganism in industrial wastewater treatment plants. Their potential for the storage of polyhydroxyalkanoates (PHAs) is suggested to favour these organisms with the intermittent availability of carbon in these systems. An ability to fix nitrogen and take up urea may provide them with an additional advantage with the characteristically high carbon to nitrogen content of industrial wastes. The genome and preliminary findings of this study provide a foundation for further research into these biotechnologically relevant organisms. PMID- 30476039 TI - Doublesex evolution is correlated with social complexity in ants. AB - The Dmrt (Doublesex and Mab-3 Related Transcription factor) genes are transcription factors crucial for sex determination and sexual differentiation. In some social insects, Doublesex (dsx) exhibits widespread caste-specific expression across different tissues and developmental stages and has been suggested as a candidate gene for regulating division of labor in social insects. We therefore conducted a molecular evolution analysis of the Dmrt gene family in 20 ants. We found that the insect-specific oligomerization domain of DSX, oligomerization domain 2 (OD2), was absent in all ants, except for the two phylogenetically basal ant species (Ponerinae), whose social structure and organization resemble the presumed ancestral condition in ants. Phylogenetic reconstruction and selection analysis revealed that dsx evolved faster than the other three members of the Dmrt family. We found evidence for positive selection for dsx in the ant subfamilies with more advanced social organization (Myrmicinae and Formicinae), but not in the Ponerinae. Furthermore, we detected expression of two Dmrt genes, dsx and DMRT11E, in adult ants, and found a clear male-biased expression pattern of dsx in most species for which data are available. Interestingly, we did not detect male-biased expression of dsx in the two ant species that possess a genetic caste determination (GCD) system. These results possibly suggest an association between the evolution of dsx and social organization as well as reproductive division of labor in ants. PMID- 30476040 TI - Old trade, new tricks: insights into the spontaneous mutation process from the partnering of classical mutation accumulation experiments with high-throughput genomic approaches. AB - Mutations spawn genetic variation which, in turn, fuels evolution. Hence, experimental investigations into the rate and fitness effects of spontaneous mutations are central to the study of evolution. Mutation accumulation (MA) experiments have served as a cornerstone for furthering our understanding of spontaneous mutations for four decades. In the pregenomic era, phenotypic measurement of fitness-related traits in MA lines were used to indirectly estimate key mutational parameters such as the genomic mutation rate, new mutational variance per generation, and the average fitness effect of mutations. Rapidly emerging next-generating sequencing technology has supplanted this phenotype-dependent approach, enabling direct empirical estimates of the mutation rate and a more nuanced understanding of the relative contributions of different classes of mutations to the standing genetic variation. Whole genome sequencing of MA lines (MA-WGS) bears immense potential to provide a unified account of the evolutionary process at multiple levels - the genetic basis of variation, and the evolutionary dynamics of mutations under the forces of selection and drift. In this review, we have attempted to synthesize key insights into the spontaneous mutation process that are rapidly emerging from the partnering of classical MA experiments with high-throughput sequencing, with particular emphasis on the spontaneous rates and molecular properties of different mutational classes in nuclear and mitochondrial genomes of diverse taxa, the contribution of mutations to the evolution of gene expression, and the rate and stability of transgenerational epigenetic modifications. Future advances in sequencing technologies will enable greater species representation to further refine our understanding of mutational parameters and their functional consequences. PMID- 30476041 TI - When Distress Becomes Somatic: Dementia Family Caregivers' Distress and Genetic Vulnerability to Pain and Sleep Problems. AB - Background and Objectives: Stress can trigger physical pain and disturb sleep. Whether dementia family caregivers experience heightened pain is unknown. Cycles of unwanted thoughts about caregiving stressors and avoidance of these thoughts that is, caregiving-related distress-may exacerbate both pain and sleep disturbances, and genetic susceptibility to stress may further modulate these associations. Research Design and Methods: Dementia caregivers (72 spouses, 58 adult children, ages 34-89) rated the extent to which they experienced unintended thoughts about caregiving and tried to suppress such thoughts. They also reported their pain levels, sleep problems, and depressive symptoms. Peripheral blood leukocytes were genotyped for 5-HTTLPR (serotonin-transporter-linked polymorphic region) and 5-HT1A receptor polymorphism rs6295 on the 5HTR1A locus. Results: Short-allele carriers for 5-HTTLPR experienced more pain and sleep problems in association with greater caregiving-related distress than those with other genotypes. For rs6295, C carriers also showed the strongest links between distress and sleep problems. Those who experienced more avoidance and intrusive thoughts about caregiving had more severe depressive symptoms, consistent with past work. Discussion and Implications: Caregivers' genetic profiles helped to explain whether caregiving-related distress predicted worse pain and sleep problems. These data reveal new somatic risks of caregiver distress and provide targets for intervention. According to plasticity theories, caregivers genetically predisposed to greater stress reactivity may also respond particularly well to interventions, and many brief treatments may effectively address caregivers' intrusions and avoidance. PMID- 30476042 TI - Virulence factor-dependent basolateral invasion of choroid plexus epithelial cells by pathogenic Escherichia coli in vitro. AB - Escherichia coli (E. coli) is the most common Gram-negative causative agent of neonatal meningitis and E. coli meningitis is associated with a high morbidity and mortality. Previous research has been carried out with regards to the blood brain barrier and thereby unveiled an assortment of virulence factors involved in E. coli meningitis. Little, however, is known about the role of the blood cerebrospinal fluid (CSF) barrier (BCSFB), in spite of several studies suggesting that the choroid plexus (CP) is a possible entry point for E. coli into the CSF spaces. Here, we used a human CP papilloma (HIBCPP) cell line that was previously established as valid model for the study of the BCSFB. We show that E. coli invade HIBCPP cells in a polar fashion preferentially from the physiologically relevant basolateral side. Moreover, we demonstrate that deletion of outer membrane protein A, ibeA, or neuDB genes result in decreased cell infection, while absence of fimH enhances invasion, although causing reduced adhesion to the apical side of HIBCPP cells. Our findings suggest that the BCSFB might constitute an entry point for E. coli into the central nervous system and HIBCPP cells are a valuable tool for investigating E. coli entry of the BCSFB. PMID- 30476043 TI - Molecular cloning and characterization of a methyl parathion hydrolase from an organophosphorus-degrading bacterium, Serratia marcescens MEW06. AB - An organophosphorus-degrading bacterium MEW06, which exhibited excellent biodegradation capabilities towards 50 mg/L of methyl parathion (MP), paraoxon and dimethoate, was isolated from Sand Lake (Wuhan, China) and identified as Serratia marcescens subsp. marcescens based on physiological-biochemical characteristics and a 16S rDNA sequence-based phylogenetic tree. MEW06 genome contains a 31.09-kDa methyl parathion hydrolase (MPH) (MPHGM004539) that was 54.9% similar to Pseudomonas sp. WBC-3's MPH. RT-qPCR revealed that mphGM004539 gene expression was significant up-regulated when co-cultured with MP. mphGM004539 without signal peptide (mphGM004539Deltasp) was successful cloned and expressed in Escherichia coli BL21 (DE3). Optimized specific enzyme activity of MPHGM004539DeltaSP was 5.26 U/mg under 35 degrees C and pH 11.0 conditions when MP as the substrate. Additionally, Co2+, Cd2+and Fe2+ increased the enzyme activity level. MP could be degraded by MPHGM004539DeltaSP into p-nitrophenol probably by hydrolyzing the P-O ester bond. Virulence of MP towards Drosophila melanogaster W1118 was reduced by MEW06 or MPHGM004539DeltaSP biodegradation. This is the first cloning and characterization of MPH from the organophosphorus degrading bacterium S. marcescens. MEW06 and its MPH have potential roles in the bioremediation of organophosphorus pesticide-contaminated eco-systems. PMID- 30476044 TI - Nicotine enhances the thickness of biofilm and adherence of Candida albicans ATCC 14053 and Candida parapsilosis ATCC 22019. AB - Candida albicans ATCC 14053 and Candida parapsilosis ATCC 22019 HWP1 (hyphal-wall protein 1) are involved in hyphae formation and pathogenesis. The transcriptional ALS3 (agglutinin-like sequence 3) gene in both species are responsible for the development of biofilm and colonization on tooth surfaces. Therefore, we investigated the expression of HWP1 and ALS3 quantitatively in C. albicans and C. parapsilosis and examined the biofilm structure upon exposure to various nicotine concentrations. In vitro, biofilms of Candida species were developed directly on slides using the Lab-Tek Chamber Slide System and visualized by confocal laser scanning microscopy. Quantitative real-time PCR was used to measure HWP1 and ALS3 expression in C. albicans ATCC 14053 and C. parapsilosis ATCC 22019. The results indicated that nicotine has multiplied the number of yeast cells and increased the extracellular polysaccharides (EPS) of Candida species. We also found that 1 to 2 mg/ml nicotine could enhance the formation of biofilm. The findings also revealed that the expression of HWP1 and ALS3 in Candida species were increased as the nicotine concentration increased. Therefore, nicotine influences the biofilm development of oral-associated C. albicans ATCC 14053 and C. parapsilosis ATCC 22019. PMID- 30476045 TI - Extracellular membrane vesicles (EVs) in the three domains of life and beyond. AB - Cells from all three domains of life, Archaea, Bacteria and Eukarya, produce extracellular vesicles (EVs) which are sometimes associated to filamentous structures known as nanopods or nanotubes. The mechanisms of EV biogenesis in the three domains remain poorly understood, although studies in Bacteria and Eukarya indicate that the regulation of lipid composition plays a major role in initiating membrane curvature. EVs are increasingly recognized as important mediators of intercellular communication via transfer of a wide variety of molecular cargoes. They have been implicated in many aspects of cell physiology such as stress response, inter-cellular competition, lateral gene transfer (via RNA or DNA), pathogenicity, and detoxification. Their role in various human pathologies and aging has aroused much interest in recent years. EVs can be used as decoys against viral attack but virus infected cells also produce EVs that boost viral infection. Here, we review current knowledge on EVs in the three domains of life and their interactions with the viral world. PMID- 30476046 TI - The Volcano Rabbit in the Phylogenetic Network of Lagomorphs. AB - The order Lagomorpha unifies pikas (Ochotonidae) and the hares plus rabbits (Leporidae). Phylogenetic reconstructions of the species within the family Leporidae based on traditional morphological or molecular sequence data provide support for conflicting hypotheses. The retroposon presence/absence patterns analyzed in this study revealed strong support for the broadly accepted splitting of lagomorphs into ochotonids and leporids with Pronolagus as the first divergence in the leporid tree. Furthermore, the retroposon presence/absence patterns nested the rare volcano rabbit, Romerolagus diazi, within an unresolved network of deeper leporid relationships and provide the first homoplasy-free image of incomplete lineage sorting and/or ancestral hybridization/introgression in rapidly radiated Leporidae. At the same time, the strongest retroposon presence/absence signal supports the volcano rabbit as a separate branch between the Pronolagus junction and a unified cluster of the remaining leporids. PMID- 30476047 TI - Durability of pulmonary homografts for reconstruction of the right ventricular outflow tract: how relevant are donor-related factors? AB - OBJECTIVES: Our goal was to evaluate the influence of donor-related factors on the durability of pulmonary homografts (PHGs) for right ventricular outflow tract reconstruction of congenital heart defects. METHODS: Between 1990 and 2016, 223 PHGs were used in 197 patients for right ventricular outflow tract reconstruction. Long-term durability was investigated in relation to patient- and disease-specific as well as to donor-related factors, based on the PHG replacement rate. To minimize the effect of outgrowth, a subgroup analysis was performed on patients with PHG size >22 mm, as the discriminant cut-off identified by the classification tree method. RESULTS: During a median follow-up of 8.5 years [interquartile range (IQR) 12.3], 47 (21%) PHGs were explanted within a mean interval of 9.5 +/- 5.3 years, resulting in a freedom from PHG replacement of 82 +/- 6% at 10 years. The risk factors for PHG explantation determined by univariable analysis were predominantly patient-related, including younger age (P = 0.003), extra-anatomic implantation (P = 0.006), bicuspidalization (P = 0.002) and younger donor age (P = 0.032). PHG size [hazard ratio (HR) 0.80, 95% confidence interval 0.73-0.88; P < 0.001] was the only independent determinant in multivariable analysis. The subgroup analysis comprised 119 PHG >22 mm, implanted at a median age of 15 years (IQR 7). A significant beneficial effect of ABO matching on the explantation rate was only identified with univariable analysis (HR 0.24, 95% confidence interval 0.12-4.68; P = 0.010). CONCLUSIONS: Cryopreserved PHGs provide a durable substitute for right ventricular outflow tract reconstruction in congenital heart disease. PHG size at the time of implantation remains the principal determinant of PHG explantation during late follow-up. However, once an adult-sized homograft is required, matching for ABO blood group compatibility between host and donor might help to improve homograft durability. PMID- 30476048 TI - A system for the expression and release of heterologous proteins from the core of Bacillus subtilis spores. AB - Methodologies that exploit the durability of Bacillus subtilis spores by displaying heterologous proteins or antigenic molecules on the spore surface for mucosal vaccine delivery and other applications are well established. Here we extend the concept by engineering spores intended as oral delivery vehicles for therapeutic proteins. The method is exemplified by the expression and deposition of human growth hormone in the developing spore core, where the protein is shielded from physicochemical and biological degradation by the protective spore structure. Lysates from physically disrupted spores are shown to stimulate differentiation of a pre-adipocyte cell line to mature adipocyte cells, indicating that the spore-core located human growth hormone is folded correctly and functional. We also introduce a methodology for controlled release of heterologous proteins from the spore core, which utilises components of the PBSX prophage to lyse spores during germination and outgrowth. With further development, spore core expression, coupled with an engineered autolytic germination mechanism, may permit the use of spores as oral delivery carriers of therapeutic proteins. PMID- 30476049 TI - Planctomycetes in boreal and subarctic wetlands: diversity patterns and potential ecological functions. AB - Members of the phylum Planctomycetes are common inhabitants of boreal Sphagnum peat bogs and lichen-dominated tundra wetlands. These bacteria colonize both oxic and anoxic peat layers and reach the population size of 107 cells per gram of wet peat. The 16S rRNA gene sequences from planctomycetes comprise 5%-22% of total 16S rRNA gene reads retrieved from peat samples. Most abundant peat-inhabiting planctomycetes affiliate with the families Isosphaeraceae and Gemmataceae, and with as-yet-uncultured Phycisphaera-related group WD2101. The use of metatranscriptomics to assess the functional role of planctomycetes in peatlands suggested the presence of versatile hydrolytic capabilities in these bacteria. This evidence was further confirmed by the analysis of genome-encoded capabilities of isolates from wetlands. Large (up to 12 Mbp) genomes of planctomycetes encode wide repertoires of carbohydrate-active enzymes including many unclassified putative glycoside hydrolases, which suggests the presence of extremely high glycolytic potential in these bacteria. Experimental tests confirmed their ability to grow on xylan, pectin, starch, lichenan, cellulose, chitin and polysaccharides of microbial origin. These results provide an insight into the ecological roles of peat-inhabiting planctomycetes and suggest their participation in degradation of plant-derived polymers, exoskeletons of peat inhabiting arthropods as well as exopolysaccharides produced by other bacteria. PMID- 30476050 TI - Linking cross-bridge cycling kinetics to response to cardiac resynchronization therapy: a multiscale modelling study. AB - Aims: Cardiac resynchronization therapy (CRT) is currently the most widely used treatment for heart failure patients with left bundle branch block (LBBB). In recent years, the presence of septal rebound stretch (SRS) has been found to be a positive indicator for CRT response although the mechanism is unknown. Methods and results: In an attempt to understand the relation between cellular mechanics and global pump function in CRT patients, we utilize the CircAdapt closed-loop cardiovascular system model in combination with the MechChem model of cardiac sarcomere contraction. Left bundle branch block has been simulated with increasing delay in left ventricular free wall and septal wall activation. In addition to the electrical dyssynchrony, myocardial mechanical function was diminished by decreasing the cross-bridge cycling rate. Our results have shown that a decrease in the cross-bridge cycling rate in addition to LBBB resulted in a decrease in SRS with a concomitant decreased response to resynchronization. Conclusions: The results of our multiscale modelling study suggest that, while greater SRS during systole clearly indicates electrical dyssynchrony, it also predicts mechanical viability and healthy cross-bridge cycling rates in the myocardium. Hence, SRS positively indicates response to CRT. PMID- 30476051 TI - Electrocardiogram phenotypes in hypertrophic cardiomyopathy caused by distinct mechanisms: apico-basal repolarization gradients vs. Purkinje-myocardial coupling abnormalities. AB - Aims: To identify key structural and electrophysiological features explaining distinct electrocardiogram (ECG) phenotypes in hypertrophic cardiomyopathy (HCM). Methods and results: Human heart-torso anatomical models were constructed from cardiac magnetic resonance (CMR) images of HCM patients, representative of ECG phenotypes identified previously. High performance computing simulations using bidomain models were conducted to dissect key features explaining the ECG phenotypes with increased HCM Risk-SCD scores, namely Group 1A, characterized by normal QRS but inverted T waves laterally and coexistence of apical and septal hypertrophy; and Group 3 with marked QRS abnormalities (deep and wide S waves laterally) and septal hypertrophy. Hypertrophic cardiomyopathy abnormalities characterized from CMR, such as hypertrophy, tissue microstructure alterations, abnormal conduction system, and ionic remodelling, were selectively included to assess their influence on ECG morphology. Electrocardiogram abnormalities could not be explained by increased wall thickness nor by local conduction abnormalities associated with fibre disarray or fibrosis. Inverted T wave with normal QRS (Group 1A) was obtained with increased apico-basal repolarization gradient caused by ionic remodelling in septum and apex. Lateral QRS abnormalities (Group 3) were only recovered with abnormal Purkinje-myocardium coupling. Conclusion: Two ECG-based HCM phenotypes are explained by distinct mechanisms: ionic remodelling and action potential prolongation in hypertrophied apical and septal areas lead to T wave inversion with normal QRS complexes, whereas abnormal Purkinje-myocardial coupling causes abnormal QRS morphology in V4-V6. These findings have potential implications for patients' management as they point towards different arrhythmia mechanisms in different phenotypes. PMID- 30476052 TI - Beat-to-beat P-wave morphological variability in patients with paroxysmal atrial fibrillation: an in silico study. AB - Aims: P-wave beat-to-beat morphological variability can identify patients prone to paroxysmal atrial fibrillation (AF). To date, no computational study has been carried out to mechanistically explain such finding. The aim of this study was to provide a pathophysiological explanation, by using a computer model of the human atria, of the correlation between P-wave beat-to-beat variability and the risk of AF. Methods and results: A physiological variability in the earliest activation site (EAS), on a beat-to-beat basis, was introduced into a computer model of the human atria by randomizing the EAS location. A methodology for generating multi scale, spatially-correlated regions of heterogeneous conduction was developed. P wave variability in the presence of such regions was compared with a control case. Simulations were performed with an eikonal model, for the activation map, and with the lead field approach, for P-wave computation. The methodology was eventually compared with a reference monodomain simulation. A total of 60 P-waves were simulated for each sinus node exit location (12 in total), and for each of the 15 patterns of heterogeneous conduction automatically generated by the model. A P-wave beat-to-beat variability was observed in all cases. Variability was significantly increased in presence of heterogeneous slow conducting regions, up to two-fold the variability in the control case. P-wave variability increased non linearly with respect to the EAS variability and total area of slow conduction. Distribution of the heterogeneous conduction was more effective in increasing the variability when it surrounded the EAS locations and the fast conducting bundles. P-waves simulated by the eikonal approach compared excellently with the monodomain-based ones. Conclusion: P-wave variability in patients with paroxysmal AF could be explained by a variability in sinoatrial node exit location in combination with slow conducting regions. PMID- 30476054 TI - A left bundle branch block activation sequence and ventricular pacing influence voltage amplitudes: an in vivo and in silico study. AB - Aims: The aim of this study was to investigate the influence of the activation sequence on voltage amplitudes by evaluating regional voltage differences during a left bundle branch block (LBBB) activation sequence vs. a normal synchronous activation sequence and by evaluating pacing-induced voltage differences. Methods and results: Twenty-one patients and three computer models without scar were studied. Regional voltage amplitudes were evaluated in nine LBBB patients who underwent endocardial electro-anatomic mapping (EAM). Pacing-induced voltage differences were evaluated in 12 patients who underwent epicardial EAM during intrinsic rhythm and right ventricular (RV) pacing. Three computer models customized for LBBB patients were created. Changes in voltage amplitudes after an LBBB (intrinsic), a normal synchronous, an RV pacing, and a left ventricular pacing activation sequence were assessed in the computer models. Unipolar voltage amplitudes in patients were approximately 4.5 mV (4.4-4.7 mV, ~33%) lower in the septum when compared with other segments. A normal synchronous activation sequence in the computer models normalized voltage amplitudes in the septum. Pacing-induced differences were larger in electrograms with higher voltage amplitudes during intrinsic rhythm and furthermore larger and more variable at the epicardium [mean absolute difference: 3.6-6.2 mV, 40-53% of intrinsic value; interquartile range (IQR) differences: 53-63% of intrinsic value] compared to the endocardium (mean absolute difference: 3.3-3.8 mV, 28-30% of intrinsic value; IQR differences: 37-40% of intrinsic value). Conclusion: In patients and computer models without scar, lower septal unipolar voltage amplitudes are exclusively associated with an LBBB activation sequence. Pacing substantially affects voltage amplitudes, particularly at the epicardium. PMID- 30476056 TI - Fast personalized electrophysiological models from computed tomography images for ventricular tachycardia ablation planning. AB - Aims: Clinical application of patient-specific cardiac computer models requires fast and robust processing pipelines that can be seamlessly integrated into clinical workflows. We aim at building such a pipeline from computed tomography (CT) images to personalized cardiac electrophysiology (EP) model. The simulation output could be useful in the context of post-infarct ventricular tachycardia (VT) radiofrequency ablation (RFA) planning for pre-operative targets prediction. Methods and results: The support for model personalization is a patient-specific virtual three-dimensional heart obtained from CT images. Here, the scar is identified as thinning of the myocardial wall on automatically computed thickness maps. We then use an Eikonal model of wave front propagation with reduced velocity in the damaged areas. An image-based vessel enhancement algorithm can automatically identify VT isthmuses. The personalized model is used for virtual pacing. We obtained a very fast pipeline that enables simulations in only a few minutes. It is fully automated starting from the semi-automated image segmentation phase. The computational time frame is compatible with the construction of a virtual pacing tool. In this tool, onset points and an optional directional block could be interactively selected. The directional block is a simple way to model tissue refractoriness. Output activation maps are compared with EP data acquired pre-operatively. We show that this framework allows the reproduction of recorded re-entrant VT activation patterns. Conclusion: Our simulation framework has an application in VT RFA intervention planning. It could be used to guide EP explorations and even predict ablation targets pre operatively. This could reduce intervention duration and improve success rate. PMID- 30476053 TI - Arrhythmia dynamics in computational models of the atria following virtual ablation of re-entrant drivers. AB - Aims: Efforts to improve ablation success rates in persistent atrial fibrillation (AF) patients by targeting re-entrant driver (RD) sites have been hindered by weak mechanistic understanding regarding emergent RDs localization following initial fibrotic substrate modification. This study aimed to systematically assess arrhythmia dynamics after virtual ablation of RD sites in computational models. Methods and results: Simulations were conducted in 12 patient-specific atrial models reconstructed from pre-procedure late gadolinium-enhanced magnetic resonance imaging scans. In a previous study involving these same models, we comprehensively characterized pre-ablation RDs in simulations conducted with either 'average human AF'-based electrophysiology (i.e. EPavg) or +/-10% action potential duration or conduction velocity (i.e. EPvar). Re-entrant drivers seen under the EPavg condition were virtually ablated and the AF initiation protocol was re-applied. Twenty-one emergent RDs were observed in 9/12 atrial models (1.75 +/- 1.35 emergent RDs per model); these dynamically localized to boundary regions between fibrotic and non-fibrotic tissue. Most emergent RD locations (15/21, 71.4%) were within 0.1 cm of sites where RDs were seen pre-ablation in simulations under EPvar conditions. Importantly, this suggests that the level of uncertainty in our models' ability to predict patient-specific ablation targets can be substantially mitigated by running additional simulations that include virtual ablation of RDs. In 7/12 atrial models, at least one episode of macro reentry around ablation lesion(s) was observed. Conclusion: Arrhythmia episodes after virtual RD ablation are perpetuated by both emergent RDs and by macro reentrant circuits formed around lesions. Custom-tailoring of ablation procedures based on models should take steps to mitigate these sources of AF recurrence. PMID- 30476055 TI - Patient-specific simulations predict efficacy of ablation of interatrial connections for treatment of persistent atrial fibrillation. AB - Aims: Treatments for persistent atrial fibrillation (AF) offer limited efficacy. One potential strategy aims to return the right atrium (RA) to sinus rhythm (SR) by ablating interatrial connections (IAC) to isolate the atria, but there is limited clinical data to evaluate this ablation approach. We aimed to use simulation to evaluate and predict patient-specific suitability for ablation of IAC to treat AF. Methods and results: Persistent AF was simulated in 12 patient specific geometries, incorporating electrophysiological heterogeneity and fibres, with IAC at Bachmann's bundle, the coronary sinus, and fossa ovalis. Simulations were performed to test the effect of left atrial (LA)-to-RA frequency gradient and fibrotic remodelling on IAC ablation efficacy. During AF, we simulated ablation of one, two, or all three IAC, with or without pulmonary vein isolation and determined if this altered or terminated the arrhythmia. For models without structural remodelling, ablating all IAC terminated RA arrhythmia in 83% of cases. Models with the LA-to-RA frequency gradient removed had an increased success rate (100% success). Ablation of IACs is less effective in cases with fibrotic remodelling (interstitial fibrosis 50% success rate; combination remodelling 67%). Mean number of phase singularities in the RA was higher pre ablation for IAC failure (success 0.6 +/- 0.8 vs. failure 3.2 +/- 2.5, P < 0.001). Conclusion: This simulation study predicts that IAC ablation is effective in returning the RA to SR for many cases. Patient-specific modelling approaches have the potential to stratify patients prior to ablation by predicting if drivers are located in the LA or RA. We present a platform for predicting efficacy and informing patient selection for speculative treatments. PMID- 30476058 TI - Simulated P wave morphology in the presence of endo-epicardial activation delay. AB - Aims: Evidences of asynchrony between epicardial and endocardial activation in the atrial wall have been reported. We used a computer model of the atria and torso to investigate the consequences of such activation delay on P wave morphology, while controlling for P wave duration. Methods and results: We created 390 models of the atria based on the same geometry. These models differed by atrial wall thickness (from 2 to 3 mm), transmural coupling, and tissue conductivity in the endocardial and epicardial layers. Among them, 18 were in baseline, 186 had slower conduction in the epicardium layer and 186 in the endocardial layer. Conduction properties were adjusted in such a way that total activation time was the same in all models. P waves on a 16-lead system were simulated during sinus rhythm. Activation maps were similar in all cases. Endo epicardial delay varied between -5.5 and 5.5 ms vs. 0 +/- 0.5 ms in baseline. All P waves had the same duration but variability in their morphology was observed. With slower epicardial conduction, P wave amplitude was reduced by an average of 20% on leads V3-V5 and P wave area decreased by 50% on leads V1-V2 and by 40% on lead V3. Reversed, lower magnitude effects were observed with slower endocardial conduction. Conclusion: An endo-epicardial delay of a few milliseconds is sufficient to significantly alter P wave morphology, even if the activation map remains the same. PMID- 30476059 TI - Influence of left atrial size on P-wave morphology: differential effects of dilation and hypertrophy. AB - Aims: Chronic left atrial enlargement (LAE) increases the risk of atrial fibrillation. Electrocardiogram (ECG) criteria might provide a means to diagnose LAE and identify patients at risk; however, current criteria perform poorly. We seek to characterize the potentially differential effects of atrial dilation vs. hypertrophy on the ECG P-wave. Methods and results: We predict effects on the P wave of (i) left atrial dilation (LAD), i.e. an increase of LA cavity volume without an increase in myocardial volume, (ii) left atrial concentric hypertrophy (LACH), i.e. a thickened myocardial wall, and (iii) a combination of the two. We performed a computational study in a cohort of 72 anatomical variants, derived from four human atrial anatomies. To model LAD, pressure was applied to the LA endocardium increasing cavity volume by up to 100%. For LACH, the LA wall was thickened by up to 3.3 mm. P-waves were derived by simulating atrial excitation propagation and computing the body surface ECG. The sensitivity regarding changes beyond purely anatomical effects was analysed by altering conduction velocity by 25% in 96 additional model variants. Left atrial dilation prolonged P-wave duration (PWd) in two of four subjects; in one subject a shortening, and in the other a variable change were seen. Left atrial concentric hypertrophy, in contrast, consistently increased P-wave terminal force in lead V1 (PTF-V1) in all subjects through an enlarged amplitude while PWd was unaffected. Combined hypertrophy and dilation generally enhanced the effect of hypertrophy on PTF-V1. Conclusion: Isolated LAD has moderate effects on the currently used P-wave criteria, explaining the limited utility of PWd and PTF-V1 in detecting LAE in clinical practice. In contrast, PTF-V1 may be a more sensitive indicator of LA myocardial hypertrophy. PMID- 30476057 TI - Determinants of new wavefront locations in cholinergic atrial fibrillation. AB - Aims: Atrial fibrillation (AF) wavefront dynamics are complex and difficult to interpret, contributing to uncertainty about the mechanisms that maintain AF. We aimed to investigate the interplay between rotors, wavelets, and focal sources during fibrillation. Methods and results: Arrhythmia wavefront dynamics were analysed for four optically mapped canine cholinergic AF preparations. A bilayer computer model was tuned to experimental preparations, and varied to have (i) fibrosis in both layers or the epicardium only, (ii) different spatial acetylcholine distributions, (iii) different intrinsic action potential duration between layers, and (iv) varied interlayer connectivity. Phase singularities (PSs) were identified and tracked over time to identify rotational drivers. New focal wavefronts were identified using phase contours. Phase singularity density and new wavefront locations were calculated during AF. There was a single dominant mechanism for sustaining AF in each of the preparations, either a rotational driver or repetitive new focal wavefronts. High-density PS sites existed preferentially around the pulmonary vein junctions. Three of the four preparations exhibited stable preferential sites of new wavefronts. Computational simulations predict that only a small number of connections are functionally important in sustaining AF, with new wavefront locations determined by the interplay between fibrosis distribution, acetylcholine concentration, and heterogeneity in repolarization within layers. Conclusion: We were able to identify preferential sites of new wavefront initiation and rotational activity, in order to determine the mechanisms sustaining AF. Electrical measurements should be interpreted differently according to whether they are endocardial or epicardial recordings. PMID- 30476060 TI - Effect of Na+-channel blockade on the three-dimensional substrate of atrial fibrillation in a model of endo-epicardial dissociation and transmural conduction. AB - Aims: Atrial fibrillation (AF) is a progressive arrhythmia characterized by structural alterations that increase its stability. Both clinical and experimental studies showed a concomitant loss of antiarrhythmic drug efficacy in later stages of AF. The mechanisms underlying this loss of efficacy are not well understood. We hypothesized that structural remodelling may explain this reduced efficacy by making the substrate more three-dimensional. To investigate this, we simulated the effect of sodium (Na+)-channel block on AF in a model of progressive transmural uncoupling. Methods and results: In a computer model consisting of two cross-connected atrial layers, with realistic atrial membrane behaviour, structural remodelling was simulated by reducing the number of connections between the layers. 100% of endo-epicardial connectivity represented a healthy atrium. At various degrees of structural remodelling, we assessed the effect of 60% sodium channel block on AF stability, endo-epicardial electrical activity dissociation (EED), and fibrillatory conduction pattern complexity quantified by number of waves, phase singularities (PSs), and transmural conduction ('breakthrough', BT). Sodium channel block terminated AF in non remodelled but not in remodelled atria. The temporal excitable gap (EG) and AF cycle length increased at all degrees of remodelling when compared with control. Despite an increase of EED and EG, sodium channel block decreased the incidence of BT because of transmural conduction block. Sodium channel block decreased the number of waves and PSs in normal atrium but not in structurally remodelled atrium. Conclusion: This simple atrial model explains the loss of efficacy of sodium channel blockers in terminating AF in the presence of severe structural remodelling as has been observed experimentally and clinically. Atrial fibrillation termination in atria with moderate structural remodelling in the presence of sodium channel block is caused by reduction of AF complexity. With more severe structural remodelling, sodium channel block fails to promote synchronization of the two layers of the model. PMID- 30476061 TI - Support vector machine-based assessment of the T-wave morphology improves long QT syndrome diagnosis. AB - Aims: Diagnosing long QT syndrome (LQTS) is challenging due to a considerable overlap of the QTc-interval between LQTS patients and healthy controls. The aim of this study was to investigate the added value of T-wave morphology markers obtained from 12-lead electrocardiograms (ECGs) in diagnosing LQTS in a large cohort of gene-positive LQTS patients and gene-negative family members using a support vector machine. Methods and results: A retrospective study was performed including 688 digital 12-lead ECGs recorded from genotype-positive LQTS patients and genotype-negative relatives at their first visit. Two models were trained and tested equally: a baseline model with age, gender, RR-interval, QT-interval, and QTc-intervals as inputs and an extended model including morphology features as well. The best performing baseline model showed an area under the receiver operating characteristic curve (AUC) of 0.821, whereas the extended model showed an AUC of 0.901. Sensitivity and specificity at the maximal Youden's indexes changed from 0.694 and 0.829 with the baseline model to 0.820 and 0.861 with the extended model. Compared with clinically used QTc-interval cut-off values (>480 ms), the extended model showed a major drop in false negative classifications of LQTS patients. Conclusion: The support vector machine-based extended model with T wave morphology markers resulted in a major rise in sensitivity and specificity at the maximal Youden's index. From this, it can be concluded that T-wave morphology assessment has an added value in the diagnosis of LQTS. PMID- 30476062 TI - Species differences in the morphology of transverse tubule openings in cardiomyocytes. AB - Aims: The ultrastructure of ventricular cardiomyocyte T-tubule connections with the outer cell surface ('mouth' regions) has been reported to differ between mice and rabbits. In mice, T-tubule mouths form convoluted narrow spaces filled with electron-dense matter that impedes diffusion between T-tubular lumen and bulk extracellular space. Here, we explore whether T-tubule mouths are also constricted in rat (another murine model used frequently for cardiac research) and whether pig and human T-tubule mouth configurations are structurally more similar to mice or rabbits. Methods and results: We used chemically-fixed tissue and high-pressure frozen isolated cardiomyocytes to compare T-tubule mouth architecture using transmission electron microscopy and three-dimensional electron tomography. We find that rat T-tubular mouth architecture is more similar to that of rabbits than mice, lacking the marked tortuosity and electron dense ground substance that obstructs access to deeper portions of the T-tubular system in mice. Pilot observations in larger mammals (pig, human) suggest that mouse may be the least representative animal model of T-tubule connectivity with the outer cell surface in larger mammals. Conclusion: Rat T-tubular system architecture appears to be more similar in size and topology to larger mammals than mice. T-tubular mouth topology may contribute to differences in experimental model behaviour, underscoring the challenge of appropriate model selection for research into cell and tissue function. PMID- 30476063 TI - Bioinformatic analysis of a plakophilin-2-dependent transcription network: implications for the mechanisms of arrhythmogenic right ventricular cardiomyopathy in humans and in boxer dogs. AB - Aims: Previous studies in murine hearts and in cell systems have shown that modifications in the expression or sequence integrity of the desmosomal molecule plakophilin-2 (PKP2) can alter the downstream expression of transcripts necessary for the electrical and mechanical function of the heart. These findings have provided support to mechanistic hypotheses that seek to explain arrhythmogenic right ventricular cardiomyopathy (ARVC) in humans. However, the relation between PKP2 expression and the transcriptome of the human heart remains poorly explored. Furthermore, while a number of studies have documented the clinical similarity between familial ARVC in humans and inheritable ARVC in boxer dogs, there is a puzzling lack of convergence as to the possible genetic causes of disease in one species vs. the other. Methods and results: We implemented bioinformatics analysis tools to explore the relation between the PKP2-dependent murine and human transcriptomes. Our data suggest that genes involved in intracellular calcium regulation, and others involved in intercellular adhesion, form part of a co-ordinated gene network. We further identify PROX1 and PPARA (coding for the proteins Prox1 and PPAR-alpha, respectively) as transcription factors within the same network. Conclusion: On the basis our analysis, we hypothesize that the molecular cascades initiated by the seemingly unrelated genetic mutations in humans and in boxers actually converge downstream into a common pathway. This can explain the similarities in the clinical manifestation of ARVC in humans and in the boxer dogs. PMID- 30476064 TI - 9th Theo Rossi di Montelera forum on computer simulation and experimental assessment of cardiac function: from model to clinical outcome. PMID- 30476065 TI - Fit & Strong! Plus Trial Outcomes for Obese Older Adults with Osteoarthritis. AB - Background and Objectives: We compared the effectiveness of standard Fit & Strong! (F&S!; targets physical activity [PA]) to Fit & Strong! Plus (F&S! Plus; targets PA and dietary weight loss) on weight, diet quality, and PA outcomes. Research Design and Methods: We randomly assigned 413 overweight older adults with OA to the F&S! or F&S! Plus programs and assessed outcomes at 2 and 6 months. Results: The F&S! Plus group lost -2.0 +/- 0.2 kg (mean +/- SE, 2% of starting weight) at 2 months that was maintained at 6 months. Two- and 6-month BMI and waist circumference improved significantly in the F&S! Plus group (p < .001). Diet quality at 2 months showed greater improvement in the F&S! Plus group: 4.6 +/- 0.7 versus 2.0 +/- 0.7, p = .006, with no significant difference between groups at 6 months. The F&S! Plus group differentially improved on PA engagement at 2 months and at 2 and 6 months in joint pain (6-month mean +/- SE: 1.5 +/- 0.3 vs -0.6 +/- 0.3, p = .02), function (-4.7 +/- 0.9 vs -1.5 +/- 0.9, p = .01), and 6-min walk test (29.5 +/- 5.1 m vs 14.1 +/- 5.2 m, p = .04). Discussion and Implications: Adding a dietary weight loss component to F&S! achieved weight and waist circumference benefits that were maintained at 6 months. Importantly, the weight loss was accompanied by clinically meaningful improvements in OA symptoms and mobility. Future work should investigate minimum thresholds for weight reduction that improve long-term function in this population. PMID- 30476066 TI - Dynamic Transcriptome Profiling Dataset of Vaccinia Virus Obtained from Long-read Sequencing Techniques. AB - Background: Poxviruses are large DNA viruses infecting humans and animals. Vaccinia virus (VACV) has been applied as a live vaccine for immunization against smallpox, which was eradicated by 1980 as a result of worldwide vaccination. VACV is the prototype of poxviruses in the investigation of the molecular pathogenesis of the virus. Short-read sequencing methods have revolutionized transcriptomics; but, they are not efficient in distinguishing between the RNA isoforms and transcript overlaps. Long-read sequencing (LRS) is much better suited to solve these problems, and also allow direct RNA sequencing. Despite the scientific relevance of VACV, no LRS data have been generated for the viral transcriptome so far. Findings: For the deep characterization of the VACV RNA profile, various LRS platforms and library preparation approaches were applied. The raw reads were mapped to the VACV reference genome and also to the host (Chlorocebus sabaeus) genome. In this study, we applied the Pacific Biosciences RSII and Sequel platforms, which altogether resulted in 937,531 mapped reads of inserts (1.42 Gb), while we obtained 2,160,348 aligned reads (1.75 Gb) from the different library preparation methods, using the MinION device from Oxford Nanopore Technologies. Conclusions: By applying cutting-edge technologies, we were able to generate a large dataset that can serve as a valuable resource for the investigation of the dynamic VACV transcriptome, the virus-host interactions and RNA base modifications. These data can provide useful information for novel gene annotations in the VACV genome. Our dataset can also be applied for analyzing the currently available LRS platforms, library preparation methods and bioinformatics pipelines. PMID- 30476067 TI - Emerging and threatening infectious diseases. PMID- 30476068 TI - Toxin-antitoxin systems shows variability among Mycobacterium tuberculosis lineages. AB - The Toxin-Antitoxin (TA) systems are operons involved in the formation of persistent cells and in stress situations in microorganism. TAs are widely distributed in Mycobacterium tuberculosis (MTB). The objective of this study was to determine the distribution and variability of protein sequences of TA systems in seven MTB lineages. Protein prediction on 73 genomes of different lineage was made using Prodigal, and profile hidden Markov models (PHMMs) of 225 reference TA proteins were constructed with HMMER. A homology search was made comparing the predicted proteins to PHMMs. Consecutive proteins that matched PHMMs (forming an operon) were selected. Thereafter, clustering of orthologous genes was made for further mutation scanning through multiple alignments. All proteins found belong to TA type II and IV, and 45 proteins were found completely conserved. Six uncharacterized antitoxins homologous to VapB11, VapB5, VapB45, VapB13, ParD1 and RelB were found. Multiple alignments revealed differences among lineages with specific mutations suitable for genotyping. Significant changes in amino acid sequences caused by frameshift mutations were found in 46 TA proteins. PMID- 30476069 TI - Protective vascular coagulation in response to bacterial infection of the kidney is regulated by bacterial lipid A and host CD147. AB - Bacterial infection of the kidney leads to a rapid cascade of host protective responses, many of which are still poorly understood. We have previously shown that following kidney infection with uropathogenic Escherichia coli (UPEC), a rapid vascular coagulation is initiated in local perivascular capillaries that protect the host from progressing from a local infection to systemic sepsis. The signaling mechanisms behind this response have not however been described. In this study we use a number of in vitro and in vivo techniques, including intravital microscopy, to identify two previously unrecognized components influencing this protective coagulation response. The acylation state of the Lipid A of UPEC LPS is shown to alter the kinetics of local coagulation onset in vivo. We also identify epithelial CD147 as a potential host factor influencing infection-mediated coagulation. CD147 is expressed by renal proximal epithelial cells infected with UPEC, contingent to bacterial expression of the alpha hemolysin toxin. The epithelial CD147 subsequently can activate tissue factor on endothelial cells, a primary step in the coagulation cascade. This study emphasizes the rapid, multifaceted response of the kidney tissue to bacterial infection and the interplay between host and pathogen during the early hours of renal infection. PMID- 30476070 TI - Differential influences of complement on neutrophil responses to N. meningitidis infection. AB - The complement system is the primary innate immune determinant protecting against invasive diseases caused by the Gram-negative bacterium Neisseria meningitidis (Nme, meningococcus), as evidenced by the extreme susceptibility of individuals with complement deficiencies. In contrast, the role of phagocytes such as neutrophils is much less well understood, although they are recruited in great numbers to the cerebrospinal fluid during meningococcal meningitis. Here, we consider the interaction of Nme with primary human neutrophils using either purified cells or a whole blood model of infection. We found that neutrophils are capable of non-opsonic uptake and killing of different Nme strains. However, in presence of immune serum featuring active complement, Nme-association is strongly increased, whereas this is not the case in heat-inactivated immune serum. Blockade of complement at the level of C3 using the inhibitor compstatin Cp20 reduces the uptake dramatically. In addition, purified neutrophils did not mount an oxidative burst towards Nme unless complement was added and, vice versa, the oxidative burst was strongly reduced in whole blood upon complement inhibition. In contrast, there was no significant impact of complement on neutrophil degranulation or IL-8 secretion. Taken together, neutrophils require complement activation in order to mount a full response towards Nme. PMID- 30476071 TI - Genome reduction in the mosquito symbiont Asaia. AB - Symbiosis is now recognized as a driving force in evolution, a role that finds its ultimate expression in the variety of associations bonding insects with microbial symbionts. These associations have contributed to the evolutionary success of insects, with the hosts acquiring the capacity to exploit novel ecological niches, and the symbionts passing from facultative associations to obligate, mutualistic symbioses. In bacterial symbiont of insects, the transition from the free-living life style to mutualistic symbiosis often resulted in a reduction in the genome size, with the generation of the smallest bacterial genomes thus far described. Here we show that the process of genome reduction is still occurring in Asaia, a group of bacterial symbionts associated with a variety of insects. Indeed, comparative genomics of Asaia isolated from different mosquito species revealed a substantial genome size and gene content reduction in Asaia from Anopheles darlingi, a South-American malaria vector. We thus propose Asaia as a novel model to study genome reduction dynamics, within a single bacterial taxon, evolving in a common biological niche. PMID- 30476072 TI - Care Arrangements of Older Adults: What They Prefer, What They Have, and Implications for Quality of Life. AB - Background and Objectives: Meeting individual preferences for long-term services and supports (LTSS) is a policy priority that has implications for quality of care. Evidence regarding preferences is sparse. In addition, little is known regarding whether preferences and care arrangements match for those receiving care, and implications for quality of life. Research Design and Methods: A random sample (n = 1,783 in 2012) of National Health and Aging Trends Study participants were asked the best care option for someone 80+ who needs help with personal care and mobility. Analyses examine variations in care preferences, the relationship of preferences to care arrangements, and the association of matched preference and care arrangements to quality of life indicators. Results: Care preferences vary by demographics. Equal proportions (3 in 10) of older adults chose assisted living or continuing care retirement communities (CCRC), care in own home with family help, and care in own home with paid help, as the best options. Persons in assisted living/CCRC settings were significantly more likely to choose this option as best. Only 1 in 3 older persons receiving care are in arrangements that match preferences. No association with quality of life indicators was found. Discussion and Implications: Aging in place remains the care preference of a majority, but close to one-third chose assisted living/CCRC, suggesting preferences are evolving. Aligning care preferences and arrangements is a policy goal, but many do not achieve a match and there remain gaps in understanding trajectories in preferences and care arrangements and implications for quality of life. PMID- 30476074 TI - Inflammatory Bowel Diseases Were Associated With Risk of Sexual Dysfunction in Both Sexes: A Meta-analysis. AB - Background: An association between inflammatory bowel diseases (IBD) and increased susceptibility to sexual dysfunction (SD) was reported in a number of studies. Method: MEDLINE (PubMed), EMBASE, and the Cochrane Library were systematically searched for all relevant studies reporting the sexual function in IBD patients. Relative risk (RR) with a 95% confidence interval (CI) was used to summarize the association between IBD and risk of SD. Subgroup and sensitivity analyses were applied to detect potential bias. Results: Overall, 351,668 male individuals and 1309 female individuals (the mean age ranged from 33.6 years to 52.4 years) were included from 8 studies (of which 4 studies provided the outcomes of both sexes). Synthesis of results revealed that IBD was significantly associated with an elevated risk of SD in male subjects (7 studies, RR = 1.41, 95% CI, 1.09-1.81, P = 0.008; heterogeneity: I2 = 80.2%, P < 0.001) and female subjects (5 studies, RR = 1.76, 95% CI, 1.28-2.42, P < 0.001; heterogeneity: I2 = 69.6%, P = 0.011). Stratified analysis by the mean age of the individuals indicated that patients with IBD with a relatively young age (male: younger than 50 years; female: younger than 40 years) exhibited a significantly increased odds of SD. Sensitivity analyses showed that no single study dominated the overall combined RR. Conclusion: Evidence from this meta-analysis revealed that both male and female patients with IBD have a significantly increased risk of SD, which should remind both gastroenterologists and urologists to be aware of the potential hazardous effect of IBD for developing SD. PMID- 30476075 TI - Minimally invasive mitral valve repair or replacement for degenerative mitral regurgitation. AB - OBJECTIVES: This study describes our experience with minimally invasive mitral valve (MV) repair and chordal-sparing replacement in patients with degenerative MV regurgitation. METHODS: Between February 2009 and October 2015, a total of 960 patients underwent isolated minimally invasive MV repair, whereas 95 patients underwent chordal-sparing MV replacement. We performed a propensity score-matched analysis in 85 pairs to compare overall survival and major adverse cardiac and cerebrovascular event (MACCE) -free survival over an 8-year follow-up period. For sensitivity analyses, in the entire study cohort, we used the multivariable adjusted Cox regression analysis to assess the overall mortality and MACCE. RESULTS: In the propensity score-matched pairs, the 7-year probability of survival was 76.3% in the repair group and 78.8% in the replacement group (P = 0.60). Similarly, freedom from MACCE at year 7 of follow-up did not differ between the repair and replacement groups (78.6% and 72.3%, respectively; P = 0.48). The corresponding values for 7-year freedom from valve reintervention were 95.6% and 98.8%, respectively (P = 0.31). In the entire study cohort, the multivariable-adjusted hazard ratio (HR) of mortality for the replacement versus the repair group was 1.31 [95% confidence interval (CI) 0.68-2.50; P = 0.42], and the multivariable-adjusted HR of MACCE was 1.03 (95% CI 0.61-1.74; P = 0.91). CONCLUSIONS: Our findings suggest that mid-term clinical outcomes do not significantly differ between patients undergoing MV repair or chordal-sparing MV replacement. Clinical trial registration: The Ethics Committee of the Ruhr University Bochum at Bad Oeynhausen, Germany, reference No. 2018-325. PMID- 30476073 TI - Increased risk of central nervous system tumours with carbamate insecticide use in the prospective cohort AGRICAN. AB - Background: Pesticide exposures are suspected to be implicated in the excess of central nervous system (CNS) tumours observed in farmers, but evidence concerning individual pesticides remains limited. Carbamate insecticides, used on a wide range of crops, have shown evidence of carcinogenicity in some experimental studies. In the cohort AGRICAN (AGRIculture & CANcer), we assessed the associations between potential exposures to carbamate insecticides and the incidence of CNS tumours, overall and by histological subtype. Methods: AGRICAN enrolled 181 842 participants involved in agriculture. Incident CNS tumours were identified by linkage with cancer registries from enrolment (2005-07) until 2013. Carbamate exposure was assessed by combining information on lifetime periods of pesticide use on crop or livestock and the French crop-exposure matrix PESTIMAT, individually for each of the 19 carbamate insecticides registered in France since 1950. Associations were estimated using proportional hazards models with age as the underlying time scale, adjusting for gender, educational level and smoking. Results: During a 6.9-year average follow-up, 381 incident cases of CNS tumours occurred, including 164 gliomas and 134 meningiomas. Analyses showed increased risks of CNS tumours with overall exposure to carbamate insecticides and linear trends with duration of use of each carbamate. Considering tumour subtypes, hazard ratios for gliomas ranged from 1.18 for thiofanox to 4.60 for formetanate, and for meningiomas from 1.51 for carbaryl to 3.67 for thiofanox. Conclusions: Findings reinforce carcinogenicity evidence for already suspected active ingredients and draw attention to additional active ingredients, notably used on fruit trees, vineyards, potatoes and beets. PMID- 30476076 TI - Animal Models for Influenza A Virus Infection Incorporating the Involvement of Innate Host Defenses: Enhanced Translational Value of the Porcine Model. AB - Influenza is a viral respiratory disease having a major impact on public health. Influenza A virus (IAV) usually causes mild transitory disease in humans. However, in specific groups of individuals such as severely obese, the elderly, and individuals with underlying inflammatory conditions, IAV can cause severe illness or death. In this review, relevant small and large animal models for human IAV infection, including the pig, ferret, and mouse, are discussed. The focus is on the pig as a large animal model for human IAV infection as well as on the associated innate immune response. Pigs are natural hosts for the same IAV subtypes as humans, they develop clinical disease mirroring human symptoms, they have similar lung anatomy, and their respiratory physiology and immune responses to IAV infection are remarkably similar to what is observed in humans. The pig model shows high face and target validity for human IAV infection, making it suitable for modeling many aspects of influenza, including increased risk of severe disease and impaired vaccine response due to underlying pathologies such as low-grade inflammation. Comparative analysis of proteins involved in viral pattern recognition, interferon responses, and regulation of interferon stimulated genes reveals a significantly higher degree of similarity between pig, ferret, and human compared with mice. It is concluded that the pig is a promising animal model displaying substantial human translational value with the ability to provide essential insights into IAV infection, pathogenesis, and immunity. PMID- 30476077 TI - A Quantitative Analysis of Colonic Mucosal Oxylipins and Endocannabinoids in Treatment-Naive and Deep Remission Ulcerative Colitis Patients and the Potential Link With Cytokine Gene Expression. AB - Background: The bioactive metabolites of omega 3 and omega 6 polyunsaturated fatty acids (omega-3 and omega-6) are known as oxylipins and endocannabinoids (eCBs). These lipid metabolites are involved in prompting and resolving the inflammatory response that leads to the onset of inflammatory bowel disease (IBD). This study aims to quantify these bioactive lipids in the colonic mucosa and to evaluate the potential link to cytokine gene expression during inflammatory events in ulcerative colitis (UC). Methods: Colon biopsies were taken from 15 treatment-naive UC patients, 5 deep remission UC patients, and 10 healthy controls. Thirty-five oxylipins and 11 eCBs were quantified by means of ultra-high-performance liquid chromatography coupled with tandem mass spectrometry. Levels of mRNA for 10 cytokines were measured by reverse transcription polymerase chain reaction. Results: Levels of omega-6-related oxylipins were significantly elevated in treatment-naive patients with respect to controls, whereas the levels of omega-3 eCBs were lower. 15S-Hydroxy eicosatrienoic acid (15S-HETrE) was significantly upregulated in UC deep remission patients compared with controls. All investigated cytokines had significantly higher mRNA levels in the inflamed mucosa of treatment-naive UC patients. Cytokine gene expression was positively correlated with several omega-6 arachidonic acid-related oxylipins, whereas negative correlation was found with lipoxin, prostacyclin, and the eCBs. Conclusions: Increased levels of omega-6 related oxylipins and decreased levels of omega-3-related eCBs are associated with the debut of UC. This highlights the altered balance between pro- and anti inflammatory lipid mediators in IBD and suggests potential targets for intervention. PMID- 30476078 TI - Transcriptional activation of fucosyltransferase (FUT) genes using the CRISPR dCas9-VPR technology reveals potent N-glycome alterations in colorectal cancer cells. AB - Aberrant fucosylation in cancer cells is considered as a signature of malignant cell transformation and it is associated with tumor progression, metastasis and resistance to chemotherapy. Specifically, in colorectal cancer cells, increased levels of the fucosylated Lewisx antigen are attributed to the deregulated expression of pertinent fucosyltransferases, like fucosyltransferase 4 (FUT4) and fucosyltransferase 9 (FUT9). However, the lack of experimental models closely mimicking cancer-specific regulation of fucosyltransferase gene expression has, so far, limited our knowledge regarding the substrate specificity of these enzymes and the impact of Lewisx synthesis on the glycome of colorectal cancer cells. Therefore, we sought to transcriptionally activate the Fut4 and Fut9 genes in the well-known murine colorectal cancer cell line, MC38, which lacks expression of the FUT4 and FUT9 enzymes. For this purpose, we utilized a physiologically relevant, guide RNA-based model of de novo gene expression, namely the CRISPR-dCas9-VPR system. Induction of the Fut4 and Fut9 genes in MC38 cells using CRISPR-dCas9-VPR resulted in specific neo-expression of functional Lewisx antigen on the cell surface. Interestingly, Lewisx was mainly carried by N linked glycans in both MC38-FUT4 and MC38-FUT9 cells, despite pronounced differences in the biosynthetic properties and the expression stability of the induced enzymes. Moreover, Lewisx expression was found to influence core fucosylation, sialylation, antennarity and the subtypes of N-glycans in the MC38 glycovariants. In conclusion, exploiting the CRISPR-dCas9-VPR system to augment glycosyltransferase expression is a promising method of transcriptional gene activation with broad application possibilities in glycobiology and oncology research. PMID- 30476080 TI - A review of the sustainability and impact of a healthy lifestyles programme in primary schools 2-5 years after the intervention phase. AB - There has been an emphasis on schools to promote healthy lifestyles and many intervention programmes have attempted this. Most programmes are evaluated at the time and/or shortly afterwards. This is a review of the impact and sustainability of the Health for Life programme 2-5 years after the initial phase. It captures the experiences of the senior school staff who delivered the programme through semi-structured interviews. Senior teachers recognized the importance of promoting healthy lifestyles in primary schools. They reported positively on aspects of the programme, in particular its flexibility and how it enabled schools to develop a new relationship with parents and how schools have sustained the initial programme. They discussed the main barriers to intervention and how they could be mitigated. Delivering a sustainable healthy lifestyle primary schools programme which has an impact is feasible but challenging for school staff. To maximize the likelihood of delivery, interventions must be championed by a member of the Senior Leadership Team, embedded in the curriculum, hands-on, easy to manage, and flexible to the needs of individual schools but requires support (financial, training and advisory). With these conditions the sustainability and impact of the programme was significant. PMID- 30476081 TI - NanoAmpli-Seq: A workflow for amplicon sequencing for mixed microbial communities on the nanopore sequencing platform. AB - Background: Amplicon sequencing on Illumina sequencing platforms leverages their deep sequencing and multiplexing capacity, but is limited in genetic resolution due to short read lengths. While Oxford Nanopore or Pacific Biosciences platforms overcome this limitation, their application has been limited due to higher error rates or smaller data output. Results: In this study, we introduce an amplicon sequencing workflow, i.e., NanoAmpli-Seq, that builds on Intramolecular-ligated Nanopore Consensus Sequencing (INC-Seq) approach and demonstrate its application for full-length 16S rRNA gene sequencing. NanoAmpli-Seq includes vital improvements to the aforementioned protocol that reduces sample-processing time while significantly improving sequence accuracy. The developed protocol includes chopSeq software for fragmentation and read orientation correction of INC-Seq consensus reads while nanoClust algorithm was designed for read partitioning based de novo clustering and within cluster consensus calling to obtain full length 16S rRNA gene sequences. Conclusions: NanoAmpli-Seq accurately estimates the diversity of tested mock communities with average consensus accuracy of 99.5% for 2D and 1D2 sequencing on the nanopore sequencing platform. Nearly all residual errors in NanoAmpli-Seq sequences originate from deletions in homopolymer regions, indicating that homopolymer aware basecalling or error correction may allow for sequencing accuracy comparable to short-read sequencing platforms. PMID- 30476082 TI - Globo-series glycosphingolipids enhance Toll-like receptor 4-mediated inflammation and play a pathophysiological role in diabetic nephropathy. AB - Alteration of glycosphingolipid (GSL) expression plays key roles in the pathogenesis and pathophysiology of many important human diseases, including cancer, diabetes, and glycosphingolipidosis. Inflammatory processes are involved in development and progression of diabetic nephropathy, a major complication of type 2 diabetes mellitus. GSLs are known to play roles in inflammatory responses in various diseases, and levels of renal GSLs are elevated in mouse models of diabetic nephropathy; however, little is known regarding the pathophysiological role of these GSLs in this disease process. We studied proinflammatory activity of GSLs in diabetic nephropathy using spontaneously diabetic mouse strain KK. Mice were fed a high-fat diet (HFD) (60% kcal from fat) or normal diet (ND) (4.6% kcal from fat) for a period of 8 wk. HFD-feeding resulted in quantitative and qualitative changes of renal globo-series GSLs (particularly Gb3Cer), upregulation of TNF-alpha, and induction of renal inflammation. Gb3Cer/Gb4Cer treatment enhanced inflammatory responses via TLR4 in TLR4/MD-2 complex expressing cells, including HEK293T, mouse bone marrow-derived macrophages (BMDMs), and human monocytes. Our findings suggest that HFD-induced increase of Gb3Cer/Gb4Cer positively modulate TLR4-mediated inflammatory response, and that such GSLs play an important pathophysiological role in diabetic nephropathy. PMID- 30476083 TI - Dog Visiting Programs for Managing Depressive Symptoms in Older Adults: A Meta analysis. AB - Background and Objectives: Depressive symptoms are highly prevalent in older adults and may contribute to functional impairment at old age. Animal-assisted interventions (AAIs), including interventions involving dog visiting, are increasingly recognized as an innovative approach to ameliorate social, behavioral, psychological, and physical outcomes among older adults. However, available data on their potential to manage depressive symptoms in the aging population are not clear cut. The aim of this review was to conduct a meta analysis of all prospective controlled studies evaluating the effects of dog visiting on depressive symptoms in older adults. Research Design and Methods: A comprehensive literature search was conducted on the electronic databases PubMed and Scopus. Included articles were published between 1980 and 2017 and report controlled empirical studies of dog visiting interventions to ameliorate depressive symptoms in older adults. Results: There was substantial heterogeneity between included studies, which varied in their methodological quality, sample size, and other key features. Notwithstanding such methodological variety, results all go in the same direction and indicate a large beneficial effect of interventions involving dog visiting on depressive symptoms. Discussion and Implications: This analysis confirms the potential value of dog visiting in ameliorating depressive symptoms in institutionalized and noninstitutionalized older adults. This is in line with previous research indicating AAIs as promising complementary programs for preserving/enhancing emotional and behavioral function in aged individuals. More research is still needed to allow AAIs to be effectively introduced in clinical practice. PMID- 30476084 TI - RNA binding protein Ptbp1 is essential for BCR-mediated antibody production. AB - The RNA binding protein Ptbp1 binds to the pyrimidine-rich sequence of target RNA and controls gene expression via post-transcriptional regulation such as alternative splicing. Although Ptbp1 is highly expressed in B lymphocytes, its role to date is largely unknown. To clarify the role of Ptbp1 in B-cell development and function, we generated B-cell-specific Ptbp1 deficient (P1BKO) mice. B-cell development in the bone marrow, spleen, and peritoneal cavity of the P1BKO mice was nearly normal. However, the P1BKO mice had significantly lower levels of natural antibodies in serum compared with those of the control mice. To investigate the effect of Ptbp1 deficiency on the immune response in vivo, we immunized the P1BKO mice with T cell-independent type2 (TI-2) antigen NP-Ficoll and T cell-dependent (TD) antigen NP-CGG. We found that B-cell-specific Ptbp1 deficiency causes an immunodeficiency phenotype due to defective production of antibody against both TI-2 and TD antigen. This immunodeficiency was accompanied by impaired BCR-mediated B-cell activation and plasmablast generation. These findings demonstrate that Ptbp1 is essential for the humoral immune response. PMID- 30476085 TI - Residue Distribution and Depletion of Ractopamine in Goat Tissues After Exposure to Growth-Promoting Dose. AB - The objectives of the present study was to investigated the ractopamine (RAC) distribution and depletion process in various tissues of goat including liver, kidney, spleen, lung, heart, fat, bile, brain and the eyes. The experiment was carried out on 21 goats (18 treated and 3 controls). Treated goats were orally administered RAC in a dose of 1 mg/kg body mass per day for last 28 days and randomly sacrificed on withdrawal days of 0.25, 1, 3, 7, 14 and 21. RAC in all matrices were determined by ultra-high performance liquid chromatography quadrupole orbitrap high resolution mass spectrometry. After 21 days treatment discontinuation, the levels of RAC in bile reached at 13.48 +/- 3.36 mg/L, which was significantly higher than that in the other tissues. The concentrations of RAC were followed by kidney, the excretory organ and liver, the major metabolic organ (4.49 +/- 0.16 mg/kg for kidney and 1.81 +/- 0.11 mg/kg for liver, respectively). The residual concentration of the drug in the eyes of goat was less than that in bile, kidney, liver, lung and spleen on withdrawal days 0.25. RAC residues was higher than the limits of detection = 0.15 MUg/mL in liver on Day 21. These findings demonstrated that liver can serve as an alimentary matrix and as a matrix for the control of RAC abuse hypothetically except for urine. PMID- 30476086 TI - A Meta-analysis of Sexual Function in Patients With Inflammatory Bowel Disease: Examining a Small Piece of the Puzzle. PMID- 30476087 TI - A thoracic venous aneurysm mimicking a chronic expanding haematoma. AB - Thoracic venous aneurysms are rare, and bleeding is possible. A 9-year-old female patient presented with a thoracic wall mass. No blood flow was observed in the mass, and a chronic expanding haematoma was suspected based on the differential diagnosis. However, the venous structure was identified in the wall of the mass on pathological examination, and the diagnosis of the venous aneurysm was thereby established. Because the venous aneurysm contains fresh blood and bleeding can be profuse when such lesions are not properly handled during a surgical procedure, making the visibility of the surgeon poor, the venous aneurysm must be included in the differential diagnosis. PMID- 30476088 TI - Depressive symptoms among migrants and non-migrants in Europe: documenting and explaining inequalities in times of socio-economic instability. AB - Background: With the current study, we aim to explore the extent that migrants report higher rates of depressive symptoms than non-migrant populations in light of gender, childhood experiences, socioeconomic factors and social support across European countries that have been differentially influenced by the economic crisis. Methods: Using data from the seventh round of the European Social Survey and the Greek MIGHEAL survey, we compare the prevalence of depressive symptoms among migrants and non-migrants aged 25-65 years old across 21 countries. Results: Our findings show that migrants report significantly higher levels of depressive symptoms in seven of the examined countries, while in Greece and in the UK, they report significantly lower levels compared with non-migrant populations. The current climate of socioeconomic instability does not seem to necessarily associate with increased rates of depressive symptoms across countries neither it affects migrants and non-migrants in a similar way. Financial strain, childhood experiences of economic hardship and domestic conflict, female gender, as well as experiences of perceived discrimination appear to associate with increased levels of depressive symptoms among both migrant and non-migrant populations, while social trust and living with children have a protective impact. Still, much variation exists in the range of these associations between migrants and non-migrants and across countries. Conclusion: These findings suggest that the impact of migration status on depressive symptoms is subject to additional determinants of mental health as well as to contextual factors. PMID- 30476089 TI - The migration experience of Greece and the impact of the economic crisis on its migrant and native populations. AB - Background: This paper provides the socio-economic context of the MIGHEAL study, the results of which are presented in this special issue. The aim of the MIGHEAL study was to compare the physical and mental health of the native and migrant populations of Greece in the wake of the economic crisis that commenced in 2008. Methods: The background of the migrant population of Greece is described, drawing on population censuses of Greece and data on residence permits held by foreigners. Then the migrant and native populations are compared with respect to several socio-economic outcomes, using Eurostat data on unemployment and the risk of poverty. Results: The settled migrant population of Greece is largely of Central and Eastern European origin, resulting from the massive migrant inflowsthat started at the beginning of the 1990s after the collapse of socialist regimes in the area. Before the economic crisis, migrant unemployment was lower than that of natives, but after its onset, the unemployment of migrants surpassed that of natives. Prior to the crisis, migrants were already subject to greater risk of poverty than natives, but the gap widened considerably subsequent to the crisis. Conclusion: The Greek institutional framework has restricted access to citizenship for both first- and second-generation migrants while conditions for permit renewal are onerous, rendering citizenship an important factor differentiating socio-economic outcomes. The different outcomes observed among the native and migrant populations after the onset of the Greek economic crisis create concerns regarding health inequalities between the two populations. PMID- 30476090 TI - Self-reported depression among migrant and native populations in Greece in times of crisis. AB - Background: Recent evidence indicates to the alarming increase of depression, especially in Southern European countries. According to the literature, depressive symptoms are strongly associated with socioeconomic factors, while the prevalence of depression significantly differs by gender. Several scholars point out that many of the risk factors for self-reported depression increase during an economic crisis. These studies, however, mostly overlook the fact that the impact of these factors may vary between natives and migrants. Methods: Using data from the MIGHEAL study, we examine the variation of self-reported depression by migrant status and gender in Greece during the crisis. We also investigate the association of socioeconomic status, family-related factors, social trust and perceived discrimination with self-reported depression. Separate multiple linear regression models are fitted across three examined groups (Greeks, Albanians and migrants from other countries) as well as for Greek males and females. Results: Our findings indicate the mixture of the determinants of self-reported depression by both migrant status and gender. Women report higher rates of self-reported depression than men, as do natives compared to migrants, while getting older is associated with higher levels of depression in both genders and all three citizenship groups. Further, higher socioeconomic position is associated with lower levels of depression, especially in the case of Greek males, while financial strain appears to be a significant determinant of self-reported depression for both native and migrant populations. Conclusions: Our analysis does not confirm previous evidence that migrants are at an increased risk for depression. Age, gender, perceived discrimination and subjective general health appear to be more decisive determinants of self-reported depression than migrant background. Low socioeconomic status seems to be a risk factor for depression only in the case of Greeks. PMID- 30476091 TI - Intersecting crises: migration, the economy and the right to health in Europe. PMID- 30476092 TI - Income-related health inequalities among the migrant and native-born populations in Greece during the economic crisis: a decomposition analysis. AB - Background: The economic crisis has induced detrimental socio-economic and health effects in Greece. This study aims to measure overall income-related health inequalities and examine their determinants, and to compare the respective within estimates for major subpopulations defined by citizenship (Greece, Albania, other countries) in Greece. Methods: Data for 1332 cases were collected from a cross sectional observational survey (MIGHEAL) conducted at a national level in 2016. Income-related inequalities in poor subjective health, limiting long-standing illness, elevated depressive symptoms and non-communicable diseases were measured with the standard and Erreygers concentration indices. Decomposition analysis identified key factors explaining the inequalities. Results: Overall, significant inequalities favouring the better-off were established in all ill-health indicators, particularly in depression. Greek citizens were associated with consistent health inequalities, while, concerning the other groups, significant disparities were found only in depression for Albanians. Decomposition analyses identified socio-economic status, income in particular, as the main contributor to overall income-related health inequalities, followed by barriers to healthcare access, adverse family background and hazardous working conditions. Risk behaviours and discrimination were relatively less important, whereas area of residence was mainly reducing inequality. Citizens from Albania and other countries were found to be poorer, but with fewer health problems, hence, different citizenship decreased inequalities. Conclusion: Socio-economic health inequalities in Greece can be mitigated by means of appropriate multi-sectorial policy interventions, by focussing primarily on the most socio-economically disadvantaged groups. The overall inequality-producing mechanisms and the different health needs of ethnic groups should be taken into account when formulating such policies. PMID- 30476093 TI - Health in crises. Migration, austerity and inequalities in Greece and Europe: introduction to the supplement. AB - This introduction summarizes and discusses the main findings of the supplement 'Health in crises. Migration, austerity and inequalities in Greece and Europe' to the European Journal of Public Health. The supplement applies data from the ESS (2014) health module in combination with the MIGHEAL study, which is a new source of data on the Greek population specially designed to examine health inequalities among and between migrants and natives. This has enabled the authors of the nine articles that constitute this supplement to address several pressing issues about the distribution of health and its determinants in Greece and other European countries. The main finding of the present supplement is the exceptionally high rates of reported depressive symptoms across the whole population residing in Greece and particularly among women. Levels of unmet need for healthcare were also found to be alarmingly high in Greece compared with other European countries, suggesting that the crisis and subsequent austerity policies may have impacted the provision of healthcare services and access to healthcare for broad sections of the population, whether native or migrant. PMID- 30476094 TI - Non-communicable diseases in Greece: inequality, gender and migration. AB - Background: The relationship between gender, migration status and non communicable diseases (NCDs) is rarely examined. In this study, we rely on data from the MIGHEAL Survey on health inequalities in Greece collected in 2016 comprising 1332 respondents of which 59.98% identified themselves as Greek-born, 24.02% as immigrants from Albania and 15.99% as immigrants from another country than Albania, to analyse this often neglected relationship. With the help of average risk ratios, this paper explores and explains gender inequalities in heart or circulation problems, high blood pressure, breathing problems, allergies, back or neck pain, muscular pain, stomach or digestion-related problems, skin conditions, severe headaches, and diabetes in Greece among Greek born individuals, Albanian immigrants and among immigrants of 'other origin'. We found that both among Greek-born and among immigrant groups women report substantially higher rates of NCDs although gender inequalities are more pronounced among 'other-origin' immigrants. Further, our findings show that the observed gender inequalities are fostered by occupational factors both among Greek-born and migrants. PMID- 30476079 TI - Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies. AB - Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after 'recalibration', a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied. Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at 'high' 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29-39% of individuals aged >=40 years as high risk. By contrast, recalibration reduced this proportion to 22-24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44-51 such individuals using original algorithms, in contrast to 37-39 individuals with recalibrated algorithms. Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need. PMID- 30476095 TI - Social integration and self-reported health: differences between immigrants and natives in Greece. AB - Background: Our paper assesses the relationship between social integration, in terms of social contact and social trust, and one's individual health. While a large body of research already engaged with clarifying this relationship, we know little about the role one's immigration background plays in moderating this relationship. With respect to this, we explicitly focus on how one's immigrant status moderates the relationship between social integration and self-reported health. Previous literature has demonstrably shown that the less socially integrated individuals are, the less likely they are to report good health. Moreover, we know from social capital literature that immigrants have difficulties being socially connected in their host country. Methods: With the help of the new MIGHEAL survey, we test this proposed negative relationship. We also compare the results from the MIGHEAL data with findings from the European Social Survey round 7. Our analyses follow a thorough approach testing immigrant background as potential moderating factors. We implement logistic regression models and path analysis to reveal the complex interactive relationship between social integration, immigrant status and self-reported health. Results/Conclusion: Our results suggest that immigrant status does play a moderating role in the relationship between social integration and health. This role, however, is limited to the relationship between social activity and self reported health, which points to a potential endogenous effect. PMID- 30476096 TI - Health inequalities among migrant and native-born populations in Greece in times of crisis: the MIGHEAL study. AB - This article presents the MIGHEAL study, which was developed in parallel with the European Social Survey (ESS) Round 7 (2014). Conducted in Greece in 2016 by the National Centre for Social Research, the study was specifically designed to further our understanding of how health varies by social status, focusing particularly on migrant status. In the current article, we report results on health status (non-communicable diseases, self-reported health and depressive symptoms) and health determinants (risky health behaviours, social determinants and access to health care) in Greece, among migrants and native-born. Estimates for the Greek overall population are compared with the European ones (using the ESS 2014 data) and discussed with reference to the ongoing economic and social crisis in Greece. The study provides evidence of social inequalities in health, complementing the pan-European documentation, and supports prior research, which has identified negative health consequences of the crisis. PMID- 30476097 TI - Human SPG11 cerebral organoids reveal cortical neurogenesis impairment. AB - SPG11 linked hereditary spastic paraplegia is a complex monogenic neurodegenerative disease that in addition to spastic paraplegia is characterized by childhood onset cognitive impairment, thin corpus callosum and enlarged ventricles. We have previously shown impaired proliferation of SPG11 neural progenitor cells (NPCs). For delineation of potential defect in SPG11 brain development we employ 2D culture systems and 3D human brain organoids derived from SPG11 patients' iPSC and controls. We reveal that an increased rate of asymmetric divisions of neural progenitor cells leads to proliferation defect, causing premature neurogenesis. Correspondingly, SPG11 organoids appeared smaller than controls and had larger ventricles as well as thinner germinal wall. Premature neurogenesis and organoid size were rescued by GSK3-inhibititors including the FDA-approved tideglusib. These findings shed light on the neurodevelopmental mechanisms underlying disease pathology. PMID- 30476099 TI - Development and validation of a patient-reported score to screen for mucosal inflammation in inflammatory bowel disease. AB - BACKGROUND & AIMS: Patient-reported outcome measures (PROMs) assessing inflammatory bowel disease (IBD) activity are of interest for monitoring in clinical practice, telemedicine systems or trials. Different PROMs for follow-up of disease activity are available; however, none was developed with endoscopy as golden standard. The objective of this study was to develop and validate a PROM to predict endoscopic disease activity following the recommendations of the Food and Drug Administration. METHODS: During development, 178 IBD patients undergoing a colonoscopy were asked to fill out 13 clinical questions derived from the literature. During endoscopy, inflammation was assessed with the simplified endoscopic score for Crohn's disease (CD) and the Mayo endoscopic subscore for ulcerative colitis (UC). Based on correlation with endoscopic inflammation, questions were reduced to a total of 6 for CD and 5 for UC. The newly developed Monitor IBD At Home questionnaire (MIAH) was validated in an independent cohort of 135 CD and 131 UC patients. Additionally, diagnostic accuracy of the MIAH combined with a calprotectin home-test (CHT) was assessed. RESULTS: The MIAH-CD includes questions on rectal bleeding, mucus, stool frequency, urgency, fatigue and patient-reported disease activity. The MIAH-UC contains items on rectal bleeding, stool frequency, urgency, abdominal pain and patient-reported disease activity. Both questionnaires showed to be valid, reliable, and responsive to changes. The MIAH and CHT combined had a sensitivity, specificity, NPV and PPV of 96.7%, 66.7%, 94.7%, and 76.3% for CD and of 88.2%, 81.4%, 95.6%, 60.0% for UC, compared to endoscopy. CONCLUSION: The MIAH is the first PROM developed to predict endoscopic inflammation in IBD patients. A combination of this questionnaire and a CHT shows excellent diagnostic accuracy to screen for patients who need further assessment of disease activity and can be used in daily practice, telemedicine systems and trials. PMID- 30476098 TI - Managers' perceptions of the effects of a national mandatory accreditation program in Danish hospitals. A cross-sectional survey. AB - Objective: This study aimed to examine and compare middle and senior hospital managers' perceptions of the effects of a mandatory accreditation program in Denmark, the Danish Healthcare Quality Program (Den Danske Kvalitetsmodel [DDKM]) after it was terminated in 2015. Design: A cross-sectional online questionnaire survey. Setting: All 26 somatic and psychiatric public hospitals in Denmark. Participants: All senior and middle managers. Methods: A questionnaire with open and closed response (five-point Likert scale) questions. Quantitative data were analyzed descriptively and through ordered logistic regression by management level. Qualitative data were subjected to a software-assisted content analysis. Results: The response rate was 49% (533/1059). In both the qualitative and quantitative data sets, participants perceived the DDKM as having: led to an increased focus on registration, documentation and additional and unnecessary procedures. While the DDKM was perceived as increasing a focus on quality, the time required for accreditation was at the expense of patient care. There were significant differences by management level, with middle managers having more negative perceptions of the DDKM related to time spent on documentation and registration. Conclusion: While the DDKM had some perceived benefits for quality improvement, it was ultimately considered time-consuming and outdated or having served its purpose. Including managers, particularly middle managers, in refinements to the new quality improvement model could capitalize on the benefits while redressing the problems with the terminated accreditation program. PMID- 30476100 TI - Is more better? A higher oocyte yield is independently associated with more day-3 euploid embryos after ICSI. AB - STUDY QUESTION: Is the number of oocytes retrieved after ovarian stimulation for ICSI independently associated with the number of day-3 euploid embryos (EE)? SUMMARY ANSWER: A larger oocyte yield is independently associated with more day-3 EE, although the expected benefit decreases significantly with advancing age. WHAT IS KNOWN ALREADY: Although traditionally ovarian stimulation aims at collecting more than one oocyte in order to increase the chance of pregnancy, there is evidence suggesting that excessive ovarian response leads to lower live birth rates. Whether a larger oocyte yield after ovarian stimulation is associated with the genetic composition of the resulting embryos and therefore with their reproductive potential is still largely unknown. STUDY DESIGN, SIZE, DURATION: This is a multi-centered retrospective cohort study analyzing 724 cycles of preimplantation genetic testing for aneuploidy (PGT-A) cycles using day 3 biopsy and array-comparative genomic hybridization between March 2011 and December 2016 in three laboratories. PARTICIPANTS/MATERIALS, SETTING, METHODS: The primary outcome measure was the number of EE on day-3. Statistical analysis was performed using the generalized estimating equations (GEE) framework and multivariate regression models to control for the clustered nature of the data while adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: A multivariate regression GEE model including all significant population and stimulation characteristics as covariates as well as an interaction term between female age and number of oocytes revealed that the number of oocytes retrieved was still positively associated with the number of EE (coeff: +0.40, 95% CI: 0.24 0.56). The interaction term was highly significant (coeff: -0.01, P < 0.001) indicating an effect modifying role of female age on the association of oocytes retrieved with the number of EE. The number of oocytes retrieved was also positively associated with cumulative live birth rates (odds ratio: 1.07, 95% CI: 1.03-1.12). LIMITATIONS, REASONS FOR CAUTION: This study is retrospective and the presence of residual unknown bias cannot be excluded. Furthermore, the population analyzed in this study might not be completely representative of the general population undergoing ICSI. WIDER IMPLICATIONS OF THE FINDINGS: These results provide an explanatory mechanism for the recently published positive association between the number of oocytes retrieved and cumulative live birth rates. STUDY FUNDING/COMPETING INTEREST(S): CAV is supported by a NHMRC Early Career Fellowship (GNT1147154)/ No competing interests to declare. PMID- 30476101 TI - Five Postmortem Case Reports with Qualitative Analysis of Cyclopropylfentanyl by LC-MS-MS. AB - In January 2018, the Drug Enforcement Agency temporarily designated cyclopropylfentanyl as a Schedule I drug. Over the course of 5 months (December 2017-May 2018), the Nassau County Medical Examiner Toxicology Laboratory qualitatively identified and confirmed cyclopropylfentanyl in specimens obtained from five postmortem cases. We describe the five cases and include pertinent autopsy findings and decedent histories, along with results for cyclopropylfentanyl determined in postmortem cardiac blood. Samples were prepared by an alkaline liquid-liquid extraction, with sample pH adjusted to >9 and utilizing an extraction solvent consisting of 90:10 hexane:ethyl acetate. Instrumental analysis was achieved via liquid chromatography tandem mass spectrometry with a dual jetstream electrospray source operating in positive ion mode. Two ion transitions were monitored for each analyte of interest and the internal standard. The estimated concentration range of cyclopropylfentanyl in the reported cases was 5.6 to 82 ng/mL for five postmortem cardiac blood specimens. All five cases included cyclopropylfentanyl in the established cause of death. PMID- 30476102 TI - Metabolic pathways modulate the neuronal toxicity associated with Fragile X Associated Tremor/Ataxia Syndrome. AB - Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects premutation carriers (55-200 CGG repeats) of the Fragile X Mental Retardation 1 (FMR1) gene. Much remains unknown regarding the metabolic alterations associated with FXTAS, especially in the brain, and the most affected region, the cerebellum. Investigating the metabolic changes in FXTAS will aid in the identification of biomarkers as well as in understanding the pathogenesis of disease. To identify the metabolic alterations associated with FXTAS, we took advantage of our FXTAS mouse model that expresses 90 CGG repeats in cerebellar Purkinje neurons and exhibits the key phenotypic features of FXTAS. We performed untargeted global metabolic profiling of age-matched control and FXTAS mice cerebella at 16-20 weeks and 55 weeks. Out of 506 metabolites measured in cerebellum, we identified 186 metabolites that demonstrate significant perturbations due to the (CGG)90 repeat (p<0.05), and found that these differences increase dramatically with age. To identify key metabolic changes in FXTAS pathogenesis, we performed a genetic screen using a Drosophila model of FXTAS. Out of 28 genes that we tested in the fly, 8 genes showed significant enhanced neuronal toxicity associated with CGG repeats, such as Schlank (Ceramide Synthase), Sk2 (Sphingosine Kinase) and Ras (IMP Dehydrogenase). By combining metabolic profiling with a Drosophila genetic screen to identify genetic modifiers of FXTAS, we demonstrate an effective method for functional validation of high-throughput metabolic data and show that sphingolipid and purine metabolism are significantly perturbed in FXTAS pathogenesis. PMID- 30476103 TI - Insulin Reduces Reaction of Follicular Granulosa Cell to FSH Stimulation in Obesity-Related Infertility Women during IVF. AB - Context: Obese women usually need larger doses of FSH for ovarian stimulation, resulting in poor outcomes; however, the mechanism is still unclear. Objective: To investigate the molecular regulation of FSH receptor (FSHR) expression associated with obesity. Design: Case-control study to improve IVF outcomes. Patients: Eighty-two obese and 457 overweight women undergoing IVF and 1,790 age matched controls with normal weight from our reproductive medicine center. Intervention: No special. Main Outcome Measures: FSHR expression was decreased in parallel with BMI, while the oestradiol (E2) level on the hCG trigger day was significantly lower. Results: FSHR expression in hGCs, both mRNA (P = 0.02) and protein (P = 0.001) levels, was decreased in overweight/obese women. Both insulin (P < 0.001) and glucose (P = 0.0017) levels were positively correlated with BMI in fasting blood and follicle fluids(FF) but not with FF leptin level. Treated KGN cells with insulin, E2 production was compromised, the level of p-Akt2 decreased while p-GSK3 increased, similar changes in hGCs from obese women. Stimulated hGCs from obese women with CP21, an inhibitor of GSK3beta, resulting in upregulated beta-catenin activation and increased FSHR expression. CP21 also increased the expression of IRS-1 and PI3K as well as the p-Akt2. Conclusions: Obesity was associated with reduced FSHR expression and E2 production in IVF women, caused by dysfunctional insulin pathway. Decreased FSHR expression in hGCs from obese women and insulin-treated KGN could be rescued by inhibition of GSK3beta, which might be a potential target for improving the impaired FSH response in obese women. PMID- 30476104 TI - Forms of selenium in vitamin-mineral mixes differentially affect the expression of genes responsible for prolactin, ACTH, and alpha-MSH synthesis and mitochondrial dysfunction in pituitaries of steers grazing endophyte-infected tall fescue. AB - The goal of this study was to test the hypothesis that sodium selenite (ISe), SEL PLEX (OSe), vs. a 1:1 blend (MIX) of ISe and OSe in a basal vitamin-mineral (VM) mix would differentially alter pituitary transcriptome profiles in growing beef steers grazing an endophyte-infected tall fescue (E+) pasture. Predominately Angus steers (BW = 183 +/- 34 kg) were randomly selected from fall-calving cows grazing E+ pasture and consuming VM mixes that contained 35 ppm Se as ISe, OSe, or MIX forms. Steers were weaned, depleted of Se for 98 d, and subjected to summer-long common grazing of a 10.1 ha E+ pasture containing 0.51 ppm ergot alkaloids. Steers were assigned (n = 8 per treatment) to the same Se-form treatments on which they were raised. Selenium treatments were administered by daily top-dressing 85 g of VM mix onto 0.23 kg soyhulls, using in-pasture Calan gates. As previously reported, serum prolactin was greater for MIX (52%) and OSe (59%) steers vs. ISe. Pituitaries were collected at slaughter and changes in global and selected mRNA expression patterns determined by microarray and real time reverse-transcription PCR analyses, respectively. The effects of Se treatment on relative gene expression were subjected to one-way ANOVA. The form of Se affected the expression of 542 annotated genes (P < 0.005). Integrated Pathway Analysis found a canonical pathway network between prolactin and POMC/ACTH/ alpha-MSH synthesis-related proteins, and that mitochondrial dysfunction was a top-affected canonical pathway. Targeted RT-PCR analysis found that the relative abundance of mRNA encoding prolactin and POMC/ACTH/ alpha-MSH synthesis-related proteins was affected (P < 0.05) by the form of Se, as were (P <= 0.05) mitochondrial dysfunction-related proteins (CYB5A, FURIN, GPX4, PSENEN). OSe steers appeared to have a greater prolactin synthesis capacity (more PRL mRNA) vs. ISe steers through decreased dopamine type two receptor signaling (more DRD2 mRNA), whereas MIX steers had a greater prolactin synthesis capacity (more PRL mRNA) and release potential by increasing TRH concentrations (less TRHR mRNA) than ISe steers. OSe steers also had a greater ACTH and alpha-MSH synthesis potential (more POMC, PCSK2, CPE, and PAM mRNA) than ISe steers. We conclude that form of Se in VM mixes altered expression of genes responsible for prolactin and POMC/ACTH/alpha-MSH synthesis, and mitochondrial function, in pituitaries of growing beef steers subjected to summer-long grazing an E+ pasture. PMID- 30476105 TI - World Pneumonia Day 2011-2016: Twitter contents and retweets. AB - Background: Twitter is used for World Pneumonia Day (WPD; November 12) communication. We evaluate if themes of #pneumonia tweets were associated with retweet frequency. Methods: A total of 28 181 original #pneumonia tweets were retrieved (21 November 2016), from which six subcorpora, 1 mo before and 1 mo after WPD 2011-2016, were extracted (n=6721). Underlying topics were identified via latent Dirichlet allocation and were manually coded into themes. The association of themes with retweet count was assessed via multivariable hurdle regression. Results: Compared with personal experience tweets, tweets that both raised awareness and promoted intervention were 2.62 times as likely to be retweeted (adjusted odds ratio [aOR] 2.62 [95% 1.79 to 3.85]) and if retweeted had 37% more retweets (adjusted prevalence ratio [aPR] 1.37 [95% CI 1.06 to 1.78]). Tweets that raised concerns about vaccine price were twice as likely to be retweeted (aOR 2.29 [95% CI 1.36 to 3.84]) and if retweeted, had double the retweet count (aPR 2.05 [95% CI 1.27 to 3.29]) of tweets sharing personal experience. Conclusions: The #pneumonia tweets that both raised awareness and promoted interventions and those discussing vaccine price were more likely to engage users than tweets about personal experience. These results help health professionals craft WPD messages that will engage the audience. PMID- 30476106 TI - Rare occurrence of doravirine resistance-associated mutations in HIV-1-infected treatment-naive patients. AB - Background: Doravirine is a novel HIV-1 NNRTI recently shown to be non-inferior to both darunavir/ritonavir and efavirenz in combination therapy with two NRTIs in treatment-naive patients. Doravirine has an in vitro resistance profile that is distinct from other NNRTIs and retains activity against viruses containing the most frequently transmitted NNRTI mutations. Objectives: The aim of this study was to examine the prevalence of doravirine resistance-associated mutations in HIV-1-infected treatment-naive patients in Europe. Methods: From 2010 to 2016, 9764 treatment-naive patients were tested for NNRTI antiretroviral drug resistance by bulk sequencing in Greece, Italy and France. We studied the prevalence of doravirine resistance-associated mutations previously identified in vitro: V106A/M, V108I, Y188L, V190S, H221Y, F227C/L/V, M230I/L, L234I, P236L, Y318F and K103N/Y181C. Results: Among 9764 sequences, 53.0% and 47.0% of patients had B and non-B subtypes, respectively. Overall, the presence of at least one doravirine resistance-associated mutation (n = 137; 1.4%) or the K103N/Y181C mutations (n = 5; 0.05%) was very rare. The most prevalent mutations were V108I (n = 62; 0.6%), Y188L (n = 18; 0.2%), H221Y (n = 18; 0.2%) and Y318F (n = 23; 0.2%). The frequency of doravirine resistance-associated mutations was similar between B and non-B subtypes. In comparison, the prevalence of rilpivirine, etravirine, nevirapine and efavirenz resistance was higher whatever algorithm was used (ANRS: 8.5%, 8.1%, 8.3% and 3.9%, respectively; Stanford: 9.9%, 10.0%, 7.5% and 9.4%, respectively). Conclusions: The prevalence of doravirine resistance associated mutations is very low in antiretroviral-naive patients. These results are very reassuring for doravirine use in naive patients. PMID- 30476107 TI - RAPID COMMUNICATION: Use of pressure mat gait analysis in measuring pain following normal parturition in dairy cows. AB - Research investigating the pain of normal parturition is lacking as there are few objective methods for measuring pain. The objective of this research was to describe the gait of cows following eutocia using pressure-mat gait analysis; and if meloxicam alters the gait of cows. Twenty Holstein cows within 26 h of unassisted calving were enrolled into the study. Treatment groups included: 1) post-partum cows administered meloxicam (MEL; n = 10); and 2) post-partum cows administered placebo (PLBO; n = 10). Meloxicam was administered by oral bolus at 1 mg/kg within 26 hours of calving. Placebo cows were given an oral bolus of dry whey powder within 26 hours of calving. A commercially available floor mat-based pressure/force measurement system was used to compare ambulation between treatment groups. Cows were walked across the mat before treatment administration, and 2, 4, 6, 8, 12, 24, 48 and 72 hours post-treatment. The percent of total force, percent total contact pressure, and percent total impulse of the rear limbs was calculated. Outcome measures were statistically analyzed using repeated measures, with the cow serving as the experimental unit. Cows in the MEL group placed 48.9% (95% CI: 47.4 - 50.5%) of total force on the rear limbs compared to 46.3% (95% CI: 44.7 - 47.9%) in PLBO cows (P = 0.02). Total impulse on their rear limbs for the MEL cows was 50.5% (95% CI: 48.6 - 52.4%) compared to 46.7% (95% CI: 44.8 - 48.7%) for the PLBO cows (P = 0.01). No differences in contact pressure of the rear limbs was observed (P = 0.27). The PLBO cows had a longer gait 101.3 cm (95% CI: 95.9 - 106.6 cm) versus 90.8 cm (95% CI: 85.4 - 96.1 cm) (P = 0.03). These findings show meloxicam treated cows have altered weight distribution to the rear limbs as measured by pressure mat gait analysis, suggesting meloxicam may effectively treat post-partum pain. PMID- 30476108 TI - Variability and exposure-response relationships of isavuconazole plasma concentrations in the Phase 3 SECURE trial of patients with invasive mould diseases. AB - Objectives: This analysis evaluated the variability of isavuconazole plasma concentrations between subjects and between sampling times, and assessed their relationship to outcomes for subjects with invasive fungal disease (IFD) in the SECURE trial. Methods: Isavuconazole-treated subjects received 372 mg of isavuconazonium sulphate (corresponding to 200 mg of isavuconazole) three times daily for 2 days, then once daily. Plasma samples were collected after day 4 and analysis sets were constructed as follows: analysis set 1 included all samples from subjects with proven/probable/possible IFD who received >=1 dose of isavuconazole; analysis set 2 included samples from subjects in analysis set 1 who had provided >1 sample; and analysis set 3 included samples from subjects in analysis set 1 with proven/probable invasive aspergillosis. Assessments included overall distributions of plasma concentrations and variability between samples (analysis sets 1 and 2) as well as relationships to outcomes [all-cause mortality (day 42), overall response (end of treatment) and treatment-emergent adverse events; analysis sets 1 and 3]. Results: Analysis sets 1, 2 and 3 included samples from 160, 97 and 98 subjects, respectively. Trough concentrations for each were distributed similarly [mean (SD): 3406.6 (1511.5), 3495.6 (1503.3) and 3368.1 (1523.2) ng/mL, respectively]. The mean coefficient of variation between samples in analysis set 2 was 23.2%; differences between concentrations in first samples and subsequent samples were <2-fold for 85/97 subjects. In quartiles of subject data, no concentration-dependent relationships were observed for efficacy or safety. Conclusions: Plasma concentrations of isavuconazole were reasonably consistent between subjects and sampling times, and were not associated with differences in outcomes. PMID- 30476109 TI - Insights into the evolution of the New World diploid cottons (Gossypium, subgenus Houzingenia) based on genome sequencing. AB - We employed phylogenomic methods to study molecular evolutionary processes and phylogeny in the geographically widely dispersed New World diploid cottons (Gossypium, subg. Houzingenia). Whole genome resequencing data (average of 33X genomic coverage) were generated to reassess the phylogenetic history of the subgenus and provide a temporal framework for its diversification. Phylogenetic analyses indicate that the subgenus likely originated following trans-oceanic dispersal from Africa about 6.6 mya, but that nearly all of the biodiversity evolved following rapid diversification in the mid-Pleistocene (0.5-2.0 mya), with multiple long-distance dispersals required to account for range expansion to Arizona, the Galapagos Islands, and Peru. Comparative analyses of cpDNA vs. nuclear data indicate that this history was accompanied by several clear cases of interspecific introgression. Repetitive DNAs contribute roughly half of the total 880 Mb genome, but most transposable element families are relatively old and stable among species. In the genic fraction, pairwise synonymous mutation rates average 1% per my, with non-synonymous changes being about seven times less frequent. Over 1.1 million indels were detected and phylogenetically polarized, revealing a two-fold bias toward deletions over small insertions. We suggest that this genome down-sizing bias counteracts genome size growth by TE amplification and insertions, and helps explain the relatively small genomes that are restricted to this subgenus. Compared to the rate of nucleotide substitution, the rate of indel occurrence is much lower averaging about 17 nucleotide substitutions per indel event. PMID- 30476110 TI - Locomotion behavior changes in peripartum beef cows and heifers. AB - Changes in locomotor activity of beef females during the 72 h prepartum were determined in 3 experiments: 1) a 2-yr study with spring-calving multiparous cows (Exp. 1; n = 34 and 27 for yr 1 and 2, respectively); 2) spring-calving primiparous (first pregnancy; n = 13) and multiparous (n = 21) dams (Exp. 2); and 3) fall-calving multiparous cows (Exp. 3; n = 33). For all experiments, IceQube activity monitors (iceRobotics, Edinburgh, UK) were placed above the left hind fetlock of pregnant females >= 3 d prepartum. During the calving season, females were housed in 18 x 61 m drylots with ad libitum access to hay or haylage. Parturition was closely monitored, and time of birth was noted. Motion index, standing and lying time, step count, and number of lying bouts for each dam (summed per hour) were determined for the 72 h preceding calving. Within experiment, data were analyzed by day (d -3 to d -1 prepartum), by 6-h period during the final 24 h prepartum, and by hour during the final 6 h prepartum using a mixed model with time as a repeated effect. Year was also included as a fixed effect in Exp. 1. Fixed effects of parity and time prepartum x parity were included for Exp. 2. In all 3 experiments, motion index, standing time, step count, and number of lying bouts were greater (P < 0.001) on d -1 compared with d -2 and -3 prepartum. In the 24 h prepartum, dams had greater (P < 0.01) motion index, standing time, step count, and number of lying bouts during 6 h preceding parturition compared with -11 to -6 h in all experiments. Motion index, step count, and lying bouts changed (P <= 0.02) during the last 6 h in all experiments. Primiparous dams had more (P <= 0.01) lying bouts than multiparous dams during the last day and -11 to -6 prepartum. In all experiments, number of lying bouts more than doubled (P < 0.001) from -2 to -1 prepartum, with no effect of year (P = 0.57) in Exp. 1 or parity (P >= 0.29) in Exp. 2. This suggests that lying bout changes may be the most reliable of parameters measured in detection of calving. Moreover, fall-calving cow behavioral patterns were similar to changes observed in spring-calving females, suggesting that calving season may have minimal effects on pre-calving behavior. Overall, electronic locomotor activity monitors can detect behavioral changes peripartum in beef heifers and cows. More research is necessary to determine if these can be used to remotely sense early signs of parturition in beef cattle. PMID- 30476111 TI - Diagnostic performance of conventional RDT and ultra-sensitive RDT for malaria diagnosis in febrile outpatients in Tanzania. AB - Background: A novel ultra-sensitive malaria RDT (us-RDT) has been developed for improved active P.falciparum case detection. The utility of this us-RDT in clinical diagnosis and fever management has not been evaluated to date. Methods: Diagnostic performance of us-RDT was compared retrospectively to conventional RDT (co-RDT) in 3000 children and 515 adults presenting with fever to Tanzanian outpatient clinics. Parasite density by ultra-sensitive qPCR (us-qPCR) and HRP2 concentration by ELISA were measured. Results: Us-RDT identified few additional positives (Npos=276) compared to co-RDT (Npos=265), increasing sensitivity against us-qPCR (Npos=357) only marginally (us-RDT, 75%; co-RDT, 73%). Specificity of both RDTs was >99%. 5 of 11 additional positive us-RDT were negative in us-qPCR. HRP2 concentration was above the detectable limit by co-RDT (>3653 pg /ml) in almost all (99%, 236/239) infections with parasite density above 100 parasites/ul. Below 100 parasites/ul, HRP2 concentration was above the detectable limits by us-RDT (>793pg/ml) and co-RDT in 29 (25%) and 24 (20%) of 118 infections. Conclusion: There is neither gain nor risk to apply us-RDT rather than co-RDT for clinical malaria diagnosis. In febrile patients, only a small proportion of infections are characterized by parasite density or HRP2 concentration where us-RDT confers a meaningful improvement over co-RDT. PMID- 30476112 TI - Sources of parental knowledge about the safety of vaccinations in Poland. AB - There has been a recent increase in the number of parents refusing vaccination for their children in many European countries, including Poland. This observation necessitates the need to understand parental knowledge in regard to mandatory vaccination of children in these countries. A cross-sectional survey was conducted in 2016 on 1239 parents or legal guardians of preschool and school children in the Silesian Voivodship (Poland) to evaluate their hesitancy in acquiescing to their children mandatory immunization and the relation to this habit in regard to the use of informational sources on children vaccination system in Poland. Medical doctors often provide the basic source of information about vaccination to parents. About one-third (29%) of the respondents from the survey deemed the qualification system for vaccination as either inadequate or bad. 16.9% of the respondents surveyed declared that information received from physicians regarding vaccinations were either incomplete or unconvincing. Results of multivariable analyses confirmed that respondents are less likely to seek information about mandatory vaccinations from medical professionals and more often to misjudged vaccination's qualification system. Participants who used less informative sources (e.g. leaflets) and those with a lower level of education were more likely to avoid vaccination. Greater emphasis on the quality of information provided by medical professionals is crucial in order to avoid doubts about vaccination and to create proper attitudes and adherence to vaccination schedules. PMID- 30476113 TI - Evaluation of human trophoblasts and ovine testis cell lines for the study of the intracellular pathogen Brucella ovis. AB - Since pathogenic Brucella survive and replicate inside phagocytes, cellular models of infection constitute important tools in brucellosis research. We describe the behavior of B. ovis PA (which causes a type of ovine brucellosis mainly affecting the male reproductive tract) and representative attenuated mutants in two commercially available cell lines of non-professional phagocytes related to Brucella tissue preference: OA3.Ts ovine testis cells and JEG-3 human trophoblasts. In comparison with J774.A1 macrophages and HeLa cells, intracellular bacteria were enumerated at several post-infection time points and visualized by confocal microscopy. Replication of B. ovis in OA3.Ts and JEG-3 cells was equivalent to that observed in J774.A1 macrophages-despite the more efficient internalization in the latter-and better than in HeLa cells. Multiplication and/or survival in all phagocytes was dependent on virB2 and vjbR but independent of cgs, despite the attenuation in mice of the Deltacgs mutant. However, Omp25c was required for B. ovis internalization only in HeLa cells, and removal of Omp31 increased bacterial internalization in human HeLa and JEG-3 cells. The results presented here demonstrate variability in the interaction of B. ovis with different host cells and provide advantageous models of non professional phagocytes to study the intracellular behavior of B. ovis. PMID- 30476114 TI - Dementia and Imagination: A Social Return on Investment Analysis Framework for Art Activities for People Living With Dementia. AB - Background and Objectives: Arts activities may benefit people living with dementia. Social return on investment (SROI) analysis, a form of cost-benefit analysis, has the potential to capture the value of arts interventions, but few rigorous SROI analyses exist. This article presents a framework for an SROI analysis. Research Design and Methods: One hundred twenty-five people with mild to severe dementia and 146 caregivers were recruited to the Dementia and Imagination study across residential care homes, a hospital and community venues in England and Wales for a 12-week visual arts program. Quantitative and qualitative data on quality of life, support, and program perceptions were obtained through interviews. SROI was undertaken to explore the wider social value of the arts activities. Results: An input of L189,498 ($279,320/?257,338) to deliver the groups created a social value of L980,717 ($1,445,577/?1,331,814). This equates to a base case scenario of L/$/?5.18 of social value generated for every L/$/?1 invested. Sensitivity analysis produced a range from L/$/?3.20 to L/$/?6.62 per L/$/?1, depending on assumptions about benefit materialization; financial value of participants' time; and length of sustained benefit. Discussion: To our knowledge, this is the first study applying SROI to an arts intervention for people with dementia. Arts-based activities appear to provide a positive SROI under a range of assumptions. Implications: Decision makers are increasingly seeking wider forms of economic evidence surrounding the costs and benefits of activities. This analysis is useful for service providers at all levels, from local government to care homes. PMID- 30476116 TI - Agricultural Animals as Biomedical Models: Occupational Health and Safety Considerations. AB - The use of agricultural animals in biomedical research is increasing. Their overall size and metabolic rate, organ size, longer gestation period, and other physiological similarities make them good candidates for animal models of human disease. There are a number of special considerations for use of traditional farm animals for biomedical research. Differences in physical plant infrastructure, handling equipment, training of personnel, and potential zoonoses are some of the important considerations when traditional farm animals are used in biomedical research. This article provides an overview of some of the special considerations for using traditional agricultural animals in biomedical research. With the growing need for improved translational research, it is reasonable to predict significant growth in these animal models. PMID- 30476117 TI - Coping with more people with more illness. Part 2: new generation of standards for enabling healthcare system transformation and sustainability. AB - In Part 2 of this two-part contribution made on behalf of the Innovation and Systems Change Working Group of the International Society for Quality in Health Care (ISQua), we continue the argument for refashioning health systems in response to ageing and other pressures. Massive ageing in many countries and accompanying technological, fiscal and systems changes are causing the tectonic plates of healthcare to shift in ways not yet fully appreciated. In response, while things remain uncertain, we nevertheless have to find ways to proceed. We propose a strategy for stakeholders to pursue, of key importance and relevance to the ISQua: to harness flexible standards and external assessment in support of needed change. Depending on how they are used, healthcare standards and accreditation can promote, or hinder, the changes needed to create better healthcare for all in the future. Standards should support people's care needs across the life cycle, including prevention and health promotion. New standards that emphasise better coordination of care, those that address the entire healthcare journey and standards that reflect and predict technological changes and support new models of care can play a part. To take advantage of these opportunities, governance bodies, external assessment agencies and other authorities will need to be less prescriptive and better at developing more flexible standards that apply to the entire health journey, incorporating new definitions of excellence and acceptability. The ISQua welcomes playing a leadership role. PMID- 30476115 TI - Importance of routine viral load monitoring: higher levels of resistance at ART failure in Uganda and Lesotho compared with Switzerland. AB - Objectives: Emerging resistance to antiretroviral drugs may jeopardize the achievements of improved access to ART. We compared the prevalence of different resistance mutations in HIV-infected adults with virological failure in a cohort with regular routine viral load (VL) monitoring (Switzerland) and cohorts with limited access to VL testing (Uganda and Lesotho). Methods: We considered individuals who had genotypic resistance testing (GRT) upon virological failure (>=1000 copies/mL) and were on ART consisting of at least one NNRTI and two NRTIs. From Lesotho, individuals with two subsequent VLs >=1000 copies/mL despite enhanced adherence counselling (n = 58) were included in the analysis. From Uganda, individuals with a single VL >=1000 copies/mL (n = 120) were included in the analysis. From the Swiss HIV Cohort Study (SHCS), a population without history of monotherapy or dual therapy with the first GRT upon virological failure (n = 61) was selected. Results: We found that 50.8% of individuals in the SHCS, 72.5% in Uganda and 81.0% in Lesotho harboured HIV with high-level resistance to at least two drugs from their current regimen. Stanford resistance scores were higher in Uganda compared with Switzerland for all drugs used in first-line treatment except zidovudine and tenofovir (P < 0.01) and higher in Lesotho compared with Uganda for all drugs used in first-line treatment except zidovudine (P < 0.01). Conclusions: Frequent VL monitoring and possibly pretreatment GRT as done in the SHCS pays off by low levels of resistance even when treatment failure occurs. The high-level resistance patterns in Lesotho compared with Uganda could reflect a selection of strains with multiple resistance during enhanced adherence counselling. PMID- 30476118 TI - The N-terminus of EXP2 forms the membrane-associated pore of the protein exporting translocon PTEX in Plasmodium falciparum. AB - In order to facilitate a number of processes including nutrient acquisition and immune evasion, malaria parasites extensively remodel their host erythrocyte. This remodeling is to a large extent accomplished through protein export, a crucial process mediated by the PTEX translocon which is comprised of three core components, HSP101, PTEX150 and EXP2. EXP2 has been structurally and electrophysiologically shown to form the pore that spans the vacuole membrane enveloping the parasite. Here, we biochemically investigate the structure and function of EXP2. By differential alkylation we provide direct evidence that cysteines C113 and C140 form an intramolecular disulfide bond, while C201 is predominantly in a reduced state. We demonstrate that EXP2 possesses a protease resistant, membrane-associated, N-terminal region of approximately 20 kDa that does not project into the infected erythrocyte cytosol, however its C-terminus does project into the vacuole space. We show that a putative transmembrane peptide derived from the N-terminal region of EXP2 is haemolytic and in a polymer based osmotic protection assay, we demonstrate that this peptide forms a discrete haemolytic pore. This work provides further biochemical insight into the role, function and cellular arrangement of EXP2 as the pore-forming component for protein translocation. PMID- 30476119 TI - The other office. AB - Across recent decades, profound changes in the practice of medicine have been accompanied by parallel developments in the daily mental efforts of medical professionals. Using visual metaphors and hand-drawn illustrations, the author explores the evolution of one physician's brain over the past 25 years. At the completion of training, the patient-practitioner relationship, medical knowledge, and care decisions dominated clinician thought, time, and effort. During the 1990's, the growing constraints of third-party payers and government regulations presented new challenges to delivering relationship-based care. Over the past decade, the electronic health record (EHR) has added further cognitive complexity, disrupted human relationships, and contributed significantly to the current epidemic of clinician burnout. Solutions to these challenges include rethinking education, documentation, professional standards, institutional barriers, and regulatory mandates. It is important to pursue all solutions with the underlying premise of protecting healing relationships as the foundation of clinical care. PMID- 30476120 TI - Letter to the Editor: "Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society* Clinical Practice Guideline". PMID- 30476121 TI - Nitrogen availability facilitates phosphorus acquisition by bloom-forming cyanobacteria. AB - Cyanobacterial blooms are threatening freshwater ecosystems. The physiological basis involved in the onset of cyanobacterial bloom is fundamental to advance in bloom predictions. Generally, cyanobacteria grow until the availability of nitrogen (N), phosphorus (P), or both nutrients becomes limited. Population survival may depend on physiological adjustments to nutrient deficiency as well as on the efficient use of episodic N and P inputs. This study investigated the effect of N inputs on phosphate uptake affinity and activity of N-deficient bloom forming cyanobacteria. Lake samples dominated by filamentous cyanobacteria were preincubated with and without nitrate addition, and the uptake of [32P] phosphate pulses was measured in the following days. Phosphate uptake kinetics were analyzed with a flow-force model that provides the threshold concentration, reflecting phosphate uptake affinity, and the membrane conductivity coefficient that corresponds to the activity of uptake systems. After 24 h of nitrate preincubation, phosphate uptake kinetics showed a progressive increase in affinity (nanomolar [Pe]A) and activity (25-fold) concomitant with cyanobacterial growth. It was demonstrated that the alleviation of N-deficiency by N inputs boosts the activation of phosphate uptake systems of non-N2-fixing cyanobacteria to sustain growth. Therefore, reduction of dissolved inorganic N levels in lakes is also mandatory to limit cyanobacterial phosphate uptake affinity and activity capabilities. PMID- 30476122 TI - Inpatient portal clusters: identifying user groups based on portal features. AB - Objective: Conduct a cluster analysis of inpatient portal (IPP) users from an academic medical center to improve understanding of who uses these portals and how. Methods: We used 18 months of data from audit log files, which recorded IPP user actions, of 2815 patient admissions. A hierarchical clustering algorithm was executed to group patient admissions on the basis of proportion of use for each of 10 IPP features. Post-hoc analyses were conducted to further understand IPP use. Results: Five cluster solutions were developed for the study sample. Our taxonomy included users with high levels of accessing features that were linked to reviewing schedules, results, tutorials, and ordering food. Patients tended to stay within their clusters over multiple admissions, and the clusters had differences based on patient and clinical characteristics. Discussion: Distinct groups of users exist among IPP users, suggesting that training on IPP use to enhance patient engagement could be tailored to patients. More exploration is also needed to understand why certain features were not used across all clusters. Conclusions: It is important to understand the specifics about how patients use IPPs to help them better engage with their healthcare. Our taxonomy enabled characterization of 5 groups of IPP users who demonstrated distinct preferences. These results may inform targeted improvements to IPP tools, could provide insights to improve patient training around portal use, and may help care team members effectively engage patients in the use of IPPs. We also discuss the implications of our findings for future research. PMID- 30476124 TI - Brief report: Clinical experiences after emergency use of daratumumab monotherapy for relapsed or refractory multiple myeloma in real practice. AB - Despite the recently reported efficacy of daratumumab monotherapy for patients with relapsed or refractory multiple myeloma, outcomes in real practice following daratumumab monotherapy have yet to be investigated. A multi-center retrospective study of 16 Korean patients receiving daratumumab monotherapy for relapsed or refractory multiple myeloma was conducted. The overall response rate was 56.3%. Three patients with creatinine clearance <30 ml/min even achieved an overall response. The median progression-free survival was 2.7 months with 28.9% (95% CI, 9.0-52.8) of 6-month progression-free survival. All infusion-related reactions, including >=Grade 3 back pain (6.3%) and dyspnea (6.3%), were manageable. The most common hematologic and non-hematological adverse events were anemia (62.5%) and upper respiratory infection (43.8%). >=Grade 3 bacterial infectious adverse events were identified, including upper and lower respiratory infection (12.5% and 18.8%) and death following sepsis (6.3%). We observed acceptable outcomes of daratumumab monotherapy on relapsed or refractory multiple myeloma patients including even a few subjects with high comorbidity, despite relatively frequent infectious adverse events. PMID- 30476125 TI - Undernutrition and Tuberculosis: Public Health Implications. AB - Almost 800 million people are chronically undernourished worldwide, 98% of them in low and middle-income countries where tuberculosis (TB) is endemic. In many TB endemic countries, undernutrition is a driver of TB incidence and associated with a high population attributable fraction of TB and poor treatment outcomes. Data suggest that undernutrition impairs innate and adaptive immune responses needed to control Mycobacterium tuberculosis (Mtb) infection and may affect responses to live vaccines such as Bacillus Calmette-Guerin (BCG). Given its impact on TB, addressing undernutrition will be a vital component of the End-TB strategy. This narrative review describes the effect of undernutrition on the immune response, vaccine response, and TB incidence, severity, and treatment outcomes. PMID- 30476127 TI - Corrigendum to "Emerald Ash Borer (Coleoptera: Buprestidae) Densities Over a 6-yr Period on Untreated Trees and Trees Treated With Systemic Insecticides at 1-, 2-, and 3-yr Intervals in a Central Michigan Forest". PMID- 30476126 TI - Severe TUBB4A-Related Hypomyelination With Atrophy of the Basal Ganglia and Cerebellum: Novel Neuropathological Findings. AB - Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare hypomyelinating leukodystrophy characterized by infantile or childhood onset of motor developmental delay, progressive rigidity and spasticity, with hypomyelination and progressive atrophy of the basal ganglia and cerebellum due to a genetic mutation of the TUBB4A gene. It has only been recognized since 2002 and the full spectrum of the disorder is still being delineated. Here, we review a case report of a severely affected girl with a thorough neuropathological evaluation demonstrating novel clinical and pathological findings. Clinically, our patient demonstrated visual dysfunction and hypodontia in addition to the typical phenotype. Morphologically, more severe and widespread changes in the white matter were observed, including to the optic tracts; in gray structures such as the caudate nucleus, thalamus, globus pallidus, and substantia nigra; as well as an area of focal cortical dysplasia. Overall this case offers further insight into the broad range of clinical and neuropathological findings that may be associated with H-ABC and related TUBB4A gene mutations. PMID- 30476128 TI - Post Mortem Findings in a Young Male with Congenital Generalized Lipodystrophy, Type 4 due to CAVIN1 mutations. AB - Context: Congenital generalized lipodystrophy, type 4 (CGL4) is a rare autosomal recessive disorder caused by CAVIN1 mutations. Patients with CGL4 also have myopathy and cardiomyopathy with a predisposition for sudden death due to ventricular arrhythmias. However, underlying pathology for these morbidities remains unknown. Therefore, we report the first autopsy of a Hispanic boy with CGL4. Case description: Our patient had early onset generalized lipodystrophy, feeding difficulties, myopathy, atlanto-axial dislocation and learning disabilities. He was diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) at age 8, had poor compliance with medications, and died suddenly at age 15.3 years. Autopsy showed marked loss of subcutaneous and omental fat with no inflammatory cells in adipose tissue and normal adipocytes in the parathyroid glands. There were adipocytes inter-digitating cardiac muscle fibers, with fibro-fatty infiltration in the right ventricle, near coronary sinus and atrioventricular node. There was no evidence of coronary heart disease. Quadriceps femoris muscle did not show any adipocyte infiltration, inflammation or fibrosis. Muscularis mucosa layer was thickened in esophagus and gastro duodenal junction, and esophagus had prominent, large nerves in the subserosa. The liver was 3,000 g with minimal chronic inflammation and steatosis in 40% of parenchyma, primarily in zones 2 and 3. Interestingly, there was no spermatogenesis in the spermatic tubules. Conclusions: Our data suggest that fibro-fatty infiltration of right ventricle may contribute to CPVT in CGL4 patients. Thick muscularis mucosa and large nerves in esophagus likely contributed to dysphagia and dysmotility. Lack of spermatids suggests infertility in the affected males. PMID- 30476129 TI - Infestation Levels and Molecular Identification Based on Mitochondrial COI Barcode Region of Five Invasive Gelechiidae Pest Species in Kenya. AB - Invasive Gelechiidae pest species, namely Tuta absoluta, Phthorimaea operculella, Aproaerema simplixella, Sitotroga cerealella, and Pectinophora gossypiella are among the major constraints hampering agricultural economy in Kenya. Infestation levels were determined on respective host crops sampled from different localities and P. operculella recorded the highest infestation of 68.00 +/- 4.92% on stored potato. Aproaerema simplixella and T. absoluta accounted for 61.33 +/- 5.35% and 51.56 +/- 5.22% maximal infestation on groundnuts and tomato leaves, respectively. Stored maize was significantly infested by S. cerealella (54.33 +/- 5.31%) while no infestation was observed on the freshly harvested grains. Infestation on open bolls by P. gossypiella was relatively low (6.11 +/- 3.46%) compared to Anatrachyntis simplex (45.67 +/- 7.84%) that emerged as the key pest of cotton. The species were discriminated based on sequence similarities, evolutionary divergences, and phylogenetic analyses. A 658-bp fragment of mitochondrial cytochrome c oxidase subunit I (COI) gene was obtained from 302 specimens. Generally, genetic variations were low within and between Gelechiid populations, with an average of 0.02% and all intraspecific divergences were less than 2% except for S. cerealella. The Gelechiids data set generated eight Barcode Index Numbers (BINs), five of which were concordant and three belonging to S. cerealella were singleton. All species were separated into distinct clusters on a maximum likelihood tree. Data on infestation levels will be useful in defining the pest status of these Gelechiids in Kenya. DNA barcoding is also presented as a valuable tool to complement traditional taxonomy for rapid and accurate identification of these species of agronomic interest. PMID- 30476130 TI - Thioredoxin m overexpression in tobacco chloroplasts inhibits the protein kinase STN7 and alters photosynthetic performance. AB - The activity of the protein kinase STN7, involved in phosphorylation of the light harvesting complex II (LHCII) proteins, has been reported as being cooperatively regulated by the redox state of the plastoquinone pool and the ferredoxin thioredoxin system. The present study aims to investigate the role of plastid thioredoxins (Trx) in the STN7 regulation and their impact on photosynthesis. For this purpose, tobacco plants overexpressing Trx f or m from the plastid genome were characterized, demonstrating that only Trx m overexpression was associated with a complete loss of LHCII phosphorylation that did not correlate with decreased STN7 levels. The absence of phosphorylation in Trx m-overexpressing plants impeded migration of LHCII from PSII to PSI, with the concomitant loss of PSI-LHCII complex formation. Consequently, the thylakoid ultrastructure was altered, showing reduced grana stacking. Moreover, the electron transport rate was negatively affected, showing an impact on energy demanding processes such as the Rubisco maximum carboxylation capacity and RuBP regeneration rate values, which caused a strong depletion in net photosynthetic rates. Finally, tobacco plants overexpressing a Trx m mutant lacking the reactive redox site showed equivalent physiological performance to wild-type, indicating that the overexpressed Trx m deactivates STN7 in a redox-dependent way. PMID- 30476133 TI - Retrograde Stanford type A dissection caused by a multilayer stent graft in a patient with chronic type B dissection. AB - A patient with progressive chronic type B dissection and contraindication for open surgery underwent thoracic endovascular aortic repair using a Cardiatis Multilayer Flow Modulator(r). Two weeks after the intervention, the patient experienced a ruptured retrograde type A aortic dissection caused by the stent's uncovered proximal ends. PMID- 30476132 TI - Anti-OspA DNA-Encoded Monoclonal Antibody Prevents Transmission of Spirochetes in Tick Challenge Providing Sterilizing Immunity in Mice. AB - We recently developed anti-OspA human immunoglobulin G1 monoclonal antibodies (HuMAbs) that are effective in preventing Borrelia transmission from ticks in a murine model. Here, we investigated a novel approach of DNA-mediated gene transfer of HuMAbs that provide protection against Lyme disease. Plasmid DNA encoded anti-OspA HuMAbs inoculated in mice achieved a serum antibody concentration of >6 MUg/mL. Among mice injected with DNA-encoded monoclonal antibodies, 75%-77% were protected against an acute challenge by Borrelia infected ticks. Our results represent the first demonstration of employing DNA transfer as a delivery system for antibodies that block transmission of Borrelia in animal models. PMID- 30476134 TI - Role of MIC levels of resistance to clarithromycin and metronidazole in Helicobacter pylori eradication. AB - Objectives: Antimicrobial resistance to clarithromycin and metronidazole significantly affects the cure rate of standard therapies for Helicobacter pylori infection. We tested whether different MIC levels of resistance to these antibiotics play a role in therapeutic efficacy. Methods: This was a post hoc analysis of data from a therapeutic trial in which patients with antibiotic susceptibility testing (Etest) received first-line sequential therapy. The level of antibiotic resistance was classified according to MIC values into low (MIC from >0.5 to <=8 for clarithromycin, and from >8 to <=32 for metronidazole) and high (MIC from >8 to 256 mg/L for clarithromycin, and from >32 to 256 mg/L for metronidazole). Results: Data from 1006 patients were included. There were 520 (51.7%) patients with susceptible strains, 136 (13.5%) with clarithromycin resistant strains, 144 (14.3%) with metronidazole-resistant strains and 206 (20.5%) with clarithromycin-resistant and metronidazole-resistant strains. In the presence of double resistance, the cure rate was still high (38/41, 92.7%) when MIC levels were low and it was reduced (94/112, 83.9%) only when MIC levels of both antibiotics were high. The cure rates did not significantly differ between patients with single antibiotic-resistant strains, irrespective of MIC values, and those with susceptible strains. Conclusions: We found that MIC levels of resistance to either clarithromycin or metronidazole play a role in H. pylori therapy outcome and that bacterial resistance becomes relevant in vivo when clarithromycin-resistant and metronidazole-resistant strains have high MIC values for at least one of these antibiotics. PMID- 30476131 TI - Mendelian randomization analysis of C-reactive protein on colorectal cancer risk. AB - Background: Chronic inflammation is a risk factor for colorectal cancer (CRC). Circulating C-reactive protein (CRP) is also moderately associated with CRC risk. However, observational studies are susceptible to unmeasured confounding or reverse causality. Using genetic risk variants as instrumental variables, we investigated the causal relationship between genetically elevated CRP concentration and CRC risk, using a Mendelian randomization approach. Methods: Individual-level data from 30 480 CRC cases and 22 844 controls from 33 participating studies in three international consortia were used: the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT) and the Colon Cancer Family Registry (CCFR). As instrumental variables, we included 19 single nucleotide polymorphisms (SNPs) previously associated with CRP concentration. The SNP-CRC associations were estimated using a logistic regression model adjusted for age, sex, principal components and genotyping phases. An inverse-variance weighted method was applied to estimate the causal effect of CRP on CRC risk. Results: Among the 19 CRP associated SNPs, rs1260326 and rs6734238 were significantly associated with CRC risk (P = 7.5 * 10-4, and P = 0.003, respectively). A genetically predicted one unit increase in the log-transformed CRP concentrations (mg/l) was not associated with increased risk of CRC [odds ratio (OR) = 1.04; 95% confidence interval (CI): 0.97, 1.12; P = 0.256). No evidence of association was observed in subgroup analyses stratified by other risk factors. Conclusions: In spite of adequate statistical power to detect moderate association, we found genetically elevated CRP concentration was not associated with increased risk of CRC among individuals of European ancestry. Our findings suggested that circulating CRP is unlikely to be a causal factor in CRC development. PMID- 30476135 TI - Diagnosis and Management of Pediatric Influenza in the Era of Rapid Diagnostics. AB - Influenza is a significant cause of childhood morbidity and death; it contributes to up to 16% of hospitalizations for respiratory illnesses worldwide. Novel rapid viral diagnostic tests, including molecular diagnostic tests, have the potential to significantly affect both time to diagnosis and selection of optimal anti infective therapy. However, little is known about current treatment algorithms used in US hospitals. In this study, for hospitalized children in the United States, we aimed to define the current approaches to influenza diagnosis and treatment and to explore reasons for their potential variation. In this study, we aimed to define the current approaches to pediatric influenza diagnosis and treatment in US hospitals, and to explore reasons for their potential variation. Our results suggest a rise in the availability and use of rapid molecular diagnostic testing in addition to continued variability in anti-infective management, particularly with regard to antiviral use. PMID- 30476136 TI - Psychiatric Jim Crow: Desegregation at the Crownsville State Hospital, 1948-1970. AB - The Crownsville State Hospital, located in Maryland just outside of Annapolis, provides a thought-provoking example of the impact of desegregation in the space of the mental hospital. Using institutional reports, patient records, and oral histories, this article reconstructs the three phases of desegregation at Crownsville. First, as a result of its poor conditions, lack of qualified staff, and its egregious mistreatment of patients, African American community leaders and organizations such as the NAACP called for the desegregation of the care staff of Crownsville in the late 1940s. Second, the introduction of a skilled African American staff created unprecedented and morally complex issues about access to psychiatric therapeutics. Last, in 1963, Health Commissioner Dr. Isadore Tuerk officially desegregated patients in all Maryland state hospitals. Though desegregation brought much needed improvements to Crownsville, these gains were ultimately swamped by deinstitutionalization and the shift towards outpatient psychiatric care. By the 1970s, Crownsville had returned to the poor conditions that existed during segregation. PMID- 30476137 TI - Evaluation of multiplex tandem PCR (MT-PCR) assays for the detection of bacterial resistance genes among Enterobacteriaceae in clinical urines. AB - Background: Increasing resistance drives empirical use of less potent and previously reserved antibiotics, including for urinary tract infections (UTIs). Molecular profiling, without culture, might better guide early therapy. Objectives: To explore the potential of AusDiagnostics multiplex tandem (MT) PCR UTI assays. Methods: Two MT-PCR assays were developed successively, seeking 8 or 16 resistance genes. Amplification was tracked in real time, with melting temperatures used to confirm product identity. Assays were variously performed on: (i) extracted DNA; (ii) cultured bacteria; (iii) urine spiked with reference strains; and (iv) bacteria harvested from clinical urines. Results were compared with those from sequencing, real-time SybrGreen PCR or phenotypic susceptibility. Results: Performance was similar irrespective of whether DNA, cultures or urines were used, with >90% sensitivity and specificity with respect to common beta lactamases, dfr genes and aminoglycoside resistance determinants except aadA1/A2/A3, for which carriage correlated poorly with streptomycin resistance. Fluoroquinolone-susceptible and -resistant Escherichia coli (but not other species) were distinguished by the melting temperatures of their gyrA PCR products. The time from urine to results was <3 h. Conclusions: The MT-PCR assays rapidly identified resistance genes from Gram-negative bacteria in urines as well as from cultivated bacteria. Used directly on urines, this assay has the potential to guide early therapy. PMID- 30476139 TI - C11ORF74 interacts with the IFT-A complex and participates in ciliary BBSome localization. AB - Cilia are organelles that serve as cellular antennae. Intraflagellar transport (IFT) particles containing the IFT-A and IFT-B complexes mediate bidirectional trafficking of ciliary proteins. Particularly, in concert with the BBSome complex, IFT particles play an essential role in trafficking of ciliary G-protein coupled receptors. Therefore, proteins interacting with the IFT components are potential regulators of ciliary protein trafficking. We here revealed that an uncharacterized protein, C11ORF74, interacts with the IFT-A complex via the IFT122 subunit and is accumulated at the distal tip in the absence of an IFT-A subunit IFT139, suggesting that at least a fraction of C11ORF74 molecules can be transported toward the ciliary tip by associating with the IFT-A complex, although its majority might be out of cilia at steady state. In C11ORF74-knockout cells, the BBSome components cannot enter cilia. However, trafficking of Smoothened or GPR161, both of which are ciliary G-protein-coupled receptors involved in Hedgehog signaling and undergo BBSome-dependent trafficking, was not affected in the absence of C11ORF74. In addition, C11orf74/B230118H07Rik-knockout mice demonstrated no obvious anatomical abnormalities associated with ciliary dysfunctions. Given that C11ORF74 is conserved across vertebrates, but not found in other ciliated organisms, such as nematodes and Chlamydomonas, it might play limited roles involving cilia. PMID- 30476140 TI - How do plastids and mitochondria divide? AB - Plastids and mitochondria are thought to have originated from free-living cyanobacterial and alpha-proteobacterial ancestors, respectively, via endosymbiosis. Their evolutionary origins dictate that these organelles do not multiply de novo but through the division of pre-existing plastids and mitochondria. Over the past three decades, studies have shown that plastid and mitochondrial division are performed by contractile ring-shaped structures, broadly termed the plastid and mitochondrial-division machineries. Interestingly, the division machineries are hybrid forms of the bacterial cell division system and eukaryotic membrane fission system. The structure and function of the plastid and mitochondrial-division machineries are similar to each other, implying that the division machineries evolved in parallel since their establishment in primitive eukaryotes. Compared with our knowledge of their structures, our understanding of the mechanical details of how these division machineries function is still quite limited. Here, we review and compare the structural frameworks of the plastid and mitochondrial-division machineries in both lower and higher eukaryotes. Then, we highlight fundamental issues that need to be resolved to reveal the underlying mechanisms of plastid and mitochondrial division. Finally, we highlight related studies that point to an exciting future for the field. PMID- 30476138 TI - Sequence variants associating with urinary biomarkers. PMID- 30476141 TI - A Review of Current Standards and the Evolution of Histopathology Nomenclature for Laboratory Animals. AB - The need for international collaboration in rodent pathology has evolved since the 1970s and was initially driven by the new field of toxicologic pathology. First initiated by the World Health Organization's International Agency for Research on Cancer for rodents, it has evolved to include pathology of the major species (rats, mice, guinea pigs, nonhuman primates, pigs, dogs, fish, rabbits) used in medical research, safety assessment, and mouse pathology. The collaborative effort today is driven by the needs of the regulatory agencies in multiple countries, and by needs of research involving genetically engineered animals, for "basic" research and for more translational preclinical models of human disease. These efforts led to the establishment of an international rodent pathology nomenclature program. Since that time, multiple collaborations for standardization of laboratory animal pathology nomenclature and diagnostic criteria have been developed, and just a few are described herein. Recently, approaches to a nomenclature that is amenable to sophisticated computation have been made available and implemented for large-scale programs in functional genomics and aging. Most terminologies continue to evolve as the science of human and veterinary pathology continues to develop, but standardization and successful implementation remain critical for scientific communication now as ever in the history of veterinary nosology. PMID- 30476142 TI - Pubertal Development and Pregnancy Outcomes in 46,XX Patients with Nonclassic Lipoid Congenital Adrenal Hyperplasia. AB - Context: Lipoid congenital adrenal hyperplasia (LCAH) is characterized by a disorder of steroidogenesis in both adrenal glands and gonads. 46,XX patients with classic LCAH usually have thelarche and menarche, but show anovulatory menstruations and subsequent premature menopause. Only three patients with classic LCAH have been reported to successfully achieve delivery with the aid of assisted reproductive therapies for conception and progesterone replacement therapy during early pregnancy. In contrast, pubertal development and pregnancy outcomes in patients with nonclassic LCAH have not been fully elucidated. Case description: We report four Japanese women who were diagnosed as having primary adrenal insufficiency during infancy or childhood and carried compound heterozygous STAR mutations (p.Gln258* and p.Arg188His, p.Gln258* and p.Met225Thr, and p.Gln258* and p.Arg272Cys). In all four patients, thelarche and menarche spontaneously occurred from 10 to 11 years of age and from 12 to 14 years of age, respectively. Subsequently, their menstruation cycles were regular at almost 1-month intervals. Patient 1 conceived naturally twice, and Patient 2 conceived using clomiphene citrate for ovulation induction. These two patients maintained the pregnancies without progesterone replacement therapy and successfully delivered children. Conclusion: Patients with nonclassic LCAH preserve ovarian function, which enables normal pubertal development and a successful pregnancy outcome without progesterone replacement therapy. PMID- 30476143 TI - Unrecognized Elevations of Toxic Elements in Urine and Blood Highlight the Potential Need for a Broader Approach to Exposure Assessment. AB - Heavy metals testing remains an ongoing challenge for diagnosing acute or chronic exposure to heavy metals. In this study, we determined the positivity rates of single element and panel testing for toxic elements, and evaluated the potential utility of an expanded detection protocol for screening of toxic element exposures. The retrospective analysis included data from urine (n = 19,343) and blood (n = 196,019) specimens tested using inductively coupled plasma-mass spectrometry (ICP-MS) for arsenic, cadmium, lead and mercury (blood), and arsenic, cadmium, copper, lead, mercury and zinc (urine). Lead industrial monitoring in blood and cadmium exposure in blood and urine were included to represent directed single element ordering. The percent of positive results, defined as results greater than the upper limit of the reference interval was determined. For blood, the highest positivity was observed for lead occupational exposure monitoring (26.2%) whereas for urine, the highest positivity was observed for zinc testing (28.1%). Remarkably, reanalysis using an expanded panel, of 120 blood and 174 urine specimens originally negative identified 42% (50 of 120) of the blood specimens with at least one elevated result and 48% (83 of 174) of the urine specimens with at least one elevated result. Our results indicate that a broad elemental screening panel may help ensure easier identification of elemental exposure and may eliminate the need for additional follow-up sample collections. PMID- 30476144 TI - Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability. AB - THOC6 encodes a subunit of the THO complex that is part of a highly-conserved TREX complex, known to have roles in mRNA processing and export. Few homozygous or compound heterozygote variants have been identified in the THOC6 gene in patients with a syndromic form of intellectual disability (ID) (Beaulieu-Boycott Innes syndrome, BBIS MIM# 613680). Here we report two additional individuals affected with BBIS originating from the north of Europe and sharing an haplotype composed by threevery rare missense changes in the THOC6gene: p.(Trp100Arg; Val234Leu; Gly275Asp). The first individual is a boy who is homozygous for the three-variant haplotype, due to a maternal uniparental disomy event. The second is a girl, who is compound heterozygote for this haplotype and a previously reported p.(Gly190Glu) missense variant. We analyzed the impact of these different amino acid changes on THOC6 protein expression,cellular localization, and interaction with the other THO complex subunits. We show that the different THOC6 variants alter the physiological nuclear localization of the protein and its interaction with at least two THO subunits, THOC1 and THOC5. Two amino acid changes from the three-variant-haplotype have alone specific effects and might contribute to the pathogenicity of the haplotype. Overall, we expanded the cohort of currently known BBIS affected individuals by reporting two individuals carrying the same recurrent European haplotype composed of three amino acid changes, affecting THOC6 localization and interaction with THO protein partners. PMID- 30476145 TI - Coping with more people with more illness. Part 1: the nature of the challenge and the implications for safety and quality. AB - Health systems are under more pressure than ever before, and the challenges are multiplying and accelerating. Economic forces, new technology, genomics, AI in medicine, increasing demands for care-all are playing a part, or are predicted to increasingly do so. Above all, ageing populations in many parts of the world are exacerbating the disease burden on the system and intensifying the requirements to provide effective care equitably to citizens. In this first of two companion articles on behalf of the Innovation and Systems Change Working Group of the International Society for Quality in Health Care (ISQua), in consultation with representatives from over 40 countries, we assess this situation and discuss the implications for safety and quality. Health systems will need to run ahead of the coming changes and learn how to cope better with more people with more chronic and acute illnesses needing care. This will require collective ingenuity, and a deep desire to reconfigure healthcare and re-engineer services. Chief amongst the successful strategies, we argue, will be preventative approaches targeting both physical and psychological health, paying attention to the determinants of health, keeping people at home longer, experimenting with new governance and financial models, creating novel incentives, upskilling workforces to fit them for the future, redesigning care teams and transitioning from a system delivering episodic care to one that looks after people across the life cycle. There are opportunities for the international community to learn together to revitalise their health systems in a time of change and upheaval. PMID- 30476146 TI - A newly isolated Enterobacter sp. strain produces 2,3-butanediol during its cultivation on low-cost carbohydrate-based substrates. AB - 2,3-Butanediol (BDO) is an important platform chemical with wide range of applications in various industries. In the present study, a newly isolated wild Enterobacter sp. strain (FMCC-208) was evaluated towards its ability to produce BDO on media composed of sugars derived from sucrose refinery plant. Optimum values of temperature and pH as well as substrate inhibition were determined through batch experiments. The ability of the strain to convert various monosaccharides was also investigated. Maximum BDO concentration of 90.3 g l-1 and 10 g l-1 of acetoin were obtained during a fed-batch bioreactor experiment in with cane molasses and sucrose were employed as substrates. A high volumetric productivity was noted in a fed-batch experiment using molasses and sucrose as carbon source at T = 37 degrees C, in which 73.0 g l-1 of BDO together with 12.4 g l-1 of acetoin were produced where 1.15 g l-1 h-1 of diol/acetoin were produced. In previously pasteurized media, 70.0 g l-1 of BDO and 5.0 g l-1 of acetoin were produced (yield = 0.39 g g-1). Finally, besides BDO production, growth on molasses was accompanied by non-negligible decolorization (25-35%) of the residue. Therefore the strain is a promising candidate for the conversion of sucrose-based materials into BDO. PMID- 30476147 TI - EPIDEM: A Model for Quality Improvement. AB - Background: Existing quality improvement (QI) models have been used with varied success in health care. We developed the EPIDEM Model of Quality Improvement to apply QI principles to health care and promote a widespread culture of quality and patient safety. Methods: The EPIDEM acronym can be used to teach and remember the steps of process improvement: explore relevant issues and contextual factors, promote to the right people, implement timely solutions, document steps, evaluate with meaningful measures, and make modifications to improve interventions further. Results: The EPIDEM model requires no previous QI training and can be used in conjunction with other QI tools. Our model uniquely emphasizes understanding local context, culture, and resources throughout the QI process. Conclusions: We hope that this new QI model will help facilitate an "EPIDEMic" of healthcare QI for our institution and others by providing a foundational framework to successfully implement QI initiatives. PMID- 30476148 TI - Of Mice, Dogs, Pigs, and Men: Choosing the Appropriate Model for Immuno-Oncology Research. AB - The immune system plays dual roles in response to cancer. The host immune system protects against tumor formation via immunosurveillance; however, recognition of the tumor by immune cells also induces sculpting mechanisms leading to a Darwinian selection of tumor cell variants with reduced immunogenicity. Cancer immunoediting is the concept used to describe the complex interplay between tumor cells and the immune system. This concept, commonly referred to as the three E's, is encompassed by 3 distinct phases of elimination, equilibrium, and escape. Despite impressive results in the clinic, cancer immunotherapy still has room for improvement as many patients remain unresponsive to therapy. Moreover, many of the preclinical results obtained in the widely used mouse models of cancer are lost in translation to human patients.To improve the success rate of immuno oncology research and preclinical testing of immune-based anticancer therapies, using alternative animal models more closely related to humans is a promising approach. Here, we describe 2 of the major alternative model systems: canine (spontaneous) and porcine (experimental) cancer models. Although dogs display a high rate of spontaneous tumor formation, an increased number of genetically modified porcine models exist. We suggest that the optimal immuno-oncology model may depend on the stage of cancer immunoediting in question. In particular, the spontaneous canine tumor models provide a unique platform for evaluating therapies aimed at the escape phase of cancer, while genetically engineered swine allow for elucidation of tumor-immune cell interactions especially during the phases of elimination and equilibrium. PMID- 30476150 TI - Increased trend of unnecessary use of radiological diagnostic modalities in Pakistan: radiologists perspective. AB - Background: Over the past few years, a significant overuse of radiological investigations influenced the quality and cost of healthcare of the country as it may lead to non-compliance of the patient due to non-affordability and also may harm the patient in terms of radiation hazards. Pakistan, being a low-income, resource-constraint country, is facing financial impact on families as well as health system due to multiple reasons. Objectives: The purpose of study is to identify reasons of unnecessary use of radiological diagnostic modalities in Pakistani hospitals as perceived by radiologists. Methods: A cross-sectional study was conducted on a total of all 105 radiologists, having at least 1 year experience of working in radiology, working in five tertiary care hospitals in Lahore. A self-constructed, self-administered, pretested 5-point Likert scale opinion-based questionnaire was administered after taking informed consent. It includes questions about excessive radiological use that may be attributed to the physicians, investigations, patients and other non-categorized causes. Results were analyzed using SPSS version 23. Results: Since the assessment forms were handed over and collected from the radiologists in person, the response rate was 100%. Of a total of 105 respondents, 78 (74.28%) respondentsagreed that there is an actual increase, 25 (23.80%) respondents disagreed and 2 (1.90%) respondents were unsure. Most important reasons for increased usage of radiological investigations are 'need of accuracy of diagnosis' (P = 0.009), 'trend of physicians to repeat tests in order to confirm preset diagnoses' (P-value = 0.03), 'lack of knowledge about proper usage of radiological advances' (P-value = 0.005) and 'lack of proper clinical examination' (P-value = 0.04). Conclusion: Unnecessary use of radiological investigations is actually there as perceived by radiologists, which is attributed to inadequate knowledge, attitude and training of physicians to refer patients to radiological resources. This research can be a stepping stone for future researchers as it can be used for elaborating these causes individually and finding ways as to how each of these causes can be controlled and minimized to bring about a decline in excessive usage of these modalities for the betterment of the patients. PMID- 30476149 TI - Similarities and differences in the reproductive phenotypes of women with congenital hypogonadotrophic hypogonadism caused by GNRHR mutations and women with polycystic ovary syndrome. AB - STUDY QUESTION: Does the phenotype of women with normosmic congenital hypogonadotrophic hypogonadism (nCHH) and pituitary resistance to GnRH caused by biallelic mutations in the GnRH receptor (GNRHR) (nCHH/bi-GNRHR) differ from that of women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Women with nCHH/bi-GNRHR have variable pubertal development but nearly all have primary amenorrhea and an exaggerated LH response to GnRH stimulation, similar to that seen in women with PCOS. WHAT IS KNOWN ALREADY: Women with nCHH/bi-GNRHR are very rare and their phenotype at diagnosis is not always adequately documented. The results of gonadotrophin stimulation by acute GnRH challenge test and ovarian features have not been directly compared between these patients and women with PCOS. STUDY DESIGN, SIZE, DURATION: We describe the phenotypic spectrum at nCHH/bi-GNRHR diagnosis in a series of 12 women. Their reproductive characteristics and acute responses to GnRH were compared to those of 70 women with PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients and controls (healthy female volunteers aged over 18 years) were enrolled in a single French referral centre. Evaluation included clinical and hormonal studies, pelvic ultrasonography and GnRH challenge test. We also functionally characterized two missense GNRHR mutations found in two new consanguineous families. MAIN RESULTS AND THE ROLE OF CHANCE: Breast development was highly variable at nCHH/bi-GNRHR diagnosis, but only one patient had undeveloped breasts. Primary amenorrhea was present in all but two cases. In untreated nCHH/bi-GNRHR patients, uterine height (UH) correlated (P = 0.01) with the circulating estradiol level and was shorter than in 23 nulliparous post-pubertal age-matched controls (P < 0.0001) and than in 15 teenagers with PCOS under 20-years-old (P < 0.0001) in which PCOS was revealed by primary amenorrhea or primary-secondary amenorrhea. Unexpectedly, the stimulated LH peak response in nCHH/bi-GNRHR patients was variable, and often normal or exaggerated. Interestingly, the LH peak response was similar to that seen in the PCOS patients, but the latter women had significantly larger mean ovarian volume (P < 0.001) and uterine length (P < 0.001) and higher mean estradiol (P < 0.001), anti-Mullerian hormone (AMH) (P = 0.02) and inhibin-B (P < 0.001) levels. In the two new consaguineous families, the affected nCHH/bi-GNRHR women carried the T269M or Y290F GNRHR missense mutation in the homozygous state. In vitro analysis of GnRHR showed complete or partial loss-of-function of the T269M and Y290F mutants compared to their wildtype counterpart. LIMITATIONS, REASONS FOR CAUTION: The number of nCHH/bi-GNRHR patients reported here is small. As this disorder is very rare, an international study would be necessary to recruit a larger cohort and consolidate the phenotypic spectrum observed here. WIDER IMPLICATIONS OF THE FINDINGS: In teenagers and young women with primary amenorrhea, significant breast and uterine development does not rule out CHH caused by biallelic GNRHR mutations. In rare patients with PCOS presenting with primary amenorrhea and a mild phenotype, the similar exaggerated pituitary LH responses to GnRH in PCOS and nCHH/bi-GNRHR patients could lead to diagnostic errors. This challenge test should therefore not be recommended. As indicated by consensus and guidelines, careful analysis of clinical presentation and measurements of testosterone circulating levels remain the basis of PCOS diagnosis. Also, analysis of ovarian volume, UH and of inhibin-B, AMH, estradiol and androgen circulating levels could help to distinguish between mild PCOS and nCHH/bi-GNRHR. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the French National Research Agency (ANR) grant ANR-09-GENO-017 KALGENOPATH, France; and by the Italian Ministry of Education, University and Research (MIUR) grant PRIN 2012227FLF_004, Italy. The authors declare no conflict of interest. PMID- 30476151 TI - Waning immunity after single dose yellow fever vaccination. Who needs a second shot? PMID- 30476153 TI - Interaction of ergovaline with serotonin receptor 5-HT2A in bovine ruminal and mesenteric vasculature. AB - Ergot alkaloids from endophyte-infected (Epichloe coenophiala) tall fescue (Lolium arundinaceum) induce vasoconstriction. Previous work has shown that serotonin receptor subtype, 5HT2A, is present in bovine ruminal (R) and mesenteric (M) vasculature, plays a role in vasoconstriction, and could be influenced by ergot alkaloids. To determine the influence of ergot alkaloids on 5HT2A, the vasoactivity of an agonist selective for 5HT2A, (4-bromo-3,6 dimethoxybenzocyclobuten-1-yl) methylamine HCl (TCB-2), was evaluated using bovine ruminal and mesenteric arteries and veins (RA, RV, MA, MV) that were exposed to ergovaline (ERV) prior to or during the TCB-2 additions. Ruminal and mesenteric blood vessel segments were collected, cleaned, and cut into 2- to 3-mm cross-sections. Vessel segments were incubated in Krebs-Henseleit buffer containing 0, 0.01 or 1 uM ERV for 2 h prior to TCB-2 dose response or exposed to ERV concentrations simultaneously during TCB-2 dose response. For the dose response portion of the study, vessels were suspended in a multimyograph containing 5 mL of continuously oxygenated Krebs-Henseleit buffer and equilibrated to 1 g tension for 90 min. Vessels were exposed to increasing concentrations of TCB-2 every 15 min and contractile response data were normalized as a percentage of the maximum contractile response induced by 120 mM KCl reference. Analysis of variance was evaluated separately for each vessel and each ERV exposure experiment using the mixed models procedure of SAS for effects of TCB-2 and ERV concentrations. All blood vessels with previous ERV exposure had significantly lower contractile responses to TCB-2 (P < 0.01). All blood vessels with simultaneous exposure to 1 uM ERV had higher (P < 0.01) contractile responses at lower concentrations of TCB-2. Simultaneous ERV addition at 1 * 10-4 M TCB-2 did not affect contractility of RV, MA, MV (P > 0.05), but decreased contractility of RA (P < 0.01). These results indicate that ergopeptine alkaloid exposure influences contractility of bovine ruminal and mesenteric blood vessels through serotonin receptor subtype 5HT2A by acting as both an agonist and antagonist. Additional work is needed to determine if ergot alkaloids like ERV simply occupy receptor binding sites competitively, or influence receptor internalization to cause the observed divergent responses. PMID- 30476152 TI - The effect of recovery from heat stress on circulating bioenergetics and inflammatory biomarkers. AB - Heat stress (HS) jeopardizes animal productivity and health. The intestinal barrier is sensitive to HS and heat-induced hyperpermeability plays a key role in its pathophysiology. However, the biology of recovery following HS is less understood. Thus, study objectives were to determine the temporal pattern of metabolic, inflammatory, and intestinal histological parameters during HS recovery. Female pigs (n = 32; 19.5 +/- 0.5 kg BW) were sacrificed following exposure to 1 of 4 environmental treatments: 1) constant thermoneutral (TN) conditions (TNC; 24.2 +/- 0.5 degrees C), 2) no TN recovery post HS (0D), 3) 3 d of TN recovery post HS (3D), and 4) 7 d of TN recovery post HS (7D). The HS protocol was cyclical (33.6 +/- 1.8 to 37.4 +/- 2.1 degrees C) and lasted for 3 d for all HS treatments. During the 3 d of HS, rectal temperature, skin temperature, and respiration rates were increased (1.3 degrees C, 4.8 degrees C, and 77 breaths/min, respectively; P < 0.01) and ADFI was decreased (27%; P < 0.01) compared to TNC pigs. Skin temperature tended to be decreased 0.6 degrees C in 3D pigs during days 1-3 of recovery (P = 0.06) and was decreased 1.6 and 0.7 degrees C during days 1-3 and 4-7 of recovery, respectively, in 7D pigs (P <= 0.03) compared to TNC. Relative to TNC pigs, ADFI remained 14% decreased during days 1-3 of recovery in both 3D and 7D pigs, and 17% decreased during days 4-7 in 7D pigs (P <= 0.01). Plasma glucose was decreased (10%; P = 0.03) for 0D and 3D relative to TNC pigs. Circulating lipopolysaccharide-binding protein was increased in 3D and 7D vs. TNC pigs (110 and 147%, respectively; P = 0.01) and tended to increase linearly with increasing recovery time (P = 0.08). Circulating tumor necrosis factor alpha was decreased (15%) in 0D pigs and increased linearly with advancing recovery time (P < 0.01). Jejunum and ileum villus height were reduced 17 and 11% in 0D vs. TNC pigs and increased linearly with progressive recovery time (P < 0.01). Jejunum and ileum mucosal surface areas were reduced 17 and 9% in 0D pigs and remained decreased in the jejunum while the ileum recovered to TNC levels by day 3 of recovery. Relative to TNC pigs, goblet cell area was similar in jejunum and colon of 0D pigs but was reduced in the ileum of 0D pigs and in jejunum, ileum, and colon of 3D and 7D relative to TNC pigs (P < 0.01). In summary, HS has deleterious effects on intestinal morphology that seem to improve with recovery time. In contrast, feed consumption remained suppressed and inflammatory biomarkers indicative of leaky gut increased following the heat load. PMID- 30476123 TI - Cohort Profile: Design and methods of the PREDIMED-Plus randomized trial. PMID- 30476154 TI - Technical Note: Assessment of sampling technique from feeders for copper, zinc, calcium, and phosphorous analysis. AB - Diet treatments were arranged in a split-plot design with the whole-plot consisting of 1 of 6 concentrations of dietary Cu (22 to 134 mg/kg total Cu) and the subplot using 1 of 2 sampling techniques (probe vs. hand grab). A total of 6 feeders per treatment were sampled using a brass open handle probe. The probe was inserted into the feeder 4 times to obtain a 900 g of sample. The hand-collected samples were obtained by inserting a bare hand into the feeder approximately 8 times to obtain a 900 g of sample. Within a feeder and sampling technique, subsamples (200 g) were created by using a sample splitting device. In addition to the 6 individual feeder samples, a subsample (33 g) from each individual feeder was pooled within dietary treatment and sampling technique to form a single composite sample (200 g). This process was repeated until 4 individual composite samples were created for each diet and sampling technique. Next, all samples were ground through a centrifugal mill and submitted for mineral analysis in duplicate for Cu, Zn, Ca, and P analysis. Results indicated variability when sampling feeders with a probe were reduced (P = 0.013) for Cu and marginally reduced (P = 0.058) for Ca when compared with hand-sampling. However, no evidence for differences was detected among sampling techniques for Zn and P for the individual feeder analysis. When samples were pooled from 6 feeders to form a single composite sample, there was no evidence for differences detected among sampling techniques for Cu, Zn, Ca, and P analysis. From these results, sampling frequency calculations were determined to assess sampling accuracy within a 95% confidence interval. Results indicated that the number of feeders or composite samples required to analyze was less for Cu, Zn, Ca, and P analysis when using a probe compared with a hand sampling. In summary, sampling with a probe is associated with less variability on an individual sample basis, but when individual samples are pooled to form a composite sample, there was no evidence for difference among sampling techniques. Our results suggest samples collected for these analyses with a probe and composited would be the best option to minimize variation and analytical costs. PMID- 30476155 TI - In situ degradation kinetics of 6 roughages and the intestinal digestibility of the rumen undegradable protein. AB - Three ruminally fistulated Xuanhan steers weighting 312.5 (+/-23.85) kg were used to determine the kinetics of ruminal degradation of nutrients using in situ nylon bag technique, and a modified 3-step in vitro procedure was adopted to estimate intestinal digestibility of 16-h rumen undegradable protein (RUP) of maize cob (MC), distillers grains (DG), spent mushroom substrate (SMS), starch residue of sweet potato (SRSP), citrus pulp (CPP), and rice straw (RS). Samples were incubated for 0, 2, 6, 16, 24, 36, 48 and 72 h. Additional samples were incubated for 16 h in the rumen, and the residues from these bags were transferred to the nitrogen-free polyester bags for determination of intestinal digestibility in vitro. The highest DM disappearance at 6-h incubation was in SRSP (P < 0.01), and that at 36, 48, and 72 h was in CPP (P < 0.01). The lowest DM disappearance at 2- and 6-h incubation was in RS and SMS (P < 0.01), and that at 36, 48, and 72 h incubation was in RS, MC, and DG (P < 0.01). The lowest and greatest CP disappearance was in RS and DG, respectively, at all the incubation times (P < 0.01). There was no difference (P > 0.07) on CP disappearance between DG and MC at all the time points except for 16 and 24 h. NDF and ADF disappearance for SRSP was significantly higher (P < 0.01) than other roughages at all the time points except for ADF at 72 h. The lowest NDF and ADF disappearance was in DG at all the time points (P < 0.01) except 2 and 6 h. The effective degradability (ED) of DM was the highest in CPP (P < 0.01) and the lowest in MC and RS (P < 0.01). The highest and lowest ED of CP was in DG and in RS (P < 0.01), respectively. The ED of NDF was the highest in SRSP (P < 0.01), followed by CPP and RS, and the lowest in DG (P < 0.01). The ED of ADF was the highest in SRSP and CPP (P < 0.05), and the lowest in DG (P < 0.01). For MC, DG SMS, SRSP, CPP, and RS, the intestinal digestibility of RUP was 95.28%, 37.23%, 38.72%, 48.06%, 54.49%, and 37.88%, respectively, and the content of intestinal digestible crude protein (IDCP) was 23.65, 83.63, 35.63, 15.03, 25.60, and 12.03 g/kg, respectively. Distillers grain was considered to be of good quality for the greatest content of IDCP. Although not readily degraded in rumen, CP in MC may be digested well in small intestine. PMID- 30476156 TI - Efficacy of energy supplementation on growth performance and immune response of suckling pigs. AB - Three studies were performed to determine the effects of oral energy sources on the performance, immune status, and intestinal morphology of piglets. In Exp. 1, 50 litters were selected based on genotype and parity order to determine the optimum amount of supplemental energy for neonatal pigs. They were distributed according to a 5 * 5 Latin square design, in which columns were represented by 5 sows and rows were represented by 5 newborn weight categories. Treatments consisted of 2 oral doses of 0, 2, 4, 8, or 16 mL of rice bran oil (RBO). There was a positive response of RBO on BW with a numerical difference (P = 0.12) and a significant linear effect (P = 0.04) at weaning. In Exp. 2, litters (n = 340) were randomly allotted to a 2 * 2 factorial arrangement of treatments: RBO supplemented either through oral doses (without supplementation or with 2 mL of RBO) or through prestarter feed (without supplementation or with 2% of RBO replacing 2% of soybean oil). Piglets orally receiving RBO showed a numerical increase in BW at weaning (P = 0.101) compared with the control group. Moreover, piglets supplemented by prestarter feed tended to increase feed intake (P = 0.084). In Exp. 3, litters (n = 245) were selected based on genotype and parity order and they were distributed according to a 7 * 7 Latin square design planed in the same way as in Exp. 1. Each neonatal pig within a litter was randomly assigned to 1 of 7 treatments: 1) control (no supplementation), 2) 2 mL of RBO enriched with omega-3 fatty acids, 3) 2.33 mL of pure glycerin, 4) 1.3 mL of soybean oil, 5) 1.4 mL of linseed oil, 6) 1.68 mL of coconut oil, and 7) 2 mL of RBO. Animal performance was analyzed using 2 data sets: all data (average initial BW of 1.479 kg) and low birth weight (LBW) piglet data (<=1.220 kg initial BW with average of 0.985 kg). Body weight or BW gain (BWG) were not different among treatments (P > 0.10) when all data were analyzed. However, LBW piglets fed coconut oil tended to increase BW (P = 0.099) during the first week. In conclusion, the oral use of RBO may increase BW at weaning and the supplementation by prestarter feed may enhance the feed intake of piglets. In addition, coconut oil may increase BW of LBW piglets in the first week of life without affecting mortality, immune response, or gut morphology. The routine practice of oral supplementation of energy for newborn pigs could be an important tool in swine production. PMID- 30476158 TI - Metabolites to parent 3-MeO-PCP ratio in human urine collected in two fatal cases. AB - In this article, two fatal cases related to the use of 3-methoxyphencyclidine (3 MeO-PCP) are described. This compound is a new psychoactive substance that belongs to the phencyclidine family. In the recent period, this dissociative drug has gained interest because of its proposal as a legally available alternative to phencyclidine in some countries. The scientific literature related to 3-MeO-PCP is very poor. Using standard ultra-performance liquid chromatography-mass spectrometry and ultra-performance liquid chromatography-tandem mass spectrometry, the authors focused on the detection of 3-MeO-PCP and its metabolites in human urine. 3-MeO-PCP metabolism was studied in vitro after drug incubation with human liver microsomes and the identified metabolites were investigated in the urine of the two forensic cases. 3-MeO-PCP metabolites, including O-demethyl-3-MeO-PCP, piperidine-hydroxy-3-MeO-PCP, O-demethyl piperidine-di-hydroxy-3-MeO-PCP and piperidine-di-hydroxy-3-MeO-PCP, were detectable in the urine from both cases and the ratio between metabolites and parent 3-MeO-PCP, always lower than 1, were calculated to estimate the proportionality of metabolites. At this stage, one can conclude that testing for 3-MeO-PCP metabolites does not increase the window of detection of the drug. PMID- 30476157 TI - A Novel Tomato-Soy Juice Induces a Dose-Response Increase in Urinary and Plasma Phytochemical Biomarkers in Men with Prostate Cancer. AB - Background: Tomato and soy intake is associated with reduced prostate cancer risk or severity in epidemiologic and experimental studies. Objective: On the basis of the principle that multiple bioactives in tomato and soy may act on diverse anticancer pathways, we developed and characterized a tomato-soy juice for clinical trials. In this phase 2 dose-escalating study, we examined plasma, prostate, and urine biomarkers of carotenoid and isoflavone exposure. Methods: Men scheduled for prostatectomy were recruited to consume 0, 1, or 2 cans of tomato-soy juice/d before surgery (mean +/- SD duration: 24 +/- 4.6 d). The juice provided 20.6 mg lycopene and 66 mg isoflavone aglycone equivalents/177-mL can. Plasma carotenoids and urinary isoflavone metabolites were quantified by HPLC photometric diode array and prostate carotenoids and isoflavones by HPLC-tandem mass spectrometry. Results: We documented significant dose-response increases (P < 0.05) in plasma concentrations of tomato carotenoids. Plasma concentrations were 1.86-, 1.69-, 1.73-, and 1.69-fold higher for lycopene, beta-carotene, phytoene, and phytofluene, respectively, for the 1-can/d group and 2.34-, 3.43-, 2.54-, and 2.29-fold higher, respectively, for the 2-cans/d group compared with 0 cans/d. Urinary isoflavones daidzein, genistein, and glycitein increased in a dose-dependent manner. Prostate carotenoid and isoflavone concentrations were not dose-dependent in this short intervention; yet, correlations between plasma carotenoid and urinary isoflavones with respective prostate concentrations were documented (R2 = 0.78 for lycopene, P < 0.001; R2 = 0.59 for dihydrodaidzein, P < 0.001). Secondary clustering analyses showed urinary isoflavone metabolite phenotypes. To our knowledge, this is the first demonstration of the phytoene and phytofluene in prostate tissue after a dietary intervention. Secondary analysis showed that the 2-cans/d group experienced a nonsignificant decrease in prostate specific antigen slope compared with 0 cans/d (P = 0.078). Conclusion: These findings provide the foundation for evaluating a well-characterized tomato-soy juice in human clinical trials to define the impact on human prostate carcinogenesis. This trial is registered at clinicaltrials.gov as NCT01009736. PMID- 30476159 TI - Paracoccidioides brasiliensis 14-3-3 protein is important for virulence in a murine model. AB - The Paracoccidioides brasiliensis strain downregulated the expression of adhesin Pb14-3-3 (Pb14-3-3 aRNA) was evaluated in a murine model of paracoccidioidomycosis (PCM). Pb14-3-3 aRNA displays attenuated virulence and triggered the formation of fewer granulomas by lowering the fungal burden in the lungs. Additionally, the Pb14-3-3 aRNA showed more elongated yeast cells and less ability to induce pneumocytes apoptosis in vitro. Our results show that 14-3-3 is an important virulence factor in P. brasiliensis-induced pulmonary infection. PMID- 30476160 TI - Perceptions of tick-borne encephalitis risk: a survey of travellers and travel clinics from Canada, Germany, Sweden and the UK. AB - Background: While the worldwide endemicity of tick-borne encephalitis (TBE) has been increasing, a lack of awareness of the risks of this life-threatening disease may be leading to an underutilization of preventive measures among travellers to TBE-endemic regions. This study's objectives were to assess travellers' awareness of TBE and advice-seeking attitudes, and to evaluate practices of travel clinics regarding pre-travel advice. Methods: We used an online questionnaire to identify individuals aged 18-65 years residing in the UK, Germany, Canada and Sweden, who had travelled to TBE-endemic countries between 2013 and 2016. This sample was defined as the visit-risk sample. Of these, the first 375 respondents who reported that they had engaged in pre-defined at-risk activities (e.g. hiking in forests) were asked to complete an additional online survey and were included in the activity-risk sub-sample. We also used an online/phone questionnaire to interview travel clinic personnel. Results: The TBE visit-risk sample included 4375 individuals; 69% had heard of the disease and 32% had heard of a TBE vaccine. Before travelling, travellers most commonly sought information online (26%); fewer travellers consulted family doctors (8%) or travel clinics (5%). In the activity-risk sample, 79% of the travellers were aware of at least one correct TBE prevention measure; however, only 15% reported being vaccinated within the past 3 years, with 11% of vaccinated travellers doing so following a clinic's recommendation. One hundred and eighty travel clinic representatives responded and reported that TBE vaccination was recommended to an average of 61% of travellers to endemic regions. Vaccination-reminder services such as follow-up appointments, e-mail and text reminders were offered by 50% of the clinics. Conclusions: There is a need to increase awareness of the risk and prevention of TBE among travellers to endemic countries, and travel clinics could play an important role in this process. PMID- 30476161 TI - The significance of non-communicable threats to travellers: time for a sea change? PMID- 30476162 TI - Reducing infectious disease inequities among migrants. AB - Globally, human migration has reached unprecedented levels, with 3.6% of the world's population living outside their country of birth. Migrants comprise a substantial proportion of high-income country populations, are at increased risk of a range of infectious diseases, compared to native-born populations and may experience worse health outcomes due to barriers accessing timely diagnoses and treatment. Poor access to essential healthcare services can be attributed to several factors, including language and cultural barriers and lack of specific inclusive health policies. This review draws on evidence from the immigrant health and travel medicine literature, with a focus on infectious disease risks. It presents strategies to reduce barriers to healthcare access through health promotion and screening programs both at the community and clinic level and the delivery of linguistically and culturally competent care. The Salud Entre Culturas (SEC) "Health Between Cultures" project from the Tropical Medicine Unit at the Hospital Ramon y Cajal in Madrid is described as an effective model of care. For those providing healthcare to migrant populations, the use of community consulted approaches are considered best practice in the development of health education, health promotion and the delivery of targeted health services. At the clinic-level, strategies optimising care for migrants include the use of bilingual healthcare professionals or community-based healthcare workers, cultural competence training of all clinic staff, the appropriate use of trained interpreters and the use of culturally-appropriate health promotion materials. Multifaceted strategies are needed to improve access, community knowledge, community engagement and healthcare provider training to provide appropriate care to migrant populations to reduce infectious disease disparities. PMID- 30476163 TI - A tightly regulated and adjustable CRISPR-dCas9 based AND gate in yeast. AB - The robust and precise on and off switching of one or more genes of interest, followed by expression or repression is essential for many biological circuits as well as for industrial applications. However, many regulated systems published to date influence the viability of the host cell, show high basal expression or enable only the overexpression of the target gene without the possibility of fine regulation. Herein, we describe an AND gate designed to overcome these limitations by combining the advantages of three well established systems, namely the scaffold RNA CRISPR/dCas9 platform that is controlled by Gal10 as a natural and by LexA-ER-AD as heterologous transcription factor. We hence developed a predictable and modular, versatile expression control system. The selection of a reporter gene set up combining a gene of interest (GOI) with a fluorophore by the ribosomal skipping T2A sequence allows to adapt the system to any gene of interest without losing reporter function. In order to obtain a better understanding of the underlying principles and the functioning of our system, we backed our experimental findings with the development of a mathematical model and single-cell analysis. PMID- 30476164 TI - Clinical outcome of high dose rate brachytherapy with external beam radiotherapy for high-risk prostate cancer: a single institutional retrospective study. AB - Objectives: : This study investigated the clinical outcome of neoadjuvant androgen deprivation therapy followed by high dose rate brachytherapy (HDR-BT, called NEH) with external beam radiotherapy (EBRT) in high-risk prostate cancer (PCa) patients in our institution. : From 2007 to 2012, 192 high-risk PCa patients underwent neoadjuvant treatment-EBRT-NEH ( n = 192). Relations between clinical factors (prostate-specific antigen; PSA, cT stage, Gleason score) and biochemical recurrence were retrospectively analyzed. : The 5- and 7-year overall survival rates were 97.9 and 91.1%. By PSA levels (PSA 20 ng/ml, 20 ng/ml < PSA<=50 ng/ml and PSA > 50 ng/ml), 5-year biochemical recurrence-free survival rates were 85.7, 84.7 and 54.5%, respectively. There were no significant differences between biochemical recurrence and cT stage or Gleason score. : We found that NEH can contribute to better biochemical recurrence free survival of high-risk PCa patients with PSA below 50 ng/ml. High-risk PCa patients with PSA over 50 ng/ml may require more aggressive local or systemic treatment. PMID- 30476165 TI - Dolutegravir and lamivudine maintenance therapy in HIV-1 virologically suppressed patients: results of the ANRS 167 trial (LAMIDOL). AB - Objectives: To evaluate the dolutegravir+lamivudine combination in virologically suppressed patients living with HIV. Methods: The ANRS 167 LAMIDOL trial was an open-label, single arm, multicentre trial assessing once-daily dolutegravir (50 mg)+lamivudine (300 mg) in virologically suppressed HIV-1 patients on first-line triple-drug regimens. The main criteria for inclusion in the trial were plasma viral load (pVL) <=50 copies/mL for >=2 years, CD4 nadir >200 cells/mm3 and WT HIV prior to treatment initiation. From week -8 (W-8) to day 0 (D0) (Phase 1), the current third agent was switched to dolutegravir. From D0 to W48 (Phase 2), patients received once-daily dolutegravir+lamivudine, except if intolerant or if pVL >50 copies/mL during Phase 1. Virological failure was defined as pVL >50 copies/mL in two consecutive samples. The study was designed to show that the strategy had an efficacy of >=80%, assuming a 90% success rate with a type I error of 5% and a power of 90%. Results: In total, 104 of 110 patients enrolled in Phase 1 were included in Phase 2. These 104 patients were 86% male, 72% MSM and 87% CDC stage A. Their characteristics were (median): age 45 years, CD4 nadir 339 cells/mm3, baseline CD4 743 cells/mm3 and duration of viral suppression 4.5 years. The overall success rate at W48 was 97% (95% CI: 94%-100%), meeting the design expectation/assumption. Three therapeutic failures occurred: one virological failure at W4, one lost to follow-up at W32 and one interruption of therapeutic strategy at W40 after a blip (pVL 59 copies/mL but control pVL <50 copies/mL). Three viral blips occurred in two additional patients. Neither M184V nor integrase resistance mutations were detected after failure or blips. Conclusions: Dolutegravir+lamivudine is a promising maintenance therapy in HIV-1 infected patients with controlled virological suppression. PMID- 30476166 TI - Clustered DNA double-strand break formation and the repair pathway following heavy-ion irradiation. AB - Photons, such as X- or gamma-rays, induce DNA damage (distributed throughout the nucleus) as a result of low-density energy deposition. In contrast, particle irradiation with high linear energy transfer (LET) deposits high-density energy along the particle track. High-LET heavy-ion irradiation generates a greater number and more complex critical chromosomal aberrations, such as dicentrics and translocations, compared with X-ray or gamma irradiation. In addition, the formation of >1000 bp deletions, which is rarely observed after X-ray irradiation, has been identified following high-LET heavy-ion irradiation. Previously, these chromosomal aberrations have been thought to be the result of misrepair of complex DNA lesions, defined as DNA damage through DNA double-strand breaks (DSBs) and single-strand breaks as well as base damage within 1-2 helical turns (<3-4 nm). However, because the scale of complex DNA lesions is less than a few nanometers, the large-scale chromosomal aberrations at a micrometer level cannot be simply explained by complex DNA lesions. Recently, we have demonstrated the existence of clustered DSBs along the particle track through the use of super resolution microscopy. Furthermore, we have visualized high-level and frequent formation of DSBs at the chromosomal boundary following high-LET heavy-ion irradiation. In this review, we summarize the latest findings regarding the hallmarks of DNA damage structure and the repair pathway following heavy-ion irradiation. Furthermore, we discuss the mechanism through which high-LET heavy ion irradiation may induce dicentrics, translocations and large deletions. PMID- 30476167 TI - Phylogenetic relationships and evolutionary trends in the Cactus family. AB - Members of the cactus family are keystone species of arid and semiarid biomes in the Americas, as they provide shelter and resources to support other members of ecosystems. Extraordinary examples are the several species of flies of the genus Drosophila that lay eggs and feed in their rotting stems, which provide a model system for studying evolutionary processes. Although there is significant progress in understanding the evolution of Drosophila species, there are gaps in our knowledge about the cactus lineages hosting them. Here we review the current knowledge about the evolution of Cactaceae, focusing on phylogenetic relationships and trends revealed by the study of DNA sequence data. During the last several decades, the availability of molecular phylogenies has considerably increased our understanding of the relationships, biogeography, and evolution of traits in the family. Remarkably, although succulent cacti have very low growth rates and long generation times, they underwent some of the fastest diversifications observed in the plant kingdom, possibly fostered by strong ecological interactions. We have a better understanding of the reproductive biology, population structure and speciation mechanisms in different clades. The recent publication of complete genomes for some species has revealed the importance of phenomena such as incomplete lineage sorting. Hybridization and polyploidization are common in the family, and have been studied using a variety of phylogenetic methods. We discuss potential future avenues for research in Cactaceae, emphasizing the need of a concerted effort among scientists in the Americas, together with the analyses of data from novel sequencing techniques. PMID- 30476168 TI - Enhanced estimates of carcass and meat quality effects for polymorphisms in myostatin and u-calpain genes. AB - The objective of this study was to enhance estimates of additive, dominance, and epistatic effects of marker polymorphisms on beef carcass and quality traits. Myostatin (MSTN) F94L SNP and the u-calpain (CAPN1) 316 and 4751 SNP haplotype have previously been associated with fat and muscle traits in beef cattle. Multiyear selection in a composite population segregating these polymorphisms increased minor allele (F94L L) and chosen haplotype (CAPN1 CC and GT) frequencies to intermediate levels resulting in more precise estimates of additive and non-additive genetic effects. During the 3 yr after selection, 176 steers were evaluated for growth, carcass, meat quality, tenderness (n = 103), and meat color traits. The statistical model included year, age of dam, age of the steer, and genotype in a random animal model. The 9 genotypes (3 CAPN1 diplotypes * 3 F94L genotypes) affected marbling score, ribeye area, adjusted fat thickness, vision yield grade (all P < 0.001), slice shear force (P = 0.03), and CIE L* reflectance (P = 0.01). Linear contrasts of the 9 genotypes estimated additive, recessive, and epistatic genetic effects. Significant additive effects of the F94L L allele decreased marbling score, adjusted fat thickness, vision yield grade, and slice shear force; and increased ribeye area and CIE L* reflectance. The homozygous F94L FF and LL genotypes differed by 1.3 to 1.9 phenotypic SD for most carcass traits and by 0.8 to 0.9 SD for slice shear force and CIE L* reflectance but carcass weight differed by only 3 kg (0.1 SD). The L allele was partially recessive to F for ribeye area (P = 0.02) and the heterozygous FL means tended to be closer to the FF genotype than the LL genotype for other carcass traits but differences from additive were not significant. The CAPN1 additive * F94L additive effect on slice shear force was the only significant epistatic estimate. The F94L L allele is prevalent in Limousin but nearly absent in other U.S. purebreds. This allele had about half of the effects on birth weight, muscle, and fat traits reported for severe MSTN mutations in Belgian Blue and Piedmontese breeds. The interaction between MSTN and CAPN1 genotypes may reflect the strong additive effects of MSTN F94L L allele on fat and muscle traits interfering with the phenotypic effect of CAPN1 genotype on meat tenderness. PMID- 30476169 TI - Clinical Impact of Clostridium difficile PCR Cycle Threshold-Predicted Toxin Reporting in Pediatric Patients. AB - Background: Reliance on tests that detect only the presence of toxigenic Clostridium difficile can result in overdiagnosis and overtreatment of C difficile infection (CDI). The C difficile polymerase chain reaction (PCR) cycle threshold (CT) can sensitively predict the presence of free C difficile toxins; however, the clinical application for this testing strategy remains unexplored. We evaluated the impact of dual PCR and toxin result reporting, as predicted by the CT, on CDI management and outcomes in children. Methods: Before the intervention, results for C difficile testing at Lucile Packard Children's Hospital Stanford were reported as PCR positive (PCR+) or negative (PCR-) according to the GeneXpert C diff Epi tcdB PCR assay (Cepheid, Sunnyvale, California). Beginning October 5, 2016, the presence of free toxins, as predicted by the CT, was reported also. The CDI treatment rates 1 year before and 18 months after implementation of toxin reporting were compared. Demographic and treatment related data were collected, and patient outcomes were followed up 8 weeks later. Results: CDI treatment decreased 22% after the intervention (96% [preintervention] vs 74% [postintervention]; P < .001). During the postintervention period, there were 152 PCR+C difficile results, and 94 (62%) of them were toxin positive (toxin+) according to the CT. Of the 58 PCR+/toxin negative (toxin-) results, 38 (66%) did not result in CDI treatment. Seven (18%) of the untreated PCR+/toxin- patients underwent repeat testing within 8 weeks, and 5 (13%) of them were subsequently PCR+/toxin+ and treated. No CDI-related complications were identified. Conclusions: Addition of the CT-predicted C difficile toxin result to PCR reporting reduces the proportion of PCR+ children treated for CDI. PMID- 30476170 TI - Long-term blood pressure monitoring by office and 24-h ambulatory blood pressure in renal transplant patients: a longitudinal study. AB - Background: Renal transplant patients have a high prevalence of nocturnal hypertension, and hypertension misclassification by office blood pressure (BP) is quite common in these patients. The potential impact of hypertension misclassification by office BP on hypertension management in this population has never been analysed. Methods: We performed a longitudinal study in a cohort of 260 clinically stable renal transplant patients. In all, 785 paired office and 24 h ambulatory blood pressure monitoring (24-hABPM) measurements over a median follow-up of 3.9 years were available in the whole cohort. Results: A total of 74% of patients had nocturnal hypertension (>120/70 mmHg). Average office BP and 24-hABPM remained quite stable over follow-up, as did the prevalence of nocturnal hypertension, which was 77% at the last observation. However, the global agreement between office BP and average 24 h, daytime and night-time BP was unsatisfactory (k-statistics 0.10-0.26). In 193 visits (25% of all visits) where office BP indicated the need of antihypertensive therapy institution or modification (BP >140/90 mmHg), 24-hABPM was actually normal (<130/80 mmHg), while in 94 visits (12%), 24-hABPM was in the hypertensive range while office BP was normal. Overall, in 37% of visits, office BP provided misleading therapeutic indications. Conclusions: Hypertension misclassification by office BP is a common phenomenon in stable renal transplant patients on long-term follow-up. Office BP may lead to inappropriate therapeutic decisions in over one-third of follow-up visits in these patients. PMID- 30476171 TI - Dystrophinopathy associated dysfunction of Krebs cycle metabolism. AB - Duchenne muscular dystrophy is a deadly muscle wasting disorder caused by loss of dystrophin protein. Studies suggest metabolic alterations are important to disease pathogenesis. Because muscle accounts for ~40% of body mass, we hypothesized that dystrophy-mediated metabolic changes would be measurable in biofluids and that a metabolomic analysis of urine would provide insight into the metabolic status of dystrophic muscle. Using the mdx mouse model, we performed a large-scale metabolomic screen at 1 and 3 months. While 10% of metabolites were altered at age 1 month, 40% were changed at 3 months. Principal component analysis distinguished wild-type from mdx animals, with the greatest separation at 3 months. A critical distinguishing pathway was Krebs cycle metabolite depletion in mdx urine. Five of 7 detected Krebs cycle metabolites were depleted in mdx urine, with succinate being the most robustly affected metabolite. Using selected reaction monitoring mass spectrometry, we demonstrated that muscle specific dystrophin expression corrects mdx succinate depletion. When subjected to downhill treadmill running, wild-type and mdx mice expressing recombinant dystrophin in skeletal muscle displayed significant increases in urinary succinate levels. However, mdx succinate levels were unchanged, suggesting urinary succinate depletion may reflect an inability to upregulate the Krebs cycle following exercise. Finally, we show that supplementing the Krebs cycle in an ex vivo fatigue/recovery assay significantly impacts mdx muscle performance, but has no effect on wild-type muscle. Our results suggest that global metabolic impairment is associated with mdx disease progression and that Krebs cycle deficiencies are a downstream consequence of dystrophin loss. PMID- 30476172 TI - Combination treatment with the cap-dependent endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse model of influenza A virus infection. AB - Objectives: Baloxavir marboxil (formerly S-033188) is a first-in-class, orally available, cap-dependent endonuclease inhibitor licensed in Japan and the USA for the treatment of influenza virus infection. We evaluated the efficacy of delayed oral treatment with baloxavir marboxil in combination with a neuraminidase inhibitor in a mouse model of lethal influenza virus infection. Methods: The inhibitory potency of baloxavir acid (the active form of baloxavir marboxil) in combination with neuraminidase inhibitors was tested in vitro. The therapeutic effects of baloxavir marboxil and oseltamivir phosphate, or combinations thereof, were evaluated in mice lethally infected with influenza virus A/PR/8/34; treatments started 96 h post-infection. Results: Combinations of baloxavir acid and neuraminidase inhibitor exhibited synergistic potency against viral replication by means of inhibition of cytopathic effects in vitro. In mice, baloxavir marboxil monotherapy (15 or 50 mg/kg twice daily) significantly and dose-dependently reduced virus titre 24 h after administration and completely prevented mortality, whereas oseltamivir phosphate treatments were not as effective. In this model, a suboptimal dose of baloxavir marboxil (0.5 mg/kg twice daily) in combination with oseltamivir phosphate provided additional efficacy compared with monotherapy in terms of virus-induced mortality, elevation of cytokine/chemokine levels and pathological changes in the lung. Conclusions: Baloxavir marboxil monotherapy with 96 h-delayed oral dosing achieved drastic reductions in virus titre, inflammatory response and mortality in a mouse model. Combination treatment with baloxavir acid and oseltamivir acid in vitro and baloxavir marboxil and oseltamivir phosphate in mice produced synergistic responses against influenza virus infections, suggesting that treating humans with the combination may be beneficial. PMID- 30476173 TI - Fascin-1 is a Novel Prognostic Biomarker Associated with Tumor Invasiveness in Adrenocortical Carcinoma. AB - CONTEXT: Novel tumor markers are urgently needed to better stratify adrenocortical cancer (ACC) patients and improve therapies for this aggressive neoplasm. OBJECTIVE: To assess the diagnostic and prognostic value of the actin bundling protein fascin-1 (FSCN1) in adrenocortical tumors. DESIGN, SETTING AND PARTICIPANTS: A local series of 37 malignant/37 benign adrenocortical tumors at Careggi University Hospital and two independent validation ACC cohorts (Cochin, TCGA) from the European Network for the Study of Adrenal Tumors were studied. MAIN OUTCOME MEASURES: FSCN1 expression was quantified by immunohistochemistry, Western Blot and quantitative RT-PCR analyses in ACC specimens; overall and disease-free survival associated with FSCN1 expression were assessed by Kaplan Meier analysis and compared with that of Ki67 labelling index and tumor stage. RESULTS: In spite of the low diagnostic power, in the Florence ACC series, FSCN1 immunohistochemical detection appeared as an independent prognostic factor, also refining results obtained with staging and Ki67 labelling index. The robust prognostic power of FSCN1 levels was further confirmed in two independent ACC cohorts. A positive correlation was found between FSCN1 and Steroidogenic Factor 1 (SF-1), with a significant higher expression of both factors in ACCs at advanced stages and with at least one of the three Weiss score parameters associated with invasiveness. Moreover, we demonstrated FSCN1 role in promoting cell invasion in a human ACC cell line only in the case of increased SF-1 dosage. CONCLUSIONS: These findings show that FSCN1 is a novel independent prognostic marker in ACC and may serve as a potential therapeutic target to block tumor spread. PMID- 30476174 TI - CNS inflammatory disorder after concurrent radiotherapy-temozolomide and nivolumab in a glioblastoma patient. PMID- 30476175 TI - Automated and flexible identification of complex disease: building a model for systemic lupus erythematosus using noisy labeling. AB - : Accurate and efficient identification of complex chronic conditions in the electronic health record (EHR) is an important but challenging task that has historically relied on tedious clinician review and oversimplification of the disease. Here we adapt methods that allow for automated "noisy labeling" of positive and negative controls to create a "silver standard" for machine learning to automate identification of systemic lupus erythematosus (SLE). Our final model, which includes both structured data as well as text processing of clinical notes, outperformed all existing algorithms for SLE (AUC 0.97). In addition, we demonstrate how the probabilistic outputs of this model can be adapted to various clinical needs, selecting high thresholds when specificity is the priority and lower thresholds when a more inclusive patient population is desired. Deploying a similar methodology to other complex diseases has the potential to dramatically simplify the landscape of population identification in the EHR. MeSH terms: Electronic Health Records, Machine Learning, Lupus Erythematosus, Phenotype, Algorithms. PMID- 30476176 TI - Trajectories of change in childhood obesity prevalence across local authorities 2007/08-2015/16: a latent trajectory analysis. AB - Background: We investigated differing trajectories of childhood obesity prevalence amongst English local authorities (LAs). Methods: Data on prevalence of childhood obesity (BMI >= 95th centile) for Reception year and Year 6 for 150 LAs in England from 2006/07 to 2015/16 were obtained from the National Child Measurement Programme (NCMP). Latent class mixture modelling (LCCM) was used to identify classes of change in obesity prevalence. Results: In Reception, most LAs showed little change across the period (Class 1; stable, moderate obesity prevalence;84%), with a smaller group with a high prevalence that fell thereafter (Class 2; high but falling obesity prevalence; 16%). In Year 6 we identified three classes: moderate obesity prevalence (Class 3; 43%); high and rising obesity prevalence (Class 2; 36%); and stable low obesity prevalence (Class 1; 21%). Greater LA deprivation and higher LA proportion of non-white ethnicity increased risk of being in Class 2 (Reception) or Class 2 or 3 (Year 6) compared with Class 1. Conclusions: The prevalence of childhood obesity in LAs in England follow a small number of differing trajectories that are influenced by LA deprivation and ethnic composition. LAs following a stable low obesity trajectory for Year 6 are targets for further investigation. PMID- 30476177 TI - Systemic Insecticide Applications: Effects on Citrus Mealybug (Hemiptera: Pseudococcidae) Populations Under Greenhouse Conditions. AB - The citrus mealybug, Planococcus citri (Risso) (Hemiptera: Pseudococcidae), is a major insect pest of greenhouse-grown horticultural crops. Applications of systemic insecticides as drenches to the growing medium are typically used by greenhouse producers to prevent or suppress citrus mealybug populations. A comprehensive study was conducted that included 11 experimental trials designed to assess the effects of growing medium applications of six systemic insecticides (azadirachtin, dinotefuran, flonicamid, imidacloprid, spirotetramat, and thiamethoxam) in preventing the establishment of and suppressing citrus mealybug populations on different plant species. The experimental trials included four plant species: Solenostemon scutellarioides, Gerbera jamesonii, Begonia * semperflorens-cultorum, and Salvia splendens, with six different cultivars grown in research greenhouses similar to those used in greenhouse production systems. In addition, feeding location (plant stem, leaf top, and leaf bottom) of citrus mealybugs on the various plants was also recorded. Overall, percent citrus mealybug mortality was consistently <50% (n = 255 to 1,598) for any treatment or rate of application; regardless if the systemic insecticides were applied preventatively or curatively. Percent citrus mealybug mortality did reach 78% (n = 36) for thiamethoxam at 8 times the label rate when plants were treated preventatively. Furthermore, none of the treatments prevented development of citrus mealybug F1 individuals to F2 generation egg-laying females on S. scutellarioides or G. jamesonii plants. Citrus mealybugs varied in their spatial distribution on the plant stem, leaf top, and leaf bottom with no noticeable trends. Therefore, based on the results of the study, systemic insecticides are not effective against the citrus mealybug in greenhouse production systems. PMID- 30476178 TI - Commentary: The Promise of Proton Therapy for Central Nervous System Malignancies. PMID- 30476179 TI - Impact of Route of Estrogen Administration on Bone Turnover Markers in Oligoamenorrheic Athletes and its Mediators. AB - Objective: Transdermal, but not oral, estrogen replacement improves bone mineral density (BMD) in athletes with oligo-amenorrhea (OA). Our objective was to determine mechanisms that may explain the impact of route of estrogen administration on bone outcomes. Methods: 73 OA between 14-25 years old received (i) a 17beta-estradiol transdermal patch continuously with cyclic oral micronized progesterone (PATCH), (ii) a combined ethinyl estradiol and desogestrel pill (PILL), or (iii) no estrogen/progesterone (NONE) for 12-months. We evaluated morning fasting levels of a marker of bone formation [N-terminal propeptide of type 1 procollagen (P1NP)], a marker of bone resorption [N-telopeptide (NTX)], insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP3), total testosterone, estradiol, sex hormone-binding globulin (SHBG), sclerostin, preadipocyte factor-1 (Pref-1), brain-derived neurotrophic factor (BDNF), calcium, 25(OH) vitamin D, and parathyroid hormone (PTH) levels at baseline and 12-months. Results: Groups did not differ for age, weight, exercise activity or markers of bone formation at baseline. Over 12 months, P1NP decreased the most in PILL group (p=0.03) associated with a decrease in IGF-1 levels (r=0.37; p=0.003). Sclerostin, Pref-1 and BDNF decreased in the PATCH group over 12 months. PATCH had the greatest increases in estradiol (p=<0.0001), and estradiol increases were associated with increases in bone density. Conclusion: Transdermal 17beta-estradiol given over 12 months does not cause the decrease in IGF-1 observed with oral ethinyl estradiol. It also leads to decreases in sclerostin, Pref-1 and BDNF, which may mediate the beneficial effects of estrogen. PMID- 30476180 TI - Early Clinical Indicators of Addison's Disease in Adults with Type 1 Diabetes: a Nationwide, Observational, Cohort Study. AB - Context: Patients with type 1 diabetes mellitus (T1DM) have an increased risk of Addison's disease (AD) development but prediction of those at risk is not possible. Objective: To determine whether there are early clinical indicators that may denote the development of AD in adults with T1DM. Design: Observational, matched-cohort study. Setting: Patient data from Swedish national registries (National Diabetes Register [NDR], Inpatient Register, Prescription Drug Register). Participants: All T1DM patients diagnosed with concomitant AD (n=66) among the 36,514 adult patients with T1DM in the NDR between 1998-2013. Each case was matched to five controls with T1DM alone (n=330). Main outcome measures: Clinical data and drug prescriptions were assessed prior to baseline (inclusion into the study) and prior to AD diagnosis. Analysis of covariance and estimated group proportions were used for comparisons. Results: Prior to baseline, cases had a higher frequency of thyroid/antithyroid drug prescription than controls (9.1% vs 1.8%). Prior to AD diagnosis, cases had higher frequencies of diabetic retinopathy (12.1% vs 2.1%), infections requiring hospital admission (16.7% vs 2.1%), thyroid/antithyroid drug prescription (28.8% vs 7.0%), and glucagon prescription (18.2% vs 6.4%). There was no difference in glycated hemoglobin between the groups prior to baseline or prior to AD diagnosis. Conclusions: These data suggest that medical treatment for thyroid disease, a severe infection, and glucagon prescription for severe hypoglycemia should raise the suspicion of AD development in adults with T1DM. Development of diabetic retinopathy might also be associated with glucocorticoid deficiency and the development of AD among patients with T1DM. PMID- 30476181 TI - Molecular function and biological importance of CNNM family Mg2+ transporters. AB - Cyclin M (CNNM) family proteins are evolutionarily conserved Mg2+ transporters. They extrude Mg2+ from cells and maintain intracellular Mg2+ levels within the normal range. Moreover, they play an important role in Mg2+ (re)absorption in the intestine and kidney by mediating the directional transport of Mg2+ across epithelial tissue from the tubular lumen to the body inside. Mg2+ efflux is suppressed by the direct binding with phosphatase of regenerating liver (PRL), and the formation of the complex is dynamically regulated by cysteine phosphorylation of PRL. The dysfunction of CNNM family proteins is responsible for inherited hypomagnesemia, as well as various intractable diseases, such as cancer and hypertension. Through multiple functional analyses of CNNM family proteins, the biomedical significance of the proper regulation of Mg2+ levels has been elucidated. PMID- 30476182 TI - Intractable itch in a Brazilian expatriate. PMID- 30476183 TI - Virtual microdissection in the molecular subtyping of head and neck squamous carcinoma - a 'Virtual Reality' of the tumor microenvironment? PMID- 30476184 TI - The association between HIV infection and mitochondrial DNA copy number in peripheral blood: a population-based, prospective cohort study. AB - Background: Low Mitochondrial DNA copy number (mtDNA CN) is a predictor of adverse aging outcomes, and its status may be altered in HIV-infected persons. This study evaluated the cross-sectional and longitudinal change of mtDNA CN by HIV markers. Methods: mtDNA CN was measured in participants of the ALIVE cohort of persons with history of injecting drugs. Multivariate linear regression models controlling for demographics, behavior, and HCV seropositive status assessed the relationship of mtDNA CN to HIV markers (CD4 counts, viral load, ART use). Linear mixed models tested the association between HIV markers and age-related mtDNA CN trajectories. Results: Among 741 individuals at baseline, HIV-infected persons (59%) with lower CD4 counts (p=0.01), higher viral load (p<0.01), and not on ART (p<0.01) had significantly lower mtDNA than uninfected persons; there was no difference between those uninfected and with well-controlled HIV. In longitudinal follow-up (507 participants), mtDNA CN declined significantly faster among HIV infected persons >=50 years than HIV-uninfected persons (-0.03 unit of change/year vs. 0.006 unit of change/year, p=0.04), even among those with well controlled HIV. Conclusion: mtDNA CN is similar between well-controlled HIV infected and uninfected persons before 50, but as they age declines significantly faster among all HIV-infected persons than HIV-uninfected persons. PMID- 30476185 TI - Activation of Haa1 and War1 transcription factors by differential binding of weak acid anions in Saccharomyces cerevisiae. AB - In Saccharomyces cerevisiae, Haa1 and War1 transcription factors are involved in cellular adaptation against hydrophilic weak acids and lipophilic weak acids, respectively. However, it is unclear how these transcription factors are differentially activated depending on the identity of the weak acid. Using a field-effect transistor (FET)-type biosensor based on carbon nanofibers, in the present study we demonstrate that Haa1 and War1 directly bind to various weak acid anions with different affinities. Haa1 is most sensitive to acetate, followed by lactate, whereas War1 is most sensitive to benzoate, followed by sorbate, reflecting their differential activation during weak acid stresses. We show that DNA binding by Haa1 is induced in the presence of acetic acid and that the N-terminal Zn-binding domain is essential for this activity. Acetate binds to the N-terminal 150-residue region, and the transcriptional activation domain is located between amino acid residues 230 and 483. Our data suggest that acetate binding converts an inactive Haa1 to the active form, which is capable of DNA binding and transcriptional activation. PMID- 30476187 TI - Genome size evolution within and between the sexes. AB - Genome sizes are known to vary between closely related species, but the patterns behind this variation have yet to be fully understood. While this variation has been evaluated between species and within sexes, unknown is the extent to which this variation is driven by differentiation in sex-chromosomes. In order to address this longstanding question, we examine the mode and tempo of genome size evolution for a total of 87 species of Drosophilidae, estimating and updating male genome size values for 44 of these species. We compare the evolution of genome size within each sex to the evolution of the differences between the sexes. Utilizing comparative phylogenetic methods, we find that male and female genome size evolution is largely a neutral process, reflective of phylogenetic relatedness between species, which supports the newly proposed accordion model for genome size change. When similarly analyzed, the difference between the sexes due to heteromorphic sex chromosomes is a dynamic process; the male-female genome size difference increases with time with or without known neo-Y events or complete loss of the Y. Observed instances of rapid change match theoretical expectations and known neo-Y and Y loss events in individual species. PMID- 30476186 TI - Implementation of a Pragmatic Biomarker-Driven Algorithm to Guide Antibiotic Use in the Pediatric Intensive Care Unit: the Optimizing Antibiotic Strategies in Sepsis (OASIS) II Study. AB - Background: Biomarkers can facilitate safe antibiotic discontinuation in critically ill patients without bacterial infection. Methods: We tested the ability of a biomarker-based algorithm to reduce excess antibiotic administration in patients with systemic inflammatory response syndrome (SIRS) without bacterial infections (uninfected) in our pediatric intensive care unit (PICU). The algorithm suggested that PICU clinicians stop antibiotics if (1) C-reactive protein <4 mg/dL and procalcitonin <1 ng/mL at SIRS onset and (2) no evidence of bacterial infection by exam/testing by 48 hours. We evaluated excess broad spectrum antibiotic use, defined as administration on days 3-9 after SIRS onset in uninfected children. Incidence rate ratios (IRRs) compared unadjusted excess length of therapy (LOT) in the 34 months before (Period 1) and 12 months after (Period 2) implementation of this algorithm, stratified by biomarker values. Segmented linear regression evaluated excess LOT among all uninfected episodes over time and between the periods. Results: We identified 457 eligible SIRS episodes without bacterial infection, 333 in Period 1 and 124 in Period 2. When both biomarkers were below the algorithm's cut-points (n = 48 Period 1, n = 31 Period 2), unadjusted excess LOT was lower in Period 2 (IRR, 0.53; 95% confidence interval, 0.30-0.93). Among all 457 uninfected episodes, there were no significant differences in LOT (coefficient 0.9, P = .99) between the periods on segmented regression. Conclusions: Implementation of a biomarker-based algorithm did not decrease overall antibiotic exposure among all uninfected patients in our PICU, although exposures were reduced in the subset of SIRS episodes where biomarkers were low. PMID- 30476188 TI - Development of Machine Learning Algorithms for Prediction of 30-Day Mortality After Surgery for Spinal Metastasis. AB - BACKGROUND: Preoperative prognostication of short-term postoperative mortality in patients with spinal metastatic disease can improve shared decision making around end-of-life care. OBJECTIVE: To (1) develop machine learning algorithms for prediction of short-term mortality and (2) deploy these models in an open access web application. METHODS: The American College of Surgeons, National Surgical Quality Improvement Program was used to identify patients that underwent operative intervention for metastatic disease. Four machine learning algorithms were developed, and the algorithm with the best performance across discrimination, calibration, and overall performance was integrated into an open access web application. RESULTS: The 30-d mortality for the 1790 patients undergoing surgery for spinal metastatic disease was 8.49%. Preoperative factors used for prognostication were albumin, functional status, white blood cell count, hematocrit, alkaline phosphatase, spinal location (cervical, thoracic, lumbosacral), and severity of comorbid systemic disease (American Society of Anesthesiologist Class). In this population, machine learning algorithms developed to predict 30-d mortality performed well on discrimination (c statistic), calibration (assessed by calibration slope and intercept), Brier score, and decision analysis. An open access web application was developed for the best performing model and this web application can be found here: https://sorg-apps.shinyapps.io/spinemets/. CONCLUSION: Machine learning algorithms are promising for prediction of postoperative outcomes in spinal oncology and these algorithms can be integrated into clinically useful decision tools. As the volume of data in oncology continues to grow, creation of learning systems and deployment of these systems as accessible tools may significantly enhance prognostication and management. PMID- 30476189 TI - Retrograde BMP signaling activates neuronal gene expression through widespread deployment of a conserved BMP-responsive cis-regulatory activation element. AB - Retrograde Bone Morphogenetic Protein (BMP) signaling in neurons is essential for the differentiation and synaptic function of many neuronal subtypes. BMP signaling regulates these processes via Smad transcription factor activity, yet the scope and nature of Smad-dependent gene regulation in neurons are mostly unknown. Here, we applied a computational approach to predict Smad-binding cis regulatory BMP-Activating Elements (BMP-AEs) in Drosophila, followed by transgenic in vivo reporter analysis to test their neuronal subtype enhancer activity in the larval central nervous system (CNS). We identified 34 BMP-AE containing genomic fragments that are responsive to BMP signaling in neurons, and showed that the embedded BMP-AEs are required for this activity. RNA-seq analysis identified BMP-responsive genes in the CNS and revealed that BMP-AEs selectively enrich near BMP-activated genes. These data suggest that functional BMP-AEs control nearby BMP-activated genes, which we validated experimentally. Finally, we demonstrated that the BMP-AE motif mediates a conserved Smad-responsive function in the Drosophila and vertebrate CNS. Our results provide evidence that BMP signaling controls neuronal function by directly coordinating the expression of a battery of genes through widespread deployment of a conserved Smad responsive cis-regulatory motif. PMID- 30476191 TI - The Promise of Proton Therapy for Central Nervous System Malignancies. AB - Radiation therapy plays a significant role in management of benign and malignant diseases of the central nervous system. Patients may be at risk of acute and late toxicity from radiation therapy due to dose deposition in critical normal structures. In contrast to conventional photon delivery techniques, proton therapy is characterized by Bragg peak dose deposition which results in decreased exit dose beyond the target and greater sparing of normal structure which may reduce the rate of late toxicities from treatment. Dosimetric studies have demonstrated reduced dose to normal structures using proton therapy as compared to photon therapy. In addition, clinical studies are being reported demonstrating safety, feasibility, and low rates of acute toxicity. Technical challenges in proton therapy remain, including full understanding of depth of proton penetration and the biological activity in the distal Bragg peak. In addition, longer clinical follow-up is required to demonstrate reduction in late toxicities as compared to conventional photon-based radiation techniques. In this review, we summarize the current clinical literature and areas of active investigation in proton therapy for adult central nervous system malignancies. PMID- 30476190 TI - T2Candida MR as a predictor of outcome in patients with suspected invasive candidiasis starting empirical antifungal treatment: a prospective pilot study authors' response. PMID- 30476192 TI - LncRNA Meg3 protects endothelial function by regulating the DNA damage response. AB - The role of long non-coding RNAs (lncRNAs) in regulating endothelial function through the DNA damage response (DDR) remains poorly understood. In this study, we demonstrate that lncRNA maternally expressed gene 3 (Meg3) interacts with the RNA binding protein polypyrimidine tract binding protein 3 (PTBP3) to regulate gene expression and endothelial function through p53 signaling ? a major coordinator of apoptosis and cell proliferation triggered by the DDR. Meg3 expression is induced in endothelial cells (ECs) upon p53 activation. Meg3 silencing induces DNA damage, activates p53 signaling, increases the expression of p53 target genes, promotes EC apoptosis, and inhibits EC proliferation. Mechanistically, Meg3 silencing reduces the interaction of p53 with Mdm2, induces p53 expression, and promotes the association of p53 with the promoters of a subset of p53 target genes. PTBP3 silencing recapitulates the effects of Meg3 deficiency on the expression of p53 target genes, EC apoptosis and proliferation. The Meg3-dependent association of PTBP3 with the promoters of p53 target genes suggests that Meg3 and PTBP3 restrain p53 activation. Our studies reveal a novel role of Meg3 and PTBP3 in regulating p53 signaling and endothelial function, which may serve as novel targets for therapies to restore endothelial homeostasis. PMID- 30476193 TI - Assaying RNA structure with LASER-Seq. AB - Chemical probing methods are crucial to our understanding of the structure and function of RNA molecules. The majority of chemical methods used to probe RNA structure report on Watson-Crick pairing, but tertiary structure parameters such as solvent accessibility can provide an additional layer of structural information, particularly in RNA-protein complexes. Herein we report the development of Light Activated Structural Examination of RNA by high-throughput sequencing, or LASER-Seq, for measuring RNA structure in cells with deep sequencing. LASER relies on a light-generated nicotinoyl nitrenium ion to form covalent adducts with the C8 position of adenosine and guanosine. Reactivity is governed by the accessibility of C8 to the light-generated probe. We compare structure probing by RT-stop and mutational profiling (MaP), demonstrating that LASER can be integrated with both platforms for RNA structure analyses. We find that LASER reactivity correlates with solvent accessibility across the entire ribosome, and that LASER can be used to rapidly survey for ligand binding sites in an unbiased fashion. LASER has a particular advantage in this last application, as it readily modifies paired nucleotides, enabling the identification of binding sites and conformational changes in highly structured RNA. PMID- 30476194 TI - Kinetic pathways of topology simplification by Type-II topoisomerases in knotted supercoiled DNA. AB - The topological state of covalently closed, double-stranded DNA is defined by the knot type $K$ and the linking-number difference $?Delta Lk$ relative to unknotted relaxed DNA. DNA topoisomerases are essential enzymes that control the topology of DNA in all cells. In particular, type-II topoisomerases change both $K$ and $?Delta Lk$ by a duplex-strand-passage mechanism and have been shown to simplify the topology of DNA to levels below thermal equilibrium at the expense of ATP hydrolysis. It remains a key question how small enzymes are able to preferentially select strand passages that result in topology simplification in much larger DNA molecules. Using numerical simulations, we consider the non equilibrium dynamics of transitions between topological states $(K,?Delta Lk)$ in DNA induced by type-II topoisomerases. For a biological process that delivers DNA molecules in a given topological state $(K,?Delta Lk)$ at a constant rate we fully characterize the pathways of topology simplification by type-II topoisomerases in terms of stationary probability distributions and probability currents on the network of topological states $(K,?Delta Lk)$. In particular, we observe that type-II topoisomerase activity is significantly enhanced in DNA molecules that maintain a supercoiled state with constant torsional tension. This is relevant for bacterial cells in which torsional tension is maintained by enzyme-dependent homeostatic mechanisms such as DNA-gyrase activity. PMID- 30476195 TI - Combined Microsurgical, Endovascular, and Endoscopic Approach to the Treatment of a Giant Vertebrobasilar Aneurysm. AB - BACKGROUND: Dolichoectasia is defined as elongation and dilatation of a blood vessel. In the intracranial circulation, the basilar artery is affected in 80% of cases. These are challenging lesions with an aggressive natural history, and treatment carries a relatively high rate of morbidity and mortality. We describe a case of multimodal treatment including endovascular, open microsurgical, and endoscopic endonasal approach (EEA) for management. OBJECTIVE: To describe the technical nuance of the addition of the EEA for management of posterior circulation dolichoectasia. METHODS: A 44-yr-old Hispanic woman with a 2-mo history of progressive headaches, gait disturbance, and lower cranial nerve dysfunction presented with acute neurologic decline. MRI demonstrated a dolichoectatic vertebrobasilar system with a giant 4.5-cm fusiform basilar aneurysm. RESULTS: She underwent concomitant endovascular bilateral vertebral artery sacrifice with suction decompression and trapping by clip ligation distal to the lesion. Postoperatively, she developed symptomatic pontine compression. She was then taken for a transclival EEA for intra-aneurysmal thrombectomy. Thereafter, she made a significant functional recovery. CONCLUSION: The addition of endoscopic reconstruction to the treatment of a dolichoectatic basilar aneurysm is an operative nuance that can be employed in treating these highly morbid lesions. This case describing a multimodal treatment paradigm including EEA reconstruction can serve as an example for the future of treatment select cases of dolichoectasia of the vertebrobasilar complex. PMID- 30476196 TI - Mobilization of Pack-CACTA transposons in Arabidopsis suggests the mechanism of gene shuffling. AB - Pack-TYPE transposons are a unique class of potentially mobile non-autonomous elements that can capture, merge and relocate fragments of chromosomal DNA. It has been postulated that their activity accelerates the evolution of host genes. However, this important presumption is based only on the sequences of currently inactive Pack-TYPE transposons and the acquisition of chromosomal DNA has not been recorded in real time. Analysing the DNA copy number variation in hypomethylated Arabidopsis lines, we have now for the first time witnessed the mobilization of novel Pack-TYPE elements related to the CACTA transposon family, over several plant generations. Remarkably, these elements can insert into genes as closely spaced direct repeats and they frequently undergo incomplete excisions, resulting in the deletion of one of the end sequences. These properties suggest a mechanism of efficient acquisition of genic DNA residing between neighbouring Pack-TYPE transposons and its subsequent mobilization. Our work documents crucial steps in the formation of in vivo novel Pack-TYPE transposons, and thus the possible mechanism of gene shuffling mediated by this type of mobile element. PMID- 30476197 TI - As Blind as a Bat? Opsin Phylogenetics Illuminates the Evolution of Color Vision in Bats. AB - Through their unique use of sophisticated laryngeal echolocation bats are considered sensory specialists amongst mammals and represent an excellent model in which to explore sensory perception. While several studies have shown that the evolution of vision is linked to ecological niche adaptation in other mammalian lineages, this has not yet been fully explored in bats. Recent molecular analysis of the opsin genes, which encode the photosensitive pigments underpinning color vision, have implicated high-duty cycle (HDC) echolocation and the adoption of cave roosting habits in the degeneration of colour vision in bats. However, insufficient sampling of relevant taxa has hindered definitive testing of these hypotheses. To address this, novel sequence data was generated for the SWS1 and MWS/LWS opsin genes and combined with existing data to comprehensively sample species representing diverse echolocation types and niches (SWS1 n = 115; MWS/LWS n = 45). A combination of phylogenetic analysis, ancestral state reconstruction and selective pressure analyses were used to reconstruct the evolution of these visual pigments in bats and revealed that while both genes are evolving under purifying selection in bats, MWS/LWS is highly conserved but SWS1 is highly variable. Spectral tuning analyses revealed that MWS/LWS opsin is tuned to a long wavelength, 555 - 560nm in the bat ancestor and the majority of extant taxa. The presence of UV vision in bats is supported by our spectral tuning analysis, but phylogenetic analyses demonstrated that the SWS1 opsin gene has undergone pseudogenization in several lineages. We do not find support for a link between the evolution of HDC echolocation and the pseudogenization of the SWS1 gene in bats, instead we show the SWS1 opsin is functional in the HDC echolocator, Pteronotus parnellii. Pseudogenization of the SWS1 is correlated with cave roosting habits in the majority of pteropodid species. Together these results demonstrate that the loss of UV vision in bats is more widespread in bats than was previously considered and further elucidate the role of ecological niche specialisation in the evolution of vision in bats. PMID- 30476198 TI - Results of a nationwide survey on Japanese clinical practice in breast-conserving radiotherapy for breast cancer. AB - The Breast Cancer Group of the Japanese Radiation Oncology Study Group conducted a nationwide questionnaire survey on the clinical practice of postoperative radiotherapy for breast-conserving treatment for breast cancer. This questionnaire consisted of 18 questions pertaining to the annual number of treated patients, planning method, contouring structure, field design, dose fractionated regimen, application of hypofractionated radiotherapy, boost irradiation, radiotherapy for synchronously bilateral breast cancer, and accelerated partial breast irradiation. The web-based questionnaire had responses from 293 Japanese hospitals. The results indicated the following: treatment planning is performed using relatively similar field designs and delivery methods; the field-in-field technique is used at more than one-third of institutes; the commonest criteria for boost irradiation is based on the surgical margin width (<=5 mm) and the second commonest criteria was age (<=40 or <=50 years), although some facilities applied a different age criterion (>70 years) for omitting a tumor bed boost; for conventional fractionation, almost all institutes delivered 50 Gy in 25 fractions to the conserved whole breast and 10 Gy in 5 fractions to the tumor bed. This survey revealed that 43% of hospitals offered hypofractionated radiotherapy, and the most common regimens were 42.56 Gy in 16 fractions for whole-breast irradiation and 10.64 Gy in 4 fractions for boost irradiation. Almost all of the facilities irradiated both breasts simultaneously for synchronously bilateral breast cancer, and accelerated partial breast irradiation was rarely offered in Japan. This survey provided an overview of the current clinical practice of radiotherapy for breast-conserving treatment of breast cancer in Japan. PMID- 30476199 TI - Prevention of enteric fever in travellers with typhoid conjugate vaccines. PMID- 30476200 TI - A Novel Role for the Klebsiella pneumoniae Sap (Sensitivity to Antimicrobial Peptides) Transporter in Intestinal Cell Interactions, Innate Immune Responses, Liver Abscess, and Virulence. AB - Klebsiella pneumoniae is an important human pathogen causing hospital-acquired and community-acquired infections. Systemic K. pneumoniae infections may be preceded by gastrointestinal colonization, but the basis of this bacterium's interaction with the intestinal epithelium remains unclear. Here, we report that the K. pneumoniae Sap (sensitivity to antimicrobial peptides) transporter contributes to bacterial-host cell interactions and in vivo virulence. Gene deletion showed that sapA is required for the adherence of a K. pneumoniae blood isolate to intestinal epithelial, lung epithelial, urinary bladder epithelial, and liver cells. The DeltasapA mutant was deficient for translocation across intestinal epithelial monolayers, macrophage interactions, and induction of proinflammatory cytokines. In a mouse gastrointestinal infection model, DeltasapA yielded significantly decreased bacterial loads in liver, spleen and intestine, reduced liver abscess generation, and decreased mortality. These findings offer new insights into the pathogenic interaction of K. pneumoniae with the host gastrointestinal tract to cause systemic infection. PMID- 30476201 TI - Long-term live-cell imaging approaches to study lateral root formation in Arabidopsis thaliana. AB - Lateral roots comprise the majority of the branching root system and are important for acquiring nutrients and water from soil in addition to providing anchorage. Lateral roots develop post-embryonically from existing root parts and originate from a subset of specified pericycle cells (lateral root founder cells) located deep inside roots. Small numbers of these specified pericycle cells undergo several rounds of cell division to create a dome-shaped primordium, which eventually organizes a meristem, an essential region for plant growth with active cell division, and emerges from its parental root as a lateral root. Observing cellular and molecular processes for an extended time at various scales are crucial for understanding biological processes during organogenesis. Lateral root formation is an example of the successful application of live-cell imaging approaches to understand various aspects of developmental events in plants, including cell fate determination, cell proliferation, cell-to-cell interaction and cell wall modification. Here I review the recent progress in understanding the molecular mechanisms of lateral root formation and the contribution of live cell imaging approaches. PMID- 30476202 TI - Bidirectional Effects of Sleep and Sedentary Behavior Among Toddlers: A Dynamic Multilevel Modeling Approach. AB - Objective: To examine the bidirectional effects of objectively measured nighttime sleep and sedentary activity among toddlers. Method: Actical accelerometer data were analyzed for 195 toddlers participating in an obesity prevention trial (mean age = 27 months). Toddlers wore the accelerometers for up to 7 consecutive days. Nighttime sleep was defined as the number of minutes asleep between the hours of 8 pm and 8 am the following morning. Sedentary behavior (in minutes) was defined using previously established Actical cut points for toddlers. Variables were lagged and parsed into latent within- and between-person components, using dynamic structural equation modeling (DSEM). Results: Toddlers spent an average of 172 min (~3 hr) in sedentary activity and slept an average of 460 min (~8 hr) per night. An autoregressive cross-lagged multilevel model revealed significant autoregression for both sleep and sedentary activity. Cross-lagged values revealed that decreased sleep predicted increased next-day sedentary activity, and sedentary activity predicted that night's sleep. For 89% of the sample, the within-person standardized cross-lagged effects of sleep on sedentary were larger than the cross-lagged effects of sedentary on sleep. Conclusions: Results suggest that, on average, nighttime sleep is a stronger predictor of subsequent sedentary behavior (compared with the reverse), and this is the case for the majority of toddlers. Findings highlight the importance of interindividual associations between sleep and sedentary activity. The present study is an example of how DSEM methods can be used to ask questions about Granger-causal cross-lagged relations between variables, both within and between individuals. PMID- 30476203 TI - Surgical Resection of a Cavernous Malformation of the Anterior Perforated Substance: 2-Dimensional Operative Video. AB - Cavernous malformations (CMs) are intracranial vascular anomalies of the brain blood vessels which are usually asymptomatic but sometimes may cause headache, seizures, or focal neurologic symptoms.1 The latter may be attributed to either hemorrhage of the lesion or due to associated mass effect.2 Here, we describe the case of a 27-yr-old woman who had an acute onset of headache and occasional left sided peripheral visual disturbances. A brain computed tomography scan revealed intraparenchymal hemorrhage near the right hypothalamus and a brain magnetic resonance imaging (MRI) was consistent with an anterior perforated substance CM. Medical management was pursued but severe headache persisted for several weeks to the point of interfering with normal daily function. Given the evidence of past hemorrhage and the persistence of symptoms, a microsurgical resection was indicated. She was scheduled for an elective resection through a right frontotemporal craniotomy. The lesion was found in the right anterior perforated substance, just above the optic tract and was resected without complications. The patient was neurologically stable at discharge. At 4-mo follow-up, the patient had a significantly decreased intensity of headache and an adequate resection cavity on MRI. Otherwise, she was neurologically intact. Cavernous malformations of deep brain structures, such as the anterior perforated substance can be surgically treated but carry a challenging procedure with a risk of visual deficits. In the following video illustration, we narrate this operative case and highlight the nuances of this approach. Patient consent was obtained for the submission of the video to this journal. PMID- 30476204 TI - Baseline Susceptibility of Brazilian Populations of Chrysodeixis includens (Lepidoptera: Noctuidae) to C. includens Nucleopolyhedrovirus and Diagnostic Concentration for Resistance Monitoring. AB - The Chrysodeixis includens nucleopolyhedrovirus (ChinNPV: Baculoviridae: Alphabaculovirus) is a registered insecticide for the management of soybean looper, Chrysodeixis includens (Walker, [1858]) in Brazil. We conducted studies of baseline susceptibility of Brazilian populations of C. includens to the ChinNPV (Chrysogen, AgBiTech, Fort Worth, TX) as valuable knowledge in support of Integrated Pest Management and Insect Resistance Management programs. In bioassays, neonates were infected with different concentrations of ChinNPV using the droplet feeding bioassay method. Larvae were then transferred to artificial diet and mortality was assessed at 7 d. Results confirm that neonates from Brazilian populations of C. includens are susceptible to ChinNPV. Concentrations from 1.0 * 103 to 1.0 * 108 occlusion bodies (OBs) per ml caused mortality from 1.5 to 99%, respectively. The LC50 ranged from 1.4 * 105 to 7.7 * 105 OBs per ml for populations of C. includens (5.5-fold variation). Similar variation was detected for the LC90 which ranged from 1.6 * 107 to 7.7 * 107 OBs per ml (4.8 fold variation). Importantly, the field-collected populations showed equivalent susceptibility to the reference susceptible population. This indicates a low interpopulation variation in susceptibility of Brazilian populations of C. includens to ChinNPV, representing natural geographic variation and not variation caused by previous selection pressure. The candidate diagnostic concentration of 2.9 * 108 OBs per ml was estimated based on the pooled data and caused mortality ranging from 98.6 to 100%. This concentration will be used in proactive resistance monitoring programs. The Chrysogen will be a valuable tool as a new mode of action in C. includens resistance management in Brazil. PMID- 30476205 TI - The genome of an underwater architect, the caddisfly Stenopsyche tienmushanensis Hwang (Insecta: Trichoptera). AB - Background: Caddisflies (Insecta: Trichoptera) are a highly adapted freshwater group of insects split from a common ancestor with Lepidoptera. They are the most diverse (> 16,000 species) of the strictly aquatic insect orders and are widely employed as bio-indicators in water quality assessment and monitoring. Among the numerous adaptations to aquatic habitats, caddisfly larvae use silk and materials from the environment (stones, sticks, leaf matter and etc.) to build composite structures such as fixed retreats and portable cases. Understanding how caddisflies have adapted to aquatic habitats will help explain the evolution and subsequent diversification of the group. Findings: We sequenced a retreat-builder caddisfly Stenopsyche tienmushanensis Hwang and assembled a high-quality genome from both Illumina and PacBio sequencing. In total, 601.2 M Illumina reads (90.2 Gb), and 16.9 M PacBio subreads (89.0 Gb) were generated. The 451.5 Mb assembled genome has a contig N50 of 1.29 M, a longest contig of 4.76 Mb, and covers 97.65% of the 1,658 insect single-copy genes as assessed by Benchmarking Universal Single-Copy Orthologs (BUSCO). The genome comprises 36.76% repetitive elements. A total of 14,672 predicted protein-coding genes were identified. The genome revealed gene expansions in specific groups of the cytochrome P450 family and olfactory binding proteins, suggesting potential genomic features associated with pollutant tolerance and mate finding. In addition, the complete gene complex of the highly repetitive H-fibroin, the major protein component of caddisfly larval silk, was assembled. Conclusions: We report the draft genome of Stenopsyche tienmushanensis, the highest quality caddisfly genome so far. The genome information will be an important resource for the study of caddisflies, and may shed light on the evolution of aquatic insects. PMID- 30476206 TI - Prostasin impairs epithelial growth factor receptor activation to suppress dengue virus propagation. AB - Background: Dengue virus (DENV), a common and widely spread arbovirus, causes life-threatening diseases, such as dengue hemorrhagic fever or dengue shock syndrome. There is currently no effective therapeutic or preventive treatment for DENV infection. Methods: Next-generation sequencing analysis revealed that prostasin expression was decreased upon DENV infection. Prostasin expression level were confirmed by RT-qPCR in patients with dengue fever and DENV-infected mice model. Short hairpin RNA against EGFR and LY294002 were used to investigate the molecular mechanism. Results: Based on clinical studies, we first found relatively low expression of prostasin, a glycosylphosphatidylinositol (GPI) anchored membrane protease, in blood samples from patients with dengue fever compared with healthy individuals and revealed a high correlation between prostasin expression and DENV-2 RNA copy number. DENV infection significantly decreased prostasin RNA levels in vivo and in vitro models. By contrast, exogenous expression of prostasin could protect ICR suckling mice from life threatening DENV-2 infection. Mechanistic studies showed that inhibition of DENV propagation by prostasin was due to reducing expression of epithelial growth factor receptor, leading to suppression of the Akt/NF-B -mediated cyclooxygenase 2 signaling pathway. Conclusion: Our results demonstrate prostasin expression as a noteworthy clinical feature and a potential therapeutic target against DENV infection. PMID- 30476207 TI - C and N metabolism in barley leaves and peduncles modulates responsiveness to changing CO2. AB - Balancing of leaf carbohydrates is a key process for maximising crop performance in elevated CO2 environments. With the aim of testing the role of the carbon sink source relationship under different CO2 conditions, we performed two experiments with two barley genotypes (Harrington and RCSL-89) exposed to changing CO2. In Experiment 1, the genotypes were exposed to 400 and 700 ppm CO2. Elevated CO2 induced photosynthetic acclimation in Harrington that was linked with the depletion of Rubisco protein. In contrast, a higher peduncle carbohydrate-storage capacity in RSCL-89 was associated with a better balance of leaf carbohydrates that could help to maximize the photosynthetic capacity under elevated CO2. In Experiment 2, plants that were grown at 400 ppm or 700 ppm CO2 for 5 weeks were switched to 700 ppm or 400 ppm CO2, respectively. Raising CO2 to 700 ppm increased photosynthetic rates with a reduction in leaf carbohydrate content and an improvement in N assimilation. The increase in nitrate content was associated with up-regulation of genes of protein transcripts of photosynthesis and N assimilation that favoured plant performance under elevated CO2. Finally, decreasing the CO2 from 700 ppm to 400 ppm revealed that both stomatal closure and inhibited expression of light-harvesting proteins negatively affected photosynthetic performance and plant growth. PMID- 30476208 TI - Visualization and Quantification of Mitochondrial Structure in the Endothelium of Intact Arteries. AB - Aims: To quantify the mitochondrial structure of ECs in intact arteries vs. cultured cells. Methods and Results: Cre-stop mito-Dendra2 mice, expressing the fluorescent protein Dendra2 in the mitochondrial matrix only, were used to label EC mitochondria using Cre-recombinase under the control of the VE-cadherin promoter. Conduit arteries, resistance arterioles and veins were fixed, mounted on glass slides and fluorescent images were obtained using a laser scanning confocal microscope (ex 488 nm; em 550 nm). ImageJ was used to calculate form factor (FF) and aspect ratio (AR) of the mitochondrial segments. Mitochondrial fragmentation count (MFC) was calculated by counting non-contiguous mitochondrial particles and dividing by the number of pixels which comprise the mitochondrial network. Primary aortic EC cultures (48 h on culture plates) were generated to compare the mitochondrial structure of cultured ECs vs. intact arteries. Aortic segments were also exposed to high glucose overnight (33 mM) ex vivo, and separate groups of mice were either infused with a high glucose saline solution (300 mM) via tail vein catheter for one hour or injected with Streptozotocin (STZ; 50 mg/kg) to cause hyperglycemia. Compared to cultured ECs, the mitochondria of ECs from the intact aorta were more fragmented (MFC: 6.4+/-2.5 vs. 18.6+/-9.4, respectively; p < 0.05). The mitochondrial segments of ECs within the aorta were more circular in shape (FF: 3.5+/-0.75 vs. 1.8+/-0.30, respectively; p < 0.05) and had less branching (AR: 2.9+/-0.60 vs. 2.0+/-0.25, respectively; p < 0.05) compared to cultured ECs. Ex vivo exposure of the intact aorta to high glucose overnight caused mitochondrial fission compared to normal glucose conditions (5 mM; MFC: 25.5+/-11.1 high glucose vs. 11.0+/-3.6 normal glucose; p < 0.05). Both one-hour infusion of high glucose saline (MFC: 22.4+/ 4.3) and STZ treatment (MFC: 40.3+/-14.2) caused mitochondrial fission compared to freshly fixed aortas from control mice (MFC: 18.6+/-9.4; p < 0.05 vs. high glucose infusion and STZ treatment). Conclusions: Using a novel mouse model, we were able to, for the first time, obtain high resolution images of EC mitochondrial structure in intact arteries. We reveal the endothelial mitochondrial network is more fragmented in the intact aorta compared to cultured ECs, indicating that mitochondria assume a more elongated and branched phenotype in cell culture. PMID- 30476209 TI - Patient-Physician Discussions on Lung Cancer Screening: A Missed Teachable Moment to Promote Smoking Cessation. AB - Introduction: Little is known about whether patients and physicians perceive lung cancer screening as a teachable moment to promote smoking cessation or the degree to which physicians in 'real world' settings link lung cancer screening discussions with smoking cessation counseling. We sought to characterize patient and physician perspectives of discussions about smoking cessation during lung cancer screening. Methods: We conducted a qualitative study (interviews and focus groups) with 21 physicians and 28 smokers screened in 4 diverse hospitals. Transcripts were analyzed for characteristics of communication about smoking cessation and lung cancer screening, the perceived effect on motivation to quit smoking, the degree to which physicians leverage lung cancer screening as a teachable moment to promote smoking cessation, and suggestions to improve patient physician communication about smoking cessation in the context of lung cancer screening. Results: Patients reported that lung cancer screening made them more cognizant of the health consequences of smoking, priming them for a teachable moment. While physicians and patients both acknowledged that smoking cessation counseling was frequent, they described little connection between their discussions regarding lung cancer screening and smoking cessation counseling. Physicians identified several barriers to integrating discussions on smoking cessation and lung cancer screening. They volunteered communication strategies by which lung cancer screening could be leveraged to promote smoking cessation. Conclusions: Lung cancer screening highlights the harms of smoking to patients who are chronic, heavy smokers and thus may serve as a teachable moment for promoting smoking cessation. However, this opportunity is typically missed in clinical practice. Implications: Lung cancer screening highlights the harms of smoking to heavily addicted smokers. Yet both physicians and patients reported little connection between lung cancer screening and tobacco treatment discussions due to multiple barriers. On-site tobacco treatment programs and post-screening messaging tailored to the lung cancer screening results is needed to maximize the health outcomes of lung cancer screening, including smoking quit rates and longer term smoking-related morbidity and mortality. PMID- 30476210 TI - Investigating the sequence-dependent mechanical properties of DNA nicks for applications in twisted DNA nanostructure design. AB - DNA nick can be used as a design motif in programming the shape and reconfigurable deformation of synthetic DNA nanostructures, but its mechanical properties have rarely been systematically characterized at the level of base sequences. Here, we investigated sequence-dependent mechanical properties of DNA nicks through molecular dynamics simulation for a comprehensive set of distinct DNA oligomers constructed using all possible base-pair steps with and without a nick. We found that torsional rigidity was reduced by 28-82% at the nick depending on its sequence and location although bending and stretching rigidities remained similar to those of regular base-pair steps. No significant effect of a nick on mechanically coupled deformation such as the twist-stretch coupling was observed. These results suggest that the primary structural role of nick is the relaxation of torsional constraint by backbones known to be responsible for relatively high torsional rigidity of DNA. Moreover, we experimentally demonstrated the usefulness of quantified nick properties in self-assembling DNA nanostructure design by constructing twisted DNA origami structures to show that sequence design of nicks successfully controls the twist angle of structures. Our study illustrates the importance as well as the opportunities of considering sequence-dependent properties in structural DNA nanotechnology. PMID- 30476211 TI - Void Entry by Aedes aegypti (Diptera: Culicidae) Mosquitoes Is Lower Than Would Be Expected by a Randomized Search. AB - Insects enter every passible space on the planet. Despite our best efforts, flying insects infiltrate slightly open windows in domiciles, automobiles, storage spaces, and more. Is this ubiquitous experience a consequence of insect abundance and probability, or are flying insects adept at detecting passageways? There remains a lack of understanding of insect effectiveness in finding passage through the voids and imperfections in physical barriers in response to attractants, a topic particularly critical to the area of insect-borne disease control. In this study, we recorded the passage of Aedes aegytpi mosquitoes through voids in vertically oriented bed net fabrics within a cylindrical flight arena. We model the probability mosquitoes will discover and navigate the void in response to a physical attractant by observing their search behavior and quantifying the region within a void that is physically navigable, constrained by body size. Void passage rates were lower than that would be expected by purely randomized search behaviors and decline rapidly as the void diameter approaches the in-flight width of the insect. PMID- 30476212 TI - Perceptions of rabies risk: a survey of travellers and travel clinics from Canada, Germany, Sweden and the UK. AB - Background: Extensive global experience shows that rabies pre-exposure prophylaxis (PrEP) through vaccination is effective and well tolerated, yet many travellers opt not to be vaccinated when travelling to rabies-endemic countries. Previous research has identified several factors influencing the choices travellers make to reduce the risk of rabies, including cost, time constraint and perspective on the importance of vaccination. The objectives of this study were to assess travellers' awareness of rabies and advice-seeking attitudes and to evaluate travel clinics practices regarding rabies pre-travel advice. Methods: We surveyed individuals aged 18-65 years residing in the UK, Germany, Canada and Sweden who had travelled to rabies-endemic countries between 2013 and 2016 and defined this as the rabies visit-risk sample. The first 850 respondents from the visit-risk sample who had undertaken pre-defined at-risk activities (e.g. contact with animals during the trip) completed an additional 15-min online questionnaire and were included in the activity-risk subsample. We also interviewed travel clinic personnel using a 25-min online or phone questionnaire. Results: The visit risk sample included 4678 individuals. Many sought pre-travel health information online (33%) or talked to a family doctor (24%). Within the activity-risk subsample, 83% of travellers were aware of at least a few basic facts about rabies, and 84% could identify at least one correct rabies prevention measure; 49% were aware of a rabies vaccine, however, only 8% reported receiving PrEP vaccination within the past 3 years. Among 180 travel clinic respondents, 21% reported recommending PrEP against rabies to all travellers to rabies-endemic countries. Travel clinics estimated that 81% of travellers complete their travel vaccination schedules and reported sending reminders by e-mails (38%), text (38%), phone calls (37%) or by using vaccination cards (37%). Conclusions: These findings suggest that although travellers had frequently heard of rabies, awareness of the risks of this serious infectious disease was relatively low. PMID- 30476214 TI - Opioid Prescribing Patterns by Naturopathic Physicians in Oregon. PMID- 30476215 TI - Commentary: Extent of Resection and Residual Tumor Thresholds for Postoperative Total Seizure Freedom in Epileptic Adult Patients Harboring a Supratentorial Diffuse Low-Grade Glioma. PMID- 30476216 TI - Assessing the Technical Effectiveness and Economic Feasibility of Pest Management Through Structural Heat Treatment: An Entomological and Economic Analysis in Four Mills in Sicily (Italy). AB - Heat treatments (HTs) for pest control represent a promising, fast, and non chemical method to disinfest commodities and structures with a significantly reduced environmental impact compared with the chemical approach. An entomological and economic study has been conducted to determine the technical efficacy and economic feasibility of HT in mills that produce flour and semolina in Sicily (Italy) where, for the first time, this technique has been applied. The results obtained from the entomological analysis demonstrated that this method provided a satisfactory level of control of the following insect species: Sitophilus oryzae (L.) (Coleoptera: Curculionidae), Rhyzopertha dominica (F.) (Coleoptera: Bostrichidae), Tribolium confusum (Jacquelin du Val) (Coleoptera: Tenebrionidae), Stegobium paniceum (L.) (Coleoptera: Anobiidae), and Ephestia kuehniella (Zeller) (Lepidoptera: Pyralidae). Moreover, using precautionary assumptions in terms of revenue and cost changes resulting from the adoption of HT, the economic analysis showed a good performance of the economic indices making this technique economically feasible for the mills. Overall, the results of this study demonstrate the technical and economic feasibility of HTs which ensure to Sicilian mills a reduction of environmental impact of production process and the subsequent increase of the competitive position in the agri-food markets of the processed products. PMID- 30476217 TI - Effects of a dietary synbiotic inclusion on bone health in broilers subjected to cyclic heat stress episodes. AB - The objective of this study was to determine the effects of a dietary synbiotic inclusion on broiler bone health under daily cyclic heat stress. A total of 360 Ross 708 broilers were randomly assigned to 1 of 3 dietary treatments (8 replicates per treatment): a regular diet (control) and the regular diet mixed with a commercial synbiotic product at 0.5 (0.5X) or 1.0 (1.0X) g/kg. The synbiotic contains a prebiotic (fructooligosaccharides) and a probiotic mixture of 4 microbial strains (Enterococcus faecium, Pediococcus acidilactici, Bifidobacterium animalis, and Lactobacillus reuteri). Room temperature was gradually decreased from 34 degrees C on d 1 by 0.5 degrees C/d for the first 14 d; then a cyclic heat stress episode (32 degrees C/9 h/d) was applied from d 15 to 42. Gait score assessment and the latency-to-lie test were conducted when broilers were 40 and 41 d of age, respectively. The tibia, femur, and humerus were collected for measuring bone parameters at 42 d of age. The data indicated that bone mineral density, bone mineral content, and bone area were higher and the level of gait score was lower in the 1.0X group (P = 0.05) but not in the 0.5X group (P > 0.05) compared to controls. The proportions of broilers showing signs of lameness were ranked 1.0X group (25%) < 0.5X group (45%) < control (54%). Compared to controls, broilers of 0.5X group stood longer (P = 0.03) during the latency-to-lie test. In conclusion, under the present conditions the synbiotic profoundly improves multiple indices of leg health of broilers subjected to the cyclic heat episodes, resulting in an improvement in walking ability. PMID- 30476213 TI - Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources. AB - The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO's interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes. PMID- 30476218 TI - Mesenchymal Stem Cell-Seeded High-Density Collagen Gel for Annular Repair: 6-Week Results From In Vivo Sheep Models. AB - BACKGROUND: Our group has previously demonstrated in vivo annulus fibrosus repair in animal models using an acellular, riboflavin crosslinked, high-density collagen (HDC) gel. OBJECTIVE: To assess if seeding allogenic mesenchymal stem cells (MSCs) into this gel yields improved histological and radiographic benefits in an in vivo sheep model of annular injury. METHODS: Fifteen lumbar intervertebral discs (IVDs) were randomized into 4 groups: intact, injury only, injury + acellular gel treatment, or injury + MSC-seeded gel treatment. Sheep were sacrificed at 6 wk. Disc height index (DHI), Pfirrmann grade, nucleus pulposus area, and T2 relaxation time (T2-RT) were calculated for each IVD and standardized to healthy controls from the same sheep. Quantitative histological assessment was also performed using the Han scoring system. RESULTS: All treated IVDs retained gel plugs on gross assessment and there were no adverse perioperative complications. The MSC-seeded gel treatment group demonstrated statistically significant improvement over other experimental groups in DHI (P = .002), Pfirrmann grade (P < .001), and T2-RT (P = .015). There was a trend for greater Han scores in the MSC-seeded gel-treated discs compared with injury only and acellular gel-treated IVDs (P = .246). CONCLUSION: MSC-seeded HDC gel can be delivered into injured IVDs and maintained safely in live sheep to 6 wk. Compared with no treatment and acellular HDC gel, our data show that MSC-seeded HDC gel improves outcomes in DHI, Pfirrmann grade, and T2-RT. Histological analysis shows improved annulus fibrosus and nucleus pulposus reconstitution and organization over other experimental groups as well. PMID- 30476219 TI - Probabilistic Tractography to Predict the Position of Cranial Nerves Displaced by Skull Base Tumors: Value for Surgical Strategy Through a Case Series of 62 Patients. AB - BACKGROUND: Predicting the displacement of cranial nerves by tumors could make surgery safer and the outcome better. Recent advances in imaging and processing have overcome some of the limits associated with cranial nerve tractography, such as spatial resolution and fiber crossing. Among others, probabilistic algorithms yield to a more accurate depiction of cranial nerve trajectories. OBJECTIVE: To report how cranial nerve probabilistic tractography can help the surgical strategy in a series of various skull base tumors. METHODS: After distortion correction and region of interest seeding, a probabilistic tractography algorithm used the constrained spherical deconvolution model and attempted the reconstruction of cranial nerve trajectories in both healthy and displaced conditions. RESULTS: Sixty-two patients were included and presented: vestibular schwannomas (n = 33); cerebellopontine angle meningiomas (n = 15); arachnoid or epidermoid cysts (n = 6); cavernous sinus and lower nerves schwannomas (n = 4); and other tumors (n = 4). For each patient, at least one 'displaced' cranial nerve was not clearly identified on classical anatomical MRI images. All 372 cranial nerves were successfully tracked on each healthy side; among the 175 cranial nerves considered 'displaced' by tumors, 152 (87%) were successfully tracked. Among the 127 displaced nerves of operated patients (n = 51), their position was confirmed intraoperatively for 118 (93%) of them. Conditions that led to tractography failure were detailed. On the basis of tractography, the surgical strategy was adjusted for 44 patients (71%). CONCLUSION: This study reports a cranial nerve probabilistic tractography pipeline that can: predict the position of most cranial nerves displaced by skull base tumors, help the surgical strategy, and thus be a pertinent tool for future routine clinical application. PMID- 30476221 TI - Commentary: Treatment Strategy of a Patient With a Brain Arteriovenous Malformation and Cranial Dural Fistula. PMID- 30476220 TI - Cardiovascular risk assessments at occupational health services: employee experiences. AB - Background: Across England in the UK, population screening for cardiovascular disease (CVD) primarily takes place within general practice in the form of the National Health Service Health Check. Additional screening sites such as occupational health are advocated to improve the population impact. Aims: To investigate participant experiences with cardiovascular and type 2 diabetes risk assessment (RA) at occupational health and subsequent support-seeking at general practice. Methods: Face-to-face interviews were conducted for this qualitative study. Participants were recruited at three workplaces; a steel works and two hospital sites. Using interpretive phenomenological analyses, themes were drawn from salient narratives and categorically organized. Results: There were 29 participants. Themes (n = 16) were organized into two domains; factors that facilitated (n = 9) or thwarted (n = 7) participant engagement with the RA and general practice. All participants described the RA as worthwhile and strongly valued RA at occupational health. Those with obesity and high CVD risk highlighted their difficulties in making lifestyle changes. Participants reported confusion and anxiety when GP advice about medication appeared to contradict what participants had interpreted during RA at occupational health. Conclusions: This study highlights factors that facilitate or thwart engagement in cardiovascular RA at occupational health services and general practice follow-up. Stakeholders can integrate these factors into standard operating procedures to enhance participant engagement and enable safeguards that minimize potential harm to participants. PMID- 30476222 TI - Ribosomal ambiguity (ram) mutations promote the open (off) to closed (on) transition and thereby increase miscoding. AB - Decoding is thought to be governed by a conformational transition in the ribosome open (off) to closed (on)-that occurs upon codon-anticodon pairing in the A site. Ribosomal ambiguity (ram) mutations increase miscoding and map to disparate regions, consistent with a role for ribosome dynamics in decoding, yet precisely how these mutations act has been unclear. Here, we solved crystal structures of 70S ribosomes harboring 16S ram mutations G299A and G347U in the absence A-site tRNA (A-tRNA) and in the presence of a near-cognate anticodon stem-loop (ASL). In the absence of an A-tRNA, each of the mutant ribosomes exhibits a partially closed (on) state. In the 70S-G347U structure, the 30S shoulder is rotated inward and intersubunit bridge B8 is disrupted. In the 70S-G299A structure, the 30S shoulder is rotated inward and decoding nucleotide G530 flips into the anti conformation. Both of these mutant ribosomes adopt the fully closed (on) conformation in the presence of near-cognate A-tRNA, just as they do with cognate A-tRNA. Thus, these ram mutations act by promoting the open (off) to closed (on) transition, albeit in somewhat distinct ways. This work reveals the functional importance of 30S shoulder rotation for productive aminoacylated-tRNA incorporation. PMID- 30476223 TI - Assessing the prevalence and economic significance of coccidiosis individually and in combination with concurrent infections in Pakistani commercial poultry farms. AB - Coccidiosis is one of the most economically important diseases of the poultry, around the globe. In order to assess seasonal and age-wise prevalence of coccidiosis individually and with concurrent infections, this study was conducted on commercial poultry farms in and around Multan division, province of Punjab, Pakistan. A total of 28,126 boilers, 4,052 layers and 7,699 golden bird samples, provided by regional farmers and consultants, were examined by microscopy for the diagnosis of coccidiosis. Based on postmortem lesions, several infections including coccidiosis, viral, and miscellaneous diseases were catalogued, whereas samples were cultured to identify concurrent bacterial diseases. Cumulative analysis of this large set of samples revealed a prevalence of 14.16, 11.01, and 19.57% in broiler, layer and golden birds, respectively. Ascaridia galli (A. galli) showed a higher prevalence in layer (2.47%) compared to golden (0.21%) birds (P < 0.01). Amongst all concurrent infections investigated, bacterial infections were identified in highest percentage of samples (59.24%; P < 0.05). The age-wise and season-wise prevalence of coccidiosis and A. galli was found to be significant (P < 0.05). During the study period, an estimated of 10.69 (coccidiosis) and 0.29 (A. galli) million poultry birds were treated or provided prophylaxis and supportive therapy at Pakistani commercial poultry farms. Depending upon the prevailing market conditions, the total economic losses (treatment, prophylaxis, and supportive therapy) from coccidiosis and A. galli were estimated to be US $45,405.00 and 2,638.50, respectively, while production (weight and eggs) losses for broiler (US$ 2,750,779.00), layer and golden, young (US$ 13,974.98 and 50,228.76) and adult (US$ 104.74 and 203.77) were estimated. Unit loss of coccidiosis with concurrent diseases and intestinal worm was estimated to be US$ 0.005 and 0.01, respectively. These results highlight the potential impact of coccidiosis individually and with concurrent infections on the poultry productivity and will inform farmers, policy makers, and other governmental and non-governmental stakeholders on the use of control and management measures in containing these infections. PMID- 30476225 TI - The Prognostic Significance of a Cast Fourth Ventricle in Ruptured Aneurysm Patients With Intraventricular Hemorrhage in the Barrow Ruptured Aneurysm Trial (BRAT). AB - BACKGROUND: Ruptured aneurysms causing intraventricular hemorrhage (IVH) are associated with high morbidity. The presence of blood that completely fills the fourth ventricle (cast fourth ventricle, CFV) is thought to be particularly ominous, but studies documenting the outcome of such cases are lacking. OBJECTIVE: To investigate the outcomes of patients with aneurysmal subarachnoid hemorrhage (aSAH) and CFV. METHODS: We reviewed 406 patients enrolled in the Barrow Ruptured Aneurysm Trial (BRAT, NCT01593267, clinicaltrials.gov); 238 patients with aSAH and IVH were identified, and imaging was reviewed for the presence of CFV. Outcome was evaluated at the 1-yr follow-up. A poor outcome was defined as modified Rankin Scale score >2. RESULTS: CFV was identified in 25 patients. Admission Glasgow Coma Score was lower in CFV patients, 7.8 versus 11.5 (P < .001). At discharge and the 1-yr follow-up, patients with CFV had a greater risk of a poor outcome (P < .001 and P = .002, respectively). In a subgroup analysis of 79 patients with IVH and initial Glasgow Coma Score <= 8, almost 50% of the patients with IVH but without CFV had made a good recovery versus 7% of patients with CFV (odds ratio [OR] 15, P = .002). On multivariate analysis, CFV was a greater predictor of a poor prognosis at 1 yr post-aSAH than Hunt and Hess grade >3 (6.4 OR vs 2.9 OR [P < .001], respectively). CONCLUSION: The presence of CFV is a predictor of poor outcome in patients with aSAH. When compared to other patients with IVH and aSAH, CFV is a stronger predictor of a poor outcome than a poor Hunt and Hess Grade. PMID- 30476226 TI - A Large Database Analysis of Rates of Aneurysm Screening, Elective Treatment, and Subarachnoid Hemorrhage in Patients With Polycystic Kidney Disease. AB - BACKGROUND: Professional societies provide conflicting guidelines on aneurysm screening in patients with polycystic kidney disease (PKD), and the rate of subarachnoid hemorrhage (SAH) is poorly understood. OBJECTIVE: To evaluate screening, elective treatment, and the rate of SAH in patients with known PKD. METHODS: We examined longitudinally linked claims data from a large private insurer, identifying screening, elective treatment, aneurysmal subarachnoid hemorrhage (aSAH) and secured aneurysmal SAH (saSAH) in 2004 to 2014 amongst patients with known PKD. RESULTS: We identified 20 704 patients diagnosed with PKD. Among patients with an initial PKD diagnosis, 51/446 (15.9%) underwent angiographic screening within 2 yr. Forty aneurysms were treated electively in 48 868 yr at risk in PKD patients (82/100K patient yr, 95% confidence interval [CI] 60-112) vs 24 elective treatments in 349 861 yr at risk in age- and sex-matched controls (7/100K patient yr, 95% CI 5-10, P < .0001). Eleven admissions for aSAH were identified in PKD patients (23/100K patient yr, 95% CI 13-41) and 22 admissions for aSAH in controls (6/100K patient yr, 95% CI 4-10), giving an incidence rate ratio (IRR) of 3.6 (95% CI 1.7-7.4, P < .0001) and a comorbidity adjusted IRR of 3.1 (95% CI 1.4-6.9). The incidence of saSAH was proportionally even higher in PKD patients than controls, 16 vs 2/100K patient years, IRR 9.5 (95% CI 3.3-27.5, P < .0001). CONCLUSION: Screening in PKD is performed only selectively, though resulting rates of elective treatment were over 10* those of controls. Despite screening and treatment, the rate of SAH remains significantly elevated over that of controls. PMID- 30476224 TI - Drugs linked to plasma homoarginine in chronic kidney disease patients-a cross sectional analysis of the German Chronic Kidney Disease cohort. AB - Background: Elevated plasma concentrations of symmetric and asymmetric dimethylarginine (SDMA and ADMA, respectively) and a lower plasma concentration of the structurally related homoarginine are commonly observed in patients with chronic kidney disease (CKD) and independently predict total mortality as well as progression of renal disease. We aimed to identify drugs that may alter this adverse metabolite pattern in a favourable fashion. Methods: Plasma ADMA, SDMA, homoarginine and l-arginine were determined by liquid chromatography-tandem mass spectrometry in 4756 CKD patients ages 18-74 years with an estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m2 or an eGFR >60 mL/min/1.73 m2 and overt proteinuria who were enrolled in the German Chronic Kidney Disease (GCKD) study. Associations between laboratory, clinical and medication data were assessed. Results: Intake of several commonly used drugs was independently associated with plasma concentrations of homoarginine and/or related metabolites. Among these, the peroxisome proliferator-activated receptor alpha (PPAR-alpha) agonist fenofibrate was associated with the most profound differences in ADMA, SDMA and homoarginine plasma concentrations: 66 patients taking fenofibrate had a multivariable adjusted odds ratio (OR) of 5.83 [95% confidence interval (CI) 2.82 12.03, P < 0.001] to have a plasma homoarginine concentration above the median. The median homoarginine plasma concentration in patients taking fenofibrate was 2.30 umol/L versus 1.55 in patients not taking the drug (P < 0.001). In addition, fibrates were significantly associated with lower plasma SDMA and higher l arginine concentrations. In contrast, glucocorticoids were associated with lower plasma homoarginine, with adjusted ORs of 0.52 (95% CI 0.40-0.67, P < 0.001) and 0.53 (95% CI 0.31-0.90, P = 0.018) for prednisolone and methylprednisolone, respectively. Conclusions: In a large cohort of CKD patients, intake of fenofibrate and glucocorticoids were independently associated with higher and lower plasma homoarginine concentrations, respectively. Effects on plasma homoarginine and methylarginines warrant further investigation as potential mechanisms mediating beneficial or adverse drug effects. PMID- 30476227 TI - The BioGRID interaction database: 2019 update. AB - The Biological General Repository for Interaction Datasets (BioGRID: https://thebiogrid.org) is an open access database dedicated to the curation and archival storage of protein, genetic and chemical interactions for all major model organism species and humans. As of September 2018 (build 3.4.164), BioGRID contains records for 1 598 688 biological interactions manually annotated from 55 809 publications for 71 species, as classified by an updated set of controlled vocabularies for experimental detection methods. BioGRID also houses records for >700 000 post-translational modification sites. BioGRID now captures chemical interaction data, including chemical-protein interactions for human drug targets drawn from the DrugBank database and manually curated bioactive compounds reported in the literature. A new dedicated aspect of BioGRID annotates genome wide CRISPR/Cas9-based screens that report gene-phenotype and gene-gene relationships. An extension of the BioGRID resource called the Open Repository for CRISPR Screens (ORCS) database (https://orcs.thebiogrid.org) currently contains over 500 genome-wide screens carried out in human or mouse cell lines. All data in BioGRID is made freely available without restriction, is directly downloadable in standard formats and can be readily incorporated into existing applications via our web service platforms. BioGRID data are also freely distributed through partner model organism databases and meta-databases. PMID- 30476228 TI - Low-Level Laser Therapy and Electrotherapy for Neck Pain: "Clinical Practice Guideline for Physical Therapy Assessment and Treatment in Patients With Nonspecific Neck Pain," Bier JD, Scholten-Peeters WGM, Staal JB, et al. Phys Ther. 2018;98:162-171. PMID- 30476229 TI - ENPD - A Database of Eukaryotic Nucleic Acid Binding Proteins: Linking Gene Regulations to Proteins. AB - Eukaryotic nucleic acid binding protein database (ENPD, http://qinlab.sls.cuhk.edu.hk/ENPD/) is a library of nucleic acid binding proteins (NBPs) and their functional information. NBPs such as DNA binding proteins (DBPs), RNA binding proteins (RBPs), and DNA and RNA binding proteins (DRBPs) are involved in every stage of gene regulation through their interactions with DNA and RNA. Due to the importance of NBPs, the database was constructed based on manual curation and a newly developed pipeline utilizing both sequenced transcriptomes and genomes. In total the database has recorded 2.8 million of NBPs and their binding motifs from 662 NBP families and 2423 species, constituting the largest NBP database. ENPD covers evolutionarily important lineages which have never been included in the previous NBP databases, while lineage-specific NBP family expansions were also found. ENPD also focuses on the involvements of DBPs, RBPs and DRBPs in non-coding RNA (ncRNA) mediated gene regulation. The predicted and experimentally validated targets of NBPs have both been recorded and manually curated in ENPD, linking the interactions between ncRNAs, DNA regulatory elements and NBPs in gene regulation. This database provides key resources for the scientific community, laying a solid foundation for future gene regulatory studies from both functional and evolutionary perspectives. PMID- 30476230 TI - Expression of the DNA-dependent protein kinase catalytic subunit is associated with the radiosensitivity of human thyroid cancer cell lines. AB - The prognosis and treatment of thyroid cancer depends on the type and stage of the disease. Radiosensitivity differs among cancer cells owing to their varying capacity for repair after irradiation. Radioactive iodine can be used to destroy thyroid cancer cells. However, patient prognosis and improvement after irradiation varies. Therefore, predictive measures are important for avoiding unnecessary exposure to radiation. We describe a new method for predicting the effects of radiation in individual cases of thyroid cancer based on the DNA dependent protein kinase (DNA-PK) activity level in cancer cells. The radiation sensitivity, DNA-PK activity, and cellular levels of DNA-PK complex subunits in five human thyroid cancer cell lines were analyzed in vitro. A positive correlation was observed between the D10 value (radiation dose that led to 10% survival) of cells and DNA-PK activity. This correlation was not observed after treatment with NU7441, a DNA-PK-specific inhibitor. A significant correlation was also observed between DNA-PK activity and expression levels of the DNA-PK catalytic subunit (DNA-PKcs). Cells expressing low DNA-PKcs levels were radiation sensitive, and cells expressing high DNA-PKcs levels were radiation-resistant. Our results indicate that radiosensitivity depends on the expression level of DNA PKcs in thyroid cancer cell lines. Thus, the DNA-PKcs expression level is a potential predictive marker of the success of radiation therapy for thyroid tumors. PMID- 30476231 TI - Antibiotics for Travelers' Diarrhea on Trial - is there a potential role for Rifamycin-SV? PMID- 30476232 TI - Potential Zika virus spread within and beyond India. PMID- 30476234 TI - Thymus machinery for T-cell selection. AB - An immunocompetent and self-tolerant pool of naive T cells is formed in the thymus through the process of repertoire selection. T cells that are potentially capable of responding to foreign antigens are positively selected in the thymic cortex and are further selected in the thymic medulla to help prevent self reactivity. The affinity between T-cell antigen-receptors (TCRs) expressed by newly generated T cells and self-peptide-MHC complexes displayed in the thymic microenvironments plays a key role in determining the fate of developing T cells during thymic selection. Recent advances in our knowledge of the biology of thymic epithelial cells have revealed unique machinery that contributes to positive and negative selection in the thymus. In this article, we summarize recent findings on thymic T-cell selection, focusing on the machinery unique to thymic epithelial cells. PMID- 30476233 TI - Twenty-Five Years of Intracranial Pressure Monitoring After Severe Traumatic Brain Injury: A Retrospective, Single-Center Analysis. AB - BACKGROUND: Intracranial pressure (ICP) is a clinically important variable after severe traumatic brain injury (TBI) and has been monitored, along with clinical outcome, for over 25 yr in Addenbrooke's hospital, Cambridge, United Kingdom. This time period has also seen changes in management strategies with the implementation of protocolled specialist neurocritical care, expansion of neuromonitoring techniques, and adjustments of clinical treatment targets. OBJECTIVE: To describe the changes in intracranial monitoring variables over the past 25 yr. METHODS: Data from 1146 TBI patients requiring ICP monitoring were analyzed. Monitored variables included ICP, cerebral perfusion pressure (CPP), and the cerebral pressure reactivity index (PRx). Data were stratified into 5-yr epochs spanning the 25 yr from 1992 to 2017. RESULTS: CPP increased sharply with specialist neurocritical care management (P < 0.0001) (introduction of a specific TBI management algorithm) before stabilizing from 2000 onwards. ICP decreased significantly over the 25 yr of monitoring from an average of 19 to 12 mmHg (P < 0.0001) but PRx remained unchanged. The mean number of ICP plateau waves and the number of patients developing refractory intracranial hypertension both decreased significantly. Mortality did not significantly change in the cohort (22%). CONCLUSION: We demonstrate the evolving trends in neurophysiological monitoring over the past 25 yr from a single, academic neurocritical care unit. ICP and CPP were responsive to the introduction of an ICP/CPP protocol while PRx has remained unchanged. PMID- 30476235 TI - Effect of Spinal Cord Stimulation on Early Disability Pension in 198 Failed Back Surgery Syndrome Patients: Case-Control Study. AB - BACKGROUND: Spinal cord stimulation (SCS) has proven to be a cost-effective treatment for failed back surgery syndrome (FBSS). However, the effect on patients' working capability remains unclear. OBJECTIVE: To evaluate the impact of SCS on working capability and to identify the factors behind permanent disability in FBSS patients. METHODS: The study group consisted of 198 working age patients with SCS trialed or implanted for FBSS in a single center between 1996 and 2014. For each patient, 3 living controls, matched by age, gender, and birthplace, were otherwise randomly selected by the Population Register Center. The data on working ability were obtained from the Social Insurance Institution. Patients were divided into 3 groups: SCS trial only, SCS implanted permanently, and SCS implanted but later explanted. RESULTS: A rehabilitation subsidy was given to 68 patients and 8 controls for a mean of 5.2 (95% confidence interval [CI] 2.4-8.2) and 0.2 (95% CI 0.05-0.6) days per month (P < .05). At the end of follow-up, 16 (37%), 13 (33%), 25 (22%), and 27 (5%) subjects were on disability pension (DP) in the SCS trial, SCS explanted, SCS permanent, and control groups. Patients in the SCS trial-only group were significantly more often on DP than were patients with permanent SCS (odds ratio 2.6; 95% CI 1.2-5.9; P = .02). CONCLUSION: Permanent SCS usage was associated with reduced sick leave and DP. Prospective study will be required to assess possible predictive value. PMID- 30476236 TI - Implementation of Ask-Advise-Connect in a safety net healthcare system: quitline treatment engagement and smoking cessation outcomes. AB - Ask-Advise-Connect (AAC) was designed to link smokers in primary care settings with evidence-based tobacco treatment delivered via state quitlines. AAC involves training medical staff to Ask about smoking status, Advise smokers to quit, and offer to immediately Connect smokers with quitlines through an automated link within the electronic health record. We evaluated the efficacy of AAC in facilitating treatment engagement and smoking abstinence in a 34 month implementation trial conducted in a large, safety-net health care system. AAC was implemented from April 2013 through February 2016 in 13 community clinics that provided care to low-income, predominantly racial/ethnic minority smokers. Licensed vocational nurses were trained to implement AAC as part of standard care. Outcomes included (a) treatment engagement (i.e., proportion of identified smokers that enrolled in treatment) and (b) self-reported and biochemically confirmed abstinence at 6 months. Smoking status was recorded for 218,915 unique patients, and 40,888 reported current smoking. The proportion of all identified smokers who enrolled in treatment was 11.8%. Self-reported abstinence at 6 months was 16.6%, and biochemically confirmed abstinence was 4.5%. AAC was successfully implemented as part of standard care. Treatment engagement was high compared with rates of engagement for more traditional referral-based approaches reported in the literature. Although self-reported abstinence was in line with other quitline delivered treatment studies, biochemically confirmed abstinence, which is not routinely captured in quitline studies, was dramatically lower. This discrepancy challenges the adequacy of self-report for large, population-based studies. A more detailed and comprehensive investigation is warranted. PMID- 30476237 TI - Integrative cross-platform analyses identify enhanced heterotrophy as a metabolic hallmark in glioblastoma. AB - Background: Although considerable progress has been made in understanding molecular alterations driving gliomagenesis, the diverse metabolic programs contributing towards the aggressive phenotype of glioblastoma remain unclear. The aim of this study was to define and provide molecular context to metabolic reprogramming driving gliomagenesis. Methods: Integrative cross-platform analyses coupling global metabolomic profiling with genomics in patient-derived glioma (low-grade astrocytoma [LGA; n=28] and glioblastoma [n=80]) was performed. Identified programs were then metabolomically, genomically, and functionally evaluated in preclinical models. Results: Clear metabolic programs were identified differentiating LGA from glioblastoma, with aberrant lipid, peptide and amino acid metabolism representing dominant metabolic nodes associated with malignant transformation. Although the metabolomic profiles of glioblastoma and LGA appeared mutually exclusive, considerable metabolic heterogeneity was observed in glioblastoma. Surprisingly, integrative analyses demonstrated that MGMT methylation and IDH mutation status were equally distributed among glioblastoma metabolic profiles. Transcriptional subtypes, on the other hand, tightly clustered by their metabolomic signature, with proneural and mesenchymal tumor profiles being mutually exclusive. Integrating these metabolic phenotypes with gene expression analyses uncovered tightly orchestrated and highly redundant transcriptional programs designed to support the observed metabolic programs by actively importing these biochemical substrates from the microenvironment, contributing towards a state of enhanced metabolic heterotrophy. These findings were metabolomically, genomically, and functionally recapitulated in preclinical models. Conclusion: Despite disparate molecular pathways driving the progression of glioblastoma, metabolic programs designed to maintain its aggressive phenotype remain conserved. This contributes towards a state of enhanced metabolic heterotrophy supporting survival in diverse microenvironments implicit in this malignancy. PMID- 30476238 TI - Reply to letter by Bamford et al. regarding the article: Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. PMID- 30476239 TI - Reply letter to editor: Risk of Fall Injury in Patients Taking Proton Pump Inhibitors: A Meta-Analysis. PMID- 30476240 TI - Cardiovascular Responses of Women with Fibromyalgia to a Laboratory Stressor: Does Post-traumatic Stress Disorder Comorbidity Matter? AB - Objectives: This study compared cardiovascular responses to a laboratory trauma unrelated stressor of two groups of women diagnosed with fibromyalgia (FM), one of them with comorbid post-traumatic stress disorder (PTSD), with a group of healthy controls in order to detect the possible existence of differences linked to comorbidity. Design: Case-controls. Methods: Eighteen women diagnosed with FM and comorbid PTSD, 18 women diagnosed with FM and no PTSD, and 38 healthy women were exposed to an arithmetic task with harassment while blood pressure and heart rate were measured during task exposure and recovery. Results: Although heart rate response evidenced a general blunted reactivity for both groups of FM patients, only those with comorbid PTSD presented lower levels of reactivity in terms of their systolic blood pressure response. In addition, systolic blood pressure response was sensitive to the presence of depression in both groups of FM patients and controls. Finally, although both groups of FM patients showed significantly slower rates of recovery, their final recovery state was not worse after twelve minutes of recording. Conclusions: Results of this study point to comorbid PTSD as a significant contributor to the blunted cardiovascular reactivity observed in FM patients, which may be dependent to a great extent on depressive symptomatology. As some degree of cardiovascular response to stress is functional in that it mobilizes energy and triggers the necessary compensatory mechanisms to manage stressors, this study supports the well-recognized clinical strategies of detection and treatment of PTSD and concomitant depression in the management of FM. PMID- 30476241 TI - The Leishmania PABP1-eIF4E4 interface: a novel 5'-3' interaction architecture for trans-spliced mRNAs. AB - Trans-splicing of trypanosomatid polycistronic transcripts produces polyadenylated monocistronic mRNAs modified to form the 5' cap4 structure (m7Gpppm36,6,2'Apm2'Apm2'Cpm23,2'U). NMR and X-ray crystallography reveal that Leishmania has a unique type of N-terminally-extended cap-binding protein (eIF4E4) that binds via a PAM2 motif to PABP1. This relies on the interactions of a combination of polar and charged amino acid side-chains together with multiple hydrophobic interactions, and underpins a novel architecture in the Leishmania cap4-binding translation factor complex. Measurements using microscale thermophoresis, fluorescence anisotropy and surface plasmon resonance characterize the key interactions driving assembly of the Leishmania translation initiation complex. We demonstrate that this complex can accommodate Leishmania eIF4G3 which, unlike the standard eukaryotic initiation complex paradigm, binds tightly to eIF4E4, but not to PABP1. Thus, in Leishmania, the chain of interactions 5'cap4-eIF4E4-PABP1-poly(A) bridges the mRNA 5' and 3' ends. Exceptionally, therefore, by binding tightly to two protein ligands and to the mRNA 5' cap4 structure, the trypanosomatid N-terminally extended form of eIF4E acts as the core molecular scaffold for the mRNA-cap-binding complex. Finally, the eIF4E4 N-terminal extension is an intrinsically disordered region that transitions to a partly folded form upon binding to PABP1, whereby this interaction is not modulated by poly(A) binding to PABP1. PMID- 30476242 TI - First-in-Man Clinical Experience Using a High-Definition 3-Dimensional Exoscope System for Microneurosurgery. AB - BACKGROUND: During its development and preclinical assessment, a novel, 3 dimensional (3D), high-definition (4K-HD) exoscope system was formerly shown to provide an immersive surgical experience, while maintaining a portable, low profile design. OBJECTIVE: To assess the clinical applicability of this 3D 4K-HD exoscope via first-in-man surgical use. METHODS: The operative workflow, functionality, and visual haptics of the 3D 4K-HD exoscope were assessed in a variety of microneurosurgical cases at 2 US centers. RESULTS: Nineteen microneurosurgical procedures in 18 patients were performed exclusively using the 3D 4K-HD exoscope. Pathologies treated included 4 aneurysms, 3 cavernous malformations (1 with intraoperative electrocorticography), 2 arteriovenous malformations, 1 foramen magnum meningioma, 1 convexity meningioma, 1 glioma, 1 occipital cyst, 1 chiari malformation, 1 carotid endarterectomy, 1 subdural hematoma, 1 anterior cervical discectomy and fusion, and 2 lumbar laminectomies. All patients experienced good surgical and clinical outcomes. Similar to preclinical assessments, the 3D 4K-HD exoscope provided an immersive 3D surgical experience for the primary surgeon, assistants, and trainees. The small exoscope frame, large depth of field, and hand/foot pedal controls improved exoscope mobility, decreased need to re-focus, and provided unobstructed operative corridors. Flexible positioning of the camera allows the surgeon's posture to be kept in a neutral position with uncompromised viewing angles. CONCLUSION: The first-in-man clinical experience with the 3D 4K-HD exoscope confirms its excellent optics and ergonomics for the entire operative team, with high workflow adaptability for a variety of microneurosurgical cases. Expanded clinical use of the 3D 4K-HD exoscope is justified. PMID- 30476243 TI - STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. AB - Proteins and their functional interactions form the backbone of the cellular machinery. Their connectivity network needs to be considered for the full understanding of biological phenomena, but the available information on protein protein associations is incomplete and exhibits varying levels of annotation granularity and reliability. The STRING database aims to collect, score and integrate all publicly available sources of protein-protein interaction information, and to complement these with computational predictions. Its goal is to achieve a comprehensive and objective global network, including direct (physical) as well as indirect (functional) interactions. The latest version of STRING (11.0) more than doubles the number of organisms it covers, to 5090. The most important new feature is an option to upload entire, genome-wide datasets as input, allowing users to visualize subsets as interaction networks and to perform gene-set enrichment analysis on the entire input. For the enrichment analysis, STRING implements well-known classification systems such as Gene Ontology and KEGG, but also offers additional, new classification systems based on high throughput text-mining as well as on a hierarchical clustering of the association network itself. The STRING resource is available online at https://string db.org/. PMID- 30476244 TI - Bathing and Swimming After Interventional Spine Procedures. PMID- 30476245 TI - Harnessing Integrated Omics Approaches For Plant Specialized Metabolism Research: New Insights Into Shikonin Biosynthesis. PMID- 30476246 TI - Effect of photoperiod on growth performance and quality characteristics of tibia and femur in layer ducks during the pullet phase. AB - This study aimed to evaluate the effect of photoperiod on growth performance and bone development in layer ducks during the pullet phase. A total of 480 11-wk-old Jinding layer ducks were randomly divided into 5 groups, receiving 6L (light): 18D (dark), 8L: 16D, 10L: 14D, 12L: 12D, 14L: 10D, respectively. Each group had 6 replicates of 16 birds each. The feeding trial lasted 80 d until 150 d of age. The results showed that 8L: 16D increased body weight (BW) and average daily gain (ADG; P < 0.05) compared with 6L:18D, whereas average daily feed intake, feed conversion ratio, and mortality rate had no difference among all treatments (P > 0.05). The midpoint perimeter (tibia and femur) and work to fracture (Wu; tibia) increased quadratically (P < 0.05), in response to photoperiod increment. Compared with 6L:18D, 8L:16D had higher tibia midpoint perimeter, ultimate load (Fu), and cortical cross-sectional area (P < 0.05), accompanied with higher content of total Ca, distal bone mineral content (BMC), and cortical volumetric BMC (vBMC; P < 0.05). A linear increase was observed in trabecular volumetric bone mineral density (vBMD) and vBMC (tibia and femur), elastic energy (femur), work to fracture Wu and young modulus of elasticity E (tibia) in response to photoperiod increase (P < 0.05), and treatment with 14L:10D had higher ultimate load Fu and total Ca of tibia (P < 0.05). Besides, estradiol and testosterone levels (serum), estrogen receptor gene mRNA expression (bone tissue), alkaline phosphatase and tartrate-resistant acid phosphatase activities, transforming growth factor-beta, osteocalcin and tumor necrosis factor-alpha contents increased in >=12 h photoperiods (P < 0.05). In summary, appropriate photoperiod increased BW, ADG, cortical bone generation, and bone mineralization, whereas only medullary bone formation increased with photoperiods. These results suggest that 8L:16D could be an adequate photoperiod for layer ducks' growth and bone development during the pullet phase. PMID- 30476247 TI - Sex-specific analysis of haemodialysis prevalence, practices and mortality over time: the Austrian Dialysis Registry from 1965 to 2014. AB - Background: Despite a higher prevalence of chronic kidney disease among women, more men than women start renal replacement therapy (RRT). We hypothesized that gender differences in health care access exist and therefore aimed at determining whether characteristics and outcomes of haemodialysis patients over time differ by sex. Methods: We studied all 28 323 adults who began haemodialysis during 1965 2014 in the Austrian Dialysis Registry, analysing trends in patient characteristics by sex and decade with mortality (via Cox regression), which was compared with the mortality of the Austrian general population. Results: More men than women started haemodialysis (60.1% men versus 39.9% women overall), with minor differences among decades and age groups. The male:female mortality rate ratio in the general population ranged from 1.2 to 2.4 for age groups >18 years and in haemodialysis patients ranged from 0.80 to 1.3 (closer to 1 than in the general population, but consistently >1 in Decades 3-5). In recent decades, diabetes and hypertension replaced glomerulonephritis as the primary cause of end stage renal disease in both men and women. Interaction analyses showed the mortality risk associated with haemodialysis access (only recorded in Decade 5) was significantly lower for men than for women. Conclusions: The male:female mortality rate ratio and the proportion of women starting haemodialysis were remarkably stable, which does not support the hypothesis of gender differences in health care/haemodialysis access or could imply that such differences might have persisted over decades. Future research should expand to other countries and other forms of RRT. PMID- 30476248 TI - Complex sexual behaviors during sleep as a manifestation of epilepsy: A case series. AB - Study Objectives: Complex sexual behavior during sleep (CSBS) is a well described clinical entity in NREM sleep parasomnias (i.e. sexsomnia). We report a retrospective case series of CSBS as clinical manifestation of epileptic seizures and compare them with the semiology of sexsomnia. Methods: Video-EEG-monitoring data of patients with epileptic and non-epileptic paroxysmal events from one tertiary epilepsy center between 2013-2016 were retrospectively reviewed. Clinical features and presurgical, electroclinical, and follow-up data are presented and then discussed in the context of other published cases. Results: From 4629 patients, six patients had CSBS. EEG, SPECT, MRI and histopathology confirmed an epileptic origin in 4 female patients, with temporal or frontal seizures. Two male patients had sexsomnia. None of the epilepsy patients had parasomnias. Clinical criteria to differentiate epileptic from parasomnic CSBS were: Events also occurred out of wakefulness; current presence of additional non sexual manifestations of epilepsy; sexual behavior only as part of a broad spectrum of emotional and motor automatisms; stereotyped behavior pattern without modulability by bystanders; unarousability during the event; no completion of sexual intercourse. The accuracy of the clinical diagnosis was improved by the development of an algorithm comparing patients' fulfillment of the criteria of epilepsy vs. parasomnia. Conclusions: In our cohort CSBS was a rare ictal phenomenon in temporal or frontal seizures. Symptomatological similiarities with sexsomnia might be explained by the same phylogenetically primitive "central pattern generator" manifesting in ictal CSBS by activation and in sexsomnia by disinhibition. Ictal CSBS should be considered in the differential diagnosis of sexsomnia. PMID- 30476249 TI - Budding of Ebola Virus Particles Requires the Rab11-Dependent Endocytic Recycling Pathway. AB - The Ebola virus-encoded major matrix protein VP40 traffics to the plasma membrane, which leads to the formation of filamentous viral particles and subsequent viral egress. However, the cellular machineries underlying this process are not fully understood. In the present study, we have assessed the role of host endocytic recycling in Ebola virus particle formation. We found that a small GTPase Rab11, which regulates recycling of molecules among the trans-Golgi network, recycling endosomes, and the plasma membrane, was incorporated in Ebola virus-like particles. Although Rab11 predominantly localized in the perinuclear region, it distributed diffusely in the cytoplasm and partly localized in the periphery of the cells transiently expressing VP40. In contrast, Rab11 exhibited a perinuclear distribution when 2 VP40 derivatives that lack ability to traffic to the plasma membrane were expressed. Finally, expression of a dominant-negative form of Rab11 or knockdown of Rab11 inhibited both VP40-induced clusters at the plasma membrane and release of viral-like particles. Taken together, our findings demonstrate that Ebola virus exploits host endocytic recycling machinery to facilitate the trafficking of VP40 to the cell surface and the subsequent release of viral-like particles for its establishment of efficient viral egress. PMID- 30476250 TI - Comparative Transcriptomics in Ebola Makona-Infected Ferrets, Nonhuman Primates, and Humans. AB - The domestic ferret is a uniformly lethal model of infection for 3 species of Ebolavirus known to be pathogenic in humans. Reagents to systematically analyze the ferret host response to infection are lacking; however, the recent publication of a draft ferret genome has opened the potential for transcriptional analysis of ferret models of disease. In this work, we present comparative analysis of longitudinally sampled blood taken from ferrets and nonhuman primates infected with lethal doses of the Makona variant of Zaire ebolavirus. Strong induction of proinflammatory and prothrombotic signaling programs were present in both ferrets and nonhuman primates, and both transcriptomes were similar to previously published datasets of fatal cases of human Ebola virus infection. PMID- 30476252 TI - Commentary: Effect of Carotid Siphon Anatomy on Aneurysm Occlusion After Flow Diversion. PMID- 30476251 TI - Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial. AB - BACKGROUND: More than a million Americans harbor a cerebral cavernous angioma (CA), and those who suffer a prior symptomatic hemorrhage have an exceptionally high rebleeding risk. Preclinical studies show that atorvastatin blunts CA lesion development and hemorrhage through inhibiting RhoA kinase (ROCK), suggesting it may confer a therapeutic benefit. OBJECTIVE: To evaluate whether atorvastatin produces a difference compared to placebo in lesional iron deposition as assessed by quantitative susceptibility mapping (QSM) on magnetic resonance imaging in CAs that have demonstrated a symptomatic hemorrhage in the prior year. Secondary aims shall assess effects on vascular permeability, ROCK activity in peripheral leukocytes, signal effects on clinical outcomes, adverse events, and prespecified subgroups. METHODS: The phase I/IIa placebo-controlled, double-blinded, single site clinical trial aims to enroll 80 subjects randomized 1-1 to atorvastatin (starting dose 80 mg PO daily) or placebo. Dosing shall continue for 24-mo or until reaching a safety endpoint. EXPECTED OUTCOMES: The trial is powered to detect an absolute difference of 20% in the mean percent change in lesional QSM per year (2-tailed, power 0.9, alpha 0.05). A decrease in QSM change would be a signal of potential benefit, and an increase would signal a safety concern with the drug. DISCUSSION: With firm mechanistic rationale, rigorous preclinical discoveries, and biomarker validations, the trial shall explore a proof of concept effect of a widely used repurposed drug in stabilizing CAs after a symptomatic hemorrhage. This will be the first clinical trial of a drug aimed at altering rebleeding in CA. PMID- 30476253 TI - JcMYB1, a Jatropha R2R3 MYB transcription factor, modulates lipid biosynthesis in transgenic plants. AB - The lipid biosynthesis pathway in plants is studied in detail, however, the factors that regulate the pathway at the transcription level are largely unknown. LEAFY COTYLEDON1 (LEC1), WRINKLED1 (WRI1) and FUSCA3 (FUS3) are considered master regulators to control seed oil content in Arabidopsis. Beside these master regulators, several other transcription factors that may regulate the pathway in plants are poorly studied. In the present work, we have shown the involvement of an uncharacterized Jatropha curcas R2R3MYB (JcMYB1) in seed oil biosynthesis. Seed oil analysis and expression profiling of fatty acid (FA) and triacylglyceride (TAG) biosynthetic genes in transgenic Arabidopsis and tobacco plants revealed that JcMYB1 enhances seed oil accumulation and alters FA composition by regulating the expression of endogenous pathway genes in transgenics. Using virus-induced gene silencing (VIGS) in Jatropha, we demonstrated that the suppression of JcMYB1 reduced lipid content with altered FA composition. Agro-infiltration and yeast one-hybrid assay results showed that JcMYB1 protein directly binds to the Diacylglycerol acyltransferase1 (DGAT1) promoter, a rate limiting enzyme of TAG biosynthesis, and activates its expression. These results suggested that the JcMYB1 may augment the lipid content by regulating lipid biosynthetic genes. Additionally, manipulation of JcMYB1 in oil crop plants may be used for the potential improvement of oil production and quality. PMID- 30476254 TI - Reducing calcineurin inhibitor first for treating BK polyomavirus replication after kidney transplantation: long-term outcomes. AB - Background: Reducing immunosuppression is the mainstay of treating BK polyomavirus (BKPyV) viraemia after kidney transplantation, but the best approach, efficacy and impact are undefined. We established a standard operating procedure (SOP) treating BKPyV viraemia based on first reducing calcineurin inhibitor ('CNI first'). The aim of this study was to investigate long-term outcomes in 644 consecutive transplantations using this SOP. Methods: Patients were monitored for active BKPyV infection by urinary decoy cells and, if positive, by BKPyV viraemia. In case of sustained BKPyV viraemia >1000 copies/mL, immunosuppression was reduced stepwise according to the SOP. Patients were classified as 'no decoy cells' [n = 432 (66%)], 'decoy cells/no viraemia' [n = 107 (17%)] and 'viraemia' [n = 105 (17%)]. Results: At 6-years post-transplant, graft survival was ~84%, the clinical rejection rate was ~25% and they were not different among the three groups (P = 0.14; P = 0.91). The median estimated glomerular filtration rate at the last follow-up was similar (range 49-53 mL/min, P = 0.08). Of 105 viraemic patients, 101 (96%) cleared BKPyV viraemia. In 39% of patients, viraemia clearance followed a tacrolimus reduction. A reduction of mycophenolic acid was required in 43% and discontinuation in 3%. No short-term graft loss was directly attributable to BKPyV-associated nephropathy. After a median follow-up of 5 years after clearance of BKPyV viraemia, 11/101 patients (11%) developed clinical rejection: 7 (7%) T-cell-mediated rejection and 4 (4%) antibody-mediated rejection (ABMR). Conclusions: Immunosuppression reduction based on 'CNI first' leads to similar long-term outcomes in patients with/without BKPyV viraemia and is associated with a low risk for ABMR after clearance of BKPyV viraemia. Randomized trials are needed to compare the risks and benefits of immunosuppression reduction strategies in kidney transplant patients with BKPyV viraemia. PMID- 30476255 TI - Clinical characteristics of acromegalic patients with paradoxical growth hormone response to oral glucose load. AB - Context: Paradoxical GH response to oral glucose (OG) is often found in acromegaly. However, the clinical characteristics of acromegalic patients with paradoxical GH response to OG (OG responders) remains unclear. Objective: The aim of the present study was to define the clinical characteristics of OG responders with acromegaly. Design: Retrospective study. Setting: Hospitalized care at Osaka University Hospital. Patients and methods: Sixty-three acromegalic patients admitted to our hospital between January 2006 and January 2017 were classified into OG responders (n=19) and non-responders (n=44). The clinical characteristics of these groups were compared. Results: Before surgery, OG responders had significantly higher IGF-1 SD scores than non-responders although there was no difference in basal GH levels between the two groups. With regard to glucose metabolism, 120-min PG and IRI after OG administration, and HbA1c were significantly higher in OG responders than non-responders. GH levels during octreotide or bromocriptine tests were decreased more significantly in OG responders than non-responders. The proportion of pituitary tumors with hypointensity on T2-weighted MRI was significantly higher in OG responders than non-responders. The difference in IGF-1 and parameters of glucose metabolism described above disappeared between the two groups after surgery. Conclusions: Paradoxical GH response reflected the clinical characteristics, especially IGF-I levels, glucose metabolism and drug efficacy in acromegaly. Paradoxical GH response, in addition to the nadir GH levels, to OG load can be potentially useful for evaluation of the clinical characteristics of acromegaly. PMID- 30476256 TI - Family cohesion and family size moderating burnout and recovery connection. AB - Background: It has been argued that family issues in individual cultures do not correlate with fulfilment. However, the universality of these findings is unknown as they are based on data from the Western world. Aims: To examine the connection between job burnout and recovery and the moderating effects of perceived family cohesion and family size in this relationship. Methods: Moderated hierarchical regression analyses were carried out on a sample of medical practitioners working in intensive care units from federal and state-owned hospitals in Southeastern Nigeria. Results: There were 183 participants. Job burnout was negatively related to recovery and perceived family cohesion was positively related to recovery. However, contrary to our assumption, family size was positively related to recovery. Perceived family cohesion was vital in recovery regardless of the doctors' experience of high levels of burnout. In contrast to most previous findings, family size was found to have a moderating effect in the burnout recovery connection. Conclusions: The findings of this study suggested that family bond is important in collectivistic cultures. This was underscored by the moderating effects family issues had on the relation between burnout and recovery. These findings are different from those in Western societies in which previous studies have been conducted. PMID- 30476257 TI - Towards a personalized treatment for IgA nephropathy considering pathology and pathogenesis. AB - The search of personalized treatment for a subject with immunoglobulin A nephropathy (IgAN) is appealing since the individual long-term outcome is highly variable in spite of common mild clinical signs such as microscopic haematuria, moderate proteinuria and slightly reduced glomerular filtration rate (GFR). The only risk factor considered by the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines to target corticosteroid/immunosuppressive treatment in IgAN is proteinuria persistently >1 g/day despite 3-6 months of optimized supportive care. However, proteinuria in IgAN may result not only from active lesions but also from sclerotic glomerular lesions with hyperfiltration and tubular damage. The Oxford classification study and subsequent investigations have indicated the value of pathology risk factors for progression independent of proteinuria, blood pressure and GFR at renal biopsy. Meanwhile new studies have provided an improved understanding of the pathogenetic mechanisms operating in IgAN leading to kidney tissue damage. These findings suggest the possibility for the individual patient with IgAN of using a pathology-based therapy, taking into consideration the pathogenetic mechanisms operating at the time of renal biopsy. This review is largely opinion based, since evidence-based reports are mostly incomplete: hypotheses are suggested based on interesting published investigations. The clinician faces a daily challenge: find the best management for his/her patient, modelling a rather general indication as obtained by the guidelines to the needs of the patient. This review offers some considerations that hopefully will be useful in this difficult choice. PMID- 30476258 TI - Weight-related quality of life and temperament as predictors and moderators of outcomes among treatment-seeking, low-income, ethnically diverse children with obesity. AB - Within any childhood obesity treatment program, some children have better outcomes than others. Little is known about predictors or moderators of more positive outcomes. We aimed to identify whether child temperament and weight related quality of life predict or moderate childhood obesity treatment outcomes at 6 months. From 2015 to 2016, children (n = 97) ages 5-11 years old with obesity were randomized to a clinic-community (Bull City Fit) or a clinic-only treatment program. Linear regression was used to explore whether dimensions of child temperament and weight-related quality of life predicted or moderated 6 month anthropometric and physical activity outcomes. Children who had more social avoidance due to their weight at baseline had significantly better improvements in body fat percent in the clinic-community model compared with the clinic-only model at 6 months. Across programs, better baseline social quality of life predicted greater increases in waist circumference; conversely, better physical quality of life predicted a decrease in percent of the 95th percentile. Also, children with longer attention spans had greater increases in physical activity. Our findings suggest that children who have social avoidance due to their weight may benefit most from comprehensive clinic-community treatment. Weight-related quality of life may influence outcomes across all treatments, and practitioners need to carefully counsel children experiencing weight negatively. PMID- 30476259 TI - The use of theory in process evaluations conducted alongside randomized trials of implementation interventions: A systematic review. AB - Interventions to implement changes into health care practice (i.e., implementation interventions) are critical to improving care but their effects are poorly understood. Two strategies to better understand intervention effects are conducting process evaluations and using theoretical approaches (i.e., theories, models, frameworks). The extent to which theoretical approaches have been used in process evaluations conducted alongside trials of implementation interventions is unclear. In this study context, we reviewed (a) the proportion of process evaluations citing theoretical approaches, (b) which theoretical approaches were cited, and (c) whether and how theories were used. Systematic review (PROSPERO: CRD42016042789). MEDLINE, PsycINFO, Embase, CINAHL, and Cochrane CENTRAL were searched up to July 31, 2017. For all studies, data extraction included names and types of theoretical approaches cited. For studies citing a theory, data extraction included study characteristics and extent of theory use (i.e., "informed by," "applied," "tested," "built/created" theory). We identified 123 process evaluations. Key findings: (a) 77 (63%) process evaluations cited a theoretical approach; (b) the most cited theory was normalization process theory; (c) 32 (26%) process evaluations used theory: 7 (22%) were informed by, 18 (56%) applied, 7 (22%) tested, and none built/created theory. Although nearly two thirds of process evaluations cited a theoretical approach, only a quarter were informed by, applied, or tested a theory-despite the potential complementarity of these strategies. When theory was used, it was primarily applied. Using theory more substantively in process evaluations may accelerate our understanding of how implementation interventions operate. PMID- 30476260 TI - Endovascular Flow Diversion for Hemifacial Spasm Induced by a Vertebral Artery Aneurysm: First Experience. AB - BACKGROUND AND IMPORTANCE: Flow diversion for the treatment of aneurysm-induced hemifacial spasm (HFS) has not been previously described. CLINICAL PRESENTATION: The authors present the case of a 60-yr-old woman who presented with 1 yr of progressive left HFS secondary to a vertebral artery aneurysm compressing the root entry zone of cranial nerve VII. The patient's aneurysm was successfully treated with a flow diverting stent. CONCLUSION: In the immediate postoperative period, the patient had near complete resolution of her HFS symptoms. At her 6-mo follow-up the patient had no angiographic filling of the aneurysm and her HFS symptoms had completely resolved. PMID- 30476262 TI - Letter: A Method for Cranial Nerve XI Silencing During Surgery of the Foramen Magnum Region: Technical Case Report. PMID- 30476261 TI - Ocular and systemic manifestations of Alkaptonuria. PMID- 30476263 TI - Commentary: Ernest Codman and the Impact of Quality Improvement in Neurosurgery: A Century Since the Idea of the "End Result". PMID- 30476264 TI - Proteomics reveal both photochemical and biochemical limitations involved in salt induced suppression of photosynthesis in trees. PMID- 30476265 TI - Stress Exposure in Dopamine D4 Receptor Knockout Mice Induces Schizophrenia-Like Behaviors via Disruption of GABAergic Transmission. AB - A combination of genetic and environmental risk factors has been considered as the pathogenic cause for mental disorders including schizophrenia. Here, we sought to find out whether the abnormality of the dopamine system, coupled with the exposure to modest stress, is sufficient to trigger the manifestation of schizophrenia-like behaviors. We found that exposing dopamine D4 receptor knockout (D4KO) mice with 1-week restraint stress (2 h/d) induced significant deficits in sensorimotor gating, cognitive processes, social engagement, as well as the elevated exploratory behaviors, which are reminiscent to schizophrenia phenotypes. Electrophysiological studies found that GABAergic transmission was significantly reduced in prefrontal cortical neurons from stressed D4KO mice. Additionally, administration of diazepam, a GABA enhancer, restored GABAergic synaptic responses and ameliorated some behavioral abnormalities in stressed D4KO mice. These results have revealed that the combination of 2 key genetic and environmental susceptibility factors, dopamine dysfunction and stress, is a crucial trigger for schizophrenia-like phenotypes, and GABA system in the prefrontal cortex is a downstream convergent target that mediates some behavioral outcomes. PMID- 30476266 TI - Pediatric Abusive Head Trauma: Return to Hospital System in the First Year Post Injury. AB - BACKGROUND: Abusive head trauma (AHT) may result in costly, long-term sequelae. OBJECTIVE: To describe the burden of AHT on the hospital system within the first year of injury. METHODS: Single institution retrospective evaluation of AHT cases from January 2009 to August 2016. Demographic, clinical (including injury severity graded I-III), and charge data associated with both initial and return hospital visits within 1 yr of injury were extracted. RESULTS: A total of 278 cases of AHT were identified: 60% male, 76% infant, and 54% African-American. Of these 278 cases, 162 (60%) returned to the hospital within the first year, resulting in 676 total visits (an average of 4.2 returns/patient). Grade I injuries were less likely to return than more serious injuries (II and III). The majority were outpatient services (n = 430, 64%); of the inpatient readmissions, neurosurgery was the most likely service to be involved (44%). Neurosurgical procedures accounted for the majority of surgeries performed during both initial admission and readmission (85% and 68%, respectively). Increasing injury severity positively correlated with charges for both the initial admission and returns (P < .001 for both). Total calculated charges, including initial admission and returns, were over $25 million USD. CONCLUSION: AHT has a high potential for return to the hospital system within the first year. Inpatient charges dominate and account for the vast majority of hospital returns and overall charges. A more severe initial injury correlates with increased charges on initial admission and on subsequent hospital return. PMID- 30476267 TI - Deep repeat resolution-the assembly of the Drosophila Histone Complex. AB - Though the advent of long-read sequencing technologies has led to a leap in contiguity of de novo genome assemblies, current reference genomes of higher organisms still do not provide unbroken sequences of complete chromosomes. Despite reads in excess of 30 000 base pairs, there are still repetitive structures that cannot be resolved by current state-of-the-art assemblers. The most challenging of these structures are tandemly arrayed repeats, which occur in the genomes of all eukaryotes. Untangling tandem repeat clusters is exceptionally difficult, since the rare differences between repeat copies are obscured by the high error rate of long reads. Solving this problem would constitute a major step towards computing fully assembled genomes. Here, we demonstrate by example of the Drosophila Histone Complex that via machine learning algorithms, it is possible to exploit the underlying distinguishing patterns of single nucleotide variants of repeats from very noisy data to resolve a large and highly conserved repeat cluster. The ideas explored in this paper are a first step towards the automated assembly of complex repeat structures and promise to be applicable to a wide range of eukaryotic genomes. PMID- 30476268 TI - Comment on: The ability of rheumatologists blinded to prior workup to diagnose rheumatoid arthritis by clinical assessment only: a cross-sectional study. PMID- 30476269 TI - Heart Rate Variability Rebound Following Exposure to Persistent and Repetitive Sleep Restriction. AB - While it is well established that slow wave sleep electroencephalography (EEG) rebounds following sleep deprivation, very little research has investigated autonomic nervous system recovery. We examined heart rate variability (HRV) and cardiovagal baroreflex sensitivity (BRS) during 4 blocks of repetitive sleep restriction and sequential nights of recovery sleep. Twenty-one healthy participants completed the 22-day in-hospital protocol. Following 3 nights of 8h sleep, they were assigned to a repetitive sleep restriction condition. Participants had two additional 8h recovery sleep periods at the end of the protocol. Sleep EEG, HRV and BRS were compared for the baseline (BL), the 4 blocks of sleep restriction, and the second (R2) and third (R3) nocturnal recovery sleep periods following the last sleep restriction block. Within the first hour of each sleep period, vagal activation as indexed by increase in high frequency (HF; HRV spectrum analysis), showed a rapid increase, reaching its 24h peak. HF was more pronounced (rebound) in R2 than during baseline (P<0.001). The BRS increased within the first hour of sleep and was higher across all sleep restriction blocks and recovery nights (p=0.039). Rebound REM sleep was observed during both R2 and R3 (P=0.004), whereas slow wave sleep did not differ between BL and recovery nights (P>0.05). Our results indicate that the restoration of autonomic homeostasis requires a time-course that includes at least 3 nights, following an exposure to multiple nights of sleep curtailed to about half the normal nightly amount. PMID- 30476271 TI - JJCO Best Reviewer Award. PMID- 30476270 TI - Comparison of two subsets of Chinese patients with retroperitoneal fibrosis in terms of IgG4 immunohistochemical staining. AB - Objective: To identify clinical and pathological differences between IgG4-related retroperitoneal fibrosis (IgG4-RPF) and idiopathic RPF (iRPF) in a Chinese population. Method: Clinical and pathological data of 50 RPF patients from 2006 to 2016 were retrospectively analysed. The presence of at least one characteristic histopathological feature, >30 IgG4+ plasma cells per high power field, and an IgG4+/IgG+ plasma cells ratio cutoff of >40% were used to define IgG4-RPF. Results: Patients with IgG4-RPF were significantly more likely to have pain (94.1 vs 68.8%, P = 0.048), elevated serum IgE concentration (166.1 vs 40.2 IU/ml, P = 0.029) and tissue eosinophilia (47.1 vs 12.5%, P = 0.018), compared with patients with iRPF. In the IgG4-RPF subgroup, patients with tissue eosinophilia demonstrated higher levels of CRP (4.3 vs 1.9 mg/dl, P = 0.027) and ESR (62.1 vs 22.8 mm/h, P = 0.001). Among the 50 patients with RPF, the average number of tissue IgG4+ plasma cells was positively correlated with the number of tissue eosinophils (r = 0.37, P = 0.009). Moreover, serum IgG4 concentration and serum IgE concentration showed positive correlation (r = 0.834, P = 0.000). Conclusion: The distinct serological and histopathological features of Chinese patients with IgG4-RPF were elevated serum IgE concentration and tissue eosinophilia, which potentially can aid and support the diagnosis. As serum IgG4 concentration may be normal in patients with IgG4-RPF, serum IgE may represent a useful serological marker in distinguishing IgG4-RPF from iRPF. PMID- 30476272 TI - JJCO Paper of the Year and Highly Commended Paper. PMID- 30476273 TI - Thanking All Peer Reviewers. PMID- 30476274 TI - MIR sequences recruit zinc finger protein ZNF768 to expressed genes. AB - Mammalian-wide interspersed repeats (MIRs) are retrotransposed elements of mammalian genomes. Here, we report the specific binding of zinc finger protein ZNF768 to the sequence motif GCTGTGTG (N20) CCTCTCTG in the core region of MIRs. ZNF768 binding is preferentially associated with euchromatin and promoter regions of genes. Binding was observed for genes expressed in a cell type-specific manner in human B cell line Raji and osteosarcoma U2OS cells. Mass spectrometric analysis revealed binding of ZNF768 to Elongator components Elp1, Elp2 and Elp3 and other nuclear factors. The N-terminus of ZNF768 contains a heptad repeat array structurally related to the C-terminal domain (CTD) of RNA polymerase II. This array evolved in placental animals but not marsupials and monotreme species, displays species-specific length variations, and possibly fulfills CTD related functions in gene regulation. We propose that the evolution of MIRs and ZNF768 has extended the repertoire of gene regulatory mechanisms in mammals and that ZNF768 binding is associated with cell type-specific gene expression. PMID- 30476275 TI - Erector Spinae Plane Block for Hyperalgesic Acute Pancreatitis. PMID- 30476276 TI - Arabidopsis ADF5 promotes stomatal closure by regulating actin cytoskeleton remodeling in response to ABA and drought stress. AB - Stomatal movement plays an essential role in plant responses to drought stress, and the actin cytoskeleton and abscisic acid (ABA) are two important components of this process. Little is known about the mechanism underlying actin cytoskeleton remodeling and the dynamic changes occurring during stomatal movement in response to drought stress/ABA signaling. Actin-depolymerizing factors (ADFs) are conserved actin severing/depolymerizing proteins in eukaryotes, and in angiosperms ADFs have evolved actin-bundling activity. Here, we reveal that the transcriptional expression of neofunctionalized Arabidopsis ADF5 was induced by drought stress and ABA treatment. Furthermore, we demonstrated that ADF5 loss-of-function mutations increased water loss from detached leaves, reduced plant survival rates after drought stress, and delayed stomatal closure by regulating actin cytoskeleton remodeling via its F-actin bundling activity. Biochemical assays revealed that an ABF/AREB transcription factor, DPBF3, could bind to the ADF5 promoter and activate its transcription via the ABA-responsive element core motif ACGT/C. Taken together, our findings indicate that ADF5 participates in drought stress by regulating stomatal closure, and may also serve as a potential downstream target of the drought stress/ABA signaling pathway via members of the ABF/AREB transcription factors family. PMID- 30476277 TI - Comparison of slaughter yields and some meat quality parameters in broilers reared on sepiolite-supplemented wood shavings and rice hulls. AB - Many bedding materials have been tested in broiler industry for their suitability. However, little knowledge is available regarding the usage of different bedding materials supplemented with sepiolite and their effects on animal performance and final product quality. For this purpose, a total of 288 day-old male broiler chicks were randomly allocated into two types of bedding materials (wood shavings and rice hulls). Each bedding material group was divided into 3 sub-groups: control with 0% sepiolite, 25%-sepiolite group, and 50% sepiolite group. Each sub-group was placed in 6 pens with 8 chicks per pen. The effects of bedding materials and sepiolite additions on slaughter yields and some meat quality parameters in broilers were evaluated. Slaughter parameters including hot carcass yield and relative weights of thigh and breast meat, heart, liver, gizzard and bursa Fabricius in broilers were not affected by bedding materials and sepiolite additions (P > 0.05). Also, no significant differences were observed among experimental groups for cooking loss and nutritional profile of breast and thigh meat of broilers (P > 0.05). The freshly measured pH0 of breast and thigh meats was significantly affected by the bedding material and was higher for wood shavings group (P < 0.01). Breast and thigh meats of broilers reared on rice hulls were lighter (P < 0.01), less red, and less yellow in color than those reared on wood shavings, whereas no effect of sepiolite additions was observed on the color of both meat cuts. No substantial effect of bedding material and sepiolite additions was observed on white stripping; however, their occurrence rate found was very high for meat of broilers reared on rice hulls than those reared on wood shavings (P > 0.05). In conclusion, broilers reared on either wood shavings or rice hulls with or without sepiolite additions did not show any negative effects on slaughter yields and meat quality parameters. Furthermore, sepiolite can be an option as a bedding material for broiler industry, but further research with thorough economic analysis is required. PMID- 30476278 TI - Metabolic adaptation of wheat grain contributes to a stable filling rate under heat stress. AB - Wheat (Triticum aestivum) is particularly vulnerable to heat stress during the grain filling stage, and this can adversely affect the final yield. However, the underlying physiological and molecular mechanisms are largely unknown. In this study, the effects of heat stress on grain filling were investigated using wheat varieties with different levels of thermotolerance. Decreased grain weights and filling durations, increased protein contents, and stable filling rates across diverse varieties under different heat regimes suggested a general mechanism for heat adaptation. Proteomic analysis identified 309 heat-responsive proteins (HRPs), and revealed a general decrease in protein synthesis components and metabolic proteins, but a significant increase in stress-response proteins and storage proteins. Metabolomic analysis identified 98 metabolites specifically changed by heat stress, and suggested a global decrease in the content of carbohydrate metabolites, an increased content of amino acids, and stable levels of starch synthesis precursors. The energy-consuming HRPs suggested that less energy was channelled into metabolism and protein synthesis, whereas more energy was allocated to the stress response under elevated heat conditions. Collectively, the data demonstrated a widely distributed mechanism for heat adaptation of metabolism, in which the assimilation and energy required for metabolism and protein synthesis are reallocated to heat protection and deposition of reserves, resulting in increased storage protein accumulation and a stable filling rate. PMID- 30476279 TI - Unusual spermine-conjugated hydroxycinnamic acids on pollen: function and evolutionary advantage. PMID- 30476280 TI - Mesophyll conductance and accurate photosynthetic carbon gain calculations. PMID- 30476281 TI - Cardiopulmonary Responses During Clinical and Laboratory Gait Assessment in People With Chronic Stroke. AB - Background: The 6-minute walk test (6MWT) is a common clinical assessment used to evaluate locomotor function in patients after stroke. Previous work suggests the 6MWT can estimate peak metabolic capacity (VO2peak) without cardiorespiratory assessments during graded exercise tests (GXTs) which may assist with exercise prescription. However, selected research also indicated increased heart rates (HRs) during 6MWTs beyond levels considered safe without GXTs. Objective: The goal of this study was to examine cardiorespiratory responses during 6MWTs and GXTs in individuals with chronic stroke and their associations with demographic or clinical characteristics. Design: The design was a cross-sectional observational study. Methods: Cardiorespiratory responses were assessed during 6MWTs at self-selected velocity (SSV) and fastest velocity (FV), and during GXTs. Secondary assessments included the lower extremity Fugl-Meyer Assessment, Functional Gait Assessment, gait speeds, and daily stepping activity. Correlation and regression analyses were used to evaluate associations between locomotor performance, cardiorespiratory responses, and clinical and demographic characteristics. Results: Average HRs during 6MWT-FV were 72% to 76% of the age predicted maximum (HRmax), with 20% of participants exceeding 85% predicted HRmax. When normalized to HRs during GXTs, HRs during 6MWT-FV were 86% to 88% of the observed HRmax. Primary predictors of increased HRs during 6MWTs were resting HR, body mass index, and daily stepping. Distance during 6MWT-FV was a significant predictor of VO2peak in combination with other variables. Electrocardiographic abnormalities were observed in > 80% of participants at rest and an additional 31% demonstrated distinct abnormalities during GXTs, which were not related to 6MWT or GXT performance. Limitations: In addition to sample size, a primary limitation involved the ability to accurately predict or measure HRmax in patients with motor dysfunction after stroke. Conclusions: Cardiac responses were higher than anticipated during 6MWTs and often exceeded recommended HR thresholds. Clinicians should closely monitor cardiorespiratory responses during 6MWTs. PMID- 30476282 TI - Improving Opioid Management and Resource Utilization in an Internal Medicine Residency Clinic: A Before-After Study over Two Plan-Do-Study-Act Cycles. AB - Objective: Chronic pain and opioid management are challenging in primary care, especially for trainees with discontinuous ambulatory schedules and less practice experience. The study objective was to improve adherence to quality metrics and office visit utilization in a resident clinic. Design: Before-after quality improvement intervention over two Plan-Do-Study-Act cycles. Setting. Suburban, university-affiliated Internal Medicine resident clinic. Methods: During the 2015 2017 academic years, two sequential interventions were implemented: 1) use of electronic pain and opioid management templates and workflow redesign routing opioid renewals through a registered nurse (RN); 2) RN previsit planning and daily nurse-physician huddles before patient visits. Outcomes included adherence to annual toxicology screening, risk assessment and opioid agreements, opioid dose prescribed, and office visit utilization. Results: The template and workflow redesign intervention increased annual toxicology from 53% to 81% (P < 0.0015), annual opioid agreement from 13.8% to 53.5% (P < 0.0001), and risk assessment from 0% to 75.9% (P < 0.0001). Average daily morphine milligram equivalents (MME) decreased from 96.6 MME to 67.7 MME (P < 0.0001), and annual office visits decreased from 11.1 to 8.9 (P = 0.0004). Previsit planning and huddles did not show incremental increases in adherence to quality measures but did improve clinic utilization and maintained high levels of adherence to quality measures. Conclusions: Quality improvement interventions can improve adherence to quality measures and clinic utilization. A critical role is served by midlevel nursing providers to provide continuity to patients and trainees. Teaching clinics need to develop sustainable systems of care to moderate quality assurance in opioid prescribing. PMID- 30476283 TI - Main signaling pathways involved in the control of fowl sperm motility. AB - Motility is an essential function of the mature male gamete and is widely used as an indicator of semen quality. Knowledge of signal transduction pathways regulating sperm motility is therefore important to gain insight into new methods to increase the fertilizing ability of semen samples, especially those subjected to biotechnological processes such as cryopreservation. In this article, we will briefly describe the roles of several signaling pathways involved in the motility of fowl sperm as compared to mammalian sperm. This review is intended to facilitate the design of future studies in fowl male fertility and improve the quality of frozen-thawed sperm. PMID- 30476285 TI - In Reply: A Method for Cranial Nerve XI Silencing During Surgery of the Foramen Magnum Region: Technical Case Report. PMID- 30476287 TI - Geophagy in India: a qualitative exploratory study on motivation and perception of female consumers. AB - Background: : Geophagy, the consumption of soil, is well documented in Africa and other continents, but is rarely investigated in Asia and even less so in India. The main aim of this exploratory qualitative study was therefore to understand the motivation for clay consumption, the social perception of the habit, the mode and quantity of consumption, as well as subjectively perceived effects of clay consumption in Himachal Pradesh, North India. : We conducted semi-structured interviews with 27 female geophagists aged 18-80 years. : We could show that geophagy exists across all ages and social groups. The main type of consumed soil is yellow clay used for house wall plastering. Geophagy is usually practised because of a craving for soil despite various fears of negative health effects. It is normally done secretly and under-reported to local doctors. The most common self-reported positive effect of geophagy was the feeling of relief. Geophagy was generally considered as harmful to health and various complaints were associated with it. It is not practised because of food shortages or as a remedy. On the contrary, it is generally seen as an addiction detrimental to health. : Awareness of geophagy has to be ameliorated in the Indian population and specifically among health workers to improve support for affected individuals. Geophagy should be routinely included in national antenatal care guidelines. PMID- 30476286 TI - Establishment of xMAP for the simultaneous detection of antibodies to Newcastle disease virus and avian influenza virus. AB - Using Luminex xMAP (x = analyte, MAP = multi-analyte profiling) technology, a serological method for the simultaneous detection of antibodies to Newcastle disease virus (NDV) and avian influenza virus (AIV) was established. Nano magnetic beads coated with purified NDV protein and AIV nucleoprotein were incubated with serum samples. Using biotinylated rabbit anti-chicken IgY and streptavidin-R-phycoerythrin, the optical signals measured by a Luminex 200 detection system indicated the quantification of NDV or AIV antibodies in the serum. Specific pathogen-free (SPF) chicken serum was used as a negative control. The Luminex xMAP assay developed in this study demonstrated high specificity as there was no cross-reaction with antibodies to infectious laryngotracheitis virus, infectious bronchitis virus, infectious bursal disease virus, avian leukosis virus, and Marek's disease virus. The results from reproducibility experiments showed that intra-coefficients of variation were 3.36 and 9.23% and inter-coefficients of variation were 6.50 and 7.66% for NDV and AIV, respectively. The results also indicated that the Luminex xMAP assay was 16 times more sensitive for NDV antibody detection and 1,024 times more sensitive for AIV antibody detection compared to the enzyme-linked immunosorbent assay (ELISA). A total of 300 chicken serum samples were subjected to both Luminex xMAP assay and ELISA, showing the coincidence rates of 98.67 and 98% for NDV and AIV antibody detection, respectively. This study provides a new method for the simultaneous detection NDV and AIV antibodies in the serum with high specificity and sensitivity. PMID- 30476288 TI - Letter: Paratrigeminal, Paraclival, Precavernous, or All of the Above? A Circumferential Anatomical Study of the C3-C4 Transitional Segment of the Internal Carotid Artery: Collecting Surgical Nuances. PMID- 30476289 TI - Familial Mediterranean fever: breaking all the (genetic) rules. AB - Objective: FMF is an inherited autoinflammatory syndrome, characterized by attacks of painful periodic fever caused by diffuse serositis and risk of secondary amyloidosis due to IL-1beta-mediated inflammation. The disease appears to be transmitted through autosomal recessive mutations in the MEFV gene encoding the pyrin protein Although more than 300 variants have been reported worldwide so far, their association with symptom severity, the relative frequencies in different populations and the disease penetrance are far from being completely understood. We investigated genotype-phenotype correlations in two large nuclear families and verified whether commonly used web-based tools can usefully predict variant pathogenicity in FMF. Methods: Peripheral blood samples were obtained from 15 patients of two families who had been diagnosed with FMF according to international criteria. The entire MEFV coding region was sequenced in all subjects, and 179 MEFV variants were surveyed with five different pathogenicity predictors. Results: The inheritance of FMF could not be explained by traditional autosomal recessivity in both families. In silico tools demonstrated a significant association of variants' pathogenicity with their position along the coding sequence but not with variants' frequency. Conclusion: By describing two large families with paradigmatic complexity of FMF genetics, we conclude that established concepts in assessing the causative role of variants identified in mutation screening cannot be easily translated into appropriate genetic counselling in FMF. Furthermore, we demonstrate that variants frequently associated with severe disease are not predicted to significantly impact protein function using in silico algorithms. PMID- 30476290 TI - Quantitative Assessment of Pathological Tau Burden in Essential Tremor: A Postmortem Study. AB - Essential tremor (ET) patients develop more cognitive impairment and dementia than controls, although there are surprisingly few data on the neuropathological basis for cognitive changes in ET. In this postmortem study, we assessed tau and other pathologies in 26 ET cases and 73 controls (non-ET) (1:3 matching). The mean age = 88.6 years; 55% were cognitively normal, 24% had mild cognitive impairment (MCI), and 20% had dementia. We found similar burdens of pathology using Braak, beta-amyloid and Lewy body assessments in ET and controls. In contrast, among cognitively normal subjects, ET cases had a higher number of NFT positive neurons in the neocortex than controls (p < 0.001); the number of NFT positive neurons in the medial temporal lobe was similar in these 2 groups (p = 0.22). Among subjects with MCI, ET cases also had higher numbers of NFT-positive neurons in the neocortex than controls (p < 0.001) but again, not in the medial temporal lobe (p = 0.55). Among subjects with dementia, the number of NFT positive neurons was similar in ET cases and controls. Cognitive function correlated with quantitative neurofibrillary tangle counts in ET cases and controls. In the context of ET, pre-dementia tau burden is higher than in the absence of ET, suggesting a predisposition to tau pathology. PMID- 30476291 TI - The anti-inflammatory and antioxidant effects of leonurine hydrochloride after lipopolysaccharide challenge in broiler chicks. AB - This study was carried out to investigate the protective effects of leonurine hydrochloride (LH, from Leonurus sibiricus) on lipopolysaccharide (LPS) stimulated broiler chicks. A total of 120 one-day-old male Ross broilers were randomly divided into 4 treatment groups with 6 replicates of 5 birds per cage. The experiment was designed as a 2 * 2 factorial arrangement with LH (0 or 120 mg/kg) and LPS (injection of saline or 1.5 mg/kg body weight) levels as treatments. On days 14, 16, 18, and 20 of the trial, broilers were intraperitoneally injected with LPS or saline. Blood, spleen, and liver samples were collected on days 21 and 28 for analysis. The results showed that dietary LH had no effect on growth performance or immunoglobulin concentrations in the serum. However, dietary LH prevented LPS-induced reductions in average daily gain and average daily feed intake in the broilers on days 15-21 of the trial (P > 0.05). Dietary LH supplementation dramatically attenuated the LPS-induced increases in the spleen index, reduced glutathione (GSH) activity (serum and liver) and total superoxide dismutase (T-SOD) activity (serum and spleen), and significantly reduced malondialdehyde (MDA) levels (serum, spleen, and liver) on days 21 and 28 (P < 0.05). Additionally, LH supplementation significantly mitigated the LPS-induced increases in the tumor necrosis factor (TNF)-alpha (serum and spleen), interleukin (IL)-1beta (serum, spleen and liver), IL-2 (liver), IL-6 (serum, spleen and liver), toll-like receptor 4 (TLR4) (spleen and liver), and nuclear factor (NF)-kappaB (spleen and liver) levels on days 21 and 28 (P < 0.05). Therefore, this study revealed that LH could downregulate the expression of proinflammatory factors, mainly by inhibiting the expression of TLR4 and the activation of NF-kappaB. LH may be a potential feed additive with dual efficacy as an anti-inflammatory and antioxidant agent. PMID- 30476292 TI - Cardiac Amyloidosis. PMID- 30476293 TI - A content analysis of smartphone apps for adolescent smoking cessation. AB - Adolescent cigarette smokers have an increased risk of sustained smoking into adulthood. Smartphone applications (apps) for smoking cessation are a promising treatment resource. However, research on apps for adolescent smoking cessation is limited. This study compared smoking cessation mobile apps targeting an adolescent audience with popular cessation apps for a general audience. Adolescent and general-audience apps were identified by searching the Google Play and Apple App Stores (November 2016). Two coders assessed each app for adherence to clinical practice guidelines for tobacco and adolescent-specific content (2016 2017) and developed a summary score that summed all adherence and adolescent content criteria. Eight adolescent apps were identified and compared with the top 38 general apps (as ranked by Apple and Google). Both general and adolescent apps commonly had adherence content related to developing a quit plan (general: 73.68 per cent; adolescent: 87.50 per cent) and enhancing motivation by describing the rewards of not smoking (general: 76.32 per cent; adolescent: 62.50 per cent). Adolescent-specific content such as peer influence on smoking was common in adolescent apps but not in general apps (general: 5.26 per cent; adolescent: 62.50 per cent). Adolescent apps had a higher general adherence content summary score [t (44) = 2.55, p = .01] and a higher adolescent content summary score [t (7.81) = 2.47, p = .04] than the general apps. On average, adolescent cessation apps included more adherence content and adolescent-specific content than general apps. Future research is needed to determine the extent to which adolescents engage with the adherence content available in these apps. PMID- 30476294 TI - An International Radiosurgery Research Foundation Multicenter Retrospective Study of Gamma Ventral Capsulotomy for Obsessive Compulsive Disorder. AB - BACKGROUND: Obsessive compulsive disorder (OCD) across its full spectrum of severity is a psychiatric illness affecting ~2% to 3% of the general population and results in significant functional impairment. There are few large patient series regarding Gamma ventral capsulotomy (GVC). OBJECTIVE: To evaluate clinical outcomes of severe medically refractory OCD treated with GVC. METHODS: This is an international, multicenter, retrospective cohort study. Forty patients with pre GVC Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores >= 24 (indicating severe OCD) were included. GVC was performed with 1 or 2 isocenters with a median maximum dose of 135 Gy (range, 120-180 Gy). Patients were deemed "responders" to GVC if there was >=35% reduction of follow-up Y-BOCS scores, and considered in remission if their Y-BOCS scores were <=16. The median follow-up was 36 mo (range, 6-96 mo). RESULTS: The median pre-SRS Y-BOCS score was 35 (range, 24-40). Eighteen patients (45%) were considered "responders," and 16 (40%) of them were in remission at their last follow-up. Nineteen patients (47.5%) remained stable with Y-BOCS of 33 (range, 26-36) following GVC, whereas 3 patients (7.5%) experienced worsening in Y-BOCS scores. Patients treated with 2 isocenters were more likely to have improvement in Y-BOCS score at 3 and 5 yr (P < .0005). Ten patients (25%) experienced post-GVC mood disturbance and neurological complications in 3 patients (7.5%). One patient developed radiation necrosis with edema that improved with steroids. CONCLUSION: GVC serves as a reasonable treatment strategy for severe medical refractory OCD. Patients treated with 2 isocenters were more likely to have substantial improvement in OCD. PMID- 30476295 TI - Disparities along the glioblastoma clinical trials landscape. PMID- 30476296 TI - Obstructive sleep apnea and dyslipidemia. From animal models to clinical evidence. AB - Lipid metabolism deregulation constitutes the pathogenic basis for the development of atherosclerosis and justifies a high incidence of cardiovascular related morbidity and mortality. Some data suggest that dyslipidemia may be associated with sleep-disordered breathing, mainly obstructive sleep apnea (OSA), due to alterations in fundamental biochemical processes, such as intermittent hypoxia (IH). The aim of this systematic review was to identify and critically evaluate the current evidence supporting the existence of a possible relationship between OSA and alterations in lipid metabolism. Much evidence shows that, during the fasting state, OSA and IH increase lipid delivery from the adipose tissue to the liver through an up-regulation of the sterol regulatory element-binding protein-1 and stearoyl-CoA desaturase-1, increasing the synthesis of cholesterol esters and triglycerides. In the postprandial state, lipoprotein clearance is delayed due to lower lipoprotein lipase activity, probably secondary to IH upregulation of angiopoietin-like protein 4 and decreased activity of the peroxisome proliferator-activated receptor alpha. Moreover, oxidative stress can generate dysfunctional oxidized lipids and reduce the capacity of high density lipoproteins (HDL) to prevent low density lipoprotein (LDL) oxidation.In the clinical field, several observational studies and a meta-regression analysis support the existence of a link between OSA and dyslipidemia. Although there is evidence of improved lipid profile after apnea-hypopnea suppression with continuous positive airway pressure (CPAP), the majority of the data come from observational studies. In contrast, randomized controlled trials evaluating the effects of CPAP on lipid metabolism present inconclusive results and two meta analyses provide contradictory evidence. PMID- 30476297 TI - Systemic Antimicrobial Prophylaxis and Antimicrobial-Coated External Ventricular Drain Catheters for Preventing Ventriculostomy-Related Infections: A Meta Analysis of 5242 Cases. AB - BACKGROUND: External ventricular drain (EVD) placement is essential for the management of many neurocritical care patients. However, ventriculostomy-related infection (VRI) is a serious complication, and there remains no well-established protocol guiding use of perioperative or extended antibiotic prophylaxis to minimize risk of VRI. OBJECTIVE: To analyze published evidence on the efficacy of extended prophylactic antimicrobial therapy and antibiotic-coated external ventricular drains (ac-EVDs) in reducing VRI incidence. METHODS: We searched PubMed for studies related to VRIs and antimicrobial prophylaxis. Eligible articles reported VRI incidence in control and treatment cohorts evaluating prophylaxis with either extended systemic antibiotics (> 24 hr) or ac-EVD. Risk ratios and VRI incidence were aggregated by prophylactic strategy, and pooled estimates were determined via random or mixed effects models. Study heterogeneity was quantified using I2 and Cochran's Q statistics. Rigorous assessment of study bias was performed, and PRISMA guidelines were followed throughout. RESULTS: Across 604 articles, 19 studies (3%) met eligibility criteria, reporting 5242 ventriculostomy outcomes. Extended IV and ac-EVD prophylaxis were associated with risk ratios of 0.36 [0.14, 0.93] and 0.39 [0.21, 0.73], respectively. Mixed effects analysis yielded expected VRI incidence of 13% to 38% with no prophylaxis, 7% to 18% with perioperative IV prophylaxis, 3% to 9% with either extended IV or ac-EVD prophylaxis as monotherapies, and as low as 0.8% to 2% with extended IV and ac-EVD dual prophylaxis. CONCLUSION: Management with both extended systemic antibiotics and ac-EVDs could lower VRI risk in ventriculostomy patients, but the impact on associated morbidity and mortality, healthcare costs, and length of stay remain unclear. PMID- 30476299 TI - Comment on: The ability of rheumatologists blinded to prior workup to diagnose rheumatoid arthritis only by clinical assessment: a cross-sectional study: reply. PMID- 30476298 TI - Snakebite envenomation in the Brazilian Amazon: a descriptive study. AB - Snakebite envenomation in the Brazilian Amazon is a recognized public health problem that does not receive the appropriate attention from key stakeholders. The morbidity rate is relevant, but still underestimated. Thus, the present study updates the current state of knowledge on snakebite envenomation in the Brazilian Amazon. It follows a descriptive method and contributes new knowledge about the dynamics of snakebites and the associated morbidity and mortality reported in the Brazilian Amazon. The study is based on information from cases registered and retrieved from the Brazilian Information System for Notifiable Diseases (Sistema de Informacao de Agravos de Notificacao-SINAN). The registers we studied covers a period of six years, 2010-2015. Most snakebites occurred in the states of Para (30 693 cases, 43.34%) and Amazonas (9386 cases, 13.25%), with a higher prevalence in males of an economically active age. The main genus involved in bites was Bothrops sp. The mortality rate was 0.24 per hundred thousand and the case fatality rate was 0.51%. Although low case fatality and mortality rates were observed, much can still be done to prevent snakebites as they continue to be a serious public health problem considering the severity and potentially high economic impact for the individual and to society. PMID- 30476300 TI - Validation of an automated sleep spindle detection method for mouse EEG. AB - Study Objectives: Sleep spindles are abnormal in several neuropsychiatric conditions and have been implicated in associated cognitive symptoms. Accordingly, there is growing interest in elucidating the pathophysiology behind spindle abnormalities using rodent models of such disorders. However, whether sleep spindles can reliably be detected in mouse electroencephalography (EEG) is controversial necessitating careful validation of spindle detection and analysis techniques. Methods: Manual spindle detection procedures were developed and optimized to generate an algorithm for automated detection of events from mouse cortical EEG. Accuracy and external validity of this algorithm was then assayed via comparison to sigma band (10-15 Hz) power analysis, a proxy for sleep spindles, and pharmacological manipulations. Results: We found manual spindle identification in raw mouse EEG unreliable, leading to low agreement between human scorers as determined by F1-score (0.26+/-0.07). Thus, we concluded it is not possible to reliably score mouse spindles manually using unprocessed EEG data. Manual scoring from processed EEG data (filtered, cubed root-mean-squared), enabled reliable detection between human scorers, and between human scorers and algorithm (F1-score>0.95). Algorithmically detected spindles correlated with changes in sigma-power and were altered by the following conditions: sleep-wake state changes, transitions between NREM and REM sleep, and application of the hypnotic drug zolpidem (10mg/kg, i.p.). Conclusions: Here we describe and validate an automated paradigm for rapid and reliable detection of spindles from mouse EEG recordings. This technique provides a powerful tool to facilitate investigations of the mechanisms of spindle generation, as well as spindle alterations evident in mouse models of neuropsychiatric disorders. PMID- 30476301 TI - Free-Base and Total Nicotine, Reactive Oxygen Species, and Carbonyl Emissions From IQOS, a Heated Tobacco Product. AB - Introduction: IQOS is an emerging heated tobacco product marketed by Philip Morris International (PMI). Because the tobacco in IQOS is electrically heated and not combusted, PMI claims that it generates significantly lower toxicant levels than combustible cigarettes. To date, a few independent studies have addressed IQOS toxicant emissions, and none have reported reactive oxygen species (ROS), and the form of the nicotine emitted by the device. Methods: In this study, IQOS aerosol was generated using a custom-made puffing machine. Two puffing regimens were used: Health Canada Intense and ISO. ROS, carbonyl compounds (CCs), and total nicotine and its partitioning between free-base and protonated forms were quantified in the IQOS aerosol by fluorescence, high performance liquid chromatography, and gas chromatography, respectively. The same toxicants were also quantified in combustible cigarette aerosols for comparison. In addition, propylene glycol and vegetable glycerin were also measured in the IQOS tobacco and aerosol. Results: IQOS and combustible cigarettes were found to emit similar quantities of total and free-base nicotine. IQOS total ROS (6.26 +/- 2.72 nmol H2O2/session) and CC emissions (472 +/- 19 ug/session) were significant, but 85% and 77% lower than levels emitted by combustible cigarettes. Conclusions: IQOS emits harmful constituents that are linked to cancer, pulmonary disease, and addiction in cigarette smokers. For a given nicotine intake, inhalation exposure to ROS and CCs from IQOS is likely to be significantly less than that for combustible cigarettes. Implications: IQOS is PMI's new heated tobacco product. PMI claims that because IQOS heats and does not burn tobacco it generates low toxicant yields. We found that one IQOS stick can emit similar free base and total nicotine yields as a combustible cigarette. A pack-a-day equivalent user of IQOS may experience significant inhalation exposure of ROS and CCs compared to background air. However, substituting IQOS for combustible cigarettes will likely result in far lower ROS and carbonyl inhalation exposure for a given daily nicotine intake. PMID- 30476302 TI - Tuberculous ureteritis. PMID- 30476303 TI - Mrc1 and Tof1 prevent fragility and instability at long CAG repeats by their fork stabilizing function. AB - Fork stabilization at DNA impediments is key to maintaining replication fork integrity and preventing chromosome breaks. Mrc1 and Tof1 are two known stabilizers that travel with the replication fork. In addition to a structural role, Mrc1 has a DNA damage checkpoint function. Using a yeast model system, we analyzed the role of Mrc1 and Tof1 at expanded CAG repeats of medium and long lengths, which are known to stall replication forks and cause trinucleotide expansion diseases such as Huntington's disease and myotonic dystrophy. We demonstrate that the fork stabilizer but not the checkpoint activation function of Mrc1 is key for preventing DNA breakage and death of cells containing expanded CAG tracts. In contrast, both Mrc1 functions are important in preventing repeat length instability. Mrc1 has a general fork protector role that is evident at forks traversing both repetitive and non-repetitive DNA, though it becomes crucial at long CAG repeat lengths. In contrast, the role of Tof1 in preventing fork breakage is specific to long CAG tracts of 85 or more repeats. Our results indicate that long CAG repeats have a particular need for Tof1 and highlight the importance of fork stabilizers in maintaining fork integrity during replication of structure-forming repeats. PMID- 30476304 TI - Impaired social functioning in children with narcolepsy. AB - Study objectives: To explore impairments in social functioning in pediatric narcolepsy patients compared to healthy children. Methods: Parents of 53 pediatric patients with narcolepsy type 1 and 64 matched healthy children completed the Social Responsiveness Scale (SRS) and the Child Behavior Checklist (CBCL 6-18). Results: Patients scored significantly higher on the total score of the SRS (median 56, IQR 23.5) compared to controls (median 44.5, IQR 8.5, U = 797.0, p<0.001). Patients also scored higher on the sum of the CBCL 6-18 subscales indicative of social functioning (Withdrawn/Depressed, Social Problems and Thought Problems; median 183, IQR 30.5) compared to controls (median 155, IQR 13, U = 500.0, p<0.001). A total of 24 patients (45.3%) reported at least mild to moderate difficulties in social functioning compared to 7 controls (10.9%, chi2 =17.165, p <0.001). Eleven patients (20.8%) and only 1 control (1.6%) had T scores above 75, which points to severely impaired social functioning (chi2= 11.602, p = 0.001). Within the patient group, girls reported mild to moderate difficulties in social functioning significantly more often compared to boys on the SRS (77.8% versus 28.6%, chi2= 17.560, p < 0.001). Conclusions: Impaired social functioning is common in children with narcolepsy type 1, especially in girls. Questionnaires such as the SRS and the CBCL 6-18 may help in early detection of social problems in pediatric narcolepsy. Recognition of these problems could be valuable in the management of young patients with narcolepsy. PMID- 30476305 TI - LncACTdb 2.0: an updated database of experimentally supported ceRNA interactions curated from low- and high-throughput experiments. AB - We describe LncACTdb 2.0 (http://www.bio-bigdata.net/LncACTdb/), an updated and significantly expanded database which provides comprehensive information of competing endogenous RNAs (ceRNAs) in different species and diseases. We have updated LncACTdb 2.0 with more data and several new features, including (i) manually curating 2663 experimentally supported ceRNA interactions from >5000 published literatures; (ii) expanding the scope of the database up to 23 species and 213 diseases/phenotypes; (iii) curating more ceRNA types such as circular RNAs and pseudogenes; (iv) identifying and scoring candidate lncRNA-associated ceRNA interactions across 33 cancer types from TCGA data; (v) providing illustration of survival, network and cancer hallmark information for ceRNAs. Furthermore, several flexible online tools including LncACT-Get, LncACT-Function, LncACT-Survival, LncACT-Network and LncACTBrowser have been developed to perform customized analysis, functional analysis, survival analysis, network illustration and genomic visualization. LncACTdb 2.0 also provides newly designed, user friendly web interfaces to search, browse and download all the data. The BLAST interface is convenient for users to query dataset by inputting custom sequences. The Hot points interface provides users the most studied items by others. LncACTdb 2.0 is a continually updated database and will serve as an important resource to explore ceRNAs in physiological and pathological processes. PMID- 30476306 TI - Assessing ventilation rate measurements in a mechanically ventilated laying hen facility. AB - Gaseous emission in laying hen facilities affects animal production performance and the environment. Emission is ruled by gas concentration and ventilation rate (VR), which are the key parameters to estimate precise emission factors. In this work, VR were assessed in a mechanical ventilated laying hen facility under Mediterranean climate conditions. The study was performed during a complete production cycle from July 2015 to October 2016. Direct hot wire anemometer (HWA) and fan rotational speed methods, and indirect CO2 mass balance method were used to assess the VR. Mean VR was 5.3 +/- 2.9 m3 h-1 hen-1 for the HWA method. The mean uncertainty of VR based on the HWA method was 8.5%, and it varied among ventilation stages from 2.3 to 12.8%. Uncertainty was higher in warm season (9.6%) than in cold season (5.4%). In relation to fan rotational speed method, mean VR was 5.9 +/- 3.3 m3 h-1 hen-1, which accounts for 8.3% more than the HWA method. According to the results, the fan rotational speed method would be less sensitive than the HWA method for assessing VR. VR was 6.3 +/- 2.1 m3 h-1 hen-1 for the CO2 balance method, which estimated lower VR values in warm season compared to the laser tachometer (LT) method (-5%) but higher values compared to the HWA method (+5%). In contrast, it estimated higher values in cold season compared to the HWA method (+23%) and LT method (+17%). Correlation analysis showed a strong correlation between the CO2 balance method and both direct methods (R = 0.85 and 0.86 for HWA and LT, respectively). PMID- 30476307 TI - International Regulatory and Scientific Effort for Improved Developmental Neurotoxicity Testing. AB - The Organisation for Economic Co-Operation and Development (OECD) coordinates international efforts to enhance developmental neurotoxicity (DNT) testing. In most regulatory sectors, including the ones dealing with pesticides and industrial chemicals registration, historical use of the in vivo DNT test guideline has been limited. Current challenges include a lack of DNT data and mechanistic information for thousands of chemicals, and difficulty in interpreting results. A series of workshops in the last decade has paved the way for a consensus among stakeholders that there is need for a DNT testing battery that relies on in vitro endpoints (proliferation, differentiation, synaptogenesis, etc.) and is complemented by alternative species (eg, zebrafish) assays. Preferably, a battery of in vitro and alternative assays should be anchored toward mechanistic relevance for applying an integrated approach for testing and assessment (IATA) framework. Specific activities have been initiated to facilitate this OECD project: the collation of available DNT in vitro methods and their scoring for readiness; the selection of these methods to form a DNT testing battery; the generation of a reference set of chemicals that will be tested using the battery; the case studies exemplifying how DNT in vitro data can be interpreted; and the development of an OECD guidance document. This manuscript highlights these international efforts and activities. PMID- 30476308 TI - Stochastic character mapping of state-dependent diversification reveals the tempo of evolutionary decline in self-compatible Onagraceae lineages. AB - A major goal of evolutionary biology is to identify key evolutionary transitions that correspond with shifts in speciation and extinction rates. Stochastic character mapping has become the primary method used to infer the timing, nature, and number of character state transitions along the branches of a phylogeny. The method is widely employed for standard substitution models of character evolution. However, current approaches cannot be used for models that specifically test the association of character state transitions with shifts in diversification rates such as state-dependent speciation and extinction (SSE) models. Here we introduce a new stochastic character mapping algorithm that overcomes these limitations, and apply it to study mating system evolution over a time-calibrated phylogeny of the plant family Onagraceae. Utilizing a hidden state SSE model we tested the association of the loss of self-incompatibility with shifts in diversification rates. We found that self-compatible lineages have higher extinction rates and lower net-diversification rates compared to self incompatible lineages. Furthermore, these results provide empirical evidence for the "senescing" diversification rates predicted in highly selfing lineages: our mapped character histories show that the loss of self-incompatibility is followed by a short-term spike in speciation rates, which declines after a time lag of several million years resulting in negative net-diversification. Lineages that have long been self-compatible, such as Fuchsia and Clarkia, are in a previously unrecognized and ongoing evolutionary decline. Our results demonstrate that stochastic character mapping of SSE models is a powerful tool for examining the timing and nature of both character state transitions and shifts in diversification rates over the phylogeny. PMID- 30476309 TI - Thoracic Discectomy Through a Unilateral Transpedicular or Costotransversectomy Approach With Intraoperative Ultrasound Guidance. AB - BACKGROUND: The disc location, extent of calcification, limited visualization of the ventral cord, and tenuous blood supply to the thoracic spinal cord pose unique technical challenges when surgically treating thoracic disc herniation. OBJECTIVE: To report our initial experience with a series of cases in which intraoperative ultrasound image guidance was used for thoracic discectomy through a unilateral transpedicular or costotransversectomy approach. METHODS: Five patients (n = 5) underwent a transpedicular approach and five (n = 5) underwent costotransversectomy for thoracic discectomy. Pre- and postoperative clinical records, operative reports, disc location/calcification, and complications were reviewed. RESULTS: There were 6 (n = 6) males and 4 (n = 4) females with an average age of 54 yr (range: 33-74). All patients had symptoms attributable to a single-level of thoracic disc herniation. Discs were classified as central (n = 5) and paracentral (n = 5). Preoperative CT and/or intraoperative visualization demonstrated calcified disc material in 6 (n = 6) patients. Final outcomes data at last follow-up was available for 9 of 10 patients. Eight of these nine patients experienced a return to normal baseline functional status. Postoperative imaging confirmed that no wrong-level surgeries were performed. The mean length of follow-up was 20.4 wk (range 4-48). CONCLUSION: Thoracic discectomy with ultrasound visualization via a unilateral transpedicular or costotransversectomy approach is safe and effective for treatment of central and paracentral calcified disc herniations. This tool improves the safety profile of thoracic discectomy and allows for treatment of thoracic discs through less invasive approaches. PMID- 30476310 TI - Proton pump inhibitors use and risk of falls. PMID- 30476311 TI - Effects of beta-1,3-glucan (AletaTM) on vaccination response in broiler chickens. AB - This 42-day study evaluated the effects of dietary supplementation with beta-1,3 glucan (AletaTM) on the vaccination response to Newcastle disease virus (NDV), avian infectious bronchitis virus (IBV), and infectious bursal disease (IBD) in a non-challenged environment. This trial included 600 chicks (all vaccinated with IBD at the hatchery) which were assigned to 1 of 3 treatments: vaccination (NDV, IBV), no vaccination, or vaccination combined with feed supplemented with Aleta (100 g/MT of feed). The vaccination with Aleta treatment group showed a trend for improved FCR that was not statistically significant. Control birds that were not vaccinated for IBV had significantly lower IBV titers on day 21 compared to birds that were vaccinated (both with and without Aleta). Surprisingly, there was significant separation among treatment groups for NDV titer levels, especially on day 21, where birds vaccinated and supplemented with Aleta had significantly higher titer levels compared to vaccination alone or no vaccination at all. Critically, only 14% of the birds receiving the vaccine plus Aleta had titer levels below the critical titer threshold for immunity compared to 28% of the birds receiving the vaccine alone and 40% of the unvaccinated birds. This suggests that Aleta supplementation may help to improve the vaccination response by birds, especially for NDV. PMID- 30476312 TI - A White Matter Fiber Microdissection Study of the Anterior Perforated Substance and the Basal Forebrain: A Gateway to the Basal Ganglia? AB - BACKGROUND: Studies detailing the anatomy of the basal forebrain (BF) from a neurosurgical perspective are missing. OBJECTIVE: To describe the anatomy of the BF and of the anterior perforated substance (APS), the BF emphasizing surgical useful anatomical relationship between surface landmarks and deep structures. METHODS: White matter fiber microdissection was performed on 5 brain specimens to analyze the topographic anatomy of the APS and expose layer-by-layer fiber tracts and nuclei of the BF. RESULTS: The APS, as identified anatomically, surgically, and neuroradiologically, has clear borders measured 23.3 +/- 3.4 mm (19-27) in the mediolateral and 12.5 +/- 1.2 mm (11-14) in the anteroposterior directions. A detailed stratigraphy of the BF was performed from the APS up to basal ganglia and thalamus allowing identification and dissection of the main components of the BF (septum, nucleus accumbens, amygdala, innominate substance) and its white matter tracts (band of Broca, extracapsular thalamic peduncle, ventral amygdalohypothalamic fibers). The olfactory trigone together with diagonal gyrus and the APS proper is a relevant superficial landmark for the basal ganglia (inferior to the nucleus accumbens, lateral to the caudate head, and medial to the lentiform nucleus). CONCLUSION: The findings in our study supplement available anatomic knowledge of APS and BF, providing reliable landmarks for precise topographic diagnosis of BF lesions and for intraoperative orientation. Surgically relevant relationships between surface and deep anatomic structures are highlighted offering thus a contribution to neurosurgeons willing to perform surgery in this delicate area. PMID- 30476313 TI - Genetic relationship between phytochromes and OsELF3-1 reveals the mode of regulation for the suppression of phytochrome signaling in rice. AB - EARLY FLOWERING3 (ELF3) functions as a nighttime repressor required for sustaining circadian rhythms and coordinating growth and development in various plant species. The rice genome carries two ELF3 homologs, namely OsELF3-1 and OsELF3-2. Previous studies have suggested that OsELF3-1 has a predominant role in controlling rice photoperiodic flowering, while also contributing to the transcriptional regulation of rice floral regulators expressed in the morning. However, OsELF3-1 has not been functionally characterized. Here, we observed that the oself3-1 mutation suppresses the photoperiod-insensitive early flowering of photoperiod sensitivity5 (se5), which is a chromophore-deficient rice mutant. Detailed analyses of the se5oself3-1 double mutant revealed the recovery of the phytochrome-dependent expression of Grain number, plant height, and heading date7 (Ghd7), a floral repressor, and Light-harvesting chlorophyll a/b binding protein (Lhcb) genes. Although the oself3-1 mutation recovered Ghd7 expression in the se5 background, there was a lack of Ghd7 expression in the phyAphyBphyC triple mutant background. These observations suggest OsELF3-1 represses Ghd7 expression by inhibiting the phytochrome signaling pathway. Comparative genome analyses indicated that OsELF3-1 was produced via gene duplication events in Oryza species, and that it is expressed throughout the day. A comparison between the oself3-1 mutant and transgenic rice lines in which OsELF3-1 and OsELF3-2 are simultaneously silenced uncovered a role for OsELF3-1 in addition to the canonical ELF3 function as an evolutionarily conserved role for a nighttime repressor that regulates the rice circadian clock. Our study confirmed that an ELF3 paralog, OsELF3-1, had a unique role involving the suppression of phytochrome signaling. PMID- 30476314 TI - Findings of CT-Derived Bone Strength Assessment in Inflammatory Bowel Disease Patients Undergoing CT Enterography in Clinical Practice. AB - Background: Inflammatory bowel disease (IBD) patients are at risk of developing complications from metabolic bone disease, but the exact prevalence is unknown. We evaluated fracture risk in IBD patients using (1) biomechanical CT analysis (BCT) using bone strength and bone mineral density (BMD), (2) Cornerstone guidelines, and (3) other clinical features predicting fracture risk. Methods: A retrospective review of consecutive IBD patients who underwent CT enterography (CTE) with BCT from March 2014 to March 2017 was performed. Measured outcomes were overall fracture risk classification (not increased, increased, or high) and femoral neck BMD World Health Organization classification (normal, osteopenia, or osteoporosis). Results: Two hundred fifty-seven patients with IBD underwent CTE and BCT. Fracture risk was classified as not increased in 45.5% (116/255) of patients, increased in 44.7% (114/255), and high in 9.8% (25/255). Femoral neck BMD was classified as normal in 56.8% (142/250), osteopenia in 37.6% (94/250), and osteoporosis in 5.6% (14/250). In multivariate analysis, only increasing age was associated with increased fracture risk (odds ratio, 1.06; 95% confidence interval, 1.04-1.08; P < 0.001). Cornerstone guidelines were met by 35.3% (41/116), 56.1% (64/114), and 76.0% (19/25) of patients in the not increased, increased, and high-risk groups, respectively (P = 0.0001). No Cornerstone criteria were met by 40% (56/139) of patients in the increased and high-risk groups. Conclusions: Using BCT, increased or high fracture risk was detected in more than half of this cohort, the prevalence being associated with increased age. A significant proportion of patients with increased or high fracture risk did not meet Cornerstone guidelines. Therefore, IBD patients who do not meet Cornerstone guidelines may benefit from BCT screening. PMID- 30476315 TI - Increasing the impact of randomized controlled trials: an example of a hybrid effectiveness-implementation design in psychotherapy research. AB - Randomized controlled trials (RCTs) are the gold standard for clinical research. However, significant delays between completion of RCTs and adoption of evidence based practices into clinical settings remain. Engagement of stakeholders and implementation-focused outcomes to augment traditional RCTs hold the potential to increase the impact of RCT outcomes for clinical practice and more rapidly lead to the adoption of evidence-based practices in clinical settings. The purpose of this study is to discuss hybrid effectiveness-implementation designs and use a project example to highlight important methodological considerations to enhance the impact of RCTs. A hybrid effectiveness-implementation study assessed the effectiveness and implementation potential of brief cognitive behavioral therapy (bCBT) for rural Veterans. A patient-randomized trial (bCBT vs. enhanced usual care) explored the impact on depression symptoms. Implementation elements included engagement of stakeholders and a multifaceted provider training and support program to increase bCBT use by providers in Veterans Health Administration (VA) community-based outpatient clinics. Implementation outcomes included the number of providers who adopted bCBT, provider fidelity, and delivery outcomes (e.g., use of measurement-based care, treatment engagement, and completion). Hybrid designs offer opportunities to improve the alignment between research and practice, potentially improving dissemination of evidence-based interventions and reducing known delays in the translation from research to practice. Expansion of traditional RCTs through collaborative stakeholder contributions and stakeholder/consumer-informed implementation approaches is critical to improve adoption postproject. Although hybrid designs offer significant benefits related to generalizability and adoption, these approaches involve complex procedures and processes and often come at the cost of reduced internal study controls. PMID- 30476317 TI - Commentary: Cost-Benefit Analysis of Transitional Care in Neurosurgery. PMID- 30476316 TI - Impact of the SRNT Health Disparities Network's Scholarship on Professional Development of Its Recipients. AB - Introduction: Diversifying the workforce is an important strategy to reducing health disparities. Since 2007, the Society for Research on Nicotine and Tobacco (SRNT) Health Disparities Network has funded a travel scholarship to promote inclusion, professional development, and diversity among investigators interested in tobacco-related health disparities research. This study examined indicators of productivity among former scholarship recipients. Methods: Scholarship recipients between 2007 and 2014 were invited to complete a survey online. The survey assessed demographic characteristics, academic productivity, and perceived professional benefit resulting from the scholarship. Results: Of the 117 scholarships recipients, 89 (77%) responded. Respondents were 67% female and had a mean age of 37.8 years. Twenty eight percent were African-American, 25% Asian American, and 17% Latino. Most respondents worked in academia (80%) and nearly three-quarters (74%) reported publishing manuscripts on tobacco-related disparities, with a mean of 3.8 (SD 4.4) disparities-related publications since receiving the scholarship. Respondents' work focused on a wide range of health disparities topics and nearly all respondents reported that the scholarship removed barriers to attending the meeting and reported professional benefit from receiving the travel scholarship. Conclusions: Following receipt of the SRNT travel scholarship, a diverse group of scientists demonstrated scholarly productivity, professional development, and advancement of health disparities research. Similar efforts are encouraged in other professional societies. PMID- 30476318 TI - Detection of Arithmetic Violations During Sleep. AB - Can the sleeping brain develop predictions of future auditory stimuli? Past research demonstrated disrupted prediction capabilities during sleep in the context of novel, arbitrary auditory sequences, but the availability of over learned knowledge already stored in long-term memory could still be preserved. We tested the sleeping brain capabilities to detect violations of simple arithmetic facts. Sleeping subjects were presented with spoken arithmetic facts such as "two plus two is nine" and brain responses to correct or incorrect results were recorded in electro and magneto-encephalography. Sleep responses were compared to both attentive and inattentive wakefulness. During attentive wakefulness, arithmetic violations elicited a succession of N400 and P600 effects, while no such activations could be recorded in sleep or in inattentive wakefulness. Still, small but significant effects remained in sleep, advocating for a preserved but partial accessibility to arithmetic facts stored in long-term memory and preserved predictions of low-level and already learned knowledge. Those effects were very different from residual activities seen in inattention, highlighting the differences of information processing between the sleeping and the inattentive brain. PMID- 30476319 TI - Dissemination and implementation of the ICAMP. AB - The current rate of immunizations for older adults does not meet the immunization goals for Healthy People 2020. Using a Social Ecological Model and Social Cognitive Theory, the purpose of this study was to disseminate and implement the Immunization Champions, Advocates and Mentors Program (ICAMP) into a variety of health care settings. This study used a single group pre-/post-test design. Champions were recruited nationally. Five geographically diverse face-to-face meetings were held to train health care providers to be ICAMP immunization champions. Dissemination and implementation of ICAMP was evaluated using the Reach, Efficacy/Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) model. Participants were surveyed at baseline for descriptive information and were asked to gather immunization rates for at least one particular vaccine and provide follow-up data on progress toward goal achievement. A total of 212 champions from 82 settings participated in ICAMP. The majority were nurses (111/212, 52%). With regard to reach, we obtained 212 applications from individuals in a variety of settings interested in becoming champions. With regard to effectiveness, the majority of the champions (n = 178/212, 84%) used ICAMP material, 88% (n = 186/212) made changes related to immunization processes within their setting, and all reported that immunization practices improved. The majority used the toolkit materials up through 60 days following ICAMP. Sustained use of materials after the 60-day follow-up was less evident. ICAMP was implemented as intended and was effective in changing processes around immunizations. Ongoing work is needed to determine whether ICAMP improves immunization rates. PMID- 30476320 TI - Impact of troop leader training on the implementation of physical activity opportunities in Girl Scout troop meetings. AB - Girl Scouts (GS) is a setting with large reach to target increased moderate-to vigorous physical activity (MVPA) in girls. The Scouting Nutrition and Activity Program (SNAP) increased MVPA during intervention troop meetings; therefore, further examination of implementation of SNAP components is warranted to determine the processes contributing to intervention success. The purpose of this study is to examine variability in implementation of an active recreation (AR) policy into GS troop meetings. Troop leaders (n = 7) were randomized to receive SNAP, an intervention training on implementing a policy promoting AR, or a standard control. Meetings (seven meetings/troop) were observed, and girls in attendance (n = 76, 9-13 years, mean +/- SD = 10.51 +/- 1.19 years) wore ActiGraph GT1M accelerometers. Two observers attended each meeting and recorded start/stop points of AR time segments, as well as other tasks (i.e., opening/closing, snack, and Girl Scout curriculum [GSC]). Time-segmented accelerometer data were analyzed using Evenson cut points and paired with observation data. Researchers observed 181 segments (mean/day +/- SD = 3.77 +/- 1.24). Intervention troops implemented more AR segments/day (mean/day = 0.86; 95% CI = 0.62-1.09) than control troops (mean/day = 0.18; 95% CI = 0.00-0.39). A greater percentage of time (%time) was spent in MVPA during AR segments (mean = 10.99; 95% CI = 7.16-14.82) compared with GSC segments (mean = 0.73; 95% CI = 0.00-4.10), opening/closing (mean = 3.96; 95% CI = 0.54-7.38), and snack (mean = 0.74; 95% CI = 0.00-4.10) segments, and during opening/closing segments compared with GSC and snack segments. Intervention troops implemented more AR segments than control troops. Troop meeting patterns of PA were influenced by task. Adding time segments conducive to PA could increase the %time spent in MVPA during GS troop meetings. PMID- 30476321 TI - Loop-mediated isothermal amplification: rapid molecular detection of virulence genes associated with avian pathogenic Escherichia coli in poultry. AB - Infections with pathogenic Escherichia coli can lead to different animal- and human-associated diseases. E. coli infections are common in intensive poultry farming, and important economic losses can be expected during infections with avian pathogenic E. coli (APEC) strains followed by colibacillosis. Loop-mediated isothermal amplification (LAMP) assays were developed for rapid detection of 3 APEC-associated virulence genes: sitA, traT, and ompT. All 3 LAMP assays are shown to be specific, repeatable, and reproducible. High sensitivities of the assays are shown, where as few as 1,000 bacterial cells/mL can be detected in different matrices. On-site applicability of this LAMP method is demonstrated through testing of different sample types, from animal swabs and tissues, and from environmental samples collected from 6 commercial poultry farms. All 3 virulence genes were detected at high rates (above 85%) in samples from layer and broiler chickens with clinical signs and, interestingly, high prevalence of those genes was detected also in samples collected from clinically healthy broiler flock (above 75%) while lower prevalence was observed in remaining 3 clinically healthy chicken flocks (less than 75%). Importantly, these virulence genes were detected in almost all of the air samples from 11 randomly selected poultry houses, indicating air as an important route of E. coli spread. Three LAMP assays that target APEC-associated virulence genes are shown to be sensitive and robust and are therefore applicable for rapid on-site testing of various sample types, from animal swabs to air. This on-site LAMP testing protocol offers rapid diagnostics, with results obtained in <35 min, and it can be applied to other important microorganisms to allow the required prompt measures to be taken. PMID- 30476322 TI - U.S. Police Rosters: Fatigue and Public Complaints. AB - Study Objectives: Recent experimental research indicates a substantial impact of fatigue on police officers' encounters with the public. In recent years, biomathematical models of fatigue have provided a new way to identify potential relationships between working time arrangements and job performance. This study focused on public complaints against police officers and determined whether the odds of a public complaint were associated with work schedules and/or a biomathematical model's predictions of fatigue and sleepiness. Methods: N=144 police officers from two municipal police departments in the United States reported shift start times, shift hours, court hours, and public complaints each duty day during study participation. A biomathematical model of fatigue (FAID Quantum) predicted sleep duration and sleep timing and inferred fatigue and sleepiness for 15,744 shifts. Fatigue, sleepiness, 24-hour sleep estimates, and work schedule were tested as predictors of public complaints. Results: Greater fatigue, greater sleepiness, and less sleep in the 24-hours prior to a shift increased the odds of a public complaint (F>=9.14, p<0.01). Working back-to-back night shifts increased the odds of a public complaint (OR=4.27, p<0.01), particularly when off-duty court hours were worked between the night shifts (OR=4.73, p<0.01). Conclusions: On-duty fatigue and sleepiness, sleep obtained prior to a shift, and working night shifts were strongly associated with public complaints. Off-duty court appearances reduced sleep between night shifts and further increased the odds of a public complaint. The results suggest that off duty court hours should be limited between night shifts and duty schedules should be considered when scheduling court appearances. PMID- 30476323 TI - Informal Caregiving and Network Turnover Among Older Adults. AB - Objectives: Personal network turnover, a combination of lost and added network contacts, is suggested to affect health as well as moderate access to social support and resources. This paper tests whether the caregiving process is associated with network turnover in later life and whether the process is different for men and women. Method: Network turnover was assessed using two waves of personal network data from the National Social Life, Health, and Aging Project. Network contacts were uniquely identified in each wave making it possible to document contact loss and addition. Rates of change were modeled using Poisson regression. Results: Respondents transitioning into caregiving lost and added network contacts at higher rates than non-caregivers. Conversely, respondents providing care during both waves and respondents transitioning out of the role saw no significant levels of network turnover. The analysis provided minimal evidence of gender differences. Discussion: Findings suggest that the initial shift into the caregiving role is associated with notable personal network change. This is an important consideration given that long-term network instability may lead to poor health and limited access to social resources whereas adaptive network change tends to elicit more positive outcomes. PMID- 30476324 TI - Doxorubicin induces ER calcium release via Src in rat ovarian follicles. AB - Although doxorubicin has been widely used as an anticancer drug, it has dose dependent toxic effects on ovarian follicle development and apoptosis, oocyte maturation and hormone secretion. Ca2+ signaling also has vital roles in the same cellular functions of ovarian follicles, indicating a strong link with doxorubicin-induced ovarian toxicity. In the current project, doxorubicin induced Ca2+ alternations in cultured rat ovarian follicles have been explored with the fluorescence resonance energy transfer technology. The results reveal that doxorubicin enhances the cytosolic Ca2+ level smoothly. Further experiments confirm that the endoplasmic reticulum (ER) calcium, but not the extracellular calcium influx, is the main source of intracellular calcium increase. Moreover, Src kinase activation could be the upstream of doxorubicin-induced ER calcium release. Therefore, this project demonstrates that doxorubicin increases the cytosolic Ca2+ mainly by releasing calcium from ER via Src kinase activation in ovarian follicles, which provides deeper understanding of doxorubicin induced ovarian toxicity. PMID- 30476326 TI - Reciprocal Dynamics of Solo-Living and Health among Older Adults in Contemporary China. AB - Objectives: Solo-living has far-reaching implications for older adults' well being. The causal impacts and the pathways of solo-living on health and wellbeing of older adults are still unclear. This study examines the correlates of solo living and subsequent health outcomes of solo-living among older adults in mainland China. Methods: We draw data from four waves of a nationwide survey with a total of 9,714 older adults aged 65 or older who had at least three interviews in 2005-2014. A generalized structural equation modeling approach was applied to examine what factors are associated with solo-living status and whether and how the antecedent of solo-living status subsequently affects wellbeing and health. Results: Owning a home, having no living child, and a preference to live independently are positively correlated with living alone, whereas living in a city, having economic independence, being educated, and having poor physical and cognitive functions are associated with lower odds of solo-living. Older Chinese adults who live alone are more likely to feel lonely and have a lower life satisfaction, yet they are more likely to be involved in social/leisure activities, have fewer physical disabilities and a lower mortality risk. Discussion: There is a bi-directional relationship between solo-living and wellbeing/health among the Chinese older adults. Solo-living is a conditioned choice of a set of critical factors among older Chinese. The greater involvement in social/leisure activities is likely a key for Chinese solo-living older adults to mitigate the negative impact of their lower psychological wellbeing on subsequent mortality. PMID- 30476325 TI - Upfront Magnetic Resonance Imaging-Guided Stereotactic Laser-Ablation in Newly Diagnosed Glioblastoma: A Multicenter Review of Survival Outcomes Compared to a Matched Cohort of Biopsy-Only Patients. AB - BACKGROUND: Laser ablation (LA) is used as an upfront treatment in patients with deep seated newly diagnosed Glioblastoma (nGBM). OBJECTIVE: To evaluate the outcomes of LA in patients with nGBM and compare them with a matched biopsy-only cohort. METHODS: Twenty-four nGBM patients underwent upfront LA at Cleveland clinic, Washington University in St. Louis, and Yale University (6/2011-12/2014) followed by chemo/radiotherapy. Also, 24 out of 171 nGBM patients with biopsy followed by chemo/radiotherapy were matched based on age (< 70 vs >= 70), gender, tumor location (deep vs lobar), and volume (<11 cc vs >=11 cc). Progression-free survival (PFS), overall survival (OS), and disease-specific PFS and OS were outcome measures. Three prognostic groups were identified based on extent of tumor ablation by thermal-damage-threshold (TDT)-lines. RESULTS: The median tumor volume in LA (n = 24) and biopsy only (n = 24) groups was 9.3 cm3 and 8.2 cm3 respectively. Overall, median estimate of OS and PFS in LA cohort was 14.4 and 4.3 mo compared to 15.8 mo and 5.9 mo for biopsy only cohort. On multivariate analysis, favorable TDT-line prognostic groups were associated with lower incidence of disease specific death (P = .03) and progression (P = .05) compared to other groups including biopsy only cohort. Only age (<70 yr, P = .02) and tumor volume (<11 cc, P = .03) were favorable prognostic factors for OS. CONCLUSION: The maximum tumor coverage by LA followed by radiation/chemotherapy is an effective treatment modality in patients with nGBM, compared to biopsy only cohort. The TDT-line prognostic groups were independent predictor of disease specific death and progression after LA. PMID- 30476327 TI - A blind man with an acute abdomen. PMID- 30476328 TI - Effects of dietary leucine supplementation and immune system stimulation on plasma amino acid concentrations and tissue protein synthesis in starter pigs. AB - Immune system stimulation (ISS) adversely affects protein and amino acid (AA) metabolism and reduces productivity in pigs. Leucine (Leu) has a regulatory role in skeletal muscle protein turnover, which may be affected by ISS. The objective of this study was to evaluate the effects of ISS and dietary Leu supplementation on the protein fractional synthesis rate (FSR) of various tissues in pigs. Yorkshire barrows were surgically fitted with jugular vein catheters and assigned to one of three dietary treatments: 1. CON, 1.36% standardized ileal digestible Leu (SID; n = 13); 2. LEU-M, 2.04% SID Leu (n = 8); and 3. LEU-H, 2.72% SID Leu (n = 7). The diets were formulated to contain all essential amino acids 10% above estimated requirements for maximum whole-body protein deposition for this body weight (BW) range. At the start of the 36-h challenge period (initial BW = 14.5 +/- 0.8 kg), ISS was induced in all LEU-M and LEU-H pigs and half of CON pigs with LPS (ISS+); the remaining CON pigs were injected with saline (ISS-). During challenge period, pigs were fed every 4 h and feed intake of ISS- pigs was kept equal to ISS+ pigs. At the end of the challenge period, FSR of liver, plasma, gastrocnemius, and longissimus dorsi proteins were determined with a flooding dose of L-[ring- 2H5]phenylalanine (40 mol %). All essential AA, most nonessential AA, and plasma urea-N peaked at 12 h and declined to baseline levels at 36 h after ISS was induced in ISS+ pigs (P < 0.05), whereas plasma AA and urea N concentrations were constant in ISS- pigs. At 36 h, dietary Leu supplementation resulted in a linear decline in plasma isoleucine, valine, glutamine, urea nitrogen concentrations (P < 0.05), whereas plasma Leu concentration was unaffected. Liver protein FSR was increased in ISS+ pigs (P < 0.05), whereas plasma and skeletal muscle protein FSR was not affected by ISS. Dietary Leu supplementation tended to diminish liver protein FSR (linear reduction; P = 0.052) and increase gastrocnemius protein FSR (linear increase; P = 0.085) in ISS+ pigs. Leucine supplementation above estimated requirements may support repartitioning of AA from visceral to peripheral protein deposition during ISS. PMID- 30476330 TI - In Reply: Side-to-side and End-to-Side Double-Anastomosis Using the Parietal Branch of the Superficial Temporal Artery-A Novel Technique for Extracranial to Intracranial Bypass Surgery: 3-Dimensional Operative Video. PMID- 30476329 TI - A Novel Positive Regulator of the Early Stages of the Root Nodule Symbiosis Identified by Phosphoproteomics. AB - Signals and signaling pathways underlying the symbiosis between legumes and rhizobia have been studied extensively over the past decades. In a previous phosphoproteomic study on the Medicago truncatula - Sinorhizobium meliloti symbiosis, we identified plant proteins that are differentially phosphorylated upon the perception of rhizobial signals, called Nod factors. In this study, we provide experimental evidence that one of these proteins, Early Phosphorylated Protein 1 (EPP1), is required for the initiation of this symbiosis. Upon inoculation with rhizobia, MtEPP1 expression was induced in curled root hairs. Down-regulation of MtEPP1 in M. truncatula roots almost abolished calcium spiking, reduced the expression of essential symbiosis-related genes (MtNIN, MtNF YB1, MtERN1, and MtENOD40), and strongly decreased nodule development. Phylogenetic analyses revealed that orthologs of MtEPP1 are present in legumes and specifically in plant species able to host arbuscular mycorrhizal fungi, suggesting a possible role in this association too. Short chitin oligomers induced the phosphorylation of MtEPP1 like Nod factors. However, the down regulation of MtEPP1 affected the colonization of M. truncatula roots by arbuscular mycorrhizal fungi only moderately. Altogether, these findings indicate that MtEPP1 is essential for the establishment of the legume-rhizobia symbiosis but might plays a limited role in the arbuscular mycorrhizal symbiosis. PMID- 30476332 TI - Off-label Use in Ambulatory Paediatric Clinics in a Central South African Hospital. AB - Aim: The aim of this article was to determine off-label (OL) use in paediatric ambulatory clinics in a South African central hospital. Patients and methods: OL medicine events were documented in three paediatric clinics (general, highly specialized and dedicated HIV paediatric clinics) at Tygerberg Hospital, South Africa, and analysed according to South African medicine registration information. Results: There were 2167 medicine events for 658 children. Mean age was 5.6 years (interquartile range 1.8-8.8). There were 123 OL medicine events (6%). Extemporaneous OL use was most common (n = 58, 47%), followed by weight (n = 45, 37%) and lack of paediatric data (n = 38, 31%). Of note was OL use for weight for general paediatrics (n = 32, 78%, p < 0.001), lack of appropriate paediatric data for highly specialized paediatrics (n = 26, 61%, p = 0.004) and extemporaneous use for HIV-infected children (n = 34, 87%, p < 0.001), with significant less OL use for HIV-infected children (p = 0.009). Conclusions: Of note is significant extemporaneous OL use in HIV-infected children. PMID- 30476331 TI - Ullanlinna Narcolepsy Scale in Diagnosis of Narcolepsy. AB - Study objectives: To validate Ullanlinna Narcolepsy Scale (UNS) as a screening tool for narcolepsy in a clinical population and to compare it with Swiss Narcolepsy Scale (SNS) and Epworth Sleepiness Scale (ESS). Methods: UNS questionnaires of 267 subjects visiting Helsinki Sleep Clinic were analyzed. The diagnoses of the subjects were narcolepsy type 1 (NT1, n = 89), type 2 (NT2, n = 10), other hypersomnias (n = 24), sleep apnea (n = 37), restless legs or periodic limb movement disorder (n = 56), and other sleep-related disorders (n = 51). In addition, ESS and SNS scores in a subset of sample (total n = 167) were analyzed and compared to UNS. Results: Mean UNS score in NT1 was 22.0 (95% CI 20.4, 23.6, range 9-43) which was significantly higher than in other disorders, including NT2 (mean 13.7, 95% CI 10.3, 17.1, range 7-21, P = .0013). Sensitivity and specificity of UNS in separating NT1 from other disorders were 83.5% and 84.1%, respectively. Positive and negative predictive values were 82.5% and 85.1%. Sensitivities of SNS and ESS in NT1 were 77.2% and 88.6%, and specificities 88.6% and 45.5%, respectively. There were no differences in receiver operating characteristic curves between UNS and SNS. UNS had moderate negative correlation with hypocretin-1 levels (rs -.564, P < .001), and mean sleep latency in MSLT (rs= -.608, P < .001). Conclusions: UNS has high specificity and sensitivity for NT1 in a sleep clinic setting. UNS scores below 9 strongly suggest against the diagnosis of narcolepsy. PMID- 30476333 TI - Encouraging patients to disclose their lesbian, gay, bisexual, or transgender (LGBT) status: oncology health care providers' perspectives. AB - A compelling touted strategy for reducing discrimination towards lesbian, gay, bisexual, and transgender (LGBT) patients is improving communicative competence of health care providers (HCPs); however, evidence base for describing communication practices between HCPs and LGBT patients is scarce. The purpose of this study was to qualitatively examine HCP experiences and perspectives as they relate to patient sexual orientation and gender identity (SOGI) disclosure, perceived communication and structural/administrative challenges in interactions with LGBT patients, and suggestions for improving care of LGBT patients. The sample consisted of 1,253 HCPs, who provided open-ended responses to an online cross-sectional survey conducted at a Comprehensive Cancer Center in the Northeastern United States. The open-ended responses were inductively and deductively coded for key themes and sub-themes. The results demonstrated an array of useful communication strategies employed by oncology HCPs to encourage LGBT patients' SOGI disclosure (direct questions regarding sexual orientation, use of the term "partner," and using correct pronouns), communication and structural/administrative challenges faced by HCPs in providing care (HCP own fears and biases, transgender patient care, insurance issues, and procedural challenges for LGBT patients), and suggested recommendations from oncology HCPs to improve their care delivery for LGBT patients (more provider-based training, improving awareness of LGBT-friendly resources, establishing trusting relationships, and not assuming sexuality or gender identity). These findings have implications for developing and evaluating training programs to improve LGBT sensitivity and communication among HCPs, and encourage SOGI disclosure in an open and judgment-free health care environment. PMID- 30476334 TI - In Reply: Lumboperitoneal Shunts for the Treatment of Idiopathic Normal Pressure Hydrocephalus: A Comparison of Small-Lumen Abdominal Catheters to Gravitational Add-On Valves in a Single Center. PMID- 30476335 TI - The search for the ejecting chair: a mixed-methods analysis of tool use in a sedentary behavior intervention. AB - Research is needed on interventions targeting sedentary behavior with appropriate behavior-change tools. The current study used convergent sequential mixed methods (QUAN + qual) to explore tool use during a edentary behavior intervention. Data came from a two-arm randomized sedentary behavior pilot intervention. Participants used a number of intervention tools (e.g., prompts and standing desks). Separate mixed-effects regression models explored associations between change in number of tools and frequency of tool use with two intervention targets: change in sitting time and number of sit-to-stand transitions overtime. Qualitative data explored participants' attitudes towards intervention tools. There was a significant relationship between change in total tool use and sitting time after adjusting for number of tools (beta = -12.86, p = .02), demonstrating that a one-unit increase in tool use was associated with an almost 13 min reduction in sitting time. In contrast, there was a significant positive association between change in number of tools and sitting time after adjusting for frequency of tool use (beta = 63.70, p = .001), indicating that increasing the number of tools without increasing frequency of tool use was associated with more sitting time. Twenty-four semistructured interviews were coded and a thematic analysis revealed four themes related to tool use: (a) prompts to disrupt behavior; (b) tools matching the goal; (c) tools for sit-to-stand were ineffective; and (d) tool use evolved over time. Participants who honed in on effective tools were more successful in reducing sitting time. Tools for participants to increase sit-to-stand transitions were largely ineffective.This study is registered at clincialtrials.gov. Identifier: NCT02544867. PMID- 30476336 TI - QUANTITATIVE ESTIMATION OF EXPOSURE INHOMOGENEITY IN TERMS OF EYE LENS AND EXTREMITY MONITORING FOR RADIATION WORKERS IN THE NUCLEAR INDUSTRY. AB - To manage the equivalent doses for radiation workers, exposure inhomogeneity is an important factor in the decision-making process related to protection measures and additional monitoring. Our previous study proposed the methodology to evaluate the inhomogeneity of exposure quantitatively. In this study, we applied proposed method to five different types of actual exposure situations encountered in the nuclear industry. Two of them were conventionally characterized as homogeneous exposure, and the other three were conventionally characterized as inhomogeneous exposure. The evaluation of homogeneity exposure was conducted using Monte Carlo calculations with two simplified models, which were then verified with phantom experiments. Consequently, all of the evaluations reproduced the experimental results, implying that our proposed method would be applicable for actual work conditions in the nuclear industry. Furthermore, the two presumed homogeneous exposure situations were found to be rather inhomogeneous because of the contribution of positrons and the limited source region. The results also show that the worker's posture has an impact on the inhomogeneity rather than the energy of incident radiation in nuclear works. The investigation also implies that obtaining the information on the most probable posture of the exposed worker, as well as the existence of the weekly penetrating radiation such as beta+/- ray as a main source of exposure would be the key for more precise estimation. PMID- 30476337 TI - Bacteriophage therapy increases complement mediated lysis of bacteria and enhances bacterial clearance after acute lung infection with MDR Pseudomonas aeruginosa. AB - Emergence of multidrug resistant (MDR) bacterial infections is a major problem in clinical medicine. Development of new strategies such as phage therapy may be a novel approach for treatment of life threatening infections caused by MDR bacteria. A newly isolated phage MMI-Ps1 with strong lytic activity was used for treatment of acute lung infection with P. aeruginosa in a mouse model. Intranasal administration of a single dose of MMI-Ps1 at zero time post infection provides a significant level of protection and increases the survival time. Moreover, treatment of infected mice with phage as late as 12 h post infection was still protective. Our in vitro results showed for the first time the synergistic elimination of serum resistant pseudomonas strains by phage and complement. Phage therapy increases the efficacy of complement-mediated lysis of serum resistant P. aeruginosa strains indicating the importance of intact complement system in clearing pseudomonas infection during phage therapy. PMID- 30476338 TI - Metastatic Phalangeal Disease. PMID- 30476339 TI - 'T' twist: Wellens syndrome. PMID- 30476340 TI - Reassessing "Praecox Feeling" in Diagnostic Decision Making in Schizophrenia: A Critical Review. AB - The "Praecox Feeling" (PF) is a classical concept referring to a characteristic feeling of bizarreness experienced by a psychiatrist while encountering a person with schizophrenia. Although the PF used to be considered a core symptom of the schizophrenia spectrum, it fell into disuse since the spread of operationalized diagnostic methods (Diagnostic and Statistical Manual of Mental Disorders/International Classification of Diseases systems). In contemporary research on schizophrenia, it remains largely unaddressed. This critical review investigates the evolution of the PF in historical and contemporary literature and presents an exhaustive overview of empirical evidence on its prevalence in clinical decision making, its reliability and validity. The review demonstrates that the PF is a real determinant of medical decision making in schizophrenia, although, without further research, there is not enough evidence to sustain its rehabilitation as a reliable and valid clinical criterion. PF-like experiences should not be opposed to any criteriological attitude in diagnosis and would be clinically useful if the conditions of descriptive precaution and rigorous epistemology are maintained. The aim of teaching clinical expertise is to transform this basic experience into a well-founded clinical judgment. Finally, the article discusses the possible relevance of the PF for basic science and clinical research according to a translational approach inspired by phenomenology. PMID- 30476341 TI - All-trans retinoic acid disrupts development in ex vivo cultured fetal rat testes. II: Modulation of mono-(2-ethylhexyl) phthalate toxicity. AB - Humans are universally exposed to low levels of phthalate esters (phthalates), which are used to plasticize polyvinyl chloride. Phthalates exert adverse effects on the development of seminiferous cords in the fetal testis through unknown toxicity pathways. To investigate the hypothesis that phthalates alter seminiferous cord development by disrupting retinoic acid signaling in the fetal testis, gestational day 15 fetal rat testes were exposed for 1-3 days to 10-6 M all-trans retinoic acid (ATRA) alone or in combination with 10-6 to 10-4 M mono (2-ethylhexyl) phthalate (MEHP) in ex vivo culture. As previously reported, exogenous ATRA reduced seminiferous cord number. This effect was attenuated in a concentration-dependent fashion by MEHP co-exposure. ATRA and MEHP-exposed testes were depleted of DDX4-positive germ cells but not Sertoli cells. MEHP alone enhanced the expression of the retinoic acid receptor target Rbp1 and the ovary development-associated genes Wnt4 and Nr0b1, and suppressed expression of the Leydig cell marker, Star, and the germ cell markers, Ddx4 and Pou5f1. In co exposures, MEHP predominantly enhanced the gene expression effects of ATRA, but the Wnt4 and Nr0b1 concentration-responses were non-linear. Similarly, ATRA increased the number of cells expressing the granulosa cell marker FOXL2 in testis cultures, but this induction was attenuated by addition of MEHP. These results indicate that MEHP can both enhance and inhibit actions of ATRA during fetal testis development and provide evidence that retinoic acid signaling is a target for phthalate toxicity in the fetal testis. PMID- 30476342 TI - Risk of severe dengue is higher in patients with sickle cell disease: a scoping review. PMID- 30476343 TI - Feasibility and acceptability of a faith-based mind-body intervention among African American adults. AB - Physical activity reduces cancer risk, yet African American adults remain insufficiently active, contributing to cancer health disparities. Harmony & Health (HH) was developed as a culturally adapted mind-body intervention to promote physical activity, psychosocial well-being, and quality of life among a church-based sample of overweight/obese, insufficiently active African American adults. Men and women were recruited to the study through an existing church partnership. Eligible participants (N = 50) were randomized to a movement-based mind-body intervention (n = 26) or waitlist control (n = 24). Participants in the intervention attended 16 mind-body sessions over 8 weeks and completed a physical assessment, questionnaires on moderate-to-vigorous physical activity (MVPA) and psychosocial factors, and accelerometry at baseline (T1), post-intervention (T2), and 6 week follow-up (T3). Eighty percent of participants (94% women, M age = 49.7 +/- 9.4 years, M body mass index = 32.8 +/- 5.2 kg/m2) completed the study, and 61.5% of intervention participants attended >=10 mind-body sessions. Participants self-reported doing 78.8 +/- 102.9 (median = 40.7, range: 0-470.7) min/day of MVPA and did 27.1 +/- 20.7 (median = 22.0, range: 0-100.5) min/day of accelerometer-measured MVPA at baseline. Trends suggest that mind-body participants self-reported greater improvements in physical activity and psychosocial well-being from baseline to post-intervention than waitlist control participants. HH is feasible and acceptable among African American adults. Trends suggest that the mind-body intervention led to improvements in physical activity and psychosocial outcomes. This study extends the literature on the use of mind body practices to promote physical and psychological health and reduce cancer disparities in African American adults. PMID- 30476344 TI - Strategies to address clinician hesitancy toward conservative care. PMID- 30476345 TI - Cuticle deposition improves the biosecurity of eggs through the laying cycle and can be measured on hatching eggs without compromising embryonic development. AB - The cuticle is part of the egg's natural defense and it can be improved by genetic selection. Prior to adoption of this measurement in breeding programs, questions that need to be addressed are whether improved cuticle deposition will result in a reduced risk of eggs becoming contaminated and whether selection for this trait will have any unintended consequences on the incubation process. Bacterial penetration experiments were carried out using eggs from a pedigree line of broiler breeders (BB) and Rhode Island Red (RIR) layers. Within the natural variation in cuticle deposition in each line, a good cuticle was shown to reduce an egg's susceptibility to penetration by Escherichia coli (BB, P = 0.023) and Salmonella typhimurium (RIR, P < 0.001). Deglycosylation of cuticle proteins had little effect on their antimicrobial activity. The effect of bird age on cuticle deposition was also examined. Shell color decreased with age as anticipated; however, we found no evidence that cuticle deposition decreases with age, at least up to 50 wk. A thicker cuticle could affect the water vapor conductance (WPC) of hatching eggs. The WPC of eggs was, therefore, measured on eggs selected from the top and tail of the cuticle distribution, this time in a Lohmann Selected Leghorn (LSL) pedigree line. Broiler breeder eggs were also tested. No evidence of a relationship between cuticle deposition and WPC was found for LSL or BB eggs. Cuticle deposition measurements require eggs to be stained. Here, we show that this has no adverse effect on embryo development at d 12 of incubation. Thus, we conclude that cuticle deposition is important in preventing bacterial penetration of eggs in genetically divergent breeds of chicken and that the measurement can be practically incorporated into breeding programs. This will contribute to improving the biosecurity of eggs by reducing vertical and horizontal transmission of potentially zoonotic and pathogenic organisms from parent to offspring. PMID- 30476346 TI - Towards a Complete Taxonomy of Resting State Networks Across Wakefulness and Sleep: An Assessment of Spatially Distinct Resting State Networks Using Independent Component Analysis. AB - Resting state network (RSN) functional connectivity (FC) has been investigated under a wealth of different healthy and compromised conditions. However such investigations are often dependent on the defined spatial boundaries and nodes of so-called canonical RSNs, themselves the product of extensive deliberations over distinctions between functional magnetic resonance imaging (fMRI) noise and neural signal, specifically in the context of the healthy waking state. However, a similar unbiased cataloguing of noise and networks remains to be done in other states, particularly sleep, a healthy alternate mode of the brain that supports distinct operations from wakefulness, such as dreaming and memory consolidation. The purpose of this study was to explicitly test the hypothesis that there are RSNs unique to sleep. Simultaneous electroencephalography (EEG) and fMRI was used to record brain activity of non-sleep-deprived subjects. Independent component analysis (ICA) was performed on both rapid eye movement (REM; N = 7) and non-REM sleep stage fMRI data (non-REM2; N = 28, non-REM3; N = 11), with the resulting components spatially correlated with the canonical RSNs, for the purpose of identifying spatially distinct RSNs. Surprisingly, all low-correlation components were positively identified as noise, and all high-correlation components comprised the canonical set of RSNs typically observed in wake, indicating that sleep is supported by much the same RSN architecture as wakefulness, despite the unique operations performed during sleep. This further indicates that the implicit assumptions of prior studies, i.e., that the canonical RSNs apply to sleep FC analysis, are valid and have not overlooked sleep-specific RSNs. PMID- 30476347 TI - Immune rebalancing by oral immunotherapy: A novel method for getting the immune system back on track. AB - Immune modulating treatments are often associated with immune suppression or an opposing anti-inflammatory paradigm. As such, there is a risk of exposing patients to infections and malignancies. Contrarily, eliciting only mild immune modulation can be insufficient for alleviating immune-mediated damage. Oral immunotherapy is a novel approach that uses the inherent ability of the gut immune system to generate signals that specifically suppress inflammation at affected sites, without inducing generalized immune suppression. Oral immunotherapy is being developed as a method to rebalance systemic immunity and restore balance, getting it back on track, rather than pushing the immune response too much or too little in opposing directions. Here, I review recent preclinical and clinical data examining the technique and describe its primary advantages. PMID- 30476348 TI - Access to All-Carbon Spirocycles through a Carbene and Thiourea Cocatalytic Desymmetrization Cascade Reaction. AB - A new catalytic approach for asymmetric quick access to spirocycles is disclosed. The reaction involves a carbene and thiourea co-catalyzed desymmetrization process with simultaneous installation of a spirocyclic core. The use of a thiourea co-catalyst is critical to turn on this reaction, as no product was formed without the presence of the thioureas. Our study constitutes the first success in carbene-catalyzed enantioselective synthesis of all-carbon spirocycles. Products from our reactions can be readily transformed to sophisticated multi-cyclic molecules and chiral ligands. PMID- 30476349 TI - The S-S bridge: An experimental-computational mixed estimation of the equilibrium structure of diphenyl disulfide. AB - The disulfide bridge (-S-S-) is an important structural motif in organic and protein chemistry, but only a few accurate equilibrium structures are documented. We report the results of supersonic-jet microwave spectroscopy experiments on the rotational spectra of diphenyl disulfide, C6H5-S-S-C6H5 (including all 13C and 34S monosubstituted isotopologues), and the determination of the equilibrium structure by the mixed estimation (ME) method. A single conformation of C2 symmetry was observed in the gas phase. However, this disulfide is a challenging target since its structure is determined by 34 independent parameters. Additionally, ab initio calculations revealed the presence of three low-frequency vibrations (< 50 cm-1) associated to phenyl torsions which would prevent the calculation of an accurate force field. For this reason, instead of the semiexperimental method, we used the mass-dependent (rm) method to fit the structural parameters concurrently to moments of inertia and predicate parameters, affected with appropriate uncertainties. The predicates were obtained by high-level quantum-chemical computations. A careful analysis of the results of different fits and a comparison with the ab initio optimizations confirms the validity of the used methods, providing detailed structural information on the title compound and the disulfide bridge. PMID- 30476350 TI - Aromatic Charge Resonance Interaction Probed by Infrared Spectroscopy. AB - Charge resonance is a strong attractive intermolecular force in aromatic dimer radical ions. For cations, this stabilization arises from sharing a positive charge between two identical or different molecules (A2+ or AB+) with comparable ionization energies within the pi-stacked dimer. Despite its importance, this fundamental interaction has not been characterized at high resolution by spectroscopy of isolated dimers. Herein, we employ vibrational infrared spectroscopy of cold aromatic pyrrole dimer cations to precisely probe the charge distribution by measuring the frequency of the isolated NH stretch mode (nuNH). We observe a linear correlation between nuNH and the partial charge q on the pyrrole molecule in different environments. Subtle effects of symmetry reduction, such as substitution of functional groups (here pyrrole -> N-methylpyrrole) or asymmetric solvation (here by an inert N2 ligand), sensitively shifts the charge distribution toward the moiety with lower ionization energy. This general approach provides a precise experimental probe of the asymmetry of the charge distribution in such aromatic homo- and heterodimer cations. PMID- 30476351 TI - Factors Associated With Cysticidal Treatment Response in Extraparenchymal Neurocysticercosis. AB - Extraparenchymal neurocysticercosis is the most severe form of cysticercosis, and response to treatment is suboptimal. We sought to determine how demographic and clinical characteristics and albendazole sulfoxide concentrations were related to cysticidal treatment response. We conducted a longitudinal study of 31 participants with extraparenchymal vesicular parasites who received the same treatment, albendazole 30 mg/kg/day for 10 days with dexamethasone 0.4 mg/kg/day for 13 days, followed by a prednisone taper. Response to treatment was determined by parasite volumes before and 6 months after treatment. Eight participants (25.8%) had a complete treatment response, 16 (51.6%) had a treatment response > 50% but < 100%, and 7 (22.6%) had a treatment response < 50%. Complete treatment response was significantly associated with higher concentrations of albendazole sulfoxide (P = .032), younger age (P = .032), fewer cysts (P = .049) and lower pretreatment parasite volume (P = .037). Higher number of previous cysticidal treatment courses was associated with a noncomplete treatment response (P = .023). Although the large proportion of participants with less than a complete response emphasizes the need to develop more efficacious pharmacologic regimens, the association of albendazole sulfoxide concentrations with treatment response highlights the importance of optimizing existing therapeutic regimens. In addition, the association of treatment response with parasite volume emphasizes the importance of early diagnosis. PMID- 30476352 TI - Hypomagnetic fields cause anxiety in adult male mice. AB - Hypomagnetic fields (HMF), that is, the elimination of the geomagnetic field (GMF), are a risk factor to the health of astronauts in outer space. It has been established that continuous HMF exposure affects cytoskeleton assembly, cell proliferation, embryonic development, and even learning and memory. In addition, although there were some previous studies that focused on the effects of long term HMF-exposure, so far very limited investigations have been conducted to examine the short-term HMF effect in animals. In this study, we exposed adult male C57BL/6 mice to a 3-axis Helmholtz-coil HMF-simulation system for 72 h and found that short-term HMF-exposure induced a significant increase in anxiety related behaviors. And our findings provide important information for both psychological intervention and the health care of astronauts. Bioelectromagnetics. (c) 2018 Wiley Periodicals, Inc. PMID- 30476353 TI - Validation of Sysmex XT-2000iV analyzer-generated quantitative bone marrow differential counts in cynomolgus monkeys, Beagle dogs, and CD-1 mice. AB - BACKGROUND: In a previous study, the validation of rat bone marrow (BM) collection, processing, and analysis using the Sysmex XT-2000iV (Sysmex Corporation, Kobe, Japan) hematology analyzer showed that the Sysmex hematology analyzer produced BM differential counts that were comparable to those obtained with microscopic differential counts. OBJECTIVE: This study was conducted to expand the validation of the Sysmex TNCC (total nucleated cell count) and 5-part BM differential in cynomolgus monkeys, Beagle dogs, and CD-1 mice, which are alternate species that are also frequently used in preclinical safety studies. METHODS: The Sysmex 5-part BM differential counts were generated with a two-step process, whereby proliferating and maturing erythroid and myeloid cells were determined by preset gating and lymphocytes were determined using species specific B- and T-lymphocyte antibodies and a magnetic cell-sorting method (MACS). Agreement with microscopic myelograms with 500-cell differential counts was determined from BM suspensions of 62 cynomolgus monkeys, 47 Beagle dogs, and 44 CD-1 mice. RESULTS: The correlation coefficients between methods for myeloid to erythroid (M:E) ratios in all three species was > 0.928. The Bland-Altman differences between methods were approximately +/- 0.3 units for the M:E ratio in dogs and mice, and +0.6 and -0.4 in monkeys. The upper limits of agreement for all three species were <=7% for maturing myeloid cells, <=6% for maturing erythroid cells, and <=4% for proliferating myeloid cells, proliferating erythroid cells, and lymphocytes. CONCLUSIONS: The Sysmex XT-2000iV produces an automated M:E ratio and a 5-part differential count equivalent to microscopic differential counts in cynomolgus monkeys, Beagle dogs, and CD-1 mice. PMID- 30476354 TI - Same Magic Number but Different Arrangement: Alkynyl-Protected Au25 with D3 Symmetry Jiao-Jiao Li, Zong-Jie Guan, Zhen Lei, Feng Hu, and Quan-Ming Wang. AB - We synthesize two homoleptic alkynyl-protected gold clusters with compositions of Na[Au25(C=CAr)18] and (Ph4P)[Au25(C=CAr)18] (Na.1 and Ph4P.1, Ar = 3,5 bis(trifluoromethyl)phenyl) via direct reduction method. 1 is a magic cluster analogous to [Au25(SR)18]- in terms of electron counts and metal-to-ligand ratio. Single crystal structure analysis reveals that 1 has identical Au13 kernel to [Au25(SR)18]-, but adopts distinctly different arrangement of the six peripheral dimer staple motifs. The steric hindrance of alkynyl ligands is responsible for the D3 arrangement of Au25. The introduction of alkynyl also significantly changes the optical absorption features of the nanocluster as supported by DFT calculations. This magic cluster confirms that there is a similar but quite different parallel alkynyl-protected metal cluster universe in comparison to the thiolated one. PMID- 30476355 TI - In utero effects of maternal phthalate exposure on male genital development. AB - BACKGROUND: Phthalates are used extensively in commercial and personal care products and maternal exposure is ubiquitous. Phthalates are anti-androgenic but the potential effects of phthalates on male penile development have not been assessed in utero. OBJECTIVE: To investigate the association between early pregnancy phthalate exposure and fetal penile development, overall and by race. METHODS: Prospective cohort study of women with singleton pregnancies presenting for prenatal ultrasound between 18-22 weeks' gestation. Maternal urine samples were assayed for 8 phthalate monoester metabolites. We used maternal phthalate levels at 18-22 weeks' gestation as predictors of fetal size using multiple linear regression models, adjusted for fetal gestational age, maternal age, race, smoking, and education. We incorporated a phthalate by race interaction into a second set of regression models. RESULTS: We detected statistically significant race interactions for continuous phthalates with penile width. Race interactions were also suggested for penile length and volume using tertiles of phthalates with point estimates generally positive for whites and negative for African Americans. CONCLUSION: Penile development is significantly influenced by race, and the impact of maternal phthalates on penile measurements also varies by race. Maternal phthalate exposure can adversely affect in utero penile growth and development, especially among African Americans. PMID- 30476356 TI - HOW COMPETENT ARE PEOPLE WHO USE OPIOIDS AT RESPONDING TO OVERDOSES? QUALITATIVE ANALYSES OF ACTIONS AND DECISIONS TAKEN BY LAY FIRST-RESPONDERS DURING OVERDOSE EMERGENCIES. AB - BACKGROUND AND AIMS: Providing take-home naloxone (THN) to people who use opioids is an increasingly common strategy for reversing opioid overdose. However, implementation is hindered by doubts regarding the ability of people who use opioids to administer naloxone and respond appropriately to overdoses. We aimed to increase understanding of the competencies required and demonstrated by opioid users who had recently participated in a THN program and were subsequently confronted with an overdose emergency. DESIGN: Qualitative study designed to supplement findings from a randomized controlled trial of overdose education and naloxone distribution. Interviews were audio-recorded, transcribed, systematically coded, and analyzed via Iterative Categorization. SETTING: New York City, USA. PARTICIPANTS: 39 people who used opioids (32 men, 7 women; ages 22-58 years). INTERVENTION: Trial participants received brief or extended overdose training and injectable or nasal naloxone. MEASUREMENTS: The systematic coding frame comprised deductive codes based on the topic guide and more inductive codes emerging from the data. FINDINGS: In 38/39 cases the victim was successfully resuscitated; the outcome of one overdose intervention was unknown. Analyses revealed five core overdose response 'tasks': 1. Overdose identification; 2. Mobilizing support; 3. Following basic first aid instructions; 4. Naloxone administration; and 5. Post-resuscitation management. These tasks comprised actions and decisions that were themselves affected by diverse cognitive, emotional, experiential, interpersonal and social factors over which lay first-responders often had little control. Despite this, participants demonstrated high levels of competency. They had acquired new skills and knowledge through training and brought critical 'insider' understanding to overdose events and the resuscitation actions which they applied. CONCLUSIONS: People who use opioids can be trained to respond appropriately to opioid overdoses and thus to save their peers' lives. Overdose response requires both practical competency (e.g. skills and knowledge in administering basic first aid and naloxone) and social competency (e.g. willingness to help others, having the confidence to be authoritative and make decisions, communicating effectively, and demonstrating compassion and care to victims post-resuscitation). PMID- 30476357 TI - Understanding the Bone in Cancer Metastasis. AB - The bone is the third most common site of metastasis for a wide range of solid tumors including lung, breast, prostate, colorectal, thyroid, gynecologic, and melanoma, with 70% of metastatic prostate and breast cancer patients harboring bone metastasis.1 Unfortunately, once cancer spreads to the bone, it is rarely cured and is associated with a wide range of morbidities including pain, increased risk of fracture, and hypercalcemia. This fact has driven experts in the fields of bone and cancer biology to study the bone, and has revealed that there is a great deal that each can teach the other. The complexity of the bone was first described in 1889 when Stephen Paget proposed that tumor cells have a proclivity for certain organs, where they "seed" into a friendly "soil" and eventually grow into metastatic lesions. Dr. Paget went on to argue that although many study the "seed" it would be paramount to understand the "soil." Since this original work, significant advances have been made not only in understanding the cell-autonomous mechanisms that drive metastasis, but also alterations which drive changes to the "soil" that allow a tumor cell to thrive. Indeed, it is now clear that the "soil" in different metastatic sites is unique, and thus the mechanisms that allow tumor cells to remain in a dormant or growing state are specific to the organ in question. In the bone, our knowledge of the components that contribute to this fertile "soil" continues to expand, but our understanding of how they impact tumor growth in the bone remains in its infancy. Indeed, we now appreciate that the endosteal niche likely contributes to tumor cell dormancy, and that osteoclasts, osteocytes, and adipocytes can impact tumor cell growth. Here, we discuss the bone microenvironment and how it impacts cancer cell seeding, dormancy, and growth. (c) 2018 American Society for Bone and Mineral Research. PMID- 30476358 TI - An empirical formula for temperature adjustment of complex permittivity of human skin in the terahertz frequencies. PMID- 30476359 TI - Binding of a Telomestatin Derivative Changes Mechanical Anisotropy of Human Telomeric G-quadruplex. AB - Mechanical anisotropy is an essential property for biomolecules to assume structural and functional roles in mechanobiology. However, there is insufficient information on the mechanical anisotropy of ligand-biomolecule complexes. Herein, we investigated the mechanical property of individual human telomeric G quadruplexes bound with a telomestatin ligand by optical tweezers. Stacking of the ligand to the G-tetrad planes changes the conformation of the G-quadruplex, which resembles a balloon squeezed at certain directions. Such a squeezed balloon effect strengthens the G-tetrad planes whereas dislocates and weakens the loops in the G-quadruplex upon ligand binding. These dynamic interactions indicate that the binding between the ligand and G-quadruplex follows the induced-fit model. We anticipate that the altered mechanical anisotropy of the ligand-G-quadruplex complex can add additional level of regulations on the motor enzymes that process DNA or RNA molecules. PMID- 30476360 TI - A Chemiluminescent Probe for HNO Quantification and Real-time Monitoring in Living Cells. AB - Azanone (HNO) is a reactive nitrogen species with pronounced biological activity and high therapeutic potential for cardiovascular dysfunction. A critical barrier to understanding the biology of HNO and furthering clinical development is quantification and real-time monitoring of delivery in living systems. Here, we describe the design and synthesis of the first chemiluminescent probe for HNO, HNOCL-1, which can detect HNO generated from as low as 138 nM Angeli's salt with high selectivity based on reaction with a phosphine group to form a self cleavable azaylide intermediate. We have capitalized on this high sensitivity to develop a generalizable kinetics-based approach, which provides real-time quantitative estimates of HNO concentration that show good agreement with computational simulations. This method can be used to quantify picomolar HNO concentrations generated from hydrogen sulfide (H2S) and nitric oxide (NO). HNOCL 1 can monitor dynamics of HNO delivery in living cells and tissues, demonstrating the versatility of this method for tracking HNO in living systems. PMID- 30476361 TI - Abuse Potential of Samidorphan: A Phase I, Oxycodone-, Pentazocine-, Naltrexone-, and Placebo-Controlled Study. AB - Samidorphan is a MU-opioid receptor antagonist in development for the treatment of schizophrenia, in combination with olanzapine, and major depressive disorder, in combination with buprenorphine, at proposed therapeutic doses of samidorphan 10 mg and 2 mg, respectively. A double-blind, double-dummy, active- and placebo controlled, crossover study evaluated the abuse potential of samidorphan in healthy, nondependent, recreational opioid users. Following a qualification phase, participants were randomized to 1 of 6 treatment sequences of study drugs: placebo, samidorphan (10 or 30 mg), oxycodone (40 mg), pentazocine (30 mg), and naltrexone (100 mg) in a 6 * 6 Williams design. The primary end point was maximum effect (Emax ) for "at-the-moment" Drug Liking visual analog scale scores. Secondary end points included Emax visual analog scale scores for Take Drug Again and Overall Drug Liking and safety assessments. Among 47 participants, at-the moment Emax Drug Liking scores for positive study controls oxycodone and pentazocine were significantly higher than placebo (P < .001) and samidorphan (both doses; P < .001). Both samidorphan doses had Emax Drug Liking scores similar to placebo and naltrexone (median within-subject differences of 0.0). Emax Take Drug Again scores for samidorphan (both doses) were higher than placebo, but similar to naltrexone, an unscheduled MU-opioid receptor antagonist. Adverse events to evaluate abuse potential occurred less frequently with samidorphan, naltrexone, and placebo than with oxycodone and pentazocine. Findings from this study support a lack of abuse potential with samidorphan at doses up to 30 mg and a safety profile consistent with previous samidorphan clinical studies. PMID- 30476362 TI - Notes from the field: Multiple cyclosporiasis outbreaks - United States, 2018. PMID- 30476364 TI - Th17 Cells Changing Colors. PMID- 30476363 TI - A challenging case of chorioretinitis and skin lesions in a lung transplant recipient. PMID- 30476365 TI - Organ(elle) Transplants. PMID- 30476366 TI - Erratum. PMID- 30476367 TI - The Safety Profile of Tumor Necrosis Factor Inhibitors in Ankylosing Spondylitis: Are TNF Inhibitors Safer Than We Thought? AB - Tumor necrosis factor (TNF) inhibitors significantly improved the treatment options for patients with ankylosing spondylitis. Unfortunately, currently, there is no strategy for sustaining remission of the disease with TNF inhibitors; after discontinuation, a high percentage of patients experience flares in a short time. Therefore, up-to-date, long-term use of TNF inhibitors in patients with ankylosing spondylitis remains necessary. For this reason, the issue of the long term safety of TNF inhibitors in patients with ankylosing spondylitis raises concerns. Although TNF inhibitors are well established in ankylosing spondylitis treatment, the majority of studies on TNF inhibitors' safety have been performed in patients with rheumatoid arthritis. Until recently, there were very few studies of TNF inhibitors' safety in ankylosing spondylitis. Meanwhile, TNF inhibitors appear to have different safety profiles in ankylosing spondylitis and rheumatoid arthritis. In this review, we describe available data on the occurrence of adverse events associated with TNF inhibitor treatment in ankylosing spondylitis, including serious adverse events, infections, serious infections, tuberculosis, opportunistic infections, hepatitis B reactivation, malignancies, laboratory test abnormalities, autoimmune diseases, paradoxical adverse events, and heart failure. PMID- 30476369 TI - Tardive Oculogyric Crisis With Low-Dose Antipsychotic in an Adolescent: A Case Report. PMID- 30476368 TI - Intermolecular Regio- and Stereoselective Hetero-[5+2] Cycloaddition between Oxidopyrylium Ylide and Cyclic Imine: Facile Access to Highly Substituted Azepanes. AB - We developed the first intermolecular hetero-[5+2] cycloaddition reaction between oxidopyrylium ylide and cyclic imine with excellent control of regio- and stereoselectivity. Surprisingly, divergent stereochemistry was observed depending on the substitution pattern of the oxidopyrylium ylide. This new reaction provides quick access to highly substituted nitrogen-containing seven-membered rings - azepanes. Notably, a broad range of oxidopyrylium ylides and cyclic imines participated in this novel hetero-[5+2] cycloaddition reaction and the cycloadducts can be readily transformed into core skeletons of bioactive natural products. DFT calculations reveals that the cycloaddition proceeds through a stepwise pathway and the imine nitrogen atom serves as the nucleophile to initiate the cycloaddition. PMID- 30476370 TI - Suvorexant-Induced Delirium. PMID- 30476371 TI - Therapeutic Aspects of Trichotillomania: A Review of Current Treatment Options. AB - Trichotillomania (TTM) is a disorder characterized by recurrent episodes of hair pulling that affects a growing and diverse patient population. The behavior is a result of conscious or unconscious stimuli aimed at alleviating stress. TTM can be diagnosed, typically by a psychiatrist or dermatologist, with various assessment tools and scales. Although researchers continue to discover new pharmacologic regimens and nonpharmacologic therapies, there is no single, effective, US Food and Drug Administration-approved option available for patients. Treatment of TTM with the least occurrence of relapse consists of a combination of pharmacologic and nonpharmacologic options and calls for the involvement of a multidisciplinary team along with family members and friends. This review provides an analysis of the current treatment modalities in the management of TTM and highlights the need for further epidemiologic, genetic, neuroimaging, and dietary research to better understand the complicated nature of the disorder. PMID- 30476372 TI - An Energy Drink-Induced Manic Episode in an Adolescent. PMID- 30476373 TI - A Comparison of Early, Late, and No Treatment of Intensive Care Unit Delirium With Antipsychotics: A Retrospective Cohort Study. AB - Objective: To investigate the effect of early versus late versus no antipsychotic administration on intensive care unit (ICU) delirium. Methods: This retrospective cohort study was conducted in 2 adult medical ICUs at a single tertiary care center in Boston, Massachusetts, from October 1, 2015, to May 31, 2016. The study included 322 patients stratified into those who first received antipsychotics < 48 hours after first positive or unscorable (due to sedation) modified Confusion Assessment Method (CAM-ICU-m) (early), > 48 hours after first positive or unscorable CAM-ICU-m (late), and never received antipsychotics. Primary outcomes were hours alive without delirium or coma and likelihood of delirium-coma resolution. Secondary outcomes included ventilator-free hours, likelihood of extubation, and 10-day mortality. In post hoc exploratory analyses, outcomes were reanalyzed excluding comatose patients. Results: Mean +/- SD delirium-coma-free hours were 63 +/- 87 for patients who received antipsychotics early, 66 +/- 92 for those who received antipsychotics late, and 89 +/- 107 for those who never received antipsychotics (P = .71). Antipsychotic exposure did not impact delirium coma resolution. Mean ventilator-free hours were 103 +/- 87 for patients who received antipsychotics early, 90 +/- 83 for those who received antipsychotics late, and 89 +/- 101 for patients who never received antipsychotics (P = .11). The hazard ratio (HR) for 10-day mortality among patients who received antipsychotics early was 0.68 (95% CI, 0.37-1.22) and 0.30 (95% CI, 0.10-0.88) for those who received antipsychotics late compared to those who never received antipsychotics (P = .03). After excluding comatose patients, the effect of antipsychotics on 10-day mortality was no longer observed (early HR = 0.57, 95% CI, 0.30-1.07; late HR = 0.57, 95% CI, 0.28-1.18; never HR = 1 [reference]; P = .14). Conclusion: Antipsychotics were not associated with changes in delirium coma-free hours or ventilator-free hours. PMID- 30476374 TI - Rules Imposed by Providers on Medical and Surgical Inpatients With Substance Use Disorders: Arbitrary or Appropriate? PMID- 30476375 TI - A Case Report of the Oral Ingestion of Aripiprazole Long-Acting Injectable. PMID- 30476376 TI - Hiccups With Dose Titration of Aripiprazole. PMID- 30476377 TI - Repeat Ischemic Colitis in a Patient Taking Quetiapine. PMID- 30476378 TI - Ephrin type-B receptor 4 is an essential mediator in drug-resistance of acute myeloid leukemia cells to Adriamycin. AB - Objective: Ephrin type-B receptor 4 (EphB4) plays an important role in human carcinogenesis. This study investigated the effects of EphB4 expression in drug resistance of acute myeloid leukemia cells to Adriamycin using myeloid leukemia cell lines with different degrees of differentiation, including an Adriamycin resistant HL60 cell line as a model. The data showed that the EphB4 protein was differentially expressed in these myeloid leukemia cell lines, which expression was associated with sensitivity of myeloid leukemia cells to Adriamycin treatment in vitro. Furthermore, EphB4 protein stimulated by EphrinB2-Fc sensitized HL60/ADM cells to Adriamycin in a dose-dependent manner. Specifically, pre incubation of HL60/ADM with 4 ug/ml EphrinB2-Fc protein for 30 min significantly sensitized tumor cell to Adriamycin treatment by reduction of tumor cell viability and induction of apoptosis (p<0.001), while there was no significant change in other groups (p>0.05). These data provided a proof-of-principle for further development of the EphB4-based strategy for treatment of drug-resistant leukemia. PMID- 30476379 TI - The potential of less radical surgery without parametrectomy. Are we safe? AB - Aim: The aim of this study is to evaluate whether omission of parametrial removal in low risk patients with early stage cervical cancer is safe, taking into account the favorable prognostic characteristics that are usually used in recent studies debating a more conservative treatment in such patients. Methods: A comprehensive search conducted in PubMed and MEDLINE databases. Results: In low risk patients with favorable prognostic factors such as tumor size <=2 cm, depth of stromal invasion <=10 mm and no LVSI, there are 5% of patients having positive pelvic lymph nodes. Although parametrial involvement is associated with positive pelvic lymph node metastasis, there are studies which report patients with negative pelvic lymph node involvement with parametrial metastases. This indicates that although negative pelvic lymph nodes in low risk patients is a favorable criterion among of those previously reported for conservative treatment, does not eliminate the possibility of parametrial involvement. Conclusions: Although specific favorable prognostic characteristics may indicate less radical treatment for low risk patients with early stage cervical cancer, more research is needed to estimate the risk of parametrial involvement in low risk patients without pelvic node involvement. PMID- 30476380 TI - Estimation of serum beta-carotene level in patients suffering from oral submucous fibrosis. AB - Introduction: Oral submucous fibrosis (OSMF), an insidious disease, has not been widely studied with respect to levels of serum beta-carotene (b-carotene). Hence present study aimed to estimate level of serum beta carotene in patients with OSMF. Material and Methods: 40 subjects (study subjects) with different grades of OSMF and 40 apparently healthy subjects without OSMF (control subjects with age and sex matched as that of study subjects) were screened for serum b-carotene levels employing Sobel and Snow's method. Subjects in both the groups had areca nut or gutkha chewing habit. Results: Study subjects with OSMF showed lower levels of serum b-carotene as compared to control group subjects without OSMF. When the levels were compared between different disease stages, least levels of serum b-carotene were seen in Grade III OSMF subjects, as compared with Grade I and II subjects. Females showed higher levels of serum b-carotene than males in both the groups. Smokers showed depleted levels as compared to non-smokers in both groups. Conclusion: b-carotene plays an important role in the pathogenesis of OSMF, and its level decreases with disease progression. PMID- 30476381 TI - Writing oral pathology biopsy report: a guide for beginners. AB - Objective: Descriptive pathology in surgical biopsy reports is mainly about writing histopathology reports. However, it is almost always performed under the pressure of time and accuracy. Accuracy is critical because the patient is still alive and the clinician is going to act on the diagnosis quickly. Most reports are evaluated and generated by a single pathologist. Therefore, possibility of making mistakes in writing a biopsy report is usually existing. A clear concise unambiguous writing style is extremely important to meet the needs of the report. In some reports there is insufficient information and in others excess verbiage is included with no medical value. The lack of a professional standard has resulted in some of the inconsistency in biopsy reports. Although much has been studied and written about biopsy reports but no such compiled studies along with descriptive pathology mentioned in oral and maxillofacial pathology literature. Therefore, extensive literature search had been made and various articles have been retrieved from various databases such as PubMed, Medline, google science direct etc. Duration of studies or articles have not been decided as there are very few such descriptive articles in reputed journals. Articles in the form of PDF, word and even website articles have been included. This review article presents extensive review of various parameters to be considered in writing histopathology report of oral lesions. PMID- 30476382 TI - Low-grade endometrial stromal sarcoma combined with leiomyoma (stromomyoma): A bizarre tumor of the uterus in a premenopausal woman. AB - Objective: Uterine sarcomas are very rare malignancies, and when a hysterectomy is performed for benign causes, a risk of about 1/500 is mentioned for possible uterine sarcomas. Endometrial stromal neoplasms are a rare subgroup of uterine sarcomas that account for less than 10% of all uterine sarcomas. Mixed endometrial stromal and smooth muscle tumors, also known as stromomyomas, are defined as having at least 30% each of endometrial stromal and smooth muscle components. As a result, stromomyoma is an extremely rare malignant mixed mesenchymal tumor of the uterus. Both clinically and histologically, the differential diagnosis is challenging. Stromomyoma should be kept in mind in the differential diagnosis of large uterine masses, even if these masses are seen in an asymptomatic woman of reproductive age. In this study, we aimed to present this bizarre tumor of the uterus detected in a premenopausal woman. PMID- 30476383 TI - Unusual behavior of diffuse large B-cell lymphoma as cardiac invasion with rapid spontaneous regression after fine needle aspiration cytology. AB - Objective: Spontaneous regression (SR) of lymphoma is a rare phenomenon. While the precise mechanism of SR remains unknown, apoptosis may be associated with its process. Here, we present a case of a 52-year-old woman was admitted to our hospital with cough and orthopnea for 2 weeks. Multi-detector computed tomography of whole body showed anterior and middle mediastinal soft tissue mass with multiple adjacent malignant lymphadenopathy. The mediastinal mass invaded right atrium and pericardium. Another left subphrenic retro-pancreatic mass was detected. This mass surrounded upper pole of left kidney. Fine needle aspiration cytology was done and revealed lymphocytic smear with advised tru-cut biopsy. CT guided tru-cut was taken after 8 days. During CT guided technique; marked regression of left subphrenic mass was detected. Post-contrast MDCT scan was done and revealed partial response of the masses after 8 days. The partial regressive course of this disease suggests the effectiveness of fine needle aspiration cytology in initiating spontaneous regression. Tru-cut biopsy revealed non Hodgkin lymphoma (diffuse large B-cell type). We report a case of NHL with abnormal location and spontaneous regression. PMID- 30476384 TI - Hemangioma-like telangiectatic granuloma: A diagnostic pitfall. AB - Objective: A telangiectatic granuloma is a localized reactive lesion associated with prolonged irritation to the soft tissues. It may be misdiagnosed as a vascular malformation, hemangiomas, angiosarcomas, etc; as clinical presentation of the lesions resembles each other. Here, we present a case of asymptomatic swelling in the maxilla of a 17-year old female patient. The case highlights the importance of clinicopathologic correlation for the correct diagnosis and management of the case. PMID- 30476385 TI - Odontogenic cyst with diverse histopathological features: report of an unusual case. AB - Objective: It is a well established fact that all inflammatory and developmental cysts of odontogenic origin have squamous epithelial linings. They may show various forms of metaplasia from a stratified squamous to more highly differentiated ciliated columnar or mucous cells. Dentigerous cyst represents is the most common developmental odontogenic cyst usually associated with an impacted tooth after complete formation of the crown. A dentigerous cyst encloses is seen attached to the neck of the tooth at the cementoenamel junction associated with an unerupted/ impacted tooth and grows by expansion of the dental follicles. We report a similar case of dentigerous cyst associated with an impacted tooth, histologically demonstrates the characteristics of a glandular odontogenic cyst with pseudo- stratified ciliated columnar epithelium lining with goblet cells and mucous cells. PMID- 30476386 TI - Basal cell ameloblastoma: a rare entity expressed in a middle aged female. AB - Objective: Ameloblastoma is a true neoplasm of enamel organ type tissue which does not undergo differentiation to the point of enamel formation. It is a benign, locally invasive tumour of the oral cavity, most commonly affecting the maxilla and the mandible. Histologically there are several variants of ameloblastoma, the basal cell type being the least reported one. In this paper, we are presenting a case of basal cell ameloblastoma of the mandible with a brief review of literature. PMID- 30476387 TI - A mismatch of tumor grade and biologic behaviour in a rare case of Sclerosing Mucoepidermoid Carcinoma of Parotid - with review of literature. AB - Objective: Although mucoepidermoid carcinoma is the most common primary malignancy of the salivary glands, the sclerosing morphologic variant of this tumor is extremely rare and only 26 cases have been reported till date in the english literature. This report describes a case involving a 35-year-old female with an intermediate-grade sclerosing mucoepidermoid carcinoma of parotid gland and we review the litreture. Immunohitochemical markers, Her-2/neu and MIB-1 evaluated to help predict the clinical outcome and to determine whether an association exists between the histologic grade and immunohistochemical findings. A PAS stain revealed cytic spaces filled with basophilic material. We found MIB-1 labeling indices of >50% and strong positivity for Her-2/neu suggesting poor prognosis. Our case did not show any correlation between MIB-1 index and tumor grade as shown in other case reports. This unusual but distinctive variant of mucoepidermoid carcinoma can be difficult to recognize and is frequently misdiagnosed as a benign lesion. PMID- 30476388 TI - A radiolucent lesion presenting calcification histopathologically: a classical case of CEOT. AB - Objective: The calcifying epithelial odontogenic tumor (CEOT) is a rare benign odontogenic neoplasm that accounts for approximately 1% of all odontogenic tumors. Histologically, it shows sheets of polyhedral epithelial cells with deep eosinophilic cytoplasm and prominent nuclei. Globules of amyloid like material among tumor cells which undergoes calcification are evident. We present a case of CEOT which presented classical histopathologic picture but clinico- radiological it presented variably. Its non association with impacted tooth, no calcifications in the incisional material and finally on excision giving its classical picture of prominent intercellular bridges, hyperchromatic polyhedral cells and amyloid with calcifications made it an interesting case to report. PMID- 30476389 TI - Prevalence of oral squamous cell carcinoma in Bareilly Region: A seven year institutional study. AB - Background: Oral squamous cell carcinoma is a major contributor to disability and death caused by malignant tumors. Variations in social, cultural, and geographic factors affect the tumor behavior and response to treatment. In this study, we undertake a seven years institutional review and analysis of Oral squamous cell carcinoma cases in Bareilly. Materials and Methods: A total of 1938 histologically diagnosed cases during the period of seven years i.e. from 2010 to 2016 were extracted from the archives of Department of Oral & Maxillofacial Pathology, Institute of Dental Sciences, Bareilly and evaluated to know the prevalence of Oral squamous cell carcinoma. The details like age, sex, habits and anatomical site were also recorded from the archived patient's case sheets. Results: Out of the total 1938 cases, 318 were found to be Oral squamous cell carcinoma of which 232 were males and 86 were females. Incidence was highest in 40-49 year age group. The most common site was buccal mucosa (190 cases), followed by tongue (68 cases). Most lesions were well differentiated Oral squamous cell carcinoma (230 cases). Patients with poorly differentiated lesions had a comparatively lower mean age than their counterparts with other histological varieties. Conclusion: The pattern of Oral squamous cell carcinoma differs from that of previous studies in relation to incidence and age correlation with the grade of carcinoma. The majority of the lesions were well differentiated. There is a need for intensive oral health awareness to encourage early presentation to cancer center as early detection will further enhance prognosis. PMID- 30476390 TI - A direction to prepare the cancer vaccine. AB - Objective: The vaccine of the cancer can be prepared. This paper presents a direction for preparing the vaccine of cancer by algebraic and geometric study of the cancer cell. PMID- 30476392 TI - Trump's first 100 days marred by failed ACA repeal effort. PMID- 30476391 TI - Curing cancer by cancer function. AB - Objective: Cancer is the disease which exists when the cell is uncontrolled. This paper presents a controller for the same. The cancer cell is reviewed via algebraic structures. PMID- 30476393 TI - Hospitals urge Trump administration to end mandatory bundled-pay plans. AB - Hospital groups say they don't have the financial resources to implement bundled payment models. PMID- 30476394 TI - Health insurer CEOs score 2016 pay raises despite uncertain future. AB - Despite a year of uncertainty and tumult, most of the CEOs at eight of the largest publicly traded insurance companies got a pay raise in 2016. PMID- 30476395 TI - Bayer faces dilemma over fate of controversial Essure device. AB - Companies face significant legal, financial and PR pitfalls when patient-safety issues arise. PMID- 30476396 TI - PBM scrutiny likely to increase after Anthem, Express Scripts breakup. AB - Anthem is on the hunt for a new PBM in a highly consolidated industry that doesn't switch partners often. PMID- 30476397 TI - The long and winding road to patient data, interoperablility. AB - True interoperability remains just out of reach, as data stay trapped in documents. PMID- 30476398 TI - Hospital mega-mergers hit fast and furious in 1Q. AB - The need for scale and space is accelerating tie-ups between hospital giants. PMID- 30476400 TI - High-performance healthcare is simple to describe, yet hard to deliver. Together we can change that. AB - For the most vulnerable, chronically ill among us-many of whom cope with behavioral health challenges and struggle to secure housing, food or transportation-the journey to receive the care they need can be daunting. PMID- 30476399 TI - The phony war on high drug prices. AB - Politics, like nature, abhors a vacuum. Witness how the pharnaceutical industry has succeeded in taking advantage of President Donald Trump's failure to do something-anything-about high drug prices. PMID- 30476401 TI - Guiding providers' prescribing practices. PMID- 30476402 TI - 'We don't need to be bigger for the sake of being bigger'. AB - Kaiser Permanente features basketball star Steph Curry in a new mental-health ad campaign that illustrates how even the Golden State shooting phenom must overcome doubts about his game. Kaiser Permanente, the nation's largest Integrated health system, has made mental-health awareness a priority this year as It seeks to promote the total health of the Individuals and communities It serves, according to Chairman and CEO Bernard Tyson. Earlier this year, Tyson sat down with Southern Bureau Chief Dave Barkholz in San Francisco, just across the bay from Kaiser Permanente's Oakland headquarters, to discuss mental health, the social determinants of health and Kaiser Permanente's always-active expansion strategy. The following is an edited transcript. PMID- 30476403 TI - Delivering new bundles to control cost of maternal care. AB - Maternal care has the makings of the next frontier for bundled payments--except there's no national regulatory vehicle to help the industry get there. PMID- 30476405 TI - Finalists chosen for Marketing IMPACT Awards. PMID- 30476404 TI - Dignity's transgender bias case could signal more religious freedom clashes. AB - Legal disputes over coverage of transgender-related care may become a source of tension for Catholic health systems and other employees. PMID- 30476406 TI - HIPAA at 2O: Hitting its prime or over the hill? PMID- 30476408 TI - Few docs ready for risk. AB - Most physicians and physician practices will opt for being measured on quality under Medicare's new payment system since they're not ready to assume the downside risk of alternative payment models. PMID- 30476407 TI - Helping Medicaid docs cope with quality reporting. AB - Clinicians in Medicaid are turning to quality- reporting services to help them track managed-care plans' rising demand for patient data, which is driving some physicians from the program. PMID- 30476409 TI - Wage stagnation in healthcare. AB - It's been a little over a year since Ascension, the nation's largest Catholic healthcare system, announced it would join a handful of large corporations in raising its minimum wage to $11 an hour. PMID- 30476410 TI - Supporting 'team science' to achieve ambitious Cancer Moonshot goals. AB - Since President Barack Obama laid out a vision for a Cancer Moonshot research initiative during his 2016 State of the Union address, the public and private sectors have moved swiftly to respond with multiple activities aimed at achieving progress against the many diseases we classify under the heading of cancer. PMID- 30476411 TI - Addressing errors with Candor. PMID- 30476413 TI - Hospitals with the biggest changes in readmissions penalties 2016-17 Ranked by penalty percentage point changes. PMID- 30476412 TI - 'We should be in the vanguard of reducing utilization, improving quality'. AB - New York-Presbyterian, a sprawling $5 billion academic medical center complex based in Manhattan, houses two Ivy League medical schools. Yet in recent years, the system has grown to nine hospitals, including several in New York City's outer boroughs and nearby suburbs. Modern Healthcare recently spoke with CEO Dr. Steven Corwin about the system's evolving strategy. This is an edited transcript. PMID- 30476414 TI - A Message from the President. PMID- 30476415 TI - Persons for Sale-Human Trafficking in Mississippi. PMID- 30476416 TI - Executive Director's Column. PMID- 30476418 TI - Dual-eligibles could offer relief for hospital readmissions penalties. AB - The CMS is exploring how to levy excess readmission penalties fairly on hospitals, based on their patient population. PMID- 30476417 TI - Stricter chargemaster regulations needed to rein in healthcare pricing. AB - Many states don't regulate hospital chargemasters, but rising prices on the itemized lists are lading to higher healthcare costs. PMID- 30476420 TI - Kaiser seeks San Diego edge with super-green hospital. AB - Kaiser seeks San Diego edge with super-green hospital. PMID- 30476419 TI - FDA user-fee bill seen as speeding approvals, but harming smaller firms. AB - Supporters claim the fees will help healthcare companies streamline operations, while critics argue that smaller firms cannot accommodate the fee hikes. PMID- 30476421 TI - States, insurers undermining Medicaid managed care. AB - Strong administrative processes at the state and plan level are key to making Medicaid managed care work. PMID- 30476423 TI - Playing with fire on cost-sharing subsidies. AB - It's time to check in with the governing party to see how its plan to replace Obamacare is progressing. PMID- 30476422 TI - Never settle: Top health systems always looking for ways to improve. AB - Top systems are arming their physicians and nurses with data to encourage them to find performance areas that can be improved. PMID- 30476424 TI - Many changes in payment, practice are only paving the road to further physician discontent. AB - We live in challenging times for physicians, who are required to do things that are wearing them out and making them feel bad about their jobs. PMID- 30476425 TI - Using music to stabilize NICU babies--as well as their parents. AB - Active, informed interventions, not passive background music, are the basis of music therapy. Use music and sound to calm not just infants but parents and the hospital environment, too. Include parents in music therapy, so they can continue interventions after babies are discharged. PMID- 30476428 TI - The Psychiatric Assistance Line: Six-Month Follow-up on Consultations to Primary Care. AB - The shortage of child and adolescent psychiatrists in the United States has resulted in more and more patients presenting to primary care clinics with mental health concerns. Consequently, clinicians often find themselves dealing with issues outside their expertise. The Psychiatric Assistance Line was created in 2014 to connect primary care clinicians with mental health professionals for consultations and provide assistance with psychiatry referrals. This article looks at the use of the service and outcomes following its first six months of operation. PMID- 30476427 TI - 8 big (and 14 small) ideas for building resiliency. How to tend to the well-being of a medical staff. PMID- 30476426 TI - 'Repealing the medical device tax is important for the industry'. AB - From user fees and the medical device tax to increased worries about cyberattacks, 2017 is shaping up to be a busy year for the medical device industry. Having just completed his two-year term as Advanced Medical Technology Association board chairman, Vincent Forlenza is bullish on the industry's ability to tackle these priority issues. As CEO of Becton, Dickinson and Co., Forlenza supports the current iteration of medical device user-fee amendments in front of Congress. He also said the industry will continue to push for repealing the Affordable Care Act's medical device tax, either as part of full replacement bill or a stand- alone measure. Forlenza recently sat down with Modern Healthcare's Adam Rubenfire to talk about his tenure as AdvaMed chair and how the industry can support customers in a changing healthcare environment. The following is an edited transcript. PMID- 30476429 TI - Sulfide Mining and Human Health in Minnesota. AB - Sulfide mining (specifically copper-nickel sulfide mining) represents a significant departure from Minnesota's iron mining tradition. Sulfide mining can produce acid waste and sulfates that mobilize the release of heavy metals into the environment. These metals include known neurotoxins such as lead and mercury. Mining activities also create airborne fibers and pollutants that can contribute to increased morbidity. The short- and long-term effects of exposure to these substances on human health should be considered in present and future sulfide mining proposals. In addition, Minnesota physicians need to understand the potential adverse mental and physical health effects of sulfide mining on mine workers and residents of communities near mining operations. PMID- 30476430 TI - Influenza: diagnosis and management in the emergency department. AB - Emergency clinicians must be aware of the current diagnostic and therapeutic recommendations for influenza and the available resources to guide management. This comprehensive review outlines the classification of influenza viruses, influenza pathophysiology, the identification of high-risk patients, and the importance of vaccination. Seasonal variations of influenza are discussed, as well as the rationale for limiting testing during periods of high prevalence. Differences between strains of influenza are discussed, as well as the challenges in achieving optimal vaccine effectiveness. Recommendations for use of the currently available oral, intranasal, and intravenous antiviral treatments are provided, as well as utilizing shared decision-making with patients regarding risks and benefits of treatment. PMID- 30476431 TI - Bioterrorism attacks involving pediatric patients: preparedness and early recognition are critical. AB - Due to their anatomic, physiologic, developmental, and behavioral characteristics, children are particularly vulnerable to bioterrorism agents. Symptoms associated with most bioterrorism agents can be difficult to differentiate from common childhood illnesses. It is extremely important that emergency clinicians are able to recognize unusual illness patterns that could distinguish a natural outbreak from a bioterrorism attack. Resources available through government agencies and leading pediatric organizations can aid in diagnosis and treatment. This issue reviews the highest-risk bioterrorism agents and provides guidance for diagnosing and managing pediatric patients who have been exposed to these agents. PMID- 30476432 TI - Exploration of highly efficient blue-violet light conversion agents for agricultural film based on structure optimization of TPA. AB - To obtain highly efficient blue-violet light conversion agents used for agricultural film, six triarylacrylonitrile derivatives and their doping films were prepared. Further, the luminogens have the ability to convert UV light into blue-violet light, and exhibit aggregation dependent fluorescence emission and high-contrast fluorescence quantum yields from 0.004 to 0.833. Based on X-ray single crystal diffraction analysis and aggregation-induced emission activity tests, the variant fluorescence quantum yields are attributed to intermolecular pi-pi stacking and phase transition between crystalline state and amorphous state. In simulated greenhouse environment, the luminogens exhibit excellent photostability. However, their fluorescence intensity drop to 17%-40% of prime intensity after outdoor radiation for one month due to the ring-closing oxidation reaction (In summer). By comprehensively considering the above photophysical properties and mechanical properties of the doping film, Ph4TPA is a potential light conversion agent for agricultural film in winter. More importantly, the results indicate the properties of the light conversion films are expected to be further improved by molecular design inhibiting the ring-closing oxidation reaction and dispersion of crystalline nanoparticles in the doping film. PMID- 30476433 TI - An Unnatural Pathway for Efficient 5-Aminolevulinic Acid Biosynthesis with Glycine from Glyoxylate Based on Retrobiosynthetic Design. AB - The design of novel metabolic pathways for efficient biosynthesis of natural products has received much interest, but often lacks systematic approach and chemistry-based guideline. Here we propose carbon skeleton reconstruction based on retrobiosynthetic design as a new approach and chemistry-guideline to solve the problem of properly matching precursors, one of the key issues for efficient biosynthesis. It is demonstrated for the development of an unnatural pathway for efficient biosynthesis of 5-aminolevulinic acid. The new pathway has several advantages compared to the existing natural ones such as high carbon utilization efficiency and orthogonality. It is particularly useful for overcoming the problem of glycine supply. The unnatural pathway is verified in vitro in an enzymatic cascade and in vivo in recombinant E. coli with an exogenous glyoxylate transaminase as a key enzyme. PMID- 30476434 TI - Obstructive Sleep Apnea with Chronic Obstructive Pulmonary Disease among Medicare Beneficiaries. PMID- 30476435 TI - Coping With Anterior Cruciate Ligament Injury From Childhood to Maturation: A Prospective Case Series of 44 Patients With Mean 8 Years' Follow-up. AB - BACKGROUND:: There is no consensus regarding the best treatment approach for skeletally immature children with anterior cruciate ligament (ACL) injuries. High quality studies with long-term follow-up are lacking, and evidence to support decision making is limited. PURPOSE:: To evaluate functional and patient-reported outcome, surgical history, and complications among young adults who sustained an ACL injury before the age of 13 years and were treated with active rehabilitation and the option of delayed ACL reconstruction if needed. STUDY DESIGN:: Case series; Level of evidence, 4. METHODS:: Forty-six children aged <13 years with a total intrasubstance ACL injury were included. None of these patients had additional injuries that warranted early surgery. At final follow-up at a mean 8 years after the time of injury, 44 patients remained in the study. The same test battery was conducted at baseline, 1 and 2 years, and final follow-up at approximately 18 years of age. The test battery included functional tests (hop tests and isokinetic muscle strength tests of quadriceps and hamstrings), patient reported outcome measures (including the Knee injury and Osteoarthritis Outcome Score and the International Knee Documentation Committee Subjective Knee Form), and clinical examination. Medical records were reviewed to assess surgical history and complications. RESULTS:: At a mean 8 years of follow-up, 24 patients (55%) had undergone ACL reconstruction, and 16 (36%) had undergone meniscal surgery. Quadriceps muscle strength symmetry was >90% for 30 patients (68%). Mean leg symmetry indexes for hop and strength tests were consistently >90%, except for the single-hop test and hamstrings muscle strength for ACL-reconstructed knees. Mean +/- SD International Knee Documentation Committee scores were 86.3 +/ 13.7 for the ACL-reconstructed knees and 90.6 +/- 11.8 for the nonreconstructed knees. At final follow-up, forty patients (91%) remained active in sports, but 29 (66%) restricted their activity level to nonpivoting sports. CONCLUSION:: Active rehabilitation may have a role in treatment of children with ACL injury. Approximately 50% of children may cope well, even to adulthood, without a surgical intervention. The other half may develop instability that warrants ACL reconstruction, and one-third may require meniscal surgery. PMID- 30476436 TI - Recommended Reading from the University of Pittsburgh Pulmonary and Critical Care Medicine Research Fellows. PMID- 30476437 TI - 5-Year Survival of Pediatric Anterior Cruciate Ligament Reconstruction With Living Donor Hamstring Tendon Grafts. AB - BACKGROUND:: It is well accepted that there is a higher incidence of repeat anterior cruciate ligament (ACL) injuries in the pediatric population after ACL reconstruction (ACLR) with autograft tissue compared with adults. Hamstring autograft harvest may contribute to the risk for repeat ACL injuries in this high functional demand group. A novel method is the use of a living donor hamstring tendon (LDHT) graft from a parent; however, there is currently limited research on the outcomes of this technique, particularly beyond the short term. PURPOSE/HYPOTHESIS:: The purpose was to determine the medium-term survival of the ACL graft and the contralateral ACL (CACL) after primary ACLR with the use of an LDHT graft from a parent in those aged less than 18 years and to identify factors associated with subsequent ACL injuries. It was hypothesized that ACLR with the use of an LDHT provides acceptable midterm outcomes in pediatric patients. STUDY DESIGN:: Case series; Level of evidence, 4. METHODS:: Between 2005 and 2014, 247 (of 265 eligible) consecutive patients in a prospective database, having undergone primary ACLR with the use of an LDHT graft and aged less than 18 years, were included. Outcomes were assessed at a minimum of 2 years after surgery including data on ACL reinjuries, International Knee Documentation Committee (IKDC) scores, and current symptoms, as well as factors associated with the ACL reinjury risk were investigated. RESULTS:: Patients were reviewed at a mean of 4.5 years (range, 24-127 months [10.6 years]) after ACLR with an LDHT graft. Fifty-one patients (20.6%) sustained an ACL graft rupture, 28 patients (11.3%) sustained a CACL rupture, and 2 patients sustained both an ACL graft rupture and a CACL rupture (0.8%). Survival of the ACL graft was 89%, 82%, and 76% at 1, 2, and 5 years, respectively. Survival of the CACL was 99%, 94%, and 86% at 1, 2, and 5 years, respectively. Survival of the ACL graft was favorable in patients with Tanner stage 1-2 at the time of surgery versus those with Tanner stage 3-5 at 5 years (87% vs 69%, respectively; hazard ratio, 3.7; P = .01). The mean IKDC score was 91.7. A return to preinjury levels of activity was reported by 59.1%. CONCLUSION:: After ACLR with an LDHT graft from a parent in those aged less than 18 years, a second ACL injury (ACL graft or CACL injury) occurred in 1 in 3 patients. The 5-year survival rate of the ACL graft was 76%, and the 5-year survival rate of the CACL was 86%. High IKDC scores and continued participation in sports were maintained over the medium term. Importantly, there was favorable survival of the ACL graft in patients with Tanner stage 1-2 compared with patients with Tanner stage 3-5 over 5 years. Patients with Tanner stage 1-2 also had a significantly lower incidence of second ACL injuries over 5 years compared with those with Tanner stage 3-5, occurring in 1 in 5 patients. Thus, an LDHT graft from a parent is an appropriate graft for physically immature children. PMID- 30476439 TI - Not One More Life: A Health and Faith Partnership Engaging At-Risk African Americans with Asthma in Atlanta. PMID- 30476438 TI - Associations between Theileria orientalis Ikeda type infection and the growth rates and haematocrit of suckled beef calves in the North Island of New Zealand. AB - AIM: The principle aim of this study was to examine the association between infection with Theileria orientalis Ikeda type and growth rates of suckled beef calves on four beef farms. In addition, associations between calf sex, sampling time, and individual farm and T. orientalis Ikeda type infection intensity and haematocrit (HCT) were investigated. METHODS: The study was a prospective longitudinal study in which 240 calves from four purposively selected beef farms in the North Island of New Zealand were blood sampled and weighed in late spring, mid-summer and early autumn. Two farms were from high-risk (A and B) and two from low-risk (C and D) tick areas. Blood samples were analysed to determine HCT, and the number of T. orientalis Ikeda type organisms/uL of blood (infection intensity) using a quantitative PCR assay. A calf was defined as infected if >415 organisms/uL were detected in a blood sample. Linear mixed models were used to examine associations between infection intensity, mean daily live weight gain (MDG), HCT, calf sex and time of sampling on the four farms. RESULTS: On Farms A and B nearly all calves were infected at each sampling time, on Farm C <30% were infected at any sampling and on Farm D infection prevalence increased from 32 to 79% between late spring and early autumn. On Farms C and D, from mid-summer to early autumn, mean MDG was 0.127 (95% CI = 0.072-0.183) kg/day less for infected than uninfected calves (p < 0.001). On all farms MDG was negatively associated with infection intensity for mid-summer and early autumn sampling times (p = 0.037). The relationship between time of sampling and infection intensity varied between farms (p < 0.001), and between male and female calves (p = 0.018). Females had a higher infection intensity than males at the mid-summer and early autumn samplings. The association between HCT and infection intensity varied with sampling time and farm (p = 0.018). There was a strong negative association between infection intensity and HCT at the late spring sampling, but in mid summer there was no association, and in early autumn only a weak association. CONCLUSIONS AND CLINICAL RELEVANCE: This study has shown that beef farmers in the North Island of New Zealand should be concerned about the welfare effects and economic impacts of T. orientalis Ikeda type infection in suckled beef calves. PMID- 30476440 TI - Heterogeneity in the Diagnostic Criteria Physicians Use in Pediatric Asthma. PMID- 30476441 TI - Thermal Inactivation of Listeria monocytogenes in Crab Meat. AB - Listeria monocytogenes is an important bacterial pathogen in seafood products, but limited information is currently available on the thermal resistance of relevant isolates in seafood. Thermal inactivation studies were undertaken (i) to provide much needed thermal inactivation data for L. monocytogenes in crab meat and (ii) to investigate whether tryptone soya broth (TSB) is representative of crab meat in thermal inactivation studies involving L. monocytogenes. D-values were obtained for a cocktail of two crab isolates (serotypes 1/2a and 4b) at 50, 55, and 60 degrees C. In crab meat, D-values were 174.4, 28.2, and 1.6 min, respectively. Similar D-values of 176.4, 28.8, and 1.4 min were obtained in TSB. The corresponding z-values were 4.9 degrees C (crab meat) and 4.8 degrees C (TSB), respectively. The conclusions were that (i) current pasteurization conditions (e.g., 70 degrees C for 2 min) would achieve complete destruction of any L. monocytogenes present in crab meat and (ii) TSB could be used as a model matrix for assessing the thermal inactivation of L. monocytogenes in crab meat. PMID- 30476442 TI - Application of Concanavalin A-Linked Magnetic Beads for the Detection of Hepatitis A Virus. AB - Prompt and inexpensive detection of hepatitis A virus (HAV) is essential to control acute hepatitis outbreaks associated with the consumption of contaminated raw or minimally processed food. In this study, various carbohydrate-binding lectins, including concanavalin A (Con A), wheat germ agglutinin, and soybean agglutinin, were compared for their binding affinity to HAV. Con A, which showed significantly higher binding affinity than other lectins, was used to develop an alternative and affordable method to conventional antibody-linked immunomagnetic separation prior to detection of HAV using reverse transcriptase PCR. This method, Con A-linked immunomagnetic separation combined with reverse transcriptase PCR, can detect HAV at a dilution concentration of 10-4 of the virus stock (titer: 104 median tissue culture infective dose per mL), indicating that Con A could be a promising candidate for concentrating HAV. PMID- 30476443 TI - Similar Levels of Antimicrobial Resistance in U.S. Food Service Ground Beef Products with and without a "Raised without Antibiotics" Claim. AB - U.S. ground beef with "raised without antibiotics" (RWA) label claims are perceived as harboring fewer bacteria with antimicrobial resistance (AMR) than are found in conventional (CONV) ground beef with no such label claim. A total of 370 ground beef samples from CONV ( n = 191) and RWA ( n = 179) production systems were collected over 13 months from three food service suppliers. The following bacteria were cultured: Escherichia coli, tetracycline-resistant (TETr) E. coli, third-generation cephalosporin-resistant (3GCr) E. coli, Salmonella enterica, TETr S. enterica, 3GCr S. enterica, nalidixic acid-resistant S. enterica, Enterococcus spp., erythromycin-resistant Enterococcus spp., TETr Enterococcus spp., Staphylococcus aureus, and methicillin-resistant S. aureus. TETr E. coli was more frequently detected in CONV ground beef (CONV, 54.2%; RWA, 35.2%; P < 0.01), but supplier ( P < 0.01) and production system * suppler interaction ( P < 0.01) effects were also significant. Metagenomic DNA was isolated from each sample, and equal amounts of metagenomic DNA were pooled by supplier, month, and production system for 75 pooled samples (38 CONV, 37 RWA). The abundance of aac(6')-Ie-aph(2")-Ia, aadA1, blaCMY-2, blaCTX-M, blaKPC-2, erm(B), mecA, tet(A), tet(B), and tet(M) genes was assessed by quantitative PCR. The tet(A) (2.9-log2-fold change, P = 0.04) and tet(B) (5.6-log2-fold change) ( P = 0.03) genes were significantly more abundant in RWA ground beef. Phylogenetic analyses revealed that ground beef microbiomes differed more by supplier than by production system. These results were consistent with prior research suggesting antimicrobial use in U.S. beef cattle has minimal impact on the AMR of bacteria found in these products. These results should spur a reevaluation of assumptions regarding the impact of antimicrobial use during U.S. beef production on the AMR of bacteria in ground beef. PMID- 30476444 TI - Contamination and Prevalence of Histamine in Canned Tuna from Iran: A Systematic Review, Meta-Analysis, and Health Risk Assessment. AB - HIGHLIGHTS: Data from 11 articles and a total of 693 samples were used for a meta analysis. Pooled mean histamine, 77.86 mg kg-1, was lower than the FDA limit (200 mg kg-1). Pooled mean histamine prevalence was 9.19% with considerable heterogeneity. THQ value <1 indicates that adult consumers are not at risk of histamine poisoning. PMID- 30476445 TI - The Smc5/6 Complex: New and Old Functions of the Enigmatic Long-Distance Relative. AB - Smc5 and Smc6, together with the kleisin Nse4, form the heart of the enigmatic and poorly understood Smc5/6 complex, which is frequently viewed as a cousin of cohesin and condensin with functions in DNA repair. As novel functions for cohesin and condensin complexes in the organization of long-range chromatin architecture have recently emerged, new unsuspected roles for Smc5/6 have also surfaced. Here, I aim to provide a comprehensive overview of our current knowledge of the Smc5/6 complex, including its long-established function in genome stability, its multiple roles in DNA repair, and its recently discovered connection to the transcription inhibition of hepatitis B virus genomes. In addition, I summarize new research that is beginning to tease out the molecular details of Smc5/6 structure and function, knowledge that will illuminate the nuclear activities of Smc5/6 in the stability and dynamics of eukaryotic genomes. PMID- 30476446 TI - Ribosome Hibernation. AB - Protein synthesis consumes a large fraction of available resources in the cell. When bacteria encounter unfavorable conditions and cease to grow, specialized mechanisms are in place to ensure the overall reduction of costly protein synthesis while maintaining a basal level of translation. A number of ribosome associated factors are involved in this regulation; some confer an inactive, hibernating state of the ribosome in the form of 70S monomers (RaiA; this and the following are based on Escherichia coli nomenclature) or 100S dimers (RMF and HPF homologs), and others inhibit translation at different stages in the translation cycle (RsfS, YqjD and paralogs, SRA, and EttA). Stationary phase cells therefore exhibit a complex array of different ribosome subpopulations that adjusts the translational capacity of the cell to the encountered conditions and ensures efficient reactivation of translation when conditions improve. Here, we review the current state of research regarding stationary phase-specific translation factors, in particular ribosome hibernation factors and other forms of translational regulation in response to stress conditions. PMID- 30476447 TI - Mechanisms of Neural Crest Migration. AB - Neural crest cells are a transient embryonic cell population that migrate collectively to various locations throughout the embryo to contribute a number of cell types to several organs. After induction, the neural crest delaminates and undergoes an epithelial-to-mesenchymal transition before migrating through intricate yet characteristic paths. The neural crest exhibits a variety of migratory behaviors ranging from sheet-like mass migration in the cephalic regions to chain migration in the trunk. During their journey, neural crest cells rely on a range of signals both from their environment and within the migrating population for navigating through the embryo as a collective. Here we review these interactions and mechanisms, including chemotactic cues of neural crest cells' migration. PMID- 30476448 TI - Allan Campbell (April 27, 1929-April 19, 2018). PMID- 30476450 TI - Unexpected Abnormal Uptake in the Breasts at Dedicated Breast PET: Incidentally Detected Small Cancers or Nonmalignant Features? AB - OBJECTIVE: The purposes of this study were to evaluate the diagnostic performance of dedicated breast PET (dbPET) in cases of unexpected uptake and to define parameters associated with malignancy. MATERIALS AND METHODS: There are two types of high-resolution dbPET systems. One has two platelike detectors that compress the breast. This study was conducted with the other type, on which the patient lies prone and the breast hangs through a ring without compression. In total, 627 consecutively registered women underwent 18F-FDG PET/CT and dbPET for pretherapeutic or posttherapeutic evaluation of breast cancer, prior suspicion of breast cancer, or cancer screening. Areas of abnormal FDG uptake, excluding known breast cancers, were analyzed. Uptake was morphologically categorized as focus, mass, or non-mass. Quantitative values were obtained, including the maximum standardized uptake value (SUVmax), peak SUV (SUVpeak), total lesion glycolysis (TLG), metabolic tumor volume (MTV), and lesion-to-background ratio (LBR). Clinical parameters were also assessed. Parameters were compared between breast cancer and noncancer groups; multivariate logistic regression analysis was performed. RESULTS: Of 40 instances of abnormal uptake, 13 were breast cancer. Morphologic features differed between cancer and noncancer groups (p = 0.0122). Among the cancers, 76.9% (10/13) had mass, 15.4% (2/13) had nonmass, and 7.7% (1/13) had focus uptake. Of noncancerous findings, 3.7% (1/27) were mass, 40.7% (11/27) nonmass, and 55.6% (15/27) focus uptake. SUVpeak (p = 0.0234), TLG (p = 0.0017), MTV (p = 0.004), and LBR (p = 0.0432) also differed between groups. Results of multivariate analysis indicated that morphologic category at dbPET was independently associated with malignancy. CONCLUSION: Morphologic features of abnormal uptake at dbPET are associated with breast cancer and may be useful for diagnosing lesions of unknown histologic composition. PMID- 30476449 TI - piRNA-Guided Genome Defense: From Biogenesis to Silencing. AB - PIWI-interacting RNAs (piRNAs) and their associated PIWI clade Argonaute proteins constitute the core of the piRNA pathway. In gonadal cells, this conserved pathway is crucial for genome defense, and its main function is to silence transposable elements. This is achieved through posttranscriptional and transcriptional gene silencing. Precursors that give rise to piRNAs require specialized transcription and transport machineries because piRNA biogenesis is a cytoplasmic process. The ping-pong cycle, a posttranscriptional silencing mechanism, combines the cleavage-dependent silencing of transposon RNAs with piRNA production. PIWI proteins also function in the nucleus, where they scan for nascent target transcripts with sequence complementarity, instructing transcriptional silencing and deposition of repressive chromatin marks at transposon loci. Although studies have revealed numerous factors that participate in each branch of the piRNA pathway, the precise molecular roles of these factors often remain unclear. In this review, we summarize our current understanding of the mechanisms involved in piRNA biogenesis and function. PMID- 30476451 TI - Effect of Clinical Decision Support-Generated Report Cards Versus Real-Time Alerts on Primary Care Provider Guideline Adherence for Low Back Pain Outpatient Lumbar Spine MRI Orders. AB - OBJECTIVE: The purpose of this study is to determine whether the type of feedback on evidence-based guideline adherence influences adult primary care provider (PCP) lumbar spine (LS) MRI orders for low back pain (LBP). MATERIALS AND METHODS: Four types of guideline adherence feedback were tested on eight tertiary health care system outpatient PCP practices: no feedback during baseline (March 1, 2012-October 4, 2012), randomization by practice to either clinical decision support (CDS)-generated report cards comparing providers to peers only or real time CDS alerts at order entry during intervention 1 (February 6, 2013-December 31, 2013), and both feedback types for all practices during intervention 2 (January 14, 2014-June 20, 2014 and September 4, 2014-January 21, 2015). International Classification of Disease codes identified LBP visits (excluding Medicare fee-for-service). The primary outcome of the likelihood of LS MRI order being made on the day of or 1-30 days after the outpatient LBP visit was adjusted by feedback type (none, report cards only, real-time alerts only, or both); patient age, sex, race, and insurance status; and provider sex and experience. RESULTS: Half of PCPs (54/108) remained for all three periods, conducting 9394 of 107,938 (8.7%) outpatient LBP visits. The proportion of LBP visits increased over the course of the study (p = 0.0001). In multilevel hierarchic regression, report cards resulted in a lower likelihood of LS MRI orders made the day of and 1-30 days after the visit versus baseline: 38% (p = 0.009) and 37% (p = 0.006) for report cards alone, and 27% (p = 0.020) and 27% (p = 0.016) with alerts, respectively. Real-time alerts alone did not affect MRI orders made the day of (p = 0.585) or 1-30 days after (p = 0.650) the visit. No patient or provider variables were associated with LS MRI orders being generated on the day of or 1 30 days after the LBP visit. CONCLUSION: CDS-generated evidence-based report cards can substantially reduce outpatient PCP LS MRI orders on the day of and 1 30 days after the LBP visit. Real-time CDS alerts do not. PMID- 30476452 TI - Refining Convolutional Neural Network Detection of Small-Bowel Obstruction in Conventional Radiography. AB - OBJECTIVE: The purpose of this study was to evaluate improvement of convolutional neural network detection of high-grade small-bowel obstruction on conventional radiographs with increased training set size. MATERIALS AND METHODS: A set of 2210 abdominal radiographs from one institution (image set 1) had been previously classified into obstructive and nonobstructive categories by consensus judgments of three abdominal radiologists. The images were used to fine-tune an initial convolutional neural network classifier (stage 1). An additional set of 13,935 clinical images from the same institution was reduced to 5558 radiographs (image set 2) primarily by retaining only images classified positive for bowel obstruction by the initial classifier. These images were classified into obstructive and nonobstructive categories by an abdominal radiologist. The combined 7768 radiographs were used to train additional classifiers (stage 2 training). The best classifiers from stage 1 and stage 2 training were evaluated on a held-out test set of 1453 abdominal radiographs from image set 1. RESULTS: The ROC AUC for the neural network trained on image set 1 was 0.803; after stage 2, the ROC AUC of the best model was 0.971. By use of an operating point based on maximizing the validation set Youden J index, the stage 2-trained model had a test set sensitivity of 91.4% and specificity of 91.9%. Classification performance increased with training set size, reaching a plateau with over 200 positive training examples. CONCLUSION: Accuracy of detection of high-grade small bowel obstruction with a convolutional neural network improves significantly with the number of positive training radiographs. PMID- 30476453 TI - Utility of Attenuation Coefficient Measurement Using an Ultrasound-Guided Attenuation Parameter for Evaluation of Hepatic Steatosis: Comparison With MRI Determined Proton Density Fat Fraction. AB - OBJECTIVE: Recently, a new method was developed to diagnose hepatic steatosis by measuring attenuation coefficients that are based on the ultrasound-guided attenuation parameter (UGAP). We investigated the diagnostic ability of these coefficients to detect steatosis that was identified using the proton density fat fraction (PDFF) on MRI in patients with chronic liver disease. MATERIALS AND METHODS: A total of 126 patients with chronic liver disease (non-hepatitis B, non hepatitis C) were analyzed. The diagnostic ability of UGAP-determined attenuation coefficients was evaluated using ROC curve analysis, and the correlation between MRI-determined PDFF values and attenuation coefficient values was determined. RESULTS: The correlation coefficient (r) between PDFF values and attenuation coefficient values was 0.746 (95% CI, 0.657-0.815) (p < 0.001), corresponding to a strong relationship. The diagnostic ability of attenuation coefficients for steatosis grades >= 1, >= 2, and 3 as determined by PDFF were 0.922 (95% CI, 0.870-0.973), 0.874 (95% CI, 0.814-0.934), and 0.892 (95% CI, 0.835-0.949), respectively. The r between PDFF values and attenuation coefficient values was 0.559 (95% CI, 0.391-0.705) (p < 0.001) in patients with mild or no steatosis (grade <= 1). In addition, the r between PDFF values and attenuation coefficient values was 0.773 (95% CI, 0.657-0.853) (p < 0.001) in obese patients (body mass index [weight in kilograms divided by the square of height in meters] >= 25). The diagnostic ability of attenuation coefficients for patients with steatosis grades >= 1, >= 2, and 3 as determined by PDFF were 0.884 (95% CI, 0.792-0.976), 0.863 (95% CI, 0.778-0.947), and 0.889 (95% CI, 0.813-0.965), respectively. CONCLUSION: UGAP-determined attenuation coefficient values had a good diagnostic ability to detect hepatic steatosis. PMID- 30476454 TI - Patient Photographs: Privacy Versus Protection. AB - OBJECTIVE: Technologies to obtain point-of-care photographs along with medical imaging studies are now available. We discuss the protections that photographs can provide in radiology and the potential privacy and legal issues that can arise with their incorporation. CONCLUSION: Point-of-care photographs that are simultaneously obtained with medical imaging studies can provide biometric identification that enables detection of wrong-patient errors. Photographs also provide image-related clinical context. However, successful implementation of such technologies requires consideration of the privacy and legal issues perceived by stakeholders. PMID- 30476455 TI - The American Board of Radiology B. Leonard Holman Research Pathway to Initial Certification: Opportunities Lost for Diagnostic Radiology. AB - OBJECTIVE: In 1998, the American Board of Radiology introduced the B. Leonard Holman Research Pathway (HRP) to initial certification for trainees in diagnostic radiology (DR) and radiation oncology (RO) motivated to pursue research-oriented careers in academic DR and RO. CONCLUSION: The HRP Committee anticipated that there would be a relatively even distribution between DR and RO participants, but with 18 years of experience that has not been the case. This article focuses on the HRP and DR. PMID- 30476456 TI - Effect of CT Reconstruction Algorithm on the Diagnostic Performance of Radiomics Models: A Task-Based Approach for Pulmonary Subsolid Nodules. AB - OBJECTIVE: We investigated whether the diagnostic performance of machine learning based radiomics models for the discrimination of invasive pulmonary adenocarcinomas (IPAs) among subsolid nodules (SSNs) was affected by the proportion of images reconstructed with filtered back projection (FBP) and model based iterative reconstruction (MBIR) in datasets used for feature extraction. MATERIALS AND METHODS: This retrospective study included 60 patients (23 men and 37 women; mean age, 61.4 years) with 69 SSNs (54 part-solid and 15 pure ground glass nodules). Preoperative CT scans were reconstructed with both FBP and MBIR. A total of 860 radiomics features were obtained from the entire nodule volume, and 70 resampled nodule datasets with an increasing proportion of nodules with MBIR-derived features (from 0/69 to 69/69) were prepared. After feature selection using neighborhood component analysis, support vector machines (SVMs) and an ensemble model were used as classifiers for the differentiation of IPAs. The diagnostic performances of all blending proportions of reconstruction algorithms were calculated and analyzed. RESULTS: The ROC AUC and the diagnostic accuracy of the radiomics models decreased significantly as the number of nodules with MBIR derived features increased, and this relationship followed cubic functions (R2 = 0.993 and 0.926 for SVM; R2 = 0.993 and 0.975 for the ensemble model; p < 0.001). The magnitude of variation in AUC due to the reconstruction algorithm heterogeneity was 0.39 for SVM and 0.39 for the ensemble model. CONCLUSION: Inclusion of CT scans reconstructed with MBIR for radiomics modeling can significantly decrease diagnostic performance for the identification of IPAs. PMID- 30476457 TI - MR Arthrogram Features That Can Be Used to Distinguish Between True Inferior Glenohumeral Ligament Complex Tears and Iatrogenic Extravasation. AB - OBJECTIVE: The purpose of this study is to identify features seen at shoulder MR arthrography that distinguish between iatrogenic contrast material extravasation and inferior glenohumeral ligament (IGHL) complex tears. MATERIALS AND METHODS: MR arthrograms (n = 1740) were screened for extravasation through the IGHL complex. Cases were defined on the basis of surgical findings or definitive lack of extravasation in a fully distended joint immediately after contrast agent injection. The location of the disruption and the morphologic features of the torn margin were assessed and compared between groups. RESULTS: Anterior band disruption was present in eight of 16 patients with true tears and in zero of 19 patients with iatrogenic contrast material extravasation (p < 0.001). Isolated extravasation through the posterior half of the axillary pouch was present in 12 patients with iatrogenic extravasation, compared with none of the patients with true tears (p < 0.001). Thick ends were present in 10 of the true tears, whereas none of the cases of iatrogenic extravasation showed this finding (p < 0.001). Scarred margins were seen in eight true tears and none of the iatrogenic extravasation cases (p < 0.001). The presence of a torn anterior band, thick ligament, reverse-tapered caliber, and scarred appearance of the torn margin were shown to be 100.0% specific, and a torn posterior band showed 84.2% specificity for true tears. The presence of isolated involvement of the posterior portion of axillary pouch showed 63.2% sensitivity and 100.0% specificity for iatrogenic extravasation. CONCLUSION: A torn anterior band, a thickened ligament (> 3 mm), reverse-tapered caliber, and scarred margin were 100.0% specific for a tear. Isolated disruption of the posterior axillary pouch was 100.0% specific for iatrogenic extravasation. PMID- 30476458 TI - Do Deauville Scores Improve the Clinical Utility of End-of-Therapy FDG PET Scans for Pediatric Hodgkin Lymphoma? AB - OBJECTIVE: The purpose of this study was to evaluate the clinical utility of Deauville scores in interpretation of end-of-chemotherapy FDG PET scans. CONCLUSION: Deauville scores improve the clinical utility of end-of-chemotherapy PET, as evidenced by an increase in positive predictive value to 72.7% from 44.4% on the basis of report alone. The negative predictive value remains greater than 95%. PMID- 30476459 TI - Management of Palpable Pediatric Breast Masses With Ultrasound Characteristics of Fibroadenoma: A More Conservative Approach. AB - OBJECTIVE: The purpose of this study is to describe our experience with pathologically proven breast masses at a tertiary care pediatric institution, review published management strategies, and propose new management recommendations for the pediatric population. MATERIALS AND METHODS: All pediatric breast ultrasound examinations performed at a dedicated pediatric facility over a 4-year period were reviewed. Maximum measurements of solid masses with features of a fibroadenoma were recorded. The subsequent management and histopathologic findings for patients undergoing biopsy were reviewed, and management strategies were compared with published recommendations. RESULTS: Of 277 breast masses with features typical of fibroadenomas, 115 (42%) underwent pathologic evaluation. All were benign; there were 107 simple fibroadenomas, four juvenile fibroadenomas, three benign phyllodes tumors, and one granular cell tumor. Simple fibroadenomas ranged in size from 0.9 to 9.1 cm and were statistically significantly different in size compared with juvenile fibroadenomas and phyllodes tumors (range, 1.7-12.5 cm). All 47 masses undergoing follow-up ultrasound before tissue diagnosis were fibroadenomas; five showed 50% or greater interval growth. The retrospective application of published pediatric breast management criteria yielded no difference in sensitivity for the detection of nonsimple fibroadenoma masses. CONCLUSION: Management of pediatric breast masses resembling fibroadenomas at sonography can be based on size and interval growth rate. The routine performance of surgical excision or biopsy of masses with ultrasound characteristics typical of fibroadenomas is not recommended. PMID- 30476460 TI - Virtual Monochromatic Dual-Energy Aortoiliac CT Angiography With Reduced Iodine Dose: A Prospective Randomized Study. AB - OBJECTIVE: The purpose of this study was to assess the feasibility of performing abdominopelvic aortoiliac CT angiography (CTA) with 16.0 g of iodine contrast medium acquired with low-energy (40 and 50 keV) virtual monochromatic (VMC) images with rapid-kilovoltage-switching dual-energy CT. SUBJECTS AND METHODS: A total of 52 adults with abdominal aortoiliac aneurysm and prior 120-kVp single energy CTA (SECTA) with 33 g iodine (standard dose) underwent follow-up dual energy CTA (DECTA) with a 52% reduced iodine dose. Subjects were randomly assigned to a contrast medium protocol for DECTA examinations: one group (n = 26) received 16.2 g (270 mg I/mL) and the other (n = 26) received 16.0 g (320 mg I/mL). Two readers independently assessed SECTA and VMC DECTA datasets for image quality using a 5-point scale. Aortoiliac intravascular attenuation was measured, and ANOVA was used to compare measurements between VMC DECTA and SECTA images. In a subset of patients with DECTA after endovascular aortic repair, endoleak detection was evaluated on VMC images. Volume CT dose index, dose-length product, and size-specific dose estimate were compared between DECTA and SECTA. RESULTS: All DECTA examinations (n = 52) were rated diagnostic with image quality scores comparable to those of 120-kVp single-energy CTA (40 keV, 4.2-4.4; 50 keV, 4.6 4.8; SECTA, 4.4-4.5). Intravascular attenuation was uniform in all reduced-iodine DECTA examinations and was significantly higher on 40- and 50-keV images than on standard-iodine-dose SECTA images (720 +/- 125 HU and 482 +/- 82 HU vs 303 +/- 65 HU) (p < 0.01). There was no difference in intravascular attenuation between the 16.2-g and the 16.0-g doses (p = 0.82). Sensitivity and specificity for endoleak detection were 78.9-94.7% and 100%. Total dose-length product was lower for DECTA (788 +/- 166 mGy . cm) than for SECTA (1114 +/- 468 mGy . cm). CONCLUSION: Low energy VMC DECTA images (40 and 50 keV) acquired with two contrast protocols at approximately 50% reduced iodine dose (16.0 and 16.2 g) provide adequate intravascular attenuation and diagnostic quality for aortoiliac evaluation. PMID- 30476461 TI - Getting pre-exposure prophylaxis (PrEP) to the people: opportunities, challenges and emerging models of PrEP implementation. AB - Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) is now accepted as an efficacious approach to preventing HIV acquisition among people at high risk of HIV infection but, in most places, PrEP uptake to date has not been sufficient to have a large effect on HIV incidence. In this paper we consider several key elements of the effort to expand PrEP uptake for at-risk populations who would benefit most, such as increasing access to PrEP, integrating PrEP programs with other services, promoting PrEP persistence and developing systems for monitoring PrEP use. We used a PrEP Continuum framework to describe barriers to equitable uptake of PrEP, and to illustrate possible solutions to barriers. Access to PrEP includes regulatory issues and geographic proximity to PrEP providers. Integrating PrEP programs with other comprehensive sexual health services, through clinic-based programs or technology-based approaches, offers opportunities to identify PrEP candidates and improve linkages to PrEP care. Once at-risk people are prescribed PrEP, lowering barriers to persistence on PrEP is critical to realising the most population benefits. To understand progress and identify underserved groups and communities, systems to monitor the uptake of PrEP are needed. Making the most of a new biomedical intervention tool requires ongoing research about implementation, scale-up through multiple channels, including community-based organisations, and high-quality monitoring of uptake. We must turn to questions of PrEP implementation and continue to seek innovative approaches to reduce barriers to PrEP uptake and persistence on PrEP. PMID- 30476463 TI - Correction. PMID- 30476462 TI - HIV knowledge, sexual health and sexual behaviour among Black and minority ethnic men who have sex with men in the UK: a cross-sectional study. AB - Background: Black and minority ethnic (BME) men who have sex with men (MSM) face a major burden in relation to HIV infection. Using a cross-sectional correlational survey design, the present study explored the relationships between HIV knowledge and reported sexual health and sexual behaviour in this population. Methods: A convenience sample of 538 BME MSM was recruited in London, Leicester and Leeds: 346 (64%) self-identified as South Asian, 88 (16%) self-identified as Latin American, 76 (14%) self-identified as Black, 13 (2%) self-identified as mixed, and 15 (3%) self-identified as other. Results: HIV knowledge was low across the board, and South Asian MSM manifested the lowest scores. Respondents who perceived their HIV risk to be low possessed the least HIV knowledge. There were interethnic differences in the frequency of gay sauna visits, sex-seeking on mobile applications, drug use and attendance at sex parties. Respondents reported a high frequency of racism and discrimination, with Black MSM reporting highest frequency. Conclusions: There is an urgent need to raise awareness of HIV in BME MSM, and a culturally competent approach to HIV awareness-raising in BME MSM is required. These findings shed light on the contexts in which HIV prevention efforts should be targeted to reach specific ethnic groups, as well as some of the potential syndemics that can increase HIV risk or undermine HIV outcomes in BME MSM patients. PMID- 30476464 TI - Correction. PMID- 30476465 TI - Cryopreservation of embryos and larvae of the edible sea urchin loxechinus albus (Molina, 1782). AB - The natural population of the edible red sea urchin, Loxechinus albus, is decreasing due to overfishing. The embryos and larvae of the species are highly useful for monitoring marine pollution, which makes it necessary to conserve gametes, embryos and larvae to facilitate their use in diverse areas of aquaculture and environmental quality monitoring. This need can be met by cryopreserving individuals representing the different developmental stages to provide an ongoing supply of genetic material of the species. The present study establishes a reproducible protocol for cryopreserving red sea urchin blastula and larvae. Toxicity tests were conducted in the first stage of this study using two permeable cryoprotectors, dimethyl sulfoxide (DMSO) and propylene glycol (PG), at three concentrations (5%, 10% and 15%). The tests were repeated in the second stage, but mixing the cryoprotectors with 0.04 M of trehalose (TRE), a non permeable cryoprotector. Cryopreservation tests were conducted in the third stage employing different freezing rates: 2 degrees C/min, 3 degrees C/min, 3.5 degrees C/min, 4 degrees C/min and 4.5 degrees C/min, using the cryoprotectors that yielded the highest post-incubation survival rates. The highest post freezing survival rates for blastula (76 +/- 7%) and larvae (79 +/- 7%) were obtained with DMSO at 10% + 0.04 M of trehalose, with freezing rates of 3 degrees C/min and 4.5 degrees C/min, respectively. PMID- 30476466 TI - Re: Accuracy of general hospital dementia diagnoses in England: Sensitivity, specificity, and predictors of diagnostic accuracy 2008-2016. PMID- 30476467 TI - In a Critical State: Ongoing Barriers to Treatment for Hepatitis C Virus (HCV). PMID- 30476468 TI - Medicine as a Meritocracy. PMID- 30476469 TI - The potential role of the orexin reward system in future treatments for opioid drug abuse. AB - Despite a history of more than a century of intense research in drug addiction, with currently available medication and behavioral therapy, the rate of relapse to drug use is 40-60 percent within a year after the cessation of treatment. The discovery of the neuropeptide orexin/hypocretin in 1998 and subsequent research during the past 20 years revealed an important role for the lateral hypothalamus (LH) in driving the reward pathway. The present review includes an overview of the orexinergic system and focuses on the role of LH orexin neurons targeting different components of the brain's reward pathway in addictive behaviors. Among major animal models of drug reinforcement and addictive behaviors, we narrowed our focus to include conditioned place preference (CPP) and self-administration methods. In this regard, studies on both orexin-1 receptors (OX1Rs) and orexin-2 receptors (OX2Rs) have shown some positive results, suggesting that single orexin receptor antagonists (SORAs) and dual orexin receptor antagonists (DORAs) may hold promising efficacy in the treatment of addiction compared to the currently used methods. We conclude that since current evidence is still preliminary, development of new SORA and DORA compounds and their evaluation in animal and clinical studies will guide us in our future efforts for developing effective medication. PMID- 30476470 TI - Exposure to synthetic glucocorticoids during pregnancy alters the expression of p73 gene variants in fetal brains in a sex-specific manner. AB - Fetal exposure to dexamethasone (DEX) alters brain plasticity and cognitive functions during adulthood in a sex-dependent manner. The mechanisms underlying such long-lasting sex-dependent change of prenatal DEX is not well understood. The p73 gene plays an important role in brain development. It encodes for two protein variants; the neural cell death protein (TAp73) and the anti-neural cell death protein (DeltaNp73). Therefore, we sought to determine how prenatal exposure to DEX alters the expression of these p73 gene variants in the brain of male and female fetuses. Pregnant dams received daily injections of either DEX (0.4 mg/kg, i.p.) or saline from gestation day (GD) 14 until GD21. On GD21, body and brain weights were monitored and mRNA and protein levels of TAp73 and DeltaNp73 were measured in male and female fetal brains using RT-PCR, Western blot, and immunohistochemistry. Prenatal exposure to DEX significantly reduced the body and brain weights of both male and female fetuses, although reduction in brain weight was less severe than that of the body weight. Administration of DEX to pregnant dams led to enhanced expression of both TAp73 and DeltaNp73 gene/protein variants in the brain of male but not in that of female fetuses. Dexamethasone induced a sex-dependent effect on the expression of p73 gene variants. DEX-induced growth restriction in the brain of female fetuses is independent of p73 gene. This study strongly suggests that survival/death programs operate differently during the development of male and female brains. PMID- 30476471 TI - Long-term impact of cytomegalovirus serologic status on lung transplantation in the United States. AB - BACKGROUND: Cytomegalovirus (CMV) infection has been associated with poor outcomes following solid organ transplantation. However, the long-term impact of donor and recipient CMV serological status on lung transplant outcomes remains unclear. Accordingly, we evaluated the impact of donor and recipient CMV status on long-term patient as well as allograft survival following single (SLT) and double lung transplantation (BLT). METHODS: The Scientific Registry of Transplant Recipients was used to track all adult lung transplants in United States from May 2005 to June 2016. Patient mortality and bronchiolitis obliterans syndrome were determined up to 5 years using Cox proportional hazards modeling. Additionally, landmark analysis was performed conditional on survival at 1-year. RESULTS: Compared to donor negative-recipient CMV-IgG negative (D-R-), donor positive recipient negative (D+R-) and donor positive-recipient positive (D+R+) groups had increased mortality at 1- and 5-years following BLT with the former demonstrating highest risk. While mortality was not increased with CMV seropositive donors following SLT at 1-year, both (D+R-) and (D+R+) groups demonstrated greater mortality at 5-year. Risk of bronchiolitis obliterans syndrome was not affected by CMV serological status. Conditional landmark analysis confirmed that lungs from CMV seropositive donors conferred highest risk for long-term mortality. CONCLUSIONS: CMV seronegative recipients undergoing either BLT or SLT from CMV seropositive donors have the highest risk of long-term mortality which extends beyond the first year. Further studies are needed to determine the causes of higher mortality observed in the CMV seronegative recipients and risks benefits of extension of CMV prophylaxis, particularly in the high-risk group. PMID- 30476472 TI - Total anomalous pulmonary venous connection with an intact interatrial septum. AB - The presence of an interatrial communication is essential for adequate mixing and survival in total anomalous pulmonary venous connection. We report a 5-month-old infant with total anomalous pulmonary venous connection (cardiac type) without an interatrial communication and a large ventricular septal defect. PMID- 30476473 TI - Alternative Implantation Technique for Rapid Deployment Valve. AB - We present a simpler and faster way of implanting the Edwards Intuity Elite rapid deployment valve system. Annular sizing and guiding suture placement are performed in the usual manner. After the valve is parachuted down to the annulus, the balloon catheter is detached and a vent catheter is placed through the center hole to maximize exposure of the valve. The guiding sutures are tied down using an automated suture fastening device instead of securing snares. Visualization of the tip of the suture fastener on the annulus ensures proper valve seating. The sealing frame is ballooned and the valve is deployed. PMID- 30476474 TI - Prothrombin Complex Concentrates for Warfarin Reversal Prior to Heart Transplantation. AB - BACKGROUND: Anticoagulation with warfarin is common prior to heart transplantation and complicates perioperative management. METHODS: This single center, non-interventional, retrospective cohort study evaluated heart transplants before and after institution of a PCC-based preoperative warfarin reversal protocol for heart transplantation. Patients with international normalized ratio (INR) > 1.5 received who PCC prior to heart transplant surgery were compared to a control group prior to implementation of a PCC protocol. Co primary endpoints were utilization of individual blood products. Secondary endpoints included in-hospital mortality, reoperation for bleeding, delayed sternal closure, thromboembolic events, duration of chest tube use, time to extubation, ICU length of stay, and hospital length of stay. RESULTS: The study included 106 consecutive heart transplant patients (PCC cohort = 57, historical control cohort = 49). There was a significant reduction in FFP utilization in the PCC cohort (6 units vs 8 units, p=0.002). Rates of PRBC and platelet transfusion were similar between groups. There was a significant increase in the incidence of cryoprecipitate utilization in the PCC cohort, which can likely be attributed to decreased antifibrinolytic utilization. There were no differences in secondary endpoints between groups, including thromboembolic events. CONCLUSIONS: This study found that a PCC-based warfarin reversal protocol significantly reduced FFP utilization compared to historical controls without impacting other clinically important surgical outcomes. These data suggest that PCC is a valuable tool for INR normalization that could safely reduce FFP administration and offer a practical alternative to traditional approaches for INR reversal prior to heart transplantation. PMID- 30476476 TI - The probability of incomplete or hypoplastic circle of Willis (Reply). PMID- 30476475 TI - Severity of presentation, not sex, increases risk of surgery for infective endocarditis. AB - BACKGROUND: Cardiac surgery for infective endocarditis (IE) is associated to substantial short- and long-term mortality and female sex seems to be associated with even worse outcomes. The aim of our study was to analyze the impact of sex on 30-day and long-term mortality and to identify sex-related risk factors in IE patients requiring cardiac surgery. METHODS: Relevant clinical data of all consecutive 305 patients undergoing cardiac surgery for IE between 2009-2016 were extracted from our institutional database and retrospectively analyzed. IE was defined according to the recent modified Duke Criteria and surgery indicated in compliance to current ESC guidelines. Sex-related postoperative outcomes including 30-day and 1-year mortality were recorded. Univariate and multivariable analysis (MVA) was performed to identify potential sex-dependent risk factors. RESULTS: 229 male (75.1%) and 76 female (24.9%) patients underwent surgery for IE. Female patients showed significantly more mitral valve infection (52.6% vs. 33.6%; p=0.003), and Staphylococcus aureus as causative microorganisms was diagnosed in 44.7% of female patients compared to 24.5% of male patients (p=0.001). Female sex was associated with a higher 30-day (18.4% vs. 8.3%, p=0.014) and 1-year mortality (46.1% vs. 27.1%, p=0.002). MVA revealed not female sex, but EuroSCORE II, re-exploration for bleeding and postoperative acute kidney injury (AKI) as independent risk factor for 30-day and preoperative dialysis for 1-year mortality, respectively. CONCLUSIONS: In this study, female sex was associated with more severe manifestations of IE and a significantly higher 30 day and 1-year mortality. After MVA, not female sex, but the underlying comorbidities seem to determine clinical outcomes. PMID- 30476477 TI - Expert Consensus Document on Pulmonary Metastasectomy. PMID- 30476478 TI - Isolated Congenital Dysgenesia of a Pulmonary Valve Cusp Presenting as Pulmonary Artery Aneurysm. AB - Pulmonary artery aneurysm is a rare disorder with the underlying pathology remaining obscure in many instances. More common causes include pulmonary hypertension, post stenotic dilation or vasculitis . In this case series we report three patients presenting with isolated pulmonary artery aneurysms in whom multi-modality imaging revealed the dysgenesia of a single pulmonary valve cusp as the cause of the huge pulmonary aneurysm. PMID- 30476479 TI - The Incidence and Outcomes of Surgical Pulmonary Embolectomy in North America. AB - BACKGROUND: There has been renewed interest in surgical pulmonary embolectomy (SPE) for the treatment of pulmonary embolism, but the real-world incidence and outcomes of SPE have yet to be well described using a large, granular dataset. We, therefore, examined the modern experience with SPE in North America as reported to the Society of Thoracic Surgery Adult Cardiac Surgery Database (STS ACSD). METHODS: The STS ACSD was queried for all isolated SPE for the treatment of acute pulmonary embolism (2011-2015). Groups were stratified based on presentation: no cardiogenic shock (NCS), cardiogenic shock without arrest (CS), and cardiogenic shock with cardiac arrest (CS/CA). Preoperative characteristics, intraoperative variables, postoperative in-hospital complications, and operative mortality were compared. Multivariable logistic regression was performed to identify risk factors for in-hospital mortality. RESULTS: Of the 1,144 centers reporting during the study period, only 310 performed at least one SPE (overall mean 0.42+/-1.03 cases/year/center). 1,075 eligible SPE were identified (NCS=719, CS=203, CS/CA=153). Median age was 57 years (interquartile range (IQR) 45-67), 54% were male, and preoperative thrombolysis was used in 8%. Overall, operative mortality was 16%, but increased with presenting acuity (NCS=8%, CS=23%, CS/CA=44%, p<0.001). Independent predictors of operative mortality included age, obesity, cardiogenic shock, pre-operative arrest, chronic lung disease, unresponsive neurologic state, and prolonged cardiopulmonary bypass time. CONCLUSIONS: SPE is uncommonly performed in North America, and in selected patients, it may be associated with favorable outcomes. Nevertheless, significant mortality exists, and attention to patient presentation and other risk factors may help distinguish patients appropriate for SPE. PMID- 30476480 TI - Synchronous Oligometastatic Lung Cancer deserves a dedicated management. AB - BACKGROUND: Oligometastatic stage IV Non-small Lung Cancer (NSCLC) patients have a 5-years overall survival of 30% versus 4-6% . We reviewed data and patterns of care of patients affected by oligometastatic NSCLC in our centre between 2001 and 2017. METHODS: We retrospectively reviewed clinical and pathological files of all patients with lung cancer and synchronous isolated adrenal and/or brain metastases, treated by locally ablative treatments (surgery and/or, radiotherapy) of both primary cancer and distant metastasis. Statistical analysis was performed to assess the impact on overall survival of patient and tumour-related characteristics and therapeutic approaches. Overall survival was assessed by Kaplan-Meier method. Survival rates were compared by log rank test. Significance was accepted at a level of p<0.05. RESULTS: Fifty- one patients affected by NSCLC and synchronous brain metastasis (n=41) or adrenal metastasis (n=9) or both (n=1) were treated in our department. Median survival was 42 months (CI 95% 22.3-63.7). Two-years and 5- years overall survival was 62% and 34.4% respectively. a univariate and multivariate analysis the positive prognostic factors for survival was cessation of smoking (p=0.006) and lymphovascular and perineural spreading in the tissues (p=0.024). CONCLUSIONS: In selected oligometastatic synchronous NSCLC patients, multimodality approach encompassing radical treatment of the primary tumour and ablative treatment of concurrent metastases is recommended, with encouraging results. Smoking cessation is a part of the treatment sequence. PMID- 30476481 TI - Standardization within the groups is necessary (Reply). PMID- 30476482 TI - Stopping Vs Continuing Aspirin Prior to Coronary Artery Surgery for Desensitized Cardiac Patients. PMID- 30476483 TI - Role of caveolin-1 in epidermal stem cells during burn wound healing in rats. AB - Local transplantation of stem cells has therapeutic effects on skin damage but cannot provide satisfactory wound healing. Studies on the mechanisms underlying the therapeutic effects of stem cells on skin wound healing will be needed. Hence, in the present study, we explored the role of Caveolin-1 in epidermal stem cells (EpiSCs) in the modulation of wound healing. We first isolated EpiSCs from mouse skin tissues and established stable EpiSCs with overexpression of Caveolin 1 using a lentiviral construct. We then evaluated the epidermal growth factor (EGF)-induced cell proliferation ability using cell counting Kit-8 (CCK-8) assay and assessed EpiSC pluripotency by examining Nanog mRNA levels in EpiSCs. Furthermore, we treated mice with skin burn injury using EpiSCs with overexpression of Caveolin-1. Histological examinations were conducted to evaluate re-epithelialization, wound scores, cell proliferation and capillary density in wounds. We found that overexpression of Caveolin-1 in EpiSCs promoted EGF-induced cell proliferation ability and increased wound closure in a mouse model of skin burn injury. Histological evaluation demonstrated that overexpression of Caveolin-1 in EpiSCs promoted re-epithelialization in wounds, enhanced cellularity, and increased vasculature, as well as increased wound scores. Taken together, our results suggested that Caveolin-1 expression in the EpiSCs play a critical role in the regulation of EpiSC proliferation ability and alteration of EpiSC proliferation ability may be an effective approach in promoting EpiSC-based therapy in skin wound healing. PMID- 30476484 TI - "Rafts": a nickname for putative transient nanodomains. AB - The membrane raft hypothesis, proposed in 1997 by K. Simons and E. Ikonen, has played a paradoxical role in the history of biomembrane research. While it has generated a large amount of investigations, thus helping to increase our understanding of membranes, the object that gives name to the hypothesis, i.e. the raft itself, has been and still is an object of controversy, in which its very reality is often questioned. In this contribution I review the history of the hypothesis and its reception by membrane biologists, and summarize some of the valuable physico-chemical results that have been obtained while testing the raft hypothesis. To save a useful concept from its many misuses I propose that the expression "(transient) nanodomains" be employed instead of "rafts". PMID- 30476485 TI - Visualizing Sphingolipid biosynthesis in cells. AB - Biosynthetic pathways play a fundamental role in the building and operation of the cell by synthesizing the constituents by which the cell is constructed, and by producing signalling intermediates that play a key role in cell regulation. While a lot is known about the metabolite profile of the cells and about the biochemical pathways through which these metabolites are produced, the cellular localization of the biosynthetic machineries and the importance of this localization to the regulation of the metabolism has often been given less attention. This derives from the fact that, for several of these pathways, the enzymes involved are found colocalized in one compartment where their specific localization is unlikely to influence their function. The sphingolipid (SL) metabolic pathway is a notable exception to this as SL synthetic enzymes are laid out on a specific pattern across the secretory compartments. Such compartmentalized organization of the SL synthesis has functional implications as it makes the fine-tuned regulation of the process possible by allowing cells to regulate specific segments of the pathway in response to stimuli and for adaptation. The organization, dynamics, and regulation of the SLs and their biosynthetic machinery have been investigated using imaging-based methods. Here we provide a brief introduction to the techniques that have been or that could be employed to visualize the SL biosynthetic machinery and SLs themselves and discuss the insights provided by these studies in understanding this metabolism. PMID- 30476486 TI - Calculating the 'chain splay' of amphiphilic molecules: Towards quantifying the molecular shapes. AB - We report the first method to calculate a very important molecular level parameter of amphiphilic molecules- the 'chain splay'. The calculations employed a truncated cone geometry, as it is the most probable configuration adopted by various amphiphiles. This approach utilized known parameters including lipid length, cross-sectional area at the head group and molecular volume. This new parameter, i.e. the area at the chain end, perceived to be more sensitive than Israelachvili's famous shape factor or critical packing parameter (CPP). With relevant calculations, we demonstrate the fundamental roles of 'chain splay' to: a) reveal the critical contribution of molecular structure on average molecular shape and consequent self-assemblies, b) track the finest changes in molecular shapes within different bicontinuous cubic phases, c) obtain non-zero areas at the chain ends of amphiphiles that form normal (type 1) phases, d) back-calculate molecular volumes close to theoretical values, and e) find the link between molecular shapes and global curvatures of self-assemblies. This powerful feature advances our abilities towards quantitative estimation of spatial configurations adopted by amphiphilic molecules; moreover, it has a strong impact on predicting biomembrane structuring and nanoscale design of corresponding self-assemblies for a range of emerging applications. PMID- 30476487 TI - Concentration of Costs among High Utilizers of Healthcare Services over the First 10 Years after Spinal Cord Injury Rehabilitation: A Population-based Study. AB - OBJECTIVE: (1) Categorize individuals into high, medium, and low utilizers of healthcare services over a 10-year period after the onset of spinal cord injury (SCI) and (2) Identify the pattern of causes of hospitalizations and the characteristics associated with high utilization. DESIGN: Retrospective analysis of self-report assessment linked to administrative data. SETTING: Data were collected from participants living in and utilizing hospitals in the state of South Carolina. PARTICIPANTS: Adult participants with traumatic SCI were identified through a state SCI Surveillance System Registry, a population-based system capturing all incident cases treated in non-federal facilities. Among 963 participants who completed self-report assessments, we matched those with a minimum of 10 years of administrative records for a final sample of 303 participants. INTERVENTIONS: N/A MAIN OUTCOME MEASURES: Costs related to healthcare utilization for emergency department visits and hospitalizations, as measured operationally by hospital charges at full and established rates; causes of hospitalizations RESULTS: Over two-thirds of the total $49.4 million in charges for hospitalization over the 10-year timeframe (69%) occurred among 16.5% of the cohort (high utilizers), whereas those in the low utilizer group comprised 53% of the cohort with only 3.5% of the charges. The primary diagnoses were septicemia (50%), other urinary tract disorder (48%), mechanical complication of device, implant, or graft (48%), and chronic ulcer of skin (40%). Primary diagnoses were frequently accompanied by secondary diagnoses, indicating the co occurrence of multiple secondary health conditions. High utilizers were more likely to be male, nonwhite, have a severe SCI, have reported frequent pressure ulcers and have income of less than $35,000 per year. CONCLUSIONS: The high cost of chronic healthcare utilization over a 10-year timeframe was concentrated in a relatively small portion of the SCI population who have survived more than a decade after SCI onset. PMID- 30476488 TI - Inpatient Rehabilitation Quality of Care from the Patient's Perspective: Impact of Data Collection Timing and Patient Characteristics. AB - OBJECTIVE: To compare, by collection time and patient characteristics, inpatient rehabilitation quality measure scores calculated using patient-reported data. DESIGN: Cohort study of rehabilitation inpatients with neurologic conditions who reported their experience of care and pain status at discharge and one-month after discharge. SETTING: Two inpatient rehabilitation facilities (IRFs) PARTICIPANTS: 391 patients with neurologic conditions INTERVENTIONS: Not Applicable MAIN OUTCOME MEASURES: We calculated 18 quality measure scores using participants' responses to 55 experience of care and health status questions addressing communication, support and encouragement, care coordination, discharge information, goals, new medications, responsiveness of staff, cleanliness, quietness, pain management, care transitions, overall hospital rating, willingness to recommend, and pain. RESULTS: Of the 391 participants reporting at discharge, 277 (71%) also reported post-discharge after multiple attempts by email, mail, and telephone. Discharge experience of care quality scores ranged from 25% (responsiveness of hospital staff) to 75% (willingness to recommend hospital); corresponding post-discharge scores were 32% to 87%, respectively. Five of the 16 experience of care quality scores increased significantly between discharge and post-discharge. The percentage of participants reporting high pain levels at discharge did not change across time periods. Patients with less education, older age, higher motor and cognitive function, and those who were non Hispanic Black had more favorable quality measure scores. CONCLUSION: Patients' experience of care responses tended to be more favorable after discharge compared to discharge, suggesting that survey timing is important. Responses were more favorable for patients with selected characteristics, suggesting the possible need for risk adjustment if patient-reported quality measure scores are compared across IRFs. PMID- 30476489 TI - Influence of peer-led wheelchair training on wheelchair skills and participation in older adults: Clinical outcomes of a randomized controlled feasibility trial. AB - OBJECTIVES: To estimate treatment effect size of a peer-led 'Wheelchair training self-efficacy enhanced for use' (WheelSeeU) program on objective wheelchair skills (primary); and on perceived wheelchair skills capacity and performance, wheelchair use-self-efficacy, satisfaction with participation, life-space mobility, and participation frequency (secondary); and to evaluate retention six months later (secondary). DESIGN: Randomized controlled trial. SETTING: Rehabilitation centres, communities. PARTICIPANTS: Community-living older adults. INTERVENTION: WheelSeeU comprised six, 90 minutes peer-led sessions of customized training (in pairs) according to participants' goals. A support-trainer provided spotting. The control group comprised six, 90-minute professional-led didactic information sessions (in pairs). MAIN OUTCOME MEASURES: The Wheelchair Skills Test (WST), Wheelchair Skills Test Questionnaire (WST-Q), Wheelchair Use Confidence Scale for Manual Wheelchair Users (WheelCon), Wheelchair Outcomes Measure (WhOM), Life Space Mobility (LSA), and Late Life Function and Disability Index (LLFDI) were collected at baseline (T1), post-intervention (T2), and six months post-intervention (T3). RESULTS: Of 121 screened, 39 individuals did not meet the inclusion criteria and 41 declined to participate. Forty participants (64.5 years of age; 60% male) were randomized, 38 completed the intervention, and 35 completed T3 assessments. There were no adverse effects. WheelSeeU did not have a statistically significant greater effect on objective WST (primary) or WST Q capacity, WheelCon, LSA, and LLFDI at T2 compared to the control group. Effect sizes were statistically significant and large for WST-Q performance (Cohen's d = 0.72) and the WhOM (Cohen's d = 0.82) at T2, and effects were retained at T3. CONCLUSIONS: Compared to an active control group, WheelSeeU did not have a greater effect on wheelchair skills capacity. However, WheelSeeU should not be prematurely dismissed as an approach to potentially improve wheelchair skills performance and satisfaction with participation in meaningful activities. Gender and depression are important when designing interventions for older adults. PMID- 30476490 TI - Bone Regeneration of Canine Peri-implant Defects Using Cell Sheets of Adipose Derived Mesenchymal Stem Cells and Platelet-Rich Fibrin Membranes. AB - PURPOSE: Insufficient bone volume compromises the success rate and osseointegration of immediate implantation. The objective of the present study was to engineer bone tissue by using adipose-derived stem cell (ASC) sheets and autologous platelet-rich fibrin (PRF) to enhance new bone formation and osseointegration around dental implants. MATERIAL AND METHODS: The proliferation and osteogenic potential of ASCs treated with autologous PRF were evaluated with CCK-8 assays, alkaline phosphatase staining, and real-time quantitative polymerase chain reaction. A 3-wall bone defect around each immediate implant was generated in the mandible and randomly treated with ASC sheets plus PRF (group A), ASC sheets only (group B), PRF only (group C), or no treatment (group D). Micro-computed tomography, biomechanical tests, fluorescent bone labeling, and histologic assessments were performed to evaluate bone regeneration capacity. RESULTS: The proliferation and osteogenic potential of canine ASCs were markedly enhanced by PRF. Group A exhibited considerably more new bone formation and re osseointegration (41.17 +/- 1.44 and 55.06 +/- 0.06%, respectively) than did the other 3 groups. Fluorescent labeling showed that the most rapid bone remodeling activity occurred in group A (P < .05). CONCLUSION: These results suggest that sheets of ASC combined with autologous PRF could be a promising tissue engineering strategy for bone formation in immediate implantation. PMID- 30476491 TI - Low Ca2+ levels in the culture media support the heterologous expression of insect odorant receptor proteins in HEK cells. AB - BACKGROUND: Heterologous expression of insect odorant receptors (ORs) in mammalian or insect cells is challenging due to the insufficient intracellular trafficking of ORs and their ability to form leak ion channels. NEW METHOD: We tested whether reducing the Ca2+ levels in the cell culture medium after electroporation by means of a Dulbecco's Modified Eagle Medium (DMEM) without calcium, in a 1:1 ratio with Ham's F12 nutrient mixture, together with 10% fetal calf serum, can improve the success rate of insect OR expression in HEK293 cells. RESULTS: We show that a reduced extracellular Ca2+ level supports functional expression of insect ORs by increasing the fraction of cells responding to the co receptor agonist VUAA1 and by reducing the intracellular Ca2+ base level of transfected cells. COMPARISON WITH EXISTING METHOD(S): A DMEM formula without calcium outperforms standard DMEM in a 1:1 ratio with Ham's F12 mix and 10% serum, when culturing HEK293 cells transiently expressing insect OR proteins. CONCLUSIONS: Reducing the extracellular Ca2+ level of HEK293 cell culture media after transfection increases the success of functional insect OR expression. PMID- 30476492 TI - Invasive meningococcal disease as a cause of sudden and unexpected death in a teenager: the public health importance of confirming the diagnosis. PMID- 30476493 TI - Next-generation sequencing of the BALF in the diagnosis of community-acquired pneumonia in immunocompromised patients. PMID- 30476494 TI - Redefining influenza seasonality at a global scale and aligning it to the influenza vaccine manufacturing cycle: a descriptive time series analysis. AB - OBJECTIVES: Annual seasonal influenza vaccine manufacturing cycles align with temperate country seasonality in each hemisphere, yet influenza seasonality is poorly defined for many countries. The study introduces a novel and universal approach to defining and classifying seasonality that can be used to classify any country's influenza vaccine cycle alignment. METHODS: Countries reporting to the World Health Organization's FluNet influenza virology database in 90% of weeks during 2011 through 2017 were included. A smoothed, standardised, average proportion of influenza occurring in each week of the year was used to determine degree of seasonality based on the range of average weekly variation. The proportion of activity occurring May through October was used to align influenza activity with a hemisphere's vaccine manufacturing cycle. RESULTS: From 84 included countries, there were 2,239,208 positive influenza results, of which 26% were influenza type B. Degree of seasonality was moderately positively correlated with absolute value of latitude (r= 0*69, p < 0*0001). Latitude was strongly negatively correlated with the proportion of influenza occurring during May through October (r = -0*83, p < 0*0001). Thirteen countries (12% of the included global population), mainly in tropical zones, had influenza occurrence aligned with the opposite hemisphere's influenza vaccine manufacturing cycle. In tropical zones, concordance in the degree of seasonality and vaccine cycle alignment within regions and between adjacent countries was limited. In temperate zones, on average, influenza B peaked four weeks later than A. CONCLUSIONS: Influenza activity in many countries aligns with the vaccine manufacturing cycle of the opposite hemisphere. In tropical regions, there is limited scope for grouping countries for vaccine distribution and administration. PMID- 30476495 TI - Development and fate of the residual body of Toxoplasma gondii. AB - As the tachyzoite form of Toxoplasma gondii divides inside the parasitophorous vacuole, the daughter cells remain attached to each other at the posterior end through the so-called residual body (RB). Here, we studied this process using field emission scanning electron microscopy of dry scraped infected cells, transmission electron microscopy of random ultrathin sections, X-ray microanalysis, and 3-D modelling of tomographic volumes and slice and view series obtained by FIB SEM at 7, 24, and 48 h post infection. Combining these methods of observation, we traced a timeline of events for the formation, development, and fate of the RB. The RB is formed as the first endodyogenic division is complete. Before that, finger-like invaginations at the posterior end of the tachyzoite secrete tubules from the intravacuolar network. The RB is roughly spherical and measures 1 MUm in diameter at random. Its size does not vary considerably as the division cycles that form the rosette proceed. The contents of the RB are similar to the cytoplasm of the parasites. It contains ER membranous profiles and vacuolar structures identified as acidocalcisomes. This was confirmed by microanalysis. Mitochondrial profiles seen inside the RB are actually branches of mother cell mitochondrion not yet split between the two daughter cells. Acidocalcisomes of a mother cell are distributed between the two daughter cells, but as the rosette of parasites grow, acidocalcisomes seem to concentrate inside the RB where they are usually larger and tend to fuse to each other, filling most of the space in the RB. Here we hypothesize that, upon egress, the acidocalcisomes would ultimately fuse with the RB membrane liberating its contents inside the parasitophorous vacuole (PV) and, by doing so; the RB would disintegrate, releasing its contents in the PV. PMID- 30476496 TI - Endocrine-disrupting chemicals: Effects on neuroendocrine systems and the neurobiology of social behavior. AB - A contribution to SBN/ICN special issue. Endocrine-disrupting chemicals (EDCs) are pervasive in the environment. They are found in plastics and plasticizers (bisphenol A (BPA) and phthalates), in industrial chemicals such as polychlorinated biphenyls (PCBs), and include some pesticides and fungicides such as vinclozolin. These chemicals act on hormone receptors and their downstream signaling pathways, and can interfere with hormone synthesis, metabolism, and actions. Because the developing brain is particularly sensitive to endogenous hormones, disruptions by EDCs can change neural circuits that form during periods of brain organization. Here, we review the evidence that EDCs affect developing hypothalamic neuroendocrine systems, and change behavioral outcomes in juvenile, adolescent, and adult life in exposed individuals, and even in their descendants. Our focus is on social, communicative and sociosexual behaviors, as how an individual behaves with a same- or opposite-sex conspecific determines that individual's ability to exist in a community, be selected as a mate, and reproduce successfully. PMID- 30476497 TI - Modeling Human Digestive Diseases with CRISPR-Cas9-modified Organoids. AB - Insights into the stem cell niche have allowed researchers to cultivate adult tissue stem cells as organoids that display structural and phenotypic features of healthy and diseased epithelial tissues. Organoids derived from patients' tissues are used as models of disease and to test drugs. CRISPR-Cas9 technology can be used to genetically engineer organoids for studies of monogenic diseases and cancer. We review the derivation of organoids from human gastrointestinal tissues and how CRISPR-Cas9 technology can be used to study these organoids. We discuss burgeoning technologies that are broadening our understanding of diseases of the digestive system. PMID- 30476498 TI - Slow and fast grouping of cargo velocities in axonal transport due to single versus multi-motor transport. AB - We have recently been exploring the idea that axonal transport velocity is "track and motor limited." That is, microtubule length as well as microtubule-associated obstructions interact with the number of motors attached to a specific cargo to determine average cargo velocities. We assert that "slow" and "fast" transport as they are commonly referred to in the literature are really single- versus multi motor transport along interrupted and obstructed track. To this end, we have recently developed a cargo-level motor model that appears to readily reproduce fast and slow transport simply by altering the number of motors. In the work presented here, we explore the ramifications of this model across a wide range of cargo sizes and motor-motor interactions. We find that categorization of cargo transport into "slow" and "fast" might be a natural consequence of track and motor limited transport as cargo load versus average velocity distribution produced by this model are clearly bi-modal with a curved (roughly square-root) relationship between number of motors and cargo load being the best at reproducing experimental data. PMID- 30476499 TI - The Microbiome in Atopic Dermatitis. AB - As an interface with the environment, the skin is a complex ecosystem, colonized by many microorganisms that coexist in an established balance. The cutaneous microbiome inhibits colonization with pathogens such as S. aureus and is a crucial component for function of the epidermal barrier. Moreover, crosstalk between commensals and the immune system is now recognized, as microorganisms can modulate innate, as well as adaptive, immune responses. Host-commensal interactions also have an impact on the developing immune system in infants and subsequently the occurrence of diseases such as asthma and atopic dermatitis. Later in life, the cutaneous microbiome contributes to the development and course of skin disease. Accordingly, in patients with atopic dermatitis, a decrease in microbiome diversity correlates with disease severity and increased colonization with pathogenic bacteria such as S. aureus. Early clinical studies suggest that topical application of commensal organisms (e.g., S. hominis or R. mucosa) reduces atopic dermatitis severity and support an important role for commensals in decreasing S. aureus colonization in patients with atopic dermatitis. Advancing knowledge of the cutaneous microbiome and its function in modulating the course of skin disorders such as atopic dermatitis may result in novel therapeutic strategies. PMID- 30476500 TI - pH and thermo dual stimulus-responsive liposome nanoparticles for targeted delivery of platinum-acridine hybrid agent. AB - The complexes of the type [PtCl(L2)(ACRAMTU)](NO3)2 (ACRAMTU = 1-[2-(acridin-9 ylamino)ethyl]-1,3-dimethylthiourea) were synthesized: PT-ACRAMTU (1), L2 = ethane-1,2-diamine (en); PT(dach)-ACRAMTU (2), L2 = (1R,2R)-1,2 diaminocyclohexane (dach); PT(pda-OH)-ACRAMTU (3), L2 = 2-hydroxy-1,3 propanediamine (pda-OH). The complexes containing diverse diamines exhibit different DNA binding capacity and cytotoxicity. Complex 3 shows excellent capability not only on the strongest non-cisplatin-type DNA damage, but also superior anticancer activity in NCI-H460 cells (IC50 = 0.23 +/- 0.05 MUM). For overcoming water insolubly and side effects, we encapsulated complex 3 into liposomes. PT@NPs were characterized in terms of particle size, morphology, drug loading capacity (DLC), encapsulation efficiency (EE) and stability. In vitro triggered release showed that the release of the platinum drug was steerable and the release rate was fast under low pH (<7.0) and high temperature (>Tm = 41 degrees C). PT@NPs showed significant inhibitory effect in NCI-H460 cells. Flow cytometry analysis indicates G0/G1 phase arrest of cells treated with complex 3, whereas cells treated with cisplatin progress to G2/M of the cell cycle. The mechanistic differences validate that complex 3 is a potent anticancer agent superior than current clinical platinum-based therapies. PT@NPs have the potential in drug delivery systems (DDS) for non-small cell lung cancer (NSCLC) therapy. PMID- 30476501 TI - Comprehensive optical design model of the goldfish eye and quantitative simulation of the consequences on the accommodation mechanism. AB - To further extent our understanding of aquatic vision, we introduce a complete optical model of a goldfish eye, which comprises all important optical parameters for the first time. Especially a spherical gradient index structure for the crystalline lens was included, thus allowing a detailed analysis of image quality, regarding spot size, and wavelength dependent aberration. The simulation results show, that our realistic eye model generates a sufficient image quality, with a spot radius of 4.9 MUm which is below the inter cone distance of 5.5 MUm. Furthermore, we optically simulate potential mechanical processes of accommodation and compare the results with contradictory findings of previous experimental studies. The quantitative simulation of the accommodation capacity shows that the depth of field is strongly dependent on the resting position and becomes significantly smaller when shorter resting positions are assumed. That means, to enable an extended depth perception with high acuity for the goldfish an adaptive, lens shifting mechanism would be required. In addition, our model allows a clear prediction of the expected axial lens-shift, which is necessary to ensure a sufficient resolution over a large object range. PMID- 30476502 TI - Differential response to lead toxicity in rat primary microglia and astrocytes. AB - Lead (Pb) is one of the most widely studied occupational and environmental toxins. Chronic exposure to Pb affects neural function in the central nervous system (CNS). Glial cells in the CNS, such as microglia and astrocytes, respond differently to Pb-induced toxicity. However, the underlying mechanism has not yet been identified. We measured the cell viability and intracellular Pb uptake in rat primary microglia and astrocytes using the CCK-8 assay and inductively coupled plasma mass spectrometry, and found that Pb decreased microglial viability at lower dosages than in astrocytes, while Pb uptake was greater in astrocytes. Pb-induced oxidative stress in microglia results in increased production of reactive oxygen species, down-regulation of glutathione, and enhanced Nrf2 protein expression, while there was no obvious change in astrocytes. The role of Nrf2 in Pb-induced oxidative stress has also been confirmed in primary microglia with the use of Nrf2 small interfering RNA and an Nrf2 agonist. These data indicate that primary microglia were more sensitive to Pb exposure than astrocytes, which is associated with an obvious oxidative stress response and up-regulation of Nrf2 might be involved in this process. PMID- 30476503 TI - Associations of health-behavior patterns, mental health and self-rated health. AB - Diet quality, physical activity, alcohol use, smoking, sleep and sitting-time are behaviors known to influence health. The aims of this study were to identify how these behaviors co-occur to form distinct health-behavior patterns, and to investigate the relationship between these patterns, and mental and self-rated health. Members of the Australian 10,000 Steps project were invited to participate in an online survey in November-December 2011. The participants self reported demographic and behavioral characteristics (fruit and vegetable intake, fast food, soft drink and alcohol consumption, smoking, physical activity, sitting-time and sleep), frequency of mental distress and self-rated health. Latent Class Analysis was used to identify health-behavior patterns. Latent class regression was used to examine relationships between behavior patterns, mental and self-rated health, and socio-demographic and economic factors. Data were analyzed in October 2017. Complete datasets were obtained from 10,638 participants. Four latent classes were identified, characterized by 'Low-Risk Behavior', 'Poor Sleep, Low-Risk Daytime Behavior', 'Sound Sleep, High-Risk Daytime Behavior' and 'High-Risk Behavior'. The latter two classes, both characterized by high-risk daytime behaviors, were associated with poor self rated health. Participants in classes with high-risk daytime behaviors were more likely to be younger, non-partnered, non-university educated, from lower income households and work longer hours. Classes characterized by poor sleep quality were associated with higher frequency of mental distress. Findings suggest that experiencing poor sleep is partly independent of daytime behaviors, demographic and socioeconomic factors, but has a strong association with mental health. PMID- 30476504 TI - Pediatric partial nephrectomy for upper urinary tract duplication anomalies: a comparison between different surgical approaches and techniques. AB - OBJECTIVE: To review and compare four different surgical approaches for partial nephrectomy of a nonfunctioning moiety in children with upper urinary tract duplication anomalies. MATERIALS AND METHODS: A retrospective review of all pediatric patients who underwent open (OPN), laparoscopic (LPN), robotic (RPN), or laparoendoscopic single site (LESS-PN) partial nephrectomy for the treatment of a nonfunctioning moiety in a duplicated collecting system at two medical centers between 2007 and 2017. Patient demographics, perioperative data, surgical techniques, complications, and results were compared. RESULTS: A total of 59 pediatric patients underwent partial nephrectomy for an upper urinary tract duplication anomaly during a 10-year period: 24 OPN, 7 LPN, 18 RPN, and 10 LESS PN. Median age was 16 months (IQR 9-49.7). Median weight was 10.7 Kg (IQR 8.8 16.4). Median EBL was comparable between all minimally invasive approaches, but significantly increased in the open approach. OPN required more narcotics (0.554 mg Morphine equivalent/Kg/day, range 0.03-6.13) and Acetaminophen (72.12 mg/Kg/day, range 0-209.06) than all other groups in the study. Median operating time in OPN (154.5 min, range 108-413) and LESS-PN (140 min, range 65-245) were found to be significantly shorter in comparison to LPN (190 min, range 159-355) and RPN (256 min, range 163-458); (p=0.03, 0.005, 0.02, 0.005). CONCLUSIONS: Minimally invasive approaches (LPN, RPN, and LESS-PN) for partial nephrectomy in upper urinary tract duplication anomalies may be associated with decreased postoperative analgesia requirements, shorter hospital stay, less blood loss, and less use of drains in comparison to the open approach, while demonstrating efficacy and safety. PMID- 30476505 TI - Quantitative neurosymptomatics; linking quantitative biology to neuropsychiatry. PMID- 30476506 TI - Toxoplasmosis: A pathway to neuropsychiatric disorders. AB - Toxoplasma gondii is an obligate intracellular parasite that resides, in a latent form, in the human central nervous system. Infection with Toxoplasma drastically alters the behaviour of rodents and is associated with the incidence of specific neuropsychiatric conditions in humans. But the question remains: how does this pervasive human pathogen alter behaviour of the mammalian host? This fundamental question is receiving increasing attention as it has far reaching public health implications for a parasite that is very common in human populations. Our current understanding centres on neuronal changes that are elicited directly by this intracellular parasite versus indirect changes that occur due to activation of the immune system within the CNS, or a combination of both. In this review, we explore the interactions between Toxoplasma and its host, the proposed mechanisms and consequences on neuronal function and mental health, and discuss Toxoplasma infection as a public health issue. PMID- 30476507 TI - Distinct influence of COX-1 and COX-2 on neuroinflammatory response and associated cognitive deficits during high altitude hypoxia. AB - High-altitude hypoxia (HH) causes a spectrum of pathophysiological effects, including headaches, gliovascular dysfunction, and cognitive slowing. Previous studies have shown arachidonic acid (AA) metabolism due to cyclooxygenase (COX) activity before clinical manifestations in many diseases. AA metabolites, including COXs and prostaglandin E2 (PGE2), are well known immunomodulators. However, the relative contribution of COX-2 and COX-1 isoforms in the downstream proinflammatory responses and cognitive deficit in HH remains unknown. In the present study, AA metabolism via the COX pathway was investigated in Sprague Dawley rats after 0, 1, 3, and 7 days of HH exposure. Furthermore, we investigated the inflammatory response and cell-type-specific induction of both COXs. Our data revealed that AA metabolites peaked on day 3 of HH exposure. Interestingly, we observed endothelial and microglial activation on day 1, accompanied by an increase in the levels of proinflammatory cytokines, followed by astrocyte activation on day 3. We showed that the increase in COX activity during HH culminated in a significant increase in hippocampal inflammation, concomitant with spatial memory impairment and neuronal injury at day 7 of HH. We showed HH induced distinct COX-1 expression in endothelial and microglial cells, whereas it induced COX-2 expression predominantly in neurons, endothelial cells, and astrocytes. Notably, our data showed that the inhibition of COX-1 using valeryl salicylate had a prominent role in containing hippocampal inflammation by reducing microglial activation. COX-2 inhibition using celecoxib, along with COX 1 inhibition, ameliorated spatial memory impairment, astrocyte activation, and neurodegeneration after HH exposure. PMID- 30476508 TI - Biopharmaceutic IVIVE - Mechanistic Modelling of Single- and Two-Phase In Vitro Experiments to Obtain Drug-Specific Parameters for Incorporation into PBPK Models. AB - The physiological relevance of single-phase (aqueous only) and two-phase (aqueous and organic phase) in vitro dissolution experiments was compared by mechanistic modelling. For orally dosed dipyridamole, stepwise, sequential estimation/confirmation of biopharmaceutical parameters from in vitro solubility dissolution data was followed, before applying them within a PBPK model. The PBPK model predicted clinical dipyridamole luminal and plasma concentration profiles reasonably well for a range of doses only where the precipitation rate constant was derived from the two-phase experiment. The population model predicted a distribution of maximal precipitated fractions from 0 to 45% of the 90 mg dose (mean 7.6%). Such population information cannot be obtained directly from a few in vitro experiments however well they may represent an "average" and several extreme subjects (those with low-high luminal fluid volumes, pH etc.) because there is no indication of outcome likelihood. For this purpose, direct input of in vitro dissolution/precipitation profiles to a PBPK model is insufficient - mechanistic modelling is required. Biopharmaceutical In Vitro-In Vivo Extrapolation (IVIV_E) tools can also simulate the effect of key experimental parameters (dissolution volumes, pH, paddle speed, etc.) on dissolution/precipitation behaviour, thereby helping to identify critical variables which may impact the number or design of in vitro experiments. PMID- 30476509 TI - Models for antibody behaviour in hydrophobic interaction chromatography, and in self-association. AB - Monoclonal antibodies (mAbs) form an increasingly important sector of the pharmaceutical market, and their behaviour in production, processing, and formulation is a key factor in development. With datasets of solution properties for mAbs becoming available, and with amino acid sequences, and structures for many Fabs, it is timely to examine what features correlate with measured data. Here, previously published data for hydrophobic interaction chromatography (HIC) and the formation of high molecular weight species (HMWS) are studied. Unsurprisingly, aromatic sidechain content of complementarity determining regions (CDRs), underpins much of the variability in HIC data. However, this is not reflected in non-polar solvent accessible surface enrichment at the antigen combining site, consistent with a view in which hydrophobic interaction strength is dependent on curvature as well as extent of an interface. Sequence properties are also superior to surface-based structural properties in correlations to the HMWS data. Combined length of CDRs is the most important factor, which could be an indication of flexibility that facilitates CDR-CDR interactions in mAb self association. These observations couple to our understanding of protein physicochemical properties, laying the groundwork for improved developability models. PMID- 30476510 TI - Enhancing the pharmaceutical behavior of nateglinide by cocrystallization. Physico chemical assessment of cocrystal formation and informed use of DSC for its quantitative characterization. AB - The aim of this study was to synthetize cocrystals of nateglinide, an antidiabetic agent of Biopharmaceutic Classification System Class-IIa, as a strategy to improve both the solubility and the dissolution rate of the drug. Benzamide was selected by a screening procedure as a suitable coformer and binary mixtures with different composition were prepared and analyzed by DSC. An in depth analysis of DSC data allowed to obtain both the eutectic mixture and cocrystal compositions. The rationale of such an analysis was highlighted and explained. Cocrystals were prepared by kneading and solvent evaporation. Their formation was proved by differential scanning calorimetry and confirmed by X-ray powder diffraction, solid-state NMR and FT-IR spectroscopy. The functional groups involved in the interaction leading to cocrystals formation were investigated by spectroscopic techniques. The in vitro dissolution profiles show that cocrystals have definite better pharmaceutical performances than the pure drug. PMID- 30476511 TI - Tailor-made ultra-crystalline, high molecular weight poly(epsilon-caprolactone) films with improved oxygen gas barrier and optical properties: a facile and scalable approach. AB - The work presents a facile and scalable approach for fabricating tailor-made ultra-crystalline, high molecular weight biodegradable polymer poly(epsilon caprolactone) [PCL] through ring-opening polymerization. Linear homopolymer of PCL were fabricated by tuning the molar ratio of monomer: initiator: catalyst in associated with organometallic catalyst (tin octoate) and a non-toxic and structurally symmetric initiator ethylene glycol (EG). High molecular weight PCL homopolymer formation with molecular weight higher than 90,000 Da was examined by FTIR, NMR and GPC. The ultra-crystalline characteristics (percent crystallinity, %Xc >70%) and unique crystal morphology of PCL were thoroughly scrutinized using DSC, XRD, HRTEM, SAED patterns and POM analysis. The developed protocol for the solvent-free technology allows high conversion ~99% at lowest possible reaction time of 1 h suggesting it a cost effective process, which is scalable to larger volume (5000 mL) without compromising the final product properties. The fabricated ultra-crystalline, high molecular weight PCL films showed good oxygen barrier property (~197 cm3 mm-1 day-1), surface free energy (133.7 mN/m) and optical transparency, recommending its niche in envisioned applications like low temperature flexible packaging and biomedical field. PMID- 30476512 TI - U32 collagenase from Pseudoalteromonas agarivorans NW4327: Activity, structure, substrate interactions and molecular dynamics simulations. AB - A protease of the primary pathogen (Pseudoalteromonas agarivorans NW4327) of the disease affecting the Great Barrier Reef sponge Rhopaloeides odorabile was purified. Zymography demonstrated calcium-dependent collagenase and gelatinase activity of the purified protein. This metalloprotease was identified by matrix assisted laser desorption ionization time-of-flight mass spectrophotometry as a 52,509 Da U32 collagenase. Predicted tertiary structure of U32 collagenase (by Phyre2 fold recognition server) demonstrated 13% identity with known hydrolases establishing novelty of the enzyme. Molecular docking conceived two interacting loops of the collagenase that bound with collagen triple helices and two calcium ions remained centered between the loops. According to ConSurf multiple sequence alignment, the residues of loop1 of the collagenase were mostly conserved while variations among residues of loop2 were comparatively higher than loop1. Asp262, Glu263 of loop1 and Thr363, Lys364, Gln365 of loop2 participated in the interaction with Ca2+ and collagen. Root mean square deviation and root mean square fluctuation values signified higher stability of the collagen-Ca2+ collagenase complex and greater structural stability of the residues of the loops in the complex compared to apocollagenase. Observed properties of NW4327 U32 collagenase and its interaction with collagen were different from similar enzymes of thermophilic bacteria and terrestrial pathogens. PMID- 30476513 TI - Investigation of morphological, mechanical and biological properties of cellulose nanocrystal reinforced electrospun gelatin nanofibers. AB - Incorporation of nanoparticles into biomaterials is of interest due to the high demand for medical devices with enhanced mechanical properties. In this study, cellulose nanocrystals (CNC) were incorporated in electrospun gelatin nanofibers at various loadings (0-15% w/w) and characterized using XRD, TGA, TEM, SEM, FTIR, and tensile tests. Results obtained from TGA and tensile properties indicate that CNC were agglomerated at loadings exceeding 5%; however, TEM showed excellent dispersion of nanoparticles at 5% CNC. A slight increase in biodegradability of crosslinked gelatin nanofibers was observed with CNC incorporation. MTT cytotoxicity, fluorescent staining, and SEM images showed that CNC had no significant effect on cell growth and proliferation. PMID- 30476514 TI - Hexamethyldisiloxane cold plasma treatment and amylose content determine the structural, barrier and mechanical properties of starch-based films. AB - In this study, the effect of amylose content and cold plasma treatment on starch films properties was investigated. Films from normal (30%) and high amylose (50 and 70%) starches were subjected to hexamethyldisiloxane (HMDSO) cold plasma treatment. Morphological, structural, mechanical and barrier properties of the films were evaluated. The amount of remnant starch granules (RSG) in the films depended on the amylose content and on the gelatinization extent of the starch. This behavior was corroborated on the films from starch with 50% amylose, where the loss of RSG resulted in poor barrier properties and high hydrophilicity. Moreover, HMDSO cold plasma treatment incorporated methyl groups improving the hydrophobic properties and favored the helix ordering of the starch components resulting in a limited water-film interaction. Furthermore, the simultaneous effect of HMDSO coating and the ordering of the structures reinforced the surface of the films, improving the mechanical properties. PMID- 30476515 TI - Mixed gels from whey protein isolate and cellulose microfibrils. AB - Whey proteins can form different gel structures ranging from fine-stranded to particulate when appropriate conditions are applied. By incorporating polysaccharides, the gelation of WPI can be influenced. We investigated the heat induced gelation of whey protein isolate (WPI) in the presence of bacterial cellulose (BC) microfibrils at pH 7 at different concentrations of NaCl. Our results showed that WPI and BC microfibrils form a homogeneous dispersion at pH 7. Upon heating, the WPI gel was formed independently in the presence of the BC microfibril gel, resulting in the formation of a composite gel. The gel structure and gelation dynamics of WPI was not influenced by the presence of BC microfibrils. However, the presence of BC microfibrils increased the storage modulus of the WPI gel, with an increase being negligible when the strength of the WPI gel is above a certain value. With an increase of NaCl concentration, the WPI gel structure changes from fine-stranded to a particulate gel, while the BC microfibril gel structure remains unchanged. No macroscopic phase separation could be observed in the WPI-BC microfibril gels. Our results showed that the rheological properties and water holding capacity of the WPI-BC microfibril mixed gels are mainly dominated by the WPI. PMID- 30476516 TI - Optimization of chitosan nanoparticle synthesis and its potential application as germination elicitor of Oryza sativa L. AB - The worldwide rice production has been dwindling due to biotic and abiotic causes. Chitosan is a proven biofunctional material that induces many biological responses in plants. However, the growth and yield increasing properties of chitosan nanoparticles (ChNP) on rice crop are not well understood. In the present work, effect of ChNP on germination of rice has been studied. Seed toxicity of ChNP was also analyzed to ensure the safety of ChNP application. The toxicity study was done according to EPA guidelines and ChNP was found to be non toxic. Rice seeds were treated with ChNP at different concentrations for different time periods and kept for germination. Upon complete germination, the seedlings were sown in seed trays and growth was evaluated at 21 days after sowing. All treatments showed better results than the untreated control. Treatment T22 (1 mg/ml ChNP for 120 mins) gave the highest growth rates. Therefore we could deduce that ability of ChNP to elicit growth was associated with the concentration of ChNP and soaking time. The shelf life of ChNP was studied over a period of one year by analyzing the germination eliciting capacity on rice seeds. ChNP was found to effective for seven months when stored under room temperature. PMID- 30476517 TI - Follow up at 5 Years of Non-Fibrotic Scars in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). AB - OBJECTIVE: To describe changes in visual acuity (VA) and macular morphology at 5 years in eyes with non-fibrotic scars (NFS) identified at 1 year in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). DESIGN: Prospective cohort study within a randomized clinical trial. PARTICIPANTS: Participants in CATT. METHODS: Participants assigned to ranibizumab or bevacizumab and to 1 of 3 dosing regimens were released from the clinical trial protocol after 2 years and recalled at 5 years. NFS was identified on color images at year 1 as flat, small, well-circumscribed areas of pigmentation with varying degrees of central hypopigmentation without exposure of underlying choroidal vessels, at the site of baseline choroidal neovascularization (CNV). Follow-up images were assessed for changes in and around the NFS. MAIN OUTCOME MEASURES: Changes in pigmentation, VA, development of fibrotic scar (FS), non geographic (NGA) and geographic atrophy (GA), retinal fluid on optical coherent tomography, and fluorescein leakage. RESULTS: Among 474 eyes with images at 1, 2 and 5 years, 39 (8.2%) had NFS at 1 year with a mean VA of 80 letters (~ 20/25). Among these eyes, FS developed in 5% at 2 and 28% at 5 years. NGA was observed in 34%, 47% and 65% of eyes at 1, 2 and 5 years, respectively. GA developed in 5% of eyes at 2 and 21% at 5 years. Among eyes with NFS, FS or no scar at 1 year, mean VA at 5 years was 73 letters (~ 20/32), 48 (~ 20/100) and 62 (~ 20/63), respectively. At 5 years, NFS eyes had less GA, less intraretinal fluid, more subretinal fluid, and less sub-RPE fluid (all p<0.01). Among NFS eyes, mean thickness of the retina, subretinal tissue complex and total retina did not change across years 1 to 5 (p>0.50). The proportion of eyes with fluid on OCT also did not change (p=0.36). Subretinal hyperreflective material disappeared by 5 years in 40% of eyes with NFS. CONCLUSION: These results indicate that, on average, eyes with NFS after anti-VEGF treatment have good visual acuity not only at 1 and 2 years, but also through 5 years. PMID- 30476518 TI - Orthokeratology for the Prevention of Myopic Progression in Children A report by the American Academy of Ophthalmology. AB - OBJECTIVE: To review the published evidence to evaluate the ability of orthokeratology (Ortho-K) treatment to reduce myopic progression in children and adolescents compared with the use of spectacles or daytime contact lenses for standard refractive correction. METHODS: Literature searches of the PubMed database, the Cochrane Library, and the databases of clinical trials were last conducted on May 23, 2017 with no date restrictions but limited to articles published in English. These searches yielded 162 citations, of which 13 were deemed clinically relevant for full-text review and inclusion in this assessment. The panel methodologist then assigned a level of evidence rating to the selected studies. RESULTS: The 13 articles selected for inclusion include 3 prospective, randomized clinical trials; 7 nonrandomized, prospective comparative studies; and 3 retrospective case series. One study provided level I evidence, 11 studies provided level II evidence, and 1 study provided level III evidence. Most studies were performed in populations of Asian ethnicity. Change in axial length was the primary outcome for 10 of 13 studies, and change in refraction was the primary outcome for 3 of 13 studies. In these studies, Ortho-K typically reduced axial elongation by approximately 50% over a 2-year study period. This corresponds to average axial length change values of about 0.3 mm for Ortho-K patients compared with 0.6 mm for control patients, which corresponds to a typical difference in refraction of about 0.5 D. Younger-age groups and individuals with larger than average pupil size may have a greater effect with Ortho-K. Rebound can occur after discontinuation or change to alternative refractive treatment. CONCLUSIONS: Orthokeratology may be effective in slowing myopic progression for children and adolescents, with a potentially greater effect when initiated at an early age (6 8 years). Safety remains a concern because of the risk of potentially blinding microbial keratitis from contact lens wear. PMID- 30476519 TI - Elective caesarean delivery and offspring's cognitive impairment: Implications of methylation alteration in hippocampus glucocorticoid signaling genes. AB - Elective caesarean delivery (CD) is an atypical early-life stressful event towards infants. It can pose a long-term effect to children's development by programming hypothalamus-pituitary-adrenal axis. However, the effect of elective CD on offspring's long-term cognitive function and the potential molecular mechanism remains unknown. In this study, by establishing CD mice model, we found that mice born with CD had lower corticosterone level at birth compared with those born by vaginal delivery (VD). Impairment in learning and memory was observed in CD offspring in adolescence, while the effect did not persist in the adulthood. In hippocampus, the expression of glucocorticoid receptor gene (Nr3c1) and FK506 binding protein gene 5 (Fkbp5) was higher in CD offspring in all postnatal time points. In hippocampus, the average methylation level at nerve growth factor-inducible protein A (NGFI-A) binding sites in exon 17 of Nr3c1, and the methylation in intron 1, intron 5 of Fkbp5 were all lower in CD offspring at infancy. Our data implicated that elective CD will cause delayed but non permanent cognitive impairment in offspring. Insufficient glucocorticoid function caused by elective CD may bridge the association between this operative delivery mode and offspring's cognitive impairment. Methylation alterations in key regions of glucocorticoid signaling genes may partially explain the function of glucocorticoid related with elective CD. PMID- 30476520 TI - Sympathetic responding to unconditioned stimuli predicts subsequent threat expectancy, orienting, and visuocortical bias in human aversive Pavlovian conditioning. AB - Threat expectancy is the ability to predict an aversive outcome. What is not known is the influence of initial threat responding on the acquisition of verbal, attentional and perceptual biases towards conditioned threat cues. This study evaluated the extent to which initial unconditioned stimulus (UCS) responding was related to trial-by-trial self-reported expectancy, sensory processing (visuocortical EEG) and orienting (heart rate deceleration) to threat cues during extinction learning. Participants (n = 38) viewed oriented Gabor gratings, associated with the presence (CS+) or absence (CS-) of a 96 dB white noise (UCS), flickering at 12 Hz to elicit steady state visually evoked potentials (ssVEPs). Multivariate multiple regression revealed greater initial UCS skin conductance responding to predict extinction responding: enhanced visuocortical discrimination, greater heart rate deceleration to CS+, and greater threat expectancy endorsements. These results suggest that the motivational intensity of initial threat reactivity (sympathetic UCS responding) drives learning-induced defensive dispositions across multiple response systems. PMID- 30476521 TI - An office based evaluation of various Itraconazole brands. PMID- 30476522 TI - Quantifying the imprecision of energy intake of humans to compensate for imposed energetic errors: A challenge to the physiological control of human food intake. AB - To assess the precision of the biological control of energy intake we performed a systematic review of studies that measured acute changes in human food intake in response to energetic errors. The imposed errors were grouped into the following categories of studies: alternate day fasting, changes in diet composition, exercise, meal skipping, overfeeding, energy substitutes, underfeeding and changes in portion size. Seven hundred thirty-nine studies published between 1980 and 2017 were identified from which the data from 592 groups from 200 studies were extracted and subjected to analysis consisting of a total of 13,203 participants. For each category of imposing an energetic error, an Energetic Error was calculated as (Observed Mean Energy Intake - Expected Mean Energy Intake)/Expected Mean Energy Intake. In no category of studies was the Energetic Error equal to zero. In studies where participants were expected to increase energy intake, the increase was not sufficient to overcome the deficit. Similarly, in studies where a reduction in energy intake was expected, the reduction was insufficient to restore energy balance to zero. The average energetic error resulting from imposed energetic challenges is about twenty-four percent, a value sufficiently large to account for the increase in body weight observed in the U.S. population over the past 50 years. PMID- 30476523 TI - Nanotechnology-based photoimmunological therapies for cancer. AB - Phototherapy is a non-invasive or minimally invasive therapeutic strategy. Immunotherapy uses different immunological approaches, such as antibodies, vaccines, immunoadjuvants, and cytokines to stimulate the host immune system to fight against diseases. In cancer treatment, phototherapy not only destroys tumor cells, but also induces immunogenic tumor cell death to initiate a systemic anti tumor immune response. When combined with immunotherapy, the effectiveness of phototherapy can be enhanced. Because of their special physical, chemical, and sometimes immunological properties, nanomaterials have also been used to enhance phototherapy. In this article, we review the recent progress in nanotechnology based phototherapy, including nano-photothermal therapy, nano-photochemical therapy, and nano-photoimmunological therapy in cancer treatment. Specifically, we focus on the immunological responses induced by nano-phototherapies. PMID- 30476524 TI - Selective pi-1 oxidation of fatty acids by CYP147G1 from Mycobacterium marinum. AB - BACKGROUND: Cyp147G1 is one of 47 cytochrome P450 encoding genes in Mycobacterium marinum M, a pathogenic bacterium with a high degree of sequence similarity to Mycobacterium tuberculosis and Mycobacterium ulcerans. Cyp147G1 is one of only two of these cyp genes which are closely associated with a complete electron transfer system. METHODS: The substrate range of the enzyme was tested in vitro and the activity of CYP147G1 was reconstituted in vivo by co-producing the P450 with the ferredoxin and ferredoxin reductase. RESULTS: Substrates of CYP147G1 include fatty acids ranging from octanoic to hexadecanoic acid. CYP147G1 catalysed the selective hydroxylation of linear and omega-2 methyl branched fatty acids at the omega-1 position (>= 98%). Oxidation of omega-1 methyl branched fatty acids generated the omega and omega-1 hydroxylation products in almost equal proportions, indicating altered position of hydrogen abstraction. CONCLUSIONS: This selectivity of fatty acid hydroxylation inferred that linear species must bind in the active site of the enzyme with the terminal methyl group sequestered so that abstraction at the CH bonds of the omega-1 position is favoured. With branched substrates, one of the methyl groups must be close to the compound I oxygen atom and enable hydroxylation at the terminal methyl group to compete with the reaction at the omega-1CH bond. GENERAL SIGNIFICANCE: Hydroxy fatty acids are widely used for industrial, food and medical purposes. CYP147G1 demonstrates high regioselectivity for hydroxylation at a sub-terminal position on a broad range of linear fatty acids, not seen in other CYP enzymes. PMID- 30476526 TI - En Masse Analysis of Genetic Modifiers Informs Players and Processes in ALS. PMID- 30476525 TI - Zebrafish models of diabetes-related CNS pathogenesis. AB - Diabetes mellitus (DM) is a common metabolic disorder that affects multiple organ systems. DM also affects brain processes, contributing to various CNS disorders, including depression and Alzheimer's disease. Despite active research in humans, rodent models and in-vitro systems, the pathogenetic link between DM and brain disorders remains poorly understood. Novel translational models and new model organisms are therefore essential to more fully study the impact of DM on CNS. The zebrafish (Danio rerio) is a powerful novel model species to study metabolic and CNS disorders. Here, we discuss how DM alters brain functions and behavior in zebrafish, and summarize their translational relevance to studying DM-related CNS pathogenesis in humans. We recognize the growing utility of zebrafish models in translational DM research, as they continue to improve our understanding of different brain pathologies associated with DM, and may foster the discovery of drugs that prevent or treat these diseases. PMID- 30476527 TI - The Control of Neuronal Calcium Homeostasis by SNAP-25 and its Impact on Neurotransmitter Release. AB - The process of neurotransmitter release is central to the control of cell-to-cell communication in brain. SNAP-25 is a component of the SNARE complex, which, together with syntaxin-1 and synaptobrevin, mediates synaptic vesicle fusion with the plasma membrane. The genetic ablation of the protein or its proteolytic cleavage by botulinum neurotoxins results in a complete block of synaptic transmission. In the last years, several evidences have indicated that SNAP-25 also plays additional modulatory roles in neurotransmission through the control of voltage-gated calcium channels and presynaptic calcium ion concentration. Consistently, reduced levels of the protein affect presynaptic calcium homeostasis and result in pathologically enhanced glutamate exocytosis. The SNAP 25-dependent alterations of synaptic calcium dynamics may have direct impact on the development of neuropsychiatric disorders where the Snap-25 gene has been found to be involved. PMID- 30476528 TI - Efficient PD-L1 gene silence promoted by hyaluronidase for cancer immunotherapy. AB - The immune checkpoint blockade of programmed death ligand-1 (PD-L1) or programmed death-1 (PD-1) has been a promising strategy to restore T cell mediated tumor suppression. In this study, a plasmid DNA which expressed small hairpin RNA of PD L1 (shPD-L1) was loaded in the ultrasensitive pH triggered charge/size dual rebound P[(GP)D] nanoparticles (NPs) to silence the PD-L1 gene for reducing the PD-L1/PD-1 interactions between tumors and T cells. To increase the penetration of the shPD-L1 loaded P[(GP)D] NPs (shPD-L1@NPs) in tumors, hyaluronidase (HAase) was utilized to degrade the overexpressed hyaluronicacid (HA) in the extracellular matrix (ECM) of the tumor tissues. The HAase-enhanced tumor accumulation and penetration of the P[(GP)D] NPs were carefully explored. Further in vivo antitumor therapy was carried out in the malignant melanoma mouse tumor model, and a significant tumor inhibition effect was achieved by the combination treatment of HAase and shPD-L1@NPs. Our results verified that the HAase could effectively degrade the HA in tumors and increase the penetration of the shPD L1@NPs for achieving more efficient PD-L1 gene silence and finally realizing potent tumor suppression. This combination treatment strategy has great potentials to be adopted for other nanomedicines, and it will have broad applications for cancer therapy in the future. PMID- 30476529 TI - Positive verbal feedback about task performance is related with adaptive physiological responses: An experimental study of the effort-reward imbalance stress model. AB - Effort-reward imbalance in the workplace has been related with poor mental and physical health and a variety of negative organisational outcomes including increased rates of absenteeism, presentism, and job turnover, but the model has rarely been assessed using experimental designs. Female participants (N = 90) were randomly assigned to positive verbal feedback and no verbal feedback conditions. Within a simulated office environment, all participants were under time-pressure to successfully complete computer-based tasks in order to gain remuneration. Positive verbal feedback about task performance was provided to improve the aspect of 'esteem reward' (while keeping effort constant) using a mixed within-between subjects design. Psychological, behavioural (task performance), and physiological (heart rate variability, salivary alpha amylase) measures assessed the impact of the positive verbal feedback. Participants receiving the esteem manipulation did not self-report increased rewards, but performed moderately better on the task, and had more adaptive physiological reactivity in the high reward versus the standard condition. Similar to recent research our findings highlight the importance of concurrent assessments of both self-reports and physiological measures of stress, and suggest that positive verbal feedback about work performance can elicit adaptive physiological responses and may also positively influence task efficacy. PMID- 30476530 TI - Welcome from the new Editor-in-Chief! PMID- 30476531 TI - Regulation of microglial process elongation, a featured characteristic of microglial plasticity. AB - Microglia, a type of glia within the brain characterized by a ramified morphology, are essential for removing neuronal debris and restricting the expansion of a lesion site. Upon moderate activation, they undergo a transformation in morphology inducing beneficial responses. However, upon strong stimulation, they mediate neuronal damage via production of pro-inflammatory cytokines. The inhibition of this cascade is considered an effective strategy for neuroinflammation-associated disorder therapy. During this pathological activation microglia also undergo a shortening of process length which contributes to the pathogenesis of such disorders. Thus, microglial plasticity should be considered to have two components: one is the production of inflammatory mediators, and the other is the dynamic changes in their processes. The former role has been well-documented in previous studies, while the latter one remains largely unknown. Recently, we and others have reported that the elongation of microglial process is associated with the transformation of microglia from a pro-inflammatory to an anti-inflammatory state, suggesting that the shortening of process length would make the microglia lose their ability to restrict pathological injury, while the elongation of microglial process would help attenuate neuroinflammation. Compared with the traditional anti neuroinflammatory strategy, stimulating elongation of microglial process not only reduces the production of pro-inflammatory cytokines, but restores the ability of microglia to scan their surrounding environments, thus rendering their homeostasis regulation more effective. In this review, we provide a discussion of the factors that regulate microglial process elongation in vitro and in vivo, aiming to further drive the understanding of microglial process plasticity. PMID- 30476532 TI - Induction of a senescent like phenotype and loss of gap junctional intercellular communication by carbon nanoparticle exposure of lung epithelial cells. AB - Inhalation of combustion-derived particles is associated with the development of age-related diseases like chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. In both diseases senescence of lung epithelial cells has been observed. Employing an in vitro system of repetitive exposure to pure carbon nanoparticles we asked whether this kind of particles are able to induce a senescent like phenotype, which might be accompanied by a loss of functionality at the level of gap junctional intercellular communication. Non-cytotoxic doses of carbon nanoparticles but not of bigger carbon particles led to an irreversible reduction of the proliferative capacity accompanied by the accumulation of the cell cycle blocking proteins p21 and p16 as well as a loss of both redox sensitive histone deacetylase SIRT1 and connexin-43. Gap junction intercellular communication detected by microinjection of fluorescent lucifer yellow was dramatically decreased after exposure. This loss of functionality was associated with a reduction of Connexin 43 at the plasma membrane. As the experimental system was chosen to study the effects of pure carbon nanoparticles in the absence of inflammatory cells, the data indicate that cumulative long-term exposure of the lung epithelium to low doses of combustion-derived nanoparticles might contribute to epithelial senescence and age-associated diseases of the airways. PMID- 30476533 TI - The anti-oxidation and anti-aging effects of Ganoderma lucidum in Caenorhabditis elegans. AB - As a traditional herbal medicine, the clinical efficacy of Ganoderma lucidum (G. lucidum, also known as Lingzhi in China) has been proved by clinical research and a large number of animal experiments. However, its pharmacological mechanism is not clear. Here, we used the Caenorhabditis elegans as an animal model to study the anti-oxidative stress and anti-aging effects of G. lucidum water extract. Our results showed that G. lucidum effectively promoted the nematodes to resist the oxidative stress of paraquat and heavy metal Cr6+, and significantly prolonged the lifespan of the nematodes. The underlining mechanisms were further investigated by focusing on the signaling pathways that regulate the stress responses and the lifespan. We found that G. lucidum protected the nematode against the insults of paraquat and heavy metals through the diet restriction pathway and the mTOR/S6K signaling pathway, respectively. Whereas, the effect of G. lucidum on the longevity of the nematode mainly depended on the germline signaling pathway. Microarray assays were conducted to reveal the gene expression profiles. The expression levels of 2746 genes were significantly changed during the aging process, of which 34 genes were reversed in their expression by the treatment of G. lucidum in aged nematodes. These results suggest that G. lucidum regulates the biophysiological processes in the nematodes through multiple signaling pathways. PMID- 30476534 TI - Cracking The Mystery Of Pulmonary Vein Stenosis. PMID- 30476535 TI - Behavioural and epigenetic effects of paternal exposure to cannabinoids during adolescence on offspring vulnerability to stress. AB - Chronic cannabinoid exposure during adolescence in male rats induces chronic cognitive and emotional impairments. However, the impact of this form of exposure on offspring vulnerability to stress is unknown. The aim of this study was to evaluate the behavioural and epigenetic effects of stress in the offspring of male rats whose fathers were exposed to cannabinoids during adolescence. Male adolescent offspring of Win55,212-2 (1.2 mg/kg) treated rats were exposed during one week to variable stressors and subjected to behavioural tests of anxiety and episodic-like memory, followed by an assessment of global DNA methylation and expression of DNA methyltransferases enzymes DNMT1 and DNMT3a mRNA in the prefrontal cortex. Stress exposure induced a significant anxiogenic-like effect but did not affect the episodic-like memory in the offspring of Win55,212-2 exposed fathers in comparison to the offspring of non-exposed fathers. These behavioural changes were subsequent to a significant increase in global DNA methylation and DNMT1 and DNMTa3 transcription in the prefrontal cortex. These data suggest that the deleterious effect of chronic exposure to cannabinoids during adolescence are not limited to the exposed individuals but may increase the vulnerability to stress-induced anxiety in the offspring and alter their epigenetic programming. PMID- 30476536 TI - An integrated serum and urinary metabonomic research of Rhizoma Curcumae-Rhizoma Sparganii drug pair in hysteromyoma rats based on UPLC-Q-TOF-MS analysis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Rhizoma Curcumae and Rhizoma Sparganii (RCRS), a celebrated traditional Chinese medicine drug pair, has been used to treat hysteromyoma (HY). AIM OF THE STUDY: We aimed to identify the endogenous biomarkers of RCRS against HY. MATERIALS AND METHODS: HY rat model was established by injecting intramuscularly estradiol benzoate and progesterone injection from inner thigh in sequence. Body weight, uterus morphological indexes, immunohistochemistry (IHC) and hematoxylin and eosin (HE) staining experiments were used to evaluate the efficacy of RCRS (The rats were treated with RCRS extract, which was made by soxhlet reflux method. The rats were administrated intragastrically with 2mL of RCRS extract). UPLC-Q-TOF-MS based metabonomics was adopted to analyze the serum and urine biomarkers from HY rats before and after RCRS treatment. Principle component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were utilized to identify differences of metabolic profiles in rats among the four groups. RESULTS: 16 potential biomarkers from serum and 18 potential biomarkers from urine in both positive and negative mass spectrometry detection modes were identified, primarily related to Linoleic acid metabolism and Glyoxylate and dicarboxylate metabolism. RCRS drug pair has therapeutic effects on rats with HY via the regulation of multiple metabolic pathways. CONCLUSIONS: This study provides a useful method to get insight into the integrated metabonomic mechanism of RCRS drug pair on HY rats. PMID- 30476537 TI - Gadolinium tissue deposition in the periodontal ligament of mice with reduced renal function exposed to Gd-based contrast agents. AB - Gadolinium deposition in tissue is linked to nephrogenic systemic fibrosis (NSF): a rare disorder occurring in patients with severe chronic kidney disease and associated with administration of Gd-based contrast agents (GBCAs) for Magnetic Resonance Imaging (MRI). It is suggested that the GBCAs prolonged permanence in blood in these patients may result in a Gd precipitation in peripheral or central organs, where it initiates a fibrotic process. In this study we investigated new sites of retention/precipitation of Gd in a mouse model of renal disease (5/6 nephrectomy) receiving two doses (closely after each other) of a linear GBCA. Two commercial GBCAs (Omniscan(r) and Magnevist(r)) were administered at doses slightly higher than those used in clinical practice (0.7 mmol/kg body weight, each). The animals were sacrificed one month after the last administration and the explanted organs (kidney, liver, femur, dorsal skin, teeth) were analysed by X-ray fluorescence (XRF) at two synchrotron facilities. The XRF analysis with a millimetre-sized beam at the SYRMEP beamline (Elettra, Italy) produced no detectable levels of Gd in the examined tissues, with the notable exception of the incisors of the nephrectomised mice. The XRF analyses at sub-micron resolution performed at ID21 (ESRF, France) allowed to clearly localize Gd in the periodontal ligaments of teeth both from Omniscan(r) and Magnevist(r) treated nephrectomised mice. The latter results were further confirmed by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). The study prompts that prolonged permanence of GBCAs in blood may result in Gd retention in this particular muscular tissue, opening possibilities for diagnostic applications at this level when investigating Gd-related toxicities. PMID- 30476538 TI - Inactivation of the PtdIns(4)P phosphatase Sac1 at the Golgi by H2O2 produced via Ca2+-dependent Duox in EGF-stimulated cells. AB - Binding of epidermal growth factor (EGF) to its cell surface receptor induces production of H2O2, which serves as an intracellular messenger. We have shown that exogenous H2O2 reversibly inactivates the phosphatidylinositol 4-phosphate [PtdIns(4)P] phosphatase Sac1 (suppressor of actin 1) at the Golgi complex of mammalian cells by oxidizing its catalytic cysteine residue and thereby increases both the amount of Golgi PtdIns(4)P and the rate of protein secretion. Here we investigated the effects of EGF on Sac1 oxidation and PtdIns(4)P abundance at the Golgi in A431 cells. EGF induced a transient increase in Golgi PtdIns(4)P as well as a transient oxidation of Sac1 in a manner dependent on elevation of the intracellular Ca2+ concentration and on H2O2. Oxidation of Sac1 occurred at the Golgi, as revealed with the use of the Golgi-confined Sac1-K2A mutant. Knockdown of Duox enzymes implicated these Ca2+-dependent members of the NADPH oxidase family as the major source of H2O2 for Sac1 oxidation. Expression of a Golgi targeted H2O2 probe revealed transient EGF-induced H2O2 production at this organelle. Our findings have thus uncovered a previously unrecognized EGF signaling pathway that links intracellular Ca2+ mobilization to events at the Golgi including Duox activation, H2O2 production, Sac1 oxidation, and PtdIns(4)P accumulation. PMID- 30476539 TI - Printfills: 3D printed systems combining Fused Deposition Modeling and Injection Volume Filling. Application to colon-specific drug delivery. AB - Three-dimensional printing has become a feasible manufacturing technique for pharmaceutical products providing cheap and accurate freeform systems with a great potential for personalized-dose drugs. Fused Deposition Modeling (FDM) highlights among other 3D technologies due to its low cost and easy to operate but, until now, it has the drawbacks of the low drug loaded and the impossibility to print thermosensitive drugs. So, intermediate processes such as hot melt extrusion are frequently associated with FDM. Here, pharmaceutical dosage forms have been manufactured for the first time with a 3D printer combining two different printing technologies: FDM and injection volume filling (IVF), performing customized extruded scaffolds in which a liquid or semisolid system can be injected at room temperature. A model drug and a pH-sensitive polymer were successfully incorporated during the construction of the extruded backbone of the systems, called printfills (printed systems filled with a liquid or semisolid). SEM microphotographs of printfills show the sealing of the structure in the perimeter and the homogeneity of the colonic film formed in the upper side. Thus, the addition of the pH-sensitive polymer does not need an additional process in a fluidized bed or coating pan. Results from drug release studies performed at different pH confirm the ability of printfills for colon-specific drug delivery. Therefore, IVF technology complements FDM, solving its main limitations providing an easy, automatized and versatile technology to manufacture tailored drug delivery platforms, avoiding other intermediate processes. PMID- 30476540 TI - Dietary phytochemicals in colorectal cancer prevention and treatment: A focus on the molecular mechanisms involved. AB - Worldwide, colorectal cancer (CRC) remains a major cancer type and leading cause of death. Unfortunately, current medical treatments are not sufficient due to lack of effective therapy, adverse side effects, chemoresistance and disease recurrence. In recent decades, epidemiologic observations have highlighted the association between the ingestion of several phytochemical-enriched foods and nutrients and the lower risk of CRC. According to preclinical studies, dietary phytochemicals exert chemopreventive effects on CRC by regulating different markers and signaling pathways; additionally, the gut microbiota plays a role as vital effector in CRC onset and progression, therefore, any dietary alterations in it may affect CRC occurrence. A high number of studies have displayed a key role of growth factors and their signaling pathways in the pathogenesis of CRC. Indeed, the efficiency of dietary phytochemicals to modulate carcinogenic processes through the alteration of different molecular targets, such as Wnt/beta catenin, PI3K/Akt/mTOR, MAPK (p38, JNK and Erk1/2), EGFR/Kras/Braf, TGF beta/Smad2/3, STAT1-STAT3, NF-kB, Nrf2 and cyclin-CDK complexes, has been proven, whereby many of these targets also represent the backbone of modern drug discovery programs. Furthermore, epigenetic analysis showed modified or reversed aberrant epigenetic changes exerted by dietary phytochemicals that led to possible CRC prevention or treatment. Therefore, our aim is to discuss the effects of some common dietary phytochemicals that might be useful in CRC as preventive or therapeutic agents. This review will provide new guidance for research, in order to identify the most studied phytochemicals, their occurrence in foods and to evaluate the therapeutic potential of dietary phytochemicals for the prevention or treatment of CRC by targeting several genes and signaling pathways, as well as epigenetic modifications. In addition, the results obtained by recent investigations aimed at improving the production of these phytochemicals in genetically modified plants have been reported. Overall, clinical data on phytochemicals against CRC are still not sufficient and therefore the preventive impacts of dietary phytochemicals on CRC development deserve further research so as to provide additional insights for human prospective studies. PMID- 30476541 TI - Calibration of sperm concentration for in vitro fertilization in a mouse reprotoxicity model. AB - Xenobiotics, such as chemicals and pesticides, may result in adverse effects on reproduction in human and animals. Using in-vitro embryo production as a testing system reveals details of fertilization (IVF) and early embryonic development (IVC). The aim of our study was to perform a systematical calibration of sperm concentration in an IVF/IVC system, using an outbred mouse strain, and further determine the sperm concentration that furnishes a sensitive assessment of sperm fertilizing capacity in relation to reprotoxic evaluations. By performing breakpoint analysis, the results revealed a maximum two-cell percentage (51%, 95% CI: 38 to 69%) at 3.6 * 104 sperm/ml (95% CI: 2.1 * 104 to 6.1 * 104). For future application of the IVF/IVC system, a sperm concentration lower than this breakpoint concentration is required to be within the responsive range for determining sperm fertilizing capacity. We conclude that a relatively low sperm concentration (2.5 * 104 sperm/ml) is a precondition in a mouse IVF/IVC system in order to detect potential reprotoxic effects on sperm fertilizing capacity. Our study illustrates that a systematic approach is necessary for validation and appropriate use of such in-vitro system used for reproductive toxicity testing. PMID- 30476542 TI - The Benefit of Implantable Cardioverter Defibrillators beyond the First Generator. PMID- 30476543 TI - Development of a Biomarker Panel to Predict Cardiac Resynchronization Therapy Response: Results from the SMART-AV Trial. AB - BACKGROUND: Predicting a favorable cardiac resynchronization therapy (CRT) response holds great clinical importance. OBJECTIVE: To examine proteins from broad biological pathways and develop a prediction tool for response to CRT. METHODS: Plasma was collected from patients prior to CRT (SMART-AV trial) whereby a CRT response was pre-specified as a >=15 mL reduction in LV end-systolic volume (LVESV) at 6 months, which resulted in a binary CRT response (Responders: 52%, Non-Responders: 48%; n=758). RESULTS: Candidate proteins (n=74) were evaluated from the inflammatory, signaling, and structural domains, which yielded 12 candidate biomarkers, but only a subset of these demonstrated predictive value for CRT response: soluble suppressor of tumorgenicity-2, soluble tumor necrosis factor receptor-II (sTNFr-II), matrix metalloproteinases-2, and C-reactive protein. These biomarkers were used in a composite categorical scoring algorithm (Biomarker CRT Score), which identified patients with a high/low probability of a response to CRT (p<0.001) when adjusted for a number of clinical covariates. For example, a Biomarker CRT Score of 0 yielded 5 times higher odds of a response to CRT compared to a Biomarker CRT Score of 4 (p<0.001). The Biomarker CRT Score demonstrated additive predictive value when considered against a composite of clinical variables. CONCLUSION: These unique findings demonstrate that developing a biomarker panel for predicting individual response to CRT is feasible and holds potential for point of care testing and integration into evaluation algorithms for patients presenting for CRT. PMID- 30476544 TI - Arrhythmias in Myocarditis: State of the Art. AB - Many kinds of arrhythmias may occur in patients with myocarditis at any stage of the disease. However, as compared to the other clinical presentations, arrhythmic myocarditis has been poorly described so far in the literature. In fact, arrhythmias occurring in either ongoing or previous myocardial inflammation are complex and heterogeneous, and the disease itself is often underdiagnosed, thus limiting data collection and interpretation. However, differently from the other clinical presenations, arrhythmic myocarditis require specific diagnostic, prognostic and therapeutic considerations. The aim of the current paper is to critically summarize the state of the art on myocarditis presenting with arrhythmias in terms of epidemiology, aetiology, diagnosis, prognosis and treatment. PMID- 30476545 TI - CXCR6 protects from inflammation and fibrosis in NEMOLPC-KO mice. AB - Chronic inflammation in the liver provokes fibrosis and, on long-term, carcinogenesis. This sequence is prototypically recapitulated in mice with hepatocyte-specific knock-out of the NF-kappaB essential modulator (NEMO), termed NEMOLPC-KO mice, in which increased hepatocyte apoptosis and compensatory regeneration cause steatosis, inflammation and fibrosis. Natural killer T (NKT) cells carrying the chemokine receptor CXCR6 participate in liver inflammation and injury responses. Here, we investigated the role of CXCR6 in the NEMOLPC-KO mouse model. Unexpectedly, genetic deletion of CXCR6 enhanced hepatocyte death, inflammation and fibrosis in NEMOLPC-KO mice. Although CXCR6 expression is restricted to immune cells in the liver, the adoptive transfer of CXCR6+ cells did not protect NEMOLPC-KOCxcr6-/- mice from hepatic injury. Gene array analyses revealed up-regulated stress response and metabolism pathways in hepatocytes from NEMOLPC-KOCxcr6-/- mice, functionally corresponding to an increased susceptibility of these hepatocytes to TNFalpha-induced cell death in vitro. These data revealed a novel CXCR6-dependent mechanism of suppressing inflammatory hepatocytic responses to cellular stress. PMID- 30476547 TI - Development of a Pediatric Asthma Predictive Index for Hospitalization. PMID- 30476546 TI - Involvement of tetraspanin 8 in the innate immune response of the giant prawn, Macrobrachium rosenbergii. AB - The tetraspanins, representing a conserved superfamily of four-span membrane proteins, are highly involved in viral and bacterial infections. Thus far, the function of the tetraspanins in crustaceans remains largely unknown. In this study, we report the cloning and expression analysis of a tetraspanin 8 from the giant freshwater prawn, Macrobrachium rosenbergii (named as MrTspan8). MrTspan8 contains a 720-bp open reading frame encoding a 239-amino acids protein, which exhibits four transmembrane domains and two extracellular loops that are typical for tetraspanins. MrTspan8 was found to be widely expressed in a variety of prawn tissues including heart, gill, muscle, gut, and hepatopancreas. Additionally, MrTspan8 expression was significantly increased in the hepatopancreas and gill of the prawns challenged by the bacterial pathogen Aeromonas hydrophila. Moreover, we show that pre-incubation of the peptides from the large extracellular loop of MrTSPAN8 protein reduced the cell death caused by A. hydrophila infection in prawn tissue, suggesting that MrTSPAN8 could be a mediator for bacterial infection to prawn. PMID- 30476548 TI - Measurement of exhaled nitric oxide in young children with NIOX VERO. PMID- 30476549 TI - Effect of Pre-Hospital Use of the Assessment of Blood Consumption Score and Pre Thawed Fresh Frozen Plasma on Resuscitation and Trauma Mortality. AB - BACKGROUND: Early blood product resuscitation reduces trauma patient mortality from hemorrhage. This mortality benefit depends on a system that can rapidly identify actively bleeding patients, initiate massive transfusion protocol (MTP), and mobilize resources to the bedside. We hypothesized that process improvement efforts that identify patients early and mobilize appropriate blood products to the bedside for immediate use would improve mortality. STUDY DESIGN: Pre implementation, MTP activation was at the discretion of the trauma surgeon and only PRBCs were immediately available. In June 2016, the ABC score was incorporated in our pre-hospital triage process and a process for thawed plasma to be available was developed. A retrospective review of patients who were hypotensive on arrival or had MTP activated was performed. We compared mortality and MTP component ratios 15 months pre- versus 15 months post-implementation. RESULTS: MTP activations increased six-fold, while the specificity of the process remained the same. In patients receiving MTP, appropriate blood product transfusion ratios increased 44%. Both overall and penetrating trauma mortality improved by 23% and 41%. When divided by ISS, penetrating trauma mortality decreased by 65% for ISS subgroup 15-24 and by 38 % for ISS subgroup > 25. Length of stay, ICU length of stay, and readmission rates were not significantly different. CONCLUSIONS: Delivery of balanced blood product resuscitation is essential to confer mortality benefits. Process improvement directed at early recognition of the hemorrhagic patient, immediate product availability, and product delivery to the bedside for transfusion allows for mortality reduction without increased resource utilization. PMID- 30476550 TI - Meeting the discovery challenge of drug-resistant infections: progress and focusing resources. AB - Following multiple warnings from governments and health organisations, there has been renewed investment, led by the public sector, in the discovery of novel antimicrobials to meet the challenge of rising levels of drug-resistant infection, particularly in the case of resistance to antibiotics. Initiatives have also been announced to support and enable the antibiotic discovery process. In January 2018, the Medicines Discovery Catapult, UK, hosted a symposium: Next Generation Antibiotics Discovery, to consider the latest initiatives and any remaining challenges to inform and guide the international research community and better focus resources to yield a novel class of antibiotic. PMID- 30476551 TI - Cytomegalovirus (CMV) infection in allogeneic HCT managed by the preemptive approach: Estimating the impact on health care resource utilization and outcomes. AB - BACKGROUND: We quantified CMV antiviral use and hospital length of stay (LOS) associated with CMV infection in a contemporary cohort of conventional (CONV) and CD34-selected (T-cell depleted) HCT recipients managed by preemptive therapy (PET) in a single US center. METHODS: Adults who received first allogeneic HCT at MSKCC from June 2010 through December 2014 were analyzed. Days on PET, number and LOS of readmissions by day 180 post HCT were summarized. Estimated unit value (EUV) was defined as the expected number of PET days for a cohort of 100 HCT with characteristics as the analyzed cohort. Standardized incidence ratio (SIR) was calculated as the ratio of observed outcomes of patients with CMV viremia over the outcomes of patients without CMV viremia. RESULTS: Of 318 patients, 88 received CONV and 230 CD34-selected HCT. Rates of CMV viremia were 26.3% for CONV and 41.9% for CD34-selected (P = 0.003). Among pts with viremia 68.2% CONV and 97.9% CD34-selected received PET. EUV for PET was 852 days and 2,821 days for CONV and CD34-selected respectively. The SIR for number of readmission and readmission LOS were 1.7 [95% CI (1.4-2.1)) and 1.2 (1.1-1.3) respectively for CONV and 1.7 (1.3-2.1) and 1.6 (1.5-1.7) respectively for CD34-selected. Overall survival (OS) was similar between patients with and without CMV viremia by HCT type. CMV end-organ disease was associated with lower OS only in CD34-selected HCT (P = 0.0007). CONCLUSION: CMV infection managed by PET requires substantial antiviral utilization and is associated with longer readmission LOS and larger numbers of readmissions particularly among CD34-selected HCT. PMID- 30476552 TI - Persistence of phylogeographic footprints helps to understand cryptic diversity detected in two marine amphipods widespread in the Mediterranean basin. AB - Amphipods of the genus Gammarus are a vital component of macrozoobenthic communities in European inland and coastal, marine and brackish waters of the Mediterranean and the Black Sea. Exceptional levels of cryptic diversity have been revealed for several widespread freshwater Gammarus species in Europe. No comprehensive assessment has yet been made for brackishwater counterparts, such as Gammarus aequicauda and G. insensibilis, which are among the most widely dispersed members of the so-called "G. locusta group" in the Mediterranean and in the Black Sea. Here we probe the diversity of these morphospecies examining the partitioning of mtDNA and nDNA across multiple populations along their distribution range and discuss it within the regional paleogeographic framework. We gathered molecular data from a collection of 166 individuals of G. aequicauda and G. insensibilis from 47 locations along their distribution range in the Mediterranean including the Black Sea. They were amplified for both mitochondrial COI and 16S rRNA as well as the nuclear 28S rRNA. All five MOTU delimitation methods (ABGD, BIN, bPTP, GMYC single and multiple threshold models) applied revealed deep divergence between Black Sea and Mediterranean populations in both G. aequicauda and G. insensibilis. There were eight distinct MOTUs delimited for G. aequicauda (6-18% K2P) and 4 MOTUs for G. insensibilis (4-14% K2P). No sympatric MOTUs were detected throughout their distribution range. Multimarker time-calibrated phylogeny indicated that divergence of both G. aequicauda and G. insensibilis species complexes started already in the late Oligocene/early Miocene with the split between clades inhabiting eastern and western part of the Mediterranean occurring in both species at the similar time. Our results indicate a high cryptic diversity within Mediterranean brackishwater Gammarus, similar to that observed for freshwater counterparts. Moreover, the phylogenetic history combined with the current geographic distribution indicate that the evolution of both studied Gammarus morphogroups has been strongly connected with the geological events in the Mediterranean Basin and it reflect the turbulent history of the area. PMID- 30476553 TI - The Mini-Gastric Bypass Original Technique. AB - INTRODUCTION: Mini-Gastric Bypass (MGB) is becoming more and more popular as shown by the numerous articles published over the past 15 years, supporting the operation as a short and simple procedure with excellent outcomes and low complication rates. There is still confusion amongst surgeons on the technique of the operation. The purpose of this paper is to review and describe the technique of MGB by its originators. METHODS: With 20 years of experience of performing the original MGB, the authors present the details of the MGB. RESULTS: The MGB consists of a long conduit from below the crow's foot extending up to the left of the angle of His. It is similar to, but importantly, not the same as the pouch of the Sleeve Gastrectomy. MGB has a wide gastro-jejunal anastomosis to an anti colic loop of jejunum 150-200 cm distal to the ligament of Trietz. The power of MGB comes from the fact that it is both a "Non-Obstructive" restrictive procedure and it also has a significant fatty food intolerance component with minimal malabsorption. CONCLUSION: In this article we describe the original Rutledge technique of Mini-Gastric Bypass. Notably this is neither a "Single Anastomosis bypass", nor an "Omega Loop Bypass" and also not the "One Anastomosis Bypass of Carbajo". It is a particular technique first created by Rutledge in 1997 and associated with low risk and excellent outcomes. The goal of this manuscript is to help avoid complications and problems seen when the operation deviates from some of the basic principles of general surgery used in the original operation. PMID- 30476554 TI - Impact of hypobaric flight simulation on walking distance and oxygenation in COPD patients. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a disease that compromises fitness to fly. OBJECTIVE: To investigate, whether hypobaric mid distance flight simulation limits exercise endurance in COPD patients. METHODS: Patients with COPD GOLD stages 2-4 were challenged by hypobaric flight simulation. Patients completed 6-minute walking distances before and after the simulation test. Pulse oximetry and Borg dyspnea scale were measured every 30 min during the test. RESULTS: Thirty-five patients were included in the study. The distance of the 6-min walking exercise decreased from 343 +/- 93 m to 308 +/- 101 m (p < 0.0001). The oxygen saturation nadir for the whole group was 72.2% +/- 9.1%. The Borg-dypnea-score did not correlate with oxygen desaturation (R-square 0.009, p > 0.05). CONCLUSIONS: A 3-h hypobaric flight simulation compromises exercise endurance by 35 m or 10%. Hypoxia was well tolerated and more liberal recommendations might by justifiable since hypoxemia appears to be unrelated to dyspnea perception. PMID- 30476555 TI - The role of miRNA in somatic embryogenesis. AB - Somatic embryogenesis (SEG) is one of the best techniques for mass production of economically important plants. It is also used for the study of morphology, anatomy, physiology, genetics and molecular mechanism of embryo development. Somatic Embryos (SE) are bipolar structures that develop from a cell other than a gamete or zygote. SEG reflects the unique developmental potential of plant somatic cells, resulting in the transition of the differentiated somatic cells to embryogenic cells to follow the zygotic embryo stages. There are several biochemical and physiological processes that transformed a single somatic cell to a whole plant. SE studies provide insight into cell mechanisms governing the totipotency process in plants. Previously, in vitro studies have suggested the role of various regulatory genes in embryogenic transition that are triggered by plant hormones in response to stress. The omic studies identify the specific genes, transcripts, and proteins required for somatic embryogenesis development. MicroRNAs (miRNAs) are small, 19-24 nucleotides (nt), non-coding small RNA regulatory molecules controlling a large number of biological processes. In addition to their role in SEG, miRNAs play vital role in plant development, secondary metabolite synthesis and metabolism of macromolecules, hormone signal transduction, and tolerance of plants to biotic and abiotic stresses. During last decade several types of miRNAs involved in SEG have been reported. Among these miRNAs, miR156, miR162, miR166a, miR167, miR168, miR171a/b, miR171c, miR393, miR397 and miR398 played very active role during various stages of SEG. In this review, we highlighted the role of these as well as other miRNAs in some economically important plants. PMID- 30476556 TI - Genomewide identification and annotation of SNPs in Bubalus bubalis. AB - The present study was carried out to identify and annotate the genome wide SNPs in Murrah buffalo genome. A total of 21.2 million raw reads from 4 pooled female Murrah buffalo samples were obtained using restriction enzyme digestion followed by sequencing with Illumina Hiseq 2000. After quality filtration, the reads were aligned to Murrah buffalo genome (ICAR-NBAGR) and Water buffalo genome (UMD_CASPUR_WB_2.0) which resulted in 99.37% and 99.67% of the reads aligning, respectively. A total of 130,688 high quality SNPs along with 35,110 indels were identified versus the Murrah bufffalo genome. Similarly 219,856 high quality SNPs along with 15,201 indels were identified versus the Water buffalo genome. We report 483 SNPs in 66 genes affecting Milk Production, 436 SNPs in 38 genes affecting fertility and 559 SNPs in 72 genes affecting other major traits. The average genome coverage was 13.4% and 14.8% versus the Murrah and Water buffalo genomes, respectively. PMID- 30476557 TI - High throughput screening of small immune peptides and antimicrobial peptides from the Fish-T1K database. AB - Analyses of transcriptomic datasets have the potential to reveal genetic markers underlying ecological adaptations. In the present study, we leverage the expanding dataset generated by the Fish-T1K Project (Transcriptomes of 1000 Fishes) to characterize small peptides that may be implicated in the immune system of fishes. We focused our analyses on sequences smaller than 360 bp obtained from gill transcriptomes of 87 ray-finned fishes (Actinopterygii). Functional annotation of short transcripts revealed that the number of small immune peptides varied significantly among the studied species. High-throughput screening of antimicrobial peptides (AMPs) with homologous searches was used to characterize the composition of innate immune defense factors present in fishes. We analyzed the putative effects of habitat, climatic zone and genetic system on the distribution of small peptides among species. Our results highlight the utility of large transcriptomic datasets such as Fish-T1K to explore patterns of variation at macroevolutionary scales and to discover novel peptides that may be used for further investigation and drug development. PMID- 30476558 TI - Glu2.53(90) of the GnRH receptor is part of the conserved G protein-coupled receptor structure and does not form a salt-bridge with Lys3.32(121). AB - GnRH receptor mutations, Glu2.53(90)Lys and Glu2.53(90)Asp, cause congenital hypogonadotropic hypogonadism. The Glu2.53(90) side-chain has been proposed to form an intramolecular salt-bridge with Lys3.32(121), but conserved intramolecular interaction networks in G protein-coupled receptor crystal structures predict that it interacts with Ser3.35(124) and Trp6.48(280). We investigated interhelical interactions of Glu2.53(90) that stabilise GnRH receptor folding using functional analyses and computational modelling of mutant receptors. The Glu2.53(90)Asp mutant was non-functional, but mutants with hydrophobic amino acids or Arg substituted for Glu2.53(90) were functional, excluding a salt-bridge interaction. The Glu2.53(90)Arg and Trp6.48(280)Arg mutants had decreased affinity for GnRH. Models showed that congenital Glu2.53(90)Lys and Glu2.53(90)Asp mutations disrupt interactions with Ser3.35(124) and Trp6.48(280) respectively, whereas the Glu2.53(90)Arg and Trp6.48(280)Arg mutations preserve intramolecular contacts, but increase distance between the transmembrane helices. Our results show that disruption of interhelical contacts that are conserved in G protein-coupled receptors accounts for the effects of some disease-associated GnRH receptor mutations. PMID- 30476559 TI - Factors contributing to the resistance of the thyrocyte to hydrogen peroxide. AB - We studied the mechanism that may explain the relative resistance of thyrocytes to H2O2 compared to other cell types. Ability to degrade H2O2, glutathione peroxidase (GPx) activity, heme oxygenase-1 (HO-1) expression, cell survival and capacity to repair DNA damage after H2O2 exposure or irradiation were measured in human thyrocytes in primary culture and compared to the values obtained in human T-cells and different cell lines. Compared to other cell types, thyrocytes presented a low mortality rate after H2O2 exposure, rapidly degraded extracellular H2O2 and presented a high basal seleno-dependent GPx activity. Only in thyrocytes, H2O2 up-regulated GPx activity and expression of HO-1 mRNA. These effects were not reproduced by irradiation. DNA damage caused by H2O2 was more slowly repaired than that caused by irradiation and not repaired at all in T cells. Our study demonstrates that the thyrocyte has specific protective mechanisms against H2O2 and its mutagenic effects. PMID- 30476560 TI - Effects of spermatogenic cycle on Stem Leydig cell proliferation and differentiation. AB - We reported previously that stem Leydig cells (SLC) on the surfaces of rat testicular seminiferous tubules are able to differentiate into Leydig cells. The proliferation and differentiation of SLCs seem likely to be regulated by niche cells, including nearby germ and Sertoli cells. Due to the cyclical nature of spermatogenesis, we hypothesized that the changes in the germ cell composition of the seminiferous tubules as spermatogenesis proceeds may affect tubule-associated SLC functions. To test this hypothesis, we compared the ability of SLCs associated with tubules at different stages of the cycle to differentiate into Leydig cells in vitro. SLCs associated with stages IX-XI were more active in proliferation and differentiation than SLCs associated with stages VII-VIII. However, when the SLCs were isolated from each of the two groups of tubules and cultured in vitro, no differences were seen in their ability to proliferate or differentiate. These results suggested that the stage-dependent local factors, not the SLCs themselves, explain the stage-dependent differences in SLC function. TGFB, produced in stage-specific fashion by Sertoli cells, is among the factors shown in previous studies to affect SLC function in vitro. When TGFB inhibitors were included in the cultures of stages IX-XI and VII-VIII tubules, stage dependent differences in SLC development were reduced, suggesting that TGFB may be among the paracrine factors involved in the stage-dependent differences in SLC function. Taken together, the findings suggest that there is dynamic interaction between SLCs and germ/Sertoli cells within the seminiferous tubules that may affect SLC proliferation and differentiation. PMID- 30476561 TI - Cellular stress is a prerequisite for glucose-induced mitochondrial matrix alkalinization in pancreatic beta-cells. AB - Changes in mitochondrial and cytosolic pH alter the chemical gradient across the inner mitochondrial membrane. The proton chemical gradient contributes to mitochondrial ATP synthesis as well as the uptake and release of metabolites and ions from the organelle. Here mitochondrial pH and DeltapH were studied for the first time in human pancreatic beta-cells. Adenoviruses were used for rat insulin promoter dependent expression of the pH sensor SypHer targeted to either the mitochondrial matrix or the cytosol. The matrix pH in resting human beta-cells is low (pH = 7.50 +/- SD 0.17) compared to published values in other cell types. Consequently, the DeltapH of beta-cells mitochondria is small. Glucose stimulation consistently resulted in acidification of the matrix pH in INS-1E insulinoma cells and beta-cells in intact human islets or islet monolayer cultures. We registered acidification with similar kinetics but of slightly smaller amplitude in the cytosol of beta-cells, thus glucose stimulation further reduced the DeltapH. Infection of human islets with high levels of adenoviruses caused the mitochondrial pH to increase. The apoptosis inducer and broad-spectrum kinase inhibitor staurosporine had similar effects on pH homeostasis. Although staurosporine alone does not affect the mitochondrial pH, glucose slightly increases the matrix pH of staurosporine treated cells. These two cellular stressors alter the normal mitochondrial pH response to glucose in pancreatic beta-cells. PMID- 30476562 TI - Modulation of RXR-DNA complex assembly by DNA context. AB - Retinoid X Receptors (RXRs) act as dimer partners for several nuclear receptors including itself, binding to genomic DNA response elements and regulating gene transcription with cell and gene specificity. As homodimers, RXRs bind direct repeats of the half-site (A/G)G(G/T)TCA separated by 1 nucleotide (DR1) and little variability of this consensus site is observed for natural DR1s. However, these variations are responsible of the modulation of RXR receptors function through differential binding affinity and conformational changes. To further our understanding of the molecular mechanisms underlying RXR-DNA interactions, we examined how RXR DBDs bind to different DR1s using thermodynamics, X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. We show that the half-site sequences modulate the binding cooperativity that results from the protein-protein contacts between the two DBDs. Chemical shifts perturbation NMR experiments revealed that sequence variations in half-sites induce changes that propagate from the protein-DNA interface to the dimerization interface throughout the DBD fold. PMID- 30476563 TI - History of Major Depression is Associated with Neuropsychiatric Symptoms but not Systemic Inflammation in a Cross-Sectional Study in Obese Patients. AB - Obesity is a major public health burden associated with neuropsychiatric comorbidities leading to social and occupational impairment. Given the growing prevalence of both obesity and mental disorders worldwide, understanding the risk factors of obesity-related neuropsychiatric comorbidities is crucial to develop preventive strategies and individualized treatments. Recent findings suggest that adiposity-driven inflammation contributes to neuropsychiatric comorbidities in obesity. However, not all obese subjects afflicted with chronic inflammation develop neuropsychiatric symptoms, suggesting additional risk factors. The aim of this study was to investigate the impact of personal history of major depressive disorder (MDD) on obesity-related inflammation and neuropsychiatric symptoms, and their relationship. A case-control study was conducted comparing 66 obese patients (body mass index > 35 kg/m2) and 22 healthy non-obese participants, free of any current neuropsychiatric diseases including MDD. Neuropsychiatric symptoms were assessed using the Neurotoxicity Rating Scale (NRS). Sociodemographic and clinical variables were gathered and blood was collected for the measurement of serum levels of high-sensitivity C-reactive protein (hs-CRP). Multiple regression analyses were performed to assess the contribution of obesity and personal history of MDD to clinical outcomes and inflammatory status in study participants. Hs-CRP levels as well as NRS scores were significantly increased in the obese group. Overall, personal history of depression accounted for increased NRS scores but no significant association was found with inflammatory status. In addition, history of depression did not significantly modulate the relationship of obesity-related inflammation with NRS scores. Interestingly, obese individuals with history of recurrent MDD (n=13) exhibited higher scores in the cognitive and sickness symptoms dimensions of the NRS compared to obese subjects with history of one depressive episode only. Findings indicate that history of depression contributes to neuropsychiatric symptoms, but not to systemic inflammation, in obese subjects free of current depressive episode. These results provide relevant information on the risk factors that may help identify obese subjects with increased risk of neuropsychiatric comorbitity. PMID- 30476564 TI - Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis. AB - Collagen type II-induced arthritis (CIA) in Dark Agouti rats, a model of rheumatoid arthritis (RA), reproduces sexual dimorphism in the incidence and severity of the human disease. Th17 cells are central in the induction/propagation of autoimmune inflammation in CIA and RA. To assess mechanisms underlying this dimorphism in CIA rats, in lymph nodes draining inflamed joints and adjacent tissues (dLNs) from CIA rats of both sexes Th17/CD25+Foxp3+CD4+ T-regulatory cell (Treg) ratio, Th17 cell redifferentiation in functionally distinct subsets and Treg transdifferentiation into IL-17 producing cells (exTregs) were examined. In female rats (developing more severe CIA than their male counterparts) the higher frequency of all Th17 cells (reflecting partly their greater proliferation), followed by the higher frequency of highly pathogenic IFN-gamma/GM-CSF-co-producing cells, but lower frequency of less pathogenic/immunoregulatory IL-10-producing cells among them was found. Additionally, compared with male rats, in female rats the lower frequency of Tregs was observed. Moreover, Tregs from female rats exhibited diminished proliferative and suppressive capacity (judging by PD-1 expression) and enhanced conversion into IL-17-producing cells. Given that TGF-beta concentration was comparable in collagen-type II-stimulated dLN cell cultures from female and male rats, the shift in Th17/Treg ratio followed by augmented Th17 cell redifferentiation into IFN-gamma/GM-CSF-co-producing cells and Treg transdifferentiation into IL-17-producing cells in female rats was associated with increased concentration of IL-6 in female rat dLN cell cultures, and the higher frequency of IL-1beta- and IL-23-producing cells among their dLN cells. The lower frequency of IL-10-producing B cells, presumably B regulatory cells (Bregs) could also contribute to the shift in Th17/Treg ratio in female rat compared with male rat dLNs. Consistently, the lower expression of IL-35 (the cytokine promoting Treg expansion directly and indirectly, by favoring Breg expansion and conversion into IL-10/IL-35-producing cells) in female rat dLN cells was detected. Thus, the study identified putative cellular and molecular substrates of the sexual dimorphism in the immunopathogenesis and clinical outcome of CIA and suggested mechanisms to be targeted in females to improve control of Th17 response, and consequently clinical outcome of CIA, and possibly RA. PMID- 30476565 TI - HMGB1-mediated differential response on hippocampal neurotransmitter disorder and neuroinflammation in adolescent male and female mice following cold exposure. AB - Stress induces many different sex-specific physiological and psychological responses during adolescence. Although the impact of certain brain stressors has been reported in the literature, the influence of cold stress on the mechanisms underlying hippocampal neurotransmitter disorder and neuroinflammation remain unstudied. Adolescent male and female C57BL/6 mice were exposed to 4 degrees C temperatures, 3 h per day for 1 week. Serum CORT and blood gas analysis was then used to assess body status. Using western blotting, immunofluorescence and immunohistochemistry we also assessed glial cell number and microglial activation, as well as inflammatory cytokine levels and related protein expression levels. The phenomena of excessive CORT, microglial activation, increased acetylate-HMGB1 levels, NF-kappaB signaling pathway activation, pro inflammatory cytokine release, neuronal apoptosis and neurotransmitter disorder were demonstrated in mouse hippocampal tissue following cold exposure. We believe that these phenomena are mediated by the HMGB1/TLR4/NFkappaB pathway. Finally, the male inflammatory response in hippocampal tissue was more severe and the influence of cold exposure on neurotransmitter was greater in females. PMID- 30476566 TI - Temporal window of integration estimated by omission in bone-conducted ultrasound. AB - Bone-conducted ultrasound (BCU) can be heard for both normal-hearing and some profoundly deaf individuals. Moreover, amplitude-modulated BCU can transmit the speech signal. These characteristics of BCU provide the possibility of the developing a bone-conducted ultrasonic hearing aid. Previous studies on the perception mechanism of speech-modulated BCU have pointed to the importance of temporal rather than frequency information. In order to elucidate the perception of speech-modulated BCU, further investigation is need concerning the processing of temporal information. The temporal processing of air-conducted audible sounds (ACASs) involves the integration of closely presented sounds into a single information unit. The long-temporal window of integration was estimated approximately 150-200 ms, which contribute to the discrimination of speech sound. The present study investigated the long-temporal integration system for BCU evaluated by stimulus omission using magnetoencephalography. Eight participants with normal hearing took part in this study. Ultrasonic tone burst with the duration of 50 ms and frequency of 30 kHz was used as the standard stimulus and presented with steady onset-to-onset times or stimulus-onset asynchronies (SOAs). In each sequence, the duration of the SOAs were set to 100, 125, 150, 175, 200, or 350 ms. For deviant, tones were randomly omitted from the stimulus train. Definite mismatch fields were elicited by sound omission in the stimulus train with an SOA of 100-150 ms, but weren't with an SOA of 200 and 350 ms for all participants. We found that stimulus train for BCUs can be integrated within a temporal window of integration with an SOA of 100-150 ms, but are regarded as a separate event when the SOA is 200 or 350 ms in duration. Therefore, we demonstrated that the long-temporal window of integration for BCUs estimated by omission was 150-200 ms, which was similar to that for ACAS (Yabe et al. NeuroReport 8 (1997) 1971-1974 and Psychophysiology. 35 (1998) 615-619). These findings contribute to the elucidation and improvement of the perception of speech-modulated BCU. PMID- 30476567 TI - A novel virtual plus-maze for studying electrophysiological correlates of spatial reorientation. AB - Quick reorientation is an essential part of successful navigation. Despite growing attention to this ability, little is known about how reorientation happens in humans. To this aim, we recorded EEG from 34 participants. Participants were navigating a simple virtual reality plus-maze where at the beginning of each trial they were randomly teleported to either the North or the South alley. Results show that the teleportation event caused a quick reorientation effect over occipito-parietal areas as early as 100 msec; meaning that despite the known stochastic nature of the teleportation, participants built up expectations for their place of arrival. This result has important consequences for the optimal design of virtual reality locomotion. PMID- 30476568 TI - Glutamate receptors and white matter stroke. AB - White matter (WM) damage during ischemia occurs at multiple sites including myelin, oligodendrocytes, astrocytes and axons. A major driver of WM demise is excitoxicity as a consequence of excessive glutamate release by vesicular and non vesicular mechanisms from axons and glial cells. This results in over-activation of ionotropic glutamate receptors (GluRs) profusely expressed by all cell compartments in WM. Thus, blocking excitotoxicity in WM with selective antagonists of those receptors has a potential therapeutic value. The significance of WM GluR expression for WM stroke injury is the focus of this review, and we will examine the role of GluRs in injury to myelin, oligodendrocytes, astrocytes and the axon cylinder. PMID- 30476570 TI - Class 1 integrons in Acinetobacter baumannii: a weak expression of gene cassettes to counterbalance the lack of LexA-driven integrase repression. AB - Integrons are able to recruit resistance genes through integrase-driven recombination events that are regulated by the bacterial SOS response and require the repressor LexA. Class 1 integrons genes are expressed from a common promoter, Pc, of which at least 5 predominant variants, classified from weak to strong, have been described. In Escherichia coli, there is an intertwined regulation between gene cassette expression and integrase activity: the stronger the promoter is, the weaker the integrase is. Class 1 integrons have been frequently described in Acinetobacter baumannii. However, Acinetobacter spp. lack the LexA repressor suggesting that the integrase is constitutively expressed. We characterized the integron content of 83 clinical and environmental A. baumannii strains. We found a predominance of Pc variants described as strong in E. coli. The Pc expression level was 2 to 4-fold lower in A. baumannii than in E. coli, and the diversity of the gene cassette array was low. In A.baumannii integrons with a PcS promoter might have been selected to allow a sufficient resistance level while avoiding the toxicity of a highly active integrase. Furthermore, a transcriptional interference between PcS and PintI1 (as shown in E.coli) may limit the expression of the integrase and thus counterbalance the lack of LexA driven integrase repression to prevent the cost of the integrase. PMID- 30476569 TI - Identification of an anti-Gram-negative bacteria agent disrupting the interaction between LPS transporters LptA and LptC. AB - The emergence of drug-resistant Gram-negative bacteria is a serious clinical problem that causes increased morbidity and mortality. However, the slow discovery of new antibiotics is unable to meet the need for the treatment of bacterial infections caused by drug-resistant strains. Lipopolysaccharide (LPS) is synthesized in the cytoplasm and transported to cell envelope by LPS transport (Lpt) system. LptA and LptC form a complex that transports LPS from inner membrane to outer membrane. We performed a screen for agents that disrupt the transport of LPS in Gram-negative bacteria Escherichia coli. We established a yeast two-hybrid system to detect LptA-LptC interaction and used this system to identified a compound, IMB-881, that blocks this interaction and shows antibacterial activity. We further demonstrated that this compound binds specifically to LptA to disrupt LptA-LptC interaction using Surface Plasmon Resonance assay. Overproduction of LptA protein but not that of LptC lowers the antibacterial activity of IMB-881. Strikingly, E. coli cells accumulate "extra" membrane material in the periplasm and exhibit filament morphology after treatment with IMB-881. Therefore, by using yeast two-hybrid system, we have successfully identified an antibacterial agent that likely blocks LPS transport in Gram-negative bacteria. PMID- 30476571 TI - Occurence of carbapenemase-producing Enterobacteriaceae in Togo, West Africa. PMID- 30476572 TI - Cefazolin versus anti-staphylococcal penicillins for the treatment of methicillin susceptible Staphylococcus aureus bloodstream infections in acutely-ill adult patients: results of a systematic review and meta-analysis. AB - A systematic literature review and meta-analysis was conducted to evaluate the comparative efficacy and tolerability of cefazolin versus anti-staphylococcal penicillins (ASPs) for methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream infections (BSI). Utilizing published regression models, included studies were stratified into high and low pre-probability of mortality subgroups. Cefazolin was associated with significantly lower rates of treatment failure (OR: 0.70; 95% CI: 0.61-0.82; P<0.001; I2=14%) and crude, all-cause mortality (OR: 0.69; 95% CI: 0.59-0.81; P<0.001; I2=18%) when compared to ASP therapy. The overall risk of treatment-related adverse drug reactions was numerically lower with cefazolin (OR: 0.39; 95% CI: 0.15-1.00; P=0.05). Subgroup sensitivity analyses of studies conducted in less severely ill patients were similar to the combined analysis. The role of cefazolin in the most severely ill patients with MSSA BSI should be prospectively evaluated. PMID- 30476573 TI - Why do arthropods secrete beta-lactams? PMID- 30476575 TI - Spindle cell Nuclear-in-Testis Carcinoma of the Lung: A Challenging Tumor. PMID- 30476574 TI - Electromagnetic Navigation Bronchoscopy for Peripheral Pulmonary Lesions: One Year Results of the Prospective, Multicenter NAVIGATE Study. AB - INTRODUCTION: Electromagnetic navigation bronchoscopy (ENB) is a minimally invasive technology that guides endoscopic tools to pulmonary lesions. ENB has been evaluated primarily in small, single-center studies; thus, the diagnostic yield in a generalizable setting is unknown. METHODS: NAVIGATE is a prospective, multicenter, cohort study that evaluated ENB using the superDimensionTM navigation system. In this United States cohort analysis, 1,215 consecutive subjects were enrolled at 29 academic and community sites from April 2015 to August 2016. RESULTS: The median lesion size was 20.0 mm. Fluoroscopy was used in 91% of cases (lesions visible in 60%) and radial endobronchial ultrasound in 57%. The median ENB planning time was 5 minutes; the ENB-specific procedure time was 25 minutes. Among 1,157 subjects undergoing ENB-guided biopsy, 94% (1,092/1,157) had navigation completed and tissue obtained. Follow-up was completed in 99% of subjects at 1 month and 80% at 12 months. The 12-month diagnostic yield was 73%. Pathology results of the ENB-aided tissue samples showed malignancy in 44% (484/1,092). Sensitivity, specificity, positive predictive value, and negative predictive value for malignancy were 69%, 100%, 100%, and 56%, respectively. ENB related CTCAE Grade >=2 pneumothoraces (requiring admission or chest tube placement) occurred in 2.9%. The ENB-related CTCAE Grade >=2 bronchopulmonary hemorrhage and Grade >=4 respiratory failure rates were 1.5% and 0.7%, respectively. CONCLUSIONS: NAVIGATE demonstrates that an ENB-aided diagnosis can be obtained in approximately three quarters of evaluable patients across a generalizable cohort based on prospective 12-month follow-up in a pragmatic setting, with a low procedural complication rate. PMID- 30476576 TI - Impact of Age on Outcomes with Immunotherapy in Patients with Non-Small Cell Lung Cancer (NSCLC). AB - INTRODUCTION: Immunotherapy has revolutionized the treatment of non-small cell lung cancer (NSCLC), but little is known about the activity of PD-(L)1 blockade across age groups. METHODS: We retrospectively evaluated patients with NSCLC initiated on PD-(L)1 inhibitors from 1/2013-7/2017. Medical records and radiographic imaging were reviewed to determine progression-free survival (PFS) and overall survival (OS). We also compared immunotherapy-related toxicities, steroid use, and hospitalizations by age. RESULTS: Of 245 patients, 26.1% were age<60 years, 31.4% were age 60-69, 31.0% were age 70-79, and 11.4% were >=80 years. Median PFS by age group was: age<60, 1.81 months; 60-69, 2.53 months; 70 79, 3.75 months; >=80, 1.64 months (log-rank p-value=0.055). Median OS by age group was: age<60, 13.01 months; 60-69, 14.56 months; 70-79, 12.92 months; >=80, 3.62 months (log-rank p-value=0.011). Rates of immunotherapy-related toxicities, steroid use, and hospitalizations did not differ by age. CONCLUSIONS: Although the OS and PFS benefits of immunotherapy differ by age, rates of toxicity are similar regardless of age. PMID- 30476577 TI - Ferulic acid potentiates the antibacterial activity of quinolone-based antibiotics against Acinetobacter baumannii. AB - Ferulic acid is a cinnamic derivative of phenolic acid and its pharmacophore (catechol) is responsible for antioxidant, prooxidant and antibacterial activities. In this study, we evaluated the influence of ferulic acid on the antibacterial activity of quinolone-based antibiotics against Acinetobacter baumannii. The minimum inhibitory concentration of ferulic acid against Acinetobacter baumannii AB5075 were considerably lowered for DeltasodB and DeltakatG mutants. Checkerboard assay shows synergistic interactions between ferulic acid and quinolones. In a murine sepsis model, ferulic acid potentiated the antibacterial activities of quinolones. Ferulic acid amplified quinolones induced redox imbalance by increasing superoxide ion generation, NAD+/NADH ratio and ADP/ATP ratio. Conversely, the level of reduced glutathione was significantly lowered. We conclude that ferulic acid potentiates the antibacterial activity of quinolone-based antibiotics against A. baumannii by increasing ROS generation, energy metabolism and electron transport chain activity with a concomitant decrease in glutathione. PMID- 30476578 TI - Plantamajoside attenuates inflammatory response in LPS-stimulated human gingival fibroblasts by inhibiting PI3K/AKT signaling pathway. AB - Periodontitis is an important inflammatory disease that often causes by periodontopathic bacteria. The present study, we tested the anti-inflammatory effects of plantamajoside on LPS-stimulated human gingival fibroblasts. Human gingival fibroblasts (HGFs) were stimulated with LPS from Porphyromonas gingivalis. Plantamajoside was administrated 1 h before LPS treatment. The results demonstrated that plantamajoside decreased the production of PGE2, NO, IL 6, and IL-8 in LPS-stimulated HGFs. LPS-induced NF-kappaB p65 and IkappaB phosphorylation were also suppressed by plantamajoside. Furthermore, plantamajoside inhibited LPS-induced PI3K and AKT phosphorylation. In conclusion, these results suggested that the mechanism of plantamajoside was through inhibiting PI3K/AKT signaling pathway, which lead to the inhibition of NF-kappaB activation and inflammatory response. PMID- 30476580 TI - Broad-spectrum quorum sensing and biofilm inhibition by green tea against gram negative pathogenic bacteria: Deciphering the role of phytocompounds through molecular modelling. AB - The emerging prevalence of multidrug-resistance in Gram-negative pathogens, due to conventional antimicrobial therapeutics, has led the researchers to emphasize on development of alternative novel strategies to suppress the bacterial virulence and pathogenicity through inhibition of quorum sensing (QS) and biofilms. QS is a bacterial communication system to produce density-dependent response via chemical signalling that controls pathogenesis and biofilms formation. Leaves of green tea are used worldwide as beverage which is also known for its broad-spectrum therapeutic efficacy. In this work, we have identified and characterized the most bioactive faction of green tea extract and evaluated the anti-QS and antibiofilm activity of green tea ethyl acetate fraction (GTEF) i.e. most active fraction, on three different Gram-negative bacterial pathogens. GTEF inhibited the violacein production by >75% in C. violaceum 12472. Many virulence factors of P. aeruginosa PAO1 viz. pyocyanin, pyoverdin, exoprotease, elastase, rhamnolipid production, and swimming motility were remarkably reduced in presence of sub-MICs of GTEF. Moreover, prodigiosin, protease activity, cell surface hydrophobicity, and swimming of S. marcescens MTCC 97 were also decreased significantly by the supplementation of GTEF in culture media. GTEF exhibited broad-spectrum antibiofilm action with >80% reduction in biofilm formation of test pathogens. In silico studies gave a mechanistic insight of action of GTEF. Molecular modelling revealed that phytoconstituents detected by GC/MS exhibited affinity (in order of 104 M-1) towards AHL synthases (LasI and EsaI). The molecular binding between phytocompounds and receptor proteins (LasR, RhlR, and PqsR) of QS circuit was also energetically favourable (DeltaG degrees >= 5.0 kcal mol-1) and supported by hydrogen bonds and hydrophobic interactions. These compounds were found to be docked in ligand binding domain of CviR and occupied same cavity as that of its antagonist. Squalene and thunbergol interacted with LasA at tartaric acid binding pocket and the complex was strengthened with binding energy -5.9 kcal mol-1. Moreover, interaction of thunbergol with biofilm associated proteins viz. PilT and PilY1, might be disabling the pilus assembly and consequently inhibiting biofilm formation. In vivo validation of results suggested the protective role GTEF against QS-mediated pathogenicity and it might become a novel non-antibiotic QS inhibitor to control bacterial infection. PMID- 30476579 TI - DosR proteins of Mycobacterium tuberculosis upregulate effector T cells and down regulate T regulatory cells in TB patients and their healthy contacts. AB - It is well established that the current problem of tuberculosis (TB) can be combated by overcoming the drawbacks of the currently available BCG vaccine. This would involve incorporation of antigens that can control TB at all stages including the dormant phase which is generally ignored. Hence, DosR regulon proteins, which are expressed in latent infection, could prove to be very good vaccine candidates as they can possibly target the silent but most predominant form of TB infection. In the present study, the immune response to two DosR proteins Rv2627 and Rv2628 has been studied in PBMCs derived from normal individuals, TB patients and healthy contacts of TB patients. It was found that these antigens were capable of stimulating a strong IFN-gamma+ T cell response along with accentuation of memory T cells and other protective cytokines such as IL-2 and IL-17. At the same time these proteins decreased the frequencies of immune-suppressor regulatory T cells in in vitro stimulation of PBMC from both patients and their contacts. Considering all these facts together, we suggest Rv2627 and Rv2628 to be one of the extremely promising candidates for incorporation into a post exposure subunit vaccine against TB. PMID- 30476581 TI - Porous scaffolds from droplet microfluidics for prevention of intrauterine adhesion. AB - Severe intrauterine adhesions (IUAs) have a great negative impact on women's psychological and reproductive health. It remains a significant challenge to prevent postoperative IUAs because of the complications of various clinical preventive measures and incompatibility of uterine cavity morphology. Herein, we present a new drug-loadedporous scaffold based on a microfluidic droplet template, which combines the characteristics of the artificial biocompatible material GelMA and the natural polysaccharide material Na-alginate. By changing the containers that collect the microfluidic droplets, the porous scaffold conforming to the shape of the uterine cavity could be obtained. The porous structure, mechanical property, and flexibility impart the scaffold with compressibility and send it to the uterus through the vagina. In addition, the external-internal connected open structures could load and control the release of drugs to repair the damaged region continuously in vivo. To verify the antiadhesion and repair of drug-loaded porous scaffolds, we tested the system in the rat model of IUAs, and it was demonstrated that the system had the ability to improve neovascularization, cellularize the damaged tissue, and repair the endometrium. These features provide the drug-loaded porous scaffolds with new options for the improvement of postoperative IUAs. STATEMENT OF SIGNIFICANCE: Intrauterine adhesions are caused by various causes of damage to the endometrial basal layer, thus leading to part or entire adhesions in the cervical or uterine cavity. Clinically, various preventive measures reach the barrier effect through the physical barrier, which are difficult to further promote the repair of the damaged endometrium, and most of them have apparent side effects. This study aims to prepare compressible and biodegradable three-dimensional porous drug-loading biological scaffolds. GelMA and Na-alginate have desirable biocompatibility. The interconnect porous scaffolds, which were prepared through the combination of biomaterials and single emulsion microfluidics, not only have compressibility but also provide space for drug delivery and release. This system can further promote the repair of the endometrium while preventing adhesion. PMID- 30476582 TI - Characterization of a tissue-engineered choroid. AB - The choroid of the eye is a vascularized and pigmented connective tissue lying between the retina and the sclera. Increasing evidence demonstrates that, beyond supplying nutrients to the outer retina, the different choroidal cells contribute to the retina's homeostasis, especially by paracrine signaling. However, the precise role of each cell type is currently unclear. Here, we developed a choroidal substitute using the self-assembly approach of tissue engineering. Retinal pigment epithelial (RPE) cells, as well as choroidal stromal fibroblasts, vascular endothelial cells and melanocytes, were isolated from human eye bank donor eyes. Fibroblasts were cultured in a medium containing serum and ascorbic acid. After six weeks, cells formed sheets of extracellular matrix (ECM), which were stacked to produce a tissue-engineered choroidal stroma (TECS). These stromal substitutes were then characterized and compared to the native choroid. Their ECM composition (collagens and proteoglycans) and biomechanical properties (ultimate tensile strength, strain and elasticity) were similar. Furthermore, RPE cells, human umbilical vein endothelial cells and choroidal melanocytes successfully repopulated the stromas. Physiological structures were established, such as a confluent monolayer of RPE cells, vascular-like structures and a pigmentation of the stroma. Our TECS thus recaptured the biophysical environment of the native choroid, and can serve as study models to understand the normal interactions between the RPE and choroidal cells, as well as their reciprocal exchanges with the ECM. This will consequently pave the way to derive accurate insight in the pathophysiological mechanisms of diseases affecting the choroid. STATEMENT OF SIGNIFICANCE: The choroid is traditionally known for supplying blood to the avascular outer retina. There has been a renewed attention directed towards the choroid partly due to its implication in the development of age related macular degeneration (AMD), the leading cause of blindness in industrialized countries. Since AMD involves the dysfunction of the choroid/retinal pigment epithelium (RPE) complex, a three-dimensional (3D) model of RPE comprising the choroid layer is warranted. We used human choroidal cells to engineer a choroidal substitute. Our approach takes advantage of the ability of cells to recreate their own environment, without exogenous materials. Our model could help to better understand the role of each choroidal cell type as well as to advance the development of new therapeutics for AMD. PMID- 30476583 TI - Liver Fat is Associated With Markers of Inflammation and Oxidative Stress in Analysis of Data From the Framingham Heart Study. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease is an inflammatory condition that results in progressive liver disease. It is unknown if individuals with hepatic steatosis, but not known to have liver disease, have higher serum concentrations of markers of systemic inflammation and oxidative stress METHODS: We collected data from 2482 participants from the Framingham Heart Study (mean age, 51+/-11 years; 51% women) who underwent computed tomography and measurement of 14 serum markers of systemic inflammation. Heavy alcohol users were excluded. Liver:Phantom ratio (LPR, a continuous parameter of liver attenuation relative to a calibration phantom) was used to identify individuals with radiographic evidence of liver fat. Primary covariates included age, sex, smoking, alcohol, aspirin use, hypertension, dyslipidemia, diabetes, and cardiovascular disease. Body mass index and visceral fat were secondary covariates. We used multivariable linear regression models to assess the association between liver fat and systemic inflammatory markers. RESULTS: In multivariable-adjusted models, liver fat was associated with the following inflammatory markers: high-sensitivity C-reactive protein (P<.001), urinary isoprostanes (P<.001), interleukin 6 (P<.001), intercellular adhesion molecule 1 (P<.001), and P-selectin (P=.002). Additional adjustment for body mass index or visceral fat attenuated the results slightly, although all associations remained statistically significant (P for all <=.01). CONCLUSION: In a community-based cohort, individuals with hepatic steatosis without known liver disease had higher mean serum concentrations of systemic markers of inflammation. Studies are needed to determine whether treatment of hepatic steatosis reduces systemic inflammation. PMID- 30476584 TI - Safety of Tofacitinib for Treatment of Ulcerative Colitis, Based on 4.4 Years of Data From Global Clinical Trials. AB - BACKGROUND & AIMS: Tofacitinib is an oral, small-molecule inhibitor of JAK approved in several countries for the treatment of ulcerative colitis (UC). We report integrated safety analyses of tofacitinib-treated patients with moderate to severe UC. METHODS: Patients receiving placebo or tofacitinib (5 or 10 mg) twice daily were analyzed as 3 cohorts: induction (phase 2 and 3 induction studies, n=1220), maintenance (phase 3 maintenance study, n=592), and overall (patients receiving tofacitinib 5 or 10 mg twice daily in phase 2, phase 3, or open-label, long-term extension studies, n=1157; 1613 patient-years' exposure). Incidence rates (IRs; patients with events per 100 patient-years of exposure) were evaluated for select adverse events. RESULTS: In the maintenance cohort, IRs for select adverse events were similar among treatment groups, except for a numerically higher IR of herpes zoster infection among patients who received tofacitinib 5 mg twice daily (2.1; 95% CI, 0.4-6.0) and statistically higher IR among patients who received tofacitinib 10 mg twice daily (IR, 6.6; 95% CI, 3.2 12.2) vs placebo (IR, 1.0, 95% CI, 0.0-5.4). For the overall cohort (84% received average dose of tofacitinib 10 mg twice daily), IRs were: death, 0.2 (95% CI, 0.1 0.6); serious infections, 2.0 (95% CI, 1.4-2.8); opportunistic infections, 1.3 (95% CI, 0.8-2.0); herpes zoster infection, 4.1 (95% CI, 3.1-5.2); malignancy (excluding non-melanoma skin cancer), 0.7; 95% CI, 0.3-1.2); non-melanoma skin cancer, 0.7 (95% CI, 0.3-1.2); major adverse cardiovascular events, 0.2 (95% CI, 0.1-0.6); and gastrointestinal perforations, 0.2 (95% CI, 0.0-0.5). CONCLUSIONS: In a safety analyses of patients with moderate to severe UC treated with tofacitinib, we observed a dose relationship with herpes zoster infection. Although follow-up time was relatively short, the safety profile of tofacitinib for patients with UC appeared similar to that reported for patients with rheumatoid arthritis and for patients with UC treated with biologic agents, except for the higher IR of herpes zoster infection. ClinicalTrials.gov, no: NCT00787202, NCT01465763, NCT01458951, NCT01458574, and NCT01470612. PMID- 30476586 TI - Association Between Cigarette Smoking and Alcohol Consumption and Sessile Serrated Polyps in Subjects 30 to 49 Years Old. AB - BACKGROUND & AIMS: We investigated the prevalence of sessile serrated polyps (SSPs) and the association between SSP risk and modifiable lifestyle factors in asymptomatic young adults. METHODS: We performed a cross-sectional study using a screening colonoscopy database of 13,618 asymptomatic subjects, 30-49 years old, and 17,999 subjects, 50-75 years old. We investigated risk factors of SSP by multivariable analyses of clinical data that included cigarette smoking and alcohol consumption. RESULTS: In subjects 30-49 years old, the prevalence of SSP was 2.0% (275/13,618 individuals). Of all SSPs, 40.7% (112/275 SSPs) were large (>= 10 mm). Smoking for >= 20 pack-years was associated with overall SSPs (odds ratio [OR], 1.87; 95% CI, 1.17-2.99) and large SSP (OR, 3.03; 95% CI, 1.62-5.66). The association between anatomic location and >= 20 pack-years of smoking was stronger for distal SSPs than for proximal SSPs (OR, 2.71; 95% CI, 1.27-5.77 vs OR, 1.60; 95% CI, 1.00-2.54). Cessation of smoking for >= 5 years decreased the risk of SSPs (OR, 0.49; 95% CI, 0.28-0.86) and of large SSPs (OR, 0.23; 95% CI, 0.10-0.54). Alcohol consumption was associated with large SSPs. These findings were similar for subjects 50-75 years old. CONCLUSION: In an analysis of a screening colonoscopy database, we found that in asymptomatic young adults, smoking and alcohol consumption were associated with any SSPs and large SSPs. Cessation of smoking decreased the risk of SSPs. Therefore, early lifestyle modification may be recommended for primary prevention of SSPs in young adults. PMID- 30476585 TI - Effects of Alcohol Consumption and Metabolic Syndrome on Mortality in Patients with Non-alcoholic and Alcohol-Related Fatty Liver Disease. AB - BACKGROUND & AIMS: Non-alcoholic and alcohol-related fatty liver disease are overlapping diseases in which metabolic syndrome and alcohol consumption each contribute to progressive liver disease. We aimed to assess the effects of alcohol consumption and metabolic syndrome on mortality in individuals with fatty liver. METHODS: We searched the National Health and Nutrition and Examination Survey III for adults (20-74 years old) with hepatic steatosis, detected by ultrasound, for whom mortality and follow-up data were available. We collected data from the alcohol use questionnaire (self-reported number of days a participant drank alcohol; the number of drinks [10 g alcohol] per day on a drinking day; the number of days the participant had 5 or more drinks) and calculated the average amount of alcohol consumption in drinks/day for each participant during the year preceding enrollment. Excessive alcohol consumption for men was >3 drinks/day and for women was >1.5 drinks/day. We also collected clinical data, and mortality data were obtained from the National Death Index. Demographic and clinical parameters were compared among consumption groups using the chi2 test for independence or survey regression models. We used Cox proportional hazard models to identify independent predictors of all-cause and cause-specific mortality. RESULTS: The study cohort included 4264 individuals with hepatic steatosis (mean age, 45.9 years; 51% male; 76% white; 46% with metabolic syndrome; 6.2% with excessive alcohol use). There was no significant difference in mean age between individuals with vs without excessive alcohol consumption (P=.65). However, overall mortality was significantly higher among participants with excessive alcohol consumption (32.2%) vs participants with non excessive alcohol use (22.2%) after mean 20 years of follow up (P=.003), as well as after 5 years of follow up. In multivariate analysis, the presence of metabolic syndrome (adjusted hazard ratio [aHR], 1.43; 95% CI, 1.12-1.83) and excessive alcohol consumption (aHR, 1.79; 95% CI, 1.21-2.66) were independently associated with an increased risk of death in individuals with hepatic steatosis; any lower average amount of alcohol consumption was not associated with mortality (all P>.60). In a subgroup analysis, the association of excessive alcohol use with mortality was significant in individuals with metabolic syndrome (aHR, 2.46; 95% CI, 1.40-4.32) but not without it (P=.74). CONCLUSION: In review of data from the National Health and Nutrition and Examination Survey III, we associated alcohol consumption with increased mortality in participants with fatty liver and metabolic syndrome. These findings indicate an overlap between non-alcoholic and alcohol-related fatty liver disease. PMID- 30476587 TI - Variation in Endoscopic Activity Assessment and Endoscopy Score Validation in Adults with Eosinophilic Esophagitis. AB - BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is assessed endoscopically (endoscopic activity), based on grades of edema, rings, exudates, furrows, and strictures (EREFS). We examined variations in endoscopic assessments of severity, developed and validated 3 EREFS-based scoring systems, and assessed responsiveness of these systems using data from a randomized placebo-controlled trial of patients with EoE. METHODS: For the development set, 5 gastroenterologists reviewed EREFS findings from 266 adults with EoE and provided endoscopist global assessment scores (EndoGA, scale of 0 to 10); variation (DeltaEndoGA) was assessed using linear regression. We evaluated simple scores (features given arbitrary values from 0 to 3) and developed 2 scoring systems (adjusted score range, 0-100). We then fitted our linear regression model with mean EndoGA to data from 146 adults recruited in centers in Switzerland and the United States between April 2011 and December 2012. For the validation set, we collected data from 120 separate adults (recruited in centers in Switzerland and the United States between May 2013 and July 2014), assessing regression coefficient-based scores using Bland-Altman method. We assessed the responsiveness of our scoring systems using data from a randomized trial of patients with EoE given fluticasone (n=16) or placebo (n=8). RESULTS: The distribution of EndoGA values differed among endoscopists (mean DeltaEndoGA, 2.6+/-1.8; range 0-6.6). We developed 2 regression-based scoring systems to assess overall and proximal and distal esophageal findings; variation in endoscopic features accounted for more than 90% of the mean EndoGA variation. In the validation group, differences between mean EndoGA and regression-based scores were small (ranging from -4.70 to 2.03), indicating good agreement. In analyses of data from the randomized trial, the baseline to end of study change in patients given fluticasone was a reduction of 24.3 in simple score (reduction of 4.6 in patients given placebo, P=.052); a reduction of 23.5 in regression-based overall score (reduction of 6.56 in patients given placebo, P=.12), and a reduction of 23.8 (reduction of 8.44 in patients given placebo, P=.11). CONCLUSION: Assessments of endoscopic activity in patients with EoE vary among endoscopists. In an analysis of data from a randomized controlled trial, we found that newly developed scoring systems are no better than simple scoring system in detecting changes in endoscopic activity. These results support the use of a simple scoring system in evaluation of endoscopic activity in patients with EoE. clinicaltrials.gov no: NCT00939263 and NCT 01386112. PMID- 30476590 TI - Vitamin D attenuates rhinovirus-induced expression of intercellular adhesion molecule-1 (ICAM-1) and platelet-activating factor receptor (PAFR) in respiratory epithelial cells. AB - Human rhinoviruses commonly cause upper respiratory infections, which may be complicated by secondary bacterial infection. Vitamin D replacement reduces risk of acute respiratory infections in vitamin D-deficient individuals, but the mechanisms by which such protection is mediated are incompletely understood. We therefore conducted experiments to characterise the influence of the major circulating metabolite 25-hydroxyvitamin D (25[OH]D) and the active metabolite 1,25-dihydroxyvitamin D (1,25[OH]2D) on responses of a respiratory epithelial cell line (A549 cells) to infection with a major group human rhinovirus (RV-16). Pre-treatment of A549 respiratory epithelial cells with a physiological concentration (10-7M) of 25(OH)D induced transient resistance to infection with RV-16 and attenuated RV-16-induced expression of the genes encoding intercellular adhesion molecule 1 (ICAM-1, a cell surface glycoprotein that acts as the cellular receptor for major group rhinoviruses) and platelet-activating factor receptor (PAFR, a G-protein coupled receptor implicated in adhesion of Streptococcus pneumoniae to respiratory epithelial cells). These effects were associated with enhanced expression of the genes encoding the NF-kappaB inhibitor IkappaBalpha and the antimicrobial peptide cathelicidin LL-37. Our findings suggest possible mechanisms by which vitamin D may enhance resistance to rhinovirus infection and reduce risk of secondary bacterial infection in vitamin D-deficient individuals. PMID- 30476589 TI - Variations in the vitamin D receptor gene are not associated with measures of muscle strength, physical performance, or falls in elderly men. Data from MrOS Sweden. AB - The vitamin D receptor (VDR) has been proposed as a candidate gene for several musculoskeletal phenotypes. However, previous results on the associations between genetic variants of the VDR with muscle strength and falls have been contradictory. The MrOS Sweden survey, a prospective population-based cohort study of 3014 elderly men (mean age 75 years, range 69-81) offered the opportunity to further investigate these associations. At baseline, data were collected on muscle strength and also the prevalence of falls during the previous 12 months. Genetic association analysis was performed for 7 Single Nucleotide Polymorphisms (SNPs), covering the genetic region surrounding the VDR gene in 2924 men with available samples of DNA. Genetic variations in the VDR were not associated with five different measurements of muscle strength or physical performance (hand grip strength right and left, 6 m walking test (easy and narrow) and timed-stands test). However, one of the 7 SNPs of the gene for the VDR receptor, rs7136534, was associated with prevalence of falls (33.6% of the AA, 14.6% of the AG and 16.5% of the GG allele). In conclusion, VDR genetic variants are not related to muscle strength or physical performance in elderly Swedish men. The role of the rs7136534 SNP for the occurrence of falls is not clear. PMID- 30476588 TI - Association Between Intake of Red and Processed Meat and Survival in Patients With Colorectal Cancer in a Pooled Analysis. AB - BACKGROUND & AIMS: Red and processed meat intake is associated with colorectal cancer (CRC) incidence, but it is not clear if intake is associated with patient survival after diagnosis METHODS: We pooled data from 7627 patients with stage I IV CRC from 10 studies in the International Survival Analysis in Colorectal Cancer Consortium. Cox proportional hazards regression models were used to evaluate the associations of intake of red and processed meat before diagnosis with overall and CRC-specific survival. RESULTS: Among 7627 patients with CRC, 2338 died, including 1576 from CRC, over a median follow-up time of 5.1 years. In multivariable-adjusted analyses, higher intake of red or processed meat was not associated with overall survival of patients with stage I-III CRC: Q4 vs Q1 red meat hazard ratio [HR], 1.08 (95% CI, 0.93-1.26) and Q4 vs Q1 processed meat HR, 1.10 (95% CI, 0.93-1.32) or with CRC-specific survival: Q4 vs Q1 red meat HR, 1.09 (95% CI, 0.89-1.33) and Q4 vs Q1 processed meat HR, 1.11 (95% CI, 0.87 1.42). Results were similar for patients with stage IV CRC. However, patients with stage I-III CRC who reported an intake of processed meat above the study specific medians had a higher risk of death from any cause (HR, 1.12; 95% CI, 1.01-1.25) than patients who reported eating at or less than the median. CONCLUSION: In this large consortium of CRC patient cohorts, intake of red and processed meat before a diagnosis of CRC was not associated with shorter survival time after diagnosis, although a possible weak adverse association cannot be excluded. Studies that evaluate dietary data from several time points before and after cancer diagnosis are required to confirm these findings. PMID- 30476591 TI - External Quality Assessment of 24,25-Dihydroxyvitamin D3 (24,25(OH)2D3) Assays. AB - The discovery that mutations of the CYP24A1 gene are a cause of idiopathic infantile hypercalcemia (IIH) has revived interest in measuring serum 24,25(OH)2D3. Several studies have also suggested that a high 25-hydroxyvitamin D3(25-OHD3):24,25(OH)2D3 ratio might provide additional diagnostic information in the investigation of vitamin D deficiency. Measurement of 24,25(OH)2D3 is necessarily restricted to laboratories with mass spectrometry methods although cross reactivity of the metabolite in immunoassays for 25-OHD is a potential cause of misleading results. The international External Quality Assessment (EQA) scheme for vitamin D metabolites (DEQAS) was set up in 1989. In 2013 DEQAS became an accuracy based EQA for 25-OHD with 'target values' assigned by the National Institute of Standards and Technology (NIST) Reference Measurement Procedure (RMP). A pilot scheme for serum 24,25(OH)2D3 was started in 2015 and participants were asked to measure the metabolite on each of the 5 samples sent out for 25 OHD. Inter-laboratory agreement was poor but this may reflect methodological differences, in particular different approaches to assay standardization. An important potential contribution to reducing variability among assays was the development by NIST of a 24,25(OH)2D3 RMP and its use in assigning values to SRMs 972a, 2973 and 2971, supported by the NIH Office of Dietary Supplements (ODS) as part of the Vitamin D Standardization Program (VDSP) effort. PMID- 30476592 TI - Rapid liquid chromatography-tandem mass spectrometry method for determination of 24,25(OH)2D and 25OHD with efficient separation of 3-epi analogs. AB - This study establishes and validates a rapid method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) without derivatization steps to simultaneously measure of 24,25(OH)2D2, 24,25(OH)2D3, 25OHD2, and 25OHD3, while efficiently separating the 3-epi analogs. Samples were prepared by precipitation and liquid-liquid extraction. The linearity, precision, accuracy, recovery and matrix effect of the method were thoroughly evaluated according to the Clinical & Laboratory Standards Institute guidelines. Additionally, the four vitamin D metabolites in the serum of 38 apparently healthy Chinese volunteers were evaluated. The total analysis time was 8.0 min, with efficient separation of 3-epi 24,25(OH)2D3 and 3-epi 25OHD3, without interference from isomers such as 23,25(OH)2D3 or 1,25(OH)2D2, 1,25(OH)2D3. Good reproducibility was obtained for all four metabolites with within-run coefficient variations (CVs) of 4.07%-6.55%, 4.26%-7.84%, 2.46%-7.21%, and 4.90%-6.87% for 25OHD3, 25OHD2, 24,25(OH)2D3, and 24,25(OH)2D2, respectively, and the total CVs were 4.29%-6.64%, 6.14%-7.84%, 4.33%-7.21%, 5.82%-9.90%, respectively. The limit of quantification was 0.625 ng/mL for 25OHD3 and 25OHD2, and 0.5 ng/mL for 24,25(OH)2D3 and 24,25(OH)2D2. The relative bias of the LC-MS/MS method compared to the certified results of SRM 972a for 25OHD3, 25OHD2 and 24,25(OH)2D3 was -2.21% to 1.01%, 3.38% to 6.73%, and -7.72% to -3.9%, respectively. The mean+/-SD values for 25OHD, 24,25(OH)2D and 25OHD/24,25(OH)2D in the volunteers were 13.5+/-4.4 ng/mL(range:7.6-27.5 ng/mL), 0.84+/-0.42 ng/mL (range:0.26-2.1 ng/mL), and 18+/-7(range:8-37), respectively. Thus, a simple, precise LC-MS/MS method for appropriate retention and separation of vitamin D metabolites and their epi analogs was developed. PMID- 30476593 TI - Effectors of thioredoxin reductase: Brevetoxins and manumycin-A. AB - The activities of two effectors, brevetoxin (PbTx) and manumycin-A (Man-A), of thioredoxin reductase (TrxR) have been evaluated against a series of fourteen TrxR orthologs originating from mammals, insects and protists and several mutants. Man-A, a molecule with numerous electrophilic sites, forms a covalent adduct with most selenocystine (Sec)-containing TrxR enzymes. The evidence also demonstrates that Man-A can form covalent adducts with some non-Sec-containing enzymes. The activities of TrxR enzymes towards various substrates are moderated by Man-A either positively or negatively depending on the enzyme. In general, the reduction of substrates by Sec-containing TrxR is inhibited and NADPH oxidase activity is activated. For non-Sec-containing TrxR the effect of Man-A on the reduction of substrates is variable, but NADPH oxidase activity can be activated even in the absence of covalent modification of TrxR. The effect of PbTx is less pronounced. A smaller subset of enzymes is affected by PbTx. With a single exception, the activities of most of this subset are activated. Although both PbTx variants can react with selenocystine, a stable covalent adduct is not formed with any of the TrxR enzymes. The key findings from this work are (i) the identification of an alternate mechanism of toxicity for the algal toxin brevetoxin (ii) the demonstration that covalent modification of TrxR is not a prerequisite for the activation of NADPH oxidase activity of TrxR and (iii) the identification of an inhibitor which can discriminate between cytosolic and mitochondrial TrxR. PMID- 30476594 TI - Characterization of function and genetic feature of UDP-glucuronosyltransferase in avian species. AB - Birds are exposed to many xenobiotics during their lifetime. For accurate prediction of xenobiotic-induced toxic effects on avian species, it is necessary to understand metabolic capacities in a comprehensive range of bird species. However, there is a lack of information about avian xenobiotic metabolizing enzymes (XMEs), particularly in wild birds. Uridine diphosphate glucuronosyltransferase (UGT) is an XME that plays an important role in phase II metabolism in the livers of mammals and birds. This study was performed to determine the characteristics of UGT1E isoform in avian species, those are related to mammals UGT 1A. To understand the characteristics of avian UGT1E isoforms, in vitro metabolic activity and genetic characteristics were investigated. Furthermore, mRNA expression levels of all chicken UGT1E isoforms were measured. On in vitro enzymatic analysis, the white-tailed eagle, great horned owl, and Humboldt penguin showed lower UGT-dependent activity than domestic birds. In synteny analysis, carnivorous birds were shown to have fewer UGT1E isoforms than herbivorous and omnivorous birds, which may explain why they have lower in vitro UGT activity. These observations suggested that raptors and seabirds, in which UGT activity is low, may be at high risk if exposed to elevated levels of xenobiotics in the environment. Phylogenetic analysis suggested that avian UGT1Es have evolved independently from mammalian UGT1As. We identified the important UGT isoforms, such as UGT1E13, and suspected their substrate specificities in avian xenobiotic metabolism by phylogenetic and quantitative real-time PCR analysis. This is the first report regarding the genetic characteristics and interspecies differences of UGT1Es in avian species. PMID- 30476595 TI - Thyroid hormones mediate metabolic rate and oxidative, anti-oxidative balance at different temperatures in Mongolian gerbils (Meriones unguiculatus). AB - Oxidative damage is a potential physiological cost of thermoregulation during seasonal adjustments to air temperature (Ta) in small mammals. Here, we hypothesized that Ta affects serum thyroid hormone levels and these hormones can mediate the changes in metabolic rate and oxidative damage. Mongolian gerbils (Meriones unguiculatus) were acclimated at different Tas (5 degrees C, 23 degrees C and 37 degrees C) for 3 weeks. Serum tri-iodothyronine (T3) levels increased at 5 degrees C but decreased at 37 degrees C compared to the control (23 degrees C). Protein carbonyls increased in liver at 37 degrees C compared with control, however, lipid damage (malonaldehyde, MDA) in both serum and liver was unrelated to Ta. After the effects of different Tas on thyroid hormone levels and oxidative damage markers were determined, we further investigate whether thyroid hormones mediated metabolic rate and oxidative damage. Another set of gerbils received 0.0036% L-thyroxin (hyperthyroid), 0.04% Methylimazol (hypothyroid) or water (control). Hypothyroid group showed a 34% reduction in resting metabolic rate (RMR) also 42% and 26% increases in MDA and liver protein carbonyl respectively, whereas hyperthyroid group had higher RMR, liver mass and superoxide dismutase (SOD) compared to control. Serum T3 or T3/T4 levels were correlated positively with RMR, liver mass, and SOD, but negatively with MDA and uncoupling protein 2 (UCP2). We concluded that high Ta induced hypothyroidism, decreased RMR and increased oxidative damage, whereas low Ta induced hyperthyroidism, increased RMR and unchanged oxidative damage. These data supported our hypothesis that thyroid hormones can be a cue to mediate metabolic rate and different aspects of oxidative and antioxidant activities at different Tas. PMID- 30476596 TI - Thoracic aneurysm sac endoleak. Not only a risk of rupture. PMID- 30476597 TI - Evaluation of the BASIL Survival Prediction Model in Patients Undergoing Infrapopliteal Interventions for Critical Limb Ischemia: Methodological Issue. PMID- 30476598 TI - Racial Disparities in Endovascular Aortic Aneurysm Repair. AB - OBJECTIVE: Racial and ethnic disparities are a critical issue in access to care within all fields of medicine. We hypothesized that analysis of a statewide administrative dataset would demonstrate disparities based on race with respect to access to this latest technology and the associated outcomes following EVAR. METHODS: Utilizing de-identified data from the Florida State Agency for Health Care Administration, we identified patients based on ICD-9 procedure codes who underwent EVAR between the years 2000-2014. We then assigned these procedures with the specialty of the operating physician and then analyzed outcomes based on the race of the patient. RESULTS: We identified 36,601 EVAR procedures during the study period. The average age of the total sample was 73.38 (+/- 9.87), with the majority of the cohort being male (n = 29034, 81.2%). Breakdown of patients within each race category were as follows: 17,056 (47.7%) non-Hispanic Whites, 1,630 (4.6%) non-Hispanic African Americans, 16,431 (46.0%) Hispanics, and 632 (1.8%) patients identified as "Other". Data analysis showed significant differences between age at presentation, sex of patient, and comorbidity score of patients at presentation. There were significant differences in outcomes based on race with respect to total hospital charges, length of stay, disposition, and payer status. CONCLUSION: Racial disparities were discovered with respect to EVAR treatment. African Americans present at younger ages, have the highest percentage of females requiring intervention, have the longest hospital stays, have the highest Medicaid payer source, have the highest in-hospital total charges of any racial group, and are more likely to be treated by academic practitioners. Hispanics present with the highest comorbidity scores as compared to their counterparts and, along with African Americans, are more likely to be treated by non-vascular surgeons. PMID- 30476599 TI - Reproducibility of Hemodynamic, Cardiac Autonomic Modulation and Blood Flow Assessments in Patients with Intermittent Claudication. AB - OBJECTIVE: To identify, in patients with peripheral artery disease and intermittent claudication (IC), the reproducibility of heart rate (HR), blood pressure (BP), rate pressure product (RPP), heart rate variability (HRV), and forearm and calf blood flow (BF) and vasodilatory assessments. METHODS: Twenty nine patients with IC underwent test and retest sessions, 8-12 days apart. During each session, HR, BP, HRV, BF and vasodilatory responses were measured by electrocardiogram, auscultation, spectral analysis of HRV (low frequency, LFR-R; high frequency, HFR-R) and strain gauge plethysmography (baseline BF, post occlusion BF, post-occlusion area under the curve, AUC). Reproducibility was determined by intraclass coefficient correlation (ICC), typical error, coefficient of variation (CV) and limits of agreement. RESULTS: The ICC for HR and BP were > 0.8 with CV < 9%. For most HRV measures, ICC were > 0.9 while CV were < 7%, except for LF/HF (ICC = 0.737; CV = 93.8%). The ICC for forearm and calf baseline BF assessments were > 0.9 while CV were < 19%; variable ICC and CV for vasodilatory responses were exhibited for calf (0.653 - 0.770; 35.2 - 37.7%) and forearm (0.169 - 0.265; 46.2 - 55.5%). CONCLUSIONS: In male patients with IC, systemic hemodynamic (HR and BP), cardiac autonomic modulation (LFR-R and HFR-R) and forearm and calf baseline BF assessments exhibited excellent reproducibility, whereas the level of reproducibility for vasodilatory responses were moderate to poor. Assessment reproducibility has highlighted appropriate clinical tools for the regular monitoring of disease/intervention progression in patients with IC. PMID- 30476600 TI - Endovascular Reconstruction of Subclavian Artery Aneurysms in Patients with Arterial Thoracic Outlet Syndrome. AB - INTRODUCTION: Subclavian artery aneurysms associated with thoracic outlet syndrome (TOS) have traditionally been managed by open surgical reconstruction. Endovascular subclavian artery reconstruction is novel in the setting of arterial TOS (aTOS). Our objective is to report our results with endovascular subclavian artery reconstruction in arterial TOS patients over a ten-year period with attention to surgical approach and late results. METHODS: Patients who underwent stent graft reconstruction of subclavian artery aneurysms associated with aTOS between 2006-2016 were identified in a prospective database. Data collected included age, gender, presentation, surgical details, and outcomes. RESULTS: Over the study period, 869 TOS procedures were performed. Of these, 7 (0.8%) were aTOS related subclavian artery aneurysms managed with stent graft repair. All presented with upper extremity pain (7) and a majority with limb threatening ischemia (6). Other significant findings included subclavian artery aneurysm (7), cervical rib (4) and clavicular fracture (3). TOS decompression was accomplished via transaxillary cervical and first rib resection. Stent graft deployment was performed concurrently with TOS decompression via brachial artery approach. The mean follow up period was 24.9 months (range 1-60). Two patients required reintervention for stent thrombosis (1.5 month, 36 months) and 1 required balloon angioplasty for in-stent restenosis (24 months). Limb salvage was achieved in all patients with no major amputation, no minor amputations, and restoration of normal function in all. CONCLUSION: Our experience indicates that stent graft reconstruction of subclavian artery aneurysms associated with arterial thoracic outlet syndrome is successful. This procedure was characterized by short surgical times, low blood loss and no complications. It may be subject to late graft thrombosis or stenosis and requires life-long surveillance. PMID- 30476601 TI - Surveillance Recommendations Following TEVAR Should be Based on Initial Indication for Repair. AB - INTRODUCTION: Current surveillance recommendations following thoracic endovascular aortic repair (TEVAR) include contrast-enhanced CT scans at one-, two-, six-, and 12-month intervals, with annual scans thereafter. Patient compliance with such schedules remains inconsistent for all etiologies of aortic disease. It remains unclear which boundaries prevent compliance and whether compliance is associated with improved aorta-specific outcomes. METHODS: A retrospective analysis was performed of a multicenter healthcare system's electronic medical records to include all patients who underwent TEVAR from 7/1/2011 to 4/1/2016. Patients were assigned a compliance score of 0 through 4 based upon the number of images received at the recommended time intervals. Whether patients underwent any postoperative imaging within one year of discharge was also recorded. Patients who died within 12 months of discharge were excluded. Aorta-specific complications included postoperative sac expansion, rupture, or need for additional aortic intervention. RESULTS: 262 total patients were included, of which 203 (77.5%) received at least one post-operative contrast enhanced CT scan. Race, insurance status, and distance to hospital were not associated with twelve-month compliance or compliance score (all p >0.05). Regarding 12-month compliance, 76.2% of aneurysm patients, 81.6% of dissection patients, 72.2% of transection patients, and 72.2% of penetrating aortic ulcer patients underwent at least one CT scan within the first year (all p>0.05). There were no differences in compliance score based on indication for repair. The overall aorta-related complication rate was 34.7%. TEVAR for dissection was associated with increased long-term aorta-specific complications (49.5%, p<0.05 when compared with other indications). DISCUSSION: In this large, multi-hospital analysis of TEVAR outcomes, there was no difference in compliance amongst patients undergoing TEVAR for major indications, but patients with dissection who required TEVAR had a significant difference in aorta-specific complication rates. TEVAR for dissection should be subject to stricter surveillance guidelines than TEVAR for other indications. PMID- 30476602 TI - Re. "Open vs Endovascular repair of descending thoracic aortic aneurysm disease: a systematic review and meta-analysis". PMID- 30476603 TI - The Intra-rater and Inter-rater Reliability of measures derived from Cardiopulmonary Exercise Testing (CPET) in patients with Abdominal Aortic Aneurysms (AAA). AB - INTRODUCTION: Patients with abdominal aortic aneurysms (AAA) often have low exercise tolerance due to comorbidities and advance age. Cardiopulmonary exercise testing (CPET) is predictive of post-operative morbidity and mortality in patients with AAA. We aimed to assess the intra- and inter-rater reliability of both treadmill and cycle ergometer based CPET variables. METHODS: Patients with a AAA (>3.5cm) were randomised to treadmill or bike CPET. Participants were asked to perform two separate CPET tests seven days apart after a familiarisation protocol. All CPETs were carried out using a ramp cycle or modified Bruce treadmill protocol with breath-by-breath gas analysis. RESULTS: Twenty-two male and 2 female patients, aged 73.6 +/- 6.0, completed the study. Intra-rater analysis (intraclass correlation coefficients) demonstrated high reliability on both the treadmill and bike for VAT (r = 0.834 and r = 0.975, respectively). All other CPET variables demonstrated high intra-rater reliability on both modalities bar the highest point for VE/VO2 on the treadmill (substantial agreement r = 0.755). Further, inter-rater reliability demonstrated high agreement for VAT on both the treadmill and cycle (r = 0.983 and 0.905, respectively). All other CPET variables demonstrated high intra-rater reliability on both modalities, with the exception of VO2PEAK on the cycle ergometer (fair agreement r = 0.400). DISCUSSION: CPET in AAA patients is reliable on short-term repeat testing patients and between CPET test reviewers for common testing modalities/protocols. These findings provide further support for the use of CPET, especially treadmill walking, as a clinical measure of peri-operative cardiorespiratory fitness in patients with AAA. PMID- 30476604 TI - Q-TWiST and Cost-Effectiveness Analysis of Endovascular vs. Open Repair in Ruptured Abdominal Aortic Aneurysms in a High Deliberate Practice Volume Centre. AB - OBJECTIVES: To compare the cost-effectiveness of endovascular (rEVAR) vs. open surgical repair (rOSR) for ruptured abdominal aortic aneurysm (rAAA) where rEVAR is regularly performed outside of IFU (shorter and more angulated necks). Primary endpoint is incremental-cost-effectiveness ratio (ICER) of rEVAR vs. rOSR and aneurysm-related mortality. Secondary endpoints are cost-per-Quality-Adjusted Life-Years (QALY), perioperative morbidity and mortality, re-intervention and all cause mortality. METHODS: All rAAA repairs between 2002-2016 in a single center were scrutinized. Between 2002-2007, most ruptured AAAs were repaired using rOSR. From 2007-2016, we implemented a rEVAR when anatomically possible protocol. During this time, severe angulation was rarely seen as a contraindication to rEVAR and rEVAR was performed on aneurysms with an infra-renal aortic neck cranial to the aneurysm with a diameter of 20-33mm and a length of at least 5mm. Demographics and outcomes were reported according to the Society for Vascular Surgery (SVS) guidelines. QALY was measured based on Quality-of-Time-Spent Without-Symptoms-of-Disease-or-Toxicity-of-Treatment (Q-TWiST) assessment. RESULTS: 800 aneurysm surgeries were performed. 135 of these were emergency surgeries of whom 88 were for rAAA; (42 rEVARs and 46 rOSRs).Primary technical success (rEVAR 89.1% vs. rOSR 87.8%; p=0.1), perioperative morbidity (rEVAR 56.5% vs. rOSR 64.3%; p=0.457) and mortality (rEVAR 26.1% vs. rOSR 28.6%; p=0.794) were non-significantly favorable in rEVAR patients. Freedom from re-intervention was significantly lower in rEVAR patients at 3 years (rEVAR 74% vs. rOSR 90%; p=0.038). Three-year aneurysm-related survival (rEVAR 65% vs. rOSR 62%; p=0.848) and all-cause survival (rEVAR 56% vs. rOSR 51%; p=0.577) were higher in rEVAR patients. At 3 years, rEVAR patients had a higher QALY of 1.671 vs. OSR 1.549 (p=0.502). Operating room (p=0.001) and total accommodation costs (p=0.139) were lower in rEVAR patients, while equipment (p<0.001), surveillance and re intervention (p<0.001) costs were higher. Median cost of rEVAR at 3 years was ?23,352 vs. ?20,494 for OSR (p<0.084) (power>80%). Median cost per QALY of rEVAR at 3 years was ?13,974 vs. ?13,230 for rOSR (p=0.296). ICER for rEVAR vs. rOSR was ?23,426 (95% CI < ?0 to > ?30,000). At three years, the AUC and 95% CI for Q TWiST was higher in rEVAR compared to OSR (rEVAR 500.819 vs. rOSR 437.838). CONCLUSION: There is no significant difference in cost or QALY between rEVAR and rOSR even when rEVAR is performed on complex cases outside of IFU (shorter and more angulated necks). There is a significantly higher freedom from secondary intervention in rOSR patients compared to rEVAR patients at 3 years. PMID- 30476605 TI - Diagnosis and treatment of aortic saddle embolism. AB - OBJECTIVE: Acute aortic occlusion is a rare but life-threatening medical condition that can result from aortic saddle embolism, thrombosis of an atherosclerotic aorta, or aortic dissection. Herein are described the diagnostic and therapeutic characteristics for a series of patients with aortic saddle embolism. METHODS: A retrospective review of medical records was performed for patients receiving treatment for aortic saddle embolism at a university hospital in China between January 2001 and September 2017. Demographic, clinical, ancillary testing, treatment, and outcome data were collected and analyzed. RESULTS: Eighteen patients (ten women and eight men) with a mean age of 53.8 years were included. The most commonly associated cardiac diseases were atrial fibrillation or atrial flutter (89%); rheumatic heart disease, valvular heart disease, or both (72%); and congestive heart failure (56%). Rest pain was present in all patients, and sensory or motor deficits were present in 12 patients (67%). Computed tomography (CT) angiography was performed for all patients. Seventeen patients (94%) presented with aortic embolism below the renal arteries. Fifteen patients (83%) underwent bilateral transfemoral embolectomy, and three patients (17%) received no intervention. Fasciotomy was performed for nine patients in 14 limbs. The overall mortality rate was 33%, with a post-procedure mortality rate of 20%. Major morbidity occurred in 60% of patients. Six lower extremities were amputated in four patients, and acute renal failure developed in four patients. The incidence of post-embolectomy internal iliac artery embolism was 58% (11 out of 19 iliac arteries), and pelvic ischemia developed in one young patient. CONCLUSION: Aortic saddle embolism is uncommon but associated with high morbidity and mortality. CT angiography is recommended for diagnosis, and bilateral transfemoral embolectomy is the preferred treatment. Post-embolectomy internal iliac artery embolism was common, and prevention of pelvic ischemia should be considered for young patients. PMID- 30476606 TI - Debranching of Supra-aortic Vessels via Femoral Artery Inflow for Late Ascending Aortic Rupture. AB - A 56-year-old male with history of Marfan's syndrome, total arch replacement, descending thoracic endovascular aortic repair, and twice redo-sternotomy for pseudoaneurysm repair, presented with a pulsatile chest mass secondary to a contained rupture of the ascending aorta. The patient underwent supra-aortic debranching via the superficial femoral artery and ascending thoracic stent graft placement under continuous transesophageal echocardiography. Completion angiography demonstrated successful exclusion of the contained rupture. Post operatively, the patient was neurologically intact, the pulsatile mass resolved, and bypass grafts remained patent. Chronic respiratory failure and multi-drug resistant pneumonia led to late mortality. This case demonstrates that hybrid repair is effective in the emergent setting of ascending aortic rupture. Debranching of the ascending arch using the superficial femoral artery as inflow is feasible and provides adequate cerebral perfusion despite long segment bypass. The use of transesophageal echocardiography during stent graft deployment allows precise device placement in the high risk area of the ascending aorta proximal to the innominate artery. PMID- 30476607 TI - Echocardiography guided false lumen catheterization for "Cheese-wire" Technique in complicated type A aortic dissection. AB - Endovascular treatment of both type A and type B aortic dissection complicated by organ malperfusion is gaining increasing interest and evidence. Different fenestration techniques of the dissection membrane have already been described. We present a 53-year-old patient with complicated type A aortic dissection after previous repair of the ascending aorta. The patient was treated with dissection membrane fenestration and 'chees-wire' technique. Due to the mobility of the dissection flap, we encountered problems to perforate the dissection membrane with the use of a needle. Finally, on transesophageal echocardiography (TEE), a small dynamic dissection flap was visualized in the aortic arch, which could be catheterized TEE guided. Downward traction of the through-wire caused infrarenal intima accumulation. Iliac outflow obstruction could be solved by placement of a bare metal stent. Extensive screening for dynamic dissection (re)-entry holes with use of TEE is a valuable auxiliary in case needle perforation is difficult to achieve in complicated type A or Type B dissection. PMID- 30476608 TI - The outcome of technical intraoperative complications occurring in standard aortic endovascular repair. AB - OBJECTIVES: Technical intraoperative complications (TIC) may occur during standard EVAR with possible effects on the outcome. This study evaluates the early and mid-term effects of TIC on EVARs. METHODS: All EVARs (from 2012 to 2016) were analysed in order to identify all TIC: endoluminal defects (stenosis/dissection/rupture/compression of native arteries or endograft); type I III endoleaks; unplanned artery coverage; surgical access complications. Follow up was performed by DUS/CEUS/CT-Scan at yearly intervals. Outcome was compared with that of uneventful cases (UC) through Fisher's test and Kaplan-Maier curve. RESULTS: TIC occurred in 68 (18%) of 377 patients undergoing EVAR. Thirty-two endoluminal defects were relined endovascularly; 24 type I-III endoleaks were treated with cuff deployment/forced ballooning (23) and surgical conversion (1); 3/8 unplanned artery coverages were revascularized (2 renal, 1 hypogastric), 5 hypogastric had an unsuccessful correction; 4 access artery injuries were repaired. Although fluoroscopy time and contrast employed were significantly higher in TIC compared with UC (309 cases), 30-day outcome was similar for death (1.4% TIC vs 0% UC, P=0.18), reintervention (0% TIC vs 0.3% UC, P=1), type I-III endoleak (0% TIC vs 0.9% UC, P=1), steno-occlusions (0% TIC vs 0.3% UC, P=1), buttock claudication and renal failure (0% in both groups). At 24 months, TIC and UC had similar survival (91.7 +/- 8% vs 96.2 +/- 2.1%, P=0.5), freedom from reintervention (81.4+/-9.9% vs 96+/-2.2%, P=0.49), overall complication rate (13.4+/-7.6% vs 11.4+/-3.5%, P=0.49), type I-III endoleak (11.2+/-7.5% vs 7+/ 2.9%, P=0.8), buttock claudication (0% vs 2+/-2% P=0.6) and haemodialysis (0% in both). Mid-term iliac leg occlusion was significantly higher in TIC (26.9+/-12.3% vs 3 +/- 2.1%, P=0.01). CONCLUSIONS: TIC may affect several aspects during EVAR, leading to the necessity of adjunctive maneuvers, which have no impact on early outcome, but may cause an increased rate of mid-term iliac leg occlusion. PMID- 30476609 TI - Endovascular and Hybrid Management of Patients Affected by Abdominal Aortic Aneurysm and Occlusion of the Iliac Arteries. AB - : The presence of a concomitant aortoiliac occlusive disease and abdominal aortic aneurysm (AAA) is rare and limits the implant of a bifurcated endograft. OBJECTIVES: Evaluation of early and mid-term results of an endovascular or a hybrid approach in patients undergoing iliac revascularization and AAA exclusion. METHODS: We reviewed our clinical series of patients from January 2016 to February 2018. Inclusion criteria were an iliac occlusion with concomitant aortic aneurysm. RESULTS: We treated 8 male patients: eight common iliac arteries (CIA), five external iliac arteries (EIA). We implanted eight bifurcated devices and thirteen covered stents, eight in CIA and five in EIA. In five cases, when the EIA was involved, we also performed a common femoral artery endarterectomy with a patch. During a mean follow up of 10 months the primary patency of the recanalized iliac arteries was 100%, no endoleaks, sac growth or rupture were also recorded. CONCLUSIONS: Endovascular or hybrid treatment of the iliac occlusion combined with infrarenal aortic aneurysm is feasible with favourable early and mid-term results. PMID- 30476610 TI - Late-onset malignant neoplasms and their prognostic factors after abdominal aortic aneurysm repair. AB - OBJECTIVES: Little is known about late-onset primary malignant neoplasms after repair of abdominal aortic aneurysms (AAAs), despite malignancy being one of the primary causes of late death. We investigated the incidence and prognostic factors related to the occurrence of malignancy after AAA repair. METHODS: We performed a retrospective analysis of 589 patients who underwent AAA repair, including 264 endovascular AAA repairs (EVAR) and 325 open surgical repairs (OSR); 482 patients had no history of previous malignancy or concomitant malignancy, 72 had previous malignancy, and 35 had concomitant malignancy in remission at the time of AAA repair. The cumulative incidence rates of late-onset malignancy occurrence and cancer death were estimated using the cumulative incidence function in the presence of competing risks, that is non-cancer death, and prognostic factors were investigated using the Fine-Gray hazard model. RESULTS: After hospital discharge, 128 malignancies occured in 116 patients. Overall cumulative incidence rates of late-onset malignancy occurrence at 1, 3, 5, and 10 years were 4.0%, 11.7%, 18.2%, and 38.1%, respectively. Multivariate analysis revealed that significant prognostic factors for late-onset malignancy included history of previous malignancy, current smoker, higher intraoperative blood loss, absence of allogeneic blood transfusion, lower C-reactive protein levels, and lower serum HDL-cholesterol levels. The type of surgical procedures for AAA repair did not affect the occurrence of malignancy. In addition, current smoker and higher intraoperative blood loss significantly increased the risk of cancer death. CONCLUSION: Current smoker and higher intraoperative blood loss were independent risk factors for late-onset malignancy after AAA repair. Late onset malignancy after AAA repair should be monitored among patients at high risk and requires aggressive management to improve long-term survival. PMID- 30476611 TI - Peripheral Blood Mononuclear Cells Therapy For Treatment of Lower Limb Ischemia In Diabetic Patient: It is really true? PMID- 30476612 TI - Functional results of cervical rib resection for thoracic outlet syndrome: impact on professional activity. AB - OBJECTIVE: The aim of this study is to report long-term functional results following cervical rib (CR) resection for thoracic outlet syndrome (TOS). METHODS: This monocentric study included all cases of resection of CR for TOS performed between January 2004 and December 2016. Data were retrospectively collected from the hospital electronic database including pre-operative symptoms and the evaluation of occupational well-being, intraoperative data, and early clinical evaluation and occupational well-being during the post-operative period. Patients were categorized as neurogenic TOS (NTOS), arterial TOS (ATOS), arterial and neurogenic (ANTOS), venous TOS (VTOS) or asymptomatic according to preoperative evaluation. We evaluated the improvement in work life between the preoperative and the post-operative period. Further assessment was a negative Roos or elevated arm stress test (EAST) during the post-operative period. RESULTS: Thirty-three patients with a median age of 38.5 years (30-46) were included. Thirty-six procedures were performed: 33 % to treat ATOS (12/36), 39% for NTOS (14/36), 19% for ANTOS (7/36), 3% for VTOS (1/36) and 6% (2/36) for asymptomatic lesions. There were 9 cases of subclavian artery aneurysms leading to additional arterial repair. Due to distal embolization, a cervical sympathectomy was associated in 5 procedures. First rib resection (FRR) was associated in 4 procedures (11%) and C7 transverse process resection was performed in 15 procedures (42%). The technical success rate was 100% and intra operative complications were observed in 4 patients (11%) with favorable postoperative outcomes. During the early postoperative period, 3 Claude Bernard Horner's syndrome and 1 asymptomatic subclavian dissection were detected. Late complications included 2 bypass thromboses (6%) at 6 weeks and 16 months. Post operative EAST improved in 16 limbs (44%). Prior to the procedure, only 27% (9/33) patients had normal work lives. After the procedure, 64% (21/33) of patients were able to return to their normal work activity. CONCLUSION: Cervical rib resection for TOS seems to be a safe procedure leading to good short and long term clinical results with a favorable impact on recovering a normal work life in these young patients. PMID- 30476613 TI - Fourth time redo common femoral vein reconstruction with a novel hybrid technique. AB - INTRODUCTION: Iliofemoral vein thrombosis can lead to debilitating edema and venous claudication that significantly worsens quality of life, especially in young active individuals. Venous reconstruction becomes increasingly complex and has worsening patency with subsequent revisions so preoperative planning is critical to success. METHODS: We report a case of a 54 year-old man in active military service with profoundly symptomatic leg swelling after failure of three previous common femoral vein (CFV) reconstructions. The CFV and distal external iliac vein were thrombosed up to a few centimeters above the inguinal ligament. Direct proximal control would have required a retroperitoneal or transabdominal incision. However, a hybrid approach utilizing through-wire access, remote balloon control of the external iliac vein, cryopreserved vein graft, stent graft, and arteriovenous fistula (AVF) was able to address the factors (graft size, external compression, adequate flow) contributing to his previous graft failures with a novel, less invasive approach. RESULTS: At one-year follow-up, he was asymptomatic and the graft remained patent with normal vascular duplex studies. His leg swelling subsided and he was able to return to his previous physical activity level. CONCLUSIONS: A hybrid approach to complex venous reconstruction can provide a minimally invasive and durable alternative to more invasive procedures and alleviate mechanical causes of early graft failure. PMID- 30476614 TI - Trends and Outcomes of Pediatric Vascular Injuries in the United States: an Analysis of the National Trauma Data Bank. AB - BACKGROUND: According to the Center for Disease Control and Prevention, trauma is the leading cause of death in children >1 year in the United States (US). Although vascular injuries occur in only 0.6-1% of pediatric trauma patients, they are a major mortality contributor. This study aims to examine epidemiology and outcomes after pediatric vascular injuries (Ped VIs) in the US. METHODS: National Trauma Data Bank (2002-2012) was queried to identify children (0-16) with PedVIs. Patients were categorized based on their demographics, locations and mechanisms and presenting trauma severity (injury severity score (ISS) and shock). Study was divided into two 5-year periods (P1:2002-2006, P2:2007-2012) to study the trends in pediatric vascular trauma presentation and outcomes (hospital death and extended length of stay (LOS >8 days) using adjusted analyses. RESULTS: Analyses were performed on 3408 cases; male (73.7%) and Caucasian (52.8%) with mean age of 10.5+/-4.5 years. US Southern region saw the highest increase in PedVIs (P2 vs P1:38.3% vs. 25.0%, p<0.05). Blunt injuries constituted the majority of these injuries (57%). Firearm (36.9%) and motor vehicle crash (MVC) (34%) were the most common lethal mechanisms of injury. Despite the significant decrease in MVC rates (P2 vs. P1:17.4% vs. 22.6%, p<0.05), firearm rates were unchanged. Upper extremity injuries were the most common anatomically (34.9%). ISS and shock were significantly decreased during P2. Mortality occurred in 7.9% of patients which was significantly decreased (P2 vs. P1:6.3% vs. 10.9%, p<0.001) without a significant change in LOS. Odds of mortality decreased by 32% during P2 (p=0.08) and was independently associated with penetrating mechanism of injury (Odds Ratio (OR): 1.97; 95% confidence Interval (CI): 1.22-3.19, p=0.006); shock at presentation (OR:5.48; 95% CI: 3.55-8.46, p<0.001); ISS (OR:1.08; 95% CI: 1.06 1.27, p<0.001) and Glasgow Coma Score (GCS) <9 (OR:11.21; 95% CI:7.18-17.49, p<0.001). CONCLUSIONS: We observed a significant decrease in the overall severity of injury and in-hospital mortality concurrent with the observation of a significant decrease in the rates of pediatric MVC vascular injuries. Public health policies directed toward firearm safety may further decrease PedVIs and mortality among this vulnerable population. PMID- 30476615 TI - Psoas muscle area and quality are independent predictors of survival in patients treated for abdominal aortic aneurysms. AB - BACKGROUND: Sarcopenia is associated with mortality after abdominal aortic aneurysm (AAA) repair. The reliability of computed tomography (CT) core muscle areas and quality i.e. densities and their association with postoperative survival in patients undergoing AAA treatment were retrospectively studied. METHODS: Psoas and multifidus areas (PMA, MFA) and densities (PMD, MFD) were measured from CT images and analysed to lean values. Results were standardized by z-scoring. Measurement reliability was ascertained using intraclass correlation coefficient (ICC) analysis (three independent observers). Clinical data was collected from an institutional database and the hospital's patient record database. RESULTS: The study included 301 patients (89% male, mean age 74.4 years, endovascular treatment 73.1%, rupture 7.6%). Median duration of follow-up was 2.70 (IQR 3.54) years and mortality 31.2%. Age, female gender, and BMI were associated with PMA, PMD and lean psoas muscle area (LPMA). L3 left PMD, total psoas muscle density (TPMD), right and left LPMA, lean total psoas muscle area (LTPMA) and L2 right LPMA and LTPMA (HR 0.74-0.78 per one standard deviation, P<.05 - P<.01) were independently associated with improved survival in multivariable analysis. CONCLUSIONS: L2-L3 PMD and LPMA are reliable, feasible and independent predictors of mortality in patients treated for AAA. For every standard deviation increase in these standardized z-score muscle parameters, there was a 22% - 26% decrease in the probability of death during follow-up. PMID- 30476616 TI - Covered Stent-Assisted Open Surgery in the Treatment of an Extracranial Carotid Artery Pseudoaneurysm. AB - Extracranial carotid artery pseudoaneurysms (ECAPs) are rare vascular lesions that, if untreated, can lead to severe neurologic deficits and significant mortality. Although conservative therapy, surgical ligation or reconstruction, and endovascular techniques can be curative, the literature demonstrates that the best therapy remains controversial and consensus is lacking. We report a case of a 53-year-old patient who developed a giant ECAP on the left side of her neck, which had been presented for 10 years and was successfully treated by covered stent-assisted open surgery. During the 6 months of follow-up, computed tomography angiography (CTA) confirmed complete occlusion of the ECAP and patency of the carotid artery. In addition to this report, a brief review of the literature is presented. PMID- 30476617 TI - Outcomes of Open Repair, Fenestrated Stent Grafting, and Chimney Grafting in Juxtarenal Abdominal Aortic Aneurysm: Is it Time for a Randomized Trial? AB - BACKGROUND: The well-established, gold standard treatment for juxtarenal abdominal aortic aneurysms (JAAA) is open repair (OR). However, endovascular treatment with fenestrated or chimney grafts has been increasingly performed in the past decade. This study compared the outcomes of OR with two endovascular methods in JAAA. METHODS: We retrospectively reviewed consecutive patients with JAAA who underwent OR (n = 32), repair with fenestrated stent grafts (FEVAR, n = 20), or chimney grafts (Ch-EVAR, n = 23) during the period from January 2011 to December 2016 at a single center. Our primary endpoint was perioperative mortality. Secondary endpoints included renal function impairment, new-onset dialysis, procedural details, and postoperative complications. Kaplan-Meier analysis was used to estimate freedom from late reintervention, primary patency of target vessel stent grafts, and overall survival. RESULTS: There were no significant differences between groups in baseline characteristics. Perioperative mortality was similar in all three groups (3.1% (1/32) in the OR group, 0% in the FEVAR group, and 4.3% (1/23) in the Ch-EVAR group. Mean follow-up duration was 36.7 months (range 1-75 months). There were no significant differences between groups regarding any of the secondary endpoints, except for blood loss (which was significantly greatest in the OR group), and there was no significant difference in overall survival. Estimated target vessel stent patency at 1 and 4 years was 93.8% and 93.8% in the FEVAR group, and 89.5% and 89.5% in the Ch-EVAR group. There was no significant difference between groups in estimated freedom from late reintervention (96.4% in the OR group, 77.2% in the FEVAR group, and 82.3% in the Ch-EVAR group). CONCLUSIONS: Open surgery is an acceptable and effective treatment for JAAA. However, FEVAR and Ch-EVAR also showed high technical success rates and low perioperative mortality, with acceptable reintervention rates during follow-up. PMID- 30476618 TI - Kinetic Elephant Trunk Technique, Early Results in Chronic Symptomatic Aortic Dissection Management. AB - OBJECTIVE: The aim was to expand our understanding of the dynamic evolution of the aorta throughout the dissection time course. We investigated how the disease process can be modulated to equalise lumen pressure, enhance perfusion, and stabilise the aorta along its entire length using the kinetic elephant trunk (kET) technique. TECHNIQUE: We performed the kET on nine patients with chronic symptomatic aortic dissection (CSAD) as a primary or secondary intervention regardless of the chronicity of the dissection. Endovascular scissoring of the intraluminal septum is performed in the infra-diaphragmatic dissected aorta to equalise pressure between true and false lumens, and allow all branched vessels to be supplied from one lumen. The Streamliner Multilayer Flow Modulator (SMFM), an uncovered cobalt-alloy aortic device, is deployed from the aortic sinus, covering the supra-aortic branches, distally into the distal aorta (primary intervention). In the case of a previous ascending aorta Dacron graft, the SMFM is deployed (secondary intervention) at the level of the Dacron graft so that it is overlapped with the graft, and landed in the distal aorta. RESULTS: In the initial study period, all-cause and aortic-related survival were 100%, respectively, all great vessels and visceral branches were patent, and freedom of stroke, end-organ ischaemia, paraplegia and renal failure were 100%. CONCLUSION: The kET is a treatment process for managing CSAD. Its simplicity, consistency and reproducibility in high-risk patients with low morbidity and mortality adds to the armamentarium of the cardiovascular specialist. Further assessment of the medium- and long-term outcomes is needed to fully establish benefits of kET. PMID- 30476619 TI - Individual variability in female and male mice in a test-retest protocol of the forced swim test. AB - BACKGROUND: The challenges to embody the complexity of symptoms and biological mechanism of affective disorders question the value of animal models as well as their reproducibility and validity. Validity is further hindered by large individual variability in many models. Whereas individual variability presents a challenge, it can also be used to study susceptibility and resistance. One of the frequently used models for screening antidepressants and interventions related to depression is the forced swim test (FST). The FST is typically performed only once. METHODS: The current study was designed with a number of objectives: (1) Examine the group effects of repeated FST (2) Examine the interaction between sex and repeated FST and (3) examine the consistency of individual variability across test and retest in the FST. We exposed ICR female and male mice to the FST 3 or 5 times with two days between exposures. Immobility time was analyzed across exposures at the group and the individual levels using repeated measures ANOVA as well as Pearson's correlations. RESULTS: As expected, repeated exposure to the FST resulted in increased immobility across exposures with no consistent effect of sex. At the level of individual mice, immobility time showed correlation across exposures. DISCUSSION: The current study demonstrates the effects of repeating the FST in both sexes with attention to individual variability. The results suggest that the FST can be used more than once and that mice show a consistent individual pattern of responding in the test. PMID- 30476620 TI - Influence of incubation conditions on microsomal metabolism of xanthine-derived A1 adenosine receptor ligands. AB - INTRODUCTION: In vitro metabolism models such as liver microsomes represent an important tool for the development of novel radioligands. Comparability and physiological relevance of in vitro metabolism data critically depend on the careful evaluation and optimization of assay protocols. We therefore investigated the influence of incubation conditions on the microsomal stability of xanthine derived A1 adenosine receptor (A1AR) ligands which have been developed for positron emission tomography (PET). METHODS: Substrate depletion assays using rat liver microsomes (RLM) were performed for three analogous compounds which differ with regard to the metabolically vulnerable substituent at the xanthine C8 position. Incubation conditions were varied systematically. Additionally, the stability of the cofactor NADPH during incubation was investigated. RESULTS: Microsomal metabolism was strongly influenced by buffer pH, organic solvents and preincubation time. Substrate depletion values varied up to 5-fold depending on incubation matrix composition, however, the rank order of metabolic stability remained unchanged. Prolonged incubation periods led to drastic loss in enzyme activity which could not be prevented by addition of metal chelators or antioxidants. Cofactor NADPH was rapidly oxidized in microsomal matrix, even in the absence of cytochrome P450 substrates. DISCUSSION: In summary, short incubation times, precise pH control and minimal concentrations of organic solvents are mandatory to obtain reliable microsomal stability data. Furthermore, in vitro metabolic stability of the tested A1AR ligands varied largely depending on the particular C8 substituent. Consequently, structural modifications at the xanthine C8 position appear to be a promising strategy for the improvement of A1AR PET radioligands. PMID- 30476621 TI - A novel experimental intraperitoneal infection model for Haemophilus parasuis in neutropenic guinea pigs. AB - INTRODUCTION: Haemophilus parasuis, one of the major swine pathogens, has at least fifteen different types, all of which have significant economic effects on the global swine industry. The aim of this study was to establish an experimental intraperitoneal infection model for H. parasuis in neutropenic guinea pigs. METHODS: Intraperitoneal administration of cyclophosphamide and Haemophilus parasuis was conducted in guinea pigs. Clinical signs, gross pathology, and histopathology were observed in neutropenic guinea pigs infected with H. parasuis. RESULTS: Intraperitoneal administration of 100 mg/kg cyclophosphamide led to immunosuppression with white blood cells, lymphocytes, and neutrophils all <1000 mm3, while no histological tissue damage was observed. Intraperitoneal administration of 109 colony-forming units (CFU) of H. parasuis led to typical respiratory symptoms, 90% morbidity, and 20% mortality in a 72 h-period. Bacteriological screening revealed that multiple organs, including the heart, liver, spleen, lungs, kidneys, and blood, were infected with H. parasuis. The threshold loads of bacteria in blood and the lungs were (7.04 +/- 0.53)log10 CFU/mL and (6.24 +/- 0.62)log10 CFU/g, respectively, at 3 d after infection. Gross pathology examination showed celiac effusion, intestinal mucosal hemorrhage, and liver, spleen, or lung swelling, necrosis, and hemorrhage. Congestion, mild interstitial pneumonia, inflammatory exudation, and endothelial cell proliferation were observed in the histological examination. DISCUSSION: All the results suggest that we have established an experimental intraperitoneal infection model for H. parasuis in neutropenic guinea pigs. It is especially useful as a tool for pharmacokinetics, pharmacodynamics, or a pharmacokinetics/pharmacodynamics (PK/PD) model of antimicrobial agents against respiratory disease. PMID- 30476622 TI - Relative equivalence of CNS safety (FOB) assessment outcomes in male and female Wistar-Han and Sprague-Dawley rats. AB - In 2006 the National Toxicology Program (NTP) of the FDA shifted to the preferred use of Wistar-Han rats from the more commonly used Sprague-Dawley (SD) strain - and industry followed. While European laboratories preferred the Wistar-Han line, there was a paucity of relevant historical control data in many US research institutions for the new "industry standard" rat strain. In 2010 the NTP reversed its decision and shifted back to SD rats because of reproductive issues with the Wistar strain. For post hoc comparative analyses, we report minimal practical differences in Functional Observational Battery (FOB) data from a large sample of male and female Wistar-Han and SD rats. In summarizing data from the preclinical safety evaluations of the CNS effects of new drugs using the FOB, it is crucial to understand the value of not only how the functional expression of drug effects in the rat are predictive of the human response, but also how and why they differ. What we can predict from the behavioral and physiological response of the designated test system to drug administration is the foundation of "generalizability" to the human's response. Here, we conclude that the use of either SD or WH rat strains in standard CNS safety studies provide equivalent supportive data for CNS safety assessment required for IND approval under the harmonized guidelines. PMID- 30476623 TI - A novel high-content imaging-based technique for measuring binding of Dickkopf-1 to low-density lipoprotein receptor-related protein 6. AB - INTRODUCTION: Dickkopf-related protein 1 (Dkk1) is a secreted protein ligand of low-density lipoprotein receptor-related protein 6 (LRP6), which antagonises canonical Wnt signalling. Elevated Dkk1 levels have been linked to Alzheimer's disease (AD), with protein blockade protective in pre-clinical AD models, suggesting inhibitors of Dkk1-LRP6 binding may have therapeutic utility against AD. Cell-based Dkk1-LRP6 assays reported in the literature use either modified Dkk1 protein and/or do not possess suitable throughput for drug screening. Here we report a novel immunocytochemical-based assay utilising high-content imaging (HCI) and automated data analysis suitable for the screening of protein and small molecule inhibitors of Dkk1-LRP6 binding. METHODS: We developed an immunocytochemical (ICC) protocol to detect specific binding of exogenous human Dkk1 protein to human LRP6 transiently expressed in HEK293 cells. Images were generated using the PerkinElmer Operetta HCI System, after which quantitative data was generated using the PerkinElmer ColumbusTM System. RESULTS: Our ICC technique and analysis pipeline allowed measurement of cell membrane-localised, LRP6-specific Dkk1 binding, normalised at individual cellular events. Saturation binding demonstrated concentration-dependent Dkk1 binding to LRP6, with a KD in keeping with reported values. Association kinetic experiments demonstrated the utility of the technique to investigate Dkk1 binding kinetics. Human Dkk members Dkk2 and Dkk4 fully displaced Dkk1 binding in a competition assay, while Dkk3 and Soggy-1/DkkL1 exhibited non-complete displacement of Dkk1. Finally gallocyanine, a previously reported inhibitor of Dkk1-LRP6 binding, fully displaced Dkk1 near the expected IC50. DISCUSSION: In conclusion, we provide a validated cell-based assay, suitable for the screening of inhibitors of Dkk1-LRP6 binding, and provide the basis for additional assay development, investigating Dkk1-LRP6 pharmacology. PMID- 30476624 TI - Advances in gradient echo myelin water imaging at 3T and 7T. AB - Gradient echo myelin water imaging (GRE-MWI) is an MRI technique to measure myelin concentration and involves the analysis of signal decay characteristics of the multi-echo gradient echo data. The method provides a myelin water fraction as a quantitative biomarker for myelin. In this work, a new sequence and post processing methods were proposed to generate high quality GRE-MWI images at 3T and 7T. In order to capture the rapidly decaying myelin water signals, a bipolar readout GRE sequence was designed with "gradient pairing," compensating for the eddy current effects. The flip angle dependency from the multi-compartmental T1 effects was explored and avoided using a 2D multi-slice acquisition with a long TR. Additionally, the sequence was tested for the effects of inflow and magnetization transfer and demonstrated robustness to these error sources. Lastly, the temporal and spatial B0 inhomogeneity effects were mitigated by using the B0 navigator and field inhomogeneity corrections. Using the method, high quality myelin water images were successfully generated for the in-vivo human brain at both field strengths. When the myelin water fraction at 3T and 7T were compared, they showed a good correlation (R2>= 0.88; p < 0.001) with a larger myelin water fraction at 7T. The proposed method also opens the possibility of high resolution (isotropic 1.5 mm resolution) myelin water mapping at 7T. PMID- 30476626 TI - A narrative overview of the patients' outcomes after multigene cancer panel testing, and a thorough evaluation of its implications for genetic counselling. AB - Massively parallel sequencing is being implemented in clinical practice through the use of multigene panel testing, whole exome sequencing and whole genome sequencing. In this manuscript we explore how the use of massively parallel sequencing, and in particular multigene cancer panel testing, is potentially changing the process of genetic counselling and how patients cope with pre-test genetic counselling and results. We found that the main challenges are around uncertainty, hopes and expectations and the amount and complexity of information that needs to be discussed. This may impact the process of genetic counselling, although genetic counsellors can still use their core skills and enhance some of them in order to evolve and meet patients' needs in the genomics era. Available data suggests that patients can cope with multigene cancer panels although more research is needed to fully understand the psychosocial implications of multigene cancer panels for patients, especially for those who have variants of unknown significance or moderate penetrance variants. Research is also needed to explore and develop communication models that maximize patients' understanding and empower them to make informed decisions. PMID- 30476625 TI - Neural activity in human visual cortex is transformed by learning real world size. AB - The way that our brain processes visual information is directly affected by our experience. Repeated exposure to a visual stimulus triggers experience-dependent plasticity in the visual cortex of many species. Humans also have the unique ability to acquire visual knowledge through instruction. We introduced human participants to the real-world size of previously unfamiliar species, and to the functional motion of novel tools, during a functional magnetic resonance imaging scan. Using machine learning, we compared activity patterns evoked by images of the new items, before and after participants learned the animals' real-world size or tools' motion. We found that, after acquiring size information, participants' visual activity patterns for the new animals became more confusable with activity patterns evoked by similar-sized known animals in early visual cortex, but not in ventral temporal cortex, reflecting an influence of new size knowledge on posterior, but not anterior, components of the ventral stream. In contrast, learning the functional motion of new tools did not lead to an equivalent change in recorded activity. Finally, the time-points marked by evidence of new size information in early visual cortex were more likely to show size information and greater activation in the right angular gyrus, a key hub of semantic knowledge and spatial cognition. Overall, these findings suggest that learning an item's real-world size by instruction influences subsequent activity in visual cortex and in a region that is central to semantic and spatial brain systems. PMID- 30476627 TI - LHFPL5 mutation: A rare cause of non-syndromic autosomal recessive hearing loss. AB - Hearing loss is a debilitating disorder that impairs language acquisition, resulting in disability in children and potential isolation in adulthood. Its onset can have a genetic basis, though environmental factors, which are often preventable, can also cause the condition. The genetic forms are highly heterogeneous, and early detection is necessary to arrange appropriate patient support. Here we report the molecular basis of hereditary hearing loss in a consanguineous family with multiple affected members from Oman. Combining homozygosity mapping with whole exome sequencing identified a novel homozygous nucleotide substitution c.575T > C in the lipoma HMGIC fusion partner-like 5 gene (LHFPL5), that converted the 192nd amino acid residue in the protein from a leucine to a proline, p.(Leu192Pro). Sanger sequencing confirmed segregation with the disease phenotype as expected for a recessive condition and the variant was absent in 123,490 subjects from various disease-specific and population genetic studies as well as 150 unrelated individuals and 35 deaf patients of Omani ethnicity. This study, which describes a novel LHFPL5 mutation in a family of Omani origin with hereditary hearing loss, supports previous clinical descriptions of the condition and contributes to the genetic spectrum of mutations in this form of deafness. PMID- 30476628 TI - Attitudes of publics who are unwilling to donate DNA data for research. AB - With the use of genetic technology, researchers have the potential to inform medical diagnoses and treatment in actionable ways. Accurate variant interpretation is a necessary condition for the utility of genetic technology to unfold. This relies on the ability to access large genomic datasets so that comparisons can be made between variants of interest. This can only be successful if DNA and medical data are donated by large numbers of people to 'research', including clinical, non-profit and for-profit research initiatives, in order to be accessed by scientists and clinicians worldwide. The objective of the 'Your DNA, Your Say' global survey is to explore public attitudes, values and opinions towards willingness to donate and concerns regarding the donation of one's personal data for use by others. Using a representative sample of 8967 English speaking publics from the UK, the USA, Canada and Australia, we explore the characteristics of people who are unwilling (n = 1426) to donate their DNA and medical information, together with an exploration of their reasons. Understanding this perspective is important for making sense of the interaction between science and society. It also helps to focus engagement initiatives on the issues of concern to some publics. PMID- 30476629 TI - Molecular analysis of 19 Spanish patients with mixed porphyrias. AB - Porphyrias are rare diseases caused by alterations in the heme biosynthetic pathway. Depending on the afected enzyme, porphyrin precursors or porphyrins are overproduced, causing acute neurovisceral attacks or dermal photosensitivity, respectively. Hereditary Coproporphyria (HCP) and Variegate Porphyria (VP) are mixed porphyrias since they can present acute and/or cutaneous symptoms. These diseases are caused by a deficiency of coproporphyrinogen oxidase (CPOX) in HCP, and protoporphyrinogen oxidase (PPOX) in VP. Herein, we studied nineteen unrelated Spanish patients with mixed porphyrias. The diagnosis of either, HCP or VP was made on the basis of clinical symptoms, biochemical findings and the identification of the mutation responsible in the CPOX or PPOX genes. Two patients presented both acute and cutaneous symptoms. In most patients, the biochemical data allowed the diagnosis. Among eleven patients with HCP, ten CPOX mutations were identified, including six novel ones: two frameshift (c.32delG and c.1102delC), two nonsense (p.Cys239Ter and p.Tyr365Ter), one missense (p.Trp275Arg) and one amino acid deletion (p.Gly336del). Moreover, seven previously described PPOX mutations were identified in eight patients with VP. The impacts of CPOX mutations p.Trp275Arg and p.Gly336del, were evaluated using prediction softwares and their functional consequences were studied in a prokaryotic expression system. Both alterations were predicted as deleterious by in silico analysis. Aditionally, when these alleles were expressed in E. coli, only p.Trp275Arg retained some residual activity. These results emphasize the usefulness of integrated the biochemical tests and molecular studies in the diagnosis. Furthermore, they extend knowledge on the molecular heterogeneity of mixed porphyrias in Spain. PMID- 30476630 TI - On-road bicycle lane types, roadway characteristics, and risks for bicycle crashes. AB - Bicycle lanes reduce real and perceived risks for bicycle vs. motor vehicle crashes, reducing the burden of traffic injuries and contributing to greater cycling participation. Previous research indicates that the effectiveness of bicycle lanes differs according to roadway characteristics, and that bicycle lane types are differentially associated with reduced crash risks. The aim of this study is to combine these perspectives and identify the types of on-road bicycle lanes that are associated with the greatest reductions in bicycle crashes given the presence of specific roadway characteristics. We compiled a cross sectional spatial dataset consisting of 32,444 intersection polygons and 57,285 street segment polygons representing the roadway network for inner Melbourne, Australia. The dependent measure was a dichotomous indicator for any bicycle crash (2014 2017). Independent measures were bicycle lanes (exclusive bicycle lanes, shared bicycle and parking lanes, marked wide kerbside lanes, and kerbside bicycle lanes) and other roadway characteristics (speed limit, bus routes, tram routes, bridges, one-way flow, traffic lane width). In Bayesian conditional autoregressive logit models, bicycle lanes of all types were associated with decreased crash odds where speeds were greater, bus routes and tram stops were present, and traffic lanes were narrower. Only exclusive bicycle lanes were associated with reduced crash odds (compared to the expected odds given the presence of the bicycle lane and the roadway conditions) in all these setting. The extent to which on-road bicycle lanes reduce crash risks depends on the bicycle lane type, the roadway conditions, and the combination of these two factors. Bicycle lanes that provide greater separation between cyclists and vehicular traffic are most consistently protective. PMID- 30476631 TI - Prevalence of junctional ST-depression with tall symmetrical T-waves in a pre hospital field triage system for STEMI patients. AB - INTRODUCTION: The prevalence of the junctional ST-depression with tall symmetrical T-waves in a field triage system for ST-Elevation Myocardial Infarction (STEMI) is unknown. MATERIAL AND METHODS: We prospectively collected all transmitted 12-lead electrocardiograms (ECGs) from the STEMI field triage system in Amsterdam from 2011 to 2013. Electrocardiograms with junctional ST depression with tall symmetrical T-waves were recognized and angiographic documentation and clinical follow up were collected. RESULTS: A total of 5588 patients with at least 1 transmitted field ECG were identified from the database. ST-elevation infarction was present on the field ECG in 1864 patients (33%) and 701 ECGs (12,5%) showed anterior infarction. In 11 patients, junctional ST depression with tall symmetrical T-waves was identified (0,2% of total transmitted ECGs and 1,6% of anterior infarctions). The 11 angiograms invariably showed involvement of the proximal Left Anterior Descending (LAD) artery (segment 5,6 and 7). Mortality was 27% within the first week. CONCLUSIONS: An ECG with junctional ST-depression with tall symmetrical T-waves is an infrequent finding. Because this pattern of STEMI equivalent is associated with LAD occlusions, it is important to recognize this pattern, so patients can be transported to the catheterization laboratory without delay. PMID- 30476632 TI - Atrial flutter and embolic risk: The relationship between atrial flutter cycle length and left atrial appendage function. AB - BACKGROUND: The potential for thromboembolism in atrial flutter (AFL) is different from atrial fibrillation. AFL cycle length (AFL-CL) may be related to reduced left atrial appendage (LAA) function. Very rapid AFL-CL can lead to mechanical and electrophysiological disorders that contribute to lower LAA emptying velocity (LAEV). The aim of this study is to relate atrial flutter cycle length with LAEV and its role in thrombogenesis. METHODS: Cross-sectional study of patients with atrial flutter AFL who underwent transoesophageal echocardiography (TEE) before catheter ablation or electric cardioversion. AFL-CL in milliseconds was measured with a 12-lead EKG or in intracardiac records. RESULTS: We included 123 patients. There was correlation between AFL-CL and LAEV (r = 0.34; p = 0.003) in typical AFL. Cycle length, LA size and atypical flutter were predictors of low LAEV on multivariate analysis. An index multiplying atrial rate (bpm) during the arrhythmia versus left atrial size(mm) >11,728 was associated with spontaneous echogenic contrast and/or left atrial thrombus on TEE (C-statistic = 0.71; CI95%0.60-0.81). CONCLUSIONS: There was a significant relationship between the AFL-CL and LAEV. The LAEV was affected by the LA size, the type of atrial flutter and the AFL-CL. A new index, relating the atrial rate with the left atrial size, was able to identify a higher occurrence of spontaneous echogenic contrast and/or left atrial thrombus. PMID- 30476633 TI - Long-term prognostic significance of terminal QRS distortion on patients with stemi and its correlation with the GRACE scoring system. PMID- 30476634 TI - Continuous heart rate monitoring for automatic detection of atrial fibrillation with novel bio-sensing technology. AB - BACKGROUND: Asymptomatic atrial fibrillation [AF] is an important cause of fatal or disabling stroke. A continuous heart-rate monitoring device, comfortable enough to be worn continuously and reliable enough to detect AF, would allow for prompt initiation of anticoagulation therapy to prevent stroke. METHODS: We studied a new custom-made wearable photo-plethysmograph [PPG] wrist-watch sensor, specifically designed for continuous heart rate monitoring and incorporating contact and motion noise-filters. We tested its ability to automatically detect AF in patients undergoing elective cardioversion of AF, using simultaneously recorded electrocardiogram [ECG] as gold standard. RESULTS: A total of 18,608 consecutive R-R-interval measurements were recorded simultaneously with PPG and ECG in 20 patients, including 12,521 [67.3%] R-R-intervals during AF and 6087 [32.7%] R-R intervals during sinus rhythm. Scatter plots and Bland-Altman plots demonstrated that the PPG signals were highly correlated to the simultaneously recorded ECG [R = 0.980, p < 0.001], both during AF and during sinus rhythm. The automatic algorithm distinguished AF from sinus rhythm with a sensitivity of 100% and specificity of 93.1%. CONCLUSIONS: This PPG-based wrist-watch sensor reliably detected AF in non-ambulatory patients. PMID- 30476635 TI - Electrocardiographic changes after implantation of a left ventricular assist device - Potential implications for subcutaneous defibrillator therapy. AB - BACKGROUND: Implantation of a left ventricular assist device (LVAD) leads to a diverse spectrum of changes on the twelve-lead surface electrocardiogram (ECG). We aimed to elucidate the changes of the surface ECG in patients after LVAD implantation potentially impacting ECG based screening tests of subcutaneous implantable cardioverter-defibrillators (S-ICD). METHODS: Patients from 2005 until 2017 with a documented twelve-lead ECG before and after LVAD implantation were included. Baseline parameters were obtained through hospital records. The twelve-lead ECGs registered before and after LVAD implantation were analyzed. RESULTS: From 415 patients undergoing an LVAD implantation, complete datasets were available for 253 patients. 216 patients (85%) were male. Mean age at time of LVAD implantation was 54.7 +/- 12.4 years. The underlying etiology was ischemic cardiomyopathy in 119 (47%), dilated cardiomyopathy in 112 (44%), myocarditis in 8 (3%) and other in 14 (6%). We observed a reduction in the amplitude of the R wave in lead I (p < 0.0001), lead II (p < 0.0001), lead III (p < 0.004), lead aVL (p < 0.001) and lead aVF (p < 0.0001) as well as of the S wave in lead III (p < 0.001) and lead aVR (p < 0.0001) after LVAD implantation. We also noticed a reduction of the R:T ratio in lead I (p < 0.0001) as well as in lead II (p = 0.100) and lead aVF (p = 0.292) although statistically non significant. CONCLUSION: LVAD implantation leads to significant alterations of the surface ECG, especially the R:T ratio in leads I, II and aVF. These leads correlate with the vectors of the ECG based S-ICD screening test. Thus, these ECG changes may impact the continuous eligibility for subcutaneous ICD therapy in patients after LVAD implantation. PMID- 30476636 TI - Case report: Apical variant hypertrophic cardiomyopathy simulating an acute inferior myocardial infarction. AB - We present a female patient who arrived to the emergency department with chest pain without known medical history at the time of consultation. Considering her risk factors and electrocardiographic findings, it was decided to perform a coronary catheterization under the suspicion of acute myocardial infarction. The catheterization and another studies was negative for coronary artery disease. Additional studies were conclusive for apical variant hypertrophic cardiomyopathy or Yamaguchi syndrome. PMID- 30476637 TI - Association between T-wave discordance and the development of heart failure in left bundle branch block patients: Results from the Copenhagen ECG study. AB - BACKGROUND: In left bundle branch block (LBBB), discrepancies between depolarization and repolarization of the heart can be assessed by similar direction (concordant) or opposite direction (discordant) of the lateral T-waves compared to the direction of the QRS complex and by the QRS-T angle. We examined the association between discordant T-waves and high QRS-T angles for heart failure development in primary care LBBB patients. METHODS: Between 2001 and 2011, we identified 2540 patients from primary care with LBBB without overt heart failure. We examined the development of heart failure in relation to two ECG measures: (1) LBBB as either discordant (two or three monophasic T-waves in the opposite direction of the QRS complex in leads I, V5 or V6) or concordant, and (2) the frontal plane QRS-T angle in quartile groups. RESULTS: In total, 244 of 913 patients (26.7%) with discordant LBBB developed heart failure compared to 302 of 1627 patients (16.7%) with concordant LBBB. Multivariable Cox regression comparing discordant with concordant LBBB showed a hazard ratio (HR) of 2.58 (95% Confidence interval [CI] 1.71-3.89) for heart failure development within 30 days of follow-up and a HR of 1.45 (95%CI 1.19-1.77) after 30 days. For QRS-T angle, comparing the highest quartile (160 degrees -180 degrees ) with the lowest quartile (0 degrees -110 degrees ) we found a HR of 2.25 (95%CI 1.26-4.02) within 30 days and a HR of 1.67 (95%CI 1.25-2.23) after 30 days. CONCLUSION: T-wave discordance in lateral ECG leads and a high QRS-T angle are associated with heart failure development in primary care LBBB patients. PMID- 30476638 TI - Poor reliability of P-wave terminal force V1 in ischemic stroke. AB - INTRODUCTION: Several ECG markers are postulated to represent underlying atrial remodelling and have been associated with ischemic stroke. P-wave terminal force in lead V1 (PTFV1) is one such marker. We examined the factors that contribute to the reliability of PTFV1 and its association with ischemic stroke. MATERIAL AND METHODS: Four hundred and thirty-five patients that presented with an ischemic stroke or transient ischemic attack (TIA) were identified through a prospectively maintained multi-site institutional stroke database. Control group consisted of age matched patients without prior history of an ischemic stroke or TIA. All patients underwent a 12-lead ECG and 24-hour Holter monitoring during the study period to exclude atrial fibrillation. RESULTS: Morphology consistent with PTFV1 occurred commonly in both the stroke/TIA and control groups. There was no significant difference in the median PTFV1 value between the stroke 3.96 mV ms [Interquartile range (IQR) 2.78-5.58] and control 4.23 mV ms [IQR 2.91-5.57] groups. Measurements of PTFV1 demonstrated excellent intra-observer reliability on assessment of the same P-wave (Intra class correlation (ICC) 0.91, p < 0.001) with narrow limits of agreement 2.21 to -2.95 mV ms. A change in the P wave assessed led to a significant reduction in reliability (ICC 0.79, p < 0.001). Inter-observer, inter P-wave assessment demonstrated further reduction in reliability (ICC 0.68, p < 0.002) with wide limits of agreement 6.17 to -5.78 mV ms, indicating significant under and overestimation of PTFV1. CONCLUSION: The utility of PTFV1 as a clinical marker for ischemic stroke is limited by the reduction in reliability associated with inter-observer and inter P-wave measurements. PMID- 30476639 TI - Electrocardiographic characteristics before and after correction of right-sided congenital heart defects in children and its relation to prognosis. PMID- 30476640 TI - The predictive value of aVR in determining the infarct related artery during primary percutaneous coronary intervention. AB - BACKGROUND: Isolation of infract related artery and timely revascularisation remains vital in the setting of primary percutaneous coronary intervention. OBJECTIVES: To analyse the predictive value of ST-T changes in lead aVR in inferior myocardial infarction in terms of prognosis and timely risk stratification. METHODS: We conducted a prospective analysis of acute inferior wall myocardial infarction patients. One hundred patients were categorised into two groups according to the culprit artery: group I, right coronary artery (RCA) and group II, left circumflex coronary artery (LCX), with 50 patients in each group. A comparative study was performed between the two groups, comprising the following data outputs: electrocardiogram (ECG) changes that could help determine the culprit artery, cardiac enzyme levels, echocardiographic findings, coronary angiography findings and in-hospital complications. The same patients were divided into two groups according to the presence or absence of 1 mm ST depression in lead aVR. A comparison analysis was performed between the two groups including: cardiac enzyme levels, echocardiographic findings, coronary angiography findings and in-hospital complications. RESULTS: ST depression in aVR >= 1 mm predicted the LCX as a culprit artery with sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV) recorded at 66%, 84%, 80.5% and 71.2%, respectively. Also, patients with ST depression in aVR >= 1 mm showed significantly higher cardiac enzyme levels, indicating larger infarct size, with mean peak creatinine kinase (CK) = 1560 (1057-2375) IU/L versus 970 (613-1683) IU/L, (P value = 0.014), lower ejection fraction (Ef) with mean Ef = 47.93 +/- 8.04 versus 54.66 +/- 6.52, (P value < 0.001) and more significant mitral regurgitation: 17 (41.5%) patients versus 11 (18.6%) patients (P value = 0.012). Regarding in-hospital complications, there were no significant differences. CONCLUSIONS: ST depression of >1 mm in lead aVR predicts LCX as the infarct related artery and is a predictor of poor outcome in patients with inferior myocardial infarction. PMID- 30476641 TI - Shift in the retrograde atrial activation sequence after radiofrequency catheter ablation in left variant atypical atrioventricular nodal reentrant tachycardia. AB - The role of left AV nodal (SVN) connections in the genesis of "left-variant" atypical atrioventricular nodal reentrant tachycardia (AVNRT) and those with multiple retrograde pathways remain unclear. We describe an unusual case of "left variant" atypical AVNRT, where change in the retrograde earliest atrial activation site (REAAS) at the coronary sinus (CS) following radiofrequency catheter ablation (RFCA) was observed. Our observation suggests that the REAAS, that is, the left AVN connections, could participate in the formation of the reentrant circuit of "left-variant" atypical AVNRT. Furthermore, its atrial breakthroughs involved as a circuit of SVT could be (functionally) multiple. PMID- 30476643 TI - Flecainide overdose presenting with long QT and acute Takotsubo cardiomyopathy. PMID- 30476642 TI - A case of successful radiofrequency catheter ablation of ventricular tachycardia from the noncoronary cusp. AB - Idiopathic ventricular tachycardias (VTs) originating from the non-coronary cusp (NCC) are very rare. The previous reports suggested NCC-VTs were characterized by a narrower QRS duration and smaller III/II ratio than VTs originating from other coronary-cusps. We present a rare case of an NCC-VT with a local fragmented potential recorded at the NCC inconsistent with the known ECG characteristics of NCC-VTs. PMID- 30476644 TI - The role of heart rate variability, heart rate turbulence, and deceleration capacity in predicting cause-specific mortality in chronic heart failure. AB - BACKGROUND: The volume of regional denervated myocardium (D-M) on positron emission tomography has been recently suggested as a strong independent predictor of cause-specific mortality from sudden cardiac arrest (SCA) in chronic heart failure. We sought to evaluate whether ECG indices of global autonomic function predict risk of SCA to a similar degree as regional D-M. METHODS: Subjects enrolled in the Prediction of Arrhythmic Events using Positron Emission Tomography (PAREPET) study were included in this study. Patients completed a 24 hour Holter ECG at enrollment and were followed up at 3-month intervals. SCA events were adjudicated by two board-certified cardiologists. Other cardiovascular death events were classified as nonsudden cardiac death (NSCD). Eight measures of heart rate variability were analyzed: SDNN, RMSSD, low frequency (LF) and high-frequency (HF) power, heart rate turbulence onset and slope, and acceleration and deceleration capacity. We used competing risk regression to delineate cause-specific mortality from SCA versus NSCD. RESULTS: Our sample included 127 patients (age 67 +/- 12, 92% male). After a median follow up of 4.1 years, there were 22 (17%) adjudicated SCA and 18 (14%) adjudicated NSCD events. In multivariate Cox-regression, LF power was the only HRV parameter to predict time-to-SCA. However, in competing risk analysis, reduced LF power was preferentially associated with NSCD rather than SCA (HR = 0.92 [0.85-0.98], p = 0.019). CONCLUSION: Depressed LF power might indicate impaired vagal reflex, which suggests that increasing vagal tone in these patients would have a protective effect against NSCD beyond that achieved by the mere slowing of heart rate using beta-blockers. PMID- 30476645 TI - Unexpected reappearance of ST elevation in the anterior precordial leads shortly after an acute anterior myocardial infarction. PMID- 30476646 TI - Transient left septal fascicular block in a patient with stable effort angina and critical proximal obstruction of left anterior descending coronary artery. AB - Several publications from our group and others have shown that a main cause of middle fiber block or left septal fascicular block of the left bundle of His is proximal obstruction of the left anterior descending coronary artery, before its first septal perforator branch, since this fascicle is the only one of the three fascicles irrigated exclusively by this artery. We present a case in which the phenomenon occurred transiently, causing prominent anterior QRS forces, confirmed by coronary angiography. PMID- 30476647 TI - Lack of influence of sex hormones on Brugada syndrome-associated mutant Nav1.5 sodium channel. AB - Brugada syndrome (BS) is an autosomal dominant disease. The most common causes of BS are loss-of-function mutations occur in the SCN5A gene which encodes the sodium channel protein Nav1.5. BS has a higher incidence rate in males and the underlying mechanisms of the gender inequality are not yet fully understood. Considering sex hormones are among the most important factors behind gender differences and have previously been shown to regulate the activity of multiple cardiac ion channels, we hypothesized that sex hormones also affect Nav1.5 function which lead to BS predominantly affecting males. In this study, we investigate the protein expression level and current of Nav1.5 in the HEK293 cells cotransfected with SCN5A and sex hormone receptor plasmids using both wild type SCN5A and BS-associated SCN5A channel mutants R878C and R104W. Our findings showed that sex hormones have no effects on the protein expression level and current of the wild-type Nav1.5, neither does it affect the protein expression level and current of BS-associated Nav1.5 mutants R878C and R104W, regardless of homozygous or heterozygous state. Our results suggest that the male preponderance of BS does not arise from the effects of the sex hormones on Nav1.5. Further studies are needed to explain the male preponderance of this disease. PMID- 30476648 TI - A deep neural network learning algorithm outperforms a conventional algorithm for emergency department electrocardiogram interpretation. AB - BACKGROUND: Cardiologs(r) has developed the first electrocardiogram (ECG) algorithm that uses a deep neural network (DNN) for full 12-lead ECG analysis, including rhythm, QRS and ST-T-U waves. We compared the accuracy of the first version of Cardiologs(r) DNN algorithm to the Mortara/Veritas(r) conventional algorithm in emergency department (ED) ECGs. METHODS: Individual ECG diagnoses were prospectively mapped to one of 16 pre-specified groups of ECG diagnoses, which were further classified as "major" ECG abnormality or not. Automated interpretations were compared to blinded experts'. The primary outcome was the performance of the algorithms in finding at least one "major" abnormality. The secondary outcome was the proportion of all ECGs for which all groups were identified, with no false negative or false positive groups ("accurate ECG interpretation"). Additionally, we measured sensitivity and positive predictive value (PPV) for any abnormal group. RESULTS: Cardiologs(r) vs. Veritas(r) accuracy for finding a major abnormality was 92.2% vs. 87.2% (p < 0.0001), with comparable sensitivity (88.7% vs. 92.0%, p = 0.086), improved specificity (94.0% vs. 84.7%, p < 0.0001) and improved positive predictive value (PPV 88.2% vs. 75.4%, p < 0.0001). Cardiologs(r) had accurate ECG interpretation for 72.0% (95% CI: 69.6-74.2) of ECGs vs. 59.8% (57.3-62.3) for Veritas(r) (P < 0.0001). Sensitivity for any abnormal group for Cardiologs(r) and Veritas(r), respectively, was 69.6% (95CI 66.7-72.3) vs. 68.3% (95CI 65.3-71.1) (NS). Positive Predictive Value was 74.0% (71.1-76.7) for Cardiologs(r) vs. 56.5% (53.7 59.3) for Veritas(r) (P < 0.0001). CONCLUSION: Cardiologs' DNN was more accurate and specific in identifying ECGs with at least one major abnormal group. It had a significantly higher rate of accurate ECG interpretation, with similar sensitivity and higher PPV. PMID- 30476649 TI - Anti-melanogenesis potential of a new series of Morita-Baylis-Hillman adducts in B16F10 melanoma cell line. AB - Melanin is a natural polymer pigment which provides skin photoprotection against ultraviolet radiation. An excessive synthesis of melanin leads to hyperpigmentation disorders. Tyrosinase catalyzes the rate limiting steps on melanogenesis. Therefore, tyrosinase inhibitors have potential applications in medicine and cosmetic fields. We carried out herein the screening of a family of cyclic Morita-Baylis-Hillman adducts (MBH) to find out their effects on tyrosinase activity and on melanogenesis in murine melanoma B16F10 cell line. Kinetic analysis of tyrosinase inhibition showed that compounds 1a (2 hydroxymethyl) cyclohex-2-enone) and 3f (diethyl (1-(6-oxocyclohex-1-en-1-yl) ethyl-phosphonate) were competitive inhibitors, whereas the compound 2b (6 oxocyclohex-1-en-1-yl) ethyl acetate) was a non-competitive one. Additionally we have found that (1a, 2b and 3f) compounds had a strong melanogenesis inhibition effect in isobutylmethylxanthine (IBMX)-treated murine melanoma B16F10 cells when tested at low and non cytotoxic dose (10-50 uM), by attenuating the melanin production, intracellular tyrosinase activity and tyrosinase expression. Thus, we suggest that these compounds could be used as effective skin-whitening agents. PMID- 30476650 TI - An alkali tolerant alpha-l-rhamnosidase from Fusarium moniliforme MTCC-2088 used in de-rhamnosylation of natural glycosides. AB - Analkali tolerant alpha-l-rhamnosidase has been purified to homogeneity from the culture filtrate of a new fungal strain, Fusarium moniliforme MTCC-2088, using concentration by ultrafiltration and cation exchange chromatography on CM cellulose column. The molecular mass of the purified enzyme has been found to be 36.0 kDa using SDS-PAGE analysis. The Km value using p-nitrophenyl-alpha-l rhamnopyranoside as the variable substrate in 0.2 M sodium phosphate buffer pH10.5 at50 degrees C was 0.50 mM. The catalytic rate constant was15.6 s-1giving the values of kcat/Km is 3.12 * 104M-1 s-1. The pH and temperature optima of the enzyme were 10.5 and 50 degrees C, respectively. The purified enzyme had better stability at 10 degrees C in basic pH medium. The enzyme derhamnosylated natural glycosides like naringin to prunin, rutin to isoquercitrin and hesperidin to hesperetin glucoside. The purified alpha-l-rhamnosidase has potential for enhancement of wine aroma. PMID- 30476651 TI - Effects of mechanical thrombectomy for acute stroke patients with etiology of large artery atherosclerosis. AB - AIMS: Atherosclerosis is more prevalent in Asian population. This distinct etiology of stroke might disadvantage Asian patients when applying. mechanical thrombectomy (MT). The purpose of this research was to evaluate the efficacy and safety of MT in a cohort of Chinese patients with acute ischemic stroke. due to large artery atherosclerosis (LAA). METHODS AND RESULTS: A total of 649 patients treated with MT were included. Patients were classified according to etiology of stroke as LAA and cardioembolism ones. Successful revascularization was defined as modified Thrombolysis in Cerebral Infarction (mTICI) grade >= 2b. Favorable outcome was defined as modified Rankin Scale (mRS) score <= 2 at 90 days. Logistic regression was used to identify predictors for functional outcomes. The patients with stroke of LAA etiology had significantly higher rate of favorable functional outcome (50.2% vs 36.5%, p < .001) and good collateral (grade of ASITN/SIRI: 2-3) (58.8% versus 43.2%, p < .001), and lower median baseline National Institutes of Health Stroke Scale score (NIHSS) (15.6 versus 18.2, p < .001), compared to patients with stroke of cardioembolism etiology. There was no significant difference in the rate of successful postprocedural mTICI between groups (84.5% versus 83.2%, p = .671). Rates of symptomatic intracranial hemorrhage (20.0% versus 11.7%, p = .004) and mortality (31.8% versus 18.8%, p < .001) within 3 months were notably higher in the cardioembolism group than that in the LAA group. CONCLUSION: Mechanical thrombectomy may be more efficacious in treating acute ischemic stroke of LAA etiology than that of cardioembolism etiology. PMID- 30476652 TI - Long-Standing evolution of paraneoplastic cerebellar degeneration in a diffuse large B-cell lymphoma. PMID- 30476653 TI - Type A competitiveness traits correlate with downregulation of c-Fos expression in patients with type 1 diabetes. AB - AIM: Type A personality has been associated with increased survival in people with type 1 diabetes (T1D). Systemic low-grade inflammation may play a critical role, as suggested in recent reports, although the links between the inflammatory circulating transcriptome and Type A remain unknown. This prompted our exploration of the potential associations between Type A personality and c-Fos gene expression, a candidate gene closely linked to inflammatory processes, in T1D. METHODS: Type A personality was assessed by Bortner questionnaire in patients with T1D, and two subscales - 'speed' and 'competitiveness' - were used to measure these specific dimensions of Type A. Expression of the c-Fos gene was assessed by a quantitative real-time polymerase chain reaction technique. RESULTS: This pilot study included 20 men with T1D. Multivariable analyses showed an independent inverse association between Type A competitiveness score and c-Fos expression, while a regression model adjusted for age, body mass index and HbA1c levels revealed a significant inverse relationship between c-Fos transcripts and Type A competitiveness (P = 0.003). CONCLUSION: This strong association between Type A competitiveness and reduced c-Fos expression is in line with recent data suggesting a psychobiological influence of the Type A profile in T1D via inflammatory pathways. PMID- 30476654 TI - Colistin Monotherapy Versus Colistin and Rifampin Combination Therapy in Pneumonia Caused by Colistin-resistant Acinetobacter baumannii: A Randomized Controlled Trial. AB - OBJECTIVES: We aimed to confirm the synergistic effects of colistin and rifampin combination therapy compared to colistin monotherapy in pneumonia caused by colistin-resistant Acinetobacter baumannii (CoRAB). In addition, we aimed to assess the utility of the Epsilometer-test (E-test). METHODS: We enrolled 9 subjects who had pneumonia caused by CoRAB from July 20, 2016 to June 21, 2018. They were randomized to a colistin and rifampin combination therapy group or colistin monotherapy group. After exclusion of one patient dropped out, microbiological response (MR) and clinical response (CR) on day 14 and mortality on day 30 were assessed. The E-test was conducted using CoRAB isolated at enrollment. RESULTS: The MR rate in the colistin and rifampin combination group (100.0%) seems to be better than that in the colistin group (40.0%); however, it was not statistically significant. CR rate was not significantly different between the two groups. The MR rate (100.0%) and CR rate (100.0%) in subjects with "partial synergy," as proven by the E-test, was higher than those (25.0% and 50.0%, respectively) in subjects with "indifferent" results (it means no synergic effects); however, it was not statistically significant (P-value=0.143 and 0.429, respectively). Mortality occurred in 2 subjects who showed "indifferent" results, as proven by the E-test. CONCLUSIONS: Colistin and rifampin combination therapy may have potential to reach MR in pneumonia caused by CoRAB; however, reaching CR with this treatment method is doubtful. "Partial synergy" of colistin and rifampin, as proven by the E-test, can be a good prognostic factor. TRIAL REGISTRATION: ClinicalTrial.gov; No. NCT03622918, URL: www.clinicaltrials.gov. PMID- 30476655 TI - Preoperative Psychosocial and Psychophysical Phenotypes as Predictors of Acute Pain Outcomes after Breast Surgery. AB - The severity and impact of acute pain after breast surgery varies markedly among individuals, underlining the importance of comprehensively identifying specific risk factors, including psychosocial and psychophysical traits. In this prospective observational study, women (n=234) undergoing breast-conserving surgery, mastectomy, or mastectomy with reconstruction completed a brief bedside quantitative sensory testing (QST) battery, along with measures of psychosocial characteristics. Postoperative pain severity, impact, and opioid use at 2 weeks were assessed using Brief Pain Inventory (BPI) and procedure-specific breast cancer pain questionnaires. Moderate-severe average pain (>3/10) was reported by 29% of patients at 2 weeks. Regression analysis of pain outcomes revealed that pain severity was independently predicted by axillary dissection, pre-surgical pain, temporal summation of pain (TSP), (-)positive affect, and behavioral coping style. Pain impact was predicted by age, education, axillary dissection, reconstruction, but also by negative affect and depression scores. Lastly, opioid use was predicted by age, education, axillary dissection, reconstruction, TSP and reinterpreting coping style. Our findings suggest that, individuals with certain phenotypic characteristics, including high TSP and negative affect may be at greater risk of significant pain and continued opioid use at 2 weeks after surgery, independent of known surgical risk factors. Perspective: We measured differences in the psychosocial and psychophysical processing of pain amongst patients before breast surgery using simple validated questionnaires and brief quantitative sensory testing. Independent of younger age and procedural extent (axillary surgery and reconstruction), affect and greater temporal summation of pain predicted acute postoperative pain and opioid use. PMID- 30476656 TI - Minimally Invasive Sacroiliac Joint Fusion with Cylindrical Threaded Implants Using Intraoperative Stereotactic Navigation. AB - INTRODUCTION: Over the last decade there has been significant progress in hardware and surgical techniques for sacroiliac joint (SIJ) fusion surgeries, facilitating safer and more efficacious procedures for patients. Triangular shaped implants for SIJ fusions are the most studied devices of its kind and have demonstrated good short- and long-term clinical outcomes. There are very limited reports available, however, on cylindrical threaded implants. Due to the biomechanical differences in the implants and the surgical techniques required for their placement, previously reported results may not applicable to cylindrical threaded implants. The purpose of this study was to report our preliminary clinical experience with minimally invasive (MI) SIJ fusion using intraoperative stereotactic navigation and the Rialto SI Fusion System. METHODS: We retrospectively reviewed a total of 24 patients who underwent SIJ fusions between May of 2015 and October of 2017 performed by a single surgeon. RESULTS: The mean total satisfaction score was 89.0+/- 27.6%. A statistically significant reduction (p=0.0028) in low back pain scores was noted from an average baseline score of 6.6 +/- 2.4 to 3.7 +/- 3.3 postoperatively. Leg pain scores decreased from 4.8 +/- 3.8 to 1.5 +/- 2.9 (p=0.0034). The mean surgery time was 53.0 +/- 13.9 min. It took significantly longer (p=0.0089) to perform the initial 13 cases (59.9 +/- 15.2 min) compared with the subsequent cases (45.4 +/- 7.3 min). The EBL was minimal - 10.4 +/- 5.2 mL. CONCLUSION: Minimally invasive SI joint fusion using cylindrical threaded implants can be safely performed with minimal morbidity and good clinical outcomes. PMID- 30476657 TI - Rapid Progression of Metastatic Pan-spinal Epidural Non-Small Cell Lung Cancer Following Discontinuation of Alectinib. AB - BACKGROUND: Rapid progression of metastatic non-small cell lung cancer (NSCLC) following discontinuation of tyrosine kinase inhibitors (TKI) or anaplastic lymphoma kinase (ALK) inhibitors has been described and is associated with a poor prognosis. We describe the first reported case of accelerated NSCLC tumor extension throughout the entire spinal epidural space. CASE DESCRIPTION: A 68 year-old woman with stage IV ALK-positive metastatic NSCLC presented with acute neck pain, urinary retention, and lower extremity weakness 15 days following discontinuation of alectinib. MRI with contrast was significant for new compressive lesion spanning the entire cervical, thoracic, and lumbar spine which was new compared to MRI obtained 20 days prior and was suspicious for infection. Cervical (C3-C7), thoracic (T9-T12), and lumbar (L3-L5) decompression were performed with collection of culture and pathology specimens. Repeat MRI obtained for acute neurologic deterioration on postoperative day 2 noted further progression of disease and continued thoracic cord compression. Following urgent T1-9 laminectomy, specimens were again sent for pathology, cultures, and cytology. No evidence of infection was noted, and all pathologic specimens evaluated were consistent with metastatic adenocarcinoma. Despite operative intervention, the patient continued to decline, suffering from recurrent pleural effusions, and eventual cardiopulmonary arrest 11 days following admission. CONCLUSIONS: The differential diagnosis when evaluating presumed spine epidural abscess should include tumor and metastatic disease, even in cases of rapid development. Recent termination of TKI or ALK inhibitors may result in severe disease flares, and a history of such should raise clinical suspicion for metastatic progression. In addition to cultures, biopsy for pathologic diagnosis should be collected during decompressive surgery. PMID- 30476658 TI - Irreducible Posterior C1-2 dislocation with retrolisthesis of dens:-'hind-sights' from 10 cases. AB - BACKGROUND AND OBJECTIVES: The posterior C1-2 dislocation secondary to fracture of dens or os-odontoideum is uncommon. Little is known about posterior dislocations in which close reduction fails, requiring intraoperative maneuvers. The objective of this retrospective study is to analyze clinical presentations, factors causing irreducibility and nuances to achieve intraoperative reduction. MATERIALS AND METHODS: clinicoradiological features of 10 cases with irreducible posterior C1-2 dislocation were studied. Six were post-traumatic with odontoid fracture and 4 had os-odontoideum. The radiology was studied to analyze the cause of irreducibility and the operative management of these cases has been discussed. RESULTS: The patients with traumatic dislocation had persistent neck pain (n=6), early onset (n=1) or delayed onset myelopathy (n=4). Fracture line was oblique extending antero-superior to posttero-inferior in all except one, with fracture fragments distracted in 4 and interlocked in 2. There was associated lateral translation in 2. All had facet locking. Intraoperative reduction was achieved in all by unlocking the facets and/or intrafracture reduction. All 4 patients with congenital posterior dislocations had retrolisthesis of dens with lateral translation. They presented with neck tilt (n=4) and severe myelopathy (n=3). They were easier to reduce intraoperatively but the improvement was to a lesser extent compared to the traumatic counterpart. CONCLUSION: The posterior C1-2 dislocation associated with fracture of dens or os-odontoideum is distinct entity. Lateral translation is often seen with retrolisthesis of os-odontoiduem and occasionally in traumatic posterior dislocations. It is necessary to address the cause of irreducibility and achieve multiplanar realignment for a good outcome. PMID- 30476659 TI - Transsphenoidal Approaches for Microsurgical Resection of Pituitary Adenomas in Pediatric Patients. AB - OBJECTIVE: Pituitary adenomas are uncommon in the pediatric population. Although medical treatment can be effective in treating prolactinomas and some growth hormone-secreting tumors, resection is indicated in the setting of pituitary apoplexy, large or giant pituitary adenomas causing mass effect or visual loss, or when medical therapy becomes ineffective or intolerable. Modern microsurgical transsphenoidal approaches are potential avenues for resection in pediatric patients. The authors evaluated the outcomes and safety of this approach. METHODS: A retrospective cohort analysis was performed from February 2002 through May 2017 for patients <19 years that underwent a transsphenoidal approach for pituitary adenoma resection. RESULTS: Among a total of 634 patients who underwent transsphenoidal approach for pituitary adenoma resection, 24 pediatric cases were identified. Prolactinomas (29.2%) and adrenocorticotropic hormone-secreting (20.8%) pituitary adenomas were the most commonly encountered histologies. Gross total resection was achieved in 75.0% of patients, and complete hormone function normalization was seen in 91.7% of patients. Eight (33.3%) patients required postoperative hormone replacement therapy. Twelve (50.0%) patients underwent fat/fascia use and 1 (4.2%) underwent lumbar puncture perioperatively for management of cerebrospinal fluid leak. There were no tumor recurrences during a follow-up period of 24.7+/-32.1 months. CONCLUSIONS: A modern transsphenoidal microsurgical approach proved to be a safe, well-tolerated, and effective modality in the setting of pediatric pituitary adenomas. PMID- 30476660 TI - Management of Root Level Double Crush: a Case Report with Technical Notes on Contralateral Interlaminar Foraminotomy (PECILF) with Full Endoscopic Uniportal Approach. PMID- 30476661 TI - First UK experience of navigated Transcranial Magnetic Stimulation in pre surgical mapping of brain tumours. PMID- 30476662 TI - Ankylosing spinal disease - diagnosis and treatment of spine fractures. AB - BACKGROUND: In patients with ankylosing spinal diseases (ASD) including ankylosing spondylitis (AS) and diffuse idiopathic skeletal hyperostosis (DISH) even low-impact trauma can lead to complex injury. They seem to be highly unstable and associated with higher mortality rates when compared to the general spine trauma population. METHODS: We reviewed the charts of a consecutive series of 41(34 male, 7 female) patients with ASD and unstable traumatic spine injuries who were admitted to our department between 2007 and 2016. RESULTS: Mean patient age was 73.4+/-12.7 years. 24(58.5%) patients suffered from AS, 17(41.5%) patients manifested DISH. Low-velocity accidents were documented in 38(92.7%) cases.The most frequent injuries were type B spine fractures (61.0%).Accompanying spinal epidural hematoma (sEDH) on MRI was present in 12(29.3%) patients, but did not show on x-rays or CT.Twenty-four patients (58.5%) presented with American Spinal Injury Association impairment scale (AIS) grade E, 6(14.6%) with grade D, eight (19.6%) with grade C or worse.All patients were treated with internal fixation. All but one (97.6%) received posterior fixation, in 25(61%) cases a combined approach was performed.Five patients died of early complications. Of the 36 discharged patients, 11 had died during follow up, 1 was lost to follow up.The surviving twenty-four patients had a median follow up of 733+/- 576 days, N=21 were AIS grade E, N=2 AIS grade D, N=1 AIS grade C. CONCLUSIONS: A thorough diagnostic routine with multi slice CT and MRI can reveal injuries that would remain undetected on conventional radiographs.A combined approach or posterior only fixation seems safe. PMID- 30476663 TI - Spontaneous fractures in the setting of extensive craniocervical pneumatisation - case report and literature review. PMID- 30476664 TI - Primary lymphoma of the skull base in Chinese: clinical, radiological, pathological and therapeutic experience in a series of 8 cases. AB - BACKGROUND: Primary lymphoma of the skull base (PLSB) is an extremely rare neoplasm, and not much is known about the clinical features, treatment strategies and prognoses of these lesions. The aim of this study was to investigate the manifestations and clinical outcomes of patients with PLSB in Chinese. METHODS: We retrospectively reviewed 8 consecutive patients with PLSB treated in our center between October 2008 and December 2016 and analyzed their clinical features, treatment strategies and prognoses. RESULTS: There were 3 men and 5 women, with a male-to-female ratio of 0.6. The median age was 53.5 years. In most instances, the onset was characterized by headache followed by dysfunction of the cranial nerves. The most frequently affected region was the cavernous sinus. On magnetic resonance imaging, the main characteristic was that the internal carotid artery was encased by the tumor without obvious tendency to be deformed, dislocated or narrowed. All patients underwent surgical biopsy via a transphenoidal or sublabial-transmaxillary approach. The pathological diagnoses were all non-Hodgkin lymphoma, with diffuse large B cell lymphoma (DLBCL) in 7 cases. The patients were treated with chemotherapy and involved-field radiotherapy. The median overall survival was 52 months, and the one-year progression-free survival rate was 87.5%. CONCLUSIONS: PLSB is a rare disease and a diagnostic challenge, most of which is DLBCL in Chinese. The incidence peaks in middle and old age, and the cavernous sinus is usually affected. Multidisciplinary treatment involving surgical biopsy, chemotherapy and radiotherapy is an effective therapeutic strategy. PMID- 30476665 TI - Malpractice Litigation in Brain Tumor Surgery: A 31-Year Analysis of Causative Factors in the United States from the Westlaw Database. AB - INTRODUCTION: Medical malpractice litigation is an issue of major concern in neurosurgery, with 19.1% of neurosurgeons facing a claim annually. Neurosurgery possesses the greatest risk of malpractice of any specialty, likely due to the complex clinical environment and disease severity. In this study, the authors characterize such litigation to determine common factors that compel plaintiffs to file these claims. METHODS: WestLawNext, a prominent legal database, was utilized to identify all cases from 1985-2016 related to brain tumors. In total, 225 cases were identified and each was analyzed for cause of litigation (multiple causes were permitted). Since many have >1 ground for litigation, reported percentages were based on total counts of litigation rather than on number of cases. Additional information was collected on each case including location, tumor type, and physician specialty. RESULTS: The cases were distributed across 36 states/US territories: California (n=42, 20%) and New York (n=28, 13%) had the highest number of cases. The top reasons for litigation were: failure to diagnose (n=109, 28%), failure to treat (n=72, 18%), procedural error (n=63, 16%), and failure to refer diagnostic tests (n=55, 14%). The most common diagnoses included: pituitary adenoma (n=26, 12%), acoustic neuroma (n=27, 12%), and meningioma (n=23, 10%). CONCLUSIONS: Malpractice litigation contributes to high overhead and physician burnout while escalating the cost of patient care. This study reveals that benign brain tumors are the most common in litigation and that surgical issues accounted for only a small percentage. PMID- 30476666 TI - Exophytic primary spinal intramedullary glioblastoma: A case report and critical review of literature. AB - BACKGROUND: Primary spinal intramedullary glioblastoma is an extremely rare entity; we report the first case of primary spinal intramedullary glioblastoma presenting with exophytic involvement. The prognosis of glioblastoma remains poor due to the aggressive nature of the disease and lack of effective treatment. CASE DESCRIPTION: A 27-year-old Asian female presented to our hospital with a one month history of dysuria, incomplete bladder emptying, progressive numbness and weakness of both lower limbs, and a one-year history of back pain. Spinal magnetic resonance imaging (MRI) revealed an intramedullary lesion and exophytic growth in the T4-T12 and T5-12 regions, respectively. The patient's MRI findings were atypical of spinal glioblastoma. The diagnosis was made based on the immunohistochemical and pathological analyses of tissue samples obtained from an open biopsy. The patient received a standard course of glioblastoma radiotherapy and adjuvant temozolomide chemotherapy, which improved her symptoms in the absence of an apparent reduction in tumor size. CONCLUSION: Although MRI is of indisputable importance in the diagnosis of spinal cord lesions, immunohistochemical and histopathological studies are often required to establish a definitive diagnosis. It remains unclear how the unusual involvement of exophytic growth will affect the prognosis of primary spinal intramedullary glioblastoma. PMID- 30476667 TI - Dural based marginal zone lymphoma in a patient with sarcoidosis: a case report. AB - BACKGROUND: Primary dural based lymphoma is a rare disease entity. It has beenhypothesized that patients with sarcoidosis are at increased risk of developing lymphoma, an association known as "sarcoidosis-lymphoma syndrome", although dural disease has been not yet reported in the literature. CASE DESCRIPTION: Here we report the first case of dural based lymphoma in a 60-year old; man with a history of sarcoidosis, in keeping with sarcoidosis-lymphoma syndrome. His; dural based tumour was surgically resected. Pathology examination revealed a marginal zone B-cell lymphoma. Subsequent neural and systemic staging confirmed a localized lymphoma. The patient received local radiotherapy to control leptomeningeal disease. CONCLUSIONS: Given the association between sarcoidosis and lymphoma, we suggest lymphoma to be considered as one of the top differentials for a dural based mass lesion in patients with sarcoidosis. PMID- 30476668 TI - Optical coherence tomography for intracranial aneurysms: a new method for assessing the aneurysm structure. AB - BACKGROUND: There is a lack of precise methods for predicting the risk of aneurysm rupture. Therefore, prophylactic treatment is used, which leads to unnecessary potential complications. A new modality enabling a more accurate risk assessment is needed. Optical coherence tomography (OCT) is a new-generation imaging technology that has astonishing resolution for vascular imaging. In this study, OCT was used for the evaluation of intracranial aneurysms. METHODS: In vivo OCT imaging was performed for aneurysms induced in 6 rabbits and in 9 intracranial aneurysm patients. Catheters were cut short to prevent any extra length from damaging aneurysms and tissues. Images of both the parent artery and the aneurysm at multiple viewing angles were obtained using rotational OCT scanning. RESULTS: OCT images of rabbits correlated well with histological sections. Three-layered architecture of the parent arteries was explicitly exhibited. Ruptured intracranial aneurysms manifested complete breakdown of the wall structure; however, this was not observed in any unruptured aneurysms. OCT images of unruptured intracranial aneurysms exhibited a trend of degradation by showing the gradual disappearance of the demarcation between the layers or incomplete apoptosis in layer structures. CONCLUSION: OCT is the most precise imaging modality because it provides detailed information regarding the aneurysm structures, thus enabling more distinct insight into the vascular construction of intracranial aneurysms. PMID- 30476669 TI - Nervus intermedius section to mobilize the anterior inferior cerebellar artery in microvascular decompression surgery for hemifacial spasm: a technical case report. AB - BACKGROUND: The course of the the anterior inferior cerebellar artery (AICA) in the cerebellopontine angle may affect the technical options in microvascular decompression surgery (MVD) for hemifacial spasm. Complex relationship between the AICA and the nervus intermedius has rarely been discussed in patients with hemifacial spasms. CASE DESCRIPTION: A 74-year-old woman presented with left facial spasms for 8 years. Intraoperative endoscopic observation confirmed that the left nervus intermedius crossed over the left AICA and limited its mobilization from the root exit zone (REZ) of the left facial nerve. Nervus intermedius section enabled mobilization of the AICA to decompress the facial nerve REZ. Her hemifacial spasm was resolved completely after the surgery with no significant complication. CONCLUSION: The AICA may be found between the nervus intermedius and the facial nerve proper in patients with hemifacial spasm. Endoscope can visualize the relationship between the AICA and the nervus intermedius. Nervus intermedius section is a useful option in case that the nervus intermedius limits adequate mobilization of the AICA from the facial nerve REZ. PMID- 30476670 TI - Subsidence Rates After Lateral Lumbar Interbody Fusion: A Systematic Review. AB - OBJECTIVE: The evidence regarding the consequences of subsidence with lateral lumbar interbody fusion (LLIF) has been sparse. The objective of this study is to calculate the incidence of subsidence and reoperation for subsidence following LLIF. A secondary outcome examined the quantitative degree of subsidence by calculating the percent change in the height of the intervertebral space secondary to interbody subsidence at various postoperative follow up times. METHODS: Following the Meta-analysis (and Systematic Review) Of Observational Studies in Epidemiology (MOOSE) Guidelines, a systematic review searched for all cohort studies that focused on subsidence rates after LLIF, including Extreme Lateral Interbody Fusions (XLIF) and Direct Lateral Interbody Fusion (DLIF). Neoplastic, infectious, and/or metabolic indications for LLIF were similarly excluded as these pathologies may compromise bone quality and, thus, confound the rate of cage subsidence. Corpectomies were removed from the systematic review because 1) indications for removal of vertebral body typically reflect those excluded pathologies, and 2) subsidence refers to a different biomechanical process RESULTS: This systematic review identified a subsidence incidence with LLIF of 10.3% (N=141/ 1362 patients in 14 articles) and reoperation rate for subsidence of 2.7% (N=41/ 1470 patients in 16 articles). In the secondary outcome measure, the disc height decreased from 5.6% after 3 months, 6.0% after 6 months, 10.2% after 12 months, to 8.9% after 24 months (p<.001). CONCLUSIONS: Subsidence after LLIF carries a non-negligible risk that may be incorporated in surgical consent discussions in selected patients. PMID- 30476671 TI - Pipeline Treatment of Intracranial Aneurysms is Safe and Effective in Patients with Cutaneous Metal Allergy. AB - BACKGROUND: The Pipeline Embolization Device (PED) has expanded the range of aneurysms amenable to endovascular treatment, including some that were previously untreatable. The PED contains several metals, including nickel, cobalt, chromium, platinum and tungsten. The safety of implanting the PED in patients with cutaneous metal allergy is unknown. The purpose of this study was to assess the clinical and angiographic outcomes of PED treatment in patients with nickel allergy. METHODS: A single-institution neurointerventional database was retrospectively reviewed for patients with a documented cutaneous metal allergy treated with the PED. Patient, aneurysm, and procedural data were collected, including perioperative and delayed complications. Post-treatment angiograms were reviewed for in-Pipeline stenosis and aneurysm occlusion. RESULTS: Twenty patients with metal allergy underwent 23 PED treatments for 26 aneurysms. The cohort was 95% (19/20) female, mean age 55.7 years (range, 28-75 years). Aneurysms were primarily anterior circulation (92%, 24/26) and saccular (92%; 24/26), with mean size of 8.8 mm (range, 2-32 mm). A single PED was implanted in 70% (14/20) of patients, 25% (5/20) had two devices placed, and one patient had three devices. One major procedural complication occurred (4.3%, 1/23) in which a stroke was caused by perioperative PED thrombosis. Angiographic follow up was available for all patients, mean duration 15.7 months (range, 6-64 months), which demonstrated a complete aneurysm occlusion rate of 88% (23/26). Asymptomatic in Pipeline stenosis occurred in two cases, resulting in 65% and 50% parent artery stenosis,respectively. CONCLUSION: Preliminary results suggest that PED implantation in patients with cutaneous metal allergy is safe and effective. PMID- 30476672 TI - Clinical Management of Prostate Cancer Metastasis to the Pineal Gland: case report and review of the literature. AB - BACKGROUND: Prostate Cancer is the most common cancer among American men, with an incidence of approximately 233,000 cases per year.Intracranial metastases are rare and specifically, metastasis to the pineal gland has only been reported in 2 post mortem cases in the literature. CASE DESCRIPTION: We present the first documented case of confirmed prostate cancer metastasis to the pineal gland in a living patient. The patient underwent an endoscopic third ventriculostomy and pineal lesion biopsy with complete resolution of his hydrocephalus and presenting symptoms. His biopsy results confirmed the prostate origin of the metastasis, and he subsequently underwent stereotactic radiosurgery for treatment of this lesion. CONCLUSION: This is the first report of the clinical management of metastatic prostate cancer to the pineal region and description of the clinical outcome. Although prostate cancer is the most common cancer in American men, metastasis to the pineal has only been reported twice from autopsy examinations. Overall, pineal tumors in the geriatric population are exceedingly rare, and the age and co-morbidities in this patient made management quite unique. PMID- 30476673 TI - Dynamic chess-table cranial expansion for treatment of craniocerebral disproportion: Technical note and volumetric results. AB - OBJECTIVE: Craniocerebral disproportion (CCD) is a challenging pathology, and several expansile procedures have been used for its treatment. This report describes the dynamic chess-table cranial expansion technique and presents nine patients with primary and secondary CCD treated with this procedure. METHODS: Nine patients affected by CCD were treated with chess-table cranial expansion and reviewed. Symptoms of increased intracranial pressure (ICP) and radiological findings were analyzed. ICP was monitored using epidural or telemetric sensors. Intracranial volume was measured using computed tomography image processing tools before the surgery, 24 hours after the surgery and 1 month later. A mathematical model was developed to explain the clinical and surgical results. RESULTS: Five subjects suffered from secondary CCD and four from primary CCD. The mean age for cranial expansion was 16.78 years. The most frequent symptoms were headaches, nausea / vomiting, and decreased consciousness. Slit ventricles and sutural sclerosis were observed in 33.3% and 55.6% of cases. The mean ICP before the procedure was 48.67 mmHg. Progressive cranial expansion was seen in all cases after surgery. The mean ICP decreased to 11 mmHg and mean intracranial volume expansion was 85.8 cm3 at 1 month after surgery. There were no serious complications after surgery. All patients improved their symptoms, and no patient needed additional cranial-expansion procedures. CONCLUSIONS: Chess-table cranial expansion is a safe and effective procedure and may be used as an alternative treatment for CCD. Progressive expansion of the intracranial volume is related to a decrease in ICP recordings and an improvement of symptoms. PMID- 30476674 TI - Are incoming pediatric interns ready to obtain the essential components of an informed consent for lumbar puncture? AB - OBJECTIVE: In 2013, the Association of American Medical Colleges created the "Core Entrustable Professional Activities (EPAs) for Entering Residency" to more clearly define the set of activities that entering residents should be able to perform on day one of residency without direct supervision. EPA #11 is obtaining informed consent for tests and/or procedures. This EPA acknowledges that an entrustable learner should be able to document a complete consent among other components. The aim of this study is to explore if incoming pediatric interns demonstrated the behaviors of an "entrustable learner" in the domain of documenting informed consent for a common pediatric procedure. METHODS: All incoming interns in our program (2007-2017) completed a six-station Objective Structured Clinical Examination during residency orientation. One of the scenarios involves obtaining parental consent for a lumbar puncture (LP). The researchers determined and agreed what components would be important for a complete and accurately documented consent. A retrospective review of the resident's written informed consents occurred looking for accuracy of documented components. RESULTS: Of the 258 consents reviewed, 8 were complete and accurate. Incoming interns appear to be skilled when completing the basics of the informed consent form such as documenting names, obtaining signatures, and correctly identifying the procedure. However, detailing all the risks of the LP were areas for which they did not demonstrate proficiency. CONCLUSION: Documenting informed consent is not adequately demonstrated by our learners prior to the beginning of internship and would recommend specific training before entrusting pediatric interns to obtain LP consent independently. PMID- 30476675 TI - The association between inflammatory markers and general psychological distress symptoms. AB - OBJECTIVE: This study explored the association between low-grade inflammation measured using multiple common inflammatory markers and general psychological distress symptoms. METHOD: A total of 68,463 Korean adults were included. White blood cell counts with differential count, fibrinogen, C-reactive protein (CRP), ferritin and rheumatoid factor were measured. General psychological distress symptoms were assessed using 18 questions of psychosocial well-being index short form (PWI-SF). RESULTS: Among the eight inflammatory markers measured, WBC count, segmented neutrophil count, monocyte and CRP level were significantly and independently associated with broad psychological symptoms. In contrast, fibrinogen and ferritin showed a weak association with limited number of items. No significant association was detected with lymphocyte and RF. CONCLUSION: General psychological distress symptoms were associated with multiple inflammatory markers in Korean adults. The association patterns differed by the types of inflammatory markers. Additional investigation into the relationship between general inflammatory markers and diverse psychological distress symptoms is warranted. PMID- 30476676 TI - Precaval positive sentinel lymph node with bilateral negative pelvic sentinel lymph node in low-risk endometrial cancer patient. AB - We here describe a case report of a positive precaval sentinel lymph node with negative pelvic sentinel lymph node in a patient with endometrial cancer. A 45 years-old woman was diagnosed with a grade 2 endometrioid carcinoma of the endometrium. She was treated with a hysterectomy and bilateral salpingo oophorectomy, associated with dissection of sentinel lymph nodes (SLNs). We detected bilateral external and common bilateral iliac nodes and one precaval node. At pathological examination the pelvic nodes were non-metastatic, but the precaval node was positive. In this patient, sentinel node biopsy improved risk assessment and adjuvant treatment. PMID- 30476677 TI - Postpartum hemorrhage: incidence, risk factors, and causes in Western French Guiana. AB - INTRODUCTION: Postpartum hemorrhage remains the leading cause of maternal death in France. Parturients in western French Guiana have specific sociodemographic features and a high rate of pathological pregnancies. The objective of this study was to determine the incidence of immediate postpartum hemorrhage (IPPH) in western French Guiana, and to describe the etiologies and risk factors. METHODS: A case control study with incident cases was conducted in the Maternity Department of the Western French Guiana Hospital over a period of one year. The cases included women giving birth to a child of 22 weeks' GA and/or a child weighing 500 g, and who presented with IPPH. Two control subjects were included per case (after pairing for mode of delivery). The data were collected by questionnaire and from medical records. Multivariate analyses by logistic regression were conducted. RESULTS: 154 cases and 308 controls were included. The incidence rate of IPPH was 6.7%. The primary etiologies were: atony, placenta retention, and cervico-vaginal lesions. The factors associated with IPPH were: past history of IPPH (ORadj = 3.36 [1.65-6.87]), pre-eclampsia (ORadj = 2.56 [1.07-6.14]), labor induction by oxytocin (ORadj = 2.03 [1.03-3.99]), the absence of managed placental delivery (ORadj = 2.46 [1.24-4.91]), a gap of more than 30 min between birth and placental delivery (ORadj = 10.92 [2.17-54.99]), and macrosomia (ORadj = 6.38 [1.97-20.67]). CONCLUSION: The incidence rate of IPPH is similar to that found in metropolitan France and in the literature. The risk factors identified here will enable the development of appropriate preventive protocols. PMID- 30476678 TI - Embolization of a congenital arteriovenous malformation arising off the internal mammary artery. AB - Congenital arteriovenous malformations (AVM) of the internal mammary artery (IMA) are exceptionally rare. Patients with AVMs arising off the left IMA may present with continuous precordial murmurs and/or a pulsatile chest mass. AVMs in this location pose a risk of enlargement, rupture, infection, or high-output cardiac failure. The potential risks associated with AVMs warrant early therapeutic intervention. We describe a case of a congenital AVM originating from the left IMA, which was successfully embolized with n-butyl cyanoacrylate (NBCA) using a transcatheter arterial approach. PMID- 30476679 TI - Intra-arterial ampicillin and gentamicin and the incidence of splenic abscesses following splenic artery embolization: A 20-year case control study. AB - PURPOSE: Splenic abscesses represent a major complication following splenic artery embolization. The purpose of this study was to assess the effectiveness of intra-arterial antibiotics administered during splenic artery embolization in reducing splenic abscess formation. MATERIALS AND METHODS: 406 patients were screened. 313 (77.1%) patients who underwent splenic artery embolization and were >18 years old were included. Mean age of the cohort was 58 +/- 15 years (range: 18-88 years). There were 205 (65.5%) male patients and 108 (34.5%) female patients. 197 (62.9%) patients underwent embolization without intra-arterial antibiotics and 116 (37.1%) patients underwent embolization with 1 g ampicillin and 80 mg gentamicin administered in an intra-arterial fashion. Primary outcome was splenic abscess formation. Secondary outcomes included type of splenic artery embolization, embolic agent, and technical success. RESULTS: Partial splenic embolization was performed in 229 (73.1%) patients. Total splenic embolization was performed in 84 (26.8%) patients. Platinum coils were the most commonly used embolic agent overall (n = 178; 56.9%) followed by particulates (n = 114; 36.4%). Embolization technical success was achieved in 312 (99.7%) patients. 7 (3.6%) splenic abscesses were detected in the non-intra-arterial antibiotic group and 1 (0.9%) in the intra-arterial antibiotic cohort (P = 0.27). Coils were found to be statistically more likely to result in splenic abscesses than any other embolic agent (P = 0.03). Mean time to abscess identification was 74 days +/-120 days (range: 9-1353 days). CONCLUSION: Splenic abscesses occurred more frequently in patients who did not receive intra-arterial antibiotics during splenic embolization; however, this did not reach statistical significance. PMID- 30476680 TI - Characterization of acute myeloid leukemia with del(9q) - Impact of the genes in the minimally deleted region. AB - Acute myeloid leukemia is an aggressive disease that arises from clonal expansion of malignant hematopoietic precursor cells of the bone marrow. Deletions on the long arm of chromosome 9 (del(9q)) are observed in 2% of acute myeloid leukemia patients. Our deletion analysis in a cohort of 31 del(9q) acute myeloid leukemia patients further supports the importance of a minimally deleted region composed of seven genes potentially involved in leukemogenesis: GKAP1, KIF27, C9ORF64, HNRNPK, RMI1, SLC28A3 and NTRK2. Importantly, among them HNRNPK, encoding heterogeneous nuclear ribonucleoprotein K is proposed to function in leukemogenesis. We show that expression of HNRNPK and the other genes of the minimally deleted region is significantly reduced in patients with del(9q) compared with normal karyotype acute myeloid leukemia. Also, two mRNAs interacting with heterogeneous nuclear ribonucleoprotein K, namely CDKN1A and CEBPA are significantly downregulated. While the deletion size is not correlated with outcome, associated genetic aberrations are important. Patients with an additional t(8;21) show a good prognosis. RUNX1-RUNX1T1, which emerges from the t(8;21) leads to transcriptional down-regulation of CEBPA. Acute myeloid leukemia patients with mutations in CEBPA have a good prognosis as well. Interestingly, in del(9q) patients with CEBPA mutation mRNA levels of HNRNPK and the other genes located in the minimally deleted region is restored to normal karyotype level. Our data indicate that a link between CEBPA and the genes of the minimally deleted region, among them HNRNPK contributes to leukemogenesis in acute myeloid leukemia with del(9q). PMID- 30476681 TI - Impact of abdominal visceral adiposity on adult asthma symptoms. AB - BACKGROUND: Previous studies have shown the association of anthropometric measures with poor asthma symptoms, especially among women. However, the potential influence of visceral adiposity on asthma symptoms has not been investigated well. OBJECTIVE: In this study, we have evaluated whether visceral adiposity is related to poor adult asthma symptoms independent of anthropometric measures and sex. If this relationship presented, we investigated whether it is explained by influence on pulmonary functions and/or obesity-related comorbidities. METHODS: We analyzed data from 206 asthmatic subjects from Japan. In addition to anthropometric measures (BMI and waist circumference), abdominal visceral and subcutaneous fat were assessed by computed tomography (CT) scan. Quality of life was assessed using the Japanese version of the Asthma Quality of Life Questionnaire (AQLQ). RESULTS: All obesity indices had inverse association with reduced asthma quality of life among females. However, only the visceral fat area showed a statistical inverse association with AQLQ in males. Only abdominal visceral fat was associated with higher gastroesophageal reflux disease (GERD) and depression scores. Although all obesity indices showed inverse association with functional residual capacity, only visceral fat area had a significant inverse association with FEV1 % predicted, independent of other obesity indices. CONCLUSION: Regardless of sex, abdominal visceral fat was associated with reduced asthma quality of life independent of other obesity indices, and this may be explained by the impact of abdominal visceral fat on reduced FEV1 % predicted and higher risk for GERD and depression. Therefore, visceral adiposity may have more clinical influence on asthma symptoms than any other obesity indices. PMID- 30476682 TI - Emergency Management of Anaphylaxis due to an Unknown Trigger: An 8-year follow up study in Canada. AB - BACKGROUND: Anaphylaxis due to Unknown Trigger (AUT) is anaphylaxis not explained by a proved or presumptive cause or stimulus at the time of the reaction. Research describing the management and follow-up of AUT is limited. OBJECTIVE: This study assesses and compares the demographics, clinical characteristics and management of adult and pediatric AUT cases across Canada. METHODS: Participants were identified between 2011 and 2018 in emergency departments at eight centers across Canada as part of the Cross-Canada Anaphylaxis Registry. A standardized form documenting the reaction and management in children and adults was completed. Patients were contacted for follow-up to determine assessment by an allergist. RESULTS: A total of 295 (7.5%) AUT cases were recruited among 3,922 cases of anaphylaxis. In the pre-hospital setting, children (adjusted Odds Ratio (aOR): 1.20 [95%CI: 1.05, 1.37]) and those with a known food allergy (aOR: 1.14 [95%CI: 1.02, 1.28]) were more likely to receive treatment with epinephrine. Children were also more likely to be assessed by an allergist following their reaction (aOR:1.43 [95%CI: 1.13, 1.81]) and were more likely to have an identified trigger for their reaction (aOR:1.35 [95%CI: 1.07, 1.70]). Among patients contacted for follow-up, food was identified as the cause of reaction in 11 of 76 patients. A new food allergy was diagnosed in four patients (2 children and 2 adults). CONCLUSIONS: Our findings highlight important differences between management and follow-up of adult and pediatric AUT cases. It is crucial to follow up all cases of AUT and establish appropriate treatment and management guidelines. PMID- 30476683 TI - Insights into the interactions between triclosan (TCS) and extracellular polymeric substance (EPS) of activated sludge. AB - Triclosan (TCS) contaminant has aroused wide concerns due to the high risk of converting into toxic dioxin in aquatic environments. During the wastewater treatment process, considerable amounts of TCS are accumulated in activated sludge but the mechanisms are still unclear. Especially, roles of extracellular polymeric substances (EPS), the main components of activated sludge, in TCS removal have never been addressed. In this work, the binding properties of loosely-bound EPS (LB-EPS) and tightly-bound EPS (TB-EPS) of activated sludge to TCS are investigated by fluorescence quenching approach. The influences of aquatic conditions including solution pH, ionic strength and temperature on the interactions between EPS and TCS are explored. Possible interaction mechanisms are discussed as well as the corresponding environmental implication. Results indicate that binding processes of EPS to TCS are exothermic mainly driven by the enthalpy changes. The proteins components in EPS dominate the interactions between EPS and TCS by hydrogen bond and hydrophobic interaction. The binding strength could be improved under the condition of weak alkaline and relative high ionic strength. Generally, LB-EPS exhibit stronger binding ability to TCS than TB EPS under neutral environment, playing more crucial roles in the binding process. This work highlights the important contributions of EPS to TCS removal, that is beneficial to comprehensively understand the migration of TCS in activated sludge system. PMID- 30476684 TI - Heavy metal leaching and distribution in glass products from the co-melting treatment of electroplating sludge and MSWI fly ash. AB - Melting is a common solidification treatment that concentrates and encapsulates heavy metals into a glass matrix for waste containing heavy metals (Chae et al., 2016). To control the risk of heavy metal leaching into the glass product, a reduction in the amount of heavy metal was achieved in a pilot-scale furnace by co-melting electroplating sludge (EPS) and municipal solid waste incineration fly ash (MSWI FA). Through the melting process, the chloride from MSWI FA led to heavy metals volatilization in the form of chlorine salts. The fly ash additionally increased heavy metals volatilization by 4%-91%. The highest volatilization ratios of Zn, Pb, Cu, Cd, Cr and Ni were 33%, 96%, 33%, 79%, 81% and 31%, respectively. The concentrations of Pb and Zn in the secondary fly ash were close to the Pb and Zn concentrations in lead-zinc ore that are required in smelting industry. Moreover, glass sand was produced after the melting treatment. With an increase in the fly ash mixing ratio, the leaching concentration of Zn and Cu decreased to 3.8 mg/L and 2.1 mg/L. The leaching concentrations of other heavy metals stayed below 1 mg/L in all cases. When the ratio of MSWI FA reached 10%, the glass sand contained the least amount of impurities and a large amount of phosphate and silicate, which were probably responsible for the stability of the heavy metals. Therefore, our results provided a promising approach to the stability of the waste by the recovery of heavy metals in the co-treatment of heavy metal-bearing wastes. PMID- 30476685 TI - Bacteriological synthesis of iron hydroxysulfate using an isolated Acidithiobacillus ferrooxidans strain and its application in ametryn degradation by Fenton's oxidation process. AB - The investigation reports the application of biogenic jarosite, an iron hydroxy sulfate mineral in Fenton's Oxidation process. Ametryn, a herbicide detrimental to aquatic life and also to human is treated by Fenton's oxidation process using synthesized iron mineral, jarosite. The jarosite synthesis was carried out by using an isolated Acidithiobacillus ferrooxidans bacterial strain with ferrous as an iron supplement. The isolated strain was characterized by molecular techniques and biooxidation activity to ferrous to ferric iron was checked. On Fenton's treatment ametryn degradation upto 84.9% and COD removal to the extent of 56.1% was observed within 2 h of treatment and the reaction follows the pseudo first order kinetics with the curve best fit. The slight increase in kinetic rate constant on jarosite loading rate increase from 0.1 g/L to 0.5 g/L with H2O2 dosage of 100 mg/L confirms that jarosite has a catalytic role in the removal of ametryn. Mass spectroscopy analysis of treated synthetic ametryn solution at various intervals reveal the degradation follows dealkylation and hydroxylation pathway with the formation of three major intermediate compounds discussed here. PMID- 30476686 TI - Pathways of change: Predicting the effects of fire on flammability. AB - Impacts of wildfire on humans are increasing as urban populations continue to expand into fire prone landscapes. Effective fire risk management can only be achieved if we understand and quantify how ecosystems change in response to fire and how these changes affect flammability. However, there have been limited studies to this effect with the dominant paradigm being the assumption that recently burnt vegetation is less flammable than older vegetation. To better quantify changes in flammability, we first need to quantify trajectories of changes in response to fire within individual vegetation communities. Second, we need to examine the extent to which these changes alter flammability. Here, we quantify the flammability pathways with increasing time since fire for five vegetation communities in south-eastern Australia. A total of 116 sites were measured across a range of heathland, woodland and forest ecosystems. Flammability was measured using an ecological point based mechanistic fire behaviour model that estimates three measures of flammability relevant to both fire management and research. Predicted changes in flammability varied between vegetation types with heathland and wet forests generally increasing in flammability with time since fire and tall mixed, foothills and forby forests decreasing or showing limited changes with time since fire. Variations in flammability pathways suggest fire management activities that alter fuel structure, such as prescribed burning, may only reduce flammability in a limited set of ecosystems. Incorporating these results into a landscape analysis will improve the quantification of fire risk. PMID- 30476687 TI - Transforming waterworks sludge into controlled low-strength material: Bench-scale optimization and field test validation. AB - In order to reduce landfill disposal of waterworks sludge (alum sludge) and incinerated sewage sludge ash (ISSA), this study proposed an innovative approach for upcycling them into value-added controlled low-strength materials (CLSM). Waterworks sludge interfered with cement hydration reaction and delayed the stiffening time of CLSM (>10 h) due to its high organics content (5%). The addition of triethanolamine (TEA) with a dosage of 0.1 wt% of binder effectively shortened the stiffening time to 4.5 h. The lab-scale results suggested that the optimal CLSM design (6% cement, 14% ISSA, 8% sludge, and 72% recycled fine aggregate at a water/binder ratio of 1.2) complied with the standard requirement of flowability (>200 mm), stiffening time (<5 h), and compressive strength (0.3 2.1 MPa). The pilot-scale field tests further confirmed that the sludge incorporated CLSM achieved a high flowability (220 mm), short stiffening time (4 h), low compressive strength (1.38 MPa), and easy re-excavatability after 3 months. This study demonstrated that waterworks sludge can be potentially transformed into sustainable construction materials for urban development. PMID- 30476688 TI - The evolution of compost stability and maturity during the full-scale treatment of the organic fraction of municipal solid waste. AB - Composting is the method most commonly applied worldwide for the recovery of the source sorted organic waste. The process aims at stabilizing the organic matter, so as to produce a material with soil improver properties, referred to as compost. The effective recovery of the organic waste fraction via composting implies compost safe use on soil. In this view, the assessment of compost characteristics, depending on both the quality of the input material and the process operation, is fundamental. At full scale, the process monitoring usually relies on parameters enabling the indirect control of its evolution, whereas the biological stability and maturity are usually evaluated on the final product. Aim of this work was in assessing both biological stability and maturity during the composting process of the organic fraction of municipal solid waste performed at industrial scale. Representative samples were collected over time in a composting facility operating in the South of Italy and analysed by the dynamic respirometric index, the content of humic substances as well as by their phytotoxicity. Results showed the key role of stability and maturity parameters in the monitoring of composting processes. Experimental outcomes further addressed wider considerations on the operational procedures for a sustainable compost production process. PMID- 30476689 TI - Protein identification strategies in MALDI imaging mass spectrometry: a brief review. AB - Matrix assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is a powerful technology used to investigate the spatial distributions of thousands of molecules throughout a tissue section from a single experiment. As proteins represent an important group of functional molecules in tissue and cells, the imaging of proteins has been an important point of focus in the development of IMS technologies and methods. Protein identification is crucial for the biological contextualization of molecular imaging data. However, gas phase fragmentation efficiency of MALDI generated proteins presents significant challenges, making protein identification directly from tissue difficult. This review highlights methods and technologies specifically related to protein identification that have been developed to overcome these challenges in MALDI IMS experiments. PMID- 30476690 TI - Walking on a treadmill improves the stride length-cadence relationship in individuals with Parkinson's disease. AB - BACKGROUND: The gait pattern in Parkinson's disease (PD) is characterized by a deficit in the internal regulation of stride length (SL), while the control of cadence (Cad) remains intact. The use of the treadmill as a gait rehabilitation tool has provided novel options for treatment of gait impairments in PD. However, it remains unclear whether walking on the treadmill changes the stride length cadence relationship (SLCrel) in PD. The purpose of the present study was to analyze the SLCrel in PD subjects walking on a treadmill vs. overground, and to further compare the SLCrel to that of age-matched healthy subjects. METHODS: Fifteen PD subjects and fifteen age-matched controls walked overground and on a treadmill at five different self-selected speeds. Gait speed, SL and Cad were recorded at each self-selected speed. A linear regression analysis was conducted to explore the SLCrel and to determine the slope and intercept for each participant. RESULTS: PD subjects showed a lower intercept than control subjects when walking both overground and on a treadmill (F = 8.51, p = 0.007). In comparison with walking overground, walking on a treadmill resulted in a significant increase in the intercept in both PD and control groups (F = 12.17, p = 0.002). There were no significant differences in the slope of the SLCrel. CONCLUSION: PD subjects are able to improve the internal regulation of SL when walking on a treadmill. Our results confirm the potential therapeutic effects of treadmill training for gait rehabilitation in PD and suggest that the mechanisms underlying the positive effects of treadmill training on PD subjects are sustained. PMID- 30476691 TI - Calibration of wrist-worn ActiWatch 2 and ActiGraph wGT3X for assessment of physical activity in young adults. AB - BACKGROUND: The validity of Actiwatch 2 in assessing sleep was evident, but its validity in assessing physical activity (PA) level was unknown. RESEARCH QUESTION: The objective of this study was to validate the wrist-worn Actiwatch 2 and ActiGraph wGT3X as a measurement of PA level against energy expenditure measured by indirect calorimetry. METHODS: Twenty-seven university students aged 18-26 were recruited from July 2016 to May 2017. They were instructed to run at different speeds (4, 6, 8, 10, and 12 km/h) on a treadmill, each speed for 10 min. Oxygen consumption and carbon dioxide production of the subjects was measured by indirect calorimetry using the Cosmed K4b2 gas analyzer. Each subjects wore a single pair of accelerometers (Actiwatch 2 and ActiGraph wGT3X) on both wrists. RESULTS: All the accelerometers were strongly correlated (rho=0.83-0.94, all p-values <0.001), and all four accelerometers were strongly correlated with the METs obtained from the Cosmed K4b2 (rho=0.72-0.74, all p values <0.001). Regression analysis showed that the non-dominant wrist-worn Actiwatch 2 cutoff cpm for moderate and vigorous PA were 399 and 1,404, respectively; for the ActiGraph wGT3X-BT the corresponding cutoffs were 4,514 and 15,044, respectively. The goodness-of-fit of the MET prediction equations were all >75%. When classifying the activities as either sedentary, light activity, moderate-intensity activity, or vigorous-intensity activity using the MET prediction equations, the agreements between the four accelerometers and that by the Cosmed K4b2 were high, all AUCs were above 80% except those of the Actiwatch worn on the left (non-dominant) wrist. The Bland-Altman plots show that, for all four accelerometers, the biases were close to zero and error variances were largest when the mean measurements were around 6 METs. SIGNIFICANCE: We showed that wrist-worn Actiwatch 2 and ActiGraph wGT3X-BT were strongly correlated in PA assessment. PMID- 30476692 TI - A quantitative description of self-selected walking in adults with Achondroplasia using the gait profile score. AB - BACKGROUND: Achondroplasia is characterised by a shorter appendicular limb-to torso ratio, compared to age matched individuals of average stature (controls). Previous work shows gait kinematics of individuals with Achondroplasia differing to controls, but no global quantification of gait has been made in adults with Achondroplasia. AIM: The aim of this study was to quantify gait differences between a group of adult males with Achondroplasia and controls during self selected walking (SSW) using the Gait Profile Score (GPS). DESIGN: Whole body motion analysis of 10 adults with Achondroplasia (22 +/- 3 yrs) who had not undergone leg lengthening and 17 adult controls (22 +/- 2 yrs) was undertaken using a 14 camera VICON system (100 Hz). For each group, fifteen root mean squared Gait Variable Scores (GVS, units degrees ) were computed from lower limb kinematic data and then summed to calculate GPS ( degrees ). RESULTS: The group with Achondroplasia had higher GVSs than controls in 10 of the 15 measures (P < 0.05) with the largest differences found in ankle plantar/dorsiflexion (P < 0.001), knee flexion/extension (P < 0.001), and hip internal/external rotation (P < 0.001). The GPS value of the group with Achondroplasia was 64% higher than controls (11.4 degrees (2.0) v 4.1 degrees (1.8), P < 0.001). CONCLUSION: Gait is quantitatively different in adults with Achondroplasia compared to controls. The differences in GPS between groups are due to differences in joint kinematics, which are possibly manifested by maintaining toe-clearance during swing. Gait models derived from the anatomy of individuals with Achondroplasia may improve these data. PMID- 30476693 TI - Lexical access and competition in bilingual children: The role of proficiency and the lexical similarity of the two languages. AB - Using a picture-auditory word recognition task, we examined how early child bilinguals access their languages and how the languages affect one another. Accuracy and response times in "false friends" (i.e., words with similar form but unrelated meanings) and semantically related words were compared with control conditions within and across languages and grades. Study 1 tested the performance of school-age children with balanced versus unbalanced knowledge of first language (L1) Italian and second-language (L2) German. Study 2 compared unbalanced bilingual children with L1 Italian and L2 French or German to investigate the effect of lexical similarity in the children's languages. Children were found to activate both languages on receiving an auditory stimulus; performance in each language was affected by proficiency in the other language, degree of between-language similarity, and length of experience with each language. The BLINCS (Bilingual Language Interactive Network for Comprehension of Speech) model was invoked as a plausible framework for conceptualizing the nature of bilingual phonolexical representation and its effect on word recognition. PMID- 30476694 TI - Performance predictions and postdictions in prospective memory of school-aged children. AB - Prospective memory (PM) undergoes important developmental changes during the primary school years, particularly around 7 and 8 years of age. Recent studies have suggested that, as well as executive functions (EFs), PM development also benefits from age-related increments in metamemory (MM) abilities. The primary aim of the current study was to explore the role of MM monitoring and control processes (i.e., procedural MM) of 7- and 8-year-old children in a PM task including specific cues. Monitoring processes were assessed by asking children to judge their own PM performance before (predictions) and after (postdictions) in performing a PM task. In addition, children were asked to report the strategy they used to remember the PM task. Reactive effects of making predictions and using strategies were assessed via both an ongoing task (OT) and PM performance. EF and declarative MM performance was also examined. Results showed that children who were asked to predict PM performance had faster PM response times (RTs), but not higher accuracy rates, than children in a control group. However, strategy use affected both PM and OT performance, with those children reporting active strategy use obtaining higher PM accuracy rates and slower OT RTs. Finally, switching abilities were also predictive of OT performance. This investigation highlights the importance of studying MM monitoring and control processes in relation to children's PM. PMID- 30476695 TI - Object complexity modulates the association between action and perception in childhood. AB - Vision for action and vision for perception both rely on shape representations derived within the visual system. Whether the same psychological and neural mechanisms underlie both forms of behavior remains hotly contested, and whether this arrangement is equivalent in adults and children is controversial as well. To address these outstanding questions, we used an established psychophysical heuristic, Weber's law, which, in adults, has typically been observed for perceptual judgment tasks but not for actions such as grasping. We examined whether this perception-action dissociation in Weber's law was present in childhood as it is in adulthood and whether it was modulated by stimulus complexity. Two major results emerged. First, although adults evinced visuomotor behavior that violated Weber's law, young children (4.5-6.5 years) adhered to Weber's law when they grasped complex objects ("Efron" blocks), which varied along both the graspable and non-graspable dimensions to maintain a constant surface area, but not when they grasped simple objects, which varied only along the graspable dimension. Second, adherence to Weber's law was found across all ages in the context of a perceptual task. Together, these findings suggest that, in early childhood, visuomotor representations are modulated by perceptual representations, particularly when a refined description of object shape is needed. PMID- 30476696 TI - What makes a shape "baba"? The shape features prioritized in sound-shape correspondence change with development. AB - Crossmodal sound-shape correspondence, the association of abstract shapes and nonsense words (e.g., "bouba-kiki" effect), is seen across cultures and languages. Recent research suggests that the sensitivity for such sound-shape pairings might increase with development. Here we examined one possible mechanism underlying developmental changes in sensitivity to sound-shape correspondences-if and how shape features, such as contour spikiness and the number and size of protrusions, might be weighted differently by children and adults. In Experiment 1, we asked participants to choose which of two nonsense words matched a given visual shape while manipulating contour spikiness and number and size of protrusions independently. We found that adults associated /i/ sounds with shapes having spiky contours and 3 small protrusions. Of these shape features, contour spikiness showed the strongest association. Whereas 9- to 11-year-olds showed adult-like responses, 6- to 8-year-olds prioritized protrusion number, not contour spikiness. Importantly, in Experiment 2, where contour spikiness was highlighted by presenting round and spikey shapes side by side, 6- to 8-year-olds could make associations based on contour spikiness. Our findings suggest that 6- to 8-year-olds prioritize different features of a shape when making sound-shape correspondence compared with adults. Interestingly, these shape-processing biases can be altered by context such that children can resemble adults when the relevant shape features are highlighted. Our results suggest that biases in visual shape processing and the ability to extract contextual information might be additional factors explaining developmental changes in sensitivity toward sound-shape correspondences. These changing developmental biases highlight the contribution of perceptual processing styles in crossmodal correspondence. PMID- 30476697 TI - Looking for the negative: Depressive symptoms in adolescent girls are associated with sustained attention to a potentially critical judge during in vivo social evaluation. AB - Attention biases toward negative stimuli are implicated in the development and maintenance of depression. However, research is needed to understand how depression affects attention biases as they unfold in a dynamic social environment, particularly during adolescence when depression rates significantly increase due to enhanced reactivity to social stress. To examine attention biases in a live, socially evaluative environment, 26 adolescent girls from the community gave a speech in front of a potentially critical judge and a positive judge while wearing mobile eye tracking glasses. Girls' depressive symptoms were measured using the Moods and Feelings Questionnaire. Across the sample, girls looked at the positive judge more frequently and for longer periods of time compared with the potentially critical judge. In contrast, higher depressive symptoms were associated with looking at the potentially critical judge for longer periods of time. When directly comparing attention to the potentially critical judge relative to the positive judge, dysphoric girls looked at the potentially critical judge more frequently and for longer periods of time compared with the positive judge. Findings suggest that adolescent depressive symptoms are related to sustained attention toward potentially critical evaluation at the exclusion of positive evaluation. This novel approach allowed for an in vivo examination of attention biases as they unfold during social evaluation, which begins to illuminate the interpersonal significance of attention biases. If replicated and extended longitudinally, this research could be used to identify adolescents at high risk for future depression and potentially be leveraged clinically in attention bias modification treatment. PMID- 30476698 TI - GAS: A genetic atlas selection strategy in multi-atlas segmentation framework. AB - Multi-Atlas based Segmentation (MAS) algorithms have been successfully applied to many medical image segmentation tasks, but their success relies on a large number of atlases and good image registration performance. Choosing well-registered atlases for label fusion is vital for an accurate segmentation. This choice becomes even more crucial when the segmentation involves organs characterized by a high anatomical and pathological variability. In this paper, we propose a new genetic atlas selection strategy (GAS) that automatically chooses the best subset of atlases to be used for segmenting the target image, on the basis of both image similarity and segmentation overlap. More precisely, the key idea of GAS is that if two images are similar, the performances of an atlas for segmenting each image are similar. Since the ground truth of each atlas is known, GAS first selects a predefined number of similar images to the target, then, for each one of them, finds a near-optimal subset of atlases by means of a genetic algorithm. All these near-optimal subsets are then combined and used to segment the target image. GAS was tested on single-label and multi-label segmentation problems. In the first case, we considered the segmentation of both the whole prostate and of the left ventricle of the heart from magnetic resonance images. Regarding multi-label problems, the zonal segmentation of the prostate into peripheral and transition zone was considered. The results showed that the performance of MAS algorithms statistically improved when GAS is used. PMID- 30476699 TI - Bromocriptine-responsive supersellar germinoma with the expression of dopamine receptors: A case report. AB - BACKGROUND: Germinomas are sensitive to radiotherapy and chemotherapy. However, there has been no report involving in the potential therapeutic effect of dopamine agonists (DAs) such as bromocriptine on germinomas. CASE DESCRIPTION: A 20-year-old female was presented with bitemporal visual disturbance and amenorrhea. Magnetic resonance imaging demonstrated a huge sellar tumor with upward extension and invasion of the parasellar region. The blood tests showed an exceedingly high level of prolactin. A sellar tumor with hyperprolactinemia was diagnosed, and bromocriptine was initially given. After three months, the tumor volume had been obviously decreased by 82%. However, the tumor re-grew after ten months and the endoscopic endonasal surgery was performed. Histopathological and immunohistochemical examination indicated the patient had a pure sellar germinoma. The tumor cells strongly expressed dopamine 2 receptor and dopamine 5 receptor, which located in the membrane and cytoplasm. CONCLUSIONS: The transient but significant partial responsiveness of germinoma to bromocriptine treatment in this patient is a novel discovery, suggesting that DAs may be a potential therapeutic choice for tumors with the expression of dopamine 2/5 receptors. PMID- 30476701 TI - Laparoscopic cholecystectomy and postoperative pain control in a patient with chronic non-spherocytic hemolytic anemia from glucose-6-phosphate dehydrogenase deficiency. PMID- 30476700 TI - Percutaneous endoscopic lumbar discectomy and minimally invasive transforaminal lumbar interbody fusion for massive lumbar disc herniation. AB - OBJECTIVES: To compare the clinical outcomes of patients with massive lumbar disc disease undergoing percutaneous endoscopic lumbar discectomy and minimally invasive transforaminal lumbar interbody fusion at a single clinic. PATIENTS AND METHODS: From January 2008 to January 2014, 360 consecutive patients with massive lumbar disc herniation were treated with PELD(184 patients) or MIS-TLIF(176 patients). Data collected prospectively for analysis included clinical and radiographic results after revision surgery and complications. RESULTS: During the follow-up period, postoperative data between two treatment groups showed no significant difference in the mean total postoperative VAS score for leg pain, JOA and ODI scores. The recovery rate was 89.3% in the PELD and 93.4% in MIS-TLIF groups, respectively. Satisfaction rates were 86.3% in the PELD group and 92.2% in the MIS-TLIF group. Four cases of dural tear were observed in the MIS-TLIF group. Recurrence manifested in 14 patients in the PELD group, and one patient in this group also suffered permanent neurologic deficit. One case of postoperative intervertebral infection was recorded in the MIS-TLIF group. CONCLUSION: A comparison of PELD and MIS-TLIF for treating massive lumbar disc herniation revealed that both showed favorable clinical outcomes but had different sets of complications. Compared to MIS-TLIF, PELD had the following advantages: (1) its feasibility under local anesthesia and (2) the rarity of "fusion disease," such as ASD. However, the PELD is also revealed several problems, including a relatively lower success rate and satisfaction,a relative higher rate of postoperative long-term chronic low back pain and the possibility of recurrence, despite low opportunity. Therefore, the main difference between these two treatments was related to postoperative complications and the satisfaction and recovery rates. We suggest that, in the future, multi-center studies, recruiting a larger number of patients, should be undertaken to better understand the clinical relevance of these complications. PMID- 30476702 TI - Transcriptome profilling analysis characterized the gene expression patterns responded to combined drought and heat stresses in soybean. AB - Heat and drought are the two major abiotic stress limiting soybean growth and output worldwide. Knowledge of the molecular mechanisms underlying the responses to heat, drought, and combined stress is essential for soybean molecular breeding. In this study, RNA-sequencing was used to determine the transcriptional responses of soybean to heat, drought and combined stress. RNA-sequencing analysis demonstrated that many genes involved in the defense response, photosynthesis, metabolic process, etc. are differentially expressed in response to drought and heat. However, 1468 and 1220 up-regulated and 1146 and 686 down regulated genes were confirmed as overlapping differentially expressed genes at 8 h and 24 h after treatment, and these genes are mainly involved in transport, binding and defense response. Furthermore, we compared the heat, drought and the combined stress-responsive genes and identified potential new targets for enhancing stress tolerance of soybean. Comparison of single and combined stress suggests the combined stress did not result in a simple additive response, and that there may be a synergistic response to the combination of drought and heat in soybean. PMID- 30476703 TI - Complementary cathodoluminescence lifetime imaging configurations in a scanning electron microscope. AB - Cathodoluminescence (CL) spectroscopy provides a powerful way to characterize optical properties of materials with deep-subwavelength spatial resolution. While CL imaging to obtain optical spectra is a well-developed technology, imaging CL lifetimes with nanoscale resolution has only been explored in a few studies. In this paper we compare three different time-resolved CL techniques and compare their characteristics. Two configurations are based on the acquisition of CL decay traces using a pulsed electron beam that is generated either with an ultra fast beam blanker, which is placed in the electron column, or by photoemission from a laser-driven electron cathode. The third configuration uses measurements of the autocorrelation function g(2) of the CL signal using either a continuous or a pulsed electron beam. The three techniques are compared in terms of complexity of implementation, spatial and temporal resolution, and measurement accuracy as a function of electron dose. A single sample of InGaN/GaN quantum wells is investigated to enable a direct comparison of lifetime measurement characteristics of the three techniques. The g(2)-based method provides decay measurements at the best spatial resolution, as it leaves the electron column configuration unaffected. The pulsed-beam methods provide better detail on the temporal excitation and decay dynamics. The ultra-fast blanker configuration delivers electron pulses as short as 30 ps at 5 keV and 250 ps at 30 keV. The repetition rate can be chosen arbitrarily up to 80 MHz and requires a conjugate plane geometry in the electron column that reduces the spatial resolution in our microscope. The photoemission configuration, pumped with 250 fs 257 nm pulses at a repetition rate from 10 kHz to 25 MHz, allows creation of electron pulses down to a few ps, with some loss in spatial resolution. PMID- 30476704 TI - Evaluating an abbreviated three-factor version of the Eating Disorder Examination Questionnaire in three samples. AB - A brief, three-factor structure for the Eating Disorder Examination-Questionnaire (EDE-Q) has been identified that has stronger psychometric properties than the original four-factor EDE-Q structure. However, there is a need for independent replication of the brief version in different samples, and examination of how comparable the brief version is in women and men of diverse ages. This study compared factor structure fit and other psychometric properties between the original and brief versions in three independent samples of adults to evaluate the reliability and validity of this brief version. It also examined measurement invariance across gender in a middle-aged community sample. Participants included university women (N = 659), university women and men (N = 358), and crowdsourced community women and men (N = 544). Across samples, compared to the original version the brief version demonstrated greater internal consistency, somewhat less item overlap, and superior model fit in confirmatory factor analyses, although some fit indices fell below recommended cut-offs. Separate confirmatory factor analyses of the brief version in community women and men suggested the brief version may better fit community men than women, and measurement invariance across gender for the brief version was not supported for the community sample. This independent replication supports the factorial validity of the brief version in three samples of students and crowdsourced community adults, and highlights the importance of further examination of the psychometric properties of this brief three-factor version across gender and age categories, among others sample characteristics. PMID- 30476705 TI - Interferon-beta treated-multiple sclerosis patients exhibit a decreased ratio between immature/transitional B cell subset and plasmablasts. AB - Our aim was to quantify circulating B cell subsets; immature/transitional, naive, CD27- and CD27+ memory cells and plasmablasts, in relapsing-remitting multiple sclerosis patients treated with IFN-beta. The most relevant findings were a significant increase of plasmablasts and a decrease of immature/transitional B cells, resulting in a decreased ratio between those cells in relapse RRMS, together with an increase of CD27- and CD27+IgM+ memory B cell subsets in both phases of the disease. These alterations point to an active B cell response, particularly in relapse, and the above referred ratio could constitute a good biomarker of relapse in patients that underwent IFN-beta treatment. PMID- 30476706 TI - Identification of transcription factor-miRNA-lncRNA feed-forward loops in breast cancer subtypes. AB - Previous studies have demonstrated that transcription factor-miRNA-gene feed forward loops (FFLs) played important roles in tumorigenesis. However, the lncRNA involved FFLs have not been explored very well. Understanding the characteristics of lncRNA-involved FFLs in breast cancer subtypes may be a key question with clinical implications. In this study, we firstly constructed an integrated background regulatory network. Then, based on mRNA, miRNA, and lncRNA differential expression, we identified 147, 140, 284, 1031 dysregulated FFLs for luminal A, luminal B, HER2+ and basal-like subtype of breast cancer, respectively. Importantly, the known breast cancer-associated lncRNAs and miRNAs were enriched in the identified dysregulated FFLs. Through merging the dysregulated FFLs, we constructed the regulatory sub-network for each subtype. We found that all sub-networks were enriched in the well-known cancer-related pathways, such as cell cycle, pathways in cancer. Next, we also identified potential prognostic FFLs for subtypes of breast cancer, such as the hsa-miR-182 5p_JUN_XIST in basal-like subtype. Finally, we also discussed the potential application of inferring the candidate drugs for breast cancer treatment through modulating the lncRNA expression in the dysregulated FFLs. Collectively, this study elucidated the roles of lncRNA-involved FFLs in breast cancer subtypes, which could contribute to understanding breast cancer pathogenesis and improving the treatment. PMID- 30476707 TI - Erratum to "LQTA-R: A new 3D-QSAR methodology applied to a set of DGAT1 inhibitors" [Computat. Biol. Chem. 74 (2018) 123-131]. PMID- 30476708 TI - Molecular docking studies, charge transfer excitation and wave function analyses (ESP, ELF, LOL) on valacyclovir : A potential antiviral drug. AB - Valacyclovir is the l-valyl ester prodrug of the antiviral drug acyclovir that exhibits activity against Herpes simplex virus types and varicella zoster virus. An explicit surface analysis on the title compound was carried out theoretically using the wavefunction analyser multiwfn software, inorder to study the reactivity of the compound. The input wavefunction files were generated by Gaussian 09W software using B3LYP/6-311++G(d,p) as the basis set. The structure of the title compound was optimized; wave function analyses and the molecular docking studies were completed. The UV spectrum was experimentally recorded in solvent phase and in addition to it the electronic absorption spectrum of the compound was evaluated by TD-DFT in the gas and solvent phase. The ESP (Electrostatic potential) map points out the surface extremas where the global surface minimum is seen at the oxygen atom with the value -61.5675 and global surface maximum near the hydrogen atom with the value 67.862. The energy band gap obtained from the HOMO-LUMO gap (E = 3.6023 eV) were found to be in agreement with the energy gap (E = 3.6174 eV) calculated using lambdamax from the UV spectrum. The electron-hole distribution of the molecule indicated a charge transfer within the molecule. Electron Localization Function, Local Orbital Localizer, Thermodynamic functions were discussed. The reactive sites of the compound were studied from the fukui function calculations and chemical descriptors define the reactivity of the molecule on the whole. The antiviral activities of the title compound against various viral proteins (VZV, HSV, Dengue) were studied using molecular docking. PMID- 30476709 TI - Neurophysiological effects of continuous cortical stimulation in epilepsy - Spike and spontaneous ECoG activity. AB - OBJECTIVE: The effect of continuous subthreshold cortical stimulation (CSCS) over the seizure onset zone (SOZ) in epilepsy was analyzed to delineate the affected physiological processes. METHOD: ECoG data was recorded over SOZ and adjacent regions in patients (n = 7) with refractory-epilepsy. Data was reviewed before and during 2 Hz cortical electrical stimulation. Group differences were estimated using ANOVA and correlation with Pearson's r. RESULTS: CSCS reduced background ECoG power at SOZ (p < 0.05), increased spectral coherence (p < 0.05) and reduced spike rate (p < 0.01) over all recorded sites. Spectral power and coherence (p < 0.01) correlated with spike rate at SOZ but not with each other at any location. Spike morphology correlated with spike-rate over all recorded sites (p < 0.0001) and with spectral power and coherence at SOZ (p < 0.01). CONCLUSION: This study shows changes in cortical electrophysiology during CSCS over the SOZ where spike rate reduction correlated with two independent electrophysiological parameters, background power and coherence. These results suggest the possibility of a causal relationship between spectral power, coherence and interictal spikes which may be related to seizure rate. SIGNIFICANCE: Improved understanding of the effect of electrical stimulation on epileptic tissue could suggest improvements in stimulation paradigms to reduce seizure frequency. PMID- 30476710 TI - Predicting prognosis in patients with first-episode psychosis using auditory P300: A 1-year follow-up study. AB - OBJECTIVE: To clarify the role of auditory P300 in predicting prognosis in patients with first-episode psychosis (FEP) during a 1-year follow-up. METHODS: Auditory P300 of 24 patients with FEP and 24 matched healthy control (HC) participants were measured at baseline. The clinical status of the FEP patients was assessed at baseline and reassessed after 1 year. P300 amplitudes and latencies among the groups were analyzed using repeated measures analysis of variance. Multiple regression analysis was conducted to assess the predictive value of P300 in patients with FEP during the 1-year follow-up. RESULTS: Auditory P300 amplitudes were significantly smaller in FEP patients than HCs. Higher baseline P300 amplitudes at CPz significantly predicted better improvements in the Positive and Negative Syndrome Scale total, positive, and general scores, as well as in the Global Assessment of Functioning and Brief Psychiatric Rating Scale. CONCLUSIONS: P300 may predict improvements in symptoms, functional status, and overall psychiatric status in patients with FEP. SIGNIFICANCE: We first show that P300 amplitude at baseline predicts symptomatic and functional improvements after 1 year of treatment in patients with FEP. This finding may aid in effective interventions from the beginning of a psychotic episode to improve subsequent outcomes in clinical practice. PMID- 30476711 TI - Electroencephalogram dynamics during general anesthesia predict the later incidence and duration of burst-suppression during cardiopulmonary bypass. AB - OBJECTIVE: Electroencephalogram burst-suppression during general anesthesia is associated with post-operative delirium (POD). Whether burst-suppression causes POD or merely reflects susceptibility to POD is unclear. We hypothesized decreased intraoperative alpha (8-12 Hz) and beta (13-33 Hz) power prior to the occurrence of burst-suppression in susceptible patients. METHODS: We analyzed intraoperative electroencephalogram data of cardiac surgical patients undergoing cardiopulmonary bypass (CPB). We detected the incidence and duration of CPB burst suppression with an automated burst-suppression detection algorithm. We analyzed EEG data with multitaper spectral estimation methods. We assessed associations between patient characteristics and burst-suppression using Binomial and Zero inflated Poisson Regression Models. RESULTS: We found significantly decreased alpha and beta power (7.8-22.95 Hz) in the CPB burst-suppression cohort. The odds ratio for the association between point estimates for alpha and beta power (7.8 22.95 Hz) and the incidence of burst-suppression was 0.88 (95% CI: 0.79-0.98). The incidence rate ratio for the association between point estimates for power between the alpha and beta range and the duration of burst-suppression was 0.89 (95% CI: 0.84-0.93). CONCLUSION: Decreased intra-operative power within the alpha and beta range was associated with susceptibility to burst-suppression during CPB. SIGNIFICANCE: This dynamic may be used to develop principled neurophysiological-based approaches to aid the preemptive identification and targeted care of POD vulnerable patients. PMID- 30476712 TI - Stuttering as a matter of delay in neural activation: A combined TMS/EEG study. AB - OBJECTIVE: Brain dynamics in developmental stuttering (DS) are not well understood. The supplementary motor area (SMA) plays a crucial role, since it communicates with regions related to planning/execution of movements, and with sub-cortical regions involved in paced/voluntary acts (such as speech). We used TMS combined with EEG to shed light on connections in DS, stimulating the SMA. METHODS: TMS/EEG was recorded in adult DS and fluent speakers (FS), stimulating the SMA during rest. TMS-evoked potentials and source distribution were evaluated. RESULTS: Compared to FS, stutterers showed lower activity of neural sources in early time windows: 66-82 ms in SMA, and 91-102 ms in the left inferior frontal cortex and left inferior parietal lobule. Stutterers, however, showed higher activations in later time windows (i.e. from 260-460 ms), in temporal/premotor regions of the right hemisphere. CONCLUSIONS: These findings represent the functional counterpart to known white matter and cortico-basal thalamo-cortical abnormalities in DS. They also explain how white matter abnormalities and cortico-basal-thalamo-cortical dysfunctions may be associated in DS. Finally, a mechanism is proposed in which compensatory activity of the non dominant (right) hemisphere is recruited. SIGNIFICANCE: DS may be a disorder of neural timing that appears to be delayed compared to FS; new mechanisms that support stuttering symptoms are inferred; the SMA may be a promising target for neuro-rehabilitation. PMID- 30476713 TI - Metal-mediated base pairing in DNA involving the artificial nucleobase imidazole 4-carboxylate. AB - The use of imidazole-4-carboxylate (X) as an artificial nucleobase in metal mediated base pairing is reported. Towards this end, the corresponding deoxyribonucleoside was synthesized and structurally characterized as its sodium salt (sodium 1,2-dideoxy-1-(4-carboxyimidazol-1-yl)-d-ribofuranose). The deoxyribonucleoside was incorporated into different DNA duplexes (parallel stranded and antiparallel-stranded), and their Cu(II)- and Ag(I)-binding behavior was investigated. It was shown that both X-Cu(II)-X and X-Ag(I)-X base pairs can be formed, with the former being more stabilizing than the latter. The formation of an X-Cu(II)-X base pair is accompanied by an increase in the duplex melting temperature of approximately 20 degrees C for antiparallel-stranded duplexes and of 12 degrees C for the parallel-stranded duplex under investigation. Imidazole 4-carboxylate represents the first imidazole-based nucleoside for Cu(II)-mediated base pairing. Moreover, it is the smallest nucleoside known to form stable Cu(II) mediated base pairs. Structures of the X-Cu(II)-X and X-Ag(I)-X base pairs are proposed, too, based on molecular structures obtained using the model nucleobase 1-benzyl-1H-imidazole-4-carboxylate. PMID- 30476714 TI - In-depth synthetic, physicochemical and in vitro biological investigation of a new ternary V(IV) antioxidant material based on curcumin. AB - Curcumin is a natural product with a broad spectrum of beneficial properties relating to pharmaceutical applications, extending from traditional remedies to modern cosmetics. The biological activity of such pigments, however, is limited by their solubility and bioavailability, thereby necessitating new ways of achieving optimal tissue cellular response and efficacy as drugs. Metal ion complexation provides a significant route toward improvement of curcumin stability and biological activity, with vanadium being a representative such metal ion, amply encountered in biological systems and exhibiting exogenous bioactivity through potential pharmaceuticals. Driven by the need to optimally increase curcumin bioavailability and bioactivity through complexation, synthetic efforts were launched to seek out stable species, ultimately leading to the synthesis and isolation of a new ternary V(IV)-curcumin-(2,2'-bipyridine) complex. Physicochemical characterization (elemental analysis, FT-IR, Thermogravimetry (TGA), UV-Visible, NMR, ESI-MS, Fluorescence, X-rays) portrayed the solid-state and solution properties of the ternary complex. Pulsed-EPR spectroscopy, in frozen solutions, suggested the presence of two species, cis- and trans-conformers. Density Functional Theory (DFT) calculations revealed the salient features and energetics of the two conformers, thereby complementing EPR spectroscopy. The well-described profile of the vanadium species led to its in vitro biological investigation involving toxicity, cell metabolism inhibition in S. cerevisiae cultures, Reactive Oxygen Species (ROS)-suppressing capacity, lipid peroxidation, and plasmid DNA degradation. A multitude of bio-assays and methodologies, in comparison to free curcumin, showed that it exhibits its antioxidant potential in a concentration-dependent fashion, thereby formulating a bioreactivity profile supporting development of new efficient vanado pharmaceuticals, targeting (extra)intra-cellular processes under (patho)physiological conditions. PMID- 30476715 TI - Bleeding and thrombotic events occur early in children on durable ventricular assist devices. AB - INTRODUCTION: Durable Ventricular Assist Devices (VADs) are increasingly used in children with end-stage heart failure. Major complications are bleeding and thromboembolism (TE). Our objective was to determine the timing, incidence and risk factors for bleeding and TE in children implanted with VADs. METHODS: This was a retrospective cohort of 8 years experience for children implanted with HeartWare HVAD and Berlin Heart EXCOR VADs at the Royal Children's Hospital, Melbourne. RESULTS: 44 patients were implanted with Berlin Heart EXCOR or HeartWare HVAD devices. Major bleeding occurred in 17 patients (39%), 7 (16%) experienced thromboembolic strokes, 13 (30%) required device exchange for TE, and 4 (9%) experienced arterial thromboembolism. Twenty-seven patients (61%) were transplanted, three (7%) recovered, and six (14%) remain on device when censored. Eight patients (18%) died on VAD, with leading causes being thromboembolic stroke and intracranial bleeding. The majority of bleeding events and thromboembolic events occurred while patients were on unfractionated heparin (bleeding 66%, TE 40.5%) or transitioning between heparin and warfarin (bleeding 22%, TE 38%). Majority of patients were on more than one antiplatelet agent at the time of a major bleeding (87%) or thromboembolic (89%) event. CONCLUSIONS: The majority of bleeding and TE events occurring in children supported with durable VADs occur when they are on unfractionated heparin or transitioning to warfarin. Modifications to anticoagulation and monitoring in the early post-operative periods should be a research focus. PMID- 30476716 TI - Effect of low and moderate dose FEIBA to reverse major bleeding in patients on direct oral anticoagulants. AB - OBJECTIVE: Management of acute, major or life threatening bleeding in the presence of direct acting oral anticoagulants (DOAC) is unclear. In the absence of a specific antidote, or in situations where there is a need for adjunctive therapy, the ideal prothrombin complex concentrate and dose is unclear. The goal of our study was to evaluate the outcomes of our reduced dosing strategy with FEIBA in patients experiencing a DOAC-related bleeding event. DESIGN: Retrospective analysis of patients treated with FEIBA for a DOAC-related bleeding event. SETTING: Academic medical center PATIENTS: Consecutive patients between May 2011 and April 2017 receiving FEIBA for a DOAC-related bleed INTERVENTIONS: None MEASUREMENTS & MAIN RESULTS: Of the 64 patients included in this analysis, 38 patients received low dose FEIBA (mean 10.0 +/- 3.6 units/kg) and 26 received moderate dose (mean 24.3 +/- 2.1 units/kg) FEIBA; an additional dose was requested in 6 patients. Six dabigatran patients received idarucizumab. 30 day event rates included 5 thromboembolic events (8%) and 9 (14%) patients expired. Follow-up CT-imaging for ICH, endoscopy/colonoscopy, or interventional radiology exams did not reveal any clinically concerning active bleeding or hematoma expansion except in 2 ICH patients with slight expansion between imaging sessions. CONCLUSIONS: Low (<20 units/kg) to moderate (20-30 units/kg) doses of FEIBA, with the option for a repeat dose, may be an effective management strategy for obtaining hemostasis in DOAC-related major bleeding events. PMID- 30476717 TI - Pancreatic stellate cells derived from human pancreatic cancer demonstrate aberrant SPARC-dependent ECM remodeling in 3D engineered fibrotic tissue of clinically relevant thickness. AB - Desmoplasia is a hallmark of pancreatic cancer and consists of fibrotic cells and secreted extracellular matrix (ECM) components. Various in vitro three dimensional (3D) models of desmoplasia have been reported, but little is known about the relevant thickness of the engineered fibrotic tissue. We thus measured the thickness of fibrotic tissue in human pancreatic cancer, as defined by the distance from the blood vessel wall to tumor cells. We then generated a 3D fibrosis model with a thickness reaching the clinically observed range using pancreatic stellate cells (PSCs), the main cellular constituent of pancreatic cancer desmoplasia. Using this model, we found that Collagen fiber deposition was increased and Fibronectin fibril orientation drastically remodeled by PSCs, but not normal fibroblasts, in a manner dependent on Transforming Growth Factor (TGF) beta/Rho-Associated Kinase (ROCK) signaling and Matrix Metalloproteinase (MMP) activity. Finally, by targeting Secreted Protein, Acidic and Rich in Cysteine (SPARC) by siRNA, we found that SPARC expression in PSCs was necessary for ECM remodeling. Taken together, we developed a 3D fibrosis model of pancreatic cancer with a clinically relevant thickness and observed aberrant SPARC-dependent ECM remodeling in cancer-derived PSCs. PMID- 30476718 TI - Determination of the small amount of proteins interacting with TiO2 nanotubes by AFM-measurement. AB - Detecting the small amounts of proteins interacting effectively with the solid film electrodes surface still remains a challenge. To address this, in this work, a new approach was proposed by the combination of the adhesion forces and the molecular interaction measured with AFM. Cytochrome c (Cyt C) interacting effectively with TiO2 nanotube arrays (TNAs) was chosen as a probe. The amounts of Cyt C molecules interacting effectively on TNAs surface (CTNA) range from 5.5*10-12 to 7.0*10-12 mol/cm2 (68.2-86.8 ng/cm2) and they are comparable with the values obtained by the electrochemistry method in the literature, in evidence of the accuracy of this AFM-based approach. The reliability of the proposed approach was further verified by conducting Surface Enhanced Raman Scattering (SERS) measurements and estimating the enhancement factor (EF). This interaction based AFM approach can be used to accurately obtain the small amounts of adsorbed substances on the solid film electrodes surface in the applications such as biosensors, biocatalysis, and drug delivery, etc. PMID- 30476719 TI - Structural gymnastics of RAG-mediated DNA cleavage in V(D)J recombination. AB - A hallmark of vertebrate immunity is the diverse repertoire of antigen-receptor genes that results from combinatorial splicing of gene coding segments by V(D)J recombination. The (RAG1-RAG2)2 endonuclease complex (RAG) specifically recognizes and cleaves a pair of recombination signal sequences (RSSs), 12-RSS and 23-RSS, via the catalytic steps of nicking and hairpin formation. Both RSSs immediately flank the coding end segments and are composed of a conserved heptamer, a conserved nonamer, and a non-conserved spacer of either 12 base pairs (bp) or 23 bp in between. A single RAG complex only synapses a 12-RSS and a 23 RSS, which was denoted the 12/23 rule, a dogma that ensures recombination between V, D and J segments, but not within the same type of segments. This review recapitulates current structural studies to highlight the conformational transformations in both the RAG complex and the RSS during the consecutive steps of catalysis. The emerging structural mechanism emphasizes distortion of intact RSS and nicked RSS exerted by a piston-like motion in RAG1 and by dimer closure, respectively. Bipartite recognition of heptamer and nonamer, flexibly linked nonamer-binding domain dimer relatively to the heptamer recognition region dimer, and RSS plasticity and bending by HMGB1 together contribute to the molecular basis of the 12/23 rule in the RAG molecular machine. PMID- 30476721 TI - Therapeutic effects of melatonin on cerebral ischemia reperfusion injury: Role of Yap-OPA1 signaling pathway and mitochondrial fusion. AB - The role of OPA1-related mitochondrial fusion in brain reperfusion stress has remained elusive. The aim of our study is to explore whether melatonin alleviates cerebral IR injury by modulating OPA1-related mitochondrial fusion. We found that melatonin reduced infarct area and suppressed neuron death during reperfusion stress. Biological studies have revealed that IR-inhibited mitochondrial fusion was largely reversed by melatonin via upregulated OPA1 expression. Knocking down OPA1 abrogated the protective effects of melatonin on mitochondrial energy metabolism and mitochondrial apoptosis. In addition, we also found that melatonin modified OPA1 expression via the Yap-Hippo pathway; blockade of the Yap-Hippo pathway induced neuron death and mitochondrial damage despite treatment with melatonin. Altogether, our data demonstrated that cerebral IR injury is closely associated with defective OPA1-related mitochondrial fusion. Melatonin supplementation enhances OPA1-related mitochondrial fusion by activating the Yap Hippo pathway, ultimately reducing brain reperfusion stress. PMID- 30476720 TI - Mandatory reporting of child maltreatment when delivering family-based treatment for eating disorders: A framework analysis of practitioner experiences. AB - BACKGROUND: Increasingly, evidence-based treatment guidelines emphasize the role of parents in first-line treatment approaches for child and adolescent psychiatric disorders. Yet there are no best practice guidelines for practitioners on the identification and reporting of suspicions and disclosures of child maltreatment to child protection services (CPS) in these circumstances. This is particularly concerning given that undetected and unreported child maltreatment may exacerbate the vulnerabilities of youth with mental illness. OBJECTIVE: The objective of this study is to describe family-based practitioners' experiences of reporting child emotional abuse (CEA) and child exposure to intimate partner violence (CEIPV) to CPS. PARTICIPANTS AND SETTING: Data from 30 practitioners based in five countries were included in this study. METHODS: We use deductive framework analysis of qualitative interviews with practitioners providing family-based treatment to youth diagnosed with eating disorders. Interviews for the primary study elicited participants' perceptions and experiences of identifying and responding to CEA and CEIPV in practice. All transcripts were analysed by two authors using constructs identified by a qualitative meta-synthesis of mandatory reporting experiences among service providers. RESULTS: Three participants identified as male, 27 as female. Practitioners described negative experiences when reporting CEA and CEIPV to CPS, as well as variable CPS responses to their reports. Findings confirm the need for additional training for mental health practitioners to recognize and report CEA and CEIPV. CONCLUSIONS: Management of CEA and CEIPV while delivering family-based treatment remains an important area of practice that requires further inquiry. PMID- 30476722 TI - Cytokine augments the sorafenib-induced apoptosis in Huh7 liver cancer cell by inducing mitochondrial fragmentation and activating MAPK-JNK signalling pathway. AB - Sorafenib is a standard targeted drug used to treat hepatocellular carcinoma (HCC). Notably, cytokine has been found to further enhance the therapeutic effectiveness of the targeted drug. Thereby, the aim of this study is to verify whether cytokine IL-2 could increase the anti-cancer effects of sorafenib on liver cancer in vitro. Huh7 cells were used in the present study and the cell apoptosis and migration were determined in response to sorafenib treatment. Then, siRNA and pathway blocker were used to determine the molecular mechanisms by which IL-2 enhance the therapeutic effectiveness of Huh7 liver cancer cell in vitro. The data in our study illustrated that sorafenib treatment induced apoptosis in Huh7 liver cancer cell in vitro, an effect that was accompanied with a drop in cell proliferation and migration. Biological investigation demonstrated that IL-2 supplementation further augmented the pro-apoptotic effects of sorafenib in vitro. At the molecular levels, the combination of IL-2 and sorafenib impaired mitochondrial respiratory function, reduced mitochondrial potential, promoted mitochondrial ROS overloading and activated mitochondrial apoptotic pathway. Meanwhile, we found that IL-2 supplementation induced mitochondrial stress via activating mitochondrial fragmentation in a manner dependent on MAPK-JNK signalling pathway and TAZ protein. Blockade of the JNK signalling pathway and/or knockdown of TAZ could abrogate the inhibitor effects of IL-2/sorafenib on liver cancer survival, growth and mobility. Collectively, these data indicated that IL-2 supplementation could further augment the anti cancer effectiveness of sorafenib via activating mitochondrial fragmentation in a manner dependent on MAPK-JNK signalling pathway and TAZ protein. This finding identifies mitochondrial stress and the JNK-Hippo pathway as the potential targets to treat liver cancer. PMID- 30476723 TI - Apabetalone downregulates factors and pathways associated with vascular calcification. AB - BACKGROUND AND AIMS: Apabetalone is an inhibitor of bromodomain and extraterminal (BET) proteins. In clinical trials, apabetalone reduced the incidence of major adverse cardiac events (MACE) in patients with cardiovascular disease and reduced circulating factors that promote vascular calcification (VC). Because VC contributes to MACE, effects of apabetalone on pro-calcific processes were examined. METHODS AND RESULTS: Apabetalone inhibited extracellular calcium deposition and opposed induction of transdifferentiation markers in human coronary artery vascular smooth muscle cells (VSMCs) under osteogenic culture conditions. Tissue-nonspecific alkaline phosphatase (TNAP) is a key contributor to VC, and apabetalone suppressed osteogenic induction of the mRNA, protein and enzyme activity. The liver is a major source of circulating TNAP, and apabetalone also downregulated TNAP expression in primary human hepatocytes. BRD4, a transcriptional regulator and target of apabetalone, has been linked to calcification. Osteogenic transdifferentiation of VSMCs resulted in disassembly of 100 BRD4-rich enhancers, with concomitant enlargement of remaining enhancers. Apabetalone reduced the size of BRD4-rich enhancers, consistent with disrupting BRD4 association with chromatin. 38 genes were uniquely associated with BRD4-rich enhancers in osteogenic conditions; 11 were previously associated with calcification. Apabetalone reduced levels of BRD4 on many of these enhancers, which correlated with decreased expression of the associated gene. Bioinformatics revealed BRD4 may cooperate with 7 specific transcription factors to promote transdifferentiation and calcification. CONCLUSIONS: Apabetalone counters transdifferentiation and calcification of VSMCs via an epigenetic mechanism involving specific transcription factors. The mechanistic findings, combined with evidence from clinical trials, support further development of apabetalone as a therapeutic for VC. PMID- 30476724 TI - Variation in the barriers to compassion across healthcare training and disciplines: A cross-sectional study of doctors, nurses, and medical students. AB - BACKGROUND: Despite the established importance of compassion in health, studies examining the specific barriers to compassionate care in healthcare are few. Recent work suggests that examining differences as a function of professional development and identifying variation in barriers to compassionate care across professions may highlight the origins of barriers and inform the development of compassion-enhancing interventions suited to the unique challenges of different professions and stages of training. OBJECTIVES: To explore whether the barriers to compassion vary (a) between physicians and nurses and (b) across samples of physicians and medical students (i.e., as a function of development and clinical experience). It was expected that medical students would report greater barriers than physicians and that nurses would generally report lower barriers to compassion, other than for external barriers. METHODS: Registered nurses, physicians, and medical students were recruited using convenience sampling in New Zealand. Following consent, 1700 participants (801 nurses, 516 physicians, and 383 medical students) completed a survey including the Copenhagen Burnout Inventory and the Barriers to Physician Compassion questionnaire. RESULTS: As expected, medical students reported greater barriers to compassion than physicians and nurses, with both professions generally reporting lower barriers. However, and also consistent with hypotheses, nurses reported greater work environment-related barriers relative to physicians. DISCUSSION: Students reported greater barriers than physicians. While nurses generally reported lower barriers than physicians, they specifically reported greater work environment related barriers. For nurses, results highlight the importance of implementing interventions that reduce external barriers to compassion, specifically the need to alleviate the structural barriers and restrictions that nurses face. For medical students and younger healthcare professionals, the results highlight the importance of mentorship, support, and ongoing professional and emotional development. PMID- 30476725 TI - Why articles continue to be cited after they have been retracted: An audit of retraction notices. AB - BACKGROUND: Papers continue to be cited by authors even after they have been retracted. Retraction notices provide readers with information about retracted papers and may help minimise post-retraction citation. To date, a review of the quality of retraction notices in nursing science has not been reported. DESIGN: An audit of retraction notices associated with 29 retracted manuscripts published in nursing science journals. METHODS: Retraction notices were reviewed again using the Committee on Publication Ethics (COPE) guidelines. RESULTS: In total, 28 retraction notices were retrieved and reviewed (one retracted paper did not have a retraction notice). Details of the retracted manuscripts were included in all reviewed notices and, in all but two, author names were reported. Details of the time between a paper being published and retracted were not reported and generally there was a little information in notices about how the retraction decisions were made. All retraction notices were freely available. Seven notices stated who had made the decision to retract. Twenty-two (77%) notices stated the reason for retraction. Notices were brief and contained factual information. The webpages of three retracted articles did not clearly indicate that the paper had been retracted. CONCLUSION: More detailed and informative retraction notices will inform readers and may help reduce post- retraction citation. PMID- 30476726 TI - p-mTOR, p-4EBP-1 and eIF4E expression in canine prostatic carcinoma. AB - The mTOR/4E-BP1/eIF4E pathway plays important roles in the neoplastic transformation process and in tumour growth. In men, the mTOR/4E-BP1/eIF4E pathway was described as altered in different tumours, including prostate cancer (PC). Apart from humans, the dog is the only species that develops PC with high frequency and is considered a good model for comparative oncology initiatives. Due to limited information on this pathway in canine tumours, this study aimed to investigate mTOR, 4E-BP1 and eIF4E gene and protein expression in canine PC, as well as in metastatic and normal prostatic tissues, and to evaluate the correlations between gene/protein expression and Gleason score (GS) in PC. A total of 35 formalin-fixed paraffin-embedded (FFPE) samples, including 13 of normal prostatic tissue, 17 PC samples and 5 metastasis samples, were evaluated by immunohistochemistry and qPCR. mTOR gene mutation in the kinase domain was also investigated. We identified higher p-mTOR and eIF4E protein levels in canine PC with higher GS values (>= 8) and a significant positive correlation in expression between these proteins. eIF4E overexpression was observed in metastasis relative to expression in normal samples. Our data suggest that p-mTOR and eIF4E expression is positively correlated with GS in canine PC, similar to the pattern in humans. More studies of the mTOR/4EBP1/eIF4E pathway should be performed to identify possible correlations of the proteins involved with clinical and pathologic findings in canine PC and the roles of these proteins as therapeutic targets for the treatment of canine PC. PMID- 30476727 TI - abcb1ab p-glycoprotein is involved in the uptake of the novel antidepressant vortioxetine into the brain of mice. AB - A clinically important and well-studied transporter of the blood-brain barrier (BBB) is P-glycoprotein (P-gp), the gene product of ABCB1. Animal studies have shown that brain concentrations of many antidepressants depend on P-gp. However, biochemical properties, which might allow the prediction of pharmacodynamical involvement of P-gp have not yet been identified, hence thorough experimental testing of each novel drug is needed to determine its P-gp substrate status. In the current study, we tested the P-gp substrate status for the antidepressant vortioxetine using double abcb1ab knock-out (KO) mice. Cerebral concentrations of vortioxetine were 2.3 times higher in P-gp deficient mice compared to wildtype (WT) controls. No significant difference was found regarding the concentration of the drug in the plasma and other organs (liver, kidney, spleen) between KO and WT mice. The results of our study provide conclusive in-vivo evidence that in mice vortioxetine's brain bioavailability is P-gp dependent, expanding previous findings on this topic. PMID- 30476728 TI - Skills for safe practice - A qualitative study to evaluate the use of simulation in safeguarding children teaching for pre-registration children's nurses. AB - Safeguarding children teaching is a required component in all pre-registration nursing curricula. A structured approach to this teaching as part of preparation for registration as a children's nurse was developed jointly by the Course Leader and the Designated Nurse for Safeguarding Children. This approach aims to equip children's nurses with the necessary theoretical knowledge and practical skills needed for safe practice. A key element in this curriculum is simulation, where students must assess injuries on manikins, select and complete appropriate documentation, and perform a nursing handover. Simulation has recognised value in nurse education but its use in safeguarding children teaching for student children's nurses has not previously been widely reported. This small-scale qualitative study explored the student experience and the impact of simulation teaching in the development of relevant knowledge and the core safeguarding skill set of observation, interpretation, documentation and communication. The methodology for this small, qualitative study was triangulated, comprising observation of the simulation teaching and two sets of semi-structured interviews. The resultant data was investigated using thematic analysis. The outcome of the study suggested that students were able to transfer learning from the simulation into clinical practice, and that simulation as an approach to safeguarding children teaching resonated with the students' preferred learning style and merits further consideration and evaluation. PMID- 30476729 TI - Epilepsy identification based on EEG signal using RQA method. AB - PURPOSE: Epilepsy is one of the most common neurological diseases and its cause is not unequivocal. Thus, additional methods and searches that may help to diagnose the disease are used in the clinical practice. In this study, we tested the possibility of using the Recurrence Quantification Analysis (RQA) method to identify epilepsy and present the analysis of EEG signals of healthy patients and epileptic patients by the RQA method. MATERIALS/METHODS: The recordings of signals belong to 13 patients, which were divided into 2 groups: Group A (5 epileptic patients) and Group B (8 healthy patients). In this study Fp1, Fp2, T3 and T4 electrodes were considered in the analysis using the RQA method. RESULTS: It is difficult to explore the dynamics of signals by linear methods. In this study, another way of analyzing the dynamics of signals by the RQA method is presented. The RQA method revealed differences in the dynamics between the epileptic and normal signals, which seemed important in an organoleptic way. It was found that the dynamics of epileptic signals is more periodic than normal signals. To confirm the correctness of the statements issued for the RQA data the Principal Component Analysis mapping was applied. This method showed more clearly the differences in the dynamics of both signals. CONCLUSIONS: The RQA method can be used to identify nonlinear biomedical signals such as EEG signals. PMID- 30476730 TI - Evolution and recurrence of gastrointestinal immune-related adverse events induced by immune checkpoint inhibitors. AB - BACKGROUND: Immune checkpoint inhibitors (ICIs), such as anti-CTLA-4 and anti-PD 1 antibodies, are effective against several malignancies. They are associated with gastrointestinal immune-related adverse events (GI-IrAEs), which may be severe and lead to ICI discontinuation. We assessed the risk of evolution of GI IrAEs to chronic GI inflammation and the risk of recurrence after a second line of ICI. PATIENTS AND METHODS: This was a single-centre study. Included patients had a GI-IrAE due to ICIs between September 2010 and July 2017. We assessed the persistence of symptoms, endoscopic and/or histological inflammation, and the risk of recurrent GI-IrAEs after the second line of ICIs. RESULTS: Eighty patients were included. The median follow-up was 8.4 months (0.36-72.3). The median duration of GI symptoms was 1.5 months (5 days-10.3 months): 1.4 months (7 days-4.9 months) with anti-CTLA-4, 2.0 months (5 days-10.3 months) with anti-PD-1 and 1.0 month (8 days-3.4 months) with combination therapy (log-rank test: p = 0.02). Three and 6 months after the beginning of GI-IrAEs, 22% (95% confidence interval: 14%-33%) and 5.4% (2.0%-14.7%) of patients had persistent symptoms, respectively. After a median of 6 months, 20/27 patients had endoscopic and/or histological inflammation, of whom, seven were symptom free. After the first episode, 6/26 patients relapsed after receiving another course of ICIs. Among these 26, 89% (77%-100%) had no recurrence after 3 months, 71% or 95% if the second line was anti-CTLA-4 or anti-PD-1, respectively. CONCLUSION: GI-IrAEs seem to be acute or subacute, not chronic. Reintroduction of ICIs is possible in patients who had GI-IrAE. PMID- 30476731 TI - Efficacy of bevacizumab in first-line treatment of metastatic colorectal cancer: A systematic review and meta-analysis. AB - BACKGROUND: This systematic review and meta-analysis aims to evaluate the additive effect of bevacizumab when combined with first-line chemotherapy in metastatic colorectal cancer (mCRC). METHODS: We searched EMBASE, MEDLINE, the Cochrane Library in April 2018. When possible, data were pooled to estimate summary effects. The present analysis evaluated treatment related efficacy based on progression-free survival (PFS) and overall survival (OS). The analysis was performed to define the overall effect and the effect observed in currently used chemotherapy regimens. RESULTS: Seven randomised studies were included. In the analysis of the overall effect, PFS (hazard ratio [HR] 0.71, p < 0.00001) and OS (HR 0.85, p = 0.0008) clearly favoured bevacizumab plus chemotherapy versus chemotherapy alone. When the analysis was focused on currently used chemotherapy excluding 5-FU bolus regimens and including only infusional 5-FU plus irinotecan or oxaliplatin, the addition of bevacizumab prolonged PFS (HR 0.79, p < 0.0001) but not OS (HR 0.92, p = 0.18). However, addition of bevacizumab to fluoropyrimidine monotherapy lead to a significant prolongation of PFS (HR 0.57, p < 0.00001) and OS (HR 0.83, p = 0.03). CONCLUSION: The present meta-analysis demonstrates that the effect of bevacizumab on survival is not consistent throughout the included regimens. Considering only presently used regimens, a significant effect on PFS and OS was only observed when bevacizumab was added to fluoropyrimidine monotherapy. PMID- 30476732 TI - Association between primary origin (head, body and tail) of metastasised pancreatic ductal adenocarcinoma and oncologic outcome: A population-based analysis. AB - INTRODUCTION: The relation between the primary origin of metastasised pancreatic ductal adenocarcinoma (PDAC)-head, body or tail-metastatic patterns and outcomes has not yet been investigated in large population-based studies. METHODS: Patients with metastasised PDAC at diagnosis from the Netherlands Cancer Registry were included (2005-2015). We compared number of metastatic organ sites (1, 2, >=3) and specific metastatic organ sites (peritoneum, liver, lung and extra regional lymph nodes) for the different primary tumour locations. Cox regression analyses were used to determine the association of tumour location and metastatic organ site(s) with overall survival. RESULTS: Overall, we included 9952 patients with metastasised PDAC. The primary origin was head in 5644 (57%), body in 1671 (17%) and tail in 2637 (26%) patients. Differences between primary origins were the number of metastatic organ sites (proportions >=3 sites for head: 4%, for body: 8% and for tail: 13%, p < 0.0001) and peritoneal metastases (present in 13% for head, 24% for body and 30% for tail; p < 0.0001). Median overall survival was 2.6 months for head PDAC (reference), 2.4 months for body PDAC (HR 1.02 [0.97 1.08]) and 1.9 months for tail PDAC (HR 1.20 [1.15-1.26]). Of patients with one metastatic organ site, the worst survival compared with other sites was seen with liver only metastases (2.5 months vs. 2.7-5.1 months), and the best survival for patients, with extra-regional lymph node only metastases (5.1 months). CONCLUSION: Metastatic patterns differ among the primary origins for PDAC with metastasised tail tumours having more metastatic sites, more often peritoneal metastases and worse survival. PMID- 30476733 TI - A time and memory efficient recipe for fast normal mode computations of complexes with icosahedral symmetry. AB - With the recent breakthroughs in experimental technologies, structure determination of extremely large assemblies, many with icosahedral symmetry, has been rapidly accelerating. Computational studies of their dynamics are important to deciphering their functions as well as to structural refinement but are challenged by their extremely large size, which ranges from hundreds of thousands to even millions of atoms. Group theory can be used to significantly speed up the normal mode computations of these symmetric complexes, but the derivation is often obscured by the complexity of group theory and consequently is not widely accessible. To address this problem, this work presents an easy recipe for normal mode computations of complexes with icosahedral symmetry. The recipe details how the Hessian matrix in symmetry coordinates can be constructed in a few easy steps of matrix multiplications, without going through the complexity of group theory. All the "ingredient" matrices required in the recipe are fully provided in the Supplemental Information for easy reproduction. The work is timely considering the expected large in-flux of many more icosahedral assemblies in the near future. The recipe uses a minimum amount of memory and solves the normal modes in a significantly reduced amount of time, making it feasible to perform normal mode computations of these assemblies on most computer systems. PMID- 30476734 TI - Effects of his-tags on physical properties of parvalbumins. AB - A comparative study of His-tagged and non-tagged rat beta-parvalbumin (rWT beta PA), calcium binding protein with the EF-hand calcium binding domains, has been carried out. The attachment of His-tag increases alpha-helical content and decreases beta-sheets and beta-turns content of the metal free form (apo-state) of beta-PA. In contrast to this, the attachment of His-tag decreases alpha helical content by more than 10% and increases contents of beta-sheets and beta turns of the Ca2+-loaded state. According to the dynamic light scattering analysis, apo-state of His-tagged rat beta-PA seems to be less compact compared with the apo-state of non-tagged rat beta-PA. Surprisingly, the attachment of His tag practically does not change mean hydrodynamic radius of Ca2+-loaded rat beta PA. The attachment of His-tag shifts thermal denaturation peaks of both apo- and Ca2+-loaded states of rat beta-PA towards higher temperatures by 3-4 degrees C and slightly decreases its Ca2+ affinity. These results should be taken into consideration in the use of His-tagged parvalbumins. PMID- 30476735 TI - Downregulation of TRPC6 expression is a critical molecular event during FK506 treatment for overactive bladder. AB - PURPOSE: It has been suggested that FK506 could improve some symptoms of OAB in both clinical settings and animal models; however, its mechanism of action is not well-understood. Here, we investigated the effect of FK506 on TRPC6 in bladder smooth muscle, and explored the possible involvement of TRPC6 in OAB. METHODS: FK506 was injected intraperitoneally into rats in which OAB was induced via BOO, and urodynamic indices were recorded. Rats and human bladder smooth muscle tissues with or without OAB were examined for TRPC6 expression by western blot, RT-PCR and IF staining. Cultured BSMCs were treated with PDGF, TRPC6 siRNAs and FK506. Then the TRPC6 expression and cellular proliferation were examined, and the Ca2+ influx and contractility of BSMCs were examined by time-lapse Ca2+ imaging and collagen gel contraction. Finally, IF and Co-IP were performed to test the effects of FK506 on NFAT translocation to the nucleus and the interaction of TRPC6 with FKBP12, respectively. RESULTS: FK506 improved urodynamic indices of OAB rats, and TRPC6 was expressed in rats and human bladder tissues. TRPC6 elevation in OAB rats was inhibited by FK506, and this inhibition coincided with improvements in urodynamic indices. PDGF enhanced TRPC6 expression, cellular proliferation, Ca2+ influx and contractility of BSMCs, and these effects were inhibited by TRPC6 siRNAs and FK506. FK506 inhibited NFAT translocation to the nucleus and disrupted the interaction of TRPC6 with FKBP12. CONCLUSIONS: Our results collectively indicate that FK506 may be used to treat OAB, and that TRPC6 may serve as an attractive target for therapeutic intervention in OAB. PMID- 30476736 TI - Antifungal activity of silver nanoparticles and simvastatin against toxigenic species of Aspergillus. AB - Aspergillus spp. are ubiquitous fungi that grow on stored grains. Some species produce toxins that can harm human and animal health, leading to hepato- and nephrotoxicity, immunosuppression and carcinogenicity. Major fungicides used to prevent fungal growth may be toxic to humans and their repeated use over time increases levels of resistance by microorganisms. Nanotechnology is an emerging field that allows use of antimicrobial compounds in a more efficient manner. In this study, was evaluated the antifungal activity of biogenic silver nanoparticles (AgNPs, synthesized by fungi) and simvastatin (SIM, a semi synthetic drug), alone and in combination against three toxigenic species belonging to the genera Aspergillus section Flavi (Aspergillus flavus, Aspergillus nomius and Aspergillus. parasiticus) and two of section Circumdati (Aspergillus ochraceus and Aspergillus melleus). SIM exhibited a MIC50 of 78 MUg/mL against species of Section Flavi and a MIC50 of 19.5 MUg/mL against species of Section Circumdati. The MIC50 of AgNPs against Aspergillus flavus, Aspergillus nomius and Aspergillus parasiticus was 8 MUg/mL, while the MIC50 was 4 MUg/mL against Aspergillus melleus and Aspergillus ochraceus. Checkerboard assay showed that these compounds, used alone and in combination, have synergistic and additive effects against toxicogenic species of Aspergillus. Analysis by SEM gives an idea of the effect of SIM and AgNPs alone and in combination on spore germination and vegetative growth. Ultrastructural analysis revealed that spore germination was prevented, or aberrant hyphae were formed with multilateral branches upon treatment with SIM and AgNPs. These results reveal potential benefits of using combination of AgNPs and SIM to control fungal growth. PMID- 30476737 TI - Colistin resistance prevalence in Escherichia coli from domestic animals in intensive breeding farms of Jiangsu Province. AB - The global dissemination of colistin resistance has received a great deal of attention. Recently, the plasmid-mediated colistin resistance encoded by mcr genes in Escherichia coli (E. coli) strains from animals, food, and patients in China has been reported frequently. To investigate the colistin resistance and mcr-1 and mcr-2 genes spread in domestic animals in Jiangsu Province, we collected fecael swabs from pigs, chicken and cattle at different ages distributed in intensive feeding farms. The selective chromogenic agar and mcr PCR were used to screen the colistin resistance and mcr gene carriage. Colistin resistant E. coli colonies were identified in 54.25% (440/811), 35.96% (443/1232), and 26.92% (42/156) faecal swabs from pigs, chickens, and cattle, respectively. The prevalence of mcr-1 in colistin resistant E. coli isolates from pigs, chickens and cattle was 68.86% (303/440), 87.58% (388/443), and 71.43% (30/42), respectively, compared to mcr-2 which was present in 46.82% (206/440), 14.90% (66/443), and 19.05% (8/42) of the colistin-resistant E. coli isolated from pigs, chickens and cattle, respectively. Co-occurrence of mcr-1 and mcr-2 was identified in 20% (88/440) in pigs, 7.22% (32/443) in chickens, and 9.52% (4/42) in cattle. Interventions and alternative options are necessary to minimise further dissemination of mcr between food-producing animals and human. PMID- 30476738 TI - Influence of the early bacterial biofilms developed on vats made with seven wood types on PDO Vastedda della valle del Belice cheese characteristics. AB - Early vat bacterial biofilms developed spontaneously through contact with whey have been characterized on seven wood types (Castanea sativa Miller, Cedrus libani, A. Rich., Prunus avium L., Fraxinus ornus L., Juglans regia L., Pinus nigra J.F. Arnold and Populus nigra L.). The present study aimed to evaluate the influence of these biofilms on the microbiological, chemical, physical and sensory characteristics of PDO Vastedda della valle del Belice (VdB) cheese, processed traditionally from raw ewe's milk using wooden tools. To this purpose, the experimental cheeses after 15 d of refrigerated storage were examined. Lactic acid bacteria (LAB) populations dominated the microbial community of all samples. The species more frequently identified were Lactococcus lactis among starter LAB and Lactobacillus paracasei, Lactobacillus rhamnosus, Lactobacillus fermentum and Pediococcus pentosaceus among non starter LAB. Culture-independent analysis of microbiota diversity was performed by MiSeq Illumina that identified Streptococcus as major group followed by members of Enterobacteriaceae family, Lactococcus and Lactobacillus. Generally, the seven tree species did not negatively affect the physicochemical composition of VdB cheeses. Chestnut (both Sicilian and Calabrian) vats produced cheeses with significant lower hue angle (a*/b*) than other wood types. Among chemical parameters, significant variations were registered for aw, primary and secondary lipid oxidation state (significantly lower for the VdB cheeses produced with poplar wood), and volatile organic compounds (VOCs). The significant differences detected among the VOCs emitted from cheeses were not perceived by the panelists who recognized all cheeses from the different trials as similar. This study confirmed the suitability of cedar, cherry, ash, walnut, black pine and poplar as alternative woods to chestnut for the production of the wooden vats employed in cheese making for the Sicilian traditional dairy productions. PMID- 30476739 TI - The role of chemotaxis during Campylobacter jejuni colonisation and pathogenesis. AB - Campylobacter jejuni is a ubiquitous gastrointestinal pathogen, transmitted to humans from birds and animals, where C. jejuni is part of normal intestinal flora. In C. jejuni, similar to other motile bacteria, chemotaxis pathway and the array of chemosensors sense and respond to external stimuli with unique precision and sensitivity and are considered to be critical for bacterial colonisation and pathogenicity. Disruption of any component of the signal transduction pathway consisting of receptor-CheA/CheW-CheY-flagella cascade, the signal adaptation system, and even a loss of a single chemosensory receptor, dramatically reduce the ability of C. jejuni to colonise various animal hosts and to cause disease. PMID- 30476740 TI - Agents and spectres: Life-space on a medium secure forensic psychiatric unit. AB - Medium secure forensic psychiatric units are unique environments within the broader 'post asylum' landscape of mental health services. Length of stay is much greater, a recovery-focused care system is much more difficult to implement, and there is a paucity of suitable "step-down" services. The aim of this study was to examine how forensic psychiatric environments contribute to the shaping of recovery, by examining key features such as social interactions and agency. Here, we report on the findings from patients participating in a qualitative-visual study. This analysis forms part of larger study on staff and patient experiences of secure hospital space. In this paper, the analytical focus is directed towards two key elements of recovery - agency and relationality, using the concept of 'topology' and 'life-space', developed by the social psychologist Kurt Lewin. First, we explore how patients have relative freedom to move within institutional spaces, yet lack relational space. Secondly, we explore how life-space is expanded or compressed by the manner in which the patient's present life in hospital is connected or disconnected from their past or pending future. Finally, we discuss the implications of these findings for a recovery model within secure forensic settings, focused on personalisation and expanded life-space. PMID- 30476741 TI - Politics, economics, how about our health? Impacts of large-scale land acquisitions on therapeutic spaces and wellbeing in coastal Tanzania. AB - One question that has remained unexplored in the global land rush debate is how large-scale land acquisitions affect health and wellbeing of local populations. As part of a larger study, this study advances our understanding in this area by applying the concept of therapeutic landscapes to analyze interviews conducted in two coastal communities in Tanzania where land investments have been prevalent. Our analysis found that local populations perceived traditional lands with sacred sites as therapeutic spaces, which embodied cultural values, and promoted health and wellbeing when protected. Intrusion into these spaces through large-scale land investment is believed to remove their therapeutic attributes, thereby turning them into unhealthy landscapes. Dispossession of these spaces is perceived to heighten community distress resulting in poor psychosocial health. Based on our findings, we suggest that health consequences of land investments should move to the center of the large-scale land acquisition discourse. Health policy should refocus on the psychosocial health impacts of global land investments in Tanzania and other low-income countries. Ultimately local participation in land governance should be strengthened through land reforms in Tanzania and similar contexts, as this may provide a buffer to poor psychosocial health. PMID- 30476742 TI - Measuring management practices in India's district public health bureaucracy. AB - Weak management is widely recognised as a key impediment to scaling-up coverage of health interventions and ensuring health systems are responsive to population needs. Yet there is scant evidence linking management practices in the public administration to effective health service delivery. We report on the development of a tool to measure management practices in India's district health bureaucracy. We first developed a conceptual framework based on a review of the literature and qualitative interviews with district public health managers. Across 16 management practices, we then drafted and piloted questions to be used with a scoring grid to evaluate process-orientated management practices. We implemented the tool in 34 districts of Maharashtra between April and July 2016, interviewing up to three district public health managers per district (n = 99). Using rigorous psychometric methods, we assessed the acceptability, reliability and validity of the tool. We present three key findings. First, the tool was feasible to implement, response rates were high, and there were no missing data. Second, internal consistency of the tool was high and test-retest reliability was comparable with other management tools used in the literature. Third, there was evidence of validity. The number of staff with a management qualification was positively associated with better management practices. Factor analysis showed that one principal component loaded positively on all the management practices although there was little support for management sub-scales. These findings provide novel evidence on the psychometric properties of a tool designed to measure management practices in the public administration of a developing country. Our framework and tool provide the basis to examine associations between district health management practices and health service delivery, and test the effectiveness of management strengthening interventions in India's public health sector. PMID- 30476743 TI - Transcriptomic analysis revealing hepcidin expression in Oryzias melastigma regulated through the JAK-STAT signaling pathway upon exposure to BaP. AB - Our previous study revealed that an antimicrobial peptide hepcidin, can be significantly up-regulated either with LPS challenge or upon exposure to Benzo[a]pyrene (BaP) in red sea bream, but the molecular mechanism involved in whether the transcriptional expression of hepcidin induced by LPS or BaP is regulated through a similar signaling pathway is not yet known. To elucidate the underlying molecular mechanism, the marine model fish Oryzias melastigma was exposed to 1 MUg/L BaP as well as challenged with 5 MUg of LPS per fish. Samples at 3 h post-LPS challenge, and 2 d and 3 d post-BaP exposure were separately collected for transcriptome analysis. General analysis of the predicted immune associated unigenes based on the transcriptomic data showed that the percentages of modulated immune-associated genes were 7% with LPS challenge, and 3% and 7% with BaP exposure at 2 and 3 days, respectively. Genes involved in functions like antimicrobial activity, neutrophil activation, and leukocyte chemotaxis were up regulated with LPS challenge, whereas more than half of the immune associated genes including the KLF family were down-regulated upon BaP exposure, indicating a difference in the modulated immune genes between LPS challenge and BaP exposure. Specific comparative analyses of the immune-associated signal pathways NOD, TOLL, NF-kappaB and JAK-STAT with LPS challenge or upon exposure to BaP, indicated that most of the modulated genes in association with the NOD, TOLL and NF-kappaB pathways were induced with LPS challenge but only a few after exposure to BaP, suggesting that BaP exposure was generally not associated with any of the three signal pathways. Interestingly, further transcriptomic analysis revealed that 5 of the 8 modulated genes associated with the JAK-STAT pathway were down regulated, while 2 inhibiting genes were up-regulated after BaP exposure for 2 days whereas LPS challenge resulted in only less than half modulated, suggesting the possibility of down-regulation caused by BaP exposure through JAK-STAT pathway. Further testing using an EPC cell culture demonstrated that expression of the hepcidin1 gene was less involved in the known signal pathways, such as c/EBP, BMP, and NF-kappaB, but instead mostly in association with the JAK-STAT pathway upon BaP exposure. PMID- 30476744 TI - Profiling microRNA expression in Atlantic killifish (Fundulus heteroclitus) gill and responses to arsenic and hyperosmotic stress. AB - The Atlantic killifish (Fundulus heteroclitus), native to estuarine areas of the Atlantic coast of the United States, has become a valuable ecotoxicological model as a result of its ability to acclimate to rapid environmental changes and adapt to polluted habitats. MicroRNAs (miRNAs) are highly conserved small RNAs that regulate gene expression and play critical roles in stress responses in a variety of organisms. Global miRNA expression in killifish and the potential roles miRNA have in environmental acclimation have yet to be characterized. Accordingly, we profiled miRNA expression in killifish gill for the first time and identified a small group of highly expressed, well-conserved miRNAs as well as 16 novel miRNAs not yet identified in other organisms. Killifish respond to large fluctuations in salinity with rapid changes in gene expression and protein trafficking to maintain osmotic balance, followed by a secondary phase of gene and protein expression changes that enable remodeling of the gills. Arsenic, a major environmental toxicant, was previously shown to inhibit gene expression responses in killifish gill, as well the ability of killifish to acclimate to a rapid increase in salinity. Thus, we examined the individual and combined effects of salinity and arsenic on miRNA expression in killifish gill. Using small RNA sequencing, we identified 270 miRNAs expressed in killifish, and found that miR 135b was differentially expressed in response to arsenic and at 24 h following transfer to salt water. Predicted targets of miR-135b are involved in ion transport, cell motility and migration, GTPase mediated signal transduction and organelle assembly. Consistent with previous studies of these two environmental stressors, we found a significant interaction (i.e., arsenic dependent salinity effect), whereby killifish exposed to arsenic exhibited an opposite response in miR-135b expression at 24 h post hyperosmotic challenge compared to controls. By examining mRNA expression of predicted miRNA targets during salinity acclimation and arsenic exposure, we found that miR-135b targets were significantly more likely to decrease during salinity acclimation than non-targets. Our identification of a significant interaction effect of arsenic and salinity on miR 135b expression supports the hypothesis that arsenic alters upstream regulators of stress response networks, which may adversely affect the killifish response to osmotic stress. The characterization of miRNAs in this ecotoxicological model will be a valuable resource for future studies investigating the role of miRNAs in response to environmental stress. PMID- 30476745 TI - Real-time CO2 uptake/emission measurements as a tool for early indication of toxicity in Lemna-tests. AB - This paper presents an application of continuous monitoring of the emission and uptake rate of CO2 in Lemna toxicity test. On a real-time basis, the CO2 concentration data were collected by the Arduino platform-based respiratory activity measuring system (ResTox) and reported as CO2 concentration dynamic curves. The results of CO2 measurements demonstrated that tested metals (Co, Cu, Hg, and Cd), as well as herbicides (nicosulfuron, diquat, and tembotrione), stimulated the CO2 exchange rates at low doses, while at high doses CO2 exchange rates were inhibited. The addition of higher concentrations of clopyralid stimulated photosynthetic activity and caused a higher increase in respiration rates indicating its mode of action as auxin mimic herbicide. The results obtained underline the necessity of considering other biological endpoints like continuous measurements of gas exchange from the very beginning of exposure to toxicants. Simultaneous measurements of real-time CO2 concentrations, as the primary effect of toxicant mode of action, and processes that are supported by carbon flux, as the secondary effect or endpoint, are needed to relate actual and substrate-induced or inhibited respiration and photosynthesis to those processes. Therefore, continuous measurements of CO2 exchange rates can be implemented for the initial screening of potential toxicity to give valuable information that is needed for further examination of toxicity mechanisms and risk assessment. PMID- 30476746 TI - Metal organic frameworks MIL-100(Fe) as an efficient adsorptive material for phosphate management. AB - The excessive discharge of phosphate in water bodies is one of the primary factors causing eutrophication. Therefore, its removal is of significant research interest. The present study deals with the development and performance of highly effective phosphate-adsorbent. Here, we have synthesized MIL-100(Fe) metal organic frameworks as a facile strategy to effectively remove phosphate from eutropic water samples. The adsorbent was characterized by Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), thermogravimetric analysis (TGA), Brunauer-Emmett-Teller (BET), scanning electron microscopy (SEM), and wavelength dispersive X-ray fluorescence (WDXRF). The phosphate adsorption performance of MIL-100(Fe) was evaluated with the help of different batch experiments relating to the effect of adsorbent/adsorbate concentrations and the solution pH. The MOF offered a maximum adsorption capacity of 93.6 mg g-1 for phosphate from aqueous solutions with Langmuir isotherm model (R2 = 0.99). MIL 100(Fe) offered an absolute phosphate adsorption performance with a partition co efficient of 15.98 mg g-1 uM-1 at pH 4 and room temperature conditions. Final experiments with real water samples were also performed to examine the effectiveness of MIL-100(Fe) for phosphate adsorption even in the presence of other ions. These findings support the potential utility of MIL-100(Fe) as nanoadsorbent in phosphate removal for water management. PMID- 30476747 TI - Particle deposition in the human lung: Health implications of particulate matter from different sources. AB - Although ambient particulate matter or particles have been found to be associated with morbidity and mortality all over the world, specific health effects of particles from different sources need further elucidation. The objective of this work is to predict the deposition of particles from different sources in the human lung. The whole lung, consisting of 24 generations of branches from trachea to alveoli, was approximated using a one-dimensional lumped "trumpet" model with a variable cross-sectional area. The aerosol dynamics equation was numerically solved using a finite difference method to investigate the transport and deposition of particles in the lung model. Particles from various sources were assumed to be different in both size and density. We found that in general, coarse particles (> 2.5 um) were mainly deposited in the tracheobronchial (TB) region by impaction, and fine particles (< 2.5 um) were mainly deposited in the pulmonary (P) region by sedimentation and diffusion. However, the coarse particles with low density can be deposited in P region by sedimentation. As a comparison, our results found that soil particles, which are coarse with low density, were deposited in the deep lung more than traffic particles, which are fine with high density. Modeling of particle deposition in the human lung indicated that coarse particles generated by crustal sources may have adverse health effects as strong as those resulting from fine particles generated from combustion sources. PMID- 30476748 TI - Early-life intake of major trace elements, bisphenol A, tetrabromobisphenol A and fatty acids: Comparing human milk and commercial infant formulas. AB - In the present study, the presence of a wide spectrum of major and trace elements (As, Ag, Al, Ba, Cd, Co, Cr, Cu, Hg, Mn, Ni, Sr, Sb, Se, Sn, Pb, V, and Zn), fatty acids, as well as some pollutants like free and total BPA and tetrabromobisphenol A (TBBPA), was analysed in human milk (n = 53) and infant formula (n = 50) samples. In addition, the infant exposure to these chemicals was assessed. The content of free BPA and several elements (Al, Ca, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, Sn, Sr, and Zn) was higher (p < 0.01) in infant formula samples. Furthermore, human milk contained levels of BPA and elements that, in almost all cases, were well below their respective EFSA and/or WHO thresholds, being also independent of the maternal characteristics (e.g., age, BMI or breastfeeding period). The fatty acid profiling also revealed major differences between human milk and infant formulas, which should be taken in account in the development of new formulas as well as in specific recommendations for the diet of breastfeeding mothers. Anyway, the results of this study reinforce that breastfeeding should be always the first feeding option in early life. PMID- 30476749 TI - Successful analysis of a 100 years old semen stain generating a complete DNA STR profile. AB - We performed forensic investigations on a handkerchief containing seminal fluid deposited 100 years earlier. The aim was to verify the possibility to achieve a complete genetic profile exceeding the limit of success reached until today with a partial semen stain profile stored up to 50 years. The current forensic methods were carried out: Alternative Light Source (ALS), Prostate-Specific Antigen (PSA) Test, autosomal and Y-chromosome Short Tandem Repeats (STRs). ALS inspection was a crucial method in the success of the analysis. On a dried semen stain, fluorescence remains constant for a very long time, allowing possibility to minimize the fabric sample to analyze, in order to preserve specimen for future defense guarantees or to protect historical finding. We achieved positive results in 3 of 6 traces, PSA and DNA results were concordant, only those cuttings that tested positive for PSA yielded DNA profiles. A complete male profile was generated by AmpFlSTR Identifiler Plus and 16 loci profile by AmpFLSTR Yfiler. Considering some historical sources that attributed this handkerchief dated 1916, to a famous Italian poet, the DNA profile found on the handkerchief was compared with a living male descendant, and the comparison of the Y-STR between the two gave positive results, confirming the reliability of the outcomes. The findings achieved by the current forensic method empower the application of this methodology to other forensic cases, especially in past unresolved cases. PMID- 30476750 TI - Targeting the PI3K/AKT/mTOR pathway in biliary tract cancers: A review of current evidences and future perspectives. AB - Biliary tract cancers (BTCs) are a group of invasive neoplasms, with increasing incidence and dismal prognosis. In advanced disease, the standard of care is represented by first-line chemotherapy with cisplatin and gemcitabine. In subsequent lines, no clear recommendations are currently available, highlighting the need for novel therapeutic approaches. The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, growth and survival, and is involved in BTCs carcinogenesis and progression. Mutations, gene copy number alterations and aberrant protein phosphorylation of PI3K, AKT, mTOR and PTEN have been thoroughly described in BTCs and correlate with poor survival outcomes. Several pre-clinical evidences state the efficacy of PI3K/AKT/mTOR pathway inhibitors in BTCs, both in vitro and in vivo. In the clinical setting, initial studies with rapamycin analogs have shown interesting activity with an acceptable toxicity profile. Novel strategies evaluating AKT and PI3K inhibitors have risen serious safety concerns, pointing out the need for improved patient selection and increased target specificity for the clinical development of these agents, both alone and in combination with chemotherapy. This review extensively describes the role of the PI3K/AKT/mTOR pathway in BTCs and examines the rationale of its targeting in these tumors, with particular focus on clinical activity, toxicities and perspectives on further development of PI3K/AKT/mTOR pathway inhibitors. PMID- 30476751 TI - AIM-SNPtag: A computationally efficient approach for developing ancestry informative SNP panels. AB - Inferring an individual's ancestry or group membership using a small set of highly informative genetic markers is very useful in forensic and medical genetics. However, given the huge amount of SNP data available from a diverse of populations, it is challenging to develop informative panels by exhaustively searching for all possible SNP combinations. In this study, we formulate it as an algorithm problem of selecting an optimal set of SNPs that maximizes the inference accuracy while minimizes the set size. Built on this conception, we develop a computational approach that is capable of constructing ancestry informative panels from multi-population genome-wide SNP data efficiently. We evaluated the performance of the method by comparing the panel size and membership inference accuracy of the constructed SNP panels to panels selected through empirical procedures in previous studies. For the membership inference of population groups including Asian, European, African, East Asian and Southeast Asian, a 36-SNP panel developed by our approach has an overall accuracy of 99.07%, and a 21-SNP subset of the panel has an overall accuracy of 95.36%. In comparison, an existing panel requires 74 SNPs to achieve an accuracy of 94.14% on the same set of population groups. We further apply the method to four subpopulations within Europe (Finnish, British, Spanish and Italian); a 175-SNP panel can discriminate individuals of those European subpopulations with an accuracy of 99.36%, of which a 68-SNP subset can achieve an accuracy of 95.07%. We expect our method to be a useful tool for constructing ancestry informative markers in forensic genetics. PMID- 30476752 TI - Adult report of childhood imaginary companions and adversity relates to concurrent prodromal psychosis symptoms. AB - Hallucination and dissociation have been found to be associated with imaginary friend play in childhood (CIC). Past studies have not investigated how this play relates to adult prodromal symptoms or how childhood adversity mediates the relationship. CIC play was examined in 278 participants, 18-24 years. CIC status predicted prodromal symptoms of hallucination only, whereas childhood adversity predicted all other symptoms. Mediation analysis found CIC's relation to hallucination symptoms was partially mediated by childhood adversity. Findings fit with views that CIC are a positive childhood experience which may convert to a negative developmental trajectory through the impact of childhood adversity. PMID- 30476754 TI - Moving out but keeping in touch: contacts between endoplasmic reticulum and lipid droplets. AB - The formation of neutral lipid filled and phospholipid monolayer engulfed lipid droplets (LDs) from the bilayer of the endoplasmic reticulum (ER) is an active area of investigation. This process harnesses the biophysical properties of the lipids involved and necessitates cooperation of protein machineries in both organelle membranes. Increasing evidence suggests that once formed, LDs keep close contact to the mother organelle and that this may be achieved via several, morphologically distinct and potentially functionally specialized connections. These may help LDs to dynamically respond to changes in lipid metabolic status sensed by the ER. In this review, we will discuss recent progress in understanding how LDs interact with the ER. PMID- 30476753 TI - Development and preliminary validation of a mandarin Chinese language questionnaire measuring betel quid dependency among adults in Taiwan. AB - The purposes of this study were to develop the Chinese-version betel quid dependence instrument (BQDI) and to test its reliability and validity. An item pool relevant to betel quid dependence was generated. A panel of three experts assessed content validity including content relevance, clarity, and domain coverage. A cross-sectional study was conducted, consisting of 113 participants from a construction site, betel quid stalls, and a teaching hospital in Taichung, Taiwan. Construct validity was assessed by hypothesizing a significant correlation between the BQDI score and number of pieces-years for betel quid chewing and betel quid biomarkers. The overall Cronbach's alpha coefficient was 0.94. Factor analysis indicated the BQDI consisted of a three-factor structure, including physical and psychological cravings, lack of resistance to betel quid, and maladaptive use. We observed significant associations of BQDI total and factor scores with arecaidine (adjusted odds ratio [OR] for medium total BQDI score: 12.87, 95% CI: 1.45-114.5; high total BQDI score: 28.9, 3.53-236.6) and N methylnipecotate (medium total BQDI score: 6.18, 1.21-31.62; high total BQDI score: 13.10, 2.72-63.03, respectively). Our results provide preliminary good internal consistency and construct validation of the Chinese-version BQDI as a measure of betel quid dependence in community adults. PMID- 30476755 TI - Development of a colorimetric PNGase activity assay. AB - PNGases are crucial targets and valuable tools in analyzing asparagine-linked carbohydrate moieties (N-glycans) of glycoproteins. Activity tests of PNGases have been little improved since their discovery four decades ago, and still rely on observing deglycosylation patterns of glycoproteins or glycopeptides using SDS PAGE or HPLC analysis. These techniques cannot be easily adapted for automated sampling and high-throughput procedures. Herein, we describe a PNGase activity assay which relies on the conversion of WST-1, a yellowish, water-soluble tetrazolium dye (sodium 2-(4-Iodophenyl)-3-(4-nitro-phenyl)-5-(2,4-disulfophenyl) 2H-tetrazolate), into a blue formazan dye. In this work, we showed that WST-1 could be reduced by N-glycans, which were enzymatically released from glycoprotein substrates. After optimization of the assay conditions, the robustness of the method was challenged by quantifying the activity of various PNGase isoforms at different purification stages using a microwell plate reader. Furthermore, the assay could be used to obtain steady-state kinetics of PNGase H+ wild-type and mutant variants, which showed significant differences in their enzymatic reaction rates. The simplicity and robustness of this method might be of benefit for the detection of PNGase activity in routine applications of large amounts of samples. PMID- 30476756 TI - Early luteal phase progestin concentration influences endometrial function in pregnant mares. AB - In the horse, it is still unclear if and to what extent low progestin concentration contributes to early conceptus loss. In the present study, we have investigated if reduced or elevated progestin concentration in the early luteal phase influences endometrial function and conceptus development. We hypothesized that reduced progestin concentration via delayed downregulation of endometrial progesterone receptors (PR) influences endometrial function in healthy fertile mares while progestin substitution does not. Genitally healthy estrous mares (n = 8; age 4-14 years) were inseminated and treated with either altrenogest (0.044 mg/kg once daily orally) on days 5-10 after ovulation (ALT), cloprostenol (125 MUg once daily intramuscularly) on days 0-3 after ovulation (CLO) or left untreated (CON). ALT and CLO treatment were chosen to increase and decrease total peripheral progestin concentration, respectively. Each treatment was given to every mare in consecutive cycles. On day 14 after ovulation, endometrial fluid was collected with a cotton roll inserted into the uterus and an endometrial biopsy for immunohistological demonstration of progesterone (PR) receptor distribution was collected. In endometrial fluid, free amino acid concentrations were analyzed by ion exchange liquid chromatography with an amino acid analyzer. Cell nuclei staining positive for the PR were determined in the luminal and glandular epithelium as well as in the stroma. Pregnancy rate tended to differ among treatments. The percentage of luminal epithelial cells staining positive for PR differed among treatments (p < 0.05) and was higher in CLO (84.1 +/- 1.9%) than in ALT (70.7 +/- 4.7%) and CON cycles (72.8 +/- 4.1%). Concentrations of the amino acids isoleucine (CON 0.17 +/- 0.03, CLO 0.14 +/- 0.02, ALT 0.23 +/- 0.04 MUmol) and lysine (CON 0.27 +/- 0.08, CLO 0.18 +/- 0.05, ALT 0.44 +/- 0.13 MUmol) were influenced by treatment (p < 0.05) and lower in CLO than in ALT and CON cycles. In conclusion, impaired luteal function due to CLO treatment during the early luteal phase of pregnant mares delayed downregulation of progesterone receptors in the endometrial epithelium on day 14. This influenced endometrial function as reflected in lower concentrations of the amino acids lysine and isoleucine in endometrial secretions. Enhanced progestin concentration had less clear effects in healthy fertile mares. PMID- 30476757 TI - Cryopreservation of donkey embryos by the cryotop method: Effect of developmental stage, embryo quality, diameter and age of embryos. AB - Cryopreservation of embryos has the potential to become a valuable tool for the conservation of endangered donkey breeds. However, there are several factors that can affect cryosurvival of embryos. This study evaluates the effectiveness of the Cryotop method to vitrify donkey embryos and factors affecting the survival of vitrified-warmed embryos. Day 6-8 embryos were measured and morphologically evaluated. Embryos were then vitrified-warmed using the Cryotop technique. After 24 h post-warming, the embryos were measured and evaluated for their morphology, development and viability (Propidium Iodide-Hoechst 33342 dyes). A total of 25 embryos were used, of which 17 were classified as Grade 1 (excellent), 5 as Grade 2 (good) and 3 as Grade 3 (fair). Based on their diameter, embryos were grouped as follows: <=220 MUm (n = 10), >220-300 MUm (n = 8), and >300 MUm (n = 7). Post warming survival of vitrified embryos was similar (P > 0.05) to the control fresh embryos, regardless of embryonic diameter, developmental stage, and age of the embryos before vitrification. However, the proportion of embryos that survived vitrification procedures was numerically higher but not significantly different (P > 0.05) for Day 7 embryos (84.6%). The ability of Grade 1 (70.6%) and 2 (80%) embryos to survive vitrification procedures was higher (P = 0.0214) than those of Grade 3 (0%). The proportion of dead cells in Grade 3 embryos (56.5%) was higher (P < 0.01) than that of Grade 1 (3.2%) and 2 (1.5%) embryos. In conclusion, the Cryotop technique seems to be useful for Grade 1 and 2 donkey embryos. It is likely that donkey embryos show similar survival rates after vitrification in Cryotops irrespective of age, diameter and development stage. PMID- 30476758 TI - Karyomapping for simultaneous genomic evaluation and aneuploidy screening of preimplantation bovine embryos: The first live-born calves. AB - In cattle breeding, the development of genomic selection strategies based on single nucleotide polymorphism (SNP) interrogation has led to improved rates of genetic gain. Additionally, the application of genomic selection to in-vitro produced (IVP) embryos is expected to bring further benefits thanks to the ability to test a greater number of individuals before establishing a pregnancy and to ensure only carriers of desirable traits are born. However, aneuploidy, a leading cause of developmental arrest, is known to be common in IVP embryos. Karyomapping is a comprehensive screening test based on SNP typing that can be used for simultaneous genomic selection and aneuploidy detection, offering the potential to maximize pregnancy rates. Moreover, Karyomapping can be used to characterize the frequency and parental origin of aneuploidy in bovine IVP embryos, which have remained underexplored to date. Here, we report the use of Karyomapping to characterize the frequency and parental origin of aneuploidy in IVP bovine embryos in order to establish an estimate of total aneuploidy rates in each parental germline. We report an estimate of genome wide recombination rate in cattle and demonstrate, for the first time, a proof of principle for the application of Karyomapping to cattle breeding, with the birth of five calves after screening. This combined genomic selection and aneuploidy screening approach was highly reliable, with calves showing 98% concordance with their respective embryo biopsies for SNP typing and 100% concordance with their respective biopsies for aneuploidy screening. This approach has the potential to simultaneously improve pregnancy rates following embryo transfer and the rate of genetic gain in cattle breeding, and is applicable to basic research to investigate meiosis and aneuploidy. PMID- 30476759 TI - Development of novel oocyte activation approaches using Zn2+ chelators in pigs. AB - Artificial oocyte activation is an essential step in somatic cell nuclear transfer (SCNT) and can enhance viability of embryos as a form of assisted reproductive technology (ART) in clinics. Most artificial activation methods have been developed to increase cytosolic calcium (Ca2+) level in oocytes. Interestingly, recent studies have demonstrated that mammalian oocytes can be activated using N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), a Zn2+ chelator. Although effective, TPEN is also known to induce apoptosis and shows poor selectivity between free Zn2+ and protein-bound Zn2+. The aim of this study was to identify different Zn2+ chelators that can activate pig oocytes. Among five Zn2+ chelators examined, 1,10-phenanthroline (Phen), and tris(2 pyridylmethyl)amine (TPA) successfully activated pig oocytes. The level of available Zn2+ was reduced without any increase in Ca2+ in oocytes incubated with Phen or TPA, indicating that the oocyte activation occurred independently of Ca2+ signal. When various concentrations (100-500 MUM) and incubation durations (10 120 min) of Phen and TPA were used to activate pig oocytes, 500 MUM for 60 min and 100 MUM for 60 min of Phen and TPA treatments, respectively, were found to be most effective in supporting embryo development. The frequency of blastocyst formation after the treatments was higher than 40% at day 7. When oocytes were incubated with TPEN, Phen, or TPA under their optimal treatment conditions, there was no significant difference in the frequencies of day 7 blastocyst formation among the three treatments. However, day 5 blastocyst formation was observed from the Phen- and TPA-treated oocytes, whereas no blastocyst was formed at day 5 in the TPEN-treated oocytes. The average total cell number in day 7 blastocysts was higher in the Phen treatment group than in the TPEN treatment (P < 0.05). These results suggest that Phen and TPA can be used as powerful agents to artificially activate oocytes and to increase the developmental potential of SCNT embryos or embryos going through clinical ART procedures. PMID- 30476760 TI - Interactions of CDH13 gene polymorphisms and ambient PM10 air pollution exposure with blood pressure and hypertension in Korean men. AB - Associations between air pollution and blood pressure (BP) traits can be modified by several candidate genes, which might explain differences in individual genetic susceptibility. Based on recent evidence hypothesized to link air pollution and BP traits, we examined whether the polymorphisms of CDH13-a candidate gene-would modify the relationship between them in adult Korean men. A total of 1816 subjects were included. We divided them into two groups of high or low to moderate exposure using the annual average concentration of particulate matter with an aerodynamic diameter <=10 MUm (PM10). We conducted an interaction analysis of PM10 exposure using 200 single-nucleotide polymorphisms (SNPs), located within CDH13, in subjects with regard to BP traits and hypertension. The rs7500599 intronic SNP of CDH13 had the strongest signals for all BP traits including systolic blood pressure (SBP), diastolic blood pressure, and hypertension, by interacting with PM10 exposure. An additional stratified analysis showed that the effects of PM10 exposure on elevated BP and hypertension increased gradually in proportion to the number of minor alleles in this SNP. In addition, PM10 exposure in the TT or GT genotype groups did not show significant associations with BP traits, whereas in a homozygous risk allele (GG) group, PM10 exposure was significantly associated with BP traits and hypertension. For SBP, these patterns were reproducible at two independent sampling sites. This CDH13 polymorphism amplifies the negative associations of PM10 exposure and elevated BP or hypertension in Korean men. PMID- 30476761 TI - Efficient degradation of diclofenac by LaFeO3-Catalyzed peroxymonosulfate oxidation---kinetics and toxicity assessment. AB - Diclofenac was frequently found in various waters, indicating conventional wastewater treatment methods ineffective in its removal. In this study, LaFeO3 (LFO) was synthesized and its catalytic activity of LFO as the activator of different oxidants such as persulfate (PS), hydrogen peroxide and peroxylmonosulfate (PMS) was evaluated in terms of DCF degradation. The influence of calcination temperature was examined on the catalytic activity of LFO. The effects of various parameters including pH levels, PMS concentration, LFO dose and initial DCF concentration were investigated on DCF degradation rate. The marginal effects of PMS concentration and LFO dose were compared. Langmuir Hinshelwood (LH) model was used to quantitatively describe DCF degradation reaction in LFO/PMS system. The two constants, k (Limiting reaction rate at maximum coverage) and K (Equilibrium adsorption constant), were determined on the basis of LH model. The performance of LFO/PMS process was also estimated in the presence of various inorganic anions. The potential toxicity of LFO and PMS were evaluated using phytoplankton and the toxicity evolution during DCF degradation was also investigated using luminescent bacteria. This contribution provides a basic study regarding the potential application of heterogeneous PMS activation by perovskite LFO for both DCF removal and toxicity elimination. PMID- 30476762 TI - Adsorption behaviour and mechanisms of cadmium and nickel on rice straw biochars in single- and binary-metal systems. AB - Adsorption mechanisms and competition between Cd2+ and Ni2+ for adsorption by rice straw biochars prepared at 400 degrees C (RB400) and 700 degrees C (RB700) were investigated in this study. Based on the Langmuir model, the maximum adsorption capacities (mg g-1) of Cd2+ and Ni2+ on RB400 and RB700 were in the order of Cd2+ (37.24 and 65.40) > Ni2+ (27.31 and 54.60) in the single-metal adsorption isotherms and Ni2+ (25.20 and 32.28) > Cd2+ (24.22 and 26.78) in the binary-metal adsorption isotherms. Cd2+ competed with Ni2+ for binding sites at initial metal concentrations >10 mg L-1 for RB400 and > 20 mg L-1 for RB700. The adsorption sites for Cd2+ and Ni2+ on the biochars largely overlapped, and the binding of Cd2+ and Ni2+ to these sites was affected by the occupation sequence of these metals. For Cd2+ and Ni2+ adsorption in the binary system, cation exchange and precipitation were the dominant adsorption mechanisms on RB400 and RB700, respectively, accounting for approximately 36% and 60% of the adsorption capacity. Competition decreased the contribution of cation exchange but increased that of precipitation and other potential mechanisms. Results from this study suggest that types and concentrations of metal ions should be taken into account when removing metal contaminants from water or soil using biochars. PMID- 30476763 TI - Home-based and informal work exposes the families to high levels of potentially toxic elements. AB - The city of Limeira presents a relevant productive chain of jewelry and fashion jewelry, including a scenario of outsourcing informal home practices. It is highly complex to understand the potentially toxic elements (PTE: Cr, Mn, Ni, Cu, Zn, As, Cd, Sn, Sb, Hg, and Pb) exposures of the workers because this productive chain encompasses households. This study aimed to investigate the associations between blood PTE levels and informal work in the home environment. Fifty-two families divided into Exposed group (n = 112) and Control group (n = 53) were included. Families' blood (n = 165) and welder's breathing zone air samples (n = 9) were collected and PTEs concentrations were determined by ICP-MS. Questionnaires were applied to collect sociodemographic information and workplace details. Principal component analysis, Mann-Whitney test, cluster and a logistic regression analysis based on environment-wide association studies (EWAS) were carried out. Ni, Cu, Zn, Cd and Pb concentrations in the air samples were higher than occupational guidelines. Eighty percent of the workers were female, and 43.5% of those females then worked as welder. A significant difference was found for Pb concentration between the exposed and control group (p < 0.0001) and between sexes (p = 0.0046). For Cu (p < 0.0001) and Sb (p = 0.0434), differences were found between the sexes. The receiver operating characteristic of the EWAS was 0.80, providing evidence of a potential model to associate exposure levels and occupational factors. PTEs concentrations in the air samples raised concerns, particularly for children, who were in the same exposure scenario. Inadequate work conditions were observed in the houses, revealing the need of public actions to protect these families. PMID- 30476764 TI - Effects of defined mixtures of POPs and endocrine disruptors on the steroid metabolome of the human H295R adrenocortical cell line. AB - The presence of environmental pollutants in our ecosystem may impose harmful health effects to wildlife and humans. Several of these toxic chemicals have a potential to interfere with the endocrine system. The adrenal cortex has been identified as the main target organ affected by endocrine disrupting chemicals. The aim of this work was to assess exposure effects of defined and environmentally relevant mixtures of chlorinated, brominated and perfluorinated chemicals on steroidogenesis, using the H295R adrenocortical cell line model in combination with a newly developed liquid chromatography tandem mass spectrometry (LC-MS/MS) method. By using this approach, we could simultaneously analyze 19 of the steroids in the steroid biosynthesis pathway, revealing a deeper insight into possible disruption of steroidogenesis. Our results showed a noticeable down regulation in steroid production when cells were exposed to the highest concentration of a mixture of brominated and fluorinated compounds (10,000-times human blood values). In contrast, up-regulation was observed with estrone under the same experimental condition, as well as with some other steroids when cells were exposed to a perfluorinated mixture (1000-times human blood values), and the mixture of chlorinated and fluorinated compounds. Interestingly, the low concentration of the perfluorinated mixture alone produced a significant, albeit small, down-regulation of pregnenolone, and the total mixture a similar effect on 17-hydroxypregnenolone. Other mixtures resulted in only slight deviations from the control. Indication of synergistic effects were noted when we used a statistical model to improve data interpretation. A potential for adverse outcomes of human exposures is indicated, pointing to the need for further investigation into these mixtures. PMID- 30476765 TI - Quercus ilex L. leaves as filters of air Cd, Cr, Cu, Ni and Pb. AB - The study of particulate matter pollution in urban areas is of great concern due its adverse effects on human health. Roadside vegetation, intercepting and filtering it, contributes to improve air quality. The aim of the research was to investigate the capability of Q. ilex leaves, already known good biomonitors of air quality, in filtering air metals. Besides, the main derivation (i.e. air or root uptake) of the investigated metals in leaf tissue was evaluated. The concentrations of Cd, Cr, Cu, Ni and Pb were measured in three groups of Q. ilex leaves (unwashed, water washed and chloroform washed). Besides, several leaf traits (i.e. length, width, petiole length, leaf area, leaf mass area and thickness) were evaluated. The findings highlighted that Cd, Cr, Cu, Ni and Pb in Q. ilex leaves exceeded the chemical fingerprint. In particular, Cd and Pb appeared the main contaminants of the investigated area as also after water washing of the leaves, their concentrations exceeded the chemical fingerprint. Ni, Cr and Pb appeared to be accumulated on leaf deposit; whereas, Cd appeared mainly adsorbed to leaf cuticle. Higher leaf width, lower leaf area and shorter petiole favoured leaf metal accumulation. Root uptake and translocation to leaves cannot be excluded for Cr and Ni; whereas, leaf Cu content would seem to depend on both leaf deposit and soil content. In conclusion, Q. ilex can be useful in filtering air metal pollution, especially for Ni, Cd, Cr and Pb, and improving air quality. PMID- 30476766 TI - Usefulness of fish cell lines for the initial characterization of toxicity and cellular fate of graphene-related materials (carbon nanofibers and graphene oxide). AB - Graphene-related materials (GRMs) are one of the most attractive materials from an application perspective, consequently their release into aquatic environments is highly likely. In the present work, the potential of fish hepatocytes (topminnow fish hepatoma cell line, PLHC-1) and macrophages (carp leukocyte cell line, CLC) to study the toxicity and intracellular fate of helical-ribbon carbon nanofibers (CNFs) and graphene oxide (GO) used in a variety of intermediate industrial products was evaluated, allowing a first ranking of GRMs according to their cytotoxicity. Cells were exposed to a concentration range of 0-200 MUg ml-1 of GRMs for 24 and 72 h and cell viability was assessed by measuring mitochondrial activity (AlamarBlue assay), plasma membrane integrity (5 carboxyfluorescein diacetate-acetoxymethyl ester assay) and lysosomal function (neutral red uptake assay). Results showed that both the cell type and the choice of endpoint determined the toxicity of GRMs. In both cell lines, CNFs appeared to have higher toxicity than GO and the highest degree of graphitization in fibers was associated with lower toxicity. Transmission electron microscopy revealed that CNFs were taken up into membrane-bound compartments of PLHC-1 cells in a size-independent manner, whereas in CLC, longer CNFs were encountered free in the cytoplasm and only the shorter CNFs were localized in membrane-surrounded vesicles. GO sheets were present within vesicles as well as free in the cytoplasm of both cell types. These findings contribute to the understanding of the toxicity and behaviour of these GRMs in living systems, therefore aiding in designing safer materials for the environment. PMID- 30476767 TI - Occurrence, sources and ecotoxicological risks of polychlorinated biphenyls (PCBs) in sediment cores from urban, rural and reclamation-affected rivers of the Pearl River Delta, China. AB - Sediment cores were collected to a depth of 40 cm (50 cm for urban river sediments) in the Pearl River Delta of China from rural river sediments and river sediments undergoing the process of urbanization and reclamation. Polychlorinated biphenyls (PCBs) in sediment cores were determined to evaluate their levels, distribution, possible sources and potential risks aimed at providing effective information of management practices for local governments. Our results showed that the total concentrations of PCBs (?16PCBs) in urban, rural and reclamation affected river sediments ranged from 16.15 to 477.85 MUg kg-1 (dry weight), with mean values of 121.94, 150.49 and 124.20 MUg kg-1 (dry weight), respectively. The most abundant PCB congeners among the study area were light PCBs. Generally, PCBs showed a decreasing trend with depth along sediment cores at most sampling sites. Source analysis indicated that PCBs in the three types of river sediments mainly originated from Aroclor 1242, 1248, 1254 and 1016. Risks evaluation based on sediment quality guideline quotient (SQGQ) showed PCBs at most sampling sites would cause no or moderate adverse biological effects on benthic organisms except surface sediments of U4 and R5 (high adverse biological effects). However, threshold effects level (TEL) is ignored when calculating SQGQ, which might underestimate the risks of PCBs. Thus, a new SQGQ (NSQGQ) taken TEL into consideration was established. Results showed that NSQGQ could evaluate ecotoxicological risks of PCBs better. Redundancy analysis (RDA) showed that PCBs in sediments were positively correlated with sand content and microbial biomass carbon (MBC) (p < 0.05). PMID- 30476768 TI - Influence of smear matrix types on detection behaviors and efficiencies of polycyclic aromatic hydrocarbons using ion mobility spectrometry. AB - Influence of smear matrix types on detection behaviors and efficiencies of polycyclic aromatic hydrocarbons (PAHs) with different molecular weights in ion mobility spectrometry (IMS) were investigated. Various smear matrices of stainless steel mesh (SM), cellulose paper (CP), and cotton fabric (CF) were employed. Anisole was used as the solvent and IMS analysis was performed without evaporation step of the solvent to apply charge transfer reactions between PAH molecules and the molecular ions of solvent. Shapes of reactant ion peaks (RIPs) were varied according to the smear matrix types. At the beginning of the sample inlet, intensity of RIPs of air and moisture notably decreased due to the lots of solvent vapor. The SM with good gas permeability showed relatively strong RIPs of air and moisture, whereas the CP with no gas permeability showed weak ones. Detection times and efficiencies of PAH ions were varied according to the smear matrix types as well as the kinds of PAHs. PAHs were on the whole detected well in 1-3 s after the sample inlet. Detection limits of PAHs measured using the SM were slightly better than those measured using the CP, while those measured using the CP were much better than those measured using the CF. The experimental results could be explained by structures of the smear matrices and evaporation behaviors of the PAH solutions. PMID- 30476769 TI - Correlation between antibiotic-induced feeding depression and body size reduction in zooplankton (rotifer, Brachionus calyciflorus): Neural response and digestive enzyme inhibition. AB - The study analyzed the correlation between the antibiotic-induced feeding depression and body size reduction in rotifer, Brachionus calyciflorus, involving exposure, post-exposure and re-exposure periods. The filtration and ingestion rates of the rotifers were inhibited in these three exposure periods at any given concentration of the antibiotic sulfamethazine (SMZ). As food for rotifer, the cell size of the green algae was unchanged, which indicated that it could not drive feeding depression. Secondly, several corresponding physiological responses were considered. Reactive oxygen species (ROS) levels increased in the post exposure and the re-exposure; acetylcholinesterase (AChE) activity was significantly decreased in the exposure and the re-exposure, whereas it was induced in the post-exposure. The activities of amylase and lipase were always inhibited in these three exposure periods. Additionally, significant decreases in lorica length, width and biovolume of rotifers occurred after the feeding depression. Statistical analysis indicated a positive correlation between the activity of the digestive enzyme and the body size. Our results demonstrated that SMZ could influence the neurotransmission, inhibit the activity of the digestive enzyme, and finally result in body size reduction. These results provided an integrated perspective on assessing the toxicity effects of antibiotic in non lethal dosage on the feeding behavior of non-target aquatic organisms. PMID- 30476770 TI - Decomposition of 15 aromatic compounds in supercritical water oxidation. AB - Supercritical water oxidation (SCWO) of 15 aromatic compounds, including bisphenol A (BPA), nonylphenol (NP) and octylphenol (OP), was investigated under temperature and reaction time ranged of 350-550 degrees C and 0.5-6 min, respectively, with 300% excess oxygen, resulted in the degradation rate constants of total organic carbon (kTOC) were 0.130-0.392 min-1. To further explore the relationship between TOC removal and molecular characteristics, density functional theory (DFT) method had been used to calculate the quantum descriptors of the 15 aromatic compounds. The result of correlation analysis showed that the most positive partial charge on the H atom, namely q(H)x, played a significant role in TOC removal, which implied the more q(H)x value was, the easier H atom could lose, resulted in higher kTOC constant. Different substituent groups in the phenyl ring could lead to different TOC removal efficiencies. It presented that the more F(0) value was, the more easily to be attacked by radicals, as a result, the kTOC followed the order that benzenesulfonic acid (BSA) > phenol > methylbenzene (MB) > 3-phenylpropionic acid (3-PPA), as well as BPA < OP < NP. PMID- 30476771 TI - Iron oxide/carbon nanotubes/chitosan magnetic composite film for chromium species removal. AB - An adsorbent in the form of a CLCh/MWCNT/Fe film was prepared using multiple walled carbon nanotubes (MWCNT) doped with magnetic iron oxide and deposited in crosslinked chitosan (CLCh). The CLCh/MWCNT/Fe was characterized by Inductively Coupled Plasma Mass Spectrometry (ICP-MS), nitrogen (N2) adsorption/desorption, X ray Diffraction (XRD), Scanning Electron Microscopy (SEM), Energy Dispersive Spectrometry (EDS), Infrared Spectroscopy (IR) and Raman Spectroscopy. The CLCh/MWCNT/Fe film presented a maximum adsorption capacity for Cr(III) of 66.25 mg/g (150 min) and for Cr(VI) of 449.30 mg/g (60 min) at 25 degrees C. The CLCh/MWCNT/Fe can be easily removed from the aqueous solution by a mechanical separation or by magnetization due to its magnetic properties. In ten consecutive reutilization adsorption cycles the CLCh/MWCNT/Fe film presented efficiency losses of only 12% and 6% for the removal of Cr(III) and Cr(VI), respectively. PMID- 30476772 TI - Removal efficiency and mechanism of phycocyanin in water by zero-valent iron. AB - The efficiencies and mechanism of phycocyanin removal from water by zero-valent iron (ZVI) were studied. The trend for dissolved organic nitrogen removal was similar to phycocyanin and the removal efficiency was high at ~81% and 95%, respectively, in 90 min. The experimental results showed that the phycocyanin removal efficiency was higher at pH < 6, with an almost complete removal. However, only 68% was removed at pH 9. Within 30 min, the removal efficiency of phycocyanin for 1-4 tested cycles was reduced from 55.8% to 15.2%. Scanning electron microscopy and energy dispersive spectroscopy, Fourier transform infrared spectroscopy analysis and X-ray photoelectron spectroscopy were used to analyze the mechanisms of phycocyanin removal, which indicated that a small amount of phycocyanin was immobilized on the ZVI surface by adsorption. In addition, the main removal pathway was coagulation by dissolved iron ions. The Fe oxide formed in situ from ZVI had a higher removal efficiency than that in FeCl3, which can play improved roles in charge neutralization. The production of disinfection byproducts also decreased because of the decrease of precursors. PMID- 30476773 TI - Selenium and mercury in Brazilian Cerrado soils and their relationships with physical and chemical soil characteristics. AB - The objective of this study was to determine the natural concentrations of Hg and Se in 45 representative soil profiles from the Cerrado biome in central Brazil, and to correlate their concentrations with soil chemical and physical characteristics. The study area was composed of three sub-regions: Goias, Northwest of Minas Gerais, and Minas Gerais Triangle. Selenium and Hg concentrations were determined by acid digestion and atomic absorption spectroscopy. Data were subjected to analysis of variance on the means of the Hg and Se variables within each soil class at two depths, followed by multivariate statistical methods. The Hg concentrations ranged from 15 to 182 MUg kg-1 and the Se concentrations ranged from 22 to 72 MUg kg-1. The soil characteristics that most contributed to Hg concentrations in the soils, according to principal component analysis, were Fe2O3, FeO, TiO2, pH, P2O5, and effective CEC. In general, the soils of the Cerrado biome have deficient Se concentrations. The Humic Rhodic Acrustoxes have Hg concentrations above the prevention reference value for soils of Minas Gerais. PMID- 30476774 TI - Parameters of oxidative stress, cholinesterase activity, Cd bioaccumulation in the brain and midgut of Lymantria dispar (Lepidoptera: Lymantriidae) caterpillars from unpolluted and polluted forests. AB - Cadmium (Cd) can display a variety of different effects on living organisms. The objectives of the present study were to investigate Cd bioaccumulation and differences in parameters of oxidative stress (activities of the enzymes: superoxide dismutase, catalase, glutathione reductase, ascorbate peroxidase, glutathione S-transferase, and amounts of non-enzymatic free sulfhydryl groups and total glutathione) and cholinesterase activity in larval brain and midgut tissues of the polyphagous forest insect Lymantria dispar collected from unpolluted and polluted oak forests. Fourth instar L. dispar caterpillars from the unpolluted forest had higher body mass but accumulated more Cd in comparison to caterpillars from the polluted forest. In both populations the midgut was more sensitive than the brain to the prooxidative effects of Cd. Enzyme activities and amounts of non-enzymatic parameters tended to be greater in midgut tissues than in the brain, except for cholinesterase activity. Parameters of oxidative stress had higher values in caterpillar tissues from the polluted than from the unpolluted oak forest. The observed differences between the two natural populations point to the importance of knowing the history of population exposure to environmental pollution when monitoring forest ecosystems. PMID- 30476775 TI - Occupational exposure to pesticides and thyroid function in Brazilian soybean farmers. AB - INTRODUCTION: Agriculture production has been supported especially by the use of pesticides for crop protection and pest control. Although the agricultural production has been increased by pesticides use, these substances also reach non target organisms and may become a risk to the health of farmers. Several epidemiological studies in human have investigated the association between exposure to pesticides and altered serum levels of thyroid hormones, reporting both positive and negative results. Overall, the impact of pesticides on human thyroid function is still limited. OBJECTIVE: The aim of this study was to access serum levels of free thyroxin (FT4), total triiodothyronine (TT3), thyroid stimulating hormone (TSH), and butyrylcholinesterase (BChE) in soybean farmers in southern Brazil. METHODS: The exposed group was composed by 46 rural workers and 27 subjects not exposed to pesticides composed the control group. All subjects had blood samples collected by venipuncture in order to analyze the serum levels of FT4, TT3, TSH and BChE. RESULTS: The results showed a significant decreasing in TSH and increasing in TT3 and FT4 in rural workers, compared to control group. BChE levels were lower in exposed group than in control group. The results suggest that farmers are exposed to mixtures of pesticides with endocrine disruptor properties. PMID- 30476776 TI - A unified thermodynamic mechanism underlying fouling behaviors of soluble microbial products (SMPs) in a membrane bioreactor. AB - Soluble microbial products (SMPs) are the predominate foulants determining fouling extent in membrane bioreactors (MBRs). However, exact mechanism underlying their typical fouling behaviors remains unrevealed. In this study, the typical fouling behaviors of SMPs during initial operational period of a MBR were characterized. It was found that, although being low content, SMPs rather than sludge particulates preferentially adhered to membrane surface to accumulate a gel layer, and moreover, specific filtration resistance (SFR) of SMPs was approximately 700 times larger than that of the sludge particulates at operational day 3. According to energy balance principle, a unified thermodynamic mechanism underlying these fouling behaviors of SMPs was proposed. Thermodynamic analyses demonstrated that, the attractive interaction energy strength in contact between SMPs and membrane was larger by around 3700 times than that between sludge particulates and membrane, well explaining the extremely high adhesive ability of SMPs over sludge particlulates. Meanwhile, filtration through a SMPs layer was modelled and simulated as a thermodynamic process. Simulation on an agar gel showed that, about 92.6% of SFR was originated from mixing free energy change during filtration. Such a result satisfactorily interpreted the extremely high SFR of SMPs layer over sludge cake layer. The revealed thermodynamic mechanism underlying SMPs fouling behaviors significantly deepened understanding of fouling, and facilitated to development of effective fouling control strategies. PMID- 30476777 TI - Pilot-scale comparison of cyclically and continuously operated drinking water biofilters: Evaluation of biomass, biological activity and treated water quality. AB - The objective of this pilot study was to evaluate the impact of cyclical (operated 8-12 h per day) and continuous biofilter operation with respect to biomass development, biological enzyme activity and treated water quality (in terms of organics, nutrients and disinfection by-product (DBP) formation potential). Continuously operated biofilters developed greater densities of biomass, as measured by ATP, when compared to cyclically operated filters; reducing the empty bed contact time (EBCT) increased biomass density under continuous flow conditions. However, once normalized to biomass, it was shown that cyclically operated filters exhibited higher enzyme activity, indicating that this method of operation may improve bacterial function. Reduction of organics was generally similar for both continuous and cyclical filters with the same EBCT, however, cyclical filters demonstrated higher variability during the first 4 h following start-up. Overall, HAA formation potential was better controlled by continuously operated filters, due to poor performance by the cyclical filters upon start-up while THM precursors were removed equally well by all filters. To understand the removal capacity for NDMA precursors through biological filters, both naturally occurring NDMA FP and NDMA FP resulting from spiked anthropogenic precursors was monitored through the filter depth. All the filters removed 90% of the naturally occurring NDMA FP within the first 45 cm; cyclical operation resulted in higher reduction of spiked anthropogenic NDMA precursors (50% higher than continuously operated) demonstrating the advantage of routine shut down on overall microbial activity. Tools to monitor and predict biofilter performance are in high demand. Here we present an "effective activity" term which combines enzyme activity with contact time (EBCT). Effective esterase activity was strongly correlated to DOC reduction as a function of filter operation (cyclical or continuous) and EBCT; effective phosphatase activity was indicative of phosphate removal. The results of this study indicate that routine shut down of the filters as this location improved enzyme activity without compromising control of chlorinated DBPs (THMs and HAAs) or NDMA derived from natural and anthropogenic precursors. PMID- 30476778 TI - Polyphosphate-accumulating organisms in full-scale tropical wastewater treatment plants use diverse carbon sources. AB - Enhanced biological phosphorus removal (EBPR) is considered challenging in the tropics, based on a great number of laboratory-based studies showing that the polyphosphate-accumulating organism (PAO) Candidatus Accumulibacter does not compete well with glycogen accumulating organisms (GAOs) at temperatures above 25 degrees C. Yet limited information is available on the PAO community and the metabolic capabilities in full-scale EBPR systems operating at high temperature. We studied the composition of the key functional PAO communities in three full scale wastewater treatment plants (WWTPs) with high in-situ EBPR activity in Singapore, their EBPR-associated carbon usage characteristics, and the relationship between carbon usage and community composition. Each plant had a signature community composed of diverse putative PAOs with multiple operational taxonomic units (OTUs) affiliated to Ca. Accumulibacter, Tetrasphaera spp., Dechloromonas and Ca. Obscuribacter. Despite the differences in community composition, ex-situ anaerobic phosphorus (P)-release tests with 24 organic compounds from five categories (including four sugars, three alcohols, three volatile fatty acids (VFAs), eight amino acids and six other carboxylic acids) showed that a wide range of organic compounds could potentially contribute to EBPR. VFAs induced the highest P release (12.0-18.2 mg P/g MLSS for acetate with a P release-to-carbon uptake (P:C) ratio of 0.35-0.66 mol P/mol C, 9.4-18.5 mg P/g MLSS for propionate with a P:C ratio of 0.38-0.60, and 9.5-17.3 mg P/g MLSS for n-butyrate), followed by some carboxylic acids (10.1-18.1 mg P/g MLSS for pyruvate, 4.5-11.7 mg P/g MLSS for lactate and 3.7-12.4 mg P/g MLSS for fumarate) and amino acids (3.66-7.33 mg P/g MLSS for glutamate with a P:C ratio of 0.16 0.43 mol P/mol C, and 4.01-7.37 mg P/g MLSS for aspartate with a P:C ratio of 0.17-0.48 mol P/mol C). P-release profiles (induced by different carbon sources) correlated closely with PAO community composition. High micro-diversity was observed within the Ca. Accumulibacter lineage, which represented the most abundant PAOs. The total population of Ca. Accumulibacter taxa was highly correlated with P-release induced by VFAs, highlighting the latter's importance in tropical EBPR systems. There was a strong link between the relative abundance of individual Ca. Accumulibacter OTUs and the extent of P release induced by distinct carbon sources (e.g., OTU 81 and amino acids, and OTU 246 and ethanol), suggesting niche differentiation among Ca. Accumulibacter taxa. A diverse PAO community and the ability to use numerous organic compounds are considered key factors for stable EBPR in full-scale plants at elevated temperatures. PMID- 30476779 TI - Effects of decentralization of primary health care on diabetes mellitus in Brazil. AB - OBJECTIVES: The aim of this study was to investigate the effects of primary healthcare decentralization on type 2 diabetes mellitus mortality and morbidity in different municipalities of a developing country. STUDY DESIGN: This was a retrospective study based on a panel of annual data from 5560 Brazilian municipalities from 2000 to 2011. METHODS: The investigation used the staggered municipal adoption of a federal health information program as a quasi-experiment to identify the treatment effects of health decentralization on diabetes indicators. Using Difference-in-Differences models and instrumental variables, we analyzed the effects of primary healthcare decentralization on diabetes rates (i.e. diabetes deaths and hospitalizations by the number of people with a diabetes diagnosis and by population). RESULTS: Evidence suggests improvements in universal access to primary health care and progress in the average health outcomes related to diabetes mortality (reduction of 30%) and hospitalization (reduction of 2.3%) due to decentralization. Effects are further pronounced in developed regions with higher incomes, while the poorest and less developed regions showed virtually no effect. CONCLUSIONS: These results demonstrate that there are particular preconditions for successful primary health decentralization, especially related to returns of scale (big health facilities are associated with low cost per treatment), lack of human and physical capital, and government coordination problems. PMID- 30476780 TI - Abuse and depression among Filipino foreign domestic helpers. A cross-sectional survey in Hong Kong. AB - OBJECTIVES: The objectives of this study are to (1) explore physical and verbal abuse experience, perpetrators of abuse and abuse reporting behaviours of Filipino foreign domestic helpers in Hong Kong and (2) examine associations between their abuse experience and depression level. STUDY DESIGN: A cross sectional survey METHODS: We purposively sampled participants at the Statue Square of Hong Kong on three Sunday afternoons between June and August 2017. Using a self-administered questionnaire, measures include sociodemographic and housing environment variables, physical and verbal abuse experience and depression level measured using the Depression Subscale of Depression Anxiety Stress Scale 21 (DASS-21-D). Multiple linear regression was performed to identify factors associated with the DASS-21-D score. RESULTS: The response rate was 86.1% and 105 participants completed the questionnaire. Overall, 20.5% and 34.4% had experienced physical and verbal abuse, respectively, in the past 12 months. Majority of perpetrators were female employers and children. Meanwhile, 16.7% of the abuse victims did not report their cases. Among those who reported, only a few (19.4%) reported their cases to formal organizations (agency and police). Factors significantly associated with the DASS-21-D score include physical abuse (unstandardized beta coefficient [B] = 1.68, 95% confidence interval [95% CI] = 0.12-3.34), verbal abuse (B = 1.58, 95% CI = 0.16-3.00), non-disclosure of physical abuse experience (B = 5.68, 95% CI = 0.18-11.18) and living space satisfaction (B = -1.50, 95% CI = -2.12 to -0.88). CONCLUSIONS: Physical and verbal abuse among foreign domestic workers in Hong Kong were underreported to formal organizations and were associated with depression. Legislative enforcement of a comprehensive abuse reporting mechanism and mental health service should be considered. PMID- 30476781 TI - Eat, play, learn well-a novel approach to co-production and analysis grid for environments linked to obesity to engage local communities in a child healthy weight action plan. AB - OBJECTIVES: To describe the process of combining Analysis Grid for Environments Linked to Obesity (ANGELO) with community engagement, qualitative and co production methods to promote local strategies around child healthy weight (CHW) and to highlight steps taken to engage local people in developing a community CHW action plan around two school communities in Dundee, Scotland. STUDY DESIGN: The Eat, Play, Learn Well (Learn Well) approach applied an action-oriented research approach, using qualitative methods. METHODS: Focus group discussions (FGDs), a co-production approach, and ANGELO were linked by applying a novel three-step process. FGDs were recorded by scribe and following face-to-face interview's key themes were identified using a novel, predefined five-step process, and ANGELO grids were populated. Prioritization events allowed local people to rank most important health statements, with community conversations offering further insights to help create a local CHW action plan. RESULTS: Three FGDs were conducted with parents (n = 24) and two with workers (n = 15). Eighty-seven attended a prioritization event at school B (41 adults), 59 attended at school A (35 adults), where each school community chose its top four priorities from 11 health statements developed. Two further community conversations then took place and led to the creation of a CHW action plan with five overarching themes. CONCLUSIONS: The Learn Well test approach helped gain important insights into local environments linked to obesity and production of a pragmatic, step-by-step process suitable for real-life public health practice that can enable local people to identify key early intervention and prevention priorities, in a tangible way. PMID- 30476782 TI - Broadband ultrasound-trapping barrier based on hollow cylinder with a periodic grating. AB - It is important to modulate ultrasonic waves in some ultrasonic application fields. We formed an ultrasound-trapping barrier through a hollow cylinder with a periodic grating on the surface and simulated the barrier using the finite element method. Using the Schlieren imaging technique, we visualized the ultrasound field distribution in the structure. Both the experimental and simulation results revealed that the structure can work in a broadband frequency range, demonstrating the effectiveness and practicability of the structure as a virtual ultrasound barrier. We also describe how the silent region and the ultrasound intensity can be adjusted in the hollow cylinder. PMID- 30476783 TI - An acoustic emission characterization of the failure process of shallow foundation resting on sandy soils. AB - Shallow foundation is a common foundation type that is usually used for small to medium size structures. The bearing ability and the failure mechanism of shallow foundation are the fundamental concerns for geotechnical engineers, and the demand for new insights into the relevant issue is still increasing. This paper presents an acoustic emission (AE) characterization of the failure process of shallow foundation, with the aim of revealing the fundamental information on AE signals associated with shallow foundation loading as well as its connection with the ground bearing behavior. Experiments were carried out to model the failure process of shallow foundation resting on sandy ground with different densities (i.e. loose and dense) and subjected to different loading conditions (i.e. monotonic and cyclic loading). Comparisons between AE activities and ground bearing behavior are presented. The feasibility of using AE for stability monitoring of shallow foundation is revealed and discussed. PMID- 30476784 TI - Development of ultrasonic guided wave inspection methodology for steam generator tubes of prototype fast breeder reactor. AB - An ultrasonic guided wave based methodology is developed for inspection of steam generator tubes of the prototype fast breeder reactor. To this aim, axisymmetric longitudinal mode (L(0,2)) at the frequency of 250 kHz is optimized using 3D finite element simulation and experiments. The group velocity of mode L(0,2) at 250 kHz is found to be 5387 m/s. First, the long range propagation of the L(0,2) mode at 250 kHz is examined and the mode is found to propagate over a distance of 45.6 m with a sufficiently good SNR. Secondly, the detection of multiple defects such as circumferential, axial, partial-pinholes and tapered defects lying in the same line of sight is investigated using 3D-finite element simulation and the results obtained are validated experimentally for the first three cases. The sensitivities achieved are 0.23 mm depth (10%WT) for circumferential, axial and tapered defects and for partial-pinholes: 1 mm diameter and 1.38 mm depth (60%WT). Thirdly, 3D-FE simulations with ID and OD pinhole defects are performed which show that the ID and OD defects are detected by L(0,2) with a fairly similar sensitivity. Finally, study on the thermal expansion bend (with three successive bends) shows that the bend does not have much influence on the mode and the multiple circumferential defects considered in the bend are detected with good sensitivity. PMID- 30476785 TI - Amplitude modified sparse imaging for damage detection in quasi-isotropic composite laminates using non-contact laser induced Lamb waves. AB - Composite structure is increasingly used in civil and aerospace applications due to its high mechanical performance. Lamb wave based sparse reconstruction imaging for damage localization is promising for structural health monitoring (SHM) and nondestructive evaluation (NDE) by using few measurements. However, this dictionary based method requires accurate atoms to represent Lamb wave propagating features in structure very well. Besides dispersion, signal changes caused by amplitude modulation should be considered for waveform distortion when constructing the dictionary for sparse imaging method. In this paper, a non contact laser is used for Lamb wave excitation which exhibits a strong amplitude modulation in low frequency. Additionally, the strong attenuation resulting from material damping would also presents a distance-dependent amplitude modulation. To reconstruct an amplitude model of Lamb wave, the decomposition method of system response and attenuation is proposed. Then, the influence of amplitude modulation on signal representation is analyzed, which shows the restriction of dictionary without considering amplitude modulation. On this basis, the amplitude considered dictionary is built together with the phase considered dictionary for sparse imaging in terms of damage detection. Furthermore, according to Lamb wave reflection model, the solution for sparse reconstruction imaging is given. Finally, the performance of sparse imaging method is discussed by experimental investigation with different parameters. The results show the efficiency of the proposed method with improved imaging performance and give comparisons for better parameter choice. PMID- 30476786 TI - Modeling and simulation of vibro-thermography including nonlinear contact dynamics of ultrasonic actuator. AB - In this paper, a thermodynamically consistent generalized three-dimensional modeling scheme is developed to simulate vibro-thermography and subsequently perform a quantitative investigation on a test structure. Simulation results are analyzed considering a plate with Structural Features (SF) which are used in a gas turbine engine structural components to reduce structural mass and enhance cooling. The modeling framework includes (i) coupled thermo-elastic heat generation and (ii) effects of various sources of nonlinear vibration arising due to the amplitude of the excitation, the engagement force on the target structure due to the ultrasonic horn, and structural boundary conditions. Transient heat generation behavior in the target structure with SF is analyzed. Dynamic contact models are used to capture the nonlinear harmonics. The effects of engagement force on the dynamic response are analyzed. Simulation results are obtained by incorporating the model in a finite element scheme. The simulation results show that the thermographic inspection can be optimally designed using a relationship between the SF sizes with reference to wavelength based resonance phenomenon. The spectral components obtained at various locations in the SF reveals the presence of both sub- and super-harmonics. PMID- 30476787 TI - High-power piezoelectric vibration model considering the interaction between nonlinear vibration and temperature increase. AB - For high-power piezoelectric devices, nonlinear vibrations and related increases in temperature are critical problems produced by large internal stress and strain. Such nonlinear vibrations have been studied by some researchers; however, the related increase in temperature has not been taken into consideration, because it is a complicated phenomenon. In this study, the mechanism underlying the interaction between nonlinear vibration and temperature increase in a piezoelectric transducer under high-power conditions was clarified. For this purpose, cubic terms of the mechanical strain, the nonlinear transfer matrix method, and the heat conduction equation were combined. Additionally, it is necessary to utilize the distributed parameter model because the temperature increase is not uniform. The calculation results obtained using the measured temperature dependence of material constants verified that the temperature increase significantly degrades the piezoelectric vibration. It is expected that the proposed model will prove indispensable in the development of piezoelectric materials for high-power piezoelectric devices. PMID- 30476788 TI - Identification of insect-specific flaviviruses in areas of Brazil and Paraguay experiencing endemic arbovirus transmission and the description of a novel flavivirus infecting Sabethes belisarioi. AB - Viral infection was examined with pan-flavivirus and pan-alphavirus sets of primers in mosquitoes collected in four South American regions with confirmed pathogenic arbovirus circulation. Positive pools for flavivirus infection were sequenced and screened for specific arboviruses, which were not detected. However, NS5 gene sequencing showed that most sequences corresponded to the insect-specific Culex flavivirus. One sequence retrieved from an Aedes albopictus pool grouped with the insect-specific Aedes flavivirus and two Sabethes belisarioi pools were infected by a previously unknown flavivirus, tentatively named Sabethes flavivirus (SbFV). Phylogenetic inference placed SbFV as ancestral to a clade formed by Culiseta flavivirus, Mercadeo, and Calbertado. SbFV polyprotein showed an average aminoacidic identity of 51% in comparison to these flaviviruses. In vitro studies suggest that SbFV infects insect cells, but not vertebrate cells, therefore, we propose it as a new insect-specific flavivirus. These results highlight the wide distribution of insect-specific flaviviruses concomitant with the circulation of emergent arboviruses. PMID- 30476789 TI - Chiral Syn-1,3-diol Derivatives via a One-Pot Diastereoselective Carboxylation/ Bromocyclization of Homoallylic Alcohols. AB - Chiral syn-1,3-diols are fundamental structural motifs in many natural products and drugs. The traditional Narasaka-Prasad diastereoselective reduction from chiral beta-hydroxyketones is an important process for the synthesis of these functionalized syn-1,3-diols, but it is of limited applicability for large-scale synthesis because (1) highly diastereoselective control requires extra explosive and flammable Et2BOMe as a chelating agent under cryogenic conditions and (2) only a few functional syn-1,3-diol scaffolds are available. Those involving halogen-functionalized syn-1,3-diols are much less common. There are no reported diastereoselective reactions involving chemical fixation of CO2/bromocyclization of homoallylic alcohols to halogen-containing chiral syn-1,3-diols. Herein, we report an asymmetric synthesis of syn-1,3-diol derivatives via direct diastereoselective carboxylation/bromocyclization with both relative and absolute stereocontrol utilizing chiral homoallylic alcohols and CO2 in one pot with up to 91% yield, > 99% ee, and >19:1 dr. The power of this methodology has been demonstrated by the asymmetric synthesis of statins at the pilot plant scale. PMID- 30476790 TI - Yolk-Shell Germanium@Polypyrrole Architecture with Precision Expansion Void Control for Lithium Ion Batteries. AB - The key properties of yolk-shell architecture in improving electrochemical performance lies in its uniformity and the appropriate void space, which can expand/contract freely upon lithium alloying and leaching without damaging the outer shell, while being achievable with minimal sacrifice of volumetric energy density. Therefore, we developed a highly controllable strategy to fabricate a uniform porous germanium@polypyrrole (PGe@PPy) yolk-shell architecture with conformal Al2O3 sacrificial layer by atomic layer deposition (ALD) process. The PGe@PPy yolk-shell anode fabricated with 300 ALD cycles delivers excellent electrochemical performance: high reversible capacity (1,220 mA hr g-1), long cycle performance (>95% capacity retention after 1,000 cycles), and excellent rate capability (>750 mA hr g-1 at 32 A g-1). Electrodes with high areal capacity and current density were also successfully fabricated, opening a new pathway to develop high-capacity electrode materials with large volume expansion. PMID- 30476791 TI - Effect of cholesterol on monolayer structure of different acyl chained phospholipids. AB - In this work we have investigated the effect of cholesterol (CHOL) in phospholipid monolayers on a series of phosphatidylcholines differing in acyl chain composition. We have used the CHOL proportion that abolishes the gel (Lbeta)-to-liquid-crystalline (Lbeta) transition in bilayers in order to investigate the mixing properties and laterally-segregated domains formed by specific phospholipid-CHOL ratios at the air-water interface. The binary monolayers where formed by mixing CHOL with 1,2-palmitoyl-sn-glycero-3-phos phatidylcholine (DPPC);1,2-distearoyl-sn-glycero-3-phosphatidylcholine (DSPC); 1 pal-mitoyl-2-stearoyl-sn-glycero-3-phosphatidylcholine (PSPC); 1-palmitoyl-2 oleoyl-sn-gly-cero-3-phosphatidylcholine (POPC) and 1-palmitoyl-2-linoleyl-sn glycero-3-phosphatidyl-choline (PLPC), respectively. From surface pressure-area (pi-A) isotherms the isothermal compression modulus were calculated, and the mixing properties of the monolayers obtained by performing a basic surface thermodynamic analysis. From the excess Gibbs energy, the interaction parameter and the activity coefficients were also calculated. The study of the monolayers was complemented by determining the molecular dipole moment normal to the plane of the monolayer. The existence of laterally segregated domains was assessed by atomic force microscopy (AFM) of Langmuir-Blodgett films (LBs) extracted at 30 mNm-1. To get insight into the nature and composition of the observed domains force spectroscopy (FS) based on AFM was applied to the LBs. PMID- 30476792 TI - Near-infrared fluorescent carbon dots encapsulated liposomes as multifunctional nano-carrier and tracer of the anticancer agent cinobufagin in vivo and in vitro. AB - Integrating the optical properties of near-infrared fluorescent carbon dots into liposomes may construct a multifunctional nano-system with the potential as a drug carrier, tracer and efficacy intensifier of the anticancer agent. In this study, the liposomes loaded with hydrophilic near-infrared carbon dots as a nano carrier and tracer of lipophilic anticancer agent cinobufagin were developed. Prepared liposomes were characterized by particle size, morphology and entrapment efficiency. The drug release behavior, the tracer function, the anticancer effect and the side effect were investigated in vitro and in vivo. It was observed that the photoluminescence emission of carbon dots could be strongly enhanced up to 5 times by nano-liposomes. Due to this property, the bio-imaging of CDs + CB liposomes in vitro and in vivo could be clearly obtained. Our results also showed that the CDs + CB liposomes could be uptaken by cells (the lysosomes targeted) and delivered to the tumor site, and undoubtedly, the CDs + CB liposomes demonstrated sustained drug release, enhanced anticancer efficacy and low side effects in vivo. With the assistance of imaging function of CDs, the CDs + CB liposomes can easily display the distribution of drugs, which is very helpful for drug development and may open a novel avenue for drug delivery. PMID- 30476793 TI - Fluorine-containing block/branched polyamphiphiles forming bioinspired complexes with biopolymers. AB - Colloidal-chemical characteristics of block/branched cationic and non-ionic polyamphiphiles containing poly(fluorine-alkyl methacrylate) (poly(FMA)) block and their intermolecular complexes with biopolymers were studied. The dependences of their surface activity and micelle size on the length of hydrophobic and hydrophilic blocks, as well as the length of side fluorine-alkyl branches were established. Poly(FMA)-block-poly(DMAEMA) was used for formation of interpolyelectrolyte complexes with plasmid DNA (pDNA) via their electrostatic interaction. Novel non-viral polyplexes were tested as gene delivery systems for mammalian cells. The results of DLS, TEM and MALDI-ToF studies demonstrated disaggregation of lysozyme (LYZ) aggregates in the presence of poly(FMA)-block poly(NVP) and formation of the polyamphiphile...LYS complex possessing antibacterial action. PMID- 30476794 TI - Proline functionalized gold nanoparticles modulates lysozyme fibrillation. AB - Amyloid fibrils are the hallmarks of neurodegenerative diseases like Alzheimer's, Parkinson's and other proteopathies. Inhibition of fibrillation is a potential strategy to check the progress of amyloid associated diseases and further allied deterioration. In this study, we have synthesized proline functionalized gold nanoparticles (Pro-AuNPs) and scrutinized its antifibrillation property towards Hen Egg White Lysozyme (HEWL) aggregation. Pro-AuNPs were characterized using various biophysical methods like ultraviolet-visible spectroscopy, fourier transform infra-red spectroscopy, zeta potential measurement, dynamic light scattering and transmission electron microscopy. The effect of Pro-AuNPs on HEWL fibrillation was analyzed employing thioflavin T (ThT) and 8-Anilino-1 naphthalenesulfonic acid (ANS) assays. The kinetics of HEWL exhibited a typical sigmoidal nature of protein aggregation and was fitted to Boltzmann model. HEWL in the presence of bare gold nanoparticles (bAuNPs) exhibited similar aggregation kinetics as HEWL alone. However, HEWL fibrillation substantially reduced upon co incubation with proline and Pro-AuNPs, and two slightly different intermediate species were formed with these two systems as predicted by CD spectroscopy. TEM images also supported the above observation displaying different morphological states of HEWL aggregates in the presence of proline and Pro-AuNPs. Using computational methods, the nature of interaction of HEWL and proline was found to be hydrogen bonding and hydrophobic interaction in multiple amyloidogenic regions. These interactions inhibited the formation of prefibrils (beta-sheet rich intermediates) and also found to disintegrate fibrils. Furthermore, HEWL-Pro AuNPs system resulted HEWL adsorption through hydrophobic patches, which blocked the intermolecular beta-sheet formation. The present study successfully established Pro-AuNPs as a potential inhibitor of HEWL aggregation. PMID- 30476795 TI - Gene expression signature in brain regions exposed to long-term psychosocial stress following acute challenge with cannabinoid drugs. AB - Repeated exposure to life stressors can overwhelm the body's capacity to restore homeostasis and result in severe negative consequences. Cannabinoid CB1 receptors are highly expressed in the Central Nervous System (CNS) and regulate both glucocorticoid signalling and neurotransmitter release. In rodents, WIN55212.2 is a full agonist at the cannabinoid receptor type-1, while Rimonabant is a potent and selective cannabinoid inverse agonist at this receptor. This study aims to investigate the effect of long-term psychosocial stress following acute challenge with cannabinoid drugs on gene expression in distinct brain regions; this is done by employing digital multiplexed gene expression analysis. We found that repeated stress increased cortical mRNA levels of dopamine receptor D2, while the expression of neuregulin-1 decreased in both the prefrontal cortex and cerebellum. Further, we found that the acute injection of the agonist WIN55212.2 reduced striatal levels of dopamine receptor D2, while the use of inverse agonist Rimonabant acted in the opposite direction. The analysis of the interaction between the drugs and repeated stress revealed that defeat mice treated with WIN55212.2 showed lower expression of a set of myelin-related genes, as did the expression of SRY-box 10 and dopamine receptors-D1 and -D2 in the prefrontal cortex when compared to vehicle. In addition, in the hippocampus of stressed mice treated with WIN55212.2, we found an elevated expression of oligodendrocyte transcription factor-1, -2 and zinc finger protein 488 when compared to vehicle. In comparison to vehicle, an increase in 2',3'-Cyclic nucleotide 3' phosphodiesterase and oligodendrocyte transcription factor-1 occurred in the cerebellum of stressed animals treated with the agonist. Moreover, treatment with Rimonabant under the influence of stress induced an overexpression of a set of myelin-related genes in the prefrontal cortex when compared to WIN-treated animals. In conclusion, repeated stress interfered with the dopaminergic system in the prefrontal cortex. We demonstrated that the expression of dopamine receptor D2 in the striatum was mediated by the CB1 receptor. Stressed mice exposed to either WIN55212.2 or Rimonabant displayed pronounced deficits in CNS myelination. In addition, the pharmacological blockage of CB1 receptor in stressed mice deregulated the expression of dopamine receptors and might lead to dysfunctions in dopamine metabolism. PMID- 30476796 TI - Rapid and direct determination of fatty acids and glycerides profiles in Schisandra chinensis oil by using UPLC-Q/TOF-MSE. AB - Fatty acids and glycerides are globally accepted quality and nutrition indicators of oils. Schisandra chinensis (S. chinensis) is a good functional oil source, with an oil content of 10-50% (dry weight). In this study, the UPLC-Q/TOF-MSE technique was developed to profile FFA and glycerides in the S. chinensis oils directly. The results showed that all of the 36 FFA calibration equations of the mixture standard had good linear relationships (R2 > 0.99). The limit of detection for the tested compounds ranged from 0.0001 to 0.0200 MUg/mL, while the limit of quantification ranged from 0.0005 to 0.1300 MUg/mL. In total, seventeen FFAs, six diglycerides and 20 triglycerides were identified. Linoleic, oleic, stearic and palmitic acids were the most abundant FFAs in the S. chinensis oils. It was also found that S. chinensis oil is rich in the L-L, L-L-L, O-L-L and O-L O glycerides. These results will be helpful for the use of this technique in physicochemical evaluation and for further application development. PMID- 30476797 TI - Catalytic ozonation of 4-chloronitrobenzene by goethite and Fe2+-modified goethite with low defects: A comparative study. AB - In this study, Fe2+-modified goethite with low defects (alpha-Fe(Fe2+)OOH) was synthesized and characterized. Results revealed that alpha-Fe(Fe2+)OOH is a nano magnetic material with goethite (alpha-FeOOH) -type structures and has fewer Lewis acid of Fe3+ on its surface. Moreover, alpha-Fe(Fe2+)OOH was effective in catalytic ozonation of 4-chloronitrobenzene (4-CNB), which is a probe contaminant that cannot be efficiently removed through sole ozonation. The removal of 4-CNB increased with ozone concentration and alpha-Fe(Fe2+)OOH dosage, but decreased with the presence of carbonate, sulfate and phosphate. The catalytic activity of alpha-Fe(Fe2+)OOH also showed a dependence on solution pH. The presence of humic acid accelerated 4-CNB removal at low concentration but inhibited the removal at high concentration. In comparison with alpha-FeOOH, alpha-Fe(Fe2+)OOH significantly enhanced hydroxyl radicals generation and reduced Fe ions release in this process. The hydroxyl groups of Fe3+ on alpha-FeOOH and alpha-Fe(Fe2+)OOH surface was active site for ozone decomposition into hydroxyl radicals. Introducing Fe2+ significantly increased the density of surface hydroxyl groups relative to alpha-FeOOH. This enhancement significantly promoted hydroxyl radicals generation and 4-CNB degradation in the solution. PMID- 30476798 TI - Novel synthesis of nanoscale zerovalent iron from coal fly ash and its application in oxidative degradation of methyl orange by Fenton reaction. AB - We firstly developed a novel synthesis method of nanoscale zerovalent iron (NZVI) using Fe sources in coal fly ash (CFA) for the oxidative degradation of methyl orange by Fenton reaction. Hydrochloric acid (HCl) and methyl isobutyl ketone (MIBK) were used for Fe dissolution from CFA and selective Fe(III) chelation, respectively. Among varied HCl concentrations, 7 N HCl showed the best performance for the oxidation of aqueous Fe(II) to Fe(III) and efficient chelation of Fe(III) with MIBK. The NZVI-CFA was synthesized by adding NaBH4 to a solution of Fe(III)-chelated MIBK, yielding NZVI transformation >95% from Fe(III) in HCl. Various surface analyses were performed to characterize the NZVI-CFA, which was almost identical to typical NZVI-Bare. HCl and MIBK could be reused several times, indicating potential reusability of chemicals used in the synthesis. Remarkable >96% decolorization of methyl orange was obtained by the NZVI-CFA-induced Fenton reaction at pH 3, with a ~22% decrease in total organic carbon in 7 min. The heterogeneous Fenton reaction initiated by NZVI-CFA with H2O2 showed reactivity similar to that of the homogeneous Fenton reaction (i.e., aqueous Fe(II) with H2O2), indicating the importance of homogeneous reaction for the oxidative degradation of methyl orange. PMID- 30476799 TI - Unary and binary adsorption studies of lead and malachite green onto a nanomagnetic copper ferrite/drumstick pod biomass composite. AB - Modern-day practices are the major contributors in water quality deterioration, consequently results in clean water scarcity. Herein, co-precipitation procedure was adopted to develop a nanomagnetic copper ferrite/drumstick pod biomass (CuFe2O4/DC) composite, which was characterized, and optimized to sequester malachite green (MG) and lead (Pb(II)) in unary and binary systems from aqueous environment. Mesoporous CuFe2O4/DC surface with 16.96 m2/g BET surface area and acid functionalities predominance was observed. Under the studied experimental conditions, MG adsorption on CuFe2O4/DC in unary system was comparatively higher than that of Pb(II). MG and Pb(II) equilibrium results were fitted to Langmuir isotherm model, their respective maximum monolayer adsorption capacities at 328 K being 952.4 and 921.1 mg/g. On the other hand, binary system (in presence of MG) fastened Pb(II) adsorption kinetics and increased its uptake capacity. Additionally, humic acid (HA) matrix enhanced Pb(II) adsorption kinetics. Recovery studies showed maximal MG and Pb(II) elution with C2H5OH and 0.1 mol/L HCl, respectively. An 82.7% drop in Pb(II) adsorption was found after the first regeneration cycle, while only 17.6% fall in MG adsorption was witnessed after five consecutive regeneration cycles. Hence, it could be concluded that CuFe2O4/DC is a cost-effective and promising adsorbent for an efficient and rapid removal of Pb(II) and MG from both unary and binary systems. PMID- 30476800 TI - Effect of air pollutants and toxic emissions from various mileage of motorcycles and aerosol related carcinogenicity and mutagenicity assessment. AB - This research investigates the mileage and the health risk assessment of aerosol carcinogenicity and mutagenicity emitted by ten in-use motorcycles. The total p PAHs emission factor of ten in-use motorcycles are 676.3 MUg km-1 with average of 67.6 +/- 13.6 MUg km-1. Naphthalene (Nap) shows the largest emission factors, followed by phenanthrene (PA) and fluoranthen (FL). The mileage present high correlation coefficient (Rsp = 0.681) with CO. CO is associated with cumulative mileage leading to bad combustion efficiency, which caused low to high relationship for total p-PAHs (Rsp = 0.388), PM2.5 (Rsp = 0.680) and NOx (Rsp = 0.799). Both PM2.5 and total p-PAHs are generally generated via incomplete combustion and the results expressed the moderate to high correlation (Rsp = 0.578, 0.898) with NOx. Taking into consideration of high-mileage motorcycles (30,001-50,000 km), the toxic equivalent of carcinogenicity and mutagenicity exhaust are about 4.67, 1.99 and 3.89, 2.0 times higher than low (10,001-20,000 km) and middle (20,001-30,000 km) cumulative mileages, respectively. Therefore, in the conclusion of our study in compared with that of other research directed the fact that lower carcinogenicity and mutagenicity emission factor were found at lower cumulative mileages motorcycles however, the impact increases with the high cumulative mileage motorcycles. PMID- 30476801 TI - A new method for ranking potential hazards and risks from wastes. AB - A quantitative approach for assessing hazards facilitates decision making on hazardous waste management practices. In this study, a scoring approach was developed to evaluate the physical, human health, environmental and amenity hazard aspects and risks (in case of exposure) of waste streams. The approach was based on the 15 hazard properties (HPs) defined in European Commission Waste Framework Directive 2008/98/EC and their related Globally Harmonised System of Classification and Labelling of Chemicals (GHS) hazard statement codes (H-codes). Additionally, amenity and other hazards including space requirement, odour, dust, vermin, visual impact, radioactivity and physical injury were considered. A score of 0-3 was assigned to each of the H-codes or amenity and other hazards. The scoring approach consisted of: 1) determining the waste composition; 2) searching H-codes based on waste composition and assigning H-codes to the associated HPs; 3) calculating the hazard score for each of the four hazard aspects; and 4) calculating the total score for each waste. Two methods were used to calculate the total hazard score for 29 hazardous wastes. The wastes were ranked over a hazard spectrum to indicate the potential degree of hazard. The new hazard scoring approach can be used for prioritising efforts in managing wastes. PMID- 30476802 TI - Biocatalytic membrane reactor development for organophosphates degradation. AB - Organophosphates (OPs) are highly toxic compounds used as pesticides and nerve agents. The devastating effects, reported in different studies, on the environment and human health indicate a serious scenario for both instantaneous and long terms effects. Bio-based strategies for OPs degradation seem the most promising solutions, particularly when extremophiles enzymes are used. These systems permit OPs degradation with high efficiency and specificity under mild conditions. However, as frequently observed, enzymes can easily lose activity in batch systems, so that a strategy to improve biocatalyst stability is highly needed, in order to develop continuous systems. In this work, for the first time, a continuous biocatalytic system for organophosphates (OPs) detoxification has been proposed by using a triple mutant of the thermostable phosphotriesterase (named SsoPox) isolated from the hyperthermophilic archaeon Sulfolobus solfataricus. The enzyme was covalently immobilized on polymeric membranes to develop a biocatalytic membrane reactor (BMR) able to hydrolyse a pesticide (paraoxon) contained in water. High paraoxon degradation (about 90%) and long term stability (1 year) were obtained when the enzyme was covalently immobilized on hydrophilic membranes. On the contrary, the enzyme in batch system completely loses its activity within few months after its solubilisation in buffer. PMID- 30476803 TI - Determining the long-term operational performance of pump and treat and the possibility of closure for a large TCE plume. AB - The purpose of this study is to evaluate the impact of heterogeneity on the long term performance of a large pump-and-treat (PAT) system that has been in operation for 30 years at a site located in Tucson, AZ. A 3D numerical model was developed. Three different concentrations were examined: composite concentration in the influent to the treatment plant, resident concentration in the aquifer, and concentration for downgradient boundary discharge. The time scales needed for concentrations measured in these ways to reach the Maximum Contaminant Levels (MCLs) are significantly different, with ~125 years required for treatment-plant influent compared to ~225 years for downgradient boundary discharge and >>227 years (total simulated time) for the resident concentration in the aquifer. These large time scales, compared to 36 years for a hypothetical homogeneous system, demonstrate the significant impacts of permeability heterogeneity on remediation at this site. The possibility of closure of the site was investigated by examining the mass discharge from the site boundary and the concentration rebound after simulating shutdown of the PAT system. The results of this study provide insight on evaluation of closure potential for large, complex contamination sites and a reference on selecting performance metrics for site management. PMID- 30476804 TI - Identification of first and second generation ozonation transformation products of niflumic acid by LC-QToF-MS. AB - In this study, the removal of niflumic acid (NA) and the identification of its transformation products (TPs) during ozonation was investigated. The influence of initial ozone concentration and pH value on NA's removal was tested, while suspect and non-target screening approaches were followed for the identification of ozonation TPs. The structure elucidation was based on accurate mass and isotopic pattern criteria and interpretation of the acquired MS/MS spectra. Moreover, an in-house retention time prediction model was used as a supporting tool for their identification. Results indicated the highly reactivity of NA with the molecular ozone, since the reaction was extremely fast and was completed within the first minute of the reaction. A total of thirteen TPs of NA were identified, and their proposed structures show that the oxidation occurred in the heterocyclic ring of the molecule, while the aniline-like part remained intact by ozone attack due to the presence of the three fluoride atoms, which act as electron withdrawing groups. Ozonation experiments were conducted also using the most abundant TP of NA as parent compound. Three second generation TPs of NA were detected and possible structures were proposed. PMID- 30476805 TI - Immobilization of hexavalent chromium in contaminated soil using nano-magnetic MnFe2O4. AB - Nano-magnetic MnFe2O4 was prepared and examined to immobilize Cr(VI) in the soil. According to the results of scanning electron microscopy (SEM) and X-ray diffraction (XRD) the formation of nano-magnetic MnFe2O4 with the particle size of less than 200 nm was demonstrated. Compared with the untreated soil, the leachability of Cr(VI) was reduced from 70.95% to 4.22% through toxicity characteristic leaching procedure (TCLP) at a dosage of 2 g/L of nanoparticles and 192 h remediation time. At the same condition, the physiologically based extraction test (PBET) human bioaccessibility of chromium was reduced from 86.76% to 4.42%. Moreover, the plant bioavailability of hexavalent chromium (using EDTA) was reduced from 83.72% to 5.53%. According to the sequential extraction procedure (SEP) the loosely bounds Cr (90.28%) was converted to the relatively strong bound (Fe-Mn oxides fraction, 92.09%) revealed the significant decrease in risk of release and availability of chromium after immobilization procedure. Further, results of column experiments of Cr(VI) elution revealed that almost all of the water-soluble chromium was converted to the associated synthesized nanoparticles phase. Overall, the present study proved that nano-magnetic MnFe2O4 significantly enhanced the hexavalent chromium immobilization through a decrease in leachability, plant bioavailability, human bioaccessibility, and risk of release. PMID- 30476806 TI - The association between visual impairment and dental care utilization in the Korean elderly. AB - INTRODUCTION: Individuals with visual impairment cannot recognize early-stage oral diseases, thus fail to receive prompt treatment. AIMS: To evaluate the association between visual impairment and dental care utilization in patients aged >=65 years. DESIGN: Retrospective analysis. MATERIALS AND METHODS: We analyzed annual pooled data collected by the Korean Health Panel between 2011 and 2014; a total of 1472 patients and 13,285 dental visits were analyzed. Visual impairment was categorized as follows: normal vision, moderate vision impairment, and severe vision impairment. Dental treatments were categorized as conservative, prosthodontic, implant, periodontal, surgical, preventive, or others. All data were statistically analyzed using a negative binomial regression. MAIN OUTCOME MEASURE: Frequency of dental care utilization. RESULTS: Approximately 50% of the subjects had visual impairment. The frequency of dental care utilization for patients with severe vision impairment was 41% less than patients with normal vision. The dental care utilization for implant treatment was two times higher and periodontal treatment was 1.7 times lower than the conservative treatments among patients who reported moderate and severe vision impairment, respectively. CONCLUSIONS: Visual impairment has a negative association with dental care utilization among older adults. It is imperative to implement systematic interventions to prevent visual impairment from becoming a barrier to dental care in this population. PMID- 30476807 TI - Development of graphene oxide/calcium phosphate coating by pulse electrodeposition on anodized titanium: Biocorrosion and mechanical behavior. AB - In this work, graphene oxide (GO) reinforcement was used to improve the strength and fracture toughness of the calcium phosphate (CaP) coating applied on the anodized titanium using pulse electrodeposition. Based on the results, the CaP coating consisted of mixed phases of octa-calcium phosphate (OCP), dicalcium phosphate dehydrate (DCPD) and hydroxyapatite (HAp); however, compositing of this coating with GO caused deposition of the pure HAp phase. Moreover, the nanohardness and Young's modulus of the CaP-GO coating increased over 52% and 41%, respectively, as compared to those measured for the GO-free coating. An improvement of about 16% in the adhesion strength of the CaP coating composited with GO to the anodized titanium was also arisen from improving integrity, crystallinity and decreasing the Young's modulus mismatch of this coating with titanium substrate. Finally, uniformity in the microstructure and more biostability of the CaP-GO coating led to its better protection against the corrosion of anodized titanium. PMID- 30476808 TI - Experiences of self-conscious emotions in temporal lobe epilepsy. AB - Self-conscious emotions (SCEs) with a negative valence (such as shame and guilt) or a positive valence (such as pride) are moral emotions that emerge from self reflection and self-evaluation processes in social contexts. In some neurologic and psychiatric disorders, experiences of SCEs are dysregulated. The objectives of the present study were to (i) evaluate whether patients with temporal lobe epilepsy (TLE) experience SCEs in the same way as nonclinical (control) participants and (ii) probe the relationships between experiences of SCEs on the one hand and the psychological symptoms frequently diagnosed in patients with TLE (anxiety and depression), the patients' clinical characteristics, and their functional outcomes in everyday life on the other. Sixty-one patients with TLE and 61 matched controls completed a self-questionnaire (the Positive and Negative Affect Schedule (PANAS)) that enabled us to evaluate the extent to which they experienced shame, guilt, and pride. Demographic data, cognitive data, the severity of anxiety symptoms, and the severity of depressive symptoms were recorded for all participants. In patients with TLE, data of clinical characteristics and quality of life were also evaluated. Relative to controls, patients with TLE were more likely to experience negative-valence SCEs to a higher extent and positive SCEs to a lesser extent. The patients who experienced negative-valence SCEs to a higher extent (rather than to a lesser extent) had a higher frequency of seizures, more severe anxiety and depressive symptoms, and a greater prevalence of anxiety and depressive disorders. Furthermore, patients who experienced positive-valence SCEs to a lesser extent (rather than to a higher extent) displayed a higher level of anxiety. Lastly, differences in experiences of SCEs by patients with TLE were associated with a lower quality of life. In conclusion, experiences of SCEs can be dysregulated in patients with TLE. This dysregulation is linked to the patients' clinical and psychological symptoms and quality of life. In this context, SCEs might be a target of interest in the management of epilepsy. PMID- 30476809 TI - Analysis of tissue Doppler parameters and 24-hour heart rate variations in children with newly diagnosed untreated idiopathic epilepsy in interictal period. AB - INTRODUCTION: Cardiac mortality has increased in patients with epilepsy. Although majority of cardiac autonomic and ventricular function abnormalities were detected in ictal and postictal period, interictal epileptogenic activity may induce the autonomic imbalance as well. In our study, we aimed to investigate the interictal, subclinical cardiac changes in terms of cardiac autonomic balance via 24-hour Holter electrocardiography (ECG) and ventricular functions by tissue Doppler echocardiography (TDI) in children with newly diagnosed untreated idiopathic epilepsy. MATERIAL AND METHODS: Thirty children with newly diagnosed untreated idiopathic epilepsy (12 males, 18 females; mean age: 125.13 +/- 35.2 months) (patient group) and 40 healthy, age and body mass index (BMI)-matched children (18 males, 22 females; mean age: 129.43 +/- 38.5 months) (control group) were enrolled. Included patients underwent 24-hour Holter electrocardiographic and tissue Doppler echocardiographic study. RESULTS: Time domain measures were found significantly lower in the patient group. Mean high frequency (HF) values were significantly lower, and mean low frequency (LF) and mean LF/HF parameters were significantly higher in the patient group. Mean isovolumetric contraction time (ICT), isovolumetric relaxation time (IRT), and myocardial performance index (MPI) values were significantly higher, and mean ejection time (ET) values were significantly lower among the patients with untreated idiopathic epilepsy. CONCLUSION: We found that patients with untreated newly diagnosed epilepsy have a significant subclinical deterioration of left ventricular functions, and they also showed changes in heart rate variability (HRV) regarding the sympathovagal imbalance in interictal period. These findings can be related with increased cardiac mortality. PMID- 30476810 TI - Coronary vasodilation impairment in pilocarpine model of epilepsy. AB - We investigated the coronary arteries reactivity alterations in rats with epilepsy induced by pilocarpine. To do so, male Wistar rats weighing between 250 g and 300 g were used. Status epilepticus (SE) was induced in rats using 385 mg/kg (i.p.) of pilocarpine. After 60 days from the first spontaneous seizure, rats were submitted to heart rate measurements and then, one day after, euthanized, and the heart was dissected and submitted to constant flow Langendorff approaches to evaluate coronary reactivity. Rats with epilepsy showed higher resting heart rate and impairment of coronary vasodilation induced by bradykinin. Endothelial nitric oxide synthase (eNOS) and superoxide dismutase (SOD) presented a reduced staining in coronary arteries, and eNOS expression was also reduced in the left ventricle of rats with epilepsy. Our findings demonstrated, for the first time, that epilepsy can cause impairment of coronary arteries reactivity, probably because of an endothelial dependent mechanism. PMID- 30476811 TI - Alpha particle autoradiography for high spatial resolution mapping of radionuclides. AB - An autoradiographic technique capable of determining the spatial location of radioactive isotopes within materials on the scale of micrometers is demonstrated in low-activity mineral samples, where the concentrations of radionuclides with short half lives is small and below the detection limits of current measurement techniques. The location of certain radionuclide species within samples with complex structures on the micron scale can yield valuable information, however current methods do not have the spatial resolution required for this purpose. We demonstrate the use of an autoradiographic emulsion to directly image alpha particle events in samples with low radionuclide concentrations, allowing spatial resolution of radionuclide locations on the order of several microns. Exposure over a long time period allows sufficient integration of decay events enabling analysis of samples with low activity but large area, (less than 1*10-4 Bq/mm2). The use of polarising filters to increase contrast between the alpha particle tracks and the substrate during imaging demonstrates the viability of the technique on samples with a complex structure. PMID- 30476812 TI - Ictal onset patterns of subdural intracranial electroencephalogram in children: How helpful for predicting epilepsy surgery outcome? AB - AIMS: We aimed to classify ictal onset patterns (IOPs) in pediatric patients undergoing intracranial electroencephalography (IEEG) to guide surgery for refractory epilepsy. We aimed to determine if morphology of IOPs can predict surgical outcome. MATERIALS AND METHODS: We performed a retrospective review of pediatric patients who underwent epilepsy surgery guided by subdural IEEG from 2007 to 2016. IEEG seizures were reviewed by a blinded epileptologist. Data was collected on outcomes. RESULTS: Twenty-three patients with 784 seizures were included. Age at seizure onset was 0.2-11 (mean 4.3, standard deviation 3.2) years. Age at time of IEEG was 4-20 (mean 13.5, standard deviation 4.4) years. Five distinct IOPs were seen at seizure onset: A) Low voltage fast activity (LVFA) with spread to adjacent electrodes (n = 7 patients, 30%), B) Burst of LVFA followed by electrodecrement (n = 12 patients, 52%), C) Burst of rhythmic spike waves (RSW) followed by electrodecrement (n = 9 patients, 39%), D) RSW followed by LVFA (n = 7 patients, 30%), E) Rhythmic spikes alone (n = 10 patients, 43%). Twelve patients (52%) had the same IOP type with all seizures. When the area of the IOP was resected, 14 patients (61%) had Engel I outcomes. Patients who had LVFA seen within their predominant IOP type were more likely to have good surgical outcomes (odds ratio 7.50, 95% confidence interval 1.02-55.0, p = 0.05). Patients who had only one IOP type were more likely to have good outcomes than patients who had multiple IOP types (odds ratio 12.6, 95% confidence interval 1.19-134, p = 0.04). Patients who had LVFA in their predominant IOP type were older than patients who did not have LVFA (mean age 15.0 vs. 9.9 years, p = 0.02). CONCLUSIONS: LVFA at ictal onset and all seizures having the same IOP morphology are associated with increased likelihood of surgical success in children, but LVFA is less common in children who are younger at the time of IEEG. PMID- 30476813 TI - The molecular hallmarks of epigenetic effects mediated by antiepileptic drugs. AB - Epilepsy is associated with several epigenetic changes, such as DNA methylation, histone modification, and alterations in the synthesis and functioning of non coding RNAs (ncRNAs). Paradoxically, antiepileptic drugs (AEDs) that are widely used to control epilepsy may also induce epigenetic modifications and alter the structure of chromatin. As a consequence, changes in the expression of various factors involved in the pathology of epilepsy may positively or negatively affect the course of the disease. It should be noted that while AEDs are widely used in the treatment of epilepsy and other neurological disorders, many of their epigenetic consequences are still unknown. Moreover, an improved understanding of AED-induced epigenetic alterations could provide new targets for future therapeutic interventions. In this review, we give a general overview of the current scientific evidence concerning the epigenetic effects of AEDs that are currently in clinic use and have been evaluated to date. PMID- 30476814 TI - Exposure to thiamethoxam during the larval phase affects synapsin levels in the brain of the honey bee. AB - Thiamethoxam (TMX) is a neurotoxic insecticide widely used for insect pest control. TMX and other neonicotinoids are reported to be potential causes of honey bee decline. Due to its systematic action, TMX may be recovered in pollen, bee bread, nectar, and honey, which make bees likely to be exposed to contaminated diet. In this study, we used immunolabeling to demonstrate that sublethal concentrations of TMX decrease the protein levels of synapsin in the mushroom bodies (MBs) and the antennal lobes (ALs) of pupae and newly emerged worker bees that were exposed through the food to TMX during the larval phase. A decrease in the synapsin level was observed in the MBs of pupae previously exposed to 0.001 and 1.44 ng/uL and in newly emerged bees previously exposed to 1.44 ng/uL and no changes were observed in the optical lobes (OLs). In the ALs, the decrease was observed in pupae and newly emerged bees exposed to 1.44 ng/uL. Because the MBs and ALs are brain structures involved in stimuli reception, learning, and memory consolidation and because synapsin is important for the regulation of neurotransmitter release, we hypothesize that exposure to sublethal concentrations of TMX during the larval stage may cause neurophysiological disorders in honey bees. PMID- 30476815 TI - Genetic impacts induced by BaP and Pb in Mytilus coruscus: Can RAPD be a validated tool in genotoxicity evaluation both in vivo and in vitro? AB - Benzo(alpha)pyrene (BaP) and lead (Pb) are common pollutants discharged greatly in ocean and causing detrimental impacts on marine organisms. Although mussels are one of the most prominent and frequently studied biological models, the research on their genomic alterations induced by the mixture of two totally different chemicals, is still rare. In present study, local marine mussels Mytilus coruscus were exposed in vivo to BaP (53.74 +/- 19.79 MUg/L), Pb (2.58 +/ 0.11 mg/L) and their mixture for 6 days. The genotoxic damages were assessed by comet assay, micronucleus (MNi) test, and random amplified polymorphic DNA (RAPD) analysis. Significantly increased though transitory genomic damage was investigated after the exposure and showed consistency using various detecting methods. Additive genotoxicity was only found after 3 days combined exposure by means of MNi test, suggesting that BaP and Pb may play with alternative biological targets during metabolism and/or interaction with the genome. The geno stability and the recovery capability were further detected both in vivo and in vitro after challenged by BaP. RAPD results showed coherence in BaP induced genotoxicity, together with time-specific alterations. The genomic instability was found to recover in both in vivo and in vitro exposure scenarios in present study. To our knowledge, this is the first study to focus on the genotoxicitiy induced by BaP, Pb and their mixture by multiple detecting techniques. The attempt to utilize model pollutants and marine organism to validate the potential value of RAPD analysis highlighted that it might be a useful tool in the research of genotoxicology, especially on the effect-mechanism interplay at genetic level. PMID- 30476816 TI - Heavy metals accumulation and endocrine disruption in Prochilodus argenteus from a polluted neotropical river. AB - Heavy metals are considered major pollutants of aquatic environments due to the difficulty of metabolization and the bioaccumulative potential in tissues of aquatic organisms, especially fish muscle that is often used as food worldwide. In addition to causing cell damage, some metals such as aluminium (Al), cadmium (Cd), copper (Cu), and lead (Pb) can act as endocrine disrupting chemicals in fish. The Paraopeba and Abaete Rivers are important tributaries of the upper Sao Francisco River basin, but the Paraopeba River receives, along its course, the discharge of many types of effluents that affect fish species, including widely consumed species such as Prochilodus argenteus. This study evaluated histological and molecular changes caused by chronic exposure to heavy metals in P. argenteus from the Paraopeba River and compared this to fish from the non-impacted Abaete River. Sampled fish from both rivers were used in histological analyses and immunohistochemical assays. The results showed increased incidence of histopathologies and changes in number and morphology of germline cells in both sexes. In addition, up-regulated expression of oestrogens-induced proteins in the liver of males were detected in polluted environment. All the alterations were related to the concentration of metals in water and fish. The high concentration of various metals observed in water and fish from Paraopeba River serves as an alert to the environmental and public health regulatory authorities. PMID- 30476817 TI - PM2.5 exposure impairs sperm quality through testicular damage dependent on NALP3 inflammasome and miR-183/96/182 cluster targeting FOXO1 in mouse. AB - Exposure to ambient fine particular matter (PM2.5) has been clearly associated with male reproductive disorders. However, very limited toxicological studies were carried out to investigate the potential mechanisms underlying the PM2.5 induced sperm quality decline. In the present study, we established a real time whole-body PM2.5 exposure mouse model to investigate the effects of PM2.5 on sperm quality and its potential mechanisms. Sixty male C57BL/6 mice were randomly subjected to three groups: filtered air group, unfiltered air group and concentrated air group. Half of the mice from each group were sacrificed for study when the exposure duration accumulated to 8 weeks and the rest of the mice were sacrificed when exposed for 16 weeks. Our results suggested that PM2.5 exposure could induce significant increases in circulating white blood cells and inflammation in lungs. PM2.5 exposure induced apparently DNA damages and histopathologic changes in testes. There were significantly decreased sperm densities of mice, which were paralleled with the down-regulated testosterone levels in testes tissue of mice after exposure to PM2.5 for 16 weeks. The numbers of motile sperms were decreased and sperms with abnormal morphology were increased after PM2.5 exposure in a time-depended and dose-depended manner. PM2.5 exposure significantly increased the expression of the major components of the NACHT, LRR and PYD domains-containing protein3 (NALP3) inflammasome, accompanied by the increased expression of miR-183/96/182 targeting FOXO1 in testes. The present data demonstrated that sperm quality decline induced by PM2.5 could be partly explained by the inflammatory reaction in testes which might be a consequence of systemic inflammation. The molecular mechanism was depended on the activation of NALP3 inflammasome accompanied by miR-183/96/182 targeting FOXO1 in testes. PMID- 30476818 TI - Environmental and human relevant PFOS and PFOA doses alter human mesenchymal stem cell self-renewal, adipogenesis and osteogenesis. AB - PFOS and PFOA are two of the most abundant perfluorinated compounds (PFCs) in the environment. Previous studies have reported they have a long half-life (up to five years) once they enter into the human body. Moreover, they can potentially promote the adipogenic process by activating PPARgamma. However, little is known about PFOS and PFOA chronic health impacts on humans. In this study, we employed primary human mesenchymal stem cells (hMSCs) and demonstrated that PFOS and PFOA exerted acute cytotoxicity and affected adipogenesis and osteogenesis at environmental and human relevant doses. In fact, PFOS and PFOA impaired the proper expression of CD90 (a surface antigen highly enriched in undifferentiated hMSCs) and promoted adipogenesis, presumably via their interaction with PPARgamma. Moreover, PFOA partly disturbed osteogenesis. Thus, our findings not only validated the health risks of PFOS and PFOA, but also revealed new potential long-term PFOS/PFOA impacts on humans. PMID- 30476819 TI - Aging and retinoid X receptor agonists on masculinization of female Pomacea canaliculata, with a critical appraisal of imposex evaluation in the Ampullariidae. AB - Ampullariidae are unique among gastropods in that females normally show a primordium of the copulatory apparatus (CApp). The aims of this study were (a) to quantitatively evaluate the development and growth of the female CApp with age; (b) to compare the effects of RXR and PPARgamma agonists in adult females of known age and (c) to explore the effect of masculinizing RXR agonists on the expression of RXR in the CApp. It was found that the CApp grows and develops with age. A significant increase in penile sheath length (PsL) and also in a developmental index (DI) was observed in 7-8 months old females, as compared with 4-5 months old ones. A reported endogenous agonist of RXR, 9-cis retinoic acid (9cis-RA), as well as two organotin compounds, tributyltin (TBT) and triphenyltin (TPT) which have been also reported to bind to RXR, were injected and its masculinizing effects were measured. Also, the effect of a PPARgamma agonist, rosiglitazone, was studied. All studied RXR agonists, but not the PPARgamma agonist, were effective in increasing PsL, penile length (PL) and DI. Finally, the expression of the RXR in the CApp was studied (Western blot) in control, TBT, TPT, and 9cis-RA treated females. A significantly increased expression of RXR was only observed after 9cis-RA treatment. It is concluded that (a) development and growth of the CApp is significantly affected by female age; (b) reported RXR agonists, but not a PPARgamma agonist, cause female masculinization of young females. An appraisal of previous studies of female masculinization in the Ampullariidae has also been made and it is emphasized that the masculinizing effect of aging should be considered, particularly when interpreting field data. PMID- 30476820 TI - Structural characteristics of cake layer in membrane bioreactor with chromate exposure. AB - Chromate (CrO42-) exposure, especially high concentration (mg/L), still probably occurs in the industrial and mining area due to industrial accidents or even illegal discharge, though CrO42- has been restricted to be discharged into wastewater treatment system (WWTS). Therefore, this study was applied to better understand the structural characteristics of cake layer in membrane bioreactor (MBR), which is one of best alternative for WWTS of industrial or mining area, with CrO42- exposure. Three submerged MBRs with CrO42- exposure (10 mg/L was normal high concentration CrO42-; 50 mg/L as extreme level for better identification; 0 mg/L as control condition) were applied in this study. Results showed that CrO42- exposure caused an obvious variation of cake layer structure. Because of organic component variation, cake layer structure with CrO42- exposure was re-constructed into loose and porous with biomicromolecules, and resulted in the rapid cake layer thickness increase, finally leading to severe membrane biofouling. Additionally, CrO42- distributed evenly along the cross-sectional cake layer. CrO42- only induced the inorganic structure variations of cake layer, but without any obvious effects on the other inorganic elements structure. CrO42- exposure induced the bacterial community structure variation and led to tolerated CrO42- microorganisms as the majority in cake layer community, but had no obvious effects on the population diversity. PMID- 30476821 TI - Simultaneous biodegradation of mixture of carbamates by newly isolated Ascochyta sp. CBS 237.37. AB - In this study, a mixture of carbamates (CRBs) degrading Carb.1b strain was isolated from soil. Based on the morphology and 18S rRNA sequence analysis, the strain was identified as an Ascochyta sp. CBS 237.37 with accession number MG786925. The isolate was employed in two growth mediums (added carbon and carbon free) enriched with varied concentrations of CRBs ranging from 25 to 85 mg L-1 to assess its degradation efficacy. As determined by the Response Surface Methodology (RSM), optimum parameters for the degradation were: pH value of 7.5 and temperature of 28 degrees C. The degradation was inhibited at higher concentrations and was found to be 91.2%/94.8%, 67.25%/71.75%, 55.81%/59.81%, 46.85%/49.57% and 36%/40.80% (in carbon-free/added carbon) after 20 d. The removal of the higher concentration CRBs was comparatively slower, and the obtained degradation rate constant (Kavg) 0.03412 d-1. Added carbon and carbon free medium removed over 86.7%/90.15% of CRBs (85 mgL-1) with the half-life (t1/2) of 26 d and R2 ranging from 0.982 to 0.999; indicating the high tolerance of carb.1b strain towards CRBs. Residual analysis of CRBs biodegradation was performed using GC/MS analysis. This is the first report of degradation of a mixture of CRBs by Ascochyta sp. CBS 237.37. The results of this study can possibly impact the development strategies of bioremediation for the elimination of CRBs. PMID- 30476822 TI - Language lateralisation measured across linguistic and national boundaries. AB - The visual half-field technique has been shown to be a reliable and valid neuropsychological measurement of language lateralisation, typically showing higher accuracy and faster correct responses for linguistic stimuli presented in the right visual field (RVF) than left visual field (LVF). The RVF advantage corresponds to the well-known dominance of the left hemisphere (LH) in processing language(s). However, clinical and experimental neuroscientists around the globe use different variations of the visual half-field paradigm, making direct comparisons difficult. The current study used a word/non-word visual half-field paradigm with translingual stimuli. In total, 496 participants from seven European countries were investigated: Belgium (64), England (49), Germany (85), Italy (34), The Netherlands (87), Norway (51), and Switzerland (126), covering six international languages (Dutch, English, French, German, Italian, Norwegian). All language groups revealed a significant RVF/LH advantage in accuracy and reaction times that accounted for up to 26.1% of the total variance in performance. We found some variation in the degree of the RVF/LH advantage across language groups, accounting for a maximum of 3.7% of the total variance in performance. The RVF/LH advantage did not differ between subsamples speaking English, French or German as first or second languages or between monolingual and early/late bi/multilinguals. The findings suggest that the translingual lexical decision task (TLDT) is a simple but reliable measurement of language lateralisation that can be applied clinically and experimentally across linguistic and national boundaries. PMID- 30476823 TI - Use of simulation-based learning among perioperative nurses and students: A scoping review. AB - OBJECTIVES: Simulation-based learning has been extensively explored, especially in baccalaureate nursing programmes. Recently, simulation-based learning has been introduced in perioperative nursing. The aim of this scoping review is to investigate work published on the use of simulation-based learning in the field of perioperative nursing. DESIGN AND DATA SOURCES: A scoping review was conducted using the methodological framework of Arksey and O'Malley to identify a broad range of relevant literature, regardless of study design. A comprehensive and systematic search was performed using Medline, CINAHL, Eric, Svemed+, PsychINFO and Embase in May 2016 and then was updated in February 2018. Each database was searched for literature published between 1st January 2005 and 8th February 2018. REVIEW METHOD: Two authors independently assessed literature eligibility and extracted data to answer our research question 'What is known about the use of simulation-based learning in the field of perioperative nursing?' RESULTS: Nine articles and one doctoral thesis were included in the review. There appears to be a paucity of research or results-oriented evidence regarding the use of simulation-based learning in the field of perioperative nursing. Different goals of simulation-based learning were reported. It was difficult to confirm whether these goals had been reached as none of the articles included control groups, and no evaluations had been undertaken against Kirkpatrick's level 3 to see changes in participants' behaviours, and level 4, to determine whether the training had a positive impact on, for example, patient outcomes. CONCLUSION: Owing to the lack of research and the inadequate descriptions of design and method in simulation based learning in most of the articles included, there is little evidence in the existing literature to guide practitioners of this learning in the field of perioperative nursing. This indicates a need for further research in this area. PMID- 30476824 TI - S1P promotes inflammation-induced tube formation by HLECs via the S1PR1/NF-kappaB pathway. AB - Inflammation-induced lymphangiogenesis is a widely accepted concept. However, most of the inflammatory factors and their related mechanisms have not been clarified. It has been reported that sphingosine-1-phosphate (S1P) is not only closely related to the chronic inflammatory process but also affects angiogenesis. Therefore, we investigated the inflammatory effects of S1P on human lymphatic endothelial cells (HLECs). Our results showed that S1P promotes tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) secretion in HLECs. We also confirmed that S1P-stimulated TNF-alpha and IL-1beta secretion is mediated through S1P receptor 1 (S1PR1). Using TNF-alpha siRNA and IL-1beta siRNA, we found that TNF-alpha and IL-1beta play essential roles in S1P-induced HLEC proliferation, migration, and tube formation. S1P induces phosphorylation of NF-kappaB p65 and activation of NF-kappaB nuclear translocation. A S1PR1 antagonist (W146) and NF-kappaB inhibitor (BAY11-7082) inhibited S1P-induced TNF alpha and IL-1beta secretion and prevented NF-kappaB nuclear translocation. Taken together, the results demonstrated for the first time that S1P promotes the secretion of TNF-alpha and IL-1beta in HLECs via S1PR1-mediated NF-kappaB signaling pathways, thus affecting lymphangiogenesis. The study provides a new strategy for finding treatments for lymphangiogenesis-related diseases. PMID- 30476825 TI - 1-Arylsulfonyl indoline-benzamides as a new antitubulin agents, with inhibition of histone deacetylase. AB - We report structure-activity relationships of 1-arylsulfonyl indoline based benzamides. The benzamide (9) exhibits striking tubulin inhibition with an IC50 value of 1.1 MUM, better than that of combretastain A-4 (3), and substantial antiproliferative activity against a variety of cancer cells, including MDR positive cell lines with an IC50 value of 49 nM (KB), 79 nM (A549), 63 nM (MKN45), 64 nM (KB-VIN10), 43 nM (KB-S15), and 46 nM (KB-7D). Dual inhibitory potential of compound 9 was found as it demonstrated significant inhibitory potential against HDAC1, 2 and 6 in comparison to MS-275 (6). Some key interactions of 9 with the amino acid residues of the active site of tubulin and with amino acid residues of HDAC 1 isoform have been figured out by molecular modeling. Compound 9 also demonstrated significant in vivo efficacy in the human non-small cell lung cancer A549 xenograft model as well as B-cell lymphoma BJAB xenograft tumor model. PMID- 30476826 TI - Structure-based exploration and pharmacological evaluation of N-substituted piperidin-4-yl-methanamine CXCR4 chemokine receptor antagonists. AB - Using the available structural information of the chemokine receptor CXCR4, we present hit finding and hit exploration studies that make use of virtual fragment screening, design, synthesis and structure-activity relationship (SAR) studies. Fragment 2 was identified as virtual screening hit and used as a starting point for the exploration of 31 N-substituted piperidin-4-yl-methanamine derivatives to investigate and improve the interactions with the CXCR4 binding site. Additionally, subtle structural ligand changes lead to distinct interactions with CXCR4 resulting in a full to partial displacement of CXCL12 binding and competitive and/or non-competitive antagonism. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and binding model studies were used to identify important hydrophobic interactions that determine binding affinity and indicate key ligand-receptor interactions. PMID- 30476827 TI - Altered trunk head co-ordination in those with persistent neck pain. AB - BACKGROUND: Decreased neck motion and sensorimotor deficits have been identified in those with neck pain. It is thought that these might be related to altered reflex mechanisms between the neck, eyes and the vestibular system. Trunk, head co-ordination might also be altered in neck pain. OBJECTIVES: This study investigated trunk head co-ordination ability in subjects with neck pain compared to asymptomatic controls. METHOD: Twenty-four subjects with persistent neck pain and twenty-six age and gender matched healthy controls performed 3 trials of 3 trunk movements whilst trying to keep the head still - (1) alternate trunk movement to the left and right (2) trunk movement to the left (3) trunk movement to the right. Wireless motion sensors positioned over the sternum and the forehead measured trunk and head range and velocity of motion. ANALYSIS: ANOVA was used to compare trunk and head range and velocity of motion during the 3 tasks. RESULTS: Neck pain subjects had significantly less trunk movement (p < 0.05) and velocity (p=<0.02) as well as significantly increased head movement (p=<0.03) during most tasks compared to control subjects. DISCUSSION: The results of the study suggest that neck pain subjects have difficulty moving their trunk independently of their head. They are less able to keep the head still while moving the trunk and perform the tasks more slowly. These findings might be related to altered reflex activity of the cervico-collic reflex and sensorimotor control. Further research is required. PMID- 30476828 TI - Quantifying high-resolution spatial variations and local source impacts of urban ultrafine particle concentrations. AB - To quantify the fine-scale spatial variations and local source impacts of urban ultrafine particle (UFP) concentrations, we conducted 3-6 weeks of continuous measurements of particle number (a proxy for UFP) and other air pollutant (CO, NO2, and PM2.5) concentrations at 32 sites in Pittsburgh, Pennsylvania during the winters of 2017 and 2018. Sites were selected to span a range of urban land use attributes, including urban background, near local and arterial roads, traffic intersections, urban street canyon, near-highway, near large industrial source, and restaurant density. The spatial variations in urban particle number concentrations varied by about a factor of three. Particle number concentrations are 2-3 times more spatially heterogeneous than PM2.5 mass. The observed order of spatial heterogeneity is UFP > NO2 > CO > PM2.5. On average, particle number concentrations near local roads with a cluster of restaurants and near arterial roads are roughly two times higher than the urban background. Particle number concentrations in the urban street canyon, downwind of a major highway, and near large industrial sources are 2-4 times higher than background concentrations. While traffic is known as an important contributor to particle number concentrations, restaurants and industrial emissions also contribute significantly to spatial variations in Pittsburgh. Particle size distribution measurements using a mobile laboratory show that the local spatial variations in particle number concentrations are dictated by concentrations of particles smaller than 50 nm. A large fraction of urban residents (e.g., ~50%) in Pittsburgh live near local sources and are therefore exposed to 50%-300% higher particle number concentrations than urban background location. These locally emitted particles may have greater health effects than background particles. PMID- 30476829 TI - Dryland changes under different levels of global warming. AB - Drylands are vital ecosystems which cover almost 47% of the Earth's surface, hosting 39% of the global population. Dryland areas are highly sensitive to climatic changes and substantial impacts are foreseen under a warming climate. Many studies have examined the evolution of drylands in the future highlighting the need for improved capability of climate models to simulate aridity. The present study takes advantage of new higher resolution climate projections by the HadGEM3A Atmosphere Global Climate Model using prescribed time varying SSTs and sea ice, provided by a range of CMIP5 climate models under RCP8.5. The aim of the higher resolution models is to examine the benefit of the improved representation of atmospheric processes in the dryland research and to see where these results lie in the range of results from previous studies using the original CMIP5 ensemble. The transient response of aridity from the recent past until the end of the 21st century was examined as well as the expansion of global drylands under specific levels of global warming (1.5 degrees C, 2 degrees C and 4 degrees C). Dryland changes were further assessed at the watershed level for a number of major global river basins to discuss implications on hydrological changes and land degradation. The areal coverage of drylands could increase by an additional 7% of the global land surface by 2100 under high end climate change. At a 4 degrees C warmer world above pre-industrial, 11.2% of global land area is projected to shift towards drier types and 4.24% to wetter. At the same level of warming the number of humans projected to live in drylands varies between 3.3 and 5.2 billion, depending on the socioeconomic developments. By keeping global warming levels to 1.5 degrees C, up to 1.9 billion people could avoid living in drylands compared to a 4 degrees C warmer world of low environmental concern. PMID- 30476830 TI - Modeling groundwater nitrate exposure in private wells of North Carolina for the Agricultural Health Study. AB - Unregulated private wells in the United States are susceptible to many groundwater contaminants. Ingestion of nitrate, the most common anthropogenic private well contaminant in the United States, can lead to the endogenous formation of N-nitroso-compounds, which are known human carcinogens. In this study, we expand upon previous efforts to model private well groundwater nitrate concentration in North Carolina by developing multiple machine learning models and testing against out-of-sample prediction. Our purpose was to develop exposure estimates in unmonitored areas for use in the Agricultural Health Study (AHS) cohort. Using approximately 22,000 private well nitrate measurements in North Carolina, we trained and tested continuous models including a censored maximum likelihood-based linear model, random forest, gradient boosted machine, support vector machine, neural networks, and kriging. Continuous nitrate models had low predictive performance (R2 < 0.33), so multiple random forest classification models were also trained and tested. The final classification approach predicted <1 mg/L, 1-5 mg/L, and >=5 mg/L using a random forest model with 58 variables and maximizing the Cohen's kappa statistic. The final model had an overall accuracy of 0.75 and high specificity for the higher two categories and high sensitivity for the lowest category. The results will be used for the categorical prediction of private well nitrate for AHS cohort participants that reside in North Carolina. PMID- 30476831 TI - Turn the potential greenhouse gases into biomass in harmful algal blooms waters: A microcosm study. AB - Carbon sources are a critical requirement for the proliferation of algae and the occurrence of harmful algal blooms (HABs), but are often turned into methane (CH4) after the collapse of severe HABs. Here, we attempt to remove HABs, reduce algal-derived CH4 emissions, and repair the broken carbon biogeochemical cycle in aquatic systems using an integrated ecological approach including flocculation, capping, and submerged macrophyte induction, preliminary at a microcosm scale. This strategy sustainably reached 98% algal removal after 65 days of incubation and resulted in an aerobic microenvironment (ORP = +12 mv) at the sediment-water interface. The approach contributed to an approximate 60% decline in CH4 released from the aquatic environment into the atmosphere jointly through assimilation of mineralized organic carbon by submerged macrophytes, production of carbon dioxide (CO2) under aerobic conditions, and aerobic CH4 oxidation. Some of the CO2 produced in the aquatic phase contributed to inorganic carbon and formed the submerged macrophytes biomass. A combination of flocculation, capping, and submerged macrophyte incubation were significant contributors to altering the carbon budget and sealing nearly 99% of the carbon in the simulated ecosystem (the majority in sediment, followed by submerged macrophytes), providing a sustainable way to reuse algal-derived carbon and reduce CH4 emissions. PMID- 30476832 TI - Process performance and microbial community structure in thermophilic trickling biofilter reactors for biogas upgrading. AB - This study evaluated the process performance and determined the microbial community structure of two lab-scale thermophilic trickling biofilter reactors used for biological methanation of hydrogen and carbon-dioxide for a total period of 94 days. Stable and robust operation was achieved by means of a single-pass gas flow. The quality of the output gas (>97%) was comparable to the methane purity achieved by commercial biogas upgrading systems fulfilling the specifications to be used as substitute to natural gas. The reactors' methane productivity reached >1.7 LCH4/(LR.d) at hydrogen loading rate of 7.2 LH2/(LR.d). The spatial distribution of the microbial consortia localized in the liquid media and biofilm enabled us to gain a deeper understanding on how the microbiome is structured inside the trickling biofilter. Sequencing results revealed a significant predominance of Methanothermobacter sp. in the biofilm. Unknown members of the class Clostridia were highly abundant in biofilm and liquid media, while acetate utilising bacteria predominated in liquid samples. PMID- 30476833 TI - The impact of wipe sampling variables on method performance associated with indoor pesticide misuse and highly contaminated areas. AB - Pesticide misuse incidents in residential indoor areas are typically associated with misapplications that are inconsistent with the label directions of the product. Surface wipe sampling and analysis procedures are relied upon to evaluate the extent of indoor contamination and the remediation efforts successfully. In general, surface wipe sampling procedures are widely varied, which can complicate the comparison of the results and data interpretation. Wipe sampling parameters were studied for the insecticides malathion and carbaryl. The parameters evaluated include wipe media, wetting solvents, composite sampling, surface concentration, and the influence of differing product formulations. Porous and nonporous surfaces tested include vinyl tile, plywood and painted drywall (porous/permeable) and stainless steel and glass (nonporous/impermeable). Specific wipe materials included pre-packaged sterile-cotton gauze, pre-cleaned cotton twill, cotton balls, and a pre-packaged, pre-wetted wipe. Commercially available insecticide formulations were tested, and the results were compared to surfaces fortified with neat analytes to determine surface recovery results (efficiency). A sampling procedure to measure pesticide residues was developed, and variables associated with the sampling methods were evaluated to clarify how estimations of surface residues are impacted. Malathion recoveries were 73-86% for twill and pre-wetted, pre-packaged isopropanol wipes on nonporous materials. Malathion formulations ranged from 78 to 124% for pre-wetted, pre-packaged isopropanol wipes and cotton gauze wipes on nonporous materials. Carbaryl and carbaryl formulation recoveries were 82-115% and 77-110%, respectively, on nonporous surfaces for all tested wipe materials. While not every wipe sampling variable could be tested, the collected information from this study may be useful and applied to sampling plans for classes of chemicals with similar physicochemical properties. PMID- 30476834 TI - Imatinib: Major photocatalytic degradation pathways in aqueous media and the relative toxicity of its transformation products. AB - Imatinib (IMA) is a highly potent tyrosine kinase inhibitor used as first-line anti-cancer drug in the treatment of chronic myeloid leukemia. Due to its universal mechanism of action, IMA also has endocrine and mutagenic disrupting effects in vivo and in vitro, which raises the question of its environmental impact. However, to date, very little information is available on its environmental fate and the potential role of its transformation products (TPs) on aquatic organisms. Given the IMA resistance to hydrolysis and direct photolysis according to the literature, we sought to generate TPs through oxidative and radical conditions using the AOPs pathway. Thus, the reactivity of the cytotoxic drug IMA in water in the presence of OH and h+ was investigated for the first time in the present work. In this regard, a non-targeted screening approach was applied in order to reveal its potential TPs. The tentative structural elucidation of the detected TPs was performed by LC-HRMSn. The proposed approach allowed detecting a total of twelve TPs, among which eleven are being described for the first time in this work. Although the structures of these TPs could not be positively confirmed due to lack of standards, their chemical formulas and product ions can be added to databases, which will allow their screening in future monitoring studies. Using the quantitative structure-activity relationship (QSAR) approach and rule-based software, we have shown that the detected TPs possess, like their parent molecule, comparable acute toxicity as well as mutagenic and estrogenic potential. In addition to the in silico studies, we also found that the samples obtained at different exposure times to oxidative conditions, including those where IMA is no longer detected, retained toxicity in vitro. Such results suggest further studies are needed to increase our knowledge of the impact of imatinib on the environment. PMID- 30476835 TI - Integration of juvenile habitat quality and river connectivity models to understand and prioritise the management of barriers for Atlantic salmon populations across spatial scales. AB - Diadromous fish populations are strongly affected by in-stream barriers that cause river network fragmentation, constraining productivity or preventing completion of their lifecycle. Removal or reduction of barrier impacts is a restoration measure associated with unambiguous benefits. Management of barriers is therefore often prioritised above other restoration actions. Barrier management is prioritised at local and national scales depending on funding. However, barrier prioritisation is potentially sub-optimal because existing tools do not consider habitat quality. Furthermore, effects of partial barriers (those passable under certain conditions) are uncertain, depending on location and potential cumulative effects. A framework is presented for assessing effects of impassable manmade barriers (IMBs) on longitudinal river network connectivity (percentage of upstream habitat accessible from the river mouth) for Atlantic salmon across spatial scales, using Scotland as an example. The framework integrates juvenile habitat quality and network connectivity models to (1) provide information necessary for local and national prioritisation of barriers, and (2) assess potential effects of passable manmade barriers (PMBs) within a sensitivity framework. If only IMBs are considered, high levels of longitudinal connectivity are observed across most of Scotland's rivers. Barrier prioritisation is sensitive to habitat weighting: not accounting for habitat quality can lead to over- or underestimating the importance of IMBs. Prioritisation is also highly sensitive to the passability of PMBs: if passability drops to <97% (combined up- and downstream passability), the mean effect of PMBs becomes greater than IMBs at the national level. Moreover, impacts on catchment connectivity, and thus production (number of juvenile salmon produced by the river), could be severe, suggesting a better understanding of the passability of PMBs is important for future management of migration barriers. The presented framework can be transferred to other catchments, regions, or countries where necessary data are available, making it a valuable tool to the broader restoration community. PMID- 30476836 TI - Colour and size influences plastic microbead underestimation, regardless of sediment grain size. AB - The quantification of microplastics in environmental samples often requires an observer to determine whether a particle is plastic or non-plastic, prior to further verification procedures. This implies that inconspicuous microplastics with a low natural detection may be underestimated. The present study aimed at assessing this underestimation, looking at how colour (white, green and blue), size (large; ~1000 MUm and small; <400 MUm) and grain size fraction may affect detection. Sediment treatments varying in grain size were inoculated with known quantities of low-density polyethylene microbeads extracted from commercially bought facial scrubs. These microbeads varied in colour and size. Once extracted using a density separation method microbeads were counted. An overall underestimation of 78.59% may be a result of observer error and/or technical error. More specifically, the results suggested that microbeads varying in colour and size have a different detection probability and that these microbead features are more important in underestimation likelihoods than grain sizes. PMID- 30476837 TI - Removal of Microcystin-LR from spiked natural and synthetic waters by anion exchange. AB - Cyanobacterial blooms are becoming a serious challenge across the globe due to changing climate and rainfall patterns as a consequence of human activities. In the present study, the fundamental interactions involved during the removal of Microcystin-LR (MCLR), one of the most commonly occurring cyanobacterial toxins, were investigated by employing strongly basic anion exchange (IX) resins. Several factors including the stoichiometric coefficients, competitive fractions and solute affinities were determined under various concentrations of inorganic ions and natural organic matter. The results indicated that suphates were the most competitive fractions with high affinity (alpha (affinity coefficient) values ~ 9) followed by nitrates (alpha ~ 4.7) and NOM fractions (alpha ~ 4.5, p < 0.05). The Equivalent Background Concentration Mode (EBC), that arises from the Ideal Adsorption Solution Theory (IAST), indicated a competitive fraction of ~2 MUeq/L NOM, which approximates to <10% of the initial NOM concentrations, indicating a small fraction of the NOM resulting in the competitive effect. Further, studies with natural surface waters indicated that the MCLR uptake could be modeled using the IAST-EBC model and the IX resin could simultaneously removal of >90% of NOM, inorganic ions and MCLR at resin dosages of 3.6 meq/L or higher. PMID- 30476838 TI - Atmospheric levels, variations, sources and health risk of PM2.5-bound polycyclic aromatic hydrocarbons during winter over the North China Plain. AB - PM2.5-bound polycyclic aromatic hydrocarbons (PAHs) during winter 2015 at three urban sites, including Beijing, Tianjin and Shijiazhuang, and one background site (Xinglong) over the North China Plain (NCP) were investigated. The spatial variations of PAHs showed the same trends with PM2.5 mass concentrations, i.e. the highest PAHs concentrations was in Shijiazhuang, followed by Tianjin, Beijing and the lowest PAHs concentrations was in Xinglong. The diurnal variations of PAHs exhibited PAHs concentrations during nighttime were higher than those during daytime. The dominant species in PAHs were fluranthene and benzo[b + k]fluoranthene, indicating that diesel vehicle emission, coal combustion and biomass burning could be important and potential sources for PAHs over the NCP. There results were supported by diagnostic ratios analysis. But coefficient of divergence analysis showed that a high extent of spatial contrast among four sampling sites, except between Beijing and Tianjin. Analysis of toxicity equivalent quantities (TEQ) and the lifetime excess cancer risk (ECR) from inhalation exposure to PAHs showed that 818, 1517, 5129 and 182 cases per 100,000 people exposed in Beijing, Tianjin, Shijiazhuang and Xinglong, respectively, which were much higher than the threshold value suggested by US-EPA, i.e. 1 case per 100,000 people, and indicating that the NCP suffered from very serious health risk from PAHs, especially in Shijiazhuang. PMID- 30476839 TI - Quantifying the bioaccumulation of nanoplastics and PAHs in the clamworm Perinereis aibuhitensis. AB - The impact of nanometer-scale plastics (<1000 nm nanoplastics, NPs) on the bioaccumulation of hydrophobic organic pollutants, and especially polycyclic aromatic hydrocarbons (PAHs), in marine organisms has become of urgent concern. However, simultaneous determinations of the bioaccumulation of NPs and PAHs have been hindered by the lack of an efficient digestion method that removes background interference from the tissue without altering the surface properties of the plastic and destroying the PAHs. To solve this problem, an enzymatic digestion-based protocol using proteinase K and subsequent quantification methods were developed on a typical marine benthic invertebrate - the clamworm Perinereis aibuhitensis. Enzymatic digestion removed 91% of the biological tissues, comparable to the amount removed using 65% HNO3 (93% removed) and better than that removed using 30% H2O2 or 10% KOH digestion (76% and 66%, respectively). After enzymatic digestion, roughly 92% of the NPs and 88% of the amount of pyrene were recovered, without significant modification of the NPs or pyrene degradation. By contrast, the NP and pyrene recovery achieved with HNO3 digestion was only 1.4% and 0.1%, respectively. The newly developed protocol was successfully applied to a 96-h bioaccumulation study. The use of radioactively labeled 14C-pyrene and fluorescently labeled NPs allowed the simultaneous quantification of NPs and PAHs in the clamworm and revealed a bioconcentration factor (BCF) of 1.96 +/- 0.93 and 402.7 +/- 47.0, respectively. The quantification of NPs and pyrene indicated that NP-adsorbed pyrene accounted for <1% of the total pyrene accumulation in the clamworm body when the concentration of NPs in seawater was as low as 0.4 mg/L. Our enzymatic digestion and dual labeling technique thus provides the first reported BCF value of NPs in a marine benthic organism and new insights into the vector effects of these particles on the bioaccumulation of organic contaminants in a marine ecosystem. PMID- 30476840 TI - Formation of perfluorocarboxylic acids from photodegradation of tetrahydroperfluorocarboxylic acids in water. AB - Tetrahydroperfluorocarboxylic acids (2H,2H,3H,3H-PFCAs) have aroused the interest of scholars worldwide due to their potential to generate perfluorinated compounds. In this work, we systematically examined the photodegradation kinetics and mechanisms of typical 2H,2H,3H,3H-PFCAs (CnF2n+1C2H4COOH, n = 6, 7, 8) in aqueous solution by a 500 W Hg lamp. The photodecomposition of 2H,2H,3H,3H-PFCAs all followed pseudo-first-order kinetics, and the photolysis rate coefficients increased with the increasing carbon chain length. Under the same reaction condition, 2H,2H,3H,3H-PFCAs degraded much faster than the corresponding PFCAs. The photodecomposition rate coefficient of C8F17CH2CH2COOH was accelerated by low pH and Fe3+ addition, but decreased by the existence of humic acid, carbonate and bicarbonate. Compared with ultrapure water, a decreased removal of 2H,2H,3H,3H PFCAs was observed in four types of natural waters, i.e., tap water, Jiuxiang river water, primary effluent and secondary effluent. According to mass analysis, C8F17CH2CH2COOH was mainly decomposed into 8:2 fluorotelomer acid (C8F17CH2COOH), shorter-chain perfluorocarboxylic acids (PFCAs), perfluoro-1-enes (CnF2n) and perfluoroketenes (CnF2n+1CF = C = O). Thus, alpha-oxidation, decarboxylation and elimination reaction were proposed as reaction pathways. ECOSAR predictions showed that photolysis generally decreased the aquatic toxicity of C8F17CH2CH2COOH. PMID- 30476841 TI - Occurrence and exposure assessment of bisphenol analogues in source water and drinking water in China. AB - Bisphenol analogues (BPs) are widely used in the production of epoxy resins and polycarbonate plastics. In recent years, the demand and production capacity of BPs are growing rapidly in China. However, knowledge on the occurrence of BPs other than bisphenol A (BPA) in the aquatic environment, especially in source and drinking water, is still limited. In this study, occurrence of 16 BPs, which have been used in various industrial applications, was investigated in source and drinking water from twenty drinking water treatment plants (DWTPs) across China. In source water, BPA, bisphenol AF (BPAF), bisphenol B (BPB), bisphenol E (BPE), bisphenol F (BPF), and bisphenol S (BPS) were detected at the following concentration ranges: BPA (n.d.-34.9 ng/L), BPAF (n.d.-10.8 ng/L), BPB (n.d.-14.3 ng/L), BPE (n.d.-6.2 ng/L), BPF (n.d.-12.6 ng/L), and BPS (n.d.-5.2 ng/L). In drinking water BPA, BPAF, BPB, BPE, BPF, and BPS were detected as follows: BPA (n.d. - 6.5 ng/L), BPAF (n.d.-4.7 ng/L), BPB (n.d.-3.2 ng/L), BPE (n.d.-0.6 ng/L), BPF (n.d.-0.9 ng/L), and BPS (n.d.-1.6 ng/L). In addition, to assess the exposure of BPs through drinking water consumption, the estimated daily intake of each detected BPs was calculated. The estimated daily intake (EDIs) was below 0.25 ng/kg bw/day for each detected BPs, much lower than the tentative oral reference dose (RfD) values for BPA (4 MUg/kg bw/day) recommended by the European Food Safety Authority. PMID- 30476842 TI - Activation of persulfate with 3D urchin-like CoO-CuO microparticles for DBP degradation: A catalytic mechanism study. AB - Rational modification of the surface structure and interface structure can effectively optimize the catalytic performance and stability of a heterogeneous catalyst. A CoO-CuO bimetallic catalyst with a special urchin-like structure was prepared by a hydrothermal urea precipitation method. This carbon nanosphere template method significantly improves the dispersibility of the material. The special urchin-like nanorod structure expands the specific surface area, resulting in excellent adsorption performance and high catalytic performance. The materials were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The oxidative degradation mechanism of dibutyl phthalate (DBP) using sodium persulfate (SPS) activated by the CoO-CuO double metal oxide catalyst was explored. The synergy between the two metals gives the material a stable and highly catalytic ability. PMID- 30476843 TI - LncRNA expression profiling and its relationship with DNA damage in Cr(VI) treated 16HBE cells. AB - Compounds containing hexavalent chromium [Cr(VI)] were Group I human carcinogens which were mutagenic and can induce DNA damage. Cr(VI) exposure could cause a lot of changes in mRNA, protein and microRNA expression as well as DNA methylation. There were still few studies on the role of long non-coding RNA (lncRNA) in the carcinogenic process of Cr(VI). In current study, lncRNA expression profiling and bioinformatics analysis in 16HBE cells treated by Cr(VI) were performed. The cell counting kit-8 (CCK-8) assay and the comet assay were done to assess the cell viability and DNA damage in Cr(VI)-treated 16HBE cells respectively. The lncRNA expression profile was performed by Arraystar Microarray V3.0 in 16HBE cells treated with 0.00 and 10.00 MUmol/L Cr(VI). Real-time quantitative polymerase chain reaction (RT-qPCR) was applied to verify some significantly altered lncRNAs. Gene ontology (GO), kyoto encyclopedia of genes and genomes (KEGG) analysis and mRNA-lncRNA network analysis were conducted to identify related biological processes, signal pathway and critical lncRNAs. It was found that Cr(VI) could induce cells viability decline and alter lncRNA expression profile of 16HBE cells. 1868 lncRNAs were significantly up-regulated and 2203 lncRNAs were significantly down-regulated which formed a complex regulation network. With the increase of Cr(VI) concentration, some lncRNAs increased or decreased gradually. The differentially expressed LncRNA profiling induced by Cr(VI) were associated with immune response, cell cycle, DNA damage and repair and so on. RP11-388M20.9 and AC092620.3 were nonlinearly decreasing with the change of the DNA content of comet tails (Tail DNA), tail length (TLL), tail moment (TM) and Olive Tail Moment (OTM), and the fitting results of Tail DNA and TM were statistically significant (P < 0.05). It was possible for RP11-388M20.9 to regulate DNA damage by interacting with the target gene after Cr(VI) exposure, and was likely to be a potential biomarker of DNA damage in Cr(VI)-treated 16HBE cells. PMID- 30476844 TI - Application of encapsulated magnesium peroxide (MgO2) nanoparticles in permeable reactive barrier (PRB) for naphthalene and toluene bioremediation from groundwater. AB - One of the challenges in the petroleum hydrocarbon contaminated groundwater remediation by oxygen releasing compounds (ORCs) is to identify the remediation mechanism and determine the impact of ORCs on the environment and the intrinsic groundwater microorganisms. In this research, the application of encapsulated magnesium peroxide (MgO2) nanoparticles in the permeable reactive barrier (PRB) for bioremediation of the groundwater contaminated by toluene and naphthalene was studied in the continuous flow sand-packed plexiglass columns within 50 d experiments. For the biodiversity studies, next generation sequencing (NGS) of the 16S rRNA gene was applied. The results showed that naphthalene was metabolized (within 20 days) faster than toluene (after 30 days) by microorganisms of the aqueous phase. By comparing the contaminant removal in the biotic (which resulted in the complete contaminant removal) and abiotic (around 32% removal for naphthalene and 36% for toluene after 50 d) conditions, the significant role of microorganisms on the decontamination process was proved. Furthermore, the attached microbial communities on the porous media were visualized by scanning electron microscopy (SEM). Microbial community structure analysis by NGS technique revealed that the microbial species which were able to degrade toluene and naphthalene such as P. putida and P. mendocina respectively were stimulated by addition of MgO2 nanoparticles. The presented study resulted in a momentous insight into the application of MgO2 nanoparticles in the hydrocarbon compounds removal from groundwater. PMID- 30476845 TI - Global vegetation productivity responses to the West Pacific Warm Pool. AB - Sea surface temperatures (SSTs) strongly influence atmospheric circulation and the Earth's climate, which in turn significantly affects vegetation productivity. Most of the previous studies on the subject have focused on links between the El Nino-Southern Oscillation (ENSO) and vegetation productivity, but few studies have addressed the effects of West Pacific Warm Pool (WPWP) on that although the early stages of the ENSO phenomenon may first develop there. In this paper, we use the mean SST values in the WPWP to construct a climate index, known as the WPWP index (WPI), and study the impacts of the WPWP on global vegetation productivity. We provide evidence for a robust link among the alternating warm and cool WPI pattern, terrestrial vegetation productivity and carbon balance. The analysis is based on both satellite observations and model simulations. The results of this study show that the warm and cool WPWP phases have inverse effects on land surface temperature and precipitation. A warm (cool) WPWP is associated with a warmer (cooler) climate on global land surfaces as well as a drier (wetter) climate in southern hemisphere, and hence enhances (suppresses) vegetation productivity in the latitudes of approximately 10-70 degrees N and suppresses (enhances) vegetation growth in the latitudes of approximately 10-30 degrees S. The underlying mechanism is also discussed. The WPI serves as a meaningful climate index for studying the ocean-vegetation teleconnections. PMID- 30476846 TI - The footprint of urban heat island effect in 302 Chinese cities: Temporal trends and associated factors. AB - The urban heat island (UHI) effect has been a concern for decades due its adverse influence on energy consumption, air and water quality, and, most importantly, the health of urban dwellers. Researchers have paid much attention to the magnitude of the UHI effect, but ignored its spatial extent (i.e. footprint) which is another important aspect of the UHI effect. In this study, we systematically analyzed the footprint of surface UHI (SUHI) effect in 302 Chinese cities, especially temporal trends of the footprint, by using multi-source remote sensing data. The footprint of SUHI effect (FP) was estimated by the Gaussian surface, and its temporal trend was examined by the Mann-Kendal and the Sen's slope estimator non-parametric tests. We found the FP showed evident diurnal (daytime > nighttime), seasonal (summer > winter) and inter-city (big cities > small and medium-sized cities) differences. During the period 2003-2016, over 80% of the 302 cities exhibited increasing trends of the FP in annual days and summer days, and the increasing trends were statistically significant (p < 0.05) in about half of these cities. In the nights, the FP increased in more than 70% of the cities, and about one-third of the 302 cities experienced significantly increasing trends of the FP. On average, the annual daytime and annual nighttime FPs increased at a rate of 5.0% per year and 3.8% per year, respectively. More importantly, the correlation analysis indicated that the increase of anthropogenic heat emissions and the decrease of vegetation activities and surface albedos should take lead responsibility for the expansion of the FP in the urbanization process. These results reveal that the spatial extent of heat island effect has expanded significantly in numerous Chinese cities, and this increasing trend will be sustained in the coming years if no more effective measures are carried out. PMID- 30476847 TI - Cd induced generation of free radical species in Brassica juncea is regulated by supplementation of earthworms in the drilosphere. AB - The antioxidant defense system of Brassica juncea under Cd stress was examined on supplementation of earthworms in the rhizosphere at different concentrations of Cd (0.50, 0.75, 1.00 and 1.25 mM i.e. 56, 84, 112 and 140 mg kg-1 respectively). Seedlings were raised in small pots containing soil spiked with Cd and earthworms under controlled conditions for 15 days. Improved Cd accumulation, as well as enhanced plant dry weight and metal tolerance were observed following the addition of earthworms. Earthworm supplementation reduced reactive oxygen species (ROS) generation by 7.3% for hydrogen peroxide (H2O2), 7.1% for superoxide anion (O2-), and 8.4% for malondialdehyde (MDA) in plants treated with 1.25 mM (140 mg kg-1) Cd. Confocal microscopy revealed improved cell viability and reduced H2O2 content due to enhanced antioxidative activity. Activity and expression levels of genes coding for antioxidative enzymes (superoxide dismutase; SOD, catalase; CAT, guaicol peroxidase; POD, glutathione reductase; GR, and glutathione-S transferase; GST) were higher in plants raised in soils inoculated with earthworms, with expression of SOD increasing by 58.8%, CAT by 75%, POD by 183%, GR by 106.6%, and GST by 11.8%. Moreover, plant pigment (chlorophyll a, chlorophyll b, total chlorophyll, and carotenoids) concentrations increased by 8%, 9.1%, 9.1%, and 7.7% respectively, in plants grown in soils supplemented with earthworms. The results of our study suggest that the addition of earthworms to soil increases antioxidative enzyme activities, gene expression in plants, and ROS inhibition, which enhances tolerance to Cd during the phytoextraction process. PMID- 30476848 TI - A regional approach for the calculation of characteristic toxicity factors using the USEtox model. AB - The lack of the spatial coverage as one of the main limitations of the Life-cycle impact assessment (LCIA) models leads to disagreement between their results. The USEtox model is only model that provides 8 continental and 17 subcontinental zones but does not consider the wind and water transfers affected areas around the source of pollution. Current investigation proposes the way to reduce this limitation by using the results of chemical analysis (instrumental neutron activation analysis "INAA") of pork meat as a regional indicator of anthropogenic influence. The concentration coefficient of Cr by replacing the Bioaccumulation factor (BAF) is extrapolated into the calculation of Exposure factor (XF) to modify Characterization factor (CF). Impacted and clean areas of Tomsk district (Russia) placed around Northern industrial hub (Seversk city) are studied. Neither area is located directly in the industrial hub, but the impacted area is under an anthropogenic influence due to air and water transfer of pollution. Results of our investigation present the difference between results of own investigation and default values of USEtox. Probably the model can minimize the impact because of lack of experiment data in the database. The database can be extended more with other analytical results for wide range of metals and geographical locations. PMID- 30476849 TI - Modelling gully-erosion susceptibility in a semi-arid region, Iran: Investigation of applicability of certainty factor and maximum entropy models. AB - Gully erosion susceptibility mapping is a fundamental tool for land-use planning aimed at mitigating land degradation. However, the capabilities of some state-of the-art data-mining models for developing accurate maps of gully erosion susceptibility have not yet been fully investigated. This study assessed and compared the performance of two different types of data-mining models for accurately mapping gully erosion susceptibility at a regional scale in Chavar, Ilam, Iran. The two methods evaluated were: Certainty Factor (CF), a bivariate statistical model; and Maximum Entropy (ME), an advanced machine learning model. Several geographic and environmental factors that can contribute to gully erosion were considered as predictor variables of gully erosion susceptibility. Based on an existing differential GPS survey inventory of gully erosion, a total of 63 eroded gullies were spatially randomly split in a 70:30 ratio for use in model calibration and validation, respectively. Accuracy assessments completed with the receiver operating characteristic curve method showed that the ME-based regional gully susceptibility map has an area under the curve (AUC) value of 88.6% whereas the CF-based map has an AUC of 81.8%. According to jackknife tests that were used to investigate the relative importance of predictor variables, aspect, distance to river, lithology and land use are the most influential factors for the spatial distribution of gully erosion susceptibility in this region of Iran. The gully erosion susceptibility maps produced in this study could be useful tools for land managers and engineers tasked with road development, urbanization and other future development. PMID- 30476850 TI - From classical water-ecosystem theories to nature-based solutions - Contextualizing nature-based solutions for sustainable city. AB - Growing interest in the concept of nature-based solutions (NBS) raises the question of its applicability as a broadly-understood approach to resource management and spatial planning. Although both the European Commission and United Nations consider the use of NBS as a vehicle to achieve numerous sustainability goals, the concept itself remains under-defined. We analyse the NBS concept against the background of classical water-ecosystem theories. We also review a range of potential contributions by NBS to various aspects of city management, resilience and adaptation. Finally we introduce the concept of a continuum of ecosystem service transfer across city management zones, with NBS acting as the medium, minimizing the net loss of regulatory services, and optimizing the cost efficiency of solutions. We summarize with analysis of existing best practices in urban water management from the perspective of utilizing natural processes according to the supply and demand of services, and with a threefold target: enabling, restoring or preserving nature. PMID- 30476851 TI - Land use change, urbanization, and change in landscape pattern in a metropolitan area. AB - This paper analyzes land use change, urbanization and their impact on the change in landscape pattern in Tabriz metropolitan area (TMA) during the time period from 1996 to 2016 in order to provide support sustainable regional planning. For this purpose, land use data obtained from satellite images including Landsat Thematic Mapper (TM), Enhanced Thematic Mapper (ETM), and Operational Land Imager (OLI) sensors for 1996, 2006, and 2016 with 30 * 30 m spatial resolution. This paper first seeks to analyze the changes in land use and urbanization, followed by changes in landscape patterns by using spatial metrics and Landscape Expansion Index (LEI). Then, using two methods of Ordinary Least Squares (OLS) and Geographically Weighted Regression (GWR), magnitude and direction of the relationship between land use changes, urbanization, and change in landscape patterns are analyzed. The findings show that most ecological lands such as grasslands have been converted into bare and urban lands over the past two decades. Therefore, in the whole landscape, the expansion of urbanization has led to the prevailing pattern, resulting in increased fragmentation and reduced aggregation. The results also show that changes in landscape patterns have a strong relationship with changes in various land uses. In addition, GWR analysis was used to analyze the impact of urbanization on changes in landscape patterns, indicating that urbanization expansion has different effects with changes in spatial positions, so that in areas adjacent to the built-up lands and the central regions of TMA, with increasing urbanization, we see increasing aggregation in the landscape, but as we move away from the built-up areas, are faced with an increase in fragmentation and heterogeneity, especially in the northeastern, south and southwest areas of TMR. PMID- 30476852 TI - Interstitial water microbial communities as an indicator of microbial denitrifying capacity in wood-chip bioreactors. AB - The discharge from food production greenhouses (greenhouse effluent) contains high nutrient and salt concentrations, which, if directly released, can have adverse effects on the environment. Wood-chip bioreactors are increasingly popular passive water treatment systems favoured for their economical denitrification in treating agricultural field tile drainage. Microbial communities are central to denitrification; however little is known about the maturation of microbial communities in wood-chip bioreactors treating greenhouse effluents. In this study, multiple subsurface flow wood-chip bioreactors, each vegetated with a different plant species, together with an unplanted unit, received synthetic greenhouse effluent with elevated nitrate concentrations. The hybrid bioreactors were operated for over 2 years, during which time water samples were collected from the inlet, outlet and within the reactors. The increasing denitrification rate in the bioreactor planted with Typha angustifolia (narrowleaf cattail) correlated with increasing microbial activity and metabolic richness, measured by the carbon utilization patterns in Biolog(r) EcoPlates. Increased denitrifying gene (nirS) copies (determined by quantitative polymerase chain reaction, qPCR), and near-complete nitrate removal were observed in the T. angustifolia and unplanted reactors after 16 and 23 months of operation respectively. The findings suggested that an acclimation period of at least one year can be expected in unseeded bioreactors planted with T. angustifolia, while bioreactors without vegetation may require a longer time to maximize their denitrification capacity. These results are important for the design and operation of wood-chip bioreactors, which are expected to be more commonly applied in the future. PMID- 30476853 TI - The large-scale distribution of Cu and Zn in sub- and topsoil: Separating topsoil bioaccumulation and natural matrix effects from diffuse and regional contamination. AB - A realistic estimate of diffuse contamination requires to recognize and assess the dominant natural and anthropogenic element sources. For eight large-scale geochemical surveys, the relations between geogenic, anthropogenic and biogenic Cu and Zn sources are estimated by comparing the cumulative distribution functions (CDF) of the elements in top- and subsoil using cumulative probability (CP) diagrams. Strong local contamination distorts the high-concentration end of the distribution function considerably in topsoil. In contrast the impact of diffuse contamination can best be recognized at the lower end of the data distribution. Copper and Zn are important plant micronutrients, studying their concentrations in a variety of plant materials and soils along a number of transects demonstrates that both are adjusted to narrow concentration levels in many plant materials. Plants regulating the element concentrations to certain fixed levels will distort the low-concentration end of a topsoil CDF, the bio adjustment thus limits the accuracy of diffuse contamination estimates. Combining CDF analysis with spatial mapping provides insight into the dominant contamination processes that distort the topsoil CDF relative to the subsoil CDF. For Cu a most likely diffuse contamination signal of 1-2 mg/kg with a maximum of 5 mg/kg is obtained for soils at the European scale. The higher estimate is clearly influenced by bio-adjustment. For Zn diffuse contamination appears to be higher on first glance, about 5-10 mg/kg, but again the lower end of the investigated CDFs is strongly shifted by biosphere adjustment, plants striving to avoid Zn deficiency. The true input through diffuse contamination will thus be considerably lower. Data from projects that sampled minerogenic instead of organogenic topsoil lead to lower estimates for diffuse Zn contamination in the range of <1-5 mg/kg at the continental scale. PMID- 30476854 TI - Four decades' dynamics of coastal blue carbon storage driven by land use/land cover transformation under natural and anthropogenic processes in the Yellow River Delta, China. AB - Land reclamation can impact a variety of ecosystem services provided by coastal wetlands. The dynamics of coastal blue carbon storage (CBCS) altered by land use/land cover (LULC) transformation and its linkage with natural and anthropogenic driving processes was analyzed in the Yellow River Delta (YRD), China. Using LULC data in the YRD during 1970-2010, the LULC transformation in four periods (i.e., 1970-1980, 1980-1990, 1990-2000 and 2000-2010) and their cumulative conversions within coastal wetlands were tracked to investigate the flow of LULC transformation. The spatiotemporal dynamics of the CBCS were then modeled and investigated by InVEST based on the LULC transformation in relation to their driving processes. The results indicated that the CBCS in the YRD has been substantially altered by continuous LULC transformation driven by the natural and anthropogenic processes, totally decreased by 10.2% (1.63 * 106 Mg) during 1970-2010 followed the loss of 2028 km2 natural wetlands converted to socioeconomic land use. The 78% of increased CBCS were contributed by single natural (e.g., succession) or anthropogenic (e.g., restoration) driving process at the seaward edge within tidal area, whereas 71% of decreased CBCS was linked with multiple driving processes in inland areas. In addition, the anthropogenic driving processes caused much greater loss (-5.97 * 105 Mg) than gain (6.81 * 104 Mg) in CBCS, compared with a net gain of CBCS (1.04 * 104 Mg) brought by the natural driving processes. The study can facilitate to develop coastal management strategy to balance and mitigate the conflicted LULC between socioeconomic development and maintenance of multiple ecosystem services incorporating CBCS. PMID- 30476855 TI - Effect of production temperature on lead removal mechanisms by rice straw biochars. AB - Production temperature significantly affects biochar properties and consequently the removal mechanisms of heavy metals. In this study, rice straw biochars were produced at 300, 500 and 700 degrees C (RSB300, RSB500 and RSB700). The influence of production temperature on the adsorption characteristics and removal mechanisms of lead on this set of rice straw biochars were investigated by batch adsorption tests, micro-structural analyses and sequential metal extractions. Biochars produced at higher temperatures had significantly higher pH values and surface areas, resulting in higher metal removal capacities and faster uptake kinetics. Precipitation was a key mechanism for lead removal from solution for all biochars: lead oxalate was precipitated on RSB300, and hydrocerussite was precipitated on RSB500 and RSB700. The immobilized lead fraction on the biochars could be divided into exchangeable, acid soluble and non-available fractions. RSB300 had 11.34% of the total immobilized Pb attributed to the exchangeable fraction, whereas for RSB500 and RSB700, it was <1%. Immobilized Pb on RSB500 and RSB700 was almost exclusively attributable to the acid soluble and non-available fractions (>99%). Based on our results, RSB500 and RSB700 are likely much more appropriate for soil remediation of Pb as compared with RSB300. PMID- 30476856 TI - Another look at the relationship between energy consumption, carbon dioxide emissions, and economic growth in South Africa. AB - This study explores the energy use and economic growth nexus from 1960 to 2016 in South Africa while accounting for capital, labour, and carbon dioxide emissions. We applied Bayer and Hanck (2013) combined co-integration approach, Pesaran et al. (2001) bounds test and Kripfganz and Schneider (2018) critical values and approximate p-values. The empirical evidence finds support for a long-run equilibrium relationship among investigated variables. The Granger causality test indicates one-way causality from energy use to economic growth, validating the energy-led growth hypothesis. Our study found an inverted U-shaped pattern between energy use and economic growth in the long run. This finding suggests that at a higher level of economic development there is less intensification of energy consumption, hence, signifying a decline in energy intensity while validating energy efficiency in South Africa. PMID- 30476857 TI - Impacts of different types and intensities of El Nino events on winter aerosols over China. AB - El Nino is a strong signal of interannual climate variability. The occurrence of an El Nino event may have an important impact on atmospheric pollutant concentrations in China through changes to the regional climate. This study quantitatively examines the differences among the effects of different types and intensities of El Nino events on winter mean aerosol concentration and severe haze days in China. It is found that Central Pacific (CP) El Nino events lead to larger increases in the aerosol burden over southern China relative to the same intensity of Eastern Pacific (EP) events. For El Nino events of the same type but with different intensities, moderate events induce large increases in surface aerosol concentrations over the entire eastern China, while strong and weak events lead to obvious decreases in the surface aerosol concentration over northern China. These differences are mainly attributed to changes in atmospheric circulation, with the resulting changes in aerosol mass transport occurring in response to the different types of El Nino event. Except for moderate CP events, all kinds of El Nino events lead to an increase in severe haze days in winter over northern China. Strong and weak EP El Nino events and weak CP El Nino events lead to an increase in severe haze days in winter over southern China. A change in the south-north transport of aerosols caused by El Nino events also play a dominate role in changing the occurrence of winter haze days in China. PMID- 30476858 TI - Penile reconstruction in a newborn following complicated circumcision: A case report. PMID- 30476859 TI - Chemometric characterization of the trace element profile of raw meat from Rubia Gallega x Holstein Friesian calves from an intensive system. AB - This study was conducted to compare the essential and toxic element content of seven veal cuts: shoulder clod (SC), inside round (IR), eye of round (ER), bottom round (BR), heel of round (HR), knuckle (KK) and tenderloin (TL). Eighty-four meat samples were determined by ICP-MS. Overall, essential trace elements (Co, Cu, Fe, Mn and Zn), except Se, varied significantly between the different meat cuts. By contrast, there were no significant variations for the minor trace elements (Cr, Mo and Ni) or the toxic elements (As, Cd and Pb). Chemometric analysis of the data identified four clusters: (1) the main trace elements, except (2) Se, which was closely related to (3) the toxic elements, and finally (4) the minor trace elements. TL and ER cuts constituted two separated groups; most of the SC and KK samples were associated, and IR and BR samples overlapped. TL and SC contained the highest amounts of trace elements, whereas ER and KK the lowest. PMID- 30476860 TI - Understanding the consumer's perception of traditional frankfurters and frankfurters with healthy attributes through sorting task and hard laddering techniques. AB - This study evaluated the consumer's perception towards traditional frankfurters and frankfurters with healthy attributes through sorting task and hard laddering techniques. Images with descriptions of various frankfurter types (traditional, with natural antioxidants, reduced sodium, reduced fat, as a source of dietary fibre, with omega 3, no phosphate added, no nitrite added) were presented as stimuli to 164 previously recruited consumers. The lack of information, natural, flavour issues and not being appealing characterised the no phosphate and no nitrite frankfurter groups. The consequences mentioned by the consumers that justified the choice of frankfurters with reduced sodium and fat were to avoid high blood pressure, concern about the prevention of diseases, negative perception of sodium and fat in the diet and help in weight control. It can be concluded that consumers are willing to substitute a product in traditional frankfurter with a healthier option. Among the more promising prospects for the market, are the frankfurters with reduced sodium and reduced fat. PMID- 30476861 TI - An application of QSRR approach and multiple linear regression method for lipophilicity assessment of flavonoids. AB - The analysis of quantitative structure-retention relationships (QSRR) is useful tool for assessment of compound's lipophilicity/hydrophobicity due to similarity between its retention in chromatographic system and ability to permeation through biological membranes. The main goal of this study was to compare usefulness of two reversed-phase chromatographic columns (Synergy POLAR and Synergy-FUSION) for lipophilicity assessment of 30 structurally diverse flavonoids using the QSRR approach and multiple linear regression method. The developed MLR models included the mechanistically interpretable geometrical descriptors: 3D Molecule Representation of Structure based on Electron diffraction (3D-MoRSE) and Radial Distribution Function (RDF). Both models were evaluated by the internal and external validation and selected descriptors were further interpreted. According to obtained results the FUSION-RP column can be recommended to log kw prediction of flavonoids. The comprehensive interpretation of molecular descriptors was used to present the molecular mechanisms and structural features governing the chromatographic retention of tested compounds. PMID- 30476862 TI - Validated analytical method to determine new salivary lipid peroxidation compounds as potential neurodegenerative biomarkers. AB - Lipid peroxidation is closely related to neurodegenerative diseases since brain shows high lipid composition and oxygen consumption. The determination of lipid peroxidation compounds in non-invasive biological samples would help to monitor the patients' oxidative stress status. A new analytical method based on ultrasound-assisted liquid-liquid semi-microextraction (UA-LLsME) followed by Ultra Performance Liquid Chromatography coupled to tandem Mass Spectrometry was developed to determine 18 lipid peroxidation biomarkers in saliva samples. The variables affecting the UA-LLsME efficiency were systematically studied. Under the optimum conditions, the methodology was validated and showed high-throughput, high sensitivity (limits of detection 0.02-2 nmol L-1), and satisfactory precision (coefficients of variation 2-11% (intra-day) and 5-12% (inter-day)). The reliability of the described method was assessed analysing spiked saliva samples, and the recoveries were between 80% and 120% for most of the analytes. Then, the method suitability was demonstrated by analysing saliva samples (n = 30) from elderly people with neurodegenerative diseases. To conclude, the new developed analytical method is a useful tool to determine salivary lipid peroxidation compounds as potential biomarkers in further clinical studies in which oxidative stress plays an important role. PMID- 30476863 TI - An integrative urinary metabolomic study of the therapeutic effect of Guizhi Fuling capsule on primary dysmenorrheal rats based 1H NMR and UPLC-MS. AB - Guizhi Fuling capsule (GFC) was an important traditional Chinese herbal medicine used for the treatment of primary dysmenorrheal (PD). The aim of this study was to evaluate the anti-dysmenorrheal effect of GFC on dysmenorrheal rats induced by oxytocin and to investigate its mechanism of action. An integrative urinary metabolomic study based on 1H NMR and UPLC-MS was used to investigate the therapeutic effect of GFC on PD rats. In addition, in order to obtain more potential biomarkers and to investigate the global urine metabolic profile associated with PD, we combined the characteristics of RP-UPLC-MS with HILIC-UPLC MS on metabolomic platform to find non-polar and polar metabolites. Finally, a total of 36 potential biomarkers were identified as being primarily involved in the TCA cycle, gluconeogenesis, glycolysis, pentose phosphate pathway, lipid metabolism, energy metabolism, amino acid metabolism and intestinal flora metabolism, and PD could influence the balance of many of these metabolic pathways in vivo. Furthermore, these results also suggested that the GFC had therapeutic effects on PD rats via the regulation of multiple metabolic pathways. In conclusion, the variations in potential biomarkers revealed the therapeutic mechanism of GFC, and these potential biomarkers were both significant for early diagnosis and predicting PD. PMID- 30476864 TI - Sequential cultivation of microalgae in raw and recycled dairy wastewater: Microalgal growth, wastewater treatment and biochemical composition. AB - In this study, two cycles of mixotrophic and one cycle of heterotrophic cultivation of Scenedesmus quadricauda (freshwater) and Tetraselmis suecica (marine water) microalgae in dairy wastewater (DWW) were investigated. Dry weights of S. quadricauda and T. suecica were found to be 0.43 and 0.58 g/L after the first cycle and 0.36, and 0.65 g/L after the second cycle of mixotrophic cultivation, respectively. Chlorophyll a content of both microalgae in the first cycle was significantly higher than the second cycle. S. quadricauda removed 92.15% of total nitrogen, 100% of phosphate, 100% of sulfate and 76.77% of total organic carbon, after two cycles of cultivation. The dominant fatty acids during the first and second cycle of S. quadricauda and T. suecica cultivation were C18:1 and C18:3n-3, respectively. The results suggest that by reusing DWW in two consecutive cycles of microalgal cultivation, higher pollutants removal efficiency and microalgal biomass production can be achieved. PMID- 30476865 TI - The effects of surfactants (sodium dodecyl sulfate, triton X-100 and cetyl trimethyl ammonium bromide) on the dewaterability of microalgae biomass using pressure filtration. AB - The application of pressure filtration in microalgae harvesting requires chemical pretreatment in order to reduce membrane fouling and to increase water flux. Surfactants have shown potential to enhance microalgae dewaterability by charge neutralization, bridging and releasing extracellular polymeric substances (EPS) and bound water. In this study, the effect of three surfactants including anionic sodium dodecyl sulfate (SDS), non-ionic triton X-100 and cationic cetyl trimethyl ammonium bromide (CTAB) on the dewaterability of Chlamydomonas sp. was investigated. Filtration fluxes and biomass concentrations were used to evaluate the microalgae dewaterability. Based on the results, SDS and Triton X-100 had a negative effect on the dewaterability of microalgae biomass. However, CTAB improved the dewaterability by decreasing the reversible and irreversible fouling resistance. The optimum dosage of CTAB was found to be 1500 mg/L, and resulted in 95.8% and 140% improvement on average water flux and biomass recovery efficiency, respectively. PMID- 30476866 TI - Effect of ciprofloxacin dosages on the performance of sponge membrane bioreactor treating hospital wastewater. AB - This study aimed to evaluate treatment performance and membrane fouling of a lab scale Sponge-MBR under the added ciprofloxacin (CIP) dosages (20; 50; 100 and 200 ug L-1) treating hospital wastewater. The results showed that Sponge-MBR exhibited effective removal of COD (94-98%) during the operation period despite increment of CIP concentrations from 20 to 200 ug L-1. The applied CIP dosage of 200 ug L-1 caused an inhibition of microorganisms in sponges, i.e. significant reduction of the attached biomass and a decrease in the size of suspended flocs. Moreover, this led to deteriorating the denitrification rate to 3-12% compared to 35% at the other lower CIP dosages. Importantly, Sponge-MBR reinforced the stability of CIP removal at various added CIP dosages (permeate of below 13 ug L 1). Additionally, the fouling rate at CIP dosage of 200 ug L-1 was 30.6 times lower compared to the control condition (no added CIP dosage). PMID- 30476867 TI - Performance of a compost and biochar packed biofilter for gas-phase hydrogen sulfide removal. AB - The main aim of this study was to evaluate the performance of an aerobic biofilter packed with compost for the removal of gas-phase hydrogen sulfide (H2S). After 52 d of operation, the biofilter was re-packed by replacing a certain portion (25%, v/v) of the existing compost with biochar and its performance was tested. The steady and transient performance of the biofilter was evaluated by varying the H2S concentrations from 0.1 to 2.9 g m-3 at an empty bed residence time (EBRT) of 119 and 80 s, respectively. The maximum elimination capacity (ECmax) of the compost and compost + biochar biofilter were ~19 and 33 g m-3 h-1, respectively, with >99% removal efficiency at an EBRT of 119 s. The compost biofilter showed a quick response to shock loads and the critical load to the biofilter during the shock loading step was ~81 g m-3 h-1. PMID- 30476868 TI - Dynamic viscosity of colloidal silica suspensions at low and high volume fractions. AB - A comprehensive study was carried out on the dynamic viscosity of X30 silica dispersions at both high and low volume fractions of colloidal silica particles at various electrolyte ionic strength and pH values. Booth and Ruiz-Reina and Carrique theoretical models (R-R&C) were compared in predicting the primary electroviscous effect (PEE) for viscosity at low volume fractions. To this respect the colloidal dispersion was well characterised with regards to electrolyte properties such as the Debye length, kappa-1, calculated from the ionic strength, and zeta potential, zeta, calculated from the electrophoretic mobility using the full numerical model by O'Brien and White (O'B&W). R-R&C hard sphere model (which is a modified version of Simha hard sphere model that includes a boundary condition by Happel on the outer radius of the cell) and the semi-empirical Krieger-Dougherty (K-D) models were fitted to the experimental data at high volume fractions. At both low and high volume fractions the viscosity increased with pH and decreased with ionic strength. At low volume fractions both theoretical models significantly underestimated the experimental dynamic viscosities obtained in this work. This could be attributed to the fuzzy structures for silica particles in aqueous conditions reported previously in the literature, where a significantly larger electroviscous parameter, p, was obtained experimentally for silica particles. The experimental electroviscous parameter, pexp, in this work was found to be roughly an order of magnitude up to 26 times larger than that predicted by Booth and around 5 +/- 1 times larger than the predicted p by R-R&C model allowing the introduction of a correction factor in the PEE coefficient obtained from R-R&C model enabling good prediction for X30 silica dispersions by the latter model. The significant improvement of the electroviscous effect predictions by R-R&C model compared to Booth model may be attributed to the limitations invalidating the Booth model at the electrolyte conditions in this study. At high volume fractions, the R-R&C hard sphere cell model, gave a much better fit to the experimental data compared to the K-D model, which also had the advantage of being only dependent on a coefficient that linearly relates an effective volume fraction postulated for the fuzzy silica particles to the experimental. The K-D model however, depends on the intrinsic viscosity, [eta], which requires the calculation of the experimental slope of the dynamic viscosity against volume fraction in the dilute limit, and also on a maximum packing fraction as a fitting parameter. Due to the effect of the fuzzy structures on the viscosity, the latter effective volume fraction phieff was calculated using two approaches: (i) as a fitting parameter by fitting the R-R&C hard sphere model to the experimental viscosity data over the entire volume fraction range, and (ii) by fitting only the linear part of the experimental viscosity at low volume fractions, It is concluded that the R-R&C hard sphere model with the effective volume fraction accounting for the fuzzy structures fits reasonably well the full range of experimental results at low and high volume fractions. When the model was used with the Adamczyk effective volume fraction (i.e., considering only the dilute region in the fitting procedure), the predictions became worse at high volume fractions where significant deviations from the experimental results were found upon the increase of pH. PMID- 30476869 TI - Facile synthesis of carbon nanotubes covalently modified with ZnO nanorods for enhanced photodecomposition of dyes. AB - Utilizing a one-pot solvothermal procedure novel one-dimensional zinc oxide carbon nanotube nanohybrids (ZnCT) were synthesized in alcohol-alkali solution, free of catalytic assistance. The ZnCT hybrids were prepared through covalent modification of zinc oxide nanorods (ZnO NRs) with functionalized carbon nanotubes (f-CNTs). The morphology and microstructure of as-prepared ZnCT hybrids were characterized by scanning electron microscopy (SEM), powder X-ray diffraction, Raman, X-ray photoelectron and UV-vis absorption spectroscopies. SEM images of the ZnCT hybrids indicated that the ZnOethanol NRs grew longer along the vertical radial (0 0 0 1) surface and aggregated to a lesser extent than the analogous ZnOmethanol NRs. Photodegradation analysis showed that the off-white ZnCTethanol hybrid with ascendant UV-visible light absorption had displayed superior photocatalytic activity towards Rhodamine B (RhB) dyes than either pure ZnOethanol, ZnOmethanol NRs or ZnCTmethanol hybrid, among which the photocatalytic activity of ZnOethanol NRs was better than that of ZnOmethanol NRs. Raman and X-ray photoelectron spectroscopy analyses confirmed a strong interaction between f-CNTs and ZnOethanol NRs in ZnCTethanol hybrid, in which Zn ions were chemically bonded to negatively charged oxygen-containing groups at the graphene-like surface of f-CNTs. The enhanced separation lifetime of the photogenerated electron-hole observed by surface photovoltage and photocurrent measurements of the ZnCTethanol hybrid was attributed to the efficient covalent linking of ZnOC and close contact configuration between the f-CNTs and ZnOethanol NRs. Further controlled photodegradation and electron spin resonance (ESR) analyses revealed that the photodegradation of RhB dyes resulted from photogenerated holes, and radical species, such as O2-, OH-, which were formed in situ. Details of the photocatalytic mechanism were also explored herein. PMID- 30476870 TI - Engineering hydrogenated manganese dioxide nanostructures for high-performance supercapacitors. AB - Improving the rate capability of transition metal oxides is of great important for the development of high-performance electrodes for supercapacitors. Here, a novel strategy of hydrogenation to enhance the electron transfer rate of manganese dioxide (MnO2) is proposed. Detailed preparative parameters (i.e. hydrogenation temperature and time) are systematically investigated. The hydrogenated MnO2 (H-MnOx) exhibits modified crystal phase/surface structures and increased electrical conductivity. The prepared H-MnOx exhibits high specific capacitance (640 mF cm-2 at current density of 1 mA cm-2), good rate capability (89.6% of capacitance retained from 1 to 10 mA cm-2), and good cycling stability (84.6% retention after 1000 cycles). The high specific capacitance is ascribed to the unique interconnected ultrathin nanosheets structure, which could not only provide porous channels for electrolyte infiltration to offer sufficient electrode/electrolyte interface, but also shorten the ions diffusion distance inside the active material. The good rate capability could be attributed to the good conductivity of the H-MnOx nanosheets, which was confirmed by the DFT calculation. These results highlight the importance of hydrogenation as a facile yet effective strategy to improve the rate capability of transition metal oxides for supercapacitors. PMID- 30476871 TI - Autoimmune diseases associated with Neuromyelitis Optica Spectrum Disorders: A literature review. AB - INTRODUCTION: Neuromyelitis Optica (NMO) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) which predominantly involves optic nerves and spinal cord. Since the introduction of Neuromyelitis Optica Spectrum Disorders (NMOSD) as a separate entity, there have been many reports on its association with other disorders including systemic and organ specific autoimmune diseases. Here, we reviewed other immune-mediated diseases associated with NMOSD and tried to categorize them. METHODS: The present review was conducted using the PUBMED database based on papers from 1976 (i.e., since the first NMO comorbidity with SLE was reported) to 2017. We included all articles published in English. The keywords utilized included Neuromyelitis optica, Neuromyelitis Optica Spectrum Disorders, Devic's disease, in combination with comorbidity or comorbidities. RESULTS: Diseases with immune-based pathogenesis are the most frequently reported co-morbidities associated with NMOSD, most of which are antibody-mediated diseases. According to literature, Sjogren's Syndrome (SS) and Systemic Lupus Erythematosus (SLE) are the most frequently reported diseases associated with NMOSD among systemic autoimmune diseases. Further, myasthenia gravis in neurological and autoimmune thyroid diseases in non-neurological organ-specific autoimmune diseases are the most reported comorbidities associated with NMOSD in the literature. CONCLUSIONS: NMOSD may be associated with a variety of different types of autoimmune diseases. Therefore, systemic or laboratory signs which are not typical for NMOSD should be properly investigated to exclude other associated comorbidities. These comorbidities may affect the treatment strategy and may improve the patients' care and management. PMID- 30476872 TI - Persistence and adherence to the new oral disease-modifying therapies for multiple sclerosis: A population-based study. AB - OBJECTIVE: To examine persistence and adherence to the oral disease-modifying therapies (DMTs) for multiple sclerosis (MS). METHODS: Population-based health administrative databases in British Columbia, Canada were accessed to identify all individuals filling an oral DMT prescription for MS (fingolimod, dimethyl fumarate, teriflunomide) between January 2011 and December 2015. Predictors of persistence and adherence at 6 and 12 months were assessed using logistic regression, with estimates expressed as adjusted odds ratios (aORs), and 95% confidence intervals (CIs). RESULTS: Of 858 individuals with >=6 months of follow up, the mean age at first prescription was 43.0 (SD:10.3) years; 74.2% were women. By 6 months 11.0% (94/858) had discontinued their initial oral DMT; by 12 months the proportion was 19.6% (113/577). Over 6 and 12 months, among those persisting with their oral DMT, 82.5% (630/764) and 81.7% (379/464) exhibited optimal adherence (proportion of days covered >=80%). Age, sex, calendar year and comorbidity were not associated with persistence or adherence. Individuals with higher neighbourhood-level socioeconomic status had higher odds of discontinuation within 6 months (aOR = 2.2; 95%CI:1.3-3.7). Those who had previously used another DMT had higher odds of optimal adherence (6 months aOR = 2.4;95%CI:1.6-3.6, and 12 months aOR = 2.4; 95%CI:1.5-3.9). CONCLUSION: Approximately 1 in 10 individuals discontinued their first oral DMT within 6 months, and 1 in 5 did so within one year. However, among those who did continue drug, a high proportion (>80%) exhibited optimal adherence. Predictors of persistence or adherence with immediate practical application were lacking; this highlights the challenges in optimizing drug therapy. PMID- 30476873 TI - Understanding treatment decisions from the perspective of people with relapsing remitting multiple Sclerosis: A critical interpretive synthesis. AB - BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system that mainly affects young adults. While there is no cure for MS, disease modifying treatments (DMTs) reduce the relapse rate and partial accrual of disability. More effective DMTs may have higher risks including life-threatening infections or secondary autoimmunity. The complexity and novelty of available treatments cause challenges for clinicians when prescribing treatments and for people with MS (PwMS) when deciding what trade offs they are willing and ready to make. OBJECTIVE: To explore the experience of people with relapsing remitting MS (PwRRMS) and their perspectives in choosing treatments. METHODS: Critical interpretive synthesis was employed to review and synthesis the published literature. Eighty-three publications were selected in a multi-step systematic process. RESULTS: Findings are presented in four interrelated areas: the influence of the clinical evidence-base in decision making; the meaning of DMT efficacy for PwRRMS; the influence of models of decision-making and information acquisition practices in PwRRMS; and the importance of psychosocial dimensions in DMT decision making. Synthesis of the findings revealed that alongside medical and individual reasoning, contextual circumstances play an important role in making treatment decisions. CONCLUSION: This review identifies and explains the importance of diverse contextual circumstances (clinical, social, psychological) that are important for PwRRMS when making treatment decisions. The findings demonstrate the importance of eliciting, understanding and addressing such contextual factors. PMID- 30476875 TI - Interaction of graphene oxide with bovine serum albumin: A fluorescence quenching study. AB - Fluorescence quenching was used to elucidate the binding interaction mechanism between bovine serum albumin (BSA) and graphene oxide (GO). By analyzing the values of Stern-Volmer quenching constant (KSV) and binding constant (KA) which were affected by temperature, we supposed that the quenching process between GO and BSA was mainly determined by static quenching, combined with dynamic quenching. The study of thermodynamics showed that the values of enthalpy change (?H), entropy change (?S) and Free Energy (?G) were all negative, which implied that the weak interaction of the molecular between BSA and GO was Van der Waals interaction or hydrogen bond, and the quenching process was exothermic and spontaneous. The red shift in the synchronous fluorescence spectra suggested that the conformation of tryptophan was changed in the presence of GO. According to Forster's non-radiative energy transfer theory, the distance r between BSA (donor) and GO (acceptor) was calculated and indicated the occurrence of energy transfer from BSA to GO had high probability. The AFM observation and Raman spectroscopy revealed that the interaction between BSA and GO has occurred. Compared with other literatures, the explosion of surface topography about BSA and GO was paid more attention on in this study. PMID- 30476874 TI - Chlorination and oxidation of the extracellular matrix protein laminin and basement membrane extracts by hypochlorous acid and myeloperoxidase. AB - Basement membranes are specialized extracellular matrices that underlie arterial wall endothelial cells, with laminin being a key structural and biologically active component. Hypochlorous acid (HOCl), a potent oxidizing and chlorinating agent, is formed in vivo at sites of inflammation via the enzymatic action of myeloperoxidase (MPO), released by activated leukocytes. Considerable data supports a role for MPO-derived oxidants in cardiovascular disease and particularly atherosclerosis. These effects may be mediated via extracellular matrix damage to which MPO binds. Herein we detect and quantify sites of oxidation and chlorination on isolated laminin-111, and laminin in basement membrane extracts (BME), by use of mass spectrometry. Increased modification was detected with increasing oxidant exposure. Mass mapping indicated selectivity in the sites and extent of damage; Met residues were most heavily modified. Fewer modifications were detected with BME, possibly due to the shielding effects. HOCl oxidised 30 (of 56 total) Met and 7 (of 24) Trp residues, and chlorinated 33 (of 99) Tyr residues; 3 Tyr were dichlorinated. An additional 8 Met and 10 Trp oxidations, 14 chlorinations, and 18 dichlorinations were detected with the MPO/H2O2/Cl- system when compared to reagent HOCl. Interestingly, chlorination was detected at Tyr2415 in the integrin-binding region; this may decrease cellular adhesion. Co-localization of MPO-damaged epitopes and laminin was detected in human atherosclerotic lesions. These data indicate that laminin is extensively modified by MPO-derived oxidants, with structural and functional changes. These modifications, and compromised cell-matrix interactions, may promote endothelial cell dysfunction, weaken the structure of atherosclerotic lesions, and enhance lesion rupture. PMID- 30476876 TI - Perceptions and self-reported competency related to testing, management and treatment of hepatitis C virus infection among physicians prescribing opioid agonist treatment: The C-SCOPE study. AB - BACKGROUND: This study evaluated competency related to HCV testing, management and treatment among physicians practicing in clinics offering opioid agonist treatment (OAT). METHODS: C-SCOPE is a study consisting of a self-administered survey among physicians practicing at clinics providing OAT in Australia, Canada, Europe and USA between April-May 2017. A 7-point scale was used to measure < average competence (score >4 of 7) related to HCV testing, management and treatment. RESULTS: Among 203 physicians (40% USA, 45% Europe, 14% Australia/Canada) 21% were addiction medicine specialists, 29% psychiatrists, and 70% were metro/urban [mean PWID managed, 51; years of experience, 11]. The majority perceived HCV testing (82%) and treatment (85%) among PWID as important. The minority reported < average competence with respect to regular screening (12%) and interpretation of HCV test results (14%), while greater proportions reported < average competence in advising patients about new HCV therapies (28%), knowledge of new treatments (37%), and treatment/management of HCV (40%). In adjusted analysis, factors independently associated with < average self-reported competency related to the ability to treat HCV and manage side effects included fewer years in medical practice, fewer numbers of patients treated for HCV infection in the past six months, not having obtained information on screening, diagnosing or treatment of HCV, not having attended any training on HCV in the past year, and not having read or consulted AASLD/IDSA, EASL or other guidelines for HCV. CONCLUSION: Physicians treating HCV infection among PWID attending OAT clinics recognized the importance of HCV testing and treatment. However, self perceived competency related to HCV management and treatment was low, highlighting the importance of improved HCV education and training among physicians practicing in clinics offering OAT. PMID- 30476877 TI - Off the rails-Evaluating the nightlife impact of Melbourne, Australia's 24-h public transport trial. AB - BACKGROUND: This paper evaluates the impact of the AU$83 million introduction of 24-h public transport (PT) in Melbourne, Australia on Friday and Saturday nights on a sample of nightlife venues and venue patrons. This sample was selected because a primary reason for the introduction of 24 h PT was to provide a safe means of travel home for nightlife attendees. METHODS: Covert venue observations (pre-post) and a convenience sample of nightlife patron interviews (post-only) were conducted to measure the impact of 24-h PT on venues and venue patrons. Specifically, the impact of 24-h PT on the proportion of people observed within venues (as rated on a 0-100% scale of venue capacity), patrons in venues showing any sign of intoxication, those who were observed to be too intoxicated to remain in the venue, patron drinking or drug taking behavior, train use, and the time and money spent in the night time economy were assessed. RESULTS: After 24-h PT was introduced there were no significant differences overall in the proportion of people observed within venues, or significant associations with the proportion of patrons showing any sign of intoxication or proportions who were observed to be too intoxicated to remain in the venue. However, when accounting for seasonality (matching-months), observed patron intoxication increased significantly after the introduction of 24-h PT. The majority of nightlife patrons did not report a change in their pre-drinking or drug taking behavior after 24-public transport, but 44% indicated spending more time in the night time economy, 27% reported spending more money, and 56% reported increasing their train use. CONCLUSION: Patron reports suggest that 24-h public transport has increased the amount of time people spend in nightlife settings without obviously impacting on drinking behavior. However, supplying 24-h public transport has resulted in greater self reported use of public transport. PMID- 30476878 TI - Bovine milk-derived extracellular vesicles enhance inflammation and promote M1 polarization following agricultural dust exposure in mice. AB - Occupational agricultural dust exposure can cause severe lung injury, including COPD and asthma exacerbations. Cell-derived extracellular vesicles can mediate inflammatory responses and immune activation, but the contribution of diet derived extracellular vesicles to these processes is poorly understood. We investigated whether bovine milk-derived extracellular vesicles modulate inflammatory responses to agricultural dust exposures in a murine model. C57BL/6 mice were fed either an extracellular vesicle-enriched modification of the AIN 93G diet with lyophilized bovine milk (EV) or a control diet wherein the milk was presonicated, disrupting the milk extracellular vesicles and thereby leading to RNA degradation (DEV). Mice were maintained on the diets for 5-7 weeks and challenged with a single (acute) intranasal instillation of a 12.5% organic dust extract (DE) or with 15 instillations over 3 weeks (repetitive exposure model). Through these investigations, we identified significant interactions between diet and DE when considering numerous inflammatory outcomes, including lavage inflammatory cytokine levels and cellular infiltration into the lung airways. DE treated peritoneal macrophages also demonstrated altered polarization, with EV fed mouse macrophages exhibiting an M1 shift compared to an M2 phenotype in DEV fed mice (IL-6, TNF, IL-12/23 all significantly elevated, and IL-10 and arginase decreased in EV macrophages, ex vivo). In complementary in vitro studies, mouse macrophages treated with purified milk-derived EV were found to express similar polarization phenotypes upon DE stimulation. These results suggest a role for dietary extracellular vesicles in the modulation of lung inflammation in response to organic dust which may involve macrophage phenotype polarization. PMID- 30476879 TI - Robot-assisted transabdominal cerclage for the prevention of preterm birth: A multicenter experience. AB - OBJECTIVE: High-risk pregnancy stratification and the use of Progesterone and prophylactic cerclage based on prior obstetrical outcomes and cervical length screening have been successful in curbing the impact of preterm birth. However, a large number of women will still suffer from preterm delivery even with optimal management. Experts agree that a transabdominal cerclage is the next best option for women who fail a transvaginal cerclage in a prior pregnancy. Our primary objective with this study is to assess the obstetric benefits and feasibility of robotic-assisted transabdominal cerclage in high-risk women projected to have poor obstetric outcomes. STUDY DESIGN: A multicenter retrospective cohort analysis of consecutive patients undergoing a robotic-assisted transabdominal cerclage (RA-TAC) for obstetric indications at two urban teaching university hospital and one academically affiliated community hospital. High-volume gynecologic surgeons performed all transabdominal cerclage procedures (N = 68). To assess whether the transabdominal cerclage had any effect on subsequent pregnancies, we categorized gestational age into ordinal variables and used a two proportion z-test to compare pregnancy outcomes and neonatal survival pre (n = 200) and post (n = 59) abdominal cerclage placement. RESULTS: A total of 68 consecutive patients undergoing a RA-TAC for obstetric indications were selected. We compared 200 pregnancies pre-robot-assisted cerclage to 59 pregnancies post robot-assisted cerclage. The odds of delivering after 34 and 37 weeks gestational age was 4.0 and 3.6 times greater post-robot-assisted cerclage, respectively (P < 0.001). The RA-TAC also had a significant effect on neonatal survival. The odds of neonatal survival was 12.6 times greater after RA-TAC placement when compared to prior pregnancy outcomes. Surgical outcomes were also favorable with no conversions to laparotomy or perioperative pregnancy loss. CONCLUSION: The RA-TAC influences an increase in gestational age and improves neonatal survival in women projected to have poor pregnancy outcomes. The robot-assisted transabdominal cerclages provide excellent obstetric outcomes without the morbidity of a laparotomy or the technical challenges associated with a conventional straight stick laparoscopy. This procedure is not intended to replace any other minimally invasive modality for cerclage placement but rather increase awareness of a less technically challenging option for transabdominal cerclage placement to help propagate the procedure to more patients. PMID- 30476880 TI - An electrochemical immunobiosensor for ultrasensitive detection of Escherichia coli O157:H7 using CdS quantum dots-encapsulated metal-organic frameworks as signal-amplifying tags. AB - We report here cadmium sulfide quantum dots (CdS QDs)-encapsulated metal-organic frameworks as signal-amplifying tags for ultrasensitive electrochemical detection of Escherichia coli O157:H7 (E. coli O157:H7). CdS QDs were encapsulated in zeolitic imidazolate framework-8 (ZIF-8) to form CdS@ZIF-8 muti-core-shell particles by in situ growth of ZIF-8 in the presence of CdS QDs. To specifically recognize E. coli O157:H7 cells, CdS@ZIF-8 particles were coated with polyethyleneimine to introduce amino groups on their surfaces, followed by surface modification of anti-E. coli O157:H7 antibody. A sandwich-type electrochemical immunobiosensor for the detection of E. coli O157:H7 was fabricated using CdS@ZIF-8 particles as signal tags. Cd(II) ions were released from CdS@ZIF-8 tags by HCl leaching, enabling the detection of E. coli O157:H7 by differential pulse voltammetry. Under the optimized conditions, the linear range of the biosensor is from 10 to 108 colony forming units (CFU) per mL for E. coli O157:H7 detection, with the detection limit of 3 CFU mL-1 (S/N = 3). The sensitivity of the biosensor for E. coli O157:H7 detection using CdS@ZIF-8 particles as signal tags is 16 times that of a biosensor using CdS QDs as signal tags, because the number of CdS QDs labeled to each bacterial cell increases greatly resulting from a great number of CdS QDs encapsulated in each CdS@ZIF-8 label. This method was successfully used to detect E. coli O157:H7 in milk samples. PMID- 30476881 TI - Rapid detection of Escherichia coli using fiber optic surface plasmon resonance immunosensor based on biofunctionalized Molybdenum disulfide (MoS2) nanosheets. AB - The molybdenum disulfide (MoS2) nanosheets functionalized fiber optic surface plasmon resonance (SPR) immunosensor has been reported for the sensitive detection of Escherichia coli (E. coli). The MoS2 nanosheets were prepared by chemical exfoliation method. The synthesised nanostructures were characterized for their structural, morphological and optical properties. The E. coli monoclonal antibodies were successfully immobilized on the MoS2 functionalized sensing platform via hydrophobic interactions. An alternative method simplifying the antibodies immobilization process by functionalization of 2D nanomaterial (MoS2 nanosheets) for rapid (~15 mins) bacterial quantification is presented in this study. The immunosensor uses wavelength interrogation method and a strong linear relationship (R2 = 0.994) was observed between spectral response of immunosensor and different concentration of E. coli. The nonspecificity and cross reactivity studies of the developed immunosensor were investigated with detection of Salmonella Typhimurium and Staphylococcus aureus. To demonstrate the practical application, spiked samples of water and orange juice were analysed with acceptable recovery results. The label-free immunosensor exhibits better performance, detection limit (94 CFU/mL), high sensitivity (2.9 nm/1000 CFU mL-1; 3135 nm/RIU) and profound specificity as compared to conventional fiber optic SPR sensor (detection limit: 391 CFU/mL, sensitivity: 0.6 nm/1000 CFU mL-1; 1646 nm/RIU). This sensing platform shows promising applications in regular water and food quality monitoring for various pathogenic microorganisms. PMID- 30476882 TI - Surface regeneration and reusability of label-free DNA biosensors based on weak polyelectrolyte-modified capacitive field-effect structures. AB - The reusability of capacitive field-effect electrolyte-insulator-semiconductor (EIS) sensors modified with a cationic weak polyelectrolyte (poly(allylamine hydrochloride) (PAH)) for the label-free electrical detection of single-stranded DNA (ssDNA), in-solution- and on-chip-hybridized double-stranded DNA (dsDNA) has been studied. It has been demonstrated that via simply regeneration of the gate surface of the EIS sensor by means of an electrostatic adsorption of a new PAH layer, the same biosensor can be reused for at least five DNA-detection measurements. Because of the reversal of the charge sign of the outermost layer after each surface modification with the cationic PAH or negatively charged DNA molecules, the EIS-biosensor signal exhibits a zigzag-like behavior. The amplitude of the signal changes has a tendency to decrease with increasing number of macromolecular layers. The direction of the EIS-signal shifts can serve as an indicator for a successful DNA-immobilization or -hybridization process. In addition, we observed that the EIS-signal changes induced by each surface modification step (PAH adsorption, immobilization of ssDNA or dsDNA molecules and on-chip hybridization of complementary target cDNA) is decreased with increasing the ionic strength of the measurement solution, due to the more efficient macromolecular charge-screening by counter ions. The results of field-effect experiments were supported by fluorescence-intensity measurements of the PAH- or DNA-modified EIS surface using various fluorescence dyes. PMID- 30476883 TI - Fluorescence immunoassay of E. coli using anti-lipopolysaccharide antibodies isolated from human serum. AB - In this work, the gram-negative bacterium Escherichia coli strain BL21(DE3) (with lipopolysaccharide (LPS) in its outer membrane) and its modified ClearColiTM strain (lacking LPS) were used for the separation of anti-LPS antibodies from human serum by the following steps: (1) binding of the serum proteins to BL21(DE3); (2) dissociation of the bound proteins (including anti-LPS antibodies) from BL21(DE3) with acid; (3) filtering of the dissociated proteins using ClearColi to remove unwanted proteins; and (4) separation of the antibody fraction by protein-A column chromatography. The binding properties of the separated antibodies were analyzed by fluorescence-activated cell sorting to confirm their selective binding to LPS on the outer membrane of BL21(DE3), and by thermophoretic immunoassay to estimate their dissociation constant. The in vitro applicability of the separated anti-LPS antibodies was demonstrated through a fluorescence assay of BL21(DE3), after immobilizing the antibodies onto a modified microplate surface. The electrochemical detection of BL21(DE3) was also achieved after immobilizing the anti-LPS antibodies onto a gold electrode. PMID- 30476884 TI - Copper ion-assisted gold nanoparticle aggregates for electrochemical signal amplification of lipopolysaccharide sensing. AB - A signal amplification electrochemical aptasensor for ultrasensitive detection of lipopolysaccharide (LPS) was fabricated. The sensor was constructed with a probe of LPS aptamer and a copper ions-mediated gold nanoparticles aggregate (Cu/Au NA) as a signal amplification material. The Cu/Au NAs comprising copper ions (Cu2+) and L-cysteine modified AuNPs were fabricated by a self-assembly process. For functionalization of the electrode, the carboxylic group of a mercaptoacetic acid self-assembly layer was covalently coupled with the amine group of the aptamer. The aptamer with high specificity and affinity can effectively gather the dissociative LPS firstly, and the Cu/Au NAs were captured by anionic groups of the carbohydrate portions from LPS molecules based on the specific interactions. With the employment of the sandwich-type biosensor, the strategy can significantly amplify the electrochemical signal for determination of trace amount of LPS. The sensing performance of the electrochemical sensor was investigated by differential pulse voltammetry (DPV) and the stripping peak currents of Cu re-oxidized to Cu2+ was used to monitor the level of LPS. The electrochemical aptasensor exhibited excellent sensitivity toward LPS with a detection limit of 0.033 pg/mL (S/N = 3). The biosensor also exhibited a high specificity toward LPS in the presence of other common interfering substances and was easily regenerated. Furthermore, the fabricated biosensor showed a good practical application for LPS determination in human serum samples. PMID- 30476885 TI - Synthesis and initial in vitro characterization of a new P2X7R radioligand [18F]IUR-1602. AB - The overexpression of P2X7R is associated with neuroinflammation and plays an important role in various neurodegenerative diseases. The [18F]fluoropropyl derivative of GSK1482160, [18F]IUR-1602, has been first prepared and examined as a new potential P2X7R radioligand. The reference standard IUR-1602 was synthesized from tert-butyl (S)-5-oxopyrrolidine-2-carboxylate, fluoropropylbromide, and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 13% in three steps. The target tracer [18F]IUR-1602 was synthesized from desmethyl-GSK1482160 with 3-[18F]fluoropropyl tosylate, prepared from propane-1,3-diyl bis(4-methylbenzenesulfonate) and K[18F]F/Kryptofix2.2.2, in two steps and isolated by HPLC combined with SPE in 2-7% decay corrected radiochemical yield. The radiochemical purity was >99%, and the molar activity at end of bombardment (EOB) was 74-370 GBq/MUmol. The potency of IUR-1602 in comparison with GSK1482160 was determined by a radioligand competitive binding assay using [11C]GSK1482160, and the binding affinity Ki values for IUR-1602 and GSK1482160 are 23.6 and 3.07 nM, respectively. The initial in vitro evaluation results, 8-fold less potency of [18F]IUR-1602 compared to [11C]GSK1482160, prevent further in vivo evaluation of [18F]IUR-1602 in animals and human. PMID- 30476886 TI - Improving the quality of data presentation in health sciences. PMID- 30476887 TI - Leptin stimulates DMP-1 and DSPP expression in human dental pulp via MAPK 1/3 and PI3K signaling pathways. AB - INTRODUCTION: To investigate the physiological function of leptin in human dental pulp, and to determine the specific pathways implicated in its effect. METHODS: Twenty-seven dental pulp samples were obtained from human third molars. Pulp samples were treated with or without human recombinant leptin. Leptin functional effect was analyzed in terms of regulation of the synthesis levels of DSPP and DMP-1, determined by immunoblot. RESULTS: Leptin stimulated DMP-1 and DSPP synthesis in all human dental pulp specimens. The stimulatory effect of leptin on DMP-1 and DSPP synthesis was partially prevented by blocking mitogen-activated protein kinase (MAPK 1/3) and phosphatidylinositol 3 kinase (PI3K) pathways, respectively. CONCLUSIONS: The present study demonstrates the functional effect of leptin in human dental pulp stimulating the expression of DMP-1 and DSPP, both proteins implicated in dentinogenesis. Leptin stimulates DSPP expression via PI3K pathway and DMP-1 synthesis via MAPK 1/3 pathway. These results support the role of leptin in pulpal reparative response, opening a new research line that could have translational application to the clinic in vital pulp therapy procedures. PMID- 30476888 TI - Effects of pyrethroid insecticides on hypothalamic-pituitary-gonadal axis: A reproductive health perspective. AB - Pyrethroids, a class of ubiquitous insecticides, have been recognized as endocrine-disrupting chemicals (EDCs). A lot of studies have implied the endocrine-disrupting effects of pyrethroids on the hypothalamic-pituitary-gonadal (HPG) axis. However, there are few review articles regarding the effects of pyrethroids on the HPG axis of mammal and human, especially new research progress made in this area. The present review sums up the effects of pyrethroids on the HPG axis-related reproductive outcomes, including epidemiological investigations based on human biomonitoring, animal studies and in vitro tests. Mechanisms have described that the endocrine-disrupting effects of pyrethroids on mammal can be mediated via the interaction with steroid receptors, the direct action on ion channels and signaling molecules. Finally, we summarize the current research gaps and suggest future directions in this topic. PMID- 30476889 TI - An assessment of the ability to ingest and excrete microplastics by filter feeders: A case study with the Mediterranean mussel. AB - Plastic debris has been recognized as a growing threat to marine biota due to its widespread distribution and possible interactions with marine species. Concerns over the effects of plastic polymers in marine ecosystems is reflected in the high number of toxicological studies, regarding microplastics (<5 mm) and marine fauna. Although several studies reported that organisms ingest and subsequently eliminate microplastics (MP), the potential effects at organ and tissue level remain unclear, especially considering exposure to different microplastic sizes and concentrations. The present study aimed at investigating potential pathophysiological effects of the ingestion of MP by marine filter-feeders. For the purpose, Mediterranean mussel (Mytilus galloprovincialis) was exposed to spherical polystyrene MP (2 and 10 MUm O) over short- and medium-term exposure periods, under single and combined concentrations that represent high, yet realistic doses (10 and 1000 MP mL-1). Overall, results suggest rapid MP' clearance from water column by filtering, regardless of MP size. Ingestion occurred, identified by MP in the lumen of the gut (mostly in midgut region), followed by excretion through faeces. However, no MP were found in gills or digestive gland diverticula. Biochemical indicators for oxidative stress were generally irresponsive regardless of organ and time of exposure. Small foci of haemocytic infiltration in gastric epithelia were found, albeit not clearly related to MP ingestion. Globally, no evident histopathological damage was recorded in whole-body sections of exposed animals. The present findings highlight the adaptative ability of filter-feeding bivalves to cope with filtration of suspended MP, resulting in rapid elimination and reduced internal damage following ingestion of spherical MP. Nevertheless, the fact that the animals are able to translocate MP to the gut reveals that filter feeding organisms may indeed became a target of concern for fragmented materials with smaller, mixed sizes and sharper edges. PMID- 30476890 TI - A combined Arctic-tropical climate pattern controlling the inter-annual climate variability of wintertime PM2.5 over the North China Plain. AB - In recent years, the Chinese government has made tremendous efforts to reduce the emissions of atmospheric pollutants throughout the country. An apparent improvement in air quality was observed in Beijing and its adjacent region during the winter of 2017/2018. However, caution should be taken in directly attributing this improvement to air control actions without taking the effects of climate variability into account. Here, we develop a statistical prediction model that can successfully predict the variability of wintertime PM2.5 concentrations observed over these regions. Our analysis indicates that the remarkable decrease in PM2.5 concentrations over the North China Plain (NCP) observed during the winter of 2017/2018 can be largely explained by changes in meteorological conditions. To clarify which climate factors control the inter-annual variability of wintertime PM2.5 pollution over the NCP, we further reconstructed a 30-year time series of wintertime PM2.5 levels over the NCP over the period of 1988-2017 using our statistical model. Through our analysis, we found that the combined Arctic-tropical climate effects related to the ENSO and Arctic warming controlled the inter-annual variability of wintertime PM2.5 over the NCP. Specifically, the rapid warming of the Barents-Kara Sea region enhances the Siberian High and thus plays an important role in improving the air quality over the NCP during the 2017/2018 wintertime. These results help us understand the role of climate variability in modulating air quality, especially its contributions to the winter of 2017/2018. These results may assist in the evaluation of current air control actions and the revision of relevant policy for the future, which are urgently needed for China. PMID- 30476891 TI - Temporal-spatial analysis of crop residue burning in China and its impact on aerosol pollution. AB - China has performed crop residue burning (CRB) for a long time and has suffered from resultant environmental pollution. High temporal resolution has not been fully discussed in attempts to address the temporal and spatial impact of CRB in China on air quality. Our study used the MOD14A1 product of the MODerate resolution Imaging Spectrometer (MODIS) to extract the daily CRB for China during the period from 2014 to 2016, and the daily aerosol optical depth (AOD) provided by MODIS Collection 6 was obtained to simultaneously reflect the air pollution. First, the study area was classified into five subregions. A temporal analysis was conducted on the daily variation in the number of CRB events and the regional mean value of AOD, the spatial contribution ratio of CRB on aerosol pollution was then calculated, and finally, a temporal and spatial Pearson correlation was calculated to find the spatially varying relationship between CRB and aerosol. The results suggest the following: (1) CRB possesses seasonal characteristics that are associated with the harvest time or sowing time of major crops in the region. (2) The impact of CRB on aerosol was delayed by 1-6 days. (3) High contribution ratios (70%-90%) occurred in northeast China on a large scale; even when the impact of the CRB on aerosol pollution in the Huang-Huai-Hai river basin occurred on a large scale, the value was merely approximately 30%. Relatively low contributions of CRB have been found in other places, whereas the contribution of CRB was severe in some places with high-density populations. (4) Temporal-spatial correlation provided an accurate index to reflect the correlation of CRB and aerosol in a specific location, which suggests that, in places with large scale and dense CRB, CRB tends to have a high positive correlation with aerosol pollution for each day. PMID- 30476892 TI - Geographical detection of groundwater pollution vulnerability and hazard in karst areas of Guangxi Province, China. AB - Groundwater pollution is a critical concern in karst areas. This study used the PLEIK (P: protective cover; L: land use; E: epikarst development; I: infiltration conditions; K: karst development) method to assess the vulnerability of groundwater pollution in Guangxi Province, which is the largest karst area in China. The pollution sources and attenuation consist of groundwater pollution hazards. The attributions for the vulnerability and hazard were measured using the geodetector method from geographical information system in Luzhai County in Guangxi. The results confirmed that the vulnerability of groundwater pollution was higher in karst areas than in non-karst areas. In Guangxi, 36.35% of the groundwater samples were polluted. A total of 49.73% of the areas in Luzhai County contained hazardous levels of pollution. The risk assessment map, which interacted with the vulnerability and hazards, was 58.2% similar to the groundwater pollution distribution. The influence of the hazard on groundwater pollution was 2.6 times that of the vulnerability. It is crucial to control pollution sources to prevent groundwater pollution. PMID- 30476893 TI - Repeated detection of polystyrene microbeads in the lower Rhine River. AB - Microplastics are emerging pollutants in water bodies worldwide. The environmental entry areas must be studied to localise their sources and develop preventative and remedial solutions. Rivers are major contributors to the marine microplastics load. Here, we focus on a specific type of plastic microbead (diameter 286-954 MUm, predominantly opaque, white-beige) that was repeatedly identified in substantial numbers between kilometres 677 and 944 of the Rhine River, one of Europe's main waterways. Specifically, we aimed (i) to confirm the reported abrupt increase in microbead concentrations between the cities of Leverkusen and Duisburg and (ii) to assess the concentration gradient of these particles along this stretch at higher resolution. Furthermore, we set out (iii) to narrow down the putative entry stretch from 81.3 km, as reported in an earlier study, to less than 20 km according to our research design, and (iv) to identify the chemical composition of the particles and possibly reveal their original purpose. Surface water filtration (mesh: 300 MUm, n = 9) at regular intervals along the focal river stretch indicated the concentration of these spherules increased from 0.05 to 8.3 particles m-3 over 20 km. This spot sampling approach was supported by nine suspended solid samples taken between 2014 and 2017, encompassing the river stretch between Leverkusen and Duisburg. Ninety-five percent of microbeads analysed (202/212) were chemically identified as crosslinked polystyrene-divinylbenzene (PS-DVB, 146/212) or polystyrene (PS, 56/212) via Raman or Fourier-transform infrared spectroscopy. Based on interpretation of polymer composition, surface structure, shape, size and colour, the PS(-DVB) microbeads are likely to be used ion-exchange resins, which are commonly applied in water softening and various industrial purification processes. The reported beads contribute considerably to the surface microplastic load of the Rhine River and their potential riverine entry area was geographically narrowed down. PMID- 30476894 TI - Somatostatin receptor SSTR2A and SSTR5 expression in neuroendocrine breast cancer. AB - Neuroendocrine breast cancer (NEBC) is a group of rare tumors, which could benefit from therapy targeting the somatostatin receptors (SSTRs). In particular, SSTR2A and SSTR5 are potential targets given their consistent expression in gastrointestinal and pancreatic primary and metastatic neuroendocrine cancers. Currently, there are no studies describing the expression of SSTRs in NEBC. The purpose of our study was to characterize the immunohistochemical expression of SSTR2A and SSTR5 in a cohort of NEBC. Thirty-one primary NEBC cases were analyzed, and SSTR2A and SSTR5 immunohistochemistry performed and scored using the modified immunoreactive score proposed by Remmele and Stanger. All patients were females with a mean age of 66.6 years (SD = 14). 77% of cases were histological grade 2. SSTR2A showed a weak positivity in 11 cases (35.5%), moderate positivity in 6 cases (19.4%) and strong positivity in 5 cases (16.1%). Nine cases were negative for SSTR2A (29%). SSTR5 showed a weak positivity in 16 cases (51.6%), moderate positivity in 6 cases (19.4%), while no cases showed strong positivity. Nine cases were negative for SSTR5 (29%). Five cases were negative for both SSTR2A and SSTR5. A weak to moderate SSTR2A and SSTR5 expression was observed in 50-70% of the cases. A subset of NEBCs with strong SSR2A expression may benefit from SSTRs targeted therapy. These results need further validation in a larger series including metastatic NEBC, to provide potential therapeutic targets for patients with advanced disease. PMID- 30476895 TI - The relationship of anxiety and smoking behaviors to medication adherence among cigarette smokers living with HIV. AB - INTRODUCTION: People living with HIV/AIDS [PLWH] who smoke cigarettes report lower medication adherence. The purpose of the current study was to examine the relationship between anxiety and smoking behaviors (e.g., smoking quantity and frequency) and medication adherence in a sample of PLWH who smoke. METHODS: PLWH who reported current cigarette smoking and use of antiretroviral medication were recruited from Center for Positive Living at Montefiore Medical Center (New York, US). Participants completed questions about their current smoking behavior, anxiety symptoms, and medication adherence. RESULTS: The analytic sample included sixty-eight PLWH who smoked cigarettes (female 48.5%, mean age = 49.1 +/- 8.8 years, 52.2% Latino/a). The participants smoked an average of 10.53 (SD = 8.6) cigarettes daily and just over half of participants (55.9%) reported high medication adherence. There was a significant association between greater anxiety symptoms and poorer medication adherence (OR = 1.09, CI = 1.04-1.15, p = .001). Participants with higher anxiety symptoms were more likely to report forgetting to take their medication, forgetting to take medication when leaving on a trip, stopping medication when feeling symptoms are under control, and when feeling hassled about sticking to the treatment plan. Within this sample of current smokers, there were no significant associations between smoking quantity or frequency and medication adherence and no interactive effects of these smoking behaviors and anxiety on medication adherence. DISCUSSION: Current cigarette smoking PLWH who reported greater anxiety symptoms were less likely to adhere to their medication than current smoking PLWH who reported fewer anxiety symptoms. PLWH who smoke may benefit from assessment and management of anxiety. PMID- 30476896 TI - Perceived addiction to smoking and associations with motivation to stop, quit attempts and quitting success: A prospective study of English smokers. AB - AIMS: Some argue that perceived addiction to smoking (PAS) might undermine motivation to stop. We examined the association of PAS with motivation to stop in a population sample and assessed its association with past and future quit attempts and future quit success. METHOD: 12,700 smokers in England were surveyed between September 2009-March 2012 as part of the Smoking Toolkit Study. 2796 smokers were followed up after 6 months. PAS was assessed at baseline by a single self-report item. The outcome variables were ratings of motivation to stop and reports of past-year quit attempts at baseline, and quit attempts in the past 6 months and smoking status at follow-up. Baseline covariates were sex, age, social grade and daily cigarette consumption. RESULTS: In adjusted analyses, PAS was positively associated with at least some degree of motivation to stop versus no motivation (ORs = 1.97-2.96, all p's < 0.001). PAS was also positively associated with past-year quit attempts (OR = 1.43, 95% CI = 1.32-1.55, p < 0.001), but not with future quit attempts (OR = 1.17, 95% CI = 0.99-1.39, p = 0.064) or quit success (OR = 1.04, 95% CI = 0.73-1.47, p = 0.83). CONCLUSION: In smokers in England, perceived addiction to smoking is positively associated with motivation to stop and having recently made a quit attempt but is not clearly associated with future quit attempts or success. These findings provide no grounds for believing that increasing smokers' perceived addiction through promotion of stop smoking support has undermined motivation to stop. PMID- 30476897 TI - Enhanced production of unusual triterpenoids from Kadsura angustifolia fermented by a symbiont endophytic fungus, Penicillium sp. SWUKD4.1850. AB - Highly oxygenated schitriterpenoids are interesting for study of their structures, bioactivities and synthesis. From Kadsura angustifolia fermented by an associated symbiotic endophytic fungus, Penicillium sp. SWUKD4.1850, nine undescribed triterpenoids, kadhenrischinins A-H, and 7beta-schinalactone C together with four known triterpenoids, henrischinins A and B, schinalactone C and nigranoic acid were isolated and established by the extensive 1D-, 2D-NMR, HR ESI-MS and ECD data analysis. Except nigranoic acid, all these metabolites have been first detected in non-fermented K. angustifolia. Structurally, kadhenrischinins A-D belong to the relatively rare class of highly oxygenated schitriterpenoids that contain a unique 3-one-2-oxabicyclo [3,2,1]-octane motif, while kadhenrischinins E-H feature a cyclopentane ring in a side chain rarely found in the family Schisandraceae. These results indicated that fermentation of K. angustifolia with SWUKD4.1850 induced the production of highly oxygenated schitriterpenoids from nigranoic acid, which provided a guidance to obtain desired compounds from those plants initially thought not to produce. This is the first report on the fermentation of K. angustifolia medical plant and the first discovery of highly oxygenated schitriterpenoids by microbial technology. PMID- 30476898 TI - Stigmastane-type steroids with unique conjugated Delta7,9(11) diene and highly oxygenated side chains from the twigs of Vernonia amygdalina. AB - Veramyosides A-J, eleven undescribed stigmastane-type steroids, including one aglycone and ten glycosides, along with three known homologues were isolated from the twigs of Vernonia amygdalina Delile (compositae). All compounds featured a stigmastane-type steroid skeleton with a unique conjugated Delta7,9(11) diene segment and highly oxygenated side chains with a gamma-lactone or an alpha, beta unsaturated five-membered lactone ring. The structures of veramyosides A-J and their absolute configurations were unambiguously elucidated by HR-ESI-MS, extensive NMR spectroscopy, in situ dimolybdenum CD methods, modified Mosher's method, quantum chemical calculation of their ECD curves, and CD comparison methods on basis of their biogenetic pathway. In addition, all isolates were investigated for their effects on RXRalpha transcription, and their effects on the NF-kappaB signaling pathway were also evaluated. PMID- 30476899 TI - Diterpenoids from the Chinese liverwort Frullania hamatiloba and their Nrf2 inducing activities. AB - Six previously undescribed labdane diterpenoids, frullanians A-F, along with five known diterpenoids, were isolated from the Chinese liverwort Frullania hamatiloba Stephani. Their structures were determined using NMR data, electronic circular dichroism (ECD) calculations as well as the single crystal X-ray diffraction measurement. NAD(P)H: QR (quinone reductase) assay demonstrated that frullanian D and four known compounds displayed antioxidant effect mediated via Nrf2 (Nuclear factor-erythroid 2-related factor 2) induction. Further investigation of the most bioactive frullanian D in MOVAS cells revealed that it ameliorated H2O2-induced oxidative insults without toxicity by increasing cell viability, attenuating morphological changes, and reducing intracellular ROS production. In addition, frullanian D promoted the nuclear translocation of Nrf2 and upregulated the expressions of antioxidant proteins NQO1 (NAD(P)H quinone oxidoreductase 1) and gamma-GCS (gamma-glutamyl cysteine synthetase). Docking analysis using MOE software further supported the activation of the Nrf2 pathway by frullanian D. PMID- 30476900 TI - REPRINTED WITH PERMISSIOn OF EDITOR-IncHIEF OF AnnALS OF SURGERY: Annals of Surgery: Vol. 266, nr 5, November 2017; 703 - 705: Modern Surgeons: Still Masters of Their Trade or Just Operators of Medical Equipment? AB - My surgical education began at a time when Poland formed part of the communist bloc and was isolated from the world, or in today's Terms - it remained behind the Iron Curtain. This was true of all areas of life, including medicine. When after 40 years of work, I look back at my professional career; I wonder whether I owe my proficiency in surgery to my experience and dexterity or, like many others, to technological progress. Two of the great Polish surgeons were my mentors and teachers. Professor Zdzislaw Lapinski was the one I met first. He was a manual genius and an unusual operational strategist. Granted, he had one character defect, but nobody's perfect after all. In 1975, I defended my dissertation. I was convinced that I should continue my education at a center abroad, preferably within a postdoctoral scholarship. Professor Lapinski wanted me to learn everything about surgery from him. I decided otherwise, and in 1978 with his tacit agreement, I obtained a Humboldt Fellowship and went to Heidelberg, to the department headed by none other than Professor Fritz Linder.1 I started my research for the habilitation thesis at the Experimentelle Chirurgie Abteilung of his Department. PMID- 30476901 TI - miR-150-5p suppresses tumor progression by targeting VEGFA in colorectal cancer. AB - MicroRNA-150-5p (miR-150-5p) has been implicated in tumor initiation and progression in a variety of cancers. However, its roles in colorectal cancer (CRC) remain largely unknown. In our study, a decreased miR-150-5p expression in CRC tissues was found to be associated with poor overall survival. Moreover, miR 150-5p inhibited CRC cell proliferation, migration, invasion and angiogenesis in vitro and in vivo, and its inhibitory effect could be reversed by transfection of vascular epithelial growth factor A (VEGFA) expression plasmid. Lastly, we demonstrated that miR-150-5p inactivated VEGFA/VEGFR2 and the downstream Akt/mTOR signaling pathway in CRC. Based on these results, we conclude that miR-150-5p may function as a tumor suppressor in CRC, and miR-150-5p/VEGFA axis may be a potential therapeutic target candidate in CRC treatment. PMID- 30476902 TI - Role of echocardiography in CRT. PMID- 30476903 TI - Gender, GABAergic dysfunction and AD. PMID- 30476905 TI - Comparison of Digital Breast Tomosynthesis (DBT) and Digital Mammography (DM) for Detection of Breast Cancer in Women in Kuwait. AB - OBJECTIVE: To investigate the sensitivity and specificity of dig!ital mammography (DM) and digital breast tomosynthesis (DBT) for the detection of breast cancer in comparison to histopathology findings. SUBJECTS AND METHODS: We included 65 breast lesions in 58 women, each detected by two diagnostic mammography techniques: DM and DBT using Senographe Essential machine (GE Healthcare, Buc, France), and subsequently confirmed by histopathology. The Breast Imaging Reporting and Data System (BI-RADS) was used for charac!terizing the lesions. RESULTS: The average age of women was 48.3 years (range; 26-81 years). There were 34 malignant and 31 benign breast lesions. The sensitivity for DM and DBT, was 73.5% and 100%, respectively, while the specificity was 67.7% and 94%, respectively. Receiver-operating characteristic curve analysis showed an overall diagnostic advantage of DBT over DM, with significant a difference between DBT and DM (p < 0.001). By performing Cohen's kappa test, we found that there was a strong level of agreement according to Altman guidelines between DBT and histopathology findings (0.97), but there was weak agreement between DM and histopathology findings (0.47). CONCLUSION: DBT improves the clinical accuracy of mammography by increasing both sensitivity and specificity. We believe this improvement is due to improved image visibility and quality. These results could be of interest to health care institutions as it may impact their decision on whether to upgrade to DBT not only for diagnosis but also for screening. PMID- 30476904 TI - Angiopoietin-1 and alphanubeta3 integrin peptide promote the therapeutic effects of L-serine in an amyotrophic lateral sclerosis/Parkinsonism dementia complex model. AB - Amyotrophic lateral sclerosis (ALS) is an adult disorder of neurodegeneration that manifests as the destruction of upper and lower motor neurons. Beta-N methylamino-L-alanine (L-BMAA), an amino acid not present in proteins, was found to cause intraneuronal protein misfolding and to induce ALS/Parkinsonism dementia complex (PDC), which presents symptoms analogous to those of Alzheimer's-like dementia and Parkinsonism. L-serine suppresses the erroneous incorporation of L BMAA into proteins in the human nervous system. In this study, angiopoietin-1, an endothelial growth factor crucial for vascular development and angiogenesis, and the integrin alphavbeta3 binding peptide C16, which inhibits inflammatory cell infiltration, were utilized to improve the local microenvironment within the central nervous system of an ALS/PDC rodent model by minimizing inflammation. Our results revealed that L-serine application yielded better effects than C16+ angiopoietin-1 treatment alone for alleviating apoptotic and autophagic changes and improving cognition and electrophysiological dysfunction, but not for improving the inflammatory micro-environment in the central nerve system, while further advances in attenuating the functional disability and pathological impairment induced by L-BMAA could be achieved by co-treatment with C16 and angiopoietin-1 in addition to L-serine. Therefore, C16+ angiopoietin-1 could be beneficial as a supplement to promote the effects of L-serine treatment. PMID- 30476906 TI - Lentivirus-Mediated Gene Silencing of Lymphocyte Function-Associated Antigen 1 Inhibits Apoptosis of Hippocampal Neurons in Rats with Acute Cerebral Ischemia After Cerebral Lymphatic Blockage. AB - BACKGROUND/AIMS: Cerebral ischemia is considered to be the most common cause of stroke with high mortality. It occurs as a result of the damage of the hippocampal neurons with lymphocyte function-associated antigen (LFA)-1 being emphasized to play a role in the biological functions of hippocampal neurons. This study was conducted in order to investigate the effects of specific knockdown of LFA-1 expression by lentivirus had on the apoptosis of the hippocampal neurons, simulated by rat models of acute cerebral ischemia after cerebral lymphatic blockage. METHODS: A total of 60 Wistar rats were selected as subjects, among which 50 were used to establish models of the acute cerebral ischemia after cerebral lymphatic blockage, while the remaining 10 rats were treated with the sham operation. The underlying regulatory mechanisms regarding LFA-1 were analyzed with the treatment of si-LFA-1 and LFA-1 vector in the hippocampal CA1 area of brain tissues isolated from the rats with acute cerebral ischemia. The brain water content, electrolyte content, and blood-brain barrier permeability located in ischemic area of rats were measured. TUNEL staining and immunochemistry methods were employed in order to determine the apoptosis rate and positive levels of LFA-1, MMP-9, and Caspase-3. The mRNA and protein levels of related genes were also detected by means of RT-qPCR and western blot assay. RESULTS: The brain water content, Na+ and Ca+ contents, blood-brain barrier permeability, apoptosis rate, positive levels of LFA-1, MMP-9, and Caspase-3 were decreased, and the K+ content was increased in ischemic tissues treated with si LFA-1. The mRNA and protein levels of LFA-1, MMP-9, Caspase-3, and Bax had all decreased, while the mRNA and protein levels of Bcl-2 were elevated in the hippocampal CA1 area of rat brain tissues treated with si-LFA-1. These situations could be reversed through the up-regulation of LFA-1. CONCLUSION: In conclusion, LFA-1 gene silencing could improve the acute cerebral ischemia after cerebral lymphatic blockage by inhibiting apoptosis of the hippocampal neurons in rats. PMID- 30476907 TI - miR-16-2* Interferes with WNT5A to Regulate Osteogenesis of Mesenchymal Stem Cells. AB - BACKGROUND/AIMS: Osteoporosis is a bone metabolic disease characterized by a systemic impairment of bone mass, which results in increased propensity of fragility fractures. A reduction in the differentiation of MSCs into osteoblasts contributes to the impaired bone formation observed in osteoporosis. Mesenchymal stem cells (MSCs) are induced to differentiate into preosteoblasts, which are regulated by the signaling cascades initiated by the various signals, including miRNAs. miR-16-2* is a newly discovered miRNA that participates in diagnosis and prognosis of hepatocellular carcinoma, cervical cancer and chronic lymphocytic leukemia. However, the effect of miR-16-2* on the regulation of osteoblast differentiation and the mechanism responsible are still unclear. Here we discuss the contribution of miR-16-2* to osteoporosis, osteoblast differentiation and mineralization. METHODS: The expression pattern of miR-16-2* during osteogenesis or in osteoporosis bone samples was validated by quantitative real-time PCR (qRT PCR). The human bone marrow mesenchymal stem cells (hBMSCs) were induced to differentiate into osteoblasts by osteogenic induced medium containing dexamethasone, ascorbate-2-phosphat, beta-glycerophosphate and vitamin-D3. The target genes of miR-16-2* were predicted by TargetScan and PicTar. The mRNA and protein levels of osteogenic key markers were detected using qRT-PCR or western blot respectively. The WNT signal activity was analyzed by TOP/FOP reporter assay. RESULTS: The expression of miR-16-2* in patient bone tissue with osteoporosis was negatively correlated with bone formation related genes. During osteoblast differentiation process, the expression of miR-16-2* was significantly decreased. Upregulation of miR-16-2* in hBMSCs impaired the osteogenic differentiation while the downregulation of miR-16-2* increased this process. Upregulation the expression of miR-16-2* could also block the WNT signal pathway by directly target WNT5A. Furthermore, knockdown of miR-16-2* could promote the activation of RUNX2, possibly by lifting the inhibitory effect of miR-16-2* on WNT pathway. CONCLUSION: Taken together, we report a novel biological role of miR 16-2* in osteogenesis through regulating WNT5A response for the first time. Our data support the potential utilization of miRNA-based therapies in regenerative medicine. PMID- 30476908 TI - Therapies for Pain in Parkinson Disease: Concerns Related to a Meta-Analysis on Treating Different Types of Pain as if They Were the Same. PMID- 30476910 TI - Erratum. PMID- 30476909 TI - Multiple Sclerosis Incidence and Prevalence Trends in the Province of Padua, Northeast Italy, 1965-2018. AB - BACKGROUND: Previous studies, dating back to the 1960s disclosed a progressive increase in multiple sclerosis (MS) incidence and prevalence in the Province of Padua. To further analyze whether this trend is the effect of the improved diagnostic procedures or is primarily related to a real increase risk of MS, we analyzed MS incidence and prevalence of the 5-year period 2011-2015. METHODS: Patients with a diagnosis of MS or clinically isolated syndrome highly suggestive of MS were included in the study. All available sources of clinical and administrative information were evaluated. Mean annual incidence in the 5-year period 2011-2015 and the prevalence on December 31, 2015 were calculated. RESULTS: The 2011-2015 mean incidence was 6.5/100,000/year, 7.9 for females, 4.1 for males. The overall prevalence was 182/100,000, 241 for females, 116 for males. Compared to the 2000-2009 period, mean age at onset, onset-diagnosis delay and F/M ratio did not significantly change. Since the 1960s, incidence and prevalence of MS linearly increased with no interposed plateau periods. CONCLUSIONS: MS incidence and prevalence further and significantly increased in the period 2011-2015. Our 1965-2015 data indicate a real increased risk of MS and stress a role of exogenous factors in MS susceptibility. PMID- 30476911 TI - Cognitive Function and Impairment in Older, Rural South African Adults: Evidence from "Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in Rural South Africa". AB - BACKGROUND/AIMS: We aimed to estimate the prevalence of cognitive impairment, and the sociodemographic and comorbid predictors of cognitive function among older, rural South African adults. METHODS: Data were from a population-based study of 5,059 adults aged >=40 years in rural South Africa in 2015. Cognitive impairment was defined as scoring <=1.5 SDs below the mean composite time orientation and memory score, or requiring a proxy interview with "fair" or "poor" proxy-reported memory. Multiple linear regression estimated the sociodemographic and comorbid predictors of cognitive score, with multiplicative statistical interactions between each of age and sex with education. RESULTS: Cognitive impairment increased with age, from 2% of those aged 40-44 (11/516) to 24% of those aged >=75 years (214/899). The independent predictors of lower cognitive score were being older, female, unmarried, not working, having low education, low household wealth, and a history of cardiovascular conditions. Education modified the negative associations between female sex, older age, and cognitive function score. CONCLUSIONS: The prevalence of cognitive impairment increased with age and is comparable to rates of dementia reported in other sub-Saharan African countries. Age and sex differences in cognitive function scores were minimized as education increased, potentially reflecting the power of even poor-quality education to improve cognitive reserve. PMID- 30476912 TI - Decreased TLR3 in Hyperplastic Adipose Tissue, Blood and Inflamed Adipocytes is Related to Metabolic Inflammation. AB - BACKGROUND/AIMS: Obesity is characterized by the immune activation that eventually dampens insulin sensitivity and changes metabolism. This study explores the impact of different inflammatory/ anti-inflammatory paradigms on the expression of toll-like receptors (TLR) found in adipocyte cultures, adipose tissue, and blood. METHODS: We evaluated by real time PCR the impact of acute surgery stress in vivo (adipose tissue) and macrophages (MCM) in vitro (adipocytes). Weight loss was chosen as an anti-inflammatory model, so TLR were analyzed in fat samples collected before and after bariatric surgery-induced weight loss. Associations with inflammatory and metabolic parameters were analyzed in non-obese and obese subjects, in parallel with gene expression measures taken in blood and isolated adipocytes/ stromal-vascular cells (SVC). Treatments with an agonist of TLR3 were conducted in human adipocyte cultures under normal conditions and upon conditions that simulated the chronic low-grade inflammatory state of obesity. RESULTS: Surgery stress raised TLR1 and TLR8 in subcutaneous (SAT), and TLR2 in SAT and visceral (VAT) adipose tissue, while decreasing VAT TLR3 and TLR4. MCM led to increased TLR2 and diminished TLR3, TLR4, and TLR5 expressions in human adipocytes. The anti-inflammatory impact of weight loss was concomitant with decreased TLR1, TLR3, and TLR8 in SAT. Cross sectional associations confirmed increased V/ SAT TLR1 and TLR8, and decreased TLR3 in obese patients, as compared with non-obese subjects. As expected, TLR were predominant in SVC and adipocyte precursor cells, even though expression of all of them but TLR8 (very low levels) was also found in ex vivo isolated and in vitro differentiated adipocytes. Among SVC, CD14+ macrophages showed increased TLR1, TLR2, and TLR7, but decreased TLR3 mRNA. The opposite patterns shown for TLR2 and TLR3 in V/ SAT, SVC, and inflamed adipocytes were observed in blood as well, being TLR3 more likely linked to lymphocyte instead of neutrophil counts. On the other hand, decreased TLR3 in adipocytes challenged with MCM dampened lipogenesis and the inflammatory response to Poly(I:C). CONCLUSION: Functional variations in the expression of TLR found in blood and hypertrophied fat depots, namely decreased TLR3 in lymphocytes and inflamed adipocytes, are linked to metabolic inflammation. PMID- 30476913 TI - Extracellular Matrix Elasticity Regulates Osteocyte Gap Junction Elongation: Involvement of Paxillin in Intracellular Signal Transduction. AB - BACKGROUND/AIMS: Osteocytes can sense and respond to extracellular stimuli, including biochemical factors throughout the cell body, dendritic processes, and cilia bending. However, further exploration is required of osteocyte function in response to substrate stiffness, an important passive mechanical cue at the interface between osteocytes and the extracellular matrix, and the deep bio mechanism in osteocytes involving mechanosensing of cell behavior. METHODS: We fabricated silicon-based elastomer polydimethylsiloxane substrates with different stiffnesses but with the same surface topologies. We then seeded osteocytes onto the substrates to examine their responses. Methodologies used included scanning electron microscopy (SEM) for cell morphology, confocal laser scanning microscopy (CLSM) for protein distribution, western blot for protein levels, co immunoprecipitation for protein interactions, and quantitative real-time polymerase chain reaction for gene expression. RESULTS: SEM images revealed that substrate stiffness induced a change in osteocyte morphology, and CLSM of F-actin staining revealed that substrate stiffness can alter the cytoskeleton. These results were accompanied by changes in focal adhesion capacity in osteocytes, determined via characterization of vinculin expression and distribution. Furthermore, on the exterior of the cell membrane, fibronectin was altered by substrate stiffness. The fibronectin then induced a change in paxillin on the inner membrane of the cell via protein-protein interaction through transmembrane processing. Paxillin led to changes in connexin 43 via protein-protein binding, thereby influencing osteocyte gap junction elongation. CONCLUSION: This process from mechanosensing and mechanotransduction to cell function - not only indicates that the effects of mechanical factors on osteocytes can be directly sensed from the cell body, but also indicates the involvement of paxillin transduction. PMID- 30476915 TI - miR-135a Protects Dextran Sodium Sulfate-Induced Inflammation in Human Colorectal Cell Lines by Activating STAT3 Signal. AB - BACKGROUND/AIMS: miR-135a is reduced in several cancers and has been suggested to mediate immune and inflammatory responses. However, the effect of miR-135a on inflammatory bowel diseases was obscure. This study firstly attempted to investigate the hypothesis that miR-135a alleviates dextran sodium sulfate (DSS) induced inflammation in colonic cells and potential mechanisms are also studied. METHODS: Caco-2 and HT-29 cells in this study were treated with DSS, miR-135a mimic, and S3I-201, and then CKK-8 assay was used to test cell viability. Expressions of miR-135a, cytokines, and signal transducers and activators of transcription factors (STATs) were determined by RT-PCR. Also, cytokine productions were further tested by using ELISA kits. Activation or inactivation of STAT3 signal was validated by western blotting analysis. RESULTS: The results showed that DSS markedly downregulated miR-135a expression (P< 0.05) and induced inflammatory response in Caco-2 and HT-29 cells evidenced by the up regulations and productions of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) (P< 0.05). Transfection with miR-135a mimic significantly alleviated DSS-induced upregulation and productions of IL-1beta and TNF-alpha in Caco-2 and HT-29 cells (P< 0.05). STATs were analyzed and miR-135a mimic treatment reversed STAT3 downregulation in DSS-challenged Caco-2 and HT-29 cells compared with the mimic control (P< 0.05). Also, STAT3 phosphorylation was inhibited in DSS challenged Caco-2 cells and miR-135a mimic activated STAT3 signal (P< 0.05). S3I 201, an inhibitor of STAT3 signal, further used to inactivate STAT3 signal and the results showed that S3I-201 blocked the anti-inflammatory effect of miR-135a mimic on Caco-2 and HT-29 cells evidenced by the lowered expressions and productions of proinflammatory cytokines ((IL-1beta and TNF-alpha) (P< 0.05). CONCLUSION: Our results indicated that miR-135a alleviated DSS-induced inflammation and activated STAT3 signal in colonic cells. Inhibition of STAT3 reversed the anti-inflammatory function of miR-135a by regulating proinflammatory cytokines. Thus, STAT3 signal might serve, at least in part, as the potential mechanism of miR-135a-mediated anti-inflammatory effect in colonic cells. PMID- 30476914 TI - Identification of Potential Biomarkers and Metabolic Profiling of Serum in Ovarian Cancer Patients Using UPLC/Q-TOF MS. AB - BACKGROUND/AIMS: Ovarian cancer (OC) is a malignant neoplasm of the female reproductive system with a high mortality rate. Identifying useful biomarkers and clarifying the molecular pathogenesis of OC are critical for early diagnosis and treatment. The aim of the study was to identify candidate biomarkers and explore metabolic changes of OC. METHODS: A two-stage design was used in our study, with a discovery cohort of OC cases (n = 30) and controls (n = 30) and an independent cohort of cases (n = 17) and controls (n = 18) for validation. The serum metabolic profiling was investigated by ultra-performance liquid chromatography and quadrupole time-of-fight mass spectrometry with positive electrospray ionization. RESULTS: A total of 18 metabolites closely related to OC were identified in the discovery stage, of which 12 were confirmed in the validation cohort. Metabolic pathways in OC related to these biomarkers included fatty acid beta-oxidation, phospholipid metabolism, and bile acid metabolism, which are closely related to the proliferation, invasion, and metastasis of cancer cells. Multiple logistic regression analysis of these metabolites showed that 2 piperidinone and 1-heptadecanoylglycerophosphoethanolamine were potential biomarkers of OC, with high sensitivity (96.7%), specificity (66.7%), and area under the receiver operating characteristic curve value (0.894). CONCLUSION: These findings provide insight into the pathogenesis pathogenesis of OC and may be useful for clinical diagnosis and treatment. PMID- 30476916 TI - Diabetic Nephropathy Can Be Treated with Calcium Dobesilate by Alleviating the Chronic Inflammatory State and Improving Endothelial Cell Function. AB - BACKGROUND/AIMS: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease. However, no effective treatments for this disease are available. Calcium dobesilate (CaD) is widely used to treat diabetic retinopathy. DKD and retinopathy often co-exist and have similar mechanisms of pathogenesis. The aim of the present study was to elucidate the safety and efficacy of CaD in the treatment of DKD. METHODS: In the prospective randomised controlled study, 100 DKD from Type 2 diabetes mellitus (DM) patients with a urinary albumin/ creatinine ratio (ACR) >=30 mg/g and urinary protein level between 150 mg/24 h and 2 g/24 h with GFR> 90ml/min were enrolled. The patients were randomly divided into the treatment group (500 mg of CaD, administered orally, 3 times per day) and the control group. DKD patients were treated for 3 months. In the case control study, DM patients without proteinuria and healthy individuals were also enrolled. Clinical data and related biochemical parameters were collected. Endothelial function markers (VEGF, ET-1, eNOS, NO) and inflammatory markers (MCP 1, ICAM, PTX3) were detected by ELISA. RESULTS: In the prospective randomised controlled study, the 24 h urinary albumin and 24 h urinary protein levels significantly decreased after three months of treatment with CaD in the patients with DKD, but the cystatin C-based glomerular filtration rate (GFR) remained unchanged. In addition, the levels of inflammatory markers (PTX3, MCP-1, hsCRP, ICAM) and endothelial dysfunction markers (VEGF, ET-1) were significantly reduced compared to pre-treatment levels, NO was signifcantly increased post treatment. In the case control study, we found that PTX3, MCP-1, ICAM, VEGF and ET-1 levels were positively correlated with urinary albumin in DKD patients, while the NO level was negatively correlated. Logistic regression analysis showed that PTX3, NO and HbAlc were influential factors in DKD. After patients with DKD were treated with CaD for three months, the 24 h urinary albumin and 24 h urinary protein levels significantly decreased, but the cystatin C-based glomerular filtration rate (GFR) remained unchanged. In addition, the levels of inflammatory markers (PTX3, MCP-1, hsCRP, ICAM) and endothelial dysfunction markers (VEGF, NO, ET-1) were significantly reduced compared to pre-treatment levels. CONCLUSION: CaD can be safely and effectively used to treatdiabetic nephropathy. PMID- 30476917 TI - Nuclear Translocation of Argonaute 2 in Cytokine-Induced Senescence. AB - BACKGROUND/AIMS: Cellular senescence, or permanent growth arrest, is known as an effective tumor suppressor mechanism that can be induced by different stressors, such as oncogenes, chemotherapeutics or cytokine cocktails. Previous studies demonstrated that the growth-repressing state of oncogene-induced senescent cells depends on argonaute protein 2 (Ago2)-mediated transcriptional gene silencing and Ago2/Rb corepression of E2F-dependent cell cycle genes. Cytokine-induced senescence (CIS) likewise depends on activation of the p16Ink4a/Rb pathway, and consecutive inactivation of the E2F family of transcription factors. In the present study, we therefore analyzed the role of Ago2 in CIS. METHODS: Human cancer cell lines were treated with interferon-gamma (IFN-gamma) and tumor necrosis factor (TNF) to induce senescence. Senescence was determined by growth assays and measurement of senescence-associated beta-galactosidase (SA-beta-gal) activity, Ago2 translocation by Ago2/ Ki67 immunofluorescence staining and western blot analysis, and gene transcription by quantitative polymerase chain reaction (qPCR). RESULTS: IFN-gamma and TNF permanently stopped cell proliferation and time-dependently increased SA-beta-gal activity. After 24 - 48 h of cytokine treatment, Ago2 translocated from the cytoplasm into the nucleus of Ki67-negative cells, an effect which was shown to be reversible. Importantly, the proinflammatory cytokine cocktail suppressed Ago2-regulated cell cycle control genes, and siRNA-mediated depletion of Ago2 interfered with cytokine-induced growth inhibition. CONCLUSION: IFN-gamma and TNF induce a stable cell cycle arrest of cancer cells that is accompanied by a fast nuclear Ago2 translocation and repression of Ago2-regulated cell cycle control genes. As Ago2 downregulation impairs cytokine-induced growth regulation, Ago2 may contribute to tissue homeostasis in human cancers. PMID- 30476918 TI - [Langanhaltende Besserung von somatischen und psychovegetativen Storungen unter Procain-Infusionen: Eine multizentrische Anwendungsbeobachtung]. AB - Hintergrund: Procain besitzt wie das strukturverwandte Cocain zentralnervose Wirkungen unabhangig von seinem lokalanasthetischen Effekt. Procain-Infusionen werden Patienten mit psychovegetativen Storungen seit Jahrzehnten verabreicht, zumeist im Rahmen einer Neuraltherapie. Untersuchungen zur Wirksamkeit einer alleinigen Gabe von Procain im Praxisalltag stehen aus. Patienten und Methoden: Im Rahmen einer Anwendungsbeobachtung (AWB) wurde bei 56 Patienten aus 3 Arztpraxen die Wirkung von intravenosen Procain-Infusionen (1-3 Ampullen a 5 ml einer 2%igen Procain-Losung in 250 ml Natriumchlorid pro Arztbesuch) auf das somatische und psychovegetative Befinden dokumentiert. Hierzu wurde ein validierter, 21 Fragen umfassender Befindlichkeitsskalierungsfragebogen verwendet, den die Patienten vor Beginn und nach 1, 2, 4 und 6 Monaten ausfullten. Neben der laufenden Medikation waren keine weiteren therapeutischen Mabetanahmen erlaubt. Ergebnisse: Nach 4 oder 6 Monaten zeigten 42 Patienten (75%) eine Verbesserung bei den 9 positiven Items (d.h. erfragte Eigenschaften) wie "Freude", "Genussfahigkeit" oder "Schlaf"; 35 Patienten (62,5%) verbesserten sich bei den 12 negativen Items wie "Stressbelastung", "Energielosigkeit" oder "Angstlichkeit". Diese Veranderungen waren nach 2, 4 und 6 Monaten signifikant gegenuber dem Ausgangswert. Schlussfolgerungen: Procain ruft im zentralen Nervensystem nachweislich Veranderungen in der Aktivitat spezifischer Kerngebiete wie des limbischen und kortikalen Systems hervor. Die Ergebnisse dieser AWB deuten auf eine langanhaltende Verbesserung von somatischen und psychovegetativen Storungen unter der Infusion von Procain. PMID- 30476919 TI - Global and Regional Trends of Multiple Sclerosis Disability-Adjusted Life Years Rates: A 25-Year Assessment. AB - BACKGROUND: Multiple sclerosis (MS) burden of disease has been described by reporting the disability-adjusted life years (DALY) index. So far, no study has assessed the trend of MS DALY rates over time. METHOD: Age-standardized MS DALY rates for both sexes were reported every 5 years from 1990 to 2015 in 195 countries in the Global Burden of Disease Database (GBD) database. To assess the MS DALY rates' trends in each super region and throughout the world, we applied the Latent Growth Models. We also utilized the linear mixed model to evaluate the effect of development factor on MS DALY rates. RESULTS: Our results showed that 5 out of 7 GBD super regions had negative trends in MS DALY rates during these years and the remaining 2 - Latin America and the Caribbean (slope = 0.196, p < 0.05) and South Asia - slope = 0.057, p > 0.05 - had upward trends. Using a linear mixed model, we found that the mean difference of MS DALY rates was about 25 DALYs higher in developed countries compared to developing ones (p < 0.0001). CONCLUSION: In general, our findings revealed a global downward trend in the MS DALY rate. We also conclude that MS DALY rates are decreasing both in developed and developing countries, with a steeper slope in the developed world. PMID- 30476920 TI - Advances in Bone Marrow Diagnostics of Patients with Cytopenia. PMID- 30476921 TI - Sex Differences in the Prevalence of and Risk Factors for Cognitive Impairment No Dementia among the Elderly in a Rural Area of Northern China: A Population-Based Cross-Sectional Study. AB - BACKGROUND/AIMS: The burden of dementia among women in China, especially among women from rural areas, has increased due to their longevity and lower education levels compared with that among men. Thus, we aimed to assess sex differences in the prevalence of cognitive impairment and its relevant determinants among rural residents in North China. METHODS: Adults aged 60 years and older with cognitive impairment no dementia (CIND) were recruited to this study. Demographic characteristics, traditional risk factors, and lifestyle characteristics were obtained and analyzed on the basis of sex. RESULTS: There were 1,295 individuals with CIND (489 [37.8%] men and 806 [62.2%] women). The prevalence of CIND was 23.3% overall (19.8% for men, 26.1% for women; p < 0.001). Age, education level, history of stroke, and social activity were significantly associated with CIND for both men and women. Widowed status compared to married status was an independent risk factor for CIND in men (OR [95% CI] 1.50 [1.14-1.98]; p = 0.004). CONCLUSION: These findings suggest that it is crucial to address the secondary prevention of stroke and to consider the psychological status among the elderly with low educational attainment in order to reduce the burden of CIND in China. PMID- 30476923 TI - The Global Burden of Disease Brain Summit, Auckland 2018. PMID- 30476922 TI - Ascertainment of Dementia Cases in the Spanish European Prospective Investigation into Cancer and Nutrition-Murcia Cohort. AB - BACKGROUND: Cohort studies generally focus on a particular disease, although they offer the possibility of evaluating different outcomes with minimal additional investment. The objective of this study was to describe the methodology used to assess dementia in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Murcia study. METHODS: The EPIC-Murcia cohort consists of 8,515 healthy participants (68% women, aged 30-70 years), recruited between 1992 and 1996 and followed up for over 20 years. Incident cases were ascertained by a 2 step protocol: a record linkage with health databases to identify potential events and a review of medical records of potential cases to validate incident cases. RESULTS: Overall, 1,202 potential cases were identified, and 275 dementia cases were validated. Medical reports were the source of information in 243 cases, with complete neurological information in 227, and a high degree of certainty of the diagnosis in 229 cases. P70 (dementia code) and/or antidementia drugs and/or ICD codes identified 259 cases (sensitivity: 94.2%, 95% CI 90.7 96.6; specificity: 98.1%, 95% CI 97.8-98.4). CONCLUSION: Ascertainment of incident dementia in the EPIC-Murcia cohort study was feasible using information from medical records. This systematic 2-step validation protocol is proposed as a feasible way to ascertain dementia in cohort studies originally designed for other endpoints. PMID- 30476924 TI - Tumor-Infiltrating Podoplanin+ Fibroblasts Predict Worse Outcome in Solid Tumors. AB - BACKGROUND/AIMS: Tumor-infiltrating fibroblasts are a heterogeneous population, and different subpopulations play differential roles in tumor microenvironment. However, the prognostic role of podoplanin+ fibroblasts in human solid tumors still remains controversial. Therefore, we performed the meta-analysis to better understand the role of this subpopulation in prognosis prediction for patients with solid tumor. METHODS: We searched PubMed and EBSCO to identify the studies evaluating the association of intratumoral podoplanin+ fibroblast density detected by immunohistochemical method and overall survival (OS) and/or disease free survival (DFS) in patients with solid tumor, then computed extracted data into hazard ratios for OS, DFS and clinicopathological features with STATA 12.0. RESULTS: A total of 4883 patients from 29 published studies were incorporated into this meta-analysis. We found that podoplanin+ fibroblast infiltration significantly decreased OS and DFS in all types of solid tumors. In stratified analyses, podoplanin+ fibroblast infiltration was significantly associated with worse OS in cholangiocarcinoma, breast, lung and pancreatic cancer. And these cells were inversely associated with DFS in breast, lung and pancreatic cancer. In addition, high density of these cells significantly correlated with unfavorable clinicopathological features such as lymph node metastasis, TNM stage, lymphatic and vascular invasion of solid tumor. CONCLUSION: Podoplanin+ fibroblast infiltration leads to worse clinical outcome in solid tumors, implicating that it is a valuable prognostic biomarker and targeting it may have a potential for effective treatment. PMID- 30476925 TI - The Clinicopathological Significance and Correlative Signaling Pathways of an Autophagy-Related Gene, Ambra1, in Breast Cancer: a Study of 25 Microarray RNA Seq Datasets and in-House Gene Silencing. AB - BACKGROUND/AIMS: The activating molecule in Beclin1-regulated autophagy (Ambra1) has been observed to be over-expressed in several cancers, but the clinical contribution of Ambra1 in breast cancer (BC) remains unknown. Hence, in this study, we conducted a comprehensive investigation into the expression, biological role, and underlying functional mechanism of Ambra1 in BC. METHODS: Microarray and RNA-seq datasets providing Ambra1 expression data were obtained from Gene Expression Omnibus (GEO), ArrayExpress, Oncomine, and The Cancer Genome Atlas (TCGA). Both standard mean deviation (SMD) and summary receiver operating characteristic methods were employed to assess Ambra1 expression in BC. We then silenced Ambra1 in MDA-MB-231 cells and performed in vitro experiments to explore the biological effects of Ambra1 on BC cells. Furthermore, differentially expressed genes (DEGs) after Ambra1 knock-down were profiled with a microarray and overlapped with the genes correlated with Ambra1 from Multi Experiment Matrix (MEM) and genes similar to Ambra1 from Gene Expression Profiling Interactive Analysis. These overlapping genes were collected for further bioinformatics analyses to investigate the underlying molecular mechanism of Ambra1 in BC. RESULTS: A total of 25 microarray and RNA-seq datasets involving 2460 breast cancer samples were included. The pooled results demonstrated that Ambra1 was markedly up-regulated in BC tissues (SMD=0.39, 95% CI=0.15-0.63; P=0.002), and the Ambra1 level was also significantly related to the progression of BC, especially metastasis status (P=0.004). In vitro experiments suggested that the proliferation of MDA-MB-231 cells transfected with Ambra1 short hairpin RNA (sh RNA 2450) showed a decreasing trend at 48 h compared with the control (CK) group. However, apoptosis was similar in cells transfected with Ambra1 sh-RNAs and in the CK cells. Furthermore, we performed a microarray-based comparison of genes after Ambra1 knock-down. The 828 DEGs from microarray analysis were intersected with 4266 Ambra1 co-expressed genes from MEM. Eventually, the overlapped 183 genes were found to be enriched in several well-known cancer-related pathways, including the MAPK signaling pathway, chronic myeloid leukemia pathway, and VEGF signaling pathway. CONCLUSION: These results indicate that the level of Ambra1 up regulation is clearly related to tumorigenesis and progression of BC, probably via influencing several vital pathways. However, this hypothesis needs to be validated with more in-depth experiments in the future. PMID- 30476926 TI - Medical History and Multiple Sclerosis: A Population-Based Incident Case-Control Study. AB - BACKGROUND: Consistent evidence regarding the potential role of medical history in multiple sclerosis (MS) etiology is lacking. OBJECTIVE: The association of medical history variables, that is, head injury and 9 autoimmune diseases with MS onset was investigated. METHODS: This was a population-based incident case control study in Iran with 547 incident cases and 1,057 general population controls (August 7, 2013 - February 17, 2015). Multiple logistic regression models were used for estimating the adjusted ORs. RESULTS: Lifetime history of head trauma was not significantly associated with risk of MS after adjustment for well-known confounders (OR 1.24 [0.93-1.66, p = 0.14]). Similarly, there was no statistically significant association between cumulative numbers of head injury and MS (OR 1.02 [0.90-1.15, p = 0.79]). A history of autoimmune disease did not increase the risk of MS (p > 0.1). Similarly, the cumulative number of autoimmune diseases is not significantly associated with the risk of MS (p > 0.70). CONCLUSION: Lifetime histories of head trauma as well as 9 investigated autoimmune diseases are not associated with increased risk of MS. PMID- 30476927 TI - Saccular Intracranial Aneurysms in Children When Both Parents Are Sporadic or Familial Carriers of Saccular Intracranial Aneurysms. AB - BACKGROUND AND PURPOSE: To study the penetrance of saccular intracranial aneurysm (IA) disease in children when both parents carry the disease. PATIENTS AND METHODS: The Kuopio IA Patient and Family Database includes all 4,411 IA patients admitted to the Kuopio University Hospital from its defined Eastern Finnish catchment population since 1980. We fused IA database with hospital diagnoses for IA patients and their 46,021 relatives from a national registry to identify couples concordant for IA disease. Penetrance of IA disease and hypertension were studied in these families. RESULTS: A total of 3,659 IA patients had 1 or more children. In total, 18 couples concordant for the IA disease with a total of 48 children, all born healthy, were identified. Hypertension was diagnosed in 23 (64%) of the 36 parents, and 7 of the 12 sporadic-sporadic couples were concordant for hypertension. Six sporadic-sporadic couples were concordant for subarachnoid haemorrhage (SAH). None of the 24 children to the 12 sporadic sporadic couples had been diagnosed with SAH or IA disease. Instead, 11 (46%) of the 24 children to the 6 familial-sporadic couples had a diagnosed with SAH or IA disease. CONCLUSIONS: Couples concordant for IA disease are uncommon but not exceedingly rare. Biparental sporadic exposure does not seem to increase the risk of a clinically diagnosed IA disease or SAH in the offspring. IAs were common in the children with biparental sporadic-familial exposure. PMID- 30476929 TI - Nucleolar and Spindle Associated Protein 1 (NUSAP1) Inhibits Cell Proliferation and Enhances Susceptibility to Epirubicin In Invasive Breast Cancer Cells by Regulating Cyclin D Kinase (CDK1) and DLGAP5 Expression. AB - BACKGROUND Differentially expressed genes (DEGs) of IBC were selected from the Gene Expression Omnibus (GEO) chip data: GSE21422 and GSE21974. Network analysis of the DEGs and IBC-related genes was performed in STRING database to find the core gene. Thus, this study aimed to determine the role of NUSAP1 in invasive breast cancer (IBC) and to investigate its effect on drug susceptibility to epirubicin (E-ADM). MATERIAL AND METHODS The mRNA expression of NUSAP1 was determined by quantitative polymerase chain reaction (q-PCR). The protein expression was detected by Western blotting. Cell growth and growth cycle were detected by MTT assay and flow cytometry, respectively. Cell migration and invasion were tested by Transwell assay. RESULTS Through use of gene network analysis, we found that NUSAP1 interacts with IBC-related genes. NUSAP1 presented high expression in IBC tissue samples and MCF-7 cells. NUSAP1 overexpression promoted the growth, migration, and invasion of MCF-7 cells. While NUSAP1 gene silencing downregulated the expression of genes associated with cell cycle progression in G2/M phase, cyclin D kinase (CDK1) and DLGAP5 arrested cells in G2/M phase and significantly inhibited the growth, migration, and invasion of MCF 7 cells. si-NUSAP1 increased the susceptibility of MCF-7 cells to E-ADM-induced apoptosis. CONCLUSIONS Our study provides evidence that downregulation of NUSAP1 can inhibit the proliferation, migration, and invasion of IBC cells by regulating CDK1 and DLGAP5 expression and enhances the drug susceptibility to E-ADM. PMID- 30476928 TI - Molecular Epidemiology of ALK Rearrangements in Advanced Lung Adenocarcinoma in Latin America. AB - OBJECTIVE: Latin American countries are heterogeneous in terms of lung cancer incidence and exposure to potential carcinogens. We evaluated the frequency and clinical characteristics of ALK rearrangements (ALKr) in Latin America. METHODS: A total of 5,130 lung cancer patients from 10 Latin American countries were screened for inclusion. ALKr detection was performed by fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) to assess method variability. Demographic and clinicopathologic characteristics were analyzed. RESULTS: Among the 5,130 patients screened, 8.4% (n = 433) had nonevaluable FISH tests. Evaluable FISH analyses revealed positive ALKr in 6.8% (320/4,697) of the study population, which included patients from 9 countries. ALKr distribution for each country was: Mexico 7.6% (79/1,034), Colombia 4.1% (10/242), Argentina 6.0% (153/2,534), Costa Rica 9.5% (13/137), Panama 4.4% (5/114), Uruguay 5.4% (2/37), Chile 8.6% (16/185), Venezuela 8.9% (13/146), and Peru 10.8% (29/268). RT-PCR showed high positive (83.6%) and negative (99.7%) predictive values when compared to the gold standard FISH. In contrast, IHC only showed a high negative predictive value (94.6%). CONCLUSIONS: Although there is a clear country and continental variability in terms of ALKr frequency, this difference is not significant and the overall incidence of ALKr in Latin America does not differ from the rest of the world. PMID- 30476931 TI - Errors in Legend of Figure 3. PMID- 30476930 TI - Clinical features of 2041 human brucellosis cases in China. AB - BACKGROUND: Human brucellosis has become a major public health problem in China. However, the available clinical data on brucellosis cases are limited. METHODS: We retrospectively reviewed medical charts of 2041 patients with confirmed human brucellosis and prospectively recorded their outcomes by telephone interview. These patients were admitted to the Sixth People's Hospital of the Xinjiang Uygur Autonomous region between 1st January and 31st December 2014. Data on these patients were collected from hospital medical records. RESULTS: Many patients presented with fatigue (67%), fever (64%), arthralgia (63%) and sweating (54%). High erythrocyte sedimentation rate (ESR) (69%), high C-reactive protein (CRP) (39%), high alanine aminotransferase (ALT) (33%) and high aspartate aminotransferase (AST) (20%) were the most common laboratory findings, especially in acute patients. There was evidence of focal involvement in 90% of patients. A total of 61.5% of brucellosis patients recovered. Multivariate logistic regression analyses suggested that the risk factors key to unfavorable prognosis were: age>=45 years (OR = 1.75, 95% CI 1.36-2.24), back pain (OR = 1.50, 95% CI 1.16-1.94) and joint tenderness (OR = 1.73, 95% CI 1.13-2.65). The increasing duration of the illness increased the risk of poor prognosis. CONCLUSION: Patients with brucellosis showed different characteristics in different clinical stages. In China, the chronicity rate of human brucellosis is high. The risk of poor prognosis is increased in patients aged 45 years or older, patients who have had brucellosis for a substantial period of time, and patients with back pain or joint tenderness. The clinical management of brucellosis should be improved to include sensitive diagnostic methods for subacute and chronic brucellosis. PMID- 30476933 TI - More Evidence to Help Guide Decision Making About Aspirin for Primary Prevention. PMID- 30476932 TI - Bilateral Sequential Acute Proptosis in a Woman With No History of Trauma. PMID- 30476934 TI - Association of Comorbid Serious Mental Illness Diagnosis With 30-Day Medical and Surgical Readmissions. PMID- 30476935 TI - What Coats Disease and Age-Related Macular Degeneration Have in Common. PMID- 30476937 TI - Is Mesh Prophylaxis the Answer to the Prevention of Incisional Hernia? PMID- 30476936 TI - The Burden of Candidate Pathogenic Variants for Kidney and Genitourinary Disorders Emerging From Exome Sequencing. AB - Background: Exome sequencing is increasingly being used for clinical diagnostics, with an impetus to expand reporting of incidental findings across a wide range of disorders. Analysis of population cohorts can help reduce risk for genetic variant misclassification and resultant unnecessary referrals to subspecialists. Objective: To examine the burden of candidate pathogenic variants for kidney and genitourinary disorders emerging from exome sequencing. Design: Secondary analysis of genetic data. Setting: A tertiary care academic medical center. Patients: A convenience sample of exome sequence data from 7974 self-declared healthy adults. Measurements: Assessment of the prevalence of candidate pathogenic variants in 625 genes associated with Mendelian kidney and genitourinary disorders. Results: Of all participants, 23.3% carried a candidate pathogenic variant, the majority of which were attributable to previously reported variants that have implausibly high allele frequencies. In particular, 25 genes (discovered before the creation of the Exome Aggregation Consortium, a genetic database comprising data from a large control population) accounted for 67.7% of persons with candidate pathogenic variants. After stringent filtering based on allele frequency, 1.4% of persons still had a candidate pathogenic variant, an excessive rate given the prevalence of monogenic kidney and genitourinary disorders. Manual annotation of a subset of variants showed that the majority would be classified as nonbenign under current guidelines for clinical sequence interpretation and could prompt subspecialty referrals if returned. Limitation: Limited access to health record data prevented comprehensive assessment of the phenotypic concordance with genetic diagnoses. Conclusion: Widespread reporting of incidental genetic findings related to kidney and genitourinary disorders will require stringent curation of clinical variant databases and detailed case-level review to avoid genetic misdiagnosis and unnecessary referrals. These findings motivate similar analyses for genes relevant to other medical subspecialties. Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases and National Human Genome Research Institute. PMID- 30476938 TI - Metastatic Calcinosis Cutis Associated With a Selective FGFR Inhibitor. PMID- 30476939 TI - A Rare Case of a Nasopharyngeal Mass. PMID- 30476940 TI - Effectiveness of Prophylactic Intraperitoneal Mesh Implantation for Prevention of Incisional Hernia in Patients Undergoing Open Abdominal Surgery: A Randomized Clinical Trial. AB - Importance: Incisional hernia is a frequent complication after open abdominal surgery. Prophylactic mesh implantation in the onlay or sublay position requires dissection of the abdominal wall, potentially leading to wound-associated complications. Objective: To compare the incidence of incisional hernia among patients after prophylactic intraperitoneal mesh implantation with that among patients after standard abdominal closure. Design, Setting, and Participants: An open-label randomized clinical trial was performed in 169 patients undergoing elective open abdominal surgery from January 1, 2011, to February 29, 2014. Follow-up examinations were performed 1 year and 3 years after surgery. The study was conducted at Bern University Hospital, Bern, Switzerland, a referral center that offers the whole spectrum of abdominal surgical interventions. Patients with 2 or more of the following risk factors were included: overweight or obesity, diagnosis of neoplastic disease, male sex, or history of previous laparotomy. Patients were randomly assigned to prophylactic intraperitoneal mesh implantation or standard abdominal closure. Data were analyzed in August 2017. Interventions: Intraperitoneal implantation of a polypropylene-polyvinylidene fluoride mesh with circumferential fixation. Main Outcomes and Measures: The primary end point was the incidence of incisional hernia 3 years after surgery. Secondary end points included mesh-related complications. Results: After the exclusion of 19 patients, 150 patients (81 in the control group and 69 in the mesh group; mean [SD] age, 64.2 [11.1] years; 102 [68.0%] male) were studied. The cumulative incidence of incisional hernia was significantly lower in the mesh group compared with the control group (5 of 69 [7.2%] vs 15 of 81 [18.5%], log-rank test P = .03). Abdominal pain was observed in significantly more patients in the mesh group compared with the control group at 6 weeks (34 of 52 [65%] vs 26 of 59 [44%], P = .04) but not at 12 and 36 months postoperatively. No difference in surgical site infections was observed, but time to complete wound healing of surgical site infection was significantly longer in patients with mesh implantation (median [interquartile range], 8 [6-24] weeks compared with 5 [1-9] weeks; P = .03). Trunk extension was significantly decreased after mesh implantation compared with the control group (mean [SD], 1.73 [0.97] cm vs 2.40 [1.23] cm, P = .009). Conclusions and Relevance: In patients at elevated risk for incisional hernia, prophylactic intraperitoneal mesh implantation reduces the incidence of hernia formation but with increased early postoperative pain and prolonged wound healing of surgical site infection. Trial Registration: ClinicalTrials.gov Identifier: NCT01203553. PMID- 30476941 TI - Assessment of Duration of Facial Plastic Ambulatory Surgery and Risk of Complications: A Systematic Review. PMID- 30476942 TI - World Health Organization Baby-Friendly Hospital Initiative Guideline and 2018 Implementation Guidance. PMID- 30476943 TI - Body Composition and Overall Survival in Patients With Nonmetastatic Breast Cancer. PMID- 30476944 TI - Professionalism, Performance, and the Future of Physician Incentives. PMID- 30476945 TI - Risk of Suicide After Cancer Diagnosis in England. AB - Importance: A diagnosis of cancer carries a substantial risk of psychological distress. There has not yet been a national population-based study in England of the risk of suicide after cancer diagnosis. Objectives: To quantify suicide risk in patients with cancers in England and identify risk factors that may assist in needs-based psychological assessment. Design, Setting, and Participants: Population-based study using data from the National Cancer Registration and Analysis Service in England linked to death certification data of 4 722 099 individuals (22 million person-years at risk). Patients (aged 18-99 years) with cancer diagnosed from January 1, 1995, to December 31, 2015, with follow-up until August 31, 2017, were included. Exposures: Diagnosis of malignant tumors, excluding nonmelanoma skin cancer. Main Outcomes and Measures: All deaths in patients that received a verdict of suicide or an open verdict at the inquest. Standardized mortality ratios (SMRs) and absolute excess risks (AERs) were calculated. Results: Of the 4 722 099 patients with cancer, 50.3% were men and 49.7% were women. A total of 3 509 392 patients in the cohort (74.3%) were aged 60 years or older when the diagnosis was made. A total of 2491 patients (1719 men and 772 women) with cancer died by suicide, representing 0.08% of all deaths during the follow-up period. The overall SMR for suicide was 1.20 (95% CI, 1.16 1.25) and the AER per 10 000 person-years was 0.19 (95% CI, 0.15-0.23). The risk was highest among patients with mesothelioma, with a 4.51-fold risk corresponding to 4.20 extra deaths per 10 000 person-years. This risk was followed by pancreatic (3.89-fold), esophageal (2.65-fold), lung (2.57-fold), and stomach (2.20-fold) cancer. Suicide risk was highest in the first 6 months following cancer diagnosis (SMR, 2.74; 95% CI, 2.52-2.98). Conclusions and Relevance: Despite low absolute numbers, the elevated risk of suicide in patients with certain cancers is a concern, representing potentially preventable deaths. The increased risk in the first 6 months after diagnosis may indicate an unmet need for psychological support. The findings of this study suggest a need for improved psychological support for all patients with cancer, and attention to modifiable risk factors, such as pain, particularly in specific cancer groups. PMID- 30476946 TI - Comparison of Optical Coherence Tomography With Fundus Photographs, Fluorescein Angiography, and Histopathologic Analysis in Assessing Coats Disease. AB - Importance: Coats disease is a rare pediatric vitreoretinopathy that can cause devastating visual and anatomic outcomes. Objective: To compare optical coherence tomography (OCT) with fundus photographs, fluorescein angiography (FA), and histopathologic findings in Coats disease. Design, Setting, and Participants: This retrospective cohort study was conducted in a single tertiary institution (Duke Eye Center) and identified 28 children with Coats disease through a review of medical records from December 2002 to January 2018. Four eyes were obtained from a biorepository for histopathologic analysis. Main Outcomes and Measures: Macular OCT, fundus photographs, and FA results were reviewed and compared for morphological changes. These were compared with retinal histopathological findings. Results: The mean (SD) age was 9.5 (5.5) years for the 28 children (and 29 eyes) with clinical imaging results, and 24 (86%) were boys. A comparison between imaging modalities revealed OCT features that were not visible in photographs or FA, including exudates in multiple retinal layers (23 [82.1%]), small pockets of subretinal fluid (4 [14.3%]), an outer retinal atrophy overlying fibrotic nodules (7 [25.0%]), and small preretinal hyperreflective OCT dots (25 [89.3%]). Next, a comparison with light micrographs introduced an association of OCT findings with possible pathological features, including hyperreflective linear structures on OCT that appeared consistent with cholesterol crystals, small hyperreflective dots with macrophages, outer retinal tubulations with rosettes, and analogous OCT histopathology features such as intraretinal vessels entering fibrotic nodules and retinal pigment epithelium excrescences under the subretinal fluid. An OCT analysis revealed intraretinal cystoid spaces in 19 eyes, but in 9 of 19 (47.4) this was not associated with cystoid macular leakage; rather, fluorescein leakage was observed from peripheral telangiectatic vessels. Additionally, exudates were intraretinal only (6 [21.4%]) or both intraretinal and subretinal (17 [60.7%]); none were subretinal only. In eyes with follow-up results, new fibrosis developed in 8 of 17 eyes (47.1%). Fibrosis developed in 5 of 5 eyes (100%) with baseline subretinal fluid vs 3 of 12 without (25%; 95% CI, 22%-92%) and in 7 of 9 eyes (77.8%) with subretinal exudates vs 1 of 8 (12.5%) without (95% CI, 16%-89%). Conclusions and Relevance: Optical coherence tomography may show the transient and permanent effects of Coats disease on the retina. These results suggest that exudates and fluid in the macular subretinal space appear later in the disease and may result in fibrosis formation. Further studies are needed to confirm if early treatment could prevent vision-threatening macular fibrosis. PMID- 30476947 TI - Revealing the Effects of Zika-Detection of Brain Abnormalities and Other Disabilities Associated With Congenital Infection. PMID- 30476949 TI - Circulating Tumor Cells and Radiotherapy Benefit in Early Breast Cancer-Reply. PMID- 30476948 TI - Association of Timing of Colostomy Reversal With Outcomes Following Hartmann Procedure for Diverticulitis. AB - Importance: The Hartmann procedure (end colostomy) remains a common operation for diverticulitis requiring surgery. However, the timing of subsequent colostomy reversal remains widely varied, and the optimal timing remains unknown. Objective: To investigate the association of the timing of colostomy reversal with operative outcomes. Design, Setting, and Participants: This retrospective analysis of the Healthcare Cost and Utilization Project State Inpatient Databases for California, Florida and Maryland included patients with colostomy for diverticulitis linked to their colostomy reversal. Patients with readmissions between the index surgery and reversal were excluded, leaving a final cohort of 1660 patients. Data were collected from January 1, 2010, to December 31, 2016, and analyzed from December 1, 2017, through May 31, 2018. Exposures: Patients were divided based on timing of colostomy reversal following the index surgery into early (45-110 days), middle (111-169 days), and late (>=170 days) reversal timing. Main Outcomes and Measures: Primary outcomes of interest after reversal included mortality, morbidity, and readmissions and were compared among all groups using logistic regression adjusted for comorbidities and age. Results: In total, 7165 patients with at least 1 year of follow-up were identified, and 2028 (28.3%) underwent reversal within 1 year. Of patients who underwent reversal within 1 year, 1660 had no readmissions before reversal (860 men [51.8%]; median age, 61 years [interquartile range {IQR}, 51-70 years]). The median time to reversal was 129 days (IQR, 99-182 days). On multivariable analysis, patient characteristics associated with early reversal included being 60 years or younger (odds ratio [OR], 1.31; 95% CI, 1.00-1.70; P = .0497), white race (OR, 1.32; 95% CI, 1.05-1.67; P = .02), and private insurance vs Medicaid (OR, 2.45; 95% CI, 1.67-3.60; P < .001). Mortality, transfusion, ileus, and major complications were not significantly different among the reversal timing groups. However, prolonged length of stay (OR, 1.62; 95% CI, 1.19-2.21; P = .002) and 90-day readmissions (OR, 1.61; 95% CI, 1.18-2.22; P = .003) were significantly more likely in the late vs early timing groups. Conclusions and Relevance: Less than one-third of patients undergo colostomy reversal within 1 year after end colostomy for diverticulitis, and reversal timing is associated with socioeconomic disparities. In selected patients with an uncomplicated course, improved outcomes are associated with earlier reversal, and colostomy reversal is safe as early as 45 to 110 days after the initial procedure. PMID- 30476950 TI - Association of Transcatheter Mitral Valve Repair With Quality of Life Outcomes at 30 Days and 1 Year: Analysis of the Transcatheter Valve Therapy Registry. AB - Importance: Improvements in symptoms, functional capacity, and quality of life are among the key goals of edge-to-edge transcatheter mitral valve repair (TMVR) for mitral regurgitation. Objective: To examine health status outcomes among patients undergoing TMVR in clinical practice and the factors associated with improvement. Design, Setting, and Participants: This cohort study used the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry, which contains data on patients with severe mitral regurgitation treated with TMVR from 2013 through 2017 in 217 US hospitals. Main Outcomes and Measures: Change in disease-specific health status (Kansas City Cardiomyopathy Questionnaire-Overall Summary score [KCCQ-OS]; range 0-100 points, with higher scores indicating better health status) at 30 days and 1 year after TMVR. We also examined factors associated with health status at 30 days after TMVR, by means of multivariable linear regression using a generalized estimating equations approach to account for clustering of patients within sites. Results: The KCCQ data were available in 81.2% at baseline, 69.3% of survivors at 30 days, and 47.4% of survivors at 1 year. Among 4226 patients who underwent TMVR, survived 30 days, and completed the KCCQ at baseline and follow-up, the KCCQ-OS increased from 41.9 before TMVR to 66.7 at 30 days (mean change 24.8 [95% CI, 24.0-25.6] points; P < .001), representing a large clinical improvement. The KCCQ scores remained stable from 30 days to 1 year after TMVR, with no further significant increase or decline. On multivariable analysis, atrial fibrillation ( 2.2 [95% CI, -3.7 to -0.6] points; P = .01), permanent pacemaker (-2.1 [95% CI, 3.7 to -0.4] points; P = .01), severe lung disease (-3.9 [95% CI, -6.2 to -1.5] points; P = .001), home oxygen (-2.7 [95% CI, -4.9 to -0.4] points; P = .02), and lower KCCQ scores at baseline (3.9 points for each 10-point increase [95% CI, 3.6 4.2]; P < .001) were independently associated with lower 30-day KCCQ-OS scores. In-hospital renal failure was uncommon but was also associated with significant reductions in 30-day KCCQ-OS scores (-7.3 [95% CI -13.3 to -1.2] points). In estimates calculated with inverse probability weighting, after 1 year after TMVR, 54.2% (95% CI 52.2%-56.1%) of patients were alive and well; 23.0% had died, 21.9% had persistently poor health status (KCCQ-OS <60 points), 5.5% had a health status decline from baseline, and 4.6% had both poor health status and health status decline. Conclusions and Relevance: In a national cohort of US patients undergoing edge-to-edge TMVR in clinical practice, health status was impaired prior to the procedure, improved within 30 days, and remained stable through 1 year among surviving patients with available data. While long-term mortality remains high, most surviving patients demonstrate improvements in symptoms, functional status, and quality of life, with only modest differences by patient level factors. PMID- 30476951 TI - Association of Team-Based Primary Care With Health Care Utilization and Costs Among Chronically Ill Patients. AB - Importance: Empirical study findings to date are mixed on the association between team-based primary care initiatives and health care use and costs for Medicaid and commercially insured patients, especially those with multiple chronic conditions. Objective: To evaluate the association of establishing team-based primary care with patient health care use and costs. Design, Setting, and Participants: We used difference-in-differences to compare preutilization and postutilization rates between intervention and comparison practices with inverse probability weighting to balance observable differences. We fit a linear model using generalized estimating equations to adjust for clustering at 18 academically affiliated primary care practices in the Boston, Massachusetts, area between 2011 and 2015. The study included 83 953 patients accounting for 138 113 patient-years across 18 intervention practices and 238 455 patients accounting for 401 573 patient-years across 76 comparison practices. Data were analyzed between April and August 2018. Exposures: Practices participated in a 4-year learning collaborative that created and supported team-based primary care. Main Outcomes and Measures: Outpatient visits, hospitalizations, emergency department visits, ambulatory care-sensitive hospitalizations, ambulatory care-sensitive emergency department visits, and total costs of care. Results: Of 322 408 participants, 176 259 (54.7%) were female; 64 030 (19.9%) were younger than 18 years and 258 378 (80.1%) were age 19 to 64 years. Intervention practices had fewer participants, with 2 or more chronic conditions (n = 51 155 [37.0%] vs n = 186 954 [46.6%]), more participants younger than 18 years (n = 337 931 [27.5%] vs n = 74 691 [18.6%]), higher Medicaid enrollment (n = 39 541 [28.6%] vs n = 81 417 [20.3%]), and similar sex distributions (75 023 women [54.4%] vs 220 097 women [54.8%]); however, after inverse probability weighting, observable patient characteristics were well balanced. Intervention practices had higher utilization in the preperiod. Patients in intervention practices experienced a 7.4% increase in annual outpatient visits relative to baseline (95% CI, 3.5%-11.3%; P < .001) after adjusting for patient age, sex, comorbidity, zip code level sociodemographic characteristics, clinician characteristics, and plan fixed effects. In a subsample of patients with 2 or more chronic conditions, there was a statistically significant 18.6% reduction in hospitalizations (95% CI, 1.5% 33.0%; P = .03), 25.2% reduction in emergency department visits (95% CI, 6.6% 44.0%; P = .007), and a 36.7% reduction in ambulatory care-sensitive emergency department visits (95% CI, 9.2%-64.0%; P = .009). Among patients with less than 2 comorbidities, there was an increase in outpatient visits (9.2%; 95% CI, 5.10% 13.10%; P < .001), hospitalizations (36.2%; 95% CI, 12.2-566.6; P = .003), and ambulatory care-sensitive hospitalizations (50.6%; 95% CI, 7.1%-329.2%; P = .02). Conclusions and Relevance: While establishing team-based care was not associated with differences in the full patient sample, there were substantial reductions in utilization among a subset of chronically ill patients. Team-based care practice transformation in primary care settings may be a valuable tool in improving the care of sicker patients, thereby reducing avoidable use; however, it may lead to greater use among healthier patients. PMID- 30476952 TI - Characterizing High-Performing Articles by Altmetric Score in Major Cardiovascular Journals. PMID- 30476953 TI - Routine Inpatient Mobility Assessment and Hospital Discharge Planning. PMID- 30476954 TI - alpha-Gal Syndrome vs Chronic Urticaria. PMID- 30476955 TI - Emerging Role of Combination Immunotherapy in the First-line Treatment of Advanced Renal Cell Carcinoma: A Review. AB - Importance: Novel immunotherapies, notably the immune checkpoint inhibitors, have been shown to be efficacious in patients with advanced renal cell carcinoma, but innate or adaptive resistance is observed with single-agent immunotherapy. New combination treatment strategies are needed that can improve efficacy in a broader patient population, without exacerbating the toxic effects. Observations: Numerous late-phase trials are ongoing to investigate (1) dual immune checkpoint inhibition or (2) combined inhibition of immune checkpoints and vascular endothelial growth factor. Initial results from studies of the nivolumab plus ipilimumab and atezolizumab plus bevacizumab combinations have demonstrated efficacy compared with sunitinib malate in treatment-naive patients with advanced renal cell carcinoma; moreover, the safety profile of these combinations compare favorably with sunitinib. Nevertheless, immune checkpoint inhibition is associated with unique immune-related adverse events, and practicing physicians must be educated on how to best identify and manage these events. Conclusions and Relevance: Evidence suggests that immunotherapy-based combination regimens will be an important addition to the treatment of advanced renal cell carcinoma in both the first- and later-line setting; however, clinical study data and clinical practice experience indicate that optimizing the management of the associated immune-related adverse events is essential to maximizing the advantages of these therapies. PMID- 30476958 TI - Anatomy and Physiology of Primary Care Teams. PMID- 30476957 TI - Association of Mild to Moderate Aortic Valve Stenosis Progression With Higher Lipoprotein(a) and Oxidized Phospholipid Levels: Secondary Analysis of a Randomized Clinical Trial. AB - Importance: Several studies have reported an association of levels of lipoprotein(a) (Lp[a]) and the content of oxidized phospholipids on apolipoprotein B (OxPL-apoB) and apolipoprotein(a) (OxPL-apo[a]) with faster calcific aortic valve stenosis (CAVS) progression. However, whether this association is threshold or linear remains unclear. Objective: To determine whether the plasma levels of Lp(a), OxPL-apoB, and OxPL-apo(a) have a linear association with a faster rate of CAVS progression. Design, Setting, and Participants: This secondary analysis of a randomized clinical trial tested the association of baseline plasma levels of Lp(a), OxPL-apoB, and OxPL-apo(a) with the rate of CAVS progression. Participants were included from the ASTRONOMER (Effects of Rosuvastatin on Aortic Stenosis Progression) trial, a multicenter study conducted in 23 Canadian sites designed to test the effect of statin therapy (median follow-up, 3.5 years [interquartile range, 2.9-4.5 years]). Patients with mild to moderate CAVS defined by peak aortic jet velocity ranging from 2.5 to 4.0 m/s were recruited; those with peak aortic jet velocity of less than 2.5 m/s or with an indication for statin therapy were excluded. Data were collected from January 1, 2002, through December 31, 2005, and underwent ad hoc analysis from April 1 through September 1, 2018. Interventions: After the randomization process, patients were followed up by means of echocardiography for 3 to 5 years. Main Outcomes and Measures: Progression rate of CAVS as assessed by annualized progression of peak aortic jet velocity. Results: In this cohort of 220 patients (60.0% male; mean [SD] age, 58 [13] years), a linear association was found between plasma levels of Lp(a) (odds ratio [OR] per 10-mg/dL increase, 1.10; 95% CI, 1.03-1.19; P = .006), OxPL-apoB (OR per 1-nM increase, 1.06; 95% CI, 1.01-1.12; P = .02), and OxPL-apo(a) (OR per 10-nM increase, 1.16; 95% CI, 1.05-1.27; P = .002) and faster CAVS progression, which is marked in younger patients (OR for Lp[a] level per 10-mg/dL increase, 1.19 [95% CI, 1.07-1.33; P = .002]; OR for OxPL-apoB level per 1-nM increase, 1.06 [95% CI, 1.02-1.17; P = .01]; and OR for OxPL-apo[a] level per 10-nM increase, 1.26 [95% CI, 1.10-1.45; P = .001]) and remained statistically significant after comprehensive multivariable adjustment (beta coefficient, >= 0.25; SE, <= 0.004 [P <= .005]; OR, >=1.10 [P <= .007]). Conclusions and Relevance: This study demonstrates that the association of Lp(a) levels and its content in OxPL with faster CAVS progression is linear, reinforcing the concept that Lp(a) levels should be measured in patients with mild to moderate CAVS to enhance management and risk stratification. Trial Registration: ClinicalTrials.gov Identifier: NCT00800800. PMID- 30476959 TI - Utility of Bladder-Sparing Therapy vs Radical Cystectomy for Muscle-Invasive Bladder Cancer-Reply. PMID- 30476960 TI - Circulating Tumor Cells and Radiotherapy Benefit in Early Breast Cancer. PMID- 30476962 TI - Diagnosis and Management of Nonalcoholic Liver Disease. PMID- 30476961 TI - Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease: A Review. AB - Importance: Cerebral cavernous malformations (CCMs) are vascular lesions of the brain that may lead to hemorrhage, seizures, and neurologic deficits. Most are linked to loss-of-function mutations in 1 of 3 genes, namely CCM1 (originally called KRIT1), CCM2 (MGC4607), or CCM3 (PDCD10), that can either occur as sporadic events or are inherited in an autosomal dominant pattern with incomplete penetrance. Familial forms originate from germline mutations, often have multiple intracranial lesions that grow in size and number over time, and cause an earlier and more severe presentation. Despite active preclinical research on a few pharmacologic agents, clinical translation has been slow. Open surgery and, in some cases, stereotactic radiosurgery remain the only effective treatments, but these options are limited by lesion accessibility and are associated with nonnegligible rates of morbidity and mortality. Observations: We discuss the limits of CCM management and introduce findings from in vitro and in vivo studies that provide insight into CCM pathogenesis and indicate molecular mechanisms as potential therapeutic targets. These studies report dysregulated cellular pathways shared between CCM, cardiovascular diseases, and cancer. They also suggest the potential effectiveness of proper drug repurposing in association with, or as an alternative to, targeted interventions. Conclusions and Relevance: We propose methods to exploit specific molecular pathways to design patient tailored therapeutic approaches in CCM, with the aim to alter its natural progression. In this scenario, the lack of effective pharmacologic options remains a critical barrier that poses an unfulfilled and urgent medical need. PMID- 30476963 TI - Long-Term Protection After Fractional-Dose Yellow Fever Vaccination: Follow-up Study of a Randomized, Controlled, Noninferiority Trial. AB - Background: Outbreaks of yellow fever and a frequently depleted vaccine stock increase demand for a dose-sparing strategy. A fractional dose of 17D yellow fever virus (17D-YFV) vaccine has been shown to be noninferior to the standard dose in inducing seroprotection. Objective: To evaluate whether fractional-dose vaccination can confer long-term immunity. Design: 10-year follow-up of a subgroup of a randomized, controlled, noninferiority trial. (Dutch Trial Register: NTR7094 [current study] and ISRCTN46326316 [original study]). Setting: The Netherlands. Participants: Seventy-five of 155 participants in the original trial provided a blood sample for this study. These 75 participants had received primary vaccination with 17D-YFV vaccine 10 years before. Forty received a 0.1-mL fractional dose intradermally, and 35 received the standard 0.5-mL dose subcutaneously. Measurements: Virus-neutralizing antibody responses were measured by a plaque reduction neutralization test. Results: Thirty-nine of 40 (98% [95% CI, 89% to 100%]) participants had protective levels of yellow fever-neutralizing antibodies more than 10 years after receiving a fractional dose of 17D-YFV vaccine compared with 34 of 35 (97% [CI, 87% to 100%]) in the standard-dose group. Limitation: Only 48% of participants from the original trial participated in this study. Conclusion: Intradermal administration of a one-fifth dose of yellow fever vaccine induced a protective immune response that lasted for 10 years after vaccination. Persons receiving a fractional dose of yellow fever vaccine do not require a booster vaccination for long-term protection against yellow fever. Primary Funding Source: Leiden University Medical Center and the International Society of Travel Medicine. PMID- 30476964 TI - Safety and Feasibility of a Nonpledgeted Suture Technique for Heart Valve Replacement. PMID- 30476965 TI - Association of Hospital Volume With Laryngectomy Outcomes in Patients With Larynx Cancer. AB - Importance: A volume-outcome association exists for larynx cancer surgery, but to date it has not been investigated for specific surgical procedures. Objectives: To characterize the volume-outcome association specifically for laryngectomy surgery and to identify a minimum hospital volume threshold associated with improved outcomes. Design, Setting, and Participants: In this cross-sectional study, the Nationwide Inpatient Sample was used to identify 45 156 patients who underwent laryngectomy procedures for a malignant laryngeal or hypopharyngeal neoplasm between January 2001 and December 2011. The analysis was performed in 2018. Hospital laryngectomy volume was modeled as a categorical variable. Main Outcomes and Measures: Associations between hospital volume and in-hospital mortality, complications, length of hospitalization, and costs were examined using multivariate logistic regression analysis. Results: Among 45 156 patients (mean age, 62.6 years; age range, 20-96 years; 80.2% male) at 5516 hospitals, higher-volume hospitals were more likely to be teaching hospitals in urban locations; were more likely to treat patients who had hypopharyngeal cancer, were of white race/ethnicity, were admitted electively, had no comorbidity, and had private insurance; and were more likely to perform flap reconstruction or concurrent neck dissection. After controlling for all other variables, hospitals treating more than 6 cases per year were associated with lower odds of surgical and medical complications, with a greater reduction in the odds of complications with increasing hospital volume. High-volume hospitals in the top-volume quintile (>28 cases per year) were associated with decreased odds of in-hospital mortality (odds ratio, 0.45; 95% CI, 0.23-0.88), postoperative surgical complications (odds ratio, 0.63; 95% CI, 0.50-0.79), and acute medical complications (odds ratio, 0.63; 95% CI, 0.48-0.81). A statistically meaningful negative association was observed between very high-volume hospital care and the mean incremental length of hospitalization (-3.7 days; 95% CI, -4.9 to -2.4 days) and hospital-related costs (-$4777; 95% CI, -$9463 to -$900). Conclusions and Relevance: Laryngectomy outcomes appear to be associated with hospital volume, with reduced morbidity associated with a minimum hospital volume threshold and with reduced mortality, morbidity, length of hospitalization, and costs associated with higher hospital volume. These data support the concept of centralization of complex care at centers able to meet minimum volume thresholds to improve patient outcomes. PMID- 30476966 TI - Herpes-Associated Erythema Multiforme. PMID- 30476967 TI - Sequential Neuroimaging of the Fetus and Newborn With In Utero Zika Virus Exposure. AB - Importance: The evolution of fetal brain injury by Zika virus (ZIKV) infection is not well described. Objectives: To perform longitudinal neuroimaging of fetuses and infants exposed to in utero maternal ZIKV infection using concomitant magnetic resonance imaging (MRI) and ultrasonography (US), as well as to determine the duration of viremia in pregnant women with ZIKV infection and whether the duration of viremia correlated with fetal and/or infant brain abnormalities. Design, Setting, and Participants: A cohort of 82 pregnant women with clinical criteria for probable ZIKV infection in Barranquilla, Colombia, and Washington, DC, were enrolled from June 15, 2016, through June 27, 2017, with Colombian women identified by community recruitment and physician referral and travel-related cases of American women recruited from a Congenital Zika Program. Interventions and Exposures: Women received 1 or more MRI and US examinations during the second and/or third trimesters. Postnatally, infants underwent brain MRI and cranial US. Blood samples were tested for ZIKV. Main Outcomes and Measures: The neuroimaging studies were evaluated for brain injury and cerebral biometry. Results: Of the 82 women, 80 were from Colombia and 2 were from the United States. In 3 of 82 cases (4%), fetal MRI demonstrated abnormalities consistent with congenital ZIKV infection. Two cases had heterotopias and malformations in cortical development and 1 case had a parietal encephalocele, Chiari II malformation, and microcephaly. In 1 case, US results remained normal despite fetal abnormalities detected on MRI. Prolonged maternal polymerase chain reaction positivity was present in 1 case. Of the remaining 79 cases with normal results of prenatal imaging, postnatal brain MRI was acquired in 53 infants and demonstrated mild abnormalities in 7 (13%). Fifty-seven infants underwent postnatal cranial US, which detected changes of lenticulostriate vasculopathy, choroid plexus cysts, germinolytic/subependymal cysts, and/or calcification in 21 infants (37%). Conclusions and Relevance: In a cohort of pregnant women with ZIKV infection, prenatal US examination appeared to detect all but 1 abnormal fetal case. Postnatal neuroimaging in infants who had normal prenatal imaging revealed new mild abnormalities. For most patients, prenatal and postnatal US may identify ZIKV-related brain injury. PMID- 30476969 TI - Nonsurgical, Minimally Invasive, and Surgical Methods in Management of Acute Diverticulitis. PMID- 30476968 TI - Rechallenge for Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer With Acquired Resistance to First-line Cetuximab and Irinotecan: A Phase 2 Single Arm Clinical Trial. AB - Importance: Based on a small retrospective study, rechallenge with cetuximab based therapy for patients with KRAS wild-type metastatic colorectal cancer (mCRC) who were previously treated with the same anti-epidermal growth factor receptor-based regimen might be efficacious. Recent data suggest the role of liquid biopsy as a tool to track molecular events in circulating tumor DNA (ctDNA). Objective: To prospectively assess the activity of cetuximab plus irinotecan as third-line treatment for patients with RAS and BRAF wild-type mCRC who were initially sensitive to and then resistant to first-line irinotecan- and cetuximab-based therapy. Design, Setting, and Participants: Multicenter phase 2 single-arm trial conducted from January 7, 2015, to June 19, 2017. Liquid biopsies for analysis of ctDNA were collected at baseline. Main eligibility criteria included RAS and BRAF wild-type status on tissue samples; prior first line irinotecan- and cetuximab-based regimen with at least partial response, progression-free survival of at least 6 months with first-line therapy, and progression within 4 weeks after last dose of cetuximab; and prior second-line oxaliplatin- and bevacizumab-based treatment. Interventions: Biweekly cetuximab, 500 mg/m2, plus irinotecan, 180 mg/m2. Main Outcomes and Measures: Overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included progression-free survival and overall survival and, as an exploratory analysis, RAS mutations in ctDNA. Results: Twenty eight patients (9 women and 19 men; median age, 69 years [range, 45-79 years]) were enrolled. Six partial responses (4 confirmed) and 9 disease stabilizations were reported (response rate, 21%; 95% CI, 10%-40%; disease control rate, 54%; 95% CI, 36%-70%). Primary end point was met because lower limit of 95% CI of response rate was higher than 5%. RAS mutations were found in ctDNA collected at rechallenge baseline in 12 of 25 evaluable patients (48%). No RAS mutations were detected in samples from patients who achieved confirmed partial response. Patients with RAS wild-type ctDNA had significantly longer progression-free survival than those with RAS mutated ctDNA (median progression-free survival, 4.0 vs 1.9 months; hazard ratio, 0.44; 95% CI, 0.18-0.98; P = .03). Conclusions and Relevance: This is the first prospective demonstration that a rechallenge strategy with cetuximab and irinotecan may be active in patients with RAS and BRAF wild-type mCRC with acquired resistance to first-line irinotecan- and cetuximab-based therapy. The evaluation of RAS mutational status on ctDNA might be helpful in selecting candidate patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02296203. PMID- 30476972 TI - Secondary Endolymphatic Hydrops Associated With Spontaneous Intracranial Hypotension. PMID- 30476973 TI - Safety and Immunogenicity of Early Bacillus Calmette-Guerin Vaccination in Infants Who Are Preterm and/or Have Low Birth Weights: A Systematic Review and Meta-analysis. AB - Importance: Bacillus Calmette-Guerin (BCG) vaccination is commonly delayed in infants who are preterm and have low birth weights (LBW) despite the association of early vaccination with better vaccination coverage and potentially nonspecific benefits for survival. Objective: To determine the safety, immunogenicity, and protective efficacy against tuberculosis (TB) of BCG vaccination given at or before 7 days after birth vs vaccination more than 7 days after birth among infants who are preterm and/or had LBW. Data Sources: Searches of Medline, Embase, and Global Health databases were conducted from inception until August 8, 2017. Study Selection: Clinical trials, cohort studies, and case-control studies that included infants who were preterm and/or had LBW and reported safety, mortality, immunogenicity, proxies of vaccine take, and/or efficacy against TB. Data Extraction and Synthesis: Two authors independently extracted data and assessed the quality of the studies. Data extracted included demographics, covariates, sources of bias, and effect estimates. Meta-analysis was performed using a random-effects model. Main Outcomes and Measures: Safety, mortality, immunogenicity, or other proxies of vaccine take, such as tuberculin skin test (TST) conversion and efficacy against tuberculosis. Results: Forty studies were included in a qualitative synthesis; infants who were preterm (born at 26-37 weeks' gestational age) and/or had LBW (0.69-2.5 kg at birth) were included. The BCG vaccine was administered at or before 7 days to 10 568 clinically stable infants who were preterm and/or had LBW; vaccination was administered to 4310 infants at varying times between 8 days and 12 months after birth. Twenty-one studies reporting safety found no cases of BCG-associated death or systemic disease in 8243 infants. Four studies reported no increase in all-cause mortality for infants who had LBW and who received early BCG vaccination compared with infants who had LBW with later vaccination or BCG-vaccinated infants of normal birth weight. Four studies reported lymphadenitis incidence; combined, these reported 0% to 2.9% incidence of vaccination within 7 days and 0% to 4.2% of vaccination after 7 days. Meta-analysis of 7 studies revealed no differences between early and delayed BCG vaccination for scar formation (n = 515; relative risk [RR], 1.01 [95% CI, 0.95-1.07]) or TST conversion (n = 397; RR, 0.97 [95% CI, 0.84-1.13]). Published data were insufficient to assess immunogenicity or protective efficacy against TB disease. Conclusions and Relevance: Early BCG vaccination in healthy infants who are preterm and/or had LBW has a similar safety profile, reactogenicity, and TST conversion rate as delayed vaccination. Based on current evidence, early BCG vaccination in stable infants who are preterm and/or have LBW to optimize uptake is warranted. PMID- 30476974 TI - Pricing a Year of Progression-Free Survival: When Is the Cost of Cancer Drugs Unreasonable? PMID- 30476975 TI - Evaluation of Second Solid Cancers After Hematopoietic Stem Cell Transplantation in European Patients. AB - Importance: Incidence and risk factors of second solid cancers (SSCs) that occur after hematopoietic stem cell transplantation (HSCT) are well documented. However, clinical outcome data of patients who developed an SSC after HSCT are limited. Objective: To assess the outcome of patients with an SSC occurring after HSCT from the time of SSC diagnosis. Design, Setting, and Participants: This cohort study used data of 4065 patients from 26 countries registered with the European Society for Blood and Marrow Transplantation, which has maintained clinical data since 1977 of patients who received a transplant. Information from all patients who underwent a transplant in Europe and had an SSC diagnosis between January 1, 2000, and December 31, 2014, was extracted. The cohort included patients with 18 different cancers. Data analysis was conducted from September 3, 2017, to March 17, 2018. Main Outcomes and Measures: Median and 5 year age-standardized overall survival, causes of death, risk factor multivariate analysis using a clustered Cox proportional hazard regression model, and standardized mortality ratio were calculated for each of the 18 types of SSC. Results: In total, 220 617 patients underwent a transplant, of whom only 4065 (1.8%) patients with a second solid cancer after HSCT were included in the study. Among the 4065 patients, 2321 (57.1%) were men and 1744 (42.9%) were women, with a mean (range) age of 59.1 (3.2-82.3) years at diagnosis of second solid cancer. The 5-year age-standardized overall survival was 47% (95% CI, 45%-49%). The 5 year overall survival rate after SSC diagnosis was poor for pancreas, lung, hepatobiliary, esophageal, brain, and gastric cancers, with a median survival between 0.6 and 1 year. The 5-year overall survival was intermediate for endometrial, colorectal, sarcomas, ovarian, bladder, oropharyngeal, and kidney cancers, with a median survival between 2 and 10 years. The 5-year overall survival was more favorable for melanoma, breast, prostate, cervix, and thyroid cancers, with a median survival of 10 or more years. Additional transplant associated factors for mortality for patients treated with allogeneic HSCT were age at transplant, donor type, conditioning regimen, and graft-vs-host disease. In total, 1777 patients (43.7%) died, of which 1256 (74.8%) were from SSC, 344 (20.5%) from primary disease, and 79 (4.7%) from other causes. Standardized mortality ratio was higher, compared with de novo solid cancers, for melanoma, prostate, breast, kidney, bladder, colorectal, and endometrial cancers but not for the other cancers. Conclusions and Relevance: The outcome of SSC is mainly dependent on the type of second cancer; thus, future studies should investigate the reasons the standardized mortality ratio is higher for some cancers to identify whether patients with these cancers should be treated differently and to help in screening and counseling patients who developed an SSC after HSCT. PMID- 30476976 TI - Use of Dapsone in the Treatment of Chronic Idiopathic and Autoimmune Urticaria. AB - Importance: The first-line treatment for patients with chronic spontaneous urticaria (CSU), which is divided into idiopathic and autoimmune subtypes, consists of H1-antihistamines. However, limited evidence guides the treatment of CSU after maximal therapy with antihistamines fails. Two randomized clinical trials suggest that dapsone may be a successful second-line therapy. Objective: To evaluate the efficacy and safety of dapsone therapy in patients with CSU. Design, Setting, and Participants: This retrospective medical record review included 79 patients with CSU treated with dapsone who presented to the tertiary care academic medical center at the New York University School of Medicine, New York, New York, from January 1, 2005, through April 15, 2017. Follow-up was completed on February 28, 2018. Data were analyzed from March 1 through May 31, 2018. Exposures: Treatment with oral dapsone for CSU. Main Outcomes and Measures: Efficacy of dapsone therapy for CSU was evaluated as improvement, complete response, and remission. Results: Seventy-nine patients (65% women; mean [SD] age, 49.8 [16.1] years [range, 20-79 years]) were included in the analysis. Forty five patients had chronic idiopathic urticaria and 34 had chronic autoimmune urticaria. Improvement in CSU was observed in 62 patients (78%) (36 [80%] with idiopathic and 26 [76%] with autoimmune disease) with dapsone. Mean (SD) time to improvement was 1.1 (1.0) months. A complete response was achieved in 29 (47%) of these 62 patients (16 [44%] with idiopathic and 13 [50%] with autoimmune disease). Mean (SD) time to complete response was 5.2 (5.2) months. Dapsone therapy was tapered in 21 patients after a mean (SD) of 2.4 (2.2) months and discontinued in 18. Ten patients experienced remission with no subsequent flares, even after dapsone therapy was discontinued with follow-up of 0.3 to 10.0 months. Sixteen patients experienced mild adverse effects. Two serious adverse effects were reported. Conclusions and Relevance: Results of this study suggest that dapsone is a useful and well-tolerated second-line therapy for patients with CSU in whom antihistamines and other first-line agents have failed. PMID- 30476977 TI - Decision Making in Colostomy Closure: Acceptable vs Optimal Safety and Selection vs Bias. PMID- 30476978 TI - Body Composition and Overall Survival in Patients With Nonmetastatic Breast Cancer-Reply. PMID- 30476979 TI - Errors in Abstract, Figure 1, Table, Conclusion, and Author Contributions. PMID- 30476982 TI - Surgical Volumes and Outcomes-Does Practice Make Perfect? PMID- 30476983 TI - Prevalence of Eating Disorders Among US Children Aged 9 to 10 Years: Data From the Adolescent Brain Cognitive Development (ABCD) Study. PMID- 30476984 TI - Learning to Surf. PMID- 30476986 TI - Investigating the Influence of Vitamin D Replacement Therapy on Magnesium Status. PMID- 30476985 TI - Principles for Patient and Family Partnership in Care: An American College of Physicians Position Paper. AB - In this position paper, the American College of Physicians (ACP) examines the rationale for patient and family partnership in care and reviews outcomes associated with this concept, including greater adherence to care plans, improved satisfaction, and lower costs. The paper also explores and acknowledges challenges associated with implementing patient- and family-centered models of care. On the basis of a comprehensive literature review and a multistakeholder vetting process, the ACP's Patient Partnership in Healthcare Committee developed a set of principles that form the foundation for authentic patient and family partnership in care. The principles position patients in their rightful place at the center of care while acknowledging the importance of partnership between the care team and patient in improving health care and reducing harm. The principles state that patients and families should be treated with dignity and respect, be active partners in all aspects of their care, contribute to the development and improvement of health care systems, and be partners in the education of health care professionals. This paper also recommends ways to implement these principles in daily practice. PMID- 30476987 TI - Response. PMID- 30476988 TI - Guns and Older Adults: The Physician's Role. PMID- 30476989 TI - Industry Payments in Cardiology: A Cross-sectional Analysis of Open Payments Data. AB - Background: The goal of Open Payments and the Physician Payments Sunshine Act is to foster transparency and accountability to help stakeholders better understand financial ties between physicians and teaching hospitals and the pharmaceutical and medical device industries. Objective: To evaluate the nature of industry relationships among cardiologists using the Open Payments database. Methods: The authors used the Centers for Medicare & Medicaid Services Open Payments data for calendar year 2015 to evaluate the financial relationship between cardiologists and medical industries (manufacturers of medications, devices, biologics, and medical supplies). The database used in this specific investigation included general payments reported for 2015. Payments were broken down by totals, type, company, and range. Results: In the 2015 calendar year, 81,977 payments were made to 12,078 cardiologists, amounting to $13,906,167.43. The minimum payment made to a cardiologist was $1.16 and the maximum, $2,805,825. The most frequent category was $11 to $50, with 53,722 payments made (65.5%), followed by less than $10, with 12,307 payments made (15.0%). Conclusion: Payments to cardiologists were highly variable. Additional studies regarding the effects of these payments may be warranted. PMID- 30476990 TI - Utility of 4-Factor Prothrombin Complex Concentrate in Trauma and Acute-Care Surgical Patients. AB - Context: Since 2013, prothrombin complex concentrate (PCCs) have been approved in the United States for the reversal of anticoagulation induced by vitamin K antagonists. However, there has been limited investigation into their use in trauma and acute-care surgery (ACS). Objective: To investigate the role that 4 factor PCC may have in reversing anticoagulation in the setting of trauma and ACS. Methods: All trauma and ACS patients who presented between March 14, 2014, and August 1, 2015, were included in this retrospective descriptive analysis. Patients receiving 4-factor PCC were compared with patients receiving fresh frozen plasma (FFP) alone. The following data were collected from medical records: age, sex, race, international normalized ratio (INR) at admission (baseline) and after reversal, blood products given, dosing of medication, injury severity score, length of stay, thromboembolic event, death during admission, and death within 90 days after admission. Results: There were 188 trauma and ACS patients who required reversal of anticoagulation. Of these, 98 patients received FFP and 90 received PCC. Patients who received PCC were at increased risk for death during admission (20% vs 9.2% for FFP group) or within 90 days (39% vs 15%, respectively). Patients in the PCC group had a higher median baseline INR (2.9 vs 2.5 in the FFP group) and a lower postintervention INR (1.4 vs 1.8); consequently, the decrease in INR was greater in the PCC group than in the FFP group (1.5 vs 0.7, respectively). The number of total units of packed red blood cells transfused was significantly higher in patients receiving PCC. Conclusion: Patients receiving PCC had worse outcomes than those who received FFP. Given that these differences may have resulted from baseline differences between groups, these results mandate further prospective analysis of the use of PCC in trauma and ACS patients. PMID- 30476991 TI - Adjuvant Lymphatic Osteopathic Manipulative Treatment in Patients With Lower Extremity Ulcers: Effects on Wound Healing and Edema. AB - Context: In 2012, the US wound registry estimated that the cost of managing chronic wounds in the United States exceeded $50 billion. A large percentage of these wounds are venous stasis ulcers of the lower extremity. Evidence suggests that adjuvant osteopathic manipulative treatment (OMT) may provide a benefit by reducing edema and subsequent healing times in venous stasis ulcers of the lower extremity. Objective: To determine whether a lymphatic OMT protocol improves wound healing rates among patients with lower-extremity edema. Methods: This pilot study was a nonrandomized before-after community trial of lymphatic OMT in patients with lower-extremity wounds and edema. Wound surface area measurements for the preliminary phase were obtained retrospectively. During the intervention period, patients received 10 minutes of OMT twice per week. The OMT protocol, which aimed to improve lymphatic flow, included myofascial thoracic outlet release, doming of the diaphragm, pelvic diaphragm release, popliteal release, and pedal pump (2-3 minutes of continuous pump) performed in sequence. Rates of wound healing were compared between the preliminary (standard therapy), intervention (standard therapy plus OMT), and follow-up (standard therapy) phases. Rates of change in edema (measured using leg volume) were evaluated during the intervention phase. A custom-designed questionnaire was used to assess patients' satisfaction with their treatment and confidence that its effects on their health were good. Results: Eight patients were included in the study. The wound surface area increased during the preliminary phase by a mean of 10 cm2/wk and decreased during the intervention phase by a mean of 4.9 cm 2/wk. Patients' mean leg volume decreased during the intervention phase. Six patients were "very satisfied" with their treatment. Conclusion: The adjunctive OMT protocol may have reduced edema and reversed the trend of wound growth in patients with venous stasis ulcers. Edema reduction is a mainstay of current wound therapy, and any modality that decreases edema may subsequently decrease healing times. PMID- 30476992 TI - Moving Toward Milestone-Based Assessment in Osteopathic Manipulative Medicine. AB - Osteopathic medicine is continuing to move toward competency-based education at undergraduate and graduate levels. Competencies and Entrustable Professional Activities (EPAs) have been implemented to guide educators on the skills and abilities that osteopathic medical students and residents should be able to perform as physicians. Unfortunately, many of these skills have not been well described, and the threshold of "competence" or "entrustability" for each of these tasks remains elusive. The author presents an approach to measuring competence in the domain of osteopathic manipulative medicine using a milestone rubric to assess skills related to osteopathic screening, diagnosis, technique, and explanation. This rubric can be applied to all levels of osteopathic training and across many diagnostic and treatment modalities. Clearly defining and assessing the individual skills composing competence in osteopathic manipulative medicine will be increasingly important as medical education continues to evolve and modernize. PMID- 30476993 TI - Exodus From the Classroom: Student Perceptions, Lecture Capture Technology, and the Inception of On-Demand Preclinical Medical Education. AB - Context: Some medical educators have noted a decline in classroom attendance. Understanding student preferences for content delivery and the relationship between student attendance and learning outcomes may enhance curricular design and best practices for technology-supported learning. Objective: To measure the attendance of first-year osteopathic medical students, evaluate the relationship between classroom attendance and aggregate mean course grades, and characterize factors that influence attendance decisions when recorded lectures are available. Methods: In nonmandatory class sessions during the 2015-2016 academic year, student attendance data were collected using audience response technology and were linked to course grades. Pearson product moment and partial correlations, controlling for Medical College Admissions Test scores, were calculated to quantify the relationship between classroom attendance and aggregate mean course grades. Students were surveyed to characterize factors influencing attendance decisions and compare the perceived convenience, efficiency, and effectiveness of classroom attendance vs lecture capture technology. The preferred modality for receiving didactic content was assessed, and open-ended questions were included about the advantages or disadvantages of lecture capture, classroom attendance, and podcasts. Responses were analyzed using open and axial coding. Results: A 78% reduction in first-year student classroom attendance was measured from the beginning to the end of the academic year (P<.001). The correlation between classroom attendance and aggregate mean course grades (r=0.17; P=.29) and the partial correlation between them after controlling for admission test scores (r=0.18; P=.08) were not significant, except in the Neuromusculoskeletal A course (r=0.22; P=.027). Students regarded lecture capture recordings as more convenient, efficient, and effective than classroom attendance, and podcasting was the preferred method of content delivery. Major themes associated with the open-ended questions were effective or ineffective time management, enhanced interaction, learning advantages or challenges, and positive or negative content characteristics. Conclusion: First-year classroom attendance decreased significantly during the academic year, but the authors found no significant relationship between attendance and aggregate mean course grades. Students regarded lecture capture recordings as a practical alternative to attending class; however, podcasts were the preferred modality for receiving didactic content. These findings may help in developing learning-centered curricula at colleges of osteopathic medicine. PMID- 30476994 TI - Scalp Sarcoidosis Presenting as Cicatricial Alopecia. AB - Sarcoidosis is a granulomatous condition that has a highly variable presentation. One rare presentation of sarcoidosis is cutaneous scalp sarcoidosis. Usually scalp sarcoid presents as a scarring alopecia, but it can be nonscarring. The presence of sarcoidal lesions on the scalp is associated with systemic disease, as are other cutaneous manifestations of sarcoidosis. The authors present the case of a 64-year-old woman with a history of sarcoidosis who presented with alopecia and hypopigmented patches on her scalp. She also had papular sarcoid lesions on her upper back and a history of pulmonary involvement, which is consistent with previous reports in the literature. The condition subsequently improved with topical clobetasol propionate. PMID- 30476995 TI - Spontaneous Infrarenal Aortic Dissection in an Athlete Managed Emergently With Endovascular Stent Grafts, Occluders, and Femoral-Femoral Artery Bypass. AB - While competing in an obstacle course race, a 57-year-old male athlete developed left groin and leg pain. Several days later, infrarenal aortic dissection with clinically worsening left leg ischemia was diagnosed. An emergent repair was performed and consisted of an aorto-uni-iliac endovascular stent graft, an occluder in the left iliac artery, and a right-to-left femoral-femoral artery bypass. To the authors' knowledge, the present report is the first case of a spontaneous infrarenal aortic dissection in a competitive athlete associated with participation in an extreme athletic event. PMID- 30476996 TI - Bullous Diabeticorum. PMID- 30476997 TI - Posterior Cortical Atrophy. PMID- 30476998 TI - An Osteopathic Approach to Stasis Dermatitis and Chronic Venous Insufficiency. PMID- 30477000 TI - Economic Evaluation of Talimogene Laherparepvec Plus Ipilimumab Combination Therapy vs Ipilimumab Monotherapy in Patients With Advanced Unresectable Melanoma. AB - Importance: A phase 2 trial comparing talimogene laherparepvec plus ipilimumab vs ipilimumab monotherapy in patients with advanced unresectable melanoma found no differential benefit in progression-free survival (PFS) but noted objective response rates (ORRs) of 38.8% (38 of 98 patients) vs 18.0% (18 of 100 patients), respectively. Objective: To perform an economic evaluation of talimogene laherparepvec plus ipilimumab combination therapy vs ipilimumab monotherapy. Design, Setting, and Participants: For PFS, cost-effectiveness and cost-utility analyses using a 2-state Markov model (PFS vs progression or death) was performed. For ORRs, cost-effectiveness analysis of the incremental cost of 1 additional patient achieving objective response was performed. In this setting based on a US payer perspective (2017 US dollars), participants were patients with advanced unresectable melanoma. Main Outcomes and Measures: The PFS life years and PFS quality-adjusted life-years were determined, and the associated incremental cost-effectiveness ratios (ICERs) and incremental cost-utility ratios (ICURs) were estimated. Also estimated was the ICER per 1 additional patient (out of 100 treated patients) achieving objective response. Base-case analyses were validated by sensitivity analyses. Results: In PFS analyses, the cost of talimogene laherparepvec plus ipilimumab ($494 983) exceeded the cost of ipilimumab monotherapy ($132 950) by $362 033. The ICER was $2 129 606 per PFS life-years, and the ICUR was $2 262 706 per PFS quality-adjusted life-year gained. Probabilistic sensitivity analyses yielded an ICER of $1 481 208 per PFS life-year gained and an ICUR of $1 683 191 per PFS quality-adjusted life-year gained. In 1-way sensitivity analyses, the PFS hazard ratio and the utility of response were the most influential parameters. Talimogene laherparepvec plus ipilimumab has a 50% likelihood of being cost-effective at a willingness-to-pay threshold of $1 683 191 per PFS quality-adjusted life-year gained. In ORR analyses, talimogene laherparepvec plus ipilimumab ($474 904) vs ipilimumab alone ($132 810), a $342 094 difference, yielded an ICER of $1 629 019 per additional patient achieving objective response. In subgroup analyses by disease stage and BRAFV600E mutation status, ICERs ranged from $1 069 044 to $17 104 700 per 1 additional patient achieving objective response. Conclusions and Relevance: The cost to gain 1 additional progression-free quality-adjusted life-year, 1 additional progression-free life-year, or to have 1 additional patient attain objective response is about $1.6 million. This amount may be beyond what payers typically are willing to pay. Combination therapy of talimogene laherparepvec plus ipilimumab does not offer an economically beneficial treatment option relative to ipilimumab monotherapy at the population level. This should not preclude treatment for individual patients for whom this regimen may be indicated. PMID- 30477001 TI - Is It Possible to Get a Flu Shot Too Early? PMID- 30476999 TI - Effect of Cerebellar Stimulation on Gait and Balance Recovery in Patients With Hemiparetic Stroke: A Randomized Clinical Trial. AB - Importance: Gait and balance impairment is associated with poorer functional recovery after stroke. The cerebellum is known to be strongly implicated in the functional reorganization of motor networks in patients with stroke, especially for gait and balance functions. Objective: To determine whether cerebellar intermittent theta-burst stimulation (CRB-iTBS) can improve balance and gait functions in patients with hemiparesis due to stroke. Design, Setting, Participants: This randomized, double-blind, sham-controlled phase IIa trial investigated efficacy and safety of a 3-week treatment of CRB-iTBS coupled with physiotherapy in promoting gait and balance recovery in patients with stroke. Thirty-six patients with consecutive ischemic chronic stroke in the territory of the contralateral middle cerebral artery with hemiparesis were recruited from a neuro-rehabilitation hospital. Participants were screened and enrolled from March 2013 to June 2017. Intention-to-treat analysis was performed. Interventions: Patients were randomly assigned to treatment with CRB-iTBS or sham iTBS applied over the cerebellar hemisphere ipsilateral to the affected body side immediately before physiotherapy daily during 3 weeks. Main Outcomes and Measures: The primary outcome was the between-group difference in change from baseline in the Berg Balance Scale. Secondary exploratory measures included the between-group difference in change from baseline in Fugl-Meyer Assessment scale, Barthel Index, and locomotion assessment with gait analysis and cortical activity measured by transcranial magnetic stimulation in combination with electroencephalogram. Results: A total of 34 patients (mean [SD] age, 64 [11.3] years; 13 women [38.2%]) completed the study. Patients treated with CRB-iTBS, but not with sham iTBS, showed an improvement of gait and balance functions, as revealed by a pronounced increase in the mean (SE) Berg Balance Scale score (baseline: 34.5 [3.4]; 3 weeks after treatment: 43.4 [2.6]; 3 weeks after the end of treatment: 47.5 [1.8]; P < .001). No overall treatment-associated differences were noted in the Fugl-Meyer Assessment (mean [SE], baseline: 163.8 [6.8]; 3 weeks after treatment: 171.1 [7.2]; 3 weeks after the end of treatment: 173.5 [6.9]; P > .05) and Barthel Index scores (mean [SE], baseline: 71.1 [4.92]; 3 weeks after treatment: 88.8 [2.1]; 3 weeks after the end of treatment: 92.2 [2.4]; P > .05). Patients treated with CRB-iTBS, but not sham iTBS, showed a reduction of step width at the gait analysis (mean [SE], baseline: 16.8 [4.8] cm; 3 weeks after treatment: 14.3 [6.2] cm; P < .05) and an increase of neural activity over the posterior parietal cortex. Conclusions and Relevance: Cerebellar intermittent theta-burst stimulation promotes gait and balance recovery in patients with stroke by acting on cerebello-cortical plasticity. These results are important to increase the level of independent walking and reduce the risk of falling. Trial Registration: ClinicalTrials.gov Identifier: NCT03456362. PMID- 30477002 TI - Eyebrow-lift With Frontal Muscle Plication. PMID- 30477003 TI - Association of Phenotypic Characteristics and UV Radiation Exposure With Risk of Melanoma on Different Body Sites. AB - Importance: Two pathways have been hypothesized for the development of cutaneous melanoma: one typically affects the head and neck, a site with chronic sun damage, and the other affects the trunk, which is less exposed to the sun. However, the possible cause of limb melanomas is less studied under this hypothesis. Objective: To investigate the association between phenotypic characteristics, pattern of UV radiation exposure, and risk of melanoma on different body sites. Design, Setting, and Participants: This study used data on 161 540 women with information on phenotypic characteristics and UV radiation exposure who were part of the Norwegian Women and Cancer study, a population based prospective study established in 1991 with exposure information collected by questionnaires at baseline and every 4 to 6 years during follow-up through 2015. Data analysis was performed from October 2017 through May 2018. Exposures: Participants reported hair color, eye color, untanned skin color, number of small symmetric and large asymmetric nevi, and freckling, as well as histories of sunburns, sunbathing vacations, and indoor tanning in childhood, adolescence, and adulthood. Main Outcomes and Measures: The Norwegian Women and Cancer study was linked to the Cancer Registry of Norway for data on cancer diagnosis and date of death or emigration. Primary melanoma site was categorized as head and neck, trunk, upper limbs, and lower limbs. Results: During follow-up of the 161 540 women in the study (mean age at study entry, 50 years [range, 34-70 years]; mean age at diagnosis, 60 years [range, 34-87 years]), 1374 incident cases of melanoma were diagnosed. Having large asymmetric nevi was a significant risk factor for all sites and was strongest for the lower limbs (relative risk [RR], 3.38; 95% CI, 2.62-4.38) and weakest for the upper limbs (RR, 1.96; 95% CI, 1.22-3.17; P = .02 for heterogeneity). Mean lifetime number of sunbathing vacations was significantly associated with risk of trunk melanomas (RR, 1.14; 95% CI, 1.07 1.22) and lower limb melanomas (RR, 1.12; 95% CI, 1.05-1.19) but not upper limb melanomas (RR, 0.98; 95% CI, 0.88-1.09) and head and neck melanomas (RR, 0.87; 95% CI, 0.73-1.04; P = .006 for heterogeneity). Indoor tanning was associated only with trunk melanomas (RR for the highest tertile, 1.49; 95% CI, 1.16-1.92) and lower limb melanomas (RR for the highest tertile, 1.33; 95% CI, 1.00-1.76; P = .002 for heterogeneity). Skin color, hair color, small symmetric nevi, and history of sunburns were associated with risk of melanoma on all sites. Conclusions and Relevance: These results appear to support the hypothesis of divergent pathways to melanoma and that recreational sun exposure and indoor tanning are associated with melanoma on the lower limbs, the most common site of melanoma in women. These findings appear to have important preventive implications. PMID- 30477004 TI - Improving Dermatologic Care for Sexual and Gender Minority Patients Through Routine Sexual Orientation and Gender Identity Data Collection. PMID- 30477005 TI - Utility of Bladder-Sparing Therapy vs Radical Cystectomy for Muscle-Invasive Bladder Cancer. PMID- 30477006 TI - Misinterpretation of Study Data. PMID- 30477007 TI - Coordinating Clinical Trials to Confirm Drug Safety and Efficacy-Resolving Uncertainty. PMID- 30477008 TI - Electrocardiographic Harbingers of Ventricular Tachycardia Arrest-A Moment of Pause. PMID- 30477009 TI - Remission and Progression-Free Survival in Patients With Newly Diagnosed Multiple Myeloma Treated With Carfilzomib, Lenalidomide, and Dexamethasone: Five-Year Follow-up of a Phase 2 Clinical Trial. PMID- 30477010 TI - Assessment of Pregabalin Postapproval Trials and the Suggestion of Efficacy for New Indications: A Systematic Review. AB - Importance: After a drug receives regulatory approval, researchers often pursue small, underpowered trials, called exploratory trials, aimed at testing additional indications. If favorable early findings from exploratory trials are not promptly followed by confirmatory trials, then physicians, patients, and payers can be left uncertain about a drug's clinical value (clinical agnosticism). Such findings may encourage the off-label use of ineffective drugs. Objective: To characterize the relationship between exploratory and confirmatory postapproval trials for the blockbuster drug, pregabalin (Lyrica). Evidence Review: Ovid MEDLINE and Embase databases were used to identify clinical trials published prior to January 2018 and that tested the efficacy of pregabalin for nonapproved indications. Indications, trial outcomes, publication dates, and trial design elements were recorded. Time elapsed was calculated between the generation of clinical agnosticism about pregabalin (ie, publications reporting positive or inconclusive evidence of efficacy on a primary endpoint) and it being addressed (publication of at least 1 confirmatory trial in the same indication, regardless of outcome). Findings: There were 238 trials identified that tested the efficacy of pregabalin in at least 33 indications; 5 indications eventually received European Medicines Agency and/or US Food and Drug Administration marketing approval. Sixty-seven percent (22 of 33) of first publications for new indications may have generated clinical agnosticism. Of those indications with at least 5 years of follow-up, 63% (17 of 27) may have generated agnosticism that was not addressed in confirmatory trials within 5 years. As pregabalin development expanded from indications that received regulatory approval to other indications, the linkage of exploratory to confirmatory trial publication diminished. Conclusions and Relevance: After initial approval, exploratory evidence suggesting the value of pregabalin for new indications often went unconfirmed for extended periods of time. Poor coordination between exploratory and confirmatory testing may represent an important vehicle through which off label prescription is recommended in clinical practice guidelines and encouraged in the absence of confirmatory trial evidence. PMID- 30477011 TI - Utility of Bladder-Sparing Therapy vs Radical Cystectomy for Muscle-Invasive Bladder Cancer. PMID- 30477012 TI - Estimated Filtration: The Continued Need for Expert Classification of Genetic Variants. PMID- 30477013 TI - Association Between Flat-Panel Computed Tomographic Imaging-Guided Place-Pitch Mapping and Speech and Pitch Perception in Cochlear Implant Users. AB - Importance: Cochlear implant users generally display poor pitch perception. Flat panel computed tomography (FPCT) has recently emerged as a modality capable of localizing individual electrode contacts within the cochlea in vivo. Significant place-pitch mismatch between the clinical implant processing settings given to patients and the theoretical maps based on FPCT imaging has previously been noted. Objective: To assess whether place-pitch mismatch is associated with poor cochlear implant-mediated pitch perception through evaluation of an individualized, image-guided approach toward cochlear implant programming on speech and music perception among cochlear implant users. Design, Setting, and Participants: A prospective cohort study of 17 cochlear implant users with MED-EL electrode arrays was performed at a tertiary referral center. The study was conducted from June 2016 to July 2017. Interventions: Theoretical place-pitch maps using FPCT secondary reconstructions and 3-dimensional curved planar re formation software were developed. The clinical map settings (eg, strategy, rate, volume, frequency band range) were modified to keep factors constant between the 2 maps and minimize confounding. The acclimation period to the maps was 30 minutes. Main Outcomes and Measures: Participants performed speech perception tasks (eg, consonant-nucleus-consonant, Bamford-Kowal-Bench Speech-in-Noise, vowel identification) and a pitch-scaling task while using the image-guided place pitch map (intervention) and the modified clinical map (control). Performance scores between the 2 interventions were measured. Results: Of the 17 participants, 10 (58.8%) were women; mean (SD) was 59 (11.3) years. A significant median increase in pitch scaling accuracy was noted when using the experimental map compared with the control map (4 more correct answers; 95% CI, 0-8). Specifically, the number of pitch-scaling reversals for notes spaced at 1.65 semitones or greater decreased when an image-based approach to cochlear implant programming was used vs the modified clinical map (4 mistakes; 95% CI, 0.5-7). Although there was no observable median improvement in speech perception during use of an image-based map, the acute changes in frequency allocation and electrode channel deactivations used with the image-guided maps did not worsen consonant-nucleus-consonant (-1% correct phonemes, 95% CI, -2.5% to 6%) and Bamford-Kowal-Bench Speech-in-Noise (0.5-dB difference; 95% CI, -0.75 to 2.25 dB) median performance results relative to the clinical maps used by the patients. Conclusions and Relevance: An image-based approach toward ochlear implant mapping may improve pitch perception outcomes by reducing place-pitch mismatch. Studies using a longer acclimation period with chronic stimulation over months may help assess the full range of the benefits associated with personalized image-guided cochlear implant mapping. PMID- 30477014 TI - Association of Trauma Type, Age of Exposure, and Frequency in Childhood and Adolescence With Psychotic Experiences in Early Adulthood. AB - Importance: Cross-sectional and longitudinal studies have consistently reported associations between childhood trauma and psychotic experiences and disorders. However, few studies have examined whether the age of exposure or specific trauma types are differently associated with the risk of developing psychotic experiences. Objective: To examine whether exposure to trauma, assessed at multiple age periods between 0 and 17 years of age, is associated with an increased risk of psychotic experiences by age 18 years and whether this association varies according to trauma type as well as age and frequency of exposure. Design, Setting, and Participants: This study used data from the Avon Longitudinal Study of Parents and Children, a large population-based birth cohort in the United Kingdom that recruited women who resided in the Avon Health Authority area and had an expected delivery date between April 1, 1991, and December 31, 1992. Data on psychotic experiences were included in the study, along with trauma variables derived from assessments completed by the parents or self-reported by the participants. The variables represent exposure to any trauma type between ages 0 and 17 years; any trauma type within a distinct age period: early childhood (0-4.9 years), middle childhood (5-10.9 years), or adolescence (11-17 years); specific trauma types between ages 0 and 17 years; and specific trauma types within early childhood, middle childhood, or adolescence. Data were analyzed from January 9, 2017, to November 30, 2017. Main Outcomes and Measures: Suspected or definite psychotic experiences were assessed using the psychosis like symptoms semistructured interview at age 12 years and then at age 18 years. Results: The sample of 4433 participants included 2504 (56.5%) females, with a mean (SD) age of 17.8 (0.38) years. Exposure to any trauma up to age 17 years was associated with increased odds of psychotic experiences at age 18 years (adjusted odds ratio, 2.91; 95% CI, 2.15-3.93). All trauma types from age 0 to 17 years were associated with an increased odds of psychotic experiences. The population attributable fraction for childhood and adolescent trauma on psychotic experiences at age 18 years was 45% (95% CI, 25%-60%). Effect sizes for most trauma types were greater for exposure that was more proximal to the outcome, although CIs overlapped with those for more distal trauma. Evidence supported dose-response associations for exposure to multiple trauma types and at multiple age periods. In an analysis aimed at minimizing reverse causality, adolescent trauma was also associated with past-year incident psychotic experiences at age 18 years. Conclusions and Relevance: These findings are consistent with the thesis that trauma could have a causal association with psychotic experiences; if so, identification of modifiable mediators is required to inform prevention strategies. PMID- 30477015 TI - Ten Essential Characteristics of Care Coordination. PMID- 30477017 TI - Errors in Programming and Coding Affecting Cohorts Included in the Study Deriving and Validating the PROMISE Minimal-Risk Tool. PMID- 30477016 TI - Vision Impairment and Receipt of Eye Care Among Older Adults in Low- and Middle Income Countries. AB - Importance: Vision impairment (VI), including blindness, affects hundreds of millions globally, and 90% of those with VI live in low- and middle-income countries. Cross-national comparisons are important to elucidate the unique and shared factors associated with VI and receipt of eye care in different countries and to target those most in need. Objective: To identify the characteristics associated with VI and receipt of eye care in a sample of low- and middle-income countries. Design, Setting, and Participants: In this study of cross-sectional survey data from wave 1 of the World Health Organization Study on Global Aging and Adult Health, data on sociodemographic characteristics and health were collected from nationally representative samples in China, Ghana, India, Mexico, Russia, and South Africa from 2007 to 2010. Probability sampling with multistage, stratified, random-cluster samples was used to identify households and participants. The survey was completed by 34 159 adults 50 years and older. Data were analyzed from December 2017 to February 2018. Main Outcomes and Measures: We analyzed associations of individual-level and household-level covariates with 3 primary outcomes: distance VI (visual acuity worse than 6/18 in the better-seeing eye), near VI (visual acuity worse than 6/18 in the better-seeing eye), and receipt of an eye examination within the previous 2 years. Results: The study sample in China consisted of 13 350 participants (50.2% female; mean [SD] age, 62.6 [9.0] years); in Ghana, 4725 participants (50.4% female; mean [SD] age, 64.2 [10.8] years); in India, 7150 participants (48.9% female; mean [SD] age, 61.5 [9.0] years); in Mexico, 2103 participants (52.3% female; mean [SD] age, 69.2 [9.2] years); in Russia, 3763 participants (61.1% female; mean [SD] age, 63.9 [10.4] years); and in South Africa, 3838 participants (55.9% female; mean [SD] age 61.6 [9.5]) (all demographic characteristics weighted to reflect respective populations). The weighted proportion of the study sample with distance VI ranged from 9.9% (95% CI, 9.3-10.5) in China to 25.4% (95% CI, 22.0-29.2) in Russia; near VI, from 28.5% (95% CI, 26.9-30.1) in Ghana to 43.1% (95% CI, 41.1-45.1) in India; and receipt of a recent eye examination, from 15.0% (95% CI, 13.8-16.2) in Ghana to 53.1% (95% CI, 49.3-56.8) in Russia. Educational attainment, medical comorbidities, and memory were significantly associated with all outcomes across most low- and middle-income countries. Female sex, low household wealth, food insecurity, no health insurance, rurality, disability, being unmarried, and low social participation were significantly associated with adverse vision-related outcomes, though less consistently. Conclusions and Relevance: There are both common and unique characteristics associated with VI and receipt of eye care across low- and middle-income countries. Our findings suggest that recognizing these factors is important to identify those most at risk and allocate resources optimally. Additional local epidemiological studies are needed. PMID- 30477018 TI - Pediatric Care Coordination. PMID- 30477019 TI - Assessment of Surrogates' Knowledge of Patients' Treatment Goals and Confidence in Their Ability to Make Surrogate Treatment Decisions. PMID- 30477020 TI - Programming and Coding Errors in a Secondary Analysis of a Randomized Clinical Trial. PMID- 30477021 TI - Preparing Surrogates for Complex Decision Making: The Often Neglected Piece of the Advance Care Planning Equation. PMID- 30477022 TI - Misinterpretation of Study Data-Reply. PMID- 30477024 TI - A Global Public Health Victory for Tobacco Plain-Packaging Laws in Australia. PMID- 30477023 TI - Advancing Our Understanding of the Who, When, and Why of Suicide Risk. PMID- 30477025 TI - Looking Within Rather Than Between Countries to Understand the Risk Factors for Vision Impairment. PMID- 30477026 TI - Harnessing the Consumer Movement. PMID- 30477027 TI - Esophageal Diameters in Children Correlated to Body Weight. AB - INTRODUCTION: The development of stenoses after correction of an esophageal atresia or acid and lye burn of the esophagus are well-known problems in pediatric surgery. Currently, stenoses are treated in the majority of cases by repeated balloon dilatations. The diameter of the balloons used is not standardized; standard curves do not exist. The aim of this study was to evaluate the diameter of the esophagus correlated to the body weight of the children as measured in upper gastrointestinal (GI) studies to answer the important question to what extent a stenosis should be dilated. PATIENTS: Within the time period from 2011 through 2016, 60 patients with upper GI studies were selected. Evaluations were blinded to two different examiners. The diameters were measured under maximum contrast filling between the second and third rib (cranial point of measurement) and between the seventh and eighth rib (caudal point of measurement). For both, the anteroposterior and lateral aspect was examined. The diameter was calculated as the arithmetic average of both measurements within one level. The diameters were correlated to the weight of the children. RESULTS: All children (n = 38) within the 3rd to 97th weight percentile were analyzed. Linear correlation and coefficients of 0.67 at the cranial point and 0.70 at the caudal point were found. Mean diameter at the cranial point of measurement was 6.75 mm at the lowest weight (2.6 kg) and 14 mm at 74 kg. Mean weight of these children (standard deviation [SD]) was 25.3 (18.8) kg and median age was 7 years. Within weight groups (0-10 kg; 10-20 kg; 20-35 kg; 35-50 kg; >50 kg), we calculated SD and two side tested critical 95% confidence interval for all measurements (n = 74). CONCLUSION: Although the variation in measurements is considerable, this evaluation gives a reliable hint to which extent esophageal stenoses should be dilated in relation to the body weight. To the best of our knowledge, this is the first investigation to evaluate the diameter of the esophagus in children in relation to the body weight. PMID- 30477028 TI - Black-Colored Ligamentum Flavum Due to Alkaptonuria. AB - Alkaptonuria is a rare metabolic disease caused by deficiency of homogentisic acid oxidase and characterized by bluish-black discoloration of cartilages and skin (ochronosis). Defective production of this enzyme results in the accumulation of homogentisic acid (HGA), a tyrosine degradation product, in the bloodstream. Accumulation of HGA and its metabolites in tissues causes ochronosis. The word ochronosis refers to the dark bluish-black discoloration of connective tissues including the sclera, cornea, auricular cartilage, heart valves, articular cartilage, tendons, and ligaments. Neurogenic claudication resulting from focal hypertrophy of the ligamentum flavum in the lumbar spine due to ochronotic deposits has only been previously reported once in the literature. In this article, we present a 71-year-old male patient with alkaptonuria associated degenerative L3-L4-L5 stenosis, diagnosed after lumbar decompressive laminectomy. PMID- 30477029 TI - ? PMID- 30477030 TI - Adenosine Kinase Deficiency: Report and Review. AB - Adenosine kinase (ADK) deficiency (OMIM [online mendelian inheritance in man]: 614300) is an autosomal recessive disorder of adenosine and methionine metabolism, with a unique clinical phenotype, mainly involving the central nervous system and dysmorphic features. Patients usually present early in life with sepsis-like symptoms, respiratory difficulties, and neonatal jaundice. Subsequently, patients demonstrate hypotonia and global developmental delay. Biochemically, methionine is elevated with normal homocysteine levels and the diagnosis is confirmed through molecular analysis of the ADK gene. There is no curative treatment; however, a methionine-restricted diet has been tried with variable outcomes. Herein, we report a 4-year-old Saudi female with global developmental delay, hypotonia, and dysmorphic features. Interestingly, she has a tall stature, developmental dysplasia of the hip, optic nerve gliosis, and tigroid fundus. We found a mutation not reported previously and we compared the current case with previously reported cases. We alert clinicians to consider ADK deficiency in any neonate presenting with global developmental delay, hypotonia, dysmorphic features, and high methionine levels. PMID- 30477031 TI - Mycoplasma Pneumoniae and Antibodies against Galactocerebroside in a 9-Year-Old Boy with Encephalitis. AB - We report the case of a 9 year-old boy, presenting with an acute encephalitis with cerebrospinal fluid pleiocytosis. MRI showed T2/FLAIR (fluid attenuated inversion recovery) hyperintense signals of basal ganglia and cortex, EEG (electro encephalogram) showed diffuse slowing with epileptic discharges. A repetitively elevated IgM/IgG serologic response against Mycoplasma pneumoniae was observed with polymerase chain reaction in serum and cerebrospinal fluid remaining negative. No other pathogen or antigen could be identified. High IgG and IgM levels against the glycolipid galactocerebroside were detected in serum but not in CSF. After treatment with corticosteroids, the patient fully recovered. Brain MRI and EEG investigation returned completely normal. Besides a primary infection of the central nervous system, M. pneumoniae is associated with a parainfectious encephalitis in children which may be mediated by antibodies to galactocerebroside. PMID- 30477032 TI - Does Time of Wound Complication after Cesarean Delivery Differ by Type of Skin Closure? AB - OBJECTIVE: A high proportion of postcesarean wound complications occur after patients have been discharged from the hospital, increasing personal and health care costs. We undertook this study to evaluate the association between skin closure methods (suture vs. staple) following a cesarean delivery and the frequency of wound complications occurring after hospital discharge. METHODS: This is a secondary analysis of data from a randomized trial in which women undergoing cesarean delivery at >=24 weeks' gestation were randomized to receive metallic staples or subcuticular suture for skin closure after surgery. Staples were removed at the time of hospital discharge on postoperative days 3 to 4 for Pfannenstiel incisions or days 7 to 10 for vertical. The primary outcome for this analysis was any wound complication occurring after hospital discharge. Wound complications were infections or any wound disruption without infection (including seromas and hematomas). Associations were examined using chi-square and Fisher's exact tests, as appropriate, and multivariable logistic regression. RESULTS: A total of 350 patients with follow-up through 4 to 6 weeks postpartum were included in the analysis: n = 171 received suture closure and n = 179 received staples. In the primary trial, wound complications occurred in 14.5% (n = 26) of individuals with staples and 5.9% (n = 10) with sutures (p = 0.008). Twenty-one (58.3%) of the 36 wound complications occurred after hospital discharge. The incidence of wound complications occurring after hospital discharge was 6.7% (n = 12) of patients receiving staples and 5.3% (n = 9) of those receiving sutures; p = 0.57; relative risk [95% confidence interval]: 1.27 [0.55-2.95]). After multivariable adjustment, type of skin closure method was not associated with wound complication after discharge from the hospital (odds ratio: 1.29; 0.52-3.17). CONCLUSION: Although suture closure compared with staples was associated with fewer wound complications after cesarean delivery, we found no significant differences between closure types in the frequency of wound complications occurring after hospital discharge. PMID- 30477033 TI - Maternal Hypothyroidism during Pregnancy and the Risk of Pediatric Endocrine Morbidity in the Offspring. AB - OBJECTIVE: Previous studies suggested maternal hypothyroidism during pregnancy to be associated with cognitive impairment of the offspring. Scarce data exist regarding long-term endocrine health of the offspring. This study was aimed to assess whether children born to mothers with hypothyroidism during pregnancy are at an increased risk for long-term endocrine morbidity. STUDY DESIGN: A retrospective population-based cohort study compared long-term endocrine morbidity of children born between the years 1991 and 2014 to mothers with and without hypothyroidism. Multiple gestations, fetuses with congenital malformations, and women lacking prenatal care were excluded. Hospitalizations of the offspring up to the age of 18 years involving endocrine morbidity were evaluated according to a predefined set of ICD-9 codes. Kaplan-Meier's survival curves were used to compare the cumulative risk and a Cox multivariable model was used to adjust for confounders. RESULTS: During the study period, 217,910 deliveries met the inclusion criteria; 1.1% of which were with maternal hypothyroidism (n = 2,403). During the follow-up period, the cumulative incidence of endocrine morbidity among children born to mothers with hypothyroidism was 27 per 1,000 person-years and 0.47 per 1,000 person-years in the comparison group (relative risk: 2.14; 95% confidence interval [CI]: 1.21-3.79). The Kaplan Meier's survival curve demonstrated a significantly higher cumulative endocrine morbidity in children born to mothers with hypothyroidism (log-rank test, p = 0.007). In the Cox regression model controlled for maternal age, birth weight, preterm birth, maternal diabetes, hypertensive disorders of pregnancy, induction of labor, and mode of delivery, maternal hypothyroidism was found to be independently associated with pediatric endocrine morbidity in the offspring (adjusted hazard ratio = 1.92, 95% CI: 1.08-3.4, p = 0.025). CONCLUSION: Maternal hypothyroidism appears to be independently associated with long-term pediatric endocrine morbidity of the offspring. PMID- 30477034 TI - Association between the Degree of Twin Birthweight Discordance and Perinatal Outcomes. AB - BACKGROUND: Twin birthweight discordance is associated with adverse outcomes. OBJECTIVE: To determine what degree of twin birthweight discordance is associated with adverse outcomes. STUDY DESIGN: This is a retrospective cohort study of twins with vertex twin A delivered vaginally at 36 to 40 weeks (U.S. Vital Statistics Natality birth certificate registry data 2012-2014). The primary outcome was a composite of neonatal morbidity: 5-minute Apgar < 7, neonatal intensive care unit admission, neonatal mechanical ventilation > 6 hours, neonatal seizure, and/or neonatal transport to a higher level of care. Effect estimates were expressed as incidence rate and adjusted odds ratio (aOR) controlling for confounding using multivariate clustered analysis for between pair effects, and multilevel random effect generalized estimating equation regressions to account for within-pair effects. We adjusted for sex discordance, breech delivery of the second twin, maternal race/ethnicity, nulliparity, age, marital status, obesity, and socioeconomic status. RESULTS: In comparison to birthweight discordance of <=20%, aORs with 95% confidence intervals (CIs) by weight discordance of the primary outcome among 27,276 twin deliveries were as follows: 20.01 to 25% (aOR: 1.46 [95% CI: 1.29-1.65]); 25.01 to 30% (aOR: 1.96 [95% CI: 1.68-2.29]); and 30.01 to 60% (aOR: 2.97 [95% CI: 2.52-3.50]). CONCLUSION: Twin birthweight discordance >20% was associated with increased odds of adverse neonatal outcome. PMID- 30477035 TI - Preterm Delivery Phenotypes in Systemic Lupus Erythematosus Pregnancies. AB - OBJECTIVE: Women with systemic lupus erythematosus (SLE) are at a greater risk of preterm delivery, many of which may be medically indicated (iatrogenic). We investigated preterm delivery phenotypes in SLE and general population comparators and assessed the role of preeclampsia. STUDY DESIGN: We used population-based Swedish Register data (2001-2013) and defined maternal SLE as >=2 SLE-coded discharge diagnoses from the Patient Register with >=1 coded by an appropriate specialist. Women from the general population were identified using the Total Population Register. Preterm delivery was defined as <37 weeks and separated into spontaneous and iatrogenic, as well as later versus extremely preterm (32 to <37 weeks vs. <32 weeks). Maternal comorbidity was assessed, and the proportion mediated by preeclampsia was calculated examining first, subsequent, and all pregnancies. RESULTS: Preterm delivery was more common in SLE for the first (22 vs. 6%) and subsequent (15 vs. 4%) pregnancies among 781 SLE-exposed pregnancies and 11,271 non-SLE pregnancies. Of SLE-exposed first births, 27% delivered before 32 weeks, and 90% were iatrogenic (compared with 47% of non-SLE first births). CONCLUSION: Preterm delivery complicates a greater proportion of SLE pregnancies than general population pregnancies, and a considerable proportion of risk is mediated through preeclampsia. PMID- 30477036 TI - Barriers and Facilitators to Recurrent Preterm Birth Prevention among Low-Income Women: A Qualitative Study. AB - OBJECTIVE: To examine patient perspectives on the experience of preterm birth (PTB) and recommended PTB prevention strategies, focusing on barriers to and facilitators of PTB prevention among low-income women. MATERIALS AND METHODS: This is an observational study using qualitative methodology to investigate barriers to and facilitators of recurrent PTB prevention among low-income pregnant and postpartum women. Participants were either (1) postpartum from an initial spontaneous PTB, (2) pregnant and receiving 17-alpha-hydroxyprogesterone caproate (17P), or (3) pregnant or postpartum and declined/discontinued 17P. Participants completed individual interviews, and transcripts were analyzed using modified grounded theory techniques. RESULTS: Of 33 participants, the majority identified as non-Hispanic black (64%) or Hispanic (27%). Four facilitator themes included patient-centered environment, informed choice, social network, and motivation for a healthy family. Barriers included competing demands, resources, skepticism, and normalization. Three considerations, termed subjective influencers, could support women's decisions to use or decline 17P, including personal beliefs about one's body, the role of the fetus, and beliefs on interventionism. CONCLUSION: The facilitators and barriers identified herein offer insight into the lived experiences of women at a risk of recurrent PTB. Future programs aimed at reducing PTB disparities may benefit from addressing low income minority women's structural and social determinants of PTB prevention. PMID- 30477038 TI - [Are Facebook Ratings Associated with Hospital Quality and Patient Satisfaction? A Cross-Sectional Analysis of Obstetrics Care in German Hospitals]. AB - OBJECTIVE: Social media websites, such as Facebook, have been gaining popularity. Little is known about the usefulness of such online ratings when searching for a hospital. We therefore assessed the association between online Facebook ratings and clinical quality of care measures as well as patient satisfaction for German hospitals in obstetrics care. METHODS: (1) We identified all German hospitals providing services in obstetrics care based on the German external quality assurance system (2015) and gathered relevant data. (2) Based on a structured dialogue, we determined quality of care results for all hospitals and (3) assigned them to 3 different performance groups. (4) We collected Facebook online ratings as well as (5) patient satisfaction (Patients' Experience Questionnaire, PEQ) results for all included hospitals. (6) We applied the Spearman rank coefficient of correlation. RESULTS: We could find a Facebook page for almost all of the included hospitals (728/752; 96.8%). Facebook hospital ratings in general were mostly positive, especially in obstetrics care. There was no association between Facebook hospital ratings (rho=0.007; p=0.860) or those for obstetrics care (rho=0.008; p=0.856) and clinical quality of care measures. In contrast, we could detect an association between Facebook ratings and patient satisfaction scores. The association was stronger for overall hospital ratings (rho=0.383 0.543; p<0.001) than those for obstetrics care (rho=0.111-0.250; p<0.05) in particular. CONCLUSION: So far, Facebook online ratings are of limited usefulness in guiding patients towards high-performing hospitals from a clinical point of view. However, our findings suggest that Facebook ratings may serve as an indicator of patient satisfaction when searching for hospitals. PMID- 30477037 TI - Development of the Metabolic Syndrome: Study Design and Baseline Data of the Lufthansa Prevention Study (LUPS), A Prospective Observational Cohort Survey. AB - The Lufthansa Prevention Study (LUPS) study is a prospective observation of a healthy worker cohort to identify early changes in metabolism leading to the Metabolic Syndrome (MetS) and to analyze their relation to behavioral factors like nutrition, physical activity, psychological status, and to underlying genetic conditions. The LUPS study recruited a sample of 1.962 non-diabetic healthy adults between 25-60 years, employed at a flight base of Lufthansa Technik GmbH in Hamburg, Germany. Baseline assessments included anthropometric measures, blood and urine samples and medical history. Psychosocial variables, dietary habits and life-style risk factors were assessed via self-reported questionnaires.In this report we describe the study design and present baseline parameters including the prevalence of the MetS using different classification criteria. The MetS was present in 20% of male and 12% of female subjects according to the 'Harmonizing the metabolic syndrome' definition. The prevalence varies between 2.6% in male and 2.3% in female subjects up to 48% in male and 41% in female subjects according to different classification criteria of MetS.In conclusion, this first cross-sectional view on the LUPS data confirms the expectation that this cohort is rather healthy and thus provides the opportunity to analyze early changes associated with the development of the MetS. The LUPS study is registered as a clinical trial NCT01313156. PMID- 30477039 TI - [Recognised Occupational Disease and Squamous Cell Carcinoma in Periocular Region]. PMID- 30477040 TI - [Intravitreal Therapy Combining Dexamethasone and Bevacizumab in Treating Radiation Retinopathy and Opticopathy]. AB - Radiation Retinopathy is a progressive chronic disease triggered by ionising radiation and is characterised by vascular endothelial damage that can lead to macular edema, optic disc edema and proliferative retinopathy. We discuss a case of a patient with radiation retinopathy and optic disc edema who we treated with a combination of intravitreal bevacizumab and dexamethasone. After 3 injections of bevacizumab, and one of dexamethasone, the patient experienced a resolution of optic disc edema and a marked increase of his visual acuity and remained stable throughout the follow-up period. PMID- 30477041 TI - A Review of Plants Used in South African Traditional Medicine for the Management and Treatment of Hypertension. AB - South Africa contains 9% of the world's higher plants, and despite its rich biodiversity, it has one of the highest prevalence of hypertension in Africa. This review provides information on medicinal plants embraced in South Africa for hypertension management, with the aim of reporting pharmacological information on the indigenous use of these plants as antihypertensives. This review not only focuses on the activity of antihypertensive medicinal plants but also reports some of its phytochemical constituents and other ethnopharmacological and therapeutic properties. Information obtained from scientific and or unpublished databases such as Science Direct, PubMed, SciFinder, JSTOR, Google Scholar, Web of Science, and various books revealed 117 documented antihypertensive plant species from 50 families. Interestingly, Asteraceae topped the list with 16 species, followed by Fabaceae with 8 species; however, only 25% of all plant species have demonstrated antihypertensive effects originating from both in vitro and in vivo studies, lending credence to their folkloric use. Only 11 plant species reportedly possess antihypertensive properties in animal models, with very few species subjected to analytical processes to reveal the identity of their bioactive antihypertensive compounds. In this review, we hope to encourage researchers and global research institutions (universities, agricultural research councils, and medical research councils), particularly those showing an interest in natural products, for the need for concerted efforts to undertake more studies aimed at revealing the untapped potential of these plants. These studies are very important for the development of new pharmaceuticals of natural origin useful for the management of hypertension. PMID- 30477042 TI - The Effect of Remnant Preservation on Tibial Tunnel Enlargement in Anterior Cruciate Ligament Reconstruction with Polyethylene Terephthalate Artificial Ligament in a Large Animal Model. AB - An enlarged bone tunnel may affect the graft-bone integration and pose a problem for revision anterior cruciate ligament (ACL) surgery. The purpose of this study was to evaluate the effect of remnant preservation on tibial tunnel enlargement in ACL reconstruction with polyethylene terephthalate (PET) artificial ligament. Twenty-four skeletally mature male beagles underwent ACL reconstruction with PET artificial ligament for both knees. One knee was reconstructed with remnant preservation using sleeve technique (remnant group), while the contralateral was reconstructed without remnant preservation (control group). The animals were sacrificed at 1 day, 6 weeks, and 12 weeks after surgery for further evaluation including macroscopic observation, microcomputed tomography (micro-CT), histological assessment, and biomechanical testing. The remnant group had better synovial coverage than the control group at 6 and 12 weeks after surgery. The micro-CT analysis showed the tibial tunnel area (TTA) of the remnant group was significantly smaller and the bone volume/total volume fraction (BV/TV) value was higher than those of the control group at 6 and 12 weeks. Moreover, TTA and BV/TV at each time point were divided into three groups according to the different grade of synovial coverage. Significant association was observed between the synovial coverage degree and the TTA and BV/TV values. The histological assessment revealed that the interface width between the graft and host bone in the remnant group was smaller than that in the control group in the tibial tunnels at 6 and 12 weeks. Moreover, the remnant group had better failure load and stiffness than the control group at 12 weeks. The remnant preservation using sleeve technique could effectively promote the synovial coverage of the graft, decrease the risk of tibial tunnel enlargement by sealing the bone tunnel entrance, and enhance the biological environment for graft-bone healing after ACL reconstruction using PET artificial ligament. This technique provides a potential solution for bone tunnel enlargement following artificial ligament surgery for the acute ACL rupture in the clinical practice. PMID- 30477043 TI - Effective Graft Preservation by Following a Standard Protocol for the Treatment of Knee Joint Infection after Anterior Cruciate Ligament Reconstruction. AB - Knee joint infections constitute a rare but devastating complication after anterior cruciate ligament (ACL) reconstruction. We hypothesized that effective infection therapy and graft preservation is possible following a standard treatment protocol. We retrospectively analyzed all patients admitted to our center with suspected infection of the knee after ACL reconstruction between 2010 and 2012. Following a standardized protocol, blood samples were drawn and synovial fluid was analyzed. Furthermore, the protocol consisted of arthroscopic lavages and debridements of the anterior and posterior joint compartments over three incisions, and targeted antibiotic therapy over a period of 6 weeks. Surgeries were repeated every 2 days until clinical signs of infections resolved, but at least two times. Mean observation period was 10 months. Forty-one patients aged 31 ( +/- 9.9) years and admitted 14 ( +/- 7.5) days after ACL reconstruction were included. Pathogens were found in 34 patients and coagulase negative staphylococci were isolated most commonly (31 isolates in 28 patients). Quinolones were the most commonly used antibiotic agents. Mean number of operations was 3.8 ( +/- 1.4). Following the standard protocol, primary successful infection treatment with graft preservation was possible in 37 of the included 41 patients. Graft preservation was achieved in 100% of the included patients with Gaechter stage 1 and 2 infections. Knee joint infection after ACL reconstruction was successfully treated following a standardized protocol, and graft preservation was reliably achieved especially in cases with infections at an early stage. PMID- 30477044 TI - Total Knee Arthroplasty in Patients of Advanced Age: A Look at Outcomes and Complications. AB - Total knee arthroplasty (TKA) is one of the most highly successful orthopaedic procedures performed in North America. It is also one of the most common procedures performed, and its incidence continues to increase. Despite this, it is the opinion of many that patients of advanced age groups are not ideal candidates to undergo such procedures secondary to the concern over higher complication rates and poorer functional outcomes. This review article attempts to analyze the current body of literature concerning TKA outcomes and to evaluate some of the issues that are more specific to this population when they undergo TKA. It is our hypothesis that the literature does not support this popular misconception, and that older patients who do not have significant medical comorbidities are good candidates to undergo primary TKA. However, certain cohorts of this population are not ideal candidates to undergo this procedure. Also, certain joint reconstructive procedures, such as simultaneous and staged bilateral TKA, are higher risk procedures in this patient cohort. PMID- 30477045 TI - Noninterventional Therapies for the Management of Knee Osteoarthritis. AB - The goal of the practitioner managing a patient with knee osteoarthritis (OA) is to minimize pain and optimize their function. Several noninterventional (noninjectable) therapies are available for these individuals, each having varying levels of efficacy. An individualized approach to the patient is most beneficial in individuals with knee OA and the treatment plan the practitioner chooses should be based on this principle. The focus of this article is to provide an up-to-date overview of the treatment strategies available, evidence to support them, and in whom these treatments would be most appropriate. These include exercise (aerobic and resistance), weight loss, bracing and orthotics, topical and oral analgesic medications, therapeutic modalities, and oral supplements. PMID- 30477047 TI - Paediatric and adult bronchiectasis: Vaccination in prevention and management. AB - Bronchiectasis has received increased attention recently, including an emphasis on preventing infective exacerbations that are associated with disease progression and lung function decline. While there are several bacteria and viruses associated with bronchiectasis, licensed vaccines are only currently available for Streptococcus pneumoniae, Haemophilus influenzae (H. influenzae protein D as a conjugate in a pneumococcal vaccine), Mycobacterium tuberculosis, Bordetella pertussis and influenza virus. The evidence for the efficacy and effectiveness of these vaccines in both preventing and managing bronchiectasis in children and adults is limited with the focus of most research being on other chronic lung disorders, such as chronic obstructive pulmonary diseases, asthma and cystic fibrosis. We review the existing evidence for these vaccines in bronchiectasis and highlight the existing gaps in knowledge. High-quality experimental and non-experimental studies using current state-of-the-art microbiological methods and validated, standardised case definitions are needed across the depth and breadth of the vaccine development pathway. PMID- 30477046 TI - Paediatric intentional head injuries in the emergency department: A multicentre prospective cohort study. AB - OBJECTIVE: Although there is a large body of research on head injury (HI) inflicted by caregivers in young children, little is known about intentional HI in older children and inflicted HI by perpetrators other than carers. Therefore, we set out to describe epidemiology, demographics and severity of intentional HIs in childhood. METHODS: A planned secondary analysis of a prospective multicentre cohort study was conducted in 10 EDs in Australia and New Zealand, including children aged <18 years with HIs. Epidemiology codes were used to prospectively code the injuries. Demographic and clinical information including the rate of clinically important traumatic brain injury (ciTBI: HI leading to death, neurosurgery, intubation >1 day or admission >=2 days with abnormal computed tomography [CT]) was descriptively analysed. RESULTS: Intentional injuries were identified in 372 of 20 137 (1.8%) head-injured children. Injuries were caused by caregivers (103, 27.7%), by peers (97, 26.1%), by siblings (47, 12.6%), by strangers (35, 9.4%), by persons with unknown relation to the patient (21, 5.6%), other intentional injuries (8, 2.2%) or undetermined intent (61, 16.4%). About 75.7% of victims of assault by caregivers were <2 years, whereas in other categories, only 4.9% were <2 years. Overall, 66.9% of victims were male. Rates of CT performance and abnormal CT varied: assault by caregivers 68.9%/47.6%, by peers 18.6%/27.8%, by strangers 37.1%/5.7%. ciTBI rate was 22.3% in assault by caregivers, 3.1% when caused by peers and 0.0% with other perpetrators. CONCLUSIONS: Intentional HI is infrequent in children. The most frequently identified perpetrators are caregivers and peers. Caregiver injuries are particularly severe. PMID- 30477048 TI - Candida tropicalis biofilm formation and expression levels of the CTRG ALS-like genes in sessile cells. AB - Candida tropicalis is an emergent pathogen with a high rate of mortality associated with it; however, less is known about its pathogenic capacity. Biofilm formation (BF) has important clinical repercussions, and it begins with adherence to a substrate. The adherence capacity depends principally on the cell surface hydrophobicity (CSH) and, at a later stage, on specific adherence due to adhesins. The ALS family in C. tropicalis, implicated in adhesion and BF, is represented in several CTRG genes. In this study, we determined the biofilm forming ability, the primary adherence, and the CSH of C. tropicalis, including six isolates from blood and seven from urine cultures. We also compared the expression of four CTRG ALS-like genes (CTRG_01028, CTRG_02293, CTRG_03786, CTRG_03797) in sessile vs planktonic cells, selected for their possible contribution to BF. All the C. tropicalis strains were biofilm producers, related to its filamentation capacity; all the strains displayed a high adherence ability correlated to the CSH, and all the strains expressed the CTRG genes in both types of growth. Urine isolates present, although not significantly, higher CSH, adherence and biofilm formation than blood isolates. This study reveals that three CTRG ALS-like genes - except CTRG_03797 - were more upregulated in biofilm cells, although with a considerable variation in expression across the strains studied and between the CTRG genes. C. tropicalis present a high biofilm capacity, and the overexpression of several CTRG ALS-like genes in the sessile cells suggest a role by the course of the biofilm formation. PMID- 30477050 TI - Thyroid Dysfunction and Systemic Rheumatic Diseases. PMID- 30477051 TI - Factors for Severe Outcome in Scrub Typhus: A Hospital Based Study in Sub Himalayan Region. AB - Background: Scrub typhus is a re-emerging zoonotic rickettsial infection. Mortality is approximately 15% in some areas due to missed or delayed diagnosis. There had been only few studies on the markers for the severity of the disease, so this study has been planned to provide the knowledge regarding various aspects of scrub typhus in adult age group to detect early signs of severity . Methods: All the patients more than 18 years of age admitted with febrile illness with positive IgM ELISA for scrub typhus with or without eschar were included in the study. The clinical profile was observed. The predictors of mortality were explored using univariate and multivariate analysis. Results: On linear regression analysis and logistic regression analysis altered sensorium, low serum albumin, hepatic dysfunction, renal dysfunction, septic shock, MODS, ARDS, duration of fever > 7 days, day of receiving treatment > 7 days at presentation were significantly associated with high in- hospital mortality. Conclusions: Early treatment with doxycycline should be instituted at the clinical suspicion of scrub pending investigation as it is life saving. Close follow up of the patient should be done to indentify subtle signs of organ dysfunction to start early supportive treatment. PMID- 30477049 TI - Gastro Oesophageal Reflux Disease Shadowing Anxiety Disorder Causing Prolonged Exposure to Proton Pump Inhibitor. AB - Anxiety disorders are the most prevalent psychiatric disorders in the general population. The relationship between dyspepsia and particularly gastroesophageal reflux disease (GERD) and psychiatric comorbidity such as anxiety is poorly defined. However, GERD was noted to be strongly associated and often coincident in onset with generalized anxiety disorder in the community. In this paper, we report the case of an adult man who presented with severe weight loss and underlying GERD, and was later found to have an anxiety disorder as the cause of both. PMID- 30477052 TI - Anaemia in Newly Diagnosed Patients of Rheumatoid Arthritis and its Correlation with Disease Activity. AB - Method: Fifty nine patients of RA fulfilling 2010 ACR/EULAR criteria of RA having disease duration less than two years were included in the study. Haemoglobin (Hb) levels were measured. Disease activity was assessed by DAS-28 score. Results: Among 40/59 (67.80%) anemic cases, 22/40 (55%) patients had anaemia of chronic disease (ACD), 11/40 (27.50%) patients had Iron deficiency anemia (IDA), 3/40 (7.5%) patients had vitamin B12 deficiency, 1/40 (2.50%) patient had folate deficiency and 3/40 (7.50%) patients had combined IDA and vitamin B12 deficiency. Duration of disease, rheumatoid factor positivity and occurrence of erosive disease were not significantly different among anaemic and nonanaemic patients (p>0.05 for each). Mean ESR (p>0.02) and DAS-28 (p>0.001) were statistically significantly different among anaemic and nonanaemic patients. Haemoglobin level had significant negative correlation with disease activity (DAS28) in RA cases (r -0.5533, p<=00.001). Conclusion: Anemia was seen in higher frequency in RA patients. Haemoglobin had significantly negative correlation with disease activity (DAS 28) in RA. . PMID- 30477053 TI - Thiopurine S-methyltransferase (TPMT) Mutation Prevalence and Myelosuppression Frequency in North Indian Patients with Autoimmune Disorders. AB - Background: For many years, azathioprine and its active metabolite 6 merceptopurine are used as immunosuppressants for treatment of autoimmune disorders. However, azathioprine has low therapeutic index with myelosuppression as its predominant toxicity which is linked with thiopurine S-methyltransferase (TPMT) enzyme activity, which is involved in drug metabolism. TPMT activity is controlled by variants in TPMT gene. We aimed to estimate prevalence of TPMT gene mutations in North Indian patients with autoimmune disorders and to assess myelosuppression in these patients. Methods: We analysed 176 adult patients with autoimmune disorders coming to SGR hospital. TPMT mutation was analysed by PCR RFLP and further validated by reverse dot blot. Patients with wild type TPMT genotype were followed for development of myelosuppression. Results: Out of total 176 patients studied, TPMT mutation was present in 3 patients showing prevalence of 1.7%. Two patients (1.13%) were heterozygous for TPMT*1/*3C genotype and only one patient (0.56%) was heterozygous for TPMT*1/*3A. Other TPMT mutant alleles (TPMT*2 and *3B) were not identified. No homozygous TPMT mutants were identified. Allele frequencies of TPMT*3A; TPMT*3C were 0.28% and 0.56% respectively. Three patients positive by PCR-RFLP were also found to be positive by reverse dot blot analysis; depicting 100% concordance between two methods. Excluding three positive patients, follow up was available in 114/173 patients. Follow up ranged from 28 days to 1.5 years. Twenty (17.5%) patients developed myelosuppression with majority (60%) within 1-5 months of therapy. Leucopenia along with neutropenia was the most common presentation (11.4%) followed by anaemia (7.8%) and thrombocytopenia (6.1%) . Conclusion: TPMT mutation prevalence is low in North Indian adult patients with autoimmune disorders as compared to Western population. In our study patients even with wild type TPMT genotype (17.5%) developed myelosuppression underscoring the importance of TPMT mutation as the only factor contributing to myelosuppression. PMID- 30477054 TI - Serum IgE Level among Coir Workers with Asthma: A Hospital Based Descriptive Study from Alappuzha, Kerala. AB - Background: Coir industry provides a major share of occupation to the natives of Alappuzha district of Kerala State, South India. A significant proportion of workers in this industry have been found to have nasobronchial symptoms. A pilot study conducted in our institute, among coir workers revealed that more than 35% of coir workers suffered from nasobronchial allergy and it is directly proportional the years spent in the work field. This study was conducted to find out whether coir worker's asthma is immunologically mediated or not and also to find out the difference if any in the Ig E level between males and females with coir workers asthma. Methods: The study was done as a descriptive study. Coir workers with symptoms suggestive of asthma who attended the outpatient clinic of Government TD Medical College Hospital Alappuzha during 2005-2006 were included in the study. Detailed occupational history was taken using a semi structured interview schedule. Symptom profile of the patients were assessed in detail followed by clinical examination and spirometry. The serum Ig E level was estimated by ELISA technique. Data were entered in MS Excel and statistical analysis was performed with Mann-Whitney U test using SPSS version 16. P value < 0.05 was taken as the cut off point for statistical significance. Results: The total number of patients included in the study was 62 out of which 25 were males and 37 were females. (Mean age: 36 years, Males: 33 years and Females: 38 years). All except one patient showed latent period before developing asthmatic symptoms and it varied from 6 months to 44 years, with a mean of 9.9 years. The latency period was considerably more in males.56 patients (91%) had elevated total serum IgE (mean of 1311 IU). Male patients had a considerably higher value of serum Ig E. Conclusion: The serum IgE levels were found to be higher in coir workers with asthmatic symptoms and hence it is reasonable to believe that coir workers asthma is of largely immunological in origin. PMID- 30477055 TI - Hyponatremia in ICU. AB - Background: :Hyponatremia is defined as serum sodium level <135 meq/L. It is the most common electrolyte abnormality seen in hospital admissions worldwide. The proportion is even higher in the ICU setting. A wide variety of factors influence the outcome of the hyponatremic patient. Present study is designed to approach to analyse etiology, clinical features, co-morbid factors, severity of hyponatremia, rate of correction, and impact of treatment on outcome of these diverse group of patients in ICU. Aim: 1) To find proportion of patients presenting with hyponatremia and requiring medical ICU admission in a tertiary care set up. 2) To study the etiology and clinical features of hyponatremia in patients requiring ICU admission. 3) To compare and study the effect of various factors on the outcome of hyponatremic patients in the ICU. Methods: This study was a cross sectional observational study in tertiary care hospital. All indoor general medicine ward admissions over a period of 18 months were screened for the presence of hyponatremia and patients requiring Medical ICU care and satisfying inclusion criteria were studied. Serial serum electrolytes and urine sodium were tested for all patients in the ICU satisfying the inclusion criteria. Type of fluid given and daily correction of serum sodium of all patients were noted. Outcome was measured in terms of mortality, duration of stay in ICU, number of days required for sodium correction and complications of treatment if any. Patients were followed up till hospital discharge or death.. Results: In this study, 5.2% of total admissions had hyponatremia. Among the ICU admissions, the different symptoms attributed to hyponatremia included nausea (69.3%), malaise (80%), drowsiness (61.3%), confusion (41.3%), lethargy (24%), frequent falls (1.3%), convulsions (2.7%), altered sensorium (41.3%) and delirium (9.3%). SIADH was the most common cause of hyponatremia in these patients (32%). Serum sodium levels of patients on admission ranged from 82 - 133 meq/L, with average serum sodium being 124meq/L. Overall mortality among the hyponatremic ICU admissions was 26/75, 34.6%, which was higher than the total ICU mortality of 26% in same duration (p = 0.1). There was a significant increase in duration of stay in ICU in patients with various co-morbidities (p=0.003). There was a significant association between Glasgow Coma Scale (GCS) and serum sodium levels, (p = 0.002). Blood pressure and hydration status did not significantly influence outcome. Lower serum sodium on admission was associated with a lower survival (p= 0.041). Sodium correction of < 5 m eq/day was associated with an increased mortality(p = 0.04), whereas sodium correction of > 10 m eq/day was not associated with increased mortality, but an increased risk of EPM, which was seen in one patient. Conclusion: Most common cause of hyponatremia in ICU patients is SIADH. Longer duration of stay is seen in the presence of different co morbidities. A lower GCS and a lower serum sodium on admission is associated with lower survival. Type of fluid used for hyponatremia correction did not influence the outcome. Under correction of hyponatremia in first 24 hours or inadequate correction was associated with a poorer outcome. Overcorrection was not associated with any survival benefit, but was associated with risk of EPM. PMID- 30477056 TI - Prevalence and Clinical Use of Anti-Thyroid Antibodies in RA Patients: A Prospective Case-Control Study. AB - Aim: To evaluate the prevalence of anti-thyroid antibodies in a cohort of rheumatoid arthritis (RA) patients from south India and their clinical use. Methods: A cross-sectional epidemiological study was conducted including 1217 patients aged more than 14 years with fever and thrombocytopenia admitted in the medical wards from October 2013 to September 2014. Detailed clinical examination and routine investigations were done; specific investigations like blood culture, widal test, antigen test for malaria, IgM ELISA leptospira, IgM ELISA dengue, bone marrow aspiration/biopsy etc. were done as and when indicated. The data are presented as percentage and numbers. Rates and ratios are computedThe prospective case-control study, conducted for 3 consecutive months in a tertiary care hospital based in India, evaluated 103 RA patients (active group) and 36 age matched healthy controls without the disease. Both the control and active groups were compared for thyroid autoantibodies, and the clinical evaluation included assessment of swollen joint counts (SJC), tender joint counts (TJC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), pain scale, disease activity score (DAS), rheumatoid factor (RF), anti-nuclear antibody (ANA) and anti-cyclic citrullinated peptide (anti-CCP). The active group subjects were further subdivided into RA patients with and without hypothyroidism, and were compared for normal and abnormal levels of thyroid autoantibodies and the variations were statistically analysed. Results: The corresponding mean age of the subjects belonging to the active and control groups were 47.09+/-11.29 and 41.03+/-11, with a female to male ratio of 1:0.12 and 1:0.29 respectively. Among the various thyroid autoantibodies compared between the active and control groups, a significant correlation (P=0.00936) was observed for anti-TTG antibodies. Also, the study has noted a significantly elevated level of anti-TPO antibodies in RA patients with hypothyroidism compared to the group without hypothyroidism (P=0.0074). Conclusion: A significantly increased level of anti-TPO antibodies was noted in RA patients with hypothyroidism. PMID- 30477057 TI - Socio-demographic and Clinico-Epidemiological Study of Scrub Typhus in Two Tertiary Care Hospitals of Kolkata. AB - Background and Aims : Scrub typhus is the commonest of the rickettsial diseases in India and is difficult to diagnose. Untreated cases have fatality rates of 30 45%. Eschar is present in 7-97% cases. Pneumonia and acute respiratory distress syndrome (ARDS) are frequent complications. Serum immunoglobulin M capture ELISA is the most sensitive test. Doxycycline is the drug of choice. Our objectives were to study the socio-demographic and clinic-epidemiological profiles of scrub typhus cases in two tertiary care hospitals in Kolkata, India. This was the first study of scrub typhus in Southern West Bengal and its neighboring areas. . Methods: Study was conducted over 16 months and all fever cases of Tropical Medicine / Medicine outpatients' clinics were evaluated. Results: Fourteen cases were diagnosed. 78.6% were from rural areas and 35.7% were farmers. Headache and fever were the commonest presenting complaints while eschar was found in only 21.4%. Serum IgM scrub typhus antibody was positive in all cases . Conclusion: Scrub typhus should be a differential diagnosis in acute febrile illness cases, as early diagnosis and therapy prevents complications. PMID- 30477058 TI - A Study of Prevalence of Peripheral Arterial Disease in Type 2 Diabetes Mellitus Patients in a Teaching Hospital. AB - Introduction: Diabetes mellitus is a major health problem in India as also the world. Peripheral arterial disease (PAD) is a known complication of diabetes which is relatively less commonly studied in comparison to other complications. The present study was undertaken to study the prevalence of PAD in diabetic patients in a teaching hospital. Materials and Methods: 200 type 2 diabetic patients from indoor as well as outdoor of a teaching hospital were included in the study. Ankle brachial pressure index was used to assess PAD. ABPI values of 0.9 or less were taken as indicative of PAD. Results: Out of 200 patients 72(36%) had evidence of PAD. There was a significant association between PAD and duration of diabetes, waist circumference, hypertension and microvascular complications. Conclusion: The prevalence of PAD in Type 2 diabetics was found to be 36% in our study. Screening for PAD should be done in all diabetic patients to detect this complication early. PMID- 30477059 TI - Prevalence and Clinical Correlates of Microalbuminuria in Patients with Essential Hypertension - A Tertiary Care Center Cross Sectional Study. AB - Introduction: Albuminuria is predictor of target organ damage and worse cardiovascular outcomes. Microalbuminuria has been found in a large number of patients with essential hypertension. Aim of our study was to evaluate the frequency of microalbuminuria in essential hypertension and to study its correlation with severity of hypertension and target organ damage. Materials and Methods: This cross-sectional study was conducted at the outpatient clinic of General Medicine department of Pt. B D Sharma PGIMS, Rohtak. Hundred patients of essential hypertension (group A) in the age group of 18-65 years were included in the study. A control group (group B) consisting of hundred healthy normotensive, age and sex matched volunteers were also entered into the study. Arterial blood pressure was measured by digital sphygmomanometer after five minutes of rest; the values reported represented the average of three consecutive measurements taken over a 15-minute period. Urine albumin excretion (UAE) was estimated by an immunoturbidometry method. Microalbuminuria was defined as UAE between 30 and 300 mg/24 hours. Statistical analysis was performed by standard methods to measure rates and proportions; chi square test was used for analyzing the associations between the variables. Results: In this study it was observed that prevalence of microalbuminuria in essential hypertension was 47%. Risk factors for microalbuminuria included higher age, SBP and MAP. Microalbuminuria was associated with dyslipidemia, deranged renal parameters and end organ damage in form of LVH, ischemic changes, hypertensive retinopathy and renal dysfunction. In conclusion, this study confirmed that increased urinary albumin excretion is associated with a worse pattern of cardiovascular risk factors and is a marker of concomitant cardiovascular damage in essential hypertension. Conclusion: Microalbuminuria can therefore be regarded as a useful, relatively inexpensive, integrated marker to help identify patients at higher cardiovascular risk for whom more aggressive preventive strategies and additional treatment measures may be advisable. PMID- 30477060 TI - Cerebrospinal Fluid Lactate in Tubercular Meningitis: Diagnostic or Prognostic Marker. AB - Background: Diagnosis of tubercular meningitis (TBM) continues to be a clinical challenge and available microbiological tests fail to attain the required accuracy standards. As a result, most guidelines for the diagnosis and management of TBM depend on clinical setting, cerebrospinal fluid (CSF) analyses including adenosine deaminase activity (ADA), and imaging to guide decisionmaking. Delay in diagnosis leads to high mortality and morbidity. As there is scarcity of data on CSF lactate in TBM and its role as a diagnostic and prognostic marker, study of CSF Lactate in TBM Patients was undertaken. Materials and Methods: In this hospital based cross sectional study all admitted patients of meningo encephalitis aged more than 15 years who fulfilled the diagnostic criteria for TBM were included. Routine haematological and biochemical investigations were done in all the patients. The CSF analysis was done including all routine microscopic parameters, lactate, Gram's stain, AFB and culture. Patients included were classified as definite, probable, or possible TBM as per WHO diagnostic criteria and were classified into three clinical stages using criteria laid down by the British Medical Research Council. Results: Fifty five patients fulfilling the diagnostic criteria for tubercular meningitis were studied. Most of the patients were in stage II according to severity. An increase in CSF lactate and CSF ADA levels with increase in severity of clinical stage of TBM was observed. Other CSF parameters and imaging were not significantly different in various groups. Conclusion: CSF lactate levels of study patients were higher than normal and showed increasing trend from possible to definite diagnosis of TBM suggesting that CSF lactate could be a predictor of definite diagnostic class of TBM though more studies with large number of patients are needed to prove its utility as prognostic tool. PMID- 30477061 TI - Evaluation of Febrile Thrombocytopenia Cases in a South Indian Tertiary Care Hospital. AB - Objective: This study is aimed at analyzing the clinical symptomatology and hematological evaluation with an emphasis on platelet indices in relation to predicting the outcome of the febrile thrombocytopenic patients admitted in Coimbatore medical college hospital.. Methods: This is a prospective study involving 100 adult patients who presented to our hospital with fever and thrombocytopenia (platelet <1,50,000). This study excluded patients with known causes of thrombocytopenia like ITP and patients on chemotherapy etc. Results: Out of 100 patients 34 were dengue positive, 66 were dengue negative. Dengue specific symptoms like myalgia and retro-orbital pain were present in 58.88% of dengue positive and 10.60% of dengue negative patients. Laboratory evaluation revealed sharp rise in hematocrit with fall in platelet count in both the groups more significant in dengue positive group. Bleeding manifestation and rashes were 29.4% and 26.4% in dengue positive, 12.12% and 7.57% in dengue negative group respectively. MPV was significantly lower in patients with bleeding manifestations irrespective of platelet count in both the groups. Mortality in our study was 2%. Conclusion: : MPV is an independent predictor of bleeding manifestation and poor outcome. Dengue virus may suppress the bone marrow as evidenced by alteration in MPV in addition to other mechanisms of thrombocytopenia. PMID- 30477062 TI - Clinical Study of Cardiac Autonomic Dysfunction and QT Dispersion in Newly Diagnosed HIV/AIDS Patients and its Correlation with CD4 Count. AB - Objective: To evaluate the cardiac autonomic dysfunction and QT dispersion in newly diagnosed HIV/AIDS patients and to correlate the cardiac autonomic dysfunction with CD4 count. Methods: It was a prospective study conducted on 50 patients (25 HIV positive without AIDS and 25 HIV with AIDS) and 50 healthy controls in the department of General Medicine, JLN Hospital, Ajmer. Autonomic function was assessed by Ewing battery of autonomic function tests and QT dispersion was calculated. Results: In the present study 16% of HIV positive with AIDS had abnormal autonomic dysfunction and 4% of HIV positive without AIDS had abnormal autonomic dysfunction. 48% of patients in AIDS group and 16% of patients in HIV positive without AIDS group showed abnormal QT dispersion. There was no statistically significant correlation with CD4 count. Conclusion: Apart from opportunistic infections, autonomic dysfunction itself can contribute to mortality and morbidity in HIV/AIDS patients. Our study showed that cardiac autonomic dysfunction is a common and relevant clinical problem. It is significantly affected in both HIV positive without AIDS and HIV positive with AIDS groups. QT dispersion is a sensitive predictor of cardiac dysautonomia. But there is no statistically significant correlation with CD4 count. PMID- 30477063 TI - Clinical Profile of Primary Sjogrens Syndrome with Hypokalemic Periodic Paralysis. AB - Introduction: Primary Sjogren's Syndrome (pSS) with Hypokalemic Periodic Paralysis(HPP) whether an association or a different clinical subset needs review. Methods: Cross-sectional retrospective study of subjects of Primary Sjogren's Syndrome with Hypokalemic Periodic Paralysis(HPP) identified from database maintained at Centre For Rheumatic Diseases, Pune since 1996 with records of over 50000 patients. The diagnosis was clinical. Clinical and investigations data was extracted pertaining to initial examination and follow up. Standard investigations & ELISA, immunoblot and nephelometry to assay autoantibodies (AAb) were done. Results: 16 patients of Primary Sjogren's Syndrome (pSS) with Hypokalemic Periodic Paralysis (HPP) were identified in the period 2000-2014. Presenting feature was HPP in 86% with Dry eye (4%) and Arthralgias (10%) in remaining. Distal Renal Tubular Acidosis was identified in all. All were females with average age of 26 years. Symptomatic ocular sicca noted in 60% & Oral sicca in 50% patients. Other features - Arthralgias (91%), arthritis (42%), mucositis (38%), Neuropathy (30%), skin rash (20%) cytopenias (19%), Erosive arthritis (10%), interstitial lung disease (10%) and Raynaud Phenomenon (10%). 100% were positive for ANA. SSA was positive in 100%, SSB in 50% of patients & Rheumatoid Factor in 70 %. Hypothyroidism was associated in 70% patients. Conclusion: We present a large series of Primary Sjogren's Syndrome with Hypokalemic Periodic Paralysis(HPP) from India. Prominent features of female dominance, younger age of onset and SSA positivity noted in this cohort of patients on Routine clinical and serology phenotype suggests existence of a distinct subset. HPP was presenting feature in majority. PMID- 30477064 TI - Efficacy and Safety of Levocloperastine in the Treatment of Dry Cough: A Prospective Observational Study. AB - Purpose/Aim: To evaluate effectiveness and safety of Levocloperastine in the treatment of dry cough in adult Indian patients. Methods: In this prospective, observational study, patients aged 18-60 years, presenting with dry cough and prescribed with Levocloperastine at baseline or a day prior to enrolment, as per standard clinical practice, were recruited from 3 centers in India. The scores of cough severity (100 mm VAS), cough frequency since last 24 h (7-point Likert scale), sleep disruption due to night-time awakenings (10 cm VAS), quality of life (QoL) (Leicester Cough Questionnaire [LCQ]), and number of days for achieving minimal important difference (MID) in cough severity (17 mm improvement on VAS) were assessed from baseline to Day 14. In addition, physicians' assessment of effectiveness of Levocloperastine at Day 14, adverse drug reactions (ADRs) and proportion of patients reporting sedation and other central nervous system side effects were also reported during the study. Descriptive statistics was used to summarize the data. Results: A total of 100 patients were enrolled in the study. The mean scores of cough severity, cough frequency and sleep disruption due to night-time awakening were significantly reduced from baseline to Day 14 (p<=0.0001). A significant improvement in QoL scores (total and by domain) was noted from baseline to Day 14 (p<0.0001). Post treatment with Levocloperastine, the mean time for achieving MID was 5.3+/-0.26 days. Disappearance of cough was reported in 44% of patients; 54% patients reported improvement of cough by Day 14. No ADRs, cases of sedation or other side-effects were reported in the study. Conclusion: Levocloperastine was found to be effective and safe in the management of dry cough. A significant reduction in severity scores, frequency of cough and sleep disruption was reported, with an overall improvement in patient's QoL. PMID- 30477065 TI - Pharmaco-invasive Therapy with Fibrinolytic Agents: A Potent Lifesaving Reperfusion Strategy in STEMI Patients in Metro Tier-I Cities in India. AB - Background: Primary Sjogren's Syndrome (pSS) with Hypokalemic Periodic Paralysis(HPP) whether an association or a different clinical subset needs review. Aim: To generate a consensus on the importance of pharmaco-invasive therapy for STEMI patients when primary PCI cannot be expeditiously performed in metro and tier-I cities in India. Methodology: A total of 8 expert panel groups comprising 48 experts from Cardiology specialty in India were convened. These groups individually reviewed the evidence on various types of fibrinolytic agents, their importance in STEMI management in general and in India and finally shared their experience and views on the importance of pharmaco-invasive therapy during STEMI management in metro and tier-I cities in India. Individual group opinions were compiled into one document and the consensus was finalized after it was approved by all panel members. Results: The board concluded that in metro and tier-I cities, pharmaco-invasive therapy, preferably using third generation fibrinolytic agents such as Reteplase and Tenecteplase, should be instituted to all patients for whom a delay in primary PCI of greater than 120 minutes from the time of ECG confirmation is anticipated. This will enhance the time window to preserve the myocardium from further damage arising due to patient related, transportation related or in- hospital delays. The present article also highlights the importance of third generation fibrinolytics in pharmaco-invasive therapy and looks at strategies to augment their use. Conclusion: Pharmaco invasive therapy is recommended in STEMI patients even in metro and tier-I cities of India, where delay in access to PCI is anticipated, in place of a strategy of promoting only primary PCI. PMID- 30477066 TI - Powering Precision in OAD Management from Diagnosis to Delivery. PMID- 30477067 TI - Pseudohypotension. PMID- 30477068 TI - Hot Cross Bun Sign - Multisystem Atrophy (Cerebellar Type). PMID- 30477069 TI - Polycythemia Rubra Vera Presenting as Unilateral Clubbing Due to Left Subclavian Artery Thrombosis. PMID- 30477070 TI - Diffuse Large B Cell Lymphoma of Larynx. PMID- 30477071 TI - Primary Tubercular Granulomatous Thyroiditis, Presenting as Thyroid Nodule with Hyperthyroidism, Pyrexia of Unknown Origin and Severe Anemia. PMID- 30477072 TI - Acquired Factor VII Deficiency in Association with Pyelonephritis. PMID- 30477073 TI - An Unusual Sequelae of Uncomplicated Vivax Malaria. PMID- 30477074 TI - Capsule Endoscopy. PMID- 30477075 TI - Interstitial Lung Disease at High Altitude. PMID- 30477076 TI - Pyelonephritis Due to Dual Infection in a Diabetic Patient. PMID- 30477077 TI - Neglected Tropical Diseases Vs Tuberculosis in HIV-A Cohort Study. PMID- 30477078 TI - EBSD Investigation of the Microtexture of Weld Metal and Base Metal in Laser Welded Al-Li Alloys. AB - Autogenous laser welding of 5A90 Al-Li alloy sheets in a butt-joint configuration was carried out in this study. The microstructure characteristics of the weld metal and base metal in the horizontal surface and the transverse section of the welded joints were examined quantitatively using electron back scattered diffraction (EBSD) technique. The results show that the weld metal in the horizontal surface and the transverse section exhibits similar grain structural features including the grain orientations, grain shapes, and grain sizes, whereas distinct differences in the texture intensity and misorientation distributions are observed. However, the base metal in the horizontal surface and the transverse section of the joints reveals the obvious different texture characteristics in terms of the grain orientation, grain morphology, predominate texture ingredients, distribution intensities of textures, and grain boundary misorientation distribution, resulting in the diversity of the microhardness in the base metal and the softening of the weld metal. However, the degree of the drop in the hardness of the weld metal is highly correlated to the microtexture developed in the base metal. PMID- 30477079 TI - Of Viroids and Prions. AB - In 2017, Hadidi et al. edited a voluminous monograph entitled "Viroids and Satellites", in which each known viroid and viroid-like satellite species was described in detail from many perspectives by more than 100 experts from 24 countries. In its 700+ pages, the book is a much needed detailed and reliable compendium of a subject, which, undoubtedly, is still little known by many potential readers. Because most users of the book may be expected to be practical plant pathologists, it appears essential that the book contain, in addition to the detailed viroid and satellite descriptions, one chapter, in which the basic molecular biology of viroids and satellites is described. PMID- 30477080 TI - Combining Dietary Sulfur Amino Acid Restriction with Polyunsaturated Fatty Acid Intake in Humans: A Randomized Controlled Pilot Trial. AB - Dietary and plasma total cysteine (tCys) have been associated with adiposity, possibly through interaction with stearoyl-CoA desaturase (SCD), which is an enzyme that is involved in fatty acid and energy metabolism. We evaluated the effect of a dietary intervention with low cysteine and methionine and high polyunsaturated fatty acids (PUFAs) on plasma and urinary sulfur amino acids and SCD activity indices. Fourteen normal-weight healthy subjects were randomized to a seven-day diet low in cysteine and methionine and high in PUFAs (Cys/Metlow + PUFA), or high in saturated fatty acids (SFA), cysteine, and methionine (Cys/Methigh + SFA). Compared with the Cys/Methigh + SFA group, plasma methionine and cystathionine decreased (p-values < 0.05), whereas cystine tended to increase (p = 0.06) in the Cys/Metlow + PUFA group. Plasma total cysteine (tCys) was not significantly different between the groups. Urinary cysteine and taurine decreased in the Cys/Metlow + PUFA group compared with the Cys/Methigh + SFA group (p-values < 0.05). Plasma SCD-activity indices were not different between the groups, but the change in cystine correlated with the SCD-16 index in the Cys/Metlow + PUFA group. A diet low in methionine and cysteine decreased plasma methionine and urinary cysteine and taurine. Plasma tCys was unchanged, suggesting that compensatory mechanisms are activated during methionine and cysteine restriction to maintain plasma tCys. PMID- 30477081 TI - On the Possible Chemical Justification of the Ethnobotanical Use of Hyptis obtusiflora in Amazonian Ecuador. AB - In rural areas of Latin America, Hyptis infusions are very popular. Hyptis obtusiflora extends from Mexico throughout Central America to Bolivia and Peru. It has added value in Ecuador where it has been used by different ethnic groups. We aimed to learn about the traditional knowledge of ancient Kichwa cultures about this plant, and to contrast this knowledge with the published information organized in occidental databases. We proposed to use traditional knowledge as a source of innovation for social development. Our specific objectives were to catalogue the uses of H. obtusiflora in the community, to prospect on the bibliography on a possible chemical justification for its medicinal use, to propose new products for development, and to give arguments for biodiversity conservation. An ethnobotanical survey was made and a Prisma 2009 Flow Diagram was then followed for scientific validation. We rescued data that are novel contributions for the ethnobotany at the national level. The catalogued main activity of anti-inflammation can be related to the terpene composition and the inhibition of xanthine oxidase. This opens the possibility of researching the extract of this plant as an alternative to allopurinol or uricosuric drugs. This is a concrete example of an argument for biodiversity conservation. PMID- 30477082 TI - Herpes Simplex Virus 1 Deregulation of Host MicroRNAs. AB - Viruses utilize microRNAs (miRNAs) in a vast variety of possible interactions and mechanisms, apparently far beyond the classical understanding of gene repression in humans. Likewise, herpes simplex virus 1 (HSV-1) expresses numerous miRNAs and deregulates the expression of host miRNAs. Several HSV-1 miRNAs are abundantly expressed in latency, some of which are encoded antisense to transcripts of important productive infection genes, indicating their roles in repressing the productive cycle and/or in maintenance/reactivation from latency. In addition, HSV-1 also exploits host miRNAs to advance its replication or repress its genes to facilitate latency. Here, we discuss what is known about the functional interplay between HSV-1 and the host miRNA machinery, potential targets, and the molecular mechanisms leading to an efficient virus replication and spread. PMID- 30477083 TI - Radiological and Clinical Outcome after Multilevel Anterior Cervical Discectomy and/or Corpectomy and Fixation. AB - BACKGROUND: Multilevel anterior cervical decompression and fixation of four and more levels is a common surgical procedure used for several diseases. METHODS: We reviewed the radiological and clinical outcomes after anterior cervical discectomy or corpectomy and fixation of four and more levels in 85 patients (55 men and 30 women) with an average age of 59.6 years. Surgical indication was multilevel cervical degenerative myelopathy and radiculopathy in 72 (85%) patients, multilevel cervical spondylodiscitis in four (5%), complex traumatic cervical fractures in four (5%), metastatic cervical spine tumor in two (2%), and ossification of the posterior longitudinal ligament in three (3%) patients. RESULTS: There were no severe intraoperative complications such as spinal cord or vertebral artery injury or dissection. Seventy-three patients had four, 10 patients had five, and two patients had six anterior cervical level fixations. The visual analog scale (VAS) and Japanese Orthopedic Association (mJOA) scale scores improved (6.9 to 1.3 (p < 0.001) and 13.9 to 16.5 (p < 0.001), respectively). The Cobb angle increased from 5.7 degrees to 17.6 degrees postoperatively (p < 0.001). Secondary posterior fixation was necessary in three cases due to pseudarthrosis. CONCLUSION: The anterior approach appears to be optimal for ventral compressive pathology and lordosis restoration to the cervical spine. Limitations of multiple level decompression and fixation included increasing pseudoarthrosis rates, especially after corpectomy, and increasing fused level numbers. PMID- 30477084 TI - Animal Ethical Views and Perception of Animal Pain in Veterinary Students. AB - Veterinary students face several ethical challenges during their curriculum. We used the Animal Ethics Dilemma to study animal ethical views of Finnish veterinary students, and also asked them to score the level of pain perception in 13 different species. Based on the 218 respondents, the utilitarian view was the dominating ethical view. Mammals were given higher pain scores than other animals. The proportion of the respect for nature view correlated negatively, and that of the animal rights view positively, with most animal pain scores. Fifth year students had a higher percentage of contractarian views, as compared to 1st and 3rd year students, but this might have been confounded by their age. Several pain perception scores increased with increasing study years. We conclude that the utilitarian view was clearly dominating, and that ethical views differed only slightly between students at different stages of their studies. Higher pain perception scores in students at a later stage of their studies might reflect an increased knowledge of animal capacities. PMID- 30477085 TI - Functional Roles of O-Glycosylation. AB - O-Glycosylation in general has impact on a diversity of biological processes covering cellular aspects (targeted transport of glycoproteins), molecular aspects (protein conformation, resistance to proteolysis), and aspects involved in cellular communication (cell-cell and cell-matrix interaction). [...]. PMID- 30477086 TI - Brain Iron Homeostasis: A Focus on Microglial Iron. AB - Iron is an essential trace element required for important brain functions including oxidative metabolism, synaptic plasticity, myelination, and the synthesis of neurotransmitters. Disruptions in brain iron homeostasis underlie many neurodegenerative diseases. Increasing evidence suggests that accumulation of brain iron and chronic neuroinflammation, characterized by microglia activation and secretion of proinflammatory cytokines, are hallmarks of neurodegenerative disorders including Alzheimer' s disease. While substantial efforts have led to an increased understanding of iron metabolism and the role of microglial cells in neuroinflammation, important questions still remain unanswered. Whether or not increased brain iron augments the inflammatory responses of microglial cells, including the molecular cues that guide such responses, is still unclear. How these brain macrophages accumulate, store, and utilize intracellular iron to carry out their various functions under normal and disease conditions is incompletely understood. Here, we describe the known and emerging mechanisms involved in microglial cell iron transport and metabolism as well as inflammatory responses in the brain, with a focus on AD. PMID- 30477087 TI - Amphiphilic Nanocarrier Systems for Curcumin Delivery in Neurodegenerative Disorders. AB - Neurodegenerative diseases have become a major challenge for public health because of their incurable status. Soft nanotechnology provides potential for slowing down the progression of neurodegenerative disorders by using innovative formulations of neuroprotective antioxidants like curcumin, resveratrol, vitamin E, rosmarinic acid, 7,8-dihydroxyflavone, coenzyme Q10, and fish oil. Curcumin is a natural, liposoluble compound, which is of considerable interest for nanomedicine development in combination therapies. The neuroprotective effects of combination treatments can involve restorative mechanisms against oxidative stress, mitochondrial dysfunction, inflammation, and protein aggregation. Despite the anti-amyloid and anti-tau potential of curcumin and its neurogenesis stimulating properties, the utilization of this antioxidant as a drug in neuroregenerative therapies has huge limitations due to its poor water solubility, physico-chemical instability, and low oral bioavailability. We highlight the developments of soft lipid- and polymer-based delivery carriers of curcumin, which help improve the drug solubility and stability. We specifically focus on amphiphilic liquid crystalline nanocarriers (cubosome, hexosome, spongosome, and liposome particles) for the encapsulation of curcumin with the purpose of halting the progressive neuronal loss in Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis (ALS). PMID- 30477088 TI - The Effect of Sex and Performance Level on Pacing in Duathlon. AB - The purpose of the present research was to study the effect of sex and performance on pacing in short (Run1-10 km, Bike-50 km and Run2-5 km) and long distance (Run1-10 km, Bike-150 km and Run2-30 km) in the Powerman World Championship 'Powerman Zofingen'. All finishers (n = 6671; women, n = 1037; men, n = 5634) competing either in the short or long distance versions of 'Powerman Zofingen' from 2003 to 2017 were analyzed for the time spent in each discipline (Run1, Bike and Run2), and in transition (Tran) from Run1 to Bike (Tran1) and from Bike to Run2 (Tran2). Athletes were ranked in quartile (Q) groups (Q1, Q2, Q3 and Q4), with Q1 the fastest and Q4 the slowest. In short distance, in both sexes, a medium discipline/transition * quartile interaction on relative time was observed (p < 0.001, eta2p = 0.103 and eta2p = 0.119, respectively), where Q1 was relatively the fastest in Tran1, Tran2 and Run2, and the slowest in Bike (p < 0.001). In long distance, in both sexes, a large discipline/transition * quartile interaction on relative time was observed (p < 0.001, eta2p = 0.208 and eta2p = 0.180, respectively), where Q1 was relatively the fastest in Tran1, Tran2 and Run2, and the slowest in Bike (p < 0.001). In summary, a similar trend of variation of pacing by performance level was observed in both sexes and distances with the fastest duathletes being the fastest in Run2 and both transitions, and the slowest in Bike. PMID- 30477089 TI - Effect of Combined Treatment of Ketorolac and Remote Ischemic Preconditioning on Renal Ischemia-Reperfusion Injury in Patients Undergoing Partial Nephrectomy: Pilot Study. AB - We evaluated postoperative renal function in patients with/without combined therapy of ketorolac and remote ischemic preconditioning during partial nephrectomy. Sixteen patients were randomly allocated to either the ketorolac combined with RIPC group (KI, n = 8) or control group (n = 8). The KI group received both remote ischemic preconditioning before surgery and intravenous ketorolac of 1 mg/kg before renal artery clamping. Renal parameters were measured before induction, after anesthesia induction, and 2, 12, 24, 48, and 72 h after renal artery declamping. Acute kidney injury was assessed by Acute Kidney Injury Network criteria. The estimated glomerular filtration rate decreased in both groups, but then increased significantly at 48 h and 72 h after declamping only in the KI group compared to 24 h (p = 0.001 and p = 0.016). Additionally, it was higher at 48 h and 72 h after declamping in the KI group compared to the control group (p = 0.025 and p = 0.044). The incidence of acute kidney injury was significantly reduced in the KI group (13%) compared to the control group (83%) (p = 0.026). FENa was markedly increased at 2 h after declamping, and recovered in both groups, but it was more significant at 12 h after declamping in the KI group (p = 0.022). Urinary N-acetyl-1-beta-D-glucosoaminidase and serum neutrophil gelatinase-associated lipocalin were similar (p = 0.291 and p = 0.818). There is a possibility that combined therapy of ketorolac and remote ischemic preconditioning prior to ischemia may alleviate renal dysfunction and reduce the incidence of acute kidney injury in patients undergoing partial nephrectomy. PMID- 30477090 TI - Study on Thermal Decomposition Behaviors of Terpolymers of Carbon Dioxide, Propylene Oxide, and Cyclohexene Oxide. AB - The terpolymerization of carbon dioxide (CO2), propylene oxide (PO), and cyclohexene oxide (CHO) were performed by both random polymerization and block polymerization to synthesize the random poly (propylene cyclohexene carbonate) (PPCHC), di-block polymers of poly (propylene carbonate-cyclohexyl carbonate) (PPC-PCHC), and tri-block polymers of poly (cyclohexyl carbonate-propylene carbonate-cyclohexyl carbonate) (PCHC-PPC-PCHC). The kinetics of the thermal degradation of the terpolymers was investigated by the multiple heating rate method (Kissinger-Akahira-Sunose (KAS) method), the single heating rate method (Coats-Redfern method), and the Isoconversional kinetic analysis method proposed by Vyazovkin with the data from thermogravimetric analysis under dynamic conditions. The values of ln k vs. T-1 for the thermal decomposition of four polymers demonstrate the thermal stability of PPC and PPC-PCHC are poorer than PPCHC and PCHC-PPC-PCHC. In addition, for PPCHC and PCHC-PPC-PCHC, there is an intersection between the two rate constant lines, which means that, for thermal stability of PPCHC, it is more stable than PCHC-PPC-PCHC at the temperature less than 309 degrees C and less stable when the decomposed temperature is more than 309 degrees C. Pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS) and thermogravimetric analysis/infrared spectrometry (TG/FTIR) techniques were applied to investigate the thermal degradation behavior of the polymers. The results showed that unzipping was the main degradation mechanism of all polymers so the final pyrolysates were cyclic propylene carbonate and cyclic cyclohexene carbonate. For the block copolymers, the main chain scission reaction first occurs at PC-PC linkages initiating an unzipping reaction of PPC chain and then, at CHC-CHC linkages, initiating an unzipping reaction of the PCHC chain. That is why the T-5% of di-block and tri-block polymers were not much higher than that of PPC while two maximum decomposition temperatures were observed for both the block copolymer and the second one were much higher than that of PPC. For PPCHC, the random arranged bulky cyclohexane groups in the polymer chain can effectively suppress the backbiting process and retard the unzipping reaction. Thus, it exhibited much higher T-5% than that of PPC and block copolymers. PMID- 30477091 TI - Soft Tissue Contour Impression with Analogic or Digital Work Flow: A Case Report. AB - PURPOSE: Transferring precise information to the dental laboratory is one of the key factors to achieving clinical success. The aim of the present study was to describe classical and digital work-flows used to rehabilitate an implant with a convergent collar in the aesthetic zone following the BOPT (biologically oriented preparation technique) approach and to report the three years follow-up outcomes of two patients rehabilitated following such procedures. MATERIALS AND METHODS: Two central incisors of two different patients were rehabilitated with a tissue level implant with a convergent collar and, after a provisional and healing phase, one implant was "impressed" using a classical workflow and one using a digital one. The primary outcome measured was the mean bone loss. An intraoral radiograph was taken at crown delivery and at the three years follow-up visit. Secondary Esthetic outcomes pre-op and post-op were evaluated using the PES (pink esthetic score). RESULTS: At the three years follow-up visit, radiographic analysis showed no signs of bone resorption. For the analogic procedure, the pre and post-op PES scores were 8, whereas for the digital procedure the pre-op PES score was 4 and a post-op score of 9 was obtained. CONCLUSIONS: classical and digital work flows succeeded in giving precise and complete anatomical information of implant position, including the soft tissue contour. Minimum bone loss and an esthetic success were obtained in both procedures. PMID- 30477092 TI - Separation of Volatile Metabolites from the Leaf-Derived Essential Oil of Piper mollicomum Kunth (Piperaceae) by High-Speed Countercurrent Chromatography. AB - The technique of high-speed countercurrent chromatography was applied to the isolation of compounds in essential oil derived from the leaves of Piper mollicomum species. Plant leaves (200.0 g) were submitted to hydrodistillation in a modified Clevenger apparatus. The resulting crude leaf essential oil was analyzed by gas chromatography with flame ionization detector (GC-FID) and gas chromatography-mass spectrometry (GC-MS) to determine the profile of the components. The purified fractions were composed of monoterpenes and sesquiterpenes such as camphor (85.0 mg at 98.5% purity), (E)-nerolidol (100.0 mg at 92.8% purity), and camphene (150.0 mg at 82.0% purity). A minor component of the essential oil, bornyl acetate (16.2 mg at 91.2% purity) was also isolated in the one-step separation protocol in 2 h. The countercurrent chromatography technique proved to be a fast and efficient method for the separation of volatile metabolites that conserved the solvent while delivering various fractions of high purity. PMID- 30477093 TI - A Diffusion-Based pH Regulator in Laminar Flows with Smartphone-Based Colorimetric Analysis. AB - A strategy for an on-chip pH regulator is demonstrated computationally and experimentally, based on the diffusion characteristics of aqueous ionic solutions. Micro-flows with specific pH values are formed based on the diffusion behaviors of hydrogen and hydroxide ions in laminar flows. The final achieved pH value and its gradient in the channel can be regulated by the amount of ions transported between laminar flows, and the experimental results can be further generalized based on the normalized Nernst-Planck equation. A smartphone was applied as an image capture and analysis instrument to quantify pH values of liquids in a colorimetric detection process, with monotonic response range of ~1 13. PMID- 30477094 TI - Flavonoids from Nelumbo nucifera Gaertn., a Medicinal Plant: Uses in Traditional Medicine, Phytochemistry and Pharmacological Activities. AB - Nelumbo nucifera Gaertn. has been used as an important ingredient for traditional medicines since ancient times, especially in Asian countries. Nowadays, many new or unknown phytochemical compounds from N. nucifera are still being discovered. Most of the current research about pharmacological activity focus on nuciferine, many other alkaloids, phenolic compounds, etc. However, there is no current review emphasizing on flavonoids, which is one of the potent secondary metabolites of this species and its pharmacological activities. Therefore, following a taxonomic description, we aim to illustrate and update the diversity of flavonoid phytochemical compounds from N. nucifera, the comparative analysis of flavonoid compositions and contents in various organs. The uses of this species in traditional medicine and the main pharmacological activities such as antioxidant, anti-inflammatory, anti-diabetic, anti-obesity, anti-angiogenic and anti-cancer activities are also illustrated in this works. PMID- 30477095 TI - Sclerostin Modulation Holds Promise for Dental Indications. AB - Sclerostin modulation is a novel therapeutic bone regulation strategy. The anti sclerostin drugs, proposed in medicine for skeletal bone loss may be developed for jaw bone indications in dentistry. Alveolar bone responsible for housing dentition share common bone remodeling mechanisms with skeletal bone. Manipulating alveolar bone turnover can be used as a strategy to treat diseases such as periodontitis, where large bone defects from disease are a surgical treatment challenge and to control tooth position in orthodontic treatment, where moving teeth through bone in the treatment goal. Developing such therapeutics for dentistry is a future line for research and therapy. Furthermore, it underscores the interprofessional relationship that is the future of healthcare. PMID- 30477096 TI - Challenges and Progress with Diagnosing Pulmonary Tuberculosis in Low- and Middle Income Countries. AB - Case finding and the diagnosis of tuberculosis (TB) are key activities to reach the World Health Organization's End TB targets by 2030. This paper focuses on the diagnosis of pulmonary TB (PTB) in low- and middle-income countries. Sputum smear microscopy, despite its many limitations, remains the primary diagnostic tool in peripheral health facilities; however, this is being replaced by molecular diagnostic techniques, particularly Xpert MTB/RIF, which allows a bacteriologically confirmed diagnosis of TB along with information about whether or not the organism is resistant to rifampicin within two hours. Other useful diagnostic tools at peripheral facilities include chest radiography, urine lipoarabinomannan (TB-LAM) in HIV-infected patients with advanced immunodeficiency, and the loop-mediated isothermal amplification (TB-LAMP) test which may be superior to smear microscopy. National Reference Laboratories work at a higher level, largely performing culture and phenotypic drug susceptibility testing which is complemented by genotypic methods such as line probe assays for detecting resistance to isoniazid, rifampicin, and second-line drugs. Tuberculin skin testing, interferon gamma release assays, and commercial serological tests are not recommended for the diagnosis of active TB. Linking diagnosis to treatment and care is often poor, and this aspect of TB management needs far more attention than it currently receives. PMID- 30477097 TI - Angelica Stem: A Potential Low-Cost Source of Bioactive Phthalides and Phytosterols. AB - Chinese Angelica is a significant medical plant due to the various therapeutic constituents in its root; whereas the aerial part is considered worthless and often discarded as agricultural waste. In this work, phytochemicals from the stem were first systematically analyzed by means of GC-MS after derivatization and HPLC-MS/MS in multiple reaction monitoring (MRM) mode. Phthalides, ferulic acid, and coniferyl ferulate were detected in the stem; although their content is relatively low in comparison with the root. Some specific compounds, such as p hydroxybenzoic acid, vanillic acid, protocatechuic acid, caffeic acid, 4 hydroxyphenyl-1, 2-ethanediol, thymol-beta-d-glucopyranoside, etc. and a significant amount of phytosterols (1.36 mg/g stem, mainly beta-sitosterol) were detected in the stem. The extracted oil from the stem contained a considerable amount of phthalides (48.5 mg/g), beta-sitosterol (56.21 mg/g), and stigmasterol (14.03 mg/g); no other bioactive compounds were found that could be potentially used as pharmaceuticals or additives to healthcare food. PMID- 30477098 TI - Triple-Helical DNA in Drosophila Heterochromatin. AB - Polynucleotide chains obeying Watson-Crick pairing are apt to form non-canonical complexes such as triple-helical nucleic acids. From early characterization in vitro, their occurrence in vivo has been strengthened by increasing evidence, although most remain circumstantial particularly for triplex DNA. Here, different approaches were employed to specify triple-stranded DNA sequences in the Drosophila melanogaster chromosomes. Antibodies to triplex nucleic acids, previously characterized, bind to centromeric regions of mitotic chromosomes and also to the polytene section 59E of mutant strains carrying the brown dominant allele, indicating that AAGAG tandem satellite repeats are triplex-forming sequences. The satellite probe hybridized to AAGAG-containing regions omitting chromosomal DNA denaturation, as expected, for the intra-molecular triplex DNA formation model in which single-stranded DNA coexists with triplexes. In addition, Thiazole Orange, previously described as capable of reproducing results obtained by antibodies to triple-helical DNA, binds to AAGAG repeats in situ thus validating both detection methods. Unusual phenotype and nuclear structure exhibited by Drosophila correlate with the non-canonical conformation of tandem satellite arrays. From the approaches that lead to the identification of triple helical DNA in chromosomes, facilities particularly provided by Thiazole Orange use may broaden the investigation on the occurrence of triplex DNA in eukaryotic genomes. PMID- 30477099 TI - Ceratinadins D and E, New Bromotyrosine Alkaloids from an Okinawan Marine Sponge Pseudoceratina sp. AB - Two new bromotyrosine alkaloids, ceratinadins D (1) and E (2), were isolated from an Okinawan marine sponge Pseudoceratina sp. as well as a known bromotyrosine alkaloid, psammaplysin F (3). The gross structures of 1 and 2 were elucidated on the basis of spectroscopic data. The absolute configurations of 1 and 2 were assigned by comparison of the NMR and ECD data with those of a known related bromotyrosine alkaloid, psammaplysin A (4). Ceratinadins D (1) and E (2) are new bromotyrosine alkaloids possessing an 8,10-dibromo-9-methoxy-1,6-dioxa-2 azaspiro[4.6]undeca-2,7,9-trien-4-ol unit with two or three 11-N methylmoloka'iamine units connected by carbonyl groups, respectively. Ceratinadin D (1) exhibited antimalarial activities against a drug-resistant and a drug sensitive strains of Plasmodium falciparum (K1 and FCR3 strains, respectively). PMID- 30477100 TI - A Review of Sampling and Monitoring Methods for Beneficial Arthropods in Agroecosystems. AB - Beneficial arthropods provide many important ecosystem services. In agroecosystems, pollination and control of crop pests provide benefits worth billions of dollars annually. Effective sampling and monitoring of these beneficial arthropods is essential for ensuring their short- and long-term viability and effectiveness. There are numerous methods available for sampling beneficial arthropods in a variety of habitats, and these methods can vary in efficiency and effectiveness. In this paper I review active and passive sampling methods for non-Apis bees and arthropod natural enemies of agricultural pests, including methods for sampling flying insects, arthropods on vegetation and in soil and litter environments, and estimation of predation and parasitism rates. Sample sizes, lethal sampling, and the potential usefulness of bycatch are also discussed. PMID- 30477101 TI - College Students and Eating Habits: A Study Using An Ecological Model for Healthy Behavior. AB - Overweightness and obesity rates have increased dramatically over the past few decades and they represent a health epidemic in the United States (US). Unhealthy dietary habits are among the factors that can have adverse effects on weight status in young adulthood. The purpose of this explorative study was to use a qualitative research design to analyze the factors (barriers and enablers) that US college students perceived as influencing healthy eating behaviors. A group of Cornell University students (n = 35) participated in six semi-structured focus groups. A qualitative software, CAQDAS Nvivo11 Plus, was used to create codes that categorized the group discussions while using an Ecological Model. Common barriers to healthy eating were time constraints, unhealthy snacking, convenience high-calorie food, stress, high prices of healthy food, and easy access to junk food. Conversely, enablers to healthy behavior were improved food knowledge and education, meal planning, involvement in food preparation, and being physically active. Parental food behavior and friends' social pressure were considered to have both positive and negative influences on individual eating habits. The study highlighted the importance of consulting college students when developing healthy eating interventions across the campus (e.g., labeling healthy food options and information campaigns) and considering individual-level factors and socio ecological aspects in the analysis. PMID- 30477102 TI - Novel Methinic Functionalized and Dendritic C-Scorpionates. AB - The study of chelating ligands is undoubtedly one of the most significant fields of research in chemistry. The present work is directed to the synthesis of new functionalized derivatives of tripodal C-scorpionate compounds. Tris-2,2,2-(1 pyrazolyl)ethanol, HOCH2C(pz)3 (1), one of the most important derivatives of hydrotris(pyrazolyl)methane, was used as a building block for the synthesis of new functionalized C-scorpionates, aiming to expand the scope of this unexplored class of compounds. The first dendritic C-scorpionate was successfully prepared and used in the important industrial catalytic reactions, Sonogashira and Heck C C cross-couplings. PMID- 30477103 TI - Most Women with Previous Gestational Diabetes Mellitus Have Impaired Glucose Metabolism after a Decade. AB - Of 1324 women diagnosed with gestational diabetes mellitus (GDM) in Sweden, 25% reported >10 years after the delivery that they had developed diabetes mellitus. We assessed the long-term risk of all glucose metabolic abnormalities in a subgroup of these women. Women (n = 51) previously diagnosed with GDM by capillary blood glucose >=9.0 mmol/L (~plasma glucose >=10.0 mmol/L) after a 2 h 75 g oral glucose tolerance test (OGTT) were included. All underwent a clinical and biochemical evaluation, including a second 2 h 75 g OGTT. Individuals with known type 1 diabetes were excluded. At the follow-up, 12/51 (24%) reported previously diagnosed type 2 diabetes. Another four cases were diagnosed after the second OGTT, increasing the prevalence to 16/51 cases (31%). Impaired fasting plasma glucose (IFG) was diagnosed in 13/51 women and impaired glucose tolerance (IGT) in 10/51 women, leaving only 12 women (24%) with normal glucose tolerance. In addition, 2/51 women had high levels of glutamic acid decarboxylase (GAD) antibodies; of these, one woman classified as type 2 diabetes was reclassified as type 1 diabetes, and the second GAD-positive woman was diagnosed with IGT. Of the women diagnosed with GDM by a 2 h 75 g OGTT, a large proportion had impaired glucose metabolism a decade later, including type 1 and type 2 diabetes. PMID- 30477104 TI - Identification of Ubiquinones in Honey: A New View on Their Potential Contribution to Honey's Antioxidant State. AB - Honey is composed of macromolecules arranged into multicomponent colloidal particles dispersed in a supersaturated sugar solution. The core part of colloidal particles in honey is made up of high-molecular weight protein polyphenol complexes. We designed a multi-step extraction process to gain better insight into the phenolic compounds strongly bound to proteins in honey. Honeys were sequentially extracted by solvents of reduced polarities and the extraction process was monitored by LC-ESI-MS/MS. Unexpectedly, the results revealed ubiquinone-like compounds that partitioned to both, soluble supernatants and protein-bound insoluble residues from which they were released after the pronase digestion of proteins. The accurate mass measurement and MS/MS fragmentation patterns using UPHLC-MS/MS coupled to quadrupole orbitrap confirmed their identification as ubiquinones. Distribution of ubiquinone-bound proteins was further investigated by the fractionation of honey protein-polyphenol complexes by size-exclusion chromatography followed by LC-ESI-MS analysis. Mass spectra revealed the presence of ubiquinones (UQs) in fractions of high polyphenol to protein ratio. The dominant mass peaks observed in these fractions were identified as UQ-3, UQ-5, and UQ-7. Since the quinone group of UQs is involved in redox reaction, we discuss the possibility that UQs may contribute to the antioxidant/proxidant activity of these complexes. PMID- 30477105 TI - Development of a Brazilian Food Truck Risk Assessment Instrument. AB - This study aimed to develop and validate a checklist instrument as a first step for the risk assessment of the hygienic-sanitary practices and conditions of food trucks. We invited sixteen experienced experts in the food safety field to take part in the process. The checklist was designed based on the Codex Alimentarius, Brazilian resolutions Collegiate Board Resolution 216, Brazilian Collegiate Board Resolution 275, Brazilian Federal District Law no. 5.627 and Brazilian Federal District Normative Instruction 11. The preliminary version of the checklist composed of 29 items (nine sections)-was evaluated by 13 experts. They evaluated the items regarding their importance (content validation) and clarity (semantic evaluation) by the Delphi technique. The criteria for the approval of the content validation (Likert scale from 1 to 5) and semantic evaluation (Likert scale from 0 to 5) processes were as follows: a minimum of 75% agreement among the experts (W-values >= 0.75) and a mean grade >= 4. We performed the complete validation process in three rounds. The final version of the assessment instrument comprised 39 items, following suggestions from experts to add or subdivide some questions. The checklist can be used to conduct inspections of food trucks by health surveillance auditors, of food truck vendors' decision-making processes and also as a diagnostic tool. The application of this checklist will allow the effective risk assessment of the hygienic-sanitary practices and conditions in food trucks and potentially ensure consumers' access to safe street food. PMID- 30477106 TI - Sparse Ultrasound Imaging via Manifold Low-Rank Approximation and Non-Convex Greedy Pursuit. AB - Model-based image reconstruction has improved contrast and spatial resolution in imaging applications such as magnetic resonance imaging and emission computed tomography. However, these methods have not succeeded in pulse-echo applications like ultrasound imaging due to the typical assumption of a finite grid of possible scatterer locations in a medium-an assumption that does not reflect the continuous nature of real world objects and creates a problem known as off-grid deviation. To cope with this problem, we present a method of dictionary expansion and constrained reconstruction that approximates the continuous manifold of all possible scatterer locations within a region of interest. The expanded dictionary is created using a highly coherent sampling of the region of interest, followed by a rank reduction procedure. We develop a greedy algorithm, based on the Orthogonal Matching Pursuit, that uses a correlation-based non-convex constraint set that allows for the division of the region of interest into cells of any size. To evaluate the performance of the method, we present results of two dimensional ultrasound imaging with simulated data in a nondestructive testing application. Our method succeeds in the reconstructions of sparse images from noisy measurements, providing higher accuracy than previous approaches based on regular discrete models. PMID- 30477107 TI - Probiotics in Celiac Disease. AB - Recently, the interest in the human microbiome and its interplay with the host has exploded and provided new insights on its role in conferring host protection and regulating host physiology, including the correct development of immunity. However, in the presence of microbial imbalance and particular genetic settings, the microbiome may contribute to the dysfunction of host metabolism and physiology, leading to pathogenesis and/or the progression of several diseases. Celiac disease (CD) is a chronic autoimmune enteropathy triggered by dietary gluten exposure in genetically predisposed individuals. Despite ascertaining that gluten is the trigger in CD, evidence has indicated that intestinal microbiota is somehow involved in the pathogenesis, progression, and clinical presentation of CD. Indeed, several studies have reported imbalances in the intestinal microbiota of patients with CD that are mainly characterized by an increased abundance of Bacteroides spp. and a decrease in Bifidobacterium spp. The evidence that some of these microbial imbalances still persist in spite of a strict gluten-free diet and that celiac patients suffering from persistent gastrointestinal symptoms have a desert gut microbiota composition further support its close link with CD. All of this evidence gives rise to the hypothesis that probiotics might play a role in this condition. In this review, we describe the recent scientific evidences linking the gut microbiota in CD, starting from the possible role of microbes in CD pathogenesis, the attempt to define a microbial signature of disease, the effect of a gluten-free diet and host genetic assets regarding microbial composition to end in the exploration of the proof of concept of probiotic use in animal models to the most recent clinical application of selected probiotic strains. PMID- 30477108 TI - Roux-en-Y Gastric Bypass Surgery Induces Distinct but Frequently Transient Effects on Acylcarnitine, Bile Acid and Phospholipid Levels. AB - Roux-en-Y gastric bypass (RYGB) is an effective method to achieve sustained weight loss, but the mechanisms responsible for RYGB effects have not yet been fully characterized. In this study, we profiled the concentrations of 143 lipid metabolites in dry blood spots (DBS) of RYGB patients. DBS from obese patients (BMI range 35-44 kg/m2) were collected 7 days before, 15 and 90 days after the surgery. LC-MS/MS was used to quantify acylcarnitines, phosphatidylcholines, sphingomyelins and bile acids. RYGB caused a rapid increase in acylcarnitine levels that proved to be only transient, contrasting with the sustained decrease in phosphatidylcholines and increase of sphingomyelins and bile acids. A PLS-DA analysis revealed a 3-component model (R2 = 0.9, Q2 = 0.74) with key metabolites responsible for the overall metabolite differences. These included the BCAA derived acylcarnitines and sphingomyelins with 16 and 18 carbons. We found important correlations between the levels of BCAA-derived acylcarnitines and specific sphingomyelins with plasma cholesterol and triacylglycerol concentrations. Along with the marked weight loss and clinical improvements, RYGB induced specific alterations in plasma acylcarnitines, bile acid and phospholipid levels. This calls for more studies on RYGB effects aiming to elucidate the metabolic adaptations that follow this procedure. PMID- 30477109 TI - In Vivo Toxicity of Solasonine and Its Effects on cyp450 Family Gene Expression in the Livers of Male Mice from Four Strains. AB - Solasonine was reported to inhibit tumour cell growth in several different models. The in vivo toxicity of solasonine, the effects of genetic background on its toxicity, and its possible roles in regulating the expression of cyp450 family genes were still unclear and required characterisation. Here, Horn's assays were performed on male mice from four different strains, and the expression of cyp450 family genes in their livers was examined by RT-PCR and ELISA. Mice treated by intraperitoneal injection with high levels of solasonine showed immediate post-excitatory depression, intraperitoneal tissue adhesion, and dissolving of cells in the liver. Furthermore, these four mouse strains showed different toxicological sensitivity to solasonine. The strains, in decreasing order of LD50 value, rescuing speed of body weight, and more severe pathological symptoms, were KM, ICR, C57BL/6, and BALB/c. Interestingly, more cyp450 genes were downregulated at the mRNA and/or protein level in the livers of male mice from C57BL/6 or BALB/c strains than those from KM or ICR strains. These results suggest that (1) Solasonine has hepatic toxicity and downregulates cyp450 genes expression at transcriptional and/or post-transcriptional levels; (2) Genetic background is an important factor which can affect the in vivo toxicity; (3) Downregulation of cyp450 gene expression in the liver may be a clue to help understand whether or not a given strain is sensitive to solasonine; (4) Influences on the expression of cyp450 genes should be considered when using solasonine alone, or in combination with other drugs. PMID- 30477110 TI - Fatigue is Highly Prevalent in Patients with Asthma and Contributes to the Burden of Disease. AB - The 2018 update of the Global Strategy for Asthma Management and Prevention does not mention fatigue-related symptoms. Nevertheless, patients with asthma frequently report tiredness, lack of energy, and daytime sleepiness. Quantitative research regarding the prevalence of fatigue in asthmatic patients is lacking. This retrospective cross-sectional study of outpatients with asthma upon referral to a chest physician assessed fatigue (Checklist Individual Strength-Fatigue (CIS Fatigue)), lung function (spirometry), asthma control (Asthma Control Questionnaire (ACQ)), dyspnea (Medical Research Council (MRC) scale), exercise capacity (six-minute walk test (6MWT)), and asthma-related Quality-of-Life (QoL), Asthma Quality of Life Questionnaire (AQLQ) during a comprehensive health-status assessment. In total, 733 asthmatic patients were eligible and analyzed (47.4 +/- 16.3 years, 41.1% male). Severe fatigue (CIS-Fatigue >= 36 points) was detected in 62.6% of patients. Fatigue was not related to airflow limitation (FEV1, rho = 0.083); was related moderately to ACQ (rho = 0.455), AQLQ (rho = -0.554), and MRC (rho = 0.435; all p-values < 0.001); and was related weakly to 6MWT (rho = 0.243, p < 0.001). In stepwise multiple regression analysis, 28.9% of variance in fatigue was explained by ACQ (21.0%), MRC (6.5%), and age (1.4%). As for AQLQ, 42.2% of variance was explained by fatigue (29.8%), MRC (8.6%), exacerbation rate (2.6%), and age (1.2%). Severe fatigue is highly prevalent in asthmatic patients; it is an important determinant of disease-specific QoL and a crucial yet ignored patient-related outcome in patients with asthma. PMID- 30477111 TI - Assessment of Patient and Occupational Safety Culture in Hospitals: Development of a Questionnaire with Comparable Dimensions and Results of a Feasibility Study in a German University Hospital. AB - (1) Background: Both patient and occupational safety cultures should be considered when promoting safety culture. To our knowledge, there are no studies that capture patient safety culture (PSC) and occupational safety culture (OSC) in hospitals while using a common questionnaire. The aim of this feasibility study in a German university hospital was to develop a questionnaire to assess both issues analogously. In addition to feasibility outcomes, we report results of PSC-OSC comparisons. (2) Methods: To assess PSC, we used the existing Hospital Survey on Patient Safety Culture (HSPSC) questionnaire. Developing new OSC "twin items" for certain parts of the HSPSC was supported by a previous literature review. Additionally, we developed multiple choice questions to examine knowledge and competencies regarding specific PS/OS aspects. (3) Results: Developing and implementing a combined PSC and OSC assessment instrument was feasible. The overall response rate was 33% (407 nurses, 140 physicians). In general, the statistical reliability of almost all scales was sufficient. Positive PSC perceptions (agreement rates 46-87%) were found in 16 out of 18 scales. Of the four twin scales, the PSC values were significantly better. Individual PS- and OS related knowledge and competencies were lower than expected. (4) Conclusion: The comparative investigation of patient and occupational safety in a large hospital is a promising approach and can be recommended for further studies. We used our experiences that are presented here in an ongoing bicentric study on the associations between working conditions, occupational safety culture, patient safety culture, and patient safety outcomes (WorkSafeMed). PMID- 30477112 TI - Lipid Myopathies. AB - Disorders of lipid metabolism affect several tissues, including skeletal and cardiac muscle tissues. Lipid myopathies (LM) are rare multi-systemic diseases, which most often are due to genetic defects. Clinically, LM can have acute or chronic clinical presentation. Disease onset can occur in all ages, from early stages of life to late-adult onset, showing with a wide spectrum of clinical symptoms. Muscular involvement can be fluctuant or stable and can manifest as fatigue, exercise intolerance and muscular weakness. Muscular atrophy is rarely present. Acute muscular exacerbations, resulting in rhabdomyolysis crisis are triggered by several factors. Several classifications of lipid myopathies have been proposed, based on clinical involvement, biochemical defect or histopathological findings. Herein, we propose a full revision of all the main clinical entities of lipid metabolism disorders with a muscle involvement, also including some those disorders of fatty acid oxidation (FAO) with muscular symptoms not included among previous lipid myopathies classifications. PMID- 30477113 TI - Combination of High- and Low-Rate GPS Receivers for Monitoring Wind-Induced Response of Tall Buildings. AB - High-rise buildings are susceptible to wind-induced displacements, which can be precisely monitored by using GPS technology. However, GPS monitoring applications may be subject to signal interference and high hardware costs. This study presents a new wind-induced vibration monitoring approach that is based on the mixed use of high-rate and low-rate GPS receivers. In the proposed approach, high rate receivers are only required in the monitoring stations, where we apply time differenced positioning to obtain position changes between adjacent epochs. The derived high-rate monitoring station position changes are then integrated with low-rate single epoch relative positioning results between the monitoring and reference stations. Experimental results with both simulated and real data show that the proposed method has a comparable performance with the traditional relative positioning approach, in terms of determining buildings' vibration frequency, displacement, and acceleration. PMID- 30477114 TI - 2-D Minimum Variance Based Plane Wave Compounding with Generalized Coherence Factor in Ultrafast Ultrasound Imaging. AB - Plane wave compounding (PWC) is an effective modality for ultrafast ultrasound imaging. It can provide higher resolution and better noise reduction than plane wave imaging (PWI). In this paper, a novel beamformer integrating the two dimensional (2-D) minimum variance (MV) with the generalized coherence factor (GCF) is proposed to maintain the high resolution and contrast along with a high frame rate for PWC. To specify, MV beamforming is adopted in both the transmitting aperture and the receiving one. The subarray technique is therefore upgraded into the sub-matrix division. Then, the output of each submatrix is used to adaptively compute the GCF using a 2-D fast Fourier transform (FFT). After the 2-D MV beamforming and the 2-D GCF weighting, the final output can be obtained. Results of simulations, phantom experiments, and in vivo studies confirm the advantages of the proposed method. Compared with the delay-and-sum (DAS) beamformer, the full width at half maximum (FWHM) is 90% smaller and the contrast ratio (CR) improvement is 154% in simulations. The over-suppression of desired signals, which is a typical drawback of the coherence factor (CF), can be effectively avoided. The robustness against sound velocity errors is also enhanced. PMID- 30477115 TI - PI3K Signaling in Neurons: A Central Node for the Control of Multiple Functions. AB - Phosphoinositide 3-kinase (PI3K) signaling contributes to a variety of processes, mediating many aspects of cellular function, including nutrient uptake, anabolic reactions, cell growth, proliferation, and survival. Less is known regarding its critical role in neuronal physiology, neuronal metabolism, tissue homeostasis, and the control of gene expression in the central nervous system in healthy and diseased states. The aim of the present work is to review cumulative evidence regarding the participation of PI3K pathways in neuronal function, focusing on their role in neuronal metabolism and transcriptional regulation of genes involved in neuronal maintenance and plasticity or on the expression of pathological hallmarks associated with neurodegeneration. PMID- 30477116 TI - Injection Molding of Thermoplastic Cellulose Esters and Their Compatibility with Poly(Lactic Acid) and Polyethylene. AB - Interest in biobased polymers from renewable resources has grown in recent years due to environmental concerns, but they still have a minimal fraction of the total global market. In this study, the injection molding of thermoplastic cellulose octanate (cellulose C8) and cellulose palmitate (cellulose C16) were studied. The mechanical properties of injection-molded test specimens were analyzed by using tensile testing, and the internal structure of injection-molded objects was studied by using a field emission scanning electron microscopy (FE SEM). We showed that thermoplastic cellulose C8 and cellulose C16 were completely processable without the addition of a plasticizer, which is very unusual in the case of cellulose esters. The compatibility of cellulose esters with poly(lactic acid) (PLA) and biopolyethylene (bio-PE) was also tested. By compounding the cellulose esters with PLA, the elongation of PLA-based blends could be improved and the density could be reduced. The tested thermoplastic cellulose materials were fully biobased, and have good future potential to be used in injection molding applications. PMID- 30477117 TI - Unleashing the Full Potential of Oncolytic Adenoviruses against Cancer by Applying RNA Interference: The Force Awakens. AB - Oncolytic virus therapy of cancer is an actively pursued field of research. Viruses that were once considered as pathogens threatening the wellbeing of humans and animals alike are with every passing decade more prominently regarded as vehicles for genetic and oncolytic therapies. Oncolytic viruses kill cancer cells, sparing healthy tissues, and provoke an anticancer immune response. Among these viruses, recombinant adenoviruses are particularly attractive agents for oncolytic immunotherapy of cancer. Different approaches are currently examined to maximize their therapeutic effect. Here, knowledge of virus-host interactions may lead the way. In this regard, viral and host microRNAs are of particular interest. In addition, cellular factors inhibiting viral replication or dampening immune responses are being discovered. Therefore, applying RNA interference is an attractive approach to strengthen the anticancer efficacy of oncolytic viruses gaining attention in recent years. RNA interference can be used to fortify the virus' cancer cell-killing and immune-stimulating properties and to suppress cellular pathways to cripple the tumor. In this review, we discuss different ways of how RNA interference may be utilized to increase the efficacy of oncolytic adenoviruses, to reveal their full potential. PMID- 30477118 TI - A Functional Connection between the Circadian Clock and Hormonal Timing in Arabidopsis. AB - The rotation of the Earth entails changes in environmental conditions that pervasively influence an organism's physiology and metabolism. An internal cellular mechanism known as the circadian clock acts as an internal timekeeper that is able to perceive the changes in environmental cues to generate 24-h rhythms in synchronization with daily and seasonal fluctuations. In plants, the circadian clock function is particularly important and regulates nearly every aspect of plant growth and development as well as proper responses to stresses. The circadian clock does not function in isolation but rather interconnects with an intricate network of different pathways, including those of phytohormones. Here, we describe the interplay of the circadian clock with a subset of hormones in Arabidopsis. The molecular components directly connecting the circadian and hormone pathways are described, highlighting the biological significance of such connections in the control of growth, development, fitness, and survival. We focus on the overlapping as well as contrasting circadian and hormonal functions that together provide a glimpse on how the Arabidopsis circadian system regulates hormone function in response to endogenous and exogenous cues. Examples of feedback regulation from hormone signaling to the clock are also discussed. PMID- 30477119 TI - Preparation of ZnO Nanorods/Graphene Composite Anodes for High-Performance Lithium-Ion Batteries. AB - ZnO is a promising anode material for lithium-ion batteries (LIBs); however, its practical application is hindered primarily by its large volume variation upon lithiation. To overcome this drawback, we synthesized ZnO/graphene composites using the combination of a simple hydrothermal reaction and spray drying. These composites consisted of well-dispersed ZnO nanorods anchored to graphene. The folded three-dimensional graphene spheres provided a high conductivity, high surface area, and abundant defects. LIB with an anode composed of our novel ZnO/graphene material demonstrated a high initial discharge capacity of 1583 mAh g-1 at 200 mA g-1. PMID- 30477120 TI - Mitochondrial Metabolism in Major Neurological Diseases. AB - Mitochondria are bilayer sub-cellular organelles that are an integral part of normal cellular physiology. They are responsible for producing the majority of a cell's ATP, thus supplying energy for a variety of key cellular processes, especially in the brain. Although energy production is a key aspect of mitochondrial metabolism, its role extends far beyond energy production to cell signaling and epigenetic regulation-functions that contribute to cellular proliferation, differentiation, apoptosis, migration, and autophagy. Recent research on neurological disorders suggest a major metabolic component in disease pathophysiology, and mitochondria have been shown to be in the center of metabolic dysregulation and possibly disease manifestation. This review will discuss the basic functions of mitochondria and how alterations in mitochondrial activity lead to neurological disease progression. PMID- 30477122 TI - Assessing Health Vulnerabilities and Adaptation to Climate Change: A Review of International Progress. AB - Climate change is increasing risks to human health and to the health systems that seek to protect the safety and well-being of populations. Health authorities require information about current associations between health outcomes and weather or climate, vulnerable populations, projections of future risks and adaptation opportunities in order to reduce exposures, empower individuals to take needed protective actions and build climate-resilient health systems. An increasing number of health authorities from local to national levels seek this information by conducting climate change and health vulnerability and adaptation assessments. While assessments can provide valuable information to plan for climate change impacts, the results of many studies are not helping to build the global evidence-base of knowledge in this area. They are also often not integrated into adaptation decision making, sometimes because the health sector is not involved in climate change policy making processes at the national level. Significant barriers related to data accessibility, a limited number of climate and health models, uncertainty in climate projections, and a lack of funding and expertise, particularly in developing countries, challenge health authority efforts to conduct rigorous assessments and apply the findings. This paper examines the evolution of climate change and health vulnerability and adaptation assessments, including guidance developed for such projects, the number of assessments that have been conducted globally and implementation of the findings to support health adaptation action. Greater capacity building that facilitates assessments from local to national scales will support collaborative efforts to protect health from current climate hazards and future climate change. Health sector officials will benefit from additional resources and partnership opportunities to ensure that evidence about climate change impacts on health is effectively translated into needed actions to build health resilience. PMID- 30477121 TI - Mutations in the GLA Gene and LysoGb3: Is It Really Anderson-Fabry Disease? AB - Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the partial or total deficit of the lysosomal enzyme alpha galactosidase A (alpha-Gal A). It is an X-linked, lysosomal enzymopathy due to mutations in the galactosidase alpha gene (GLA), encoding the alpha-Gal A. To date, more than 900 mutations in this gene have been described. In our laboratories, the study of genetic and enzymatic alterations related to FD was performed in about 17,000 subjects with a symptomatology referable to this disorder. The accumulation of globotriaosylsphingosine (LysoGb3) was determined in blood of positives. Exonic mutations in the GLA gene were detected in 471 patients (207 Probands and 264 relatives): 71.6% of mutations were associated with the classic phenotype, 19.8% were associated with the late-onset phenotype, and 8.6% of genetic variants were of unknown significance (GVUS). The accumulation of LysoGb3 was found in all male patients with a mutation responsible for classic or late-onset FD. LysoGb3 levels were consistent with the type of mutations and the symptomatology of patients. alpha-Gal A activity in these patients is absent or dramatically reduced. In recent years, confusion about the pathogenicity of some mutations led to an association between non causative mutations and FD. Our study shows that the identification of FD patients is possible by associating clinical history, GLA gene analysis, alpha Gal A assay, and blood accumulation of LysoGB3. In our experience, LysoGB3 can be considered a reliable marker, which is very useful to confirm the diagnosis of Fabry disease. PMID- 30477123 TI - Development of Phosphatized Calcium Carbonate Biominerals as Bioactive Bone Graft Substitute Materials, Part II: Functionalization with Antibacterial Silver Ions. AB - Porous calcium phosphate (CaP) materials as bone graft substitutes can be prepared from Ca carbonate biomineral structures by hydrothermal conversion into pseudomorphic CaP scaffolds. The present study aims at furnishing such phosphatized Ca carbonate biomineral (PCCB) materials with antibacterial Ag ions in order to avoid perisurgical wound infections. Prior to this study, PCCB materials with Mg and/or Sr ions incorporated for stimulating bone formation were prepared from coral skeletons and sea urchin spines as starting materials. The porous PCCB materials were treated with aqueous solutions of Ag nitrate with concentrations of 10 or 100 mmol/L, resulting in the formation of Ag phosphate nanoparticles on the sample surfaces through a replacement reaction. The materials were characterized using scanning electron microscopy (SEM) energy dispersive X-ray spectroscopy (EDS) and X-ray diffractometry (XRD). In contact with Ringer's solution, the Ag phosphate nanoparticles dissolved and released Ag ions with concentrations up to 0.51 mg/L, as shown by atomic absorption spectroscopy (AAS) analyses. In tests against Pseudomonas aeruginosa and Staphylococcus aureus on agar plates, antibacterial properties were similar for both types of Ag-modified PCCB materials. Concerning the antibacterial performance, the treatment with AgNO3 solutions with 10 mmol/L was almost as effective as with 100 mmol/L. PMID- 30477124 TI - Use of an Argentine Ant, Linepithema humile, Semiochemical to Deliver an Acute Toxicant. AB - The Argentine ant, Linepithema humile, is an invasive nuisance, agricultural, and ecological pest from South America. In the United States, its primary distribution is in California and the Southeast. The structural pest control industry responds to property owner complaints when this ant's populations become problematic and a persistent nuisance. Actions taken to control Argentine ants in the urban and suburban environment are typically complaint-driven, and often involve the application of insecticide sprays applied to the outdoor environment by professional pest managers. In California, and elsewhere, spray treatments of various residual insecticides by property owners and pest management professionals has resulted in significant runoff and in subsequent surface water contamination. As a result, an immediate need exists to develop alternative methods of ant control targeted at reducing environmental contamination. The purpose of this study was to investigate the potential for the development of an alternative method of toxicant delivery focused on the Argentine ant's behavior modifying cuticular chemistry. In short, methanol and hexane washes of Argentine ant pupae applied to paper dummies were handled significantly more by worker ants than the paper dummies that did not contain the solvent extracts. Additionally, paper wicks soaked in a methylene chloride wash from Argentine ant cadavers, air dried, and then treated with fipronil, were removed by worker ants and placed on a midden pile at the same rate (~86% to 99% removal at 1 h) as untreated and fipronil-treated ant cadavers. The paper wicks that did not contain the methylene chloride extract were ignored by the worker ants. After three days, the mortality of the ants exposed to the fipronil-treated wicks or the ant cadavers were dose related. In conclusion, our study suggests that there is potential for the use of ant semiochemicals for the delivery of acute toxicants. PMID- 30477125 TI - Preparation Method of Porous Dressing Materials Based on Butyric-Acetic Chitin Co Polyesters. AB - A method for obtaining highly porous materials in the form of film, based on the butyric-acetic chitin co-polyesters, containing 90% of butyryl and 10% of acetyl groups, was developed. The highly porous films, with thickness up to 0.11 mm, were obtained by two methods: (a) pouring 5% BAC 90/10 solution in ethanol on the layer of solid salts (porophor agent) which after solidification was eluted with water; (b) application of the suspension of porophor agent in BAC 90/10 solution in the solvent mixture with density similar to bulk porophor agent. In the final stage, the materials were obtained with porosity up to 95-99% and tensile strength 5 cN, which can be used as an active layer of medical dressings. The optimised procedure was used in the production of porous medical dressings (Medisorb) on an industrial scale. In the industrial method, NaCl was used as a porophor agent in the solid form and as a 3% solution in polymer. The final materials were characterised by porosity and other functional parameters at the level recommended for medical dressings. Medisorb series materials do not show in vitro cytotoxic activity. PMID- 30477126 TI - Decentralized 3D Collision Avoidance for Multiple UAVs in Outdoor Environments. AB - The use of multiple aerial vehicles for autonomous missions is turning into commonplace. In many of these applications, the Unmanned Aerial Vehicles (UAVs) have to cooperate and navigate in a shared airspace, becoming 3D collision avoidance a relevant issue. Outdoor scenarios impose additional challenges: (i) accurate positioning systems are costly; (ii) communication can be unreliable or delayed; and (iii) external conditions like wind gusts affect UAVs' maneuverability. In this paper, we present 3D-SWAP, a decentralized algorithm for 3D collision avoidance with multiple UAVs. 3D-SWAP operates reactively without high computational requirements and allows UAVs to integrate measurements from their local sensors with positions of other teammates within communication range. We tested 3D-SWAP with our team of custom-designed UAVs. First, we used a Software-In-The-Loop simulator for system integration and evaluation. Second, we run field experiments with up to three UAVs in an outdoor scenario with uncontrolled conditions (i.e., noisy positioning systems, wind gusts, etc). We report our results and our procedures for this field experimentation. PMID- 30477127 TI - Use of Electronic Noses in Seawater Quality Monitoring: A Systematic Review. AB - Electronic nose (eNose) systems are particularly appreciated for their portability, usability, relative low cost, and real-time or near real-time response. Their application finds space in several domains, including environmental monitoring. Within this field, marine monitoring is of particular scientific relevance due to the fragility of this specific environment, daily threatened by human activities that can potentially bring to catastrophic and irreversible consequences on marine wildlife. Under such considerations, a systematic review, complying with the PRISMA guidelines, was conducted covering the period up to 15 October 2018, in PubMed, ScienceDirect, and Google Scholar. Despite the relatively low number of articles published on this specific topic and the heterogeneity of the technological approaches employed, the results obtained by the various groups highlight the positive contribution eNose has given and can provide in near future for the monitoring and safeguarding of this delicate environment. PMID- 30477128 TI - Antimicrobial Activity of Divaricatic Acid Isolated from the Lichen Evernia mesomorpha against Methicillin-Resistant Staphylococcus aureus. AB - One hundred and seventy seven acetone extracts of lichen and 258 ethyl acetate extracts of cultured lichen-forming fungi (LFF) were screened for antimicrobial activity against Staphylococcus aureus and Enterococcus faecium using a disk diffusion method. Divaricatic acid was isolated from Evernia mesomorpha and identified by LC-MS, 1H-, 13C- and DEPT-NMR. Purified divaricatic acid was effective against Gram + bacteria, such as Bacillus subtilis, Staphylococcus epidermidis, Streptococcus mutans, and Enterococcus faecium, with the minimum inhibitory concentration (MIC) values ranging from 7.0 to 64.0 MUg/mL, whereas vancomycin was effective in the MICs ranging from 0.78 to 25.0 MUg/mL. Interestingly, the antibacterial activity of divaricatic acid was higher than vancomycin against S. epidermidis and E. faecium, and divaricatic acid was active against Candida albicans. In addition, divaricatic acid was active as vancomycin against S. aureus (3A048; an MRSA). These results suggested that divaricatic acid is a potential antimicrobial agent for the treatment of MRSA infections. PMID- 30477129 TI - Geospallins A-C: New Thiodiketopiperazines with Inhibitory Activity against Angiotensin-Converting Enzyme from a Deep-Sea-Derived Fungus Geosmithia pallida FS140. AB - Three new thiodiketopiperazines, geospallins A-C (1-3), together with nine known analogues (4-12), were isolated from the culture of the deep-sea sediment-derived fungus Geosmithia pallida FS140. Among them, geospallins A and B (1 and 2) represent rare examples of thiodiketopiperazines featuring an S-methyl group at C 10 and a tertiary hydroxyl group at C-11. Their structures were determined by high-resolution electrospray mass spectrometry (HRESIMS), spectroscopic analyses, and electronic circular dichroism (ECD) calculations. Their angiotensin converting enzyme (ACE) inhibitory activity was reported, and geospallins A-C (1 3) showed inhibitory activity with IC50 values of 29-35 uM. PMID- 30477130 TI - Whole-Genome Sequencing of Chinese Yellow Catfish Provides a Valuable Genetic Resource for High-Throughput Identification of Toxin Genes. AB - Naturally derived toxins from animals are good raw materials for drug development. As a representative venomous teleost, Chinese yellow catfish (Pelteobagrus fulvidraco) can provide valuable resources for studies on toxin genes. Its venom glands are located in the pectoral and dorsal fins. Although with such interesting biologic traits and great value in economy, Chinese yellow catfish is still lacking a sequenced genome. Here, we report a high-quality genome assembly of Chinese yellow catfish using a combination of next-generation Illumina and third-generation PacBio sequencing platforms. The final assembly reached 714 Mb, with a contig N50 of 970 kb and a scaffold N50 of 3.65 Mb, respectively. We also annotated 21,562 protein-coding genes, in which 97.59% were assigned at least one functional annotation. Based on the genome sequence, we analyzed toxin genes in Chinese yellow catfish. Finally, we identified 207 toxin genes and classified them into three major groups. Interestingly, we also expanded a previously reported sex-related region (to ~6 Mb) in the achieved genome assembly, and localized two important toxin genes within this region. In summary, we assembled a high-quality genome of Chinese yellow catfish and performed high-throughput identification of toxin genes from a genomic view. Therefore, the limited number of toxin sequences in public databases will be remarkably improved once we integrate multi-omics data from more and more sequenced species. PMID- 30477131 TI - Rapid Tartrazine Determination in Large Yellow Croaker with Ag Nanowires Using Surface-Enhanced Raman Spectroscopy. AB - In this work, surface-enhanced Raman spectroscopy (SERS) technology coupled with Ag nanowires was shown to be a promising tool in the detection of tartrazine in large yellow croaker for the first time. Ag nanowires with a uniform diameter were fabricated by an efficient and manageable polyol method. The partial least square model was established for the quantitative analysis of tartrazine, which showed a relatively high linear correlation between actual and predicted concentrations of standard tartrazine solutions. An optimal sample preparation method was also selected and used to extract tartrazine from large yellow croaker within 20 min. The lowest concentration detected was 20.38 ng/cm2, which fully meets the requirements of tartrazine testing in aquatic products. This study indicated that SERS technology combined with the as-prepared Ag nanowires could detect tartrazine sensitively and provide an easily operable and time-saving way to monitor tartrazine in large yellow croaker. PMID- 30477132 TI - Tracking Lysosome Migration within Chinese Hamster Ovary (CHO) Cells Following Exposure to Nanosecond Pulsed Electric Fields. AB - Above a threshold electric field strength, 600 ns-duration pulsed electric field (nsPEF) exposure substantially porates and permeabilizes cellular plasma membranes in aqueous solution to many small ions. Repetitive exposures increase permeabilization to calcium ions (Ca2+) in a dosage-dependent manner. Such exposure conditions can create relatively long-lived pores that reseal after passive lateral diffusion of lipids should have closed the pores. One explanation for eventual pore resealing is active membrane repair, and an ubiquitous repair mechanism in mammalian cells is lysosome exocytosis. A previous study shows that intracellular lysosome movement halts upon a 16.2 kV/cm, 600-ns PEF exposure of a single train of 20 pulses at 5 Hz. In that study, lysosome stagnation qualitatively correlates with the presence of Ca2+ in the extracellular solution and with microtubule collapse. The present study tests the hypothesis that limitation of nsPEF-induced Ca2+ influx and colloid osmotic cell swelling permits unabated lysosome translocation in exposed cells. The results indicate that the efforts used herein to preclude Ca2+ influx and colloid osmotic swelling following nsPEF exposure did not prevent attenuation of lysosome translocation. Intracellular lysosome movement is inhibited by nsPEF exposure(s) in the presence of PEG 300-containing solution or by 20 pulses of nsPEF in the presence of extracellular calcium. The only cases with no significant decreases in lysosome movement are the sham and exposure to a single nsPEF in Ca2+-free solution. PMID- 30477133 TI - Over One-Year Long-Term Laboratory Tests of pH Electrodes in Terms of Industrial Applications Checking Stabilities of Their Parameters and Their Influence on Uncertainties of Measurements. AB - Glass pH electrodes are still successfully applied in the chemical and environmental industry. During their long-term use, periodic calibration is required to maintain the required accuracy of measurements because the parameters of the electrodes change over time. This work presents an aging of 11 pH electrodes within approximately 600 days in tap water. During this period, potentials of all electrodes in five buffer solutions were measured 44 times. This allowed determining the aging models of the electrodes. Models in other mediums might be different. Changes in slope, standard potential, hysteresis, and linearity of the characteristics were the objects of observations. A method for predicting electrode parameters is proposed. Furthermore, the procedure for estimating the uncertainty of pH measurements considering the aging of the electrodes is described. As a result of this work, a model of the aging process of pH electrodes in tap water can be constructed and subsequently, the measurement accuracy in the periods between calibrations can be improved. PMID- 30477134 TI - Segmental and Tandem Duplications Driving the Recent NBS-LRR Gene Expansion in the Asparagus Genome. AB - Garden asparagus is an important horticultural plant worldwide. It is, however, susceptible to a variety of diseases, which can affect the potential yield, spear quality, and lifespan of production fields. Screening studies have identified resistant germplasm. The genetic resistance is usually complex, and the genes underlying that resistance are still unknown. Most often, disease resistance is determined by resistance genes (R). The most predominant R-genes contain nucleotide binding site and leucine-rich repeat (NBS-LRR) domains. Using bioinformatics and data mining approaches, we identified and characterized 68 NBS predicted proteins encoded by 49 different loci in the asparagus genome. The NBS encoding genes were grouped into seven distinct classes based on their domain architecture. The NBS genes are unevenly distributed through the genome and nearly 50% of the genes are present in clusters. Chromosome 6 is significantly NBS-enriched and one single cluster hosts 10% of the genes. Phylogenetic analysis points to their diversification into three families during their evolution. Recent duplications are likely to have dominated the NBS expansion with both tandem genes and duplication events across multiple chromosomes. Transcriptome sequencing data provided evidence for their transcription and tissue-specific expression. The total number of cis-regulatory elements as well as their relative positions within the NBS promoters suggests a complex transcriptional network regulating defense responses. Our study provides a strong groundwork for the isolation of candidate R-genes in garden asparagus. PMID- 30477135 TI - NeVOmics: An Enrichment Tool for Gene Ontology and Functional Network Analysis and Visualization of Data from OMICs Technologies. AB - The increasing number of OMICs studies demands bioinformatic tools that aid in the analysis of large sets of genes or proteins to understand their roles in the cell and establish functional networks and pathways. In the last decade, over representation or enrichment tools have played a successful role in the functional analysis of large gene/protein lists, which is evidenced by thousands of publications citing these tools. However, in most cases the results of these analyses are long lists of biological terms associated to proteins that are difficult to digest and interpret. Here we present NeVOmics, Network-based Visualization for Omics, a functional enrichment analysis tool that identifies statistically over-represented biological terms within a given gene/protein set. This tool provides a hypergeometric distribution test to calculate significantly enriched biological terms, and facilitates analysis on cluster distribution and relationship of proteins to processes and pathways. NeVOmics is adapted to use updated information from the two main annotation databases: Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG). NeVOmics compares favorably to other Gene Ontology and enrichment tools regarding coverage in the identification of biological terms. NeVOmics can also build different network-based graphical representations from the enrichment results, which makes it an integrative tool that greatly facilitates interpretation of results obtained by OMICs approaches. NeVOmics is freely accessible at https://github.com/bioinfproject/bioinfo/. PMID- 30477136 TI - Impact of Antibiotics on Efficacy of Cry Toxins Produced in Two Different Genetically Modified Bt Maize Varieties in Two Lepidopteran Herbivore Species, Ostrinia nubilalis and Spodoptera littoralis. AB - The insecticidal crystal proteins from Bacillus thuringiensis (Bt) are widely used biopesticides that are used both as Bt spore-crystal preparations in sprayable formulations and as activated toxins in genetically modified (GM) plants. Models for their modes of action have been proposed but many issues remain unresolved. Among those is the role of commensal gut bacteria in target insect death: previous studies showed that antibiotics attenuate the toxicity of Bt sprays. We tested whether antibiotics interfere with the effects of GM plant produced Bt toxins in larvae of two Lepidopteran species, the European corn borer Ostrinia nubilalis and the cotton leafworm Spodoptera littoralis. The larvae were reared on artificial diet with or without antibiotics and, thereafter, fed two varieties of Bt GM maize in comparison to conventional non-Bt maize leaves sprayed with antibiotic solution and/or with a Bt formulation. Antibiotics significantly reduced or delayed the toxicity of Cry toxins, although to a lesser extent than previously reported for Bt-sprays. This supports the hypothesis that Cry toxins induce mortality by themselves in the absence of Bt bacteria and spores, and of commensal gut bacteria. However, larvae that were not treated with antibiotics died faster and at a higher rate which was further compounded by plant variety and species sensitivity. These findings support a hypothesis that toxicemia alone can inflict significant mortality. However, in the absence of antibiotics, the gut bacteria likely enhance the Cry toxin effect by inflicting, additionally, bacterial septicemia. This has important implications in field situations where antibiotic substances are present-e.g., from manure of animals from conventional production systems-and for ecotoxicological testing schemes of Bt toxins and nontarget organisms that are often using artificial diets enriched with high concentrations of antibiotics. PMID- 30477137 TI - Endocrine Disruptors and Autism Spectrum Disorder in Pregnancy: A Review and Evaluation of the Quality of the Epidemiological Evidence. AB - Exposure to environmental contaminants during pregnancy has been linked to adverse health outcomes later in life. Notable among these pollutants are the endocrine disruptors chemicals (EDCs), which are ubiquitously present in the environment and they have been measured and quantified in the fetus. In this systematic review, our objective was to summarize the epidemiological research on the potential association between prenatal exposure to EDCs and Autism Spectrum Disorder (ASD) published from 2005 to 2016. The Navigation Guide Systematic Review Methodology was applied. A total of 17 studies met the inclusion criteria for this review, including: five cohorts and 12 case-control. According to the definitions specified in the Navigation Guide, we rated the quality of evidence for a relationship between prenatal exposure to EDCs and ASD as "moderate". Although the studies generally showed a positive association between EDCs and ASD, after considering the strengths and limitations, we concluded that the overall strength of evidence supporting an association between prenatal exposure to EDCs and later ASD in humans remains "limited" and inconclusive. Further well conducted prospective studies are warranted to clarify the role of EDCs on ASD development. PMID- 30477138 TI - Design and Evaluation of a Structural Analysis-Based Fault Detection and Identification Scheme for a Hydraulic Torque Converter. AB - A hydraulic torque converter (HTC) is a key component in an automatic transmission. To monitor its operating status and to detect and locate faults, and considering the high-efficiency fault detection and identification (FDI) scheme design by the methodology of structural analysis (SA), this paper presents an SA-based FDI system design and validation for the HTC. By the technique of fault mode and effect analysis (FMEA), eight critical faults are obtained, and then two fault variables are chosen to delegate them. Fault detectability and isolability, coupled with different sensor placements, are analyzed, and as a result, two speed sensors and two torque sensors of pump and turbine are selected to realize the maximal fault detectability and fault isolability: all six faults are detectable, four faults are uniquely isolable, and two faults are isolated from the other faults, but not from each other. Then five minimal structurally overdetermined (MSO) sets are easily acquired by SA to generate five corresponding residuals. The proposed FDI scheme of the HTC by SA is first validated by a theoretical model, then by an offline experiment in a commercial SUV, and the testing results indicate a consistent conclusion with the simulations and theory analysis. PMID- 30477139 TI - Relationship of Circulating Irisin with Body Composition, Physical Activity, and Cardiovascular and Metabolic Disorders in the Pediatric Population. AB - Exercise-induced irisin, a recently discovered myokine, has been linked to insulin resistance, obesity, and other diseases in adults; however, information in children is scarce and contradictory. We analyzed the limited evidence of irisin's effects in children and adolescents, and its association with body composition, exercise training, cardiovascular risk factors, and metabolic diseases, as well as the results of dietetic interventions. Both positive and negative correlations between irisin concentrations and body mass index, fat mass, fat-free mass, and other anthropometric parameters were found. Likewise, contradictory evidence was shown associating irisin plasma levels with cardiovascular and metabolic parameters such as glucose, insulin resistance, and cholesterol and other lipid and fatty acid plasma levels in healthy children, as well as in those with obesity and the metabolic syndrome. Gender, puberty, and hormonal differences were also examined. Furthermore, important contradictory findings according to the type and duration of exercise and of dietetic interventions in healthy and unhealthy subjects were demonstrated. In addition, correlations between mother-infant relations and circulating irisin were also identified. This review discusses the potential role of irisin in health and disease in the pediatric population. PMID- 30477140 TI - Spectroscopic Analysis of Melatonin in the Terahertz Frequency Range. AB - There is a need for fast and reliable quality and authenticity control tools of pharmaceutical ingredients. Among others, hormone containing drugs and foods are subject to scrutiny. In this study, terahertz (THz) spectroscopy and THz imaging are applied for the first time to analyze melatonin and its pharmaceutical product Circadin. Melatonin is a hormone found naturally in the human body, which is responsible for the regulation of sleep-wake cycles. In the THz frequency region between 1.5 THz and 4.5 THz, characteristic melatonin spectral features at 3.21 THz, and a weaker one at 4.20 THz, are observed allowing for a quantitative analysis within the final products. Spectroscopic THz imaging of different concentrations of Circadin and melatonin as an active pharmaceutical ingredient in prepared pellets is also performed, which permits spatial recognition of these different substances. These results indicate that THz spectroscopy and imaging can be an indispensable tool, complementing Raman and Fourier transform infrared spectroscopies, in order to provide quality control of dietary supplements and other pharmaceutical products. PMID- 30477141 TI - Intersections Between Systems Thinking and Market Shaping for Assistive Technology: The SMART (Systems-Market for Assistive and Related Technologies) Thinking Matrix. AB - The Sustainable Development Goals (SDGs) aspire to "leave no-one behind". Universal access to assistive products is a critical link between the realization of the SDGs and those most likely to be left behind. However, assistive technology provision in many countries, particularly low- and middle-income countries, has traditionally been conducted through small-scale local providers, manufacturing products of varying degrees of quality at a limited price range. An effective way to scale these production and provision enterprises to the required level is needed to close the gap between available and required assistive technology. We argue that better access to assistive technology will only be realized through the adoption of a far stronger systems thinking and market shaping approach. We undertook a rapid literature review to explore the relationship between market shaping and assistive technology. Based on our review, we present an emergent framework for conceptualizing intersections between systems thinking and market shaping for assistive technology-the SMART (Systems-Market for Assistive and Related Technologies) Thinking Matrix. PMID- 30477142 TI - First Report of Okadaic Acid and Pectenotoxins in Individual Cells of Dinophysis and in Scallops Argopecten purpuratus from Peru. AB - Causative species of Harmful Algal Bloom (HAB) and toxins in commercially exploited molluscan shellfish species are monitored weekly from four classified shellfish production areas in Peru (three in the north and one in the south). Okadaic acid (OA) and pectenotoxins (PTXs) were detected in hand-picked cells of Dinophysis (D. acuminata-complex and D. caudata) and in scallops (Argopecten purpuratus), the most important commercial bivalve species in Peru. LC-MS analyses revealed two different toxin profiles associated with species of the D. acuminata-complex: (a) one with OA (0.3-8.0 pg cell-1) and PTX2 (1.5-11.1 pg cell 1) and (b) another with only PTX2 which included populations with different toxin cell quota (9.3-9.6 pg cell-1 and 5.8-9.2 pg cell-1). Toxin results suggest the likely presence of two morphotypes of the D. acuminata-complex in the north, and only one of them in the south. Likewise, shellfish toxin analyses revealed the presence of PTX2 in all samples (10.3-34.8 ug kg-1), but OA (7.7-15.2 ug kg-1) only in the northern samples. Toxin levels were below the regulatory limits established for diarrhetic shellfish poisoning (DSP) and PTXs (160 ug OA kg-1) in Peru, in all samples analyzed. This is the first report confirming the presence of OA and PTX in Dinophysis cells and in shellfish from Peruvian coastal waters. PMID- 30477143 TI - Oxidative Stress as Cause, Consequence, or Biomarker of Altered Female Reproduction and Development in the Space Environment. AB - Oxidative stress has been implicated in the pathophysiology of numerous terrestrial disease processes and associated with morbidity following spaceflight. Furthermore, oxidative stress has long been considered a causative agent in adverse reproductive outcomes. The purpose of this review is to summarize the pathogenesis of oxidative stress caused by cosmic radiation and microgravity, review the relationship between oxidative stress and reproductive outcomes in females, and explore what role spaceflight-induced oxidative damage may have on female reproductive and developmental outcomes. PMID- 30477144 TI - Elicited ROS Scavenging Activity, Photoprotective, and Wound-Healing Properties of Collagen-Derived Peptides from the Marine Sponge Chondrosia reniformis. AB - Recently, the bioactive properties of marine collagen and marine collagen hydrolysates have been demonstrated. Although there is some literature assessing the general chemical features and biocompatibility of collagen extracts from marine sponges, no data are available on the biological effects of sponge collagen hydrolysates for biomedical and/or cosmetic purposes. Here, we studied the in vitro toxicity, antioxidant, wound-healing, and photoprotective properties of four HPLC-purified fractions of trypsin-digested collagen extracts-marine collagen hydrolysates (MCHs)-from the marine sponge C. reniformis. The results showed that the four MCHs have no degree of toxicity on the cell lines analyzed; conversely, they were able to stimulate cell growth. They showed a significant antioxidant activity both in cell-free assays as well as in H2O2 or quartz stimulated macrophages, going from 23% to 60% of reactive oxygen species (ROS) scavenging activity for the four MCHs. Finally, an in vitro wound-healing test was performed with fibroblasts and keratinocytes, and the survival of both cells was evaluated after UV radiation. In both experiments, MCHs showed significant results, increasing the proliferation speed and protecting from UV-induced cell death. Overall, these data open the way to the use of C. reniformis MCHs in drug and cosmetic formulations for damaged or photoaged skin repair. PMID- 30477145 TI - Bandwidth Cost Minimization via User Association for Enterprise WLANs. AB - Enterprise Wireless LANs (E-WLANs) such as airport WiFi, have become a convenient way for Internet access for mobile users. In an E-WLAN, access points (APs) are usually deployed with high-density around the infrastructure to provide sufficient coverage and for a better service, where a mobile user chooses one AP to associate with among multiple available APs in the vicinity. Many studies have been done on developing user association techniques to increase system performance, with various objectives including network throughput maximization, load balancing etc. Our work is unique in that we focused on bandwidth cost minimization via user association from the perspective of the E-WLAN operators. Specifically, by considering the bandwidth demands from mobile users, we modeled the joint user association and cost minimization problem in the heterogeneous E WLAN with additional constraints from individual bandwidth demands as an optimization problem. To solve the optimization problem efficiently, we propose an approximation algorithm using relaxation and rounding techniques. We prove that the proposed algorithm has performance bound with a constant ratio to the optimization problem. Furthermore, our simulation results exhibit the superiority of our proposed algorithm over prior schemes. PMID- 30477146 TI - Engineered Mesenchymal Stem Cells Expressing Stromal Cell-derived Factor-1 Improve Erectile Dysfunction in Streptozotocin-Induced Diabetic Rats. AB - Effective therapies for erectile dysfunction (ED) associated with diabetes mellitus (DM) are needed. In this study, the effects of stromal cell-derived factor-1 (SDF-1)-expressing engineered mesenchymal stem cells (SDF-1 eMSCs) and the relevant mechanisms in the corpus cavernosum of a streptozotocin (STZ) induced DM ED rat model were evaluated. In a randomized controlled trial, Sprague Dawley (SD) rats (n = 48) were divided into four groups (n = 12/group): Normal (control), DM ED (diabetes induced by STZ), DM ED + BM-MSC (treated with bone marrow [BM]-derived MSCs), and DM ED + SDF-1 eMSC (treated with SDF-1-expressing BM-MSCs). After four weeks, intracavernosal pressure (ICP), an indicator of erectile function, was 0.75 +/- 0.07 in the normal group, 0.27 +/- 0.08 in the DM ED group, 0.42 +/- 0.11 in the DM ED + BM-MSC group, and 0.58 +/- 0.11 in the DM ED + SDF-1 eMSC group. BM-MSCs, especially SDF-1 eMSCs, improved ED (p < 0.05). SDF-1 eMSC treatment improved the smooth muscle content in the corpus cavernosum (p < 0.05). As SDF-1 expression increased, ED recovery improved. In the SDF-1 eMSC group, levels of neuronal nitric oxide synthase (nNOS) and phosphorylated endothelial NOS (p-eNOS) were higher than those in other groups (p < 0.05). In addition, high stromal cell-derived factor-1 (SDF-1) expression was associated with increased vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in DM ED rats (p < 0.05). Higher levels of phosphorylated protein kinase B (p-AKT)/protein kinase B (AKT) (p < 0.05) and B-cell lymphoma-2 (Bcl-2) and lower levels of the apoptosis factors Bcl2-associated x (Bax) and caspase-3 were observed in the MSC-treated group than in the DM ED group (p < 0.05). SDF-1 eMSCs showed beneficial effects on recovery from erectile function. PMID- 30477147 TI - Novel 5'-Norcarbocyclic Pyrimidine Derivatives as Antibacterial Agents. AB - A series of novel 5'-norcarbocyclic derivatives of 5-alkoxymethyl or 5 alkyltriazolyl-methyl uracil were synthesized and the activity of the compounds evaluated against both Gram-positive and Gram-negative bacteria. The growth of Mycobacterium smegmatis was completely inhibited by the most active compounds at a MIC99 of 67 MUg/mL (mc2155) and a MIC99 of 6.7-67 MUg/mL (VKPM Ac 1339). Several compounds also showed the ability to inhibit the growth of attenuated strains of Mycobacterium tuberculosis ATCC 25177 (MIC99 28-61 MUg/mL) and Mycobacterium bovis ATCC 35737 (MIC99 50-60 MUg/mL), as well as two virulent strains of M. tuberculosis; a laboratory strain H37Rv (MIC99 20-50 MUg/mL) and a clinical strain with multiple drug resistance MS-115 (MIC99 20-50 MUg/mL). Transmission electron microscopy (TEM) evaluation of M. tuberculosis H37Rv bacterial cells treated with one of the compounds demonstrated destruction of the bacterial cell wall, suggesting that the mechanism of action for these compounds may be related to their interactions with bacteria cell walls. PMID- 30477148 TI - Vascular Plant One-Zinc-Finger (VOZ) Transcription Factors Are Positive Regulators of Salt Tolerance in Arabidopsis. AB - Soil salinity, a significant problem in agriculture, severely limits the productivity of crop plants. Plants respond to and cope with salt stress by reprogramming gene expression via multiple signaling pathways that converge on transcription factors. To develop strategies to generate salt-tolerant crops, it is necessary to identify transcription factors that modulate salt stress responses in plants. In this study, we investigated the role of VOZ (VASCULAR PLANT ONE-ZINC FINGER PROTEIN) transcription factors (VOZs) in salt stress response. Transcriptome analysis in WT (wild-type), voz1-1, voz2-1 double mutant and a VOZ2 complemented line revealed that many stress-responsive genes are regulated by VOZs. Enrichment analysis for gene ontology terms in misregulated genes in voz double mutant confirmed previously identified roles of VOZs and suggested a new role for them in salt stress. To confirm VOZs role in salt stress, we analyzed seed germination and seedling growth of WT, voz1, voz2-1, voz2-2 single mutants, voz1-1 voz2-1 double mutant and a complemented line under different concentrations of NaCl. Only the double mutant exhibited hypersensitivity to salt stress as compared to WT, single mutants, and a complemented line. Expression analysis showed that hypersensitivity of the double mutant was accompanied by reduced expression of salt-inducible genes. These results suggest that VOZ transcription factors act as positive regulators of several salt-responsive genes and that the two VOZs are functionally redundant in salt stress. PMID- 30477149 TI - Steering Algorithm for a Flexible Microrobot to Enhance Guidewire Control in a Coronary Angioplasty Application. AB - Magnetically driven microrobots have been widely studied for various biomedical applications in the past decade. An important application of these biomedical microrobots is heart disease treatment. In intravascular treatments, a particular challenge is the submillimeter-sized guidewire steering; this requires a new microrobotic approach. In this study, a flexible microrobot was fabricated by the replica molding method, which consists of three parts: (1) a flexible polydimethylsiloxane (PDMS) body, (2) two permanent magnets, and (3) a micro spring connector. A mathematical model was developed to describe the relationship between the magnetic field and the deformation. A system identification approach and an algorithm were proposed for steering. The microrobot was fabricated, and the models for steering were experimentally validated under a magnetic field intensity of 15 mT. Limitations to control were identified, and the microrobot was steered in an arbitrary path using the proposed model. Furthermore, the flexible microrobot was steered using the guidewire within a three-dimensional (3D) transparent phantom of the right coronary artery filled with water, to show the potential application in a realistic environment. The flexible microrobot presented here showed promising results for enhancing guidewire steering in percutaneous coronary intervention (PCI). PMID- 30477150 TI - Influence of Industrialization and Environmental Protection on Environmental Pollution: A Case Study of Taihu Lake, China. AB - In order to quantitatively study the effect of environmental protection in China since the twenty-first century and the environmental pollution projected for the next ten years (under the model of extensive economic development), this paper establishes a Bayesian regulation back propagation neural network (BRBPNN) to analyze the typical pollutants (i.e., cadmium (Cd) and benzopyrene (BaP)) for Taihu Lake, a typical Chinese freshwater lake. For the periods 1950-2003 and 1950 2015, the neural network model estimated the BaP concentration for the database with Nash-Sutcliffe model efficiency (NS) = 0.99 and 0.99 and root-mean-square error (RMSE) = 3.1 and 9.3 for the total database and the Cd concentration for the database with NS = 0.93 and 0.98 and RMSE = 45.4 and 65.7 for the total database, respectively. In the model of extensive economic development, the concentration of pollutants in the sediments of Taihu reached the maximum value at the end of the twentieth century and early twenty-first century, and there was an inflection point. After the early twenty-first century, the concentration of pollutants was controlled under various environmental policies and measures. In 2015, the environmental protection ratio of Cd and BaP reached 52% and 89%, respectively. Without environmental protection measures, the concentrations of Cd and BaP obtained from the neural network model is projected to reach 2015.5 MUg kg-1 and 407.8 ng g-1, respectively, in 2030. Based on the results of this study, the Chinese government will need to invest more money and energy to clean up the environment. PMID- 30477151 TI - Heterogeneity in Colorectal Cancer: A Challenge for Personalized Medicine? AB - High inter-patient variability and high spatial heterogeneity are features of colorectal cancer (CRC). This may influence the molecular characterization of tumor tissue, now mandatory for patients with metastatic CRC who are candidates for treatment with an anti-EGFR mAb, as false-negative results can occur, leading to non optimal therapy. Moreover, temporal molecular heterogeneity during treatment is known to influence the response to therapy and prognosis. We present a literature overview of advances made in characterizing molecular heterogeneity in CRC, underlining that the analysis of liquid biopsy could represent an efficient non-invasive tool to overcome the problem. We believe that understanding CRC heterogeneity is fundamental for a more accurate diagnosis, for selecting the best targets to ensure prolonged antitumor response, and for monitoring minimal residual disease and the onset of resistance to therapy, all essential components of successful personalized treatment. PMID- 30477152 TI - Dual Convolutional Neural Network Based Method for Predicting Disease-Related miRNAs. AB - Identification of disease-related microRNAs (disease miRNAs) is helpful for understanding and exploring the etiology and pathogenesis of diseases. Most of recent methods predict disease miRNAs by integrating the similarities and associations of miRNAs and diseases. However, these methods fail to learn the deep features of the miRNA similarities, the disease similarities, and the miRNA disease associations. We propose a dual convolutional neural network-based method for predicting candidate disease miRNAs and refer to it as CNNDMP. CNNDMP not only exploits the similarities and associations of miRNAs and diseases, but also captures the topology structures of the miRNA and disease networks. An embedding layer is constructed by combining the biological premises about the miRNA-disease associations. A new framework based on the dual convolutional neural network is presented for extracting the deep feature representation of associations. The left part of the framework focuses on integrating the original similarities and associations of miRNAs and diseases. The novel miRNA and disease similarities which contain the topology structures are obtained by random walks on the miRNA and disease networks, and their deep features are learned by the right part of the framework. CNNDMP achieves the superior prediction performance than several state-of-the-art methods during the cross-validation process. Case studies on breast cancer, colorectal cancer and lung cancer further demonstrate CNNDMP's powerful ability of discovering potential disease miRNAs. PMID- 30477153 TI - Characterization of Gene Families Encoding Beta-Lactamases of Gram-Negative Rods Isolated from Ready-to-Eat Vegetables in Mexico City. AB - Beta-lactam resistant bacteria, which are commonly resident in tertiary hospitals, have emerged as a worldwide health problem because of ready-to-eat vegetable intake. We aimed to characterize the genes that provide resistance to beta-lactam antibiotics in Enterobacteriaceae, isolated from five commercial salad brands for human consumption in Mexico City. In total, twenty-five samples were collected, grown in blood agar plates, and the bacteria were biochemistry identified and antimicrobial susceptibility testing was done. The carried family genes were identified by endpoint PCR and the specific genes were confirmed with whole genome sequencing (WGS) by Next Generation Sequencing (NGS). Twelve positive cultures were identified and their microbiological distribution was as follows: 8.3% for Enterobacter aerogene (n = 1), 8.3% for Serratia fonticola (n = 1), 16.7% for Serratia marcesens (n = 2), 16.7% for Klebsiella pneumoniae (n = 2), and 50% (n = 6) for Enterobacter cloacae. The endpoint PCR results showed 11 colonies positive for blaBIL (91.7%), 11 for blaSHV (91.7%), 11 for blaCTX (97.7%), 12 for blaDHA (100%), four for blaVIM (33.3%), two for blaOXA (16.7%), two for blaIMP (16.7%), one for blaKPC (8.3%), and one for blaTEM (8.3%) gen; all samples were negative for blaROB, blaCMY, blaP, blaCFX and blaLAP gene. The sequencing analysis revealed a specific genotype for Enterobacter cloacae (blaSHV 12, blaCTX-M-15, blaDHA-1, blaKPC-2); Serratia marcescens (blaSHV-1, blaCTX-M-3, blaDHA-1, blaVIM-2); Klebsiella pneumoniae (blaSHV-12, blaCTX-M-15, blaDHA-1); Serratia fonticola (blaSHV-12, blaVIM-1, blaDHA-1); and, Enterobacter aerogene (blaSHV-1, blaCTX-M-1, blaDHA-1, blaVIM-2, blaOXA-9). Our results indicate that beta-lactam-resistant bacteria have acquired integrons with a different number of genes that provide pan-resistance to beta-lactam antibiotics, including penicillins, oxacillins, cefalosporins, monobactams, carbapenems, and imipenems. PMID- 30477154 TI - Studies on the Dual Activity of EGFR and HER-2 Inhibitors Using Structure-Based Drug Design Techniques. AB - HER-2 and EGFR are biological targets related to the development of cancer and the discovery and/or development of a dual inhibitor could be a good strategy to design an effective drug candidate. In this study, analyses of the chemical properties of a group of substances having affinity for both HER-2 and EGFR were carried out with the aim of understanding the main factors involved in the interaction between these inhibitors and the biological targets. Comparative analysis of molecular interaction fields (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques were applied on 63 compounds. From CoMFA analyses, we found for both HER-2 (r2 calibration = 0.98 and q2cv = 0.83) and EGFR (r2 calibration = 0.98 and q2cv = 0.73) good predictive models. Good models for CoMSIA technique have also been found for HER-2 (r2 calibration = 0.92 and q2cv = 0.74) and EGFR (r2 calibration = 0.97 and q2cv = 0.72). The constructed models could indicate some important characteristics for the inhibition of the biological targets. New compounds were proposed as candidates to inhibit both proteins. Therefore, this study may guide future projects for the development of new drug candidates for the treatment of breast cancer. PMID- 30477155 TI - The Past, Present, and Future of the Hemlock Woolly Adelgid (Adelges tsugae) and Its Ecological Interactions with Eastern Hemlock (Tsuga canadensis) Forests. AB - The nonnative hemlock woolly adelgid is steadily killing eastern hemlock trees in many parts of eastern North America. We summarize impacts of the adelgid on these forest foundation species; review previous models and analyses of adelgid spread dynamics; and examine how previous forecasts of adelgid spread and ecosystem dynamics compare with current conditions. The adelgid has reset successional sequences, homogenized biological diversity at landscape scales, altered hydrological dynamics, and changed forest stands from carbon sinks into carbon sources. A new model better predicts spread of the adelgid in the south and west of the range of hemlock, but still under-predicts its spread in the north and east. Whether these underpredictions result from inadequately modeling accelerating climate change or accounting for people inadvertently moving the adelgid into new locales needs further study. Ecosystem models of adelgid-driven hemlock dynamics have consistently forecast that forest carbon stocks will be little affected by the shift from hemlock to early-successional mixed hardwood stands, but these forecasts have assumed that the intermediate stages will remain carbon sinks. New forecasting models of adelgid-driven hemlock decline should account for observed abrupt changes in carbon flux and ongoing and accelerating human-driven land-use and climatic changes. PMID- 30477156 TI - Research on an Improved Method for Foot-Mounted Inertial/Magnetometer Pedestrian Positioning Based on the Adaptive Gradient Descent Algorithm. AB - Foot-mounted Inertial Pedestrian-Positioning Systems (FIPPSs) based on Micro Inertial Measurement Units (MIMUs), have recently attracted widespread attention with the rapid development of MIMUs. The can be used in challenging environments such as firefighting and the military, even without augmenting with Global Navigation Satellite System (GNSS). Zero Velocity Update (ZUPT) provides a solution for the accumulated positioning errors produced by the low precision and high noise of the MIMU, however, there are some problems using ZUPT for FIPPS, include fast-initial alignment and unobserved heading misalignment angle, which are addressed in this paper. Our first contribution is proposing a fast-initial alignment algorithm for foot-mounted inertial/magnetometer pedestrian positioning based on the Adaptive Gradient Descent Algorithm (AGDA). Considering the characteristics of gravity and Earth's magnetic field, measured by accelerometers and magnetometers, respectively, when the pedestrian is standing at one place, the AGDA is introduced as the fast-initial alignment. The AGDA is able to estimate the initial attitude and enhance the ability of magnetic disturbance suppression. Our second contribution in this paper is proposing an inertial/magnetometer positioning algorithm based on an adaptive Kalman filter to solve the problem of the unobserved heading misalignment angle. The algorithm utilizes heading misalignment angle as an observation for the Kalman filter and can improve the accuracy of pedestrian position by compensating for magnetic disturbances. In addition, introducing an adaptive parameter in the Kalman filter is able to compensate the varying magnetic disturbance for each ZUPT instant during the walking phase of the pedestrian. The performance of the proposed method is examined by conducting pedestrian test trajectory using MTi-G710 manufacture by XSENS. The experimental results verify the effectiveness and applicability of the proposed method. PMID- 30477157 TI - Structure and Properties of ZrO2-20%Al2O3 Ceramic Composites Obtained Using Additive Technologies. AB - This investigation focused on obtaining samples from ceramic composite materials, based on the ZrO2-20%Al2O3 system, using the additive layer-by-layer fusion technology for thermoplastic systems. The structure and phase composition of the initial powders were studied, experimental samples were produced, and the structure and properties of the experimental samples that were obtained using additive technologies were analysed. The measured static bending strength of the samples was 450 +/- 70 MPa, microhardness was 14 GPa, and the elasticity modulus was 280 +/- 25 GPa. The strength of these samples are slightly inferior to that of similar materials, obtained using Ceramic Injection Molding technology because our samples were characterised by the residual porosity of about 15%. PMID- 30477158 TI - The Use of the FEM to Identify the Optimal Groove Dimensions Ensuring the Least Stressed Connection between a Zirconia Coping and Veneering Ceramic. AB - Background: To examine the influence of coping notches with varying groove widths and depths on the quality of the connection with ceramic. Methods: Ten rectangular sintered zirconia (3Y-TZP) samples were etched with a neodymium-yag laser Nd:YAG. Then, a profilometer was used to test the depths and spacing of the grooves. A notch profile was used to design the shapes and spacing of the grooves based on a finite element method (FEM) simulating zirconia. The following situations were simulated: an increase in groove width from 100% to 180% and depth from 40% and 80%; and a 40% depth and width. Results: An increase of 10% in the baseline width caused an insignificant reduction of the strain in the connection. A further increase in this dimension led to a 50% increase in strain with a 40% increase in width. An increase in the groove depth by 40% reduced the strain level by 13%, while an increase in the groove depth by 80% reduced the strain level by 22%. Simultaneous deepening and widening of the groove by 40% had no significant impact on the strain level. Conclusion: Maintaining the width of the groove bottom while increasing the depth offers fewer advantages than deepening and narrowing the groove bottom. PMID- 30477159 TI - In Silico Profiling of Clinical Phenotypes for Human Targets Using Adverse Event Data. AB - We present a novel approach for the molecular transformation and analysis of patient clinical phenotypes. Building on the fact that drugs perturb the function of targets/genes, we integrated data from 8.2 million clinical reports detailing drug-induced side effects with the molecular world of drug-target information. Using this dataset, we extracted 1.8 million associations of clinical phenotypes to 770 human drug-targets. This collection is perhaps the largest phenotypic profiling reference of human targets to-date, and unique in that it enables rapid development of testable molecular hypotheses directly from human-specific information. We also present validation results demonstrating analytical utilities of the approach, including drug safety prediction, and the design of novel combination therapies. Challenging the long-standing notion that molecular perturbation studies cannot be performed in humans, our data allows researchers to capitalize on the vast tomes of clinical information available throughout the healthcare system. PMID- 30477160 TI - The MTNR1B rs10830963 Variant in Interaction with Pre-Pregnancy BMI is a Pharmacogenetic Marker for the Initiation of Antenatal Insulin Therapy in Gestational Diabetes Mellitus. AB - The rs10830963 variant of the Melatonin Receptor 1B (MTNR1B) gene is associated with the development of gestational diabetes mellitus (GDM). We hypothesized that carrying the rs10830963/G risk allele had effect on antenatal insulin therapy (AIT) initiation in GDM in a body mass index (BMI)-dependent manner. Design: In this post hoc analysis the MTNR1B rs10830963 genotype and the clinical data of 211 Caucasian GDM patients were assessed. As a first step, a pre-pregnancy BMI threshold was determined where the effect of MTNR1B rs10830963/G allele carrying on AIT initiation was the most significant using logistic regression. Maternal age adjusted real-life odds ratios (OR) values were calculated. The chi-square test was also used to calculate the p value and 10.000 bootstrap simulations were performed in each case to re-assess the statistical power and the OR. Carrying the MTNR1B rs10830963/G allele increased the odds of AIT initiation (OR = 5.2, p = 0.02 [chi2 test], statistical power = 0.53) in GDM patients with pre-pregnancy BMI >= 29 kg/m2. The statistical power reached 0.77, when the pre-pregnancy BMI cutoff of 27 kg/m2 was used and the genetic effect on AIT initiation was still significant, but only using the logistic regression model. Carrying the MTNR1B rs10830963/G risk allele-in interaction with pre-pregnancy BMI-is likely be considered as a candidate pharmacogenetic marker of antenatal insulin therapy initiation and should be further assessed in precision medicine trials in GDM. PMID- 30477161 TI - UrdA Controls Secondary Metabolite Production and the Balance between Asexual and Sexual Development in Aspergillus nidulans. AB - The genus Aspergillus includes important plant pathogens, opportunistic human pathogens and mycotoxigenic fungi. In these organisms, secondary metabolism and morphogenesis are subject to a complex genetic regulation. Here we functionally characterized urdA, a gene encoding a putative helix-loop-helix (HLH)-type regulator in the model fungus Aspergillus nidulans. urdA governs asexual and sexual development in strains with a wild-type veA background; absence of urdA resulted in severe morphological alterations, with a significant reduction of conidial production and an increase in cleistothecial formation, even in the presence of light, a repressor of sex. The positive effect of urdA on conidiation is mediated by the central developmental pathway (CDP). However, brlA overexpression was not sufficient to restore wild-type conidiation in the DeltaurdA strain. Heterologous complementation of DeltaurdA with the putative Aspergillus flavus urdA homolog also failed to rescue conidiation wild-type levels, indicating that both genes perform different functions, probably reflected by key sequence divergence. UrdA also represses sterigmatocystin (ST) toxin production in the presence of light by affecting the expression of aflR, the activator of the ST gene cluster. Furthermore, UrdA regulates the production of several unknown secondary metabolites, revealing a broader regulatory scope. Interestingly, UrdA affects the abundance and distribution of the VeA protein in hyphae, and our genetics studies indicated that veA appears epistatic to urdA regarding ST production. However, the distinct fluffy phenotype of the DeltaurdADeltaveA double mutant suggests that both regulators conduct independent developmental roles. Overall, these results suggest that UrdA plays a pivotal role in the coordination of development and secondary metabolism in A. nidulans. PMID- 30477162 TI - Biological Activities of Extracts from Aerial Parts of Salvia pachyphylla Epling Ex Munz. AB - The antioxidant, antimicrobial, antiproliferative, and enzyme inhibitory properties of five extracts from aerial parts of Salvia pachyphylla Epling ex Munz were examined to assess the prospective of this plant as a source of natural products with therapeutic potential. These properties were analyzed by performing a set of standard assays. The extract obtained with dichloromethane showed the most variety of components, as they yielded promising results in all completed assays. Furthermore, the extract obtained with ethyl acetate exhibited the greatest antioxidant activity, as well as the best xanthine oxidase inhibitory activity. Remarkably, both extracts obtained with n-hexane or dichloromethane revealed significant antimicrobial activity against the Gram-positive bacteria; additionally, they showed greater antiproliferative activity against three representative cell lines of the most common types of cancers in women worldwide, and against a cell line that exemplifies cancers that typically develop drug resistance. Despite that, other extracts were less active, such as the methanolic or aqueous; their results are promising for the isolation and identification of novel bioactive molecules. PMID- 30477163 TI - Effects of Wet Oxidation Process on Biochar Surface in Acid and Alkaline Soil Environments. AB - Biochar has been studied for remediation of heavy metal-contaminated soils by many researchers. When in external conditions, biochar in soils ages, which can transform its structural properties and adsorption capacity. This study was conducted with two oxidation processes, HNO3/H2SO4 and NaOH/H2O2, to simulate the effects of biochar in acid and alkaline soil conditions. The results show that the oxygen-containing functional groups increased in aged biochar, which led to improve the ratio of oxygen and carbon (O/C). Nitro functional groups were found in the acid-oxidation treated biochar. Destroyed ditches and scars were observed on the surface of aged biochar and resulted in growth in their specific surface area and porosity. Specific surface area increased by 21.1%, 164.9%, and 63.0% for reed-derived biochar treated with water washing, acid oxidation, and basic oxidation, respectively. Greater peaks in the Fourier Transform Infrared Spectroscopy (FTIR) results were found in C-O and O-H on the surface of field aged biochar. Meanwhile, mappings of energy-dispersive spectroscopy showed that biochar aged in soil was abundant in minerals such as silicon, iron, aluminum, and magnesium. In summary, biochar subjected to wet oxidation aging had an increased capacity to immobilize Cd compared to unaged biochar, and the adsorption capacity of oxidized biochar increased by 28.4% and 13.15% compared to unaged biochar due to improvements in porosity and an increase in functional groups. PMID- 30477164 TI - Evaluation of Prestress Loss Distribution during Pre-Tensioning and Post Tensioning Using Long-Gauge Fiber Bragg Grating Sensors. AB - Prestress loss evaluation in prestressed strands is essential for prestressed structures. However, the sensors installed outside the duct can only measure the total prestress loss. The sensors attached on strands inside the duct also have several problems, such as inadequate durability in an aggressive environment and vulnerability to damage during tensioning. This paper proposes a new installation method for long-gauge fiber Bragg grating (LFBG) sensors to prevent accidental damage. Then the itemized prestress losses were determined in each stage of the pre-tensioning and post-tensioning according to the LFBG measurements. We verified the applicability of the LFBG sensors for prestress monitoring and the accuracy of the proposed prestress loss calculation method during pre-tensioning and post-tensioning. In the pre-tensioning case, the calculated prestress losses had less deviation from the true losses than those obtained from foil-strain gauges, and the durability of the LFBG sensors was better than foil-strain gauges, whereas in post-tensioning case, the calculated prestress losses were close to those derived from theoretical predictions. Finally, we monitored prestress variation in the strand for 90 days. The itemized prestress losses at each stages of post-tensioning were obtained by the proposed calculation method to show the prospect of the LFBG sensors in practical evaluation. PMID- 30477165 TI - Crystal Structure of Chloroplastic Thioredoxin f2 from Chlamydomonas reinhardtii Reveals Distinct Surface Properties. AB - Protein disulfide reduction by thioredoxins (TRXs) controls the conformation of enzyme active sites and their multimeric complex formation. TRXs are small oxidoreductases that are broadly conserved in all living organisms. In photosynthetic eukaryotes, TRXs form a large multigenic family, and they have been classified in different types: f, m, x, y, and z types are chloroplastic, while o and h types are located in mitochondria and cytosol. In the model unicellular alga Chlamydomonas reinhardtii, the TRX family contains seven types, with f- and h-types represented by two isozymes. Type-f TRXs interact specifically with targets in the chloroplast, controlling photosynthetic carbon fixation by the Calvin-Benson cycle. We solved the crystal structures of TRX f2 and TRX h1 from C. reinhardtii. The systematic comparison of their atomic features revealed a specific conserved electropositive crown around the active site of TRX f, complementary to the electronegative surface of their targets. We postulate that this surface provides specificity to each type of TRX. PMID- 30477166 TI - Cyano-Bridged Cu-Ni Coordination Polymer Nanoflakes and Their Thermal Conversion to Mixed Cu-Ni Oxides. AB - Herein, we demonstrate the bottom-up synthesis of 2D cyano-bridged Cu-Ni coordination polymer (CP) nanoflakes through a controlled crystallization process and their conversion to Cu-Ni mixed oxides via a thermal treatment in air. The chelating effect of citrate anions effectively prevents the rapid coordination reaction between Cu2+ and K2[Ni(CN)4], resulting in the deceleration of the crystallization process of CPs. Specifically, with addition of trisodium citrate dehydrate, the number of nuclei formed at the early stage of the reaction is decreased. Less nuclei undergo a crystal growth by interacting with [Ni(CN)4]2-, leading to the formation of larger Cu-Ni CP nanoflakes. Following heat treatment in air, the -CN- groups present within the CP nanoflakes are removed and nanoporous Cu-Ni mixed oxide nanoflakes are generated. When tested as an electrode material for supercapacitors using a three-electrode system, the optimum Cu-Ni mixed oxide sample shows a maximum specific capacitance of 158 F g 1 at a current density of 1 A g-1. It is expected that the proposed method will be useful for the preparation of other types of 2D and 3D CPs as precursors for the creation of various nanoporous metal oxides. PMID- 30477167 TI - Association between Diabetic Retinopathy and Chronic Periodontitis-A Cross Sectional Study. AB - Periodontal disease (PD), a chronic inflammatory condition characterized by destruction of the supporting tissues of the teeth, increases the risk of complications in diabetics. Diabetic retinopathy (DR) is a microvascular complication of prolonged hyperglycaemia. There appears to be a similarity in the pathogenesis of DR and PD. Hence, this study aimed to investigate the association, if any, between DR and PD, correlate the severity of DR with the severity of PD, and investigate the association between glycated haemoglobin (HbA1c), serum creatinine and periodontal variables. The periodontal status of 200 adult diabetic patients in the age group of 30-65 years with varying severity of DR was assessed. Evaluation of the severity of PD was assessed by recording clinical parameters. Haematological investigations including glycated haemoglobin (HbA1c) and serum creatinine were estimated before the initiation of treatment for DR. A statistically significant association between the mean duration of diabetes mellitus (DM) and the severity of DR and PD was found. The severity of PD was directly correlated with the severity of DR. There was a significant association between the levels of HbA1c and serum creatinine and severity of DR and PD. There could be a plausible relationship between DR and PD. Further prospective studies on a larger population with longer follow-ups are required to ascertain whether PD and its severity directly affect the progression and severity of DR. PMID- 30477168 TI - Compressibility of High-Density EEG Signals in Stroke Patients. AB - Stroke is a critical event that causes the disruption of neural connections. There is increasing evidence that the brain tries to reorganize itself and to replace the damaged circuits, by establishing compensatory pathways. Intra- and extra-cellular currents are involved in the communication between neurons and the macroscopic effects of such currents can be detected at the scalp through electroencephalographic (EEG) sensors. EEG can be used to study the lesions in the brain indirectly, by studying their effects on the brain electrical activity. The primary goal of the present work was to investigate possible asymmetries in the activity of the two hemispheres, in the case one of them is affected by a lesion due to stroke. In particular, the compressibility of High-Density-EEG (HD EEG) recorded at the two hemispheres was investigated since the presence of the lesion is expected to impact on the regularity of EEG signals. The secondary objective was to evaluate if standard low density EEG is able to provide such information. Eighteen patients with unilateral stroke were recruited and underwent HD-EEG recording. Each EEG signal was compressively sensed, using Block Sparse Bayesian Learning, at increasing compression rate. The two hemispheres showed significant differences in the compressibility of EEG. Signals acquired at the electrode locations of the affected hemisphere showed a better reconstruction quality, quantified by the Structural SIMilarity index (SSIM), than the EEG signals recorded at the healthy hemisphere (p < 0.05), for each compression rate value. The presence of the lesion seems to induce an increased regularity in the electrical activity of the brain, thus an increased compressibility. PMID- 30477169 TI - Whole Genome Sequencing of a Vietnamese Family from a Dioxin Contamination Hotspot Reveals Novel Variants in the Son with Undiagnosed Intellectual Disability. AB - Although it has been a half-century since dioxin-contaminated herbicides were used to defoliate the landscape during the Vietnam War, dioxin contamination "hotspots" still remain in Vietnam. Environmental and health impacts of these hotspots need to be evaluated. Intellectual disability (ID) is one of the diseases found in the children of people exposed to the herbicides. This study aims to identify genetic alterations of a patient whose family lived in a dioxin hotspot. The patient's father had a highly elevated dioxin concentration. He was affected with undiagnosed moderate ID. To analyze de novo mutations and genetic variations, and to identify causal gene(s) for ID, we performed whole genome sequencing (WGS) of the proband and his parents. Two de novo missense mutations were detected, each one in ETS2 and ZNF408 genes, respectively. Compound heterozygosity was identified in CENPF and TTN genes. Existing knowledge on the genes and bioinformatics analyses suggest that EST2, ZNF408, and CENPF might be promising candidates for ID causative genes. PMID- 30477170 TI - Performance Analysis of GNSS/INS Loosely Coupled Integration Systems under Spoofing Attacks. AB - The loosely coupled integration of Global Navigation Satellite System (GNSS) and Inertial Navigation System (INS) have been widely used to improve the accuracy, robustness and continuity of navigation services. However, the integration systems possibly affected by spoofing attacks, since integration algorithms without spoofing detection would feed autonomous INSs with incorrect compensations from the spoofed GNSSs. This paper theoretically analyzes and tests the performances of GNSS/INS loosely coupled integration systems with the classical position fusion and position/velocity fusion under typical meaconing (MEAC) and lift-of-aligned (LOA) spoofing attacks. Results show that the compensations of Inertial Measurement Unit (IMU) errors significantly increase under spoofing attacks. The compensations refer to the physical features of IMUs and their unreasonable increments likely result from the spoofing-induced inconsistency of INS and GNSS measurements. Specially, under MEAC attacks, the IMU error compensations in both the position-fusion-based system and position/velocity-fusion-based system increase obviously. Under LOA attacks, the unreasonable compensation increments are found from the position/velocity-fusion based integration system. Then a detection method based on IMU error compensations is tested and the results show that, for the position/velocity fusion-based integration system, it can detect both MEAC and LOA attacks with high probability using the IMU error compensations. PMID- 30477171 TI - Prognostic Markers in Head and Neck Cancer Patients Treated with Nivolumab. AB - To investigate whether peripheral blood biomarkers predict the outcome of anti-PD 1 antibody treatment for head and neck squamous cell carcinoma (HNSCC). Patients treated with nivolumab for platinum-refractory recurrent or metastatic HNSCC were retrospectively reviewed. Fifty-three patients treated between April 2017 and March 2018 were included in the study. The median progression-free survival (PFS) and overall survival (OS) were 2.5 and 8.7 months, respectively. In the univariate analysis, performance status (PS) >= 3, relative neutrophil count >= 0.65, relative lymphocyte count >= 0.17, and relative eosinophil count (REC) >= 0.015 were significantly associated with both PFS and OS. On multivariate analysis, PS >= 3 and REC >= 0.015 were significantly associated with PFS and OS. Low REC and poor PS were independent poor prognostic factors for both PFS and OS in patients with recurrent or metastatic HNSCC treated with nivolumab. PMID- 30477172 TI - A Vehicle Recognition Algorithm Based on Deep Transfer Learning with a Multiple Feature Subspace Distribution. AB - Vehicle detection is a key component of environmental sensing systems for Intelligent Vehicles (IVs). The traditional shallow model and offline learning based vehicle detection method are not able to satisfy the real-world challenges of environmental complexity and scene dynamics. Focusing on these problems, this work proposes a vehicle detection algorithm based on a multiple feature subspace distribution deep model with online transfer learning. Based on the multiple feature subspace distribution hypothesis, a deep model is established in which multiple Restricted Boltzmann Machines (RBMs) construct the lower layers and a Deep Belief Network (DBN) composes the superstructure. For this deep model, an unsupervised feature extraction method is applied, which is based on sparse constraints. Then, a transfer learning method with online sample generation is proposed based on the deep model. Finally, the entire classifier is retrained online with supervised learning. The experiment is actuated using the KITTI road image datasets. The performance of the proposed method is compared with many state-of-the-art methods and it is demonstrated that the proposed deep transfer learning-based algorithm outperformed existing state-of-the-art methods. PMID- 30477173 TI - HAS4: A Heuristic Adaptive Sink Sensor Set Selection for Underwater AUV-Aid Data Gathering Algorithm. AB - In this paper, we target solving the data gathering problem in underwater wireless sensor networks. In many underwater applications, it is not quick to retrieve sensed data, which gives us the opportunity to leverage mobile autonomous underwater vehicles (AUV) as data mules to periodically collect it. For each round of data gathering, the AUV visits part of the sensors, and the communication between AUV and sensor nodes is a novel high-speed magnetic induction communication system. The rest of the sensors acoustically transmit their sensed data to the AUV-visit sensors. This paper deploys the HAS 4 (Heuristic Adaptive Sink Sensor Set Selection) algorithm to select the AUV visited sensors for the purpose of energy saving, AUV cost reduction and network lifetime prolonging. By comparing HAS 4 with two benchmark selection methods, experiment results demonstrate that our algorithm can achieve a better performance. PMID- 30477174 TI - PZT-Based Ultrasonic Guided Wave Frequency Dispersion Characteristics of Tubular Structures for Different Interfacial Boundaries. AB - For tubular structures, ultrasonic guided waves (UGWs) which are closely related to interfacial boundary conditions such as gas, liquid and solid materials, are usually used in damage detection. Due to the different phase materials inside tubes, the interfacial boundary (connection) conditions are variable, which has a great influence on the dispersion-related UGW propagation characteristics. However, most UGW-based damage detection methods only consider the pipeline structures as hollow tubes, ignoring the interfacial boundary condition influences on the UGW propagation. Based on the UGW theory, this paper aims to propose a novel method for describing the UGW propagation characteristics for different interfaces, and lay a foundation for the UGW-based tubular structure damage detection. Based on the Navier's equation of motion and combined with interfacial boundary conditions and coordinate conditions, the dispersion equations for a hollow steel tube, a tube filled with liquid, and a concrete filled steel tube (CFST) were established, respectively. Under the given conditions of both materials and geometric parameters, the transcendental dispersion equations were established and solved by using a numerical method. The UGW propagation characteristics in different interfaces were classified and discussed, and the dispersion curves of both group and phase velocities are drawn. To validate the efficiency of theoretical and numerical results, three kinds of model tubular structure experiments filled in air (hollow), water and concrete, respectively, were performed based on lead zirconate titanate (PZT) transducer UGWs. The results showed that the UGWs propagation in different interfaces has the dispersion and multi-modes characters, which are not only related to the product of frequency and thickness, but also to the internal dielectric material parameters and interfacial boundary conditions. PMID- 30477175 TI - LSTM-Guided Coaching Assistant for Table Tennis Practice. AB - Recently, wearable devices have become a prominent health care application domain by incorporating a growing number of sensors and adopting smart machine learning technologies. One closely related topic is the strategy of combining the wearable device technology with skill assessment, which can be used in wearable device apps for coaching and/or personal training. Particularly pertinent to skill assessment based on high-dimensional time series data from wearable sensors is classifying whether a player is an expert or a beginner, which skills the player is exercising, and extracting some low-dimensional representations useful for coaching. In this paper, we present a deep learning-based coaching assistant method, which can provide useful information in supporting table tennis practice. Our method uses a combination of LSTM (Long short-term memory) with a deep state space model and probabilistic inference. More precisely, we use the expressive power of LSTM when handling high-dimensional time series data, and state space model and probabilistic inference to extract low-dimensional latent representations useful for coaching. Experimental results show that our method can yield promising results for characterizing high-dimensional time series patterns and for providing useful information when working with wearable IMU (Inertial measurement unit) sensors for table tennis coaching. PMID- 30477176 TI - Energy Harvesting Technologies for Achieving Self-Powered Wireless Sensor Networks in Machine Condition Monitoring: A Review. AB - Condition monitoring can reduce machine breakdown losses, increase productivity and operation safety, and therefore deliver significant benefits to many industries. The emergence of wireless sensor networks (WSNs) with smart processing ability play an ever-growing role in online condition monitoring of machines. WSNs are cost-effective networking systems for machine condition monitoring. It avoids cable usage and eases system deployment in industry, which leads to significant savings. Powering the nodes is one of the major challenges for a true WSN system, especially when positioned at inaccessible or dangerous locations and in harsh environments. Promising energy harvesting technologies have attracted the attention of engineers because they convert microwatt or milliwatt level power from the environment to implement maintenance-free machine condition monitoring systems with WSNs. The motivation of this review is to investigate the energy sources, stimulate the application of energy harvesting based WSNs, and evaluate the improvement of energy harvesting systems for mechanical condition monitoring. This paper overviews the principles of a number of energy harvesting technologies applicable to industrial machines by investigating the power consumption of WSNs and the potential energy sources in mechanical systems. Many models or prototypes with different features are reviewed, especially in the mechanical field. Energy harvesting technologies are evaluated for further development according to the comparison of their advantages and disadvantages. Finally, a discussion of the challenges and potential future research of energy harvesting systems powering WSNs for machine condition monitoring is made. PMID- 30477177 TI - Cerium Oxide-Tungsten Oxide Core-Shell Nanowire-Based Microsensors Sensitive to Acetone. AB - Gas sensitive cerium oxide-tungsten oxide core-shell nanowires are synthesized and integrated directly into micromachined platforms via aerosol assisted chemical vapor deposition. Tests to various volatile organic compounds (acetone, ethanol, and toluene) involved in early disease diagnosis demonstrate enhanced sensitivity to acetone for the core-shell structures in contrast to the non modified materials (i.e., only tungsten oxide or cerium oxide). This is attributed to the high density of oxygen vacancy defects at the shell, as well as the formation of heterojunctions at the core-shell interface, which provide the modified nanowires with 'extra' chemical and electronic sensitization as compared to the non-modified materials. PMID- 30477178 TI - Computation of Propagating and Non-Propagating Lamb-Like Wave in a Functionally Graded Piezoelectric Spherical Curved Plate by an Orthogonal Function Technique. AB - Non-propagating waves have great potential for crack evaluation, but it is difficult to obtain the complex solutions of the transcendental dispersion equation corresponding to the non-propagating wave. This paper presents an analytical approach based on the orthogonal function technique to investigate non propagating Lamb-like waves in a functionally graded piezoelectric spherical curved plate. The presented approach can transform the set of partial differential equations for the acoustic waves into an eigenvalue problem that can give the generally complex wave numbers and the field profiles. A comparison of the obtained results with the well-known ones in plates is provided. The obtained solutions of the dispersion equation are shown graphically in three dimensional frequency-complex wave number space, which aids in understanding the properties of non-propagating waves better. The properties of the guided wave, including real, purely imaginary, and complex branches in various functionally graded piezoelectric spherical curved plates, are studied. The effects of material piezoelectricity, graded fields, and mechanical and electrical boundary conditions on the dispersion characteristics, are illustrated. The amplitude distributions of displacement and electric potential are also discussed, to analyze the specificities of non-propagating waves. PMID- 30477179 TI - A High-Birefringence Microfiber Sagnac-Interferometer Biosensor Based on the Vernier Effect. AB - We propose a high-sensitive Sagnac-interferometer biosensor based on theVernier effect (VE) with a high-birefringence microfiber. The sensitivity enhancement is achieved by utilizing two cascaded Sagnac interferometers. One of the two interference loops consists of a panda polarization-maintaining fiber as a filter, whilst the other is comprised of high-birefringent microfiber coated Graphene oxide (GO) as a sensing channel. We theoretically analyzed the sensitivity of the sensor and verified it with experiments. The results of the simulation show that the refractive index sensitivity is more than five times that of the fiber sensor based on a single Sagnac loop. The sensitivity of the refractive index in the experiments can reach 2429 nm/refractive index unit (RIU), which is basically in accordance with the simulation. We also use electrostatic adsorption to coat GO on the surface of the sensing channel. GO is employed to adsorb bovine serum albumin (BSA) molecules to achieve the desired detection results, which has good biocompatibility and large specific surface area. The sensitivity to detect BSA can reach 9.097 nm/(mg*mL-1). PMID- 30477180 TI - Cereus jamacaru D.C. Hydroalcoholic Extract Promotes Anti-Cytotoxic and Antitumor Activity. AB - Cereus jamacaru D.C. (mandacaru) is a cactus used as food and in the traditional medicine. In the present study, hydroalcoholic extract of C. jamacaru was evaluated for its chemical composition, antioxidant activity, cytotoxic and anti cytotoxic effects in human lymphocytes and sarcoma 180 cells in vitro by MTT assay and antitumoral, mutagenic and cytotoxic effects on mice sarcoma-induced in vivo. Phytochemical characterization showed positive reactions for coumarin, flavanol and tyramine and total flavonoid content of 0.51 ug/mL. C. jamacaru showed antioxidant activity following DPPH (EC50 = 427.74 ug/mL), ABTS (EC50 = 270.57 ug/mL) and Fe2+ chelating ions assays (EC50 = 41.18 ug/mL). C. jamacaru induced significant decrease of sarcoma 180 viability at 24 h and 48 h of treatment, did not induce cytotoxicity in human lymphocytes and inhibits the cytotoxicity of cisplatin in vitro. Following in vivo assays, C. jamacaru promoted tumor reduction (86.07% of tumor inhibition), without inducing mutagenic or cytotoxic damage on mice blood cells. We propose that phenolic and alkaloid compounds in the extract are related to antioxidant activity, increasing its ability in metal chelating activity and promoting anti-cytotoxic activity against cisplatin, as well as these compounds may act on the cell cycle of the tumor cells in vitro and in vivo, leading to anticancer effects and tumor reduction. PMID- 30477181 TI - Comparative Transcriptome Analysis between a Resistant and a Susceptible Wild Tomato Accession in Response to Phytophthora parasitica. AB - Phytophthora parasitica is one of the most widespread Phytophthora species, which is known to cause multiple diseases in tomato and is capable of infecting almost all plant parts. Our current understanding of tomato-Phytophthora parasitica interaction is very limited and currently nothing is known at the whole genome or transcriptome level. In this study, we have analyzed and compared the transcriptome of a resistant and a susceptible wild tomato accession in response to P. parasitica infection using the RNA-seq technology. We have identified 2657 and 3079 differentially expressed genes (DEGs) in treatment vs control comparison of resistant (Sp-R) and susceptible (Sp-S) samples respectively. Functional annotation of DEGs revealed substantial transcriptional reprogramming of diverse physiological and cellular processes, particularly the biotic stress responses in both Sp-R and Sp-S upon P. parasitica treatment. However, subtle expression differences among some core plant defense related genes were identified and their possible role in resistance development against P. parasitica is discussed. Our results revealed 1173 genes that were differentially expressed only in Sp-R accession upon P. parasitica inoculation. These exclusively found DEGs in Sp-R accession included some core plant defense genes, for example, several protease inhibitors, chitinases, defensin, PR-1, a downy mildew susceptibility factor, and so on, were all highly induced. Whereas, several R genes, WRKY transcriptions factors and a powdery mildew susceptibility gene (Mlo) were highly repressed during the resistance outcome. Analysis reported here lays out a strong foundation for future studies aimed at improving genetic resistance of tomato cultivars against to Phytopphthora species. PMID- 30477182 TI - The Fever Tree: from Malaria to Neurological Diseases. AB - This article describes the discovery and use of the South American cinchona bark and its main therapeutic (and toxic) alkaloids, quinine and quinidine. Since the introduction of cinchona to Europe in the 17th century, it played a role in treating emperors and peasants and was central to colonialism and wars. Over those 400 years, the medical use of cinchona alkaloids has evolved from bark extracts to chemical synthesis and controlled clinical trials. At the present time, the use of quinine and quinidine has declined, to a large extent due to their toxicity. However, quinine is still being prescribed in resource-limited settings, in severe malaria, and in pregnant women, and quinidine made a limited comeback in the treatment of several cardiac and neurological syndromes. In addition, the article presents more recent studies which improved our understanding of cinchona alkaloids' pharmacology. The knowledge gained through these studies will hopefully lead to a wider use of these drugs in precision medicine and to design of new generation, safer quinine and quinidine derivatives. PMID- 30477183 TI - A Novel Method for the Quantification of White Wine Mannoproteins by a Competitive Indirect Enzyme-Linked Lectin Sorbent Assay (CI-ELLSA). AB - Mannoproteins (MPs) are cell wall proteoglycans released in wine by yeast during fermentation and ageing on lees, a procedure used for the production of several wines to enrich them in these components with consequences from both a technological and sensory point of view. Given the significance that wine MPs have for wine quality, winemakers would welcome a simple and accurate method for their quantification, as this would allow them to have a better control of this aspect at different winemaking stages. This study develops and validates a novel, simple and accurate method for MPs quantification in white wines based on a competitive indirect enzyme-linked lectin sorbent assay (CI-ELLSA), using the highly mannosylated yeast invertase as the standard. The method utilizes the lectin concanavalin A (ConA) as the immobilized ligand for MPs, and peroxidase, an enzyme rich in mannose, as the competitor for ConA. After addition of the peroxidase substrate, the intensity of the signal produced by the activity of this enzyme (absorbance at 450 nm) is inversely proportional to the amount of mannosylated proteins in the sample. Results have been validated on several wine styles including still, sparkling and sweet wines. PMID- 30477185 TI - Sensor Selection for Decentralized Large-Scale Multi-Target Tracking Network. AB - A new optimization algorithm of sensor selection is proposed in this paper for decentralized large-scale multi-target tracking (MTT) network within a labeled random finite set (RFS) framework. The method is performed based on a marginalized delta-generalized labeled multi-Bernoulli RFS. The rule of weighted Kullback-Leibler average (KLA) is used to fuse local multi-target densities. A new metric, named as the label assignment (LA) metric, is proposed to measure the distance for two labeled sets. The lower bound of LA metric based mean square error between the labeled multi-target state set and its estimate is taken as the optimized objective function of sensor selection. The proposed bound is obtained by the information inequality to RFS measurement. Then, we present the sequential Monte Carlo and Gaussian mixture implementations for the bound. Another advantage of the bound is that it provides a basis for setting the weights of KLA. The coordinate descent method is proposed to compromise the computational cost of sensor selection and the accuracy of MTT. Simulations verify the effectiveness of our method under different signal-to- noise ratio scenarios. PMID- 30477184 TI - DNA Aptamers for the Functionalisation of DNA Origami Nanostructures. AB - DNA origami has emerged in recent years as a powerful technique for designing and building 2D and 3D nanostructures. While the breadth of structures that have been produced is impressive, one of the remaining challenges, especially for DNA origami structures that are intended to carry out useful biomedical tasks in vivo, is to endow them with the ability to detect and respond to molecules of interest. Target molecules may be disease indicators or cell surface receptors, and the responses may include conformational changes leading to the release of therapeutically relevant cargo. Nucleic acid aptamers are ideally suited to this task and are beginning to be used in DNA origami designs. In this review, we consider examples of uses of DNA aptamers in DNA origami structures and summarise what is currently understood regarding aptamer-origami integration. We review three major roles for aptamers in such applications: protein immobilisation, triggering of structural transformation, and cell targeting. Finally, we consider future perspectives for DNA aptamer integration with DNA origami. PMID- 30477186 TI - Physiological Analysis and Transcriptome Profiling of Inverted Cuttings of Populus yunnanensis Reveal That Cell Wall Metabolism Plays a Crucial Role in Responding to Inversion. AB - Inverted cuttings of Populus yunnanensis remain alive by rooting from the original morphological apex and sprouting from the base, but the lateral branches exhibit less vigorous growth than those of the upright plant. In this study, we examined the changes in hormone contents, oxidase activities, and transcriptome profiles between upright and inverted cuttings of P. yunnanensis. The results showed that the indole-3-acetic acid (IAA) and gibberellic acid (GA3) contents were significantly lower in inverted cuttings than in upright cuttings only in the late growth period (September and October), while the abscisic acid (ABA) level was always similar between the two direction types. The biosynthesis of these hormones was surprisingly unrelated to the inversion of P. yunnanensis during the vegetative growth stage (July and August). Increased levels of peroxidases (PODs) encoded by 13 differentially expressed genes (DEGs) served as lignification promoters that protected plants against oxidative stress. Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis showed that most DEGs (107) were related to carbohydrate metabolism. Furthermore, altered activities of uridine diphosphate (UDP)-sugar pyrophosphorylase (USP, 15 DEGs) for nucleotide sugars, pectin methylesterase (PME, 7 DEGs) for pectin, and POD (13 DEGs) for lignin were important factors in the response of the trees to inversion, and these enzymes are all involved cell wall metabolism. PMID- 30477187 TI - Similarities in Blood Mononuclear Cell Membrane Phospholipid Profiles During Malignancy. AB - Phospholipids (PLs), key elements of cellular membranes, are regulated reciprocally with membrane proteins and can act as sensors for alterations in physiological or pathological states of cells including initiation and development of cancer. On the other hand, peripheral blood mononuclear cells (MNCs) play an important role in antitumor immune response by reacting to cancerous modifications in distant organs. In the current study, we tested the hypothesis that tumor initiation and development are reflected in the alteration pattern of the MNC PL component. We analyzed MNC membrane PL fractions in samples from healthy individuals and from patients with diverse types of cancers to reveal possible alterations induced by malignancy. Compared to healthy controls, the cancer samples demonstrated shifts in several membrane PL profiles. In particular, when analyzing cancer data pooled together, there were significantly higher levels in lysophosphatidylcholine, phosphatidylcholine, and phosphatidylethanolamine fractions, and significantly lower quantities in phosphatidylinositol, phosphatidylserine, and phosphatidic acid fractions in cancer samples compared to controls. The levels of sphingomyelins and diphosphatidylglycerols were relatively unaffected. Most of the differences in PLs were sustained during the analysis of individual cancers such as breast cancer and chronic lymphocytic leukemia. Our findings suggest the presence of a common pattern of changes in MNC PLs during malignancy. PMID- 30477188 TI - Genomic Islands Confer Heavy Metal Resistance in Mucilaginibacter kameinonensis and Mucilaginibacter rubeus Isolated from a Gold/Copper Mine. AB - Heavy metals (HMs) are compounds that can be hazardous and impair growth of living organisms. Bacteria have evolved the capability not only to cope with heavy metals but also to detoxify polluted environments. Three heavy metal resistant strains of Mucilaginibacer rubeus and one of Mucilaginibacter kameinonensis were isolated from the gold/copper Zijin mining site, Longyan, Fujian, China. These strains were shown to exhibit high resistance to heavy metals with minimal inhibitory concentration reaching up to 3.5 mM Cu(II), 21 mM Zn(II), 1.2 mM Cd(II), and 10.0 mM As(III). Genomes of the four strains were sequenced by Illumina. Sequence analyses revealed the presence of a high abundance of heavy metal resistance (HMR) determinants. One of the strain, M. rubeus P2, carried genes encoding 6 putative PIB-1-ATPase, 5 putative PIB-3 ATPase, 4 putative Zn(II)/Cd(II) PIB-4 type ATPase, and 16 putative resistance nodulation-division (RND)-type metal transporter systems. Moreover, the four genomes contained a high abundance of genes coding for putative metal binding chaperones. Analysis of the close vicinity of these HMR determinants uncovered the presence of clusters of genes potentially associated with mobile genetic elements. These loci included genes coding for tyrosine recombinases (integrases) and subunits of mating pore (type 4 secretion system), respectively allowing integration/excision and conjugative transfer of numerous genomic islands. Further in silico analyses revealed that their genetic organization and gene products resemble the Bacteroides integrative and conjugative element CTnDOT. These results highlight the pivotal role of genomic islands in the acquisition and dissemination of adaptive traits, allowing for rapid adaption of bacteria and colonization of hostile environments. PMID- 30477189 TI - Adaptable and Automated Small UAV Deployments via Virtualization. AB - In this paper, we present a practical solution to support the adaptable and automated deployment of applications of Small Unmanned Aerial Vehicles (SUAVs). Our solution is based on virtualization technologies, and considers SUAVs as programmable network platforms capable of executing virtual functions and services, which may be dynamically selected according to the requirements specified by the operator of the aerial vehicles. This way, SUAVs can be flexibly and rapidly adapted to different missions with heterogeneous objectives. The design of our solution is based on Network Function Virtualization (NFV) technologies, developed under the umbrella of the fifth generation of mobile networks (5G), as well as on existing Internet protocol standards, including flying ad hoc network routing protocols. We implemented a functional prototype of our solution using well-known open source technologies, and we demonstrated its practical feasibility with the execution of an IP telephony service. This service was implemented as a set of virtualized network functions, which were automatically deployed and interconnected over an infrastructure of SUAVs, being the telephony service tested with real voice-over-IP terminals. PMID- 30477190 TI - Structural Health Monitoring of a Prestressed Concrete Bridge Based on Statistical Pattern Recognition of Continuous Dynamic Measurements Over 14 Years. AB - This work describes a vibration-based structural health monitoring of a prestressed-concrete box girder bridge on the A100 Highway in Berlin by applying statistical pattern recognition technique to a huge amount of data continuously collected by an integrated monitoring system during the period from 2000 to 2013. Firstly, the general condition and potential damage of the bridge is described. Then, the dynamic properties are extracted from 20 velocity sensors. Environmental variability captured by five thermal transducers and traffic intensity approximately estimated by strain measurements are also reported. Nonlinear influences of temperature on natural frequencies are observed. Subsequently, the measurements during the first year are used to build a baseline health index. The multiple linear regression (MLR) method is used to characterize the nonlinear relationship between natural frequencies and temperatures. The Euclidean distance of the residual errors is calculated to build a statistical health index. Finally, the indices extracted from the following years gradually deviate; which may indicate structural deterioration due to loss of prestress in the prestressed tendons. PMID- 30477191 TI - Confined Concrete in Fiber-Reinforced Polymer Partially Wrapped Square Columns: Axial Compressive Behavior and Strain Distributions by a Particle Image Velocimetry Sensing Technique. AB - Strengthening existing reinforced concrete (RC) columns using a partial wrapping strengthening technique (PWST) by fiber-reinforced polymer (FRP) strips has been widely implemented. However, compared with the confinement mechanism of confined concrete in columns strengthened with the FRP full wrapping strengthening technique (FWST), the confinement mechanism of confined concrete in FRP partially wrapped columns is less understood. This paper presents the results of an experimental investigation into the behavior of confined concrete in FRP partially wrapped square columns under axial compression. The effects of FRP strip width and thickness on stress-strain behavior were thoroughly investigated. The novel particle image velocimetry (PIV) non-contact strain sensing technique was adopted to measure the strain in the specimens. Results show that the axial strains as well as the hoop strains are generally larger at the mid-plane of adjacent FRP strips than those at the mid-plane of each FRP strip, and considerable variation in hoop strains along the height of the specimens was observed. Comparisons between the experimental results and predictions by existing design-oriented stress-strain models were carried out to examine the accuracy of the models. A new design-oriented stress-strain model is proposed for confined concrete in FRP partially wrapped square columns and the comparisons between laboratory results and predictions from the proposed model show that the proposed model is superior to the existing models. PMID- 30477192 TI - Study on the Preparation and Chemical Structure Characterization of Melanin from Boletus griseus. AB - In this study, melanin (BgM) was obtained from Boletus griseus. The chemical composition and structure of BgM were characterized by UV-visible absorption spectrum, Fourier transform infrared spectrum, elemental analysis, nuclear magnetic resonance, pyrolysis gas chromatography mass spectrometry, and ultra performance liquid chromatography-high resolution mass spectrometry. The percentage contents of C, H, N, S and O elements were 56.38%, 5.86%, 6.17%, 2.44%, and 28.04%, and the S/N and C/N ratios were 0.17 and 10.66, respectively. The UV-vis spectrum of BgM showed a maximum absorption peak at 214 nm. Characteristic absorption peaks were observed at 3426, 1600 and 1105 cm-1, and BgM contained phenolic hydroxyl, amidogen, carbonyl, methylene, and methyl groups. Moreover, BgM is an eumelanin, and its main skeleton has both a benzene ring and an indole, and the branched chain mainly consists of alkanes, alcohols, and fatty acids. BgM was hydrolyzed by H2O2 and four compounds were tentatively analyzed from the UPLC-MS/MS profile. The chemical structure of BgM was characterized as 5,6-dihydroxyindole eumelanin, and the condensed molecular formula is [C28(OR1)4(OR2)3H11O6N4]n. PMID- 30477193 TI - A Two-Cohort RNA-seq Study Reveals Changes in Endometrial and Blood miRNome in Fertile and Infertile Women. AB - The endometrium undergoes extensive changes to prepare for embryo implantation and microRNAs (miRNAs) have been described as playing a significant role in the regulation of endometrial receptivity. However, there is no consensus about the miRNAs involved in mid-secretory endometrial functions. We analysed the complete endometrial miRNome from early secretory (pre-receptive) and mid-secretory (receptive) phases from fertile women and from patients with recurrent implantation failure (RIF) to reveal differentially expressed (DE) miRNAs in the mid-secretory endometrium. Furthermore, we investigated whether the overall changes during early to mid-secretory phase transition and with RIF condition could be reflected in blood miRNA profiles. In total, 116 endometrial and 114 matched blood samples collected from two different population cohorts were subjected to small RNA sequencing. Among fertile women, 91 DE miRNAs were identified in the mid-secretory vs. early secretory endometrium, while no differences were found in the corresponding blood samples. The comparison of mid secretory phase samples between fertile and infertile women revealed 21 DE miRNAs from the endometrium and one from blood samples. Among discovered novel miRNAs, chr2_4401 was validated and showed up-regulation in the mid-secretory endometrium. Besides novel findings, we confirmed the involvement of miR-30 and miR-200 family members in mid-secretory endometrial functions. PMID- 30477194 TI - Cloud Update of Tiled Evidential Occupancy Grid Maps for the Multi-Vehicle Mapping. AB - Nowadays, many intelligent vehicles are equipped with various sensors to recognize their surrounding environment and to measure the motion or position of the vehicle. In addition, the number of intelligent vehicles equipped with a mobile Internet modem is increasing. Based on the sensors and Internet connection, the intelligent vehicles are able to share the sensor information with other vehicles via a cloud service. The sensor information sharing via the cloud service promises to improve the safe and efficient operation of the multiple intelligent vehicles. This paper presents a cloud update framework of occupancy grid maps for multiple intelligent vehicles in a large-scale environment. An evidential theory is applied to create the occupancy grid maps to address sensor disturbance such as measurement noise, occlusion and dynamic objects. Multiple vehicles equipped with LiDARs, motion sensors, and a low-cost GPS receiver create the evidential occupancy grid map (EOGM) for their passing trajectory based on GraphSLAM. A geodetic quad-tree tile system is applied to manage the EOGM, which provides a common tiling format to cover the large-scale environment. The created EOGM tiles are uploaded to EOGM cloud and merged with old EOGM tiles in the cloud using Dempster combination of evidential theory. Experiments were performed to evaluate the multiple EOGM mapping and the cloud update framework for large-scale road environment. PMID- 30477195 TI - The Myeloid-Epithelial-Reproductive Tyrosine Kinase (MERTK) rs4374383 Polymorphism Predicts Progression of Liver Fibrosis in Hepatitis C Virus-Infected Patients: A Longitudinal Study. AB - BACKGROUND: The myeloid-epithelial-reproductive tyrosine kinase (MERTK) is involved in hepatic steatosis, inflammation, and liver fibrosis. Here we evaluated the association between the MERTK rs4374383 single nucleotide polymorphism (SNP) and liver fibrosis progression in hepatitis C virus (HCV) infected patients. METHODS: We performed a retrospective study (repeated measures design) in 208 patients who had liver stiffness measurement (LSM), which was assessed using transient elastography. No patient had cirrhosis at baseline (LSM >= 12.5 kPa). RESULTS: At baseline, 53.8% were male, the median age was 47.1 years, 13.5% reported a high intake of alcohol, 10.1% were prior injection drug users, 85.3% were infected with HCV genotype 1, and 22.6% had previously failed antiviral therapy (pegylated-interferon-alpha/ribavirin). During a median follow up of 46.6 months, 26 patients developed cirrhosis. The rs4374383 G carriers had a higher risk of increasing LSM (adjusted arithmetic mean ratio (aAMR) = 1.14; p = 0.006) and a higher likelihood of having an increase in LSM greater than 5 kPa (DeltaLSM >= 5 kPa) (adjusted odds ratio (aOR) = 2.37; p = 0.029), and greater than 7 kPa (DeltaLSM >= 7 kPa) (aOR = 3.24; p = 0.032), after controlling for confounding. The SNP's association with cirrhosis progression was close to statistical significance (aOR = 2.18; p = 0.070). CONCLUSIONS: MERTK rs4374383 A carriers had a lower risk of liver fibrosis progression than G carriers, supporting the hypothesis that this SNP seems to have a critical role in the pathogenesis of liver disease in HCV-infected patients. PMID- 30477196 TI - De-Ritis Ratio Improves Long-Term Risk Prediction after Acute Myocardial Infarction. AB - BACKGROUND: Recent evidence suggested levels of aspartate aminotransferase (AST), alanine transaminase (ALT), and AST/ALT ratio (De-Ritis ratio) were associated with a worse outcome after acute myocardial infarction (AMI). However, their value for predicting long-term prognosis remained unknown. Therefore, we investigated the prognostic potential of transaminases on patient outcome after AMI from a long-term perspective. METHODS: Data of a large AMI registry including 1355 consecutive patients were analyzed. The Cox regression hazard analysis was used to assess the impact of transaminases and the De-Ritis ratio on long-term mortality. RESULTS: The median De-Ritis ratio for the entire study population was 1.5 (interquartile range [IQR]: 1.0-2.6). After a median follow-up time of 8.6 years, we found that AST (crude hazard ratio (HR) of 1.19 per 1-SD [95% confidence interval (CI): 1 .09-1.32; p < 0.001]) and De-Ritis ratio (crude HR of 1.31 per 1-SD [95% CI: 1.18-1.44; p < 0.001]), but not ALT (p = 0.827), were significantly associated with long-term mortality after AMI. After adjustment for confounders independently, the De-Ritis ratio remained a strong and independent predictor for long-term mortality in the multivariate model with an adjusted HR of 1.23 per 1-SD (95% CI: 1.07-1.42; p = 0.004). Moreover, the De-Ritis ratio added prognostic value beyond N-terminal pro-B-Type Natriuretic Peptide, Troponin T, and Creatine Kinase. CONCLUSION: The De-Ritis ratio is a strong and independent predictor for long-term mortality after AMI. As a readily available biomarker in clinical routine, it might be used to identify patients at risk for fatal cardiovascular events and help to optimize secondary prevention strategies after AMI. PMID- 30477197 TI - Virus-Derived Small Interfering RNAs Affect the Accumulations of Viral and Host Transcripts in Maize. AB - RNA silencing is a conserved surveillance mechanism against invading viruses in plants, which involves the production of virus-derived small interfering RNAs (vsiRNAs) that play essential roles in the silencing of viral RNAs and/or specific host transcripts. However, how vsiRNAs function to target viral and/or host transcripts is poorly studied, especially in maize (Zea mays L.). In this study, a degradome library constructed from Sugarcane mosaic virus (SCMV) inoculated maize plants was analyzed to identify the cleavage sites in viral and host transcripts mainly produced by vsiRNAs. The results showed that 42 maize transcripts were possibly cleaved by vsiRNAs, among which several were involved in chloroplast functions and in biotic and abiotic stresses. In addition, more than 3000 cleavage sites possibly produced by vsiRNAs were identified in positive strand RNAs of SCMV, while there were only four cleavage sites in the negative strand RNAs. To determine the roles of vsiRNAs in targeting viral RNAs, six vsiRNAs were expressed in maize protoplast based on artificial microRNAs (amiRNAs), of which four could efficiently inhibit the accumulations of SCMV RNAs. These results provide new insights into the genetic manipulation of maize with resistance against virus infection by using amiRNA as a more predictable and useful approach. PMID- 30477198 TI - Does the Immunocompetent Status of Cancer Patients Have an Impact on Therapeutic DC Vaccination Strategies? AB - Although different types of therapeutic vaccines against established cancerous lesions in various indications have been developed since the 1990s, their clinical benefit is still very limited. This observed lack of effectiveness in cancer eradication may be partially due to the often deficient immunocompetent status of cancer patients, which may facilitate tumor development by different mechanisms, including immune evasion. The most frequently used cellular vehicle in clinical trials are dendritic cells (DCs), thanks to their crucial role in initiating and directing immune responses. Viable vaccination options using DCs are available, with a positive toxicity profile. For these reasons, despite their limited therapeutic outcomes, DC vaccination is currently considered an additional immunotherapeutic option that still needs to be further explored. In this review, we propose potential actions aimed at improving DC vaccine efficacy by counteracting the detrimental mechanisms recognized to date and implicated in establishing a poor immunocompetent status in cancer patients. PMID- 30477199 TI - The Impacts of the High-Quality Workplace Relationships on Job Performance: A Perspective on Staff Nurses in Vietnam. AB - Employees' working relationships were long determined to be crucial to their overall wellbeing and performance ratings at work. However, a few studies were found to examine the effects of positive workplace relationships on employees' working manners. This study aimed to investigate the effects of healthy workplace relationships on employees' working behaviors, which in turn affect their performance. In doing so, an integrated model was developed to examine the primary performance drivers of nurses in Vietnamese hospitals and focus on the effects of high-quality workplace relationships on the working attitudes of the staff. This study analyzed a questionnaire survey of 303 hospital nurses using a structural equation modeling approach. The findings demonstrated the positive effects of high-quality workplace relationships on working manners including higher commitment, lower level of reported job stress, and increased perception of social impact. Notably, the results also demonstrated that relationships between leaders and their staff nurses make a significant contribution to the quality of workplace relationship and nurses' performance. In addition, the social impact was illustrated to positively moderate the association between healthy workplace interactions and job stress; however, it had no significant effect on job commitment. Unfortunately, job commitment was surprisingly found to not be related to performance ratings. This paper provides some suggestions for the divergence of performance drivers in the hospital context in Vietnam. PMID- 30477200 TI - Decreasing Phosphatidylcholine on the Surface of the Lipid Droplet Correlates with Altered Protein Binding and Steatosis. AB - Alcoholic fatty liver disease (AFLD) is characterized by an abnormal accumulation of lipid droplets (LDs) in the liver. Here, we explore the composition of hepatic LDs in a rat model of AFLD. Five to seven weeks of alcohol consumption led to significant increases in hepatic triglyceride mass, along with increases in LD number and size. Additionally, hepatic LDs from rats with early alcoholic liver injury show a decreased ratio of surface phosphatidylcholine (PC) to phosphatidylethanolamine (PE). This occurred in parallel with an increase in the LD association of perilipin 2, a prominent LD protein. To determine if changes to the LD phospholipid composition contributed to differences in protein association with LDs, we constructed liposomes that modeled the LD PC:PE ratios in AFLD and control rats. Reducing the ratio of PC to PE increased the binding of perilipin 2 to liposomes in an in vitro experiment. Moreover, we decreased the ratio of LD PC:PE in NIH 3T3 and AML12 cells by culturing these cells in choline-deficient media. We again detected increased association of specific LD proteins, including perilipin 2. Taken together, our experiments suggest an important link between LD phospholipids, protein composition, and lipid accumulation. PMID- 30477201 TI - Relationship between Dietary n-6 Fatty Acid Intake and Hypertension: Effect of Glycated Hemoglobin Levels. AB - The relationship between dietary n-6 fatty acids and hypertension is not clear. The metabolic products of n-6 fatty acids include those that control blood pressure, such as prostaglandin and thromboxane, and that differ depending on the extent of glucose tolerance. This cross-sectional study investigated the association of dietary n-6 fatty acid intake on hypertension, and the effects of glycated hemoglobin (HbA1c) value in 633 Japanese subjects aged 40 years and older. Dietary intake was measured using a validated brief self-administered diet history questionnaire. We defined hypertension as the use of antihypertensive medication or a blood pressure of 140/90 mmHg. The prevalence of hypertension was 55.3%. A high n-6 fatty acids intake inversely correlated with hypertension in subjects with HbA1c values less than 6.5% (odds ratio, 0.857; 95% confidence interval, 0.744 to 0.987). On the contrary, in subjects with an HbA1c value of 6.5% or higher, the n-6 fatty acids intake was significantly associated with hypertension (odds ratio, 3.618; 95% confidence interval, 1.019 to 12.84). Regular dietary n-6 fatty acid intake may contribute to the prevention and treatment of hypertension in a healthy general population. By contrast, in subjects with diabetes, regular n-6 fatty acids intake may increase the risk of hypertension. PMID- 30477202 TI - The Role of Peroxiredoxin 6 in Cell Signaling. AB - Peroxiredoxin 6 (Prdx6, 1-cys peroxiredoxin) is a unique member of the peroxiredoxin family that, in contrast to other mammalian peroxiredoxins, lacks a resolving cysteine and uses glutathione and pi glutathione S-transferase to complete its catalytic cycle. Prdx6 is also the only peroxiredoxin capable of reducing phospholipid hydroperoxides through its glutathione peroxidase (Gpx) activity. In addition to its peroxidase activity, Prdx6 expresses acidic calcium independent phospholipase A2 (aiPLA2) and lysophosphatidylcholine acyl transferase (LPCAT) activities in separate catalytic sites. Prdx6 plays crucial roles in lung phospholipid metabolism, lipid peroxidation repair, and inflammatory signaling. Here, we review how the distinct activities of Prdx6 are regulated during physiological and pathological conditions, in addition to the role of Prdx6 in cellular signaling and disease. PMID- 30477203 TI - A Novel Machine Learning Algorithm to Automatically Predict Visual Outcomes in Intravitreal Ranibizumab-Treated Patients with Diabetic Macular Edema. AB - PURPOSE: Artificial neural networks (ANNs) are one type of artificial intelligence. Here, we use an ANN-based machine learning algorithm to automatically predict visual outcomes after ranibizumab treatment in diabetic macular edema. METHODS: Patient data were used to optimize ANNs for regression calculation. The target was established as the final visual acuity at 52, 78, or 104 weeks. The input baseline variables were sex, age, diabetes type or condition, systemic diseases, eye status and treatment time tables. Three groups were randomly devised to build, test and demonstrate the accuracy of the algorithms. RESULTS: At 52, 78 and 104 weeks, 512, 483 and 464 eyes were included, respectively. For the training group, testing group and validation group, the respective correlation coefficients were 0.75, 0.77 and 0.70 (52 weeks); 0.79, 0.80 and 0.55 (78 weeks); and 0.83, 0.47 and 0.81 (104 weeks), while the mean standard errors of final visual acuity were 6.50, 6.11 and 6.40 (52 weeks); 5.91, 5.83 and 7.59; (78 weeks); and 5.39, 8.70 and 6.81 (104 weeks). CONCLUSIONS: Machine learning had good correlation coefficients for predicating prognosis with ranibizumab with just baseline characteristics. These models could be the useful clinical tools for prediction of success of the treatments. PMID- 30477205 TI - Enhanced Photocatalytic Performance of Nitrogen-Doped TiO2 Nanotube Arrays Using a Simple Annealing Process. AB - Nitrogen-doped TiO2 nanotube arrays (N-TNAs) were successfully fabricated by a simple thermal annealing process in ambient N2 gas at 450 degrees C for 3 h. TNAs with modified morphologies were prepared by a two-step anodization using an aqueous NH4F/ethylene glycol solution. The N-doping concentration (0-9.47 at %) can be varied by controlling N2 gas flow rates between 0 and 500 cc/min during the annealing process. Photocatalytic performance of as-prepared TNAs and N-TNAs was studied by monitoring the methylene blue degradation under visible light (lambda >= 400 nm) illumination at 120 mW.cm-2. N-TNAs exhibited appreciably enhanced photocatalytic activity as compared to TNAs. The reaction rate constant for N-TNAs (9.47 at % N) reached 0.26 h-1, which was a 125% improvement over that of TNAs (0.115 h-1). The significant enhanced photocatalytic activity of N-TNAs over TNAs is attributed to the synergistic effects of (1) a reduced band gap associated with the introduction of N-doping states to serve as carrier reservoir, and (2) a reduced electron-hole recombination rate. PMID- 30477204 TI - Resistance-Related l-Pyroglutamic Acid Affects the Biosynthesis of Trichothecenes and Phenylpropanoids by F. graminearum Sensu Stricto. AB - Fungicide application remains amongst the most widely used methods of fungal control in agroecosystems. However, the extensive use of fungicides poses hazards to human health and the natural environment and does not always ensure the effective decrease of mycotoxins in food and feed. Nowadays, the rising threat from mycotoxin contamination of staple foods has stimulated efforts in developing alternative strategies to control plant pathogenic fungi. A substantial effort is focused on the identification of plant-derived compounds inhibiting mycotoxin production by plant pathogenic fungi. l-Pyroglutamic acid has recently been suggested as playing a role in the response of barley to toxigenic Fusaria. Considering the above, we studied the response of various strains of F. graminearum sensu stricto to different levels of l-pyroglutamic acid on solid YES (yeast extract sucrose) media. l-Pyroglutamic acid decreased the accumulation of trichothecenes in all examined strains. Gene expression studies addressing Tri genes (Tri4, Tri5, and Tri10), which induce the biosynthesis of trichothecenes, revealed the production of mycotoxins by l-pyroglutamic acid to be inhibited at the transcriptional level. Besides inhibitory effects on mycotoxin production, l pyroglutamic acid exhibited variable and concentration-related effects on phenylpropanoid production by fungi. Accumulation of most of the fungal-derived phenolic acids decreased in the presence of 100 and 400 ug/g of l-pyroglutamic acid. However, a higher dose (800 ug/g) of l-pyroglutamic acid increased the accumulation of trans-cinnamic acid in the media. The accumulation of fungal derived naringenin increased in the presence of l-pyroglutamic acid. Contrasting results were obtained for quercetin, apigenin, luteolin, and kaempferol, the accumulation of which decreased in the samples treated with 100 and 400 ug/g of l pyroglutamic acid, whereas the highest l-pyroglutamic acid concentration (800 ug/g) seemed to induce their biosynthesis. The results obtained in this study provide new insights for breeders involved in studies on resistance against Fusaria. PMID- 30477206 TI - Peroxiredoxin 6: The Protector of Male Fertility. AB - The spermatozoon is a terminal cell with the unique purpose of delivering the paternal genome to the oocyte during fertilization. Once spermatozoa enter into the female reproductive tract, they count on only the antioxidant protection that they received during spermatogenesis and epididymal maturation. Peroxiredoxins (PRDXs), particularly PRDX6, are important players in the antioxidant protection and regulation of reactive oxygen species (ROS) levels in spermatozoa. PRDX6, through its peroxidase and calcium-independent phospholipase A2 activities, plays a major role in the regulation of ROS to maintain viability and motility and allow the spermatozoon to achieve fertilizing ability during the complex process of capacitation. The absence of PRDX6 is sufficient to promote abnormal reproductive outcomes in mice that resemble what we observe in infertile men. Indeed, Prdx6-/- spermatozoa display low motility and severe DNA damage, which is translated into reduced ability to fertilize oocytes in vitro or produce a low number of pups compared to wild-type controls. This review focuses on the role of PRDX6 as the primary antioxidant enzyme that protects the spermatozoon from oxidative-stress-associated damages to protect the paternal genome and assure fertility. PMID- 30477207 TI - Ku-Band 50 W GaN HEMT Power Amplifier Using Asymmetric Power Combining of Transistor Cells. AB - In this paper, we present a Ku-band 50 W internally-matched power amplifier that asymmetrically combines the power transistor cells of the GaN high electron mobility transistor (HEMT) (CGHV1J070D) from Wolfspeed. The amplifier is designed using a large-signal transistor cell model in the foundry process, and asymmetric power combining, which consists of a slit pattern, oblique wire bonding and an asymmetric T-junction, is applied to obtain the amplitude/phase balance of the combined signals at the transistor cell combining position. Input and output matching circuits are implemented using a thin film process on a titanate substrate and an alumina substrate with the relative dielectric constants of 40 and 9.8, respectively. The pulsed measurement of a 330 MUs pulse period and 6% duty cycle shows the maximum saturated output power of 57 to 66 W, drain efficiency of 40.3 to 46.7%, and power gain of 5.3 to 6.0 dB at power saturation from 16.2 to 16.8 GHz. PMID- 30477208 TI - Applications of CRISPR/Cas9 for the Treatment of Duchenne Muscular Dystrophy. AB - Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disease prevalent in 1 in 3500 to 5000 males worldwide. As a result of mutations that interrupt the reading frame of the dystrophin gene (DMD), DMD is characterized by a loss of dystrophin protein that leads to decreased muscle membrane integrity, which increases susceptibility to degeneration. CRISPR/Cas9 technology has garnered interest as an avenue for DMD therapy due to its potential for permanent exon skipping, which can restore the disrupted DMD reading frame in DMD and lead to dystrophin restoration. An RNA-guided DNA endonuclease system, CRISPR/Cas9 allows for the targeted editing of specific sequences in the genome. The efficacy and safety of CRISPR/Cas9 as a therapy for DMD has been evaluated by numerous studies in vitro and in vivo, with varying rates of success. Despite the potential of CRISPR/Cas9-mediated gene editing for the long-term treatment of DMD, its translation into the clinic is currently challenged by issues such as off-targeting, immune response activation, and sub optimal in vivo delivery. Its nature as being mostly a personalized form of therapy also limits applicability to DMD patients, who exhibit a wide spectrum of mutations. This review summarizes the various CRISPR/Cas9 strategies that have been tested in vitro and in vivo for the treatment of DMD. Perspectives on the approach will be provided, and the challenges faced by CRISPR/Cas9 in its road to the clinic will be briefly discussed. PMID- 30477209 TI - Assessment of the Impact of Deformable Registration of Diagnostic MRI to Planning CT on GTV Delineation for Radiotherapy for Oropharyngeal Carcinoma in Routine Clinical Practice. AB - BACKGROUND: Aim of study was to assess impact of deformable registration of diagnostic MRI to planning CT upon gross tumour volume (GTV) delineation of oropharyngeal carcinoma in routine practice. METHODS: 22 consecutive patients with oropharyngeal squamous cell carcinoma treated with definitive (chemo)radiotherapy between 2015 and 2016, for whom primary GTV delineation had been performed by a single radiation oncologist using deformable registration of diagnostic MRI to planning CT, were identified. Separate GTVs were delineated as part of routine clinical practice (all diagnostic imaging available side-by-side for each delineation) using: CT (GTVCT), MRI (GTVMR), and CT and MRI (GTVCTMR). Volumetric and positional metric analyses were undertaken using contour comparison metrics (Dice conformity index, centre of gravity distance, mean distance to conformity). RESULTS: Median GTV volumes were 13.7 cm3 (range 3.5 41.7), 15.9 cm3 (range 1.6-38.3), 19.9 cm3 (range 5.5-44.5) for GTVCT, GTVMR and GTVCTMR respectively. There was no significant difference in GTVCT and GTVMR volumes; GTVCTMR was found to be significantly larger than both GTVMR and GTVCT. Based on positional metrics, GTVCT and GTVMR were the least similar (mean Dice similarity coefficient (DSC) 0.71, 0.84, 0.82 for GTVCT-GTVMR, GTVCTMR-GTVCT and GTVCTMR-GTVMR respectively). CONCLUSIONS: These data suggest a complementary role of MRI to CT to reduce the risk of geographical misses, although they highlight the potential for larger target volumes and hence toxicity. PMID- 30477210 TI - Does Instruction of Oral Health Behavior for Workers Improve Work Performance? Quasi-Randomized Trial. AB - Oral disease can cause economic loss due to impaired work performance. Therefore, improvement of oral health status and prevention of oral disease is essential among workers. The purpose of this study was to investigate whether oral health related behavioral modification intervention influences work performance or improves oral health behavior and oral health status among Japanese workers. We quasi-randomly separated participants into the intervention group or the control group at baseline. The intervention group received intensive oral health instruction at baseline and a self-assessment every three months. Both groups received oral examinations and answered the self-questionnaire at baseline and at one-year follow-up. At follow-up, the prevalence of subjects who use fluoride toothpastes and interdental brushes/dental floss were significantly higher in the intervention group than in the control group. Three variables (tooth brushing in workplace, using fluoride toothpaste, and experience of receiving tooth brushing instruction in a dental clinic) showed significant improvement only in the intervention group. On the other hand, work performance and oral status did not significantly change in either group. Our intensive oral health-related behavioral modification intervention improved oral health behavior, but neither work performance nor oral status, among Japanese workers. PMID- 30477211 TI - Regulating the Regulators: The Control of Transcription Factors in Plant Defense Signaling. AB - Being sessile, plants rely on intricate signaling pathways to mount an efficient defense against external threats while maintaining the cost balance for growth. Transcription factors (TFs) form a repertoire of master regulators in controlling various processes of plant development and responses against external stimuli. There are about 58 families of TFs in plants and among them, six major TF families (AP2/ERF (APETALA2/ethylene responsive factor), bHLH (basic helix-loop helix), MYB (myeloblastosis related), NAC (no apical meristem (NAM), Arabidopsis transcription activation factor (ATAF1/2), and cup-shaped cotyledon (CUC2)), WRKY, and bZIP (basic leucine zipper)) are found to be involved in biotic and abiotic stress responses. As master regulators of plant defense, the expression and activities of these TFs are subjected to various transcriptional and post transcriptional controls, as well as post-translational modifications. Many excellent reviews have discussed the importance of these TFs families in mediating their downstream target signaling pathways in plant defense. In this review, we summarize the molecular regulatory mechanisms determining the expression and activities of these master regulators themselves, providing insights for studying their variation and regulation in crop wild relatives (CWR). With the advance of genome sequencing and the growing collection of re sequencing data of CWR, now is the time to re-examine and discover CWR for the lost or alternative alleles of TFs. Such approach will facilitate molecular breeding and genetic improvement of domesticated crops, especially in stress tolerance and defense responses, with the aim to address the growing concern of climate change and its impact on agriculture crop production. PMID- 30477212 TI - Influence of the Heat Treatment on the Particles Size and on the Crystalline Phase of TiO2 Synthesized by the Sol-Gel Method. AB - Titanium biomaterials' response has been recognized to be affected by particles size, crystal structure, and surface properties. Chemical and structural properties of these nanoparticle materials are important, but their size is the key aspect. The aim of this study is the synthesis of TiO2 nanoparticles by the sol-gel method, which is an ideal technique to prepare nanomaterials at low temperature. The heat treatment can affect the structure of the final product and consequently its biological properties. For this reason, the chemical structure of the TiO2 nanoparticles synthesized was investigated after each heat treatment, in order to evaluate the presence of different phases formed among the nanoparticles. FTIR spectroscopy and XRD have been used to evaluate the different structures. The results of these analyses suggest that an increase of the calcination temperature induces the formation of mixed-crystalline-phases with different content of anatase and rutile phases. The results obtained by SEM measurements suggest that an increase in the particles size accompanied by a noticeable aggregation of TiO2 nanoparticles is due to high temperatures achieved during the thermal treatments and confirmed the presence of different content of the two crystalline phases of titanium dioxide. PMID- 30477213 TI - Mycoviral Population Dynamics in Spanish Isolates of the Entomopathogenic Fungus Beauveria bassiana. AB - The use of mycoviruses to manipulate the virulence of entomopathogenic fungi employed as biocontrol agents may lead to the development of novel methods to control attacks by insect pests. Such approaches are urgently required, as existing agrochemicals are being withdrawn from the market due to environmental and health concerns. The aim of this work is to investigate the presence and diversity of mycoviruses in large panels of entomopathogenic fungi, mostly from Spain and Denmark. In total, 151 isolates belonging to the genera Beauveria, Metarhizium, Lecanicillium, Purpureocillium, Isaria, and Paecilomyces were screened for the presence of dsRNA elements and 12 Spanish B. bassiana isolates were found to harbor mycoviruses. All identified mycoviruses belong to three previously characterised species, the officially recognised Beauveria bassiana victorivirus 1 (BbVV-1) and the proposed Beauveria bassiana partitivirus 2 (BbPV 2) and Beauveria bassiana polymycovirus 1 (BbPmV-1); individual B. bassiana isolates may harbor up to three of these mycoviruses. Notably, these mycovirus species are under distinct selection pressures, while recombination of viral genomes increases population diversity. Phylogenetic analysis of the RNA dependent RNA polymerase gene sequences revealed that the current population structure in Spain is potentially a result of both vertical and horizontal mycovirus transmission. Finally, pathogenicity experiments using the Mediterranean fruit fly Ceratitis capitata showed no direct correlation between the presence of any particular mycovirus and the virulence of the B. bassiana isolates, but illustrated potentially interesting isolates that exhibit relatively high virulence, which will be used in more detailed virulence experimentation in the future. PMID- 30477214 TI - Fungal Endophytes Control Fusarium graminearum and Reduce Trichothecenes and Zearalenone in Maize. AB - Fusarium graminearum can cause Giberella Ear Rot (GER) and seedling blight in maize, resulting in major yield losses. Besides GER, the infected grains are consequently contaminated with multiple mycotoxins of F. graminearum. Zearalenone and trichothecenes, such as deoxynivalenol and its acetylated forms, are among the major mycotoxins associated with F. graminearum infection in maize. In the current work, we explored the effect of the endophytic fungal genera of Epicoccum and Sordaria, to control F. graminearum infection in comparative trials with Piriformospora spp., an elusive endophytic genus. Furthermore, we investigated the effect of these endophytes on zearalenone, deoxynivalenol, and 15 acetyldeoxynivalenol levels using in vitro and in planta assays. As plants are endowed with several detoxification mechanisms comprising e.g., glucosylation of trichothecenes, the effect of the isolated fungal endophytes on the deoxynivalenol-3-glucoside level was also assessed. In general, results showed a considerable variability in the antifungal activity, both among species and among isolates within one species. Additionally, the effect on mycotoxin levels was variable, and not necessarily related to the antifungal activity except for zearalenone levels which were consistently reduced by the endophytes. These results highlight the great potential of certain endophytic fungal strains as new biocontrol agents in agricultural science. PMID- 30477215 TI - The Release of Antimony from Mine Dump Soils in the Presence and Absence of Forest Litter. AB - This study examined the changes in antimony (Sb) solubility in soils, using organic matter introduced with forest litter, in various moisture conditions. Soils containing 12.8-163 mg/kg Sb were taken from the top layers of dumps in former mining sites in the Sudetes, South-West Poland. Soils were incubated for 90 days either in oxic or waterlogged conditions, with and without the addition of 50 g/kg of beech forest litter (FL). Water concentrations of Sb in some experimental treatments greatly exceeded the threshold values for good quality underground water and drinking water, and reached a maximum of 2.8 mg/L. The changes of Sb solubility caused by application of FL and prolonged waterlogging were, in various soils, highly divergent and in fact unpredictable based on the main soil properties. In some soils, the application of forest litter prompted the release of Sb from soil solid phase, while in the others it acted contradictorily. Soil waterlogging resulted, in most cases, in the increased release of Sb compared to oxic conditions, and this effect was enhanced by the addition of forest litter. However, in two soils the presence of forest litter counteracted the effects of waterlogging and diminished the quantities of released Sb. PMID- 30477216 TI - Interstitial Lung Disease and Pulmonary Fibrosis: A Practical Approach for General Medicine Physicians with Focus on the Medical History. AB - Interstitial lung disease (ILD) and pulmonary fibrosis comprise a wide array of inflammatory and fibrotic lung diseases which are often confusing to general medicine and pulmonary physicians alike. In addition to the myriad of clinical and radiologic nomenclature used in ILD, histopathologic descriptors may be particularly confusing, and are often extrapolated to radiologic imaging patterns which may further add to the confusion. We propose that rather than focusing on precise histologic findings, focus should be on identifying an accurate etiology of ILD through a comprehensive and detailed medical history. Histopathologic patterns from lung biopsy should not be dismissed, but are often nonspecific, and overall treatment strategy and prognosis are likely to be determined more by the specific etiology of ILD rather than any particular histologic pattern. In this review, we outline a practical approach to common ILDs, highlight important aspects in obtaining an exposure history, clarify terminology and nomenclature, and discuss six common subgroups of ILD likely to be encountered by general medicine physicians in the inpatient or outpatient setting: Smoking-related, hypersensitivity pneumonitis, connective tissue disease-related, occupation related, medication-induced, and idiopathic pulmonary fibrosis. Accurate diagnosis of these forms of ILD does require supplementing the medical history with results of the physical examination, autoimmune serologic testing, and chest radiographic imaging, but the importance of a comprehensive environmental, avocational, occupational, and medication-use history cannot be overstated and is likely the single most important factor responsible for achieving the best possible outcomes for patients. PMID- 30477217 TI - Healthy Lifestyle: Relationship between Mediterranean Diet, Body Composition and Physical Fitness in 13 to 16-Years Old Icelandic Students. AB - Childhood and adolescent obesity are currently among the greatest challenges for public health. Physical activity, physical fitness, and adherence to the Mediterranean diet (MD), representing powerful indicators of healthy lifestyles, are shown as determinant factors in the prevention and treatment of obesity. The aim of the present study has been to analyse the relationship between health related physical fitness components, body composition, and adherence to MD in 387 Icelandic adolescents of 13-16-years old (54% boys). The ALPHA Fitness Test was used to measure physical fitness and body composition. The KIDMED questionnaire was used to assess the adherence to MD among participants. Associations between variables were tested according to gender and age using linear regression models and analysis of variance. Participants with high/medium adherence to MD showed significantly higher endurance scores in both the boys and the girls. Gender differences were found. The boys in high/medium MD categories had significantly lower fat percentages and ran a 4 * 10 m sprint faster than the girls. The girls scored higher than the boys in endurance and speed-agility tests. It can be concluded that a high and medium adherence to MD is associated with high and very high endurance in both the girls and the boys. PMID- 30477218 TI - Effects of 12-week Aerobic Exercise on Arterial Stiffness, Inflammation, and Cardiorespiratory Fitness in Women with Systemic LUPUS Erythematosus: Non Randomized Controlled Trial. AB - This study assessed the effect of 12-week aerobic exercise on arterial stiffness (primary outcome), inflammation, oxidative stress, and cardiorespiratory fitness (secondary outcomes) in women with systemic lupus erythematosus (SLE). In a non randomized clinical trial, 58 women with SLE were assigned to either aerobic exercise (n = 26) or usual care (n = 32). The intervention comprised 12 weeks of aerobic exercise (2 sessions * 75 min/week) between 40-75% of the individual's heart rate reserve. At baseline and at week 12, arterial stiffness was assessed through pulse wave velocity (PWV), inflammatory (i.e., high-sensitivity C reactive protein [hsCRP], tumor necrosis factor alpha [TFN-alpha], and inteleukin 6 [IL-6]) and oxidative stress (i.e., myeloperoxidase [MPO]) markers were obtained from blood samples, and cardiorespiratory fitness was assessed (Bruce test). There were no between-group differences in the changes in arterial stiffness (median PWV difference -0.034, 95% CI -0.42 to 0.36 m/s; p = 0.860) or hsCRP, TNF-alpha, IL-6, and MPO (all p > 0.05) at week 12. In comparison to the control group, the exercise group significantly increased cardiorespiratory fitness (median difference 2.26 minutes, 95% CI 0.98 to 3.55; p = 0.001). These results suggest that 12 weeks of progressive treadmill aerobic exercise increases cardiorespiratory fitness without exacerbating arterial stiffness, inflammation, or oxidative stress in women with SLE. PMID- 30477219 TI - Effects of Kisspeptin-10 on Hypothalamic Neuropeptides and Neurotransmitters Involved in Appetite Control. AB - Besides its role as key regulator in gonadotropin releasing hormone secretion, reproductive function, and puberty onset, kisspeptin has been proposed to act as a bridge between energy homeostasis and reproduction. In the present study, to characterize the role of hypothalamic kisspeptin as metabolic regulator, we evaluated the effects of kisspeptin-10 on neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF) gene expression and the extracellular dopamine (DA), norepinephrine (NE), serotonin (5-hydroxytriptamine, 5-HT), dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIIA) concentrations in rat hypothalamic (Hypo-E22) cells. Our study showed that kisspeptin-10 in the concentration range 1 nM-10 MUM was well tolerated by the Hypo-E22 cell line. Moreover, kisspeptin-10 (100 nM-10 MUM) concentration independently increased the gene expression of NPY while BDNF was inhibited only at the concentration of 10 MUM. Finally, kisspeptin-10 decreased 5-HT and DA, leaving unaffected NE levels. The inhibitory effect on DA and 5-HT is consistent with the increased peptide induced DOPAC/DA and 5-HIIA/5-HT ratios. In conclusion, our current findings suggesting the increased NPY together with decreased BDNF and 5-HT activity following kisspeptin-10 would be consistent with a possible orexigenic effect induced by the peptide. PMID- 30477220 TI - Impact of tRNA Modifications and tRNA-Modifying Enzymes on Proteostasis and Human Disease. AB - Transfer RNAs (tRNAs) are key players of protein synthesis, as they decode the genetic information organized in mRNA codons, translating them into the code of 20 amino acids. To be fully active, tRNAs undergo extensive post-transcriptional modifications, catalyzed by different tRNA-modifying enzymes. Lack of these modifications increases the level of missense errors and affects codon decoding rate, contributing to protein aggregation with deleterious consequences to the cell. Recent works show that tRNA hypomodification and tRNA-modifying-enzyme deregulation occur in several diseases where proteostasis is affected, namely, neurodegenerative and metabolic diseases. In this review, we discuss the recent findings that correlate aberrant tRNA modification with proteostasis imbalances, in particular in neurological and metabolic disorders, and highlight the association between tRNAs, their modifying enzymes, translational decoding, and disease onset. PMID- 30477221 TI - Arsenic Trioxide Suppressed Migration and Angiogenesis by Targeting FOXO3a in Gastric Cancer Cells. AB - Arsenic trioxide (As2O3), a traditional remedy in Chinese medicine, has been used in acute promyelocytic leukemia (APL) research and clinical treatment. Previous studies have shown that As2O3 exerts its potent antitumor effects in solid tumors by regulating cell proliferation and survival. The aim of this study was to investigate whether As2O3 inhibited gastric cancer cell migration and angiogenesis by regulating FOXO3a expression. We found that As2O3 reduced gastric cancer cell viability in a dose-dependent manner and also inhibited cell migration and angiogenesis in vitro. Western blotting and immunofluorescence showed that As2O3 downregulated the levels of p-AKT, upregulated FOXO3a expression in the nucleus, and attenuated downstream Vascular endothelial growth factor (VEGF) and Matrix metallopeptidase 9 (MMP9) expression. Moreover, we demonstrated that knockdown of FOXO3a significantly reversed the inhibition of As2O3 and promoted cell migration and angiogenesis in vitro. Further, As2O3 significantly inhibited xenograft tumor growth and angiogenesis by upregulating FOXO3a expression in vivo. However, knockdown of FOXO3a attenuated the inhibitory effect of As2O3 in xenograft tumors, and increased microvessel density (MVD) and VEGF expression. Our results demonstrated that As2O3 inhibited migration and angiogenesis of gastric cancer cells by enhancing FOXO3a expression. PMID- 30477222 TI - Microfabrication of Micropore Array for Cell Separation and Cell Assay. AB - Micropore arrays have attracted a substantial amount of attention due to their strong capability to separate specific cell types, such as rare tumor cells, from a heterogeneous sample and to perform cell assays on a single cell level. Micropore array filtration has been widely used in rare cell type separation because of its potential for a high sample throughput, which is a key parameter for practical clinical applications. However, most of the present micropore arrays suffer from a low throughput, resulting from a low porosity. Therefore, a robust microfabrication process for high-porosity micropore arrays is urgently demanded. This study investigated four microfabrication processes for micropore array preparation in parallel. The results revealed that the Parylene-C molding technique with a silicon micropillar array as the template is the optimized strategy for the robust preparation of a large-area and high-porosity micropore array, along with a high size controllability. The Parylene-C molding technique is compatible with the traditional micromechanical system (MEMS) process and ready for scale-up manufacture. The prepared Parylene-C micropore array is promising for various applications, such as rare tumor cell separation and cell assays in liquid biopsy for cancer precision medicine. PMID- 30477223 TI - TSPO Ligands Promote Cholesterol Efflux and Suppress Oxidative Stress and Inflammation in Choroidal Endothelial Cells. AB - Choroidal endothelial cells supply oxygen and nutrients to retinal pigment epithelial (RPE) cells and photoreceptors, recycle metabolites, and dispose of metabolic waste through the choroidal blood circulation. Death of the endothelial cells of the choroid may cause abnormal deposits including unesterified and esterified cholesterol beneath RPE cells and within Bruch's membrane that contribute to the progression of age-related macular degeneration (AMD), the most prevalent cause of blindness in older people. Translocator protein (TSPO) is a cholesterol-binding protein that is involved in mitochondrial cholesterol transport and other cellular functions. We have investigated the role of TSPO in choroidal endothelial cells. Immunocytochemistry showed that TSPO was localized to the mitochondria of choroidal endothelial cells. Choroidal endothelial cells exposed to TSPO ligands (Etifoxine or XBD-173) had significantly increased cholesterol efflux, higher expression of cholesterol homeostasis genes (LXRalpha, CYP27A1, CYP46A1, ABCA1 and ABCG1), and reduced biosynthesis of cholesterol and phospholipids from [14C]acetate, when compared to untreated controls. Treatment with TSPO ligands also resulted in reduced production of reactive oxygen species (ROS), increased antioxidant capacity, and reduced release of pro-inflammatory cytokines (IL-1beta, IL-6, TNF-alpha and VEGF) induced by oxidized LDL. These data suggest TSPO ligands may offer promise for the treatment of AMD. PMID- 30477224 TI - Preparation and Properties of Highly Electroconductive and Heat-Resistant CMC/Buckypaper/Epoxy Nanocomposites. AB - Self-assembled buckypapers have been successfully prepared using sodium carboxyl methyl cellulose (CMC) as a binder. The lowest resistivity that was reached was 0.43 +/- 0.03 Omega.m, when the buckypapers were prepared by the same mass of CMC and carboxy-modified carbon nanotubes (CNTs). A heat-resistant electroconductive nanocomposite with epoxy resin as the matrix and CMC/buckypapers as the reinforcement was fabricated by a resin impregnation molding technique. The effects of CMC/buckypaper layers on the conductivity, thermal stability, and mechanical and dynamic mechanical performance of the epoxy resin polymer nanocomposites were investigated. It was found that CMC/buckypapers hold great promise for improving the properties of nanocomposites, and the buckypapers' performance can be enhanced by using modified CNTs to prepare them. The obtained nanocomposites showed an approximate 71.23% bending strength improvement (125.04 +/- 5.62 MPa) and a 30.71% bending modulus improvement (5.83 +/- 0.68 GPa), with an increased number of CMC/buckypaper layers. An enhanced degradation temperature and residual mass were also achieved for the nanocomposites when compared with a pure polymer. The nanocomposites with four CMC/buckypaper layers possessed the highest storage modulus (1934 MPa), which was approximately 60% higher than that of a neat polymer (1185 MPa). Therefore, CMC/buckypapers could be effectively used to manufacture heat-resistant electroconductive polymer nanocomposites with improved properties. PMID- 30477225 TI - Application of Additive Layer Manufacturing Technique on the Development of High Sensitive Fiber Bragg Grating Temperature Sensors. AB - This paper presents the development of temperature sensors based on fiber Bragg gratings (FBGs) embedded in 3D-printed structures made of different materials, namely polylatic acid (PLA) and thermoplastic polyurethane (TPU). A numerical analysis of the material behavior and its interaction with the FBG sensor was performed through the finite element method. A simple, fast and prone to automation process is presented for the FBG embedment in both PLA and TPU structures. The temperature tests were made using both PLA- and TPU-embedded FBGs as well as an unembedded FBG as reference. Results show an outstanding temperature sensitivity of 139 pm/ degrees C for the FBG-embedded PLA structure, which is one of the highest temperature sensitivities reported for FBG-based temperature sensors in silica fibers. The sensor also shows almost negligible hysteresis (highest hysteresis below 0.5%). In addition, both PLA- and TPU embedded structures present high linearity and response time below 2 s. The results presented in this work not only demonstrate the feasibility of developing fully embedded temperature sensors with high resolution and in compliance with soft robot application requirements, but also show that the FBG embedment in such structures is capable of enhancing the sensor performance. PMID- 30477226 TI - Effect of Torsion Stress on the Offset and Sensitivity of Diagonal and Off Diagonal GMI in Amorphous Wires. AB - In this paper, the torsional stress effect on Giant Magneto-Impedance (GMI) was studied in Co-rich amorphous wires. The study, which was conducted in the context of the development of a current clamp based on GMI, considered torsion as a parameter of the influence of this sensor. Both diagonal, Z11, and off-diagonal, Z21, components of the impedance tensor were investigated. The samples were Co rich wires with a 100 u diameter. The wires were twisted positive and negative angles with respect to a reference position. For each component of the impedance, the intrinsic sensitivity and offset were measured as a function of the rotation angle. The results showed that the sensitivity of the diagonal component at a given working point slightly increased for angles between -90 degrees to +90 degrees , whereas the sensitivity was almost constant for the off-diagonal component at zero-field. The intrinsic offset in the diagonal configuration was almost unchanged for the rotation angles considered, whereas this offset increased in the off-diagonal configuration. Furthermore, the GMI ratio of Z11 was also measured as a function of the rotation angle for comparison purposes with known data. The maximum of this ratio was obtained for a rotation angle of about 50 degrees . PMID- 30477227 TI - Energy Harvesting from a Thermoelectric Zinc Antimonide Thin Film under Steady and Unsteady Operating Conditions. AB - In practice, there are some considerations to study stability, reliability, and output power optimization of a thermoelectric thin film operating dynamically. In this study stability and performance of a zinc antimonide thin film thermoelectric (TE) specimen is evaluated under transient with thermal and electrical load conditions. Thermoelectric behavior of the specimen and captured energy in each part of a thermal cycle are investigated. Glass is used as the substrate of the thin film, where the heat flow is parallel to the length of the thermoelectric element. In this work, the thermoelectric specimen is fixed between a heat sink exposed to the ambient temperature and a heater block. The specimen is tested under various electrical load cycles during a wide range of thermal cycles. The thermal cycles are provided for five different aimed temperatures at the hot junction, from 160 to 350 degrees C. The results show that the specimen generates approximately 30% of its total electrical energy during the cooling stage and 70% during the heating stage. The thin film generates maximum power of 8.78, 15.73, 27.81, 42.13, and 60.74 kW per unit volume of the thermoelectric material (kW/m3), excluding the substrate, corresponding to hot side temperature of 160, 200, 250, 300, and 350 degrees C, respectively. Furthermore, the results indicate that the thin film has high reliability after about one thousand thermal and electrical cycles, whereas there is no performance degradation. PMID- 30477228 TI - Map1lc3b and Sqstm1 Modulated Autophagy for Tumorigenesis and Prognosis in Certain Subsites of Oral Squamous Cell Carcinoma. AB - Oral squamous cell carcinoma (OSCC) is one of the most common cancer types worldwide and can be divided into three major subsites: buccal mucosal SCC (BMSCC), tongue SCC (TSCC), and lip SCC (LSCC). The autophagy marker microtubule associated protein light chain 3B (MAP1LC3B) and adaptor sequestosome 1(SQSTM1) are widely used proteins to evaluate autophagy in tumor tissues. However, the role of MAP1LC3B and SQSTM1 in OSCC is not fully understood, particularly in certain subsites. With a tissue microarray comprised of 498 OSCC patients, including 181 BMSCC, 244 TSCC, and 73 LSCC patients, we found that the expression levels of MAP1LC3B and cytoplasmic SQSTM1 were elevated in the tumor tissues of three subsites compared with those in adjacent normal tissues. MAP1LC3B was associated with a poor prognosis only in TSCC. SQSTM1 was associated with poor differentiation in three subsites, while the association with lymph node invasion was only observed in BMSCC. Interestingly, MAP1LC3B was positively correlated with SQSTM1 in the tumor tissues of BMSCC, whereas it showed no correlation with SQSTM1 in adjacent normal tissue. The coexpression of higher MAP1LC3B and SQSTM1 demonstrated a significantly worse disease-specific survival (DSS) and disease free survival (DFS) in patients with BMSCC and LSCC, but not TSCC. The knockdown of MAP1LC3B and SQSTM1 reduced autophagy, cell proliferation, invasion and tumorspheres of BMSCC cells. Additionally, silencing both MAP1LC3B and SQSTM1 enhanced the cytotoxic effects of paclitaxel in the tumorspheres of BMSCC cells. Taken together, MAP1LC3B and SQSTM1 might modulate autophagy to facilitate tumorigenesis and chemoresistance in OSCC, particularly in BMSCC. PMID- 30477229 TI - Direct Determination of Ni2+-Capacity of IMAC Materials Using Near-Infrared Spectroscopy. AB - The present paper reports a new method for the quantification of the Ni2+ capacity of an immobilized metal affinity chromatography (IMAC) material using near-infrared spectroscopy (NIRS). Conventional analyses using UV absorption spectroscopy or atomic absorption spectrometry (AAS) need to dissolve the silica based metal chelate sorbent as sample pretreatment. In the first step, those methods were validated on the basis of an ideal homogenous NiSO4-solution and unveiled that UV with an intermediate precision of 2.6% relative standard deviation (RSD) had an advantage over AAS with an intermediate precision of 6.5% RSD. Therefore, UV analysis was chosen as reference method for the newly established NIRS model which has the advantage of being able to measure the material directly in diffuse reflection mode. Partial least squares regression (PLSR) analysis was used as multivariate data analysis tool for quantification. The best PLSR result obtained was: coefficient of determination (R2) = 0.88, factor = 2, root mean square error of prediction (RMSEP) = 22 umol/g (test-set validation) or 7.5% RSDPLSR. Validation of the Ni2+-capacity using UV absorption spectroscopy resulted in an intermediate precision of +/-18 umol/g or 5.0% RSD. Therefore, NIRS provides a fast alternative analysis method without the need of sample preparation. PMID- 30477230 TI - Integration of a Gold-Specific Whole E. coli Cell Sensing and Adsorption Based on BioBrick. AB - Detection and recovery of heavy metals from environmental sources is a major task in environmental protection and governance. Based on previous research into cell based visual detection and biological adsorption, we have developed a novel system combining these two functions by the BioBrick technique. The gold-specific sensory gol regulon was assembled on the gold-chaperone GolB (Gold-specific binding protein), which is responsible for selectively absorbing gold ions, and this led to an integration system with increased probe tolerance for gold. After being incorporated into E. coli, this system featured high-selective detection and recycling of gold ions among multi-metal ions from the environment. It serves as an efficient method for biological detection and recovery of various heavy metals. We have developed modular methods for cell-based detection and adsorption of heavy metals, and these offer a quick and convenient tool for development in this area. PMID- 30477231 TI - Screening of a Library of Oligosaccharides Targeting Lectin LecB of Pseudomonas Aeruginosa and Synthesis of High Affinity Oligoglycoclusters. AB - The Gram negative bacterium Pseudomonas aeruginosa (PA) is an opportunistic bacterium that causes severe and chronic infection of immune-depressed patients. It has the ability to form a biofilm that gives a selective advantage to the bacteria with respect to antibiotherapy and host defenses. Herein, we have focused on the tetrameric soluble lectin which is involved in bacterium adherence to host cells, biofilm formation, and cytotoxicity. It binds to l-fucose, d mannose and glycan exposing terminal fucose or mannose. Using a competitive assay on microarray, 156 oligosaccharides and polysaccharides issued from fermentation or from the biomass were screened toward their affinity to LecB. Next, the five best ligands (Lewisa, Lewisb, Lewisx, siayl-Lewisx and 3-fucosyllactose) were derivatized with a propargyl aglycon allowing the synthesis of 25 trivalent, 25 tetravalent and 5 monovalent constructions thanks to copper catalyzed azide alkyne cycloaddition. The 55 clusters were immobilized by DNA Directed immobilization leading to the fabrication of a glycocluster microarray. Their binding to LecB was studied. Multivalency improved the binding to LecB. The binding structure relationship of the clusters is mainly influenced by the carbohydrate residues. Molecular simulations indicated that the simultaneous contact of both binding sites of monomer A and D seems to be energetically possible. PMID- 30477232 TI - Alignment System and Application for a Micro/Nanofluidic Chip. AB - In this paper, a direct pre-bonding technology after alignment of the chip is presented to avoid the post-misalignment problem caused by the transferring process from an alignment platform to a heating oven. An alignment system with a high integration level including a microscope device, a vacuum device, and an alignment device is investigated. To align the chip, a method of 'fixing a chip with microchannels and moving a chip with nanochannels' is adopted based on the alignment system. With the alignment system and the assembly method, the micro/nanofluidic chip was manufactured with little time and low cost. Furthermore, to verify the performance of the chip and then confirm the practicability of the device, an ion enrichment experiment is carried out. The results demonstrate that the concentration of fluorescein isothiocyanate (FITC) reaches an enrichment value of around 5 MUM and the highest enrichment factor is about 500-fold. Compared with other devices, an alignment system presented in this paper has the advantages of direct pre-bonding and high integration level. PMID- 30477233 TI - The Construction and Validation of Child, Adolescent and Parental Decision Aids for Considering Methylphenidate Drug Holidays in ADHD. AB - Guidelines recommend encouraging young people with attention deficit hyperactivity disorder (ADHD) who are taking medication long-term, to discuss their preferences for stopping or changing their treatment, including a discussion about 'drug holidays', with their doctor. Yet, to date, no written information has been available to empower children and adolescents with ADHD and their parents to make informed decisions about drug holidays. The aim of this study was to design and develop a suite of decision aids to help families decide if they want to take a drug holiday from methylphenidate. The material was designed with reference to the literature and in consultation with a secondary care specialist, and validated with two panels composed of specialists and parents using content validity questionnaires and interviews; before being finished and branded by a design service. Three decision aids were produced, with parental and adolescent versions composed of a booklet and a pull-out form for self-completion, and the child version being a booklet for reading and self completion. Existing research calls for suitable written materials to feasibly increase the uptake of practitioner-initiated planned drug holidays from methylphenidate. We envisage these materials will open up the space to discuss drug holidays in ADHD during annual reviews, in line with UK government guidelines. PMID- 30477234 TI - Kupffer Cells Survive Plasmodium berghei Sporozoite Exposure and Respond with a Rapid Cytokine Release. AB - The liver stage of the Plasmodium life cycle features sporozoite traversal of the liver sinusoidal barrier through Kupffer cells (KCs) followed by invasion of hepatocytes. Little is known about the interaction of Plasmodium sporozoites with KCs, the liver-resident macrophages. Previous reports suggest KCs do not mount a pro-inflammatory response and undergo cell death following this interaction. Our work explores this interaction using primary rat KCs (PRKCs) and Plasmodium berghei sporozoites. We analyzed PRKC culture supernatants for markers of an immunological response through cytokine arrays. Additionally, cell wounding and death were assessed by monitoring lactate dehydrogenase (LDH) levels in these supernatants and by live/dead cell imaging. We found that PRKCs mount an immunological response to P. berghei sporozoites by releasing a diverse set of both pro- and anti-inflammatory cytokines, including IFNgamma, IL-12p70, Mip 3alpha, IL-2, RANTES, IL-1alpha, IL-4, IL-5, IL-13, EPO, VEGF, IL-7, and IL 17alpha. We also observed no difference in LDH level or live/dead staining upon sporozoite exposure, suggesting that the KCs are not deeply wounded or dying. Overall, our data suggest that sporozoites may be actively modulating the KC's reaction to their presence and altering the way the innate immune system is triggered by KCs. PMID- 30477235 TI - A Novel Highly Divergent Strain of Cell Fusing Agent Virus (CFAV) in Mosquitoes from the Brazilian Amazon Region. AB - Classical insect-specific flaviviruses (cISFs) have been widely detected in different countries in the last decades. Here, we characterize the near full length genomes of two cISFs detected in mosquitoes collected in the city of Macapa, state of Amapa, Amazon region of Brazil. A total of 105 pools of female mosquitos were analyzed by next-generation sequencing (NGS). Comparative genomics and phylogenetic analysis identified three strains of cell fusing agent virus (CFAV) and two of Culex flavivirus (CxFV). All sequences were obtained from pools of Culex sp., except for one sequence of CFAV detected in a pool of Aedes aegypti. Both CxFV strains are phylogenetically related to a strain isolated in 2012 in the Southeast region of Brazil. The CFAV strains are the first of this species to be identified in Brazil and one of them is highly divergent from other strains of CFAV that have been detected worldwide. In conclusion, CFAV and CxFV, circulate in mosquitoes in Brazil. One strain of CFAV is highly divergent from others previously described, suggesting that a novel strain of CFAV is present in this region. PMID- 30477236 TI - Long Non-Coding RNAs as Mediators of Tumor Microenvironment and Liver Cancer Cell Communication. AB - The tumor microenvironment is an important concept that defines cancer development not only through tumor cells themselves but also the surrounding cellular and non-cellular components, including stromal cells, blood vessels, infiltrating inflammatory cells, cancer stem cells (CSC), cytokines, and growth factors, which act in concert to promote tumor cell survival and metastasis. Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies worldwide. Poor prognosis is largely attributable to the high rate of tumor metastasis, highlighting the importance of identifying patients at risk in advance and developing novel therapeutic targets to facilitate effective intervention. Long non-coding RNAs (lncRNA) are a class of non-protein coding transcripts longer than 200 nucleotides frequently dysregulated in various cancer types, which have multiple functions in widespread biological processes, including proliferation, apoptosis, metastasis, and metabolism. lncRNAs are involved in regulation of the tumor microenvironment and reciprocal signaling between cancer cells. Targeting of components of the tumor microenvironment or cancer cells has become a considerable focus of therapeutic research and establishing the effects of different lncRNAs on this network should aid in the development of effective treatment strategies. The current review provides a summary of the essential properties and functional roles of known lncRNAs associated with the tumor microenvironment in HCC. PMID- 30477237 TI - Less Data Same Information for Event-Based Sensors: A Bioinspired Filtering and Data Reduction Algorithm. AB - Sensors provide data which need to be processed after acquisition to remove noise and extract relevant information. When the sensor is a network node and acquired data are to be transmitted to other nodes (e.g., through Ethernet), the amount of generated data from multiple nodes can overload the communication channel. The reduction of generated data implies the possibility of lower hardware requirements and less power consumption for the hardware devices. This work proposes a filtering algorithm (LDSI-Less Data Same Information) which reduces the generated data from event-based sensors without loss of relevant information. It is a bioinspired filter, i.e., event data are processed using a structure resembling biological neuronal information processing. The filter is fully configurable, from a "transparent mode" to a very restrictive mode. Based on an analysis of configuration parameters, three main configurations are given: weak, medium and restrictive. Using data from a DVS event camera, results for a similarity detection algorithm show that event data can be reduced up to 30% while maintaining the same similarity index when compared to unfiltered data. Data reduction can reach 85% with a penalty of 15% in similarity index compared to the original data. An object tracking algorithm was also used to compare results of the proposed filter with other existing filter. The LDSI filter provides less error ( 4 . 86 +/- 1 . 87 ) when compared to the background activity filter ( 5 . 01 +/- 1 . 93 ). The algorithm was tested under a PC using pre-recorded datasets, and its FPGA implementation was also carried out. A Xilinx Virtex6 FPGA received data from a 128 * 128 DVS camera, applied the LDSI algorithm, created a AER dataflow and sent the data to the PC for data analysis and visualization. The FPGA could run at 177 MHz clock speed with a low resource usage (671 LUT and 40 Block RAM for the whole system), showing real time operation capabilities and very low resource usage. The results show that, using an adequate filter parameter tuning, the relevant information from the scene is kept while fewer events are generated (i.e., fewer generated data). PMID- 30477238 TI - Kinase Inhibitory Activities and Molecular Docking of a Novel Series of Anticancer Pyrazole Derivatives. AB - A series of novel 1,3,4-triarylpyrazoles containing different heterocycles has been prepared, characterized and screened for their in vitro antiproliferative activity against HePG-2, MCF-7, PC-3, A-549 and HCT-116 cancer cell lines. The biological results revealed that compound 6 showed the highest anticancer activity so it was subjected to a kinase assay study where it reduced the activity of several protein kinases including AKT1, AKT2, BRAF V600E, EGFR, p38alpha and PDGFRbeta at 100 MUM using the radiometric or ADP-Glo assay method. Molecular docking simulation supported the initial kinase assay and suggested a common mode of interaction at the ATP-binding sites of these kinases, which demonstrates that compound 6 is a potential agent for cancer therapy deserving further research. PMID- 30477239 TI - BiPred: A Bilevel Evolutionary Algorithm for Prediction in Smart Mobility. AB - This article develops the design, installation, exploitation, and final utilization of intelligent techniques, hardware, and software for understanding mobility in a modern city. We focus on a smart-campus initiative in the University of Malaga as the scenario for building this cyber-physical system at a low cost, and then present the details of a new proposed evolutionary algorithm used for better training machine-learning techniques: BiPred. We model and solve the task of reducing the size of the dataset used for learning about campus mobility. Our conclusions show an important reduction of the required data to learn mobility patterns by more than 90%, while improving (at the same time) the precision of the predictions of theapplied machine-learning method (up to 15%). All this was done along with the construction of a real system in a city, which hopefully resulted in a very comprehensive work in smart cities using sensors. PMID- 30477240 TI - Disposable Voltammetric Immunosensors Integrated with Microfluidic Platforms for Biomedical, Agricultural and Food Analyses: A Review. AB - Disposable immunosensors are analytical devices used for the quantification of a broad variety of analytes in different areas such as clinical, environmental, agricultural and food quality management. They detect the analytes by means of the strong interactions between antibodies and antigens, which provide concentration-dependent signals. For the herein highlighted voltammetric immunosensors, the analytical measurements are due to changes in the electrical signals on the surface of the transducers. The possibility of using disposable and miniaturized immunoassays is a very interesting alternative for voltammetric analyses, mainly, when associated with screen-printing technologies (screen printed electrodes, SPEs), and microfluidic platforms. The aim of this paper is to discuss a carefully selected literature about different examples of SPEs-based immunosensors associated with microfluidic technologies for diseases, food, agricultural and environmental analysis. Technological aspects of the development of the voltammetric immunoassays such as the signal amplification, construction of paper-based microfluidic platforms and the utilization of microfluidic devices for point-of-care testing will be presented as well. PMID- 30477241 TI - High Frequency Hysteresis Losses on gamma-Fe2O3 and Fe3O4: Susceptibility as a Magnetic Stamp for Chain Formation. AB - In order to understand the properties involved in the heating performance of magnetic nanoparticles during hyperthermia treatments, a systematic study of different gamma-Fe2O3 and Fe3O4 nanoparticles has been done. High-frequency hysteresis loops at 50 kHz carried out on particles with sizes ranging from 6 to 350 nm show susceptibility chi increases from 9 to 40 for large particles and it is almost field independent for the smaller ones. This suggests that the applied field induces chain ordering in large particles but not in the smaller ones due to the competition between thermal and dipolar energy. The specific absorption rate (SAR) calculated from hysteresis losses at 60 mT and 50 kHz ranges from 30 to 360 W/gFe, depending on particle size, and the highest values correspond to particles ordered in chains. This enhanced heating efficiency is not a consequence of the intrinsic properties like saturation magnetization or anisotropy field but to the spatial arrangement of the particles. PMID- 30477242 TI - Circulating Tumor and Invasive Cell Gene Expression Profile Predicts Treatment Response and Survival in Pancreatic Adenocarcinoma. AB - Previous studies have shown that pharmacogenomic modeling of circulating tumor and invasive cells (CTICs) can predict response of pancreatic ductal adenocarcinoma (PDAC) to combination chemotherapy, predominantly 5-fluorouracil based. We hypothesized that a similar approach could be developed to predict treatment response to standard frontline gemcitabine with nab-paclitaxel (G/nab P) chemotherapy. Gene expression profiles for responsiveness to G/nab-P were determined in cell lines and a test set of patient samples. A prospective clinical trial was conducted, enrolling 37 patients with advanced PDAC who received G/nab-P. Peripheral blood was collected prior to treatment, after two months of treatment, and at progression. The CTICs were isolated based on a phenotype of collagen invasion. The RNA was isolated, cDNA synthesized, and qPCR gene expression analyzed. Patients were most closely matched to one of three chemotherapy response templates. Circulating tumor and invasive cells' SMAD4 expression was measured serially. The CTICs were reliably isolated and profiled from peripheral blood prior to and during chemotherapy treatment. Individual patients could be matched to distinct response templates predicting differential responses to G/nab-P treatment. Progression free survival was significantly correlated to response prediction and DeltaSMAD4 was significantly associated with disease progression. These findings support phenotypic profiling and DeltaSMAD4 of CTICs as promising clinical tools for choosing effective therapy in advanced PDAC, and for anticipating disease progression. PMID- 30477243 TI - Design, Synthesis, and Evaluation of Alkyl-Quinoxalin-2(1H)-One Derivatives as Anti-Quorum Sensing Molecules, Inhibiting Biofilm Formation in Aeromonas caviae Sch3. AB - With the increasing antibiotic resistance of bacterial strains, alternative methods for infection control are in high demand. Quorum sensing (QS) is the bacterial communication system based on small molecules. QS is enables bacterial biofilm formation and pathogenic development. The interruption of QS has become a target for drug discovery, but remains in the early experimental phase. In this study, we synthesized a set of six compounds based on a scaffold (alkyl quinoxalin-2(1H)-one), new in the anti-QS of Gram-negative bacteria Aeromonas caviae Sch3. By quantifying biofilm formation, we were able to monitor the effect of these compounds from concentrations of 1 to 100 uM. Significant reduction in biofilm formation was achieved by 3-hexylylquinoxalin-2(1H)-one (11), 3 hexylylquinoxalin-2(1H)-one-6-carboxylic acid (12), and 3-heptylylquinoxalin 2(1H)-one-6-carboxylic acid (14), ranging from 11% to 59% inhibition of the biofilm. This pilot study contributes to the development of anti-QS compounds to overcome the clinical challenge of resistant bacteria strains. PMID- 30477244 TI - Comparing Ozonation and Biofiltration Treatment of Source Water with High Cyanobacteria-Derived Organic Matter: The Case of a Water Treatment Plant Followed by a Small-Scale Water Distribution System. AB - High cyanobacteria-derived dissolved organic carbon (DOC) in source water can cause drinking water quality to deteriorate, producing bad taste, odor, toxins, and possibly elevated levels of disinfection byproduct (DBP) precursors. Conventional water treatment processes do not effectively remove algal organic substances. In this study, rapid-sand-filtration effluent from a water treatment plant on Kinmen Island, where serious cyanobacterial blooms occurred, was used to evaluate the DOC- and DBP-removal efficiency of ozonation and/or biofiltration. To simulate a small-scale water distribution system following water treatment, 24 h simulated distribution system (SDS) tests were conducted. The following DBPs were analyzed: trihalomethanes (THMs), haloacetic acids (HAAs), haloacetonitriles (HANs), and trichloronitromethane (TCNM). Applying biological activated-carbon filtration (BAC) on its own achieved the greatest reduction in SDS-DBPs. Ozonation alone caused adverse effects by promoting THM, HAA, and TCNM formation. Ozonation and BAC filtration yielded better DOC removal (51%) than BAC filtration alone (41%). Considering the cost of ozonation, we suggest that when treating high cyanobacterial organic matter in water destined for a small-scale water distribution system, BAC biofiltration alone could be an efficient, economical option for reducing DBP precursors. If DOC removal needs to be improved, preceding ozonation could be incorporated. PMID- 30477245 TI - Model Driven Development Applied to Complex Event Processing for Near Real-Time Open Data. AB - Nowadays, data are being produced like never before because the use of the Internet of Things, social networks, and communication in general are increasing exponentially. Many of these data, especially those from public administrations, are freely offered using the open data concept where data are published to improve their reutilisation and transparency. Initially, the data involved information that is not updated continuously such as budgets, tourist information, office information, pharmacy information, etc. This kind of information does not change during large periods of time, such as days, weeks or months. However, when open data are produced near to real-time such as air quality sensors or people counters, suitable methodologies and tools are lacking to identify, consume, and analyse them. This work presents a methodology to tackle the analysis of open data sources using Model-Driven Development (MDD) and Complex Event Processing (CEP), which help users to raise the abstraction level utilised to manage and analyse open data sources. That means that users can manage heterogeneous and complex technology by using domain concepts defined by a model that could be used to generate specific code. Thus, this methodology is supported by a domain-specific language (DSL) called OpenData2CEP, which includes a metamodel, a graphical concrete syntax, and a model-to-text transformation to specific platforms, such as complex event processing engines. Finally, the methodology and the DSL have been applied to two near real-time contexts: the analysis of air quality for citizens' proposals and the analysis of earthquake data. PMID- 30477246 TI - Wnt/beta-Catenin Signaling Pathway Governs a Full Program for Dopaminergic Neuron Survival, Neurorescue and Regeneration in the MPTP Mouse Model of Parkinson's Disease. AB - Wingless-type mouse mammary tumor virus (MMTV) integration site (Wnt) signaling is one of the most critical pathways in developing and adult tissues. In the brain, Wnt signaling contributes to different neurodevelopmental aspects ranging from differentiation to axonal extension, synapse formation, neurogenesis, and neuroprotection. Canonical Wnt signaling is mediated mainly by the multifunctional beta-catenin protein which is a potent co-activator of transcription factors such as lymphoid enhancer factor (LEF) and T-cell factor (TCF). Accumulating evidence points to dysregulation of Wnt/beta-catenin signaling in major neurodegenerative disorders. This review highlights a Wnt/beta catenin/glial connection in Parkinson's disease (PD), the most common movement disorder characterized by the selective death of midbrain dopaminergic (mDAergic) neuronal cell bodies in the subtantia nigra pars compacta (SNpc) and gliosis. Major findings of the last decade document that Wnt/beta-catenin signaling in partnership with glial cells is critically involved in each step and at every level in the regulation of nigrostriatal DAergic neuronal health, protection, and regeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, focusing on Wnt/beta-catenin signaling to boost a full neurorestorative program in PD. PMID- 30477247 TI - Parenting Style and Reactive and Proactive Adolescent Violence: Evidence from Spain. AB - The aim of the present study was to analyze the relationship between the parenting styles-authoritative, indulgent, authoritarian, and neglectful-and reactive and proactive school violence among peers. These analyses were also performed by sex and age groups. The sample consisted of 2399 Spanish adolescents (50.2% male), aged between 12 and 18 years, mean (M) = 14.69, standard deviation (SD) = 1.82. A multivariate analisys of variance (MANOVA, 4 * 2 * 2) was applied, considering parenting style, sex, and age group (12-14 and 15-18 years) as independent variables to analyze the possible effects of interaction. Reactive, proactive, and pure violence were the dependent variables. The results showed the main effects of parenting styles, sex, and age, as well as an interaction between sex, age, and parenting styles. The interpretation of the findings suggested that the authoritarian parenting style was related to greater engagement in proactive and reactive violent behaviors. In relation to the effect of the interaction between sex, age, and parenting styles, it was observed that adolescents from indulgent families, of both sexes and in any of the studied age groups, obtained lower scores in proactive violence. The discussion highlights the importance of affection and warmth for well-adjusted children's behavior. PMID- 30477248 TI - Optical Biosensors for Label-Free Detection of Small Molecules. AB - Label-free optical biosensors are an intriguing option for the analyses of many analytes, as they offer several advantages such as high sensitivity, direct and real-time measurement in addition to multiplexing capabilities. However, development of label-free optical biosensors for small molecules can be challenging as most of them are not naturally chromogenic or fluorescent, and in some cases, the sensor response is related to the size of the analyte. To overcome some of the limitations associated with the analysis of biologically, pharmacologically, or environmentally relevant compounds of low molecular weight, recent advances in the field have improved the detection of these analytes using outstanding methodology, instrumentation, recognition elements, or immobilization strategies. In this review, we aim to introduce some of the latest developments in the field of label-free optical biosensors with the focus on applications with novel innovations to overcome the challenges related to small molecule detection. Optical label-free methods with different transduction schemes, including evanescent wave and optical fiber sensors, surface plasmon resonance, surface enhanced Raman spectroscopy, and interferometry, using various biorecognition elements, such as antibodies, aptamers, enzymes, and bioinspired molecularly imprinted polymers, are reviewed. PMID- 30477249 TI - Skin Permeation of Solutes from Metalworking Fluids to Build Prediction Models and Test A Partition Theory. AB - Permeation of chemical solutes through skin can create major health issues. Using the membrane-coated fiber (MCF) as a solid phase membrane extraction (SPME) approach to simulate skin permeation, we obtained partition coefficients for 37 solutes under 90 treatment combinations that could broadly represent formulations that could be associated with occupational skin exposure. These formulations were designed to mimic fluids in the metalworking process, and they are defined in this manuscript using: one of mineral oil, polyethylene glycol-200, soluble oil, synthetic oil, or semi-synthetic oil; at a concentration of 0.05 or 0.5 or 5 percent; with solute concentration of 0.01, 0.05, 0.1, 0.5, 1, or 5 ppm. A single linear free-energy relationship (LFER) model was shown to be inadequate, but extensions that account for experimental conditions provide important improvements in estimating solute partitioning from selected formulations into the MCF. The benefit of the Expanded Nested-Solute-Concentration LFER model over the Expanded Crossed-Factors LFER model is only revealed through a careful leave one-solute-out cross-validation that properly addresses the existence of replicates to avoid an overly optimistic view of predictive power. Finally, the partition theory that accompanies the MCF approach is thoroughly tested and found to not be supported under complex experimental settings that mimic occupational exposure in the metalworking industry. PMID- 30477250 TI - Efficacy and Safety of Denosumab Therapy for Osteogenesis Imperfecta Patients with Osteoporosis-Case Series. AB - Osteogenesis imperfecta (OI) is a connective tissue disorder that is characterized by low bone density leading to recurrent fractures. The efficacy of the anti-resorption drug denosumab for OI with osteoporosis is still largely unknown. We herein describe the clinical outcomes of eight osteoporotic cases of OI to examine the effects and safety of denosumab. This retrospective, consecutive case series included eight patients respectively aged 42, 40, 14, 22, 3, 51, 37, and 9 years. We measured the bone mineral density (BMD) of the lumbar 1-4 spine (L-BMD) and bilateral hips (H-BMD), bone-specific alkaline phosphatase, urinary type I collagen amino-terminal telopeptide, and tartrate-resistant acid phosphatase 5b before and during denosumab therapy. Despite multiple pretreatment fractures in the cohort, no fractures or severe side effects, such as hypocalcemia, were observed during the observational period apart from a fracture in a young pediatric girl. Both L-BMD and H-BMD were increased by denosumab in seven of eight cases. Bone turnover markers were inhibited in most cases by denosumab therapy. Denosumab treatment could generally raise BMD without any adverse effects. The agent therefore represents a good therapeutic option for OI with osteoporosis. PMID- 30477251 TI - In-and-Out Molecular Changes Linked to the Type 2 Diabetes Remission after Bariatric Surgery: An Influence of Gut Microbes on Mitochondria Metabolism. AB - Different kinds of gastrointestinal tract modulations known as "bariatric surgery" are actually the most effective treatment for obesity and associated co morbidities, such as type 2 diabetes (T2DM). The potential causes of those effects have yet to be explained. In our study, we focused on molecular changes evoked by laparoscopic sleeve gastrectomy leading to T2DM remission. Two complementary metabolomics techniques, namely, liquid chromatography coupled with mass spectrometry (LC-MS) and gas chromatography mass spectrometry (GC-MS), were used to study those effects in a group of 20 obese patients with T2DM selected from a cohort of 372 obese individuals who underwent bariatric surgery and did not receive anti-diabetic treatment afterward. Modified levels of carnitines, lipids, amino acids (including BCAA) and alpha- and beta-hydroxybutyric acids were detected. Presented alterations suggest a major role of mitochondria activity in T2DM remission process. Moreover, some of the observed metabolites suggest that changes in gut microbiota composition may also correlate with the tempo of diabetes recovery. Additional analyses confirmed a relationship between biochemical and clinical parameters and the aforementioned metabolites, thereby, highlighting a role of mitochondria and microbes. Our data suggests that there is a previously undescribed relationship between mitochondria and gut microbiota, which changes after the bariatric surgery. More investigations are needed to confirm and explore the observed findings. PMID- 30477252 TI - Effect of Acute Stress on the Expression of BDNF, trkB, and PSA-NCAM in the Hippocampus of the Roman Rats: A Genetic Model of Vulnerability/Resistance to Stress-Induced Depression. AB - The Roman High-Avoidance (RHA) and the Roman Low-Avoidance (RLA) rats, represent two psychogenetically-selected lines that are, respectively, resistant and prone to displaying depression-like behavior, induced by stressors. In the view of the key role played by the neurotrophic factors and neuronal plasticity, in the pathophysiology of depression, we aimed at assessing the effects of acute stress, i.e., forced swimming (FS), on the expression of brain-derived neurotrophic factor (BDNF), its trkB receptor, and the Polysialilated-Neural Cell Adhesion Molecule (PSA-NCAM), in the dorsal (dHC) and ventral (vHC) hippocampus of the RHA and the RLA rats, by means of western blot and immunohistochemical assays. A 15 min session of FS elicited different changes in the expression of BDNF in the dHC and the vHC. In RLA rats, an increment in the CA2 and CA3 subfields of the dHC, and a decrease in the CA1 and CA3 subfields and the dentate gyrus (DG) of the vHC, was observed. On the other hand, in the RHA rats, no significant changes in the BDNF levels was seen in the dHC and there was a decrease in the CA1, CA3, and DG of the vHC. Line-related changes were also observed in the expression of trkB and PSA-NCAM. The results are consistent with the hypothesis that the differences in the BDNF/trkB signaling and neuroplastic mechanisms are involved in the susceptibility of RLA rats and resistance of RHA rats to stress-induced depression. PMID- 30477253 TI - Fat Replacers in Baked Food Products. AB - Fat provides important sensory properties to baked food products, such as colour, taste, texture and odour, all of which contribute to overall consumer acceptance. Baked food products, such as crackers, cakes and biscuits, typically contain high amounts of fat. However, there is increasing demand for healthy snack foods with reduced fat content. In order to maintain consumer acceptance whilst simultaneously reducing the total fat content, fat replacers have been employed. There are a number of fat replacers that have been investigated in baked food products, ranging from complex carbohydrates, gums and gels, whole food matrices, and combinations thereof. Fat replacers each have different properties that affect the quality of a food product. In this review, we summarise the literature on the effect of fat replacers on the quality of baked food products. The ideal fat replacers for different types of low-fat baked products were a combination of polydextrose and guar gum in biscuits at 70% fat replacement (FR), oleogels in cake at 100% FR, and inulin in crackers at 75% FR. The use of oatrim (100% FR), bean puree (75% FR) or green pea puree (75% FR) as fat replacers in biscuits were equally successful. PMID- 30477254 TI - Physiological Effects of Viewing Bonsai in Elderly Patients Undergoing Rehabilitation. AB - The benefits of various nature-derived stimuli that can be used for stress relief and relaxation has recently gained immense attention; however, there are very few studies about their influence on elderly patients. The present study aims to present the effects of viewing bonsai on autonomic nervous activity, prefrontal cortex activity, and subjective assessment findings of psychological relaxation in elderly patients undergoing rehabilitation. Fourteen participants aged 64-91 years (mean age +/- standard deviation, 78.6 +/- 9.6 years) participated in this study. Miniature potted 10-year-old Japanese cypress bonsai trees were used as visual stimuli. Participants viewed the bonsai for 1 min, and the control comprised of no experimental stimulus. Physiological effects on autonomic nervous activity were assessed by measuring the heart rate variability (HRV) and pulse rate. The effects on prefrontal cortex activity were determined using near infrared spectroscopy, which involved assessment of oxyhemoglobin concentrations in the left and right prefrontal cortices. Subjective evaluations were achieved by the modified semantic differential method. Viewing bonsai resulted in a significant increase in parasympathetic nervous activity, a significant decrease in sympathetic nervous activity, and a significant increase in the perceptions of feeling "comfortable" and "relaxed." In conclusion, our findings indicated that viewing bonsai induces physiological and psychological relaxation. PMID- 30477255 TI - Inclusion Body Bead Size in E. coli Controlled by Physiological Feeding. AB - The Gram-negative bacterium E. coli is the host of choice for producing a multitude of recombinant proteins relevant in the pharmaceutical industry. Generally, cultivation is easy, media are cheap, and a high product titer can be obtained. However, harsh induction procedures combined with the usage of IPTG (isopropyl beta-d-1 thiogalactopyranoside) as an inducer are often believed to cause stress reactions, leading to intracellular protein aggregates, which are so known as so-called inclusion bodies (IBs). Downstream applications in bacterial processes cause the bottleneck in overall process performance, as bacteria lack many post-translational modifications, resulting in time and cost-intensive approaches. Especially purification of inclusion bodies is notoriously known for its long processing times and low yields. In this contribution, we present screening strategies for determination of inclusion body bead size in an E. coli based bioprocess producing exclusively inclusion bodies. Size can be seen as a critical quality attribute (CQA), as changes in inclusion body behavior have a major effect on subsequent downstream processing. A model-based approach was used, aiming to trigger a distinct inclusion body size: Physiological feeding control, using qs,C as a critical process parameter, has a high impact on inclusion body size and could be modelled using a hyperbolic saturation mechanism calculated in form of a cumulated substrate uptake rate. Within this model, the sugar uptake rate of the cells, in the form of the cumulated sugar uptake-value, was simulated and considered being a key performance indicator for determination of the desired size. We want to highlight that the usage of the mentioned screening strategy in combination with a model-based approach will allow tuning of the process towards a certain inclusion body size using a qs based control only. Optimized inclusion body size at the time-point of harvest should stabilize downstream processing and, therefore, increase the overall time-space yield. Furthermore, production of distinct inclusion body size may be interesting for application as a biocatalyst and nanoparticulate material. PMID- 30477256 TI - Food Safety Knowledge and Practices among Saudi Mothers. AB - This study examines food safety knowledge and practices of mothers in Saudi Arabia. A total of 979 respondents participated in the study and completed a questionnaire that assessed their knowledge of food storage, food handling, usage, and maintenance of kitchen facilities, personal hygiene, and food poisoning. Results showed that mothers in Saudi Arabia had moderate knowledge of food storage (passing rate 64.9%) and usage and maintenance of kitchen facilities (passing rate 66.5%). While they had good knowledge of personal hygiene (passing rate 83.8%) and food poisoning (passing rate 78.5%), their knowledge with regard to food handling was poor (passing rate 30.4%). Results also highlighted that food safety knowledge and practices amongst mothers in Saudi Arabia improved with the level of education, while their age, employment status, monthly income, and number of children had no significant association with their food safety knowledge and practices. This research revealed the importance of education and that advance education and training program can further improve mothers' food safety knowledge and practices and thereby result in reducing the risks of foodborne illnesses at homes. PMID- 30477257 TI - A Study on Drilling High-Strength CFRP Laminates: Frictional Heat and Cutting Temperature. AB - High-strength carbon fiber reinforced polymer (CFRP) composites have become popular materials to be utilized in the aerospace and automotive industries, due to their unique and superior mechanical properties. An understanding of cutting temperatures is rather important when dealing with high-strength CFRPs, since machining defects are likely to occur because of high temperatures (especially in the semi-closed drilling process). The friction behavior at the flank tool workpiece interface when drilling CFRPs plays a vital role in the heat generation, which still remains poorly understood. The aim of this paper is to address the friction-induced heat based on two specially-designed tribometers to simulate different sliding velocities, similar to those occurring along the flank tool-work interface in drilling. The elastic recovery effect during the drilling process was considered during the tribo-drilling experiments. The drilling temperatures were calculated by the analytical model and verified by the in-situ experimental results gained using the embedded thermocouples into the drills. The results indicate that the magnitudes of the interfacial friction coefficients between the cemented carbide tool and the CFRP specimen are within the range between 0.135-0.168 under the examined conditions. Additionally, the friction caused by the plastic deformation and elastic recovery effects plays a dominant role when the sliding velocity increases. The findings in this paper point out the impact of the friction-induced heat and cutting parameters on the overall drilling temperature. PMID- 30477258 TI - Analysis of the Fungal Community in Ziziphi Spinosae Semen through High Throughput Sequencing. AB - Ziziphi Spinosae Semen (ZSS) has been widely used in traditional Chinese medicine system for decades. Under proper humidity and temperature, ZSS is easily contaminated by fungi and mycotoxins during harvest, storage, and transport, thereby posing a considerable threat to consumer health. In this study, we first used the Illumina MiSeq PE250 platform and targeted the internal transcribed spacer 2 sequences to investigate the presence of fungi in moldy and normal ZSS samples collected from five producing areas in China. Results showed that all 14 samples tested were contaminated by fungi. Ascomycota was the dominant fungus at the phylum level, accounting for 64.36-99.74% of the fungal reads. At the genus level, Aspergillus, Candida, and Wallemia were the most predominant genera, with the relative abundances of 13.52-87.87%, 0.42-64.56%, and 0.06-34.31%, respectively. Meanwhile, 70 fungal taxa were identified at the species level. Among these taxa, three potential mycotoxin-producing fungi, namely, Aspergillus flavus, A. fumigatus, and Penicillium citrinum that account for 0.30-36.29%, 0.04 7.37%, and 0.01-0.80% of the fungal reads, respectively, were detected in all ZSS samples. Moreover, significant differences in fungal communities were observed in the moldy and normal ZSS samples. In conclusion, our results indicated that amplicon sequencing is feasible for the detection and analysis of the fungal community in the ZSS samples. This study used a new approach to survey the fungal contamination in herbal materials. This new approach can provide early warning for mycotoxin contamination in herbal materials, thereby ensuring drug efficacy and safety. PMID- 30477259 TI - Development of Dispersion-Optimized Photonic Crystal Fibers Based on Heavy Metal Oxide Glasses for Broadband Infrared Supercontinuum Generation with Fiber Lasers. AB - In this work a photonic crystal fiber made of a heavy metal oxide glass with optimized dispersion profile is proposed for supercontinuum generation in a broad range of wavelengths in the near-infrared, when pumped by a mode-locked fiber based laser. The fiber is modelled and optimal geometrical parameters are selected to achieve flat and low dispersion in the anomalous regime. Supercontinuum generation in the range of 0.76-2.40 um, within the dynamics of 30 dB, when pumped at 1.56 um with 400 fs-long pulses and an average power 660 mW is possible. The applicability of such fibers is also discussed. PMID- 30477260 TI - Quasi-Distributed Active-Mode-Locking Laser Interrogation with Multiple Partially Reflecting Segment Sensors. AB - A new type of quasi-distributed sensor system is implemented using an active mode locking (AML) laser cavity with multiple partially reflecting segments. The mode locking frequency of the AML laser is linearly proportional to the overall lasing cavity length. To implement multiple resonators having multiple reflection points installed in a sensing fiber, two types of partial reflectors (PRs) are implemented for an in-line configuration, one with fiber Bragg grating and the other with a fiber Fabry-Perot interferometer. Since the laser has oscillated only when the modulation frequencies for the mode locking frequency match with the corresponding resonator lengths, it is possible to read the multiple partially reflecting segments along the sensing fiber. The difference between two corresponding mode locking frequencies is changing proportionally with the segment length variation between two PRs upon strain application. The segment length change caused by the applied strain can be successfully measured with a linear sensitivity between mode locking frequency and displacement, linearity over 0.99, and spatial position resolution below meter order. PMID- 30477261 TI - Contact-Hardening Behavior of Calcium Silicate Hydrate Powders. AB - Calcium silicate hydrate (C-S-H) synthesized by a hydrothermal process from lime and siliceous materials was oven-dried and compressed into compacts. The microstructure and compaction properties of the resulting powders were characterized. The results show that the powders containing an amorphous structure become hardened compacts immediately after compression. Compacts with high strength but a relatively lower bulk density were produced. Amorphous C-S-H plays a key role in the bonding formation during powder compaction. According to the Heckel plots, particle rearrangement and plastic deformation were involved in the compaction of C-S-H powders. Point contact between C-S-H particles due to particle rearrangement dominates at a low compression pressure (i.e., <20 MPa). Van der Waals forces and hydrogen bonding are the main bonding types. Plastic deformation occurs at a higher compression pressure (i.e., >60 MPa), which results in surface contact. Consequently, a solid bridge forms, and the strength of compacts increases rapidly. These findings provide novel insight into the utilization of materials containing amorphous calcium silicate hydrate. PMID- 30477262 TI - Respiratory Symptoms in Relation to Living near a Crude Oil First Treatment Plant in Italy: A Cross-Sectional Study. AB - Exposure to air pollution has been shown to increase the risk of developing chronic respiratory diseases. The largest crude oil first treatment plant in Italy emits harmful polluting substances. This cross-sectional study assesses the occurrence of respiratory symptoms in a sample of the adult population living near the plant. A proximal and a reference area were defined in order to recruit 200 subjects. Each subject performed a spirometry test and completed a questionnaire. Associations between the distance from the plant and selected respiratory outcomes were assessed (distance-based approach). The prevalence of outcomes between a proximal and a reference area (area-based approach) were also compared. Odds ratios were adjusted for potential confounders. Living near the plant was associated with a higher prevalence of respiratory symptoms, with significant associations for severe dyspnoea equivalent to the halving of risk as the distance of residence from the plant increased by 1 km (adjusted odds ratio (OR) 0.48, confidence interval at the 95% probability level (95% CI): 0.25-0.92). Several signals emerged for respiratory allergic symptoms. The area-based approach generally confirmed the results obtained with the distance-based approach. This is the first study to be carried out on a crude oil first treatment plant aimed at assessing the association with the occurrence of respiratory symptoms. These findings contribute to the evidence supporting the need for a space-time surveillance system in the investigated area. PMID- 30477263 TI - Degradation of Paracetamol by an UV/Chlorine Advanced Oxidation Process: Influencing Factors, Factorial Design, and Intermediates Identification. AB - The combination of a low-pressure mercury lamp and chlorine (UV/chlorine) was applied as an emerging advanced oxidation process (AOP), to examine paracetamol (PRC) degradation under different operational conditions. The results indicated that the UV/chlorine process exhibited a much faster PRC removal than the UV/H2O2 process or chlorination alone because of the great contribution of highly reactive species (*OH, *Cl, and ClO*). The PRC degradation rate constant (kobs) was accurately determined by pseudo-first-order kinetics. The kobs values were strongly affected by the operational conditions, such as chlorine dosage, solution pH, UV intensity, and coexisting natural organic matter. Response surface methodology was used for the optimization of four independent variables (NaOCl, UV, pH, and DOM). A mathematical model was established to predict and optimize the operational conditions for PRC removal in the UV/chlorine process. The main transformation products (twenty compound structures) were detected by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). PMID- 30477264 TI - Nitrogen-Fixing Bacteria Associated with Peltigera Cyanolichens and Cladonia Chlorolichens. AB - Lichens have been extensively studied and described; however, recent evidence suggests that members of the bacterial community associated with them could contribute new functions to the symbiotic interaction. In this work, we compare the nitrogen-fixing guild associated with bipartite terricolous lichens with different types of photobiont: Peltigera cyanolichens and Cladonia chlorolichens. Since cyanobacteria contribute nitrogen to the symbiosis, we propose that chlorolichens have more diverse bacteria with the ability to fix nitrogen compared to cyanolichens. In addition, since part of these bacteria could be recruited from the substrate where lichens grow, we propose that thalli and substrates share some bacteria in common. The structure of the nitrogen-fixing guild in the lichen and substrate bacterial communities of both lichens was determined by terminal restriction fragment length polymorphism (TRFLP) of the nifH gene. Multivariate analyses showed that the nitrogen-fixing bacteria associated with both types of lichen were distinguishable from those present in their substrates. Likewise, the structure of the nitrogen-fixing bacteria present in the cyanolichens was different from that of chlorolichens. Finally, the diversity of this bacterial guild calculated using the Shannon index confirms the hypothesis that chlorolichens have a higher diversity of nitrogen-fixing bacteria than cyanolichens. PMID- 30477265 TI - Electrospun Alginate Fibers: Mixing of Two Different Poly(ethylene oxide) Grades to Improve Fiber Functional Properties. AB - The aim of the present work was to investigate how the molecular weight (MW) of poly(ethylene oxide) (PEO), a synthetic polymer able to improve alginate (ALG) electrospinnability, could affect ALG-based fiber morphology and mechanical properties. Two PEO grades, having different MWs (high, h-PEO, and low, l-PEO) were blended with ALG: the concentrations of both PEOs in each mixture were defined so that each h-PEO/l-PEO combination would show the same viscosity at high shear rate. Seven ALG/h-PEO/l-PEO mixtures were prepared and characterized in terms of viscoelasticity and conductivity and, for each mixture, a complex parameter rH/rL was calculated to better identify which of the two PEO grades prevails over the other in terms of exceeding the critical entanglement concentration. Thereafter, each mixture was electrospun by varying the process parameters; the fiber morphology and mechanical properties were evaluated. Finally, viscoelastic measurements were performed to verify the formation of intermolecular hydrogen bonds between the two PEO grades and ALG. rH/rL has been proved to be the parameter that better explains the effect of the electrospinning conditions on fiber dimension. The addition of a small amount of h-PEO to l-PEO was responsible for a significant increase in fiber mechanical resistance, without affecting the nano-scale fiber size. Moreover, the mixing of h-PEO and l PEO improved the interaction with ALG, resulting in an increase in chain entanglement degree that is functional in the electrospinning process. PMID- 30477266 TI - Identification of Maize Kernel Vigor under Different Accelerated Aging Times Using Hyperspectral Imaging. AB - Seed aging during storage is irreversible, and a rapid, accurate detection method for seed vigor detection during seed aging is of great importance for seed companies and farmers. In this study, an artificial accelerated aging treatment was used to simulate the maize kernel aging process, and hyperspectral imaging at the spectral range of 874-1734 nm was applied as a rapid and accurate technique to identify seed vigor under different accelerated aging time regimes. Hyperspectral images of two varieties of maize processed with eight different aging duration times (0, 12, 24, 36, 48, 72, 96 and 120 h) were acquired. Principal component analysis (PCA) was used to conduct a qualitative analysis on maize kernels under different accelerated aging time conditions. Second-order derivatization was applied to select characteristic wavelengths. Classification models (support vector machine-SVM) based on full spectra and optimal wavelengths were built. The results showed that misclassification in unprocessed maize kernels was rare, while some misclassification occurred in maize kernels after the short aging times of 12 and 24 h. On the whole, classification accuracies of maize kernels after relatively short aging times (0, 12 and 24 h) were higher, ranging from 61% to 100%. Maize kernels with longer aging time (36, 48, 72, 96, 120 h) had lower classification accuracies. According to the results of confusion matrixes of SVM models, the eight categories of each maize variety could be divided into three groups: Group 1 (0 h), Group 2 (12 and 24 h) and Group 3 (36, 48, 72, 96, 120 h). Maize kernels from different categories within one group were more likely to be misclassified with each other, and maize kernels within different groups had fewer misclassified samples. Germination test was conducted to verify the classification models, the results showed that the significant differences of maize kernel vigor revealed by standard germination tests generally matched with the classification accuracies of the SVM models. Hyperspectral imaging analysis for two varieties of maize kernels showed similar results, indicating the possibility of using hyperspectral imaging technique combined with chemometric methods to evaluate seed vigor and seed aging degree. PMID- 30477267 TI - Optimization of County-Level Land Resource Allocation through the Improvement of Allocation Efficiency from the Perspective of Sustainable Development. AB - Land resources provide stable support for economic development in China. However, due to the scarcity of land, the contradiction between agricultural land protection and construction land expansion is prominent. Under such circumstances, optimal allocation of land resources between agricultural and nonagricultural uses is vitally important. In view of the fact that land resources are indispensable inputs for production activities in agricultural and nonagricultural sectors, reducing the efficiency loss of land resource allocation between agricultural and nonagricultural uses is the only way to optimize the process. Counties are the basic administrative units in China, and their improvement of allocation efficiency will help optimize nationwide land resource allocation. This paper constructs models for estimating county-level land resource allocation efficiency from the perspective of sustainable development and searches for countermeasures to improve allocation efficiency. W County is used as an example to demonstrate how to choose these targeted countermeasures. It is concluded that the best way to optimize county-level land resource allocation between agricultural and nonagricultural uses can be found by estimating allocation efficiency from the perspective of sustainable development. PMID- 30477268 TI - Anti-Inflammatory Activity of Populus deltoides Leaf Extract via Modulating NF kappaB and p38/JNK Pathways. AB - Populus deltoides, known as eastern cottonwood, has been commonly used as a medicinal plant. The aim of the present study was to investigate the mechanism underlying the anti-inflammatory activity of P. deltoides leaf extract (PLE). PLE effectively inhibited the expression of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells, but not that of cyclooxygenase-2 (COX-2) and prostaglandin E2. Proinflammatory tumor necrosis factor alpha (TNF-alpha) levels were also reduced by the extract. PLE inhibited the phosphorylation of nuclear factor-kappa B (NF kappaB) and inhibitor of Kappa Balpha (IkappaBalpha), and blunted LPS-triggered enhanced nuclear translocation of NF-kappaB p65. In mitogen-activated protein kinase (MAPK) signaling, PLE effectively decreased the phosphorylation of p38 and c-Jun N-terminal protein kinase (JNK), but not of extracellular signal-regulated kinase 1/2 (ERK1/2). Taken together, these results suggest that anti-inflammatory activity of P. deltoides leaf extract might be driven by iNOS and NO inhibition mediated by modulation of the NF-kappaB and p38/JNK signaling pathways. PMID- 30477269 TI - A Thioredoxin Domain-Containing Protein Interacts with Pepino mosaic virus Triple Gene Block Protein 1. AB - Pepino mosaic virus (PepMV) is a mechanically-transmitted tomato pathogen of importance worldwide. Interactions between the PepMV coat protein and triple gene block protein (TGBp1) with the host heat shock cognate protein 70 and catalase 1 (CAT1), respectively, have been previously reported by our lab. In this study, a novel tomato interactor (SlTXND9) was shown to bind the PepMV TGBp1 in yeast-two hybrid screening, in vitro pull-down and bimolecular fluorescent complementation (BiFC) assays. SlTXND9 possesses part of the conserved thioredoxin (TRX) active site sequence (W__PC vs. WCXPC), and TXND9 orthologues cluster within the TRX phylogenetic superfamily closest to phosducin-like protein-3. In PepMV-infected and healthy Nicotiana benthamiana plants, NbTXND9 mRNA levels were comparable, and expression levels remained stable in both local and systemic leaves for 10 days post inoculation (dpi), as was also the case for catalase 1 (CAT1). To localize the TXND9 in plant cells, a polyclonal antiserum was produced. Purified alpha-SlTXND9 immunoglobulin (IgG) consistently detected a set of three protein bands in the range of 27-35 kDa, in the 1000 and 30,000 g pellets, and the soluble fraction of extracts of healthy and PepMV-infected N. benthamiana leaves, but not in the cell wall. These bands likely consist of the homologous protein NbTXND9 and its post-translationally modified derivatives. On electron microscopy, immuno-gold labelling of ultrathin sections of PepMV-infected N. benthamiana leaves using alpha-SlTXND9 IgG revealed particle accumulation close to plasmodesmata, suggesting a role in virus movement. Taken together, this study highlights a novel tomato-PepMV protein interaction and provides data on its localization in planta. Currently, studies focusing on the biological function of this interaction during PepMV infection are in progress. PMID- 30477270 TI - Elastomeric Polyurethane Foams Incorporated with Nanosized Hydroxyapatite Fillers for Plastic Reconstruction. AB - Plastic surgeons have long searched for the ideal materials to use in craniomaxillofacial reconstruction. The aim of this study was to obtain a novel porous elastomer based on designed aliphatic polyurethane (PU) and nanosized hydroxyapatite (n-HA) fillers for plastic reconstruction. The physicochemical properties of the prepared composite elastomer were characterized by infrared spectroscopy (IR), X-ray diffraction (XRD), scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX), transmission electron microscopy (TEM), thermal analysis, mechanical tests, and X-ray photoelectron spectroscopy (XPS). The results assessed by the dynamic mechanical analysis (DMA) demonstrated that the n-HA/PU compounded foams had a good elasticity, flexibility, and supporting strength. The homogenous dispersion of the n-HA fillers could be observed throughout the cross-linked PU matrix. The porous elastomer also showed a uniform pore structure and a resilience to hold against general press and tensile stress. In addition, the elastomeric foams showed no evidence of cytotoxicity and exhibited the ability to enhance cell proliferation and attachment when evaluated using rat-bone-marrow-derived mesenchymal stem cells (BMSCs). The animal experiments indicated that the porous elastomers could form a good integration with bone tissue. The presence of n-HA fillers promoted cell infiltration and tissue regeneration. The elastomeric and bioactive n-HA/PU composite foam could be a good candidate for future plastic reconstruction. PMID- 30477271 TI - TfOH-Promoted Reaction of 2,4-Diaryl-1,1,1-Trifluorobut-3-yn-2-oles with Arenes: Synthesis of 1,3-Diaryl-1-CF3-Indenes and Versatility of the Reaction Mechanisms. AB - The TfOH-mediated reactions of 2,4-diaryl-1,1,1-trifluorobut-3-yn-2-oles (CF3 substituted diaryl propargyl alcohols) with arenes in CH2Cl2 afford 1,3-diaryl-1 CF3-indenes in yields up to 84%. This new process for synthesis of such CF3 indenes is complete at room temperature within one hour. The synthetic potential, scope, and limitations of this reaction were illustrated by more than 70 examples. The proposed reaction mechanism invokes the formation of highly reactive CF3-propargyl cation intermediates that can be trapped at the two mesomeric positions by the intermolecular nucleophilic attack of an arene partner with a subsequent intramolecular ring closure. PMID- 30477272 TI - Mapping Multi-Disease Risk during El Nino: An Ecosyndemic Approach. AB - El Nino is a quasi-periodic pattern of climate variability and extremes often associated with hazards and disease. While El Nino links to individual diseases have been examined, less is known about the cluster of multi-disease risk referred to as an ecosyndemic, which emerges during extreme events. The objective of this study was to explore a mapping approach to represent the spatial distribution of ecosyndemics in Piura, Peru at the district-level during the first few months of 1998. Using geographic information systems and multivariate analysis, descriptive and analytical methodologies were employed to map disease overlap of 7 climate-sensitive diseases and construct an ecosyndemic index, which was then mapped and applied to another El Nino period as proof of concept. The main findings showed that many districts across Piura faced multi-disease risk over several weeks in the austral summer of 1998. The distribution of ecosyndemics were spatially clustered in western Piura among 11 districts. Furthermore, the ecosydemic index in 1998 when compared to 1983 showed a strong positive correlation, demonstrating the potential utility of the index. The study supports PAHO efforts to develop multi-disease based and interprogrammatic approaches to control and prevention, particularly for climate and poverty related infections in Latin America and the Caribbean. PMID- 30477273 TI - Satisfaction of Physicians Working in Polish Hospitals-A Cross-Sectional Study. AB - Physician satisfaction is a multidimensional concept associated with numerous factors. The objectives of the study were to evaluate the satisfaction of physicians practicing in hospitals in Poland and to identify factors associated with higher levels of satisfaction. A quantitative, cross-sectional survey of Polish hospitals was conducted between March and June 2018. All doctors working in the hospitals invited to the study were asked to fill in an online survey. Fifteen hospitals were included: seven general, five specialist, and three university ones. The total number of questionnaires analyzed was 1003. The questionnaire included 17 items to measure the level of satisfaction, classified into four dimensions: personal, professional, performance, and inherent. The statistical analyses included: assessment of association between levels of career satisfaction and basic demographic and work-related variables; and multivariable logistic regressions, conducted to determine which variables were associated with higher levels of career satisfaction. The mean level of career satisfaction, on a scale from 1 to 6, was 4.1 (SD = 0.69). Respondents reported high levels of inherent satisfaction: mean = 4.4 (SD = 0.66) and a low personal satisfaction: mean = 3.78 (SD = 0.98). 56.6% of respondents reported being satisfied, but only 8.2% reported a higher level of satisfaction (>=5). The satisfaction of Polish physicians is moderate. Gender, numbers of working hours/week, years of work experience, type of hospital, and stage of professional development were the identified factors associated with higher levels of career satisfaction. PMID- 30477274 TI - Correlation between the Microstructures of Bonding Interfaces and the Shear Strength of Cu-to-Cu Joints Using (111)-Oriented and Nanotwinned Cu. AB - Highly (111)-oriented Cu pillar-bumps were bonded to highly (111)-oriented Cu films at temperatures ranging from 200 degrees C/100 degrees C to 350 degrees C/100 degrees C in N2 ambient conditions. The microstructures of the bonded interfaces affected the shear strength performance of the bonded Cu joints. The bonded interfaces at 300 degrees C/100 degrees C and 350 degrees C/100 degrees C had far fewer voids than interfaces bonded at 200 degrees C/100 degrees C and 250 degrees C/100 degrees C. In addition, grain growth took place across the bonding interfaces at temperatures above 300 degrees C/100 degrees C. The corresponding orientation map (OIM) showed the preferred orientation of large grown grains to be <100>. Shear tests revealed that the fracture mode was brittle for joints bonded at 200 degrees C/100 degrees C, but became ductile after bonded above 300 degrees C/100 degrees C. Based on the results, we found that voids and grain growth behavior play import roles in the shear strength performance of bonded Cu joints. PMID- 30477275 TI - Use of Red Wine Polyphenols as a Natural Preservative in Health-Promoting Omega-3 Fatty Acids-Enriched Lamb Patties. AB - Meat consumption has been related to a higher risk of heart disease due to its saturated fat content. As a consequence, there has been a growth in research on how to increase unsaturated fat content in meat. However, a high content of unsaturated fat favours the development of oxidative processes. The aim of the study was to evaluate the effectiveness of a red wine extract (RWE) rich in polyphenols (50, 100, and 200 mg gallic acid equivalents/kg meat) as a natural antioxidant in lamb meat patties enriched with omega-3 polyunsaturated fatty acids (n-3 PUFA) (100 mg n-3 PUFA/100 g meat), compared to using -tocopherol (TOC) (100 mg/kg meat). Adding RWE delayed metmyoglobin formation, lipid oxidation and loss of n-3 PUFA relative to controls, while TOC had no effect on preventing meat oxidation. Lamb odour was lower (p < 0.01) and odd odour higher (p < 0.001) in patties at the highest dose of RWE, compared to controls, but the overall liking score was not affected. The results suggest that RWE could be used as a natural antioxidant in the meat industry, even when n-3 PUFA content is high. PMID- 30477276 TI - Association between 25-Hydroxyvitamin D Status and Components of Body Composition and Glucose Metabolism in Older Men and Women. AB - Obesity and sarcopenia are major causes of morbidity and mortality among seniors. Vitamin D deficiency is very common especially among seniors and has been associated with both muscle health and obesity. This study investigated if 25 hydroxyvitamin D (25(OH)D) status is associated with body composition and insulin resistance using baseline data of a completed RCT among relatively healthy community-dwelling seniors (271 seniors age 60+ years undergoing elective surgery for unilateral total knee replacement due to osteoarthritis). Cross-sectional analysis compared appendicular lean mass index (ALMI: lean mass kg/height m2) and fat mass index (FMI: fat mass kg/height m2) assessed by DXA and insulin resistance between quartiles of serum 25(OH)D concentration using multivariable linear regression adjusted for age, sex, smoking status, physical activity, and body mass index (BMI). Participants in the lowest serum 25(OH)D quartile (4.7 17.5 ng/mL) had a higher fat mass (9.3 kg/m2) compared with participants in the third (8.40 kg/m2; Q3 = 26.1-34.8 ng/mL) and highest (8.37 kg/m2; Q4 = 34.9-62.5 ng/mL) quartile (poverall = 0.03). Higher serum 25(OH)D quartile status was associated with higher insulin sensitivity (poverall = 0.03) and better beta cell function (p = 0.004). Prevalence of insulin resistance tended to be higher in the second compared with the highest serum 25(OH)D quartile (14.6% vs. 4.8%, p = 0.06). Our findings suggest that lower serum 25(OH)D status may be associated with greater fat mass and impaired glucose metabolism, independent of BMI and other risk factors for diabetes. PMID- 30477277 TI - A Parallel Architecture for the Partitioning Around Medoids (PAM) Algorithm for Scalable Multi-Core Processor Implementation with Applications in Healthcare. AB - Clustering is the most common method for organizing unlabeled data into its natural groups (called clusters), based on similarity (in some sense or another) among data objects. The Partitioning Around Medoids (PAM) algorithm belongs to the partitioning-based methods of clustering widely used for objects categorization, image analysis, bioinformatics and data compression, but due to its high time complexity, the PAM algorithm cannot be used with large datasets or in any embedded or real-time application. In this work, we propose a simple and scalable parallel architecture for the PAM algorithm to reduce its running time. This architecture can easily be implemented either on a multi-core processor system to deal with big data or on a reconfigurable hardware platform, such as FPGA and MPSoCs, which makes it suitable for real-time clustering applications. Our proposed model partitions data equally among multiple processing cores. Each core executes the same sequence of tasks simultaneously on its respective data subset and shares intermediate results with other cores to produce results. Experiments show that the computational complexity of the PAM algorithm is reduced exponentially as we increase the number of cores working in parallel. It is also observed that the speedup graph of our proposed model becomes more linear with the increase in number of data points and as the clusters become more uniform. The results also demonstrate that the proposed architecture produces the same results as the actual PAM algorithm, but with reduced computational complexity. PMID- 30477278 TI - G Proteins and GPCRs in C. elegans Development: A Story of Mutual Infidelity. AB - Many vital processes during C. elegans development, especially the establishment and maintenance of cell polarity in embryogenesis, are controlled by complex signaling pathways. G protein-coupled receptors (GPCRs), such as the four Frizzled family Wnt receptors, are linchpins in regulating and orchestrating several of these mechanisms. However, despite being GPCRs, which usually couple to G proteins, these receptors do not seem to activate classical heterotrimeric G protein-mediated signaling cascades. The view on signaling during embryogenesis is further complicated by the fact that heterotrimeric G proteins do play essential roles in cell polarity during embryogenesis, but their activity is modulated in a predominantly GPCR-independent manner via G protein regulators such as GEFs GAPs and GDIs. Further, the triggered downstream effectors are not typical. Only very few GPCR-dependent and G protein-mediated signaling pathways have been unambiguously defined in this context. This unusual and highly intriguing concept of separating GPCR function and G-protein activity, which is not restricted to embryogenesis in C. elegans but can also be found in other organisms, allows for essential and multi-faceted ways of regulating cellular communication and response. Although its relevance cannot be debated, its impact is still poorly discussed, and C. elegans is an ideal model to understand the underlying principles. PMID- 30477279 TI - Characterization of MgCl2.6H2O-Based Eutectic/Expanded Perlite Composite Phase Change Material with Low Thermal Conductivity. AB - The melting points of the phase change materials (PCMs) incorporated into the walls of buildings should be within the human thermal comfort temperature range. In this paper, 15 wt.% of MgCl2.6H2O was mixed with CaCl2.6H2O to obtain the eutectic with a melting point of 23.9 degrees C. SrCl2.6H2O suppresses the supecooling of the eutectic. The combination with expanded perlite (EP) via the impregnation method overcomes the phase separation and liquid leakage of the CaCl2?6H2O-MgCl2?6H2O mixture. The composite PCM is form-stable with the maximum loading mass fraction up to 50 wt.% and latent heat of 73.55 J/g. EP also significantly reduces the thermal conductivity of the CaCl2?6H2O-MgCl2?6H2O from 0.732 to 0.144 W/(m.K). The heating-cooling cycling test reveals that the composite PCM is thermally stable. The cheap eutectic salt hydrate, with little supercooling, no phase separation and liquid leakage, low thermal conductivity and good thermal reliability, show great potential as envelope materials to save energy consumption in buildings. PMID- 30477280 TI - Dissecting the Immune Landscape of Acute Myeloid Leukemia. AB - Acute myeloid leukemia (AML) is a molecularly heterogeneous hematological malignancy with variable response to treatment. Recurring cytogenetic abnormalities and molecular lesions identify AML patient subgroups with different survival probabilities; however, 50-70% of AML cases harbor either normal or risk indeterminate karyotypes. The discovery of better biomarkers of clinical success and failure is therefore necessary to inform tailored therapeutic decisions. Harnessing the immune system against cancer with programmed death-1 (PD-1) directed immune checkpoint blockade (ICB) and other immunotherapy agents is an effective therapeutic option for several advanced malignancies. However, durable responses have been observed in only a minority of patients, highlighting the need to gain insights into the molecular features that predict response and to also develop more effective and rational combination therapies that address mechanisms of immune evasion and resistance. We will review the state of knowledge of the immune landscape of AML and identify the broad opportunity to further explore this incompletely characterized space. Multiplexed, spatially resolved immunohistochemistry, flow cytometry/mass cytometry, proteomic and transcriptomic approaches are advancing our understanding of the complexity of AML-immune interactions and are expected to support the design and expedite the delivery of personalized immunotherapy clinical trials. PMID- 30477281 TI - Geographical Variation in Oral and Oropharynx Cancer Mortality in Brazil: A Bayesian Approach. AB - Recent studies have shown a high number of deaths from oral and oropharyngeal cancer worldwide, Brazil included. For this study, the deaths data (ICD-10, chapter II, categories C00 to C14) was obtained from Mortality Information System (SIM) and standardized by gender and population for each of the 554 Microregions of Brazil. The raw mortality rates were adopted as the standard and compared to the application of smoothing by the Bayesian model. In order to describe the geographical pattern of the occurrence of oral cancer, thematic maps were constructed, based on the distributions of mortality rates for Microregions and gender. Results: There were 7882 deaths registered due to oral and oropharyngeal cancer in Brazil, of which 6291 (79.81%) were male and 1591 (20.19%) female. The Empirical Bayesian Model presented greater scattering with mosaic appearance throughout the country, depicting high rates in Southeast and South regions interpolated with geographic voids of low rates in Midwest and North regions. For males, it was possible to identify expressive clusters in the Southeast and South regions. Conclusion: The Empirical Bayesian Model allowed an alternative interpretation of the oral and oropharynx cancer mortality mapping in Brazil. PMID- 30477282 TI - Raman Spectroscopic Analysis to Detect Reduced Bone Quality after Sciatic Neurectomy in Mice. AB - Bone mineral density (BMD) is a commonly used diagnostic indicator for bone fracture risk in osteoporosis. Along with low BMD, bone fragility accounts for reduced bone quality in addition to low BMD, but there is no diagnostic method to directly assess the bone quality. In this study, we investigated changes in bone quality using the Raman spectroscopic technique. Sciatic neurectomy (NX) was performed in male C57/BL6J mice (NX group) as a model of disuse osteoporosis, and sham surgery was used as an experimental control (Sham group). Eight months after surgery, we acquired Raman spectral data from the anterior cortical surface of the proximal tibia. We also performed a BMD measurement and micro-CT measurement to investigate the pathogenesis of osteoporosis. Quantitative analysis based on the Raman peak intensities showed that the carbonate/phosphate ratio and the mineral/matrix ratio were significantly higher in the NX group than in the Sham group. There was direct evidence of alterations in the mineral content associated with mechanical properties of bone. To fully understand the spectral changes, we performed principal component analysis of the spectral dataset, focusing on the matrix content. In conclusion, Raman spectroscopy provides reliable information on chemical changes in both mineral and matrix contents, and it also identifies possible mechanisms of disuse osteoporosis. PMID- 30477283 TI - The effect of vitamin D administration on inflammatory markers in patients with inflammatory bowel disease. AB - Background/Aims: The exact relationship between vitamin D deficiency and inflammatory bowel disease (IBD) remains unclear. We evaluated the effect of vitamin D3 administration on inflammatory responses and disease severity in patients with IBD. Methods: We investigated the serum 25-hydroxyvitamin D3 [25 (OH)D] and C-reactive protein (CRP) levels and the partial Mayo score (PMS) in patients with IBD. Vitamin D3 was administered in patients with either vitamin D deficiency or insufficiency and CRP serum vitamin D levels and PMS were re examined at 6 months of administration. Results: In 88 patients with Crohn's disease (CD), a negative correlation was found between serum vitamin D and CRP. In 178 patients with ulcerative colitis (UC), serum vitamin D showed no association with CRP or PMS. Serum vitamin D increased from 11.08+/-3.63 to 22.69+/-6.11 ng/mL in 29 patients with CD and from 11.45+/-4.10 to 24.20+/-6.61 ng/mL in 41 patients with UC who received vitamin D3 treatment (P<0.001 and P<0.001, respectively). In patients with CD, median DeltaCRP was -0.24 in the normalized vitamin D group and -0.11 in the non-normalized group (P=0.308). In patients with UC, median DeltaCRP was -0.01 in the normalized vitamin D group and 0.06 in the non-normalized group (P=0.359). Conclusions: Although a negative correlation was found between serum vitamin D and CRP levels in patients with CD, administration of vitamin D did not improve the CRP level in patients with CD. In patients with UC, serum vitamin D level was unrelated to CRP or PMS. PMID- 30477284 TI - Efficacy and safety of cold forceps polypectomy utilizing the jumbo cup: a prospective study. AB - Background/Aims: There are few prospective studies on cold forceps polypectomy (CFP) using jumbo cup forceps. Therefore, we examined patients with diminutive polyps (5 mm or smaller) treated with CFP using jumbo cup forceps to achieve an adenoma-free colon and also assessed the safety of the procedure and the recurrence rate of missed or residual polyp after CFP by performing follow-up colonoscopy 1 year later. Methods: We included patients with up to 5 adenomas removed at initial colonoscopy and analyzed data from a total of 361 patients with 573 adenomas. One-year follow-up colonoscopy was performed in 165 patients, at which 251 lesions were confirmed. Results: The one-bite resection rate with CFP was highest for lesions 3 mm or smaller and decreased significantly with increasing lesion size. Post-procedural hemorrhage was observed in 1 of 573 lesions (0.17%). No perforation was noted. The definite recurrence rate was 0.8% (2/251 lesions). The probable recurrence rate, which was defined as recurrence in the same colorectal segment, was 17%. Adenoma-free colon was achieved in 55% of patients at initial resection. Multivariate analysis revealed that achievement of an adenoma-free colon was significantly associated with number of adenomas and years of endoscopic experience. Conclusions: CFP using jumbo biopsy forceps was safe and showed a high one-bite resection rate for diminutive lesions of 3 mm or smaller. The low definite recurrence rate confirms the reliability of CFP using jumbo biopsy forceps. Number of adenomas and years of endoscopic experience were key factors in achieving an adenoma-free colon. PMID- 30477285 TI - De novo mutations in COL4A5 identified by whole exome sequencing in two girls with Alport syndrome in Korea. AB - Alport syndrome (ATS) is an inherited glomerular disease caused by mutations in one of the type IV collagen novel chains (alpha3, alpha4, and alpha5). ATS is characterized by persistent microscopic hematuria starting from infancy, eventually leading to either progressive nephritis or end-stage renal disease. There are three known genetic forms of ATS, i.e., X-linked ATS, autosomal recessive ATS, and autosomal dominant ATS. About 80% of patients with ATS have X linked ATS, caused by mutations in the type IV collagen alpha5 chain gene, COL4A5. Mutation detection rates are about 80% in males with X-linked ATS, however, there are some difficulties in the genetic diagnosis of ATS. Most mutations are point mutations without hot spots in the COL4A3, COL4A4, and COL4A5 genes. Further, there is insufficient data on COL4A3 and COL4A4 mutation detection for the mutations to be compared between patients with either autosomal recessive or dominant ATS. Therefore, diagnosis can be a challenge from a clinical perspective in female patients with ATS with no apparent family history. Therefore, in this study, we used whole-exome sequencing (WES) to identify mutations in type IV collagen in two girls with suspicious glomerular basement membrane structural changes associated with ATS, but no relevant family history. Our results revealed de novo c.4688G>A (p.Arg1563Gln) and c.2714G>A (p.Gly905Asp) mutations in COL4A5. We therefore suggest that WES is an effective approach to obtain genetic information in ATS, particularly in female patients without a relevant family history, to detect unexpected DNA variations. PMID- 30477286 TI - Serum alanine aminotransferase levels are closely associated with metabolic disturbances in apparently healthy young adolescents independent of obesity. AB - Purpose: Liver metabolism plays a pivotal role in the development of metabolic disorders. We aimed to investigate the clinical and laboratory risk factors associated with alanine aminotransferase (ALT) levels in young adolescents from an urban population in Korea. Methods: A population of 120 apparently healthy adolescents aged 12-13 years was included in the cross-sectional design study; 58 were overweight or obese and 62 were of normal weight. We estimated anthropometric and laboratory measurements, including waist-to-height ratio, blood pressure, insulin sensitivity, aspartate and alanine aminotransferases (AST and ALT), and lipid profiles. Results: The mean ages of the overweight or obese and normal weight participants were 12.9 +/- 0.3 and 13.0 +/- 0.3 years, respectively. Height, weight, body mass index, waist circumference, waist-to height ratio, systolic and diastolic blood pressure, AST/ALT, total cholesterol, low-density lipoprotein-cholesterol, triglyceride, insulin, and the homeostatic model assessment of insulin resistance (HOMA-IR) score were significantly higher and the high-density lipoprotein-cholesterol and quantitative insulin-sensitivity check index were significantly lower in the overweight/obese participants in comparison to the normal-weight participants (all P<0.05). In multivariate linear regression analysis, waist-to-height ratio, systolic blood pressure, and HOMA-IR score were independently and positively associated with serum ALT levels. Conclusion: Screening for ALT levels in adolescents may help to differentiate those at risk of metabolic abnormalities and thus prevent disease progression at an early age. PMID- 30477287 TI - A Single Arm, Phase II Study of Simvastatin Plus XELOX and Bevacizumab as First Line Chemotherapy in Metastatic Colorectal Cancer Patients. AB - Purpose: Simvastatin has demonstrated anti-tumor activity in preclinical studies via tumor cell senescence, apoptosis, and anti-angiogenesis. This phase II trial evaluated the efficacy and toxicity profile of conventional XELOX and bevacizumab chemotherapy plus simvastatin in metastatic colorectal cancer patients (MCRC). Materials and Methods: Patients with MCRC received first-line XELOX in 3-week treatment cycles of intravenous oxaliplatin 130 mg/m2 plus bevacizumab 7.5 mg/kg (day 1), followed by oral capecitabine 1,000 mg/m2 twice daily (day 1-14). Simvastatin 80 mg tablets were taken orally once daily every day during the period of chemotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, duration of response, overall survival (OS), time to progression, and toxicity. Results: From January 2014 to April 2015, 60 patients were enrolled and 55 patients were evaluable for tumor response. The median follow-up duration was 30.1 months (range, 28.5 to 31.7 months). The median PFS was 10.4 months (95% confidence interval [CI], 9.6 to 11.1). The median OS of all patients was 19.0 months (95% CI, 11.9 to 26.0). The disease-control rate and overall response rate were 88.3% (95% CI, 74 to 96) and 58.3% (95% CI, 44 to 77), respectively, by intent-to-treat protocol analysis. There was 1 complete response and 34 partial responses. One patient experienced grade 3 creatine kinase elevation and liver enzyme elevation. Conclusion: Based on the current study, the addition of 80mg simvastatin to XELOX and bevacizumab showed comparable clinical efficacy in patients with MCRC as first-line chemotherapy and did not increase toxicity. PMID- 30477288 TI - Backgrounding steers on temperate grasses mixed with vetch and/or using energy supplementation. AB - Objectves: The aim was to evaluate backgrounding beef steers on oat + ryegrass pastures mixed with vetch and/or using energy supplementation. Methods: A randomized block design with three treatments and three replications was used. The treatments were: grass+supplement (oat + ryegrass + supplementation), legume+supplement (oat + ryegrass + vetch + supplementation) and grass+legume (oat + ryegrass + vetch). A continuous grazing system with a variable stocking rate was used. Twenty-seven intact crossbred steers (1/4 Marchigiana, 1/4 Aberdeen Angus and 2/4 Nellore) with 7 months old and average weight of 190 kg were used. Steers were supplemented at 1% of the body weight of ground corn. The experiment lasted 84 days, between May and August 2014. Behavioral assessments were performed two times per experimental period, for 24 hours. Conclusion: Feeding behavior was not altered by mixed with vetch or supplementation. Non supplemented animals started the grazing peak earlier and spent more time in grazing than those supplemented; however, the average daily gain was similar between treatments. The live weight gain per hectare was 47% higher in pastures in which the animals received supplementation compared with those mixed with vetch, a consequence of the substitutive effect. PMID- 30477289 TI - Changes in microbial population and chemical composition of corn stover during field exposure and their evaluation on silage fermentation and in vitro digestibility. AB - Objectve: To effectively use corn stover as animal feed, we studied the changes in microbial population and chemical composition of three cultivar corn stover during field exposure and their effects on silage fermentation and in vitro digestibility. Methods: The corn stover silages were prepared from stovers exposed in the field for 0, 7, 15, 30, 60, 90, and 180 d. The microbial composition, chemical composition, fermentation quality, and in vitro digestibility were analyzed. Results: Aerobic bacteria were dominant population in fresh corn stover. After ensiling, the natural lactic acid bacteria (LAB) became the dominant bacteria, while other microbes decreased or dropped below the detection level. The crude protein and water-soluble carbohydrate content in stover decreased greatly during exposure. Fresh stover had a relatively low moisture content, high water-soluble carbohydrate content, and LAB counts, and their silage was preserved well, but the dry stover did not. Silage fermentation not only inhibited nutrient loss, but also improved the fermentation quality and in vitro digestibility. Conclusion: The results confirm that fresh corn stover has good ensiling characteristics and that silage can prepare as good of quality. PMID- 30477290 TI - Essential oil mixture on rumen fermentation and microbial community - an in vitro study. AB - Objectve: The objective of this study was to investigate the effects of essential oil mixture (EOM) supplementation on rumen fermentation characteristics and microbial changes in an in vitro. Methods: Three experimental treatments were used: control (CON, no additive), EOM 0.1 (supplementation of 1 g EOM/kg of substrate), and EOM 0.2 (supplementation of 2 g EOM/kg of substrate). An in vitro fermentation experiment was carried out using strained rumen fluid for 12 and 24 h incubation periods. At each time point, in vitro dry matter digestibility (IVDMD), neutral detergent fiber digestibility (IVNDFD), pH, ammonia nitrogen (NH3-N) and volatile fatty acid (VFA) concentrations, and relative microbial diversity were estimated. Results: After 24 h incubation, treatments involving EOM supplementation led to significantly higher IVDMD (treatments and quadratic effect; P = 0.019 and 0.008) and IVNDFD (linear effect; P = 0.068) than did the CON treatment. The EOM 0.2 supplementation group had the highest NH3-N concentration (treatments; P = 0.032). Both EOM supplementations did not affect total VFA concentration and the proportion of individual VFAs; however, total VFA tended to increase in EOM supplementation groups, after 12 h incubation (linear; P = 0.071). Relative protozoa abundance significantly increased following EOM supplementation (treatments, P < 0.001). Selenomonas ruminantium and Ruminococcus albus (treatments; P <0.001 and = 0.005), abundance was higher in the EOM 0.1 treatment group than in CON. The abundance of Butyrivibrio fibrisolvens, fungi and Ruminococcus flavefaciens (treatments; P < 0.001, <0.001, and = 0.005) was higher following EOM 0.2 treatment. Conclusion: The addition of newly developed EOM increased IVDMD, IVNDFD, and tended to increase total VFA indicating that it may be used as a feed additive to improve rumen fermentation by modulating rumen microbial communities. Further studies would be required to investigate the detailed metabolic mechanism underlying the effects of EOM supplementation. PMID- 30477291 TI - Effects of ambient temperature and rumen-protected fat supplementation on growth performance, rumen fermentation and blood parameters during cold season in Korean cattle steers. AB - Objectve: This study was performed to evaluate whether ambient temperature and dietary rumen-protected fat (RPF) supplementation affect growth performance, rumen fermentation, and blood parameters in Korean cattle steers. Methods: Twenty Korean cattle steers [BW: 550.6 +/- 9.14 kg, age: 19.7 +/- 0.13 months] were divided into a conventional control diet group (n = 10) and a 0.5% RPF supplementation group (n = 10). Steers were fed a concentrate diet (1.6% BW) and a rice straw diet (1 kg/day) for 16 weeks [January 9 to February 5 (P1), February 6 to March 5 (P2), March 6 to April 3 (P3), and April 4 to May 2 (P4)]. Results: The mean and minimum indoor ambient temperatures in P1 (-3.44 C, -9.40 C) were lower (P < 0.001) than those in P3 (5.87 C, -1.86 C) and P4 (11.18 C, 4.28 C). The minimum temperature in P1 fell within the moderate cold-stress (CS) category, as previously reported for dairy cattle, and the minimum temperatures of P2 and P3 were within the mild CS category. Neither month nor RPF supplementation affected the ADG or G:F ratio (P > 0.05). Ruminal NH3-N concentrations were higher (P < 0.05) in winter than spring. Plasma cortisol concentrations were lower (P < 0.05) in the coldest month than the other months. Serum glucose concentrations were generally higher in colder months than in the other months, but were unaffected by RPF supplementation. RPF supplementation increased both total cholesterol (P = 0.004) and HDL concentrations (P = 0.03). Conclusions: Korean cattle may not be significantly affected by moderate CS, considering that the growth performance of cattle remained unchanged, although variations in blood parameters were observed among the studied months. RPF supplementation altered cholesterol and HDL concentrations but did not affect growth performance. PMID- 30477292 TI - Effects of lactic acid bacteria and molasses on fermentation dynamics, structural and nonstructural carbohydrate composition and in vitro ruminal fermentation of rice straw silage. AB - Objectve: This study was to evaluate the fermentation dynamics, structural and nonstructural carbohydrate composition and in vitro gas production of rice straw ensiled with lactic acid bacteria (LAB) and molasses. Methods: Fresh rice straw was ensiled in 1-L laboratory silos with no additive control (C), Lactobacillus plantarum (L), molasses (M) and molasses + L. plantarum (ML) for 6, 15, 30 and 60 days. After storage, the silages were subjected to microbial and chemical analyses as well as the further in vitro fermentation trial. Results: All additives increased lactic acid concentration, and reduced pH, DM loss and structural carbohydrate content relative to the control (p < 0.05). The highest organic acid and residual sugar contents and lignocellulose reduction were observed in ML silage. L silage had the highest V-score with 88.10 followed by ML silage. L and ML silage improved in vitro DM digestibility (IVDMD) as compared with other treatments, while in vitro NDF degradability (IVNDFD) was increased in M and ML silage (p < 0.05). M silage significantly (p < 0.05) increased PA content and decreased BA content and AA/PA as well as 72-h cumulative gas production (GP72). Conclusion: The application of ML was effective for improving both the fermentation quality and in vitro digestibility of rice straw silage. Inclusion with molasses to rice straw could reduce in vitro ruminal gas production. PMID- 30477293 TI - Temperature and microbial changes of corn silage during aerobic exposure. AB - Objectve: This study was conducted to estimate the temperature and microbial changes of corn silages during aerobic exposure. Methods: Kwangpyeongok (KW) and Pioneer 1543 (PI) corn hybrids were harvested at 29.7% of dry matter and chopped to 3-5 cm lengths. Homo (Lactobacillus plantarum; LP) or hetero (L. buchneri; LB) fermentative inoculants at 1.2 * 105 cfu/g of fresh forage was applied to the chopped corn forage which was then ensiled in quadruplicate with a 2 x 2 (hybrid * inoculant) treatment arrangement for 100 days. After the silo was opened, silage was sub-sampled for analysis of chemical compositions, in vitro digestibility, and fermentation indices. The fresh silage was continued to determine aerobic exposure qualities by recorded temperature and microbial changes. Results: The KW silages had higher (P<0.01) in vitro digestibilities of dry matter and neutral detergent fiber than those of PI silages. Silages applied with LB had higher (P<0.001) acetate concentration, but lower (P<0.01) lactate concentration and lactate to acetate ratio than those of LP silages. The interaction effect among hybrid and inoculant was detected in acetate production (P=0.008), aerobic stability (P=0.006), and lactic acid bacteria count (P=0.048). The yeast was lower (P=0.018) in LB silages than that in LP silages. During the aerobic exposure, PI silages showed higher (P<0.05) temperature and mold than KW silages, while LP silages had higher (P<0.05) lactic acid bacteria and yeast than LB silages. Conclusion: The results indicated that the changes of silage temperature during aerobic exposure seems mainly affected by mold growth, while applied LB only enhanced aerobic stability of PI silages. PMID- 30477294 TI - Growth performance, carcass and meat quality of lambs supplemented different vegetable oils. AB - Objectve: The purpose of this study was to evaluate the effect of rapeseed and linseed oil supplementations on performance and meat quality of lambs. Methods: The experiment was conducted on 18 growing (100-day-old) lambs of 19.7 +/- 1.9 kg live weight, assigned to 3 groups of 6 animals each. Control lambs were fed meadow hay and concentrate alone. Experimental animals additionally received rapeseed or linseed oils at a dose of 50 g/d. The lambs were slaughtered at an average body weight of 35.7 +/- 0.5 kg. Results: The dressing percentage was higher in lambs fed rapeseed oil. Total saturated fatty acids (SFA) and C15:0, C16:0, C17:0, C21:0, C24:0 were lower in longissimus dorsi muscle (MLD) in lambs fed linseed oil. Supplementation of diet with linseed oil decreased concentrations of total monounsaturated fatty acids and C16:1, C17:1, C18:1 cis-9 in MLD. The concentrations of n-3 polyunsaturated fatty acids (PUFA) and C18:3 n 3, C20:5 n-3 in MLD were higher in lambs fed linseed oil than in other groups. Oils supplementation to diets resulted in increased concentration of C22:6 n-3 in MLD. The inclusion of linseed oil into the diet increased the contents of total PUFA, n-3 PUFA and C18:3 n-3, C20:5 n-3, C22:6 n-3 in semitendinosus muscle in comparison to control. A tendency towards a lower n:6/n:3 ratio in MLD was observed when lambs were supplemented linseed oil. Conclusion: The supplementation of linseed oil to diets seems to reduce the concentration of SFA and increase the concentration of n-3 PUFA. The n-6/n-3 ratio is an important nutritional factor, and its value has been favorably decreased below 2, thereby achieving an important target related to human health. Due to these changes carcass fatty acid profile was improved, and so enhanced lamb meat healthy properties. PMID- 30477295 TI - Expression profiles of microRNAs in skeletal muscle of sheep by deep sequencing. AB - Objectve: MicroRNAs are a class of endogenous small regulatory RNAs that regulate cell proliferation, differentiation and apoptosis. Recent studies on miRNAs are mainly focused on mice, human and pig. However, the studies on miRNAs in skeletal muscle of sheep are not comprehensive. Methods: RNA-seq technology was used to perform genomic analysis of miRNAs in prenatal and postnatal skeletal muscle of sheep. Targeted genes were predicted using miRanda software and miRNA-mRNA interactions were verified by quantitative Real-time PCR. To further investigate the function of miRNAs, candidate targeted genes were enriched for analysis using GO and KEGG enrichment. Results: The results showed total of 1086 known miRNAs and 40 new candidate miRNAs were detected in prenatal and postnatal skeletal muscle of sheep. In addition, 345 miRNAs (151 up-regulated, 94 down-regulated) were differentially expressed. Moreover, miRanda software was performed to predict targeted genes of miRNAs, resulting in a total of 2833 predicted targets, especially miR-381 which targeted multiple muscle-related mRNAs. Furthermore, GO Ontology and KEGG pathway analysis confirmed that targeted genes of miRNAs were involved in development of skeletal muscles. Conclusions: This study supplements the miRNA database of sheep, which provides valuable information for further study of the biological function of miRNAs in sheep skeletal muscle. PMID- 30477296 TI - Nanoporous Organic Network Coating of Nanostructured Polymer Films with Enhanced Adsorption Performance toward Particulate Matter. AB - This work shows that the surface properties of polyurethane acrylate (PUA) films can be controlled by the coating of na-noporous organic networks (NONs). By the NON coating, the hydrophilic nature of nanostructured PUA (N-PUA) film was converted to superhydrophobic surface. The NON-coated N-PUA films (N-PUA-NONs) were applied as stationary adsor-bents for the capture of particulate matter (PM) in air. Compared with the original PUA films, the N-PUA-NON films showed much enhanced capture performance toward PM and recyclability through water washing, indicating the potential of out-door application as stationary self-cleaning adsorbents under natural surroundings. PMID- 30477297 TI - Molecular Mechanism for the Role of the H2A and H2B Histone Tails in Nucleosome Repositioning. AB - The nucleosome core particle (NCP) is the basic packaging unit of DNA. Recently reported structures of the NCP suggest that the histone octamer undergoes conformational changes during the process of DNA translocation around the histone octamer. Herein, we demonstrate with long-time all-atomistic molecular dynamics simulations that the histone tails play a critical role in this nucleosome repositioning. We simulate the NCP at high salt concentrations an order of magnitude higher than physiological conditions to screen the electrostatic interactions. We find that the posi-tively charged H2B tail collapses and complexes with the minor groove of nucleosomal DNA. Upon collapse of the tail, counterions are released. This promotes the formation of a ~ 10 bp loop of nucleosomal DNA. The complexation of the tail increases the local flexibility of the DNA, as characterized by local force constants. Using normal mode analysis, we identify a 'wave-like motion' of nucleosomal DNA. We perform umbrella sampling to characterize two possible pathways of the initial stages of unwrapping, symmetric and asymmetric. These results suggest that regulation of the histone tail interactions with nucleosomal DNA may play a critical role in nucleosomal dynamics by acting as a switch to determine the initial pathway of unwrapping. PMID- 30477298 TI - Single particle mass spectrometry of titanium and niobium carbonitride precipitates in steels. AB - We introduce a new method for the characterization of particles extracted from steels. Microalloyed steels were dissolved to extract niobium and titanium carbonitride particles that are of critical importance for the mechanical properties of the steel. Size distribution and chemical composition of the particles were analyzed by single particle inductively coupled plasma mass spectrometry and compared to electron microscopy. Mass spectrometry rapidly provided data on a large number of particles (> 2000 in 1 min) and indicated two particle populations that differ in size and composition: smaller particles contained only niobium, while larger particles contained both niobium and titanium. Electron microscopy of a much smaller particle number confirmed the results and indicated that larger particles had complex, overgrown structures. The combination of single-particle mass spectrometry and electron microscopy enables a better understanding of the precipitation processes that form the particles during steel production at different stages of the thermomechanical rolling process. A better understanding of the processes helps to improve the rolling process in order to exploit the alloying elements optimally. PMID- 30477299 TI - Raising the Bar in Aromatic Donor-Acceptor Interactions with Cyclic Trinuclear Gold(I) Complexes as Strong pi-Donors. AB - Aromatic donor-acceptor interactions are of high importance in supramolecular chemistry, materials science and biology. Compared to other non-covalent interactions, such as hydrogen bonding, the binding is often weak. Here we show that strong donor-acceptor interactions between planar aromatics with binding free energies down to -10.1 kcal mol-1 and association constants of up to 2.34 * 107 L mol-1 for 1:1 complexes can be realized using cyclic trinuclear complexes of gold(I) with pyridinate, imidazolate or carbeniate ligands. Data were obtained through NMR and UV/Vis absorption spectroscopic studies and supported by quantum chemical calculations for a variety of acceptors. By using a specifically designed bridged naphthalene diimide-based acceptor with only one binding site, we furthermore show that a 1:2 (donor:acceptor) binding model is best suited to quantify the donor and acceptor/complex equilibrium. Scanning electron microscopy on selected donor-acceptor pairs shows crystalline supramolecular assemblies. We anticipate this study to be relevant for the future design of supramolecular systems and chemical sensors and the determination of binding energies between planar donors and acceptors. PMID- 30477300 TI - Microfluidic Manufacturing of SN-38-Loaded Polymer Nanoparticles with Shear Processing Control of Drug Delivery Properties. AB - Two-phase gas-liquid microfluidic reactors provide shear processing control of SN 38-loaded polymer nanoparticles (SN-38-PNPs). We prepare SN-38-PNPs from the block copolymer poly(methyl caprolactone-co-caprolactone)-block-poly(ethylene oxides) (P(MCL-co-CL)-b-PEO) using bulk and microfluidic methods and at different drug-to-polymer loading ratios and on-chip flow rates. We show that as the microfluidic flow rate (Q) increases, encapsulation efficiency and drug loading increase and release half times increase. Slower SN-38 release is obtained at the highest Q value (Q = 400 uL/min) than is achieved using a conventional bulk preparation method. For all SN-38-PNP formulations, we find a dominant population (by number) of nanosized particles (< 50 nm) along with a small number of larger aggregates (> 100 nm). As Q increases, the size of aggregates decreases through a minimum and then increases, attributed to a flow-variable competition of shear induced particle breakup and shear-induced particle coalescence. IC25 and IC50 values of the various SN-38-PNPs against MCF-7 show strong flow rate dependencies that mirror trends in particle size. SN-38-PNPs manufactured on-chip at intermediate flow rates show both minimum particle sizes and maximum potencies with a significantly lower IC25 value than the bulk-prepared sample. Compared to conventional bulk methods, microfluidic shear processing in two-phase reactors provides controlled manufacturing routes for optimizing and improving the properties of SN-38 nanomedicines. PMID- 30477301 TI - Does Ionic Screening Lower Activation Barriers for Conformational Transitions in Proteins? AB - In this work we investigated the kinetics of binding of hen egg-white lysozyme with tri-N-acetylglucosamine in aqueous solutions, at two values of pH, 3.2 and 11, as a function of ionic strength, by a stopped-flow method with tryptophyl fluorescence observation of the transients. We analyzed registered reaction progress curves employing a numerical integration of appropriate chemical master equations. We discriminated between several binding models and established that the process observed in experiments follows a two-step mechanism, composed of four elementary stages: diffusional formation of an encounter complex, dissociation of the encounter complex, conformational transition of the encounter complex to the final complex, and the reverse transformation, i.e. from the final complex to the the encounter complex. We evaluated rate constants of these elementary stages and determined their dependencies on solution ionic strength. Regardless of solution pH, rate constants of both forward and reverse conformational transitions increase with an increasing ionic strength. This suggests that ionic screening of intramolecular electrostatic interactions may act to lower the activation barrier for conformational transition in proteins. PMID- 30477302 TI - Benzimidazoles as Metal-Free and Renewable Hydrides for CO2 Reduction to Formate. AB - We report a novel metal-free chemical reduction of CO2 by a recyclable benzimidazole-based organo-hydride, whose choice was guided by quantum chemical calculations. Notably, benzimidazole-based hydride donors rival the hydride donating abilities of noble metal-based hydrides such as [Ru(tpy)(bpy)H]+ and [Pt(depe)2H]+. Chemical CO2 reduction to the formate anion (HCOO-) was carried out in the absence of biological enzymes, a sacrificial Lewis acid, or a base to activate the substrate or reductant. 13CO2 experiments confirmed the formation of H13COO- by CO2 reduction with the formate product characterized by 1H-NMR and 13C NMR spectroscopies, and ESI-MS. The highest formate yield of 66% was obtained in the presence of potassium tetrafluoroborate under mild conditions. The likely role of exogenous salt additives in this reaction is to stabilize and shift the equilibrium towards the ionic products. After CO2 reduction, the benzimidazole based hydride donor was quantitatively oxidized to its aromatic benzimidazolium cation, establishing its recyclability. In addition, we electrochemically reduced the benzimidazolium cation to its organo-hydride form in quantitative yield, demonstrating its potential for electrocatalytic CO2 reduction. These results serve as a proof of concept for the electrocatalytic reduction of CO2 by sustainable, recyclable and metal-free organo-hydrides. PMID- 30477303 TI - Potentiating antigen specific immune response by targeted delivery of PLGA based model cancer vaccine. AB - Targeted delivery of vaccine has the potential to localize the therapeutic agent to a target tissue with minimum side-effects. This article presents the development of a model targeted immunotherapeutic approach that will harness effective T cell response. Here, we investigated the impact of a model nanoparticulate cancer vaccine on the immune system of in vivo mice models. The nanoparticles (NPs) were prepared by double emulsification solvent evaporation technique. The anti-CD205 targeted formulations were obtained either through physical adsorption or covalent conjugation method. The structural integrity of Ovalbumin (OV) was confirmed by circular dichroism spectroscopy. Flow cytometry and enzyme-linked immunosorbent assay experiments was performed to evaluate T cell proliferation and cytokine secretion. Our results indicate that the antigen adjuvant combined formulation induced more powerful responses compared to formulations with either of these alone. Wild type balb/c mice immunized with the targeted PLGA NPs encapsulated with OV and monophosphoryl lipid A (MP) induced profound secretion of antigen-specific IgG antibodies, cytokines and generation of memory T cells. OV specific T cell receptor (TCR) transgenic OT1 mice showed highest production of cytotoxic T cells and increased secretion of cytokines upon immunization with the targeted OV-MP formulations. The enhanced response might be attributed to OV depot effect at the subcutaneous site of injection that triggered effective induction of dendritic cells activation and helper T (Th) cell differentiation in the lymph nodes. Therefore, the developed targeted PLGA based delivery system could be utilized as a successful model vaccine in future. PMID- 30477304 TI - CeO2 Nanowire-BODIPY-Adenosine Triphosphate Fluorescent Sensing Platform for Highly Specific and Sensitive Detection of Arsenate. AB - Effective and sensitive monitoring of arsenate in drinking water is significant for risk management of public health. Here, we demonstrated that CeO2 nanowire acted as an efficient quencher for small fluorescent molecules with phosphate group, BODIPY-adenosine triphosphate (BODIPY-ATP) and riboflavin-5'-phosphate (Rf P), and developed CeO2 nanowire-BODIPY-ATP platform for highly selective and sensitive detection of arsenate. The response strategy was based on the competitive coordination chemistry of CeO2 nanowire between arsenate and phosphate group of BODIPY-ATP. Arsenate displaced adsorbed BODIPY-ATP to enhance fluorescence, allowing detection of arsenate down to 7.8 nM, which is lower than the WHO defined limit 130 nM. Excellent linear range of 20-150 nM and 150-1000 nM was obtained. Importantly, this system is simple in design and convenient in operation. And the platform exhibits excellent selectivity for arsenate with-out the interference of phosphate ions. Finally, the proposed method has been successfully employed for determination of arsenate in real water samples. PMID- 30477305 TI - Catalytic Radical-Polar Crossover Reactions of Allylic Alcohols. AB - Radical-polar crossover hydrofunctionalizations of tertiary allylic alcohols are described. Depending on the structure of the catalyst, corresponding epoxides or semipinacol rearrangement products are selectively obtained in good yields. Experimental evidence points to the participation of alkylcobalt complexes as electrophilic intermediates. PMID- 30477306 TI - Surface chemistry of the frog sticky-tongue mechanism. AB - Frogs capture their prey with a highly specialized tongue. Recent studies indicate this tongue is covered with fibril-forming mucus that acts as a pressure sensitive adhesive. However, no analysis of the interfacial chemistry of frog tongue mucus has been performed. The goal of this study is to examine the chemical structure of the surface of mucus after a tongue strike. Previous studies of mucus from other animals suggest that mucus from a frog's tongue consists of mucins-serine-, threonine-, and proline-rich glycoproteins. Therefore, the authors expect to observe chemical bonds associated with glycoproteins, as well as fibrils formed at the mucus-tongue interface. To test this hypothesis, they collected both near-edge x-ray absorption fine structure (NEXAFS) microscopy images and sum frequency generation (SFG) vibrational spectra from layers of mucus left after frog tongue strikes on cleaned glass slides. NEXAFS imaging demonstrates a uniform distribution of amide, hydroxyl, and carbon carbon bonds across the mucus surface. Difference spectra of individual N1s and C1s K-edge spectra pulled from these images indicate a structure consistent with fibril formation as well as disorder of oligosaccharide groups near the mucus surface. C-H region SFG spectra reveal surface active modes which likely stem from serine and threonine within the mucin protein. Combined, this work suggests that glycoproteins are well-ordered at the mucus-tongue interface. PMID- 30477307 TI - Place-based predictors of HIV viral suppression and durable suppression among heterosexuals in New York city. AB - Scant research has explored place-based correlates of achieving and maintaining HIV viral load suppression among heterosexuals living with HIV. We conducted multilevel analyses to examine associations between United Hospital Fund (UHF) level characteristics and individual-level viral suppression and durable viral suppression among individuals with newly diagnosed HIV in New York City (NYC) who have heterosexual HIV transmission risk. Individual-level independent and dependent variables came from NYC's HIV surveillance registry for individuals diagnosed with HIV in 2009-2013 (N = 3,159; 57% virally suppressed; 36% durably virally suppressed). UHF-level covariates included measures of food distress, demographic composition, neighborhood disadvantage and affluence, healthcare access, alcohol outlet density, residential vacancy, and police stop and frisk rates. We found that living in neighborhoods where a larger percent of residents were food distressed was associated with not maintaining viral suppression. If future research should confirm this is a causal association, community-level interventions targeting food distress may improve the health of people living with HIV and reduce the risk of forward transmission. PMID- 30477308 TI - Pediatric Sports-Related Injuries. AB - At any time there are millions of athletes ages 6 to 18 years participating in sports-related activities and the number is increasing. Unfortunately, the number of overuse injuries is also on the rise. This increase is most likely associated with single-sport specialization before the onset of puberty. As physicians and health care providers, we must educate these young athletes, their parents, and coaches to ensure safety. Short breaks are recommended and everyone involved should understand the athlete should not train more than 5 days per week and must take off 2 to 4 months per year consecutively depending on the specific sport and position on the team. To understand the complexity of these overuse injuries, it is important to have knowledge of the unique characteristics of the immature musculoskeletal system, periods of rapid growth, and the function of the growth plate, which is often involved in these injuries. PMID- 30477309 TI - NAVIGATE I: Randomized, Placebo-Controlled, Double-Blind Trial of the Exhalation Delivery System With Fluticasone for Chronic Rhinosinusitis With Nasal Polyps. AB - BACKGROUND: Chronic rhinosinusitis is a common, high-morbidity chronic inflammatory disease, and patients often experience suboptimal outcomes with current medical treatment. The exhalation delivery system with fluticasone (EDS FLU) may improve care by increasing superior/posterior intranasal corticosteroid deposition. OBJECTIVE: To evaluate the efficacy and safety of EDS-FLU versus EDS placebo in patients with nasal polyps (NP). Coprimary end points were change in nasal congestion and polyp grade. Key secondary end points were Sino-Nasal Outcome Test-22 (SNOT-22) and Medical Outcomes Study Sleep Scale-Revised (MOS Sleep-R). Other prespecified end points included all 4 cardinal symptoms of NP, 36-Item Short Form Health Survey (SF-36), Patient Global Impression of Change (PGIC), Rhinosinusitis Disability Index (RSDI), and key indicators for surgical intervention. DESIGN: Randomized, double-blind, EDS-placebo-controlled, multicenter study. METHODS: Three hundred twenty-three subjects with NP and moderate-severe congestion/obstruction, most with history of corticosteroid use (94.4%) and/or prior surgery (60.4%), were randomized to EDS-FLU 93 ug, 186 ug, or 372 ug or EDS-placebo twice daily (BID) for 24 weeks (16 double-blind + 8 single-arm extension with EDS-FLU 372 ug BID). RESULTS: All EDS-FLU doses produced significant improvement in both coprimary end points ( P < .05) and in SNOT-22 total score ( P <= .005). EDS-FLU significantly improved all 4 cardinal symptoms of NP ( P < .05), including congestion/obstruction, facial pain/pressure, rhinorrhea/post-nasal drip, and hyposmia/anosmia. Approximately 80% of subjects reported improvement with EDS-FLU, with 65% reporting "much" or "very much" improvement by week 16. Adverse events were generally local in nature and similar to other intranasal steroids studied for similar durations in similar populations, with the most common being epistaxis. CONCLUSIONS: In patients with chronic rhinosinusitis with NP (CRSwNP) who were symptomatic despite high rates of prior intranasal steroid use and/or surgery, EDS-FLU produced statistically significant and clinically meaningful improvements compared to EDS-placebo in multiple subjective and objective outcomes (symptoms, SNOT-22, RSDI, SF-36, PGIC, and NP grade), including all 4 cardinal symptoms of CRSwNP. PMID- 30477310 TI - Artificial Light at Night of Different Spectral Compositions Differentially Affects Tumor Growth in Mice: Interaction With Melatonin and Epigenetic Pathways. AB - Lighting technology is rapidly advancing toward shorter wavelength illuminations that offer energy-efficient properties. Along with this advantage, the increased use of such illuminations also poses some health challenges, particularly breast cancer progression. Here, we evaluated the effects of artificial light at night (ALAN) of 4 different spectral compositions (500-595 nm) at 350 Lux on melatonin suppression by measuring its urine metabolite 6-sulfatoxymelatonin, global DNA methylation, tumor growth, metastases formation, and urinary corticosterone levels in 4T1 breast cancer cell-inoculated female BALB/c mice. The results revealed an inverse dose-dependent relationship between wavelength and melatonin suppression. Short wavelength increased tumor growth, promoted lung metastases formation, and advanced DNA hypomethylation, while long wavelength lessened these effects. Melatonin treatment counteracted these effects and resulted in reduced cancer burden. The wavelength suppression threshold for melatonin-induced tumor growth was 500 nm. These results suggest that short wavelength increases cancer burden by inducing aberrant DNA methylation mediated by the suppression of melatonin. Additionally, melatonin suppression and global DNA methylation are suggested as promising biomarkers for early diagnosis and therapy of breast cancer. Finally, ALAN may manifest other physiological responses such as stress responses that may challenge the survival fitness of the animal under natural environments. PMID- 30477311 TI - Is Annual Income a Predictor of Completion of Advance Directives (ADs) in Patients With Cancer. AB - CONTEXT:: Completion of advance directives (ADs) enhances the likelihood of receiving goal-concordant treatments near the end of life. Previous research on community samples have shown that completion of ADs is less common in lower socioeconomic status demographic group; there is a paucity of such research in patients with cancer. OBJECTIVES:: To study the effect of income and education on the completion of ADs. HYPOTHESIS:: Patients with cancer having lower incomes and education levels would be less likely to report completing ADs. METHODS:: We conducted cross-sectional analyses of data provided by patients (n = 265) enrolled in the Values and Options in Cancer Care clinical trial. Patients with advanced cancer reported whether they had (1) completed a living will or (2) designated a health-care proxy. Response options for both questions were yes (scored 1), no (scored 0), and unsure (scored 0). We studied the association of lower household income (<=US$20 000) and education level (never attended college) with AD scores. RESULTS:: Patients with lower annual incomes had lower AD scores (estimate -0.44; confidence intervals [CI]: -0.71 to -0.16, P = .001); the association between higher educational attainment (some college or more) and completion of ADs was not statistically significant (estimate 0.04, CI: -0.16 to 0.24, P = .70). CONCLUSION:: Interventions to promote completion of ADs among lower income patients with serious illnesses are needed. PMID- 30477312 TI - COPE for Adolescent Syrian Refugees in Lebanon: A Brief Cognitive-Behavioral Skill-Building Intervention to Improve Quality of Life and Promote Positive Mental Health. AB - Lebanon has the highest per-capita concentration of refugees worldwide. There is an urgent need to offer psychosocial interventions to vulnerable groups such as Syrian refugee adolescents. To assess the feasibility, acceptability, and preliminary effects of a cognitive-behavioral intervention (Creating Opportunities for Patient Empowerment [COPE]) on depression, anxiety, and quality of life (QOL) in a sample of adolescent refugees (13-17 years) living in Lebanon. A preexperimental study design was used. COPE 7-Session was delivered to 31 adolescent Syrian refugees. Participants were assessed for depression (Personal Health Questionnaire-9), anxiety (General Anxiety Disorders Scale), and QOL (Pediatric Quality of Life Inventory). Feasibility and acceptability findings indicated that the COPE program was a positive experience for teens. Significant decreases in depression and anxiety, and increases in QOL were also reported. COPE is an effective cognitive-behavioral intervention that can be delivered in an Arabic/Middle-Eastern setting for teen refugees to improve mental health and QOL. PMID- 30477313 TI - Modified risk scoring system for acute exacerbation of interstitial lung disease. AB - BACKGROUND: Lung cancer patients with interstitial lung disease often develop acute exacerbation of their interstitial lung disease after lung resection. Special care is needed in selection of the surgical procedure to reduce acute exacerbation and provide long-term survival. METHODS: The Japanese Association for Chest Surgery devised a risk scoring system based on 7 risk factors to predict the probability of postoperative acute exacerbation. We excluded surgical procedures and used a modified system categorizing 4 groups: group A (risk score 0-6), group B (risk score 7-10), group C (risk score 11-14), and group D (risk score 15-18). We retrospectively examined 60 lung cancer patients with interstitial lung disease to determine whether the modified risk scoring system is useful for selecting the optimal surgical procedure in anticipation of curability and risk of postoperative acute exacerbation. RESULTS: Eight (13.3%) patients experienced postoperative acute exacerbation. In group A ( n = 20), there was no difference in the incidence of acute exacerbation between wedge (0%) and anatomic resection (6.3%, p = 0.800). In group B ( n = 40), the incidence was significantly higher after anatomic resection (5.0% vs. 30.0%, p = 0.046). Thus group A had high-quality outcomes with anatomic resection, and in group B, the incidence of postoperative acute exacerbation can be reduced if wedge resection is performed. CONCLUSIONS: Our modified risk scoring can be useful for selecting the optimal surgical procedure in anticipation of curability and the risk of acute exacerbation of interstitial lung disease after lung cancer surgery. PMID- 30477314 TI - Preferred Place of Death for Patients With Incurable Cancer and Their Family Caregivers in Egypt. AB - BACKGROUND:: Little is known about the place of death of patients with cancer in Eastern Mediterranean countries including Egypt, where palliative care is underdeveloped. Identifying the preferred place of death (PPoD) is important for the development of appropriate palliative care models in these countries. OBJECTIVES:: To know the PPoD of Egyptian patients with incurable cancer and their family caregivers (FCGs) and to determine the factors that may impact their preferences. METHODS:: An observational cross-sectional study that included 301 dyads of patients with incurable cancer and one of their FCGs. A questionnaire was designed to collect data about the characteristics of patients and FCGs as well as their preferences. RESULTS:: The majority of dyads (272/301, 90.4%) answered the PPoD question. Home was the PPoD in 93% of patients and 90.1% of FCGs ( P = .218). The congruence between patients' and FCGs' PPoD was 92.7% (kappa = 0.526). In multivariate analysis, poorer performance status (Eastern Cooperative Oncology Group 3 or 4) and full employment of FCGs associated significantly with patients' preference to die in hospital (odds ratio [OR] = 3.015 [95% confidence interval [CI]: 1.004-9.054], P = .049 and OR = 4.402 [95% CI: 1.561-12.417], P = .005, respectively), while poorer performance status and nonreferral to the palliative medicine unit were associated with FCGs' preference of hospital death (OR = 2.705 [95% CI: 1.105-6.626], P = .029 and OR = 2.537 [95% CI: 1.082-5.948], P = .032, respectively). CONCLUSIONS:: The results of the current study suggest that home is the PPoD for the vast majority of Egyptian patients with incurable cancer and their FCGs. Palliative care interventions that promote home death of patients with incurable cancer are needed in Egypt. PMID- 30477315 TI - Bioartificial Organ Manufacturing Technologies. AB - Bioartificial organ manufacturing technologies are a series of enabling techniques that can be used to produce human organs based on bionic principles. During the last ten years, significant progress has been achieved in the development of various organ manufacturing technologies. According to the degree of automation, organ manufacturing technologies can be divided into three main groups: (1) fully automated; (2) semi-automated; (3) handworked (or handmade); each has the advantages and disadvantages for bioartificial organ manufacturing. One of the most promising bioartificial organ manufacturing technologies is to use combined multi-nozzle three-dimensional printing techniques to automatically assemble personal cells along with other biomaterials to build exclusive organ substitutes for defective/failed human organs. This is the first time that advanced bioartificial organ manufacturing technologies have been reviewed. These technologies hold the promise to greatly improve the quality of health and average lifespan of human beings in the near future. PMID- 30477316 TI - Autologous Gene and Cell Therapy Provides Safe and Long-Term Curative Therapy in A Large Pig Model of Hereditary Tyrosinemia Type 1. AB - Orthotopic liver transplantation remains the only curative therapy for inborn errors of metabolism. Given the tremendous success for primary immunodeficiencies using ex-vivo gene therapy with lentiviral vectors, there is great interest in developing similar curative therapies for metabolic liver diseases. We have previously generated a pig model of hereditary tyrosinemia type 1 (HT1), an autosomal recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH). Using this model, we have demonstrated curative ex-vivo gene and cell therapy using a lentiviral vector to express FAH in autologous hepatocytes. To further evaluate the long-term clinical outcomes of this therapeutic approach, we continued to monitor one of these pigs over the course of three years. The animal continued to thrive off the protective drug NTBC, gaining weight appropriately, and maintaining sexual fecundity for the course of his life. The animal was euthanized 31 months after transplantation to perform a thorough biochemical and histological analysis. Biochemically, liver enzymes and alpha fetoprotein levels remained normal and abhorrent metabolites specific to HT1 remained corrected. Liver histology showed no evidence of tumorigenicity and Masson's trichrome staining revealed minimal fibrosis and no evidence of cirrhosis. FAH-immunohistochemistry revealed complete repopulation of the liver by transplanted FAH-positive cells. A complete histopathological report on other organs, including kidney, revealed no abnormalities. This study is the first to demonstrate long-term safety and efficacy of hepatocyte-directed gene therapy in a large animal model. We conclude that hepatocyte-directed ex-vivo gene therapy is a rational choice for further exploration as an alternative therapeutic approach to whole organ transplantation for metabolic liver disease, including HT1. PMID- 30477317 TI - Prognostic significance of emergency department bypass in stable and unstable patients with ST-segment elevation myocardial infarction. AB - BACKGROUND:: In ST-segment elevation myocardial infarction (STEMI) patients treated with percutaneous coronary intervention, direct transport from the scene to the catheterisation laboratory bypassing the emergency department has been shown to shorten times to reperfusion. The aim of this study was to investigate the effects of emergency department bypass on mortality in both haemodynamically stable and unstable STEMI patients. METHODS:: The analysis is based on a large cohort of STEMI patients prospectively included in the German multicentre Feedback Intervention and Treatment Times in ST-Elevation Myocardial Infarction (FITT-STEMI) trial. RESULTS:: Out of 13,219 STEMI patients who were brought directly from the scene by emergency medical service transportation and were treated with percutaneous coronary intervention, the majority were transported directly to the catheterisation laboratory bypassing the emergency department ( n=6740, 51% with emergency department bypass). These patients had a significantly lower in-hospital mortality than their counterparts with no emergency department bypass (6.2% vs. 10.0%, P<0.0001). The reduced mortality related to emergency department bypass was observed in both stable ( n=11,594, 2.8% vs. 3.8%, P=0.0024) and unstable patients presenting with cardiogenic shock ( n=1625, 36.3% vs. 46.2%, P<0.0001). Regression models adjusted for the Thrombolysis In Myocardial Infarction (TIMI) risk score consistently confirmed a significant and independent predictive effect of emergency department bypass on survival in the total study population (odds ratio 0.64, 95% confidence interval 0.56-0.74, P<0.0001) and in the subgroup of shock patients (OR 0.69, 95% CI 0.54-0.88, P=0.0028). CONCLUSION:: In STEMI patients, emergency department bypass is associated with a significant reduction in mortality, which is most pronounced in patients presenting with cardiogenic shock. Our data encourage treatment protocols for emergency department bypass to improve the survival of both haemodynamically stable patients and, in particular, unstable patients. Clinical Trial Registration: NCT00794001 ClinicalTrials.gov: NCT00794001. PMID- 30477318 TI - The Influence of Number of Categories and Threshold Values on Fit Indices in Structural Equation Modeling with Ordered Categorical Data. AB - This study examines the unscaled and scaled root mean square error of approximation (RMSEA), comparative fit index (CFI), and Tucker-Lewis index (TLI) of diagonally weighted least squares (DWLS) and unweighted least squares (ULS) estimators in structural equation modeling with ordered categorical data. We show that the number of categories and threshold values for categorization can unappealingly impact the DWLS unscaled and scaled fit indices, as well as the ULS scaled fit indices in the population, given that analysis models are misspecified and that the threshold structure is saturated. Consequently, a severely misspecified model may be considered acceptable, depending on how the underlying continuous variables are categorized. The corresponding CFI and TLI are less dependent on the categorization than RMSEA but are less sensitive to model misspecification in general. In contrast, the number of categories and threshold values do not impact the ULS unscaled fit indices in the population. PMID- 30477319 TI - Patterns of treatment with antiplatelet therapy after an acute coronary syndrome: Data from a large database in a community setting. AB - AIMS: Current guidelines strongly recommend antiplatelet therapy with aspirin plus a P2Y12 receptor inhibitor (dual therapy) for patients with acute coronary syndrome (ACS). To better understand how antiplatelet treatment is prescribed in clinical practice, the aim of this study was to provide a more detailed description of real-world patients with and without antiplatelet treatment after an ACS, their outcomes at one-year follow-up and the related integrated cost. METHODS: The ReS database, including more than 12 million inhabitants, was evaluated. During the accrual period ACS patients discharged alive were identified on the basis of ICD-IX-CM code. Antiplatelet drug prescriptions and healthcare costs were analysed over one-year follow-up. RESULTS: In 2014, of the 25,129 patients discharged alive after an ACS, 5796 (23%) did not receive any antiplatelet therapy during the first month after hospital discharge. Among them, 3846 (66%) subjects were prescribed an antiplatelet drug subsequently, while 7.7% did not receive any antiplatelet treatment during the whole following year. Dual therapy in the subgroup of patients undergoing a revascularization procedure ( n = 8436) was prescribed to 79.2% of cases and to 46.1% ( n = 4009) of medically managed patients. The patients not treated with an antiplatelet treatment in the first month showed the highest one-year healthcare costs, mostly due to hospital re-admissions. CONCLUSIONS: This analysis of a large patient community shows that a considerable proportion of patients remained untreated with antiplatelet treatment after an ACS event. A clearer characterization of these subjects can help to improve the adherence to the current guidelines and recommendations. PMID- 30477320 TI - Long-term exposure to air pollution raises circulating levels of proprotein convertase subtilisin/kexin type 9 in obese individuals. AB - AIMS: Exposure to airborne particulate matter has been consistently associated with early death and increased morbidity, particularly raising the risk of cardiovascular disease. Obesity, one of the leading cardiovascular disease risk factors, increases susceptibility to the adverse effects of particulate matter exposure. Proprotein convertase subtilisin/kexin type 9 has been related to a large number of cardiovascular risk factors, e.g. atherogenic lipoproteins, arterial stiffness and platelet activation. Thus, the present study was aimed at evaluating, in a series of obese individuals, the effects of particulate matter less than 10 um in diameter (PM10) on proprotein convertase subtilisin/kexin type 9 circulating levels. METHODS AND RESULTS: In 500 obese subjects, participating in the cross-sectional Susceptibility to Particle Health Effects, miRNAs and Exosomes (SPHERE) study, we evaluated the effects of long- and short-term PM10 exposure on circulating proprotein convertase subtilisin/kexin type 9 levels. In the studied individuals (body mass index: 33.3 +/- 5.2 kg/m2) with an annual average PM10 exposure of 40.12 +/- 4.71 ug/m3, proprotein convertase subtilisin/kexin type 9 levels were 248.7 +/- 78.6 ng/mL. In univariate analysis, PM10 exposure (annual average) was associated with proprotein convertase subtilisin/kexin type 9 levels (beta=1.83, standard error = 0.75, p = 0.014). Interestingly, in a multivariable linear regression model, this association was observed only for carriers of lower concentrations of interferon-gamma, whereas it was lost in the presence of higher interferon-gamma levels. Proprotein convertase subtilisin/kexin type 9 levels were positively associated with the Framingham Risk Score, which was raised by 15.8% for each 100 ng/ml rise of proprotein convertase subtilisin/kexin type 9. CONCLUSIONS: In obese individuals, more sensitive to the damaging effects of environmental air pollution, PM10 exposure positively associates with proprotein convertase subtilisin/kexin type 9 plasma levels especially in those with low levels of interferon-gamma. PMID- 30477321 TI - A data-zone scoring system to assess the generalizability of clinical trial results to individual patients. AB - INTRODUCTION: Evaluating the applicability of a clinical trial to a specific patient is difficult. A novel framework, the Trial Score, was created to quantify the generalizability of a trial's result based on participants' baseline characteristics and not on the trial's inclusion and exclusion criteria. METHODS: For each Systolic Blood Pressure Intervention Trial (SPRINT) participant, the Euclidean distance in six-dimensional space from the theoretical "average" participant was calculated to produce an individual Trial Score that incorporates multiple distinct continuous-variable baseline characteristics. We prospectively defined the "data-rich," "data-limited," and "data-free" zones as Trial Scores < 90th percentile, the 90th-97.5th percentile, and >97.5th percentile, respectively. Trial Scores were then calculated for National Health and Nutrition Examination Survey participants to map data zones of the general population. Individual participant data from the Action to Control Cardiovascular Risk in Diabetes blood pressure trial (ACCORD-BP) was used to test if participants further from the average SPRINT participant behave differently than the overall SPRINT results. RESULTS: The National Health and Nutrition Examination Survey cohort and the ACCORD-BP trial demonstrate large percentages of participants in SPRINT's data-free and data-limited zones. Time-to-event rates seen with intensive and standard blood pressure control in SPRINT were the same as ACCORD BP participants within SPRINT's data-rich zone (hazard ratio 0.97, p = 0.84 and hazard ratio 0.95, p = 0.70). However, these rates were significantly different than those of ACCORD-BP participants outside SPRINT's data-rich zone (hazard ratio 0.64, p < 0.01 and hazard ratio 0.77, p < 0.01). CONCLUSIONS: ACCORD-BP participants with SPRINT Trial Scores in the 90th percentile or below have similar event rates to SPRINT participants in both the intensive and standard blood pressure groups. Quantifying the difference between an individual patient and the average clinical trial participant holds promise as a tool to more precisely determine applicability of a specific trial to individual patients. PMID- 30477322 TI - Smoking and heart failure: A call for action. PMID- 30477323 TI - The rise of activity monitoring. PMID- 30477324 TI - Advances in cancer modeling: fluidic systems for increasing representativeness of large 3D multicellular spheroids. PMID- 30477325 TI - 3D-printed magnetic tweezers for dorsal traction force measurement. AB - In this study, economic magnetic tweezers (EMT) with a sharp gradient field were designed and built, in order to facilitate accurate force measurement. Our design costs less than 40 USD and is easy to mount onto most microscope stages. We leverage the computational fluidic dynamics techniques to calculate the forces based on the results obtained using our simple device. The EMT device is especially suitable to measure the traction forces at the dorsal side of a cell. As a proof of concept it was demonstrated that the EMT device could be applied to measure the dorsal traction forces exerted via the CD80-CTLA4 bond in metastatic cancer cells. PMID- 30477326 TI - Tech news: stem cells for modeling and curing disease. AB - Freya Leask explores developments in cell culture and stem cell research that are revolutionizing how diseases are studied and treated. PMID- 30477328 TI - Updates from the Society for Neuroscience 2018. PMID- 30477327 TI - QuickCount(r): a novel automated software for rapid cell detection and quantification. AB - We describe a novel automated cell detection and counting software, QuickCount(r) (QC), designed for rapid quantification of cells. The Bland-Altman plot and intraclass correlation coefficient (ICC) analyses demonstrated strong agreement between cell counts from QC to manual counts (mean and SD: -3.3 +/- 4.5; ICC = 0.95). QC has higher recall in comparison to ImageJauto, CellProfiler and CellC and the precision of QC, ImageJauto, CellProfiler and CellC are high and comparable. QC can precisely delineate and count single cells from images of different cell densities with precision and recall above 0.9. QC is unique as it is equipped with real-time preview while optimizing the parameters for accurate cell count and needs minimum hands-on time where hundreds of images can be analyzed automatically in a matter of milliseconds. In conclusion, QC offers a rapid, accurate and versatile solution for large-scale cell quantification and addresses the challenges often faced in cell biology research. PMID- 30477329 TI - DNA barcodes from snake venom: a broadly applicable method for extraction of DNA from snake venoms. AB - DNA barcoding is a simple technique used to develop a large-scale system of classification that is broadly applicable across a wide variety of taxa. DNA based analysis of snake venoms can provide a system of classification independent of currently accepted taxonomic relationships by generating DNA barcodes specific to each venom sample. DNA purification from dried snake venoms has previously required large amounts of starting material, has resulted in low yields and inconsistent amplification, and was possible with front-fanged snakes only. Here, we present a modified DNA extraction protocol applied to venoms of both front- and rear-fanged snakes that requires significantly less starting material (1 mg) and yields sufficient amounts of DNA for successful PCR amplification of regions commonly used for DNA barcoding. [Formula: see text]. PMID- 30477330 TI - Samasy: an automated system for sample selection and robotic transfer. AB - Sample automation and management is increasingly important as the number and size of population-scale and high-throughput projects grow. This is particularly the case in large-scale population studies where sample size is far outpacing the commonly used 96-well plate format. To facilitate management and transfer of samples in this format, we present Samasy, a web-based application for the construction of a sample database, intuitive display of sample and batch information, and facilitation of automated sample transfer or subset. Samasy is designed with ease-of-use in mind, can be quickly set up, and runs in any web browser. PMID- 30477331 TI - Rapid selection of single-stranded DNA aptamers binding Staphylococcus epidermidis in platelet concentrates. AB - Staphylococcus epidermidis is the most common transfusion-associated pathogen contaminating platelet concentrates. Methods to reduce or eliminate contaminating bacteria from platelet units are critical for improving the safety of blood transfusions. We used rapid isolation of DNA aptamers (RIDA) to identify single stranded (ss)DNA aptamers as ligands that specifically bind to S. epidermidis. Five target-specific ssDNA aptamers (76 mer) were obtained under stringent selection conditions. Aptamer SE43 demonstrated higher binding affinity compared with scrambled control. Furthermore, when binding assays were conducted in platelet concentrate, there was a twofold increase in binding affinity compared with the SE43 binding in buffer alone. Our data identified an aptamer that may be useful as a ligand to capture, detect or remove S. epidermidis contaminant from platelet concentrates. PMID- 30477332 TI - Oxford nanopore sequencing enables rapid discovery of single-domain antibodies from phage display libraries. AB - Antibody (Ab) repertoire sequencing using high-throughput massively parallel technologies has contributed substantially to the understanding of Ab responses following infection, vaccination and autoimmunity. Because individual B-cell receptors are recombined and diversified somatically, genomic comparisons are limited, and distinguishing rare variants from sequencing errors is a major challenge. Oxford Nanopore Technologies' MinION is a highly portable and cost effective third-generation sequencing instrument, but has not been used for Ab repertoire sequencing due to its high error rate (approximately 1/10 bases). Here, we applied nanopore sequencing to single-domain Ab (sdAb) repertoires and phage-displayed sdAb libraries. We show that despite low overall data fidelity, sdAb sequences could be reconstructed above a frequency threshold (~100 copies); however, distinguishing clonal sdAb variants was not always possible. The data quality was sufficient to enable rapid identification of antigen-specific sdAb sequences enriched during panning of phage display libraries, obviating the need for screening single clones. PMID- 30477333 TI - Implementation of Occupational Sun Safety at a 2-Year Follow-Up in a Randomized Trial: Comparison of Sun Safe Workplaces Policy Intervention to Attention Control. AB - PURPOSE:: Implementation of employer sun safety actions was assessed in a 2-year follow-up to an occupational sun protection policy intervention. DESIGN:: Two year follow-up assessment in a randomized pretest-posttest controlled design. SETTING:: Local government organizations with workers in public safety, public works, and parks and recreation. PARTICIPANTS:: Sixty-three local government organizations (participation = 64%) and 330 frontline supervisors and 1454 workers. INTERVENTION:: Sun Safe Workplaces (SSW) intervention promoting occupational sun safety policy and education. MEASURES:: Observations of SSW messages and sun safety items and surveys on organizations' communication and actions on sun safety. ANALYSIS:: Comparison between SSW and control groups was conducted using regression models and adjusted for clustering where appropriate, with alpha criterion set at P = .05 (2-tailed). RESULTS:: At intervention worksites, more SSW messages ( P < .001) and sun safety items ( P = .025) were observed; more frontline supervisors reported organizations provided free/reduced price sunscreen ( P = .005) and communicated about sun safety ( P < .001); and more workers recalled receiving sun safety messages ( P < .001) and sun safety training ( P <.001) compared to control organizations. Implementation was greater at larger than smaller intervention organizations for wide-brimmed hats ( P = .009), long work pants ( P = .017), and shade structures ( P = .036). Older workers received the most written messages ( P = .015). CONCLUSIONS:: Sun Safe Workplaces appeared to produce actions by organizations to support employee sun safety. Large organizations may have processes, communication channels, and slack resources to achieve more implementation. PMID- 30477334 TI - Evaluation of Risk Factors for Limb-Specific Peripheral Vascular Events in Patients With Peripheral Artery Disease: A Post Hoc Analysis of the SEASON Prospective Observational Study. AB - Surveillance of cardiovascular Events in Antiplatelet-treated arterioSclerosis Obliterans patients in JapaN (SEASON) is a 2-year, prospective, real-world, registry study conducted in Japan from 2009 to 2013. This post hoc analysis evaluated risk factors for limb ischemia in patients with peripheral arterial disease (PAD) and ankle-brachial index (ABI) <0.90. Vascular events were adjudicated by an Efficacy Endpoint Review Committee. Cox regression identified predictors of limb-specific peripheral vascular events (amputation, development of critical limb ischemia, and acute limb ischemia). Patients (n = 6565) were stratified according to ABI: normal (>=1.0; n = 1300), borderline (0.90 <= ABI <= 1.0; n = 776), and abnormal (<0.90; n = 4489). Compared to normal ABI, patients with ABI <0.90 had a significantly higher risk of any vascular event, all-cause death, and any limb-specific peripheral vascular event. Risk factors for limb specific vascular events included history of lower extremity revascularization/amputation (adjusted hazard ratio: 2.18; 95% confidence interval [CI]: 1.49-3.20), chronic kidney disease (2.00; 1.33-3.00), diabetes (1.71; 1.16-2.52), and ABI <0.4 (4.45; 2.62-7.55) or <0.7 (1.78; 1.15-2.76). These findings from a Japanese real-world population confirm the increased vascular risk of patients with PAD and ABI <0.90 and identified risk factors for limb-specific peripheral vascular events. PMID- 30477335 TI - What Are PWDs (People With Diabetes) Doing Online? A Netnographic Analysis. AB - BACKGROUND:: Social media have become a crucial channel for patient empowerment and peer support. New qualitative research underscores the fact that this "support" transcends mental health concerns, to actually provide patients with important practical tips and tricks for diabetes self-care, and product selection/decision-making information from peers. METHODS:: Netnography is an emerging methodology that applies an ethnographic research approach to studying activity on the social web. Researchers embed themselves in the online environment to take an observational "deep dive" into online conversations to identify themes, sentiments, and perceptions. Using this methodology in summer 2017, a team of researchers captured and analyzed hundreds of diabetes-related posts on prominent platforms Facebook, Twitter, YouTube, Instagram, Tumblr, Pinterest, Reddit, and Quora. RESULTS:: Our team identified 6 major trends, or "life themes," in diabetes patient social media, providing insights into patient sentiments and needs. A topology of social media channels emerged, indicating which platforms are used most often for each life theme. CONCLUSIONS:: Findings indicate that social media provides a significant source not only of moral support and camaraderie, but also critical education on thriving with diabetes. Importantly, we observed strong evidence of peer influence on patients' therapy and diabetes technology purchasing decisions. PMID- 30477336 TI - An observational study on the clinical features of esophageal cancer followed by multiple primary cancers. AB - AIM: To investigate the nature of multiple primary cancers initiated by esophageal cancer-multiple primary cancers (EC-MPC). PATIENTS & METHODS: SEER data about patients'/tumor characteristics, and survival were analyzed and compared. RESULTS AND CONCLUSION: 1727 of 29,733 registered EC patients have EC MPC. Individuals diagnosed at 60-79 years old, earlier stage and/or moderately differentiated EC were more likely to get EC-MPC. Fewer patients in the EC-MPC group suffered from metastases. Patients in the EC-MPC group showed a longer survival rate and lower EC-specific deaths. Other factors like age, sex, race, tumor differentiation and Tumor, Node, Metastasis stage also affected survival. Radiation can improve survival. EC-MPC patients have some distinct features compared with solitary EC. PMID- 30477337 TI - Commentary: The Emergence of Pod Mods at Vape Shops. AB - The vape shop industry is a rapidly growing market sector with a constantly changing product landscape. The rapid evolution of nicotine delivery systems, most notably the emergence of salt nicotine e-juice and pod mod devices, have resulted in a sudden shift in the product market, suggesting new implications for the health professions in addressing electronic cigarette use. PMID- 30477338 TI - Evaluation of Point of Care Analyzer for Hemoglobin A1c. PMID- 30477339 TI - Structural Equation Modeling of Social Networks: Specification, Estimation, and Application. AB - Psychologists are interested in whether friends and couples share similar personalities or not. However, no statistical models are readily available to test the association between personalities and social relations in the literature. In this study, we develop a statistical model for analyzing social network data with the latent personality traits as covariates. Because the model contains a measurement model for the latent traits and a structural model for the relationship between the network and latent traits, we discuss it under the general framework of structural equation modeling (SEM). In our model, the structural relation between the latent variable(s) and the outcome variable is no longer linear or generalized linear. To obtain model parameter estimates, we propose to use a two-stage maximum likelihood (ML) procedure. This modeling framework is evaluated through a simulation study under representative conditions that would be found in social network data. Its usefulness is then demonstrated through an empirical application to a college friendship network. PMID- 30477340 TI - Coping Processes, Self-Efficacy, and CPAP Use in Adults With Obstructive Sleep Apnea. AB - BACKGROUND: Coping strategies are predictive of 1 week CPAP use. Coping strategies may predict longer-term CPAP use among adults with obstructive sleep apnea (OSA). OBJECTIVES: To investigate the influence of two coping styles (active and passive) and individual coping processes on CPAP use at 1 week and 1 month; and explore the association between self-efficacy and coping on CPAP use. PARTICIPANTS: CPAP-naive adults (52.3% male, 90.9% White) newly diagnosed with OSA (AHI >= 5 events/hr) from two U.S. clinical sleep centers (n = 66). METHODS: A post-hoc analysis from a prospective, longitudinal study that examined influential factors on CPAP use among CPAP-naive patients with newly diagnosed OSA. The Ways of Coping Questionnaire and the Self-Efficacy Measure for Sleep Apnea were completed immediately after CPAP titration polysomnography. Objective 1 week and 1 month CPAP use (mean hr/night) were the primary outcomes. Descriptive analyses and stepwise multiple linear regression analyses modeling for CPAP use (mean hr/night). RESULTS: Active coping was significantly associated with greater CPAP use (mean hr/night) at 1 week, but not at 1 month (p = 0.0397; p = 0.0556, respectively). Higher Planful Problem Solving was significantly associated with greater average CPAP use at 1 week and 1 month (p = 0.0117, p = 0.0378, respectively). Self-efficacy was significantly associated with greater average CPAP use at 1 week (p = 0.0056) and 1 month (p = 0.0056). CONCLUSIONS: Self-efficacy and Planful Problem Solving coping are promising behavioral intervention targets to promote CPAP use in newly diagnosed OSA. PMID- 30477341 TI - Event-Related Potentials Are Associated With Unexpected Gain and Loss: Using a Gambling Paradigm. AB - OBJECTIVE: Previous neuroimaging studies have described altered activity in brain areas associated with reward processing following reward or punishment. This study examines the extent to which feedback-based experience of gain and loss is associated with electrophysiological correlates. METHODS: Twenty-nine healthy participants used a gambling task that focused on actual nonpredictable gains and losses. During the task, an electroencephalography recording was performed in order to assess reward processing. Event-related potentials were analyzed when participants were receiving gain/loss feedback. RESULTS: Event-related potentials revealed higher feedback-related negativity for both overall gain and loss compared with a neutral condition in fronto-centro-parietal electrodes. P3 potentials were significantly increased for high gains/losses compared to neutral and small gains/losses. CONCLUSION: These results indicate that the paradigm is suitable to evoke specific patterns of reward-related electrophysiological responses. The wavelet analysis showed that electroencephalography frequency variations depended on the amount of gains/losses. SIGNIFICANCE: This gambling paradigm is appropriate to measure aspects of feedback processing and could help analyze disease-specific alterations of the reward system in patients. PMID- 30477342 TI - Identifying Imperatives for an Effective Nutrition Surveillance Policy Framework for Maternal and Child Health in Lesotho. AB - BACKGROUND:: Surveillance of nutrition indicators is critical for informing nutrition policies and programs. The failure by many sub-Saharan countries to maintain functional surveillance systems for maternal and child health (MCH) hampers their capacity to achieve the 2030 Sustainable Development Goals relevant for MCH. The nutrition surveillance system (NSS) for MCH in the southern African country of Lesotho is no exception to this problem despite the country having some of the highest maternal and child mortality ratios globally. OBJECTIVE:: The study reviewed Lesotho's quantitative nutrition surveillance data and qualitatively analyzed the structure and functionality of Lesotho's NSS to identify imperatives for an effective nutrition surveillance policy framework for MCH in the country. METHODS:: Descriptive quantitative analyses were based on NSS data and nationally representative Lesotho Demographic and Health Survey (LDHS) data while qualitative analysis on data obtained through interviews with purposefully selected key informants working in the NSS of Lesotho was based on grounded theory. RESULTS:: Nutrition surveillance system data were inconsistently compiled across Lesotho's 10 districts, while LDHS data suggested that stunting, maternal anemia, child overweight, and low birth weight remain high. Challenges with the NSS were linked to poor coordination of the NSS due to an indistinct organogram of nutrition offices and poor cooperation among stakeholders in the NSS. CONCLUSIONS:: To improve the NSS in Lesotho, the most critical imperative is to capacitate the Food & Nutrition Coordinating Office which in turn should create distinct nutrition offices yet with adequate cooperation and clear benchmarks for monitoring and evaluation of the NSS. PMID- 30477343 TI - Antimicrobial mechanism and the effect of atmospheric pressure N2 plasma jet on the regeneration capacity of Staphylococcus aureus biofilm. AB - This study systematically assessed the inactivation mechanism on Staphylococcus aureus biofilms by a N2 atmospheric-pressure plasma jet and the effect on the biofilm regeneration capacity from the bacteria which survived, and their progenies. The total bacterial populations were 7.18 +/- 0.34 log10 CFU ml-1 in biofilms and these were effectively inactivated (>5.5-log10 CFU ml-1) within 30 min of exposure. Meanwhile, >80% of the S. aureus biofilm cells lost their metabolic capacity. In comparison, ~20% of the plasma-treated bacteria entered a viable but non-culturable state. Moreover, the percentage of membrane-intact bacteria declined to ~30%. Scanning electron microscope images demonstrated cell shrinkage and deformation post-treatment. The total amount of intracellular reactive oxygen species was observed to have significantly increased in membrane intact bacterial cells with increasing plasma dose. Notably, the N2 plasma treatment could effectively inhibit the biofilm regeneration ability of the bacteria which survived, leading to a long-term phenotypic response and dose dependent inactivation effect on S. aureus biofilms, in addition to the direct rapid bactericidal effect. PMID- 30477344 TI - Confessions of a Reluctant Caregiver Palliative Educational Program: Using Readers' Theater to Teach End-of-Life Communication in Undergraduate Medical Education. AB - End-of-life care can be stressful for patients, caregivers, and providers. Caregivers often experience high levels of burden from caregiving duties such as performing medical tasks, communicating with providers, and making decisions. Similarly, many physicians feel unprepared to provide end-of-life care or communicate with patients and families about sensitive issues associated with death and dying. Physicians often attribute their lack of preparation to inadequate training in medical school. Previous research suggests that drama based learning opportunities are valuable supplements to existing end-of-life curricula. The current study evaluates the success of the Confessions of a Reluctant Caregiver Palliative Educational Program - a drama-based educational program that depicts patient and caregiver experiences. A total of 477 osteopathic medical students participated in the program, which includes viewing a play, engaging in a facilitated post-performance talkback session, and completing an evaluation survey. The results suggest the program is a valuable learning experience that is positively associated with important facets of experiential learning using narratives such as perceived realism, increased reflection, strong emotions, and increased comfort with difficult behaviors. The program offers a safe environment for medical students to identify, understand, and process the sensitive and complex issues associated with end-of-life care. Moreover, the play offers insight into the often-overlooked experiences of family caregivers who are at risk of experiencing high caregiver burden while managing health-related communication and decision-making. PMID- 30477345 TI - Whole-genome characterization of Shewanella algae strain SYT3 isolated from seawater reveals insight into hemolysis. AB - AIM: To describe the genomic characteristics of seawater-borne hemolytic Shewanella algae and its resistance genes. MATERIALS & METHODS: Whole genome sequence of S. algae SYT3 was determined using llumina MiSeq platform. Multiple database-based analysis was performed to identify the genetic background of its hemolytic activity and the antibiotic resistance genes. RESULTS: S. algae SYT3 possesses a homolog of the hly operon involved in the synthesis of hemolysin. We also identified candidate genes associated with resistance to beta-lactam antibiotics (bla OXA-55) and fluoroquinolone (qnrA3). CONCLUSION: The study provides an insight into the hemolytic activity of S. algae. Our findings also suggested S. algae as a potential reservoir of antimicrobial resistance determinants. PMID- 30477346 TI - Comments on "Nonsurgical Treatment of De Quervain Tenosynovitis: A Prospective Randomized Trial". PMID- 30477347 TI - Development of classification models for predicting chronic toxicity of chemicals to Daphnia magna and Pseudokirchneriella subcapitata. AB - Both the acute toxicity and chronic toxicity data on aquatic organisms are indispensable parameters in the ecological risk assessment priority chemical screening process (e.g. persistent, bioaccumulative and toxic chemicals). However, most of the present modelling actions are focused on developing predictive models for the acute toxicity of chemicals to aquatic organisms. As regards chronic aquatic toxicity, considerable work is needed. The major objective of the present study was to construct in silico models for predicting chronic toxicity data for Daphnia magna and Pseudokirchneriella subcapitata. In the modelling, a set of chronic toxicity data was collected for D. magna (21 days no observed effect concentration (NOEC)) and P. subcapitata (72 h NOEC), respectively. Then, binary classification models were developed for D. magna and P. subcapitata by employing the k-nearest neighbour method (k-NN). The model assessment results indicated that the obtained optimum models had high accuracy, sensitivity and specificity. The model application domain was characterized by the Euclidean distance-based method. In the future, the data gap for other chemicals within the application domain on their chronic toxicity for D. magna and P. subcapitata could be filled using the models developed here. PMID- 30477348 TI - Internal and external factors of plagiarism: Evidence from Chinese public sector universities. AB - AIMS: This study explores the effects of internal and external factors that encourage plagiarism from the perspective of students. METHODS: We collected student data from five public sector universities in Anhui Province, China, by randomly distributing survey questionnaires to 250 students, 176 of which were usable. We analyzed the collected quantitative data through multiple regression analysis. RESULTS: Our research results demonstrate that external and internal factors have a great influence on plagiarism. The control behavior and teaching factors have a significant positive impact on plagiarism, while information technology does not have a considerable impact on plagiarism. Among the external factors, a significant positive correlation exists between external stress, pride, and plagiarism; however, no significant relationship exists between academic skills and plagiarism. CONCLUSION: The article concludes that grade level and enrollment status (full-time or part-time) are inversely correlated to plagiarism, which proves that the higher the academic level, the less the plagiarism behaviors occurs. This concept may be due to the fact that the higher the academic level, the stronger the plagiarism constraints might be, which in turn leads to a drastic decrease in plagiarism. Moreover, a negative relationship emerges between enrollment status (full-time or part-time) and plagiarism because part-time students who are committed to an employment are less likely to give their full attention to their studies. PMID- 30477350 TI - The Protective Effects of Omega3 on Ubiquitination and Protamination of Rat Sperm after Bleomycin, Etoposide, and Cisplatin Treatment. AB - The purpose of this study is evaluation the protective effect of omega3 on rat sperm protamination and ubiquitination after treatment with Bleomycin, Etoposide and Cisplatin (BEP) drugs. In present study, 40 male rats were divided into four groups: Control, BEP, Omega3 and BEP + Omega3. Sperm protamination and ubiquitination were assessed using chromomycin A3 and immunofluorescence staining respectively. The mean percentage of ubiquitinated sperm in BEP group was significantly increased relative to control group (P < .001). But, the mean percentage of sperm protamination significantly decreased in BEP group relative to control group (P < .001). Rats in BEP + Omega3 group showed a significantly decreased in the mean percentage of sperm ubiquitination as compared to BEP group (P < .05) while, sperm protamination increased significantly relative to BEP group (P < .001). Administration of Omega3 after chemotherapy showed an improvement in sperm ubiquitination and protamination. Our data indicated that omega3 after chemotherapy may be beneficial for chromatin remodeling during spermatogenesis following BEP treatment. PMID- 30477351 TI - Proliferation of rheumatoid arthritis fibroblast-like synoviocytes is enhanced by IL-17-mediated autophagy through STAT3 activation. AB - Fibroblast-like synoviocytes (FLSs), with their tumor-like proliferation, play an important role in rheumatoid arthritis (RA), and interleukin-17 (IL-17) participates in RA pathology by affecting FLSs. The aims of this study were to investigate the effects of IL-17 on the proliferation and autophagy of FLSs and the role of signal transducer and activator of transcription-3 (STAT3) in RA. FLSs were treated with IL-17 at different concentrations (0, 1, 10, and 20 ng/mL); then, autophagy was assayed with western blotting, immunofluorescence and transmission electron microscopy. The effects of IL-17 on FLSs proliferation were measured with the Cell Counting Kit-8 assay and flow cytometry to analyze cell cycle distribution, and proliferating cell nuclear antigen (PCNA) was detected by western blotting. The autophagy inhibitors, 3-methyladenine (3-MA) and chloroquine (CQ), were used to determine the effect of autophagy on proliferation in IL-17-treated FLSs. Finally, the STAT3 inhibitor STA21 was used to examine the relationship between STAT3 and autophagy in IL-17-treated FLSs. Our results showed that IL-17 positively affected autophagy and proliferation in FLSs. Inhibition of autophagy suppressed the IL-17-mediated proliferation of FLSs. Additionally, suppression of STAT3 activation decreased autophagy in IL-17 treated FLSs. Our findings showed that IL-17 promoted the tumor-like proliferation of FLSs by upregulating autophagy via STAT3 activation. PMID- 30477352 TI - Preventing complications by persistence with iron replacement therapy: a comprehensive literature review. AB - OBJECTIVE: Iron deficiency and particularly iron deficiency anemia (IDA) can lead to negative health consequences. This review describes the importance of adherence and persistence (adhering to treatment for the recommended duration) with iron replacement therapy in the prevention of complications, particularly regarding its recommended dosing schedule. METHODS: Comprehensive literature searches were performed of Medline and the Cochrane library from 2000-2018. Keywords included iron deficiency or IDA, compliance or adherence, persistence, health beliefs, risk factor, complications, dosing cycles, oral iron replacement therapy and recommendations for duration, ferrous compounds, iron supplementation, dietary iron, and delayed-action/slow-release preparations. RESULTS: Identified articles focused on IDA as a risk factor (particularly for worsened comorbidities or surgical outcomes), guidelines, adherence and persistence, and differences between iron formulations. Current guidelines and expert opinion continue to support oral iron supplementation as first-line therapy. While it is recommended to take iron therapy for 2 months to normalize the hemoglobin, then 2-3 months to build up iron stores, many patients face difficulties in adhering to and persisting with the full iron treatment regimen. Patient education and understanding, social support, simple dosing, perceived efficacy including reduced symptoms, and tolerability were factors noted to promote medication adherence and persistence. Adherence to iron therapies appears to be facilitated by using ferrous sulfate due to its optimal absorption, and particularly extended-release forms due to their improved tolerability for iron deficiency. CONCLUSIONS: Proper adherence and persistence with iron supplementation may prevent or reduce the risk of complications of iron deficiency and IDA. PMID- 30477353 TI - Stand Alone or Join Forces? Stem Cell Therapy for Stroke. AB - INTRODUCTION: Stroke is a major cause of mortality and disability with a narrow therapeutic window after onset. Stem cell therapy may enhance the functional and neurological outcome after stroke. Areas Covered: Regenerative medicine via stem cells stands as a novel approach for stroke therapy. In particular, bone marrow derived mesenchymal stem cells (MSCs) have neuroprotective and anti-inflammatory properties that improve brain function after stroke. Here, we discuss the use of bone marrow-derived MSCs for stroke treatment and the safety, efficacy, and mechanism of action underlying their therapeutic effects. We also examine the discrepant transplant protocols between preclinical studies and clinical trials. Laboratory studies show the safety and efficacy of bone marrow-derived MSCs in stroke models. However, while safe, MSCs remain to be fully evaluated as effective in clinical trials. Furthermore, recognizing the multiple cell death processes associated with stroke, we next discuss the potential therapeutic benefits of a combination therapy. With preliminary results and on-going clinical trials, a careful assessment of dosing, timing, and delivery route regimens will further direct the future of stem cell therapy for neurological disorders, including stroke. Expert Opinion: Bone marrow-derived MSCs appear to be the optimal stem cell source for stroke therapy. Optimizing dosing, timing, and delivery route should guide the clinical application of bone marrow-derived MSCs. PMID- 30477354 TI - Patient and public involvement in the design, administration and evaluation of patient feedback tools, an example in psychiatry: a systematic review and critical interpretative synthesis. AB - BACKGROUND: Patient feedback is considered integral to healthcare design, delivery and reform. However, while there is a strong policy commitment to evidencing patient and public involvement (PPI) in the design of patient feedback tools, it remains unclear whether this happens in practice. METHODS: A systematic review using thematic analysis and critical interpretative synthesis of peer reviewed and grey literature published between 2007 and 2017 exploring the presence of PPI in the design, administration and evaluation of patient feedback tools for practising psychiatrists. The research process was carried out in collaboration with a volunteer mental health patient research partner. RESULTS: Fourteen articles (10 peer-reviewed, four grey literature) discussing the development of nine patient feedback tools were included. Six of the nine tools reviewed were designed from a professional perspective only. Tool content and its categorization primarily remained at the professional's discretion. Patient participation rates, presence of missing data and psychometric validation were used to determine validity and patient acceptability. In most instances, patients remained passive recipients with limited opportunity to actively influence change at any stage. No article reviewed reported PPI in all aspects of tool design, administration or evaluation. CONCLUSIONS: The majority of patient feedback tools are designed, administered and evaluated from the professional perspective only. Existing tools appear to assume that: professional and patient agendas are synonymous; psychometric validation is indicative of patient acceptability; and psychiatric patients do not have the capacity or desire to be involved. Future patient feedback tools should be co-produced from the outset to ensure they are valued by all those involved. A reconsideration of the purpose of patient feedback, and what constitutes valid patient feedback, is also required. PMID- 30477355 TI - Heart failure and right ventricular pacing - how to avoid the need for cardiac resynchronization therapy. AB - INTRODUCTION: Heart failure is a common finding in patients with pacemakers implanted for bradycardia, with cross-sectional and longitudinal studies contributing to the growing consensus that right ventricular pacing can cause adverse cardiac remodeling and left ventricular systolic dysfunction increasing the risk of hospitalization and death. An unselected approach using cardiac resynchronization therapy from the time of first implant in patients with heart block has produced equivocal results. Contemporary research has therefore begun to focus on the stratification of patients' risk of pacemaker-associated impairment to permit focused, personalized management. Areas covered: The present review will describe the incidence and relevance of heart failure in the pacemaker population and discuss current management options for such patients. Expert commentary: At present there are few contemporary data to guide the identification of patients with and at risk of pacemaker-associated cardiac remodeling and dysfunction. Emphasis must be placed on precise and personalized treatment approaches which currently remain under-investigated due to a number of challenges, for example, small sample sizes, limited clarity on programmed settings, and short follow-up periods. PMID- 30477356 TI - Kaempferol inhibits proliferation, migration, and invasion of liver cancer HepG2 cells by down-regulation of microRNA-21. AB - Liver cancer is one of the most common and lethal cancers in human digestive system, which kills more than half a million people every year worldwide. This study aimed to investigate the effects of kaempferol, a flavonoid compound isolated from vegetables and fruits, on hepatic cancer HepG2 cell proliferation, migration, invasion, and apoptosis, as well as microRNA-21 (miR-21) expression. Cell viability was detected using cell counting kit-8 (CCK-8) assay. Cell proliferation was measured using 5-bromo-2'-deoxyuridine (BrdU) incorporation assay. Cell apoptosis was assessed using Guava Nexin assay. Cell migration and invasion were determined using two-chamber migration (invasion) assay. Cell transfection was used to change the expression of miR-21. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to analyze the expressions of miR-21 and phosphatase and tensin homologue (PTEN). Expression of key proteins involved in proliferation, apoptosis, migration, invasion, and phosphatidylinositol 3-kinase/protein kinase 3/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway were evaluated using western blotting. Results showed that kaempferol significantly inhibited HepG2 cell proliferation, migration, and invasion, and induced cell apoptosis. Kaempferol remarkably reduce the expression of miR-21 in HepG2 cells. Overexpression of miR-21 obviously reversed the effects of kaempferol on HepG2 cell proliferation, migration, invasion, and apoptosis. Moreover, miR-21 negatively regulated the expression of PTEN in HepG2 cells. Kaempferol enhanced the expression of PTEN and inactivated PI3K/AKT/mTOR signaling pathway in HepG2 cells. In conclusion, kaempferol inhibited proliferation, migration, and invasion of HepG2 cells by down-regulating miR-21 and up-regulating PTEN, as well as inactivating PI3K/AKT/mTOR signaling pathway. PMID- 30477357 TI - Evaluation of antidiabetic activity of Ipomoea batatas L. extract in alloxan induced diabetic rats. AB - Different allopathic drugs are being used for the treatment of diabetes mellitus but more emphasis are being placed on the use of medicinal plants, herbs, and natural extracts of fruits and vegetables due to their easy availability, easy consummation with low cost, and with no well-reported side effects. White skinned sweet potato (WSSP; Ipomoea batatas L.) peel-off was selected to find out its antidiabetic potential as well as to explore the effects on selected biochemical parameters in diabetes-induced Wistar rats. In young (3-4 months) and old (up to 1 year) diabetic Wistar rats, it was found that WSSP ( I. batatas L.) peel-off significantly ( P < 0.05) decreased blood glucose level, protein glycation level, total cholesterol, triglycerides, and low-density lipoprotein (LDL)-cholesterol. A significant ( P < 0.05) increase in high-density lipoprotein (HDL)-cholesterol level after treatment was also reported. Furthermore, it was also found that WSSP peel-off also had beneficial effects on total protein concentration, albumin, globulin, and liver enzymes (serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT)). It might be concluded that antidiabetic potential of WSSP extract is due to the presence of bioactive compounds like glycoprotein, anthocyanins, alkaloids, and flavonoids, which act as insulin-like molecules or insulin secretagogues constituents in sweet potatoes peel-off and these antidiabetic proteins were extracted out in more concentration in methanol due to its organic nature. Further research is needed to purify and quantify the antidiabetic components responsible for antidiabetic effects of WSSP and it should be available in compact dose form for the treatment of diabetic patients. PMID- 30477358 TI - Transfusion rates with intravenous tranexamic acid in total hip arthroplasty performed using the direct anterior approach. AB - INTRODUCTION:: Tranexamic acid (TXA) has been shown to reduce blood loss and transfusion requirements in patients undergoing total hip arthroplasty (THA). Most studies have focused on TXA in THA performed using a posterior approach (PA) or lateral approach. The aim of this study was to analyse the efficacy of TXA in patients undergoing THA using the direct anterior approach (DAA). PATIENTS AND METHODS:: Using our institutional database, a retrospective analysis was conducted on consecutive primary THA performed for osteoarthritis to determine transfusion rates in patients undergoing THA with the DAA with and without TXA. RESULTS:: 146 consecutive THA were performed using DAA: 83 (56.8%) patients had TXA and 63 (43.2%) did not have TXA. Among patients who had TXA, 1 patient required a blood transfusion compared to 7 patients among those who did not have TXA (1.2% vs. 11.12%, p = 0.02). The relative risk of 0.11 (95% confidence interval 0.01-0.86) indicates an 89% reduction in the risk of requiring blood transfusion with TXA administration compared to no TXA. CONCLUSION:: TXA is effective in reducing blood transfusion requirements for patients undergoing DAA THA. PMID- 30477359 TI - Prevalence and predictors of mortality in gastroschisis: a population-based study of 4803 cases in the USA. AB - PURPOSE: Gastroschisis is a rare congenital anomaly consisting of an abdominal wall defect resulting in extrusion of the abnormal organs. Survival of these infants exceeds 90%. Few large-scale studies have examined the predictors of mortality for these infants. Our objective was to conduct a population-based study to determine prevalence and predictors of mortality among infants born with gastroschisis. MATERIALS AND METHODS: We used the "Period Linked Birth-Infant Death" database to create a cohort of all births occurring between 2009 and 2013. Infants were categorized by the presence of gastroschisis, excluding infants born at <24-week gestation. Baseline maternal and newborn characteristics were compared for infants who survived and those who died. Multivariate logistic regression models were used to estimate the effect of maternal and fetal factors on mortality, while adjusting for appropriate baseline characteristics. RESULTS: There were 4803 cases of gastroschisis, with 287 deaths. The prevalence of gastroschisis increased from 2.04 to 2.49/10,000 births over the study period. The rate of death stayed constant at about 5.9%. We found that 38.1% of these infants died on day 0 of life. Statistically significant predictors of mortality were the presence of an additional congenital anomaly, birth weight <2500 g, prepregnancy diabetes, gestational age <34 weeks, paying out of pocket for healthcare, and maternal obesity. CONCLUSIONS: The prevalence of gastroschisis in the USA increased, yet the mortality rate remained stable. Infants born preterm <34 weeks, with birth weights <2500 g, or with an additional congenital anomaly were at the highest risk of death. PMID- 30477360 TI - Advances and challenges in drug design against tuberculosis: application of in silico approaches. AB - INTRODUCTION: Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains the deadliest infectious disease in the world with one-third of the world's population thought to be infected. Over the years, TB mortality rate has been largely reduced; however, this progress has been threatened by the increasing appearance of multidrug-resistant Mtb. Considerable recent efforts have been undertaken to develop new generation antituberculosis drugs. Many of these attempts have relied on in silico approaches, which have emerged recently as powerful tools complementary to biochemical attempts. Areas covered: The authors review the status of pharmaceutical drug development against TB with a special emphasis on computational work. They focus on those studies that have been validated by in vitro and/or in vivo experiments, and thus, that can be considered as successful. The major goals of this review are to present target protein systems, to highlight how in silico efforts compliment experiments, and to aid future drug design endeavors. Expert opinion: Despite having access to all of the gene and protein sequences of Mtb, the search for new optimal treatments against this deadly pathogen are still ongoing. Together with the geometric growth of protein structural and sequence databases, computational methods have become a powerful technique accelerating the successful identification of new ligands. PMID- 30477361 TI - Adherence to Diet and Body Weight Recommendations among Cancer Survivors after Completion of Initial Cancer Treatment: A Systematic Review of the Literature. AB - This systematic review of the literature aimed to 1) provide an overview of the extent to which cancer survivors adhere to diet and body weight recommendations after completion of initial treatment and 2) gain insight into characteristics associated with adherence to these recommendations. Four databases were searched for relevant papers. We included observational studies describing adherence to recommendations on body mass index (BMI), waist-to-hip ratio and waist circumference, fruit and vegetable intake, and alcohol consumption of adult (>=18 yr) cancer survivors after the completion of initial treatment (i.e. surgery, chemotherapy, and radiotherapy). Of the 2,830 articles retrieved from the database search, 12 articles were included. Adherence to the recommendation on BMI varied from 34% to 77%; adherence to the fruit and vegetable recommendation varied from 9% to 83%; and adherence to the recommendation on alcohol consumption varied from 62% to 96.8%. Adherence to waist-to-hip ratio (43%) and waist circumference recommendations (11%) was described in one study among overweight breast cancer survivors. The results of these studies generally suggest that adherence to the recommendation on alcohol intake is relatively high and that adherence to the recommendation on body weight and fruit and vegetable intake should particularly be promoted. PMID- 30477362 TI - Comments of manuscript: ultrasound characteristics and outcome of prenatally diagnosed fetal cholelithiasis. PMID- 30477363 TI - Potential effect of inflammation on the failure risk of in vitro fertilization and embryo transfer among infertile women. AB - This study investigated the association between inflammation in infertile women and the risk of IVF-ET failure, as well as the potential effects of various lifestyles on this association. A total of 84 women undergoing IVF-ET in Beijing China were recruited, including 38 women who did not achieve pregnancy after undergoing IVF-ET and 46 women who conceived. Serum samples were collected on the second day of menstruation before the treatment cycle and the inflammatory cytokines (interleukin-1beta, interleukin-6, interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1)) were measured. Information about their lifestyle was collected by questionnaire. It was found that the serum IL-8 concentration in the women who did not become pregnant (cases) was significantly higher than in the women who did achieve a pregnancy (controls). A dose-response relationship between the serum IL-8 concentration and the risk of IVF-ET failure was observed, especially when the IL-8 concentration was >11.2 pg/mL. The same relationship was not found for MCP-1. Among the environmental factors investigated, only the frequency of staying up late was positively correlated with the serum IL-8 concentration, as well as positively associated with the risk of IVF-ET failure. It was concluded that excessive inflammation may have an adverse effect on the IVF-ET success rate in infertile women. PMID- 30477364 TI - Sororicides in Ghana: A Study of Homicidal Aggression Against Sisters. AB - Sororicide has received scarce attention in the homicide literature. This is particularly the case for sororicide incidents occurring in the nonindustrialized, non-Western world. To help address this gap in the literature and extend the study of sororicides, the current exploratory, descriptive study examined the major characteristics of 18 media-reported sororicides that occurred in Ghana from 1990 to 2017, including the sociodemographic characteristics of victims and offenders, victim-offender relationship, incident location, modus operandi, motive, and criminal justice outcomes. The results show that sororicide represents a minuscule proportion of all homicides that occur in the country annually. Brothers were overwhelmingly the perpetrators of sororicide, accounting for 17 of the 18 killings. The findings indicate that a substantial proportion of the sororicides occurred in the context of disputes over money, land, property, or inheritance. Two brothers killed sisters they suspected of maleficent witchcraft. PMID- 30477365 TI - Assessing the Incremental Validity of Andrews and Bonta's "Moderate Four" Predictors of Recidivism Using a Diverse Sample of Offending and Truant Youth. AB - Bonta and Andrews suggest that there are eight factors that predict recidivism among offenders, which they call the "Central Eight." They split up the Central Eight into the "Big Four" and the "Moderate Four," with the Big Four hypothesized to be more strongly associated with recidivism than the Moderate Four. The purpose of this study was to assess the incremental validity of the Moderate Four relative to the Big Four as they are measured on the Youth Level of Service/Case Management Inventory (YLS/CMI). The sample comprised 2,436 youth between the ages of 9 and 18 ( M = 14.34) in the formal probation and truancy division from a juvenile county court in the Midwest. Recidivism was measured as a new petition filed against a youth in court within 2 years of a youth's initial offense. Results indicated that the Moderate Four predictors provided no incremental validity beyond the Big Four but did not reduce the predictive validity of the YLS/CMI. PMID- 30477366 TI - Impact of micronized progesterone on body weight, body mass index, and glucose metabolism: a systematic review. AB - In women, body weight increases with age. Often menopausal hormone therapy (MHT) is blamed for enhancing this effect. In recent years, the debate on bioidentical MHT including micronized progesterone (MP) has increased. Among others, the question has been raised of whether MHT containing MP has an impact on body weight and glucose metabolism. Based on a systematic literature review on the impact of MHT containing MP on body weight, body mass index (BMI), and glucose metabolism, the following conclusions can be drawn: estrogens combined with MP (1) either do not change or reduce body weight in normal weight postmenopausal women, (2) do not change BMI in normal and overweight postmenopausal women, (3) do not change or improve fasting serum glucose levels in (non-)diabetic postmenopausal women, (4) do not change or improve fasting serum insulin levels in (non-)diabetic postmenopausal women, and (5) do not have an impact on serum glycated hemoglobin in postmenopausal diabetic women. This beneficial effect is probably mostly due to the estrogen MHT component. PMID- 30477367 TI - Cannabis Prevalence and National Drug Policy in 27 Countries: An Analysis of Adolescent Substance Use. AB - Prior research that assesses the relationship between cannabis policy and prevalence rates has yielded mixed results, perhaps due to the varying rigor of these investigations. Addressing some of these issues in rigor and informed by a rational choice theory (RCT), we hypothesize that those policies on the more punitive end of McDonald and colleagues' classification will be most effective. Examining legislation in 27 countries utilizing the Second International Self Report Delinquency Study (ISRD-2) through hierarchical linear modeling (HLM) models with both individual- and country-level controls, we find little support for these hypotheses. Instead, results from our analysis largely indicate that the variation in country prevalence rates from 2005 to 2007 was not significantly related to cannabis control policy. We comment on possible policy implications for these preliminary results. PMID- 30477368 TI - Dealing With Conflicts of Interest. PMID- 30477369 TI - Utility of serum galactomannan antigen testing combined with chest computed tomography for early diagnosis of invasive pulmonary aspergillosis in patients with hematological malignancies with febrile neutropenia after antifungal drug treatment. AB - OBJECTIVE: To investigate the value of serum galactomannan antigen (GM) testing combined with chest computed tomography (CT) as a noninvasive method for early diagnosis of invasive pulmonary aspergillosis (IPA) in patients with hematological malignancies with febrile neutropenia after antifungal drug treatment. METHODS: We retrospectively analyzed the data of 376 patients with febrile neutropenia from January 2015 to August 2017. All patients were given broad-spectrum antibiotics and divided into the control group (effective antibiotic treatment, no antifungal drugs given) and the observational group (ineffective antibiotic treatment, antifungal drugs given). The serum GM testing, chest CT, and microbiological examination findings were compared between the two groups. RESULTS: The false-positive rates of GM testing for IPA in the control and observational groups were 4.04% and 8.65%, respectively, and the false negative rates in the two groups were 1.10% and 9.62%, respectively. Sixty-five patients in the observational group and 11 in the control group had typical features of CT imaging. CONCLUSION: Clinical weekly screening of serum GM and chest CT may be an effective combined approach to the early diagnosis of IPA in patients with febrile neutropenia, even if they have undergone antifungal treatment. PMID- 30477370 TI - Onset of menarche is not delayed in Slovenian patients with celiac disease. AB - OBJECTIVE: Celiac disease (CD) is an autoimmune disorder associated with numerous health problems, including reproductive disorders. This study was performed to analyze the association between CD and the menstrual cycle in a group of patients with CD and compare these patients' characteristics with those of healthy women. METHODS: The study included 145 patients with CD (age, 15-51 years) and 162 healthy women (age, 18-55 years). Age at menarche and characteristics of the menstrual cycle were obtained by an anonymous questionnaire developed for the study. RESULTS: The age at onset of menarche was 12 to 14 years in 72.9% of the patients with CD and 77.3% of the healthy controls. For most patients (74.2%), the length of the menstrual cycle was around 27 to 28 days with 4 to 5 days of bleeding. Furthermore, 8.4% of patients versus 5.9% of controls experienced bleeding between cycles. CONCLUSIONS: Our results suggest that in Slovenia, the age at menarche in patients with CD is 12.7 years, which is comparable with that in healthy women. We conclude that CD (treated or untreated) may not be associated with late menarche. PMID- 30477371 TI - N-Acetylcysteine reverses silver nanoparticle intoxication in rats. AB - The increasing use of silver nanoparticles (AgNPs) in consumer products raises the risk of human toxicity. Currently, there are no therapeutic options or established treatment protocols in cases of AgNPs intoxication. We demonstrated previously that thiol antioxidants compounds can reverse the cytotoxicity induced by AgNPs in Huh-7 hepatocarcinoma cells. Here, we investigated the use of N acetylcysteine (NAC) against the systemic toxic effects of AgNPs (79.3 nm) in rats. Biochemical, histopathological, hematological, and oxidative parameters showed that a single intravenous injection of AgNPs (5 mg/kg b.w.) induced deleterious effects such as hepatotoxicity, potentially as a result of AgNPs accumulation in the liver. Treatment with a single intraperitoneal injection of NAC (1 g/kg b.w.) one hour after AgNPs exposure significantly attenuated all toxic effects evaluated and altered the bioaccumulation and release patterns of AgNPs in rats. The findings show that NAC may be a promising candidate for clinical management of AgNPs intoxication. PMID- 30477372 TI - Evaluation of the Swedish Colorectal Cancer Registry: an overview of completeness, timeliness, comparability and validity. AB - BACKGROUND: The Swedish Colorectal Cancer Registry (SCRCR) is a national registry established in 1995 for rectal cancer, and also including colon cancer since 2007. Knowledge of the quality of the registry is vital in order to draw correct conclusions from studies based on the registry. The aim of this study was to assess the completeness, timeliness, comparability and validity of the SCRCR. MATERIAL AND METHODS: Completeness, timeliness and comparability of the registry were estimated. From the SCRCR year 2008, 500 cases were randomly selected to examine the validity of the registry and 486 cases were retrieved. Using hospital patient records as source documents, 130 variables in the SCRCR were reabstracted using the SCRCR registration forms and then compared with the original files. RESULT: During the period 2008-2015, the average completeness of the SCRCR was 98.5% for colon cancer and 98.8% for rectal cancer. Timeliness improved between the years 2008 and 2015, with 98% of the patients registered within 12 months for the year 2015. For most of the variables, comparability was estimated to be reproducible and comparable with other registries. Regarding the validity of the registry, when comparing reabstracted data with the original SCRCR data, average agreement was 90%. CONCLUSION: The SCRCR can be considered a reliable registry useful for quality assurance and research. Standardization and improvements in journal documentation are needed to improve future evaluation of the source documents. PMID- 30477373 TI - Risk factors for acute liver failure among inpatients with anti-tuberculosis drug induced liver injury. AB - OBJECTIVE: To analyze the clinical and laboratory features and determine the predictors of acute liver failure (ALF) among inpatients with anti-tuberculosis (TB) drug-induced liver injury (DILI). METHOD: Patients diagnosed with anti-TB DILI from 2010 to 2016 at The First Affiliated Hospital of Zhejiang University were retrospectively included in this study. Demographic and clinical data were collected by reviewing electronic medical records. RESULTS: Among 155 inpatients with anti-TB DILI, 55 (35.48%) developed ALF, with an overall mortality of 9.68%. The median time to DILI onset was significantly longer in the ALF compared with the non-ALF group (51 versus 24 days). Eighty-three patients (53.55%) developed DILI (53.55%) within the first month of anti-TB treatment, and 60% of ALF cases occurred within 2 months. Multivariable models for ALF incorporating aspartate aminotransferase, total bilirubin, platelets, white blood cell count, and pre existing hepatitis yielded a concordance (C-statistic) of 98.93%. CONCLUSIONS: The results of this study suggest that approximately half of all cases of DILI occur within the first month, while 60% of ALF cases occur within 2 months. Elevated total bilirubin, aspartate aminotransferase, white blood cell count, pre existing hepatitis, and low platelet count are independent risk factors for the development of anti-TB drug-induced ALF. PMID- 30477374 TI - Increased Intracranial Pressure in Acute Disseminated Encephalomyelitis. AB - OBJECTIVE:: To assess the intracranial pressure in pediatric acute disseminated encephalomyelitis using spinal tap opening pressure on lumbar puncture, which is routinely performed as part of suspected acute disseminated encephalomyelitis workup. Compared to other cerebrospinal fluid parameters such as cell count, protein concentration, and presence of oligoclonal bands, cerebrospinal fluid opening pressure is infrequently recorded. METHODS:: A retrospective chart review of demographic, clinical, and laboratory data of children diagnosed with acute disseminated encephalomyelitis admitted to a tertiary referral hospital between 2005 and 2016. RESULTS:: Of the 36 children diagnosed with acute disseminated encephalomyelitis, 24 had the cerebrospinal fluid opening pressure documented in their records. The mean cerebrospinal fluid opening pressure was 27.6+/-12.6 cmH2O, range 9-55 cmH2O (95% confidence interval 21.9-33.6). Cerebrospinal fluid opening pressure in the acute disseminated encephalomyelitis group was statistically significantly higher ( P = .0013, 95% confidence interval 4.2-15.0) than the accepted upper limit in this age group (18 cmH2O). In 10 of 24 patients (42%), the opening pressure was above 28 cmH2O. CONCLUSIONS:: Increased opening pressure was the most frequent cerebrospinal fluid abnormal finding in our cohort, which suggests a potential role of increased intracranial pressure in the acute disseminated encephalomyelitis pathophysiological disease mechanism. In certain cases, the opening pressure value could have monitoring and therapeutic implications, and therefore its measurement is highlighted by this study. PMID- 30477375 TI - Efficacy of Cognitive Rehabilitation in Alzheimer Disease: A 1-Year Follow-Up Study. AB - INTRODUCTION:: The benefit of cognitive rehabilitation (CR) for patients with early-stage Alzheimer disease (AD) remains difficult to assess. METHOD:: An observational, prospective study was conducted in a sample of 52 patients with AD included in a clinical, individualized CR program. Cognitive rehabilitation consisted of 1 weekly session during 3 months at home, followed by 1 monthly contact for 9 months. Rehabilitation techniques were used by experienced therapists to adapt activities important for the patient. Evaluation of patient's dependence in activities and objective and subjective caregiver's burden was performed with a research quantitative scale immediately after the intervention and at 6-month and 1-year follow-up. RESULTS:: Analyses with repeated measure analysis of variance showed decreased patient's dependence for adapted activities at 3 months, 6 months, and 1 year. Objective and subjective percentage of caregiver's burden was also decreased at all evaluations with our research functional scale, while there was no change on Zarit's burden scale. Global cognition slightly decreased over 1 year. CONCLUSIONS:: This observational study in a clinical setting is in line with the benefit of CR for patients with mild AD reported in recent randomized controlled trials. The benefit obtained for adapted activities remained after 1 year, even if global cognition declined. Moreover caregiver's burden related to all individually relevant daily activities (from a list of 98) evaluated within the CR program was decreased after 1 year. Those preliminary results emphasize the importance of choice for the measurement instrument to report CR efficacy and claim for further validation of such tools. PMID- 30477377 TI - Diagnostic and predictive performance of biomarkers in patients with sepsis in an intensive care unit. AB - OBJECTIVE: This study was performed to compare the predictive performance of serum procalcitonin (PCT), N-terminal brain natriuretic propeptide (NT-proBNP), interleukin-6 (IL-6), prothrombin time (PT), thrombin time (TT), and Sequential Organ Failure Assessment (SOFA) score in the intensive care unit (ICU). METHODS: This retrospective cohort study enrolled 150 patients with sepsis and septic shock and 30 control patients without sepsis. Each patient was followed until death or 28 days. Correlations between variables were assessed with Spearman's rho test. The Kruskal-Wallis and Mann-Whitney U tests were used for between-group comparisons. RESULTS: Receiver operating characteristic curve analysis of the SOFA score, PCT, NT-proBNP, IL-6, PT, and TT showed an area under the curve of 0.872, 0.732, 0.711, 0.706, 0.806, and 0.691, respectively, for diagnosing sepsis. Binary logistic regression demonstrated that the SOFA score was an independent predictor of 28-day mortality and septic shock. The correlation coefficient (r) between SOFA and PCT, NT-proBNP and SOFA, IL-6 and SOFA, PT and SOFA, and TT and SOFA was 0.79, 0.52, 0.57, 0.56, and 0.58, respectively. CONCLUSION: While the SOFA score is the gold standard, analysis of multiple biomarkers could increase the performance capacity for diagnosis and prognosis in patients with sepsis in the ICU. PMID- 30477376 TI - Sleep quality associated with mood in elite athletes. AB - OBJECTIVES: This study aimed to analyze the association between sleep quality and mood in elite athletes of different competitive levels. METHODS: Participants were 1,041 elite athletes (aged 20.82 +/- 6.62 years), with 671 men (64.5%/21.52 +/- 6.90 years) and 370 women (35.5%/19.55 +/- 5.89 years) from 10 individual sports and 6 team sports. Participants self-reported sleep quality on a Likert type scale and mood was measured with the Brunel Mood Scale (BRUMS). The data were analyzed using the Kruskal-Wallis test, and binary logistic regression. RESULTS: Results revealed that athletes who compete internationally are 84% more likely to have poor sleep quality than athletes who compete at a regional level. International athletes with good sleep quality showed greater vigor. National athletes with poor sleep quality showed more confusion, depression, and fatigue. Thus, mood and competitive level are factors associated with sleep quality. Confusion, fatigue, and tension impair sleep, and vigor reduces the likelihood of poor sleep. CONCLUSIONS: Sleep should be monitored, especially in international level athletes, in order to prevent sleep disorders during competitions. Coaches and athletes should use techniques and strategies for appropriate management of sleep and mood, to maintain the athletes in optimal condition before important competitions. PMID- 30477378 TI - Sentinel vascular access monitoring after endovascular intervention predicts access outcome. AB - BACKGROUND AND OBJECTIVES:: The vascular access pressure ratio test identifies dialysis vascular access dysfunction when three consecutive vascular access pressure ratios are >0.55. We tested whether the magnitude of the decline in vascular access pressure ratio 1-week post-intervention could alert of subsequent access failure. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS:: The retrospective study included all vascular access procedures at one institution from March 2014 to June 2016. Data included demographics, comorbidities, vascular access features, %DeltaVAPR = ((Pre-Post)/Pre] * 100% assessed within the first 2 weeks post-percutaneous transluminal balloon angioplasty, time-to-next procedure, and patency. The log-rank test compared the area under the curve, receiver operating curve, Kaplan-Meier arteriovenous graft and arteriovenous fistula survival curves. A multivariable Cox proportional hazard (CP) model was used to determine the association of %DeltaVAPR with access patency. RESULTS:: Analysis of 138 subjects (females 51%; Black 87%) included 64 arteriovenous fistulas with 104 angioplasties and 74 arteriovenous grafts with 134 angioplasties. The area under the receiver operating characteristic curve for fistula failure at 3 months was 0.59, with optimal screening characteristics of 33.3%, sensitivity of 56.1%, and specificity of 63.2%. Arteriovenous fistula with <33.3% decline compared to >33.3% required earlier subsequent procedure (136 vs 231 days), lower survival on Kaplan-Meier analysis (P = 0.01), and twofold greater risk of failure (P = .006). Area under the receiver operating characteristic for arteriovenous graft failure at 3 months had a sensitivity of 52.3% and specificity of 67.4%. Arteriovenous graft with a post-intervention vascular access pressure ratio decline of <28.8% also required earlier subsequent procedure (144 vs 189 days), lower survival on Kaplan-Meier (P = 0.04), and a 59% higher risk for failure. The area under the receiver operating characteristic curve for combined access failure (arteriovenous fistula + arteriovenous graft) at 3 months had an optimal cut point value of 31.2%, a sensitivity of 54.6%, and a specificity of 63.1%. Access with a <31.2% drop had a 62% increase in the risk of failure (hazard ratio 1.62; confidence interval 1.16, 2.27; P = 0.005). CONCLUSION:: The magnitude of post intervention reduction in vascular access pressure ratio provides a novel predictive measure of access outcomes. PMID- 30477379 TI - Suicidal ideation in gay adolescents in the context of cultural stigma and criminalized homosexuality in Sri Lanka. PMID- 30477380 TI - Clinicopathological characteristics of costal hemangiomas: a case report and literature review. AB - Bone hemangioma accounts for approximately 1% of all bone neoplasms and commonly occurs in the vertebral body and skull. However, costal hemangiomas are extremely rare. We herein present a case involving a 52-year-old woman with a hemangioma in the third rib and review 29 cases of rib hemangiomas available in the literature. Rib hemangioma mainly affects women in their 50s and has expansile osteolytic features in radiographs and a weak maximum standardized uptake value in 18F fluorodeoxyglucose positron emission tomography images. When these findings are displayed, clinicians should include rib hemangioma as a differential diagnosis and consider avoidance of preoperative biopsy because of the risk of life threatening bleeding. PMID- 30477381 TI - Validation of Questionnaire on Violence in Affective Relationships. AB - The aim was to describe the criteria for construction, validation of content, and appearance of a questionnaire for the identification of violence in affective relationships in adolescence. Transverse methodological study, with a quantitative approach, conducted in the period between June and November 2017, with the construction of a questionnaire and validation of the content and appearance, by means of a Delphi survey with 20 experts on the area of violence and adolescence. To evaluate the clarity and pertinence of the items of the questionnaire, a pilot test was conducted with 76 adolescents, and analysis of the validity of content and reliability of the items by means of Content Validity Index (CVI), the Interrater Agreement (IRA), and the Cronbach alpha. The data were analyzed and processed by means of the Excel and Stata, version 14.0, programs. The indexes calculated in the first round of Delphi provided the following results: CVI = 0.93 and IRA = 0.93, showing evidence of the validity and reliability of the construct content, and in the second round, the questionnaire yielded a percentage of 100% agreement among the professionals and researchers. Verification of the internal consistency presented a mean value of 0.803, calculated by means of the Cronbach alpha. The questionnaire has validity of content and appearance in accordance with the proposed objective, bearing in mind that the indexes of faithfulness and agreement and the Cronbach alpha attained values above those of the established pattern of 80%. PMID- 30477382 TI - Implication of Fast Activities of Spectral Analysis in Subjective Sleep Complaints of Elderly Women. AB - OBJECTIVE:: In elderly patients, women have better qualities of sleep than men in objective parameters; however, women subjectively complain more about sleep disturbances than men. We performed visual scoring and spectral analysis of sleep electroencephalograms to explain these gender differences in the degree of arousal, the most representative marker in insomnia. METHODS:: A total of 354 participants (>=60 years old) were recruited from a Korean community underwent nocturnal polysomnography (NPSG). A Fast Fourier transform was used for the spectral analysis of the NPSG data. Relative power was calculated as absolute power of each band divided by total absolute power. Difference in total sleep time (D_TST) is obtained by subtracting the total sleep time reported in Pittsburgh Sleep Quality Index (PSQI) from the TST measured by the NPSG. RESULTS:: A total of 75 participants (women, 51) were finally analyzed. Women had higher PSQI, longer sleep latencies, sleep inefficiencies, and daytime dysfunctions compared to men. The percentage of stage 1 sleep was higher in men versus in women, whereas percentage of stage 3 sleep was higher in women than in men ( P = .001; P = .001). Women had higher relative alpha and beta powers than men during nonrapid eye movement (NREM) sleep ( P = .017; P = .015). During NREM sleep, beta power was negatively correlated with D_TST ( R = -0.250, P = .033), and relative alpha power in stage 3 sleep was positively correlated with sleep latency in PSQI ( R = 0.267, P = .022). CONCLUSION:: Spectral analysis showed that women had more disturbed sleep than men. The result from the spectral analysis may explain hyperarousal in elderly women. PMID- 30477383 TI - Regulation of capillary tubules and lipid formation in vascular endothelial cells and macrophages via extracellular vesicle-mediated microRNA-4306 transfer. AB - OBJECTIVE: This study aimed to examine regulation of capillary tubules and lipid formation in vascular endothelial cells and macrophages via extracellular vesicle mediated microRNA (miRNA)-4306 transfer. METHODS: Whole blood samples (12 mL) were collected from 53 patients, and miR-4306 levels in extracellular vesicles (EVs) were analyzed by reverse transcription-polymerase chain reaction. Human coronary artery vascular endothelial cells (HCAECs) and human monocyte-derived macrophages (HMDMs) were transfected with a scrambled oligonucleotide, an miR 4306 mimic, or an anti-miR-4306 inhibitor. The direct effect of miR-4306 on the target gene was analyzed by a dual-luciferase reporter assay. RESULTS: EV contained miR-4306 released from HMDMs was significantly upregulated in coronary artery disease. Oxidized low-density lipoprotein (ox-LDL)-stimulated HMDM-derived EVs inhibited proliferation, migration, and angiogenesis abilities of HCAECs in vitro. However, ox-LDL-stimulated HCAEC-derived EVs enhanced lipid formation of HMDMs. The possible mechanism of these findings was partly due to EV-mediated miR 4306 upregulation of the Akt/nuclear factor kappa B signaling pathway. CONCLUSIONS: Paracrine cellular crosstalk between HCAECs and HMDMs probably supports the pro-atherosclerotic effects of EVs under ox-LDL stress. PMID- 30477384 TI - Suicide Among Persons With Dementia, Georgia, 2013 to 2016. AB - INTRODUCTION:: Findings from studies examining the relationship between dementia and suicide have been inconsistent. This study examined the characteristics, precipitants, and risk factors for suicide among persons with dementia. METHODS:: Data from the Georgia Alzheimer's Disease and Related Dementia registry were linked with 2013 to 2016 data from Georgia Vital Records and Georgia Violent Death Reporting System. Descriptive statistics were calculated and logistic regression was used to examine risk factors for suicide. RESULTS:: Ninety-one Georgia residents with dementia who died by suicide were identified. Among decedents with known circumstances, common precipitants included depressed mood (38.7%) and physical health problems (72.6%). Suicide rate among persons with dementia was 9.3 per 100 000 person-years overall and substantially higher among those diagnosed in the past 12 months (424.5/100 000 person-years). Being male, dementia diagnosis before age 65, and a recent diagnosis of dementia independently predicted suicide, but not depression or cardiovascular diseases. CONCLUSION:: Prevention strategies that identify at-risk individuals, provide support, and ensure continuity of care for persons diagnosed with dementia may help reduce suicide in this population. PMID- 30477385 TI - Fundamental Frequency in Excised Human Larynges after Anterior Glottic Web Formation of Various Extents. AB - OBJECTIVE: To determine the effect of vocal fold anterior web formation on fundamental frequency with a cadaveric excised larynx model. STUDY DESIGN: Experimental study with excised human larynges. SETTING: Academic tertiary care hospital. SUBJECTS AND METHODS: Sixteen freshly excised human larynges were evaluated with high-speed videoendoscopy and digital kymography during artificially produced vibration. Each larynx was assessed in 4 conditions: preoperative controls and after 25%, 33%, and 50% decreases in the vibratory portion of the vocal folds. The following parameters were evaluated: fundamental frequency, periodicity, vocal fold vibration amplitude, phase symmetry, and glottic closure. RESULTS: The mean fundamental frequencies were 208.87, 250.20, 292.37, and 342.67 Hz for preoperative controls and 25%, 33%, and 50% reductions in vibratory length of the vocal folds, respectively. Fundamental frequency increased with each increase in anterior glottic web extent, and the difference among the groups was statistically significant in absolute values in hertz and in semitone elevation. The mathematical models for estimating postoperative fundamental frequency had a statistically significant coefficient. The vibration of the vocal folds remained periodic in all larynges before and after the procedures. CONCLUSION: There was a significant and progressive increase in the fundamental frequency with each enlargement of anterior glottic web. Based on the control frequency, mathematical models could estimate the value of the fundamental frequency after the procedure. PMID- 30477386 TI - Novel Viruses: Update on the significance of papillomavirus infections in cats. AB - PRACTICAL RELEVANCE:: Prior to 1990 papillomaviruses (PVs) were not recognised to infect or cause disease in domestic cats. Since this time, the use of histology, immunohistochemistry and, more recently, molecular techniques has revealed that PVs almost certainly cause feline viral plaques and Bowenoid in situ carcinomas, oral papillomas and feline sarcoids. In addition, there is increasing evidence that PVs play a significant role in the development of feline cutaneous squamous cell carcinomas, one of the most common skin cancers of cats. Recent studies have also revealed that most cats are asymptomatically infected with PVs. This raises a critical question that is currently unanswered: why do only a small proportion of infected cats develop disease? In the future it may be possible to prevent PV induced diseases by using a vaccine to prevent PV infection. Alternatively, novel therapies may be developed that prevent PVs from causing clinical disease by stimulating the host immune response. CLINICAL CHALLENGES:: A recognition of the skin diseases caused by PVs is important to more accurately predict disease progression. Unfortunately, there are currently no non-surgical treatments that have been proven to be beneficial in cats and clinical management of PV-induced skin disease in cats can be challenging. GLOBAL IMPORTANCE:: PVs have a worldwide distribution and negatively impact feline health and welfare globally. AUDIENCE:: This review is aimed at clinicians, especially those who regularly treat cats with skin disease. The review will also be useful to oncologists and researchers who have an interest in how cancer develops in cats. Evidence base: In producing this update the authors have drawn on recently published peer-reviewed literature. PMID- 30477387 TI - Sexual Assault and Cancer Screening Among Men and Women. AB - Emerging research has shown that experiences of sexual violence are associated with cancer screening behaviors. However, to date, little attention has been given to the impact of sexual assault on cancer screening behaviors, particularly among men. To address this, we used data from the 2014 Kansas Behavioral Risk Factor Surveillance System. This survey is conducted annually via telephone. Logistic regressions were used to calculate odds of ever engaging (i.e., lifetime) in specific screening behaviors (clinical breast exam [CBE], mammogram, Pap test, colonoscopy/sigmoidoscopy, fecal occult blood test and prostate specific antigen [PSA] test) and current compliance with cancer screening recommendations (CBE, mammogram, Pap test, colorectal cancer screening, and PSA test), with lifetime sexual assault as the independent variables. Colorectal cancer screening models were stratified by gender. All models adjusted for confounders. Sexual assault was associated with lower odds of ever receiving a PSA test and, for women, higher odds of ever receiving a colonoscopy or sigmoidoscopy. Sexual assault was associated with lower odds of current compliance with CBE, mammogram, Pap test, and PSA test screening recommendations. A history of sexual assault was associated with lower odds of current compliance with cancer screening procedures, with the notable exception of colorectal cancer screening. Less consistent patterns were seen for lifetime screenings. Results suggest that alternatives to currently recommended procedures (like self collection of HPV [human papilloma virus] DNA) or modified screening procedures may be a promising route to increase current compliance with cancer screening among a population that may avoid these procedures due to pain or fear of retraumatization. PMID- 30477388 TI - Daratumumab, pomalidomide, and dexamethasone as a bridging therapy to autologous stem cell transplantation in a case of systemic light-chain amyloidosis with advanced cardiac involvement. AB - Systemic light-chain (AL) amyloidosis is a rare hematologic disorder where proteins infiltrate tissues leading to organ failure and death. Cardiac involvement, present in ~70% of patients, determines stage and prognosis of the disease, with advanced involvement having a median survival of six months. The treatment of light-chain amyloidosis is directed at recovering organ function with therapeutic strategies following those of multiple myeloma with plasma cell directed therapies. The use of single agent daratumumab has been reported in light-chain amyloidosis achieving rapid and deep responses. The combination of daratumumab, pomalidomide, and dexamethasone (DaraPomD) is particularly interesting for severe AL based on success in multiple myeloma. A 43-year-old female with light-chain amyloidosis and concomitant multiple myeloma presented with severe bowel dysmotility causing abdominal pain, anemia, and a 100-pound unintentional weight loss. A combination of cyclophosphamide, bortezomib, and dexamethasone was initiated but after five cycles her symptoms were progressing and therapy was switched to DaraPomD to optimize response. At the conclusion of two cycles she had achieved an amyloid complete-hematologic response, with her recurring ileus and abdominal pain significantly improved. Additionally, cardiac markers also suggested a rapid response without a common paradoxical worsening of congestive heart failure, and was overall well tolerated. Given the severe symptoms and refractory nature of our patient's disease DaraPomD was reasonable. With the tolerability and response seen, this patient experience supports a formal clinical trial evaluating the safety and efficacy of DaraPomD in light chain amyloidosis. PMID- 30477389 TI - Readmission after Adult Uvulopalatopharyngoplasty: A Population-Based Inpatient Cohort Study in Taiwan. AB - OBJECTIVE: To investigate readmissions among adult inpatients who underwent uvulopalatopharyngoplasty (UPPP) in Taiwan. DESIGN: Population-based survey. SETTING: Retrospective study with the National Health Insurance Database. METHODS: All cases of inpatient adult UPPP (age >20 years) from 1997 to 2012 were identified through International Classification of Diseases, Ninth Revision, Clinical Modification. Factors associated with readmission within 30 days after surgery were analyzed. RESULTS: A total of 38,839 adults with UPPP were identified (mean age, 39.3 years; men, 73.7%). The incidence of UPPP was 14.6 per 100 000 adults, which increased from 1997 to 2012 (6.7 to 16.7 per 100,000, Ptrend < .001). The rates of readmission for any reason, readmission for bleeding, reoperation for bleeding, and 30-day mortality were 4.2%, 1.7%, 1.0%, and 0.14%, respectively. Young age increased the risk of reoperation for bleeding, and old age increased the risk of readmission for any reason and mortality. Men had an increased risk of readmission and reoperation. Hypertension was associated with an increased risk of readmission for any reason (odds ratio [OR], 1.29; 95% CI, 1.10-1.51), bleeding-related readmission (OR, 1.89; 95% CI, 1.52-2.36), and reoperation (OR, 2.47; 95% CI, 1.84-3.30). Concurrent hypopharyngeal surgery was associated with an increased risk of readmission for any reason (OR, 1.34; 95% CI, 1.07-1.66) and bleeding-related readmission (OR, 1.69; 95% CI, 1.25-2.27). Finally, the use of steroids was associated with an increased risk of bleeding-related readmission and reoperation. CONCLUSIONS: The incidence of adult UPPP increased from 1997 to 2012 in Taiwan. Age, sex, comorbidity, concurrent hypopharyngeal surgery, and drug administration were associated with readmission after inpatient UPPP. PMID- 30477390 TI - Cognitive impairment following chemotherapy for breast cancer: The impact of practice effect on results. AB - : Chemotherapy-Related Cognitive Impairment (CRCI) can be an adverse effect in women treated for breast cancer. Some longitudinal studies reported deficits in attention, memory, and executive function following treatment, but other studies did not find cognitive changes. It is known that practice effects (PE) on repeated assessments with cognitive tests contribute to the discrepancies in these results, but its influence on scores has not been systematically explored. The present study examines the impact of PE on retest scores in a group of women with breast cancer treated with chemotherapy and evaluated longitudinally. METHOD: 51 women with breast cancer treated with a combination of 5-fluorouracil, epirubicin, and cyclophosphamide with or without taxanes were assessed after surgery but before chemotherapy (T1), post-chemotherapy (T2), and at one year after T2 (T3). Longitudinal changes on cognitive performance were analyzed twice: when retest scores were not corrected for PE and when correction for PE was applied to T2 and T3 scores. RESULTS: When PE was not corrected, progressive improvement over time in measures of memory and divided attention at T2 and T3 was observed. In contrast, when PE was corrected, worsening was found in measures of memory, fluency, executive function, and attention at T2 and in attention and executive function at T3. Results after correction for PE are in line with previous longitudinal studies that report cognitive impairment after treatment with chemotherapy for breast cancer. CONCLUSION: Accounting for PE is recommended to identify true change on cognition through treatment with chemotherapy for breast cancer. PMID- 30477391 TI - Clinical Predictors for Unsafe Direct Discharge Home Patients From Intensive Care Units. AB - PURPOSE:: To describe factors (demographics and clinical characteristics) that predict patients who are at an increased risk of adverse events or unplanned return visits to a health-care facility following discharge direct to home (DDH) from intensive care units (ICUs). METHODS:: Prospective cohort study of all adult patients who survived their stay in our medical-surgical-trauma ICU between February 2016 and 2017 and were discharged directly home. Patients were followed for 8 weeks postdischarge. Univariable and multivariable logistic regression analyses were performed to identify factors associated with adverse events or unplanned return visits to a health-care facility following DDH from ICU. RESULTS:: A total of 129 DDH patients were enrolled and completed the 8-week follow-up. We identified 39 unplanned return visits (URVs). There was 0% mortality at 8 weeks postdischarge. Eight potential predictors of hospital URVs ( P < .2) were identified in the univariable analysis: prior substance abuse (odds ratio [OR] of URV of 2.50 [95% confidence interval: 1.08-5.80], hepatitis (OR: 6.92 [1.68-28.48]), sepsis (OR: 11.03 [1.19-102.29]), admission nine equivalents of nursing manpower score (NEMS) <24 (OR: 2.28 [1.03-5.04], no fixed address (OR: 22.9 [1.2-437.3]), ICU length of stay (LOS) <2 days (OR: 2.95 [1.28-6.78]), home discharge within London, Ontario (OR: 2.44 [1.00-5.92]), and left against medical advice (AMA; OR: 6.06 [2.04-17.98]). CONCLUSIONS:: Our study identified 8 covariates that were potential predictors of URV: prior substance abuse, hepatitis, sepsis, admission NEMS <24, no fixed address, ICU LOS <2 days, home discharge within London, Ontario, and left AMA. The practice of direct discharges home from the ICU would benefit from adequately powered multicenter study in order to construct a clinical prediction model (that would require further testing and validation). PMID- 30477392 TI - Reflections on 30 years of Cognition & Emotion. AB - The publication of the first issue of Cognition & Emotion in 1987 helped open the floodgates to what has become a golden age of emotion research in the social and biological sciences. In this article, I describe the intellectual landscape of that era and trace key developments that helped foster the growth of the field of affective science. Looking back from a present-day perspective, I offer some thoughts on the major changes that have occurred over the past three decades, the opportunities and challenges that lie ahead, and my own personal journey toward becoming an affective scientist (which largely occurred during this period). Finally, I offer three considerations that might be helpful for young researchers who are already in the field of affective science or are considering entering it. PMID- 30477393 TI - Non-Vitamin K Antagonist Oral Anticoagulants in the Treatment of Atrial Fibrillation. AB - Atrial fibrillation (AF) increases a patient's stroke risk four- to five-fold. Anticoagulation with the vitamin K antagonist (VKA) warfarin reduces the risk of stroke by 67%, but warfarin carries a significant risk of major bleeding and has unpredictable pharmacodynamics with a narrow therapeutic window, necessitating frequent monitoring of its anticoagulant effect. The non-vitamin K antagonist oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, and edoxaban provide more predictable anticoagulant activity than warfarin with a lower risk of major bleeding, and each is noninferior to warfarin for the prevention of stroke. All have earned regulatory approval in the past eight years. At least one of the NOACs is approved for use in all patients with AF, except those with mechanical valves and rheumatic mitral valve disease, for whom warfarin remains the only option. Recent clinical trials have shown that antithrombotic regimens including NOACs are safe and effective in patients with AF who need potent antiplatelet therapy. Expected final online publication date for the Annual Review of Medicine Volume 70 is January 27, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30477394 TI - Entering the Modern Era of Gene Therapy. AB - Gene therapies are gaining momentum as promising early successes in clinical studies accumulate and examples of regulatory approval for licensing increase. Investigators are advancing with cautious optimism that effective, durable, and safe therapies will provide benefit to patients-not only those with single-gene disorders but those with complex acquired diseases as well. While the strategies being translated from the lab to the clinic are numerous, this review focuses on the clinical research that has forged the gene therapy field as it currently stands. Expected final online publication date for the Annual Review of Medicine Volume 70 is January 27, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30477395 TI - A questionnaire-based study of sleep-wake patterns and sleep quality in a TMJ and orofacial pain clinic. AB - OBJECTIVE: To determine the relationships among sleep quality, perceived pain, and psychological distress among patients with TMJ and orofacial pain. METHODS: The authors examined 3276 patients with temporomandibular disorder (TMD) who visited the Orofacial Pain Clinic at Yonsei University College of Dentistry. The authors conducted a survey using the sleep-quality questionnaire and classified TMD patients into two groups based on Diagnostic Criteria for TMD. For statistical analysis, the authors calculated the correlations between pain intensity as measured using a numeric rating scale (NRS) and various factors. RESULTS: The statistical analysis revealed correlations between pain intensity on the NRS and some of the factors in the sleep questionnaire. The pain intensity increased with age and for lower sleep efficiency (both p < 0.05). CONCLUSION: These results imply that clinicians treating patients with orofacial pain should examine their sleep-wake patterns and sleep quality. PMID- 30477396 TI - Kinetics, mechanism, and identification of photodegradation products of phenazine 1-carboxylic acid. AB - Phenazine-1-carboxylic acid (PCA) is a broad-spectrum antibiotic against many plant pathogens, produced by Pseudomonas and other species. The biosynthesis and regulation of PCA has been well documented, but there is no report about its photochemical properties. Herein, the photodegradation of PCA was carried out in an aqueous solution under the irradiation of visible light to investigate the kinetics, mechanism, and identification of photodegradation products of PCA. Results revealed that photodegradation of PCA accorded well with first-order reaction kinetics. The measured half-life of PCA was 2.2 days at pH 5.0 and increased to 37.6 days at pH 6.8 when exposed to visible light. When oxygen was removed from its solution, the half-life of PCA was doubled. Different units of superoxide dismutase (SOD) enzyme (i.e. 0 units, 300 units, and 3000 units) and varying concentrations of sodium azide (i.e. 0 mg, 5 mg, 10 mg, and 20 mg) were used to decipher the mechanism for PCA photodegradation. Hydroxyl PCA and hydroxy phenazine were tentatively identified as the degradation products of PCA photodegradation process by high-performance liquid chromatography (HPLC). The obtained degradation products were further characterized and confirmed by HPLC mass spectrometry and LC-MS/MS-based analytical approaches. In conclusion, the degradation of PCA was found to be light dependent, which could be accelerated by hydrogen ion and oxidant in the solution. The results suggest that PCA was more stable when stored in a neutral or alkaline environment or in the dark. Therefore, it is important to modify the PCA structure or use a suitable dosage for its broad-spectrum applications. PMID- 30477397 TI - Profiles and Predictors of Smart Home Technology Adoption by Older Adults. AB - The commercial popularity of smart home (SH) technology has broadened the scope of aging-in-place and home health occupational therapy. The objective of this article is to examine ownership of SH technology by older adults, their readiness to adopt SH technology, and identify the client factors relating to the adoption. A survey of older adults aged 60 and above living in the community was conducted. Respondents ( N = 445) who were women; in the age group of 60 to 70 years; living in a two-level home, with a body function impairment; with a fall history; and experienced in information and communication technology (ICT) were significantly likely to be "brisk adopters" of SH ( p < .05). Stepwise regression model identified marital status, home security, and overall ICT ownership as the predictors of SH ownership, whereas being female, concern over home security, and perceived independence contributed to SH readiness ( p < .05). Consideration of the identified client profiles, health, and personal factors will strengthen SH integration for aging-in-place. PMID- 30477398 TI - Phenome-wide association study identifies dsDNA as a driver of major organ involvement in systemic lupus erythematosus. AB - In systemic lupus erythematosus (SLE), dsDNA antibodies are associated with renal disease. Less is known about comorbidities in patients without dsDNA or other autoantibodies. Using an electronic health record (EHR) SLE cohort, we employed a phenome-wide association study (PheWAS) that scans across billing codes to compare comorbidities in SLE patients with and without autoantibodies. We used our validated algorithm to identify SLE subjects. Autoantibody status was defined as ever positive for dsDNA, RNP, Smith, SSA and SSB. PheWAS was performed in antibody positive vs. negative SLE patients adjusting for age and race and using a false discovery rate of 0.05. We identified 1097 SLE subjects. In the PheWAS of dsDNA positive vs. negative subjects, dsDNA positive subjects were more likely to have nephritis ( p = 2.33 * 10-9) and renal failure ( p = 1.85 * 10-5). After adjusting for sex, race, age and other autoantibodies, dsDNA was independently associated with nephritis and chronic kidney disease. Those patients negative for dsDNA, RNP, SSA and SSB negative subjects were all more likely to have billing codes for sleep, pain and mood disorders. PheWAS uncovered a hierarchy within SLE specific autoantibodies with dsDNA having the greatest impact on major organ involvement. PMID- 30477399 TI - Rectification ratio based determination of disulfide bonds of beta2 extracellular loop of BK channel. AB - Large-conductance Ca2+-activated K+ (BK) channels are composed of a pore-forming alpha and a variable number of auxiliary beta subunits and play important roles in regulating excitability, action potential waveforms and firing patterns, particularly in neurons and endocrine and cardiovascular cells. The beta2 subunits increase the diversity of gating and pharmacological properties. Its extracellular loop contains eight cysteine residues, which can pair to form a high-order structure, underlying the stability of the extracellular loop of beta2 subunits and the functional effects on BK channels. However, how these cysteines form disulfide bonds still remains unclear. To address this, based on the fact that the rectification and association of BK alpha to beta2 subunits are highly sensitive to disruption of the disulfide bonds in the extracellular loop of beta2, we developed a rectification ratio based assay by combining the site directed mutagenesis, electrophysiology and enzymatic cleavage. Three disulfide bonds: C1(C84)-C5(C113), C3(C101)-C7(C148) and C6(C142)-C8C(174) are successfully deduced in beta2 subunit in complex with a BK alpha subunit, which are helpful to predict structural model of beta2 subunits through computational simulation and to understand the interface between the extracellular domain of the beta subunits and the pore-forming alpha subunit. PMID- 30477400 TI - Ultrasonographic Multimodality Diagnostic Model of Thyroid Nodules. AB - The aim of this study was to identify independent risk factors for thyroid cancer, establish an ultrasonographic multimodality diagnostic model for thyroid nodules, and explore the diagnostic value of the model. From November 2011 to February 2015, 307 patients with a total of 367 thyroid nodules underwent conventional ultrasound, contrast-enhanced ultrasound (CEUS), and ultrasound elastography examinations before surgery. A binary logistic regression analysis was performed to identify independent risk factors for thyroid cancer and to establish a multimodality diagnostic model for thyroid nodules. The diagnostic performance of conventional ultrasound, CEUS, ultrasound elastography, and the multimodality diagnostic model was assessed and compared. The following seven independent risk factors were included in the logistic regression models: age, irregular shape, hypoechoic pattern, marked hypoechoic pattern, irregular blood flow distribution, heterogeneous enhancement, and an elastic score of 3/4. The multimodality diagnostic model had a diagnostic accuracy of 86.9%, with a sensitivity of 93.5% and a specificity of 77.3%. The multimodality diagnostic model improved the diagnostic accuracy compared with that of conventional ultrasound, CEUS, and ultrasound elastography. Independent risk factors for thyroid cancer included age, irregular shape, hypoechoic pattern, marked hypoechoic pattern, irregular blood flow distribution, heterogeneous enhancement, and an elastic score of 3/4. The multimodality diagnostic model was demonstrated to be effective in the diagnosis of thyroid nodules. PMID- 30477401 TI - Impaired introspective accuracy in schizophrenia: an independent predictor of functional outcomes. AB - INTRODUCTION: Individuals with schizophrenia present across a spectrum of symptomatology. Disability remains a debilitating reality across varying disease presentations and remains pervasive despite psychiatric medications. Cognition (neuro/social cognition) and negative symptoms have emerged as the strongest predictors of real-world disability, but account for <50% of the variance in outcomes. METHODS: Our attempts to determine what accounts for the remaining 50% of variance has shown that poor introspective accuracy (IA) may be the most potent predictor of functional outcomes 25% of individuals with schizophrenia. We define IA as the adequacy of self-assessments of ability, skills, performance, or decisions. We suggest that IA is a progression of metacognition and can extend beyond cognition to include misestimation of prior and likely future performance in social or other adaptively relevant situations. RESULTS: Additionally, IA is bidirectional and self-orientated. Emerging research has found that IA of neurocognitive ability better predicts everyday functional deficits than scores on performance-based measures or neurocognitive skills and has found that IA of social cognition accounts unique variance in real-world disability above social cognitive performance. DISCUSSION: We argue that impaired IA, affecting 25-50% of patients with schizophrenia, in the absence or minimal presence of other impairments might be the most powerful predictor of functional outcomes. PMID- 30477402 TI - Protein-G-based lateral flow assay for rapid serodiagnosis of brucellosis in domesticated animals. AB - This study was conducted to develop and evaluate protein-G-based lateral flow assay (LFA) for rapid serodiagnosis of brucellosis in various domesticated animal species. The assay diagnostic performance was tested with 144 reference and 356 field sera samples and then compared with other serological assays. Results revealed that LFA showed 89% and 99% sensitivity and specificity, respectively, when compared with competitive ELISA as the gold standard. This study demonstrated LFA alone as a potential serodiagnostic assay for rapid serodiagnosis of brucellosis in various domesticated animal species. PMID- 30477403 TI - ER Stress, CREB, and Memory: A Tangled Emerging Link in Disease. AB - The brain undergoes several changes at structural, molecular, and cellular levels leading to alteration in its functions and these processes are primarily maintained by proteostasis in cells. However, an imbalance in proteostasis due to the abnormal accumulation of protein aggregates induces endoplasmic reticulum (ER) stress. This event, in turn, activate the unfolded protein response; however, in most neurodegenerative conditions and brain injury, an uncontrolled unfolded protein response elicits memory dysfunction. Although the underlying signaling mechanism for impairment of memory function following induction of ER stress remains elusive, recent studies have highlighted that inactivation of a transcription factor, CREB, which is essential for synaptic function and memory formation, plays an essential role for ER stress-induced synaptic and memory dysfunction. In this review, current studies and most updated view on how ER stress affects memory function in both physiological and pathological conditions will be highlighted. PMID- 30477404 TI - Prediction, docking study and molecular simulation of 3D DNA aptamers to their targets of endocrine disrupting chemicals. AB - Typical endocrine disrupting chemicals, including BPA (Bisphenol A), E2 (17-beta Estradiol) and PCB 72 (polychlorinated biphenyl 72), commonly and widely present in the environment with good chemical stability that are difficult to decompose in vitro and in vivo. Most of the high-qualified antibodies are required as the key bio-materials to fabricate the immunosensor for capturing and detection. As an ideal alternative, the short chain oligonucleotide (aptamer) are essentially and effectively employed with the advantages of small size, chemical stability and high effectiveness for monitoring of these environmental contaminants. However, the molecular interaction, acting site and mode are still not well understood. In this work, we explored the binding features of the aptamers with their targeting ligands. The molecular dynamics simulations were performed on the aptamer-ligand complex systems. The stability of each simulation system was evaluated based on its root mean square deviation. The affinities of these proposed ligands and the predicted binding sites are analyzed. According to the binding energy analysis, the affinities between ligands and aptamers and the stability of the systems are BPA > PCB 72 >E2. Trajectory analysis for these three complexes indicated that these three ligands were able to steadily bind with aptamers at docking site from 0 to 50 ns and contributed to alteration of conformation of aptamers. PMID- 30477405 TI - Abiraterone and spironolactone in prostate cancer: a combination to avoid. AB - OBJECTIVES: Disease progression in metastatic castration-resistant prostate cancer (mCRPC) is dependent on androgen signaling. This case describes the complex adaptive androgen signaling mechanisms in mCRPC and illustrates that caution should be exercised when treating these patients with drugs influencing the androgen axis. METHODS: Single case report and review of the literature. RESULTS: We report the case of an 86-year-old man with mCRPC, treated with the secondary antihormonal agent abiraterone acetate. Following association of spironolactone to deal with symptoms related to mineralocorticoid excess, biochemical and radiographic disease progression occurred. Spironolactone was discontinued and 8 months after withdrawal, the patient continues to show a biochemical response to abiraterone. CONCLUSIONS: Although spironolactone generally exerts anti-androgenic effects, experimental evidence exists that it acts as an androgen receptor agonist in an androgen-depleted environment, capable of inducing prostate cancer proliferation. This is supported by the observations described in this case report. Therefore, spironolactone should be avoided in prostate cancer patients suffering from treatment-associated side effects of abiraterone. PMID- 30477406 TI - Prevalence of patients treated with anti-diabetic medicine in Greenland and Denmark. A cross-sectional register study. AB - Diabetes mellitus is a large and growing worldwide health issue. Prior to this publication, a direct comparison of the prevalence of persons treated with anti diabetic medicine in Greenland and Denmark has not been found. Therefore, the aim of this study is to estimate and compare the age- and gender-specific prevalence of patients treated with anti-diabetic medicine comparing Greenland and Denmark. The study was performed as a cross-sectional register study using data from population and medical registers in Greenland and Denmark. A total of 784 Greenlandic and 215,580 Danish patients treated with anti-diabetic medicine were included. The prevalence of patients aged 20-79 years treated with anti-diabetic medicine in Greenland was 2.6% (95% CI 2.4-2.8), much lower (p < 0.001) compared to Denmark with 5.2% (95% CI 5.2-5.2). The difference was less pronounced after excluding those treated with insulin and women below 45 years treated with metformin. In conclusion, this study showed a lower prevalence of patients treated with anti-diabetic medicine in Greenland than Denmark. The main reason may be a much higher prevalence of undiagnosed diabetes in Greenland, particularly among the middle-aged. Differences in awareness of diabetes and access to continued primary healthcare may be contributing factors. PMID- 30477407 TI - Replacing hospital-based epilepsy clinics with rural epilepsy clinics and education in Uganda: impact on attendance. AB - BACKGROUND: A high proportion of the Ugandan population with epilepsy receive no treatment. AIM: To determine whether introduction of an agreed multidisciplinary guideline and establishment of a local clinic outside the hospital and four rural satellite clinics improved attendance and follow-up by children with epilepsy in Western Uganda. METHODS: A multidisciplinary team from Kagando Hospital, Kasese, south-west Uganda created a guideline for the management of epilepsy. A clinic local to the hospital and rural satellite clinics were established.Attendance and follow-up were audited for three months before the intervention. Attendance, follow-up and the cost of the hospital, local and rural clinics were audited 6 months and 5 years post intervention. RESULTS: Pre-intervention, one patient a month attended the free Kagando Hospital epilepsy clinic. Post-intervention, a median of eight patients (range 2-12) attended the local clinic and 100% attended booked follow-up appointments; the cost per clinic was L15 (L1.88 per patient, range 1.25-7.50). A median of 42 (range 15-56) patients per clinic attended the rural clinics and 70% of patients attended follow-up appointments; the cost per clinic was L34 (L0.81 per patient, range 0.61-2.23). Rural clinic attendance was higher than in the hospital clinic (p = 0.007) and in the local clinic (p = 0.004). Five years post-intervention, the attendance was 44 patients (range 25 85) per rural clinic and the cost per clinic was L34. CONCLUSIONS: Rural epilepsy clinics were associated with higher attendance than the hospital or local clinic and the attendance rate remained higher 5 years post-intervention. PMID- 30477408 TI - The evidence for prolonged muscle stretching in ankle joint management in upper motor neuron lesions: considerations for rehabilitation - a systematic review. AB - BACKGROUND: As clinicians, muscles stretching approaches are one of the most commonly used interventions in rehabilitation. However, there is a need for an in depth evaluation of research on prolonged stretching in terms of the features of the stretching approaches, such as duration and frequency, as well as the compatible measures of a successful stretching approach. OBJECTIVE: This review is an effort to synthesize findings from studies on "prolonged" stretching approaches in patients with UMNs including stroke, spinal cord injuries, and traumatic brain injuries. We investigated the compatible features of successful stretching regimens in terms of reducing spasticity, improving the Active Range of Motion (AROM), Passive Range of Motion (PROM), and gait training of spastic patient with upper motor neuron lesions. METHODS: Studies evaluating the effectiveness of "prolonged" stretching on spastic ankle planterflexor muscles and its complications were critically reviewed, and the level of evidence was analyzed. RESULTS: There is a sufficient level of evidence to support the use of stretching as and effective techniques in rehabilitation. However, more research is yet to be done to objectively examine the ideal parameters of a successful stretching approach using functional assessments, such as walking, speed, walking capacity, and balance. CONCLUSION: The review adds stronger understanding with regard to stretching considerations in rehabilitation following UMNs. The ideal approach, as well as the functional implications on motor performance are yet to be further studied. PMID- 30477409 TI - The Persistent High Rates of Heroin Use Among the Puerto Rican Population in the United States: A Qualitative Study. AB - For a half- century, the Puerto Rican population in the United States has experienced very high rates of heroin usage with significant health ramifications. At substance misuse programs in the Bronx, New York, two focus groups consisting of a total of 13 Puerto Rican counselors, and four focus groups consisting of a total of 35 Puerto Rican clients, discussed the impact of heroin usage on Puerto Rican communities as part of a qualitative study using a phenomenological perspective. Societal marginalization and social dislocation were identified as major contributors to heroin usage in Puerto Rican communities. The findings indicate that full access to economic, vocational, and educational opportunities, along with a decrease in institutional racial discrimination, would appear to be the most effective way to decrease heroin usage among this population. PMID- 30477410 TI - Optimization of nimesulide-loaded Solid Lipid Nanoparticles (SLN) by factorial design, release profile and cytotoxicity in human colon adenocarcinoma cell line. AB - The aim of this work has been the development of a non-toxic, long-term stable solid lipid nanoparticles (SLN) formulation for the loading of Nimsulide (NiM) by a 22 factorial design. The optimized formulation was composed of 10 wt% of glyceryl behenate and 2.5 wt% of poloxamer 188. Immediately after production, Z Ave of NiM-SLN was 166.1 +/- 0.114 nm, with a polydispersity index (PI) of 0.171 +/- 0051 and zeta potential nearly neutral (-3.10 +/- 0.166 mV). A slight increase of Z-Ave was recorded for NiM-SLN stored at 25 degrees C for a period of 15 days, whereas at 4 degrees C particles kept size within similar range. Long-term stability was monitored using TurbiscanLab(r), showing a high stability of the nanoparticles with variations in the backscattering profiles below 10%. The release profile of NiM-SLN followed a sustained pattern with ca. 30% of drug released up to 24 h. Empty-SLN and NiM-SLN were non-toxic after exposing Caco-2 cells to the highest concentration (100 MUg/mL) up to 48 hours (cell viability higher than 80%). NiM-SLN were lyophilized using different cryoprotectants, producing particles of 463.1 +/- 36.63 nm (PI 0.491 +/- 0.027) with 5% trehalose. Solid character of NiM-SLN was confirmed by DSC, recording a recrystallization index of 83% for NiM-SLN and of 74% for lyophilized SLN. PMID- 30477411 TI - Decrease in VEGF-Induced Pericardial Adhesion Formation Using Bevacizumab After Surgery. AB - OBJECTIVES: Some degrees of postoperative cardiac adhesions occur in response to the first cardiac surgery in patients that may limit surgeons for subsequent operations and increase the risk of heart injury. In this article, we established a model of postoperative pericardial adhesions, and because vascular endothelial growth factor (VEGF) seems to initiate adhesion formation through inflammatory responses, we used an anti-VEGF antibody, that is, bevacizumab, to examine its effects on postoperative adhesion formation. METHODS: Twenty Wistar rats were divided in 2 groups: control and bevacizumab. After chest opening, pericardial sac was opened and the heart was fully exposed. In the bevacizumab group, bevacizumab (2.5 mg/kg) was applied locally on the heart and then the chest was closed. The control group received saline solution as placebo. After 42 days, high-sensitivity C-reactive protein in peripheral blood was measured, and re sternotomy was performed to measure severity of pericardial adhesions. Then, the hearts were collected from all rats to evaluate percentage of CD-31-positive cells (as a marker of angiogenesis) using immunohistochemical staining. RESULTS: When the bevacizumab group was compared with the control group, we found that the mean score of adhesion (0.89 +/- 0.38 vs 2.56 +/- 0.41) and CD-31 expression (27.45 +/- 3.75% vs 56.26 +/- 1.98%) was decreased significantly after bevacizumab administration. However, we did not find any difference in high sensitivity C-reactive protein levels of control and bevacizumab animals. CONCLUSION: In the current study, bevacizumab administration could effectively reduce adhesion formation after first sternotomy by preventing VEGF-induced angiogenesis through CD-31 downregulation. PMID- 30477412 TI - In silico hit optimization towards AKT inhibition: Fragment-based approach, molecular docking and molecular dynamics study. AB - Protein kinase B also known as AKT is a cardinal node in different signaling pathways that regulates diverse cell processes. AKT has three isoforms that share high homology. Hyperactivation of each isoform is related with different types of cancer. This work describes the computational search for new inhibitors using a hit optimization process of the previously reported AKT pan-inhibitor, a 2,4,6 trisubstituted pyridine. A database of new molecules was proposed using a variant of fragment-based docking methodology and previous reported considerations. Molecular docking followed by molecular dynamics studies were performed to select the best compounds and analyze their behavior. Protein-ligand complexes energy was calculated using Molecular Mechanics Poisson-Boltzmann Surface Area protocol. Further, proposed molecules were compared with the ChEMBL database of compounds assayed against AKT. Data analysis lead to determine the structural requirements necessary for a favorable interaction of the proposed ligands with the AKT pocket. Molecular dynamics data suggested that the pKa of the ligands is important for the stability in the AKT pocket. Molecular similarity analysis shows that proposed ligands have not been previously reported. Thus, ligands with high docking scores and favorable behavior on molecular dynamics simulations are proposed as potential AKT inhibitors. PMID- 30477413 TI - Medical Screening Society members' talks. PMID- 30477414 TI - Activities of daily living and life satisfaction of persons with stroke after rehabilitation in China: a longitudinal descriptive study. AB - OBJECTIVES: The information regarding to the long-term outcome of stroke after rehabilitation is limited in China. The aims were to investigate activities of daily living (ADLs) and life satisfaction after stroke in China within 3 years after rehabilitation, and to explore the possible predictors of life satisfaction. METHODS: A longitudinal descriptive study was conducted to evaluate ADLs and life satisfaction of persons with stroke. Participants completed Life Satisfaction Checklist-11 (LiSat-11), and Barthel Index (BI) at discharge, 6, 12 months, and 3 years after discharge. RESULTS: A total of 69 participants were followed at discharge, and 32 of them finished 3 years' follow-up. BI increased significantly within 3 years compared with that at discharge (p < 0.01). Total score and all items of LiSat-11 indicated low satisfaction and was maintained relatively stable within 3 years except for a decreased satisfaction in "sexual life" (p < 0.05). Life satisfaction at 12 months was predicted by stroke severity, marital status, and return to work (R2 = 0.38) and life satisfaction at 3 years was predicted by disability (R2 = 0.27). Age was found as a predictor for items "Vocation" and "Leisure" (R2 = 0.26 and 0.31, respectively). CONCLUSIONS: Functional independence in ADLs increased within 3 years after discharge from rehabilitation, while life satisfaction was reported low and constant. Life satisfaction was predicted by severity of stroke, marital status, and return back to work at 1 year post discharge and by disability at 3 years post discharge. PMID- 30477415 TI - A Subjective Quality of Life Proxy for Older Adults in the PAQUID Cohort Study. AB - OBJECTIVES:: Quality of life is regarded as a major outcome in epidemiologic research, especially in the older population. Nevertheless, some cohort studies lack a specific instrument to evaluate it. The aim of this study was to propose a subjective quality of life proxy using easily accessible items, available in most epidemiologic studies. METHOD:: We used data from the PAQUID (Personnes Agees Quid) cohort study (1991-1992, France). A subjective quality of life proxy was created based on items on positive affects, subjective health, and life satisfaction. Logistic and linear regression models as well as Cox survival models were used to assess the association between the proxy score and depression, dependence, cognitive complaints, adverse life events, comorbidities, and death. Analyses were replicated in an independent cohort study, AMI (Approche Multidisciplinaire integree; 2007-2008, France). All models were adjusted for age, sex, Mini-Mental State Examination score, and place of residence. RESULTS:: In the PAQUID sample (n = 2135), we found significant associations between the proxy score and the selected health outcomes. We found the same associations in the AMI cohort. CONCLUSION:: This proxy might be useful when no gold standard for quality of life assessment is available or when in need of a short but reliable instrument that will not require extended administration time. PMID- 30477416 TI - Predictors of Response and Remission to Antidepressants in Geriatric Depression: A Systematic Review. AB - BACKGROUND:: Geriatric depression is a heterogeneous disorder that increases morbidity and mortality in a population that is already vulnerable. Predicting response and remission to antidepressants could help clinicians to optimize the management of antidepressants and reduce the consequences of depression. METHOD:: The aim of this article is to present results of a systematic review of the literature on predictive factors related to antidepressant response and remission in older adults with depression. MAIN FINDINGS:: We identified sociodemographic, clinical, neuropsychological, neuroimaging, and genetic factors that could be potential predictors of outcomes. Inconsistent findings and methodological differences among studies, however, limit the generalizability and application of these predictors in clinical practice. The results of our review confirm that geriatric depression includes many subgroups of patients with particular endophenotypes that may influence the course of depression. CONCLUSION:: Further studies are needed to characterize depression subgroups in order to better understand the pathophysiology of late life depression and to find specific predictors for each group of patients. PMID- 30477417 TI - Four-week training involving ankle mobilization with movement versus static muscle stretching in patients with chronic stroke: a randomized controlled trial. AB - BACKGROUND: Patients with stroke generally have diminished balance and gait. Mobilization with movement (MWM) can be used with manual force applied by a therapist to enhance talus gliding movement. Furthermore, the weight-bearing position during the lunge may enhance the stretch force. OBJECTIVES: This study aimed to compare the effects of a 4-week program of MWM training with those of static muscle stretching (SMS). Ankle dorsiflexion passive range of motion (DF PROM), static balance ability (SBA), the Berg balance scale (BBS), and gait parameters (gait speed and cadence) were measured in patients with chronic stroke. METHODS: Twenty patients with chronic stroke participated in this study. Participants were randomized to either the MWM (n = 10) or the SMS (n = 10) group. Patients in both groups underwent standard rehabilitation therapy for 30 min per session. In addition, MWM and SMS techniques were performed three times per week for 4 weeks. Ankle DF-PROM, SBA, BBS score, and gait parameters were measured after 4 weeks of training. RESULTS: After 4 weeks of training, the MWM group showed significant improvement in all outcome measures compared with baseline (p < 0.05). Furthermore, SBA, BBS, and cadence showed greater improvement in the MWM group compared to the SMS group (p < 0.05). CONCLUSIONS: This study demonstrated that MWM training, combined with standard rehabilitation, improved ankle DF-PROM, SBA, BBS scores, and gait speed and cadence. Thus, MWM may be an effective treatment for patients with chronic stroke. PMID- 30477418 TI - pyHIVE, a health-related image visualization and engineering system using Python. AB - BACKGROUND: Imaging is one of the major biomedical technologies to investigate the status of a living object. But the biomedical image based data mining problem requires extensive knowledge across multiple disciplinaries, e.g. biology, mathematics and computer science, etc. RESULTS: pyHIVE (a Health-related Image Visualization and Engineering system using Python) was implemented as an image processing system, providing five widely used image feature engineering algorithms. A standard binary classification pipeline was also provided to help researchers build data models immediately after the data is collected. pyHIVE may calculate five widely-used image feature engineering algorithms efficiently using multiple computing cores, and also featured the modules of Principal Component Analysis (PCA) based preprocessing and normalization. CONCLUSIONS: The demonstrative example shows that the image features generated by pyHIVE achieved very good classification performances based on the gastrointestinal endoscopic images. This system pyHIVE and the demonstrative example are freely available and maintained at http://www.healthinformaticslab.org/supp/resources.php . PMID- 30477419 TI - COMBImage: a modular parallel processing framework for pairwise drug combination analysis that quantifies temporal changes in label-free video microscopy movies. AB - BACKGROUND: Large-scale pairwise drug combination analysis has lately gained momentum in drug discovery and development projects, mainly due to the employment of advanced experimental-computational pipelines. This is fortunate as drug combinations are often required for successful treatment of complex diseases. Furthermore, most new drugs cannot totally replace the current standard-of-care medication, but rather have to enter clinical use as add-on treatment. However, there is a clear deficiency of computational tools for label-free and temporal image-based drug combination analysis that go beyond the conventional but relatively uninformative end point measurements. RESULTS: COMBImage is a fast, modular and instrument independent computational framework for in vitro pairwise drug combination analysis that quantifies temporal changes in label-free video microscopy movies. Jointly with automated analyses of temporal changes in cell morphology and confluence, it performs and displays conventional cell viability and synergy end point analyses. The image processing algorithms are parallelized using Google's MapReduce programming model and optimized with respect to method specific tuning parameters. COMBImage is shown to process time-lapse microscopy movies from 384-well plates within minutes on a single quad core personal computer. This framework was employed in the context of an ongoing drug discovery and development project focused on glioblastoma multiforme; the most deadly form of brain cancer. Interesting add-on effects of two investigational cytotoxic compounds when combined with vorinostat were revealed on recently established clonal cultures of glioma-initiating cells from patient tumor samples. Therapeutic synergies, when normal astrocytes were used as a toxicity cell model, reinforced the pharmacological interest regarding their potential clinical use. CONCLUSIONS: COMBImage enables, for the first time, fast and optimized pairwise drug combination analyses of temporal changes in label-free video microscopy movies. Providing this jointly with conventional cell viability based end point analyses, it could help accelerating and guiding any drug discovery and development project, without use of cell labeling and the need to employ a particular live cell imaging instrument. PMID- 30477420 TI - Characterization of Dehydrin protein, CdDHN4-L and CdDHN4-S, and their differential protective roles against abiotic stress in vitro. AB - BACKGROUND: Dehydrins play positive roles in regulating plant abiotic stress responses. The objective of this study was to characterize two dehydrin genes, CdDHN4-L and CdDHN4-S, generated by alternative splicing of CdDHN4 in bermudagrass. RESULTS: Overexpression of CdDHN4-L with phi-segment and CdDHN4-S lacking of phi-segment in Arabidopsis significantly increased tolerance against abiotic stresses. The growth phenotype of Arabidopsis exposed to NaCl at 100 mM was better in plants overexpressing CdDHN4-L than those overexpressing CdDHN4-S, as well as better in E.coli cells overexpressing CdDHN4-L than those overexpressing CdDHN4-S in 300 and 400 mM NaCl, and under extreme temperature conditions at - 20 degrees C and 50 degrees C. The CdDHN4-L had higher disordered characterization on structures than CdDHN4-S at temperatures from 10 to 90 degrees C. The recovery activities of lactic dehydrogenase (LDH) and alcohol dehydrogenase (ADH) in presence of CdDHN4-L and CdDHN4-S were higher than that of LDH and ADH alone under freeze-thaw damage and heat. Protein-binding and bimolecular fluorescence complementation showed that both proteins could bind to proteins with positive isoelectric point via electrostatic forces. CONCLUSIONS: These results indicate that CdDHN4-L has higher protective ability against abiotic stresses due to its higher flexible unfolded structure and thermostability in comparison with CdDHN4-S. These provided direct evidence of the function of the phi-segment in dehydrins for protecting plants against abiotic stress and to show the electrostatic interaction between dehydrins and client proteins. PMID- 30477421 TI - Targeted mutagenesis using the Agrobacterium tumefaciens-mediated CRISPR-Cas9 system in common wheat. AB - BACKGROUND: Recently, the CRISPR/Cas9 system has been widely used to precisely edit plant genomes. Due to the difficulty in Agrobacterium-mediated genetic transformation of wheat, the reported applications in CRISPR/Cas9 system were all based on the biolistic transformation. RESULTS: In the present study, we efficiently applied targeted mutagenesis in common wheat (Triticum aestivum L.) protoplasts and transgenic T0 plants using the CRISPR/Cas9 system delivered via Agrobacterium tumefaciens. Seven target sites in three genes (Pinb, waxy and DA1) were selected to construct individual expression vectors. The activities of the sgRNAs were evaluated by transforming the constructed vectors into wheat protoplasts. Mutations in the targets were detected by Illumina sequencing. Genome editing, including insertions or deletions at the target sites, was found in the wheat protoplast cells. The highest mutation efficiency was 6.8% in the DA1 gene. The CRISPR/Cas9 binary vector targeting the DA1 gene was then transformed into common wheat plants by Agrobacterium tumefaciens-mediated transformation, resulting in efficient target gene editing in the T0 generation. Thirteen mutant lines were generated, and the mutation efficiency was 54.17%. Mutations were found in the A and B genomes of the transgenic plants but not in the D genome. In addition, off-target mutations were not detected in regions that were highly homologous to the sgRNA sequences. CONCLUSIONS: Our results showed that our Agrobacterium-mediated CRISPR/Cas9 system can be used for targeted mutations and facilitated wheat genetic improvement. PMID- 30477422 TI - Incidence of human rabies virus exposure in northwestern Amhara, Ethiopia. AB - BACKGROUND: Clinical Rabies is a widely distributed almost 100% fatal viral zoonotic disease. Most human rabies cases occur in developing countries, especially in Asia and Africa. It can be prevented by immunization, post exposure prophylaxis. Ethiopia is assumed to be among African countries with high incidence of human rabies exposure cases. However, there is limited documented data on the incidence of human rabies exposure in the study area in particular and in Ethiopia in general. Thus, this study aimed to determine the Incidence of Human Rabies Virus exposure in Northwestern Amhara, Ethiopia. METHODS: Retrospective cross-sectional study was conducted during August and September, 2017. The study was conducted at Addis Alem Hospital, a district level hospital in Bahir Dar. Data on human rabies exposure cases registered from September 1, 2015 to August 31, 2017 were collected from anti-rabies post exposure prophylaxis registration log book. Data was collected using a structured data collection questionnaire developed for this purpose. Descriptive statistics was used to describe relevant variables. THE RESULTS: A total of 924 human rabies exposure cases was recorded. The overall human rabies incidence per 100, 000 population was 6.5 in 2015 and 7.5 in 2016. Males (55.2%, 510/924) and children of age less than fifteen (46.3%, 428/924) were most affected groups. The majority of human rabies exposure cases (71.9%, 664/924) were from rural settings. Dogs were the principal sources of exposure (96.3%) followed by cat (1.5%) and donkey (1.3%). High incidence rate of rabies exposure was reported during spring (360, 39%) and summer (244, 26.4%) seasons. There was significant difference between rural and urban exposure cases (p = 0.001) in respect to the time of arrival to the hospital. CONCLUSION: Taking these into account, a significant proportion of the population was exposed to rabies virus during the study years. There was high human rabies exposure rate in children and in the rural community. This shows the need for organizing preventive and control strategies and to build community awareness. PMID- 30477423 TI - Application of the emergency medical services trigger tool to measure adverse events in prehospital emergency care: a time series analysis. AB - BACKGROUND: Emergency Care has previously been identified as an area of significant concern regarding the prevalence of Adverse Events (AEs). However, the majority of this focus has been on the in-hospital setting, with little understanding of the identification and incidence of AEs in the prehospital environment. METHOD: The early development and testing of Emergency Medical Services (EMS) specific triggers for the identification of AEs and Harm has been previously described. To operationalise the Emergency Medical Services Trigger Tool (EMSTT), the processes developed by the Institute for Healthcare Improvement for use with the Global Trigger Tool were adapted to a prehospital emergency care setting. These were then applied using a stepwise approach to the analysis of 36 consecutive samples of patient care records over an 18-month period (n = 710). Inter-rater reliability was measured for each trigger item and level of Harm classification. Total Triggers per 10,000 Patient Encounters, AEs per 10,000 Patient Encounters and Harm per 10,000 Patient Encounters were measured. All measures were plotted on Statistical Process Control Charts. RESULTS: There was a high level of inter-rater agreement across all items (range: 85.6-100%). The EMSTT found an average rate of 8.20 Triggers per 10,000 Patient Encounters, 2.48 AEs per 10,000 Patient Encounters and 0.34 Harm events per 10,000 Patient Encounters. Three triggers: Change in Systolic Blood Pressure Greater Than 20%; Temp > 38 degrees C without subsequent reduction; and SpO2 < 94% without supplemental Oxygen or SpO2 < 85% without assisted ventilation accounted for 93% (n = 180) of the triggers found throughout the longitudinal analysis. DISCUSSION: With sufficient focus on implementation and data collection, as well as the inclusion of a contextually relevant system for classifying AE/Harm, the EMSTT represents a potentially successful strategy towards identifying the rate of AEs within EMS across a large patient population with limited commitment of time and resources. PMID- 30477424 TI - Intramuscular preadipocytes impede differentiation and promote lipid deposition of muscle satellite cells in chickens. AB - BACKGROUND: Skeletal muscle satellite cells (MSC) are crucial for postnatal growth and regeneration of skeletal muscle. An interaction exists between MSC and intramuscular preadipocytes (IMPA). This study is the first to investigate the effects of IMPA on MSC in chickens and unveil the molecular mechanisms by transcriptome analysis. RESULTS: Primary MSC and IMPA were isolated from the pectoralis major muscle of 7-day-old chickens. After both cell types reached confluence, MSC were cultured alone or co-cultured with IMPA for 2 or 4 d. MSC treated for 2 d were subjected to RNA-seq. A total of 1653 known differentially expressed genes (DEG) were identified between co-cultured and mono-cultured MSC (|log2 FC| >= 1, FDR < 0.01). Based on Gene Ontology analysis, 48 DEG related to muscle development were screened, including the key genes MYOD1, MYOG, PAX7, and TMEM8C. The 44 DEG related to lipid deposition included the key genes CD36, FABP4, ACSBG2, CYP7A1 and PLIN2. Most of the DEG related to muscle development were downregulated in co-cultured MSC, and DEG related to lipid deposition were upregulated. Immunofluorescence of MHC supported IMPA impeding differentiation of MSC, and Oil Red O staining showed concurrent promotion of lipid deposition. Pathway analysis found that several key genes were enriched in JNK/MAPK and PPAR signaling, which may be the key pathways regulating differentiation and lipid deposition in MSC. Additionally, pathways related to cell junctions may also contribute to the effect of IMPA on MSC. CONCLUSIONS: The present study showed that IMPA impeded differentiation of MSC while promoting their lipid deposition. Pathway analysis indicated that IMPA might inhibit differentiation via the JNK/MAPK pathway, and promote lipid deposition via the PPAR pathway. This study supplies insights into the effect of IMPA on MSC, providing new clues on exposing the molecular mechanisms underlying the interplay between skeletal muscle and intramuscular fat in chickens. PMID- 30477425 TI - Transcriptome analysis reveals a composite molecular map linked to unique seed oil profile of Neocinnamomum caudatum (Nees) Merr. AB - BACKGROUND: Neocinnamomum caudatum (Nees) Merr., a biodiesel tree species in the subtropical areas of South China, India and Burma, is distinctive from other species in Lauraceae family and its seed oil is rich in linoleic acid (18:2) and stearic acid (18:0). However, there is little genetic information about this species so far. In this study, a transcriptomic analysis on developing seeds of N. caudatum was conducted in an attempt to discern the molecular mechanisms involving the control of the fatty acid (FA) and triacylglycerol (TAG) biosynthesis. RESULTS: Transcriptome analysis revealed 239,703 unigenes with an average length of 436 bp and 137 putative biomarkers that are related to FA formation and TAG biosynthesis. The expression patterns of genes encoding beta ketoacyl-acyl carrier protein synthase I (KASI), beta- ketoacyl-acyl carrier protein synthase II (KASII), stearoyl-ACP desaturase (SAD), fatty acid desaturase 2 (FAD2), fatty acid desaturase 8 (FAD8) and acyl-ACP thioesterase A/B (FATA/B) were further validated by qRT-PCR. These genes displayed a very similar expression pattern in two distinct assays. Moreover, sequence analysis of different FATBs from diverse plant species revealed that NcFATB is structurally different from its counterpart in other species in producing medium-chain saturated FAs. Concertedly, heterologous expression of NcFATB in E. coli BL21 (DE3) strain showed that this corresponding expressed protein, NcFATB, prefers long-chain saturated fatty acyl-ACP over medium-chain fatty acyl-ACP as substrate. CONCLUSIONS: Transcriptome analysis of developing N. caudatum seeds revealed a composite molecular map linked to the FA formation and oil biosynthesis in this biodiesel tree species. The substrate preference of NcFATB for long-chain saturated FAs is likely to contribute to its unique seed oil profile rich in stearic acid. Our findings demonstrate that in the tree species of Lauraceae family, the FATB enzymes producing long-chain FAs are structurally distinct from those producing medium-chain FAs, thereby suggesting that the FATB genes may serve as a biomarker for the classification of tree species of Lauraceae family. PMID- 30477426 TI - High-density genetic map construction and mapping of the homologous transformation sterility gene (hts) in wheat using GBS markers. AB - BACKGROUND: Homologous transformation sterility-1 (HTS-1) is a novel wheat mutant that exhibits pistillody, the transformation of stamens into pistils or pistil like structures. More extreme phenotypes of this mutation can have six pistils or pistil-like structures without any stamens in a floret. Thus, HTS-1 is highly valuable for studies of wheat hybrid breeding and flower development. Previous studies have shown that two major genes (Pis1 and hts) control pistillody in HTS 1. The Pis1 gene controls the three-pistil trait in the three-pistil wheat mutant and has been mapped on chromosome 2D, but the hts gene has not been mapped or identified. To do so, we crossed HTS-1 with CM28TP (three-pistil mutant) and constructed a high-density linkage map with the F2 population (200 individuals). RESULTS: The map covered 2779.96 cM, and the genetic distance per chromosome ranged from 37.59 cM to 318.95 cM. The average distance between markers was 1.04 cM. We then mapped hts between GBS-SNP markers 4A_109 and 4A_119, separated by 2.0 cM and 5.2 Mb. To find the candidate genes, the hts region was enlarged to 7.2 Mb, encompassing 752 protein-coding genes. We identified TaWin1 as a possible candidate gene after comparing the 752 genes with 206 common differentially expressed genes between pistillody stamens (PS) versus normal stamens (S) and pistils (P) versus S. Real-time PCR indicated that TaWin1 was highly expressed in HTS-1 during the pistil-and-stamen-differentiating stage, at levels approximately 120 times greater than those in CM28TP. Further analysis indicated that TaWin1 was mainly expressed in HTS-1 PS, supporting its status as a candidate gene of hts. Thus, TaWin1 overexpression probably leads to the transformation of stamens into pistils in wheat. CONCLUSIONS: The results of this study provide a foundation for further research on stamen and pistil development, with implications for wheat-hybrid breeding programs. PMID- 30477427 TI - A rapid and sensitive system for recovery of nucleic acids from Mycobacteria sp. on archived glass slides. AB - BACKGROUND: The field of diagnostics continues to advance rapidly with a variety of novel approaches, mainly dependent upon high technology platforms. Nonetheless much diagnosis, particularly in developing countries, still relies upon traditional methods such as microscopy. Biological material, particularly nucleic acids, on archived glass slides is a potential source of useful information both for diagnostic and epidemiological purposes. There are significant challenges faced when examining archived samples in order that an adequate amount of amplifiable DNA can be obtained. Herein, we describe a model system to detect low numbers of bacterial cells isolated from glass slides using (laser capture microscopy) LCM coupled with PCR amplification of a suitable target. RESULTS: Mycobacterium smegmatis was used as a model organism to provide a proof of principle for a method to recover bacteria from a stained sample on a glass slide using a laser capture system. Ziehl-Neelsen (ZN) stained cells were excised and catapulted into tubes. Recovered cells were subjected to DNA extraction and pre amplified with multiple displacement amplification (MDA). This system allowed a minimum of 30 catapulted cells to be detected following a nested real-time PCR assay, using rpoB specific primers. The combination of MDA and nested real-time PCR resulted in a 30-fold increase in sensitivity for the detection of low numbers of cells isolated using LCM. CONCLUSIONS: This study highlights the potential of LCM coupled with MDA as a tool to improve the recovery of amplifiable nucleic acids from archived glass slides. The inclusion of the MDA step was essential to enable downstream amplification. This platform should be broadly applicable to a variety of diagnostic applications and we have used it as a proof of principle with a Mycobacterium sp. model system. PMID- 30477428 TI - Analysis of transcripts and splice isoforms in red clover (Trifolium pratense L.) by single-molecule long-read sequencing. AB - BACKGROUND: Red clover (Trifolium pratense L.) is an important cool-season legume plant, which is the most widely planted forage legume after alfalfa. Although a draft genome sequence was published already, the sequences and completed structure of mRNA transcripts remain unclear, which limit further explore on red clover. RESULTS: In this study, the red clover transcriptome was sequenced using single-molecule long-read sequencing to identify full-length splice isoforms, and 29,730 novel isoforms from known genes and 2194 novel isoforms from novel genes were identified. A total of 5492 alternative splicing events was identified and the majority of alter spliced events in red clover was corrected as intron retention. In addition, of the 15,229 genes detected by SMRT, 8719 including 186,517 transcripts have at least one poly(A) site. Furthermore, we identified 4333 long non-coding RNAs and 3762 fusion transcripts. CONCLUSIONS: We analyzed full-length transcriptome of red clover with PacBio SMRT. Those new findings provided important information for improving red clover draft genome annotation and fully characterization of red clover transcriptome. PMID- 30477429 TI - The type 2 acyl-CoA:diacylglycerol acyltransferase family of the oleaginous microalga Lobosphaera incisa. AB - BACKGROUND: Oleaginous microalgae are promising sources of energy-rich triacylglycerols (TAGs) for direct use for food, feed and industrial applications. Lobosphaera incisa is a fresh water unicellular alga, which in response to nutrient stress accumulates a high amount of TAGs with a high proportion of arachidonic acid (ARA). The final committed step of de novo TAG biosynthesis is catalyzed by acyl-CoA:diacylglycerol acyltransferases (DGATs), which add a fatty acid (FA) to the final sn-3 position of diacylglycerol (DAG). RESULTS: Genome analysis revealed the presence of five putative DGAT isoforms in L. incisa, including one DGAT of type 1, three DGATs of type 2 and a single isoform of a type 3 DGAT. For LiDGAT1, LiDGAT2.1, LiDGAT2.2 and LiDGAT2.3 enzyme activity was confirmed by expressing them in the TAG-deficient yeast strain H1246. Feeding experiments of yeast transformants with fatty acids suggest a broad substrate specificity spectrum for LiDGAT1. A significant TAG production in response to exogenous ARA was found for LiDGAT2.2. Cellular localization of the four type 1 and type 2 DGATs expressed in yeast revealed that they all localize to distinct ER domains. A prominent association of LiDGAT1 with ER domains in close proximity to forming lipid droplets (LDs) was also observed. CONCLUSIONS: The data revealed a distinct molecular, functional and cellular nature of type 1 and type 2 DGATs from L. incisa, with LiDGAT1 being a major contributor to the TAG pool. LiDGATs of type 2 might be in turn involved in the incorporation of unusual fatty acids into TAG and thus regulate the composition of TAG. This report provides a valuable resource for the further research of microalgae DGATs oriented towards production of fresh-water strains with higher oil content of valuable composition, not only for oil industry but also for human and animal nutrition. PMID- 30477430 TI - Using the Beta distribution in group-based trajectory models. AB - BACKGROUND: We demonstrate an application of Group-Based Trajectory Modeling (GBTM) based on the beta distribution. It is offered as an alternative to the normal distribution for modeling continuous longitudinal data that are poorly fit by the normal distribution even with censoring. The primary advantage of the beta distribution is the flexibility of the shape of the density function. METHODS: GBTM is a specialized application of finite mixture modeling designed to identify clusters of individuals who follow similar trajectories. Like all finite mixture models, GBTM requires that the distribution of the data composing the mixture be specified. To our knowledge this is the first demonstration of the use of the beta distribution in GBTM. A case study of a beta-based GBTM analyzes data on the neurological activity of comatose cardiac arrest patients. RESULTS: The case study shows that the summary measure of neurological activity, the suppression ratio, is not well fit by the normal distribution but due to the flexibility of the shape of the beta density function, the distribution of the suppression ratio by trajectory appears to be well matched by the estimated beta distribution by group. CONCLUSIONS: The addition of the beta distribution to the already available distributional alternatives in software for estimating GBTM is a valuable augmentation to extant distributional alternatives. PMID- 30477431 TI - Health and frailty among older spousal caregivers: an observational cohort study in Belgium. AB - BACKGROUND: Among older couples, spouses are first in line to provide care, and they are key elements in the home support of dependent older persons. In this context, ensuring the health of these older spousal caregivers should be an important issue for all of the providers who care for older adults. The aim of this study was to longitudinally assess the health of older spousal caregivers considering frailty, nutrition, cognition, physical performance and mood disorders. METHODS: In this longitudinal, observational cohort study, participants were assessed at home in Wallonia, Belgium. At baseline, 82 community-dwelling spouses of older patients with cognitive deficits or functional impairment were assessed; 78 caregivers were assessed at follow-up (16 months). The clinical instruments used included Frailty Phenotype (Fried), the Mini Nutritional Assessment-short form (MNA-SF), Short Physical Performance Battery (SPPB), Geriatric Depression Scale (GDS-15), clock drawing test, medications, Zarit Burden Index (ZBI), and Caregiver Reaction Assessment (CRA). Biological assessments included plasma interleukin-6 (IL-6), ultrasensitive C reactive protein (CRP), cortisol, albumin and insulin growth factor-1 (IGF-1). RESULTS: Among caregivers, 54% were women, and the mean age was 80 years. Among care-receivers, 83% had cognitive impairment. Caregivers were more likely to be in a pre-frail stage. In one-third of the caregivers, the frailty status worsened. Transitions were observed between each of the states, except from frail to robust. In contrast to frailty, items including nutrition, cognitive status, SPPB and mood assessments were stable over time, with approximately 70% of the caregivers not experiencing significant change at follow-up. Caregiver experiences assessed with the Zarit Burden Interview and CRA were relatively stable over 16 months. CONCLUSION: Many caregivers of geriatric patients are spouses who are old themselves. A failure in the health of the caregiver may anticipate an undesired care breakdown. Caregiver health and its determinants should be explored in future longitudinal studies that cover a longer time period. PMID- 30477433 TI - SMuRF: a novel tool to identify regulatory elements enriched for somatic point mutations. AB - BACKGROUND: Single Nucleotide Variants (SNVs), including somatic point mutations and Single Nucleotide Polymorphisms (SNPs), in noncoding cis-regulatory elements (CREs) can affect gene regulation and lead to disease development. Several approaches have been developed to identify highly mutated regions, but these do not take into account the specific genomic context, and thus likelihood of mutation, of CREs. RESULTS: Here, we present SMuRF (Significantly Mutated Region Finder), a user-friendly command-line tool to identify these significantly mutated regions from user-defined genomic intervals and SNVs. We demonstrate this using publicly available datasets in which SMuRF identifies 72 significantly mutated CREs in liver cancer, including known mutated gene promoters as well as previously unreported regions. CONCLUSIONS: SMuRF is a helpful tool to allow the simple identification of significantly mutated regulatory elements. It is open source and freely available on GitHub ( https://github.com/LupienLab/SMURF ). PMID- 30477432 TI - Resilience to cognitive impairment in the oldest-old: design of the EMIF-AD 90+ study. AB - BACKGROUND: The oldest-old (subjects aged 90 years and older) population represents the fastest growing segment of society and shows a high dementia prevalence rate of up to 40%. Only a few studies have investigated protective factors for cognitive impairment in the oldest-old. The EMIF-AD 90+ Study aims to identify factors associated with resilience to cognitive impairment in the oldest old. In this paper we reviewed previous studies on cognitive resilience in the oldest-old and described the design of the EMIF-AD 90+ Study. METHODS: The EMIF AD 90+ Study aimed to enroll 80 cognitively normal subjects and 40 subjects with cognitive impairment aged 90 years or older. Cognitive impairment was operationalized as amnestic mild cognitive impairment (aMCI), or possible or probable Alzheimer's Disease (AD). The study was part of the European Medical Information Framework for AD (EMIF-AD) and was conducted at the Amsterdam University Medical Centers (UMC) and at the University of Manchester. We will test whether cognitive resilience is associated with cognitive reserve, vascular comorbidities, mood, sleep, sensory system capacity, physical performance and capacity, genetic risk factors, hallmarks of ageing, and markers of neurodegeneration. Markers of neurodegeneration included an amyloid positron emission tomography, amyloid beta and tau in cerebrospinal fluid/blood and neurophysiological measures. DISCUSSION: The EMIF-AD 90+ Study will extend our knowledge on resilience to cognitive impairment in the oldest-old by extensive phenotyping of the subjects and the measurement of a wide range of potential protective factors, hallmarks of aging and markers of neurodegeneration. TRIAL REGISTRATION: Nederlands Trial Register NTR5867 . Registered 20 May 2016. PMID- 30477434 TI - Histoplasma capsulatum causing sinusitis: a case report in French Guiana and review of the literature. AB - BACKGROUND: American histoplasmosis is a mycosis caused by Histoplasma capsulatum. A variety of clinical features of histoplasmosis have been commonly described ranging from asymptomatic infections to severe pulmonary infections. In immunocompromised individuals, progressive disseminated forms are frequent, leading to fatal outcome if untreated. However, H. capsulatum sinusitis is unusual with a few cases documented over the last three decades and may be underdiagnosed or confused with other fungal aetiologies, especially outside endemic regions. CASE PRESENTATION: In this study, we report an atypical case of Histoplasma capsulatum sinus fungus ball-like in a patient with Acquired Immunodeficiency Syndrome due to Human Immunodeficiency Virus complicated by a disseminated histoplasmosis with a death ending. Diagnosis relied on CT-Scan imaging and on both direct examination of H. capsulatum yeast forms (Gomory methenamine Grocott) in the sinus specimen (aspirate, biopsy) and on positivity of the culture further confirmed by qPCR. CONCLUSIONS: Since last few decades, among the eight reviewed patients, H. capsulatum sinusitis occurred mostly in HIV immunocompromised patients and for three cases as a sinusitis with disseminated histoplasmosis. Even if this is a rare clinical presentation, its diagnosis is crucial as it could represent an early expression of an Histoplasma capsulatum exposure that can evolve into a disseminated fatal infection when immunity decreases. PMID- 30477435 TI - Body proportions for the facilitation of walking, running and flying: the case of partridges. AB - BACKGROUND: Predation is one of the most important natural selection forces. Prey species can optimize feeding behavior and escape from predators based on mobility conditioned by body proportions. With age, mobility capacity increases and individuals are more efficient in finding resources and safety (e.g., food and refuge). Birds' mobility is driven by the dimensions, of the head and torso, as well as the extremities and flight feathers. To assess the relationship between body traits and to understand how body proportions are organized in wild Red legged partridges (Alectoris rufa), we used biometric data from nearly 14,000 individuals, obtained during a long-term study (1988-2011) on a wild population. RESULTS: We used GLMs and regressions to model the relationship between body mass and the size of body parts. We found that wing length was the morphological part best explained by other body trait measures. Wing length models were better predictors in juveniles than in adults and in females than in males. Wing length and feather length, mass and total length are the most strongly related parts; mass and wing length, total length and feather length are moderately related. The association between mass and wing length is intermediated by feather length and total length. CONCLUSIONS: Social inclusion, feeding and predator evasion may be affected by body structure intermediated by mobility and health. Our results suggest that proportions of the body, extremities and flight feathers drive mobility which is intimately associated with ecology, biological efficiency, health and physical optimization. Our findings showed that wing size was strongly allied to other body part measurements, enhancing the importance of body structure conformation for flight. Our study highlights the scaled relationship of body structure among age-sex classes and its relevance to social cohesion, flock movement and the balance between predation and starvation. PMID- 30477436 TI - The Norwegian Cognitive impairment after stroke study (Nor-COAST): study protocol of a multicentre, prospective cohort study. AB - BACKGROUND: Early and late onset post-stroke cognitive impairment (PCI) contributes substantially to disability following stroke, and is a high priority within stroke research. The aetiology for PCI is complex and related to the stroke itself, brain resilience, comorbid brain diseases, prestroke vulnerability and complications during the hospital stay. The aim of the Norwegian Cognitive Impairment After Stroke study (Nor-COAST) is to quantify and measure levels of cognitive impairments in a general Norwegian stroke population and to identify biological and clinical markers associated with prognosis for cognitive disorders following incident stroke. The study will be organised within five work packages: 1) Incidence and trajectories 2) Pathological mechanisms 3) Development of a risk score 4) Impact of physical activity and 5) Adherence to secondary prevention. METHODS: Nor-COAST is an ongoing multicentre (five participating hospitals), prospective, cohort study with consecutive inclusion during the acute phase and with follow-up at three and 18 months, and at three years. Inclusion criteria are stroke defined according to the WHO criteria. During the recruitment period from 18.05.2015 to 31.03.2017, 816 participants have been included. Cognitive impairment will be classified according to the DSM-5 criteria using a consensus group. Cognitive function is assessed by a standardised neuropsychological test battery, the Montreal Cognitive Assessment, Trail making A and B, ten-word immediate and delayed recall test, the Controlled Oral Word Association, Global Deterioration Scale and proxy based information by and the Ascertain Dementia 8 item informant questionnaire. Biomarkers include magnetic resonance imaging, routine blood samples and bio-banking. Clinical assessments include characteristics of the stroke, comorbidity, delirium, frailty and tests for cognitive and physical function, sensor based activity monitoring and adherence to secondary prophylaxis. DISCUSSION: Nor-COAST is the first Norwegian multicentre study to quantify burden of PCI that will provide reliable estimates in a general stroke population. A multidisciplinary approach aiming to identify biomarkers and clinical markers of overall prognosis will add new knowledge about risk profiles, including pre-stroke vulnerability and modifiable factors such as physical activity and secondary prophylaxis of relevance for clinical practice and later intervention studies. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02650531 . Retrospectively registered January 8, 2016. First participant included May 18, 2015. PMID- 30477437 TI - 2D/3D CMR tissue tracking versus CMR tagging in the assessment of spontaneous T2DM rhesus monkeys with isolated diastolic dysfunction. AB - BACKGROUND: Spontaneous T2DM in rhesus monkeys manifests as isolated diastolic dysfunction in the early stage of diabetic cardiomyopathy, similar to humans. Myocardial deformation measurements have emerged as a superior way to measure left ventricular (LV) function in the early stage of cardiac dysfunction, making it possible to further evaluate early-stage LV dysfunction in spontaneous T2DM rhesus monkeys. METHODS: Spontaneous T2DM rhesus monkeys with isolated diastolic dysfunction (T2DM-DD, n = 10) and corresponding nondiabetic healthy animals (ND, n = 9) were prospectively scanned for a CMR study. Circumferential and longitudinal peak systolic strain (Ecc, Ell), time to peak strain (tEcc, tEll) and peak diastolic strain rate (CSR, LSR) obtained from 2D/3D CMR-TT were compared with those obtained from CMR tagging separately. In addition, all CMR imaging protocols were performed twice in 9 ND animals to assess test-retest reproducibility. RESULTS: Compared with the ND group, the T2DM-DD monkeys demonstrated significantly impaired LV Ecc (- 10.63 +/- 3.23 vs - 14.18 +/- 3.19, p < 0.05), CSR (65.50 +/- 14.48 vs 65.50 +/- 14.48, p < 0.01), Ell (- 9.11 +/- 2.59 vs - 14.17 +/- 1.68, p < 0.05), and LSR (59.43 +/- 19.17 vs 108.46 +/- 22.33, p < 0.01) with the tagging. Only Ecc (- 13.10 +/- 2.47 vs - 19.03 +/- 3.69, p < 0.01) and CSR (148.90 +/- 31.27 vs 202.00 +/- 51.88, p < 0.01) were significantly reduced with 2D CMR-TT, and only Ecc (- 13.77 +/- 1.98 vs - 17.26 +/- 3.78, p < 0.05) was significantly reduced with 3D CMR-TT. Moreover, 2D/3D CMR TT-derived Ecc and CSR correlated with the corresponding tagging values collectively, with a statistically significant ICC value (p < 0.05). Test-retest repeatability analysis showed that most tagging-derived biomarkers had acceptable repeatability (p < 0.01). In addition, 2D CMR-TT-derived indicators were poorer than those derived from the tagging method but better than those obtained using the 3D method, with larger ICCs except for tEcc (p < 0.05). CONCLUSIONS: LV systolic and diastolic deformations were impaired in spontaneous T2DM rhesus monkeys previously diagnosed with isolated diastolic dysfunction by echocardiography. The 2D CMR-TT-derived Ecc and CSR were effective in the evaluation of the myocardial systolic and diastolic functions of early-diabetic cardiomyopathy, with relatively higher test-retest reproducibility and acceptable correlation with the tagging method compared with the 3D CMR-TT method. PMID- 30477438 TI - Key stakeholders' views on the quality of care and services available to frail seniors in Canada. AB - BACKGROUND: Frail seniors often receive ineffective care, which does not meet their needs. It is still unclear how healthcare systems should be redesigned to be more sensitive to the needs and values of frail seniors and their caregivers. We thus aimed to describe key stakeholders' perspectives on the current healthcare and services available to frail seniors. METHODS: In this qualitative descriptive study, we conducted semi-structured interviews with a convenience sample of 42 frail seniors, caregivers, clinicians, or healthcare administrators/decision makers involved in frail senior care from five Canadian provinces. We explored participants' perspectives on the quality of care and services for frail seniors. We used an inductive/deductive thematic data analysis approach based on the Square-of-Care model, including emerging themes using the constant comparison method. RESULTS: We grouped participants' perspectives into strengths, weaknesses and opportunities for improvement, and then into nine themes: care processes, continuity of care, social frailty, access to healthcare and services, models of healthcare delivery, cost of care, healthcare staff management and professional development of healthcare providers, material resources and environmental design of healthcare facilities, and coordination of care. Our findings suggest redesigning assessment, communication with frail seniors and their caregivers, targeting care and services to the needs, and integrating care better across settings and in time. CONCLUSIONS: A systematic identification of frail older people is the first step to adapt healthcare systems to this population's needs. Participation of frail older people and their caregivers to decision making would also allow choosing care plans meeting their care goals. The integration of care and services across settings, over time, and with various providers, is also needed to meet frail senior needs. PMID- 30477439 TI - The murine vaginal microbiota and its perturbation by the human pathogen group B Streptococcus. AB - BACKGROUND: Composition of the vaginal microbiota has significant influence on female urogenital health and control of infectious disease. Murine models are widely utilized to characterize host-pathogen interactions within the vaginal tract, however, the composition of endogenous vaginal flora remains largely undefined with modern microbiome analyses. Here, we employ 16S rRNA amplicon sequencing to establish the native microbial composition of the vaginal tract in adult C57Bl/6 J mice. We further interrogate the impact of estrous cycle and introduction of the human vaginal pathobiont, group B Streptococcus (GBS) on community state type and stability, and conversely, the impact of the vaginal microbiota on GBS persistence. RESULTS: Sequencing analysis revealed five distinctive community states of the vaginal microbiota dominated largely by Staphylococcus and/or Enterococcus, Lactobacillus, or a mixed population. Stage of estrus did not impact microbial composition. Introduction of GBS decreased community stability at early timepoints; and in some mice, GBS became the dominant bacterium by day 21. Endogenous Staphylococcus abundance correlated with GBS ascension into the uterus, and increased community stability in GBS challenged mice. CONCLUSIONS: The murine vaginal flora is diverse and fluctuates independently of the estrous cycle. Endogenous flora may impact pathogen colonization and dissemination and should be considered in urogenital infection models. PMID- 30477440 TI - The lived experiences of patients undergoing hemodialysis with the concept of care: a phenomenological study. AB - BACKGROUND: Providing patient-centered care needs in patients with chronic renal failure undergoing hemodialysis is important in inspiring their confidence to continue their treatment and promote their mental and social health. Therefore, recognizing the concept of care from the viewpoint of these patients can be helpful in designing the care programs of this vulnerable group. Accordingly, the aim of this study was to reveal the meaning and concept of care based on the experience of patients with chronic renal failure undergoing hemodialysis. METHODS: Using a descriptive phenomenological method, this study was conducted on 17 patients who were undergoing hemodialysis. Purposive sampling was performed and data was collected through 30 to 60 min, face-to-face and in-depth semi structured interviews. Data analysis was performed using Colaizzi's method. RESULTS: Seventeen patients (9 women 8 men) aged between 24 and 83, and a minimum of 10 and maximum of 168 months history of hemodialysis participated in the study. After data analysis, 4 themes and 9 sub-themes were extracted, and the concept of care emerged for the participants as empathy, companionship in everyday needs, social support and concern, and good-quality dialysis. CONCLUSIONS: Based on the results of this study, the concept of care from the viewpoint of patients emerged in the form of empathy, companionship in everyday needs, social support and concern, and good-quality dialysis. It is recommended that caregivers of patients consider these concepts in the design of patient centered care programs. PMID- 30477441 TI - Prevalence of chlamydia trachomatis infection among reproductive age women in sub Saharan Africa: a systematic review and meta-analysis. AB - BACKGROUND: Chlamydia trachomatis is the most common curable sexual transmitted bacterial infection in the world, including Sub-Saharan Africa. There is nil systematic review and meta-analysis on Chlamydia trachomatis infection in Sub Saharan Africa among reproductive age women. Therefore, this study was carried out to determine the pooled prevalence of chlamydia trachomatis infection in Sub Saharan Africa among reproductive age women. METHODS: A comprehensive literature search was conducted from biomedical data bases: Medline, PubMed, EMBASE, Google scholar, HINARI and Cochrane Library using a special index search terms (medical subject headings (MeSH), title and abstract. The Cochrane Q test and I2 statistics was used to test heterogeneity and publication bias was assessed using Begg's and Egger's tests. Results were presented in tables, figures and funnel plot. Data were pooled in a meta-analysis using a random effects model. RESULTS: Twenty-four studies were included in this meta-analysis. There was a high level of heterogeneity among studies. The pooled prevalence of Chlamydia trachomatis infection in Sub-Saharan Africa among reproductive age women was 7.8% (95% CI: 5.6-10.6). CONCLUSION: This review showed that Chlamydia trachomatis infection is high in Sub-Saharan Africa among reproductive age group women. This evidence suggests that governmental and non-governmental organization shall give attention for primary prevention of this infection. Likewise, in resource limited countries policy makers, stakeholders and health care providers' due attention for Chlamydia trachomatis specific and rapid diagnostic test, treatment in any medical out and in patient clinics for reproductive age women. PMID- 30477442 TI - Braun anastomosis lowers the incidence of delayed gastric emptying following pancreaticoduodenectomy: a meta-analysis. AB - BACKGROUND: Delayed gastric emptying (DGE) is one of the most frequent complications following pancreaticoduodenectomy. This meta-analysis aimed to evaluate the impact of Braun enteroenterostomy on DGE following pancreaticoduodenectomy. METHODS: A systematic review of the literature was performed to identify relevant studies. Statistical analysis was carried out using Review Manager software 5.3. RESULTS: Eleven studies involving 1672 patients (1005 in Braun group and 667 in non-Braun group) were included in the meta-analysis. Braun enteroenterostomy was associated with a statistically significant reduction in overall DGE (odds ratios [OR] 0.32, 95% confidence intervals [CI] 0.24 to 0.43; P <0.001), clinically significant DGE (OR 0.27, 95% CI 0.15 to 0.51; P <0.001), bile leak (OR 0.50, 95% CI 0.29 to 0.86; P = 0.01), and length of hospital stay (weighted mean difference -1.66, 95% CI -2.95 to 00.37; P = 0.01). CONCLUSIONS: Braun enteroenterostomy minimizes the rate and severity of DGE following pancreaticoduodenectomy. PMID- 30477444 TI - Coding Prony's method in MATLAB and applying it to biomedical signal filtering. AB - BACKGROUND: The response of many biomedical systems can be modelled using a linear combination of damped exponential functions. The approximation parameters, based on equally spaced samples, can be obtained using Prony's method and its variants (e.g. the matrix pencil method). This paper provides a tutorial on the main polynomial Prony and matrix pencil methods and their implementation in MATLAB and analyses how they perform with synthetic and multifocal visual-evoked potential (mfVEP) signals. This paper briefly describes the theoretical basis of four polynomial Prony approximation methods: classic, least squares (LS), total least squares (TLS) and matrix pencil method (MPM). In each of these cases, implementation uses general MATLAB functions. The features of the various options are tested by approximating a set of synthetic mathematical functions and evaluating filtering performance in the Prony domain when applied to mfVEP signals to improve diagnosis of patients with multiple sclerosis (MS). RESULTS: The code implemented does not achieve 100%-correct signal approximation and, of the methods tested, LS and MPM perform best. When filtering mfVEP records in the Prony domain, the value of the area under the receiver-operating-characteristic (ROC) curve is 0.7055 compared with 0.6538 obtained with the usual filtering method used for this type of signal (discrete Fourier transform low-pass filter with a cut-off frequency of 35 Hz). CONCLUSIONS: This paper reviews Prony's method in relation to signal filtering and approximation, provides the MATLAB code needed to implement the classic, LS, TLS and MPM methods, and tests their performance in biomedical signal filtering and function approximation. It emphasizes the importance of improving the computational methods used to implement the various methods described above. PMID- 30477443 TI - Retention strategies in longitudinal cohort studies: a systematic review and meta analysis. AB - BACKGROUND: Participant retention strategies that minimise attrition in longitudinal cohort studies have evolved considerably in recent years. This study aimed to assess, via systematic review and meta-analysis, the effectiveness of both traditional strategies and contemporary innovations for retention adopted by longitudinal cohort studies in the past decade. METHODS: Health research databases were searched for retention strategies used within longitudinal cohort studies published in the 10-years prior, with 143 eligible longitudinal cohort studies identified (141 articles; sample size range: 30 to 61,895). Details on retention strategies and rates, research designs, and participant demographics were extracted. Meta-analyses of retained proportions were performed to examine the association between cohort retention rate and individual and thematically grouped retention strategies. RESULTS: Results identified 95 retention strategies, broadly classed as either: barrier-reduction, community-building, follow-up/reminder, or tracing strategies. Forty-four of these strategies had not been identified in previous reviews. Meta-regressions indicated that studies using barrier-reduction strategies retained 10% more of their sample (95%CI [0.13 to 1.08]; p = .01); however, studies using follow-up/reminder strategies lost an additional 10% of their sample (95%CI [- 1.19 to - 0.21]; p = .02). The overall number of strategies employed was not associated with retention. CONCLUSIONS: Employing a larger number of retention strategies may not be associated with improved retention in longitudinal cohort studies, contrary to earlier narrative reviews. Results suggest that strategies that aim to reduce participant burden (e.g., flexibility in data collection methods) might be most effective in maximising cohort retention. PMID- 30477445 TI - Comprehensive proteome analyses of lysine acetylation in tea leaves by sensing nitrogen nutrition. AB - BACKGROUND: Nepsilon-Acetylation of lysine residues, a frequently occurring post translational modification, plays important functions in regulating physiology and metabolism. However, the information of global overview of protein acetylome under nitrogen-starvation/resupply in tea (Camellia sinensis) leaves was limited. And the full function of lysine acetylated proteins of tea plants in nitrogen absorption and assimilation remains unclear. RESULTS: Here, we performed the global review of lysine acetylome in tea leaves under nitrogen (N) starvation/resupply, using peptide prefractionation, immunoaffinity enrichment, and coupling with high sensitive LC-MS/MS combined with affinity purification analysis. Altogether, 2229 lysine acetylation sites on 1286 proteins were identified, of which 16 conserved motifs in E*KacK, Kac*K, Kac*R, Kac*HK, Kac*N, Kac*S, Kac*T, Kac*D, were extracted from 2180 acetylated peptides. Approximately, 36.76% of the acetylated lysines were located in the regions of ordered secondary structures. The most of the identified lysine acetylation proteins were located in the chloroplast (39%) and cytoplasm (29%). The largest group of acetylated proteins consisted of many enzymes, such as ATP synthase, ribosomal proteins and malate dehydrogenase [NADP], which were related to metabolism (38%) in the biological process. These acetylated proteins were mainly enriched in three primary protein complexes of photosynthesis: photosystem I, photosystem II and the cytochrome b6/f complex. And some acetylated proteins related to glycolysis and secondary metabolite biosynthesis were increased/decreased under N-resupply. Moreover, the PPI (protein-protein interaction) analysis revealed that the diverse interactions of identified acetylated proteins mainly involved in photosynthesis and ribosome. CONCLUSION: The results suggested that lysine acetylated proteins might play regulating roles in metabolic process in tea leaves. The critical regulatory roles mainly involved in diverse aspects of metabolic processes, especially in photosynthesis, glycolysis and secondary metabolism. A lot of proteins related to the photosynthesis and glycolysis were found to be acetylated, including LHCA1, LHCA3, LHCB6, psaE, psaD, psaN, GAPDH, PEPC, ENL and petC. And some proteins related to flavonoids were also found to be acetylated, including PAL, DFR, naringenin 3-dioxygenase and CHI. The provided data may serve as important resources for exploring the physiological, biochemical, and genetic role of lysine acetylation in tea plants. Data are available via ProteomeXchange with identifier PXD008931. PMID- 30477446 TI - Prediction of plant-derived xenomiRs from plant miRNA sequences using random forest and one-dimensional convolutional neural network models. AB - BACKGROUND: An increasing number of studies reported that exogenous miRNAs (xenomiRs) can be detected in animal bodies, however, some others reported negative results. Some attributed this divergence to the selective absorption of plant-derived xenomiRs by animals. RESULTS: Here, we analyzed 166 plant-derived xenomiRs reported in our previous study and 942 non-xenomiRs extracted from miRNA expression profiles of four species of commonly consumed plants. Employing statistics analysis and cluster analysis, our study revealed the potential sequence specificity of plant-derived xenomiRs. Furthermore, a random forest model and a one-dimensional convolutional neural network model were trained using miRNA sequence features and raw miRNA sequences respectively and then employed to predict unlabeled plant miRNAs in miRBase. A total of 241 possible plant-derived xenomiRs were predicted by both models. Finally, the potential functions of these possible plant-derived xenomiRs along with our previously reported ones in human body were analyzed. CONCLUSIONS: Our study, for the first time, presents the systematic plant-derived xenomiR sequences analysis and provides evidence for selective absorption of plant miRNA by human body, which could facilitate the future investigation about the mechanisms underlying the transference of plant derived xenomiR. PMID- 30477447 TI - A novel mutation in the VHL gene in a Chinese family with von Hippel-Lindau disease. AB - BACKGROUND: Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited cancer syndrome, and VHL is identified as a tumor suppressor gene. The main objective of this study was to identify disease-causing mutations in a Chinese family affected with VHL disease. METHODS: Genomic DNA was extracted from peripheral blood from a Chinese family with VHL. A predicted pathogenic variant was identified by targeted exome capture technology and next-generation sequencing. RESULTS: A novel heterozygous mutation (c.349 T > A, p.W117R) was detected in affected family members. No mutation was detected in unaffected family members or in the 150 normal controls. The mutation segregated with the disease phenotype throughout three generations. Histopathological examination revealed the characteristics of hemangioblastoma. CONCLUSIONS: A novel W117R was detected in the VHL gene that caused retinal hemangioblastomas in affected members of a Chinese family. PMID- 30477448 TI - Pregnancy outcomes following nonobstetric surgery during gestation: a nationwide population-based case-control study in Taiwan. AB - BACKGROUND: Whether nonobstetric surgery during gestation is associated with a higher risk of spontaneous abortion or adverse delivery outcomes is still unclear. METHODS: We performed a retrospective case-control study using a Longitudinal Health Insurance Database (LHID 2000) containing claim-data of 1 million randomly selected beneficiaries. We compared the incidences and estimated the adjusted odds ratios (aOR) with 95% confidence interval (95% CI) for spontaneous abortion, adverse delivery outcomes, cesarean delivery, and prolonged hospital stay to determine the risk of adverse outcomes in women who had nonobstetric surgery during gestation as compared to those who did not have any surgery during gestation. RESULTS: After exclusion, we were left with 114,852 delivery and 3999 abortion cases in our study; and 462 (0.39%) of them had nonobstetric surgery under general or regional anesthesia during pregnancy. The leading surgeries were repair of cervical os (33.12%), appendectomy (17.32%), ovarian surgeries (13.64%), and fixation of fractured bone (8.01%).The risk of spontaneous abortion (4.23% vs. 2.43%, aOR:1.53; 95% CI: 1.01-2.31), antepartum hemorrhage (7.14% vs. 2.83%, aOR: 2.51; 95% CI: 1.74-3.61), pre eclampsia/eclampsia (2.60% vs. 1.01%, aOR: 2.35; 95% CI: 1.30-4.23), gestational diabetes (2.38% vs. 0.69%, aOR: 3.12; 95% CI: 1.69-5.78), prematurity (9.06 vs. 4.90%, aOR: 3.31; 95% CI: 2.54-4.31), cesarean section (43.55% vs. 33.76%, aOR: 1.41; 95% CI: 1.17-1.71), and prolonged hospital stay (1.82% vs. 5.91%, aOR: 3.23; 95% CI: 2.16-4.83) were higher in those women who had nonobstetric surgery after adjusting for age and comorbidities. CONCLUSIONS: Nonobstetric surgery during gestation were associated with a higher risk of spontaneous abortion, adverse delivery outcomes, cesarean section, and prolonged hospital stay. PMID- 30477449 TI - Incidence of maternal near miss in the public health sector of Harare, Zimbabwe: a prospective descriptive study. AB - BACKGROUND: Maternal 'near miss' can be a proxy for maternal death and it describes women who nearly died due to obstetric complications. It measures life threatening pregnancy related complications and allows the assessment of the quality of obstetric care. METHODS: A prospective descriptive study was carried out from October 1 2016 to 31 December 2016, using the WHO criteria for maternal 'near miss' at the two tertiary public hospitals which receive referrals of all obstetric complications in Harare city, Zimbabwe. The objective was to calculate the ratio of maternal 'near miss' and associated factors. All pregnant women who developed life threatening complications classified as maternal near miss using the WHO criteria were recruited and followed up for six weeks from discharge, delivery or termination of pregnancy or up to the time of death. RESULTS: During this period there were 11,871 births. One hundred and twenty three (123) women developed severe maternal outcomes, 110 were maternal 'near miss' morbidity and 13 were maternal deaths. The maternal 'near miss' ratio was 9.3 per 1000 deliveries, the mortality index (MI) was 10.6% and the maternal mortality ratio was 110 per 100,000 deliveries. The major organ dysfunction among cases with severe maternal outcomes (SMO) was cardiovascular dysfunction (76.9%). The major causes of maternal near miss were obstetric haemorrhage (31.8%), hypertensive disorders (28.2%) and complications of miscarriages (20%). The intensive care unit (ICU) admission rate was 7.3 per 100 cases of SMO and 88.8% of maternal deaths occurred without ICU admission. CONCLUSION: The MNM ratio was comparable to that in the region. Obstetric haemorrhage was a leading cause of severe maternal morbidity though with less mortality when compared to hypertensive disorders and abortion complications. Zimbabwe should adopt maternal near miss ratio as an indicator for evaluating its maternal health services. PMID- 30477450 TI - Mindfulness-based interventions and cognitive function among breast cancer survivors: a systematic review. AB - BACKGROUND: Breast cancer survivors have an elevated risk of cognitive impairment compared to age-matched women without cancer. Causes of this impairment are complex, including both treatment and psychological factors. Mindfulness-based interventions, which have been shown to improve cognitive function in the general population, may be one approach to mitigate cognitive impairment in this survivor population. Our objective was to conduct a systematic literature review of studies on the effect of mindfulness-based interventions on cognition among breast cancer survivors. METHODS: We conducted searches of three electronic databases (Scopus, PubMed and Cochrane Database of Systematic Reviews) in September 2017 for studies pertaining mindfulness and cognitive function among breast cancer survivors. Abstracts were manually searched by two reviewers and additional articles were identified through reference lists. RESULTS: A total of 226 articles were identified through our systematic search and six met inclusion criteria for this review. The reviewed studies lacked consistency in terms of the cognition domains studied (e.g. executive function, recent memory, etc) and in the measures used to assess cognition. Of the included studies, two found no association between mindfulness interventions and cognitive function, two found improvement that was not sustained at the follow-up, and another two found sustained improvement at 2- or 6-months. CONCLUSIONS: Mindfulness-based interventions have shown some evidence for improving cognition among breast cancer survivors, but further research using validated and comprehensive cognitive assessments is needed. More research is also needed related to the timing, duration and content of mindfulness interventions. PMID- 30477451 TI - Learning curve of laparoscopic Kasai portoenterostomy for biliary atresia: report of 100 cases. AB - BACKGROUND: Laparoscopic Kasai portoenterostomy (LKPE) is performed for biliary atresia (BA). As LKPE is a technically demanding operation, a learning curve should be defined to guide training. The aim of this study was to identify the learning curve of LKPE for BA. METHODS: Metrics of perioperative safety and efficiency for 100 cases of LKPE were evaluated. Outcomes were followed to 67.2 +/- 12.1 months. Cumulative sum (CUSUM) analysis was used to identify inflexion point corresponding to the learning curve. Outcome measures included operative time (ORT), rate of clearance of jaundice (CJ) and survival with native liver (SNL). RESULTS: Between May 2009 and May 2013, 100 consecutive patients with BA underwent LKPE. The rate of conversion from LKPE to open Kasai portoenterostomy (OKPE), intraoperative transfusion and any perioperative complications was 11, 26 and 16%, respectively. There was no perioperative mortality. The CUSUM analysis revealed a learning curve of 50 for LKPE. Precipitous ORT reductions from an initial mean operative time of 316.3 min that was observed in the first 50 to 232.2 min of the late 50 cases (P < 0.01). Subsequently, cases 1 to 50 were considered 'early experience', whereas cases 51 and higher were considered as 'late experience' for statistical analysis. The rate of CJ and SNL was significantly higher after the early 50 cases (P < 0.05). In contrast, the rate of intraoperative transfusion, the median time of oral feeding initiated after operation, and the length of hospital stay was not different between the both groups (P > 0.05). CONCLUSIONS: In this experience, improved perioperative and postoperative parameters for LKPE were observed in the last 50 patients when compared with the first 50 patients. The dedicated training is likely to contribute to significantly shorter learning curves in future adopters. PMID- 30477452 TI - Prevalence of color blindness among school children in three primary schools of Gish -Abay town district, Amhara regional state, north-west Ethiopia. AB - BACKGROUND: Although there are limited studies, recent data are lacking to accurately determine the magnitude of color blindness in Ethiopia and there is no evidence of such a study in Gish Abay town district. The purpose of thie study was to assess the prevalence of color blindness among school children in Gish Abaya town district, Ethiopia. METHODS: The study used a community-based analytical cross-sectional study design with multistage cluster random sampling technique from September to October 2016. Three primary schools were selected randomly in the district of Gish Abay town district. Ishihara color plates (24 edition) was used for color vision test and Snellen' tumbling 'E' chart was used for visual acuity test. The data was analyzed using Statistical Package for Social Sciences (SPSS) version 20 statistical software and binary logistic regression was used to identify factors associated with color blindness. RESULTS: Among a total of 854 subjects, 850 participants with age range of 8-18 years were screened for color vision test giving a response rate of 99.53%. Among the participants, 452 (53.2%) were males and 398 (46.8%) were females. There were 36 (4.24%) cases of impaired color vision. Among these, 27 (3.18%) were males and 9 (1.06%) were females. Out of 36 cases of color blindness, 15 (1.77%) were deutan, 7 (0.82%) were protan and 14(1.65%) were unclassified (both deutan and protan forms). The variables; sex adjusted odds ratio (AOR [95% Confidence Interval] =3.19 [1.45; 6.98], p-value = 0.004); and visual impairment (AOR [95% CI] =4.15 [1.77; 9.75], p-value = 0.001) were significantly associated with color impairment. CONCLUSION: The prevalence of childhood color blindness in Gish Abay town district was relatively similar with other studies in Ethiopia. Sex and visual impairment are factors found to be related with the children's color blindness. Periodical eye examination at the time of school admission is recommended to adjust the children's occupation early in life. PMID- 30477453 TI - Acyclic retinoid and angiotensin-II receptor blocker exert a combined protective effect against diethylnitrosamine-induced hepatocarcinogenesis in diabetic OLETF rats. AB - BACKGROUND: Insulin resistance (IR) is closely associated with the progression of hepatocellular carcinoma (HCC). Acyclic retinoid (ACR) targets retinoid X receptor alpha and reportedly prevents HCC recurrence in clinical practice. Angiotensin-II receptor blocker (ARB) can also inhibit experimental hepatocarcinogenesis and HCC development. These are reported to suppress IR-based hepatocarcinogenesis; however, limited data are available regarding the combined effects of both these agents. This study aimed to investigate the combined chemopreventive effect of ACR and ARB on liver tumorigenesis on rats with congenital diabetes. METHODS: Male diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats underwent 70% partial hepatectomy following a single intraperitoneal injection of diethylnitrosamine to induce hepatocarcinogenesis and the administration of ACR (peretinoin, 40 mg/kg/day), ARB (losartan, 30 mg/kg/day), and a combination of ACR and ARB. Six weeks thereafter, we assessed the size and number of the pre neoplastic lesions (PNL) as well as the altered angiogenesis, oxidative stress, and chronic inflammation in the liver. Moreover, we assessed the effects exerted by ACR and ARB on in vitro cell growth in human HCC cell lines and human umbilical vascular endothelial cells (HUVECs). RESULTS: OLETF rats showed increase in the size and number of PNLs compared to LETO rats. ACR suppressed the augmentation in size and number of PNLs in the OLETF rats with suppression of cell growth, intrahepatic angiogenesis, lipid peroxidation, oxidative DNA damage, and proinflammatory cytokine production. Combining ACR with ARB enhanced the tumor-suppressive effect and ameliorated intrahepatic angiogenesis, lipid peroxidation, and proinflammatory status; however, cell growth and oxidative DNA damage remained unchanged. IR-mimetic condition accelerated in vitro proliferative activity in human HCC cells, while ACR inhibited this proliferation with G0/G1 arrest and apoptosis. Furthermore, ACR and ARB significantly attenuated the HUVECs proliferation and tubular formation under the IR-mimetic condition, and a combination of both agents demonstrated greater inhibitory effects on HUVEC growth than each single treatment. CONCLUSIONS: ACR and ARB exert a combined inhibitory effect against IR-based hepatocarcinogenesis by the inhibition of cell growth, intrahepatic angiogenesis, and oxidative stress. Thus, this combination therapy appears to hold potential as a chemopreventive treatment therapy against HCC. PMID- 30477454 TI - Hospital utilization and disposition among patients with malignant bowel obstruction: a population-based comparison of surgical to medical management. AB - BACKGROUND: Malignant bowel obstruction (MBO) is often a terminal event in end stage cancer patients. The decision to intervene surgically is complex, given the risk of harm in patients with a limited lifespan. Therefore, we sought to compare clinically meaningful outcomes in MBO patients treated with surgical versus medical management using population-based data. METHODS: We performed a retrospective analysis of hospitalized patients with MBO from 2006 to 2010 using the California Office of Statewide Health Planning and Development dataset. Hospital-free days (HFDs) at 30-, 90-, and 180-days were calculated accounting for all hospitalization, emergency department visit, and skilled nursing facility lengths of stay. Adjusted regression models were used to compare HFDs, disposition, complications, in-hospital death, and survival for surgical versus medical MBO cohorts, using inverse probability of treatment weighting with propensity scores. RESULTS: Of 4576 MBO patients, 3421 (74.8%) were treated medically and 1155 (25.2%) were treated surgically. Surgical patients had higher rates of complications (44.0% vs. 21.3%, p < 0.0001) and in-hospital death (9.5% vs. 3.9%, p < 0.0001) with lower rates of disposition to home (76.3% vs. 89.8%, p < 0.0001). Surgical patients had fewer 30- and 90-day HFDs compared to medical patients (p < 0.01). However, at 180-days, there were no differences in HFDs between treatment groups. There was no difference in overall survival between surgical and medical patients (median 6.5 vs. 6.4 months). CONCLUSION: In this population-based analysis, medical management was associated with less hospital utilization at 30- and 90-days, fewer in-hospital deaths, and more frequent discharges to home. These data underscore the potential benefits of medical management for MBO patients at the end-of-life. PMID- 30477455 TI - Treatment with PBI-4050 in patients with Alstrom syndrome: study protocol for a phase 2, single-Centre, single-arm, open-label trial. AB - BACKGROUND: Alstrom syndrome (ALMS) is a very rare autosomal recessive monogenic disorder caused by a mutation in the ALMS1 gene and characterised by childhood onset obesity, dyslipidaemia, advanced non-alcoholic fatty liver disease, diabetes and extreme insulin resistance. There is evidence of multi-organ fibrosis in ALMS and severity of the disease often leads to organ failure with associated morbidities, resulting in reduced life expectancy. There are no specific treatments for this disease, and current management consists of only symptomatic therapies. PBI-4050 is a new molecular entity with demonstrated anti inflammatory and anti-fibrotic activities in preclinical models, including animal models of human diseases characterized by progressive fibrosis in the kidney, heart, liver and lungs. Moreover, completed Phase 2 studies in type 2 diabetes mellitus with metabolic syndrome and idiopathic pulmonary fibrosis further support the anti-inflammatory and anti-fibrotic activity of PBI-4050. Together, these data suggest that PBI-4050 has the potential to treat the pathological inflammatory and fibrotic features of ALMS. The aim of this study is to evaluate the safety and anti-inflammatory & anti-fibrotic activities of PBI-4050 in subjects with ALMS. METHODS: This is a Phase 2, single-centre, single-arm, open label trial. A total of 18 patients with ALMS will be enrolled to receive PBI 4050 at a total daily oral dose of 800 mg for an initial 24 weeks with continuation for an additional 36 or 48 weeks. Standard assessments of safety include adverse events, clinical laboratory tests, vital signs, physical examination and electrocardiograms. Efficacy assessments include adipose tissue biopsy, hyperinsulinaemic-euglycaemic glucose clamp, adipose tissue microdialysis, liver transient elastography, liver and cardiac magnetic resonance imaging, and laboratory blood tests. DISCUSSION: This is the first clinical study of PBI-4050 in subjects with ALMS. Given the rarity and complexity of the disease, a single-centre, single-arm, open-label design has been chosen to maximise subject exposure and increase the likelihood of achieving our study endpoints. The results will provide valuable safety and preliminary evidence of the effects of PBI-4050 in ALMS, a rare heterogeneous disease associated with progressive fibrosis and premature mortality. TRIAL REGISTRATION: The trial is registered on ClinicalTrials.gov (Identifier; NCT02739217 , February 2016) and European Union Drug Regulating Authorities Clinical Trials (EudraCT Number 2015 001625-16, Sept 2015). PMID- 30477456 TI - Satisfactory results of a psychometric analysis and calculation of minimal clinically important differences of the World Health Organization quality of life BREF questionnaire in an observational cohort study with lung cancer and mesothelioma patients. AB - BACKGROUND: To determine the psychometric properties and minimal clinically important differences (MCIDs) of the World Health Organization Quality of Life BREF (WHOQOL-BREF) in advanced stage lung cancer patients. METHODS: Patients (n = 153) completed the WHOQOL-BREF and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Confirmatory factor analysis (CFA) was performed and reliability and construct validity determined. MCIDs were estimated with two distribution-based methods (0.5 standard deviation (SD) and 1 standard error of measurement (1 SEM)). RESULTS: CFA confirmed WHOQOL-BREF domain structure. All domains demonstrated good internal consistency (alpha > 0.70), except Social Relationships (alpha = 0.57). Nineteen of the 24 WHOQOL-BREF items had correlations of >= 0.40 with their intended domain. Four items had higher correlations with a domain other than their intended domain. Moderate to strong correlations were observed for corresponding domains of the two questionnaires, except for the social domains (r = 0.07). For 0.5 SD, MCIDs ranged from 0.88 to 1.55, and for 1 SEM MCIDs ranged from 1.76 to 2.72. CONCLUSIONS: The WHOQOL-BREF has satisfactory psychometric properties in patients with advanced stage lung cancer, whereas the observed MCIDs provide a method for interpretation of scores. PMID- 30477457 TI - The correlation between family food handling behaviors and foodborne acute gastroenteritis: a community-oriented, population-based survey in Anhui, China. AB - BACKGROUND: Foodborne acute gastroenteritis is a significant public health concern. Food handling plays a key role in the risk of foodborne acute gastroenteritis. However, research focused on the correlation between foodborne acute gastroenteritis and food handling in the family environment is limited. The purpose of the current study was to determinate the association between food handling behaviors in the family environment and foodborne acute gastroenteritis. METHODS: A cross-sectional investigation was conducted from September 1, 2015 to August 30, 2016 in Anhui Province, China. A multistage stratified cluster sampling method was designed to select subjects. Data on foodborne acute gastroenteritis and food handling were collected via questionnaire survey. RESULTS: Of the 1516 subjects included in the study, 165 (10.9%) reported having experienced symptoms of foodborne acute gastroenteritis in the past 4 weeks. The following behaviors were more prevalent in those that experienced acute gastroenteritis: (1) infrequently thoroughly heating milk (75.6%); (2) infrequently thoroughly heating cooked food purchased from outside (71.3%); (3) infrequently thoroughly heating leftovers stored in the refrigerator (32.5%), and (4) infrequently storing leftovers in the refrigerator (41.6%). A multivariate logistic regression analysis found that foodborne acute gastroenteritis was associated with the following behaviors: (1) often eating raw seafood (P < 0.001, OR = 3.250, 95% CI = 2.136-4.946); (2) often storing raw meat and cooked meat in the same container (P < 0.001, OR = 4.291, 95% CI = 2.722-6.765); (3) infrequently thoroughly heating milk (P < 0.001, OR = 4.665, 95% CI = 2.526 8.617); (4) infrequently thoroughly heating leftovers stored in the refrigerator (P < 0.001, OR = 3.416, 95% CI = 2.139-5.454); (5) infrequently storing leftovers in the refrigerator (P < 0.05, OR = 1.775, 95% CI = 1.169-2.696); and (6) infrequently thoroughly cooking green beans (P < 0.001, OR = 2.859, 95% CI = 1.798-4.545). CONCLUSIONS: Poor food handling behaviors in the family environment are associated with foodborne acute gastroenteritis. Infrequent thorough heating and improper food storage are the most critical risk factors in foodborne acute gastroenteritis. PMID- 30477458 TI - Cetuximab for esophageal cancer: an updated meta-analysis of randomized controlled trials. AB - BACKGROUND: Increasing evidence indicates that cetuximab (CET) combined with chemoradiotherapy may be effective for patients with esophageal cancer. However, the recent results are still contradictory and no consensus has yet been reached on this issue. To evaluate the clinical effects and safety of CET, we conducted an updated meta-analysis by retrieving published data up to June 2018. METHODS: A comprehensive literature search was performed in several electronic databases, including PubMed, Embase, the Cochrane Library, CNKI database and Chinese Biomedicine Database using subject terms and free terms. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to determine the efficiency and safety of CET. RESULTS: This meta-analysis included 10 randomized controlled trials (RCTs). Five RCTs reported localized esophageal cancer and other five RCTs reported metastatic esophageal cancer. For these patients with localized esophageal cancer, CET could not significantly improve the response rate, overall survival and progression-free survival (PFS, 1-5 years). But CET treatment might increase the incidences of diarrhea (OR = 2.07; CI = 1.01-4.25) and rash (OR = 16.91; CI = 3.20-89.42). For other patients with metastatic esophageal cancer, the addition of CET significantly increased the response rate (OR = 3.34; CI = 1.90-5.88), disease control rate (OR = 2.92; CI = 1.49-5.71) and 2-year overall survival (OR = 2.78; CI = 1.20-6.46) compared with the control group. However, CET could not improve the 1-year overall survival and might make patients with metastatic esophageal cancer more susceptible to rash (OR = 5.50; CI = 2.14 14.14). No significant differences in other adverse effects were found between the two groups. CONCLUSIONS: Our findings suggested that adding CET to multimodal therapy significantly improved response rate and disease control rate for patients with metastatic esophageal cancer rather than patients with localized esophageal cancer. CET might be a safe therapeutic choice, but CET failed to significantly improve the overall survival and PFS for patients with localized or metastatic esophageal cancer. PMID- 30477459 TI - Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma. AB - BACKGROUND: Germline mutations in BAP1 have been associated with BAP1-Tumor Predisposition Syndrome (BAP1-TPDS), a predisposition to multiple tumors within a family that includes uveal melanoma (UM), cutaneous melanoma, malignant mesothelioma and renal cell carcinoma. Alternatively, somatic mutations in BAP1 in UM have been associated with high risk for metastasis. In this study, we compare the risk of metastasis in UM that carry germline versus somatic BAP1 mutations and mutation-negative tumors. METHODS: DNA extracted from 142 UM and matched blood samples was sequenced using Sanger or next generation sequencing to identify BAP1 gene mutations. RESULTS: Eleven of 142 UM (8%) carried germline BAP1 mutations, 43 (30%) had somatic mutations, and 88 (62%) were mutation negative. All BAP1 mutations identified in blood samples were also present in the matched UM. There were 52 unique mutations in 54 tumors. All were pathogenic or likely pathogenic. A comparison of tumors carrying somatic vs. germline mutations, or no mutations, showed a higher frequency of metastasis in tumors carrying somatic mutations: 74% vs. 36%, P=0.03 and 74% vs. 26% P<0.001, respectively. Tumors with a somatic mutation compared to mutation-negative had an older age of diagnosis of (61.8 vs. 52.2 years, P=0.002), and shorter time to metastasis (16 vs. 26 months, P=0.04). Kaplan-Meier analysis further showed that tumors with somatic (vs. germline) mutations demonstrated a greater metastatic risk (P=0.03). Cox multivariate analysis showed in addition to chromosome-3 monosomy and larger tumor diameter, the presence of BAP1 somatic, but not germline mutations, was significantly associated with risk of metastasis(P=0.02). Personal or family history of BAP1-TPDS was available for 79 of the cases. All eight cases with germline mutations reported a history of BAP1-TPDS, which was significantly greater than what was observed in cases with somatic mutations (10 of 23, P=0.009) or mutation-negative cases (11 of 48, P<0.001). CONCLUSIONS: Defining germline vs. somatic nature of BAP1 mutations in UM can inform the individual about both the risk of metastasis, and the time to metastasis, which are critically important outcomes for the individual. This information can also change the cascade screening and surveillance of family members. PMID- 30477460 TI - Estimating the incidence of tuberculosis cases reported at a tertiary hospital in Ghana: a time series model approach. AB - BACKGROUND: The incidence of Tuberculosis (TB) differs among countries and contributes to morbidity and mortality especially in the developing countries. Trends and seasonal changes in the number of patients presenting with TB have been studied worldwide including sub-Saharan Africa. However, these changes are unknown at the Korle-Bu Teaching Hospital (KBTH). The aim of this study was to obtain a time series model to estimate the incidence of TB cases at the chest clinic of the Korle-Bu Teaching hospital. METHODS: A time series analysis using a Box-Jenkins approach propounded as an autoregressive moving average (ARIMA) was conducted on the monthly TB cases reported at the KBTH from 2008 to 2017. Various models were stated and compared and the best was found to be based on the Akaike Information Criterion and Bayesian Information Criterion. RESULTS: There was no evidence of obvious increasing or decreasing trend in the TB data. The log transformed of the data achieved stationarity with fairly stable variations around the mean of the series. ARIMA (1, 0, 1) or ARMA (1,1) was obtained as the best model. The monthly forecasted values of the best model ranged from 53 to 55 for the year 2018; however, the best model does not always produce the best results with respect to the mean absolute and mean square errors. CONCLUSIONS: Irregular fluctuations were observed in the 10 -year data studied. The model equation to estimate the expected monthly TB cases at KBTH produced an AR coefficient of 0.971 plus an MA coefficient of - 0.826 with a constant value of 4.127. The result is important for developing a hypothesis to explain the dynamics of TB occurrence so as to outline prevention programmes, optimal use of resources and effective service delivery. PMID- 30477461 TI - Flavonoids modulate multidrug resistance through wnt signaling in P-glycoprotein overexpressing cell lines. AB - BACKGROUND: Wnt signaling has been linked with P-glycoprotein (P-gp) overexpression and which was mainly mediated by beta-catenin nuclear translocation. Flavonoids have already been reported as modulators of the Wnt/beta-catenin pathway and hence they may serve as promising agents in the reversal of P-gp mediated cancer multi drug resistance (MDR). METHODS: In this study, we screened selected flavonoids against Wnt/beta-catenin signaling molecules. The binding interaction of flavonoids (theaflavin, quercetin, rutin, epicatechin 3 gallate and tamarixetin) with GSK 3beta was determined by molecular docking. Flavonoids on P-gp expression and the components of Wnt signaling in drug-resistant KBCHR8-5 cells were analyzed by western blotting and qRT-PCR. The MDR reversal potential of these selected flavonoids against P-gp mediated drug resistance was analyzed by cytotoxicity assay in KBCHR8-5 and MCF7/ADR cell lines. The chemosensitizing potential of flavonoids was further analyzed by observing cell cycle arrest in KBCHR8-5 cells. RESULTS: In this study, we observed that the components of Wnt/beta-catenin pathway such as Wnt and GSK 3beta were activated in multidrug resistant KBCHR8-5 cell lines. All the flavonoids selected in this study significantly decreased the expression of Wnt and GSK 3beta in KBCHR8-5 cells and subsequently modulates P-gp overexpression in this drug-resistant cell line. Further, we observed that these flavonoids considerably decreased the doxorubicin resistance in KBCHR8-5 and MCF7/ADR cell lines. The MDR reversal potential of flavonoids were found to be in the order of theaflavin > quercetin > rutin > epicatechin 3 gallate > tamarixetin. Moreover, we observed that flavonoids pretreatment significantly induced the doxorubicin mediated arrest at the phase of G2/M. Further, the combinations of doxorubicin with flavonoids significantly modulate the expression of drug response genes in KBCHR8-5 cells. CONCLUSION: The present findings illustrate that the studied flavonoids significantly enhances doxorubicin-mediated cell death through modulating P-gp expression pattern by targeting Wnt/beta-catenin signaling in drug-resistant KBCHR8-5 cells. PMID- 30477462 TI - Platelet count on preoperative day 1 predicts the long-term responses to laparoscopic splenectomy for Chinese patients with medically refractory idiopathic thrombocytopenic purpura. AB - BACKGROUND: Laparoscopic splenectomy (LS) is regarded as a second-line treatment for medically refractory idiopathic thrombocytopenic purpura (ITP), but the predictive factors for the long-term postoperative responses to ITP are still a matter of debate. We aimed to investigate the factors that can predict the long term response after LS for Chinese patients with medically refractory ITP. METHODS: From January 2011 to September 2016, 78 Chinese patients with ITP who underwent LS were retrospectively analyzed. Twelve parameters were analyzed by univariate and multivariate methods. RESULTS: Univariate analysis revealed that platelet count on preoperative day (PRD) 1 (P < 0.001) and operative time (P = 0.011) were significantly associated with long-term response of ITP after LS. Multivariate analysis revealed that platelet count on PRD 1 was a predictive factor of long-term response (P < 0.001). Furthermore, a long-term, stable response of platelet count on PRD 1 of > 30.0 * 109/L was easier to achieve than a platelet count on PRD 1 <= 30.0 * 109/L after LS for ITP. CONCLUSIONS: LS is a valuable and effective option in the treatment of medically refractory ITP. Platelet count on PRD 1 is an independent predicting factor for long-term response after LS for Chinese patients with ITP. PMID- 30477463 TI - Preliminary evaluation of an intensive integrated individual and family therapy model for self-harming adolescents. AB - BACKGROUND: To investigate the outcome of an integrated individual and family therapy (Intensive Contextual Treatment: ICT) in terms of reducing suffering and increasing functional adjustment among self-harming and/or suicidal adolescents with high symptom loads and their families. METHODS: Forty-nine self-harming and/or suicidal adolescents, Mage = 14.6, of predominantly Swedish origin and female gender (85.7%) participated with their parents. The study had a within group design with repeated measures at pre- and post-treatment, as well as six- and twelve-months follow-ups. Self-reports were used for the main outcomes; self harm rates, suicide attempts, parent-reported days of inpatient/institutional care, internalized and externalized symptoms, perceived stress, emotion regulation, school hours and adjustment. Secondary outcomes were levels of reported expressed emotions within family dyads, as well as parental anxiety, depression and stress. RESULTS: From pre- to post-assessment, the adolescents reported significant reductions of self-harm (p = .001, d = 0.54) and suicide attempts (p < .0001, d = 1.38). Parent-reported days of inpatient/institutional care were reduced, as well as parent- and adolescent-reported internalizing and externalizing symptoms. Furthermore, school attendance and adjustment were improved, and the adolescents reported experiencing less criticism while parents reported less emotional over-involvement. The results were maintained at follow ups. CONCLUSIONS: The adolescents and the parents reported improvements for the main outcomes. This treatment appears promising in keeping the families in treatment and out of hospital, suggesting that an integrative approach may be beneficial and feasible for this group. TRIAL REGISTRATION: This study has been approved 19/12 2011, by the regional review board in Stockholm (Dnr 2011/1593 31/5). PMID- 30477464 TI - Can pre-diagnostic serum levels of sodium and potassium predict prostate cancer survival? AB - There is evidence that derangement in serum electrolytes like sodium and potassium is associated with increased morbidity and mortality among hospitalized critically ill patients, but their role in the context of cancer survival remains poorly understood. We sought to investigate the association of pre-diagnostic serum sodium and potassium with risk of overall, cancer-specific, and cardiovascular (CV) death among 11,492 men diagnosed with prostate cancer (PCa) from the Swedish AMORIS study. Multivariable Cox proportional hazards regression was used to assess the risk of death by clinical categories of pre-diagnostic serum sodium and potassium. During a mean follow-up of 5.7 years, 1649 men died of PCa. Serum levels of sodium were not indicative of PCa-specific or CV death. A weak positive association was found between pre-diagnostic higher serum potassium (> 5 mEq/L) and overall death [HR: 1.26 (95% CI: 1.01-1.59)] as compared to low/normal levels of clinical cut-offs. The current study did not find strong evidence for a role of electrolytes in PCa mortality. To further disentangle the potential role of electrolytes in cancer development, future studies should use repeated measurement of serum electrolytes.This research project was reviewed and approved by the Stockholm Ethical Committee (Dnr 2010/1:7). PMID- 30477465 TI - Progress in the performance of HIV early infant diagnosis services in Zambia using routinely collected data from 2006 to 2016. AB - BACKGROUND: Early diagnosis and treatment initiation of HIV-infected infants can greatly reduce the risk of infant mortality. The WHO recommends testing HIV exposed infants at 6 weeks of age and immediate initiation of antiretroviral therapy if positive. This study aimed to determine the feasibility of using an electronic health records system to evaluate the performance of Zambia's HIV Early Infant Diagnosis services. METHODS: A retrospective analysis of routinely collected data from the Zambian SmartCare database was performed for the period January 2006 to December 2016. The study population includes all HIV-infected infants (n = 32,593) registered during this period on treatment for HIV. Univariable logistic regression was conducted to identify factors associated with later infant testing and treatment initiation. RESULTS: The mean age at infant HIV test decreased from 10.10 months in 2006 to 3.49 months in 2016. Infants born in 2015 were almost 4 times more likely to be tested under 2 months of age compared to infants born in 2006 (OR: 3.72, p-value: < 0.001). The mean time from diagnosis to treatment initiation decreased from 220 days in 2006 to 9 days in 2015. There was substantial regional variability with infants in the provinces of Copperbelt, Luapula and Southern performing best in outcomes and Eastern, Lusaka and Western performing the worst. CONCLUSIONS: HIV-exposed infants born more recently have significantly better outcomes than infants born a decade ago in Zambia, which could be as a result of increased attention and funding for HIV programmes. PMID- 30477466 TI - Comparing occasional and persistent frequent attenders in occupational health primary care - a longitudinal study. AB - BACKGROUND: The aim of the study was to compare occasional and persistent frequent attenders in occupational health (OH) primary care and to identify the diagnoses associated with persisting frequent attendance. METHODS: This is a longitudinal study using electronic medical record data from 2014 to 2016 from an OH service provider. Frequent attenders were defined as patients in the top decile of annual visits to healthcare professionals (frequent attender 10%, FA10). FA10 were categorized to three groups according to the persistence of frequent attendance (1-year-FA, 2 year-FA, and persistent-FA = frequent attenders in all three years). This was used as the dependent variable. We used patient sex, age, employer size, industry and distribution of visits and diagnostic codes to characterize the different frequent attender groups. RESULTS: In total, 66,831 patients were included, of which 592 persistent frequent attenders (0.9% of the study population) consulted the OH unit on average 13 times a year. They made altogether 23,797 visits during the study years. The proportion of women and employees of medium and large employers increased among persistent-FAs when compared to the other groups. Multinomial logistic regression accentuated musculoskeletal disorders and to a lesser extent diseases of the respiratory and nervous system and mental disorders. One in five FA becomes a persistent-FA. CONCLUSIONS: Our results indicate that in the context of a working population the association of musculoskeletal disorders and persistent frequent attendance is emphasized. Persistent frequent attenders also create a substantial demand on physician resources. When planning interventions aimed at working age frequent attenders, subgroups suffering from musculoskeletal disorders should be identified as they are associated with persisting frequent attendance. PMID- 30477467 TI - Low vitamin D levels are associated with cognitive impairment in patients with Hashimoto thyroiditis. AB - BACKGROUND: Cognitive impairment is commonly observed in patients with Hashimoto thyroiditis (HT). Low levels of vitamin D have been correlated with cognitive impairment in non-HT population. We examined the association of vitamin D levels with cognitive impairment in patients with HT. METHODS: We recruited 194 patients with HT and 200 healthy volunteers. Levels of serum 25-hydroxyvitamin D (25(OH)D) were measured using a competitive protein-binding assay. Cognitive funtion was assessed using Montreal Cognitive Assessment score (MoCA). Subjects with a MoCA scores < 26 are considered as having mild cognitive impairment (MCI). Multivariate analysis was performed using logistic regression models. RESULTS: Fifty-five HT patients (28.4%) were diagnosed as having MCI. Patients with MCI had significantly lower 25(OH)D levels when compared with patients without MCI (33.9 +/- 6.2 vs. 44.3 +/- 9.6 nmol/L, P < 0.001). Significant differences in 25(OH)D quartiles of HT patients were observed between the patients with MCI and the patients without MCI (P < 0.001). In multivariate analyses, serum 25(OH)D levels (<= 34.0 and >= 47.1 nmol/L) were significantly associated with cognitive impairment in patients with HT (OR 6.279, 95% CI 2.673-14.834, P < 0.001; OR 0.061, 95% CI 0.008-0.491, P = 0.009, respectively). CONCLUSION: Our results demonstrate an important association between serum vitamin D levels and cognitive impairment in patients with HT. PMID- 30477468 TI - Is children's weight a public health or a private family issue? A qualitative analysis of online discussion about National Child Measurement Programme feedback in England. AB - BACKGROUND: The National Child Measurement Programme (NCMP) is a child weight monitoring system in England, taking place in the first and final years of primary school. Many local authorities consider it important to inform parents if their child is overweight, and do so by letter alongside the offer of support and advice. Such letters have been met with mixed reactions from parents, but research seeking to better understand parents' responses is often limited by reliance on survey data and low participation rates. This study aimed to collect a broad variety of perspectives on the programme by analyzing views expressed in parent-to-parent discussions posted online. METHODS: UK-based online parenting fora were used to identify discussion threads based around the NCMP between 2010 and 2017. Thirty-one discussion threads from two parent fora were identified. Thematic analysis was used to identify themes in these data. RESULTS: The primary themes identified related to (1) the legitimacy of feedback and judgement from health professionals, (2) the relative importance of collecting population level data above individual preferences, and (3) risks versus benefits of having conversations with children about weight. Most threads adopted an 'argument, counter-argument' format, providing two sides to each issue raised. Information and opinions consistent with public health messages were frequently provided, such as how data are used, that feedback is intended to be helpful, and the importance of collecting national data. There was little evidence of individual parents shifting their views in response to others' arguments. CONCLUSIONS: This study provides novel insight into peer-to-peer debates about the NCMP, including the arguments parents find convincing and acceptable for and against a national programme to weigh children and provide feedback to parents about their weight. Online fora were used as an opportunity to express criticism or distress, but also to seek advice from peers regarding concerns about whether or not to opt out. Thus, both general issues related to the legitimacy of population screening and outcomes for individual children were of concern to parents. PMID- 30477469 TI - Prognostic significance of supradiaphragmatic lymph node metastasis detected by 18F-FDG PET/CT in advanced epithelial ovarian cancer. AB - BACKGROUND: Supradiaphragmatic lymph node metastases (SdLNM) are frequently identified using 18F-FDG positron emission tomography/computed tomography (PET/CT) in advanced epithelial ovarian cancers (AEOC). This study aimed to determine the prognostic significance of SdLNM detected by PET/CT in patients with AEOC. METHODS: Medical records of patients diagnosed with AEOC were retrospectively registered from January 2009 to July 2015. Patients were categorized according to PET/CT stage: PET/CT stage III, PET/CT stage IV with SdLNM, and PET/CT stage IV with other metastases. Clinicopathologic characteristics, recurrence patterns, survival outcomes were compared according to PET/CT stage. Anatomical distribution of SdLNM and effect of thoracic debulking surgery were estimated. RESULTS: A total of 295 patients were identified, including 176 patients who underwent primary debulking surgeries (PDS). Progression-free (P = 0.671) and overall (P = 0.525) survival did not differ significantly between patients with PET/CT IV with SdLNM and PET/CT IV with other metastases; however, patients with PET/CT IV with SdLNM had significantly poorer progression-free (P < 0.001) and overall (P = 0.016) survival than those with PET/CT stage III. Recurrence patterns were similar in all groups; intraperitoneal metastasis was the most common (78.8%) and thoracic recurrence alone accounted for less than 10%. Debulking of SdLNM lesions did not improve progression-free survival (P = 0.425) or overall survival (P = 0.465) of patients with AEOC. CONCLUSIONS: SdLNM detected using preoperative PET/CT are a negative prognostic factor in AEOC. Resection of suspicious SdLNM may not have effect to survival of patients with AEOC. PMID- 30477470 TI - Crizotinib in advanced non-small-cell lung cancer with concomitant ALK rearrangement and c-Met overexpression. AB - OBJECTIVE: Crizotinib can target against mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK), which has been considered as a multi targeted tyrosine kinase inhibitor (TKI). The objective of this study was to explore the efficacy of crizotinib in advanced non-small-cell lung cancer (NSCLC) with concomitant ALK rearrangement and c-Met overexpression. METHODS: Totally, 4622 advanced NSCLC patients from two institutes (3762 patients at the Guangdong Lung Cancer Institute from January 2011 to December 2016 and 860 cases at the Perking Cancer Hospital from January 2015 to December 2016) were screened for ALK rearrangement with any method of IHC, RACE-coupled PCR or FISH. C-Met expression was performed by IHC in ALK-rearranged patients, and more than 50% of cells with high staining were defined as c-Met overexpression. The efficacy of crizotinib was explored in the ALK-rearranged patients with or without c-Met overexpression. RESULTS: Sixteen patients were identified with c-Met overexpression in 160 ALK rearranged cases, with the incidence of 10.0% (16/160). A total of 116 ALK rearranged patients received the treatment of crizotinib. Objective response rate (ORR) was 86.7% (13/15) in ALK-rearranged patients with c-Met overexpression and 59.4% (60/101)in those without c-Met overexpression, P = 0.041. Median PFS showed a trend of superiority in c-Met overexpression group (15.2 versus 11.0 months, P = 0.263). Median overall survival (OS) showed a significant difference for ALK rearranged patients with c-Met overexpression group of 33.5 months with the hazard ratio (HR) of 3.2. CONCLUSIONS: C-Met overexpression co-exists with ALK rearrangement in a small population of advanced NSCLC. There may be a trend of favorable efficacy of crizotinib in such co-altered patients. PMID- 30477471 TI - Myogenic differentiation of primary myoblasts and mesenchymal stromal cells under serum-free conditions on PCL-collagen I-nanoscaffolds. AB - BACKGROUND: The creation of functional skeletal muscle via tissue engineering holds great promise without sacrificing healthy donor tissue. Different cell types have been investigated regarding their myogenic differentiation potential under the influence of various media supplemented with growth factors. Yet, most cell cultures include the use of animal sera, which raises safety concerns and might lead to variances in results. Electrospun nanoscaffolds represent suitable matrices for tissue engineering of skeletal muscle, combining both biocompatibility and stability. We therefore aimed to develop a serum-free myogenic differentiation medium for the co-culture of primary myoblasts (Mb) and mesenchymal stromal cells derived from the bone marrow (BMSC) and adipose tissue (ADSC) on electrospun poly-epsilon-caprolacton (PCL)-collagen I-nanofibers. RESULTS: Rat Mb were co-cultured with rat BMSC (BMSC/Mb) or ADSC (ADSC/Mb) two dimensionally (2D) as monolayers or three-dimensionally (3D) on aligned PCL collagen I-nanofibers. Differentiation media contained either AIM V, AIM V and Ultroser(r) G, DMEM/Ham's F12 and Ultroser(r) G, or donor horse serum (DHS) as a conventional differentiation medium. In 2D co-culture groups, highest upregulation of myogenic markers could be induced by serum-free medium containing DMEM/Ham's F12 and Ultroser(r) G (group 3) after 7 days. Alpha actinin skeletal muscle 2 (ACTN2) was upregulated 3.3-fold for ADSC/Mb and 1.7-fold for BMSC/Mb after myogenic induction by group 3 serum-free medium when compared to stimulation with DHS. Myogenin (MYOG) was upregulated 5.2-fold in ADSC/Mb and 2.1 fold in BMSC/Mb. On PCL-collagen I-nanoscaffolds, ADSC showed a higher cell viability compared to BMSC in co-culture with Mb. Myosin heavy chain 2, ACTN2, and MYOG as late myogenic markers, showed higher gene expression after long term stimulation with DHS compared to serum-free stimulation, especially in BMSC/Mb co cultures. Immunocytochemical staining with myosin heavy chain verified the presence of a contractile apparatus under both serum free and standard differentiation conditions. CONCLUSIONS: In this study, we were able to myogenically differentiate mesenchymal stromal cells with myoblasts on PCL collagen I-nanoscaffolds in a serum-free medium. Our results show that this setting can be used for skeletal muscle tissue engineering, applicable to future clinical applications since no xenogenous substances were used. PMID- 30477472 TI - Implementing prevention of seasonal affective disorder from patients' and physicians' perspectives - a qualitative study. AB - BACKGROUND: Seasonal affective disorder (SAD) is a seasonally recurrent type of major depression that has detrimental effects on patients' lives during winter. Little is known about how it affects patients during summer and about patients' and physicians' perspectives on preventive SAD treatment. The aim of our study was to explore how SAD patients experience summers, what type of preventive treatment patients implement, which preventive treatment methods, if any, physicians recommend, and what factors facilitate or hinder implementation/recommendation of SAD prevention. METHODS: We conducted 15 semi structured interviews, ten with adult patients with a history of SAD and five with physicians. Transcripts were analyzed by two researchers using an inductive thematic analysis approach. RESULTS: One group of patients was able to enjoy summer and ignore thoughts of the upcoming winter. The other group feared the impending depressive episode in winter, and this fear negatively impacted these patients' well-being during the summer. Preventive treatment was a relevant issue for all patients, and all but one person implemented SAD prevention during summer. We identified six factors that influenced patient use of preventive treatment of SAD. Four factors occur on an individual level (knowledge about disease and preventive treatment options, experience with treatment in acute phase, acceptability of intervention, willingness to take responsibility for oneself), one on an interpersonal level (social and work environment), and one on a structural level (healthcare system). All psychiatrists recommended some kind of preventive intervention, most commonly, lifestyle changes. Four factors influenced psychiatrists in recommending prevention of SAD (patient expectations, disease history and stability, risk/benefit ratio, lack of evidence). CONCLUSIONS: Success in the implementation of SAD prevention does not solely depend on the willingness of the patients, but is also influenced by external factors. Raising awareness of SAD among general practitioners and low-level access to mental-health support could help patients find appropriate help sooner. To better guide the optimal treatment choice, comparative effectiveness research on treatments to prevent a new onset in patients with a history of SAD and clinical practice guidelines on SAD are needed. PMID- 30477473 TI - TRPM7 overexpression enhances the cancer stem cell-like and metastatic phenotypes of lung cancer through modulation of the Hsp90alpha/uPA/MMP2 signaling pathway. AB - BACKGROUND: Waixenicin A, a bioactive extract of soft coral Sarcothelia edmondsoni, has been shown to be anti-neoplastic. However, its mechanisms of action remain unclear. Cancer stem cells (CSCs) and associated stemness factors are implicated in lung cancer. Here, we investigated the role of Waixenicin A on CSCs-like and metastatic lung cancer cells. METHODS: We demonstrated and compared TRPM7 expression in the non-tumor lung tissues or bronchial epithelial 16-HBE cell line. TRPM7 was aberrantly expressed in the cancer tissues and SPCA-1, NCI H520, SK-MES-1, A549 and 95D cell lines. RESULTS: Increased TRPM7 expression was associated with enhanced SOX2, KLF4, and CD133, Hsp90alpha, uPA, and MMP2 expression in lung cancer cells. TRPM7-silencing inhibited epithelial-to mesenchymal transition (EMT), suppressed stemness markers and phenotypes, concomitantly suppressed Hsp90alpha/uPA/MMP2 axis. Coincidently, Waixenicin A treatment downregulated TRPM7 and oncogenic markers; Waixenicin A also attenuated the ability of lung cancer cells to form tumorspheres, in vitro. In validation, our clinicopathological analyses showed that a higher TRPM7 expression was positively correlated with the larger tumor size (p = 0.007), positive lymph node metastasis (p = 0.005) and disease grade (p = 0.003). CONCLUSIONS: Through its ability to inhibit Hsp90alpha/uPA/MMP2 signaling and suppress TRPM7 expression, we showed that Waixenicin A is a potential anticancer therapeutic agent for treating malignant lung cancer. PMID- 30477474 TI - Bathing adaptations in the homes of older adults (BATH-OUT): results of a feasibility randomised controlled trial (RCT). AB - BACKGROUND: Housing adaptations have been identified as an important environmental and prevention intervention for older adults, which may improve health and quality of life. The onset of disability in bathing can act as a warning for further disability in other activities and may therefore be a judicious time-point for intervention. The aim of this study was to determine the feasibility of conducting a Randomised Controlled Trial (RCT) of bathing adaptations, to evaluate whether they improve older adults' perceived health status and quality of life, prevent further functional deterioration, and reduce the use of other health and social care resources. This study was conducted in preparation for a powered RCT. METHOD: Eligibility criteria were aged > 65 and referred to local authority housing adaptations service for an accessible flush floor shower. Participants were randomised to either usual adaptations (3-4 month wait) or immediate adaptations (no wait). Outcomes were assessed at 3, 6 and 9 months and included perceived physical and mental health status, health and social care related quality of life, independence in activities of daily living (ADL) and bathing, and falls. Data on costs and the use of health and social care resources were collected during follow-up in order to inform a definitive health economic evaluation. RESULTS: Sixty participants were recruited and randomised, 31 to immediate adaptations and 29 to waiting list control. Mean age was 77(SD8), 58% women and 58% living alone. Follow-ups were completed with 90, 85 and 72% at 3, 6 and 9 months respectively. Adaptations were delivered to 65% of participants within the requisite timescales as there were delays with some privately owned properties. There were improvements from baseline in both groups on all outcome measures following the completion of the adaptations. CONCLUSIONS: This is the first RCT of housing adaptations in the UK. We demonstrated the feasibility of using a waiting list control, subject to minor alterations to the timescales for privately owned properties. A powered trial would evaluate the impact on older adults' quality of life and investigate the impact of waiting times on functional outcomes and health and care resource use. TRIAL REGISTRATION: ISRCTN14876332 Registered 12 July 2016. PMID- 30477475 TI - Challenges to the improvement of obstetric care in maternity hospitals of a large Brazilian city: an exploratory qualitative approach on contextual issues. AB - BACKGROUND: Maternal morbidity and mortality are still serious public health concerns in Brazil, and access to quality obstetric care is one critical point of this problem. Despite efforts, obstetric care quality problems and sub optimal/poor outcomes persist. The study aimed to identify contextual elements that would potentially affect the implementation of an obstetric care quality improvement intervention. METHODS: A qualitative study was conducted in three public maternity hospitals of a large Brazilian city, with high annual volume of births and buy-in from high-level managers. Individual interviews with doctors and nurses were conducted from July to October 2015. Semi-structured interviews sought to explore teamwork, coordination and communication, and leadership, being open to capture other contextual elements that could emerge. Interviews were recorded and transcribed, and the categories of analysis were identified and updated based on the constant comparative method. RESULTS: Twenty-seven interviews were carried out. Extra-organizational context concerning the dependence of the maternity hospitals on primary care units, responsible for antenatal care, and on other healthcare organizations' services emerged from interviews, but the main findings of the study centered on intra-organizational context with potential to affect healthcare quality and actions for its improvement, including material resources, work organization design, teamwork, coordination and communication, professional responsibility vis-a-vis the patient, and leadership. A major issue was the divergence of physicians' and nurses' perspectives on care quality, which in turn negatively affected their capacity to work together. CONCLUSION: Overall, the findings suggest that care on the maternity hospitals was fragmented and lacked continuity, putting at risk the quality. Redesigning work organization, promoting conditions for multi professional teamwork, better communication and coordination, improving more systemic accountability/lines of authority, and investing in team members' technical competence, and fitness of organizational structures and processes are all imbricated actions that may contribute to obstetric care quality improvement. PMID- 30477476 TI - Prognostic value of metabolic tumor volume of pretreatment 18F-FAMT PET/CT in non small cell lung Cancer. AB - BACKGROUND: This study aimed to determine the prognostic value of positron emission tomography (PET) metabolic parameters-namely metabolic tumor volume (MTV), total lesion glycolysis (TLG), and total lesion retention (TLR)-on fluorine-18 (18F) fluorodeoxyglucose (FDG) and L- [3-18F]-alpha-methyltyrosine (18F-FAMT) PET/CT in patients with non-small-cell lung cancer (NSCLC). METHODS: The study group comprised 112 NSCLC patients who underwent 18F-FDG and 18F-FAMT PET/CT prior to any therapy. The MTV, TLG, TLR, and maximum standardized uptake value (SUVmax) of the primary tumors were determined. Automatic MTV measurement was performed using PET volume computer assisted reading software. (GE Healthcare). Cox proportional hazards models were built to assess the prognostic value of MTV, TLG (for 18F-FDG), TLR (for 18F-FAMT), SUVmax, T stage, N stage, M stage, clinical stage, age, sex, tumor histological subtype, and treatment method (surgery or other therapy) on overall survival (OS). RESULTS: Higher TNM, higher clinical stage, inoperable status, and higher values for all PET parameters (both 18F-FAMT and 18F-FDG PET) were significantly associated (P < 0.05) with shorter OS. Multivariate analysis revealed that a higher MTV of 18F-FAMT (hazard ratio [HR]: 2.88, CI: 1.63-5.09, P < 0.01) and advanced clinical stage (HR: 5.36, CI: 1.88-15.34, P < 0.01) were significant predictors of shorter OS. CONCLUSIONS: MTV of 18F-FAMT is of prognostic value for OS in NSCLC cases and can help guide decision-making during patient management. PMID- 30477477 TI - Knowledge and use of family planning among men in rural Uganda. AB - BACKGROUND: Unmet need for family planning exceeds 33% in Uganda. One approach to decreasing unmet need is promoting male involvement in family planning. Male disapproval of use of family planning by their female partners and misconceptions about side effects are barriers to family planning globally and in Uganda in particular. Researchers have conducted a number of qualitative studies in recent years to examine different aspects of family planning among Ugandan men. The present study aimed to quantify men's knowledge of family planning in rural Uganda to understand how better to involve men in couples' contraceptive decision making, particularly in low-resource settings. METHODS: Data were derived from in person, researcher-administered surveys of men in a rural agrarian district in Uganda (N = 178). Participant demographics and knowledge of family planning methods, side effects, and use were queried. Descriptive statistics were used for analysis. RESULTS: Men were 34 years of age on average (range 18-71) and about half (56%) had a primary school education or less. Ninety-eight percent reported any knowledge of family planning, with 73% of men reporting obtaining information via radio and only 43% from health workers. The most common method known by men was the male condom (72%), but more than half also knew of injections (54%) and pills (52%). Relatively few men reported knowing about the most effective reversible contraceptive methods, intrauterine devices and implants (both 16%). Men identified many common contraceptive side-effects, such as vaginal bleeding (31%), and misconceptions about side effects, such as increased risk of infertility and birth defects, were relatively uncommon (both < 10%). About half of all men reported ever using a family planning method (53%), and 40% reported current use. CONCLUSIONS: This study's quantitative results build on those of recent qualitative studies and provide information about the types of family planning information men are lacking and avenues for getting this information to them. PMID- 30477478 TI - Analysis of influencing factor of coexisting prediabetes and prehypertension in adult residents of Jilin Province. AB - BACKGROUND: To explore the risk factors of coexisting prediabetes and prehypertension, to provide theoretical basis for early intervention. METHODS: A multi-stage stratified random cluster sampling method was used to randomly select adult residents from Jilin Province in 2013 for questionnaire surveys, physical examinations, and laboratory tests. RESULTS: The prevalence of coexisting prediabetes and prehypertension in Jilin Province was 11.3%. The binary Logistic regression results showed that age, sex, education, triglyceride (TG), BMI, waist circumference and alcohol consumption were the effects of factor coexisting prediabetes and prehypertension. CONCLUSION: It is important to pay attention to the early stage of hypertension and diabetes, control the transition from prehypertension and prediabetes to hypertension and diabetes, and improve the health of residents. PMID- 30477479 TI - An intensive milk replacer feeding program benefits immune response and intestinal microbiota of lambs during weaning. AB - BACKGROUND: Pre-weaning milk replacer (MR) feeding program is a key factor affecting the health and welfare of lambs during their weaning. Weaning stress is well known as an inducement that negatively impacts the immune system of young ruminants, whose physiological and immune state is closely linked to the community of microbiota in their intestines. This study had two objectives: 1) To evaluate the innate immune response to weaning stress at both the physiological and molecular level; 2) To investigate changes to the jejunal chyme and mucosal adhesive microbiota between the control and high plane of MR groups. RESULTS: In this experiment, the plasma concentrations of cortisol, norepinephrine (NE) and tumor necrosis factor-alpha (TNFalpha) were higher in the C than the H group (P < 0.05), as was the expression of pro-inflammatory cytokines such as TNFalpha and CXCL8 (P < 0.05) in plasma. In jejunal tissue, the expression of TLR4 and TNFalpha were also higher in the C group (P < 0.01); histopathology showed the H group had lower lymphocyte infiltration. In the C group, however, major pathological changes were associated with extensive infiltration of lymphocytes, eosinophils, and neutrophils. Principal component analysis indicated the lamb immune response was influenced by weaning stress and modulated by the MR treatments. 16S-rRNA sequencing was used to evaluate jejunal mucosa and chyme bacterial diversity and composition. The C group's chyme had a greater alpha index (ACE: P = 0.095; Chao1: P = 0.085) than H group. In jejunal mucosa, the relative abundance of Plesiomonas was 4-fold higher (P = 0.017) in the C than the H group. CONCLUSIONS: This study's results revealed that weaning stress induced alterations to the lambs' immune system that lasted beyond the 21 d measured, and that a long-term inflammatory response effect was evidenced by changes in their hematological and expressed pro-inflammatory cytokines. Pre-weaning with a differing MR allowance resulted in complicated biological responses and compositional changes to the lambs' jejunal microbiota. Clearly, an intensive MR feeding program induced a milder immunity response and lower relative abundance of pathogenic bacteria when compared with the traditional feeding program. PMID- 30477480 TI - Timing of physical therapy consultation on 1-year healthcare utilization and costs in patients seeking care for neck pain: a retrospective cohort. AB - BACKGROUND: Patients seek care from physical therapists for neck pain but it is unclear what the association of the timing of physical therapy (PT) consultation is on 1-year healthcare utilization and costs. The purpose of this study was to compare the 1-year healthcare utilization and costs between three PT timing groups: patients who consulted a physical therapist (PT) for neck pain within 14 days (early PT consultation), between 15 and 90 days (delayed PT consultation) or between 91 and 364 days (late PT consultation). METHODS: A retrospective cohort of 308 patients (69.2% female, ages 48.7[+/-14.5] years) were categorized into PT timing groups. Descriptive statistics were calculated for each group. In adjusted regression models, 1-year healthcare utilization of injections, imaging, opioids and costs were compared between groups. RESULTS: Compared to early PT consultation, the odds of receiving an opioid prescription (aOR = 2.79, 95%CI: 1.35-5.79), spinal injection (aOR = 4.36, 95%CI:2.26-8.45), undergoing an MRI (aOR = 4.68, 95%CI:2.25-9.74), X-ray (aOR = 2.97, 95%CI:1.61-5.47) or CT scan (aOR = 3.36, 95%CI: 1.14-9.97) were increased in patients in the late PT consultation group. Similar increases in risk were found in the delayed group (except CT and Opioids). Compared to the early PT consultation group, mean costs were $2172 ($557, $3786) higher in the late PT contact group and $1063 (95%CI: $ 138 - $1988) higher in the delayed PT consultation group. DISCUSSION: There was an association with the timing of physical therapy consultation on healthcare utilization and costs, where later consultation was associated with increases costs and healthcare utilization. This study examined the association of timing of physical therapy consultation on costs and healthcare utilization, but not the association of increased access to physical therapy consultation. Therefore, the findings warrant further investigation to explore the effects of increased access to physical therapy consultation on healthcare utilization and costs in a prospective study. PMID- 30477481 TI - Mouse intestinal microbiota reduction favors local intestinal immunity triggered by antigens displayed in Bacillus subtilis biofilm. AB - BACKGROUND: We previously engineered Bacillus subtilis to express an antigen of interest fused to TasA in a biofilm. B. subtilis has several properties such as sporulation, biofilm formation and probiotic ability that were used for the oral application of recombinant spores harboring Echinococcus granulosus paramyosin and tropomyosin immunogenic peptides that resulted in the elicitation of a specific humoral immune response in a dog model. RESULTS: In order to advance our understanding of the research in oral immunization practices using recombinant B. subtilis spores, we describe here an affordable animal model. In this study, we show clear evidence indicating that a niche is required for B. subtilis recombinant spores to colonize the densely populated mice intestinal microbiota. The reduction of intestinal microbiota with an antibiotic treatment resulted in a positive elicitation of local humoral immune response in BALB/c mice after oral application of recombinant B. subtilis spores harboring TasA fused to E. granulosus (102-207) EgTrp immunogenic peptide. Our results were supported by a lasting prevalence of spores in mice feces up to 50 days after immunization and by the presence of specific secretory IgA, isolated from feces, against E. granulosus tropomyosin. CONCLUSIONS: The reduction of mouse intestinal microbiota allowed the elicitation of a local humoral immune response in mice after oral application with spores of B. subtilis harboring immunogenic peptides against E. granulosus. PMID- 30477482 TI - Towards equity in organised cancer screening: the case of cervical cancer screening in France. AB - BACKGROUND: The French national cancer institute (INCa) conducted a series of studies to assist decision-making in view of the implementation of organised cervical cancer screening that will be launched in 2018. The programme will concern all women aged 25-65 and targeted interventions will be developed for underscreened populations. This is an evolution from an equality-based approach to a step-by-step strategy of equity aiming to tackle health cancer inequalities that are avoidable and represents unfair differences. Here we present the work of the expert-group in ethics drafted by INCa to review the ethical issues prior to the programme implementation. DISCUSSION: We discuss the value of such a strategy and presents reflections with regard to issues of stigmatization, respect for individual freedom and autonomy. Indeed, the balance has to be found between the search for beneficence and the potential occurrence of perverse effects, which should be considered with particular attention. CONCLUSION: Moving toward an equity-oriented policy under a strategy of proportionate universalism faces a number of challenges, thus an overview of ethics and social sciences must be an integral part of the process. PMID- 30477483 TI - Estimating institutional physician turnover attributable to self-reported burnout and associated financial burden: a case study. AB - BACKGROUND: Awareness of the economic cost of physician attrition due to burnout in academic medical centers may help motivate organizational level efforts to improve physician wellbeing and reduce turnover. Our objectives are: 1) to use a recent longitudinal data as a case example to examine the associations between physician self-reported burnout, intent to leave (ITL) and actual turnover within two years, and 2) to estimate the cost of physician turnover attributable to burnout. METHODS: We used de-identified data from 472 physicians who completed a quality improvement survey conducted in 2013 at two Stanford University affiliated hospitals to assess physician wellness. To maintain the confidentially of survey responders, potentially identifiable demographic variables were not used in this analysis. A third party custodian of the data compiled turnover data in 2015 using medical staff roster. We used logistic regression to adjust for potentially confounding factors. RESULTS: At baseline, 26% of physicians reported experiencing burnout and 28% reported ITL within the next 2 years. Two years later, 13% of surveyed physicians had actually left. Those who reported ITL were more than three times as likely to have left. Physicians who reported experiencing burnout were more than twice as likely to have left the institution within the two-year period (Relative Risk (RR) = 2.1; 95% CI = 1.3-3.3). After adjusting for surgical specialty, work hour categories, sleep-related impairment, anxiety, and depression in a logistic regression model, physicians who experienced burnout in 2013 had 168% higher odds (Odds Ratio = 2.68, 95% CI: 1.34 5.38) of leaving Stanford by 2015 compared to those who did not experience burnout. The estimated two-year recruitment cost incurred due to departure attributable to burnout was between $15,544,000 and $55,506,000. Risk of ITL attributable to burnout was 3.7 times risk of actual turnover attributable to burnout. CONCLUSIONS: Institutions interested in the economic cost of turnover attributable to burnout can readily calculate this parameter using survey data linked to a subsequent indicator of departure from the institution. ITL data in cross-sectional studies can also be used with an adjustment factor to correct for overestimation of risk of intent to leave attributable to burnout. PMID- 30477484 TI - Geographical and temporal trends and seasonal relapse in Plasmodium ovale spp. and Plasmodium malariae infections imported to the UK between 1987 and 2015. AB - BACKGROUND: Plasmodium ovale spp. and P. malariae cause illness in endemic regions and returning travellers. Far less is known about these species than P. falciparum and P. vivax. METHODS: The UK national surveillance data, collected 1987 to 2015, were collated with the International Passenger Survey and climatic data to determine geographical, temporal and seasonal trends of imported P. ovale spp. and P. malariae infection. RESULTS: Of 52,242 notified cases of malaria, 6.04% (3157) were caused by P. ovale spp. and 1.61% (841) by P. malariae; mortality was 0.03% (1) and 0.12% (1), respectively. Almost all travellers acquired infection in West or East Africa. Infection rate per travel episode fell fivefold during the study period. The median latency of P. malariae and P. ovale spp. was 18 and 76 days, respectively; delayed presentation occurred with both species. The latency of P. ovale spp. infection imported from West Africa was significantly shorter in those arriving in the UK during the West African peak malarial season compared to those arriving outside it (44 days vs 94 days, p < 0.0001), implying that relapse synchronises with the period of high malarial transmission. This trend was not seen in P. ovale spp. imported from East Africa nor in P. malariae. CONCLUSION: In West Africa, where malaria transmission is highly seasonal, P. ovale spp. may have evolved to relapse during the malarial high transmission season. This has public health implications. Deaths are very rare, supporting current guidelines emphasising outpatient treatment. However, late presentations do occur. PMID- 30477485 TI - Effects of transcutaneous electrical nerve stimulation in the Management of Post Injection Sciatic Pain in a non-randomized controlled clinical trial in Nnewi, Nigeria. AB - BACKGROUND: Many studies on transcutaneous electrical nerve stimulation (TENS) had been undertaken to explore its pain relieving efficiency on several medicals/surgical conditions but none, specifically, had been carried out to determine the effect it has on post-injection sciatic pain (PISP) which comes about from wrong administration of intramuscular pain. This study aims to assess the effects of TENS in the management of PISP. METHODS: A total of 72 PISP subjects comprising 40 test subjects and 32 control subjects participated in a non-randomized controlled clinical trial in the current study. Participants were recruited from Department of Physiotherapy, Nnamdi Azikiwe University Teaching Hospital, Nnewi and Landmark Physiotherapy Services, Nnewi. The participants were however blinded to the intervention method they will receive before being allotted conveniently to test/experimental group (TG) or control group (CG). A written informed consent was obtained from participants before enrollments in the study. TENS and sham TENS (STENS) was applied to 40 test and 32 subjects respectively, 3 times a week, and 1 hour per session for the 10 weeks the study lasted. The Visual Analogue Scale was used to collect baseline data as well as those of 2nd, 4th, 6th, 8th and 10th weeks after TENS and STENS interventions. The data analysis was performed with the Descriptive statistic of Mean +/- SD, mean comparison test, repeated analysis of variance and paired wise t-test. Statistical level of significance was set at P < 0.05. RESULT: Results of repeated measure ANOVA showed that the pain level among participants in the treatment group at the end (after 10 weeks) of the intervention was significantly lower than that of their counterparts in the control group (F = 16.26; p = 0.01); with the intervention accounting for the 19% of the variance. The effect size (partial eta squared) = 0.19. CONCLUSION: The outcome of this research has proved the effectiveness of TENS in the management of PISP and is being recommended in the management of PISP. TRIAL REGISTRATION: Pan Africa Clinical Trial Registry ( PACTR201805003408271 ). The study was registered retrospectively on the 29th May, 2018. PMID- 30477486 TI - Fifteen years of progress in understanding frailty and health in aging. AB - The notion of frailty has evolved for more than 15 years. Although there is no consensus definition, frailty reflects a state of increased vulnerability to adverse health outcomes for individuals of the same chronological age. Two commonly used clinical tools, the frailty index and the frailty phenotype, both measure health-related deficits. The frailty index is a ratio of the number of deficits that an individual has accumulated divided by all deficits measured, whereas the phenotype specifies frailty as represented by poor performance in three of five criteria (i.e., weight loss, exhaustion, weakness, slowness, lack of activity). From human studies, animal models of both approaches have been developed and are beginning to shed light on mechanisms underlying frailty, the influence of frailty on disease expression, and new interventions to attenuate frailty. Currently, back-translation to humans is occurring. As we start to understand subcellular mechanisms involved in damage and repair as well as their response to treatment, we will begin to understand the molecular basis of aging and, thus, of frailty. PMID- 30477487 TI - Professionals' self-rated quality of care and its relation to competence, national guidelines and policies - a cross-sectional study among Finnish elderly care workers. AB - BACKGROUND: In the future, elderly care workers need to have competence of various different conditions due to greater amount of multimorbid elderly. Further, knowledge of national level guidelines is important since they are closely linked to improving quality of care and implementing better practices at work places. The impact of national level guidelines on quality of care at care units is, however, not widely examined in the Finnish context. In this study, the aim was to find out if worker's experience of his/her own competence is associated with quality of care. Secondly, we aimed to see how common is addressing national guidelines and policies at workplaces, and if they are associated with quality of care. Thirdly, we aimed to see whether there are differences between different occupational statuses in competence and addressing national guidelines and policies. METHODS: Total number of respondents was 1997 from 273 different units. Xtreg procedure was used for examining the associations of age, occupational status, unit type, professional competence and addressing the guidelines and policies with quality of care. RESULTS: Higher grade for QoC was associated with age, supervisor position, working in institutionalized care, better competence in supporting the self-determination of a person with memory disorders and falls prevention and addressing the act for elderly care and memory policy. CONCLUSION: This study demonstrated that national policies and guidelines are not widely addressed among Finnish elderly care workers. The study also showed that experienced competence of workers and discussion of policies and guidelines are related to quality of care. Especially competence related to memory disorders was associated with higher QoC. However, the relationship between quality of care and things influencing it seems complex and a major part of the variation in QoC remained unexplained. Although the relationships between guidelines, competences and quality of care are weak, national policies and competences seem to have impact on actual care provided. Therefore, sufficient time to address the guidelines should be provided at workplace and competences developed, which can be seen as a supervisor's task. With knowledge about the guidelines, workers are able to change their practices at work places. PMID- 30477488 TI - The impact of patient safety culture on handover in rural health facilities. AB - BACKGROUND: Effective handover is crucial for patient safety. Rural health care organisations have particular challenges in relation to handover of information, placing them at higher risk of adverse events. Few studies have examined the relationship between handover and patient safety in rural contexts, particularly in Australia. This study aimed to explore the effect of handover on overall perceptions of patient safety and the effect of other patient safety dimensions on handover in a rural Australian setting. METHODS: A cross-sectional online survey using The Agency for Healthcare Research and Quality Hospital Survey on Patient Safety Culture was implemented across six rural Local Health Districts in NSW, Australia and resulted in 1587 respondents. Hierarchical multiple linear regression analysis was conducted to account for the nested nature of the data. Models were developed to assess the effect of handover on patient safety perceptions, and the effect of other patient safety culture composites on handover variables. Open-ended questions about patient safety were inductively analyzed for themes. Quotes from the handover theme are presented. RESULTS: All models were significant overall (p < .001), with explanatory powers ranging from 29 to 48%. Within rural health settings, effective handover is significantly related to patient safety perceptions (R2 = .29). A strong teamwork culture and management support culture was found to enhance effective handover of patient information (R2 = .47), and effective handover of personal responsibility (R2 = .37). A strong teamwork, management support, and open communication culture enhances handover of department accountability (R2 = .41). Despite the implementation of standardised communication tools and frameworks for handover, patient safety is compromised by inadequate coordination, poor or absent documentation between departments, between other health care agencies and in transfer of care from acute facilities to primary/community care. CONCLUSION: Approaches to handover need to consider the particular challenges associated with rurality and strengthening elements found to be associated with increased safety, such as a strong teamwork and management culture and good reporting practices. Research is required to examine how communication at transition of care, particularly between facilities, is conducted and ways in which to enhance patients' and families' participation. PMID- 30477490 TI - Beneficial effect of compound essential oil inhalation on central fatigue. AB - BACKGROUNDS: Although the physical and mental enhancement effect of essential oils have been proved, the beneficial effect of essential oil in central fatigue remains unclear. In this study, we extracted essential oils from nine aromatic plants to make a compound essential oil, and detected the therapeutic effect of central fatigue by daily aerial diffusion. METHODS: Thirty-three rats were randomly and equally divided into control group, chronic sleep deprivation group, and compound essential oil inhalation group. Central fatigue was generated by chronic sleep deprivation. RESULTS: After 21-day various interferences, it is found that the sleep deprivation rats showed an evident decrease in physical endurance, negative emotion, and cognitive dysfunction compared with the control group, and the group that treated with the compound essential oil behaved significantly better than central fatigue group. CONCLUSION: We concluded that this formula of essential oils could alleviate central fatigue on rats, and our study provides a new direction of application of aromatic therapy, which could be expanded to insomnia, depression and other healthy issue in the further research. PMID- 30477489 TI - Migration through a small pore disrupts inactive chromatin organization in neutrophil-like cells. AB - BACKGROUND: Mammalian cells are flexible and can rapidly change shape when they contract, adhere, or migrate. The nucleus must be stiff enough to withstand cytoskeletal forces, but flexible enough to remodel as the cell changes shape. This is particularly important for cells migrating through confined spaces, where the nuclear shape must change in order to fit through a constriction. This occurs many times in the life cycle of a neutrophil, which must protect its chromatin from damage and disruption associated with migration. Here we characterized the effects of constricted migration in neutrophil-like cells. RESULTS: Total RNA sequencing identified that migration of neutrophil-like cells through 5- or 14 MUm pores was associated with changes in the transcript levels of inflammation and chemotaxis-related genes when compared to unmigrated cells. Differentially expressed transcripts specific to migration with constriction were enriched for groups of genes associated with cytoskeletal remodeling. Hi-C was used to capture the genome organization in control and migrated cells. Limited switching was observed between the active (A) and inactive (B) compartments after migration. However, global depletion of short-range contacts was observed following migration with constriction compared to migration without constriction. Regions with disrupted contacts, TADs, and compartments were enriched for inactive chromatin. CONCLUSION: Short-range genome organization is preferentially altered in inactive chromatin, possibly protecting transcriptionally active contacts from the disruptive effects of migration with constriction. This is consistent with current hypotheses implicating heterochromatin as the mechanoresponsive form of chromatin. Further investigation concerning the contribution of heterochromatin to stiffness, flexibility, and protection of nuclear function will be important for understanding cell migration in relation to human health and disease. PMID- 30477491 TI - Does Computerized Physician Order Entry Benefit from Dynamic Structured Data Entry? A Quasi-Experimental Study. AB - BACKGROUND: With advancements in information technology, computerized physician order entry (CPOE) and electronic Medical Records (eMR), have become widely utilized in medical settings. The predominant mode of CPOE in Taiwan is free text entry (FTE). Dynamic structured data entry (DSDE) was introduced more recently, and has increasingly drawn attention from hospitals across Taiwan. This study assesses how DSDE compares to FTE for CPOE. METHODS: A quasi-experimental study was employed to investigate the time-savings, productivity, and efficiency effects of DSDE in an outpatient setting in the gynecological department of a major hospital in Taiwan. Trained female actor patients were employed in trials of both entry methods. Data were submitted to Shapiro-Wilk and Shapiro-Francia tests to assess normality, and then to paired t-tests to assess differences between DSDE and FTE. RESULTS: Relative to FTE, the use of DSDE resulted in an average of 97% time saved and 55% more abundant and detailed content in medical records. In addition, for each clause entry in a medical record, the time saved is 133% for DSDE compared to FTE. CONCLUSION: The results suggest that DSDE is a much more efficient and productive entry method for clinicians in hospital outpatient settings. Upgrading eMR systems to the DSDE format would benefit both patients and clinicians. PMID- 30477493 TI - Consent requirements for research with human tissue: Swiss ethics committee members disagree. AB - BACKGROUND: In Switzerland, research with identifiable human tissue samples, and/or its accompanying data, must be approved by a research ethics committee (REC) before it can be allowed to take place. However, as the demand for such tissue has rapidly increased in recent years, and biobanks have been created to meet these needs, committees have had to deal with a growing number of such demands. Detailed instructions for evaluating every kind of tissue request are scarce. Committees charged with evaluating research protocols therefore sometimes face uncertainty in their decision-making. METHODS: We examine how a pool of Swiss REC members deal with a number of cases involving human tissue, in order to determine the standards they adhere to, and their understanding and implementation of existing laws and guidelines. RESULTS: There is considerable divergence in the approaches and decisions of Swiss REC members regarding human tissue sample requests, particularly concerning the issue of informed consent. Despite recent trends towards less strict consent requirements for biosample research, many of our respondents continue to employ demanding standards for researchers. The question of informed consent, and the circumstances in which it is required, continues to result in differences of opinion. CONCLUSIONS: While room for local and cultural interpretation is essential to the workings of an REC, misunderstanding of existing guidelines, or an absence of regulation in sensitive areas, will only lead to suboptimal functioning of the REC itself. Our data suggests that there is uncertainty and disagreement on the question of consent for human tissue sample, which existing laws and guidelines may not fully clarify. Methods to address these uncertainties should be implemented in order to ensure efficient and harmonious review of research protocols. PMID- 30477492 TI - Barriers and facilitators to the integration of mental health services into primary healthcare: a qualitative study among Ugandan primary care providers using the COM-B framework. AB - BACKGROUND: Uptake of clinical guideline recommendations into routine practice requires changes in attitudes and behaviors of the health care providers. The World Health Organization (WHO) has heavily invested in public health and health promotion globally by developing policy recommendations to guide clinical practice; however, clinical guidelines are often not applied. The success of the implementation of any guidelines depends on consideration of existing barriers and adequately addressing them. Therefore, exploring the context specific barriers and facilitators affecting the primary care providers (PCPs) in Mbarara district, Uganda may provide a practical way of addressing the identified barriers thus influence the PCPs action towards integration of mental healthcare services into PHC. METHODS: We adopted a theoretical model of behavior change; Capability, Opportunity and Motivation developed to understand behavior (COM-B). This was a cross-sectional study which involved using a semi-structured qualitative interview guide to conduct in-depth interviews with PCP's (clinical officers, nurses and midwives). RESULTS: Capability - inadequacy in knowledge about mental disorders; more comfortable managing patients with a mental problem diagnosis than making a new one; knowledge about mental health was gained during pre-service training; no senior cadre to consultations in mental health; and burdensome to consult the Uganda Clinical Guidelines (UCG). Opportunity - limited supply of hard copies of the UCG; guidelines not practical for local setting; did not regularly deal with clients having mental illness to foster routine usage of the UCG; no sensitization about the UCG to the intended users; and no cues at the health centers to remind the PCPs to use UCG. Motivation - did not feel self reliant; not seen the UCG at their health facilities; lack of trained mental health specialists; conflicting priorities; and no regulatory measures to encourage screening for mental health. CONCLUSIONS: Efforts to achieve successful integration of mental health services into PHC need to fit in the context of the implementers; thus the need to adapt the UCG into local context, have cues to enforce implementation, and optimize the available expertize (mental healthcare providers) in the process. PMID- 30477494 TI - Influence of response instructions and response format on applicant perceptions of a situational judgement test for medical school selection. AB - BACKGROUND: This study examined the influence of two Situational Judgement Test (SJT) design features (response instructions and response format) on applicant perceptions. Additionally, we investigated demographic subgroup differences in applicant perceptions of an SJT. METHODS: Medical school applicants (N = 372) responded to an online survey on applicant perceptions, including a description and two example items of an SJT. Respondents randomly received one of four SJT versions (should do-rating, should do-pick-one, would do-rating, would do-pick one). They rated overall favourability and items on four procedural justice factors (face validity, applicant differentiation, study relatedness and chance to perform) and ease-of-cheating. Additionally, applicant perceptions were compared for subgroups based on gender, ethnic background and first-generation university status. RESULTS: Applicants rated would-do instructions as easier to cheat than should-do instructions. Rating formats received more favourable judgements than pick-one formats on applicant differentiation, study-relatedness, chance to perform and ease of cheating. No significant main effect for demographic subgroup on applicant perceptions was found, but significant interaction effects showed that certain subgroups might have more pronounced preferences for certain SJT design features. Specifically, ethnic minority applicants - but not ethnic majority applicants - showed greater preference for should-do than would-do instructions. Additionally, first-generation university students - but not non-first-generation university students - were more favourable of rating formats than of pick-one formats. CONCLUSIONS: Findings indicate that changing SJT design features may positively affect applicant perceptions by promoting procedural justice factors and reducing perceived ease of cheating and that response instructions and response format can increase the attractiveness of SJTs for minority applicants. PMID- 30477495 TI - Patient satisfaction with outpatient physical therapy in Saudi Arabia. AB - BACKGROUND: Patient satisfaction (PS) is a key measure of the quality and outcome of healthcare systems which reflects patients' experiences. The purpose of this study was to assess overall PS with outpatient physical therapy (PT) care in Saudi Arabia and identify associated characteristics and components. METHODS: Four hundred patients who received PT treatment during 2017 were invited to participate in this study. The MedRisk Instrument for Measuring Patient Satisfaction with Physical Therapy Care (MRPS) was used to assess PS. RESULTS: The average age of 358 (90%) respondents was 38.1 (SD 12.7) years, and a majority (77%) of them were female. At least 76% respondents reported feeling better after PT treatment, while the mean global satisfaction score of all respondents as per the MRPS was 3.56, indicating high satisfaction. CONCLUSION: PT is still at an early stage of development in Saudi Arabia and is an integral part of the healthcare sector. PS is the key to identify areas for improvement and provide high quality healthcare to the public. PMID- 30477496 TI - An evaluation of TAZ and YAP crosstalk with TGFbeta signalling in canine osteosarcoma suggests involvement of hippo signalling in disease progression. AB - BACKGROUND: Osteosarcoma (OSA) is the most common bone cancer in canines. Both transforming growth factor beta (TGFbeta) and Hippo pathway mediators have important roles in bone development, stemness, and cancer progression. The role of Hippo signalling effectors TAZ and YAP has never been addressed in canine OSA. Further, the cooperative role of TGFbeta and Hippo signalling has yet to be explored in osteosarcoma. To address these gaps, this study investigated the prognostic value of TAZ and YAP alone and in combination with pSmad2 (a marker of active TGFbeta signalling), as well as the involvement of a TGFbeta-Hippo signalling crosstalk in tumourigenic properties of OSA cells in vitro. An in house trial tissue microarray (TMA) which contained 16 canine appendicular OSA cases undergoing standard care and accompanying follow-up was used to explore the prognostic role of TAZ, YAP and pSmad2. Published datasets were used to test associations between TAZ and YAP mRNA levels, metastasis, and disease recurrence. Small interfering RNAs specific to TAZ and YAP were utilized in vitro alone or in combination with TGFbeta treatment to determine their role in OSA viability, proliferation and migration. RESULTS: Patients with low levels of both YAP and pSmad2 when evaluated in combination had a significantly longer time to metastasis (log-rank test, p = 0.0058) and a longer overall survival (log rank test, p = 0.0002). No similar associations were found for TAZ and YAP mRNA levels. In vitro, TAZ knockdown significantly decreased cell viability, proliferation, and migration in metastatic cell lines, while YAP knockdown significantly decreased viability in three cell lines, and migration in two cell lines, derived from either primary tumours or their metastases. The impact of TGFbeta signaling activation on these effects was cell line-dependent. CONCLUSIONS: YAP and pSmad2 have potential prognostic value in canine appendicular osteosarcoma. Inhibiting YAP and TAZ function could lead to a decrease in viability, proliferation, and migratory capacity of canine OSA cells. Assessment of YAP and pSmad2 in larger patient cohorts in future studies are needed to further elucidate the role of TGFbeta-Hippo signalling crosstalk in canine OSA progression. PMID- 30477497 TI - Unintended pregnancy and subsequent postpartum long-acting reversible contraceptive use in Zimbabwe. AB - BACKGROUND: The postpartum period is an opportune time for contraception adoption, as women have extended interaction with the reproductive healthcare system and therefore more opportunity to learn about and adopt contraceptive methods. This may be especially true for women who experience unintended pregnancy, a key target population for contraceptive programs and programs to eliminate mother-to-child HIV transmission. Among women in Zimbabwe surveyed in 2014, we examined the relationship between pregnancy intention associated with a woman's most recent pregnancy, and her subsequent postpartum contraceptive use. METHODS: In our analysis we utilized a dataset from a random selection of catchment areas in Zimbabwe to examine the association between pregnancy intention of most recent pregnancy and subsequent postpartum contraceptive use using multinomial logistic regression models. We also explored whether this association differed by women's HIV status. Finally, we examined the association between pregnancy intention and changes in contraception from the pre- to postpartum periods. RESULTS: Findings suggest that women who reported that their pregnancy was unintended adopted less modern (all non-traditional) contraceptive methods overall, but adopted long-acting reversible contraception (LARC) more frequently than women reporting an intended pregnancy (OR 1.41; CI 1.18, 1.68). Among HIV-positive women, this relationship was particularly strong (OR 3.12; CI 1.96, 4.97). However, when examining changes in contraceptive use from the pre pregnancy to the postpartum period, women who had an unintended pregnancy had lower odds of changing to a more effective method postpartum overall (OR 0.71; CI 0.64, 0.79). CONCLUSIONS: We did not find evidence of higher modern method adoption in the postpartum period among women with an unintended pregnancy. However, women who were already on a method in the pre-pregnancy period were catalyzed to move to more effective methods (such as LARC) postpartum. This study provides evidence of low modern (non-traditional) method adoption in general in the postpartum period among a vulnerable sub-population in Zimbabwe (women who experience unintended pregnancy). Simultaneously, however, it shows a relatively greater portion specifically of LARC use among women with an unintended pregnancy. Further research is needed to more closely examine the motivations behind these contraceptive decisions in order to better inform distribution and counseling programs. PMID- 30477498 TI - Inflammatory pathways are upregulated in the nasal epithelium in patients with idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring of the lung parenchyma, leading to respiratory failure and death. High resolution computed tomography of the chest is often diagnostic for IPF, but its cost and the risk of radiation exposure limit its use as a screening tool even in patients at high risk for the disease. In patients with lung cancer, investigators have detected transcriptional signatures of disease in airway and nasal epithelial cells distal to the site of disease that are clinically useful as screening tools. Here we assessed the feasibility of distinguishing patients with IPF from age-matched controls through transcriptomic profiling of nasal epithelial curettage samples, which can be safely and repeatedly sampled over the course of a patient's illness. We recruited 10 patients with IPF and 23 age-matched healthy control subjects. Using 3' messenger RNA sequencing (mRNA-seq), we identified 224 differentially expressed genes, most of which were upregulated in patients with IPF compared with controls. Pathway enrichment analysis revealed upregulation of pathways related to immune response and inflammatory signaling in IPF patients compared with controls. These findings support the concept that fibrosis is associated with upregulation of inflammatory pathways across the respiratory epithelium with possible implications for disease detection and pathobiology. PMID- 30477499 TI - Overcoming species barriers: an outbreak of Lagovirus europaeus GI.2/RHDV2 in an isolated population of mountain hares (Lepus timidus). AB - BACKGROUND: Prior to 2010, the lagoviruses that cause rabbit hemorrhagic disease (RHD) in European rabbits (Oryctolagus cuniculus) and European brown hare syndrome (EBHS) in hares (Lepus spp.) were generally genus-specific. However, in 2010, rabbit hemorrhagic disease virus 2 (RHDV2), also known as Lagovirus europaeus GI.2, emerged and had the distinguishing ability to cause disease in both rabbits and certain hare species. The mountain hare (Lepus timidus) is native to Sweden and is susceptible to European brown hare syndrome virus (EBHSV), also called Lagovirus europaeus GII.1. While most mountain hare populations are found on the mainland, isolated populations also exist on islands. Here we investigate a mortality event in mountain hares on the small island of Hallands Vadero where other leporid species, including rabbits, are absent. RESULTS: Post-mortem and microscopic examination of three mountain hare carcasses collected from early November 2016 to mid-March 2017 revealed acute hepatic necrosis consistent with pathogenic lagovirus infection. Using immunohistochemistry, lagoviral capsid antigen was visualized within lesions, both in hepatocytes and macrophages. Genotyping and immunotyping of the virus independently confirmed infection with L. europaeus GI.2, not GII.1. Phylogenetic analyses of the vp60 gene grouped mountain hare strains together with a rabbit strain from an outbreak of GI.2 in July 2016, collected approximately 50 km away on the mainland. CONCLUSIONS: This is the first documented infection of GI.2 in mountain hares and further expands the host range of GI.2. Lesions and tissue distribution mimic those of GII.1 in mountain hares. The virus was most likely initially introduced from a concurrent, large-scale GI.2 outbreak in rabbits on the adjacent mainland, providing another example of how readily this virus can spread. The mortality event in mountain hares lasted for at least 4.5 months in the absence of rabbits, which would have required virus circulation among mountain hares, environmental persistence and/or multiple introductions. This marks the fourth Lepus species that can succumb to GI.2 infection, suggesting that susceptibility to GI.2 may be common in Lepus species. Measures to minimize the spread of GI.2 to vulnerable Lepus populations therefore are prudent. PMID- 30477500 TI - Thank you and farewell after 15 years editing respiratory research. PMID- 30477501 TI - Positive predictive value of ICD-10 codes for acute myocardial infarction in Japan: a validation study at a single center. AB - BACKGROUND: In Japan, several large healthcare databases have become available for research since the early 2000's. However, validation studies to examine the accuracy of these databases remain scarce. We conducted a validation study in order to estimate the positive predictive value (PPV) of local or ICD-10 codes for acute myocardial infarction (AMI) in Japanese claims. In particular, we examined whether the PPV differs between claims in the Diagnosis Procedure Combination case mix scheme (DPC claims) and in non-DPC claims. METHODS: We selected a random sample of 200 patients from all patients hospitalized at a large tertiary-care university hospital between January 1, 2009 and December 31, 2011 who had an inpatient claim assigned a local or ICD-10 code for AMI. We used a standardized data abstraction form to collect the relevant information from an electronic medical records system. Abstracted information was then categorized by a single cardiologist as being either definite or not having AMI. RESULTS: In a random sample of 200 patients, the average age was 67.7 years and the proportion of males was 78.0%. The PPV of the local or ICD-10 code for AMI was 82.5% in this sample of 200 patients. Further, of 178 patients who had an ICD-10 code for AMI based on any of the 7 types of condition codes in the DPC claims, the PPV was 89.3%, whereas of the 161 patients who had an ICD-10 code for AMI based on any of 3 major types of condition codes in the DPC claims, the PPV was 93.8%. CONCLUSION: The PPV of the local or ICD-10 code for AMI was high for inpatient claims in Japan. The PPV was even higher for the ICD-10 code for AMI for those patients who received AMI care through the DPC case mix scheme. The current study was conducted in a single center, suggesting that a multi-center study involving different types of hospitals is needed in the future. The accuracy of condition codes for DPC claims in Japan may also be worth examining for conditions other than AMI such as stroke. PMID- 30477502 TI - Controlled release spatial repellent devices (CRDs) as novel tools against malaria transmission: a semi-field study in Macha, Zambia. AB - BACKGROUND: The emergence of mosquitoes that can avoid indoor-deployed interventions, such as treated bed nets and indoor residual spraying, threatens the mainstay of malaria control in Zambia. Furthermore, the requirement for high coverage of these tools poses operational challenges. Spatial repellents are being assessed to supplement these vector control tools, but limitations exist in the residual effect of the repellent and the need for external power or heat for diffusion of the volatiles. METHODS: A semi-field evaluation of a novel controlled release spatial repellent device (CRD) was conducted in Macha, Zambia. These devices emanate metofluthrin with no need for external power. Devices were deployed in huts within the semi-field system (SFS). Female Anopheles gambiae sensu stricto released within the SFS were trapped overnight by light traps and collected by aspiration the next morning inside and outside of huts to determine the extent of mosquito repellency and the impact on host-seeking and survival. Experiments studied the impact of number of devices as well as the presence of hut occupants. The study was complemented with numerical methods based on computational fluid dynamics to simulate spatial distribution of metofluthrin. RESULTS: Presence of CRDs was associated with significant reductions in indoor counts of mosquitoes, regardless of whether huts were occupied or not. Repellency ranged from 15 to 60% compared to huts with no devices. Reducing the number of devices from 16 to 4 had little impact on repellency. When huts were occupied, indoor mosquito host-seeking was higher in the presence of CRDs, whilst survival was significantly reduced. CONCLUSIONS: This study demonstrated that deployment of as few as four CRDs within a hut was associated with reduced indoor mosquito densities. As would be expected, presence of occupants within huts, resulted in greater indoor catches (both with and without devices). The increased indoor mosquito host-seeking and mortality in huts when devices were present may be explained by the excito-repellency activity of metofluthrin. These semi-field experiments provide preliminary data on the utility of CRD spatial repellents to reduce indoor densities of An. gambiae mosquitoes. Studies will further investigate the impact of CRDs on mosquito behaviour as well as epidemiological protective efficacy. PMID- 30477503 TI - Congenital mid-ureteral stricture: a case report of two patients. AB - BACKGROUND: Congenital hydronephrosis is a common foetal anomaly. There are numerous causes of hydronephrosis. The diagnosis of ureteral anomalies remains challenging. Congenital mid-ureteral stricture (CMS) is less common than proximal and distal strictures. In most cases involving CMS, this condition is diagnosed intra-operatively. The gold standard treatment is resection of the stenosed segment and ureteroureterostomy. CASE PRESENTATION: We report two patients with CMS which presented as antenatal hydronephrosis with postnatal workup showed a picture of pelviuretric junction obstruction which required surgical correction. Intraoperative retrograde pyelography (RGP) confirmed the diagnosis of mid ureteral stricture which make us to change the planned surgical intervention from pyeloplasty to excision of the ureteral stricture and ureteroureterostomy as definitive management. CONCLUSION: CMS should be considered whenever proximal mega-ureter is an associated finding. Despite advanced radiological modalities, RGP remains the mainstay approach for diagnosing ureteral anomalies. PMID- 30477504 TI - Gender differences in the perception of quality of life during internal medicine training: a qualitative and quantitative analysis. AB - BACKGROUND: The higher level of participation by women in medicine may impact this profession's evolution due to gender differences perceived during medical school, after graduation and during residency. Gender differences regarding quality of life are associated with higher states of anxiety and depression among female physicians. We aimed to assess gender differences in the perception of quality of life with quantitative methods and to understand further, from the female residents' point of view, the reasons that may influence the perception of quality of life using qualitative method. Resilience, empathy and daytime sleepiness were also scored. METHODS: We performed a cross-sectional study with first-year internal medicine residents to evaluate self-reported quality of life factors specific to medical residents (VERAS-Q), including empathy (Jefferson Scale of Empathy), resilience (Wagnild and Young Brief Resilience Scale) and daytime sleepiness (Epworth Scale). We explored, from the female residents' view which factors may influence the perception of quality of life using a focus group method. RESULTS: In our study, one hundred and nine residents completed the survey: 31 (28.4%) were female and 78 (71.6%) were male. Female residents exhibited significantly lower scores than those of male residents for quality of life in the domains of time management (30.3, females vs 41.1, males; p < 0.001), psychology (48.1, females vs 56.7, males; p < 0.01) and physical health (42.8, females vs 53.6, males; p < 0.05). Female residents also scored higher for daytime sleepiness (13.0, females vs 9.0, males; p < 0.001), with pathological scores for daytime sleepiness. No significant gender differences were found in the resilience or empathy scores. The focus group assessment revealed difficulty in concentration and knowledge acquisition, insecurity, feelings of loss, greater critical perception, self-doubt and difficulty in creating effective bonds to support the training period as the main factors involved in the lower perception of quality of life among the women. CONCLUSIONS: In conclusion, female residents had lower scores for quality of life and higher scores for daytime sleepiness. Measures to improve quality of life among female residents during this critical period of medical training might include investing in mentoring to help them better manage their time and encouraging activities that facilitate relationship development. PMID- 30477505 TI - Unplanned readmission or death after discharge for Aboriginal and non-Aboriginal people with chronic disease in NSW Australia: a retrospective cohort study. AB - BACKGROUND: Admitted patients with chronic disease are at high risk of an unplanned hospital readmission, however, little research has examined unplanned readmission among Aboriginal people in Australia. This study aimed to examine whether rates of unplanned 28 day hospital readmission, or death, significantly differ between Aboriginal and non-Aboriginal patients in New South Wales, Australia, over a nine-year period. METHODS: A retrospective cohort analysis of a sample of de-identified linked hospital administrative data was conducted. Eligible patients were: 1) aged >=18 years old, 2) admitted to an acute facility in a NSW public hospital between 30th June 2005 and 1st July 2014, and 3) admitted with either cardiovascular disease, chronic respiratory disease, diabetes or renal disease. The primary composite outcome was unplanned readmission or death within 28 days of discharge. Generalized linear models and a test for trend were used to assess rates of unplanned readmission or death over time in Aboriginal and non-Aboriginal patients with chronic disease, accounting for sociodemographic variables. RESULTS: The final study cohort included 122,145 separations corresponding to 48,252 patients (Aboriginal = 57.2%, n = 27,601; non Aboriginal = 42.8%, n = 20,651). 13.9% (n = 16,999) of all separations experienced an unplanned readmission or death within 28 days of discharge. Death within 28 days of discharge alone accounted for only a small number of separations (1.4%; n = 1767). Over the nine-year period, Aboriginal separations had a significantly higher relative risk of an unplanned readmission or death (Relative risk = 1.34 (1.29, 1.40); p-value < 0.0001) compared with non Aboriginal separations once adjusted for sociodemographic, disease variables and restricted to < 75 years of age. A test for trend, including an interaction between year and Aboriginal status, showed there was no statistically significant change in proportions over the nine-year period for Aboriginal and non-Aboriginal separations (p-value for trend = 0.176). CONCLUSION: Aboriginal people with chronic disease had a significantly higher risk of unplanned readmission or death 28 days post discharge from hospital compared with non-Aboriginal people, and there has been no significant change over the nine year period. It is critical that effective interventions to reduce unplanned readmissions for Aboriginal people are identified. PMID- 30477506 TI - Gluteal fibrosis, post-injection paralysis, and related injection practices in Uganda: a qualitative analysis. AB - BACKGROUND: Iatrogenic injection injury is a major cause of disability in Ugandan children. Two injuries thought to result from injection of medications into the gluteal region include post-injection paralysis (PIP) and gluteal fibrosis (GF). This study aimed to describe perceptions of local health care workers regarding risk factors, particularly injections, for development of GF and PIP. Specifically, we examine the role of injection practices in the development of these injuries by interviewing a diverse cohort of individuals working in the health sector. METHODS: We conducted a qualitative study in the Kumi and Wakiso Districts of Uganda in November 2017, utilizing 68 key informant interviews with individuals working in healthcare related fields. Interviews were structured utilizing a moderator guide focusing on injection practices, gluteal fibrosis and post-injection paralysis. RESULTS: We identified six themes regarding perceptions of the cause of GF and PIP and organized these themes into a theoretical framework. There was a consensus among the individuals working in healthcare that inadequacies of the health care delivery system may lead to inappropriate intramuscular injection practices, which are presumed to contribute to the development of GF and PIP. Poor access to medications and qualified personnel has led to the proliferation of private clinics, which are often staffed by under trained practitioners. Misaligned economic incentives and a lack of training may also motivate practitioners to administer frequent intramuscular injections, which cost more than oral medications. A lack of regulatory enforcement enables these practices to persist. However, due to limited community awareness, patients often perceive these practitioners as appropriately trained, and the patients frequently prefer injections over alternative treatment modalities. CONCLUSION: This qualitative study suggests that inappropriate intramuscular injections, may arise from problems in the health care delivery system. To prevent the disability of GF and PIP, it is important to not only address the intramuscular injections practices in Uganda, but also to examine upstream deficits in access, education, and policy enforcement. PMID- 30477507 TI - Practical utility of general practice data capture and spatial analysis for understanding COPD and asthma. AB - BACKGROUND: General practice-based (GP) healthcare data have promise, when systematically collected, to support estimating local rates of chronic obstructive pulmonary disease (COPD) and asthma, variations in burden of disease, risk factors and comorbid conditions, and disease management and quality of care. The use of GP information systems for health improvement has been limited, however, in the scope and quality of data. This study assessed the practical utility of de-identified clinical databases for estimating local rates of COPD and asthma. We compared COPD and asthma rates to national benchmarks, examined health related risk factors and co-morbidities as correlates of COPD and asthma, and assessed spatial patterns in prevalence estimates at the small-area level. METHODS: Data were extracted from five GP databases in western Adelaide, South Australia, for active patients residing in the region between 2012 and 2014. Prevalence estimates were computed at the statistical area 1 (SA1) spatial unit level using the empirical Bayes estimation approach. Descriptive analyses included summary statistics, spatial indices and mapping of geographic patterns. Bivariate associations were assessed, and disease profiles investigated to ascertain multi-morbidities. Multilevel logistic regression models were fitted, accounting for individual covariates including the number of comorbid conditions to assess the influence of area-level socio-economic status (SES). RESULTS: For 33,725 active patients, prevalence estimates were 3.4% for COPD and 10.3% for asthma, 0.8% higher and 0.5% lower for COPD and asthma, respectively, against 2014-15 National Health Survey (NHS) benchmarks. Age-specific comparisons showed discrepancies for COPD in the '64 years or less' and 'age 65 and up' age groups, and for asthma in the '15-25 years' and '75 years and up' age groups. Analyses confirmed associations with individual-level factors, co-morbid conditions, and area-level SES. Geographic aggregation was seen for COPD and asthma, with clustering around GP clinics and health care centres. Spatial patterns were inversely related to area-level SES. CONCLUSION: GP-based data capture and analysis has a clear potential to support research for improved patient outcomes for COPD and asthma via knowledge of geographic variability and its correlates, and how local prevalence estimates differ from NHS benchmarks for vulnerable age groups. PMID- 30477508 TI - The eukaryotic translation elongation factor 1A regulation of actin stress fibers is important for infectious RSV production. AB - Cellular protein eukaryotic translation elongation factor 1A (eEF1A) is an actin binding protein that plays a role in the formation of filamentous actin (F-actin) bundles. F-Actin regulates multiple stages of respiratory syncytial virus (RSV) replication including assembly and budding. Our previous study demonstrated that eEF1A knock-down significantly reduced RSV replication. Here we investigated if the eEF1A function in actin bundle formation was important for RSV replication and release. To investigate this, eEF1A function was impaired in HEp-2 cells by either knock-down of eEF1A with siRNA, or treatment with an eEF1A inhibitor, didemnin B (Did B). Cell staining and confocal microscopy analysis showed that both eEF1A knock-down and treatment with Did B resulted in disruption of cellular stress fiber formation and elevated accumulation of F-actin near the plasma membrane. When treated cells were then infected with RSV, there was also reduced formation of virus-induced cellular filopodia. Did B treatment, similarly to eEF1A knock-down, reduced the release of infectious RSV, but unlike eEF1A knock down, did not significantly affect RSV genome replication. The lower infectious virus production in Did B treated cells also reduced RSV-induced cell death. In conclusion, the cellular factor eEF1A plays an important role in the regulation of F-actin stress fiber formation required for RSV assembly and release. PMID- 30477510 TI - Correction to: Conditional ablation of p130Cas/BCAR1 adaptor protein impairs epidermal homeostasis by altering cell adhesion and differentiation. AB - Following publication of the original article [1], the authors reported an error in the name of the 11th author. The author's name was incorrectly published as "Vincenzo Calautti", instead of "Enzo Calautti". PMID- 30477509 TI - Validity of objective methods for measuring sedentary behaviour in older adults: a systematic review. AB - BACKGROUND: The evidence showing the ill health effects of prolonged sedentary behaviour (SB) is growing. Most studies of SB in older adults have relied on self report measures of SB. However, SB is difficult for older adults to recall and objective measures that combine accelerometry with inclinometry are now available for more accurately assessing SB. The aim of this systematic review was to assess the validity and reliability of these accelerometers for the assessment of SB in older adults. METHODS: EMBASE, PubMed and EBSCOhost databases were searched for articles published up to December 13, 2017. Articles were eligible if they: a) described reliability, calibration or validation studies of SB measurement in healthy, community-dwelling individuals, b) were published in English, Portuguese or Spanish, and c) were published or in press as journal articles in peer reviewed journals. RESULTS: The review identified 15 studies in 17 papers. Of the included studies, 11 assessed the ActiGraph accelerometer. Of these, three examined reliability only, seven (in eight papers) examined validity only and one (in two papers) examined both. The strongest evidence from the studies reviewed is from studies that assessed the validity of the ActiGraph. These studies indicate that analysis of the data using 60-s epochs and a vertical magnitude cut point < 200 cpm or using 30- or 60-s epochs with a machine learning algorithm provides the most valid estimates of SB. Non-wear algorithms of 90+ consecutive zeros is also suggested for the ActiGraph. CONCLUSIONS: Few studies have examined the reliability and validity of accelerometers for measuring SB in older adults. Studies to date suggest that the criteria researchers use for classifying an epoch as sedentary instead of as non-wear time (e.g., the non-wear algorithm used) may need to be different for older adults than for younger adults. The required number of hours and days of wear for valid estimates of SB in older adults was not clear from studies to date. More older-adult-specific validation studies of accelerometers are needed, to inform future guidelines on the appropriate criteria to use for analysis of data from different accelerometer brands. TRIAL REGISTRATION: PROSPERO ID# CRD42017080754 registered December 12, 2017. PMID- 30477511 TI - Dosimetric analysis of tangent-based volumetric modulated arc therapy with deep inspiration breath-hold technique for left breast cancer patients. AB - BACKGROUND: Tangent-based intensity modulated radiation therapy (TIMRT) is a common adjuvant radiotherapy strategy for breast cancer patients. This study compared the dosimetric characteristics of tangent-based volumetric modulated arc therapy (TVMAT) and TIMRT for left breast cancer patients during deep inspiration breath-hold (DIBH) and free breathing (FB) techniques. METHODS: Fourteen patients with left breast cancer after breast-conserving surgery were included. The first arc started at 331.8-353.6 degrees and stopped at 281.8-315.0 degrees. The third arc started at 123.2-149.1 degrees and stopped at 88.0-96.0 degrees. The second and fourth arcs were reverse arcs of first and third arcs. DIBH-TIMRT inversing plans were generated using opposing tangential fields. Wilcoxon signed rank test and Spearman correlation were used to examine the significance of dose difference. RESULTS: Compared with FB-TVMAT, the mean heart dose of DIBH-TVMAT plans was reduced from 7.9 Gy to 3.2 Gy (p < 0.001). The average left lung volume receiving 30 Gy or more (V30Gy) was reduced from 12.9 to 5.7% (p < 0.001). DIBH TVAMT plans resulted in a lower mean dose to the contralateral breast and lung (2 Gy and 0.7 Gy vs 3.4 Gy and 1.5 Gy, respectively) as compared to FB-TVMAT plans. Compared with DIBH-TIMRT, the average left lung V30Gy of DIBH-TVMAT plans was reduced from 8.5 to 5.7% (p = 0.031). As for low-dose areas, exposure of the left lung, right breast, heart and right lung volume with 10 Gy or more was not significantly different between the IMRT- and VMAT-plans. CONCLUSIONS: DIBH-TVMAT for left breast cancer treatment retains treatment plan quality similar to the DIBH-IMRT technique without compromising dose restrictions to the heart, right breast and right lung. DIBH-TVMAT increased left lung protection but still had higher V5Gy to right breast and substantially higher V5Gy to heart. For left breast cancer patients receiving treatment with the DIBH technique, DIBH-TVMAT provides better treatment quality and is a safe and feasible treatment strategy. PMID- 30477512 TI - Prevalence of adverse birth outcome and associated factors among women who delivered in Hawassa town governmental health institutions, south Ethiopia, in 2017. AB - BACKGROUND: Most pregnancies are unplanned in Ethiopia. This is due to ignorance of the types and efficacy of each method of contraception they are associated with vast and unpredictable complications. Most of the time, these complications result in adverse birth outcomes. Information about prevalence of adverse birth outcome and it's factors are relevant for designing, and initiating and intervening programs to decrease these undesirable out comes. OBJECTIVE: To assess prevalence of adverse birth outcome and associated factors among women who delivered in Hawassa town governmental health institutions, south Ethiopia, in 2017. METHOD: We conducted institutional based cross sectional study among 580 pregnant women from december1-30/2017, by multistage systematic random sampling method in governmental health institution in Hawassa town. Data were collected through structured pre-tested, close ended and interview administered questionnaire in their post-partum period. Collected data was entered in Epi-info version 7 and analyzed using SPSS. Odds ratio with 95% confidence interval on multivariable logistic regression was computed and P-value< 0.05 considered as significance. RESULT: From a total of 580 respondents 106(18.3%) respondent's had child related adverse birth outcome. Previous History of child related adverse pregnancy outcome 4.2 (95%,CI = 2.5-6.9), Attend at list one antenatal care visit 2.3 (95%CI = 1.1-4.3), Own cat in the house 2.2 (95%,CI = 1.3-3.7), Had any chronic disease/s 2.1(95%,CI = 1.1-4.8), Age of the mother (from 35 to 45 Years) 2.3(95%,CI = 1.1-4.8), Poor participants' Knowledge on preconception care 3 (95%CI = 1.4-1.6) were significant predictor of adverse birth outcome in this study . CONCLUSION AND RECOMMENDATION: Prevalence of adverse birth outcome was found to be significant in the current study. Presence of Previous History of adverse pregnancy outcome, on ante-natal attendance, presence of cat in the house, presence of chronic disease/s, younger mother and Poor Knowledge of preconception care were significant predictor of adverse pregnancy outcome. Therefore it is better to give more attention on expanding preconception and antenatal care. Creating awareness about family planning methods type and efficacy for women of reproductive health is mandatory. Services, increasing health education on personal hygiene vaccination of cats. Moreover, early detecting and treatment of chronic disease. PMID- 30477514 TI - Crystal structure of Usutu virus envelope protein in the pre-fusion state. AB - BACKGROUND: Usutu virus (USUV) is a mosquito-born flavivirus that can infect multiple avian and mammalian species. The viral surface envelope (E) protein functions to initiate the viral infection by recognizing cellular receptors and mediating the subsequent membrane fusion, and is therefore a key virulence factor involved in the pathogenesis of USUV. The structural features of USUV-E, however, remains un-investigated thus far. FINDINGS: Using the crystallographic method, we determined the structure of USUV-E in the pre-fusion state at 2.0 angstrom. As expected, the overall fold of USUV-E, with three beta-barrel domains (DI, DII, and DIII), resembles those of other flaviviral E proteins. In comparison to other pre-fusion E structures, however, USUV-E exhibits an apparently enlarged inter domain angle between DI and DII, leading to a more extended conformation. Using our structure and other reported pre-fusion E structures, the DI-DII domain-angle difference was analyzed in a pairwise manner. The result shows a much higher degree of variations for USUV-E, indicating the potential for remarkable DI-DII domain angle plasticity among flaviviruses. CONCLUSION: We report the crystal structure of USUV-E and show that its pre-fusion structure has an enlarged DI-DII domain-angle which has not been observed in other reported flaviviral E structures. PMID- 30477513 TI - Influence of food preparation behaviors on 5-year weight change and obesity risk in a French prospective cohort. AB - BACKGROUND: Food preparation behaviors may markedly determine dietary intake and consequently influence weight status. However, the few available studies have found equivocal results. No study has prospectively investigated the association between food preparation behaviors and weight change over time. We estimated the associations of food preparation behaviors with the 5-year relative weight change and the risk of developing obesity in 12,851 French adults participating in the NutriNet-Sante cohort study. The mediating effect of dietary intake was also addressed. METHODS: Frequency and time for meal preparation, cooking skills, preparation from scratch, kitchen equipment, cooking enjoyment, willingness to cook better/more frequently and dietary intake were assessed at baseline using web-based questionnaire and 24 h records, respectively. Self-reported anthropometric data were collected using questionnaire, at baseline and after 5 years of follow-up. Associations of such behaviors with 5-year relative weight change and the mediation analyses were assessed through multivariate linear regression models, and obesity risk was analyzed with logistic regression, stratified by sex and adjusted for age, household composition, education, occupation, income, physical activity, smoking and history of dieting. RESULTS: In women, preparation from scratch was prospectively associated with a decreased risk of obesity over the 5-year follow-up (OR = 1.32 (1.08; 2.32)) after adjustment. After including dietary mediating factors, the association between preparation from scratch and obesity risk in women did not remain significant (P = 0.08). This association appeared to be partly mediated by dietary factors with a difference of 59% of the estimate, in the group with the low score, between the adjusted model and those with mediators (OR = 1.13 (0.71; 1.77)). Regarding 5 year relative weight change, after adjustment for confounding factors, all associations between indicators of food preparation behaviors and weight change became non significant. CONCLUSIONS: In the context from reduced time spent preparing meals that could have an impact on dietary quality and health in industrialized countries, our prospective study does not show effect of food preparation behaviors on 5-year relative weight change and obesity risk, except for preparation from scratch on obesity risk in women. Our study provides useful information about the long term implications of food preparation behaviors on health and should be corroborated by future studies, particularly on the effect of food preparation behaviors on chronic diseases such as incident diabetes, hypertension or cardiovascular diseases, compared with other determinants. TRIAL REGISTRATION: NCT03335644 on ClinicalTrials.gov. PMID- 30477515 TI - Lack of significant recovery of chloroquine sensitivity in Plasmodium falciparum parasites following discontinuance of chloroquine use in Papua New Guinea. AB - BACKGROUND: Chloroquine treatment for Plasmodium falciparum has been discontinued in almost all endemic regions due to the spread of resistant isolates. Reversal of chloroquine susceptibility after chloroquine discontinuation has been reported in dozens of endemic regions. However, this phenomenon has been mostly observed in Africa and is not well documented in other malaria endemic regions. To investigate this, an ex vivo study on susceptibility to chloroquine and lumefantrine was conducted during 2016-2018 in Wewak, Papua New Guinea where chloroquine had been removed from the official malaria treatment regimen in 2010. Genotyping of pfcrt and pfmdr1 was also performed. RESULTS: In total, 368 patients were enrolled in this study. Average IC50 values for chloroquine were 106.6, 80.5, and 87.6 nM in 2016, 2017, and 2018, respectively. These values were not significantly changed from those obtained in 2002/2003 (108 nM). The majority of parasites harboured a pfcrt K76T the mutation responsible for chloroquine resistance. However, a significant upward trend was observed in the frequency of the K76 (wild) allele from 2.3% in 2016 to 11.7% in 2018 (P = 0.008; Cochran Armitage trend test). CONCLUSIONS: Eight years of chloroquine withdrawal has not induced a significant recovery of susceptibility in Papua New Guinea. However, an increasing tendency of parasites harbouring chloroquine-susceptible K76 suggests a possibility of resurgence of chloroquine susceptibility in the future. PMID- 30477516 TI - The present and future burden of previously treated advanced non-small cell lung cancer (NSCLC) by histology and line of therapy in France, Germany, Italy, and Spain: model-based predictions. AB - BACKGROUND: The burden of advanced non-small cell lung cancer (NSCLC) is not well understood, and the number of patients likely to receive treatment in Europe has not been quantified. The aim of this study was to forecast the annual number of patients with squamous and non-squamous advanced NSCLC likely to receive second and third lines of therapy (LOT) from 2016 to 2020 in France, Germany, Italy, and Spain. METHODS: A patient count model (PCM) was developed in Microsoft Excel to estimate the number of patients with refractory advanced NSCLC eligible to receive systemic treatment. Using historical population-based cancer registry data, segmented linear regression ("Joinpoint") was used to forecast age- and sex stratified lung cancer incidence rates in each country through 2020. Yearly incident case count totals by country were apportioned according to NSCLC histology and stage at diagnosis. Country-specific treatment rates came from a recent medical chart review study, and early- to advanced-stage disease progression rates were estimated over a 10-year interval. A probabilistic sensitivity analysis (PSA) was performed to estimate variability in the patient counts. RESULTS: The combined number of squamous and non-squamous advanced NSCLC patients estimated to receive second and third LOT, respectively, in 2016 were France = 11,600 and 3500; Germany = 15,100 and 4900; Italy = 13,500 and 2500; Spain = 9400 and 2100. The forecasted numbers of patients receiving second and third LOT, respectively, in 2020 were France = 13,900 and 4200; Germany = 16,200 and 5200; Italy = 15,100 and 2600; Spain = 11,000 and 2500. CONCLUSIONS: Driven by growth in the incidence of NSCLC among women, the model forecasts an overall increase in the number of patients with advanced-stage squamous and non-squamous NSCLC likely to receive systemic treatment in the year 2020. The results highlight the significant burden of refractory advanced NSCLC and the need for more robust surveillance data to accurately quantify the burden of disease. PMID- 30477517 TI - Evaluation of a quality improvement intervention for labour and birth care in Brazilian private hospitals: a protocol. AB - BACKGROUND: In Brazilian private hospitals, caesarean section (CS) is almost universal (88%) and is integrated into the model of birth care. A quality improvement intervention, "Adequate Birth" (PPA), based on four driving components (governance, participation of women and families, reorganisation of care, and monitoring), has been implemented to help 23 hospitals reduce their CS rate. This is a protocol designed to evaluate the implementation of PPA and its effectiveness at reducing CS as a primary outcome of birth care. METHODS: Case study of PPA intervention conducted in 2017/2018. We integrated quantitative and qualitative methods into data collection and analysis. For the quantitative stage, we selected a convenient sample of twelve hospitals. In each of these hospitals, we included 400 women. This resulted in a total sample of 4800 women. We used this sample to detect a 2.5% reduction in CS rate. We interviewed managers and puerperal women, and extracted data from hospital records. In the qualitative stage, we evaluated a subsample of eight hospitals by means of systematic observation and semi-structured interviews with managers, health professionals and women. We used specific forms for each of the four PPA driving components. Forms for managers and professionals addressed the decision-making process, implemented strategies, participatory process in strategy design, and healthcare practice. Forms for women and neonatal care addressed socio-economic, demographic and health condition; prenatal and birth care; tour of the hospital before delivery; labour expectation vs. real experience; and satisfaction with care received. We will estimate the degree of implementation of PPA strategies related to two of the four driving components: "participation of women and families" and "reorganisation of care". We will then assess its effect on CS rate and secondary outcomes for each of the twelve selected hospitals, and for the total sample. To allow for clinical, socio-demographic and obstetric characteristics in women, we will conduct multivariate analysis. Additionally, we will evaluate the influence of internal context variables (the PPA driving components "governance" and "monitoring") on the degree of implementation of the components "participation of women and families" and "reorganisation of care", by means of thematic content analysis. This analysis will include both quantitative and qualitative data. DISCUSSION: The effectiveness of quality improvement interventions that reduce CS rates requires examination. This study will identify strategies that could promote healthier births. PMID- 30477518 TI - 24-h movement behaviors from infancy to preschool: cross-sectional and longitudinal relationships with body composition and bone health. AB - BACKGROUND: New physical activity guidelines for children address all movement behaviors across the 24-h day (physical activity, sedentary behavior, sleep), but how each component relates to body composition when adjusted for the compositional nature of 24-h data is uncertain. AIMS: To i) describe 24-h movement behaviors from 1 to 5 years of age, ii) determine cross-sectional relationships with body mass index (BMI) z-score, iii) determine whether movement behaviors from 1 to 5 years of age predict body composition and bone health at 5 years. METHODS: 24-h accelerometry data were collected in 380 children over 5-7 days at 1, 2, 3.5 and 5 years of age to determine the proportion of the day spent: sedentary (including wake after sleep onset), in light (LPA) and moderate to-vigorous physical activity (MVPA), and asleep (including naps). BMI was determined at each age and a dual-energy x-ray absorptiometry (DXA) scan measured fat mass, bone mineral content (BMC) and bone mineral density (BMD) at 5 years of age. 24-h movement data were transformed into isometric log-ratio co-ordinates for multivariable regression analysis and effect sizes back-transformed. RESULTS: At age 1, children spent 49.6% of the 24-h day asleep, 38.2% sedentary, 12.1% in LPA, and 0.1% in MVPA, with corresponding figures of 44.4, 33.8, 19.8 and 1.9% at 5 years of age. Compositional time use was only related significantly to BMI z score at 3.5 years in cross-sectional analyses. A 10% increase in mean sleep time (65 min) was associated with a lower BMI z-score (estimated difference, - 0.25; 95% CI, - 0.42 to - 0.08), whereas greater time spent sedentary (10%, 47 min) or in LPA (10%, 29 min) were associated with higher BMI z-scores (0.12 and 0.08 respectively, both p < 0.05). Compositional time use from 1 to 3.5 years was not related to future BMI z-score or percent fat. Although MVPA at 2 and 3.5 years was consistently associated with higher BMD and BMC at 5 years, actual differences were small. CONCLUSIONS: Considerable changes in compositional time use occur from 1 to 5 years of age, but there is little association with adiposity. Although early MVPA predicted better bone health, the differences observed had little clinical relevance. TRIAL REGISTRATION: ClinicalTrials.gov number NCT00892983 . PMID- 30477519 TI - Brain swelling is independent of peripheral plasma cytokine levels in Malawian children with cerebral malaria. AB - BACKGROUND: Cerebral malaria (CM) is often fatal, and severe brain swelling is a predictor of CM-related mortality. CM is characterized by elevated circulating pro-inflammatory cytokines TNF and IFN-gamma and anti-inflammatory cytokine IL 10, however whether cytokine levels correlate with brain swelling severity is unknown. This study therefore was conducted to investigate the relationship between cytokine levels and brain swelling severity in children presenting with CM. METHODS: A total of 195 Malawian children presenting with CM were recruited and had the concentrations of plasma cytokines determined and compared to brain swelling severity, determined by MRI examination, and graded as severe, moderate, mild or none. RESULTS: Levels of IL-1beta, IL-6, IL-8 and IL-10 did not differ between CM patients with and without severe brain swelling. Compared to children without brain swelling, IL-12 levels were higher in children with severe swelling (p < 0.01, no swelling 1 pg/mL, IQR [1] vs. severe swelling 18.7 pg/mL, IQR [1 27]), whereas TNF concentrations were higher in children with moderate brain swelling compared to children with no swelling (p < 0.01, no swelling 3 pg/mL, IQR [1-20] vs. moderate swelling 24 pg/mL, IQR [8-58]. Multivariate analysis showed that no single cytokine independently predicted brain swelling. CONCLUSION: Severe brain swelling in paediatric CM was independent of tested blood pro-inflammatory and anti-inflammatory cytokines which are markers of systemic inflammation. PMID- 30477520 TI - Effects of tumor metabolic microenvironment on regulatory T cells. AB - Recent studies have shown that on one hand, tumors need to obtain a sufficient energy supply, and on the other hand they must evade the body's immune surveillance. Because of their metabolic reprogramming characteristics, tumors can modify the physicochemical properties of the microenvironment, which in turn affects the biological characteristics of the cells infiltrating them. Regulatory T cells (Tregs) are a subset of T cells that regulate immune responses in the body. They exist in large quantities in the tumor microenvironment and exert immunosuppressive effects. The main effect of tumor microenvironment on Tregs is to promote their differentiation, proliferation, secretion of immunosuppressive factors, and chemotactic recruitment to play a role in immunosuppression in tumor tissues. This review focuses on cell metabolism reprogramming and the most significant features of the tumor microenvironment relative to the functional effects on Tregs, highlighting our understanding of the mechanisms of tumor immune evasion and providing new directions for tumor immunotherapy. PMID- 30477521 TI - Development of a dental handpiece angle correction device. AB - BACKGROUND: Preparation of a uniform angle of walls is essential for making an ideal convergence angle in fixed prosthodontics. We developed a de novo detachable angle-correction apparatus for dental handpiece drills that could help the ideal tooth preparation. METHODS: We utilized a gyro sensor to measure the angular velocities to calculate the slope of an object by integrating the values, acceleration sensor to calculate the slope of an object by measuring the acceleration relative to gravity, and Kalman filter algorithm. Converting the angulation of the handpiece body to its drill part could be performed by a specific matrix formulation set on two reference points (2 degrees and 6 degrees ). A flexible printed circuit board was used to minimize the size of the device. For convergence angle investigation, 16 volunteers were divided randomly into two groups for performing tooth preparation on a mandibular first molar resin tooth. All abutments were scanned by a 3D scanner (D700(r), 3Shape Co., Japan), the convergence angle and tooth axis deviation were analyzed by a CAD program (SolidWorks 2013(r), Dassault Systems Co., USA) with statistical analysis by Wilcoxon signed-rank test (alpha = 0.05) using SPSS statistical software (Version 16.0, SPSS Inc.). RESULTS: This device successfully maintained the stable zero point (less than 1 degrees deviation) at different angles (0 degrees , 30 degrees , 60 degrees , 80 degrees ) for the first 30 min. In single tooth preparation, without this apparatus, the average bucco-lingual convergence angle was 20.26 degrees (SD 7.85), and the average mesio-distal (MD) convergence angle was 17.88 degrees (SD 7.64). However, the use of this apparatus improved the average BL convergence angle to 13.21 degrees (SD 4.77) and the average MD convergence angle to 10.79 degrees (SD 4.48). The angle correction device showed a statistically significant effect on reducing the convergence angle of both directions regardless of the order of the directions. CONCLUSIONS: The angle correction device developed in this study is capable of guiding practitioners with high accuracy comparable to that of commercial navigation surgery. The volume of the angle correction device is much smaller than that of any other commercial navigation surgery system. This device is expected to be widely utilized in various fields of orofacial surgery. PMID- 30477522 TI - Assessing staining resistance of a CAD/CAM interpenetrating network composite material. AB - BACKGROUND: Color change of dental materials over time because of staining agents has important effects on the long-term prognosis of dental esthetic treatments. In the present study, staining resistance of an interpenetrating network composite material with different translucency levels (translucent and high translucent) and various surface procedures for finishing were investigated. METHODS: Same shade CAD/CAM interpenetrating network composite specimens having two different translucency levels were prepared using by a water cooling cutting saw. Specimens were grouped and different finishing procedures were performed. Then, specimens were kept in distilled water, red wine and coffee for different periods. Color was evaluated before and after exposure to staining liquids using a clinical spectrophotometer. RESULTS: In the 7 days Glaze group (DeltaE00 > 2.2), color difference was only perceivable in the specimens kept in red wine. In the 28 days red wine high translucent groups, only the high translucent Clinical group showed a clinically acceptable (DeltaE00 < 2.2) color change. In the translucent groups kept in red wine, only the translucent Glaze group showed a clinically perceivable color change (DeltaE00 > 2.2). In the 28 day measurements, all the translucent groups showed a clinically perceivable color change (DeltaE00 > 2.2). Of the translucent groups kept in coffee for 28 days, it was observed that only the translucent Clinical group demonstrated a clinically non perceivable color change (DeltaE00 < 2.2). CONCLUSIONS: All the translucent groups kept in red wine showed a clinically perceivable color change after 28 days. Only the high translucent Clinical Kit group showed a clinically acceptable color change. Among high translucent and translucent specimens kept in coffee only the translucent Clinical group showed a clinically acceptable color change after 28 days. PMID- 30477524 TI - Functioning and time utilisation by female multi-purpose health workers in South India: a time and motion study. AB - BACKGROUND: Auxillary nurse midwives (ANMs) are the most important frontline multi-purpose workers in rural India. This study was conducted to assess the spectrum of service delivery, time utilisation, work planning, and factors affecting functioning of ANMs in South India. METHODS: We conducted a time and motion study in three districts across two states in South India. The districts selected in such a manner that they had a considerable tribal population. We conducted multi-stage sampling to select ANMs. We directly observed 43 ANMs consecutively for six working days and in-depth interviewed all selected ANMs, their supervisors, medical officers, and district health officials. We conducted an FGD to substantiate the findings from observations and interviews. Observation findings were analysed under three broad domains: (i) programme activities, (ii) programme support activities, and (iii) other work. Time spent was calculated in median (interquartile range, IQR) minutes/ANM per week or day. Qualitative data were coded and analysed using grounded theory, and appropriate themes and sub themes were identified. RESULTS: ANMs worked for median 7 h a day (7:10 h, non tribal; 6:20 h, tribal). There is variation in the hours of work, the pattern of service provided and time utilisation across days of a week. ANMs spent 60% of their on-job time on programmatic activities (median 22:38 h; IQR, 20:48-27:01 h) in a week. Emphasis is more on home visits, universal immunisation, antenatal care, school health, and seasonal diseases. ANMs spent negligible time on non communicable diseases, adolescent health, nutrition, etc. ANMs spent the remaining time in program support activities, such as meetings with seniors, community meetings, and other non-health related work. There are no renewed job description, work plans, and supervision guidelines, even with newly added programs and tasks. ANMs prioritised work as per the priorities set by the supervisors and leaders. Health administration often disrupts the regular functioning of ANMs for training, meetings and other ad hoc work. CONCLUSION: ANMs are overworked; they often multi-task and fail to deliver efficiently. The administration needs to re-assess the workload. The administration may reduce expected work, provide strong supervisory support, and make conscious efforts to pose fewer disruptions in regular working of ANMs. PMID- 30477523 TI - Pedobarographic analysis of body weight distribution on the lower limbs and balance after ankle arthrodesis with Ilizarov fixation and internal fixation. AB - BACKGROUND: A number of various techniques were proposed to stabilized ankle arthrodesis, among them external and internal fixation. Appropriate balance and adequate distribution of lower limb loads determine normal biomechanics of the locomotor system. We hypothesized that various techniques used to stabilize ankle arthrodesis may exert different effects on (1) balance and (2) distribution of lower limb loads. METHODS: Retrospective analysis included 47 patients who underwent ankle arthrodesis with external stabilization with Ilizarov fixator (group 1, n = 21) or internal stabilization with screws (group 2, n = 26) between 2007 and 2015. Balance and distribution of lower limb loads were determined with a pedobarographic platform. RESULTS: In group 1, average load of the operated and non-operated limb amounted to 48.8% and 51.2%, respectively, and in group subjected to internal stabilization to 48.4% and 51.6%, respectively. Neither the intragroup nor the intergroup differences in the distribution of lower limb loads were statistically significant. Mean length of the center of gravity (COG) path was 137.9 cm for group 1 and 134 cm for group 2, and mean COG area amounted to 7.41 cm2 and 6.16 cm2, respectively. The latter intergroup difference was statistically significant. CONCLUSIONS: Balance after ankle arthrodesis with Ilizarov fixation is worse than after the same procedure with internal stabilization. Despite correction of ankle deformity, musculoskeletal biomechanics still remains impaired. While ankle fusion with either Ilizarov or internal fixation provide appropriate distribution of lower limb loads, none of these procedures normalize patients' balance. PMID- 30477525 TI - Aspidosperma pyrifolium, a medicinal plant from the Brazilian caatinga, displays a high antiplasmodial activity and low cytotoxicity. AB - BACKGROUND: Several species of Aspidosperma plants are referred to as remedies for the treatment of malaria, especially Aspidosperma nitidum. Aspidosperma pyrifolium, also a medicinal plant, is used as a natural anti-inflammatory. Its fractionated extracts were assayed in vitro for activity against malaria parasites and for cytotoxicity. METHODS: Aspidosperma pyrifolium activity was evaluated against Plasmodium falciparum using extracts in vitro. Toxicity towards human hepatoma cells, monkey kidney cells or human monocytes freshly isolated from peripheral blood was also assessed. Anti-malarial activity of selected extracts and fractions that presented in vitro activity were tested in mice with a Plasmodium berghei blood-induced infection. RESULTS: The crude stem bark extract and the alkaloid-rich and ethyl acetate fractions from stem extract showed in vitro activity. None of the crude extracts or fractions was cytotoxic to normal monkey kidney and to a human hepatoma cell lines, or human peripheral blood mononuclear cells; the MDL50 values of all the crude bark extracts and fractions were similar or better when tested on normal cells, with the exception of organic and alkaloidic-rich fractions from stem extract. Two extracts and two fractions tested in vivo caused a significant reduction of P. berghei parasitaemia in experimentally infected mice. CONCLUSION: Considering the high therapeutic index of the alkaloidic-rich fraction from stem extract of A. pyrifolium, it makes the species a candidate for further investigation aiming to produce a new anti-malarial, especially considering that the active extract has no toxicity, i.e., no mutagenic effects in the genototoxicity assays, and that it has an in vivo anti-malarial effect. In its UPLC-HRMS analysis this fraction was shown to have two major components compatible with the bisindole alkaloid Leucoridine B, and a novel compound, which is likely to be responsible for the activity against malaria parasites demonstrated in in vitro tests. PMID- 30477526 TI - Long-term virological outcome in children receiving first-line antiretroviral therapy. AB - BACKGROUND: Studies relating to long-term virological outcomes among children on first-line antiretroviral therapy (ART) from low and middle-income countries are limited. METHODS: Perinatally HIV infected, ART-naive children, between 2 and 12 years of age, initiating NNRTI-based ART during 2010-2015, with at least 12 months of follow-up, were included in the analysis. CD4 cell counts and plasma HIV-1 RNA were measured every 24 weeks post-ART initiation. Immunologic failure was defined as a decrease in the CD4 count to pre-therapy levels or below and virologic failure as HIV-RNA of > 1000 copies/ml at 48 weeks after ART initiation. Genotypic resistance testing was performed for children with virologic failure. Logistic regression analysis was done to identify predictors of virologic failure. RESULTS: Three hundred and ninety-three ART-naive children living with HIV [mean (SD) age: 7.6 (3) years; mean (SD) CD4%: 16% (8); median (IQR) HIV-RNA: 5.1 (3.5-5.7) log10 copies/ml] were enrolled into the study. At 48 weeks, significant improvement occurred in weight-for-age and height-for-age z scores from baseline (all p < 0.001). The immunologic response was good; almost 90% of children showing an increase in their absolute CD4+ T cell count to more than 350 cells/mm3. Immunological failure was noted among 11% (28/261) and virologic failure in 29% (94/328) of children. Of the 94 children with virologic failure at 12 months, 36 children showed immunologic failure while the rest had good immunologic improvement. There was no demonstrable correlation between virologic and immunologic failure. 62% had reported > 90% adherence to ART. At the time of virologic failure, multiple NNRTI-associated mutations were observed: 80%-K103N and Y181C being the major NNRTI mutations-observed. Sensitivity (95% CI) of immunologic failure to detect virologic failure was 7% (2-12), specificity 97% (92.4-98.9), PPV 44% (13.7-78.8) and NPV was 72% (65-77.9). There were no statistically significant predictors to detect children who will develop virologic failure on treatment. CONCLUSIONS: Considerable immunological improvement is seen in children with ART initiation, but may not be an effective tool to monitor treatment response in the long-term. There is a lack of correlation between immunologic and virologic response while on ART, which may lead to a delay in identifying treatment failures. Periodic viral load monitoring is, therefore, a priority. PMID- 30477527 TI - Virtual reality experiences, embodiment, videogames and their dimensions in neurorehabilitation. AB - BACKGROUND: In the context of stroke rehabilitation, new training approaches mediated by virtual reality and videogames are usually discussed and evaluated together in reviews and meta-analyses. This represents a serious confounding factor that is leading to misleading, inconclusive outcomes in the interest of validating these new solutions. MAIN BODY: Extending existing definitions of virtual reality, in this paper I put forward the concept of virtual reality experience (VRE), generated by virtual reality systems (VRS; i.e. a group of variable technologies employed to create a VRE). Then, I review the main components composing a VRE, and how they may purposely affect the mind and body of participants in the context of neurorehabilitation. In turn, VRS are not anymore exclusive from VREs but are currently used in videogames and other human computer interaction applications in different domains. Often, these other applications receive the name of virtual reality applications as they use VRS. However, they do not necessarily create a VRE. I put emphasis on exposing fundamental similarities and differences between VREs and videogames for neurorehabilitation. I also recommend describing and evaluating the specific features encompassing the intervention rather than evaluating virtual reality or videogames as a whole. CONCLUSION: This disambiguation between VREs, VRS and videogames should help reduce confusion in the field. This is important for databases searches when looking for specific studies or building metareviews that aim at evaluating the efficacy of technology-mediated interventions. PMID- 30477528 TI - Treatment outcomes of proton or carbon ion therapy for skull base chordoma: a retrospective study. AB - BACKGROUND: The usefulness of particle therapy for skull base chordoma has not been established. The aim of this retrospective study was to analyse the treatment outcomes of proton therapy (PT) and carbon ion therapy (CIT) in patients with skull base chordoma at a single institution. METHODS: All patients who underwent PT or CIT with curative intent between 2003 and 2014 at Hyogo Ion Beam Medical Center were included in this study. Twenty-four patients were enrolled. Eleven (46%) received PT and 13 (54%) received CIT. Overall survival (OS), progression-free survival (PFS) and local control (LC) were calculated using the Kaplan-Meier method. Late toxicities were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: The median follow-up was 71.5 months (range, 14-175 months). The five-year LC, PFS and OS rates were 85, 81, and 86%, respectively. The LC (P = 0.048), PFS (P = 0.028) and OS (P = 0.012) were significantly improved in patients who had undergone surgery before particle therapy. No significant differences were observed in the LC rate and the incidence of grade 2 or higher late toxicities between patients who received PT and CIT. CONCLUSIONS: Both PT and CIT appear to be effective and safe treatments and show potential to become the standard treatments for skull base chordoma. To increase the local control, surgery before particle therapy is preferable. PMID- 30477530 TI - Therapeutic value of surgical paraaortic staging in locally advanced cervical cancer: a multicenter cohort analysis from the FRANCOGYN study group. AB - BACKGROUND: The prognostic impact of surgical paraaortic staging remains unclear in patients with locally advanced cervical cancer (LACC). The objective of our study was to evaluate the survival impact of surgical staging in patients with LACC and no evidence of paraaortic lymph node (PALN) metastasis on pre-operative imaging work-up. METHODS: Data of 1447 patients with cervical cancer treated between 1996 and 2016 were extracted from maintained databases of 10 French University hospitals. Patients with locally advanced disease (IB2 or more) treated by concurrent chemoradiation therapy (CRT) and no evidence of paraaortic metastasis on pre-operative imaging work-up were selected for further analysis. The Kaplan-Meier method was used to estimate the survival distribution. A Cox proportional hazards model was used to account for the influence of multiple variables. RESULTS: Six hundred and forty-seven patients were included, 377 (58.3%) with surgical staging and 270 (41.7%) without, with a mean follow up of 38.1 months (QI 13.0-56.0). Pathologic analysis revealed positive lymph nodes in 47 patients (12.5%). In multivariate model analysis, surgical staging remained an independent prognostic factor for DFS (OR 0.64, CI 95% 0.46-0.89, p = 0.008) and OS (OR 0.43, CI 95% 0.27-0.68, p < 0.001). The other significant parameter in multivariate analysis for both DFS and OS was treatment by intracavitary brachytherapy (OR respectively of 0.7 (0.5-1.0) and 0.6 (0.4-0.9), p < 0.05). CONCLUSION: Nodal surgical staging had an independent positive impact on survival in patients with LACC treated with CRT with no evidence of metastatic PALN on imaging. PMID- 30477529 TI - Evaluation of different doses of transcutaneous nerve stimulation for pain relief during labour: a randomized controlled trial. AB - BACKGROUND: Pain during labour is one of the most intense pain that women may experience in their lifetime. There are several non-pharmacological analgesic methods to relieve pain during labour, among them transcutaneous electrical nerve stimulation (TENS). TENS is a low-frequency electrotherapy technique, analgesic type, generally used in musculoskeletal pathology, but it has also come to be used as an alternative treatment during labour. The purpose of this study is to investigate the pain-relieving effect of a TENS application during labour and to find out the most effective dose. METHODS: This study is a randomized, double blind, placebo-controlled trial. TENS therapy was initiated at the beginning of the active phase of labour. Participants were randomly assigned to three groups (21 per group: two active TENS and one placebo). Active TENS 1 intervention consisted in a constant frequency of 100-Hz, 100-MUs, active TENS 2 intervention consisted in a varying high-frequency (80-100 Hz), 350 MUs, and in a placebo group, participants were connected to the TENS unit without electrical stimulation. TENS was applied with two self-adhesive electrodes placed parallel to the spinal cord (T10-L1 and S2-S4 levels). The primary outcome was pain intensity (0-10 cm) measured on a visual analogue scale (VAS) at several stages (at baseline and at 10 and 30 min later). Secondary outcomes included women's satisfaction (via the Care in Obstetrics: Measure for Testing Satisfaction scale). RESULTS: Sixty-three women participated. Regarding baseline characteristics, no differences were found among the three groups. The active TENS 2 group obtained an improvement with clinically significant VAS results (- 2.9, 95% confidence interval - 4.1 to - 1.6, p < 0.001). Regarding satisfaction, the results also revealed better results in the active TENS than in the placebo group. CONCLUSIONS: TENS with high frequencies modified in time as well as high pulse width are effective for relieving labour pain, and they are well considered by pregnant participants. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03137251 . Registered on 2 May 2017. PMID- 30477531 TI - Outcomes of concurrent chemoradiotherapy versus chemotherapy alone for stage IV esophageal squamous cell carcinoma: a retrospective controlled study. AB - BACKGROUND: The purpose of this study is to compare the efficacy and safety of concurrent chemoradiotherapy (CCRT) versus chemotherapy alone for patients with stage IV esophageal squamous cell carcinoma (ESCC). METHODS: Eligible patients were retrospectively enrolled at the authors's institution from January 2010 to October 2015. Of the 141 patients enrolled, 55 (39.0%) received CCRT and 86 (61.0%) received chemotherapy alone. The outcomes and adverse events (AEs) were compared between the two groups. RESULTS: The baseline clinical characteristics of the two groups were similar. However, the CCRT group showed a significantly better primary tumor objective response rate (ORR) than that of the chemotherapy group (74.5% versus 45.3%, p = 0.001). The 1-year, 2-year, 3-year overall survival (OS) rates and median OS were 58.0% versus 43.0%, 25.5% versus 14.0%, 10.7% versus 4.7%, and 14 months versus 11 months for patients treated with CCRT or chemotherapy, respectively (p = 0.007). The 1-year and median progression-free survival (PFS) were 29.8% versus 14.9% and 8 months versus 6 months (p = 0.005). Multivariate analysis identified CCRT (p = 0.013) and solitary metastasis (p = 0.037) as independent factors for greater OS. The frequency of leucocytopenia (grade 3 or higher) was significantly higher in the CCRT group than in the chemotherapy-alone group (p = 0.040), whereas the rates of other AEs did not differ. CONCLUSIONS: In this study, it is suggested that CCRT is more effective than chemotherapy alone for stage IV ESCC, yielding better primary responses and survival outcomes with tolerable side effects. PMID- 30477532 TI - Development of within-herd immunity and long-term persistence of antibodies against Schmallenberg virus in naturally infected cattle. AB - BACKGROUND: In 2011, the teratogenic, insect-transmitted Schmallenberg virus (SBV) emerged at the German/Dutch border region and subsequently spread rapidly throughout the European continent. In cattle, one of the major target species of SBV, first antibodies are detectable between one and three weeks after infection, but the duration of humoral immunity is unknown. To assess the course of immunity in individual animals and the development of the within-herd seroprevalence, cattle kept in a German farm with a herd size of about 300 lactating animals were annually blood sampled between December 2011 and December 2017 and tested for the presence of SBV-specific antibodies. RESULTS: During the monitored period, the within-herd seroprevalence declined from 74.92% in 2011 to 39.93% in 2015 and, thereafter, slightly increased to 49.53% in 2016 and 48.44% in 2017. From the animals that were tested in 2014 and 2015 for the first time (between 24 and 35 months of age) only 14.77% and 7.45%, respectively, scored positive. Thereafter, the seropositivity rate of this age group rose markedly to 58.04% in 2016 and 48.10% in 2017 indicating a circulation of SBV. Twenty-three individual animals were consistently sampled once per year between 2011 and 2017 after the respective insect vector season, 17 of them tested positive at the first sampling. Fourteen animals were still seropositive in December 2017, while three cattle (17.65%) became seronegative. CONCLUSIONS: The regular re-emergence of SBV in Central Europe is a result of decreasing herd immunity caused by the replacement of animals by seronegative youngstock rather than of a drop of antibody levels in previously infected individual animals. The consequences of the overall decline in herd seroprevalence may be increasing virus circulation and more cases of fetal malformation caused by infection of naive dams during gestation. PMID- 30477534 TI - Inflammation is correlated with severity and outcome of cerebral venous thrombosis. AB - BACKGROUND: Few studies have suggested a relationship between inflammation and cerebral venous thrombosis (CVT). This retrospective study aimed to explore the changes in inflammation in different CVT stages and the correlation between inflammation and severity and outcome of CVT. METHODS: In total, 95 suitable patients with CVT and 41 controls were compared. Patients with CVT were divided into three groups. The inflammatory factors studied included hypersensitive C reactive protein (Hs-CRP), interleukin-6 (IL-6), and neutrophil-to-lymphocyte ratio (NLR) in the peripheral blood and immunoglobulin A (IgA), immunoglobulin M (IgM), and immunoglobulin G (IgG) in the cerebrospinal fluid (CSF). The severity of CVT was evaluated with the modified Rankin Scale (mRS), the National Institutes of Health Stroke Scale (NIHSS), fundus condition, intracranial pressure (ICP), and complications on admission. The short-term outcome was evaluated with the mRS at discharge. RESULTS: The following results were obtained: (1) Inflammatory factor levels in patients with CVT were higher than those in the controls. (2) Inflammatory factor levels in the acute and subacute stages were significantly higher than those in the chronic stage (all P < 0.05). (3) Serum NLR and CSF IgM levels were positively related to baseline degree of disability (odds ratio [OR], 1.279, 95% confidence interval [CI] 1.009-1.621, P = 0.042; OR 1.402, 95% CI 1.036-1.896, P = 0.028). The Hs-CRP level was positively correlated with the baseline occurrence of seizure (OR 1.040, 95% CI 1.001-1.080, P = 0.043). The baseline serum NLR (r = 0.244, P = 0.017), CSF IgA (r = 0.615, P < 0.001), CSF IgM (r = 0.752, P < 0.001), and CSF IgG (r = 0.248, P = 0.015) levels were positively associated with NIHSS. (4) The baseline NLR was significantly associated with high risk of poor outcome at discharge (OR 1.339, 95% CI 1.097-1.784, P = 0.007). Moreover, the ROC showed that NLR >= 4.205 could better predict the poor outcome at discharge. The data were analyzed using SPSS. CONCLUSIONS: Inflammation may develop after CVT and gradually decrease during the course. Inflammation was significantly correlated with severity on admission and short-term poor outcome at discharge in CVT. PMID- 30477533 TI - Patient-derived tumor immune microenvironments in patient-derived xenografts of lung cancer. AB - BACKGROUND: Because patient-derived xenografts (PDXs) are grown in immunodeficient mouse strains, PDXs are regarded as lacking an immune microenvironment. However, whether patients' immune cells co-exist in PDXs remains uncharacterized. METHODS: We cultured small pieces of lung PDX tissue in media containing human interleukin-2 and characterized the proliferated lymphocytes by flow cytometric assays with antibodies specific for human immune cell surface markers. Presence of immune cells in PDXs was also determined by immunohistochemical staining. RESULTS: Human tumor-infiltrating lymphocytes (TILs) were cultured from nine of 25 PDX samples (36%). The mean time of PDX growth in immunodeficient mice before obtaining TILs in culture was 113 days (range 63-292 days). The TILs detected in PDXs were predominantly human CD8+ T cells, CD4+ T cells, or CD19+ B cells, depending on cases. DNA fingerprint analysis showed that the TILs originated from the same patients as the PDXs. Further analysis of two PDX-derived CD8+ T cells showed that they were PD-1-, CD45RO+, and either CD62L+ or CD62L-, suggesting they were likely memory T cells. Immunohistochemical staining showed that human T cells (CD8+ or CD4+), B cells (CD19+), and macrophages (CD68+) were present in stroma or intraepithelial cancer structures and that human PD-L1 was expressed in stromal cells. Moreover, the patient-derived immune cells in PDX can be passaged to the F2 generation and may migrate to spleens of PDX-bearing mice. CONCLUSIONS: Patient-derived immune cells co-exist in early passages of PDXs in some lung cancer PDX models. The CD8+ cells from PDXs were likely memory T cells. These results suggest that PDXs can be used for evaluating the functionality of immune components in tumor microenvironments. PMID- 30477535 TI - Effect of NAC treatment and physical activity on neuroinflammation in subchronic Parkinsonism; is physical activity essential? AB - BACKGROUND: Neuroprotective strategies are becoming relevant to slow down dopaminergic cell death and inflammatory processes related to the progressive neurodegeneration in Parkinson's disease (PD). Interestingly, among others, physical activity (PA) or anti-oxidant agents (such as N-acetyl-L-cysteine, NAC) are common therapeutic strategies. Therefore, this study aims to analyze if there is a synergistic effect of physical activity along with NAC treatment on dopaminergic degeneration and neuroinflammatory response in a 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism model after subchronic intoxication. METHODS: To ascertain this possibility, 48 8-week-old male mice (C57BL/6 strain) were used. Twenty four of them were placed individually in cages where voluntary physical activity was automatically monitored during 30 days and were divided into groups: (i) control; (ii) NAC; (iii) MPTP, and (iv) MPTP+NAC. The other 24 mice were divided into the same four groups but without physical activity. RESULTS: The data collected during the treatment period showed that there was an overall increase in the total running distance in all groups under physical activity, including Parkinsonian animals. However, the monitoring data per day showed that the activity routine by MPTP and MPTP+NAC groups was disrupted by alterations in the circardian rhythm because of MPTP intoxication. Results from post-mortem studies in the substantia nigra pars compacta (SNpc) showed significant decrease in the number of TH+ cells in all MPTP groups. Moreover, TH+ expression in the striatum was significantly decreased in all MPTP groups. Thus, PA + NAC treatment do not protect dopaminergic neurons against a subchronic intoxication of MPTP. Regarding glial response, the results obtained from microglial analysis do not show significant increase in the number of Iba-1+ cell in MPTP+NAC and MPTP+PA + NAC. In the striatum, a significant decrease is observed only in the MPTP+NAC group compared with that of the MPTP group. The microglial results are reinforced by those obtained from the analysis of astroglial response, in which a decrease in the expression of GFAP+ cells are observed in MPTP+NAC and MPTP+PA + NAC compared with MPTP groups both in the SNpc and in the striatum. Finally, from the study of the astroglial response by the co localization of GFAP/S100b, we described some expression patterns observed based on the severity of the damage produced by the MPTP intoxication in the different treated groups. CONCLUSIONS: These results suggest that the combination of physical activity with an anti-oxidant agent does not have a synergistic neuroprotective effect in the nigrostriatal pathway. Our results show a potential positive effect, only due to NAC treatment, on the neuroinflammatory response after subchronic MPTP intoxication. Thus, physical activity is not essential, under these conditions. However, we believe that physical activity, used for therapeutic purposes, has a beneficial long-term effect. In this line, these results open the door to design longer studies to demonstrate its promising effect as neuroprotective strategy. PMID- 30477536 TI - Artemisinin derivatives inactivate cancer-associated fibroblasts through suppressing TGF-beta signaling in breast cancer. AB - BACKGROUND: Cancer-associated fibroblasts (CAFs) are activated fibroblasts associated with cancer. They have an important role in tumor growth and metastasis. Artemisinin (ART) is a sesquiterpene lactone extracted from Chinese herb qinghao, and artemether (ARM), artesunate (ARS) and dihydroartemisinin (DHA) were synthesized derivatives of artemisinin, which also have anti-malarial and anti-cancer effects such as artemisinin. METHODS: In this study, we investigated the in-vitro and in-vivo effects of artemisinin derivatives on inactivating cancer-associated fibroblasts and uncovered its underlying mechanism. RESULTS: We demonstrated that ARS and DHA could revert L-929-CAFs and CAFs from activated to inactivated state in vitro. Mechanically, ARS and DHA could suppress TGF-beta signaling to inhibit activation of L-929-CAFs and CAFs, and decreased interaction between tumor and tumor microenvironment. The results showed that ARS and DHA could suppress CAFs-induced breast cancer growth and metastasis in the orthotopic model. Conformably, ARS and DHA suppressed TGF-beta signaling to inactivate cancer-associated fibroblasts and inhibit cancer metastasis in vivo. CONCLUSIONS: Artemisinin derivatives are potential therapeutic agents for the treatment of breast cancer. PMID- 30477537 TI - Distinct expression profiles and functions of Kindlins in breast cancer. AB - BACKGROUND: Kindlin-1, - 2, and - 3 are the three members of the Kindlin family. They are best known as regulators of integrin functions, contributing to fundamental biological processes such as cell survival, adhesion and migration. Their deregulation leads to diverse pathologies including a broad range of cancers in which both, tumor-promoting and tumor-inhibiting functions have been described. METHODS: To better characterize Kindlins implication in breast cancer, in vitro experiments were performed in a series of cancer cell lines. We first assessed their expression profiles and subcellular distributions. Then, their involvement in breast cancer cell morphology, migration and invasion was verified by examining phenotypic changes induced by the depletion of either isoforms using RNA interference. An expression study was performed in a series of breast cancer patient derived xenografts (n = 58) to define the epithelial and stromal contribution of each Kindlin. Finally, we analyzed the expression levels of the three Kindlins in a large series of human breast tumors, at the RNA (n = 438) and protein (n = 129) levels and we evaluated their correlation with the clinical outcome. RESULTS: We determined that Kindlin-1 and Kindlin-2, but not Kindlin-3, were expressed in breast tumor cells. We uncovered the compensatory roles of Kindlin-1 and -2 in focal adhesion dynamics and cell motility. Remarkably, Kindlin-2 had a predominant effect on cell spreading and Kindlin-1 on cell invasion. In line with these experimental observations, Kindlin-1 overexpression was associated with a worse patients' outcome. Notably, Kindlin-3, expressed by tumor infiltrating leukocytes, also correlated with a poor prognosis of breast cancer patients. CONCLUSION: This study demonstrates that each one of the Kindlin family members has a different expression profile emphasizing their redundant and complementary roles in breast tumor cells. We highlight the specific link between Kindlin-1 and breast cancer progression. In addition, Kindlin-3 overexpression in the tumor microenvironment is associated with more aggressive breast tumors. These results suggest that Kindlins play distinctive roles in breast cancer. Kindlins may be useful in identifying breast cancer patients with a worst prognosis and may offer new avenues for therapeutic intervention against cancer progression. PMID- 30477540 TI - Survival status and predictors of mortality among children with severe acute malnutrition admitted to general hospitals of Tigray, North Ethiopia: a retrospective cohort study. AB - OBJECTIVE: Despite the presence standard protocol for management of severe acute malnutrition case-fatality rates in African hospitals remain unacceptably high. The case in Ethiopia is not different from others. Therefore, this study was aimed to assess survival status and predictors of mortality among children with severe acute malnutrition admitted to stabilization centers of general hospitals in Tigray region, northern Ethiopia. A 24 months retrospective longitudinal study was conducted among 569 randomly selected medical records of children admitted to stabilizing centers. Both bi-variable and multivariable Cox regression analysis was conducted to identify predictors of mortality. Association was summarized using AHR, and statistical significances were declared at 95% CI and P-value < 0.05. RESULTS: During follow up, 456 [82%] of children had got cured, 37 [6.65%] were absconded and 21 [3.8%] were died. The overall mean survival time was 41.93 [95% CI 40.17-43.68] days. Impaired conscious level [AHR = 6.69, 95% CI 2.43 19.93], development of comorbidity after admission [AHR 12.71, 95% CI 2.79-57.94] and being urban in residence [AHR = 2.73, 95% CI 1.12-6.64] were predictors of mortality. Therefore, interventions to reduce further mortality should focus in children having impaired consciousness level and who developed comorbidity after admission. PMID- 30477538 TI - MNAT1 is overexpressed in colorectal cancer and mediates p53 ubiquitin degradation to promote colorectal cancer malignance. AB - BACKGROUND: MNAT1 (menage a trois 1, MAT1), a cyclin-dependent kinase-activating kinase (CAK) complex, high expresses in various cancers and is involved in cancer pathogenesis. However, mechanisms underlying its regulation in carcinogenesis are unclear. METHODS: The tissue microarray of colorectal cancer (CRC) was used to evaluate MNAT1 expressions in CRC tissues using immunohistochemistry, CRC cell lines were also detected MNAT1 expression using Western-blotting. MNAT1 and shMNAT1 vectors were constructed, and transfected into CRC cells. Cell growths of the transfected cells were observed using MTT and colony formation. The affects of MNAT1 on p53 expression were analyzed using Western-blotting and Real-time PCR. Immunoprecipitation assay was used to analyze the interaction p53 and MNAT1, and Western-blotting was used to test the effects of MNAT1 on p53 downstream molecules. The apoptosis of CRC cells with MNAT1 or shMNAT1 were analyzed using flow cytometry. BABL/c athymic nude mice were used to observe the effect of MNAT1 on CRC cell growth in vivo. RESULTS: MNAT1 was found to be overexpressed in CRC tissues and cells, and MNAT1 expressions in CRC tissue samples were associated with CRC carcinogenesis and poor patient outcomes. MNAT1-knockin increased CRC cell growth and colony formation, and MNAT1-knockdown dramatically decreased cell motility and invasion. MNAT1 physically interacted with p53, MNAT1 also increased the interaction of MDM2 with p53. Strikingly, MNAT1 mediated p53 ubiquitin degradation. MNAT1 shortened p53 half-life, and ectopic MNAT1 expression decreased p53 protein stability. Moreover, MNAT1 induced RAD51 and reduced p21, cleaved-caspase3, cleaved-PARP and BAX expression. MNAT1 inhibited CRC cell apoptosis. shMANT1 decreased tumor growths in nude mice following p53 increase. CONCLUSION: MNAT1 binds to p53, mediates p53 ubiquitin-degradation through MDM2, increases cell growth and decreases cell apoptosis, and finally promotes CRC malignance. MNAT1 binding to p53 and mediating p53 ubiquitin-degradation axis represents a novel molecular joint in the p53 pathway. PMID- 30477539 TI - Livestock 2.0 - genome editing for fitter, healthier, and more productive farmed animals. AB - The human population is growing, and as a result we need to produce more food whilst reducing the impact of farming on the environment. Selective breeding and genomic selection have had a transformational impact on livestock productivity, and now transgenic and genome-editing technologies offer exciting opportunities for the production of fitter, healthier and more-productive livestock. Here, we review recent progress in the application of genome editing to farmed animal species and discuss the potential impact on our ability to produce food. PMID- 30477541 TI - Positive end-expiratory pressure (PEEP) level to prevent expiratory flow limitation during cardiac surgery: study protocol for a randomized clinical trial (EFLcore study). AB - BACKGROUND: Lung dysfunction commonly occurs after cardiopulmonary bypass (CPB). Randomized evidence suggests that the presence of expiratory flow limitation (EFL) in major abdominal surgery is associated with postoperative pulmonary complications. Appropriate lung recruitment and a correctly set positive end expiratory pressure (PEEP) level may prevent EFL. According to the available data in the literature, an adequate ventilation strategy during cardiac surgery is not provided. The aim of this study is to assess whether a mechanical ventilation strategy based on optimal lung recruitment with a best PEEP before and after CPB and with a continuous positive airway pressure (CPAP) during CPB would reduce the incidence of respiratory complications after cardiac surgery. METHODS/DESIGN: This will be a single-center, single-blind, parallel-group, randomized controlled trial. Using a 2-by-2 factorial design, high-risk adult patients undergoing elective cardiac surgery will be randomly assigned to receive either a best PEEP (calculated with a PEEP test) or zero PEEP before and after CPB and CPAP (equal to the best PEEP) or no ventilation (patient disconnected from the circuit) during CPB. The primary endpoint will be a composite endpoint of the incidence of EFL after the weaning from CPB and postoperative pulmonary complications. DISCUSSION: This study will help to establish a correct ventilatory strategy before, after, and during CPB. The main purpose is to establish if a ventilation based on a simple and feasible respiratory test may preserve lung function in cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02633423 . Registered on 6 December 2017. PMID- 30477542 TI - Protective role of Ficus deltoidea against BPA-induced impairments of the follicular development, estrous cycle, gonadotropin and sex steroid hormones level of prepubertal rats. AB - Ficus deltoidea is one of the well-known medicinal plants in Malaysia that is traditionally used by the Malay community to treat various ailments and for maintenance of female reproductive health. The objective of this study is to evaluate the potential protective roles of Ficus deltoidea against BPA-induced toxicity of the pituitary-ovarian axis in pre-pubertal female rats. In this study, four groups of pre-pubertal female Sprague Dawley rats were administered with the followings by oral gavage for a period of six weeks: NC (negative control- treated with vehicle), PC (positive control-treated with BPA at 10 mg/kg/BW), F (treated with Ficus deltoidea at 100 mg/kg/BW, then exposed to BPA at 10 mg/kg/BW) and FC (Ficus deltoidea control - treated with Ficus deltoidea at 100 mg/kg/BW). Daily vaginal smear, ovarian follicular development as well as gonadotropin and sexual-steroid hormone levels were determined. The findings showed that Ficus deltoidea demonstrated preventive role against BPA-induced toxicity on the ovaries. This was evident by the increased percentage of rats with normal estrous cycle, qualitatively reduced number of atretic follicles (as observed in histopathological examination) and normalization of the gonadotropins hormone (FSH) and sexual steroid hormone (progesterone) levels. In conclusion, Ficus deltoidea has the capability to prevent the effects of BPA toxicity in the hypothalamus-pituitary-gonadal axis of prepubertal female reproductive system, possibly due to its variety of phytochemical properties. Therefore, these findings strongly support the traditional belief that this medicinal plant is beneficial as daily dietary supplement for the maintenance of female reproductive health. PMID- 30477543 TI - Long-term clinical outcomes after coronary artery bypass grafting with pedicled saphenous vein grafts. AB - BACKGROUND: Coronary artery bypass grafting (CABG) using saphenous vein grafts (SVG) is vitiated by poor long-term patency of the vein grafts. Pedicled SVG harvested with the "no-touch" (NT) technique have demonstrated improved patency and could confer better outcomes. We aim to compare long-term results after CABG where NT or conventional technique was used for vein graft harvesting in a hypothesis-generating registry-based study. METHODS: Two propensity score matched cohorts (1349 patients) undergoing CABG with veins harvested with NT (NTT) or conventional (CT) technique in Sweden over the period 2005-2015 were used to compare long-term outcomes. Mortality, postoperative incidence of coronary angiography and need for reintervention was recorded and multivariable hazard ratios adjusted for risk factors were calculated. RESULTS: The mean follow-up time (SD) was 6.8 (3.3) years for NTT and 6.6 (3.2) years for CT. The adjusted hazard ratios for death, first angiography and need for reintervention for NTT patients were (95% CI) 0.97 (0.80-1.19), 0.76 (0.63-0.93), 0.91 (0.78-1.05), and 0.91 (0.71-1.17), respectively. Failed grafts were found in 43.2% of NTT patients and 53.6% of CT patients at angiography. CONCLUSIONS: In this study NT grafting was associated with a lower risk for repeat angiography, however no difference could be observed for mortality and need for reintervention. The earlier reported improvements in patency of NT veins could possibly be reflected in an improved clinical outcome during the first 10 years after surgery. PMID- 30477544 TI - Rapid agitation control with ketamine in the emergency department (RACKED): a randomized controlled trial protocol. AB - BACKGROUND: The rapid control of patients presenting to the emergency department (ED) with psychomotor agitation and violent behavior is paramount for the safety of patients and ED staff. The use of intramuscular (IM) ketamine in the pre hospital and ED settings has demonstrated promising preliminary results to provide rapid and safe behavioral control. A prospective, randomized controlled trial is required to measure the potential superiority of IM ketamine compared to current standard care (IM benzodiazepines plus antipsychotics). METHODS: This will be a parallel, prospective, randomized, controlled trial of 5 mg/kg IM ketamine compared to a combination of 5 mg IM midazolam and 5 mg IM haloperidol. The study will enroll approximately 184 patients, randomized equally to two study arms. There will be one study visit during which study medication will be administered and assessments will be completed. A follow-up safety visit will occur on day 3. The primary objective of this study is to compare IM ketamine to a combination of IM midazolam and haloperidol with regards to the time required for adequate behavioral control, in minutes, in patients presenting to the ED with psychomotor agitation and violent behavior, as measured by the Richmond Agitation-Sedation Scale (RASS). DISCUSSION: We present a novel study to determine whether ketamine is a rapid and safe option, compared to a combination of midazolam and haloperidol for the sedation of patients presenting to the ED with psychomotor agitation and violent behavior. To our knowledge, this study is the first randomized controlled trial to compare ketamine to current standard care for this indication. We have attempted to address numerous logistical issues with the design of this study including a waiver of consent, ensuring adequate blinding of outcome assessors, patient enrolment, and data monitoring. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03375671 . Registered on 18 December 2017. PMID- 30477545 TI - GRIPT: a novel case-control analysis method for Mendelian disease gene discovery. AB - Despite rapid progress of next-generation sequencing (NGS) technologies, the disease-causing genes underpinning about half of all Mendelian diseases remain elusive. One main challenge is the high genetic heterogeneity of Mendelian diseases in which similar phenotypes are caused by different genes and each gene only accounts for a small proportion of the patients. To overcome this gap, we developed a novel method, the Gene Ranking, Identification and Prediction Tool (GRIPT), for performing case-control analysis of NGS data. Analyses of simulated and real datasets show that GRIPT is well-powered for disease gene discovery, especially for diseases with high locus heterogeneity. PMID- 30477547 TI - Correction to: Emerging roles of Myc in stem cell biology and novel tumor therapies. AB - In the publication of this article [1] there are three errors. PMID- 30477546 TI - The in vitro effect of progesterone on the orexin system in porcine uterine tissues during early pregnancy. AB - BACKGROUND: Orexin A (OXA) and orexin B (OXB) are hypothalamic-derived peptides that participate in the regulation of energy metabolism, food intake and reproductive function by influencing the hypothalamic-pituitary-ovarian axis. Orexins are also produced in the endometrium, myometrium and placenta, which suggests that they could act as a link between energy metabolism and the reproductive system. Changes in the expression of orexin and the orexin receptor genes and proteins during the oestrous cycle and early gestation in pigs imply that orexin activity may be regulated by local factors within the uterus. The aim of this study was to investigate the influence of progesterone (P4) on the expression of orexin system genes, and proteins in the porcine uterus during early gestation. Gene expression was analyzed by real-time PCR. Adiponectin secretion was determined by ELISA, and the receptors proteins content was defined using western blot analysis. RESULTS: In the endometrium, P4 enhanced OXA secretion on days 10 to 11 of gestation and OXB secretion on days 12 to 13. In the myometrium, P4 inhibited the secretion of both orexins on days 15 to 16 and OXB secretion also on days 12 to 13. In the endometrium, P4 inhibited the expression of orexin receptor 1 (OX1R) protein at nearly all times analyzed, whereas the expression of orexin receptor 2 (OX2R) protein was inhibited only on days 15 to 16 of gestation. In the myometrium, P4 stimulated OX1R protein expression on days 12 to 13 and 15 to 16 of gestation and inhibited OX1R protein expression on days 27 to 28. The expression of OX2R protein in the myometrium increased on days 12 to 13 and decreased on days 10 to 11 and 15 to 16. CONCLUSIONS: The results indicate that P4 could regulate the expression of the orexin system in the porcine uterus during early pregnancy, which suggests the presence of a local feedback loop that could play an important role in the regulation of maternal metabolism during pregnancy. The findings may contribute to the existing knowledge of the mechanisms linking maternal energy metabolism with the regulation of the reproductive system during pregnancy. PMID- 30477548 TI - Improving eye care in residential aged care facilities using the Residential Ocular Care (ROC) model: study protocol for a multicentered, prospective, customized, and cluster randomized controlled trial in Australia. AB - BACKGROUND: Older adults in residential aged care facilities have unnecessarily high levels of vision impairment (VI) which are largely treatable or correctable. However, no current comprehensive eye health service model exists in this setting in Australia. We aimed to determine the clinical, person-centered, and economic effectiveness of a novel eye care model, the Residential Ocular Care (ROC). METHODS/DESIGN: This protocol describes a multicentered, prospective, randomized controlled trial. A total of 395 participants with distance vision < 6/12 (0.30 LogMAR) and/or near vision N8 (1.00 M) or worse will be recruited from 38 urban and rural aged care facilities across Victoria, Australia. Aged care facilities will be randomized (1:1) to one of two parallel groups. Participants in the ROC group will receive a comprehensive and tailored eye care pathway that includes, as necessary, refraction and spectacle provision, cataract surgery, low vision rehabilitation, and/or a referral to an ophthalmologist for funded treatment. Usual care participants will be referred for an evaluation to the eye care service associated with the facility or an eye care provider of their choice. The primary outcome will be presenting near and distance vision assessed at the two- and six-month follow-up visits, post baseline. Secondary outcomes will include vision-specific quality of life, mobility, falls, depression, and eye care utilization at two and six months. An incremental cost-effectiveness analysis will also be undertaken. DISCUSSION: The ROC study is the first multicentered, prospective, customized, and cluster randomized controlled trial in Australia to determine the effectiveness of a comprehensive and tailored eye care model for people residing in aged care facilities. Results from this trial will assist health and social care planners in implementing similar innovative models of care for this growing segment of the population in Australia and elsewhere. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry, ACTRN12615000587505 . Registered on 4 June 2015 - retrospectively registered. PMID- 30477549 TI - Virome analyses of Hevea brasiliensis using small RNA deep sequencing and PCR techniques reveal the presence of a potential new virus. AB - BACKGROUND: Hevea brasiliensis is an important commercial crop due to the high quality of the latex it produces; however, little is known about viral infections in this plant. The only virus described to infect H. brasiliensis until now is a Carlavirus, which was described more than 30 years ago. Virus-derived small interfering RNA (vsiRNAs) are the product of the plant's antiviral defense triggered by dsRNA viral intermediates generated, during the replication cycle. These vsiRNAs are complementar to viral genomes and have been widely used to identify and characterize viruses in plants. METHODS: In the present study, we investigated the virome of leaf and sapwood samples from native H. brasiliensis trees collected in two geographic areas in the Brazilian Amazon. Small RNA (sRNA) deep sequencing and bioinformatic tools were used to assembly, identify and characterize viral contigs. Subsequently, PCR amplification techniques were performed to experimentally verify the presence of the viral sequences. Finally, the phylogenetic relationship of the putative new virus with related viral genomes was analyzed. RESULTS: Our strategy allowed the identification of 32 contigs with high similarity to viral reference genomes, from which 23 exhibited homology to viruses of the Tymoviridae family. The reads showed a predominant size distribution at 21 nt derived from both strands, which was consistent with the vsiRNAs profile. The presence and genome position of the viral contigs were experimentally confirmed using droplet digital PCR amplifications. A 1913 aa long fragment was obtained and used to infer the phylogenetic relationship of the putative new virus, which indicated that it is taxonomically related to the Grapevine fleck virus, genus Maculavirus. The putative new virus was named Hevea brasiliensis virus (HBrV) in reference to its host. CONCLUSION: The methodological strategy applied here proved to be efficient in detecting and confirming the presence of new viral sequences on a 'very difficult to manage' sample. This is the second time that viral sequences, that could be ascribed as a putative novel virus, associated to the rubber tree has been identified. PMID- 30477550 TI - Arginine does not rescue p.Q188R mutation deleterious effect in classic galactosemia. AB - BACKGROUND: Classic galactosemia is a rare genetic metabolic disease with an unmet treatment need. Current standard of care fails to prevent chronically debilitating brain and gonadal complications. Many mutations in the GALT gene responsible for classic galactosemia have been described to give rise to variants with conformational abnormalities. This pathogenic mechanism is highly amenable to a therapeutic strategy based on chemical/pharmacological chaperones. Arginine, a chemical chaperone, has shown beneficial effect in other inherited metabolic disorders, as well as in a prokaryotic model of classic galactosemia. The p.Q188R mutation presents a high prevalence in the Caucasian population, making it a very clinically relevant mutation. This mutation gives rise to a protein with lower conformational stability and lower catalytic activity. The aim of this study is to assess the potential therapeutic role of arginine for this mutation. METHODS: Arginine aspartate administration to four patients with the p.Q188R/p.Q188R mutation, in vitro studies with three fibroblast cell lines derived from classic galactosemia patients as well as recombinant protein experiments were used to evaluate the effect of arginine in galactose metabolism. This study has been registered at https://clinicaltrials.gov (NCT03580122) on 09 July 2018. Retrospectively registered. RESULTS: Following a month of arginine administration, patients did not show a significant improvement of whole-body galactose oxidative capacity (p = 0.22), erythrocyte GALT activity (p = 0.87), urinary galactose (p = 0.52) and urinary galactitol levels (p = 0.41). Patients' fibroblasts exposed to arginine did not show changes in GALT activity. Thermal shift analysis of recombinant p.Q188R GALT protein in the presence of arginine did not exhibit a positive effect. CONCLUSIONS: This short pilot study in four patients homozygous for the p.Q188R/p.Q188R mutation reveals that arginine has no potential therapeutic role for galactosemia patients homozygous for the p.Q188R mutation. PMID- 30477551 TI - Bias due to MEasurement Reactions In Trials to improve health (MERIT): protocol for research to develop MRC guidance. AB - BACKGROUND: There is now clear systematic review evidence that measurement can affect the people being measured; much of this evidence focusses on how asking people to complete a questionnaire can result in changes in behaviour. Changes in measured behaviour and other outcomes due to this reactivity may introduce bias in otherwise well-conducted randomised controlled trials (RCTs), yielding incorrect estimates of intervention effects. Despite this, measurement reactivity is not currently adequately considered in risk of bias frameworks. The present research aims to produce a set of guidance statements on how best to avoid or minimise bias due to measurement reactivity in studies of interventions to improve health, with a particular focus on bias in RCTs. METHODS: The MERIT study consists of a series of systematic and rapid reviews, a Delphi study and an expert workshop to develop guidance on how to minimise bias in trials due to measurement reactivity. An existing systematic review on question-behaviour effects on health-related behaviours will be updated and three new rapid reviews will be conducted to identify (1) existing guidance on measurement reactivity; (2) systematic reviews of studies that have quantified the effects of measurement on outcomes relating to behaviour and affective outcomes in health and non-health contexts and (3) trials that have investigated the effects of objective measurements of behaviour on concurrent or subsequent behaviour itself. A Delphi procedure will be used to combine the views of experts with a view to reaching agreement on the scope of the guidance statements. Finally, a workshop will be held in autumn 2018, with the aim of producing a set of guidance statements that will form the central part of new MRC guidance on how best to avoid bias due to measurement reactivity in studies of interventions to improve health. DISCUSSION: Our ambition is to produce MRC guidance on measurement reactions in trials which will be used by future trial researchers, leading to the development of trials that are less likely to be at risk of bias. PMID- 30477553 TI - Self-care practice and associated factors among Diabetes Mellitus patients on follow up in Benishangul Gumuz Regional State Public Hospitals, Western Ethiopia: a cross-sectional study. AB - OBJECTIVE: The aim of this study was to assess the self-care practice among patients with diabetes and their associated factors in Benishangul Gumuz Public Hospitals, Western Ethiopia, 2018. RESULT: Out of the total 399 selected patients, 383 were participated in the study with a response rate of 96%. From 383 respondents, 45.7% had poor diabetes self-care practice. Unable to read and write (AOR = 3.63, 95% CI 1.33-9.89, p = 0.011), never had a diabetic health education (AOR = 4.09, 95% CI 1.89, 8.84, p = 0.000), not having glucometer (AOR = 2.66, 95% CI 1.30, 5.46 p = 0.007), poor diabetic knowledge (AOR = 5.01, 95% CI 2.44, 10.28, p = 0.000), poor self-efficacy (AOR = 3.00, 95% CI 1.76, 5.11, p = 0.000) and not having social support (AOR = 1.84, 95% CI 1.08, 3.13, p = 0.023) were significantly associated with poor self-care practice of diabetes patients. These findings request for the need of integrated interventional management approach, which will improve the health and quality of life of the diabetes patients. PMID- 30477552 TI - Long-term, health-enhancing physical activity is associated with reduction of pain but not pain sensitivity or improved exercise-induced hypoalgesia in persons with rheumatoid arthritis. AB - BACKGROUND: We aimed to evaluate the 1-year and 2-year outcome of a health enhancing physical activity (HEPA) support program on global pain, pressure pain sensitivity, and exercise-induced segmental and plurisegmental hypoalgesia (EIH) in persons with rheumatoid arthritis (RA). METHODS: Thirty participants (27 women and 3 men) were recruited from a larger intervention cohort that engaged in strength training and moderate-intensity aerobic activity. Assessments were performed before the HEPA intervention and at 1-year and 2-year follow-ups. Global pain was assessed on a visual analogue scale (0-100). Pressure pain thresholds (PPTs) and suprathreshold pressure pain at rest corresponding to 4/10 (medium pain) (SP4) and 7/10 (strong pain) (SP7) on Borg CR 10 scale were assessed by algometry. In a subsample (n = 21), segmental and plurisegmental EIH were assessed during standardized submaximal static contraction (30% of the individual maximum), by algometry, alternately at the contracting right M. quadriceps and the resting left M. deltoideus. RESULTS: Global pain decreased from before the intervention to 2-year follow-up (median 11 to median 6, P = 0.040). PPTs and SP4 pressure pain at rest did not change from before the intervention to 2-year follow-up, while SP7 decreased from mean 647 kPa to mean 560 kPa (P = 0.006). Segmental EIH during static muscle contraction increased from the assessment before the intervention (from mean 1.02 to mean 1.42, P = 0.001), as did plurisegmental EIH (from mean 0.87 to mean 1.41, P <0.001). There were no statistically significant changes in segmental or plurisegmental EIH from before the intervention to 2-year follow-up. CONCLUSION: Participation in a long term HEPA support program was associated with reduced global pain, whereas pressure pain sensitivity at rest was not reduced and EIH did not change. Thus, our results do not favor the hypothesis that long-term HEPA reduces pain by improving descending pain inhibition in persons with RA. TRIAL REGISTRATION: ISRCTN25539102 , ISRCTN registry, date assigned March 4, 2011. The trial was retrospectively registered. PMID- 30477554 TI - CODEX2: full-spectrum copy number variation detection by high-throughput DNA sequencing. AB - High-throughput DNA sequencing enables detection of copy number variations (CNVs) on the genome-wide scale with finer resolution compared to array-based methods but suffers from biases and artifacts that lead to false discoveries and low sensitivity. We describe CODEX2, as a statistical framework for full-spectrum CNV profiling that is sensitive for variants with both common and rare population frequencies and that is applicable to study designs with and without negative control samples. We demonstrate and evaluate CODEX2 on whole-exome and targeted sequencing data, where biases are the most prominent. CODEX2 outperforms existing methods and, in particular, significantly improves sensitivity for common CNVs. PMID- 30477555 TI - A nomenclature and classification for the congenital myasthenic syndromes: preparing for FAIR data in the genomic era. AB - BACKGROUND: Congenital myasthenic syndromes (CMS) are a heterogeneous group of inherited neuromuscular disorders sharing the common feature of fatigable weakness due to defective neuromuscular transmission. Despite rapidly increasing knowledge about the genetic origins, specific features and potential treatments for the known CMS entities, the lack of standardized classification at the most granular level has hindered the implementation of computer-based systems for knowledge capture and reuse. Where individual clinical or genetic entities do not exist in disease coding systems, they are often invisible in clinical records and inadequately annotated in information systems, and features that apply to one disease but not another cannot be adequately differentiated. RESULTS: We created a detailed classification of all CMS disease entities suitable for use in clinical and genetic databases and decision support systems. To avoid conflict with existing coding systems as well as with expert-defined group-level classifications, we developed a collaboration with the Orphanet nomenclature for rare diseases, creating a clinically understandable name for each entity and placing it within a logical hierarchy that paves the way towards computer-aided clinical systems and improved knowledge bases for CMS that can adequately differentiate between types and ascribe relevant expert knowledge to each. CONCLUSIONS: We suggest that data science approaches can be used effectively in the clinical domain in a way that does not disrupt preexisting expert classification and that enhances the utility of existing coding systems. Our classification provides a comprehensive view of the individual CMS entities in a manner that supports differential diagnosis and understanding of the range and heterogeneity of the disease but that also enables robust computational coding and hierarchy for machine-readability. It can be extended as required in the light of future scientific advances, but already provides the starting point for the creation of FAIR (Findable, Accessible, Interoperable and Reusable) knowledge bases of data on the congenital myasthenic syndromes. PMID- 30477556 TI - Cetirizine per os: exposure and antihistamine effect in the dog. AB - BACKGROUND: Cetirizine is an antihistamine used in dogs, but plasma concentrations in relation to effect after oral administration are not well studied. This study investigated cetirizine exposure and the plasma cetirizine concentration-antihistamine response relation in the dog following oral administration of cetirizine. RESULTS: Eight Beagle dogs were included in a cross over study consisting of two treatments. In treatment one, cetirizine 2-4 mg/kg was administered per os once daily for 3 days. The other treatment served as a control. Wheal diameter induced by intra-dermal histamine injections served as response-biomarker. Cetirizine plasma concentration was quantified by UHPLC MS/MS. Median (range) cetirizine plasma terminal half-life was 10 h (7.9-16.5). Cetirizine significantly inhibited wheal formation compared with the premedication baseline. Maximum inhibition of wheal formation after treatment with cetirizine per os was 100% compared with premedication wheal diameter. The median (range) IC50-value for reduction in wheal area was 0.33 ug/mL (0.07-0.45). The median (range) value for the sigmoidicity factor was 1.8 (0.8-3.5). A behavioral study was also conducted and revealed no adverse effects, such as sedation. CONCLUSION: The results indicate that a once-daily dosing regimen of 2 4 mg/kg cetirizine per os clearly provides a sufficient antihistamine effect. Based on this experimental protocol, cetirizine may be an option to treat histamine-mediated inflammation in the dog based on this experimental protocol but additional clinical studies are required. PMID- 30477558 TI - Assessment of students' attitude and level of community involvement in community based education at training sites in Gedeo zone, South Ethiopia. AB - OBJECTIVE: This study was aimed to assess the students' attitude towards community based education and the level of community involvement in community based education. RESULT: Among the 634 community members participated in this study, 64.4% were aware of the community-based education program and 86.5% of these participants have favorable attitude towards the program. The level of community involvement in the activities of students in this study is 40.9%. About 72% of the students have favorable attitude towards community based education. Female students were more likely to have favorable attitude toward the program [AOR: 7.64 (CI 1.80, 32.50)]. On the other hand, students who have low participation during group assignment [AOR: 0.07 (CI 0.01, 0.95)] and those with lower socially conscious attitude [AOR: 0.02 (0.01, 0.08)] were less likely to have favorable attitude. PMID- 30477557 TI - Low birth weight and its associated factors in Ethiopia: a systematic review and meta-analysis. AB - BACKGROUND: Different primary studies in Ethiopia showed the burden of low birth weight. However, variation among those studies was seen. This study was aimed to estimate the national prevalence and associated factors of low birth weight in Ethiopia. METHODS: PubMed, Web of Science, Cochrane library, and Google Scholar were searched. A funnel plot and Egger's regression test were used to see publication bias. I-squared statistic was applied to check heterogeneity of studies. A weighted inverse variance random-effects model was applied to estimate the national prevalence and the effect size of associated factors. The subgroup analysis was conducted by region, study design, and year of publication. RESULT: A total of 30 studies with 55,085 participants were used for prevalence estimation. The pooled prevalence of LBW was 17.3% (95% CI: 14.1-20.4). Maternal age < 20 years (AOR = 1.7; 95% CI:1.5-2.0), pregnancy interval < 24 months (AOR = 2.8; 95%CI: 1.4-4.2), BMI < 18.5 kg/m2 (AOR = 5.6; 95% CI: 1.7-9.4), and gestational age < 37 weeks at birth (AOR = 6.4; 95% CI: 2.5-10.3) were identified factors of LBW. CONCLUSIONS: The prevalence of low birth weight in Ethiopia remains high. This review may help policy-makers and program officers to design low birth weight preventive interventions. PMID- 30477559 TI - EBV-miR-BART8-3p induces epithelial-mesenchymal transition and promotes metastasis of nasopharyngeal carcinoma cells through activating NF-kappaB and Erk1/2 pathways. AB - BACKGROUND: Epstein-Barr virus (EBV) is ubiquitously associated with nasopharyngeal carcinoma (NPC). EBV encodes two groups of microRNAs (miRNAs) which are divided into BamHI fragment H rightward open reading frame 1 (BHRF1) and BamHI-A rightward transcripts (BART) microRNAs. EBV miR-BART has been found to be involved in the development and progression of NPC. However, so far the role of EBV-miR-BART8-3p in NPC progression remains unknown. This study aimed to investigate the role of EBV-miR-BART8-3p in NPC and explore the underlying mechanisms. METHODS: miRNA expression was profiled in NPC and normal nasopharyngeal mucosal specimens using miRNA sequencing. EBV-miR-BART8-3p and RNF38 expression was quantified with qPCR assay. The migration, invasion and metastasis of NPC cells were evaluated using CCK-8, colony-forming, wound healing, and migration and invasion assays. The expression levels of epithelial mesenchymal transition (EMT)-related markers,metastasis-related markers and NF kappaB and Erk1/2 signaling proteins were determined using Western blotting. Tumorigenic assay was performed to evaluate the pulmonary metastatic ability of NPC cells in vivo. RESULTS: EBV BART miRNAs were highly over-expressed and co expressed in NPC and might be associated with deactivated immune response in NPC according to the sequencing analysis. EBV-miR-BART8-3p expression was significantly higher in human NPC specimens than in normal nasopharyngeal mucosal specimens. EBV-miR-BART8-3p was found to promote NPC migration, invasion and metastasis, drove an EMT process and upregulated expression of metastasis-related proteins expression in NPC cells. Our data showed EBV-miR-BART8-3p directly targeted RNF38 in NPC cells. CONCLUSION: The present study demonstrates that EBV miR-BART8-3p plays a significant role in inducing EMT and promoting metastasis through directly targeting RNF38 in NPC cells via the activation of NF-kappaB and Erk1/2 signaling pathways. Our findings suggest that EBV-miR-BART8-3p is a potential therapeutic target for NPC. PMID- 30477560 TI - Phase II trial on SBRT for unresectable liver metastases: long-term outcome and prognostic factors of survival after 5 years of follow-up. AB - BACKGROUND: The aim of this study was to evaluate long-term efficacy and survival prognostic factors of stereotactic body radiation therapy (SBRT) for un resectable liver metastases in patients enrolled in a prospective phase II trial. METHODS AND MATERIALS: 5-year local control (LC), overall survival (OS), progression free survival (PFS) and toxicity rates were analyzed in patients with un-resectable liver metastases enrolled in a Phase II Trial on liver SBRT, with a prescription dose of 75Gy in 3 consecutive fractions. RESULTS: A total of 61 patients with 76 lesions were enrolled, with a median follow-up time of 6.1 years. One, three and 5 year LC rates were 94 +/- 3.1%, 78.0 +/- 5.9% and 78.0 +/ 5.9%, without reaching the median LC time. Median OS was 27.6 months and the survival rates were 85.2 +/- 4.5%, 31.1 +/- 5.9% and 18.0 +/- 4.9% at 1, 3 and 5 year after SBRT, respectively. Univariate analysis showed that favorable primary site (colorectal, breast and gynecological) of metastases (p = 0.001) improved survival. Toxicity was moderate. One patient experienced G3 late chest wall pain, which resolved within 1 year from SBRT. No cases of Radiation Induced Liver Disease (RILD) were detected. CONCLUSIONS: Long-term results of this Phase II study suggest the efficacy and safety of SBRT for un-resectable liver metastases after 5-year of follow up. Selection of cases with positive prognostic factors may improve long-term survival of these oligo-metastastic patients and may confirm the role of SBRT as an effective alternative local therapy for liver metastases. PMID- 30477561 TI - Abnormal resting state activity of left middle occipital gyrus and its functional connectivity in female patients with major depressive disorder. AB - BACKGROUND: Women are more susceptible to major depressive disorder (MDD). A possible explanation is that women have a trait tendency to engage in a ruminative response style. Depending on cognitive model of depression, attention bias, memory bias and self-referential bias were closely related among depressed patients. Previous studies have explored the neural mechanism of the cognitive biases by using amplitude of low frequency fluctuations (ALFF) or functional connectivity (FC), and few combined these two metrics, especially focusing on female patients. METHODS: We assessed 25 female patients diagnosed with MDD and 13 well matched healthy controls (HCs) using Rs-fMRI. Two metrics ALFF and FC based on abnormal ALFF were explored and made comparisons. RESULTS: Compared with HCs, female patients with MDD showed that one cluster with significantly decreased ALFF in the left middle occipital gyrus(L-MOG). Furtherly we founded depressed female subjects showed significantly lower FC between the L-MOG seed and left orbitofrontal cortex, and significantly higher FC between the L-MOG seed and left medial prefrontal gyrus and left hippocampus. CONCLUSIONS: Our results showed L-MOG may act as a connection, which involved in the processing of cognitive biases of MDD by connected with limbic-cortical regions in resting state. These findings may enhance the understanding of the neurobiological mechanism in female patients with MDD. PMID- 30477562 TI - Career perspectives of senior dental students from different backgrounds at a single Middle Eastern institution. AB - BACKGROUND: Differences between dental students in terms of social, economic and cultural backgrounds are likely to impact their professional career plans. The aim of this study was to explore the professional career plans among final year dental students from different backgrounds at a single Middle Eastern institution (Jordan university of Science and Technology-JUST). METHODS: Fifth year dental students at JUST were invited to fill out a paper based self-administered questionnaire. Data was collected on students' demographics, their future career plans and the impact of social and economic changes on such plans, their interest in postgraduate studies and the specialty of choice in addition to the influence of a group of factors on that choice. Data was also collected on the value of non academic workshops, guidance regarding career plans, participants' preferred pattern of work (full-time versus part-time) and retirement plans. Students were categorized according to their nationalities. Pearson's chi squared test, one way ANOVA and post hoc tests were used to measure statistical significance between measured variables and backgrounds of participants. The level of significance was set at P <= 0.05. RESULTS: A total of 227 students completed the survey (response rate = 84%). 47% of the participants were Jordanians, 27% were Malaysians, 11% were from Gulf States (Saudi Arabia, Bahrain, Kuwait and Qatar), 10% were from conflict zones in the Middle East (Syria, Iraq, Palestine and Yemen) and 5% comprised students from other nationalities. Significant differences were found between students from different backgrounds in their funding sources (Chi square = 132, P < 0.01), practice plans (Chi square = 43, P < 0.01), the impact of social and economic changes on their career choices (Chi square = 34, P < 0.01), planned work pattern within the first 10 years post-graduation (chi square = 18, P < 0.05) and 10-20 years after graduation (69%, Chi square = 22, P < 0.01) and retirement plans (Chi square = 25, P < 0.05). Students from different nationalities agreed on most factors affecting their choice of a specialty, except for the reputation of the specialty (P < 0.05). CONCLUSION: Several differences in career plans were found between dental students from variable backgrounds studying a single institution. Many of these disparities could reflect variations in socioeconomic backgrounds. PMID- 30477564 TI - Utilization and determinants of long term and permanent contraceptive methods among married reproductive age women at Janamora district, northwest Ethiopia. AB - OBJECTIVE: This study is aimed at determining the prevalence and factors associated with utilization of long acting and permanent methods among married reproductive age (15-49) females at Janamora district, in 2018. RESULT: Prevalence of long acting and permanent contraceptive method utilization was 12.9% (95% confidence interval (CI) 10%, 15%).Of those utilizers, 96.8% use implants, 2.1% use female sterilization and 1.1% use Intrauterine Contraceptive Device. Women's occupation, student as compared to housewife (Adjusted odds ratio (AOR) = 3.12, 95% CI 1.05-9.29), a women whose husband was government employed as compared to merchant (AOR = 2.51, 95% CI 1.1-5.75), and women who had high knowledge as compared to poor knowledge (AOR = 4.20, 95% CI 1.32-13.39) were positively associated with utilization of long acting and permanent contraceptive method. PMID- 30477563 TI - Next steps in studying the human microbiome and health in prospective studies, Bethesda, MD, May 16-17, 2017. AB - The National Cancer Institute (NCI) sponsored a 2-day workshop, "Next Steps in Studying the Human Microbiome and Health in Prospective Studies," in Bethesda, Maryland, May 16-17, 2017. The workshop brought together researchers in the field to discuss the challenges of conducting microbiome studies, including study design, collection and processing of samples, bioinformatics and statistical methods, publishing results, and ensuring reproducibility of published results. The presenters emphasized the great potential of microbiome research in understanding the etiology of cancer. This report summarizes the workshop and presents practical suggestions for conducting microbiome studies, from workshop presenters, moderators, and participants. PMID- 30477565 TI - Case reports: old-timers and evergreens. PMID- 30477566 TI - Development of a conversation approach for practice nurses aimed at making shared decisions on goals and action plans with primary care patients. AB - BACKGROUND: Primary care nurses play a crucial role in setting personal goals and action plans together with chronically ill patients. This may be a challenge for practice nurses, who are often trained to adopt protocol-based work routines. The aim of this study was to systematically develop a conversation approach, and a corresponding training course, for practice nurses aimed at making shared decisions about goals and actions with their chronically ill patients. METHODS: The 6-step iterative Intervention Mapping protocol was used as a framework. This paper describes the first four steps of the protocol. After the first step, in which literature studies as well as qualitative studies were conducted, the overall aim and objectives for the approach were formulated (step 2). In step 3, methods and strategies for the approach were chosen, which were translated into practical components in step 4. In addition, a pilot study was conducted. RESULTS: The main objectives of the approach focus on the ability of practice nurses to explore the patients' perspectives from a holistic point of view, to explicitly formulate goals and action plans, to tailor shared decision making about goals and action plans to individual patients, and to continuously reflect on work-related attitudes. The approach consists of a practical framework for shared decision making about goals and actions. The framework involves a tool for exploring patients' perspectives and a tool for identifying patient profiles, to facilitate tailoring shared decision making. A comprehensive training course for practice nurses was developed. CONCLUSION: We systematically developed a conversation approach, involving a practical framework with several tools, which aims to support practice nurses in making shared decisions about goals and actions with their patients. As practice nurses need support in their learning process to be able to share decisions with patients, we also developed a comprehensive training course for them. The approach and the training course were developed in close collaboration with important stakeholders. Some critical factors for the implementation of the approach were revealed. These factors will be addressed in the next step, a process evaluation (not part of this paper). PMID- 30477567 TI - Developing an equation for estimating body height from linear body measurements of Ethiopian adults. AB - BACKGROUND: Measurements of erect height in older people, hospitalized and bedridden patients, and people with skeletal deformity is difficult. As a result, using body mass index for assessing nutritional status is not valid. Height estimated from linear body measurements such as arm span, knee height, and half arm span was shown to be useful surrogate measures of stature. However, the relationship between linear body measurements and stature varies across populations implying the need for the development of population-specific prediction equation. The objective of this study was to develop a formula that predicts height from arm span, half arm span, and knee height for Ethiopian adults and assess its agreement with measured height. METHODS: A cross-sectional study was conducted from March 15 to April 21, 2016 in Jimma University among a total of 660 (330 females and 330 males) subjects aged 18-40 years. A two-stage sampling procedure was employed to select study participants. Data were collected using interviewer-administered questionnaire and measurement of anthropometric parameters. The data were edited and entered into Epi Data version 3.1 and exported to SPSS for windows version 20 for cleaning and analyses. Linear regression model was fitted to predict height from knee height, half arm span, and arm span. Bland-Altman analysis was employed to see the agreement between actual height and predicted heights. P values < 0.05 was used to declare as statistically significance. RESULTS: On multivariable linear regression analyses after adjusting for age and sex, arm span (beta = 0.63, p < 0.001, R2 = 87%), half arm span (beta = 1.05, p < 0.001, R2 = 83%), and knee height (beta = 1.62, p < 0.001, R2 = 84%) predicted height significantly. The Bland-Altman analyses showed a good agreement between measured height and predicted height using all the three linear body measurements. CONCLUSION: The findings imply that in the context where height cannot be measured, height predicted from arm span, half arm span, and knee height is a valid proxy indicator of height. Arm span was found to be the best predictor of height. The prediction equations can be used to assess the nutritional status of hospitalized and/or bedridden patients, people with skeletal deformity, and elderly population in Ethiopia. PMID- 30477568 TI - The relevance of cerebrospinal fluid alpha-synuclein levels to sporadic and familial Alzheimer's disease. AB - Accumulating evidence demonstrating higher cerebrospinal fluid (CSF) alpha synuclein (alphaSyn) levels and alphaSyn pathology in the brains of Alzheimer's disease (AD) patients suggests that alphaSyn is involved in the pathophysiology of AD. To investigate whether alphaSyn could be related to specific aspects of the pathophysiology present in both sporadic and familial disease, we quantified CSF levels of alphaSyn and assessed links to various disease parameters in a longitudinally followed cohort (n = 136) including patients with sporadic mild cognitive impairment (MCI) and AD, and in a cross-sectional sample from the Dominantly Inherited Alzheimer's Network (n = 142) including participants carrying autosomal dominant AD (ADAD) gene mutations and their non-mutation carrying family members.Our results show that sporadic MCI patients that developed AD over a period of two years exhibited higher baseline alphaSyn levels (p = 0.03), which inversely correlated to their Mini-Mental State Examination scores, compared to cognitively normal controls (p = 0.02). In the same patients, there was a dose-dependent positive association between CSF alphaSyn and the APOEepsilon4 allele. Further, CSF alphaSyn levels were higher in symptomatic ADAD mutation carriers versus non-mutation carriers (p = 0.03), and positively correlated to the estimated years from symptom onset (p = 0.05) across all mutation carriers. In asymptomatic (Clinical Dementia Rating < 0.5) PET amyloid positive ADAD mutation carriers CSF alphaSyn was positively correlated to 11C Pittsburgh Compound-B (PiB) retention in several brain regions including the posterior cingulate, superior temporal and frontal cortical areas. Importantly, APOEepsilon4-positive ADAD mutation carriers exhibited an association between CSF alphaSyn levels and mean cortical PiB retention (p = 0.032). In both the sporadic AD and ADAD cohorts we found several associations predominantly between CSF levels of alphaSyn, tau and amyloid-beta1-40.Our results suggest that higher CSF alphaSyn levels are linked to AD pathophysiology at the early stages of disease development and to the onset of cognitive symptoms in both sporadic and autosomal dominant AD. We conclude that APOEepsilon4 may promote the processes driven by alphaSyn, which in turn may reflect on molecular mechanisms linked to the asymptomatic build-up of amyloid plaque burden in brain regions involved in the early stages of AD development. PMID- 30477571 TI - The challenges of muscle biopsy in a community based geriatric population. AB - OBJECTIVES: To describe the difficulties of obtaining muscle samples using a Bergstrom needle technique in a frail older adult population. The data were obtained from a study primarily investigating immunosenescence in frailty. An intended research technique was skeletal muscle biopsy in a small subset of participants to investigate muscle morphology and local inflammatory factors. RESULTS: Forty healthy older adults and 37 frail older adults were considered for a Bergstrom needle muscle biopsy. Of these, 17.5% of healthy older adults and 94.6% of the frail older adults had single or multiple participant factors resulting in a contra-indication to muscle biopsy. 40.7% of healthy older female participants were at risk of a failed muscle biopsy due to low muscle mass. Considering only muscle mass muscle biopsy would have been successful in 18.7% of the frail older women and 21.4% of the frail older men. In this population, muscle biopsy was not feasible because of contra-indications in the majority of participants. This questions whether a biopsy sample obtained from frail older individuals, is actually representative of this population and supports the need to disclose biopsy failure rate in this population. PMID- 30477570 TI - Pazopanib: Evidence review and clinical practice in the management of advanced renal cell carcinoma. AB - BACKGROUND: Pazopanib is indicated in the first-line treatment of metastatic renal cell cancer (mRCC). The aim of this study was to review the efficacy, safety, and pharmacokinetics of pazopanib and see how these aspects are linked to clinical practice. METHODS: A non-exhaustive systematic review was conducted according to the three topics. No publication restrictions were imposed and the selected languages were Spanish and English. After that, a summary of the main results and findings of the review was presented and discussed during three meetings (one for each topic) with 13 medical oncologists that usually treat mRCC. At these meetings, a questionnaire on the first-line use of pazopanib in clinical practice was also drawn up. After the meetings, the questionnaire was completed by 60 specialist medical oncologists in renal cancer. RESULTS: The efficacy and safety of pazopanib have been demonstrated in several clinical trials, and subsequently confirmed in studies in real-world clinical practice. In addition to its clinical benefit and good safety profile, quality of life results for pazopanib, which compare favorably to sunitinib, make it a good option in the first-line treatment of patients. Special populations have been included in studies conducted with pazopanib, and it is safe for use in elderly patients, poor functional status, kidney failure, and mild or moderate hepatic impairment, and in patients with concomitant cardiovascular disease. The results of the questionnaire have shown that pazopanib is perceived as an effective drug, in which quality of life (QoL) outcomes are valued above all. CONCLUSIONS: This paper offers a comprehensive and critical summary of efficacy, tolerability, and pharmacokinetics of pazopanib in the treatment of mRCC. Pazopanib is an effective treatment with an acceptable safety profile. Its QoL and tolerability results offer certain advantages when compared with other therapeutic alternatives, and its use appears to be safe in different patient profiles. PMID- 30477569 TI - Skin and gut microbiomes of a wild mammal respond to different environmental cues. AB - BACKGROUND: Animal skin and gut microbiomes are important components of host fitness. However, the processes that shape the microbiomes of wildlife are poorly understood, particularly with regard to exposure to environmental contaminants. We used 16S rRNA amplicon sequencing to quantify how exposure to radionuclides impacts the skin and gut microbiota of a small mammal, the bank vole Myodes glareolus, inhabiting areas within and outside the Chernobyl Exclusion Zone (CEZ), Ukraine. RESULTS: Skin microbiomes of male bank voles were more diverse than females. However, the most pronounced differences in skin microbiomes occurred at a larger spatial scale, with higher alpha diversity in the skin microbiomes of bank voles from areas within the CEZ, whether contaminated by radionuclides or not, than in the skin microbiomes of animals from uncontaminated locations outside the CEZ, near Kyiv. Similarly, irrespective of the level of radionuclide contamination, skin microbiome communities (beta diversity) showed greater similarities within the CEZ, than to the areas near Kyiv. Hence, bank vole skin microbiome communities are structured more by geography than the level of soil radionuclides. This pattern presents a contrast with bank vole gut microbiota, where microbiomes could be strikingly similar among distant (~ 80 km of separation), uncontaminated locations, and where differences in microbiome community structure were associated with the level of radioactivity. We also found that the level of (dis)similarity between the skin and gut microbiome communities from the same individuals was contingent on the potential for exposure to radionuclides. CONCLUSIONS: Bank vole skin and gut microbiomes have distinct responses to similar environmental cues and thus are structured at different spatial scales. Our study shows how exposure to environmental pollution can affect the relationship between a mammalian host's skin and gut microbial communities, potentially homogenising the microbiomes in habitats affected by pollution. PMID- 30477572 TI - Differential open chromatin profile and transcriptomic signature define depot specific human subcutaneous preadipocytes: primary outcomes. AB - BACKGROUND: Increased lower body fat is associated with reduced cardiometabolic risk. The molecular basis for depot-specific differences in gluteofemoral (GF) compared with abdominal (A) subcutaneous adipocyte function is poorly understood. In the current report, we used a combination of Assay for Transposase-Accessible Chromatin followed by sequencing (ATAC-seq), RNA-seq, and chromatin immunoprecipitation (ChIP)-qPCR analyses that provide evidence that depot specific gene expression patterns are associated with differential epigenetic chromatin signatures. METHODS: Preadipocytes cultured from A and GF adipose tissue obtained from premenopausal apple-shaped women were used to perform transcriptome analysis by RNA-seq and assess accessible chromatin regions by ATAC seq. We measured mRNA expression and performed ChIP-qPCR experiments for histone modifications of active (H3K4me3) and repressed chromatin (H3K27me3) regions respectively on the promoter regions of differentially expressed genes. RESULTS: RNA-seq experiments revealed an A-fat and GF-fat selective gene expression signature, with 126 genes upregulated in abdominal preadipocytes and 90 genes upregulated in GF cells. ATAC-seq identified almost 10-times more A-specific chromatin-accessible regions. Using a combined analysis of ATAC-seq and global gene expression data, we identified 74 of the 126 abdominal-specific genes (59%) with A-specific accessible chromatin sites within 200 kb of the transcription start site (TSS), including HOXA3, HOXA5, IL8, IL1b, and IL6. Interestingly, only 14 of the 90 GF-specific genes (15%) had GF-specific accessible chromatin sites within 200 kb of the corresponding TSS, including HOXC13 and HOTAIR, whereas 25 of them (28%) had abdominal-specific accessible chromatin sites. ChIP-qPCR experiments confirmed that the active H3K4me3 chromatin mark was significantly enriched at the promoter regions of HOXA5 and HOXA3 genes in abdominal preadipocytes, while H3K27me3 was less abundant relative to chromatin from GF. This is consistent with their A-fat specific gene expression pattern. Conversely, analysis of the promoter regions of the GF specific HOTAIR and HOXC13 genes exhibited high H3K4me3 and low H3K27me3 levels in GF chromatin compared to A chromatin. CONCLUSIONS: Global transcriptome and open chromatin analyses of depot specific preadipocytes identified their gene expression signature and differential open chromatin profile. Interestingly, A-fat-specific open chromatin regions can be observed in the proximity of GF-fat genes, but not vice versa. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01745471 . Registered 5 December 2012. PMID- 30477573 TI - Molecular and biochemical characterization of key enzymes in the cysteine and serine metabolic pathways of Acanthamoeba castellanii. AB - BACKGROUND: Acanthamoeba spp. can cause serious human infections, including Acanthamoeba keratitis, granulomatous amoebic encephalitis and cutaneous acanthamoebiasis. Cysteine biosynthesis and the L-serine metabolic pathway play important roles in the energy metabolism of Acanthamoeba spp. However, no study has confirmed the functions of cysteine synthase (AcCS) in the cysteine pathway and phosphoglycerate dehydrogenase (AcGDH) or phosphoserine aminotransferase (AcSPAT) in the non-phosphorylation serine metabolic pathway of Acanthamoeba. METHODS: The AcCS, AcGDH and AcSPAT genes were amplified by PCR, and their recombinant proteins were expressed in Escherichia coli. Polyclonal antibodies against the recombinant proteins were prepared in mice and used to determine the subcellular localisation of each native protein by confocal laser scanning microscopy. The enzymatic activity of each recombinant protein was also analysed. Furthermore, each gene expression level was analysed by quantitative PCR after treatment with different concentrations of cysteine or L-serine. RESULTS: The AcCS gene encodes a 382-amino acid protein with a predicted molecular mass of 43.1 kDa and an isoelectric point (pI) of 8.11. The AcGDH gene encodes a 350 amino acid protein with a predicted molecular mass of 39.1 kDa and a pI of 5.51. The AcSPAT gene encodes a 354-amino acid protein with a predicted molecular mass of 38.3 kDa and a pI of 6.26. Recombinant AcCS exhibited a high cysteine synthesis activity using O-acetylserine and Na2S as substrates. Both GDH and SPAT catalysed degradation, rather than synthesis, of serine. Exogenous L-serine or cysteine inhibited the expression of all three enzymes in a time- and dose dependent manner. CONCLUSIONS: This study demonstrated that AcCS participates in cysteine biosynthesis and serine degradation via the non-phosphorylation serine metabolic pathway, providing a molecular basis for the discovery of novel anti Acanthamoeba drugs. PMID- 30477574 TI - Innominate artery bifurcation pseudoaneurysm repair by "kissing stent-grafts technique": a case report. AB - BACKGROUND: We introduce the "kissing stent-grafts technique" for a patient who suffered from a pseudoaneurysm in bifurcation of innominate artery. This technique repaired an innominate artery bifurcation pseudoaneurysm; it successfully isolated the pseudoaneurysm and preserved both right subclavian and right common carotid artery. CASE PRESENTATION: A 60-year-old Asian (Chinese) woman complained of discovering a cervical pulsatile mass. A pseudoaneurysm at the location of innominate artery bifurcation is a rare and difficult situation that should be treated by vascular surgeons. To our knowledge, this is the first case to use the "kissing stent-grafts technique" in treating innominate bifurcation pseudoaneurysm. With this minimally invasive endovascular treatment, our patient avoided open surgery and recovered quickly. CONCLUSIONS: When treating vascular lesions with complicated anatomy, endovascular treatment always has the merit of being minimally invasive. "Kissing stent-grafts technique" can be useful in locations other than coronary and aortic bifurcation. PMID- 30477575 TI - The 150 most important questions in cancer research and clinical oncology series: questions 94-101 : Edited by Cancer Communications. AB - Since the beginning of 2017, Cancer Communications (former title: Chinese Journal of Cancer) has published a series of important questions regarding cancer research and clinical oncology, to provide an enhanced stimulus for cancer research, and to accelerate collaborations between institutions and investigators. In this edition, the following 8 valuable questions are presented. Question 94. The origin of tumors: time for a new paradigm? Question 95. How can we accelerate the identification of biomarkers for the early detection of pancreatic ductal adenocarcinoma? Question 96. Can we improve the treatment outcomes of metastatic pancreatic ductal adenocarcinoma through precision medicine guided by a combination of the genetic and proteomic information of the tumor? Question 97. What are the parameters that determine a competent immune system that gives a complete response to cancers after immune induction? Question 98. Is high local concentration of metformin essential for its anti-cancer activity? Question 99. How can we monitor the emergence of cancer cells anywhere in the body through plasma testing? Question 100. Can phytochemicals be more specific and efficient at targeting P-glycoproteins to overcome multi-drug resistance in cancer cells? Question 101. Is cell migration a selectable trait in the natural evolution of carcinoma? PMID- 30477576 TI - Interventions to reduce readmissions: can complex adaptive system theory explain the heterogeneity in effectiveness? A systematic review. AB - BACKGROUND: Successfully transitioning patients from hospital to home is a complex, often uncertain task. Despite significant efforts to improve the effectiveness of care transitions, they remain a challenge across health care systems. The lens of complex adaptive systems (CAS) provides a theoretical approach for studying care transition interventions, with potential implications for intervention effectiveness. The aim of this study is to examine whether care transition interventions that are congruent with the complexity of the processes and conditions they are trying to improve will have better outcomes. METHODS: We identified a convenience sample of high-quality care transition intervention studies included in a care transition synthesis report by Kansagara and colleagues. After excluding studies that did not meet our criteria, we scored each study based on (1) the presence or absence of 5 CAS characteristics (learning, interconnections, self-organization, co-evolution, and emergence), as well as system-level interdependencies (resources and processes) in the intervention design, and (2) scored study readmission-related outcomes for effectiveness. RESULTS: Forty-four of the 154 reviewed articles met our inclusion criteria; these studies reported on 46 interventions. Nearly all the interventions involved a change in interconnections between people compared with care as usual (96% of interventions), and added resources (98%) and processes (98%). Most contained elements impacting learning (67%) and self-organization (69%). No intervention reflected either co-evolution or emergence. Almost 40% of interventions were rated as effective in terms of impact on hospital readmissions. Chi square testing for an association between outcomes and CAS characteristics was not significant for learning or self-organization, however interventions rated as effective were significantly more likely to have both of these characteristics (78%) than interventions rated as having no effect (32%, p = 0.005). CONCLUSIONS: Interventions with components that influenced learning and self-organization were associated with a significant improvement in hospital readmissions-related outcomes. Learning alone might be necessary but not be sufficient for improving transitions. However, building self-organization into the intervention might help people effectively respond to problems and adapt in uncertain situations to reduce the likelihood of readmission. PMID- 30477578 TI - Forced turnover of aged microglia induces an intermediate phenotype but does not rebalance CNS environmental cues driving priming to immune challenge. AB - Microglia are the resident innate immune cells of the central nervous system. Limited turnover throughout the lifespan leaves microglia susceptible to age associated dysfunction. Indeed, we and others have reported microglia develop a pro-inflammatory or "primed" profile with age, characterized by increased expression of inflammatory mediators (e.g., MHC-II, CD68, IL-1beta). Moreover, immune challenge with lipopolysaccharide (LPS) causes an exaggerated and prolonged neuroinflammatory response mediated by primed microglia in the aged brain. Recent studies show colony-stimulating factor 1 receptor (CSF1R) antagonism results in rapid depletion of microglia without significant complications. Therefore, we hypothesized that CSF1R antagonist-mediated depletion of microglia in the aged brain would result in repopulation with new and unprimed microglia. Here we provide novel evidence that microglia in the brain of adult (6-8 weeks old) and aged (16-18 months old) BALB/c mice were depleted following 3-week oral PLX5622 administration. When CSF1R antagonism was stopped, microglia repopulated equally in the adult and aged brain. Microglial depletion and repopulation reversed age-associated increases in microglial CD68+ lysosome enlargement and lipofuscin accumulation. Microglia-specific RNA sequencing revealed 511 differentially expressed genes with age. Of these, 117 genes were reversed by microglial repopulation (e.g., Apoe, Tgfb2, Socs3). Nevertheless, LPS challenge still induced an exaggerated microglial inflammatory response in the aged brain compared to adults. RNA sequencing of whole-brain tissue revealed an age-induced inflammatory signature, including reactive astrocytes, that was not restored by microglial depletion and repopulation. Furthermore, the microenvironment of the aged brain produced soluble factors that influenced developing microglia ex vivo and induced a profile primed to LPS challenge. Thus, the aged brain microenvironment promotes microglial priming despite repopulation of new microglia. Collectively, aged microglia proliferate and repopulate the brain, but these new cells still adopt a pro-inflammatory profile in the aged brain. PMID- 30477577 TI - Pain management in living related adult donor hepatectomy: feasibility of an evidence-based protocol in 100 consecutive donors. AB - OBJECTIVE: Living donor hepatectomy (LDH) has important consequences in terms of acute and chronic pain. We proposed an anesthetic protocol based on the best currently available evidence. We report the results of this protocol's application. RESULTS: We performed a retrospective descriptive study of 100 consecutive donors undergoing LDH. The protocol included standardized information provided by the anesthetist, pharmacological anxiolysis and preventive analgesia. Specifically, pregabalin premedication (opioid-free) intravenous anesthesia (with clonidine, ketamine, magnesium sulphate and ketorolac) and epidural analgesia were proposed. Postoperative follow-up was conducted by the Postoperative Pain Service. This analysis included 100 patients (53 women, 47 men, median age 32.7 years old [28.4-37.3]), operated by xypho-umbilical laparotomy. All elements of our anesthetic protocol were applied in over 75% of patients, except for the preoperative consultation with a senior anesthesiologist (55%). The median number of applied item was 7 [interquartile range, IQR 5-7]. Median postoperative pain scores were, at rest and at mobilization respectively 3 [IQR 2-4] and 6 [IQR 4.5 7] on day 1; 2 [IQR 1-3] and 5 [IQR 3-6] on day 2; and 2 [IQR 0-3] and 4 [IQR 3 5] on day 3. In conclusion, LDH leads to severe acute pain. Despite the proposal of a multimodal evidence-based protocol, its applicancy was not uniform and the pain scores remained relatively high. PMID- 30477580 TI - A comparison between raw and predicted mortality in a paediatric intensive care unit in South Africa. AB - OBJECTIVE: Paediatric intensive care resources are limited in sub-Saharan Africa. The mortality rate in a combined Paediatric/Neonatal Intensive Care Unit in Johannesburg, South Africa was almost double that in a dedicated paediatric intensive care unit in the same country. This study aimed to compare the raw mortality rate with that predicted with the Paediatric Index of Mortality (version 3), by doing a retrospective analysis of an existing database. RESULTS: A total of 530 patients admitted to the intensive care unit between 1 January 2015 and 31 December 2017 were included. The raw mortality rate was 27.1% and the predicted mortality rate was 27.0% (p = 0.971). Cardiac arrest during ICU admission (p < 0.001), non-reactive pupils (0.035), inotropic support (p < 0.001) and renal disease (p = 0.002) were all associated with an increased risk of mortality. These findings indicate that the high mortality rate is due to the severity of illness in the patients that are admitted. It also indicates that the quality of care delivered is acceptable. PMID- 30477579 TI - Effects of ambient carbon monoxide on daily hospitalizations for cardiovascular disease: a time-stratified case-crossover study of 460,938 cases in Beijing, China from 2013 to 2017. AB - BACKGROUND: Evidence focused on exposure to ambient carbon monoxide (CO) and the risk of hospitalizations for cardiovascular diseases (CVD) is lacking in developing countries. This study aimed to examine the effect of CO exposure on hospitalizations for CVD in Beijing, China. METHODS: A total of 460,938 hospitalizations for cardiovascular diseases were obtained from electronic hospitalization summary reports from 2013 to 2017. A time-stratified case crossover design was conducted to investigate the association between CO exposure and hospitalizations for total and cause-specific CVD, including coronary heart disease (CHD), atrial fibrillation (AF), and heart failure (HF). Stratified analysis was also conducted by age group (18-64 years and >= 65 years) and sex. RESULTS: Linear exposure-response curves for the association between ambient CO exposure and hospitalizations for CVD was observed. Ambient CO was positively associated with hospitalizations for total CVD and CHD. However, the observed increased risk was not statistically significant for hospitalizations for AF and HF. The strongest effect of CO concentration was observed on the current- and previous-day of exposure (lag 0-1 day). For a 1 mg/m3 increase in a 2-day moving average CO concentration, an increase of 2.8% [95% confidence interval (CI): 2.2 to 3.3%] and 3.0% (95% CI: 2.4 to 3.6%) in daily hospital admissions for CVD and CHD were estimated, respectively. This association was robust after adjusting for other copollutants and did not vary by age group and sex. CONCLUSIONS: Ambient CO exposure increased the risk of hospitalizations for CVD, especially for CHD in Beijing. Further studies are warranted to explore the association between ambient CO and hospitalizations for AF and HF. PMID- 30477581 TI - HIV-1 immunogens and strategies to drive antibody responses towards neutralization breadth. AB - Despite enormous efforts no HIV-1 vaccine has been developed that elicits broadly neutralizing antibodies (bNAbs) to protect against infection to date. The high antigenic diversity and dense N-linked glycan armor, which covers nearly the entire HIV-1 envelope protein (Env), are major roadblocks for the development of bNAbs by vaccination. In addition, the naive human antibody repertoire features a low frequency of exceptionally long heavy chain complementary determining regions (CDRH3s), which is a typical characteristic that many HIV-1 bNAbs use to penetrate the glycan armor. Native-like Env trimer immunogens can induce potent but strain-specific neutralizing antibody responses in animal models but how to overcome the many obstacles towards the development of bNAbs remains a challenge. Here, we review recent HIV-1 Env immunization studies and discuss strategies to guide strain-specific antibody responses towards neutralization breadth. PMID- 30477582 TI - Evaluation of the prognostic value of paraoxonase 1 in the recurrence and metastasis of hepatocellular carcinoma and establishment of a liver-specific predictive model of survival. AB - BACKGROUND: Hepatocellular carcinoma is a malignant tumor with a highly invasive and metastatic phenotype, and the detection of potential indicators associated with its recurrence and metastasis after surgical resection is critical for patient survival. METHODS: Transcriptome data for large cohorts (n = 1432) from multicenter sources were comprehensively analyzed to explore such potential signatures. The prognostic value of the selected indicators was investigated and discussed, and a comparison with conventional clinicopathological features was performed. A survival predictive nomogram for 5-year survival was established with the selected indicator using the Cox proportional hazards regression. To validate the indicator at the protein level, we performed immunohistochemical staining with paraffin-embedded slides of hepatocellular carcinoma samples (n = 67 patients) from our hospital. Finally, a gene set enrichment analysis (GSEA) was performed to detect the underlying biological processes and internal mechanisms. RESULTS: The liver-specific protein paraoxonase 1 (PON1) was found to be the most relevant indicator of tumor recurrence, invasiveness, and metastasis in the present study, and the downregulation of PON1 might reveal poor survival for patients with hepatocellular carcinoma. The C-index of the PON1-related nomogram was 0.714, thus indicating a more effective predictive performance than the 7th American Joint Committee on Cancer (AJCC) tumor stage (0.534), AJCC T stage (0.565), or alpha-fetoprotein (0.488). The GSEA revealed that PON1 was associated with several hepatocellular carcinoma-related pathways, including the cell cycle, DNA replication, gap junction and p53 downstream pathways. CONCLUSIONS: The downregulation of paraoxonase 1 may suggest worse outcomes and a higher recurrence rate. Thus, paraoxonase 1 might represent an indicator for predicting the survival of patients with hepatocellular carcinoma. PMID- 30477584 TI - Evaluation of a short, interactive diabetes self-management program by pharmacists for type 2 diabetes. AB - OBJECTIVE: Numerous barriers prevent patients with type 2 diabetes (T2D) from completing a diabetes self-management program. We investigated whether patients with T2D exhibited improved clinical outcomes after attending a relatively short, interactive diabetes self-management program conducted by pharmacist diabetes educators, compared to a physician's usual care. RESULTS: We retrospectively analyzed the data of adults with T2D who attended a diabetes self-management program (>= 1 group meeting or individual appointment followed by a telephone interview from a pharmacist diabetes educator between May 2010 and Dec. 2012; n = 513) and compared their outcomes with those of T2D patients who received only their physician's usual care (n = 857). Each patient's A1C was assessed at baseline, 3 months, and 6 months post-intervention. The mean [SD] reduction in A1C percentage points in the T2D patients was significantly greater in the diabetes self-management program group compared to the physician's usual care group at both 3 months (- 0.8% [1.5] vs. - 0.2% [0.9], p < 0.001) and 6 months post-intervention (- 0.6% [1.3] vs. - 0.2% [1.1], p < 0.001). T2D patients significantly improved their glycemic control within 3-6 months of attending the diabetes self-management program compared to patients who only received their physician's usual care. PMID- 30477583 TI - Immune cell phenotype and functional defects in Netherton syndrome. AB - BACKGROUND: Netherton syndrome (NS) is a rare life-threatening syndrome caused by SPINK5 mutations leading to a skin barrier defect and a severe atopic diathesis. NS patients are prone to bacterial infections, but the understanding of the underlying immune deficiency is incomplete. RESULTS: We analyzed blood lymphocyte phenotypes and function in relation to clinical infections in 11 Finnish NS patients, aged 3 to 17 years, and healthy age-matched controls. The proportion of B cells (CD19+) and naive B cells (CD27-, IgD+) were high while memory B cells (CD27+) and switched memory B cells (CD27+IgM-IgD-), crucial for the secondary response to pathogens, was below or in the lowest quartile of the reference values in 8/11 (73%) and 9/11 (82%) patients, respectively. The proportion of activated non-differentiated B cells (CD21low, CD38low) was below or in the lowest quartile of the reference values in 10/11 (91%) patients. Despite normal T cell counts, the proportion of naive CD4+ T cells was reduced significantly and the proportion of CD8+ T central memory significantly elevated. An increased proportion of CD57+ CD8+ T cells indicated increased differentiation potential of the T cells. The proportion of cytotoxic NK cells was elevated in NS patients in phenotypic analysis based on CD56DIM, CD16+ and CD27- NK cells but in functional analysis, decreased expression of CD107a/b indicated impaired cytotoxicity. The T and NK cell phenotype seen in NS patients also significantly differed from that of age-matched atopic dermatitis (AD) patients, indicating a distinctive profile in NS. The frequency of skin infections correlated with the proportion of CD62L+ T cells, naive CD4+ and CD27+ CD8+ T cells and with activated B cells. Clinically beneficial intravenous immunoglobulin therapy (IVIG) increased naive T cells and terminal differentiated effector memory CD8+ cells and decreased the proportion of activated B cells and plasmablasts in three patients studied. CONCLUSIONS: This study shows novel quantitative and functional aberrations in several lymphocyte subpopulations, which correlate with the frequency of infections in patients with Netherton syndrome. IVIG therapy normalized some dysbalancies and was clinically beneficial. PMID- 30477585 TI - Pooled extracellular receptor-ligand interaction screening using CRISPR activation. AB - Extracellular interactions between cell surface receptors are necessary for signaling and adhesion but identifying them remains technically challenging. We describe a cell-based genome-wide approach employing CRISPR activation to identify receptors for a defined ligand. We show receptors for high-affinity antibodies and low-affinity ligands can be unambiguously identified when used in pools or as individual binding probes. We apply this technique to identify ligands for the adhesion G-protein-coupled receptors and show that the Nogo myelin-associated inhibitory proteins are ligands for ADGRB1. This method will enable extracellular receptor-ligand identification on a genome-wide scale. PMID- 30477586 TI - Perception of childhood anaemia among mothers in Kumasi: a quantitative approach. AB - BACKGROUND: Anaemia is the world's second cause of disability and it affects over half of pre-school children in developing countries and at least 30-40% in industrial countries. In poorer malaria-endemic countries, anemia is one of the commonest preventable causes of death in children under 5 years. This study sought to determine the perceived causes, signs and symptoms as well prevention of childhood anaemia among mothers of children under 5 years in Kumasi, Ghana. METHODS: A descriptive hospital-based cross-sectional study design with a sample of 228 patients attending the University Hospital, KNUST was used. A simple random sampling technique was applied in sampling and a structured questionnaire was used to collect data which was analyzed using SPSS statistical tools. RESULTS: The study found that anemia was mostly perceived to be caused by poor feeding practices (43%) and fever (37%). The signs and symptoms mentioned mostly were pale conjunctiva (47%) and pale palm (44%). It was suggested that it could be prevented by giving adequate nutrition (23%), regular deworming (19%) as well as exclusive breastfeeding (25%). Mothers education and the number of children were found to be associated with the perception regarding anaemia as respondents who had completed SHS/A level were 5.14 times likely to have a higher knowledge score on Anaemia (AOR = 5.14; 95% CI; 1.01-21.8). Also, mothers who had 5 to 6 children were 1.65 times likely to have higher knowledge score on Anaemia (AOR = 1.65; 95% CI; 0.02-2.32). CONCLUSION: Previous experience with Anaemia and higher educational level results in better understanding of Anaemia. Therefore, extensive health education on anemia should be undertaken by the hospital authorities in collaboration with the Ministry of Health to improve knowledge of Anaemia. PMID- 30477587 TI - Mono, bi- and tri-exponential diffusion MRI modelling for renal solid masses and comparison with histopathological findings. AB - PURPOSE: To compare diffusion tensor imaging (DTI), intravoxel incoherent motion (IVIM), and tri-exponential models of the diffusion magnetic resonance imaging (MRI) signal for the characterization of renal lesions in relationship to histopathological findings. METHODS: Sixteen patients planned to undergo nephrectomy for kidney tumour were scanned before surgery at 3 T magnetic resonance imaging (MRI), with T2-weighted imaging, DTI and diffusion weighted imaging (DWI) using ten b-values. DTI parameters (mean diffusivity [MD] and fractional anisotropy [FA]) were obtained by iterative weighted linear least squared fitting of the DTI data and bi-, and tri-exponential fit parameters (Dbi, fstar,and Dtri, ffast,finterm) using a nonlinear fit of the multiple b-value DWI data. Average parameters were calculated for regions of interest, selecting the lesions and healthy kidney tissue. Tumour type and specificities were determined after surgery by histological examination. Mean parameter values of healthy tissue and solid lesions were compared using a Wilcoxon-signed ranked test and MANOVA. RESULTS: Thirteen solid lesions (nine clear cell carcinomas, two papillary renal cell carcinoma, one haemangioma and one oncocytoma) and four cysts were included. The mean MD of solid lesions are significantly (p < 0.05) lower than healthy cortex and medulla, (1.94 +/- 0.32*10- 3 mm2/s versus 2.16 +/- 0.12*10- 3 mm2/s and 2.21 +/- 0.14*10- 3 mm2/s, respectively) whereas ffast is significantly higher (7.30 +/- 3.29% versus 4.14 +/- 1.92% and 4.57 +/- 1.74%) and finterm is significantly lower (18.7 +/- 5.02% versus 28.8 +/- 5.09% and 26.4 +/- 6.65%). Diffusion coefficients were high (>=2.0*10- 3 mm2/s for MD, 1.90*10- 3 mm2/s for Dbi and 1.6*10- 3 mm2/s for Dtri) in cc-RCCs with cystic structures and/or haemorrhaging and low (<=1.80*10- 3 mm2/s for MD, 1.40*10- 3 mm2/s for Dbi and 1.05*10- 3 mm2/s for Dtri) in tumours with necrosis or sarcomatoid differentiation. CONCLUSION: Parameters derived from a two- or three-component fit of the diffusion signal are sensitive to histopathological features of kidney lesions. PMID- 30477588 TI - Temporal trend of the proportion of patients presenting with advanced HIV in French Guiana: stuck on the asymptote? AB - OBJECTIVE: In French Guiana, the French territory with the most preoccupying HIV epidemic, there have been great efforts to intensify and diversify HIV testing strategies. The aim of the present study was to review the temporal trends of patients diagnosed with advanced HIV disease in French Guiana. Data trends from the HIV cohort of French Guiana between 1996 and 2016 were thus analyzed. RESULTS: The proportion of patients diagnosed with advanced disease did not decline over time. Males had lower CD4 counts at the time of diagnosis and there was a plateau for both males (around 40%) and females (around 25%) with no apparent reduction of the proportion of advanced disease. Older age groups and migrants presented more often with advanced disease. By contrast, the proportion of patients diagnosed with stage B and C disease declined over time and the CD4 count at antiretroviral initiation and the CD4 nadir increased over time. Despite some progress, the group of patients with advanced disease reached a plateau around 30% suggesting this particular group still has epidemiological importance in driving the epidemic and in fueling morbidity and mortality, and thus remains a challenge for testing strategies. PMID- 30477589 TI - Centrality of Event and Mental Health Outcomes in Child and Adolescent Natural Disaster Survivors. AB - The experience of trauma could be considered a central event in one's life, such that it could be a core component of one's identity and life story. Indeed, trauma memories are well-remembered, vivid, intense, and easily accessible (Berntsen & Rubin, 2006). The present study investigated the mediating role of sensory-based trauma memory quality in the relationship between centrality of event and mental health outcomes among child and adolescent survivors of a natural disaster (N = 225) in its immediate aftermath. Results of mediation analyses revealed that centrality of trauma event is related to symptoms of acute stress disorder and depression through sensory-based trauma memory quality (indirect effect 95% C.I. [.06, .11] and [.04, .10], respectively). These findings support the contention that centrality of event is associated to heightened accessibility and vividness of sensory-based trauma memory quality, which in turn is related to an increase in trauma-related symptoms in the immediate aftermath of a natural disaster, where the reminders of trauma are particularly salient in the survivors' environment and daily activities. PMID- 30477590 TI - Psychometric Properties of the French Version of the Young Schema Questionnaire - Short Form 3 (YSQ-S3). AB - The purpose was to assess the psychometric properties of the French version of the Young Schema Questionnaire - Short Form 3 (YSQ-S3). The main non-clinical sample (N = 605, M = 20.63, 78% women) was divided into two subsamples: One was used for exploratory factor analyses (EFA) and the other was used for confirmatory analyses. Next, internal consistency, convergent validity and criterion-related validity were studied. The EFA to each of the five domains was similar to the theoretical structure postulated by Young. The confirmatory analysis of each of the five domains appeared to favor our solution over a single factor solution and Young's solution. The confirmatory factor analyses of high order structures did not give fully satisfactory results but appeared to favor our solution (RMSEA =.11, CFI =.76, TLI =.71, SRMR =.07, AIC = 58,566.44). In our best model, the reliability (> .70) was satisfactory for fourteen schemas. The relationships between the schemas and the neuroticism, extraversion and psychoticism scores went in the expected directions. Detrimental parental rearing behaviors were linked to high scores for the various schemas. Lastly, 4 schemas differentiated between the clinical and non-clinical groups. In conclusion, the overall psychometric qualities of the French version of the YSQ-S3 allow its use in clinical populations. PMID- 30477591 TI - Phenology of the sugar beet weevil, Bothynoderes punctiventris Germar (Coleoptera: Curculionidae), in Croatia. AB - The sugar beet weevil (SBW), Bothynoderes punctiventris Germar, 1824, is a significant pest in most of Eastern Europe. Here, the SBW is described and its seasonal activity characterized, in terms of its different developmental stages in relation to Julian days (JDs), degree-day accumulations (DDAs), and precipitation, as a key to improving monitoring and forecasting of the pest. The phenology and population characteristics of SBW were investigated in sugar beet fields in eastern Croatia over a 4-year period (2012-2015). By using the degree day model (lower development threshold of 5 degrees C, no upper development threshold, biofix 1 January), the first emergence of overwintering adults was determined as becoming established when the DDA reached 20. The adult emergence was completed when the DDA reached 428. SBW males emerged first, following which the females dominated the adult population. Overwintering adults were present in the field until early July. In August, adults of the offspring generation began to appear. The eggs laid by the overwintering generation required, on average, 10 15 days to develop into larvae; however, eggs were found in soil samples over a period of 102 days (between JDs 112 and 214). Larvae were present in the soil samples over a period of a maximum of 143 days (the first larvae were established on JD 122 and the last one on JD 265), and pupae were established in the soil over a period of 102 days (between JDs 143 and 245). This study provides important data for understanding SBW population dynamics and developing potential population dynamic models for pest forecasting on a regional scale. PMID- 30477592 TI - Timing of Parents' Concerns Related to Autism Spectrum Disorder and its Diagnosis: A Mediation Analysis. AB - Parents are the first to indicate concerns about their child's development in up to 80% of children with autism spectrum disorder (ASD). They often notice symptoms related to ASD around the first two years, but the average age of diagnosis is 3.5 years old. This study examined the relationships between parents' early concerns and the time lag between suspicion and diagnosis. Forty eight Spanish-speaking families were enrolled in this study. Parents were asked about early signs that made them think that their child could possibly have ASD. Mediation analyses showed that the child's age at suspicion mediated between sibling status and the time lag between suspicion and a formal diagnosis (beta = .53, p < .01). Having another child with typical development accelerated parents' detection of ASD signs (beta = -.62, p < .001). The number of social communication concerns that parents detected mediated this relationship (beta = .28, p < .01). Parents who reported more social-communication concerns perceived these signs earlier, but have to cope with a longer time lag until diagnosis than those who reported more concerns related to restrictive and repetitive behaviors and interests, or other developmental concerns. Moreover, this relationship between concerns of ASD and the diagnoses was explained by the child's age. Training pediatricians on how to respond to parent questions and concerns could reduce the time lag between parents' concerns and diagnosis of ASD. PMID- 30477593 TI - Trends of serum phospholipid fatty acids over time in rural Uganda: evidence of nutritional transition? AB - Non-communicable diseases are projected to become the most common causes of death in Africa by 2030. The impact on health of epidemiological and nutritional transitions in sub-Saharan Africa remains unclear. To assess the trends of dietary fatty acids over time in Uganda, we examined fatty acids in serum collected from individuals in rural south-west Uganda, at three time points over two decades. Independent cross-sectional samples of 915 adults and children were selected from the general population cohort in 1990 (n 281), 2000 (n 283) and 2008 (n 351). Serum phospholipid fatty acids were measured by GC. Multivariate regression analyses were performed to compare the geometric means of fatty acids by time period. Serum fatty acid profiling showed high proportions of SFA, cis MUFA and industrial trans-fatty acids (iTFA), likely to be biomarkers of high consumption of palm oil and hydrogenated fats. In contrast, proportions of n-6 and n-3 PUFA from vegetable oils and fish were low. From 1990 to 2008, serum phospholipids showed increases in absolute amounts of SFA (17.3 % increase in adults and 26.4 % in children), MUFA (16.7 % increase in adults and 16.8 % in children) and n-6:n-3 PUFA (40.1 % increase in adults and 39.8 % in children). The amount of elaidic acid, iTFA from hydrogenated fats, increased in children (60.1 % increase). In this rural Ugandan population, we show evidence of unfavourable trends over time of dietary fatty acids. PMID- 30477594 TI - Altered functional connectivity in the fear network of firefighters with repeated traumatic stress. AB - BACKGROUND: Firefighters are routinely exposed to various traumatic events and often experience a range of trauma-related symptoms. Although these repeated traumatic exposures rarely progress to the development of post-traumatic stress disorder, firefighters are still considered to be a vulnerable population with regard to trauma.AimsTo investigate how the human brain responds to or compensates for the repeated experience of traumatic stress. METHOD: We included 98 healthy firefighters with repeated traumatic experiences but without any diagnosis of mental illness and 98 non-firefighter healthy individuals without any history of trauma. Functional connectivity within the fear circuitry, which consists of the dorsal anterior cingulate cortex, insula, amygdala, hippocampus and ventromedial prefrontal cortex (vmPFC), was examined using resting-state functional magnetic resonance imaging. Trauma-related symptoms were evaluated using the Impact of Event Scale - Revised. RESULTS: The firefighter group had greater functional connectivity between the insula and several regions of the fear circuitry including the bilateral amygdalae, bilateral hippocampi and vmPFC as compared with healthy individuals. In the firefighter group, stronger insula amygdala connectivity was associated with greater severity of trauma-related symptoms (beta = 0.36, P = 0.005), whereas higher insula-vmPFC connectivity was related to milder symptoms in response to repeated trauma (beta = -0.28, P = 0.01). CONCLUSIONS: The current findings suggest an active involvement of insular functional connectivity in response to repeated traumatic stress. Functional connectivity of the insula in relation to the amygdala and vmPFC may be potential pathways that underlie the risk for and resilience to repeated traumatic stress, respectively.Declaration of interestNone. PMID- 30477595 TI - Informed choice or guessing game? Understanding caregivers' perceptions and use of infant formula labelling. AB - OBJECTIVE: Although breast-feeding is the recommended way to feed an infant, a safe and nutritious substitute for breast milk is needed for infants who are not breast-fed. Labelling information on infant formula (IF) products aims to enable caregivers (who have already made the decision to use IF) to make informed product choices. Yet, there is limited data on how caregivers understand and use the information provided on IF packaging. The present study aimed to increase understanding of caregivers' interpretation and use of the following label elements on IF products: the nutrition information statement; the ingredients list; and statements around nutrition content and health claims. DESIGN: Qualitative data were obtained from twenty-one focus group discussions. To enable comparison of findings by education level and ethnicity, focus group participants were homogeneous with respect to educational attainment (Australian groups) or ethnic background (New Zealand groups). SETTING: Focus groups were conducted in metropolitan and regional areas of Australia and New Zealand.ParticipantsCaregivers (n 136) of formula-fed infants. RESULTS: Framework analysis revealed that caregivers commonly experience difficulties when using labelling information, particularly when trying to identify and understand key differences between products. Moreover, comparing products can be a complex task regardless of education level and ethnicity. CONCLUSIONS: Further research is required to determine the most effective strategies for meeting information needs of caregivers and allowing easier identification and understanding of product differences. This is especially important given that the vast range of IF products across large price ranges in the market adds to the complexity of purchase decisions. PMID- 30477596 TI - Description of the home food environment in Black, White, Hmong, Latino, Native American and Somali homes with 5-7-year-old children. AB - OBJECTIVE: To categorize the home food environment and dietary intake of young children (5-7 years old) from racially/ethnically diverse households using objectively collected data. DESIGN: Cross-sectional study. SETTING: In-home observations in Minneapolis/Saint Paul, Minnesota, USA. SUBJECTS: Families with 5 7-year-old children who identified as Black, White, Hmong, Latino, Native American or Somali. RESULTS: There were many significant differences by race/ethnicity for child dietary intake and for the home food environment, with specific patterns emerging by race/ethnicity. For example, Somali children had high Healthy Eating Index-2010 (HEI-2010) scores, but low daily intakes of fruits and vegetables. Black children had low HEI-2010 scores and a pattern of low intake of healthful foods and high intake of unhealthful foods. White and Latino families had high levels of both healthful and unhealthful home food availability and children with high HEI-2010 scores. CONCLUSIONS: Results indicate that the home food environment of young children varies across racial/ethnic group. Study findings also provide new information regarding the home food environment of young children in previously understudied racial/ethnic groups and indicate that interventions working to improve the home food environment and dietary intake of children may want to consider race/ethnicity. PMID- 30477597 TI - Validation of the Bipolar Spectrum Diagnostic Scale in Mexican Psychiatric Patients. AB - The Bipolar Spectrum Diagnostic Scale (BSDS) is widely validated and used as a screening tool for bipolar disorder. However, there is no BSDS validated version for its use in Mexican population. The aim of the present study was to examine the BSDS diagnostic capacity, and to evaluate its criterion validity and internal consistency for its use in Mexican psychiatric patients. We recruited 200 patients who attended the psychiatric outpatient service of a Mental Health Specialized Hospital and were screened for bipolar disorder using BSDS. To determine the cut-off point, sensitivity and specificity, we used the SCID-I diagnosis as the gold standard in 100 participants with bipolar disorder and 100 with major depression. Internal consistency according to Cronbach's coefficient alpha was .81. The area under ROC curve for the overall discriminability of BSDS against the criterion of SCID-I for bipolar disorder was .90. Finally, a cut-off value of 12 reached the most stable sensitivity and specificity, with predictive powers higher than .80. In conclusion, the properties of the scale including internal consistency, sensitivity and specificity, make of BSDS a valuable instrument for screening bipolar disorder in Mexican psychiatric population. PMID- 30477598 TI - Exploring the homolog of a novel proinflammatory microfilarial sheath protein (MfP) of Wuchereria bancrofti in the adult-stage bovine filarial parasite Setaria cervi. AB - A novel microfilarial sheath protein (MfP) of the human filarial parasite Wuchereria bancrofti and its proinflammatory activity on host macrophages were identified recently. MfP is a homolog of the nematode bestrophin-9 superfamily that acts as a ligand of macrophage Toll-like receptor 4 (TLR4) to induce inflammation through NF-kappaB activation. Therefore, the presence and functional implication of this novel protein in adult-stage parasites were open questions to answer. In this study, the bovine filarial parasite Setaria cervi was used to simulate adult W. bancrofti. We detected the presence of MfP in adult-stage S. cervi through clear immunological cross-reactivity and immunolocalization employing an anti-MfP antibody developed in mice. Therefore, our findings put forward S. cervi as a cost-effective source of immunodominant filarial antigen MfP to simulate its future utilization in the immunotherapeutic intervention of lymphatic filariasis. PMID- 30477599 TI - Treatment resistant schizophrenia - review and a call to action. AB - Recovery rates in schizophrenia remain suboptimal with up to one-third resistant to standard treatments, a population prevalence of 0.2%. Clozapine is the only evidenced-based treatment for treatment resistant schizophrenia (TRS), yet there are significant delays in its use or it may not be trialled, potentially impacting the chance of recovery. Better outcomes with earlier use of clozapine may be possible. There is emerging evidence that early treatment resistance is not uncommon from the earliest stages of psychosis. In this review, we provide an update on TRS, its epidemiology and its management, with a specific focus on the optimal use and timing of clozapine and augmentation strategies for the one-third of patients who do not respond to clozapine. PMID- 30477600 TI - A critical review of the role of milk and other dairy products in the development of obesity in children and adolescents. AB - Existing reviews suggest that milk and other dairy products do not play a role in the development of obesity in childhood, but they do make an important contribution to children's nutrient intake. It is thus curious that public health advice on the consumption of dairy products for children is often perceived as unclear. The present review aimed to provide an overview of the totality of the evidence on the association between milk and other dairy products, and obesity and indicators of adiposity, in children. Our search identified forty-three cross sectional studies, thirty-one longitudinal cohort studies and twenty randomised controlled trials. We found that milk and other dairy products are consistently found to be not associated, or inversely associated, with obesity and indicators of adiposity in children. Adjustment for energy intake tended to change inverse associations to neutral. Also, we found little evidence to suggest that the relationship varied by type of milk or dairy product, or age of the children, although there was a dearth of evidence for young children. Only nine of the ninety-four studies found a positive association between milk and other dairy products and body fatness. There may be some plausible mechanisms underlying the effect of milk and other dairy products on adiposity that influence energy and fat balance, possibly through fat absorption, appetite or metabolic activity of gut microbiota. In conclusion, there is little evidence to support a concern to limit the consumption of milk and other dairy products for children on the grounds that they may promote obesity. PMID- 30477601 TI - Contribution of the Five Factors of Personality and Peers on Adolescent Alcohol Use: A Cross-National Study. AB - Personality characteristics such as extraversion, low agreeableness and low conscientiousness are relevant for alcohol use during adolescence. In addition, having friends who use alcohol is one of the strongest predictors of adolescent alcohol consumption and its negative outcomes. The selection model posits that friends display similar alcohol consumption when their friendships are formed on the basis of common characteristics as, among others, personality. Thus, the aim of this study was to examine the mediation role of peers in the association between the five-factor model of personality and adolescent alcohol use in two cultures. One hundred and twenty Scottish and 221 Spanish respondents, all aged 12-15 years, answered the Alcohol Intake Scale (AIS). Adolescents were asked about the alcohol used at the weekend and also about the alcohol consumed by their friends. Scottish adolescents' personality was measured by the NEO Personality Inventory-3 (NEO-PI-3). The Junior Spanish version of the Revised NEO Personality Inventory (JS NEO) was used to assess personality in the Spanish sample. Low agreeableness and low conscientiousness correlated with own alcohol quantity in both countries. We performed an independent structural equation modeling for each country. Extraversion (beta = .205, p < .05) and low agreeableness (beta = -.196, p < .01) for Scottish adolescents, and low conscientiousness (beta = -.175, p < .05) for Spanish youths, predicted alcohol use through peer alcohol consumption at weekends. These findings support the relevance of personality traits and peer affiliation in relation to alcohol consumption in adolescence. PMID- 30477602 TI - Prediction of physical characteristics of the lamb carcass using in vivo bioimpedance analysis. AB - The increase of sheep meat competitiveness in international markets can be attributed to the rise of the quantity and the improvement of the quality of the edible portion of sheep carcasses. Usually, carcass yield is established after the slaughter of the animals. Yet, when carcass yield is determined in vivo, it can be both a costly and subjective method. This study proposes models for predicting the physical characteristics of lamb carcass using bioimpedance analysis (BIA) in live animals. Thirty-one Texel * Ile de France crossbreed ram lambs were slaughtered at 20, 26, 32 or 38 kg of BW. Before the slaughter, values of resistance (Rs) and reactance (Xc) were collected using a single-frequency BIA equipment (Model RJL Quantum II Bioelectrical Body Composition Analyzer). Then, BIA main variables such as body bioelectrical volume (V), phase angle (PA), resistive density (RsD) and reactive density (XcD) were calculated. After slaughter, cold carcass weight (CCW), cold carcass yield (CCY), subcutaneous fat thickness (SFT), soft tissue weight (STW) and soft tissue yield (STY) were also measured. Multiple regression analyses were carried out using the physical characteristics as dependent variables and the bioimpedance values as independent variables. Predictive performance of the models was assessed using leave-one-out cross-validation. The prediction model of CCW was obtained using the V, PA and RsD (R2 = 0.97), STW through the V, RsD and XcD (R2 = 0.97), CCY by Rs, Z and XcD (R2 = 0.69), STY by V and XcD (R2 = 0.67), and SFT only for XcD (R2 = 0.84). The results indicated that BIA has the potential to predict carcass characteristics of lambs at different body masses. PMID- 30477603 TI - Associations of adverse childhood experiences and social support with self injurious behaviour and suicidality in adolescents. AB - BACKGROUND: There is little investigation on the interaction effects of adverse childhood experiences (ACEs) and social support on non-suicidal self-injury (NSSI), suicidal ideation and suicide attempt in community adolescent populations, or gender differences in these effects.AimsTo examine the individual and interaction effects of ACEs and social support on NSSI, suicidal ideation and suicide attempt in adolescents, and explore gender differences. METHOD: A school based health survey was conducted in three provinces in China between 2013-2014. A total of 14 820 students aged 10-20 years completed standard questionnaires, to record details of ACEs, social support, NSSI, suicidal ideation and suicide attempt. RESULTS: Of included participants, 89.4% reported one or more category of ACEs. The 12-month prevalence of NSSI, suicidal ideation and suicide attempt was 26.1%, 17.5% and 4.4%, respectively; all were significantly associated with increased ACEs and lower social support. The multiple adjusted odds ratio of NSSI in low versus high social support was 2.27 (95% CI 1.85-2.67) for girls and 1.81 (95% CI 1.53-2.14) for boys, and their ratio (Ratio of two odds ratios, ROR) was 1.25 (P = 0.037). Girls with high ACEs scores (5-6) and moderate or low social support also had a higher risk of suicide attempt than boys (RORs: 2.34, 1.84 and 2.02, respectively; all P < 0.05). CONCLUSIONS: ACEs and low social support are associated with increased risk of NSSI and suicidality in Chinese adolescents. Strategies to improve social support, particularly among female adolescents with a high number of ACEs, should be an integral component of targeted mental health interventions.Declaration of interestNone. PMID- 30477604 TI - Determination of 2- and 3-MCPD as well as 2- and 3-MCPD Esters and Glycidyl Esters (GE) in Infant and Adult/Pediatric Nutritional Formula by Gas Chromatography Coupled to Mass Spectrometry Method, First Action 2018.03. AB - Background: Monochloropropanediol (MCPD) and its fatty acid esters as well as glycidyl fatty acid esters are substances generated during oil refining or food processing. The free form released during digestion, 3-MCPD and glycidol, have shown adverse effects in animal studies. Objective: So far, the available analytical methods have not been validated in a collaborative study for infant and adult nutritional formulas. This manuscript describes a single-laboratory validation method in view of a future multilaboratory validation trial. Methods: The method described is for the direct determination of 2- and 3-MCPD and indirect determination of 2- and 3-MCPD esters and glycidyl esters in infant and adult/pediatric nutritional formulas by GC coupled to MS. Results: The analytical range was found to be 4-2000 MUg/kg powder formula and 0.7-333 MUg/kg liquid formula for fatty acid esters of MCPD and glycidol, and 2.5-750 MUg/kg samples for free MCPD. The recovery rates were within 91-124% for all samples. Repeatability precision was <20% at levels close to the LOQ. Conclusions: The results met the Standard Method Performance Requirements(r) (SMPR) set by the AOAC Stakeholder Panel on Infant Formula and Adult Nutritionals. Highlights: The AOAC Expert Review Panel approved the present method as AOAC Official First Action 2018.03. PMID- 30477605 TI - Tracing the Geographical Origin of Roasted and Green Coffee Using Isotope Fingerprints. AB - Background: Coffee is one of the most popular beverages worldwide, sourced from different geographical regions. To ensure that coffee beans come from labelled locations, laboratories need an analytical solution that can discriminate geographical origin. Coffee beans have a fingerprint, a unique chemical signature that allows them to be identified: Isotope fingerprints of carbon, nitrogen, sulfur, hydrogen, and oxygen have been reliably used for origin claim verification. Objective: Show that hydrogen and oxygen isotope fingerprints from green and roasted coffee beans can determine the origin of coffee beans. Methods: The coffee beans were initially ground to as fine as possible a powder using a cryo-mill. Following, samples were weighed into tin capsules and introduced to the Thermo Scientific EA IsoLinkTM IRMS System via the Thermo Scientific MAS Plus autosampler, where they were pyrolyzed at 1450 degrees C, and converted to H2 and CO for analysis. Results: The hydrogen and oxygen isotope fingerprints of the coffee beans show that they can be clearly differentiated at the continent scale. Conclusions: It is evident that measuring the isotope fingerprint of coffee beans helps support legislation on food integrity and labelling (EC Reg. No. 1169/2011) and product geographical indication/origin (EC Reg. No. 510/2006), therefore protecting consumers and brands. The origin of a coffee bean can be determined using their hydrogen and oxygen isotope fingerprints. Highlights: Hydrogen and oxygen isotope fingerprints can help determine the origin of coffee beans, allowing the label claim to be verified. PMID- 30477606 TI - Patellar Tendon Stiffness in Elite Breakdancers Assessed by Myotonometric Measurement. AB - Studies that have investigated the epidemiology of injuries in breakdancing have concluded that the second most common injury site is the knee and that the majority of breakdancers have experienced overuse syndrome. Tendon stiffness, the relationship between force applied to a tendon and the resulting displacement, has been identified as a primary mechanical factor in such injuries. However, patellar tendon stiffness has not yet been evaluated in elite breakdancers. Hence, the purpose of this study was to determine mean patellar tendon stiffness in this population by using myotonometric measurements and to compare those results with healthy control subjects. Twenty-five elite male breakdancers and 25 male control subjects were included in the study. A Myoton Pro device was used to assess their tendon stiffness. The mean patellar tendon stiffness of the breakdancers was 1,045 +/- 202 Nm and 1,084 +/- 193 Nm for the dominant and non dominant limb, respectively; for the control group it was 902 +/- 166 Nm and 862 +/- 159 Nm for the dominant and non-dominant limb, respectively. Statistical analyses showed higher stiffness values for breakdancers compared to controls for both limbs. This is consistent with studies reporting patellar tendon adaptation after training. PMID- 30477607 TI - Influence of Mirror Feedback and Ankle Joint Laxity on Dynamic Balance in Trained Ballet Dancers. AB - Enhanced understanding of dynamic postural stability (DPS) has the potential to curtail lower extremity injuries with important implications for athletic and scientific populations. The ability to stabilize following dynamic tasks such as jumping is dependent on several intrinsic factors, including ligamentous laxity, proprioception, and neuromuscular control. Ballet dancers are a unique group of aesthetic performers who frequently must perform unipedal balance during dynamic tasks. The purpose of this study was to evaluate the effects of mirror feedback and ankle laxity on dynamic balance and muscle activation in 15 trained ballet dancers during a hop-to-stabilization task with and without mirror feedback. Anteroposterior and inversion-eversion ankle laxity was measured with an arthrometer. Surface electromyography was then applied to the tibialis anterior, peroneus longus, and lateral gastrocnemius muscles to record activity during the task in question. The main finding was that time-to-stabilization during the task was unaffected by mirror feedback (F = 0.105, p = 0.900; mirror = 3.31 +/- 0.10 s; no-mirror = 3.37 +/- 0.12 s). Greater antero-posterior laxity, however, negatively affected DPS with (r = 0.655, p = 0.008) and without the mirror (r = 0.858, p < 0.001). These results suggest that visual feedback does not affect performance during a DPS task; however, increased ankle laxity may influence balancing ability in ballet dancers. PMID- 30477608 TI - Some Effects of Supplemental Pilates Training on the Posture, Strength, and Flexibility of Dancers 17 to 22 Years of Age. AB - Proper alignment in dancers is a pre-requisite for achieving aesthetic line and form and for efficient execution of movement. Pelvic alignment is a common deficit in dancers that results in faulty technique and impaired performance. Dancers must be able to obtain their personal neutral alignment to avoid injury and achieve ease of execution. This study was designed to examine the effects, qualitatively and quantitatively, of Pilates training on pelvic alignment, strength, and flexibility in dancers. Twenty female dancers, 17 to 22 years of age, participated in a screening that consisted of an AlignaBod posture screen, upper abdominal manual muscle test, double leg lower test, straight leg raise test, and modified Thomas test. Participants were screened, engaged in dance classes for 14 weeks without Pilates, and screened a second time. They then attended a 2-hour pelvic alignment workshop followed by two weekly Pilates classes, one mat and one apparatus, for 14 weeks. The study concluded with a final screening and collection of qualitative data regarding participant perceptions of their experience. Analysis demonstrated a decrease in the number of postural misalignments with Pilates intervention compared to no significant change in total misalignments when taking dance classes only. The prevalence of forward head posture, knee hyperextension, and foot-ankle pronation or supination all decreased significantly. After participating in the Pilates intervention, the prevalence of iliotibial band and hamstring inflexibility decreased and lower abdominal muscle strength improved significantly. All participants reported they felt that Pilates improved their core stability, pelvic alignment, strength, and body awareness. This study suggests that Pilates, when added to dance training, can improve postural alignment, flexibility, and abdominal strength in dancers. Additionally, it is well tolerated by dancers, making it a potentially valuable cross-training tool. PMID- 30477610 TI - Quantitative Measures Utilized in Determining Pointe Readiness in Young Ballet Dancers. AB - While an important step in a young dancer's ballet career is the transition to pointe work, there is much controversy as to when her body is physically prepared to meet the increased demands of this development. Pointe screening protocols are being used by many in both the dance studio and dance science communities, but these protocols have not yet been standardized. The purpose of this study was to evaluate objectively the attributes of ballet dancers who are pre-pointe compared to those who have recently begun pointe training, and secondarily to correlate these quantitative findings with qualitative evaluations by the dancers' teachers. Participants were 49 healthy young female dancers with at least 1 year of formal ballet training. Twentyeight were pre-pointe students (age: 10.21 +/- 1.17 years; height: 124.05 +/- 13.45 cm; weight: 39.13 +/- 13.18 kg; and 6.04 +/- 1.84 years dance experience), and 21 were pointe students (age: 11.42 +/- 0.81 years; height: 136.91 +/- 16.04 cm; weight: 40.79 +/- 8.77 kg; and 6.45 +/- 2.07 years dance experience). Six dependent variables were evaluated: non weightbearing (NWB) plantar flexion (PF) and dorsiflexion (DF) range of motion (ROM); weightbearing lunge test (WBL); releve endurance (heel raise test); PF isometric strength; Airplane test; and Star Excursion Balance Test (SEBT) in three directions. These tests were broken into three categories for statistical analysis: ROM (NWB PF and DF, WBL), muscular capacity (releve endurance, PF isometric strength), and balance (Airplane, SEBT). The analysis demonstrated that the pointe group performed significantly better than the pre-pointe group on the muscular capacity and balance testing (p < 0.01). Calculations for both tests indicated that 15 continuous single-leg releves and two repetitions of the Airplane test may be the best cut-off levels when using these tests as part of a pre-pointe screening protocol. In conclusion, the releve endurance test and the Airplane test are appropriate for use in differentiating between pre-pointe and pointe dancers. PMID- 30477609 TI - Functional Movement Screening as a Predictor of Mechanical Loading and Performance in Dancers. AB - Dance requires effective functional movement for the prevention of injury, with implications for the biomechanical response to performance. This study investigated the efficacy of the Functional Movement Screening (FMS) in predicting mechanical loading during the Dance Aerobic Fitness Test (DAFT). Twenty-five university dancers (19 females; age: 20.3 +/- 0.94 years; height: 162.55 +/- 0.05 cm; mass: 58.73 +/- 6.3 kg; and 6 males; age: 21.08 +/- 2.01 years; height: 175 +/- 6.54 cm; mass: 68.16 +/- 4.97 kg) were screened using the FMS. Subjects then completed the DAFT with a GPS-mounted triaxial accelerometer located at the cervico-thoracic junction. Accelerometry data were sampled at 100 Hz and used to calculate total accumulated PlayerLoad, Playerload medial-lateral (PLML), PlayerLoad anterior-posterior (PLAP), and PlayerLoad vertical (PLV) over the duration of the DAFT. Linear regression analysis was used to determine the strength of correlation between FMS and PlayerLoad, PLML, PLAP, and PLV, and forward stepwise hierarchical modelling was performed to establish which FMS components were the primary predictors of mechanical loading. The Deep Squat (DS) demonstrated statistical significance for PLVTotal and PLTotal. The non-dominant Hurdle Step (HS) was a statistically significant predictor of PLMLTotal. The FMS composite score was a statistically significant predictor for PLVTotal. Forward stepwise regression analysis demonstrated that DS was the sole predictor for PLTotal and the primary predictor for PLVTotal. Non-dominant HS was identified as the primary predictor of PLMLTotal. It is concluded that the DS, non-dominant HS, and the FMS composite score can be used to predict mechanical loading in performance of the DAFT, which may have implications for dance performance and injury prevention. PMID- 30477611 TI - Saute External Rotation in Beginner and Advanced Ballet Dancers Trained in Different Backgrounds The Turnout Paradigm. AB - This study compared lower limb external rotation kinematic patterns during sautes in first position in beginners and experienced ballet dancers with various training backgrounds. The ability to attain a perfect turnout is traditionally thought to be a fundamental aspect of classical ballet, and turnout is identified in the literature as one of the leading causes of dance-related injuries and technical limitations among dancers. Twenty-eight ballet dancers of different technical levels and methods (three groups) were assessed. Coefficients of variation (CV), range of motion (ROM), and mean external rotation angles of hip, knee, and ankle in first position saute were calculated. Differences among groups were tested with ANOVAs (Tukey's post hoc; p < 0.05). The hip mean external rotation values found during the jump were different between both experienced groups from different training backgrounds (p = 0.02). The inexperienced group presented a significantly greater hip external rotation CV compared to the experienced groups (p <= 0.001). There were no differences between groups for values of external rotation at the knee and ankle. It is concluded that higher technical level dancers produce lower variability of hip external rotation while performing saute in first position. Ballet training background also seems to influence the hip external rotation pattern. Moreover, the knee contributes decisively to turnout composition, not only the hip, as expected. PMID- 30477612 TI - Can Elite Dancers Return to Dance After Ultrasound-Guided Platelet-Rich Plasma (PRP) Injections? AB - Dancers exert tremendous stresses on the lower extremities rendering them prone to injuries that can curtail training and performance. The goal of this study was to evaluate clinical improvement in a population of elite dancers following treatment with ultrasound-guided platelet-rich plasma (PRP) injections of various lower extremity sites by assessing when they were able to return to dance. Nineteen dancers (13 female, 6 male; ages 15 to 42) were treated between 2009 and 2016 at sites that included: hamstring tendon (1), proximal iliotibial band (1), patellar tendon (3), posterior tibial tendon (5), peroneus brevis tendon (3), plantar fascia (3), and the first metatarsophalangeal (MTP) joint capsule (3). Injections were performed by a single radiologist using the same PRP kit under ultrasound guidance. All patients adhered to standard post-care instructions, including non-weightbearing and avoidance of NSAIDs for at least 2 weeks post injection. Clinical charts were reviewed for factors including: adherence to post injection immobilization and physical therapy, physical exam assessments, and milestones in returning to dance. The time-point for returning to dance was defined by attendance of class or rehearsal without symptoms referring to the treated site. Eighteen subjects achieved return to dance, 13 in 6 months or less, and the majority (10) within 3 months of injection. Five subjects required more than 6 months recovery time. These cases all involved foot and ankle sites; of these, two subjects required repeat injections, and both returned to dance within 11 months of the second injection. In the single case where PRP treatment failed, the injury treated was severe plantar fasciopathy with a high-grade central cord tear. It is concluded that ultrasound-guided PRP injections may play a role in the treatment of various lower extremity injuries in elite dancers, with the majority of subjects in this series returning to dance within 6 months. Recovery time may vary depending on the site treated and severity of the presenting injury. PMID- 30477613 TI - Ischial Tuberosity Avulsion Fracture in a Young Female Ballet Dancer. AB - A 14-year-old female ballet dancer sustained an injury during a routine ballet movement that was diagnosed as an ischial tuberosity avulsion fracture. This diagnosis was complicated by extensive soft tissue injury to the hamstrings, adductors, and external rotator musculature. Although uncommon, the potential for this injury should be uniformly considered in adolescent dancers due to the unique stresses in ballet training and the added risk of growth spurts during this stage of development. Prevention targeting individual deficiencies in flexibility and strength is essential to avoid similar devastating injuries. In most cases that are diagnosed early, avulsions heal with conservative treatment. Early imaging and correct diagnosis can serve to guide clinical management and prevent unnecessary surgery in the young dancer. PMID- 30477614 TI - Abstracts from the Current Literature. PMID- 30477615 TI - Book Reviews. PMID- 30477616 TI - [Some thoughts on influenza vaccine and regular influenza vaccination for healthcare workers]. AB - It has been 100 years since the 1918 influenza pandemic but influenza is still an uncontrolled infectious disease. In some developed countries, the coverage rate of influenza vaccine can reach as high as 60%-70%, and even up to 90% or higher in some specific population, such as the elderly and healthcare workers. The coverage rate of influenza vaccination in Chinese people, however, is very low, only about 2%-3% per year. The limitations of influenza vaccine, and the purpose and significance of influenza vaccination, the imbalance of vaccine information and the importance of inoculation for healthcare workers are discussed in this paper. The resistance to popularize influenza vaccination is explored from different perspectives. It is hoped that more people will recognize the objective epidemiological data, and get rid of misunderstandings based on their experiences. Healthcare workers in particular, and the general population, should be encouraged to have an influenza vaccination. PMID- 30477617 TI - [An interpretation of the expert consensus on standards for the management of patients with primary mitochondrial disease from the Mitochondrial Medicine Society]. AB - Primary mitochondrial disease is the most common inborn error of metabolism and is highly heterogeneous in terms of clinical manifestations and inheritance pattern. It has high mortality and disability rates. Multiple systems are often involved in this disease, and it is necessary to perform comprehensive evaluation and multidisciplinary management. The Mitochondrial Medicine Society issued the standard for the management of patients with primary mitochondrial disease: consensus statements from the Mitochondrial Medicine Society in 2017. The statements provided recommendations based on such consensus to guide the management and care of patients. This article interprets and summarizes the screening of organs and systems commonly involved in primary mitochondrial disease and the management of patients according to the consensus. PMID- 30477618 TI - [Clinical features and prognosis of bronchopulmonary dysplasia complicated by pulmonary hypertension in preterm infants]. AB - OBJECTIVE: To study the clinical features and prognosis of bronchopulmonary dysplasia (BPD) complicated by pulmonary hypertension (PH) in preterm infants. METHODS: A retrospective analysis was performed on the clinical data of 191 preterm infants with BPD. RESULTS: In the 191 preterm infants with BPD, 37 (19.4%), all with moderate or severe BPD, developed PH beyond 36 weeks' corrected age. The incidence rates of PH in infants with moderate and severe BPD were 5.7% (5/87) and 47.8% (32/67) respectively. Gestational age and birth weight were lower in infants with PH than in those without PH (P<0.01). Infants with PH had higher incidence rates of small for gestational age (SGA), severe BPD, surgical ligation of patent ductus arteriosus (PDA), neonatal respiratory distress syndrome, hemodynamically significant PDA, and pneumonia than those without PH (P<0.01). Durations of oxygen therapy, intubation, and positive pressure ventilation were longer in infants with PH than in those without PH (P<0.01). Infants with PH had higher incidence rates of retinopathy of prematurity and extrauterine growth retardation, a higher mortality, and a longer length of hospital stay compared with those without PH (P<0.01). In the 37 infants with PH (6 with mild PH, 14 with moderate PH, and 17 with severe PH), those with mild or moderate PH all survived; 15(88%) out of 17 infants with severe PH died. CONCLUSIONS: The incidence of PH is high in preterm infants with moderate or severe BPD. Regular screening of pulmonary artery pressure is recommended for infants with BPD. Infants with low gestational age and birth weight, SGA, and severe BPD are more likely to develop PH. Infants with BPD complicated by PH have relatively high incidence rates of complications, high mortality, and poor prognosis. PMID- 30477619 TI - [Clinical efficacy of nasal high-frequency ventilation in treatment of neonatal respiratory distress syndrome: a Meta analysis]. AB - OBJECTIVE: To systematically evaluate the clinical efficacy of nasal high frequency ventilation (nHFV) in the treatment of neonatal respiratory distress syndrome (NRDS). METHODS: A literature search was performed in PubMed, Cochrane Library, EMBase (Ovid), Chinese Biomedical Literature Database, Chinese Journal Full-text Database, Wanfang Data, and Weipu Data to collect the randomized controlled trials (RCTs) that compared the clinical efficacy of nHFV and nasal continuous positive airway pressure (nCPAP) in the treatment of NRDS. A Meta analysis was performed on the included RCTs using Rev Man 5.3 software after data extraction and quality evaluation by Cochrane 5.1.0. RESULTS: A total of 4 RCTs involving 218 patients were included. The Meta analysis showed that compared with the nCPAP group, the nHFV group had a significantly better treatment outcome (RR=1.73, 95%CI: 1.39-2.15, P<0.00001). There were no significant differences in the incidence rates of intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, necrotizing enterocolitis, pneumothorax and retinopathy of prematurity. CONCLUSIONS: Compared with nCPAP, nHFV has better clinical efficacy in the treatment of NRDS, without increasing the risk of related complications. PMID- 30477620 TI - [A molecular epidemiological study of respiratory syncytial virus circulating in southern Zhejiang Province, China, from 2009 to 2014]. AB - OBJECTIVE: To find out the prevalence of respiratory syncytial virus (RSV) genotypes in southern Zhejiang Province, China, and to study the genetic characteristics of G protein from subtype A of RSV. METHODS: The lower respiratory tract secretions of children under 5 years of age who were hospitalized for pneumonia and bronchiolitis in three hospitals in southern Zhejiang Province from July 2009 to June 2014 were collected. Direct immunofluorescence assay was used to detect RSV antigens from the collected secretions. A total of 200 samples were randomly selected from RSV-positive specimens in each prevailing year (from July of a specific year to June of the next year). RT-PCR was used to determine RSV subtypes, and the near-full length gene sequence of G protein from subtype A was amplified and sequenced to identify the genotype. RESULTS: A total of 25 449 samples of lower respiratory tract secretions were collected from 2009 to 2014, among which 6 416 (25.21%) samples were RSV-positive. Among the 1 000 RSV-positive specimens randomly sampled, 462 strains (46.2%) were subtype A, and 538 strains (53.8%) were subtype B. Subtype A accounted for 22.5%, 74.5%, 84.5%, 19.0%, and 30.5% of the total strains in each year from 2009 to 2014. A total of 25 RSV subtype A strains were randomly sampled and sent out for bidirectional sequencing in each year, which confirmed 52 positive subtype A strains. Four genotypes of subtype A strains were obtained from the above strains, including NA1 (39 strains), NA4 (1 strain), ON1 (10 strains), and GA2 (2 strains). NA1 was the dominant genotype between 2009 and 2012, and ON1 was the only genotype of subtype A during 2013-2014. The nucleotide homology and amino acid homology between the G protein of subtype A and the prototype strain A2 were 80.7%-89.3% and 74.4%-82.6%, respectively. The nucleotide homology and amino acid homology between the isolates of subtype A were 81.5%-100% and 80.2%-100%, respectively. CONCLUSIONS: In southern Zhejiang Province from 2009 to 2014, there was a co-circulation of RSV subtypes A and B, as well as a co-circulation of several different genotypes of RSV subtype A, which had highly variable G protein genes. PMID- 30477621 TI - [Dynamic change in vitamin D level in infants/toddlers with severe pneumonia and a correlation analysis]. AB - OBJECTIVE: To study the correlation of dynamic change in serum 25-hydroxy vitamin D [25(OH)D] level with the disease severity and related laboratory markers in infants/toddlers with severe pneumonia. METHODS: A total of 132 infants/toddlers with severe pneumonia who were hospitalized between March 2017 and March 2018 were enrolled as the severe pneumonia group. According to the disease severity on admission and after one week of treatment, they were further divided into non critical group (41 children on admission and 78 after one week of treatment), critical group (59 children on admission and 35 after one week of treatment), and extremely critical group (32 children on admission and 19 after one week of treatment). A total of 142 infants/toddlers who underwent physical examination during the same period of time were enrolled as the healthy control group. The serum levels of 25(OH)D, procalcitonin (PCT), and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured on admission and after one week of treatment for the severe pneumonia group, and the serum level of 25(OH)D was measured on admission for the healthy control group. According to the 25(OH)D level after one week of treatment, the children with severe pneumonia were divided into increased vitamin D (VD) group with 81 children and reduced VD group with 51 children, and a comparative analysis and a correlation analysis were performed. RESULTS: The severe pneumonia group had a significantly lower mean 25(OH)D level than the healthy control group (P<0.05), and all the three subgroups of different severities had significantly lower 25(OH)D level than the healthy control group (P<0.05). On admission and after one week of treatment, the non-critical group had a significantly higher 25(OH)D level than the critical and extremely critical groups (P<0.01), and the critical group had a significantly higher 25(OH)D level than the extremely critical group (P<0.05). The extremely critical and critical groups had significantly higher serum levels of PCT and NT proBNP than the non-critical group on admission and after one week of treatment (P<0.05). After one week of treatment, compared with the reduced VD group, the increased VD group had a significantly less serious condition. At discharge, the increased VD group had a significantly better outcome compared with the reduced VD group (P<0.01). In the children with severe pneumonia, the change value of serum 25(OH)D level after treatment was negatively correlated with the change values of PCT and NT-proBNP (r=-0.597 and -0.404 respectively; P<0.01). CONCLUSIONS: The change in VD level is correlated with the severity of severe pneumonia in infants/toddlers and can be used as an index for disease monitoring. VD supplementation may help with disease recovery. PMID- 30477622 TI - [Clinical features of children with Kawasaki disease aged over 5 years]. AB - OBJECTIVE: To study the clinical and laboratory features of children with Kawasaki disease (KD) aged >5 years. METHODS: A retrospective analysis was performed for the clinical data of 250 elderly children (aged >5 years) who were diagnosed with KD or incomplete KD (divided into 5-9 years and >9 years groups) and 266 KD children aged 1-5 years. Clinical and laboratory features were compared between groups. RESULTS: The >9 years group had the lowest incidence rates of hand and foot swelling and fingertip or perianal desquamation (P<0.05). The 5-9 years group had the highest incidence rate of neck lymph node enlargement (P<0.05). The >9 years group had the longest course of fever (P<0.05). There were no significant differences among the three groups in the incidence rates of rash, bulbar conjunctival hyperaemia and the change in lips, the proportion of children with incomplete KD, and the proportion of children with no response to intravenous immunoglobulin (IVIG). The >9 years group had the lowest platelet count and albumin (P<0.05). The 5-9 years group had the highest percentage of neutrophils (P<0.05). There were no significant differences among the three groups in white blood cell count, C-reactive protein, erythrocyte sedimentation rate, and alanine aminotransferase (P>0.05). As for the degree of CAL, the 1-5 years group had the highest incidence of mild coronary dilation, and the >9 years group had the highest incidence rate of moderate coronary aneurysm (P<0.05). There was no significant difference in the incidence rate of large coronary aneurysm among the three groups (P>0.05). CONCLUSIONS: KD children aged >5 years have atypical clinical manifestations, with a high incidence rate of neck lymph node enlargement, a high percentage of neutrophils, and a low level of albumin and platelet. The risk of moderate coronary aneurysm increases with age. PMID- 30477623 TI - [Clinical features and drug resistance in children with Salmonella infection]. AB - OBJECTIVE: To study the clinical features and drug resistance in children with Salmonella infection. METHODS: A total of 163 children with positive fecal cultures for Salmonella who were hospitalized between 2013 and 2017 were enrolled. A retrospective analysis was performed for their data on clinical features, distribution of Salmonella serotypes, and drug sensitivity test results. RESULTS: Among the 163 children with Salmonella infection, 79 (48.5%) were aged <=1 year. Main clinical manifestations included fever and diarrhea. Of all the children, 121 (74.2%) reached a body temperature of above 39 degrees C, 52 (31.9%) had diarrhea more than 10 times a day, and 56 (34.4%) had respiratory infection. Salmonella infection often occurred in summer and autumn. Of all the children, 131 (80.4%) had the infection in May to October. Salmonella typhimurium was observed in 100 children (61.3%) and Salmonella enteritidis was observed 15 children (9.2%). All serotypes of Salmonella had a drug resistance rate of >20% to cefotaxime, as well as high sensitivities to beta-lactamase inhibitors (amoxicillin/clavulanic acid and piperacillin/tazobactam). There were no strains resistant to carbapenems including imipenem. CONCLUSIONS: Infants aged <=1 year are susceptible to Salmonella infection in summer and autumn, and the most common serotype is Salmonella typhimurium. Main clinical manifestations are fever and diarrhea in children with Salmonella infection, and most children also have respiratory infection. Salmonella has an increased rate of drug resistance to third-generation cephalosporins. In clinical treatment, antimicrobial drugs should be used according to the results of drug sensitivity test. PMID- 30477624 TI - [Clinical and genetic features of Kallmann syndrome: an analysis of 5 cases]. AB - Kallmann syndrome (KS) is a rare pediatric disease with major manifestations of olfactory dysfunction and hypogonadotropic hypogonadism. Five children (4 boys and 1 girl) with KS reported in this article were aged between 6 months and 19 years at the time when they attended the hospital. All the children had the clinical manifestation of hypogonadotropic hypogonadism; in addition, three children had olfactory dysfunction (two were found to have olfactory bulb dysplasia on magnetic resonance imaging), one had cleft lip and palate, and one had micropenis and cryptorchidism with right renal agenesis during infancy. All the five children had normal karyotype and their parents had normal clinical phenotypes. The uncle of one child had underdeveloped secondary sexual characteristics and olfactory disorder since childhood. High-throughput sequencing found two known heterozygous missense mutations in the FGFR1 gene, i.e., c.1097C>T(p.P366L) and c.809G>C(p.G270A), in two children. One child had a novel frameshift mutation, c.1877_1887/p.S627Tfs*6, in the KAL1 gene; this deletion mutation caused a frameshift in base sequence and produced truncated proteins, which led to a significant change in protein structure, and thus it was highly pathogenic. It is concluded that KS has great clinical and genetic heterogeneity and can be accompanied by incomplete dominant inheritance and that gene detection helps with the diagnosis of this disease. PMID- 30477625 TI - [Mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase deficiency: a case report and literature review]. AB - Mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase deficiency (HMCSD) is caused by HMGCS2 gene mutation. This paper reports the clinical and genetic features of an infant with this disease. The 8-month-old female infant was admitted to the hospital with diarrhea for 1 week and fever and convulsion for 1 day. The child presented with seizures, acidosis, hypoglycemia, abnormal liver function, myocardial injury and coagulation dysfunction. The new homozygous mutation c.1502G>A(p.R501Q) in the HMGCS2 gene was found in the infant by genetic testing. The mutant gene was found to be harmful by bioinformatics software analysis. Urine organic acid analysis indicated that 4-hydroxy-6-methyl-2 pyranone was significantly increased, which was consistent with the results of genetic testing. The infant was definitely diagnosed with HMCSD. PMID- 30477626 TI - [Prevalence of simple obesity and its high-risk factors in preschool children in Fuzhou, China]. AB - OBJECTIVE: To investigate the prevalence of simple obesity and its risk factors in preschool children in Fuzhou, China. METHODS: The physical examination data of 14 kindergartens in Fuzhou, China were collected by stratified cluster random sampling. The detection rate of simple obesity was calculated. The children with normal body weight were selected as the control group by 1:1 case-control method. The risk factors for childhood simple obesity were investigated by self-made questionnaire and multivariate logistic regression analysis. RESULTS: A total of 5 767 children aged 3-6 years were enrolled in this study. A total of 289 (5.01%) children with simple obesity were screened out, including 153 with mild obesity and 136 with moderate to severe obesity. The prevalence rate of simple obesity gradually increased with the age of children. The multivariate logistic regression analysis showed that the following factors were independent risk factors for simple obesity: preference for fried food (OR=4.789, P<0.05), caregivers' over-concern about diet (OR=4.620, P<0.05), eating before sleep (OR=4.006, P<0.05), eating fast (OR=3.221, P<0.05), preference for sweets (OR=2.282, P<0.05), high birth weight (OR=2.202, P<0.05), overweight or obesity in father (OR=2.074, P<0.05), overweight or obesity in mother (OR=2.047, P<0.05), more than 1.2 times the food intake at the same age (OR=2.013, P<0.05), watching TV (OR=1.665, P<0.05), and lack of exercise (OR=1.463, P<0.05). CONCLUSIONS: The prevalence rate of simple obesity is 5.01% in preschool children in Fuzhou, China. The development of simple obesity is multifactorial. It is suggested that doctors, parents, and teachers should strengthen health education for preschool children, help them develop good living and eating habits, and encourage them to take more exercise, in order to reduce the development of simple obesity. PMID- 30477627 TI - [Persistent hypertension for two months in a preterm infant]. AB - A boy aged 2 months (born at 36 weeks of gestation) was admitted due to cough and dyspnea. After admission, he was found to have persistent hypertension, proteinuria, and persistent convulsion, and imaging examination showed extensive calcification of the aorta and major branches and stenosis of local lumens of the abdominal aorta and the right renal artery with increased blood flow velocity. The boy was admitted during the neonatal period due to wet lung and pulmonary arterial hypertension and was found to have hypertension and proteinuria. High throughput whole-exome sequencing was performed and found two compound heterozygous mutations in the ENPP1 gene from his parents, c.130C>T (p.Q44X) and c.1112A>T (p.Y371F). c.130C>T was a nonsense mutation, which could cause partial deletion of protein from 44 amino acids, and was defined as a primary pathogenic mutation. c.1112A>T was a missense mutation which had been reported as a pathogenic mutation associated with idiopathic infantile arterial calcification (IIAC). Therefore, he was diagnosed with IIAC. He was given phosphonate drugs, antihypertensive drugs, anticonvulsion treatment, and respiratory support. Blood pressure was maintained at the upper limit of normal value. There was no deterioration of arterial calcification. It is concluded that IIAC should be considered for infants with persistent hypertension and extensive vascular calcification, and imaging and genetic examinations should be performed as early as possible to make a confirmed diagnosis. PMID- 30477628 TI - [Reye syndrome and sudden death symptoms after oral administration of nimesulide due to upper respiratory tract infection in a boy]. AB - A boy aged 6 years and 3 months developed upper respiratory tract infection and pyrexia 2 months ago and was given oral administration of nimesulide by his parents according to directions. Half an hour later, the boy experienced convulsions and cardiopulmonary arrest, and emergency examination found hypoketotic hypoglycemia, metabolic acidosis, significant increases in serum aminotransferases and creatine kinase, and renal damage. Recovery of consciousness and vital signs was achieved after cardiopulmonary resuscitation, but severe mental and movement regression was observed. The boy had a significant reduction in free carnitine in blood and significant increases in medium- and long-chain fatty acyl carnitine, urinary glutaric acid, 3-hydroxy glutaric acid, isovalerylglycine, and ethylmalonic acid, suggesting the possibility of multiple acyl-CoA dehydrogenase deficiency. After the treatment with vitamin B2, L carnitine, and bezafibrate, the boy gradually improved, and reexamination after 3 months showed normal biochemical parameters. The boy had compound heterozygous mutations in the ETFDH gene, i.e., a known mutation, c.341G>A (p.R114H), from his mother and a novel mutation, c.1484C>G (p.P495R), from his father. Finally, he was diagnosed with multiple acyl-CoA dehydrogenase deficiency. Reye syndrome and sudden death symptoms were caused by nimesulide-induced acute metabolic crisis. It is concluded that inherited metabolic diseases may be main causes of Reye syndrome and sudden death, and biochemical and genetic analyses are the key to identifying underlying diseases. PMID- 30477629 TI - [Interactive regulatory effect of histone H3K9ac acetylation and histone H3K9me3 methylation on cardiomyogenesis in mice]. AB - OBJECTIVE: To study the interactive regulatory effect of histone acetylation and methylation on cardiomyogenesis, and to provide a theoretical basis for the prevention and treatment of congenital heart disease. METHODS: A total of 24 Kunming mice were randomly divided into embryo day 14.5 (ED 14.5) group, embryo day 16.5 (ED 16.5) group, postnatal day 0.5 (PND 0.5) group, and postnatal day 7 (PND 7) group, with 6 mice in each group, and the heart tissue of fetal and neonatal mice was collected. Colorimetry was used to measure the activities of histone acetylases (HATs) and histone methyltransferases (HMTs) in the myocardium. Western blot was used to measure the expression of H3K9ac and H3K9me3 in the myocardium. RESULTS: Colorimetry showed that the activities of HATs and HMTs were higher before birth and were lower after birth. There was a significant difference in the activity of HATs in the myocardium between the PND 0.5 and PND 7 groups and the ED 14.5 group (P<0.05), as well as between the PND 7 group and the ED 16.5 group (P<0.05). There was also a significant difference in the activity of HMTs in the myocardium between the PND 7 group and the ED 14.5 and ED 16.5 groups (P<0.05). Western blot showed higher expression of H3K9ac and H3K9me3 before birth and lower expression of H3K9ac and H3K9me3 after birth, and there were significant differences in the expression H3K9ac and H3K9me3 in the myocardium between the PND 0.5 and PND 7 groups and the ED 14.5 and ED 16.5 groups (P<0.05). CONCLUSIONS: The dynamic expression of HATs, HMTs, H3K9ac, and H3K9me3 is observed during cardiomyogenesis, suggesting that histone H3K9ac acetylation and histone H3K9me3 methylation mediated by HATs and HMTs may play a role in interactive regulation during cardiomyogenesis. PMID- 30477630 TI - [Clinical features and INS mutations of an infant with neonatal diabetes mellitus]. PMID- 30477631 TI - [Advances in the treatment of juvenile myelomonocytic leukemia]. AB - Juvenile myelomonocytic leukemia (JMML) is a rare chronic myeloid leukemia in children and has the features of both myelodysplastic syndrome and myeloproliferative neoplasm. It is highly malignant and has a poor treatment outcome. Children with JMML have a poor response to conventional chemotherapy. At present, hematopoietic stem cell transplantation is the only possible cure for this disease. In recent years, significant progress has been made in targeted therapy for mutant genes in the Ras signaling pathway and demethylation treatment of aberrant methylation of polygenic CpG islands. This article reviews the treatment and efficacy evaluation of JMML. PMID- 30477632 TI - [Association between iron deficiency and brain developmental disorder in children]. AB - Iron deficiency (ID) is the most common trace element deficiency in childhood. Recent studies have shown that late fetus period, neonatal period, and infancy are important periods for brain development, and ID during these periods may cause irreversible damage to brain development, including abnormal emotion and behavior, cognitive decline, and attention deficit, which may still be present in adulthood. Therefore, it should be taken seriously. This article summarizes the research advances in major mechanisms involved in brain developmental disorder due to ID in the early stage of life and related intervention measures. PMID- 30477633 TI - [A review on the management of tic disorders in children: psychoeducation and behavioral intervention]. AB - Tic disorders (TD) are a group of neurodevelopmental disorders that are characterized by motor and/or vocal tics in children and adolescents. The etiology and pathogenesis of TD remain unclear, and it is believed to be caused by a combination of genetic, biological, psychological, and environmental factors. The major treatment for TD includes psychoeducation, behavioral intervention, and drug treatment. To further explore the management of TD, this article reviews the research advances in psychoeducation and behavioral intervention for patients with TD. PMID- 30477634 TI - [A review on the role of gamma-aminobutyric acid signaling pathway in autism spectrum disorder]. AB - The etiology and pathogenesis of autism spectrum disorder (ASD) are not yet clear. Studies have shown that there are many neurotransmitter abnormalities in children with ASD, mainly involving in glutamate, gamma-aminobutyric acid (GABA), dopamine, 5-HT and oxytocin. The imbalance of excitatory glutamatergic neurotransmitters and inhibitory GABAergic neurotransmitters is closely related to the pathogenesis of ASD. Both animal model studies and clinical studies on ASD suggest that GABA signaling pathway may play an important role in the pathogenesis of ASD. This article reviews the research on the association between GABA signaling pathway and the pathogenesis of ASD to further explore the pathogenesis of ASD and provide theoretical basis for the treatment of ASD. PMID- 30477636 TI - Erratum. PMID- 30477635 TI - Theoretical tool bridging cell polarities with development of robust morphologies. AB - Despite continual renewal and damages, a multicellular organism is able to maintain its complex morphology. How is this stability compatible with the complexity and diversity of living forms? Looking for answers at protein level may be limiting as diverging protein sequences can result in similar morphologies. Inspired by the progressive role of apical-basal and planar cell polarity in development, we propose that stability, complexity, and diversity are emergent properties in populations of proliferating polarized cells. We support our hypothesis by a theoretical approach, developed to effectively capture both types of polar cell adhesions. When applied to specific cases of development - gastrulation and the origins of folds and tubes - our theoretical tool suggests experimentally testable predictions pointing to the strength of polar adhesion, restricted directions of cell polarities, and the rate of cell proliferation to be major determinants of morphological diversity and stability. PMID- 30477637 TI - Identifying Barriers to Treatment for Women With Cervical Dysplasia in Rural Northern British Columbia. AB - OBJECTIVE: This study seeks to identify barriers to colposcopy examination faced by patients living in Northern BC to improve outcomes for women at risk of developing cervical cancer. METHODS: A retrospective chart review (n = 309) was conducted in the four colposcopy clinics in Northern BC to collect information regarding patients who were referred for colposcopy after abnormal cytology. Demographic factors associated with non-attendance were identified as barriers to accessing care. Aggregate data from the Cervical Cancer Screening Program (n = 4265) were used to calculate wait times by health region across BC. RESULTS: The odds of having missed an appointment was highest for women who were pregnant (OR 4.0) or attending site D vs. site A (OR 6.0); however, only clinic location remained significant in a multivariable model. Wait times were longer for women who had ever missed appointments, and varied among the sites, with site A and D having significantly longer wait times than the remaining sites. The Northern Health Authority had the longest overall median colposcopy wait time for high grade cytology in the province at 41 days longer than the provincial average of 62 days. CONCLUSION: The Northern Health Authority faces unique challenges associated with geography and patient population that are associated with longer wait times for colposcopy when compared with other health authorities in the province. PMID- 30477638 TI - SnapshotDx Quiz: June 2017. PMID- 30477639 TI - Cells to Surgery Quiz: June 2017. PMID- 30477640 TI - Contribution of biomarkers for pancreatic cancer-associated new-onset diabetes to pancreatic cancer screening. AB - BACKGROUND: Pancreatic cancer (PaC) is one of the deadliest types of tumor, and it is regarded as a fatal disease, with a 5-year survival rate less than 10%. Most clinical diagnoses for PaC are made at an advanced stage because of the insidious onset of the disease, which leads to an extremely poor prognosis. RECENT FINDINGS: The relationship between diabetes mellitus (DM) and PaC has been established by several decades of research, and the prevalence of DM in patients with PaC has been reported to be 40%, with half of the patients having developed new-onset DM within 2 years or less. Increasing evidence suggests that new-onset DM is associated with a high prevalence of PaC, and PaC resection ameliorates DM. Therefore, screening for PaC may be needed in patients with newly developed DM. PURPOSE: The objective of this review was to present our current understanding of biomarkers for PaC-associated new-onset DM (PCAND), to offer a perspective on the prospects and problems of using this strategy for early screening to differentiate PCAND from new-onset type 2 DM not associated with PaC and to suggest candidate biomarkers to use for PaC screening in patients with new-onset DM. Finding sensitive and specific biomarkers to manage these patients constitutes a challenge for the research community and for public health policies. PMID- 30477641 TI - The application of transgenic and gene knockout mice in the study of gastric precancerous lesions. AB - Gastric intestinal metaplasia is a precursor for gastric dysplasia, which is in turn, a risk factor for gastric adenocarcinoma. Gastric metaplasia and dysplasia are known as gastric precancerous lesions (GPLs), which are essential stages in the progression from normal gastric mucosa to gastric cancer (GC) or gastric adenocarcinoma. Genetically-engineered mice have become essential tools in various aspects of GC research, including mechanistic studies and drug discovery. Studies in mouse models have contributed significantly to our understanding of the pathogenesis and molecular mechanisms underlying GPLs and GC. With the development and improvement of gene transfer technology, investigators have created a variety of transgenic and gene knockout mouse models for GPLs, such as H/K-ATPase transgenic and knockout mutant mice and gastrin gene knockout mice. Combined with Helicobacter infection, and treatment with chemical carcinogens, these mice develop GPLs or GC and thus provide models for studying the molecular biology of GC, which may lead to the discovery and development of novel drugs. In this review, we discuss recent progress in the use of genetically-engineered mouse models for GPL research, with particular emphasis on the importance of examining the gastric mucosa at the histological level to investigate morphological changes of GPL and GC and associated protein and gene expression. PMID- 30477642 TI - Elevated TRIM23 expression predicts poor prognosis in Chinese gastric cancer. AB - The gene TRIM23 (tripartite motif containing 23) is a member of the tripartite motif (TRIM) family whose expression putatively participates in many pathophysiological processes. Nonetheless, the role of TRIM23 in gastric cancer (GC) remains uncertain. Our study evaluated the expression of TRIM23 in GC tissues and cell lines, and investigated an association between TRIM23 and survival. In the present study, our results demonstrated that TRIM23 mRNA and protein were frequently over-expressed in GC cell lines and GC tissues. High level of TRIM23 protein correlated with tumor size, tumor-node-metastasis (TNM) stage, depth of invasion, lymph node metastasis (LNM), tumor differentiation, and nerve invasion. Compared with the low TRIM23 protein group, the high TRIM23 protein group was significantly associated with worse prognosis of GC patients. Consistently, the KM-plot database suggested that high TRIM23 mRNA expression was also linked to a poor prognosis in GC patients both in positive and negative subgroups of human epidermal growth factor receptor 2 (HER2). But in the HER2 positive subgroup, the advantages of the low TRIM23 expression on overall survival were much more statistically significant. The univariate analysis indicated that TRIM23 expression correlated with overall survival. The multivariate analysis showed that independent factors of prognosis in GC were lymph node metastasis, vascular invasion, and depth of invasion. In summary, TRIM23 may be associated with progression of GC, and may be considered a therapeutic target for GC patients. PMID- 30477643 TI - PD-L1 expression in pancreatic adenosquamous carcinoma: PD-L1 expression is limited to the squamous component. AB - AIM: We examined the programmed death-ligand 1 (PD-L1) expression in surgically resected pancreatic adenosquamous carcinoma (PASC) samples. Furthermore, the detection rate was also assessed using biopsy cases obtained from endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). METHODS: Fifteen cases of PASC (six resected and nine EUS-FNA biopsied) from the Kurume University Hospital between 2009 and 2016 were used for the evaluation of PD-L1 expression. As a control group, 34 cases of pancreatic ductal adenocarcinomas (PDACs) were selected. To compare the positivity and intensity of PD-L1, two types of clones (SP263, E1L3N) were examined for immunostaining. Only the membrane expression of PD-L1 was regarded as positive. The PD-L1 expressions in the squamous cell carcinoma component (SCc), adenocarcinoma component (ACc), and immune cells were assessed separately. The ratio of PD-L1 expression was calculated by counting the positive tumor cells, and tumor proportion score (TPS) was applied (TPS; Null < 1%, low expression; 1 <= TPS <= 49% and high expression; >= 50%). RESULTS: PD-L1 expression was observed in five surgical PASC samples (83%). This shows that SCc presented a high expression in these cases. However, the overall TPS indicated a low expression. In contrast, only one case (3%) was positive for PD-L1 in PDACs, and the TPS indicated a low expression. No differences in PD-L1 expression were observed between the two clones, SP263 and E1L3N. High PD-L1 expression in the EUS-FNA sample was found in only one case (11%). DISCUSSION: Although assessment using the tumor cells of PASC samples obtained from EUS-FNA was difficult, this study suggests the selective expression of PD-L1 in the SCc of PASC. Furthermore, it was considered that immune checkpoint inhibitors could provide therapeutic effects selectively on the SCc for the entire range of TPSs, though the PD-L1 expression was low. PMID- 30477644 TI - DAB2IP with tumor-inhibiting activities exhibits frameshift mutations in gastrointestinal cancers. AB - A scaffold protein DAB2 and its interaction partner DAB2IP have putative tumor suppressor gene (TSG) functions. Previous studies identified that both DAB2 and DAB2IP genes were inactivated by promoter hypermethylation in human cancers, but their mutational alterations in cancers remain largely unknown. The aim of our study was to find whether DAB2 and DAB2IP were mutated in gastric (GCs) and colorectal cancers (CRCs) by DNA sequencing. Both DAB2 and DAB2IP have mononucleotide repeats in their coding sequence that could be mutation targets in high microsatellite instability (MSI-H) cancers. We analyzed GC and CRC tissues and found that 8 of 34 GCs (23.5%) and 15 of 79 CRCs (20.0%) with MSI-H harbored DAB2IP frameshift mutations. DAB2 frameshift mutations were found in 2 of 79 CRCs (2.5%) with MSI-H. These mutations were not detected in microsatellite stable (MSS) cancers. We also found intratumoral heterogeneity (ITH) of DAB2IP frameshift mutations in 7 of 16 CRCs (43.8%). Loss of DAB2IP protein expression was found in approximately 20% of GCs and CRCs irrespective of MSI and DAB2IP frameshift mutation status. Our study shows that the TSG DAB2IP harbored frameshift mutations and ITH as well as expression loss. Together these tumor alterations might play a role in tumorigenesis of GC and CRC with MSI-H by down regulating the tumor-inhibiting activities of DAB2IP. PMID- 30477645 TI - Identification of miRNA profiling in prediction of tumor recurrence and progress and bioinformatics analysis for patients with primary esophageal cancer: Study based on TCGA database. AB - OBJECT: This study focused on the identification of prognostic miRNAs for the prediction of tumor recurrence and progress in esophageal cancer. METHODS: MiRNA profiling and clinical characteristics of esophageal cancer patients was downloaded from the TCGA database. Univariate analysis was performed to select potential prognostic miRNAs and covariates. LASSO based logistic regression was conducted to identify the prognostic miRNAs given covariates. Bioinformatics analysis including gene ontology, disease ontology and pathway enrichment analysis were performed. A nomogram was generated based on multivariate logistic regression to illustrate the association between the identified miRNAs and the risk of tumor recurrence and progress. RESULTS: A total of 1881 miRNAs and 10 clinical characteristics were obtained from TCGA database. 18 miRNAs were finally identified in which 6 miRNAs were identified for the first time to be associated with the tumor recurrence and progress of esophageal cancer given covariates. Bioinformatics analysis suggested that the identified miRNAs were associated with the tumor recurrence and progress of esophageal cancer. The association between identified miRNAs and risk of tumor recurrence and progress were presented in a nomogram. CONCLUSION: The 6 newly identified miRNAs may be potential biomarkers for the prediction of tumor recurrence and progress of esophageal cancer. PMID- 30477646 TI - Primary cutaneous peripheral T-cell lymphoma with a late relapse solely in the ileum mimicking monomorphic epitheliotropic intestinal T-cell lymphoma. AB - BACKGROUND: Primary cutaneous peripheral T-cell lymphomas (PC-PTCLs) are classified into mycosis fungoides (MF) and other rare specific types; and those do not fit into any specific entities are designated as PTCL, not otherwise specified (NOS), an aggressive neoplasm. Monomorphic epitheliotropic intestinal T cell lymphoma (MEITL) is an aggressive primary intestinal T-cell lymphoma with enteropathy in the non-neoplastic mucosa. We report a rare case of PC-PTCL-NOS with a late relapse solely in the ileum after complete remission. We discuss the importance of evaluating enteropathy, megakaryocyte-associated tyrosine kinase (MATK) immunostaining, and the implication of clonal relationship of metachronous lymphomas. CASE REPORT: We reviewed the histopathology and immunohistochemistry of the skin tumor from a 68-year-old female and the relapsed intestinal T-cell lymphoma. The tumor cells "trans-regressed" from large and pleomorphic in the skin to small/medium-sized cells with clear cytoplasm in the ileum; and furthermore, there was immunophenotypic alteration. However, there was no enteropathy in the non-tumoral ileal mucosa adjacent to the tumor proper and both the cutaneous and ileal tumors were negative for MATK. Clonality study showed clonal TRG and TRB rearrangement with identical band sizes of the amplicons, confirming primary cutaneous tumor with a late relapse in the ileum. CONCLUSIONS: Although PC-PTCL-NOS is an aggressive neoplasm, rare cases such as this might have a long-term survival. Furthermore, the late relapse mimicking MEITL is intriguing and exceptional, in spite the fact that MEITL is a primary intestinal T-cell lymphoma with a typical histopathology and immunophenotype. Detailed clinicopathological and molecular studies are mandatory to elucidate the clonal relationship of metachronous lymphomas, as this has important clinical implication for treatment. Evaluation of the non-tumoral intestinal mucosa for enteropathy and immunostaining for MATK might help to differentiate a mimicker from a true MEITL. PMID- 30477647 TI - Cerebrospinal fluid leakage after posterior fossa surgery may impair brain metabolite clearance. AB - The discovery of the important role of cerebrospinal fluid (CSF) drainage of cerebral metabolite waste, known as the glymphatic system, has changed our view of brain waste clearance. We recently performed experiments to evaluate the glymphatic system in non-human primates (NHP). Here, we report the case of an NHP with iatrogenic CSF leakage. In this animal, solute transport through the brain, assessed by gadolinium injection in the CSF, was severely impaired by iatrogenic pseudomeningocele. This observation raises an important question: does brain surgery, and particularly posterior fossa surgery, lead to chronic impairment of parenchymal CSF circulation and solute transport? PMID- 30477648 TI - Corrigendum to "Detection of tobamoviruses by RT-PCR using a novel pair of degenerate primers" [J. Virol. Methods 259 (2018) 122-128]. PMID- 30477649 TI - The most wonderful time of the year. PMID- 30477650 TI - Researching, practising, and debating mental health care. PMID- 30477651 TI - Advancing our understanding of loneliness and mental health problems in young people. PMID- 30477652 TI - Need for further analysis to explore the association between ADHD and asthma - Authors' reply. PMID- 30477653 TI - Need for further analysis to explore the association between ADHD and asthma. PMID- 30477654 TI - Purpose, humility, civility, and science. PMID- 30477655 TI - Non-diagnostic recording of mental health difficulties in ICD-11. PMID- 30477658 TI - St Petersburg, Russia. PMID- 30477657 TI - Alessandro Serretti: focusing on the end target. PMID- 30477659 TI - A film of the moment: Bad Timing. PMID- 30477660 TI - The urgent need for more research on bipolar depression. PMID- 30477661 TI - The surgical principles of conjoined twin separation. AB - The surgical management of conjoined twin separation is a complex, multidisciplinary process that requires extensive pre operative planning and organization for optimal outcomes. Identification of detailed anatomic relationships is necessary prior to the separation. The use of 3D modeling is extremely helpful for conceptualization of the operation. The principles of the separation are dependent on the type of twin, although each variant of symmetric twins has certain commonalities related to their embryology that can be considered when planning the operation. The use of tissue expansion in the pre operative planning stage is highly recommended due to known issues with closure after separation. In order to ensure a safe, successful operation, we recommend organized pre operative planning meetings with at least one simulation of the separation event with multidisciplinary involvement. PMID- 30477662 TI - SnapshotDx Quiz: August 2016. PMID- 30477663 TI - Cells to Surgery Quiz: August 2016. PMID- 30477664 TI - Immunohistochemical Analysis of Cyclooxygenase-2 and Tumor Necrosis Factor Alpha in Periapical Lesions. AB - INTRODUCTION: The purpose of this study was to evaluate the expression of cyclooxygenase-2 (COX-2) and tumor necrosis factor alpha (TNF-alpha) in periapical granuloma (PG) and radicular cyst (RC) samples and to correlate it with the type of lesion, the intensity of the inflammatory infiltrate, and the thickness of the epithelial lining. METHODS: A total of 51 cases of periapical lesions (25 PGs and 26 RCs) were subjected to morphologic analysis and immunohistochemical study. The anti-COX-2 and anti-TNF-alpha antibodies were applied using the immunoperoxidase technique. Data were analyzed by the Mann Whitney test, Pearson chi-square test, Fisher exact test, and Spearman correlation. RESULTS: Analysis of the inflammatory infiltrate revealed that 80% of PGs exhibited a grade III infiltrate as opposed to a 19% rate in RCs (P < .001). Morphologic evaluation of the epithelial thickness of RCs revealed the presence of atrophic epithelium in 73% of cases. The majority of PGs had a score of 1 for COX-2 immunoexpression (n = 14, 54%) and a score of 2 for TNF-alpha expression (n = 16, 64%), whereas in cases of RCs a score of 1 was more prevalent for COX-2 and TNF-alpha expression (n = 17, 65%). Significant differences in the expression scores of COX-2 and TNF-alpha were detected in periapical lesions (P < .001). CONCLUSIONS: Based on these findings, we emphasize that RCs and PGs have a similar expression of inflammatory mediators (COX-2 and TNF-alpha) although the secretion of TNF-alpha by macrophages and of COX-2 by several cells was higher in PGs, indicating a greater inflammatory response in these lesions. PMID- 30477665 TI - Effect of Residual Dental Pulp Tissue on Regeneration of Dentin-pulp Complex: An In Vivo Investigation. AB - INTRODUCTION: Current pulp revascularization procedures in teeth with necrotic pulps and open apices have produced histologic evidence of connective tissue growth, cementum, and bone within the root canals of experimental animals. This study aims to investigate the effect of maintaining uninflamed residual apical pulp tissue on the histologic outcome of pulp-dentin complex regeneration after a revascularization procedure in immature ferret cuspid teeth. METHODS: Twenty eight cuspid teeth from 7 young male ferrets were used in this experiment. Seven teeth were reserved to serve as positive control samples without any treatment. In another 7 teeth, the pulp was completely extirpated (negative control), whereas the pulp of the remaining 14 teeth were removed to either 1-2 mm short of the apex (7 samples) or 2-4 mm short of the apex (7 samples). Blood clots were covered with mineral trioxide aggregate at the cementoenamel junction level of each tooth. Three months later, block sections were removed for histologic evaluations, and the data were statistically analyzed with the chi-square test (P < .05). RESULTS: All teeth with complete pulp extirpation showed the presence of bone inside the root canal. In contrast, the root canals for most teeth with pulp amputation 1-4 mm from the radiographic apex were filled with normal pulp, which extended coronally to the mineral trioxide aggregate, where hard tissue bridges had formed. CONCLUSIONS: Based on these results, we concluded that regeneration of the pulp-dentin complex is possible when the apical 1-4 mm of the apical pulp remains intact in immature teeth. PMID- 30477666 TI - Comprehensive Characterization of 2 Immature Teeth Treated with Regenerative Endodontic Procedures. AB - INTRODUCTION: Regeneration of the pulp-dentin complex is the penultimate goal of regenerative endodontic procedures (REPs). Histological outcomes have demonstrated reparative tissue formation in human teeth extracted post-REPs. However, lack of accurate characterization has precluded identification of the true nature of tissues formed post-REP. METHODS: Here, we present 2 case reports of tooth #29 and #9 treated with REPs and demonstrate their clinical, radiographic, and histological outcomes. RESULTS: Clinical outcomes revealed healing of apical periodontitis in both teeth and re-establishment of vitality responses in tooth #29. Moreover, radiographic assessments using 2D and 3D volumetric analyses demonstrate considerable increase in root development for both teeth. Further, histological outcomes evaluated using Hematoxylin and Eosin and immunohistochemical staining demonstrates presence of vascular and lymphatic structures as well as immune cell markers indicative of regeneration of an immunocompetent pulp. Lastly, examination of hard tissue deposition shows dentin like tissue in parts of tooth #29 demonstrating for the first time, regeneration of a pulp-dentin complex post-REP. CONCLUSIONS: Collectively, this is the first study demonstrating recapitulation of several tissues commonly found as part of a pulp-dentin complex in teeth treated with REPs. PMID- 30477667 TI - Influence of the Vehicle and Antibiotic Formulation on Cytotoxicity of Triple Antibiotic Paste. AB - INTRODUCTION: The aim of this study was to assess the influence of antibiotic formulations (tablet/capsule [TC] or United States Pharmacopeia [USP]-grade antibiotics) and vehicles (water [H2O] or macrogol + propylene glycol [MP]) on the cytotoxicity and pH of triple antibiotic pastes (TAPs). METHODS: L929 fibroblasts were exposed to TAPs prepared with TC or USP-grade antibiotics mixed with H2O or MP for 72 hours. Each isolated antibiotic with each vehicle, each isolated vehicle, and the culture medium were used as controls. Cytotoxicity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and neutral red assays. The pH was measured after 3 and 8 hours of immersion of the pastes in water. Data were analyzed using analysis of variance, the Bonferroni or Tukey posttests (alpha = 0.05), and the Pearson correlation test (alpha = 0.05). RESULTS: The pastes prepared with TC were less cytotoxic than pastes prepared with USP-grade antibiotics (P < .05), and pastes with the MP vehicle were less cytotoxic than pastes with H2O (P < .05). TC TAP + MP showed the lowest cytotoxicity, whereas USP-grade TAP + H2O showed the highest cytotoxicity (P < .05). All TAPs showed a pH ranging from 4.64-5.20. Irrespective of the vehicle, USP-grade TAP showed a lower pH than TC TAP (P < .05). TAPs with H2O had a lower pH than TAPs with MP (P < .05). CONCLUSIONS: The vehicle and the antibiotic formulations influenced the cytotoxicity and pH of TAP. The pastes prepared with TC and MP were less acidic and less cytotoxic than the type prepared with USP grade antibiotics and H2O. PMID- 30477668 TI - Pentraxin 3 Modulates the Inflammatory Response in Human Dental Pulp Cells. AB - INTRODUCTION: Pentraxin 3 (PTX3) has been suggested as a novel inflammatory biomarker in inflammation-associated diseases. The aim of this study was to examine the role of PTX3 in the inflammatory response of human dental pulp cells (HDPCs). METHODS: HDPCs were treated with tumor necrosis factor alpha (TNF alpha), and total RNA and protein were extracted. PTX3 messenger RNA and protein expression levels were analyzed using reverse transcription polymerase chain reaction and Western blotting, respectively. For PTX3 knockdown, HDPCs were transfected with a small interfering RNA against human PTX3. Macrophage chemotaxis after PTX3 silencing in HDPCs was assessed by transwell migration assays. RESULTS: TNF-alpha increased PTX3 messenger RNA and protein levels in HDPCs. TNF-alpha-induced PTX3 expression was mediated by extracellular signal regulated kinase 1/2 and nuclear factor kappa B. PTX3 knockdown decreased the expression levels of interleukin 6, interleukin 8, and monocyte chemoattractant protein 1 after stimulation with TNF-alpha in HDPCs. Moreover, PTX3 silencing in HDPCs significantly decreased the chemotactic migration of macrophages. CONCLUSIONS: Our findings indicate PTX3 plays a critical role in the regulation of pulp inflammatory processes and reveal its underlying molecular mechanism. PMID- 30477669 TI - Comparison between Single-file Rotary Systems: Part 2-The Effect of Length of the Instrument Subjected to Cyclic Loading on Cyclic Fatigue Resistance. AB - INTRODUCTION: The aim of this study was to compare the cyclic fatigue resistance of XP Shaper (XP), HyFlex EDM One File (EDM), and WaveOne Gold Primary (WOG) when operated according to their manufacturers' recommendations at different lengths and to investigate the cyclic fatigue limit of XP Shaper when operated at 3000 rpm. METHODS: One hundred fifty instruments from 4 different rotary systems (F2 Protaper Universal [PTU], WOG, EDM, and XP) were tested for their cyclic fatigue resistance in a simulated 90 degrees curved canal at a 37 degrees C water bath temperature at 3 different working lengths (15 mm, 17 mm, and 19 mm). The time taken for instruments to fracture was recorded, and the number of cycles to failure was calculated. Statistical analyses were performed by using Levene's test, Kruskal-Wallis test to identify specific groups with statistically significantly higher cyclic fatigue resistance at 5% significance level. Weibull analysis was performed to determine the predictability of survival for each instrument. RESULTS: XP Shaper had the highest cyclic fatigue resistance compared with all other instruments, followed by EDM, WOG, and then PTU. There was no statistically significant difference in the number of cycles to failure between the XP operated at 3000 or 1000 rpm in any of the tested working lengths. There was a reduction in the number of cycles to failure when the working length increased from 15 to 19 mm in EDM, WOG, and PTU. Scanning electron microscopy showed ductile fractures with classic dimpled features in all samples. CONCLUSIONS: XP has a very high resistance to cyclic fatigue compared with WOG, EDM, and F2 PTU. The time to fracture will decrease by almost one third when XP is operated at 3000 rpm. The results of both parts of this study suggest that XP appears to be safe to operate at 3000 rpm in endodontic retreatment. PMID- 30477670 TI - Virtual Simulation of Autotransplantation Using 3-dimensional Printing Prototyping Model and Computer-assisted Design Program. AB - This case report describes an innovative virtual simulation method using a computer-aided rapid prototyping (CARP) model and a computer-aided design (CAD) program for autotransplantation of an immature third molar.A compromised left mandibular second molar (#18) was extracted and replaced by autotransplantation using an immature left mandibular third molar (#17). In order to minimize the surgical time and injury to the donor tooth, a virtual 3-dimensional (3D) rehearsal surgery was planned. Cone-beam computed tomographic images were taken to fabricate the 3D printing CARP model of the donor tooth and tentative extraction socket. Subsequently, both CARP models were scanned with an intraoral scanner (CEREC Omnicam; Dentsply Sirona, Bensheim, Germany) followed by superimposition and virtual simulation of osteotomy preparation of the recipient alveolus using the CAD analysis program. During the surgery, the extraction socket was precisely prepared according to the predetermined location and dimensions via virtual simulation rehearsal surgery using CAD analysis. The donor tooth was atraumatically transplanted into the prepared socket. The follow-up examination revealed that the root developed with a normal periodontal ligament and lamina dura.Virtual simulation using a 3D printing CARP model and a CAD program could be clinically useful in autotransplantation of an immature third molar by ensuring an atraumatic and predictable surgery. PMID- 30477671 TI - Retraction Notice. PMID- 30477672 TI - SnapshotDx Quiz: November 2016. PMID- 30477673 TI - Cells to Surgery Quiz: November 2016. PMID- 30477674 TI - Core versus specialty rotations do not affect students' surgical development. AB - BACKGROUND: Research is scarce on how the diversity of surgical rotations affects students. We sought to assess the effect of core rotations compared to specialty rotations on students' development. METHODS: Students were given a suturing workshop at the beginning of their surgical clerkship along with a questionnaire. They performed both a simple and a complex suturing task at the beginning and end of the 2-month clerkship. The students were divided into 2 groups based on their surgical rotations. Technical skill and exam scores were compared. RESULTS: Thirty-eight students were included in the study. Objective scores increased for the simple task (14.2, standard deviation 4.5 vs 16.4, standard deviation 4.2, P = .04) and the complex task (12.9, standard deviation 5.3 vs 16.5, standard deviation 4.1, P < .01). Times decreased for the simple task (5.1, standard deviation 1.8 vs 4.1, standard deviation 1.3, min, P < .01) and the complex task (7.9, standard deviation 2.7 vs 6.3, standard deviation 1.5, min, P < .01). Using multivariate analysis, we found that reported hours in the operating room per week and previous hands-on experience affected proficiency of the simple suturing task only. Sixteen students had predominantly core surgical rotations. When compared to the 22 students with more specialty rotations, the only difference was gender (87.5% male vs 50.0% male, P = 0.02). There was no significant difference in the completion times (P = .96, .82), the objective scores (P = .06, .120), the written exam scores (P = .57), or the oral exam scores (P = .89). CONCLUSION: In this small study, it was found that the type of students' rotations does not affect surgical skill or knowledge acquisition. PMID- 30477675 TI - SnapshotDx Quiz: June 2016. PMID- 30477676 TI - Cells to Surgery Quiz: June 2016. PMID- 30477677 TI - Predictors for global perceived effect after physiotherapy in patients with neck pain: an observational study. AB - OBJECTIVE: To investigate the prognostic importance of a number of sensorimotor and psychological factors for global perceived effect (GPE) after physiotherapy in patients with neck pain. In addition to baseline values, change scores were used as independent variables to identify treatment-modifiable factors. DESIGN: Clinical cohort study. SETTING: Primary and secondary healthcare physiotherapy clinics. PARTICIPANTS: Patients (n=70) with non-specific neck pain. INTERVENTION: Usual care physiotherapy. METHODS: A three-dimensional motion tracking system was used to measure neck motion and sensorimotor variables, in addition to self reported outcomes covering personal, somatic and psychological factors at baseline (before treatment) and at 2 months. Logistic regression was used to analyse associations between the prognostic variables and the primary outcome (GPE) at 2 months. RESULTS: At baseline, neck motion and motor control, pain duration and functioning were the strongest predictors for GPE, with no effect of psychological factors. Among the change variables, reduced pain intensity [odds ratio (OR) 1.86; 95% confidence interval (CI) 1.31 to 2.62], increased functioning (OR 1.46; 95% CI 1.11 to 1.92), reduced disability (OR 1.12; 95% CI 1.05 to 1.20), reduced kinesiophobia (OR 1.21; 95% CI 1.07 to 1.37), reduced catastrophising (OR 1.09; 95% CI 1.09 to 1.18) and increased self-efficacy (OR 1.12; 95% CI 1.03 to 1.21) were significantly associated with GPE. CONCLUSIONS: Both baseline values and change in pain intensity and functioning predicted GPE at 2 months. Psychological factors such as kinesiophobia, catastrophising and self-efficacy were only able to predict outcome by their change scores, indicating that these factors are modifiable by common physiotherapy practice and are important for GPE. PMID- 30477678 TI - Effects of exercise training in water and on land in patients with COPD: a randomised clinical trial. AB - OBJECTIVES: To compare the effects of two similar 6-month protocols of high intensity exercise training, in water and on land, in patients with chronic obstructive pulmonary disease (COPD). DESIGN: Randomised controlled trial. SETTING: University-based outpatient clinic. PARTICIPANTS: Thirty-six patients with predominantly moderate-to-severe COPD completed the study. INTERVENTION: Patients were evaluated at baseline, at 3 months and at the end of the programme (i.e. 6 months). For both groups, the 6-month protocol consisted of high intensity endurance and strength exercises with gradual increase in time and/or workload, totalling 60 sessions. MAIN OUTCOMES: Objective monitoring of physical activity in daily life (PADL, primary outcome), lung function, peripheral and respiratory muscle strength, body composition, maximal and submaximal exercise capacity, functional status, quality of life, and symptoms of anxiety and depression. RESULTS: After 6 months of training, a significant improvement in PADL was seen for both groups [mean difference (95% confidence interval): land group 993 (358 to 1628) steps/day; water group 1669 (404 to 2934) steps/day]. Significant improvements were also seen in inspiratory, expiratory and peripheral muscle strength; maximal and submaximal exercise capacity; quality of life and functional status for both groups. There were no significant improvements in lung function, body composition, and symptoms of anxiety and depression for either group. No difference was found in the magnitude of improvement between the two types of training for any outcome. CONCLUSION: High-intensity exercise training in water generates similar effects compared with training on land in patients with moderate-to-severe COPD, rendering it an equally beneficial therapeutic option for this population. CLINICAL TRIAL REGISTRATION NUMBER: NCT01691131. PMID- 30477679 TI - Standardized Tracheostomy Education Across the Enterprise. AB - PURPOSE: The purpose of this quality improvement project was to create a Tracheostomy Subject Matter Expert (Trach SME) Committee to standardize tracheostomy care, education, and the discharge process across Boston Children's Hospital. DESIGN AND METHODS: Boston Children's Hospital (BCH) is a free-standing urban tertiary pediatric hospital with 15 inpatient units. The newly formed Trach SME Committee evaluated the discharge process across the enterprise including hospital satellites and intra-hospital practice. Education materials were centralized, and policies were reviewed, revised and standardized to reflect current best practice. The Trach SME provided education to Trach Champions from each area that became resources for their respective units. The Trach SME also developed measurement outcomes to assess the effectiveness of the education process. RESULTS: In the implementation year of 2104, our 7-day unplanned readmission rate for tracheostomy patients was 18.18%. This rate decreased to 6.67% in 2015 and to 0% in 2016. In 2015, we began to monitor 30-day unplanned readmissions and the rate was 6.67% in 2015 and decreased to 0% in 2016. CONCLUSIONS AND PRACTICE IMPLICATIONS: Standardization of policies, procedures and caregiver educational materials for the management of patients with a tracheostomy tube improved tracheostomy care across the enterprise and reduced tracheostomy readmission rates. PMID- 30477680 TI - ? AB - The incidence of basal cell carcinoma (BCC) is increasing as the population is aging and doubles every ten years. Surgery is the first-line treatment of BCC. Dermatological surgery is an oncological skin surgery whose first objective is to obtain a complete resection of the tumor. Its aim is also to reconstruct the defect using the optimal repair technique for the best cosmetic and scarring outcome and without functional impairment. The dermatological approach with the "oncological reading" of cutaneous tumors constitutes the essential preliminary time to the diagnosis of BCC and the identification of its limits. The perfect knowledge of the security margins in accordance with the guidelines allows a complete excision and a reconstruction in one stage under local anesthesia in the majority of cases. The surgical treatment must use 3D histology techniques or micrographic surgery to manage difficult cases of aggressive BCC in high risk zone or recurrence. Management of very aggressive BCC or locally advanced BCC is discussed in a multidisciplinary consultation by assessing the benefit/risk ratio of the surgical treatment and by identifying the appropriate surgeon after documenting the tumor, its operability and patient's adherence to the surgical treatment. (c) 2018. Published by Elsevier Masson SAS. All rights reserved. Cet article fait partie du numero supplement Prise en charge des carcinomes basocellulaires difficiles a traiter realise avec le soutien institutionnel de Sun Pharma. PMID- 30477681 TI - ? AB - Basal cell carcinoma (BCC) is a very common tumor, of which the diagnosis is generally easy. Clinical prediction of histopathological subtype however is however often difficult, i.e. the majority of sclerosing BCCs believed to be morpheaform are in fact trabecular or nodular. There is a subgroup of aggressive BCCs, including trabecular (the most common), morpheaform (rare) and micronodular (very rare) subtypes. Differentiating trichoblastoma from BCC is not always easy, but there are distinctive histopathologic criteria and preferential expression of Berp4 in BCC and PHLDA1 in trichoblastoma that may be of help. The group of trichoblastic tumors comprises giant but benign trichoblastomas and trichoblastic carcinomas at the end of the spectrum (of low or high grade). In case of metastatic BCC, one must rule out trichoblastic carcinoma. Morphologic variants of BCC such as pigmented, clear cell, granular cell BCC or BCC with areas of keratinisation are not of poorer prognosis than the classic types. On the opposite, BCC with sebaceous differentiation (in fact sebaceomas) belong to the spectrum of tumors found in Muir-Torre and must be identified. Basosquamous BCCs should be treated like squamous cell carcinomas as they are more aggressive than the nodular subtype. Cet article fait partie du numero supplement Prise en charge des carcinomes basocellulaires difficiles a traiter realise avec le soutien institutionnel de Sun Pharma. PMID- 30477682 TI - ? AB - Radiotherapy is an available but not well-known treatment for management of basal cell carcinoma. National organizations have established that standard therapy is complete surgical removal and radiation therapy is an option for inoperable tumors or those where the post-operative defect would be cosmetically disfiguring or functionally disabling. These therapeutic options, with histological sample, should be considered in the multidisciplinary management of patients with basal cell carcinoma. There are several types of radiotherapy: external radiation or interstitial brachytherapy, unfortunately, there is no consensus in the literature and the range of radiation regimens in common use is large. Very few randomized studies have been conducted to defi the optimum treatment in terms of recurrence rate, cosmetic outcome and side-eff In most of studies, the overall local control rate was between 80-100% and over 90% of patients reported good or excellent cosmetic outcome. Side-eff of radiotherapy most commonly reported are minor but in young patients one must be alert to the theoretical possibility of the induction of secondary malignancies. Cet article fait partie du numero supplement Prise en charge des carcinomes basocellulaires difficiles a traiter realise avec le soutien institutionnel de Sun Pharma. PMID- 30477683 TI - ? AB - Until recently, advanced BCC were only accessible to a highly morbid surgery not necessarily proving to be carcinologic, and leaving terrible dysmorphic sequelae hard to accept by the patient. Another possibility, the only one in case of metastatic BCC, was chemotherapy which efficacy has never been proven in a clinical trial. Radiotherapy is most often not accessible because of previous radiotherapy or because of the localization or the extension of the lesion. The discovery of the importance of the sonic hedgehog pathway in the physiopathology of BCC has opened a new strategy with the development of targeted anti SMO drugs inactivating the pathway. Two molecules have become available following Phase I and II studies: vismodegib (Erivedge(r)) the first in class indicated for locally advanced and metastatic BCC and sonidegib (Odomzo(r)) indicated only for locally advanced BCC. The pharmacokinetic profiles of sonidegib and vismodegib showed several differences. No head to head comparative studies are available between these two drugs. Their pivotal phase II studies had similar study designs and endpoints. The objective response rate (ORR) by central review for vismodegib was 47.6% (95% CI 35.5-60.6) at 21 months follow-up. The ORR for sonidegib according to central review at 18 months follow-up is 56.1% (95% CI 43.3-68.3). Although both treatments share a similar adverse event profile with possible numerically differences in incidence, most patients will discontinue hedgehog inhibitors treatment in the long term because of side effects. Some resistant cases to these drugs have been described but are rather rare. In case of resistance or bad tolerability to the drug future hopes rely on immunotherapy currently under investigation. (c) 2018. Published by Elsevier Masson SAS. All rights reserved. Cet article fait partie du numero supplement Prise en charge des carcinomes basocellulaires difficiles a traiter realise avec le soutien institutionnel de Sun Pharma. PMID- 30477684 TI - The biological and the social in the origin and development of language: Comment on "Rethinking foundations of language from a multidisciplinary perspective" by Tao Gong, Lan Shuai, Yicheng Wu. PMID- 30477685 TI - Language as a human-driven complex adaptive system: Comment on "Rethinking foundations of language from a multidisciplinary perspective" by T. Gong et al. PMID- 30477686 TI - "Socio-cultural transmission" in language evolution?: Comment on "Rethinking [the] foundations of language from a multidisciplinary perspective" by Tao Gong, Lan Shuai, & Yicheng Wu. PMID- 30477687 TI - Effects of geometrical and mechanical properties of cells on micro-jet and bubbles: Comment on "Shock wave-induced permeabilization of mammalian cells" by Luz M. Lopez-Marin et al. PMID- 30477688 TI - Moving toward realistic models: Comment on "Modeling thrombosis in silico: Frontiers, challenges, unresolved problems and milestones" by A.V. Belyaev et al. PMID- 30477689 TI - Sexuality and sexual experiences during gender transition: A thematic synthesis. AB - AIM: To establish what impact, if any, the gender-affirmation process, has on sexuality and sexual experiences. INTRODUCTION: Sexuality is a multi-faceted construct that influences our attraction to others. Gender transition is the process of aligning our physical sex characteristics with our psychological gender. Our sexuality and our gender identity are often mistakenly assumed to be inextricably linked. It is important to consider and understand the influence of the gender-affirmation process on sexuality and sexual experiences. METHOD: A thematic synthesis of the available qualitative literature regarding sexuality, and sexual experiences in both transgender people and their partners were appraised, and synthesised. Thomas and Harden's (2008) stepwise process for conducting a thematic synthesis was followed. RESULTS: A total of seven articles were of relevance and included in the review. Two analytical and six sub-themes were found. The two analytical themes are: 'Re-negotiating previous 'norms" and 'Establishing identity'. CONCLUSION: During the gender-affirmation process, sexuality, and sexual experiences alter. This has clinical implications for transgender people and their partners, in particular, valuable therapeutic discussion points that need to be considered during the gender-affirmation process. PMID- 30477690 TI - Variance component estimates for post-thaw sperm variables measured by computer assisted semen analyzer for inbred and non-inbred Hereford bulls. AB - Inbreeding has been shown to have negative effects on animal reproductive performance. It, however, has not been documented as to the extent that inbreeding impacts sperm cell characteristics especially after cells have undergone cryopreservation. In the present study, therefore, there was evaluation of sperm motion and size characteristics from two inbred lines and non-inbred Hereford bulls using Computer Assisted Sperm Analysis (CASA). Pre-frozen semen samples were obtained from Line 1, Prospector, and a non-inbred Hereford bulls. Average inbreeding of each group was 27%, 45%, and 0%, for Line 1, Prospector, and non-inbred groups, respectively. For each bull, two straws (0.5 ml) were evaluated, within each straw two slides with ten fields per slide analyzed with the CASA. Cells were analyzed by mixed model analysis using a model that contained line as fixed effect and individual bull, straw, slide, and fields are random effects. No significant differences between lines of bulls were found for motility or progressive motility. For the head elongation (ELON), and head area (AREA) significant differences existed between lines. Mean separation indicated that Line 1 group had a larger head area and the heads were not as elongated as the Prospector and non-inbred group cells. The lack of significant differences for motility and progressive motility across lines was surprising and indicates there was no inbreeding depression for post-thaw semen characteristics. One explanation for this could be that indirect selection pressure was placed on these characteristics as inbreeding was increased. PMID- 30477691 TI - Contribution of microRNAs to the immunosuppressive function of mesenchymal stem cells. AB - Mesenchymal stem/stromal cells (MSCs) are progenitor cells identified in many adult tissues, in particular in bone marrow or adipose tissue and, in placental tissues. MSCs exert pleiotropic functions that render them attractive for many clinical applications, both in degenerative and inflammatory diseases. Their main mode of action is through the secretion of trophic factors that can be released in the extracellular milieu or packaged within extracellular vesicles. These factors can be proteins, lipids, mRNAs or miRNAs that possess diverse effects, notably pro-angiogenic, anti-fibrotic, anti-apoptotic or anti-inflammatory. The anti-inflammatory role of a number of miRNAs has been demonstrated with different types of immune cells but few have been associated with the immunomodulatory function of MSCs. In this review, we summarize the data on the miRNAs that have been validated as participating to the anti-inflammatory role of MSCs. PMID- 30477692 TI - SnapshotDx Quiz: April 2017. PMID- 30477693 TI - Cells to Surgery Quiz: April 2017. PMID- 30477694 TI - First case of proven invasive pulmonary infection due to Trichoderma longibrachiatum in a neutropenic patient with acute leukemia. AB - Trichoderma species are saprophytic filamentous fungi that can be found all over the word. These fungi show increasing medical importance as opportunistic human pathogens, particularly in immunocompromised patients. Invasive infections due to Trichoderma are rare and definitive diagnosis is complex to achieve because of the lack of specific diagnosis tools. We report in this work the first proven case of invasive pulmonary infection due to T. longibrachiatum in a 69-year-old white male with hematologic malignancy. The patient was successfully treated initially with voriconazole alone followed by a combination of voriconazole and caspofungine. PMID- 30477695 TI - SnapshotDx Quiz: February 2016. PMID- 30477696 TI - Cells to Surgery Quiz: February 2016. PMID- 30477697 TI - Sleep & work, work & sleep. PMID- 30477698 TI - Control Strategies for Infection Prevention in Total Joint Arthroplasty. AB - Despite the development of newer preventative measures, the rate of infection continues to be approximately 1% for patients undergoing total joint arthroplasty (TJA). The extent of the infection can range from a mild superficial infection to a more serious periprosthetic joint infection (PJI). PJIs not only play a significant role in the clinical well-being of the TJA patient population, but also have substantial economic implications on the health care system. Several approaches are currently being used to mitigate the risk of PJI after TJA. The variety of prophylactic measures to prevent infection after TJA must be thoroughly discussed and evaluated. PMID- 30477699 TI - Technologies to Augment Rotator Cuff Repair. AB - Healing rates after rotator cuff repair vary widely. New technologies seek to improve tendon to bone healing with the addition of platelet-rich plasma, stem cells, and biological and synthetic grafts. Platelet-rich plasma and mesenchymal stem cells are used to help create a favorable environment for tendon to bone healing, and grafts and scaffolds provide structural support for repair. The efficacy of platelet-rich plasma and stem cell products seems to be variable, with different products offering different levels of cytokine and growth factors. Scaffold material is also variable with a wide range of synthetic and biological grafts. PMID- 30477700 TI - New Technology in the Treatment of Hallux Rigidus with a Synthetic Cartilage Implant Hemiarthroplasty. AB - Synthetic cartilage implant surgery is an excellent option for the patient with great toe arthritis and good alignment of the toe who wishes to retain first metatarsophalangeal motion and obtain 90% improved pain relief and function. Patients with osteoporosis, osteopenia, or bone defects from surgery or disease may not maintain the implant position due to poor bone quality, resulting in less than desired outcomes. Despite this being a straightforward surgery, patients need to be aware that the pain relief may not begin until 3+ months after surgery because this procedure does require bone resection and implant placement. PMID- 30477701 TI - The Use of Tantalum Metal in Foot and Ankle Surgery. AB - There are several reconstructive procedures in foot and ankle surgery wherein structural grafts are needed to fill defects, restore height, and maintain correction while providing an osteoconductive environment until fusion occurs. Traditionally used autografts and allografts have their disadvantages and limitations. Porous tantalum, with stiffness similar to bone and its biocompatibility, can be a viable option in foot and ankle reconstructive procedures. PMID- 30477702 TI - Additive Manufacturing in Total Joint Arthroplasty. AB - Additive manufacturing (AM) has demonstrated the potential to revolutionize manufacturing for various applications across the medical, aerospace, automobile, and energy sectors. It is a layer-by-layer manufacturing process in which the computer-aided design model is sliced into layers and each layer is deposited successively to realize the final product. This article provides a general overview of AM and discusses current state-of-the-art AM methodologies as they apply to total joint arthroplasty. Specifically, details on their applications and current challenges are summarized to provide orthopedic surgeons with a basic understanding of current and potential applications of AM in total joint arthroplasty. PMID- 30477703 TI - Technologies in the Treatment of Bone Marrow Edema Syndrome. AB - Bone marrow edema syndrome is a rare and self-limited syndrome with an unknown cause. The natural time course for improvement of clinical symptoms and normalization in MRI lasts from 3 to 18 months. This entity must be distinguished from other causes of marrow abnormality, such as stress fractures and osteonecrosis, for the best treatment options. Various treatments from conservative to surgical have been made to provide pain relief and accelerate the natural course of the disease. This article reviews bone marrow edema syndrome with a focus on treatment in the foot and ankle. PMID- 30477704 TI - Nanopatterning and Bioprinting in Orthopedic Surgery. AB - In part 1 of this article, the authors explore nanoscale modifications of the surfaces of biomaterials, which offer an exciting potential venue for the prevention of bacterial adhesion and growth. Despite advances in the design and manufacture of implants, infection remains an important and often devastating mode of failure. In part 2, additive technologies for tissue engineering, live cell printing (bioprinting), and tissue fabrication are briefly introduced. The similarities and differences between bioprinting and non-bio 3D-printing approaches and requirements are discussed, along with terminological definitions, current processes, requirements, and biomaterial and cell-type selection and sourcing. PMID- 30477705 TI - A Randomized Study of Exercise and Fitness Trackers in Obese Patients After Total Knee Arthroplasty. AB - Functional limitations persist in obese patients after total knee arthroplasty (TKA). This study assessed the effect of an exercise program (EP) and fitness trackers (FT) in obese patients with TKA. Sixty patients 1 year after orthopedic surgery were recruited and received a 16-week tailored EP; half were randomized to receive an FT. FT had no measurable effect compared with EP alone. EP improved knee range of motion, strength, and quality-of-life scores. This study provides preliminary evidence that a 16-week EP in obese individuals 1 year post TKA is feasible and effective in improving function and quality of life. PMID- 30477706 TI - New Imaging, Diagnostic, and Assessment Techniques in Orthopedic Trauma. AB - This article examines new imaging, diagnostic, and assessment techniques that may affect the care of patients with orthopedic trauma and/or infection. Three dimensional imaging has assisted in fracture assessment preoperatively, whereas improvement in C-arm technology has allowed real-time evaluation of implant placement and periarticular reduction before leaving the operating room. Advances in imaging techniques have allowed earlier and more accurate diagnosis of nonunion and infection. Innovations in bacteriologic testing have improved the sensitivity and specificity of perioperative and peri-implant infections. It is critical that surgeons remain up to date on the options available for optimal patient care. PMID- 30477708 TI - New Technologies in Pediatric Deformity Correction. AB - The ability to correct limb deformities is one of the core elements of pediatric orthopedics. The term, orthopedics, is derived from the Greek language and means straightening (ortho) children (paidos). New advances in the evaluation and management of children with limb alignment or limb length issues are constantly appearing. This review highlights some of the recent technologies that have been developed to improve the care of these children. PMID- 30477707 TI - New Technologies in Pediatric Spine Surgery. AB - Spinal fusion in young children for treatment of early onset scoliosis is not optimal because it limits growth and contributes to long-term lung compromise. Various types of growth-friendly spinal implants and newer technologies have been introduced in the past few years. Similarly, in adolescent idiopathic scoliosis, fusion decreases spinal mobility and may lead to development of adjacent level disc degeneration. A variety of different new technologies have been developed for alternative surgical approaches that halt curve progression while maintaining spinal mobility. PMID- 30477709 TI - Emerging Technologies in Upper Extremity Surgery: Polyvinyl Alcohol Hydrogel Implant for Thumb Carpometacarpal Arthroplasty and Processed Nerve Allograft and Nerve Conduit for Digital Nerve Repairs. AB - In the field of upper extremity surgery there are myriad new and developing technologies. The purpose of this article is to highlight a few of the most compelling new technologies and review their background, indications for use, and most recently reported outcomes in clinical practice. PMID- 30477710 TI - Safety and Efficacy of Intraoperative Computer-Navigated Versus Non-Navigated Shoulder Arthroplasty at a Tertiary Referral. AB - Emerging technologies in shoulder arthroplasty, such as 3-dimensional planning software and real-time intraoperative navigation, are now available for surgeons to perform more accurate placement of the glenoid component without malposition or perforation. Using these tools, the surgeon can visualize the version, inclination, and containment of the implant and determine whether augmented components would be necessary. This review provides an updated investigation of the present literature to elucidate the role of computer navigation in modern shoulder arthroplasty. PMID- 30477711 TI - New Technologies in Orthopedics. PMID- 30477712 TI - Mitochondrial DNA diversity of the Roma from northeastern Bosnia, Bosnia and Herzegovina. AB - This study is the first report on the mtDNA diversity in the Roma population from Bosnia. The main aim of this study was to analyse the mtDNA diversity in the studied population, evaluate the genetic relations with other European Roma populations, and analyse the influences of the Roma gene flow on the mitochondrial profile of the Roma from northeastern Bosnia. MtDNA variability in the analysed population has been studied by means of hypervariable segment I and II (HVSI/II) of the control region sequencing and analysis of restriction fragment-length polymorphisms of the coding region. Our results show that genetic structure of the Roma from northeastern Bosnia has a combination of lineages of three main layers: specific founder of Indian origin (M5a1 and M35b) and founder non-M lineages of Indian/European origin (H7a, X2b and X2d) and lineages of European/Middle East origin (H, H1, H11a, V, T2b, K1b and W). The distribution of the haplogroups in the gene pool of the comparative European Roma populations indicates the separate origin of the Bosnian Roma and the Bulgarian Vlax and Croatian Vlax Roma. The data suggest that mitochondrial gene pool of the Roma population from northeastern Bosnia might be a consequence of early parting and the later different migration routes that are part of their demographic history. Our data confirm the high genetic heterogeneity of the Roma populations that can be shaped by effects of genetic drift, isolation and low effective population size, and this correlates with the migratory history of the Roma. PMID- 30477713 TI - Porous organic cage incorporated monoliths for solid-phase extraction coupled with liquid chromatography-mass spectrometry for identification of ecdysteroids from Chenopodium quinoa Willd. AB - Here, a porous organic cage (POC)-incorporated polymeric monolith was fabricated in a syringe through the introduction of the POC into poly(ethylene glycol dimethacrylate) monolith in a one-step traditional free-radical polymerization proceess. The resulting monolithic phases were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FT-IR), powder X-ray diffraction (PXRD), nitrogen adsorption/desorption experiments and thermogravimetric analysis (TGA), which confirmed the successful incorporation of the POC in the monolithic matrix. The functionality of the POC-incorporated poly(EDMA) monolith facilitated for the solid phase extraction (SPE) of 20-hydroxecdysone (an ecdysteroid) from Chenopodium quinoa Willd. extract coupled with UPLC-QqQ-MS/MS, exhibiting satisfactory accuracy (93-106%), precision (< 6.5%) and reusability. In addition, UPLC-Q-Exactive-Orbitrap-MS/MS analysis of the quinoa sample after SPE by POC incorporated monolith provided the identification of 20-hydroxecdysone and three other ecdysteroids. These results demonstrate the potential of POC-incorporated monoliths for the SPE of ecdysteroids from complex plant systems. PMID- 30477714 TI - Pulsed elution modulation for on-line comprehensive two-dimensional liquid chromatography coupling reversed phase liquid chromatography and hydrophilic interaction chromatography. AB - In this work, a reversed phase liquid chromatography (RPLC) coupling to hydrophilic interaction chromatography (HILIC) system has been constructed, combining with pulsed elution reversed phase liquid chromatography (PE-RPLC) and HILIC to comprehensively analyze P. ginseng root extract, which is rich in saponins. By the application of pulsed elution (PE) modulation technique, the proposed RPLC * HILIC system allows the chromatographic separation to be optimized independently in both dimensions. In the first dimension (1D), PE modulation is achieved by the separation of a complex mixture, such as P. ginseng root extract, with a PE gradient. This PE gradient contains a set of pulses where the solvent strength increases gradually. Thus, the modulation of 1D eluent is realized by stepwise-pulse fractionation, rather than by a traditional two dimensional interface. Furthermore, the number of fractions and the fractionated period can be regulated independently, which leads to independent adjustment of the separation cycle in the second dimension (2D) separation without the loss of D1 separation efficiency. To overcome the inherent solvent incompatibility of RPLC * HILIC, we introduced a newly developed trapping interface, equipped with bypass. The result indicates excellent separation of saponins in P. ginseng root extract. Compared with the traditional modulation method, the proposed RPLC * HILIC system has extreme flexibility, those modulation time could be regulated in a large range without re-optimizing the 1D PE gradient. Worthily mentioned, the proposed RPLC * HILIC system shows excellent orthogonality, and 20% more peaks could be obtained with current method compared to the traditional value based modulation method. Independent regulation of both dimensions could enable the proposed modulation method to be widely applied for complex samples analysis in ordinary laboratory. PMID- 30477715 TI - Ionic liquids as stationary phases for gas chromatography-Unusual selectivity of ionic liquids with a phosphonium cation and different anions in the flavor, fragrance and essential oil analyses. AB - Room-temperature ionic liquids (ILs) have been shown to be successful as stationary phases (SPs) for gas chromatography in several fields of applications because of their unique and tunable selectivity, low vapor pressure and volatility, high thermal stability (over 300 degrees C), and good chromatographic properties. This study has been focused on two ILs based on a phosphonium cation (trihexyl(tetradecyl)phosphonium, P66614) combined with different anions, previously shown to be suitable as gas chromatography (GC) SPs. In particular, trihexyl(tetradecyl)phosphonium bis[(trifluoromethyl)sulfonyl]imide ([P66614+] [NTf2-]) and trihexyl(tetradecyl)phosphonium chloride ([P66614+] [Cl-]) were investigated, as the Abraham linear solvation energy relationship has shown their ability to interact with the solute(s) when tested with a set of 26-34 probe analytes. The chromatographic performance were investigated on narrow bore and conventional test columns using the following: i) Grob test, ii) a group of model mixtures of compounds characteristic of the flavor, fragrance and essential oil fields (FFMix), iii) a standard mixture of 29 volatile allergens (AlMix), and iv) two essential oils of different complexity (sage and vetiver essential oils). The columns coated with the investigated IL SPs were characterized by similar polarity (Polarity Number (PN): 37 for [P66614+] [Cl-] and 33 for [P66614+] [NTf2 ]), high efficiency and highly satisfactory inertness. The two IL SPs also exhibited a completely different separation performance, with [P66614+] [Cl-] test columns mainly characterized by high retention and selectivity based on the analyte functional groups, and [P66614+] [NTf2-] test columns featured by short retention and selectivity mainly related to the analyte volatility and polarity. These results were also confirmed with the analysis of sage and vetiver essential oils. PMID- 30477716 TI - Determination of non-volatile components of a biodegradable food packaging material based on polyester and polylactic acid (PLA) and its migration to food simulants. AB - Bioplastic materials are increasingly used due to its benefits for the environment preservation. Among them, food packaging materials based on polylactic acid (PLA) are among the most employed. In this work, a sample treatment methodology based on dissolution/precipitation has been optimized, selecting finally dichloromethane/ethanol as solvent/antisolvent system. The extracts obtained were analysed by UPLC-MS(QTOF), that allowed the identification of the main PLA non-volatile components. The recovery results were between 100.9 to 114.0%. The methodology was applied to the analysis of pellets and films of a PLA-polyester blend sample. A total of 37 different compounds were detected, where the four compounds with the highest intensity in pellet samples were cyclic oligomers coming from the polyester part of the blend and composed by adipic acid (AA), phthalic acid (PA) and butanediol (BD). Migration experiments to 3 food simulants were also performed: ethanol 95% (v/v), ethanol 10% (v/v) and acetic acid 3% (w/v). The results showed that in addition to those compounds previously detected in the film, new compounds coming from the reaction of PLA components with food simulants were present in migration solutions. PMID- 30477717 TI - MXene/reduced graphene oxide hydrogel film extraction combined with gas chromatography-tandem mass spectrometry for the determination of 16 polycyclic aromatic hydrocarbons in river and tap water. AB - In this study, MXene/reduced graphene oxide (MXene/rGO) hydrogel film, a novel nanomaterial was prepared and used as adsorbent for extraction of 16 polycyclic aromatic hydrocarbons (PAHs) in river and tap water prior to gas chromatography tandem mass spectrometric analysis (GC-MS/MS). The properties of MXene/rGO hydrogel film were characterized by scanning electron microscope (SEM) and X-ray diffractometer (XRD). The PAHs in water samples were enriched with MXene/rGO, then eluted with n-hexane, finally separated with HP-5MS column (30 m * 0.32 mm, 0.25 MUm), and finally detected by mass spectrometer with SIM mode. The method had linear ranges of 0.005-2.00 MUg/L with the correlation coefficients greater than 0.995. The recoveries of the method ranged from 80.3% to 109.9%, with the relative standard deviations (RSDs) less than 10.01%. The limits of detection (LODs) were less than 0.005 MUg/L. The method is simple, sensitive, precise, accurate, environmentally-friendly and it has been successfully applied to the determination of 16 PAHs in river and tap water samples. PMID- 30477718 TI - High performance liquid chromatography as a molecular probe in quantitative structure-retention relationships studies of selected lipid classes on polar embedded stationary phases. AB - Studies on the retention mechanism of lipid classes (phospholipids, sphingomyelin) were performed using three polar-embedded stationary phases for which diol, phosphate, amino, and amide moieties were incorporated into the alkyl chains of the stationary phases. Their structural descriptors were determined using the quantum-mechanical method. The retention behavior of the analytes was investigated as a function of different binary hydro-organic mobile phases containing (90%/10% acetonitrile (or methanol)/0.1% formic acid). It was found that the elution order on the tested stationary phases was governed chiefly by the hydrophilicity of the analyte and indicated the existence of a hydrophilic interaction liquid chromatography retention mechanism. Quantitative structure retention relationships studies were performed to further elucidate the retention mechanism. These studies showed that the dominant analyte descriptor influencing retention on the alkyl-amine stationary phase was the logarithm of the octanol water partition coefficient. For the phospho-diol and alkyl-amide stationary phases, the dominant analyte descriptor influencing retention was the molar volume and solvent accessible area of the analyte, respectively. PMID- 30477719 TI - Efficacy and safety of preservative-free timolol 0.1% gel in open-angle glaucoma and ocular hypertension in treatment-naive patients and patients intolerant to other hypotensive medications. AB - GOALS: To assess the efficacy and safety of preservative-free timolol 0.1% gel in patients with primary open-angle glaucoma (POAG) and ocular hypertension (OHT). METHODS: In this multicenter, open-label, non-controlled clinical trial in Algeria, treatment-naive patients with intraocular pressure (IOP)>20mmHg and<31mmHg (treatment-naive patients, group 1) and patients with IOP controlled by current ocular monotherapy but presenting with local intolerance in at least one eye (intolerant patients; group 2) were eligible. Timolol gel was administered once daily in the morning for 84 days. The primary efficacy criteria were reduction in IOP (group 1) and maintenance of baseline IOP (group 2). RESULTS: Overall, 93 patients were included (53 in group 1, 40 in group 2). All patients in group 2 had been previously treated with preserved eye drops. In group 1, patients showed a significant reduction in IOP with mean changes in the worse eye of -10.3+/-3.0mmHg at D28 and -10.8+/-2.5mmHg at D84 (P<0.0001). In group 2, the maintenance of efficacy on IOP at D84 was satisfactory in 91.7% of patients (worse eye). Preservative-free timolol gel was well tolerated in both groups. In group 2, the overall symptom score was significantly reduced from 8.6+/-5.1 to 0.9+/-1.6 at D28 and 0.7+/-1.2 at D84 (P<0.0001), and the overall ocular sign score from 3.7+/-2.1 to 0.8+/-1.0 at D28 and 0.6+/-0.8 at D84 (P<0.0001). CONCLUSIONS: This preservative-free timolol 0.1% gel was effective in decreasing IOP in treatment-naive patients and in controlling IOP and reducing ocular signs and symptoms in patients intolerant to their previous preserved medications. PMID- 30477720 TI - SnapshotDx Quiz: July 2016. PMID- 30477721 TI - Cells to Surgery Quiz: July 2016. PMID- 30477722 TI - SnapshotDx Quiz: May 2017. PMID- 30477723 TI - Cells to Surgery Quiz: May 2017. PMID- 30477724 TI - Meta-Analysis Evaluating the Effect of Left Coronary Dominance on Outcomes After Percutaneous Coronary Intervention. AB - Prognostic significance of coronary circulation dominance remains controversial. The primary objective of this meta-analysis was to pool all the available evidence to assess the influence of left coronary dominance (LD) on outcomes in patients who underwent percutaneous coronary intervention (PCI). MEDLINE, Cochrane CENTRAL, and Scopus databases were searched for all observational studies and randomized controlled trials that investigated the association between coronary dominance and outcomes in patients who underwent PCI. Odds ratios (OR) and 95% confidence intervals from individual studies were pooled using a random effects model. A total of nine studies including 266,119 patients were included. On pooled analysis, it was noted that LD was associated with significantly increased odds of in-hospital (OR: 1.54 [1.12, 2.11]; p = 0.007), 30-day (OR: 2.16 [1.22, 3.84]; p = 0.008), and long-term mortality (OR: 1.83 [1.33 to 2.50]; p < 0.001). LD patients also experienced a significantly higher incidence of major adverse cardiac events (OR: 1.27 [1.03, 1.58]; p = 0.03) and failed PCI (OR: 1.30 [1.03, 1.65]; p = 0.03). In contrast, no significant difference was noted between LD and non-LD patients in the incidence of stent thrombosis (OR: 1.28 [0.55, 3.01]; p = 0.57; I2 = 0%) or reinfarction (OR: 1.73 [0.90, 3.35]; p = 0.10; I2 = 63%). In conclusion, this meta-analysis suggests that patients with LD coronary anatomy are at significantly increased risk for mortality after PCI compared with patients with a non-LD anatomy. PMID- 30477726 TI - Comparison of the Utility of Transesophageal Echocardiography in Patients With Acute Ischemic Stroke and Transient Ischemic Attack Stratified by Age Group (<60, 60 to 80, >=80 Years). AB - The objective was to study the utility of transesophageal echocardiography (TEE) in affecting acute ischemic stroke treatment of older adults (age >=80 years). Patients hospitalized in January 2010 and February 2015 were included who had TEE ordered as part of their diagnostic workup at a tertiary medical center. We studied 515 hospitalized patients with acute stroke or transient ischemic attack who underwent TEE. The proportion of patients with important TEE findings was 35%. However, TEE changed management in only 2.5% of cases. When anticoagulation for proximal mobile aorta atheroma was excluded, no change in management resulted from TEE for patients older than 80 years. In conclusion, TEE has a low likelihood of a pathologic finding that resulted in a change in treatment strategy, especially in patients >=80 years of age. PMID- 30477727 TI - SnapshotDx Quiz: October 2016. PMID- 30477725 TI - Association of Plasma Lipoprotein(a) With Long-Term Adverse Events in Patients With Chronic Kidney Disease Who Underwent Percutaneous Coronary Intervention. AB - We aimed to determine the association of plasma lipoprotein(a) (Lp[a]) with long term clinical outcomes in patients with chronic kidney disease (CKD) after percutaneous coronary intervention (PCI) in an observational cohort study. Four hundred and twenty-seven consecutive patients with CKD who underwent PCI from January 2013 to December 2013 were included in this study. Patients were divided into 2 groups according to median levels of Lp(a). Outcomes included 2-year risk of major adverse cardiovascular and cerebrovascular events (MACCEs) and bleeding according to Bleeding Academic Research Consortium definitions. Overall, median of Lp(a) in all the patients was 217.8 mg/L. The 2-year MACCE rate across the high Lp(a) and low Lp(a) group was 23.0% versus 15.4% (p = 0.047) and bleeding event rate of the two groups 8.9% versus 4.2% (p = 0.049). The Lp(a) was significantly and positively correlated with high-sensitivity C-reactive protein levels (r2 = 0.03, p < 0.001). Kaplan-Meier curves revealed that high Lp(a) had higher incidence of bleeding than low Lp(a) (p = 0.043) and had higher risk of MACCE (p = 0.049). Multivariable Cox regression analysis indicated that high Lp(a) was an independent predictor of Bleeding Academic Research Consortium bleeding compared with low Lp(a) (hazard ratios 2.29, 95% confidence intervals 1.01 to 5.15, p = 0.046). In conclusion, a high Lp(a) value may be associated with a poor prognosis after PCI for patients with CKD. PMID- 30477729 TI - The multi-individuality of handwriting. AB - The scientific research conducted so far as well as rich practical expert experience point to the fact that handwriting is individual to each person. On the other hand, there are quite infrequent cases of developing two or more different styles of writing by the same person, during learning-to-write process. These various styles of handwriting are used interchangeably, either spontaneously or intentionally; the effect being as if different persons can be attributed to authorship. The Author proposes to refer to this barely known phenomenon as "the multi-individuality of handwriting". The identification of writer of this type of handwriting is possible, however may pose serious problems. Variations of handwriting of the same person may lead forensic examiners to faulty expert opinion, if a known sample does not reflect the writing style of a questioned entry. The purpose of this paper is to present the results of study of multi-individual handwriting. PMID- 30477728 TI - Cells to Surgery Quiz: October 2016. PMID- 30477730 TI - Eicosanoid and Specialized Proresolving Mediator Regulation of Lymphoid Cells. AB - Eicosanoids and specialized proresolving mediators (SPMs) regulate leukocyte function and inflammation. They are ideally positioned at the interface of the innate and adaptive immune responses when lymphocytes interact with leukocytes. Receptors for leukotriene B4 (LTB4), prostaglandin E2 (PGE2), and SPMs are expressed on lymphocytes. Evidence points toward an essential role of these lipid mediators (LMs) in direct regulation of lymphocyte functions. SPMs, which include lipoxins, demonstrate comprehensive protective actions with lymphocytes. LTB4 and PGE2 regulation of lymphocytes is diverse and depends on the interaction of lymphocytes with other cells. Importantly, both LTB4 and PGE2 are essential regulators of T cell antitumor activity. These LMs are attractive therapeutic targets to control dysregulated innate and adaptive immune responses, promote lymphocyte antitumor activity, and prevent tumor immune evasion. PMID- 30477731 TI - [The importance of epidemiological surveillance of emerging enteroviruses]. PMID- 30477733 TI - Effects of glucose-lowering agents on surrogate endpoints and hard clinical renal outcomes in patients with type 2 diabetes. AB - Diabetic kidney disease (DKD) represents an enormous burden in patients with type 2 diabetes mellitus (T2DM). Preclinical studies using most glucose-lowering agents have suggested renal-protective effects, but the proposed mechanisms of renoprotection have yet to be defined, and the promising results from experimental studies remain to be translated into human clinical findings to improve the prognosis of patients at risk of DKD. Also, it is important to distinguish effects on surrogate endpoints, such as decreases in albuminuria and estimated glomerular filtration rate (eGFR), and hard clinical endpoints, such as progression to end-stage renal disease (ESRD) and death from renal causes. Data regarding insulin therapy are surprisingly scarce, and it is nearly impossible to separate the effects of better glucose control from those of insulin per se, whereas favourable preclinical data with metformin, thiazolidinediones and dipeptidyl peptidase (DPP)-4 inhibitors are plentiful, and positive effects have been observed in clinical studies, at least for surrogate endpoints. The most favourable renal results have been reported with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter type-2 inhibitors (SGLT2is). Significant reductions in both albuminuria and eGFR decline have been reported with these classes of glucose-lowering medications compared with placebo and other glucose-lowering agents. Moreover, in large prospective cardiovascular outcome trials using composite renal outcomes as secondary endpoints, both GLP 1RAs and SGLT2is added to standard care reduced renal outcomes combining persistent macro-albuminuria, doubling of serum creatinine, progression to ESRD and kidney-related death; however, to date, only SGLT2is have been clearly shown to reduce such hard clinical outcomes. Yet, as the renoprotective effects of SGLT2is and GLP-1RAs appear to be independent of glucose-lowering activity, the underlying mechanisms are still a matter of debate. For this reason, further studies with renal outcomes as primary endpoints are now awaited in T2DM patients at high risk of DKD, including trials evaluating the potential add-on benefits of combined GLP-1RA-SGLT2i therapies. PMID- 30477732 TI - Argon Laser Photocoagulation For Macular Edema In Branch Vein Occlusion. AB - The Branch Vein Occlusion Study is a multi-center, randomized, controlled clinical trial designed to answer several questions regarding the management of complications of branch vein occlusion. This report discusses the question, "Is argon laser photocoagulation useful in improving visual acuity in eyes with branch vein occlusion and macular edema reducing vision to 20/40 or worse?" One hundred thirty-nine eligible eyes were assigned randomly to either a treated or an untreated control group. Comparing treated patients to control patients (mean follow-up 3.1 years for all study eyes), the gain of at least two lines of visual acuity from baseline maintained for two consecutive visits was significantly greater in treated eyes (P = .00049, logrank test). Because of this improvement in visual acuity with argon laser photocoagulation of macular edema from branch vein occlusion, we recommend laser photocoagulation for patients with macular edema associated with branch vein occlusion who meet the eligibility criteria of this study. PMID- 30477734 TI - Establishing a human adrenocortical carcinoma (ACC)-specific gene mutation signature. AB - Adrenocortical carcinoma (ACC) is a rare and aggressive tumor whose molecular signaling pathways are not fully understood. Using an in-silico clinical data analysis approach we retrieved human gene mutation data from the highly reputed Cancer Genome Atlas (TCGA). ACC-specific gene mutations were correlated with proliferation marker FAM72 expression and Mutsig along with the algorithmic implementation of the 20/20 rule were used to validate their oncogenic potential. The newly identified oncogenic driver gene set (ZFPM1, LRIG1, CRIPAK, ZNF517, GARS and DGKZ), specifically and most repeatedly mutated in ACC, is involved in tumor suppression and cellular proliferation and thus could be useful for the prognosis and development of therapeutic approaches for the treatment of ACC. PMID- 30477735 TI - ASIA (Autoimmune/Inflammatory Syndrome Induced by Adjuvants): A new case? PMID- 30477736 TI - What is driving HTA decision-making? Evidence from cancer drug reimbursement decisions from 6 European countries. AB - BACKGROUND: Decisions on the reimbursement of the same cancer drugs are different across European countries, but empirical work on the reasons behind these differences has been scarce. The main objective of this paper is to make a methodological contribution to existing research, specifically by outlining the systematic process of analysis to address such questions and determining the factors that might lead to different drug reimbursement decisions, and to explore its application in the field of oncology. METHODS: Reimbursement decisions on cancer drugs in six European countries (Belgium, England, Poland, Portugal, Scotland, and Sweden) between 2006 and 2014 were included in the study. A taxonomy was developed, comprising two groups of variables (system-level and product-specific) and an econometric model was specified (multilevel mixed effects ordered probit). RESULTS: Only one in six evaluations in the sample reach the same reimbursement recommendation. Most health system variables were not determinants of a higher or lower probability of a positive reimbursement recommendation. However, the probability of reimbursement was higher when a drug was considered cost-effective by NICE/SMC and when there was a financial Managed Entry Agreement. This work also demonstrated a possible econometric approach for analysing differences in reimbursement decisions and contributes a structured approach for collecting and preparing data for such analyses. CONCLUSIONS: Drug reimbursement decisions can be analysed in detail along a set of factors that are related to each decision. This information is essential, not only for understanding why a particular drug is accepted in one country and not in another but also when trying to implement a new HTA system or reform an existing one. This analysis provides policy makers and stakeholders with a model that enables a better understanding of the factors that drive HTA decisions and is adaptable to answer similar questions. Moreover, the data collection limitations encountered and described in this work shed light on the need for greater accessibility and transparency in HTA systems and regarding HTA outcomes. PMID- 30477737 TI - Corrigendum to "Psoriatic arthritis disease activity during pregnancy and the first-year postpartum" [Semin. Arthritis Rheum. 46 (6) (2017) 740-745]. PMID- 30477738 TI - Microbial Consortium Design Benefits from Metabolic Modeling. AB - Consortia outperform single microorganisms at multiple tasks. However, consortium design is challenging and successful application examples are rare. A major challenge is the selection of consortium members such that performance is optimized. In a recent publication, metabolic modeling has been successfully applied to aid consortium design. PMID- 30477739 TI - Lignin-Enzyme Interactions in the Hydrolysis of Lignocellulosic Biomass. AB - Lignin is central to overcoming recalcitrance in the enzyme hydrolysis of lignocellulose. While the term implies a physical barrier in the cell wall structure, there are also important biochemical components that direct interactions between lignin and the hydrolytic enzymes that attack cellulose in plant cell walls. Progress toward a deeper understanding of the lignin synthesis pathway - and the consistency between a range of observations over the past 40 years in the very extensive literature on cellulose hydrolysis - is resulting in advances in reducing a major impediment to cellulose conversion: the cost of enzymes. This review addresses lignin and its role in the hydrolysis of hardwood and other lignocellulosic residues. PMID- 30477740 TI - Stereotactic Body Radiotherapy for Early-Stage Multiple Primary Lung Cancers. AB - BACKGROUND: Patients with multiple primary lung cancers increasingly receive multiple courses of stereotactic body radiotherapy (SBRT). We aimed to clarify the efficacy and safety of such treatments. PATIENTS AND METHODS: We reviewed a prospective lung SBRT database of patients treated for stage I non-small-cell lung cancer between June 2004 and December 2015. RESULTS: A total of 374 patients received a single course of SBRT, 14 received synchronous SBRT, 48 received metachronous SBRT alone, and 108 received surgery and metachronous SBRT. Median follow-up was 37.0 months for survivors. Patients who received a single course had a 3-year overall survival (OS) of 54.2% (95% confidence interval [CI], 48.8 59.3), 3-year freedom from progression (FFP) of 67.3% (95% CI, 60.9-72.9), and grade 3 or higher toxicity of 3.5%. Compared to single-course patients, patients receiving metachronous SBRT alone and patients receiving surgery and metachronous SBRT had improved OS (79.7% [95% CI, 64.4-88.9%], P < .0001 and 95.4% [95% CI, 89.2-98.0%], P < .0001, respectively) and FFP (85.8% [95% CI, 70.7-93.5], P = .03 and 95.4% [95% CI, 89.2-98.0%], P < .0001, respectively). Patients receiving synchronous SBRT had similar OS (46.4% [95% CI, 19.3-69.9%], P = .75) and similar FFP (57.5% [95% CI, 25.3-80.0%], P = .17) as single-course patients. There were no significant differences in rates of grade 3 or higher toxicity or of grade 1 or higher toxicity between single-course patients and the other groups. CONCLUSION: Patients who received either synchronous or metachronous SBRT had no significant detriment in OS or toxicity compared to single-course patients. This supports the use of SBRT in patients with multiple primary lung cancers. PMID- 30477741 TI - Novel Homozygous Mutation of the AIMP1 Gene: A Milder Neuroimaging Phenotype With Preservation of the Deep White Matter. AB - BACKGROUND: Mutations in AIMP1, which plays an important role in the development and maintenance of axon-cytoskeleton integrity and regulating neurofilaments, cause neurodegeneration of variable severity and white matter abnormalities. METHODS: From the patient records we analyzed the clinical evaluation, molecular genetics, neurodiagnostic, and neuroradiological investigations. RESULTS: We describe six members of a large consanguineous family with a phenotype of severe neurodegeneration in the form of developmental delays, progressive microcephaly, epilepsy, and failure to thrive. MRI showed callosal atrophy and T2 hyperintensity in the superficial white matter. The periventricular and deep white matter structures were, however, preserved. MR spectroscopy demonstrated N acetylaspartate preservation without evidence of neuroinflammation. Exome sequencing showed a novel homozygous mutation of the AIMP1 gene in all individuals: c.917A>G (p.(Asp306Gly)). CONCLUSIONS: This novel homozygous mutation of the AIMP1 gene is characterized by preserved development of the periventricular and deep white matter structures as demonstrated by MRI and MR spectroscopy correlation. PMID- 30477742 TI - What We Need to Know? PMID- 30477743 TI - Epilepsy Surgery for Children With Low-Grade Epilepsy-Associated Tumors: Factors Associated With Seizure Recurrence and Cognitive Function. AB - OBJECTIVE: Low-grade epilepsy-associated tumors (LEATs) are associated with childhood seizures that are typically drug-resistant, necessitating surgical interventions. In this study, we aimed to investigate the efficacy of surgical intervention in children with LEATs and to identify factors associated with seizure and cognitive outcomes. METHODS: We reviewed 58 children less than 18 years of age who underwent epilepsy surgery due to histopathologically confirmed LEATs and had a minimum postoperative follow-up duration of 24 months. RESULTS: Of the 58 patients who were followed for a median duration of 5.6 (IQR 3.2 to 10.0) years, 51 (87.9%) were seizure-free after surgery. In univariate analysis, shorter epilepsy duration, fewer antiepileptic drugs at time of surgery, gross total resection, and unilobar tumor involvement were associated with seizure freedom. In multivariate analysis, gross total resection was independently associated with seizure freedom. The preoperative and postoperative full-scale intelligence quotient (FSIQ) scores were 78.9 +/- 27.1 and 80.9 +/- 28.7, respectively. In univariate analysis, younger age at seizure onset, longer epilepsy duration, more antiepileptic drugs at time of surgery, multilobar tumor involvement, and presence of generalized epileptic discharges were associated with lower preoperative FSIQ. In multivariate analysis, longer epilepsy duration was independently associated with lower preoperative FSIQ scores. Postoperative FSIQ scores were significantly influenced by preoperative FSIQ scores. CONCLUSIONS: Epilepsy surgery for LEATs in children resulted in excellent seizure outcome. Gross total resection was the only independent factor associated with favorable seizure outcome. Preoperative and postoperative cognitive abilities were significantly influenced by epilepsy duration, so early surgical intervention should be considered. PMID- 30477744 TI - Long noncoding RNA ANRIL contributes to the development of ulcerative colitis by miR-323b-5p/TLR4/MyD88/NF-kappaB pathway. AB - The aim of this study was to investigate the role and possible mechanism of long noncoding RNA ANRIL in the development of ulcerative colitis (UC). The expression of ANRIL in colonic mucosa tissues collected from the sigmoid colon of UC patients and healthy control was determined. Subsequently, fetal human cells (FHCs) were treated with lipopolysaccharide (LPS) to stimulate UC-caused inflammatory injury, followed by detection of the effects of suppression of ANRIL on cell viability, apoptosis and cytokines production in LPS-stimulated FHCs. Moreover, the regulatory relationship between ANRIL and miR-323b-5p as well as the target relationship between miR-323b-5p and TLR4 were investigated. Furthermore, the effects of ANRIL/miR-323b-5p axis on the activation of TLR4/MyD88/NF-kappaB pathway in LPS-stimulated FHCs were investigated. LncRNA ANRIL was highly expressed in colonic mucosa tissues of UC patients. In addition, LPS markedly induced cell injury in FHC cells (inhibited cell viability and promoted cell apoptosis and cytokine production). Suppression of ANRIL alleviated LPS-induced injury in FHC cells, which was achieved by negatively regulating miR 323b-5p. Moreover, miR-323b-5p negatively regulated TLR4 expression and TLR4 was a target of miR-323b-5p. Knockdown of TLR4 reversed the effects of miR-323b-5p suppression on LPS-induced injury in LPS-stimulated FHCs. Furthermore, the effects of ANRIL on LPS-induced cell injury were achieved by TLR4/MyD88/NF-kappaB pathway. Our data indicate that suppression of ANRIL may inhibit the development of UC by regulating miR-323b-5p/TLR4/MyD88/NF-kappaB pathway. ANRIL/miR-323b 5p/TLR4/MyD88/NF-kappaB pathway may provide a new strategy for UC therapy. PMID- 30477745 TI - Schisandrin B alleviates diabetic nephropathy through suppressing excessive inflammation and oxidative stress. AB - Diabetic nephropathy (DN) is a progressive kidney disease due to glomerular capillary damage in diabetic patients, with inflammation and oxidative stress implicated as crucial pathogenic factors. There is an urgent need to develop effective therapeutic drug. Natural medicines are rich resources for active lead compounds. They would provide new opportunities for the treatment of DN. The present study was designed to investigate the protective effects of Schisandrin B (SchB) on DN and to delineate the underlying mechanism. Oral administration of SchB in the diabetic mouse model significantly alleviated hyperglycemia-induced renal injury, which was accompanied by maintenance of urine creatinine and albumin levels at similar to those of control non-diabetic mice. Histological examination of renal tissue indicated that both development of fibrosis and renal cell apoptosis were dramatically inhibited by SchB. The protective effect of SchB on DN associated with suppression of inflammatory response and oxidative stress. These results strongly suggested that SchB could be a potential therapeutic agent for treatment of DN. Moreover, our findings provided a fuller understanding of the regulatory role of NF-kappaB and Nrf2 in DN, indicating that they could be important therapeutic targets. PMID- 30477746 TI - Production of extracellular PETase from Ideonella sakaiensis using sec-dependent signal peptides in E. coli. AB - Poly(ethylene terephthalate) (PET) is the most commonly used polyester polymer resin in fabrics and storage materials, and its accumulation in the environment is a global problem. The ability of PET hydrolase from Ideonella sakaiensis 201 F6 (IsPETase) to degrade PET at moderate temperatures has been studied extensively. However, due to its low structural stability and solubility, it is difficult to apply standard laboratory-level IsPETase expression and purification procedures in industry. To overcome this difficulty, the expression of IsPETase can be improved by using a secretion system. This is the first report on the production of an extracellular IsPETase, active against PET film, using Sec dependent translocation signal peptides from E. coli. In this work, we tested the effects of fusions of the Sec-dependent and SRP-dependent signal peptides from E. coli secretory proteins into IsPETase, and successfully produced the extracellular enzyme using pET22b-SPMalE:IsPETase and pET22b-SPLamB:IsPETase expression systems. We also confirmed that the secreted IsPETase has PET degradation activity. The work will be used for development of a new E. coli strain capable of degrading and assimilating PET in its culture medium. PMID- 30477747 TI - Hydrodynamic delivery of IL-38 gene alleviates obesity-induced inflammation and insulin resistance. AB - Obesity is associated with a chronic inflammatory response. Interleukin (IL)-38 is a poorly characterized cytokine of the IL-1 family with anti-inflammatory activity. The role of IL-38 in obesity-induced inflammation and insulin resistance remains unknown. In this study, we investigated the effects of IL-38 expression by hydrodynamic-based gene delivery on high-fat diet-induced obesity in mice. Transfer of plasmid DNA encoding IL-38 reduced weight gain, liver fat content, adipose tissue weight, and obesity-induced insulin resistance compared with administration of a control plasmid. Moreover, IL-38 gene delivery inhibited the production of inflammatory mediators including IL-1beta, IL-6, and monocyte chemotactic protein-1. These results suggest that IL-38 is a potential new target for the treatment of obesity. PMID- 30477748 TI - [Multiple ulcerated tracheobronchial mucosal lesions in the eosinophilic granulomatosis with polyangiitis]. PMID- 30477749 TI - Pharmacoepidemiology of non-steroidal anti-inflammatory drugs. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are reversible inhibitors of cyclo oxygenase (COX), mainly used for the symptomatic relief of pain, whether traumatic, infectious, episodic or rheumatologic. Use for the long-term relief of inflammation is waning with the emergence of specific biotherapies. Their effects are related to potency, dosage, and pharmacokinetic or galenic considerations. Adverse reactions are mostly related to COX inhibition, and to the relative COX1 and COX2 inhibition. Over the years have resulted in the withdrawal of some NSAIDs. The most common adverse reactions are: gastrointestinal (COX1) which have declined over time with the emergence of more COX1 sparing drugs and gastroprotection; renal, with an impact on renal function and sodium extraction that is associated with hypertension, heart failure exacerbation, and stress related renal failure; allergic skin reactions; increased transaminases and acute liver injury which may be idiosyncratic or immunoallergic; increased risk of acute coronary syndromes, initially associated with high-dose long-term use of COX2 specific inhibitors in controlled clinical trials, though more recently there have been indications from poorly controlled observational studies that they could occur with most NSAIDs. Event rates in patients with no overt coronary heart disease are vanishingly low, and the real magnitude of the issue in the treatment of common pain is still unknown. Considering their purely symptomatic effects, they should be used at the lowest possible dose for the shortest possible time, based on the symptomatic relief of pain or fever. PMID- 30477750 TI - Selecting noncoplanar beam directions in a patient coordinate system for radiotherapy planning. AB - To introduce a beam angle selection method based on the patient coordinate system for treatment planning of noncoplanar intensity-modulated radiation therapy (IMRT). Traditionally, in radiotherapy planning, beam directions are selected in the machine coordinate system. A noncoplanar beam direction is established through a treatment table rotation followed by a gantry rotation. However, visualizing the beam direction relative to the patient is difficult. The suggestion here is to describe the beam direction in the patient coordinate system. First, a coplanar beam direction is selected in the transverse plane of the patient coordinate system. The noncoplanar beam direction is then obtained by adjusting the coplanar beam toward the foot or head in the patient coordinate system. Finally, the noncoplanar beam direction is expressed in terms of gantry and table angles in the machine coordinate system via formulae developed in this study. A 3D computer-aided design model of the linear accelerator (linac) is established with Solidworks and used to validate the feasibility of the proposed method. A clinical case was chosen to demonstrate the effectiveness of this method. Treatment plans with the conventional coplanar and noncoplanar beam settings were made. Compared with the conventional coplanar IMRT plan, improved normal tissue sparing of the organs at risk using the noncoplanar IMRT plan is evident. The proposed method for noncoplanar treatment planning makes beam direction selection simpler and straightforward. PMID- 30477751 TI - Conbercept for Treatment of Neovascular Age-related Macular Degeneration: Results of the Randomized Phase 3 Phoenix Study. PMID- 30477752 TI - Comment on: evaluating the safety of intragastric balloon: an analysis of the metabolic and bariatric surgery accreditation and quality improvement program. PMID- 30477753 TI - Molecular pathogenesis of parathyroid tumours. AB - Parathyroid tumors represent an elusive endocrine neoplasia, which lead to primary hyperparathyroidism, pHPT, a common endocrine calcium disorder characterized by hypercalcemia and normal-high parathormone secretion. Parathyroid tumours are benign adenomas or multiple glands hyperplasia in the vast majority (>99% of cases), while malignant neoplasms are rare (less than 1%). Despite pHPT is a common disorder, our knowledge about the genetic predisposition and molecular pathophysiology is limited to the familial syndromic forms of parathyroid tumour, that, however, represent not more than the 10% of all the cases; instead, the pathophysiology of sporadic forms remains an open field, although data about epigenetic mechanisms or private genes have been supposed. Here we present an overview of more recent acquisitions about the genetic causes along with their molecular mechanisms of benign, but also, malignant parathyroid tumours either in sporadic and familial presentation. PMID- 30477754 TI - Primary hyperparathyroidism. AB - Primary hyperparathyroidism (PHPT), the most common cause of hypercalcemia, is most often identified in postmenopausal women with hypercalcemia and parathyroid hormone (PTH) levels that are either frankly elevated or inappropriately normal. The clinical presentation of PHPT includes three phenotypes: target organ involvement of the renal and skeletal systems; mild asymptomatic hypercalcemia; and more recently, high PTH levels in the context of persistently normal albumin corrected and ionized serum calcium values. The factors that determine which of these three clinical presentations is more likely to predominate in a given country include the extent to which biochemical screening is employed, the prevalence of vitamin D deficiency, and whether a medical center or practitioner tends to routinely measure PTH levels in the evaluation of low bone density or frank osteoporosis. When biochemical screening is common, asymptomatic primary hyperparathyroidism is the most likely form of the disease. In countries where vitamin D deficiency is prevalent and biochemical screening is not a feature of the health care system, symptomatic disease with skeletal abnormalities is likely to predominate. Finally, when PTH levels are part of the evaluation for low bone mass, the normocalcemic variant is seen. Guidelines for surgical removal of hyperfunctioning parathyroid tissue apply to all three clinical forms of the disease. If guidelines for surgery are not met, parathyroidectomy can also be an appropriate option if there are no medical contraindications to surgery. In settings where either the serum calcium or bone mineral density is of concern, and surgery is not an option, pharmacological approaches are available and effective. Referencing in this article the most current published articles, we review the different presentations of PHPT, with particular emphasis on recent advances in our understanding of target organ involvement and management. PMID- 30477755 TI - How time to healthy singleton delivery could affect decision-making during infertility treatment: a Delphi consensus. AB - RESEARCH QUESTION: How might time to healthy singleton delivery affect decision making during infertility treatment? DESIGN: This was a Delphi consensus investigating expert opinion that comprised three steps. In Step 1, 12 experts developed statements. In Step 2, 27 experts (including 12 from Step 1) voted (online survey) on their agreement/disagreement with each statement (providing reasons). Consensus was reached if >=66% of participants agreed/disagreed. Statements not reaching consensus were revised and the process repeated until consensus was achieved. In Step 3 details of the final agreed statements were communicated. RESULTS: Twelve statements were developed, and consensus (agreement) was reached on all after one round of voting. CONCLUSIONS: Time to healthy singleton delivery should be taken into consideration when making decisions related to infertility treatment, and it is important that fertility treatment is provided in a timely manner, avoiding over- or under-treatment. In all subfertile women <40 years old, IVF outcomes could be optimized by performing up to six single-embryo transfers and certain procedures might reduce time to healthy singleton delivery. These procedures include preimplantation genetic testing for aneuploidies, frozen replacement cycles immediately after failed fresh cycles and use of gonadotrophin-releasing hormone antagonists. Finally, the number of oocytes retrieved should be maximized to increase cumulative live birth rate. PMID- 30477756 TI - Reference values for cardiometabolic risk scores in children and adolescents: Suggesting a common standard. AB - BACKGROUND AND AIMS: International reference values for cardiometabolic risk variables, to allow for standardization of continuous risk scores in children, are not currently available. The aim of this study was to provide international age- and gender-specific reference values for cardiometabolic risk factors in children and adolescents. METHODS: Cohorts of children sampled from different parts of Europe (North, South, Mid and Eastern) and from the United States were pooled. In total, 22,479 observations (48.7% European vs. 51.3% American), 11,234 from girls and 11,245 from boys, aged 6-18 years were included in the study. Linear mixed-model regression analysis was used to analyze the associations between age and each cardiometabolic risk factor. RESULTS: Reference values for 14 of the most commonly used cardiometabolic risk variables in clustered risk scores were calculated and presented by age and gender: systolic blood pressure (SBP), diastolic blood pressure (DBP), waist circumference (WC), body mass index (BMI), sum of 4 skinfolds (sum4skin), triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), TC:HDL-C ratio, glucose, insulin, homeostatic model assessment-score (HOMA-score), and cardiorespiratory fitness (CRF). CONCLUSIONS: This study suggests a common standard to define cardiometabolic risk in children. Adapting this approach makes single risk factors and clustered cardiometabolic disease risk scores comparable to the reference material itself and comparable to cardiometabolic risk values in studies using the same strategy. This unified approach therefore increases the prospect to estimate and compare prevalence and trends of cardiometabolic risk in children when using continuous cardiometabolic risk scores. PMID- 30477757 TI - Total body proteoglycan 4 (Prg4) deficiency increases atherosclerosis susceptibility in apolipoprotein E knockout and low-density lipoprotein receptor knockout mice. PMID- 30477758 TI - 100 Questions in Livestock Helminthology Research. AB - An elicitation exercise was conducted to collect and identify pressing questions concerning the study of helminths in livestock, to help guide research priorities. Questions were invited from the research community in an inclusive way. Of 385 questions submitted, 100 were chosen by online vote, with priority given to open questions in important areas that are specific enough to permit investigation within a focused project or programme of research. The final list of questions was divided into ten themes. We present the questions and set them briefly in the context of the current state of knowledge. Although subjective, the results provide a snapshot of current concerns and perceived priorities in the field of livestock helminthology, and we hope that they will stimulate ongoing or new research efforts. PMID- 30477759 TI - Development of the Burn Frailty Index: A prognostication index for elderly patients sustaining burn injuries. AB - BACKGROUND: Frailty has demonstrated enhanced prognostic ability for elderly patient morbidity. The aim was to create a burn-specific frailty index for elderly patients and compare it to commonly used scoring systems in burn management. METHODS: From 2013 to 2017, we prospectively surveyed a randomized cohort of patients >=65-years-old previously admitted to our burn unit. Prognostic comparisons with 6 commonly used indices and multivariate risk analyses were performed. RESULTS: Of 100 included patients, n = 32 were classified as frail. The mean patient age was 73.0 +/- 6.8-years with a median follow up of 20.9 months. There were 13 moralities in total, 12 occurred in the frail group including 5 in-house mortalities. Patients classified as frail had significantly more complications (p < 0.001), non-home discharges (p < 0.001), ICU admissions, and longer hospital and ICU lengths of stay (p < 0.001), decreased 1 and 3-year survival (p = 0.001). The BFI was identified as an independent predictor of mortality (p = 0.001) and course-altering diagnoses including sepsis/septic shock, ARDS/ALI, and AKI. CONCLUSIONS: The Burn Frailty Index accurately predicts morbidity and mortality in elderly frail patients suffering burn injuries. PMID- 30477760 TI - Development and implementation of a national quality improvement skills curriculum for urology residents in the United Kingdom: A prospective multi method, multi-center study. AB - BACKGROUND: Surgical quality improvement (QI) is a global priority. We report the design and proof-of concept testing of a QI skills curriculum for urology residents. METHODS: 'Umbrella review' of QI curricula (Phase-1); development of draft QI curriculum (Phase-2); curriculum review by Steering Committee of urologists (Attendings & Residents), QI and medical education experts and patients (Phase-3); proof-of-concept testing (Phase-4). RESULTS: Phase-1: Six systematic reviews were identified of 4332 search hits. Most curricula are developed/evaluated in the USA; use mixed teaching methods (incl. didactic, QI exercises & self-reflection); and introduce core QI techniques (e.g., Plan-Do Study-Act). Phase-2: curriculum drafted. Phase-3: the curriculum was judged to represent state-of-the-art, relevant QI training. Stronger patient involvement element was incorporated. Phase-4: the curriculum was delivered to 43 urology residents. The delivery was feasible; the curriculum implementable; and a knowledge-skills-attitudes evaluation approach successful. CONCLUSION: We have developed a practical QI curriculum, for further evaluation and national implementation. PMID- 30477762 TI - GOLD 2019: a new way forward. PMID- 30477761 TI - Clinical effects and risk factors of far cortical locking system in the treatment of lower limb fractures. AB - INTRODUCTION: This study aims to analyze clinical effects between far cortical locking (FCL) system and standard plating techniques in the treatment of lower limb fractures and identify potential preoperative risk factors for complications in patients treated with FCL system. METHOD: We retrospectively analyzed 76 patients treated with FCL system (the study group) and 68 patients treated with standard plating techniques (the control group) between January 2014 and January 2017. Patients were followed up for a minimum of one year. Surgery-related complications, fixation features, fracture healing rates, the radiographic union scores, and knee functions (Kolment scores) were analyzed between the two groups in the study. Besides, we analyzed eight preoperative characteristics for surgery related complications, including age, gender, presence of risk factors affecting bone healing, cause of injury, AO/OTA fracture classifications, facture sites, presence of open fractures, and presence of bone losses. RESULTS: The distributions of baseline date were similar between the two groups (P>0.05). The average number of FCL screws was 4.5 (range: 3-9) in the study group. The average time to union was 2.8 +/- 0.9 months in the study group and 3.6 +/- 1.0 months in the control group (P<0.001), and average time to whole weight bearing was 2.3 +/- 0.8 months and 2.8 +/- 1.2 months, respectively (P = 0.004). Regarding radiographic union score, the study group scores were significantly higher than the control group scores at 1 and 3 months after surgery (P<0.001), while it becomes insignificant between the two groups at 6 and 12 months after surgery (P = 0.19 and P = 0.15).The working lengths, fracture healing rates, complication rates, and Kolment scores were similar between the two groups (P>0.05). In the multivariate analysis, fracture sites (OR = 5.34; 95% CI, 1.11-25.75; P = 0.03) and presence of open fractures (OR = 6.19; 95% CI, 1.05-36.38; P = 0.04) were significant associated with complications, whereas other variables were not included. DISCUSSION: FCL system can truly accelerating bone healing and allow earlier whole weight bearing. Fracture healing rates and complication rates were similar between patients treated with FCL implants or conventional plating techniques. Patients with shaft fractures and open fractures trended to have higher complication rates. CONCLUSIONS: FCL system is superior to standard plating technique in terms of early callus formation, but standard plating technique is not inferior to FCL system in terms of final fracture healing, surgery-related complication, and function outcome. Fracture site and presence of open fracture are the independent factors for complications in patients treated with FCL system. PMID- 30477764 TI - Subcutaneous treprostinil: a new treatment for chronic thromboembolic pulmonary hypertension? PMID- 30477763 TI - Subcutaneous treprostinil for the treatment of severe non-operable chronic thromboembolic pulmonary hypertension (CTREPH): a double-blind, phase 3, randomised controlled trial. AB - BACKGROUND: Treprostinil, a prostacyclin analogue, is effective for the treatment of pulmonary arterial hypertension. However, information is scarce regarding treprostinil for treatment of chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to examine the efficacy and safety of subcutaneous treprostinil in this setting. METHODS: In this 24-week, randomised, double-blind controlled trial, we enrolled patients with CTEPH, classified as non operable, or with persistent or recurrent pulmonary hypertension after pulmonary endarterectomy, in six European expert centres in Austria, Czech Republic, Germany, and Poland. Patients in WHO functional class III or IV with a 6-min walk distance of 150-400 m were randomly assigned at a 1:1 allocation ratio to continuous high-dose subcutaneous treprostinil (target dose around 30 ng/kg per min at week 12) or low-dose subcutaneous treprostinil (target dose around 3 ng/kg per min at week 12). The primary endpoint was the change from baseline in 6-min walk distance at week 24. All patients who received at least one dose of the study drug were included in the intention-to-treat efficacy and safety analyses based on assessment of adverse events. The trial was registered at ClinicalTrialsRegister.eu EudraCT number 2008-006441-10 and ClinicalTrials.gov, number NCT01416636. FINDINGS: From March 9, 2009, to June 9, 2016, 105 patients were enrolled with 53 (50%) patients randomly assigned to high-dose and 52 (50%) patients to low-dose subcutaneous treprostinil. At week 24, marginal mean 6-min walk distance improved by 44.98 m (95% CI 27.52 to 62.45) in the high-dose group, and by 4.29 m (95% CI -13.34 to 21.92) in the low-dose group (treatment effect 40.69 m, 95% CI 15.86 to 65.53, p=0.0016). 12 serious adverse events were reported in ten (19%) of 52 patients from the low-dose group and 16 serious adverse events were reported in nine (17%) of 53 patients from the high-dose group. The most common treatment-related adverse events in both groups were infusion site pain and other infusion site reactions. INTERPRETATION: Treatment with subcutaneous treprostinil was safe, and improved exercise capacity in patients with severe CTEPH. Subcutaneous treprostinil provides a parenteral treatment option for patients of WHO functional class III or IV and those who do not tolerate other therapies or need combination treatment. FUNDING: SciPharm Sarl. PMID- 30477765 TI - Graph theory analysis reveals how sickle cell disease impacts neural networks of patients with more severe disease. AB - Sickle cell disease (SCD) is a hereditary blood disorder associated with many life-threatening comorbidities including cerebral stroke and chronic pain. The long-term effects of this disease may therefore affect the global brain network which is not clearly understood. We performed graph theory analysis of functional networks using non-invasive fMRI and high resolution EEG on thirty-one SCD patients and sixteen healthy controls. Resting state data were analyzed to determine differences between controls and patients with less severe and more severe sickle cell related pain. fMRI results showed that patients with higher pain severity had lower clustering coefficients and local efficiency. The neural network of the more severe patient group behaved like a random network when performing a targeted attack network analysis. EEG results showed the beta1 band had similar results to fMRI resting state data. Our data show that SCD affects the brain on a global level and that graph theory analysis can differentiate between patients with different levels of pain severity. PMID- 30477766 TI - Orthodontic imaging: The future is now. PMID- 30477767 TI - Authors' response. PMID- 30477768 TI - Is the quality of manipulated images adequate? PMID- 30477769 TI - Authors' response. PMID- 30477770 TI - Erratum. PMID- 30477771 TI - Erratum. PMID- 30477772 TI - When the patient is his own doctor .... PMID- 30477773 TI - Anchorage reinforcement with miniscrews and molar blocks in adolescents: A randomized controlled trial. AB - INTRODUCTION: Anchorage can be reinforced in many ways. Due to the variety of anchorage concepts, only a few general conclusions can be drawn. Therefore, more research is needed to investigate specific concepts with specific indications. The objective of this trial was to compare the anchorage capacities of miniscrews and molar blocks. METHODS: This randomized controlled trial was conducted on 2 parallel arms. The trial was conducted at the Public Dental Service Orthodontic Clinic in Gavle, Sweden. Participants were adolescents who needed orthodontic treatment with a fixed appliance, extraction of the maxillary first premolars, and anchorage reinforcement. In group A, miniscrews were used as direct anchorage during space closure. In group B, molar blocks were used as anchorage reinforcement during leveling and alignment and space closure. The primary outcome was loss of anchorage assessed as maxillary first molar movement. Random allocation was maintained with a simple randomization stratified by sex. The observer was blinded to the allocations during the measurements. RESULTS: Forty participants each were randomized to groups A and B. Results were analyzed on an intention-to-treat basis, meaning that all participants, successful or not, were included in the analysis. Group A showed a mean anchorage loss of 1.2 mm during leveling and alignment. During space closure with miniscrews, no significant anchorage loss was found. Group B showed mean anchorage losses of 1.4 mm during leveling and alignment and 2.4 mm during space closure. No serious harms were detected. The first molar rotation, torque, and tipping showed different characteristics during the treatment phases. CONCLUSIONS: Miniscrews can be recommended for anchorage reinforcement. Depending on the need for anchorage reinforcement, miniscrews can be inserted at the beginning of treatment or when space closure starts. Molar blocks cannot be recommended for anchorage reinforcement. REGISTRATION: This trial was registered at www.clinicaltrials.gov (NCT02644811). PROTOCOL: The protocol was published after trial commencement. FUNDING: This trial received funding from the Center for Research and Development, Uppsala University/Region Gavleborg; Thureus Foundation for the Promotion of Dental Science; and the Swedish Dental Associations Scientific Funds. PMID- 30477774 TI - Effects of vibrational devices on orthodontic tooth movement: A systematic review. AB - INTRODUCTION: The aim of this systematic review was to investigate the ability of vibrational devices to increase the rate of orthodontic tooth movement or reduce pain associated with orthodontic treatment. METHODS: An electronic search for relevant randomized controlled trials (RCTs) was conducted using Medline via OVID (January 1, 1966, through March 30, 2018), and EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials until August 2017. Hand searching of selected orthodontic journals was also undertaken. RESULTS: Through the electronic searches, 152 titles and abstracts were identified. From these, 10 articles were retrieved for review, and 4 of these met the inclusion criteria. Two additional articles were identified by hand searching. This resulted in 6 studies from 5 separate randomized controlled trials that were included in this systematic review. One RCT reported increased tooth movement with vibrational devices, but the other 4 RCTs reported no difference. Three studies investigated the effect of vibrational devices on pain reduction and found no effect. CONCLUSIONS: The ability of vibrational forces to increase the rate of tooth movement and reduce pain in orthodontic patients has been studied in several RCTs. The results from all but 1 of the included studies indicate no advantage from the use of vibrational devices during orthodontic treatment. Future studies should focus on total treatment duration, the mechanism by which vibration may speed up tooth movement, and the use of vibration with aligners. FUNDING: No funding was received for this review. PMID- 30477775 TI - Computerized measurement of the location and value of the minimum sagittal linear dimension of the upper airway on reconstructed lateral cephalograms compared with 3-dimensional values. AB - INTRODUCTION: Identifying the location and value of the smallest airway dimension can be useful in screening and planning treatment for patients with obstructive sleep apnea. Our objectives in this study were to (1) objectively identify the vertical location and value of the minimum sagittal linear dimension (MSLD) on 2 dimensional reconstructed lateral cephalograms (RLCs), (2) compare the location and value of the MSLD on RLCs with the vertical location and sagittal dimension of the minimum cross-sectional area (MCSA), and (3) investigate the association between the MSLD on RLCs and both the MCSA and the airway volume. METHODS: Cone beam computed tomography (CBCT) scans of 91 patients, in 3 age groups (<20, 20 40, and >40 years), were used to perform 3-dimensional assessments of the upper airway and reconstruct lateral cephalograms. Airway volume, MCSA, vertical level, and sagittal dimension of MCSA on the CBCT scans were obtained using Dolphin 3D software (version 11.7; Dolphin Imaging, Chatsworth, Calif). Customized software was used to objectively obtain the location and value of the MSLD of the airway on RLCs. RESULTS: In all age groups, correlation tests showed significant correlations between the MSLD on RLCs and both the MCSA (rs >=0.59; P <0.001) and the airway volume (rs >=0.37; P <0.05). Additionally, there were significant correlations between the vertical location of the MSLD and the vertical location of the MCSA (rs >=0.41; P <0.05) and between the MSLD and the sagittal dimension of the MCSA (r >=0.61; P <0.001). Bland-Altman plots for the MSLD and the sagittal dimension of the MCSA showed much narrower 95% limits of agreement compared with the Bland-Altman plots for the vertical locations of the MSLD and the MCSA. CONCLUSIONS: Two-dimensional images may be used as a screening tool and to identify the sagittal dimension of the smallest airway dimension. However, comprehensive assessment of airway characteristics is better achieved with CBCT based 3-dimensional evaluation. PMID- 30477776 TI - Micro-osteoperforations accelerate orthodontic tooth movement by stimulating periodontal ligament cell cycles. AB - INTRODUCTION: The aim of this study was to investigate the mechanism of how micro osteoperforations (MOPs) accelerate tooth movement. We focused on inflammation, cell proliferation, and apoptosis of periodontal ligament cells and performed immunostaining of MOPs exposed to tumor necrosis factor-alpha (TNF-alpha), proliferating cell nuclear antigen (PCNA), and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) during experimental tooth movement. METHODS: Eleven-week-old male Wistar rats were divided into 2 groups: (1) 10 g of orthodontic force applied to the maxillary first molar (TM) and (2) force application plus 3 small perforations of the cortical plate (TM + MOPs). On days 1, 4, 7, 10, and 14 after force application, we investigated tooth movement and alveolar bone microstructure using microcomputed tomography (n = 5). We also determined the expression of TNF-alpha and PCNA in the pressure sides of periodontal ligaments via an immunohistochemical analysis. The expression of apoptotic cells was also determined by the TUNEL method. RESULTS: The tooth movement in the TM + MOPs group was significantly greater on days 4 to 14 than in the TM group. The TM + MOPs group showed statistically significant decreases in bone volume/tissue volume ratio and bone mineral density compared with the TM group. The ratios of TNF-alpha positive cells in the TM + MOPs group were increased on days 1, 4. 7, and 10 compared with the TM group. The ratios of PCNA positive cells in the TM + MOPs group were increased on days 1, 4, and 7 compared with the TM group, and the ratios of TUNEL positive cells in the TM + MOPs group were increased on days 1 and 7 compared with the TM group. CONCLUSIONS: These results suggest that MOPs may accelerate tooth movement through activation of cell proliferation and apoptosis of periodontal ligament cells. PMID- 30477777 TI - Assessment of hypoxic lip training for lip incompetence by electromyographic analysis of the orbicularis oris muscle. AB - INTRODUCTION: The aims of this study were to determine the difference in electromyography (EMG) of the orbicularis oris muscles between subjects with lip incompetence and lip competence and to elucidate the effectiveness of hypoxic lip training with EMG. METHODS: Twenty-five subjects (14 men, 11 women; mean age, 24.5 +/- 2.6 years) were divided into 2 groups by sealed lip ratio: 13 subjects with lip incompetence (LI) and 12 subjects with lip competence (LC). Integral values of EMG for the orbicularis oris muscle during lip closing were estimated (baseline, T1). Then the subjects in the LI group performed the hypoxic lip training every day for 4 weeks. The EMG recordings were repeated during the training (T2), immediately after the training (T3), 4 weeks after the training (T4), and 8 weeks after the training (T5). RESULTS: In the LI group, the EMG values during lip closing were significantly higher than those of the LC group, and the values of EMG during lip closing at T3 were significantly lower than those at T1. In the posttraining period, the values of EMG at T4 and T5 were significantly lower than those at T1. The results suggested that subjects with lip incompetence need greater orbicularis oris muscle activity to keep their lips closed. CONCLUSIONS: The suggested standardized lip training could be used as a training method for patients with lip incompetence. PMID- 30477778 TI - High-performance liquid chromatography analysis of salivary bisphenol A levels from light-cured and chemically cured orthodontic adhesives. AB - INTRODUCTION: Our objective was to assess the levels of bisphenol A (BPA) released from light-cured and chemically cured resins used for orthodontic bracket bonding in 1 month. METHODS: Saliva specimens were obtained at 5 time periods from 40 healthy patients treated with orthodontic mechanotherapeutics. The periods of collections were just before bonding orthodontic brackets, followed by 30 minutes, 1 day, 1 week, and 1 month after orthodontic bonding. The specimens were analyzed with the high-performance liquid chromatography/mass spectrometry method for quantitative evaluation of BPA levels. RESULTS: We observed a large increase in BPA levels 30 minutes after orthodontic bonding in the 2 groups. Thereafter, there was sudden decline in BPA levels as time passed, and the levels reached a statistically significant level at 1 month after orthodontic bonding. Interestingly, the amount of BPA released from chemically cured resin was much higher; this was also significant statistically compared with light-cured resins. CONCLUSIONS: The results of this in-vivo approach with high-performance liquid chromatography on salivary specimens confirmed continued release of BPA after bonding brackets for 1 month, although in smaller quantities. The release during the initial 30 minutes is high, making it essential to introduce measures to dilute it for better patient safety. PMID- 30477779 TI - In-vitro comparison of different palatal sites for orthodontic miniscrew insertion: Effect of bone quality and quantity on primary stability. AB - INTRODUCTION: This experiment was undertaken to assess the primary stability of orthodontic miniscrews inserted at different sites in human cadaveric palatal bone for temporary skeletal anchorage, and to determine the effect of bone quality and quantity on their primary stability using microcomputed tomography imaging. METHODS: A total of 10 cadaveric maxillary hard palates were used for insertion of 130 orthodontic miniscrews (VectorTAS; Ormco, Orange, Calif; length, 6 mm; diameter, 1.4 mm). Upon insertion, maximal insertion torque (IT) was recorded. Imaging (microcomputed tomography) was performed before and after insertion for assessment of bone quality and quantity parameters (bone mineral density [BMD], bone thickness [BT], and length of screw engagement [LSE]). Differences in each parameter were assessed at the various insertion sites. Correlations between IT and measurements of BMD, BT, and LSE were evaluated. RESULTS: Significant differences (P < 0.001) were found among insertion sites for IT, BT, and LSE, but not for BMD (P = 0.004). Correlations were found between IT and BMD (rs = 0.42; P < 0.001), IT and BT (rs = 0.58; P < 0.001), and IT and LSE (rs = 0.58; P < 0.001). Most perforations of miniscrews into the nasal cavity occurred posterior to the permanent second premolars. CONCLUSIONS: The primary stability of orthodontic miniscrews in the palate is affected by bone quality and quantity, with higher primary stability obtained anterior to the second premolars and parasagittally at the level of the permanent first molars. PMID- 30477780 TI - New perspective for evaluation of tooth widths in patients with missing or peg shaped maxillary lateral incisors: Quadrant analysis. AB - INTRODUCTION: Missing or peg-shaped maxillary lateral incisors can affect the mesiodistal dimensions of the dentition. METHODS: The pretreatment casts of patients with bilateral (BMLI, n = 35) or unilateral (UMLI, n = 29) missing maxillary lateral incisors or bilateral peg-shaped maxillary lateral incisors (BPLI, n = 16) were evaluated. The mesiodistal widths of all permanent teeth except the second and third molars were measured, and the sums of total and quadrant tooth widths were calculated. The results were compared with a control group (n = 32) with normal maxillary lateral incisors. A quadrant analysis was performed by comparing the quadrants with lateral incisor agenesis, peg-shaped lateral incisors, and normal lateral incisors with each other. Statistical analysis was performed by 1-way analysis of variance followed by Tukey and Tamhane tests. RESULTS: In the BMLI and BPLI groups, significant reductions in individual tooth widths and total tooth widths were seen. The size discrepancies were the greatest in the maxillary central incisors and decreased gradually from the incisors to the molars. Compared with the control group, the tooth-size discrepancy was more pronounced in the BPLI group followed by the BMLI and UMLI groups. Due to the variability in clinical presentations of the UMLI group, the association with the reduction of the tooth sizes was not significant. But the quadrant analysis showed that in quadrants with a missing or peg-shaped lateral incisor, the teeth were significantly narrower than in quadrants with normal incisors; this indicates the importance of the contralateral side in unilaterally affected patients during analysis. CONCLUSIONS: Bilateral missing or peg-shaped maxillary lateral incisors were significantly associated with reduction of individual mesiodistal tooth widths as well as their total and quadrant sums. Patients with a unilaterally missing lateral incisor should be analyzed individually with quadrant analysis, since the variability in the contralateral side would affect the traditional analysis results. PMID- 30477781 TI - Patients' preferences regarding age, sex, and attire of orthodontists. AB - INTRODUCTION: We investigated whether patients in different age groups are influenced by the age, sex, and attire of an orthodontist. METHODS: The opinions of 360 patients regarding 4 orthodontists and 3 types of attire (from photos) were investigated using a questionnaire. Patients were classified as children (8 11 years; n = 120; group 1), adolescents (12-17 years; n = 120; group 2), and young adults (18-25 years; n = 120; group 3). The chi-square test was used to evaluate age- and sex-based preferences for orthodontists and attire types, and a statistical test of proportion (significance level, 5%) was used for multiple comparisons. RESULTS: Young female orthodontists were preferred (41.1%). A white coat was the preferred attire (48.1%), followed by social clothing (31.7%) and a thematic pediatric coat (19.7%). Groups 1 and 2 preferred a young female orthodontist, whereas group 3 had no apparent age and sex preferences. Regarding attire, group 1 preferred social clothing, whereas groups 2 and 3 preferred a white coat. CONCLUSIONS: Patients of all ages consider appearance to be an important factor when choosing an orthodontist. The participants largely preferred younger professionals who dressed in white coats, because this type of attire was considered clean and hygienic. PMID- 30477782 TI - Torturous path of an elastic gap band: Interdisciplinary approach to orthodontic treatment for a young patient who lost both maxillary central incisors after do it-yourself treatment. AB - Spacing between the maxillary anterior teeth is a common concern for young patients and their parents. Patients often consider a diastema to be an annoying but minor problem; they might consult their general dentists for help, or try to address the issue themselves by applying elastic "gap bands." Moreover, parents, without any informed consent, sometimes accept this erroneous method as an easy and inexpensive treatment approach. A 9-year-old boy had severe acute periodontitis involving the maxillary central incisors caused by the placement of an elastic band and its apical migration. Despite periodontal and surgical interventions, the maxillary central incisors were finally extracted, and the patient started orthodontic treatment. The orthodontic treatment plan included maxillary lateral incisor substitution to replace the lost central incisors and mesialization of the maxillary posterior dentition. An interdisciplinary approach with excellent cooperation among the orthodontist, general dentist, and other dental specialists obtained an esthetically pleasing and optimized functional result. Treating the diastema between the anterior teeth with elastic gap bands and without fixed orthodontic appliances should be avoided. Patients should seek proper orthodontic advice for even small-scale orthodontic problems to prevent catastrophic outcomes, as exhibited in this case report. PMID- 30477783 TI - Anterior open bite due to temporomandibular joint osteoarthrosis with muscle dysfunction treated with temporary anchorage devices. AB - Skeletal Class II high-angle open bite is often accompanied by osteoarthrosis of the temporomandibular joint (TMJ-OA). This type of malocclusion is challenging to correct, and it has been reported that patients with TMJ-OA treated with orthognathic surgery often experience skeletal relapse and a poor prognosis. This case report describes the treatment of a 25-year-old woman with retrognathia and TMJ-OA, whose masseter and temporal muscle activities were weak. Temporary anchorage devices were placed in the maxilla and the mandible, and the first molars were intruded. We used improved superelastic nickel-titanium alloy wires with tip-back bends for both arches, and intermaxillary elastics were used to upright the molars. After treatment, intrusion of the maxillary and mandibular first molars, counterclockwise rotation of the mandible, and improvement of occlusion and profile had been achieved. The patient's condyles were repositioned into ideal positions, and masticatory muscle activity was augmented and balanced. After 2 years of retention, the mandibular and condylar positions were stable, and acceptable occlusion was maintained without recurrence of TMJ symptoms; harmonious activity of the masticatory muscles was retained. The findings of this case report suggest that molar intrusion using temporary anchorage devices for a patient with severe anterior open bite and TMJ-OA may be useful for improving stomatognathic function, occlusion, and facial esthetics. PMID- 30477784 TI - Class II correction: Extraction or nonextraction? AB - The patient with a Class II malocclusion, proclination, or moderate crowding of the mandibular anterior teeth, and a moderate-to-low mandibular plane angle is a treatment-planning challenge. The records of 3 patients are presented. For 2 of them, extraction treatment was used to resolve the Class II malocclusion problem. Each of these patients was treated with the removal of maxillary first premolars and mandibular second premolars. The third patient was treated with Class II elastics without extractions. The clinician must weigh the pros and cons of each approach and decide which approach will give the patient the best long-term benefit. PMID- 30477785 TI - CAD-CAM design and 3-dimensional printing of mini-implant retained orthodontic appliances. AB - The objective of this article was to illustrate the digital process in the custom fabrication of metallic mini-implant supported appliances. An implant-supported appliance was produced for a patient using a CAD-CAM procedure without a physical impression or a printed model. The work flow consisted of mini-implant insertion into the palate, recording an intraoral digital scan, digital design with incorporation of a scanned expansion mechanism, direct 3-dimensional metal printing via laser melting, laser welding of the hyrax mechanism, insertion, and activation of the appliance. The favorable clinical outcome demonstrated that this procedure is an efficient and viable method for constructing an implant supported palatal metallic appliance. PMID- 30477786 TI - I want to see everything. PMID- 30477787 TI - Letter by Briche et al. Bystanders, Dispatchers, Rescuers, and Defibrillator must recognize agonal breathing. PMID- 30477788 TI - Out-of-hospital cardiac arrest termination of resuscitation. PMID- 30477789 TI - Relationship Between Symptoms and Health-Related Quality-of-Life Benefits in Patients With Carcinoid Syndrome: Post Hoc Analyses From TELESTAR. AB - PURPOSE: Patients with metastatic neuroendocrine tumors and carcinoid syndrome (CS) may experience chronic, recurring symptoms despite somatostatin analogue therapy. Little is known about the relationship between bowel movement (BM) frequency, patient-reported symptoms and health-related quality of life (QoL). Data from the TELESTAR study were used in exploratory, post hoc analyses to understand the relationship between durable reductions in BM frequency, symptom relief, and health-related QoL. METHODS: Patients with metastatic neuroendocrine tumors and CS in the Phase III TELESTAR study were randomized (1:1:1) to receive telotristat ethyl (TE) 250 mg, TE 500 mg, or placebo three times daily (TID) during a 12-week double-blind treatment period (DBTP). All patients received TE 500 mg TID in an open-label extension (OLE) to Week 48. Durable response was predefined. Analyses compared durable responders (DRs) and non-durable responders (NDRs), irrespective of treatment group, at Weeks 12, 24, and 48. FINDINGS: At the start of the DBTP, 135 patients were randomized, 45 patients each to TE 250 mg, TE 500 mg, and placebo. After the 12-week DBTP, 48 of 135 patients were DRs (TE 250 mg, n = 20; TE 500 mg, n = 19; placebo, n = 9). Of the 115 patients who entered the OLE, 35 were DRs initially randomized to TE 250 mg (n = 18) or 500 mg (n = 17), 29 of whom maintained a durable response throughout the OLE. Of the 71 DBTP-NDRs (inclusive of patients initially randomized to placebo), 28 became OLE DRs. There were 29 NDRs initially randomized to placebo who entered the OLE, 16 of whom became DRs when switched to TE 500 mg. DRs during the DBTP had greater symptom improvements in the DBTP; these improvements continued over the OLE. DBTP DRs also maintained more meaningful QoL improvements in EORTC QLQ-C30 global health status, nausea and vomiting, pain, diarrhea, and EORTC QLQ-GINET21 gastrointestinal symptoms over the DBTP and OLE periods than DBTP-NDRs. IMPLICATIONS: These results suggest that sustained improvements in BM frequency in patients with CS may have multifaceted, long-term effects on a patient's well being. ClinicalTrials.gov identifiers: NCT01677910. (Clin Ther. 2018;40:XXX-XXX) (c) 2018 Elsevier HS Journals, Inc. PMID- 30477790 TI - Metal Organic Frameworks (MOFs) and ultrasound: A review. AB - Metal-organic frameworks (MOFs) have received a lot of attention due to their unique properties and abundant functionalities. Permanent porosity and high surface area are just a few traits that have made them attractive to researchers. They can be prepared as task-specific materials by exploiting the functional group variety and tuning their size and geometry. The main purpose of this review is to present an alternative method of preparing MOF crystals and underline the advantages of ultrasound assisted (sonochemical) synthesis. State of the art ultrasound assisted techniques for the preparation of MOFs in nanoscale are presented. Optimization of morphology and particle size is highlighted throughout this work, as we discuss the effects of various factors, such as energy input, reagent concentration, adequate solvents, reaction time and more. PMID- 30477791 TI - Hydrodynamic and mass transfer investigation of oxidative desulfurization of a model fuel using an ultrasound horn reactor. AB - Ultrasound assisted oxidative desulfurization (UAOD) is a promising technology, which can result in ultra-low sulfur fuels in order to reduce the environmental crisis. Most of the researches have been conducted with the experimental approaches. In the present study, a computational fluid dynamic (CFD) model has been developed to investigate the hydrodynamics as well as the reactions involved in a sonoreactor. The results indicate that the physical and chemical effects associated with the ultrasonic field can contribute to the enhancement of the reaction and sulfur removal rates. However, the physical effects are predominant as compared to the chemical effects. Indeed, homogenous mixing and fine micro emulsification caused by the physical effects lead to increase the interfacial area and mass transfer rate between the immiscible aqueous and oil phases. The dibenzothiophene concentration predicted by the simulation was in a reasonably good agreement with the corresponding experimental data. Another key hydrodynamic parameter induced by ultrasonic field was turbulent kinetic energy, which can play an important role in the sulfur removal rate. The results indicate the higher desulfurization efficiency has been attained at the regions with the higher velocity fluctuations. PMID- 30477792 TI - Ultrasonic semi-solid soldering 6061 aluminum alloys joint with Sn-9Zn solder reinforced with nano/nano+micron Al2O3 particles. AB - In this study, the joint at low temperature with nano-Al2O3 particles and Al2O3 nano + micro particles were fabricated by semisolid assisted ultrasonic vibration with nano-Al2O3 particle of 50 nm and volume fractions of 1% and micron-Al2O3 particle of 10 MUm and volume fractions of 1%. The joints were examined in order to understand the effects of Al2O3 additions as microstructure, interface morphology and shear strength as well as mechanical properties of soldering 6061 aluminum alloys. Due to different size, the scallop-shaped solid solution layer was changed into a groove layer, and its thickness of Al3Zn2 solid solution layer was decreased. The grain refinement mechanism of Sn-9Zn-1 nmAl2O3 is mainly sono crystallization (enhanced nucleation). However, the grain refinement mechanisms of Sn-9Zn-1 nm1 MUm Al2O3 change to be mainly sono-crystallization + sono fragmentation. With the increase of different size particles, the fracture mode transforms from brittleness to ductile fracture and finally to dimple structure. Micro particles may contribute less to the strength compared to the refining effect, but significantly improve the plasticity. PMID- 30477793 TI - PMS activation using reduced graphene oxide under sonication: Efficient metal free catalytic system for the degradation of rhodamine B, bisphenol A, and tetracycline. AB - This study addresses the influence of ultrasound irradiation on the activation of peroxymonosulfate (PMS) using reduced graphene oxide (rGO) under metal-free conditions for the catalytic degradation of rhodamine B (RhB), bisphenol A (BPA) and tetracycline (TC). Our results revealed that the combination of PMS/rGO and ultrasonication enhanced significantly the degradation rate, reaching full degradation in relatively short times with total organic carbon (TOC) removal exceeding 85% of the investigated pollutants. In contrast, under these experimental conditions, rGO/ultrasound and PMS/ultrasound achieved less than 20% degradation of the same pollutants. Electron paramagnetic resonance (EPR) studies along with quenching experiments suggested that hydroxyl radicals (OH) are the dominant reactive species in the degradation process. Furthermore, inductively coupled plasma atomic emission spectroscopy (ICP-AES) and EPR data revealed the presence of trace manganese (Mn) in rGO. To elucidate the role of Mn on the degradation process, rGO was subjected to hot acid treatment for 48 h to remove trace Mn. While the chemical composition of rGO was not significantly altered by this chemical treatment, the degradation efficiency decreased upon Mn dissolution. The result suggests that trace metal in rGO might account for the efficiency of PMS activation. Finally, plausible degradation pathways were proposed based on LC-MS analysis of the reaction intermediates. PMID- 30477794 TI - Effect of geometrical configuration of reactor on a ZrP nano-dispersion process using ultrasonic irradiation. AB - This study investigated the position of ultrasonic irradiation source and reactor geometry on fragmentation rate of a layered compound, alpha-zirconium phosphate (alpha-ZrP). By numerically solving the acoustic pressure distribution using COMSOL Multiphysics(r), it is clarified the mechanism whereby the operating factors influenced the alpha-ZrP dispersion to make a suggestion of guideline of the process design method. Two vessels made of glass with a flat-bottom and a spherical-bottom, respectively, were used. Although the flat-bottom vessel at lower horn position showed the best performance of fragmentation, the region of high acoustic pressure field in the flat bottom vessel sharply narrowed and the transmittance became prominently low. On the other hand, no significant difference of the transmittance value in the spherical bottom vessel between the cases of low and high horn positions could be observed and the spherical bottom vessel was robust for the horn position. These results suggest that not only the magnitude of acoustic pressure but also the size of high acoustic pressure region is also an important factor and a spherical bottom vessel is one of suitable shape which gives large size of high acoustic pressure region regardless of the horn position. PMID- 30477795 TI - Study of encapsulated microbubble cluster based on association schemes perspective. AB - Ultrasound contrast agents have been recently utilized in therapeutical implementations for targeted delivery of pharmaceutical substances. Radial pulsations of a cluster of encapsulated microbubbles under the action of an ultrasound field are complex and highly nonlinear, particularly for drug and gene delivery applications with high acoustic pressure amplitudes. In this paper, based on Qin-Ferrara's model (Qin and Ferrara, 2010), the complete synchronization and cluster formation in targeted microbubbles network are studied. Also, association schemes as a novel approach are suggested for finding a relationship between coupled microbubbles elements which are immersed in blood or surrounding soft tissue. A significant advantage of this method is that the stability of the synchronized state (or symmetric eigenmode of mutual bubble oscillation) with respect to another state (another eigenmode) can now predict. More interestingly, we find a significant relationship between an isolated and multiple microbubbles. The results show that the problem of studying the dynamics of encapsulated microbubble cluster at synchronization state is dependent on the dynamical characteristics of isolated cases, shell thickness, density. Also, the distance between microbubbles has an important role in their synchronous modes. PMID- 30477796 TI - Ultrasound assisted preparation, characterization and adsorption study of ternary chitosan-ZnO-TiO2 nanocomposite: Advantage over conventional method. AB - In the present work, the synthesis of ternary chitosan/zinc oxide/titanium dioxide (CTS-ZnO-TiO2) nanocomposite was carried out with the use of mechanical stirring (conventional) and ultrasound assisted method. The characterization of prepared CTS-ZnO-TiO2 adsorbent was carried out using XRD, TEM, FTIR and the results of these analysis methods proved the successful preparation of ternary nanocomposite. Crystal violet (CV) dye was used as a pollutant to observe the adsorption ability of the prepared nanocomposite and the nanocomposite prepared by ultrasonic-assisted method proved to be a better adsorbent. The CV dye adsorption was significant for CTS-ZnO-TiO2 nanocomposite synthesized with the use of ultrasound assisted method compared to that prepared by conventional method. It is due to the physical effects of the ultrasonic irradiations due to which formation of finely dispersed nanocomposite takes place than that by conventional method. For batch adsorption the effect of various operating parameters such as initial dye concentration, time, temperature and adsorbent dose has been evaluated. The obtained data were processed using isotherm models, adsorption kinetics and the thermodynamic behavior of the cationic dye adsorption was also studied. The isotherm data was correlated reasonably well by the Temkin adsorption isotherm. Pseudo-second-order kinetic model provided a better correlation for the experimental data compared to pseudo first order, Elovich model and power function kinetics model. Thermodynamic parameters for adsorption indicated that the dye adsorption was spontaneous and endothermic in nature. PMID- 30477797 TI - Ultrasonic cavitation erosion mechanism and mathematical model of HVOF sprayed Fe based amorphous/nanocrystalline coatings. AB - A Fe-based amorphous/nanocrystalline coating was prepared on the AISI 321 steel by the high-velocity oxygen-fuel (HVOF) thermal spraying technology in this paper. Cavitation erosion behavior and mechanism of the coating was studied through the analysis of curves for cavitation erosion resistance versus time and the observation of eroded particles, with the AISI 321 steel as a reference. It was found that the Fe-based coating had better cavitation erosion resistance than the AISI 321 steel, and exhibited obvious periodic failure behavior in the cavitation erosion process. Besides, the crystallization of the amorphous phase under the effect of shock wave was observed. The cavitation erosion mathematic model of the coating was also established. The model indicated that the cavitation erosion resistance of the coating was related to the grain size and the fracture energy per unit area of the coating. Small grain size and high fracture energy per unit area were benefit to improve the cavitation erosion resistance of the Fe-based coating. PMID- 30477798 TI - Cocaine, Amphetamine, and Cannabis Use Increases the Risk of Acute Myocardial Infarction in Teenagers. PMID- 30477799 TI - Usefulness of Oximetry Paradoxus to Diagnose Cardiac Tamponade. AB - Although echocardiography is usually diagnostic of cardiac tamponade, it may not be readily available at the point-of-care. We sought to develop and validate a measurement of respirophasic variation in the amplitude of pulse oximetry plethysmographic waveforms as a diagnostic tool for cardiac tamponade. Pulse oximetry plethysmographic waveforms were recorded, and the ratio of maximum-to minimum measured amplitude of these waveforms from one respiratory cycle was calculated by blinded observers. Ratios from 3 consecutive respiratory cycles were then averaged to derive an "oximetry paradoxus" ratio. Cardiac tamponade was independently confirmed or excluded according to a "blinded" objective interpretation of echocardiography or right heart catheterization. Seventy four subjects were enrolled (51% men; mean age 54 +/- 15 years); 19 of whom had cardiac tamponade. Oximetry paradoxus area under the curve for diagnosis of cardiac tamponade was 0.90 (95% confidence interval, 0.84 to 0.97); its diagnostic performance was superior to sphygmomanometer-measured pulsus paradoxus (area under the curve difference = 0.16, p = 0.022). In a derivation cohort (n = 37; tamponade, 9 cases), 3 diagnostic oximetry paradoxus thresholds were identified and validated in an independent validation cohort (n = 37; tamponade, 10 cases): 1.2 (100% sensitivity, 44% specificity), 1.5 (80% sensitivity, 81% specificity), and 1.7 (80% sensitivity, 89% specificity). Furthermore, oximetry paradoxus was significantly reduced after draining pericardial fluid. In conclusion, we defined and validated oximetry paradoxus as a simple and ubiquitous point-of-care test to diagnose cardiac tamponade using respirophasic changes in pulse plethysmography waveforms. This test can aid in identifying patients with cardiac tamponade, thus expediting confirmatory testing and life saving treatment. PMID- 30477800 TI - Relation of Serum and Urine Renal Biomarkers to Cardiovascular Risk in Patients with Type 2 Diabetes Mellitus and Recent Acute Coronary Syndromes (From the EXAMINE Trial). AB - A deeper understanding of the interplay between the renal axis and cardiovascular (CV) disease is needed in type 2 diabetes mellitus (T2DM). We aimed to explore the prognostic value of a comprehensive panel of renal biomarkers in patients with T2DM at high CV risk. We evaluated the prognostic performance of both serum (Cystatin C) and urine renal biomarkers (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1 protein, and indices of urinary protein excretion) in 5,380 patients with T2DM and recent acute coronary syndromes in the EXAMINE trial. Patients requiring dialysis within 14 days were excluded. Single- and multimarker covariate-adjusted Cox proportional hazards models were developed to predict times to events. Primary endpoint was composite nonfatal myocardial infarction, nonfatal stroke, or CV death. Median age was 61 years, 68% were men, and mean baseline estimated glomerular filtration rate (eGFR) was 74 mL/min/1.73 m2. During median follow-up of 18 months, 621 (11.5%) experienced the primary endpoint and 326 (6.1%) patients had died. All renal biomarkers were robustly associated with adverse CV events in step-wise fashion, independent of baseline eGFR. However, in the multimarker prediction model, only Cystatin C (per 1 SD) was associated with the primary endpoint (hazard ratio [HR] 1.28 [1.14 to 1.45]; p <= 0.001), death (HR 1.51 [1.30 to 1.74]; p <= 0.001), and heart failure hospitalization (HR 1.20 [0.96 to 1.49]; p = 0.11). Association between Cystatin C and the primary endpoint was similar in baseline eGFR above and below 60 mL/min/1.73 m2 (Pinteraction > 0.05). In conclusion, serum and urine renal biomarkers, when tested alone, independently predict long-term adverse CV events in high-risk patients with T2DM. In an integrative panel of renal biomarkers, only serum Cystatin C remained independently associated with subsequent CV risk. Renal biomarkers informing various aspects of kidney function may further our understanding of the complex interplay between diabetic kidney disease and CV disease. PMID- 30477801 TI - Risk of Ascending Aortic Aneurysm in Patients With Autosomal Dominant Polycystic Kidney Disease. AB - In recent years, simple renal cysts have been associated with an increased risk of aortic aneurysms. There is little data regarding aortic dilation in patients with autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to compare Sinuses of Valsalva (SoV) and tubular ascending aorta diameters in ADPKD patients with matched controls. From 2008 to 2016, 61 consecutive ADPKD patients who had an echocardiogram performed in our institution were matched 1:1 with controls for sex, age, blood pressure, and beta-blocker therapy use. SoV and tubular ascending aorta were measured at end-diastole, using the leading-edge to leading-edge convention. Paired t Tests were used for quantitative variables and McNemar-tests for qualitative variables. The mean age of patients was 56 +/- 12 years, 54% were men, 38% received beta-blockers, and mean systolic and diastolic BP were 137 +/- 25 and 78 +/- 19 mm Hg. SoV diameters were significantly larger in ADPKD patients than in controls (36.4 +/- 4.1 vs 34.0 +/- 3.7 mm, p <0.0001). The Z-scores (normalized for sex, age, and body surface area) were significantly higher in ADPKD patients, both for SoV and tubular ascending aorta. Moreover, aortic aneurysms, as defined by a Z score >2 standard deviations, were present in 27 ADPKD patients (44%) versus 9 controls (15%, p <0.001). In conclusion, there is an increased prevalence of aortic aneurysms in ADPKD patients as compared with controls matched for common confounding factors for aortic dilation. PMID- 30477802 TI - Meta-Analysis of Relation of Epicardial Adipose Tissue Volume to Left Atrial Dilation and to Left Ventricular Hypertrophy and Functions. AB - Many studies have explored the hypothesis that epicardial adipose tissue (EAT) accumulation adversely affects cardiac remodeling. We assessed, through a systematic review and meta-analysis, whether EAT is linked to left atrial (LA) and left ventricular (LV) structure and function, irrespective of global or abdominal visceral adiposity. We searched MEDLINE, Scopus, and Web of Science for studies evaluating the association of EAT volume quantified by computed tomography with cardiac morphology and function. We used DerSimonian and Laird random-effects models to summarize the adjusted-effect of 10 ml variation of EAT on LA size, LV mass, LV diastolic and systolic functions parameters, and presence of diastolic dysfunction. We quantified heterogeneity using I2 statistic. We included 19 studies. Quantitative analysis by cardiac parameters, including LA dimension (n = 2,719), LV mass (n = 2,519), diastolic function (n = 3,741), and systolic function (n = 2,037) showed that EAT was associated with LA dilation (pooled B-coefficient: 0.12 mm; 95% confidence interval [CI] 0.08 to 0.17; I2: 97%), LV hypertrophy (pooled B-coefficient: 1.21 g; 95% CI 0.63 to 1.79; I2: 77%), diastolic dysfunction (odds ratio: 1.35; 95% CI 1.16 to 1.57; I2: 0%), higher E/E' ratio (pooled B-coefficient: 0.28 cm/s; 95% CI 0.08 to 0.49; I2: 67%), lower E' velocity (pooled B-coefficient: -0.16 cm/s; 95% CI -0.22 to -0.09; I2: 43%), and E/A ratio (pooled B-coefficient: -0.01; 95% CI -0.02 to -0.001; I2: 70%), independently of body mass index. There was no association between EAT and LV systolic function. In conclusion, EAT volume measured by computed tomography was independently associated with LA dilation, LV hypertrophy, and diastolic dysfunction. PMID- 30477803 TI - Contrast-Induced Nephropathy and Long-Term Clinical Outcomes Following Percutaneous Coronary Intervention in Patients With Advanced Renal Dysfunction (Estimated Glomerular Filtration Rate <30 ml/min/1.73 m2). AB - The incidence of contrast-induced nephropathy (CIN) increases with the progression of renal dysfunction. Recent reports have shown that percutaneous coronary intervention (PCI) can be safely performed even in patients with advanced renal dysfunction by appropriate CIN-prevention strategies. However, data are limited regarding the occurrence and prognostic influence of CIN in patients with advanced renal dysfunction. We examined the data obtained from 323 consecutive patients with advanced renal dysfunction (eGFR <30 ml/min/1.73 m2) who underwent PCI at 5 hospitals. CIN was defined as a >=25% increase in baseline serum creatinine levels and/or a >=0.5 mg/dl increase in absolute serum creatinine levels within 72 hours after PCI. Incidence of all-cause death and the initiation of permanent dialysis were examined during follow-up. The prevalence of emergency/urgent PCI was 53.3%. Intravascular ultrasound was used in 266 patients (82.4%), and the volume of contrast used was 71.7 +/- 57.2 ml. CIN was observed in 31 patients (9.7%). The median follow-up duration was 656 days (interquartile range 257-1143 days). The cumulative rates of all-cause death or the initiation of permanent dialysis, all-cause death, and the initiation of permanent dialysis were 38.1%, 25.9%, and 18.2%, respectively, at 2 years. A comparison between patients with and without CIN showed no significant intergroup differences in the occurrence of the aforementioned events. In conclusion, the incidence of CIN was not high in Japanese patients with advanced renal dysfunction in routine clinical practice. Whereas, the long-term prognosis following PCI is observed to be poor in this studied population, and CIN did not show a significant prognostic influence. PMID- 30477804 TI - Frequency, Predictors, and Prognostic Impact of Pulmonary Artery Aneurysms in Patients With Pulmonary Arterial Hypertension. AB - Detection of pulmonary artery aneurysms (PAA) in pulmonary arterial hypertension (PAH) is increasing. We sought to determine the frequency of PAA in a PAH cohort, variables related to its development and its prognostic impact. We conducted a retrospective analysis of PAH patients who underwent a computed tomography or magnetic resonance. PAA was defined as a pulmonary artery >40 mm. Baseline, echocardiographic, and hemodynamic findings at PAH diagnosis were compared. Freedom from death or lung transplant was estimated by Kaplan-Meier method and compared by log-rank test. Predictors of PAA development were analyzed with multivariate models. Two-hundred patients underwent a computed tomography and/or magnetic resonance. In 77 (38%), a PAA (48.3 +/- 7.2 mm) was detected. Time course (months) of PAH was an independent risk factor for PAA (hazard ratio 1.01; 95% confidence interval 1.002 to 1.019; p = 0.016) whilst connective tissue disease was associated with a lower risk (hazard ratio 0.236; 95% confidence interval 0.060 to 0.920; p = 0.037). PAA patients showed lower rates of death and lung transplant from PAH diagnosis (p = 0.005), but no differences appeared when survival analysis was performed from first imaging test (p = 0.269). PAA patients presented a nonsignificant higher rate of sudden death (5% PAA vs 1% no-PAA; p = 0.073). In conclusion, the frequency of PAA was 38%. PAH time-course was an independent risk factor for PAA development whereas connective tissue disease related PAH patients showed a lower risk. PAA patients showed lower rates of death or lung transplant from PAH diagnosis but no differences were found from imaging test. PAA patients had a nonsignificant higher rate of sudden death. PMID- 30477805 TI - Conditions and Factors Associated With Spontaneous Coronary Artery Dissection (from a National Population-Based Cohort Study). AB - The pathophysiology of spontaneous coronary artery dissection (SCAD) is heterogeneous, associated with systemic arteriopathies and inflammatory diseases, and often compounded by environmental precipitants, genetics, or stressors. However, the frequency of these associated conditions with SCAD on a population level remains unknown. Therefore, the objective of this analysis was to evaluate heterogeneous phenotypes of SCAD in the United States using data from the Nationwide Inpatient Sample collected from January 1, 2004, to September 31, 2015. Among 66,360 patients diagnosed with SCAD, the mean age was 63.1 +/- 13.2 years and 44.2% were women. A total of 3,415 (5.14%) had depression, 670 (1.0%) had rheumatoid arthritis, 640 (0.96%) had anxiety, 545 (0.82%) had a migraine disorder, 440 (0.66%) used steroids, 385 (0.58%) had malignant hypertension, 280 (0.42%) had systemic lupus erythematosus, 250 (0.38%) had cocaine abuse, 215 (0.32%) had hypertensive heart or renal disease, 130 (0.19%) had coronary spasm, 105 (0.16%) had fibromuscular dysplasia, 85 (0.13%) had Crohn's disease, 75 (0.11%) had celiac disease, 60 (0.09%) had adult autosomal dominant polycystic kidney disease, 60 (0.09%) had hormone replacement therapy, 55 (0.08%) had sarcoidosis, 55 (0.08%) had amphetamine abuse, 15 (0.02%) had granulomatosis polyangiitis, 10 (0.02%) had alpha1-antitrypsin deficiency, 10 (0.02%) had Marfan syndrome, 10 (0.02%) had Ehlers-Danlos syndrome, 10 (0.02%) had Kawasaki disease, 10 (0.02%) had polyarteritis nodosa, and 5 (0.01%) had multiparity. In conclusion, most cases of SCAD had no apparent concomitant arteriopathy, inflammatory disorder, or evident risk factor. PMID- 30477806 TI - Potential for afatinib as an optimal treatment for advanced non-small cell lung carcinoma in patients with uncommon EGFR mutations. PMID- 30477807 TI - Elevated attention deficit hyperactivity disorder symptoms in children who stutter. AB - PURPOSE: This study described the proportion of children who stutter who exhibit Attention Deficit Hyperactivity Disorder (ADHD) symptoms, manifesting in inattentive and hyperactive/impulsive behaviours. Children who stutter with these challenging behaviours may not respond as quickly and successfully to stuttering treatment. A preliminary exploration of differences in treatment responsiveness for children with and without ADHD symptoms was undertaken. METHOD: Participants were 185 preschool children who stutter who had completed stuttering therapy within 3 months prior to study commencement. Differences between groups of children who stutter with and without elevated ADHD symptoms were investigated, in terms of pre-treatment stuttering features (stuttering severity and typography), demographic variables (age at onset, time between onset and commencement of therapy, family history and sex) and treatment data (post treatment stuttering severity and number of sessions to achieve discharge criteria). RESULTS: One-half (50%) of participants exhibited elevated ADHD symptoms. These children required 25% more clinical intervention time to achieve successful fluency outcomes than children without elevated ADHD symptoms. Findings suggest that more ADHD symptoms, increased pre-treatment stuttering severity, and male sex were associated with poorer responsiveness to stuttering treatment. CONCLUSION: The large proportion of children exhibiting elevated ADHD symptoms, and the increase in clinical contact time required in this subgroup to achieve successful fluency outcomes, is suggestive of the need for clinicians to tailor stuttering intervention to address these concomitant behaviour challenges. Findings support the use of careful caseload management strategies to account for individual differences between children, and strengthen prognostic information available to parents and clinicians. PMID- 30477808 TI - The cost-effectiveness of opportunistic salpingectomy versus standard tubal ligation at the time of cesarean delivery for ovarian cancer risk reduction. AB - OBJECTIVES: Opportunistic salpingectomy is a cost-effective strategy recommended for ovarian cancer (OvCa) risk reduction at the time of gynecologic surgery in women who have completed childbearing. We aimed to evaluate the cost effectiveness of opportunistic salpingectomy compared to standard tubal ligation (TL) during cesarean delivery. STUDY DESIGN: A cost-effectiveness analysis using decision modeling to compare opportunistic salpingectomy to TL at the time of cesarean using probabilities of procedure completion derived from a trial. Probability and cost inputs were derived from local data and the literature. The primary outcome was the incremental cost-effectiveness ratio (ICER) in 2017 U.S. dollars per quality-adjusted life year (QALY) at a cost-effectiveness threshold of $100,000/QALY. One- and two-way sensitivity analyses were performed for all variables. A probabilistic sensitivity analysis determined the proportion of simulations in which each strategy would be cost-effective. RESULTS: Opportunistic salpingectomy was cost-effective compared to TL with an ICER of $26,616 per QALY. In 10,000 women desiring sterilization with cesarean, opportunistic salpingectomy would result in 17 fewer OvCa diagnoses, 13 fewer OvCa deaths, and 25 fewer unintended pregnancies compared to TL - with an associated cost increase of $4.7 million. The model was sensitive only to OvCa risk reduction from salpingectomy and TL. Opportunistic salpingectomy was not cost-effective if its cost was >$3163.74 more than TL, if the risk-reduction of salpingectomy was <41%, or if the risk-reduction of TL was >46%. In probabilistic sensitivity analysis opportunistic salpingectomy was cost effective in 75% of simulations. CONCLUSIONS: In women undergoing cesarean with sterilization, opportunistic salpingectomy is likely cost-effective and may be cost-saving in comparison to TL for OvCa risk reduction. PMID- 30477809 TI - Hepatitis case finding among migrants in primary care. PMID- 30477810 TI - Case finding and therapy for chronic viral hepatitis in primary care (HepFREE): a cluster-randomised controlled trial. AB - BACKGROUND: The prevalence of viral hepatitis (hepatitis B virus and hepatitis C virus) in migrants is higher than among the general population in many high income countries. We aimed to determine whether incentivising and supporting primary-care physicians in areas with a high density of migrants increases the numbers of adult migrants screened for viral hepatitis. METHODS: HepFREE was a multicentre, open, cluster-randomised controlled trial in general practices in areas of the UK with a high density of migrants (Bradford, Yorkshire, and northeast and southeast London). Participants were adult patients (aged 18 years or older) in primary care, who had been identified as a first or second generation migrant from a high-risk country. General practices were randomly assigned (1:2:2:2:2) to an opportunistic screening (control) group or to one of four targeted screening (interventional) groups: standard (ie, hospital-based) care and a standard invitation letter; standard care and an enhanced invitation letter; community care and a standard invitation letter; or community care and an enhanced invitation letter. In control screening, general practitioners (GPs) were given a teaching session on viral hepatitis and were asked to test all registered migrants. In the intervention, GPs were paid a nominal sum for setting up searches of records, reimbursed for signed consent forms, and supported by a dedicated clinician. Patients who were eligible for testing and tested positive for viral hepatitis in the intervention groups were eligible to enrol in a second embedded trial of community versus hospital based care. The primary outcomes were the proportion of patients eligible for screening, the proportion of those eligible who were sent an invitation letter in the intervention groups, the uptake of viral hepatitis screening (in the intention-to-treat population), the proportion of patients who tested positive for viral hepatitis, the proportion who complied with treatment, and the cost-effectiveness of the intervention. This trial is registered with ISRCTN, number ISRCTN54828633. FINDINGS: Recruitment and testing ran from Oct 31, 2013, to Feb 4, 2017, and each practice recruited for 18 consecutive calendar months. We approached 70 general practices in three areas with a high density of migrants, of which 63 general practices agreed to participate. Five practices withdrew and 58 practices were randomly assigned: eight to control and 50 to an intervention. In control practices, 26 046 (38.4%) of 67 820 patients who were initially registered were eligible for testing, as were 152 321 (43.3%) of 351 710 patients in the interventional groups in London and Bradford. Of 51 773 randomly selected eligible patients in the intervention groups in London and Bradford, letters were sent to 43 585 (84.2%) patients. In the eight control general practices, screening was taken up by 543 (1.7%) of 31 738 eligible participants, which included 5692 newly registered patients. However, in the 50 general practices that used the intervention, screening was taken up by 11 386 (19.5%) of 58 512 eligible participants (including 6739 newly registered patients; incidence rate ratio 3.70, 95% CI 1.30-10.51; p=0.014) and this intervention was cost-effective. 720 (4.5%) of 15 844 patients who received a standard letter versus 1032 (3.7%) of 28 095 patients who received the enhanced letter were tested (0.70, 0.38-1.31; p=0.26). In the control group, 17 patients tested positive for viral hepatitis, as did 220 patients (one with a co infection) in the intervention groups. In the embedded study, 220 patients were randomly assigned to either hospital-based care or community care; 80 (87.9%) of 91 patients in the hospital setting complied with treatment versus 105 (81.4%) of 129 patients in the community setting. The intervention was cost-effective at willingness to pay thresholds in excess of L8540. One serious adverse event (thyroiditis) was noted. INTERPRETATION: Screening migrants for viral hepatitis in primary care is effective if doctors are incentivised and supported. Community care is expensive and there is no evidence that this offers benefits in this setting or that bespoke invitation letters add value. We suggest that bespoke invitation letters should not be used, and we suggest that outreach, community based services for migrants should not be developed. FUNDING: National Institute for Health Research. PMID- 30477811 TI - Transjugular intrahepatic portosystemic shunt as a bridge to liver transplant: Current state and future directions. AB - Liver transplantation is one of the mainstays of treatment for liver failure due to severe chronic liver disease. Bridging therapies, such as placement of a transjugular intrahepatic portosystemic shunt (TIPS), are frequently employed to control complications of portal hypertension such as ascites, hydrothorax, and variceal bleeding, and thereby reduce morbidity in patients awaiting transplant. There is no significant difference seen in either graft survival or patient survival between those receiving TIPS pre-transplant and those who do not, although those receiving TIPS placement on average have a longer waiting time on the transplant waitlist. Locoregional therapies, such as thermal ablation or chemoembolization, can be efficacious in patients with HCC and pre-existing TIPS; however there is a risk for increased adverse events in patients receiving these therapies who have TIPS compared to those who do not. In summary, TIPS is a safe, effective treatment that can be used to ameliorate the complications that are sequelae of portal hypertension. While it does not appear to improve survival post-transplant, TIPS placement pre-transplant may increase survival time to transplant, thus improving overall survival as well as quality of life. PMID- 30477812 TI - Three-Dimensional Printing Facilitates Creation of a Biliary Endoscopy Phantom for Interventional Radiology-Operated Endoscopy Training. AB - PURPOSE: To create a three-dimensional endoscopic model of the biliary tract from magnetic-resonance cholangiopancreatography imaging and to evaluate its effectiveness as a tool for training in endoscopic biliary interventions. MATERIALS AND METHODS: A magnetic-resonance cholangiopancreatography study was performed on a patient with biliary obstruction secondary to a distal bile duct cholangiocarcinoma. Using Vitrea, a three-dimensional volume-rendered image was created, and exported as a standard tessellated language file. The standard tessellated language model was then edited with MeshMixer. Three cylindrical entry ports were created. The ports were aligned and overlapped with the dominant ducts in three separate areas of the model and fused to the model. A 0.2 cm shell was created around the model and the model was hollowed. The ends of the ports were cut off, allowing access to the hollowed-out model. The model was printed at 125% scale to allow easy access with a 9.5-French (<=3.23 mm) endoscope. The model was printed using a Stratasys Dimension Elite Plus printer. After printing, the model was post-processed to remove support materials. A 10-question survey was administered to all trainees before and after use of the printed phantom to practice endoscopy skills. RESULTS: 11 trainees participated in the three dimensional endoscopy simulation with most of the trainees (73%) having no prior formal endoscopy training. Using a 10-point Likert scale, the mean comfort-level of the trainees to use endoscopy alone for cholecystostomy, percutaneous biliary drainage, percutaneous nephrostomy, and percutaneous gastrostomy increased by 38.9%, 32.8%, 32.8%, and 34.3%, respectively, following the training experience. CONCLUSION: The use of a three-dimensionally printed endoscopic model as a simulation tool has the potential to improve trainee comfort using endoscopy during interventional radiology procedures. PMID- 30477813 TI - Management of anteromedially displaced acetabular fractures using a collinear reduction clamp through modified ilioinguinal approach. AB - The authors present a surgical technique using a collinear reduction clamp through the modified ilioinguinal approach (MIA) for anteromedially displaced acetabular fractures along with the surgical outcomes. Between October 2010 and June 2015, 15 patients underwent surgical treatment for anteromedially displaced acetabular fractures; 10 both-column fractures and 5 anterior column and posterior hemitransverse fractures. Anteriorly displaced anterior column fragment and medially displaced quadrilateral plate fragment were simultaneously reduced using a collinear clamp and fixed with a 3.5mm-reconstruction plate through MIA. Postoperatively, anatomical reduction was achieved in 12 patients, while imperfect reduction was achieved in 3. At a mean follow-up of 49.0 months (range, 24-93 months), the mean Postel Merle d'Aubigne score were 16.3 and the mean VAS score was 0.9. Final radiographic grades according to Matta system were excellent in 13 patients and good in 2. Surgical technique using a collinear reduction clamp through the MIA can provide satisfactory outcomes in anteromedially displaced acetabular fractures. PMID- 30477814 TI - Variability of urinary concentrations of phthalate metabolites during pregnancy in first morning voids and pooled samples. AB - BACKGROUND: Because phthalates are quickly metabolized and excreted in urine, and human exposures tend to be episodic, phthalate metabolite concentrations measured in a maternal spot urine sample are only indicative of recent exposure. OBJECTIVE: To examine temporal variability of pregnant women's phthalate exposure using multiple first morning voids (FMV) and pooled samples. METHODS: We quantified 14 metabolites of eight phthalates in 577 urine samples collected from 188 pregnancies in the MARBLES (Markers of Autism Risk in Babies - Learning Early Signs) study. We calculated intraclass correlation coefficients (ICCs) using two samples of the same urine type (i.e., two FMVs or two pools) collected across the 2nd and 3rd trimesters. We also calculated ICCs and FMV/pool concentration ratios using two samples (i.e., two FMVs or one FMV and one pool) collected within the same trimester. RESULTS: Overall, ICCs were higher in pooled samples (0.24-0.87) than in FMVs (0.08-0.69). Regardless of the sample type, ICCs tended to be higher for metabolites for which exposure sources are personal care products or indoor residential materials than those for which diet is an important exposure source. ICCs tended to increase and FMV/pool ratios tended to decrease with an increasing number of composite samples in the pools. CONCLUSIONS: Our study helped determine the number of samples needed to capture moderate to high reproducibility of individual's average exposure to phthalates and the average exposure can be differently characterized depending on the number of samples in the pools. PMID- 30477815 TI - Cross-sectional associations between urinary triclosan and serum thyroid function biomarker concentrations in women. AB - INTRODUCTION: Exposure to the antimicrobial agent triclosan is ubiquitous. Research in animals shows that triclosan can cause decreases in thyroxine concentrations. However, the potential effects of triclosan on thyroid function in humans are unclear. OBJECTIVE: To estimate the association between urinary triclosan concentrations and serum thyroid function biomarkers in women seeking assisted reproduction treatment in the Environment and Reproductive Health (EARTH) Study. METHODS: We conducted a cross-sectional study of 317 women enrolled in the EARTH Study, a prospective preconception cohort that recruits Boston area couples. Using samples collected at study entry, we quantified urinary triclosan and serum thyroid function biomarker concentrations, specifically free and total thyroxine and triiodothyronine, thyroid-stimulating hormone (TSH), and thyroid antibodies. We estimated covariate-adjusted differences in thyroid function biomarkers per 10-fold increase in triclosan using linear regression models. We examined effect modification by body mass index (BMI) and infertility diagnosis. RESULTS: The median urinary triclosan concentration was 7.8 MUg/L (IQR: 3.0-59 MUg/L). Each 10-fold increase in triclosan was inversely associated with free triidothyronine (T3) (beta: -0.06 pg/mL; 95% CI: -0.1, -0.01), thyroperoxidase antibody (TPOAb) (-10%; 95% CI: -19, -0.4), and thyroglobulin antibody (TgAb) (-12%; 95% CI: -23,0.9) concentrations. BMI and infertility diagnosis modified the association of triclosan with free T3 and TPOAb, respectively. CONCLUSION: Urinary triclosan concentrations were inversely associated with specific serum thyroid function biomarkers in this cohort, suggesting that triclosan may affect thyroid homeostasis and autoimmunity. PMID- 30477816 TI - An interventional study of rice for reducing cadmium exposure in a Chinese industrial town. AB - BACKGROUND: Reducing cadmium (Cd) exposure in Cd-polluted areas in Asia is urgently needed given the toxic effects of Cd. The short-term and long-term benefits of lowering Cd exposure are unknown because of its long half-life in the body. OBJECTIVES: We aimed to investigate whether an intervention with low-Cd rice in a contaminated area of China reduced urinary Cd (UCd) levels and improved blood pressure and kidney function outcomes compared to no-intervention in consumers of high-Cd rice in the same region. METHODS: 106 non-smoking subjects were divided into three treatment groups: the intervention group (replacing homegrown high-Cd rice with market low-Cd rice, n = 34), the non-intervention group (continue eating high-Cd rice, n = 36) and the control group (continued eating low-Cd rice they have been eating for years, n = 36). The intervention period lasted for almost 8 months, during which participants were visited on up to 4 occasions and UCd, systolic and diastolic blood pressure (SBP, DBP), kidney function biomarkers (beta2-microglobulin and N-acetyl-beta-D-glucosaminidase) were measured. RESULTS: After 3 months, the geometric mean UCd in the intervention (Int) group decreased significantly by 0.32 MUg/g (p = 0.007), while changes were not significant in the non-intervention (non-Int) group (0.13 MUg/g, p = 0.95) or the control group (-0.01 MUg/g, p = 0.52). UCd in the Int group remained lower than in the non-Int group but higher than in the Control group through the end of follow up. DBP in the Int group decreased significantly from 80 mm Hg at month three (p = 0.03) and stayed around 74 mm Hg for the remainder of the study. SBP also decreased in the Int group but with variations similar to those observed in the other two groups. The two kidney biomarkers showed variations without a clear pattern. CONCLUSION: This study suggested that UCd reflected both short-term (<3 months) and long-term Cd exposure. In addition, the low-Cd rice intervention showed initial benefits in lowering blood pressure levels, especially DBP, but not kidney biomarkers. PMID- 30477817 TI - Hospital-acquired complications alter quality of life in adult burn survivors: Report from a burn model system. AB - INTRODUCTION: Successful burn care should facilitate comprehensive, functional recovery after an injury. But we have a poor understanding of which risk factors influence long-term outcomes after burn injury. Studies have correlated hospital acquired complications (HACs) with poor long-term outcomes in some populations. The purpose of this study was to determine whether HACs alter patient-reported quality of life in adult burn survivors. METHODS: We followed 496 adults with major burn injury longitudinally as part of a burn outcomes study (1993-2014). Study participants completed SF-12(r) Health Surveys providing mental (MCS) and physical (PCS) component summary scores at discharge, 12- and 24-months following injury. We reviewed inpatient medical records for complications during the acute care of a thermal injury. Complications were identified using discharge summary and chart ICD-9 codes. We used descriptive statistics to compare demographic and injury characteristics. Stepwise linear regression analyses determined the impact of significant variables on longitudinal MCS and PCS scores. Burn and graft total body surface area, age, and gender were included as predictor variables in univariate models and added to multivariate models when they were significant. RESULTS: Patients who suffered urinary tract infection, venousthromboembolism, pulmonary complications and renal failure during hospitalization for their burn injury reported decreased quality of life as indicated by lower SF-12(r) PCS scores at 12 and 24months after injury. CONCLUSIONS: We demonstrate that inpatient complications negatively impact long-term quality of life, especially physical functioning for patients with burn injuries. Our data confirm the need to consider the influence of hospital-acquired complications on patient-reported long-term outcomes and to support national efforts to reduce complications in burn patients. PMID- 30477818 TI - Burn injury and multiple sclerosis: A retrospective case-control study. AB - OBJECTIVES: The purpose of this study was to determine whether having a previous diagnosis of multiple sclerosis (MS) changed acute care needs in burn-injured patients. METHODS: This was a retrospective case-control study that included adult (aged >=18years) patients with an acute burn injury. Control patients were matched with eleven patients with a history of MS at a 4:1 ratio. Outcomes included fluid resuscitation volumes, temperature, heart rate, mean arterial pressure, in-hospital complications, and hospital length of stay (LOS). RESULTS: There were fifty-five patients included and of those, eleven had a documented history of MS. Fluid resuscitation volumes, temperature, heart rate, and mean arterial pressure were similar between groups during the resuscitation period (p>0.05). LOS was similar between both groups (12, IQR: 2-17 vs. median 16, IQR: 12-21; p=0.090). However, when normalized to % TBSA burn, patients with MS had a significantly higher median LOS/% TBSA burned (1.2, IQR: 0.7-2.0 vs. 2.1, IQR: 1.1-7.1; p=0.031). CONCLUSIONS: Patients with concurrent burn injuries and MS have a significantly longer LOS/% TBSA burn suggesting that more time is required to heal their wounds. Surprisingly, there were no other significant differences in the after the burn acute phase between these two cohorts. PMID- 30477819 TI - A videogame intervention for tobacco product use prevention in adolescents. AB - PURPOSE: This pilot study evaluated the short-term effects of an interactive videogame on changing adolescent knowledge, beliefs and risk perceptions, and intentions to use e-cigarettes, cigarettes, and other tobacco products. A secondary aim was to evaluate players' game experience. METHODS: Participants (N = 80 11-14 year olds) were recruited from 7 community-based afterschool programs in New Haven, Connecticut and Los Angeles, California. The design was a single group pre-post design with replication. A pre-test survey was administered that included demographic variables and knowledge, risk perceptions, beliefs, and intentions to use e-cigarettes, cigarettes, and other tobacco products. An interactive videogame focusing on risky tobacco use situations was subsequently played in four 60-min sessions over a four-week period, followed by a post-test survey. Analyses included paired t-tests of pre-post videogame change, regression analyses, and path analyses testing mediational effects of beliefs and risk perceptions on the relationship between knowledge and intentions. RESULTS: The videogame changed knowledge of e-cigarettes and other tobacco products (p's < 0.001), risk perceptions of cigarettes and e-cigarettes (p < .01 and p < .001, respectively), and beliefs about e-cigarettes and other tobacco products (p's < 0.05), but not intentions. Older adolescents reported greater e-cigarette knowledge and risk perceptions (p's < 0.05), and females reported greater risk perception of cigarettes (p < .05). Beliefs mediated the relationship between knowledge and intentions to use e-cigarettes (indirect effect p < .05). CONCLUSION: Results suggest that brief exposure (4 h over 4 weeks) to a videogame focused on changing knowledge and attitudes towards tobacco products may have a promising effect on preventing risk for early adolescent tobacco product use, particularly for e-cigarettes. PMID- 30477820 TI - Psychological distress and responses to comparative risk messages about electronic and combusted cigarettes. AB - BACKGROUND: People with mental illness suffer disproportionately high health burdens of smoking. Communicating to these smokers that electronic cigarettes (e cigarettes) are a less harmful alternative to combusted cigarettes might help them reduce their health risks by encouraging complete switching to e-cigarettes. However, such messages might also cause unintended consequences (e.g., dual use of both combusted and e-cigarettes). Our study examined how smokers with vs. without serious psychological distress (SPD) responded to messages communicating reduced harm of e-cigarettes in relation to cigarettes. METHOD: In an online experiment, 1400 U.S. adult smokers with and without SPD viewed 1 of 6 messages about reduced harm of e-cigarettes compared to cigarettes or a control message. Then participants reported e-cigarette- and cigarette-related beliefs, and behavioral intentions. RESULTS: Message type (comparative risk messages vs. control) did not interact with SPD status to produce differential impacts on smokers with and without SPD. Regardless of being exposed to a comparative risk message or a control message, smokers with SPD reported greater perceived absolute risk of e-cigarettes and cigarettes, greater support for tobacco control, greater intentions to switch to e-cigarettes completely and seek help with quitting, and were less likely to report e-cigarettes were less harmful than cigarettes compared to smokers without SPD. DISCUSSION: Smokers with SPD had greater intentions to switch to e-cigarettes completely and seek help quitting compared to smokers without SPD, which indicates that smokers with SPD may be optimistic about e-cigarettes to help them quit smoking. PMID- 30477821 TI - Risk tradeoffs associated with traditional food advisories for Labrador Inuit. AB - The traditional Inuit diet includes wild birds, fish and marine mammals, which can contain high concentrations of the neurotoxicant methylmercury (MeHg). Hydroelectric development may increase MeHg concentrations in traditional foods. Consumption advisories are often used to mitigate such risks and can result in reduced intake of traditional foods. Data from a dietary survey, MeHg exposure assessment and risk analysis for individuals in three Inuit communities in Labrador, Canada (n = 1145) in 2014 indicate reducing traditional food intake is likely to exacerbate deficiencies in n-3 polyunsaturated fatty acids and vitamins B12 and B2. Traditional foods accounted for < 5% of per-capita calories but up to 70% of nutrients consumed. Although consumption advisories could lower neurodevelopmental risks associated with an increase in MeHg exposure (90th percentile ?IQ = - 0.12 vs. - 0.34), they may lead to greater risks of cardiovascular mortality (90th-percentile increase: + 58% to + 116% vs. + 25%) and cancer mortality (90th-percentile increase + 2% to + 4% vs. no increase). Conversely, greater consumption of locally caught salmon mostly unaffected by hydroelectric flooding would lower all these risks (90th-percentile ?IQ = + 0.4; cardiovascular risk: - 45%; cancer risk: - 1.4%). We thus conclude that continued consumption of traditional foods is essential for Inuit health in these communities. PMID- 30477822 TI - Prenatal particulate air pollution exposure and cord blood homocysteine in newborns: Results from the ENVIRONAGE birth cohort. AB - INTRODUCTION: Particulate air pollution is probably causally related to increased risk of cardiovascular disease. Plasma homocysteine is an established cardiovascular disease risk factor. Recent studies show that exposure to particulate air pollution is associated with plasma homocysteine levels in adults but no studies on the association between prenatal air pollution and neonatal homocysteine levels exist. METHODS: In 609 newborns of the ENVIRONAGE (ENVIRonmental influence ON early AGEing) birth cohort, we investigated the association between prenatal particulate matter exposure with a diameter <= 2.5 um (PM2.5) and cord plasma homocysteine levels, and in a subset (n = 490) we studied the interaction with 11 single nucleotide polymorphism (SNPs) in oxidative stress-related genes (CAT, COMT, GSTP1, SOD2, NQO1 and HFE), through multiple linear regression. PM2.5 levels were obtained using a high resolution spatial temporal interpolation method. Homocysteine levels were measured by the homocysteine enzymatic assay on a Roche/Hitachi cobas c system. SNPs were assessed on the Biotrove OpenArray SNP genotyping platform. RESULTS: In multivariable-adjusted models, cord plasma homocysteine levels were 8.1% higher (95% CI: 1.9 to 14.3%; p = 0.01) for each 5 ug/m3 increment in average PM2.5 exposure during the entire pregnancy. With regard to pregnancy trimesters, there was only an association in the 2nd trimester: 3.6% (95% CI: 0.9% to 6.4%; p = 0.01). The positive association between PM2.5 in and homocysteine was (borderline) statistically significantly modified by genetic variants in MnSOD (p interaction = 0.02), GSTP1 (p interaction = 0.07) and the sum score of the 3 studied SNPs in the CAT gene (p interaction=0.09), suggesting oxidative stress as an underlying mechanism of action. CONCLUSIONS: Exposure to particulate air pollution in utero is associated with higher cord blood homocysteine levels, possibly through generating oxidative stress. Increased air pollution-induced homocysteine levels in early life might predispose for cardiovascular and other diseases later in life. PMID- 30477823 TI - Predictive antidiabetic activities of plants used by persons with Diabetes mellitus. AB - BACKGROUND: There are several ways to identify medicinal power of phytoconstituents, such as in silico evaluations. Furthermore, ethnopharmacological researches are important alternatives for the identification of plants with medicinal potential. Significantly, medicinal plants are widely used by persons with Diabetes mellitus (DM) to treat manifestations of this syndrome. OBJECTIVES: i) to investigate the use of medicinal plants for individuals with DM and their health profile; ii) to evaluate in silico possible antidiabetic activities for main phytoconstituents of the commonly used plants. METHODS: A questionnaire was used to measure consumption of medicinal plants. The Prediction of Activity Spectra for Substances (PASS) platform was employed to perform in silico evaluations. In silico predictions for antidiabetic activities were performed with the main compounds identified in a literature review which focused on the more utilized plants. RESULTS: We interviewed 105 persons with DM, most them women (73.34%). Overall mean age was 59.35 years, and 97.14% of them were diagnosed with type 2 DM. An evaluation of the routine exams of the interviewees showed that they have a poor metabolic control. Among the interviewees, 67.62% confirmed the use medicinal plants. Main forms of consumed plant preparation were infusion of leaves and in association with mate (a typical beverage of southern Brazil). Most interviewees consume five or more cups of infusion per day, and when consumed with the mate, 1.73 liters per day. Forty-six medicinal plants were mentioned, and cow's paw (Bauhinia) and jambolan (Syzygium cumini) were the most used. The main informed objective for the plant use was blood glucose control (69.01%). The PASS analysis presented six phytoconstituents with high antidiabetic prediction, especially, vicenin-2, the main phytochemical identified in Passiflora genus (Pa = 0.822). CONCLUSION: Our data show that persons with DM use many plants as a complementary treatment to the traditional medicine. Moreover, part of these plants presented phytoconstituents with antidiabetic potential. These data can serve as a basis for future investigations, with the objective of exploring in vitro and in vivo antidiabetic effects of these plants and its compounds. PMID- 30477824 TI - Pediatric Tui Na for acute diarrhea in children under 5 years old: A systematic review and meta-analysis of randomized clinical trials. AB - OBJECTIVE: To evaluate the benefits and harms of pediatric Tui Na as a non pharmaceutical Chinese medicine therapy for acute diarrhea in children under 5 years of age. DESIGN: Systematic review and meta-analysis of randomized clinical trials. METHODS: We searched seven major English and Chinese databases from their inception to January 2018 for randomized clinical trials (RCTs) comparing pediatric Tui Na therapy with conventional medicine (montmorillonite/diosmectite or probiotics used alone or in combination). Two authors extracted data and assessed the Cochrane risk of bias, independently. The primary outcomes are clinical cure rate and diarrhea duration from admission to the cessation of diarrhea. 'Clinical cure' is defined as the frequency, timing and character of stool back to normal status, as well as disappearance of diarrhea symptoms. We present dichotomous data as risk ratio (RR), and continuous data as mean difference (MD) with their 95% confidence interval (CI). We used the Cochrane's Revman software (v.5.3) for data analysis. Trial sequential analysis (TSA) was applied to calculate the required sample size in a meta-analysis and detect the robustness of the results. The GRADEpro was used to generate a summary of finding table. RESULTS: Totally 26 RCTs were included, involving 2410 children with acute diarrhea. Most of the included trials had high or unclear risk of bias in terms of random sequence generation, blinding, and incomplete outcome reporting. The pooled results demonstrated that pediatric Tui Na was superior to montmorillonite after three-session treatment (RR 1.45, 95% CI 1.29-1.62, n = 772, 10 trials), and also superior to montmorillonite combined with probiotics after three-session treatment (RR 2.04, 95% CI 1.49-2.78, n = 533, 7 trials) and after six-session treatment (RR 1.52, 95% CI 1.34-1.73, n = 631, 5 trials) in improving clinical cure rate. Pediatric Tui Na significantly decreased the duration of acute diarrhea (hrs) (MD -0.40 h, 95% CI -15.31 to -5.48 h, n = 410, 6 trials) and daily stool frequency (MD -1.71times, 95% CI -2.37 to -1.04, n = 217, 3 trials, after three-session treatment). No adverse event related to pediatric Tui Na was reported in the included trials. The quality of evidence of included trials was generally moderate to low. TSA for cure rate demonstrated that the pooled data reached a sufficient power regarding both numbers of trials and participants. CONCLUSIONS: This review shows pediatric Tui Na appears to be effective and safe in improving clinical cure rate and shortening diarrhea duration in childhood aged less than five years of age with acute diarrhea. However, rigorously designed well-reported RCTs are warranted to confirm the findings. PMID- 30477825 TI - Information needs and usage of complementary and alternative medicine in members of a German self-help group for gastrointestinal stroma tumours, sarcoma, and renal cancer. AB - OBJECTIVE: 40-50% of German cancer patients use some method of complementary and alternative medicine (CAM) and both patients and doctors often feel insufficiently informed. We examined the information-seeking behaviour and satisfaction with information on patients' interest in CAM and the therapy decision. DESIGN AND SETTING: An anonymous, voluntary online survey was conducted among the members of "Das Lebenshaus e.V." (House of Life), a decentralized support group for patients with gastrointestinal stroma tumours (GIST), sarcoma, and renal cancer. Data was collected from March 2015 until January 2016 using closed questions with multiple choice if appropriate and in case of ranking, a 5 point Likert scale. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Correlations between CAM interest, usage, information needs, sources of information and therapy decision were calculated using chi square tests for univariate analyses. RESULTS: Overall, 431 patients took part in our survey, thus return rate was 19.6%. 43.9% (n = 189) of the participants were female, 37.1% (n = 160) were male, 19.0% (n = 82) did not respond. Mean age was 59.8 years. The most common tumours were GIST (346%, n = 149), renal cancer (22.3%, n = 96) and sarcoma (20.0%, n = 86). 55.2% (n = 138) of the respondents were patients undergoing treatment, 19.7% (n = 85) were after treatment, 2.6% (n = 11) were relatives and 4.4% (n = 19) others while 18.1% (n = 78) did not respond. A total of 81.8% (n = 337) of the participants were interested in CAM, but only 44.7% (n = 152) used one of the methods. Women were more commonly interested in CAM (87.2%, n = 163) and used it more often: 53.0% (n = 97) vs. 36.2% (n = 55). Information about CAM was considered important by 85.5% (n = 360) and the Internet was the most commonly used source for information about CAM (77.9%, n = 205). However, 61.4% (n = 233) were not satisfied with the information received about CAM, especially from doctors and hospitals. Patients unsatisfied with the information they had formally received about the course of their disease significantly more often used CAM (p = 0.029). Users would also make the therapy decision by themselves more often (p = 0.036). Nearly a fifth did not disclose their use to a doctor. CONCLUSIONS: Dissatisfaction with received information reveals a strong need for scientific information to be available to both patients and doctors. Physicians should get special training about CAM. As the Internet is an important source, high-quality and scientific information should be portrayed on webpages easily accessible to patients. PMID- 30477826 TI - Yoga for systemic lupus erythematosus (SLE): Clinician experiences and qualitative perspectives from students and yoga instructors living with SLE. AB - : Systemic lupus erythematosus (SLE) is an autoimmune disease associated with widespread inflammation and tissue damage. It is more common and severe among Blacks, Hispanics, and Asians; with higher incidence in women. While the goals of medical treatment are to prevent flares and reduce organ damage, up to 50% of patients perceive their health to be suboptimal with unaddressed needs including fatigue and pain. Recent SLE treatment guidelines focus on improving quality of life. Yoga has shown improvements in quality-of-life and fatigue in various diagnoses. While there is growing evidence that yoga therapy may help osteoarthritis and rheumatoid arthritis symptoms, there is only one reference in the literature related to SLE. METHODS/SETTING: An adjunct study was undertaken to evaluate adapting the Yoga as Self Care for Arthritis in Minority Communities study for a bilingual population living with SLE in the Washington, DC area. Informants included 7 patients enrolled onto the study, and 3 yoga instructors living with SLE. Qualitative methods included journals and semi-structured interviews. RESULTS: Enrolling patients clarified revisions for intake questionnaires, and symptoms that may impact class participation. Participants demonstrated increased balance, body awareness, and tolerated a faster-paced yoga class when compared to those in the parent study. Yoga instructors' recommendations included modifying yoga based on energy levels and frequent changes in physical ability. CONCLUSION: This paper shares perspectives from various informants and affirms the feasibility of progressing to a larger study. It summarizes our findings and recommendations towards creating a randomized controlled trial, as there are currently none in the literature. PMID- 30477827 TI - The effects of Zataria multiflora Boiss. (Shirazi thyme) on nonalcoholic fatty liver disease and insulin resistance: A randomized double-blind placebo controlled clinical trial. AB - OBJECTIVE: The aim of the study is to evaluate the effects of Zataria multiflora Boiss. (Shirazi thyme) (ZM) supplementation on nonalcoholic fatty liver disease (NAFLD) and related insulin resistance (IR). DESIGN: In this randomized double blind placebo-controlled clinical trial, 85 patients with NAFLD were administered either 700 mg ZM powder or placebo twice daily for 12 weeks. All patients were advised to follow the recommendations for diet modification. RESULTS: ZM supplementation resulted in a significant reduction in serum insulin level (-2.72 +/- 0.80 vs -0.67 +/- 0.90, P=0.030), insulin resistance (-0.80 +/- 0.22 vs 0.06 +/- 0.22, P=0.023), systolic (-3.44 +/- 1.05 vs 1.03 +/- 0.98, P= 0.002) and diastolic (-2.33 +/- 0.77 vs 0.26 +/- 0.63, P= 0.009) blood pressure in patients with NAFLD in comparison with the placebo group. There was no significant difference between two groups regarding serum levels of alanine aminotransferase (ALT), high sensitive C-reactive protein (hs-CRP), Tumor necrosis factor-alpha (TNF-alpha), grade of fatty liver in ultrasonography, lipid profiles, and other outcomes. CONCLUSION: ZM supplementation with daily dose of 1400 mg for 12 weeks improved insulin resistance in patients with NAFLD. Further studies with longer duration and larger sample size are recommended. PMID- 30477828 TI - The effect of reminiscence therapy on the adaptation of elderly women to old age: A randomized clinical trial. AB - BACKGROUND AND AIM: The changes and limitations that occur in the aging process effect people's adaptation to old age. This study aimed to assess the effect of reminiscence therapy on the adaptation levels of non-institutionalized elderly women to old age. METHODS: We used a randomized controlled trial design. We conducted the study with 50 elderly women, including 27 women in the intervention group and 23 women in the control group. Study data were recollected by using an introductory information form, Mini-Mental State Examination (MMSE) and Assessment Scale of Adaptation Difficulty for the Elderly (ASADE). Reminiscence therapy was applied to the participants in the intervention group through individual sessions for 8 weeks by making house visits once a week. RESULTS: At the end of reminiscence therapy made through weekly house visits, we compared the mean ASADE and MMSE scores of intervention and control groups and found that there was a statistically significant difference between the mean ASADE and MMSE scores of the participants in the intervention group (p < 0.05). CONCLUSIONS: This study found that reminiscence therapy increased the elderly women's adaptation to old age and cognitive level. PMID- 30477829 TI - Pilates for women with breast cancer: A systematic review and meta-analysis. AB - OBJECTIVES: To identify and evaluate the characteristics and methodological quality of the studies that have proposed Pilates as a rehabilitation strategy for women with breast cancer and to determine its benefits on health outcomes in this population. METHODS: A systematic review and meta-analysis were conducted. Medline/PubMed, Pedro, SPORTDiscuss, Scopus and Web of Science were systematically searched up to January 2017. The methodological quality was evaluated by means of the Jadad Scale and the Quality Assessment Tool for Before After Studies with No Control Group. Risk of bias was assessed by means of the Cochrane Collaboration's tool. RESULTS: Five randomized controlled trials and two un-controlled studies were selected. Four of the randomized controlled trials were pooled in the meta-analysis for effects of Pilates on shoulder range of motion, quality of life, pain, and self-reported upper extremity function. According to the findings reported in the studies analysed in the review, Pilates had a positive and significant effect on the aforementioned variables, as well as on functional status, mood, fitness and upper extremity circumference. The meta analysis carried out showed that the effects that Pilates had on shoulder range of motion and quality of life, was not significantly greater than those resulting from other exercise programs. CONCLUSIONS: Pilates relieves the impact of breast cancer-related symptoms. These effects are not significantly greater than those derived from the performance of other therapies, with the exception of pain and self-reported upper extremity function. Systematic review registration number: PROSPERO CRD42018076852. PMID- 30477830 TI - Exploring the effect of adaptogenic Rhodiola Rosea extract on neuroplasticity in humans. AB - OBJECTIVES: Rhodiola rosea extract is one of the most common herbal treatment for stress. Its mechanism of action in humans still need to be determined. We investigated the effect of a single dose intake of Rhodiola rosea extract on the plastic after-effects induced by anodal and cathodal motor cortex transcranial Direct Current Stimulation in humans. METHODS: Twenty-eight healthy volunteers were required to intake 500 mg of either RRE or placebo. Transcranial Magnetic Stimulation was used to investigate cortical excitability. Motor threshold, recruitment of motor-evoked potentials, cortical silent period, short-interval intracortical inhibition and intracortical facilitation were assessed at different time points. Spinal excitability and peripheral nerve conduction were measured by F-response and M-wave. Furthermore, we assessed the modulation of cortical plasticity using transcranial direct current stimulation after-effects on Motor Evoked Potentials amplitudes. RESULTS: Rhodiola rosea extract acute intake prevented cathodal transcranial Direct Current Stimulation-induced Long term depression-like plasticity. The extract intake did not affect cortical excitability. CONCLUSIONS: Our findings suggest that a single oral dose of Rhodiola rosea extract intake modulates cortical plasticity in humans preventing the activity-dependent reduction in the efficacy of neuronal synapses. These results suggest that the adaptogenic and antidepressant effects of Rhodiola rosea extract might be based on its modulation of brain plasticity. PMID- 30477831 TI - An experimental study on oil-dispersion baths generated by the Jungebad apparatus. AB - BACKGROUND: Since the very early documentation of medical treatments, bathing is an essential part of almost all traditional medical systems. In this context the oil-dispersion bath, developed in the 1930s by Werner Junge has been developed from anthroposophic medicine. We aimed at analyzing the apparatus, which churns water and essential oils into an oil-water dispersion, by means of an experimental study. MATERIAL AND METHODS: Using three different oils (rheumatic oil, citrus oil and rosemary oil) oil volumetric flow rate and oil droplet size distribution were examined at three different water volumetric flow rates of 5, 10, and 15 l/min at a constant temperature of 40 degrees C. Additionally, for the rheumatic oil measurements are taken at three different temperatures, 35, 40, and 45 degrees C at a constant volumetric flow rate of 10 l/min. Finally results were compared with a manual oil dispersion process. RESULTS: Oil volumetric flow rate increases with increasing water volumetric flow rates. Oil flow rate increases with increasing water temperature. Droplet-size distribution shows an optimal fit with a log-normal distribution for a volumetric flow rate of 5 l/min in all oils applied with citrus and rosemary oil showing a larger mean diameter compared to the rheumatic oil. Comparing the oil droplet size distribution for a traditional oil bath, distributions behaved completely different in comparison to our distributions. Moreover it seemed not possible to create an oil-dispersion with repeatable droplet size distributions whereas the Jungebad apparatus created similar oil dispersions with predictable results, independent of the user. DISCUSSION: This is the first study to explore the mechanisms of creation of the oil-dispersion bath by means of an experimental set up. Based on these experimental results, a more fundamental theoretical approach should be carried out to complement our findings and to gain deeper insights in the hydrodynamic and droplets forming processes in the Jungebad apparatus. PMID- 30477832 TI - Long-term effects of honey on cardiovascular parameters and anthropometric measurements of postmenopausal women. AB - OBJECTIVE: To investigate the long-term effects of Tualang Honey versus Honey Cocktail (mixture of honey, bee bread, and royal jelly) on cardiovascular markers and anthropometric measurements of postmenopausal women. METHODS: We conducted a randomised, double blinded, two-armed parallel study comparing 20 g/day of Tualang Honey versus 20 g/day Honey Cocktail among postmenopausal women aged 45 65 years. The cardiovascular parameters and anthropometrics measurements were assessed at baseline, 6 months, and 12 months of the intervention. RESULTS: 100 subjects were successfully randomised into the groups. There was a significant decrease in the diastolic blood pressure from 77.92 mmHg at baseline to 73.45 mmHg at 12 months (F-statistic = 2.55, p-value = 0.047) in the Tualang Honey group compared to Honey Cocktail. There was also a significant decrease in the fasting blood sugar from 6.11 mmol/L at baseline to 5.71 mmol/L at 12 months (F statistic = 4.03, p-value = 0.021) in the Tualang Honey group compared to the Honey Cocktail group. The body mass index remained unchanged at 27 kg/m2 (F statistic = 1.60, p-value = 0.010) throughout 12 months of the intervention in the Honey Cocktail group. CONCLUSION: Subjects who received Honey Cocktail showed remarkable effects on body mass index. However, Tualang Honey supplementation showed superior effect in lowering diastolic blood pressure and fasting blood sugar compared to Honey Cocktail. Further studies are required to ascertain the underlying mechanism(s) of Tualang Honey and Honey Cocktail on each observed parameter. PMID- 30477833 TI - Exploratory study on the natural ground electric current that flows through human body as a possible pathway for the therapeutic effects of beach going. AB - This paper explores the electrical nature of sandy beach and proposes a pathway for the therapeutic effects of beach going. The electric potential and current generated on the ground across the human body and resistors were measured. The ground was found to have a non-homogenous electric potential which generated a potential difference between any two points on the ground. A power curve, similar to a battery, in the nanowatt range was obtained. This power appeared to be stable across time but varies across ground location. Standing on the beach with dry feet did not allow any current in the micro-ampere range to conduct. But upon moistening the feet, the body electrical resistance was reduced by 94% and the ground potential difference across the two feet was sufficient to drive a micro ampere range current through the body. This may be one reason for the therapeutic effects of being on the beach. PMID- 30477834 TI - Effects of lipoic acid on walking performance, gait, and balance in secondary progressive multiple sclerosis. AB - BACKGROUND: Gait and balance impairment is common in secondary progressive multiple sclerosis (SPMS). Lipoic acid (LA), an over-the-counter antioxidant, is effective in MS animal models and may improve walking speed, but effects on mobility are unreported. OBJECTIVE: Examine the effects of 1200 mg daily oral dose of LA versus placebo (PLA) on gait and balance in a 2-year, randomized, double-blind pilot study. METHODS: 134 participants were screened for eligibility before assignment to LA (n = 28) or PLA (n = 26). Included here were, 21 participants with SPMS who took LA (N = 11) or PLA (N = 10) capsules for 2 years (enrolled May 2, 2011 - August 14, 2015) and completed all tasks without the use of an assistive device. Participants completed the Timed Up and Go (TUG) and quiet standing tasks every 6 months while wearing inertial sensors (APDM Opals) to quantify mobility. RESULTS: LA had a medium effect on time to complete TUG at 2 years (g = 0.51; 95% CI = -0.35, 1.38). In a subset of 18 participants with less disability (EDSS < 6, no use of ambulatory device), turning time was significantly shorter with LA (p = 0.048, Delta= 0.48 s). No differences in balance metrics were found between groups. CONCLUSIONS: LA had an effect on walking performance in people with SPMS, particularly in those with lower baseline disability. TRIAL REGISTRATION: Lipoic Acid for Secondary Progressive Multiple Sclerosis https://clinicaltrials.gov/ct2/show/NCT01188811?term=spain+lipoic+acid&rank=1 NCT0118881. PMID- 30477835 TI - Attitudes and barriers towards using complementary and alternative medicine among university students in Jordan. AB - BACKGROUND: Perceptions towards Complementary and Alternative Medicine (CAM) are highly variable but are improving globally. However, studies conducted in Jordan about CAM are insufficient. This study aims to explore the attitudes and barriers towards using CAM among university students in Jordan. DESIGN AND METHODS: This cross-sectional study was conducted at the University of Jordan. A self administered paper questionnaire was distributed to 475 students from the Faculties of Medicine, Pharmacy and Engineering of all academic years. Descriptive and multivariate data analysis was done using SPSS v.20. RESULTS: Seventy percent of all the participants have used at least one type of CAM. Younger female pharmacy students were most likely to use CAM. There were significant differences between students of different academic years regarding their opinions on CAM (p < 0.024). The percentage of medical students who believed that combining CAM with modern medicine would improve the overall treatment quality was significantly lower than the other two faculties (p < 0.001). Of the students who never used CAM, 39% did not do because they doubted its effectiveness. CONCLUSION: There is a need for including CAM in the universities' curriculum as mandatory courses for health faculties and elective courses for other disciplines. PMID- 30477836 TI - Effectiveness of group art therapy on quality of life in paediatric patients with cancer: A randomized controlled trial. AB - OBJECTIVES: Children with cancer undergoing chemotherapy experience many adverse effects. The effectiveness of painting- and handcrafting-based art therapy on the various dimensions of health-related quality of life in paediatric outpatients previously diagnosed with heterogeneity of malignancy was evaluated in the present study. DESIGN: In an experimental randomized controlled trial, a total of 60 children aged 7-13 years previously diagnosed with malignancy together with their parents were assigned randomly either to an experimental (30 patients) or a control group (30 patients) in 2017 in Iraq. The patients in the experimental group participated in painting and handcrafting group art therapy (creative art therapy) conducted by a professional fine artist for a one-month period. The dimensions of health-related quality of life in both study groups were measured through the KIDSCREEN-10 Index after project completion. RESULTS: The patients in the experimental group were significantly more physically active and energetic (P < 0.001), were less depressed and emotional, and had fewer stressful feelings (P = 0.004). Moreover, they enjoyed their social and leisure time more and participated more in social activities (P = 0.003) in addition to an improvement in their relationships with other children (P = 0.043) and had better overall health status (P < 0.001). However, the children's overall interaction with other children, parents, and healthcare providers (P = 0.074) and their perception of cognitive capacity for school performance (P = 0.257) were not significantly different between the two groups. CONCLUSIONS: The findings of the study suggest that exposure to painting- and handcrafting-based art therapy improves the overall health-related quality of life in children with cancer. PMID- 30477837 TI - "I think you can achieve quite a lot if all of the staff stands behind it"-A qualitative study about the experience, knowledge and application of complementary therapies and integrative medicine in pediatrics. AB - BACKGROUND: In the United States there is an increasing use of complementary and alternative medicine (CAM) as well as integrative medicine (IM) in pediatrics. This study investigates the extent of knowledge and practical application of and attitudes towards the use and integration of CAM/IM therapies in two German pediatric clinics. METHODS: A semi-standardized qualitative interview study was conducted in a rural children's hospital in Bavaria and in a children's clinic in the metropolitan area of Ruhr. Sixteen employees (7 nurses, 9 medical doctors, 68.8% female), who had volunteered through a local contact, were questioned during their shift on CAM/IM therapies. The data collected were analyzed with MAXQDA 12 using a qualitative technique for content analysis (by Mayring). RESULTS: On average all respondents had little to superficial knowledge about the possibilities or evidence base of the therapies concerned, but did believe that CAM/IM could be an enhancement. In addition, many took interest in learning more about CAM/IM medical options. Nurses desired more practical and theoretical knowledge; while medical doctors focused on standardization and evidence base. All of them agreed that self-care strategies could enhance parental independence when treating symptoms of minor illnesses. They further agreed, that a symbiosis of conventional medicine and CAM/IM has great potential for patients and employees. It was stated that training of staff would be indispensable in order to implement standardized procedures. CONCLUSIONS: There is great potential and interest in CAM/IM among pediatric care employees. Regardless of the challenges, this investigation did find that implementing CAM/IM might be a promising extension to the daily care routine. PMID- 30477838 TI - Utilization of complementary and alternative medicine and conventional medicine for headache or migraine during pregnancy: A cross-sectional survey of 1,835 pregnant women. AB - OBJECTIVES: Little is known about women's use of health services affected by headache or migraine during pregnancy. This paper directly addresses the research gap reporting on the healthcare utilization among Australian pregnant women experiencing headache or migraine. DESIGN AND SETTING: In this retrospective observational study, data on 1,835 Australian pregnant women were obtained from the nationally-representative Australian Longitudinal Study on Women's Health. Information on quality of life and health seeking behaviors regarding conventional medicine and complementary and alternative medicine providers was identified among these participants. Factors associated with healthcare use were analyzed using regression analyses. RESULTS: A total of 16% of the pregnant women surveyed experienced headache or migraine, and over 20% sought help from more than two types of healthcare practitioners for their headache or migraine. General practitioners (37.8%) were the most commonly consulted providers of pregnant women for their headache or migraine. Women with headache or migraine during pregnancy had worse health-related quality of life than those without. Education level and private health insurance status of pregnant women are the predictors of the use of healthcare practitioners for their management of headache or migraine (both p < 0.05). CONCLUSIONS: Headache or migraine during pregnancy significantly impacts upon pregnant women's quality of life. The use of multiple healthcare practitioners, including conventional medicine and complementary and alternative medicine practitioners, highlights the need for further research investigating health services utilization of pregnant women with headache or migraine in different severity and frequency to help inform effective and safe treatment. PMID- 30477839 TI - The effects of alcoholic extract of saffron (Crocus satious L.) on mild to moderate comorbid depression-anxiety, sleep quality, and life satisfaction in type 2 diabetes mellitus: A double-blind, randomized and placebo-controlled clinical trial. AB - OBJECTIVE: Depression and anxiety are major health problems throughout the world. Metabolic changes in type 2 diabetes mellitus induces and aggravates mental disorders, such as depression and anxiety. Saffron as a therapeutic herb may attenuate Comorbid Depression- Anxiety (CDA). So, this trial is designed to investigate the effect of saffron alcoholic extract on symptoms of CDA in type 2 diabetic patients. METHODS: Fifty-four outpatients suffered from mild to moderate CDA diagnosed by using Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV), were assessed by Hamilton Depression and anxiety measurements, the Pittsburgh Sleep Quality Index (PSQI), and the Satisfaction with Life Scale (SWLS). The participants of this double-blind, placebo-controlled, single center and randomized trial were randomly assigned to intake 30 mg/day saffron or placebo capsules for 8 weeks. RESULTS: After the intervention, mild to moderate CDA, anxiety and sleep disturbance, but not depression alone, were relieved significantly in the saffron group (P < 0.05), whereas, the changes were not significant in the placebo group. Anthropometric measures and blood pressure parameters of the patients in either groups did not change significantly (P > 0.05) during the intervention. Moreover, dietary intake and physical activity did not differ during the study in the two groups. Changes in the life satisfaction were not significant. CONCLUSION: The results indicate the beneficial effect of saffron on the mild to moderate CDA in type 2 diabetic patients. PMID- 30477840 TI - "We need them as much as they need us": A systematic review of the qualitative evidence for possible mechanisms of effectiveness of animal-assisted intervention (AAI). AB - OBJECTIVE: Although Animal-Assisted Interventions (AAI) are effective treatments for a variety of psychological problems, the mechanism of treatment effectiveness remains unclear. Qualitative studies of AAI may reveal possible mechanisms. This review aims to synthesize qualitative research and identify factors that might contribute to the effectiveness of AAI. METHODS: A literature search of qualitative evidence published before August 8th, 2018 was conducted using the following databases: PubMed, ERIC, PsycARTICLES, PsycINFO, and HABRI, with the aim of identifying qualitative research conducted with individuals undergoing AAI. Quality assessment was undertaken by CASP and the certainty of the evidence was evaluated using CERQual. RESULTS: A total of 1866 articles were reviewed, and seven were included in the final analysis. A total of six themes were identified as factors relating to the effectiveness of AAI: 1. Fostering feelings of normalcy, 2. Improving behavioral activation, 3. Self-esteem enhancement, 4. Physical contact, belonging, and companionship, 5. Calming and comforting, and 6. Distraction. Barriers to AAI effectiveness were also identified. CONCLUSION: The results of these studies suggest that AAI was viewed as a positive and highly accepted intervention across populations and settings. AAI might be a useful intervention among people who suffer from a variety of mental disorders. All themes consistently demonstrated that contact with a live animal is more important than the appearance of the animal. Additional investigations of AAI treatment mechanisms are needed. PMID- 30477841 TI - Efficacy of exercise as a treatment for Obstructive Sleep Apnea Syndrome: A systematic review. AB - INTRODUCTION: Obstructive Sleep Apnea Syndrome (OSAS) is a prevalent condition associated with numerous adverse health consequences. Exercise therapy was described as a valuable OSAS treatment alternative to continuous positive airway pressure. OBJECTIVE: The objective of the present systematic review was to assess the efficacy of exercise in reducing OSAS severity and associated comorbidities. SETTING: We queried MEDLINE and SCOPUS and ScienceDirect databases with the following keywords: "sleep apnea" and "sleep disordered breathing" for the population and "physical activity", "fitness" and "exercise" for the intervention. RESULTS: Eight studies including a total number of 354 patients showed that OSAS severity was significantly reduced after intervention. This reduction was associated with significant improvement in cardio-vascular fitness, sleep quality and quality of life. Conversely, this effect was not directly related to body weight reduction. CONCLUSION: This systematic review suggests that physical activity should be recommended as a treatment for OSAS patients. However, further research is necessary to demonstrate this long-term efficiency with a higher level of confidence and to better understand the underlying physiological mechanisms. PMID- 30477842 TI - Vitamin A supplementation decreases disease activity index in patients with ulcerative colitis: A randomized controlled clinical trial. AB - INTRODUCTION: Considering the link between vitamin A deficiency and disease activity in ulcerative colitis (UC) and also the association between dietary intake of vitamin A and gastrointestinal symptoms in these patients, this study aimed to investigate the effect of vitamin A supplementation on disease activity in patients with UC. METHOD: In the present double-blind randomized controlled clinical trial, one hundred and fifty patients with Mayo score of 6-12 were randomly assigned to receive 25,000 IU/day vitamin A supplements or placebo for two months. The disease activity was calculated by the Mayo clinic score. Within groups and between groups comparisons were performed using paired sample t-test and one-way ANCOVA respectively. For measuring the treatment effect, the response ratio and number needed to treat (NNT) was calculated for the rate of clinical response and mucosal healing. RESULTS: One hundred and forty three patients completed the study. After two months of supplementation, significant decreases in Mayo clinic score (p < 0.001) and subscores (p < 0.001) was observed in the intervention group. There were significant differences between the two groups regarding Mayo clinic score and subscores after adjusting for age, sex, BMI, disease duration and baseline values (P < 0.05). Moreover, there were significant differences between two groups regarding clinical response ratio (P < 0.001) and mucosal healing ratio (P < 0.001). The NNT [95%CI] values for the clinical response was 3 [2-40] and for the mucosal healing was 5 [2.90-10.4]. CONCLUSION: Although according to the results, daily dose of 25,000 IU vitamin A had positive clinical and endoscopic effects, considering the limitations, further studies with longer duration and larger sample size and considering dietary intake are needed to confirm these preliminary results. PMID- 30477843 TI - The prevalence and predictors of herbal medicines usage among adult rheumatoid arthritis patients: A case-control study. AB - OBJECTIVES: This study was performed to evaluate the prevalence and predictors of herbal medicines usage among adult Rheumatoid Arthritis (RA) patients. DESIGN: In this cross-sectional, case-control study, the case group included 500 RA patients and the control group contained 500 control individuals. SETTING: The study was performed in three rheumatology, surgical, and orthopedic clinics affiliated to Shiraz University of Medical Sciences. MAIN OUTCOME MEASURES: The pattern of herbal medicines usage was assessed by a researcher-made questionnaire. RESULTS: In this study, 51.4% of the subjects in the RA group and 36.4% of those in the control group used herbal medicines. The most frequently used herbal medicines were thyme (43.4%), chamomile (36.9%), borage (36.8%), lavender (31.2%), ginger (28.5%), and cinnamon (21.5%) among RA patients. The results showed a significant difference between the two groups with regard to usage of herbal medicines, such as chamomile, cinnamon, and ginger. Besides, the results of logistic regression analysis on RA patients showed that males (odds ratio = 0.50, p = 0.001) used herbal medicines less compared to females. Additionally, married RA patients (odds ratio = 0.35, p = 0.03), illiterate ones (odds ratio = 2.45, p = 0.001), and those with high school diplomas (odds ratio = 1.64, p = 0.02) used herbal medicines more compared to other patients. CONCLUSION: This study showed that more than half of RA patients used herbal medicines. All herbal medicines (thyme, chamomile, borage, lavender, ginger, and cinnamon) had anti-inflammatory effects. Yet, further studies have to be conducted to evaluate the efficacy and safety of herbal medicines usage in RA patients. PMID- 30477844 TI - Gastrointestinal symptom improvement from fiber, STW 5, peppermint oil, and probiotics use-Results from an online survey. AB - OBJECTIVES: Several common supplements are used by a significant number of patients affected by gastrointestinal (GI) disorders to improve symptoms and quality of life. We investigated the impact of GI symptom improvement with the use of fiber, STW 5, probiotics, and peppermint oil in relation to overall GI pain and quality of life via an online survey. DESIGN: We used a cross-sectional, descriptive, correlation design. A Qualtrics online survey was utilized to collect data from January to June 2013 through various websites. Areas evaluated included participant demographics, use of supplements, and gastrointestinal symptom severity. RESULTS: The rate of supplement use among patients with GI disorders was high (90% in past year) and consultation with healthcare providers was reported by 80%. Participants who completed the survey (n = 68) reported a strong correlation between GI symptom severity and overall quality of life (r2 = 0.8682, p < 0.001). The use of fiber improved GI symptom severity while both STW 5 and probiotics were linked to specific improvements. CONCLUSIONS: Persons with chronic GI disorders often choose the complementary use of common supplements to mitigate GI symptoms and consult with their healthcare providers frequently. The use of STW 5 and probiotics specifically is linked to overall reduction in GI symptoms and improvement of quality of life. PMID- 30477845 TI - Evaluation of bleeding-related adverse events following acupuncture treatment in patients on anticoagulant or antiplatelet drugs: A prospective observational study. AB - OBJECTIVE: To evaluate the risk of bleeding-related adverse events after acupuncture treatment in patients receiving anticoagulant or antiplatelet drugs. DESIGN AND SETTING: A total of 428 inpatients who received acupuncture treatment underwent two assessments for bleeding-related adverse events, such as micro bleeding, hematoma, and ecchymosis: 1) immediately after acupuncture treatment on the first day and 2) before acupuncture treatment on the following day. Additional analyses were performed using the number of acupuncture needles as independent variables. Multivariable analysis using factors likely related to bleeding and subgroup analysis according to regions of needle insertion were also performed. RESULTS: A total of 169 patients receiving anticoagulant or antiplatelet drugs (exposure group) and 259 patients not receiving either drug (non-exposure group) were studied. Sixty-five (38.5%) patients in the exposure group and 115 (44.4%) patients in the non-exposure group had bleeding-related mild adverse events. There was no difference in the risk of bleeding-related adverse events between the two groups per sessions (relative risk (RR) 0.87, 95% confidence interval (CI), 0.69-1.10) and per needles (RR 0.89, 95% CI 0.70-1.13). In multivariable analysis, thickness of needle only increased risk of bleeding. Subgroup analysis showed that taking these drugs did not increase the risk of bleeding in any of the regions. CONCLUSION: Our findings suggest that anticoagulant and antiplatelet drugs do not increase the incidence of bleeding related adverse events after acupuncture treatment. PMID- 30477846 TI - Hypnotherapy for insomnia: A randomized controlled trial comparing generic and disease-specific suggestions. AB - STUDY OBJECTIVES: Hypnotherapy is commonly used for treating insomnia, but a definite conclusion regarding its safety and effectiveness is unavailable due to a lack of adverse event monitoring and comparison between generic and disease specific hypnotic suggestions in previous studies. DESIGN: Randomized controlled, participant-blind, parallel-group with subject recruitment after trial registry. INTERVENTIONS: Sixty participants were randomized to receive 4-week once-weekly 1 hour hypnotherapy with disease-specific suggestions (using counter-hyperarousal hypnotic exercise and screen visualization technique targeted at insomnia-related anxieties) or generic suggestions (using thought distraction technique and suggestions for self-confidence and self-care enhancement). MAIN OUTCOME MEASURES: Primary outcome was sleep efficiency (SE) derived from 1-week sleep diary at weeks 4, 6 and 9. Secondary outcomes included other sleep-diary parameters, Insomnia Severity Index, Hospital Anxiety and Depression Scale, and Sheehan Disability Index. Treatment expectancy, adverse events (AEs), and subjective experiences were obtained after hypnotherapy sessions 2 and 4. RESULTS: Mixed linear modeling showed that time effect was significant for most variables. Within-group effect size of sleep-diary-derived SE from baseline to follow-up ranged from 0.70 to 0.90 for disease-specific suggestions (mean difference: 8.5-10.4%); for generic suggestions, it was 0.65-0.69 (mean difference: 6.8-8.3%); however, no significant between-group difference was found. Discontinuation rate was 10%, report of unpleasantness varied from 5.5 to 7.4%, while the incidence of AEs ranged from 37.0 to 51.8%, depending on session content. CONCLUSION: Hypnotherapy using disease-specific and generic suggestions produced similar improvements in sleep and daytime functioning. AEs were common but mostly mild. The finding raises doubts about the value of disease-specific suggestions in hypnotherapy for insomnia. TRIAL REGISTRATION: This clinical trial was registered on 23 May 2014 at the University of Hong Kong Clinical Trials Registry as "Hypnotherapy for insomnia: a randomized placebo-controlled trial" (HKUCTR-1874). PMID- 30477847 TI - Physiological and emotional effects of pentatonic live music played for preterm neonates and their mothers in the Newborn Intensive Care Unit: A randomized controlled trial. AB - OBJECTIVE: Despite attempts to increase calmness in the Newborn Intensive Care Unit (NICU), preterm neonates still experience stress. The question arises how to further promote the infants' wellbeing. Therefore, the immediate effects of pentatonic live music on preterm infants and their mothers were examined. DESIGN AND METHODS: In a two-centre randomized controlled trial with crossover design preterm infants were exposed sequentially to two conditions: live pentatonic harp music (LPHM) used in Anthroposophic Medicine or standard care. The order of the conditions was randomized within each subject. The primary outcome was change of the number of oxygen desaturations < 90%/h, whereas secondary outcomes were: heart rate, respiratory rate, oxygen saturation, heart rate variability (HRV), the perfusion index, pulse-transit-time and maternal anxiety and others not reported on in this article. RESULTS: 21 preterm infants were randomized (14 girls), mean gestational age at measurement 35 + 0 weeks (SD 1 week). The primary outcome parameter showed no significant changes. Regarding the secondary outcomes the comparison of the pre-post-differences between the conditions showed significant effects for the HRV parameters pNN50 (DeltapNN50 = 1.46%, z = -2.47, p = .001) and SDNN (DeltaSDNN=-0.06 ms, z = -2.25, p = .002). The music intervention significantly increased the values of pNN50 (Mdn 1.2% vs. 2.6%, p = 0.04) and marginally those of SDNN (Mdn 31.7 ms vs. 36.4 ms, p = 0.05). No changes were found in the other parameters. CONCLUSIONS: While the use of music in the NICU had no effect on the number of oxygen desaturations, it increased two HRV parameters indicative of infants' parasympathetic tone. PMID- 30477848 TI - Integrative care for children with cancer. Project design for the development of an integrative care programme for use in paediatric oncology. AB - PURPOSE: Purpose of this paper is to describe the project design for the development of a context-specific and patient-focused integrative care programme for an intensive care unit for paediatric oncology to ease the strain of the treatments for patients and their families. Integrative care interventions based on anthroposophical medicine such as wraps, compresses and rhythmic body oiling can be used to ease typical side effects such as nausea, pain and agitation. METHODS: Conduct of a literature research on existing integrative care programmes in medical hospitals and biomedical settings and the identification of appropriate methods to achieve the research aim. RESULTS: A project design was developed which can be used as a basis for developing, introducing and evaluating an integrative care programme for a paediatric oncological intensive care unit in a German university hospital. A qualitative study design was chosen to develop this programme. This included participant observations and interviews with all stakeholders at the respective oncology ward as well as in existing oncology wards that work with an integrative care programme. The primary emphasis was on the criteria appropriateness for the specific setting, sustainability and financial viability as well as on the development of an appropriate evaluation model. CONCLUSIONS: When developing an integrative care programme for use in the specific setting of a paediatric oncology ward and selecting the appropriate interventions for inclusion in the programme, particular attention should be paid to the needs of the patients as well as to the practicability for the nursing staff, particularly with regard to resources such as time and personnel. Both the nursing team and nursing management should be actively involved in the project design from the outset. In the evaluation particular importance is attached to feasibility. The challenge for the economic evaluation is to create a robust database for negotiation of financing possibilities. PMID- 30477849 TI - Chinese herbal medicines for the treatment of non-structural abnormal uterine bleeding in perimenopause: A systematic review and a meta-analysis. AB - OBJECTIVE: Chinese herbal medicines (CHM) have been the mainstream therapy in Asia for thousands of years and become more popular as the alternative treatment recently. The objective of this study is to evaluate the efficacy and safety of CHM for non-structural abnormal uterine bleeding (AUB) in perimenopause. METHODS: Seven databases were searched from inception to December 31 st, 2017. Randomized controlled trials (RCTs) which compared CHM versus western therapy in treating non-structural AUB in perimenopause were extracted. The primary outcome measures were hemostasis rate, normalization rate of menstruation, hemoglobin count, and improvement of menopausal symptoms. The secondary outcome measures were adverse effects and recurrence rate. The methodological quality of included trials was assessed in line with the criteria of the Cochrane Risk of Bias assessment tool. Data analyses were performed by Review Manager 5.3 software. The results were expressed as risk ratio (RR) or mean difference (MD) with a 95% confidence interval (CI). RESULTS: Fifteen RCTs with 1344 participants were analyzed. Compared with Western therapies, CHM showed advantages in normalization rate of menstruation (RR 1.20; 95% CI 1.06-1.34;P = 0.003), improving menopausal symptoms (RR 1.20, 95% CI 1.10-1.31, P <0.0001; MD -2.80, 95% CI -3.35 to -2.25, P <0.00001) and the hemoglobin count (MD 7.85, 95% CI 4.05-11.65, P <0.0001) with lower incidence of adverse reactions (RR 0.23, 95% CI 0.12 to 0.43, P <0.00001) and lower recurrence rate (RR 0.38, 95% CI 0.26 to 0.54, P <0.00001). However, we found insufficient evidence that CHM was any more or less effective than CWT for hemostasis rate (RR 1.02, 95% CI 0.95-1.10, P = 0.62). CONCLUSIONS: The findings of our study suggest that CHM may be the effective, acceptable and safe treatment for non-structural abnormal uterine bleeding during perimenopause when compared with Western medicine. However, due to high clinical heterogeneity, low methodological quality and without a proper placebo control, the conclusion is inconclusive and limited, and it should be further examined and updated in future work. PMID- 30477850 TI - A prospective study evaluating wound healing with sea cucumber gel compared with hydrogel in treatment of skin graft donor sites. AB - BACKGROUND: Gamat (sea-cucumber) is a natural occurring fauna which is popularly used as traditional medication in Southeast Asian countries. There have been many animal studies done on its' biochemical properties and its' effects in vivo. The effect of gamat on human cutaneous wounds was studied using a split-skin graft donor site wound. METHODS: This was a comparative case-control study done on patients in Hospital Universiti Sains Malaysia (Hospital USM), requiring split thickness skin grafting, whereby, the skin graft donor site was divided to almost equal halves, and applied with both gamat-based gel on one side, with Duoderm(r) hydrogel on the other side. The epithelialization of the wounds was observed and compared on days 10, 14 and 21. Pain score, and pruritus score were also observed. Repeated measure analysis of variance (ANOVA) test and Paired t-test was used to test statistical significance accordingly. RESULTS: No significant differences were seen in rates of epithelialization of wounds on days 10, 14 and 21 (p > 0.01). No significant difference was also seen in the pain score and pruritus score (p > 0.01). CONCLUSIONS: A gamat-based gel is comparable to conventional hydrogels in treatment of split-skin graft donor site. No adverse effects were observed in either group. PMID- 30477851 TI - Complementary individual homeopathy in paediatric cancer care: A case series from a University Hospital, Switzerland. AB - The Department of Haematology/Oncology at the University Children's Hospital Bern (HONK), has adopted an integrative approach in addition to state of the art oncological care and implemented a collaboration with the Institute of Complementary Medicine IKOM, University of Bern, over the past 10 years. Stakeholder satisfaction with this service was high. We present descriptive data and report on 4 exemplary patients treated with additional individualized homeopathy (iHOM). Data concerning frequency of consultations, pathologies, follow-ups and clinical results were reviewed and summarized using descriptive statistics. 94 paediatric oncologic patients consulted for iHOM. Indications for the complementary treatment was wide-ranging. No interactions with conventional treatment and no adverse side-effects of iHOM were detected. We present four characteristic patient histories, in which iHOM was used in addition to standard treatment for mucositis, permissive tissue infection, insomnia and affective dysfunctions. All four patients clinically improved in an immediate temporal relationship to the additional treatment. CONCLUSION: The collaboration between HONK and IKOM established iHOM in paediatric oncology in Bern. In this setting, iHOM was a safe and supportive additional treatment for various indications during the conventional cancer care. However, no generalizable results can be deducted from these data. We emphasize future research on this topic. PMID- 30477852 TI - Short- and long-term effects of using a facial massage roller on facial skin blood flow and vascular reactivity. AB - Massage rollers are commonly used for beauty care, but their effects on skin blood flow (SkBF) and vascular reactivity remain unclear. We hypothesized that the short-term usage of a massage roller increases the SkBF, while a long-term massage intervention improves vascular dilatation. We measured the facial SkBF change to 5 min massage roller to the right cheek in 12 subjects. We also assessed the effect of 5-week daily use of facial massage roller on the SkBF in the right cheek and the reactivity to local heat in 14 subjects. The short-term massage significantly increased facial SkBF solely in the right cheek for at least 10 min after the massage. The 5-week intervention significantly increased the vasodilatation response to the heat stimulation solely in the right cheek. These findings suggested that performing short-term facial massage with a roller increases SkBF, and long-term use improves the vascular dilatation response. PMID- 30477853 TI - Vitamin B12 for herpetic neuralgia: A meta-analysis of randomised controlled trials. AB - BACKGROUND: Postherpetic neuralgia (PHN) is the most distressful complication of herpes zoster. PHN results in an impaired quality of life and higher healthcare utilization. Vitamin B12 has been proven to be effective in pain relief for various conditions. OBJECTIVE: We conducted a systematic review and a meta analysis to evaluate the efficacy of vitamin B12 supplementation in PHN patients. METHODS: PubMed, Embase, Cochrane Library, CINAHL, and ClinicalTrials.gov registry were searched. Randomised control trials evaluating the efficacy and safety of vitamin B12 in PHN patients were selected. Eligible trials were abstracted and assessed for the risk of bias by two reviewers, and the results of pain indicators in the selected trials were analysed. RESULTS: Four trials including 383 participants were published between 2013 and 2016. Compared with the placebo group, the Vitamin B12 group exhibited a significant decrease in the Numeric Rating Scale score, with a mean difference of -4.01 (95% confidence interval = -4.70 to -3.33). Vitamin B12 administration improved the quality of life of PHN patients with moderate quality evidence and significantly decreased the number of patients using analgesics. CONCLUSION: Vitamin B12 appears to be an attractive complementary therapy for PHN patients. Further investigation is needed before conclusive recommendations can be made. PMID- 30477854 TI - Can complementary medicine enhance doctor-patient communication skills? Insights from an international medical student project. AB - INTRODUCTION: Communication is an essential component of patient care, and although medical schools provide training on this topic, patients and physicians alike express the need to improve their communication skills. An international medical student collaboration explored whether complementary medicine (CM) has the ability to further enhance patient-doctor communication. METHODS: Twenty-two medical students, nine mentors and two public representatives from Israel and Germany participated in this 18-month international group project. The goal was to explore CM methods that could enrich doctor-patient communication in several aspects. The group eventually chose to focus on four CM modalities, which included Chinese medicine; Mind-Body medicine; Touch therapies; Mindfulness and Herbal medicine. One workshop took place in Haifa and two workshops in Berlin, with continued inter-group work in-between. The workshops included interactive group formats such as "World Cafe", self-experience sessions in CM, working in small groups and delivering presentations to the entire group. RESULTS: Besides benefitting from cultural exchange and networking, students learned various aspects of CM, with a particular focus on their relevance for enriching their communication skills. The main CM aspects that were highlighted included patient characterization in the context of Chinese medicine diagnosis, mindfulness, anamnesis regarding herbal use, and a physical exam based on concepts from touch therapies. Students summarized and condensed their observations into five educational modules, which are available online: http://www.b zion.org.il/pages_e/6683.aspx. CONCLUSION: The cultural exchange and explorative process in this international medical student collaboration led to insights regarding the potential contribution of CM to patient-doctor communication. The outcomes of this international collaboration, specifically the educational modules it produced, should be further explored by medical schools, and assessed in clinical trials. PMID- 30477855 TI - Effects of Footbaths with Mustard, Ginger, or Warm Water Only on Objective and Subjective Warmth Distribution in Healthy Subjects: A Randomized Controlled Trial. AB - OBJECTIVE: To analyze the short-term thermogenic effects of footbaths with warm water alone (WA) versus when combined with medicinal powders. DESIGN: Randomized controlled trial with cross-over. INTERVENTIONS AND OUTCOMES: Seventeen healthy volunteers (mean age 22.1 years, SD = 2.4; 11 female) received three footbaths with WA or WA combined with mustard (MU) or ginger (GI) in a randomized order. Self-perceived warmth (Herdecke warmth perception questionnaire) and actual skin temperatures (thermography) were assessed before (t0), immediately after footbaths (t1), and 10 minutes later (t2). The primary outcome was perceived warmth in the feet. Secondary outcomes were warmth perception in the face, hands and overall, as well as actual skin temperature in the feet, face, and hands. RESULTS: Perceived warmth at the feet (primary outcome) increased significantly (all p's < .001) for MU and GI at t1 as well as for GI at t2 when compared to t0 with high effect sizes. At t2, GI differed significantly from WA (p < .001) and MU (p = .048). With regards to the secondary measures of outcome, no significant effects were seen for perceived warmth at the face or hands. Overall warmth was significantly higher at t1 compared to t0 (p = .01). Thermography assessments of skin temperature at the feet at t1 increased after all conditions (p < .001). No effects were seen in the face. At the hands, temperature decreased at t1 (p = .02) and t2 compared to t0 (p < .001). CONCLUSION: The present study provides preliminary evidence that mustard and ginger increase warmth perception at the feet more than warm water alone, with only the effects for GI enduring at the brief follow-up. PMID- 30477856 TI - Perceptions and experiences of MediYoga among patients with paroxysmal atrial fibrillation-An interview study. AB - OBJECTIVES: We investigated the perceptions and experiences of a therapeutic yoga form, MediYoga, which is evolved from Kundaliniyoga among patients with symptomatic paroxysmal atrial fibrillation (PAF). DESIGN AND SETTING: an inductive exploratory design was chosen with individual semi-structured interviews. The study was conducted with 12 participants (7 men and 5 women, average age 63.5) at a university hospital, Sweden. Informed consent was obtained from all participants. The data were analyzed using a qualitative content analysis with an inductive method and a manifest approach. RESULTS: Three categories were found in the analysis. In the category "A time for a sense of existence and presence", the patients described an increased thoughtfulness and experiences of gaining access to an inner self. The category "A way of gaining well-being and increased consciousness" describes patients' feelings of relaxation and feeling of comfort, with components of mental and physical well being. Furthermore, "Access to a tool to gain willpower and relieve symptoms" describes the perceptions from patients to obtained access to a tool for handling the emotions, such as fear and anxiety, as well as symptoms that they could struggling with between, and during, their episodes of atrial fibrillation. No adverse events were reported by the yoga group, during the study. CONCLUSIONS: Patients with PAF described MediYoga as an accessible tool to manage emotions and symptoms related to episodes of AF. MediYoga may also assist in enhancing body awareness, whereby physical, mental and spiritual components are integrated. MediYoga may strengthen self-management among patients with PAF. PMID- 30477857 TI - Distribution of licensed acupuncturists and educational institutions in the United States at the start of 2018. AB - This study was conducted to identify the approximate number and density of actively licensed acupuncturists, as well as the number of schools in acupuncture and oriental medicine (AOM) by January 1, 2018 in the United States (U.S.). We contacted the appropriate department governing acupuncturists, such as the Board of Acupuncture or Board of Medicine, etc. in each state and U.S. territories, to collect the data. We also conducted online license information searches in order to collect the most accurate numbers of licensed acupuncturists, especially for those states in which a board could not be reached. We found that the number of actively licensed acupuncturists as of January 1, 2018 in the U.S. was 37,886. The ten states with the largest number of acupuncturists (28,452 or 75.09% of the U.S. total), in order by total, included California, New York, Florida, Colorado, Washington, Oregon, Texas, New Jersey, Maryland and Massachusetts. The number of practitioners was greater than 1000 for each of these states. Among them, the largest three were California (12,135; 32.03%), New York (4438; 11.71%) and Florida (2705; 7.13%). These three states accounted for more than half of the overall total. The number of total licensed acupuncturists has increased 257% since 1998. The overall acupuncturist density in the U.S. - measured as number of acupuncturists per 100,000 - was 11.63 (total number of licensed acupuncturists: 37,886, divided by the total population: 325,719,178 at the start of 2018). There were 20 states with an acupuncturist density of more than 10 per 100,000 population. Hawaii (52.82) was the highest, followed by Oregon (34.88), Vermont (30.79), California (30.69) and then New Mexico (30.27). There were 62 active, accredited AOM schools which altogether offered 100 programs: 32 master degrees in Acupuncture, 53 master degrees in Oriental medicine, 13 postgraduate doctorate degrees and 2 entry-level doctorate degrees. Among these active accredited schools, institutions in the West and East Coast states comprised 77.42% of the national total. California, Florida, and New York represented 41.94%. There were 48 jurisdictions (47 States and the District of Columbia) with acupuncture practice laws in place. States without acupuncture laws included Alabama, Oklahoma and South Dakota. The data suggests that acupuncture profession has steadily grown in the United States. PMID- 30477858 TI - Effect of water-soluble cinnamon extract on electrocardiographic parameters: An analysis of the CiNNaMON trial. AB - OBJECTIVE: To ensure that cinnamon extract does not cause electrocardiographic (ECG) effects in patients with prediabetes. DESIGN: A subgroup analysis was carried out on data from 103 prediabetic patients participating in the "Effect of Lifestyle Intervention Plus Water-Soluble Cinnamon Extract on Lowering Blood Glucose in Prediabetics" trial. The trial was a randomized, double-blind, placebo controlled trial comparing cinnamon extract versus placebo in prediabetic adults who committed to participate in a standard-of-care, aggressive lifestyle therapy program. SETTING: Family Medicine Residency, Mike O'Callaghan Military Medical Center; Family Medicine Residency, David Grant Medical Center, Travis AFB; Wilford Hall Ambulatory Surgical Center, Family Medicine Residency; Eglin AFB, Family Medicine residency; Offutt AFB, Family Medicine Residency. MAIN OUTCOME MEASURES: QTc interval, QT interval, PR interval, QRS duration and heart rate from ECGs at baseline, 3 months, and 6 months. RESULTS: Analysis of the ECGs showed no time-matched intra-group differences in any of the ECG parameters (QTc interval, QT interval, PR interval, QRS duration and heart rate; all p-values >0.05). CONCLUSIONS: Use of cinnamon extract in prediabetic patients does not affect electrocardiographic measures. PMID- 30477859 TI - A qualitative analysis of the naming process of complementary and alternative medicine by chronically ill patients. AB - OBJECTIVES: A chronic illness/condition typically generates some disturbance in people. In the context of this turmoil, some individuals might make a choice to use healing options outside of regular allopathic medicine. This study is an attempt to understand the processes through which health practices/healing options get named as Complementary and Alternative Medicine (CAM) by chronic illness patients. DESIGN AND SETTING: This study used a grounded theory methodology to collect and analyze data. Following the principles of theoretical sampling, in-depth face to face interviews were conducted with a total of 21 individuals with varied chronic illnesses/conditions residing in Miami. The study sample constituted of 16 women and 5 men, belonging to different ethnicities and using varied health practices and healing options. FINDINGS: Through the findings it is suggested, that there is nothing definite about the definition of CAM. Individuals name and rename activities and health practices as CAM based on their perceptions and the way they approach such health practices/healing options. The naming process of CAM is contextual and even food and activities or pastimes can get named as CAM if they hold meaning for a person. CONCLUSION: Research in the US continually shows that CAM is widely used, but what actually constitutes CAM differs based on whom you ask. Whether what can be named as CAM should be circumscribed or left open is a debate that has policy implications and needs to be explored by future researchers. PMID- 30477860 TI - The effects of silymarin supplementation on metabolic status and oxidative stress in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of clinical trials. AB - OBJECTIVE: The effect of silymarin supplementation on metabolic status and oxidative stress of subjects with type 2 diabetes mellitus (T2DM) has not been conclusively studied. Therefore, the efficacy of silymarin supplementation in these patients was assessed through a meta-analysis. METHODS: The following databases were searched up to May 15, 2018: PubMed, Scopus, Ovid (Cochrane library), Google scholar and ISI web of science. All randomized clinical trials using silymarin supplements to improve T2DM included in this meta-analysis. Mean Difference (MD) was pooled using a random-effects model. RESULTS: Eight eligible publications from seven trials were identified for the present meta-analysis. Our results revealed that supplementation with silymarin can decrease fasting blood sugar, hemoglobin A1C, insulin, low-density lipoprotein cholesterol and malondialdehyde and increase high-density lipoprotein cholesterol levels. However, silymarin did not have any significant effects on total cholesterol or triglyceride concentrations. CONCLUSION: Our data suggest that silymarin supplements have beneficial effects on metabolic status and oxidative stress among patients with T2DM. However, there is currently insufficient evidence to make firm conclusions about the full efficacy of supplementation. PMID- 30477861 TI - What makes a group fitness program for people with Parkinson's disease endure? A mixed-methods study of multiple stakeholders. AB - OBJECTIVE: Identify key features of an enduring group exercise program for people with Parkinson's disease (PD) by exploring experiences of participants, student assistants and the exercise instructor through a convergent mixed methods design. METHODS: Fourteen people with PD (modified Hoehn & Yahr: 1-3.5) who regularly participated in a group exercise program (>= 50% of classes for >= 1 year) were interviewed to explore their perceptions of the program. The exercise instructor was also interviewed and weekly written reflections were collected from 18 undergraduate student assistants. Using a grounded theory approach, interviews and written reflections were thematically analyzed via qualitative content analysis. Quantitative data from the Physical Fitness and Exercise Activity Levels of Older Adults Scale were used as part of a convergent mixed-methods design to move towards theory formation. RESULTS: Thematic analysis of the PD participant interviews revealed 4 themes: 1) Quality of the program, 2) Social interactions, 3) Facilitators to exercise, 4) Barriers to exercise. The exercise instructor interview revealed 2 themes: individualization and functionality of exercises, and creating a nurturing atmosphere. Themes from students' data included student learning, and positive in-class experiences. Means (sd) were 1.6 (0.5) for facilitators and 3.0 (0.5) for barriers subscales (1=strongly agree to 4=strongly disagree). CONCLUSION: These varied sources of data converge to identify and characterize key features of an enduring group exercise program for people with PD: a positive and nurturing environment, varied and individually tailored exercise content, and the importance of social cohesion. These findings also highlight the critical role of multiple stakeholders in fostering an environment that facilitates long-term adherence to group exercise. PMID- 30477862 TI - Differences among health care students' attitudes, knowledge and use of dietary supplements: a cross-sectional study. AB - OBJECTIVES: The objectives of this study were to evaluate the difference among pharmacy, dental and medical students' attitudes, knowledge and use of dietary supplements. Furthermore, factors likely to influence their personal use and willingness to recommend supplement to patient were investigated. DESIGN: A cross sectional survey study. SETTING: The study was carried out at a single university. MAIN OUTCOME MEASURES: Survey gathered socio-demographic data and questioned students' attitudes, knowledge and use of dietary supplements. RESULTS: A total of 506 students were included in the study. Pharmacy students showed more positive attitudes about dietary supplements, and achieved higher knowledge scores when compared to dental or medical students (p < 0.001). Medical students were more likely to use evidence based sources of information about dietary supplements. There was no difference in supplements use across study programs (p = 0.177). As many as 59.7% of students that participated in the study reported using dietary supplements. Data analysis showed that the previous personal use supplements was a significant independent predictor whether students would recommend supplements to their patients (OR 27.03, 95% CI 14.08-50, p < 0.001). CONCLUSIONS: Students' education did not influence their personal use of dietary supplements. However, their personal experience seems to influence their willingness to recommend supplements to patients. Pharmacy students showed greater knowledge about supplements than their dental or medical colleagues. In future practice, health care students could benefit from collaboration with pharmacists when they provide care to patients seeking advice about the use of dietary supplements. PMID- 30477863 TI - Complementary and alternative medicine use amongst Turkish type 2 diabetic patients: A cross-sectional study. AB - BACKGROUND: There is a worldwide tendency in the use of complementary and alternative medicine (CAM). Type 2 diabetic patients' attitude towards CAM use differs depending on several patient characteristics. OBJECTIVE: To determine the awareness, knowledge and the frequency of CAM use; to determine the independent demographic characteristics making it more probable to use CAM in patients with type 2 diabetes mellitus (T2DM). METHODS: 400 patients with T2DM visiting outpatient diabetes education clinic in Turkey from September 2015 to June 2016 were included in this cross-sectional study. On the basis of patients' responses to our questionnaire interrogating the CAM use, all participants were divided into 2 groups: CAM users and non-users. The independent predictors of CAM use were determined after a multivariate analysis including the parameters with a p value <0.25 in univariate analysis. RESULTS: In our study the rate of CAM use was 36,7% (n = 147) and CAM use among female gender was significantly more frequent. HbA1c, fasting blood glucose, post-prandial blood glucose serum levels were significantly higher in CAM non-user group. (p < 0.001,p < 0.001 and p < 0.001 respectively). The independent predictive factors proved to be a determinant of CAM use were the age of 50-64 years, female gender and healthy eating habits. CONCLUSIONS: The use of CAM methods in the field of T2DM is growing. Our study reported the prevalence of CAM use, the baseline comparison of CAM users and non users and demonstrated three independent notable predictors of CAM use among patients with T2DM. PMID- 30477864 TI - Effect of crocetin on quality of sleep: A randomized, double-blind, placebo controlled, crossover study. AB - OBJECTIVES: The aim of the present study was to investigate the effect of crocetin on sleep architecture and subjective sleep parameters in healthy adult participants with mild sleep complaints. DESIGN: A randomized, double-blind, placebo-controlled, crossover study with two intervention periods of 14 days each, separated by a 14-day wash-out period. INTERVENTIONS: Thirty participants were randomly assigned to one of two sequence groups. Each group was given crocetin at 7.5 mg/day, or placebo. We measured objective sleep parameters using single-channel electroencephalography and assessed subjective sleep parameters using the Oguri-Shirakawa-Azumi Sleep Inventory, Middle-age and Aged version (OSA MA). MAIN OUTCOME MEASURES: Differences between crocetin and placebo in an objective sleep parameter (delta power), and OSA-MA scores. RESULTS: Delta power was significantly increased with crocetin compared with placebo. There were no significant differences in the other sleep parameters, including sleep latency, sleep efficiency, total sleep time, and wake after sleep onset. Subjective scores for sleepiness on rising and feeling refreshed were significantly improved with crocetin compared with placebo. CONCLUSIONS: The findings of the present study suggest that crocetin supplementation contributes to sleep maintenance, leading to improved subjective sleep quality. PMID- 30477865 TI - The prevalence and characteristics of complementary medicine use by Australian and American adults living with gastrointestinal disorders: A systematic review. AB - AIM: To report the prevalence and sociodemographic characteristics of complementary medicine (CM) use by Australian and American adults living with gastrointestinal (GI) disorders. METHOD: Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Medline, Pubmed, Scopus and Web of Science were searched for studies published in English language between 1st January 2008 and 8th April 2018. Additionally, a Google Scholar search and risk of bias assessment were conducted. RESULTS: Twelve (five American and seven Australian) studies, involving 53,991 adults were included. Data were extracted from studies reporting CM use by both specific populations with medically diagnosed GI disorders and the general population with self-reported GI disorders. CM use ranged from 23.6% to 44% (American) and 27.2% to 58% (Australian) by adults with medically diagnosed GI disorders. Whilst CM use was higher amongst females, with higher incomes and education levels. The prevalence of CM use by those with self reported GI disorders varied from 0.31% to 80%. Herbal, probiotic supplements and mind-body practices were the most prevalent CMs used. The risk of bias assessment identified weaknesses in the external validity, principally related to poor study design. CONCLUSIONS: There is a substantial use of CMs by American and Australian adults with GI disorders. Females with higher education and income are predominant users. There is a need to conduct up-to-date and well-designed prevalence and sociodemographic studies. Additionally, future studies should consider including health literacy and medicines disclosure scales in order to better understand CM use by this population. PMID- 30477866 TI - The effects of music therapy on the interaction of the self and emotions-An interim analysis. AB - OBJECTIVES: Music therapy is a well-established non-verbal treatment method in psychiatry and psychosomatic medicine. However, empirical data of its impact on emotion modulation processes and personality dimensions are still sparce. An interesting concept is the use of music for emotion modulation in everyday life. The purpose of this interim study was to assess the interplay of personality dimensions and emotion modulation strategies in patients treated with music therapy versus patients without music therapy. DESIGN: A cross-sectional design was used. SETTING: The study was conducted during the course of inpatient treatment in a general psychiatric hospital. Data from n = 137 patients was included in the analysis. MAIN OUTCOME MEASURES: According to the mediator model a regression analysis was performed using personality variables as potential predictors and emotion modulation variables as outcome criteria. RESULTS: In the music therapy group, insecurity predicted the use of music for both cognitive problem solving and positive stimulation in everyday life. In the non-music therapy group, cooperation and insouciance predicted the use of music for reduction of negative activation. CONCLUSIONS: Specific personality dimensions predict greater targeted emotion modulation strategies if music therapy is applied than without it. That is, music therapy helps patients acquire more conscious (i.e. cognitive-related strategies) emotion modulation techniques by means of including their individual personality, whereas patients without music therapy simply "vent" their negative emotions (i.e. non-cognitive strategies). Conversely, the data suggest that music therapy can contribute to modify personality dimensions through the development of these emotion modulation strategies. This could be a plausible explanation for beneficial long-term effects of music therapy. PMID- 30477867 TI - An integrative review of dietetic and naturopathic approaches to functional bowel disorders. AB - OBJECTIVES: Naturopathy and dietetics have evolved as two separate but parallel professions that use diet to promote optimal health and manage many illnesses and diseases. Given the increasing recognition of the influence of diet on health outcomes, there is increasing demand for the services of both professions. The aim of this research was to investigate similarities and differences between naturopathic and dietetic approaches to functional bowel disorders (FBDs). DESIGN: For this integrative review AMED, CINAHL, the Cochrane Database of Systematic Reviews, EMBASE, Medline and PubMed databases were searched for articles that focused on dietetic or naturopathic diagnosis and treatment of food intolerance expressing as a FBD in adults. (Registration: PROSPERO 2016 CRD42016049469). RESULTS: Of the 55 papers in the final review, 10 discussed complementary medicine approaches to FBDs. Both dietitians and naturopaths used similar holistic approaches to diagnosis and treatment, adjusted diets as a primary treatment approach, and individualised treatment for their patients. The professions differed in their use of vitamin, mineral and herbal supplements and in their willingness to recommend other treatments like osteopathy and acupuncture. CONCLUSIONS: There is much overlap between dietetic and naturopathic approaches to assessment and treatment of FBDs. Further publications that describe naturopathic treatments for FBDs are needed to confirm these results and to provide opportunities for increased recognition and scrutiny of any distinctively naturopathic approaches. Without doing so, naturopathic practices are likely to remain marginalised and poorly understood. Moreover, the opportunity to fully contribute to the management of lifestyle-related diseases will be missed. PMID- 30477868 TI - Standardizing music characteristics for the management of pain: A systematic review and meta-analysis of clinical trials. AB - PURPOSE: To evaluate if music characteristics like tempo, harmony, melody, instrumentation, volume, and pitch, as defined by musical theory, are described in randomized clinical trials (RCTs) evaluating the effects of music-listening on the quantified pain perception of adults, and if these characteristics influence music's overall therapeutic effect. METHODS: A systematic review and meta analysis of RCTs evaluating music-listening for pain management on adults was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement. The databases Pubmed, Scopus, SCIELO, SpringerLink, Global Health Library, Cochrane, EMBASE, and LILACS were searched. Studies published between 2004 and 2017 with quantified measurements of pain were included. Quality was evaluated using the Scottish Intercollegiate Guidelines Network methodology checklist for RCT, and effect sizes were reported with standardized mean differences. RESULTS: A total of 85 studies were included for qualitative analysis but only 56.47% described at least one music characteristic. Overall meta-analysis found a significant effect, with high heterogeneity, of music for pain management (SMD -0.59, I2 = 85%). Only instrumentation characteristics (lack of lyrics, of percussion or of nature sounds), and 60-80 bpm tempo were described sufficiently for analysis. All three instrumentation characteristics had significant effects, but only the lack of lyrics showed an acceptable heterogeneity. CONCLUSIONS: Results show that music without lyrics is effective for the management of pain. Due to insufficient data, no ideal music characteristics for the management of pain were identified suggesting that music, as an intervention, needs standardization through an objective language such as that of music theory. PMID- 30477869 TI - Acupuncture improves symptoms in patients with mild-to-moderate atopic dermatitis: A randomized, sham-controlled preliminary trial. AB - OBJECTIVES: To assess the feasibility of a definitive trial investigating the effects of acupuncture on atopic dermatitis symptoms including itching. DESIGN: A randomized, sham-controlled preliminary trial with three arms with a 4-week intervention period and a 4-week follow-up. INTERVENTIONS: Thirty participants were allocated to three arms (the verum acupuncture group 1 [VA1, 3 times weekly for 4 weeks], the verum acupuncture group 2 [VA2, twice weekly for 4 weeks], and the sham acupuncture group [SA, twice weekly for 4 weeks]) at a 1:1:1 ratio. MAIN OUTCOME MEASURES: We determined the visual analogue scale (VAS) for itching and insomnia, SCORing Atopic Dermatitis (SCORAD), Eczema Area and Severity Index (EASI), Patient Oriented Eczema Measure (POEM), and Dermatology Life Quality Index (DLQI) scores over the course of the study. Baseline index score (BIS) comparison according to general symptom was performed. RESULTS: The SCORAD, VAS (Pruritus), VAS (Insomnia), POEM, DLQI, and EASI were significantly improved in the VA groups. Significant BIS mean differences were observed most predominantly in epigastric tenderness and dyspepsia. There was no significant difference between VA1 and VA2 groups in all the main evaluation indices. CONCLUSIONS: For the following research, the authors suggest SCORAD (Total) as primary outcome and SCORAD (objective), VAS (Itch), VAS (insomnia), EASI, POEM, and DLQI as secondary outcomes. Thirty six participants should be conducted a 4-week acupuncture period (twice weekly) and a 4-week follow-up. It is necessary to compare the differences of general symptoms according to presence of epigastric tenderness or dyspepsia at the screening level. PMID- 30477871 TI - "Let there be light." Research on phototherapy, light therapy, and photobiomodulation for healing - Alternative therapy becomes mainstream. PMID- 30477870 TI - Yoga as adjunct therapy for adolescents with inflammatory bowel disease: A pilot clinical trial. AB - OBJECTIVES: To determine whether utilizing yoga as an adjunctive therapy to the medical standard of care for adolescents with inflammatory bowel disease (IBD) is: (1) feasible and acceptable, (2) effective in reducing disease severity, intestinal inflammation and improving wellness. DESIGN: Prospective, non randomized, 8-week pilot study for adolescents with a diagnosis of IBD. Feasibility and acceptability of the intervention were assessed weekly and post intervention via surveys and a focus group (week 8). Disease severity, intestinal inflammation, and wellness measures were assessed at baseline and post intervention (week 8). INTERVENTION: Over the 8-week study period, patients were assigned three 60-minute, in-person yoga classes at weeks 1, 3 and 8, and three 30-minute, online yoga videos per week. MAIN OUTCOME MEASURES: Primary outcome measures were feasibility and acceptability. Secondary outcome measures assessed preliminary clinical efficacy by examining pre- and post-intervention change in disease severity (PUCAI), intestinal inflammation (fecal calprotectin), and six wellness measures (PROMIS-37). RESULTS: Nine adolescents with IBD participated. Eight participated in one or more yoga videos per week and all nine attended at least two in-person yoga classes. Focus group themes revealed that the intervention was well liked, with all participants reporting reduced stress, improved emotional self-awareness, and increased ability to identify and manage the physical symptoms of IBD. Participants had difficulty, however, completing the yoga videos due to time limitations and competing priorities. We lacked power to detect any statistically significant changes in PUCAI, calprotectin, or any of the six PROMIS-37 domains. CONCLUSIONS: A combination of in-person instructor led yoga with video-based yoga is a feasible and acceptable adjunct therapy for adolescents with IBD. Participants reported reduced stress and improved ability to identify and manage physical symptoms. A larger, randomized controlled trial is necessary to determine if the yoga protocol results in clinically and statistically significant improvements in inflammatory biomarkers and patient reported outcomes. PMID- 30477872 TI - Water reuse, food production and public health: Adopting transdisciplinary, systems-based approaches to achieve water and food security in a changing climate. AB - Climate change and population growth are contributing to a growing global freshwater crisis that is exacerbating agricultural water scarcity and compromising food security and public health. In light of these challenges, the increased reliance on nontraditional irrigation water sources, such as reclaimed or recycled water, is emerging as a potentially viable strategy to address water and food insecurity worldwide. This editorial provides an overview of the global need for agricultural water reuse and outlines the environmental and public health impacts associated with this practice. Policy implications, including an emphasis on "One Water" approaches, are discussed. Finally, the editorial leads off a Special Issue that includes a collection of articles reporting on the initial research and extension/outreach findings of CONSERVE: A Center of Excellence at the Nexus of Sustainable Water Reuse, Food and Health, funded by the U.S. Department of Agriculture, National Institute of Food and Agriculture. Taken together, this compilation of articles addresses the overarching theme that transdisciplinary teams are key with regard to moving the science of agricultural water reuse forward to achieve water and food security and advance public health in a changing climate. PMID- 30477873 TI - Aerodynamic investigation of the thermo-dependent flow structure in the wake of a cyclist. AB - The main purpose of this study was to assess the influence of the environmental temperature on both the aerodynamic flow evolving around the bicycle and cycling power output. The CFD method was used to investigate the detailed flow field around the cyclist/bicycle system for a constant speed of 11.1 m/s (40 km/h) without wind. In complement, a mathematical model was used to determine the temperature-dependent power output in the range [-10; 40 degrees C]. The numerical investigation gives valuable information about the turbulent flow field in the cyclist's wake which evolves accordingly the surrounding temperature. A major result of this study is that the areas of overpressure upstream of the cyclist and of underpressure downstream of him are less extensive for a temperature of 40 degrees C compared to -10 degrees C. The results suggest that the aerodynamic braking effect of the bicycle is minimized when the air temperature is high, as a lower air density results in a reduction in drag on the cyclist. This study showed that the power required to maintain a constant speed is reduced when the temperature is high, the reason being a lower aerodynamic resistance. PMID- 30477874 TI - Virtual structural analysis of tibial fracture healing from low-dose clinical CT scans. AB - Quantitative assessment of bone fracture healing remains a significant challenge in orthopaedic trauma research. Accordingly, we developed a new technique for assessing bone healing using virtual mechano-structural analysis of computed tomography (CT) scans. CT scans from 19 fractured human tibiae at 12 weeks after surgery were segmented and prepared for finite element analysis (FEA). Boundary conditions were applied to the models to simulate a torsion test that is commonly used to access the structural integrity of long bones in animal models of fracture healing. The output of each model was the virtual torsional rigidity (VTR) of the healing zone, normalized to the torsional rigidity of each patient's virtually reconstructed tibia. This provided a structural measure to track the percentage of healing each patient had undergone. Callus morphometric measurements were also collected from the CT scans. Results showed that at 12 weeks post-op, more than 75% of patients achieved a normalized VTR (torsional rigidity relative to uninjured bone) of 85% or above. The predicted intact torsional rigidities compared well with published cadaveric data. Across all patients, callus volume and density were weakly and non-significantly correlated with normalized VTR and time to clinical union. Conversely, normalized VTR was significantly correlated with time to union (R2 = 0.383, p = 0.005). This suggests that fracture scoring methods based on the visual appearance of callus may not accurately predict mechanical integrity. The image-based structural analysis presented here may be a useful technique for assessment of bone healing in orthopaedic trauma research. PMID- 30477875 TI - Does epimuscular myofascial force transmission occur between the human quadriceps muscles in vivo during passive stretching? AB - This study sought to examine the shear modulus (i.e., an force index) of three quadriceps muscles [i.e., vastus medialis (VM), vastus lateralis (VL), and rectus femoris (RF)] during passive stretching to determine whether epimuscular myofascial force transmission occurs across muscles. Secondly, this study compared the shear modulus between the quadriceps muscles, in both proximal and distal regions. Twelve healthy individuals were assessed during a passive knee flexion maneuver between 0 degrees and 90 degrees of knee flexion with the hip in two positions: flexed (80 degrees ) vs. neutral (0 degrees ). Muscle electrical activity was also assessed during the testing. No differences were observed between the hip testing positions for myoelectric activity (p > 0.43), and for VL and VM shear modulus (p = 0.12-0.98). Similarly, there were no differences between the proximal and distal regions for all muscles (p = 0.42 0.93). RF showed a higher shear modulus with the hip in the neutral position (p = 0.004). With the hip flexed, the VL showed the greatest shear modulus among the tested muscles (p < 0.025); while with the hip in the neutral position, no differences were observed for shear modulus between VL and RF (p = 0.817). These findings suggest that epimuscular myofascial force transmission (at a muscle belly level) does not occur between the quadriceps muscles when passively flexing the knee until 90 degrees . Whether epimuscular myofascial force transmission occurs in the quadriceps muscles bellies with greater muscle stretch (either through knee flexion or hip extension) remains to be examined. PMID- 30477876 TI - Sand gapers' breath: Respiration of Mya arenaria (L. 1758) and its contribution to total oxygen utilization in sediments. AB - To estimate the contribution of a Mya arenaria population to total oxygen utilization (TOU) at different temperatures, the respiration rate of M. arenaria was measured for a full size range at 5 and 15 degrees C. In this study we measured respiration rates in a closed system while the clams were burrowed in sandy sediment, resembling their natural habitat. Rates were measured over a sufficient time span (24 h) to average varying activity phases during the measurements. We calculated a size-dependent respiration rate for M. arenaria and its variation with temperature. Temperature strongly affects the total population respiration and the contribution of different size classes to respiration of the total M. arenaria population. M. arenaria was estimated to contribute up to 70% to the total oxygen utilization of benthic communities analyzed in this study very much depending on the size distribution of the bivalve population present. Given a specific size distribution, smaller individuals had a stronger influence on the total oxygen utilization at colder temperature, while the influence of larger individuals grew with warmer temperature. Even though sizes contribute differently, a significant relation between abundance and respiration could be drawn in most cases analyzed. However, this relation should not be used as a general rule, but when estimating a population's metabolism the size distribution within that population has to be regarded. PMID- 30477877 TI - Otolith shape and isotopic ratio analyses as a tool to study Spondyliosoma cantharus population structure. AB - Knowledge on population units is critical for understanding population dynamics and providing an adequate fisheries management. Despite its vast distribution and commercial importance, there is no information on black seabream population structure. Different approaches to otolith analysis were used to elucidate on the stock structure of this species. Otoliths from seven areas along the eastern Atlantic: English Channel, Bay of Biscay, Galicia (Spain), Peniche (west coast of Portugal), Algarve (south coast of Portugal), the Canary Islands and Angola were compared through elliptical Fourier analysis and oxygen and carbon stable isotopes ratio. Otolith shape analysis data achieved 80% of correct assigned specimens in discriminant analysis while poor correct assignment levels were achieved with the stable isotopes ratio. However, the PERMANOVA conducted on delta13C and delta18O values revealed significant differences between all areas, with exception of the two Portuguese areas. The results of this study indicate that black seabream spends most of its life in the same area and that the studied populations should probably be considered as different stock units. However, some mixture was detected in the European region pointing for the usefulness of life history parameters and genetic studies to enlighten the stock structure of the species. PMID- 30477878 TI - Energy metabolism and survival of the juvenile recruits of the American lobster (Homarus americanus) exposed to a gradient of elevated seawater pCO2. AB - The transition from the last pelagic larval stage to the first benthic juvenile stage in the complex life cycle of marine invertebrates, such as the American lobster Homarus americanus, a species of high economic importance, represents a delicate phase in these species development. Under future elevated pCO2 conditions, ocean acidification and other elevated pCO2 events can negatively affect crustaceans. This said their effects on the benthic settlement phase are virtually unknown. This study aimed to identify the effects of elevated seawater pCO2 on stage V American lobsters exposed to seven pCO2 levels. The survival, development time, metabolic and feeding rates, carapace composition, and energy metabolism enzyme function were investigated. Results suggested an increase in mortality, slower development and an increase in aerobic capacity with increasing pCO2. Our study points to potential reduction in juvenile recruitment success as seawater pCO2 increases, thus foreshadowing important socio-economic repercussions for the lobster fisheries and industry. PMID- 30477879 TI - Ectopic cervical well differentiated thymic carcinoma: report of a diagnostically challenging rare case. PMID- 30477880 TI - High reproducibility is attainable in assessing histoprognostic parameters of pT1 colorectal cancer using routine histopathology slides and immunohistochemistry analyses. AB - Assessment of the risk of lymph node invasion and tumour recurrence is critical to determine whether additional surgery is required in patients with endoscopically-removed pT1 colorectal cancer (CRC). A reproducible assessment of this risk of recurrence based on histopathological parameters is crucial for relevant therapeutic decisions. The inter-observer reproducibility of these parameters was the subject of our study. Two pathologists independently analysed 163 endoscopically-removed pT1 CRC recorded in a local digestive cancer registry database (Finistere, France). Using haematoxylin-eosin-saffron (HES) and immunohistochemistry slides, they evaluated several parameters related to the risk of tumour recurrence according to the international pT1 CRC-dedicated guidelines. Based on Kappa and intra-class correlation coefficients, good to very good inter-observer agreement was obtained by analysing vertical and lateral margins, submucosal invasion, tumour differentiation and lymphovascular invasion. The reproducibility of tumour budding quantification was only fair on the basis of HES slides but reached a very good agreement using cytokeratin immunohistochemistry. Dual colour cytokeratin and podoplanin immunohistochemistry also improved inter-observer agreement for the detection of lymphovascular invasion. All patients with loco-regional nodal metastases (7 of 101 who underwent complementary surgery) or distant metastases (3 patients) were diagnosed as having a high risk of recurrence and requiring an additional surgery by the two observers. Our study showed that good to very good inter-observer agreement is achievable in evaluating the pathological parameters of recurrence risk in endoscopically-removed pT1 CRC. In addition to HES slides, the detection of lymphovascular invasion and tumour budding can benefit with more reproducible immunohistochemical analyses. PMID- 30477881 TI - Approximately 1% of chronic myeloid leukaemia cases present with isolated thrombocytosis and express common major breakpoints: a finding from a laboratory audit. PMID- 30477882 TI - Dataset for the reporting of prostate carcinoma in core needle biopsy and transurethral resection and enucleation specimens: recommendations from the International Collaboration on Cancer Reporting (ICCR). AB - The International Collaboration on Cancer Reporting (ICCR) is a project which issues datasets and guidelines for international standardisation of cancer reporting. This review summarises the required and recommended elements of the datasets for prostate core needle biopsies and transurethral resection (TURP) and enucleation specimens of the prostate. To obtain as much information as possible from needle biopsies there should be only one core in each specimen jar with the exception of saturation biopsies. The gross description of the specimens should include core lengths of needle biopsies and weight of resection specimens. The tumours should be classified according to the 4th World Health Organization (WHO) classification and graded both by Gleason scores and the grouping of these in International Society of Urological Pathology (ISUP) grades (Grade groups). Percent high-grade cancer is an optional component of the report. Tumour extent in needle biopsies should be reported both by number of cores positive for cancer and the linear extent measured in either millimetre or percent core involvement by tumour. In needle biopsies where low-grade cancer is discontinuous and seen in few cores, it is recommended that the tumour extent should be reported both by including and subtracting intervening benign tissue. For resection specimens, the percentage of the tissue area (or percentage of number of TURP chips) involved with cancer should be estimated. Extraprostatic extension should be reported when seen, while the reporting of perineural, seminal vesicle/ejaculatory duct and lymphovascular invasion is only recommended. Intraductal carcinoma of the prostate (IDC-P) should be reported when present, because of its strong link with aggressive cancer. The current recommendation is that the IDC-P component should not be graded. The structured and standardised reporting of prostate cancer contributes to safer and more efficient patient care and facilitates the compilation and understanding of multiparametric diagnostic and prognostic data. PMID- 30477883 TI - Rhabdomyosarcoma with FUS re-arrangement: additional case in support of a novel subtype. PMID- 30477884 TI - Chronic kidney cortical damage is associated with baseline kidney function and albuminuria in patients managed with radical nephrectomy for kidney tumours. AB - This study evaluated the relationship between histological markers of chronic kidney damage in patients undergoing radical nephrectomy for kidney tumours and preoperative kidney function, degree of albuminuria, and changes in glomerular volume. A schema to grade chronic kidney damage could be used to identify patients at risk of developing CKD following nephrectomy. Non-neoplastic cortical tissue was sourced from 150 patients undergoing radical nephrectomy for suspected kidney cancer. This tissue was evaluated for indicators of chronic damage, specifically: glomerulosclerosis, arteriosclerosis, interstitial fibrosis, and tubular atrophy. Glomerular volume was determined using the Weibel and Gomez method. Associations between these parameters and both estimated glomerular filtration rate (eGFR) and albumin-creatinine ratio (ACR) were determined using either a Mann-Whitney U-test or a Kruskal-Wallis ANOVA. Associations between both eGFR and ACR and glomerular volume were assessed using linear regression. eGFR was inversely associated with the degree of glomerulosclerosis (p < 0.001), vascular narrowing (p = 0.002), tubular atrophy (p < 0.001), and interstitial fibrosis (p < 0.001). ACR was associated only with the degree of interstitial fibrosis (p = 0.02) and tubular atrophy (p = 0.02). Glomerular volume was greater for males, diabetics, hypertensive patients, and patients with a greater degree of interstitial fibrosis. Glomerular volume was positively associated with ACR. A schema to grade chronic damage was developed. The proposed schema is associated with baseline clinical indices of kidney function and damage. Longitudinal validation is necessary to determine the prognostic utility of this schema. PMID- 30477885 TI - Unintentional hypothermia in the surgical patient. Old solutions to an old problem, or new solutions to an old problem? PMID- 30477886 TI - Erratum to: "Density spectral array of BIS VISTATM monitoring system in a functional hemispherectomy". PMID- 30477887 TI - Enhanced Recovery After Surgery for Cardiac Surgery: Will We Have the Techniques Needed to Reduce Opioid Use and Still Provide Appropriate Analgesia? PMID- 30477888 TI - Ultrasound-Guided Single-Shot Preemptive Erector Spinae Plane Block for Postoperative Pain Management. PMID- 30477889 TI - Mitral Annular Plane Systolic Excursion: A Simple, Reliable Echocardiographic Parameter to Detect Left Ventricular Systolic Dysfunction in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting with Transesophageal Echocardiography. AB - OBJECTIVES: This study's objective was to test the hypothesis that transesophageal echocardiography (TEE)-based mitral annular plane systolic excursion (MAPSE) measurement is useful in perioperative settings to detect left ventricular (LV) systolic dysfunction in patients undergoing off-pump coronary artery bypass grafting (OPCAB). DESIGN: Retrospective observational study. SETTING: Tertiary-care level hospitals. PARTICIPANTS: The study comprised 116 patients undergoing OPCAB to obtain cutoffs of MAPSE to detect LV dysfunction. These cutoffs were validated in another 105 patients from 2 other institutions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In 116 patients who had undergone OPCAB during the study period with TEE monitoring, MAPSE was measured post hoc at the lateral and septal mitral (and average) annulus using the software tool M.mode.ify (http://www.ultrasoundoftheweek.com/M.mode.ify). Receiver operating curves were constructed to obtain cutoff values of MAPSE at the lateral and septal (and average) annulus of the mitral valve to predict LV systolic dysfunction, which was defined by an ejection fraction <52% for men and <54% for women as measured using the biplane method of disks. These cutoff values then were validated in another 105 patients. LV systolic dysfunction was present in 43% patients. Youden's index values of 9 mm for lateral MPASE (area under the receiver operating curve [AUC] 0.93 [confidence interval {CI} 0.87-0.97]; p < 0.0001); 7 mm for septal MAPSE (AUC 0.87 [CI 0.79-0.92]; p < 0.0001); and 9 mm for average MAPSE (AUC 0.92 [CI 0.86-0.96]; p < 0.0001) were obtained. These cutoffs were statistically significant in the validation cohort (p < 0.0001) with an AUC of 0.84 (CI 0.75-0.90), sensitivity of 86.2%, specificity of 80.8%, positive predictive value of 84.8%, and negative predictive value of 82.6%. CONCLUSIONS: MAPSE is a simple, rapid, and reliable method to detect LV dysfunction using TEE in patients undergoing OPCAB. Its use as screening tool for LV dysfunction is recommended. PMID- 30477890 TI - Outcomes of patients with Guillain Barre Syndrome - Experience from a tertiary care hospital of a developing Asian country and review of regional literature. AB - Outcomes of Guillain Barre Syndrome (GBS), particularly those require mechanical ventilation have been reported from a number of Asian countries, albeit, scarcely from Pakistan. We conducted this study to determine the short-term outcomes of GBS and compare the results of mechanically ventilated and non-ventilated patients. Case records of patients admitted with GBS during 2011-2016 at a large tertiary care centre of Pakistan were retrospectively reviewed. 216 patients satisfying inclusion criteria were included. Patients were divided into 2 groups based on requirement of MV (MV and non-MV group). Short term outcomes were assessed by Modified Rankin Scale (MRS) at discharge, 2 weeks and 3 months and comparison done between MV and non-MV group. Outcome based on MRS score is categorized as good (MRS = 0-3) or poor (MRS = 4-6). Requirement for MV was noted in 24.5%. MV patients had severe weakness at presentation, longer length of hospital stay (LOS) and higher frequency of in-hospital complications. Overall mortality was 7.9%. Good outcomes at discharge and at 3 months were noted in significantly higher frequency in non-MV group (50.3% and 93.2% respectively) as compared to MV group (11.3% and 33.3% respectively). In MV group, increasing age, areflexia and longer LOS stay were found as independent predictors of poor outcome. Overall outcomes of GBS in our population are comparable to both regional and international studies. However, poor outcomes in MV group are seen in higher frequency in our study. Increasing age, areflexia and longer LOS may predict poor outcome in MV patients. PMID- 30477891 TI - Evaluation of neomycin analogues for HIV-1 RRE RNA recognition identifies enhanced activity simplified neamine analogues. AB - Synthetic neamine mimetics have been evaluated for binding to the HIV-1 Rev response element. Modified neamine derivatives, obtained from reductive amination of neamine, led to identification of new 6-amino modified neamine-type ligands with HIV-1 RRE binding affinity up to 20* that of neamine and up to 6* that of the more complex neomycin itself. This provides a noteworthy structure-activity increase and a useful lead to simplified, chemically accessible mimetics. PMID- 30477892 TI - Comparative effectiveness of convolutional neural network (CNN) and recurrent neural network (RNN) architectures for radiology text report classification. AB - This paper explores cutting-edge deep learning methods for information extraction from medical imaging free text reports at a multi-institutional scale and compares them to the state-of-the-art domain-specific rule-based system - PEFinder and traditional machine learning methods - SVM and Adaboost. We proposed two distinct deep learning models - (i) CNN Word - Glove, and (ii) Domain phrase attention-based hierarchical recurrent neural network (DPA-HNN), for synthesizing information on pulmonary emboli (PE) from over 7370 clinical thoracic computed tomography (CT) free-text radiology reports collected from four major healthcare centers. Our proposed DPA-HNN model encodes domain-dependent phrases into an attention mechanism and represents a radiology report through a hierarchical RNN structure composed of word-level, sentence-level and document-level representations. Experimental results suggest that the performance of the deep learning models that are trained on a single institutional dataset, are better than rule-based PEFinder on our multi-institutional test sets. The best F1 score for the presence of PE in an adult patient population was 0.99 (DPA-HNN) and for a pediatrics population was 0.99 (HNN) which shows that the deep learning models being trained on adult data, demonstrated generalizability to pediatrics population with comparable accuracy. Our work suggests feasibility of broader usage of neural network models in automated classification of multi-institutional imaging text reports for a variety of applications including evaluation of imaging utilization, imaging yield, clinical decision support tools, and as part of automated classification of large corpus for medical imaging deep learning work. PMID- 30477893 TI - CPAF, HSP60 and MOMP antigens elicit pro-inflammatory cytokines production in the peripheral blood mononuclear cells from genital Chlamydia trachomatis-infected patients. AB - BACKGROUND: Persistent inflammation caused by Chlamydia trachomatis in the female genital compartment represents one of the major causes of pelvic inflammatory disease (PID), ectopic pregnancy and infertility in females. Here, we examined the pro-inflammatory cytokine response following stimulation with three different types of C. trachomatis antigens, viz. chlamydial protease-like factor (CPAF), heat shock protein 60 (HSP60) and major outer membrane protein (MOMP). METHODS: A total of 19 patients with genital C. trachomatis infection and 10 age-matched healthy controls were recruited for the study. Peripheral blood mononuclear cells (PBMCs) isolated from genital C. trachomatis-infected females were cultured in the presence of CPAF, HSP60 and MOMP antigens, and cytokines were measured by ELISA assay. RESULTS: We reported that pro-inflammatory cytokines (TNF-alpha, IL 1beta and IL-6) were robustly secreted following antigenic exposure. Notably, CPAP and MOMP were more potent in triggering IL-1beta, as compared to HSP60. Elevated levels of the proinflammatory cytokines were also noted in the samples infected with plasmid-bearing C. trachomatis as compared to those infected with plasmid-free strains. CONCLUSIONS: Our study highlights distinct ability of chlamydial antigens in triggering pro-inflammatory response in the host immune cells. PMID- 30477894 TI - Mesenchymal stem cells preconditioned by staphylococcal enterotoxin B enhance survival and bacterial clearance in murine sepsis model. AB - Sepsis, a health-threatening progressive infectious disease, is the major cause of morbidity and mortality worldwide. Cell therapy using mesenchymal stromal cells (MSCs) is an innovative strategy with excessive therapeutic potential in the treatment of sepsis. Staphylococcal enterotoxin B (SEB) preconditioning aims to prolong the interval of survival of transplanted MSCs which induces the production of cytoprotective agents, anti-apoptotic and anti-inflammatory factors. The MSCs were preconditioned with an optimum dose of SEB (470 MUmol/L). The expression levels of apoptosis genes and antibacterial activity of MSC and SEB-MSC and their conditioned medium (CM), as well as cell survival, were studied in vitro in an oxidative stress and serum deprivation condition. Following treatment of the septic mice with MSCs and SEB-MSCs, pro/anti-inflammatory cytokines, hematological factors, bacterial clearance and animal survival were assessed. The apoptotic and pro-inflammatory cytokine's genes expression was down regulated while antibacterial peptides and anti-inflammatory cytokines were up regulated in SEB-MSC-treated mice. The animal survival rates were improved; bacterial clearance was enhanced in the peritoneal fluids, blood and organs; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were reduced in blood, compared with saline and MSCs alone. This research concludes that transplantation of SEB-MSCs presents improved therapeutic effects on a live bacterial model of sepsis. PMID- 30477895 TI - Urinary metabolomics reveals unique metabolic signatures in infants with cystic fibrosis. AB - BACKGROUND: Biologic pathways and metabolic mechanisms underpinning early systemic disease in cystic fibrosis (CF) are poorly understood. The Baby Observational and Nutrition Study (BONUS) was a prospective multi-center study of infants with CF with a primary aim to examine the current state of nutrition in the first year of life. Its secondary aim was to prospectively explore concurrent nutritional, metabolic, respiratory, infectious, and inflammatory characteristics associated with early CF anthropometric measurements. We report here metabolomics differences within the urine of these infants as compared to infants without CF. METHODS: Urine metabolomics was performed for 85 infants with predefined clinical phenotypes at approximately one year of age enrolled in BONUS via Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS). Samples were stratified by disease status (non-CF controls (n = 22); CF (n = 63, All-CF)) and CF clinical phenotype: respiratory hospitalization (CF Resp, n = 22), low length (CF LL, n = 23), and low weight (CF LW, n = 15). RESULTS: Global urine metabolomics profiles in CF were heterogeneous, however there were distinct metabolic differences between the CF and non-CF groups. Top pathways altered in CF included tRNA charging and methionine degradation. ADCYAP1 and huntingtin were identified as predicted unique regulators of altered metabolic pathways in CF compared to non-CF. Infants with CF displayed alterations in metabolites associated with bile acid homeostasis, pentose sugars, and vitamins. CONCLUSIONS: Predicted metabolic pathways and regulators were identified in CF infants compared to non-CF, but metabolic profiles were unable to discriminate between CF phenotypes. Targeted metabolomics provides an opportunity for further understanding of early CF disease. TRIAL REGISTRATION: United States ClinicalTrials.Gov registry NCT01424696 (clinicaltrials.gov). PMID- 30477896 TI - Ovulation, Sex Hormones, and Women's Mating Psychology. AB - The dual mating strategy hypothesis proposes that women's preferences for uncommitted sexual relationships with men displaying putative fitness cues increase during the high-fertility phase of the menstrual cycle. Results consistent with this hypothesis are widely cited as evidence that sexual selection has shaped human mating psychology. However, the methods used in most of these studies have recently been extensively criticized. Here we discuss (i) new empirical studies that address these methodological problems and largely report null results and (ii) an alternative model of hormonal regulation of women's mating psychology that can better accommodate these new data. PMID- 30477897 TI - A New Look at Visual System Plasticity. AB - Reward-based learning is known to induce cortical plasticity in primary sensory areas. A new study by Goltstein, Meijer, and Pennartz [1] (eLife2018;7:e37683), adopting a dual-scale approach (single-unit and population level), shows how associative learning in mice tunes cortical processing, but unlike other primary sensory cortices it does not modify the retinotopic map. PMID- 30477898 TI - Performance validation of the ALPPS risk model. AB - BACKGROUND: Based on the International ALPPS registry, we have recently proposed two easily applicable risk models (pre-stage1 and 2) for predicting 90-day mortality in ALPPS but a validation of both models has not been performed yet. METHODS: The validation cohort (VC) was composed of subsequent cases of the ALPPS registry and cases of centers outside the ALPPS registry. RESULTS: The VC was composed of a total of 258 patients including 70 patients outside the ALPPS registry with 32 cases of early mortalities (12%). Development cohort (DC) and VC were comparable in terms of patient and surgery characteristics. The VC validated both models with an acceptable prediction for the pre-stage 1 (c-statistic 0.64, P = 0.009 vs. 0.77, P < 0.001) and a good prediction for the pre-stage 2 model (c statistic 0.77, P < 0.001 vs. 0.85, P < 0.001) as compared to the DC. Overall model performance measured by Brier score was comparable between VC and DC for the pre-stage 1 (0.089 vs. 0.081) and pre-stage 2 model (0.079 vs. 0087). CONCLUSION: The ALPPS risk score is a fully validated model to estimate the individual risk of patients undergoing ALPPS and to assist clinical decision making to avoid procedure-related early mortality after ALPPS. PMID- 30477899 TI - [An example of post-discharge monitoring after a suicide attempt: VigilanS]. AB - BACKGROUND: Attempted suicide is a major risk factor of further re-attempts and death. Self-harm behaviors are related to multiple causes explaining why it is ineffective to have a single and simple strategy to offer after the clinical assessment in reducing morbidity and mortality. Furthermore, treatment adherence is known to be especially poor in a context where social connection seems compromised and a source of pain. Effective interventions can be divided into two categories: intensive intervention programs (care at home, supported by a series of brief psychotherapy interventions) and case management programs that rely on a "stay in contact" dimension. These programs, initiated by Jerome Motto and its short letters may consist of: (1) sending letters or postcards after discharge of the ER; (2) giving a crisis card that offers a crisis telephone line and a crisis unit for hospitalization if needed, and; (3) placing a phone call at some time distance after the discharge. The aim is to enhance a "connectedness feeling" with the patient. These different strategies have proven to be even more effective in some specific subgroups, highlighting the heterogeneity of this population. Each modality of contact was well accepted and generated a positive involvement of the patients. METHOD: It led to the idea of combining these different strategies in an algorithm built on the specificity of identified subgroups. A randomized controlled trial, named ALGOS was carried out in France to test this algorithm in 2011. The algorithm consisted of: (1) delivering a crisis card for first attempters; (2) giving a phone call for re-attempters to re assess their situation between the 10th and 21st day after their discharge, and to propose a new intervention if needed, and; (3) in case of an unsuccessful call or a refusal of proposed care, sending personalized postcards for 6 months. All of this was supported with shared information to the general practitioner of the patient. This study was further adapted to routine care in 2015 in the northern departments of France, Nord and Pas-de-Calais (4.3 million people), taking the name of VigilanS. The inclusion consists of sending a form for every patient assessed after a suicide attempt in the two departments to the medical staff of VigilanS in order to provide information about the patient and the context of his suicide attempt. The algorithm has been modified in giving the crisis card to all the patients whether it is a first attempt or not. An information letter, explaining the aim of the monitoring is also given to the patient, and to his general practitioner. The calling staff is composed of 4 nurses and 4 psychologists, all trained in suicidal crisis management. They use a phone platform located in the Emergency Medical Assistance Service (SAMU) of the Nord department on a halftime basis and manage the incoming calls from the patients as well as the outgoing calls towards the patients, their relatives and their medical contacts. A set of 4 postcards (1 per month) can be sent if needed in case of an inconclusive or a failed phone call. CONCLUSION: Built on a monitoring philosophy, VigilanS has further developed a real crisis case management dimension requiring enough time to insure an effective medical supervision and strong networking abilities. A specific time is also needed to take care of all the technical aspects of the organization. This program expertise, designed by Northern departments to prevent suicide, can be shared with other French or even foreign territories. PMID- 30477900 TI - [Prevention of suicide of the elderly in France. To a multimodal strategy against depression and isolation: CQFDi]. AB - ISSUE: Suicide is a major problem of public health around the world, and if suicidal mortality rates have declined in recent years, the elderly remain a category of the world's population at major risk of suicide. Seventeen percent of deaths by suicide across the world are individuals over the age of 65. The existence of suicidal ideas for an individual in this age group increases the risk of suicide attempt in the year by 34. In France, about a little less than a quarter of suicides belong to persons over 60-years-old. More risk factors found in the international literature are in the foreground of mental disorders and in particular the major depression episode, then secondarily addictions, neuro degenerative disorders as well as pain and other diseases. Depression is found in 60% to 90% of suicides. We notice also that older people privileged the general practitioner as interlocutor to discuss their problems and worries much more than psychiatrists or psychologists. In fact, two-thirds of the elderly who committed suicide had consulted their general practioner in the month prior to suicide and half in the 10 last days. That raises the question of the identification of depression and the evaluation of suicidal risk. On the other side, there is an abundant literature about psychosocial risk factors especially on the influence of isolation and lack of social support as well as on conflicts and family losses. In France, more than 4 million of the elderly live alone. So, while the world population is increasing and life expectancy lengthens, it is important to already act for elderly suicide prevention. PERSPECTIVES: Suicide prevention actions whose efficacity have been demonstrated around the world are designed as part of multimodal strategies combining several levers of action. The consensual recommendations for prevention of elderly suicide recommend the association of actions on the reduction of depression and combating social isolation in connection with the training of front-line actors such as general practitioners. As a result of these experiments and recommendations, the first francophone multimodal strategy was developed to act both on depression and social isolation: the Cooperation Quebec France sur la depression et l'isolement (CQFDi) program which will be implemented in France and Quebec in 2019. CONCLUSION: It has been proven that multimodal suicide prevention strategies allow a reduction in the number of suicides. The CQFDi program focuses on at risk of suicide population and aims to reduce the suicide rate of elderly people in France. PMID- 30477901 TI - Candidatus Krumholzbacterium zodletonensis gen. nov., sp nov, the first representative of the candidate phylum Krumholzbacterota phyl. nov. recovered from an anoxic sulfidic spring using genome resolved metagenomics. AB - The accumulation of genomes of uncultured organisms has highlighted the need for devising a taxonomic and nomenclature scheme to validate names and prevent redundancies. We here report on the recovery and analysis of four phylogenetically related genomes recovered from an anoxic sulfide and sulfur-rich spring (Zodletone spring) in southwestern Oklahoma. Phylogenetic analysis based on 120 single copy markers attested to their position as a novel distinct bacterial phylum. Genomic analysis suggests Gram-negative flagellated organisms that possess type IV pili. The organisms are predicted to be rod-shaped, slow growers, with an anoxic, heterotrophic, and fermentative lifestyle. Predicted substrate utilization pattern includes multiple amino acids, dipeptides, tripeptides, and oligpopeptides; as well as few sugars. Predicted auxotrophies include proline, vitamin B6, lipoic acid, biotin, and vitamin B12. Assessment of the putative global distribution pattern of this novel lineage suggests its preference to anoxic marine, terrestrial, hydrocarbon-impacted, and freshwater habitats. We propose the candidatus name Krumholzbacterium zodletonensis gen. nov, sp. nov. for Zgenome0171T, with the genome serving as the type material for the novel family Krumholzbacteriaceae fam. nov., order Krumholzbacteriales ord. nov., class Krumholzbacteria class nov., and phylum Krumholzbacterota phyl. nov. The type material genome assembly is deposited in GenBank under accession number QTKG01000000. PMID- 30477902 TI - Effect of inoculation with nitrogen-fixing bacterium Pseudomonas stutzeri A1501 on maize plant growth and the microbiome indigenous to the rhizosphere. AB - Plant growth promoting diazotrophs with the ability to associate with plant roots are in common use as inoculants to benefit crop yield and to mitigate chemical nitrogen fertilization. However, limited information is available in understanding to what extent the plant growth-promoting effect of the inoculum has on the plant's nitrogen acquisition as well as on the impact of inoculation on the indigenous rhizosphere microbial population. Here we reported on experiments that assessed how endophytic Pseudomonas stutzeri A1501 inoculated on maize improved plant growth and plant nitrogen content using a 15N dilution technique under two water regime conditions. The effects of inoculation and different water regimes were also assessed for the maize rhizospheric and surface soil communities by MiSeq community sequencing combined with qPCR of functional genes and transcripts (nifH and amoA) related to nitrogen cycling. Results support maize inoculated with P. stutzeri A1501 grew better and accumulated more nitrogen with a lower delta15N signature after 60 days than did plants inoculated with nifH-mutant and sterilized A1501 cells (non N2-fixing controls). Inoculant contribution to the plant was estimated to range from 0.30 to 0.82g N/plant, depending on water conditions. Inoculation with P. stutzeri A1501 significantly altered the composition of the diazotrophic community that P. stutzeri became dominant in the rhizosphere, and also increased the population of indigenous diazotrophs and ammonia oxidizers and functional genes transcripts. Redundancy analysis revealed that soil compartment and A1501 inoculation treatments were the main factors affecting the distribution of the diazotrophic community. PMID- 30477903 TI - Factors Affecting the Development of Confidence Among Surgical Trainees. AB - OBJECTIVE: The objective of this study was to explore and better characterize the factors affecting confidence during surgical training. DESIGN: This was a qualitative research study in which we conducted semistructured interviews with surgical residents to explore factors affecting their confidence. SETTING: This study was conducted at the University of Alberta Hospital, a tertiary care center located in Edmonton, Alberta, Canada. PARTICIPANTS: Residents from the University of Alberta General Surgery residency program were invited to participate from each postgraduate year (PGY) 2, 3, and 4 for a total of 7 participants (3 PGY-2, 3 PGY-3, and 1 PGY-4; 3 male, and 4 female). We excluded residents who had completed or were currently enrolled in dedicated research years. RESULTS: Resident confidence was found to be influenced by internal and external factors operating before, during, and after a particular surgical task. Internal factors incorporated personal experiences (including operative experience), personal expectations, self-perception, and individual skill development. External factors involved feedback, patient outcomes, relationships with staff, and working within a supportive environment. Interestingly, residents discussed external social factors more than case volume, technical skills, or underlying knowledge. Residents did not feel that their personal lives (e.g. marital status or having children) directly affected their surgical confidence. Regardless of the factor itself, positive experiences helped build and maintain confidence by providing feelings of reassurance, encouragement, comfort, and acceptance. CONCLUSIONS: Surgical confidence is influenced by a range of internal and external factors. Understanding these factors can help educators improve learning experiences for residents and accelerate their progress towards being confident, independent surgeons. PMID- 30477904 TI - Effect of mono/dual antiretroviral therapy on suppression of HCV and HIV during treatment of HCV infection in HIV/HCV-coinfected patients. AB - OBJECTIVE: Data of hepatitis C treatment with direct-acting antivirals (DAAs) in HIV infected patients are limited to a few number of antiretroviral therapies (ART). The aim of this study was to assess the effectiveness and safety of non conventional ART as monotherapy or dual therapy (MDT) when combined with DAA. METHODS: Retrospective review of HIV/HCV-coinfected patients treated with DAAs during one year in 3 centers. Sustained virologic response 12 weeks after therapy (SVR) and maintenance of HIV viral suppression were compared between patients receiving triple ART (TT) or MDT. RESULTS: Overall 485 patients were included (359 receiving TT and 126 MDT). HCV SVR was 93.4% (95%CI, 90.8% to 95.3%) in the intention-to-treat analysis without differences between groups: 92.8% on TT vs 95.2% on MDT (p=0.3). HCV virological failure was associated with lower CD4+cell count at baseline (for every 100-cell/MUl increment: OR, 0.8; 95%CI, 0.7-0.9; p=0.01) and with liver stiffness (for every 10-unit increment: OR, 1.5; 95%CI 1.2 1.8; p<0.01). HIV-RNA during HCV treatment or 12 weeks after was detectable in 23 patients on TT (6.6%) and 9 (7.2%) patients on MDT (p=0.8). The median (IQR) change in CD4+cell count was not significantly different between the groups: 15 ( 55 to 115) in TT vs -12 (-68 to 133) cells/MUl in MDT (p=0.8). CONCLUSION: DAAs obtain high rates of SVR among HIV/HCV-coinfected patients independently of whether TT or non-conventional ART is used. Suppression of HIV was maintained in both groups. PMID- 30477905 TI - Behavioral empathy failures and suicidal behavior. AB - Impaired decision-making has recently gained recognition as a component of the suicidal diathesis. Yet, although precipitants and particularly deterrents to suicidal behavior are often interpersonal, little is known about social decision making in suicidal individuals. This study employed a novel version of the Ultimatum Game to investigate how empathy moderates responses to social conflict in 149 older adults, comprising groups of suicide attempters (n = 49), suicide ideators (n = 32), non-suicidal depressed controls (n = 33), and a non psychiatric control group (n = 35). Participants acted as responder to a series of single-shot financial offers that varied in fairness. Some offers were paired with social context information on the proposer, designed to evoke either empathy or punishment. Offer acceptance was sensitive to Fairness and Social Context, such that participants accepted more offers in the empathy condition and fewer offers in the punishment condition. A Group * Context interaction was observed, wherein the suicide attempters adjusted their acceptance rates less in the empathy condition than the non-psychiatric controls. Thus, older adults with a history of suicide attempt were less influenced by empathy scenarios, indicating that a failure to integrate others' emotions into decisions may undermine social deterrents to suicide. PMID- 30477906 TI - Patient satisfaction: Concept analysis in the healthcare context. AB - OBJECTIVE: Patient satisfaction had been the focus of many scientific studies worldwide. However, very few studies published had addressed the definition of the concept of patient satisfaction. Therefore this present concept analysis is to explore the attributes of the concept in the broader healthcare context. METHODS: The Rodgers method, an inductive method of concept analysis, was selected to guide this concept analysis. RESULTS: The attributes of patient satisfaction in the healthcare context identified were provider attitude, technical competence, accessibility, and efficacy. Perception in relation to expectation, patient demographics and personality, and market competition were regarded as prerequisites of patient satisfaction. Consequences of patient satisfaction identified in this analysis were: patient compliance, clinical outcomes, loyalty and referrals. CONCLUSION: As healthcare is becoming an increasingly competitive marketplace, studying patient experience could certainly help practitioners to better encompass patient perspectives in service delivery and improve patient satisfaction. PRACTICE IMPLICATIONS: To ensure the validity of patient satisfaction measurement and subsequently improve healthcare quality, practitioners should involve patients in identifying important factors relevant to each attributes of patient satisfaction. PMID- 30477907 TI - Analysis of a clinical pathway for home enteral nutrition in the Region of Murcia. Consumption and associated expenses and adaptation to the National Health System Guide. AB - OBJECTIVE: To analyze the compliance with the Guide for home enteral nutrition (HEN) of the Spanish national health system of the prescriptions made in a specific area (Health Area I of the Region of Murcia) before and after implementation of a clinical pathway based on that guide, and to compare the changes in healthcare costs of diet therapy during the 2007-2014 period in the Regional and National Health system. METHOD: A descriptive study to quantify compliance with the main criteria of the HEN guide before (2010) and after (2013 2014) implementation of the clinical pathway. Changes in health expenditure and consumption during the 2007-2014 period were also analyzed. RESULTS: All markers of compliance with the national HEN guide improved after implementation of the clinical pathway. In addition, Murcia has one of the Spanish lowest expenditures per population, below the national average. CONCLUSION: The clinical pathway implemented improves compliance with the national guide of prescriptions to patients in the Region of Murcia while containing health resources expenditure and consumption, thus making diet therapy prescription more sustainable. PMID- 30477908 TI - MicroRNAs at the Host-Bacteria Interface: Host Defense or Bacterial Offense. AB - MicroRNAs are a class of small noncoding RNAs that act as major post transcriptional regulators of gene expression. They are currently recognized for their important role in the intricate interaction between host and bacterial pathogens, either as part of the host immune response to neutralize infection, or as a molecular strategy employed by bacteria to hijack host pathways for their own benefit. Here, we summarize recent advances on the function of miRNAs during infection of mammalian hosts by bacterial pathogens, highlighting key cellular pathways. In addition, we discuss emerging themes in this field, including the participation of miRNAs in host-microbiota crosstalk and cell-to-cell communication. PMID- 30477910 TI - Important factor for pain relief in patients with eagle syndrome: Excision technique of styloid process. PMID- 30477909 TI - MTHFR AND ApoE genetic variants association with sudden sensorineural hearing loss. AB - HYPOTHESIS: Although the pathogenesis of sudden sensorineural hearing loss (SSNHL) is not clear, however several causes including genetic factors seems to be implicated. We hypothesized that common genetic variants might be involved in SSNHL. BACKGROUND: SSNHL is known to be an idiopathic disease because the causative factors have not been identified. Several causes including genetic and viral infection besides immune system reaction, neurological disorders, medications, etc. have been previously reported. We examined the association between ApoE and MTHFR gene variants in SSNHL. METHODS: This study includes case control scheme encompassing a total of 177 individuals, include patients inflicted with SSNHL and healthy subjects as control group. Genotyping of MTHFR and ApoE variants was conducted by PCR - RFLP method. RESULT: Our study showed that MTHFR rs1801133 allele frequency is significantly different between cases and controls. Also genotype distribution of ApoE was significantly different between patients and healthy controls. CONCLUSIONS: MTHFR C677T and ApoE gene variant may be associated with sudden sensorineural hearing loss in an Iranian population. PMID- 30477911 TI - Clinical efficacy of cognitive behavioral therapy for chronic subjective tinnitus. AB - BACKGROUND: Although cognitive behavioral therapy (CBT) has been known with a theoretical basis for tinnitus patients, there still were lack of clinical evidence. OBJECTIVE: To evaluate the clinical efficacy of cognitive behavioral therapy (CBT) for treatment of chronic subjective tinnitus. METHODS: One hundred patients with chronic subjective tinnitus patients were randomly divided into control (50 cases) and intervention (50 cases) groups, which received the masking therapy and sound treatment and masking therapy and sound treatment plus CBT. The treatment efficacy was evaluated. RESULTS: The total effective rate in intervention group was significantly higher than control group (P < 0.01). After treatment, compared with control group, in intervention group the psychotic somatization, interpersonal sensitivity, depression, anxiety, hostility, terror, and phobic anxiety scores in Symptom Checklist-90 and Tinnitus Handicap Inventory score were significantly decreased (P < 0.05), the serum cortisol level was significantly decreased (P < 0.05), and the serum interleukin-2 level was significantly increased (P < 0.05). CONCLUSION: Based on the elimination the mood disorders and reduce the stress, CBT can significantly relieve the symptoms of chronic subjective tinnitus. PMID- 30477912 TI - A narrative review of bariatric surgery in Indigenous peoples. AB - INTRODUCTION: Indigenous peoples suffer high rates of obesity and obesity-related disease worldwide. Currently, bariatric surgery is the most effective intervention for severe obesity and obesity-related disease. The role bariatric surgery plays in alleviating the obesity burden amongst Indigenous peoples is unknown. We aimed to collate studies investigating bariatric surgery in Indigenous peoples and to provide a simple framework to use in future research surrounding this important issue. MATERIALS AND METHODS: We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies that investigated outcomes for Indigenous peoples at any point along the bariatric surgery journey were included. RESULTS: Six articles were included in this review. Three studies investigated access to bariatric surgery and the remaining three studies investigated short to long-term outcomes following bariatric surgery. A narrative review was performed given study heterogeneity and quality of included studies. Indigenous peoples had lower access to bariatric surgery and in one study had greater weight loss in comparison to non-Indigenous peoples. CONCLUSION: Despite a paucity of studies, it appears that there is emerging interest in investigating bariatric surgery among Indigenous peoples. We encourage those who seek to investigate this important issue at any point along the bariatric surgery journey, to do so using an equity-based approach. PMID- 30477913 TI - Systems Delivery Innovation for Alzheimer Disease. AB - OBJECTIVE: The authors describe a comprehensive care model for Alzheimer disease (AD) that improves value within 1-3 years after implementation by leveraging targeted outpatient chronic care management, cognitively protective acute care, and timely caregiver support. METHODS: Using current best evidence, expert opinion, and macroeconomic modeling, the authors designed a comprehensive care model for AD that improves the quality of care while reducing total per capita healthcare spending by more than 15%. Cost savings were measured as reduced spending by payers. Cost estimates were derived from medical literature and national databases, including both public and private U.S. payers. All estimates reflect the value in 2015 dollars using a consumer price index inflation calculator. Outcome estimates were determined at year 2, accounting for implementation and steady-state intervention costs. RESULTS: After accounting for implementation and recurring operating costs of approximately $9.5 billion, estimated net cost savings of between $13 and $41 billion can be accomplished concurrently with improvements in quality and experience of coordinated chronic care ($0.01-$6.8 billion), cognitively protective acute care ($8.7-$26.6 billion), timely caregiver support ($4.3-$7.5 billion), and caregiver efficiency ($4.1-$7.2 billion). CONCLUSION: A high-value care model for AD may improve the experience of patients with AD while significantly lowering costs. PMID- 30477914 TI - Refining Postoperative Delirium: The Case of a Gene * Protein Interaction. PMID- 30477915 TI - Autologous mitochondrial transfer as a complementary technique to intracytoplasmic sperm injection to improve embryo quality in patients undergoing in vitro fertilization-a randomized pilot study. AB - OBJECTIVE: To study if autologous mitochondrial transfer (AUGMENT) improves outcome in patients with previously failed in vitro fertilization (IVF). DESIGN: Randomized, controlled, triple-blind, experimental study. SETTING: Private infertility center, Valencian Institute of Infertility (IVI-RMA), Valencia, Spain. PATIENT(S): Infertile women <=42 years of age, body mass index <30 kg/m2, antimullerian hormone >=4 pmol/L, >5 million/mL motile sperm, at least one previous IVF with at least five metaphase oocytes (MIIs) collected, and low embryo quality. INTERVENTIONS(S): An ovarian cortex biopsy was performed to isolate egg precursor cells to obtain their mitochondria. Sibling MIIs were randomly allocated to AUGMENT (experimental) or intracytoplasmic sperm injection (Control). In AUGMENT, mitochondrial suspension was injected along with the sperm. Viable blastocysts from both groups were biopsied for preimplantation genetic testing for aneuploidy. MAIN OUTCOME MEASURE(S): Pregnancy, embryo quality. RESULT(S): An interim analysis was conducted. The patients' mean age was 36.3 +/- 3.6 years, and they had an average of 2.5 +/- 1.5 previous IVF cycles. Two of the 59 enrolled patients spontaneously conceived (one miscarried). Fifty seven patients had ovarian biopsies and underwent stimulation. Oocyte retrieval was performed in 56 patients (premature ovulation; n = 1). A total of 253 MIIs were inseminated in AUGMENT and 250 in Control; fertilization rates were 62.7 +/- 30.0% and 68.7 +/- 29.1%, respectively. Statistical differences were observed in day 5 blastocyst formation rates (23.3 +/- 32.0% vs. 41.1 +/- 36.9%). Neither the euploid rate per biopsied blastocyst (43.8 +/- 41.7% vs. 63.8 +/- 44.1%) nor the euploid rate per MII (9.8 +/- 20.5% vs. 11.9 +/- 16.1%) between AUGMENT and Control achieved statistical significance. Moreover, no differences were seen regarding mitochondrial DNA content and relevant morphokinetic variables. Thirty patients were able to undergo embryo transfer. Cumulative live birth rates per transferred embryo were 41.6% in AUGMENT and 41.2% in Control. CONCLUSION(S): AUGMENT does not seem to improve prognosis in this population. Therefore, the study has been discontinued. CLINICAL TRIAL REGISTRATION NUMBER: NCT02586298. PMID- 30477916 TI - Elevation of antimullerian hormone in women with polycystic ovary syndrome undergoing assisted reproduction: effect of insulin. AB - OBJECTIVE: To measure blood and follicular antimullerian hormone (AMH) levels in women with polycystic ovary syndrome (PCOS) undergoing assisted reproductive technologies (ART) and to examine the direct action of insulin on AMH expression in human granulosa cells. DESIGN: Prospective clinical and experimental study. SETTING: University Hospital-based laboratory. PATIENT(S): Women with (n = 86) and without (n = 172) PCOS in ART. INTERVENTION(S): Blood, follicular fluid, and luteinized granulosa cells were collected from PCOS and non-PCOS women in ART. MAIN OUTCOME MEASURE(S): Hormone levels in blood and fluid, and gene expression in granulosa cells. RESULT(S): Serum levels of AMH were elevated and inversely correlated with embryo cleavage rate in PCOS women in ART. Significant higher levels of AMH were also found in small and large follicles collected from PCOS women compared with non-PCOS women. Luteinized granulosa cells from PCOS women showed higher expression of AMH and its receptor AMHR2. Direct effect of insulin in increasing the expression of AMH in the isolated luteinized granulosa cells was observed, with the PCOS granulosa cells responding to a high dose of insulin. Cotreatment with AMH attenuated insulin-induced aromatase expression in the luteinized granulosa cells. CONCLUSION(S): These results suggest that insulin may contribute to AMH elevation in PCOS and that AMH counteracts insulin-promoted aromatase expression in granulosa cells. PMID- 30477917 TI - Reply to the Letters to the Editor regarding Elevated body mass index is a risk factor associated with possible liver cirrhosis across different etiologies of chronic liver disease: More questions than answer? PMID- 30477918 TI - Impact of mass migrations on the clonal variation of clinical Staphylococcus aureus strains isolated from the Western region of Saudi Arabia. AB - OBJECTIVES: A rapid molecular typing system was used to determine the impact of mass migration on the clonal variation of Staphylococcus aureus isolates recovered from King Abdulaziz University Hospital (KAUH) Jeddah, in the western region of Saudi Arabia. This region experiences an annual influx of millions of pilgrims. METHODS: SmaI-multiplex PCR typing (SMT) was used for the initial analysis of strains and the resulting data subsequently supported by Multi-Locus Sequence Typing (MLST). RESULTS: A total of 89 S. aureus isolates were SMT typed and revealed a high degree of genetic variation, with 40 SMT profiles detected among the isolates. Representatives of all forty SMT types were subsequently analysed by MLST, identifying 26 sequence types. A novel sequence type (ST), named ST3303, was identified in two methicillin-sensitive S. aureus (MSSA) isolates. MSSA strains exhibited more diversity than methicillin-resistant S. aureus (MRSA) strains, with community acquired MSSA and MRSA strains reaching alarmingly high levels. CONCLUSION: The relatively high degree of genetic diversity found among S. aureus isolates of single hospital was attributed to the fact that Jeddah is the principal gateway to Mecca, visited each year by millions of pilgrims from many countries. The observed diversity clearly reflects the impact of such mass migrations in the rapid dissemination of strains world-wide. Our findings suggest the importance of surveillance programmes in locations affected by mass migrations, both to monitor their impact on endemic strains and for the detection of pandemic strains. SMT provides a cost-effective and sensitive typing method for achieving this objective. PMID- 30477919 TI - Synthesis, characterization, and antibacterial potential of silver nanoparticles synthesized from Coriandrum sativum L. AB - INTRODUCTION: Nanoparticles (NPs) have become very important owing to their various uses. In this research, an environmentally friendly biological technique was used to synthesize silver nanoparticles with Coriandrum sativum L. The objective of this research to use the source for the fabrication of silver NPs from C. sativum L., and to check the activity of the fabricated silver NPs was determined versus a couple of gram negative and a couple of gram positive bacteria in the presence of antibiotic viz. gentamicin to judge their impact. METHODOLOGY: A silver nitrate solution, which served as the reducing and capping agent, was mingled with coriander leaf extract. The solution's temperature and pH were maintained at 75 degrees C and 8.6, respectively. The observed mean particle size (z-average) and polydispersity index were 390.2nm and 0.452, respectively. The synthesized Ag NPs were characterized using different techniques, including scanning electron microscopy (SEM), X-ray diffraction, and Fourier transmission infrared (FTIR) analysis. The globular shape of the silver nanoparticles was depicted in SEM illustrations. RESULTS: XRD data revealed the mean size of the particles was 11.9nm. The FTIR analysis showed the existence of various functional groups, including CO and OH. When their antibacterial ability was tested, it was found that the fabricated Ag NPs inhibited Bacillus subtilis, Pasteurella multocida, Enterobacter aerogenes, and Staphylococcus aureus, with a greater effect against B. subtilis and P. multocida compared to E. aerogenes and S. aureus. CONCLUSION: It has been concluded small silver NPs benefited from a higher surface area ratio, as shown by the results of experiments where smaller particles had a better bactericidal proficiency than large silver-based NPs. Silver-based NPs infiltrate bacterial cells, as well as interfere with their exterior membrane. Silver ions also have the potential to interact with bacterial DNA, inhibiting the reproductive system of the cell. PMID- 30477920 TI - Epidemiology of carbapenemase-producing Enterobacteriaceae in a pediatric hospital in a country with high endemicity. AB - BACKGROUND: Little is known about epidemiology of carbapenemase-producing Enterobacteriaceae (CPE) in children. Aim of this study was to describe CPE epidemiology in a tertiary care pediatric hospital in Italy that admits patients coming from geographic areas with high diffusion of CPE. METHODS: Prospective evaluation of the proportion and rates per 100,000 hospital discharges (D) or hospitalization-days (HD) of invasive infections due to CPE from 2013 to 2017 and of CPE infections and colonizations from 2014 to 2017. Disease-preventing strategies comprised patients' screening at admission, pre-emptive contact isolation precautions pending cultures results, and bundles for prevention of healthcare associated infections. RESULTS: From 2013 to 2017 CPE represented 3.5% of all invasive infections due to Enterobacteriaceae, with rates ranging 7.30 14.33 for D and 1.03-2.06 for HD, without major changes over time. On the contrary, overall rates of isolates increased from 83.03 to 191.34 for D and from 12.21 to 28.35 for HD. The intra-hospital diffusion consisted of 2 small outbreaks without invasive diseases in 2014-2015, and sporadic, not epidemiologically-related cases in 2016-2017. Globally, Escherichia coli and Klebsiella pneumoniae represented 64% of identified CPE, while 70% of carbapenemases identified were metallo-beta-lactamases (VIM or NDM), with changes over time. CONCLUSIONS: In our center metallo-beta lactamases were the most frequently identified carbapenemases in Enterobacteriaceae and E. coli and K. pneumoniae the most frequently isolated pathogens carrying these enzymes. A proactive management strategy was effective in containing in-hospital spreading. PMID- 30477921 TI - Three-dimensional endodontic guide for adhesive fiber post removal: A dental technique. AB - This dental technique describes a protocol for adhesive fiber post removal using a prototyped endodontic guide. The removal of an adhesive fiber post is an important step for endodontic retreatment and the resolution of prosthetic problems. Computer-aided design and computer-aided manufacturing (CAD-CAM) technology was used to generate guides with prototyping and is a useful tool for fiber post removal. PMID- 30477922 TI - Effect on patient satisfaction of mandibular denture tooth arrangement in the neutral zone. AB - STATEMENT OF PROBLEM: The effect of the neutral zone (NZ) technique on different functional aspects (masticatory performance, speech, and muscle activity) has been studied objectively. Subjectively, some studies reported that their participants felt that NZ dentures were more stable, retentive, and comfortable than conventionally fabricated dentures. These studies, however, lacked a measurable assessment scale or a specifically designed questionnaire. PURPOSE: The purpose of this within-subject, crossover clinical trial was to investigate patient satisfaction levels in edentulous patients after rehabilitation with dentures fabricated using the NZ concept as compared with conventional dentures using a specific, question-oriented patient satisfaction questionnaire. MATERIAL AND METHODS: The clinical trial included 52 participants. Each received one set of conventional dentures and another fabricated based on the NZ concept with a 1 month wash-out period. Participants randomly chose 1 of 2 closed opaque envelopes with 2 denture sequences, either conventional then NZ or NZ then conventional. Hence, participants were blinded to the dentures they wore. Patient satisfaction with each denture type was assessed 6 weeks after insertion by a blinded staff member using a 5-scale questionnaire developed for the most important functional aspects (esthetics, masticatory ability, retention, stability, speech, and comfort). The Wilcoxon Signed Rank test was used to compare the satisfaction scores of the 2 denture types (alpha=.05). RESULTS: Patient satisfaction scores were significantly higher with the NZ dentures than with the conventional dentures in all aspects; P=.001 for question 2 (opinion of denture appearance) and P<.001 for all other questions. CONCLUSIONS: NZ dentures offer significantly higher levels of patient satisfaction than conventional dentures in all functional aspects (retention, stability, masticatory ability, and speech) as well as in comfort and appearance. PMID- 30477923 TI - Color and translucency of zirconia infrastructures and porcelain-layered systems. AB - STATEMENT OF PROBLEM: A good color match combined with a proper translucency match results in excellent esthetics for a metal-free restoration, yet basic color and translucency comparisons between available zirconia systems are not well described. PURPOSE: The purpose of this in vitro study was to compare the color and translucency of commercially available zirconia materials. MATERIAL AND METHODS: Eight specimen disks were formed in each of the single-layer (0.5-mm thick) groups and double-layer (0.5-mm zirconia with 1.0-mm porcelain) groups for each of 5 zirconia-based substructure systems. Colors on black, gray, and white backings were used to obtain CIEDE2000 color differences between the zirconia systems in the layering groups and to obtain relative translucency parameter (RTP) values. Color differences were compared with perceptibility and acceptability thresholds, and comparisons in RTP were made using analyses of variance and the Bonferroni corrected Student t tests (alpha=.05). RESULTS: The Shrout-Fleiss random set reliability for the duplicate L* determinations was 0.9992, 0.9756 for a*, and 0.9959 for b*. Although some mean color differences were below or at the perceptibility threshold, most differences were at or above the acceptability threshold. For the single-layer configuration, 1 material system had higher RTP values than every other material (P<.001), and another material had lower RTP values than every other material (P<.001). CONCLUSIONS: The results of this study present significant differences in both color and translucency among 5 ceramic substrate systems when studied in single layers. Perceivable and often unacceptable differences in color were also found among these materials when layered with porcelain. It is concluded that the esthetics of restorations which use a ceramic substrate is notably affected by the ceramic system used. PMID- 30477924 TI - Influence of different implant-abutment connection designs on the mechanical and biological behavior of single-tooth implants in the maxillary esthetic zone: A systematic review. AB - STATEMENT OF PROBLEM: A consensus regarding which implant-abutment connection type would perform best in the anterior maxilla is lacking. PURPOSE: The purpose of this systematic review was to determine the best implant-abutment connection type for anterior single-tooth implants considering esthetics, success, and survival rates. MATERIAL AND METHODS: An electronic search was conducted in MEDLINE, Scopus, Embase, and the Cochrane Library databases to identify clinical studies on single-tooth implants with external and internal hexagon, and/or Morse taper connections. These studies needed to describe at least one of the following outcomes: esthetic score, survival/success rate, or marginal bone loss. The included studies and reports were assessed for bias using the Cochrane risk of bias tool. RESULTS: Of the 891 articles identified, 29 were selected and analyzed. The most common technical complications were abutment screw loosening and crown-cement loosening, while dehiscence and recession were the most common biological complications. The most frequent complications were dehiscence for external hexagon, crown-cement loosening for the internal hexagon, and ceramic fracture for the Morse taper. Esthetics were favorable for all connections, but the internal hexagon performed better. However, better results for marginal bone loss, success, and survival were found for the Morse taper. The global annual failure rate was 0.90% and 0.2% for Morse taper, 0.3% for external hexagon, and 2.2% for internal hexagon. CONCLUSIONS: This review suggests that Morse taper performs better for survival, success, and marginal bone loss. Internal hexagon performed better for esthetic parameters. Additional controlled studies are needed to provide stronger evidence because the evidence generated in this study was considered low. PMID- 30477925 TI - Revisional surgery after removal of eroded adjustable gastric bands. AB - BACKGROUND: The aim of the study is to present surgical techniques and treatment outcomes for re-banding and sleeve gastrectomy as a revisional surgery after removing eroded adjustable gastric bands. METHODS: A retrospective analysis was performed to study laparoscopic re-banding or sleeve gastrectomy as revisional surgery for band erosion. Main outcome measures were success of therapeutic strategies, morbidity, body mass index, and percentage total excess weight loss before and after revision. RESULTS: From March 2013 to June 2017, a total of 11 patients underwent the revisional surgery. Six patients underwent sleeve gastrectomy at median 15.7 months (13.2-73.3 months) after band removal, and 5 patients gastric re-banding at median 5.4 months (3.1-43.8 months). One of the six patients that underwent sleeve gastrectomy was diagnosed to have a minor leak. No other critical postoperative complication was observed in each group. Median BMI at revision in the sleeve gastrectomy group was 32.7 kg/m2 (31.2-40.8 kg/m2). Median follow-up after revision was 33.8 months (15.5-63.7 months), and at last follow-up, median BMI was 26.4 kg/m2 (23.6-34.6 kg/m2), and median %TWL was 17.6% (9.5-31.5%). In the rebanding group, median BMI at revision was 30.7 kg/m2 (27.0-41.4 kg/m2). Median follow-up after revision was 25.5 months (13.5 45.4 months), and at last follow-up, median BMI was 23.5 kg/m2 (22.0-30.1 kg/m2) and median %TWL was 23.9% (9.1-29.0%). CONCLUSION: Given the surgical techniques adopted, both re-banding and sleeve gastrectomy were found to be safe and effective revisional surgery after removal of eroded gastric band. PMID- 30477926 TI - Comparative effectiveness and safety of warfarin and dabigatran in patients with non-valvular atrial fibrillation in Japan: A claims database analysis. AB - BACKGROUND: Antithrombotic therapy, including direct oral anticoagulants, is recommended in patients with non-valvular atrial fibrillation (NVAF) who are at intermediate-to-high risk of stroke. The aims of this study were to assess the patterns of oral anticoagulant (OAC) prescription in Japanese patients with NVAF and compare the effectiveness and safety of dabigatran and warfarin. METHODS: This was a retrospective observational study of adults with NVAF who initiated dabigatran or warfarin between March 14, 2011 and June 30, 2016, using electronic claims data of approximately 12.94 million patients from 230 hospitals. Propensity score matching was used to derive equal patient cohorts. Outcomes included the combined incidence of stroke, systemic embolism, and intracranial bleeding (primary endpoint) and the incidence of major bleeding (secondary endpoint). RESULTS: Overall, 400,884 patients were included. Among those prescribed an OAC, warfarin was the most common (34.3%). For the comparison of dabigatran and warfarin, 4606 patients were propensity-score matched in each cohort. Dabigatran recipients had lower incidences of stroke, systemic embolism, and intracranial bleeding [29.0 vs. 35.6 per 1000 patient-years; hazard ratio (HR), 0.72; 95% confidence interval (CI): 0.53-0.97; p=0.031] and major bleeding (6.4 vs. 11.3 per 1000 patient-years; HR, 0.55; 95% CI: 0.30-0.99; p=0.048). The most common type of bleeding in both groups was gastrointestinal and the incidence was lower in dabigatran recipients (1.6 vs. 6.4 per 1000 patient-years; HR, 0.24; 95% CI: 0.08-0.69; p=0.009). CONCLUSIONS: In Japan, dabigatran was associated with a lower risk of stroke, systemic embolism, and intracranial bleeding and major bleeding compared with warfarin in patients with NVAF. PMID- 30477927 TI - The outcome of adults born with pulmonary atresia: High morbidity and mortality irrespective of repair. AB - OBJECTIVES: To describe the characteristics and long-term outcome of a large adult cohort with pulmonary atresia. BACKGROUND: Patients with pulmonary atresia (PA) are a heterogeneous population in terms of anatomy, physiology and surgical history, and their management during adulthood remains challenging. METHODS: Data on all patients with PA followed in our center between January 2000 and March 2015 were recorded. Patients were classified into the following groups: PA with ventricular septal defect (PA-VSD, 1), PA with intact ventricular septum (PA-IVS, 2) and other miscellaneous PA (PA-other, 3). RESULTS: Two-hundred twenty-seven patients with PA were identified, 66.1% female, mean age 25.5 +/- 8.7 years. Over a median follow-up of 8.8 years, 49 (21.6%) patients had died: heart failure (n = 21, 42.8%) and sudden cardiac death (n = 8, 16.3%) were the main causes. There was no significant difference in mortality between the 3 Groups (p = 0.12) or between repaired and unrepaired patients in Group 1 (p = 0.16). Systemic ventricular dysfunction and resting oxygen saturations were the strongest predictors of mortality. Additionally, 116 (51%) patients were hospitalized, driven mainly by the need for invasive procedures, heart failure and arrhythmias. CONCLUSIONS: Adult survivors with pulmonary atresia have a high morbidity and mortality irrespective of underlying cardiac anatomy and previous reparative or palliative surgery. We present herewith predictors of outcome in adult life that may assist with their tertiary adult congenital care. PMID- 30477928 TI - First-in-man pulmonary artery stenting in children using the Bentley(r) BeGrowTM stent system for newborns and infants. AB - BACKGROUND: Stent implantation into growing vessels is a common treatment option in infants and children with congenital heart disease (CHD) and corresponding vessel lesions. After stent implantation in small children, repetitive stent redilations are frequently necessary to accommodate for somatic growth. Until now, all available stents have limited final expansion diameters. MATERIAL AND RESULTS: The new Bentley BeGrowTM stent system for newborns and infants is a L605 cobalt-chromium, pre-mounted, balloon expandable stent, which is compatible with a 4 French sheath and 0.014 inch guide wire thus allowing implantation in small vessels (4-6 mm). It offers a new, unique stent design that allows post-dilation steps up to O11.5 mm. While re-dilating up to O11.5 mm this new stent maintains radial force and shows uniform expansion with only minimal foreshortening. Predetermined breaking points allow the stent struts to break in a controlled manner when exceeding a diameter of 11.5 mm. Residual radial force maintains even after stent opening due to spiral arrangement of the predetermined breaking points. The 2 first-in-man pulmonary artery stent implantations in a newborn with univentricular circulation and a toddler with biventricular circulation are reported as part of the currently performed licencing trial (ClinicalTrials.govNCT03287024). CONCLUSION: The low-profile BeGrowTM stent system offers new treatment options for transcatheter stent implantations in newborns and infants. In our first experience, it can be effectively implanted. Longer follow-up will evaluate multiple, stepwise redilations and controlled stent strut breakage, which have the potential to accommodate for somatic vessel growth and/or subsequent implantation of larger stents. PMID- 30477929 TI - Sudden cardiac death risk prediction - As easy as ECG? PMID- 30477930 TI - Modeling and simulation of the impact behavior of soft polymeric-foam-based back protectors for winter sports. AB - OBJECTIVES: Winter sports are high-energy outdoor activities involving high velocities and acrobatic maneuvers, thus raising safety concerns. Specific studies on the impact mechanics of back protectors are very limited. In this study analytical and numerical models are developed to rationalize results of impact experiments and propose new design procedures for this kind of equipment. DESIGN: Different soft-shell solutions currently available on the market are compared. In particular, the role of dynamic material constitutive properties and of environmental temperature (which affects mainly material stiffness) on energy absorption capability are evaluated. METHODS: Starting from dynamic mechanical thermal characterization of the closed-cell polymeric foams constituting the protectors, we exploited analytical modeling and Finite Element Method simulations to interpret experimental data from drop weight impact test and to characterize protectors at different temperatures and after multiple impacts. RESULTS: The temperature and frequency dependent properties of these materials characterize their impact behavior. Modeling results are in good agreement with impact tests. Results demonstrate how ergonomic soft-shell solution provides an advantage with respect to traditional hard-shell in terms of impact protection. Moreover, it can maintain nearly unaltered its protective properties after multiple impacts on the same point. CONCLUSIONS: The coupled analytical simulation approach here presented could be extensively used to predict the impact behavior of such equipment, starting from material characterization, allowing to save costs and time for physical prototyping and tests for design and optimization. PMID- 30477931 TI - Female rugby union injuries in New Zealand: A review of five years (2013-2017) of Accident Compensation Corporation moderate to severe claims and costs. AB - OBJECTIVES: To provide epidemiological data and related costs for moderate-to serious and serious injury claims for women's rugby union in New Zealand. DESIGN: A retrospective analytical review of injury entitlement claims for women's rugby from 2013 to 2017. METHODS: Data were analysed by year of competition, age, body site and injury type for total and moderate-to-severe (MSC) Accident Compensation Corporation (ACC) claims and costs. RESULTS: Over 2013 to 2017 there were 26,070 total claims for female rugby union costing $18,440,812 [AD$16,956,998]. The 15 19-year age group recorded 40% (n=1,009) of the total female rugby union Moderate to-serious and serious (MSC) claims and 41% ($5,419,157 [AD$4,983,112]) of the total female rugby union MSC costs. The knee was the most commonly recorded injury site accounting for 40.3% (n=1,007) of MSC claims and 46.9% ($6,229,714 [AD$5,728732]) of MSC costs with an average cost of $1,245,943 +/-$217,796 [AD$595,351 +/-AD$104,070] per-year for female rugby union. CONCLUSIONS: This is the first study to report the nature and related costs for moderate-to-serious and serious injury claims for women's rugby union in New Zealand. A total of 26,070 injury claims were lodged over the duration of the study but only 9.6% (n=2,501) of these were classified as MSC injury entitlement claims. Participants 25 years and older accounted for 31% of the female rugby union player claims. Females in the over 35-year age groups compete against younger participants which may account for the higher mean cost per-claim seen as the age groups increase in years until they retire from the game. PMID- 30477932 TI - Increased amino acid turnover and myofibrillar protein breakdown in advanced cancer are associated with muscle weakness and impaired physical function. AB - BACKGROUND & AIMS: Muscle wasting in cancer negatively affects physical function and quality of life. This study investigates amino acid metabolism and the association with muscle mass and function in patients with cancer. METHODS: In 16 patients with advanced cancer undergoing chemotherapy and 16 healthy controls, we administered an intravenous pulse and prime of stable amino acid tracers. We took blood samples to measure the Rate of appearance (Ra), whole body production (WBP), clearance (Cl), and post absorptive whole body net protein breakdown (WBnetPB). Plasma amino acid concentrations and enrichments were analysed by LC MS/MS. We assessed muscle mass, handgrip/leg/respiratory muscle strength and reported physical activity, quality of life, and physical function. RESULTS: Muscle strength was lower in cancer patients than in healthy controls. Total and limb muscle mass, reported physical activity and WBnetPB were comparable. WBP and Cl of tau-methylhistidine, leucine, glutamine and taurine were higher in cancer patients as well as glycine Cl. Amino acid metabolism was correlated with low muscle mass, strength, physical function and quality of life. CONCLUSIONS: Myofibrillar protein breakdown and production of amino acids involved in muscle contractility are up regulated in patients with cancer undergoing chemotherapy and related to muscle weakness and reduced physical outcomes. PMID- 30477933 TI - Translation and content validity of a brief scale of mindfulness for Peruvian adolescents. AB - OBJECTIVE: To translate into Spanish and analyze the evidence of validity based on the content of the items in the brief version of the Mindful Attention Awareness Scale of 5 items (MAAS-5). METHOD: An instrumental study that involved the translation to Spanish of the items of the short version of the MAAS-5 scale, using the back-translation procedure. We analyzed the evidence of validity based on the test content, with the participation of a total of 14 expert judges. The degree of clarity, coherence and relevance of the items was quantified using the Aiken V coefficient and their 95% confidence intervals using an ad hoc template developed in the MS Excel program. RESULTS: The items of the MAAS-5 show favourable evaluations of their clarity, coherence and relevance, where all the values of V were statistically significant and greater than 0.70. On the other hand, the lower limit of 95% confidence intervals of all the items satisfies the criterion at population level (Li?0.59). CONCLUSION: The empirical evidence of validity based on the test content of the MAAS-5 reports that all are sufficiently relevant, coherent and clear to adequately represent the construct mindfulness, both at sample and population level. This suggests that the MAAS-5 can be a brief and useful measure to assess mindfulness. On the other hand we suggest carrying out further studies that analyze other sources of evidence of validity of the MAAS-5. PMID- 30477934 TI - Assessment of the knowledge of usage of blood and blood products amongst medical doctors in the Department of Medicine at the Faculty of Health Sciences, University of the Witwatersrand affiliated academic hospitals. AB - BACKGROUND: Rational and appropriate use of blood and blood products is important in a resource limited setting like South Africa. Proper education is required in decision-making and management with regard to blood transfusion. Status of the current knowledge of blood transfusion practice is also necessary in order to identify target areas of teaching and patient management. OBJECTIVE: To assess the knowledge regarding blood and blood products among doctors of varying ranks at the University of the Witwatersrand affiliated academic hospitals. RESEARCH DESIGN AND METHODS: This is an observational, descriptive study using a self administered questionnaire, comprising of 40 questions, equally divided into 6 sections covering different areas of transfusion medicine. Demographics of the participants and an opinion on how to impart further information was also included. RESULTS: A response rate of 33% was obtained from the distributed questionnaires. After grouping medical professionals together, an average score of 61% was obtained. As individual groups, the consultants achieved the highest score of 64%, while the interns, who averaged 56%, achieved the lowest score. The medical officers and registrars averaged 63%, while community service doctors averaged 58%. Participants scored the best in the section pertaining to 'consent' averaging 87%. This was followed by 64%, achieved for the section regarding 'adverse effects'. The section regarding 'red blood cell usage' and 'blood product ordering' was scored at 60%, while the section on 'platelet usage' attained a score of 44%. The lowest score was achieved in the section regarding 'plasma product usage', 30%. A statistically significant gap in knowledge (p = 0.0139) was noted from intern up to medical officer level, after which the increase in knowledge up to consultant level was not found to be statistically significantly different. CONCLUSIONS: The overall results obtained appear to be suboptimal and can be improved upon. Formalized and on-going teaching around blood and blood product usage is required at both undergraduate and postgraduate levels, to ensure that this scarce, but invaluable resource is used judiciously and appropriately. PMID- 30477935 TI - Automated antibody identification using the Bio-Rad IH-AbID software. PMID- 30477936 TI - Analysis of hospital blood components wastage in Iran (2005-2015). AB - BACK GROUND: Although blood components are precious resources, their wastage is still a problem in hospitals all over the world. As no comprehensive study has evaluated hospital wastage in Iran, the main aim of the study was to identify the wastage as a percentage of issue during 2005-2015 and the secondary objective was to focus on the reasons of the blood components wastage. STUDY DESIGNS AND METHODS: Wastage as a percentage of issues was calculated for red blood cells, plasma and platelet concentrate separately. Also, for each product, the percentage of wastage was calculated as the number of units wasted for each reason divided by the total number of units wasted. RESULTS: The wastage rate of red blood cells, plasma and platelet concentrate was 5.7 +/- 0.7, 1.4 +/- 0.4, and 3.2 +/- 0.5, respectively. The main cause of red blood cells, plasma, and platelet concentrate wastage was date expiry and reserved/returned units of operating room and or ward. In 2015 compared to 2005, despite a significant decrease (p value<0.0001) in red blood cells and plasma expired units, there was a remarkable increase in expired PC units (p value<0.0001). In contrast to expired units, there was a significant increase (p value<0.0001) in reserved/returned units of operating room and or ward for red blood cells and plasma. CONCLUSION: Time expiry and reserved/returned from operating room were the most important reasons of blood component wastage. The percentage of wastage could be decreased by implementing MSBOS program and designing a software application for efficient management of reserved hospital inventories. PMID- 30477938 TI - Metastatic osteosarcoma challenged by regorafenib. PMID- 30477937 TI - Efficacy and safety of regorafenib in adult patients with metastatic osteosarcoma: a non-comparative, randomised, double-blind, placebo-controlled, phase 2 study. AB - BACKGROUND: Regorafenib has proven activity in patients with pretreated gastrointestinal stromal tumours and colorectal and hepatocellular carcinoma. We designed REGOBONE to assess the efficacy and safety of regorafenib for patients with progressive metastatic osteosarcoma and other bone sarcomas. This trial comprised four parallel independent cohorts: osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma. In this Article, we report the results of the osteosarcoma cohort. METHODS: In this non-comparative, double-blind, placebo controlled, phase 2 trial, patients aged 10 years or older with histologically confirmed osteosarcoma whose disease had progressed after treatment with one to two previous lines of chemotherapy for metastatic disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled. Patients were randomly assigned (2:1) to receive either oral regorafenib (160 mg/day, for 21 of 28 days) or matching placebo. Patients in both groups also received best supportive care. Randomisation was done using a web-based system and was stratified (permuted block) by age at inclusion (<18 vs >=18 years old). Investigators and patients were masked to treatment allocation. Patients in the placebo group, after centrally confirmed progressive disease, could cross over to receive regorafenib. The primary endpoint was the proportion of patients without disease progression at 8 weeks. Analyses were done by modified intention to treat (ie, patients without any major entry criteria violation who initiated masked study drug treatment were included). All participants who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02389244, and the results presented here are the final analysis of the osteosarcoma cohort (others cohorts are ongoing). FINDINGS: Between Oct 10, 2014, and April 4, 2017, 43 adult patients were enrolled from 13 French comprehensive cancer centres. All patients received at least one dose of assigned treatment and were evaluable for safety; five patients were excluded for major protocol violations (two in the placebo group and three in the regorafenib group), leaving 38 patients who were evaluable for efficacy (12 in the placebo group and 26 in the regorafenib group). 17 of 26 patients (65%; one-sided 95% CI 47%) in the regorafenib group were non-progressive at 8 weeks compared with no patients in the placebo group. Ten patients in the placebo group crossed over to receive open-label regorafenib after centrally confirmed disease progression. 13 treatment-related serious adverse events occurred in seven (24%) of 29 patients in the regorafenib group versus none of 14 patients in the placebo group. The most common grade 3 or worse treatment-related adverse events during the double-blind period of treatment included hypertension (in seven [24%] of 29 patients in the regorafenib group vs none in the placebo group), hand-foot skin reaction (three [10%] vs none), fatigue (three [10%] vs one [3%]), hypophosphataemia (three [10%] vs none), and chest pain (three [10%] vs none). No treatment-related deaths occurred. INTERPRETATION: Regorafenib demonstrated clinically meaningful antitumour activity in adult patients with recurrent, progressive, metastatic osteosarcoma after failure of conventional chemotherapy, with a positive effect on delaying disease progression. Regorafenib should be further evaluated in the setting of advanced disease as well as potentially earlier in the disease course for patients at high risk of relapse. Regorafenib might have an important therapeutic role as an agent complementary to standard cytotoxic chemotherapy in the therapeutic armamentarium against osteosarcoma. FUNDING: Bayer HealthCare. PMID- 30477939 TI - Factors associated with postoperative renal dysfunction and the subsequent impact on survival after open juxtarenal abdominal aortic aneurysm repair. AB - BACKGROUND: Renal dysfunction is a well-described complication of open juxtarenal abdominal aortic aneurysm repair, but the associated risk factors and corresponding impact on survival are not well described. METHODS: We identified all patients not on hemodialysis undergoing open repair of nonruptured juxtarenal aneurysms in the Vascular Quality Initiative from 2003 to 2017. We used mixed effects logistic regression to determine factors associated with in-hospital postoperative renal dysfunction, including acute kidney injury (AKI, defined as serum creatinine concentration increase >0.5 mg/dL) and new renal replacement therapy (RRT), as well as the association between postoperative renal function and perioperative mortality. Cox regression was used to determine the association between postoperative renal complications and long-term survival. RESULTS: We identified 2635 open juxtarenal repairs, of which 621 (24%) were complicated by AKI. The majority of these (20% of the overall cohort) were AKI alone, but 2.2% required temporary RRT and an additional 1.7% were permanently dialysis dependent. Factors independently associated with postoperative renal dysfunction included renal-visceral ischemia time (per minute: odds ratio [OR], 1.01 [1.01 1.02]; P < .001), clamp site (above both renal arteries: OR, 1.4 [1.1-1.8; P = .02]; supraceliac: OR, 1.7 [1.1-2.5; P = .01]), statin use (OR, 1.5 [1.1-2.0]; P = .01), male sex (OR, 1.7 [1.2-2.2]; P = .002), and preoperative renal function (glomerular filtration rate [GFR] of 45-60 mL/min/1.73 m2: OR, 1.8 [1.3-2.5; P < .001]; GFR of 30-45 mL/min/1.73 m2: OR, 1.9 [1.2-2.8; P = .003]; GFR of <30 mL/min/1.73 m2: OR, 6.2 [3.1-12.2; P < .001]). When renal-visceral ischemia time was categorized, there was no difference in risk of postoperative renal dysfunction until >25 minutes, but risk increased stepwise thereafter (25-39 minutes: OR, 1.6 [1.2-2.1; P = .004]; 40+ minutes: OR, 2.6 [1.9-3.5; P < .001]). Neither mannitol nor the use of cold renal perfusion was associated with renal complications or mortality in the overall cohort, but cold renal perfusion was associated with lower risk of AKI when clamp times exceeded 25 minutes (OR, 0.4 [0.2-0.97]; P = .041). Postoperative renal dysfunction was associated with higher adjusted perioperative mortality (AKI: OR, 2.6 [1.4-5.0; P < .01]; RRT: OR, 10.5 [4.0-27.6; P < .001]) and significantly higher risk of long-term mortality (AKI: hazard ratio, 1.5 [1.0-2.1; P = .049]; RRT: hazard ratio, 5.8 [3.2-10.3; P < .001]). CONCLUSIONS: Postoperative renal dysfunction, even a mild elevation in creatinine concentration, is associated with higher perioperative and long-term mortality. Although the routine use of mannitol and cold renal perfusion was not associated with postoperative renal dysfunction after open juxtarenal repair, cold renal perfusion was associated with lower risk of AKI if clamp times exceeded 25 minutes. PMID- 30477940 TI - Predictors of perioperative and late survival in octogenarians undergoing elective endovascular abdominal aortic repair. AB - OBJECTIVE: The appropriateness of endovascular aneurysm repair (EVAR) of uncomplicated abdominal aortic aneurysm depends on the risk-benefit ratio, particularly in elderly patients with short life expectancy. The aim of this study was to assess the efficacy of EVAR in >80-year-old patients by evaluating their postoperative survival and analyzing the possible predictors of late mortality. METHODS: All consecutive patients aged >80 years undergoing elective EVAR from 2006 to 2015 were prospectively evaluated. The 30-day mortality and long-term survival were assessed, and independent risk factors for mortality were determined by multivariate logistic and Cox analysis. RESULTS: Of a total of 1135 EVARs performed in a 10-year period, 201 (18%) occurred in patients older than 80 years. The median age was 84 years (interquartile range, 3 years), and 85% were male. Thirty-four patients (17%) had a score of 4 according to the American Society of Anesthesiologists (ASA) classification. Overall 30-day mortality was 2% (n = 4); it was significantly higher in those with ASA score of 4 compared with ASA score <4 (9.4% vs 0.6%; P = .04) and was also confirmed by multivariate analysis (odds ratio, 12.7; 95% confidence interval [CI], 1.1-141.8; P = .04). The mean follow-up was 36 +/- 18 months, and the overall survival at 1 year, 3 years, and 5 years was 85% +/- 2%, 77% +/- 3%, and 52% +/- 4%, respectively. Using multivariate Cox regression, ASA score of 4 and peripheral artery obstructive disease (PAOD) were the only independent predictors for midterm mortality (hazard ratio of 2.0 [95% CI, 1.2-2.9; P = .04] and 3.07 [95% CI, 1.06 5.2; P = .04], respectively). The 2-year survival was significantly influenced by the presence of both (ASA score of 4 and PAOD; survival, 33% +/- 2%) or one (ASA score of 4 or PAOD; survival, 67% +/- 8%) of the two independent predictors. If neither ASA score of 4 nor PAOD was present, survival was significantly improved (92% +/- 3%; P = .02). CONCLUSIONS: The performance of EVAR in >80-year-old patients is associated with an overall early mortality rate as low as 2%. In patients with no or only one risk factor, the survival rate warrants the treatment of abdominal aortic aneurysm; in contrast, patients with ASA score of 4 and PAOD have a significantly higher mortality rate and reduction of life expectancy. PMID- 30477941 TI - Single-center experience with an inner branched arch endograft. AB - OBJECTIVE: Whereas open repair is the "gold standard" for most aortic arch diseases, a subgroup of patients might benefit from an endovascular approach. The introduction of branched stent grafts with dedicated design to address the challenges of the ascending aorta and the aortic arch has opened an entirely new area of treatment for these patients. We investigated the early outcomes of branched thoracic endovascular aortic repair (b-TEVAR) in various types of disease of the aortic arch. METHODS: A retrospective analysis was conducted of prospectively collected data from a single center of all consecutive patients treated with b-TEVAR. The indication for elective endovascular repair was consented in an interdisciplinary case conference. All patients were treated with a custom-made inner branched arch endograft with two internal branches (Cook Medical, Bloomington, Ind) and left-sided carotid-subclavian bypass. Study end points were technical success, 30-day mortality, and complications as well as late complications and reinterventions. RESULTS: Between 2012 and 2017, there were 54 patients (38 male; median age, 71 years) treated with diseases of the aortic arch. Indications for therapy involved degenerative aortic arch or proximal descending aortic aneurysms requiring arch repair (n = 24), dissection with or without false lumen aneurysms (n = 26), and penetrating aortic ulcers (n = 4). Forty-three cases (80%) were performed electively and 11 urgently for contained ruptures (n = 3) or symptomatic aneurysms (n = 8) with endografts already available for the patient or with grafts of other patients with similar anatomy. Technical success was achieved in 53 cases (98%). The 30-day mortality and major stroke incidence were 5.5% (3/54) and 5.5% (3/54), respectively; in hospital mortality was 7.4% (n = 4), and minor strokes (including asymptomatic new cerebral lesions) occurred in 5.5% (n = 3). There were two cases of transient spinal cord ischemia with complete recovery and one of paraplegia. No retrograde type A dissections or cardiac injuries were observed. Three early stent graft related reinterventions were necessary to correct proximal endograft kinking with type IA endoleak in one patient, a bridging stent graft stenosis in another patient, and false lumen persistent perfusion from dissected supra-aortic vessels in the last patient. Mean in-hospital stay was 14 +/- 8 days. During a mean follow-up of 12 +/- 9 months, three nonaorta-related deaths and one aorta-related death distal to the arch repair were observed. CONCLUSIONS: Treatment of aortic arch diseases with b-TEVAR is feasible and safe with acceptable mortality and stroke rates. PMID- 30477942 TI - Anatomic predictors for late mortality after standard endovascular aneurysm repair. AB - OBJECTIVE: Abdominal aortic aneurysm (AAA) management involves a decision process that takes into account anatomic characteristics, surgical risks, patients' preferences, and expected survival. Whereas larger AAA diameter has been associated with increased mortality after both standard endovascular aneurysm repair (EVAR) and open repair, it is unclear whether survival after EVAR is influenced by other anatomic characteristics. The purpose of this study was to determine the importance of baseline anatomic features on survival after EVAR. METHODS: All patients treated at a tertiary teaching center with EVAR for intact standard infrarenal AAA from 2000 to 2014 were included. The civil data registry was queried to determine survival status; causes of death were obtained from death certificates. The primary study end point was to determine the impact of baseline morphologic features on all-cause and cardiovascular mortality after EVAR. RESULTS: This study included 404 EVAR patients (12.1% women; mean age, 73 years) with a median follow-up of 5.8 years (interquartile range, 3.1-7.4 years). The 5- and 10-year overall survival rates for the entire population after EVAR were 70% (95% confidence interval [CI], 66%-75%) and 43% (95% CI, 37%-50%), respectively. Only AAA diameter >70 mm (hazard ratio [HR], 1.75; 95% CI, 1.20 3.56) was identified as an independent anatomic predictor of all-cause mortality. Death due to cardiovascular causes occurred in 60 (38.5%) patients. Aneurysm related mortality was responsible for six of the cardiovascular-related deaths. In multivariable analysis, both neck diameter >=30 mm (HR, 2.16; 95% CI, 1.05 4.43) and AAA diameter >70 mm (HR, 2.45; 95% CI, 1.34-4.46) were identified as independent morphologic risk factors for cardiovascular mortality, whereas >25% circumferential neck thrombus (HR, 0.32; 95% CI, 0.13-0.77) was protective. CONCLUSIONS: This study suggests that patients with AAA diameters >70 mm are at increased risk of all-cause and cardiovascular mortality. In addition, patients with infrarenal neck diameters >=30 mm have a greater risk of cardiovascular mortality, although AAA-related deaths were not more frequent in this group of patients. Consequently, a more aggressive management of cardiovascular medical comorbidities may be warranted to improve survival after standard EVAR in these patients. PMID- 30477943 TI - Risk factors for early and late mortality after fenestrated and branched endovascular repair of complex aneurysms. AB - BACKGROUND: The objective of this study was to evaluate outcomes after fenestrated and branched endovascular aneurysm repair (F-BEVAR) performed in high risk patients to treat pararenal (PR) aneurysms and thoracoabdominal aortic aneurysms (TAAAs) and to identify those patients likely to benefit from this treatment. METHODS: A prospective single-center review of patients treated electively for PR aneurysm and TAAA using F-BEVAR between 2004 and 2016 was performed. Survival was estimated using the Kaplan-Meier method. Risk factors associated with 30-day morbidity and mortality during follow-up were determined using multivariate statistical techniques and a Cox regression model including all variables that were significant on univariate analysis (P < .05). RESULTS: There were 468 patients (median age, 71.6 years) identified, with American Society of Anesthesiologists score >=3 in 94.7%. There were 221 (47.2%) type I to type III TAAAs and 247 (52.8%) type IV and type V TAAAs and PR aneurysms, with a median diameter of 58 mm. Technical success for target vessel stenting was 99.1% (1493/1506). The 30-day mortality rate was 4.9% (23 patients). The spinal cord ischemia rate was 3.8% (18 patients). Twenty patients (4.3%) required postoperative dialysis and four patients (0.8%) long-term dialysis after discharge. Median follow-up was 29 months. Survival at 1 year, 3 years, and 5 years was 86.7% (95% confidence interval [CI], 83.1-89.6), 73.3% (95% CI, 68.3 77.6), and 59.6% (95% CI, 53.4-65.2), respectively. Freedom from any target vessel occlusion and freedom from secondary procedures were 96.2% (95% CI, 93.8 97.7) and 88.2% (95% CI, 84.8-90.9) at 1 year and 90.0% (95% CI, 84.5-91.9) and 70.2% (95% CI, 63.9-75.6) at 5 years, respectively. In multivariate analysis, early mortality was associated with procedure time (hazard ratio [HR], 1.007 per minute; 95% CI, 1.003-1.010; P < .001), TAAA preoperative diameter (HR, 1.053 per millimeter; 95% CI, 1.020-1.087; P = .001), and chronic kidney disease (HR, 3.139; 95% CI, 1.369-7.196; P = .007). Mortality during the first 24 months of follow-up was associated with Crawford types I to III (HR, 1.526; 95% CI, 1.061 2.196; P = .023) compared with infradiaphragmatic repairs, chronic kidney disease (HR, 1.874; 95% CI, 1.294-2.712; P < .001), and TAAA preoperative diameter (HR, 1.027 per millimeter; 95% CI, 1.010-1.044; P = .002). In addition to these risk factors, mortality after 24 months of follow-up was also associated with age at repair (HR, 1.055 per year; 95% CI, 1.021-1.090; P = .001). CONCLUSIONS: F-BEVAR performed in high-risk patients is associated with favorable outcomes. Judicious selection of patients should take into consideration the reported risk factors associated with early and late mortality. PMID- 30477944 TI - Adaptive super-twisting fractional-order nonsingular terminal sliding mode control of cable-driven manipulators. AB - This paper proposes a novel adaptive super-twisting fractional-order nonsingular terminal sliding mode (AST-FONTSM) control scheme using time delay estimation (TDE) for the cable-driven manipulators. The designed control scheme utilizes TDE to obtain the estimation of system dynamics, and therefore no system dynamic model information will be required. Afterwards, AST and FONTSM schemes are applied to ensure good control performance in both reaching and sliding mode phases. Due to the adoption of AST scheme, good robustness and high control precision are obtained in the reaching phase, while the boundary information of the lumped uncertainties will be no longer required. Thanks to the utilization of FONTSM error dynamics, fast convergence and accurate tracking and strong robustness can be simultaneously ensured in the sliding mode phase. Corresponding comparative simulation and experimental results demonstrate the effectiveness and superiorities of our proposed method over the existing control methods. PMID- 30477945 TI - The Application of the First Year Inventory for ASD Screening in China. AB - PURPOSE: The First Year Inventory (FYI) is a parent-report instrument, and is developed to assess behaviors of 12-month-old infants that could suggest risk for an eventual diagnosis of autism. This study was designed to examine the application of the FYI in the Chinese community. DESIGN AND METHODS: FYIs were completed at a community health center by 541 families during the child's physical examination at 12 months of age from 2013 to 2015. The weighted risk scores used in this study were based on US norms, and compared the FYI differences between China and the U.S. RESULTS: The total risk scores ranged from 5 to 42 points; the 95th percentile cutoff was 27.00(9.8 points higher than the 95th percentile cutoff in the US), the 98th percentile cutoff was 29.66(7.04 points higher than the 98th percentile cutoff in the US), and the 99th percentile cutoff was 31.83. Higher risk scores were found for boys than girls. Mothers with a junior college education reported significantly higher FYI risk scores than other three groups including high school, college graduates and post-graduates. CONCLUSIONS: There were no significant effects of birth parity, investigator, or investigation year on risk scores. Large-scale longitudinal research is encouraged in the future to develop an early detection model of autism in China. PMID- 30477946 TI - Oncology is Missing out on the FOAM Party. PMID- 30477947 TI - Is it Time to Have a Further Debate on Separating Radiation and Medical Oncology Specialties Rather than Continue the Clinical Oncology Model? PMID- 30477948 TI - When Residents Hear the Bell Toll. PMID- 30477949 TI - Machine Learning Algorithms Utilizing Functional Respiratory Imaging May Predict COPD Exacerbations. AB - RATIONALE AND OBJECTIVES: Acute chronic obstructive pulmonary disease exacerbations (AECOPD) have a significant negative impact on the quality of life and accelerate progression of the disease. Functional respiratory imaging (FRI) has the potential to better characterize this disease. The purpose of this study was to identify FRI parameters specific to AECOPD and assess their ability to predict future AECOPD, by use of machine learning algorithms, enabling a better understanding and quantification of disease manifestation and progression. MATERIALS AND METHODS: A multicenter cohort of 62 patients with COPD was analyzed. FRI obtained from baseline high resolution CT data (unenhanced and volume gated), clinical, and pulmonary function test were analyzed and incorporated into machine learning algorithms. RESULTS: A total of 11 baseline FRI parameters could significantly distinguish ( p < 0.05) the development of AECOPD from a stable period. In contrast, no baseline clinical or pulmonary function test parameters allowed significant classification. Furthermore, using Support Vector Machines, an accuracy of 80.65% and positive predictive value of 82.35% could be obtained by combining baseline FRI features such as total specific image-based airway volume and total specific image-based airway resistance, measured at functional residual capacity. Patients who developed an AECOPD, showed significantly smaller airway volumes and (hence) significantly higher airway resistances at baseline. CONCLUSION: This study indicates that FRI is a sensitive tool (PPV 82.35%) for predicting future AECOPD on a patient specific level in contrast to classical clinical parameters. PMID- 30477950 TI - Predictive factors of pathological lateral pelvic lymph node metastasis in patients without clinical lateral pelvic lymph node metastasis (clinical stage II/III): The analysis of data from the clinical trial (JCOG0212). AB - BACKGROUND: Mesorectal excision (ME) is the standard surgical procedure for lower rectal cancer. However, in Japan, total or tumor-specific ME with lateral pelvic lymph node dissection (LLND) is the standard surgical procedure for patients with clinical stages II or III lower rectal cancer, because lateral pelvic lymph node metastasis occasionally occurs in these patients. The aim of study was to elucidate the predictive factors of pathological lateral pelvic lymph node metastasis in patients without clinical lateral pelvic lymph node metastasis. METHODS: Data form the clinical trial (JCOG0212) was analyzed. The JCOG0212 was a randomized controlled trial to confirm the non-inferiority of mesorectal excision alone to mesorectal excision with lateral lymph node dissection for clinical stage II/III patients who don't have clinical lateral pelvic lymph node metastasis in terms of relapse free survival. This study was conducted at a multitude of institution33 major hospitals in Japan. Among the 351 patients who underwent lateral lymph node dissection in the JCOG0212 study, 328 patients were included in this study. Associations between pathological lateral pelvic lymph node metastasis and preoperative and postoperative factors were investigated. The preoperative factors were age, sex, clinical stage, tumor location, distance from anal verge, tumor size, and short-axis diameter of lateral pelvic lymph node on computed tomography and the postoperative factors were pathological T, pathological N, and histological grade. RESULTS: Among the 328 patients, 24 (7.3%) had pathological lateral pelvic lymph node metastasis. In multivariable analysis of the preoperative factors, patient age (p = 0.067), tumor location (p = 0.025), and short-axis diameter of lateral pelvic lymph node (p = 0.002) were significantly associated with pathological lateral pelvic lymph node metastasis. CONCLUSIONS: Patient age, tumor location, and short-axis diameter of lateral pelvic lymph node were predictive factors of pathological lateral pelvic lymph node metastasis. PMID- 30477951 TI - Circulating Galectin-3 Following Heart Transplant: Long-Term Dynamics and Prognostic Value. AB - INTRODUCTION AND OBJECTIVES: Circulating galectin-3 (Gal-3) is elevated and significantly correlates with all-cause and cardiovascular mortality in patients with heart failure. However, the relationship between serum Gal-3 and heart transplant (HT) outcomes is unclear. The aim of this study was to describe the longitudinal trend and prognostic value of Gal-3 levels after HT. METHODS: Banked serum samples were available from 122 HT recipients, collected before transplant and at 1, 3, 6, and 12 months posttransplant. Gal-3 levels in these serum samples were measured by enzyme immune assay. Multivariable Cox regression was performed to determine the prognostic value of 12-month posttransplant Gal-3 serum levels. The primary endpoint was the composite variable all-cause death or graft failure over long-term posttransplant follow-up. RESULTS: Circulating Gal-3 concentration steadily decreased during the first year after HT (median values: pretransplant, 19.1 ng/mL; 1-year posttransplant, 14.6 ng/mL; P<.001). Circulating Gal-3 levels 1-year posttransplant were associated with an increased risk of all-cause death or graft failure (adjusted HR per 1 ng/mL, 1.04; 95%CI, 1.01-1.08; P=.008). The predictive accuracy of this biomarker was moderate (area under the receiver operator curve 0.72 (95%CI, 0.60-0.82; P<.001). CONCLUSIONS: Circulating Gal-3 steadily decreased during the first year after HT. However, 1-year posttransplant Gal-3 serum levels that remained elevated were associated with increased long term risk of death and graft failure. PMID- 30477952 TI - First report of mcr-1-harboring Salmonella enterica serovar Schwarzengrund isolated from poultry meat in Brazil. AB - Brazilian poultry meat samples were screened for colistin-resistant Salmonella enterica. Sixty Salmonella isolates were tested for in vitro colistin resistance and mcr-1, mcr-2, mcr-3 and mcr-4 genes. Two isolates harbored the mcr-1 gene and whole-genome analysis determined the serovar to be Schwarzengrund, ST96, harboring the IncX4 plasmid. This is the first report of mcr-1-harboring Salmonella enterica serovar Schwarzengrund in Brazil. PMID- 30477953 TI - Reliability of the Verigene system for the identification for Gram-positive Bacteria and detection of antimicrobial resistance markers from children with bacteremia. AB - BACKGROUND: Targeted antimicrobial therapy can reduce morbidity in patients with sepsis. Molecular methodologies used in the clinical laboratory can provide information about infectious agents faster than traditional culture methods. Using molecular information to make clinical decisions more quickly has been shown to improve patient outcomes, and reduce length of stay and healthcare cost in adults. Its effect on pediatric care is less well described. METHODS: Blood cultures growing Gram-positive cocci or Gram-positive bacilli on Gram stain were evaluated by molecular and traditional methodologies. Results from the molecular platform, Luminex Verigene(r) Blood Culture - Gram-positive Panel (BC-GP) were compared to results from standard culture and susceptibility testing (VitekTM MS, VitekTM, E-test(r)). Overall statistical agreement is evaluated. RESULTS: 1231 positive pediatric blood cultures grew single isolates detectable by the BC-GP panel. 899 were correctly identified to species, 282 to genus, 50 isolates were not detected. All organisms detected by BC-GP that grew in single isolate cultures were identified as the same organism by VitekTM MS with the exception of 7 organisms.112 cultures were found to have polymicrobial growth of Gram-positive organisms. Excellent overall agreement was noted for antimicrobial resistance markers with only 5 samples displaying discordant results. DISCUSSION: In general, clinicians can use the identification and antimicrobial resistance marker data gained from Luminex Verigene(r) BC-GP with confidence to alter empiric coverage. Rare instances of disagreement with traditional culture data led to maintaining the empiric clinical approach and did not result in patient harm. PMID- 30477954 TI - In vitro activity of telavancin against Staphylococcus aureus causing pneumonia or skin and skin structure infections with concomitant bloodstream infections in United States hospitals (2012-2016). AB - Pneumonia and skin and skin structure infections (SSSIs) caused by S. aureus can lead to serious bloodstream infections (BSIs). This study reports on potent telavancin in vitro activity (MIC90, 0.06 MUg/mL; 100% susceptible) against 674 US S. aureus causing pneumonia or SSSI with associated BSI in hospitalized patients during 2012-2016. PMID- 30477955 TI - Combination of oximetry and sleep questionnaires as screening tools for CPAP initiation in patients with obstructive sleep apnea. AB - OBJECTIVES: Obstructive sleep apnea syndrome (OSA) is a cause of high morbidity and mortality so diagnosis and treatment is essential. Questionnaires and oximetry have been used for OSA screening. AIM: To evaluate the clinical utility of different sleep questionnaires (Stop Bang (S-B), Berlin (BQ), Epworth Sleepiness Scale (ESS)) in deciding on treatment with Continuous Positive Airway Pressure (CPAP) and to examine whether the combination of the questionnaires alone or with oximetry improves their predictive value for CPAP initiation. METHODS: Patients visiting a Sleep Clinic were prospectively studied. They completed the questionnaires. Home oximetry and in laboratory polysomnography (PSG) were performed within 3-20 days. Patients received CPAP if they were symptomatic with AHI>=5 or had AHI>15. RESULTS: 204 patients were studied (77.5%males, mean age 51.8+/-13.8 years, BMI 32.8+/-6.2kg/m2). There was a good correlation between Oxygen Desaturation Index of oximetry (ODIox) and ODI of PSG (r=0.95, p<0.0001) and between ODIox and AHI (r=0.811, p<0.0001). ODIox>=15 presented sensitivity 89.3%, specificity 83.5%, PPV 87% NPV 86.4% for CPAP initiation. ESS had the best specificity (68.6%) and PPV (68.6%) and S-B had the highest sensitivity (98%) and NPV (80%) but the lowest specificity (11%) for CPAP initiation. The combination of different questionnaires or questionnaires with oximetry did not improve their predictive value for CPAP initiation. CONCLUSIONS: Oximetry accurately predicted CPAP initiation. Questionnaires alone had limited value as screening tools for CPAP initiation; the combination of oximetry with questionnaires did not improve their predictive value. PMID- 30477956 TI - Panoramic radiography is of limited value in the evaluation of maxillary sinus disease. AB - OBJECTIVES: The aim of this study was to determine (1) the diagnostic efficacy of orthopantomography (OPG) in the diagnosis of sinus diseases by using cone beam computed tomography (CBCT) as the imaging gold standard, (2) which diseases can be diagnosed by using panoramic radiography or CBCT, and (3) the interobserver agreement of 2 experienced dental radiologists. STUDY DESIGN: The images of 714 individuals who underwent OPG and CBCT on the same day were assessed separately by 2 dental radiologists. The results were compared by using Gwet's AC1 statistical methods. RESULTS: In total, 1322 maxillary sinuses were imaged. The sensitivity of OPG for the detection of any maxillary sinus pathology was poor compared with CBCT, but the specificity was high. The sensitivity of OPG for detecting mucosal thickening was 36.7%. The positive predictive value of OPG for diagnosing mucosal thickening was 79.9 %, but the negative predictive value was 51.9%. Interobserver agreement was strong (>=0.912) for all lesions except mucosal thickening. CONCLUSIONS: Panoramic imaging has low efficacy in the diagnosis of sinus disease, even when examined by experienced dental radiologists. OPG can be useful in excluding disease, but 3-dimensional scanning is necessary for the definitive investigation of sinus lesions. PMID- 30477957 TI - The evaluation of an immunoperoxidase assay applicable in antiviral drug screening. AB - Bovine viral diarrhea virus (BVDV) fall into cytopathic (CP) and noncytopathic (NCP) biotypes, based on their ability to kill cultured cells. NCP-BVDV can not be titrated by conventional means as used for CP-BVDV, which has impeded the identification of antiviral drugs targeting NCP-BVDV virus strains. In this study, the application of an immunoperoxidase assay in the screening of antiviral drugs was tested using two known BVDV inhibitors, ribavirin and ammonium chloride (NH4Cl). Phospholipase C inhibitor U73122 was identified to affect BVDV infection by using this immunoperoxidase assay. In addition, the results of immunoperoxidase assay were validated by real-time PCR. Taken together, the immunoperoxidase assay is a useful and versatile method suitable for antiviral drug screening targeting NCP-BVDV. PMID- 30477958 TI - Post-Translational Modification, Phase Separation, and Robust Gene Transcription. AB - A few recent reports reveal fundamental new insights into the intricate regulatory mechanisms that govern RNA polymerase II (Pol II)-mediated gene transcription. Whereas a histidine-rich domain (HRD) triggers phase separation, promoting transcription elongation, a phosphatase switch promotes transcription termination. A paradigm that might govern the underlying mechanisms leading to robust gene transcription is now starting to emerge. PMID- 30477959 TI - [Current state regarding fertility cryopreservation in pre-pubertal boys]. AB - Some treatments for any cancer therapy and hematological diseases may have gonadotoxic side effects that can result in infertility, and thus sperm cryopreservation is routinely offered to patients as the strategy to preserve their fertility. However, there are many cases where sperm banking cannot be applied, as is the case of pre-pubertal cancer patients and others unable to produce mature gametes at the moment of diagnosis. Regarding this, recent breakthroughs have gained public attention to the fertility preservation options that Regenerative Medicine can offer to these patients. In this review, we tried to compile and discuss the latest updates about all these strategies from a critical point of view. PMID- 30477960 TI - The investigation of the protective effects of nimesulide on experimental testicular ischemia-reperfusion injury in rats. AB - INTRODUCTION AND OBJECTIVES: Testicular ischemia/reperfusion (I/R) injury develops after torsion and following detorsion of the testis. Reactive oxygen species were produced and oxidative damage begins to occur due to I/R process. Nimesulide, which is a specific cyclooxygenase-2 inhibitor drug, have antioxidant, antiinflammatory, analgesics and antipyretic effects. We aimed to investigate biochemically and histopathologically effect of nimesulide on testis I/R injury in rats induced by the testicular torsion-detorsion. MATERIAL AND METHODS: In this study, 24 albino Wistar male rats were divided into four groups (6 rats in each group): ischemia/reperfusion applied+50mg/kg nimesulide administrated (NIM-50), ischemia/reperfusion applied+100mg/kg nimesulide administrated (NIM-100), ischemia/reperfusion applied (IR) and Sham surgery (SS) groups. Nimesulide was administered to NIM-50 and NIM-100 groups at the 50mg/kg and 100mg/kg doses before 2h applied I/R procedures. The IR group were applied only I/R procedures, no drug treatment was applied. Animals were sacrificed under high dose anesthesia and left testes were extracted. Testes were examined biochemically and histopathologically. RESULTS: Total glutathione (tGSH) and cyclooxygenase-1 (COX-1) levels were increased in the NIM-50 and NIM-100 groups compared to IR group. The levels of COX-2, malondialdehyde (MDA), interleukin 1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) were lower in the NIM-50 and NIM-100 groups than in the IR group. Some histopathological changes seen in IR group. This findings were decreased in NIM-50 group and prevented in NIM-100 group. CONCLUSION: Nimesulide prevented inflammation and oxidative stress. Our results suggest that nimesulide may be have a protective effect on testicular I/R injury. PMID- 30477962 TI - Regimen design and pharmacokinetic-pharmacodynamic science: lessons learned. PMID- 30477961 TI - Substitution of ethambutol with linezolid during the intensive phase of treatment of pulmonary tuberculosis: a prospective, multicentre, randomised, open-label, phase 2 trial. AB - BACKGROUND: Linezolid improves the treatment outcomes of multidrug-resistant tuberculosis substantially. We investigated whether use of linezolid instead of ethambutol increases the proportion of sputum culture conversion at 8 weeks of treatment in patients with pulmonary tuberculosis. METHODS: We did a phase 2, multicentre, randomised, open-label trial for patients with pulmonary tuberculosis at the three affiliated hospitals to Seoul National University and National Medical Center (Seoul-Seongnam, South Korea). Patients, aged 20-80 years, with a positive sputum for pulmonary tuberculosis, but without resistance to rifampicin, and current treatment administered for 7 days or fewer, were randomly assigned at a 1:1:1 ratio into three groups. The control group received ethambutol (2 months) with isoniazid, rifampicin, and pyrazinamide. The second group used linezolid (600 mg/day) for 2 weeks and the third group for 4 weeks instead of ethambutol for 2 months. We used a minimisation method to randomise, and stratified according to institution, cavitation on chest radiographs, and diabetes. The primary endpoint was the proportion of patients with negative culture conversion of sputum in liquid media after 8 weeks of treatment. The results of this trial were analysed primarily in the modified intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT01994460. FINDINGS: Between Feb 19, 2014, and Jan 13, 2017, a total of 429 patients were enrolled and 428 were randomly assigned into either the control group (142 patients), the linezolid 2 weeks group (143 patients), or the linezolid 4 weeks group (143 patients). Among them, 401 were eligible for primary efficacy analyses. In the modified intention-to-treat analyses, negative cultures in liquid media at 8 weeks of treatment were observed in 103 (76.9%) of 134 control patients, 111 (82.2%) of 135 in the linezolid 2 weeks group, and 100 (75.8%) of 132 in the linezolid 4 weeks groups. The difference from the control group was 5.4% (95% CI -4.3 to 15.0, p=0.28) for the linezolid 2 weeks group and -1.1% ( 11.3 to 9.1, p=0.83) for the linezolid 4 weeks group. Numbers of patients who experienced at least one adverse event were similar across the groups (86 [62.8%] of 137 in control, 79 [57.2%] of 138 in the linezolid 2 weeks group, and 75 [62.0%] of 121 in the linezolid 4 weeks group). Resistance to linezolid was not identified in any patient. INTERPRETATION: Higher rates of culture conversion at 8 weeks of treatment with short-term use of linezolid were not observed. However, safety analyses and the resistance profile suggested the potential role of linezolid in shortening of treatment for drug-susceptible tuberculosis. FUNDING: Ministry of Health and Welfare, South Korea. PMID- 30477963 TI - [Pharmacological profile of isavuconazole]. AB - Isavuconazole is a new azole, structurally related to fluconazole and voriconazole, that presents a very high oral absorption with no first-pass effect which is not interfered by the presence of food, gastric pH modifications, or mucositis. Its distribution volume is very high, probably also to cerebrospinal fluid, in spite of the fact that it circulates highly bound to plasma proteins. It is extensively metabolized through the CYP3A4 isoenzyme. Due to this reason, it is recommended to avoid co-administration with strong CYP3A4 inducers. In addition, isavuconazole may inhibit CYP3A4. Moreover, it may induce CYP2B6 and P glycoprotein. Interestingly, this inhibitory activity seems to be lower compared to other azoles. Therefore, the management of any interaction with other medicines is easier, which is probably the most important advantage of this antifungal. PMID- 30477964 TI - Maternal emotions during the first three postnatal months: Gaining an hermeneutic understanding. AB - BACKGROUND: Maternal emotions in the first three postnatal months are rarely explored yet in the German context despite it is known that they play an important role in the complexity of maternal health and well-being. AIM: Gaining understanding of maternal emotions and how the developmental process of the infant circadian rhythm influences them during the first three months of the postnatal period. METHODS: A Gadamerian-based research method was used to explore the experiences of 15 mothers in Germany. FINDINGS: 'Being needed' and 'being in need' emerged as the first two themes and were further explored hermeneutically. This resulted in the findings of 'emotional balance and conflicting emotions' as underlying maternal emotions during the first three months following birth. DISCUSSION: Understanding maternal emotions during the first three months of the postnatal period has the potential of opening new pathways for improving maternal health and well-being. CONCLUSION: A spectrum of maternal emotions, maternal uncertainties and maternal needs exists in the first three months of the postnatal period. PMID- 30477965 TI - Predictors of 30-Day Readmission After Total Knee Arthroplasty: Analysis of 566,323 Procedures in the United Kingdom. AB - BACKGROUND: All-cause 30-day readmission after total knee arthroplasty (TKA) is currently used as a measure of hospital performance in the United States and elsewhere. Readmissions from surgical causes may more accurately reflect preventability and costs. However, little is known about whether predictors of each type of readmission differ. METHODS: All primary TKAs recorded in England's National Health Service administrative database from 2006 to 2015 were included. Multilevel logistic regression analysis was used to describe the effects of patient-related factors on 30-day readmission risk using 3 different readmission metrics: all-cause, surgical (defined using International Classification of Disease-10 primary admission diagnoses), and those resulting in return to theater (RTT). RESULTS: In total, 566,323 procedures were recorded. The comorbidity with the highest odds ratio (OR) for all types of readmission was psychoses (RTT OR 2.52, P < .001). Obesity was a strong independent predictor of RTT (OR 1.36, P < .001) and had the highest population attributable fraction of any comorbidity (4.7%). Unicompartmental arthroplasty was associated with a significantly lower risk of all types of readmission when compared with TKA, with the effect being most pronounced for surgical readmission (OR 0.66, P < .001). RTT in the index episode increased the risk of RTT readmission (OR 2.80, P < .001), as did any emergency admission to hospital in the preceding 12 months (for >2 emergency admissions, all-cause OR 2.38, P < .001). Length of stay either more than or less than 2 days was associated with an increased risk of all-cause and surgical readmission but not RTT readmission. CONCLUSION: Patient-related predictors of surgical and RTT readmission following TKA differ from those for all-cause readmission, but only the latter metric is in widespread use. PMID- 30477966 TI - Web-Based, Self-Directed Physical Therapy After Total Hip Arthroplasty Is Safe and Effective for Most, but Not All, Patients. AB - BACKGROUND: Recent data suggested that unsupervised, self-directed physical therapy (SDPT) is both safe and efficacious for patients undergoing total hip arthroplasty (THA) and that formal outpatient physical therapy (OPPT) may not be routinely required. The purpose of this study was to evaluate the routine use of an SDPT program in a nonselect patient population. METHODS: This is a multi surgeon, single-institution, retrospective study of 941 consecutive patients discharged home, from January 2016 to December 2016, after primary, unilateral THA and enrolled in a web-based SDPT program. Patients were seen 4 weeks after surgery and OPPT was prescribed for perceived need, patient request, or if unable to use the web-based program. Patient-reported outcomes, medical comorbidities, and assessment of home environment were prospectively recorded. RESULTS: Overall, 646 of 941 patients (68.7%) were not prescribed OPPT (SDPT-only group) while 295 of 941 patients (31.3%) were prescribed OPPT (SDPT + OPPT group). In the SDPT + OPPT group, 88.2% were for perceived need, 10.8% for patient request, and 1.0% due to inability to use the web-based platform. Multivariate analysis identified male sex (odds ratio, 0.64; 0.45-0.90; P = .012) and a higher preoperative Short Form-12 physical component (odds ratio, 0.98; 0.96-0.99; P = .036) as independent variables protective against requiring OPPT. At a minimum 6-month follow-up, the SDPT-only group had statistically higher hip disability and osteoarthritis outcome score junior compared to the SDPT + OPPT cohort (85.0 vs 80.9; P = .012). CONCLUSION: Web-based SDPT is safe and effective for most, but not all, patients eligible for home discharge after THA. It is critical to preserve OPPT services for the one-third of patients who require them. LEVEL OF EVIDENCE: Level III. PMID- 30477967 TI - Intra-articular Corticosteroid Injection Following Total Knee Arthroplasty: Is It Effective? AB - BACKGROUND: Total knee arthroplasty (TKA) for the majority of patients with severe knee osteoarthritis provides relief of symptoms and improved function. However, there remains a subset of dissatisfied patients despite an unremarkable workup. A corticosteroid injection (CSI) is a commonly used nonsurgical treatment for painful knee osteoarthritis but its efficacy in a replaced knee remains unknown. METHODS: A retrospective chart review identified primary TKA patients who subsequently received a CSI into a replaced knee from 2015 to 2016 by a single surgeon. Patients receiving a CSI underwent clinical examination, laboratory analysis to rule out infection, and radiographic evaluation before CSI. Patient variables were recorded and a patient satisfaction survey assessed the efficacy of the injection. The survey response rate was 70.1%. RESULTS: Of the 129 responders, 82.9% remembered the injection. The average time from index arthroplasty to injection was median 5.3 months (interquartile range, 2.1-23.4) and 30.8% of patients received more than 1 injection (range, 1-5). Overall, 76.6% reported decreased pain, 57.9% reported increased motion, and 65.4% reported long term decreased swelling. Improvement lasted greater than 1 month for 56.1% of patients, and overall 84.1% reported improvement (slight to great) in the knee following CSI. No patient developed a periprosthetic joint infection (PJI) within 1 year of injection. CONCLUSION: This study suggests that certain patients following TKA may benefit from a CSI. However, this should only be performed once clinical, radiographic, and laboratory examination has ruled out conditions unlikely to improve long term from a CSI. PMID- 30477968 TI - Ceramides as Novel Disease Biomarkers. AB - Ceramides are sphingolipids and integral components of the eukaryotic cell membrane. Apart from providing structural integrity, ceramides have also been shown to act as second messengers in cell signaling processes. In recent publications, ceramide modulation has been reported in pathological conditions such as cancer, diabetes, Alzheimer's disease (AD), coronary artery disease (CAD), multiple sclerosis (MS), as well as depression. Ceramides or ceramide panel combinations have been proposed as specific disease biomarkers that could be detected in diseased tissue, synovial fluid, cerebrospinal fluid (CSF), and blood. This article reviews ceramide modulation in a selection of different diseases and the potential use of ceramides as biomarkers in diagnostics, determination of disease stage and personalized medicine. PMID- 30477969 TI - Associated factors that influenced persistence with basal analog insulin therapy among people with type 2 diabetes: An exploratory analysis from a UK real-world sample. AB - AIM: Real-world effectiveness of insulin therapy is affected by poor treatment persistence, often occurring soon after initiation. An international cross sectional survey of people with type 2 diabetes mellitus (T2DM) has been conducted to describe reasons for non-persistence with insulin therapy. METHODS: Responders to an online survey in 7 countries were classified as continuers (no gap of >=7days), interrupters (interrupted therapy for >=7days within first 6 months, then restarted), and discontinuers (terminated therapy for >=7days within first 6 months, no restart before survey). We present the results from the United Kingdom (UK) cohort. RESULTS: Of 942 global respondents, 131 were from the UK, having a mean age of 37years and a mean of 7years since first T2DM diagnosis. Reasons contributing to insulin continuation (n=50) were improved physical feeling (52.0%) and improved glycemic control (48.0%). Common reasons for interruption (n=50) or discontinuation (n=31), respectively were weight gain (50.0%, 48.4%) and hypoglycemia (38.0%, 25.8%). Most important reason for possible re-initiation for interrupters and discontinuers, respectively was persuasion by physician/healthcare professional (74.0%, 64.5%). CONCLUSION: The benefits of basal insulin therapy motivated continuers to persist with the treatment; experienced or anticipated side effects contributed to interruption and discontinuation. PMID- 30477970 TI - Predicting risk of type 2 diabetes mellitus in Korean adults aged 40-69 by integrating clinical and genetic factors. AB - AIMS: The purpose of our investigation was to identify the genetic and clinical risk factors of type 2 diabetes mellitus (T2DM) and to predict the incidence of T2DM in Korean adults aged 40-69 at follow-up intervals of 5, 7, and 10years. METHODS: Korean Genome and Epidemiology Study (KoGES) cohort data (n=10,030) were used to develop T2DM prediction models. Both clinical-only and integrated (clinical factors+genetic factors) models were derived using the Cox proportional hazards model. Internal validation was performed to evaluate the prediction capabilities of the clinical and integrated models. RESULTS: The clinical model included 10 selected clinical risk factors. The selected SNPs for the integrated model were rs9311835 in PTPRG, rs10975266 in RIC1, rs11057302 in TMED2, rs17154562 in ADAM12, and rs8038172 in CGNL1. For the clinical model, validated c indices with time points of 5, 7, and 10 years were 0.744, 0.732, and 0.732, respectively. Slightly higher validated c-indices were observed for the integrated model at 0.747, 0.736, and 0.738, respectively. The p-values of the survival net reclassification improvement (NRI) for the SNP point-based score were statistically significant. CONCLUSIONS: Clinical and integrated models can be effectively used to predict the incidence of T2DM in Koreans. PMID- 30477971 TI - Combined Clinical Parameters and Multiparametric Magnetic Resonance Imaging for the Prediction of Extraprostatic Disease-A Risk Model for Patient-tailored Risk Stratification When Planning Radical Prostatectomy. AB - BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) facilitates the detection of significant prostate cancer. Therefore, addition of mpMRI to clinical parameters might improve the prediction of extraprostatic extension (EPE) in radical prostatectomy (RP) specimens. OBJECTIVE: To investigate the accuracy of a novel risk model (RM) combining clinical and mpMRI parameters to predict EPE in RP specimens. DESIGN, SETTING, AND PARTICIPANTS: We added prebiopsy mpMRI to clinical parameters and developed an RM to predict individual side-specific EPE (EPE-RM). Clinical parameters of 264 consecutive men with mpMRI prior to MRI/transrectal ultrasound fusion biopsy and subsequent RP between 2012 and 2015 were retrospectively analysed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariate regression analyses were used to determine significant EPE predictors for RM development. The prediction performance of the novel EPE-RM was compared with clinical T stage (cT), MR-European Society of Urogenital Radiology (ESUR) classification for EPE, two established nomograms (by Steuber et al and Ohori et al) and a clinical nomogram based on the coefficients of the established nomograms, and was constructed based on the data of the present cohort, using receiver operating characteristics (ROCs). For comparison, models' likelihood ratio (LR) tests and Vuong tests were used. Discrimination and calibration of the EPE-RM were validated based on resampling methods using bootstrapping. RESULTS AND LIMITATIONS: International society of Urogenital Pathology grade on biopsy, ESUR criteria, prostate-specific antigen, cT, prostate volume, and capsule contact length were included in the EPE-RM. Calibration of the EPE-RM was good (error 0.018). The ROC area under the curve for the EPE-RM was larger (0.87) compared with cT (0.66), Memorial Sloan Kettering Cancer Center nomogram (0.73), Steuber nomogram (0.70), novel clinical nomogram (0.79), and ESUR classification (0.81). Based on LR and Vuong tests, the EPE-RM's model fit was significantly better than that of cT, all clinical models, and ESUR classification alone (p<0.001). Limitations include monocentric design and expert reading of MRI. CONCLUSIONS: This novel EPE-RM, incorporating clinical and MRI parameters, performed better than contemporary clinical RMs and MRI predictors, therefore providing an accurate patient-tailored preoperative risk stratification of side specific EPE. PATIENT SUMMARY: Extraprostatic extension of prostate cancer can be predicted accurately using a combination of magnetic resonance imaging and clinical parameters. This novel risk model outperforms magnetic resonance imaging and clinical predictors alone and can be useful when planning nerve-sparing radical prostatectomy. PMID- 30477972 TI - [Formal and informal support of patients with dementia at home: A mixed methods study within the Actifcare project]. AB - BACKGROUND: Formal care services are less often used in dementia care than in care for people without dementia. The Actifcare project, in which eight European countries participated, emphasized the point in time in the trajectory of dementia when formal care becomes more and more important for supporting caregivers at home. A mixed-method study conducted over 12 months aimed to improve the understanding of care needs and the influencing factors for using informal and formal support for care at home. This report focuses on the German sample of the cohort study. METHODS: People with dementia with their informal caregivers from the German federal states of North Rhine-Westphalia, Saxony Anhalt and Saxony were interviewed between January 2015 and July 2016. A set of validated questionnaires was used for the baseline interviews and two follow-ups. Additional guideline-based semi-structured interviews were conducted with a subgroup of informal caregivers at the last follow-up interview. The standardized questionnaires were analyzed using a descriptive approach, and the semi structured interviews were subjected to qualitative content analysis. Similar to the data collection processes, the results of both analyses were synthesized using a data triangulation approach. RESULTS: A total of 52 people with dementia and their informal caregivers participated in the standardized interviews. A subsample of 12 informal caregivers was included in the qualitative interviews. At baseline, 28 out of 51 informal caregivers cared for their relatives with dementia without additional informal support (T2: 22 of 41). The social network of approximately half of the informal caregivers included three to four relatives, who were open to help if necessary. On average, 3.4 support services were used (T2: 3.6). During the study period, the interest in educational, informational and counselling services decreased (T0: 11 of 52 informal caregivers; T2: 5 of 41). Formal care was more often rejected by people with dementia than by informal caregivers. Sometimes, the available services were considered insufficient in terms of personal needs of formal support, which should be flexible, unbureaucratic and tailored to the needs of the individual patient's situation. It is important for people with dementia and their informal caregivers to be involved in the decision-making processes of caregiving. Since dementia is a progressive disease, early participation is a prerequisite for making shared decisions about healthcare services. CONCLUSION: People with dementia and their informal caregivers should be informed about formal care services and involved in decision-making processes as early as possible. To this purpose, account must be taken of the various informal social networks. This could improve the use of formal care services and the further development of these offers and thus prolong care at home. PMID- 30477973 TI - Significant others' experience of hospitalized patients' transfer to home: A systematic review and meta-synthesis. AB - BACKGROUND: Significant others are individuals representing family members or neighbors, friends, colleagues or members of the same household, who act as relatives or surrogates. Significant others play an important role when patients are transferred or discharged after hospitalization. OBJECTIVE: The objective of this review is to identify, appraise and synthesize the best available evidence exploring significant others' experiences of the discharge or transfer of adult patients after hospitalization. METHODS: A qualitative comprehensive systematic review and meta aggregation. TYPES OF PARTICIPANTS: Participants of this review are the 'significant other(s); persons who are important or influential to the patient's life. PHENOMENA OF INTEREST: How the significant others' experience hospitalized patients' transitions and the psychosocial and existential issues during transfer from hospital to home. CONTEXT: Studies that investigate the organizational culture during hospitalization. TYPES OF STUDIES: Studies that focus on qualitative data including, but not limited to, designs such as phenomenology, grounded theory, ethnography, action research and feminist research. SEARCH STRATEGY: The search aimed at finding published and unpublished studies in English, German, Danish, Swedish and Norwegian, and was unrestricted by time. Eleven electronic databases and eleven websites were searched. CRITICAL APPRAISAL: Methodological validity of the qualitative papers was assessed independently by two reviewers using the standardized critical appraisal instruments from the Joanna Briggs Institute Qualitative Assessment and Review Instrument. DATA EXTRACTION: Data were extracted from papers included in the review using the standardized data extraction tool from the Joanna Briggs Institute Qualitative Assessment and Review Instrument. DATA SYNTHESIS: Qualitative research findings were synthesized. RESULTS: A total of 189 findings from twelve studies were aggregated into three categories. An aggregated finding was generated based on the primary studies: SOs existential strength is linked to preparations for the discharge including care planning meeting(s) and learning-by doing care activities led by health care providers during hospitalizations. CONCLUSIONS: The studies in this review provided useful and credible statements from caregivers' voices that are not previously aggregated nor presented. The findings enlighten both positive and burdensome experiences in the everyday life of caring for a significant other after discharge. PMID- 30477974 TI - [The role of migrant organizations in health care: An integrative review]. AB - BACKGROUND AND QUESTION: People with a migration background are exposed to greater health risks and burdens due to their often less favorable social situation. At the same time, conventional health services and programs do not sufficiently reach them. Migrant organizations (MOs) are said to have the potential to reach this otherwise difficult target group. This review examines whether there are any indications in the scientific literature that MOs could improve target group attainment. METHODS: A broad-based systematic literature search was carried out in German and English databases with predefined search terms for the period from 2005 to 2015 (inclusive). RESULTS: Out of 3,236 hits, 8 studies fulfilled the inclusion and exclusion criteria. These studies provide indications that MOs are effectively reaching and addressing the target group. Due to a lack of comparability of the MOs involved and different study populations, the interpretation of the results is difficult, though. CONCLUSION: MOs, as protected social spaces in everyday life, provide an opportunity to offer healthcare services to organizationally affine people with a migration background. However, the research process (e.g., selection of MOs, field access, recruitment of participants) does not seem to be methodologically stringent. Above all, it is still unclear which principles are effective when MOs are integrated into health services. This is where future projects should be started. PMID- 30477975 TI - [Estimating the incidence of venous thromboembolism (VTE) using various types of routine data of the German healthcare system]. AB - BACKGROUND: Venous thromboembolism (VTE) mainly manifests as deep vein thrombosis (TVT) or pulmonary embolism (LE), and is the third most common cardiovascular disease worldwide. However, robust evidence on the incidence of VTE in Germany is lacking. OBJECTIVE: Estimation and comparison of the incidence of VTE based on different routine data sources of the German healthcare system. METHODS: Estimates and comparisons of the incidence of VTE, TVT and LE were made using two databases that both covered the inpatient and the outpatient setting; the DaTraV database comprising information of all persons subject to compulsory health insurance, and the Health Risk Institute (HRI) database derived from approximately 70 statutory health insurance funds. In addition, IMS Disease Analyzer, a medical record database comprising information from the outpatient setting, was used as a data source. RESULTS: Patterns of age- and sex-specific VTE incidence estimates were comparable between all databases used. However, estimates based on the medical record database were comparatively high. Analyses of DaTraV data led to a VTE incidence of 0.14%. Use of HRI data yielded comparable results (0.17-0.20%). VTE incidence based on data of the IMS Disease Analyzer was comparatively high (0.32%). DISCUSSION: Results on the VTE incidence based on DaTraV or HRI date are comparable to international evidence, whereas the use of the IMS Disease Analyzer data presumably led to an overestimation due to double-counting of VTE cases. Different types of routine healthcare data sources can therefore lead to very heterogeneous results. Thus, the selection of adequate data sources strongly depends on the study question and the quality of the dataset. PMID- 30477976 TI - Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza A H1N1 acute respiratory distress syndrome patients. AB - BACKGROUND: An association between increased venous thromboembolism (VTE) events and influenza A H1N1 (H1N1) was noted in the first 10 patients with severe acute respiratory distress syndrome (ARDS). An empirical systemic anticoagulation protocol (heparin intravenous infusion) was initiated when autopsy of patients with severe hypoxemia confirmed multiple primary pulmonary thrombi and emboli. The purpose of this study was to examine the relationship between H1N1 and VTE events and to assess the efficacy of empirical systemic heparin anticoagulation in preventing VTE and death in H1N1 severe ARDS patients. METHODS: An observational cohort study of critically ill severe ARDS patients with possible H1N1 viral pneumonia was performed in a surgical intensive care unit in a single 990-bed academic tertiary care center. Early empirical systemic heparin anticoagulation for all severe ARDS patients with possible H1N1 viral pneumonia was initiated as a VTE preventive strategy. RESULTS: Univariate comparisons and multivariate logistic regression were used to identify risk factors for VTE. Independent risk factors for VTE included H1N1, culture-positive bacterial pneumonia, and vasopressor requirement. Independent risk factors for pulmonary embolism included H1N1, culture-positive bacterial pneumonia, and male sex. H1N1 ARDS patients had 23.3-fold higher risk for pulmonary embolism and 17.9-fold increased risk for VTE. Kaplan-Meier analysis and log-rank test confirmed that empirical systemic heparin anticoagulation provided significant protection from thrombotic events in the H1N1-positive but not in the H1N1-negative critically ill ARDs patients. In multivariate analysis, adjusting for H1N1 status, patients without empirical systemic anticoagulation were 33 times more likely to have any VTE compared with those treated with empirical systemic heparin anticoagulation (P = .01). CONCLUSIONS: Critically ill patients with H1N1 ARDS have increased risk of venous thrombotic complications, particularly pulmonary thromboembolism. Empirical systemic heparin anticoagulation in this cohort of patients significantly reduced VTE incidence without increased hemorrhagic complications. PMID- 30477977 TI - The mortality for surgical repair is similar to ligation in patients with traumatic portal vein injury. AB - BACKGROUND: Portal vein injury is uncommon, and the optimal treatment is controversial. We compared the outcomes of ligation vs repair of portal injury using the National Trauma Data Bank. METHODS: Adult patients who suffered portal injury were identified from the National Trauma Data Bank (2002-2014) by International Classification of Diseases, Ninth Revision diagnosis codes. Patients were stratified by treatment modality into no surgery, ligation, and surgical repair using International Classification of Diseases procedure codes. Outcomes including hospital mortality, bowel resection, and length of stay between ligation and surgical repair were compared by Kruskal-Wallis or Fisher exact test as appropriate. Multivariable analyses were performed with logistic regression. RESULTS: Among 752 patients with portal vein injury, 345 patients (45.9%) underwent no surgery, 103 patients (13.7%) had ligation, and 304 (40.4%) underwent surgical repair. Overall mortality was 49%. Age, sex, Injury Severity Score, Glasgow Coma Scale score, presenting blood pressure, and heart rate were similar between groups that underwent ligation and surgical repair. The hospital mortality (59.2% vs 47.7%; P = .08), bowel resection (1.9% vs 1.0%; P = .55), and length of stay (12.5 vs 15.0 days; P = .08) were also comparable between ligation and repair in univariate analysis. In multivariable analysis, hospital mortality for surgical repair was similar to ligation (risk ratio, 0.69; 95% confidence interval, 0.41-1.16; P = .16). CONCLUSIONS: Portal vein injury is associated with significant mortality and morbidity. Surgical repair showed a trend for lower postoperative mortality than ligation, but this was not statistically significant on multivariate analysis. Repair of a traumatic portal vein injury should be attempted, but ligation is an acceptable alternative without an increase in bowel resection rates or a statistically significant increase in mortality. PMID- 30477978 TI - Duplex ultrasound findings and clinical classification of lower extremity chronic venous insufficiency in a Thai population. AB - BACKGROUND: The objective of this study was to evaluate the association between the clinical classification of chronic venous insufficiency and duplex ultrasound findings. METHODS: A total of 1010 limbs with clinically suspected chronic venous insufficiency were stratified according to the Clinical, Etiology, Anatomy, and Pathophysiology (CEAP) classification and underwent duplex ultrasound evaluation consecutively between January 2012 and June 2015. Venous thrombosis, venous reflux, and anatomic distribution of the deep and superficial venous systems were investigated across the CEAP clinical classes. RESULTS: There were 259 male limbs (25.6%) and 751 female limbs (74.4%) in clinical class C0 (24 limbs [2.4%]), C1 (130 limbs [13.1%]), C2 (452 limbs [44.8%]), C3 (183 limbs [18.1%]), C4 (163 limbs [16.1%]), C5 (31 limbs [3.1%]), and C6 (27 limbs [2.7%]). The mean age in clinical class C4-C6 (60.77 +/- 14.67 years) was statistically significantly higher than in C0-C3 (55.73 +/- 18.85 years; P < .001). Male limbs were shown to have a predilection for presenting with clinical class C4-C6 over female limbs (36.3% vs 16.9%; odds ratio, 2.8; 95% confidence interval, 2.0-3.8). Positive findings were predominantly displayed in clinical class C4-C6 compared with C0-C3 (deep venous thrombosis, 3.2% vs 1.3%; deep venous reflux, 30.8% vs 26.9%; superficial vein thrombosis, 2.7% vs 2.0%; superficial venous reflux, 56.6% vs 47.6%; perforator vein reflux, 12.7% vs 8.2% [P = .049]). A low prevalence of small saphenous vein and perforator vein reflux in C1 limbs (0.3% and 4.6%) and C3 limbs (3.8 and 6.6%) was discovered. CONCLUSIONS: The prevalence of CEAP class C0-C3 was found to be higher than C4-C6. However, men were shown to have a predilection for presenting in clinical class C4-C6 over women. The mean age of patients with clinical class C4-C6 limbs was statistically significantly higher than of those with clinical class C0-C3 limbs. The prevalence of deep venous reflux, superficial venous reflux, and coincident deep and superficial venous reflux in clinical class C4-C6 limbs was higher than in clinical class C0-C3 limbs. Detection of incompetent perforator veins was shown to have a statistically significant correlation with clinical class C4-C6 limbs. PMID- 30477979 TI - Transient increased tumescence of the glans penis during penile erection after endovenous ablation of the great saphenous vein. AB - OBJECTIVE: The primary objective of our study was to investigate the impact of endovenous ablation of the great saphenous vein (GSV) on the degree of tumescence of the glans penis during penile erection as well as on global erectile function (EF). METHODS: We included patients scheduled for one of three different methods of endoluminal treatment. Our questionnaire was composed of the EF domain of the International Index of Erectile Function, an additional question that has been validated for assessment of swelling (tumescence) of the glans penis, and a question on the use of erectogenic medication. RESULTS: There were 62 patients enrolled in the study. Seven patients (11%) reported a postoperative enlargement of the glans penis on penile erection compared with the subjectively assessed glans tumescence before surgery. Three patients (5%) reported an increased tumescence of the glans 1 week after surgery, and four (7.4%) different patients reported the effect 3 months after surgery. Of these seven men, three had normal EF (score >=26) at any time. One patient had mild erectile dysfunction before the operation, with an improvement to normal EF from week 1 throughout the observation in the study (3 months). CONCLUSIONS: This is the first prospective study that confirms an unexpected side effect of endoluminal treatment of the GSV occurring in approximately 10% of men. It might be of interest for insufficient responders to phosphodiesterase type 5 inhibitors with varicosis of the GSV in the future. PMID- 30477980 TI - Endobronchial forceps-assisted complex retrieval of inferior vena cava filters. AB - OBJECTIVE: The objective of this study was to assess the safety, feasibility, and effectiveness of endobronchial forceps-assisted retrieval of inferior vena cava (IVC) filters when standard retrieval techniques fail. METHODS: An Institutional Review Board-approved single-center retrospective review during a 6-year period identified 60 consecutive patients (23 men and 37 women; mean age, 49.3 years; range, 19-77 years) in whom rigid endobronchial forceps were required for IVC filter retrieval after standard techniques failed. Factors affecting retrieval success, including an embedded or tilted filter, overall dwell time, filter fracture, and caval penetration, were recorded, as were success rates, procedural details, and complications. RESULTS: Mean dwell time between filter placement and removal was 565 days (range, 15-7366 days). Various IVC filters were encountered: 33 Option (Argon Medical, Frisco, Tex), 8 Celect (Cook Medical, Bloomington, Ind), 9 Gunther Tulip (Cook Medical), 4 G2 and 3 Eclipse (Bard, Murray Hill, NJ), 2 OptEase (Cordis, Bridgewater, NJ), and 1 Simon Nitinol (Bard). Imaging before retrieval showed grade 1 (3/60), grade 2 (44/60), and grade 3 (13/60) filter interaction with IVC wall. The degree of secondary tilt as assessed on images acquired before attempted retrieval was <10 degrees (n = 22; 36.7%), 10 to 20 degrees (n = 26; 43.3%), and >20 degrees (n = 12; 20%), with an average tilt of 13.8 degrees (range, 0-48.9 degrees). Of the 60 filters, 58 were retrieved successfully (96.7%). Two of these required a second attempt (one because of migration into the right atrium and the other because of extreme discomfort of the patient requiring subsequent general anesthesia). Five of 60 procedures were forceps-assisted loop snare retrievals in which the forceps were used to dissect the embedded hook free from surrounding hyperplastic caval venous endothelium. Mean fluoroscopy retrieval time was 33.2 minutes (range, 10-76.9 minutes). Intraprocedural inconsequential filter fracture was observed in 10 patients. There were four complications: one retroperitoneal hemorrhage, one IVC dissection flap, and two filter fractures with subsequent migration of filter components to the right side of the heart and to the right pulmonary artery. The first two complications required hospital admission and conservative management; in the last two, the fractured and migrated filter limbs were retrieved successfully using a snare device. CONCLUSIONS: Rigid endobronchial forceps can be safely and reliably used to remove embedded, fractured, or tilted retrievable IVC filters from patients in whom standard retrieval techniques are unsuccessful. There is a high success rate and minimal complications. We propose that the degree of filter tilt, caval penetration, and filter fracture are predictive of the need for the use of forceps as a first-line retrieval technique. PMID- 30477982 TI - Re: Liselotte M.S. Boeve, Maarten C.C.M. Hulshof, Andre N. Vis, et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2018.09.008: High-volume Disease Has a Different Standard of Care. PMID- 30477981 TI - Head-to-head Comparison of Transrectal Ultrasound-guided Prostate Biopsy Versus Multiparametric Prostate Resonance Imaging with Subsequent Magnetic Resonance guided Biopsy in Biopsy-naive Men with Elevated Prostate-specific Antigen: A Large Prospective Multicenter Clinical Study. AB - BACKGROUND: There is growing interest to implement multiparametric magnetic resonance imaging (mpMRI) and MR-guided biopsy (MRGB) for biopsy-naive men with suspected prostate cancer. OBJECTIVE: Primary objective was to compare and evaluate an MRI pathway and a transrectal ultrasound-guided biopsy (TRUSGB) pathway in biopsy-naive men with prostate-specific antigen levels of >=3ng/ml. DESIGN, SETTING, AND POPULATION: A prospective, multicenter, powered, comparative effectiveness study included 626 biopsy-naive patients (from February 2015 to February 2018). INTERVENTION: All patients underwent prebiopsy mpMRI followed by systematic TRUSGB. Men with suspicious lesions on mpMRI also underwent MRGB prior to TRUSGB. MRGB was performed using the in-bore approach. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinically significant prostate cancer (csPCa) was defined as grade group >=2 (Gleason score >=3+4) in any core. The main secondary objectives were the number of men who could avoid biopsy after nonsuspicious mpMRI, the number of biopsy cores taken, and oncologic follow-up. Differences in proportions were tested using McNemar's test with adjusted Wald confidence intervals for differences of proportions with matched pairs. RESULTS AND LIMITATIONS: The MRI pathway detected csPCa in 159/626 (25%) patients and insignificant prostate cancer (insignPCa) in 88/626 patients (14%). TRUSGB detected csPCa in 146/626 patients (23%) and insignPCa in 155/626 patients (25%). Relative sensitivity of the MRI pathway versus the TRUSGB pathway was 1.09 for csPCa (p=0.17) and 0.57 for insignPCa (p<0.0001). The total number of biopsy cores reduced from 7512 to 849 (-89%). The MRI pathway enabled biopsy avoidance in 309/626 (49%) patients due to nonsuspicious mpMRI. Immediate TRUSGB detected csPCa in only 3% (10/309) of these patients, increasing to 4% (13/309) with 1-yr follow-up. At the same time, TRUSGB would overdetect insignPCa in 20% (63/309). "Focal saturation" by four additional perilesional cores to MRGB improved the detection of csPCa in 21/317 (7%) patients. Compared with the literature, our proportion of nonsuspicious mpMRI cases is significantly higher (27-36% vs 49%) and that of equivocal cases is lower (15-28% vs 6%). This is probably due to the high-quality standard in this study. Therefore, a limitation is the duplication of these results in less experienced centers. CONCLUSIONS: In biopsy-naive men, the MRI pathway compared with the TRUSGB pathway results in an identical detection rate of csPCa, with significantly fewer insignPCa cases. In this high quality standard study, almost half of men have nonsuspicious MRI, which is higher compared with other studies. Not performing TRUS biopsy is at the cost of missing csPCa only in 4%. PATIENT SUMMARY: We compared magnetic resonance imaging (MRI) with MRI-guided biopsy against standard transrectal ultrasound biopsy for the diagnosis of prostate cancer in biopsy-naive men. Our results show that patients can benefit from MRI because biopsy may be omitted in half of men, and fewer indolent cancers are detected, without compromising the detection of harmful disease. Men also need fewer needles to make a diagnosis. PMID- 30477983 TI - Predicting Renal Function Outcomes After Partial and Radical Nephrectomy. AB - BACKGROUND: Partial nephrectomy (PN) is generally favored for cT1 tumors over radical nephrectomy (RN) when technically feasible. However, it can be unclear whether the additional risks of PN are worth the magnitude of renal function benefit. OBJECTIVE: To develop preoperative tools to predict long-term estimated glomerular filtration rate (eGFR) beyond 30d following PN and RN, separately. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, patients who underwent RN or PN for a single nonmetastatic renal tumor between 1997 and 2014 at our institution were identified. Exclusion criteria were venous tumor thrombus and preoperative eGFR <15ml/min/1.73m2. INTERVENTION: RN and PN. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Hierarchical generalized linear mixed effect models with backward selection of candidate preoperative features were used to predict long-term eGFR following RN and PN, separately. Predictive ability was summarized using marginal RGLMM2, which ranges from 0 to 1, with higher values indicating increased predictive ability. RESULTS AND LIMITATIONS: The analysis included 1152 patients (13 206 eGFR observations) who underwent RN and 1920 patients (18 652 eGFR observations) who underwent PN, with mean preoperative eGFRs of 66ml/min/1.73m2 (standard deviation [SD]=18) and 72ml/min/1.73m2 (SD=20), respectively. The model to predict eGFR after RN included age, diabetes, preoperative eGFR, preoperative proteinuria, tumor size, time from surgery, and an interaction between time from surgery and age (marginal RGLMM2=0.41). The model to predict eGFR after PN included age, presence of a solitary kidney, diabetes, hypertension, preoperative eGFR, preoperative proteinuria, surgical approach, time from surgery, and interaction terms between time from surgery and age, diabetes, preoperative eGFR, and preoperative proteinuria (marginal RGLMM2). Limitations include the lack of data on renal tumor complexity and the single-center design; generalizability needs to be confirmed in external cohorts. CONCLUSIONS: We developed preoperative tools to predict renal function outcomes following RN and PN. Pending validation, these tools should be helpful for patient counseling and clinical decision-making. PATIENT SUMMARY: We developed models to predict kidney function outcomes after partial and radical nephrectomy based on preoperative features. This should help clinicians during patient counseling and decision-making in the management of kidney tumors. PMID- 30477984 TI - Prefrontal cortical trkB, glucocorticoids, and their interactions in stress and developmental contexts. AB - The tropomyosin/tyrosine receptor kinase B (trkB) and glucocorticoid receptor (GR) regulate neuron structure and function and the hormonal stress response. Meanwhile, disruption of trkB and GR activity (e.g., by chronic stress) can perturb neuronal morphology in cortico-limbic regions implicated in stressor related illnesses like depression. Further, several of the short- and long-term neurobehavioral consequences of stress depend on the developmental timing and context of stressor exposure. We review how the levels and activities of trkB and GR in the prefrontal cortex (PFC) change during development, interact, are modulated by stress, and are implicated in depression. We review evidence that trkB- and GR-mediated signaling events impact the density and morphology of dendritic spines, the primary sites of excitatory synapses in the brain, highlighting effects in adolescents when possible. Finally, we review the role of neurotrophin and glucocorticoid systems in stress-related metaplasticity. We argue that better understanding the long-term effects of developmental stressors on PFC trkB, GR, and related factors may yield insights into risk for chronic, remitting depression and related neuropsychiatric illnesses. PMID- 30477985 TI - The role of brain reward pathways in stress resilience and health. AB - While it is well established that stress can increase risk for a broad range of health and disease outcomes (e.g., major depression, cardiovascular disease), less is known about factors supporting resilience. An emerging literature indicates that activation of the brain's reward system can mitigate subsequent stress responses to a broad range of stressors in animals and humans, suggesting reward pathways as a novel mechanistic target for fostering resilience under stress. This perspective will: 1) describe the emerging evidence linking primary and secondary rewards with stress buffering effects; 2) identify plausible neurobiological mechanisms; and 3) introduce new links between brain reward activation and reduced stress-related health and disease outcomes. We conclude with a discussion of research opportunities and clinical implications of brain reward effects. PMID- 30477986 TI - Association of an IRF3 putative functional uORF variant with resistance to Brucella infection: A candidate gene based analysis of InDel polymorphisms in goats. AB - Brucellosis is an important zoonotic disease caused by infection with Brucella spp. It generates major economic losses in livestock production worldwide. Goats are the principal hosts of B. melitensis, the main infection agent of caprine and human brucellosis. The selection of resistance-related genes is considered one of the best long-term means to improve control to bacterial infection in domestic ruminants. We performed a candidate gene association study to test if six short insertion/deletion polymorphisms (InDels) at bacterial-infection related genes influence the resistance to Brucella infection in female creole goats. InDels (IRF3-540: rs660531540, FKBP5-294: rs448529294, TIRAP-561: rs657494561, PTPRT 588: rs667380588, KALRN-989: rs667660989 and RAB5a-016: rs661537016) were resolved by PCR-capillary electrophoresis in samples from 64 cases and 64 controls for brucellosis. Allelic frequencies were significantly different between cases and controls at IRF3-540 and KALRN-989 (p = 0.001 and 0.005). Indeed, the minor alleles (a and k) at InDels IRF3-540 and KALRN-989 were more frequent among controls than cases, providing evidence that these alleles confer protection against Brucella infection. Moreover, IRF3-540 a-containing genotypes (Aa and aa) were associated with absence of Brucella-specific antibodies in goats (p = 0.003; OR = 3.52; 95% CI = 1.55-7.96), and more specifically, a-allele was associated with resistance to Brucella infection in a dose-dependent manner. Also, we observed that the IRF3-540 deletion (a-allele) extends a conserved upstream ORF by 75 nucleotides to the main ORF, and thus it may decrease gene expression by reducing translation efficiency from the main ORF. These results suggest a potential functional role of IRF3-540 deletion in genetic resistance to Brucella infection in goats. PMID- 30477987 TI - The relationship between visfatin and cardiac markers on induced myocardial infarction in rats. AB - Myocardial infarction (MI) is one of the most important reason of mortality into worldwide. Visfatin is a novel adipokine which was reported increased in metabolic syndrome and obesity. Moreover, it is known that visfatin increases in aterosclerotic endotelial dysfunction. In our study we want to demonstrate how visfatin changes in isoproterenol (ISO) induced MI. Rats were allocated into 4 groups in which each group included 6 rats in this study. 200 mg/kg ISO was administered into rats except control group to induce MI. I. and II. Group rats in 6th hour, III. Group rats in 24th hour and IV. Group rats in 7th day were decapitated. Visfatin was searched in cardiac tissues of all groups by immunohistochemistry stainning. Visfatin and cardiac markers' levels were measured in serum samples. Serum visfatin levels gradually increased in 6th and 24th hour in MI rats compared to controls. In 7th day visfatin levels decreased to control levels. These changes correlated with serum troponin T levels. These findings were supported by immunohistochemistry stainning of visfatin in cardiac tissues. It has been shown that visfatin could be useful in diagnosing MI and may be a biomarker for cardiac ischemia because of increasing in systemic circulation and cardiac tissues in MI like troponins. PMID- 30477988 TI - Fibroblast activation protein is dispensable for control of glucose homeostasis and body weight in mice. AB - OBJECTIVE: Fibroblast Activation Protein (FAP), an enzyme structurally related to dipeptidyl peptidase-4 (DPP-4), has garnered interest as a potential metabolic drug target due to its ability to cleave and inactivate FGF-21 as well as other peptide substrates. Here we investigated the metabolic importance of FAP for control of body weight and glucose homeostasis in regular chow-fed and high fat diet-fed mice. METHODS: FAP enzyme activity was transiently attenuated using a highly-specific inhibitor CPD60 and permanently ablated by genetic inactivation of the mouse Fap gene. We also assessed the FAP-dependence of CPD60 and talabostat (Val-boroPro), a chemical inhibitor reportedly targeting both FAP and dipeptidyl peptidase-4 RESULTS: CPD60 robustly inhibited plasma FAP activity with no effect on DPP-4 activity. Fap gene disruption was confirmed by assessment of genomic DNA, and loss of FAP enzyme activity in plasma and tissues. CPD60 did not improve lipid tolerance but modestly improved acute oral and intraperitoneal glucose tolerance in a FAP-dependent manner. Genetic inactivation of Fap did not improve glucose or lipid tolerance nor confer resistance to weight gain in male or female Fap-/- mice fed regular chow or high-fat diets. Moreover, talabostat markedly improved glucose homeostasis in a FAP- and FGF-21-independent, DPP-4 dependent manner. CONCLUSION: Although pharmacological FAP inhibition improves glucose tolerance, the absence of a metabolic phenotype in Fap-/-mice suggest that endogenous FAP is dispensable for the regulation of murine glucose homeostasis and body weight. These findings highlight the importance of characterizing the specificity and actions of FAP inhibitors in different species and raise important questions about the feasibility of mouse models for targeting FAP as a treatment for diabetes and related metabolic disorders. PMID- 30477989 TI - Determining the cost of first-ever seizures: A narrative review and future directions. PMID- 30477990 TI - Epilepsy surgery for children with severe developmental delay: An ethical double jeopardy. PMID- 30477991 TI - The Shanfield anastomosis revisited: Its applications and early outcome. AB - BACKGROUND: Shanfield first described a simple ureteric implantation technique involving a U-stitch anchoring the spatulated end of the transplant ureter to the interior of the intact bladder through a small stab wound. We present an extrapolation of this principle to Mitrofanoff channels and native ureteric reimplantations and further extend it to a laparoscopic approach in some. METHODS: A retrospective case-note reviewing the Shanfield ureteric reimplantation in fifteen children between October 2014 and May 2017 was performed. RESULTS: Fifteen children (females n = 9), median age 6 years (range 8 months-15 years), underwent a Shanfield anastomosis for ureteric (n = 3) or Mitrofanoff (n = 12) implantation into the bladder. Their diagnoses were: vesicoureteric reflux (n = 2), vesicoureteric obstruction (n = 1), neuropathic bladder (n = 4), exstrophy (n = 2, bladder and cloacal), nonneuropathic bladder (n = 3), cloaca (n = 2), and one with failed urethral reconstruction of a Y duplication. Two ureteric reimplantations and one appendix-Mitrofanoff were undertaken entirely laparoscopically. The bladder was not opened in 9/15, with the remaining six in an ileocystoplasty and one complex cloaca. Fourteen patients were available for follow-up at a median 18.2 (5.8-43.3) months. There was no anastomotic leakage in any, and one stenosis was successfully managed with simple dilatation. One complex patient required a new Mitrofanoff channel. CONCLUSION: Our preliminary data suggest that the Shanfield anastomosis offers a safe, robust, and simple antireflux implantation technique without the need to formally open the bladder. The technique offers several advantages as it allows overcoming the problem of inadequate tunnelling when the bladder template is deficient. Meanwhile, its simplicity permits it to be faithfully reproduced with laparoscopy in select patients. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: IV. PMID- 30477992 TI - Medical manslaughter: Resolving circularity. AB - The legal basis for prosecution and conviction for gross negligence manslaughter has failed to provide prosecutors, judges, and juries with sufficient certainty as to what constitutes the offense in the nineteenth or twentieth centuries. It remains to be seen whether 'revised guidance' or a plea for clearer understanding of the elements of the offense of gross negligence manslaughter as set out in the rapid policy review will be a sufficient remedy to allay doctors fears, or whether an entirely new approach is required. If the latter, then founding the charge on the basis of a betrayal of trust between the patient and her doctor may represent a concept that the jury can recognize and empathize with. If a jury can understand a binary decision of betrayal vs nonbetrayal, then the judge's task of direction will be simplified, less ambiguous, providing certainty. At the same time, the Crown Prosecution Service of the UK may find it easier to identify the rare cases of betrayal of trust that merit prosecution. LEVEL OF EVIDENCE: V; expert opinion. PMID- 30477993 TI - Commentary to 'Modified staged repair of bladder exstrophy: a strategy to prevent penile ischemia while maintaining advantage of the complete primary repair of bladder exstrophy'. PMID- 30477994 TI - Open ureteroureterostomy for repair of upper-pole ectopic ureters in children with duplex systems: is stenting really necessary? AB - BACKGROUND: Ectopic upper-pole (UP) ureters in duplex kidneys can be managed surgically by ipsilateral distal ureteroureterostomy (U-U) with or without ureteric stenting. Evidence to support routine stenting during this procedure is lacking. OBJECTIVE: The authors present their outcomes of children with ectopic UP ureters who underwent ipsilateral distal U-U. They also compared outcomes of those who underwent routine ureteric stenting to those who did not. STUDY DESIGN: Between 2009 and 2015, the authors performed a prospective analysis on consecutive patients with duplex collecting systems who underwent distal U-U via an inguinal incision for ectopic UP ureters by one of two pediatric urologists. The demographic information, operative factors, and any postoperative complications on follow-up were recorded. RESULTS: The study included 47 patients (28 female) who underwent distal U-U with a mean age of 9.8 months. There were 30 patients who were routinely stented, and 17 who were not based on the routine practices of the operating surgeons without any selection bias. The mean operative time was 90 min, and the mean hospital stay was 0.9 days. No major complications were observed in this series, with 96% of patients showing resolution of hydronephrosis. There were no statistical differences between the stented and stentless U-U groups in terms of operative time, hospital stay, hydronephrosis resolution, time to resolution of hydronephrosis, and major complications. Only stented patients were found to have minor complications (2 urinary tract infection, 2-dysuria, and 2-stent displacement). All patients who underwent routine stent placement required a secondary planned procedure under general anesthesia for the cystoscopic removal of stent. CONCLUSION: Stenting was associated with a higher number of minor complications compared to the stentless group and thus, may not be routinely necessary when performing distal U-U for management of UP ectopic ureters associated with duplicated collecting systems. PMID- 30477995 TI - Detecting pulmonary edema in multiple pregnancy through point-of-care lung ultrasonography. PMID- 30477996 TI - Increasing body mass index and abdominal subcutaneous fat thickness are associated with increased skin-to-epidural space distance in pregnant women. AB - BACKGROUND: Body mass index does not indicate the distribution of adipose tissue. Central adiposity may be measured using ultrasound measurement of subcutaneous fat thickness. This study determined if the abdominal subcutaneous fat thickness measured correlated with skin-to-epidural space distance at delivery, and compared this with the booking body mass index. METHODS: We analysed a sub-set of participants from a single-centre, prospective cohort study that assessed the relationship between subcutaneous fat thickness and maternity outcomes. Abdominal subcutaneous fat thickness measurements were obtained during the routine fetal anomaly scan. The skin-to-epidural space distance was obtained in those having epidural or combined spinal-epidural analgesia. Linear regression was used to test for strength of association and adjusted R2 values calculated to determine if subcutaneous fat thickness or body mass index was more strongly associated with skin-to-epidural space distance. RESULTS: The 463 women had a median (IQR) booking body mass index of 25.0 kg/m2 (21.8-29.3) and subcutaneous fat thickness of 16.2 mm (13.0-21.0). The median (IQR) skin-to-epidural space distance was 5.0 cm (4.5-6.0). Both parameters significantly correlated with skin-to-epidural space distance (r=0.53 and 0.68 respectively, P <0.001. Adjusted linear regression coefficient (95% CI) for subcutaneous fat thickness was 0.09 (0.08 0.11), R2=0.30 and for body mass index 0.12 (0.11-0.13), R2=0.47. CONCLUSIONS: Booking body mass index had a stronger relationship with skin-to-epidural space distance at delivery than subcutaneous fat thickness, explaining 47% of the variation in the skin-to-epidural distance. PMID- 30477997 TI - Ephedrine versus phenylephrine as a vasopressor for spinal anaesthesia-induced hypotension in parturients undergoing high-risk caesarean section: meta-analysis, meta-regression and trial sequential analysis. AB - BACKGROUND: Phenylephrine is the preferred vasopressor for the prevention and treatment of spinal anaesthesia-induced hypotension during caesarean section, because studies on low-risk elective patients found it to have a less detrimental effect on umbilical artery pH compared with ephedrine. However, limited data exist from high-risk parturients and parturients with uteroplacental insufficiency. METHODS: We systematically searched for randomised, controlled, double-blinded trials of these two vasopressors in high-risk caesarean sections. We applied conventional meta-analysis, trial sequential analysis, computing the required information size that would exclude type I and II errors, contour enhanced funnel plot testing for publication bias, meta-regression to assess the dose-response relationship, and the Grading of Recommendations Assessment, Development, and Evaluation system (GRADE). The incidence of fetal acidosis (umbilical arterial pH <7.2) was the primary outcome. RESULTS: Eight trials (712 patients) with low risk of bias were identified. Pooling six studies of patients with preeclampsia and other reasons for fetal compromise, as well as subgroup analysis of the preeclampsia studies, revealed no significant differences in the incidence of fetal acidosis. Trial sequential analysis showed that the required information size was not reached. The funnel plot was not suggestive of publication bias. Meta-regression showed no dose-response relationship. The GRADE score was moderate quality. CONCLUSIONS: Despite several studies and a large number of patients there was insufficient evidence to make a recommendation for choice of vasopressor in high-risk caesarean section. Trials with adequate power to detect differences in the incidence of fetal acidosis between ephedrine and phenylephrine are required to provide evidence-based guidance. PMID- 30477998 TI - Effect of companion presence on maternal satisfaction during neuraxial catheter placement for labor analgesia: a randomized clinical trial. AB - BACKGROUND: Neuraxial labor analgesia is frequently achieved after placing an epidural catheter under sterile conditions. There is no consensus on the risk versus benefit of allowing a parturient's companion to remain during the procedure. We sought to assess the effect of the presence of a companion on maternal satisfaction and anxiety during neuraxial catheter placement for labor analgesia. METHODS: Healthy nulliparous parturients planning to receive neuraxial labor analgesia after admission to labor, and who had a companion with them at the time of interview, were randomized to having a companion present or not present in the labor and delivery room during neuraxial catheter placement. Participants completed questionnaires to assess maternal anxiety, pain catastrophizing, and health literacy. Satisfaction was scored on 5-point Likert scale (1- highly dissatisfied, 2- dissatisfied, 3- neutral, 4- satisfied, 5- highly satisfied). RESULTS: A total of 143 participants completed the study. The Wilcoxon-Mann-Whitney odds ratio for a random pair of satisfaction scores for a woman with her companion present compared with companion not present was 1.93 (95% CI 1.30 to 2.81, P=0.001). Anxiety scores were decreased following the procedure (P=0.39) in both groups. Eighty-nine percent of women randomized to companion not present would have preferred to have a companion present (P <0.001) compared with only one with their companion present who would have preferred her companion to be not present (P=0.99). CONCLUSION: Maternal satisfaction can be improved with the presence of a companion in the labor and delivery room at the time of neuraxial catheter placement for labor analgesia. PMID- 30477999 TI - Incidence of respiratory depression after epidural administration of morphine for cesarean delivery: findings using a continuous respiratory rate monitoring system. AB - BACKGROUND: Epidural morphine is widely used for postoperative analgesia after cesarean delivery. However, respiratory depression can occur after neuraxial administration of morphine. Previous reports describing respiratory depression in obstetric patients have relied on intermittent visual counting of the respiratory rate. In this study, we estimated the incidence of respiratory depression in patients who had received epidural morphine after cesarean delivery, using a continuous respiratory rate monitoring system with a finger sensor. METHODS: One hundred patients scheduled to undergo elective cesarean delivery and receive intraoperative neuraxial morphine between April and December 2016 were recruited for this single-center, prospective observational study. Postoperatively, all patients received epidural morphine 3 mg and were equipped with the Nellcor respiratory rate monitoring system. Respiratory depression was defined as both bradypnea (respiratory rate <=10 breaths/min) and oxygen desaturation (mild <=95%; moderate <=90%; severe <=85%) for greater than one minute. The number of patients with respiratory depression between administration of morphine and first ambulation was recorded hourly. RESULTS: Complete monitoring was obtained for 89 of 100 women. The median duration of monitoring was 19.0 hours. Forty-six patients (52%) developed mild respiratory depression at least once before ambulation, but only one (1%) developed moderate respiratory depression. None required supplemental oxygen or naloxone. CONCLUSIONS: Approximately half the women experienced mild respiratory depression, but only one developed moderate respiratory depression. Continuous respiratory rate monitoring until ambulation may assist in early identification of respiratory depression after neuraxial administration of morphine. PMID- 30478000 TI - Determination of ChloraPrep(r) drying time before neuraxial anesthesia in elective cesarean delivery. A prospective observational study. AB - BACKGROUND: ChloraPrep(r) is a skin antiseptic commonly used before neuraxial anesthesia. It is believed that skin must be allowed to dry to prevent nerve damage by seeding ChloraPrep(r) solution into the neuraxis. We aimed to determine ChloraPrep(r) drying time in pregnant women before initiation of neuraxial anesthesia. METHODS: In 18 parturients undergoing elective cesarean delivery the skin 'wetness' after standardized ChloraPrep(r) application was prospectively assessed by blotting the skin with tissue paper and observing for residual orange tint. The isopropyl alcohol drying time was indirectly assessed by measuring the alcohol vapor concentration above the skin with a volatile organic compound analyzer. The primary outcome was the time measured from the end of skin preparation until tissue paper was no longer stained with orange tint. The secondary outcome was the time measured from the end of skin preparation until an abrupt reduction of isopropyl alcohol vapor concentration indicating that no further significant evaporation of alcohol was occurring. RESULTS: The mean ChloraPrep(r) drying time assessed by blotting the skin with tissue paper was 123 s (SD 32 s, 95% CI 107 to 140 s, range 85-195 s). The estimated isopropyl alcohol drying time was 82 s (95% CI 77.4 to 86.3 s). CONCLUSION: Our results suggest that ChloraPrep(r) drying time may be greater than the current manufacturer recommended guideline of three minutes. The amount of ChloraPrep(r) used, application methods, patient characteristics, and environmental factors could influence the drying time. PMID- 30478001 TI - Short- and long-term impacts of azithromycin treatment on the gut microbiota in children: A double-blind, randomized, placebo-controlled trial. AB - BACKGROUND: Macrolides are commonly prescribed for respiratory infections and asthma-like episodes in children. While their clinical benefits have been proved, concerns regarding the side-effects of their therapeutic use have been raised. Here we assess the short- and long-term impacts of azithromycin on the gut microbiota of young children. METHODS: We performed a randomized, double-blind, placebo-controlled trial in a group of children aged 12-36 months, diagnosed with recurrent asthma-like symptoms from the COPSAC2010 cohort. Each acute asthma-like episode was randomized to a 3-day course of azithromycin oral solution of 10 mg/kg per day or placebo. Azithromycin reduced episode duration by half, which was the primary end-point and reported previously. The assessment of gut microbiota after treatment was the secondary end-point and reported in this study. Fecal samples were collected 14 days after randomization (N = 59, short term) and again at age 4 years (N = 49, long-term, of whom N = 18 were placebo treated) and investigated by 16S rRNA gene amplicon sequencing. FINDINGS: Short term, azithromycin caused a 23% reduction in observed richness and 13% reduction in Shannon diversity. Microbiota composition was shifted primarily in the Actinobacteria phylum, especially a reduction of abundance in the genus Bifidobacterium. Long-term (13-39 months after treatment), we did not observe any differences between the azithromycin and placebo recipients in their gut microbiota composition. INTERPRETATION: Azithromycin treatment induced a perturbation in the gut microbiota 14 days after randomization but did not have long-lasting effects on the gut microbiota composition. However, it should be noted that our analyses included a limited number of fecal samples for the placebo treated group at age 4 years. FUND: Lundbeck Foundation, Danish Ministry of Health, Danish Council for Strategic Research, Capital Region Research Foundation, China Scholarship Council. PMID- 30478002 TI - Neurocognitive Pathways in Attention-Deficit/Hyperactivity Disorder and White Matter Microstructure. AB - BACKGROUND: This study sought to identify attention-deficit/hyperactivity disorder (ADHD) abnormalities in relationships between brain white matter structure and individual differences in several types of impulsive behavior. METHODS: Adolescents, n = 67 with ADHD combined subtype and n = 68 without ADHD, were given neuropsychological tests and underwent diffusion tensor imaging scans. Principal component analysis reduced test scores into factors representing different types of impulsive behavior. Tract-based spatial statistics quantified white matter integrity in relationship to components of impulsive behavior. ADHD versus non-ADHD differences in the strength and nature of linear relationships between regional white matter and three impulsivity components were examined using multiple regression. RESULTS: Principal component analysis found three separate impulsivity-related factors that were interpreted as motor response inhibition, impulsive choice, and delay aversion. Relationships between regional fractional anisotropy and response inhibition or impulsive choice did not differ between ADHD and non-ADHD groups. There was a significant interaction between diagnostic group and delay aversion test performance relationships with regional fractional anisotropy. For youths without ADHD, greater anisotropy in numerous tracts predicted better delay aversion test performance. In contrast, anisotropy in regions including the corpus callosum, corona radiata, internal capsule, and corticospinal tracts had either a negative or no relationship with delay aversion test performance in ADHD. CONCLUSIONS: The results provide additional support that different proposed etiological pathways to ADHD have discretely different neurobiological features. Large disorganization of white matter microstructure appears to contribute to reward-based ADHD pathways rather than motor inhibition. PMID- 30478003 TI - Post-exposure prophylaxis for measles with immunoglobulins revised recommendations of the standing committee on vaccination in Germany. AB - Passive immunisation with immunoglobulins as post-exposure prophylaxis after contact with measles is recommended by the German Standing Committee on Vaccination (STIKO) particularly for unprotected individuals at high risk of complications for whom active immunization is contraindicated, such as infants <6 months of age, immunocompromised patients and pregnant women. The efficacy of passive immunisation in preventing measles depends on how soon after exposure it is administered, the concentration of measles antibodies in the immunoglobulin products and dosage. Since the global introduction of standard active immunisation against measles and the concomitant reduction in virus circulation, the levels of measles virus (MV)-specific IgG antibodies in the population have dropped. Thus, the concentration of MV-specific antibodies in immunoglobulin products derived from human plasma donors has declined as the proportion of vaccinated donors has increased. The MV-neutralizing capacity of immunoglobulin products is not routinely tested in Germany. No official data exist on the concentrations of MV-specific IgG antibodies in individual batches of immunoglobulins available in Germany and the required minimum level for MV specific IgG is not stipulated. The STIKO re-evaluated available data and measurements of MV-neutralizing capacities of available immunoglobulin (IgG) products in Germany at the National Reference Centre Measles, Mumps, Rubella at the Robert Koch Institute. Based on the findings, STIKO modified its previous recommendations on the post-exposure use of immunoglobulins (2001), especially with respect to risk groups, application and dosage. STIKO now recommends a single intravenous administration of immunoglobulins (400 mg/kg body weight) as soon as possible, preferably within six days, after exposure to measles, specifically for infants aged <6 months, susceptible pregnant women and immunocompromised patients. PMID- 30478004 TI - Vaccine preventable invasive bacterial diseases in Italy: A comparison between the national surveillance system and recorded hospitalizations, 2007-2016. AB - BACKGROUND: Vaccine-preventable invasive bacterial diseases (IBDs) caused by Neisseria meningitidis (Nm), Streptococcus pneumoniae (Sp), and Haemophilus influenzae (Hi) have been notified in Italy since 2007 without assessing reporting completeness. METHODS: Our study compared the number of cases of IBDs identified from the Italian Hospital Discharge Records (HDRs), using specific diagnostic ICD-9-CM codes, with those notified to the National Surveillance System (NSS) from 2007 to 2016. A multinomial logistic regression model was used to impute the aetiology of all discharges with a diagnosis of unspecified bacterial meningitis. RESULTS: Over a 10-year period, 14,243 hospital discharges with diagnosis of IBD were estimated in Italy (12,671 with specified aetiology and 1,572 with imputed aetiology). Among those, 2,513 (17.6%) were caused by Nm, 10,441 (73.3%) by Sp, and 1289 (9.1%) by Hi. Most invasive meningococcal diseases were coded as meningitis (72.3%), while Hi and Sp were more frequently coded as septicaemia (51.6% and 60.4%, respectively). The highest mean annual incidence rate was found for IBD caused by Sp (1.74 per 100,000), followed by Nm (0.42 per 100,000) and by Hi (0.21 per 100,000). Comparing NSS with HDR data, we found an initially high underreporting of all IBDs, and particularly for Hi. Data from the two systems overlapped in more recent years, due to an improved reporting completeness. The increasing IBD incidence observed in NSS data was not confirmed by HDR data trends, although with pathogen-related differences with Hi cases rising in both data sources, suggesting that is mainly due to an improved disease notification rather than to a true incidence increase. CONCLUSIONS: Comparing surveillance data with other data sources is useful to better interpret observed trends of notifiable diseases. PMID- 30478005 TI - Similar relative risks of seizures following measles containing vaccination in children born preterm compared to full-term without previous seizures or seizure related disorders. AB - BACKGROUND: Febrile seizures are associated with the first dose of measles containing vaccines and the risk increases with chronologic age during the second year of life. We used the Vaccine Safety Datalink (VSD) to determine if the relative increase in risk of seizures following receipt of measles-containing vaccine differs by gestational age at birth. METHODS: Children were eligible if they received their first dose of measles-containing vaccine at age 12 through 23 months from January 2003 through September 2015. Children were excluded if they had a history of seizure or conditions strongly related to seizure prior to 12 months of age. Seizures were identified by diagnostic codes in the inpatient or emergency department settings. Using risk-interval analysis, we estimated the incidence rate ratio (IRR) for seizures in the 7 through 10 days (risk period) vs 15 through 42 days (control period) following receipt of measles-containing vaccines in children born preterm (<37 weeks gestation age) and those born full term (>=37 weeks). RESULTS: There were 532,375 children (45,343 preterm and 487,032 full-term) who received their first dose of measles-containing vaccine at age 12 through 23 months. The IRRs of febrile seizures 7 through 10 days compared with 15 through 42 days after receipt of measles-containing vaccine were 3.9 (95% CI: 2.5-6.0) in preterm children and 3.2 (2.7-3.7) in full-term children; the ratio of IRRs: was 1.2 (0.76-1.9), p = 0.41. IRRs were also similar across gestational age groups, by vaccine type received (measles-mumps-rubella [MMR] or measles-mumps-rubella-varicella [MMRV]) and age at vaccination (12-15 or 16-23 months). CONCLUSION: Vaccination with a measles-containing vaccine in the second year of life is associated with a similar relative risk of a first seizure in children born preterm as in those who were born full-term. PMID- 30478006 TI - Drivers of vaccination preferences to protect a low-value livestock resource: Willingness to pay for Newcastle disease vaccines by smallholder households. AB - Vaccination can be an effective risk management approach to minimize the burden of disease and increase livestock productivity for smallholder households in low income countries. In contrast to vaccination of cattle, a high-value smallholder asset, there is a significant knowledge gap for the drivers of vaccine adoption of smallholder poultry. Newcastle disease virus (NDV) causes high mortality in chickens and is one of the greatest constraints to East African poultry production. To determine preferences and willingness to pay for NDV vaccines by chicken-owning households in Tanzania, we administered a survey with a contingent valuation activity to 535 households across six villages in Arusha, Singida, and Mbeya regions. Given the low current vaccination rate, we tested the null hypothesis that smallholder households do not value NDV vaccines and found overwhelming evidence that smallholders do value NDV vaccines. The willingness to pay (WTP) estimate was 5853 Tanzanian shillings ($2.64) to vaccinate ten chickens given the vaccine was protective for a period of three months. This estimate is about twice the market price reported by households in the study areas suggesting chicken-owning households value and benefit from NDV vaccines, but face other barriers to vaccination. Previous vaccination had the largest positive effect size on WTP suggesting smallholders observe benefits from vaccinating. In contrast to studies of vaccination of higher-cost cattle where off-farm income sources often drive willingness to pay, on-farm income was a driver of WTP for NDV vaccines suggesting different drivers affect protection of low-value livestock assets as compared to high-value assets. PMID- 30478007 TI - Increasing FIM2/3 antigen-content improves efficacy of Bordetella pertussis vaccines in mice in vivo without altering vaccine-induced human reactogenicity biomarkers in vitro. AB - Current acellular-pertussis (aP) vaccines appear inadequate for long-term pertussis control because of short-lived efficacy and the increasing prevalence of pertactin-negative isolates which may negatively impact vaccine efficacy. In this study, we added fimbriae (FIM)2 and FIM3 protein to licensed 2-, 3- or 5 component aP vaccines (Pentavac(r), Boostrix(r), Adacel(r), respectively) to assess whether an aP vaccine with enhanced FIM content demonstrates enhanced efficacy. Vaccine-induced protection was assessed in an intranasal mouse challenge model. In addition, potential reactogenicity was measured by biomarkers in a human whole blood assay (WBA) in vitro and benchmarked the responses against licensed whole cell pertussis (wP) and aP vaccines including Easyfive(r), Pentavac(r) and Pentacel(r). The results show that commercial vaccines demonstrated reduced efficacy against pertactin-negative versus pertactin positive strains. However, addition of higher amounts of FIM2/3 to aP vaccines reduced lung colonization and increased vaccine efficacy against a pertactin negative strain in a dose-dependent manner. Improvements in efficacy were similar for FIM2 and FIM3-expressing strains. Increasing the amount of FIM2/3 proteins in aP formulations did not alter vaccine-induced biomarkers of potential reactogenicity including prostaglandin E2, cytokines and chemokines in human newborn cord and adult peripheral blood tested in vitro. These results suggest that increasing the quantity of FIM proteins in current pertussis vaccine formulations may further enhance vaccine efficacy against B. pertussis infection without increasing the reactogenicity of the vaccine. PMID- 30478008 TI - Herpes simplex virus 1 infection and valacyclovir treatment in schizophrenia: Results from the VISTA study. AB - BACKGROUND: Several studies have implicated herpes simplex virus-type 1 (HSV-1) in the pathophysiology of schizophrenia. A recent trial demonstrated that the anti-viral medication valacylovir, which prevents replication of activated HSV-1, improved selected cognitive deficits in people with schizophrenia. In this study, we examined demographic and illness related differences between HSV-1 positive versus HSV-1 negative subjects with early phase schizophrenia and attempted to replicate the previous valacyclovir treatment results in this population. METHODS: 170 subjects with schizophrenia (HSV-1 positive N = 70; HSV-1 negative N = 96) from 12 US sites participated in the HSV-1 positive versus negative comparisons, and were randomized 1:1 to valacyclovir (1.5 g BID) or placebo for a 16-week, double-blind efficacy trial. The primary endpoints were working and verbal memory. RESULTS: The HSV-1 positive group, as compared to the HSV-1 negative group, were older (p < 0.001) with fewer males (p = 0.003), and had a longer duration of illness (p = 0.008), more positive symptoms (p = 0.013), poorer quality of life (p = 0.034) and more impairment on the letter-number sequencing test, which is a measure of working memory (p = 0.045). Valacyclovir failed to significantly improve any of the cognitive indices, symptom or functioning measures. CONCLUSIONS: HSV-1 sero-positivity appears to be a marker of a subgroup with a more severe form of schizophrenia. Valacyclovir was not efficacious in the study, perhaps because the herpes virus was in the dormant, non-activated state and therefore non-responsive to valacyclovir effects. ClinicalTrials.gov Identifier: NCT02008773. PMID- 30478009 TI - Infection of newly identified phleboviruses in ticks and wild animals in Hokkaido, Japan indicating tick-borne life cycles. AB - Recent discoveries of tick-borne pathogens have raised public health concerns on tick-borne infectious diseases and emphasize the need to assess potential risks of unrecognized tick-borne pathogens. First, to determine the existence of tick borne phleboviruses (TBPVs), genetic surveillance of phleboviruses in ticks was conducted mainly in Hokkaido, the northernmost island in Japan from 2013 to 2015. Genes of two TBPVs, previously reported as Mukawa virus (MKWV) and a newly identified relative of MKWV, Kuriyama virus (KURV), were detected and the viruses were isolated from Ixodes persulcatus collected in Hokkaido, but not in I. persulcatus collected from other areas of Japan. These viruses were phylogenetically and antigenically similar to each other. Next, to investigate the infection of MKWV in mammals, serum samples from wildlife captured in Hokkaido from 2007 to 2011 were used for serological screening. Neutralizing antibodies against MKWV were detected in both Yezo-deer (Cervus nippon yesoensis) (2/50) and raccoons (Procyon lotor) (16/64). However, no infectious MKWV was recovered from laboratory mice in experimental infections, though viral RNAs were detected in their tissues. Thus, MKWV and KURV may maintain tick-mammalian life cycles in Hokkaido, suggesting their potential as causative agents of tick-borne diseases in mammals. PMID- 30478010 TI - Age-related variations in gene expression patterns of renal cell carcinoma. AB - BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is known to occur across the adult lifetime traversing the spectrum of age-related organismal changes. Little is known as to how the aging process may affect the course of renal cell carcinoma (RCC) and the repertoire of genes involved. METHODS: Using The Cancer Genome Atlas (n = 436) and Cancer Genomics of the Kidney (n = 89) datasets, we applied regression analysis to examine associations between patient age and gene expression profiles in ccRCC tumors and normal kidney tissues. Pathway enrichment analysis was performed to identify cellular process that is affected by aging in ccRCC. Moreover, connectivity mapping analysis was used to predict age-dependent response to drug treatments. RESULTS: Our analysis revealed different age dependent gene expression spectra in ccRCC and normal kidney tissues. These findings were significant and independently reproducible in both datasets examined. Age up-regulated genes, showing higher expression in older patients, were significantly enriched (false discovery rate <0.05) in normal tissues for pathways associated with immune response and extracellular matrix organization, whereas age up-regulated genes in tumors were enriched for metabolism and oxidation pathways. Strikingly, age down-regulated genes in normal cells were also enriched for metabolism and oxidation, while those in tumors were enriched for extracellular matrix organization. Further in silico analysis of potential drug targets predicted preferential efficacy of Phosphoinositide 3-kinase inhibitor or immunotherapy in association with age. CONCLUSION: We report on previously unrecognized associations between age and molecular underpinnings of RCC, including age-associated expression of genes implicated in RCC development or treatment. PMID- 30478011 TI - Delivery of chemotherapy for testicular cancer in routine practice: A population based study. AB - INTRODUCTION: Maintenance of chemotherapy dose intensity is a cornerstone of management in testicular germ cell tumors. We describe chemotherapy delivery and outcomes of patients in routine practice. METHODS: The Ontario Cancer Registry was linked to electronic records of treatment to identify patients diagnosed with testicular cancer treated with orchiectomy and chemotherapy from 2005 to 2010. We describe chemotherapy delivery and dose intensity. Overall survival was measured from the start of chemotherapy. RESULTS: During the study period, 552 new cases of testicular cancer were treated with orchiectomy and chemotherapy; drug/regimen details were available for 475 (86%) cases. The study population included 324 patients with nonseminoma and 151 with seminoma. The majority of patients were treated with bleomycin, etoposide, and cisplatin (BEP) (83%, 394/475) or etoposide and cisplatin (EP) (6%, 30/475); 89% (379/424) received 3 to 4 cycles of treatment. Thirty two percent of all BEP patients (125/394) had at least 1 dose omission of bleomycin; this rate increased to 51% of patients treated with BEP * 4. Eight percent (33/397) of evaluable BEP/EP patients had a dose reduction/omission of cisplatin and 21% (82/397) had a dose delay of >6 days. Among the BEP/EP cases, 44% (174/397) had reduced chemotherapy dose intensity. Five-year overall survival for all cases was 95%. CONCLUSIONS: Almost half of patients treated with BEP/EP chemotherapy in routine practice have some form of reduced chemotherapy delivery. Despite this, long-term survival in the general population is very high. Further studies are required to understand the extent to which dose delivery might influence outcomes. PMID- 30478012 TI - Prognostic significance of serum gamma-glutamyltransferase in patients with advanced urothelial carcinoma. AB - OBJECTIVES: Serum gamma-glutamyltransferase (GGT) is reportedly associated with prognosis in patients with various malignancies. However, the prognostic role of GGT is unknown among patients with advanced urothelial carcinoma (aUC). This study was designed to examine the prognostic role of serum GGT in patients with aUC. MATERIALS AND METHODS: Charts of 125 consecutive aUC patients (inoperable cT4 and/or metastasis to lymph nodes/distant organs) managed at a single cancer center between 2004 and 2016 were retrospectively reviewed. Variables collected included age, sex, body mass index, Karnofsky performance status, primary site, clinical tumor stage, lymph node/visceral metastasis, hepatic comorbidities, the presence of curative treatment before the diagnosis of aUC, white blood cell count, neutrophil-to-lymphocyte ratio, hemoglobin, albumin, lactate dehydrogenase, alkaline phosphatase, GGT, C-reactive protein, and treatments given after the diagnosis of aUC. Associations of variables with overall survival (OS) were analyzed using the Cox proportional hazard model. RESULTS: Serum GGT was elevated (>=60 U/l) at the diagnosis of aUC in 16 patients (13%). During follow-up period (median 12.1 months), 101 patients died (2-year OS rate, 32%). Patients with elevated GGT at the diagnosis of aUC had a significantly poorer prognosis than those with normal GGT with respective 2-year OS rates of 0% and 37% (P < 0.001). On multivariate analysis, elevated GGT was a significant and independent risk factor for shorter OS (hazard ratio, HR = 2.97; P < 0.001) as were poorer Karnofsky performance status (HR = 3.47; P < 0.001), elevated lactate dehydrogenase (HR = 1.86; P = 0.033), advanced age (HR = 1.82; P = 0.013), elevated neutrophil-to-lymphocyte ratio (HR = 1.80; P = 0.015), elevated C reactive protein (HR = 1.73; P = 0.018), the absence of systemic chemotherapy (HR = 1.71; P = 0.035), and primary site of upper urinary tract (HR = 1.71; P = 0.014) in descending order by HR. The prognostic significance of elevated GGT was also observed in a subset of 101 patients who had been diagnosed with aUC at their first presentation. CONCLUSION: The present study for the first time demonstrated that elevated serum GGT was an independent adverse prognostic factor in aUC patients. PMID- 30478013 TI - Mutations in renal cell carcinoma. AB - Renal cell carcinoma (RCC) is a commonly diagnosed and histologically diverse urologic malignancy. Clear cell RCC (ccRCC) is by far the most common, followed by the papillary and chromophobe subtypes. Sarcomatoid differentiation is a morphologic change that can be seen in all subtypes that typically portends a poor prognosis. In the past, treatment options for RCC were limited to cytokine based therapy with a high-toxicity profile and low response rate. An increased understanding of the molecular basis of RCC has led to substantial improvement in treatment options in the form of targeted therapy and immunotherapy. A significant early discovery in RCC was frequent inactivation of the Von Hippel Lindau gene in ccRCC, which ultimately led to the development of vascular endothelial growth factor and mammalian target of rapamycin inhibitors. Further genomic sequencing of ccRCC tumors has identified other common mutations including BAP-1, PBRM1, SETD2, and PIK3CA. Many recent studies have explored how these mutations can affect prognosis and response to treatment. Likewise, papillary RCC has also been studied at the molecular level, which has shown a high level of mutations in the MET gene; early clinical data suggest the utility of MET targeted therapy. Finally, regarding the rarer sarcomatoid tumors, mutations in TP53 and NF2 may be important to their development. As we continue to learn more about what drives RCC at the molecular level, treatment options for RCC patients are diversifying. PMID- 30478014 TI - Individualized small-incision orbicularis-levator fixation blepharoplasty for unilateral single-eyelid Asians. AB - Unilateral double-eyelid blepharoplasty is often required by people with unilateral single eyelid. The full incisional method may cause permanent skin scar formation, and the buried suture method may lead to early eyelid fold loosening, which could not reduce the soft tissue thickness of eyelid. A total of 85 patients (8 males and 77 females) with unilateral single eyelids were studied between January 2015 and January 2016, with a mean age of 25.57 +/- 6.5 years. Small-incision orbicularis-levator fixation blepharoplasty was performed on all patients on the single eyelid side. During surgery, the orbicularis oculi (OO) muscle and the orbital fat (OF) were selectively removed through the small skin incisions. The thicknesses of upper eyelid were measured preoperatively and at 6 months postoperatively. The position and tension of the eyelid creases, eyelids symmetry, and satisfaction status were also evaluated. Eighty patients (10 left eyes and 70 right eyes) were followed up for 19 +/- 3.4 months. Before surgery, the average thickness of OO muscle is 0.895 +/- 0.199 mm (left) and 0.970 +/- 0.185 mm (right) (P = 0.0127), the thickness of OF is 0.717 +/- 0.154 mm (left) and 0.867 +/- 0.143 mm (right) (P = 0.0187). Six months postsurgery, the average thickness of OO muscle is 0.894 +/- 0.199 mm (left) and 0.907 +/- 0.188 mm (right) (P = 0.293), the thickness of OF is 0.703 +/- 0.143 mm (left) and 0.747 +/- 0.0957 mm (right) (P = 0.534). In conclusion, small-incision orbicularis levator fixation blepharoplasty can produce a desired aesthetic effect for unilateral single-eyelid patients as its personalized designing, symmetrical eyelid thickness, and slight skin scar formation. PMID- 30478015 TI - Chronic deltoid ligament insufficiency repair with Internal BraceTM augmentation. AB - BACKGROUND: Patients with chronic deltoid ligament insufficiency (CDLI) present a challenging situation. Although numerous procedures have been described, optimal treatment is still a matter of debate. While the treatment armamentarium ranges from simple ligament repair to complex reconstructions with or without realignment osteotomies, direct repair augmented with an Internal BraceTM device appears to be an attractive intermediate option. We investigated functional outcomes and complications in patients with CDLI operated on using Internal BraceTM augmentation. METHODS: A prospective study was conducted. Patients were included if they presented medial ankle pain and/or giving way, exhibited asymmetric flexible hindfoot valgus, failed conservative treatment, and had a positive MRI evaluated by an independent radiologist. Patients with stage IV flatfoot deformity, neuropathy and/or inflammatory arthritis were excluded. CDLI was confirmed intraoperatively with the arthroscopic drive-through sign. Patients were evaluated preoperatively and postoperatively using FAAM, SF-36 and grade of satisfaction. Paired t-tests were used to assess FAAM and SF-36 scores variation. RESULTS: Thirteen patients met inclusion criteria. No patient was lost to follow up, with a mean follow-up time of 13.5 months (range 6-21). Preoperative FAAM and SF-36 scores improved from 58.7 to 75.3 and from 60.2 to 84.4 postoperatively, respectively (p<.01). Two implant failures were observed, with no apparent compromise of construct stability. No patient was re-operated. CONCLUSIONS: Our results suggest that deltoid ligament repair with Internal BraceTM augmentation in patients with CDLI is a reliable option with good functional outcomes and high satisfaction grade in short term follow-up. LEVEL OF EVIDENCE: Level IV. PMID- 30478016 TI - The role of neuroplasticity in cholinergic neurons of the laterodorsal tegmental nucleus for cocaine addiction. AB - A large body of literature indicates that neural adaptations induced by cocaine in the mesocorticolibic system cause addictive behaviors. Emerging evidence suggests that the laterdorsal tegmental nucleus (LDT), which contains cholinergic, glutamatergic and GABAergic neurons and innervates the ventral tegmental area (VTA), might also contribute to the development of cocaine addiction. In this review, we summarize our recent findings showing that neuroplasticity elicited by cocaine administration in LDT cholinergic neurons is involved in the expression of addictive behaviors. Ex vivo electrophysiological recordings obtained from repeatedly cocaine administered rats revealed and increased excitatory synaptic transmission to and enhanced intrinsic membrane excitability in LDT cholinergic neurons. The former depended on enhanced glutamate release probability form presynaptic terminals and the latter was mediated by increased persistent sodium conductance. Additionally, intra-LDT administration of AMPA/HMDA receptor antagonists or a persistent sodium channel blocker attenuated the expression of cocaine-induced conditioned place preference. These findings suggest that chronic cocaine exposure-induced neuroplasticity in LDT cholinergic neurons may activate LDT cholinergic neurons, which in turn may enhance the activity of dopamine neurons in the VTA, leading to the development of cocaine addiction. PMID- 30478017 TI - Molecular effects of a variable environment on Sydney rock oysters, Saccostrea glomerata: Thermal and low salinity stress, and their synergistic effect. AB - Bivalves are frequently exposed to salinity and temperature fluctuations in the estuary. This study explored the molecular effect of these fluctuations by exposing Sydney rock oysters, (Saccostrea glomerata), native to Australia, to either low salinity, elevated temperature or a combined salinity and temperature stress. Following the exposures, RNA-Seq was carried out on the collected oyster tissues. Differential transcript analysis resulted in a total of 1473, 1232 and 2571 transcripts, which were differentially expressed in S. glomerata exposed to low salinity (10 ppt), elevated temperature (30 degrees C) or the combined stressor (15 ppt and 30 degrees C), respectively, when compared to control oysters. All stress treatments had some effect on molecular processes such as innate immune response or respiration, with overall the strongest effects seen in S. glomerata exposed to the combined stressor. Additionally, most transporters putatively involved in osmoregulation were found to be suppressed in response to the combined stressor and the low salinity exposure. This study provides insight into the oyster's responses to both, single and dual stressors commonly found in an estuarine environment. PMID- 30478018 TI - Components of variation in female common cuckoo calls. AB - Investigations on bird vocalizations have largely focused on males. Female vocalizations are widespread in birds but few studies have investigated female vocal characteristics, particularly in non-Passeriformes. In this study, we use new field recordings from China, and calls available from an online sound library to examine temporal patterns, call consistency and geographical variation in vocalizations of female common cuckoos Cuculus canorous. The peak in vocal activity (both male and female) was in the morning, which contrasts to what would be predicted if the sole function of the female call was to distract the attention of hosts after parasitizing a host's nest in the afternoon. Both male and female common cuckoos were more vocally active in sunny weather, than rainy weather. We also found larger intra-individual variation in female rather than in male calls, which may benefit female cuckoos by increasing stimulation to host species. Peak frequency of female calls decreased with increased latitude, while differences in female call features were not associated with geographic distance. In summary, our findings that female calls are used in the morning, rather than at peak egg laying, yet are highly variable and show little geographic patterns suggest that the function of these female calls may be more variable and intricate than previously thought. However, because research on female vocalizations is underrepresented, future studies are still needed. PMID- 30478019 TI - The Perceived Benefits of an Artificial Intelligence-Embedded Mobile App Implementing Evidence-Based Guidelines for the Self-Management of Chronic Neck and Back Pain: Observational Study. AB - BACKGROUND: Chronic musculoskeletal neck and back pain are disabling conditions among adults. Use of technology has been suggested as an alternative way to increase adherence to exercise therapy, which may improve clinical outcomes. OBJECTIVE: The aim was to investigate the self-perceived benefits of an artificial intelligence (AI)-embedded mobile app to self-manage chronic neck and back pain. METHODS: A total of 161 participants responded to the invitation. The evaluation questionnaire included 14 questions that were intended to explore if using the AI rehabilitation system may (1) increase time spent on therapeutic exercise, (2) affect pain level (assessed by the 0-10 Numerical Pain Rating Scale), and (3) reduce the need for other interventions. RESULTS: An increase in time spent on therapeutic exercise per day was observed. The median Numerical Pain Rating Scale scores were 6 (interquartile range [IQR] 5-8) before and 4 (IQR 3-6) after using the AI-embedded mobile app (95% CI 1.18-1.81). A 3-point reduction was reported by the participants who used the AI-embedded mobile app for more than 6 months. Reduction in the usage of other interventions while using the AI-embedded mobile app was also reported. CONCLUSIONS: This study demonstrated the positive self-perceived beneficiary effect of using the AI embedded mobile app to provide a personalized therapeutic exercise program. The positive results suggest that it at least warrants further study to investigate the physiological effect of the AI-embedded mobile app and how it compares with routine clinical care. PMID- 30478020 TI - Use of a Digital Medication Management System for Effective Assessment and Enhancement of Patient Adherence to Therapy (ReX): Feasibility Study. AB - BACKGROUND: Medication nonadherence is a major problem in health care, imposing poor clinical outcomes and a heavy financial burden on all stakeholders. Current methods of medication adherence assessment are severely limited: they are applied only periodically, do not relate to actual pill intake, and suffer from patient bias due to errors, misunderstanding, or intentional nonadherence. ReX is an innovative medication management system designed to address poor patient adherence and enhance patient engagement with their therapy. ReX controls and tracks pills from the point of packaging right through to the patient's mouth. ReX generates robust, real-time adherence data. The system enables patients to report outcomes, complete surveys, and receive messages and instructions. ReX includes a reusable drug dispensing unit, disposable cassette containing pills, and a cloud-based data portal. OBJECTIVE: We aimed to evaluate ReX feasibility by human factor studies including evaluation of ReX safety; ReX acceptance and usability; and ReX efficacy of providing pills according to a preprogrammed dose regimen, managing reminders and adherence data, and enhancing the adherence rate compared with the standard of care. METHODS: The ReX system was evaluated in 2 human factor, nonclinical feasibility studies. Human subjects used ReX for the administration of pill-shaped Tic Tac sweets. The initial study evaluated ReX use and pill intake administration; second was a self-controlled, 4-day home-use study. All subjects took pills at home, according to a preprogrammed dose regimen, for 4 days each via the device (ReX test) or from standard packaging (control test). The adherence rate (percent of pills taken) was measured by the study subject's report, remaining pills count, and ReX records (in the ReX test). ReX safety and usability were evaluated by a questionnaire filled out by the subject. RESULTS: The initial feasibility study evaluated usability and acceptance of the ReX novel approach to pill dispensing. All subjects successfully managed 2 pill intakes. The ReX device was rated as easy to use by 81% (48/59) of subjects. The 4-day home-use study evaluated the safety, efficacy, and usability of the ReX system. No adverse event occurred; no pill overdose or pill malformation was reported. The overall adherence rate in the ReX test was 97.6% compared with 76.3% in the control test (P<.001). Real-time, personalized reminders provided in the event of a delay in pill intake contributed to 18.0% of doses taken during the ReX test. The ReX system was found easy to use by 87% (35/40) of subjects; 90% (36/40) felt comfortable using it for their medication. CONCLUSIONS: ReX's novel "tracking to the mouth" technology was found usable and accepted by subjects. The assessment of adherence rates was reliable; adherence of subjects to the dose regimen was significantly enhanced when using ReX compared with the standard of care. PMID- 30478021 TI - Economic Evaluation of an Internet-Based Preventive Cognitive Therapy With Minimal Therapist Support for Recurrent Depression: Randomized Controlled Trial. AB - BACKGROUND: Major depressive disorder (MDD) is highly recurrent and has a significant disease burden. Although the effectiveness of internet-based interventions has been established for the treatment of acute MDD, little is known about their cost effectiveness, especially in recurrent MDD. OBJECTIVES: Our aim was to evaluate the cost effectiveness and cost utility of an internet based relapse prevention program (mobile cognitive therapy, M-CT). METHODS: The economic evaluation was performed alongside a single-blind parallel group randomized controlled trial. Participants were recruited via media, general practitioners, and mental health care institutions. In total, 288 remitted individuals with a history of recurrent depression were eligible, of whom 264 were randomly allocated to M-CT with minimal therapist support added to treatment as usual (TAU) or TAU alone. M-CT comprised 8 online lessons, and participants were advised to complete 1 lesson per week. The economic evaluation was performed from a societal perspective with a 24-month time horizon. The health outcomes were number of depression-free days according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV) criteria assessed with the Structured Clinical Interview for DSM-IV axis I disorders by blinded interviewers after 3, 12, and 24 months. Quality-adjusted life years (QALYs) were self assessed with the three level version of the EuroQol Five Dimensional Questionnaire (EQ-5D-3L). Costs were assessed with the Trimbos and Institute for Medical Technology Assessment Questionnaire on Costs Associated with Psychiatric Illness (TiC-P). Incremental cost-effectiveness ratios were calculated and cost effectiveness planes and cost-effectiveness acceptability curves were displayed to assess the probability that M-CT is cost effective compared to TAU. RESULTS: Mean total costs over 24 months were ?8298 (US $9415) for M-CT and ?7296 (US $8278) for TAU. No statistically significant differences were found between M-CT and TAU regarding depression-free days and QALYs (P=.37 and P=.92, respectively). The incremental costs were ?179 (US $203) per depression-free day and ?230,816 (US $261,875) per QALY. The cost-effectiveness acceptability curves suggested that for depression-free days, high investments have to be made to reach an acceptable probability that M-CT is cost effective compared to TAU. Regarding QALYs, considerable investments have to be made but the probability that M-CT is cost effective compared to TAU does not rise above 40%. CONCLUSIONS: The results suggest that adding M-CT to TAU is not effective and cost effective compared to TAU alone. Adherence rates were similar to other studies and therefore do not explain this finding. The participants scarcely booked additional therapist support, resulting in 17.3 minutes of mean total therapist support. More studies are needed to examine the cost effectiveness of internet-based interventions with respect to long-term outcomes and the role and optimal dosage of therapist support. Overall, more research is needed on scalable and cost-effective interventions that can reduce the burden of recurrent MDD. TRIAL REGISTRATION: Netherlands Trial Register NTR2503; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2503 (Archived by WebCite at http://www.webcitation.org/73aBn41r3). PMID- 30478022 TI - Conurbation, Urban, and Rural Living as Determinants of Allergies and Infectious Diseases: Royal College of General Practitioners Research and Surveillance Centre Annual Report 2016-2017. AB - BACKGROUND: Living in a conurbation, urban, or rural environment is an important determinant of health. For example, conurbation and rural living is associated with increased respiratory and allergic conditions, whereas a farm or rural upbringing has been shown to be a protective factor against this. OBJECTIVE: The objective of the study was to assess differences in general practice presentations of allergic and infectious disease in those exposed to conurbation or urban living compared with rural environments. METHODS: The population was a nationally representative sample of 175 English general practices covering a population of over 1.6 million patients registered with sentinel network general practices. General practice presentation rates per 100,000 population were reported for allergic rhinitis, asthma, and infectious conditions grouped into upper and lower respiratory tract infections, urinary tract infection, and acute gastroenteritis by the UK Office for National Statistics urban-rural category. We used multivariate logistic regression adjusting for age, sex, ethnicity, deprivation, comorbidities, and smoking status, reporting odds ratios (ORs) with 95% CIs. RESULTS: For allergic rhinitis, the OR was 1.13 (95% CI 1.04-1.23; P=.003) for urban and 1.29 (95% CI 1.19-1.41; P<.001) for conurbation compared with rural dwellers. Conurbation living was associated with a lower OR for both asthma (OR 0.70, 95% CI 0.67-0.73; P<.001) and lower respiratory tract infections (OR 0.94, 95% CI 0.90-0.98; P=.005). Compared with rural dwellers, the OR for upper respiratory tract infection was greater in urban (OR 1.06, 95% CI 1.03 1.08; P<.001) but no different in conurbation dwellers (OR 1.00, 95% CI 0.97 1.03; P=.93). Acute gastroenteritis followed the same pattern: the OR was 1.13 (95% CI 1.01-1.25; P=.03) for urban dwellers and 1.04 (95% CI 0.93-1.17; P=.46) for conurbation dwellers. The OR for urinary tract infection was lower for urban dwellers (OR 0.94, 95% CI 0.89-0.99; P=.02) but higher in conurbation dwellers (OR 1.06, 95% CI 1.00-1.13; P=.04). CONCLUSIONS: Those living in conurbations or urban areas were more likely to consult a general practice for allergic rhinitis and upper respiratory tract infection. Both conurbation and rural living were associated with an increased risk of urinary tract infection. Living in rural areas was associated with an increased risk of asthma and lower respiratory tract infections. The data suggest that living environment may affect rates of consultations for certain conditions. Longitudinal analyses of these data would be useful in providing insights into important determinants. PMID- 30478023 TI - Extraction of Information Related to Adverse Drug Events from Electronic Health Record Notes: Design of an End-to-End Model Based on Deep Learning. AB - BACKGROUND: Pharmacovigilance and drug-safety surveillance are crucial for monitoring adverse drug events (ADEs), but the main ADE-reporting systems such as Food and Drug Administration Adverse Event Reporting System face challenges such as underreporting. Therefore, as complementary surveillance, data on ADEs are extracted from electronic health record (EHR) notes via natural language processing (NLP). As NLP develops, many up-to-date machine-learning techniques are introduced in this field, such as deep learning and multi-task learning (MTL). However, only a few studies have focused on employing such techniques to extract ADEs. OBJECTIVE: We aimed to design a deep learning model for extracting ADEs and related information such as medications and indications. Since extraction of ADE-related information includes two steps-named entity recognition and relation extraction-our second objective was to improve the deep learning model using multi-task learning between the two steps. METHODS: We employed the dataset from the Medication, Indication and Adverse Drug Events (MADE) 1.0 challenge to train and test our models. This dataset consists of 1089 EHR notes of cancer patients and includes 9 entity types such as Medication, Indication, and ADE and 7 types of relations between these entities. To extract information from the dataset, we proposed a deep-learning model that uses a bidirectional long short-term memory (BiLSTM) conditional random field network to recognize entities and a BiLSTM-Attention network to extract relations. To further improve the deep-learning model, we employed three typical MTL methods, namely, hard parameter sharing, parameter regularization, and task relation learning, to build three MTL models, called HardMTL, RegMTL, and LearnMTL, respectively. RESULTS: Since extraction of ADE-related information is a two-step task, the result of the second step (ie, relation extraction) was used to compare all models. We used microaveraged precision, recall, and F1 as evaluation metrics. Our deep learning model achieved state-of-the-art results (F1=65.9%), which is significantly higher than that (F1=61.7%) of the best system in the MADE1.0 challenge. HardMTL further improved the F1 by 0.8%, boosting the F1 to 66.7%, whereas RegMTL and LearnMTL failed to boost the performance. CONCLUSIONS: Deep learning models can significantly improve the performance of ADE-related information extraction. MTL may be effective for named entity recognition and relation extraction, but it depends on the methods, data, and other factors. Our results can facilitate research on ADE detection, NLP, and machine learning. PMID- 30478024 TI - Negative-Pressure Wound Therapy Versus Standard Treatment of Adult Patients With Conflict-Related Extremity Wounds: Protocol for a Randomized Controlled Trial. AB - BACKGROUND: In armed conflict, injuries commonly affect the extremities and contamination with foreign material often increases the risk of infection. The use of negative-pressure wound therapy has been described in the treatment of acute conflict-related wounds, but reports are retrospective and with limited follow-up. OBJECTIVE: The objective of this study is to investigate the effectiveness and safety of negative-pressure wound therapy use in the treatment of patients with conflict-related extremity wounds. METHODS: This is a multisite, superiority, pragmatic randomized controlled trial. We are considering for inclusion patients 18 years of age and older who are presenting with a conflict related extremity wound within 72 hours after injury. Patients are block randomly assigned to either negative-pressure wound therapy or standard treatment in a 1:1 ratio. The primary end point is wound closure by day 5. Secondary end points include length of stay, wound infection, sepsis, wound complications, death, and health-related quality of life. We will explore economic outcomes, including direct health care costs and cost effectiveness, in a substudy. Data are collected at baseline and at each dressing change, and participants are followed for up to 3 months. We will base the primary statistical analysis on intention-to treat. RESULTS: The trial is ongoing. Patient enrollment started in June 2015. We expect to publish findings from the trial by the end of 2019. CONCLUSIONS: To the best of our knowledge, there has been no randomized trial of negative-pressure wound therapy in this context. We expect that our findings will increase the knowledge to establish best-treatment strategies. TRIAL REGISTRATION: ClinicalTrials.gov NCT02444598; http://clinicaltrials.gov/ct2/show/NCT02444598 (Archived by WebCite at http://www.webcitation.org/72hjI2XNX). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/12334. PMID- 30478025 TI - A Tablet-Based Interactive Movement Tool for Pediatric Rehabilitation: Development and Preliminary Usability Evaluation. AB - BACKGROUND: Motivating interactive tools may increase adherence to repetitive practice for children with disabilities, but many virtual reality and active video gaming systems are too challenging for children with significant needs. OBJECTIVE: The objective of this study was to develop and conduct a usability evaluation of the Fun, Interactive Therapy Board (FITBoard), a movement toy bridging digital and physical interactions for children with disabilities. METHODS: The FITBoard is a tablet app involving games controlled by hand, head, or foot touch of configurable, wired surfaces. Usability evaluation involved a cognitive walkthrough and think-aloud processes. Participants verbalized aloud while completing a series of 26 task actions involved in selecting a game and configuring the FITBoard to achieve the therapeutic goal. Therapists then responded to questions about usability perceptions. Unsuccessful actions were categorized as goal or action failures. Qualitative content analysis supported understanding of usability problems. RESULTS: Participants included 5 pediatric physical therapists and 2 occupational therapists from 2 clinical sites. Goal failure was experienced by all participants in 2 tasks, and action failure was experienced by all participants in 2 tasks. For 14 additional tasks, 1 or more patients experienced goal or action failure, with an overall failure rate of 69% (18 of 26 tasks). Content analysis revealed 4 main categories: hardware usability, software usability, facilitators of therapy goals, and improvement suggestions. CONCLUSIONS: FITBoard hardware and software changes are needed to address goal and action failures to rectify identified usability issues. Results highlight potential FITBoard applications to address therapeutic goals and outline important practical considerations for product use by therapists. Subsequent research will evaluate therapist, parent, and child perspectives on FITBoard clinical utility when integrated within regular therapy interventions. PMID- 30478026 TI - Prediction of Glucose Metabolism Disorder Risk Using a Machine Learning Algorithm: Pilot Study. AB - BACKGROUND: A 75-g oral glucose tolerance test (OGTT) provides important information about glucose metabolism, although the test is expensive and invasive. Complete OGTT information, such as 1-hour and 2-hour postloading plasma glucose and immunoreactive insulin levels, may be useful for predicting the future risk of diabetes or glucose metabolism disorders (GMD), which includes both diabetes and prediabetes. OBJECTIVE: We trained several classification models for predicting the risk of developing diabetes or GMD using data from thousands of OGTTs and a machine learning technique (XGBoost). The receiver operating characteristic (ROC) curves and their area under the curve (AUC) values for the trained classification models are reported, along with the sensitivity and specificity determined by the cutoff values of the Youden index. We compared the performance of the machine learning techniques with logistic regressions (LR), which are traditionally used in medical research studies. METHODS: Data were collected from subjects who underwent multiple OGTTs during comprehensive check-up medical examinations conducted at a single facility in Tokyo, Japan, from May 2006 to April 2017. For each examination, a subject was diagnosed with diabetes or prediabetes according to the American Diabetes Association guidelines. Given the data, 2 studies were conducted: predicting the risk of developing diabetes (study 1) or GMD (study 2). For each study, to apply supervised machine learning methods, the required label data was prepared. If a subject was diagnosed with diabetes or GMD at least once during the period, then that subject's data obtained in previous trials were classified into the risk group (y=1). After data processing, 13,581 and 6760 OGTTs were analyzed for study 1 and study 2, respectively. For each study, a randomly chosen subset representing 80% of the data was used for training 9 classification models and the remaining 20% was used for evaluating the models. Three classification models, A to C, used XGBoost with various input variables, some including OGTT data. The other 6 classification models, D to I, used LR for comparison. RESULTS: For study 1, the AUC values ranged from 0.78 to 0.93. For study 2, the AUC values ranged from 0.63 to 0.78. The machine learning approach using XGBoost showed better performance compared with traditional LR methods. The AUC values increased when the full OGTT variables were included. In our analysis using a particular setting of input variables, XGBoost showed that the OGTT variables were more important than fasting plasma glucose or glycated hemoglobin. CONCLUSIONS: A machine learning approach, XGBoost, showed better prediction accuracy compared with LR, suggesting that advanced machine learning methods are useful for detecting the early signs of diabetes or GMD. The prediction accuracy increased when all OGTT variables were added. This indicates that complete OGTT information is important for predicting the future risk of diabetes and GMD accurately. PMID- 30478027 TI - Assessing the Impact of Video-Based Assignments on Health Professions Students' Social Presence on Web: Case Study. AB - BACKGROUND: Web-based education is one of the leading learning pedagogies in health professions education. Students have access to a multitude of opinions, knowledge, and resources on Web, but communication among students in Web-based courses is complicated. Technology adds a filter that makes it difficult to decipher the emotions behind words or read nonverbal cues. This is a concern because students benefit more from Web-based classes when they have a high perception of social presence. To enhance social presence on Web, we planned to use video-based assignments (VBAs) that encourage students to interact with each other. OBJECTIVE: This case study examines the impact of VBAs on health professions students and their experiences with the technology. This study aims to provide information to the growing body of literature about strategies to develop social presence on Web. METHODS: A total of 88 students from various nursing programs participated in the study. While the control group comprised 36 students who submitted only written-based assignments (WBAs), the experimental group of 52 students submitted VBAs besides WBAs. No enrolled student had previously participated in the course, and there were no repeaters in either of the groups. Both groups participated in a weekly survey comprising 4 open-ended questions and 3 Likert items on a scale of 1-5 (1=strongly disagree and 5=strongly agree). The social presence questionnaire assessed by the experimental group comprised 16 items and a 5-point Likert scale in which higher scores represented higher levels of social presence. While quantitative data were analyzed using descriptive statistics, qualitative responses were analyzed using content analysis. RESULTS: No significant differences were noted between the groups regarding the program (F1,87=0.36, P=.54). Regarding students' engagement, no statistically significant difference was observed between the 2 groups (t14=0.96, P=.35). However, the experimental group's average score for engagement was slightly higher (4.29 [SD 0.11]) than that of the control group (4.21 [SD 0.14]). Comparison of the total number of responses to the weekly engagement survey revealed 88.0% (287/326) as either strongly agree or agree in the control group, whereas 93.1% (525/564) in the experimental group. No statistically significant difference was observed between VBAs and WBAs weeks (t6=1.40, P=.21) in the experimental group. Most students reported a positive experience using VBAs, but technical issues were barriers to embracing this new approach to learning. CONCLUSIONS: This study reveals that social presence and engagement are positively associated with student learning and satisfaction in Web-based courses. Suggestions are offered to enhance social presence on Web that could generate better learning outcomes and students' experiences. PMID- 30478028 TI - US judge drops FGM charges against two doctors, saying law is unconstitutional. PMID- 30478029 TI - Mouse Idh3a mutations cause retinal degeneration and reduced mitochondrial function. AB - Isocitrate dehydrogenase (IDH) is an enzyme required for the production of alpha ketoglutarate from isocitrate. IDH3 generates the NADH used in the mitochondria for ATP production, and is a tetramer made up of two alpha, a beta and a gamma subunit. Loss of function and missense mutations in both IDH3A andIDH3B have previously been implicated in families exhibiting retinal degeneration. Using mouse models we have investigated the role of IDH3 in retinal disease and mitochondrial function.We identified mice with late-onset retinal degeneration in a screen of ageing mice carrying an ENU-induced mutation, E229K, in Idh3a Mice homozygous for this mutation exhibit signs of retinal stress, indicated by GFAP staining, as early as 3 months, but no other tissues appear to be affected. We produced a knockout of Idh3a and found that homozygous mice do not survive past early embryogenesis. Idh3a-/E229K compound heterozygous mutants exhibit a more severe retinal degeneration when compared to Idh3aE229K/E229K Analysis of mitochondrial function in mutant cell lines highlighted a reduction in mitochondrial maximal respiration and reserve capacity levels in both Idh3a E229K/E229K and Idh3a -/E229K cells. Loss-of function Idh3b mutants do not exhibit the same retinal degeneration phenotype, with no signs of retinal stress or reduction in mitochondrial respiration.It has been previously reported that the retina operates with a limited mitochondrial reserve capacity and we suggest that this, in combination with the reduced reserve capacity in mutants, explains the degenerative phenotype observed in Idh3a mutant mice. PMID- 30478030 TI - How lobbying blocked European safety checks for dangerous medical implants. PMID- 30478031 TI - Dopamine D2/3 binding potential modulates neural signatures of working memory in a load-dependent fashion. AB - Dopamine (DA) modulates cortico-striatal connections. Studies in which imaging of the DA system is integrated with functional imaging during cognitive performance have yielded mixed findings. Some work has shown a link between striatal DA measured by PET and fMRI activations, whereas others have failed to observe such a relation. A possible reason for the discrepant findings is differences in task demands, such that a more demanding task, with greater prefrontal activations, may yield a stronger association with DA. Moreover, a potential DA-BOLD association might be modulated by task performance. We studied 155 (104 normal performing and 51 low-performing subgroups) healthy older humans (43% females), who underwent fMRI scanning while performing a working memory (WM) n-back task, along with DA D2/3 assessment with [11C]raclopride and PET. Using multivariate partial-least-squares analysis, we observed a significant network showing positive associations of striatal as well as extrastriatal DA D2/3 receptors to BOLD response in the thalamo-striatal-cortical circuit, which supports WM functioning. Critically, DA-BOLD association in the normal, but not low performing, individuals was expressed in a load-dependent fashion, with stronger associations during 3-back than 1-/2-back. Moreover, normal-performing individuals, with up-regulated BOLD in response to increasing task demands, showed a stronger DA-BOLD association during 3-back, whereas low-performing individuals showed a stronger association during 2-back. This pattern suggests a nonlinear DA-BOLD-performance association, with the strongest link at the maximum capacity level. Taken together, our results suggest that DA might have a stronger impact on functional brain integrity during more demanding cognitive tasks.SIGNIFICANCE STATEMENTDopamine (DA) is a major neuromodulator in the central nervous system, and plays a key role in several cognitive processes via modulating the blood-oxygenation level-dependent (BOLD) signal. Some work has shown a link between DA and BOLD, whereas others have failed to observe such a relation. A possible reason for the discrepancy is differences in task demands, such that a more demanding task, with greater prefrontal activations, may yield a stronger association with DA. We examined the relation of DA to BOLD during working memory under three load conditions, and found that DA-BOLD association is expressed in a load-dependent fashion. These findings explain disproportionate impairment in effortful cognitive tasks in neurodegenerative diseases such as Parkinson, but also in normal aging. PMID- 30478032 TI - alpha2A-adrenergic receptor activation decreases parabrachial nucleus excitatory drive onto BNST CRF neurons and reduces their activity in vivo. AB - Stress contributes to numerous psychiatric disorders. CRF signaling and CRF neurons in the bed nucleus of the stria terminalis (BNST) drive negative affective behaviors, thus agents that decrease activity of these cells may be of therapeutic interest. Here, we show that acute restraint stress increases cFos expression in CRF neurons in the mouse dorsal BNST, consistent with a role for these neurons in stress-related behaviors. We find that activation of alpha2A adrenergic receptors (ARs) by the agonist guanfacine reduced cFos expression in these neurons both in stressed and unstressed conditions. Further, we find that alpha- and beta-ARs differentially regulate excitatory drive onto these neurons. Pharmacological and channelrhodopsin-assisted mapping experiments suggest that alpha2A-ARs specifically reduce excitatory drive from parabrachial nucleus (PBN) afferents onto CRF neurons. Given that the alpha2A-AR is a Gi-linked GPCR, we assessed the impact of activating the Gi-coupled DREADD hM4Di in the PBN on restraint stress regulation of BNST CRF neurons. CNO activation of PBN hM4Di reduced stress-induced Fos in BNST Crh neurons. Further, utilizing Prkcd as an additional marker of BNST neuronal identity, we uncovered a female-specific upregulation of the co-expression of Prkcd/Crh in BNST neurons following stress, which was prevented by ovariectomy. These findings show that stress activates BNST CRF neurons, and that alpha2A-AR activation suppresses the in vivo activity of these cells, at least in part by suppressing excitatory drive from PBN inputs onto CRF neurons.SIGNIFICANCE STATEMENTStress is a major variable contributing to mood disorders. Here, we show that stress increases activation of BNST CRF neurons that drive negative affective behavior. We find that the clinically well tolerated alpha2A-AR agonist guanfacine reduces activity of these cells in vivo, and reduces excitatory PBN inputs onto these cells ex vivo Additionally, we uncover a novel sex-dependent co-expression of Prkcd with Crh in female BNST neurons after stress, an effect abolished by ovariectomy. These results demonstrate input-specific interactions between NE and CRF, and point to an action by which guanfacine may reduce negative affective responses. PMID- 30478033 TI - Locus coeruleus phasic, but not tonic, activation initiates global remapping in a familiar environment. AB - Locus coeruleus (LC) neurons, the source of hippocampal norepinephrine (NE) are activated by novelty and changes in environmental contingencies. Based on the role of monoamines in reconfiguring invertebrate networks, and data from mammalian systems, a network reset hypothesis for the effects of LC activation has been proposed.We utilized the cellular compartmental analysis of temporal fluorescence in situ hybridization (catFISH) technique based on the cellular distribution of immediate early genes (IEGs) to examine the effect of LC activation and inactivation, on regional hippocampal maps in male rats, when LC activity was manipulated just prior to placement in a second familiar (A/A) and/or novel environment (A/B). We found that bilateral phasic, but not tonic, activation of LC reset hippocampal maps in the A/A condition while silencing the LC with clonidine prior to placement in the A/B condition blocked map reset and a familiar map emerged in the DG, proximal and distal CA1, and CA3c. However, CA3a and CA3b encoded the novel environment.These results support a role for phasic LC responses in generating novel hippocampal sequences during memory encoding and potentially, memory updating. The silencing experiments suggest novel environments may not be recognized as different by DG and CA1 without LC input. The functional distinction between phasic and tonic LC activity argues these parameters are critical for determining network changes. These data are consistent with the hippocampus (HPC) activating internal network representations to encode novel experiential episodes and suggest LC input is critical for this role.SIGNIFICANCE STATEMENTBurst activation of the broadly projecting novelty signaling system of the locus coeruleus initiates new network representations throughout the HPC despite unchanged external environments. Tonic activation does not alter network representations in the same condition. This suggests differences in the temporal parameters of neuromodulator network activation are critical for neuromodulator function. Silencing this novelty signaling system prevented the appearance of new network representations in a novel environment. Instead, familiar representations were expressed in a subset of hippocampal areas, with another subset encoding the novel environment. This 'being in two places at once' argues for independent functional regions within the HPC. These experiments strengthen the view that internal states are major determinants of the brain's construction of environmental representations. PMID- 30478034 TI - Dissociable Disruptions in Thalamic and Hippocampal Resting-State Functional Connectivity in Youth with 22q11.2 Deletions. AB - 22q11.2 deletion syndrome (22q11DS) is a recurrent copy number variant (CNV) with high penetrance for developmental neuropsychiatric disorders. Study of individuals with 22q11DS therefore may offer key insights into neural mechanisms underlying such complex illnesses. Resting-state functional connectivity MRI (rs fcMRI) studies in idiopathic schizophrenia have consistently revealed disruption of thalamic and hippocampal circuitry. Here, we sought to test whether this circuitry is similarly disrupted in the context of this genetic high-risk condition. To this end, resting-state functional connectivity patterns were assessed in a sample of human youth with 22q11DS (n=42; 59.5% female) and demographically matched healthy controls (n=39; 53.8% female). Neuroimaging data were acquired via single-band protocols, and analyzed in line with methods provided by the Human Connectome Project (HCP). We computed functional relationships between individual-specific anatomically-defined thalamic and hippocampal seeds and all gray matter voxels in the brain. Whole-brain type I error protection was achieved through nonparametric permutation-based methods. 22q11DS patients displayed dissociable disruptions in thalamic and hippocampal functional connectivity relative to control subjects. Thalamo-cortical coupling was increased in somatomotor regions, and reduced across associative networks. The opposite effect was observed for the hippocampus in regards to somatomotor and associative network connectivity. The thalamic and hippocampal dysconnectivity observed in 22q11DS suggest that high genetic risk for psychiatric illness is linked with disruptions in large-scale cortico-subcortical networks underlying higher-order cognitive functions. These effects highlight the translational importance of large-effect CNVs for informing mechanisms underlying neural disruptions observed in idiopathic developmental neuropsychiatric disorders.SIGNIFICANCE STATEMENTInvestigation of neuroimaging biomarkers in highly penetrant genetic syndromes represents a more biologically tractable approach to identify neural circuit disruptions underlying developmental neuropsychiatric conditions. 22q11.2 deletion syndrome confers particularly high risk for psychotic disorders, and is thus an important translational model in which to investigate systems-level mechanisms implicated in idiopathic illness. Here, we show resting-state fMRI evidence of large-scale sensory and executive network disruptions in youth with 22q11DS. In particular, this study provides the first evidence that these networks are disrupted in a dissociable fashion with regard to the functional connectivity of the thalamus and hippocampus, suggesting circuit-level dysfunction. PMID- 30478035 TI - Ipsilateral-dominant control of limb movements in rodent posterior parietal cortex. AB - It is well known that the posterior parietal cortex (PPC) and frontal motor cortices in primates preferentially control voluntary movements of contralateral limbs. The PPC of rats has been defined based on patterns of thalamic and cortical connectivity. The anatomical characteristics of this area suggest that it may be homologous to the PPC of primates. However, its functional roles in voluntary forelimb movements have not been well understood, particularly in the lateralization of motor limb representation, that is, the limb-specific activity representations for right- and left-forelimb movements. We examined functional spike activity of the PPC and two motor cortices, the primary motor cortex (M1) and the secondary motor cortex (M2), when head-fixed male rats performed right or left unilateral movements. Unlike primates, PPC neurons in rodents were found to preferentially represent ipsilateral forelimb movements, in contrast to the contralateral preference of M1 and M2 neurons. Consistent with these observations, optogenetic activation of PPC and motor cortices, respectively, evoked ipsilaterally and contralaterally biased forelimb movements. Finally, we examined the effects of optogenetic manipulation on task performance. PPC or M1 inhibition by optogenetic GABA release shifted the behavioral limb preference contralaterally or ipsilaterally, respectively. In addition, weak optogenetic PPC activation, which was insufficient to evoke motor responses by itself, shifted the preference ipsilaterally; although similar M1 activation showed no effects on task performance. These paradoxical observations suggest that the PPC plays evolutionarily different roles in forelimb control between primates and rodents.SIGNIFICANCE STATEMENTIn rodents, the primary and secondary motor cortices (M1 and M2) are involved in voluntary movements with contralateral preference. However, it remains unclear whether and how the posterior parietal cortex (PPC) participates in controlling multiple limb movements. We recorded functional activity from these areas using a behavioral task to monitor movements of the right and left forelimbs separately. PPC neurons preferentially represented ipsilateral forelimb movements, and optogenetic PPC activation evoked ipsilaterally biased forelimb movements. Optogenetic PPC inhibition via GABA release shifted the behavioral limb preference contralaterally during task performance, while weak optogenetic PPC activation, which was insufficient to evoke motor responses by itself, shifted the preference ipsilaterally. Our findings suggest rodent PPC contributes to ipsilaterally biased motor response and/or planning. PMID- 30478036 TI - Biparental Inheritance of Mitochondrial DNA in Humans. AB - Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is generally believed that mitochondria and mtDNA are exclusively maternally inherited in humans. Here, we identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a total of 17 individuals. Heteroplasmy of mtDNA was independently examined by high-depth whole mtDNA sequencing analysis in our research laboratory and in two Clinical Laboratory Improvement Amendments and College of American Pathologists-accredited laboratories using multiple approaches. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominantlike inheritance mode. Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent to offspring and may even lead to the development of new avenues for the therapeutic treatment for pathogenic mtDNA transmission. PMID- 30478038 TI - Interplay of the Norrin and Wnt7a/Wnt7b signaling systems in blood-brain barrier and blood-retina barrier development and maintenance. AB - beta-Catenin signaling controls the development and maintenance of the blood brain barrier (BBB) and the blood-retina barrier (BRB), but the division of labor and degree of redundancy between the two principal ligand-receptor systems-the Norrin and Wnt7a/Wnt7b systems-are incompletely defined. Here, we present a loss of-function genetic analysis of postnatal BBB and BRB maintenance in mice that shows striking threshold and partial redundancy effects. In particular, the combined loss of Wnt7a and Norrin or Wnt7a and Frizzled4 (Fz4) leads to anatomically localized BBB defects that are far more severe than observed with loss of Wnt7a, Norrin, or Fz4 alone. In the cerebellum, selective loss of Wnt7a in glia combined with ubiquitous loss of Norrin recapitulates the phenotype observed with ubiquitous loss of both Wnt7a and Norrin, implying that glia are the source of Wnt7a in the cerebellum. Tspan12, a coactivator of Norrin signaling in the retina, is also active in BBB maintenance but is less potent than Norrin, consistent with a model in which Tspan12 enhances the amplitude of the Norrin signal in vascular endothelial cells. Finally, in the context of a partially impaired Norrin system, the retina reveals a small contribution to BRB development from the Wnt7a/Wnt7b system. Taken together, these experiments define the extent of CNS region-specific cooperation for several components of the Norrin and Wnt7a/Wnt7b systems, and they reveal substantial regional heterogeneity in the extent to which partially redundant ligands, receptors, and coactivators maintain the BBB and BRB. PMID- 30478037 TI - Genetically encodable bioluminescent system from fungi. AB - Bioluminescence is found across the entire tree of life, conferring a spectacular set of visually oriented functions from attracting mates to scaring off predators. Half a dozen different luciferins, molecules that emit light when enzymatically oxidized, are known. However, just one biochemical pathway for luciferin biosynthesis has been described in full, which is found only in bacteria. Here, we report identification of the fungal luciferase and three other key enzymes that together form the biosynthetic cycle of the fungal luciferin from caffeic acid, a simple and widespread metabolite. Introduction of the identified genes into the genome of the yeast Pichia pastoris along with caffeic acid biosynthesis genes resulted in a strain that is autoluminescent in standard media. We analyzed evolution of the enzymes of the luciferin biosynthesis cycle and found that fungal bioluminescence emerged through a series of events that included two independent gene duplications. The retention of the duplicated enzymes of the luciferin pathway in nonluminescent fungi shows that the gene duplication was followed by functional sequence divergence of enzymes of at least one gene in the biosynthetic pathway and suggests that the evolution of fungal bioluminescence proceeded through several closely related stepping stone nonluminescent biochemical reactions with adaptive roles. The availability of a complete eukaryotic luciferin biosynthesis pathway provides several applications in biomedicine and bioengineering. PMID- 30478039 TI - Eurasian river spring flood observations support net Arctic Ocean mercury export to the atmosphere and Atlantic Ocean. AB - Midlatitude anthropogenic mercury (Hg) emissions and discharge reach the Arctic Ocean (AO) by atmospheric and oceanic transport. Recent studies suggest that Arctic river Hg inputs have been a potentially overlooked source of Hg to the AO. Observations on Hg in Eurasian rivers, which represent 80% of freshwater inputs to the AO, are quasi-inexistent, however, putting firm understanding of the Arctic Hg cycle on hold. Here, we present comprehensive seasonal observations on dissolved Hg (DHg) and particulate Hg (PHg) concentrations and fluxes for two large Eurasian rivers, the Yenisei and the Severnaya Dvina. We find large DHg and PHg fluxes during the spring flood, followed by a second pulse during the fall flood. We observe well-defined water vs. Hg runoff relationships for Eurasian and North American Hg fluxes to the AO and for Canadian Hg fluxes into the larger Hudson Bay area. Extrapolation to pan-Arctic rivers and watersheds gives a total Hg river flux to the AO of 44 +/- 4 Mg per year (1sigma), in agreement with the recent model-based estimates of 16 to 46 Mg per year and Hg/dissolved organic carbon (DOC) observation-based estimate of 50 Mg per year. The river Hg budget, together with recent observations on tundra Hg uptake and AO Hg dynamics, provide a consistent view of the Arctic Hg cycle in which continental ecosystems traffic anthropogenic Hg emissions to the AO via rivers, and the AO exports Hg to the atmosphere, to the Atlantic Ocean, and to AO marine sediments. PMID- 30478040 TI - Termite mounds mitigate half of termite methane emissions. AB - Termites are responsible for ~1 to 3% of global methane (CH4) emissions. However, estimates of global termite CH4 emissions span two orders of magnitude, suggesting that fundamental knowledge of CH4 turnover processes in termite colonies is missing. In particular, there is little reliable information on the extent and location of microbial CH4 oxidation in termite mounds. Here, we use a one-box model to unify three independent field methods-a gas-tracer test, an inhibitor approach, and a stable-isotope technique-and quantify CH4 production, oxidation, and transport in three North Australian termite species with different feeding habits and mound architectures. We present systematic in situ evidence of widespread CH4 oxidation in termite mounds, with 20 to 80% of termite-produced CH4 being mitigated before emission to the atmosphere. Furthermore, closing the CH4 mass balance in mounds allows us to estimate in situ termite biomass from CH4 turnover, with mean biomass ranging between 22 and 86 g of termites per kilogram of mound for the three species. Field tests with excavated mounds show that the predominant location of CH4 oxidation is either in the mound material or the soil beneath and is related to species-specific mound porosities. Regardless of termite species, however, our data and model suggest that the fraction of oxidized CH4 (f ox) remains well buffered due to links among consumption, oxidation, and transport processes via mound CH4 concentration. The mean f ox of 0.50 +/- 0.11 (95% CI) from in situ measurements therefore presents a valid oxidation factor for future global estimates of termite CH4 emissions. PMID- 30478041 TI - Integrative approach using Yersinia pestis genomes to revisit the historical landscape of plague during the Medieval Period. AB - Over the last few years, genomic studies on Yersinia pestis, the causative agent of all known plague epidemics, have considerably increased in numbers, spanning a period of about 5,000 y. Nonetheless, questions concerning historical reservoirs and routes of transmission remain open. Here, we present and describe five genomes from the second half of the 14th century and reconstruct the evolutionary history of Y. pestis by reanalyzing previously published genomes and by building a comprehensive phylogeny focused on strains attributed to the Second Plague Pandemic (14th to 18th century). Corroborated by historical and ecological evidence, the presented phylogeny, which includes our Y. pestis genomes, could support the hypothesis of an entry of plague into Western European ports through distinct waves of introduction during the Medieval Period, possibly by means of fur trade routes, as well as the recirculation of plague within the human population via trade routes and human movement. PMID- 30478042 TI - Bottom-up modeling of chromatin segregation due to epigenetic modifications. AB - We use a chromosome-scale simulation to show that the preferential binding of heterochromatin protein 1 (HP1) to regions high in histone methylation (specifically H3K9me3) results in phase segregation and reproduces features of the observed Hi-C contact map. Specifically, we perform Monte Carlo simulations with one computational bead per nucleosome and an H3K9me3 pattern based on published ChIP-seq signals. We implement a binding model in which HP1 preferentially binds to trimethylated histone tails and then oligomerizes to bridge together nucleosomes. We observe a phase reminiscent of heterochromatin dense and high in H3K9me3-and another reminiscent of euchromatin-less dense and lacking H3K9me3. This segregation results in a plaid contact probability map that matches the general shape and position of published Hi-C data. Analysis suggests that a roughly 20-kb segment of H3K9me3 enrichment is required to drive segregation into the heterochromatic phase. PMID- 30478044 TI - Correction for Yoon et al., Control of movement vigor and decision making during foraging. PMID- 30478043 TI - Phylogenomics and the evolution of hemipteroid insects. AB - Hemipteroid insects (Paraneoptera), with over 10% of all known insect diversity, are a major component of terrestrial and aquatic ecosystems. Previous phylogenetic analyses have not consistently resolved the relationships among major hemipteroid lineages. We provide maximum likelihood-based phylogenomic analyses of a taxonomically comprehensive dataset comprising sequences of 2,395 single-copy, protein-coding genes for 193 samples of hemipteroid insects and outgroups. These analyses yield a well-supported phylogeny for hemipteroid insects. Monophyly of each of the three hemipteroid orders (Psocodea, Thysanoptera, and Hemiptera) is strongly supported, as are most relationships among suborders and families. Thysanoptera (thrips) is strongly supported as sister to Hemiptera. However, as in a recent large-scale analysis sampling all insect orders, trees from our data matrices support Psocodea (bark lice and parasitic lice) as the sister group to the holometabolous insects (those with complete metamorphosis). In contrast, four-cluster likelihood mapping of these data does not support this result. A molecular dating analysis using 23 fossil calibration points suggests hemipteroid insects began diversifying before the Carboniferous, over 365 million years ago. We also explore implications for understanding the timing of diversification, the evolution of morphological traits, and the evolution of mitochondrial genome organization. These results provide a phylogenetic framework for future studies of the group. PMID- 30478045 TI - Role of human Hv1 channels in sperm capacitation and white blood cell respiratory burst established by a designed peptide inhibitor. AB - Using a de novo peptide inhibitor, Corza6 (C6), we demonstrate that the human voltage-gated proton channel (hHv1) is the main pathway for H+ efflux that allows capacitation in sperm and permits sustained reactive oxygen species (ROS) production in white blood cells (WBCs). C6 was identified by a phage-display strategy whereby ~1 million novel peptides were fabricated on an inhibitor cysteine knot (ICK) scaffold and sorting on purified hHv1 protein. Two C6 peptides bind to each dimeric channel, one on the S3-S4 loop of each voltage sensor domain (VSD). Binding is cooperative with an equilibrium affinity (K d) of ~1 nM at -50 mV. As expected for a VSD-directed toxin, C6 inhibits by shifting hHv1 activation to more positive voltages, slowing opening and speeding closure, effects that diminish with membrane depolarization. PMID- 30478046 TI - Knockout of both miR-15/16 loci induces acute myeloid leukemia. AB - MicroRNAs (miRNAs) have been extensively reported to be associated with hematological malignancies. The loss of miR-15a/16-1 at chromosome 13q14 is a hallmark of most of human chronic lymphocytic leukemia (CLL). Deletion of murine miR-15a/16-1 and miR-15b/16-2 has been demonstrated to promote B cell malignancies. Here, we evaluate the biological role of miR-15/16 clusters, crossbreeding miR-15a/16-1 and miR-15b/16-2 knockout mice. Unexpectedly, the complete deletion of both clusters promoted myeloproliferative disorders in the majority of the mice by the age of 5 months with a penetrance of 70%. These mice showed a significant enlargement of spleen and abnormal swelling of lymph nodes. Flow cytometry characterization demonstrated an expanded CD11b/Gr-1 double positive myeloid population both in spleen and in bone marrow. The transplantation of splenocytes harvested from double-KO mice into wild-type recipient mice resulted in the development of myeloproliferative disorders, as observed in the donors. In vivo, miR-15/16 cluster deletion up-regulated the expression of Cyclin D1, Cyclin D2, and Bcl-2. Taken together, our findings identify a driver oncogenic role for miR-15/16 cluster deletion in different leukocytic cell lineages. PMID- 30478047 TI - Strong impact of wildfires on the abundance and aging of black carbon in the lowermost stratosphere. AB - Wildfires inject large amounts of black carbon (BC) particles into the atmosphere, which can reach the lowermost stratosphere (LMS) and cause strong radiative forcing. During a 14-month period of observations on board a passenger aircraft flying between Europe and North America, we found frequent and widespread biomass burning (BB) plumes, influencing 16 of 160 flight hours in the LMS. The average BC mass concentrations in these plumes (~140 ng.m-3, standard temperature and pressure) were over 20 times higher than the background concentration (~6 ng.m-3) with more than 100-fold enhanced peak values (up to ~720 ng.m-3). In the LMS, nearly all BC particles were covered with a thick coating. The average mass equivalent diameter of the BC particle cores was ~120 nm with a mean coating thickness of ~150 nm in the BB plume and ~90 nm with a coating of ~125 nm in the background. In a BB plume that was encountered twice, we also found a high diameter growth rate of ~1 nm.h-1 due to the BC particle coatings. The observed high concentrations and thick coatings of BC particles demonstrate that wildfires can induce strong local heating in the LMS and may have a significant influence on the regional radiative forcing of climate. PMID- 30478048 TI - Benefits of phenotypic plasticity for population growth in varying environments. AB - Phenotypic plasticity refers to the capacity of the same organisms to exhibit different characteristics under varied environmental conditions. A plastic developmental program allows organisms to sense environmental cues in early stages of life and express phenotypes that are better fitted to environments encountered later in life. This is often considered an adaptive strategy for living in varying environments as long as the plastic response is sufficiently fast, is accurate, and is not too costly. However, despite direct costs of maintaining plasticity and producing phenotypes, a fundamental constraint on the benefit of phenotypic plasticity comes from the predictability of the future environment based on the environmental cues received during development. Here, we analyze a model of plastic development and derive the limits within which this strategy can promote population growth. An explicit expression for the long-term growth rate of a developmentally plastic population is found, which can be decomposed into several easily interpretable terms, representing the benefits and the limitations of phenotypic plasticity as an adaptation strategy. This growth rate decomposition has a remarkably similar form to the expressions previously obtained for the bet-hedging strategy, in which a population randomly diversifies into coexisting subgroups with different phenotypes, implying that those evolutionary strategies may be unified under a common general framework. PMID- 30478049 TI - Retraction for Baradaran-Heravi et al., Gentamicin B1 is a minor gentamicin component with major nonsense mutation suppression activity. PMID- 30478050 TI - Scientific communication in a post-truth society. AB - Within the scientific community, much attention has focused on improving communications between scientists, policy makers, and the public. To date, efforts have centered on improving the content, accessibility, and delivery of scientific communications. Here we argue that in the current political and media environment faulty communication is no longer the core of the problem. Distrust in the scientific enterprise and misperceptions of scientific knowledge increasingly stem less from problems of communication and more from the widespread dissemination of misleading and biased information. We describe the profound structural shifts in the media environment that have occurred in recent decades and their connection to public policy decisions and technological changes. We explain how these shifts have enabled unscrupulous actors with ulterior motives increasingly to circulate fake news, misinformation, and disinformation with the help of trolls, bots, and respondent-driven algorithms. We document the high degree of partisan animosity, implicit ideological bias, political polarization, and politically motivated reasoning that now prevail in the public sphere and offer an actual example of how clearly stated scientific conclusions can be systematically perverted in the media through an internet based campaign of disinformation and misinformation. We suggest that, in addition to attending to the clarity of their communications, scientists must also develop online strategies to counteract campaigns of misinformation and disinformation that will inevitably follow the release of findings threatening to partisans on either end of the political spectrum. PMID- 30478051 TI - Dual functions for OVAAL in initiation of RAF/MEK/ERK prosurvival signals and evasion of p27-mediated cellular senescence. AB - Long noncoding RNAs (lncRNAs) function through a diverse array of mechanisms that are not presently fully understood. Here, we sought to find lncRNAs differentially regulated in cancer cells resistant to either TNF-related apoptosis-inducing ligand (TRAIL) or the Mcl-1 inhibitor UMI-77, agents that act through the extrinsic and intrinsic apoptotic pathways, respectively. This work identified a commonly up-regulated lncRNA, ovarian adenocarcinoma-amplified lncRNA (OVAAL), that conferred apoptotic resistance in multiple cancer types. Analysis of clinical samples revealed OVAAL expression was significantly increased in colorectal cancers and melanoma in comparison to the corresponding normal tissues. Functional investigations showed that OVAAL depletion significantly inhibited cancer cell proliferation and retarded tumor xenograft growth. Mechanically, OVAAL physically interacted with serine/threonine-protein kinase 3 (STK3), which, in turn, enhanced the binding between STK3 and Raf-1. The ternary complex OVAAL/STK3/Raf-1 enhanced the activation of the RAF protooncogene serine/threonine-protein kinase (RAF)/mitogen-activated protein kinase kinase 1 (MEK)/ERK signaling cascade, thus promoting c-Myc-mediated cell proliferation and Mcl-1-mediated cell survival. On the other hand, depletion of OVAAL triggered cellular senescence through polypyrimidine tract-binding protein 1 (PTBP1) mediated p27 expression, which was regulated by competitive binding between OVAAL and p27 mRNA to PTBP1. Additionally, c-Myc was demonstrated to drive OVAAL transcription, indicating a positive feedback loop between c-Myc and OVAAL in controlling tumor growth. Taken together, these results reveal that OVAAL contributes to the survival of cancer cells through dual mechanisms controlling RAF/MEK/ERK signaling and p27-mediated cell senescence. PMID- 30478052 TI - Citrate-based materials fuel human stem cells by metabonegenic regulation. AB - A comprehensive understanding of the key microenvironmental signals regulating bone regeneration is pivotal for the effective design of bioinspired orthopedic materials. Here, we identified citrate as an osteopromotive factor and revealed its metabonegenic role in mediating citrate metabolism and its downstream effects on the osteogenic differentiation of human mesenchymal stem cells (hMSCs). Our studies show that extracellular citrate uptake through solute carrier family 13, member 5 (SLC13a5) supports osteogenic differentiation via regulation of energy producing metabolic pathways, leading to elevated cell energy status that fuels the high metabolic demands of hMSC osteodifferentiation. We next identified citrate and phosphoserine (PSer) as a synergistic pair in polymeric design, exhibiting concerted action not only in metabonegenic potential for orthopedic regeneration but also in facile reactivity in a fluorescent system for materials tracking and imaging. We designed a citrate/phosphoserine-based photoluminescent biodegradable polymer (BPLP-PSer), which was fabricated into BPLP PSer/hydroxyapatite composite microparticulate scaffolds that demonstrated significant improvements in bone regeneration and tissue response in rat femoral condyle and cranial-defect models. We believe that the present study may inspire the development of new generations of biomimetic biomaterials that better recapitulate the metabolic microenvironments of stem cells to meet the dynamic needs of cellular growth, differentiation, and maturation for use in tissue engineering. PMID- 30478053 TI - Structure and architecture of immature and mature murine leukemia virus capsids. AB - Retroviruses assemble and bud from infected cells in an immature form and require proteolytic maturation for infectivity. The CA (capsid) domains of the Gag polyproteins assemble a protein lattice as a truncated sphere in the immature virion. Proteolytic cleavage of Gag induces dramatic structural rearrangements; a subset of cleaved CA subsequently assembles into the mature core, whose architecture varies among retroviruses. Murine leukemia virus (MLV) is the prototypical gamma-retrovirus and serves as the basis of retroviral vectors, but the structure of the MLV CA layer is unknown. Here we have combined X-ray crystallography with cryoelectron tomography to determine the structures of immature and mature MLV CA layers within authentic viral particles. This reveals the structural changes associated with maturation, and, by comparison with HIV-1, uncovers conserved and variable features. In contrast to HIV-1, most MLV CA is used for assembly of the mature core, which adopts variable, multilayered morphologies and does not form a closed structure. Unlike in HIV-1, there is similarity between protein-protein interfaces in the immature MLV CA layer and those in the mature CA layer, and structural maturation of MLV could be achieved through domain rotations that largely maintain hexameric interactions. Nevertheless, the dramatic architectural change on maturation indicates that extensive disassembly and reassembly are required for mature core growth. The core morphology suggests that wrapping of the genome in CA sheets may be sufficient to protect the MLV ribonucleoprotein during cell entry. PMID- 30478054 TI - Short-term impact of PM2.5 on contemporaneous asthma medication use: Behavior and the value of pollution reductions. AB - Asthma ranks among the most costly of chronic diseases, accounting for over $50 billion annually in direct medical expenditures in the United States. At the same time, evidence has accumulated that fine particulate matter pollution can exacerbate asthma symptoms and generate substantial economic costs. To measure these costs, we use a unique nationwide panel dataset tracking asthmatic individuals' use of rescue medication and their exposure to PM2.5 (particulate matter with an aerodynamic diameter of <2.5 MUm) concentration between 2012 and 2017, to estimate the causal relationship between pollution and inhaler use. Our sample consists of individuals using an asthma digital health platform, which relies on a wireless sensor to track the place and time of inhaler use events, as well as regular nonevent location and time indicators. These data provide an accurate measurement of inhaler use and allow spatially and temporally resolute assignment of pollution exposure. Using a high-frequency research design and individual fixed effects, we find that a 1 MUg/m3 (12%) increase in weekly exposure to PM2.5 increases weekly inhaler use by 0.82%. We also show that there is seasonal, regional, and income-based heterogeneity in this response. Using our response prediction, and an estimate from the literature on the willingness to pay to avoid asthma symptoms, we show that a nationwide 1 MUg/m3 reduction in particulate matter concentration would generate nearly $350 million annually in economic benefits. PMID- 30478055 TI - Quantifying the role of mineral bridges on the fracture resistance of nacre-like composites. AB - The nacreous layer of mollusk shells holds design concepts that can effectively enhance the fracture resistance of lightweight brittle materials. Mineral bridges are known to increase the fracture resistance of nacre-inspired materials, but their role is difficult to quantify due to the lack of experimental systems where only this parameter is controllably varied. In this study, we fabricate tunable nacre-like composites that are used as a model to experimentally quantify the influence of the density of mineral bridges alone on the fracture properties of nacre-like architectures. The composites exhibit a brick-and-mortar architecture comprising highly aligned alumina platelets that are interconnected by titania mineral bridges and infiltrated by an epoxy organic phase. By combining experimental mechanical data with image analysis of such composite microstructures, an analytical model is put forward based on a simple balance of forces acting on an individual bridged platelet. Based on this model, we predict the flexural strength of the nacre-like composite to scale linearly with the density of mineral bridges, as long as the mineral interconnectivity is low enough to keep fracture in a platelet pullout mode. Increasing the mineral interconnectivity beyond this limit leads to platelet fracture and catastrophic failure of the composite. This structure-property correlation provides powerful quantitative guidelines for the design of lightweight brittle materials with enhanced fracture resistance. We illustrate this potential by fabricating nacre like bulk composites with unparalleled flexural strength combined with noncatastrophic failure. PMID- 30478056 TI - How to communicate large-scale social challenges: The problem of the disappearing American corporation. AB - Social science has distinct advantages and challenges when it comes to communicating its findings to the public. Its topics are often highly accessible to the general public, yet its findings may be counterintuitive and politically contentious. Conveying recent changes in the organization of the American economy provides an illustration of the difficulties and opportunities for engaging the public. The declining number of public corporations in the United States is associated with a shrinking middle class, lower opportunities for upward mobility, and a fraying social safety net, with important implications for individuals and public policy. Attempting to convey this set of findings to a broad public has demonstrated that some strategies and communication channels work better than others, and that some online media are particularly effective. PMID- 30478057 TI - Coordinated histone modifications and chromatin reorganization in a single cell revealed by FRET biosensors. AB - The dramatic reorganization of chromatin during mitosis is perhaps one of the most fundamental of all cell processes. It remains unclear how epigenetic histone modifications, despite their crucial roles in regulating chromatin architectures, are dynamically coordinated with chromatin reorganization in controlling this process. We have developed and characterized biosensors with high sensitivity and specificity based on fluorescence resonance energy transfer (FRET). These biosensors were incorporated into nucleosomes to visualize histone H3 Lys-9 trimethylation (H3K9me3) and histone H3 Ser-10 phosphorylation (H3S10p) simultaneously in the same live cell. We observed an anticorrelated coupling in time between H3K9me3 and H3S10p in a single live cell during mitosis. A transient increase of H3S10p during mitosis is accompanied by a decrease of H3K9me3 that recovers before the restoration of H3S10p upon mitotic exit. We further showed that H3S10p is causatively critical for the decrease of H3K9me3 and the consequent reduction of heterochromatin structure, leading to the subsequent global chromatin reorganization and nuclear envelope dissolution as a cell enters mitosis. These results suggest a tight coupling of H3S10p and H3K9me3 dynamics in the regulation of heterochromatin dissolution before a global chromatin reorganization during mitosis. PMID- 30478058 TI - Engineered occluded apo-intermediate of LacY. AB - The lactose permease of Escherichia coli (LacY) utilizes an alternating access symport mechanism with multiple conformational intermediates, but only inward (cytoplasmic)- or outward (periplasmic)-open structures have been characterized by X-ray crystallography. It is demonstrated here with sugar-binding studies that cross-linking paired-Cys replacements across the closed cytoplasmic cavity stabilize an occluded conformer with an inaccessible sugar-binding site. In addition, a nanobody (Nb) that stabilizes a periplasmic-open conformer with an easily accessible sugar-binding site in WT LacY fails to cause the cytoplasmic cross-linked mutants to become accessible to galactoside, showing that the periplasmic cavity is closed. These results are consistent with tight association of the periplasmic ends in two pairs of helices containing clusters of small residues in the packing interface between N- and C-terminal six-helix bundles of the symporter. However, after reduction of the disulfide bond, the Nb markedly increases the rate of galactoside binding, indicating unrestricted access to the Nb epitope and the galactoside-binding site from the periplasm. The findings indicate that the cross-linked cytoplasmic double-Cys mutants resemble an occluded apo-intermediate in the transport cycle. PMID- 30478059 TI - Interspecific conflict structures urban avian assemblages. PMID- 30478060 TI - Hinge region of Arabidopsis phyA plays an important role in regulating phyA function. AB - Phytochrome A (phyA) is the only plant photoreceptor that perceives far-red light and then mediates various responses to this signal. Phosphorylation and dephosphorylation of oat phyA have been extensively studied, and it was shown that phosphorylation of a serine residue in the hinge region of oat phyA could regulate the interaction of phyA with its signal transducers. However, little is known about the role of the hinge region of Arabidopsis phyA. Here, we report that three sites in the hinge region of Arabidopsis phyA (i.e., S590, T593, and S602) are essential in regulating phyA function. Mutating all three of these sites to either alanines or aspartic acids impaired phyA function, changed the interactions of mutant phyA with FHY1 and FHL, and delayed the degradation of mutant phyA upon light exposure. Moreover, the in vivo formation of a phosphorylated phyA form was greatly affected by these mutations, while our data indicated that the abundance of this phosphorylated phyA form correlated well with the extent of phyA function, thus suggesting a pivotal role of the phosphorylated phyA in inducing the far-red light response. Taking these data together, our study reveals the important role of the hinge region of Arabidopsis phyA in regulating phyA phosphorylation and function, thus linking specific residues in the hinge region to the regulatory mechanisms of phyA phosphorylation. PMID- 30478061 TI - Communicating uncertainty in policy analysis. AB - The term "policy analysis" describes scientific evaluations of the impacts of past public policies and predictions of the outcomes of potential future policies. A prevalent practice has been to report policy analysis with incredible certitude. That is, exact predictions of policy outcomes are routine, while expressions of uncertainty are rare. However, predictions and estimates often are fragile, resting on unsupported assumptions and limited data. Therefore, the expressed certitude is not credible. This paper summarizes my work documenting incredible certitude and calling for transparent communication of uncertainty. I present a typology of practices that contribute to incredible certitude, give illustrative examples, and offer suggestions on how to communicate uncertainty. PMID- 30478062 TI - Supernova, nuclear synthesis, fluid instabilities, and interfacial mixing. AB - Supernovae and their remnants are a central problem in astrophysics due to their role in the stellar evolution and nuclear synthesis. A supernova's explosion is driven by a blast wave causing the development of Rayleigh-Taylor and Richtmyer Meshkov instabilities and leading to intensive interfacial mixing of materials of a progenitor star. Rayleigh-Taylor and Richtmyer-Meshkov mixing breaks spherical symmetry of a star and provides conditions for synthesis of heavy mass elements in addition to light mass elements synthesized in the star before its explosion. By focusing on hydrodynamic aspects of the problem, we apply group theory analysis to identify the properties of Rayleigh-Taylor and Richtmyer-Meshkov dynamics with variable acceleration, discover subdiffusive character of the blast wave-induced interfacial mixing, and reveal the mechanism of energy accumulation and transport at small scales in supernovae. PMID- 30478063 TI - Evaluating science communication. AB - Effective science communication requires assembling scientists with knowledge relevant to decision makers, translating that knowledge into useful terms, establishing trusted two-way communication channels, evaluating the process, and refining it as needed. Communicating Science Effectively: A Research Agenda [National Research Council (2017)] surveys the scientific foundations for accomplishing these tasks, the research agenda for improving them, and the essential collaborative relations with decision makers and communication professionals. Recognizing the complexity of the science, the decisions, and the communication processes, the report calls for a systems approach. This perspective offers an approach to creating such systems by adapting scientific methods to the practical constraints of science communication. It considers staffing (are the right people involved?), internal collaboration (are they talking to one another?), and external collaboration (are they talking to other stakeholders?). It focuses on contexts where the goal of science communication is helping people to make autonomous choices rather than promoting specific behaviors (e.g., voter turnout, vaccination rates, energy consumption). The approach is illustrated with research in two domains: decisions about preventing sexual assault and responding to pandemic disease. PMID- 30478064 TI - An open window to close the hole. PMID- 30478065 TI - What's happening in Neurology (r) Neuroimmunology & Neuroinflammation. PMID- 30478066 TI - Retrospective review of thienopyridine therapy in migraineurs with patent foramen ovale. AB - OBJECTIVE: We retrospectively reviewed our clinical experience using off-label thienopyridine agents in patients with migraine headache (MHA) and patent foramen ovale (PFO). METHODS: Between 2011 and 2017, MHA/PFO patients referred to our practice were clinically treated with clopidogrel specifically for MHA. Those with >=50% reduction in monthly MHA days compared with baseline were deemed MHA responders. MHA nonresponders with inadequate platelet inhibition by PRU testing were offered prasugrel. Thienopyridine-responsive patients were then offered PFO closure. RESULTS: Of 136 patients (86% female, mean age 37.9 years, mean MHA burden 14.7 days/month), 80 (59%) were MHA responders to clopidogrel. The clopidogrel responder rate was equivalent in episodic, chronic, aura, and nonaura subgroups. A total of 19/45 (40%) MHA nonresponders had inadequate platelet inhibition by PRU testing on clopidogrel. Sixteen of those patients received prasugrel, were adequately platelet inhibited by PRU, and 10/16 (62%) converted to MHA responders. A total of 56/90 thienopyridine-responsive patients underwent subsequent PFO closure with thienopyridine discontinuation after 3 months. Ninety four percent had ongoing MHA relief. A total of 8/8 responders who stopped thienopyridine without PFO closure had resumption of MHA symptoms. CONCLUSION: Successful P2Y12 platelet inhibition seemed to reduce MHA symptoms in some patients with PFO, suggesting a platelet-based mechanism/trigger. The nearly parallel response to PFO closure may mechanistically link venous platelet activation with the right-to-left shunt of PFO. Thienopyridine responsiveness could be used to enrich the study population for a new MHA/PFO trial. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with PFO, P2Y12 inhibition improved MHA symptoms. PMID- 30478067 TI - Ticagrelor for Refractory Migraine/Patent Foramen Ovale (TRACTOR): An open-label pilot study. AB - OBJECTIVE: After finding that the thienopyridines clopidogrel and prasugrel reduced migraine headache (MHA) symptoms in some patients with patent foramen ovale (PFO), this small pilot study was undertaken to determine whether ticagrelor, a nonthienopyridine P2Y12 inhibitor, would have similar MHA effects and might be better suited for a future randomized trial. METHODS: MHA patients were screened for PFO. Participants with documented right to left shunt (RLS) and >=6 monthly MHA days received ticagrelor therapy for 28 days. Those with >=50% reduction in monthly MHA days were deemed responders and completed 2 additional treatment months. RESULTS: The 40 participants had a mean age of 36.2 years and mean MHA frequency of 17.4 d/mo. A total of 39/40 were female. A total of 14/40 met criteria for episodic MHA, 26/40 for chronic MHA, 14/40 had migraine with aura, and 22/40 had a moderate-large RLS (Spencer grade >=4). Seventeen of 40 participants (43%) were responders. MHA reduction continued through 3 treatment months in all responders. MHA responder rates were not statistically different in participants with episodic or chronic MHA, with or without aura, or with small/larger RLS shunt magnitude. Thirteen (32%) patients had medication side effects, without serious adverse events. CONCLUSION: P2Y12 inhibition with ticagrelor reduced MHA symptoms similarly to our previous thienopyridine experience, but participants seemed to have a less robust MHA benefit and more frequent side effects than with the thienopyridines, making it an inferior choice for a randomized trial. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that ticagrelor reduced MHA symptoms in patients with PFO. PMID- 30478068 TI - Anosmia as the initial presentation of neurosarcoidosis. PMID- 30478069 TI - Resident & Fellow Rounds. PMID- 30478070 TI - Emerging Subspecialties in Neurology: Pain medicine. PMID- 30478071 TI - Editors' note: Demoralization in Parkinson disease. PMID- 30478072 TI - Reader response: Demoralization in Parkinson disease. PMID- 30478073 TI - Author response: Demoralization in Parkinson disease. PMID- 30478074 TI - Editors' note: Teaching NeuroImages: Multimodality imaging of carotid web. PMID- 30478075 TI - Reader response: Teaching NeuroImages: Multimodality imaging of carotid web. PMID- 30478076 TI - Clinical Reasoning: Transient speech deficits in a patient with history of medulloblastoma. PMID- 30478077 TI - Financial relationships between neurologists and industry: The 2015 Open Payments database. PMID- 30478078 TI - Mystery Case: Pontine tegmental cap dysplasia in a neonate. PMID- 30478079 TI - Teaching NeuroImages: The heart sign in a patient with apparent locked-in syndrome. PMID- 30478080 TI - Teaching Video NeuroImages: Oculopalatal myoclonus: A possible consequence of brainstem injury. PMID- 30478081 TI - Parkinson disease and mortality: Understanding how the two are connected. PMID- 30478082 TI - Conditional Inactivation of Nf1 and Pten in Schwann Cells Results in Abnormal Neuromuscular Junction Maturation. AB - The neuromuscular junction (NMJ) consists of three components, namely presynaptic motor neurons, postsynaptic muscle fibers and perisynaptic Schwann cells (PSCs). The role of Schwann cells (SCs) in regulating NMJ structural and functional development remains unclear. In this study, mice with conditional inactivation of neurofibromin 1 (Nf1) and phosphatase and tensin homolog (Pten), specifically in SCs, resulted in delayed NMJ maturation that led to delayed muscle growth, recapitulating the muscular dystrophy condition observed in human neurofibromatosis type I syndrome (NF1) patients. Expression levels of NMJ development related molecules such as cholinergic receptor, nicotinic, alpha polypeptide 1 (Chrna1), agrin (Agrn), dystrophin, muscular dystrophy (Dmd), laminin, beta 2 (Lamb2) and dystroglycan 1 (Dag1) were also downregulated. To further explore the molecular alterations in these SCs, NF1- and PTEN-related pathways were analyzed in mutant sciatic nerves. As expected, hyperactive RAS/PI3K/AKT/mTOR signaling pathways were identified, suggesting the importance of these pathways for NMJ development, and subsequent muscle maturation. PMID- 30478083 TI - The Core and Holoenzyme forms of RNA Polymerase from Mycobacterium smegmatis. AB - Bacterial RNA polymerase (RNAP) is essential for gene expression and as such is a valid drug target. Hence, it is imperative to know its structure and dynamics. Here, we present two so far unreported forms of Mycobacteium smegmatis RNAP: core, and holoenzyme containing sigmaA but no other factors. Each form was detected by cryo-EM in two major conformations. Comparisons of these structures with known structures of other RNAPs reveal a high degree of conformational flexibility of the mycobacterial enzyme, and confirm that region 1.1 of sigmaA is directed into the primary channel of RNAP. Taken together, the presented study illuminates the conformational changes of unrestrained mycobacterial RNAP.IMPORTANCE We describe here 3D structures of core and holoenzyme forms of mycobacterial RNA polymerase (RNAP) solved by cryo-EM. These structures fill the so far empty spots in the gallery of the pivotal forms of mycobacterial RNAP and illuminate the extent of conformational dynamics of this enzyme. The presented findings may facilitate future designs of antimycobacterial drugs targeting RNAP. PMID- 30478084 TI - SfnR2 Regulates Dimethylsulfide-Related Utilization in Pseudomonas aeruginosa PAO1. AB - Dimethylsulfide (DMS) is a volatile sulfur compound produced mainly from the degradation of dimethylsulfoniopropionate (DMSP) in marine environments. DMS undergoes oxidation to form dimethylsulfoxide (DMSO), dimethylsulfone (DMSO2) and methanesulfonate (MSA), all of which occur in terrestrial environments and are accessible for consumption by various microorganisms. The purpose of the current study was to determine how the enhancer-binding proteins SfnR1 and SfnR2 contribute to the utilization of DMS and its derivatives in Pseudomonas aeruginosa PAO1. First, results from cell-growth experiments showed that deletion of either sfnR2 or sfnG, a gene encoding for a DMSO2-monooxygenase, significantly inhibits the ability of P. aeruginosa PAO1 to use DMSP, DMS, DMSO and DMSO2 as sulfur sources. Deletion of the sfnR1 or msuEDC genes, which encode for a MSA desulfurization pathway, did not abolish the growth of P. aeruginosa PAO1 on any sulfur compound tested. Second, data collected from beta-galactosidase assays revealed that the msuEDC-sfnR1 operon and the sfnG gene are induced in response to sulfur limitation or non-preferred sulfur sources such as DMSP, DMS, DSMO, etc Importantly, SfnR2 (and not SfnR1) is essential for this induction. Expression of sfnR2 is induced under sulfur limitation but independently of SfnR1 or SfnR2. Finally, the results of this study suggest that the main function of SfnR2 is to direct the initial activation of the msuEDC-sfnR1 operon in response to sulfur limitation or non-preferred sulfur sources. Once expressed, SfnR1 contributes to the expression of msuEDC-sfnR1, sfnG and other target genes involved in DMS related metabolism in P. aeruginosa PAO1.IMPORTANCE Dimethylsulfide (DMS) is an important environmental source of sulfur, carbon and/or energy for microorganisms. For various bacteria, including Pseudomonas, Xanthomonas and Azotobacter, DMS utilization is thought to be controlled by the transcriptional regulator SfnR. Adding more complexity, some bacteria such as Acinetobacter baumannii, Enterobacter cloacae and Pseudomonas aeruginosa possess two, non identical SfnR proteins. In this study, we demonstrate that SfnR2 and not SfnR1 is the principal regulator of DMS metabolism in P. aeruginosa PAO1. Results suggest that SfnR1 has a supportive but non-essential role in the positive regulation of genes required for DMS utilization. This study not only enhances our understanding of SfnR regulation, but importantly, provides a framework for addressing gene regulation through dual SfnR proteins in other bacteria. PMID- 30478085 TI - Direct interaction between the two Z ring membrane anchors FtsA and ZipA. AB - Initiation of Escherichia coli cell division requires three proteins, FtsZ, FtsA and ZipA, which assemble in a dynamic ring-like structure at mid-cell. Along with the transmembrane protein ZipA, the actin-like FtsA helps to tether treadmilling polymers of tubulin-like FtsZ to the membrane. In addition to forming homo oligomers, FtsA and ZipA interact directly with the C terminal conserved domain of FtsZ. Gain of function mutants of FtsA are deficient in forming oligomers and can bypass the need for ZipA, suggesting that ZipA may normally function to disrupt FtsA oligomers, although no direct interaction between FtsA and ZipA has been reported. Here, we use in vivo crosslinking to show that FtsA and ZipA indeed interact directly. We identify the exposed surface of FtsA helix 7, which also participates in binding to ATP through its internal surface, as a key interface needed for the interaction with ZipA. This interaction suggests that FtsZ's membrane tethers may regulate each other's activities.IMPORTANCE To divide, most bacteria first construct a protein machine at the plane of division, and then recruit the machinery that will synthesize the division septum. In Escherichia coli, this first stage involves the assembly of FtsZ polymers at midcell, which directly bind to membrane-associated proteins FtsA and ZipA to form a discontinuous ring structure. Although FtsZ directly binds both FtsA and ZipA, it is unclear why FtsZ requires two separate membrane tethers. Here, we uncover a new direct interaction between the tethers, which involves a helix within FtsA that is adjacent to its ATP binding pocket. Our findings infer that in addition to their known roles as FtsZ membrane anchors, FtsA and ZipA may regulate each other's structure and function. PMID- 30478086 TI - Phosphorylation at the D53 but not T65 residue of CovR determines the repression of rgg and speB transcription in emm1- and emm49-type group A streptococci. AB - CovR/CovS is a two-component regulatory system in group A Streptococcus and primarily acts as the transcriptional repressor. The D53 residue of CovR is phosphorylated by the sensor kinase CovS, and the phosphorylated CovRD53 protein binds to the intergenic region of rgg-speB to inhibit speB transcription. Nonetheless, the transcription of rgg and speB is suppressed in covS mutants. The T65 residue of CovR is phosphorylated in a CovS-independent manner, and phosphorylation at the D53 and T65 residue of CovR is mutually exclusive. Therefore, how phosphorylation at the D53 and T65 residue of CovR contributes to regulating rgg and speB expression was elucidated. The transcription of rgg and speB were suppressed in the strain that cannot phosphorylate D53 residue of CovR (CovRD53A mutant) but restored to levels similar to the wild-type strain in the CovRT65A mutant. Nonetheless, inactivation of the T65 residue phosphorylation in the CovRD53A mutant cannot derepress the rgg and speB transcription, indicating that phosphorylation at the T65 residue of CovR is not required for repressing rgg and speB transcription. Furthermore, trans-complementation of CovRD53A protein in the strain that expresses the phosphorylated CovRD53 resulted in the repression of the rgg and speB transcription. Unlike the direct binding and transcriptional inhibition of the phosphorylated CovRD53 protein to the speB transcription demonstrated previously, the present study showed that inactivation of phosphorylation at the D53 residue of CovR contributes dominantly in suppressing rgg and speB transcription.IMPORTANCE CovR/CovS is a two-component regulatory system in GAS. The D53 residue of CovR is phosphorylated by CovS, and the phosphorylated CovRD53 binds to the rgg-speB intergenic region and acts as the transcriptional repressor. Nonetheless, the transcription of rgg and Rgg controlled speB is upregulated in the covR mutant but inhibited in the covS mutant. The present study showed that nonphosphorylated CovRD53 protein inhibits the rgg and speB transcription in the presence of the phosphorylated CovRD53 in vivo, indicating that nonphosphorylated CovRD53 has dominant roles in suppressing rgg transcription. These results reveal the roles of nonphosphorylated CovRD53 in regulating the rgg transcription, which could contribute significantly to invasive phenotypes of covS mutants. PMID- 30478087 TI - DksA controls the response of the Lyme disease spirochete Borrelia burgdorferi to starvation. AB - The pathogenic spirochete Borrelia burgdorferi senses and responds to changes in the environment, including changes in nutrient availability, throughout its enzootic cycle in Ixodes ticks and vertebrate hosts. This study examined the role of DnaK suppressor protein (DksA) in the transcriptional response of B. burgdorferi to starvation. Wild-type and dksA mutant B. burgdorferi strains were subjected to starvation by shifting cultures grown in rich complete medium, BSK II, to a defined mammalian tissue culture medium, RPMI 1640, for 6 h under microaerobic conditions (5% CO2, 3% O2). Microarray analyses of wild-type B. burgdorferi revealed that genes encoding flagellar components, ribosomal proteins, and DNA replication machinery were downregulated in response to starvation. DksA-mediated transcriptomic responses to starvation in B. burgdorferi as the dksA-deficient strain differentially expressed only 47 genes in response to starvation compared to the 500 genes differentially expressed in wild-type strains. Consistent with a role for DksA in the starvation response of B. burgdorferi, fewer CFUs were observed for dksA mutants after prolonged starvation in RPMI compared to wild-type B. burgdorferi Transcriptomic analyses revealed a partial overlap between the DksA regulon and the regulon of RelBbu, the guanosine tetraphosphate and guanosine pentaphosphate [(p)ppGpp] synthetase that controls the stringent response; the DksA regulon also included many plasmid borne genes. Additionally, the dksA mutant exhibited constitutively elevated (p)ppGpp levels compared to the wild-type strain, implying a regulatory relationship between DksA and (p)ppGpp. Together, these data indicate DksA along with (p)ppGpp direct the stringent response to effect B. burgdorferi adaptation to its environment.IMPORTANCE The Lyme disease bacterium Borrelia burgdorferi survives diverse environmental challenges as it cycles between its tick vectors and various vertebrate hosts. B. burgdorferi must withstand prolonged periods of starvation while it resides in unfed Ixodes ticks. In this study, the regulatory protein DksA is shown to play a pivotal role controlling the transcriptional responses of B. burgdorferi to starvation. The results suggest that DksA gene regulatory activity impacts B. burgdorferi metabolism, virulence gene expression, and the ability of this bacterium to complete its natural life cycle. PMID- 30478088 TI - New guidance for mental health trusts aims to improve learning from patients' deaths. PMID- 30478089 TI - Myeloablative haploidentical transplantation is superior to chemotherapy for patients with intermediate-risk acute myelogenous leukemia in first complete remission. AB - PURPOSE: Although myeloablative human leukocyte antigen (HLA) haploidentical hematopoietic stem cell transplantation (haplo-HSCT) following pretransplant ATG and granulocyte colony-stimulating factor (G-CSF) stimulated grafts (ATG+G-CSF) has been confirmed as an alternative to HSCT from HLA-matched sibling donors(MSDs), the effect of haplo-HSCT on postremission treatment of patients with AML with intermediate risk (int-risk AML) who achieved first complete remission (CR1) has not been defined. EXPERIMENTAL DESIGN: In this prospective trial, among 443 consecutive patients aged 16-60 years with newly diagnosed de novo AML with int-risk cytogenetics, 147 patients with molecular int-risk AML who achieved CR1 within two courses of induction and remained in CR1 at 4 months postremission either received chemotherapy (n=69) or underwent haplo-HSCT (n=78). RESULTS: The 3-year leukemia-free survival (LFS) and overall survival (OS) were significantly higher in the haplo-HSCT group than in the chemotherapy group (74.3% vs 47.3%, P=0.0004 and 80.8% vs 53.5%, P=0.0001, respectively). In the multivariate analysis with propensity score adjustment, postremission treatment (haplo-HSCT vs chemotherapy) was an independent risk factor affecting the LFS (HR 0.360, 95% CI 0.163-0.793, P=0.011), OS (HR 0.361, 95% CI 0.156-0.832, P=0.017) and cumulative incidence of relapse (CIR; HR 0.161, 95% CI 0.057-0.459, P=0.001) either in entire cohort or stratified by minimal residual disease after the second consolidation. CONCLUSIONS: Myeloablative haplo-HSCT with ATG+G-CSF is superior to chemotherapy as a postremission treatment in patients with int-risk AML during CR1. Haplo-HSCT might be a first-line postremission therapy for int risk AML in the absence of MSDs. PMID- 30478090 TI - How sociophenomenology of the body problematises the 'problem-oriented approach' to growth hormone treatment. AB - This article examines how people who are shorter than average make sense of their lived experience of embodiment. It offers a sociophenomenological analysis of 10 semistructured interviews conducted in the Netherlands, focusing on if, how, and why height matters to them. It draws theoretically on phenomenological discussions of lived and objective space, intercorporeality and norms about bodies. The analysis shows that height as a lived phenomenon (1) is active engagement in space, (2) coshapes habituated ways of behaving and (3) is shaped by gendered norms and beliefs about height. Based on this analysis, the article challenges what we label as the 'problem-oriented approach' to discussions about growth hormone treatment for children with idiopathic short stature. In this approach, possible psychosocial disadvantages or problems of short stature and quantifiable height become central to the ethical evaluation of growth hormone treatment at the expense of first-hand lived experiences of short stature and height as a lived phenomenon. Based on our sociophenomenological analysis, this paper argues that the rationale for giving growth hormone treatment should combine medical and psychological assessments with investigations of lived experiences of the child. Such an approach would allow considerations not only of possible risks or disadvantages of short stature but also of the actual ways in which the child makes sense of her or his height. PMID- 30478091 TI - Hippo Pathway Kinase Mst1 Is Required for Long-Lived Humoral Immunity. AB - The protein kinase Mst1 is a key component of the evolutionarily conserved Hippo pathway that regulates cell survival, proliferation, differentiation, and migration. In humans, Mst1 deficiency causes primary immunodeficiency. Patients with MST1-null mutations show progressive loss of naive T cells but, paradoxically, mildly elevated serum Ab titers. Nonetheless, the role of Mst1 in humoral immunity remains poorly understood. In this study, we found that early T cell-dependent IgG1 responses in young adult Mst1-deficient mice were largely intact with signs of impaired affinity maturation. However, the established Ag specific IgG1 titers in Mst1-deficient mice decayed more readily because of a loss of Ag-specific but not the overall bone marrow plasma cells. Despite the impaired affinity and longevity of Ag-specific Abs, Mst1-deficient mice produced plasma cells displaying apparently normal maturation markers with intact migratory and secretory capacities. Intriguingly, in immunized Mst1-deficient mice, T follicular helper cells were hyperactive, expressing higher levels of IL 21, IL-4, and surface CD40L. Accordingly, germinal center B cells progressed more rapidly into the plasma cell lineage, presumably forgoing rigorous affinity maturation processes. Importantly, Mst1-deficient mice had elevated levels of CD138+Blimp1+ splenic plasma cell populations, yet the size of the bone marrow plasma cell population remained normal. Thus, overproduced low-affinity plasma cells from dysregulated germinal centers seem to underlie humoral immune defects in Mst1-deficiency. Our findings imply that vaccination of Mst1-deficient human patients, even at the early stage of life, may fail to establish long-lived high affinity humoral immunity and that prophylactic Ab replacement therapy can be beneficial to the patients. PMID- 30478092 TI - RORgammat Represses IL-10 Production in Th17 Cells To Maintain Their Pathogenicity in Inducing Intestinal Inflammation. AB - The role of retinoid-related orphan receptor gamma t (RORgammat) in Th17 cell differentiation has been well established; however, how it regulates other T cell lineages is still not clearly understood. In this study, we report that in mice, while promoting Th17 cell differentiation, RORgammat inhibited IL-10 production by T cells, thereby preserving the pathogenicity of Th17 cells. Treatment with RORgammat-specific inhibitor suppressed Th17 cell signature cytokines, but promoted IL-10 production. RORgammat inhibitor-treated Th17 cells induce less severe colitis compared with control Th17 cells. Mechanistically, the RORgammat inhibitor induced T cell expression of Blimp-1 (encoded by Prdm1). Prdm1-/- T cells produced significantly fewer IL-10 when treated with RORgammat inhibitor compared with wild-type T cells. Furthermore, RORgammat inhibitor-treated Prdm1-/ Th17 cells induce more severe colitis compared with RORgammat inhibitor-treated wild-type Th17 cells. Collectively, our studies reveal a novel mechanism by which RORgammat drives and maintains pathogenic Th17 cell development by inhibiting IL 10 production. PMID- 30478093 TI - How I treat cancer-associated venous thromboembolism. AB - Venous thromboembolism, which includes deep vein thrombosis and pulmonary embolism, is a common complication of cancer and is associated with significant morbidity and mortality. Several cancer-related risk factors contribute to the development of venous thromboembolism including cancer type/stage, chemotherapy, surgery, and patient-related factors such as advanced age and immobilization. Patients with cancer frequently undergo diagnostic imaging scans for cancer staging and treatment response evaluation, which is increasing the underlying risk of venous thromboembolism detection. The management of cancer-associated venous thromboembolism is challenging. Over the years, important advances have been made and recently, randomized controlled trials have been published helping clinicians' managements of this patient population. In this review, we will discuss common cancer-associated venous thromboembolism scenarios and critically review available evidence to guide treatment decisions. PMID- 30478094 TI - Carfilzomib vs bortezomib in patients with multiple myeloma and renal failure: a subgroup analysis of ENDEAVOR. AB - In ENDEAVOR, carfilzomib (56 mg/m2) and dexamethasone (Kd56) demonstrated longer progression-free survival (PFS) over bortezomib and dexamethasone (Vd) in patients with relapsed/refractory multiple myeloma (RRMM). Here we evaluated Kd56 vs Vd by baseline renal function in a posthoc exploratory subgroup analysis. The intent-to-treat population included 929 patients (creatinine clearance [CrCL] >=15 to <50 mL/min: Kd56, n=85 and Vd, n=99; CrCL 50 to <80 mL/min: n=186 and 177; CrCL >=80: n=193 and 189). In these subgroups, respectively, median (hazard ratio [HR; 95% confidence interval (CI)]) PFS was 14.9 (Kd56) vs 6.5 months (Vd; 0.49 [0.320-0.757]), 18.6 vs 9.4 months (0.48 [0.351-0.652]), and not reached (NR) vs 12.2 months (0.60 [0.434-0.827]). Median (HR [95% CI]) overall survival (OS) was 42.1 vs 23.7 months (0.66 [0.443-0.989]), 42.5 vs 32.8 months (0.83 [0.626-1.104]), and NR vs 42.3 months (0.75 [0.554-1.009]). Complete renal response (CrCL improvement to >=60 mL/min in any 2 consecutive visits if baseline CrCL <50 mL/min) rates were 15.3% (Kd56; 95% CI, 8.4-24.7) and 14.1% (Vd; 95% CI, 8.0-22.6). In a combined Kd56 and Vd analysis, complete renal responders had longer median (HR [95% CI]) PFS (14.1 vs 9.4 months; 0.805 [0.438-1.481]) and OS (35.3 vs 29.7 months; 0.91 [0.524-1.577]) vs non-responders. Grade >=3 adverse event rates in these subgroups (Kd56 vs Vd) were 87.1% vs 79.4%, 84.4% vs 71.8%, and 77.1% vs 65.9%. Thus, Kd56 demonstrated PFS and OS improvements over Vd in RRMM patients regardless of their baseline renal function. PMID- 30478095 TI - Future Promises and Concerns of Ubiquitous Next-Generation Sequencing. AB - Since the first draft of the human genome was completed, next-generation DNA sequencing technology has dramatically reduced the cost of sequencing a genome. Computational analysis has not advanced as fast as the instruments that generate the data, and storing all the data remains a challenge. Nevertheless, personal genomics has arrived and is already being used in the clinic. Significant privacy issues remain, however, and these are not widely understood. The Genetic Information Non-Discrimination Act (GINA) needs to be extended and the probabilistic nature of genetic predisposition must be better explained to both the public and physicians. We must also be wary that this promising new technology and its applications do not amplify existing healthcare disparities. PMID- 30478096 TI - Bioelectronic Medicine-Ethical Concerns. AB - Bioelectronic medicine (BEM) offers exciting opportunities to treat diseases such as movement disorders and refractory inflammatory disease. The many variations of BEM allow for noninvasive aspects of treatment that might eliminate or reduce the need for pharmaceuticals; therefore, the term "electroceuticals" may be suitable. BEM has been effective for movement disorders and improvement of prosthetic devices. Based on this implication, there is an allowance to impact many focus areas that include but are not limited to autoimmune disease, sensory motor conditions, and neurological conditions. There are a wide array of ethical issues that relate to BEM, which include informed consent, research ethics, innovation, academic-industry relationships, intellectual property, and the conundrum that needs to be addressed when altering the brain such as the issues of autonomy and free beneficence and social justice. The major goal is to heighten awareness of ethical issues and facilitate a proactive ethical approach regarding BEM research. PMID- 30478098 TI - What happens when the world's biggest medical device maker becomes a "health services provider"? PMID- 30478097 TI - Next-Generation Sequencing Technologies. AB - Although DNA and RNA sequencing has a history spanning five decades, large-scale massively parallel sequencing, or next-generation sequencing (NGS), has only been commercially available for about 10 years. Nonetheless, the meteoric increase in sequencing throughput with NGS has dramatically changed our understanding of our genome and ourselves. Sequencing the first human genome as a haploid reference took nearly 10 years but now a full diploid human genome sequence can be accomplished in just a few days. NGS has also reduced the cost of generating sequence data and a plethora of sequence-based methods for probing a genome have emerged using NGS as the readout and have been applied to many species. NGS methods have also entered the medical realm and will see an increasing use in diagnosis and treatment. NGS has largely been driven by short-read generation (150 bp) but new platforms have emerged and are now capable of generating long multikilobase reads. These latter platforms enable reference-independent genome assemblies and long-range haplotype generation. Rapid DNA and RNA sequencing is now mainstream and will continue to have an increasing impact on biology and medicine. PMID- 30478099 TI - England has failed to close gap with similar countries in cancer outcomes, analysis finds. PMID- 30478100 TI - Obesity is linked to increased asthma risk in children, finds study. PMID- 30478101 TI - Effectiveness of implementation strategies for the improvement of guideline and protocol adherence in emergency care: a systematic review. AB - OBJECTIVE: Guideline and protocol adherence in prehospital and in-hospital emergency departments (EDs) is suboptimal. Therefore, the objective of this systematic review was to identify effective strategies for improving guideline and protocol adherence in prehospital and ED settings. DESIGN: Systematic review. DATA SOURCES: PubMed (including MEDLINE), CINAHL, EMBASE and Cochrane. METHODS: We selected (quasi) experimental studies published between 2004 and 2018 that used strategies to increase guideline and protocol adherence in prehospital and in-hospital emergency care. Pairs of two independent reviewers performed the selection process, quality assessment and data extraction. RESULTS: Eleven studies were included, nine of which were performed in the ED setting and two studies were performed in a combined prehospital and ED setting. For the ED setting, the studies indicated that educational strategies as sole intervention, and educational strategies in combination with audit and feedback, are probably effective in improving guideline adherence. Sole use of reminders in the ED setting also showed positive effects. The two studies in the combined prehospital and ED setting showed similar results for the sole use of educational interventions. CONCLUSIONS: Our review does not allow firm conclusion on how to promote guideline and protocol adherence in prehospital emergency care, or the combination of prehospital and ED care. For ED settings, the sole use of reminders or educational interventions and the use of multifaceted strategies of education combined with audit and feedback are all likely to be effective in improving guideline adherence. PMID- 30478102 TI - Effects of managed care on the proportion of inappropriate elective diagnostic coronary angiographies in non-emergency patients in Switzerland: a retrospective cross-sectional analysis. AB - OBJECTIVE: Guidelines recommend non-invasive ischaemia testing (NIIT) for the majority of patients with suspected ischaemic heart disease in a non-emergency setting. A substantial number of these patients undergo diagnostic coronary angiography (CA) without therapeutic intervention inappropriately due to lacking preceding NIIT. The aim of this study was to evaluate the effect of voluntary healthcare models with limited access on the proportion of patients without NIIT prior to elective purely diagnostic CA. DESIGN: Retrospective cross-sectional analysis of insurance claims data from 2012 to 2015. Data included claims of basic and voluntary healthcare models from approximately 1.2 million patients enrolled with the Helsana Insurance Group. Voluntary healthcare models with limited health access are divided into gate keeping (GK) and managed care (MC) capitation models. INCLUSION CRITERIA: patients undergoing CA. EXCLUSION CRITERIA: Patients<18 years, incomplete health insurance data coverage, acute cardiac ischaemia and emergency procedures, therapeutic CA (coronary angioplasty/stenting or coronary artery bypass grafting). The effect of voluntary healthcare models on the proportion of NIIT undertaken within 2 months before diagnostic CA was assessed by means of multiple logistic regression analysis, controlled for influencing factors. RESULTS: 9173 patients matched inclusion criteria. 33.2% (3044) did not receive NIIT before CA. Compared with basic healthcare models, MC was independently associated with a higher proportion of NIIT (p<0.001, OR 1.17, CI 1.045 to 1.312), when additionally controlled for demographics, insurance coverage, inpatient treatment, cardiovascular medication, chronic comorbidities, high-risk status (patients with therapeutic cardiac intervention 1 month after or 18 months prior to diagnostic CA). GK models showed no significant association with the rate of NIIT (p=0.07, OR 1.11, CI 0.991 to 1.253). CONCLUSIONS: In a non-GK healthcare system, voluntary MC healthcare models with capitation were associated with a reduced inappropriate use of diagnostic CA compared with GK or basic models. PMID- 30478103 TI - Cluster randomised controlled trial of an online intervention to prevent ecstasy and new psychoactive substance use among adolescents: final results and implications for implementation. AB - OBJECTIVES: To evaluate the effectiveness of the online Climate Schools: Ecstasy and Emerging Drugs module over 2 years, and examine the impact of intervention dose on outcomes. DESIGN: Cluster randomised controlled trial. SETTING: Secondary schools in Australia. PARTICIPANTS: 1126 students (aged 14.9 years) from 11 schools. INTERVENTION: Five schools were randomly allocated to the four-lesson internet-based Climate Schools: Ecstasy and Emerging Drugs module. This universal intervention uses cartoon storylines to deliver harm-minimisation information about ecstasy and new psychoactive substances (NPS). It was delivered during health education classes over 4 weeks. Six schools were randomised to the control group (health education as usual). Participants were not blinded to intervention allocation. OUTCOMES MEASURES: Students completed self-report surveys at baseline, post-test, 6, 12 and 24 months post-baseline. Intentions to use ecstasy and NPS (including synthetic cannabis and synthetic stimulants), knowledge about ecstasy and NPS and lifetime use of ecstasy and NPS were assessed. This paper reports the results at 24 months post-baseline. ANALYSIS: Mixed effects regressions were conducted to analyse intervention effects from baseline to 24 months. Post hoc analyses using Inverse Probability of Treatment Weighting compared controls with students who: i) completed all four lessons ('full dose') and ii) partially completed the intervention (<=three lessons, 'incomplete dose'). RESULTS: Primary analyses found that controls were significantly more likely to intend on using synthetic cannabis compared with intervention group students (OR=3.56, p=0.01). Results from the weighted analyses indicated that controls reported significantly lower knowledge about ecstasy (p=0.001) and NPS (p=0.04) compared with the full-dose group. No significant differences were observed between the incomplete dose and control groups. CONCLUSIONS: The online intervention was effective in modifying students' intentions to use synthetic cannabis up to 24 months; however, this study highlights the importance of delivering prevention programmes in full to maximise student outcomes. TRIAL REGISTRATION NUMBER: ACTRN12613000708752. PMID- 30478104 TI - Prevalence and associated factors of khat chewing among students in Ethiopia: a protocol for systematic review and meta-analysis. AB - INTRODUCTION: These days, in Ethiopia, khat chewing is one of the widely spreading public health problems affecting the most productive segment of the population. The health implications of khat chewing among students are strongly linked with poor mental, physical and social performances. However, the national magnitude of khat chewing and the associated factors among Ethiopian students are unknown. Therefore, this systematic review and meta-analysis will answer the national prevalence of khat chewing and the associated factors among students in Ethiopia. METHODS: Published primary relevant articles will be accessed using various databases, such as Medline, PubMed, EMBASE and Scopus. Other electronic search engines, for instance, Google Scholar and Google, will be used. Furthermore, additional studies will be collected by communicating with the author(s) and following the references of relevant articles. To select eligible studies, the Joanna Briggs Institute quality appraisal checklist will be used. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist will be followed to keep the scientific rigour of the study. Heterogeneity between studies will be examined through forest plot and I2 heterogeneity tests. To identify influential studies, sensitivity analysis will be done. For substantial heterogeneity (I2>50%), the DerSimonian and Laird random-effects model will be employed. Subgroup analyses will be conducted using the random effect model. Moreover, small studies' publication bias will be checked by funnel plots and objectively by Egger's regression test. If in case Egger's test was found to be statistically significant (p<0.05), trim and fill (Duval and Tweedie) analysis will be performed. The presence of association will be declared using p<=0.05 and OR with corresponding 95% CI. ETHICS AND DISSEMINATION: Since the intention of the study is to describe earlier primary studies qualitatively and pool the results of those articles, ethical clearance will not be a concern. The results of the study will be published in a reputable peer-reviewed journal and presented at different scientific research conferences. It will also be disseminated to academic as well as other concerned institutions. PROSPERO REGISTRATION NUMBER: CRD-42,017,081,886. PMID- 30478105 TI - Biomedical authors' awareness of publication ethics: an international survey. AB - OBJECTIVE: The extent to which biomedical authors have received training in publication ethics, and their attitudes and opinions about the ethical aspects of specific behaviours, have been understudied. We sought to characterise the knowledge and attitudes of biomedical authors about common issues in publication ethics. DESIGN: Cross-sectional online survey. SETTING AND PARTICIPANTS: Corresponding authors of research submissions to 20 journals. MAIN OUTCOME MEASURES: Perceived level of unethical behaviour (rated 0 to 10) presented in five vignettes containing key variables that were experimentally manipulated on entry to the survey and perceived level of knowledge of seven ethical topics related to publishing (prior publication, author omission, self-plagiarism, honorary authorship, conflicts of interest, image manipulation and plagiarism). RESULTS: 4043/10 582 (38%) researchers responded. Respondents worked in 100 countries and reported varying levels of publishing experience. 67% (n=2700) had received some publication ethics training from a mentor, 41% (n=1677) a partial course, 28% (n=1130) a full course and 55% (n=2206) an online course; only a small proportion rated training received as excellent. There was a full range (0 to 10 points) in ratings of the extent of unethical behaviour within each vignette, illustrating a broad range of opinion about the ethical acceptability of the behaviours evaluated, but these opinions were little altered by the context in which it occurred. Participants reported substantial variability in their perceived knowledge of seven publication ethics topics; one-third perceived their knowledge to be less than 'some knowledge' for the sum of the seven ethical topics and only 9% perceived 'substantial knowledge' of all topics. CONCLUSIONS: We found a large degree of variability in espoused training and perceived knowledge, and variability in views about how ethical or unethical scenarios were. Ethical standards need to be better articulated and taught to improve consistency of training across institutions and countries. PMID- 30478106 TI - Protective effects of oral anticoagulants on cerebrovascular diseases and cognitive impairment in patients with atrial fibrillation: protocol for a multicentre, prospective, observational, longitudinal cohort study (Strawberry study). AB - INTRODUCTION: Non-valvular atrial fibrillation (NVAF) is known as a robust risk factor for stroke. Recent reports have suggested a risk of dementia with NVAF, but much remains unknown regarding the relationship between this mechanism and the potential protective effects of novel anticoagulants (direct oral anticoagulants (DOACs), or non-vitamin K oral anticoagulants). METHODS AND ANALYSIS: This study, the strategy to obtain warfarin or DOAC's benefit by evaluating registry, is an investigator-initiated, multicentre, prospective, observational, longitudinal cohort study comparing the effects of warfarin therapy and DOACs on cerebrovascular diseases and cognitive impairment over an estimated duration of 36 months. Once a year for 3 years, the activities of daily living and cognitive functioning of non-demented patients with NVAF will be assessed. Demographics, risk factors, laboratory investigations, lifestyle, social background and brain MRI will be assessed. ETHICS AND DISSEMINATION: This protocol has been approved by the ethics committee of the National Center for Geriatrics and Gerontology (No. 1017) and complies with the Declaration of Helsinki. Informed consent will be obtained before study enrolment and only coded data will be stored in a secured database. The results will be published in peer reviewed journals and presented at scientific meetings to ensure the applicability of the findings in clinical practice. TRIAL REGISTRATION NUMBER: UMIN000025721. PMID- 30478107 TI - Between-hospital and between-neighbourhood variance in trauma outcomes: cross sectional observational evidence from the Detroit metropolitan area. AB - OBJECTIVE: Disparities in treatment outcomes for traumatic injury are an important concern for care providers and policy makers. Factors that may influence these disparities include differences in risk exposure based on neighbourhood of residence and differences in quality of care between hospitals in different areas. This study examines geographical disparities within a single region: the Detroit metropolitan area. DESIGN: Data on all trauma admissions between 2006 and 2014 were obtained from the Michigan State Inpatient Database. Admissions were grouped by patient neighbourhood of residence and admitting hospital. Generalised linear mixed modelling procedures were used to determine the extent of shared variance based on these two levels of categorisation on three outcomes. Patients with trauma due to common mechanisms (falls, firearms and motor vehicle traffic) were examined as additional subgroups. SETTING: 66 hospitals admitting patients for traumatic injury in the Detroit metropolitan area during the period from 2006 to 2014. PARTICIPANTS: 404 675 adult patients admitted for treatment of traumatic injury. OUTCOME MEASURES: In-hospital mortality, length of stay and hospital charges. RESULTS: Intraclass correlation coefficients indicated that there was substantial shared variance in outcomes based on hospital, but not based on neighbourhood of residence. Among all injury types, hospital-level differences accounted for 12.5% of variance in mortality risk, 28.5% of variance in length of stay and 32.2% of variance in hospital charges. Adjusting the results for patient age, injury severity, mechanism and comorbidities did not result in significant reduction in the estimated variance at the hospital level. CONCLUSIONS: Based on these data, geographical disparities in trauma treatment outcomes were more strongly attributable to differences in access to quality hospital care than to risk factors in the neighbourhood environment. Transfer of high-risk cases to hospitals with greater institutional experience in the relevant area may help address mortality disparities in particular. PMID- 30478108 TI - Surgical quality in organ procurement during day and night: an analysis of quality forms. AB - OBJECTIVES: To analyse a potential association between surgical quality and time of day. DESIGN: A retrospective analysis of complete sets of quality forms filled out by the procuring and accepting surgeon on organs from deceased donors. SETTING: Procurement procedures in the Netherlands are organised per region. All procedures are performed by an independent, dedicated procurement team that is associated with an academic medical centre in the region. PARTICIPANTS: In 18 months' time, 771 organs were accepted and procured in The Netherlands. Of these, 17 organs were declined before transport and therefore excluded. For the remaining 754 organs, 591 (78%) sets of forms were completed (procurement and transplantation). Baseline characteristics were comparable in both daytime and evening/night-time with the exception of height (p=0.003). PRIMARY OUTCOME MEASURE: All complete sets of quality forms were retrospectively analysed for the primary outcome, procurement-related surgical injury. Organs were categorised based on the starting time of the procurement in either daytime (8:00-17:00) or evening/night-time (17:00-8:00). RESULTS: Out of 591 procured organs, 129 organs (22%) were procured during daytime and 462 organs (78%) during evening/night time. The incidence of surgical injury was significantly lower during daytime; 22 organs (17%) compared with 126 organs (27%) procured during evening/night-time (p=0.016). This association persists when adjusted for confounders. CONCLUSIONS: This study shows an increased incidence of procurement-related surgical injury in evening/night-time procedures as compared with daytime. Time of day might (in)directly influence surgical performance and should be considered a potential risk factor for injury in organ procurement procedures. PMID- 30478109 TI - Impoverishment and catastrophic expenditures due to out-of-pocket payments for antenatal and delivery care in Yangon Region, Myanmar: a cross-sectional study. AB - OBJECTIVES: (1) To assess the levels of impoverishment and catastrophic expenditure due to out-of-pocket (OOP) payments for antenatal care (ANC) and delivery care in Yangon Region, Myanmar; and (2) to explore the determinants of impoverishment and catastrophic expenditure. DESIGN, SETTING AND PARTICIPANTS: A community-based cross-sectional survey among women giving birth within the past 12 months in Yangon, Myanmar, was conducted during October to November 2016 using three-stage cluster sampling procedure. OUTCOME MEASURES: Poverty headcount ratio, normalised poverty gap and catastrophic expenditure incidence due to OOP payments in the utilisation of ANC and delivery care as well as the determinants of impoverishment and catastrophic expenditure. RESULTS: Of 759 women, OOP payments were made by 75% of the women for ANC and 99.6% for delivery care. The poverty headcount ratios after payments increased to 4.3% among women using the ANC services, to 1.3% among those using delivery care and to 6.1% among those using both ANC and delivery care. The incidences of catastrophic expenditure after payments were found to be 12% for ANC, 9.1% for delivery care and 20.9% for both ANC and delivery care. The determinants of impoverishment and catastrophic expenditure were women's occupation, number of household members, number of ANC visits and utilisation of skilled health personnel and health facilities. The associations of the outcomes with these variables bear both negative and positive signs. CONCLUSIONS: OOP payments for all ANC and delivery care services are a challenge to women, as one of fifteen women become impoverished and a further one fifth incur catastrophic expenditures after visiting facilities that offer these services. PMID- 30478110 TI - Exploring the developmental tasks of emerging adults after paediatric heart transplantation: a cross-sectional case control study. AB - OBJECTIVE: Paediatric heart transplantation (PHTX) comprises 12% of all cardiac transplants and many of the children now survive into adulthood. Only a few studies have investigated the long-term psychosocial well-being of young adult patients after PHTX; no studies have investigated developmental tasks of emerging adulthood in different domains (family, social environment, education and profession, partnership, social environment). SETTING: Specialised heart centre in Germany. PARTICIPANTS: Thirty-eight young adults aged 22.11 years (SD=4.7) who underwent PHTX and a control group of 46 participants with no known chronic diseases, aged 22.91 years (SD=1.8), participated in the study. OUTCOME MEASURES: All participants completed the following questionnaires: sociodemographic, the F SozU, to measure perceived social support, the Giebetaener Beschwerde-Bogen to measure subjective complaints experienced by patients, the KIDSCREEN-27 to measure well-being and the SF-36 to measure health-related quality of life (QoL). RESULTS: 'Family': the quality of the relationship with the parents was found to be equal in both groups, while PHTX patients stayed in closer spatial proximity to their parents. 'Social environment': PHTX patients reported lower social support by peers than the control group. 'Education and profession': PHTX patients most often worked full-time (23%), had no job and/or received a pension (21%). In comparison, most of the healthy controls did an apprenticeship (40%) and/or worked part time (32%). 'Partnership': fewer of the PHTX patients had a partner than the control group while relationship duration did not differ. In exploratory regression analyses, social support by peers predicted physical QoL, whereas physical complaints and the physical role predicted mental QoL in PHTX patients. CONCLUSIONS: Our exploratory findings highlight important similarities and differences in specific developmental tasks between PHTX patients and healthy controls. Future studies should focus on developmental tasks of PHTX patients in this age group more systematically, investigating their role in physical and mental well-being in a confirmatory manner. PMID- 30478111 TI - Differences in infant and child mortality before and after the Great East Japan Earthquake and Tsunami: a large population-based ecological study. AB - OBJECTIVES: To examine associations between access to medical care, geological data, and infant and child mortality in the area of North-Eastern Japan that was impacted by the Great East Japan Earthquake and Tsunami (GEJET) in 2011. DESIGN: A population-based ecological study using publicly available data. SETTING: Twenty secondary medical areas (SMAs) in the disaster-affected zones in the north eastern prefectures of Japan (Iwate, Fukushima and Miyagi). PARTICIPANTS: Children younger than 10 years who died in the 20 SMAs between 2008 and 2014 (n=1 748). Primary and secondary outcome measures: Multiple regression analysis for infant and child mortality rate. The mean values were applied for infant and child mortality rates and other factors before GEJET (2008-2010) and after GEJET (2012-2014). RESULTS: Between 2008 and 2014, the most common cause of death among children younger than 10 years was accidents. The mortality rate per 100 000 persons was 39.1+/-41.2 before 2011, 226.7+/-43.4 in 2011 and 31.4+/-39.1 after 2011. Regression analysis revealed that the mortality rate was positively associated with low age in each period, while the coastal zone was negatively associated with fewer disaster base hospitals in 2011. By contrast, the number of obstetrics and gynaecology centres (beta=-189.9, p=0.02) and public health nurses (beta=-1.7, p=0.01) was negatively associated with mortality rate per person in 2011. CONCLUSIONS: In 2011, the mortality rate among children younger than 10 years was 6.4 times higher than that before and after 2011. Residence in a coastal zone was significantly associated with higher child mortality rates. PMID- 30478112 TI - Using the extended self-regulatory model to characterise diabetes medication adherence: a cross-sectional study. AB - OBJECTIVES: To cluster the adherence behaviours of patients with type 2 diabetes based on their beliefs in medicines and illness perceptions and examine the psychosocial, clinical and sociodemographic characteristics of patient clusters. DESIGN: Cross-sectional study. SETTING: A face-to-face survey was administered to patients at two family medicine clinics in the Midwest, USA. PARTICIPANTS: One hundred and seventy-four >=20-year-old, English-speaking adult patients with type 2 diabetes who were prescribed at least one oral diabetes medicine daily were recruited using convenience sampling. PRIMARY AND SECONDARY OUTCOME MEASURES: Beliefs in medicines and illness perceptions were assessed using the Beliefs about Medicines Questionnaire and the Brief Illness Perception Questionnaire, respectively. Self-reported medication adherence was assessed using the Morisky Medication Adherence Scale. Psychosocial correlates of adherence, health literacy and self-efficacy were measured using the Newest Vital Sign and the Self-efficacy for Appropriate Medication Use, respectively. Two-step cluster analysis was used to classify patients. RESULTS: Participants' mean age was 58.74 (SD=12.84). The majority were women (57.5%). Four clusters were formed (non-adherent clusters: ambivalent and sceptical; adherent clusters: indifferent and accepting). The ambivalent cluster (n=30, 17.2%) included low-adherent patients with high necessity beliefs, high concern beliefs and high illness perceptions. The sceptical cluster (n=53, 30.5%) included low adherent patients with low necessity beliefs but high concern beliefs and high illness perceptions. Both the accepting (n=40, 23.0%) and indifferent (n=51, 29.3%) clusters were composed of patients with high adherence. Significant differences between the ambivalent, sceptical, accepting and indifferent adherent clusters were based on self-efficacy, illness perception domains (treatment control and coherence) and haemoglobin A1c (p<0.01). CONCLUSIONS: Patients with diabetes in specific non-adherent and adherent clusters still have distinct beliefs as well as psychosocial characteristics that may help providers target tailored medication adherence interventions. PMID- 30478113 TI - From embracing to managing risks. AB - OBJECTIVE: To assess developments over time in the capture, curation and use of quality and safety information in managing hospital services. SETTING: Four acute National Health Service hospitals in England. PARTICIPANTS: 111.5 hours of observation of hospital board and directorate meetings, and 72 hours of ward observations. 86 interviews with board level and middle managers and with ward managers and staff. RESULTS: There were substantial improvements in the quantity and quality of data produced for boards and middle managers between 2013 and 2016, starting from a low base. All four hospitals deployed data warehouses, repositories where datasets from otherwise disparate departmental systems could be managed. Three of them deployed real-time ward management systems, which were used extensively by nurses and other staff. CONCLUSIONS: The findings, particularly relating to the deployment of real-time ward management systems, are a corrective to the many negative accounts of information technology implementations. The hospital information infrastructures were elements in a wider move, away from a reliance on individual professionals exercising judgements and towards team-based and data-driven approaches to the active management of risks. They were not, though, using their fine-grained data to develop ultrasafe working practices. PMID- 30478114 TI - How does a new patient education programme for renal recipients become situated and adapted when implemented in the daily teaching practice in a university hospital? An ethnographic observation study. AB - OBJECTIVE: To understand how a new patient education programme for renal recipients becomes situated and adapted when implemented in daily hospital teaching practice. The analysis focuses in particular on how principles of individual tailoring and patient involvement are adapted. DESIGN: Ethnographic observation study. 19 teaching sessions were observed, resulting in 35 pages of data written observation notes. SETTING: A Norwegian University hospital. The study included the transplantation (TX) post, the medical post and the outpatient clinic. PARTICIPANTS: 10 newly transplanted patients receiving the education programme, and 13 nurses trained in the new programme participated in the study. RESULTS: We observed that the nurses attempted to implement the programme's core principles of individual tailoring and patient involvement as intended, but that patients found it difficult to formulate their knowledge needs and interest. Patients and nurses developed an approach to individual tailoring and patient involvement, which used knowledge about the patients' life and experiences as basis for translating generalised knowledge into knowledge that is individualised and meaningful for the patient. The individual tailoring was however also limited, as the nurses balanced between responsibilities for the programme's principles of individual adaption and patient involvement at the one hand, and responsibilities of safety and economy from a health systems perspective on the other hand. CONCLUSION: Individual tailoring is observed to be a comprehensive practice which includes verbal, practical and emotional involvement with the patient's life world. This extends the notion and practice of individual tailoring as selecting among predefined, generalised knowledge based on an initial mapping of the patients' knowledge. While the adaptions to individual tailoring could have been seen as inaccurate implementation, in-depth analyses discloses that the extended approach to individual tailoring is in fact what retains the programme's core principles in the implementation context. PMID- 30478115 TI - Determining the optimal time for liberation from renal replacement therapy in critically ill patients: protocol for a systematic review and meta-analysis (DOnE RRT). AB - INTRODUCTION: Renal replacement therapy (RRT) is a complex and expensive form of life-sustaining therapy, reserved for our most acutely ill patients. While a number of randomised trials have evaluated the optimal timing to start RRT among critically ill patients in the intensive care unit (ICU), there has been a paucity of trials providing guidance on when and under what circumstances to ideally liberate a patient from RRT. We are conducting a systematic review and meta-analysis to identify clinical and biochemical markers that predict kidney recovery and successful liberation from acute RRT among critically ill patients with acute kidney injury. METHODS AND ANALYSIS: Our comprehensive search strategy was developed in consultation with a research librarian and independently peer reviewed by a second librarian. We will search electronic databases: Ovid Medline, Ovid Embase and Wiley Cochrane Library. Selected grey literature sources will also be searched. Our search strategies will focus on concepts related to RRT (ie, intermittent haemodialysis, slow low-efficiency dialysis, continuous renal replacement therapy), intensive care (ie, involving any ICU setting) and discontinuation of therapy (ie, either clinical, physiological and biochemical parameters of weaning acute RRT) from 1990 to October 10, 2017. Citation screening, selection, quality assessment and data abstraction will be performed in duplicate. Studies will, where possible, be pooled in statistical meta analysis. When deemed sufficiently clinically homogenous, and we have four or more studies reporting, sensitivities and specificities will be pooled simultaneously using a hierarchical summary receiver operator characteristic curve and bivariate analysis. ETHICS AND DISSEMINATION: Our systematic review will synthesise the literature on clinical and biochemical markers that predict liberation from RRT. Research ethics approval is not required. TRIAL REGISTRATION NUMBER: CRD42018074615. PMID- 30478116 TI - Prognostic factors for recovery and non-recovery in patients with non-specific neck pain: a protocol for a systematic literature review. AB - INTRODUCTION: Neck pain is a common musculoskeletal disorder worldwide. It can result in significant disability and impaired quality of life. More than 50% of patients with neck pain still report symptoms 1 year later despite receiving different forms of non-pharmacological and pharmacological treatment. Identifying patient characteristics that are modifiable or predict recovery and non-recovery for an individual patient might identify ways of improving outcomes. This systematic review aims to comprehensively summarise the existing evidence regarding baseline patient characteristics associated with recovery and non recovery, as defined by measures of pain intensity, disability and global perceived improvement. METHODS AND ANALYSIS: Six electronic databases, PubMed, CINAHL, PEDro Database, EMBASE, Cochrane Library and Web of Science, will be searched, with terms related to the review question such as neck pain, prognostic or predictive research, from inception to 28 September of 2018. Studies will be included if they have investigated an association between patient characteristics and outcomes, with at least one follow-up time point. Two independent reviewers will screen the titles and abstracts followed by a full-text review to assess papers regarding their eligibility. Data from included papers will be extracted using standardised forms, including study and participants' characteristics, outcomes, prognostic factors and effect size of the association. The risk of bias of each study will be assessed using the Quality in Prognostic Studies tool. A narrative synthesis will be conducted considering the strength, consistency of results and the methodological quality. ETHICS AND DISSEMINATION: This systematic review does not require ethical approval. The results will be disseminated through publication in a peer-review journal, as a chapter of a doctoral thesis and through presentations at national and international conferences. PROSPERO REGISTRATION NUMBER: CRD42018091183. PMID- 30478117 TI - Associations of lifestyle and vascular risk factors with Alzheimer's brain biomarker changes during middle age: a 3-year longitudinal study in the broader New York City area. AB - OBJECTIVE: To investigate the associations between lifestyle and vascular risk factors and changes in Alzheimer's disease (AD) biomarkers (beta-amyloid load via 11C-PiB PET, glucose metabolism via 18F-FDG PET and neurodegeneration via structural MRI) and global cognition in middle-aged asymptomatic participants at risk for AD. DESIGN: Prospective, longitudinal. SETTING: The study was conducted at New York University Langone/Weill Cornell Medical Centres in New York City. PARTICIPANTS: Seventy cognitively normal participants from multiple community sources, aged 30-60 years with lifestyle measures (diet, intellectual activity and physical activity), vascular risk measures and two imaging biomarkers visits over at least 2 years, were included in the study. OUTCOME MEASURES: We examined MRI-based cortical thickness, fluoro-deoxy-glucose (FDG) glucose metabolism and PiB beta-amyloid in AD-vulnerable regions. A global cognitive z-score served as our summary cognition measure. We used regression change models to investigate the associations of clinical, lifestyle and vascular risk measures with changes in AD biomarkers and global cognition. RESULTS: Diet influenced changes in glucose metabolism, but not amyloid or cortical thickness changes. With and without accounting for demographic measures, vascular risk and baseline FDG measures, lower adherence to a Mediterranean-style diet was associated with faster rates of FDG decline in the posterior cingulate cortex (p<=0.05) and marginally in the frontal cortex (p=0.07). None of the other lifestyle variables or vascular measures showed associations with AD biomarker changes. Higher baseline plasma homocysteine was associated with faster rates of decline in global cognition, with and without accounting for lifestyle and biomarker measures (p=0.048). None of the lifestyle variables were associated with cognition. CONCLUSIONS: Diet influenced brain glucose metabolism in middle-aged participants, while plasma homocysteine explained variability in cognitive performance. These findings suggest that these modifiable risk factors affect AD risk through different pathways and support further investigation of risk reduction strategies in midlife. PMID- 30478118 TI - Influences of facial disfigurement and social support for psychosocial adjustment among patients with oral cancer in Taiwan: a cross-sectional study. AB - OBJECTIVE: To explore the influences of facial disfigurement and social support for psychosocial adjustment in patients with oral cancer. DESIGN: A cross sectional design was used for the study. PARTICIPANTS AND SETTING: A convenience sample of 77 patients with oral cancer was recruited from the otolaryngology and oral and maxillofacial surgery outpatient clinics of three general hospitals in Taiwan. MEASURES: Data were collected using the study questionnaires, including the Facial Disfigurement Scale, the Social Support Scale and the Psychosocial Adjustment to Illness Scale. RESULTS: The mean score on the Psychosocial Adjustment to Illness Scale was 413.01 (SD=32.32); 71.4% of the participants were maladjusted. Results of multiple regression analysis showed statistically significant main effects of tumour site (beta=0.37), facial disfigurement (beta=0.35) and social support (beta=-1.01), and the interaction effect of facial disfigurement and social support (beta=0.79) (all p<0.05) on psychosocial adjustment after controlling for other sociodemographic and clinical variables. All variables together explained 62% of the variance in psychosocial adjustment (F(16, 55)=14.98, p<0.001). CONCLUSIONS: The level of psychosocial adjustment in patients with oral cancer was suboptimal. Poorer psychosocial adjustment was reported by patients with more severe facial disfigurement and less social support. Patients with cancers in other areas of the oral cavity also reported poorer psychosocial adjustment than patients with cancers in the buccal mucosa. Medical professionals may use these variables to identify higher risk groups for early intensive intervention. PMID- 30478119 TI - 'Primary care sensitive' situations that result in an ambulance attendance: a conversation analytic study of UK emergency '999' call recordings. AB - OBJECTIVES: To explore common features of conversations occurring in a sample of emergency calls that result in an ambulance dispatch for a 'primary care sensitive' situation, and better understand the challenges of triaging this cohort. DESIGN: A qualitative study, applying conversation analytic methods to routinely recorded telephone calls made through the '999' system for an emergency ambulance. Cases were identified by a primary care clinician, observing front line UK ambulance service shifts. A sample of 48 '999' recordings were analysed, corresponding to situations potentially amenable to primary care management. RESULTS: The analysis focuses on four recurring ways that speakers use talk in these calls. Progress can be impeded when call-taker's questions appear to require callers to have access to knowledge that is not available to them. Accordingly, callers often provide personal accounts of observed events, which may be troublesome for call-takers to 'code' and triage. Certain question formats notably 'alternative question' formats-appear particularly problematic. Callers deploy specific lexical, grammatical and prosodic resources to legitimise the contact as 'urgent', and ensure that their perception of risk is conveyed. Difficulties encountered in the triage exchange may be evidence of misalignment between organisational and caller perceptions of the 'purpose' of the questions. CONCLUSIONS: Previous work has focused on exploring the presentation and triage of life-threatening medical emergencies. Meaningful insights into the challenges of EMS triage can also be gained by exploring calls for 'primary care sensitive' situations. The highly scripted triage process requires precise, 'codeable' responses to questions, which can create challenges when the exact urgency of the problem is unclear to both caller and call-taker. Calling on behalf of someone else may compound this complexity. The aetiology of some common interactional challenges may offer a useful frame for future comparison between calls for 'primary care sensitive' situations and life-threatening emergencies. PMID- 30478120 TI - Serum alkaline phosphatase and the risk of coronary heart disease, stroke and all cause mortality: Tehran Lipid and Glucose Study. AB - OBJECTIVES: To investigate the association of alkaline phosphatase (ALP) levels with the risk of the composite end point of cardiovascular disease (CVD), and all cause mortality as well as each of them separately. DESIGN: Prospective cohort study. SETTING: Within the framework of the Tehran Lipid and Glucose Study (TLGS) cohort, participants were followed from baseline examination (1999-2001) until March 2014. PARTICIPANTS: A total of 2578 participants, aged >=30 years free of prevalent CVD at baseline examination. PRIMARY OUTCOME: The main outcome measures were composite end point of coronary heart disease (CHD), stroke, all-cause mortality and each per se. RESULTS: During a median follow-up of 11.3 years, 369, 68, 420, 170 and 495 participants experienced CHD, stroke, CVD, all-cause mortality and the composite outcome, respectively. In the multivariable Cox regression models, the adjusted HRs (95% CI) for mentioned events per one SD increase in ALP level after full adjustment were 1.11 (1.01 to 1.22), 1.20 (0.97 to 1.49, p=0.058), 1.10 (1.01 to 1.21), 1.16 (1.01 to 1.33) and 1.11 (1.02 to 1.21), respectively. Furthermore, participants with ALP levels in the highest tertile had significant adjusted HRs (95% CI) for stroke (1.88 (1.00 to 3.61)), CVD (1.30 (1.01 to 1.68)) and composite outcome (1.27 (1.00 to 1.61)). The cut off value of ALP >=199 IU/L for predicting composite outcome was derived using Youden's index, based on which this cut-off point was associated with significant risk of 80%, 26%, 43% and 26% for incident stroke, CVD, all-cause mortality and composite outcome. Additionally, no improvement was seen in the predictive ability of traditional risk factors models after adding ALP values, considering the levels of Akaike information criterion, C-index and Net Reclassification Index. CONCLUSION: Independent associations between ALP levels and the risks of CVD and mortality events were shown, despite the fact that adding the data of ALP to known risk factors did not improve the prediction of these events. PMID- 30478121 TI - Eczema and subsequent suicide: a matched case-control study. AB - OBJECTIVE: To assess the association of eczema with a patient's subsequent risk of death from suicide. We hypothesised that persistent eczema would be associated with an increased risk for death from suicide. DESIGN: Double matched case control study. SETTING: General population of Ontario, Canada. PARTICIPANTS: Patients 15-55 years old. We identified cases of suicide from coroners' reports between 1 January 1994 and 31 December 2014 and matched 1:2 with alive controls based on age, sex and socioeconomic status. EXPOSURE: The primary predictor was a history of persistent eczema, defined as five or more physician visits for the diagnosis over the preceding 5 years. MAIN OUTCOME AND MEASURE: Logistic regression to estimate the association between eczema and death from suicide. RESULTS: We identified 18 441 cases of suicide matched to 36 882 controls over the 21-year accrual period. Persistent eczema occurred in 174 (0.94%) suicide cases and 285 (0.77%) controls yielding a 22% increased risk of suicide associated with persistent eczema (OR 1.22, 95% CI 1.01 to 1.48, p=0.037). In mediation analyses, this association was largely explained through major suicide risk factors. Two-thirds of patients with eczema who died from suicide had visited a physician in the month before their death and one in eight had visited for eczema in the month before their death. Among patients who died by suicide, jumping and poisoning were relatively more frequent mechanisms among patients with eczema. CONCLUSIONS: Patients with persistent eczema have a modestly increased subsequent risk of death from suicide, but this is not independent of overall mental health and the absolute risk is low. Physicians caring for these patients have opportunities to intervene for suicide prevention. PMID- 30478122 TI - 'Secretly, it's a competition': a qualitative study investigating what helped employees quit smoking during a workplace smoking cessation group training programme with incentives. AB - OBJECTIVES: Smoking cessation programmes in combination with financial incentives have shown to increase quit rates in smokers, but it is not clear which elements of this intervention help smokers to succeed in their quit attempt. The aim of this study was to explore the view of successful and unsuccessful quitters about which factors had affected their ability to quit smoking. DESIGN: Semistructured qualitative interviews were conducted and analysed using the Framework method. SETTING: Interviews were conducted in 2017 with employees from nine different Dutch companies. PARTICIPANTS: 24 successful and unsuccessful quitters from the intervention group of a cluster randomised controlled trial (RCT) who participated in a workplace smoking cessation group training programme in which smoking abstinence was rewarded with financial incentives. RESULTS: Themes that emerged were the workplace setting, quitting with colleagues, motivation, family support, strategies and the financial incentives. The interviewees reported that the smoking cessation programme was appreciated in general, was convenient, lowered the threshold to sign up, stimulated peer support and competition and provided strategies to resist smoking. Personal motivation and a mind set to never smoke again were regarded as important factors for quit success. The financial incentives were not considered as a main motivator to quit smoking, which contradicts the results from the RCT. The financial incentives were considered as more attractive to smokers with a low income. CONCLUSIONS: According to participants, contributors to quitting smoking were the workplace cessation programme, personal motivation and peer support, but not the incentives. More research is needed on the contradiction between the perceived effects of financial incentives on quit success and the actual difference in quit rates. TRIAL REGISTRATION NUMBER: NTR5657. PMID- 30478123 TI - Improving household surveys and use of data to address health inequities in three Asian cities: protocol for the Surveys for Urban Equity (SUE) mixed methods and feasibility study. AB - INTRODUCTION: As rapid urbanisation transforms the sociodemographic structures within cities, standard survey methods, which have remained unchanged for many years, under-represent the urban poorest. This leads to an overly positive picture of urban health, distorting appropriate allocation of resources between rural and urban and within urban areas. Here, we present a protocol for our study which (i) tests novel methods to improve representation of urban populations in household surveys and measure mental health and injuries, (ii) explores urban poverty and compares measures of poverty and 'slumness' and (iii) works with city authorities to understand, and potentially improve, utilisation of data on urban health for planning more equitable services. METHODS AND ANALYSIS: We will conduct household surveys in Kathmandu, Hanoi and Dhaka to test novel methods: (i) gridded population sampling; (ii) enumeration using open-access online maps and (iii) one-stage versus two-stage cluster sampling. We will test reliability of an observational tool to categorise neighbourhoods as slum areas. Within the survey, we will assess the appropriateness of a short set of questions to measure depression and injuries. Questionnaire data will also be used to compare asset based, consumption-based and income-based measures of poverty. Participatory methods will identify perceptions of wealth in two communities in each city. The analysis will combine quantitative and qualitative findings to recommend appropriate measures of poverty in urban areas. We will conduct qualitative interviews and establish communities of practice with government staff in each city on use of data for planning. Framework approach will be used to analyse qualitative data allowing comparison across city settings. ETHICS AND DISSEMINATION: Ethical approvals have been granted by ethics committees from the UK, Nepal, Bangladesh and Vietnam. Findings will be disseminated through conference papers, peer-reviewed open access articles and workshops with policy makers and survey experts in Kathmandu, Hanoi and Dhaka. PMID- 30478124 TI - Study of Concussion in Rugby Union through MicroRNAs (SCRUM): a study protocol of a prospective, observational cohort study. AB - INTRODUCTION: The diagnosis of mild traumatic brain injury or sports-related concussion is a challenge for all clinicians, players, coaches and parents involved in contact sports. Currently, there is no validated objective biomarker available to assess the presence or severity of concussion in sport, and so it is necessary to rely on subjective measures like self-reporting of symptoms which depend on the cooperation of the athlete. There is a significant health risk associated with repetitive injury if the diagnosis is missed, and so there is great value in an objective biomarker to assist diagnostic and prognostic decisions. OBJECTIVE: To establish a panel of non-invasive MicroRNA biomarkers in urine and saliva for the rapid diagnosis of sports-related concussion and investigate the kinetics and clinical utility of these biomarkers in assisting diagnostic, prognostic and return-to-play decisions. METHODS AND ANALYSIS: Observational, prospective, multicentre cohort study recruiting between the 2017 2018 and 2018-2019 Rugby Union seasons. Professional rugby players in the two highest tiers of senior professional domestic rugby competition in England will be recruited prospectively to the study. During the season, three groups will be identified: athletes entering the World Rugby Head Injury Assessment (HIA) protocol, uninjured control athletes and control athletes with musculoskeletal injuries. Saliva and urine will be collected from these athletes at multiple timepoints, coinciding with key times in the HIA protocol and return-to-play process. ETHICS AND DISSEMINATION: Ethics approval has been obtained. The compiled and analysed results will be presented at national and international conferences concerning the care of patients with traumatic brain injury. Results will also be submitted for peer review and publication in the subject journals/literature. PMID- 30478125 TI - Patient-reported gout attack frequency and allopurinol use in general practice in the Netherlands: a prospective observational cohort study protocol. AB - INTRODUCTION: Gout is the most common inflammatory arthritis in the Dutch general practice population and is often managed with long-term uric acid lowering treatment. The clinical relevance of this treatment in preventing gout attacks is unclear. PRIMARY RESEARCH QUESTION: What is the frequency of self-reported gout attacks and what is the effect of allopurinol use in patients diagnosed with gout in general practice? METHODS AND ANALYSIS: Adult patients with a diagnostic consultation code for gout in the year 2013, 2014 or 2015 will be invited to participate in this prospective observational cohort study. Patients with a limited life expectancy will be excluded. Baseline measurements will include blood pressure, body mass index and a blood sample (estimated glomerular filtration rate, serum uric acid, cholesterol (low-density lipoprotein (LDL) and high-density lipoprotein), glucose (fasting)). At the 2-year follow-up, patients will receive questionnaires every 3 months. The questionnaires at baseline, 12 months and 24 months assess the frequency of gout attacks, the presence of tophi, comorbidity, medication use, quality of life, diet and lifestyle. The questionnaires in between only assess the frequency of gout attacks and medication use for gout. Descriptive statistics will be used to calculate the mean frequency of self-reported gout attacks during the 2-year follow-up. The propensity score for each patient being offered allopurinol is estimated and used to match patients with and without allopurinol treatment. We will compare the frequency of gout attacks in these groups using multilevel Poisson regression analyses. With this type of analysis, we can calculate the corrected estimated effect of allopurinol on gout attack frequency. ETHICS AND DISSEMINATION: The research protocol was approved by the Medical Ethical Committee of the Erasmus Medical Centre in Rotterdam. The knowledge generated by this study will be transferred to the Dutch College of General Practitioners, conferences and to (inter)national peer-reviewed journals. TRIAL REGISTRATION NUMBER: NTR6329; Pre results. PMID- 30478126 TI - Experiences with approaches to advance care planning with older people: a qualitative study among Dutch general practitioners. AB - OBJECTIVES: Advance care planning (ACP) with older people needs to be approached differently than ACP with patients with a terminal illness. ACP is still used with only a minority of older patients due to a lack of knowledge regarding appropriate approaches to ACP with older people. General practitioners (GPs) may play a key role in ACP with older people. Therefore, we explored their experiences with and views on approaches to ACP with older patients in daily practice. DESIGN, SETTING AND PARTICIPANTS: A qualitative study among a purposive sample of 19 Dutch GPs based on semistructured interviews. RESULTS: Approaches to ACP with older patients can be divided into two categories: systematic and ad hoc. Systematic approaches consisted of discussing a fixed combination of topics with community-dwelling older patients who are frail, cognitively impaired or are aged >75 years, and with older patients living in residential care homes during group information meetings, intakes, comprehensive geriatric assessments and periodic assessments. Meetings were aimed at making agreements in anticipation of future care, at providing information and encouraging older people to take further steps in ACP. With ad hoc approaches, respondents discussed only one or two topics related to the near future. Ad hoc ACP was mainly done with deteriorating patients or when patients or family initiated ACP. Systematic and ad hoc approaches were used simultaneously or sequentially and were both used for initiating and following up on ACP. Due to a lack of time and knowledge of other occasions and topics than the ones respondents used, respondents seemed to underuse many occasions and topics. CONCLUSIONS: Awareness of appropriate systematic and ad hoc approaches for ACP, and the focus on providing information and encouraging older people to take further steps in ACP reported in this study can support GPs and improve older patients' access to ACP. PMID- 30478127 TI - Formalisation and subordination: a contingency theory approach to optimising primary care teams. AB - OBJECTIVE: While there is consensus on the need to strengthen primary care capacities to improve healthcare systems' performance and sustainability, there is only limited evidence on the best way to organise primary care teams. In this article, we use a conceptual framework derived from contingency theory to analyse the structures and process optimisation of multiprofessional primary care teams. DESIGN: We focus specifically on inter-relationships between three dimensions: team size, formalisation of care processes and nurse autonomy. Interview-based qualitative data for each of these three dimensions were converted into ordinal scores. Data came from eight pilot sites in Quebec (Canada). RESULTS: We found a positive association between team size and formalisation (correlation score 0.55) and a negative covariation (correlation score -0.64) between care process formalisation and nurses' autonomy/subordination. Despite the study being exploratory in nature, such relationships validate the idea that these dimensions should be analysed conjointly and are coherent with our suggestion that using a framework derived from a contingency approach makes sense. CONCLUSIONS: The results provide insights about the structural design of nurse-intensive primary care teams. Non-physicians' professional autonomy is likely to be higher in smaller teams. Likewise, a primary care team that aims to increase nurses' and other non-physicians' professional autonomy should be careful about the extent to which it formalises its processes. PMID- 30478128 TI - How are risk ratios reported in orthopaedic surgery journals? A descriptive study of formats used to report absolute risks. AB - PURPOSE: The numerical format in which risks are communicated can affect risk comprehension and perceptions of medical professionals. We investigated what numerical formats are used to report absolute risks in empirical articles, estimated the frequency of biasing formats and rated the quality of figures used to display the risks. DESIGN: Descriptive study of reporting practices. METHOD: We randomly sampled articles published in seven leading orthopaedic surgery journals during a period of 13 years. From these, we selected articles that reported group comparisons on a binary outcome (eg, revision rates in two groups) and recorded the numerical format used to communicate the absolute risks in the results section. The quality of figures was assessed according to published guidelines for transparent visual aids design. OUTCOME MEASURES: Prevalence of information formats and quality of figures. RESULTS: The final sample consisted of 507 articles, of which 14% reported level 1 evidence, 13% level 2 and 73% level 3 or lower. The majority of articles compared groups of different sizes (90%), reported both raw numbers and percentages (64%) and did not report the group sizes alongside (50%). Fifteen per cent of articles used two formats identified as biasing: only raw numbers (8%, '90 patients vs 100 patients') or raw numbers reported alongside different group sizes (7%, '90 out of 340 patients vs 100 out of 490 patients'). The prevalence of these formats decreased in more recent publications. Figures (n=79) had on average two faults that could distort comprehension, and the majority were rated as biasing. CONCLUSION: Authors use a variety of formats to report absolute risks in scientific articles and are likely not aware of how some formats and graph design features can distort comprehension. Biases can be reduced if journals adopt guidelines for transparent risk communication but more research is needed into the effects of different formats. PMID- 30478129 TI - Case management in primary care for frequent users of healthcare services with chronic diseases and complex care needs: an implementation and realist evaluation protocol. AB - INTRODUCTION: Significant evidence in the literature supports case management (CM) as an effective intervention to improve care for patients with complex healthcare needs. However, there is still little evidence about the facilitators and barriers to CM implementation in primary care setting. The three specific objectives of this study are to: (1) identify the facilitators and barriers of CM implementation in primary care clinics across Canada; (2) explain and understand the relationships between the actors, contextual factors, mechanisms and outcomes of the CM intervention; (3) identify the next steps towards CM spread in primary care across Canada. METHODS AND ANALYSIS: We will conduct a multiple-case embedded mixed methods study. CM will be implemented in 10 primary care clinics in five Canadian provinces. Three different units of analysis will be embedded to obtain an in-depth understanding of each case: the healthcare system (macro level), the CM intervention in the clinics (meso level) and the individual/patient (micro level). For each objective, the following strategy will be performed: (1) an implementation analysis, (2) a realist evaluation and (3) consensus building among stakeholders using the Technique for Research of Information by Animation of a Group of Experts method. ETHICS AND DISSEMINATION: This study, which received ethics approval, will provide innovative knowledge about facilitators and barriers to implementation of CM in different primary care jurisdictions and will explain how and why different mechanisms operate in different contexts to generate different outcomes among frequent users. Consensual and prioritised statements about next steps for spread of CM in primary care from the perspectives of all stakeholders will be provided. Our results will offer context-sensitive explanations that can better inform local practices and policies and contribute to improve the health of patients with complex healthcare needs who frequently use healthcare services. Ultimately, this will increase the performance of healthcare systems and specifically mitigate ineffective use and costs. PMID- 30478130 TI - Characterising Arm Recovery in People with Severe Stroke (CARPSS): protocol for a 12-month observational study of clinical, neuroimaging and neurophysiological biomarkers. AB - INTRODUCTION: In individuals with early (indexed <=7 days poststroke) and severe upper limb paresis (shoulder abduction and finger extension score of <5 out of 10), our objectives are to: (1) determine if biomarkers of brain structure and function collected at <1 month poststroke explain who will experience clinically important recovery over the first 12 months poststroke; (2) compare stroke survivors' perceptions of personally meaningful recovery to clinically important recovery; and (3) characterise the trajectory of change in measures of motor function, brain structure and function. METHODS AND ANALYSIS: Prospective observational study with an inception cohort of 78 first-time stroke survivors. Participants will be recruited from a single, large tertiary stroke referral centre. Clinical and biomarker assessments will be completed at four follow-up time points: 2 to 4 weeks and 3, 6 and 12 months poststroke. Our primary outcome is achievement of clinically important improvement on two out of three measures that span impairment (Fugl-Meyer Upper Limb, change >=10 points), activity (Motor Assessment Scale item 6, change >=1 point) and participation (Rating of Everyday Arm-use in the Community and Home, change >=1 point). Brain biomarkers of structure and function will be indexed using transcranial magnetic stimulation and MRI. Multilevel modelling will be performed to examine the relationship between clinically important recovery achieved (yes/no) and a priori defined brain biomarkers related to the corticospinal tract and corpus callosum. Secondary analyses will compare stroke survivor's perception of recovery, as well as real-world arm use via accelerometry, to the proposed metric of clinically meaningful recovery; and model trajectory of recovery across clinical, a priori defined biomarkers and exploratory variables related to functional connectivity. ETHICS AND DISSEMINATION: Approved by the hospital and university ethics review boards. Results will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT02464085. PMID- 30478131 TI - Namaste Care in nursing care homes for people with advanced dementia: protocol for a feasibility randomised controlled trial. AB - INTRODUCTION: Many people living with advanced dementia live and die in nursing care homes. The quality of life, care and dying experienced by these people is variable. Namaste Care is a multisensory programme of care developed for people with advanced dementia. While there is emerging evidence that Namaste Care may be beneficial for people with dementia, there is a need to conduct a feasibility study to establish the optimum way of delivering this complex intervention and whether benefits can be demonstrated in end-of-life care, for individuals and service delivery. The aim of the study is to ascertain the feasibility of conducting a full trial of the Namaste Care intervention. METHODS AND ANALYSIS: A feasibility study, comprising a parallel, two-arm, multicentre cluster controlled randomised trial with embedded process and economic evaluation. Nursing care homes (total of eight) who deliver care to those with advanced dementia will be randomly allocated to intervention (delivered at nursing care home level) or control. Three participant groups will be recruited: residents with advanced dementia, informal carers of a participating resident and nursing care home staff. Data will be collected for 6 months. Feasibility objectives concern the recruitment and sampling of nursing homes, residents, informal carers and staff; the selection and timing of primary (quality of dying and quality of life) and secondary clinical outcome measures (person centredness, symptom presence, agitation, quality of life, resource use and costs and residents' activity monitored using actigraphy). Acceptability, fidelity and sustainability of the intervention will be assessed using semistructured interviews with staff and informal carers. ETHICS AND DISSEMINATION: This protocol has been approved by NHS Wales Research Ethics Committee 5 (ref: 17/WA0378). Dissemination plans include working with a public involvement panel, through a website (http://www.namastetrial.org.uk), social media, academic and practice conferences and via peer reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN14948133; Pre-results. PMID- 30478132 TI - Acknowledgment of Ad Hoc Reviewers. PMID- 30478133 TI - Medical students consider abandoning degree because of financial pressures, survey finds. PMID- 30478134 TI - Threats to doctor-patient confidentiality. PMID- 30478135 TI - Differences Between Men and Women in Mortality and the Health Dimensions of the Morbidity Process. AB - BACKGROUND: Do men have worse health than women? This question is addressed by examining sex differences in mortality and the health dimensions of the morbidity process that characterize health change with age. We also discuss health differences across historical time and between countries. CONTENT: Results from national-level surveys and data systems are used to identify male/female differences in mortality rates, prevalence of diseases, physical functioning, and indicators of physiological status. Male/female differences in health outcomes depend on epidemiological and social circumstances and behaviors, and many are not consistent across historical time and between countries. In all countries, male life expectancy is now lower than female life expectancy, but this was not true in the past. In most countries, women have more problems performing instrumental activities of daily living, and men do better in measured performance of functioning. Men tend to have more cardiovascular diseases; women, more inflammatory-related diseases. Sex differences in major cardiovascular risk factors vary between countries-men tend to have more hypertension; women, more raised lipids. Indicators of physiological dysregulation indicate greater inflammatory activity for women and generally higher cardiovascular risk for men, although women have higher or similar cardiovascular risk in some markers depending on the historical time and country. SUMMARY: In some aspects of health, men do worse; in others, women do worse. The lack of consistency across historical times and between countries in sex differences in health points to the complexity and the substantial challenges in extrapolating future trends in sex differences. PMID- 30478136 TI - Vestibular dysfunction: a frequent problem for adults with mitochondrial disease. PMID- 30478137 TI - Biallelic disruption of PKDCC is associated with a skeletal disorder characterised by rhizomelic shortening of extremities and dysmorphic features. AB - BACKGROUND: During mouse embryonic development the protein kinase domain containing, cytoplasmic (Pkdcc) gene, also known as Vlk, is expressed in several tissues including the ventral midbrain, with particularly strong expression in branchial arches and limb buds. Homozygous Pkdcc knockout mice have dysmorphic features and shortened long bones as the most obvious morphological abnormalities. The human PKDCC gene has currently not been associated with any disorders. OBJECTIVE: To use clinical diagnostic exome sequencing (DES) for providing genetic diagnoses to two apparently unrelated patients with similar skeletal abnormalities comprising rhizomelic shortening of limbs and dysmorphic features. METHODS: Patient-parents trio DES was carried out and the identified candidate variants were confirmed by Sanger sequencing. RESULTS: Each patient had a homozygous gene disrupting variant in PKDCC considered to explain the skeletal phenotypes shared by both. The first patient was homozygous for the nonsense variant p.(Tyr217*) (NM_1 38 370 c.651C>A) expected to result in nonsense mediated decay of the mutant transcripts, whereas the second patient was homozygous for the splice donor variant c.639+1G>T predicted to abolish the donor splice site by three in silico splice prediction algorithms. CONCLUSIONS: Biallelic gene disrupting variants in PKDCC in humans, just like in mice, cause dysmorphic features and rhizomelic shortening of limbs. PMID- 30478138 TI - EARLY DETECTION OF IMMINENT ENCAPSULATING PERITONEAL SCLEROSIS: FREE WATER TRANSPORT, SELECTED EFFLUENT PROTEINS, OR BOTH? AB - BACKGROUND: No diagnostic tool or methodology is currently available for early detection of imminent encapsulating peritoneal sclerosis (EPS). The objective of this study was to investigate the predictive value of free water transport (FWT) and construct a panel of peritoneal effluent proteins for EPS alone or in combination with FWT. These parameters could be incorporated in the follow-up of peritoneal dialysis (PD) patients. METHODS: A case-control study, nested in a longitudinal PD patient cohort, was conducted. Time-specific areas under the receiver operating characteristic (ROC) curve were calculated for FWT and effluent biomarkers at a lag time up to 3 years before EPS diagnosis. Free water transport was combined with appearance rates (AR) of biomarkers to assess their clinical validity. RESULTS: Free water transport volume and AR of effluent biomarkers were investigated in 11 EPS patients and 34 long-term PD patients. Diagnostic performance was best for FWT (area under the curve [AUC] 0.94) followed by plasminogen activator inhibitor (PAI-1) AR. Throughout, diagnostic panels of FWT and AR of cancer antigen 125 (CA125), interleukin-6 (IL-6), or (PAI 1) yielded specificity estimates above 84%. The combination of FWT and PAI-1 AR identified the largest proportion of EPS patients at 1 year prior to diagnosis (sensitivity 100%, specificity 94%). CONCLUSION: Measurement of FWT is simple and has the highest predictive value for imminent EPS. The addition of effluent biomarkers provides an all-round insight into the state of the peritoneum. Our data indicate that combining FWT with either PAI-1, CA125, or IL-6 has the highest specificity. This is required to avoid unnecessary discontinuation of PD treatment. PMID- 30478139 TI - OUTCOMES OF THE WEIGHTED PERITONEAL DIALYSIS CATHETER IN PATIENTS AT RISK OF PERCUTANEOUS CATHETER FAILURE. AB - BACKGROUND: The weighted catheter has shown promising results in retrospective and randomized studies. We examined its usefulness in patients with previous failed non-weighted peritoneal dialysis (PD) catheters or previous abdominal surgery. METHODS: The insertion, start, end, and removal dates were recorded for all-type catheter insertions from 2011 to 2016. Primary and secondary failure rates were recorded, defined as failure to ever establish flow (primary) or failure after a period of successful PD (secondary). Patients were censored from analysis if PD ended due to death, transfer of care, transfer to hemodialysis, transplantation, or if the patient recovered renal function. RESULTS: There were 44 weighted, 75 non-weighted open surgical, and 143 percutaneous catheters. There was previous abdominal surgery in 29% and 6% of patients receiving surgically inserted and percutaneous catheters, respectively (p < 0.0001). Primary failure rates were 4/44 (9%), 20/75 (27%), and 26/143 (18%) in weighted, non-weighted surgical, and percutaneous catheters, respectively. There were reduced primary and secondary failure rates in the weighted (9% primary and 15% secondary) versus non-weighted surgically inserted group (27% primary and 46% secondary) (p = 0.04). There was no difference between primary (p= 0.15) and secondary (p = 0.5) failure rates between weighted and percutaneously inserted catheters. Kaplan Meier survival analysis revealed overall increased catheter survival in the weighted group (p = 0.02). CONCLUSION: Weighted catheters were associated with increased survival and decreased failure rates compared with non-weighted surgical catheters, despite usage in patients at higher risk of catheter failure due to previous failed catheters and abdominal surgery. PMID- 30478140 TI - ASSOCIATION OF B-TYPE NATRIURETIC PEPTIDE LEVEL WITH RESIDUAL KIDNEY FUNCTION IN INCIDENT PERITONEAL DIALYSIS PATIENTS. AB - BACKGROUND: Residual kidney function (RKF) is an important factor influencing both technique and patient survival in peritoneal dialysis (PD) patients. B-type natriuretic peptide (BNP) is considered a marker of cardio-renal syndrome. The relationship between BNP and RKF in PD patients remains unclear. METHODS: We conducted a prospective study of 89 patients who had started and continued PD for 6 months or more in Kyushu University Hospital between June 2006 and September 2015. Participants were divided into low BNP (<= 102.1 ng/L) and high BNP (>102.1ng/L) groups according to median plasma BNP level at PD initiation. The primary outcome was RKF loss, defined as 24-hour urine volume less than 100 mL. We estimated the association between BNP and RKF loss using a Kaplan-Meier method and Cox proportional hazards model and compared the rate of RKF decline between the 2 groups. To evaluate the consistency of the association, we performed subgroup analysis stratified by baseline characteristics. RESULTS: During the median follow-up of 30 months, 30 patients lost RKF. Participants in the high BNP group had a 5.87-fold increased risk for RKF loss compared with the low BNP group after adjustment for clinical and cardiac parameters. A high plasma BNP level was more clearly associated with RKF loss in younger participants compared with older participants in subgroup analysis. CONCLUSIONS: B-type natriuretic peptide may be a useful risk marker for RKF loss in PD patients. The clinical importance of plasma BNP level as a marker of RKF loss might be affected by age. PMID- 30478141 TI - EPITHELIAL-TO-MESENCHYMAL TRANSITION AND MIGRATION OF HUMAN PERITONEAL MESOTHELIAL CELLS UNDERGOING SENESCENCE. AB - BACKGROUND: Epithelial-to-mesenchymal transition (EMT) of human peritoneal mesothelial cells (HPMCs) contributes to fibrotic thickening of the peritoneum that develops in patients on peritoneal dialysis (PD). The process is thought to be largely mediated by transforming growth factor-beta (TGF-beta). As TGF-beta has also been implicated in senescence of HPMCs, we have performed an exploratory study to examine if senescent HPMCs can undergo EMT. METHODS: Omentum-derived HPMCs were rendered senescent by repeated passages in culture. Features of EMT were assessed by immunostaining and quantitative polymerase chain reaction (qPCR) at various stages of the HPMC lifespan and after treatment with or without TGF beta. The motility of HPMCs was assessed in a scratch wound migration assay. RESULTS: Replicative senescence of HPMCs was associated with a gradual increase in the constitutive expression of EMT markers, including increased production of extracellular matrix proteins. However, senescent HPMCs also retained epithelial cell features such as cytokeratin, calretinin, and E-cadherin and showed decreased, rather than increased, motility. In contrast, exposure to TGF-beta resulted in an up-regulation of mesenchymal markers and down-regulation of epithelial markers. Such effects of TGF-beta occurred both in young and senescent cells, although they were less pronounced in senescence. CONCLUSIONS: Senescence of HPMCs is associated with spontaneous development of several EMT features. At the same time, senescent HPMCs preserve epithelial cell-like characteristics and are less prone to develop a full EMT phenotype in response to TGF-beta. These observations may support the concept of cellular senescence being antagonistically pleiotropic with regard to EMT. PMID- 30478142 TI - EXERCISE CAPACITY AND ASSOCIATION WITH QUALITY OF LIFE IN PERITONEAL DIALYSIS PATIENTS. AB - BACKGROUND: Muscle wasting, common and progressive in uremic patients, is associated with a high probability for morbidity, lower health-related quality of life (HRQOL), and mortality. However, exercise tolerance in peritoneal dialysis (PD) patients has not been fully elucidated. The aim of this study was to evaluate exercise capacity, its determinants, and its association with HRQOL in PD patients. METHODS: Outpatients treated with PD at Keio University Hospital from December 2016 to March 2018 were included in this single-center cross sectional observational study. Exercise capacity was assessed by incremental shuttle walking test (ISWT) and handgrip and quadriceps strength. In addition to evaluation of PD-related parameters, HRQOL was assessed by the Kidney Disease Quality of Life-Short Form questionnaire. RESULTS: Among the 50 recruited PD outpatients, age and PD vintage were 63.8 +/- 9.6 and 3.8 +/- 2.8 years, respectively. Physical examination revealed ISWT of 312.0 +/- 138.2 m, handgrip strength of 27.5 +/- 6.9 kg, and quadriceps strength of 23.3 +/- 10.0 kg. Multivariate analysis showed that younger age and male sex were significantly associated with higher ISWT and handgrip and quadriceps strength. Skeletal mass index (SMI) remained a significant predictor of handgrip and quadriceps strength. Moreover, only ISWT was strongly correlated with higher HRQOL scores, including physical, mental, and kidney-specific domains, even after adjustment for age and sex. CONCLUSIONS: Exercise tolerance in PD patients was partially determined by age, sex, and SMI. Moreover, this is the first study to demonstrate the strong relationship between aerobic capacity and HRQOL in PD patients. PMID- 30478143 TI - HEALTH LITERACY-HOW DO WE IMPROVE THE CONVERSATION AT THE HEART OF HEALTHCARE WHEN WE KNOW SO MANY PEOPLE ARE STRUGGLING WITH IT? AB - The Scottish Government published "Making it Easy - A Health Literacy Action Plan for Scotland" in 2014, and in 2017 the next steps were set out in "Making it Easier - A Health Literacy Action Plan for Scotland 2017-2025." This article discusses what health literacy is, outlining the key points from these national action plans. The importance of understanding and addressing health literacy in relation to renal services, and dialysis in particular, is highlighted by use of an example of a Scottish renal unit's practice to outline the principles being used in a service. PMID- 30478144 TI - hnRNP Q regulates IRES-mediated fmr1 translation in neurons. AB - Fragile X syndrome (FXS) caused by loss of fragile X mental retardation protein (FMRP) is the most common cause of inherited intellectual disability. Numerous studies show that FMRP is a RNA binding protein that regulates translation of its binding targets and plays key roles in neuronal functions. However, the regulatory mechanism for FMRP expression is incompletely understood. Conflicting results regarding internal ribosome entry site (IRES)-mediated fmr1 translation were reported. Here, we unambiguously demonstrated that the fmr1 gene, which encodes FMRP, exploits both IRES-mediated translation and canonical cap-dependent translation. Furthermore, we found that heterogeneous nuclear ribonucleoprotein Q (hnRNP-Q) acts as IRES transacting factor (ITAF) for IRES-mediated fmr1 translation in neurons. We also showed that semaphorin 3A (Sema3A) induced axonal growth cone collapse is due to upregulation of hnRNP-Q and subsequent IRES mediated expression of FMRP. These data elucidate the regulatory mechanism of FMRP expression and its role in axonal growth cone collapse. PMID- 30478145 TI - Influence of chronic diseases on societal participation in paid work, volunteering and informal caregiving in Europe: a 12-year follow-up study. AB - BACKGROUND: This study aims to provide insight into (1) the associations between having a chronic disease and participation in paid work, volunteer activities or informal care, (2) the associations between the onset of a chronic disease and these forms of societal participation, and (3) whether these associations differ across educational level and gender. METHODS: The study population consisted of n=21 875 respondents of the Survey of Health, Ageing and Retirement in Europe aged between 50 years and the country-specific retirement age. The influence of having and the onset of a chronic disease on societal participation was analysed using a hybrid Poisson regression model, combining fixed and random effects, and presented by relative risks (RRs). RESULTS: Individuals with a chronic disease were less likely to participate in paid work (RR: 0.69; 95% CI 0.67 to 0.71) and volunteer activities (RR: 0.92; 95% CI 0.88 to 0.97), but more likely to give informal care (RR: 1.05; 95% CI 1.01 to 1.08). Onset of a chronic disease was associated with a higher likelihood to quit paid work (RR: 0.91; 95% CI 0.86 to 0.97) and to give informal care (RR: 1.08; 95% CI 1.01 to 1.16). Lower educated individuals with a chronic disease or with the onset of a chronic disease were less likely to have paid work than higher educated individuals. CONCLUSION: Individuals with a chronic disease were less likely to participate in paid work and volunteer activities, and more likely to provide informal care. Educational inequalities were present for paid work. More insight into which factors hinder societal participation among individuals with a chronic disease is needed. PMID- 30478146 TI - Assessing function of electronic health records for real-world data generation. PMID- 30478148 TI - Roundup from LMC meeting. PMID- 30478147 TI - Cannabis based drugs: accessing information in Scotland. PMID- 30478149 TI - 3D growth of cancer cells elicits sensitivity to kinase inhibitors but not lipid metabolism modifiers. AB - Tumour cells exhibit altered lipid metabolism compared to normal cells. Cell signalling kinases are important for regulating lipid synthesis and energy storage. How upstream kinases regulate lipid content, versus direct targeting of lipid metabolising enzymes, is currently unexplored. We evaluated intracellular lipid concentrations in prostate and breast tumour spheroids, treated with drugs directly inhibiting metabolic enzymes FASN, ACC, DGAT and PDHK, or cell signalling kinase enzymes PI3K, AKT and mTOR with lipidomic analysis. We assessed whether baseline lipid profiles corresponded to inhibitors' effectiveness in modulating lipid profiles in 3D-growth, and their relationship to therapeutic activity. Inhibitors against PI3K, AKT and mTOR significantly inhibited MDA-MB 468 and PC3 cell growth in 2D and 3D spheroid growth, while moderately altering lipid content. Conversely, metabolism inhibitors against FASN and DGAT altered lipid content most effectively, while only moderately inhibiting growth compared to kinase inhibitors. The FASN and ACC inhibitors' effectiveness in MDA-MB-468, versus PC3, suggested the former depended more on synthesis whereas the latter may salvage lipids. Although baseline lipid profiles didn't predict growth effects, lipid changes on therapy matched the growth effects of FASN and DGAT inhibitors. Several phospholipids, including phosphatidylcholine, were also upregulated following treatment, possibly via the Kennedy pathway. As this promotes tumour growth, combination studies should include drugs targeting it. Two-dimensional drug screening may miss important metabolism inhibitors or underestimate their potency. Clinical studies should consider serial measurements of tumour lipids to prove target modulation. Pre-therapy tumour classification by de novo lipid synthesis versus uptake may help demonstrate efficacy. PMID- 30478150 TI - Targeting of BRM sensitizes BRG1 mutant lung cancer cell lines to radiotherapy. AB - Targeting of epigenetic regulators as the chromatin remodeler SWI/SNF is proving to be a promising therapeutic strategy for individualized treatment of cancer patients. Here we tested whether targeting one of the two mutually exclusive subdomains of the SWI/SNF complex BRM/SMARCA2 can sensitize specifically NSCLC cells with mutations in the other subunit BRG1/SMARCA4 towards ionizing radiation (IR). Knock-down of BRM with siRNA or shRNA and its consequences for radiation sensitivity as measured by clonogenic survival and plaque-monolayer control was studied in different NSCLC lines with or without BRG1 mutations and in primary fibroblasts. Furthermore, the effect on double strand break (DSB) repair markers measured by immunofluorescence staining of 53BP1-, gamma-H2AX- and Rad51-foci was investigated. BRG1-mutated cell lines showed an increased surviving fraction compared to BRG1 proficient cells. Depletion of BRM lead (i) to a decreased proliferation rate and plating efficiency specifically in BRG1-mutated cells, (ii) specifically sensitized BRG1-mutant NSCLC cells towards IR as characterized by a survival reducing factor of 0.63 (95% ci: 0.57 - 0.69) in the dose range between 2 Gy and 6 Gy and (iii) decreased the tumor control doses after daily fractionation at 4 Gy in BRG1-mutant NSCLC cell lines A549 and H1299 in mini monolayers by 9.9+1.3% and 13.6+1.8%. In addition, an increase of residual Rad51 foci at 24 h after irradiation in BRG1-mutant cells was demonstrated. Therefore, targeting of BRM in combination with radiotherapy is supposed to improve the therapeutic outcome of lung cancer patients harboring BRG1 mutations. PMID- 30478151 TI - Therapeutic Inhibition of the Receptor Tyrosine Kinase AXL Improves Sensitivity to Platinum and Taxane in Ovarian Cancer. AB - Ovarian cancer (OvCa), one of the deadliest malignancies in female cancer patients, is characterized by recurrence and poor response to cytotoxic chemotherapies. Fewer than 30% of patients with resistant disease will respond to additional chemotherapy treatments. This study aims to determine whether and how inhibition of the receptor tyrosine kinase AXL can restore sensitivity to front line platinum and taxane therapy in OvCa. AXL staining was quantified in a patient tissue microarray and correlated with chemoresponse of patients. We used small hairpin RNAs to knock down AXL expression and the small molecule inhibitor BGB324 to inhibit AXL and assessed sensitivity of cell lines and primary patient derived cells to chemotherapy. We quantified platinum accumulation by inductivity coupled plasma phase mass spectrometry. Finally, we treated chemoresistant patient-derived xenografts with chemotherapy, BGB324, or chemotherapy plus BGB324 and monitored tumor burden. AXL expression was higher in chemoresistant patient tumors and cell lines than in chemosensitive tumors and cell lines. AXL staining significantly predicted chemoresponse. Knockdown and inhibition of AXL dose dependently improved response to paclitaxel and carboplatin in both cell lines and primary cells. AXL inhibition increased platinum accumulation by 2-fold (*P < 0.05). In vivo studies indicated that AXL inhibition enhanced the ability of chemotherapy to prevent tumor growth (****P <0.0001). AXL contributes to platinum and taxane resistance in OvCa, and inhibition of AXL improves chemoresponse and accumulation of chemotherapy drugs. This study supports continued investigation into AXL as a clinical target. PMID- 30478152 TI - Genetic accommodation and the role of ancestral plasticity in the evolution of insect eusociality. AB - For over a century, biologists have proposed a role for phenotypic plasticity in evolution, providing an avenue for adaptation in addition to 'mutation-first' models of evolutionary change. According to the various versions of this idea, the ability of organisms to respond adaptively to their environment through phenotypic plasticity may lead to novel phenotypes that can be screened by natural selection. If these initially environmentally induced phenotypes increase fitness, then genetic accommodation can lead to allele frequency change, influencing the expression of those phenotypes. Despite the long history of 'plasticity-first' models, the importance of genetic accommodation in shaping evolutionary change has remained controversial - it is neither fully embraced nor completely discarded by most evolutionary biologists. We suggest that the lack of acceptance of genetic accommodation in some cases is related to a lack of information on its molecular mechanisms. However, recent reports of epigenetic transgenerational inheritance now provide a plausible mechanism through which genetic accommodation may act, and we review this research here. We also discuss current evidence supporting a role for genetic accommodation in the evolution of eusociality in social insects, which have long been models for studying the influence of the environment on phenotypic variation, and may be particularly good models for testing hypotheses related to genetic accommodation. Finally, we introduce 'eusocial engineering', a method by which novel social phenotypes are first induced by environmental modification and then studied mechanistically to understand how environmentally induced plasticity may lead to heritable changes in social behavior. We believe the time is right to incorporate genetic accommodation into models of the evolution of complex traits, armed with new molecular tools and a better understanding of non-genetic heritable elements. PMID- 30478153 TI - CD19-positive antibody-secreting cells provide immune memory. AB - Long-lived antibody-secreting cells (ASCs) are critical for the maintenance of humoral immunity through the continued production of antibodies specific for previously encountered pathogen or vaccine antigens. Recent reports describing humoral immune memory have suggested the importance of long-lived CD19- bone marrow (BM) ASCs, which secrete antibodies recognizing previously encountered vaccine antigens. However, these reports do not agree upon the unique contribution of the CD19+ BM ASC subset toward humoral immunity. Here, we found both CD19+ and negative ASCs from human BM were similar in functional capacity to react to a number of vaccine antigens via ELISpot assays. The CD19+ cells were the predominant ASC population found in lymphoid tissues, and unlike the CD19- ASCs, which were found only in spleen and BM, the CD19+ ASCs were found in tonsil and blood. CD19+ ASCs from the BM, spleen, and tonsil were capable of recognizing polio vaccine antigens, indicating the CD19+ ASC cells play a novel role in long lasting immune defense. Comparative gene expression analysis indicated CD19+ and negative BM ASCs differed significantly by only 14 distinct messenger RNAs and exhibited similar gene expression for cell cycle, autophagy, and apoptosis control necessary for long life. In addition, we show identical CDR-H3 sequences found on both BM ASC subsets, indicating a shared developmental path. Together, these results provide novel insight for the distribution, function, genetic regulation, and development of long-lived ASCs and may not only impact improved cell therapies but also enhance strategies for vaccine development. PMID- 30478154 TI - CosR is an oxidative stress sensing MarR-type transcriptional repressor in C orynebacterium glutamicum. AB - The MarR family is unique to both bacteria and archaea. The members of this family, one of the most prevalent families of transcriptional regulators in bacteria, enable bacteria to adapt to changing environmental conditions, such as the presence of antibiotics, toxic chemicals, or reactive oxygen species, mainly by thiol-disulfide switches. Although the genome of Corynebacterium glutamicum encodes a large number of the putative MarR-type transcriptional regulators, their physiological and biochemical functions have so far been limited to only two proteins, regulator of oxidative stress response RosR and quinone oxidoreductase regulator QosR. Here we report that the ncgl2617 gene ( cosR ) of C. glutamicum encoding an MarR-type transcriptional regulator play an important role in oxidative stress resistance. The cosR null mutant is found to be more resistant to various oxidants and antibiotics, accompanied by a decrease of ROS production and protein carbonylation levels under various stresses. Protein biochemical function analysis shows that two Cys residues presenting at 49 and 62 sites in CosR are redox-active. They form intermolecular disulfide bonds in CosR under oxidative stress. This CosR oxidation leads to its dissociation from promoter DNA, depression of the target DNA, and increased oxidative stress resistance of C. glutamicum. Together, the results reveal that CosR is a redox sensitive regulator that senses peroxide stress to mediate oxidative stress resistance in C. glutamicum. PMID- 30478155 TI - Dolphin echolocation behaviour during active long-range target approaches. AB - Echolocating toothed whales generally adjust click intensities and rates according to target range to ensure that echoes from targets of interest arrive before a subsequent click is produced, presumably facilitating range estimation from the delay between clicks and returning echoes. However, this click-echo click paradigm for dolphin biosonar is mostly based on experiments with stationary animals echolocating fixed targets at ranges below ~120 m. Therefore, we trained two bottlenose dolphins instrumented with a sound recording tag to approach a target from ranges up to 400 m and either touch the target (subject TRO) or detect a target orientation change (subject SAY). We show that free swimming dolphins dynamically increase interclick interval (ICI) out to target ranges of ~100 m. TRO consistently kept ICIs above the two-way travel-time (TWTT) for target ranges shorter than ~100 m, whereas SAY switched between clicking at ICIs above and below the TWTT for target ranges down to ~25 m. Source levels changed on average by 17log10(target range), but with considerable variation for individual slopes (4.1 standard deviations for by-trial random effects), demonstrating that dolphins do not adopt a fixed automatic-gain-control matched to target range. At target ranges exceeding ~100 m, both dolphins frequently switched to click packet production in which interpacket intervals exceeded the TWTT, but ICIs were shorter than the TWTT. This study shows that echolocation following the click-echo-click paradigm is not a fixed echolocation strategy in dolphins, and we demonstrate the first use of click packets for free-swimming dolphins when solving an echolocation task. PMID- 30478156 TI - Associations of hormonal contraceptives and infertility medications on the risk of venous thromboembolism, ischemic stroke, and cardiovascular disease in women. AB - The purpose of this study was to examine the relations of hormonal contraceptives and infertility drugs with the risk of venous thromboembolism (VTE), deep vein thrombosis (DVT), pulmonary embolism (PE), ischemic stroke, and cardiovascular disease. The Taiwan National Health Institute Research Database was searched for women who had taken hormonal contraceptives or infertility medications from 2000 to 2010. The two groups were age and index date matched with controls (1:4 ratios). Cox regression analysis was used to examine the risks of VTE, DTE, PE, ischemic stroke, and cardiovascular disease. A total of 32,067 women were included in the hormonal contraceptives group and 4710 in the infertility medications group (matched controls: 127,872 and 18,840, respectively). After adjustment for age, comorbidities, and other confounders, the contraceptives group had a higher risk of VTE (adjusted HR 1.14, 95% CI 1.004 to 1.30) and cardiovascular disease (adjusted HR 1.30, 95% CI 1.26 to 1.34), and lower risk of ischemic stroke (adjusted HR 0.90, 95% CI 0.86 to 0.95). The infertility medications group had a higher risk of VTE (adjusted HR 1.996, 95% CI 1.41 to 2.72) and DVT (adjusted HR 1.86, 95% CI 1.31 to 2.63), and lower risk of ischemic stroke (adjusted HR 0.82, 95% CI 0.68 to 0.99) and cardiovascular disease (adjusted HR 0.83, 95% CI 0.74 to 0.94). Hormonal contraceptives and infertility medications appear to lower the risk of ischemic stroke and increase the risk of VTE; however, their effect on the risk of other types of cardiovascular events varies. PMID- 30478157 TI - Development and characterization of MDR1 (Mdr1a/b) CRISPR/Cas9 knockout rat model. AB - Clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR associated protein-9 nuclease (Cas9) technology is widely used as a tool for gene editing in rat genome site-specific engineering. Multidrug resistance 1 (MDR1, also known as P-glycoprotein) is a key efflux transporter that plays an important role not only in the transport of endogenous and exogenous substances, but also in tumor multidrug resistance. In this report, a novel MDR1 (Mdr1a/b) double knockout (KO) rat model was generated by CRISPR/Cas9 system without any off target effect detected. Western blot results showed that MDR1 was completely absent in liver, small intestine, brain and kidney of KO rats. Further pharmacokinetic studies of digoxin, a typical substrate of MDR1, confirmed the deficiency of MDR1 in vivo. To determine the possible compensatory mechanism of Mdr1a/b (-/-) rats, the mRNA levels of CYP3A subfamily and transporter-related genes were compared in the brain, liver, kidney and small intestine of KO and wild-type rats. In general, a new Mdr1a/b (-/-) rat model has been successfully generated and characterized. This rat model is a useful tool for studying the function of MDR1 in drug absorption, tumor multidrug resistance and drug target validation. PMID- 30478158 TI - Overcoming P-glycoprotein mediated drug resistance with noscapine derivatives. AB - The antitussive agent noscapine has previously been shown to inhibit the proliferation of cancer cells by disruption of tubulin dynamics. However, the efficacy of several anticancer drugs that inhibit tublin dynamics (vinca alkaloids and taxanes) is reduced by the multidrug resistance phenotype. In particular, these compounds are substrates for P-glycoprotein (P-gp) mediated extrusion from cells. Consequently, the anti-proliferative activity of noscapine, and a series of derivatives, was measured in drug sensitive and drug resistant cells that over-express P-gp. None of the noscapine derivatives displayed lower potency in cells over-expressing P-gp; thereby suggesting a lack of interaction with this pump. However, the cellular efflux of a fluorescent substrate by P-gp was potently inhibited by noscapine and the majority of derivatives. Further investigation with purified, reconstituted P-gp demonstrated that inhibition of P gp function was due to direct interaction of noscapine derivatives with the transporter. Moreover, co-administration of vinblastine with two of the noscapine derivatives displayed synergistic inhibition of proliferation, even in P-gp expressing resistant cell lines. Therefore, noscapine derivatives offer a dual benefit of overcoming the significant impact of P-gp in conferring multidrug resistance and synergy with tubulin-disrupting anticancer drugs. PMID- 30478159 TI - Optimization of Experimental Conditions of Automated Glucuronidation Assays in Human Liver Microsomes using a Cocktail Approach and Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry. AB - UDP-glucuronosyltransferase (UGT)-mediated metabolism is possibly the most important conjugation reaction for marketed drugs. However, there are no generally accepted standard incubation conditions for UGT microsomal assays and substantial differences in experimental design and methodology between laboratories hinders cross-study comparison of in vitro activities. This study aimed to define optimal experimental conditions to determine glucuronidation activity of multiple UGT isoforms simultaneously using human liver microsomes. Hepatic glucuronidation activities of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B10, UGT2B15 and UGT2B17 were determined using cocktail incubations of 11 UGT probe substrates. Buffer components and co-substrates were assessed over a range of concentrations including magnesium chloride (MgCl2, 0-10 mM) and uridine diphosphate glucuronic acid (UDPGA, 1-25 mM) with either Tris-HCl or potassium phosphate buffer (100 mM, pH 7.4). The utility of bovine serum albumin (BSA, 0.1-2% w/v) on glucuronidation activity was also assessed. Enhanced glucuronidation rates of UGT1A3, UGT1A4 and UGT1A9 by 50% to 87% were observed with 10 mM MgCl2, 5 mM UDPGA and Tris-HCl buffer. Enzyme- and substrate-dependent effects of BSA were observed, resulting in unchanged UGT2B10 and UGT1A6 activity, decreased UGT1A4 activity, and increased UGT1A9 and UGT2B7 activity. Inclusion of BSA did not significantly reduce the between-subject variability of UGT activity. Future in vitro UGT profiling studies under the proposed optimized experimental conditions would allow high quality positive control data to be generated in phenotyping assays; a more reliable assessment of the 'true' between-subject variability in in vitro UGT metabolic activity, and reduce technical variability observed across in vitro studies. PMID- 30478160 TI - Sudden onset of lower limb flaccid paralysis. AB - A previously well 15-year-old boy presented to the emergency department with sudden-onset severe back pain and inability to weight bear. Preceding this event, he stretched out in bed and felt a click in his back.On examination, he was alert and interactive with normal vital signs. Neurological examination of the lower limbs demonstrated bilateral hypotonia and reduced power to 2/5 proximally and distally, absent reflexes, sensory level at L2 with paraesthesia (pins and needles) and dysaesthesia bilaterally. Upper limbs, cranial nerves and general examination were unremarkable. His condition progressed with worsening lower limb weakness and urinary retention, without any respiratory compromise. QUESTIONS: List three differential diagnoses for acute flaccid paralysis.An MRI of the spine was normal. On further assessment, the patient was noticed to have pale legs with prolonged capillary refill. The right posterior tibialis pulse was thready, and the left posterior tibialis and dorsalis pedis pulses were absent bilaterally. A CT angiogram (figures 1 and 2) was performed. Based on the abnormalities demonstrated by this imaging, what is the most likely diagnosis?During subsequent surgery, the aorta was noticed to be very fragile and have tissue paper consistency. More in-depth questioning revealed a history of inguinal hernia repair at 2, features of hypermobility and easy bruising. Genetic tests showed a mutation in the COL3A1 gene that encodes for type III collagen. What is the underlying diagnosis?Vascular Ehlers-Danlos syndrome.Loeys-Dietz syndrome.Classical Ehlers-Danlos syndrome.Marfan syndrome. edpract;archdischild 2018-315903v1/F1F1F1Figure 1CT angiogram: two axial sections at L1 and L2 level.edpract;archdischild-2018-315903v1/F2F2F2Figure 2CT angiogram: midline sagittal section. Answers can be found on page 2. PMID- 30478161 TI - Molecular Analysis of Linezolid Resistant Clinical Isolates of Mycobacterium abscessus. AB - A total of 194 Mycobacterium abscessus isolates were collected from patients and the whole genomes were sequenced. Eighty-five (43.8%) showed linezolid (LZD) resistant. Only 8.2% of resistant isolates harbored 23S rRNA mutations. qRT-PCR revealed higher transcriptional levels of efflux pumps lmrS and mmpL9 in LZD resistant isolates. Genome comparative analysis identified several new LZD resistance-associated genes. This study highlights the role of efflux pumps in LZD-resistant M. abscessus and proposes potential target genes for further studies. PMID- 30478162 TI - Comparative genomics of serial Candida glabrata isolates and the rapid acquisition of echinocandin resistance during therapy. AB - The opportunistic pathogen Candida glabrata shows a concerning increase in drug resistance. Here we present the analysis of two serial bloodstream isolates, taken 12 days apart. Both isolates show pan-azole resistance and echinocandin resistance was acquired during the sampling interval. Genome sequencing identified 9 nonsynonymous SNVs between the strains, including a S663P substitution in FKS2 and previously undescribed SNVs in MDE1 and FPR1, offering insight into how C. glabrata acquires drug resistance and adapts to a human host. PMID- 30478163 TI - In vivo applicability of Neosartorya fischeri antifungal protein 2 (NFAP2) in treatment of vulvovaginal candidiasis. AB - In the consequence of emerging number of vulvovaginitis caused by azole-resistant and biofilm-forming Candida species, the fast and efficient treatment of this infection has become challenging. The problem is further exacerbated by the severe side-effects of azoles as long-term use medications in the recurrent form. There is therefore an increasing demand for novel and safely applicable effective antifungal therapeutic strategies. The small, cysteine-rich and cationic antifungal proteins from filamentous ascomycetes are potential candidates as they inhibit the growth of several Candida spp. in vitro; however no information is available about their in vivo antifungal potency against yeasts. In the present study we investigated the possible therapeutic application of one of their representatives in the treatment of vulvovaginal candidiasis, the Neosartorya fischeri antifungal protein 2 (NFAP2). NFAP2 inhibited the growth of a fluconazole (FLC)-resistant Candida albicans strain isolated from vulvovaginal infection, and it was effective against both planktonic cells and biofilm in vitro We observed that the fungal cell killing activity of NFAP2 is connected to its pore-forming ability in the cell membrane. NFAP2 did not exert cytotoxic effects on primary human keratinocytes and dermal fibroblasts at the minimal inhibitory concentration in vitro In vivo murine vulvovaginitis model experiments showed that NFAP2 significantly decreases the cell number of the FLC-resistant C. albicans, and the combined application with FLC enhances the efficacy. These results suggest that NFAP2 provides a feasible base for the development of a fundamental new, safely applicable mono- or polytherapeutic topical agent in the treatment of superficial candidiasis. PMID- 30478164 TI - LEISHMANICIDAL ACTIVITY OF ISOSELENOCYANATE DERIVATIVES. AB - Conventional chemotherapy against leishmaniasis includes agents exhibiting considerable toxicity. In addition, reports of drug-resistance are not uncommon. Thus, safe and effective therapies are urgently needed. Isoselenocyanate compounds have recently been identified with potential antitumor activity. It is well known that some antitumor agents demonstrate effects against Leishmania In this study, the in vitro leishmanicidal activities of several organo- selenium and sulfur compounds were tested against Leishmania major and Leishmania amazonensis parasites, using promastigotes and intracellular amastigote forms. The cytotoxicity of these agents was measured in murine peritoneal macrophages and their selectivity indexes were calculated. One of the tested compounds, an isoselenocyanate derivative NISC-6, showed selectivity indexes two- and ten-fold higher than those of the reference drug Amphotericin B when evaluated in L. amazonensis and L. major, respectively. The American strain (L. amazonensis) was less sensitive to NISC-6 than L. major, showing a similar trend as described previously for Amphotericin B. In addition, we also observed that NISC-6 significantly reduced the number of amastigotes per infected macrophage. On the other hand, we showed that NISC-6 decreases expression levels of Leishmania genes involved in the cell cycle, such as topoisomerase-2 (TOP-2), PCNA and MCM4, therefore contributing to its leishmanicidal activity. The effect of this compound on cell cycle progression was confirmed by flow cytometry. We observed a significant increase of cells in the G1 phase and a dramatic reduction of cells in the S phase compared to untreated cells. Altogether, our data suggest that the isoselenocyanate NISC-6 may be a promising candidate for new drug development against leishmaniasis. PMID- 30478165 TI - Emergence of resistance to quinolones and beta-lactam antibiotics in enteroaggregative and enterotoxigenic Escherichia coli causing traveler's diarrhea. AB - The objective of this study was to assess the antimicrobial resistance of enteroaggregative Escherichia coli (EAEC) and enterotoxigenic E. coli (ETEC) causing traveler's diarrhea (TD) and investigate the molecular characterization of antimicrobial resistance genes to third generation cephalosporins, chepamycins and quinolones. Overall, 39 EAEC and 43 ETEC clinical isolates were studied. The susceptibility of EAEC and ETEC against ampicillin, amoxicillin-clavulanic acid, cefotaxime, imipenem, chloramphenicol, tetracycline, cotrimoxazole, nalidixic acid, ciprofloxacin, azithromycin and rifaximin was determined. All genes encoding resistant determinants were detected by PCR or PCR and DNA sequencing. The epidemiology of selected EAEC and ETEC strains was studied using MLST. The resistance to quinolones of EAEC and ETEC strains causing TD has significantly increased over the last decades, and high percentages has been found especially in patients traveling to India and sub-Saharan Africa. The ST38 and ST131 carrying the bla CTX-M-15 and bla CTX-M-27 genes, respectively, are highly prevalent among ESBL-producing EAEC and ETEC. The cephamycinase ACT-20 is described in the present study for the first time in EAEC and ETEC strains causing TD in patients who had traveled to Central America. The percentages of resistance to azithromycin in EAEC and ETEC isolates from patients to South-East Asia/India and Africa are above 25%. Meanwhile, rifaximin is still active against EAEC and ETEC with the prevalence of resistant strains not being high. In conclusion, fluoroquinolones should no longer be considered the drugs of choice for the prevention or treatment in TD for travelers traveling to India and Africa. Azithromycin and rifaximin are still a good alternative to treat TD caused by EAEC or ETEC. PMID- 30478166 TI - SCY-078, A Novel Fungicidal Agent, Demonstrates Distribution to Tissues Associated with Fungal Infections During Mass Balance Studies with IV and PO 14C SCY-078 in Albino and Pigmented Rats. AB - SCY-078, a fungicidal beta-1,3-glucan synthesis inhibitor, administered as intravenous or oral [14C]-SCY-078 to rat, distributed primarily into tissues associated with invasive fungal disease (kidney, lung, liver, spleen, bone marrow, muscle, vaginal tissue, and skin) to levels exceeding plasma. Oral fraction absorbed was ~40%. Elimination was primarily via bile and feces (~90%) and urine (~1.5%). Mean t1/2 was ~8 h. Quantitative whole-body autoradiography showed a rapid distribution 8 h post-dose, and elimination by 168 h. PMID- 30478167 TI - Patients at Risk for Aortic Rupture Often Exposed to Fluoroquinolones During Hospitalization. AB - Several studies have indicated that fluoroquinolone use may be associated with an increased risk of aortic aneurysm or dissection (AAD). Because patients with AAD or Marfan syndrome are at increased risk for aortic rupture, we performed a retrospective cohort study to determine the prevalence of systemic fluoroquinolone exposure and predictors of fluoroquinolone use in these patients. Data were obtained from the Advisory Board billing and administrative database, which contained information on 22 million adult hospitalizations in the United States for the study period (2009-2015). International Classification of Diseases (9/10) and Current Procedural Terminology codes were used to identify patients who had AAD or Marfan syndrome or underwent aortic repair. We identified 136,789 admissions for AAD, which involved 99,818 unique patients, 20% of whom received fluoroquinolone during a hospital admission. Of the 7,045 patients with dissection, 18% were exposed to fluoroquinolone. Of the 27,876 AAD patients who underwent aortic repair, 19% received fluoroquinolone during a hospitalization before the repair. In the AAD patients, having a diagnosis of pneumonia or urinary tract infection increased the likelihood of receiving fluoroquinolone during admission by 46% and 40%, respectively (P<0.001). Additionally, we identified 2,871 admissions for Marfan syndrome, which involved 1,872 patients, 14% of whom received fluoroquinolone during an admission. In these patients, pneumonia and urinary tract infections also increased the risk of fluoroquinolone exposure. If the deleterious effects of fluoroquinolone on aortic integrity are substantiated, reducing fluoroquinolone use in hospitalized patients with aortic disorders will become an urgent safety issue for antibiotic stewardship programs. PMID- 30478168 TI - Multicenter population pharmacokinetic study of colistimethate sodium and colistin dosed as in normal renal function in patients on continuous renal replacement therapy. AB - Background: Intravenous colistimethate sodium (CMS) is used to treat infections with multi-resistant Gram-negative bacteria. Optimal dosing in patients undergoing continuous renal replacement therapy (CRRT) is unclear.Materials/methods: In a prospective study, we determined CMS and colistin pharmacokinetics in 10 critically ill patients requiring CRRT (8 underwent continuous venovenous hemofiltration (CVVHD), median blood flow 100 ml/min). Intensive sampling was performed on treatment day 1, 3 and 5 after a 9 MU intravenous CMS loading dose (6 MU if body weight < 60 kg) with a consecutive 8 hourly 3 MU (respectively 2 MU) maintenance dose. CMS and colistin were determined by liquid chromatography with mass spectroscopy. A model-based population pharmacokinetic analysis incorporating CRRT settings was applied to the observations.Results: Sequential model building indicated a monocompartmental distribution for both CMS and colistin, with interindividual variability in both volume and clearance. Hematocrit was shown to affect the efficacy of drug transfer across the filter. CRRT clearance accounted for on average 41% of total CMS and 28% of total colistin clearance, confirming enhanced elimination of colistin compared to normal renal function. Target colistin steady state trough concentrations of at least 2.5 mg/L were achieved in all patients receiving 3 MU 8-hourly.Conclusion: A loading dose of 9 MU followed after 8 h by a maintenance dosage of 3 MU 8 hourly independent of body weight is expected to achieve therapeutic colistin concentrations in patients undergoing CVVHD using low blood flows. Colistin therapeutic drug monitoring might help to further ensure optimal dosing in individual patients. PMID- 30478169 TI - The global implications of the gentamicin histamine contamination- sorting fact from fiction. AB - On the 6th of October 2017 the Therapeutics Goods Administration (TGA) in conjunction with Pfizer Australia released a statement to recall 10 batches of gentamicin Infection BP 80mg in 2ml Steriluer ampoules, due to the finding that these batches may have contained higher than expected amounts of histamine, a residual from the manufacturing process(1)..... PMID- 30478170 TI - Structures of AMP-activated protein kinase bound to novel pharmacological activators in phosphorylated, non-phosphorylated, and nucleotide-free states. AB - AMP-activated protein kinase (AMPK) is an attractive therapeutic target for managing metabolic diseases. A class of pharmacological activators, including Merck 991, binds the AMPK ADaM site, which forms the interaction surface between the kinase domain (KD) of the alpha subunit and the carbohydrate-binding module (CBM) of the beta subunit. Here, we report the development of two new 991 derivative compounds, R734 and R739, which potently activate AMPK in a variety of cell types, including beta2-specific skeletal muscle cells. Surprisingly, we found that they have only minor effects on direct kinase activity of the recombinant alpha1beta2gamma1 isoform, yet robustly enhance protection against activation loop dephosphorylation. This mode of activation is reminiscent of that of ADP, which activates AMPK by binding to the nucleotide-binding sites in the gamma subunit, more than 60 A away from the ADaM site. To understand the mechanisms of full and partial AMPK activation, we determined the crystal structures of fully active phosphorylated AMPK alpha1beta1gamma1 bound to AMP and R734/R739, as well as partially active non-phosphorylated AMPK bound to R734 and AMP, and phosphorylated AMPK bound to R734 in the absence of added nucleotides at < 3 A resolution. These structures and associated analyses identified a novel conformational state of the AMPK autoinhibitory domain associated with partial kinase activity and provide new insights into phosphorylation-dependent activation loop stabilization in AMPK. PMID- 30478171 TI - Kinetic and catalytic properties of M.HpyAXVII, a phase variable DNA methyltransferase from Helicobacter pylori. AB - The bacterium Helicobacter pylori is one of the most common infectious agents found in the human stomach. H. pylori has an unusually large number of DNA methyltransferases (MTases), prompting speculation that they may be involved in the cancerization of epithelial cells. The mod-4a/4b locus, consisting of the hp1369 and hp1370 ORFs, encodes for a truncated and inactive MTase in H. pylori strain 26695. However, slipped-strand synthesis within the phase-variable poly guanine track in hp1369 results in expression of an active HP1369-1370 fusion N6 adenine methyltransferase, designated M.HpyAXVII. Sequence analysis of the mod 4a/4b locus across 74 H. pylori strain genomes has provided insights into the regulation of M.HpyAXVII expression. To better understand the role of M.HpyAXVII in the H. pylori biology, here we cloned and over-expressed the hp1369-70 fusion construct in Escherichia coli BL21(DE3) cells. Results from size-exclusion chromatography and multi-angle light scattering (MALS) analyses suggested that M.HpyAXVII exists as a dimer in solution. Kinetic studies including product and substrate inhibition analyses, initial velocity dependence between substrates, and isotope partitioning suggested that M.HpyAXVII catalyzes DNA methylation in an ordered Bi Bi mechanism in which the S-adenosylmethionine (AdoMet) binding precedes DNA binding and AdoMet's methyl group is then transferred to an adenine within the DNA recognition sequence. Altering the highly conserved catalytic motif (DPPY/F) as well as AdoMet binding motif (FXGXG) by site directed mutagenesis abolished the catalytic activity of M.HpyAXVII. These results provide insights into the enzyme kinetic mechanism of M.HpyAXVII. We propose that AdoMet binding conformationally "primes" the enzyme for DNA binding. PMID- 30478172 TI - Electrophilic fatty acids impair RAD51 function and potentiate the effects of DNA damaging agents on growth of triple-negative breast cells. AB - Homologous recombination (HR)-directed DNA double-strand break (DSB) repair enables template-directed DNA repair to maintain genomic stability. RAD51 recombinase (RAD51) is a critical component of HR and facilitates DNA strand exchange in DSB repair. We report here that treating triple-negative breast cancer (TNBC) cells with the fatty acid nitroalkene 10-nitrooctadec-9-enoic acid (OA-NO2) in combination with the antineoplastic DNA-damaging agents doxorubicin, cisplatin, olaparib, and gamma-irradiation (IR) enhances the antiproliferative effects of these agents. OANO2 inhibited IR-induced RAD51 foci formation and enhanced H2A histone family member X (H2AX) phosphorylation in TNBC cells. Analyses of fluorescent DSB reporter activity with both static-flow cytometry and kinetic live-cell studies enabling temporal resolution of recombination revealed that OA-NO2 inhibits HR and not nonhomologous end joining (NHEJ). OA-NO2 alkylated Cys319 in RAD51, and this alkylation depended on the Michael acceptor properties of OA-NO2, since non-nitrated and saturated non-electrophilic analogs of OA-NO2, octadecanoic acid and 10-nitro-octdecanoic acid, did not react with Cys319. Of note, OA-NO2 alkylation of RAD51 inhibited its binding to ssDNA. RAD51 Cys319 resides within the SH3-binding site of ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1), so we investigated the effect of OA-NO2-mediated Cys319 alkylation on ABL1 binding and found that OANO2 inhibits RAD51-ABL1 complex formation both in vitro and in cell-based immunoprecipitation assays. The inhibition of the RAD51-ABL1 complex also suppressed downstream RAD51 Tyr315 phosphorylation. In conclusion, RAD51 Cys319 is a functionally significant site for adduction of soft electrophiles such as OA-NO2 and suggests further investigation of lipid electrophile-based combinational therapies for TNBC. PMID- 30478173 TI - Metabolomics and proteomics identify the toxic form and the associated cellular binding targets of the anti-proliferative drug AICAR. AB - AICAR (Acadesine; 5-Aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside) is a precursor of the monophosphate derivative ZMP, an intermediate in de novo purine biosynthesis. AICAR proved promising anti-proliferative properties, though the molecular basis of its toxicity is poorly understood. To exert cytotoxicity, AICAR needs to be metabolized, but the AICAR-derived toxic metabolite was not identified. Here, we show that ZMP is the major toxic derivative of AICAR in yeast and establish that its metabolization to SZMP (succinyl-ZMP), ZDP or ZTP (di- and tri-phosphate derivatives of AICAR) strongly reduced its toxicity. Affinity chromatography identified 74 ZMP-binding proteins, including 41 that were found neither as AMP-, nor as AICAR- or SZMP-binders. Overexpression of karyopherin-beta Kap123, one of the ZMP-specific binders, partially rescued AICAR toxicity. Quantitative proteomic analyses revealed 57 proteins significantly less abundant on nuclei-enriched fractions from AICAR-fed cells, this effect being compensated by overexpression of KAP123 for 15 of them. These results reveal nuclear protein trafficking as a function affected by AICAR. PMID- 30478174 TI - Parkinson's disease and multiple system atrophy have distinct alpha-synuclein seed characteristics. AB - Parkinson's disease (PD)S and multiple system atrophy (MSA) are distinct clinical syndromes characterized by the pathological accumulation of alpha-synuclein (alpha-syn) protein fibrils in neurons and glial cells. These disorders and other neurodegenerative diseases may progress via prion-like mechanisms. The prion model of propagation predicts the existence of "strains" that link pathological aggregate structure and neuropathology. Prion strains are aggregated conformers that stably propagate in vivo and cause disease with defined incubation times and patterns of neuropathology. Indeed, tau prions have been well defined, and research suggests that both alpha-syn and amyloid beta may also form strains. However, there is a lack of studies characterizing PD- vs MSA-derived alpha-syn strains or demonstrating stable propagation of these unique conformers between cells or animals. To fill this gap, we used an assay based on fluorescence resonance energy transfer that exploits a HEK293T "biosensor" cell line stably expressing alpha-syn (A53T)-CFP/YFP fusion proteins to detect alpha-syn seeds in brain extracts from PD and MSA patients. Both soluble and insoluble fractions of MSA extracts had robust seeding activity, while only the insoluble fractions of PD extracts displayed seeding activity. The morphology of MSA-seeded inclusions differed from PD-seeded inclusions. These differences persisted upon propagation of aggregation to second-generation biosensor cells. We conclude that PD and MSA feature alpha-syn conformers with very distinct biochemical properties that can be transmitted to alpha-syn monomers in a cell system. These findings are consistent with the idea that distinct alpha-syn strains underlie PD and MSA and offer possible directions for synucleinopathy diagnosis. PMID- 30478175 TI - A cysteine protease-like domain enhances the cytotoxic effects of the Photorhabdus asymbiotica toxin PaTox. AB - The nematode mutualistic bacterium Photorhabdus asymbiotica produces a large virulence-associated multifunctional protein toxin named PaTox. A glycosyltransferase domain and a deamidase domain of this large toxin function as effectors that specifically target host Rho GTPases and heterotrimeric G proteins, respectively. Modification of these intracellular regulators results in toxicity toward insects and mammalian cells. In this study, we identified a cysteine protease-like domain spanning PaTox residues 1844-2114 (PaToxP), upstream of these two effector domains and characterized by three conserved amino acid residues (Cys-1865, His-1955, and Asp-1975). We determined the crystal structure of the PaToxP C1865A variant by native single-wavelength anomalous diffraction of sulfur atoms (sulfur-SAD). At 2.0 A resolution, this structure revealed a catalytic site typical for papain-like cysteine proteases, comprising a catalytic triad, oxyanion hole, and typical secondary structural elements. The PaToxP structure had highest similarity to that of the AvrPphB protease from Pseudomonas syringae classified as a C58-protease. Furthermore, we observed that PaToxP shares structural homology also with non-C58-cysteine proteases, deubiquitinases, and deamidases. Upon delivery into insect larvae, PaToxP alone without full-length PaTox had no toxic effects. Yet, PaToxP expression in mammalian cells was toxic and enhanced the apoptotic phenotype induced by PaTox in HeLa cells. We propose that PaToxP is a C58-like cysteine protease module that is essential for full PaTox activity. PMID- 30478176 TI - Distinct mechanisms govern the phosphorylation of different SR protein splicing factors. AB - Serine-arginine (SR) proteins are essential splicing factors containing a canonical RNA recognition motif (RRM), sometimes followed by a pseudo-RRM, and a C-terminal arginine/serine-rich (RS) domain that undergoes multisite phosphorylation. Phosphorylation regulates the localization and activity of SR proteins, and thus may provide insight into their differential biological roles. The phosphorylation mechanism of the prototypic SRSF1 by serine-arginine protein kinase 1 (SRPK1) has been well studied but little is known about the phosphorylation of other SR protein members. In the present study, interaction and kinetic assays unveiled how SRSF1 and the single RRM-containing SRSF3 are phosphorylated by SRPK2, another member of the SRPK family. We showed a conserved SRPK-specific substrate-docking groove in SRPK2 impacts the binding and phosphorylation of both SR proteins, and the localization of SRSF3. We identified a non-conserved residue within the groove that affects the kinase processivity. We demonstrated that, in contrast to SRSF1, for which SRPK-mediated phosphorylation is confined to the N-terminal region of the RS domain, SRSF3 phosphorylation sites are spread throughout its entire RS domain in vitro. Despite this, SRSF3 appears to be hypophosphorylated in cells at steady state. Our results suggest that the absence of a pseudo-RRM renders the single RRM containing SRSF3 more susceptible to dephosphorylation by phosphatase. These findings suggest the single RRM- and two RRMs-containing SR proteins represent two subclasses of phosphoproteins which phosphorylation statuses are maintained by unique mechanisms, and pose new directions to explore the distinct roles of SR proteins in vivo. PMID- 30478177 TI - Aquaculture, Exaptation, and the Origin of mcr-Positive Colistin Resistance. PMID- 30478178 TI - Acknowledgment of Ad Hoc Reviewers. PMID- 30478179 TI - Erratum for Meletiadis et al., "Amplification of Antimicrobial Resistance in Gut Flora of Patients Treated with Ceftriaxone". PMID- 30478180 TI - Erratum for Rhee et al., "Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Relebactam, a beta-Lactamase Inhibitor, in Combination with Imipenem and Cilastatin in Healthy Participants". PMID- 30478181 TI - Erratum for Schooley et al., "Development and Use of Personalized Bacteriophage Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection". PMID- 30478182 TI - Correction for Stott et al., "Population Pharmacokinetic Model and Meta-analysis of Outcomes of Amphotericin B Deoxycholate Use in Adults with Cryptococcal Meningitis". PMID- 30478183 TI - Correction for Stott et al., "Population Pharmacokinetics and Cerebrospinal Fluid Penetration of Fluconazole in Adults with Cryptococcal Meningitis". PMID- 30478184 TI - Staff matter too: pilot staff support intervention to reduce stress and burn-out on a neonatal intensive care unit. PMID- 30478185 TI - EEG for the assessment of neurological function in newborn infants immediately after birth. AB - OBJECTIVE: To assess the neurological function of newborn infants in the first minutes after birth using EEG. DESIGN AND PATIENTS: We obtained electroencephalography (EEG) recordings in term infants following elective caesarean section. After delivery, disposable EEG electrodes were attached to the infants' scalp over the frontal and central regions bilaterally and EEG was recorded for 10 min. Both visual and quantitative measures were used to analyse the EEGs. SETTING: The operative delivery theatre of Cork University Maternity Hospital, Ireland. RESULTS: Forty-nine infants had EEG recordings over the frontal and central regions. The median (IQR) age at time of initial EEG recording was 3.0 (2.5-3.8) min. While movement artefact contaminated parts of many recordings, good-quality EEG, with mixed-frequency activity with a range of 25-50 MUV, was observed in all infants. The majority of EEG spectral power was within the delta band: the median (IQR) relative delta power was 87.8% (83.7% 90%). Almost all (95%) spectral power was below a median (IQR) of 7.56 Hz (6.17 9.76 Hz). CONCLUSIONS: EEG recording is very feasible in the immediate newborn period. This study provides valuable objective information about neurological function during this transitional period. PMID- 30478186 TI - Surgeons call for compulsory registers of all new medical devices. PMID- 30478187 TI - Health mind mapping has the potential to facilitate patient engagement in self management of long-term conditions. PMID- 30478188 TI - Nurses need to be aware of their professional responsibilities when engaging with social media. PMID- 30478189 TI - Systemic Therapy Use and Outcomes After Relapse from Preoperative Radiation and Extrapleural Pneumonectomy for Malignant Pleural Mesothelioma. AB - BACKGROUND: Multimodality therapy with preoperative radiation (RT) followed by extrapleural pneumonectomy (EP) for patients with operable malignant pleural mesothelioma (MPM) has demonstrated encouraging results. At relapse, there are few data on the tolerance and efficacy of systemic therapies after prior multimodality therapy. MATERIALS AND METHODS: We conducted a retrospective analysis of patients with relapsed MPM after RT and EPP +/- adjuvant chemotherapy to determine overall survival (OS; date of relapse to death) and the proportion of patients that received systemic therapy and associated response rate (RR). OS was estimated using Kaplan-Meier method and potential prognostic variables were examined. RESULTS: Fifty-three patients were included (2008-2016). Median OS was 4.8 months (median follow-up 4.4 months, range 0.03-34.8). Eastern Cooperative Oncology Group (ECOG) performance status (PS) >=2, disease-free interval (DFI) <1 year, and hemoglobin <=110 g/L at recurrence were associated with worse prognosis. Thirty-six percent of patients received any systemic therapy, whereas it was omitted in 62% because of poor PS. RR was 15% (0 complete responses, 15% partial responses) in 13 individuals with response-evaluable disease. Therapy was discontinued because of toxicity (6/15) or disease progression (5/15), and median number of cycles was four. CONCLUSION: Patients with relapsed MPM following RT and EPP, especially those with ECOG PS >=2, DFI <1 year, and hemoglobin <=110 g/L at recurrence, have poor prognosis and low RR to first-line systemic therapy. Earlier detection and novel diagnostic markers of relapse as well as potential neoadjuvant or adjuvant systemic therapy should be investigated in future studies. IMPLICATIONS FOR PRACTICE: The results of this study have reinforced the importance of careful selection of appropriate candidates for this combined modality approach and favor prompt detection of recurrence with early and regular postoperative imaging and biopsy of suspected relapsed disease along with rapid initiation of systemic therapy even in patients with very low burden of disease. Furthermore, with the emergence of new systemic agents targeting different histological subtypes of malignant pleural mesothelioma, histological sampling of recurrence could inform therapeutic decisions in the future. PMID- 30478190 TI - Phase I, First-in-Human, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Vorolanib in Patients with Advanced Solid Tumors. AB - LESSONS LEARNED: Pharmacokinetic results underscore that the vorolanib (X-82) study design was successful without the need for further dose escalation beyond 400 mg once daily (q.d.).Therefore, the recommended dose of X-82 as a single agent in patients with advanced cancer is 400 mg q.d. BACKGROUND: Vorolanib (X 82) is a novel, oral, multikinase vascular endothelial growth factor (VEGF) receptor/platelet-derived growth factor (PDGF) receptor inhibitor that was developed on the same chemical scaffold as sunitinib, but designed to improve upon the safety profile while maintaining the efficacy of sunitinib. By targeting the VEGF and PDGF receptors, X-82 was expected to disrupt tumor angiogenesis and be active in a broad spectrum of solid tumors. Therefore, we determined the maximum tolerated dose (MTD) and characterized the preliminary pharmacokinetics and clinical tumor response of X-82 as a single agent in patients with advanced solid tumors. METHODS: Adult patients with advanced solid tumors received X-82 as tablets or capsules (once daily [q.d.] or b.i.d.) every 4 weeks. Patients were evaluated for response every 8 weeks, and continued treatment until disease progression or intolerable toxicity. RESULTS: Fifty-two patients received study treatment in 17 cohorts. X-82 capsule dosing was as follows: cohorts 1-6 (20-400 mg q.d.) and cohorts 7-8 (140-200 mg b.i.d.). Patients in cohorts 9-17 received 50-800 mg q.d. tablet dosing. The median time on treatment was 58 days. X-82 blood pharmacokinetics appeared dose-independent with a t 1/2 of 5.13 hours and 6.48 hours for capsule and tablet formulations, respectively. No apparent accumulation was observed after 21 days of daily dosing. CONCLUSION: X-82 had a safety profile consistent with its mechanism of action. It has a short half-life and was well tolerated by most patients. Study enrollment ended prior to the determination of the MTD because of the apparent saturation of absorption at 400 800 mg. The recommended dose of X-82 as a single agent in patients with advanced cancer is 400 mg q.d. PMID- 30478191 TI - CNOT6L couples the selective degradation of maternal transcripts to meiotic cell cycle progression in mouse oocyte. AB - Meiotic resumption-coupled degradation of maternal transcripts occurs during oocyte maturation in the absence of mRNA transcription. The CCR4-NOT complex has been identified as the main eukaryotic mRNA deadenylase. In vivo functional and mechanistic information regarding its multiple subunits remains insufficient. Cnot6l, one of four genes encoding CCR4-NOT catalytic subunits, is preferentially expressed in mouse oocytes. Genetic deletion of Cnot6l impaired deadenylation and degradation of a subset of maternal mRNAs during oocyte maturation. Overtranslation of these undegraded mRNAs caused microtubule-chromosome organization defects, which led to activation of spindle assembly checkpoint and meiotic cell cycle arrest at prometaphase. Consequently, Cnot6l -/- female mice were severely subfertile. The function of CNOT6L in maturing oocytes is mediated by RNA-binding protein ZFP36L2, not maternal-to-zygotic transition licensing factor BTG4, which interacts with catalytic subunits CNOT7 and CNOT8 of CCR4-NOT Thus, recruitment of different adaptors by different catalytic subunits ensures stage-specific degradation of maternal mRNAs by CCR4-NOT This study provides the first direct genetic evidence that CCR4-NOT-dependent and particularly CNOT6L dependent decay of selective maternal mRNAs is a prerequisite for meiotic maturation of oocytes. PMID- 30478192 TI - R-loop formation during S phase is restricted by PrimPol-mediated repriming. AB - During DNA replication, conflicts with ongoing transcription are frequent and require careful management to avoid genetic instability. R-loops, three-stranded nucleic acid structures comprising a DNA:RNA hybrid and displaced single-stranded DNA, are important drivers of damage arising from such conflicts. How R-loops stall replication and the mechanisms that restrain their formation during S phase are incompletely understood. Here, we show in vivo how R-loop formation drives a short purine-rich repeat, (GAA)10, to become a replication impediment that engages the repriming activity of the primase-polymerase PrimPol. Further, the absence of PrimPol leads to significantly increased R-loop formation around this repeat during S phase. We extend this observation by showing that PrimPol suppresses R-loop formation in genes harbouring secondary structure-forming sequences, exemplified by G quadruplex and H-DNA motifs, across the genome in both avian and human cells. Thus, R-loops promote the creation of replication blocks at susceptible structure-forming sequences, while PrimPol-dependent repriming limits the extent of unscheduled R-loop formation at these sequences, mitigating their impact on replication. PMID- 30478193 TI - Tissue tension and not interphase cell shape determines cell division orientation in the Drosophila follicular epithelium. AB - We investigated the cell behaviors that drive morphogenesis of the Drosophila follicular epithelium during expansion and elongation of early-stage egg chambers. We found that cell division is not required for elongation of the early follicular epithelium, but drives the tissue toward optimal geometric packing. We examined the orientation of cell divisions with respect to the planar tissue axis and found a bias toward the primary direction of tissue expansion. However, interphase cell shapes demonstrate the opposite bias. Hertwig's rule, which holds that cell elongation determines division orientation, is therefore broken in this tissue. This observation cannot be explained by the anisotropic activity of the conserved Pins/Mud spindle-orienting machinery, which controls division orientation in the apical-basal axis and planar division orientation in other epithelial tissues. Rather, cortical tension at the apical surface translates into planar division orientation in a manner dependent on Canoe/Afadin, which links actomyosin to adherens junctions. These findings demonstrate that division orientation in different axes-apical-basal and planar-is controlled by distinct, independent mechanisms in a proliferating epithelium. PMID- 30478194 TI - A tissue communication network coordinating innate immune response during muscle stress. AB - Complex tissue communication networks function throughout an organism's lifespan to maintain tissue homeostasis. Using the genetic model Drosophila melanogaster, we have defined a network of immune responses activated following the induction of muscle stresses, including hypercontraction, detachment, and oxidative stress. Of these stressors, loss of genes causing muscle detachment produce the strongest levels of JAK-STAT activation. In one of these mutants, fondue (fon), we also observe hemocyte recruitment and the accumulation of melanin at muscle attachment sites (MASs), indicating a broad involvement of innate immune responses upon muscle detachment. Loss of fon results in pathogen-independent Toll signaling in the fat body and increased expression of the Toll-dependent antimicrobial peptide (AMP) Drosomycin. Interestingly, genetic interactions between fon and various Toll pathway components enhance muscle detachment. Finally, we show that JAK-STAT and Toll signaling are capable of reciprocal activation in larval tissues. We propose a model of tissue communication for the integration of immune responses at the local and systemic level in response to altered muscle physiology. PMID- 30478195 TI - Number and brightness analysis in live cells reveals that NCAM and FGF2 elicit different assembly and dynamics of FGFR1. AB - Both fibroblast growth factor-2 (FGF2) and neural cell adhesion molecule (NCAM) trigger FGF receptor 1 (FGFR1) signaling, however they induce remarkably distinct receptor trafficking and cellular responses. The molecular basis of such a dichotomy and the role of distinct types of ligand-receptor interactions remain elusive. Number of molecules and Brightness (N&B) analysis revealed that FGF2 and NCAM promote different FGFR1 assembly and dynamics at the plasma membrane. NCAM stimulation elicits long-lasting cycles of short-lived FGFR1 monomers and multimers, a behavior that might reflect a rapid FGFR1 internalization and recycling. FGF2, instead, induces stable dimerization at the dose that stimulates cell proliferation. Reducing the occupancy of FGFR1 by low FGF2 doses causes a switch towards cyclically exposed and unstable receptor dimers, consistently with previously reported biphasic response to FGF2 and with the divergent signaling elicited by different ligand concentrations. Similar instability was observed upon altering the endocytic pathway. Thus, FGF2 and NCAM induce differential FGFR1 clustering at the cell surface, which might account for the distinct intracellular fate of the receptor and, hence, for the different signaling cascades and cellular responses. PMID- 30478196 TI - SHP-2 is activated in response to force on E-cadherin and dephosphorylates vinculin Y822. AB - The response of cells to mechanical inputs is a key determinant of cell behavior. In response to external forces, E-cadherin initiates signal transduction cascades that allow the cell to modulate its contractility to withstand the force. Much attention has focused on identifying the E-cadherin signaling pathways that promote contractility, but the negative regulators remain undefined. In this study, we identify SHP-2 as a force-activated phosphatase that negatively regulates E-cadherin force transmission by dephosphorylating vinculin Y822. To specifically probe a role for SHP-2 in E-cadherin mechanotransduction, we mutated vinculin so that it retains its phosphorylation but cannot be dephosphorylated. Cells expressing the mutant vinculin have increased contractility. This work provides a mechanism for inactivating E-cadherin mechanotransduction and provides a new method for specifically targeting the action of phosphatases in cells. PMID- 30478197 TI - Reduced plasma levels of small HDL particles transporting fibrinolytic proteins in pulmonary arterial hypertension. AB - BACKGROUND: Aberrant lipoprotein metabolism has been implicated in experimental pulmonary hypertension, but the relevance to patients with pulmonary arterial hypertension (PAH) is inconclusive. OBJECTIVE: To investigate the relationship between circulating lipoprotein subclasses and survival in patients with PAH. METHODS: Using nuclear magnetic resonance spectroscopy, 105 discrete lipoproteins were measured in plasma samples from two cohorts of patients with idiopathic or heritable PAH. Data from 1124 plasma proteins were used to identify proteins linked to lipoprotein subclasses. The physical presence of proteins was confirmed in plasma lipoprotein subfractions separated by ultracentrifugation. RESULTS: Plasma levels of three lipoproteins from the small high-density lipoprotein (HDL) subclass, termed HDL-4, were inversely related to survival in both the discovery (n=127) and validation (n=77) cohorts, independent of exercise capacity, comorbidities, treatment, N-terminal probrain natriuretic peptide, C reactive protein and the principal lipoprotein classes. The small HDL subclass rich in apolipoprotein A-2 content (HDL-4-Apo A-2) exhibited the most significant association with survival. None of the other lipoprotein classes, including principal lipoprotein classes HDL and low-density lipoprotein cholesterol, were prognostic. Three out of nine proteins identified to associate with HDL-4-Apo A-2 are involved in the regulation of fibrinolysis, namely, the plasmin regulator, alpha-2-antiplasmin, and two major components of the kallikrein-kinin pathway (coagulation factor XI and prekallikrein), and their physical presence in the HDL 4 subfraction was confirmed. CONCLUSION: Reduced plasma levels of small HDL particles transporting fibrinolytic proteins are associated with poor outcomes in patients with idiopathic and heritable PAH. PMID- 30478198 TI - Crack growth in heterogeneous brittle solids: intermittency, crackling and induced seismicity. AB - Crack growth is the basic mechanism leading to the failure of brittle materials. Engineering addresses this problem within the framework of continuum mechanics, which links deterministically the crack motion to the applied loading. Such an idealization, however, fails in several situations and in particular cannot capture the highly erratic (earthquake-like) dynamics sometimes observed in slowly fracturing heterogeneous solids. Here, we examine this problem by means of innovative experiments of crack growth in artificial rocks of controlled microstructure. The dynamical events are analysed at both global and local scales, from the time fluctuation of the spatially averaged crack speed and the induced acoustic emission, respectively. Their statistics are characterized and compared with the predictions of a recent approach mapping fracture onset to the depinning of an elastic interface. Finally, the overall time-size organization of the events is characterized to shed light on the mechanisms underlying the scaling laws observed in seismology.This article is part of the theme issue 'Statistical physics of fracture and earthquakes'. PMID- 30478199 TI - Hydrodynamic descriptions for surface roughness in fracture front propagation. AB - Fracture is ubiquitous in a crystalline material. Inspired by the observed phenomenological similarities between the spatial profile of a fractured surface and velocities in hydrodynamic turbulence, we set up a hydrodynamic description for the dynamics of fracture surface propagation mode I or opening fracture front. We consider several related continuum hydrodynamic models and use them to extract the similarities between the profile of a fractured surface and velocities in hydrodynamic turbulence. We conclude that a fractured surface should be generically self-similar with an underlying multifractal behaviour.This article is part of the theme issue 'Statistical physics of fracture and earthquakes'. PMID- 30478200 TI - Mapping heterogeneities through avalanche statistics. AB - Avalanche statistics of various threshold-activated dynamical systems are known to depend on the magnitude of the drive, or stress, on the system. Such dependences exist for earthquake size distributions, in sheared granular avalanches, laboratory-scale fracture and also in the outage statistics of power grids. In this work, we model threshold-activated avalanche dynamics and investigate the time required to detect local variations in the ability of model elements to bear stress. We show that the detection time follows a scaling law where the scaling exponents depend on whether the feature that is sought is either weaker, or stronger, than its surroundings. We then look at earthquake data from Sumatra and California, demonstrate the trade-off between the spatial resolution of a map of earthquake exponents (i.e. the b-values of the Gutenberg Richter Law) and the accuracy of those exponents, and suggest a means to maximize both.This article is part of the theme issue 'Statistical physics of fracture and earthquakes'. PMID- 30478201 TI - Induced and endogenous acoustic oscillations in granular faults. AB - The frictional properties of disordered systems are affected by external perturbations. These perturbations usually weaken the system by reducing the macroscopic friction coefficient. This friction reduction is of particular interest in the case of disordered systems composed of granular particles confined between two plates, as this is a simple model of seismic fault. Indeed, in the geophysical context frictional weakening could explain the unexpected weakness of some faults, as well as earthquake remote triggering. In this manuscript, we review recent results concerning the response of confined granular systems to external perturbations, considering the different mechanisms by which the perturbation could weaken a system, the relevance of the frictional reduction to earthquakes, as well as discussing the intriguing scenario whereby the weakening is not monotonic in the perturbation frequency, so that a re-entrant transition is observed, as the system first enters a fluidized state and then returns to a frictional state.This article is part of the theme issue 'Statistical physics of fracture and earthquakes'. PMID- 30478202 TI - Geological implication of grain-size segregation in dense granular matter. AB - To the current common belief, grain size segregation in granular matter requires sufficient porosity. Therefore, grain size segregation found in a natural fault gouge could imply elevated fluid pressure and the reduced normal stress on fault, possibly caused by the frictional heat during an earthquake. To clarify whether fluidization is essential to grain size segregation, we conduct numerical simulation on a simple model of fault gouge in a plane shear geometry under constant volume condition: the volume fraction is fixed at 0.6, at which the granular system possesses yield stress. We observe apparent grain size segregation at this volume fraction, meaning that grain size segregation alone does not imply fluidization of granular matter. We also show that segregation is driven by the nonlinear velocity profile, and that the gravity is not essential to segregation. The physical condition tested here may be relevant to earthquake faults: the normal stress of 1 MPa, the sliding velocity of 1 m s-1, and the duration of 0.1 s.This article is part of the theme issue 'Statistical physics of fracture and earthquakes'. PMID- 30478203 TI - Nature of the high-speed rupture of the two-dimensional Burridge-Knopoff model of earthquakes. AB - The nature of the high-speed rupture or the main shock of the Burridge-Knopoff spring-block model in two dimensions obeying the rate- and state-dependent friction law is studied by means of extensive computer simulations. It is found that the rupture propagation in larger events is highly anisotropic and irregular in shape on longer length scales, although the model is completely uniform and the emergent rupture-propagation velocity is nearly constant everywhere at the rupture front. The manner of the rupture propagation sometimes mimics the successive ruptures of neighbouring 'asperities' observed in real, large earthquakes. Large events tend to be unilateral, with its epicentre lying at the rim of its rupture zone. The epicentre site of a large event is also located next to the rim of the rupture zone of some past event. Event-size distributions are computed and discussed in comparison with those of the corresponding one dimensional model. The magnitude distribution exhibits a power-law behaviour resembling the Gutenberg-Richter law for smaller magnitudes, which changes over to a more characteristic behaviour for larger magnitudes. For very large events, the rupture-length distribution exhibits mutually different behaviours in one dimension and in two dimensions, reflecting the difference in the underlying geometry.This article is part of the theme issue 'Statistical physics of fracture and earthquakes'. PMID- 30478204 TI - Similarities between mode III crack growth patterns and strike-slip faults. AB - Why are strike slip faults not perfectly linear but made of successive segments? Are they reminiscences of the fracture of an initially sound crust by the bottom up propagation of a crack subjected to mode III loading? The plausibility of this newly proposed scenario will be investigated here through model experiments and some theoretical explanations in the framework of brittle fracture.This article is part of the theme issue 'Statistical physics of fracture and earthquakes'. PMID- 30478205 TI - Effect of disorder on the spatial structure of damage in slowly compressed porous rocks. AB - Faults and damage zone properties control a range of important phenomena, from the hydraulic properties of underground reservoirs to the physics of earthquakes on a larger scale. Here, we investigate the effect of disorder of porous rocks on the spatial structure of damage emerging under compression. Model rock samples are numerically generated by sedimenting particles where the amount of disorder is controlled by the particle size distribution. To obtain damage bands with a sufficiently large length along axis, we performed simulations of 'Brazilian' type compression tests of cylindrical samples. As failure is approached, damage localization leads to the formation of two conjugate shear bands. The orientation angle of bands to the loading direction increases with disorder, implying a decrease in the internal coefficient of friction. The width of the damage band scales as a power law of the degree of disorder. Inside the damage band, the sample is crushed into a large number of pieces with a power law mass distribution. The shape of fragments undergoes a crossover at a disorder dependent size from the isotropy of small pieces to the anisotropic flattened form of the large ones. The results provide important constraints in understanding the role of disorder in geological fractures.This article is part of the theme issue 'Statistical physics of fracture and earthquakes'. PMID- 30478207 TI - Mechanism of memory effect of paste which dominates desiccation crack patterns. AB - When a densely packed colloidal suspension, called a paste, behaves as plastic fluid, it can remember the direction of its motion it has experienced, such as vibrational motion and flow. These memories kept in paste can be visualized as the morphology of crack patterns that appear when the paste is dried. For example, when a paste remembers the direction of vibrational motion, all primary desiccation cracks propagate in the direction perpendicular to the direction of the vibrational motion that the paste has experienced. On the other hand, when a paste remembers the direction of flow motion, all primary cracks propagate along the flow direction. To find out the mechanism of memory effect of vibration, we perform experiments to rewrite memory in paste by applying additional vibration to the paste along a different direction before the paste is dried. By investigating the process of rewriting memory in paste, we find the competitive phenomena between quasi-linear effect and nonlinear effect, which were studied in each theoretical model based on residual tension theories. That is, at the initial stage of the memory-imprinting process of the vibrational motion, the mechanism predicted by the quasi-linear analysis based on residual tension theory holds, but, as the paste is vibrated repeatedly, the mechanism shown by the nonlinear analysis gradually come to play a dominant role in the memory effect.This article is part of the theme issue 'Statistical physics of fracture and earthquakes'. PMID- 30478206 TI - Avalanches and extreme value statistics in interfacial crackling dynamics. AB - We study the avalanche and extreme statistics of the global velocity of a crack front, propagating slowly along a weak heterogeneous interface of a transparent polymethyl methacrylate block. The different loading conditions used (imposed constant velocity or creep relaxation) lead to a broad range of average crack front velocities. Our high-resolution and large dataset allows one to characterize in detail the observed intermittent crackling dynamics. We specifically measure the size S, the duration D, as well as the maximum amplitude [Formula: see text] of the global avalanches, defined as bursts in the interfacial crack global velocity time series. Those quantities characterizing the crackling dynamics follow robust power-law distributions, with scaling exponents in agreement with the values predicted and obtained in numerical simulations of the critical depinning of a long-range elastic string, slowly driven in a random medium. Nevertheless, our experimental results also set the limit of such model which cannot reproduce the power-law distribution of the maximum amplitudes of avalanches of a given duration reminiscent of the underlying fat-tail statistics of the local crack front velocities.This article is part of the theme issue 'Statistical physics of fracture and earthquakes'. PMID- 30478208 TI - Statistical physics perspective of fracture in brittle and quasi-brittle materials. AB - We discuss the physics of fracture in terms of the statistical physics associated with the failure of elastic media under applied stresses in presence of quenched disorder. We show that the development and the propagation of fracture are largely determined by the strength of the disorder and the stress field around them. Disorder acts as nucleation centres for fracture. We discuss Griffith's law for a single crack-like defect as a source for fracture nucleation and subsequently consider two situations: (i) low disorder concentration of the defects, where the failure is determined by the extreme value statistics of the most vulnerable defect (nucleation regime) and (ii) high disorder concentration of the defects, where the scaling theory near percolation transition is applicable. In this regime, the development of fracture takes place through avalanches of a large number of tiny microfractures with universal statistical features. We discuss the transition from brittle to quasi-brittle behaviour of fracture with the strength of disorder in the mean-field fibre bundle model. We also discuss how the nucleation or percolation mode of growth of fracture depends on the stress distribution range around a defect. We discuss the corresponding numerical simulation results on random resistor and spring networks.This article is part of the theme issue 'Statistical physics of fracture and earthquakes'. PMID- 30478210 TI - Formation of desiccation crack patterns in electric fields: a review. AB - Desiccation crack formation is an important and interesting part of the broad area of fracture mechanics. Generation of cracks due to drying depends on ambient conditions, which may include externally applied fields. In this review, we discuss the effect of both direct and alternating electrical fields on desiccation crack formation. After a brief introduction to materials which crack on drying, e.g. colloids, clay and ceramics we discuss how they respond to an electric field. Following that, we present an account of experiments and modelling studies performed on granular pastes or clays drying while exposed to an electric field. Specific patterns formed under different geometries, strengths and frequencies of the electric field are described and explained. The review includes work on cracks formed in clay droplets, where a memory effect has been observed and analysed using a generalized calculus formalism.This article is part of the theme issue 'Statistical physics of fracture and earthquakes'. PMID- 30478209 TI - Statistical physics models for aftershocks and induced seismicity. AB - A standard approach to quantifying the seismic hazard is the relative intensity (RI) method. It is assumed that the rate of seismicity is constant in time and the rate of occurrence of small earthquakes is extrapolated to large earthquakes using Gutenberg-Richter scaling. We introduce nowcasting to extend RI forecasting to time-dependent seismicity, for example, during an aftershock sequence. Nowcasting uses 'natural time'; in seismicity natural time is the event count of small earthquakes. The event count for small earthquakes is extrapolated to larger earthquakes using Gutenberg-Richter scaling. We first review the concepts of natural time and nowcasting and then illustrate seismic nowcasting with three examples. We first consider the aftershock sequence of the 2004 Parkfield earthquake on the San Andreas fault in California. Some earthquakes have higher rates of aftershock activity than other earthquakes of the same magnitude. Our approach allows the determination of the rate in real time during the aftershock sequence. We also consider two examples of induced earthquakes. Large injections of waste water from petroleum extraction have generated high rates of induced seismicity in Oklahoma. The extraction of natural gas from the Groningen gas field in The Netherlands has also generated very damaging earthquakes. In order to reduce the seismic activity, rates of injection and withdrawal have been reduced in these two cases. We show how nowcasting can be used to assess the success of these efforts.This article is part of the theme issue 'Statistical physics of fracture and earthquakes'. PMID- 30478211 TI - Thermally activated crack fronts propagating in pinning disorder: simultaneous brittle/creep behaviour depending on scale. AB - We study theoretically the propagation of a crack front in mode I along an interface in a disordered elastic medium, with a numerical model considering a thermally activated rheology, toughness disorder and long-range elastic interactions. This model reproduces not only the large-scale dynamics of the crack front position in fast or creep loading regimes, but also the small-scale self-affine behaviour of the front. Two different scaling laws are predicted for the front morphology, with a Hurst exponent of 0.5 at small scales and a logarithmic scaling law at large scales, consistently with experiments. The prefactor of these scaling laws is expressed as a function of the temperature, and of the quenched disorder characteristics. The cross-over between these regimes is expressed as a function of the quenched disorder amplitude, and is proportional to the average energy release rate, and to the inverse of temperature. This model captures as well the experimentally observed local velocity fluctuation probability distribution, with a high-velocity tail P(v)~v 2.6 This feature is shown to arise when the quenched disorder is sufficiently large, whereas smaller toughness fluctuations lead to a lognormal-like velocity distribution. Overall, the system is shown to obey a scaling determined by two distinct mechanisms as a function of scale: namely, the large scales display fluctuations similar to an elastic line in an annealed noise excited as the average front travels through the pinning landscape, while small scales display a balance between thresholds in possible elastic forces and quenched disorder.This article is part of the theme issue 'Statistical physics of fracture and earthquakes'. PMID- 30478212 TI - Statistical physics of fracture and earthquakes. AB - Manifestations of emergent properties in stressed disordered materials are often the result of an interplay between strong perturbations in the stress field around defects. The collective response of a long-ranged correlated multi component system is an ideal playing field for statistical physics. Hence, many aspects of such collective responses in widely spread length and energy scales can be addressed by the tools of statistical physics. In this theme issue, some of these aspects are treated from various angles of experiments, simulations and analytical methods, and connected together by their common base of complex-system dynamics.This article is part of the theme issue 'Statistical physics of fracture and earthquakes' . PMID- 30478213 TI - Stathmin is required for normal mouse mammary gland development and Delta16HER2 driven tumorigenesis. AB - Post-natal development of the mammary gland relies on the maintenance of oriented cell division and apico-basal polarity, both of which are often deregulated in cancer. The microtubule (MT) network contributes to control these processes, however very little is known about the impact of altered MT dynamics in the development of a complex organ and on the role played by MT-interacting proteins such as stathmin. In this study, we report that female stathmin knock-out (STM KO) mice are unable to nurse their litters due to frank impairment of mammary gland development. In mouse mammary epithelial cells, loss of stathmin compromised the trafficking of polarized proteins and the achievement of proper apico-basal polarity. In particular, prolactin receptor internalization and localization was altered in STM KO mammary epithelial cells, leading to decreased protein stability and downmodulation of the Prl/PrlR/STAT5 signaling pathway. Absence of stathmin induced alterations in mitotic spindle orientation, accumulation of mitotic defects, and apoptosis, overall contributing to tissue disorganization and further decreasing the expansion of the mammary epithelial compartment. Loss of stathmin in MMTV-Delta16HER2 transgenic mice decreased the incidence and increased the latency of these very aggressive mammary carcinomas. Collectively, these data identify the essential mammary protein stathmin as pro tumorigenic and suggest it may serve as a potential therapeutic target in breast cancer. PMID- 30478214 TI - Psychotropic drugs for the behavioural and psychological symptoms of dementia: no free ride. PMID- 30478216 TI - How to pay for national pharmacare. PMID- 30478215 TI - Comparative risk of harm associated with trazodone or atypical antipsychotic use in older adults with dementia: a retrospective cohort study. AB - BACKGROUND: Trazodone is increasingly prescribed for behavioural and psychological symptoms of dementia, but little is known about its risk of harm. Our objective was to describe the comparative risk of falls and fractures among older adults with dementia dispensed trazodone or atypical antipsychotics. METHODS: The study cohort included adults with dementia (excluding patients with chronic psychotic illnesses) living in long-term care and aged 66 years and older. Data were obtained from routinely collected, linked health administrative databases in Ontario, Canada. We compared new users of trazodone with new users of atypical antipsychotics (quetiapine, olanzapine or risperidone) between Dec. 1, 2009, and Dec. 31, 2015. The primary outcome was a composite of fall or major osteoporotic fracture within 90 days of first prescription. Secondary outcomes were falls, major osteoporotic fractures, hip fractures and all-cause mortality. RESULTS: We included 6588 older adults dispensed trazodone and 2875 dispensed an atypical antipsychotic, of whom 95.2% received a low dose of these medications. Compared with use of atypical antipsychotics, use of trazodone was associated with similar rates of falls or major osteoporotic fractures (weighted hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.73 to 1.07), major osteoporotic fracture (weighted HR 1.03, 95% CI 0.73 to 1.47), falls (weighted HR 0.91, 95% CI 0.75 to 1.11) and hip fractures (weighted HR 0.92, 95% CI 0.59 to 1.43). Use of trazodone was associated with a lower rate of mortality (weighted HR 0.75, 95% CI 0.66 to 0.85). INTERPRETATION: Trazodone is not a uniformly safer alternative to atypical antipsychotics, given the similar risk of falls and fractures among older adults with dementia. PMID- 30478217 TI - Buprenorphine-naloxone. PMID- 30478218 TI - Acanthosis nigricans at sites of insulin injection in a man with diabetes. PMID- 30478219 TI - Shining the light on #MeTooMedicine. PMID- 30478220 TI - Considering context within #MeToo and the medical profession. PMID- 30478221 TI - Young doctors warned that social media vitriol could harm their mental health. PMID- 30478222 TI - Tightening sanctions for physician sexual misconduct. PMID- 30478223 TI - Canada must find ways to better use health innovations, says new CIHR scientific director. PMID- 30478224 TI - Calcineurin dependent protein phosphorylation changes during egg activation in Drosophila melanogaster. AB - In almost all animals studied to date, the crucial process of egg activation, by which an arrested mature oocyte transitions into an actively developing embryo, initiates with an increase in Ca2+ in the oocyte's cytoplasm. This Ca2+ rise sets off a series of downstream events, including the completion of meiosis and the dynamic remodeling of the oocyte transcriptome and proteome, which prepares the oocyte for embryogenesis. Calcineurin is a highly conserved phosphatase that is activated by Ca2+ upon egg activation and that is required for the resumption of meiosis in Xenopus, ascidians, and Drosophila. The molecular mechanisms by which calcineurin transduces the calcium signal to regulate meiosis and other downstream events are still unclear. In this study, we investigate the regulatory role of calcineurin during egg activation in Drosophila melanogaster Using mass spectrometry, we quantify the phosphoproteomic and proteomic changes that occur during egg activation, and we examine how these events are affected when calcineurin function is perturbed in female germ cells. Our results show that calcineurin regulates hundreds of phosphosites and also influences the abundance of numerous proteins during egg activation. We find calcineurin-dependent changes in cell cycle regulators including Fizzy (Fzy), Greatwall (Gwl) and Endosulfine (Endos); in protein translation modulators including PNG, NAT, eIF4G, and eIF4B; and in important components of signaling pathways including GSK3beta and Akt1. Our results help elucidate the events that occur during the transition from oocyte to embryo. PMID- 30478225 TI - TBX2 and TBX3 act downstream of canonical WNT signaling in patterning and differentiation of the mouse ureteric mesenchyme. AB - The organized array of smooth muscle cells (SMCs) and fibroblasts in the walls of visceral tubular organs arises by patterning and differentiation of mesenchymal progenitors surrounding the epithelial lumen. Here, we show that the TBX2 and TBX3 transcription factors have novel and required roles in regulating these processes in the murine ureter. Co-expression of TBX2 and TBX3 in the inner mesenchymal region of the developing ureter requires canonical WNT signaling. Loss of TBX2/TBX3 in this region disrupts activity of two crucial drivers of the SMC program, Foxf1 and BMP4 signaling, resulting in decreased SMC differentiation and increased extracellular matrix. Transcriptional profiling and chromatin immunoprecipitation experiments revealed that TBX2/TBX3 directly repress expression of the WNT antagonists Dkk2 and Shisa2, the BMP antagonist Bmper and the chemokine Cxcl12 These findings suggest that TBX2/TBX3 are effectors of canonical WNT signaling in the ureteric mesenchyme that promote SMC differentiation by maintaining BMP4 and WNT signaling in the inner region, while restricting CXCL12 signaling to the outer layer of fibroblast-fated mesenchyme. PMID- 30478226 TI - Notchless defines a stage-specific requirement for ribosome biogenesis during lineage progression in adult skeletal myogenesis. AB - Cell fate decisions occur through the action of multiple factors, including signalling molecules and transcription factors. Recently, the regulation of translation has emerged as an important step for modulating cellular function and fate, as exemplified by ribosomes that play distinct roles in regulating cell behaviour. Notchless (Nle) is a conserved nuclear protein that is involved in a crucial step in ribosome biogenesis, and is required for the maintenance of adult haematopoietic and intestinal stem/progenitor cells. Here, we show that activated skeletal muscle satellite cells in conditional Nle mutant mice are arrested in proliferation; however, deletion of Nle in myofibres does not impair myogenesis. Furthermore, conditional deletion of Nle in satellite cells during homeostasis did not impact on their fate for up to 3 months. In contrast, loss of Nle function in primary myogenic cells blocked proliferation because of major defects in ribosome formation. Taken together, we show that muscle stem cells undergo a stage-specific regulation of ribosome biogenesis, thereby underscoring the importance of differential modulation of mRNA translation for controlling cell fate decisions. PMID- 30478227 TI - Forced Recycling of AMA1-based Genome-Editing Plasmid Allows for Efficient Multiple Gene Deletion/Integration in The Industrial Filamentous Fungus Aspergillus oryzae. AB - Filamentous fungi are used for food fermentation and industrial production of recombinant proteins. They also serve as a source of secondary metabolites, and are recently expected as hosts for heterologous production of useful secondary metabolites. Multiple-step genetic engineering is required to enhance industrial production involving these fungi, but traditional sequential modification of multiple genes using a limited number of selection markers is laborious. Moreover, efficient genetic engineering techniques for industrial strains have not yet been established. We have previously developed a clustered regulatory interspaced short palindromic repeats (CRISPR)/Cas9-based mutagenesis technique for the industrial filamentous fungus Aspergillus oryzae, enabling mutation efficiency of 10-20%. Here, we improved the CRISPR/Cas9 approach by including an AMA1-based autonomously replicating plasmid harboring the drug-resistance marker ptrA By using the improved mutagenesis technique, we successfully modified A. oryzae wild and industrial strains, with the mutation efficiency of 50-100%. Conditional expression of the Aoace2 gene from the AMA1-based plasmid severely inhibited fungal growth. This enabled forced recycling of the plasmid, allowing repeated genome editing. Further, double-mutant strains were successfully obtained with high efficiency by expressing two guide RNA molecules from the genome-editing plasmid. Co-transformation of fungal cells with the genome-editing plasmid together with a circular donor DNA enabled marker-free multiplex gene deletion/integration in A. oryzae The presented repeatable marker-free genetic engineering approach for mutagenesis and gene deletion/integration will allow for efficient modification of multiple genes in industrial fungal strains, increasing their applicability.IMPORTANCE Multiple gene modifications of specific fungal strains are required for achieving industrial-scale production of enzymes and secondary metabolites. In the present study, we developed efficient multiple genetic engineering technique for the filamentous fungus Aspergillus oryzae The approach is based on clustered regulatory interspaced short palindromic repeats (CRISPR)/Cas9 system and recycling of an AMA1-based autonomous replicating plasmid. Because the plasmid harbors a drug-resistance marker (ptrA), the approach does not require the construction of auxotrophic industrial strains prior to genome editing, and allows for forced recycling of the gene-editing plasmid. The established plasmid-recycling technique involves an Aoace2 conditional expression cassette, whose induction severely impairs fungal growth. We used the developed genetic engineering techniques for highly efficient marker free multiple gene deletion/integration in A. oryzae The genome-editing approaches established in the current study, which enable unlimited repeatable genetic engineering, will facilitate multiple gene modification of industrially important fungal strains. PMID- 30478228 TI - Butyrivibrio hungatei MB2003 competes effectively for soluble sugars released by Butyrivibrio proteoclasticus B316T from growth on xylan or pectin. AB - Rumen bacterial species belonging to the genus Butyrivibrio are important degraders of plant polysaccharides, particularly hemicelluloses (arabinoxylans) and pectin. Currently, four species are recognized which have very similar substrate utilization profiles, but little is known about how these microorganisms are able to co-exist in the rumen. To investigate this question, Butyrivibrio hungatei MB2003 and Butyrivibrio proteoclasticus B316T were grown alone or in co-culture on xylan or pectin, and their growth, release of sugars, fermentation end products and transcriptomes were examined. In mono-cultures, B316T was able to grow well on xylan and pectin, while MB2003 was unable to utilize either of these insoluble substrates to support significant growth. Co cultures of B316T grown with MB2003 revealed that MB2003 showed almost equivalent growth to B316T when either xylan or pectin were supplied as substrates. The effect of co-culture on the transcriptomes of B316T and MB2003 was assessed; B316T transcription was largely unaffected by the presence of MB2003, but MB2003 expressed a wide range of genes encoding carbohydrate degradation, central metabolism, oligosaccharide transport and substrate assimilation in order to compete with B316T for the released sugars. These results suggest that B316T has a role as an initiator of primary solubilization of xylan and pectin, while MB2003 competes effectively for the released soluble sugars to enable its growth and maintenance in the rumen.IMPORTANCE Feeding a global population of nine billion people and climate change are the primary challenges facing agriculture today. Ruminant livestock are important food-producing animals and maximizing their productivity requires an understanding of their digestive systems and the roles played by rumen microbes in plant polysaccharide degradation. Butyrivibrio are a phylogenetically diverse group of bacteria and are commonly found in the rumen where they are a substantial source of polysaccharide-degrading enzymes for the depolymerization of lignocellulosic material. Our findings suggest that closely related species of Butyrivibrio have developed unique strategies for the degradation of plant fiber and the subsequent assimilation of carbohydrates in order to co-exist in the competitive rumen environment. The identification of genes expressed during these competitive interactions gives further insight into the enzymatic machinery used by these bacteria as they degrade the xylan and pectin components of plant fiber. PMID- 30478229 TI - Nitric oxide and iron signaling cues have opposing effects on biofilm development in Pseudomonas aeruginosa. AB - While both iron and nitric oxide (NO) are redox-active environmental signals that have been shown to regulate biofilm development, their interaction and roles in regulating biofilms have not been fully elucidated. In this study, exposure of Pseudomonas aeruginosa biofilms to exogenous NO inhibited the expression of iron acquisition related genes and the production of the siderophore pyoverdine. Further, supplementation of the culture medium with high levels of iron (100 uM) counteracted NO induced biofilm dispersal by promoting the rapid attachment of planktonic cells. In the presence of iron, biofilms were found to disperse transiently to NO, while the freshly dispersed cells reattached rapidly within 15 min. This effect was not due to scavenging of NO by free iron, but rather involved a cellular response induced by iron that led to elevated production of the exopolysaccharide Psl. Interestingly, most Psl remained on the substratum after treatment with NO, suggesting that dispersal involved changes in the interactions between Psl and P. aeruginosa cells. Taken together, our results suggest that iron and NO regulate biofilm development via different pathways, both of which include regulation of Psl-mediated attachment. Moreover, the addition of an iron chelator worked synergistically with NO in the dispersal of biofilms.IMPORTANCE: Nitric oxide (NO), which induces biofilm dispersal, is a promising strategy for biofilm control in both clinical and industrial contexts. However, competing environmental signals may reduce the efficacy of NO. The results presented here suggest that the presence of iron represents one such environmental cue that could antagonize the activity of NO as a biofilm dispersing agent. Based on this understanding, we developed a strategy to enhance dispersal by combining NO with an iron scavenging agent. Overall, this study links two important environmental signals, iron and NO, with their roles in biofilm development and suggests new ways for improving the use of NO in biofilm control strategies. PMID- 30478230 TI - Remedial treatment of corroded iron objects by environmental Aeromonas isolates. AB - Using bacteria to transform reactive corrosion products into stable compounds represents an alternative to traditional methods employed in iron conservation. Two environmental Aeromonas strains (CA23 and CU5) were used to transform ferric iron corrosion products (goethite and lepidocrocite) into stable ferrous bearing minerals (vivianite and siderite). A genomic and transcriptomic approach was conducted to analyze the metabolic traits of these strains and to evaluate their pathogenic potential. Although genes involved in solid-phase iron reduction were identified, key genes present in other environmental iron-reducing species are missing from the genome of CU5. Several pathogenicity factors were identified in the genomes of both strains, but none of these was expressed under iron-reduction conditions. Additional in vivo tests showed hemolytic and cytotoxic activities for the strain CA23, but not for the strain CU5. Both strains were easily inactivated using ethanol and heat. Nonetheless, given a lesser potential for a pathogenic lifestyle, CU5 is a most promising candidate for the development of a bio-based iron conservation method stabilizing iron corrosion. Based on all the results, a prototype treatment was established using archaeological items. On those, the conversion of reactive corrosion products and the formation of a homogenous layer of biogenic iron minerals was achieved. This study shows how naturally-occurring microorganisms and their metabolic capabilities can be used to develop bio-inspired solutions to the problem of metal corrosion.IMPORTANCE Microbiology can greatly help in the quest for a sustainable solution to the problem of iron corrosion. The latter causes important economic losses in a wide range of fields, including the protection of cultural heritage and building materials. Using bacteria to transform reactive and unstable corrosion products into more stable compounds represents a promising approach. The overall aim of this study was to develop a method for the conservation-restoration of corroded iron items, starting from the isolation of iron-reducing bacteria from natural environments. This resulted in the identification of a suitable candidate (Aeromonas sp. CU5) that mediates the formation of desirable minerals at the surface of the objects. This led to the proof-of-concept of an application method on real objects. PMID- 30478231 TI - TACN (1, 4, 7-Triazacyclononane) restores the activity of beta-lactam antibiotics against Metallo-beta-Lactamase producing Enterobacteriaceae: The exploration of potential Metallo-beta-Lactamase inhibitors. AB - Metallo-beta-lactamase producing Enterobacteriaceae are of grave clinical concern particularly as there are no Metallo-beta-lactamase (MBL) inhibitors approved for clinical use. The discovery and development of MBL inhibitors to restore the efficacy of available beta-lactams are thus imperative. We investigated a zinc chelating moiety, 1, 4, 7-triazacyclononane (TACN) for its inhibitory activity against clinical carbapenem-resistant Enterobacteriaceae Minimum inhibitory concentrations (MICs), minimum bactericidal concentrations (MBCs), serum effect, fractional inhibitory concentrations index and time-kill kinetics were performed using broth microdilution techniques according to the Clinical Laboratory Standard Institute (CSLI) guidelines. Enzyme kinetic parameters and cytotoxicity effects of TACN were determined using spectrophotometric assays. The interactions of the enzyme-TACN complex were investigated by computational studies. Meropenem regained its activity against carbapenemase-producing Enterobacteriaceae, with the MIC decreasing from 8-64 mg/L to 0.03 mg/L in the presence of TACN. TACN Meropenem combinations showed bactericidal effects with MIC/MBC ratio of <=4, and synergistic activity was observed. Human serum effects on the MICs were insignificant, and TACN was found to be non-cytotoxic at concentrations above the MIC values. Computational studies predicted that TACN inhibits MBLs by targeting their catalytic active site pockets. This was supported by its inhibition constant Ki = 0.044 uM and inactivation constant kinact = 0.0406 (min-1) demonstrating that TACN inhibits MBLs efficiently and holds promise as a potential inhibitor.IMPORTANCE Carbapenem-resistant Enterobacteriaceae (CRE) mediated infections remain a significant public health concern and have been reported as critical in the World Health Organization's Priority Pathogens List for the Research and Development of New Antibiotics. CRE produce enzymes such as Metallo-beta-lactamases (MBLs), which inactivate beta-lactam antibiotics. Combination therapies involving a beta-lactam antibiotic and a beta-lactamase inhibitor remain a major treatment option for infections caused by beta-lactamase producing organisms. Currently, no MBL inhibitor-beta-lactam combination therapy is clinically available for MBL-positive bacterial infections. Hence, developing efficient molecules capable of inhibiting these enzymes could be a promising way to overcome this phenomenon. TACN played a significant role in the inhibitory activity of the tested molecules against CREs by potentiating the carbapenem. This study demonstrated that TACN inhibits MBLs efficiently and holds promises as a potential MBLs inhibitor to help curb the global health threat posed by MBL producing CREs. PMID- 30478232 TI - A new functional marker gene of polycyclic aromatic hydrocarbons (PAHs) degrading bacteria: pahE. AB - The characterization of native PAH-degrading bacteria is significant to understand the degradation process of PAHs in the natural environment and develop effective remediation technologies. Most previous investigations of PAH-degrading bacteria in environmental samples employ the pahAc, which encodes the alpha subunit of PAH ring-hydroxylating dioxygenase, as a functional marker gene. However, the poor phylogenetic resolution and non-specificity of pahAc results in misestimating of PAH-degrading bacteria. Here we propose a PAH hydratase-aldolase encoding gene, pahE, as a superior biomarker for PAH-degrading bacteria. Comparative phylogenetic analysis of the key enzymes involved in the upper pathway of PAH degradation indicated that pahE evolved dependently from a common ancestor. A phylogenetic tree constructed based on PahE is largely congruent with PahAc-based phylogenies, except the dispersion of several clades of other non-PAH degrading aromatic hydrocarbon dioxygenases present in the PahAc tree. Analysis of pure strains by PCR confirmed that pahE can specifically distinguish PAH degrading bacteria while pahAc cannot. Illumina sequencing of pahE and pahAc amplicons showed more genotypes, higher specificity and resolution of pahE Novel reads were also discovered among the pahE amplicons, suggesting the presence of novel PAH-degrading populations. These results suggest that pahE is a more powerful biomarker for exploring the ecological role and degradation potential of PAH-degrading bacteria in ecosystems, which is significant to the bioremediation of PAH pollution and environmental microbial ecology.IMPORTANCE PAHs contamination has become a worldwide environmental issue because of the potential toxic effects on natural ecosystems and human health. Biotransformation and biodegradation are considered the main natural elimination forms of PAHs from contaminated sites. Therefore, the knowledge of the degradation potential of the microbial community in contaminated sites is crucial for the PAHs pollution bioremediation. However, the non-specificity of pahAc as a functional marker of PAH-degrading bacteria has resulted in neither reliable prediction of PAH degradation potential nor an accurate assessment of degradation. Here, we introduced pahE encoding PAHs hydratase-aldolase as a new and better functional marker gene of PAH-degrading bacteria. This study provides a powerful molecular tool to more effectively explore the ecological role and degradation potential of PAH-degrading bacteria in ecosystems, which is significant to the bioremediation of PAH pollution. PMID- 30478233 TI - Comparative Biochemical and Structural Analysis of Novel Cellulose Binding Proteins (Tapirins) from Extremely Thermophilic Caldicellulosiruptor Species. AB - Genomes of extremely thermophilic Caldicellulosiruptor species encode novel cellulose binding proteins, tapirins, located proximate to the type IV pilus locus. The C-terminal domain of a tapirin (Calkro_0844) from Caldicellulosiruptor kronotskyensis is structurally unique and has a cellulose binding affinity akin to family 3 carbohydrate binding modules (CBM3). Here, full-length and C-terminal versions of tapirins from Caldicellulosiruptor bescii (Athe_1870), Caldicellulosiruptor hydrothermalis (Calhy_0908), Caldicellulosiruptor kristjanssonii (Calkr_0826), and Caldicellulosiruptor naganoensis (NA10_0869) were produced recombinantly in Escherichia coli and compared to Calkro_0844. All five tapirins bound to microcrystalline cellulose, switchgrass, poplar, filter paper, but not to xylan. Densitometry analysis of bound protein fractions visualized by SDS-PAGE revealed that Calhy_0908 and Calkr_0826 (from weakly cellulolytic species) associated with the cellulose substrates to a greater extent than Athe_1870, Calkro_0844 and NA10_0869 (from strongly cellulolytic species). Perhaps this relates to their specific needs to capture glucans released from lignocellulose by cellulases produced in Caldicellulosiruptor communities. Calkro_0844, and NA10_0869 share a high degree of amino acid sequence identity (> 80% identity), more so than with Athe_1870 (~50%). The amino acid sequence identities of Calhy_0908 and Calkr_0826 compared to Calkro_0844 were only 16% and 36%, respectively, although the three-dimensional structures of their C-terminal binding regions were closely related. Unlike the parent strain, C. bescii mutants lacking the tapirin genes did not bind to cellulose following short-term incubation, suggesting a role in cell association with plant biomass. Given the scarcity of carbohydrates in neutral terrestrial hot springs, tapirins likely help scavenge carbohydrates from lignocellulose to support growth and survival of Caldicellulosiruptor species.IMPORTANCE Mechanisms by which microorganisms attach to and degrade lignocellulose are important to understand if effective approaches for conversion of plant biomass into fuels and chemicals are to be developed. Caldicellulosiruptor species grow on carbohydrates from lignocellulose at elevated temperatures and have biotechnological significance for that reason. Novel cellulose binding proteins, called tapirins, are involved in the way Caldicellulosiruptor species interact with microcrystalline cellulose and here additional information about the diversity of these proteins across the genus is provided, including binding affinity and three-dimensional structural comparisons. PMID- 30478234 TI - Response of the Biocontrol Agent Pseudomonas pseudoalcaligenes AVO110 to Rosellinia necatrix Exudate. AB - The rhizobacterium Pseudomonas pseudoalcaligenes AVO110, isolated by enrichment of competitive avocado root tip colonizers, controls avocado white root rot disease caused by Rosellinia necatrix. Here, we applied signature-tagged mutagenesis (STM) during the growth and survival of AVO110 in fungal exudate containing medium with the goal of identifying molecular mechanisms linked to the interaction of this bacterium with R. necatrix A total of 26 STM mutants out competed by the parental strain in fungal exudate, but not in rich medium, were selected and named growth-attenuated mutants (GAM). Twenty-one genes were identified as required for this bacterial-fungal interaction, including membrane transporters, transcriptional regulators and genes related to the metabolism of hydrocarbons, amino acids, fatty acids and aromatic compounds. The bacterial traits identified here that are involved in the colonization of fungal hyphae include proteins involved in membrane maintenance (a dynamin-like protein and ColS) or cyclic-di-GMP signaling and chemotaxis. In addition, genes encoding a DNA helicase (recB) and a regulator of alginate production (algQ) were identified as required for efficient colonization of the avocado rhizosphere.IMPORTANCE Diseases associated with fungal root invasion cause significant losses on fruit tree production worldwide. The bacterium Pseudomonas pseudoalcaligenes AVO110 controls avocado white root rot disease caused by Rosellinia necatrix using mechanisms involving competition for nutrients and niches. Here, a functional genomics approach was conducted to identify bacterial traits involved in the interaction with this fungal pathogen. Our results contribute to a better understanding of the multitrophic interactions established among bacterial biocontrol agents, the plant rhizosphere and the mycelia of soilborne pathogens. PMID- 30478235 TI - Generation of Markerless Deletions in the Nosocomial Pathogen Clostridium difficile by induction of DNA Double-strand Breaks. AB - Clostridium difficile is an important nosocomial pathogen associated with potentially fatal disease induced by the use of antibiotics. Genetic characterisation of such clinically important bacteria is often hampered by availability of suitable tools. Here we describe the use of I-SceI to induce DNA double-strand breaks which increase the frequency of allelic exchange and enable the generation of markerless deletions in C. difficile The usefulness of the system is illustrated by deletion of genes encoding putative AddAB homologues. The DeltaaddAB mutants are sensitive to ultra violet light and the antibiotic metronidazole, indicating a role in homologous recombination and repair of DNA breaks. Despite the impairment in recombination, the mutants are still proficient for induction of the SOS response. In addition, deletion of the fliC gene, and subsequent complementation, reveals the importance of potential regulatory elements required for expression of a downstream gene encoding the flagellin glycosyl transferase.IMPORTANCE Most sequenced bacterial genomes contain genes encoding proteins of unknown or hypothetical function. To identify a phenotype for mutations in such genes, deletion is the preferred method for mutagenesis because it reduces the likelyhood of polar effects, although does not eliminate the possibility. Allelic exchange to produce deletions is dependent on the length of homology used to generate merodiploids. Shorter regions of homology resolve at lower frequencies. The work presented here demonstrates the utility of inducing DNA double-strand breaks to increase the frequency of merodiploid resolution in Clostridium difficile Using this approach we reveal the role of two genes, encoding homologues of AddAB, in survival following DNA damage. The method is readily applicable to production of deletions in C. difficile and expands the toolbox available for genetic analysis of this important anaerobic pathogen. PMID- 30478236 TI - The MarR Family Regulator BmrR is involved in Bile Tolerance of Bifidobacterium longum BBMN68 via Controlling the Expression of an ABC-Transporter. AB - In order to colonize the human gastrointestinal tract and exert their beneficial effects, bifidobacteria must effectively cope with the toxic bile salts in the intestine, but the molecular mechanism underlying bile tolerance is poorly understood. In this study, heterologous expression of a MarR family transcriptional regulator BmrR significantly reduced ox-bile resistance of Lactococcus lactis NZ9000, suggesting that it might play a role in bile stress response. In silico analysis combined with RT-PCR assay demonstrated that bmrR was co-transcribed with bmrA and bmrB, which encoded multidrug resistance (MDR) ABC transporters. Promoter prediction and EMSA assay revealed that BmrR could autoregulate the bmrRAB operon by binding to bmr box (ATTGTTG-6nt-CAACAAT) in the promoter region. Moreover, heterologous expression of bmrA and bmrB in L. lactis showed 20.77-fold higher tolerance to 0.10% ox-bile compared to wild type strain. In addition, ox-bile could disrupt the DNA binding activity of BmrR as a ligand. Taken together, our findings indicate that bmrRAB operon is autoregulated by transcriptional regulator BmrR and ox-bile serves as an inducer to activate the bile efflux transporter BmrAB in response to bile stress in B. longum BBMN68.IMPORTANCE Bifidobacteria are natural inhabitants of the human intestinal tract. Some bifidobacterial strains are used as probiotics in fermented dairy production because of their health-promoting effects. Following consumption, bifidobacteria finally colonize the lower intestinal tract where the concentration of bile salts remains nearly 0.05% to 2.0%. Bile salts as detergent like antimicrobial compounds can cause disruption of the cellular membrane, protein misfolding and DNA damage. Therefore, tolerance to physiological bile stress is indeed essential for bifidobacteria to survive and exert the probiotic effects in gastrointestinal tract. In B. longum BBMN68, the MarR-type regulator BmrR was involved in bile stress response by auto-regulating bmrRAB operon and ox bile as an inducer could increase the expression of BmrAB transporter to enhance the bile tolerance of BBMN68.This is the first report about functional analysis of bmrRAB operon in bile stress response, which will provide new insight into bile tolerance mechanisms in Bifidobacterium and other bacteria. PMID- 30478238 TI - Being Overweight or Obese and the Development of Asthma. AB - OBJECTIVES: Adult obesity is linked to asthma cases and is estimated to lead to 250 000 new cases yearly. Similar incidence and attributable risk (AR) estimates have not been developed for children. We sought to describe the relationship between overweight and obesity and incident asthma in childhood and quantify AR statistics in the United States for overweight and obesity on pediatric asthma. METHODS: The PEDSnet clinical data research network was used to conduct a retrospective cohort study (January 2009-December 2015) to compare asthma incidence among overweight and/or obese versus healthy weight 2- to 17-year-old children. Asthma incidence was defined as >=2 encounters with a diagnosis of asthma and >=1 asthma controller prescription. Stricter diagnostic criteria involved confirmation by spirometry. We used multivariable Poisson regression analyses to estimate incident asthma rates and risk ratios and accepted formulas for ARs. RESULTS: Data from 507 496 children and 19 581 972 encounters were included. The mean participant observation period was 4 years. The adjusted risk for incident asthma was increased among children who were overweight (relative risk [RR]: 1.17; 95% confidence interval [CI]: 1.10-1.25) and obese (RR: 1.26; 95% CI: 1.18-1.34). The adjusted risk for spirometry-confirmed asthma was increased among children with obesity (RR: 1.29; 95% CI: 1.16-1.42). An estimated 23% to 27% of new asthma cases in children with obesity is directly attributable to obesity. In the absence of overweight and obesity, 10% of all cases of asthma would be avoided. CONCLUSIONS: Obesity is a major preventable risk factor for pediatric asthma. PMID- 30478237 TI - Deep scanning lysine metabolism in Escherichia coli. AB - Our limited ability to predict genotype-phenotype relationships has called for strategies that allow testing of thousands of hypotheses in parallel. Deep scanning mutagenesis has been successfully implemented to map genotype-phenotype relationships at a single-protein scale, allowing scientists to elucidate properties that are difficult to predict. However, most phenotypes are dictated by several proteins that are interconnected through complex and robust regulatory and metabolic networks. These sophisticated networks hinder our understanding of the phenotype of interest and limit our capabilities to rewire cellular functions. Here, we leveraged CRISPR-EnAbled Trackable genome Engineering to attempt a parallel and high-resolution interrogation of complex networks, deep scanning multiple proteins associated with lysine metabolism in Escherichia coli We designed over 16,000 mutations to perturb this pathway and mapped their contribution toward resistance to an amino acid analog. By doing so, we identified different routes that can alter pathway function and flux, uncovering mechanisms that would be difficult to rationally design. This approach sets a framework for forward investigation of complex multigenic phenotypes. PMID- 30478239 TI - The Value of State Differences in Autism When Compared to a National Prevalence Estimate. PMID- 30478240 TI - Pediatric Considerations Before, During, and After Radiological or Nuclear Emergencies. AB - Infants, children, and adolescents can be exposed unexpectedly to ionizing radiation from nuclear power plant events, improvised nuclear or radiologic dispersal device explosions, or inappropriate disposal of radiotherapy equipment. Children are likely to experience higher external and internal radiation exposure levels than adults because of their smaller body and organ size and other physiologic characteristics, by picking up contaminated items, and through consumption of contaminated milk or foodstuffs. This policy statement and accompanying technical report update the 2003 American Academy of Pediatrics policy statement on pediatric radiation emergencies by summarizing newer scientific knowledge from studies of the Chernobyl and Fukushima Daiichi nuclear power plant events, use of improvised radiologic dispersal devices, exposures from inappropriate disposal of radiotherapy equipment, and potential health effects from residential proximity to nuclear plants. Policy recommendations are made for providers and governments to improve future responses to these types of events. PMID- 30478241 TI - The Prevalence of Parent-Reported Autism Spectrum Disorder Among US Children. AB - : : media-1vid110.1542/5839990273001PEDS-VA_2017-4161Video Abstract OBJECTIVES: To estimate the national prevalence of parent-reported autism spectrum disorder (ASD) diagnosis among US children aged 3 to 17 years as well as their treatment and health care experiences using the 2016 National Survey of Children's Health (NSCH). METHODS: The 2016 NSCH is a nationally representative survey of 50 212 children focused on the health and well-being of children aged 0 to 17 years. The NSCH collected parent-reported information on whether children ever received an ASD diagnosis by a care provider, current ASD status, health care use, access and challenges, and methods of treatment. We calculated weighted prevalence estimates of ASD, compared health care experiences of children with ASD to other children, and examined factors associated with increased likelihood of medication and behavioral treatment. RESULTS: Parents of an estimated 1.5 million US children aged 3 to 17 years (2.50%) reported that their child had ever received an ASD diagnosis and currently had the condition. Children with parent-reported ASD diagnosis were more likely to have greater health care needs and difficulties accessing health care than children with other emotional or behavioral disorders (attention-deficit/hyperactivity disorder, anxiety, behavioral or conduct problems, depression, developmental delay, Down syndrome, intellectual disability, learning disability, Tourette syndrome) and children without these conditions. Of children with current ASD, 27% were taking medication for ASD related symptoms, whereas 64% received behavioral treatments in the last 12 months, with variations by sociodemographic characteristics and co-occurring conditions. CONCLUSIONS: The estimated prevalence of US children with a parent reported ASD diagnosis is now 1 in 40, with rates of ASD-specific treatment usage varying by children's sociodemographic and co-occurring conditions. PMID- 30478242 TI - Screening Examination of Premature Infants for Retinopathy of Prematurity. AB - This policy statement revises a previous statement on screening of preterm infants for retinopathy of prematurity (ROP) that was published in 2013. ROP is a pathologic process that occurs in immature retinal tissue and can progress to a tractional retinal detachment, which may then result in visual loss or blindness. For more than 3 decades, treatment of severe ROP that markedly decreases the incidence of this poor visual outcome has been available. However, severe, treatment-requiring ROP must be diagnosed in a timely fashion to be treated effectively. The sequential nature of ROP requires that infants who are at-risk and preterm be examined at proper times and intervals to detect the changes of ROP before they become destructive. This statement presents the attributes of an effective program to detect and treat ROP, including the timing of initial and follow-up examinations. PMID- 30478244 TI - Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. PMID- 30478245 TI - Management Guidelines for Children With Thyroid Nodules and Differentiated Thyroid Cancer. PMID- 30478243 TI - Pediatric Considerations Before, During, and After Radiological or Nuclear Emergencies. AB - Infants, children, and adolescents can be exposed unexpectedly to ionizing radiation from nuclear power plant events, improvised nuclear or radiologic dispersal device explosions, or inappropriate disposal of radiotherapy equipment. Children are likely to experience higher external and internal radiation exposure levels than adults because of their smaller body and organ size and other physiologic characteristics as well as their tendency to pick up contaminated items and consume contaminated milk or foodstuffs. This technical report accompanies the revision of the 2003 American Academy of Pediatrics policy statement on pediatric radiation emergencies by summarizing newer scientific data from studies of the Chernobyl and the Fukushima Daiichi nuclear power plant events, use of improvised radiologic dispersal devices, exposures from inappropriate disposal of radiotherapy equipment, and potential health effects from residential proximity to nuclear plants. Also included are recommendations from epidemiological studies and biokinetic models to address mitigation efforts. The report includes major emphases on acute radiation syndrome, acute and long term psychological effects, cancer risks, and other late tissue reactions after low-to-high levels of radiation exposure. Results, along with public health and clinical implications, are described from studies of the Japanese atomic bomb survivors, nuclear plant accidents (eg, Three Mile Island, Chernobyl, and Fukushima), improper disposal of radiotherapy equipment in Goiania, Brazil, and residence in proximity to nuclear plants. Measures to reduce radiation exposure in the immediate aftermath of a radiologic or nuclear disaster are described, including the diagnosis and management of external and internal contamination, use of potassium iodide, and actions in relation to breastfeeding. PMID- 30478246 TI - Quantifying the Contribution of Obesity to Incident Childhood Asthma: It's About Time. PMID- 30478247 TI - Clinical Practice Guideline: Maintenance Intravenous Fluids in Children. AB - Maintenance intravenous fluids (IVFs) are used to provide critical supportive care for children who are acutely ill. IVFs are required if sufficient fluids cannot be provided by using enteral administration for reasons such as gastrointestinal illness, respiratory compromise, neurologic impairment, a perioperative state, or being moribund from an acute or chronic illness. Despite the common use of maintenance IVFs, there is high variability in fluid prescribing practices and a lack of guidelines for fluid composition administration and electrolyte monitoring. The administration of hypotonic IVFs has been the standard in pediatrics. Concerns have been raised that this approach results in a high incidence of hyponatremia and that isotonic IVFs could prevent the development of hyponatremia. Our goal in this guideline is to provide an evidence-based approach for choosing the tonicity of maintenance IVFs in most patients from 28 days to 18 years of age who require maintenance IVFs. This guideline applies to children in surgical (postoperative) and medical acute-care settings, including critical care and the general inpatient ward. Patients with neurosurgical disorders, congenital or acquired cardiac disease, hepatic disease, cancer, renal dysfunction, diabetes insipidus, voluminous watery diarrhea, or severe burns; neonates who are younger than 28 days old or in the NICU; and adolescents older than 18 years old are excluded. We specifically address the tonicity of maintenance IVFs in children.The Key Action Statement of the subcommittee is as follows:1A: The American Academy of Pediatrics recommends that patients 28 days to 18 years of age requiring maintenance IVFs should receive isotonic solutions with appropriate potassium chloride and dextrose because they significantly decrease the risk of developing hyponatremia (evidence quality: A; recommendation strength: strong). PMID- 30478248 TI - Phosphorylation by the stress-activated MAPK Slt2 down-regulates the yeast TOR complex 2. AB - Saccharomyces cerevisiae target of rapamycin (TOR) complex 2 (TORC2) is an essential regulator of plasma membrane lipid and protein homeostasis. How TORC2 activity is modulated in response to changes in the status of the cell envelope is unclear. Here we document that TORC2 subunit Avo2 is a direct target of Slt2, the mitogen-activated protein kinase (MAPK) of the cell wall integrity pathway. Activation of Slt2 by overexpression of a constitutively active allele of an upstream Slt2 activator (Pkc1) or by auxin-induced degradation of a negative Slt2 regulator (Sln1) caused hyperphosphorylation of Avo2 at its MAPK phosphoacceptor sites in a Slt2-dependent manner and diminished TORC2-mediated phosphorylation of its major downstream effector, protein kinase Ypk1. Deletion of Avo2 or expression of a phosphomimetic Avo2 allele rendered cells sensitive to two stresses (myriocin treatment and elevated exogenous acetic acid) that the cell requires Ypk1 activation by TORC2 to survive. Thus, Avo2 is necessary for optimal TORC2 activity, and Slt2-mediated phosphorylation of Avo2 down-regulates TORC2 signaling. Compared with wild-type Avo2, phosphomimetic Avo2 shows significant displacement from the plasma membrane, suggesting that Slt2 inhibits TORC2 by promoting Avo2 dissociation. Our findings are the first demonstration that TORC2 function is regulated by MAPK-mediated phosphorylation. PMID- 30478250 TI - Prescribing cannabis based drugs: response from NICE and Health Education England. PMID- 30478249 TI - Prefoldin 6 mediates longevity response from heat shock factor 1 to FOXO in C. elegans. AB - Heat shock factor 1 (HSF-1) and forkhead box O (FOXO) are key transcription factors that protect cells from various stresses. In Caenorhabditis elegans, HSF 1 and FOXO together promote a long life span when insulin/IGF-1 signaling (IIS) is reduced. However, it remains poorly understood how HSF-1 and FOXO cooperate to confer IIS-mediated longevity. Here, we show that prefoldin 6 (PFD-6), a component of the molecular chaperone prefoldin-like complex, relays longevity response from HSF-1 to FOXO under reduced IIS. We found that PFD-6 was specifically required for reduced IIS-mediated longevity by acting in the intestine and hypodermis. We showed that HSF-1 increased the levels of PFD-6 proteins, which in turn directly bound FOXO and enhanced its transcriptional activity. Our work suggests that the prefoldin-like chaperone complex mediates longevity response from HSF-1 to FOXO to increase the life span in animals with reduced IIS. PMID- 30478251 TI - P27 Protects Cardiomyocytes from Sepsis via Activation of Autophagy and Inhibition of Apoptosis. AB - BACKGROUND It has been reported that p27Kip1 plays an important role not only in the inhibition of cyclin-dependent kinases but also in the regulation of autophagy under various metabolically related stress conditions, including glucose deprivation and endoplasmic reticulum stress. However, its effect on lipopolysaccharide (LPS)-induced cardiomyocyte stress in vitro remains unclear. Here, we measured the increased expression of LC3-II and visualized autophagosomes in vitro by immunofluorescent assays after treatment with a p27 fusion protein. MATERIAL AND METHODS Cardiomyocyte contractile properties were assessed by measuring cell shortening and re-lengthening. Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Western blot, colorectal ligation puncture (CLP) surgery, silencing of Atg5 expression by small interfering RNA (siRNA), and immunofluorescent assays were also performed in this study. RESULTS After exogenous delivery of the p27 fusion protein and overexpression of p27 in LPS-induced cardiomyocytes, we found lower expressions of caspase-3 and caspase-8 and reduced positive TUNEL staining. Improved cardiomyocyte mechanical functions and reduced apoptosis were diminished after treatment with various autophagy inhibitors. Intravenous injections of p27 expressing adeno-associated virus serotype 9 (AAV9) vectors resulted in cardiac specific overexpression of p27, and echocardiography was used to assess cardiac function and structure in sepsis rat models. We observed improved cardiac function and reversed adverse ventricular remolding after the introduction of AAV9 vectors. Meanwhile, apoptosis was reduced, and expression of LC3-II was elevated in septic rat models treated with AAV9 vectors compared to controls. CONCLUSIONS The study data demonstrated that the overexpression of p27 protects cardiomyocytes from sepsis-induced cardiac depression via the activation of autophagy and inhibition of apoptosis. PMID- 30478252 TI - Evaluation Using an Isolated Reperfusion Model for Porcine Liver Donated After Cardiac Death Preserved with Oxygenated Hypothermic Machine Perfusion. AB - BACKGROUND Machine perfusion techniques offer a solution to the serious organ shortage. However, to assess the effects of machine perfusion, many detailed studies are required. In this study, an ex vivo reperfusion model using diluted autologous blood was confirmed to evaluate the utility of machine preservation for livers donated after cardiac death (DCD). In particular, beneficial effects of the oxygenated hypothermic machine perfusion (HMP) for DCD porcine livers are evaluated. MATERIAL AND METHODS Porcine livers were procured under warm ischemia time (WIT) of 60 min. The livers were preserved by hypothermic machine perfusion (HMP) or static cold storage (CS) for 4 h. After the preservation, the livers were perfused for 2 h using the ex vivo reperfusion model with diluted blood oxygenated by a membrane oxygenator at 35-38 degrees C. RESULTS At 2 h of ex vivo reperfusion with 60 min of warm ischemic time (WIT), the portal vein pressure for CS was higher than HMP (18.8+/-15.9 vs. 7.5+/-3.9 [mmHg] in 60 min). Furthermore, LDH in CS was higher than HMP (528.5+/-149.8 vs. 194.1+/-32.2 [IU/L/100 g liver] in 60 min. P<0.05). Lactate after CS (60) was significantly higher than HMP (60) (8.67+/-0.39 vs. 5.68+/-0.60 [mmol/L] at 60 min. p<0.01). CONCLUSIONS The ex vivo reperfusion model can be used to evaluate the utility of machine perfusion. Advantages of HMP for DCD livers are evaluated with this model. PMID- 30478253 TI - Giant Splenic Aneurysm with Arteriovenous (A-V) Shunt, Portal Hypertension, and Ascites. AB - BACKGROUND Splenic aneurysms are rare, asymptomatic, and usually derive from previous surgical interventions. Endovascular repair is the best option, but when A-V shunt is present, open repair might be more suitable. CASE REPORT A 43-year old man presented to the Internal Medicine Department of AHEPA University Hospital with symptoms of fever and ascites. He was an ex-medical student with a history of sickle cell anemia, who had undergone urgent splenectomy and cholecystectomy 26 years ago and had a transit ischemic attack at the age of 21 years. Diagnostic imaging control revealed a giant splenic aneurysm 9.8 cm in diameter and 5 cm in length, with a concomitant A-V shunt (due to common ligation of the vessels after splenectomy and long stump presence with concomitant erosion of arterial wall). The patient underwent open surgery and cross-clamping the orifice of the splenic artery, also including the splenic vein, and the vessels were ligated. Post-operatively, the patient remained in the Intensive Care Unit for 48 h and suffered a portal vein thrombosis treated with appropriate anticoagulants. One month later, he had acute hemorrhagic pancreatitis and paralytic ileus and underwent laparotomy performed by general surgeons. CONCLUSIONS Giant splenic aneurysms are rare and are usually caused by previous splenectomy and preservation of a long-vessel stump. Immediate surgical repair is mandatory because of the high risk of rupture. PMID- 30478254 TI - Calcimimetic restores diabetic peripheral neuropathy by ameliorating apoptosis and improving autophagy. AB - Decreased AMPK-eNOS bioavailability mediates the development of diabetic peripheral neuropathy (DPN) through increased apoptosis and decreased autophagy activity in relation to oxidative stress. Schwann cells are responsible for maintaining structural and functional integrity of neurons and for repairing damaged nerves. We evaluated the neuro-protective effect of cinacalcet on DPN by activating the AMPK-eNOS pathway using db/db mice and human Schwann cells (HSCs). Sciatic nerve of db/db mice was characterized by disorganized myelin, axonal shrinkage, and degeneration that were accompanied by marked fibrosis, inflammation, and apoptosis. These phenotypical alterations were significantly improved by cinacalcet treatment along with improvement in sensorimotor functional parameters. Cinacalcet demonstrated favorable effects through increased expression and activation of calcium-sensing receptor (CaSR)-CaMKKbeta and phosphorylation of AMPK-eNOS signaling in diabetic sciatic nerve. Cinacalcet decreased apoptosis and increased autophagy activity in relation to decreased oxidative stress in HSCs cultured in high-glucose medium as well. This was accompanied by increased expression of the CaSR, intracellular Ca++ ([Ca++]i) levels, and CaMKKbeta-LKB1-AMPK signaling pathway, resulting in the net effect of increased eNOS phosphorylation, NOx concentration, Bcl-2/Bax ratio, beclin 1, and LC3-II/LC3-I ratio. These results demonstrated that cinacalcet treatment ameliorates inflammation, apoptosis, and autophagy through increased expression of the CaSR, [Ca++]i levels and subsequent activation of CaMKKbeta-LKB-1-AMPK eNOS pathway in the sciatic nerve and HSCs under diabetic condition. Therefore, cinacalcet may play an important role in the restoration and amelioration of DPN by ameliorating apoptosis and improving autophagy. PMID- 30478255 TI - Canopy mortality has doubled in Europe's temperate forests over the last three decades. AB - Mortality is a key indicator of forest health, and increasing mortality can serve as bellwether for the impacts of global change on forest ecosystems. Here we analyze trends in forest canopy mortality between 1984 and 2016 over more than 30 Mill. ha of temperate forests in Europe, based on a unique dataset of 24,000 visually interpreted spectral trajectories from the Landsat archive. On average, 0.79% of the forest area was affected by natural or human-induced mortality annually. Canopy mortality increased by +2.40% year-1, doubling the forest area affected by mortality since 1984. Areas experiencing low-severity mortality increased more strongly than areas affected by stand-replacing mortality events. Changes in climate and land-use are likely causes of large-scale forest mortality increase. Our findings reveal profound changes in recent forest dynamics with important implications for carbon storage and biodiversity conservation, highlighting the importance of improved monitoring of forest mortality. PMID- 30478256 TI - Structures of Coxsackievirus A10 unveil the molecular mechanisms of receptor binding and viral uncoating. AB - Coxsackievirus A10 (CVA10), a human type-A Enterovirus (HEV-A), can cause diseases ranging from hand-foot-and-mouth disease to polio-myelitis-like disease. CVA10, together with some other HEV-As, utilizing the molecule KREMEN1 as an entry receptor, constitutes a KREMEN1-dependent subgroup within HEV-As. Currently, there is no vaccine or antiviral therapy available for treating diseases caused by CVA10. The atomic-resolution structure of the CVA10 virion, which is within the KREMEN1-dependent subgroup, shows significant conformational differences in the putative receptor binding sites and serotype-specific epitopes, when compared to the SCARB2-dependent subgroup of HEV-A, such as EV71, highlighting specific differences between the sub-groups. We also report two expanded structures of CVA10, an empty particle and uncoating intermediate at atomic resolution, as well as a medium-resolution genome structure reconstructed using a symmetry-mismatch method. Structural comparisons coupled with previous results, reveal an ordered signal transmission process for enterovirus uncoating, converting exo-genetic receptor-attachment inputs into a generic RNA release mechanism. PMID- 30478257 TI - Iron homeostasis in Mycobacterium tuberculosis is essential for persistence. AB - Tuberculosis, caused by the obligate intracellular pathogen Mycobacterium tuberculosis (Mtb), is responsible for 2-3 million deaths annually worldwide. Intracellular adaptability, which is critical for long-term persistence, requires the pathogen to neutralize host-mediated insults. The iron-sulphur (Fe-S) cofactor is essential for many enzymes critical for such 'adaptation'. The Mtb genome harbors only one putative iron-sulphur cluster (ISC) operon (rv1460-66) predicted to be involved in the generation of the Fe-S cofactor. Except for rv1460, all other genes in this operon are anticipated to be essential. The current study investigated the role of rv1460, an sufR homologue of Mtb (sufRTB), in maintaining intracellular Fe homeostasis and its implications on mycobacterial pathogenesis. We found that Mtb ISC locus (rv1461-66) was transcribed as a single multigene transcript. We successfully generated the sufRTB null mutant strain (DeltasufRTB) of Mtb, suggesting nonessentiality of the gene under normal growth conditions. The mutant strain demonstrated enhanced biofilm generation and failed to grow under a low-Fe condition. Growth characterization studies indicated that SufRTB-mediated intracellular Fe homeostasis is essential for Mtb to persist in the host. Targeting mycobacterial persistence by inhibiting SufRTB protein activity may be a novel intervention strategy in tuberculosis treatment. PMID- 30478258 TI - Study of the micro-climate and bacterial distribution in the deadspace of N95 filtering face respirators. AB - It is common for people to use N95 filtering facepiece respirators (FFRs) in daily life, especially in locations where particulate matter (PM2.5) concentration is rising. Wearing N95 FFRs is helpful to reduce inhalation of PM2.5. Although N95 FFRs block at least 95% of particles from the atmosphere, the deadspace of N95 FFRs could be a warm, wet environment that may be a perfect breeding ground for bacterial growth. This work studies the micro-climate features including the temperature distribution and water vapor condensation in the deadspace of an N95 FFR using the computational fluid dynamics (CFD) method. Then, the temperature and relative humidity inside the same type of N95 FFR are experimentally measured. There is a good agreement between the simulation and experimental results. Moreover, an experiment is conducted to study the distribution of bacteria sampled from the inner surface of an N95 FFR after donning. PMID- 30478259 TI - Author Correction: Nanometre-scale pattern formation on the surface of a photochromic crystal by optical near-field induced photoisomerization. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30478260 TI - Genetic effects of BDKRB2 and KNG1 on deep venous thrombosis after orthopedic surgery and the potential mediator. AB - Deep venous thrombosis (DVT) is a common complication of orthopedic surgery. Genetic risk factors and high heritability carried a substantial risk of DVT. In this study, we aimed to investigate the potential association in the Han Chinese population between the polymorphisms of BDKRB2 and KNG1 and DVT after orthopedic surgery (DVTAOS). A total of 3,010 study subjects comprising 892 DVT cases and 2,118 controls were included in the study, and 39 single nucleotide polymorphisms (SNPs) in total (30 for BDKRB2 and 9 for KNG1) were chosen for genotyping. Two SNPs, rs710446 (OR = 1.27, P = 0.00016) and rs2069588 (OR = 1.29, P = 0.00056), were identified as significantly associated with DVTAOS. After adjusting for BMI, the significance of rs2069588 decreased (P = 0.0013). Haplotype analyses showed that an LD block containing rs2069588 significantly correlated with the DVTAOS risk. Moreover, bioinformatics analysis indicated that hsa-miR-758-5p and BDKRB2 formed miRNA/SNP target duplexes if the rs2069588 allele was in the T form, suggesting that rs2069588 may alter BDKRB2 expression by affecting hsa-miR-758 5p/single-nucleotide polymorphism target duplexes. Our results demonstrate additional evidence supporting that there is an important role for the KNG1 and BDKRB2 genes in the increased susceptibility of DVTAOS. PMID- 30478261 TI - Exchange coupling torque in ferrimagnetic Co/Gd bilayer maximized near angular momentum compensation temperature. AB - Highly efficient current-induced motion of chiral domain walls was recently demonstrated in synthetic antiferromagnetic (SAF) structures due to an exchange coupling torque (ECT). The ECT derives from the antiferromagnetic exchange coupling through a ruthenium spacer layer between the two perpendicularly magnetized layers that comprise the SAF. Here we report that the same ECT mechanism applies to ferrimagnetic bi-layers formed from adjacent Co and Gd layers. In particular, we show that the ECT is maximized at the temperature TA where the Co and Gd angular momenta balance each other, rather than at their magnetization compensation temperature TM. The current induced velocity of the domain walls is highly sensitive to longitudinal magnetic fields but we show that this not the case near TA. Our studies provide new insight into the ECT mechanism for ferrimagnetic systems. The high efficiency of the ECT makes it important for advanced domain wall based spintronic devices. PMID- 30478262 TI - Single point mutations reveal amino acid residues important for Chromobacterium violaceum transaminase activity in the production of unnatural amino acids. AB - Unnatural amino acids (UAAs) are chiral amines with high application potential in drug discovery and synthesis of other valuable chemicals. Biocatalysis offers the possibility to synthesise novel optically pure UAAs with different physical and chemical properties. While the biocatalytic potential of transaminases in the synthesis of UAAs has been demonstrated, there is still a need to improve the activity with non-native substrates and to understand which amino acids residues are important for activity with these UAAs. Using a rational design approach, six variants of Chromobacterium violaceum DSM30191 transaminase (CV_TA) carrying a single and one variant carrying two substitutions were generated. Among the variants with a single substitution, CV_Y168F showed a 2 to 2.6-fold increased affinity for 2-oxooctanoic acid (2-OOA) and 3-oxobutyric acid (3-OBA) methyl ester used to synthesise an alpha- and beta-UAA. Analysis of the first half of the transaminase reaction showed no change in the activity with the donor (S)-1 phenylethylamine. The combination of W60C and Y168F substitutions improved the CV_TA affinity for 2-OOA 10-fold compared to the wild type. Other substitutions showed no change, or reduced activity with the tested substrates. Our findings provide structural information on CV_TA and demonstrate the potential of rational design for biosynthesis of UAAs. PMID- 30478264 TI - Complications of glans penis augmentation. AB - Despite the controversy regarding penile augmentation (PA), glans penis augmentation (GPA) is used in penile reconstructive surgery in selected patients with small glans penis. Since 2003, injectable hyaluronic acid (HA) gel has been used for GPA. The attractiveness of HA gel fillers and interest in this technique have led to the use of other fillers for GPA, particularly irreversible fillers that improve the longevity of HA gels. Conversely, indirect glans augmentation via implantation of dermofat grafts or scaffolds between the corpus spongiosum and the distal tip of the corpus cavernosum is used to overcome poor longevity of the gel and glans surface undulation, which are the primary limitations of GPA using HA gel. Unfortunately, these implants form hard painful lumps over time in most patients and are difficult to remove. Blunt dissection is an invasive procedure that may cause vascular compromise and consequent glans necrosis in a few patients. We present our review regarding the current status of GPA for a more comprehensive understanding of this subject. Additionally, we have discussed a few complicated cases that were referred to us. PMID- 30478263 TI - Treatment outcome and associated factors among patients with epilepsy. AB - Epilepsy is a major public health problem worldwide. Despite multiple drug therapies, people with epilepsy continue to have frequent seizures. There is a dearth of data on epilepsy treatment outcome and associated factors in our setting. Therefore, the aim of this was to assess treatment outcome and associated factors among epileptic patients on follow up at the neurologic clinic of Ayder comprehensive specialized hospital, Ethiopia. A cross-sectional study was conducted on randomly selected epileptic patients. Data were collected through patient interview and review of medical records. Epilepsy treatment outcome was evaluated in terms of seizure control status in the last one year follow up period. Binary logistic regression analysis was performed to identify predictors of treatment outcome. A total of 270 patients were included. Of whom, 46.6% had controlled seizures. Whereas, 38.5%, 8.8%, and 5.9% had experienced seizure attacks 1-5 times, 6-10 times, and greater than 10 times, respectively. Alcohol consumption [adjusted odds ratio [(AOR): 14.87, 95% confidence interval (CI): 3.25-68.11], negative medication belief [AOR: 3.0, 95%CI: 1.31-6.71], low medication adherence [AOR:11.52, 95%CI: 3.25-40.82], and presence of comorbidities [AOR: 10.35, 95%CI: 4.40-24.40] were predictors of uncontrolled seizure. Our finding revealed that more than half of the epileptic patients had uncontrolled seizure. Epileptic patients with a negative medication belief, comorbidities, low medication adherence, and those who consume alcohol were more likely to have uncontrolled seizure. Therefore, more emphasis should be given to these patients. PMID- 30478266 TI - Thomas Steitz 1940-2018. PMID- 30478265 TI - Architecture of the CBF3-centromere complex of the budding yeast kinetochore. AB - Kinetochores are multicomponent complexes responsible for coordinating the attachment of centromeric DNA to mitotic-spindle microtubules. The point centromeres of budding yeast are organized into three centromeric determining elements (CDEs), and are associated with the centromere-specific nucleosome Cse4. Deposition of Cse4 at CEN loci is dependent on the CBF3 complex that engages CDEIII to direct Cse4 nucleosomes to CDEII. To understand how CBF3 recognizes CDEIII and positions Cse4, we determined a cryo-EM structure of a CBF3-CEN complex. CBF3 interacts with CEN DNA as a head-to-head dimer that includes the whole of CDEIII and immediate 3' regions. Specific CEN-binding of CBF3 is mediated by a Cep3 subunit of one of the CBF3 protomers that forms major groove interactions with the conserved and essential CCG and TGT motifs of CDEIII. We propose a model for a CBF3-Cse4-CEN complex with implications for understanding CBF3-directed deposition of the Cse4 nucleosome at CEN loci. PMID- 30478267 TI - Direct observation of topoisomerase IA gate dynamics. AB - Type IA topoisomerases cleave single-stranded DNA and relieve negative supercoils in discrete steps corresponding to the passage of the intact DNA strand through the cleaved strand. Although type IA topoisomerases are assumed to accomplish this strand passage via a protein-mediated DNA gate, opening of this gate has never been observed. We developed a single-molecule assay to directly measure gate opening of the Escherichia coli type IA topoisomerases I and III. We found that after cleavage of single-stranded DNA, the protein gate opens by as much as 6.6 nm and can close against forces in excess of 16 pN. Key differences in the cleavage, ligation, and gate dynamics of these two enzymes provide insights into their different cellular functions. The single-molecule results are broadly consistent with conformational changes obtained from molecular dynamics simulations. These results allowed us to develop a mechanistic model of interactions between type IA topoisomerases and single-stranded DNA. PMID- 30478268 TI - Crack growth and energy dissipation in paper. AB - Here, we follow the stable propagation of a roughening crack using simultaneously Digital Image Correlation and Infra-Red imaging. In a quasi-two-dimensional paper sample, the crack tip and ahead of that the fracture process zone follow the slowly, diffusively moving "hot spot" ahead of the tip. This also holds when the crack starts to roughen during propagation. The well-established intermittency of the crack advancement and the roughening of the crack in paper are thus subject to the dissipation and decohesion in the hot spot zone. They are therefore not only a result of the depinning of the crack in a heterogeneous material. PMID- 30478270 TI - Challenging the gestational age for the limit of viability: proactive care. PMID- 30478269 TI - Levels of plasma neurofilament light chain and cognitive function in patients with Alzheimer or Parkinson disease. AB - Plasma neurofilament light (NFL) has been proposed as a blood-based biomarker for neurodegeneration in Alzheimer's disease (AD) and parkinsonian disorders. However, the relationship between plasma NFL and cognitive decline in dementia due to Parkinson's disease (PD) remains to be elucidated. In this research, 119 AD, 56 mild cognitive impairment (MCI), 26 non-demented PD (PDND), and 23 Parkinson's disease dementia (PDD) patients, as well as 59 cognitively healthy controls (HC) were recruited. Each subject underwent a battery of neuropsychological testing. Plasma NFL levels were measured in duplicate using an NF-Light assay and transferred onto the Simoa platform with a home-brew kit. Plasma NFL was significantly increased in the AD group, compared with the control, MCI, PDND, and PDD groups. Plasma NFL was significantly higher in the PDD group, compared with the PDND group. High plasma NFL correlated with poor cognition in AD and PD, but not with motor symptoms in PD. Plasma NFL may represent a biomarker of cognitive decline in AD and PD, with more specificity for AD. PMID- 30478272 TI - Predicting natural language descriptions of mono-molecular odorants. AB - There has been recent progress in predicting whether common verbal descriptors such as "fishy", "floral" or "fruity" apply to the smell of odorous molecules. However, accurate predictions have been achieved only for a small number of descriptors. Here, we show that applying natural-language semantic representations on a small set of general olfactory perceptual descriptors allows for the accurate inference of perceptual ratings for mono-molecular odorants over a large and potentially arbitrary set of descriptors. This is noteworthy given that the prevailing view is that humans' capacity to identify or characterize odors by name is poor. We successfully apply our semantics-based approach to predict perceptual ratings with an accuracy higher than 0.5 for up to 70 olfactory perceptual descriptors, a ten-fold increase in the number of descriptors from previous attempts. These results imply that the semantic distance between descriptors defines the equivalent of an odorwheel. PMID- 30478271 TI - Amino acids stimulate the endosome-to-Golgi trafficking through Ragulator and small GTPase Arl5. AB - The endosome-to-Golgi or endocytic retrograde trafficking pathway is an important post-Golgi recycling route. Here we show that amino acids (AAs) can stimulate the retrograde trafficking and regulate the cell surface localization of certain Golgi membrane proteins. By testing components of the AA-stimulated mTORC1 signaling pathway, we demonstrate that SLC38A9, v-ATPase and Ragulator, but not Rag GTPases and mTORC1, are essential for the AA-stimulated trafficking. Arl5, an ARF-like family small GTPase, interacts with Ragulator in an AA-regulated manner and both Arl5 and its effector, the Golgi-associated retrograde protein complex (GARP), are required for the AA-stimulated trafficking. We have therefore identified a mechanistic connection between the nutrient signaling and the retrograde trafficking pathway, whereby SLC38A9 and v-ATPase sense AA-sufficiency and Ragulator might function as a guanine nucleotide exchange factor to activate Arl5, which, together with GARP, a tethering factor, probably facilitates the endosome-to-Golgi trafficking. PMID- 30478274 TI - Strategic advantages of reactive polyiodide melts for scalable perovskite photovoltaics. AB - Despite tremendous progress in efficiency and stability, perovskite solar cells are still facing the challenge of upscaling. Here we present unique advantages of reactive polyiodide melts for solvent- and adduct-free reactionary fabrication of perovskite films exhibiting excellent quality over large areas. Our method employs a nanoscale layer of metallic Pb coated with stoichiometric amounts of CH3NH3I (MAI) or mixed CsI/MAI/NH2CHNH2I (FAI), subsequently exposed to iodine vapour. The instantly formed MAI3(L) or Cs(MA,FA)I3(L) polyiodide liquid converts the Pb layer into a pure perovskite film without byproducts or unreacted components at nearly room temperature. We demonstrate highly uniform and relatively large area MAPbI3 perovskite films, such as 100 cm2 on glass/fluorine doped tin oxide (FTO) and 600 cm2 on flexible polyethylene terephthalate (PET)/indium tin oxide (ITO) substrates. As a proof-of-concept, we demonstrate solar cells with reverse scan power conversion efficiencies of 16.12% (planar MAPbI3), 17.18% (mesoscopic MAPbI3) and 16.89% (planar Cs0.05MA0.2FA0.75PbI3) in the standard FTO/c(m)-TiO2/perovskite/spiro-OMeTAD/Au architecture. PMID- 30478273 TI - Enhanced anti-metastatic bioactivity of an IGF-TRAP re-engineered to improve physicochemical properties. AB - The insulin-like growth factor (IGF) axis has been implicated in the progression of malignant disease and identified as a clinically important therapeutic target. Several IGF-1 receptor (IGF-1R) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical use, due, at least in part, to interference with insulin receptor signalling. We previously reported on the production of a soluble fusion protein consisting of the extracellular domain of human IGF-1R fused to the Fc portion of human IgG1 (first generation IGF-TRAP) that bound human IGF-1 and IGF 2 with a 3 log higher affinity than insulin. We showed that the IGF-TRAP had potent anti-cancer activity in several pre-clinical models of aggressive carcinomas. Here we report on the re-engineering of the IGF-TRAP with the aim of improving physicochemical properties and suitability for clinical applications. We show that cysteine-serine substitutions in the Fc hinge region of IGF-TRAP eliminated high-molecular-weight oligomerized species, while a further addition of a flexible linker, not only improved the pharmacokinetic profile, but also enhanced the therapeutic profile of the IGF-TRAP, as evaluated in an experimental colon carcinoma metastasis model. Dose-response profiles of the modified IGF TRAPs correlated with their bio-availability profiles, as measured by the IGF kinase-receptor-activation (KIRA) assay, providing a novel, surrogate biomarker for drug efficacy. This study provides a compelling example of structure-based re engineering of Fc-fusion-based biologics for better manufacturability that also significantly improved pharmacological parameters. It identifies the re engineered IGF-TRAP as a potent anti-cancer therapeutic. PMID- 30478275 TI - Heat-assisted microwave amplifier. PMID- 30478276 TI - Actinia-like multifunctional nanocoagulant for single-step removal of water contaminants. AB - Current technologies for water purification are limited by their contaminant specific removal capability, requiring multiple processes to meet water quality objectives. Here we show an innovative biomimetic micellar nanocoagulant that imitates the structure of Actinia, a marine predator that uses its tentacles to ensnare food, for the removal of an array of water contaminants with a single treatment step. The Actinia-like micellar nanocoagulant has a core-shell structure and readily disperses in water while maintaining a high stability against aggregation. To achieve effective coagulation, the nanocoagulant everts its configuration, similar to Actinia. The shell hydrolyses into 'flocs' and destabilizes and enmeshes colloidal particles while the core is exposed to water, like the extended tentacles of Actinia, and adsorbs the dissolved contaminants. The technology, with its ability to remove a broad spectrum of contaminants and produce high-quality water, has the potential to be a cost-effective replacement for current water treatment processes. PMID- 30478278 TI - Drink safely with biomimetic nanotechnology. PMID- 30478277 TI - Microwave amplification in a magnetic tunnel junction induced by heat-to-spin conversion at the nanoscale. AB - Heat-driven engines are hard to realize in nanoscale machines because of efficient heat dissipation1. However, in the realm of spintronics, heat has been employed successfully-for example, heat current has been converted into a spin current in a NiFe|Pt bilayer system2, and Joule heating has enabled selective writing in magnetic memory arrays3. Here, we use Joule heating in nanoscale magnetic tunnel junctions to create a giant spin torque due to a magnetic anisotropy change. Efficient conversion from heat dynamics to spin dynamics is obtained because of a large interfacial thermal resistance at an FeB|MgO interface. The heat-driven spin torque is equivalent to a voltage-controlled magnetic anisotropy4,5 of approximately 300 fJ V-1 m-1, which is more than twice the value reported in a (Co)FeB|MgO system6,7. We demonstrate an electric microwave amplification gain of 20% in a d.c. biased magnetic tunnel junction as a result of this spin torque. While electric d.c. power amplification in spintronic devices has been realized previously8, the microwave amplification was limited to relatively small amplification gains (G = radiofrequency output voltage/radiofrequency input voltage) and has never exceeded 1 (refs 9-13). A magnetic tunnel junction driven by radiofrequency spin transfer torque using ferromagnetic resonance enabled a relatively large gain of G ~ 0.55 (ref. 12). Furthermore, radiofrequency spin waves were tuned by the spin transfer effect14,15. The heat-driven giant spin torque in the FeB|MgO16,17 magnetic tunnel junction, which shows a large magnetization precession and resistance oscillation under a d.c. bias, overcomes the above limitations and provides a gain larger than 1. PMID- 30478279 TI - Delineating Areas of Past Environmental Degradation near Smelters using Rock Coatings: A Case Study at Rouyn-Noranda, Quebec. AB - Emissions of SO2 from smelters can promote formation of acid rain, which can dissolve siliceous minerals on exposed rock surfaces and promote the formation of silica gel layers within which detrital and smelter-derived particulates can become trapped. These processes of dissolution and entrapment can result in the formation of rock coatings that contain elevated levels of heavy metals. Between 1927 and 1976, the Horne smelter processed sulfide ore derived from the Rouyn Noranda region and became one of the largest emitters of particulates and sulfur dioxide in North America, promoting the formation of coatings on nearby rock surfaces. The reflectance spectra of these coatings are relatively flat, with typical reflectance values ranging between ~5% at visible wavelengths and ~16% in the shortwave infrared. Absorption troughs in coating spectra are consistent with the presence of materials including opaline silica, olivine, pyroxene, hydrous phyllosilicates, and sulfates. Classification of Landsat 8 Operational Land Imager data indicates that rock coatings near Rouyn-Noranda comprise a total surface area of ~1.5 km2, nearly all of which is located within ~6 km of the Horne smelter. Remote sensing techniques can used to delineate the geographic extents of coatings near smelters, highlighting areas previously subjected to severe environmental degradation. PMID- 30478280 TI - Chloroquine ameliorates carbon tetrachloride-induced acute liver injury in mice via the concomitant inhibition of inflammation and induction of apoptosis. AB - This is the first study to investigate the hepatoprotective effect of CQ on acute liver injury caused by carbon tetrachloride (CCl4) in a murine model and the underlying molecular mechanisms. Ninety-six mice were randomly divided into the control (n = 8), CQ (n = 8), CCl4 (n = 40), and CCl4 + CQ (n = 40) treatment groups. In the CCl4 group, mice were intraperitoneally (i.p) injected with 0.3% CCl4 (10 mL/kg, dissolved in olive oil); in the CCl4 + CQ group, mice were i.p injected with CQ at 50 mg/kg at 2, 24, and 48 h before CCl4 administration. The mice in the control and CQ groups were administered with an equal vehicle or CQ (50 mg/kg). Mice were killed at 2, 6, 12, 24, 48 h post CCl4 treatment and their livers were harvested for analysis. The results showed that CQ pre-treatment markedly inhibited CCl4-induced acute liver injury, which was evidenced by decreased serum transaminase, aspartate transaminase and lower histological scores of liver injury. CQ pretreatment downregulated the CCl4-induced hepatic tissue expression of high-mobility group box 1 (HMGB1) and the levels of serum HMGB1 as well as IL-6 and TNF-alpha. Furthermore, CQ pre-treatment inhibited autophagy, downregulated NF-kB expression, upregulated p53 expression, increased the ratio of Bax/Bcl-2, and increased the activation of caspase-3 in hepatic tissue. This is the first study to demonstrate that CQ ameliorates CCl4-induced acute liver injury via the inhibition of HMGB1-mediated inflammatory responses and the stimulation of pro-apoptotic pathways to modulate the apoptotic and inflammatory responses associated with progress of liver damage. PMID- 30478281 TI - A rare human CEP290 variant disrupts the molecular integrity of the primary cilium and impairs Sonic Hedgehog machinery. AB - The primary cilium is a microtubule-enriched cell-communication organelle that participates in mechanisms controlling tissue development and maintenance, including cerebellar architecture. Centrosomal protein of 290 kDa (CEP290) is a protein important for centrosomal function and ciliogenesis. Mutations in CEP290 have been linked to a group of multi-organ disorders - termed ciliopathies. The neurophysiological deficits observed in ciliopathies are sometimes associated with the progression of autistic traits. Here, the cellular function of two rare variants of CEP290 identified from recent exome sequencing of autistic individuals are investigated. Cells expressing Cep290 carrying the missense mutation R1747Q in mouse exhibited a defective Sonic hedgehog (Shh) signalling response, mislocalisation of the Shh receptor Smoothened (Smo), and dysregulation of ciliary protein mobility, which ultimately disrupted the proliferation of cerebellar granule progenitors (CGPs). This data was furthermore corroborated in an autism patient-derived iPSC line harbouring the R1746Q rare CEP290 variant. Evidence from this study suggests that the R1746Q mutation interferes with the function of CEP290 to maintain the ciliary diffusion barrier and disrupts the integrity of the molecular composition in the primary cilium, which may contribute to alterations in neuroarchitecture. PMID- 30478282 TI - Advanced laser scanning for highly-efficient ablation and ultrafast surface structuring: experiment and model. AB - Ultra-short laser pulses are frequently used for material removal (ablation) in science, technology and medicine. However, the laser energy is often used inefficiently, thus, leading to low ablation rates. For the efficient ablation of a rectangular shaped cavity, the numerous process parameters such as scanning speed, distance between scanned lines, and spot size on the sample, have to be optimized. Therefore, finding the optimal set of process parameters is always a time-demanding and challenging task. Clear theoretical understanding of the influence of the process parameters on the material removal rate can improve the efficiency of laser energy utilization and enhance the ablation rate. In this work, a new model of rectangular cavity ablation is introduced. The model takes into account the decrease in ablation threshold, as well as saturation of the ablation depth with increasing number of pulses per spot. Scanning electron microscopy and the stylus profilometry were employed to characterize the ablated depth and evaluate the material removal rate. The numerical modelling showed a good agreement with the experimental results. High speed mimicking of bio inspired functional surfaces by laser irradiation has been demonstrated. PMID- 30478283 TI - Multidirectional desymmetrization of pluripotent building block en route to diastereoselective synthesis of complex nature-inspired scaffolds. AB - Octahydroindolo[2,3-a]quinolizine ring system forms the basic framework comprised of more than 2000 distinct family members of natural products. Despite the potential applications of this privileged substructure in drug discovery, efficient, atom-economic and modular strategies for its assembly, is underdeveloped. Here we show a one-step build/couple/pair strategy that uniquely allows access to diverse octahydroindolo[2,3-a]quinolizine scaffolds with more than three contiguous chiral centers and broad distribution of molecular shapes via desymmetrization of the oxidative-dearomatization products of phenols. The cascade demonstrates excellent diastereoselectivity, and the enantioselectivity exceeded 99% when amino acids are used as chiral reagents. Furthermore, two diastereoselective reactions for the synthesis of oxocanes and piperazinones, is reported. Phenotypic screening of the octahydroindolo[2,3-a]quinolizine library identifies small molecule probes that selectively suppress mitochondrial membrane potential, ATP contents and elevate the ROS contents in hepatoma cells (Hepa1-6) without altering the immunological activation or reprogramming of T- and B-cells, a promising approach to cancer therapy. PMID- 30478284 TI - Using mimicry of body movements by a virtual agent to increase synchronization behavior and rapport in individuals with schizophrenia. AB - Synchronization of behavior such as gestures or postures is assumed to serve crucial functions in social interaction but has been poorly studied to date in schizophrenia. Using a virtual collaborative environment (VCS), we tested 1) whether synchronization of behavior, i.e., the spontaneous initiation of gestures that are congruent with those of an interaction partner, was impaired in individuals with schizophrenia compared with healthy participants; 2) whether mimicry of the patients' body movements by the virtual interaction partner was associated with increased behavioral synchronization and rapport. 19 patients and 19 matched controls interacted with a virtual agent who either mimicked their head and torso movements with a delay varying randomly between 0.5 s and 4 s or did not mimic, and rated feelings of rapport toward the virtual agent after each condition. Both groups exhibited a higher and similar synchronization behavior of the virtual agent forearm movements when they were in the Mimicry condition rather than in the No-mimicry condition. In addition, both groups felt more comfortable with a mimicking virtual agent rather than a virtual agent not mimicking them suggesting that mimicry is able to increase rapport in individuals with schizophrenia. Our results suggest that schizophrenia cannot be considered anymore as a disorder of imitation, particularly as regards behavioral synchronization processes in social interaction contexts. PMID- 30478285 TI - Usp9X Regulates Cell Death in Malignant Peripheral Nerve Sheath Tumors. AB - Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of death in neurofibromatosis type 1 (NF1) patients. Current treatment modalities have been largely unsuccessful in improving MPNST patient survival, making the identification of new therapeutic targets urgent. In this study, we found that interference with Usp9X, a deubiquitinating enzyme which is overexpressed in nervous system tumors, or Mcl-1, an anti-apoptotic member of the Bcl-2 family whose degradation is regulated by Usp9X, causes rapid death in human MPNST cell lines. Although both Usp9X and Mcl-1 knockdown elicited some features of apoptosis, broad spectrum caspase inhibition was ineffective in preventing knockdown-induced MPNST cell death suggesting that caspase-independent death pathways were also activated. Ultrastructural examination of MPNST cells following either Usp9X interference or pharmacological inhibition showed extensive cytoplasmic vacuolization and swelling of endoplasmic reticulum (ER) and mitochondria most consistent with paraptotic cell death. Finally, the Usp9X pharmacological inhibitor WP1130 significantly reduced human MPNST growth and induced tumor cell death in an in vivo xenograft model. In total, these findings indicate that Usp9X and Mcl-1 play significant roles in maintaining human MPNST cell viability and that pharmacological inhibition of Usp9X deubiquitinase activity could be a therapeutic target for MPNST treatment. PMID- 30478286 TI - Revisiting the initial steps of sexual development in the malaria parasite Plasmodium falciparum. AB - Human to vector transmission of malaria requires that some blood-stage parasites abandon asexual growth and convert into non-replicating sexual forms called gametocytes. The initial steps of gametocytogenesis remain largely uncharacterized. Here, we study this part of the malaria life cycle in Plasmodium falciparum using PfAP2-G, the master regulator of sexual conversion, as a marker of commitment. We demonstrate the existence of PfAP2-G-positive sexually committed parasite stages that precede the previously known committed schizont stage. We also found that sexual conversion can occur by two different routes: the previously described route in which PfAP2-G-expressing parasites complete a replicative cycle as committed forms before converting into gametocytes upon re invasion, or a direct route with conversion within the same cycle as initial PfAP2-G expression. The latter route is linked to early PfAP2-G expression in ring stages. Reanalysis of published single-cell RNA-sequencing (RNA-seq) data confirmed the presence of both routes. Consistent with these results, using plaque assays we observed that, in contrast to the prevailing model, many schizonts produced mixed plaques containing both asexual parasites and gametocytes. Altogether, our results reveal unexpected features of the initial steps of sexual development and extend the current view of this part of the malaria life cycle. PMID- 30478287 TI - An upstream protein-coding region in enteroviruses modulates virus infection in gut epithelial cells. AB - Enteroviruses comprise a large group of mammalian pathogens that includes poliovirus. Pathology in humans ranges from sub-clinical to acute flaccid paralysis, myocarditis and meningitis. Until now, all of the enteroviral proteins were thought to derive from the proteolytic processing of a polyprotein encoded in a single open reading frame. Here we report that many enterovirus genomes also harbour an upstream open reading frame (uORF) that is subject to strong purifying selection. Using echovirus 7 and poliovirus 1, we confirmed the expression of uORF protein in infected cells. Through ribosome profiling (a technique for the global footprinting of translating ribosomes), we also demonstrated translation of the uORF in representative members of the predominant human enterovirus species, namely Enterovirus A, B and C. In differentiated human intestinal organoids, uORF protein-knockout echoviruses are attenuated compared to the wild type at late stages of infection where membrane-associated uORF protein facilitates virus release. Thus, we have identified a previously unknown enterovirus protein that facilitates virus growth in gut epithelial cells-the site of initial viral invasion into susceptible hosts. These findings overturn the 50-year-old dogma that enteroviruses use a single-polyprotein gene expression strategy and have important implications for the understanding of enterovirus pathogenesis. PMID- 30478288 TI - A widespread alternative squalene epoxidase participates in eukaryote steroid biosynthesis. AB - Steroids are essential triterpenoid molecules that are present in all eukaryotes and modulate the fluidity and flexibility of cell membranes. Steroids also serve as signalling molecules that are crucial for growth, development and differentiation of multicellular organisms1-3. The steroid biosynthetic pathway is highly conserved and is key in eukaryote evolution4-7. The flavoprotein squalene epoxidase (SQE) catalyses the first oxygenation reaction in this pathway and is rate limiting. However, despite its conservation in animals, plants and fungi, several phylogenetically widely distributed eukaryote genomes lack an SQE encoding gene7,8. Here, we discovered and characterized an alternative SQE (AltSQE) belonging to the fatty acid hydroxylase superfamily. AltSQE was identified through screening of a gene library of the diatom Phaeodactylum tricornutum in a SQE-deficient yeast. In accordance with its divergent protein structure and need for cofactors, we found that AltSQE is insensitive to the conventional SQE inhibitor terbinafine. AltSQE is present in many eukaryotic lineages but is mutually exclusive with SQE and shows a patchy distribution within monophyletic clades. Our discovery provides an alternative element for the conserved steroid biosynthesis pathway, raises questions about eukaryote metabolic evolution and opens routes to develop selective SQE inhibitors to control hazardous organisms. PMID- 30478289 TI - Pervasive acquisition of CRISPR memory driven by inter-species mating of archaea can limit gene transfer and influence speciation. AB - CRISPR-Cas systems provide prokaryotes with sequence-specific immunity against viruses and plasmids based on DNA acquired from these invaders, known as spacers. Surprisingly, many archaea possess spacers that match chromosomal genes of related species, including those encoding core housekeeping genes. By sequencing genomes of environmental archaea isolated from a single site, we demonstrate that inter-species spacers are common. We show experimentally, by mating Haloferax volcanii and Haloferax mediterranei, that spacers are indeed acquired chromosome wide, although a preference for integrated mobile elements and nearby regions of the chromosome exists. Inter-species mating induces increased spacer acquisition and may result in interactions between the acquisition machinery of the two species. Surprisingly, many of the spacers acquired following inter-species mating target self-replicons along with those originating from the mating partner, indicating that the acquisition machinery cannot distinguish self from non-self under these conditions. Engineering the chromosome of one species to be targeted by the other's CRISPR-Cas reduces gene exchange between them substantially. Thus, spacers acquired during inter-species mating could limit future gene transfer, resulting in a role for CRISPR-Cas systems in microbial speciation. PMID- 30478290 TI - Structure-function analysis of neutralizing antibodies to H7N9 influenza from naturally infected humans. AB - Little is known about the specificities and neutralization breadth of the H7 reactive antibody repertoire induced by natural H7N9 infection in humans. We have isolated and characterized 73 H7-reactive monoclonal antibodies from peripheral B cells from four donors infected in 2013 and 2014. Of these, 45 antibodies were H7 specific, and 17 of these neutralized the virus, albeit with few somatic mutations in their variable domain sequences. An additional set of 28 antibodies, isolated from younger donors born after 1968, cross-reacted between H7 and H3 haemagglutinins in binding assays, and had accumulated significantly more somatic mutations, but were predominantly non-neutralizing in vitro. Crystal structures of three neutralizing and protective antibodies in complex with the H7 haemagglutinin revealed that they recognize overlapping residues surrounding the receptor-binding site of haemagglutinin. One of the antibodies, L4A-14, bound into the sialic acid binding site and made contacts with haemagglutinin residues that were conserved in the great majority of 2016-2017 H7N9 isolates. However, only 3 of the 17 neutralizing antibodies retained activity for the Yangtze River Delta lineage viruses isolated in 2016-2017 that have undergone antigenic change, which emphasizes the need for updated H7N9 vaccines. PMID- 30478291 TI - Prediction of the intestinal resistome by a three-dimensional structure-based method. AB - The intestinal microbiota is considered to be a major reservoir of antibiotic resistance determinants (ARDs) that could potentially be transferred to bacterial pathogens via mobile genetic elements. Yet, this assumption is poorly supported by empirical evidence due to the distant homologies between known ARDs (mostly from culturable bacteria) and ARDs from the intestinal microbiota. Consequently, an accurate census of intestinal ARDs (that is, the intestinal resistome) has not yet been fully determined. For this purpose, we developed and validated an annotation method (called pairwise comparative modelling) on the basis of a three dimensional structure (homology comparative modelling), leading to the prediction of 6,095 ARDs in a catalogue of 3.9 million proteins from the human intestinal microbiota. We found that the majority of predicted ARDs (pdARDs) were distantly related to known ARDs (mean amino acid identity 29.8%) and found little evidence supporting their transfer between species. According to the composition of their resistome, we were able to cluster subjects from the MetaHIT cohort (n = 663) into six resistotypes that were connected to the previously described enterotypes. Finally, we found that the relative abundance of pdARDs was positively associated with gene richness, but not when subjects were exposed to antibiotics. Altogether, our results indicate that the majority of intestinal microbiota ARDs can be considered intrinsic to the dominant commensal microbiota and that these genes are rarely shared with bacterial pathogens. PMID- 30478292 TI - miR-146a regulates the crosstalk between intestinal epithelial cells, microbial components and inflammatory stimuli. AB - Regulation of miR-146a abundance and its role in intestinal inflammation and particularly in intestinal epithelial cells (IECs) has been poorly studied. Here we study the relationship between bacterial antigens and inflammatory stimuli, and miR-146a expression using IEC lines and models of colitis (trinitrobenzenesulfonic acid (TNBS), dextran sulfate sodium (DSS) and the CD4 + CD62L + T cell transfer model). Specific bacterial antigens and cytokines (LPS, flagelin and IL-1beta/TNF) stimulate miR-146a expression, while peptidoglycan, muramyldipeptide and CpG DNA have no effect. Overexpression of miR-146a by LPS depends on the activation of the TLR4/MyD88/NF-kB and Akt pathways. Accordingly, the induction of miR-146a is lower in TLR4, but not in TLR2 knock out mice in both basal and colitic conditions. miR-146a overexpression in IECs induces immune tolerance, inhibiting cytokine production (MCP-1 and GROalpha/IL-8) in response to LPS (IEC18) or IL-1beta (Caco-2). Intestinal inflammation induced by chemical damage to the epithelium (DSS and TNBS models) induces miR-146a, but no effect is observed in the lymphocyte transfer model. Finally, we found that miR-146a expression is upregulated in purified IECs from villi vs. crypts. Our results indicate that miR-146a is a key molecule in the interaction among IECs, inflammatory stimuli and the microbiota. PMID- 30478293 TI - Reward behaviour is regulated by the strength of hippocampus-nucleus accumbens synapses. AB - Reward drives motivated behaviours and is essential for survival, and therefore there is strong evolutionary pressure to retain contextual information about rewarding stimuli. This drive may be abnormally strong, such as in addiction, or weak, such as in depression, in which anhedonia (loss of pleasure in response to rewarding stimuli) is a prominent symptom. Hippocampal input to the shell of the nucleus accumbens (NAc) is important for driving NAc activity1,2 and activity dependent modulation of the strength of this input may contribute to the proper regulation of goal-directed behaviours. However, there have been few robust descriptions of the mechanisms that underlie the induction or expression of long term potentiation (LTP) at these synapses, and there is, to our knowledge, no evidence about whether such plasticity contributes to reward-related behaviour. Here we show that high-frequency activity induces LTP at hippocampus-NAc synapses in mice via canonical, but dopamine-independent, mechanisms. The induction of LTP at this synapse in vivo drives conditioned place preference, and activity at this synapse is required for conditioned place preference in response to a natural reward. Conversely, chronic stress, which induces anhedonia, decreases the strength of this synapse and impairs LTP, whereas antidepressant treatment is accompanied by a reversal of these stress-induced changes. We conclude that hippocampus-NAc synapses show activity-dependent plasticity and suggest that their strength may be critical for contextual reward behaviour. PMID- 30478294 TI - Reversible superdense ordering of lithium between two graphene sheets. AB - Many carbon allotropes can act as host materials for reversible lithium uptake1,2, thereby laying the foundations for existing and future electrochemical energy storage. However, insight into how lithium is arranged within these hosts is difficult to obtain from a working system. For example, the use of in situ transmission electron microscopy3-5 to probe light elements (especially lithium)6,7 is severely hampered by their low scattering cross-section for impinging electrons and their susceptibility to knock-on damage8. Here we study the reversible intercalation of lithium into bilayer graphene by in situ low voltage transmission electron microscopy, using both spherical and chromatic aberration correction9 to enhance contrast and resolution to the required levels. The microscopy is supported by electron energy-loss spectroscopy and density functional theory calculations. On their remote insertion from an electrochemical cell covering one end of the long but narrow bilayer, we observe lithium atoms to assume multi-layered close-packed order between the two carbon sheets. The lithium storage capacity associated with this superdense phase far exceeds that expected from formation of LiC6, which is the densest configuration known under normal conditions for lithium intercalation within bulk graphitic carbon10. Our findings thus point to the possible existence of distinct storage arrangements of ions in two-dimensional layered materials as compared to their bulk parent compounds. PMID- 30478295 TI - Using Frameshift Peptide Arrays for Cancer Neo-Antigens Screening. AB - It has been demonstrated that DNA mutations generating neo-antigens are important for an effective immune response to tumors as evident from recent clinical studies of immune checkpoint inhibitors (ICIs). Further, it was shown that frameshift peptides (FSP) generated in tumors from insertions and deletions (INDELs) of microsatellites (MS) in coding region are a very good correlate of positive response to PD1 treatment. However, these types of DNA-sourced FSPs are infrequent in cancer. We hypothesize that tumors may also generate FSPs in transcription errors through INDELs in MS or by exon mis-splicing. Since there are a finite number of predictable sequences of such possible FSPs in the genome, we propose that peptide arrays with all possible FSPs could be used to analyze antibody reactivity to FSPs in patient sera as a FS neo-antigen screen. If this were the case it would facilitate finding common tumor neoantigens for cancer vaccines. Here we test this proposal using an array of 377 predicted FS antigens. The results of screening 9 types of dog cancer sera indicate that cancer samples had significantly higher antibody responses against FSPs than non-cancer samples. Both common reactive FSPs and cancer-type specific immune responses were detected. In addition, the protection of a common reactive FSP was tested in mouse tumor models, comparing to the non-reactive FSPs. The mouse homologs non reactive FSPs did not offer protection in either the mouse melanoma or breast cancer models while the reactive FSP did in both models. The tumor protection was positively correlated to antibody response to the FSP. These data suggest that FSP arrays could be used for cancer neo-antigen screening. PMID- 30478296 TI - Iron removal enhances vitamin C-induced apoptosis and growth inhibition of K-562 leukemic cells. AB - Although vitamin C (VC) has recently garnered interest as an alternative cancer therapy, its clinical effects remain controversial. It was recently reported using in vitro prostate cancer cell lines that excess extracellular iron (EEI) diminishes anti-cancer effects of VC, promoting the decomposition of hydrogen peroxide (H2O2) generated by VC. Here we demonstrated that EEI diminished the inhibitory effect of VC on the survival of K562 human leukemic cells in vitro, by reducing the amount of H2O2 and abrogating the apoptosis pathways induced by VC. In vivo, in the presence of EEI, the growth inhibitory effect of VC on K562 cells was completely abrogated; in fact, VC enhanced K562 cell growth. Reduction of EEI restored the apoptosis-inducing effect of VC in vitro and enhanced the growth inhibitory effect of VC in vivo. Further studies are warranted to investigate whether the combination of VC and iron depletion has similar effects in various other leukemic or cancer cells against which VC has been effective in previous experimental studies. PMID- 30478297 TI - Three-dimensional in vitro modeling of malignant bone disease recapitulates experimentally accessible mechanisms of osteoinhibition. AB - Malignant bone disease (MBD) occurs when tumors establish in bone, causing catastrophic tissue damage as a result of accelerated bone destruction and inhibition of repair. The resultant so-called osteolytic lesions (OL) take the form of tumor-filled cavities in bone that cause pain, fractures, and associated morbidity. Furthermore, the OL microenvironment can support survival of tumor cells and resistance to chemotherapy. Therefore, a deeper understanding of OL formation and MBD progression is imperative for the development of future therapeutic strategies. Herein, we describe a novel in vitro platform to study bone-tumor interactions based on three-dimensional co-culture of osteogenically enhanced human mesenchymal stem cells (OEhMSCs) in a rotating wall vessel bioreactor (RWV) while attached to micro-carrier beads coated with extracellular matrix (ECM) composed of factors found in anabolic bone tissue. Osteoinhibition was recapitulated in this model by co-culturing the OEhMSCs with a bone-tumor cell line (MOSJ-Dkk1) that secretes the canonical Wnt (cWnt) inhibitor Dkk-1, a tumor-borne osteoinhibitory factor widely associated with several forms of MBD, or intact tumor fragments from Dkk-1 positive patient-derived xenografts (PDX). Using the model, we observed that depending on the conditions of growth, tumor cells can biochemically inhibit osteogenesis by disrupting cWnt activity in OEhMSCs, while simultaneously co-engrafting with OEhMSCs, displacing them from the niche, perturbing their activity, and promoting cell death. In the absence of detectable co-engraftment with OEhMSCs, Dkk-1 positive PDX fragments had the capacity to enhance OEhMSC proliferation while inhibiting their osteogenic differentiation. The model described has the capacity to provide new and quantifiable insights into the multiple pathological mechanisms of MBD that are not readily measured using monolayer culture or animal models. PMID- 30478298 TI - Author Correction: Tailoring diamond's optical properties via direct femtosecond laser nanostructuring. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30478299 TI - The combination of cantharidin and antiangiogenic therapeutics presents additive antitumor effects against pancreatic cancer. AB - Cantharidin, one of the active components of mylabris, is believed to have antitumor activity. Cantharidin selectively inhibits protein phosphatase 2A (PP2A), which can repress multiple oncogenic kinases (ERK, JNK, PKC, and NF kappaB). Researches in vitro have shown that cantharidin suppresses cell viability and metastasis in pancreatic cancer cells. This study aims to investigate the effects of cantharidin on pancreatic cancer xenografts in vivo. Xenograft models were established using cells stably expressing luciferase. Xenograft growth was evaluated by living imaging. Gene expression was determined using a microarray, real-time PCR, a RayBiotech antibody array, and the Milliplex assay. Surprisingly, cantharidin significantly accelerated xenograft growth. Living imaging showed a rapid distribution of D-luciferin in cantharidin-treated xenografts, suggesting a rich blood supply. Immunohistochemistry confirmed increased angiogenesis. Microarray and antibody array identified upregulated proangiogenic and downregulated antiangiogenic factors. The Milliplex assay suggested elevated secretion of IL-6, IL-8, TNF-alpha, and VEGF. Inhibitors of ERK, JNK, PKC, and NF-kappaB pathway attenuated the cantharidin-induced changes to proangiogenic gene expression. PKC pathway-inhibiting tamoxifen or antiangiogenic therapeutics, including Ginsenoside Rg3, bevacizumab, Apatinib, and Endostar, antagonized the proangiogenic effect of cantharidin or its derivatives. These regimens presented remarkable additive antitumor effects in vivo. Although cantharidin presents antitumor effects in vitro and has been applied in clinical practice, we revealed an unfavorable proangiogenic side effect. We recommend that the clinical application of cantharidin should be performed on the premise of antivascularization therapy. PMID- 30478300 TI - Evaluation of a preclinical photon-counting CT prototype for pulmonary imaging. AB - The purpose of this study was to investigate a preclinical spectral photon counting CT (SPCCT) prototype compared to conventional CT for pulmonary imaging. A custom-made lung phantom, including nodules of different sizes and shapes, was scanned with a preclinical SPCCT and a conventional CT in standard and high resolution (HR-CT) mode. Volume estimation was evaluated by linear regression. Shape similarity was evaluated with the Dice similarity coefficient. Spatial resolution was investigated via MTF for each imaging system. In-vivo rabbit lung images from the SPCCT system were subjectively reviewed. Evaluating the volume estimation, linear regression showed best results for the SPCCT compared to CT and HR-CT with a root mean squared error of 21.3 mm3, 28.5 mm3 and 26.4 mm3 for SPCCT, CT and HR-CT, respectively. The Dice similarity coefficient was superior for SPCCT throughout nodule shapes and all nodule sizes (mean, SPCCT: 0.90; CT: 0.85; HR-CT: 0.85). 10% MTF improved from 10.1 LP/cm for HR-CT to 21.7 LP/cm for SPCCT. Visual investigation of small pulmonary structures was superior for SPCCT in the animal study. In conclusion, the SPCCT prototype has the potential to improve the assessment of lung structures due to higher resolution compared to conventional CT. PMID- 30478301 TI - Zinc finger protein 32 promotes breast cancer stem cell-like properties through directly promoting GPER transcription. AB - Breast cancer is one of the leading causes of death in women. Due to the existence of a small fraction of stem cell-like subpopulations, some breast cancer subtypes exhibit very high malignancy and resistance to multiple therapies. The underlying mechanisms of how these subtypes acquire stem cell-like properties and progress more aggressively remain largely unknown. Zinc finger protein 32 (ZNF32), a newly discovered transcription factor, has been reported to be associated with breast cancer progression. However, many questions remain about its target genes and its exact mechanisms in regulating stem cell-like properties and drug resistance. In the present study, we examined the relationship between ZNF32 and GPER, a membrane-associated estrogen receptor, and we addressed their roles in stemness regulation in human breast cancer cell lines. Our results showed that ZNF32 could induce expansion of stem cell-like subpopulations and increase drug resistance by upregulating GPER expression, in which ERK activation was also implicated. We also illustrated that ZNF32 induced GPER expression via a ZNF32 binding sequence located within the GPER promoter region. A correlation between ZNF32/GPER expression and increased tumor incidence and burden was observed in xenograft mouse models. We conclude that ZNF32 can engage GPER/ERK signalling and confer breast cancer stem cell-like properties, which may indicate poor prognosis of breast cancer patients. ZNF32 and GPER targeted therapies might provide new solutions for breast cancer treatment. PMID- 30478304 TI - Encounters with archaic hominins. PMID- 30478305 TI - Multiple episodes of interbreeding between Neanderthal and modern humans. AB - Neanderthals and anatomically modern humans overlapped geographically for a period of over 30,000 years following human migration out of Africa. During this period, Neanderthals and humans interbred, as evidenced by Neanderthal portions of the genome carried by non-African individuals today. A key observation is that the proportion of Neanderthal ancestry is ~12-20% higher in East Asian individuals relative to European individuals. Here, we explore various demographic models that could explain this observation. These include distinguishing between a single admixture event and multiple Neanderthal contributions to either population, and the hypothesis that reduced Neanderthal ancestry in modern Europeans resulted from more recent admixture with a ghost population that lacked a Neanderthal ancestry component (the 'dilution' hypothesis). To summarize the asymmetric pattern of Neanderthal allele frequencies, we compiled the joint fragment frequency spectrum of European and East Asian Neanderthal fragments and compared it with both analytical theory and data simulated under various models of admixture. Using maximum-likelihood and machine learning, we found that a simple model of a single admixture did not fit the empirical data, and instead favour a model of multiple episodes of gene flow into both European and East Asian populations. These findings indicate a longer term, more complex interaction between humans and Neanderthals than was previously appreciated. PMID- 30478303 TI - IKKbeta activates p53 to promote cancer cell adaptation to glutamine deprivation. AB - One of the hallmarks of cancer is the ability to reprogram cellular metabolism to increase the uptake of necessary nutrients such as glucose and glutamine. Driven by oncogenes, cancer cells have increased glutamine uptake to support their highly proliferative nature. However, as cancer cells continue to replicate and grow, they lose access to vascular tissues and deplete local supply of nutrients and oxygen. We previously showed that many tumor cells situate in a low glutamine microenvironment in vivo, yet the mechanisms of how they are able to adapt to this metabolic stress are still not fully understood. Here, we report that IkappaB-kinase beta (IKKbeta) is needed to promote survival and its activation is accompanied by phosphorylation of the metabolic sensor, p53, in response to glutamine deprivation. Knockdown of IKKbeta decreases the level of wild-type and mutant p53 phosphorylation and its transcriptional activity, indicating a novel relationship between IKKbeta and p53 in mediating cancer cell survival in response to glutamine withdrawal. Phosphopeptide mass spectrometry analysis further reveals that IKKbeta phosphorylates p53 on Ser392 to facilitate its activation upon glutamine deprivation, independent of the NF-kappaB pathway. The results of this study offer an insight into the metabolic reprogramming in cancer cells that is dependent on a previously unidentified IKKbeta-p53 signaling axis in response to glutamine depletion. More importantly, this study highlights a new therapeutic strategy for cancer treatment and advances our understanding of adaptive mechanisms that could lead to resistance to current glutamine targeting therapies. PMID- 30478306 TI - How the entire scientific community can confront gender bias in the workplace. PMID- 30478302 TI - IL-4-dependent Jagged1 expression/processing is associated with survival of chronic lymphocytic leukemia cells but not with Notch activation. AB - As previously reported, chronic lymphocytic leukemia (CLL) cells show constitutive Notch1/2 activation and express the Notchligand Jagged1. Despite increasing knowledge of the impact of Notch alterations on CLL biology and pathogenesis, the role of Jagged1 expressed in CLL cells remains undefined. In other cell types, it has been shown that after Notch engagement, Jagged1 not only activates Notch in signal-receiving cell, but also undergoes proteolytic activation in signal-sending cell, triggering a signaling with biological effects. We investigated whether Jagged1 expressed in CLL cells undergoes proteolytic processing and/or is able to induce Notch activation through autocrine/paracrine loops, focusing on the effect that CLL prosurvival factor IL 4 could exert on the Notch-Jagged1 system in these cells. We found that Jagged1 was constitutively processed in CLL cells and generated an intracellular fragment that translocated into the nucleus, and an extracellular fragment released into the culture supernatant. IL-4 enhanced expression of Jagged1 and its intracellular fragments, as well as Notch1/2 activation. The IL-4-induced increase in Notch1/2 activation was independent of the concomitant upregulated Jagged1 levels. Indeed, blocking Notch-Jagged1 interactions among CLL cells with Jagged1 neutralizing antibodies did not affect the expression of the Notch target Hes1. Notably, anti-Jagged1 antibodies partially prevented the IL-4-induced increase in Jagged1 processing and cell viability, suggesting that Jagged1 processing is one of the events contributing to IL-4-induced CLL cell survival. Consistent with this, Jagged1 silencing by small interfering RNA partially counteracted the capacity of IL-4 to promote CLL cell survival. Investigating the pathways whereby IL-4 promoted Notch1/2 activation in CLL cells independent of Jagged1, we found that PI3Kdelta/AKT and PKCdelta were involved in upregulating Notch1 and Notch2 proteins, respectively. Overall, this study provides new insights into the Notch-ligand system in CLL cells and suggests that targeting this system may be exploited as a novel/additional therapy approach for CLL. PMID- 30478307 TI - Fires in protected areas reveal unforeseen costs of Colombian peace. AB - Armed conflict, and its end, can have powerful effects on natural resources, but the influence of war and peace on highly biodiverse tropical forests remains disputed. We found a sixfold increase in fires in protected areas across biodiversity hotspots following guerrilla demobilization in Colombia, and a 52% increase in the probability of per-pixel deforestation within parks for 2018. Peace requires urgent shifts to include real-time forest monitoring, expand programmes to pay for ecosystem services at the frontier, integrate demobilized armed groups as staff of protected areas, and establish a domestic market for frontier deforestation permits. PMID- 30478308 TI - Evolution and extinction of the giant rhinoceros Elasmotherium sibiricum sheds light on late Quaternary megafaunal extinctions. AB - Understanding extinction events requires an unbiased record of the chronology and ecology of victims and survivors. The rhinoceros Elasmotherium sibiricum, known as the 'Siberian unicorn', was believed to have gone extinct around 200,000 years ago-well before the late Quaternary megafaunal extinction event. However, no absolute dating, genetic analysis or quantitative ecological assessment of this species has been undertaken. Here, we show, by accelerator mass spectrometry radiocarbon dating of 23 individuals, including cross-validation by compound specific analysis, that E. sibiricum survived in Eastern Europe and Central Asia until at least 39,000 years ago, corroborating a wave of megafaunal turnover before the Last Glacial Maximum in Eurasia, in addition to the better-known late glacial event. Stable isotope data indicate a dry steppe niche for E. sibiricum and, together with morphology, a highly specialized diet that probably contributed to its extinction. We further demonstrate, with DNA sequencing data, a very deep phylogenetic split between the subfamilies Elasmotheriinae and Rhinocerotinae that includes all the living rhinoceroses, settling a debate based on fossil evidence and confirming that the two lineages had diverged by the Eocene. As the last surviving member of the Elasmotheriinae, the demise of the 'Siberian unicorn' marked the extinction of this subfamily. PMID- 30478309 TI - Reef fish functional traits evolve fastest at trophic extremes. AB - Trophic ecology is thought to exert a profound influence on biodiversity, but the specifics of the process are rarely examined at large spatial and evolutionary scales. We investigate how trophic position and diet breadth influence functional trait evolution in one of the most species-rich and complex vertebrate assemblages, coral reef fishes, within a large-scale phylogenetic framework. We show that, in contrast with established theory, functional traits evolve fastest in trophic specialists with narrow diet breadths at both very low and high trophic positions. Top trophic level specialists exhibit the most functional diversity, while omnivorous taxa with intermediate trophic positions and wide diet breadth have the least functional diversity. Our results reveal the importance of trophic position in shaping evolutionary dynamics while simultaneously highlighting the incredible trophic and functional diversity present in coral reef fish assemblages. PMID- 30478311 TI - Different effect of hydroxyurea and phlebotomy on prevention of arterial and venous thrombosis in Polycythemia Vera. PMID- 30478310 TI - VDAC2 enables BAX to mediate apoptosis and limit tumor development. AB - Intrinsic apoptosis is critical to prevent tumor formation and is engaged by many anti-cancer agents to eliminate tumor cells. BAX and BAK, the two essential mediators of apoptosis, are thought to be regulated through similar mechanisms and act redundantly to drive apoptotic cell death. From an unbiased genome-wide CRISPR/Cas9 screen, we identified VDAC2 (voltage-dependent anion channel 2) as important for BAX, but not BAK, to function. Genetic deletion of VDAC2 abrogated the association of BAX and BAK with mitochondrial complexes containing VDAC1, VDAC2, and VDAC3, but only inhibited BAX apoptotic function. Deleting VDAC2 phenocopied the loss of BAX in impairing both the killing of tumor cells by anti cancer agents and the ability to suppress tumor formation. Together, our studies show that efficient BAX-mediated apoptosis depends on VDAC2, and reveal a striking difference in how BAX and BAK are functionally impacted by their interactions with VDAC2. PMID- 30478312 TI - Structural basis of RIP2 activation and signaling. AB - Signals arising from bacterial infections are detected by pathogen recognition receptors (PRRs) and are transduced by specialized adapter proteins in mammalian cells. The Receptor-interacting-serine/threonine-protein kinase 2 (RIPK2 or RIP2) is such an adapter protein that is critical for signal propagation of the Nucleotide-binding-oligomerization-domain-containing proteins 1/2 (NOD1 and NOD2). Dysregulation of this signaling pathway leads to defects in bacterial detection and in some cases autoimmune diseases. Here, we show that the Caspase activation-and-recruitment-domain (CARD) of RIP2 (RIP2-CARD) forms oligomeric structures upon stimulation by either NOD1-CARD or NOD2-2CARD. We reconstitute this complex, termed the RIPosome in vitro and solve the cryo-EM filament structure of the active RIP2-CARD complex at 4.1 A resolution. The structure suggests potential mechanisms by which CARD domains from NOD1 and NOD2 initiate the oligomerization process of RIP2-CARD. Together with structure guided mutagenesis experiments at the CARD-CARD interfaces, we demonstrate molecular mechanisms how RIP2 is activated and self-propagating such signal. PMID- 30478314 TI - National and sub-national variation in patterns of febrile case management in sub Saharan Africa. AB - Given national healthcare coverage gaps, understanding treatment-seeking behaviour for fever is crucial for the management of childhood illness and to reduce deaths. Here, we conduct a modelling study triangulating household survey data for fever in children under the age of five years with georeferenced public health facility databases (n = 86,442 facilities) in 29 countries across sub Saharan Africa, to estimate the probability of seeking treatment for fever at public facilities. A Bayesian item response theory framework is used to estimate this probability based on reported fever episodes, treatment choice, residence, and estimated travel-time to the nearest public-sector health facility. Findings show inter- and intra-country variation, with the likelihood of seeking treatment for fever less than 50% in 16 countries. Results highlight the need to invest in public healthcare and related databases. The variation in public sector use illustrates the need to include such modelling in future infectious disease burden estimation. PMID- 30478313 TI - Genetic variation in PTPN1 contributes to metabolic adaptation to high-altitude hypoxia in Tibetan migratory locusts. AB - Animal and human highlanders have evolved distinct traits to enhance tissue oxygen delivery and utilization. Unlike vertebrates, insects use their tracheal system for efficient oxygen delivery. However, the genetic basis of insect adaptation to high-altitude hypoxia remains unexplored. Here, we report a potential mechanism of metabolic adaptation of migratory locusts in the Tibetan Plateau, through whole-genome resequencing and functional investigation. A genome wide scan revealed that the positively selected genes in Tibetan locusts are predominantly involved in carbon and energy metabolism. We observed a notable signal of natural selection in the gene PTPN1, which encodes PTP1B, an inhibitor of insulin signaling pathway. We show that a PTPN1 coding mutation regulates the metabolism of Tibetan locusts by mediating insulin signaling activity in response to hypoxia. Overall, our findings provide evidence for the high-altitude hypoxia adaptation of insects at the genomic level and explore a potential regulatory mechanism underlying the evolved metabolic homeostasis. PMID- 30478315 TI - Adipocyte-secreted BMP8b mediates adrenergic-induced remodeling of the neuro vascular network in adipose tissue. AB - Activation of brown adipose tissue-mediated thermogenesis is a strategy for tackling obesity and promoting metabolic health. BMP8b is secreted by brown/beige adipocytes and enhances energy dissipation. Here we show that adipocyte-secreted BMP8b contributes to adrenergic-induced remodeling of the neuro-vascular network in adipose tissue (AT). Overexpression of bmp8b in AT enhances browning of the subcutaneous depot and maximal thermogenic capacity. Moreover, BMP8b-induced browning, increased sympathetic innervation and vascularization of AT were maintained at 28 degrees C, a condition of low adrenergic output. This reinforces the local trophic effect of BMP8b. Innervation and vascular remodeling effects required BMP8b signaling through the adipocytes to 1) secrete neuregulin 4 (NRG4), which promotes sympathetic axon growth and branching in vitro, and 2) induce a pro-angiogenic transcriptional and secretory profile that promotes vascular sprouting. Thus, BMP8b and NRG4 can be considered as interconnected regulators of neuro-vascular remodeling in AT and are potential therapeutic targets in obesity. PMID- 30478316 TI - Unravelling the effect of charge dynamics at the plasmonic metal/semiconductor interface for CO2 photoreduction. AB - Sunlight plays a critical role in the development of emerging sustainable energy conversion and storage technologies. Light-induced CO2 reduction by artificial photosynthesis is one of the cornerstones to produce renewable fuels and environmentally friendly chemicals. Interface interactions between plasmonic metal nanoparticles and semiconductors exhibit improved photoactivities under a wide range of the solar spectrum. However, the photo-induced charge transfer processes and their influence on photocatalysis with these materials are still under debate, mainly due to the complexity of the involved routes occurring at different timescales. Here, we use a combination of advanced in situ and time resolved spectroscopies covering different timescales, combined with theoretical calculations, to unravel the overall mechanism of photocatalytic CO2 reduction by Ag/TiO2 catalysts. Our findings provide evidence of the key factors determining the enhancement of photoactivity under ultraviolet and visible irradiation, which have important implications for the design of solar energy conversion materials. PMID- 30478317 TI - CBX2 identified as driver of anoikis escape and dissemination in high grade serous ovarian cancer. AB - High grade serous ovarian carcinoma (HGSOC) is often diagnosed at an advanced stage. Chromobox 2 (CBX2), a polycomb repressor complex subunit, plays an oncogenic role in other cancers, but little is known about its role in HGSOC. We hypothesize that CBX2 upregulation promotes HGSOC via induction of a stem-like transcriptional profile and inhibition of anoikis. Examination of Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas (TCGA) established that increased CBX2 expression conveyed chemoresistance and worse disease-free and overall survival. In primary HGSOC tumors, we observed CBX2 expression was significantly elevated compared to benign counterparts. In HGSOC cell lines, forced suspension promoted CBX2 expression. Subsequently, CBX2 knockdown inhibited anchorage-independent proliferation and potentiated anoikis-dependent apoptosis. Furthermore, CBX2 knockdown re-sensitized cells to platinum-based chemotherapy. Forced suspension promoted increased ALDH activity and ALDH3A1 expression and CBX2 knockdown led to a decrease in both ALDH activity and ALDH3A1 expression. Investigation of CBX2 expression on a HGSOC tissue microarray revealed CBX2 expression was apparent in both primary and metastatic tissues. CBX2 is an important regulator of stem-ness, anoikis escape, HGSOC dissemination, and chemoresistance and potentially serves as a novel therapeutic target. PMID- 30478318 TI - A quaternary tetramer assembly inhibits the deubiquitinating activity of USP25. AB - USP25 deubiquitinating enzyme is a key member of the ubiquitin system, which acts as a positive regulator of the Wnt/beta-catenin signaling by promoting the deubiquitination and stabilization of tankyrases. USP25 is characterized by the presence of a long insertion in the middle of the conserved catalytic domain. The crystal structure of USP25 displays an unexpected homotetrameric quaternary assembly that is directly involved in the inhibition of its enzymatic activity. The tetramer is assembled by the association of two dimers and includes contacts between the coiled-coil insertion domain and the ubiquitin-binding pocket at the catalytic domain, revealing a distinctive autoinhibitory mechanism. Biochemical and kinetic assays with dimer, tetramer and truncation constructs of USP25 support this mechanism, displaying higher catalytic activity in the dimer assembly. Moreover, the high stabilization of tankyrases in cultured cells by ectopic expression of a constitutive dimer of USP25 supports a biological relevance of this tetramerization/inhibition mechanism. PMID- 30478319 TI - Competition between proton transfer and intermolecular Coulombic decay in water. AB - Intermolecular Coulombic decay (ICD) is a ubiquitous relaxation channel of electronically excited states in weakly bound systems, ranging from dimers to liquids. As it is driven by electron correlation, it was assumed that it will dominate over more established energy loss mechanisms, for example fluorescence. Here, we use electron-electron coincidence spectroscopy to determine the efficiency of the ICD process after 2a1 ionization in water clusters. We show that this efficiency is surprisingly low for small water clusters and that it gradually increases to 40-50% for clusters with hundreds of water units. Ab initio molecular dynamics simulations reveal that proton transfer between neighboring water molecules proceeds on the same timescale as ICD and leads to a configuration in which the ICD channel is closed. This conclusion is further supported by experimental results from deuterated water. Combining experiment and theory, we infer an intrinsic ICD lifetime of 12-52 fs for small water clusters. PMID- 30478320 TI - High-speed AFM height spectroscopy reveals us-dynamics of unlabeled biomolecules. AB - Dynamics are fundamental to the functions of biomolecules and can occur on a wide range of time and length scales. Here we develop and apply high-speed AFM height spectroscopy (HS-AFM-HS), a technique whereby we monitor the sensing of a HS-AFM tip at a fixed position to directly detect the motions of unlabeled molecules underneath. This gives Angstrom spatial and microsecond temporal resolutions. In conjunction with HS-AFM imaging modes to precisely locate areas of interest, HS AFM-HS measures simultaneously surface concentrations, diffusion coefficients and oligomer sizes of annexin-V on model membranes to decipher key kinetics allowing us to describe the entire annexin-V membrane-association and self-assembly process in great detail and quantitatively. This work displays how HS-AFM-HS can assess the dynamics of unlabeled bio-molecules over several orders of magnitude and separate the various dynamic components spatiotemporally. PMID- 30478321 TI - Acoustic tweezers for the life sciences. AB - Acoustic tweezers are a versatile set of tools that use sound waves to manipulate bioparticles ranging from nanometer-sized extracellular vesicles to millimeter sized multicellular organisms. Over the past several decades, the capabilities of acoustic tweezers have expanded from simplistic particle trapping to precise rotation and translation of cells and organisms in three dimensions. Recent advances have led to reconfigured acoustic tweezers that are capable of separating, enriching, and patterning bioparticles in complex solutions. Here, we review the history and fundamentals of acoustic-tweezer technology and summarize recent breakthroughs. PMID- 30478322 TI - Faster, sharper, and deeper: structured illumination microscopy for biological imaging. AB - Structured illumination microscopy (SIM) allows rapid, super-resolution (SR) imaging in live specimens. We review recent technical advances in SR-SIM, with emphasis on imaging speed, resolution, and depth. Since its introduction decades ago, the technique has grown to offer myriad implementations, each with its own strengths and weaknesses. We discuss these, aiming to provide a practical guide for biologists and to highlight which approach is best suited to a given application. PMID- 30478323 TI - Found In Translation: a machine learning model for mouse-to-human inference. AB - Cross-species differences form barriers to translational research that ultimately hinder the success of clinical trials, yet knowledge of species differences has yet to be systematically incorporated in the interpretation of animal models. Here we present Found In Translation (FIT; http://www.mouse2man.org ), a statistical methodology that leverages public gene expression data to extrapolate the results of a new mouse experiment to expression changes in the equivalent human condition. We applied FIT to data from mouse models of 28 different human diseases and identified experimental conditions in which FIT predictions outperformed direct cross-species extrapolation from mouse results, increasing the overlap of differentially expressed genes by 20-50%. FIT predicted novel disease-associated genes, an example of which we validated experimentally. FIT highlights signals that may otherwise be missed and reduces false leads, with no experimental cost. PMID- 30478324 TI - Proximity-CLIP provides a snapshot of protein-occupied RNA elements in subcellular compartments. AB - Methods for the systematic study of subcellular RNA localization are limited, and their development has lagged behind that of proteomic tools. We combined APEX2 mediated proximity biotinylation of proteins with photoactivatable ribonucleoside enhanced crosslinking to simultaneously profile the proteome and the transcriptome bound by RNA-binding proteins in any given subcellular compartment. Our approach is fractionation independent and allows study of the localization of RNA processing intermediates, as well as the identification of regulatory RNA cis acting elements occupied by proteins, in a cellular-compartment-specific manner. We used our method, Proximity-CLIP, to profile RNA and protein in the nucleus, in the cytoplasm, and at cell-cell interfaces. Among other insights, we observed frequent transcriptional readthrough continuing for several kilobases downstream of the canonical cleavage and polyadenylation site and a differential RBP occupancy pattern for mRNAs in the nucleus and cytoplasm. We observed that mRNAs localized to cell-cell interfaces often encoded regulatory proteins and contained protein-occupied CUG sequence elements in their 3' untranslated region. PMID- 30478325 TI - Interpretation of an individual functional genomics experiment guided by massive public data. AB - A key unmet challenge in interpreting omics experiments is inferring biological meaning in the context of public functional genomics data. We developed a computational framework, Your Evidence Tailored Integration (YETI; http://yeti.princeton.edu/ ), which creates specialized functional interaction maps from large public datasets relevant to an individual omics experiment. Using this tailored integration, we predicted and experimentally confirmed an unexpected divergence in viral replication after seasonal or pandemic human influenza virus infection. PMID- 30478326 TI - Content-aware image restoration: pushing the limits of fluorescence microscopy. AB - Fluorescence microscopy is a key driver of discoveries in the life sciences, with observable phenomena being limited by the optics of the microscope, the chemistry of the fluorophores, and the maximum photon exposure tolerated by the sample. These limits necessitate trade-offs between imaging speed, spatial resolution, light exposure, and imaging depth. In this work we show how content-aware image restoration based on deep learning extends the range of biological phenomena observable by microscopy. We demonstrate on eight concrete examples how microscopy images can be restored even if 60-fold fewer photons are used during acquisition, how near isotropic resolution can be achieved with up to tenfold under-sampling along the axial direction, and how tubular and granular structures smaller than the diffraction limit can be resolved at 20-times-higher frame rates compared to state-of-the-art methods. All developed image restoration methods are freely available as open source software in Python, FIJI, and KNIME. PMID- 30478327 TI - Systematic review of indoor residual spray efficacy and effectiveness against Plasmodium falciparum in Africa. AB - Indoor residual spraying (IRS) is an important part of malaria control. There is a growing list of insecticide classes; pyrethroids remain the principal insecticide used in bednets but recently, novel non-pyrethroid IRS products, with contrasting impacts, have been introduced. There is an urgent need to better assess product efficacy to help decision makers choose effective and relevant tools for mosquito control. Here we use experimental hut trial data to characterise the entomological efficacy of widely-used, novel IRS insecticides. We quantify their impact against pyrethroid-resistant mosquitoes and use a Plasmodium falciparum transmission model to predict the public health impact of different IRS insecticides. We report that long-lasting IRS formulations substantially reduce malaria, though their benefit over cheaper, shorter-lived formulations depends on local factors including bednet use, seasonality, endemicity and pyrethroid resistance status of local mosquito populations. We provide a framework to help decision makers evaluate IRS product effectiveness. PMID- 30478328 TI - Heart enhancers with deeply conserved regulatory activity are established early in zebrafish development. AB - During the phylotypic period, embryos from different genera show similar gene expression patterns, implying common regulatory mechanisms. Here we set out to identify enhancers involved in the initial events of cardiogenesis, which occurs during the phylotypic period. We isolate early cardiac progenitor cells from zebrafish embryos and characterize 3838 open chromatin regions specific to this cell population. Of these regions, 162 overlap with conserved non-coding elements (CNEs) that also map to open chromatin regions in human. Most of the zebrafish conserved open chromatin elements tested drive gene expression in the developing heart. Despite modest sequence identity, human orthologous open chromatin regions recapitulate the spatial temporal expression patterns of the zebrafish sequence, potentially providing a basis for phylotypic gene expression patterns. Genome wide, we discover 5598 zebrafish-human conserved open chromatin regions, suggesting that a diverse repertoire of ancient enhancers is established prior to organogenesis and the phylotypic period. PMID- 30478329 TI - Bee venom phospholipase A2 ameliorates Alzheimer's disease pathology in Abeta vaccination treatment without inducing neuro-inflammation in a 3xTg-AD mouse model. AB - Alzheimer's disease (AD) is the most common form of dementia and is characterized by an imbalance between the production and clearance of amyloid-beta (Abeta) and tau proteins. Although vaccination against Abeta peptide results in a dramatic reduction in Abeta pathology in experimental mouse models, the initial clinical trial for an active Abeta vaccine was halted early due to the development of acute meningoencephalitis in 6% of the immunized patients, which likely involved a T-cell mediated pro-inflammatory response. In this study, we aimed to determine whether bee venom phospholipase A2 (bvPLA2) treatment would induce Tregs and ameliorate AD pathology without unwanted T cell-mediated inflammation. First, we investigated the effects of bvPLA2 on the inflammatory infiltration caused by Abeta vaccination. Inflammatory aggregates of CD3+ T lymphocytes and macrophages were found in the brains and spinal cords of mice treated with Abeta. However, administration of bvPLA2 dramatically eliminated central nervous system inflammation following Abeta immunization. In AD model mice (3xTg-AD mice), bvPLA2 administration significantly ameliorated cognitive deficits and reduced Abeta burdens in the brains of Abeta-vaccinated 3xTg-AD mice. Additionally, we examined brain glucose metabolism using positron emission tomography with 18F-2 fluoro-2-deoxy-D-glucose. Cerebral glucose uptake was considerably higher in the brains of Abeta-vaccinated 3xTg-AD mice that received bvPLA2 than those that did not. The present study suggests that the modulation of Treg populations via bvPLA2 treatment may be a new therapeutic approach to attenuate the progression of AD in conjunction with Abeta vaccination therapy without an adverse inflammatory response. PMID- 30478330 TI - Molecular pain markers correlate with pH-sensitive MRI signal in a pig model of disc degeneration. AB - Intervertebral disc (IVD) degeneration is a leading cause of chronic low back pain that affects millions of people every year. Yet identification of the specific IVD causing this pain is based on qualitative visual interpretation rather than objective findings. One possible approach to diagnosing pain associated IVD could be to identify acidic IVDs, as decreased pH within an IVD has been postulated to mediate discogenic pain. We hypothesized that quantitative chemical exchange saturation transfer (qCEST) MRI could detect pH changes in IVDs, and thence be used to diagnose pathologically painful IVDs objectively and noninvasively. To test this hypothesis, a surgical model of IVD degeneration in Yucatan minipigs was used. Direct measurement of pH inside the degenerated IVDs revealed a significant drop in pH after degeneration, which correlated with a significant increase in the qCEST signal. Gene analysis of harvested degenerated IVDs revealed significant upregulation of pain-, nerve- and inflammatory-related markers after IVD degeneration. A strong positive correlation was observed between the expression of pain markers and the increase in the qCEST signal. Collectively, these findings suggest that this approach might be used to identify which IVD is causing low back pain, thereby providing valuable guidance for pain and surgical management. PMID- 30478331 TI - Unicolored phosphor-sensitized fluorescence for efficient and stable blue OLEDs. AB - Improving lifetimes and efficiencies of blue organic light-emitting diodes is clearly a scientific challenge. Towards solving this challenge, we propose a unicolored phosphor-sensitized fluorescence approach, with phosphorescent and fluorescent emitters tailored to preserve the initial color of phosphorescence. Using this approach, we design an efficient sky-blue light-emitting diode with radiative decay times in the submicrosecond regime. By changing the concentration of fluorescent emitter, we show that the lifetime is proportional to the reduction of the radiative decay time and tune the operational stability to lifetimes of up to 320 h (80% decay, initial luminance of 1000 cd/m2). Unicolored phosphor-sensitized fluorescence provides a clear path towards efficient and stable blue light-emitting diodes, helping to overcome the limitations of thermally activated delayed fluorescence. PMID- 30478332 TI - A novel fluorescein-bisphosphonate based diagnostic tool for the detection of hydroxyapatite in both cell and tissue models. AB - A rapid and efficient method for the detection of hydroxyapatite (HAP) has been developed which shows superiority to existing well-established methods. This fluorescein-bisphosphonate probe is highly selective for HAP over other calcium minerals and is capable of detecting lower levels of calcification in cellular models than either hydrochloric acid-based calcium leaching assays or the Alizarin S stain. The probe has been shown to be effective in both in vitro vascular calcification models and in vitro bone calcification models. Moreover we have demonstrated binding of this probe to vascular calcification in rat aorta and to areas of microcalcification, in human vascular tissue, beyond the resolution of computed tomography in human atherosclerotic plaques. Fluorescein BP is therefore a highly sensitive and specific imaging probe for the detection of vascular calcification, with the potential to improve not only ex vivo assessments of HAP deposition but also the detection of vascular microcalcification in humans. PMID- 30478335 TI - Coordinated Regulation of Axonal Microtubule Organization and Transport by Drosophila Neurexin and BMP Pathway. AB - Neurexins are well known trans-synaptic cell adhesion molecules that are required for proper synaptic development and function across species. Beyond synapse organization and function, little is known about other roles Neurexins might have in the nervous system. Here we report novel phenotypic consequences of mutations in Drosophila neurexin (dnrx), which alters axonal microtubule organization and transport. We show that dnrx mutants display phenotypic similarities with the BMP receptor wishful thinking (wit) and one of the downstream effectors, futsch, which is a known regulator of microtubule organization and stability. dnrx has genetic interactions with wit and futsch. Loss of Dnrx also results in reduced levels of other downstream effectors of BMP signaling, phosphorylated-Mad and Trio. Interestingly, postsynaptic overexpression of the BMP ligand, Glass bottom boat, in dnrx mutants partially rescues the axonal transport defects but not the synapse undergrowth at the neuromuscular junctions. These data suggest that Dnrx and BMP signaling are involved in many diverse functions and that regulation of axonal MT organization and transport might be distinct from regulation of synaptic growth in dnrx mutants. Together, our work uncovers a novel function of Drosophila Neurexin and may provide insights into functions of Neurexins in vertebrates. PMID- 30478334 TI - Corneal Confocal Microscopy detects a Reduction in Corneal Endothelial Cells and Nerve Fibres in Patients with Acute Ischemic Stroke. AB - Endothelial dysfunction and damage underlie cerebrovascular disease and ischemic stroke. We undertook corneal confocal microscopy (CCM) to quantify corneal endothelial cell and nerve morphology in 146 patients with an acute ischemic stroke and 18 age-matched healthy control participants. Corneal endothelial cell density was lower (P < 0.001) and endothelial cell area (P < 0.001) and perimeter (P < 0.001) were higher, whilst corneal nerve fibre density (P < 0.001), corneal nerve branch density (P < 0.001) and corneal nerve fibre length (P = 0.001) were lower in patients with acute ischemic stroke compared to controls. Corneal endothelial cell density, cell area and cell perimeter correlated with corneal nerve fiber density (P = 0.033, P = 0.014, P = 0.011) and length (P = 0.017, P = 0.013, P = 0.008), respectively. Multiple linear regression analysis showed a significant independent association between corneal endothelial cell density, area and perimeter with acute ischemic stroke and triglycerides. CCM is a rapid non-invasive ophthalmic imaging technique, which could be used to identify patients at risk of acute ischemic stroke. PMID- 30478333 TI - The Virtual-Environment-Foraging Task enables rapid training and single-trial metrics of attention in head-fixed mice. AB - Attention - the flexible allocation of processing resources based on behavioural demands - is essential to survival. Mouse research offers unique tools to dissect the underlying pathways, but is hampered by the difficulty of accurately measuring attention in mice. Current attention tasks for mice face several limitations: Binary (hit/miss), temporally imprecise metrics, behavioural confounds and overtraining. Thus, despite the increasing scope of neuronal population measurements, insights are limited without equally precise behavioural measures. Here we present a virtual-environment task for head-fixed mice based on 'foraging-like' navigation. The task requires animals to discriminate gratings at orientation differences from 90 degrees to 5 degrees , and can be learned in only 3-5 sessions (<550 trials). It yields single-trial, non-binary metrics of response speed and accuracy, which generate secondary metrics of choice certainty, visual acuity, and most importantly, of sustained and cued attention - two attentional components studied extensively in humans. This allows us to examine single-trial dynamics of attention in mice, independently of confounds like rule learning. With this approach, we show that C57/BL6 mice have better visual acuity than previously measured, that they rhythmically alternate between states of high and low alertness, and that they can be prompted to adopt different performance strategies using minute changes in reward contingencies. PMID- 30478336 TI - Spectral interferometry with waveform-dependent relativistic high-order harmonics from plasma surfaces. AB - The interaction of ultra-intense laser pulses with matter opened the way to generate the shortest light pulses available nowadays in the attosecond regime. Ionized solid surfaces, also called plasma mirrors, are promising tools to enhance the potential of attosecond sources in terms of photon energy, photon number and duration especially at relativistic laser intensities. Although the production of isolated attosecond pulses and the understanding of the underlying interactions represent a fundamental step towards the realization of such sources, these are challenging and have not yet been demonstrated. Here, we present laser-waveform-dependent high-order harmonic radiation in the extreme ultraviolet spectral range supporting well-isolated attosecond pulses, and utilize spectral interferometry to understand its relativistic generation mechanism. This unique interpretation of the measured spectra provides access to unrevealed temporal and spatial properties such as spectral phase difference between attosecond pulses and field-driven plasma surface motion during the process. PMID- 30478337 TI - Investigation of the phosphorylation of Bacillus subtilis LTA synthases by the serine/threonine kinase PrkC. AB - Bacillus subtilis possesses four lipoteichoic acid synthases LtaS, YfnI, YvgJ and YqgS involved in the synthesis of cell wall. The crystal structure of the extracellular domain of LtaS revealed a phosphorylated threonine and YfnI was identified in two independent phosphoproteome studies. Here, we show that the four LTA synthases can be phosphorylated in vitro by the Ser/Thr kinase PrkC. Phosphorylation neither affects the export/release of YfnI nor its substrate binding. However, we observed that a phosphomimetic form of YfnI was active whereas its phosphoablative form was inactive. The phenotypes of the strains deleted for prkC or prpC (coding for a phosphatase) are fairly similar to those of the strains producing the phosphoablative or phosphomimetic YfnI proteins. Clear evidence proving that PrkC phosphorylates YfnI in vivo is still missing but our data suggest that the activity of all LTA synthases may be regulated by phosphorylation. Nonetheless, their function is non-redundant in cell. Indeed, the deletion of either ltaS or yfnI gene could restore a normal growth and shape to a DeltayvcK mutant strain but this was not the case for yvgJ or yqgS. The synthesis of cell wall must then be highly regulated to guarantee correct morphogenesis whatever the growth conditions. PMID- 30478338 TI - High glycolytic activity of tumor cells leads to underestimation of electron transport system capacity when mitochondrial ATP synthase is inhibited. AB - This study sought to elucidate how oligomycin, an ATP synthase blocker, leads to underestimation of maximal oxygen consumption rate (maxOCR) and spare respiratory capacity (SRC) in tumor cells. T98G and U-87MG glioma cells were titrated with the protonophore CCCP to induce maxOCR. The presence of oligomycin (0.3-3.0 ug/mL) led to underestimation of maxOCR and a consequent decrease in SRC values of between 25% and 40% in medium containing 5.5 or 11 mM glucose. The inhibitory effect of oligomycin on CCCP-induced maxOCR did not occur when glutamine was the metabolic substrate or when the glycolytic inhibitor 2-deoxyglucose was present. ATP levels were reduced and ADP/ATP ratios increased in cells treated with CCCP, but these changes were minimized when oligomycin was used to inhibit reverse activity of ATP synthase. Exposing digitonin-permeabilized cells to exogenous ATP, but not ADP, resulted in partial inhibition of CCCP-induced maxOCR. We conclude that underestimation of maxOCR and SRC in tumor cells when ATP synthase is inhibited is associated with high glycolytic activity and that the glycolytic ATP yield may have an inhibitory effect on the metabolism of respiratory substrates and cytochrome c oxidase activity. Under CCCP-induced maxOCR, oligomycin preserves intracellular ATP by inhibiting ATP synthase reverse activity. PMID- 30478339 TI - HIF-2alpha, but not HIF-1alpha, mediates hypoxia-induced up-regulation of Flt-1 gene expression in placental trophoblasts. AB - Placental hypoxia and elevated levels of circulating soluble Fms-like tyrosine kinase-1 (sFlt-1), an anti-angiogenic factor, are closely related to the pathogenesis of preeclampsia. Although sFlt-1 secretion from the placental trophoblasts is increased under hypoxic conditions, the underlying molecular mechanism remains unclear. Previously, an authentic hypoxia response element in the Flt-1 gene promoter was shown to be a potential binding site for hypoxia inducible factors (HIFs). Here, we investigated the roles of HIF-1alpha and HIF 2alpha in Flt-1 gene expression in trophoblast-derived choriocarcinoma cell lines and cytotrophoblasts exposed to hypoxic conditions. In the cell lines, increased expression of sFlt-1 splice variants and nuclear accumulation of HIF-1alpha and HIF-2alpha were observed after hypoxic stimulation. A specific small interfering RNA or an inhibitor molecule targeting HIF-2alpha decreased hypoxia-induced up regulation of Flt-1 gene expression. Moreover, in cytotrophoblasts, increased sFlt-1 mRNA expression and elevated sFlt-1 production were induced by hypoxic stimulation. Notably, hypoxia-induced elevation of sFlt-1 secretion from the cytotrophoblasts was inhibited by silencing the HIF-2alpha, but not HIF-1alpha mRNA. These findings suggest that hypoxia-induced activation of HIF-2alpha is essential for the increased production of sFlt-1 proteins in trophoblasts. Targeting the HIF-2alpha may be a novel strategy for the treatment of preeclampsia. PMID- 30478340 TI - Selective tracking of FFAR3-expressing neurons supports receptor coupling to N type calcium channels in mouse sympathetic neurons. AB - Activation of short-chain free fatty acid receptors 3 (FFAR3) has been suggested to promote sympathetic outflow in postganglionic sympathetic neurons or hamper it by a negative coupling to N-type calcium (CaV2.2) channels. Heterogeneity of FFAR3 expression in sympathetic neurons, however, renders single neurons studies extremely time-consuming in wild-type mice. Previous studies demonstrated large variability of the degree of CaV2.2 channel inhibition by FFAR3 in a global population of rat sympathetic neurons. Therefore, we focused on a small subpopulation of mouse sympathetic neurons using an FFAR3 antibody and an Ffar3 reporter mouse to perform immunofluorescent and electrophysiological studies. Whole-cell patch-clamp recordings of identified FFAR3-expressing neurons from reporter mice revealed a 2.5-fold decrease in the CaV2.2-FFAR3 inhibitory coupling variability and 1.5-fold increase in the mean ICa2+ inhibition, when compared with unlabeled neurons from wild-type mice. Further, we found that the ablation of Ffar3 gene expression in two knockout mouse models led to a complete loss-of-function. Subpopulations of sympathetic neurons are associated with discrete functional pathways. However, little is known about the neural pathways of the FFAR3-expressing subpopulation. Our data indicate that FFAR3 is expressed primarily in neurons with a vasoconstrictor phenotype. Thus, fine-tuning of chemically-coded neurotransmitters may accomplish an adequate outcome. PMID- 30478341 TI - Transmission of Cricket paralysis virus via exosome-like vesicles during infection of Drosophila cells. AB - Viruses are classically characterized as being either enveloped or nonenveloped depending on the presence or absence of a lipid bi-layer surrounding their proteinaceous capsid. In recent years, many studies have challenged this view by demonstrating that some nonenveloped viruses (e.g. hepatitis A virus) can acquire an envelope during infection by hijacking host cellular pathways. In this study, we examined the role of exosome-like vesicles (ELVs) during infection of Drosophilia melanogaster S2 cells by Cricket paralysis virus (CrPV). Utilizing quantitative proteomics, we demonstrated that ELVs can be isolated from both mock and CrPV-infected S2 cells that contain distinct set of proteins compared to the cellular proteome. Moreover, 40 proteins increased in abundance in ELVs derived from CrPV-infected cells compared to mock, suggesting specific factors associate with ELVs during infection. Interestingly, peptides from CrPV capsid proteins (ORF2) and viral RNA were detected in ELVs from infected cells. Finally, ELVs from CrPV-infected cells are infectious suggesting that CrPV may hijack ELVs to acquire an envelope during infection of S2 cells. This study further demonstrates the diverse strategies of nonenveloped viruses from invertebrates to vertebrates to acquire an envelope in order to evade the host response or facilitate transmission. PMID- 30478342 TI - Complete mitochondrial genome of Black Soft-shell Turtle (Nilssonia nigricans) and comparative analysis with other Trionychidae. AB - The characterization of mitochondrial genome has been evidenced as an efficient field of study for phylogenetic and evolutionary analysis in vertebrates including turtles. The aim of this study was to distinguish the structure and variability of the Trionychidae species mitogenomes through comparative analysis. The complete mitogenome (16796 bp) of an endangered freshwater turtle, Nilssonia nigricans was sequenced and annotated. The mitogenome encoded for 37 genes and a major non-coding control region (CR). The mitogenome was A + T biased (62.16%) and included six overlapping and 19 intergenic spacer regions. The Relative synonymous codon usage (RSCU) value was consistent among all the Trionychidae species; with the exception of significant reduction of Serine (TCG) frequency in N. nigricans, N. formosa, and R. swinhoei. In N. nigricans, most of the transfer RNAs (tRNAs) were folded into classic clover-leaf secondary structures with Watson-Crick base pairing except for trnS1 (GCT). The comparative analysis revealed that most of the tRNAs were structurally different, except for trnE (TTC), trnQ (TTG), and trnM (CAT). The structural features of tRNAs resulted >= 10 mismatched or wobble base pairings in 12 tRNAs, which reflects the nucleotide composition in both H- and L-strands. The mitogenome of N. nigricans also revealed two unique tandem repeats (ATTAT)8, and (TATTA)20 in the CR. Further, the conserved motif 5'-GACATA-3' and stable stem-loop structure was detected in the CRs of all Trionychidae species, which play an significant role in regulating transcription and replication in the mitochondrial genome. Further, the comparative analysis of Ka/Ks indicated negative selection in most of the protein coding genes (PCGs). The constructed Maximum Likelihood (ML) phylogeny using all PCGs showed clustering of N. nigricans with N. formosa. The resulting phylogeny illustrated the similar topology as described previously and consistent with the taxonomic classification. However, more sampling from different taxonomic groups of Testudines and studies on their mitogenomics are desirable for better understanding of the phylogenetic and evolutionary relationships. PMID- 30478343 TI - Characterisation of the British honey bee metagenome. AB - The European honey bee (Apis mellifera) plays a major role in pollination and food production. Honey bee health is a complex product of the environment, host genetics and associated microbes (commensal, opportunistic and pathogenic). Improved understanding of these factors will help manage modern challenges to bee health. Here we used DNA sequencing to characterise the genomes and metagenomes of 19 honey bee colonies from across Britain. Low heterozygosity was observed in many Scottish colonies which had high similarity to the native dark bee. Colonies exhibited high diversity in composition and relative abundance of individual microbiome taxa. Most non-bee sequences were derived from known honey bee commensal bacteria or pathogens. However, DNA was also detected from additional fungal, protozoan and metazoan species. To classify cobionts lacking genomic information, we developed a novel network analysis approach for clustering orphan DNA contigs. Our analyses shed light on microbial communities associated with honey bees and demonstrate the power of high-throughput, directed metagenomics for identifying novel biological threats in agroecosystems. PMID- 30478345 TI - Publisher Correction: Trapping Phenomenon Attenuates the Consequences of Tipping Points for Limit Cycles. AB - A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30478344 TI - Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy. AB - Despite recent advances, the efficacy of androgen/androgen receptor (AR)-targeted therapy remains limited for many patients with metastatic prostate cancer. This is in part because prostate cancers adaptively switch to the androgen/AR independent pathway for survival and growth, thereby conferring therapy resistance. Tumor hypoxia is considered as a major cause of treatment resistance. However, the exact mechanism is largely unclear. Here we report that chronic androgen deprivation therapy (ADT) in the condition of hypoxia induces adaptive androgen/AR-independence, and therefore confers resistance to androgen/AR targeted therapy, e.g., enzalutamide. Mechanistically, this is mediated by glucose-6-phosphate isomerase (GPI), which is transcriptionally repressed by AR in hypoxia, but restored and increased by AR inhibition. In turn, GPI maintains glucose metabolism and energy homeostasis in hypoxia by redirecting the glucose flux from androgen/AR-dependent pentose phosphate pathway (PPP) to hypoxia induced glycolysis pathway, thereby reducing the growth inhibitory effect of enzalutamide. Inhibiting GPI overcomes the therapy resistance in hypoxia in vitro and increases enzalutamide efficacy in vivo. PMID- 30478346 TI - A vector holographic optical trap. AB - The invention of optical tweezers almost forty years ago has triggered applications spanning multiple disciplines and has also found its way into commercial products. A major breakthrough came with the invention of holographic optical tweezers (HOTs), allowing simultaneous manipulation of many particles, traditionally done with arrays of scalar beams. Here we demonstrate a vector HOT with arrays of digitally controlled Higher-Order Poincare Sphere (HOPS) beams. We employ a simple set-up using a spatial light modulator and show that each beam in the array can be manipulated independently and set to an arbitrary HOPS state, including replicating traditional scalar beam HOTs. We demonstrate trapping and tweezing with customized arrays of HOPS beams comprising scalar orbital angular momentum and cylindrical vector beams, including radially and azimuthally polarized beams simultaneously in the same trap. Our approach is general enough to be easily extended to arbitrary vector beams, could be implemented with fast refresh rates and will be of interest to the structured light and optical manipulation communities alike. PMID- 30478348 TI - Author Correction: Cluster-assembled zirconia substrates promote long-term differentiation and functioning of human islets of Langerhans. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30478349 TI - Deep Semi Supervised Generative Learning for Automated Tumor Proportion Scoring on NSCLC Tissue Needle Biopsies. AB - The level of PD-L1 expression in immunohistochemistry (IHC) assays is a key biomarker for the identification of Non-Small-Cell-Lung-Cancer (NSCLC) patients that may respond to anti PD-1/PD-L1 treatments. The quantification of PD-L1 expression currently includes the visual estimation by a pathologist of the percentage (tumor proportional scoring or TPS) of tumor cells showing PD-L1 staining. Known challenges like differences in positivity estimation around clinically relevant cut-offs and sub-optimal quality of samples makes visual scoring tedious and subjective, yielding a scoring variability between pathologists. In this work, we propose a novel deep learning solution that enables the first automated and objective scoring of PD-L1 expression in late stage NSCLC needle biopsies. To account for the low amount of tissue available in biopsy images and to restrict the amount of manual annotations necessary for training, we explore the use of semi-supervised approaches against standard fully supervised methods. We consolidate the manual annotations used for training as well the visual TPS scores used for quantitative evaluation with multiple pathologists. Concordance measures computed on a set of slides unseen during training provide evidence that our automatic scoring method matches visual scoring on the considered dataset while ensuring repeatability and objectivity. PMID- 30478347 TI - Comparison between kinetic and kinetic-kinematic driven knee joint finite element models. AB - Use of knee joint finite element models for diagnostic purposes is challenging due to their complexity. Therefore, simpler models are needed for studies where a high number of patients need to be analyzed, without compromising the results of the model. In this study, more complex, kinetic (forces and moments) and simpler, kinetic-kinematic (forces and angles) driven finite element models were compared during the stance phase of gait. Patella and tendons were included in the most complex model, while they were absent in the simplest model. The greatest difference between the most complex and simplest models was observed in the internal-external rotation and axial joint reaction force, while all other rotations, translations and joint reaction forces were similar to one another. In terms of cartilage stresses and strains, the simpler models behaved similarly with the more complex models in the lateral joint compartment, while minor differences were observed in the medial compartment at the beginning of the stance phase. We suggest that it is feasible to use kinetic-kinematic driven knee joint models with a simpler geometry in studies with a large cohort size, particularly when analyzing cartilage responses and failures related to potential overloads. PMID- 30478350 TI - A downstream molecule of 1,25-dihydroxyvitamin D3, alpha-1-acid glycoprotein, protects against mouse model of renal fibrosis. AB - Renal fibrosis, the characteristic feature of progressive chronic kidney disease, is associated with unremitting renal inflammation. Although it is reported that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D, elicits an anti-renal fibrotic effect, its molecular mechanism is still unknown. In this study, renal fibrosis and inflammation observed in the kidney of unilateral ureteral obstruction (UUO) mice were reduced by the treatment of 1,25(OH)2D3. The plasma protein level of alpha-1-acid glycoprotein (AGP), a downstream molecule of 1,25(OH)2D3, was increased following administration of 1,25(OH)2D3. Additionally, increased mRNA expression of ORM1, an AGP gene, was observed in HepG2 cells and THP-1-derived macrophages that treated with 1,25(OH)2D3. To investigate the involvement of AGP, exogenous AGP was administered to UUO mice, resulting in attenuated renal fibrosis and inflammation. We also found the mRNA expression of CD163, a monocyte/macrophage marker with anti-inflammatory potential, was increased in THP-1-derived macrophages under stimulus from 1,25(OH)2D3 or AGP. Moreover, AGP prevented lipopolysaccharide-induced macrophage activation. Thus, AGP could be a key molecule in the protective effect of 1,25(OH)2D3 against renal fibrosis. Taken together, AGP may replace vitamin D to function as an important immune regulator, offering a novel therapeutic strategy for renal inflammation and fibrosis. PMID- 30478351 TI - Author Correction: HIV-1 Transmissions Among Recently Infected Individuals in Southwest China are Predominantly Derived from Circulating Local Strains. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30478352 TI - Hypovitaminosis D exacerbates the DNA damage load in human uterine fibroids, which is ameliorated by vitamin D3 treatment. AB - Uterine fibroids (UFs) are the most common benign neoplastic threat to women's health and associated with DNA damage and genomic instability. Hypovitaminosis D is a known risk factor for UFs, especially among African Americans. Vitamin D3 has been shown to effectively inhibit UF phenotype, but its mechanisms remain unclear. We hypothesize that Vitamin D3 ameliorates UFs by recovering the damaged DNA repair system, thus inhibits tumor progression. We compared the DNA damage status and Vitamin D receptor (VDR) expression between normal myometrial and UF primary cells. Unrepaired DNA double-strand breaks (DSBs) accumulated but VDR expression decreased in UFs. The RNA and protein levels of key DNA repair members belonging to DNA DSB sensors (MRE11, NBS1, RAD50), mediators and effectors (CHECK2, BRCA1, RAD51) were downregulated in UFs compared with myometrial cells. VDR KD induced DSB accumulation and DNA damage response (DDR) defects in myometrial cells. Using the DNA damage PCR array, the expression of many additional DNA repair genes was downregulated in VDR KD cells. Treatment of UF cells with Vitamin D3 (100 nM) significantly decreased DNA damage and restored DDR concomitant with VDR induction. Notably, the PCR array demonstrated that among 75 downregulated genes after VDR KD, 67 (89.3%) were upregulated after vitamin D3 treatment. These studies demonstrate a novel link between DNA damage and the vitamin D3/VDR axis in UFs. Vitamin D3 suppresses the UF phenotype through orchestrated targeting at multiple molecules in DNA repair pathways, thus offering novel mechanistic insights into the clinical effectiveness of vitamin D3 on UFs. PMID- 30478353 TI - Topological properties of a bipartite lattice of domain wall states. AB - We propose a generalization of the Su-Schrieffer-Heeger (SSH) model of the bipartite lattice, consisting of a periodic array of domain walls. The low-energy description is governed by the superposition of localized states at each domain wall, forming an effective mono-atomic chain at a larger scale. When the domain walls are dimerized, topologically protected edge states can appear, just like in the original SSH model. These new edge states are formed exclusively by soliton like states and therefore, the new topological states are qualitatively different from the regular SSH edge states. They posses a much longer localization length and are more resistant to on-site disorder, in marked contrast to the standard SSH case. PMID- 30478354 TI - Genetic diversity and population divergences of an indigenous tree (Coffea mauritiana) in Reunion Island: role of climatic and geographical factors. AB - Oceanic islands are commonly considered as natural laboratories for studies on evolution and speciation. The evolutionary specificities of islands associated with species biology provide unique scenarios to study the role of geography and climate in driving population divergence. However, few studies have addressed this subject in small oceanic islands with heterogeneous climates. Being widely distributed in Reunion Island forest, Coffea mauritiana represents an interesting model case for investigating patterns of within-island differentiation at small spatial scale. In this study, we examined the genetic diversity and population divergences of C. mauritiana using SNP markers obtained from 323 individuals across 34 locations in Reunion Island. Using redundancy analysis, we further evaluated the contribution of geographic and climatic factors to shaping genetic divergence among populations. Genetic diversity analyses revealed that accessions clustered according to the source population, with further grouping in regional clusters. Genetic relationships among the regional clusters underlined a recent process of expansion in the form of step-by-step colonization on both sides of the island. Divergence among source populations was mostly driven by the joint effect of geographic distance and climatic heterogeneity. The pattern of isolation-by-geography was in accordance with the dispersal characteristics of the species, while isolation-by-environment was mostly explained by the heterogeneous rainfall patterns, probably associated with an asynchronous flowering among populations. These findings advance our knowledge on the patterns of genetic diversity and factors of population differentiation of species native to Reunion Island, and will also usefully guide forest management for conservation. PMID- 30478355 TI - Interpersonal Variations in Gut Microbiota Profiles Supersedes the Effects of Differing Fecal Storage Conditions. AB - Due to ease of acquisition, fecal samples are often used in studies investigating gut microbiota. Improper handling of these samples can lead to bacterial growth and alter bacterial composition. While freezing samples at -80 degrees C is considered gold standard, this is not suitable for studies utilizing self sampling by lay participants or field studies. Thus to effectively prevent bacterial growth, techniques that allow efficient fecal storage outside laboratory facilities are needed. Fecal samples were collected from three donors. From each donor feces, 45 samples were collected and stored either freshly frozen at -80 or -20 degrees C, or in three separate storage buffers at room temperature or 4 degrees C for 24 or 72 hours. Bacterial composition was analyzed using Illumina amplicon sequencing of the V4 region of the 16 S rRNA gene. While storage conditions did affect bacterial composition and diversity compared to storage at -80 degrees C, the variation between donors superseded the variations introduced by storage. Samples stored at -20 degrees C most closely resembled those stored at -80 degrees C. When investigating variations in bacterial composition between separate study populations, fecal samples can efficiently be stored in -20 degrees C freezers or in one of the presented storage buffers, without severe alterations in bacterial composition. PMID- 30478356 TI - Exploring the Magnetoelectric Coupling at the Composite Interfaces of FE/FM/FE Heterostructures. AB - Multiferroic materials have attracted considerable attention as possible candidates for a wide variety of future microelectronic and memory devices, although robust magnetoelectric (ME) coupling between electric and magnetic orders at room temperature still remains difficult to achieve. In order to obtain robust ME coupling at room temperature, we studied the Pb(Fe0.5Nb0.5)O3/Ni0.65Zn0.35Fe2O4/Pb(Fe0.5Nb0.5)O3 (PFN/NZFO/PFN) trilayer structure as a representative FE/FM/FE system. We report the ferroelectric, magnetic and ME properties of PFN/NZFO/PFN trilayer nanoscale heterostructure having dimensions 70/20/70 nm, at room temperature. The presence of only (00l) reflection of PFN and NZFO in the X-ray diffraction (XRD) patterns and electron diffraction patterns in Transmission Electron Microscopy (TEM) confirm the epitaxial growth of multilayer heterostructure. The distribution of the ferroelectric loop area in a wide area has been studied, suggesting that spatial variability of ferroelectric switching behavior is low, and film growth is of high quality. The ferroelectric and magnetic phase transitions of these heterostructures have been found at ~575 K and ~650 K, respectively which are well above room temperature. These nanostructures exhibit low loss tangent, large saturation polarization (Ps ~ 38 uC/cm2) and magnetization (Ms ~ 48 emu/cm3) with strong ME coupling at room temperature revealing them as potential candidates for nanoscale multifunctional and spintronics device applications. PMID- 30478357 TI - Proanthocyanidin subunit composition determined by functionally diverged dioxygenases. AB - Proanthocyanidins (PAs) are primarily composed of the flavan-3-ol subunits (-) epicatechin and/or (+)-catechin, but the basis for their different starter and extension unit compositions remains unclear. Genetic and biochemical analyses show that, in the model legume Medicago truncatula, two 2-oxoglutarate-dependent dioxygenases, anthocyanidin synthase (ANS) and its homologue leucoanthocyanidin dioxygenase (LDOX), are involved in parallel pathways to generate, respectively, the (-)-epicatechin extension and starter units of PAs, with (+) catechin being an intermediate in the formation of the (-)-epicatechin starter unit. The presence/absence of the LDOX pathway accounts for natural differences in PA compositions across species, and engineering loss of function of ANS or LDOX provides a means to obtain PAs with different compositions and degrees of polymerization for use in food and feed. PMID- 30478358 TI - Maize multi-omics reveal roles for autophagic recycling in proteome remodelling and lipid turnover. AB - The turnover of cytoplasmic material by autophagic encapsulation and delivery to vacuoles is essential for recycling cellular constituents, especially under nutrient-limiting conditions. To determine how cells/tissues rely on autophagy, we applied in-depth multi-omic analyses to study maize (Zea mays) autophagy mutants grown under nitrogen-replete and -starvation conditions. Broad alterations in the leaf metabolome were evident in plants missing the core autophagy component ATG12, even in the absence of stress, particularly affecting products of lipid turnover and secondary metabolites, which were underpinned by substantial changes in the transcriptome and/or proteome. Cross-comparison of messenger RNA and protein abundances allowed for the identification of organelles, protein complexes and individual proteins targeted for selective autophagic clearance, and revealed several processes controlled by this catabolism. Collectively, we describe a facile multi-omic strategy to survey autophagic substrates, and show that autophagy has a remarkable influence in sculpting eukaryotic proteomes and membranes both before and during nutrient stress. PMID- 30478359 TI - Spheres of autophagy in maize. PMID- 30478360 TI - Developing naturally stress-resistant crops for a sustainable agriculture. AB - A major problem facing humanity is that our numbers are growing but the availability of land and fresh water for agriculture is not. This problem is being exacerbated by climate change-induced increases in drought, and other abiotic stresses. Stress-resistant crops are needed to ensure yield stability under stress conditions and to minimize the environmental impacts of crop production. Evolution has created thousands of species of naturally stress resistant plants (NSRPs), some of which have already been subjected to human domestication and are considered minor crops. Broader cultivation of these minor crops will diversify plant agriculture and the human diet, and will therefore help improve global food security and human health. More research should be directed toward understanding and utilizing NSRPs. Technologies are now available that will enable researchers to rapidly improve the genetics of NSRPs, with the goal of increasing NSRP productivity while retaining NSRP stress resistance and nutritional value. PMID- 30478362 TI - Charting blackwater rivers. PMID- 30478361 TI - Unleashing meiotic crossovers in crops. AB - Improved plant varieties are important in our attempts to face the challenges of a growing human population and limited planet resources. Plant breeding relies on meiotic crossovers to combine favourable alleles into elite varieties1. However, meiotic crossovers are relatively rare, typically one to three per chromosome2, limiting the efficiency of the breeding process and related activities such as genetic mapping. Several genes that limit meiotic recombination were identified in the model species Arabidopsis thaliana2. Mutation of these genes in Arabidopsis induces a large increase in crossover frequency. However, it remained to be demonstrated whether crossovers could also be increased in crop species hybrids. We explored the effects of mutating the orthologues of FANCM3, RECQ44 or FIGL15 on recombination in three distant crop species, rice (Oryza sativa), pea (Pisum sativum) and tomato (Solanum lycopersicum). We found that the single recq4 mutation increases crossovers about three-fold in these crops, suggesting that manipulating RECQ4 may be a universal tool for increasing recombination in plants. Enhanced recombination could be used with other state-of-the-art technologies such as genomic selection, genome editing or speed breeding6 to enhance the pace and efficiency of plant improvement. PMID- 30478363 TI - Remembering winter through vernalisation. AB - Vernalisation is the programmed physiological process in which prolonged cold exposure provides competency to flower in plants; widely found in winter and biennial species, such as Arabidopsis, fruit trees, vegetables and wheat. This phenomenon is regulated by diverse genetic networks, and memory of vernalisation in a life cycle mainly depends on epigenetic mechanisms. However, less is known about how to count winter-dosage for flowering in plants. Here, we compare the vernalisation genetic framework between the dicots Arabidopsis, temperate grasses, wheat, barley and Brachypodium. We discuss vernalisation mechanisms involving crosstalk between phosphorylation and O-GlcNAcylation modification of key proteins, and epigenetic modifications of the key gene VRN1 in wheat. We also highlight the potential evolutionary origins of vernalisation in various species. Current progress toward understanding the regulation of vernalisation requirements provides insight that will inform the design of molecular breeding strategies for winter crops. PMID- 30478364 TI - Ultrastructural visualization of Orientia tsutsugamushi in biopsied eschars and monocytes from scrub typhus patients in South Korea. AB - Scrub typhus, which is caused by Orientia tsutsugamushi, is a public health problem in the Asian-Pacific region and is the third most frequently reported infectious disease in South Korea. While ultrastructural studies have been performed on O. tsutsugamushi in murine fibroblasts, its variable locations in patients have hampered similar studies in humans. Two patients with scrub typhus agreed to provide an eschar biopsy and peripheral blood, respectively. Transmission electron microscopy was performed separately on the necrotic crust and perifocal skin of the eschar, the peripheral blood, and the infected murine L cells. O. tsutsugamushi was located within or adjacent to the outermost layer of the perifocal inflamed skin of the eschar but not in the necrotic centre. O. tsutsugamushi in peripheral blood monocytes exhibited the characteristic features of O. tsutsugamushi in L cells, namely, nearly round shaped bacteria with a size of 1-2 um and a double membrane bearing a clear halo-like outer layer. The findings confirmed that the bacterium was predominantly located in the inflamed skin around the eschar and that the bacterium had the same ultrastructural features in human monocytes as in L cells. These findings suggest that the perifocal area, not the necrotic centre, should be sampled for diagnosis. PMID- 30478365 TI - Signalling and differentiation in emulsion-based multi-compartmentalized in vitro gene circuits. AB - Multicellularity enables the growth of complex life forms as it allows for the specialization of cell types, differentiation and large-scale spatial organization. In a similar way, modular construction of synthetic multicellular systems will lead to dynamic biomimetic materials that can respond to their environment in complex ways. To achieve this goal, artificial cellular communication and developmental programs still have to be established. Here, we create geometrically controlled spatial arrangements of emulsion-based artificial cellular compartments containing synthetic in vitro gene circuitry, separated by lipid bilayer membranes. We quantitatively determine the membrane pore-dependent response of the circuits to artificial morphogen gradients, which are established via diffusion from dedicated organizer cells. Utilizing different types of feedforward and feedback in vitro gene circuits, we then implement artificial signalling and differentiation processes, demonstrating the potential for the realization of complex spatiotemporal dynamics in artificial multicellular systems. PMID- 30478367 TI - The not-so-dangerous lives of Neanderthals. PMID- 30478366 TI - Total flavonoids from Semen Cuscutae target MMP9 and promote invasion of EVT cells via Notch/AKT/MAPK signaling pathways. AB - Miscarriage is a common condition during pregnancy and its mechanisms remain largely unknown. Extravillous trophoblast (EVT) cell invasion is required to maintain normal pregnancy and its malfunction has been proposed as a major cause for miscarriage. Homeostasis of matrix metalloproteinase 9 (MMP9) is a key to regulate EVT cell invasion. Total flavonoids from Semen Cuscutae (TFSC) have been applied clinically used for preventing or treating miscarriage in the past. Given its potential clinical benefit on preventing miscarriage, this study aims at examining the therapeutic effect of TFSC in the prevention of premature birth by upregulating MMP9 and promote EVT cell invasion. HTR-8 cells migration and invasion functions were analyzed using wound healing and transwell assays. The regulatory effect of TFSC on MMP9 expression and relevant signaling pathways were analyzed by Western Blot. The results show compared to control group, TFSC significantly promoted the migration of EVT cells in a dose and time-dependent manner. The migration and invasion of EVT cells were maximized at the highest dosage of 5 MUg/ml of TFSC. The expression of MMP9 in EVT cells was significantly increased after TFSC treatment. Furthermore, cells treated with TFSC significantly upregulated protein expressions in Notch, AKT and p38/MAPK signaling pathways. We believe TFSC can promote the migration and invasion of EVT cells by increasing MMP9 expression, and prevent miscarriage by activating Notch, AKT, and MAPK signaling pathways. PMID- 30478368 TI - Osamu Shimomura (1928-2018). PMID- 30478369 TI - A newly discovered mechanism driving neuronal mutations in Alzheimer's disease. PMID- 30478370 TI - A 100th birthday wish: uphold academic freedom in dark times. PMID- 30478371 TI - A spotlight on bacterial mutations for 75 years. PMID- 30478372 TI - How some wind turbines hog the breeze. PMID- 30478373 TI - Beware the rise of the radical right. PMID- 30478374 TI - Hotspots of recent hybridization between pigs and wild boars in Europe. AB - After a strong demographic decline before World War II, wild boar populations are expanding and the species is now the second-most abundant ungulate in Europe. This increase raises concerns due to wild boar impact on crops and natural ecosystems and as potential vector of diseases. Additionally, wild boar can hybridize with domestic pigs, which could increase health risks and alter wild boar adaptive potential. We analysed 47,148 Single Nucleotide Polymorphisms in wild boar from Europe (292) and the Near East (16), and commercial (44) and local (255) pig breeds, to discern patterns of hybridization across Europe. We identified 33 wild boars with more than 10% domestic ancestry in their genome, mostly concentrated in Austria, Bosnia and Herzegovina, Bulgaria and Serbia. This difference is probably due to contrasting practices, with free-ranging vs. industrial farming but more samples would be needed to investigate larger geographic patterns. Our results suggest hybridization has occurred over a long period and is still ongoing, as we observed recent hybrids. Although wild and domestic populations have maintained their genetic distinctiveness, potential health threats raise concerns and require implementation of management actions and farming practices aimed at reducing contact between wild and domestic pigs. PMID- 30478375 TI - High-entropy high-hardness metal carbides discovered by entropy descriptors. AB - High-entropy materials have attracted considerable interest due to the combination of useful properties and promising applications. Predicting their formation remains the major hindrance to the discovery of new systems. Here we propose a descriptor-entropy forming ability-for addressing synthesizability from first principles. The formalism, based on the energy distribution spectrum of randomized calculations, captures the accessibility of equally-sampled states near the ground state and quantifies configurational disorder capable of stabilizing high-entropy homogeneous phases. The methodology is applied to disordered refractory 5-metal carbides-promising candidates for high-hardness applications. The descriptor correctly predicts the ease with which compositions can be experimentally synthesized as rock-salt high-entropy homogeneous phases, validating the ansatz, and in some cases, going beyond intuition. Several of these materials exhibit hardness up to 50% higher than rule of mixtures estimations. The entropy descriptor method has the potential to accelerate the search for high-entropy systems by rationally combining first principles with experimental synthesis and characterization. PMID- 30478376 TI - Modulating the Work Function of Graphene by Pulsed Plasma Aided Controlled Chlorination. AB - Chlorine on graphene (G) matrices was doped by pulsed plasma stimulation on graphite electrode submerged in organochlorine solvents (CH2Cl2, CHCl3, CCl4). The study of work function by Kelvin probe force microscopy (KPFM) measurement clearly indicates that Cl-doped G behave like semiconductor and GG@CHCl3 exhibits the lowest value for the work function. We propose that this report not only represents a new route for tuning the semiconductivity of G but also indicates that doping level of halogen on G based carbon framework can be controlled by pulsed plasma treatment of carbon materials on various organohalogen derivatives. PMID- 30478377 TI - IL-34 promotes foam cell formation by enhancing CD36 expression through p38 MAPK pathway. AB - Atherosclerosis is characterized as a chronic inflammatory disease and macrophage derived foam cells play a central role during the pathologic processes. A newly discovered cytokine interleukin-34 (IL-34) is closely associated with various inflammatory and autoimmune diseases. Expression of IL-34 in obesity, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), lupus nephritis and coronary artery diseases (CAD) are significantly elevated. However, the role of IL-34 in atherosclerosis remains unknown. In our present study, we found that IL 34 treatment markedly increased the uptake of oxLDL, intracellular total and esterified cholesterol content but not cholesterol efflux, subsequently promoted foam cell formation through up-regulating CD36 expression via p38 MAPK signal pathway in bone marrow derived macrophages (BMDMs). Furthermore, treatment with IL-34 significantly elevated the oxLDL-induced up-regulation of pro-inflammatory cytokines. Our results conclude that IL-34 facilitates foam cell formation by increasing CD36-mediated lipid uptake and suggest a potential new risk biomarker for atherosclerosis. PMID- 30478378 TI - Cryo-EM structures of KdpFABC suggest a K+ transport mechanism via two inter subunit half-channels. AB - P-type ATPases ubiquitously pump cations across biological membranes to maintain vital ion gradients. Among those, the chimeric K+ uptake system KdpFABC is unique. While ATP hydrolysis is accomplished by the P-type ATPase subunit KdpB, K+ has been assumed to be transported by the channel-like subunit KdpA. A first crystal structure uncovered its overall topology, suggesting such a spatial separation of energizing and transporting units. Here, we report two cryo-EM structures of the 157 kDa, asymmetric KdpFABC complex at 3.7 A and 4.0 A resolution in an E1 and an E2 state, respectively. Unexpectedly, the structures suggest a translocation pathway through two half-channels along KdpA and KdpB, uniting the alternating-access mechanism of actively pumping P-type ATPases with the high affinity and selectivity of K+ channels. This way, KdpFABC would function as a true chimeric complex, synergizing the best features of otherwise separately evolved transport mechanisms. PMID- 30478379 TI - Variations in the immune and metabolic response of proactive and reactive Sparus aurata under stimulation with Vibrio anguillarum vaccine. AB - Environmental insults, such as exposure to pathogens, modulate the behavioural coping style of animals to stressors, and repeated exposure to stressful environments may lead to species-specific infection phenotypes. To analyse the influence of stress behavioural phenotypes on immune and metabolic performance, gilthead sea bream (Sparus aurata L.) were first screened for proactive and reactive coping styles. Once characterized, both behavioural phenotypes fish groups were bath vaccinated with bacterin from Vibrio anguillarum, an opportunistic widespread pathogen of fish. Gills and liver were sampled at 0 (control group), 1, 3 and 7 days post-vaccination. Immune-, oxidative stress- and metabolic-related transcripts (il1beta, tnfalpha, igm, gpx1, sod, cat, lpl, ghr1 and ghr2), metabolic endpoints (glucose, cholesterol and triglycerides), hepatic health indicators (aspartate aminotransferase, alanine transaminase and alkaline phosphatase), oxidative stress status (esterase activity, total antioxidant capacity and total oxidative status) and stress biomarkers (cortisol) were determined. Present results indicate that screening for coping styles in the gilthead sea bream segregated the two distinct phenotypes as expected: proactive and reactive. Results also indicate that under bath vaccination proactive fish show high immune response and lower metabolism, whereas reactive fish show low immune and higher metabolic responses. PMID- 30478381 TI - Radar micro-Doppler signatures of drones and birds at K-band and W-band. AB - Due to the substantial increase in the number of affordable drones in the consumer market and their regrettable misuse, there is a need for efficient technology to detect drones in airspace. This paper presents the characteristic radar micro-Doppler properties of drones and birds. Drones and birds both induce micro-Doppler signatures due to their propeller blade rotation and wingbeats, respectively. These distinctive signatures can then be used to differentiate a drone from a bird, along with studying them separately. Here, experimental measurements of micro-Doppler signatures of different types of drones and birds are presented and discussed. The data have been collected using two radars operating at different frequencies; K-band (24 GHz) and W-band (94 GHz). Three different models of drones and four species of birds of varying sizes have been used for data collection. The results clearly demonstrate that a phase coherent radar system can retrieve highly reliable and distinctive micro-Doppler signatures of these flying targets, both at K-band and W-band. Comparison of the signatures obtained at the two frequencies indicates that the micro-Doppler return from the W-band radar has higher SNR. However, micro-Doppler features in the K-band radar returns also reveal the micro-motion characteristics of drones and birds very effectively. PMID- 30478380 TI - Effects of oil and global environmental drivers on two keystone marine invertebrates. AB - Ocean warming (OW) and acidification (OA) are key features of global change and are predicted to have negative consequences for marine species and ecosystems. At a smaller scale increasing oil and gas activities at northern high latitudes could lead to greater risk of petroleum pollution, potentially exacerbating the effects of such global stressors. However, knowledge of combined effects is limited. This study employed a scenario-based, collapsed design to investigate the impact of one local acute stressor (North Sea crude oil) and two chronic global drivers (pH for OA and temperature for OW), alone or in combination on aspects of the biology of larval stages of two key invertebrates: the northern shrimp (Pandalus borealis) and the green sea urchin (Strongylocentrotus droebachiensis). Both local and global drivers had negative effects on survival, development and growth of the larval stages. These effects were species- and stage-dependent. No statistical interactions were observed between local and global drivers and the combined effects of the two drivers were approximately equal to the sum of their separate effects. This study highlights the importance of adjusting regulation associated with oil spill prevention to maximize the resilience of marine organisms to predicted future global conditions. PMID- 30478382 TI - Increase of power conversion efficiency in dye-sensitized solar cells through ferroelectric substrate induced charge transport enhancement. AB - Ferroelectric functionalized dye-sensitized solar cells were fabricated by using a positively-poled LiNbO3 substrate coated with ITO (ITO-LiNbO3) as a collector electrode and demonstrated enhanced power conversion efficiency. Surface potential properties of TiO2 nanoparticle film coated on the ITO-LiNbO3 (TiO2/ITO LiNbO3) examined by Kelvin probe force microscopy (KPFM) confirmed that a large electric field (a few 10 V/um) generated from LiNbO3 can penetrate through the ITO layer and is applied to TiO2 film. This polarization-induced electric field leads to an increased photocurrent density by attracting and promoting electrons to direct transport through the mesoporous TiO2 network toward the collector electrode and a decreased charge recombination by facilitating electrons to pass through fewer boundaries of nanoparticles, resulting in high power conversion efficiency. The power conversion efficiency was enhanced by more than 40% in comparison with that without polarization-induced electric field. Incorporating functional ferroelectrics into photovoltaic cells would be a good strategy in improving photovoltaic performance and is applicable to other types of photovoltaic devices, such as perovskite solar cells. PMID- 30478383 TI - Dclk1 in tuft cells promotes inflammation-driven epithelial restitution and mitigates chronic colitis. AB - Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by defective intestinal barrier integrity toward the microbiota and epithelial damage. Double cortin-like kinase 1 (Dclk1), a marker of intestinal tuft cells, can regulate tissue regenerative responses, but its role in epithelial repair during bacterial-dependent chronic colitis is unclear. We addressed this question using our recently developed mouse model of spontaneous microbiota-dependent colitis induced by mucin-type O-glycan deficiency (DKO), which recapitulates most features of human UC. We generated DKO mice lacking intestinal epithelial Dclk1 (DKO;Dclk1DeltaIEC) and analyzed colitis onset and severity using clinical and histologic indices, immune responses by qPCR and immunostaining, and epithelial responses using proliferation markers and organoid culture. We found 3-4-week-old DKO;Dclk1DeltaIEC mice developed worsened spontaneous colitis characterized by reduced body weight, loose stool, severe colon thickening, epithelial lesions, and inflammatory cell infiltrates compared with DKO mice. The primary defect was an impaired epithelial proliferative response during inflammation. Dclk1 deficiency also reduced inflammation-induced proliferation and growth of colon organoids ex vivo. Mechanistically, Dclk1 expression was important for inflammation-induced Cox2 expression and prostaglandin E2 (PGE2) production in vivo, and PGE2 rescued proliferative defects in Dclk1-deficient colonic organoids. Although tuft cells were expanded in both DKO and DKO;Dclk1DeltaIEC relative to WT mice, loss of Dclk1 was associated with reduced tuft cell activation (i.e., proliferation) during inflammation. Similar results were found in DKO vs. DKO;Dclk1DeltaIEC mice at 3-6 months of age. Our results support that tuft cells, via Dclk1, are important responders to bacterial-induced colitis by enhancing epithelial repair responses, which in turn limits bacterial infiltration into the mucosa. PMID- 30478384 TI - Bacterial butyrate prevents atherosclerosis. PMID- 30478385 TI - The double life of autophagy proteins. PMID- 30478386 TI - Type VI secretion system baseplate. PMID- 30478387 TI - Stop HUSHing on SIV/HIV. PMID- 30478388 TI - The interferon-inducible isoform of NCOA7 inhibits endosome-mediated viral entry. AB - Interferons (IFNs) mediate cellular defence against viral pathogens by upregulation of IFN-stimulated genes whose products interact with viral components or alter cellular physiology to suppress viral replication1-3. Among the IFN-stimulated genes that can inhibit influenza A virus (IAV)4 are the myxovirus resistance 1 GTPase5 and IFN-induced transmembrane protein 3 (refs 6,7). Here, we use ectopic expression and gene knockout to demonstrate that the IFN-inducible 219-amino acid short isoform of human nuclear receptor coactivator 7 (NCOA7) is an inhibitor of IAV as well as other viruses that enter the cell by endocytosis, including hepatitis C virus. NCOA7 interacts with the vacuolar H+ ATPase (V-ATPase) and its expression promotes cytoplasmic vesicle acidification, lysosomal protease activity and the degradation of endocytosed antigen. Step-wise dissection of the IAV entry pathway demonstrates that NCOA7 inhibits fusion of the viral and endosomal membranes and subsequent nuclear translocation of viral ribonucleoproteins. Therefore, NCOA7 provides a mechanism for immune regulation of endolysosomal physiology that not only suppresses viral entry into the cytosol from this compartment but may also regulate other V-ATPase-associated cellular processes, such as physiological adjustments to nutritional status, or the maturation and function of antigen-presenting cells. PMID- 30478390 TI - Professional titles matter. PMID- 30478389 TI - An ATG16L1-dependent pathway promotes plasma membrane repair and limits Listeria monocytogenes cell-to-cell spread. AB - Plasma membrane integrity is essential for the viability of eukaryotic cells. In response to bacterial pore-forming toxins, disrupted regions of the membrane are rapidly repaired. However, the pathways that mediate plasma membrane repair are unclear. Here we show that autophagy-related (ATG) protein ATG16L1 and its binding partners ATG5 and ATG12 are required for plasma membrane repair through a pathway independent of macroautophagy. ATG16L1 is required for lysosome fusion with the plasma membrane and blebbing responses that promote membrane repair. ATG16L1 deficiency causes accumulation of cholesterol in lysosomes that contributes to defective membrane repair. Cell-to-cell spread by Listeria monocytogenes requires membrane damage by the bacterial toxin listeriolysin O, which is restricted by ATG16L1-dependent membrane repair. Cells harbouring the ATG16L1 T300A allele associated with inflammatory bowel disease were also found to accumulate cholesterol and be defective in repair, linking a common inflammatory disease to plasma membrane integrity. Thus, plasma membrane repair could be an important therapeutic target for the treatment of bacterial infections and inflammatory disorders. PMID- 30478391 TI - Influence of visual cues on oviposition site searching and learning behavior in the parasitic beetle Dastarcus helophoroides (Fairmaire) (Coleoptera: Bothrideridae). AB - Color cues play a key role in the location of hosts and host habitats; learning behavior can allow parasitoids to explore different hosts and reduce environmental uncertainty. However, it remains unclear whether the parasitic beetle Dastarcus helophoroides (Fairmaire) uses and learns visual cues to locate oviposition sites. In this study, we investigated the ability of females to respond to colors and associate the presence of a simulated oviposition site-wood with a trough-with colored substrates after training. Two sets of experiments were conducted: (i) investigating the innate preference for substrate coloration and (ii) investigating the ability to learn to associate substrate color with the presence of simulated oviposition sites, with the beetles being trained to respond to different substrate colors with simulated oviposition sites in sessions on 10 consecutive days. The parasitic beetles displayed an innate preference for the black substrate, but this preference changed after the beetles were trained on substrates of different colors. In the associative learning tests, these beetles laid more eggs on the reward-conditioned substrates than on the black substrate after being trained. Our results suggest that visual cues are learned and used by D. helophoroides during their search for and selection of oviposition sites. PMID- 30478392 TI - Excess charge-carrier induced instability of hybrid perovskites. AB - Identifying the origin of intrinsic instability for organic-inorganic halide perovskites (OIHPs) is crucial for their application in electronic devices, including solar cells, photodetectors, radiation detectors, and light-emitting diodes, as their efficiencies or sensitivities have already been demonstrated to be competitive with commercial available devices. Here we show that free charges in OIHPs, whether generated by incident light or by current-injection from electrodes, can reduce their stability, while efficient charge extraction effectively stabilizes the perovskite materials. The excess of both holes and electrons reduce the activation energy for ion migration within OIHPs, accelerating the degradation of OIHPs, while the excess holes and electrons facilitate the migration of cations or anions, respectively. OIHP solar cells capable of efficient charge-carrier extraction show improved light stability under regular operation conditions compared to an open-circuit condition where the photo-generated charges are confined in the perovskite layers. PMID- 30478393 TI - Numerical investigations of an ultra-compact polarization beam splitter based on augmented low-index guiding and subwavelength grating structures. AB - We report the design of an ultra-compact polarization beam splitter with high performance that is based on augmented low-index guiding and subwavelength grating (SWG) structures. The transverse-electric (TE) and transverse-magnetic (TM) modes are confined in high-index silicon (Si) and low-index silicon nitride (Si3N4), respectively. They are separated by using, respectively, a gradually curved Si waveguide and a Si3N4 SWG structure with optimal grating-element. The footprint of the proposed polarization beam splitters (PBS) is 2.9 * 2.25 MUm2. The device offers high polarization extinction ratios (PERs) of ~18 dB for the two polarizations, with low insertion losses of ~0.22 dB (~0.71 dB) for the TE (TM) mode at the wavelength of 1550 nm. Over the broad band from lambda = 1500 1650 nm, the PERs of the TE and TM modes are above 17 and 16 dB, respectively. By narrowing the operating band to the range from lambda = 1500 to 1600 nm, the proposed PBS provides PERs of >17 dB for both polarizations. Finally, the fabrication tolerance of the designed PBS is also addressed and discussed in detail. PMID- 30478394 TI - Establishing a prediction model for lateral neck lymph node metastasis in patients with papillary thyroid carcinoma. AB - This study aimed to establish a model for predicting lateral neck lymph node metastasis in patients with papillary thyroid carcinoma. A total of 106 patients with papillary thyroid carcinoma undergoing initial treatment of neck lymph node dissection (including central and lateral neck lymph nodes) at the thyroid surgery department were enrolled from January 2009 to April 2017. Logistic regression analysis was used to screen the factors influencing lateral neck lymph node metastasis and develop a prediction model. The receiver operating characteristic curve was used to evaluate the predictive power and boundary value of the model for lateral neck lymph node metastasis. Prediction model: Logistic(P) = -5.699 + 0.681 * (TSH) + 0.342 * (Metastatic rate of central lymph nodes) + 1.463 * (Combined with Hashimoto's disease) + 1.525 * (Number of tumors). When logistic (P) was >= 0.821, it was predicted that lateral neck lymph node metastasis occurred in patients with papillary thyroid carcinoma. When logistic (P) was <0.821, it was predicted that no metastasis was found in the lateral neck lymph node. The prediction accuracy was 78.3%. The model helped in evaluating lateral neck lymph node metastasis in patients with papillary thyroid carcinoma. Also, it had significance in determining reasonable surgical range, reducing unnecessary lateral neck lymph node dissection, and further improving the quality of life of patients. PMID- 30478396 TI - Benzothiadiazole, a plant defense inducer, negatively regulates sheath blight resistance in Brachypodium distachyon. AB - Plant defense inducers that mimic functions of the plant immune hormone salicylic acid (SA) often affect plant growth. Although benzothiadiazole (BTH), a synthetic analog of SA, has been widely used to protect crops from diseases by inducing plant defense responses, we recently demonstrated that SA, but not BTH, confers resistance against Rhizoctonia solani, the causal agent of sheath blight disease, in Brachypodium distachyon. Here, we demonstrated that BTH compromised the resistance of Bd3-1 and Gaz4, the two sheath blight-resistant accessions of B. distachyon, which activate SA-dependent signaling following challenge by R. solani. Moreover, upon analyzing our published RNA-seq data from B. distachyon treated with SA or BTH, we found that BTH specifically induces expression of genes related to chloroplast function and jasmonic acid (JA) signaling, suggesting that BTH attenuates R. solani resistance by perturbing growth-defense trade-offs and/or by inducing a JA response that may increase susceptibility to R. solani. Our findings demonstrated that BTH does not work as a simple mimic of SA in B. distachyon, and consequently may presumably cause unfavorable side effects through the transcriptional alteration, particularly with respect to R. solani resistance. PMID- 30478395 TI - Natural variation in acyl editing is a determinant of seed storage oil composition. AB - Seeds exhibit wide variation in the fatty acid composition of their storage oil. However, the genetic basis of this variation is only partially understood. Here we have used a multi-parent advanced generation inter-cross (MAGIC) population to study the genetic control of fatty acid chain length in Arabidopsis thaliana seed oil. We mapped four quantitative trait loci (QTL) for the quantity of the major very long chain fatty acid species 11-eicosenoic acid (20:1), using multiple QTL modelling. Surprisingly, the main-effect QTL does not coincide with FATTY ACID ELONGASE 1 and a parallel genome wide association study suggested that LYSOPHOSPHATIDYLCHOLINE ACYLTRANSFERASE 2 (LPCAT2) is a candidate for this QTL. Regression analysis also suggested that LPCAT2 expression and 20:1 content in seeds of the 19 MAGIC founder accessions are related. LPCAT is a key component of the Lands cycle; an acyl editing pathway that enables acyl-exchange between the acyl-Coenzyme A and phosphatidylcholine precursor pools used for microsomal fatty acid elongation and desaturation, respectively. We Mendelianised the main-effect QTL using biparental chromosome segment substitution lines and carried out complementation tests to show that a single cis-acting polymorphism in the LPCAT2 promoter causes the variation in seed 20:1 content, by altering the LPCAT2 expression level and total LPCAT activity in developing siliques. Our work establishes that oilseed species exhibit natural variation in the enzymic capacity for acyl editing and this contributes to the genetic control of storage oil composition. PMID- 30478397 TI - Macrophage de novo NAD+ synthesis specifies immune function in aging and inflammation. AB - Recent advances highlight a pivotal role for cellular metabolism in programming immune responses. Here, we demonstrate that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD+) via the kynurenine pathway (KP) regulates macrophage immune function in aging and inflammation. Isotope tracer studies revealed that macrophage NAD+ derives substantially from KP metabolism of tryptophan. Genetic or pharmacological blockade of de novo NAD+ synthesis depleted NAD+, suppressed mitochondrial NAD+-dependent signaling and respiration, and impaired phagocytosis and resolution of inflammation. Innate immune challenge triggered upstream KP activation but paradoxically suppressed cell-autonomous NAD+ synthesis by limiting the conversion of downstream quinolinate to NAD+, a profile recapitulated in aging macrophages. Increasing de novo NAD+ generation in immune-challenged or aged macrophages restored oxidative phosphorylation and homeostatic immune responses. Thus, KP-derived NAD+ operates as a metabolic switch to specify macrophage effector responses. Breakdown of de novo NAD+ synthesis may underlie declining NAD+ levels and rising innate immune dysfunction in aging and age-associated diseases. PMID- 30478400 TI - Feasibility of delaying coronary reperfusion. PMID- 30478399 TI - Targeting PCSK9 to reduce residual risk in ACS. PMID- 30478401 TI - High relapse rate after HF medication withdrawal. PMID- 30478402 TI - Ternary crystal structure of human RORgamma ligand-binding-domain, an inhibitor and corepressor peptide provides a new insight into corepressor interaction. AB - Retinoic acid-related orphan receptor gamma (RORgamma) plays pivotal roles in autoimmune diseases by controlling the lineage of interleukin 17 (IL-17) producing CD4+ T cells (Th17 cells). Structure-based drug design has proven fruitful in the development of inhibitors targeting the ligand binding domain (LBD) of RORgamma. Here, we present the crystal structure of a novel RORgamma inhibitor co-complex, in the presence of a corepressor (CoR) peptide. This ternary complex with compound T reveals the structural basis for an inhibitory mechanism different from the previously reported inverse agonist. Compared to the inverse agonist, compound T induces about 2 A shift of helix 5 (H5) backbone and side-chain conformational changes of Met365 on H5. These conformational changes correlate to reduced CoR peptide binding to RORgamma-LBD in the presence of compound T, which suggests that the shift of H5 is responsible. This crystal structure analysis will provide useful information for the development of novel and efficacious drugs for autoimmune disorders. PMID- 30478403 TI - A biophysical study on the mechanism of interactions of DOX or PTX with alpha lactalbumin as a delivery carrier. AB - Doxorubicin and paclitaxel, two hydrophobic chemotherapeutic agents, are used in cancer therapies. Presence of hydrophobic patches and a flexible fold could probably make alpha-Lactalbumin a suitable carrier for hydrophobic drugs. In the present study, a variety of thermodynamic, spectroscopic, computational, and cellular techniques were applied to assess alpha-lactalbumin potential as a carrier for doxorubicin and paclitaxel. According to isothermal titration calorimetry data, the interaction between alpha-lactalbumin and doxorubicin or paclitaxel is spontaneous and the K (M-1) value for the interaction of alpha lactalbumin and paclitaxel is higher than that for doxorubicin. Differential scanning calorimetry and anisotropy results indicated formation of alpha lactalbumin complexes with doxorubicin or paclitaxel. Furthermore, molecular docking and dynamic studies revealed that TRPs are not involved in alpha-Lac's interaction with Doxorubicin while TRP 60 interacts with paclitaxel. Based on Pace analysis to determine protein thermal stability, doxorubicin and paclitaxel induced higher and lower thermal stability in alpha-lactalbumin, respectively. Besides, fluorescence lifetime measurements reflected that the interaction between alpha-lactalbumin with doxorubicin or paclitaxel was of static nature. Therefore, the authors hypothesized that alpha-lactalbumin could serve as a carrier for doxorubicin and paclitaxel by reducing cytotoxicity and apoptosis which was demonstrated during our in vitro cell studies. PMID- 30478404 TI - Identification of a Small Interface between the Methyltransferase and RNA Polymerase of NS5 that is Essential for Zika Virus Replication. AB - The spread of Zika virus (ZIKV) has caused an international health emergency due to its ability to cause microcephaly in infants. Yet, our knowledge of how ZIKV replicates at the molecular level is limited. For example, how the non-structural protein 5 (NS5) performs replication, and in particular whether the N-terminal methytransferase (MTase) domain is essential for the function of the C-terminal RNA-dependent RNA polymerase (RdRp) remains unclear. In contrast to previous reports, we find that MTase is absolutely essential for all activities of RdRp in vitro. For instance, the MTase domain confers stability onto the RdRp elongation complex (EC) and and is required for de novo RNA synthesis and nucleotide incorporation by RdRp. Finally, structure function analyses identify key conserved residues at the MTase-RdRp interface that specifically activate RdRp elongation and are essential for ZIKV replication in Huh-7.5 cells. These data demonstrate the requirement for the MTase-RdRp interface in ZIKV replication and identify a specific site within this region as a potential site for therapeutic development. PMID- 30478406 TI - Protecting children from known pesticides exposures: our collective duty to provide primary prevention. PMID- 30478407 TI - Early immune modulation by single-agent trastuzumab as a marker of trastuzumab benefit. AB - BACKGROUND: Optimising the selection of HER2-targeted regimens by identifying subsets of HER2-positive breast cancer (BC) patients who need more or less therapy remains challenging. We analysed BC samples before and after treatment with 1 cycle of trastuzumab according to the response to trastuzumab. METHODS: Gene expression profiles of pre- and post-treatment tumour samples from 17 HER2 positive BC patients were analysed on the Illumina platform. Tumour-associated immune pathways and blood counts were analysed with regard to the response to trastuzumab. HER2-positive murine models with differential responses to trastuzumab were used to reproduce and better characterise these data. RESULTS: Patients who responded to single-agent trastuzumab had basal tumour biopsies that were enriched in immune pathways, particularly the MHC-II metagene. One cycle of trastuzumab modulated the expression levels of MHC-II genes, which increased in patients who had a complete response on treatment with trastuzumab and chemotherapy. Trastuzumab increased the MHC-II-positive cell population, primarily macrophages, only in the tumour microenvironment of responsive mice. In patients who benefited from complete trastuzumab therapy and in mice that harboured responsive tumours circulating neutrophil levels declined, but this cell subset rose in nonresponsive tumours. CONCLUSIONS: Short treatment with trastuzumab induces local and systemic immunomodulation that is associated with clinical outcomes. PMID- 30478405 TI - Adaptive hindlimb split-belt treadmill walking in rats by controlling basic muscle activation patterns via phase resetting. AB - To investigate the adaptive locomotion mechanism in animals, a split-belt treadmill has been used, which has two parallel belts to produce left-right symmetric and asymmetric environments for walking. Spinal cats walking on the treadmill have suggested the contribution of the spinal cord and associated peripheral nervous system to the adaptive locomotion. Physiological studies have shown that phase resetting of locomotor commands involving a phase shift occurs depending on the types of sensory nerves and stimulation timing, and that muscle activation patterns during walking are represented by a linear combination of a few numbers of basic temporal patterns despite the complexity of the activation patterns. Our working hypothesis was that resetting the onset timings of basic temporal patterns based on the sensory information from the leg, especially extension of hip flexors, contributes to adaptive locomotion on the split-belt treadmill. Our hypothesis was examined by conducting forward dynamic simulations using a neuromusculoskeletal model of a rat walking on a split-belt treadmill with its hindlimbs and by comparing the simulated motions with the measured motions of rats. PMID- 30478408 TI - Development and validation of a novel risk score for the detection of insignificant prostate cancer in unscreened patient cohorts. AB - BACKGROUND: Active surveillance is recommended for insignificant prostate cancer (PCa). Tools exist to identify suitable candidates using clinical variables. We aimed to develop and validate a novel risk score (NRS) predicting which patients are harbouring insignificant PCa. METHODS: We used prospectively collected data from 8040 consecutive unscreened patients who underwent radical prostatectomy between 2006 and 2016. Of these, data from 2799 patients with Gleason 3 + 3 on biopsy were used to develop a multivariate model predicting the presence of insignificant PC at radical prostatectomy (ERSPC updated definition3: Gleason 3 + 3 only, index tumour volume < 1.3 cm3 and total tumour volume < 2.5 cm3). This was used to develop a novel risk score (NRS) which was validated in an equivalent independent cohort (n = 441). We compared the accuracy of existing predictive tools and the NRS in these cohorts. RESULTS: The NRS (incorporating PSA, prostate volume, age, clinical T Stage, percent and number of positive biopsy cores) outperformed pre-existing predictive tools in derivation and validation cohorts (AUC 0.755 and 0.76, respectively). Selection bias due to analysis of a surgical cohort is acknowledged. CONCLUSIONS: The advantage of the NRS is that it can be tailored to patient characteristics and may prove to be valuable tool in clinical decision-making. PMID- 30478410 TI - Blockade of muscarinic acetylcholine receptors facilitates motivated behaviour and rescues a model of antipsychotic-induced amotivation. AB - Disruptions to motivated behaviour are a highly prevalent and severe symptom in a number of neuropsychiatric and neurodegenerative disorders. Current treatment options for these disorders have little or no effect upon motivational impairments. We assessed the contribution of muscarinic acetylcholine receptors to motivated behaviour in mice, as a novel pharmacological target for motivational impairments. Touchscreen progressive ratio (PR) performance was facilitated by the nonselective muscarinic receptor antagonist scopolamine as well as the more subtype-selective antagonists biperiden (M1) and tropicamide (M4). However, scopolamine and tropicamide also produced increases in non specific activity levels, whereas biperiden did not. A series of control tests suggests the effects of the mAChR antagonists were sensitive to changes in reward value and not driven by changes in satiety, motor fatigue, appetite or perseveration. Subsequently, a sub-effective dose of biperiden was able to facilitate the effects of amphetamine upon PR performance, suggesting an ability to enhance dopaminergic function. Both biperiden and scopolamine were also able to reverse a haloperidol-induced deficit in PR performance, however only biperiden was able to rescue the deficit in effort-related choice (ERC) performance. Taken together, these data suggest that the M1 mAChR may be a novel target for the pharmacological enhancement of effort exertion and consequent rescue of motivational impairments. Conversely, M4 receptors may inadvertently modulate effort exertion through regulation of general locomotor activity levels. PMID- 30478409 TI - Multiparametric magnetic resonance imaging in the assessment of anti-EGFRvIII chimeric antigen receptor T cell therapy in patients with recurrent glioblastoma. AB - EGFRvIII targeted chimeric antigen receptor T (CAR-T) cell therapy has recently been reported for treating glioblastomas (GBMs); however, physiology-based MRI parameters have not been evaluated in this setting. Ten patients underwent multiparametric MRI at baseline, 1, 2 and 3 months after CAR-T therapy. Logistic regression model derived progression probabilities (PP) using imaging parameters were used to assess treatment response. Four lesions from "early surgery" group demonstrated high PP at baseline suggestive of progression, which was confirmed histologically. Out of eight lesions from remaining six patients, three lesions with low PP at baseline remained stable. Two lesions with high PP at baseline were associated with large decreases in PP reflecting treatment response, whereas other two lesions with high PP at baseline continued to demonstrate progression. One patient didn't have baseline data but demonstrated progression on follow-up. Our findings indicate that multiparametric MRI may be helpful in monitoring CAR-T related early therapeutic changes in GBM patients. PMID- 30478411 TI - Systematic Analysis and Biomarker Study for Alzheimer's Disease. AB - Revealing the relationship between dysfunctional genes in blood and brain tissues from patients with Alzheimer's Disease (AD) will help us to understand the pathology of this disease. In this study, we conducted the first such large systematic analysis to identify differentially expressed genes (DEGs) in blood samples from 245 AD cases, 143 mild cognitive impairment (MCI) cases, and 182 healthy control subjects, and then compare these with DEGs in brain samples. We evaluated our findings using two independent AD blood datasets and performed a gene-based genome-wide association study to identify potential novel risk genes. We identified 789 and 998 DEGs common to both blood and brain of AD and MCI subjects respectively, over 77% of which had the same regulation directions across tissues and disease status, including the known ABCA7, and the novel TYK2 and TCIRG1. A machine learning classification model containing NDUFA1, MRPL51, and RPL36AL, implicating mitochondrial and ribosomal function, was discovered which discriminated between AD patients and controls with 85.9% of area under the curve and 78.1% accuracy (sensitivity = 77.6%, specificity = 78.9%). Moreover, our findings strongly suggest that mitochondrial dysfunction, NF-kappaB signalling and iNOS signalling are important dysregulated pathways in AD pathogenesis. PMID- 30478413 TI - Homogeneous Multifunction Devices Designing and Layered Implementing Based on Rotary Medium. AB - Multifunctional device with homogeneous anisotropic material parameters are proposed and designed based on linear transformation optics and rotary medium. Four examples including rotating concentrator, rotating amplifying device, rotating shrinking device and rotating transparent device are reported. All of them have bi-functional effects, i.e., they possess concentrating, amplifying, shrinking and transparent effects respectively while have the fields been rotated an angle of pi/N simultaneously in common, where N is the sides number of polygon. All these devices have potential applications, such as energy accumulation or controlling, military camouflage, wireless communication system and radar/antenna protection. Furthermore, alternating isotropic layered structure based on effective medium theory is utilized to remove the anisotropic property of these devices. Simulation results show that the layered structure device behaves almost as perfect as the ideal one when it has sufficient divided layers. The feasibility of designing multifunctional device by natural isotropic materials instead of metamaterials with complicated artificial composite structure would dramatically reduce the fabrication difficulty and move the device a step further towards the practical application. PMID- 30478414 TI - Author Correction: Zircon evidence for incorporation of terrigenous sediments into the magma source of continental basalts. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30478412 TI - Genomic Analysis of Colombian Leishmania panamensis strains with different level of virulence. AB - The establishment of Leishmania infection in mammalian hosts and the subsequent manifestation of clinical symptoms require internalization into macrophages, immune evasion and parasite survival and replication. Although many of the genes involved in these processes have been described, the genetic and genomic variability associated to differences in virulence is largely unknown. Here we present the genomic variation of four Leishmania (Viannia) panamensis strains exhibiting different levels of virulence in BALB/c mice and its application to predict novel genes related to virulence. De novo DNA sequencing and assembly of the most virulent strain allowed comparative genomics analysis with sequenced L. (Viannia) panamensis and L. (Viannia) braziliensis strains, and showed important variations at intra and interspecific levels. Moreover, the mutation detection and a CNV search revealed both base and structural genomic variation within the species. Interestingly, we found differences in the copy number and protein diversity of some genes previously related to virulence. Several machine-learning approaches were applied to combine previous knowledge with features derived from genomic variation and predict a curated set of 66 novel genes related to virulence. These genes can be prioritized for validation experiments and could potentially become promising drug and immune targets for the development of novel prophylactic and therapeutic interventions. PMID- 30478416 TI - IL-12, IL-23 and IL-17 in IBD: immunobiology and therapeutic targeting. AB - IL-12 and IL-23 are closely related cytokines with important roles in the regulation of tissue inflammation. Converging evidence from studies in mice, human observational studies and population genetics supports the importance of these cytokines in the regulation of mucosal inflammation in the gut in particular. Ustekinumab, a therapeutic antibody targeting both cytokines is now widely licensed for the treatment of Crohn's disease, including in Europe, the USA, Canada and Japan, whilst agents targeting IL-23 specifically are in late phase clinical trials. We review the emerging understanding of the biology of IL 12 and IL-23, as well as that of their major downstream cytokines, including IL 17. In particular, we discuss how their biology has influenced the development of clinical trials and therapeutic strategies in IBD, as well as how findings from clinical trials, at times surprising, have in turn refocused our understanding of the underlying biology. PMID- 30478415 TI - Quantifying post-transcriptional regulation in the development of Drosophila melanogaster. AB - Even though proteins are produced from mRNA, the correlation between mRNA levels and protein abundances is moderate in most studies, occasionally attributed to complex post-transcriptional regulation. To address this, we generate a paired transcriptome/proteome time course dataset with 14 time points during Drosophila embryogenesis. Despite a limited mRNA-protein correlation (rho = 0.54), mathematical models describing protein translation and degradation explain 84% of protein time-courses based on the measured mRNA dynamics without assuming complex post transcriptional regulation, and allow for classification of most proteins into four distinct regulatory scenarios. By performing an in-depth characterization of the putatively post-transcriptionally regulated genes, we postulate that the RNA-binding protein Hrb98DE is involved in post transcriptional control of sugar metabolism in early embryogenesis and partially validate this hypothesis using Hrb98DE knockdown. In summary, we present a systems biology framework for the identification of post-transcriptional gene regulation from large-scale, time-resolved transcriptome and proteome data. PMID- 30478417 TI - Illumina-MiSeq analysis of fungi in acid lime roots reveals dominance of Fusarium and variation in fungal taxa. AB - A study was conducted to analyze fungal diversity in the roots of acid lime (Citrus aurantifolia) collected from Oman, a semi-arid country located in the South Eastern part of the Arabian Peninsula. MiSeq analysis showed the Ascomycota and Sordariomycetes were the most abundant phylum and class in acid lime roots, respectively. Glomeromycota, Basidiomycota and Microsporidia were the other fungal phyla, while Glomeromycetes and some other classes belonging to Ascomycota and Basidiomycota were detected at lower frequencies. The genus Fusarium was the most abundant in all samples, making up 46 to 95% of the total reads. Some fungal genera of Arbuscular mycorrhizae and nematophagous fungi were detected in some of the acid lime roots. Analysis of the level of fungal diversity showed that no significant differences exist among groups of root samples (from different locations) in their Chao richness and Shannon diversity levels (P < 0.05). Principle component analysis of fungal communities significantly separated samples according to their locations. This is the first study to evaluate fungal diversity in acid lime roots using high throughput sequencing analysis. The study reveals the presence of various fungal taxa in the roots, dominated by Fusarium species and including some mycorrhizae and nematophagous fungi. PMID- 30478419 TI - Identification and prioritization of gene sets associated with schizophrenia risk by co-expression network analysis in human brain. AB - Schizophrenia polygenic risk is plausibly manifested by complex transcriptional dysregulation in the brain, involving networks of co-expressed and functionally related genes. The main purpose of this study was to identify and prioritize co expressed gene sets in a hierarchical manner, based on the strength of the relationships with clinical diagnosis and with polygenic risk for schizophrenia. Weighted Gene Co-expression Network Analysis (WGCNA) was applied to RNA-quality adjusted DLPFC RNA-Seq data from the LIBD Postmortem Human Brain Repository (90 controls, 74 schizophrenia cases; all Caucasians) to construct co-expression networks and detect "modules" of co-expressed genes. After multiple internal and external validation procedures, modules of selected interest were tested for enrichment in biological ontologies, for association with schizophrenia polygenic risk scores (PRSs) and with diagnosis, and also for enrichment in genes within the significant GWAS loci reported by the Psychiatric Genomic Consortium (PGC2). The association between schizophrenia genetic signals and modules of co expression converged on one module showing not only a significant association with both diagnosis and PRS but also significant overlap with 36 PGC2 loci genes, deemed the strongest candidates for drug targets. This module contained many genes involved in synaptic signaling and neuroplasticity. Fifty-three PGC2 genes were in modules associated only with diagnosis and 59 in modules unrelated to diagnosis or PRS. Our study highlights complex relationships between gene co expression networks in the brain and clinical state and polygenic risk for SCZ and provides a strategy for using this information in selecting and prioritizing potentially targetable gene sets for therapeutic drug development. PMID- 30478418 TI - A Vaccine Based on a Modified Vaccinia Virus Ankara Vector Expressing Zika Virus Structural Proteins Controls Zika Virus Replication in Mice. AB - Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that affects humans and can cause severe neurological complications, including Guillain-Barre syndrome and microcephaly. Since 2007 there have been three large outbreaks; the last and larger spread in the Americas in 2015. Actually, ZIKV is circulating in the Americas, Southeast Asia, and the Pacific Islands, and represents a potential pandemic threat. Given the rapid ZIKV dissemination and the severe neurological and teratogenic sequelae associated with ZIKV infection, the development of a safe and efficacious vaccine is critical. In this study, we have developed and characterized the immunogenicity and efficacy of a novel ZIKV vaccine based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing the ZIKV prM and E structural genes (termed MVA-ZIKV). MVA-ZIKV expressed efficiently the ZIKV structural proteins, assembled in virus-like particles (VLPs) and was genetically stable upon nine passages in cell culture. Immunization of mice with MVA-ZIKV elicited antibodies that were able to neutralize ZIKV and induced potent and polyfunctional ZIKV-specific CD8+ T cell responses that were mainly of an effector memory phenotype. Moreover, a single dose of MVA-ZIKV reduced significantly the viremia in susceptible immunocompromised mice challenged with live ZIKV. These findings support the use of MVA-ZIKV as a potential vaccine against ZIKV. PMID- 30478420 TI - FOXO1 overexpression and loss of pSerine256-FOXO1 expression predicts clinical outcome in esophageal adenocarcinomas. AB - The function of Forkhead box O 1 (FOXO1) and pSerine256-FOXO1 immunostaining in esophageal cancer is unclear. To clarify the prognostic role of nuclear FOXO1 and cytoplasmic pSerine256-FOXO1 immunostaining, a tissue microarray containing more than 600 esophageal cancers was analyzed. In non-neoplastic esophageal mucosae, FOXO1 expression was detectable in low and pSerine256-FOXO1 expression in high intensities. Increased FOXO1 and decreased pSerine256-FOXO1 expression were linked to advanced tumor stage and high UICC stage in esophageal adenocarcinomas (EACs) (tumor stage: p = 0.0209 and p < 0.0001; UICC stage: p = 0.0201 and p < 0.0001) and squamous cell carcinomas (ESCCs) (tumor stage: p = 0.0003 and p = 0.0016; UICC stage: p = 0.0026 and p = 0.0326). Additionally, overexpression of FOXO1 and loss of pSerine256-FOXO1 expression predicted shortened survival of patients with EACs (p = 0.0003 and p = 0.0133) but were unrelated to outcome in patients with ESCCs (p = 0.7785 and p = 0.8426). In summary, our study shows that overexpression of nuclear FOXO1 and loss of cytoplasmic pSerine256-FOXO1 expression are associated with poor prognosis in patients with EACs. Thus, evaluation of FOXO1 and pSerine256-FOXO1 protein expression - either alone or in combination with other markers - might be useful for prediction of clinical outcome in patients with EAC. PMID- 30478421 TI - ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis. AB - Treatment of prostate cancer (PC) by androgen suppression promotes the emergence of aggressive variants that are androgen receptor (AR) independent. Here we identify the transcription factor ONECUT2 (OC2) as a master regulator of AR networks in metastatic castration-resistant prostate cancer (mCRPC). OC2 acts as a survival factor in mCRPC models, suppresses the AR transcriptional program by direct regulation of AR target genes and the AR licensing factor FOXA1, and activates genes associated with neural differentiation and progression to lethal disease. OC2 appears active in a substantial subset of human prostate adenocarcinoma and neuroendocrine tumors. Inhibition of OC2 by a newly identified small molecule suppresses metastasis in mice. These findings suggest that OC2 displaces AR-dependent growth and survival mechanisms in many cases where AR remains expressed, but where its activity is bypassed. OC2 is also a potential drug target in the metastatic phase of aggressive PC. PMID- 30478422 TI - A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate. AB - Understanding the mechanisms underlying autoantibody development will accelerate therapeutic target identification in autoimmune diseases such as systemic lupus erythematosus (SLE)1. Follicular helper T cells (TFH cells) have long been implicated in SLE pathogenesis. Yet a fraction of autoantibodies in individuals with SLE are unmutated, supporting that autoreactive B cells also differentiate outside germinal centers2. Here, we describe a CXCR5-CXCR3+ programmed death 1 (PD1)hiCD4+ helper T cell population distinct from TFH cells and expanded in both SLE blood and the tubulointerstitial areas of individuals with proliferative lupus nephritis. These cells produce interleukin-10 (IL-10) and accumulate mitochondrial reactive oxygen species as the result of reverse electron transport fueled by succinate. Furthermore, they provide B cell help, independently of IL 21, through IL-10 and succinate. Similar cells are generated in vitro upon priming naive CD4+ T cells with plasmacytoid dendritic cells activated with oxidized mitochondrial DNA, a distinct class of interferogenic toll-like receptor 9 ligand3. Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE. PMID- 30478423 TI - 89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer. AB - Programmed cell death protein-1/ligand-1 (PD-1/PD-L1) blockade is effective in a subset of patients with several tumor types, but predicting patient benefit using approved diagnostics is inexact, as some patients with PD-L1-negative tumors also show clinical benefit1,2. Moreover, all biopsy-based tests are subject to the errors and limitations of invasive tissue collection3-11. Preclinical studies of positron-emission tomography (PET) imaging with antibodies to PD-L1 suggested that this imaging method might be an approach to selecting patients12,13. Such a technique, however, requires substantial clinical development and validation. Here we present the initial results from a first-in-human study to assess the feasibility of imaging with zirconium-89-labeled atezolizumab (anti-PD-L1), including biodistribution, and secondly test its potential to predict response to PD-L1 blockade (ClinicalTrials.gov identifiers NCT02453984 and NCT02478099). We imaged 22 patients across three tumor types before the start of atezolizumab therapy. The PET signal, a function of tracer exposure and target expression, was high in lymphoid tissues and at sites of inflammation. In tumors, uptake was generally high but heterogeneous, varying within and among lesions, patients, and tumor types. Intriguingly, clinical responses in our patients were better correlated with pretreatment PET signal than with immunohistochemistry- or RNA sequencing-based predictive biomarkers, encouraging further development of molecular PET imaging for assessment of PD-L1 status and clinical response prediction. PMID- 30478425 TI - Second elotuzumab triplet efficacious in MM. PMID- 30478426 TI - Faecal transplantation reverses colitis. PMID- 30478424 TI - Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer. AB - Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance. PMID- 30478427 TI - Donors with CHIP are safe for allogeneic HSCT. PMID- 30478428 TI - Lorlatinib effective in multiple settings. PMID- 30478429 TI - Neoadjuvant pembrolizumab shows promise. PMID- 30478430 TI - Author Correction: Signal quality of simultaneously recorded endovascular, subdural and epidural signals are comparable. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30478431 TI - Minimising oxygen contamination through a liquid copper-aided group IV metal production process. AB - This paper demonstrates for the first time the fabrication of Zr-Cu alloy ingots from a Hf- free ZrO2 precursor in a molten CaCl2 medium to recover nuclear-grade Zr. The reduction of ZrO2 in the presence of CaO was accelerated by the formation of Ca metal in the intermediate stage of the process. Tests conducted with various amounts of ZrO2 indicate that the ZrO2 was reduced to the metallic form at low potentials applied at the cathode, and the main part of the zirconium was converted to a CuZr alloy with a different composition. The maximum oxygen content values in the CuZr alloy and Zr samples upon using liquid Cu were less than 300 and 891 ppm, respectively. However, Al contamination was observed in the CuZr during the electroreduction process. In order to solve the Al contamination problem, the fabrication process of CuZr was performed using the metallothermic reduction process, and the produced CuZr was used for electrorefining. The CuZr alloy was further purified by a molten salt electrorefining process to recover pure nuclear-grade Zr in a LiF-Ba2ZrF8-based molten salt, the latter of which was fabricated from a waste pickling acid of a Zr clad tube. After the electrorefining process, the recovered Zr metal was fabricated into nuclear-grade Zr buttons through arc melting following a salt distillation process. The results suggest that the removal of oxygen from the reduction product is a key reason for the use of a liquid CaCu reduction agent. PMID- 30478433 TI - Effect of postoperative coffee consumption on gastrointestinal function after abdominal surgery: A systematic review and meta-analysis of randomized controlled trials. AB - Coffee is believed to prevent postoperative ileus. This systematic review and meta-analysis was undertaken to determine the effectiveness of coffee consumption in stimulating gastrointestinal function after abdominal surgery. A number of databases for randomized controlled trials comparing coffee consumption following abdominal surgery versus water drinking or no intervention were searched. Cochrane's Risk of Bias tool was used to assess risk of bias in included studies. Six trials involving 601 participants were included. All studies had high risk of performance bias. Three studies had an unclear risk of selection bias. Postoperative coffee consumption reduced time to first defecation (mean difference (MD), -9.98 hours; 95% CI, -16.97 to -2.99), time to first flatus (MD, -7.14 hours; 95% CI, -10.96 to -3.33), time to first bowel sound (MD, -4.17 hours; 95% CI, -7.88 to -0.47), time to tolerance of solid food (MD, -15.55 hours; 95% CI, -22.83 to -8.27), and length of hospital stay (MD, -0.74 days; 95% CI, -1.14 to -0.33). Benefits increased with increasing complexity of the procedure. None of the included studies reported adverse events associated with coffee consumption. Postoperative coffee consumption is effective and safe for enhancing the recovery of gastrointestinal function after abdominal surgery. PMID- 30478432 TI - DNA methylation dynamics during embryonic development and postnatal maturation of the mouse auditory sensory epithelium. AB - The inner ear is a complex structure responsible for hearing and balance, and organ pathology is associated with deafness and balance disorders. To evaluate the role of epigenomic dynamics, we performed whole genome bisulfite sequencing at key time points during the development and maturation of the mouse inner ear sensory epithelium (SE). Our single-nucleotide resolution maps revealed variations in both general characteristics and dynamics of DNA methylation over time. This allowed us to predict the location of non-coding regulatory regions and to identify several novel candidate regulatory factors, such as Bach2, that connect stage-specific regulatory elements to molecular features that drive the development and maturation of the SE. Constructing in silico regulatory networks around sites of differential methylation enabled us to link key inner ear regulators, such as Atoh1 and Stat3, to pathways responsible for cell lineage determination and maturation, such as the Notch pathway. We also discovered that a putative enhancer, defined as a low methylated region (LMR), can upregulate the GJB6 gene and a neighboring non-coding RNA. The study of inner ear SE methylomes revealed novel regulatory regions in the hearing organ, which may improve diagnostic capabilities, and has the potential to guide the development of therapeutics for hearing loss by providing multiple intervention points for manipulation of the auditory system. PMID- 30478435 TI - Implementation and outcomes of suicide-prevention strategies by restricting access to lethal suicide methods in Korea. AB - For more than 10 years, the suicide rate in South Korea has been the highest among members of the Organization for Economic Cooperation and Development. Suicide-prevention strategies, such as restricting access to lethal suicide methods, have been implemented in Korea. In this paper, we discuss suicide prevention strategies that restrict access to the five leading methods for committing suicide: pesticide ingestion, inhalation of charcoal fumes, jumping from heights, placing oneself in front of moving subway trains, and hanging oneself by the neck. Of the five suicide-prevention strategies outlined in our study, prohibition of the herbicide paraquat and installation of screen doors were proven to be effective, while others need further assessments. Yet, the overall decline in suicide rate from 31.7 per 100,000 people in 2011 to 27.3 per 100,000 people in 2014 suggests that these suicide-prevention strategies have successfully decreased the suicide rate in Korea. PMID- 30478434 TI - Uncovering the mechanism of Maxing Ganshi Decoction on asthma from a systematic perspective: A network pharmacology study. AB - Maxing Ganshi Decoction (MXGSD) is used widely for asthma over thousands of years, but its underlying pharmacological mechanisms remain unclear. In this study, systematic and comprehensive network pharmacology was utilized for the first time to reveal the potential pharmacological mechanisms of MXGSD on asthma. Specifically, we collected 141 bioactive components from the 600 components in MXGSD, which shared 52 targets common to asthma-related ones. In-depth network analysis of these 52 common targets indicated that asthma might be a manifestation of systemic neuro-immuno-inflammatory dysfunction in the respiratory system, and MXGSD could treat asthma through relieving airway inflammation, improving airway remodeling, and increasing drug responsiveness. After further cluster and enrichment analysis of the protein-protein interaction network of MXGSD bioactive component targets and asthma-related targets, we found that the neurotrophin signaling pathway, estrogen signaling pathway, PI3K-Akt signaling pathway, and ErbB signaling pathway might serve as the key points and principal pathways of MXGSD gene therapy for asthma from a systemic and holistic perspective, and also provides a novel idea for the development of new drugs for asthma. PMID- 30478436 TI - High-resolution genetic mapping of putative causal interactions between regions of open chromatin. AB - Physical interaction of regulatory elements in three-dimensional space poses a challenge for studies of disease because non-coding risk variants may be great distances from the genes they regulate. Experimental methods to capture these interactions, such as chromosome conformation capture, usually cannot assign causal direction of effect between regulatory elements, an important component of fine-mapping studies. We developed a Bayesian hierarchical approach that uses two stage least squares and applied it to an ATAC-seq (assay for transposase accessible chromatin using sequencing) data set from 100 individuals, to identify over 15,000 high-confidence causal interactions. Most (60%) interactions occurred over <20 kb, where chromosome conformation capture-based methods perform poorly. For a fraction of loci, we identified a single variant that alters accessibility across multiple regions, and experimentally validated the BLK locus, which is associated with multiple autoimmune diseases, using CRISPR genome editing. Our study highlights how association genetics of chromatin state is a powerful approach for identifying interactions between regulatory elements. PMID- 30478437 TI - Reply to 'Selective effects of heterozygous protein-truncating variants'. PMID- 30478438 TI - Reply to 'No evidence for unknown archaic ancestry in South Asia'. PMID- 30478439 TI - Selective effects of heterozygous protein-truncating variants. PMID- 30478440 TI - Flexible statistical methods for estimating and testing effects in genomic studies with multiple conditions. AB - We introduce new statistical methods for analyzing genomic data sets that measure many effects in many conditions (for example, gene expression changes under many treatments). These new methods improve on existing methods by allowing for arbitrary correlations in effect sizes among conditions. This flexible approach increases power, improves effect estimates and allows for more quantitative assessments of effect-size heterogeneity compared to simple shared or condition specific assessments. We illustrate these features through an analysis of locally acting variants associated with gene expression (cis expression quantitative trait loci (eQTLs)) in 44 human tissues. Our analysis identifies more eQTLs than existing approaches, consistent with improved power. We show that although genetic effects on expression are extensively shared among tissues, effect sizes can still vary greatly among tissues. Some shared eQTLs show stronger effects in subsets of biologically related tissues (for example, brain-related tissues), or in only one tissue (for example, testis). Our methods are widely applicable, computationally tractable for many conditions and available online. PMID- 30478441 TI - A linear mixed-model approach to study multivariate gene-environment interactions. AB - Different exposures, including diet, physical activity, or external conditions can contribute to genotype-environment interactions (G*E). Although high dimensional environmental data are increasingly available and multiple exposures have been implicated with G*E at the same loci, multi-environment tests for G*E are not established. Here, we propose the structured linear mixed model (StructLMM), a computationally efficient method to identify and characterize loci that interact with one or more environments. After validating our model using simulations, we applied StructLMM to body mass index in the UK Biobank, where our model yields previously known and novel G*E signals. Finally, in an application to a large blood eQTL dataset, we demonstrate that StructLMM can be used to study interactions with hundreds of environmental variables. PMID- 30478442 TI - A primer on deep learning in genomics. AB - Deep learning methods are a class of machine learning techniques capable of identifying highly complex patterns in large datasets. Here, we provide a perspective and primer on deep learning applications for genome analysis. We discuss successful applications in the fields of regulatory genomics, variant calling and pathogenicity scores. We include general guidance for how to effectively use deep learning methods as well as a practical guide to tools and resources. This primer is accompanied by an interactive online tutorial. PMID- 30478443 TI - Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions. AB - DNA methylation and Polycomb are key factors in the establishment of vertebrate cellular identity and fate. Here we report de novo missense mutations in DNMT3A, which encodes the DNA methyltransferase DNMT3A. These mutations cause microcephalic dwarfism, a hypocellular disorder of extreme global growth failure. Substitutions in the PWWP domain abrogate binding to the histone modifications H3K36me2 and H3K36me3, and alter DNA methylation in patient cells. Polycomb associated DNA methylation valleys, hypomethylated domains encompassing developmental genes, become methylated with concomitant depletion of H3K27me3 and H3K4me3 bivalent marks. Such de novo DNA methylation occurs during differentiation of Dnmt3aW326R pluripotent cells in vitro, and is also evident in Dnmt3aW326R/+ dwarf mice. We therefore propose that the interaction of the DNMT3A PWWP domain with H3K36me2 and H3K36me3 normally limits DNA methylation of Polycomb-marked regions. Our findings implicate the interplay between DNA methylation and Polycomb at key developmental regulators as a determinant of organism size in mammals. PMID- 30478445 TI - RASA2 and NF1; two-negative regulators of Ras with complementary functions in melanoma. PMID- 30478446 TI - Chromosomal translocation-mediated evasion from miRNA induces strong MEF2D fusion protein expression, causing inhibition of PAX5 transcriptional activity. AB - MEF2D fusion genes are newly discovered recurrent gene abnormalities that are detected in approximately 5% of acute lymphoblastic leukemia cases. We previously demonstrated that the vector-driven expression of MEF2D fusion proteins was markedly stronger than that of wild-type MEF2D; however, the underlying mechanisms and significance of this expression have yet to be clarified. We herein showed that the strong expression of MEF2D fusion proteins was caused by the loss of the target site of miRNA due to gene translocation. We identified the target region of miRNA located in the coding region and selected miR-122 as a candidate of the responsible miRNA. Mutations at a putative binding site of miR 122 increased MEF2D expression, while the transfection of its miRNA mimic reduced the expression of wild-type MEF2D, but not MEF2D fusion proteins. We also found that MEF2D fusion proteins inhibited the transcriptional activity of PAX5, a B cell differentiation regulator in a manner that depended on fusion-specific strong expression and an association with histone deacetylase 4, which may lead to the differentiation disorders of B cells. Our results provide novel insights into the mechanisms underlying leukemia development by MEF2D fusion genes and the involvement of the deregulation of miRNA-mediated repression in cancer development. PMID- 30478447 TI - ERRalpha promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors. AB - Bone is the most common metastatic site for breast cancer. Estrogen-related receptor alpha (ERRalpha) has been implicated in cancer cell invasiveness. Here, we established that ERRalpha promotes spontaneous metastatic dissemination of breast cancer cells from primary mammary tumors to the skeleton. We carried out cohort studies, pharmacological inhibition, gain-of-function analyses in vivo and cellular and molecular studies in vitro to identify new biomarkers in breast cancer metastases. Meta-analysis of human primary breast tumors revealed that high ERRalpha expression levels were associated with bone but not lung metastases. ERRalpha expression was also detected in circulating tumor cells from metastatic breast cancer patients. ERRalpha overexpression in murine 4T1 breast cancer cells promoted spontaneous bone micro-metastases formation when tumor cells were inoculated orthotopically, whereas lung metastases occurred irrespective of ERRalpha expression level. In vivo, Rank was identified as a target for ERRalpha. That was confirmed in vitro in Rankl stimulated tumor cell invasion, in mTOR/pS6K phosphorylation, by transactivation assay, ChIP and bioinformatics analyses. Moreover, pharmacological inhibition of ERRalpha reduced primary tumor growth, bone micro-metastases formation and Rank expression in vitro and in vivo. Transcriptomic studies and meta-analysis confirmed a positive association between metastases and ERRalpha/RANK in breast cancer patients and also revealed a positive correlation between ERRalpha and BRCA1mut carriers. Taken together, our results reveal a novel ERRalpha/RANK axis by which ERRalpha in primary breast cancer promotes early dissemination of cancer cells to bone. These findings suggest that ERRalpha may be a useful therapeutic target to prevent bone metastases. PMID- 30478448 TI - Targeting EIF4E signaling with ribavirin in infant acute lymphoblastic leukemia. AB - The poor outcomes in infant acute lymphoblastic leukemia (ALL) necessitate new treatments. Here we discover that EIF4E protein is elevated in most cases of infant ALL and test EIF4E targeting by the repurposed antiviral agent ribavirin, which has anticancer properties through EIF4E inhibition, as a potential treatment. We find that ribavirin treatment of actively dividing infant ALL cells on bone marrow stromal cells (BMSCs) at clinically achievable concentrations causes robust proliferation inhibition in proportion with EIF4E expression. Further, we find that ribavirin treatment of KMT2A-rearranged (KMT2A-R) infant ALL cells and the KMT2A-AFF1 cell line RS4:11 inhibits EIF4E, leading to decreases in oncogenic EIF4E-regulated cell growth and survival proteins. In ribavirin-sensitive KMT2A-R infant ALL cells and RS4:11 cells, EIF4E-regulated proteins with reduced levels of expression following ribavirin treatment include MYC, MCL1, NBN, BCL2 and BIRC5. Ribavirin-treated RS4:11 cells exhibit impaired EIF4E-dependent nuclear to cytoplasmic export and/or translation of the corresponding mRNAs, as well as reduced phosphorylation of the p-AKT1, p EIF4EBP1, p-RPS6 and p-EIF4E signaling proteins. This leads to an S-phase cell cycle arrest in RS4:11 cells corresponding to the decreased proliferation. Ribavirin causes nuclear EIF4E to re-localize to the cytoplasm in KMT2A-AFF1 infant ALL and RS4:11 cells, providing further evidence for EIF4E inhibition. Ribavirin slows increases in peripheral blasts in KMT2A-R infant ALL xenograft bearing mice. Ribavirin cooperates with chemotherapy, particularly L asparaginase, in reducing live KMT2A-AFF1 infant ALL cells in BMSC co-cultures. This work establishes that EIF4E is broadly elevated across infant ALL and that clinically relevant ribavirin exposures have preclinical activity and effectively inhibit EIF4E in KMT2A-R cases, suggesting promise in EIF4E targeting using ribavirin as a means of treatment. PMID- 30478449 TI - Integrative network biology analysis identifies miR-508-3p as the determinant for the mesenchymal identity and a strong prognostic biomarker of ovarian cancer. AB - Ovarian cancer is a heterogeneous malignancy that poses tremendous clinical challenge. Based on unsupervised classification of whole-genome gene expression profiles, four molecular subtypes of ovarian cancer were recently identified. However, single-driver molecular events specific to these subtypes have not been clearly elucidated. We aim to characterize the regulatory mechanisms underlying the poor prognosis mesenchymal subtype of ovarian cancer using a systems biology approach, involving a variety of molecular modalities including gene and microRNA expression profiles. miR-508-3p emerged as the most powerful determinant that regulates a cascade of dysregulated genes in the mesenchymal subtype, including core genes involved in epithelial-mesenchymal transition (EMT) program. Moreover, miR-508-3p down-regulation, due to promoter hypermethylation, was directly correlated with metastatic behaviors in vitro and in vivo. Taken together, our multidimensional network analysis identified miR-508-3p as a master regulator that defines the mesenchymal subtype and provides a novel prognostic biomarker to improve management of this disease. PMID- 30478450 TI - The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention. AB - Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin-angiotensin system (RAS) is a major physiological regulatory pathway controlling salt-water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2). We report decreasing expression and increasing CpG island methylation of AGTR1 in metastatic versus primary melanoma and detection in serum of methylated genomic DNA from the AGTR1 CpG island in metastatic melanoma implying that AGTR1 encodes a tumour suppressor function in melanoma. Consistent with this hypothesis, antagonism of AT1R using losartan or shRNA-mediated knockdown in melanoma cell lines expressing AGTR1 resulted in acquisition of the ability to proliferate in serum-free conditions. Conversely, ectopic expression of AGTR1 in cell lines lacking endogenous expression inhibits proliferation irrespective of the presence of AngII implying a ligand-independent suppressor function for AT1R. Treatment of melanoma cell lines expressing endogenous AT2R with either AngII or the AT2R selective agonist Y6AII induces proliferation in serum-free conditions whereas the AT2R-specific antagonists PD123319 and EMA401 inhibit melanoma growth and angiogenesis and potentiate inhibitors of BRAF and MEK in cells with BRAF V600 mutations. Our results demonstrate that the RAS has both oncogenic and tumour suppressor functions in melanoma. Pharmacological inhibition of AT2R may provide therapeutic opportunities in melanomas expressing this receptor and AGTR1 CpG island methylation in serum may serve as a novel biomarker of metastatic melanoma. PMID- 30478451 TI - Real-time insight into the doping mechanism of redox-active organic radical polymers. AB - Organic radical polymers for batteries represent some of the fastest-charging redox active materials available. Electron transport and charge storage must be accompanied by ion transport and doping for charge neutrality, but the nature of this process in organic radical polymers is not well understood. This is difficult to intuitively predict because the pendant radical group distinguishes organic radical polymers from conjugated, charged or polar polymers. Here we show for the first time a quantitative view of in situ ion transport and doping in organic radical polymers during the redox process. Two modes dominate: doping by lithium ion expulsion and doping by anion uptake. The dominance of one mode over the other is controlled by anion type, electrolyte concentration and timescale. These results apply in any scenario in which electrolyte is in contact with a non conjugated redox active polymer and present a means of quantifying doping effects. PMID- 30478452 TI - Avoiding common pitfalls in machine learning omic data science. PMID- 30478453 TI - Highly mechanosensitive ion channels from graphene-embedded crown ethers. AB - The ability to tune ionic permeation across nanoscale pores profoundly impacts diverse fields from nanofluidic computing to drug delivery. Here, we take advantage of complex formation between crown ethers and dissolved metal ions to demonstrate graphene-based ion channels highly sensitive to externally applied lattice strain. We perform extensive room-temperature molecular dynamics simulations of the effects of tensile lattice strain on ion permeation across graphene-embedded crown ether pores. Our findings suggest the first instance of solid-state ion channels with an exponential permeation sensitivity to strain, yielding an order of magnitude ion current increase for 2% of isotropic lattice strain. Significant permeation tuning is also shown to be achievable with anisotropic strains. Finally, we demonstrate strain-controllable ion sieving in salt mixtures. The observed high mechanosensitivity is shown to arise from strain induced control over the competition between ion-crown and ion-solvent interactions, mediated by the atomic thinness of graphene. PMID- 30478456 TI - From EMUC18. PMID- 30478444 TI - Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. AB - Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits. PMID- 30478457 TI - A comparison of the Macintosh laryngoscope, McGrath video laryngoscope, and Pentax Airway Scope in paediatric nasotracheal intubation. AB - We evaluated the performance of the McGrath video laryngoscope and Pentax Airway Scope in comparison with the Macintosh laryngoscope for nasotracheal intubation in paediatric patients. For this, 108 patients were enrolled in an open-label, randomized controlled trial. Patients were randomly allocated to one of three groups based on use of the Macintosh laryngoscope, McGrath video laryngoscope, or Pentax Airway Scope. Time to intubation, the intubation difficulty, and the quality of navigation were compared among groups. The median nasotracheal intubation time [interquartile range] in the Macintosh group (33.5 [28.3-39.8] s) was significantly shorter than those of the McGrath (39.0 [32.0-43.0] s) and Pentax groups (43.0 [35.0-52.0] s). The difficulty of nasotracheal intubation was similar among all groups. When navigating and aligning the tube from the oropharynx into the glottic inlet, the cuff inflation method was required in significantly fewer patients for the Macintosh group (11.1%) than for the McGrath (48.6%) and Pentax (51.4%) groups. Thus, compared to the McGrath video laryngoscope and Pentax Airway Scope, the Macintosh laryngoscope allowed shorter nasotracheal intubation times and better facilitated tracheal navigation, requiring less use of the cuff inflation method to navigate the tracheal tube into the glottic inlet. PMID- 30478455 TI - Understanding flow dynamics, viability and metastatic potency of cervical cancer (HeLa) cells through constricted microchannel. AB - To understand the burgeoning challenges of metastasis, a microchannel of 35 MUm diameter, constricted to 7 MUm for a distance of 200 MUm in a total length of 3 mm, was designed and fabricated using a mask aligner made of polydimethylsiloxane (PDMS) to mimic in vivo capillaries. A thin glass cover-slide was mounted on top to monitor the motion of single or aggregated malignant HeLa cells (size 17-30 MUm) microscopically through the constricted microchannel at a constant flow rate of 30 MUl/h. Quantitative deconvolution of high-speed videographs of a single cell of 30 MUm revealed cellular deformation while passing through constriction, having elongation index, average transit velocity and entry time of 2.67, 18 mm/s and 5.1 ms, respectively. Morphological analysis of live and apoptotic cells by dual staining with Acridine Orange/Ethidium Bromide demonstrated retention of a significant viable cell population after exit through the constriction and a viability index of 50% was quantified by dye exclusion assay. The cumulative data for microfluidic parameters, morphology and relevant metastatic MMP2 gene expression efficiency measured by real-time polymerase chain reaction revealed retention of virulence potency that could possibly cause metastasis, would be beneficial in developing futuristic MEMS device for cancer theranostics. PMID- 30478458 TI - Escherichia coli "Marionette" strains with 12 highly optimized small-molecule sensors. AB - Cellular processes are carried out by many genes, and their study and optimization requires multiple levers by which they can be independently controlled. The most common method is via a genetically encoded sensor that responds to a small molecule. However, these sensors are often suboptimal, exhibiting high background expression and low dynamic range. Further, using multiple sensors in one cell is limited by cross-talk and the taxing of cellular resources. Here, we have developed a directed evolution strategy to simultaneously select for lower background, high dynamic range, increased sensitivity, and low cross-talk. This is applied to generate a set of 12 high performance sensors that exhibit >100-fold induction with low background and cross-reactivity. These are combined to build a single "sensor array" in the genomes of E. coli MG1655 (wild-type), DH10B (cloning), and BL21 (protein expression). These "Marionette" strains allow for the independent control of gene expression using 12 small-molecule inducers. PMID- 30478459 TI - Exploiting the vicinal disubstituent effect on the diastereoselective synthesis of gamma and delta lactones. AB - Trifluoroacetic acid catalysed lactonization of vicinal disubstituted gamma hydroxyesters was investigated in different solvents. The reaction kinetics, monitored by NMR spectroscopy, showed that: (i) the vic-disubstituent effect is stereoselective since the anti diastereoisomer ring closes substantially more rapidly than the syn isomer ring; (ii) the anti-vic effect is much stronger than the classical Thorpe-Ingold effect (known also as the gem-disubstituent effect), instead the syn diastereoisomers have rate constants comparable to that of the gem-disubstituted ester; (iii) the vic-effect can be enhanced by increasing the steric hindrance of one of the two substituents or carrying out the reaction in non-polar solvents. DFT computations of energy barriers (DeltaG?) were in good agreement with the experimental data. The distortion/interaction-activation strain model together with the Winstein-Holness kinetic scheme gave more insights into the origin of the vic-effect. An application of this effect consists of the diastereomeric resolution of disubstituted gamma and delta lactones, among which are the naturally occurring Nicotiana t. lactone, the whisky and cognac oak lactones, and the Aerangis lactone. Both cis and trans diastereoisomers of these lactones were isolated in good yield and with high diastereomeric excess (de >92%). The selectivities of the diastereomeric resolution process, determined by NMR spectroscopy, are reported as well. PMID- 30478460 TI - DNA flower-encapsulated horseradish peroxidase with enhanced biocatalytic activity synthesized by an isothermal one-pot method based on rolling circle amplification. AB - DNA nanotechnology has been developed to construct a variety of functional two- and three-dimensional structures for versatile applications. Rolling circle amplification (RCA) has become prominent in the assembly of DNA-inorganic composites with hierarchical structures and attractive properties. Here, we demonstrate a one-pot method to directly encapsulate horseradish peroxidase (HRP) in DNA flowers (DFs) during RCA. The growing DNA strands and Mg2PPi crystals lead to the construction of porous DFs, which provide sufficient interaction sites for spontaneously incorporating HRP molecules into DFs with high loading capacity and good stability. Furthermore, in comparison with free HRP, the DNA flower encapsulated HRP (termed HRP-DFs) demonstrate enhanced enzymatic activity, which can efficiently biocatalyze the H2O2-mediated etching of gold nanorods (AuNRs) to generate distinct color changes since the longitudinal localized surface plasmon resonance (LSPR) frequency of AuNRs is highly sensitive to the changes in the AuNR aspect ratio. Through rationally incorporating the complementary thrombin aptamer sequence into the circular template, the synthesized HRP-DF composites are readily used as amplified labels for visual and colorimetric detection of thrombin with ultrahigh sensitivity and excellent selectivity. Therefore, our proposed strategy for direct encapsulation of enzyme molecules into DNA structures shows considerable potential applications in biosensing, biocatalysis, and point-of-care diagnostics. PMID- 30478461 TI - Shape dependence of thermodynamics of adsorption on nanoparticles: a theoretical and experimental study. AB - Nanomaterials have excellent adsorption performance, which mainly depends on the adsorption thermodynamics that is related to the shape of the nanoparticles that make up the nanomaterial, but the effects of shape on the thermodynamics of adsorption are not fully clear. In this paper, theoretically, the general formulae of adsorption thermodynamic properties for nanoparticles with different shapes and different sizes were derived, and the influencing regularities and mechanisms on adsorption thermodynamic properties were discussed. Experimentally, the influences of the shape and size of nano-CeO2 on the thermodynamics of adsorption were studied in aqueous solution. The experiment results showed that the shape has significant influences on the thermodynamics of adsorption, and the smaller the particle size, the more significant the effects of shape on the thermodynamics. For the adsorption of nano-CeO2 with different shapes and the same equivalent particle size, compared with the sphere, the equilibrium constant of adsorption for the octahedron is larger, while the molar Gibbs free energy of adsorption , the molar adsorption enthalpy of adsorption and the molar adsorption entropy of adsorption are smaller. For the adsorption of nano-CeO2 with the same shape, with the decreasing particle size, increases, while , and decrease; and , , and are each linearly related to the reciprocal of particle size. The experimental results are consistent with the theoretical relations. The theories can quantitatively describe the adsorption behavior on nanoparticles, explain the regularities and mechanisms of influence of shape, and provide guidance for the research and application of nanoadsorption. PMID- 30478462 TI - Terahertz phase jumps for ultra-sensitive graphene plasmon sensing. AB - Phase behavior of the reflected terahertz radiation (THz) under surface plasmon resonance (SPR) supported by doped graphene has been comprehensively investigated via theoretical analysis with simulation verifications. For a TM-polarized wave, the dependence of the phase on the angle of incidence has a region with an abrupt jump-like change. We found in particular that the resonance phase dependence would change from step-like contour to Fano lineshape when the system passed through the optimum SPR conditions (i.e., R = 0) in terahertz regime. Monitoring the transformation could provide ultrahigh-sensitive label-free detection of biomolecules. Importantly, the characteristic of phase jumps as a readout response to achieve refractive index sensing that outperforms traditional terahertz-amplitude-based attenuated total reflection (ATR) spectroscopy is valuable. The results demonstrated a high figure of merit (FOM) of up to 171, based on the terahertz phase information. Moreover, the sensing range could be tuned by changing the surface conductivity of graphene via high doping levels or with few-layer graphene. These terahertz phase response characteristics of graphene plasmon are promising for tunable ultra-sensitivity (bio)chemical sensing applications. PMID- 30478463 TI - Total synthesis of the potent anti-inflammatory natural product solomonamide A along with structural revision and biological activity evaluation. AB - Herein, we report the total synthesis of solomonamide A along with its structural revision for the first time. The natural product possesses very potent anti inflammatory activity, and it contains a macrocyclic peptide having four consecutive stereocenters on an unnatural amino acid component. The key features in the present synthesis include the application of an Evans aldol reaction, ligand-free Heck macrocyclization and chemoselective oxidations. The challenging task of fixing the stereochemistry of OH at the C5-position was accomplished with the help of DFT calculations, applying a quantum-mechanical (QM)/NMR combined approach. Biological evaluation in a mouse paw edema model revealed that a low dose (0.3 mg kg-1) of the synthesized solomonamide A showed 74% reduction at 6 h, which was comparable to a high dose (10 mg kg-1) standard drug dexamethasone effect (75% at 6 h). Thus, we further confirmed the revised structure of solomonamide A. PMID- 30478464 TI - Achievement of ligand-field induced thermochromic luminescence via two-step single-crystal to single-crystal transformations. AB - We report here a new approach to achieve thermochromic luminescence through thermally induced ligand-field transformations. A one-dimensional chain manganese(ii) complex exhibits thermochromic luminescence from blue-green (502 nm) to red (617 nm) emission in a wide range of temperatures (480-80 K), ascribed to the conversion of a tetrahedronal to trigonal bipyramidal ligand-field via two step single-crystal to single-crystal transformations. PMID- 30478465 TI - Engineering the carrier dynamics of g-C3N4 by rolling up planar sheets into nanotubes via ultrasonic cavitation. AB - Rolling up 2D atomic layered materials into 1D nanotubes gives rise to fascinating properties due to their lower dimension, higher anisotropy, and strain effects. In this work, the curving of 2D graphitic C3N4 (g-C3N4) sheets into 1D nanotubes is demonstrated for the first time through simple and clean ultrasonic treatments. The steady-state optical transitions are slightly enhanced while the localized trapping of excited carriers is considerably suppressed after rolling up the planar sheets into nanotubes. The mechanical method to modulate the dimension scarcely changes the chemical structures, enabling the pure investigation on shape-induced physical effects. As a proof of principle, this work confirms the dynamics of excited carriers, and the photoelectronic properties of 2D semiconductors can be significantly engineered by a simple morphological evolution. PMID- 30478466 TI - Probing the cooperative mechanism of the MU-delta opioid receptor heterodimer by multiscale simulation. AB - Accumulated experimental evidence indicated that G-protein coupled receptors (GPCRs) could form biologically relevant oligomers and hetero-oligomers possess different functional properties from monomers and homo-oligomers, for example, unique pharmacology. However, the urgent lack of crystal structures of the GPCR oligomers results in very limited knowledge about their structural and functional mechanisms. In this work, we utilized a multiscale simulation strategy coupled with principal component analysis, correlation analysis and a protein structure network to study the hetero-dimerization of the MU-OR and delta-OR. We probed the cooperative mechanism involved in their activations, the allosteric communication pathways, the impact of the interface and differences from the MU-OR homodimer. The result indicates that TM1-TM2-H8 is a stable interface, but some residues of TM7 also participate in the dimer interface. Similar to the homodimer, the hetero dimerization of the two inactive receptors would enhance the constitutive activation of one subunit but weaken that of the other subunit, both presenting a negative cooperativity. However, in contrast to the homodimer, the hetero dimerization of the active protomer with the inactive one would weaken the constitutive activation of the inactive unit but maintain the activity of the active subunit. In addition, the hetero-dimerization and the activation of one subunit could significantly alter the types and the numbers of residues participating in the allosteric pathway from the ligand-binding pocket to the G protein region and the pathway between two subunits. Some important residues were identified, which play important roles in modulating activations and cooperativity between two subunits. The observations from this work indicate that the negative cooperativity should be a common feature for the homodimers and the heterodimers, but the cooperative results would be significantly different between them, depending on the activated extent of one subunit. PMID- 30478467 TI - Base mediated green synthesis of enantiopure 2-C-spiro-glycosyl-3-nitrochromenes. AB - A novel green synthetic methodology has been developed to obtain enantiopure (2S) 2-C-spiro-glycosyl-3-nitrochromenes following the oxa-Michael-aldol condensation reaction of sugar derived 3-C-vinyl nitro olefins with substituted salicylaldehydes using Et3N as a base under neat conditions at rt-40 degrees C. The stereochemistry of the product is confirmed by a single crystal X-ray study. Several advantages are associated with this protocol such as cost effectiveness, easy accessibility, short reaction time, high yields, wide substrate scope and high enantiopurity. PMID- 30478468 TI - Posterolateral corner of the knee: an expert consensus statement on diagnosis, classification, treatment, and rehabilitation. AB - PURPOSE: To develop a statement on the diagnosis, classification, treatment, and rehabilitation concepts of posterolateral corner (PLC) injuries of the knee using a modified Delphi technique. METHODS: A working group of three individuals generated a list of statements relating to the diagnosis, classification, treatment, and rehabilitation of PLC injuries to form the basis of an initial survey for rating by an international group of experts. The PLC expert group (composed of 27 experts throughout the world) was surveyed on three occasions to establish consensus on the inclusion/exclusion of each item. In addition to rating agreement, experts were invited to propose further items for inclusion or to suggest modifications of existing items at each round. Pre-defined criteria were used to refine item lists after each survey. Statements reaching consensus in round three were included within the final consensus document. RESULTS: Twenty seven experts (100% response rate) completed three rounds of surveys. After three rounds, 29 items achieved consensus with over 75% agreement and less than 5% disagreement. Consensus was reached in 92% of the statements relating to diagnosis of PLC injuries, 100% relating to classification, 70% relating to treatment and in 88% of items relating to rehabilitation statements, with an overall consensus of 81%. CONCLUSIONS: This study has established a consensus statement relating to the diagnosis, classification, treatment, and rehabilitation of PLC injuries. Further research is needed to develop updated classification systems, and better understand the role of non-invasive and minimally invasive approaches along with standardized rehabilitation protocols. LEVEL OF EVIDENCE: Consensus of expert opinion, Level V. PMID- 30478469 TI - Anterior buttress plate is successful for treating posterior sterno-clavicular dislocation. AB - PURPOSE: Traumatic posterior instability of the sternoclavicular joint is a potentially life-threatening injury. In contrast to the low incidence there is a plethora of different strategies to treat this lesion. It was the objective of this retrospective analysis to evaluate and further develop current strategies. METHODS: In this retrospective analysis all posterior dislocations that were diagnosed and treated between 2011 and 2018 were included. In this 7 year period, eight male patients (median age 32 years) were operated. RESULTS: Three patients were not diagnosed at the primary institution and were referred later. Five patients were treated with an anterior buttress plate with clavicular stabilisation only. One patient was stabilized with a temporary sternoclavicular arthrodesis. Two patients were operated using an autologous tendon graft. All of the patients underwent an immediate postoperative CT-scan that documented the anatomical articulation. All patients treated with a plate underwent implant removal. A final CT examination after removal documented the maintenance of the anatomic alignment. CONCLUSIONS: The buttress plate technique with clavicular screw fixation is a sufficient treatment to restore and preserve a normal sternoclavicular alignment. The technique finds its indication in unidirectional posterior instability. LEVEL OF EVIDENCE: IV. PMID- 30478470 TI - Peripheral fixation of meniscal allograft does not reduce coronal extrusion under physiological load. AB - PURPOSE: Meniscal graft extrusion is a concern following meniscal allograft transplantation (MAT). MAT surgical techniques continue to evolve in an effort to reduce extrusion; however, improvements remain difficult to measure in vivo. A novel MRI-compatible in vitro loading device capable of applying physiologically relevant loads has been developed, allowing for the measurement of extrusion under a variety of controllable conditions. The objective of this study was to compare maximal medial MAT extrusion (1) with and (2) without an additional peripheral third point of fixation on the tibial plateau. METHODS: Twelve human cadaveric knees underwent medial MAT, utilizing soft tissue anterior and posterior root fixation via transosseous suture, with a third transosseous suture tied over a button providing peripheral fixation on the tibial plateau. The joint was positioned at 5 degrees of flexion and loaded to 1 * body weight (647.7 +/- 159.0 N) during MR image acquisition, with and without peripheral fixation. The joint was then positioned at 30 degrees of flexion and the process was repeated. Maximal coronal extrusion was measured. RESULTS: An increase in maximal coronal meniscal extrusion was noted between the unloaded and loaded states. At 30 degrees of flexion, with the addition of a peripheral fixation point, a statistically significant difference in absolute extrusion (p = 0.02) and relative percent extrusion (p = 0.04) between the unloaded and loaded state was found. The addition of a peripheral fixation suture resulted in an overall mean percent difference of - 2.49% (SD 14.1; 95% CI - 11.95, 6.97; n.s.) in extrusion at 5 degrees of flexion and a mean percent difference of - 0.95% (SD 7.3; 95% CI 5.62, 3.71; n.s.) in extrusion at 30 degrees of flexion. These differences were not statistically significant. CONCLUSION: These results suggest that the addition of a peripheral anchor in medial MAT does not reduce the amount of maximal coronal extrusion and, therefore, may not confer any clinical benefit. Surgical techniques utilized to reduce MAT extrusion need further investigation to understand if the added technical difficulty and potential expense is warranted. PMID- 30478472 TI - ? PMID- 30478471 TI - Look to the future. PMID- 30478473 TI - Overexpression of geraniol synthase induces heat stress susceptibility in Nicotiana tabacum. AB - MAIN CONCLUSION: Transgenic tobacco plants overexpressing the monoterpene alcohol geraniol synthase exhibit hypersensitivity to thermal stress, possibly due to suppressed sugar metabolism and transcriptional regulation of genes involved in thermal stress tolerance. Monoterpene alcohols function in plant survival strategies, but they may cause self-toxicity to plants due to their hydrophobic and highly reactive properties. To explore the role of these compounds in plant stress responses, we assessed transgenic tobacco plants overexpressing the monoterpene alcohol geraniol synthase (GES plants). Growth, morphology and photosynthetic efficiency of GES plants were not significantly different from those of control plants (wild-type and GUS-transformed plants). While GES plants' direct defenses against herbivores or pathogens were similar to those of control plants, their indirect defense (i.e., attracting herbivore enemy Nesidiocoris tenuis) was stronger compared to that of control plants. However, GES plants were susceptible to cold stress and even more susceptible to extreme heat stress (50 degrees C), as shown by decreased levels of sugar metabolites, invertase activity and its products (Glc and Fru), and leaf starch granules. Moreover, GES plants showed decreased transcription levels of the WRKY33 transcription factor gene and an aquaporin gene (PIP2). The results of this study show that GES plants exhibit enhanced indirect defense ability against herbivores, but conversely, GES plants exhibit hypersensitivity to heat stress due to suppressed sugar metabolism and gene regulation for thermal stress tolerance. PMID- 30478474 TI - Factors associated with lamina cribrosa displacement after trabeculectomy. PMID- 30478475 TI - Can benign lymphoid tissue changes in 18F-FDG PET/CT predict response to immunotherapy in metastatic melanoma? AB - BACKGROUND: An association between immune-related adverse events (irAEs) caused by immunotherapeutic agents and the clinical benefit of immunotherapy has been suggested. We retrospectively evaluated by means of 18F-FDG PET/CT lymphoid tissue changes in the mediastinal/hilar lymph nodes and the spleen in response to ipilimumab administration in metastatic melanoma. METHODS: A total of 41 patients with unresectable metastatic melanoma underwent 18F-FDG PET/CT before the start of ipilimumab (baseline PET/CT), after two cycles (interim PET/CT) and at the end of treatment (late PET/CT). Data analysis was focused on the mediastinal/hilar lymph nodes and the spleen. The patients' best clinical response (BCR) was used as reference. RESULTS: According to the BCR reference, 31 patients showed disease control (DC) and 10 patients showed progressive disease (PD). Mediastinal/hilar lymph node evaluation revealed that in total 4 patients in the interim or late PET/CT (10%) demonstrated a 'sarcoid-like lymphadenopathy' as response to treatment (LN-positive). All LN-positive patients responded to ipilimumab with DC. On the other hand, no significant differences between the DC and PD groups regarding both semi-quantitative and quantitative 18F-FDG PET spleen-related parameters at baseline and as response to treatment were detected. CONCLUSION: Based on our findings, 10% patients in the interim or late PET/CT showed 'sarcoid like lymphadenopathy' as response to treatment. All these patients showed disease control, implying a relation between the appearance of sarcoid-like lymphadenopathy and the clinical benefit of anti-CTLA-4 therapy. On the other hand, quantitative 18F-FDG PET analysis of the spleen showed a poor performance in predicting clinical benefit to ipilimumab. PMID- 30478476 TI - Empiric therapy for kidney stones. AB - Careful phenotyping of patients to classify those with kidney stones has a long and important history in revealing the chemical basis for stone formation. Advances in our genetic understanding of kidney stones will lead to incredible insights regarding the pathophysiology of this common disorder. At this time, both evaluation of urine chemistry and genotyping of patients are extremely useful in the setting of a university and research-based kidney stone clinic. For much of the world, in a more clinically focused setting, these techniques are neither available nor absolutely necessary. Careful implementation of an empiric prescription based on stone composition would have an important effect to reduce stone recurrence in the world's many stone formers. Increased fluid intake, generic dietary manipulations, and prescription of potassium citrate and thiazides are all appropriate empiric therapies for people with calcium and uric acid kidney stones. PMID- 30478477 TI - Assessment of thermally comfortable urban spaces in Amsterdam during hot summer days. AB - Since it is insufficiently clear to urban planners in the Netherlands to what extent design measures can reduce heat stress and which urban spaces are most comfortable, this study evaluates the impact of shading, urban water, and urban green on the thermal comfort of urban spaces during hot summer afternoons. The methods used include field surveys, meteorological measurements, and assessment of the PET (physiological equivalent temperature). In total, 21 locations in Amsterdam (shaded and sunny locations in parks, streets, squares, and near water bodies) were investigated. Measurements show a reduction in PET of 12 to 22 degrees C in spaces shaded by trees and buildings compared to sunlit areas, while water bodies and grass reduce the PET up to 4 degrees C maximum compared to impervious areas. Differences in air temperature between the locations are generally small and it is concluded that shading, water and grass reduce the air temperature by roughly 1 degrees C. The surveys (n = 1928) indicate that especially shaded areas are perceived cooler and more comfortable than sunlit locations, whereas urban spaces near water or green spaces (grass) were not perceived as cooler or thermally more comfortable. The results of this study highlight the importance of shading in urban design to reduce heat stress. The paper also discusses the differences between meteorological observations and field surveys for planning and designing cool and comfortable urban spaces. Meteorological measurements provide measurable quantities which are especially useful for setting or meeting target values or guidelines in reducing urban heat in practice. PMID- 30478478 TI - Remote Real-Time Ultrasound Supervision via Commercially Available and Low-Cost Tele-Ultrasound: a Mixed Methods Study of the Practical Feasibility and Users' Acceptability in an Emergency Department. AB - Minor emergency departments (ED) struggle to access sufficient expertise to supervise learners of lung and cardiac point-of-care ultrasound (POCUS). Using tele-ultrasound (tele-US) for remote supervision may remedy this situation. We aimed to evaluate the feasibility of real-time supervision via tele-US when applied to an everyday ED clinic. We conducted a mixed methods study that assessed practical feasibility, determined performance, and explored users' acceptability of supervision via tele-US. Technical performance was assessed quantitatively by the ratio in mean gray value between images on site and as received by the supervisor, and by after-compression frame rate. Qualitatively, 12 exploratory semi-structured interviews were conducted with exposed junior doctors and supervisors. Remote supervision via tele-US was performed with 10 junior doctors scanning 45 included patients. During performance assessment, neither alternating internet connection nor software significantly changed the mean gray value ratio. The lowest median frame rate of 4.6 (interquartile range [IQR]: 3.1-5.0) was found by using a 4G internet connection; the highest of 28.5 (IQR: 28.5-29.0) was found with alternative computer and local area network internet connection. In interviews, supervisors stressed the importance of preserving frame rate, and junior doctors emphasized a need for shared ultrasound terminology. In the qualitative analysis, setup mobility, accessibility, and time consumption were emphasized as being of key importance for future clinical implementations. Remote supervision via a commercially available and low-cost tele-US setup is operational for both junior doctors and supervisors when applied to lung and cardiac POCUS scans of hospitalized patients. PMID- 30478479 TI - Beyond Human Perception: Sexual Dimorphism in Hand and Wrist Radiographs Is Discernible by a Deep Learning Model. AB - Despite the well-established impact of sex and sex hormones on bone structure and density, there has been limited description of sexual dimorphism in the hand and wrist in the literature. We developed a deep convolutional neural network (CNN) model to predict sex based on hand radiographs of children and adults aged between 5 and 70 years. Of the 1531 radiographs tested, the algorithm predicted sex correctly in 95.9% (kappa = 0.92) of the cases. Two human radiologists achieved 58% (kappa = 0.15) and 46% (kappa = - 0.07) accuracy. The class activation maps (CAM) showed that the model mostly focused on the 2nd and 3rd metacarpal base or thumb sesamoid in women, and distal radioulnar joint, distal radial physis and epiphysis, or 3rd metacarpophalangeal joint in men. The radiologists reviewed 70 cases (35 females and 35 males) labeled with sex along with heat maps generated by CAM, but they could not find any patterns that distinguish the two sexes. A small sample of patients (n = 44) with sexual developmental disorders or transgender identity was selected for a preliminary exploration of application of the model. The model prediction agreed with phenotypic sex in only 77.8% (kappa = 0.54) of these cases. To the best of our knowledge, this is the first study that demonstrated a machine learning model to perform a task in which human experts could not fulfill. PMID- 30478480 TI - Arabidopsis Group IIId ERF proteins positively regulate primary cell wall-type CESA genes. AB - The cell wall determines morphology and the environmental responses of plant cells. The primary cell wall (PCW) is produced during cell division and expansion, determining the cell shape and volume. After cell expansion, specific types of plant cells produce a lignified wall, known as a secondary cell wall (SCW). We functionally analyzed Group IIId Arabidopsis AP2/EREBP genes, namely ERF34, ERF35, ERF38, and ERF39, which are homologs of a rice ERF gene previously proposed to be related to SCW biosynthesis. Expression analysis revealed that these four genes are expressed in regions related to cell division and/or cell differentiation in seedlings (i.e., shoot apical meristems, the primordia of leaves and lateral roots, trichomes, and central cylinder of primary roots) and flowers (i.e., vascular tissues of floral organs and replums and/or valve margins of pistils). Overexpression of ERF genes significantly upregulated PCW-type, but not SCW-type, CESA genes encoding cellulose synthase catalytic subunits in Arabidopsis seedlings. Transient co-expression reporter analysis indicated that ERF35, ERF38, and ERF39 possess transcriptional activator activity, and that ERF34, ERF35, ERF38, and ERF39 upregulated the promoter activity of CESA1, a PCW type CESA gene, through the DRECRTCOREAT elements, the core cis-acting elements known to be recognized by AP2/ERF proteins. Together, our findings show that Group IIId ERF genes are positive transcriptional regulators of PCW-type CESA genes in Arabidopsis and are possibly involved in modulating cellulose biosynthesis in response to developmental requirements and environmental stimuli. PMID- 30478481 TI - Expression of a tobacco nicotine biosynthesis gene depends on the JRE4 transcription factor in heterogenous tomato. AB - The jasmonate-responsive transcription factor ERF189 in tobacco (Nicotiana tabacum) and its ortholog JRE4 in tomato (Solanum lycopersicum) regulate a series of biosynthetic genes involved in the nicotine and steroidal glycoalkaloid pathways. In tobacco, QUINOLINATE PHOSPHORIBOSYL TRANSFERASE 2 (NtQPT2) is regulated by ERF189; however, we found that the tomato QPT gene is not regulated by JRE4. Here, we explored whether and how NtQPT2 is regulated in a heterogenous tomato host. We used a NtQPT2 promoter-driven reporter gene to examine the cell type-specific and jasmonate-induced expression of this gene in transgenic tomato hairy roots. The downregulation of the reporter in the jre4 loss-of-function tomato mutant and its transactivation by JRE4 in transient expression experiments suggested that JRE4, like its ortholog ERF189 in tobacco, activates the NtQPT2 promoter in tomato. We discuss the evolution of QPT2 in the Nicotiana lineage, which mainly occurred through mutational changes in the promoter that altered the control of the functionally conserved transcription factors. PMID- 30478482 TI - [Does autotransplantation of parathyroid glands influence parathyroid gland function after thyroidectomy?] PMID- 30478483 TI - [Soft tissue sarcomas: limb salvage using reconstructive plastic surgery techniques]. AB - The treatment of choice for soft tissue sarcomas with local involvement is still the complete surgical removal into healthy tissue. The aim of surgery is to achieve tumor-free resection margins in the sense of a R0 resection. No other treatment option can equally replace this important oncological condition. The enormous development in the field of reconstructive plastic surgery and in particular the advances in flap techniques and microsurgery enable limb salvage and the functional reconstruction even in the case of extensive tumors. PMID- 30478484 TI - [Accidental intoxication by outdoor and garden plants : Data from two German poison centres]. AB - BACKGROUND AND OBJECTIVES: Accidental exposure of children to plants occurs often and results in numerous calls to poison centres. The aim of this study was to identify outdoor plants that led to moderate or severe poisoning after accidental exposure and to identify patterns of paediatric plant exposures. MATERIALS AND METHODS: Human exposure data on accidental exposures provided by two German poison centres were retrospectively evaluated regarding the number and the routes of exposure. Special attention was turned to the kind and severity of symptoms. Based on these data a modified Litovitz factor was calculated. RESULTS: Out of 42,344 confirmed exposures to 227 plant species, 39,346 (93%) were asymptomatic, 2415 (5.7%) experienced minor, 580 (1.3%) moderate and 3 (0.007%) severe symptoms. Twenty-six plant genera were responsible for 70% of all exposures. Only eight of these plants (Arum spec., Laburnum anagyroides, Narcissus spec., Phaseolus vulgaris/coccineus, Prunus laurocerasus, Sambucus spec., Taxus baccata, Thuja spec.) led to at least moderate symptoms. Accidental exposure of children aged 0.5-5 years was mainly by oral ingestion (98%) and involved mostly fruits (60%). CONCLUSIONS: Exposure data collected by poison centres are very useful for hazard identification of outdoor plants. The data give a comprehensive overview of observed symptoms, which offers valuable instruments for use in clinical practice. PMID- 30478485 TI - [Incident-crisis-disaster. Conceptualizing unusual biological incidents]. AB - Unusual biological threats demand adequate preparedness efforts, as demonstrated, for example, by the Ebola virus disease outbreak in West Africa in 2014/2015 and pandemic influenza in 2009/2010. In Germany, responsibilities for such efforts are located in different governmental authorities and differ from state to state. As a result, there are many different preparedness approaches using divergent core terminology.In this article a common definition for the term "unusual biological incident" is proposed. To do so, a literature review as well as semi structured expert interviews with representatives of central actors in Germany were conducted. The understanding of "unusual biological incident" was not consistent among experts; four approaches to qualify a biological incident as "unusual" were identified. These were merged in a comprehensive system-oriented approach that focuses on the health system's resilience and on shortages of knowledge and material resources during incidents.Based on this approach, we suggest a stage model for the categorization of biological threats as "incident," "crisis," "severe crisis," or "disaster." The need for central coordination is a defining characteristic to qualify a biological incident as "unusual." Based on the identified shortages, the necessary response strategies can be derived. PMID- 30478486 TI - [Mutual self-help and patient participiation: current developments in Austria]. AB - In Austria, health-related self-help groups and organisations have been growing continuously over the past decades. They are increasingly demanding to be accepted as partners of the professional health system and to be involved in health policy decisions.Practice shows that "self-help friendly hospitals" are widespread in Austria. Although some self-help groups/organisations have gained access to health policy committees, research indicates that they find the system unresponsive to their interests. Public support for self-help organisations is particularly lacking at the national level as are conducive conditions for collective patient participation.A recent initiative by the Social Health Insurance Funds, the Ministry of Health and the National Health Promotion Agency seeks to tackle these problems. A plan for public support of self-help groups/organisations, primarily those operating at the national level, has been developed in collaboration with representatives of self-help organisations. It provides financial support for the activities of indication-specific self-help organisations at regional and national levels aiming at strengthening their autonomy. In addition, two institutions were founded: an umbrella organisation of indication-specific self-help organisations and a professional national support agency. The implementation of the new concept offers opportunities for closer cooperation between system stakeholders and self-help groups/organisations, and a new stimulus for patient participation is expected from these two new institutions. PMID- 30478487 TI - [Participation in self-help groups: impact on self-management and knowledge]. AB - BACKGROUND: Self-help groups (SHGs) are an inherent part of patient involvement and play an important role in the healthcare system. Until now, however, there has been a lack of systematic investigations and quantitative data about the individual impact of self-help for patients and relatives. OBJECTIVES: This study presents the results of a comparison between members of SHGs and non-members. Thereby, the effects of self-help shall be described in terms of empowerment and self-management. The study is part of the project "Health-related Collective Self Help in Germany" (Gesundheitsbezogene Selbsthilfe in Deutschland-SHILD) funded by the Federal Ministry of Health. MATERIALS AND METHODS: The study was conducted with patients from five therapeutic areas (diabetes mellitus type 2, prostate cancer, multiple sclerosis, tinnitus, relatives of dementia patients). Participants administered a multidimensional questionnaire (paper-and-pencil or online). Of the 2870 participants in this analysis, 49% were active members of SHGs. RESULTS: Statistical analysis showed some significant, but small differences between the two groups in five out of seven scales of the Health Education Impact Questionnaire (heiQ) in favour of the SHG members. Furthermore, SHG members performed better in specific knowledge tests. Members see the importance of their group especially in social inclusion, psychosocial relief, coping with the disease and new insights in dealing with the disease. CONCLUSIONS: With respect to the study design we cannot rule out that differences might be based on personal characteristics influencing the decision to participate in a SHG or not. But as the results are controlled for confounders, the hypothesis that SHG participation has a positive impact on the outcomes rather than vice versa seems supported. PMID- 30478488 TI - Sustaining the Transition from a Petrobased to a Biobased Chemical Industry with Flow Chemistry. AB - In the current context of transitioning to more sustainable chemical processes, the upgrading of biobased platform molecules (i.e., the chemical transformation of widely available low molecular weight entities from biomass) is attracting significant attention, in particular when combined with enabling continuous flow conditions. The success of this combination is largely due to the ability to explore new process conditions and the perspective of facilitating seamless scalability while maintaining a small overall footprint. This review considers representative continuous flow processes which utilize a selection of currently popular platform molecules that target industrially relevant building blocks, including (a) commodity chemicals, (b) specialty and fine chemicals, and (c) fuels and fuel additives. PMID- 30478489 TI - The impact of an infectious disease expert team on outpatient parenteral antimicrobial treatment in the Netherlands. AB - Background There is increasing interest in outpatient parenteral antimicrobial treatment. Objective To evaluate the added value of consultation of an infectious diseases expert team (consisting of two internist-infectious diseases specialists and a microbiologist) for advice regarding type, administration route and duration of antibiotic treatment. Setting A retrospective case series was performed at the Haga Teaching Hospital, a 700-bed regional teaching hospital in The Hague, The Netherlands. Methods Complication rate and mortality was evaluated during 60 days of follow-up. Therapeutic rationality regarding outpatient parenteral antimicrobial treatment was determined by presenting randomly selected paper cases from the database to two independent infectious diseases specialists who were blinded to patient's treatment and outcomes. The concordance between the two advices were analysed using Cohen's kappa. For those with discordance, an infectious diseases expert team meeting was organized to reach consensus. The final recommendation was compared to the actual given antibiotic treatment. Main outcome measure Discrepancy between the infectious disease expert team recommendations upon type, administration route and duration of antibiotics and the real outpatient parenteral antimicrobial treatment practice. Results Out of 89 included cases, 50 were randomly selected for review by the infectious diseases specialists. The kappa statistic regarding antimicrobial policy was 0.581 (P < 0.001). In 78% (39/50 cases), they had complete agreement upon all aspects of antibiotic treatment. The remaining 11 cases were reviewed by the expert team. Comparing the consensus of 50 cases to actual practice, in 14(28%) cases there was a discrepancy suggesting potential room for improvement. Comparing the cases in whom an individual infectious diseases specialist was involved in real practice to those cases without, there was 18% versus 42% discrepancy with the recommendations of the expert team (OR 3.4; 95% CI: 0.9 12.5, P = 0.06). Complication rate was 19% including unplanned readmissions and side effects of antimicrobial agent or administration route. Conclusion Though outpatient parenteral antimicrobial treatment policies in the Netherlands appear to be safe, consultation of an ID expert team, rather than an individual ID specialist, has the potential to optimize antimicrobial treatment in patients considered suitable for outpatient parenteral antimicrobial treatment. PMID- 30478490 TI - The treatment-related experiences of parents, children and young people with regular prescribed medication. AB - Background Taking regular medication has been shown to have an impact on the daily lives of patients and their families. Objective To explore the medication related experiences of patients and their families when a child or young person is prescribed regular medication. Setting A specialist U.K. paediatric hospital. Method Semi-structured face-to-face interviews of 24 parents/carers, children or young people, who had been taking two or more medications for 6 weeks or longer. The themes explored included the medication regimen, formulation, supplies, social aspects and adverse effects. The data was analysed using NVIVO version 11. Main outcome measure The experiences of patients, and their parents/carers, when a child/young person takes regular medication. Results Participants described a range of experiences associated with taking regular medication. Medication related challenges were experienced around the timing of administration which was managed over 24 h rather than waking hours. Updating medication doses for administration at school was often delayed. Unintended nonadherence was cited as the biggest challenge with a range of strategies employed to manage this. The internet was commonly used as a source of additional information accessed for reassurance and adverse effects but there were varying experiences of using patient forums/help groups. Other challenges included the adequacy of information, travelling with medication, formulation issues, arranging supplies and adverse effects. Conclusion Patients and parents experience many challenges with children's medication. Individualised treatment options should be considered. Further research is required to determine how these experiences may be managed including the role of paediatric medication review. PMID- 30478491 TI - The impact of generics and generic reference pricing on candesartan and rosuvastatin utilisation, price and expenditure in South Africa. AB - Background In the South African private sector context, generically similar products are grouped together and the reimbursement rate is set at the average price of the generically equivalent products. Very little evidence exists in low and middle-income countries with regards to the impact of this policy over time. Objectives To determine the impact of the introduction of generics and generic reference pricing on candesartan and rosuvastatin in the South African private health care sector in terms of medicine utilisation, medicine price and medicine expenditure. Setting South African private health sector. Method Medicine claims for candesartan and rosuvastatin was obtained from a Pharmacy Benefit Manager in South Africa. The claims covered a 48-month period from January 2012 to December 2015 and provided a pre- and post-reference price period for analysis. Medicine utilisation was measured as the number of Defined Daily Doses dispensed per 100,000 beneficiaries. Medicine price and expenditure was calculated as the average per Defined Daily Dose. Main outcome measure Medicine utilisation, price and expenditure. Results Candesartan experienced an average 7.0% year-on-year decline in utilisation and rosuvastatin a 5.0% increase. Medicine expenditure reduced by an additional 34.6% and 20.9% for candesartan and rosuvastatin respectively. The total savings was 54.8% for candesartan and 31.9% for rosuvastatin. Conclusion The introduction of generics and generic reference pricing did not have an impact on medicine utilisation, but reduced the price and expenditure of both candesartan and rosuvastatin. PMID- 30478492 TI - Systematic review and network meta-analysis of treatment for moderate-to-severe ulcerative colitis. AB - Background Biological drugs for moderate-to-severe ulcerative colitis have changed the therapeutic perspective, while small-molecule inhibitors and new promising drugs suggest new options. Aim Assess comparative efficacy and safety of biological and new small oral drugs: commercialized and under-investigation ones for patients naive to biological drugs. Methods A systematic review was conducted to identify the randomized clinical trials phase 2 or 3, in adults with moderate-to-severe ulcerative colitis treated with biological drugs (infliximab, adalimumab, golimumab, vedolizumab and etrolizumab) or new oral small molecules (tofacitinib and ozanimod) as first line. A Bayesian network metaanalysis was performed to inform comparative efficacy and safety of different treatments. Efficacy outcomes were clinical remission, clinical response and mucosal healing for induction therapy and clinical remission, mucosal healing and sustained clinical remission for maintenance therapy. Safety was assessed with serious adverse events and rates of infections. Results 14 references were included for network meta-analysis. For induction therapy, infliximab was the best drug for induction of clinical response and remission, while ozanimod showed to be the best for induction of mucosal healing. Tofacitinib had the highest rate of maintaining clinical remission. All treatments were similar for serious adverse events, and vedolizumab and tofacitinib had the highest rates of infections. Conclusion This network meta-analysis suggests infliximab may be the best therapeutic option for moderate-to-severe ulcerative colitis. Vedolizumab seems to have better outcomes in maintenance than in induction therapy and it appears superior to golimumab and adalimumab. Tofacitinib, ozanimod and etrolizumab show encouraging results. PMID- 30478493 TI - Translation and validation of a tool to assess the impact of clinical pharmacists' interventions. AB - Background The tool CLEO in French language is designed for estimating the potential relevance of pharmacists' interventions (PIs) in three independent dimensions with regard to process-related, clinical, economic, and humanistic impact. Objective We aimed to translate CLEO into German (CLEOde), to demonstrate its feasibility in daily practice, and to validate the German version. Setting Convenience sample of three Swiss hospitals with established clinical pharmacy services. Method We translated CLEO according to the ISPOR Principles of Good Practice. The potential relevance of PIs performed within a 13-day period of routine clinical pharmacy services was then estimated with CLEOde. Ten clinical pharmacists experienced with CLEOde subsequently completed a 19-item questionnaire to assess user's agreement on appropriateness, acceptability, feasibility, and precision of the tool. Additionally, each pharmacist evaluated 10 model cases with CLEOde. Main outcome measure User satisfaction; interrater reliability and test-retest reliability. Results CLEOde was used to estimate the potential relevance of 324 PIs. The reported time needed to complete a single estimation was less than 1 min. The use of CLEOde was seen as appropriate, acceptable, feasible, and precise. Interrater reliability was good for the clinical and economic dimensions and was poor for the organisational dimension; test-retest correlation was strong for all three dimensions with excellent to fair reliability. Conclusion We present CLEOde as a validated tool in German language suitable to estimate the potential relevance of PIs. After further refinement of the organisational dimension, CLEOde could provide a qualitative value to quantitative information on PIs. PMID- 30478494 TI - Patients' experiences with multidose drug dispensing: a cross sectional study. AB - Background Automated multidose drug dispensing is used to support patients with their medication management. Though multidose drug dispensing systems are frequently used, little is known about patients' experiences with multidose drug dispensing systems. Objective To explore patients' experiences with the initiation and use of multidose drug dispensing systems. Setting A survey was carried out with patients using multidose drug dispensing systems through three community pharmacies. Method A semi-structured interview protocol was designed based on existing literature and a pilot study. Main outcome measures The main outcome measures were (1) patients' experiences with initiating multidose drug dispensing systems and (2) patients' experienced advantages and disadvantages of multidose drug dispensing systems. Results The start of multidose drug dispensing was discussed with 76% of the patients (n = 62). Ninety percent of patients expressed the opinion that the multidose drug dispensing system supported them with their medication management. Sixty patients reported 110 advantages, which can be organized into the following categories: improved medication adherence and medication safety (59%); patient's convenience (40%); and other (1%). Sixty-nine percent of patients reported no disadvantages, 24% had problems opening the bags or outer packaging and 13% had problems with the legibility of the printed text on the bag. Conclusion In concordance with the Dutch guideline, patients are generally involved in the decision to initiate an multidose drug dispensing system. Patients are very satisfied using the system and report multiple advantages. Multidose drug dispensing systems may be further improved by simplifying the manual opening of the bags and improving the legibility of the text on the bags. PMID- 30478495 TI - Evaluation of a hypertension-based patient education program in a stroke center. AB - Background The benefits of educational programs are recognized in chronic diseases. An education program was designed in our hospital, for hypertensive patients after an acute episode of stroke to prevent stroke recurrence. Objective Evaluate the effects of such program on patient knowledge and blood pressure management. Setting The 12-bed stroke center of the Groupe Hospitalier Paris Saint-Joseph, France. Method An individual educational session was provided to all the patients by the pharmacist a few days after admission. The effectiveness of the session was evaluated using a questionnaire completed by each patient before and after education. The patients had to identify the correct responses and to judge their answer's self-confidence. The answers were ranked based on their accuracy and the surety of the respondent. Reported medication adherence and self-measurement of blood pressure were analyzed as part of the survey. Patient satisfaction with the intervention was also measured by means of a separate questionnaire. Main outcome measure Evolution of response correctness and self-confidence as well as medication adherence and blood pressure self measurement practice. Results 64 patients were enrolled. Correct response rate increased from 77.9 to 94.1% and the absolutely sure response rate raised from 52.9 to 80.8%. Patient self-confidence was improved mainly for correct responses. Patients reported a better medication adherence and a more frequent practice of blood pressure self-measurement. They were highly satisfied. A negative correlation was found between knowledge evolution and baseline knowledge. Conclusion Education can improve stroke patient knowledge, which may enhance medication adherence and blood pressure control. Such programs should be developed even early after a stroke. PMID- 30478496 TI - Impact of deprescribing rounds on discharge prescriptions: an interventional trial. AB - Background Successful deprescribing practices are required to address issues associated with polypharmacy but are hindered by minimal interprofessional collaboration, time constraints, concern for negative outcomes, and absence of a systematic and evidence-based approach. Objective Determine the impact of pharmacist-led deprescribing rounds within a clinical teaching unit (CTU) the number of home medications discontinued upon hospital discharge. Setting Canadian tertiary care hospital. Methods Prospective, dual-arm, interventional study conducted in a single centre, from November 23rd, 2015 to August 30th, 2016. All patients >= 19 years old admitted under the CTU were considered for enrolment if on medication(s) prior to admission and patients were excluded if not taking any medications. Study arm allocation alternated daily between the two teams. The control arm operated as per standard whereas the intervention arm's pharmacist used a deprescribing guide and medication review to identify medications eligible for discontinuation prior to discussing during daily rounds. Discharge documents communicated medication changes to patient and primary healthcare providers. The study was sufficiently powered. Main outcome measure The difference of number of home medications discontinued at discharge between the intervention and control groups. Results 171 and 187 patients were allocated to the intervention and control arms, respectively. No significant differences of baseline characteristics existed between groups. Main outcome measure results showed that deprescribing rounds resulted in significantly more medications deprescribed compared to control (65% vs. 38%; p = 0.001). The rates of readmission and emergency department visits were reduced in the intervention arm. Conclusions Incorporating deprescribing rounds into routine care led to significantly greater discontinuation of medications without increasing rate of emergency department visits or hospital admissions.Trial registration ISRCTN11751440. PMID- 30478497 TI - [Descemet membrane endothelial keratoplasty in complex eyes]. AB - BACKGROUND: Descemet membrane endothelial keratoplasty (DMEK) has become the standard surgical treatment for Fuchs' endothelial corneal dystrophy (FECD) in Germany. In addition to classical FECD, there are endothelial disorders amenable to DMEK associated with complex changes in the anterior segment of the eye, such as anterior synechia of the iris, larger iris defects, after glaucoma surgery, after vitrectomy and after trauma. OBJECTIVE: This article provides an overview of the possibilities to treat patients with complex anterior segment situations in the presence of corneal endothelial decompensation with DMEK. MATERIAL AND METHODS: Description of problems and current surgical techniques when performing DMEK in complex situations. RESULTS: Reconstruction of the iris or the iris/lens diaphragm often needs to be performed either simultaneously or in a previous operation to treat patients with complex anterior segment alterations with DMEK. Both very shallow and very deep anterior chambers pose a major problem. A DMEK graft from older donors (above 70 years) is prone to less rolling and should be preferred in patients with a deep anterior chamber (e.g. after vitrectomy). The graft size should also be adapted to the available space, e. g. a smaller graft diameter should be selected for eyes with anterior synechia. CONCLUSION: There are only a few evaluations of DMEK under complex conditions; however, it appears that the rate of secondary graft failure, endothelial cell loss and the rebubbling rate are increased in this very heterogeneous group of diseases. Further studies are needed to identify risk factors for a negative progression after DMEK in "complex" eyes. PMID- 30478498 TI - [Pathogenesis and epidemiology of neurotrophic keratopathy]. AB - Neurotrophic keratopathy (NK) is a degenerative corneal disease that is based on an impairment of the corneal innervation. The damage to the sensory innervation, which is delivered through the 1st branch of the trigeminal nerve (ophthalmic nerve), can occur throughout the entire length of the nerve from the nucleus in the brainstem, e.g. caused by brain tumors, to the terminal nerve fibers in the cornea, caused for example by refractive corneal surgery (e. g. LASIK). Due to the loss of the sensory innervation, a reduced lacrimation and a reduction in the secretion of trophic factors occur. This in turn inhibits the regeneration potential of the corneal epithelium. In the most severe cases of the disease, the reduction or loss of lacrimation, together with the impaired regeneration potential of the epithelial cells, can lead to persistent epithelial defects, ulcers and corneal perforation. The NK has a prevalence of 5 or fewer individuals per 10,000 and is classified as a rare, i. e. orphan disease (ORPHA137596). A fundamental understanding of the pathogenesis and epidemiology of NK supports the early diagnosis and therefore the initiation of a specific treatment. PMID- 30478499 TI - Complications and functional outcomes of high-risk patient with cardiovascular disease on antithrombotic medication treated with the 532-nm-laser photo vaporization Greenlight XPS-180 W for benign prostate hyperplasia. AB - PURPOSE: To examine the complications and functional outcomes of high-risk patients on antithrombotic therapy (ATT) treated with photoselective vaporization of the prostate (PVP) using the Greenlight (GL) XPS-180 system. METHODS: A retrospective analysis of prospectively maintained institutional database was performed. Men with symptomatic LUTS related to BPH were treated with 523-nm GL PVP using the XPS-180 W system. They were stratified according to ATT status: group 1 (control group), group 2 (acetylsalicylic acid), group 3 (antiplatelet agents other than acetylsalicylic acid) and group 4 (anticoagulation agents). Postoperative adverse events at 30- and 90-days were prospectively recorded. Complications were stratified according to the Clavien-Dindo classification. Additionally, functional outcomes (IPSS, Qmax and PVR) were analyzed up to 48 months of follow-up after surgery. Multivariable logistic regression analyses were used to predict the effect of ATT on serious bleeding-associated complications that was defined as the sum of patients with hematuria Clavien grade >= 2, patients requiring transfusions and patient with postoperative hemoglobin drop >= 15 g/dl. RESULTS: 274 (63%), 87 (21%), 24 (6%) and 37 (9%) patients were included in groups 1, 2, 3 and 4, respectively. Patients on antiplatelet (group 3) and anticoagulant medication (group 4) were older (median age 60 vs. 68 vs. 77 vs. 76 years, p < 0.001) and had more comorbidities (ASA 3 4: 9.5 vs. 27.6 vs. 66.7 vs. 64.9%; p < 0.001) than their counterparts. The overall 30-day complications rates were 31, 28.7, 45.8 and 45.9% of patients included in groups 1, 2, 3 and 4, respectively (p = 0.4). Hematuria Clavien 1 events (p < 0.001), readmissions rates (p = 0.02), length of post-operative hospital stay (p < 0.001) and catheterization time (p < 0.001) were significantly higher in patients on antiplatelet and anticoagulation medication. In multivariable analyses, ATT status was not a predictor of serious bleeding events after surgery (p > 0.5). Finally, functional outcomes were significantly improved accross the four groups. CONCLUSION: GL PVP is safe and effective in treating high-risk patients on ATT. Although serious bleeding complications are rare and equivalent with non-high-risk patients, patients on antiplatelet and anticoagulation medication should be counseled on the increased risk of minor bleeding events and readmissions rates at 30 days after surgery. PMID- 30478500 TI - Microzonation, ecological risk and attributes of metals in highway road dust traversing through the Kaziranga National Park, Northeast India: implication for confining metal pollution in the national forest. AB - Despite the abundant literature on metal contamination through road dust (RD) in urban/suburban and residential/highway regions, the RD of highways traversing through the Kaziranga National Park, NE India, has not been studied and lacks baseline data. The objective of the present study was to ascertain the possibility of highway microzonation based on temporal and spatial variability of metal pollution level and ecological risk. It was found that the RD contains an average content of (1.7-33.5 mg/kg) for Cd, Co, Cu and Pb and (121-574 mg/kg) for Ni, Zn, Cr and Mn across the highway passing through the national forest attributed by various sources. The study revealed three possible microzones present in the studied highway NH-37 based on spatial trend of metal as well as human interference. An attempt was made to understand the possible source of metals by principal component analysis, and four sources were identified: Three were of vehicular origin, and another was related to road surface and subsurface condition. The use of noise barrier walls as an effective measure to control the translocation of RD from one place to other was recommended to reduce the hostile effects of metal accumulation in the sensitive ecosystem. Thus, the study suggested and necessitated micronizing the system based on human interference level, ecological risk factors, spatial variability of pollutants and traffic pattern for their efficient management and conservation. PMID- 30478501 TI - Risk of radiation-induced lens opacities among surgeons and interventional medical staff. AB - The main effect of ionizing radiation on the eyes is the onset of posterior cortical and subcapsular cataracts. Recent studies have raised questions about the mechanism of ocular damage and the threshold dose for the onset of such effects. Currently, operators may be exposed to ionizing radiation during surgical procedures. It has been estimated that urologists can be exposed to an annual dose close to or above 20 mSv/year. The aim of our study was to evaluate the frequency of cataracts in a group of professional radiological operators to verify their possible association with the radiation dose to the crystalline lens and the tasks performed. The records of 73 health workers exposed to ionizing radiation were reviewed. The average annual dose to the crystalline lens, the number of years of exposure, and the presence of radiation-compatible opacities were assessed for all operators. Lenticular opacities were observed in 16.4% of subjects. The presence of alterations was associated with exposure doses below 10 mSv and > 10 years' experience in fluoroscopically guided procedures. Based on our results, protection of the crystalline lens against exposure to ionizing radiation by means of goggles is recommended. In addition, examination of the lens via slit lamp examination is recommended for all operators involved in interventional procedures with the current levels of radiation exposure. PMID- 30478502 TI - Altered Local Field Potential Relationship Between the Parafascicular Thalamic Nucleus and Dorsal Striatum in Hemiparkinsonian Rats. AB - The thalamostriatal pathway is implicated in Parkinson's disease (PD); however, PD-related changes in the relationship between oscillatory activity in the centromedian-parafascicular complex (CM/Pf, or the Pf in rodents) and the dorsal striatum (DS) remain unclear. Therefore, we simultaneously recorded local field potentials (LFPs) in both the Pf and DS of hemiparkinsonian and control rats during epochs of rest or treadmill walking. The dopamine-lesioned rats showed increased LFP power in the beta band (12 Hz-35 Hz) in the Pf and DS during both epochs, but decreased LFP power in the delta (0.5 Hz-3 Hz) band in the Pf during rest epochs and in the DS during both epochs, compared to control rats. In addition, exaggerated low gamma (35 Hz-70 Hz) oscillations after dopamine loss were restricted to the Pf regardless of the behavioral state. Furthermore, enhanced synchronization of LFP oscillations was found between the Pf and DS after the dopamine lesion. Significant increases occurred in the mean coherence in both theta (3 Hz-7 Hz) and beta bands, and a significant increase was also noted in the phase coherence in the beta band between the Pf and DS during rest epochs. During the treadmill walking epochs, significant increases were found in both the alpha (7 Hz-12 Hz) and beta bands for two coherence measures. Collectively, dramatic changes in the relative LFP power and coherence in the thalamostriatal pathway may underlie the dysfunction of the basal ganglia thalamocortical network circuits in PD, contributing to some of the motor and non motor symptoms of the disease. PMID- 30478504 TI - A mental health acronym that must be stopped: PMAD. PMID- 30478503 TI - The roles of PTEN, cMET, and p16 in resistance to cetuximab in head and neck squamous cell carcinoma. AB - There is no established biomarker for cetuximab efficacy in recurrent head and neck squamous cell carcinoma (HNSCC). The aim of the present study was to evaluate the prognostic and predictive impact of PTEN, cMET, and p16 expression in recurrent HNSCC. In this retrospective study, 112 patients with recurrent HNSCC received chemotherapy (CT) alone (n = 37) or chemotherapy with cetuximab (n = 75). PTEN, cMET, and p16 protein expression were evaluated by immunohistochemistry. The median overall survival (mOS) for the patients treated with cetuximab + CT versus CT alone was 11.4 months and 7.0 months, (p = 0.949). The median progression-free survival (mPFS) was 6.2 months versus 3.0 months (p = 0.154). Patients with PTEN loss exhibited a mOS of 5.8 months versus 10.5 months (p = 0.002) and a mPFS of 3.2 months versus 4.7 months (p = 0.019). A multivariate analysis identified an independent association between PTEN loss and OS (HR 2.27; 95% confidence 95% CI 1.27-4.08; p = 0.006) and with PFS (HR 1.85; 95% CI 1.09-2.99; p = 0.022). A negative prognostic impact of PTEN loss was observed in the patients treated with cetuximab + CT, and not in the CT only group. Expression of cMET and p16 showed no impact on OS or PFS. The present findings confirm that PTEN is a prognostic factor for metastatic HNSCC and they support further studies of PTEN expression to evaluate its predictive value to cetuximab response. PMID- 30478505 TI - Preprophase-band positioning in isolated tobacco BY-2 cells: evidence for a principal role of nucleus-cell cortex interaction in default division-plane selection. AB - In some plant tissue types, new cross-walls tend to divide parental cells equally and to meet parental walls at right angles while tending to have minimal surface area. A previously proposed model that I call the reach model suggests that this feature originates from the tendency of premitotic division-plane selection or of the positioning of microtubule preprophase bands (PPBs) which predict the cortical division site, and that default division-plane selection involves nuclear centering and subsequent PPB microtubule assembly on the cell wall parts closest to the nucleus. In an initial effort to characterize truly default division-plane selection, the present study quantified division orientation and PPB positioning in protoplast-derived isolated elongate tobacco BY-2 cells. In this system, PPB-predicted and actual division planes were mostly oriented transversely, as predicted based on the reach model. Some sample elongate cells had asymmetric shapes that came from clear terminal-size differences and, in those cells, PPB-marked planes tended to be displaced from the centers of centrally located nuclei toward the narrower cell end, again as predicted based on the reach model. Such PPB positioning typically forecasted volumetrically asymmetric transverse division that would produce a smaller daughter cell from a parental cell part including the narrower cell end. These results provide experimental evidence that default division-plane selection tends to be close to or the same as the selection using the reach model's criterion, and that it does not use any criterion that specifically prioritizes the equality or verticality of division. PMID- 30478506 TI - Prognostic Impact of Intratumoral Heterogeneity Based on Fractal Geometry Analysis in Operated NSCLC Patients. AB - PURPOSE: To determine the heterogeneity of glucose uptake applying fractal analysis on positron emission tomography/computed tomography (PET/CT) with 2 deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) images in patients with non-small cell lung carcinoma (NSCLC) before surgery, and to assess whether this heterogeneity was associated with disease-free survival (DFS). PROCEDURES: [18F]FDG PET/CT scans of 113 patients' prior surgery were retrospectively revised. PET DICOM images were analyzed for fractal geometry using a ad hoc software to automatically determine the following indexes: (a) mean intensity value (MIV), (b) standard deviation (SD), (c) relative dispersion (RD), (d) three-dimensional (3D) histogram of the fractal dimension (3D HIST FR DIM), and (e) fractal dimension in 3D (3D-FD). All the fractal indexes were subsequently compared with metabolic parameters and disease-free survival (DFS). RESULTS: We found a significant correlation between 3D-FD and SUVmax, SUVmean, MTV, and TLG. Additionally, positive correlations between MIV, SD, and all metabolic parameters were also detected. Patients with high 3D-FD tumor (>= 1.62) showed significantly higher values of SUVmax, SUVmean, MTV, and TLG than those with lower 3D-FD. In univariate analysis, median 3D-FD and median TLG were significantly associated with DFS (p = 0.04 and p = 0.03, respectively). These findings were confirmed on log-rank test. On multivariate analysis, among age, stage disease, histotype, 3D FD, and metabolic parameters, only 3D-FD was identified as independent prognostic factor for DFS (p = 0.032; HR 0.418, 95 % CI 0.189-0.926). 3D-FD was different between adenocarcinoma and squamous cell carcinoma (1.60 versus 1.88, p = 0.014), and 3D-FD value was found higher in advanced stage disease. CONCLUSIONS: Metabolic heterogeneity determined applying fractal principles on PET images can be considered as a novel imaging biomarker for survival in patients with NSCLC. PMID- 30478507 TI - Development of a Non-invasive Assessment of Hypoxia and Neovascularization with Magnetic Resonance Imaging in Benign and Malignant Breast Tumors: Initial Results. AB - PURPOSE: To develop a novel magnetic resonance imaging (MRI) approach for the noninvasive assessment of hypoxia and neovascularization in breast tumors. PROCEDURES: In this IRB-approved prospective study, 20 patients with suspicious breast lesions (BI-RADS 4/5) underwent multiparametric breast MRI including quantitative BOLD (qBOLD) and vascular architecture mapping (VAM). Custom-made in house MatLab software was used for qBOLD and VAM data postprocessing and calculation of quantitative MRI biomarker maps of oxygen extraction fraction (OEF), metabolic rate of oxygen (MRO2), and mitochondrial oxygen tension (mitoPO2) to measure tissue hypoxia and neovascularization including vascular architecture including microvessel radius (VSI), density (MVD), and type (MTI). Histopathology was used as standard of reference. Appropriate statistics were performed to assess and compare correlations between MRI biomarkers for hypoxia and neovascularization. RESULTS: qBOLD and VAM data with good quality were obtained from all patients with 13 invasive ductal carcinoma (IDC) and 7 benign breast tumors with a lesion diameter of at least 10 mm in all spatial directions. MRI biomarker maps of oxygen metabolism and neovascularization demonstrated intratumoral spatial heterogeneity with a broad range of biomarker values. Bulk tumor neovasculature consisted of draining venous microvasculature with slow flowing blood. High OEF and low mitoPO2 were associated with low MVD and vice versa. The heterogeneous pattern of MRO2 values showed spatial congruence with VSI. IDCs showed significantly higher MRO2 (P = 0.007), lower mitoPO2 (P = 0.021), higher MVD (P = 0.005), and lower (i.e., more pathologic) MTI (P = 0.001) compared with benign breast tumors. These results indicate that IDCs consume more oxygen and are more hypoxic and neovascularized than benign tumors. CONCLUSIONS: We developed a novel MRI approach for the noninvasive assessment of hypoxia and neovascularization in benign and malignant breast tumors that can be easily integrated in a diagnostic MRI protocol and provides insight into intratumoral heterogeneity. PMID- 30478508 TI - Twin pregnancy in a patient on chronic haemodialysis who already had three pregnancies. AB - Pregnancy in women with end-stage renal disease is rare. Multiple pregnancies carry a high risk of complications even in healthy individuals. We report the case of a 36-year-old woman who had four pregnancies while she was on dialysis, including one twin pregnancy. The last pregnancy occurred while in the 14th year of hemodialysis. At 8 weeks of gestation (WG), ultrasonography diagnosed a dichorionic diamniotic twin pregnancy. The frequency of dialysis was increased from 3 to 6 times a week and each session lasted 4 h. At 22 WG, polyhydramnios was diagnosed. At 25 WG, the patient presented respiratory distress and was transferred to intensive care where continuous hemodialysis, non-invasive ventilation, antibiotic and tocolysis were initiated. Because of tocolysis failure, a cesarean section was performed and she delivered male twins. The two newborns weighed 790 and 870 g, respectively. To our knowledge, this is the first report of four pregnancies in hemodialysis including one twin pregnancy. The incidence of pregnancy and a better outcome in patients on hemodialysis has increased in recent years but a tight coordination between nephrologists and obstetricians is essential. PMID- 30478509 TI - Natural history and risk factors for diabetic kidney disease in patients with T2D: lessons from the AMD-annals. AB - The Associazione Medici Diabetologi (AMD) annals initiative is an ongoing observational survey promoted by AMD. It is based on a public network of about 700 Italian diabetes clinics, run by specialists who provide diagnostic confirmation and prevention and treatment of diabetes and its complications. Over the last few years, analysis of the AMD annals dataset has contributed several important insights on the clinical features of type-2 diabetes kidney disease and their prognostic and therapeutic implications. First, non-albuminuric renal impairment is the predominant clinical phenotype. Even though associated to a lower risk of progression compared to overt albuminuria, it contributes significantly to the burden of end-stage renal disease morbidity. Second, optimal blood pressure control provides significant but incomplete renal protection. It reduces albuminuria but there may be a J curve phenomenon with eGFR at very low blood pressure values. Third, hyperuricemia and diabetic hyperlipidemia, namely elevated triglycerides and low HDL cholesterol, are strong independent predictors of chronic kidney disease (CKD) onset in diabetes, although the pathogenetic mechanisms underlying these associations remain uncertain. Fourth, the long-term intra-individual variability in HbA1c, lipid parameters, uric acid and blood pressure plays a greater role in the appearance and progression of CKD than the absolute value of each single variable. These data help clarify the natural history of CKD in patients with type 2 diabetes and provide important clues for designing future interventional studies. PMID- 30478510 TI - Comparisons of Conditioned Pain Modulation and Physical Activity Between Hispanic and Non-Hispanic White Adults. AB - It is well-documented that adults of racial/ethnic minorities experience pain more frequently and suffer from more severe pain compared to non-Hispanic White (NHW) adults. These observations are consistent with laboratory findings that adults of racial/ethnic minorities show increased sensitivity to laboratory pain stimuli compared to NHW adults. Research generally shows that central pain inhibitory processing, as quantified using conditioned pain modulation (CPM), serves as a risk factor of clinical pain. Currently, racial/ethnic differences in CPM are poorly understood, and research suggests that physical activity (PA) may help understand potential racial/ethnic differences in CPM. However, very little is known regarding CPM in Hispanic compared to NHW adults. Therefore, the present study compared CPM and PA between Hispanic and NHW adults. Twenty-one young, healthy Hispanic and 21 NHW adults completed validated questionnaires to assess PA, pain catastrophizing, and dispositional optimism. The participants then completed the CPM test to quantify changes in pain ratings to electrical stimuli delivered to the ankle during concurrent application of pressure pain applied to the finger compared to baseline. Results indicated that Hispanic and NHW adults exhibited comparable CPM responses and PA levels, along with similar levels of pain catastrophizing and dispositional optimism (p > 0.05). These results suggest that young, healthy Hispanic and NHW adults may possess a similar risk of clinical pain when they are comparable in PA, pain catastrophizing, and dispositional optimism. More research is needed to explore the role of PA in racial/ethnic disparities in clinical pain and central pain inhibitory processing. PMID- 30478511 TI - Addressing the Absence of Black Men in Medicine. AB - There is a profound absence of Black men in medicine. Addressing this issue requires a concerted and holistic effort that includes learning from the current generation of medical students. This article summarizes three medical student perspectives presented as posters at the National Academies of Science, Engineering, and Medicine inaugural workshop on the growing absence of Black men in medicine. These posters present perspectives from men of color each from one of the three historically Black medical colleges in the country. The authors provide narratives on the importance of early access to resources and adequate inter-generational mentorship in preparing Black men for a career in medicine. Popular culture is also discussed as a means of facilitating further engagement of premedical Black students. Black men interested in medicine face unique challenges in the United States, and initiatives to improve the declining matriculation rate into medical schools need to be well-designed, relevant, and facilitating of early mentorship. PMID- 30478512 TI - Racial Differences in the Predictors of Interest in Bariatric Surgery in the Rural, Southeastern USA. AB - BACKGROUND: Although African-Americans have a higher prevalence of severe obesity than Whites, they are less likely to have bariatric surgery. Demographic, healthcare, and knowledge variables contribute to this racial disparity but have not been examined separately by race. OBJECTIVES: Examine the role of demographic, healthcare, and knowledge variables in African-Americans' versus Whites' interest in bariatric surgery. METHODS: A random sample of 293 African American and 259 White adults were surveyed door-to-door in the rural south. The survey assessed weight, height, demographics, access to healthcare, and knowledge of and interest in bariatric surgery. RESULTS: African-Americans had significantly lower knowledge of bariatric surgery than Whites but there were no racial differences in interest in the surgery. The logistic regression predicting African-Americans' interest in the surgery from demographic, healthcare, obesity, and knowledge variables revealed that obesity (OR = 4.7) and the health benefits (OR = 3.3) were the only predictors. The same regression for Whites found that knowing someone who had the surgery (OR = 3.7) was the sole predictor. CONCLUSIONS: Knowledge variables may be stronger than healthcare and demographic variables as predictors of interest in bariatric surgery among rural, southern, African-Americans and Whites. Whites' willingness to consider the surgery might be enhanced by favorable stories/blogs by those who had the surgery, whereas African-Americans' interest might be increased by information on the additional health benefits of the surgery. These culturally tailored messages from healthcare providers might increase utilization of and reduce racial disparities in bariatric surgery. PMID- 30478513 TI - Investigating the proteomic expression profile of tobacco (Nicotiana tabacum) leaves during four growth stages using the iTRAQ method. AB - Despite the importance of tobacco (Nicotiana tabacum) in agriculture and model organism investigations, the proteomic changes that occur in the tobacco leaf as it matures remain to be explored. In this study, an isobaric tags for relative and absolute quantification (iTRAQ) strategy was applied to investigate the proteomic profiles of K326 and Honghua Dajinyuan (HD) tobacco leaves at four growth stages. The proteomic profile varied with growth stage in both K326 and HD. Gene ontology (GO) classification was used to identify the biological processes that showed the greatest changes in protein expression between growth stages of HD and K326. Moreover, the number of differentially expressed proteins was greater in HD than in K326, especially during the rosette growth stage and the fast-growing stage. The galactose metabolism and glycosphingolipid biosynthesis-globo series pathways appeared only during the rosette growth stage of HD. It therefore appears that these pathways may be correlated with tobacco mosaic disease. The identification of these pathways should prove useful in investigations of the pathogenesis of tobacco mosaic virus. Graphical abstract ?. PMID- 30478514 TI - Competitive and noncompetitive immunoassays for the detection of benzothiostrobin using magnetic nanoparticles and fluorescein isothiocyanate-labeled peptides. AB - Phage-displayed peptides have been proven to be powerful reagents for competitive and noncompetitive immunoassays. However, they are unconventional reagents, which greatly limit their analytical commercial applications and require additional reagents for detection. In this work, the peptides that specifically bind with anti-benzothiostrobin monoclonal antibody (mAb) or benzothiostrobin-mAb immunocomplex were synthesized and conjugated with fluorescein isothiocyanate (FITC) as substitutes of the phage-displayed peptides to avoid their shortcomings and extend their applications. Competitive and noncompetitive fluorescence immunoassays (FIAs) for benzothiostrobin were developed by mAb coupling with magnetic nanoparticles as concentration elements and peptides conjugated with FITC as tracers. Compared with enzyme-linked immunosorbent assays, the FIAs reduced the number of steps from 6 to 2 and analysis time from more than 5 to 1.2 h. The competitive FIA showed the half-maximal inhibition concentration (IC50) of 16.8 ng mL-1 and detection range (IC10-IC90) of 1.0-759.9 ng mL-1, while the concentration of analyte producing 50% saturation of the signal (SC50) and detection range (SC10-SC90) of noncompetitive FIA were 93.4 and 5.9-788.2 ng mL 1, respectively. The average spiked recoveries were 68.33-98.50% and 73.33-96.67% for competitive and noncompetitive FIAs, respectively. The FIAs showed good correlation with high-performance liquid chromatography for the detection of benzothiostrobin in authentic samples. Graphical abstract Development of competitive and noncompetitive fluorescence immunoassays for benzothiostrobin by using monoclonal antibody coupling with magnetic nanoparticles as concentration elements and peptides conjugated with fluorescein isothiocyanate as tracers. PMID- 30478515 TI - Analysis of corticosteroids in samples of animal origin using QuEChERS and ultrahigh-performance liquid chromatography coupled to high-resolution mass spectrometry. AB - A rapid and sensitive method for the confirmatory analysis of eight synthetic corticosteroids (betamethasone, dexamethasone, prednisolone, 6 methylprednisolone, triamcinolone, flumethasone, beclomethasone, fluocinolone acetonide) is proposed. The method is useful for detecting illegal treatments in different animal species. It consists of an extraction and cleanup using the quick, easy, cheap, effective, rugged, and safe (QuEChERS) strategy. Quantitative determination is achieved by ultrahigh-performance liquid chromatography coupled to high-resolution mass spectrometry with heated electrospray ionization in negative mode. Quantification is performed using surrogate matrix-matched standard calibration curve with dexamethasone-D4 as the internal standard. The method was validated for analyzing liver samples according to the criteria established by Decision 2002/657/EC. Linearity was assessed in the 1-10 MUg kg-1 range and linear correlation coefficients were over 0.99 for all the analytes. CCalpha ranged from 0.04 to 0.16 MUg kg-1 for substances without maximum residue limit. The method allows confident quantification and confirmation of corticosteroids in liver samples, and its simplicity makes it suitable for analyzing large numbers of samples. PMID- 30478516 TI - Competitive light-initiated chemiluminescent assay: using 5-alpha dihydrotestosterone-BSA as competitive antigen for quantitation of total testosterone in human sera. AB - This paper described a homogeneous method, light-initiated chemiluminescent assay (LICA), for quantitation of total testosterone in human sera. The assay was bead based and built on a competitive-binding reaction format, in which 5-alpha dihydrotestosterone (5-alpha-DHT) competed with the testosterone in serum samples in binding with biotinylated anti-testosterone antibody. The more testosterone in the serum sample, the less 5-alpha-DHT that bonded with biotinylated anti testosterone antibodies. 5-alpha-DHT was coupled with emission beads (doped with thioxene derivatives and Eu(III) as a chemiluminescence emitter) via bovine serum albumin as a linker. Once streptavidin-coated sensitizer beads (modified with phthalocyanine as a photosensitizer) were added, the streptavidin/biotin reaction between 5-alpha-DHT-bound anti-testosterone antibody and sensitizer beads could bring emission and sensitizer beads together, which allowed energy transfer from sensitizer bead to emission bead. As such, an exciting light (680 nm) impinging on the sensitizer beads led to light emission at 520-620 nm by emission beads. The strength of the emitted light was inversely proportional to the testosterone in serum sample. The detection range of this assay was from 13.3 to 1200 ng/dL. The coefficient variation for intra- and inter-assay was lower than 15%. The recovery of this method ranged from 95.5 to 105.9% for different samples. Moreover, the LICA assay was highly specific with low cross-reactivity and interference. The concentration of testosterone from 58 serum samples analyzed by the LICA method significantly correlated (y = 0.97x + 1.87, R2 = 0.970, p < 0.001) with those obtained with the SIEMENS Centaur Xp System. Graphical abstract ?. PMID- 30478517 TI - High-selectivity profiling of released and labeled N-glycans via polar-embedded reversed-phase chromatography. AB - N-Glycosylation is the most complex post-translational modification of proteins and involved in many physiological processes and is therefore of major interest in academic research and in the biopharmaceutical industry. Reliable, robust, reproducible, and selective analysis of N-glycans is essential to understand the multitude of biological roles of N-glycosylation. So far, hydrophilic interaction liquid chromatography analysis of 2-AB or 2-AA derivatized N-glycans has been the standard method. In this work, the superiority of reversed-phase chromatography for complex N-glycosylation analysis is demonstrated. Separation of N-glycans derivatized with anthranilic acid on polar-embedded stationary alkyl phases with sub-2-MUm particles results in outstanding selectivity and resolution. In combination with the highly mass spectrometry-compatible mobile phase, even very complex glycan mixtures can be separated, identified, and quantified precisely and accurately. The presented methodology can be applied broadly from basic research to analytical control and release testing of biological drug products and can be implemented in analytical laboratories with minimal effort. Graphical abstract ?. PMID- 30478518 TI - Multiresidue analytical method for the determination of 41 multiclass organic pollutants in mussel and fish tissues and biofluids by liquid chromatography coupled to tandem mass spectrometry. AB - In this work, the full optimisation and validation procedure to analyse a wide set of emerging organic contaminants in biotissues (mussel and fish muscle, liver, gills and brain) and biofluids (fish plasma and bile) is described. The target families include artificial sweeteners, industrial products, hormones, pharmaceutical and personal care products, pesticides and phytoestrogens. Different clean-up strategies (hydrophilic-lipophilic-balanced (HLB) solid-phase extraction, Florisil solid-phase extraction and liquid-liquid extraction followed by HLB solid-phase extraction and microextraction based on polyethersulfone polymer) were evaluated for the clean-up of focused ultrasonic solid-liquid extraction (FUSLE) extracts before the analysis by liquid chromatography-triple quadrupole tandem mass spectrometry (LC-QqQ-MS/MS). The methods afforded satisfactory apparent recovery values (71-126%) using isotopically labelled analytes and matrix-matched calibration approach, regardless of the matrix. Method detection limits in the range of 4-48 ng/g and 0.3-111 ng/L were obtained for biotissues and biofluids, respectively. The developed method was applied to determine the uptake and tissue distribution in juvenile gilt-head bream (Sparus aurata) during 7 days in seawater, and unexpectedly, perfluoro-1-butanesulfonate tended to accumulate in liver and, to a lesser extent, in muscle and gills. Furthermore, real mussel samples collected in the Basque coast were also analysed and the presence of the highly consumed valsartan (7 ng/g) and telmisartan (6.8 ng/g) compounds in bivalves is reported for the first time here. Graphical abstract ?. PMID- 30478519 TI - Developmental trends in lineup performance: Adolescents are more prone to innocent bystander misidentifications than children and adults. AB - We tested developmental trends in eyewitness identification in biased and unbiased lineups. Our main interest was adolescent's lineup performance compared with children and adults. 7-10-year-olds, 11-13-year-olds, 14-16-year-olds, and adults (N = 431) watched a wallet-theft-video and subsequently identified the thief, victim, and witness from simultaneous target-present and target-absent six person photo lineups. The thief-absent lineup included a bystander previously seen in thief proximity. Research on unconscious transference suggested a selection bias toward the bystander in adults and 11-13-year-olds, but not in younger children. Confirming our hypothesis, adolescents were more prone to bystander bias than all other age groups. This may be due to adolescents making more inferential errors than children, as predicted by fuzzy-trace theory and associative-activation theory, combined with lower inhibition control in adolescents compared with adults. We also replicated a clothing bias for all age groups and age-related performance differences in our unbiased lineups. Consistent with previous findings, participants were generally overconfident in their decisions, even though confidence was a better predictor of accuracy in older compared with younger participants. With this study, we show that adolescents have an increased tendency to misidentify an innocent bystander. Continued efforts are needed to disentangle how adolescents in comparison to other age groups perform in forensically relevant situations. PMID- 30478520 TI - From short-term store to multicomponent working memory: The role of the modal model. AB - The term "modal model" reflects the importance of Atkinson and Shiffrin's paper in capturing the major developments in the cognitive psychology of memory that were achieved over the previous decade, providing an integrated framework that has formed the basis for many future developments. The fact that it is still the most cited model from that period some 50 years later has, we suggest, implications for the model itself and for theorising in psychology more generally. We review the essential foundations of the model before going on to discuss briefly the way in which one of its components, the short-term store, had influenced our own concept of a multicomponent working memory. This is followed by a discussion of recent claims that the concept of a short-term store be replaced by an interpretation in terms of activated long-term memory. We present several reasons to question these proposals. We conclude with a brief discussion of the implications of the longevity of the modal model for styles of theorising in cognitive psychology. PMID- 30478521 TI - Overlooked Issues on Pharmacokinetics Data Interpretation of Protein Drugs-a Case Example of Erythropoietin. PMID- 30478522 TI - MicroRNA156 amplifies transcription factor-associated cold stress tolerance in plant cells. AB - MicroRNAs may increase cold stress tolerance by regulating stress-related signal transduction pathways and by modulating the expression of transcription factors. However, the molecular mechanism by which microRNAs enhance cold stress tolerance is not fully understood. Here, we report that overexpression of rice microRNA156 (OsmiR156) results in increased cell viability and growth rate under cold stress in Arabidopsis, pine, and rice. OsmiR156 increases cold stress tolerance by targeting OsSPL3. OsSPL3 positively regulates the expression of OsWRKY71, a negative regulator of the transcription factors OsMYB2 and OsMYB3R-2. OsMYB2 counteracts cold stress by activating the expression of the stress-response genes OsLEA3, OsRab16A, and OsDREB2A. OsMYB3R-2 counteracts cold stress by activating the expression of OsKNOLLE2, OsCTP1, OsCycB1.1, OsCycB2.1, and OsCDC20.1. In OsmiR156 transgenic rice cell lines, the transcript levels of OsLEA3, OsRab16A, OsDREB2A, OsKNOLLE2, OsCTP1, OsCycB1.1, OsCycB2.1, and OsCDC20.1 were increased by OsWRKY71 knockdown and inversely regulated by OsWRKY71 overexpression, indicating that OsmiR156 enhances cold stress tolerance by regulating the expression of transcription factor genes in plant cells. These results will increase our understanding of microRNA-related cold stress tolerance in different plant species, including monocotyledonous, dicotyledonous, and gymnosperm plant species, and will be valuable in plant molecular biotechnology. PMID- 30478523 TI - Acoustic respiration rate and pulse oximetry-derived respiration rate: a clinical comparison study. AB - Respiration rate (RR) is a critical vital sign that provides early detection of respiratory compromise. The acoustic technique of measuring continuous respiration rate (RRa) interprets the large airway sound envelope to calculate respiratory rate while pulse oximetry-derived respiratory rate (RRoxi) interprets modulations of the photoplethsymograph in response to hemodynamic changes during the respiratory cycle. The aim of this study was to compare the performance of these technologies to each other and to a capnography-based reference device. Subjects were asked to decrease their RR from 14 to 4 breaths per minute (BPM) and then increase RR from 14 to 24 BPM. The effects of physiological noise, ambient noise, and head movement and shallow breathing on device performance were also evaluated. The test devices were: (1) RRa, Radical-7 (Masimo Corporation), (2) RRoxi, NellcorTM Bedside Respiratory Patient Monitoring System (Medtronic), and (3) reference device, Capnostream20pTM (Medtronic). All devices were configured with their default settings. Twenty-nine healthy adult subjects were included in the study. During abrupt changes in breathing, overall RRoxi was accurate for longer periods of time than RRa; specifically, RRoxi was more accurate during low and normal RR, but not during high RR. RRoxi also displayed a value for significantly longer time periods than RRa when the subjects produced physiological sounds and moved their heads, but not during shallow breathing or ambient noise. RRoxi may be more accurate than RRa during development of bradypnea. Also, RRoxi may display a more reliable RR value during routine patient activities. PMID- 30478524 TI - Phenylephrine-induced recruitable preload from the venous side. PMID- 30478525 TI - MonoMAC Syndrome Caused by a Novel GATA2 Mutation Successfully Treated by Allogeneic Hematopoietic Stem Cell Transplantation. PMID- 30478526 TI - Enhanced resistance to sclerotinia stem rot in transgenic soybean that overexpresses a wheat oxalate oxidase. AB - Sclerotinia stem rot (SSR), caused by the oxalate-secreting necrotrophic fungal pathogen Sclerotinia sclerotiorum, is one of the devastating diseases that causes significant yield loss in soybean (Glycine max). Until now, effective control of the pathogen is greatly limited by a lack of strong resistance in available commercial soybean cultivars. In this study, transgenic soybean plants overexpressing an oxalic acid (OA)-degrading oxalate oxidase gene OXO from wheat were generated and evaluated for their resistance to S. sclerotiorum. Integration and expression of the transgene were confirmed by Southern and western blot analyses. As compared with non-transformed (NT) control plants, the transgenic lines with increased oxalate oxidase activity displayed significantly reduced lesion sizes, i.e., by 58.71-82.73% reduction of lesion length in a detached stem assay (T3 and T4 generations) and 76.67-82.0% reduction of lesion area in a detached leaf assay (T4 generation). The transgenic plants also showed increased tolerance to the externally applied OA (60 mM) relative to the NT controls. Consecutive resistance evaluation further confirmed an enhanced and stable resistance to S. sclerotiorum in the T3 and T4 transgenic lines. Similarly, decreased OA content and increased hydrogen peroxide (H2O2) levels were also observed in the transgenic leaves after S. sclerotiorum inoculation. Quantitative real-time polymerase chain reaction analysis revealed that the expression level of OXO reached a peak at 1 h and 4 h after inoculation with S. sclerotiorum. In parallel, a significant up-regulation of the hypersensitive response-related genes GmNPR1-1, GmNPR1-2, GmSGT1, and GmRAR occurred, eventually induced by increased release of H2O2 at the infection sites. Interestingly, other defense related genes such as salicylic acid-dependent genes (GmPR1, GmPR2, GmPR3, GmPR5, GmPR12 and GmPAL), and ethylene/jasmonic acid-dependent genes (GmAOS, GmPPO) also exhibited higher expression levels in the transgenic plants than in the NT controls. Our results demonstrated that overexpression of OXO enhances SSR resistance by degrading OA secreted by S. sclerotiorum and increasing H2O2 levels, and eliciting defense responses mediated by multiple signaling pathways. PMID- 30478527 TI - Establishment of a transgenic mouse to model ETV7 expressing human tumors. AB - The ETS transcription factor ETV7 has been characterized as a hematopoietic oncoprotein, which requires cooperating mutations for its leukemogenic activity. Although the ETV7 gene is highly conserved among vertebrates, part of the rodents, including Mus musculus, deleted the Etv7 gene locus. Many human hematopoietic malignancies upregulate ETV7 expression but contrary to ETV7's role in oncogenesis, its physiological role in normal tissues is unknown. To determine the physiological function of ETV7 in vivo and determine its role in tumorigenesis in a mouse model, we have generated an ETV7 transgenic mouse that carries a single copy of human BAC DNA containing the ETV7 gene locus and its regulatory sequences. ETV7 heterozygous (ETV7Tg+/WT) mice were fertile, normal in size and born at a normal Mendelian frequency. They had a normal blood count, did not display any gross physical or behavioral abnormalities, and were not tumor prone. The ETV7 expression pattern in hematopoietic cells of ETV7Tg+/WT mice is very similar to that in human hematopoietic cells. To examine the oncogenic potential of ETV7 in vivo, we crossed ETV7Tg+/WT mice with tumor-prone mouse models. ETV7 greatly accelerated loss of Pten (phosphatase and tensin homolog) evoked leukemogenesis in PtenDelta/DeltaETV7Tg+/WT mice after deletion of the conditional Pten allele. Consistent with this observation, ETV7 expression enhanced the colony-forming and self-renewal activities of primary myeloid Pten-/ cells. In this study we established a transgenic mouse in which we can more accurately model ETV7-associated human tumorigenesis in vivo. PMID- 30478528 TI - Association between psychotic experiences and non-accidental self-injury: results from a nationally representative survey of adolescents. AB - PURPOSE: The association between psychotic experiences (PEs) and non-accidental self-injury (NASI; including self-harm and suicide attempts) is well established, although variables influencing this relationship have not been comprehensively examined. This study aimed to investigate (1) the cross-sectional PE-NASI association before and after adjustment for confounders, and (2) the individual contribution of each confounding and potentially mediating variable to the association. METHODS: A random sample of Australian adolescents aged 14-17 years (n = 1998) completed self-report questions regarding any self-harm, suicidality or PEs experienced in the past 12 months in 2013-2014 as part of the Young Minds Matter Survey, a national household survey. We conducted logistic regression analyses to investigate the association between NASI and PEs, after controlling for confounders (sociodemographics, substance use, and parental mental illness) as well as the influence of potential mediators (major depression, bullying, psychological distress, sleep, self-esteem, disordered eating behaviour, social isolation, and intervention factors). RESULTS: Except for special messages, all PE subtypes (auditory and visual hallucinatory experiences [HEs], and two of the three delusional experiences [DEs]) were associated with NASI after adjustment for confounders (OR range: 2.60-5.21). Depression and psychological distress significantly influenced all PE-NASI associations, where depression appeared to fully explain the DE-NASI association, and partially attenuate the HE-NASI association. Variables such as parental mental illness, disordered eating behaviour, and social isolation had negligible effects in nearly all self-harm and attempted suicide models. CONCLUSIONS: Adolescents reporting any PE in the past 12 months reported increased likelihood of NASI in the same time period and, auditory HEs in particular, were strongly and independently associated with self harm and suicide attempts. These results highlight the importance of PEs as indicators of risk of self-injurious behaviour among Australian youth. PMID- 30478529 TI - Postoperative Pancreatic Fistula Following Pancreaticoduodenectomy-Stratification of Patient Risk. AB - BACKGROUND: Postoperative pancreatic fistula (POPF) remains a major cause of morbidity following pancreaticoduodenectomy (PD). We sought to develop and validate a risk score system that utilized preoperative computed tomography (CT) measurements, laboratory values, and intraoperative pancreatic texture to estimate risk of developing POPF after PD. METHODS: Patients who underwent PD between 2014 and 2017 were identified. Pre- and intraoperative risk factors associated with POPF were identified. Three separate risk models were developed and assessed using multivariable analyses and receiver operating curves. RESULTS: Among the 150 patients who underwent a PD, mean age was 64 years and the majority of the patients were male (59.3%, n = 89). Overall, the incidence of BL/POPF following PD was 22%. On multivariable analysis, factors associated with POPF included preoperative total serum protein < 6 g/dL (OR 3.35, 95% CI 1.04-10.34, p = 0.04), radiologic pancreatic duct diameter (OR 0.72, 95% CI 0.53-0.97, p = 0.03), intraoperative pancreatic gland texture estimated by surgeon (OR 0.17, 95% CI 0.05-0.62, p = 0.006), as well as intraoperative pancreatic duct diameter measured by surgeon (OR 0.77, 95% CI 0.61-0.98, p = 0.030). Each risk factor was assigned a weighted score (CT pancreatic duct diameter < 5 mm: 8 points; soft pancreatic gland texture: 5 points; total serum protein < 6 g/dL: 3 points; CT visceral abdominal fat >= 230 cm2: 2 points). Patients scoring 4-5 were at low risk of POPF, while patients with a score of 6-18 had a high risk for POPF. The Harrell's c-index for the scoring system was 0.71 (standard error [SD] 0.094) for the training set and 0.67 (SD 0.034) for the test set (with n = 1000 bootstrapping resamples). CONCLUSION: A simple risk score for POPF that utilized preoperative radiologic and clinical variables combined with specific intra operative factors was able to stratify patients relative to POPF risk with good discriminatory ability. PMID- 30478530 TI - Preferences for Surveillance of Barrett's Oesophagus: a Discrete Choice Experiment. AB - PURPOSE: Endoscopic surveillance for Barrett's oesophagus is undertaken to detect dysplasia and early cancer, and to facilitate early intervention. Evidence supporting current practice is of low quality and often influenced by opinion. This study investigated the preferences of patients for surveillance of Barrett's oesophagus in an Australian cohort. METHODS: Four Barrett's oesophagus surveillance characteristics/attributes were evaluated within a discrete choice experiment based on literature and expert opinion: (1) surveillance method (endoscopy vs a blood test vs a novel breath test), (2) risk of missing a cancer over a 10-year period, (3) screening interval, and (4) out-of-pocket cost. The data from the discrete choice experiment was analysed within the framework of random utility theory using a mixed logit regression model. RESULTS: The study sample comprised patients (n = 71) undergoing endoscopic surveillance for Barrett's oesophagus of whom n = 65 completed the discrete choice experiment. The sample was predominantly male (77%) with average age of 65 years. All attributes except surveillance method significantly influenced respondents' preference for Barrett's oesophagus surveillance. Policy analyses suggested that compared to the reference case (i.e. endoscopy provided annually at no upfront cost and with a 4% risk of missing cancer), increasing test sensitivity to 0.5% risk of missing cancer would increase participation by up to 50%; surveillance every 5 years would lead to 26% reduction, while every 3 to 3.5 years would result in 7% increase in participation. Respondents were highly averse to paying A$500 for the test, resulting in 48% reduction in participation. None of the other surveillance methods was preferred to endoscopy, both resulting in 11% reduction in participation. CONCLUSION: Test sensitivity, test frequency and out-of-pocket cost were the key factors influencing surveillance uptake. Patients prefer a test with the highest sensitivity, offered frequently, that incurs no upfront costs. PMID- 30478531 TI - Prognostic Impact of Tumor Multinodularity in Intrahepatic Cholangiocarcinoma. AB - BACKGROUND: The prognostic value of tumor multinodularity in intrahepatic cholangiocarcinoma (ICC) remains debated. We aimed to evaluate the impact of tumor multinodularity according to the presence and distribution of multiples ICC's nodules. METHODS: A retrospective review of a prospectively maintained database of patients undergoing resection for ICC from January 1995 to September 2017 was performed. Prognostic factors for survival were assessed by multivariate Cox analysis. Tumoral nodules were defined according to their number (single and multiple) and localization (satellites and contralateral). RESULTS: Out of 120 selected patients, 64 (53%) had single and 56 (47%) had multiple lesions. Multiple lesions included tumors with satellites (n = 40; 71.5%) and tumors with contralateral lesions (n = 16; 28.5%). Patients with multiple tumors had significantly larger mean main lesion size (p = 0.02), required a higher rate of perioperative transfusion (p = 0.04), had a greater rate of lymph node involvement (p < 0.0001), vascular invasion (p = 0.04), and poor differentiation (p = 0.04) than single tumors. Patients with single tumors experienced a 5-year survival significantly longer (40%) than patients with multiple tumors (14%; p = 0.004). Patients having tumors with satellites had inferior median overall survival and 5-year survival rates (20 months, 7%) compared with patients with contralateral tumors (33.6 months, 29%) (p = 0.09). Multivariable analysis identified tumor multinodularity, morbidity, tumor size < 5 cm, poor differentiation, and lymph node involvement as independent prognostic factors for overall survival. CONCLUSIONS: Tumor multinodularity represents an independent risk factor for survival in ICCs and identifies a category of patients in need of more effective perioperative treatment. PMID- 30478532 TI - Long-Term Outcomes in Laparoscopic D2 Gastrectomy for Gastric Cancer: a Large Comprehensive Study Proposing Novel Hypotheses. AB - BACKGROUND: The long-term outcomes of laparoscopic gastrectomy (LG) versus open gastrectomy (OG) for gastric cancer (GC) remain obscure, especially for advanced cancer and disease affecting the upper stomach and in older patients. This study aimed to comprehensively assess the long-term efficacy of LG for GC using a large prospective database. METHODS: Totally, 1877 consecutive patients (1186 receiving LG and 691 OG) operated in 2004-2016 were analyzed, with a median follow-up of 63 months. Association of LG versus OG with disease-specific survival (DSS) and disease-free survival (DFS) overall and in various subgroups were investigated using multivariable Cox regression. Propensity score matching (PSM) was performed for sensitivity analysis. RESULTS: Before PSM, overall, there was no significant association of LG versus OG with survival after multivariable adjustment; however, in subgroup analyses, LG was associated with superior DSS in patients aged >= 70 years and those with upper GC. No significant associations regarding DFS were observed overall or in stratifications. PSM analyses revealed that LG was associated with better DSS also in patients aged >= 70 years (hazard ratio (HR) = 0.33, 95% confidence interval (CI) = 0.15-0.72) and in those with upper GC (HR = 0.51, 95% CI = 0.29-0.91), and with better DFS in those with upper GC (HR = 0.60, 95% CI = 0.37-0.99). Multivariable analysis showed that age, hepatitis B, performance status, tumor histology, stage, and vascular invasion were significantly associated with post-LG survival. LG-specific nomograms were then constructed with concordance indexes of 0.814 (DSS) and 0.809 (DFS) and excellent calibration. CONCLUSIONS: In this large institutional analysis, while LG for GC was associated with DSS and DFS similar to those for OG overall, non-inferior LG associated survival especially DSS was observed in some subgroups rarely investigated in prospective or randomized settings. There could still be biases even after PSM due to confounders not accounted for in this observational study. However, these findings offer novel hypotheses for further validation. PMID- 30478533 TI - Computer-assisted planning for a concentric tube robotic system in neurosurgery. AB - PURPOSE: Laser-induced thermotherapy in the brain is a minimally invasive procedure to denature tumor tissue. However, irregularly shaped brain tumors cannot be treated using existing commercial systems. Thus, we present a new concept for laser-induced thermotherapy using a concentric tube robotic system. The planning procedure is complex and consists of the optimal distribution of thermal laser ablations within a volume as well as design and configuration parameter optimization of the concentric tube robot. METHODS: We propose a novel computer-assisted planning procedure that decomposes the problem into task- and robot-specific planning and uses a multi-objective particle swarm optimization algorithm with variable length. RESULTS: The algorithm determines a Pareto-front of optimal ablation distributions for three patient datasets. It considers multiple objectives and determines optimal robot parameters for multiple trajectories to access the tumor volume. CONCLUSIONS: We prove the effectiveness of our planning procedure to enable the treatment of irregularly shaped brain tumors. Multiple trajectories further increase the applicability of the procedure. PMID- 30478534 TI - Sialylation is involved in cell fate decision during development, reprogramming and cancer progression. AB - Sialylation, or the covalent addition of sialic acid to the terminal end of glycoproteins, is a biologically important modification that is involved in embryonic development, neurodevelopment, reprogramming, oncogenesis and immune responses. In this review, we have given a comprehensive overview of the current literature on the involvement of sialylation in cell fate decision during development, reprogramming and cancer progression. Sialylation is essential for early embryonic development and the deletion of UDP-GlcNAc 2-epimerase, a rate limiting enzyme in sialic acid biosynthesis, is embryonically lethal. Furthermore, the sialyltransferase ST6GAL1 is required for somatic cell reprogramming, and its downregulation is associated with decreased reprogramming efficiency. In addition, sialylation levels and patterns are altered during cancer progression, indicating the potential of sialylated molecules as cancer biomarkers. Taken together, the current evidences demonstrate that sialylation is involved in crucial cell fate decision. PMID- 30478535 TI - Tongue coating microbiome as a potential biomarker for gastritis including precancerous cascade. AB - The development of gastritis is associated with an increased risk of gastric cancer. Current invasive gastritis diagnostic methods are not suitable for monitoring progress. In this work based on 78 gastritis patients and 50 healthy individuals, we observed that the variation of tongue-coating microbiota was associated with the occurrence and development of gastritis. Twenty-one microbial species were identified for differentiating tongue-coating microbiomes of gastritis and healthy individuals. Pathways such as microbial metabolism in diverse environments, biosynthesis of antibiotics and bacterial chemotaxis were up-regulated in gastritis patients. The abundance of Campylobacter concisus was found associated with the gastric precancerous cascade. Furthermore, Campylobacter concisus could be detected in tongue coating and gastric fluid in a validation cohort containing 38 gastritis patients. These observations provided biological evidence of tongue diagnosis in traditional Chinese medicine, and indicated that tongue-coating microbiome could be a potential non-invasive biomarker, which might be suitable for long-term monitoring of gastritis. PMID- 30478536 TI - The timing of permanent tooth development in a Black Southern African population using the Demirjian method. AB - BACKGROUND: Many aspects of growth have been documented for Black Southern African children, yet their dental development has not been comprehensively investigated. AIM: The present study was designed to provide information on age of attainment of dental development stages in Southern African children and to compare the findings with other populations. METHOD: This was a community-based cross-sectional study of 642 children (270 males and 372 females). Panoramic radiographs of children aged 5 to 20 years were assessed using Demirjian's eight stages of permanent tooth formation and age was estimated using Demirjian's method. Resulting dental ages were compared to the chronological ages. Probit regression analysis was employed to calculate the mean age of attainment of the developmental stages for the seven left mandibular teeth. Maturity scores and age of attainment were compared by sex and with published data on other populations. RESULTS: Females show significantly advanced dental maturity and dental ages, as well as earlier attainment of all stages of mineralization, compared to males (p < 0.05). The Demirjian method overestimated dental age in both males (0.8 +/- 1.02 years) and females (1.0 +/- 0.98 years). Cross-population comparisons illustrate that Black Southern African children are generally advanced in dental maturity compared to children of European and Asian ancestry. CONCLUSION: The Demirjian method significantly overestimated the chronological ages of Black Southern African males and females. Southern Africans attain dental maturity earlier than South Korean, Canadian, and Belgian children. These differences in dental maturity clearly illustrate the need for population-specific, rather than global, dental maturity standards. PMID- 30478537 TI - Development of a loop-mediated isothermal amplification (LAMP) assay for the detection of Anaplasma marginale. AB - Parasitemia generated by Anaplasma marginale causes significant losses in the cattle industry. A major constraint to the effective control and management of anaplasmosis in livestock is the lack of a rapid and reliable diagnostic test to identify the parasite and allow for immediate therapy. In the present study, we developed a novel DNA-based assay for the detection of A. marginale in bovine blood samples, using loop-mediated isothermal amplification (LAMP). DNA from six cattle and hemoparasite samples (Babesia bovis, Babesia bigemina, Anaplasma centrale and A. marginale) were tested for specificity, sensitivity and cross reactions. The developed LAMP procedures were also confirmed and compared with the qPCR method. The same gene sequence (major surface protein 1b, msp1b) of A. marginale was used to design a set of primers for the LAMP and qPCR assays. The results showed that LAMP is specific, as no positive signal was observed for the other tested hemoparasites. However, the sensitivity of the qPCR assay was ten times higher than LAMP. Our findings indicate that this LAMP method has a good sensitivity and high specificity for the detection of A. marginale and may have a potential application in the detection and differentiation of bovine anaplasmosis. PMID- 30478538 TI - Development of a delayed acute epidural hematoma following contralateral epidural hematoma evacuation: case report and review of literature. AB - The formation of a post-traumatic delayed epidural hematoma (DEDH) is a rare but well-described complication in the literature. It is defined as an extradural bleeding not evident at the first computed tomography (CT) scan performed after trauma, but evidenced by further radiological evaluations. The most supported hypothesis about the mechanism responsible for the formation of a DEDH concerns above all the loss of a tamponade effect given by the reduction of intracranial pressure with medical or surgical treatment. A 30-year-old man was admitted to the emergency department with an epidural hematoma (EDH) associated with a linear calvarial bitemporal coronal fracture. A few hours after the surgical procedure for hematoma evacuation, the patient developed a DEDH contralateral to the site of surgical procedure. The literature review identified other 27 analogue cases. The presence of a calvarial fracture contralateral to the site of a craniotomy and the intraoperative brain swelling during EDH removal are suspicious for the development of DEDH. A CT scan has to be urgently performed in this situation. The timing of postoperative radiological examinations after EDH removal has to consider possible complications and has to be balanced on the basis of patient's clinical condition and neuroradiological data, such as skull fractures or intraoperative anomalies. The development of a DEDH after the surgical removal of an EDH is a rare event, characterized by a high mortality rate. DEDH develops preferentially on the contralateral side and with a concomitant skull fracture. PMID- 30478540 TI - ? PMID- 30478539 TI - Posterior reversible encephalopathy syndrome in a patient with chronic obstructive pulmonary disease. PMID- 30478541 TI - ? PMID- 30478542 TI - ? PMID- 30478543 TI - ? PMID- 30478544 TI - ? PMID- 30478545 TI - ? PMID- 30478546 TI - ? PMID- 30478547 TI - ? PMID- 30478548 TI - ? PMID- 30478549 TI - ? PMID- 30478550 TI - ? PMID- 30478551 TI - ? PMID- 30478552 TI - ? PMID- 30478553 TI - [Interactions in analgesic drugs: relevance for clinical practice]. PMID- 30478554 TI - [Clinical examination of the knee joint]. PMID- 30478555 TI - [Acute dyspnoe and swollen leg in patient with heart failure]. PMID- 30478556 TI - [Burning sensation during urination]. PMID- 30478557 TI - [Discolorations of the nail plate - the causes are multiple]. PMID- 30478558 TI - [Headache again]. PMID- 30478559 TI - [I continue losing weight despite eating and eating]. PMID- 30478560 TI - ? PMID- 30478561 TI - ? PMID- 30478562 TI - ? PMID- 30478563 TI - ? PMID- 30478564 TI - ? PMID- 30478566 TI - ? PMID- 30478565 TI - ? PMID- 30478567 TI - ? PMID- 30478568 TI - ? PMID- 30478569 TI - ? PMID- 30478570 TI - ? PMID- 30478571 TI - ? PMID- 30478572 TI - ? PMID- 30478573 TI - ? PMID- 30478574 TI - ? PMID- 30478575 TI - ? PMID- 30478576 TI - ? PMID- 30478577 TI - ? PMID- 30478578 TI - ? PMID- 30478580 TI - ? PMID- 30478579 TI - ? PMID- 30478581 TI - ? PMID- 30478582 TI - ? PMID- 30478583 TI - ? PMID- 30478584 TI - ? PMID- 30478585 TI - ? PMID- 30478586 TI - ? PMID- 30478587 TI - ? PMID- 30478588 TI - ? PMID- 30478589 TI - ? PMID- 30478591 TI - ? PMID- 30478590 TI - ? PMID- 30478592 TI - ? PMID- 30478593 TI - ? PMID- 30478594 TI - ? PMID- 30478595 TI - ? PMID- 30478597 TI - A randomised controlled trial comparing completeness of responses of three methods of collecting patient-reported outcome measures in men diagnosed with prostate cancer. AB - PURPOSE: The purpose of the study was to compare completeness, timeliness and cost of patient-reported outcome measures (PROMs) collection using telephone, email and post in men with prostate cancer. METHODS: A parallel, three-arm randomised controlled equivalence trial. 1168 patients were randomised to telephone (n = 295), postal (n = 388) and email (n = 385) arms. Participants were asked to provide self-reported responses for 26 items of Expanded Prostate Cancer Index Composite. Cost and resource data were collected from a provider perspective. RESULTS: Equivalence tests showed no difference in completeness in the three arms within a 10% equivalence margin. Men diagnosed in public hospitals were less likely to complete the survey compared to those in private hospitals, OR = 0.19 (95% CI 0.04-0.89) (p = 0.035). The email survey required significantly less time to complete than telephone and postal methods [median time of 2 min (IQR 1,8) vs. 7 min (IQR 6,9) vs. 10 min (IQR 9,12), respectively (p < 0.001)]. The incremental cost effectiveness ratio for email compared to telephone was AUD$1.90, cost-effective if users valued an additional 1% improvement in survey completion greater than AUD$1.90. CONCLUSION: Email method took less time and cost and should be used as the primary PROMs collection, with telephone if men without email or do not respond to email. PMID- 30478596 TI - Manipulation of the microalgal chloroplast by genetic engineering for biotechnological utilization as a green biofactory. AB - The chloroplast is an essential organelle in microalgae for conducting photosynthesis, thus enabling the photoautotrophic growth of microalgae. In addition to photosynthesis, the chloroplast is capable of various biochemical processes for the synthesis of proteins, lipids, carbohydrates, and terpenoids. Due to these attractive characteristics, there has been increasing interest in the biotechnological utilization of microalgal chloroplast as a sustainable alternative to the conventional production platforms used in industrial biotechnology. Since the first demonstration of microalgal chloroplast transformation, significant development has occurred over recent decades in the manipulation of microalgal chloroplasts through genetic engineering. In the present review, we describe the advantages of the microalgal chloroplast as a production platform for various bioproducts, including recombinant proteins and high-value metabolites, features of chloroplast genetic systems, and the development of transformation methods, which represent important factors for gene expression in the chloroplast. Furthermore, we address the expression of various recombinant proteins in the microalgal chloroplast through genetic engineering, including reporters, biopharmaceutical proteins, and industrial enzymes. Finally, we present many efforts and achievements in the production of high-value metabolites in the microalgal chloroplast through metabolic engineering. Based on these efforts and advances, the microalgal chloroplast represents an economically viable and sustainable platform for biotechnological applications in the near future. PMID- 30478598 TI - Health-related quality of life (HRQoL) in children of ill or substance abusing parents: examining factor structure and sub-group differences. AB - PURPOSE: Health-related quality of life (HRQoL) may be helpful in identifying children at risk of developing adjustment problems. Few studies have focused on HRQoL among children of ill or substance abusing parents despite their considerable risk status. In the present study, we used the KIDSCREEN-27 to assess self-reported HRQoL in children and adolescents living in families with parental illness, or substance dependence. First, we tested whether the factor structure of the KIDSCREEN-27 was replicated in this population of children. Next, we examined differences in HRQoL according to age, gender, and type of parental illness. Finally, we compared levels of HRQoL in our sample to a normative reference population. METHOD: Two hundred and forty-six children and adolescents aged 8-17 years and their ill parents participated. The construct validity of the KIDSCREEN-27 questionnaire was examined by confirmatory factor analysis (CFA). T-tests and ANOVA were used to test differences in HRQoL levels according to age, gender, and parental patient groups, and for comparisons with reference population. RESULTS: The KIDSCREEN-27 fit the theoretical five-factor model of HRQoL reasonably well. Boys and younger children reported significantly greater well-being on physical well-being, psychological well-being, and peers and social support, compared to girls and older children. Younger children also reported significantly greater well-being at school than did older children. There were no significant differences in HRQoL between groups of children living with different type of parental illness. The children in our sample reported their physical well-being significantly lower than the reference population. CONCLUSION: The KIDSCREEN-27 questionnaire appears to work satisfactorily among children of ill or substance abusing parents. PMID- 30478599 TI - How online ADHD-related information affects Chinese parents' decisions? AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a major public health problem in China. Parents of children with confirmed, or suspected ADHD often face a difficult process in making decisions concerning diagnosis and treatment. The internet is a major source of information for parents. The purpose of this study is to survey Chinese parental motivation and experience in using the internet to retrieve ADHD-related information, and how well online information is associated with making decisions. METHODS: Parents were recruited to fill out an online questionnaire in the health portal. A total of 404 valid questionnaires were collected. RESULTS: A total of 47.8% of parents agree that the internet helps them to understand the potential treatment options, but 77.7% of all parents still have conflict during decision-making. CONCLUSIONS: Parents search for ADHD-related information online, but their acquisition skills need to be improved. Internet information affects their health decisions. Parents still have highly conflicting decision-making. Improving the ability of parents to obtain information on the Internet may reduce the conflict in decision-making. PMID- 30478600 TI - [Digital papillary adenocarcinoma : Four case reports with brief literature review]. AB - Digital papillary adenocarcinoma is a rare but well characterized carcinoma of the sweat glands, which apart from very few exceptions is localized in acral skin. This type of sweat gland carcinoma tends to recur locally and may cause delayed metastases in a few cases. We describe the clinical findings and the broad histopathologic spectrum of four cases of this rare adnexal carcinoma and give a short summary of the literature. PMID- 30478601 TI - [Interdisciplinary recommendations for action in dupilumab-related inflammatory eye diseases]. PMID- 30478602 TI - Thermal physiological performance of two freshwater turtles acclimated to different temperatures. AB - The thermal physiological performance of invasive species may play a crucial role in determining their invasion success. In this study, we acclimated two cohorts of hatchlings of freshwater turtles (native Mauremys reevesii and invasive Trachemys scripta elegans) from low and high-latitude collection sites, respectively, to different thermal conditions (20 and 30 degrees C) for 4 weeks, and then compared their thermal tolerance and locomotor performance. T. scripta elegans hatchlings could swim faster (but righted themselves more slowly), and tolerate a higher temperature and wider temperature range than M. reevesii hatchlings. Similarly, T. scripta elegans hatchlings had a greater maximal performance (Pmax) value for swimming speed (but a lower Pmax value for righting time) than M. reevesii hatchlings. Temperature acclimation had a significant impact on the thermal tolerance and locomotor ability of turtles, but the acclimation effect did not differ between the two species. T. scripta elegans hatchlings seemed to have a greater thermal plasticity than M. reevesii hatchlings. High-latitude individuals showed a greater low-temperature tolerance, but lower locomotor ability (longer righting time) than low-latitude ones. However, the thermal plasticity did not differ between latitudinal cohorts. Our results indicated that T. scripta elegans performed better than M. reevesii, which might contribute to its range expansion and invasive success. PMID- 30478603 TI - Commentary on "Enhanced recovery program for minimally invasive and vaginal urogynecologic surgery". PMID- 30478604 TI - Aggressive angiomyxoma presenting as posterior vaginal prolapse. PMID- 30478605 TI - Highlight report: Stem cell-based developmental toxicity tests. PMID- 30478606 TI - Improved production of bacteriorhodopsin from Halobacterium salinarum through direct amino acid supplement in the basal medium. AB - Enhanced production and growth of Halobacterium salinarum are achieved by direct supplement of essential amino acids in the modified nutrient culture medium. As arginine (R) and aspartate (D) are the main amino acid sources for producing bacteriorhodopsin efficiently from Halobacterium salinarum, both individual and combined effects of these two amino acids (in different compositions) in the basal medium were studied. The BR production is enhanced by 83% on the eighth day (saturated) for all individual and combined amino acid supplements. Maximum production of 201 mg/l is observed for combined amino acid (R3D2)-supplemented culture which is 4.46-fold higher than the conventional culture growth from the basal medium. The obtained results suggest the efficient method to enhance BR production at low cost and thus, open up the possibility to utilize this potential biomolecule for various photonics applications which were earlier restricted due to the high cost of protein molecules. PMID- 30478607 TI - Involuntary memories and involuntary future thinking differently tax cognitive resources. AB - During the past 20 years involuntary memories have been established as a noteworthy phenomenon, which occur spontaneously in everyday life and with greater frequency than expected. Other types of ideations also occur involuntarily and very frequently, both in the normal population and in clinical groups. The aim of this paper was to assess for the first time whether involuntary memories and involuntary future thoughts differ in the amount of cognitive resources, considering that both are experienced as being rather automatic. As in previous work on mind wandering, this was done by assessing the effect of different conditions on frequency of spontaneous thoughts about past and future. Involuntary memories and future thoughts were obtained in an experimental setting (vigilance task) that mimics a mind-wandering task. In it, participants saw slides (trials) with horizontal or vertical (target) lines. In half or one-fourth of the trials verbal cues were also presented. In a third condition one-fourth of the trials had verbal cues and one-fourth had simple arithmetic calculations. Participants were asked to report any mental content that crosses their mind when the vigilance task stopped. Results show that the manipulation modulates the number of both involuntary memories and future thoughts, and both engage cognitive resources. Future involuntary thoughts seem to require more cognitive effort than involuntary memories and, specifically, future scenarios require more cognitive resources than both involuntary memories and future plans. The results support previous findings showing that reporting spontaneous mental contents makes use of cognitive resources and are discussed linking the involuntary memory literature with mind wandering and metacognitive processes. PMID- 30478608 TI - Can we learn to learn? The influence of procedural working-memory training on rapid instructed-task-learning. AB - Humans have the unique ability to efficiently execute instructions that were never practiced beforehand. In this Rapid Instructed-Task-Learning, not-yet executed novel rules are presumably held in procedural working-memory (WM), which is assumed to hold stimulus-to-response bindings. In this study, we employed a computerized-cognitive training protocol targeting procedural WM to test this assumption and to examine whether the ability to rapidly learn novel rules can itself be learned. 175 participants were randomly assigned to one of three groups: procedural WM training (involving task-switching and N-back elements, all with novel rules; Shahar and Meiran in PLoS One 10(3):e0119992, 2015), active control training (adaptive visual-search task), and no-contact control. We examined participants' rapid instructed-task-learning abilities before and after training, by administrating 55 novel choice tasks, and measuring their performance in the first two trials (where participants had no practice). While all participants showed shorter reaction-times in post vs. pretest, only participants in the procedural WM training group did not demonstrate an increased error rate at posttest. Evidence accumulation modelling suggested that this result stems from a reduction in decision threshold (the amount of evidence that needs to be gathered to reach a decision), which was more pronounced in the control groups; possibly accompanied by an increased drift-rate (the rate of evidence accumulation) only for the training group. Implication are discussed. PMID- 30478609 TI - Preconditioning exercise reduces brain damage and neuronal apoptosis through enhanced endogenous 14-3-3gamma after focal brain ischemia in rats. AB - 14-3-3gamma is an important early ischemia-inducible protective factor against ischemic cell death in cerebral cortical neurons. We investigated the anti apoptosis mechanism of enhanced 14-3-3gamma mediated by preconditioning exercise induced brain ischemic tolerance after stroke. Rats were assigned to four groups: exercise and ischemia (Ex group), ischemia and no exercise (No-Ex group), exercise and no ischemia (Ex-only group), and no exercise and ischemia (control group). Rats were trained on a treadmill for 5 days a week for 3 weeks (running speed, 25 m/min; running duration, 30 min/day). After the exercise program, stroke was induced by left middle cerebral artery occlusion. The infarct volume, neurological deficits, and motor function, as well as expression levels of hypoxia-induced factor-1alpha (HIF-1alpha), 14-3-3gamma, P2X7 receptors, p-beta catenin Ser37, Bax, and caspase 3 were evaluated by immunohistochemistry and western blotting. The expression of HIF-1alpha and 14-3-3gamma significantly increased in neurons and astrocytes in the Ex-only group. HIF-1alpha was co expressed with P2X7 receptor- and GFAP-positive astrocytes. After stroke, the Ex group had significantly reduced brain infarction. HIF-1alpha and 14-3-3gamma significantly increased in the Ex group compared to the No-Ex group. In addition, p-beta-catenin Ser37 significantly increased following elevated 14-3-3gamma; in contrast, Bax and caspase 3 were significantly reduced in the Ex group. Our findings suggest that preconditioning exercise prior to ischemia induces neuron- and astrocyte-mediated brain ischemic tolerance through increased expression of HIF-1alpha and 14-3-3gamma, which are intrinsic protective factors; the upregulated 14-3-3gamma induced by preconditioning exercise reduces ischemic neuronal cell death through the 14-3-3gamma/p-beta-catenin Ser37/Bax/caspase 3 anti-apoptotic pathway. PMID- 30478610 TI - Hippocampal signatures of awake targeted memory reactivation. AB - Dominant theories of episodic memory propose that a key mechanism of memory consolidation is replay-a process, whereby neural patterns of activation during learning are reinstated during offline post-learning periods. Here, we tested whether key signatures of replay defined by studies in rodents, such as recapitulation of specific memory traces, as well as sequences, are apparent in humans during post-encoding memory reactivation. Thirty participants underwent functional imaging that consisted of interleaved encoding and rest periods. During an offline period of wakeful rest, we biased reactivation towards some memories by presenting sound cues that had previously been associated with particular stimulus sequences. Results showed that targeted hippocampal reactivation was biased towards cued memory sequences and that reactivation signatures preserved the temporal order of particular sequences. Importantly, the biased reactivation was related to differences in subsequent memory, suggesting that preferential reactivation may be a mechanism by which specific memory traces can be strengthened for enhanced subsequent memory retrieval. PMID- 30478611 TI - The Application of Expectation and Standard Deviation Calculations in the Evaluation of Dissolved Arsenic in the Pu River, Liaoning Province, Northeastern China. AB - Water samples were collected from the Pu River in 2017 to research the distribution and accumulation characteristics of dissolved arsenic. We mainly built three types of expectation and standard deviation calculations corresponding to discrete, weighted and continuous random variables. The continuous expectation and standard deviation calculations are defined based on the concentration function and average formula, and the weighted expectation and standard deviation calculations are defined based on the relationship between the concentration and distance. The results indicate that the discrete expectation (1.8351 [Formula: see text]/L) and standard deviation (0.6410 [Formula: see text]/L) describe the average level and the deviation degree, respectively, of dissolved arsenic, and the continuous expectation (1.8684 [Formula: see text]/L) and standard deviation (0.5375 [Formula: see text]/L) mainly describe the average level and the dispersion degree, respectively, of dissolved arsenic after its accumulation. The weighted expectation (1.2997 [Formula: see text]/L) and standard deviation (0.2816 [Formula: see text]/L) reflect the average level and the dispersion degree, respectively, of dissolved arsenic and reveal the quantitative relationship between the concentration of dissolved arsenic and distance. The combination of the three types of expectation and standard deviation calculations and the concentration function may comprehensively describe the distribution and accumulation characteristics of dissolved arsenic, which can provide a theoretical foundation for guiding the reduction of arsenic pollution in the Pu River. PMID- 30478612 TI - Arsenic Bioaccumulation and Biotransformation in Clams (Asaphis violascens) Exposed to Inorganic Arsenic: Effects of Species and Concentrations. AB - High arsenic (As) concentrations are found in marine clams, usually as less-toxic arsenobetaine (AsB). However, when clams were exposed to elevated As concentrations in the environments, As species distribution within them may be altered. This study aimed to determine As bioaccumulation and biotransformation in marine clams (Asaphis violascens) along As concentration gradients for 10 days. Nine treatments of dissolved As exposure [control, 1, 3 (low), 10, 20 (high) mg/L As(III) and As(V)] were performed. Clams could biotransform low levels of inorganic As efficiently, while they had lower biotransformation efficiencies when exposed to high As concentrations. AsB decreased with increasing As(III) and As(V) concentrations, while dimethylarsinic acid exhibited as a predominant As species in 3 mg/L exposure treatments. These results suggested that As methylation, synthesis and/or degradation of AsB should be affected by exposure concentrations. Therefore, these toxic As species within clams may cause a potential toxicological hazard to human beings. PMID- 30478613 TI - Effect of EDTA and NTA on Arsenic Bioaccumulation and Translocation Using Phytoremediation by Mimosa pudica L. from Contaminated Soils. AB - This study aimed to investigate the effects of Nitrilotriacetic acid (NTA) and Elthylenediaminetetraacetic acid (EDTA) on the bioaccumulation and translocation of arsenic (As) by Mimosa pudica L. using soils with 5 mg/kg of added As and NTA and EDTA concentrations of 50, 100, and 200 mg/kg. Soil and plant samples were collected every 30-120 days to analyze the As concentrations in the soil, underground part of the plants (root), and aboveground parts of the plants (shoots and leaves). The results showed that the plants with EDTA concentrations of 100 mg/kg had the highest As accumulation. At 120 days, M. pudica L. had a higher accumulation in the underground parts (29.71 mg/kg) than in the aboveground parts (6.32 mg/kg), with statistical significance (p < 0.05). The As translocation factor in the aboveground parts was less than 1, indicating As accumulation in the underground part only. With EDTA concentrations of 50 and 100 mg/kg, M. pudica L. had the highest bioaccumulation potential of As of 8.00 and 8.44, respectively. However, this research did not examine the reaction between As and any growth promoters. Further research should investigate the details of such a reaction at the molecular level, as well as explore how fertilizer factors might affect the As absorption of M. pudica L. PMID- 30478614 TI - Fetal Arrhythmias: Genetic Background and Clinical Implications. AB - Fetal arrhythmias are a common phenomenon of pregnancies. However, debates remain with regard to the etiologies and early treatment of choices for severe fetal arrhythmias. The gene regulatory networks govern cardiac conduction system development to produce distinct nodal and fast conduction phenotypes. The slow conduction properties of nodes that display automaticity are determined by the cardiac ion channel genes, whereas the fast conduction properties are regulated by the transcription factors. Mutations of genes specific for the developmental processes and/or functional status of cardiac conduction system including ion channel promoter (minK-lacZ), GATA family of zinc finger proteins (GATA4), the homeodomain transcription factor (Nkx2.5), the homeodomain-only protein (Hop) and the T-box transcription factors (Tbx2, Tbx3 and Tbx5), hyperpolarization activated cyclic nucleotide-gated channel 4 (HCN4) and connexins, may cause fetal arrhythmias. It is expected that development of investigational antiarrhythmic agents based on genetic researches on cardiac conduction system, and clinical application of percutaneously implantable fetal pacemaker for the treatment of fetal arrhythmias would come to true. PMID- 30478615 TI - Fine mapping and molecular marker development of the Sm gene conferring resistance to gray leaf spot (Stemphylium spp.) in tomato. AB - KEY MESSAGE: The tomato gray leaf spot resistance gene Sm was fine-mapped in a 185-kb region through a map-based cloning strategy and genome-wide association study; a candidate gene was proved to be involved in Sm-mediated resistance through transient gene silencing. Gray leaf spot, caused by Stemphylium spp., is a warm weather foliar disease in tomato (Solanum lycopersicum L). Resistance against gray leaf spot is conferred by a single incompletely dominant gene (Sm) located on chromosome 11. This study aimed to map and identify molecular marker tightly linked to the Sm gene for the use of marker-assisted selection in breeding. Using an F2 population derived from a cross between the resistant line '9706' and the susceptible line 'Heinz 1706', the Sm gene was mapped to a 185-kb interval between two markers, InDel343 and InDel-FT-32 on chromosome 11, which was consistent with the result of a genome-wide association study using 289 diverse accessions. An ORF predicted in this region was proved to be involved in Sm-mediated resistance through transient gene silencing and seems to be a good candidate of the Sm locus. To clone the Sm gene, a bacterial artificial chromosome (BAC) library was screened and one BAC clone B80B15 containing the predicted ORF was identified. The analysis of sequence and structure characteristics demonstrated that the candidate gene was not a typical type resistance gene. Additionally, a co-dominant marker Sm-InDel, which produced a 122-bp or 140-bp fragment for resistant or susceptible alleles, respectively, was developed. This marker was validated in 289 germplasm and could be used in marker assisted selection for gray leaf spot resistance. PMID- 30478616 TI - Acknowledgement to referees 2017/2018. PMID- 30478617 TI - Educational inequalities in Global Activity Limitation Indicator disability in 28 European Countries: Does the choice of survey matter? AB - OBJECTIVES: To assess the sensitivity of prevalence and inequality estimates of Global Activity Limitation Indicator (GALI) to the choice of survey in European countries. METHODS: We use logistic regression to estimate adjusted risk ratios, quantifying differences in prevalence and educational inequalities, the impact of survey characteristics and Kendall's tau to assess similarity in country rankings between surveys. We include the European Health Interview Survey (EHIS), European Social Survey (ESS) and European Union Statistics on Income and Living Conditions (EU-SILC). RESULTS: EHIS estimates higher prevalence than EU-SILC 17% (men) and 23% (women), and ESS 24% (men) and 29% (women). Prevalence does not differ significantly between EU-SILC and ESS. EU-SILC estimates 52.5% (men) and 28.1% (women) higher inequalities than EHIS and 63.2% (men) and 32.7% (women) higher inequalities than ESS. Survey characteristics do not account for differences in prevalence or inequalities. Country rankings do not agree for prevalence or inequalities. CONCLUSIONS: Survey choice strongly impacts estimates of GALI prevalence and educational inequalities. Further study is necessary to understand these discrepancies. Caution is required when using these surveys for cross country comparisons of (educational inequalities in) GALI disability. PMID- 30478618 TI - Different routes of heroin intake cause various heroin-induced leukoencephalopathies. AB - OBJECTIVE: Toxic leukoencephalopathy is a rare but critical neurological disorder in heroin abusers. Our aim is to compare the clinical manifestations, brain MRIs and prognoses of heroin-induced leukoencephalopathy by different intake routes. METHODS: We present two patients with toxic leukoencephalopathy caused by intravenous (IV) injection of heroin and 48 additional cases from systematic reviews of the literature published between 1994 and 2018. RESULTS: Among the 50 heroin abusers who developed leukoencephalopathy, inhalation was the most popular route (60%), followed by IV injection (30%) and snorting (10%). Mental changes, mutism and urine/fecal incontinence were the major symptoms in patients who IV injected heroin, while cerebellar ataxia and dysarthria were more common among those who inhaled heroin. Delayed-onset encephalopathy uniquely occurred in those who IV injected heroin, whereas progressive encephalopathy was more commonly observed in those who inhaled heroin. Clinical improvement was observed in 60% of patients, the overall mortality rate was 12%, and higher mortality was observed in patients who used the inhalation route (16.7%). The hallmarks on the MRIs of those who inhaled heroin were posterior to anterior involvement of the cerebral white matter and lesions in the posterior limbs of the internal capsules, cerebellum and brainstem. In contrast, those who IV injected heroin had more frequent lesions in the subcortical U fibers and the genu of the internal capsules. CONCLUSION: These data could help physicians make an early diagnosis and predict prognosis and suggest that prompt antioxidative or symptomatic treatments might reduce the long-term consequences and mortality of heroin induced leukoencephalopathy. PMID- 30478619 TI - Consequences of prey exoskeleton content for predator feeding and digestion: black widow predation on larval versus adult mealworm beetles. AB - Predators often feed on a wide range of prey that can vary in behavior, morphology, and physiology. The net benefits that predators gain from prey are likely related to both prey nutrient content and prey morphology or defenses. For invertebrates, the exoskeleton is a morphological trait that varies widely among species and during ontogeny and could affect nutrient extraction by predators. The goal of this study was to determine how prey exoskeleton content affected predator nutrient intake, assimilation, and excretion by comparing spiders feeding on either larval or adult mealworms of similar size. We found that the proportion of prey energy invested in digestion was greatest in spiders consuming adult mealworm beetles which had higher amounts of exoskeleton than larvae. Further, spiders extracted a greater proportion of elements, macronutrients, and energy from the larval mealworms, which had lower amounts of exoskeleton. Interestingly, total nitrogen content of prey was not a predictor of nitrogen assimilation as spiders assimilated more nitrogen from the larval mealworms, which had lower total nitrogen content. While adult beetles had higher total nitrogen content, their discarded remains of prey had large amounts of nitrogen that was nutritionally unavailable for spiders (i.e., exoskeleton). These results suggest that prey exoskeleton can affect assimilation efficiency by predators, and that a combination of macronutrient and elemental analyses may be needed to examine the quality of prey for predators and the potential consequences of predation for nutrient flows (e.g., consumer assimilation, egestion, and excretion) in ecosystems. PMID- 30478620 TI - Quantitative versus standard pupillary light reflex for early prognostication in comatose cardiac arrest patients: an international prospective multicenter double blinded study. AB - PURPOSE: To assess the ability of quantitative pupillometry [using the Neurological Pupil index (NPi)] to predict an unfavorable neurological outcome after cardiac arrest (CA). METHODS: We performed a prospective international multicenter study (10 centers) in adult comatose CA patients. Quantitative NPi and standard manual pupillary light reflex (sPLR)-blinded to clinicians and outcome assessors-were recorded in parallel from day 1 to 3 after CA. Primary study endpoint was to compare the value of NPi versus sPLR to predict 3-month Cerebral Performance Category (CPC), dichotomized as favorable (CPC 1-2: full recovery or moderate disability) versus unfavorable outcome (CPC 3-5: severe disability, vegetative state, or death). RESULTS: At any time between day 1 and 3, an NPi <= 2 (n = 456 patients) had a 51% (95% CI 49-53) negative predictive value and a 100% positive predictive value [PPV; 0% (0-2) false-positive rate], with a 100% (98-100) specificity and 32% (27-38) sensitivity for the prediction of unfavorable outcome. Compared with NPi, sPLR had significantly lower PPV and significantly lower specificity (p < 0.001 at day 1 and 2; p = 0.06 at day 3). The combination of NPi <= 2 with bilaterally absent somatosensory evoked potentials (SSEP; n = 188 patients) provided higher sensitivity [58% (49-67) vs. 48% (39-57) for SSEP alone], with comparable specificity [100% (94-100)]. CONCLUSIONS: Quantitative NPi had excellent ability to predict an unfavorable outcome from day 1 after CA, with no false positives, and significantly higher specificity than standard manual pupillary examination. The addition of NPi to SSEP increased sensitivity of outcome prediction, while maintaining 100% specificity. PMID- 30478621 TI - Clarification of errors in Abbas et al.'s conflict of interest narrative review. PMID- 30478622 TI - Prognostic relevance of serum lactate kinetics in critically ill patients. AB - PURPOSE: Changes of lactate concentration over time were reported to be associated with survival in septic patients. We aimed to evaluate delta-lactate (DeltaLac) 24 h after admission (Delta24Lac) to an intensive care unit (ICU) in critically ill patients for short- and long-term prognostic relevance. METHODS: In total, 26,285 lactate measurements of 2191 patients admitted to a German ICU were analyzed. Inclusion criterion was a lactate concentration at admission above 2.0 mmol/L. Maximum lactate concentrations of day 1 and day 2 were used to calculate Delta24Lac. Follow-up of patients was performed retrospectively. Association of Delta24Lac and both in-hospital and long-term mortality were investigated. An optimal cut-off was calculated by means of the Youden index. RESULTS: Patients with lower Delta24Lac were of similar age, but clinically sicker. As continuous variable, higher Delta24Lac was associated with decreased in-hospital mortality (per 1% Delta24Lac; HR 0.987 95%CI 0.985-0.990; p < 0.001) and an optimal Delta24Lac cut-off was calculated at 19%. Delta24Lac <= 19% was associated with both increased in-hospital (15% vs 43%; OR 4.11; 95%CI 3.23-5.21; p < 0.001) and long-term mortality (HR 1.54 95%CI 1.28-1.87; p < 0.001), even after correction for APACHE II, need for catecholamines and intubation. We matched 256 patients with Delta24Lac <= 19% to case-controls > 19% corrected for APACHE II scores, baseline lactate level and sex: Delta24Lac <= 19% remained associated with lower in-hospital and long-term survival. CONCLUSIONS: Lower Delta24Lac was robustly associated with adverse outcome in critically ill patients, even after correction for confounders. Delta24Lac might constitute an independent, easily available and important parameter for risk stratification in the critically ill. PMID- 30478623 TI - What's new in the prevention of healthcare-associated infections using chlorhexidine gluconate-impregnated washcloths. PMID- 30478624 TI - The role of de novo mutations in adult-onset neurodegenerative disorders. AB - The genetic underpinnings of the most common adult-onset neurodegenerative disorders (AOND) are complex in majority of the cases. In some families, however, the disease can be inherited in a Mendelian fashion as an autosomal-dominant trait. Next to that, patients carrying mutations in the same disease genes have been reported despite a negative family history. Although challenging to demonstrate due to the late onset of the disease in most cases, the occurrence of de novo mutations can explain this sporadic presentation, as demonstrated for severe neurodevelopmental disorders. Exome or genome sequencing of patient-parent trios allows a hypothesis-free study of the role of de novo mutations in AOND and the discovery of novel disease genes. Another hypothesis that may explain a proportion of sporadic AOND cases is the occurrence of a de novo mutation after the fertilization of the oocyte (post-zygotic mutation) or even as a late-somatic mutation, restricted to the brain. Such somatic mutation hypothesis, that can be tested with the use of novel sequencing technologies, is fully compatible with the seeding and spreading mechanisms of the pathological proteins identified in most of these disorders. We review here the current knowledge and future perspectives on de novo mutations in known and novel candidate genes identified in the most common AONDs such as Alzheimer's disease, Parkinson's disease, the frontotemporal lobar degeneration spectrum and Prion disorders. Also, we review the first lessons learned from recent genomic studies of control and diseased brains and the challenges which remain to be addressed. PMID- 30478625 TI - Knowledge of the Sexual Transmission of Zika Virus and Preventive Practices Against Zika Virus Among U.S. Travelers. AB - Individuals are often at increased risk of acquiring infectious disease while traveling. We sought to understand knowledge, attitudes and practices (KAP) regarding Zika virus among travelers from the United States. A total of 1043 study participants were recruited from a probability-based internet panel. Participants self-reported their knowledge of Zika infection and modes of transmission, and identified actions they had taken to prevent Zika infection and transmission including actions to prevent unintentional pregnancy since becoming aware of the Zika virus. Logistic regression was used to model the odds of taking preventive actions against Zika infection with adjustment for potential confounding factors. Knowledge of the sexual transmissibility of Zika virus significantly increased the odds of taking a preventive action against Zika infection, especially condom use or sexual abstention. Participants reported preferences for receiving information about Zika from private doctors and from the Internet. Discrepancies between where travelers seek information about Zika and how they would like to receive information regarding Zika were also found. These findings suggest that improving targeted messaging through online media may increase awareness of the sexual transmissibility of Zika as well as improve health communications with U.S. travelers. Travelers who are unaware of potential disease risks are less likely to adopt personal protective measures to protect themselves and reduce disease spread. Thus, future work should focus on improving communication and providing education to adopt effective prevention strategies while traveling. PMID- 30478626 TI - Quality of publications in "International Orthopaedics" and projects for the near future. PMID- 30478627 TI - [Osteitis pubis or symphysitis pubis]. AB - CLINICAL/METHODICAL ISSUE: Osteitis pubis is one of the most common causes of chronic groin pain in many professional athletes. Symphysitis pubis with instability of the joint due to softening of the joint capsule and muscular imbalance of the corresponding muscles increases the instability of the sympyseal region, thus, resulting in a vicious cycle. STANDARD RADIOLOGICAL METHODS: Magnetic resonance imaging (MRI). METHODICAL INNOVATIONS: Optimized MRI sequence protocol with oblique (axial oblique) layers parallel to the linea arcuata of iliac bone together with large image field for depiction of the entire pelvis and high-resolution sequences focused on the symphysis pubis. PERFORMANCE: Recently, the correlation between MRI signs of osteitis pubis and long-term clinical outcome in a group of professional soccer players was examined. In particular, edema in the peri-osseous tissue and isolated muscle lesions around the symphysis at the onset of symptoms were associated with partial recovery of the athletes. Furthermore, a significant association of increased normalized signal intensity in the pubic bone on STIR (short-tau inversion recovery) sequences (corresponding presence and signal intensity of bone marrow edema) and a poor complete clinical improvement was observed. ACHIEVEMENTS: An optimized MRI protocol allows the diagnosis of osteitis pubis and provides important prognostic information. PRACTICAL RECOMMENDATIONS: In case of clinical suspicion on osteitis pubis, MR imaging with an optimized sequence protocol should be performed. PMID- 30478628 TI - KIAA1199 promotes invasion and migration in non-small-cell lung cancer (NSCLC) via PI3K-Akt mediated EMT. AB - KIAA1199 is often upregulated in cancer cells, including non-small-cell lung cancer (NSCLC). Although KIAA1199 is associated with aggressive tumor phenotype and poor survival in NSCLC, little is known about its functional role in NSCLC progression. Using archived clinical samples, we evaluated KIAA1199 messenger RNA (mRNA) and protein expression in NSCLC tissues and correlated with NSCLC clinicopathological characteristics as well as overall survival. Using NSCLC cell lines, KIAA1199 was either silenced using gene-specific shRNA or overexpressed to assess the impact on EMT signaling pathways. Finally, in a mouse xenograft NSCLC model, we determine the therapeutic potential of KIAA1199 repression. Our data showed that KIAA1199 was significantly upregulated in NSCLC tissues compared to adjacent normal tissues both at the mRNA (P < 0.001) and protein levels (P < 0.05). KIAA1199 overexpression is an independent prognostic marker for overall survival (HR = 1.833). In NSCLC cell lines, KIAA1199 expression directly influences the expression of EMT markers, EMT-inducing transcription factors (EMT TFs), and EMT signaling molecules. Knocking down of KIAA1199 expression in the mouse NSCLC xenograft model significantly suppressed tumor growth and augmented the efficacy of chemotherapy (n = 5; P < 0.05). We conclude that KIAA1199 is not only a prognostic marker but a novel therapeutic target in NSCLC through regulating EMT signaling pathway. KEY MESSAGES: KIAA1199 overexpression is an independent prognostic marker in NSCLC. KIAA1199 expression directly influences the expression of EMT markers. KIAA1199 promotes invasion and migration in NSCLC via PI3K-Akt mediated EMT. PMID- 30478629 TI - Effect of growth hormone treatment on energy expenditure and its relation to first-year growth response in children. AB - PURPOSE: The effects of growth hormone (GH) treatment on linear growth and body composition have been studied extensively. Little is known about the GH effect on energy expenditure (EE). The aim of this study was to investigate the effects of GH treatment on EE in children, and to study whether the changes in EE can predict the height gain after 1 year. METHODS: Total EE (TEE), basal metabolic rate (BMR), and physical activity level (PAL) measurements before and after 6 weeks of GH treatment were performed in 18 prepubertal children (5 girls, 13 boys) born small for gestational age (n = 14) or with growth hormone deficiency (n = 4) who were eligible for GH treatment. TEE was measured with the doubly labelled water method, BMR was measured with an open-circuit ventilated hood system, PAL was assessed using an accelerometer for movement registration and calculated (PAL = TEE/BMR), activity related EE (AEE) was calculated [AEE = (0.9 * TEE) - BMR]. Height measurements at start and after 1 year of GH treatment were analysed. This is a 1-year longitudinal intervention study, without a control group for comparison. RESULTS: BMR and TEE increased significantly (resp. 5% and 7%). Physical activity (counts/day), PAL, and AEE did not change. 11 out of 13 patients (85%) with an increased TEE after 6 weeks of GH treatment had a good first-year growth response (?height SDS > 0.5). CONCLUSIONS: GH treatment showed a positive effect on EE in prepubertal children after 6 weeks. No effect on physical activity was observed. The increase in TEE appeared to be valuable for the prediction of good first-year growth responders to GH treatment. PMID- 30478631 TI - Breast Density Legislation and the Promise Not Attained. PMID- 30478632 TI - ASO Author Reflections: Safety of Abdominal Surgical Cytoreduction Combined with Locoregional Chemohyperthermia. PMID- 30478630 TI - Measuring The Bipolar Charge Distributions of Fine Particle Aerosol Clouds of Commercial PMDI Suspensions Using a Bipolar Next Generation Impactor (bp-NGI). AB - PURPOSE: To measure the charge to mass (Q/M) ratios of the impactor stage masses (ISM) from commercial FlixotideTM 250 MUg Evohaler, containing fluticasone propionate (FP), SereventTM 25 MUg Evohaler, containing salmeterol xinafoate (SX), and a combination SeretideTM 250/25 MUg (FP/SX) Evohaler metered dose inhalers (MDIs). Measurements were performed with a purpose built bipolar charge measurement apparatus (bp-NGI) based on an electrostatic precipitator, which was directly connected below Stage 2 of a Next Generation Impactor (NGI). METHODS: Five successive shots of the respective MDIs were actuated through the bp-NGI. The whole ISM doses were electrostatically precipitated to determine their negative, positive and net Q/m ratios. RESULTS: The ISM doses collected in the bp NGI were shown to be equivalent to those collected in a standard NGI. FP particles, actuated from FlixotideTM and SeretideTM MDIs, exhibited greater quantities of negatively charged particles than positive. However, the Q/m ratios of the positively charged particles were greater in magnitude. SX particles from SereventTM exhibited a greater quantity of positively charged particles whereas SX aerosol particles from SeretideTM exhibited a greater quantity of negatively charged particles. The Q/m ratio of the negatively charged SX particles in SereventTM was greater in magnitude than the positively charged particles. CONCLUSIONS: The bp-NGI was used to quantify the bipolar Q/m ratios of aerosol particles collected from the ISMs of commercial MDI products. The positive charge recorded for each of the three MDIs may have been enhanced by the presence of charged ice crystals formed from the propellant during the aerosolisation process. PMID- 30478633 TI - ASO Author Reflections: Quality Improvement in Minimally Invasive Esophagectomy. PMID- 30478634 TI - [Anterolateral stabilization using the modified Lemaire technique for ACL deficiency]. AB - OBJECTIVE: Treatment of persistent anterolateral knee instability. INDICATIONS: Subjective/objective (rotational) instability of the knee after anatomic anterior cruciate ligament (ACL) reconstruction. ACL re-rupture including special demands (e.g., high-performance athletes, hyperlaxity) RELATIVE CONTRAINDICATIONS: Osteoarthritis, additional instability of the knee, which should be treated independently; non-anatomic ACL reconstruction with persisting instability should be treated first with anatomic ACL reconstruction. ABSOLUTE CONTRAINDICATIONS: General contraindications for surgery (e. g. septic arthritis), acute irritation of the affected knee. SURGICAL TECHNIQUE: Supine position. Incision along the proximal lateral femoral epicondyle. Marking of the needed width and length of the iliotibial band (ITB) graft. Passing the ITB graft underneath the lateral collateral ligament. Find and mark the isometric point for fixation next to the lateral femoral epicondyle. Fixation of the ITB graft. Layered wound closure. POSTOPERATIVE MANAGEMENT: Knee brace for at least 6 weeks. Range of motion (RoM): from postoperative day 1: flexion-extension 90-0-0 degrees ; first 2 weeks after surgery: partial weight bearing (20 kg). RESULTS: An anterolateral extra articular reconstruction may reduce a persistent anterolateral rotatory instability as well as the re-rupture rate following ACL reconstruction with good patient-reported short-term outcomes. Based on current (biomechanical) data, anterolateral tenodesis seems to be superior to a reconstruction of the anterolateral ligament. If a tenodesis is performed, the graft should be fixed in an isometric position, with neutral rotation of the knee and low graft tension to avoid extraphysiologic load within the lateral compartment. Indications for such a procedure may include a high-grade pivot shift or revision ACL reconstruction as well as a persistent anterolateral rotatory instability following anatomic ACL reconstruction. PMID- 30478635 TI - [Acute injury of the posterior cruciate ligament with femoral avulsion : Arthroscopic ligament repair and bracing]. AB - OBJECTIVE: The aim of arthroscopic bracing of the posterior cruciate ligament (PCL) is to restore anatomic and biomechanic function in acute PCL tears. Therefore, primary augmentation of the PCL by using a stable suturing system is used. INDICATIONS: Acute tears of the PCL, femoral avulsions, isolated or combined in cases of multiligament injuries (knee dislocations of Schenk types II IV). CONTRAINDICATIONS: Chronic instabilities of the PCL, infection of the knee joint. SURGICAL TECHNIQUE: Arthroscopic preparation of the femoral PCL footprint. Suturing of the PCL stump with non-resorbable sutures. Placement of the femoral and tibial tunnel with a specific arthroscopic PCL guide. Femoral fixation of the bracing system and the PCL augmenting sutures extracortical via a button or intraarticular with a suture anchor. Tibial fixation via a button has to be performed in a minimum of 80 degrees of flexion and under permanent anterior drawer tension. POSTOPERATIVE MANAGEMENT: Brace in full extension with posterior support 24 h/day, range of motion (ROM) restricted up to 90 degrees of flexion and limited weight bearing with 20 kg for the first 6 weeks postoperatively. After 6 weeks, weight bearing and ROM can be increased and a solid frame brace with posterior support is recommended for the next 6 weeks. PMID- 30478636 TI - Proprioceptive deficits in inactive older adults are not reflected in fast targeted reaching movements. AB - During normal healthy ageing there is a decline in the ability to control simple movements, characterised by increased reaction times, movement durations and variability. There is also growing evidence of age-related proprioceptive loss which may contribute to these impairments. However, this relationship has not been studied in detail for the upper limb. We recruited 20 younger adults (YAs) and 31 older adults (OAs) who each performed 2 tasks on a 2D robotic manipulandum. The first assessed dynamic proprioceptive acuity using active, multi-joint movements constrained by the robot to a pre-defined path. Participants made perceptual judgements of the lateral position of the unseen arm. The second task required fast, accurate and discrete movements to the same targets in the absence of visual feedback of the hand, and without robotic intervention. We predicted that the variable proprioceptive error (uncertainty range) assessed in Task 1 would be increased in physically inactive OAs and would predict increased movement variability in Task 2. Instead we found that physically inactive OAs had larger systematic proprioceptive errors (bias) than YAs (t[33] = 2.8, p = 0.009), and neither proprioceptive uncertainty nor bias was related to motor performance in either age group (all regression model R2 <= 0.06). We suggest that previously reported estimates of proprioceptive decline with ageing may be exaggerated by task demands and that the extent of these deficits is unrelated to control of discrete, rapid movement. The relationship between dynamic proprioceptive acuity and movement control in other tasks with greater emphasis on online feedback is still unclear and warrants further investigation. PMID- 30478637 TI - Macrophage depletion with clodronate-containing liposomes affects the incidence and development of rheumatoid arthritis. AB - OBJECTIVE: This study investigated the effect of macrophage depletion with clodronate-containing liposomes (Clo-lip) on the incidence and development of rheumatoid arthritis (RA). METHODS: The effect of macrophage depletion with Clo lip in the spleen was assessed by HE (haematoxylin and eosin) staining and immunohistochemistry (IHC). Thirty BALB/c mice were randomly divided into three groups, which were administered PBS-lip, Clo-lip, or normal saline. RA model mice were then created and the appearance of the paws was observed. Expression of CD68 by macrophages was examined by immunofluorescence on the 49th day. Forty-five RA model mice were created and randomly divided into three groups. The experiment group was administered Clo-lip at different timepoints. The degree of arthritis score was recorded during the administration. Histological features were detected by HE staining on the 84th day. RESULTS: Compared to controls, horseshoe-shaped nuclei and multi-core large cells were reduced in the experimental group (HE stain; p < 0.05). Brown tag-CD68 and tag-CD80 macrophages were fewer in the experimental group than in the control group (immunohistochemistry; p < 0.05). Furthermore, the degree of arthritis score in the experimental group was significantly decreased (p < 0.05). HE staining showed that there was no or less inflammatory cell infiltration in the articular cavity in mice in the experimental group, and that the percentage of CD68+ macrophage cells in synovial cells was significantly lower than in the control group (p < 0.05). CONCLUSION: Macrophage depletion with Clo-lip can affect the incidence and development of RA. PMID- 30478638 TI - [Non-drug treatment of rheumatoid arthritis : An analysis of claims data and a survey of insured persons (Project PROCLAIR)]. AB - BACKGROUND: Only small amounts of data are available on the prescription frequency of physical therapies (PT) for patients with rheumatoid arthritis (RA). OBJECTIVE: The aim of the study was to evaluate prescription frequencies of PT considering functional status and sociodemographic factors. MATERIAL AND METHODS: A total of 98,963 adults diagnosed with RA in 2013 were identified in claims data from the BARMER health insurance. A questionnaire was sent to a representative sample of 6193 people requesting information on the disease status. Of these 2535 persons were included who agreed to the linking of the questionnaire and claims data and who confirmed a diagnosis of RA. From the routine claims data the prescription of PT and occupational therapy as well as the medical discipline of the prescribing physician were analyzed. Multivariable logistic regression was conducted to determine which variables (age, sex, M05/M06 diagnosis, residential area, income, functional status and rheumatological care) were associated with the use of PT. RESULTS: In 2015 a total of 47% of the study population received PT (35% physiotherapy, 15% thermotherapy, 15% manual therapy, 2% electrotherapy and 6% massage) and 3% occupational therapy. Of the PT prescriptions 37% were issued by general practitioners, 27% by orthopedists and 18% by rheumatologists. Women and persons living in the eastern states of Germany and patients with high functional impairment were prescribed PT more often. Income, educational status, seropositivity and rheumatological care did not have any influence on the frequency of prescription of PT. CONCLUSION: There are deficits in the outpatient prescription of PT but without indications of an undersupply of population groups due to low socioeconomic status. In contrast to the prescription of disease modifying antirheumatic drug (DMARD) treatment, PT is predominantly prescribed by general practitioners. PMID- 30478639 TI - Long-term hospital mortality due to small bowel obstruction after major colorectal surgery in a national cohort database. AB - PURPOSE: Adhesions following major colorectal surgery can be responsible for bowel obstruction, mostly occurring in the small intestine. Published data for long-term survival following major colorectal surgery complicated with intestinal obstruction are limited. The aim of this study was to identify the mortality rates and mortality risk factors in patients with primary colorectal surgery (PMCS) complicated with surgical small bowel obstruction (SBO). METHODS: This was a retrospective analysis of a prospective national registry of patients who underwent PMCS in 2008. RESULTS: Of 15,640 patients who underwent PMCS, 2900 required further surgery for SBO with a median follow-up of 42 months (until the end of 2014). Re-hospitalization mortality rate was 10.1%, and 65% of deaths were obstruction-related. No differences were found in SBO incidence between patients who had undergone laparoscopic or open procedures. Hospital mortality was significantly higher in patients who underwent open PMCS compared with those who underwent a laparoscopic procedure (11% vs. 2%, p = 0.0006). Overall 1- and 5 year survival rates in patients who underwent surgical SBO treatment were significantly lower when the initial surgery was an open procedure compared with a laparoscopy (96.8% vs. 99.4% and 86.6% vs. 95.1%, respectively, p = 0.0016). Multivariate analysis revealed that age, sex, a history of diabetes, cancer, and heart disease were mortality risk factors. CONCLUSIONS: The surgical incidence and mortality rate of PMCS complicated with SBO were elevated. Laparoscopy clearly reduced long-term postoperative mortality in patients with and without abdominal adhesions. PMID- 30478640 TI - DEXI, a candidate gene for type 1 diabetes, modulates rat and human pancreatic beta cell inflammation via regulation of the type I IFN/STAT signalling pathway. AB - AIMS/HYPOTHESIS: The initial stages of type 1 diabetes are characterised by an aberrant islet inflammation that is in part regulated by the interaction between type 1 diabetes susceptibility genes and environmental factors. Chromosome 16p13 is associated with type 1 diabetes and CLEC16A is thought to be the aetiological gene in the region. Recent gene expression analysis has, however, indicated that SNPs in CLEC16A modulate the expression of a neighbouring gene with unknown function named DEXI, encoding dexamethasone-induced protein (DEXI). We therefore evaluated the role of DEXI in beta cell responses to 'danger signals' and determined the mechanisms involved. METHODS: Functional studies based on silencing or overexpression of DEXI were performed in rat and human pancreatic beta cells. Beta cell inflammation and apoptosis, driven by a synthetic viral double-stranded RNA, were evaluated by real-time PCR, western blotting and luciferase assays. RESULTS: DEXI-silenced beta cells exposed to a synthetic double-stranded RNA (polyinosinic:polycytidylic acid [PIC], a by-product of viral replication) showed reduced activation of signal transducer and activator of transcription (STAT) 1 and lower production of proinflammatory chemokines that was preceded by a reduction in IFNbeta levels. Exposure to PIC increased chromatin-bound DEXI and IFNbeta promoter activity. This effect on IFNbeta promoter was inhibited in DEXI-silenced beta cells, suggesting that DEXI is implicated in the regulation of IFNbeta transcription. In a mirror image of knockdown experiments, DEXI overexpression led to increased levels of STAT1 and proinflammatory chemokines. CONCLUSIONS/INTERPRETATION: These observations support DEXI as the aetiological gene in the type 1 diabetes-associated 16p13 genomic region, and provide the first indication of a link between this candidate gene and the regulation of local antiviral immune responses in beta cells. Moreover, our results provide initial information on the function of DEXI. PMID- 30478641 TI - Correlates of Negative Attitudes towards Medication in People with Schizophrenia. AB - Attitudes towards psychiatric medication are an important factor influencing the success of treatment. Mental health care in the region of Central and Eastern Europe remains biologically oriented, yet the attitudes of people with severe mental illnesses are largely unknown. In the present study, we aimed to analyze factors of attitudes toward psychopharmacological drugs among people with schizophrenia spectrum disorder who use community social services in the Czech Republic. Drug Attitude Inventory (DAI) was used as a primary research instrument and data were analyzed using a multivariable linear regression. The majority of respondents (78%) had positive attitudes towards psychopharmacological treatment. Additionally, attitudes towards psychopharmaceutic drugs did not differ with regard to sociodemographic characteristics except for family status. There was a significant negative correlation with the level of self-stigmatization and a significant positive correlation with the duration of treatment. Respondents who had repeated experiences with discontinuation of medication without a prior consultation with a psychiatrist had significantly worse attitudes towards medication than respondents without this experience. This study revealed evidence of a strong relationship between the attitudes toward medication and a history of discontinuation of taking medication and duration of treatment. Therefore, we suggest that interventions focused preventing the internalization of stigmatizing attitudes towards mental illness should be available to people with schizophrenia spectrum disorder, especially in the early stages of the illness - irrespective of the patient's age. PMID- 30478642 TI - Correction to: Sociodemographic Variation in Increasing Needs for Mental Health Services among Canadian Adults from 2002 to 2012. AB - The original version of this article unfortunately contained a mistake. PMID- 30478643 TI - Inter-mesenteric connections between the superior and inferior mesenteric arteries for left colonic vascularization: implications for colorectal surgery. AB - PURPOSE: There is confusion regarding the names, the number, and the exact location of the colonic arterial arches which provide connections between the superior and inferior (IMA) mesenteric arteries at the level of the left colic angle. The aim of this review was to delineate the "true" colic arches arising in the meso of the left colic angle and to describe their surgical implications. METHODS: A systematic review of the literature was performed using the MEDLINE database. The search included only human studies between 1913 and 2018. All dissection, angiographic, arterial cast and corrosion studies were analyzed. RESULTS: The terms "Riolan arch", "marginal artery of Drummond", "meandering mesenteric artery" and "Villemin's arch" must no longer be used in the scientific literature. Three arterial arches were found at the level of the left colic angle, permitting the communication between the two arterial mesenteric systems: (1) the Marginal Artery (the most peripheral, found in 100% of cases); (2) the "V" termination of the ascending branch of the left colic artery (LCA), existing in more than 2/3 of cases; and (3) the inter-mesenteric trunk, found more centrally located and existing in less than 1/3 of cases. CONCLUSIONS: Three arterial arches exist at the level of the left colic angle: (1) the Marginal Artery, (2) the "V" termination of the ascending branch of the LCA, and (3) the inter-mesenteric trunk. The knowledge of this anatomy is essential for performing colorectal surgeries involving ligation of the IMA. PMID- 30478644 TI - Ultra-deep amplicon sequencing indicates absence of low-grade mosaicism with normal cells in patients with type-1 NF1 deletions. AB - Different types of large NF1 deletion are distinguishable by breakpoint location and potentially also by the frequency of mosaicism with normal cells lacking the deletion. However, low-grade mosaicism with fewer than 10% normal cells has not yet been excluded for all NF1 deletion types since it is impossible to assess by the standard techniques used to identify such deletions, including MLPA and array analysis. Here, we used ultra-deep amplicon sequencing to investigate the presence of normal cells in the blood of 20 patients with type-1 NF1 deletions lacking mosaicism according to MLPA. The ultra-deep sequencing entailed the screening of 96 amplicons for heterozygous SNVs located within the NF1 deletion region. DNA samples from three previously identified patients with type-2 NF1 deletions and low-grade mosaicism with normal cells as determined by FISH or microsatellite marker analysis were used to validate our methodology. In these type-2 NF1 deletion samples, proportions of 5.3%, 6.6% and 15.0% normal cells, respectively, were detected by ultra-deep amplicon sequencing. However, using this highly sensitive method, none of the 20 patients with type-1 NF1 deletions included in our analysis exhibited low-grade mosaicism with normal cells in blood, thereby supporting the view that the vast majority of type-1 deletions are germline deletions. PMID- 30478645 TI - Very Late Leptomeningeal Collaterals-Potential New Way to Subdivide Modified Thrombolysis in Cerebral Ischemia (mTICI) 2B. AB - BACKGROUND: Studies have shown that the modified thrombolysis in cerebral ischemia (mTICI) 2B score is associated with better functional outcome; however, 50-99% reperfusion is a large range and there may be factors which can differentiate this further. The effects of very late leptomeningeal collaterals (VLLC) on mTICI-2B patients were studied. METHOD: A prospectively collected registry of anterior circulation AIS patients treated with the EmboTrap revascularization device from 2013 to 2016 was evaluated. Imaging parameters and timings, including the mTICI score were verified by an external core laboratory blinded to the clinical data. The final angiogram was examined for the appearance of VLLC in predicting 3-month outcomes including excellent functional outcomes, defined as modified Rankin scale (mRS) 0-1, bleeding risk and mortality. RESULTS: A total of 177 consecutive anterior circulation stroke patients were included in the analysis. Of these 94 (53.1%) achieved only mTICI-2B reperfusion, 16/94 (17.0%) patients achieved excellent functional outcomes at 3 months and 26 (27.7%) had hyperdensity on follow-up computed tomography (CT). On univariate analysis, the presence of VLLC was inversely associated with excellent functional outcomes at 3 months and positively associated with mortality in patients with mTICI-2B reperfusion. On multivariate analysis VLLC was inversely associated with excellent outcomes (odds ratio 0.075, 95% confidence interval 0.007-0.765, P = 0.029) but not associated with mortality. CONCLUSION: The mTICI-2B grade may be further refined by secondary radiological markers. The VLLC sign is associated with the loss of excellent functional outcomes at 3 months. It is a simple sign to discriminate mTICI-2B into different grades but should be verified in larger populations from other centers. PMID- 30478646 TI - Diphenyl diselenide grafted onto a Fe3O4-chitosan composite as a new nanosorbent for separation of metal ions by effervescent salt-assisted dispersive magnetic micro solid-phase extraction. AB - Diphenyl diselenide was immobilized on chitosan loaded with magnetite (Fe3O4) nanoparticles to give an efficient and cost-effective nanosorbent for the preconcentration of Pb(II), Cd(II), Ni(II) and Cu(II) ions by using effervescent salt-assisted dispersive magnetic micro solid-phase extraction (EA-DM-MUSPE). The metal ions were desorbed from the sorbent with 3M nitric acid and then quantified via microflame AAS. The main parameters affecting the extraction were optimized using a one-at-a-time method. Under optimum condition, the limits of detection, linear dynamic ranges, and relative standard deviations (for n = 3) are as following: Pb(II): 2.0 ng.mL-1; 6.3-900 ng.mL-1; 1.5%. Cd(II): 0.15 ng.mL-1; 0.7 85 ng.mL-1, 3.2%; Ni(II): 1.6 ng.mL-1,.6.0-600. ng.mL-1, 4.1%; Cu(II): 1.2 ng.mL 1, 3.0-300 ng.mL-1, 2.2%. The nanosorbent can be reused at least 4 times. Graphical abstract Fe3O4-chitosan composite was modified with diphenyl diselenide as a sorbent for separation of metal ions by effervescent salt-assisted dispersive magnetic micro solid-phase extraction. PMID- 30478647 TI - Differential diagnosis of gallbladder polypoid lesions using contrast-enhanced ultrasound. AB - PURPOSE: The purpose of the study is to evaluate the utility of contrast-enhanced ultrasound (CEUS) for the differential diagnosis of gallbladder polypoid lesions (GPLs). METHODS: Thirty-six patients with GPLs (17 with gallbladder cancer, 19 with benign polyps) who underwent CEUS were enrolled in the study. The mean age of patients was 65.7 +/- 12.6 years. Perflubutane-based contrast agent and high mechanical index mode, which can eliminate the background B-mode and provide precise visualization of tumor vessels, were used for CEUS, and two blinded readers evaluated the images, retrospectively. RESULTS: Patient age and size of malignant GPLs (72.4 +/- 9.4 years and 23.4 +/- 7.5 mm) were significantly greater than those for benign lesions (59.6 +/- 12.3 years and 12.4 +/- 2.9 mm) (P < 0.01, respectively), and the receiver operating characteristic analysis showed the cut-off value as over 65 years and 16 mm. Univariate analysis showed that heterogeneity in B-mode (80% [12/15]), sessile shape (76% [13/17]), dilated vessel (71% [12/17]), irregular vessel (82% [14/17]), and heterogeneous enhancement (59% [10/17]) on CEUS were significantly correlated with malignant GPLs (P < 0.01, respectively). On CEUS, the diagnostic criterion for malignant GPLs was defined as having one or more of the above four features because of the highest accuracy. Sensitivity, specificity, and accuracy for malignant GBLs were 88%, 68%, and 78% for patient age; 76%, 89%, and 83% for size of GPLs; 80%, 68%, and 74% for B-mode; and 94%, 89%, and 92% for CEUS, respectively. CONCLUSIONS: CEUS is useful for the differential diagnosis of malignant and benign GPLs. PMID- 30478648 TI - Associations between the neutrophil-to-lymphocyte and the platelet-to-lymphocyte ratios and the presence and severity of psoriasis: a systematic review and meta analysis. AB - The diagnosis of psoriasis, an immune-mediated disease that affects 2% of the population in Western countries, is largely based on history and clinical examination. The aim of this systematic review and meta-analysis was to investigate the associations between the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) and the presence and clinical severity of psoriasis. A systematic literature search was conducted in PubMed, Web of Science, and Scopus, from inception to January 2018. Twelve case-control studies enrolling 1067 psoriasis patients (537 males and 530 females) and 799 healthy controls (404 males and 395 females) were included in the meta-analysis. The NLR was evaluated in all the studies, while the PLR was assessed in four studies. Pooled results showed that both the NLR and the PLR values were significantly higher in patients with psoriasis (SMD = 0.69, 95% CI 0.53-1.85, p < 0.001, and SMD = 0.40, 95% CI 0.12-0.68, p = 0.006, respectively). There were no significant differences in NLR values according to the severity of disease (p = 0.52). The NLR and the PLR are significantly associated with the presence, but not with the severity, of psoriasis. Further studies are required to determine the additional utility of these haematological indexes in the diagnosis of psoriasis. PMID- 30478649 TI - Cost-Effectiveness of Niraparib Versus Routine Surveillance, Olaparib and Rucaparib for the Maintenance Treatment of Patients with Ovarian Cancer in the United States. AB - OBJECTIVES: The aim was to evaluate the cost-effectiveness of niraparib compared with routine surveillance (RS), olaparib and rucaparib for the maintenance treatment of patients with recurrent ovarian cancer (OC). METHODS: A decision analytic model estimated the cost per quality-adjusted life-year (QALY) gained for niraparib versus RS, olaparib, and rucaparib from a US payer perspective. The model considered recurrent OC patients with or without germline BRCA mutations (gBRCAmut and non-gBRCAmut), who were responsive to their last platinum-based chemotherapy regimen. Model health states were: progression-free disease, progressed disease and dead. Mean progression-free survival (PFS) was estimated using parametric survival distributions based on ENGOT-OV16/NOVA (niraparib phase III trial), ARIEL3 (rucaparib phase III trial) and Study 19 (olaparib phase II trial). Mean overall survival (OS) benefit was estimated as double the mean PFS benefit based on the relationship between PFS and OS observed in Study 19. Costs included: drug, chemotherapy, monitoring, adverse events, and terminal care. EQ 5D utilities were estimated from trial data. RESULTS: Compared to RS, niraparib was associated with an incremental cost-effectiveness ratio (ICER) of US$68,287/QALY and US$108,287/QALY for gBRCAmut and non-gBRCAmut, respectively. Compared to olaparib and rucaparib, niraparib decreased costs and increased QALYs, with a cost saving of US$8799 and US$22,236 versus olaparib and US$198,708 and US$73,561 versus rucaparib for gBRCAmut and non-gBRCAmut, respectively. CONCLUSIONS: Niraparib was estimated to be less costly and more effective compared to olaparib and rucaparib, and the ICER fell within an acceptable range compared to RS. Therefore, niraparib may be considered a cost-effective maintenance treatment for patients with recurrent OC. PMID- 30478650 TI - TAMIS repair of a rectal stenosis not treatable by endoscopy. PMID- 30478651 TI - Pubovisceral muscle and anal sphincter defects in women with fecal or urinary incontinence after vaginal delivery. AB - BACKGROUND: Vaginal delivery is the most frequent cause of direct anal sphincter trauma as well as pelvic floor muscle defects in women with corresponding signs and symptoms. The aim of the present study was to identify anatomical and functional abnormalities of the anal canal and pelvic floor in women who had had a vaginal delivery and determine the relationship between such abnormalities and the symptoms and severity of fecal incontinence (FI). METHODS: Consecutive female patients with symptoms of fecal and/or urinary incontinence were recruited through the colorectal and gynecological outpatient clinics at two large university hospitals and were eligible if they had had at a vaginal delivery. All women were assessed for symptoms FI by means of the Cleveland Clinic Florida Incontinence Scale (CCFIS) and for urinary incontinence symptoms, including the presence of complaints of any involuntary leakage of urine, leakage on exertion, sneezing, or coughing, and/or leaking or losing urine associated with an urge to urinate. All women underwent anorectal and endovaginal three-dimensional ultrasonography and anal manometry. The extent of the anal sphincter and PVM defects identified by ultrasound was scored from 1 to 6 based on the longitudinal involvement of the external and internal anal sphincter, the radial angle of the anterior external anal sphincter defect and the longitudinal involvement of the PVM. RESULTS: There were 130 women and 89 (68%) had at least one defect of the anal sphincter or the pubovisceral muscle or both (42/32% had a pubovisceral muscle defect with or without sphincter defects, 47/36% women had an intact pubovisceral muscle but sphincter defect); and 41 (32%) had intact anal sphincter and pubovisceral muscles. The mean levator hiatus area at rest in women with anal sphincter and/or pubovisceral muscle defects was 18 (+/- 4 SD) which was significantly greater than in women with no defects (16 +/- 3 SD; p = 0.01). Women with PVM defects had significantly higher ultrasound scores (median ultrasound score = 4/range 1-10 vs Intact = 2/range 2-5), indicating more extensive defects (p = 0.001). Bivariate analysis revealed a positive association (p < 0.05) between increasing FI symptom severity (CCFIS score) and women with PVM defects (rho = 0.6913). Within the group of women with defects mean maximum anal squeeze pressure was significantly lower in women with PVM defect (mean 73 +/- 34 SD mmHg vs mean 93 +/- 38 SD; p = 0.04). Women with PVM defects had significantly higher median CCFIS scores (median score, 7/range 0-16) compared to women with intact PVM (4/range 0-10) (p < 0.001). There was a significant positive correlation between the CCFIS and ultrasound scores (rho = 0.625; p < 0.001). Bivariate analysis revealed a negative correlations between the CCFIS score and the lengths of the anterior EAS (rho = - 0.5621, p < 0.001), IAS (rho = - 0.40, p < 0.001) and the area of the levator hiatus (rho = 0.5211, p = 0.001). However, no significant correlations were observed between CCFIS scores and the gap measurement (rho = 0.101; p = 0.253) or the resting (rho = - 0.08, p = 0.54) or squeeze pressure (rho = - 0.12; p = 0.34) values on anal manometry. The variables associated with worsening FI symptom severity (CCFIS score) that remained significant in multiple linear regression included the shorter lengths of the anterior EAS and/or the lengths of the anterior IAS and increased area of the levator hiatus. CONCLUSIONS: The study data demonstrate that half of the women had combined defects of PVM and sphincter. There were correlations between anatomical abnormalities including the anal sphincter and/or pubovisceral muscle defects with decrease in the anal pressures and increased severity of FI. PMID- 30478652 TI - Studies on combination of oxaliplatin and dendrosomal nanocurcumin on proliferation, apoptosis induction, and long non-coding RNA expression in ovarian cancer cells. AB - Drug resistance remains a major challenge in the treatment of patients with ovarian cancer. Therefore, the development of new anticancer drugs is a clinical priority to develop more effective therapies. New approaches to improve clinical outcomes and limit the toxicity of anticancer drugs focus on chemoprevention. The aim of this study was to determine the effects of dendrosomal nanocurcumin (DNC) and oxaliplatin (Oxa) and their combination on cell death and apoptosis induction in human ovarian carcinoma cell lines analyzed by MTT assay and flow cytometry, respectively. The synergism effect of Oxa and DNC was analyzed using the equation derived from Chou and Talalay. In addition, real-time PCR was used to measure the effect of this combination on the expression levels of long non-coding RNAs with different expression in ovarian cancer and normal ovaries. Our data showed that the effect of DNC on cell death is more than curcumin alone in the same concentration. The greatest cell death effect was observed in combination of Oxa with DNC, while Oxa was added first, followed by DNC at 4 h interval (0/4 h). The findings indicated that DNC induced apoptosis significantly in both cell lines as compared to control groups; however, combination of both agents had no significant effect in apoptosis induction. In addition, combination of both agents significantly affects the relative expression of long non-coding RNAs investigated in the study as compared with mono therapy. PMID- 30478653 TI - Minimum of 10-year follow-up of V-rod technique in lumbar spondylolysis. AB - PURPOSE: To describe and analyze the use of the V-rod technique described by Gillet to repair spondylolysis in both early and late postoperative periods. METHODS: Patients submitted to surgical correction of lumbar spondylolysis with a V-rod system were selected upon exclusion of adjacent disk degenerative changes and high-grade spondylolisthesis. A preoperative clinical (ODI and VAS) and radiological evaluation was performed, along with assessments on the early (clinical evaluation-up to 1 year) and late (clinical and radiological-at least 10 years) postoperative periods. RESULTS: Twenty-two patients were included, 21 with L5 spondylolysis. Fifty percent had grade I spondylolisthesis. A significant decrease in ODI and VAS was observed from pre- to early and late post-op evaluation (all p < 0.05) but not during post-op evaluations. Changes from pre- to postoperative of both ODI and VAS were significantly higher than the minimal clinically important difference. Preoperative ODI and VAS were significantly higher in overweight/obese but similar postoperatively. No additional instability was found in late postoperative X-rays. Three patients needed revision surgery, with a survival rate of 81.8% for Gillet instrumentation at a mean follow-up of 687.7 +/- 60.0 weeks. CONCLUSIONS: Surgical treatment with V-rod system is associated with a significant improvement in ODI and VAS and radiologic stability, with an equal benefit in obese/overweight patients. This study reports for the first time an improvement that is maintained even 10 years after the initial intervention, associated with a low rate of failure. These slides can be retrieved under Electronic Supplementary Material. PMID- 30478654 TI - Letter to the Editor concerning "Relationship between sagittal spinal curves geometry and isokinetic trunk muscle strength in adults" by Elsayed W, Farrag A, Muaidi Q, Almulhim N (Eur Spine J [2018] 27:2014-2022). PMID- 30478655 TI - Correction to: A systematic review of nano formulation of natural products for the treatment of inflammatory bowel disease: drug delivery and pharmacological targets. AB - The corresponding author, Mohammad Hosein Farzaei, affiliation is Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran. The correct spelling of the 7th author surname is Iranpanah. PMID- 30478656 TI - Differential regulation of CD4+ T cell subsets by Silymarin in vitro and in ovalbumin immunized mice. AB - CD4+ T cell subsets including regulatory T cells (Tregs), Th1 and Th17 are critical for control and development of inflammation and autoimmunity. We investigated the in vitro and in vivo effects of silymarin, a well-known herbal medicine on differentiation and function of Tregs and Th1 and Th17 responses. For in vitro study, mice splenocytes treated with 20-30 MUg/ml silymarin were evaluated for gene expressions of specific transcription factors and cytokines of CD4+ T cell subsets using real-time PCR. Induction of Treg cell development in the presence of silymarin was performed on isolated naive CD4+ T cells. Effect of silymarin-induced Tregs on T cell suppression was determined by CFSE labeling method. Results of this part showed that silymarin significantly decreased IFNgamma, RORgammat and IL-17 gene expressions and upregulated Foxp3, TGF-beta and IL-10 mRNA. More silymarin-enhanced naive CD4+ T cells differentiated to Tregs (67%) than the control (47%). Silymarin-induced Tregs reduced proliferation of naive activated T cells (<50%). For in vivo study, mice were immunized with ovalbumin (Ova) on days 1 and 14. Silymarin (100 mg/Kg) was intraperitoneally administered two days before the first Ova challenge followed by on every day for two weeks. Splenocytes were then isolated for assessment of CD4+ T cell subsets and ex vivo analysis using flow cytometry. Treatment of Ova-immunized mice with silymarin increased Tregs (11.24 +/- 1.2%, p < 0.01(but decreased Th1 (1.72 +/- 0.4%, p < 0.001) and Th17 (1.07 +/- 0.04%, p < 0.001) cells. Ex vivo Ova challenge of splenocytes from Ova-immunized mice treated with silymarin decreased proliferation of splenocytes, IFNgamma (2.76% of control) and IL-17 (<8%) along with increased TGF-beta (59.7%) expressions in CD4+T-bet+, CD4+RORgammat+ and CD4+Foxp3+ T cells, respectively. In conclusion, silymarin promoted Treg differentiation and function and decreased Th1 and Th17 cells. Silymarin may differentially regulate CD4+ T cell responses which can provide potential benefits for its use as treatment of immune-related diseases. Graphical abstract ?. PMID- 30478657 TI - Feasibility of simultaneous dual isotope acquisition for myocardial perfusion imaging with a cadmium zinc telluride camera. AB - BACKGROUND: We studied the impact of technetium-99m (99mTc) in the thallium-201 (201Tl) energy window (70 keV) to determine if CZT cardiac cameras allow us to perform simultaneous dual-isotope acquisition for myocardial perfusion imaging. METHODS: We included 117 consecutive patients. We injected 0.7 MBq/kg of 201Tl at stress, performed the first scan (image T1), then injected at rest 2 MBq/kg of 99mTc-tetrofosmin and immediately acquired a second scan with reconstruction in the energy window of thallium (image T2). A corrected thallium image was created by the subtraction of 99mTc downscattered photons (image TS). We compared spectra, image quality, and semiquantitative scores on T1, T2, and TS images. RESULTS: Though T2 images were of worse quality, TS images were of equal quality compared to T1 images in most cases. Scores show an underestimation of abnormalities in 20% of patients on T2 images and in 10% on TS images. CONCLUSIONS: Despite the improved energy resolution of CZT cameras, downscatter of technetium in the 201Tl window leads to an underestimation of the pathological territory in 10% to 20% of cases. It does not allow us to use simultaneous dual isotope acquisition in clinical practice without additional tools for scatter correction. PMID- 30478658 TI - Multi-peak multi-isotopes myocardial SPECT: It's easier said than done. PMID- 30478659 TI - Simultaneous dual isotope 201Tl/99mTc myocardial perfusion imaging using CZT cameras: Clinical utility or technical challenge? PMID- 30478660 TI - Correction to: Early nuclear stress testing after CABG: The new standard or too soon to tell? AB - The Disclosure section should be updated to read: "The views expressed in this article are those of the author and do not reflect the official policy of the Department of Army/Navy/Air Force, Department of Defense, or U.S. Government." PMID- 30478661 TI - Stress-induced ischemia in the right ventricular myocardium on 99mTc-MIBI myocardial perfusion scintigraphy in a rare case of double-chambered right ventricle. PMID- 30478662 TI - How accurate is the accuracy? PMID- 30478663 TI - The beginnings of ASNC. PMID- 30478664 TI - Left ventricular dyssynchrony in diabetes mellitus. PMID- 30478665 TI - Myocardial-coronary fusion imaging with positron emission tomography and computed tomography: Benchmarking and slingshotting. PMID- 30478666 TI - Neonatal outcomes in term pregnancies treated with antenatal corticosteroids for suspected pre-term labor. AB - OBJECTIVE: To evaluate the association between antenatal corticosteroid treatment and neonatal outcome when delivery occurs at term. STUDY DESIGN: A retrospective cohort study of all women with singleton gestations who delivered at term (37 + 0 to 41 + 6 weeks) in a tertiary medical center (2012-2015). Women with diabetes, suspected fetal growth restriction, antepartum fetal death, and fetal structural or chromosomal anomalies were excluded. The cohort was divided according to prior preterm (24 + 0 to 33 + 6 weeks) antenatal corticosteroids treatment due to threatened preterm labor (study group), vs. no such treatment (control group). Primary outcome was birthweight at delivery. Secondary outcomes were composites neonatal adverse outcomes. Logistic regression analysis was utilized to adjust results for potential confounders. RESULTS: Of 25,872 women who were included in the study, 722 (3%) were treated with antenatal corticosteroids. Women in the treatment group had higher rates of nulliparity compared to controls (43% vs. 38%, p = 0.002). Birth weight was significantly lower in the corticosteroid treatment group (3077 g vs. 3264 g, p = 0.001), with higher rates of small for gestational age (11% vs. 6%, p = 0.001). Multivariate analysis adjusting for parity and gestational age demonstrated that corticosteroid treatment was associated with lower birth weight (B = - 93 g, 95% CI - 123 to - 66, p = 0.001). Treatment was not found to be associated with adverse neonatal outcomes composites. CONCLUSION: Antenatal corticosteroid treatment is associated with lower birth weight and higher rates of small for gestational age neonates among women who eventually deliver at term. However, it is not associated with short term adverse neonatal outcomes. PMID- 30478667 TI - Changes of breast and axillary surgery patterns in patients with primary breast cancer during the past decade. AB - PURPOSE: Breast-conserving therapy (BCT) is the standard procedure for most patients with primary breast cancer (BC). By contrast, axillary management is still under transition to find the right balance between avoiding of morbidity, maintaining oncological safety, and performing a staging procedure. The rising rate of primary systemic therapy creates further challenges for surgical management. METHODS: Patients with primary, non-metastatic BC treated between 01.01.2003 and 31.12.2016 under guideline-adherent conditions were included in this study. For this prospectively followed cohort, breast and axillary surgery patterns are presented in a time-trend analysis as annual rate data (%) for several subgroups. RESULTS: Overall, 6700 patients were included in the analysis. While BCT rates remained high (mean 2003-2016: 70.4%), the proportion of axillary lymph node dissection has declined considerably from 80.1% in 2003 to 16.0% in 2016, while the proportion for sentinel lymph node biopsy (SLND) has increased correspondingly from 10.3 to 76.4%. Among patients with cT1-2, cN0 breast cancer receiving BCT with positive SLND, the rate of axillary completion has decreased from 100% in 2008 to 24.4% in 2016. CONCLUSIONS: In the past decade, SLNB has been established as the standard procedure for axillary staging of clinically node-negative patients. Surgical morbidity has been further reduced by the rapid implementation of new evidence from the ACOSOG Z0011 trial into clinical routine. The results reflect the transition towards more individually tailored, less invasive treatment for selected patient subgroups, especially in regards to axillary lymph node management. PMID- 30478668 TI - Association between miRNA-152 polymorphism and risk of preeclampsia susceptibility. AB - BACKGROUND: Preeclampsia (PE) is one of the main causes of death among the pregnant women as well as newborns. Although the etiological cause of preeclampsia is not yet clear, a range of risk factors has been suggested. MicroRNAs (like miRNA-152) are small non-coding molecules that play a role in a wide spectrum of biological processes, such as cell proliferation and angiogenesis. This study aimed to investigate the possible relationship of miRNA 152 rs12940701 polymorphism and the risk of preeclampsia among the pregnant women as compared with the control group. METHODS: Genotyping of miRNA-152 rs12940701 polymorphism was performed using blood and placenta samples of 223 preeclampsia women and 229 normotensive pregnant women by a polymerase chain reaction restriction fragment length polymorphism method. RESULTS: The results obtained from maternal blood showed an increase in T alleles for PE women, that there was no significant difference between the PE and control group (OR = 1.7, P = 0.19). In addition, no significant difference was found in the TT genotype between the two groups (11.6% vs. 7%, OR = 1.4, P = 0.3). Similarly, the results obtained from placental samples were identical. CONCLUSIONS: A lack of relationship between the polymorphism of miRNA-152 rs12940701 gene and preeclampsia development has been shown. PMID- 30478669 TI - Linac-based radiosurgery or fractionated stereotactic radiotherapy with flattening filter-free volumetric modulated arc therapy in elderly patients : A mono-institutional experience on 110 brain metastases. AB - AIM: The aim of this study was to analyze the feasibility and clinical results of linear accelerator (linac-)based stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (SFRT) with flattening filter-free (FFF) volumetric modulated arc therapy (VMAT) in elderly patients affected by brain metastases (BMs). PATIENTS AND METHODS: Patients selected for the present analysis were >=65 years old with a life expectancy of >3 months, a controlled or synchronous primary tumor, and <10 BMs with a diameter <3 cm. All patients were treated with FFF linac-based SRS/SFRT. The prescribed total dose (15-30 Gy/1-5 fractions) was based on BM size and proximity to organs at risk (OAR). Toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. MedCalc v18.2 (MedCalc Software, Ostend, Belgium) was used for statistical analysis. RESULTS: From April 2014 to December 2017, 40 elderly patients with 110 BMs were treated by FFF linac-based SRS/SFRT. With a median follow-up of 28 months (range 6-50 months), median and 1-year overall survival were 9 months and 39%, respectively; median intracranial progression-free survival was 6 months. At the time of the analysis, local control was reported in 109/110 BMs (99.1%): 12 BMs had a complete response; 51 a partial response; 46 showed stable disease. One BM (0.9%) progressed after 2 months. BM volume (<1 cc) and higher SRS/SFRT dose correlated to treatment response (p = 0.01 and p = 0.0017, respectively). No adverse events higher than grade 2 were observed. CONCLUSION: The present findings highlight the feasibility, safety, and effectiveness of FFF linac-based SRS/SFRT in elderly patients with BMs. PMID- 30478670 TI - Impact of androgen deprivation therapy on apparent diffusion coefficient and T2w MRI for histogram and texture analysis with respect to focal radiotherapy of prostate cancer. AB - PURPOSE: Accurate prostate cancer (PCa) detection is essential for planning focal external beam radiotherapy (EBRT). While biparametric MRI (bpMRI) including T2 weighted (T2w) and diffusion-weighted images (DWI) is an accurate tool to localize PCa, its value is less clear in the case of additional androgen deprivation therapy (ADT). The aim of this study was to investigate the value of a textural feature (TF) approach on bpMRI analysis in prostate cancer patients with and without neoadjuvant ADT with respect to future dose-painting applications. METHODS: 28 PCa patients (54-80 years) with (n = 14) and without (n = 14) ADT who underwent bpMRI with T2w and DWI were analyzed retrospectively. Lesions, central gland (CG), and peripheral zone (PZ) were delineated by an experienced urogenital radiologist based on localized pre-therapeutic histopathology. Histogram parameters and 20 Haralick TF were calculated. Regional differences (i. e., tumor vs. PZ, tumor vs. CG) were analyzed for all imaging parameters. Receiver-operating characteristic (ROC) analysis was performed to measure diagnostic performance to distinguish PCa from benign prostate tissue and to identify the features with best discriminative power in both patient groups. RESULTS: The obtained sensitivities were equivalent or superior when utilizing the TF in the no-ADT group, while specificity was higher for the histogram parameters. However, in the ADT group, TF outperformed the conventional histogram parameters in both specificity and sensitivity. Rule-in and rule-out criteria for ADT patients could exclusively be defined with the aid of TF. CONCLUSIONS: The TF approach has the potential for quantitative image-assisted boost volume delineation in PCa patients even if they are undergoing neoadjuvant ADT. PMID- 30478671 TI - Severely bothersome fatigue in children and adolescents with cancer and hematopoietic stem cell transplant recipients. AB - BACKGROUND: Objectives were to describe bothersome fatigue in children with cancer and hematopoietic stem cell (HSCT) recipients and to identify factors associated with severely bothersome fatigue. METHODS: We included children ages 8 18 years treated for cancer or HSCT recipients from three groups: [1] receiving active cancer treatment and admitted to hospital for at least 3 days, [2] attending outpatient clinic for acute lymphoblastic leukemia maintenance therapy, and [3] attending outpatient clinic following treatment completion. Fatigue was measured using the Symptom Screening in Pediatrics Tool (SSPedi); severely bothersome fatigue was defined as a lot or extremely bothersome fatigue (score of 3-4 on 0-4 scale). Factors associated with severely bothersome fatigue were examined using univariate and multiple logistic regression. RESULTS: Of 502 children included, 414 (82.5%) reported some degree of bothersome fatigue (scores 1-4), and 123 (24.5%) reported severely bothersome fatigue (score 3 or 4). In multiple regression analysis, factors significantly associated with severely bothersome fatigue were child age 11-14 and 15-18 years vs 8-10 years (odds ratio (OR) 2.11, 95% confidence interval (CI) 1.21-3.77 and OR 2.96, 95% CI 1.66-5.44), and inpatients receiving cancer treatment vs outpatients who had completed therapy (OR 3.85, 95% CI 2.17-7.27). CONCLUSIONS: We found that 82.5% of children with cancer or HSCT recipients reported bothersome fatigue and 24.5% of children reported severely bothersome fatigue. Risk factors for severely bothersome fatigue were older age and inpatients receiving active cancer treatment. Future work should evaluate systematic symptom screening in clinical practice and apply interventions to reduce fatigue. PMID- 30478672 TI - Predictive factors for taxane acute pain syndrome determined by ordered logistic regression analysis. AB - This retrospective study was undertaken to identify predictive factors for developing taxane acute pain syndrome (TAPS) and to determine new strategies for improving QoL in patients undergoing chemotherapy. Between November 2010 and May 2018, we enrolled 121 breast cancer patients at our outpatient chemotherapy center who were undergoing chemotherapy with nanoparticle albumin-bound paclitaxel (nab-PTX) every 3 weeks. Variables related to the development of TAPS were extracted from the patients' clinical records and used for regression analysis. The degree of TAPS was classified as grade 0 = not developed; grade 1 = developed but did not require analgesics; grade 2 = developed but alleviated by analgesics such as acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs); or grade 3 = syndrome developed, causing sleep problems or interfering with daily living activities, but not alleviated by analgesics such as acetaminophen or NSAIDs thus requiring opioids. Multivariate ordered logistic regression analysis was performed to identify predictive factors for the development of TAPS. Significant factors identified for the development of TAPS included dose of nab-PTX (odds ratio (OR) = 11.717, 95% confidence interval (CI) = 11.6161-11.8182; P = 0.0421) and the administration of dexamethasone for up to 3 days (OR = 0.133, 95% CI = 0.0235-0.7450; P = 0.0223). In conclusion, a high dose of nab-PTX and the lack of dexamethasone administration for up to 3 days were identified as significant predictors of the development of TAPS. PMID- 30478673 TI - Early Skeletal Muscle Loss in Non-Small Cell Lung Cancer Patients Receiving Chemoradiation and Relationship to Survival. AB - PURPOSE: Sarcopenia is associated with reduced survival in cancer. Currently, data on sarcopenia at presentation and muscle loss throughout treatment are unknown in patients receiving chemoradiation therapy (CRT) for non-small cell lung cancer (NSCLC). This study evaluated skeletal muscle changes in NSCLC patients receiving CRT and relationship with survival. METHODS: Secondary analysis of 41 patients with NSCLC treated with CRT assessed for skeletal muscle area and muscle density by computed tomography pre-treatment and 3 months post treatment. Images at week 4 of treatment were available for 32 (78%) patients. Linear mixed models were applied to determine changes in skeletal muscle over time and related to overall survival using Kaplan-Meier plots. RESULTS: Muscle area and muscle density decreased significantly by week 4 of CRT (- 6.6 cm2, 95% CI - 9.7 to - 3.1, p < 0.001; - 1.3 HU, 95% CI - 1.9 to - 0.64, p < 0.001, respectively), with minimal change between week 4 of CRT and 3 months post-CRT follow-up (- 0.2 cm2, 95% CI - 3.6-3.1, p = 0.91; - 0.27, 95% CI - 0.91-0.36, p = 0.36, respectively). Sarcopenia was present in 25 (61%) and sarcopenic obesity in 6 (14%) of patients prior to CRT, but not associated with poorer survival. Median survival was shorter in patients with low muscle density prior to treatment although not statistically significant (25 months + 8.3 vs 53 months + 13.0, log rank p = 0.17). CONCLUSION: Significant loss of muscle area and muscle density occurs in NSCLC patients early during CRT. A high proportion of patients are sarcopenic prior to CRT; however, this was not significantly associated with poorer survival. PMID- 30478674 TI - Trans-resveratrol Inhibits Tau Phosphorylation in the Brains of Control and Cadmium Chloride-Treated Rats by Activating PP2A and PI3K/Akt Induced-Inhibition of GSK3beta. AB - This study investigated if resveratrol (RES) can protect against cadmium chloride (CdCl2)-induced memory loss and Tau protein hyperphosphorylation in rats and explored its effect on AMPK/PI3K/Akt signaling pathway. Rats (n = 10/group) were divided into seven groups as: control; control + DMSO; control + LY294002, a selective PI3K inhibitor (0.25 ug/100 g, i.p); control + RES (300 mg/kg, orally); CdCl2 (5 mg/kg, orally); CdCl2 + RES and CdCl2 + RES + LY294002. All treatments were carried out for 30 consecutive days on a daily basis. RES improved both short and long-term memory as analyzed by novel object recognition task and significantly increased brain levels of glutathione in both control and CdCl2 treated rats. It also inhibited ROS levels of malondialdehyde in the brains of CdCl2-treated rats. In both groups, RES decreased the phosphorylation rate of Tau at Ser199 and Ser296. Concomitantly, it significantly increased protein levels of p-GSK3beta (Ser9) and p-PP2A and decreased p-GSK3beta (Tyr216). Also, RES activated PI3K/Akt signaling pathway in both control and CdCl2 treated rats by increasing levels of p-PI3K (Tyr607) and p-Akt (Ser473). This was concomitant with significant increase in the levels of AMPK and p-AMPK, known upstream regulators of PI3K/Akt signaling pathway. Interestingly, all the above listed beneficial effects of RES, except their effect on AMPK/p-AMPK, were completely abolished in CdCl2 + RES + LY294002-treated rats. In conclusion, in addition to its antioxidant potential, RES inhibits Tau phosphorylation in rat's brain by activating PP2A protein and AMPK/PI3K/Akt-induced inhibition of GSK3beta. PMID- 30478675 TI - [Obituary for Prof. Dr. med. Henning Bier (1957-2018) : Director of the Otorhinolaryngology Department at the Klinikum rechts der Isar of the Technical University of Munich from 2007 to 2018]. PMID- 30478676 TI - [Histology of adenoids]. PMID- 30478677 TI - Effects of long-term dehydration on oxidative stress, apoptotic markers and neuropeptides in the gastric mucosa of the dromedary camel. AB - We investigated the effects of 20 days of dehydration and 20 days of dehydration followed by 72 h of rehydration on the gastric mucosa of the one-humped dromedary camel. The parameters addressed include biomarkers of oxidative stress, apoptosis, gastric epithelial histology, gastric neuropeptides, and their receptors. Nineteen clinically healthy, 4-5 year-old male dromedary camels were divided into three groups (five control camels, eight dehydrated for 20 days, six dehydrated for 20 days and then rehydrated for 72 h). Dehydration affected the oxidative stress biomarkers causing a significant increase in malondialdehyde, glutathione, nitric oxide, and catalase values compared with controls. Also the results revealed that dehydration caused different size cellular vacuoles and focal necrosis in the gastric mucosa. Rehydration for 72 h resulted in improvement in some parameters but was not enough to fully abolish the effect of dehydration. Dehydration caused significant increase in apoptotic markers; tumor necrosis factor alpha, caspases 8 and 3, BcL-x1 and TGFbeta whereas caspase 9, p53, Beclin 1, and PARP1 showed no significant change between the three groups indicating that apoptosis was initiated by the extrinsic pathway. Also there were significant increases in prostaglandin E2 receptors and somatostatin in plasma and gastric epithelium homogenate, and a significant decrease in cholecystokinin 8 receptors. A significant decrease of hydrogen potassium ATPase enzyme activity was also observed. Pepsinogen C was not affected by dehydration. It is concluded that long-term dehydration induces oxidative stress and apoptosis in camel gastric mucosa and that camels adjust gastric functions during dehydration towards water economy. More than 72 h are needed before all the effects of dehydration are reversed by rehydration. PMID- 30478678 TI - A novel approach for development, standardization, and safety testing of enriched alum-precipitated vaccine against hemorrhagic septicemia in different breeds of cattle. AB - Hemorrhagic septicemia is a fatal disease of cattle and buffalo all over the world including Pakistan and it causes heavy economic losses every year. The poor farmers cannot bear this loss in the form of less milk production and heavy expenditures on the animal treatment. An enriched alum-precipitated vaccine with reduced dose was prepared and standardized and safety testing of enriched vaccine was performed in Swiss albino mice as well as in natural host. In this experiment, a total of 36 cattle both male and female of different age groups ranging from 4 months to 4 years were used. All these animals belong to all major cattle breeds of Pakistan including Sahiwal, Red Sindhi (crossbred and purebred), Dhani (crossbred and purebred), Lohani (crossbred and purebred), and Cholistani, and exotic breeds including Holstein Friesian and Jersey. These animals were examined for current immune titer prior to vaccination. Animals were vaccinated subcutaneously with 2 mL and 4 mL dose of new vaccine and were observed for any untoward reaction for 48 h. All the animals were kept under close observation for the next 30 days and all were found safe. The experiment was designed to reduce the dose of the vaccine to 2 mL by using BHI as a growth medium, as well as to increase the number of doses prepared in the same infrastructure, hence reducing the cost of vaccine production. The study proved that vaccine with increased biomass in reduced dose is safe in local as well as in exotic breeds of cattle. PMID- 30478680 TI - Opportunity Lost? Diagnostic Laparoscopy in Patients with Pancreatic Cancer in the National Surgical Quality Improvement Program Database. AB - BACKGROUND: Routine preoperative staging in pancreas cancer is controversial. We sought to evaluate the rates of diagnostic laparoscopy (DLAP) for pancreatic cancer. METHODS: We queried the National Surgical Quality Improvement Program for patients with pancreas cancer (2005-2013) and compared groups who underwent DLAP, exploratory laparotomy (XLAP), pancreas resection (RSXN) or therapeutic bypass (THBP). We compared demographics, comorbidities, postoperative complications, 30 day mortality (Chi-square P < 0.05) and trends over time (R2 0-1). RESULTS: We identified 17,138 patients (RSXN 81.8%, XLAP 16.5%, THBP 8.2%, and DLAP 12.9%), with some having multiple CPT codes. Only 10.3% (n = 1432) of RSXN patients underwent DLAP prior to resection. XLAP occurred in 49.5% of non-RSXN patients, of whom 67.1% had no other operation. The percentage of patients undergoing RSXN increased 20.3% over time (R2 0.81), while DLAP decreased 52.6% (R2 0.92). XLAP patients without other operations decreased from 4.2 to 2.4%, although not linearly (R2 0.31). Only 10.3% of XLAP had a diagnostic laparoscopy as well, leaving nearly 90% of these patients with an exploratory laparotomy without RSXN or THBP. DISCUSSION: Diagnostic laparoscopy for pancreas malignancy is becoming less common but could benefit a subset of patients who undergo open exploration without resection or therapeutic bypass. PMID- 30478679 TI - Isolation and characterization of cells derived from human epithelial rests of Malassez. AB - The epithelial rests of Malassez (ERMs) might represent a valuable source of oral epithelial cells with stem cell properties. The purpose of this study was to isolate and characterize cells derived from human ERM, and compare them with cells derived from matched normal oral mucosa (NOM). Matched tissue specimens of the periodontal ligament of extracted tooth and NOM were collected. Cells were isolated in culture, then characterized by immunohistochemistry and flow cytometry for expression of pancytokeratin, ESA, PDGFRB, CD31 and CD44. 3D organotypic cultures were constructed by growing epithelial cells on top of fibroblast-populated collagen gels. Both ERM and NOM-isolated cells expressed the markers of epithelial lineage (ESA and pancytokeratin), and to some extent PDGFR, an indicator of a more mesenchymal phenotype, but not the endothelial cell marker CD31. Cells with epithelial morphology were isolated from periodontium of cervical, middle and apical parts of the root, but contained a significantly lower percentage of ESA and pancytokeratin-positive cells than when isolating cells from NOM (p < 0.001). ERM cells expressed a significantly higher percentage of the stem cell-related molecule CD44 (cervical 92.93 +/- 0.25%, middle 93.8 +/- 0.26%, apical 94.36 +/- 0.41%) than cells isolated from NOM (27.8 +/- 1.47%, p < 0.001). When grown in 3D organotypic cultures and in collagen gels, ERM cells formed a less differentiated epithelium than NOM cells, but expressing pancytokeratin and vimentin. In conclusion, epithelial cells could be isolated from human periodontium and grown in culture; their in vitro characterization indicates that they have a less differentiated phenotype compared with cells derived from normal oral epithelium. PMID- 30478681 TI - Prognoses and Clinicopathological Characteristics for Hepatocellular Carcinoma Originating from the Caudate Lobe After Surgery. AB - BACKGROUND: The aim was to evaluate the prognoses and clinicopathological characteristics of solitary hepatocellular carcinoma (HCC) originating from the caudate lobe (HCC-CL). METHODS: We analyzed 584 patients with a solitary tumor <10 cm from January 1990 to November 2014. Patients were classified into a caudate lobe group (CL; n = 39) and a non-caudate lobe group (NCL; n = 545). We investigated the prognoses and clinicopathological characteristics of solitary HCC-CL. We compared the surgical procedures performed in these cases. RESULTS: HCC-CL had a similar rate of portal venous invasion (PVI) as HCC-NCL (21% vs. 19%); however, the frequency of tumor thrombus at the first branch of the portal vein (PV) or extension to the trunk or the opposite side of the PV was significantly higher in HCC-CL (8% vs. 2%). HCC-CL had similar OS rates compared to HCC-NCL; however, HCC-CL showed significantly poorer RFS. Although there were no significant differences among the three surgical procedures, blood loss and complication rates tended to be higher in cases who underwent an isolated caudate lobectomy. Tumor size >=5 cm, PVI, and liver fibrosis or cirrhosis (LF or LC) were independent unfavorable factors for both OS and RFS. PIVKA-II >=120 mAU/ml was an independent unfavorable factor for RFS. CONCLUSION: HCC-CL presented a poorer RFS rate. Patients with a tumor size >=5 cm, PIVKA-II >=120 mAU/ml, portal venous invasion, and LF or LC should be diligently followed up as these cases have a high risk of recurrence. PMID- 30478682 TI - Postoperative Skeletal Muscle Loss Predicts Poor Prognosis of Adenocarcinoma of Upper Stomach and Esophagogastric Junction. AB - BACKGROUND: The relationship between postoperative changes in muscle mass and the prognosis of malignancies remains controversial. We aimed to determine whether a decrease in skeletal muscle mass after surgical resection can predict long-term outcomes in patients with adenocarcinoma of upper stomach (AUS) and esophagogastric junction (AEGJ). METHODS: We reviewed 146 patients who underwent curative surgery for AUS and AEGJ. We assessed the skeletal muscle index pre- and post-surgery and 6 months postoperatively. The rate of decrease in skeletal muscle index (SMI) was calculated and its relationship with clinicopathological factors and prognosis was analyzed. RESULTS: Among the 146 patients studied, 115 underwent re-assessment of SMI 6 months postoperatively. The mean decrease in SMI was more prominent in patients with recurrence than in those without recurrence (19.0 +/- 2.3 vs. 7.4 +/- 0.9%, respectively, P < 0.0001). AUS and AEGJ patients with a >19% decrease in SMI showed significantly lower 5-year overall survival and recurrence-free rates than those with a <19% decrease in SMI (recurrence-free survival: 33.4 vs. 89.2%, respectively, P < 0.0001; overall survival: 40.6 vs. 90.0%, respectively, P < 0.0001). Multivariate analyses indicated that a >=19% decrease in SMI could predict poor overall survival independently in patients with AUS and AEGJ (P = 0.0070). CONCLUSIONS: A >=19% postoperative decrease in SMI was substantially associated with poor survival in patients with AUS and AEGJ. PMID- 30478683 TI - The Short-Form Inguinal Pain Questionnaire (sf-IPQ): An Instrument for Rating Groin Pain After Inguinal Hernia Surgery in Daily Clinical Practice. AB - BACKGROUND: The Inguinal Pain Questionnaire (IPQ) is a standardised and validated instrument for assessing persisting pain after groin hernia surgery. The IPQ is often perceived as being too extensive for routine use. The aim of this study was to develop and evaluate a condensed version of the IPQ in order to facilitate its use in daily clinical practice. METHODS: The condensed form, i.e. Short-Form Inguinal Pain Questionnaire (sf-IPQ), comprises two main items taken from the IPQ. Four hundred patients were recruited from the Swedish Hernia Register and were sent the IPQ, sf-IPQ and the Short-Form McGill Pain Questionnaire (SF-MPQ) three years after hernia repair. Ratings from the IPQ and the sf-IPQ were converted to a 12-point scale. The reported scores for the two shared items in the IPQ and sf-IPQ were compared using the Intraclass Correlation Coefficient (ICC), Cohen's kappa and McNemar's test. RESULTS: After two reminders, the response rate was 69.8% (n = 279/400). The ICC for the IPQ and sf-IPQ scores was 0.78 (95% confidence interval 0.73-0.82, p < 0.001). Cohen's kappa was 0.66 (95% confidence interval 0.55-0.77, p < 0.001). The sf-IPQ systematically indicated a higher pain score than the IPQ (p = 0.013). CONCLUSIONS: Despite the systematic difference in level of pain scored, correlation, consistency and agreement were seen between the IPQ and sf-IPQ. The forms appear to be interchangeable, though the sf-IPQ may be a more sensitive instrument. The condensed structure of the sf IPQ is more user-friendly and shows promise as a useful tool in daily clinical practice. PMID- 30478684 TI - Microdialysis in Postoperative Monitoring of Gastrointestinal Organ Viability: A Systematic Review. AB - BACKGROUND: Microdialysis is a technique for continuous measurement of extracellular substances. It may be used to monitor tissue viability. The clinical implications of using microdialysis as a tool in gastrointestinal surgery have yet to be defined. The aim of the present study was to evaluate the clinical significance of microdialysis with special attention to different markers measured to predict the clinical outcome of surgical patients. METHODS: Embase, MEDLINE, and the Cochrane Library were searched systematically for human studies written in English. Study selection, data extraction, and quality assessment were performed independently by two authors. We included studies in which the microdialysis technique was used for postoperative monitoring of patients undergoing gastrointestinal surgery. To be eligible, studies had to compare patients with and without postoperative complications. RESULTS: Twenty six studies were included in this review. MINORS score ranged from 3 to 12 (median 10.5). Most studies showed that levels of biomarkers obtained by microdialysis correlated with the postoperative clinical course. Lactate, pyruvate, glucose, and glycerol were the most frequently measured biomarkers. Several studies found that changes in biomarkers in complicated patients preceded symptoms of complications and/or changes in conventional paraclinical methods of postoperative monitoring. CONCLUSIONS: Studies show that microdialysis may have the potential to become a tool in postoperative surveillance of surgical patients. Larger randomized studies are needed to define the clinical implications of microdialysis. PMID- 30478685 TI - Morbid Obesity's Silver Lining: An Armor for Hollow Viscus in Blunt Abdominal Trauma. AB - BACKGROUND: Morbid obesity is usually accompanied by both subcutaneous and visceral fat accumulation. Fat can mimic an air bag, absorbing the force of a collision. We hypothesized that morbid obesity is mechanically protective for hollow viscus organs in blunt abdominal trauma (BAT). METHODS: The National Trauma Data Bank (NTDB) was queried for BAT patients from 2013 to 2015. We looked at the rate of gastrointestinal (GI) tract injuries in all BAT patients with different BMIs. A subset analysis of BAT patients with operative GI tract injuries was performed to evaluate the need for abdominal operation. Multivariate analyses were carried out to identify factors independently associated with increased GI tract injuries and associated abdominal operations. RESULTS: A total of 100,459 BAT patients were evaluated in the NTDB. Patients with GI tract injury had a lower proportion of morbidly obese patients [body weight index (BMI) >= 40 kg/m2)] (3.7% vs. 4.2%, p = 0.015) and instead had more underweight patients (BMI < 18.5) (5.9% vs. 5.0%, p < 0.001). The risk of GI tract injury decreased 11.6% independently in morbidly obese patients and increased 15.7% in underweight patients. Of the patients with GI tract injuries (N = 11,467), patients who needed a GI operation had a significantly lower proportion of morbidly obese patients (3.2% vs. 5.3%, p < 0.001). The risk of abdominal operation for GI tract injury decreased 57.3% independently in morbidly obese patients. Compared with underweight patients, morbidly obese patients had significantly less GI tract injury (6.0% vs. 13.3%, p < 0.001) and associated abdominal operation rates (65.2% vs. 73.3%, p < 0.001). CONCLUSION: Obesity is protective in BAT. This translates into lower rates of GI tract injury and operation in morbidly obese patients. In contrast, underweight patients appear to suffer a higher rate of GI tract injury and associated GI operations. PMID- 30478686 TI - Early Laparoscopic Washout may Resolve Persistent Intra-abdominal Infection Post appendicectomy. AB - BACKGROUND: Intra-abdominal abscess (IAA) complicates 2-3% of patients having an appendicectomy. The usual management is prolonged antibiotics and drainage of the IAA. From 2006, our unit chose to use early re-laparoscopy and washout in patients with persistent sepsis following appendicectomy. The aims of this study were to assess the outcomes of early laparoscopic washout in patients with features of persistent intra-abdominal sepsis and compare those with percutaneous drainage and open drainage of post-appendicectomy IAA. METHODS: A retrospective case note review was performed for all patients having a laparoscopic washout, percutaneous drainage or open drainage following appendicectomy between January 2006 and December 2017. RESULTS: During the period, 4901 appendicectomies occurred. Forty-one (0.8%) patients had a laparoscopic washout, 16 (0.3%) had percutaneous drainage, and 6 (0.1%) had an open drainage. The demographics, ASA grade and pathology at initial appendicectomy were similar. The mean time after appendicectomy was significantly shorter for laparoscopic washout (4.1 days vs. 10.1 and 9.0 days, p = <0.003). The mean time for resolution of SIRS was significantly shorter (2.0 days vs. 3.3 and 5.2 days, p <0.02). The morbidity and length of stay were similar. CONCLUSION: Early laparoscopic washout for persistent intra-abdominal sepsis may be an alternative to non-operative management and delayed intervention for IAA and may have better outcomes than either percutaneous drainage or open drainage. A prospective randomised comparison is required to further evaluate the indications and role of early laparoscopic washout post-appendicectomy. PMID- 30478687 TI - Hurdles to Take for Adequate Treatment of Morbidly Obese Children and Adolescents: Attitudes of General Practitioners Towards Conservative and Surgical Treatment of Paediatric Morbid Obesity. AB - BACKGROUND: Bariatric surgery is regarded as the most effective treatment of morbid obesity in adults. Referral patterns for bariatric surgery in adults differ among general practitioners (GPs), partially due to restricted knowledge of the available treatment options. Reluctance in referral might be present even stronger in the treatment of morbidly obese children. OBJECTIVES: The aim of this study was to investigate the current practice of GPs regarding treatment of paediatric morbid obesity and their attitudes towards the emergent phenomenon of paediatric weight loss surgery. METHODS: All GPs enlisted in the local registries of two medical centres were invited for a 15-question anonymous online survey. RESULTS: Among 534 invited GPs, 184 (34.5%) completed the survey. Only 102 (55.4%) reported providing or referring morbidly obese children for combined lifestyle interventions. A majority (n = 175, 95.1%) estimated that conservative treatment is effective in a maximum of 50% of children. Although 123 (66.8%) expect that bariatric surgery may be effective in therapy-resistant morbid obesity, only 76 (41.3%) would consider referral for surgery. Important reasons for reluctance were uncertainty about long-term efficacy and safety. The opinion that surgery is only treatment of symptoms and therefore not appropriate was significantly more prevalent amongst GPs who would not refer (58.3% vs. 27.6%, p < 0.001). CONCLUSION: There is a potential for undertreatment of morbidly obese adolescents, due to suboptimal knowledge regarding guidelines and bariatric surgery, as well as negative attitudes towards surgery. This should be addressed by improving communication between surgeons and GPs and providing educational resources on bariatric surgery. PMID- 30478688 TI - Surgical Management of the Axilla in Breast Cancer Patients with Negative Sentinel Lymph Node: A Method to Reduce False-Negative Rate. AB - BACKGROUND: False-negative rate (FNR) of sentinel lymph node dissection (SLND) has not been eliminated. The study was conducted to optimize the surgical resection of axilla in patients with negative sentinel lymph node (SLN) for the purpose of eradicating false-negative (FN) events of SLND. METHODS: A total of 312 clinically node-negative patients without neoadjuvant therapy underwent SLND with indocyanine green (ICG), methylene blue and the combination of ICG and methylene blue. Axillary dissection was performed subsequently regardless of the status of SLN. Lymph nodes were sent for pathological examination separately by serial resection every 0.5 cm away from marginally visualized SLNs. RESULTS: SLND was successfully conducted in 98.1% (306/312) of patients using methylene blue, ICG, and its combination. Further examination revealed 97 true-positive, 189 true negative, and 13 FN results. The overall FNR was 11.8% (13/110). A horizontal line 1.5 cm away from the superior vSLN and a vertical line 1.5 cm away from the medial vSLN formed a zone of lower outer quadrant (LOQ) in axilla. Surgical resection of LOQ 'en bloc' showed a FNR of zero. CONCLUSIONS: The surgical management of axilla may benefit negative SLN patients with potential nodal involvement, reducing the FNR of SLND to zero. TRIAL REGISTRATION NUMBER AND AGENCY: This study was registered with the Chinese Clinical Trial Registry (ChiCTR1800014247). PMID- 30478690 TI - Novel genetic tools for probing individual H3 molecules in each nucleosome. AB - In eukaryotes, genomic DNA is packaged into the nucleus together with histone proteins, forming chromatin. The fundamental repeating unit of chromatin is the nucleosome, a naturally symmetric structure that wraps DNA and is the substrate for numerous regulatory post-translational modifications. However, the biological significance of nucleosomal symmetry until recently had been unexplored. To investigate this issue, we developed an obligate pair of histone H3 heterodimers, a novel genetic tool that allowed us to modulate modification sites on individual H3 molecules within nucleosomes in vivo. We used these constructs for molecular genetic studies, for example demonstrating that H3K36 methylation on a single H3 molecule per nucleosome in vivo is sufficient to restrain cryptic transcription. We also used asymmetric nucleosomes for mass spectrometric analysis of dependency relationships among histone modifications. Furthermore, we extended this system to the centromeric H3 isoform (Cse4/CENP-A), gaining insights into centromeric nucleosomal symmetry and structure. In this review, we summarize our findings and discuss the utility of this novel approach. PMID- 30478689 TI - A transcriptome analysis of the ameliorate effect of Cyclocarya paliurus triterpenoids on ethanol stress in Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae (S. cerevisiae) plays a critical role in ethanol fermentation. However, during the fermentation, yeast cells are exposed to the accumulation of ethanol, which significantly affect the cell growth and the target product yield. In the present work, we employed RNA-sequence (RNA-seq) to investigate the ameliorate effect of Cyclocarya paliurus (C. paliurus) triterpenoids on S. cerevisiae under the ethanol stress. After C. paliurus triterpenoids intervention (0.3% v/v), 84 differentially expressed genes (DEGs) were identified, including 39 up-regulated and 45 down-regulated genes. The addition of triterpenoids decreased the filamentous and invasive growth of cells, and benefit to the redox balance and glycolysis. This study offers a global view through transcriptome analysis to understand the molecular response to ethanol in Sc131 by the treatment of C. paliurus triterpenoids, which may be helpful to enhance ethanol tolerance of S. cerevisiae in the fermentation of Chinese fruit wine. PMID- 30478691 TI - Perioperative risk calculator for distal gastrectomy predicts overall survival in patients with gastric cancer. AB - BACKGROUND: Although some predictive factors of long-term survival after a distal gastrectomy for gastric cancer have been reported, only few studies have predicted long-term outcomes based on preoperative parameters. We aimed to evaluate the reliability of perioperative risk calculator for predicting overall survival (OS) after distal gastrectomy in patients with gastric cancer. METHODS: Overall, 337 patients (225 males, 112 females) who had undergone a distal gastrectomy for gastric cancer at the Keio University Hospital, Tokyo, Japan, between January 2009 and December 2013 were enrolled in this study. We investigated the reliability of a risk calculator for the prediction of OS. RESULTS: In multivariate analysis, the risk models for operative mortality and 30 day mortality were identified as predictors of death. Time-dependent receiver operating characteristics (ROC) curve analysis indicated that the estimated area under the curve (AUC) value of the risk model for operative mortality was > 0.870 during the first postoperative 3 years. We set optimal cutoff values of the risk model operative mortality for OS using the Cutoff Finder online tool. The cutoff values of 4.117% were significant risk factors of death. Similar results were observed in the external validation set. CONCLUSIONS: We elucidated the associations among risk calculator values and OS rates of patients with gastric cancer. Time-dependent ROC curve analysis suggested that the AUC value of the risk model for operative mortality was high, indicating that this risk calculator would be useful for not only short-term outcomes, but also long-term outcomes. PMID- 30478692 TI - Function, evolution, and structure of J-domain proteins. AB - Hsp70 chaperone systems are very versatile machines present in nearly all living organisms and in nearly all intracellular compartments. They function in many fundamental processes through their facilitation of protein (re)folding, trafficking, remodeling, disaggregation, and degradation. Hsp70 machines are regulated by co-chaperones. J-domain containing proteins (JDPs) are the largest family of Hsp70 co-chaperones and play a determining role functionally specifying and directing Hsp70 functions. Many features of JDPs are not understood; however, a number of JDP experts gathered at a recent CSSI-sponsored workshop in Gdansk (Poland) to discuss various aspects of J-domain protein function, evolution, and structure. In this report, we present the main findings and the consensus reached to help direct future developments in the field of Hsp70 research. PMID- 30478693 TI - Efficacy and safety of endoscopic resection for small submucosal tumors originating from the muscularis propria layer in the gastric fundus. AB - BACKGROUND: Gastric small submucosal tumors (SMTs) are becoming increasingly common. However, the fundus of stomach is regarded as a difficult area for endoscopic resection (ER). In this study, we investigated the efficacy, safety, and long-term outcomes of ER for small SMTs of the gastric fundus in a large series of patients, research that was previously lacking. METHODS: 537 consecutive patients with SMTs no more than 20 mm in diameter, occurring in the gastric fundus and originating from the muscularis propria layer, which were treated with endoscopic submucosal excavation or endoscopic full-thickness resection (EFTR) were included in this retrospective study at Zhongshan Hospital of Fudan University from January 2013 to September 2016. Clinicopathological, endoscopic, and follow-up data were collected and analyzed. RESULTS: En bloc resection was achieved in 100% of patients, and complete resection was achieved for 530 (98.7%) lesions. Although the total rate of complications was 9.3%, few serious adverse events occurred in only three (0.6%) patients, including major pneumoperitoneum, major hydrothorax, and bleeding. Unlike lager tumor sizes and longer procedure times, endoscopist experience had a positive impact on decreasing the likelihood of complications. Based on statistical analysis, tumors with greater size near the cardia, which were treated by EFTR, were the significant contributors to longer operative times. A median follow-up of 32 months was available, and all patients were free from local recurrence or distant metastasis during the study period. CONCLUSIONS: Although the gastric fundus presents technical difficulties, ER is effective for the resection of small gastric SMTs with a high complete resection rate and rare serious adverse events. PMID- 30478694 TI - Cholecystectomy following percutaneous cholecystostomy tube placement leads to higher rate of CBD injuries. AB - INTRODUCTION: Percutaneous cholecystostomy tube (PCT) placement is often the management of severe acute cholecystitis in the unstable patient. PCT can be later reversed and cholecystectomy performed. The purpose of this study is to investigate the incidence of subsequent cholecystectomy and clinical factors associated with subsequent procedure. METHODS: The SPARCS, an administrative database, was used to search all patients undergoing PCT placement between 2000 and 2012 in the state of New York. Using a unique identifier, all patients were followed for subsequent cholecystectomy procedures for at least 2 years. Patients were also followed up to 2014 for potential CBD injury during subsequent laparoscopic (LC) or open cholecystectomy (OC). Univariate and multivariable regression analysis were performed when appropriate. RESULTS: There were 9738 patients identified who underwent PCT placements. The incidence of patients who had a PCT in 2000-2012, which subsequently underwent cholecystectomy increased from 25.0% in 2000 to 31.7% in 2012. In addition, patients undergoing subsequent LC increased from 11.8% in 2000 to 22.2% in 2012, while the incidence of OC decreased from 13.2% in 2000 to 9.5% in 2012. After accounting for other confounding factors, younger male patients, race as white compared to black, who didn't have any complications during PCT placement were more likely to undergo subsequent cholecystectomy (p < 0.05). Average time to LC was 122.0 days versus 159.6 days for OC (p < 0.0001). From the patients who underwent cholecystectomy following PCT, 47 patients experienced CBD injury (1.6%). CONCLUSIONS: Incidence of cholecystectomy following PCT increased during the study period. Surgeons seem to be more comfortable performing LC as rate of LC increased from 11.8 to 22.2%. However, rate of CBD injury is higher during subsequent cholecystectomy compared to that of the general population. Caution should be used when performing subsequent cholecystectomy following PCT, as these procedures may be more technically challenging. PMID- 30478695 TI - Predictors of technical difficulty during endoscopic submucosal dissection of superficial esophageal cancer. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is the standard treatment for superficial esophageal cancer (SEC); however, it is sometimes technically difficult. Our aim was to identify the predictors of technical difficulty during ESD for SEC. METHODS: We reviewed the records of patients who underwent ESD for superficial esophageal squamous cell carcinomas at a tertiary cancer center between April 2008 and March 2016. Patients undergoing ESD after esophagectomy or for residual/recurrent lesions were excluded. Preoperative factors such as tumor subsite, localization, preoperative size, macroscopic type, endoscopic depth of invasion, and treatment for synchronous multiple SECs or previous history of radiation therapy were analyzed. Logistic regression analysis was performed to identify the predictors of technical difficulty, defined as (1) long procedure time (>= 120 min), (2) adverse events (perforation, pneumomediastinum), or (3) incomplete resection (piecemeal resection, positive or indeterminate vertical margin). RESULTS: A total of 679 lesions in 511 patients were analyzed. Difficultly was experienced in 60 cases. The procedure time was > 120 min in 43 (6.3%) patients, adverse events occurred in 16 (2.8%), and incomplete resection occurred in 17 (2.5%). Multivariate logistic regression revealed that tumors in the left esophageal wall (OR 2.15; 95% CI 1.17-3.91; p = 0.014) and those encompassing >= 1/2 its circumference (OR 5.06; 95% CI 2.40-11.34; p < 0.001) were independently associated with difficulty. CONCLUSIONS: Tumors in the left esophageal wall and tumors measuring > 1/2 of the esophageal circumference are predictors of difficult esophageal ESD. These results may contribute to better patient selection according to each endoscopist's skill. PMID- 30478696 TI - Near-infrared fluorescence laparoscopy of the ureter with three preclinical dyes in a pig model. AB - BACKGROUND: Ureteric injury is reported to occur in 1-7.6% of colorectal surgeries. To reduce the incidence of ureteral injury, it is essential to identify the ureters. The use of near-infrared fluorescence (NIRF) imaging with intravenously administered dyes might be of added value for ureteral visualization during laparoscopy. The aim of this study is to assess the performance of three preclinical dyes; IRDye(r) 800BK, IRDye(r) 800NOS and IRDye(r) 800CW, for near-infrared fluorescence laparoscopy of the ureter in pigs. METHODS: In three female Dutch landrace pigs, the new dyes were evaluated. In each pig, 1 dye was tested using a 6-mg intravenous dose in a concentration of 1 mg/ml. Imaging was performed in fluorescence mode and white light mode with a laparoscopic imaging system. In order to further evaluate the dyes, an ex vivo imaging experiment was performed, in which 8 decreasing concentrations per dye, diluted in PBS, were evaluated in a transparent test tube with NIRF mode at a distance of 1, 5 and 10 cm from the laparoscope. RESULTS: All three dyes were effective in allowing the identification of the ureter with NIRF imaging. The ureter became fluorescent after 35, 45 and 10 min, respectively, for IRDye(r) 800BK, IRDye(r) 800NOS and IRDye(r) 800CW with a maximum target-to-background ratio (TBR) of 2.14, 0.66 and 1.44, respectively. In the ex vivo imaging experiment, all three dyes produced a strong fluorescence signal at all concentrations and all distances evaluated. CONCLUSIONS: Intravenous administration of the preclinical dyes IRDye(r) 800CW, IRDye(r) 800 BK and IRDye(r) 800NOS facilitated successful identification of the anatomical course of the ureter in living pig models. The highest measured TBR occurred with the use of IRDye(r) 800BK. Ex vivo, a correlation was observed between the fluorescence intensities of the signal with the concentration of the dye and with the distance to the object. PMID- 30478697 TI - Long-term follow-up of endoscopic totally extraperitoneal direct inguinal hernia repair using the Endoloop technique. AB - INTRODUCTION: The pre-tied suture EndoloopTM technique for plication of the weakened transversalis fascia is efficient in post-operative seroma prevention, after laparoscopic/endoscopic direct inguinal hernia repair. No studies have evaluated long-term tolerability of this new technique in regards to chronic pain and hernia recurrence. METHODS: Prospective longitudinal evaluation study of consecutive patients treated with EndoloopTM for M2 or M3 direct defects, during endoscopic totally extraperitoneal approach. Meshes were secured with fibrin sealant only. All patients had a minimum 2.8 years (median 5.9 years) follow-up. First outcome was chronic groin/testicular pain; secondary outcome parameters included hernia recurrence and Quality of Life (QoL). Patients were assessed by phone interview using the validated Carolinas Comfort Scale (CCS), questioned regarding recurrence and asked to present for clinical review as needed. RESULTS: 112 patients (median age 57 years) with 141 direct hernia defects were included during the study period of 2008-2014. An EndoloopTM was used on 127 occasions-79 M2 and 48 M3 direct hernias. One patient had an early recurrence requiring an open repair and was therefore excluded. Thirty-three of the remaining one hundred and eleven patients (29.7%) were lost to long-term follow-up. According to their CCS range, 70 patients (88.6%) were very satisfied with their results, 8 (10.1%) were satisfied, and only one patient (1.3%) who reported chronic groin pain was unsatisfied. There was no reported long-term hernia recurrence. CONCLUSION: The PDS EndoloopTM technique for closure of direct inguinal hernia defects is well tolerated with low risk of hernia recurrence, chronic pain, and excellent QoL. This reliability persists to long-term follow-up. PMID- 30478698 TI - Long-term efficacy of laparoscopic Nissen versus Toupet fundoplication for the management of types III and IV hiatal hernias. AB - BACKGROUND: Laparoscopic hiatal hernia repair via Toupet or Nissen fundoplication remains the most commonly performed procedures for management of large hiatal hernia. Few studies have compared the procedures' long-term effectiveness. This study sought to characterize the efficacy of laparoscopic Toupet versus Nissen fundoplication for types III and IV hiatal hernia. METHODS: With IRB approval, a review of all laparoscopic hiatal hernia repairs with mesh reinforcement performed over 7 years at a single center by one surgeon was conducted. Hiatal hernias were classified as type III or IV using operative reports and preoperative imaging. Patients with type I, II, or recurrent hiatal hernia and patients receiving concomitant procedures were excluded. The GERD-Health Related Quality of Life Survey was administered by telephone no earlier than 18 months postoperatively. RESULTS: A total of 473 patients underwent laparoscopic fundoplication; 179 having type III or IV hiatal hernia met inclusion criteria; 62 underwent Toupet, 117 underwent Nissen fundoplication. Average patient age was 64 years; 63% of patients were female. Cohorts were similar in demographics, comorbidities, and intraoperative factors. Survey was completed by 77 patients (43%): 50 having Nissen and 27 Toupet. Median time of survey completion after surgery was 54 months (Nissen) and 25 months (Toupet). Median survey responses across all items for both groups were 0 (no symptoms) with no significant variation between groups. Of patients that had Nissen, 26% reported current proton-pump inhibitor use versus 31% of Toupet patients (p = 0.486). Patient reported satisfaction with current condition was similar between groups (67% Toupet, 72% Nissen, p = 0.351). CONCLUSIONS: Patient-reported symptoms and satisfaction did not vary for patients receiving laparoscopic Nissen versus Toupet fundoplication, which may indicate that patients with large type III and IV hiatal hernia undergoing either procedure have similar long-term postoperative symptom control. PMID- 30478699 TI - Investigating rates of reoperation or postsurgical gastroparesis following fundoplication or paraesophageal hernia repair in New York State. AB - BACKGROUND: Little is known of the natural history of fundoplication or paraesophageal hernia (PEH) repair in terms of reoperation or the incidence treatment of postsurgical gastroparesis (PSG) in large series. Repeat fundoplications or PEH repairs, as well as pyloroplasty/pyloromyotomy operations, have proven to be effective in the context of PSG or recurrence. In this study, we analyzed the incidences of PSG and risk factors for these revisional surgeries following fundoplication and PEH repair procedures in the state of New York. METHODS: The New York State Planning and Research Cooperative System (NY SPARCS) database was utilized to examine all adult patients who underwent fundoplication or PEH repair for the treatment of GERD between 2005 and 2010. The primary outcome was the incidence of each type of reoperation and the timing of the follow-up procedure/diagnosis of gastroparesis. Generalized linear mixed models were used to examine the risk factors for follow-up procedures/diagnosis. RESULTS: A total of 5656 patients were analyzed, as 3512 (62.1%) patients underwent a primary fundoplication procedure and 2144 (37.9%) patients underwent a primary PEH repair. The majority of subsequent procedures (n = 254, 65.5%) were revisional procedures (revisional fundoplication or PEH repair) following a primary fundoplication. A total of 134 (3.8%) patients who underwent a primary fundoplication later had a diagnosis of gastroparesis or a follow-up procedure to treat gastroparesis, while 95 (4.4%) patients who underwent a primary PEH repair were later diagnosed with gastroparesis or underwent surgical treatment of gastroparesis. CONCLUSION: The results revealed low reoperation rates following both fundoplication and PEH repairs, with no significant difference between the two groups. Additionally, PEH repair patients tended to be older and were more likely to have a comorbidity compared to fundoplication patients, particularly in the setting of hypertension, obesity, and fluid and electrolyte disorders. Further research is warranted to better understand these findings. PMID- 30478700 TI - "Four-Step Procedure" of laparoscopic exploration for gastric cancer in West China Hospital: a retrospective observational analysis from a high-volume institution in China. AB - BACKGROUND: The preoperative work-up has limitations on finding peritoneal dissemination (PD) in gastric cancer patients. Laparoscopic exploration (LE) can discover radiographically occult PD, obtain accurate stage and avert futile laparotomy. The aim of our study was to introduce "Four-Step Procedure" LE in West China Hospital and further evaluate its safety and feasibility. METHODS: We conducted a retrospective analysis on 165 patients from July 2016 to December 2017 who underwent "Four-Step Procedure" LE in gastrointestinal surgery department of West China Hospital. All the patients were diagnosed with gastric adenocarcinoma without explicit distant metastasis through Computed Tomography and/or Gastrointestinal Ultrasonography. Peritoneal lavage cytological examination (CY) was routinely performed during LE in our research. The "Four Step" technical process of LE was introduced comprehensively. The clinicopathologic features and the presence of PD or CY at LE were analyzed, and the stratified analysis by cT and cN stages on the proportion of P1 and/or CY1 was also reported in this study. RESULTS: Total of 165 patients accepted LE in our study, among these patients: 27 (16.4%) patients with P1 and/or CY1: 19 (11.5%) patients were found PD (P1), 17 (10.3%) patients with positive cytological examination (CY1) and 9 (3.6%) patients with P1Cy1. The stratified analysis by cT stage indicated that there was no P1 and/or Cy1 in cT1-cT2 stages, 1 (2.7%) patient with P1 and 1 (2.7%) with Cy1 in cT3 stage, 18 (20.0%) patients with P1 and 16 (17.8%) with Cy1 in cT4 stage. After LE, there were 74 (44.8%) patients underwent laparoscopic assistant gastrectomy, 25 (15.2%) patients with open gastrectomy, 50 (30.3%) patients with neoadjuvant chemotherapy and 16 (9.7%) patients with palliative chemotherapy and/or conversion therapy. CONCLUSION: "Four-Step Procedure" LE is reliable and feasible for gastric cancer. From our study, LE has unique superiority on ascertaining PD and cytological examination and LE should be recommended in cT4 stage gastric cancer before resection. PMID- 30478701 TI - Computerized model for objectively evaluating cutting performance using a laparoscopic box trainer simulator. AB - BACKGROUND: Laparoscopic box trainer simulator has recently become a tool for assessment of physicians' surgical and laparoscopic skills, and training using such a simulator has been incorporated into the curricula of surgery syllabus. With the increased use of box trainer simulators, there is a great need for obtaining reliable and objective evaluations of the trainees' performances. Here, we introduce an automated tool for assessing laparoscopic cutting performance by using image-processing algorithms. METHODS: Twenty-seven interns specializing in the fields of gynecology, urology and general surgery participated in 4-6 training sessions, in which each trainee cut a circular patch positioned inside a low-cost laparoscopic box trainer simulator. The trainees' performances were analyzed using software that we developed. The analysis of the trainees' performances was based upon quantitative measurements of the following four parameters obtained in each training session: standard deviation, circle-cutout area, skewness, and number of peaks. We believe that high performance in terms of a combination of the four parameters provides a reliable measure of good laparoscopic skills, and therefore we developed the software so as to generate, for each session, a score of a trainee's laparoscopic circle-cutout performance that results from achievements related to the four parameters in combination. RESULTS: On average, the total score of experienced interns was higher than the total score of inexperienced interns. Also, some improvement from session-to session in the scores of novice trainees was detected. CONCLUSIONS: Our proposed scoring system, which is based on various image-processing algorithms, can evaluate cutting performances of trainees and classify residents by their experience. This allows each trainee to improve his/her performance by analyzing errors indicated by our software. PMID- 30478702 TI - Clinical presentation of intussusception in Swedish children under 3 years of age and the validity of diagnostic coding. AB - PURPOSE: Intussusception has been associated with rotavirus vaccine. The rotavirus vaccine will soon be introduced in the Swedish national immunization program. A validation of the diagnosis of intussusception among Swedish children in the Swedish National Patient Register is needed, as a basis for future vaccine safety surveillance by Swedish registers. METHODS: This diagnostic study reviewed the medical admission records of 392 Swedish children with intussusception from 1987 to 2013. The records were randomly selected by The National Board of Health and Welfare from all Sweden and from both pediatric and pediatric surgery care. Positive predictive values (PPV) were calculated to study the concordance between the diagnosis coded in the Swedish Patient Register and the accepted international criteria of case definitions. RESULTS: The PPV for a definitive diagnosis, based on certain radiology findings or surgery, was 84%. When clinically probable cases were added the PPV was 87%. When cases of possible intussusception were added the PPV was 89%. The PPV for the 240 children under 1 year was 88%. CONCLUSION: Swedish health care registers can be used in the evaluation of incidences of intussusception when rotavirus vaccine will be introduced, due to a high validity of the diagnosis of intussusception in the registers. PMID- 30478703 TI - Autonomic dysfunction and HPV immunization: an overview. AB - This article reviews the case series reported from several countries describing patients with suspected severe side effects to the HPV vaccines. The described symptom clusters are remarkably similar and include disabling fatigue, headache, widespread pain, fainting, gastrointestinal dysmotility, limb weakness, memory impairment episodes of altered awareness, and abnormal movements. This constellation of symptoms and signs has been labeled with different diagnoses such as complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), small fiber neuropathy (SFN), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), or fibromyalgia. It is known that autoimmunity and autoantibodies are present in a subset of patients with CRPS, POTS, SFN, ME/CFS, and fibromyalgia. This article proposes that vaccine-triggered, immune-mediated autonomic dysfunction could lead to the development of de novo post-HPV vaccination syndrome possibly in genetically susceptible individuals. Being cognizant that a temporal relationship between vaccination and symptom onset does not necessarily equate to causality, mounting evidence of case series calls for well-designed case-control studies to determine the prevalence and possible causation between these symptom clusters and HPV vaccines. Since personalized medicine is gaining momentum, the use of adversomics and pharmacogenetics may eventually help identify individuals who are predisposed to HPV vaccine adverse events. PMID- 30478704 TI - Development of microsatellite markers and analysis of genetic diversity of Barbatia virescens in the southern coasts of China. AB - BACKGROUND: The blood clam Barbatia virescens is an ecologically and economically important species in the southern coast of China. Understanding of the genetic structure of B. virescens populations is vital to breeding strategies and conservation programs. OBJECTIVE: To develop and characterize a set of microsatellites loci primers for B. virescens, and provide helpful information for reasonable utilization and protection of B. virescens natural resources. METHODS: The microsatellites of B. virescens were detected using a RAD-seq approach based on an Illumina sequencing platform. For the test of microsatellite development, we calculated the number of alleles (Na), observed heterozygosities (Ho), expected heterozygosities (He) and exact tests for deviations from Hardy Weinberg equilibrium (HWE). Twelve polymorphic loci were used to access the genetic diversity and population structure of four B. virescens populations. RESULTS: In this study, 50,729 microsatellites of B. virescens were detected. Twenty-two polymorphic microsatellite loci were developed for B. virescens. The number of alleles per locus ranged from 6 to 15, and expected heterozygosities varied from 0. 567 to 0.911. All the PIC values of the 22 loci were greater than 0.5, indicating that these markers were highly informative for further genetic analysis. Twelve loci were selected to analyze genetic diversity and population structure of four B. virescens populations collected from different geographical regions along the southern coast of China. The results showed moderate to high levels of genetic diversity in the four populations (mean Ar = 7.756-8.133; mean Ho = 0.575-0.639; mean He = 0.754-0.775). Pairwise FST estimates indicated that there was significant divergence among the four populations. CONCLUSION: This study not only provides a large scale of sequence information of microsatellites which are valuable for future genetic mapping, trait association and kinship among B. virescens, but also offers useful information for the sustainable management of natural stocks and the development of breeding industry of B. virescens. PMID- 30478705 TI - Retraction Note to: An assessment of transgenomics as a tool for gene discovery in Populus euphratica Oliv. AB - This article (Zhou et al. 2018) has been retracted by the authors because the sequence BIBAC 002A111F06 was incorrectly assigned to the wrong bacterial species. The BIBAC 002A111F06 sequence (GenBank Accession KC129717) reported in the paper was attributed to Populus euphratica Oliv. The BLAST search of this KC129717 sequence against the nr database at NCBI showed that it has very high similarity to a genomic sequence from the gram-negative bacteria Stenotrophomonas maltophilia. The bacterium associates with Populus euphratica Oliv. and DNA isolated from Populus euphratica Oliv. for the construction of the BIBAC clone library inlcuded DNA from Stenotrophomonas maltophilia. Therefore, the phenotype of the transgenic Arabidopsis line carrying the KC129717 sequence cannot be attributed to genes from Populus euphratica Oliv. The authors apologize for the confusion and misinterpretation of our data resulting from the incorrect sequence assignment. All authors agree to this retraction. PMID- 30478707 TI - Judith Bradford (1943-2017): Tribute to a Luminary. PMID- 30478706 TI - The Role of Age and Homonegativity in Racial or Ethnic Partner Preferences Among Australian Gay and Bisexual Men. AB - We investigated the racial or ethnic partner preferences among Australian gay and bisexual men (GBM) as part of a large study of sexual preferences among GBM, to identify whether racial bias was a factor in how GBM expressed their partner preferences. We surveyed 1853 Australian GBM about their partner preferences and preferred sex practices. We used logistic regression to identify whether factors such as age, gay social engagement, or men's own ethnicity or race were associated with ethnic and racial partner preferences. Mean age was 34.8 years. Ethnic or racial background included: white or "Caucasian" (86.6%), Australian Aboriginal (2.7%), and Asian (6.6%). Mean attraction scores were highest for "Caucasian" men, and lowest for Aboriginal and Asian men. Under half (41.6%) were attracted to all racial or ethnic types; 7.7% were only attracted to "Caucasian" men. Being older and lower homonegativity scores were independently associated with finding all ethnic and racial types attractive. Being attracted only to "Caucasian" men was associated with younger age. Mental health was not associated with ethnic or racial partner preferences. Although men more commonly found most racial or ethnic types attractive, racial biases in partner selection were more evident among younger men, and among those who were less comfortable with their own sexuality. Addressing anti-gay stigma and broader exposure to gay community subcultures may be as important in countering racial bias. PMID- 30478708 TI - Caring for the critically ill patients over 80: a narrative review. AB - BACKGROUND: There is currently no international recommendation for the admission or treatment of the critically ill older patients over 80 years of age in the intensive care unit (ICU), and there is no valid prognostic severity score that includes specific geriatric assessments. MAIN BODY: In this review, we report recent literature focusing on older critically ill patients in order to help physicians in the multiple-step decision-making process. It is unclear under what conditions older patients may benefit from ICU admission. Consequently, there is a wide variation in triage practices, treatment intensity levels, end-of-life practices, discharge practices and frequency of geriatrician's involvement among institutions and clinicians. In this review, we discuss important steps in caring for critically ill older patients, from the triage to long-term outcome, with a focus on specific conditions in the very old patients. CONCLUSION: According to previous considerations, we provide an algorithm presented as a guide to aid in the decision-making process for the caring of the critically ill older patients. PMID- 30478709 TI - The effect of different light regimes on pigments in Coscinodiscus granii. AB - The influence of six different light regimes throughout the photosynthetically active radiation range (from 400 to 700 nm, including blue, green, yellow, red orange, red, and white) at two intensities (100 and 300 umol photons m-2 s-1) on pigmentation was assessed for the centric marine diatom Coscinodiscus granii for the first time. Chlorophyll (Chl) a and fucoxanthin were the dominating pigments in all treatments. The cellular concentrations of light harvesting pigment (Chl a, Chl c1 + c2, and fucoxanthin) were higher at 100 than at 300 umol photons m-2 s-1 at all wavelengths, with the largest increases at red and blue light. The normalized concentrations of photoprotective pigments (violaxanthin, zeaxanthin, diadinoxanthin, and diatoxanthin) were higher at high light intensity than in cells grown at low light intensity. An increase in beta-carotene in low light conditions is expected as the increased Chl a was related to increased photosynthetic subunits which require beta-carotene (bound to photosystem core). At 300 umol photons m-2 s-1, yellow light resulted in significantly lower concentration of most of the detected pigments than the other wavelengths. At 100 umol photons m-2 s-1, W and B light led to statistically lower and higher concentration of most of the detected pigments than the other wavelengths, respectively. PMID- 30478710 TI - Thomas John Wydrzynski (8 July 1947-16 March 2018). AB - With this Tribute, we remember and honor Thomas John (Tom) Wydrzynski. Tom was a highly innovative, independent and committed researcher, who had, early in his career, defined his life-long research goal. He was committed to understand how Photosystem II produces molecular oxygen from water, using the energy of sunlight, and to apply this knowledge towards making artificial systems. In this tribute, we summarize his research journey, which involved working on 'soft money' in several laboratories around the world for many years, as well as his research achievements. We also reflect upon his approach to life, science and student supervision, as we perceive it. Tom was not only a thoughtful scientist that inspired many to enter this field of research, but also a wonderful supervisor and friend, who is deeply missed (see footnote*). PMID- 30478711 TI - Time-resolved fluorescence measurements on leaves: principles and recent developments. AB - Photosynthesis starts when a pigment in the photosynthetic antennae absorbs a photon. The electronic excitation energy is then transferred through the network of light-harvesting pigments to special chlorophyll (Chl) molecules in the reaction centres, where electron transfer is initiated. Energy transfer and primary electron transfer processes take place on timescales ranging from femtoseconds to nanoseconds, and can be monitored in real time via time-resolved fluorescence spectroscopy. This method is widely used for measurements on unicellular photosynthetic organisms, isolated photosynthetic membranes, and individual complexes. Measurements on intact leaves remain a challenge due to their high structural heterogeneity, high scattering, and high optical density, which can lead to optical artefacts. However, detailed information on the dynamics of these early steps, and the underlying structure-function relationships, is highly informative and urgently required in order to get deeper insights into the physiological regulation mechanisms of primary photosynthesis. Here, we describe a current methodology of time-resolved fluorescence measurements on intact leaves in the picosecond to nanosecond time range. Principles of fluorescence measurements on intact leaves, possible sources of alterations of fluorescence kinetics and the ways to overcome them are addressed. We also describe how our understanding of the organisation and function of photosynthetic proteins and energy flow dynamics in intact leaves can be enriched through the application of time-resolved fluorescence spectroscopy on leaves. For that, an example of a measurement on Zea mays leaves is presented. PMID- 30478712 TI - Clipping of a superior hypophyseal artery aneurysm during endoscopic transnasal removal of a Rathke cleft cyst: a case report. AB - The concomitant presence of an aneurysm in contact with a sellar lesion usually contraindicates a transsphenoidal approach (TSS). Clipping of an intracranial aneurysm is however possible in highly selected cases also through an endoscopic TSS approach, as long as the basic principles of cerebrovascular surgery are respected. We report thus on a case of a patient harboring a Rathke cleft cyst (RCC) and an aneurysm of the carotid artery (ICA) in close contact with the RCC. The anatomical characteristics of both lesions warranted an endoscopic TSS for removal of the RCC and clipping of the aneurysm during the same approach. PMID- 30478713 TI - An improved variable selection procedure for adaptive Lasso in high-dimensional survival analysis. AB - Motivated by high-dimensional genomic studies, we develop an improved procedure for adaptive Lasso in high-dimensional survival analysis. The proposed procedure effectively reduces the false discoveries while successfully maintaining the false negative proportions, which improves the existing adaptive Lasso procedures. The implementation of the proposed procedure is straightforward and it is sufficiently flexible to accommodate large-scale problems where traditional procedures are impractical. To quantify the uncertainty of variable selection and control the family-wise error rate, a multiple sample-splitting based testing algorithm is developed. The practical utility of the proposed procedure are examined through simulation studies. The methods developed are then applied to a multiple myeloma data set. PMID- 30478714 TI - Genetic Modifiers of Fetal Haemoglobin in Sickle Cell Disease. AB - Fetal haemoglobin (HbF) levels have a clinically beneficial effect on sickle cell disease (SCD). Patients with SCD demonstrate extreme variability in HbF levels (1 30%), a large part of which is likely genetically determined. The main genetic modifier loci for HbF persistence, HBS1L-MYB, BCL11A and the beta-globin gene cluster in adults also act in SCD patients. Their effects are, however, modified significantly by a disease pathology that includes a drastically shortened erythrocyte lifespan with an enhanced survival of those red blood cells that carry HbF (F cells). We propose a model of how HbF modifier genes and disease pathology interact to shape HbF levels measured in patients. We review current knowledge on the action of these loci in SCD, their genetic architecture, and their putative functional components. At each locus, one strong candidate for a causative, functional DNA change has been proposed: Xmn1-HBG2 at the beta-globin cluster, rs1427407 at BCL11A and the 3 bp deletion rs66650371 at HBS1L-MYB. These, however, explain only part of the impact of these loci and additional variants are yet to be identified. Further progress in understanding the genetic control of HbF levels requires that confounding factors inherent in SCD, such as ethnic complexity, the role of F cells and the influence of drugs, are suitably addressed. This will depend on international collaboration and on large, well characterised patient cohorts with genome-wide single-nucleotide polymorphism or sequence data. PMID- 30478715 TI - Innovative Therapies for Cystic Fibrosis: The Road from Treatment to Cure. AB - Cystic fibrosis (CF), a life-threatening multiorgan genetic disease, is facing a new era of research and development using innovative gene-directed personalized therapies. The priority organ to cure is the lung, which suffers recurrent and chronic bacterial infection and inflammation since infancy, representing the main cause of morbidity and precocious mortality of these individuals. After the disappointing failure of gene-replacement approaches using gene therapy vectors, no single drug is presently available to repair all the CF gene defects. The impressive number of different CF gene mutations is now tackled with different chemical and biotechnological tools tailored to the specific molecular derangements, thanks to the extensive knowledge acquired over many years on the mechanisms of CF cell and organ pathology. This review provides an overview and recalls both the successes and limitations of the different experimental approaches, such as high-throughput screening on chemical libraries to discover CF gene correctors and potentiators, dual-acting compounds, read-through molecules, splicing defect repairing tools, cystic fibrosis transmembrane conductance regulator (CFTR) "amplifiers," CFTR interactome modulators and the first gene editing attempts. PMID- 30478716 TI - The effects of microdose LSD on time perception: a randomised, double-blind, placebo-controlled trial. AB - RATIONALE: Previous research demonstrating that lysergic acid diethylamide (LSD) produces alterations in time perception has implications for its impact on conscious states and a range of psychological functions that necessitate precise interval timing. However, interpretation of this research is hindered by methodological limitations and an inability to dissociate direct neurochemical effects on interval timing from indirect effects attributable to altered states of consciousness. METHODS: We conducted a randomised, double-blind, placebo controlled study contrasting oral administration of placebo with three microdoses of LSD (5, 10, and 20 MUg) in older adults. Subjective drug effects were regularly recorded and interval timing was assessed using a temporal reproduction task spanning subsecond and suprasecond intervals. RESULTS: LSD conditions were not associated with any robust changes in self-report indices of perception, mentation, or concentration. LSD reliably produced over-reproduction of temporal intervals of 2000 ms and longer with these effects most pronounced in the 10 MUg dose condition. Hierarchical regression analyses indicated that LSD-mediated over reproduction was independent of marginal differences in self-reported drug effects across conditions. CONCLUSIONS: These results suggest that microdose LSD produces temporal dilation of suprasecond intervals in the absence of subjective alterations of consciousness. PMID- 30478717 TI - Biomass allometric equation and expansion factor for a mountain moist evergreen forest in Mozambique. AB - BACKGROUND: Worldwide, forests are an important carbon sink and thus are key to mitigate the effects of climate change. Mountain moist evergreen forests in Mozambique are threatened by agricultural expansion, uncontrolled logging, and firewood collection, thus compromising their role in carbon sequestration. There is lack of local tools for above-ground biomass (AGB) estimation of mountain moist evergreen forest, hence carbon emissions from deforestation and forest degradation are not adequately known. This study aimed to develop biomass allometric equations (BAE) and biomass expansion factor (BEF) for the estimation of total above-ground carbon stock in mountain moist evergreen forest. METHODS: The destructive method was used, whereby 39 trees were felled and measured for diameter at breast height (DBH), total height and the commercial height. We determined the wood basic density, the total dry weight and merchantable timber volume by Smalian's formula. Six biomass allometric models were fitted using non linear least square regression. The BEF was determined based on the relationship between bole stem dry weight and total dry weight of the tree. To estimate the mean AGB of the forest, a forest inventory was conducted using 27 temporary square plots. The applicability of Marzoli's volume equation was compared with Smalian's volume equation in order to check whether Marzoli's volume from national forest inventory can be used to predict AGB using BEF. RESULTS: The best model was the power model with only DBH as predictor variable, which provided an estimated mean AGB of 291 +/- 141 Mg ha-1 (mean +/- 95% confidence level). The mean wood basic density of sampled trees was 0.715 +/- 0.182 g cm-3. The average BEF was of 2.05 +/- 0.15 and the estimated mean AGB of 387 +/- 126 Mg ha-1. The BAE from miombo woodland within the vicinity of the study area underestimates the AGB for all sampled trees. Chave et al.'s pantropical equation of moist forest did not fit to the Moribane Forest Reserve, while Brown's equation of moist forest had a good fit to the Moribane Forest Reserve, having generated 1.2% of bias, very close to that generated by the selected model of this study. BEF showed to be reliable when combined with stand mean volume from Marzoli's National Forestry Inventory equation. CONCLUSION: The BAE and the BEF function developed in this study can be used to estimate the AGB of the mountain moist evergreen forests at Moribane Forest Reserve in Mozambique. However, the use of the biomass allometric model should be preferable when DBH information is available. PMID- 30478718 TI - A case of functional dystonia: clinical cues to differentiate between organic and functional dystonia. PMID- 30478719 TI - Influential factors and clinical significance of an atypical presentation of posterior reversible encephalopathy syndrome in patients with eclampsia. AB - BACKGROUND AND PURPOSE: Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiologic entity for which eclampsia is one of the most common predisposing conditions. Despite the imaging changes typically reported, the predisposing factors and clinical implications of atypical presentations have yet to be fully clarified. METHODS: A total of 56 patients with PRES were selected for study. Demographic, clinical, and laboratory data were analyzed, focusing on atypical presentations of PRES. Multiple logistic regression was applied to identify factors impacting such atypical presentations, and functional outcomes were assessed upon patient discharge. RESULTS: Overall, 22 of the 56 patients (39.3%) displayed features of atypical PRES. By multiple logistic regression, headache (OR = 5.39; 95% CI, 1.24-23.51; p = 0.025) and frequent convulsions (OR = 4.41; 95% CI, 1.09-17.91; p = 0.038) proved to be independent factors associated with atypical PRES. Ultimately, outcomes of 18 patients were gauged as poor, based on the modified Rankin Scale (mRS). Logistic regression indicated that visual disturbances (OR = 9.02; 95% CI, 1.37-59.35; p = 0.02), frequent convulsions (OR = 9.47; 95% CI, 1.67-53.63; p = 0.01), and restricted diffusion on imaging (OR = 11.96; 95% CI, 1.76-81.11; p = 0.01) were independently associated with poor outcomes in patients with eclampsia-related PRES. CONCLUSION: Headache and frequent convulsions are independently associated with atypical presentations of PRES. If present, restricted diffusion may help in predicting poor outcomes of such patients upon discharge. PMID- 30478720 TI - Immunocytochemistry Based on a Cell-Type-Specific Aptamer for Rapid Immunostaining of Adenocarcinoma Cells in Clinical Serosal Fluids. AB - All too often, conventional immunocytochemistry (ICC) via an antibody on cytological samples is limited to a few smears due to scant cellularity. To circumvent these limitations, this study employed a cell-type-specific aptamer as the core tool in ICC protocols for a timely and highly specific ICC diagnosis. S6, an aptamer against A549 lung carcinoma cells, was adopted instead of antibodies in this study for differentiating cancer cells in serosal fluids. Here, we developed three different strategies for discriminating the adenocarcinoma cells in effusion cytology specimens using the S6 aptamer in ICC. These strategies included a biotin-labeled S6 aptamer, an FAM-labeled S6 aptamer, and an activatable S6 aptamer. A total of 112 serosal fluid specimens with known diagnoses were evaluated by all three modes of use of the S6 aptamer. ICC procedures based on biotin-labeled or FAM-labeled S6 aptamers required time consuming washing to avoid interference from nonspecific adsorption. ICC procedures based on an activatable S6 aptamer probe showed a weak fluorescence signal in the absence of target cells, but the procedures showed a strong fluorescence signal due to alteration of the conformation without any complicated washing steps, in the presence of targets. The specificity and sensitivity are higher in all three different ICC protocols based on the S6 aptamer than those for antibody protocols for differentiating adenocarcinoma cells in clinical effusion cytology. ICC based on cell-type-specific aptamers, instead of on a panel of a set of antibodies, is promising as an auxiliary method for the diagnosis of cancer. PMID- 30478721 TI - Correction to: Direct oral anticoagulants for the treatment of venous thromboembolism in patients with active malignancy: a systematic review and meta analysis. AB - Unfortunately the author list in the original article is incomplete. The correct list of contributing authors is given in this Correction. PMID- 30478722 TI - Increased risk of heparin induced thrombocytopenia and thrombosis in patients with essential thrombocythemia carrying the homozygous JAK2 V617F mutation. PMID- 30478723 TI - Fluid sequestration is a useful parameter in the early identification of severe disease of acute pancreatitis. AB - BACKGROUND: Early identification of severe disease of acute pancreatitis (AP) is of critical importance to improve the prognosis. Fluid sequestration (FS), calculated from administrated fluid and fluid output, is a simple prognostic parameter. We examined its utility in the early phase of AP. METHODS: We retrospectively investigated AP patients between January 2009 and April 2017. We compared FS in the first 24 h (FS24) with FS in the first 48 h (FS48) and administrated fluid volume within the first 24 h (FV24). Diagnostic yield for predicting intensive care unit (ICU) admission and persistent organ failure (POF) was assessed using receiver operating characteristic curves. We also evaluated risk factors for developing severe disease of AP. RESULTS: A total of 400 AP patients were included in the analysis (median age 64 years; male 60%). According to the Japanese severity criteria, 158 patients (40%) were diagnosed as severe disease. The rates of mortality, ICU admission and POF were 0.8%, 4.5% and 7.3%, respectively. FS24 showed a similar predictive accuracy in comparison with FS48 and was superior to FV24 in predicting ICU admission and POF. FS24 >= 1.6 L, male sex, presence of systemic inflammatory response syndrome and computed tomography severity index >= 3 on admission were independent risk factors for disease progression in AP in the multivariate analysis. CONCLUSIONS: FS24 was a simple and easily calculated parameter with high predictive accuracy for discriminating patients who needed intensive care. Patients with FS24 >= 1.6 L had an increased risk of developing severe disease. PMID- 30478724 TI - Characterization of fungal dysbiosis in Japanese patients with inflammatory bowel disease. AB - BACKGROUND AND AIMS: There are no previous reports describing the fecal fungal microbiome of a Japanese population using advanced molecular techniques. In this study, we performed a molecular analysis on the fungal microbial community of a healthy Japanese population and patients with inflammatory bowel diseases (IBDs). PATIENTS AND METHODS: Fecal samples were obtained from 18 patients with inactive ulcerative colitis (UC, n = 18), Crohn's disease (CD, n = 20) and healthy volunteers (n = 20). Bacterial and fungal microbiome was analyzed by sequencing of 16S rRNA and the internal transcribed spacer (ITS) region, respectively. RESULTS: 16S rRNA sequencing of the bacterial microbiome revealed that the alpha diversity indicated by the Chao-1 and Shannon indices was significantly lower in CD patients compared to healthy controls and/or UC patients. Principal coordinate (PCo) analysis of the bacterial community revealed significant structural differences in microbiome among healthy controls, UC and CD patients (PERMANOVA P = 0.0001). ITS sequencing of the fungal microbiome indicated no significant differences in alpha-diversity between healthy controls and IBD patients. However, the overall structure of the fungal microbial community of CD patients was significantly different from those of healthy controls and UC patients (PERMANOVA = 0.03). At the genus level, the genus Saccharomyces was dominant and this was followed by the genus Sarocladium in healthy controls. The abundance of the genus Candida was significantly higher in CD patients than healthy controls and/or UC patients. CONCLUSION: The fecal fungal microbiome of a Japanese population differed considerably from that of a Western population. We identified fungal dysbiosis in Japanese patients with IBD. PMID- 30478725 TI - Correction to: Varilactones and wortmannilactones produced by Penicillium variabile cultured with histone deacetylase inhibitor. AB - The author would like to include conflict of interest statement of the online published article. The correct conflict of interest statement should read as. PMID- 30478726 TI - Morbidity and mortality of Hispanic trauma patients with diabetes mellitus. AB - PURPOSE: DM and trauma are leading causes of death in Hispanic patients, yet the interaction between them remains obscure. We aimed to assess the complications and in-hospital mortality rate of Hispanic diabetic trauma patients. METHODS: A retrospective cohort study was carried out using data from the Puerto Rico Trauma Hospital databank. Patients were matched based on gender, age, mechanism of injury, Glasgow Coma Scale, and Injury Severity Score using propensity-score matching. From 2000 to 2014, a total of 1134 patients with DM were compared to 1134 patients who did not have DM. The outcomes measured were hospital and TICU lengths of stay, days on mechanical ventilation, complications, and in-hospital mortality rate. A logistic regression model was carried out to evaluate the relationship of DM with complications and mortality after trauma. RESULTS: Hispanic patients with DM had longer hospital and TICU stays and required mechanical ventilation for extended periods. Complications, predominantly of an infectious nature, were more common among DM patients than they were among non-DM patients: 31.3% in the DM group vs. 11.6% in the non-DM group (OR 3.46; 95% CI 2.77-4.31). Despite an increase in the number of complications, DM was not associated with higher in-hospital mortality rates. CONCLUSIONS: DM is associated with a twofold increase in complications in Hispanic diabetic trauma patients, which may account for their longer hospital and TICU stays. This indicates that diabetic Hispanic trauma patients may need earlier and more aggressive intervention to reduce their risk of developing complications. PMID- 30478727 TI - Population and oenological characteristics of non-Saccharomyces yeasts associated with grapes of Northwestern Argentina. AB - Yeasts population associated with grapes from Northwest Argentina, a region with a significant vine-growing increase over the past years, was evaluated. Ten species of non-Saccharomyces yeasts were identified from four grape varieties (Malbec, Merlot, Syrah and Torrontes) being Hanseniaspora uvarum the dominant species. Typing of isolates revealed genetic variability within Hanseniaspora genus and also high variability was observed according to their oenological characteristics. Based on the oenological properties, the most adequate strains as starter cultures were H. uvarum HuT7, HuMe15, HuS16, H. vineae HvT-mc1 and Metschnikowia pulcherrima MpT2/MpT3. These selected yeasts exhibited moderate resistance to SO2, reduced values of volatile acidity, null or low production of H2S, high levels of enzymes related to aroma and did not produce killer toxins. Further studies using mixed cultures of these non-Saccharomyces strains and S. cerevisiae are needed to validate the contribution of selected indigenous yeasts on wine organoleptic characteristics. PMID- 30478728 TI - Transcriptome and metabolome analysis of Pichia stipitis to three representative lignocellulosic inhibitors. AB - During the bioconversion of xylose to ethanol, Pichia stipitis cells are often inhibited by substances generated in the lignocellulosic hydrolysate. However, the response mechanism of P. stipitis to inhibitors has not been completely understood till date. With this aim, integrated transcriptomic and metabolomic analyses were performed on P. stipitis to investigate the interactive effects of three representative inhibitors [vanillin, 5-hydroxymethylfurfural (5-HMF), and acetic acid] present in lignocellulosic hydrolysates. The genes involved in carbohydrate metabolism were observed to significantly down-regulated in the presence of the three combined inhibitors in both lag and middle exponential phases. In addition, inhibitor addition induced amino acid metabolism (e.g., glutamine and asparagine syntheses), since the yeast cells required more amino acids in stressful conditions. The metabolomic analysis yielded similar results, particularly those related with the analysis of metabolic biomarkers including fatty acids, amino acids, and sugars. 70 intracellular metabolites were detected by gas chromatography coupled with mass spectrometry (GC-MS), and samples from different phases were clearly separated by principal component analysis (PCA). The large amount of specific responsive genes and metabolites highlighted the complex regulatory mechanisms involved in the fermentation process in the presence of the three combined inhibitors. PMID- 30478730 TI - Cold survival strategies for bacteria, recent advancement and potential industrial applications. AB - Microorganisms have evolved themselves to thrive under various extreme environmental conditions such as extremely high or low temperature, alkalinity, and salinity. These microorganisms adapted several metabolic processes to survive and reproduce efficiently under such extreme environments. As the major proportion of earth is covered with the cold environment and is exploited by human beings, these sites are not pristine anymore. Human interventions are a great reason for disturbing the natural biogeochemical cycles in these regions. The survival strategies of these organisms have shown great potential for helping us to restore these pristine sites and the use of isolated cold-adapted enzymes from these organisms has also revolutionized various industrial products. This review gives you the insight of psychrophilic enzyme adaptations and their industrial applications. PMID- 30478729 TI - Pseudomonas humi sp. nov., isolated from leaf soil. AB - An aerobic, Gram-negative, non-sporulating, motile, rod-shaped and lignin degrading bacterial strain, Pseudomonas sp. CCA1, was isolated from leaf soil collected in Japan. This strain grew at 20-45 degrees C (optimum 20 degrees C), at pH 5.0-10.0 (optimum pH 5.0), and in the presence of 2% NaCl. Its major cellular fatty acids were C16:0 and summed feature 8 (C18:1omega6c and/or C18:1omega7c). The predominant quinone system was ubiquinone-9. Comparative 16S rRNA gene sequence analysis showed that Pseudomonas sp. CCA1 was related most closely to P. citronellolis NBRC 103043T (98.9%), but multilocus sequence analysis based on fragments of the atpD, gyrA, gyrB and rpoB gene sequences showed strain CCA1 to branch separately from its most closely related Pseudomonas type strains. DNA-DNA hybridization values between Pseudomonas sp. CCA1 and type strains of closely related Pseudomonas species were less than 53%. Based on its phenotypic, chemotaxonomic and phylogenetic features, we propose that Pseudomonas sp. CCA1 represents a novel species within the genus Pseudomonas, for which the name Pseudomonas humi sp. nov. is proposed. The type strain is CCA1 (= HUT 8136T = TBRC 8616T). PMID- 30478731 TI - Protection of the kidney with sodium-glucose cotransporter 2 inhibitors: potential mechanisms raised by the large-scaled randomized control trials. AB - This communication provides a current overview on the renal protective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in diabetics. Following the epoch-making publications, the CANVAS Program and the EMPA-REG OUTCOME trial, numerous literature has discussed the mechanisms by which SGLT2 inhibition exerts its cardio-renal protective effects. Some of them reached agreement, while others did not. This review focuses on the hemodynamic aspect and the remaining potential factors relevant to the renal protection which have not been so much taken up by other review papers. Questions unanswered include factors of uric acid, lipids, erythropoiesis and oxidative stress, salt and sympathetic nerve, and the Na-H exchanger in heart and kidney. PMID- 30478732 TI - Fatal deer attack in a rutting season. AB - Animal inflicted fatal or near fatal injuries are well described in the forensic literature, with the most frequently described cases involving dogs, large cats and bears. To our knowledge, a deer inflicted fatality has not been described in the forensic literature previously. This article reports a case of a 64-year-old male, who was found lying in a pool of blood near an enclosure for stags and hinds at the end of October. There were mechanical defects on his jacket and trousers, which appeared to be torn or penetrated, as well as multiple lacerations and stab wounds in different parts of his body. The type and location of the injuries the man had sustained strongly suggested that another person had been involved in the incident that had led to his death. The cause of death was deemed as external exsanguination due to multiple stab wounds to large vessels. After evaluating all of the information regarding the circumstances around the death, the case was classified as a deer attack related fatality, and the manner of death was determined to be accidental. The man was most probably attacked by one of the deer while he was refilling the animal feeder. A substantial increase in the levels of selected hormones, especially testosterone, during the rutting season explains the increased levels of aggression shown by the deer that led to a fatal outcome for the decedent. PMID- 30478733 TI - Current scenario and future strategies to fight artemisinin resistance. AB - Despite several setbacks in the fight against malaria such as insecticide and drug resistance as well as low efficacy of available vaccines, considerable success in reducing malaria burden has been achieved in the past decade. Artemisinins (ARTs and their combination therapies, ACTs), the current frontline drugs against uncomplicated malaria, rapidly kill plasmodial parasites and are non-toxic at short exposures. Though the exact mode of action remains unclear, the endoperoxide bridge, indispensable for ART activity, is thought to react with heme released from hemoglobin hydrolysis and generate free radicals that alkylate multiple protein targets, thereby disrupting proteostasis pathways. However, rapid development of ART resistance in recent years with no potential alternatives on the horizon threaten the elimination efforts. The Greater Mekong Subregion in South-East Asia continues to churn out mutants resistant to multiple ACTs and detected in increasingly expanding geographies. Extensive research on ART-resistant strains have identified a potential candidate Kelch13, crucial for mediating ART resistance. Parasites with mutations in the propeller domains of Plasmodium falciparum Kelch13 protein were shown to have enhanced phosphatidylinositol 3-kinase levels that were concomitant with delayed parasite clearance. Current research focused on understanding the mechanism of Kelch13 mediated ART resistance could provide better insights into Plasmodium resistome. This review covers the current proposed mechanisms of ART activity, resistance strategies adopted by the parasite in response to ACTs and possible future approaches to mitigate the spread of resistance from South-East Asia. PMID- 30478734 TI - NMDA Antagonists for Treatment-Resistant Depression. AB - Fifteen to thirty percent of patients with major depressive disorder do not respond to antidepressants that target the monoaminergic systems. NMDA antagonists are currently being actively investigated as a treatment for these patients. Ketamine is the most widely studied of the compounds. A brief infusion of a low dose of this agent produces rapid improvement in depressive symptoms that lasts for several days. The improvement occurs after the agent has produced its well characterized psychotomimetic and cognitive side effects. Multiple infusions of the agent (e.g., 2-3* per week for several weeks) provide relief from depressive symptoms, but the symptoms reoccur once the treatment has been stopped. A 96-h infusion of a higher dose using add-on clonidine to mitigate the psychotomimetic effects appears to also provide relief and resulted in about 40% of the subjects still having a good response 8 weeks after the infusion. As this was a pilot study, additional work is needed to confirm and extend this finding. Nitrous oxide also has had positive results. Of the other investigational agents, CERC-301 and rapastinel remain in clinical development. When careful monitoring of neuropsychiatric symptoms has been conducted, these agents all produce similar side effects in the same dose range, indicating that NMDA receptor blockade produces both the wanted and unwanted effects. Research is still needed to determine the appropriate dose, schedule, and ways to mitigate against unwanted side effects of NMDA receptor blockade. These hurdles need to be overcome before ketamine and similar agents can be prescribed routinely to patients. PMID- 30478735 TI - Self-Experiments with Psychoactive Substances: A Historical Perspective. AB - The purpose of this chapter is to highlight the rich tradition of self experiments (SEs) with psychoactive substances carried out by scientists and therapists for more than a century. Scientifically inspired controlled SEs dominated until the end of the twentieth century, when ethical requirements minimized controlled SEs and "wild" SEs expanded particularly with the emergence of new psychoactive substances. The review focuses on laughing gas (nitrous oxide), cannabis, cocaine, hallucinogens, entactogens, and dissociative hallucinogens. This is due to the fact that substances that induce "complex" effects such as alteration of space/time experience, ego dissolution, and increased feelings and insights (e.g., hallucinogens, entactogens) represent by far the majority of SEs, whereas SEs with substances inducing "simple" effects such as euphoria, anxiolysis, dissociation, or emotional blunting (e.g., cocaine, opioids) are much rarer or even absent (e.g., benzodiazepines). Complex drug effects are much harder to describe, thus allowing SEs to fulfill a more important function.SEs with psychoactive drugs appeared to emerge in the mid eighteenth century, which triggered a long-standing tradition throughout the nineteenth and early twentieth century. SEs have been de facto performed for a variety of reasons, ranging from establishing scientific knowledge and gaining philosophical insights to compensating for personal deficits. Self-experimenters can be divided into two general types. Besides their scientific intentions, "exploratory" self-experimenters intend to expand awareness and insight, whereas "compensatory" self-experimenters might aim for coping with psychiatric symptoms or personality deficits. Scientific limitations of SEs are obvious when compared to double-blind, randomized, placebo-controlled trials. Whereas the former might lead to more "realistic" detailed description of subjective effects, the latter lead to more solid results in respect to objectively measurable "average" effects. Possible adverse effects of SEs were identified that resulted in loss of scientific objectivity and decreased control over substance use and addiction, development of isolation, problematic group dynamics, and "social autism." PMID- 30478736 TI - Regulatory Small and Long Noncoding RNAs in Brite/Brown Adipose Tissue. AB - Brite/brown adipose tissue (BAT) is a thermogenic tissue able to dissipate energy via non-shivering thermogenesis. It is naturally activated by cold and has been demonstrated to increase thermogenic capacity, elevate energy expenditure, and to ultimately contribute to fat mass reduction. Thus, it emerges as novel therapeutic concept for pharmacological intervention in obesity and other metabolic disorders. Therefore, the comprehensive understanding of the regulatory network in thermogenic adipocytes is in demand.The surprising findings that (1) all human protein-coding genes make up not more than 2% of our genome, (2) organismal complexity goes well along with the percentage of nonprotein-coding sequences, and that (3) three quarters of our genome are pervasively transcribed, provide evidence that noncoding RNAs (ncRNAs) are not junk, but a significant and even predominant part of our transcriptome representing a treasure chest worth retrieving regulatory determinants in biological processes and diseases.In this chapter, the impact of regulatory small and long ncRNAs (lncRNAs) in particular microRNAs and lncRNAs on BAT formation and metabolic function and their involvement in physiological and pathological conditions has been reviewed. PMID- 30478737 TI - Exploring the Therapeutic Landscape of Sphingomyelinases. AB - Sphingosine, ceramide, sphingosine-1-phosphate, and other related sphingolipids have emerged as important bioactive molecules involved in a variety of key cellular processes such as cell growth, differentiation, apoptosis, exosome release, and inter- and intracellular cell communication, making the pathways of sphingolipid metabolism a key domain in maintaining cell homeostasis (Hannun and Obeid, Trends Biochem Sci 20:73-77, 1995; Hannun and Obeid, Nat Rev Mol Cell Biol 9:139-150, 2008; Kosaka et al., J Biol Chem 288:10849-10859, 2013). Various studies have determined that these pathways play a central role in regulating intracellular production of ceramide and the other bioactive sphingolipids and hence are an important component of signaling in various diseases such as cancer, diabetes, and neurodegenerative and cardiovascular diseases (Chaube et al., Biochim Biophys Acta 1821:313-323, 2012; Clarke et al., Adv Enzyme Regul 51:51 58, 2011b; Horres and Hannun, Neurochem Res 37:1137-1149, 2012). In this chapter, we discuss one of the major enzyme classes in producing ceramide, sphingomyelinases (SMases), from a biochemical and structural perspective with an emphasis on their applicability as therapeutic targets. PMID- 30478738 TI - Is There an Orthographic Boost for Ambiguous Words During Their Processing? AB - The present study explores the issue of why ambiguous words are recognized faster than unambiguous ones during word recognition. To this end we contrasted two different hypotheses: the semantic feedback hypothesis (Hino and Lupker in J Exp Psychol Hum Percept Perform 22:1331-1356, 1996. https://doi.org/10.1037/0096 1523.22.6.1331 ), and the hypothesis proposed by Borowsky and Masson (J Exp Psychol Learn Mem Cognit 22:63-85, 1996. https://doi.org/10.1037/0278 7393.22.1.63 ). Although both hypotheses agree that ambiguous words benefit during recognition in that they engage more semantic activation, they disagree as to whether or not this greater semantic activation feeds back to the orthographic level, hence speeding up the orthographic coding of ambiguous words. Participants were presented with ambiguous and unambiguous words in two tasks, a lexical decision task (LDT) and a two-alternative forced-choice task (2AFC). We found differences between ambiguous and unambiguous words in both the LDT and the 2AFC tasks. These results suggest that the orthographic coding of ambiguous words is boosted during word processing. This finding lends support to the semantic feedback hypothesis. PMID- 30478739 TI - Hereditary brain tumor with a homozygous germline mutation in PMS2: pedigree analysis and prenatal screening in a family with constitutional mismatch repair deficiency (CMMRD) syndrome. AB - Precise genetic counseling and prenatal diagnosis are often hindered by incomplete penetrance of risk variance and complex patterns of inheritance. Here, we performed a clinical and genetic study of a five-generation Pakistani family with a history of multiple cases of childhood brain tumors. Six affected individuals died of brain tumors at very early ages and three were confirmed as having a homozygous mutation in exon 6 of the PMS2 gene (c.543delT). Fifteen members of the family were identified as heterozygous carriers of this mutation with a lack of cancer incidence. Both clinical manifestations and genetic test results of brain tumor patients in the family support the diagnosis of constitutional mismatch repair deficiency (CMMRD) syndrome, a condition in which individuals carry homozygous germline mutations in mismatch repair machinery genes with an early onset of malignancies such as glioma. This information was used to guide prenatal diagnosis with genetic testing on chorionic villus samples for the family. This is the first report of prenatal genetic diagnosis of hereditary brain tumor. PMID- 30478740 TI - Cadmium exposure alters steroid receptors and proinflammatory cytokine levels in endothelial cells in vitro: a potential mechanism of endocrine disruptor atherogenic effect. AB - BACKGROUND: Cadmium (Cd) is a widespread environmental pollutant that causes alterations in human health acting as endocrine disruptor. Recent data suggest that cardiovascular system might be a contamination target tissue, since Cd is found in atheromatic plaques. Thus, the purpose of this study was to evaluate the consequence of Cd exposure of endothelial cells in vitro to evaluate detrimental effect in vascular system by a potential sex-steroid hormone receptor-dependent mechanism(s). METHODS: To this aim, Human Umbilical Vein Endothelial Cells (HUVECs) were cultured and exposed to several concentrations of cadmium chloride (CdCl2) for different interval times. RESULTS: CdCl2 exposure of HUVECs induced a significant increase of ERbeta and Cyp19a1 at both mRNA and protein levels, while a drastic dose-dependent decrease of AR expression level was observed after 24 h of exposure. On the contrary, an increase of PhARser308 as well as a reduction of PhGSK-3betaser9 and PhAKTser473 was detected after 1 h treatment. This effect was consistently reduced by GSK inhibition. Furthermore, CdCl2 abolished DHT-induced cell proliferation in HUVECs suggesting an antagonist-like effect of Cd on AR mediated signaling. Remarkable, after 6 h CdCl2-treatment, a relevant increase in TNF-alpha, IL-6 and IL-8 mRNA was observed and this effect was blocked by the presence of an ERbeta-selective antagonist. Moreover, Cd-induced TxR1 overexpression, likely, correlated with the activation of p38 MAPK/NF-kappaB pathway. CONCLUSION: In conclusion, our study demonstrates for the first time that Cd alters sex-steroid hormone receptors level and activity likely affecting intracellular signaling linked to a proinflammatory state in endothelial cells. This alteration might possibly lead to endothelial cell injury and vascular dysfunction and could be a mechanism of gender-specific atherogenic damages induced by endocrine disruptors and, thus, induce atherogenic events with increased risk of cardiovascular diseases in individuals exposed to this endocrine disruptor. PMID- 30478741 TI - FK506 (tacrolimus) causes pain sensation through the activation of transient receptor potential ankyrin 1 (TRPA1) channels. AB - FK506 (tacrolimus) is an immunosuppressant widely used as an ointment in the treatment of atopic dermatitis. However, local application of FK506 can evoke burning sensations in atopic dermatitis patients, and its mechanisms are unknown. In this study, we found that FK506 activates transient receptor potential ankyrin 1 (TRPA1) channels. In Ca2+-imaging experiments, increases in intracellular Ca2+ concentrations ([Ca2+]i) by FK506 were observed in HEK293T cells expressing hTRPA1 or hTRPM8. FK506-induced currents were observed in HEK293T cells expressing hTRPA1 or mTRPA1, but less or not at all in cells expressing hTRPV1 or hTRPM8 using a patch-clamp technique. FK506 also evoked single-channel opening of hTRPA1 in an inside-out configuration. FK506-induced [Ca2+]i increases were also observed in TRPA1-expressing mouse primary sensory neurons. Furthermore, injection of FK506 evoked licking or biting behaviors and these behaviors were almost abolished in TRPA1 knockout mice. These results indicate that FK506 might cause pain sensations through TRPA1 activation. PMID- 30478742 TI - Application of transcutaneous carbon dioxide improves capillary regression of skeletal muscle in hyperglycemia. AB - The purpose of the present study was to determine the effects of transcutaneous CO2 application on the blood flow and capillary architecture of the soleus muscle in rats with streptozotocin (STZ)-induced hyperglycemia. Wistar rats were randomly divided into four groups: control, control + CO2-treated, STZ-induced hyperglycemia, and STZ-induced hyperglycemia + CO2-treated groups. Blood flow in soleus muscle increased during the transcutaneous CO2 exposure, and continued to increase for 30 min after the treatment. In addition, the transcutaneous CO2 attenuated a decrease in capillary and the expression level of eNOS and VEGF protein, and an increase in the expression level of MDM-2 and TSP-1 protein of soleus muscle due to STZ-induced hyperglycemia. These results indicate that the application of transcutaneous CO2 could improve capillary regression via the change of pro- and anti-angiogenesis factors, which might be induced by an increase in blood flow. PMID- 30478743 TI - Extending Life in Duchenne Muscular Dystrophy: Implications for Appraisals of Cost-Effectiveness. PMID- 30478744 TI - Novel Cancer Therapeutics in Geriatrics: What is Unique to the Aging Patient? AB - With the worldwide trend of aging populations, the number of older adults who develop and survive cancer is likely to increase. In the last decade, oncology drug development has shifted away from conventional chemotherapeutics towards agents that can 'target' a driver mutation of a specific cancer or 'unleash' the patient's native immune system to attack the cancer-so-called molecularly targeted therapies and immunotherapeutics. The basic algorithms of cancer treatment in elderly patients are essentially the same as in younger patients; however, one needs to pay exceptional attention to the effects of co-morbidities, interaction with other drugs, and the organ function reserve of an older individual before determining his/her 'eligibility' for a specific cancer treatment modality. Despite the growing evidence of safety and effectiveness of combination chemotherapy in fit elderly patients, the data are still lacking concerning the use of currently approved targeted agents and immunotherapies. The current evidence, though limited, suggests reasonable tolerability with comparable efficacy in patients > 65 years old treated with immune-based therapies to that in younger controls; however, it is unclear if this leads to significant patient-relevant gains such as improved survival with an acceptable quality of life. Nonetheless, these newer agents remain better tolerated than cytotoxic chemotherapy in clinical practice, particularly in older patients. Alternatively, a personalized approach for elderly patients with consideration of the incidence and management of adverse effects, as well as strategies for optimizing efficacy in the context of an aging immune system, would be of utmost value in our aging cancer population. Future trials should also explore immune markers to predict response to these therapeutics in elderly patients, taking into consideration the effects of immunosenescence and immune modulation in aging hosts. PMID- 30478745 TI - Correction to: Neuropeptides as facilitators of domestication. AB - The publisher regret that they failed to include the Table 1 before the publication of the original version of this article. The table is presented in this article. PMID- 30478746 TI - The role of p53 status on the synergistic effect of CKD-602 and cisplatin on oral squamous cell carcinoma cell lines. AB - The purpose of this study was to evaluate the synergistic apoptotic effect of CKD 602 in combination with cisplatin on different p53 statuses of oral squamous cell carcinoma (OSCC) cell lines, YD-8, YD-9, and YD-38. MTT assays were used to evaluate the inhibitory effect of the treatments modality on cell growth. The combination index was calculated using CompuSyn software. Detection of cell death was carried out using the propidium iodide (PI)/RNase staining assay, Annexin V/PI double staining assay, and Western blotting. Combination treatment using CKD 602 and cisplatin inhibited proliferation and increased the apoptotic effect on the three OSCC cell lines. Apoptotic cell death was detected in the cell lines, and significant synergistic effects of CKD-602 in combination with cisplatin were observed despite the differences in p53 status. From these results, it was suggested that the combination of CKD-602 with cisplatin might be a potential therapeutic strategy for OSCC. In particular, cell line-specific therapy is necessary because of the differences in treatment response based on p53 status. PMID- 30478747 TI - Development and application of low-cost T-ARMS-PCR assay for AGT and CYP11B1 gene polymorphisms. AB - Angiotensin II (Ang II: a truncated octapeptide of angiotensinogen, AGT) and 11 beta-hydroxylase influence regulation of blood pressure. Dysregulation of Ang II and 11-beta-hydroxylase can lead to hypertension and elevate aldosterone levels. Polymorphisms in AGT (encodes AGT) and CYP11B1 (encodes 11-beta-hydroxylase) shift the paradigm from physiological to pathological. Currently, various high throughput techniques are used to genotype these polymorphisms. These techniques require expensive infrastructure and reagents. However, in developing countries, where cost is the main limiting factor, it is not feasible to use expensive techniques. So, the aim of current study was to develop efficient low-cost method for genotyping of cardiovascular disease and hypertension associated polymorphisms of AGT (rs4762, rs5051) and CYP11B1 (rs6410). For this, tetra amplification-refractory mutation system-polymerase chain reaction (T-ARMS-PCR) method was developed and optimized for aforementioned AGT and CYP11B1 gene polymorphisms. Efficiency of T-ARMS-PCR was tested by genotyping 776 human samples. These T-ARMS-PCR assays were also validated by Sanger DNA sequencing, where 100% concordance was found, allowing the efficient use of these T-ARMS-PCR assays for polymorphism genotyping in AGT and CYP11B1 in resource limited settings. T-ARMS-PCR is low-cost, efficient and reliable assay for genotyping of AGT and CYP11B1 gene polymorphisms. PMID- 30478748 TI - Necrotizing fasciitis of the thigh due to penetrated descending colon cancer: a case report. AB - BACKGROUND: Necrotizing fasciitis (NF) caused by colorectal cancer is rare, and very few cases associated with colon cancer have been reported. We describe the case of a patient with NF in the left thigh due to penetration of descending colon cancer who was treated with one-stage surgical resection without creating a stoma. CASE PRESENTATION: An 80-year-old woman was brought to our hospital complaining of fever and difficulty with body movement. A physical examination showed subcutaneous emphysema from the left lower abdomen to the left femoral region. CT showed abscess formation with emphysema around the descending colon, and the wall of the descending colon was thickened, which led to suspicion of colon cancer. The patient was subsequently diagnosed with NF due to penetration of descending colon cancer. Left hemicolectomy and open drainage of the left femoral region was performed. The histopathological findings were well differentiated adenocarcinoma, with the tumor grown through the serosa (T4a) and with no metastasis to lymph nodes (N0). After surgery, the patient received intensive care for septic shock and lavage of the open drainage site, and sepsis was controlled progressively. After closure of the drainage site, the patient was transferred to a different hospital at 26 days after surgery, and she has had 6 month relapse-free survival. CONCLUSIONS: In NF caused by colon cancer, early one stage resection may improve the oncological outcome. Physical status should be assessed carefully, and one-stage resection should be considered if the patient has the capacity to undergo this procedure. PMID- 30478749 TI - A denture gone missing! PMID- 30478750 TI - Why and how do we measure frailty? PMID- 30478751 TI - Solid-state fermentation of distilled dried grain with solubles with probiotics for degrading lignocellulose and upgrading nutrient utilization. AB - Solid-state fermentation (SSF) was carried out in this study to improve the nutritional digestibility of two types of distilled dried grain with solubles (DDGS) by inoculating probiotic combinations. The fermented DDGS (FDDGS) contained more crude protein, small peptides and total amino acids than did unfermented DDGS. The concentrations of fiber indexes significantly declined after fermentation. The amounts of probiotics, enzymes and organic acids were significantly improved after fermentation. Microscopy revealed that SSF disrupted the surface structure and increased small fragments of DDGS substrate, thereby facilitating in vitro digestibility of FDDGS. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and high-performance liquid chromatography indicated the breakdown of macromolecular protein and lignocellulose, which contributed to the increase of small peptides and monosaccharides. These findings suggested the great potential of SSF to promote the nutritional quality and digestibility of the two DDGS and to expand their utilization. PMID- 30478752 TI - Efficacy of intravitreal aflibercept monotherapy in retinopathy of prematurity evaluated by periodic fluorescence angiography and optical coherence tomography. AB - PURPOSE: To evaluate the efficacy of intravitreal aflibercept (IVA) in vascular and macular maturation in neonates with type 1 retinopathy of prematurity (ROP) and aggressive posterior retinopathy of prematurity (APROP). MATERIALS AND METHODS: Thirty-six eyes of 18 patients with type 1 ROP or APROP in zone I or posterior zone II were enrolled in our study. At baseline, only fluorescein angiography (FA) was performed. After IVA injection, both FA and optical coherence tomography (OCT) were performed after 6.8 +/- 0.8 (range 6-8) and 19 +/ 0.9 (range 18-20) weeks to follow vascular and macular changes. RESULTS: Both diffuse flat neovascularization with leakage and abnormal vascular branching at the small arteriolar level were detected in all eyes (100%) at baseline FA. Regression of the disease was observed in 34 eyes (94.4%) in the first week with binocular indirect ophthalmoscopy. Early unresponsiveness in remaining two eyes of an infant required an IVA re-treatment. Late reactivation was detected only in 19.4% of eyes, none of which required treatment during 12 months of follow-up. The most common feature after IVA injection was abnormal branching at capillary level, which was noted in 100% in the first post-injection FA and 50.0% of all eyes in the second FA. Meanwhile, the end limit of vascularization was observed in zone III in 83.3% of eyes. No vascular abnormality was also detected in 27.3% of eyes. The OCT examination at a mean postmenstrual age of 43.4 weeks revealed cystoid macular changes in four eyes of two infants (11.1%), normal foveal contour in 30 eyes of 15 infants (83.3%) and matured ellipsoid zone at the foveal center in 28 eyes of 14 infants (77.8%). Macular maturation was complete in all eyes in the last OCT analyses. CONCLUSION: Intravitreal aflibercept monotherapy has been an effective treatment in type I ROP and APROP with much lower early and late re-treatment rates because of early unresponsiveness and late reactivation, respectively. In most of the eyes, rapid vascular outgrowth beyond zone III together with normal macular maturation was observed more precisely by periodic FA and OCT. PMID- 30478753 TI - Chromosomal microarray analysis of patients with Duane retraction syndrome. AB - PURPOSE: Duane retraction syndrome (DS) is a rare congenital strabismus with genetic heterogeneity. The genetic causes of DS are not always of monogenic origin; various chromosomal copy number variations (CNVs) have also been reported. The objective of our study was to characterize the CNVs, including gains and losses detected by high-resolution chromosomal microarray in patients with DS. METHODS: Twenty patients with DS were investigated using high-resolution chromosomal microarray analysis (CMA) (Affymetrix CytoScan Array 750 K). Conventional cytogenetic analysis was also performed. RESULTS: All samples revealed normal karyotype by cytogenetic analysis. However, in all our patients, multiple CNVs, including gains and losses, were detected using the high resolution CMA method. Chromosomal loci 1q21.2, 2p11.2-q11.1, 2q21.1-q21.2, 4p16.1, 7p11.2-q11.21, 14q32.33, 17p11.2-q11.1 and 20p11.1-q11.21 were the most frequently affected regions. CONCLUSIONS: This study emphasized that CNVs in several chromosomal regions are known to be involved in DS. We also underscore the genetic heterogeneity of DS. Our suggestion is that genes located in the most frequently affected regions should be focused on in the following candidate gene studies. PMID- 30478754 TI - Choroidal thickness in preeclampsia measured by spectral-domain optical coherence tomography. AB - PURPOSE: To compare choroidal thickness (CT) measurements in preeclamptic and healthy women in the third trimester of pregnancy using optical coherence tomography. METHODS: This cross-sectional study included 148 eyes of 74 women, divided into two groups: 27 healthy pregnant women in the third trimester (control group) and 47 age-matched pregnant women in the third trimester with preeclampsia (PE group). Of the 47 subjects in preeclampsia group, 26 were classified as having mild PE and 21 as having severe PE. Choroidal thickness was measured at ten different locations: at the fovea and every 500 um from the fovea up to 2500 um temporally and up to 2000 um nasally. RESULTS: Comparing CT of both groups, choroid always tended to be thicker in subjects with preeclampsia in comparison with healthy pregnant women, with statistical significance in nasal measures. Dividing PE group according to disease severity, women with severe preeclampsia tended to have thicker choroids in comparison with mild preeclamptic and healthy pregnant women. Choroid was also significantly thicker in preeclamptic patients with serous retinal detachment (SRD) in comparison with preeclamptic patients without SRD (P < 0.01 in all macular points). CONCLUSION: Our study showed that choroid tends to be thicker in patients with preeclampsia, with statistical significance only in nasal measures. In patients with SRD, however, choroid is markedly thicker at all points analyzed. From these findings we can hypothesize that preeclampsia can cause a choroidal thickening, which begins in the peripapillary area. As the imbalance increases, the entire choroid becomes thickened. PMID- 30478755 TI - Regulatory Architecture of the Neuronal Cacng2/Tarpgamma2 Gene Promoter: Multiple Repressive Domains, a Polymorphic Regulatory Short Tandem Repeat, and Bidirectional Organization with Co-regulated lncRNAs. AB - CACNG2 (TARPgamma2, Stargazin) is a multi-functional regulator of excitatory neurotransmission and has been implicated in the pathological processes of several brain diseases. Cacng2 function is dependent upon expression level, but currently, little is known about the molecular mechanisms that control expression of this gene. To address this deficit and investigate disease-related gene variants, we have cloned and characterized the rat Cacng2 promoter and have defined three major features: (i) multiple repressive domains that include an array of RE-1 silencing transcription factor (REST) elements, and a calcium regulatory element-binding factor (CaRF) element, (ii) a (poly-GA) short tandem repeat (STR), and (iii) bidirectional organization with expressed lncRNAs. Functional activity of the promoter was demonstrated in transfected neuronal cell lines (HT22 and PC12), but although selective removal of REST and CaRF domains was shown to enhance promoter-driven transcription, the enhanced Cacng2 promoter constructs were still about fivefold weaker than a comparable rat Synapsin-1 promoter sequence. Direct evidence of REST activity at the Cacng2 promoter was obtained through co-transfection with an established dominant-negative REST (DNR) construct. Investigation of the GA-repeat STR revealed polymorphism across both animal strains and species, and size variation was also observed in absence epilepsy disease model cohorts (Genetic Absence Epilepsy Rats, Strasbourg [GAERS] and non-epileptic control [NEC] rats). These data provide evidence of a genotype (STR)-phenotype correlation that may be unique with respect to proximal gene regulatory sequence in the demonstrated absence of other promoter, or 3' UTR variants in GAERS rats. However, although transcriptional regulatory activity of the STR was demonstrated in further transfection studies, we did not find a GAERS vs. NEC difference, indicating that this specific STR length variation may only be relevant in the context of other (Cacna1h and Kcnk9) gene variants in this disease model. Additional studies revealed further (bidirectional) complexity at the Cacng2 promoter, and we identified novel, co-regulated, antisense rat lncRNAs that are paired with Cacng2 mRNA. These studies have provided novel insights into the organization of a synaptic protein gene promoter, describing multiple repressive and modulatory domains that can mediate diverse regulatory inputs. PMID- 30478756 TI - Structural explanation for the tunable substrate specificity of an E. coli nucleoside hydrolase: insights from molecular dynamics simulations. AB - Parasitic protozoa rely on nucleoside hydrolases that play key roles in the purine salvage pathway by catalyzing the hydrolytic cleavage of the N-glycosidic bond that connects nucleobases to ribose sugars. Cytidine-uridine nucleoside hydrolase (CU-NH) is generally specific toward pyrimidine nucleosides; however, previous work has shown that replacing two active site residues with Tyr, specifically the Thr223Tyr and Gln227Tyr mutations, allows CU-NH to process inosine. The current study uses molecular dynamics (MD) simulations to gain atomic-level insight into the activity of wild-type and mutant E. coli CU-NH toward inosine. By examining systems that differ in the identity and protonation states of active site catalytic residues, key enzyme-substrate interactions that dictate the substrate specificity of CU-NH are identified. Regardless of the wild type or mutant CU-NH considered, our calculations suggest that inosine binding is facilitated by interactions of the ribose moiety with active site residues and Ca2+, and pi-interactions between two His residues (His82 and His239) and the nucleobase. However, the lack of observed activity toward inosine for wild-type CU-NH is explained by no residue being correctly aligned to stabilize the departing nucleobase. In contrast, a hydrogen-bonding network between hypoxanthine and a newly identified general acid (Asp15) is present when the two Tyr mutations are engineered into the active site. Investigation of the single CU NH mutants reveals that this hydrogen-bonding network is only maintained when both Tyr mutations are present due to a pi-interaction between the residues. These results rationalize previous experiments that show the single Tyr mutants are unable to efficiently hydrolyze inosine and explain how the Tyr residues work synergistically in the double mutant to stabilize the nucleobase leaving group during hydrolysis. Overall, our simulations provide a structural explanation for the substrate specificity of nucleoside hydrolases, which may be used to rationally develop new treatments for kinetoplastid diseases. PMID- 30478757 TI - Individually double minimum-distance definition of protein-RNA binding residues and application to structure-based prediction. AB - Identifying protein-RNA binding residues is essential for understanding the mechanism of protein-RNA interactions. So far, rigid distance thresholds are commonly used to define protein-RNA binding residues. However, after investigating 182 non-redundant protein-RNA complexes, we find that it would be unsuitable for a certain amount of complexes since the distances between proteins and RNAs vary widely. In this work, a novel definition method was proposed based on a flexible distance cutoff. This method can fully consider the individual differences among complexes by setting a variable tolerance limit of protein-RNA interactions, i.e. the double minimum-distance by which different distance thresholds are achieved for different complexes. In order to validate our method, a comprehensive comparison between our flexible method and traditional rigid methods was implemented in terms of interface structure, amino acid composition, interface area and interaction force, etc. The results indicate that this method is more reasonable because it incorporates the specificity of different complexes by extracting the important residues lost by rigid distance methods and discarding some redundant residues. Finally, to further test our double minimum distance definition strategy, we developed a classifier to predict those binding sites derived from our new method by using structural features and a random forest machine learning algorithm. The model achieved a satisfactory prediction performance and the accuracy on independent data sets reaches to 85.0%. To the best of our knowledge, it is the first prediction model to define positive and negative samples using a flexible cutoff. So the comparison analysis and modeling results have demonstrated that our method would be a very promising strategy for more precisely defining protein-RNA binding sites. PMID- 30478758 TI - Correction to: Neuropsychological Assessment in Elderly Men with Benign Prostatic Hyperplasia Treated with Dutasteride. AB - Catalano Antonino, Martino Gabriella, Bellone Federica, Papalia Maria, Lasco Carmen, Basile Giorgio, Sardella Alberto, Nicocia Giacomo, Morabito Nunziata, Lasco Antonino. PMID- 30478759 TI - A stochastic model of corneal epithelium maintenance and recovery following perturbation. AB - Various biological studies suggest that the corneal epithelium is maintained by active stem cells located in the limbus, the so-called limbal epithelial stem cell hypothesis. While numerous mathematical models have been developed to describe corneal epithelium wound healing, only a few have explored the process of corneal epithelium homeostasis. In this paper we present a purposefully simple stochastic mathematical model based on a chemical master equation approach, with the aim of clarifying the main factors involved in the maintenance process. Model analysis provides a set of constraints on the numbers of stem cells, division rates, and the number of division cycles required to maintain a healthy corneal epithelium. In addition, our stochastic analysis reveals noise reduction as the epithelium approaches its homeostatic state, indicating robustness to noise. Finally, recovery is analysed in the context of perturbation scenarios. PMID- 30478760 TI - How ticks keep ticking in the adversity of host immune reactions. AB - Ixodid ticks are acknowledged as one of the most important hematophagous arthropods because of their ability in transmitting a variety of tick-borne diseases. Mathematical models have been developed, based on emerging knowledge about tick ecology, pathogen epidemiology and their interface, to understand tick population dynamics and tick-borne diseases spread patterns. However, no serious effort has been made to model and assess the impact of host immunity triggered by tick feeding on the distribution of the tick population according to tick stages and on tick population extinction and persistence. Here, we construct a novel mathematical model taking into account the effect of host immunity status on tick population dynamics, and analyze the long-term behaviours of the model solutions. Two threshold values, [Formula: see text] and [Formula: see text], are introduced to measure the reproduction ratios for the tick-host interaction in the absence and presence of host immunity. We then show that these two thresholds (sometimes under additional conditions) can be used to predict whether the tick population goes extinct ([Formula: see text]) and the tick population grows without bound ([Formula: see text]). We also prove tick permanence (persistence and boundedness of the tick population) and the existence of a tick persistence equilibrium if [Formula: see text]. As the host species adjust their immunity to tick infestation levels, they form for the tick population an environment with a carrying capacity very much like that in logistic growth. Numerical results show that the host immune reactions decrease the size of the tick population at equilibrium and apparently reduce the tick-borne infection risk. PMID- 30478761 TI - Melatonin Rescue Oxidative Stress-Mediated Neuroinflammation/ Neurodegeneration and Memory Impairment in Scopolamine-Induced Amnesia Mice Model. AB - Cognitive decline and memory impairment induced by oxidative brain damage are the critical pathological hallmarks of Alzheimer's disease (AD). Based on the potential neuroprotective effects of melatonin, we here explored the possible underlying mechanisms of the protective effect of melatonin against scopolamine induced oxidative stress-mediated c-Jun N-terminal kinase (JNK) activation, which ultimately results in synaptic dysfunction, neuroinflammation, and neurodegeneration. According to our findings, scopolamine administration resulted in LPO and ROS generation and decreased the protein levels of antioxidant proteins such as Nrf2 and HO-1; however, melatonin co-treatment mitigated the generation of oxidant factors while improving antioxidant protein levels. Similarly, melatonin ameliorated oxidative stress-mediated JNK activation, enhanced Akt/ERK/CREB signaling, promoted cell survival and proliferation, and promoted memory processes. Immunofluorescence and western blot analysis indicated that melatonin reduced activated gliosis via attenuation of Iba-1 and GFAP. We also found that scopolamine promoted neuronal loss by inducing Bax, Pro-Caspase 3, and Caspase-3 and reducing the levels of the antiapoptotic protein Bcl-2. In contrast, melatonin significantly decreased the levels of apoptotic markers and increased neuronal survival. We further found that scopolamine disrupted synaptic integrity and, conversely, that melatonin enhanced synaptic integrity as indicated by Syntaxin, PSD-95, and SNAP-23 expression levels. Furthermore, melatonin ameliorated scopolamine-induced impairments in spatial learning behavior and memory formation. On the whole, our findings revealed that melatonin attenuated scopolamine-induced synaptic dysfunction and memory impairments by ameliorating oxidative brain damage, stress kinase expression, neuroinflammation, and neurodegeneration. Graphical Abstract The proposed schematic diagram showing the neuroprotective effect of melatonin against scopolamine-induced oxidative stress-mediated synaptic dysfunction, memory impairment neuroinflammation and neurodegeneration. PMID- 30478762 TI - Topical Pharyngeal Lidocaine Reduces Respiratory Adverse Events During Upper Gastrointestinal Endoscopies Under Ketamine Sedation in Children. AB - BACKGROUND: Upper gastrointestinal endoscopies (UGEs) performed under ketamine sedation may increase the risk of respiratory adverse events (RAEs) due to pharyngeal stimulation. Topical lidocaine prevents general anesthesia-induced laryngospasm. OBJECTIVE: Our objective was to determine whether topical lidocaine may reduce the incidence of RAEs induced by pharyngeal stimulation in UGEs performed on children sedated with ketamine. METHODS: We conducted a single center prospective study. We included every patient admitted for an elective diagnostic UGE under ketamine sedation who received lidocaine prior to the technique. Patients requiring any other medication were excluded. Our main outcome measure was the number of desaturation episodes. We then compared these results with those obtained in an historic group who did not receive topical lidocaine, in which we registered a total of 54 desaturation episodes. RESULTS: In total, 88 children (52.3% boys) were included. The median age was 7 years [interquartile range (IQR) 3-11]. The mean duration of the procedure was 6.5 +/- 2.4 min, and the median initial ketamine dose was 1.76 mg/kg (IQR 1.56-2.03). The total number of desaturation episodes was 3 (3.4%), and two of these occurred prior to the introduction of the endoscope. This result represents a lower incidence than in previously reported series, and a significant decrease (p < 0.0001) with respect to the 54 RAEs registered in the historic group of 87 children. CONCLUSIONS: Topical lidocaine premedication significantly reduced the incidence of RAEs in children during UGEs under ketamine sedation. Our findings should be confirmed by a double-blind randomized controlled trial. PMID- 30478764 TI - Demographic Inequities in Health Outcomes and Air Pollution Exposure in the Atlanta Area and its Relationship to Urban Infrastructure. AB - Environmental burdens such as air pollution are inequitably distributed with groups of lower socioeconomic statuses, which tend to comprise of large proportions of racial minorities, typically bearing greater exposure. Such groups have also been shown to present more severe health outcomes which can be related to adverse pollution exposure. Air pollution exposure, especially in urban areas, is usually impacted by the built environment, such as major roadways, which can be a significant source of air pollution. This study aims to examine inequities in prevalence of cardiovascular and respiratory diseases in the Atlanta metropolitan region as they relate to exposure to air pollution and characteristics of the built environment. Census tract level data were obtained from multiple sources to model health outcomes (asthma, chronic obstructive pulmonary disease, coronary heart disease, and stroke), pollution exposure (particulate matter and nitrogen oxides), demographics (ethnicity and proportion of elderly residents), and infrastructure characteristics (tree canopy cover, access to green space, and road intersection density). Conditional autoregressive models were fit to the data to account for spatial autocorrelation among census tracts. The statistical model showed areas with majority African-American populations had significantly higher exposure to both air pollutants and higher prevalence of each disease. When considering univariate associations between pollution and health outcomes, the only significant association existed between nitrogen oxides and COPD being negatively correlated. Greater percent tree canopy cover and green space access were associated with higher prevalence of COPD, CHD, and stroke. Overall, in considering health outcomes in connection with pollution exposure infrastructure and ethnic demographics, demographics remained the most significant explanatory variable. PMID- 30478765 TI - Real-World Success of Biologic Therapy in IBD: No More Reasons to Be Anti Antibody. PMID- 30478763 TI - Postoperative weight loss followed by radical cystectomy predicts poor prognosis in patients with muscle-invasive bladder cancer. AB - We aimed to investigate the impact of postoperative weight loss following radical cystectomy (RC) on patients' prognoses. RC and urinary diversion were performed in 512 consecutive patients with muscle-invasive bladder cancer at our hospitals between May 1996 and July 2018. Demographic clinical information, pre- and postoperative serum albumin, hemoglobin, and weight were evaluated retrospectively at 1 month. We also evaluated the association of weight loss with complications and overall survival (OS) as estimated using the Kaplan-Meier method and compared using the log-rank test. Risk factors for poor OS were determined by Inverse Probability of Treatment Weighted (IPTW)-adjusted Cox regression analysis. In 385 patients who met the study search criteria, median postoperative weight loss from baseline at 1 week and 1 month was 1.1 (- 1.8%) and 3.2 (- 5.4%) kg, respectively. Patients with significant weight loss (defined as >= 7.5% at 1 month) had higher-grade complications within 1 month and had significantly shorter OS than those with weight loss of < 7.5%. Type of urinary diversion, loss of serum albumin, and loss of hemoglobin were not significantly associated with weight loss. IPTW-adjusted Cox regression analysis showed that such significant weight loss was an independent risk factor for poor OS. Weight loss followed by radical cystectomy was significantly associated with poor prognosis in patients with muscle-invasive bladder cancer. PMID- 30478766 TI - Preventive Effects of Epinephrine for Critically Ill Patients? More Questions Waiting to Be Answered. PMID- 30478767 TI - Long-Term Efficacy of Peroral Endoscopic Myotomy for Patients with Achalasia: Outcomes with a Median Follow-Up of 36 Months. AB - OBJECTIVE: This study aimed to evaluate the long-term efficacy of peroral endoscopic myotomy (POEM) for patients with achalasia. METHODS: Prospective data collected from 115 patients (median age 45 years; interquartile range 34-57) with achalasia who underwent POEM at the First Affiliated Hospital of ZheJiang Chinese Medical University with a median follow-up of 36 months were retrospectively analyzed. The Eckardt score and lower esophageal sphincter pressure changes were analyzed, and the gastroesophageal reflux was observed. RESULTS: During the final follow-up, the mean Eckardt score reduced from 7.5 +/- 1.9 preoperatively to 2.3 +/- 1.4 after 1 month of surgery (P < 0.001). Treatment success was observed in 91.3% [confidence interval (CI) 86.2-96.4], 90.3% (CI 84.8-95.8), 89.0% (CI 83.1 94.9), 83.7% (CI 75.7-91.7), and 80.1% (CI 69.7-90.5) of patients after 12, 24, 36, 48, and 60 months, respectively. A total of 16 (13.9%) failures occurred. Four patients were nonresponders (failure within 3 months), eight had an early recurrence (between 3 months and 3 years), and four had a late recurrence (after 3 years). Further, 21 (20.6%) patients had symptoms of reflux during the two-year follow-up. Only one patient with symptomatic reflux was newly added during the subsequent three-year follow-up. Moreover, 71 (61.7%) patients underwent gastroscopy after POEM, and 13 (18.3%) patients were diagnosed with reflux esophagitis. CONCLUSION: POEM is safe and effective in treating achalasia and has a favorable long-term efficacy. PMID- 30478768 TI - Duodenal Pathology in Patients with Rumination Syndrome: Duodenal Eosinophilia and Increased Intraepithelial Lymphocytes. AB - BACKGROUND: Rumination syndrome is a functional gastrointestinal disorder characterized by effortless, postprandial regurgitation. Duodenal eosinophilia has been described in patients with functional dyspepsia. Because of the significant symptomatic overlap between functional dyspepsia and rumination syndrome, we hypothesized that histological changes might exist among patients with rumination syndrome. METHODS: We included patients with rumination syndrome in whom we had obtained duodenal biopsies and compared these with controls. Digital images of biopsy specimens were analyzed for routine pathology and eosinophil counts by a pathologist blinded to the case-control status. RESULTS: The 22 patients with rumination syndrome had a mean age of 39.2 years (range 21 71) and 77% were female. The 10 controls had a mean age of 34.3 (range 27-69) and 80% were female. There was a significant increase in the mean eosinophil count among the patients with rumination syndrome compared to controls, 26 per mm2 (range 16-42) versus 18 per mm2 (range 10-28), p = 0.006. Intraepithelial lymphocyte counts were significantly higher in rumination patients (mean 15/100 enterocytes, range 8-29) versus controls (mean 11/100 enterocytes, range 11-18), p = 0.02. CONCLUSION: Patients with rumination syndrome have subtle duodenal pathology with eosinophilia and increased intraepithelial lymphocyte counts compared to controls. PMID- 30478769 TI - Detectable Laboratory Abnormality Is Present up to 12 Months Prior to Diagnosis in Patients with Crohn's Disease. AB - BACKGROUND AND AIMS: Patients with inflammatory bowel disease (IBD) often have subjective symptoms for months or years prior to their diagnosis. Blood tests taken prior to diagnosis may provide objective evidence of duration of pre diagnosis disease. We aim to describe the pre-diagnosis laboratory pattern of patients with IBD. METHODS: A total of 838 patients diagnosed with IBD between 01/01/1996 and 01/03/2014, with pre-diagnosis laboratory testing available, contributed data for analysis. C-reactive protein, erythrocyte sedimentation rate, hemoglobin level, mean cell volume (MCV) platelet count, white blood cell count, neutrophil count, albumin level, ferritin level, serum iron level, alanine transaminase level, and fecal calprotectin were examined in the 24 months leading up to diagnosis and compared to baseline data taken between 24 and 36 months prior to diagnosis. RESULTS: For patients with Crohn's disease, a significant drop in serum albumin and MCV levels and a significant rise in platelet count were observed between 115 and 385 days prior to diagnosis (p < 0.01, two-tailed t test). For patients with ulcerative colitis, a significant change in albumin level, MCV, hemoglobin level, platelet count, and serum iron level was observed at diagnosis (p < 0.01, two-tailed t test) but was not detectable before. CONCLUSIONS: These data provide objective evidence of duration of delay between disease onset and diagnosis in a cohort of patients with IBD. Expediting diagnostic testing in patients presenting with symptoms consistent with IBD, who also have abnormal laboratory results, may reduce diagnostic delay, speed access to therapy, and improve clinical outcomes. PMID- 30478770 TI - Effect of Long-Term Mesalamine Therapy on Cancer-Associated Gene Expression in Colonic Mucosa of Patients with Ulcerative Colitis. AB - BACKGROUND: The role of 5-aminosalicylic acid (5-ASA or mesalamine) in the prevention of colorectal cancer in ulcerative colitis (UC) patients was reported, but the effect on molecular targets in UC colon mucosa is unknown. AIM: This observational study evaluates gene expression levels of 5-ASA targets using serial colon biopsy specimens from UC patients undergoing long-term 5-ASA therapy. METHODS: Transcript levels were compared between colonoscopic biopsy specimens collected from 62 patients at initial and final follow-up colonoscopy at 2-6 years. All patients had mild-to-moderate UC and were undergoing long-term 5-ASA maintenance. Stepwise multiple linear regression analyses were performed to correlate changes in transcript levels with therapeutic response (Mayo clinical score endoscopy and DAI and/or Nancy histopathology score) and nonclinical variables. RESULTS: The transcript levels of colorectal carcinogenesis-associated known 5-ASA target genes were significantly reduced after prolonged 5-ASA therapy (P < 0.005-0.03). Multiple linear regression models predicted significant association between transcript levels of Ki-67, NF-kB (p65), PPARgamma, COX-2 and IL-8, CDC25A, and CXCL10 with duration of drug (5-ASA) exposure (P <= 0.05). Ki 67, NF-kB (p65), and CXCL10 transcripts were also correlated with reduced endoscopy sub-score (P <= 0.05). COX-2, IL-8, CDC25A, and TNF transcripts strongly correlated with DAI sub-scores (P <= 0.05). Only COX-2 and IL-8 transcript levels correlated (P <= 0.05) with Nancy histological score. CONCLUSION: This study provides molecular evidence of changes in carcinogenesis related targets/pathways in colon tissue during long-term 5-ASA maintenance therapy that may contribute to the observed chemopreventive effects of 5-ASA in UC patients. PMID- 30478771 TI - The first example of multi-elemental analysis of water samples from urban monumental fountains-a case study from Zagreb (Croatia). AB - Water fountains are usually present in the urban public places and often draw the attention of citizens and tourists. Their water is often, in various ways, used by adults and children, but water from fountains is not usually a subject of researchers' interest. This paper describes the analytical procedure and the results of the multi-elemental characterisation of the waters from the selected public water fountains in the city of Zagreb, Republic of Croatia. Twenty-eight chemical elements (Al, As, B, Ba, Be, Cd, Co, Cr, Cu, Fe, Li, Mn, Mo, Ni, P, Pb, S, Sb, Se, Sr, Ti, Tl, V, Zn and Ca, K, Mg and Na) were quantified by means of ICP-AES technique. In addition to the multi-elemental analysis, determination of pH values was performed too. Pearson's correlation coefficients suggest that Al, Cu, Fe, Mn and Pb originate from the plumbing system and their leaching is strongly negatively correlated with the pH values of the tested samples. On the other hand, alkali and alkaline-earth metals as well as Mo, Ti, Zn and B, P and S are most probably of a natural origin in the water samples tested in this study. The results lead to the conclusions that (i) trace and major element content in squirt of a monumental water fountain is analogous to their content in water of the same origin and (ii) a pool of a fountain which is made of a high-quality stone, in the context of the herein performed testings, generally does not affect the quality of water which is contained in it. PMID- 30478772 TI - Characteristics and formation mechanisms of autumn haze pollution in Chengdu based on high time-resolved water-soluble ion analysis. AB - To investigate the characteristics and formation mechanisms of haze pollution in the autumn season in the Sichuan Basin, hourly concentrations of water-soluble inorganic ions in PM2.5 (Na+, K +, NH4+, Mg2+, Ca2+, Cl-, NO3-, and SO42-) and major gaseous precursors (HCl, NH3, SO2, HONO, and HNO3) were measured by a gas and aerosol collector combined with ion chromatography (GAC-IC) from September to November 2017 at an urban site in Chengdu. The average mass concentration of total water-soluble ions was 36.9 +/- 29.4 MUg m-3, accounting for 62.8% of PM2.5 mass. Nitrate was the most abundant ion, comprising 41.2% of the total ions, followed by sulfate (27.1%) and ammonium (18.1%), indicating the important contribution of motor vehicle emissions to PM2.5 in Chengdu. Secondary formation of inorganic ions and biomass burning emissions played a vital role in the haze pollution processes. The formation of nitrate aerosol was particularly dominant and exhibited the most substantial increase during haze processes. It was likely to be produced primarily through homogeneous reactions, whereas heterogeneous reactions dominated sulfate formation. Additionally, distinct differences in diurnal patterns of secondary inorganic ions between clean days and polluted days were observed, reflecting different formation characteristics under polluted conditions. Due to a large increase of acidic aerosols, most particles collected on polluted days were acidic, and ammonium in most samples existed mainly as NH4HSO4 and NH4NO3. Furthermore, backward-trajectory cluster analysis revealed that air masses originating from the northeast of Chengdu prevailed in the autumn season, and haze pollution was dominated mainly by short-distance transport within the Sichuan Basin. PMID- 30478773 TI - Biochar can improve the soil quality of new creation farmland on the Loess Plateau. AB - The Loess Plateau is the most severely degraded soil area worldwide and represents one of the lowest areas of soil productivity. To solve the conundrum between increasing populations and decreasing agricultural acreage, enhancing the quantity of cultivated land, gully land consolidation projects has been implemented. However, the new creation farmland soil is not enough to satisfy the demand of agricultural production. An incubation experiment was conducted to determine the effects of biochar on the new creation farmland soil. Five levels of amendments (0, 1%, 2%, 5%, and 10% (wt%) biochar soil) were used, and the soil columns remained in the laboratory for approximately 2 months. The results show that biochar proportion was a more important factor than incubation time across all soils tested. The soil moisture content and particle size clearly increased as the amendment level increased; however, the soil pH decreased gradually with incubation time and tended to slow soil salinization. These findings will have to be verified under field conditions. PMID- 30478774 TI - Long-term exposure to low level of fluoride induces apoptosis via p53 pathway in lymphocytes of aluminum smelter workers. AB - Long-term occupational exposure to low level of fluoride can induce oxidative stress and apoptosis in many cells, including lymphocyte. However, the underlying mechanism remains unclear. Hence, this study was designed to explore the potential oxidative stress and apoptosis of long-term occupational exposure to low level of fluoride in aluminum smelter workers. A total of 120 aluminum smelter workers were recruited in control, low-, middle-, and high-fluoride exposure groups with 30 workers for each group. The peripheral blood samples were collected, centrifuged, and isolated to obtain serum and lymphocyte suspensions. The air and serum fluoride concentrations were detected by fluoride ion-selective electrode method. The lymphocytic apoptosis rate, DNA damage, oxidative stress, and mRNA levels of p53, Bcl-2, and Bax were assessed by Annexin V/PI staining, comet assay, attenuated total reflectance Fourier transform infrared spectroscopy and real-time polymerase chain reaction, respectively. Results showed that the air and serum fluoride concentrations of fluoride-exposed groups were higher than those of the control group (p < 0.05). Fluoride exposure might induce apoptosis, DNA damage and oxidative stress in a dose-dependent manner in lymphocytes (p < 0.05). The expression levels of p53 and Bax were increased with fluoride exposure in lymphocytes (p < 0.05), whereas the Bcl-2 expression was decreased but not significantly. Taken together, these observations indicate that long-term occupational exposure to low level of fluoride may lead to oxidative stress and induce apoptosis through the p53-dependent pathway in peripheral blood lymphocytes of aluminum smelter workers. Serum fluoride level may be the potential biomarker of fluoride exposure. PMID- 30478775 TI - Amantagula Fruit (Carissa macrocarpa (Eckl.) A.DC.): Nutritional and Phytochemical Characterization. AB - Fruits are one of the most promising food matrices and they have been explored in the discovery of new natural and safer bioactive compounds. Carissa macrocarpa (Eckl.) A. DC. fruits are widely consumed in African countries for the preparation of traditional foodstuff, but also for their beneficially health effects. Thus, as the authors' best knowledge there are no studies on the chemical and bioactive characterization of these fruits. Therefore, fruits of C. macrocarpa from Tunisia were chemically characterized regarding their nutritional value and bioactive compounds. Furthermore, the hydroethanolic extract of these fruits was evaluated regarding its bioactive properties. The fruit powder sample showed high amounts of sugars and polyunsaturated fatty acids (PUFA). The organic acids and tocopherols' profiles revealed the presence of five organic acids and two tocopherol isoforms, being quinic acid and alpha-tocopherol the most abundant. The hydroethanolic extract of the fruits presented high antioxidant, cytotoxic, anti-inflammatory, and antibacterial properties, showing activity against all the bacterial strains studied, also inhibiting the cell growth of all the tested tumor cell lines, with the exception of HepG2, and did not reveal toxicity for the non-tumor cells PLP2. Therefore, the fruits of C. macrocarpa could be included in a daily basis diet as a source of high nutritional quality compounds with high bioactive potential. PMID- 30478776 TI - Effect of Sub-lethal Doses of Imidacloprid on Learning and Memory Formation of Indigenous Arabian Bee (Apis mellifera jemenitica Ruttner) Adult Foragers. AB - The indigenous bee race Apis mellifera jemenitica Ruttner of Saudi Arabia can learn and retain memories established by the classical conditioning of proboscis extension response (PER). The insecticide imidacloprid has shown a drastic effect on the olfactory behavior of A. m. jemenitica in the harsh arid climatic conditions of central Saudi Arabia. The oral feeding of single imidacloprid sub lethal doses (1.0 ng, 0.5 ng, or 0.1 ng) under laboratory conditions significantly impaired associative learning during the 2nd and 3rd conditioning trials compared to control bees (0 ng). The memory tests also revealed significant impairment in memory formation at 1 h, 2 h, and 24 h after conditioning compared to control bees. Even the lowest dose (0.1 ng/bee) can significantly impair the bees' ability to learn and memorize. This impairment effect was dose dependent and increased with increasing doses. The higher dose (1.0 ng) completely impaired the learning but still showed a little memory and reflected the potential recovery of bees from insecticide-induced impairment with the passage of time. To our knowledge, this is the first study in A. m. jemenitica that demonstrated the drastic effect of neonicotinoids on associative learning in indigenous bees. This study further expresses the possible severity of insecticidal exposure to bees in actual field conditions and its effect on the neural functions used in important behavior involved in the foraging of bees. PMID- 30478777 TI - From complexity to distinctiveness: The effect of expertise on letter perception. AB - Fluent, adult readers of alphabetic languages encounter hundreds of millions of individual letters. What is the impact of such extensive experience on the perception and identification of letters? Recent evidence indicates that expert and naive observers perceive letters differently. Here, we focus on the relationship between expertise and letter complexity (number of visual features) and distinctiveness (overlap in features with the other letters of the alphabet). Using a same-different letter judgement task, we examined the performance of individuals with high levels of expertise with Roman letters, but with different amounts of experience with the Arabic alphabet. The results reveal a trade-off between letter complexity and distinctiveness, such that while naive individuals are sensitive only to letter complexity and not distinctiveness, the opposite is true for individuals with high expertise with an alphabet. These findings reveal a learning trajectory in which, with increasing experience, the influence of letter complexity is supplanted by distinctiveness, which requires an understanding of the relationship of each letter to the other possible letter shapes in the alphabet as a whole. PMID- 30478778 TI - Functional analysis of the UL24 protein of suid herpesvirus 1. AB - The UL24 homologous genes are conserved in alphaherpesviruses. However, the proximity of the UL24 gene and the UL23 gene encoding for thymidine kinase (TK) in the genome of suid herpesvirus 1 (SuHV-1) makes it difficult to mutate UL24 without affecting the expression of the TK gene, and thus functional studies of the UL24 gene have lagged behind. In this study, CRISPR/Cas9 and homologous recombination were adopted to generate UL24 and TK mutant viruses. Deletion of either the UL24 or the TK gene resulted in significantly reduced SuHV-1 replication and spread capacity in Vero cells. However, UL24-deleted virus still maintained a certain degree of lethality in mice, while TK-deleted viruses completely lost their lethality in mice. Similarly, neurovirulence of UL24 deleted virus in mice was not significantly affected compared to parental virus. In comparison, infection with the TK-deleted viruses resulted in significantly reduced neurovirulence and complete loss of lethality. In addition, and for the first time, viral UL24 protein was found to be expressed late during SuHV-1 infection; enhanced green fluorescence protein (eGFP) labeled UL24 protein was shown to be localized in the nucleus via heterologous expression. In conclusion, the UL24 gene of SuHV-1 encodes a nuclear-localized viral protein and acts as a minor virulence-associated factor compared to the TK gene. PMID- 30478779 TI - Salinity stresses make a difference in the start-up of membrane bioreactor: performance, microbial community and membrane fouling. AB - Start-up of membrane bioreactor under different NaCl stress was investigated in this study. Results showed that nearly 90% chemical oxygen demands and ammonia nitrogen ([Formula: see text]-N) was oxidized in none and 0.5% NaCl condition during the start-up stage. While 1% NaCl dramatically depressed the utilization of [Formula: see text]-N and about 4 weeks were required for adaption of sludge biomass to saline condition. In addition, the accumulation of nitrite high to 11.84 mg/L was observed in 1% NaCl stress, indicating the more inhibition on the activity of nitrite oxidizing bacteria. Microbial community responded to the different salinity levels. The phylum Proteobacteria and Bacteroidetes occupied over 60% in all the three MBRs. Salinity enriched the relative abundance of Maribacter, Methyloversatilis, Aeromonas and Curvibacter, while reducing the proportion of Nitrospira and Haliscomenobacter. Nitrospirae decreased sharply at 1% NaCl accounting for the accumulation of nitrite. Higher content of soluble microbial products (SMP) under saliferous MBR were released, which deteriorated the permeability of membrane module. Protein-like substances and humic substances were the main ingredients of SMP, of which the former contributed more to membrane flux decline. This study provided better understanding on the impact of salinity on the start-up of MBR. PMID- 30478780 TI - [Performance control after arthroscopic arthrolysis with capsulectomy in fresh frozen elbow joints]. AB - BACKGROUND AND OBJECTIVE: Posttraumatic or postoperative movement restrictions in elbow joints can often occur (including capsular contracture) and can generate everyday limitations. In persistent elbow stiffness, arthroscopic arthrolysis with removal of the dorsal and ventral capsule portions can be carried out. The purpose of this study was to assess the efficacy of arthroscopic capsulectomy by means of an in vitro anatomical study. METHODS: A standardized elbow arthroscopy with ventral and dorsal capsulectomy was performed and image-documented in five fresh-frozen elbow specimens. Subsequently, open dissection of the elbow joint was performed to analyze the amount of residual capsule by means of photodocumentation of the specimens. RESULTS: Regardless of the surgeon and surgical experience, anterior and posterior remnants of the capsule remained in all specimens. Dorsal capsule strands around the standard arthroscopy portals were noticed particularly more often in the area of the high dorsolateral camera portal. An incomplete capsulectomy was seen on the ulnar side at the level of the posterior medial ligament (PML) in the immediate vicinity of the ulnar nerve. Ventrally, a capsulectomy was performed from the radial side and also the ulnar side until the brachialis muscle and additionally a complete capsulectomy as far as the anterior medial ligament (AML) and radial collateral ligament (RCL) was achieved. The capsule was completely resected in a proximal direction. Distally, irrelevant capsular remnants were found in the region of the annular ligament and distal of the tip of the coronoid process. CONCLUSION: Arthroscopic arthrolysis can be performed with a high degree of radicality. The radicality must be self critically taken into account in one's own action. The radicality of the portal change may even be higher ventrally than with an isolated column procedure. On the other hand, it must be critically considered that posteriorly, the PML cannot be adequately addressed by means of arthroscopy due to the risk of ulnar nerve injury. Portal changes might help to enable a more complete visualization of the joint capsule and may avoid leaving possibly relevant remnants of the capsule. If a release of the PML is required, this may have to be carried out in combination with an ulnar nerve release in a mini-open technique. PMID- 30478781 TI - The impact of a successful treatment of hepatitis C virus on glyco-metabolic control in diabetic patients: a systematic review and meta-analysis. AB - AIMS: The effect of HCV eradication following the use of direct-acting antiviral drugs (DAAs) on the glyco-metabolic control is unknown. Through a meta-analysis of available clinical studies, we investigated whether eradication of HCV infection with interferon-free DAAs is associated with improved glyco-metabolic control in diabetic patients. METHODS: We searched the PubMed, MEDLINE and Embase, up to 08th June 2018, for all studies evaluating whether eradication of HCV infection with DAAs is associated with changes in glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels from baseline in human subjects, without restrictions for study type and language. Data were independently extracted by two researchers using pre-specified forms. Random effects meta analyses were conducted on HbA1c and FPG levels before/after HCV eradication. RESULTS: We found a significant mean reduction in HbA1c levels of - 0.45% (95% CI - 0.60 to - 0.30%; P < 0.001) and in FPG levels of - 22.03 mg/dL (95% CI - 41.61 to - 2.44 mg/dL; P = 0.03), with high heterogeneity between studies (chi2 = 20.4, P < 0.001, I2 = 80% and chi2 = 35.8, P = 0.001, I2 = 94%, respectively). The number of available manuscripts did not allow conducting a meta-regression to elucidate the role of sustained virological response and other confounders in determining the effect of direct-acting antiviral agents on HbA1c reduction. CONCLUSIONS: We found a significant improvement in glyco-metabolic control after HCV eradication (in terms of glycated haemoglobin and fasting plasma glucose levels reduction) following direct-acting antiviral treatment in patients with established diabetes, including a consequent positive impact on anti-diabetic therapies. PMID- 30478782 TI - Comment on Monami et al. "Alternative treatment or alternative to treatment? A systematic review of randomized trials on homeopathic preparations for diabetes and obesity". PMID- 30478783 TI - Clinical and socio-demographic determinants of inadequate self-care in adults with type 1 diabetes mellitus: the leading role of self-care confidence. AB - AIMS: To describe self-care maintenance, monitoring, and management behaviors in adults with type 1 diabetes (T1DM), and to identify clinical and socio demographic determinants of inadequate self-care. METHODS: A cross-sectional study was conducted in two diabetes outpatient clinics in Italy. Clinical and socio-demographic characteristics were collected from the medical records of 181 consecutively enrolled T1DM patients. The Self-Care of Diabetes Inventory was used to measure self-care maintenance, self-care monitoring, self-care management and self-care confidence. A standardized 0-100 score was used for each self-care dimension. A score < 70 was considered inadequate self-care. Three multiple logistic regression models were run to find determinants of inadequate self-care maintenance, monitoring, and management. RESULTS: The majority of patients had adequate self-care maintenance (74%; n = 134), self-care monitoring (68.5%; n = 124) and self-care confidence (87.3%; n = 158), while self-care management was adequate for only a minority (34.8%; n = 63). The odds of inadequate self-care maintenance increased by 4.5 times when self-care confidence was inadequate (OR adjusted 4.589; 95% CI 1.611-13.071; p = 0.004). The odds of inadequate self-care monitoring increased four times when patients had inadequate self-care confidence (OR adjusted 4.116; 95% CI 1.457-11.628; p = 0.008). Inadequate self-care confidence increased the odds of performing inadequate self-care management more than five times (OR adjusted 5.313; 95% CI 1.143-24.686; p = 0.033). CONCLUSIONS: Self-care management is commonly inadequate in adults with T1DM. Self-care confidence is the most important determinant of self-care behaviors in this population. Educational interventions are recommended to improve self-care confidence in adults with T1DM. PMID- 30478784 TI - [The language barrier for older Turkish females, further investigated]. AB - A growing group of migrants age in an environment in which the dominant language (L2) differs from their mother tongue (L1). This study considers the occurrence of a language barrier in accessing (information on) health and healthcare provisions, and under which circumstances a limited proficiency in the L2 negatively influences well-being for a group of older Turkish women in the Netherlands. Data from interviews with 39 Turkish females reveal that a limited L2 proficiency does not automatically result in a lower level of well-being. When individuals are well-embedded in a social network (and feel belonging to it), a limited L2 proficiency can be alleviated by either L1 assistance from their environment or by facilitating an interpreter in L2 situations. However, when such a network is absent, L2 situations can cause anxiety, which may have repercussions for well-being. Even though there is no clear one-on-one relationship between language and well-being, language does play a role in many (social) processes that influence well-being. PMID- 30478785 TI - G-protein-coupled estrogen receptor GPER-1 expression in hormone receptor positive breast cancer is associated with poor benefit of tamoxifen. AB - BACKGROUND: The role of G-protein-coupled estrogen receptor 1 (GPER-1) in the development of tamoxifen resistance in breast cancer is a highly controversial issue. The aim of this study was to determine the expression of GPER-1 in the clinical routine under conditions of endocrine treatment. PATIENTS AND METHODS: GPER-1 expression was analyzed in 442 patients with primary invasive breast cancer. GPER-1 score of > 3 was determined as positive. Expression data were correlated with clinical and pathological characteristics and patient survival. RESULTS: GPER-1 expression was observed in 352 (80.9%) cases, and positively correlated with estrogen and progesterone receptor status (p = 0.0001). GPER-1 positivity was associated with an increased grade of differentiation (p = 0.0001) and with a low level of Ki-67 expression (p = 0.0001). High GPER-1 expression was associated with a decreased level upon systemic treatment (p = 0.011). In the whole cohort, GPER-1 expression was associated with prolonged disease-free survival (DFS). DFS between tamoxifen- and aromatase inhibitor-treated GPER-1 positive patients was similar (p = 0.090). Notably, after matching the analysis for the most important prognostic factors, DFS for tamoxifen-treated GPER-1 positive patients was 69.1%, which is a percentage that is significantly lower compared to DFS for GPER-1-positive patients treated with aromatase inhibitors (92.7%) (p = 0.005). CONCLUSION: GPER-1 expression is a favorable prognostic factor in breast cancer patients. Its predictive role for poor benefit form tamoxifen treatment should be investigated in further studies. PMID- 30478786 TI - ANXA2 expression in African American triple-negative breast cancer patients. AB - PURPOSE: Our aim was to determine the role of Annexin A2 (AnxA2), which we have previously found to contribute to the aggressiveness of TNBC, with AA TNBC patients and clinical outcome. METHODS: We analyzed TCGA breast cancer database (n = 1098) to observe AnxA2 expression within breast cancer subtypes and is correlation with overall survival. Further, we examined breast tissue specimens (n = 119) through chromogenic in situ hybridization (CISH) and specimen were scored independently by two pathologists in a blinded study. RESULTS: In our TCGA analysis, high expression of AnxA2 was correlated with poor survival in patients with TNBC. AnxA2 gene expression was not correlated with poor survival in other breast cancer subtypes. AnxA2 average CISH intensity score (CISH score = 0, null expression to 3, high expression) for TNBC was significantly higher in comparison to estrogen receptor and/or progesterone receptor positive, human epidermal growth factor positive, and non-malignant tissues. Furthermore, AnxA2 average score was significantly higher in AA TNBC patients (CISH average score = 2.45 +/- 0.3266) in comparison to Caucasian TNBC patients (CISH average score = 1.1 +/- 0.4069). CONCLUSION: AnxA2 is overexpressed in TNBC, implicating AnxA2 as a contributor to the aggressive biology of TNBC in AA women. PMID- 30478787 TI - Evaluation of radiation-induced cardiac toxicity in breast cancer patients treated with Trastuzumab-based chemotherapy. AB - PURPOSE: Patients with Her2-positive breast cancer treated with trastuzumab have higher rates of cardiotoxicity (CT). Left-breast radiation might increase the risk for CT from cardiac exposure to radiation. The goal of our study is to evaluate the contribution of radiotherapy (RT) in the development of CT in breast cancer patients receiving trastuzumab. METHODS: Two hundred and two patients were treated with RT and trastuzumab from 2000 to 2014. The RT plans for left-side disease were recalled from archives. The heart, each chamber, and left anterior descending artery (LAD) were independently contoured. New dose-volume histograms (DVH) were generated. Their serial left-ventricular ejection fractions (LVEF) were studied. CT for left and right side were compared using Fisher's exact test. The DVH data were correlated with the predefined cardiac events using actuarial Cox regression analysis. RESULTS: Compared to the right sided, the left-side cases showed statistically significant development of arrhythmia (14.2%) versus (< 1%) (p < 0.001). Cardiac ischemia was found in 10 patients in left and one patient in right side (p = 0.011). The equivalent uniform dose (EUD) to the left ventricle (LV), right ventricle (RV), and LAD was significantly associated with decrease in LVEF by > 10% (p = 0.037, p = 0.023 and p = 0.049, respectively). CONCLUSIONS: Among patients treated for left-sided lesions, there were no significant differences in EF decline. However, there was a higher rate of ischemia and arrhythmia compared to those with right-sided disease. The EUD index of LV, RV, and LAD could be considered as a parameter to describe the risk of radiation-induced CT. PMID- 30478788 TI - Factors related to fatalities and clinical progression of Crimean-Congo hemorrhagic fever patients and the effects of IL 28-B gene polymorphism. AB - Mortality rates of Crimean-Congo hemorrhagic fever (CCHF) vary from 5% to 80%. However, there is no clear information available about why this disease is fatal for some people while others recover. In this study, the factors related to fatalities and serious clinical progression of CCHF patients and the correlation between serious prognosis and IL 28-B gene polymorphism were investigated. The study included 107 patients with a preliminary diagnosis of CCHF, and the patients were found positive for CCHFV RNA based on polymerase chain reaction (PCR) analysis. The IL 28-B rs12979860 polymorphism was identified by PCR "restriction fragment length polymorphism" (PCR-RFLP) analysis using blood samples from the patients. In addition to the IL 28-B analysis results, a variety of data along with laboratory records obtained during the hospital stay were evaluated using statistical analysis. Of the 107 cases, nine were fatal (8.4%), while the other patients recovered and were discharged. Twenty-four patients had the CC genotype (22.43%), 64 had the CT genotype (59.81%), and 19 had the TT genotype (17.76%). Of the nine patients who died, three had the CC genotype (33.33%) and six had the CT genotype (66.67%). None of the patients who died had the TT genotype. Symptoms and findings of diarrhea, abdominal pain, hemorrhage, and rash were more common in fatal cases than in non-fatal cases. The IL 28-B rs12979860 polymorphism was not found to have a statistically significant correlation with fatality or symptoms indicating serious clinical progression in CCHF patients. As has been observed in previous studies, our study showed that leukocytosis, abdominal pain and diarrhea were more common in fatal cases. PMID- 30478789 TI - Structural analysis and proteomics studies on the Myoviridae vibriophage M4. AB - Bacteriophages play a crucial role in tracking the spread of bacterial epidemics. The frequent emergence of antibiotic-resistant bacterial strains throughout the world has motivated studies on bacteriophages that can potentially be used in phage therapy as an alternative to conventional antibiotic treatment. A recent outbreak of cholera in Haiti took many lives due to a rapid development of resistance to the available antibiotics. The properties of vibriophages, bacteriophages that infect Vibrio cholerae, are therefore of practical interest. A detailed understanding of the structure and assembly of a vibriophage is potentially useful in developing phage therapy against cholera as well as for fabricating artificial nanocontainers. Therefore, the aim of the present study was to determine the three-dimensional organization of vibriophage M4 at sub nanometer resolution by electron microscopy and single-particle analysis techniques to facilitate its use as a therapeutic agent. We found that M4 has a large capsid with T = 13 icosahedral symmetry and a long contractile tail. This double-stranded DNA phage also contains a head-to-tail connector protein complex that joins the capsid to the tail and a prominent baseplate at the end of the tail. This study also provides information regarding the proteome of this phage, which is proteins similar to that of other Myoviridae phages, and most of the encoded proteins are structural proteins that form the exquisite architecture of this bacteriophage. PMID- 30478790 TI - Effects of Biliopancreatic Diversion on Bone Turnover Markers and Association with Hormonal Factors in Patients with Severe Obesity. AB - BACKGROUND: This study evaluated early and medium-term changes in bone turnover markers, and their associations with weight loss, total bone mineral density (BMD), and hormonal changes after biliopancreatic diversion (BPD). METHODS: Ancillary study from a one-year prospective cohort of 16 individuals assessed before, 3 days, 3 and 12 months after BPD. Bone turnover markers (C-terminal telopeptide (CTX), intact osteocalcin (OC), sclerostin, and osteoprotegerin (OPG)) and several hormones were measured at each visit. Total BMD by DXA was assessed at baseline, 3 and 12 months after BPD. Three participants were lost to follow-up. RESULTS: CTX increased significantly at 3 days (+ 66%), 3 months (+ 219%), and 12 months (+ 295%). OC decreased at 3 days (- 19%) then increased at 3 months (+ 69%) and 12 months (+ 164%). Change in sclerostin was only significant between 3 days and 3 months (+ 13%), while change in OPG was significant between baseline and 3 days (+ 48%) and baseline and 12 months (+ 45%). CTX increase correlated negatively with weight loss at 3 (r = - 0.63, p = 0.009) and 12 months (r = - 0.58, p = 0.039), and total BMD decrease (r = - 0.67, p = 0.033) at 12 months. Change in insulin and adiponectin correlated with changes in bone turnover markers independently of weight loss. CONCLUSION: BPD causes an earlier and greater increase in bone resorption over bone formation markers and a decrease in total BMD. Sclerostin did not increase as expected following extensive weight loss. Changes in insulin and adiponectin seem to play a role in the activation of bone remodeling after BPD. PMID- 30478791 TI - [The practice staff in primary care dementia recognition-is there an untapped potential?] AB - BACKGROUND: It is regularly criticized that the diagnostics of dementia are not used effectively and consistently enough in general practitioner (GP) care. An important component for the optimization of early detection is the targeted training and involvement of the practice staff. To date, there is a lack of studies that capture the extent to which primary care personnel are actually integrated into dementia recognition and how they assess their own potential to contribute to a more efficient diagnosis of dementia. MATERIAL AND METHODS: The study was based on 45 qualitative individual interviews with GP practice personnel in Rhineland-Palatinate and Hesse, which were conducted orally and personally between November 2017 and June 2018 (duration: 25-70 min). RESULTS: The results show that GP personnel showed a great willingness to support the family doctor in dementia recognition and diagnostics; however, this potential is only partly used in primary care practices. Most of the sample showed marked uncertainties in assessing possible signs of incipient dementia. This corresponds to the fact that only a minority of the interviewees had ever completed training in which dementia was an important topic. The identification of dementia patients by the practice employees seems to function according to the random principle and less according to systematic criteria. CONCLUSION: The analysis showed that many GPs are not yet aware of the opportunities offered by a greater involvement of practice personnel in the recognition of dementia. Accordingly, GPs should be advised of the benefits of such a solution. At the same time, more attention should be paid to low-threshold training formats, which are tailored specifically to the perspective of practice employees and convey important dementia-specific diagnostics, action and communication skills. PMID- 30478792 TI - [How do we manage a balance between caring for family members and employment? : A study on the compatibility between home care and employment at the Alpen-Adria University]. AB - BACKGROUND: Informal family care is an essential pillar of the healthcare system whilst informal caregivers face the huge challenge of coordinating family, the care situation as well as their employment. OBJECTIVE: This article describes care situations, associated burdens, challenges and desired support measures experienced by university staff. MATERIAL AND METHODS: A total of 75 people who are currently caring for or have in the past cared for a relative, participated in the online survey. RESULTS: Informal care, often undertaken at short notice for family members, consumes a lot of time and requires a high amount of flexibility. In 64% of the reported cases the care situation lasted for more than 1 year, while being concealed by one third of the respondents and thus leading to a high risk of burnout. CONCLUSION: Informal caregivers need support within the social and professional environment by creating an awareness of this growing and unspoken topic. PMID- 30478793 TI - Juzentaihoto hot water extract alleviates muscle atrophy and improves motor function in streptozotocin-induced diabetic oxidative stress mice. AB - A decrease in skeletal muscle mass and motor function occurs in diabetic patients. In type 1 diabetic patients, in particular, fast-type fiber-dominated muscle atrophy occurs due to increased oxidative stress and inflammation. Juzentaihoto is a herbal medicine that has been found to be effective in reducing oxidative stress. In this study, juzentaihoto hot water extract (JTT) was administered prophylactically to mice with diabetic oxidative stress, which was induced by an injection of streptozotocin, and the effects on skeletal muscle mass, motor function, and antioxidant activity were evaluated. In mice that were administered JTT, skeletal muscle atrophy and loss of motor function were suppressed. Additionally, the administration of JTT increased the mRNA expression level of Sirt1 and the activity of superoxide dismutase in the gastrocnemius. In addition to skeletal muscle atrophy, atrophy of the liver, spleen and thymus gland, and kidney hypertrophy were also suppressed. Furthermore, in order to evaluate the antioxidant activity of 10 constituent crude drugs that comprise juzentaihoto, Sirt1 transcriptional activity in C2C12 cells was evaluated. The Sirt1 transcriptional activity was increased by Cinnamomi Cortex, Astragali Radix, and Glycyrrhizae Radix extracts. These three constituent crude drugs play an important function in the antioxidant action of juzentaihoto, suggesting that juzentaihoto can prevent muscle atrophy by decreasing oxidative stress. PMID- 30478794 TI - Social networks predict immigration success in wild Japanese macaques. AB - Male migration is common in mammals and comes with associated benefits and costs. Male-male affiliative relationships are behavioural strategies that migrating males can adopt in order to maximise benefits and minimize costs. While we know that such strategies primarily serve to reduce tension, little is known about how they actually affect male immigration success. We investigated the influence of male-male affiliative relationships on immigration success in a group of wild Japanese macaques (Macaca fuscata). We used social network analysis to examine the distribution of male-male affiliative interactions and their association with immigration success. We found that visiting males with high eigenvector centralities and low weighted degree centralities were more likely to be integrated into the group. Other factors such as season, age-class, and dominance rank amongst visiting males did not affect male integration success. Our results suggest that strong male affiliative bonds and a centralized position within the male-male grooming network can predict future integration success of visiting males into a social group through promoting higher tolerance of resident males and reducing aggression risks. PMID- 30478795 TI - Sustained release of amoxicillin from hydroxyapatite nanocomposite for bone infections. AB - Hydroxyapatite (HAP) is the main constituent of human bone and teeth. Hydroxyapatite nanoparticles are used for the treatment of various bone infections. Nanohydroxyapatite is a biocompatible material. It is used as a drug carrier for drugs and biomolecules for various diseases. Hydroxyapatite nanoparticles are made into nanocomposite with sodium alginate and polyvinyl alcohol. This nanocomposite is used for the sustained release of drugs. It is characterized by various characterization techniques like XRD, FTIR, TEM, and Raman. Hydroxyapatite nanoparticles are coated initially with polyvinyl alcohol and then coated with sodium alginate. Amoxicillin is used as the model drug. Studies on the drug loading and drug release have been done. The release of the drug is sustained for about 30 days. Antimicrobial studies have shown good activity against pathogens. The zone of inhibition is found to be 18 mm for a concentration of 500 ug against Bacillus subtilis and 16 ug against Klebsiella pneumonia. PMID- 30478796 TI - Recurrent strokes, central nervous system vasculitis, and acquired protein S deficiency secondary to varicella zoster in a child with AIDS. AB - A child with vertical transmission of human immunodeficiency virus refractory to therapy developed zoster-induced protein S deficiency and recurrent strokes. Extensive carotid arteritis was found postmortem. The carotid tissue was positive for herpes varicella zoster by polymerase chain reaction, as were immunofixation stains of the arterial wall. PMID- 30478797 TI - Low-frequency fluctuation characteristics in rhesus macaques with SIV infection: a resting-state fMRI study. AB - Simian immunodeficiency virus (SIV)-infected macaque is a widely used model to study human immunodeficiency virus. The purpose of the study is to discover the amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) changes in SIV-infected macaques. Seven rhesus macaques were involved in the longitudinal MRI scans: (1) baseline (healthy state); (2) SIV infection stage (12 weeks after SIV inoculation). ALFF and fALFF were subsequently computed and compared to ascertain the changes caused by SIV infection. Whole-brain correlation analysis was further used to explore the possible associations between ALFF/fALFF values and immune status parameters (CD4+ T cell counts, CD4/CD8 ratio and virus load). Compared with the baseline, macaques in SIV infection stage displayed strengthened ALFF values in left precuneus, postcentral gyrus, and temporal gyrus, and weakened ALFF values in orbital gyrus and inferior temporal gyrus. Meanwhile, increased fALFF values were found in left superior frontal gyrus, right precentral gyrus, and superior temporal gyrus, while decreased fALFF values existed in left hippocampus, left caudate, and right inferior frontal gyrus. Furthermore, ALFF and fALFF values in several brain regions showed significant relationships with CD4+ T cell counts, CD4/CD8 ratio, and plasma virus load. Our findings could promote the understanding of neuroAIDS caused by HIV infection, which may provide supplementary evidences for the future therapy study in SIV model. PMID- 30478798 TI - Childhood trauma interacts with ApoE to influence neurocognitive function in women living with HIV. AB - HIV-associated neurocognitive disorder (HAND) describes a spectrum of behavioural, motor and cognitive disturbances that can occur secondary to HIV infection. Less severe forms of the disorder persist despite advances in antiretroviral medication efficacy and availability. Childhood trauma (CT) may predispose individuals to developing HAND. As genetic variation in human apolipoprotein E (ApoE) has been implicated in cognitive decline and may mediate the development of long-term health outcomes following CT, we investigated the influence of ApoE and CT on cognitive function in the context of HIV. One hundred twenty-eight HIV-positive Xhosa women completed the Childhood Trauma Questionnaire-Short Form (CTQ-SF) as well as the HIV Neurobehavioural Research Center neurocognitive test battery. rs7412 and rs429358 were genotyped using KASP assays, and this data was used to determine the ApoE isoform. Baseline differences in demographic and clinical variables according to CT exposure were calculated. Analysis of covariance was used to assess the contributions of CT and ApoE variants, as well as their interaction, to cognitive function. Eighty-eight participants reported experiencing CT. The rs7412 C allele protected against the harmful effect of CT on motor scores using an additive model. The interaction of ApoE epsilon4 and CT was associated with worse attention/working memory scores. ApoE epsilon4, alone and in combination with CT, is associated with poorer cognitive function. Further research into this gene-environment interaction may assist in identifying at-risk individuals for targeted interventions. PMID- 30478800 TI - Tryptophan metabolism and its relationship with central nervous system toxicity in people living with HIV switching from efavirenz to dolutegravir. AB - The mechanisms underlying central nervous system (CNS) toxicities in antiretroviral-treated persons living with HIV (PLWH) remain elusive. We investigated the associations between markers of tryptophan metabolism and measurements of CNS toxicity in PLWH. In a prospective study, virologically suppressed PLWH receiving efavirenz-containing antiretroviral regimens with ongoing CNS toxicity were switched to dolutegravir-containing regimens and followed up for 12 weeks. Plasma tryptophan and kynurenine concentrations and the kynurenine/tryptophan ratio were calculated. Ten CNS toxicities were graded according to the ACTG adverse events scale. Scores ranged from 0 (none) to 3 (severe) and were summed, giving a total from 0 to 30. Paired-samples t tests and linear mixed model analyses were conducted to assess changes in, and relationships between, laboratory and clinical parameters. Mean kynurenine plasma concentration increased from baseline to week 12 (2.15 to 2.50 MUmol/L, p = 0.041). No significant changes were observed for tryptophan (54.74 to 56.42 MUmol/L, p = 1.000) or kynurenine/tryptophan ratio (40.37 to 41.08 MUmol/L, p = 0.276). Mean CNS toxicity score decreased from 10.00 to 4.63 (p < 0.001). Plasma kynurenine concentration correlated with CNS toxicity score: for every 1 MUmol/L increase in kynurenine concentration observed, a 1.7 point decrease was observed in CNS toxicity score (p < 0.038). A similar trend was observed for the kynurenine/tryptophan ratio: for every 1 MUmol/mmol increase observed in kynurenine/tryptophan ratio, a 0.1 point decrease was observed in CNS toxicity score (p = 0.054). Switching from efavirenz to dolutegravir was associated with increases in plasma kynurenine concentration and improvements in CNS toxicity scores. Underlying mechanisms explaining the rise in kynurenine concentrations need to be established. PMID- 30478799 TI - Elevated cerebrospinal fluid Galectin-9 is associated with central nervous system immune activation and poor cognitive performance in older HIV-infected individuals. AB - We previously reported that galectin-9 (Gal-9), a soluble lectin with immunomodulatory properties, is elevated in plasma during HIV infection and induces HIV transcription. The link between Gal-9 and compromised neuronal function is becoming increasingly evident; however, the association with neuroHIV remains unknown. We measured Gal-9 levels by ELISA in cerebrospinal fluid (CSF) and plasma of 70 HIV-infected (HIV+) adults stratified by age (older > 40 years and younger < 40 years) either ART suppressed or with detectable CSF HIV RNA, including a subgroup with cognitive assessments, and 18 HIV uninfected (HIV-) controls. Gal-9 tissue expression was compared in necropsy brain specimens from HIV- and HIV+ donors using gene datasets and immunohistochemistry. Among older HIV+ adults, CSF Gal-9 was elevated in the ART suppressed and CSF viremic groups compared to controls, whereas in the younger group, Gal-9 levels were elevated only in the CSF viremic group (p < 0.05). CSF Gal-9 positively correlated with age in all groups (p < 0.05). CSF Gal-9 tracked with CSF HIV RNA irrespective of age (beta = 0.33; p < 0.05). Higher CSF Gal-9 in the older viremic HIV+ group correlated with worse neuropsychological test performance scores independently of age and CSF HIV RNA (p < 0.05). Furthermore, CSF Gal-9 directly correlated with myeloid activation (CSF-soluble CD163 and neopterin) in both HIV+ older groups (p < 0.05). Among HIV+ necropsy specimens, Gal-9 expression was increased in select brain regions compared to controls (p < 0.05). Gal-9 may serve as a novel neuroimmuno-modulatory protein that is involved in driving cognitive deficits in those aging with HIV and may be valuable in tracking cognitive abnormalities. PMID- 30478801 TI - Primary intrahepatic cholangiocarcinoma with sarcomatous stroma: case report and review of the literature. AB - BACKGROUND: Hepatic carcinosarcomas, which include both carcinomatous and sarcomatous elements, are uncommon in adults. Although carcinosarcoma in hepatocellular carcinoma is occasionally reported, carcinosarcoma in intrahepatic cholangiocarcinoma (ICC) is an extremely rare ICC variant. Few such cases have been reported in English and no large study of its clinicopathological features exists. CASE PRESENTATION: Here, we report a 60-year-old man with an asymptomatic hepatic B infection who developed hepatic carcinosarcoma from an otherwise normal liver. The 6.0-cm tumor was accidentally discovered by PET-CT in a cancer examination. Serum examinations showed no elevation of tumor markers. He underwent left and caudate lobectomy of the liver. The diagnosis of intrahepatic cholangiocarcinoma with sarcomatous stroma was based on thorough pathologic examination and immunohistochemical staining. The tumor exhibited adenocarcinomatous and sarcomatous components; the adenocarcinomatous element was positive for epithelial markers, the sarcomatous element was positive for mesenchymal markers, but negative for epithelial markers. The patient made an uneventful recovery after surgery. At present, 14 months after surgery, he remains well with no evidence of tumor recurrence. CONCLUSIONS: We report an unusual case of hepatic carcinosarcoma (intrahepatic cholangiocarcinoma with sarcomatous stroma) and discuss the etiology and prognosis of this rare disease. PMID- 30478802 TI - General fluid/inductive reasoning battery for a high-ability population. AB - The validity of studies investigating interventions to enhance fluid intelligence (Gf) depends on the adequacy of the Gf measures administered. Such studies have yielded mixed results, with a suggestion that Gf measurement issues may be partly responsible. The purpose of this study was to develop a Gf test battery comprising tests meeting the following criteria: (a) strong construct validity evidence, based on prior research; (b) reliable and sensitive to change; (c) varying in item types and content; (d) producing parallel tests, so that pretest posttest comparisons could be made; (e) appropriate time limits; (f) unidimensional, to facilitate interpretation; and (g) appropriate in difficulty for a high-ability population, to detect change. A battery comprising letter, number, and figure series and figural matrix item types was developed and evaluated in three large-N studies (N = 3,067, 2,511, and 801, respectively). Items were generated algorithmically on the basis of proven item models from the literature, to achieve high reliability at the targeted difficulty levels. An item response theory approach was used to calibrate the items in the first two studies and to establish conditional reliability targets for the tests and the battery. On the basis of those calibrations, fixed parallel forms were assembled for the third study, using linear programming methods. Analyses showed that the tests and test battery achieved the proposed criteria. We suggest that the battery as constructed is a promising tool for measuring the effectiveness of cognitive enhancement interventions, and that its algorithmic item construction enables tailoring the battery to different difficulty targets, for even wider applications. PMID- 30478803 TI - Childhood Neglect and Adolescent Suicidal Ideation: a Moderated Mediation Model of Hope and Depression. AB - Using data collected on a two-wave longitudinal sample of 910 adolescents with mean age of 13.68 years in Hong Kong, China, this survey aimed to test a moderated mediation model to account for the developmental pathway from childhood experiences of neglect to suicidal ideation in adolescents. Results showed that adolescents who were neglected as children had higher levels of suicidal ideation; furthermore, this relation was mediated by adolescents' depressive symptoms, while the path between adolescents' depressive symptoms and suicidal ideation was moderated by adolescents' sense of hope. Findings of this study imply that intervention and services that help prevent childhood neglect, alleviate depression, and promote hope are potentially important to decrease adolescent suicidal ideation. PMID- 30478804 TI - A Randomized Controlled Trial to Reduce HIV-Related Risk in African American Men Who Have Sex with Men and Women: the Bruthas Project. AB - African American men who have sex with men and women (MSMW) are among the populations with the highest need for HIV prevention programs in the USA. We tested a theory-based, community participatory behavioral intervention aiming to reduce sexual risk for HIV transmission in this population. A randomized clinical trial involving 396 African American MSMW who were assigned to a 4-session intervention involving HIV testing and counseling (n = 199) or to a HIV testing and counseling only (n = 197) control. In the 4-session intervention program, counselors provided education on HIV and STI risk, condom use, HIV testing, interpersonal sexual dynamics with both male and female partners, and motivational "triggers" of condomless sex. Participants completed baseline, 6 month, and 9-month assessments, and changes in HIV behavioral risk indicators were examined by condition and time. There were no statistically significant differences in sexual risk between the intervention condition and the control condition. Regardless of condition, participants reported significant reductions in mean number of condomless sex events with female casual partners from baseline (6.04) to 6 months (2.58) and 9 months (1.47), and with male casual partners from baseline (2.61) to 6 months (1.18) and 9 months (0.60). Condition-by-time interaction effects and condition main effects were non-significant. Although there were no significant differences by condition, findings support the effects of brief behavioral counseling and HIV testing on reducing condomless sex with casual female and male partners among African American MSMW. Future research should examine further the potential for brief behavioral counseling to promote biomedical HIV prevention and to reduce co-morbid health issues such as substance use among African American MSMW. PMID- 30478805 TI - Acute median arcuate ligament syndrome after pancreaticoduodenectomy. AB - BACKGROUND: Median arcuate ligament syndrome (MALS) can cause severe complications after pancreaticoduodenectomy (PD). Most of the reported cases of MALS have been diagnosed perioperatively and can be treated efficiently by interventional radiology or division of the median acute ligament (MAL) fibers. CASE REPORT: A 69-year-old woman underwent PD with resection of the SMV for pancreatic head cancer. Intraoperative exploration showed normal anatomy of the celiac trunk. Intraoperative digital palpation revealed normal pulsation of the common hepatic artery after resection of the gastroduodenal artery. On postoperative day (POD) 3, her liver function tests were abnormal, and bloody fluids were found in the drain. Abdominal CT showed necrosis of the pancreatic body and ischemia in the liver secondary to MALS which was not detected in the preoperative CT. Interventional radiology was tried first but failed. Division of the MAL fibers markedly increased the blood flow in the hepatic artery. Resection of the remnant pancreas and spleen was also performed simultaneously. Abdominal CT on POD 20 showed re-occlusion of the celiac artery. She experienced rupture of the gastrojejunostomy site, severe hepatic cytolysis, and choledochojejunostomy stricture thereafter. CONCLUSIONS: This is the third case of MALS that has developed acutely after PD. MALS can cause refractory complications even after MAL release. PMID- 30478807 TI - Fertility preservation in women with malignancies: the accuracy of antral follicle count collected randomly during the menstrual cycle in predicting the number of oocytes retrieved. AB - PURPOSE: To evaluate the capacity of random antral follicle count (AFC), i.e., AFC recorded at any time during the menstrual cycle, to predict the number of retrieved mature oocytes in women with malignancies undergoing random start ovarian hyperstimulation METHODS: A consecutive series of 72 women with malignancies who underwent ovarian hyperstimulation aimed at egg freezing between July 2014 and December 2016 was retrospectively reviewed. A standardized random start protocol was used for all women. AFC and serum AMH were systematically assessed prior to initiating ovarian hyperstimulation. The main outcome was the retrieval of >= 10 mature oocytes. The accuracy of random AFC was tested with the c-statistics (area under the ROC curve). RESULTS: For the whole cohort, the c statistics for the prediction of >= 10 mature oocytes using AFC and serum AMH were similar. Specifically, the areas under the curve were 0.76 (95%CI 0.66-0.87) and 0.82 (95%CI 0.72-0.92), respectively (p = ns). Moreover, when considering the subgroup of women recruited after day 5 of the cycle (proper random start, n = 52), the areas under the curve did not also differ. Specifically, they resulted in 0.77 (95%CI 0.64-0.89) and 0.83 (95%CI 0.72-0.95), respectively (p = ns). CONCLUSIONS: AFC collected at any time during the menstrual cycle can provide valuable information for the counseling of women with malignancies scheduled for oocyte cryopreservation. Its reliability appears to be non-inferior to that of serum AMH. PMID- 30478806 TI - Bone marrow derived endothelial progenitor cells retain their phenotype and functions after a limited number of culture passages and cryopreservation. AB - A critical limitation for tissue engineering and autologous therapeutic applications of bone marrow derived EPCs is their low frequency, which is even lower in number and activity level in patients with cardiovascular risk factors and other diseases. New strategies for obtaining and reserving sufficient ready to-use EPCs for clinical use have hit major obstacles, because effects of serial passage and cryopreservation on EPC phenotype and functions are still needed to be explored. The present study aims at investigating effects of a limited number of culture passages as well as cryopreservation on EPC phenotype and functions. We isolated EPCs from rat bone marrow and cultured them up to passage 12 (totaling achievements of 40 population doublings). The phenotype and functions of fresh cultured and post-cryopreserved EPCs at passages 7 and 12, respectively, were evaluated. EPCs at passage 12 maintained the morphological characteristics, marker phenotype, Dil-ac-LDL uptake and FITC-UEA-1 binding functions, enhanced EPCs proliferation, tube formation and migration, but decreased CD133 expression compared with EPCs at passage 7. Cryopreservation caused limited impairment in EPC phenotype and functions. In brief, our results demonstrated that a limited number of culture passages and cryopreservation did not change EPC phenotype and functions, and can be used for the development of robust strategies and quality control criterion for obtaining sufficient and high-quality ready-to-use EPCs for tissue engineering and therapeutic applications. PMID- 30478808 TI - Responsible Attention to Conflicts of Interest Enhances the Credibility of Published Scholarship. PMID- 30478809 TI - Evaluation of recurrent ventricular tachyarrhythmias in patients who survived out of-hospital cardiac arrest due to ventricular fibrillation: eligibility for subcutaneous implantable defibrillator therapy. AB - PURPOSE: The subcutaneous implantable defibrillator (S-ICD) was developed to avoid complications related to transvenous leads. A trade-off with the S-ICD is the inability to deliver antitachycardia pacing (ATP). Data is scarce about the recurrence and characteristics of ventricular tachyarrhythmias (VTa) during a follow-up in survivors of out-of-hospital cardiac arrest due to ventricular fibrillation (OHCA-VF). The aim of the study is to determine the characteristics of VTa triggering ICD therapy in order to assess whether survivors of OHCA-VF are eligible candidates for the S-ICD. METHODS: All OHCA-VF patients who received a transvenous ICD were identified, 378 patients, age 57 +/- 14 years, predominantly male (76%) with ischemic heart disease (58%). Arrhythmic endpoints were appropriate ICD therapies for any ventricular arrhythmia. RESULTS: Over a median follow-up of 4.5 years, 690 VTa in 91 patients (24%) were terminated by ICD therapy; 70% of patients had < 5 VTa with ICD therapy. VTa with cycle length <= 300 ms were mainly (82%) treated by shock, while 83% of VTa with cycle length > 300 ms were treated by ATP. The presence of a remote myocardial infarction (OR 2.07; 95% CI 1.08-3.97) and LVEF <= 0.35 (OR 2.09; 95% CI 1.09-4.00) were significantly associated with the occurrence of VTa with cycle length > 300 ms. CONCLUSION: S-ICD implantation may be reasonable in survivors of OHCA-VF who present without a remote myocardial infarction and LVEF > 35%. PMID- 30478810 TI - Deep convolutional neural network-based speech enhancement to improve speech intelligibility and quality for hearing-impaired listeners. AB - In this paper, we propose a deep learning-based speech enhancement (DLSE) method to improve speech intelligibility for the hearing-impaired listeners. The algorithm decomposes the noisy speech signal into frames (as features) and feeds them to the deep convolutional neural networks (DCNNs) to produce an estimation of which frequency channels contain more perceptually important information (higher signal-to-noise ratio, SNR). This estimate is used to attenuate noise dominated and retain speech-dominated cochlear implant (CI) channels for electrical stimulation, as in traditional n-of-m CI coding strategies. The proposed algorithm was evaluated by measuring the speech-in-noise performance of 12 CI users using two types of background noises such as fan and music sounds. The architecture and low processing delay of the DLSE algorithm make it suitable for application in hearing devices. While DLSE was evaluated using a noise specific approach, several aspects of generalisation to unseen acoustic conditions were addressed, most importantly performance with a speaker not used during the training stage. The largest improvements for both speech intelligibility and quality are found by DCNN-based proposed method. Moreover, the results show that DCNN-based methods appeared more promising than existing methods. Graphical abstract ?. PMID- 30478811 TI - A reliable method for colorectal cancer prediction based on feature selection and support vector machine. AB - Colorectal cancer (CRC) is a common cancer responsible for approximately 600,000 deaths per year worldwide. Thus, it is very important to find the related factors and detect the cancer accurately. However, timely and accurate prediction of the disease is challenging. In this study, we build an integrated model based on logistic regression (LR) and support vector machine (SVM) to classify the CRC into cancer and normal samples. From various factors, human location, age, gender, BMI, and cancer tumor type, tumor grade, and DNA, of the cancer, we select the most significant factors (p < 0.05) using logistic regression as main features, and with these features, a grid-search SVM model is designed using different kernel types (Linear, radial basis function (RBF), Sigmoid, and Polynomial). The result of the logistic regression indicates that the Firmicutes (AUC 0.918), Bacteroidetes (AUC 0.856), body mass index (BMI) (AUC 0.777), and age (AUC 0.710) and their combined factors (AUC 0.942) are effective for CRC detection. And the best kernel type is RBF, which achieves an accuracy of 90.1% when k = 5, and 91.2% when k = 10. This study provides a new method for colorectal cancer prediction based on independent risky factors. Graphical abstract Flow chart depicting the method adopted in the study. LR (logistic regression) and ROC curve are used to select independent features as input of SVM. SVM kernel selection aims to find the best kernel function for classification by comparing Linear, RBF, Sigmoid, and Polynomial kernel types of SVM, and the result shows the best kernel is RBF. Classification performance of LR + RF, LR + NB, LR + KNN, and LR + ANNs models are compared with LR + SVM. After these steps, the cancer and healthy individuals can be classified, and the best model is selected. PMID- 30478812 TI - Effect of pregnancy on the cholinergic responses of the bladder: role of acetylcholinesterase. AB - OBJECTIVES: Pregnancy is associated with many functional changes of the urinary bladder. It was reported that most of healthy women complain from urinary symptoms during pregnancy. The parasympathetic system is mainly mediating bladder emptying. The aim of the study is to investigate the cholinergic effect and the role of acetylcholinesterase in the bladder during pregnancy. METHODS: Sixteen rats were used in the present study as control group (non-pregnant) and pregnant group (18-20 days pregnant). Isolated urinary smooth muscle strips were suspended in organ baths filled with Krebs' solution for isometric tension recording. RESULTS: Electric field stimulation (EFS), (0.1-40 Hz), of the control and pregnant bladder preparations produced frequency-dependent contractions. Atropine (1 uM) inhibited EFS-induced contractions in the two groups by 65% and 50% respectively indicating the response of cholinergic innervation. Neostigmine significantly enhanced EFS responses, confirming its selectivity for inhibiting acetylcholinesterase which is responsible for termination of acetylcholine. Concentration-response curves for acetylcholine were reduced in pregnant group than control. Concentration-response curves for ATP were increased in pregnant group than control. Neostigmine augmented concentration-response curves for acetylcholine in control and pregnant groups. The effect of neostigmine on acetylcholine contractile responses in pregnancy group was higher than in control. CONCLUSIONS: Urinary bladder dysfunction during pregnancy might be due to augmentation of acetylcholinesterase effect. This will lead to the decrease in response to cholinergic stimuli. New pharmaceutical drugs specifically affecting the enzyme in the bladder can help in avoiding the unpleasant urinary symptoms during pregnancy. PMID- 30478813 TI - Transvesical laparoendosopic single-site surgery as a valuable option to remove eroded materials from the bladder: single-center experience and a review of the literature. AB - INTRODUCTION: Currently, polypropylene materials are used widely for the treatment of various urogynecologic disorders. This type of treatment can be complicated, although rarely, with erosions of the polypropylene implants into the bladder or the urethra. There is no established treatment for such complications. We present our experience in transvesical laparoendoscopic single site surgery (T-LESS) removal of eroded materials, and a review of the literature in this field. MATERIALS AND METHODS: From June 2015 to May 2017 eight females, with an average age of 66.5 years (range 55-80 years), were referred to our Center because of the erosion of polypropylene material in the bladder, after anti-incontinence or pelvic organ prolapse treatment. Patients were diagnosed with ultrasound and cystoscopy. Seven bladder erosions and one bladder and urethral penetration were found. Patients were qualified for removal with the T LESS approach. The Tri-Port + disposable set and standard laparoscopic instruments were used. The eroded materials were dissected and cut away, and the defects of the bladder wall were closed with barbed sutures. The peri-operative efficacy and safety of the method were assessed, and the patients were scheduled for follow-up visits at 6 weeks and every 3 months thereafter. The patients were offered a cystoscopic exam during the 7-10 month period after the operation. RESULTS: The procedures were completed successfully in all patients. No blood loss or complications were observed. The mean operative time was 54.5 min, and the average hospital stay was 30 h. During a follow-up at 11 months, all patients were cured, except for one who presented urethral erosion. CONCLUSIONS: The T LESS technique for removal of eroded meshes is a safe and effective method. The precise access to the bladder minimizes morbidity, and suturing the bladder wall defects may reduce the risk of recurrence. PMID- 30478814 TI - Radiation dose and image quality with new protocol in lower extremity computed tomography angiography. AB - PURPOSE: To compare radiation dose and image quality of lower extremity computed tomography angiography (CTA) between cranio-caudal acquisition with single-source CT (SSCT) and flash caudo-cranial acquisition with dual-source CT (DSCT). MATERIALS AND METHODS: In this prospective study, 60 patients were randomly assigned to Group A (control) or Group B (experimental) to undergo lower extremity CTA for peripheral obliterative arterial disease. Group A received protocol 1 (P1) with SSCT cranio-caudal acquisition. Group B received protocol (P2) with DSCT flash caudo-cranial acquisition. Intravascular attenuation (IVA), signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and image noise were compared. Two radiologists assessed the image quality. Computed tomography volume dose index (CTDIvol) and dose-length product (DLP) were also compared. RESULTS: IVA with P2 was higher than with P1 (586.8 +/- 140.3 vs. 496.1 +/- 129.3 HU, p = 0.011), as was SNR (33.0 +/- 11.3 vs. 27.4 +/- 12.3; p = 0.042), CNR (30.1 +/- 13.3 vs. 24.2 +/- 10.3; p = 0.029) and image quality score of small arteries below the knee (3.8 +/- 0.2 vs. 3.1 +/- 0.2; p = 0.001). Radiation dose was significantly lower in P2 than in P1 with CTDIvol reduction of 40.9% (1.3 +/- 0.1 vs. 2.2 +/- 0.3 mGy; p = 0.006) and DLP reduction of 42.8% (148.7 +/- 21.9 vs 260.2 +/- 59.1 mGy * cm; p = 0.018). CONCLUSION: Lower extremity CTA with DSCT flash caudo-cranial acquisition allows lower radiation dose with higher IVA, SNR, CNR and better image quality for small arteries below the knee than SSCT cranio caudal acquisition. PMID- 30478815 TI - How to measure quantitative antibiotic use in order to support antimicrobial stewardship in acute care hospitals: a retrospective observational study. AB - A cornerstone of antimicrobial stewardship programs (ASPs) is monitoring quantitative antibiotic use. Frequently used metrics are defined daily dose (DDD) and days of therapy (DOT). The purpose of this study was (1) to explore for the hospital setting the possibilities of quantitative data retrieval on the level of medical specialty and (2) to describe factors affecting the usability and interpretation of these quantitative metrics. We performed a retrospective observational study, measuring overall systemic antibiotic use at specialty level over a 1-year period, from December 1st 2014 to December 1st 2015, in one university and 13 non-university hospitals in the Netherlands. We distinguished surgical and non-surgical adult specialties. The association between DDDs, calculated from aggregated dispensing data, and DOTs, calculated from patient level prescription data, was explored descriptively and related to organizational factors, data sources (prescription versus dispensing data), data registration, and data extraction. Twelve hospitals were able to extract dispensing data (DDD), three of which on the level of medical specialty; 13 hospitals were able to extract prescription data (DOT), 11 of which by medical specialty. A large variation in quantitative antibiotic use was found between hospitals and the correlation between DDDs and DOTs at specialty level was low. Differences between hospitals related to organizational factors, data sources, data registration, and data extraction procedures likely contributed to the variation in quantitative use and the low correlation between DDDs and DOTs. The differences in healthcare organization, data sources, data registration, and data extraction procedures contributed to the variation in reported quantitative use between hospitals. Uniform registration and extraction procedures are necessary for appropriate measurement and interpretation and benchmarking of quantitative antibiotic use. PMID- 30478816 TI - Characterization of Protein Disulfide Linkages by MS In-Source Dissociation Comparing to CID and ETD Tandem MS. AB - Direct characterization of disulfide linkages in proteins by mass spectrometry has been challenging. Here, we report analysis of disulfide linkages in insulin variant, endothelin 3, and relaxin 2 by in-source dissociation (ISD) during LC MS. A duplet insulin peptide from Glu-C digestion that contains peptides p1 and p2 (from chains A and B, respectively) was selected as a model peptide. This duplet peptide has an inter-chain disulfide bond between p1 and p2, and an intra chain disulfide bond in p1. To compare the gas-phase fragmentation, it was subjected to ISD MS and MS/MS methods, including collision-induced dissociation (CID) and electron transfer dissociation (ETD). The pattern and efficiency of peptide backbone and disulfide cleavage varied with these dissociation methods. ETD, CID, and ISD were able to generate single backbone, double backbone, and triple (double backbone and single disulfide bond) cleavages in this model peptide, respectively. Specifically, CID did not cleave disulfide bonds and ETD was able to only cleave the inter-chain disulfide bond at low efficiency, limiting their usage in this disulfide analysis. In contrast, ISD was able to cleave the intra-chain disulfide bond in addition to peptide backbone, creating multiple fragment ions that allow accurate assignment of both intra- and inter chain disulfide linkages. ISD was also successfully applied to determine double disulfide linkages in endothelin 3 and relaxin 2 peptides. This study contributes to the fundamental understanding of disulfide bond cleavages in different gas phase fragmentations and provides an efficient cleavage strategy for identification of disulfide bonds in proteins by ISD ESI-MS. Graphical Abstract ?. PMID- 30478817 TI - Investigation of Hemicryptophane Host-Guest Binding Energies Using High-Pressure Collision-Induced Dissociation in Combination with RRKM Modeling. AB - In advancing host-guest (H-G) chemistry, considerable effort has been spent to synthesize host molecules with specific and well-defined molecular recognition characteristics including selectivity and adjustable affinity. An important step in the process is the characterization of binding strengths of the H-G complexes that is typically performed in solution using NMR or fluorescence. Here, we present a mass spectrometry-based multimodal approach to obtain critical energies of dissociation for two hemicryptophane cages with three biologically relevant guest molecules. A combination of blackbody infrared radiative dissociation (BIRD) and high-pressure collision-induced dissociation (high-pressure CID), along with RRKM modeling, was employed for this purpose. For the two tested hemicryptophane hosts, the cage containing naphthyl linkages exhibited stronger interactions than the cage bearing phenyl linkages. For both cages, the order of guest stability is choline > acetylcholine > betaine. The information obtained by these types of mass spectrometric studies can provide new insight into the structural features that most influence the stability of H-G pairs, thereby providing guidance for future syntheses. Graphical Abstract. PMID- 30478818 TI - A Case Report of Scrotal Rejuvenation: Laser Treatment of Angiokeratomas of the Scrotum. AB - Scrotal rejuvenation encompasses not only the functional quality but also the aesthetic appearance of the scrotum. It includes medical therapy and procedural interventions to improve scrotal conditions that require morphologic restoration and/or aesthetic alteration. Rejuvenation of the scrotum may be appropriate for aging-related and non-aging-related changes concerning the hair (alopecia and hypertrichosis), the morphology (laxity and wrinkles), and/or the vascularity (angiokeratoma) of the scrotum. Angiokeratomas-typically small, asymptomatic, purple papules-may occur on the scrotum. However, these benign vascular lesions may be of cosmetic concern to the affected individuals; in addition, the angiokeratomas can become an issue of medical importance if they begin to bleed. Multiple locally destructive modalities are available for the treatment of scrotal angiokeratomas; indeed, several lasers have effectively been used to treat angiokeratomas of the scrotum. A 70-year-old man with numerous scrotal angiokeratomas experienced scrotal bleeding in the absence of prior trauma to the area or sexual activity. He presented for treatment to prevent future episodes of spontaneous bleeding from his scrotal angiokeratomas, but he also had not liked the aesthetic appearance of the previously asymptomatic angiokeratomas on his scrotum. His angiokeratomas were successfully treated with three sequential 532 nm potassium titanyl phosphate (KTP) laser sessions, which led to not only functional but also cosmetic improvement of his scrotum. In conclusion, men can develop scrotal changes due to either intrinsic (aging) or extrinsic (trauma) causes, but nonsurgical interventions and surgical procedures are available for the management of these conditions in individuals who desire to rejuvenate their scrotum. PMID- 30478819 TI - Social Media and Body Dissatisfaction: Investigating the Attenuating Role of Positive Parent-Adolescent Relationships. AB - Previous research has shown that adolescents' social media use predicts increased body dissatisfaction. However, little is known about social environmental factors that may attenuate this relationship. This study examines one such potential moderating social environmental factor: positive parent-adolescent relationships. A school-based survey was conducted among 440 adolescents aged 12 to 19 (M = 14.9, SD = 1.8, 47% female). On average, social media use was positively associated with body dissatisfaction, but this relationship was weaker among adolescents who reported a more positive mother-adolescent relationship. Positive father-adolescent relationship did not moderate the association between social media use and body dissatisfaction. These findings may indicate that adolescents' social environment, notably the relationship they have with their mothers, can protect them against the detrimental effects of social media use on body dissatisfaction. However, longitudinal and experimental studies are needed to examine the direction of effects and test the validity of this interpretation. PMID- 30478820 TI - Parenting Strategies and Adolescents' Cyberbullying Behaviors: Evidence from a Preregistered Study of Parent-Child Dyads. AB - Little is known about how parents may protect against cyberbullying, a growing problem-behavior among youth. Guided by self-determination theory, a theory concerned with effectively motivating and regulating behavior, six preregistered hypotheses concerning parenting strategies of regulating cyberbullying behavior were tested in 1004 parent-child dyads (45.9% female adolescents; adolescents were either 14 (49.5%) or 15 (50.5%) years old). The results largely supported hypotheses: Parents who used more autonomy-supportive strategies-understanding the adolescent's perspective, offering choice, and giving rationales for prohibitions-had adolescents who reported engaging in less cyberbullying than parents who used controlling strategies (especially using guilt, shame, and conditional regard). Further, this was mediated by lower feelings of reactance to, or a desire to do the opposite of, parents' requests. The discussion focuses on the limits of this study to investigate reciprocal effects of adolescent behavior shaping parenting strategies-a critical agenda for future research-as well as the potential benefits of interventions aimed at increasing parental autonomy support for reducing cyberbullying and other problem behaviors in adolescents. PMID- 30478821 TI - Young Adult Unemployment and Later Depression and Anxiety: Does Childhood Neighborhood Matter? AB - Young adulthood represents a developmental period with disproportionately heightened risk of losing a job. Young adult unemployment has been linked to increased mental health problems, at least in the short term. However, their possible long-term impacts, often referred as "scarring effects," have been understudied, possibly underestimating the magnitude of mental health burden that young adult unemployment generates. This longitudinal study examined whether duration of unemployment during young adulthood is associated with later mental health disorders, after accounting for mental and behavioral health problems in childhood. Furthermore, the current study investigated whether childhood neighborhood characteristics affect this association and if so, in what specific functional ways. Data were drawn from a longitudinal study of developmental outcomes in a community sample in Seattle. Data collection began in 1985 when study participants were elementary students and involved yearly assessments in childhood and adolescence (ages 10-16) and then biennial or triennial assessments (ages 18-39; N = 677 at age 39; 47% European American, 26% African American, 22% Asian American, and 5% Native American; 49% female). The current study findings suggest that duration of unemployment across young adulthood increased mental health problems at age 39, regardless of gender. Childhood neighborhood characteristics, particularly their positive aspect, exerted independent impacts on adult mental health problems beyond unemployment experiences across young adulthood. The current findings indicate a needed shift in service profiles for unemployed young adults-a comprehensive approach that not only facilitates reemployment but also addresses mental health needs to help them to cope with job loss. Further, the present study findings suggest that childhood neighborhoods, particularly positive features such as positive neighborhood involvement, may represent concrete and malleable prevention targets that can curb mental health problems early in life. PMID- 30478822 TI - Improved Thermal and Reusability Properties of Xylanase by Genipin Cross-Linking to Magnetic Chitosan Particles. AB - Enzymes are gradually increasingly preferred over chemical processes, but commercial enzyme applications remain limited due to their low stability and low product recovery, so the application of an immobilization technique is required for repeated use. The aims of this work were to produce stable enzyme complexes of cross-linked xylanase on magnetic chitosan, to describe some characteristics of these complexes, and to evaluate the thermal stability of the immobilized enzyme and its reusability. A xylanase was cross-linked to magnetite particles prepared by in situ co-precipitation of iron salts in a chitosan template. The effect of temperature, pH, kinetic parameters, and reusability on free and immobilized xylanase was evaluated. Magnetization, morphology, size, structural change, and thermal behavior of immobilized enzyme were described. 1.0 +/- 0.1 MUg of xylanase was immobilized per milligram of superparamagnetic chitosan nanoparticles via covalent bonds formed with genipin. Immobilized xylanase showed thermal, pH, and catalytic velocity improvement compared to the free enzyme and can be reused three times. Heterogeneous aggregates of 254 nm were obtained after enzyme immobilization. The immobilization protocol used in this work was successful in retaining enzyme thermal stability and could be important in using natural compounds such as Fe3O4@Chitosan@Xylanase in the harsh temperature condition of relevant industries. PMID- 30478823 TI - Drug-Induced Anaphylaxis in a Vietnamese Pharmacovigilance Database: Trends and Specific Signals from a Disproportionality Analysis. AB - INTRODUCTION: Despite the numerous studies investigating drug-induced anaphylaxis (DIA), understanding and quantitative data analysis in developing countries remain limited. The aim of our study is to describe and quantify DIA using the National Pharmacovigilance Database of Vietnam (NPDV). METHODS: Spontaneous reporting of adverse drug reactions (ADRs) recorded between 2010 and 2016 were retrospectively analysed to identify DIA reports. The trend and characteristics of DIA cases were described. Multivariate disproportionality analysis was used for signal generation. RESULTS: Overall, 4873 DIA cases (13.2% of total ADRs) were recorded in the NPDV, 111 of which resulted in death (82% of total ADR induced deaths) over a 7-year period. There was a remarkable increase in DIA reporting over time (p < 0.001). The incidence rates of DIA reporting per total ADRs and per 100,000 inhabitants remained high (mean rates [95% CI] of 12.06 [9.88-14.24] and 0.77 [0.33-1.20], respectively). Concerning suspected drugs, systemic antibiotics (n = 3318, 68%) were mostly reported with a reporting odds ratio (ROR) and 95% CI of 2.35 [2.20-2.51]. In the case of antibiotic-induced anaphylaxis, the third-generation cephalosporins were predominant (n = 1961, 40.2%, ROR 2.39 [2.24-2.55]). We also noted drugs generally associated with DIA such as contrast agents (ROR 2.43 [2.04-2.88]) and anaesthetics (ROR 4.02 [3.30 4.89]). Furthermore, unexpected signals were observed for alpha-chymotrypsin (ROR 1.75 [1.23-2.44]) and amoxicillin/sulbactam (ROR 1.59 [1.18-2.10]), uncommonly reported in western countries. CONCLUSION: In recent years, cases of drug-induced DIA have increased in Vietnam, mostly due to antibiotics and third-generation cephalosporins. The inappropriate use of these drugs should be taken into account. Our findings also highlighted typical Vietnamese signals for alpha chymotrypsin- and amoxicillin/sulbactam-induced anaphylaxis, which may relate to a specific sociological context in resource-limited countries. PMID- 30478824 TI - The C2-Pars Interarticularis Screw as an Alternative in Atlanto-Axial Stabilization. A Biomechanical Comparison of Established Techniques. AB - AIM: To compare four different atlantoaxial stabilization techniques. MATERIAL AND METHODS: Eight human cervical spines (segments C0-C3) were tested in flexion/extension, lateral bending and axial rotation. Range of Motion (ROM) at a 1.5 Nm load was recorded. After native testing, the Harms (HARMS), pars screw (PARS), intralaminar screw (INTRA) and anterior transarticular screw (ATA) constructs were applied in a random order. RESULTS: FLEXION/EXTENSION: mean ROM (+/-SD) in native state was 15.9 degrees (+/- 7.6 degrees ); HARMS 3.6 degrees (+/- 2.0 degrees ); INTRA 5.5 degrees (+/- 2.7 degrees ); PARS 2.8 degrees (+/- 1.6 degrees ); ATA 3.7 degrees (+/- 1.3 degrees ). A significant difference was found for all techniques compared to the native spine. LATERAL BENDING: ROM in native state was 3.2 degrees (+/- 1.9 degrees ); HARMS 1.4 degrees (+/- 0.4 degrees ); INTRA 2.5 degrees (+/- 1.4 degrees ); PARS 1.3 degrees (+/- 0.7 degrees ); ATA 0.9 degrees (+/- 0.6 degrees ). There were no significant differences compared to native spine, although ATA and PARS showed a strong tendency. INTRA had a significantly higher ROM than ATA. AXIAL ROTATION: ROM in native state was 15.7 degrees (+/- 6.6 degrees ); HARMS 1.5 degrees (+/- 0.7); INTRA 2.7 degrees (+/- 2.1 degrees ); PARS 1.7 degrees (+/- 0.7); ATA 1.1 degrees (+/- 0.3 degrees ). All instrumentation techniques significantly reduced ROM; there was no significant difference between the techniques. All instrumentation techniques were able to reduce ROM for most of the motions. The differences between the techniques were small. Nevertheless, the intralaminar screw showed deficits in lateral bending. CONCLUSION: Screw positioning seems to be of minor influence on stability in atlantoaxial stabilization. Therefore, the pars screw is a sound alternative to the established techniques from a biomechanical point of view. Anatomical considerations for screw placement should be kept in mind as a superior priority. PMID- 30478825 TI - Arabidopsis thaliana alpha1,2-l-fucosyltransferase catalyzes the transfer of l galactose to xyloglucan oligosaccharides. AB - l-Galactose (l-Gal) is one of the components of plant cell wall polysaccharides. In the GDP-l-fucose-deficient Arabidopsis thaliana mutant mur1, l-fucose (l-Fuc) residues in xyloglucan are substituted by l-Gal residues. l-Gal only differs from l-Fuc by the presence of an oxygen at C-6. Thus, we hypothesized that the A. thaliana xyloglucan alpha1,2-l-fucosyltransferase (AtFUT1) is also responsible for the l-galactosyl transfer to d-galactose residues in xyloglucan. In this study, we heterologously produced AtFUT1 in fission yeast and carried out an in vitro assay for the activities of AtFUT1 on GDP-l-galactose and xyloglucan oligosaccharide. We show that the recombinant AtFUT1 catalyzes l-Gal transfer to xyloglucan oligosaccharides although the initial velocity of l-Gal transfer is 3.1 times lower than that of l-Fuc transfer. This article is protected by copyright. All rights reserved. PMID- 30478827 TI - A cross-sectional study of YouTube videos about psoriasis biologics. PMID- 30478828 TI - IgA deposition in a vegetating plaque on the glans penis: a diagnostic dilemma. PMID- 30478826 TI - A guideline for the diagnosis and management of polycythaemia vera. A British Society for Haematology Guideline. PMID- 30478829 TI - Cardiovascular complications and related risk factors underlying opium consumption. AB - Opium is considered as the second most abused addictive compound in worldwide. It seems that one of the causes for common consumption of opium in many countries is a traditional belief, even among medical personnel, through which opium might have advantageous influences on cardiovascular events and be beneficial in controlling hypertension, dyslipidemia, and diabetes. According to several investigations, it is thought that opium not only has no beneficial effects on cardiovascular events, but it might have deleterious influences on these settings. As a result, people need to be trained with regard to the adverse effects of opium on cardiovascular events. In this review, we try to go through the understanding of the effects of opium cardiovascular disorders and related complications such as blood pressure, blood sugar, lipid circumstances, and finally atherosclerosis. PMID- 30478830 TI - SP1, MYC, CTNNB1, CREB1, JUN genes as potential therapy targets for neuropathic pain of brain. AB - Neuropathic pain (NP) may cause serious brain diseases, but the genes associated with the metabolic pathway and transcript factors of NP remain unclear. This study is aimed to identify the therapy target genes for NP and to investigate the metabolic pathways and transcript factors associated with NP. The differentially expressed genes of three brain tissues (nucleus accumbens, periaqueductal gray, and prefrontal cortex) dealt with NP stimulation were analyzed. Besides, The Database for Annotation, Visualization, and Integrated Discovery and Tfacts datasets were used in the analysis of the genes related to the metabolic pathway and transcript factors of the brain. Eight genes were found to coexpress in all three tissues. A functional enrichment analysis showed that the upregulated genes were mostly enriched in pathways as inflammatory response, calcium-mediated signaling, cytokine-cytokine receptor interaction, and extracellular matrix (ECM) receptor interaction, whereas the downregulated genes were mostly enriched in pathways as phospholipid metabolic processes, positive regulation of protein kinase B signaling, and metabolism of xenobiotics by cytochrome P450. Finally, 135 and 98 transcript factors genes were upregulated and downregulated, among which SP1, MYC, CTNNB1, CREB1, JUN were identified as the most critical genes because the number of up- and downregulated gene ranked at the top. In conclusion, the pathways of immune response and cytokine-cytokine receptor interaction were determined as the main metabolic pathways of NP affecting the brain, and SP1, MYC, CTNNB1, CREB1, JUN genes were recognized as the most enriched genes in this process, which may provide evidence for the diagnosis and treatment research of neuropathic pain. PMID- 30478831 TI - Induced pluripotent stem cell-derived extracellular vesicles: A novel approach for cell-free regenerative medicine. AB - In recent years, induced pluripotent stem cells (iPSCs) have been considered as a promising approach in the field of regenerative medicine. iPSCs can be generated from patients' somatic cells and possess the potential to differentiate, under proper conditions, into any cell type. However, the clinical application of iPS cells is restricted because of their tumorigenic potential. Recent studies have indicated that stem cells exert their therapeutic benefit via a paracrine mechanism, and extracellular vesicles have been demonstrated that play a critical role in this paracrine mechanism. Due to lower immunogenicity, easier management, and presenting no risk of tumor formation, in recent years, researchers turned attention to exosomes as potential alternatives to whole-cell therapy. Application of exosomes derived from iPSCs and their derived precursor provides a promising approach for personalized regenerative medicine. This study reviews the physiological functions of extracellular vesicles and discusses their potential therapeutic benefit in regenerative medicine. PMID- 30478832 TI - Downregulation of microRNA-592 protects mice from hypoplastic heart and congenital heart disease by inhibition of the Notch signaling pathway through upregulating KCTD10. AB - Evidence has demonstrated that the microRNA (miR) may play a significant role in the development of congenital heart disease (CHD). Here, we explore the mechanism of microRNA-592 (miR-592) in heart development and CHD with the involvement of KCTD10 and Notch signaling pathway in a CHD mouse model. Cardiac tissues were extracted from CHD and normal mice. Immunohistochemistry staining was performed to detect positive expression rate of KCTD10. A series of inhibitor, activators, and siRNAs was introduced to verified regulatory functions for miR-592 governing KCTD10 in CHD. Furthermore, the effect of miR-592 on cell proliferation and apoptosis was also investigated. Downregulated positive rate of KCTD10 was observed in CHD mice. Downregulation of miR-592 would upregulate expression of KCTD10 and inhibit the activation of Notch signaling pathway, thus promote cell proliferation. This study demonstrates that downregulation of miR-592 prevents CHD and hypoplastic heart by inhibition of the Notch signaling pathway via negatively binding to KCTD10. PMID- 30478833 TI - Aflatoxin G1 induced TNF-alpha-dependent lung inflammation to enhance DNA damage in alveolar epithelial cells. AB - Aflatoxin G1 (AFG1 ), a member of the AF family with cytotoxic and carcinogenic properties, could cause DNA damage in alveolar type II (AT-II) cells and induce lung adenocarcinoma. Recently, we found AFG1 could induce chronic lung inflammation associated with oxidative stress in the protumor stage. Chronic inflammation plays a critical role in cigarette smoke or benzo[a]pyrene-induced lung tissues damage. However, it is unclear whether and how AFG1 -induced lung inflammation affects DNA damage in AT-II cells. In this study, we found increased DNA damage and cytochrome P450 (CYP2A13) expression in AFG1 -induced inflamed lung tissues. Furthermore, we treated the mice with a soluble tumor necrosis factor (TNF)-alpha receptor and AFG1 and found that TNF-alpha neutralization inhibited the AFG1 -induced chronic lung inflammation in vivo, and then reversed the CYP2A13 expression and DNA damage in AT-II cells. The results suggest that AFG1 induces TNF-alpha-dependent lung inflammation to regulate 2A13 expression and enhance DNA damage in AT-II cells. Then, we treated the primary mice AT-II cells and human AT-II like cells (A549) with AFG1 and TNF-alpha and found that TNF-alpha enhanced the AFG1 -induced DNA damage in mice AT-II cells as well as A549 cells in vitro. In AFG1 -exposed A549 cells, TNF-alpha-enhanced DNA damage and apoptosis were reversed by CYP2A13 small interfering RNA. Blocking NF-kappaB pathway inhibited the TNF-alpha-enhanced CYP2A13 upregulation and DNA damage confirming that the CYP2A13 upregulation by TNF-alpha plays an essential role in the activation of AFG1 under inflammatory conditions. Taken together, our findings suggest that AFG1 induces TNF-alpha-dependent lung inflammation, which upregulates CYP2A13 to promote the metabolic activation of AFG1 and enhance oxidative DNA damage in AT-II cells. PMID- 30478834 TI - Expression and regulatory networks of Mycobacterium tuberculosis PE/PPE family antigens. AB - PE/PPE family antigens are distributed mainly in pathogenic mycobacteria and serve as potential antituberculosis (TB) vaccine components. Some PE/PPE family antigens can regulate the host innate immune response, interfere with macrophage activation and phagolysosome fusion, and serve as major sources of antigenic variation. PE/PPE antigens have been associated with mycobacteria pathogenesis; pe/ppe genes are mainly found in pathogenic mycobacteria and are differentially expressed between Mtb and Mycobacterium bovis. PE/PPE proteins were essential for the growth of Mtb, and PE/PPE proteins were differentially expressed under a variety of conditions. Multiple mycobacterial-virulence-related transcription factors, sigma factors, the global transcriptional regulation factor Lsr2, MprAB, and PhoPR two-component regulatory systems, and cyclic adenine monophosphate dependent regulators, regulate the expression of PE/PPE family antigens. Multiple scale integrative analysis revealed the expression and regulatory networks of PE/PPE family antigens underlying the virulence and pathogenesis of Mtb, providing important clues for the discovery of new anti-TB measures. PMID- 30478835 TI - Surgery of the major salivary glands and its impact on salivary flow-A review. AB - OBJECTIVE: The aim of this study was to bring attention to a rather unnoted side effect of salivary gland surgery-reduced salivary flow. METHODS: A systematic PubMed, Cochrane Library, LIVIVO, and Embase databases search was performed to identify relevant articles. RESULTS: Eight studies matched the inclusion criteria. All studies described an association between salivary gland surgery and reduced salivary flow. In five of the eight studies, patients reported on xerostomia after salivary gland surgery. CONCLUSIONS: Head and neck surgeons should inform their patients more accurately about reduced salivary flow and possible xerostomia after salivary gland surgery, and focus more on conservative strategies and minimally invasive techniques. Laryngoscope, 2018. PMID- 30478836 TI - Identification of functional lncRNAs in atrial fibrillation by integrative analysis of the lncRNA-mRNA network based on competing endogenous RNAs hypothesis. AB - A mounting body of evidence has suggested that long noncoding RNAs (lncRNAs) play critical roles in human diseases by acting as competing endogenous RNAs (ceRNAs). However, the functions and ceRNA mechanisms of lncRNAs in atrial fibrillation (AF) remain to date unclear. In this study, we constructed an AF-related lncRNA mRNA network (AFLMN) based on ceRNA theory, by integrating probe reannotation pipeline and microRNA (miRNA)-target regulatory interactions. Two lncRNAs with central topological properties in the AFLMN were first obtained. By using bidirectional hierarchical clustering, we identified two modules containing four lncRNAs, which were significantly enriched in many known pathways of AF. To elucidate the ceRNA interactions in certain disease or normal condition, the dysregulated lncRNA-mRNA crosstalks in AF were further analyzed, and six hub lncRNAs were obtained from the network. Furthermore, random walk analysis of the AFLMN suggested that lncRNA RP11-296O14.3 may function importantly in the pathological process of AF. All these eight lncRNAs that were identified from previous steps (RP11-363E7.4, GAS5, RP11-410L14.2, HAGLR, RP11-421L21.3, RP11 111K18.2, HOTAIRM1, and RP11-296O14.3) exhibited a strong diagnostic power for AF. The results of our study provide new insights into the functional roles and regulatory mechanisms of lncRNAs in AF, and facilitate the discovery of novel diagnostic biomarkers or therapeutic targets. PMID- 30478837 TI - MicroRNA: A new player in response to therapy for colorectal cancer. AB - Colorectal cancer (CRC) is one of the important malignancies that result in cancer-related deaths worldwide. Multiple lines of evidence have indicated that different responses to therapy in CRC cells led to the failure of the current therapies. Hence, identification of the underlying cellular and molecular pathways involved in the emergence of different responses from CRC cells could contribute to finding and designing new therapeutic platforms to overcome the present limitations. Among the various targets involved in CRC pathogenesis, microRNAs (miRNAs) have key roles in many signaling pathways that are associated with the initiation and progression of CRC. Increasing evidence has confirmed that miRNAs as epigenetic regulators could play critical roles in the response (resistance or sensitivity) to therapy. Cancer stem cells are well-known players in resistance to therapy in CRC. They have been shown to play significant roles via inhibition and activation of many miRNA networks. Hence, miRNAs could be involved in the resistance and sensitivity of therapy in CRC cells via affecting different mechanisms, such as activation of cancer stem cells. Here, we summarized the role of various miRNAs in response to therapy of CRC cells. Moreover, we highlighted the roles of these molecules in the function of cancer stem cells, which are known as important players in the resistance to therapy in CRC. PMID- 30478838 TI - Hugh Wirth AM 1939-2018. PMID- 30478841 TI - In this issue - December 2018: Pro bono wildlife work in Australian veterinary practices . Roaming owned dogs in Northern Australia . Snake stomach recovers after gastrectomy . Metronidazole-induced neurotoxicity in 26 dogs . Lomustine ineffective for haemophagocytic histiocytic sarcoma . Surgical swabs and dehorning wounds. PMID- 30478839 TI - Lomustine chemotherapy for the treatment of presumptive haemophagocytic histiocytic sarcoma in Flat-coated Retrievers. AB - BACKGROUND: The Flat-coated Retriever (FCR) is a breed at-risk for histiocytic sarcoma (HS). A haemophagocytic form of HS (HPHS) occurs in the spleen +/- other sites such as bone marrow, and is a CD11d+ disease of macrophage origin. Patients with HPHS typically present with regenerative anaemia. Lomustine is a well accepted, first-line chemotherapy for dogs with HS, but its specific utility in dogs with HPHS has not been previously reported. METHODS: A cohort of 10 dogs presumptively diagnosed with HPHS via splenic +/- bone marrow or liver aspiration cytology were treated with lomustine, plus supportive medications as required. Cytology of liver and bone marrow was diagnostically useful in patients where splenic cytology was less convincing. RESULTS: No dogs experienced significant constitutional or gastrointestinal adverse effects following lomustine administration, though most dogs displayed clinical signs associated with the underlying disease. No patients appeared to derive discernible clinical benefit from chemotherapy. Neutropenia was a common adverse effect of lomustine. Concurrent medications included corticosteroids in all cases, prior to the diagnosis of HPHS, for a provisional diagnosis of immune-mediated haemolytic anaemia. Median survival time of the treated dogs was 24 days from diagnosis (range, 4-67 days). CONCLUSIONS: HPHS affecting FCRs appears to have a uniformly poor outcome and is rapidly fatal. Lomustine chemotherapy was unsuccessful in significantly improving outcome in this cohort of patients. Further study of this rare and devastating disease is needed. PMID- 30478842 TI - Demographic studies of owned dogs in the Northern Peninsula Area, Australia, to inform population and disease management strategies. AB - OBJECTIVE: To generate domestic dog demographic information to aid population and disease management in the Aboriginal and Torres Strait Islander communities of the Northern Peninsula Area, Queensland, Australia. METHODS: Sight-resight surveys using standard and modified methods were conducted to estimate the free roaming dog population size. A cross-sectional questionnaire of dog owners was used to gather dog demographic information and investigate owners' dog management behaviours. A survey was also conducted to estimate the total dog population size. RESULTS: The mean total dog population size was estimated to be 813 (range, 770-868). The roaming dog population was 430 or 542 (95% confidence interval (CI) 254-608; 95% CI 405-680, standard and modified methods, respectively). Therefore, the roaming population represents 52.8% or 66.7% of the total population based on the sight-resight methodology. We surveyed 65 dog owners who owned 165 dogs (1 : 1 ratio of male : female dogs). Only 14% (95% CI 9-19) of dogs were sterilised and significantly more males were entire (P = 0.02). Although most dogs were pets (65%), hunting dogs were significantly more likely to be taken outside of the resident community (P < 0.001). The birth rate was 2.4 puppies/dog-owning house/year, which was higher than the death rate (1.7 dogs/dog-owning house/year). In the previous 12 months, 90% of the 109 deaths were dogs aged 0-2 years old. CONCLUSION: This study demonstrated that most of the dog population in the NPA is free-roaming and that the population has increased, likely because of a lack of population management strategies such as sterilisation. This information will be used to develop population and disease management strategies in the NPA. PMID- 30478843 TI - Metronidazole-induced neurotoxicity in 26 dogs. AB - BACKGROUND: Metronidazole is an antibacterial, antiprotozoal and anthelmintic medication commonly used in veterinary medicine. We describe cases of neurotoxicity associated with the drug's administration. METHODS: Medical records between 2004 and 2017 from four veterinary referral hospitals were reviewed. Inclusion criteria were the presence of neurological signs compatible with metronidazole toxicity, clinical history supporting recent metronidazole therapy and resolution of clinical signs upon discontinuation of metronidazole administration. RESULTS: A total of 26 dogs were identified with clinical signs supporting a diagnosis of metronidazole toxicity. Median age at presentation was 7.2 years (range, 0.1-12 years); median duration of treatment was 35 days (range, 5-180 days); median treatment dosage was 21 mg/kg BID (range, 13-56 mg/kg every 12 h); median resolution of the clinical signs upon discontinuation of metronidazole was 3 days (range, 1-26 days). Magnetic resonance imaging (MRI) of the brain was performed in 19 cases and only one dog had brain lesions affecting the dentate nuclei, which resembled the MRI appearance of this disease in humans. CONCLUSIONS: We found evidence of neurotoxicity in dogs at much lower doses than previously reported and we suggest caution when administering metronidazole at doses > 40 mg/kg every 24 h, regardless of the duration of the treatment. PMID- 30478844 TI - Animal welfare implications of treating wildlife in Australian veterinary practices. AB - OBJECTIVE: To evaluate the extent, costs, demands and expectations of Australian veterinary practices in the treatment of wildlife, to identify potential risks to animal welfare based on the current situation and to propose recommendations for improvements. METHODS: A survey was sent to all veterinary practices across Australia identified through the website Yellow Pages(r). The survey was designed as a cross-sectional study. Data were collected using an online self-completed questionnaire and analysed using IBM SPSS 19.0. RESULTS: Of the 902 veterinary practices contacted, 132 (14.6%) completed the questionnaire. Most practices (82%) saw less than 10 wildlife patients per week, with birds and marsupials most commonly admitted. Vehicular trauma, trauma (other) and predation made up the majority (82%) of presentations. However, wildlife cases were only examined immediately upon presentation in 20% of practices, with 74% reporting they only attended to wildlife whenever they had spare time. The majority (90%) of veterinary practices never or rarely received reimbursement for their wildlife work, indicating most is performed pro bono. Several barriers to treatment were highlighted, including time and a lack of knowledge/skills. CONCLUSION: Private veterinary practices play a more significant role in wildlife treatment than has been previously thought. The effect of perceived barriers on willingness to treat wildlife requires further research. Further investigation into educational resources to aid veterinary assessment of wildlife should also be considered. PMID- 30478845 TI - Joseph Coloman Boray 1926-2018. PMID- 30478846 TI - Postoperative healing and behaviour when surgical swabs are applied to calf dehorning wounds. AB - OBJECTIVE: To assess the effect on healing and pain-associated behaviours of covering exposed sinuses after horn amputation under extensive production conditions in northern Australia. METHODS: Horned, weaned Brahman-cross heifers (n = 50) aged approximately 6 months were alternately allocated to have their dehorning wounds either patched with a dry, non-sterile gauze swab or left untreated. Adherence of swabs and growth rates, healing and pain-associated behaviour were monitored for 88 days post-surgery. RESULTS: Half of the patches were lost by 24 h post-surgery, with most of the rest falling off 2-6 weeks later. Patching resulted in healing 5.5 days earlier (P = 0.018). Sealing of exposed frontal sinuses occurred in most heifers within 3 weeks and full healing occurred within 13 weeks. Patching reduced haemorrhage (P < 0.01) regardless of when the patches were dislodged, prevented insect invasion of the wound and reduced the incidence of secondary infection (P < 0.01). Wound patches did not affect behaviour in the weeks following surgery. In the days after surgery, the heifers did not eat and showed a high incidence of behaviours indicating pain. Behaviour was relatively normal by 2 weeks after surgery, although the heifers avoided social interaction with other unbranded calves for 4 weeks. CONCLUSION: The application of gauze swabs to dehorning wounds advanced healing, reduced the incidence of haemorrhage and secondary infections, and may reduce deaths. Efficacy is expected to improve if high rates of 24-h retention of patches can be achieved. The prolonged time to healing and the pain-associated behaviours highlight the need for better welfare of dehorned calves through improvements in analgesia, surgical procedures and post-surgical care. PMID- 30478847 TI - Compensatory gastric stretching following subtotal gastric resection due to gastric adenocarcinoma in a diamond python (Morelia spilota spilota). AB - CASE REPORT: A 7-year-old male diamond python (Morelia spilota spilota) presented with a 2-month history of anorexia and a discrete intracoelomic mass, approximately 15 cm in length, located 90 cm from the head and approximately two thirds of the snout to vent length. Physical examination determined the mass was likely to be stomach, testes or the right kidney. Radiographs showed a soft tissue opacity mass in the region of the stomach; fine needle aspirate demonstrated cellular debris admixed with bacteria and degenerate heterophils. Exploratory coeliotomy revealed a gastric mass involving 90% of the length of the stomach, partially occluding the gastric lumen. A subtotal gastrectomy was performed; the neoplastic tissue was removed with 2 cm margins, leaving 1 cm of stomach wall and the pyloric sphincter caudally that was anastomosed to the oesophagus. Four large nematodes were found within the necrotic lumen of the mass tightly adhered to the gastric mucosa. Ascarid nematodes were identified morphologically and further confirmed by molecular diagnostics as Ophidascaris spp. Histopathological evaluation of the excised mass revealed a gastric adenocarcinoma. Postoperatively the snake suffered from gastrointestinal dysfunction and maldigestion and was managed with slurry feeding for month. Three months postoperatively the snake was gaining weight, eating without assistance and digesting whole prey, which was incrementally increased in size. Gastroscopy 6 months postoperatively revealed the presence of a functional stomach with a functional pyloric sphincter and 8.5 cm of gastric mucosa caudal to the anastomosis between the oesophagus and stomach. CONCLUSION: This is the first report of almost complete subtotal gastric resection in an Australian python, with evidence of compensatory gastric stretching resulting in a functional stomach. PMID- 30478848 TI - Local and systemic adverse skin reactions following the use of herbal products believed to contain Nigella sativa seeds and oil. PMID- 30478849 TI - Comparative morphology of the deer ked Lipoptena fortisetosa first recorded from Italy. AB - Hippoboscidae flies parasitize various animal species. Knowledge about these insects remains sparse, although they are known to cause stress and damage to their hosts, and can also accidentally infest humans, causing different sanitary risks. Research conducted in Tuscany assessing the biology and distribution of Lipoptena cervi (Linnaeus, 1758) (Diptera: Hippoboscidae), the most common ectoparasite of ungulates in Italy, revealed the presence of Lipoptena fortisetosa Maa, 1965 in Italy for the first time. This study includes a morphological comparative description of L. cervi and L. fortisetosa, emphasizing the peculiar differences between the two species to facilitate their accurate identification. The most pertinent morphological differences between the two species are highlighted, such as the external features of the antennae, distribution of bristles, and different features in the external genitalia. In both species, scanning electron microscopy of mouthparts revealed strong adaptive convergence in the feeding apparatus. Modified palps and a very thin proboscis are described in relation to feeding behaviour. PMID- 30478850 TI - Large scale in-vivo micro-RNA loss of function screen identified miR-29a, miR-100 and miR-155 as modulators of radioresistance and tumor-stroma communication. AB - Micro RNAs (miR) are master regulators of cellular transcriptome. We aimed to investigate the role of miR regulation on tumor radiosensitivity and development of local tumor recurrence by a novel large-scale in-vivo loss of function screen. For stable miR silencing, human A431 tumor cells were transduced with lentiviral constructs against 170 validated human miR (miRzip library). Fractionated radiotherapy (5x6Gy) was applied to A431 miRzip library growing s.c. in NCr nude mice. Enrichment of miRZip and miR expression was assessed using multiplexed qRT PCR. The modulatory effect of miR on tumor and tumor microenvironment response to ionizing radiation was further evaluated by clonogenic survival, apoptosis (Caspase 3/7), DNA double-strand breaks (DSB, nuclear gammaH2AX foci), tumor microvessel density (MVD), transcriptome and protein analysis. Fractionated irradiation of the A431 miRzip library led to regression of tumors. However, after a latency period, tumors ultimately progressed and formed local recurrences indicating the survival of a subpopulation of miRzip expressing tumor clones. Among the selected miR for subsequent validation studies, loss of miR-29a, miR 100 and miR-155 was found to enhance clonogenic survival, reduce apoptosis and residual gammaH2AX foci of irradiated tumor cells. Moreover, knockdown of miR increased tumor angiogenesis correlating with elevated VEGF and TGFalpha expression levels. This phenomenon was most evident after tumor irradiation in vivo suggesting a critical role for tumor-stroma communication in development of the radioresistant phenotype. Engineering radioresistant tumors in-vivo by modulating miR expression may lead to identification of critical targets for conquering local therapy failure. This article is protected by copyright. All rights reserved. PMID- 30478851 TI - Latin American countries lead in Google search volumes for anorexia nervosa and bulimia nervosa: Implications for global mental health research. AB - OBJECTIVE: Although eating disorders occur worldwide, prevalence data beyond Euro American contexts are sparse, and eating disorders largely remain outside global mental health agendas. This study aims to address this gap in the epidemiological literature through a global infodemiological comparison of Google search volumes for the topics "Anorexia nervosa" and "Bulimia nervosa." METHOD: Data were generated through Google Trends, a tool that assesses the relative search volumes of keywords and topics. Google Trends data, collected from January 1, 2004 to December 31, 2016, were obtained for the relative search volumes of the topics "Anorexia nervosa" and "Bulimia nervosa" worldwide. RESULTS: The findings revealed that Latin American countries accounted for the top 10 in search volume for both topics, with Mexico ranked first until 2016, when Bolivia rose to the top of the list. DISCUSSION: The results suggest that eating disorders are of considerable and consistent salience across Latin America, and that population based, nationally representative studies to assess the prevalence of eating disorders in Latin American countries should be prioritized within global mental health research agendas. PMID- 30478852 TI - Assessing potential shared genetic aetiology between body mass index and sleep duration in 142,209 individuals. AB - Observational studies find an association between increased body mass index (BMI) and short self-reported sleep duration in adults. However, the underlying biological mechanisms that underpin these associations are unclear. Recent findings from the UK Biobank suggest a weak genetic correlation between BMI and self-reported sleep duration. However, the potential shared genetic aetiology between these traits has not been examined using a comprehensive approach. To investigate this, we created a polygenic risk score (PRS) of BMI and examined its association with self-reported sleep duration in a combination of individual participant data and summary-level data, with a total sample size of 142,209 individuals. Although we observed a nonsignificant genetic correlation between BMI and sleep duration, using LD score regression (rg = -0.067 [SE = 0.039], P = 0.092) we found that a PRS of BMI is associated with a decrease in sleep duration (unstandardized coefficient = -1.75 min [SE = 0.67], P = 6.13 * 10-7 ), but explained only 0.02% of the variance in sleep duration. Our findings suggest that BMI and self-reported sleep duration possess a small amount of shared genetic aetiology and other mechanisms must underpin these associations. PMID- 30478854 TI - Hemophagocytic Lymphohistiocytosis Secondary to Babesia in an Immunocompetent Adult. PMID- 30478855 TI - A randomized controlled trial to evaluate the effectiveness of a brief motivational intervention to improve exclusive breastfeeding rates: study protocol. AB - AIMS: To estimate the effectiveness of a brief motivational intervention (BMI) in increasing the duration of exclusive breastfeeding in the first six months postpartum. A complementary aim is to examine a potential mediating role of breastfeeding self-efficacy in the effectiveness of the BMI. BACKGROUND: Breastfeeding is associated with benefits for babies and mothers' health. Among the pool of techniques used to encourage healthy behaviours, BMI is highlighted based on the principles of motivational interviewing. One of the main components of these interventions is the promotion of self-efficacy, which, in fact, is a key factor for breastfeeding success. DESIGN: A multi-centre randomized controlled clinical trial of parallel groups. METHODS: Women who begin to breastfeed in the first hour after birth will be randomly assigned to the intervention group (receiving a BMI at immediate postpartum plus a telephone booster at the 1st and 3rd month postpartum) or the control group (receiving standard breastfeeding education at the same time). Outcome measures include the following: breastfeeding, breastfeeding self-efficacy, general self-efficacy and postnatal depression. Data will be collected before the intervention and at the 1st, 3rd and 6th month after birth. The study protocol has been approved by Badajoz Ethics Committee of Clinical Research in October 2017. DISCUSSION: This study will identify the effectiveness of BMI in improving exclusive breastfeeding rates. The findings will provide useful evidence to health professionals about how to support breastfeeding. IMPACT: This study will address the low exclusive breastfeeding rates, that in our country are far lower than WHO's recommendation. This article is protected by copyright. All rights reserved. PMID- 30478856 TI - Long noncoding RNA LINC00460 promotes carcinogenesis via sponging miR-613 in papillary thyroid carcinoma. AB - Long intergenic noncoding RNA 460 (LINC00460) has been identified as a critical regulator for multiple types of cancers. However, the biological role and underlying mechanism in human papillary thyroid carcinoma (PTC) still remain unclear and need to be uncovered. This study was aimed to ascertain the biological role and molecular mechanism of LINC00460 in PTC progression. Our findings revealed that the level of LINC00460 was significantly upregulated in PTC tissues and cell lines, which was positively correlated with advanced tumor node-metastasis (TNM) stage and lymph node metastasis. Cellular experiments exhibited that knockdown of LINC00460 decreased proliferative, migratory, and invasive abilities of PTC cells. Mechanism assays noted that knockdown of LINC00460 suppressed cell proliferation, migration, and invasion, and inhibited expression of sphingosine kinase 2 (SphK2, a target of miR-613) in PTC cells, at least in part, by regulating miR-613. These findings suggested that LINC00460 could function as a competing endogenous RNA to regulate SphK2 expression by sponging miR-613 in PTC. Targeting LINC00460 could be a promising therapeutic strategy for patients with PTC. PMID- 30478857 TI - Integrated motion correction and dictionary learning for free-breathing myocardial T1 mapping. AB - PURPOSE: To develop and evaluate an integrated motion correction and dictionary learning (MoDic) technique to accelerate data acquisition for myocardial T1 mapping with improved accuracy. METHODS: MoDic integrates motion correction with dictionary learning-based reconstruction. A random undersampling scheme was implemented for slice-interleaved T1 mapping sequence to allow prospective undersampled data acquisition. Phantom experiments were performed to evaluate the effect of reconstruction on T1 measurement. In vivo T1 mappings were acquired in 8 healthy subjects using 6 different acceleration approaches: uniform or randomly undersampled k-space data with reduction factors (R) of 2, 3, and 4. Uniform undersampled data were reconstructed with SENSE, and randomly undersampled k space data were reconstructed using dictionary learning, compressed sensing SENSE, and MoDic methods. Three expert readers subjectively evaluated the quality of T1 maps using a 4-point scoring system. The agreement between T1 values was assessed by Bland-Altman analysis. RESULTS: In the phantom study, the accuracy of T1 measurements improved with increasing reduction factors ( CONCLUSION: The MoDic method accelerates data acquisition for myocardial T1 mapping with improved T1 measurement accuracy. PMID- 30478858 TI - Iron, erythropoietin, and inflammation regulate hepcidin in Bmp2-deficient mice, but serum iron fails to induce hepcidin in Bmp6-deficient mice. AB - The bone morphogenetic protein (BMP)-SMAD signaling pathway is a key transcriptional regulator of hepcidin in response to tissue iron stores, serum iron, erythropoietic drive and inflammation to increase the iron supply when needed for erythropoiesis, but to prevent the toxicity of iron excess. Recently, BMP2 was reported to play a non-redundant role in hepcidin regulation in addition to BMP6. Here, we used a newly validated BMP2 ELISA assay and mice with a global or endothelial conditional knockout (CKO) of Bmp2 or Bmp6 to examine how BMP2 is regulated and functionally contributes to hepcidin regulation by its major stimuli. Erythropoietin (EPO) did not influence BMP2 expression in control mice, and still suppressed hepcidin in Bmp2 CKO mice. Lipopolysaccharide (LPS) reduced BMP2 expression in control mice, but still induced hepcidin in Bmp2 CKO mice. Chronic dietary iron loading that increased liver iron induced BMP2 expression, whereas acute oral iron gavage that increased serum iron without influencing liver iron did not impact BMP2. However, hepcidin was still induced by both iron loading methods in Bmp2 CKO mice, although the degree of hepcidin induction was blunted relative to control mice. Conversely, acute oral iron gavage failed to induce hepcidin in Bmp6-/- or CKO mice. Thus, BMP2 has at least a partially redundant role in hepcidin regulation by serum iron, tissue iron, inflammation and erythropoietic drive. In contrast, BMP6 is absolutely required for hepcidin regulation by serum iron. This article is protected by copyright. All rights reserved. PMID- 30478859 TI - Missing canines: a novel aetiology. AB - Infant oral mutilation is the practice of removing developing tooth germs, commonly the mandibular canine, in infants up to the age of one year. Subsequent complications include missing, impacted or hypoplastic permanent anterior and canine teeth. We report on a case of bilaterally missing lower canines thought to be due to infant oral mutilation. It is important that general dental practitioners are aware of this practice and resulting complications when treating families from sub-Saharan East Africa. This article is protected by copyright. All rights reserved. PMID- 30478860 TI - Editorial Comment from Dr Miyamoto to Male infertility in Sertoli cell-only syndrome: An investigation of autosomal gene defects. PMID- 30478861 TI - Oxysterols in intestinal immunity and inflammation. AB - Cholesterol is an essential molecule for life. It is a component of the cell membrane, and it is a precursor molecule for bile acids, vitamin D and steroid hormones. Cholesterol is actively metabolized, but the impact of endogenous cholesterol metabolites on immune function, especially in the intestine, is poorly understood. In this review, I focus on oxysterols, hydroxylated forms of cholesterol, and their specialized functions in intestinal immunity. Oxysterols act through various intracellular and extracellular receptors and serve as key metabolic signals, coordinating immune activity and inflammation. Our recent work has identified an unexpected link between cholesterol metabolism, innate lymphoid cell function and intestinal homeostasis. We discovered that oxysterol sensing through the G protein-coupled receptor 183 (GPR183) directs the migration of innate lymphoid cells, which is essential for the formation of lymphoid tissue in the colon. Moreover, we found that the interaction of GPR183 with oxysterols regulates intestinal inflammation. I will discuss the therapeutic potential of oxysterols and future possibilities of treating inflammatory bowel disease through the modulation of cholesterol metabolism. PMID- 30478863 TI - Barriers and motivators of Ghanaian and African-Surinamese migrants to donate blood. AB - African migrants are underrepresented as blood donors in many Western countries, which can lead to shortages of specific blood types for transfusion. More insight in the reasons for this underrepresentation is required to improve blood donor recruitment and retention strategies. The aim of this qualitative study was to explore barriers and motivators for donating blood among migrants of African background. The research population consisted of first and second generation African-Surinamese (n = 20) and Ghanaian (n = 16) migrants living in the Netherlands. In semi-structured personal interviews performed in 2016 and 2017, their experiences and opinions regarding blood donation, barriers, and motivators to (not) become a blood donor and their suggestions to improve recruitment were explored. Data collection was continued until data saturation was achieved. The interviews revealed that although all participants knew about blood donation in general, only four had previously heard of the Dutch national blood bank organisation. Participants expected that if blood was needed, the blood bank would directly approach them, as in their country of origin. Other main blood donation barriers were fear (e.g., of needles, losing too much blood) and issues related to health and non-eligibility to donate. Main motivators were mainly of altruistic nature (e.g., saving a life) and an increased awareness of the need via personal recruitment appeals. It is concluded that expectations regarding donor recruitment-derived from the country of origin-and unawareness of the need for blood can act as important barriers in blood donation among African migrants. Contrary to studies in the United States and Australia, perceived discrimination and social exclusion did not seem to be a donation deterrent among migrants in the Netherlands. Creating awareness of the need of blood by actively approaching, and informing migrants about the donation procedure in the host country, should be considered by blood banks. PMID- 30478862 TI - Smoking behaviours among heterosexual and sexual minority youth? Findings from 15 years of provincially representative data. AB - INTRODUCTION AND AIMS: Sexual identity disparities in smoking behaviours are well established; however, there is limited research on whether these disparities have diminished as the social and political landscape has changed for lesbian, gay and bisexual people. Thus, we examined changes in prevalence and sexual identity disparities in three smoking behaviours among Canadian adolescents from 1998 to 2013. DESIGN AND METHODS: Data are from the provincially representative British Columbia Adolescent Health Survey (N = 99 373). Using sex-stratified, age adjusted logistic regression models, we estimated: (i) trends in lifetime cigarette use, early onset, and past 30-day use for heterosexual and three subgroups of sexual minority (i.e. mostly heterosexual, bisexual and gay/lesbian) youth; (ii) sexual identity disparities in these cigarette-related behaviours within each survey year (1998, 2003, 2008, 2013); and (iii) whether the size of the disparity has changed from 1998 to 2013. RESULTS: Smoking has declined for all youth from 1998 to 2013, although less consistently for sexual minority youth. Within-year disparity estimates indicated elevated prevalence of cigarette use for sexual minority compared to heterosexual youth, particularly among females. Trends in sexual identity and smoking behaviours indicated that the degree of differences between heterosexual and sexual minority youth have remained stable or, in some cases, widened. Heterosexual and sexual minority youth differences widened for early onset among sexual minority boys and lifetime and past 30-day use for sexual minority girls. DISCUSSION AND CONCLUSIONS: Efforts to prevent smoking behaviours among youth should continue. Tailored preventive strategies for sexual minority youth might help address existing disparities. PMID- 30478864 TI - Histopathological features of skin lesions in patients affected by non-ulcerated or atypical cutaneous leishmaniasis in Honduras, Central America. AB - In Honduras visceral leishmaniasis and non-ulcerated or atypical cutaneous leishmaniasis (NUCL) are caused by the species Leishmania (L.) infantum chagasi. NUCL is the most common clinical form in the southern regions of the country, mainly affecting the young. In view of the lack of knowledge about the pathogenesis of the disease pattern caused by L. (L) infantum chagasi in individuals affected by NUCL, the aim of the present study was to describe in detail the histopathological features of the skin lesion caused by the parasite. Biopsies from human NUCL lesions with a positive parasitological diagnosis were collected and processed using standard histological techniques. Paraffin sections stained by haematoxylin and eosin were used to examine the histopathological alterations seen in the skin. The lesions varied between 3 and 5 mm, and the majority of the patients (60%) had a single lesion. Lesions were more frequently seen in females (65%), with an average age of 33.4 years. Microscopically, the skin lesions were characterized by mononuclear inflammatory infiltrate in the dermis composed of lymphocytes, macrophages and a few plasma cells. The intensity of the infiltration varied from discrete to intense. In both cases, the parasitic infection was discrete. Granulomas were present in 60% of cases and were associated with intense inflammation. The data revealed by the histopathological alterations in the skin of individuals affected by NUCL suggest activation of a cellular immune response that potentially controls parasite spreading. PMID- 30478865 TI - Volatile compounds profiling by using Proton Transfer Reaction - Time of Flight - Mass Spectrometry (PTR-ToF-MS). The case study of dark chocolates organoleptic differences. AB - Direct-injection mass spectrometry (DIMS) techniques have evolved into powerful methods to analyse volatile organic compounds (VOCs) without the need of chromatographic separation. Combined to chemometrics, they have been used in many domains to solve samples categorization issues based on volatilome determination. In this paper, different DIMS methods that have largely outperformed conventional electronic noses (e-noses) in classification tasks are briefly reviewed, with an emphasis on food-related applications. A particular attention is payed to proton transfer reaction mass spectrometry (PTR-MS) and many results obtained using the powerful PTR-Time of Flight-MS (PTR-ToF-MS) instrument are reviewed. Data analysis and features selection issues are also summarized and discussed. As a case study, a challenging problem of classification of dark chocolates that has been previously assessed by sensory evaluation in four distinct categories is presented. The VOCs profiles of a set of 206 chocolate samples classified in the four sensory categories were analysed by PTR-ToF-MS. A supervised multivariate data analysis based on partial least squares regression-discriminant analysis (PLS-DA) allowed the construction of a classification model that showed excellent prediction capability: 97 % of a test set of 62 samples were correctly predicted in the sensory categories. Tentative identification of ions aided characterisation of chocolates classes. Variable selection using dedicated methods pinpointed some volatile compounds important for the discrimination of the chocolates. Among them, the CovSel method was used for the first time on PTR MS data resulting in a selection of ten features that allowed a good prediction to be achieved. Finally, challenges and future needs in the field are discussed. PMID- 30478866 TI - Synthesis and electronic properties of novel 5,7-diazapentacene derivatives. AB - A route to the synthesis of novel 5,7-diazapentacenes and some preliminary studies on their properties is reported. A single crystal X-ray diffraction study of the dihexyl derivative showed it had formed a dimer during the analysis. The materials possess lower lying frontier orbitals than pentacene, and may have potential applications in organic electronic devices. This synthetic method may be applicable to the synthesis of other azaacenes. PMID- 30478867 TI - The influence of delayed admission to intensive care unit on mortality and nursing workload: a cohort study. AB - BACKGROUND: The results of studies regarding the relationship between length of stay of patients in emergency departments (EDs) and mortality in intensive care units (ICUs) are contradictory, and nothing is known about the impact of delayed admission of patients to ICUs on nursing workload. AIMS AND OBJECTIVES: To assess the influence of the time lapse between ED and ICU admissions on mortality and nursing workload in relation to intensive care patients. DESIGN: This was a retrospective cohort study that examined the medical records of patients who were 15 years of age or older and admitted directly to the ICU from the ED. METHODS: The data were collected between 2014 and 2016 in a hospital located in Sao Paulo, Brazil. Nursing workload was measured by the Nursing Activities Score. Multiple linear and logistic regressions were applied, with a significance level of 5%. RESULTS: Of the 534 patients analysed, the majority were men (57.49%); the mean age was 55.37 +/- 19.64 years. Length of stay in the ED was not associated with nursing workload at the time of admission of patients to the ICU or during their stay in the unit. For mortality, this variable was a risk factor along with cause of admission, length of stay in the ICU and the Simplified Acute Physiology Score 3 score. For every additional hour that patients remained in the ED, their chance of dying in the ICU increased by 1%. CONCLUSION: Length of stay of patients in the ED was a risk factor for mortality in the ICU; however, this variable did not have any influence on nursing workload. RELEVANCE TO CLINICAL PRACTICE: Strategies need to be implemented to optimize the availability of ICU beds and reduce the length of stay of critical patients in the ED as delays in admitting such patients to the ICU have an impact on mortality. PMID- 30478868 TI - Cobalt(III)/Chiral Carboxylic Acid-Catalyzed Enantioselective C(sp3)-H Amidation of Thioamides. AB - Recent advances in CpxM(III) catalyses (M = Co, Rh, Ir) have enabled a variety of enantioselective C(sp2)-H functionalization reactions, but enantioselective C(sp3)-H functionalization is still largely unexplored. Here we describe an asymmetric C(sp3)-H amidation of thioamides using an achiral Co(III)/chiral carboxylic acid hybrid catalytic system, providing easy and straightforward access to chiral beta-amino thiocarbonyl and beta-amino carbonyl building blocks with a quaternary carbon stereocenter. PMID- 30478869 TI - Treatment effect quantification for time-to-event endpoints-Estimands, analysis strategies, and beyond. AB - A draft addendum to ICH E9 has been released for public consultation in August 2017. The addendum focuses on two topics particularly relevant for randomized confirmatory clinical trials: estimands and sensitivity analyses. The need to amend ICH E9 grew out of the realization of a lack of alignment between the objectives of a clinical trial stated in the protocol and the accompanying quantification of the "treatment effect" reported in a regulatory submission. We embed time-to-event endpoints in the estimand framework and discuss how the four estimand attributes described in the addendum apply to time-to-event endpoints. We point out that if the proportional hazards assumption is not met, the estimand targeted by the most prevalent methods used to analyze time-to-event endpoints, logrank test, and Cox regression depends on the censoring distribution. We discuss for a large randomized clinical trial how the analyses for the primary and secondary endpoints as well as the sensitivity analyses actually performed in the trial can be seen in the context of the addendum. To the best of our knowledge, this is the first attempt to do so for a trial with a time-to-event endpoint. Questions that remain open with the addendum for time-to-event endpoints and beyond are formulated, and recommendations for planning of future trials are given. We hope that this will provide a contribution to developing a common framework based on the final version of the addendum that can be applied to design, protocols, statistical analysis plans, and clinical study reports in the future. PMID- 30478870 TI - Load-Bearing Capacity of Monolithic Zirconia Fixed Dental Prostheses Fabricated with Different Connector Designs and Embrasure Shaping Methods. AB - PURPOSE: To investigate the load-bearing capacity and failure mode of monolithic zirconia fixed dental prostheses (FDPs) fabricated with different connector designs and embrasure shaping methods. MATERIALS AND METHODS: Seventy four-unit zirconia FDPs (with two premolar pontics) were fabricated and divided into seven groups (n = 10) according to the different connector designs gained by using different embrasure shaping methods. The groups were as follows: monolithic FDPs fabricated with sharp embrasures, monolithic FDPs fabricated with blunt embrasures, monolithic FDPs fabricated with blunt embrasures and no occlusal embrasures, two groups of monolithic FDPs fabricated with blunt embrasures and interproximal separations made with diamond discs at the soft stage and at the fully sintered stage, and monolithic FDPs fabricated with blunt embrasures and interproximal separation accentuated by localized porcelain build-up. A final group was used as a control group, where fully veneered traditional zirconia FDPs were fabricated with default milling settings. The FDPs were artificially aged and loaded to fracture. Load to fracture and failure modes were analyzed by one way ANOVA, Tukey's post hoc test, and Fisher exact test (alpha = 0.05). RESULTS: The FDPs fabricated with interproximal porcelain separation showed significantly the highest load to fracture (1038 N +/- 82) of all groups (p < 0.001), with no significant difference compared to the FDPs with no occlusal embrasures (934 N +/ 175; p ? 0.29). The FDPs fabricated with blunt embrasures showed significantly higher load to fracture (873 N +/- 115) compared to the FDPs in the control group (689 N +/- 75) and the FDPs with sharp embrasures (417 N +/- 87; p < 0.001). There were no significant differences between the FDPs with sharp embrasures (417 N +/- 87) and the FDPs with interproximal disc separations (467 N +/- 94; p ? 0.23). Failure mode of the FDPs fabricated with sharp embrasures and interproximal disc separations differed significantly compared to the FDPs in the other groups (p < 0.001). CONCLUSIONS: Sharp embrasures and interproximal separations made with diamond discs significantly decrease the load-bearing capacity of monolithic zirconia FDPs compared to FDPs made with blunt embrasures. Blunt embrasures in combination with localized porcelain build-up produce FDPs with high load-bearing capacity in relation to loads that might be expected under clinical use. PMID- 30478871 TI - From low to high gear: there has been a paradigm shift in our understanding of evolution. AB - Experimental studies of evolution performed in nature and the associated demonstration of rapid evolution, observable on a time scale of months to years, were an acclaimed novelty in the 1980-1990s. Contemporary evolution is now considered ordinary and is an integrated feature of many areas of research. This shift from extraordinary to ordinary reflects a change in the perception of evolution. It was formerly thought of as a historical process, perceived through the footprints left in the fossil record or living organisms. It is now seen as a contemporary process that acts in real time. Here we review how this shift occurred and its consequences for fields as diverse as wildlife management, conservation biology, and ecosystems ecology. Incorporating contemporary evolution in these fields has caused old questions to be recast, changed the answers, caused new and previously inconceivable questions to be addressed, and inspired the development of new subdisciplines. We argue further that the potential of contemporary evolution has yet to be fulfilled. Incorporating evolutionary dynamics in any research program can provide a better assessment of how and why organisms and communities came to be as they are than is attainable without an explicit treatment of these dynamics. PMID- 30478872 TI - Tricolor Luminescence Switching by Thermal and Mechanical Stimuli in the Crystal Polymorphs of Pyridyl-substituted Fluorene. AB - Stimuli-responsive organic luminescence-switching materials have attracted much attention for a decade. Most of the reported examples display a reversible two color luminescence switching, and multicolor-switching materials remain extremely rare. Herein, we report a simple organic molecule, 4,4'-(9,9-dimethyl-9H-fluorene 2,7-diyl)dipyridine (MFDP), which exhibits three different crystal polymorphs (V MFDP, B-MFDP and G-MFDP) with different luminescent colors. Furthermore, the three crystal polymorphs show a reversible tricolor fluorescent switching from violet to blue and to green upon physical stimuli. The single-crystal structures of the three polymorphs were obtained, and the results indicate that the stimuli responsive properties of the three polymorphs come from the different stacking modes induced by intermolecular interactions. The competition between weak pi-pi stacking and weak hydrogen bonding is the main reason for the the phase transformations among the three crystal polymorphs. PMID- 30478873 TI - Characterization of children and adolescents with psychosis risk syndrome: The Children and Adolescents Psychosis Risk Syndrome (CAPRIS) study. AB - AIM: Despite the interest in psychosis risk syndrome (PRS) in children and adolescents, information on the syndrome in this population is scarce. METHODS: Prospective naturalistic multi-site study in which 10- to 17-year-old help seeking subjects who met PRS criteria (positive or negative attenuated symptoms; brief limited intermittent psychotic symptoms; genetic risk or schizotypal personality disorder plus impairment in functioning) were included, along with 45 age and sex-matched healthy controls (HC). All subjects were clinically and functionally assessed. RESULTS: Ninety-one PRS subjects (PRSS) with a mean age of 15.5 +/- 1.4 met inclusion criteria (IC). Compared with HC, PRSS presented worse global and academic functioning in the previous year, had experienced more psychiatric and psychological problems, and presented gestational ages outside the normal range. More than 80% of PRSS met >=2 IC, with 65.9% having one Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision diagnosis, and 61.7% of those having >=2 diagnoses. Some 49.5% of PRSS had a first- or second-degree family history (FH) of psychosis. Patients with first- and second-degree FH do not differ in their clinical expression. CONCLUSIONS: Children and adolescents with PRS are a patient group with a pattern of neurodevelopmental impairment and clinical complexity similar to patients with schizophrenia spectrum disorders, highlighting the importance of assessing these variables in child and adolescent samples. PRSS with first- and second-degree relatives with FH do not present differences in their clinical presentation, suggesting that including these two groups of patients in the genetic risk criteria would enrich knowledge of these criteria. PMID- 30478874 TI - Reproducibility of cytological smears stained with modified ultrafast Papanicolaou stain: Methodological issue. PMID- 30478875 TI - Unstable presentation: One Stent trumps two. AB - This report was a retrospective look at a large registry database. A one-stent strategy trumps a two-stent approach in patients with acute coronary syndromes in this large registry. The primary endpoint and target lesion revascularization was half the rate if a one-stent strategy was used. The incidence of stent thrombosis was more than three-fold as high using a planned two-stent strategy. PMID- 30478876 TI - Day-after PCI: Safe for the patient but perhaps not for the Interventionalist. AB - This single-center study retrospectively reviewed 12,680 percutaneous coronary interventions (PCIs) to identify those performed by an operator who was awake the previous night performing PCI. Success and outcomes of PCIs were similar regardless of whether the operator performed PCIs the previous night. This study generally confirms the results of a previous single center study and another study using the NCDR CathPCI Registry. This study suggests that day-after PCI is generally safe, but it behooves cath lab managers and interventionalists to take simple steps to minimize the risk to patients when day-after PCIs are performed. PMID- 30478877 TI - BioResorbable scaffolds: Out of sight but not out of mind. AB - The article highlights the results of a new novel BioResorbable Scaffold in "real world" practice Based on this, further design iterations could be reviewed for next generation BRS Larger and longer-term trials would be needed to define the safety and effectiveness of new BRS in daily clinical practice. PMID- 30478878 TI - Non-femoral TAVR: Time to stratify alternative vascular approaches. AB - Although transfemoral transcatheter aortic valve replacement (TAVR) is the gold standard, this approach is not be feasible in approximately 15% of the patients. Trans-carotid TAVR may be less invasive than transthoracic routes for TAVR, and has been associated with encouraging results. Further prospective studies comparing alternative access routes in patients with whom transfemoral TAVR is not feasible are warranted, to propose an evidence-based algorithm guiding the physician decision. PMID- 30478879 TI - Embolic stroke of undetermined source and patent foramen ovale closure: Practice insights from meta-analysis? AB - Closure of patent foramen ovale (PFO) in embolic stroke of undetermined source (ESUS) reduces recurrent stroke compared with antiplatelet therapy in select patients but increases risk of atrial fibrillation. Device closure is an attractive option for young patients with an anatomically higher risk PFO and imaging proven ESUS. Benefit of PFO closure in ESUS compared with oral anticoagulation remains undefined. PMID- 30478880 TI - Which embolic protection device is ideal during carotid artery stenting? AB - Embolic stroke is one of the main risks of carotid artery stenting. The EMBOLDEN trial demonstrates the safety and efficacy of the Gore(r) embolic filter. There is no clear evidence for the benefit of one filter-type over another. It is important to choose the device with which the interventionalist has significant familiarity. PMID- 30478881 TI - Septal rupture closure: Still a challenge. AB - Review of the Medicare database shows that over the past 16 years the incidence of post- myocardial infarction (MI) ventricular septal rupture (VSR) has decreased but mortality for all post-MI VSR hospitalizations remains unchanged and high During the study period, the 30-day VSR repair rate decreased from 49.9% in 1999 to 33.3% in 2014. Unadjusted mortality was lower for patients undergoing repair procedures than for those not undergoing repair both at 30 days and at 1 year. Most VSR patients underwent surgical repair (82.9%) and only a minority underwent transcatheter repair (17.1%). Regardless of the approach, outcomes remain unsatisfactory. PMID- 30478882 TI - Is the local guy, just a local guy? AB - The most important risk factors and preventive strategies for coronary atherosclerosis are systemic. However, the clinical manifestations of atherosclerotic disease frequently resemble a localized process, instead of a systemic one. In this issue of CCI, Zhang and co-workers described the association between the occurrence of stent failure and the changes in the 3D geometry of coronary segments induced by stent implantation. The investigation of local modulators of coronary disease appears as a large and fertile field of future cardiovascular research. PMID- 30478883 TI - Predicting the unpredictable mortality outcome of valve-in-valve interventions. AB - Surgical aortic valve replacement (AVR) risk scores overestimate valve-in-valve (ViV) transcatheter AVR (TAVR) mortality, with moderate discrimination Due to low prevalence of 30-day mortality, positive predictive value is low Specific risk score examining multiple outcomes for TAVR and ViV patients are needed. PMID- 30478884 TI - When small vessels become big problems! Microvascular dysfunction in NSTEMI. AB - In a carefully selected cohort of 83 NSTEMI patients, there was a wide variation in the index of microcirculatory resistance (IMR) Elevated IMR, which correlates with microvascular obstruction by MRI, was an independent predictor of adverse cardiovascular outcomes in patients with NSTEMI Further investigation is warranted to understand the influence of the microvascular on prognosis following myocardial infarction. PMID- 30478885 TI - Caution! You're approaching a gray zone: FFR outcomes and the role of CFR and IMR. AB - This study demonstrates that compared with low- fractional flow reserve (FFR) lesions (<0.75), those in the gray-zone FFR (0.75-0.80) are less likely to have improvement or more likely to have impairment in flow after percutaneous coronary intervention. The findings suggest index of microcirculatory resistance measurement may help identify lesions in the FFR gray zone that are most likely to improve. The study reinforces that FFR measurements represent a continuum of ischemic values and that a single dichotomous threshold oversimplifies the answer to whether a lesion should be revascularized. PMID- 30478886 TI - Monitoring treatment response to tafamidis by serial native T1 and extracellular volume in transthyretin amyloid cardiomyopathy. AB - Tafamidis meglumine, a transthyretin (TTR) stabilizer, is effective in delaying the progression of neuropathy in TTR amyloidosis with Val30Met mutations. However, its efficacy in TTR amyloid cardiomyopathy is not fully elucidated. Herein, we report a 73-year-old Japanese man with a diagnosis of TTR amyloid cardiomyopathy with Val30Met mutation treated with tafamidis. To evaluate treatment response, cardiac magnetic resonance imaging was performed before and after 12 months of tafamidis treatment. Native T1, extracellular volume, and left ventricular mass showed no obvious worsening, and findings of other diagnostic studies also supported the efficacy of tafamidis to delay the progression of amyloid cardiomyopathy. Our case suggests that serial native T1 and extracellular volume may be novel non-invasive imaging methods to monitor the treatment response to TTR stabilizers in cardiac amyloidosis and also that tafamidis may be effective in suppressing cardiac progression in TTR amyloid cardiomyopathy with Val30Met mutation. PMID- 30478887 TI - EGFR and Prion protein promote signaling via FOXO3a-KLF5 resulting in clinical resistance to platinum agents in colorectal cancer. AB - Epidermal growth factor receptor (EGFR) supports colorectal cancer progression via oncogenic signaling. Anti-EGFR therapy is being investigated as a clinical option for colorectal cancer, and an observed interaction between EGFR and Prion protein has been detected in neuronal cells. We hypothesized that PrPC expression levels may regulate EGFR signaling, and that detailed understanding of this signaling pathway may enable identification of resistance mechanisms and new actionable targets in colorectal cancer. We performed molecular pathway analysis following knockdown of PrPC or inhibition of EGFR signaling via Gefitinib to identify changes in expression of key signaling proteins that determine cellular sensitivity or resistance to Cisplatin. Expression of these proteins were examined in matched primary and metastatic patient samples, and were correlated for resistance to therapy and progression of disease. Utilizing three colorectal cancer cell lines, we observed a correlation between high expression of PrPC and resistance to cisplatin. Investigation of molecular signaling in a resistant cell line revealed that PrPC contributed to signaling via colocalization with EGFR, which could be overcome by targeting p38 mitogen-activated protein kinases (p38 MAPK). We revealed that the level of Kruppel-like factor 5 (KLF5), a target downstream of p38 MAPK, was predictive for cell line and patient response to platinum agents. Further, high KLF5 expression was observed in BRAF-mutant colorectal cancer. Our study indicates that the EGFR to KLF5 pathway is predictive of patient progression on platinum-based therapy. PMID- 30478888 TI - Post-discharge short message service improves short-term clinical outcome and self-care behaviour in chronic heart failure. AB - AIMS: In addition to giving optimal medical and device therapy, promoting self care of chronic heart failure (CHF) patients also plays an important role in comprehensive disease management for better outcomes. The study was aimed to investigate whether short message service (SMS) would help to improve death or readmission-free survival and self-care behaviour in CHF patients. METHODS AND RESULTS: This was a randomized controlled trial. Between December 2011 and September 2015, patients admitted with decompensated CHF in a tertiary referral hospital who fulfilled the inclusion criteria were enrolled and randomized to receive SMS, structured telephone support (STS), or usual care after discharge. All patients were followed up to 180 days after discharge by phone call or clinic visit. Primary endpoint was the 180 day composite event, defined as all-cause mortality or readmission. Secondary endpoints included self-care behaviour and quality of life. Seven hundred sixty-seven patients (61 +/- 15 years, 56.5% male) were finally randomized to receive SMS (n = 252), STS (n = 255), or usual care (n = 260). Baseline characteristics were similar among the three groups. Five hundred twenty-five (68.4%) patients were in New York Heart Association Class III or IV, and 472 (61.5%) patients had an ejection fraction of <50%. During a 180 day follow-up, 76 (9.9%) patients died and 274 (35.7%) patients experienced at least one readmission. In a short-term follow-up of 30 days, there was no difference in mortality and the composite endpoint among the three groups (SMS vs. STS vs. usual care: 2.8% vs. 3.1% vs. 3.8% for mortality, P = 0.786; 12.3% vs. 14.5% vs. 15.4% for the composite endpoint, P = 0.588). The 180 day composite event rate was significantly lower in the SMS and STS groups (50.4% vs. 41.3% and 36.5%, both P < 0.05) than in the usual care group, but no difference was observed between the two phone-based intervention groups (P = 0.268). Although there was no difference between the two groups, better self-care behaviour was reported in the SMS and STS groups than in the control group (medication compliance, 78.9% vs. 81.4% vs. 69.5%, P = 0.011; water restriction, 70.8% vs. 74.5% vs. 61.5%, P = 0.013). Quality-of-life score was similar among the three groups at 180 days (P = 0.526). CONCLUSIONS: In CHF patients, post-discharge SMS, which appeared as efficient as STS, reduced the 180 day composite event and improved self-care behaviour. SMS intervention could be integrated into CHF management. PMID- 30478889 TI - Two decades of evolutionary changes in Brassica rapa in response to fluctuations in precipitation and severe drought. AB - As climate changes at unprecedented rates, understanding population responses is a major challenge. Resurrection studies can provide crucial insights into the contemporary evolution of species to climate change. We used a seed collection of two Californian populations of the annual plant Brassica rapa made over two decades of dramatic precipitation fluctuations, including increasingly severe droughts. We compared flowering phenology, other drought response traits, and seed production among four generations, grown under drought and control conditions, to test for evolutionary change and to characterize the strength and direction of selection. Postdrought generations flowered earlier, with a reduced stem diameter, and lower water-use efficiency (WUE), while intervening wet seasons reversed these adaptations. There was selection for earlier flowering, which was adaptive, but delayed flowering after wet years resulted in reduced total seed mass, indicating a maladaptive response caused by brief wet periods. Furthermore, evolutionary changes and plastic responses often differed in magnitude between populations and drought periods, suggesting independent adaptive pathways. While B. rapa rapidly evolved a drought escape strategy, plant fitness was reduced in contemporary generations, suggesting that rapid shifts in flowering time may no longer keep up with the increasing severity of drought periods, especially when drought adaptation is slowed by occasional wet seasons. PMID- 30478890 TI - Cutaneous adverse events associated with purine analogs in the treatment of hairy cell leukemia. PMID- 30478891 TI - Clozapine and all-cause mortality in treatment-resistant schizophrenia: a historical cohort study. AB - OBJECTIVE: Large-scale epidemiological studies have demonstrated a protective effect of clozapine on mortality in people with schizophrenia. Clozapine is reserved for use in patients with treatment-resistant schizophrenia (TRS), but evidence of clozapine's effect on mortality exclusively within TRS samples is inconclusive. Hence, we aimed to investigate the effect of clozapine use on all cause mortality in TRS patients. METHODS: A historical patient cohort sample of 2,837 patients, who met criteria for TRS between 1st Jan 2008 and 1st Jan 2016, were selected from the South London and Maudsley NHS Foundation Trust (SLAM) electronic health records (EHR). The ZTAS mandatory monitoring system linked to the SLAM EHR was used to distinguish which patients were initiated on clozapine (n=1,025). Cox proportional hazard models were used, adjusting for socio demographics, clinical monitoring, mental and physical illness severity and functional status. RESULTS: After controlling for potential confounders, the protective effect of clozapine on all-cause mortality was significant (adjusted hazard ratio 0.61; 95% confidence interval 0.38-0.97; p=0.04). CONCLUSIONS: Clozapine reduces the risk of mortality in patients who meet criteria for TRS. We provide further evidence that improving access to clozapine in TRS is likely to reduce the mortality gap in schizophrenia. This article is protected by copyright. All rights reserved. PMID- 30478892 TI - A QSAR Study for Analgesic and Anti-inflammatory Activities of 5-/6-Acyl-3-alkyl 2-Benzoxazolinone Derivatives. AB - In this publication, QSAR models were developed to predict analgesic and anti inflammatory activities of some 2-benzoxazolinone derivatives using multiple linear regression method. The models were validated internally and externally according to the OECD principles. With the help of these models, pronounced molecular properties of these compounds related to activities were also explored. The developed models demonstrated that hydrophobicity, the number of halogens, and the shape of the molecular structure of these candidate drugs are prominent to represent analgesic and anti-inflammatory activities. Based on the previously tested compounds and the developed models, 77 new compounds were designed as potential analgesic and anti-inflammatory drugs. Majority of the newly designed compounds demonstrated promising analgesic and anti-inflammatory activity. PMID- 30478893 TI - A novel infram deletion in MSH6 gene in glioma: Conversation on MSH6 mutations in brain tumors. AB - OBJECTIVE AND BACKGROUND: Histological and molecular information and biopsy help in the diagnosis of the type and grade of tumors and increase the value of estimation of the biological behavior of tumors. In this study, we focused on a consanguineous Iranian Family with high prevalence of brain tumors in their pedigree and reviewed the literature on MSH6 mutations in brain tumors and the treatment responses focused on Gliomas. METHOD: We chose a family with a high prevalence of brain tumor in their pedigree. We studied the proband's neuroimaging and brain proton magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), biopsy result, and whole-genome sequencing. RESULT: The neuroimaging and brain proton MRS reported a lesion in the right frontoparietal. The MRI revealed a large enhancible heterogenous mass in the right temporo-fronto parieto-occipital lobes with involvement of corpus callosum which was suggestive of glioma. The patient revealed a homozygous pattern for a novel 9 base-pare deletion at the 912-914 codon on exon 4 of the MSH6 gene. DISCUSSION: We discuss several studies on MSH6 mutations in brain tumors and we discuss treatment responses in MSH6 mutations and the studies conducted to sensitize chemotherapy and radiotherapy resistance brain tumors to face this subject efficiently. CONCLUSION: Patients should be evaluated for MMR mutation before chemo and radiotherapy, and it is valuable to follow-up these mutations during the treatment too. In temozolomide (TMZ)-resitance cases, it is suggested to use complementary strategies such as using HDACis and a combination of a STAT3 Inhibitor and an mTOR inhibitor, BER inhibition mechanism, and PARP-1 inhibitor. PMID- 30478894 TI - Pediatric cancer care can be complicated by language barriers: A case involving parents with limited Japanese proficiency. PMID- 30478895 TI - Freeing the data from cytology databases in order to improve the quality of cytology. AB - INTRODUCTION: To review how changes in data storage and analysis can impact quality and quality assessment in cytology. METHODS: Review of the literature. RESULTS: All quality assessment is dependent on the data available for review and the methods available for evaluation. Current laboratory information systems (LISs) incorporate both a relational or hierarchical database and built in methods to analyze current quality assessment standards. In contrast, most information systems outside of medicine are separating data storage from analysis, allowing increasingly more sophisticated forms of evaluation. CONCLUSION: There is an opportunity for improvement in cytology by improving the way data can be extracted and analyzed from the cytology LIS. PMID- 30478896 TI - Human breast cancer decellularized scaffolds promote epithelial-to-mesenchymal transitions and stemness of breast cancer cells in vitro. AB - Breast cancer, with unsatisfactory survival rates, is the leading cause of cancer related death in women worldwide. Recent advances in the genetic basis of breast cancer have benefitted the development of gene-based medicines and therapies. Tissue engineering technologies, including tissue decellularizations and reconstructions, are potential therapeutic alternatives for cancer research and tissue regeneration. In our study, human breast cancer biopsies were decellularized by a detergent technique, with sodium lauryl ether sulfate (SLES) solution, for the first time. And the decellularization process was optimized to maximally maintain tissue microarchitectures and extracellular matrix (ECM) components with minimal DNA compounds preserved. Histology analysis and DNA quantification results confirmed the decellularization effect with maximal genetic compounds removal. Quantification, immunofluorescence, and histology analyses demonstrated better preservation of ECM components in 0.5% SLES-treated scaffolds. Scaffolds seeded with MCF-7 cells demonstrated the process of cell recellularization in vitro, with increased cell migration, proliferation, and epithelial-to-mesenchymal transition (EMT) process. When treated with 5 fluorouracil, the expressions of stem cell markers, including Oct4, Sox2, and CD49F, were maximally maintained in the recellularized scaffold with decreased apoptosis rates compared with monolayer cells. These results showed that the decellularized breast scaffold model with SLES treatments would help to simulate the pathogenesis of breast cancer in vitro. And we hope that this model could further accelerate the development of effective therapies for breast cancer and benefit drug screenings. PMID- 30478897 TI - Comment on "Groundwater Pumping Is a Significant Unrecognized Contributor to Global Anthropogenic Element Cycles". PMID- 30478898 TI - Smartphone telemedical emergency department consults for screening of nonacute dizziness. AB - OBJECTIVES/HYPOTHESIS: Each year, the United States spends over $4 billion on emergency department visits for evaluation of dizziness. Benign paroxysmal positional vertigo (BPPV) is a common cause of dizziness that can easily be diagnosed by observing characteristic eye movements during the Dix-Hallpike test (DHT). The DHT is easily performed; however, interpretation requires more advanced training. This may be part of the reason it is not commonly performed in emergency departments, and instead, patients undergo costly imaging tests. We evaluated whether smartphone-based video recordings of DHT could be assessed telemedically for screening of nonacute dizziness. STUDY DESIGN: Feasibility study. METHODS: Dizzy patients underwent objective vestibular testing, but also had videos of their eye movements recorded via a smartphone during the DHT. The videos were remotely reviewed by two neuro-otologists for BPPV screening and were compared to objective and in-person exam findings. RESULTS: Overall, 30 dizzy patients were evaluated with seven cases of BPPV. The sensitivity for diagnosing BPPV via a smartphone-recording of eye movements of the DHT was 92.86%, with a specificity of 100% and a negative predictive value of 97.87%. CONCLUSIONS: Our initial proof-of-concept study shows that remote screening of BPPV is possible with high specificity. Because the DHT is easily taught, having a remote otolaryngologist interpret the resulting eye movements may increase usage of the test and may lead to cost savings. LEVEL OF EVIDENCE: 4 Laryngoscope, 2018. PMID- 30478899 TI - Estrogen associated with UVB irradiation recapitulates the specific melanosome distribution observed in Caucasoid Melasma. AB - Melasma is characterized by light to dark brown macules that usually occur on the face. Melasma occurs in 10-15% of pregnant women and in 10-25% of women taking oral contraceptives. Fertile women are most likely to develop melasma. Histological examination of melasma lesional skin revealed mainly pigmentary disorders with an increased melanin deposition in all layers of the epidermis including the horny layer and a frequent presence of melanophages in the dermis. On the other hand in the upper dermis, a disruption of the basement membrane in 3.9% of cases, an abundance of elastotic material and an increased number of blood vessels and mast cells have been reported in melasma. This article is protected by copyright. All rights reserved. PMID- 30478900 TI - Outcome of secondary intention healing of full thickness lower eyelid defects in dogs. AB - OBJECTIVES: To assess healing of the canine lower eyelid without anatomical reconstruction. MATERIALS AND METHODS: The study is a retrospective case series, three client-owned dogs with lower eyelid defects. Dogs that underwent debridement of lower eyelid wounds that were left to heal by secondary intention were assessed for anatomical, functional and aesthetic outcomes. RESULTS: Two of the cases had previously undergone tumour resection with a lip-to-lid reconstruction and, following flap failure, developed a full thickness defect. The third dog presented with a traumatic laceration. Each dog lost approximately 70 to 90% of the lower eyelid margin. Two received topical antimicrobial eye drops after debridement, while the third dog required no further treatment. Follow-up periods of 3 years, 15 months and 4 months were available. All owners were satisfied with the cosmetic outcome and provided pictures. One owner reported epiphora but no other ophthalmic complications occurred. CLINICAL SIGNIFICANCE: The result of this small case series supports the notion that not all lower eyelid injuries or tumour resections require anatomical reconstruction. Selected cases can be left to heal by secondary intention with minimal post operative complications. PMID- 30478901 TI - The role of nitric oxide signaling in renoprotective effects of hydrogen sulfide against chronic kidney disease in rats: Involvement of oxidative stress, autophagy and apoptosis. AB - The interplay between H2 S and nitric oxide (NO) is thought to contribute to renal functions. The current study was designed to assess the role of NO in mediating the renoprotective effects of hydrogen sulfide in the 5/6 nephrectomy (5/6 Nx) animal model. Forty rats were randomly assigned to 5 experimental groups: (a) Sham; (b) 5/6 Nx; (c) 5/6Nx+sodium hydrosulfide-a donor of H 2 S, (5/6Nx+sodium hydrosulfide [NaHS]); (d) 5/6Nx+NaHS+ L-NAME (a nonspecific nitric oxide synthase [NOS] inhibitor); (e) 5/6Nx+NaHS+aminoguanidine (a selective inhibitor of inducible NOS [iNOS]). Twelve weeks after 5/6 Nx, we assessed the expressions of iNOS and endothelial NOS (eNOS), oxidative/antioxidant status, renal fibrosis, urine N-acetyl-b-glucosaminidase (NAG) activity as the markers of kidney injury and various markers of apoptosis, inflammation, remodeling, and autophagy. NaHS treatment protected the animals against chronic kidney injury as depicted by improved oxidative/antioxidant status, reduced apoptosis, and autophagy and attenuated messenger RNA (mRNA) expression of genes associated with inflammation, remodeling, and NAG activity. Eight weeks Nomega-nitro-l-arginine methyl ester ( L-NAME) administration reduced the protective effects of hydrogen sulfide. In contrast, aminoguanidine augmented the beneficial effects of hydrogen sulfide. Our finding revealed some fascinating interactions between NO and H 2 S in the kidney. Moreover, the study suggests that NO, in an isoform-dependent manner, can exert renoprotective effects in 5/6 Nx model of CKD. PMID- 30478902 TI - Glucagon attenuates lipid accumulation in cow hepatocytes through AMPK signaling pathway activation. AB - The ketotic cows displayed hepatic lipid metabolic disorder and high blood concentration of glucagon. Importantly, adenosine monophosphate-activated protein kinase (AMPK) signaling pathway plays an important role in the hepatic lipid homeostasis. Therefore, the aim of this study was to investigate the effect of glucagon on AMPK pathway and its underlying mechanism on lipid metabolism in cow hepatocytes. Cow hepatocytes were cultured and treated with glucagon and AMPK inhibitor (BML-275). The results showed that glucagon significantly promoted the expression of glucagon receptor and increased the phosphorylation level and activity of AMPKalpha. Activated AMPKalpha increased the expression level and transcriptional activity of peroxisome proliferator-activated receptor alpha, which further increased the expression of fatty acid oxidation genes and lipid oxidation. Furthermore, activated AMPKalpha inhibited the expression level and transcriptional activity of sterol regulatory element binding protein-1c and carbohydrate response element binding protein, which decreased the expression of lipogenic genes, thereby decreasing lipid synthesis. In addition, glucagon also increased the expression of very-low-density lipoprotein (VLDL) assembly to export intracellular triglycerides (TG). Consequently, the content of intracellular TG was significantly decreased in cow hepatocytes. These results indicate that glucagon activates the AMPK signaling pathway to increase lipid oxidation and VLDL assembly and decrease lipid synthesis in cow hepatocytes, thereby reducing liver fat accumulation. PMID- 30478903 TI - Coincidence of potato CONSTANS (StCOL1) expression and light cannot explain night break repression of tuberization. AB - In the obligate short-day potato Solanum tuberosum group Andigena (S. andigena), short days, or actually long nights, induce tuberization. Applying a night break in the middle of this long night represses tuberization. However, it is not yet understood how this repression takes place. We suggest a coincidence model, similar to the model explaining photoperiodic flowering in Arabidopsis. We hypothesize that potato CONSTANS (StCOL1), expressed in the night of a short day, is stabilized by the light of the night break. This allows for StCOL1 to repress tuberization through induction of StSP5G, which represses the tuberization signal StSP6A. We grew S. andigena plants in short days, with night breaks applied at different time points during the dark period, either coinciding with StCOL1 expression or not. StCOL1 protein presence, StCOL1 expression and expression of downstream targets StSP5G and StSP6A were measured during a 24-h time course. Our results show that a night break applied during peak StCOL1 expression is unable to delay tuberization, while coincidence with low or no StCOL1 expression leads to severely repressed tuberization. These results imply that coincidence between StCOL1 expression and light does not explain why a night break represses tuberization in short days. Furthermore, stable StCOL1 did not always induce StSP5G, and upregulated StSP5G did not always lead to fully repressed StSP6A. Our findings suggest there is a yet unknown level of control between StCOL1, StSP5G and StSP6A expression, which determines whether or not a plant tuberizes. This article is protected by copyright. All rights reserved. PMID- 30478904 TI - Synergistic anticancer action of quercetin and curcumin against triple-negative breast cancer cell lines. AB - Women with the breast cancer type 1 susceptibility protein (BRCA1) mutation and loss of BRCA1 expression are reported to have an increased risk of triple negative breast cancer (TNBC). Targeting BRCA1 modulation might offer a therapeutic option to treat TNBC patients. Our studies detected that BRCA1 is poorly expressed in TNBC cell lines and highly expressed in ER+ breast cancer cell lines. To modulate BRCA1 expression, we tested two different dietary components to find out if any would induce tumor suppressor genes. We detected that quercetin and curcumin dose-dependently enhanced the BRCA1 expression. Further, a synergistic action of quercetin and curcumin was observed in modulating the BRCA1 level and in inhibiting the cell survival and migration of TNBC cell lines. Quercetin and curcumin appeared to induce BRCA1 promoter histone acetylation. Furthermore, BRCA1 knockdown induced cell survival and cell migration in ER + cells were significantly decreased by the combined treatment of quercetin and curcumin. Our present study concluded that the combination treatment of quercetin and curcumin acts synergistically to induce anticancer activity against TNBC cells by modulating tumor suppressor genes. PMID- 30478905 TI - Testicular structure and spermatogenesis of the oviparous goodeids Crenichthys baileyi (Gilbert, 1893) and Empetrichthys latos Miller, 1948 (Teleostei, Cyprinodontiformes). AB - The cyprinodontiform family Goodeidae comprises some 51 species, including subspecies, of freshwater fishes all of which are at risk or are extinct in the wild. It is classified in two allopatric subfamilies: the Goodeinae, endemic to the Mexican Plateau, and the Empetrichthyinae, known only from relict taxa in Nevada and southern California. The 41 species of goodeins are all viviparous and share a set of well-documented reproductive characters. In contrast, the recent species or subspecies of empetrichthyins are all oviparous and relatively poorly known, yet of critical interest in understanding the evolution of livebearing in the family. We previously described ovarian structure and oogenesis in empetrichthyins using archival museum specimens of females and here extend that study to males. Testicular characters of two species of empetrichthyins, Crenichthys baileyi, and Empetrichthys latos, are studied and compared directly with those of one species of viviparous goodeid, Ataeniobius toweri. The testis is a restricted spermatogonial type in both the Empetrichthyinae and the Goodeinae: spermatogonia are found solely at the distal termini of lobules, a diagnostic character of atherinomorph fishes. Morphology of the differentiation of germinal cells during spermatogenesis is similar in both subfamilies. In the oviparous C. baileyi and E. latos spermatozoa are free in the deferent ducts. In contrast, the spermatozoa of viviparous goodeids are organized into numerous bundles called spermatozeugmata, a characteristic of most fishes that practice internal fertilization. Differences between the goodeid subfamilies are interpreted relative to the oviparous versus viviparous modes of reproduction. Archival museum specimens are a reliable source of data on reproductive morphology, including histology, and may be the only specimens available of rare or extinct taxa. PMID- 30478906 TI - Protein-protein interaction network analysis of insecticide resistance molecular mechanism in Drosophila melanogaster. AB - The problem of resistance has not been solved fundamentally at present, because the development speed of new insecticides can not keep pace with the development speed of resistance, and the lack of understanding of molecular mechanism of resistance. Here we collected seed genes and their interacting proteins involved in insecticide resistance molecular mechanism in Drosophila melanogaster by literature mining and the String database. We identified a total of 528 proteins and 13514 protein-protein interactions. The protein interaction network was constructed by String and Pajek, and we analyzed the topological properties, such as degree centrality and eigenvector centrality. Proteasome complexes and drug metabolism-cytochrome P450 were an enrichment by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. This is the first time to explore the insecticide resistance molecular mechanism of D. melanogaster by the methods and tools of network biology, it can provide the bioinformatic foundation for further understanding the mechanisms of insecticide resistance. PMID- 30478907 TI - Poly (3-hydroxybutyrate-co-3-hydroxyvalerate) improved osteogenic differentiation of the human induced pluripotent stem cells while considered as an artificial extracellular matrix. AB - Cocell polymers can be the best implants for replacing bone defects in patients. The pluripotent stem cells produced from the patient and the nanofibrous polymeric scaffold that can be completely degraded in the body and its produced monomers could be also usable are the best options for this implant. In this study, electrospun poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) nanofibers were fabricated and characterized and then osteogenic differentiation of the human-induced pluripotent stem cells (iPSCs) was investigated while cultured on PHBV scaffold. MTT results showed that cultured iPSCs on PHBV proliferation were increased compared to those cultured on tissue culture polystyrene (TCPS) as the control. Alkaline phosphatase (ALP) activity and calcium content were also significantly increased in iPSCs cultured on PHBV compared to the cultured on TCPS under osteogenic medium. Gene expression evaluation demonstrated that Runx2, collagen type I, ALP, osteonectin, and osteocalcin were upregulated in iPSCs cultured on PHBV scaffold in comparison with those cultured on TCPS for 2 weeks. Western blot analysis have shown that osteocalcin and osteopontin expression as two major osteogenic markers were increased in iPSCs cultured on PHBV scaffold. According to the results, nanofiber based PHBV has a promising potential to increase osteogenic differentiation of the stem cells and iPSCs-PHBV as a cell-co-polymer construct demonstrated that has a great efficiency for use as a bone tissue engineered bioimplant. PMID- 30478908 TI - The perils of teaching medical triads. PMID- 30478909 TI - Antileukotrienes improve naso-ocular symptoms and biomarkers in patients with NARES and asthma. AB - OBJECTIVE: The aim of our study was to analyze the montelukast effectiveness in improving oculonasal symptoms, patient-reported outcomes (PROs), and eosinophilic biomarkers in patients with nonallergic rhinitis eosinophilic syndrome (NARES). METHODS: We enrolled prospectively 80 symptomatic patients treated with 10 mg once a day of montelukast in monotherapy for 2 months. All patients were investigated before and after treatment. Nasal symptoms (nasal obstruction, rhinorrhoea, sneezing, nasal itching), ocular symptoms (redness/puffiness, watery eyes), and other PROs (olfactory dysfunction, difficulty going to sleep, nighttime awakenings, and nasal congestion on awakening) were scored by visual analogic scale. The following clinical scores were assessed: Total Nasal Symptom Score (T4NSS), Total Ocular Symptom Score (T2OSS), Total Symptom Score of Patient Reported Outcomes (TSS-PROs), and a Composite Symptoms Score (CSS). Patients were classified as responders when a reduction of at least 50% of the CSS was observed. Before and after treatment, the eosinophilic biomarkers in nasal lavage were analyzed: nasal eosinophilia (number of eosinophils per high power field), eotaxin-1 and eotaxin-2. RESULTS: After treatment, significant reductions were observed for all the symptom scores. Forty-two of 78 patients were considered responders. A significant reduction of eosinophils in nasal mucosa and of levels of eotaxin-1 and eotaxin-2 in nasal lavage were observed after treatment in responder patients. Patients with asthma had an increased probability to be responders. CONCLUSION: NARES patients may benefit from treatment with montelukast. In particular, the presence of concomitant asthma may be predictive of a greater efficacy. LEVEL OF EVIDENCE: 2. Laryngoscope, 2018. PMID- 30478910 TI - Epidemiology of status epilepticus in adults: A population-based study on incidence, causes, and outcomes. AB - OBJECTIVE: In 2015, the International League Against Epilepsy (ILAE) proposed a new definition of status epilepticus (SE): 5 minutes of ongoing seizure activity to diagnose convulsive SE (CSE, ie, bilateral tonic-clonic SE) and 10 minutes for focal SE and absence SE, rather than the earlier criterion of 30 minutes. Based on semiology, several types of SE with prominent motor phenomena at any time (including CSE) were distinguished from those without (ie, nonconvulsive SE, NCSE). We present the first population-based incidence study applying the new 2015 ILAE definition and classification of SE and report the impact of the evolution of semiology and level of consciousness (LOC) on outcome. METHODS: We conducted a retrospective population-based incidence study of all adult patients with SE residing in the city of Salzburg between January 2011 and December 2015. Patients with hypoxic encephalopathy were excluded. SE was defined and classified according to the ILAE 2015. RESULTS: We identified 221 patients with a median age of 69 years (range 20-99 years). The age- and sex-adjusted incidence of a first episode of SE, NCSE, and SE with prominent motor phenomena (including CSE) was 36.1 (95% confidence interval [CI] 26.2-48.5), 12.1 (95% CI 6.8-20.0), and 24.0 (95% CI 16.0-34.5; including CSE 15.8 [95% CI 9.4-24.8]) per 100 000 adults per year, respectively. None of the patients whose SE ended with or consisted of only bilateral tonic-clonic activity died. In all other clinical presentations, case fatality was lower in awake patients (8.2%) compared with patients with impaired consciousness (33%). SIGNIFICANCE: This first population-based study using the ILAE 2015 definition and classification of SE found an increase of incidence of 10% compared to previous definitions. We also provide epidemiologic evidence that different patterns of status evolution and LOCs have strong prognostic implications. PMID- 30478911 TI - Male infertility in Sertoli cell-only syndrome: An investigation of autosomal gene defects. AB - OBJECTIVES: To detect autosomal genetic defects and to determine candidate genes in Sertoli cell-only syndrome infertile men. METHODS: Single-nucleotide polymorphism + comparative genomic hybridization microarray technology was carried out on 39 Sertoli cell-only syndrome infertile patients in the present study. Array comparative genomic hybridization compares the patient's genome against a reference genome, and identifies uncover deletions, amplifications and loss of heterozygosity. RESULTS: A link between defective spermatogenesis genes and infertility was examined, and amplifications and deletions in several genes were detected, including homeobox gene; synaptonemal complex element protein 1; collagen, type I, alpha 1; imprinted maternally expressed transcript; and potassium voltage-gated channel subfamily Q member 1. CONCLUSIONS: The present data suggest that several genes can play an important role in spermatogenesis and progression of Sertoli cell-only syndrome. PMID- 30478912 TI - How to discontinue omalizumab in chronic spontaneous urticaria? PMID- 30478913 TI - Comparative study of laparoscopic-assisted and open total gastrectomy for Siewert Types II and III adenocarcinoma of the esophagogastric junction. AB - BACKGROUND: The potential advantages of laparoscopic-assisted total gastrectomy (LATG) compared with open total gastrectomy (OTG) for Siewert Types II and III adenocarcinoma of the esophagogastric junction (AEJ) are not very clear. Thus, the aim of this study was to investigate the surgical outcomes and potential advantages of LATG for Siewert Types II and III AEJ. METHODS: The clinical data of 75 patients (32 for LATG and 43 for OTG) with Siewert II or III AEJ from August 2009 to February 2014 were analyzed retrospectively. Patients were followed up by telephone or out-patient examination till August 2015. RESULTS: Two groups of patients were successfully performed with no perioperative death. The mean operation time was 3.23 +/- 0.35 hr in LATG group, longer than the OTG group 2.83 +/- 0.51 hr. The mean intraoperative bleeding was 122.7 +/- 50.6 ml, less than the OTG group 219.2 +/- 85.2 ml. The analgesics use was 3.00 +/- 0.67 times in the LATG group, less than the OTG group 3.43 +/- 1.03 times. The gastrointestinal function recovery time was 2.69 +/- 0.46 days in the LATG group, shorter than the OTG group 3.42 +/- 0.86 days. The mean postoperative hospital stay was 12.94 + 2.76 days in the LATG group, less than the OTG group 14.57 + 2.35 days (p < 0.05). CONCLUSIONS: LATG and OTG had no significant difference for Siewert II and III AEJ in terms of radical resection and tumor recurrence, but LATG is worthy to be promoted with less bleeding, less postoperative pain, faster recovery of gastrointestinal function, and shorter hospital stay. PMID- 30478914 TI - Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review. AB - Deregulation of the cyclin D-CDK4/6-INK4-RB pathway leading to uncontrolled cell proliferation, is frequently observed in breast cancer. Currently, three selective CDK4/6 inhibitors have been FDA approved: palbociclib, ribociclib, and abemaciclib. Despite promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited the success of these treatments; therefore, the development of various strategies to overcome this resistance is of great importance. We highlight the various mechanisms that are directly or indirectly responsible for resistance to CDK4/6 inhibitors, categorizing them into two broad groups; cell cycle-specific mechanisms and cell cycle-nonspecific mechanisms. Elucidation of the diverse mechanisms through which resistance to CDK4/6 inhibitors occurs, may aid in the design of novel therapeutic strategies to improve patient outcomes. This review summarizes the currently available knowledge regarding mechanisms of resistance to CDK4/6 inhibitors, and possible therapeutic strategies that may overcome this resistance as well. This article is protected by copyright. All rights reserved. PMID- 30478915 TI - Comparative transcriptome analysis reveals PERP upregulated during Salmonella Enteritidis challenge in laying ducks. AB - Salmonella Enteritidis (SE) can be transmitted to eggs through cecum or the ovary from infected layers and causes food poisoning in humans. The mechanism of cecal transmission has been extensively studied. However, the mechanism and route of transovarian transmission of SE remain unclear. In this study, the ducks were orally inoculated with SE, and the ovarian follicles and stroma were collected to detect SE infection. The immune responses were triggered and the innate and adaptive immune genes (TLR4, NOD1, AvbetaD7, and IL-1beta) were upregulated significantly during the SE challenge. Moreover, the ovary tissues (small follicle and stroma) of susceptible and resistant-laying ducks were performed by RNA sequencing. We obtained and identified 23 differentially expressed genes (DEGs) between susceptible and resistant-laying ducks in both small follicle and stroma tissues ( p < 0.05). The DEGs were predominately identified in the p53 signaling pathway. The expression of key genes (p53, MDM2, PERP, caspase-3, and Bcl-2) involved in the signaling pathway was significantly higher in granulosa cells (dGCs) from SE-infected ducks than those from uninfected ducks. Moreover, the overexpression of PERP resulted in further induction of p53, MDM2, caspase-3, and Bcl-2 during SE infection in dGCs. Whereas, an opposite trend was observed with the knockdown of PERP. Besides, it is further revealed that the PERP could enhance cell apoptosis, SE adhesion, and SE invasion in SE-infected dGCs overexpression. Altogether, our results demonstrate the duck PERP involved in the ovarian local immune niche through p53 signaling pathway in dGCs challenged with SE. PMID- 30478916 TI - Isolation and culture of vascular smooth muscle cells from rat placenta. AB - We developed a new separation method for isolating placental vascular smooth muscle cells (PVSMCs) from a rat in this study. Our method used the magnetic force between a magnet and ferrous ferric oxide (Fe3 O 4 ) to make the separation and extraction processes easier and more efficient. From the first to sixth generation, the cells isolated using this protocol were identified as smooth muscle cells (SMCs) by their immunoreactivity to the SMC markers and by the "hill and valley" morphology. PVSMCs were exposed to angiotensin II (1 MUmol/L) and resulted in sharply increased intracellular Ca 2+ concentration. Furthermore, activation of protein kinase C (PKC) increased concomitantly with a decrease in calponin expression. These results indicate that the isolated cells had biological activity. Our method of isolating PVSMCs from rat leads to isolation of cultured cells with activity and high purity. The approach will be useful in research studies on placental vascular diseases. PMID- 30478917 TI - Homomeric Kv7.2 current suppression is a common feature in KCNQ2 epileptic encephalopathy. AB - OBJECTIVE: To gain insight into the mechanisms underlying KCNQ2 encephalopathy by examining the electrophysiologic properties of mutant Kv7.2 channels in different multimeric configurations. METHODS: We analyzed the genotype-phenotype relationship in 4 patients with KCNQ2 encephalopathy and performed electrophysiologic analysis of M-currents mediated by homomeric Kv7.2 or heteromeric Kv7.2/Kv7.3 channels. RESULTS: Negligible or no current was recorded in cells expressing homomeric E130K, W270R, or G281R de novo mutants, and it was reduced by more than 90% for the L243F maternally inherited mutant. The E130K and G281R mutants presented a marked dominant-negative behavior, whereas the current density was partially reduced (L243F) or not affected (W270R) when coexpressed with wild-type Kv7.2 subunits. In contrast, the extent of Kv7.3 "rescue," which yields negligible currents on its own, followed the sequence E130K > L243F > W270R, whereas no rescue was observed with the G281R mutant. No significant effects on current density were observed when subunits were expressed in a 0.5:0.5:1.0 (Kv7.2:mutant:Kv7.3) DNA ratio to mimic the genetic balance. There was an increase in sensitivity to phosphatidylinositol 4,5-bisphosphate (PIP2 ) depletion for W270R/Kv7.3, but no substantial differences were observed when the mutated subunits were coexpressed with Kv7.2 or both Kv7.2 and Kv7.3. SIGNIFICANCE: There was a marked disparity of the impact of these mutations on Kv7.2 function, which varied on association with Kv7.2 or Kv7.3 subunits. Current density of homomeric channels was the most reliable property relating Kv7.2 function to encephalopathy, but other factors are required to explain the milder phenotype for some individuals carrying the maternally inherited L243F mutation. We hypothesize that the role of homomeric Kv7.2 channels for fine-tuning neuronal connections during development is critical for the severity of the KCNQ2 encephalopathy. PMID- 30478918 TI - Associations between Symptoms of Temporomandibular Disorders, Quality of Life and Psychological States in Asian Military Personnel. AB - BACKGROUND: Symptoms of Temporomandibular Disorders (TMD) could affect oral health related quality of life (OHRQoL) and psychological distress. OBJECTIVE: This study aims to determine the prevalence of TMD symptoms, and impact of type and number of TMD symptoms on OHRQoL and psychological states among Asian military personnel. METHOD: The study was conducted across 12 military dental centres using self-administered questionnaire comprising demographical data, DC/TMD symptom questionnaire, OHIP-14 and DASS-21. 3028 personnel, aged between 18-65 years old, were invited to participate with an acceptance rate of 90.5%. Data analysis was done using non-parametric tests, regression analysis and Spearman correlation (p< 0.05 RESULTS: Out of 2043 subjects (1998 males; 45 females, mean age 24.18+/-7.18 years), 36.32% (n=742) reported at least one TMD symptom. Significant differences in summary OHIP-14, depression, anxiety and stress scores were observed between subjects with and without TMD symptoms. Significant differences in OHIP-14 and DASS-21 scores were observed between dissimilar type and number of TMD symptoms in the TMD group. Those with headaches and 2-3 symptoms have substantially poorer OHRQoL and greater psychological distress. Associations between number of TMD symptoms, quality of life, depression, anxiety and stress were significant but weak (r=0.19-0.40). CONCLUSIONS: TMD symptoms were prevalent among Asian military population. Significant differences in OHRQoL and psychological states were observed between subjects with and without TMD symptoms. Specific type and number of TMD symptoms impacted OHRQoL and psychological states differently. Associations between number of TMD symptoms and quality of life, depression, anxiety and stress were significant but weak. This article is protected by copyright. All rights reserved. PMID- 30478919 TI - Evaluation of automated tool for 2D fetal biometry. AB - OBJECTIVE: To determine whether an automated tool can automatically measure the fetal head circumference (HC), abdominal circumference (AC) and femur length (FL) on frozen 2D ultrasound images. METHODS: Ultrasound images from 100 pregnancies between 20 to 40 weeks of gestation were assessed, ensuring equal distribution of data throughout gestational age. For each pregnancy, three standard biometric variables (HC, AC, FL) were measured three times (nine independent image acquisitions). An algorithm (Philips Research) was then used to detect the structure and automatically place measurement calipers. This caliper placement was assessed in two ways. Firstly, clinical assessment was undertaken to determine whether the caliper placement was correct, defined as "acceptable for clinical management"; or whether minor or major adjustment was required. Secondly, the resulting automatic measurements were compared to manual measurements, taken in real time. Differences were calculated and expressed as percentages to correct for fetal growth with advancing gestation. RESULTS: After exclusion of one pregnancy (due to technical failure), a total of 891 images, 297 for each biometric variable, were analyzed. The algorithm failed to place calipers for the AC in 9 images, whereas there were no failures on HC and FL. In the subjective quality assessment of automatic caliper placement, 475 images (53.3%) were judged to be clinically acceptable and did not require any adjustment, while 317 (35.6%) and 90 images (10.1%) required minor and major adjustments respectively. The mean error (ME) between manual and automatic HC was -0.21cm (-0.81%) with 95% limits of agreement (LOA) between -3.73% and 2.12%. For AC and FL the ME was 0.72cm (2.40%) with LOA between -9.48% and 14.27%; and 0.21cm (3.76%, LOA between -8.38% and 15.91%), respectively. CONCLUSION: The automated tool correctly identified the biometric variable in 99% of frozen images. The resulting measurements have a high degree of accuracy and compare well with previously published manual to manual agreement. The measurements exhibited bias, with the automated tool underestimating biometry; this could be overcome by further improvements in the algorithm. Nevertheless, adjustable calipers for manual correction remains a requirement. This article is protected by copyright. All rights reserved. PMID- 30478920 TI - Work Readiness, Transition and Integration: The Challenge of Specialty Practice. AB - AIM: To determine how extended orientation enhances the work readiness of new graduate nurses as they transitioned to their professional role in a specialty care hospital. BACKGROUND: Given increased complexity of care and high patient acuity, there is concern about the work readiness of new graduate nurses in specialty areas. DESIGN: Qualitative exploratory study using an inductive approach. METHODS: An integrative literature review was conducted to abstract characteristics of work readiness among new graduate nurses. Semistructured interviews were conducted with 41 participants from a large pediatric specialty hospital in Ontario, Canada, in 2014. The sample of nurses was stratified and included nurse managers, new graduates and preceptors. Interview texts were interpreted using thematic analysis. RESULTS: A framework for enhancing work readiness of new graduates transitioning to specialty care was developed from the interview and literature findings. Interview data demonstrate an extended orientation that includes mentorship, a gradual increase in clinical responsibilities and involvement in the professional role during the early stages of a nurse's career can enhance work readiness of new graduates. Four key areas of work readiness were identified in the literature: personal characteristics, clinical characteristics, relational characteristics and organizational acuity. CONCLUSION: Based on the study results, new graduate nurses can be an integral part of the team in specialty care provided certain conditions are met during their transition to practice. Our study provides further evidence that extended orientation enhances new graduates' work readiness as they transition to their professional role. This article is protected by copyright. All rights reserved. PMID- 30478921 TI - Longitudinal associations between conflict monitoring and emergent academic skills: An event-related potentials study. AB - Identifying the links between specific cognitive functions and emergent academic skills can help determine pathways to support both early academic performance and later academic achievement. Here, we investigated the longitudinal associations between a key aspect of cognitive control, conflict monitoring, and emergent academic skills from preschool through first grade, in a large sample of socioeconomically diverse children (N = 261). We recorded event-related potentials (ERPs) during a Go/No-Go task. The neural index of conflict monitoring, DeltaN2, was defined as larger N2 mean amplitudes for No-Go versus Go trials. DeltaN2 was observed over the right hemisphere across time points and showed developmental stability. Cross-lagged panel models revealed prospective links from DeltaN2 to later math performance, but not reading performance. Specifically, larger DeltaN2 at preschool predicted higher kindergarten math performance, and larger DeltaN2 at kindergarten predicted higher first-grade math performance, above and beyond the behavioral performance in the Go/No-Go task. Early academic skills did not predict later DeltaN2. These findings provided electrophysiological evidence for the contribution of conflict monitoring abilities to emergent math skills. In addition, our findings suggested that neural indices of cognitive control can provide additional information in predicting emergent math skills, above and beyond behavioral task performance. PMID- 30478922 TI - Association between miRNAs expression and signaling pathways of oxidative stress in diabetic retinopathy. AB - Diabetic retinopathy (DR) is a major cause of vision reduction in diabetic patients. Hyperglycemia is a known instigator for the development of DR, even though the role of oxidative stress pathways in the pathogenesis of DR is established. The studies indicate that microRNAs (miRNAs) are significant to the etiology of DR; changes in miRNAs expression levels may be associated with onset and progression of DR. In addition, miRNAs have emerged as a useful disease marker due to their availability and stability in detecting the severity of DR. The relationship between miRNAs expression levels and oxidative stress pathways has been investigated in several studies. The aim of this study is the examination of function and expression levels of target miRNAs in oxidative stress pathway and pathogenesis of diabetic retinopathy. PMID- 30478923 TI - Automatic identification of sleep and wakefulness using single-channel EEG and respiratory polygraphy signals for the diagnosis of obstructive sleep apnea. AB - Polysomnography (PSG) is necessary for the accurate estimation of total sleep time (TST) and the calculation of the apnea-hypopnea index (AHI). In type III home sleep apnea testing (HSAT), TST is overestimated because of the lack of electrophysiological sleep recordings. The aim of this study was to evaluate the accuracy and reliability of a novel automated sleep/wake scoring algorithm combining a single electroencephalogram (EEG) channel with actimetry and HSAT signals. The study included 160 patients investigated by PSG for suspected obstructive sleep apnea (OSA). Each PSG was recorded and scored manually using American Academy of Sleep Medicine (AASM) rules. The automatic sleep/wake-scoring algorithm was based on a single-channel EEG (FP2-A1) and the variability analysis of HSAT signals (airflow, snoring, actimetry, light and respiratory inductive plethysmography). Optimal detection thresholds were derived for each signal using a training set. Automatic and manual scorings were then compared epoch by epoch considering two states (sleep and wake). Cohen's kappa coefficient between the manual scoring and the proposed automatic algorithm was substantial, 0.74 +/- 0.18, in separating wakefulness and sleep. The sensitivity, specificity and the positive and negative predictive values for the detection of wakefulness were 76.51% +/- 21.67%, 95.48% +/- 5.27%, 81.84% +/- 15.42% and 93.85% +/- 6.23% respectively. Compared with HSAT signals alone, AHI increased by 22.12% and 27 patients changed categories of OSA severity with the automatic sleep/wake-scoring algorithm. Automatic sleep/wake detection using a single-channel EEG combined with HSAT signals was a reliable method for TST estimation and improved AHI calculation compared with HSAT. PMID- 30478924 TI - Automated Quantification of Vocal Fold Motion in a Recurrent Laryngeal Nerve Injury Mouse Model. AB - OBJECTIVES/HYPOTHESIS: The goal of this study was to objectively examine vocal fold (VF) motion dynamics after iatrogenic recurrent laryngeal nerve (RLN) injury in a mouse surgical model. Furthermore, we sought to identify a method of inducing injury with a consistent recovery pattern from which we can begin to evaluate spontaneous recovery and test therapeutic interventions. STUDY DESIGN: Animal model. METHODS: The right RLN in C57BL/6J mice was crushed for 30 seconds using an aneurysm clip with 1.3-N closing force. Transoral laryngoscopy enabled visualization of VF movement prior to surgery, immediately post-crush, and at two endpoints: 3 days (n = 5) and 2 weeks (n = 5). VF motion was quantified with our custom motion-analysis software. At each endpoint, RLN samples were collected for transmission electron microscopy for correlation with VF motion dynamics. RESULTS: Our VF tracking software permitted automated quantification of several measures of VF dynamics, such as range and frequency of motion. By 2 weeks post injury, the frequency of VF movement on the right (injured) side equaled the left, yet range of motion only partially recovered. These objective outcome measures enabled detection of VF dysfunction that persisted at 2 weeks post crush. Transmission electron microscopy images revealed RLN degeneration 3 days post-crush and partial regeneration at 2 weeks, consistent with functional results obtained with automated VF tracking. CONCLUSIONS: Our motion-analysis software provides novel objective, quantitative, and repeatable metrics to detect and describe subtle VF dysfunction in mice that corresponds with underlying RLN degeneration and recovery. Adaptation of our tracking software for use with human patients is underway. LEVEL OF EVIDENCE: NA Laryngoscope, 2018. PMID- 30478925 TI - Cytotoxicity, antiprotozoal, and anti-inflammatory activities of eight curry powders and comparison of their UPLC-ESI-QTOF-MS chemical profiles. AB - BACKGROUND: Curry powder is a blend of spices that is extensively consumed worldwide and mainly in Central Asia. Its preparation is strictly related to each locality and because of the health benefits of its constituents, eight commercial forms of this condiment were biologically and chemically investigated. This study aimed to compare their chemical profile as well as their anti-inflammatory, cytotoxic, and antiparasitic activities. RESULTS: Cur 1 and 7 inhibited leukocyte influx and myeloperoxidase activity, while only 7 was active on protein exudate and NOx species. 2, 6, and 8 displayed trypanocidal effect against T. cruzi amastigote, whereas 6 showed antileishmanial activity on L. amazonensis amastigote. 2, 6, and 8 also inhibited the growth of THP-1 cells used as the parasites host. Among the cytotoxic samples (4 and 6), cur 6 induced apoptosis in MDA-MB-231 cells. Nevertheless, 4 and 6 were unselectively cytotoxic to non tumoral and tumoral cells. The anti-inflammatory, cytotoxicity, and antiparasitic assays were respectively performed by carrageenan induced pleurisy test, Alamar blue assay, and intracellular parasite-host cell model. The spices UPLC-ESIMS data revealed similar and different metabolites in their composition. CONCLUSION: The obtained results indicate that different formulations can conduct to different health benefits because of their chemical compositions. This article is protected by copyright. All rights reserved. PMID- 30478926 TI - Drawing forward family strengths in short therapeutic conversations from a psychiatric nursing perspective. AB - PURPOSE: The aim of the narrative is to describe the therapeutic process and experience from a psychiatric nursing perspective, in therapeutic communication, with a father and his son in acute psychiatry. METHODS: In this case scenario, the Family Strength-Oriented Therapeutic Conversation Intervention (FAM-SOTC Intervention) was used. FINDINGS: The FAM-SOTC Intervention was found to be beneficial for the father-son relationship. PRACTICE IMPLICATION: It is encouraging for nurses in acute psychiatry to know that three short therapeutic conversations can make a difference within the family system. FAM-SOTC seemed to offer cognitive and emotional support to the father-and-son dyad. PMID- 30478927 TI - Identification of hsa-mir-34a, hsa-mir-124, and hsa-mir-204 as signatures for cataract. AB - Cataract, one of the common age-related diseases that remains the leading cause of blindness worldwide. There have been studies pertaining to microRNA (miRNA) effects on cataract pathogenesis. However, the results were different from each other due to the influence of sequencing platform, sample selection, filter conditions, and so on. This study aims to explore the key miRNAs underlying the pathogenesis of cataract and find prevention and treatment methods. First, six representative cataract miRNA datasets are selected and the key miRNAs are determined. The target genes of these key miRNAs are predicted using the TargetScan software, and then, the functional enrichment and transcription factor binding analysis of these target genes are completed, respectively. Three signature miRNAs associated with cataract are finally identified. Among them, hsa mir-34a seems to be significantly upregulated, while hsa-mir-124 and hsa-mir-204 are significantly downregulated. The target genes of the signature miRNAs are mainly enriched in hsa04015:Rap1 signaling pathway, hsa04142:lysosome, and hsa04360:axon guidance, indicating that these pathways may be the crucial metabolic pathways. To summarize, three key miRNAs related to cataract pathogenesis are identified, and the corresponding target genes and transcription factors are also analyzed. Moreover, the potential functions of the target genes are revealed. The results of this study may contribute to the targeted therapy of cataract through miRNAs. PMID- 30478928 TI - Children's scale errors are a natural consequence of learning to associate objects with actions: a computational model. AB - Young children sometimes attempt an action on an object, which is inappropriate because of the object size - they make scale errors. Existing theories suggest that scale errors may result from immaturities in children's action planning system, which might be overpowered by increased complexity of object representations or developing teleofunctional bias. We used computational modelling to emulate children's learning to associate objects with actions and to select appropriate actions, given object shape and size. A computational Developmental Deep Model of Action and Naming (DDMAN) was built on the dual-route theory of action selection, in which actions on objects are selected via a direct (non-semantic or visual) route, or an indirect (semantic) route. As in case of children, DDMAN produced scale errors: the number of errors was high at the beginning of training and decreased linearly but did not disappear completely. Inspection of emerging object-action associations revealed that these were coarsely organized by shape, hence leading DDMAN to initially select actions based on shape rather than size. With experience, DDMAN gradually learned to use size in addition to shape when selecting actions. Overall, our simulations demonstrate that children's scale errors are a natural consequence of learning to associate objects with actions. This article is protected by copyright. All rights reserved. PMID- 30478929 TI - Alterations in the hippocampal-thalamic pathway underlying secondarily generalized tonic-clonic seizures in mesial temporal lobe epilepsy: A diffusion tensor imaging study. AB - OBJECTIVE: The epileptogenic network underlying secondarily generalized tonic clonic seizures (sGTCS) in mesial temporal lobe epilepsy (mTLE) is not well understood. Here, we investigated alterations in the probabilistic hippocampal thalamic pathway (pHTP) underlying sGTCS using diffusion tensor imaging and resting-state functional magnetic resonance imaging in a cohort of TLE patients with hippocampal sclerosis (HS). METHODS: We consecutively recruited 51 unilateral TLE-HS patients (26 with and 25 without sGTCS) and 22 healthy controls. Probabilistic tractography was used to track the pHTP. Raw fractional anisotropy (FA) and mean diffusivity (MD) of the pHTP were corrected by the FA/MD of the hemispheric white matter on the same side. The volume of the thalamic subregion connected to the hippocampus (TSCH) was investigated. Fractional amplitude of low-frequency fluctuations of the hippocampus, the TSCH, and the thalamic subregion unconnected to the hippocampus in resting-state functional magnetic resonance imaging were also calculated. RESULTS: After correction, the sGTCS group showed lower FA than the non-sGTCS group (P = 0.03), and lower FA as well as higher MD than controls in the ipsilateral pHTP. The non-sGTCS group only showed higher corrected MD in the ipsilateral pHTP relative to controls. Corrected FA or MD in the contralateral pHTP did not differ among groups. The TSCH was located in the mesial aspect of the thalamus, and it was atrophied in the sGTCS group compared to the non-sGTCS group and controls. The sGTCS group had lower fractional amplitude of low-frequency fluctuations in the ipsilateral hippocampus and TSCH compared to controls. SIGNIFICANCE: In TLE-HS, sGTCS was associated with impaired integrity of the pHTP as well as structural and functional abnormalities in the medial thalamus. The medial thalamus is important in seizure generalization in mTLE. PMID- 30478930 TI - Diagnosis and treatment of oropharyngeal dysphagia after total laryngectomy with or without pharyngoesophageal reconstruction: A systematic review. AB - BACKGROUND: This systematic review qualitatively summarizes the current literature on diagnosis and treatment of oropharyngeal dysphagia (OD) after total laryngectomy (TLE). METHODS: Electronic databases PubMed, Embase, and the Cochrane Library were used. Two independent reviewers carried out the literature search and assessed the methodological quality of the included studies using a critical appraisal tool. RESULTS: Forty-four articles met the inclusion criteria. Of these, 35 studies were on diagnosis, four on therapy, and five on both diagnosis and treatment of OD following TLE. Study aims, swallowing-assessment methods, and main findings of the included studies were summarized and presented. CONCLUSIONS: The reviewers found heterogeneous outcomes and serious methodological limitations, which prevented us from pooling data to identify trends that would assist in designing best clinical practice protocols for OD following TLE. Further research should focus on several remaining gaps in our knowledge on diagnosis and treatment interventions for OD following TLE. PMID- 30478931 TI - Association between microRNAs expression and signaling pathways of inflammatory markers in diabetic retinopathy. AB - Diabetic retinopathy is one of the common and serious microvascular complications of diabetes mellitus, as hyperglycemia has metabolic effects on the retina. Hyperglycemia induces increased oxidative stress, which stimulates inflammation pathways and promotes vascular dysfunction of the retina that leads to increased capillary permeability and vascular leakage. One of the main factors involving diabetic retinopathy is the inflammation signaling pathways. In contemporary times, microRNAs (miRNAs) are identified as functional biomarkers for early detection and treatment of numerous diseases specifically diabetic retinopathy. MiRNAs can modulate gene expression through regulation of transcriptional and posttranscriptional of target genes. With that, miRNAs can regulate almost every cellular and developmental process, including the regulation of instinct immune responses and inflammation. The aim of this study is to investigate the role of miRNAs in inflammation pathways and the pathogenesis of diabetic retinopathy. PMID- 30478932 TI - Neighborhood bystander intervention in intimate partner abuse: The role of social cohesion. AB - This study examines the relationships among individual beliefs about intimate partner abuse (IPA), attitudes about IPA reporting, social cohesion, and the intention of intervening in neighborhood IPA. Data for this study come from a larger cross-sectional, community-based study in which participants (N = 1,626) were surveyed face to face using stratified random sampling in targeted communities in a Mountain West state (i.e., drop-off, pick-up method) and online using social media outreach in targeted communities. Linear regression results indicated that participants were less likely to intervene in IPA situations in their neighborhood if they held beliefs about the private nature of IPA or feared retaliation. Additionally, social cohesion was positively associated with participants' intention of intervening in IPA situations in their neighborhood. Our findings suggest potential avenues for community intervention that attempt to build communitywide beliefs that IPA is a community-level concern and one that demands attention from the entire community. PMID- 30478934 TI - Identifying poor adherence to antihypertensive medications in patients with resistant hypertension. PMID- 30478933 TI - Higher circulating androgens and higher physical activity levels are associated with less central adiposity and lower risk of cardiovascular death in older men. AB - OBJECTIVE: Low endogenous sex hormones and low physical activity (PA) levels have been associated with CVD risk. Whether these interact to influence CVD outcomes remains unclear. We assessed whether sex hormone concentrations and PA were additively associated with lower central adiposity and CVD risk. PATIENTS: 3,351 community-dwelling men, mean age 77 years. MEASUREMENTS: Baseline testosterone (T), dihydrotestosterone (DHT) and estradiol (E2) were assayed. Levels of PA were ascertained by questionnaire. Men were stratified using median splits into high hormone+high PA (H/H), high hormone+low PA (H/L); low hormone+high PA (L/H) and low hormone+low PA (L/L) groups. RESULTS: 865 CVD events and 499 CVD deaths occurred during 10-year mean follow-up. Men with higher T, DHT or SHBG and higher PA had the lowest BMI, waist circumference and risk of metabolic syndrome. Men with higher T had the lowest risk of incident CVD events, irrespective of PA level. Men with higher T or DHT and higher PA had the lowest risk of dying from CVD (e.g. hazard ratios for T/PA H/H 0.76 p=0.031; H/L 0.85 p=0.222; L/H 0.80 p=0.075; L/L 1.00). CONCLUSION: Higher circulating androgens and higher PA were associated with less central adiposity at baseline and fewer CVD deaths during follow-up. These findings are consistent with a potential additive effect of androgens and PA on cardiometabolic outcomes in older men. This article is protected by copyright. All rights reserved. PMID- 30478935 TI - Ligand-Promoted Non-Directed C-H Cyanation of Arenes. AB - We herein report the first example of a 2-pyridone accelerated non-directed C-H cyanation with an arene as the limiting reagent. This protocol is compatible with a broad scope of arenes, including advanced intermediates, drug molecules, and natural products. A kinetic isotope experiment (kH/kD = 4.40) indicates that the C-H bond cleavage is the rate-limiting step. Also, the reaction is readily scalable, further showcasing the synthetic utility of this method. PMID- 30478936 TI - Tracing individuals and populations of the tambaqui, Colossoma macropomum (Cuvier, 1818), from Brazilian hatcheries using microsatellites markers. AB - BACKGROUND: In recent years, tracing of alimentary produce of animal origin has become increasingly important, for economic, food safety, and ecological reasons. The tambaqui, Colossoma macropomum, is the native fish most farmed in Brazil. The reliable identification of the origin of tambaquis (wild or farmed) offered for sale to the general public has become necessary to satisfy regulatory norms and uphold consumer confidence. Molecular methods based on the analysis of DNA sequences have often been used to evaluate the potential for tracing farmed fish, given their reliability and precision. RESULTS: Full Likelihood and Bayesian approaches proved to be the most efficient for the identification, respectively, of individuals and populations for most of the fish sampled from seven hatcheries and one wild stock. The exclusion method and genetic distances were the least effective approaches for the identification of individuals and populations. The Bayesian method identified correctly more than 99% of the fry from most stocks, except those of the Santarem hatchery and River Amazon wild stock, which presented the best results for individual identification. CONCLUSION: The identification of populations was effective for most hatcheries, although the identification of individuals from most stocks was hampered by the reduced genetic variability. This article is protected by copyright. All rights reserved. PMID- 30478937 TI - DREAM5: An open-label, randomized, cross-over study to evaluate the safety and efficacy of day and night closed-loop control using the MD-Logic automated insulin delivery system compared to sensor augmented pump therapy in patients with type 1 diabetes at home. AB - AIMS: Previous DREAM studies demonstrated the safety and efficacy of the CE marked MD-Logic closed-loop system (DreaMed GlucoSitterTM) in different settings for overnight glycaemic control. The present study aims to evaluate the system for day and night use for 60 hours during weekend time at home compared to sensor augmented pump (SAP) therapy in participants with type 1 diabetes. METHODS: This was a prospective, multicenter, crossover, controlled study. All participants were connected in randomized order for one weekend to SAP therapy or the MD-Logic System: in the intervention arm only the amount of carbohydrate was entered into the bolus calculator, the rest of insulin dosing was delivered automated and wirelessly by a tablet computer. The primary endpoint was the percentage of glucose values between 70-180 mg/dl. RESULTS: The ITT population comprised of 48 (19 males, 29 females) adolescents and adults experienced in sensor use: (median, [IQR]): age 16.1y [13.2-18.5], diabetes duration 9.4 y [5.0-12.7], pump use 5.4y [3.1-9.4], HbA1c 7.6% [7.0-8.1]. A significant increase in the percentage of time within target range (70-180mg/dl) (66.6 vs 59.9 %, P=0.002) was observed in the closed-loop system versus control weekends with unchanged percentage of time below 70mg/dl (2.3 vs. 1.5 %, p=0.369). The mean weekend glucose level per participant was significantly lower (153 [142-175] vs. 164 [150-186] mg/dl, p=0.003). No safety signals were observed. CONCLUSIONS: The MD-Logic system was safe and associated with better glycemic control over SAP therapy for day and night use. The lack of remote monitoring did not lead to safety signals in adapting basal rates as well as in administration of automated bolus corrections. This article is protected by copyright. All rights reserved. PMID- 30478938 TI - CircRNA ZNF609 functions as a competitive endogenous RNA to regulate FOXP4 expression by sponging miR-138-5p in renal carcinoma. AB - Circular RNA (circRNA) play important roles in the pathological processes of many diseases. By analyzing the results of the GSE100186 chip, we found that the expression of circRNA ZNF609 (circ-ZNF609) was significantly increased in renal cell carcinoma. Recently, there are studies showing that circ-ZNF609 can regulate cell proliferation and invasion ability of various cells. In this study, we investigated whether circ-ZNF609 may affect cell invasion and proliferation in renal carcinoma. Quantitative reverse transcription polymerase chain reaction was performed to detect the expression of circ-ZNF609 in renal carcinoma cell lines and renal epithelial cells. The direct interaction between microRNA-138-5p (miR 138-5p) and forkhead box P4 (FOXP4) or circ-ZNF609 was confirmed by luciferase reporter assay and RNA immunoprecipitation assay. We use Cell Counting Kit-8, 5 ethynyl-2'-deoxyuridine, and Matrigel assays to assess the effect of miR-138-5p or circ-ZNF609 on cell proliferation or invasion ability. And we found that circ ZNF609 is significantly increased in renal carcinoma cell lines. In addition, the high expression of circ-ZNF609 promotes cell proliferation and invasion ability. In short, our current study reveals the role of the circ-ZNF609/miR-138-5p/FOXP4 regulatory network in renal carcinoma and provides a new perspective for the pathogenesis of renal carcinoma. PMID- 30478939 TI - Modified distribution in the polyphenolic profile of rosemary leaves induced by plant inoculation with an arbuscular mycorrhizal fungus. AB - BACKGROUND: Rosemary forms an arbuscular mycorrhizal (AM) symbiosis with a group of soilborne fungi belonging to the phylum Glomeromycota, which can modify the plant metabolome responsible for the antioxidant capacity and other health beneficial properties of Rosemary. RESULTS: The effect of inoculating rosemary plants with an AM fungus on their growth via their polyphenolic fingerprinting was evaluated after analyzing leaf extracts from non-inoculated and inoculated rosemary plants by ultra-high performance liquid chromatography-high resolution mass spectrometry. . Plant growth parameters indicated that mycorrhizal inoculation significantly increased plant height and biomass. Chemical modifications in the plant polyphenolic profile distribution were found after a principal components analysis (PCA) loading plots study. Four compounds hosting strong antioxidant properties: ferulic acid, asiatic acid, carnosol, and vanillin were related to mycorrhizal rosemary plants while caffeic and chlorogenic acids had a higher influence in non-mycorrhizal plants. CONCLUSION: Mycorrhization was found to stimulate growth in order to obtain a higher biomass of plant leaves in short time and avoiding chemical fertilization, while analytical results demonstrate that there is an alteration in the distribution of polyphenols in plants colonized by the symbiotic fungus, which can be related to an improvement in nutritional properties with future industrial significance. This article is protected by copyright. All rights reserved. PMID- 30478940 TI - Venetoclax for chronic lymphocytic leukaemia patients who progress after more than one B-cell receptor pathway inhibitor. PMID- 30478941 TI - Differentiation of acquired port wine stain and angioma serpiginosum: a dermoscopic perspective. PMID- 30478942 TI - Organizational determinants of bullying and work disengagement among hospital nurses. AB - AIM: To identify organizational determinants of bullying and resulting work disengagement among hospital nurses. DESIGN: A cross-sectional, web-based, anonymous questionnaire study. METHODS: The questionnaire was administered in 2017 to all Registered Nurses in a regional healthcare system in the United States (N=1780), with 331 complete responses. Logistic regression was used to identify factors associated with personally experiencing and witnessing bullying, respectively. Linear regression was conducted to identify organizational factors associated with disengagement due to bullying. RESULTS: Psychological safety, a measure of team trust and respect, was inversely associated with being personally bullied and witnessing bullying. Being personally bullied, but not witnessing bullying, was associated with disengagement due to bullying. Psychological safety and competence development, a measure of opportunities to develop skills and knowledge at work, were both inversely associated with disengagement due to bullying. CONCLUSION: Hospital units characterized by trust and respect among nurses are less likely to have a culture of bullying. Both psychological safety and competence development have a protective effect on nurse disengagement from the workplace due to bullying. Interventions to mitigate and prevent bullying and work disengagement among nurses should encompass efforts to enhance psychological safety and opportunities for competence development. IMPACT: Bullying is a pervasive hazard in the nursing profession that contributes to unhealthy workplaces. Nurse managers and staff nurses should work together to establish psychologically safe environments where nurses dare to discuss tough issues like bullying. This research contributes to understanding the characteristics of work environments in which nurses can thrive and work effectively. This article is protected by copyright. All rights reserved. PMID- 30478943 TI - Antidiabetic potential: In vitro inhibition effects of bromophenol and diarylmethanones derivatives on metabolic enzymes. AB - Aldose reductase converts glucose to sorbitol in the polyol pathway. It is an important enzyme to prevent diabetic complications. In this study, we studied the inhibitory effects of bromophenol derivatives on aldose reductase (AR), alpha glucosidase, and alpha-amylase enzymes. In the bromophenols series, compound 1f showed the maximum inhibition effect against AR with a Ki value of 0.05 +/- 0.01 MUM, while compound 1d showed the lowest inhibition effect against AR with a Ki value of 1.13 +/- 0.99 MUM. In addition, alpha-amylase from porcine pancreas and alpha-glucosidase from Saccharomyces cerevisiae were used as enzymes. In this study, all compounds were tested for the inhibition of the alpha-glucosidase enzyme and demonstrated efficient inhibition profiles with Ki values in the range of 43.62 +/- 5.28 to 144.37 +/- 16.37 nM against alpha-glucosidase. Additionally, these compounds were tested against the alpha-amylase enzyme, which determined an effective inhibition profile with IC50 values in the range of 9.63-91.47 nM. These compounds can be selective inhibitors of AR, alpha-glucosidase, and alpha amylase enzymes as antidiabetic agents. PMID- 30478944 TI - Beyond the traditional simulation design for evaluating type 1 error control: From the "theoretical" null to "empirical" null. AB - When evaluating a newly developed statistical test, an important step is to check its type 1 error (T1E) control using simulations. This is often achieved by the standard simulation design S0 under the so-called "theoretical" null of no association. In practice, the whole-genome association analyses scan through a large number of genetic markers ( G s) for the ones associated with an outcome of interest ( Y ), where Y comes from an alternative while the majority of G s are not associated with Y ; the Y-G relationships are under the "empirical" null. This reality can be better represented by two other simulation designs, where design S1.1 simulates Y from analternative model based on G , then evaluates its association with independently generated Gnew ; while design S1.2 evaluates the association between permutated Y and G . More than a decade ago, Efron (2004) has noted the important distinction between the "theoretical" and "empirical" null in false discovery rate control. Using scale tests for variance heterogeneity, direct univariate, and multivariate interaction tests as examples, here we show that not all null simulation designs are equal. In examining the accuracy of a likelihood ratio test, while simulation design S0 suggested the method being accurate, designs S1.1 and S1.2 revealed its increased empirical T1E rate if applied in real data setting. The inflation becomes more severe at the tail and does not diminish as sample size increases. This is an important observation that calls for new practices for methods evaluation and T1E control interpretation. PMID- 30478945 TI - Has carotid intima-media thickness prognostic impact in patients with high cardiovascular risk? A long-term cohort study. AB - BACKGROUND: Carotid intima-media thickness (CIMT) is an established surrogate marker for cardiovascular events in patients with intermediate risk. In patients with high cardiovascular risk or established cardiovascular disease, the impact of CMIT measurement on risk stratification for future events is less clear. Our objective was to evaluate the impact of CIMT on the occurrence of cardiovascular events in a cohort of individuals with high cardiovascular risk, in long-term follow-up. METHODS: We analyzed 296 individuals, mean follow-up of 6.9 +/- 2.2 years. Individuals were divided into tertiles according to CIMT. Tertiles were compared in terms of baseline characteristics and outcomes during follow-up-all cause mortality and composite outcome (mortality, acute coronary syndromes, coronary revascularization, stroke/transient ischemic attack, heart failure, or cardiovascular admission). RESULTS: Our population had a mean age of 65 +/- 9 years at the beginning of the study, 55% males. Patients with higher CIMT showed a trend for higher cardiovascular mortality (P = 0.084) and for the composite outcome (P = 0.049). A CIMT >= 0.85 mm was also associated with higher rate of events; however, CIMT was not an independent predictor of outcome after adjustment for age and gender. CIMT assessment was useful in patients with hypertension, hyperlipidemia, and metabolic syndrome and in nondiabetic patients. For the composite outcome, it was also useful in females, smokers, and in patients without coronary artery disease. CONCLUSIONS: Patients with higher CIMT have worst outcome, but this was mainly driven by age and gender. CIMT is useful as a prognostic marker in specific subsets of patients. PMID- 30478946 TI - Protective effect of vitamin E and vitamin C alone and in combination on testicular damage induced by sodium metabisulphite in rats: A stereological study. AB - The existing investigation was directed to consider the protective role of vitamin C and E alone and in combination on sodium metabisulphite-induced damage on testicular. Experimental animals were received sodium metabisulphite (520 mg/kg) alone and in combination with vitamin E (100 mg/kg), vitamin C (100 mg/kg) and vitamin E + C, while the control groups received 0.9% saline solution and olive oil (the solvent of the vitamin E). Finally, the changes in the testis histology were examined stereologically. Lipid peroxidation was assessed through the measurement of malondialdehyde (MDA) levels in testis tissues. Also, serum testosterone concentrations were measured. The results indicated that 80%-90% (spermatogonia A and B, spermatocyte and Leydig) and 40% of the Sertoli cells were missed in the rats that received sodium metabisulphite, respectively, compared with the controls. The co-supplementation of vitamin E with vitamin C significantly decreased MDA (p = 0.006) and increased testosterone (p = 0.001) concentrations in the rats received SMB which were as much as control and olive groups. Co-supplementation of vitamin E and vitamin C due to their synergistic effects could be an appropriate strategy in preventing testicular from sodium metabisulphite-induced damage. PMID- 30478947 TI - 22q11 microdeletion syndrome and ultra-high risk for psychosis: The role of neurological soft signs as an independent marker of vulnerability for psychosis. AB - AIM: 22q11 microdeletion syndrome has an increased risk for psychosis, similar to subjects at ultra-high risk for psychosis. Neurological soft signs are considered an endophenotype of psychotic disorders and a marker of vulnerability to Schizophrenia, consisting of overflow movements, dysrhythmia and speed of timed activities. To date, there are no studies that have evaluated the presence of the neurological soft signs in subjects with 22q11 microdeletion syndrome and there are a few studies that have analysed this issue in subjects at ultra-high risk. METHODS: We sought to measure neurological soft signs in these two conditions, compared to healthy controls and to analyse the possible correlation between neurological soft signs and positive/negative symptoms both in 22q11 microdeletion syndrome and ultra-high-risk groups. 54 drug-naive patients (29 with 22q11 microdeletion syndrome and 25 at ultra-high risk for psychosis) and 25 healthy controls were evaluated for neurological soft signs. RESULTS: Both clinical groups showed a greater number of neurological soft signs compared to healthy control, although the two clinical groups did not differ for the number of neurological soft signs. Positive correlation between speed of timed activities and negative symptoms was found in subjects at ultra-high risk. CONCLUSION: Neurological soft signs could represent a marker of atypical neurodevelopment in the two populations examined. Since we did not found a strong correlation between neurological soft signs and positive/negative symptoms, we suggest that neurological soft signs could be indicators of vulnerability to psychosis independent from the psychopathology. PMID- 30478948 TI - Novel mutation of the TINF2 gene resulting in severe phenotypic Revesz syndrome. PMID- 30478949 TI - Dermoscopy of lipidised dermatofibroma: A morphological study of 13 cases. AB - BACKGROUND/OBJECTIVES: The aim of this study was to evaluate the morphological findings of lipidised dermatofibromas under dermoscopic observation. METHODS: Dermoscopic examination of 13 cases of lipidised dermatofibromas was performed to evaluate specific dermoscopic criteria and patterns. RESULTS: The most frequently occurring dermoscopic features were as follows: (i) A yellowish homogenous pigmentation in all cases (100%); this pigmentation was total in 30.7%; (ii) White structures were seen in 46.1%, most of them were central white networks (38.4%); (iii) Pigment network was observed in 53.8%, most of them were peripheral delicate pigment networks (38.4%), but two cases showed an atypical pigment network; (iv) The presence of vascular structures was common (10 cases, 77%); (v) Regarding to dermoscopic patterns, five lipidised dermatofibromas (38.4%) showed a total yellowish homogeneous pattern; 38.4% an atypical pattern and 23.2% a 'central white network + peripheral delicate pigment network' pattern. CONCLUSIONS: The dermoscopic recognition of a total yellowish homogeneous area or a yellowish colouration in the context of a dermatofibroma can be proposed to help suspecting a lipidised dermatofibroma. PMID- 30478950 TI - Negative effects on newborn piglets caused by excess dietary tryptophan in the morning in sows. AB - BACKGROUND: This study investigated the effect of dynamic feeding models of dietary tryptophan on sows' performance during late pregnancy. RESULTS: The average piglet birth weight and live farrowing rate from sows consuming a high low tryptophan diet (0.39% Trp in the morning and 0.13% Trp in the afternoon) were decreased compared with those fed a 2*tryptophan diet (0.26% Trp in the morning and afternoon). Compared with the 2*tryptophan group, sow serum kynurenic acid and the newborn liver n-6:n-3 polyunsaturated fatty acid ratio were significantly higher, and sow serum taurine and newborn serum taurine, phosphoserine, cysteine and proline were lower in the high-low tryptophan diet group. And 88 genes were differentially expressed in newborn piglets' livers between the 2*tryptophan and high-low groups. Genes related to cytotoxic effector regulation (MHC (major histocompatibility complex) class I proteins), NADH oxidation, reactive oxygen species (ROS) metabolism and tissue development were differentially expressed between these two groups. CONCLUSION: Together, the results provide information on new biomarkers in serum or liver and provide novel insights into the variations in the fetal liver during exogenous stimulus response and biological processes of ROS metabolism in fetuses during late pregnancy caused by a single excessive tryptophan ingestion daily in the morning. This article is protected by copyright. All rights reserved. PMID- 30478951 TI - Antibody-drug conjugates (ADCs) for cancer therapy: Strategies, challenges, and successes. AB - Targeted delivery of therapeutic molecules into cancer cells is considered as a promising strategy to tackle cancer. Antibody-drug conjugates (ADCs), in which a monoclonal antibody (mAb) is conjugated to biologically active drugs through chemical linkers, have emerged as a promising class of anticancer treatment agents, being one of the fastest growing fields in cancer therapy. The failure of early ADCs led researchers to explore strategies to develop more effective and improved ADCs with lower levels of unconjugated mAbs and more-stable linkers between the drug and the antibody, which show improved pharmacokinetic properties, therapeutic indexes, and safety profiles. Such improvements resulted in the US Food and Drug Administration approvals of brentuximab vedotin, trastuzumab emtansine, and, more recently, inotuzumab ozogamicin. In addition, recent clinical outcomes have sparked additional interest, which leads to the dramatically increased number of ADCs in clinical development. The present review explores ADCs, their main characteristics, and new research developments, as well as discusses strategies for the selection of the most appropriate target antigens, mAbs, cytotoxic drugs, linkers, and conjugation chemistries. PMID- 30478952 TI - Intersectin-Cdc42 interaction is required for orderly meiosis in porcine oocytes. AB - Intersectins (ITSNs) have been shown to act as adaptor proteins that govern multiple cellular events via regulating Cdc42 activity. However, it remains to be determined whether the ITSN-Cdc42 pathway is functional in porcine oocytes. To address this question, we used a small molecule, ZCL278, to selectively disrupt the ITSN2-Cdc42 interaction. In the present study, we find that porcine oocytes exposed to ZCL278 are unable to completely progress through meiosis. Meanwhile, the spindle defects and chromosomal congression failure are frequently detected in these oocytes. In support of this, we observed the accumulated distribution of vesicle-like ITSN2 signals around the chromosome/spindle region during porcine oocyte maturation. In addition, our results also showed that inhibition of the ITSN-Cdc42 interaction impairs the actin polymerization in porcine oocytes. In summary, the findings support a model where ITSNs, through the interaction with Cdc42, modulates the assembly of meiotic apparatus and actin polymerization, consequently ensuring the orderly meiotic progression during porcine oocyte maturation. PMID- 30478953 TI - Optimal in-feed amino acid ratio for laying hens based on deletion method. AB - A total of 56 Hy-line W-36 hens from 28 to 30 weeks were used on nitrogen balance (NB) trial to estimate daily N maintenance requirements (NMR) and the genetic potential for daily N retention (NRmax T). The treatments consisted of six graded levels of nitrogen in the diets (N1 = 8; N2 = 16; N3 = 24; N4 = 32; N5 = 40; and N6 = 48 g N/kg of feed), formulated using the dilution technique. The regression analyses between nitrogen intake and excretion were performed to fit the exponential function and to determine the NMR = 292 mg/BWkg 0.67 , which was applied for further calculation of NRmax T = 1,883 mg/BWkg 0.67 . A second NB trial was conducted, and a total of 96 Hy-line W-36 hens were used in the same period to estimate the ideal amino acid ratio (IAAR). Twelve treatments with eight replicates and one bird per cage were used. A balanced diet (BD) was formulated to meet the IAAR and the requirement of other nutrients for pullets. The limiting diets were formulated diluting BD with cornstarch and refilled with synthetic AAs and other feed ingredients, except for the AA under study. In each trial, the data of nitrogen intake, excretion, deposition and retention were obtained in a NB trial. The IAAR determined by Goettingen approach was Lys 100, Met+Cys 88, Trp 21, Thr 69, Arg 109, Val 90, Ile 75, Leu 127, Phe+Tir 110, Gly+Ser 73 and His 29%. The IAAR determined by Louvain approach was Lys 100, Met+Cys 88, Trp 21, Thr 69, Arg 104, Val 91, Ile 78, Leu 121, Phe+Tir 119, Gly+Ser 77 and His 29%. PMID- 30478954 TI - Fundamental Understanding of Water-Induced Mechanisms in Li-O2 Batteries: Recent Developments and Perspectives. AB - Modern sustainability challenges in recent years have warranted the development of new energy storage technologies. Practical realization of the lithium-O2 battery holds great promise for revolutionizing energy storage as it holds the highest theoretical specific energy of any rechargeable battery yet discovered. However, the complete realization of Li-O2 batteries necessitates ambient air operations, which presents quite a few challenges, as carbon dioxide (CO2 ) and water (H2 O) contaminants introduce unwanted byproducts from side reactions that greatly affect battery performance. Although current research has thoroughly explored the beneficial incorporation of CO2 , much mystery remains over the inconsistent effects of H2 O. The presence of water in both the cathode and electrolyte has been observed to alter reaction mechanisms differently, resulting in a diverse range of effects on voltage, capacity, and cyclability. Moreover, recent preliminary research with catalysts and redox mediators has attempted to utilize the presence of water to the battery's benefit. Here, the key mechanism discrepancies of water-afflicted Li-O2 batteries are presented, concluding with a perspective on future research directions for nonaqueous Li-O2 batteries. PMID- 30478955 TI - EXPOSURES OF CHILDREN TO NEONICOTINOIDS IN PINE WILT DISEASE CONTROL AREAS. AB - Neonicotinoids insecticides that have been on market since 1992 have been used globally including Japan. Because they are sprayed over forests and agricultural areas, inadvertent toxicity in non-target insects (especially honey bees) and humans is a matter of public concern. However, information on exposure levels and potential health impacts of neonicotinoids in children living around sprayed areas is scarce. Thus, we determined neonicotinoid exposure levels in children living in communities where thiacloprid was used to control pine wilt disease. A total of 46 children (23 males and 23 females) were recruited for the study, and informed written consent was obtained from their guardians. Urine specimens were collected before, during, and after insecticide spraying events, and atmospheric particulate matter was also collected. Concentrations of thiacloprid and six other neonicotinoid compounds were determined in urine samples and in atmospheric particulate matter specimens using LC-ESI/MS/MS. In urine specimens, thiacloprid concentrations were below 0.13 ug/L and were detectable in approximately 30% of all samples. Concentrations of the other neonicotinoids, N-dm-acetamiprid, thiamethoxam, dinotefuran, and clothianidin were 18.7, 1.92, 72.3, and 6.02 ug/L, respectively. Estimated daily intake (EDI) of these neonicotinoids were then calculated from urinary levels; although EDI's of the neonicotinoids were lower Environmental Toxicology and Chemistry than current acceptable daily intake (ADI) values, the children are found to be exposed to multiple neonicotinoids on a daily basis. This article is protected by copyright. All rights reserved. PMID- 30478956 TI - Possible mechanism for disposal of degenerative cardiomyocytes in human failing hearts: phagocytosis by a neighbour. AB - The index case was a 51-year-old woman suffering from doxorubicin cardiomyopathy. In her endomyocardial biopsy specimen, we observed under electron microscopy six scenes in which degenerative cardiomyocytes were engulfed by neighbouring cardiomyocytes. The enclosed cardiomyocytes appeared more degenerative than the enclosing ones in every pair: the myofibrils were more severely damaged. At more degenerative stages, some desmosomes of the intercalated discs on the enclosed cardiomyocyte had disappeared. The membranes between the cardiomyocytes were occasionally disrupted, and there appeared to be sharing of cellular contents between the cells. One pair of such a phagocytosis-like figure was observed in one case with 5-fluorouracil cardiomyopathy (a 68-year-old man) among eight other chemotherapy-induced cardiomyopathies but none among 30 non-drug-induced dilated cardiomyopathies. The findings suggest a mechanism for disposal of degenerative cardiomyocytes in human failing hearts: phagocytosis by a neighbour, although alternative interpretations remain (e.g. giant autophagic vacuoles or two cardiomyocytes with degenerative intercalated discs). PMID- 30478957 TI - Recent Progress on Molybdenum Oxides for Rechargeable Batteries. AB - Diminution in fossil-fuel resources and rise in energy demands require us to pursuit sustainable and rechargeable energy-storage alternatives including batteries and supercapacitors, whose electrochemical properties depend largely on the electrode materials. In the past decades, numerous electrode materials with excellent electrochemical energy-storage capability, long life span, and environmentally acceptable quality have been developed. Among the existed materials, molybdenum oxides containing MoO3 and MoO2 as well as their composites are very fascinating contenders for competent energy-storage devices because of their exceptional physicochemical properties like the thermal stability, high theoretical capability and mechanical strength. This review dedicates mainly on the latest progress on molybdenum oxides as electrode materials for lithium-ion batteries (LIBs), sodium-ion batteries (SIBs) and other novel batteries like lithium-sulfur (Li-S) batteries, lithium-oxygen (Li-O2) batteries as well as the newly-developed hydrogen ion batteries with focus on the studies of the reaction mechanism, design of the electrode structures and improvement of the electrochemical properties. PMID- 30478958 TI - A functional ex vivo assay to detect PARP1-EJ repair and radiosensitization by PARP-inhibitor in prostate cancer. AB - Here, we present a functional assay to detect the repair switch to the alternative PARP1-dependent end joining (PARP1-EJ) pathway and the associated susceptibility to PARPi-mediated radiosensitization in freshly collected tumor samples from prostate cancer (PCa) patients, thereby facilitating the selection of patients who should benefit from combined PARPi plus radiotherapy (RT) treatment. Our optimized ex-vivo approach sustains tumor slices for up to 15 days under culture conditions that maintain proliferation and oxygenation rates, as measured by EdU incorporation and pimonidazole staining, respectively. We present a robust system to analyze DSB repair using, for the first time in an ex vivo tumor slice setting, two DSB-markers simultaneously i.e. gammaH2AX and 53BP1. A computer-based processing method (i) controls variations in DNA content and slicing on the number of repair foci and (ii) measures the PARPi-mediated enhancement ratio on DSB foci numbers to ensure inter-patient-comparability. We validated this approach using a PC3 xenograft model with its previously described repair switch to PARP1-EJ. More importantly, we show that approximately 30% of the analyzed tumor tissue samples collected from PCa patients display a switch to PARP1-EJ, as indicated by the enhanced number of residual gammaH2AX/53BP1 foci exclusively after PARPi+RT. Furthermore, normal prostatic tissues show no repair switch to PARP1-EJ, indicating that this repair switch and its associated radiosensitizing effect is tumor-specific. Collectively, we present here a predictive assay for the switch to PARP1-EJ that enables individualization of anti-cancer treatment using a combination of RT and radiosensitizing anticancer agents such as PARPi in PCa. This article is protected by copyright. All rights reserved. PMID- 30478960 TI - Novel placental structure in the Mexican gerrhonotine lizard, Mesaspis viridiflava (Lacertilia; Anguidae). AB - The evolution of viviparity alters the physical relationship between mothers and offspring and the prevalence of viviparity among squamate reptiles presents an opportunity to uncover patterns in the evolution of placental structure. Understanding the breadth of this diversity is limited because studies of placental structure and function have emphasized a limited number of lineages. We studied placental ontogeny using light microscopy for an embryological series of the Mexican gerrhonotine lizard, Mesaspis viridiflava. This species develops an elaborate yolk sac placenta, an omphaloplacenta, which receives vascular support arising in a structure known only from other gerrhonotine lizards. A prominent feature of the omphaloplacenta is a zone of uterine and embryonic epithelial cell hyperplasia located at the upper shoulder of the yolk mass, often extending above the yolk mass. The omphaloplacenta covers more than one-half of the surface area of maternal-embryonic contact. The chorioallantoic placenta has a more restricted distribution because the allantois remains in the embryonic hemisphere of the egg throughout development and lies internal to the vascular support for the omphaloplacenta in areas where they overlap. The structural profile of the chorioallantoic placenta indicates a potential for respiratory exchange and/or hemotrophic nutritive transport, while that of the omphaloplacenta suggests that nutritive transfer is primarily via histotrophy. An eggshell is present in the earliest embryonic stages examined but regresses relatively early in development. Placental specializations of this species are consistent with a pattern of matrotrophic embryonic nutrition and have evolved in a unique lineage specific developmental pattern. PMID- 30478959 TI - EW-7197 prevents ulcerative colitis-associated fibrosis and inflammation. AB - EW-7197 is a transforming growth factor-beta type I receptor kinase inhibitor with potential anti-inflammatory and antifibrotic properties. Here, we investigate the potential therapeutic effects of EW-7197 in a murine model of ulcerative colitis. EW-7197 attenuated the colitis disease activity index by improving rectal bleeding, body weight, and degree of stool consistency. EW-7197 also reduced colorectal tissue damage and the colon histopathological score by reducing crypt loss, mucosal damage, and tissue inflammation. Moreover, EW-7197 appeared to ameliorate the inflammatory and fibrotic responses by reducing oxidative stress, reducing submucosal edema and inflammatory cell infiltration, downregulating proinflammatory and pro-fibrotic genes, and inhibiting excessive collagen deposition in inflamed and fibrotic ulcerative colitis tissues. These results suggest that EW-7197 has potentially useful therapeutic properties against colitis, with clinically translational potential of inhibiting key pathological responses of inflammation and fibrosis in patients with colitis. PMID- 30478961 TI - Fine needle aspiration cytology in Mozambique: Report of a 15-year experience. AB - BACKGROUND: Fine needle aspiration cytology (FNAC) is an important diagnostic tool in a range of medical settings. It is fast, quick and a highly accurate diagnostic method and can be used, in settings with minimal laboratory infrastructures. METHODS: In this report, we describe the experience in the use of FNAC since it is introduction in 1996 in the Anatomical Pathology Service of the Maputo Central Hospital (MCH), along with more detailed data referring to 2009-2010. RESULTS: The number of FNAC analyses increased gradually from 269 (4.1% of all pathologic tests of the Service) in 1996, when it was introduced in Mozambique, to 3234 (17% of all tests) in 2010. Lymph nodes were the organs most frequently biopsied, followed by breast and soft tissues. Inflammatory conditions, especially tuberculosis, were the most frequent diagnoses (22.2% of the cases), followed by hyperplastic conditions (20.6%), benign tumors (13.4%) and malignant tumors (12.3%). CONCLUSION: Our results clearly demonstrate that even in an environment with poor laboratory resources, it is possible to establish a FNAC clinic that can provide a quick and precise diagnosis for clinicians to aid in early treatment interventions, especially in inflammatory diseases which were the majority of our cases. PMID- 30478962 TI - Exceptional responses to pertuzumab, trastuzumab, and docetaxel in human epidermal growth factor receptor-2 high expressing salivary duct carcinomas. AB - BACKGROUND: Alterations in the human epidermal growth factor receptor-2 (HER2) pathway have been identified in a subset of salivary duct carcinomas. Dual HER2 inhibition with trastuzumab and pertuzumab has superior antitumor efficacy to trastuzumab monotherapy in HER2-positive breast cancer, yet its efficacy in HER2 positive salivary duct carcinoma is unknown. METHODS: We report 2 cases of exceptional responses of HER2-positive salivary duct carcinomas to dual HER2 blockade and docetaxel combination and their molecular characteristics. RESULTS: A 54-year-old man with recurrent metastatic HER2 expressing salivary duct carcinoma of the parotid gland after definitive concurrent chemoradiation achieved a complete response (CR) after 6 cycles of trastuzumab, pertuzumab, and docetaxel (TPH). A 42-year-old woman with HER2-positive salivary duct carcinoma of the parotid gland with bone and liver metastases had CR with TPH and remains in remission on maintenance trastuzumab and pertuzumab. CONCLUSION: Dual HER2 blockage resulted in CR in patients with HER expressing salivary duct carcinoma and warrants further evaluation in this patient population. PMID- 30478963 TI - Outcome and potentially modifiable risk factors for candidemia in critically ill burns patients: A matched cohort study. AB - BACKGROUND: Patients with extensive burns are at risk of developing candidemia. OBJECTIVES: To identify potentially modifiable risk factors and outcomes of candidemia in critically ill burns patients. PATIENTS AND METHODS: Retrospective matched cohort study including adult burns patients. Patients who developed candidemia were matched with burns patients with Candida spp colonization and sepsis or septic shock without candidemia in a ratio of 1:3 (same severity scores and colonization index). Univariate and multiple regression analyses were performed. RESULTS: Of 130 severely burned patients with Candida spp colonization and at least one episode of sepsis or septic shock, 14 were diagnosed with candidemia. In the candidemia group, patients had a median (IQR) total burns surface area (TBSA) of 57(38-68) %, SAPSII of 43(36-58) and ABSI of 11(8-13). Multiple regression analysis showed that only duration of prior antibiotic therapy was independently associated with candidemia. ICU-mortality was higher in the candidemia group (71% versus 35%(p=0.02)). The log-rank test for 28-day mortality comparing patients with candidemia treated with an empirical strategy versus a curative strategy did not reach significance (p=0.056). CONCLUSIONS: Burns patients having received recent antibiotherapy have a higher risk of candidemia. Antifungal strategies did not influence outcome in this series. This article is protected by copyright. All rights reserved. PMID- 30478964 TI - Measurement of cortisol, dehydroepiandrosterone, and testosterone in the hair of children: Preliminary results and promising indications. AB - Hormone analysis is a valuable tool for understanding how physiology and behavior interact. Cortisol in hair has recently been examined as a measure of longer-term hormone output. The aim of this study was to investigate the relationships between other androgens in hair and anthropometric measures. In a child sample (n = 114, mean age: 8.5 years, 66 females) levels of cortisol, dehydroepiandrosterone (DHEA) and testosterone were assayed in the 0-3 cm section proximal to scalp. The 3-6 cm segment within a subsample of female participants (n = 35) was examined and compared. Results showed that testosterone strongly correlated with DHEA, and moderately correlated with cortisol (0-3 cm only). Higher hormone concentrations were present in the 3-6 cm segment. Finally, there was a weak positive association between DHEA and height. The replication of previously identified associations between androgens, particularly testosterone DHEA, and with developmental measures suggests hair may offer a valid method of hormone measurement for DHEA and testosterone. PMID- 30478965 TI - Plasma levels of soluble ST2, but not IL-33, correlate with the severity of alcoholic liver disease. AB - Alcoholic liver disease (ALD) is a complication that is a burden on global health and economy. Interleukin-33 (IL-33) is a newly identified member of the IL-1 cytokine family and is released as an "alarmin" during inflammation. Soluble suppression of tumourigenicity 2 (sST2), an IL-33 decoy receptor, has been reported as a new biomarker for the severity of systemic and highly inflammatory diseases. Here, we found the levels of plasma sST2, increased with the disease severity from mild to severe ALD. Importantly, the plasma sST2 levels in ALD patients not only correlated with scores for prognostic models (Maddrey's discriminant function, model for end-stage liver disease and Child-Pugh scores) and indexes for liver function (total bilirubin, international normalized ratio, albumin, and cholinesterase) but also correlated with neutrophil-associated factors as well as some proinflammatory cytokines. In vitro, lipopolysaccharide activated monocytes down-regulated transmembrane ST2 receptor but up-regulated sST2 mRNA and protein expression and produced higher levels of tumour necrosis factor-alpha (TNF-alpha). By contrast, monocytes pretreated with recombinant sST2 showed decreased TNF-alpha production. In addition, although plasma IL-33 levels were comparable between healthy controls and ALD patients, we found the IL-33 expression in liver tissues from ALD patients was down-regulated at both RNA and protein levels. Immunohistochemical staining further showed that the decreased of IL-33-positive cells were mainly located in liver lobule area. These results suggested that sST2, but not IL-33, is closely related to the severity of ALD. Consequently, sST2 could be used as a potential biomarker for predicting the prognosis of ALD. PMID- 30478966 TI - Phase II trial to investigate efficacy and safety of bendamustine, dexamethasone and thalidomide in relapsed or refractory multiple myeloma patients after treatment with lenalidomide and bortezomib. PMID- 30478967 TI - The effects of Nutlin-3 on morphology, cellular proliferation, and apoptosis in rat primary mesenchymal stem cells. AB - INTRODUCTION: Nutlin-3 is a powerful antagonist of murine double minute 2/p53 interaction demonstrating promising therapeutic anticancer activity, which has not been clinically approved yet. Mesenchymal stem cells (MSCs) are an important part of the bone marrow niche and support regeneration and proliferation of hematopoietic stem cells after exposure to myelotoxic anticancer agents; however, the effect of Nutlin-3 compounds on MSCs themselves remains to be elucidated. MATERIALS AND METHODS: Rat-derived bone marrow-derived MSCs (BMSCs) were cultured and treated with different concentrations (5, 10, 25, 50, and 100 MUM) and times (24, 48, and 72 hr) of Nutlin-3. The microculture tetrazolium test, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and propidium iodide and annexin-V assays, and quantitative real-time reverse-transcription polymerase chain reaction were performed to assess the effects of Nutlin-3 on the cell viability, proliferation, and apoptosis in BMSCs. RESULTS: The viability of BMSCs in the treated cells with concentrations of 100 MUM at 24 hr, 50 and 100 MUM at 48 hr, and in all concentrations at 72 hr was significantly (p < 0.05) low. The apoptotic index showed that the TUNEL-positive BMSCs were significantly higher in concentrations of 25 and 50 MUM in comparison to control group ( p < 0.05) and augmented in a dose-dependent manner. Annexin-V-PI staining showed after 72 hr of incubation, there was a slight dose-dependent increase in total apoptotic cells at 10 and 25 MUM of Nutlin-3, but a massive significant increase at 50 MUM. CONCLUSION: Here, we show that rat BMSCs are relatively resistant to Nutlin-3; however, further in vivo data with long-term exposure may help to corroborate our findings. PMID- 30478968 TI - Molecular interaction of NFkappaB and NICD in monocyte-macrophage differentiation is a target for intervention in atherosclerosis. AB - The activation of two transcription factors, NFkappaB and NICD (notch intracellular domain), plays a crucial role in different stages of atherosclerotic disease progression, from early endothelial activation by modified lipids like oxidized low-density lipoprotein (oxyLDL) to the imminent rupture of the atherosclerotic plaque. Inflammatory mediators and the notch pathway proteins were upregulated in atherogenic diet-induced rats and the same was confirmed by the differentiation of monocyte to macrophage on exposure to oxyLDL. The inflammatory transcription factor NFkappaB and the notch signaling transcription factor NICD were analysed for their molecular interaction in monocyte to macrophage differentiation. Inhibition of NFkappaB by dexamethasone in monocyte to macrophage differentiation resulted in a concomitant downregulation of NICD, whereas inhibition of NICD by N-(N-[3, 5 difluorophenacetyl])-l-alanyl)-S-phenylglycine t-butyl ester (DAPT), a gamma secretase inhibitor, did not significantly influence the expression of NFkappaB, but downregulated macrophage differentiation. These findings revealed that NFkappaB inhibition using dexamethasone regulated NICD, which turned down macrophage differentiation. Thus, inhibition of both NFkappaB-NICD is a potential target for intervention in atherosclerosis. PMID- 30478969 TI - Lateral cartilage defects and medial subchondral surface ratio are associated with knee-related disability. AB - We sought to determine the relationship between 1) full-thickness cartilage defects and tibiofemoral subchondral surface ratio (SSR) and 2) disability and quality of life in patients with mild radiographic osteoarthritis (OA) (Kellgren Lawrence grade 2) or without radiographic OA (Kellgren-Lawrence grades 0 or 1)? A total of 642 participants from the Osteoarthritis Initiative (OAI) with baseline knee MRIs and a Kellgren-Lawrence grade 2 or less on both bilateral screening radiographs were included. The independent relationship was assessed between 1) full thickness cartilage defect presence and tibiofemoral SSR and 2) Knee Injury and Osteoarthritis Outcome Score (KOOS) quality of life (QOL), KOOS function in sports and recreation (KOOS-sport/rec), and Western Ontario and McMaster Universities Arthritis Index (WOMAC) disability score after adjustment for relevant confounders with multivariate regression modeling. The prevalence of medial full-thickness defects was 10.4% (67/642) and lateral was 18.1% (116/642). Lateral defect presence was associated with worse KOOS-QOL (beta -3.61 SE 1.04; p = 0.001), KOOS-sport/rec (beta -4.70 SE 1.38; p = 0.001) and WOMAC-disability scores (beta 0.02 SE 0.01; p = 0.001); these associations were not influenced by defect size. A larger medial compartment SSR was associated with worse KOOS-QOL (beta -27.20 SE 6.80; p < 0.001), KOOS-sports/rec (beta -22.30 SE 9.01; p = 0.01) and WOMAC-disability scores (beta 0.16 SE 0.04; p < 0.001). In older adults with little to no radiographic osteoarthritis, lateral full thickness cartilage defects, irrespective of size, and a larger medial compartment tibiofemoral SSR are potential sources of knee-related symptoms that are not appreciated on standard radiographs. This article is protected by copyright. All rights reserved. PMID- 30478970 TI - Lonely ageing in a foreign land: Social isolation and loneliness among older Asian migrants in New Zealand. AB - Ageing does not reduce people's need to connect with family members, friends, and acquaintances, and neither does migration. For those older migrants living in a foreign land, connectedness with others plays a particularly important role in achieving a sense of belonging and sustaining their health and well-being. This paper explores the issues of social isolation and loneliness among older Asian migrants in New Zealand. Data were collected from in-depth semi-structured interviews with Chinese- or Korean-speaking migrants aged between 75 and 84 years (n = 10: all females), and from three focus groups consisting of Chinese- and Korean-speaking migrants (n = 10: 7 females, 3 males) and Chinese professionals (n = 5: 3 females, 2 males) between June 2016 and December 2016. The qualitative data obtained were analysed applying a thematic analysis approach using NVivo software for group analysis by a multidisciplinary research team. The findings from the study show that older Asian migrants experienced high levels of isolation and loneliness at least at some points in their migrant lives. Most participants in this study were living alone or with only their spouse, and this living arrangement was likely to provide fertile ground for isolation and loneliness to grow in the context of later-life migration. It was also observed that their lonely ageing ironically resulted from their efforts to preserve family relationships through avoiding being a burden, while allowing them a sort of space to maintain now barely connected lives. The participants revealed multiple ways of coping with lonely and isolated experiences in their limited social network, and these individual strategies allow us to make suggestions about how best to reduce older migrants' social isolation and loneliness in the New Zealand context and beyond. PMID- 30478971 TI - The dynamics of band (peak) shape development in capillary zone electrophoresis in light of the linear theory of electromigration. AB - The continuity equations that describe the movement of ions in liquid solutions under the influence of an external stationary electric field, as it is utilized in electrophoresis, were introduced a long time ago starting with Kohlrausch in 1897. From that time on, there have been many attempts to solve the equations and to discuss the results. In electrophoresis, special attention has always been devoted to the peak shapes obtained by the detector since the shapes have a tight connection with the phenomena taking place during electromigration and influence the efficiency and selectivity of the separation. Among these phenomena, the most important is electromigration dispersion. In this commented review paper, we compare various models of electromigration, try to find points that connect them, and discuss the range of their validity in light of the linear and nonlinear theory of electromigration. PMID- 30478972 TI - Introducing the Beatalk technique: using beatbox sounds and rhythms to improve speech characteristics of adults with intellectual disability. AB - BACKGROUND: Individuals with intellectual disability (ID) often demonstrate speech impairments and reduced intelligibility. However, traditional treatment methods, which involve using repetitive verbal and non-verbal exercises, may not be fully suitable for this population. As adults with ID tend to lose interest and motivation facing the demands of a typical speech therapy session, other intervention methods are needed. The current study tested a novel intervention technique, Beatalk, based on practising vocally produced sounds and rhythms, imitating the sounds produced by rhythm machines in an a cappella musical context (i.e., human beatboxing). Human beatboxing may be a particularly effective tool since it involves intense production of speech sounds (phonemes) that can be misarticulated in the presence of speech disorders; it is relatively easy to learn and practice, and is also considered 'fun'. AIMS: As many of the features of beatboxing make it a promising method for speech therapy, this pioneering study aimed to examine its effectiveness in comparison with a traditional speech therapy. METHODS & PROCEDURES: Twelve adults with moderate ID and low speech intelligibility (age 24-48 years) participated in a speech therapy group for 6 weeks. Six participants were assigned to the Beatalk (study) group and six to a traditional (control) therapy group. Pre- to post-treatment changes in speech intelligibility and voice measures were assessed. OUTCOMES & RESULTS: The preliminary data demonstrate that both types of therapy groups resulted in improved performance in articulation accuracy and voice measures, yet the Beatalk technique yielded larger gains. CONCLUSIONS & IMPLICATIONS: The results present initial evidence for the beneficial effect of the Beatalk technique as an intervention tool for adults with ID. It is an easy-to-use technique in the context of speech therapy, and may enhance verbal communication skills in this population. PMID- 30478973 TI - Using Marketing Science to Understand Contraceptive Demand in High-Fertility Niger. AB - Global initiatives aim to add 120 million new family planning (FP) users by 2020; however supply-side interventions may be reaching the limits of their effectiveness in some settings. Our case study in Niger used demand analysis techniques from marketing science. We performed a representative survey (N = 2,004) on women's FP knowledge, attitudes, needs, and behaviors, then used latent class analysis to produce a segmentation of women based on their responses. We found that Nigerien women's demand for modern FP methods was low, with majorities aware of modern methods but much smaller proportions considering use, trying modern methods, or using one consistently. We identified five subgroups of women with distinct, internally coherent profiles regarding FP needs, attitudes, and usage patterns, who faced different barriers to adopting or using modern FP. Serving subgroups of women based on needs, values, and underlying beliefs may help more effectively drive a shift in FP behavior. PMID- 30478974 TI - Invasiveness-triggered state transition in malignant melanoma cells. AB - Cancer cells are considered to have high morphological heterogeneity in human melanoma tissue. Here, we report that epithelial cancer cells are dominant in different development stages of human melanoma tissues. The cellular and molecular mechanisms that maintain melanoma cells in the epithelial state are further investigated in the A2058 cell line. We find that micropore (8 um) transwell invasion, but not superficial migration in the scratch assay, can induce remarkable morphological changes between epithelial and mesenchymal melanoma cells within 4 days. The morphological switch is associated with dynamic changes of epithelial-mesenchymal transition (EMT) hallmarks E-cadherin and vimentin. Further immunoflurencent staining and co-immunoprecipitation assay showed the uncoupling of the M3 muscarinic acetylcholine receptor (mAChR) and the p75 neurotrophin receptor (p75NTR) in epithelial melanoma cells. Specific knockdown of M3 mAChR by small interfering RNA (siRNA) significantly abrogates the transition of spindle-shaped mesenchymal cells to epithelial cells. Collectively, we report a cellular model of invasiveness-triggered state transition (ITST) in which melanoma cell invasion can induce morphological changes between epithelial and mesenchymal cells. ITST is one of the biological basis for maintaining metastatic melanoma cells in the epithelial state. Furthermore, M3 mAChR receptor-mediated ITST provides a novel therapeutic strategy to inhibit the development of malignant melanoma. PMID- 30478975 TI - Trial of personalised care after treatment-Prostate cancer: A randomised feasibility trial of a nurse-led psycho-educational intervention. AB - OBJECTIVE: The present parallel randomised control trial evaluated the feasibility of a nurse-led psycho-educational intervention aimed at improving the self-management of prostate cancer survivors. METHODS: We identified 305 eligible patients from a district general hospital, diagnosed 9-48 months previously, who completed radical treatment, or were monitored clinically (ineligible for treatment). Ninety-five patients were recruited by blinded selection and randomised to Intervention (N = 48) and Control (N = 47) groups. Participant allocation was revealed to patients and researchers after recruitment was completed. For 36 weeks, participants received augmented usual care (Control) or augmented usual care and additional nurse support (Intervention) provided in two community hospitals and a university clinic, or by telephone. RESULTS: Data from 91 participants (Intervention, N = 45; Control, N = 46) were analysed. All feasibility metrics met predefined targets: recruitment rate (31.15%; 95% CI: 25.95%-36.35%), attrition rate (9.47%; 95% CI: 3.58%-15.36%) and outcome measures completion rates (77%-92%). Forty-five patients received the intervention, with no adverse events. The Extended Prostate Cancer Index Composite can inform the minimum sample size for a future effectiveness trial. The net intervention cost was L317 per patient. CONCLUSIONS: The results supported the feasibility and acceptability of the intervention, suggesting that it should be evaluated in a fully powered trial to assess its effectiveness and cost-effectiveness. PMID- 30478976 TI - When pharmacology meets the microbiome: new targets for therapeutics? AB - LINKED ARTICLES: This article is part of a themed section on When Pharmacology Meets the Microbiome: New Targets for Therapeutics? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.24/issuetoc. PMID- 30478977 TI - Outcomes of observation without empiric intravenous antibiotics in febrile, nonneutropenic pediatric oncology patients. AB - There are no consensus guidelines for management of pediatric oncology patients presenting with fever and nonneutropenia, with limited research into the outcomes of withholding empiric i.v. antibiotics. We conducted a prospective cohort study assessing the safety and efficacy of observing well-appearing patients presenting with fever and nonneutropenia (absolute neutrophil count >= 500 cells/mm3 ). Of 238 episodes, 82.7% patients were observed with no infectious complications and low overall incidence of bacteremia (3.4%). There were no significant differences in individual clinical variables. We propose that observation alone in some well appearing febrile pediatric oncology patients is safe and limits the use of unnecessary empiric antibiotics. PMID- 30478978 TI - Relationship between coronary diastolic pressure indexes during the wave-free period and a novel pressure-derived index: Diastolic pressure ratio at the optimal point. AB - OBJECTIVES: We aimed to determine the diastolic pressure ratio at the optimal point (DROP) using a simple measurement algorithm and to compare DROP with distal coronary-to-aortic pressure ratios during the wave-free period (PRWFP ) and at the mid-diastolic point (PRMD ). METHODS: Distal coronary and aortic pressures were measured from color pressure images of 440 beats in 48 patients with coronary stenoses. The DROP measurement point was 67% for one beat between the two rising points on the aortic pressure curve according to the distribution of the wave-free period and the mid-diastolic point. RESULTS: DROP correlated closely with PRWFP (r = 0.993, P < 0.0001) and PRMD (r = 0.997, P < 0.0001). The diagnostic efficiency was excellent (area under the receiver-operating characteristic curve, 0.997) for both PRWFP <= 0.89 (specificity, 0.99; sensitivity, 0.96) and PRMD <= 0.89 (specificity, 0.95; sensitivity, 1.00). CONCLUSIONS: A simple pressure-derived physiological marker of coronary stenosis, DROP, might represent other diastolic pressure indexes with a numerical equivalency to the instantaneous wave-free ratio. DROP can be measured automatically assuming that the rising points on the aortic pressure curve are detectable. However, further large-scale clinical investigations are needed to determine whether DROP could contribute to the further generalization of physiology-guided percutaneous coronary intervention. PMID- 30478979 TI - Reconciling the theory and reality of shared decision-making: A "matching" approach to practitioner leadership. AB - Shared decision making (SDM) evolved to resolve tension between patients' entitlement to make health-care decisions and practitioners' responsibility to protect patients' interests. Implicitly assuming that patients are willing and able to make "good" decisions, SDM proponents suggest that patients and practitioners negotiate decisions. In practice, patients often do not wish to participate in decisions, or cannot make good decisions. Consequently, practitioners sometimes lead decision making, but doing so risks the paternalism that SDM is intended to avoid. We argue that practitioners should take leadership when patients cannot make good decisions, but practitioners will need to know: (a) when good decisions are not being made; and (b) how to intervene appropriately and proportionately when patients cannot make good decisions. Regarding (a), patients rarely make decisions using formal decision logic, but rely on informal propositions about risks and benefits. As propositions are idiographic and their meanings context-dependent, normative standards of decision quality cannot be imposed. Practitioners must assess decision quality by making subjective and contextualized judgements as to the "reasonableness" of the underlying propositions. Regarding (b), matched to judgements of reasonableness, we describe levels of leadership distinguished according to how directively practitioners act; ranging from prompting patients to question unreasonable propositions or consider new propositions, to directive leadership whereby practitioners recommend options or deny requested procedures. In the context of ideas of relational autonomy, the objective of practitioner leadership is to protect patients' autonomy by supporting good decision making, taking leadership in patients' interests only when patients are unwilling or unable to make good decisions. PMID- 30478980 TI - Magnetic resonance findings of presumed limber tail syndrome (caudal myopathy) in a Dobermann. PMID- 30478981 TI - Gender-responsive education and training approaches to improving physician well being. PMID- 30478982 TI - PCNA and JNK1-Stat3 pathways respectively promotes and inhibits diabetes associated centrosome amplification by targeting at the ROCK1/14-3-3sigma complex in human colon cancer HCT116 cells. AB - We have recently reported that type 2 diabetes promotes centrosome amplification via enhancing the expression, biding, and centrosome translocation of rho associated coiled-coil containing protein kinase 1 (ROCK1)/14-3-3sigma complex in HCT116 cells. In the functional proteomic study, we further investigated the molecular pathways underlying the centrosome amplification using HCT116 cells. We found that treatment of HCT116 cells with high glucose, insulin, and palmitic acid triggered the centrosome amplification and increased the expressions of proliferating cell nuclear antigen (PCNA), nucleophosmin (NPM), and 14-3-3sigma. Individual knockdown of PCNA, NPM, or 14-3-3sigma inhibited the centrosome amplification. Knockdown of PCNA inhibited the treatment-increased expression of ROCK1, whereas knockdown of ROCK1 did not affect the PCNA expression. High glucose, insulin, and palmitic acid also increased the expressions of c-Jun N terminal kinase-1 (JNK1) and signal transducer and activator of transcription 3 (Stat3), individual knockdown of which upregulated the treatment-increased expression of 14-3-3sigma and promoted the centrosome amplification. In contrast, overexpression of JNK1 inhibited the centrosome amplification. Knockdown of Stat3 enhanced the centrosome translocation of 14-3-3sigma. Moreover, we showed that knockdown of JNK1 inhibited the treatment-increased expression of Stat3. Knockdown of PCNA, JNK1, or Stat3 did not have an effect on NPM and vice versa. In conclusion, our results suggest that PCNA and JNK1-Stat3 pathways respectively promotes and feedback inhibits the centrosome amplification by targeting at the ROCK1/14-3-3sigma complex, and NPM serves as an independent signal for the centrosome amplification. PMID- 30478983 TI - Estimating the incidence of atrial fibrillation in single-chamber implantable cardioverter defibrillator patients. AB - BACKGROUND: Atrial arrhythmias are associated with major adverse cardiovascular events. Recent reports among implantable cardioverter defibrillator (ICD) patients have demonstrated a high prevalence of atrial fibrillation (AF), predominantly in dual-chamber recipients. AF incidence among patients with single chamber systems (approximately 50% of all ICDs) is currently unknown. The objective was to estimate the prevalence of new-onset AF among single-chamber ICD patients by observing the rates of new atrial tachycardia (AT)/AF among a propensity scoring matched cohort of dual-chamber ICD patients from the PainFree SST study, to better inform screening initiatives. METHODS: Among 2,770 patients enrolled, 1,862 single-chamber, dual-chamber, and cardiac resynchronization therapy (CRT) subjects with no prior history of atrial tachyarrhythmias were included. Daily AT/AF burden was estimated using a propensity score weighted model against data from dual-chamber ICDs. RESULTS: Over 22 +/- 9 months of follow-up, the estimated incidence of AT/AF - lasting at least 6 minutes, 6 hours and 24 hours per day - in the single-chamber cohort was 22.0%, 9.8% and 6.3%, whereas among dual-chamber patients, the prevalence was 26.6%, 13.1%, and 7.1%, respectively. Initiation of oral anticoagulation (OAC) was estimated to occur in 9.8% of the propensity matched single-chamber cohort, which was higher than the actual observed rate of 6.0%. Stroke and transient ischemic attack (TIA) occurred at low rates in all device subgroups. CONCLUSIONS: Atrial arrhythmias occur frequently, and significant underutilization of anticoagulation is suggested in single-chamber ICD recipients. Routine screening for AF should be considered among single-chamber ICD recipients. This article is protected by copyright. All rights reserved. PMID- 30478984 TI - A 3 months clinical evaluation comparing two professional bleaching systems of 25% and 40% hydrogen peroxide and extended treatment outcome using a power versus a manual toothbrush. AB - OBJECTIVES: To assess two professional tooth bleaching products: Philips Zoom WhiteSpeed (PZW) and Ultradent Opalescence Boost PF (UOB); and to assess bleaching maintenance after use of Philips Sonicare power toothbrush (SDC) or manual toothbrush (MTB). METHODS: There was a randomized, parallel clinical trial. Eligible subjects were 18-75 years, with VITA Classical shade (VCS) of A3 on anterior teeth. Subjects were randomized to bleaching with PZW or UOB. Tooth color and shade were assessed using VITA EasyShade (VES), VCS, and VITA Bleachedguide (VBG). Subjects returned on Days 7 and 30. On Day 30, participants were dispensed either SDC or MTB for home use until Day 90. RESULTS: A total of 135 subjects completed the study. For the primary endpoint, DeltaE at Day 7, a significantly larger reduction was observed for PZW than UOB (P value = .0059). Significant differences in shade were also observed at Day 7 for VCS (P value = 0.0106), and VBG (P value = .0489). On Day 90, the SDC was statistically superior to MTB in maintaining shade per VBG and VCS, but not DeltaE. CONCLUSIONS: At Day 7, PZW showed statistically greater change in overall color and shade than UOB. The SDC maintained tooth shade significantly better than MTB. Both bleaching regimens were safe. CLINICAL SIGNIFICANCE: The outcomes confirm the bleaching efficacy advantage of a lower H2 O2 dose-LED accelerated professional tooth bleaching system, compared to a higher-dose H2 O2 approach. The safety assessments via clinical intraoral exam and daily logged use of subjects' desensitizing agents, and the incidence and severity of reported sensitivity, provide evidence that both professional products are safe for use. Finally, powered tooth brushing may confer an advantage to manual tooth brushing in maintaining tooth shade-change results following professional whitening. PMID- 30478985 TI - Antipsychotic use and related factors among people with dementia aged 75 years or older in Japan: a comprehensive population-based estimation using medical and long-term care data. AB - OBJECTIVES: Antipsychotics are used to manage the behavioral and psychological symptoms of dementia (BPSD), despite their association with greater risks for mortality and cerebrovascular events. Previous studies in Japan have estimated the prevalence of antipsychotics among older adults who took antidementia drugs. Using long-term care (LTC) data, we aimed to obtain more accurate estimates of the prevalence of antipsychotics and to determine factors related to their use in older adults with dementia. METHODS: Medical and LTC claims data and LTC certification data between April 2012 and September 2013 were obtained from a middle-sized suburban city. The one-year prevalence of antipsychotic use was estimated among individuals with probable dementia aged >=75 years who were prescribed antidementia drugs and/or had dementia based on LTC needs certification data. RESULTS: Of 25,919 participants, 4,865 had probable dementia and 1,506 were prescribed antidementia drugs. The prevalence of antipsychotics among participants with probable dementia was 10.7%, which was lower than that in those who were prescribed antidementia drugs (16.4%). Among participants with probable dementia with LTC certification data available (N = 4,419), lower cognitive function (vs. mild; adjusted odds ratio 2.16, 95% confidence interval 1.63-2.86), antidementia drug use (2.27, 1.84-2.81), and institutional LTC services use (2.34, 1.85-2.97) were associated with greater odds of antipsychotic use, whereas older age (>=92 years) was associated with lower odds (vs. <77 years; 0.42, 0.27-0.65). CONCLUSIONS: These findings may be useful for estimating the burden of BPSD and for taking measures to reduce inappropriate antipsychotic prescription. PMID- 30478986 TI - In vitro removal of polycyclic aromatic hydrocarbons by lactic acid bacteria. AB - AIMS: The current study aimed to investigate the ability of lactic acid bacteria (LABs) in removing four PAHs namely, Benzo(a)pyrene (BaP), Benz(a)anthracene (BaA), Chrysene (Chr) and Benzo(b)fluoranthene (BbF) from contaminated phosphate buffer saline (PBS). METHOD AND RESULTS: The effect of initial PAHs concentrations (5, 10, 15, 20 MUg ml-1 ), bacterial population (107 , 108 , 109 , 1010 CFU ml-1 ) and pH (3, 5, 7) was studied to evaluate bacterial binding ability. All the tested bacteria could remove BaA, Chr, BbF and BaP from phosphate buffer solution and in almost all assays, removing of PAHs was as follows: BaP> Chr> BaA> BaF. Bifidobacterium lactis BB-12 had the lowest binding rate for all four PAHs, while the highest binding ability was related to Lactobacillus acidophilus LA-5. Moreover, cell viability was not required for the binding ability and even acid-treated, heat-treated and ultrasonic-treated bacterial cells showed more binding ability. The results showed that the bacteria PAHs complex was irreversible after washing with PBS. CONCLUSIONS: The removal of PAHs was significantly related to pH of media, strains of bacteria, type and concentration of PAHs SIGNIFICANCE AND IMPACT OF THE STUDY: This study has been focused on the reduction of polycyclic aromatic hydrocarbons using LABs and probiotics. Our results showed that not only live strains but also inactivated tested strains are able to remove PAHs from aqueous media, presenting new methods to diminish the amount of these contaminants in foods. Furthermore, the results of this study can be used in future research on evaluating the effects of oral administration of probiotic supplements and even dead probiotic strains on reducing PAHs in humans. This article is protected by copyright. All rights reserved. PMID- 30478987 TI - Active vitamin D regulates macrophage M1/M2 phenotypes via the STAT-1-TREM-1 pathway in diabetic nephropathy. AB - AIM: Imbalance of M1/M2 macrophages phenotype activation is a key point in diabetic nephropathy (DN). This study aimed to investigate whether active vitamin D (VD) suppresses macrophage transition to the M1 phenotype via inhibiting the high glucose-induced STAT-1 phosphorylation to reduce TREM-1 expression. METHODS: In vivo, pathological changes in kidney tissue were detected and the expression of CD68 TREM-1, STAT-1, M1 makers, and M2 makers were acquired in renal tissue of patients with DN and 18w DN rats. In vitro, RAW 264.7 cells were incubated in the presence of high glucose with or without VD. Silencing and overexpression of TREM 1 and silencing and activate of STAT-1 were explored to elucidate the underlying mechanism. The expression of TREM-1 and STAT-1 and the changes of macrophage phenotype were examined separately by western blot and immunofluorescence staining. RESULTS: (a) Expression of TREM-1, p-STAT-1, and M1 markers (iNOS and TNF-alpha) were increased and positively correlated in kidneys from patients with DN. (b) In DN rats, the enlargement of glomerular surface area, expansion of glomerular mesangial matrix, the expression of CD68, TREM-1, p-STAT-1, and M1 marker (iNOS) were significantly increased in comparison with the normal control group, whereas above changes were markedly decreased in the diabetic group treated with the VD group. (c) In vitro, VD significantly decreased high glucose induced CD68, TREM-1, p-STAT-1, and M1 marker (iNOS) expression. However, above mentioned effects of VD are abolished when TREM-1 is overexpressed or STAT-1 is activated. Reductions in STAT-1 expression decreased the TREM-1 expression. CONCLUSION: VD can inhibit macrophage transition to the M1 phenotype through the STAT-1/TREM-1 pathway. PMID- 30478988 TI - Long noncoding RNAs in autoimmune diseases. AB - With the completion of the human genome project and further development of high throughput genomic technologies, interest in long noncoding RNAs (lncRNAs), which are defined as non-protein-coding RNAs at least 200 nucleotides in length, has strongly increased, and lncRNAs have become a major research direction. Increasing evidence demonstrates that lncRNAs are closely related to human growth and development and to disease occurrence via various mechanisms. lncRNAs also play crucial roles in the differentiation and activation of immune cells, and their relationships with human autoimmune diseases have received increasing attention. The development of biotechnology has led to the gradual discovery of many potential lncRNA functions. In this review, we discuss various lncRNAs that have been implicated in different human autoimmune diseases, focusing on their clinical applications as potential biomarkers and therapeutic targets in the pathologies of diverse human autoimmune diseases. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 00A: 1-8, 2018. PMID- 30478989 TI - Learning Simple Spatial Terms: Core and More. AB - How do children learn the meanings of simple spatial prepositions like in and on? In this paper, I argue that children come to spatial term learning with an a priori conceptual distinction between core versus non-core concepts of containment and support, and that they learn how language maps onto this distinction by considering both the simple prepositions and the company they keep that is, the distributions of their co-occurrences with particular verbs. Core types of containment and support are largely expressed by in/on together with the light verb BE; non-core types are expressed by lexical verbs such as insert, hang, stick, and so on, which represent the specific mechanical means by which containment or support is achieved. These latter types arguably depend on extensive learning about the particular mechanisms of containment and support, many of which are invented by humans, as well as learning the specific lexical verbs that encode these mechanisms. The core versus non-core distinction is reflected in young children's and adults' linguistic descriptions of different spatial configurations, via different distributions of expression types across different configurations. Differences between children and adults are not likely to be rooted in either conceptual or semantic differences, but rather, in the probabilistic nature of available expressions, along with early limits on children's vocabulary of lexical verbs that express complex mechanical relationships between objects. PMID- 30478990 TI - Solid-State Carbon Dots with Efficient Cyan Emission towards White LEDs. AB - Efficient cyan emitting solid carbon dots (CDs) are synthesized via a one-pot hydrothermal method. The obtained solid CDs show broad absorption from 270 -460 nm with maximum around 400 nm, and emit intense cyan light around 500 nm with internal photoluminescence quantum efficiency of 34.1% under 400 nm excitation. The maximum emission of the solid CDs remains unchanged when the excitation wavelength is varied from 300 to 400 nm. Compared with the dilute aqueous CDs (2.5mg/ml), the emission of solid CDs shows an obvious red shift of 50 nm. The red shift is caused by resonant energy transfer due to spectral overlap and new surface state caused by aggregation. A white LEDs is fabricated by coating a mixture of the cyan emitting solid CDs, a red-emitting phosphor CaAlSiN3:Eu2+ and silicon resin on the top a near-ultraviolet LED chip. Under an operating current of 20 mA, the as-fabricated white LEDs generates high quality warm white light with a color rendering index of 86.1, color temperature of 4340 K and luminescence efficiency of 31.3 lm/W. PMID- 30478991 TI - Alkylated Aromatic Thioethers with Aggregation-Induced Emission Properties Assembly and Photophysics. AB - In this contribution, we present the synthesis and self-assembly of alkylated thioethers with interesting photophysical properties. To this end, the emission, absorption and excitation spectra in organic solvents and as aggregates in water were measured as well as the corresponding photoluminescence quantum yields and lifetimes. The aggregates in aqueous media were visualized and measured using transmission electron microscopy. Besides that, crystal structures of selected compounds allowed a detailed discussion of the structure-property relationship. Furthermore, the mesomorphic behavior was investigated using polarized optical microscopy (POM) as well as differential scanning calorimetry (DSC). PMID- 30478992 TI - Glucose levels and diabetes are not associated with the risk of venous thrombosis: results from the MEGA case-control study. AB - It is unclear whether hyperglycaemia or diabetes mellitus are risk factors for a first venous thrombosis (VT). Self-reported diabetes status and fasting glucose (FG) measures were collected from the Multiple Environmental and Genetic Assessment (MEGA) study to confirm these associations. FG levels were categorized based on the World Health Organization criteria [<6.1 (reference), 6.1-7.0 (2nd), >=7.0 (3rd) mmol/l]. Logistic regression was performed to quantify the associations. Neither increased FG levels [Odds ratio (95% confidence interval): 0.98 (0.69-1.37) 2nd vs. reference, 0.97 (0.58-1.63) 3rd vs. reference] nor self reported diabetes [1.12 (0.80-1.58)] were associated with an increased risk of a first VT. PMID- 30478993 TI - Squamous cell carcinoma of the nail unit: a retrospective review of 19 cases in Asia and comparative review of Western literature. AB - BACKGROUND: Reports regarding squamous cell carcinoma of the nail unit (SCCnu) are rare in Asia. OBJECTIVES: To investigate the features of SCCnu in the Asian population. METHOD: We performed a retrospective review of patients diagnosed with SCCnu at our institution between 2012 and 2017. RESULTS: Nineteen cases were included. Thirteen patients were male (68.4%). The fingers were most frequently affected (73.7%). Mean delay to diagnosis was 62.4 months. Misdiagnosis rate was high (78.9%). Frequent clinical features were subungual tumor, subungual hyperkeratosis, nail dystrophy, ulcer, and nail loss. The majority of cases were invasive SCC in 15 cases (78.9%), while SCC in situ was found in four cases (21.1%). Local recurrence was detected in two cases (10.5%) following surgical resection. However, distant metastasis was not reported. CONCLUSION: This study provides data of 19 SCCnu cases in Asia. Clinical characteristics of SCCnu in this study were similar to those of reports from Western countries. However, we found a higher frequency of more invasive cases and longer delay to diagnosis in our study; this advocates the need for greater attention on nail disorders among healthcare providers, particularly in Asia. PMID- 30478994 TI - MicroRNA detection in the pathogenesis of BAV-associated aortopathy-mediated vascular remodelling through EndMT/EMT. PMID- 30478995 TI - CtIP promotes G2/M arrest in etoposide-treated HCT116 cells in a p53-independent manner. AB - Acquired resistance to cytotoxic antineoplastic agents is a major clinical challenge in tumor therapy; however, the mechanisms involved are still poorly understood. In this study, we show that knockdown of CtIP, a corepressor of CtBP, promotes cell proliferation and alleviates G2/M phase arrest in etoposide (Eto) treated HCT116 cells. Although the expression of p21 and growth arrest and DNA damage inducible alpha (GADD45a), which are important targets of p53, was downregulated in CtIP-deficient HCT116 cells, p53 deletion did not affect G2/M arrest after Eto treatment. In addition, the phosphorylation levels of Ser317 and Ser345 in Chk1 and of Ser216 in CDC25C were lower in CtIP-deficient HCT116 cells than in control cells after Eto treatment. Our results indicate that CtIP may enhance cell sensitivity to Eto by promoting G2/M phase arrest, mainly through the ATR-Chk1-CDC25C pathway rather than the p53-p21/GADD45a pathway. The expression of CtIP may be a useful biomarker for predicting the drug sensitivity of colorectal cancer cells. PMID- 30478996 TI - G protein-coupled receptor 119 is involved in RANKL-induced osteoclast differentiation and fusion. AB - G protein-coupled receptor 119 (GPR119) is known to be a promising therapeutic target for type 2 diabetes. Recently, it has been reported that the GPR119 agonist increases bone mineral density in an animal model of diabetes, suggesting that GPR119 may play a key role in bone metabolism. In this study, we investigated the functional role of GPR119 in receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast formation. We found that the GPR119 expression was markedly increased in preosteoclasts and then downregulated in mature osteoclasts. Activation of GPR119 with AS1269574, a potent selective agonist for GPR119, inhibited the generation of multinuclear osteoclasts from bone marrow-derived macrophages. Confirming this observation, targeted silencing of GPR119 using short hairpin RNA abrogated the AS1269574-mediated suppressive effect on osteoclast formation. GPR119 activation attenuated the expression of c Fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) and blocked RANKL-stimulated phosphorylation of IkappaBalpha, c-Jun N-terminal protein kinase (JNK), and extracellular signal-regulated kinase (ERK) but not p38. In addition, GPR119 activation suppressed preosteoclast fusion by downregulating the expression of the dendritic cell-specific transmembrane (DC-STAMP), a molecule that is essential for cell-cell fusion in osteoclast formation. Furthermore, ectopic expression of DC-STAMP restored AS1269574-mediated inhibition of osteoclast fusion. Taken together, our findings demonstrate that GPR119 plays a negative role in osteoclast differentiation and fusion induced by RANKL, and therefore may represent a potential target for bone resorption-associated diseases. PMID- 30478997 TI - Identification of the novel HLA-B*35:01:01:16 allele in a Saudi individual. AB - HLA-B*35:01:01:16 differs from HLA-B*35:01:01:01 by a single nucleotide substitution (C?A) at position 3941. This article is protected by copyright. All rights reserved. PMID- 30478998 TI - Amelanotic primary vaginal melanoma: A case report with cyto-histological correlations. AB - Vaginal mucosa represents a rare site for primary melanoma. These neoplasms more commonly occur in the postmenopausal period, usually presenting with vaginal discharge, bleeding, or palpable mass. We report a case of an 89-year-old woman presenting with vaginal bleeding and a non-pigmented lesion in the lower third of the vagina at the gynaecological examination. A PAP smear and tissue incisional biopsy were concurrently performed. The cytological sample showed a subpopulation of non-cohesive, atypical epithelioid cells suggestive for malignancy. The histological examination showed the same morphological characteristics in the neoplastic population widely underlying the vaginal epithelium, with scattered intraepithelial nests and single elements. In both samples, there was no evidence of melanin pigment within the malignant cells. Immunohistochemical analysis performed on the tissue biopsy demonstrated a strong and diffuse positivity for melanocytic markers (HMB-45, S-100, Melan-A), confirming the diagnosis of primary amelanotic vaginal melanoma. PMID- 30478999 TI - Cytomorphology of ciliated foregut cyst of the pancreas. AB - Ciliated foregut cysts are benign congenital lesions that are commonly found in the mediastinum but are rare in the retroperitoneum. So far only very few cases of ciliated foregut cyst found in the pancreas have been reported, and less with cytologic findings described. We report a case of ciliated foregut cyst in pancreas in an asymptomatic patient diagnosed on fine needle aspiration cytology. We also discuss the cytology features that would help with the diagnosis, and the differential diagnosis that should be considered. PMID- 30479000 TI - Diverse roles of RNA-binding proteins in cancer traits and their implications in gastrointestinal cancers. AB - Gene expression patterns in cancer cells are strongly influenced by posttranscriptional mechanisms. RNA-binding proteins (RBPs) play key roles in posttranscriptional gene regulation; they can interact with target mRNAs in a sequence- and structure-dependent manner, and determine cellular behavior by manipulating the processing of these mRNAs. Numerous RBPs are aberrantly deregulated in many human cancers and hence, affect the functioning of mRNAs that encode proteins, implicated in carcinogenesis. Here, we summarize the key roles of RBPs in posttranscriptional gene regulation, describe RBPs disrupted in cancer, and lastly focus on RBPs that are responsible for implementing cancer traits in the digestive tract. These evidences may reveal a potential link between changes in expression/function of RBPs and malignant transformation, and a framework for new insights and potential therapeutic applications. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications. PMID- 30479002 TI - Clinical Snippets. PMID- 30479001 TI - Morphology of the mandibles and the first maxillae in the family Lithobiidae (Myriapoda, Chilopoda), with remarks on their phylogenetic significance. AB - The mandibles and the first maxillae of 37 species of the family Lithobiidae (Myriapoda, Chilopoda) were investigated and compared to provide a structural overview and evaluate their significance for the systematics of the family. The species sampling focused on the genus Lithobius, examining 33 species of four subgenera (Lithobius, Monotarsobius, Sigibius, Ezembius), as this genus represents about half of the known diversity of Lithobiidae, including more than 500 assigned species and subspecies. The microstructures on the mandibular gnathal edge and the first maxillary telopodites and coxal projections were studied using scanning electron microscopy. Although having a similar structural pattern, we demonstrate that the microstructures are variable within and between species of adult specimens and commonly show intergradation. To check for intraspecific variability of microstructures and character stability, specimen sampling was extended for the two common Austrian species Lithobius dentatus and Lithobius validus, for which seven specimens depicted no major differences in the mandibular gnathal edge and the first maxillae. Our data suggest the presence of three characters in the mandibular gnathal edge and the first maxillae useful for lithobiid phylogeny. These characters were tested in a phylogenetic analysis together with previously described and novel morphological characters. Subgenera of Lithobius are mostly non-monophyletic, and several other genera of Lithobiinae as well as other subfamilies group with particular species or clades of Lithobius. The results corroborate a close relationship between Disphaerobius loricatus and Lithobius (Ezembius) giganteus, strengthening the hypothesis that Pterygoterginae is nested within Lithobiinae and specifically within Lithobius, allied to L. (Ezembius) and Hessebius. PMID- 30479004 TI - A comparison of 3D ultrasound to MRI for the measurement and estimation of gastrocnemius muscle volume in adults and young people with and without cerebral palsy. AB - INTRODUCTION: Muscle volume (MV) is an important parameter for understanding muscle morphology and adaptations to training, growth and pathology. In this study, we assessed the validity of freehand 3D ultrasound (3DUS) for measuring medial gastrocnemius MV in adults, typically developing children (TD) and children with cerebral palsy (CP). We also assessed the validity between our direct measures of MV and estimates derived from anatomical cross sectional area (ACSA) and muscle length (ML), using previously outlined methods. MATERIALS AND METHODS: The medial gastrocnemius of all groups was scanned with 3DUS and MRI. Images from both methods were digitised to derive MV, ACSA and ML. Measured MV was compared between methods and compared to estimated MV derived from recently published algorithms. RESULTS: MV had a mean difference of -0.13% (standard error of estimate (SEE)=2.23%, R2 =0.99) between MRI and 3DUS and 19.82% (SEE=4.73% and R2 =0.99) and -3.11% (SEE=6.55%, R2 =0.99) mean differences between the measured and estimated MV from two methods of estimation. CONCLUSIONS: The 3DUS is a valid method for the measurement of MV in adults, TD children and those with CP. Estimation methods of MV may be useful in clinical practise, but require further replication on various populations and careful methodological consideration. This article is protected by copyright. All rights reserved. PMID- 30479003 TI - Central adiponectin induces trabecular bone mass partly through epigenetic downregulation of cannabinoid receptor CB1. AB - Central adiponectin (APN) in either the globular (gAPN) or full-length forms decreases sympathetic tone and increases trabecular bone mass in mice through the hypothalamus. It is known that cannabinoid type-1 (CB1) receptors are expressed in the hypothalamic ventromedial nucleus and participate in energy metabolism by controlling sympathetic activity. However, whether central APN could influence endocannabinoid signaling through CB1 receptor to regulate bone metabolism has not been characterized. Here we demonstrate that gAPN downregulated CB1 expression in embryonic mouse hypothalamus N1 cells in vitro. gAPN intracerebroventricular (icv) infusions also decreased hypothalamic CB1 expression and bone formation parameters in APN-knockout (APN-KO) and wild-type mice. Most importantly, mice pretreated with icv infusions with the CB1 receptor agonist arachidonyl-2'-chloroethylamine or antagonist rimonabant attenuated or enhanced respectively central APN induction of bone formation. We then investigated whether epigenetic signaling mechanisms were involved in the downregulation of hypothalamic CB1 expression by gAPN. We found gAPN enhanced expression levels of various histone deacetylases (HDACs), especially HDAC5. Furthermore, chromatin immunoprecipitation assays revealed HDAC5 bound to the transcriptional start site transcription start site 2 region of the CB1 promoter. In summary, our study identified a possible novel central APN-HDAC5-CB1 signaling mechanism that promotes peripheral bone formation through epigenetic regulation of hypothalamic CB1 expression. PMID- 30479005 TI - Systematic review and meta-analysis: Dose-response curve of SSRIs and SNRIs in anxiety disorders. AB - BACKGROUND: We aimed to examine the efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) for anxiety disorders examining overall symptom improvement, likelihood of treatment response, time course of treatment response, individual pharmacological agent, diagnostic indication dose, and tolerability. METHODS: We searched PubMed and Cochrane Central Register of Controlled Trials. We included randomized placebo controlled clinical trials of SSRIs/SNRIs in adult patients with anxiety disorders that provided data at three or more time points. Extracted data included trial duration, weekly/biweekly anxiety scores for 12 weeks. RESULTS: Meta-analysis included 57 trials (N = 16,056). A linear mixed model analysis based on weekly outcome data suggested that for SNRI a logarithmic model offered the best fit compared to placebo (indicating the greatest incremental improvement from baseline occurred early in treatment); whereas for SSRI a linear model provided the best fit (indicating a similar improvement over the duration of the acute treatment phase). There were no significant differences in efficacy between pharmacological agents within each class or when comparing SSRIs to SNRIs. The greatest treatment benefits were observed for social anxiety disorder for both medication classes. Higher doses of SSRIs, but not SNRIs, were associated with significantly greater symptom improvement and likelihood of treatment response. For both medical classes, higher doses were associated with an increased likelihood of dropout due to side effects. CONCLUSIONS: SSRIs and SNRIs are effective in treating anxiety disorders. Higher doses of SSRIs within the therapeutic range are associated with greater treatment benefit, whereas higher doses of SNRIs are not. PMID- 30479006 TI - Risk stratification of salivary gland cytology utilizing the Milan system of classification. AB - BACKGROUND: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is based on risk stratification. Our study is a retrospective review of salivary gland fine needle aspiration cytology (FNAC) with the goal of determining the risk of malignancy (ROM) in each of the categories proposed by the MSRSGC. METHODS: FNAC of salivary gland lesions with corresponding surgical resection specimens were retrieved over a 5-year period. Metastatic tumors were excluded. BothFNAC and corresponding surgical resections were reviewed blindly and classified as per criteria published by the MSRSGC. The ROM for each of the diagnostic categories was determined and compared with the ROM published by the MSRSGC. RESULTS: The total number of entities and ROM in 199 reviewed cases were as follows: Nondiagnostic 18 (9.2%) (ROM 0%), non-neoplastic 4(2%) (ROM 0%), atypia of undetermined significance (AUS) 12(6%) (ROM 33%), benign neoplasm 118(59.2%) (ROM 0.8%), salivary gland neoplasm of uncertain malignant potential (SUMP) 22(11%) (ROM 40.9%), suspicious for malignancy 3(1.5%) (ROM 100%), malignant 22(11%) (ROM 100%). CONCLUSION: The ROM reported in our study was mostly concordant with ROM published by the MSRSGC. This classification is helpful for the management of categories; nondiagnostic, non-neoplastic, benign neoplasm, suspicious for malignancy and malignant. The management is not standardized for the category, salivary gland neoplasm of uncertain malignant potential, as clinical information plays an important role in planning surgical procedures at an individual basis. Further studies will need to be performed using this new classification to help define appropriate management and predict ROM more accurately. PMID- 30479007 TI - Justice and global care chains: Lessons from Singapore. AB - Growing demand for direct care workers to assist care-dependent elderly people has created an opening for migrant workers from low- income nations to sell their services to middle and high-income nations. Using Singapore as a case example, we draw on capability theory to make the case that receiving nations that import direct care workers should be held to global justice standards that protect workers' floor level human capabilities. Specifically, we (1) show that Singapore and other receiving nations fail to protect human capabilities at a threshold level required by dignity; (2) identify specific human capabilities placed at risk; and (3) recommend standards for receiving nations that support central capabilities. As populations in both developed and developing nations are rapidly aging, these concerns could not be timelier. PMID- 30479008 TI - Lipids as risk markers for type 2 diabetes. PMID- 30479009 TI - The use of electrochemotherapy in combination with immunotherapy in the treatment of metastatic melanoma: a focused review. AB - Electrochemotherapy (ECT) is a treatment modality that combines low-dose chemotherapy with electroporation, thereby enhancing cytotoxicity. ECT was first utilized in the treatment of metastatic head and neck cancer. Today it is used as a local treatment for the cutaneous and subcutaneous metastases of a variety of cancers, including melanoma. In addition, recent evidence indicates that ECT in combination with immunotherapy can lead to a systemic tumor response. This review aims to summarize the efficacy of ECT in the treatment of metastatic melanoma, with a specific focus on the combination of ECT with immunotherapy. PMID- 30479010 TI - Participatory and Action Research Within and Beyond the Academy: Contesting Racism through Decolonial Praxis and Teaching "Against the Grain". AB - This article focuses on some of the epistemological and activist challenges at the center of a participatory and action research teaching-learning process developed through a student-initiated graduate seminar at Boston College, a university in the global North. The course includes participation of students and instructors in a 2.5-day Undoing RacismTM workshop facilitated by the People's Institute for Survival and Beyond (PISAB), a New Orleans based non-profit. Authors, who include a university-based co-instructor and student and a Collaborative Community Fellow, describe the decolonial, antiracist pedagogy performed in a coteaching-colearning process "against the grain." We report participants' feedback on how this teaching-learning experience facilitated their understanding of critical reflexivity and its multiple contributions towards designing PAR processes with communities that elicit and value local knowledge toward collaborative activism. We summarize our experiences and challenges in developing decolonial pedagogy within a predominantly White, elite university, and how the course generates a space through which those who have walked this walk together are able to initiate diverse processes that facilitate community collaborative knowledge generation and actions toward redressing injustice and inequity through undoing racism. PMID- 30479011 TI - Reply to Comment on "Groundwater Pumping Is a Significant and Unrecognized Contributor to Global Anthropogenic Elemental Cycles". PMID- 30479012 TI - Introduction to the Themed Issue on Activity in the Rheumatic Diseases. AB - In this issue of Arthritis Care & Research, we feature articles highly relevant to clinical practice and rheumatologic research that were submitted for our Themed Issue on Activity. Themed issues are designed to highlight state-of-the art information in the field of rheumatology. This themed issue is focused upon the effects and consequences of activity in rheumatic diseases, including activities as linked with pain, depression, disability or other factors. This article is protected by copyright. All rights reserved. PMID- 30479013 TI - Long noncoding RNA NEAT1 promotes the growth of human retinoblastoma cells via regulation of miR-204/CXCR4 axis. AB - Retinoblastoma (RB) is an aggressive eye cancer of infancy and childhood with high mortality. Studies have shown that long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) is closely related to the progression of multiple cancers. However, its role in RB remains unknown. This study aimed to investigate the role and underlying mechanism of NEAT1 in RB. We first detected the expression of NEAT1 in human RB tissues and cell lines. The effects of NEAT1 on the proliferation, migration, and apoptosis of RB cells were analyzed by loss-of function. The underlying mechanism of NEAT1 in RB was mainly focused on the microRNA 204/C-X-C chemokine receptor type 4 (miR-204/CXCR4) axis. In addition, the role and mechanism of NEAT1 in RB were further evaluated in a mouse xenograft tumor model. We found NEAT1 and CXCR4 expression levels were elevated, whereas miR-204 expression was decreased in RB tissues and cells. Downregulation of NEAT1 significantly decreased the proliferation and migration but promoted the apoptosis of RB cells. NEAT1 functioned as a competing endogenous RNA for miR-204 to regulate CXCR4 expression. Knockdown of NEAT1 suppressed the tumor volume, tumor weight, and CXCR4 expression, whereas increased miR-204 expression in mice. In conclusion, NEAT1 promotes the development of RB via miR-204/CXCR4 axis, which provides a new target for the treatment of RB disease. PMID- 30479014 TI - Editorial Comment from Dr Kuroda to Male infertility in Sertoli cell-only syndrome: An investigation of autosomal gene defects. PMID- 30479015 TI - Chemical Biology of Protein N-terminal Methyltransferases. AB - Protein alpha-N-terminal methylation is catalyzed by protein N-terminal methyltransferases. Prevalent occurrence of this methylation in ribosome, myosin and histones implies its function in protein-protein interaction. Although its full spectrum of function is not outlined yet, recent discovery revealed its emerging new roles in protein-chromatin interaction, DNA damage repair, and chromosome segregation. Here, we summarize the enzymes, cellular, and physiological consequences of alpha-N-terminal methylation. In addition, we overview the mechanism, substrate recognition, and inhibition of N-terminal methyltransferases. Opportunities and gaps in protein alpha-N-terminal methylation are also discussed. PMID- 30479016 TI - Reinforcement learning in child molesters. AB - BACKGROUND: Child molesters form a heterogeneous group, but one generally shared characteristic is maladaptive, rigid behaviour. Impairments in reinforcement learning may explain these maladaptive tendencies, but this has not been systematically investigated. Further, it is not known if such impairments vary with subtype of child molesters. AIMS: To investigate the presence of impairments in reinforcement learning among child molesters and to test for differences in patterns of impairment with subtype. METHODS: A group of 59 child molesters was recruited from several prisons in a two-stage screening process, the first using records and the second interview; a comparison group of 33 offenders who had never committed a sex offence and who denied paedophile ideation was similarly recruited; 36 nonoffender comparison men were recruited by social media and word of mouth. Each was asked to perform a probabilistic reversal learning task, in which stimulus-outcome contingencies had to be learned. RESULTS: Child molesters, as a group, made significantly more errors on the probabilistic reversal learning task than the nonoffenders; the comparison offenders and the nonoffenders gained similar scores, although findings may have been confounded by older age in the child molester group. Nonpaedophilic child molesters had significantly worse scores than paedophilic child molesters. CONCLUSIONS: Child molesters, especially those not diagnosed with paedophilia, have deficits during both the acquisition and reversal of contingencies, suggesting reinforcement learning deficits that may undermine their capacity to benefit maximally from therapy without preliminary work to repair those deficits, possibly in conjunction with extending the offender programmes. Testing before programme entry would enable accurate targeting of scarce resources in this respect. PMID- 30479017 TI - Cancer chromosome breakpoints cluster in gene-rich genomic regions. AB - Cancer cells are characterized by chromosome abnormalities, of which some, in particular balanced rearrangements, are associated with distinct tumor entities and/or with specific gene rearrangements that represent important steps in the carcinogenic process. However, the vast majority of cytogenetically detectable structural aberrations in cancer cells have not been characterized at the nucleotide level; hence, their importance and functional consequences are unknown. By ascertaining the chromosomal breakpoints in 22,344 different clonal structural chromosome abnormalities identified in the karyotypes of 49,626 cases of neoplastic disorders we here show that the distribution of breakpoints is strongly associated (P<0.0001) with gene content within the affected chromosomal bands. This association also remains highly significant in separate analyses of recurrent and non-recurrent chromosome abnormalities as well as of specific subtypes of cancer (P<0.0001 for all comparisons). In contrast, the impact of band length was negligible. The breakpoint distribution is thus not stochastic - gene-rich regions are preferentially affected. Several genomic features relating to transcription, replication, and chromatin organization have been found to enhance chromosome breakage frequencies; this indicates that gene-rich regions may be more break-prone. The salient finding in the present study is that a substantial fraction of all structural chromosome abnormalities, not only those specifically associated with certain tumor types, may affect genes that are pathogenetically important. If this interpretation is correct, then the prevailing view that the great majority of cancer chromosome aberrations is cytogenetic noise can be seriously questioned. This article is protected by copyright. All rights reserved. PMID- 30479018 TI - Identification of the novel HLA-C*04:01:01:31 allele in a Saudi individual. AB - HLA-C*04:01:01:31 differs from HLA-C*04:01:01:01 by a single nucleotide substitution (G?T) at position 72. This article is protected by copyright. All rights reserved. PMID- 30479019 TI - MicroRNA-145 induces the senescence of activated hepatic stellate cells through the activation of p53 pathway by ZEB2. AB - Activation of quiescent hepatic stellate cells (HSCs) is the major event in liver fibrosis, along with enhancement of cell proliferation and overproduction of extracellular matrix. Recent findings suggest that senescence of activated HSCs might limit the development of liver fibrosis. The p53, a guardian of the genome is associated with liver fibrosis, has been shown to regulate HSCs senescence. In this study, we report that microRNA-145 (miR-145) and p53 were downregulated in vivo and in vitro, concomitant with the enhanced expression of zinc finger E-box binding homeobox 2 (ZEB2). In addition, overexpression of miR-145 and p53 led to upregulation of the number of senescence-associated beta-galactosidase-positive HSCs and the expression of senescence markers p16 and p21, along with the reduced abundance of HSC activation markers alpha-smooth muscle actin and type I collagen in activated HSCs. Furthermore, silencing of ZEB2 promoted senescence of activated HSCs. Moreover, we also demonstrated that miR-145 specifically targeted the 3'-untranslated regions of ZEB2. In vitro promoter regulation studies show that ZEB2 could bind to the E-box of the p53 promoter as well as inhibit its promoter activity and thus suppress the expression of p53, which in turn repressed activated HSCs senescence. Taken together, our results describe a novel miR-145-ZEB2-p53 regulatory line might participate in the senescence of activated HSCs and might carry potential therapeutic targets for restraining liver fibrosis. PMID- 30479020 TI - Shared decision-making in the BREATHE asthma intervention trial: a research protocol. AB - AIM: To evaluate the preliminary effectiveness of the BRief Evaluation of Asthma THerapy intervention, a 7-minute primary care provider-delivered shared decision making protocol that uses motivational interviewing to address erroneous asthma disease and medication beliefs. DESIGN: A multi-center masked two-arm group randomized clinical trial. METHODS: This two-year pilot study is funded (September 2016) by the National Institute of Nursing Research. Eight providers will be randomized to one of two arms: the active intervention (N = 4) or a dose matched attention control (N = 4). Providers will deliver the intervention to which they were randomized to 10 Black adult patients with uncontrolled asthma (N = 80). Patients will be followed three months post-intervention to test the preliminary intervention effects on asthma control (primary outcome) and on medication adherence, lung function and asthma-related quality of life (secondary outcomes). DISCUSSION: This study will evaluate the preliminary impact of a novel shared decision-making intervention delivered in a real world setting to address erroneous disease and medication beliefs as a means of improving asthma control in Black adults. Results will inform a future, large-scale randomized trial with sufficient power to test the intervention's effectiveness. IMPACT: Shared decision-making is an evidence-based intervention with proven effectiveness when implemented in the context of labor- and time-intensive research protocols. Medication non-adherence is linked with the marked disparities evident in poor and minority adults with asthma. Addressing this requires a novel multifactorial approach as we have proposed. To ensure sustainability, shared decision-making interventions must be adapted to and integrated into real-world settings. This article is protected by copyright. All rights reserved. PMID- 30479021 TI - alpha-2-Macroglobulin induces the shedding of microvesicles from cutaneous wound myofibroblasts. AB - Microvesicles (MVs) are recognized as an important class of cell-to-cell messengers. Although the properties of MVs are increasingly documented, the mechanisms regulating MV biogenesis remain debated. Myofibroblasts are a key cellular component of wound healing and have been shown to produce MVs upon stimulation with serum. However, the mediator(s) responsible for the observed effect of serum on MV release have yet to be identified. To isolate the molecule(s) of interest, serum proteins were sequentially separated using chromatography, selective precipitation, and electrophoresis. MV production was assessed throughout the purification and after stimulation of myofibroblasts with two potent purified molecules. alpha-2-Macroglobulin (A2M) was thereby found to dose-dependently stimulate MV release. We confirmed the presence of the A2M receptor, low-density lipoprotein receptor-related protein-1 (LRP1), on myofibroblasts. Inhibition of LRP1 resulted in a significant decrease in MV production. Together, our results suggest that A2M positively regulates MV shedding through the activation of LRP1 on myofibroblasts. PMID- 30479022 TI - Increased expression of L-plastin in nasal polyp of patients with nonsteroidal anti-inflammatory drug exacerbated respiratory disease. AB - BACKGROUND: Most patients with nonsteroidal anti-inflammatory drug exacerbated respiratory disease (NERD) suffer from recurrence of nasal polyps. However, little is known about the specific cellular and molecular mechanisms contributing to the pathogenesis of nasal polyp development in patients with NERD in particular, especially at baseline when cyclooxygenase 1 inhibitors are not present. The objectives of this study were to identify proteins involved in the pathogenesis of nasal polyps in patients with NERD. METHODS: We collected nasal polyp tissue from patients with NERD and from patients with aspirin-tolerant chronic rhinosinusitis with nasal polyps (CRSwNP). Protein profiles were analyzed by 2-dimensional electrophoresis and identified several proteins, including L plastin, as highly expressed. We examined L-plastin and tissue factor (TF) expression by immunohistochemical and immunofluorescence analyses. To examine the role of L-plastin in eosinophils, we knocked down L-plastin expression in Eol-1 cells by using siRNA transfection. RESULTS: L-plastin protein levels in nasal polyp tissue were increased in patients with NERD relative to those in patients with aspirin tolerant CRSwNP. Immunofluorescence analysis revealed that L-plastin was dominantly expressed in eosinophils and L-plastin and TF were co-expressed in eosinophils in NERD nasal polyp tissue. Knockdown of L-plastin in Eol-1 cells disrupted the cell surface distribution of TF by stimulation with granulocyte macrophage colony-stimulating factor. CONCLUSIONS: Increased expression of L plastin by eosinophils may contribute to abnormal fibrin deposition through TF translocation to the eosinophil cell surface in NERD nasal polyp tissue, which in turn may contribute to the pathogenesis of NERD. This article is protected by copyright. All rights reserved. PMID- 30479023 TI - How to assess the ureters during pelvic ultrasound. AB - BACKGROUND: Endometriosis, fibroids and gynecological malignancy can all impact the pelvic ureters. Ureteric involvement is likely to be an important factor in determining the extent and timing of surgery in women with these conditions and assessment of the pelvic ureters is now a recommended component of the imaging work-up for women with endometriosis. The aim of this paper is to provide a step by-step guide for the identification and assessment of the distal ureters during pelvic ultrasound. We hope that this detailed explanation of the examination technique will help ultrasound examiners to develop this skill and enable them to integrate assessment of the pelvic urinary tract into their routine ultrasound examination. CONTENT: In this paper, we describe a '6 step' detailed approach to ultrasound assessment of the ureters during pelvic ultrasound examination. We discuss tips and common examination findings. CONCLUSION: The pelvic segments of normal ureters can be identified in almost all women on transvaginal ultrasound examination and the method described is useful in detecting urinary tract abnormalities. This article is protected by copyright. All rights reserved. PMID- 30479025 TI - Phenolic Compounds and Allelopathic Potential of Fermented and Unfermented Wheat and Corn Straw Extracts. AB - Total phenolic (TPC) and flavonoid (TFC) content, individual phenolic compounds and antioxidant activities of methanol extracts of wheat and corn straw were determined. Germination bioassay was conducted with Abutilon theophrasti, Asclepias syriaca and Chenopodium album seed. Samples were fermented by Lactobacillus plantarum and changes in TPC, TFC, antioxidant and biological activity were investigated. TPC and TFC were significant in both samples and after fermentation their recovery was improved. All samples contain mainly quercetin, cinnamic acid, p-coumaric and ferulic acid. Fermentation changed the content of phenolic and flavonoid compounds, differently in each case. All tested extracts showed high DPPH activity with IC50 being significantly lower for fermented samples. FRAP activity was also high. Crude straw extracts were overall more effective than fermented ones concerning inhibition of germination and seedlings growth, mainly without statistically significant differences between wheat and corn. Compared with mesotrione, extracts were more effective in germination and seedling growth inhibition of C. album and in seedling growth inhibition of A. theophrasti. PMID- 30479024 TI - Design features of a guideline implementation tool designed to increase awareness of a clinical practice guide to HIV rehabilitation: A qualitative process evaluation. AB - RATIONALE, AIMS, AND OBJECTIVES: A comprehensive electronic guide (e-module) describing an interprofessional, evidence-informed approach to HIV rehabilitation was developed as an education resource for rehabilitation professionals. We developed a guideline implementation tool, consisting of a 10-week, case-based education intervention delivered by email, that was perceived to increase rehabilitation professionals' (occupational therapists (OTs), physical therapists (PTs), and speech language pathologists (SLPs)) knowledge and confidence to apply best practices in HIV rehabilitation. This study aimed to increase understanding of how the design of the guideline implementation tool facilitated increased awareness of and access to the e-module among rehabilitation professionals. METHODS: We conducted a single group intervention study with rehabilitation professionals in Canada and the United Kingdom. Six case studies targeting HIV pathophysiology and associated conditions, an interprofessional approach to rehabilitation assessment and treatment, and psychosocial issues experienced by people living with HIV, were emailed to participants at 2-week intervals. Individual semi-structured interviews were conducted post-intervention. Interview transcripts were analysed using a descriptive qualitative approach. RESULTS: Twenty-six individuals (17 from Canada, and 9 from the UK; 16 PTs, 7 OTs, 3 SLPs) were interviewed. One main theme related to design features of the intervention that facilitated learning and access to the e-module emerged. Subthemes highlighted features of the case-based intervention, including technical feasibility, terminology, formatting and layout, hyperlinks, number and frequency of case studies, and diverse and realistic case scenarios relevant to the learner's practice, that participants described as facilitating access to information and learning. CONCLUSION: Electronically administered case studies were perceived as complementary knowledge tools that increased access to an evidence-informed guide to HIV rehabilitation. Findings provide guidance on using case studies as a guideline implementation tool to facilitate access to information and related resources to optimize learning. PMID- 30479026 TI - Papillary thyroid carcinoma metastatic to the pancreas: Case report. AB - Papillary thyroid carcinoma (PTC) is generally associated with an excellent long term outcome. Distant metastasis is rare with only 5-7% of patients developing distant disease. Metastasis of PTC to the pancreas is an exceedingly rare occurrence. To date, few cases have been reported. We present the case of an 81 year-old man with past medical history of PTC status post total thyroidectomy with local recurrence treated with radioactive iodine and selective neck dissection. Ten years after his initial diagnosis, PET-CT scan revealed a new hypermetabolic 1.1 cm * 0.9 cm left lower lobe lung nodule and hypermetabolism in the proximal body of the pancreas. Follow-up MRI cholangiogram showed a 1.0 * 0.8 cm T1 hypointense lesion in the proximal body of the pancreas. Endoscopic ultrasound-guided fine-needle aspiration biopsy of the pancreatic mass showed neoplastic epithelial cells arranged in papillary clusters with fibrovascular cores and syncytial sheets with high nuclear to cytoplasmic ratio, visible nucleoli, nuclear pallor, focal nuclear grooves, and rare intranuclear pseudoinclusions. Immunohistochemical stains performed on the smears showed positive nuclear expression of TTF-1 and PAX-8. The findings were consistent with metastatic PTC. Surgical resection of the lung nodule confirmed metastatic PTC. Pancreatic metastases usually occur after long time intervals with reports of up to 8 years in PTC. This makes the diagnosis more challenging, and metastatic disease should always be in the differential diagnosis in cases presenting with a pancreatic mass, especially in patients with a prior malignancy. PMID- 30479027 TI - Temporal trends and patterns in carbamazepine use, related severe cutaneous adverse reactions, and HLA-B*15:02 screening: A nationwide study. AB - OBJECTIVE: After discovering the association between the HLA-B*15:02 allele and carbamazepine-related severe cutaneous adverse reactions (SCARs), particularly in Southeastern Asian populations, clinical strategies to prevent carbamazepine related SCARs have changed. We aimed to investigate 10-year trends in carbamazepine use and carbamazepine-related SCARs and to examine the patterns and determinants of HLA-B*15:02 screening in Taiwan. METHODS: A nationwide study was performed using Taiwan's National Health Insurance Research Database. In the first part of the study, new users of carbamazepine were included, and those who experienced SCAR-related admissions were further identified. In the second part of the study, recipients of HLA-B*15:02 screening (reimbursed by Taiwan's National Health Insurance since June 2010) were included and multivariate logistic regression was used to explore factors associated with the use of screening. RESULTS: The numbers of new users of carbamazepine and SCAR cases decreased remarkably during the 10-year period (-82.6% and -87.1%, respectively), and the incidence rates of SCARs showed a downward trend after 2011. The screening rate of the HLA-B*15:02 allele increased to 24.9% in 2014. Neurologists (odds ratio 12.33, 95% confidence interval 9.30-16.35), psychiatrists (9.97, 7.31 13.61), and neurosurgeons (3.23, 2.42-4.32) were more likely to perform screening tests than other specialties were. Physicians practicing in medical centers (6.00, 5.51-6.54) were more likely to perform screening tests than those practicing in other hospitals, whereas the screening rates in clinics remained at 0.0% throughout the study period. SIGNIFICANCE: In recent years, the number of carbamazepine-related SCAR cases has decreased substantially in Taiwan. However, only one-fourth of new users of carbamazepine received HLA-B*15:02 screening, and there were considerable disparities in the screening rates across different physician groups. Policymakers should consider solutions to barriers to implementing screening tests in clinical practice and should not neglect the value of other safety communications and regulations to complement the limitations of pharmacogenomic testing. PMID- 30479028 TI - Incidence of late-acquired stent malapposition of drug eluting stents with second generation permanent and biodegradable polymer coatings-A prospective, randomized comparison using optical coherence tomography. AB - OBJECTIVES AND BACKGROUND: Polymer coatings of drug-eluting stents (DES) may induce allergic reactions and inflammation, resulting in late-acquired stent malapposition (LASM) with the risk of stent thrombosis. This study evaluated, if biodegradable polymer (BP) reduces the incidence of LASM compared to permanent polymer (PP) after treatment with newer generation DES. METHODS AND RESULTS: Fifty patients with 59 lesions were randomized (2:1) to elective treatment with second generation PP-DES (n = 32, 39 stents), either Everolimus-eluting or Zotarolimus-eluting stents, or with BP-DES (Biolimus-eluting stents [BES]; n = 18, 20 stents) and underwent optical coherence tomography directly after implantation and after 1 year. After implantation acute stent malappositions (ASM) were documented in 30 stents (51%) distributed to 22 stents treated with PP DES (56%) and 8 with BP-DES (40%; n.s.). After 1 year, late stent malappositions (LSM) were detected in 14 stents (24 %); ASM persisted (APSM) in 9 stents after one year (7 PP-DES-18%, 2 BES-10%), whereas ASM resolved in 21 stents. In addition, LASM was documented in nine stents including five stents without and four stents with additional APSM. All LASM were located in PP-DES (n = 9; 23%), none in BP-DES (P = 0.022). Compared to the reference lumen area, in-stent lumen area of stents without LASM was smaller due to neointimal hyperplasia (P = 0.021), whereas in-stent lumen area at maximum LASM of stents with LASM was larger due to positive remodeling (P = 0.002). CONCLUSIONS: In conclusion the use of BP-DES reduced the occurrence of LASM due to positive remodeling compared to second generation PP-DES. PMID- 30479029 TI - Telepsychiatry and comprehensive mental health India. AB - PURPOSE: Telemedicine in psychiatry is a validated and effective practice of medicine that increases access to health care. Telepsychiatry is also termed as telemental health or E-mental health using video conferencing which is broadly defined to provide and support psychiatric mental health services across distances. The consumption of knowledge in the mental health field has been renowned sporadically since the sixth decade of the last century. PRACTICE IMPLICATIONS: It is imperative for nurses to see the telehealth technology as a medium for care, and not a tool to replace high-quality nursing practices. Patient safety will be maintained with telenurses who are able to focus on patient care and not the technology itself. PMID- 30479030 TI - A Bayesian joint model of recurrent events and a terminal event. AB - Recurrent events could be stopped by a terminal event, which commonly occurs in biomedical and clinical studies. In this situation, dependent censoring is encountered because of potential dependence between these two event processes, leading to invalid inference if analyzing recurrent events alone. The joint frailty model is one of the widely used approaches to jointly model these two processes by sharing the same frailty term. One important assumption is that recurrent and terminal event processes are conditionally independent given the subject-level frailty; however, this could be violated when the dependency may also depend on time-varying covariates across recurrences. Furthermore, marginal correlation between two event processes based on traditional frailty modeling has no closed form solution for estimation with vague interpretation. In order to fill these gaps, we propose a novel joint frailty-copula approach to model recurrent events and a terminal event with relaxed assumptions. Metropolis Hastings within the Gibbs Sampler algorithm is used for parameter estimation. Extensive simulation studies are conducted to evaluate the efficiency, robustness, and predictive performance of our proposal. The simulation results show that compared with the joint frailty model, the bias and mean squared error of the proposal is smaller when the conditional independence assumption is violated. Finally, we apply our method into a real example extracted from the MarketScan database to study the association between recurrent strokes and mortality. PMID- 30479031 TI - Protective Effect of Acquired Long QT Syndrome in Takotsubo Syndrome. AB - BACKGROUND: Clinical variables that predict long-term mortality and recurrence of Takotsubo syndrome (TTS) are not completely understoodas the role of acquired QTc interval prolongation. METHODS AND RESULTS: QTc intervals were analysed in 105 patients presenting with symptoms of TTS. These patients were included in an ongoing retrospective cohort database. The cohort was subsequently subdivided into two groups, based on the presence (long QT group (LQT), n=73, 69.52%) or absence (non-long QT group (non-LQT), n=32, 30.43%) of QTc interval prolongation. Patients were followed over a mean-period of 4.2 years. The rate of life threatening arrhythmia during the first 30 days in the LQT group was comparable to the non-LQT group (10.9% vs. 12.5%), whereas in-hospital mortality and 30-day mortality occurred less frequently in the LQT group (2.7% vs. 18.75%, p < 0.01). During this time span 17 (23.3%) patients with acquired LQT syndrome died, whereas 14 (43.7%) patients with non-LQT duration died. Kaplan-Meier survival rates were significantly higher in the LQT group than in the non-LQT group (Log rank-test, p = 0.02). On multivariate analysis the QTc interval was an independent negative predictor of all-cause mortality (p = 0.02). CONCLUSIONS: The QTc interval at admission is an independent negative predictor of long-term adverse outcome in patients with TTS. This article is protected by copyright. All rights reserved. PMID- 30479032 TI - Factors influencing sexual risk behaviors among adolescents: A community-based participatory study. AB - Pregnancy rates and unprotected sex among Thai adolescents continue to increase. The aim of this community-based participatory study was to identify gender differences in sexual behaviors and sexual risk factors, and to examine factors associated with sexual risk behaviors among 397 adolescents in northern Thailand. Twenty two community researchers facilitated the data collection by using smart phones or tablet computers on a privacy basis. Ordinal and logistic regressions identified predictors influencing pre-coital behaviors and sexual behaviors. The results showed that males were more likely than females to engage in pre-coital and sexual behaviors. Significant predictors of higher pre-coital behaviors were age, sexual refusal self-efficacy, having boyfriends/girlfriends, authoritarian parenting style, parental approval of sex, and perceived peer norms. Pre-coital behaviors were positively correlated with sexual behaviors, and significant predictors of sexual behaviors were age, parent-adolescent communication, parental monitoring, perceived peer norms, and type of school. To better address the sexual risk behaviors of adolescents, we need to include key stakeholders to develop multi-modal culturally- and gender-specific sexual-prevention programs to account for information delivery, acceptability, and dealing with peer pressure. PMID- 30479033 TI - Patients with "ALPS-like phenotype" diagnosed with immune dysregulation due to LRBA deficiency. PMID- 30479034 TI - Direct observation of the double-stranded DNA formation through metal ion mediated base pairing in the nanoscale structure. AB - We demonstrate single-molecule imaging of metal-ion induced double-stranded DNA formation in DNA nanostructures. The formation of the metal ion-mediated base pairing in a DNA origami frame was examined using C-Ag-C and T-Hg-T metallo base pairs. The target DNA strands containing consecutive C or T were incorporated into the DNA frame, and the binding was controlled by the addition of metal ions. Double-stranded DNA formation was monitored by observing the structural changes in the incorporated DNA strands using high-speed atomic force microscopy (AFM). Using the T-Hg-T base pair, we observed the dynamic formation of unique dsDNA and its dissociation. The formation of an unusual shape of dsDNA with consecutive T Hg-T base pairs was visualized in the designed nanoscale structure. PMID- 30479035 TI - Nightmares and hallucinations with aprepitant and opium powder: a suspected drug drug interaction. AB - Polypharmacy of elderly oncology patients and fragmented medication management are well-known risk factors for drug-drug interactions (DDIs). These interactions can occur among antineoplastic, ongoing chronic treatment(s) and chemotherapy associated treatments, like antiemetics. Clinically relevant interactions based on enzyme- or transporter-inhibition phenomena of active drugs can increase the frequency of their DDIs. We describe a strongly suspected elderly cancer patient's DDI between aprepitant and opium powder in the context of an irinotecan based regimen manifested by nightmares and visual hallucinations. We discuss this DDI's hypothetical pharmacological mechanisms and management. PMID- 30479036 TI - Practical considerations for clinicians for transitioning patients on maintenance therapy with olaparib capsules to the tablet formulation of olaparib. AB - PURPOSE: Olaparib was originally formulated as 50 mg capsules with a recommended dose of 400 mg twice daily which requires patients to take 16 capsules a day. More recently, a tablet formulation with equivalent efficacy has become available and reduces the pill burden for patients to two tablets twice daily which is more convenient for patients. However, it is important to understand the key differences between the olaparib capsule and tablet formulations as they are not bioequivalent, and the doses are not interchangeable. Educating patients when transitioning from capsules to tablets is critical to avoid dosing errors and maintain both safety and efficacy of olaparib maintenance therapy. MAIN RECOMMENDATIONS: There are no established guidelines on transitioning patients from capsules to tablets. Patients taking 400 mg of the capsules twice daily should be switched to 300 mg of the tablets twice daily. In patients on a reduced dose of 200 mg capsules twice daily, consider switching to 250 mg twice daily of the tablet formulation. In patients on 100 mg capsules twice daily, consider 200 mg tablets twice daily. Particular care should be taken in transitioning patients who are on a reduced dose due to anemia and who have a low hemoglobin (9 g/dL) where a lower dose of the tablets should be considered initially. Close monitoring of patients for the first 3 months with further dose reductions based on tolerability is recommended. The tablet dose can be escalated or de-escalated depending on tolerance. PMID- 30479037 TI - The structure of Legionella effector protein LpnE provides insights into its interaction with Oculocerebrorenal syndrome of Lowe (OCRL) protein. AB - Legionella pneumophila is a freshwater bacterium that replicates in predatory amoeba and alveolar macrophage. The ability of L. pneumophila to thrive in eukaryotic host cells is conferred by the Legionella containing vacuole (LCV). Formation and intracellular trafficking of the LCV is governed by an arsenal of effector proteins, many of which are secreted by the Icm/Dot Type 4 Secretion System. One such effector, known as LpnE (L. pneumophila Entry), has been implicated in facilitating bacterial entry into host cells, LCV trafficking and substrate translocation. LpnE belongs to a subfamily of tetratricopeptide repeat proteins known as Sel1-like repeats (SLRs). All eight of the predicted SLRs in LpnE are required to promote host cell invasion. Herein, we report that LpnE(1 375) localizes to cis-Golgi in HEK293 cells via its signal peptide (aa 1-22). We further verify the interaction of LpnE(73-375) and LpnE(22-375) with Oculocerebrorenal syndrome of Lowe protein (OCRL) residues 10-208, restricting the known interacting residues for both proteins. To further characterize the SLR region of LpnE, we solved the crystal structure of LpnE(73-375) to 1.75A resolution. This construct comprises all SLRs, which are arranged in a super helical fold. The alpha-helices forming the inner concave surface of the LpnE super-helix suggest a potential protein-protein interaction interface. This article is protected by copyright. All rights reserved. PMID- 30479038 TI - Enabling High-Rate and Safe Lithium Ion-Sulfur Battery by Effective Combination of Sulfur-Copolymer Cathode and Hard-Carbon Anode. AB - Fabrication and high-rate performance of safe lithium ion-sulfur battery (LISB) with sulfur-copolymer (poly(S-co-divinylbenzene (DVB)) cathode at a sulfur content higher than 90wt% along with carbon-fiber interlayer combined with pre lithiated hard-carbon (Li-HC) anode are reported, which mitigates the problems of lithium-sulfur cells such as performance fade and safety issue due to polysulfides-dissolution and lithium-dendrite growth. Poly(S-co-DVB) cathode offers scalability due to DVB's abundance and low cost. The utilization of Li-HC anode, whose surface is passivated with solid electrolyte interphase, is found to inhibit the deposition of polysulfides. As a result, our LISB exhibits reversible and stable cycling performance at high rates up to 3C enabling a quick charge within 20 minutes, delivering the reversible capacity of ~400 mAhg-1 at 3C for 500 cycles. The data give insight into the design principle of promising, quickly charged and safe LISB. PMID- 30479039 TI - A traceless catch-and-release method for rapid peptide purification. PMID- 30479040 TI - Fat Embolism Syndrome due to Bone Marrow Necrosis in Patients with Hemoglobinopathies: A Life-threatening Complication Mimicking Thrombotic Thrombocytopenic Purpura. PMID- 30479041 TI - Protective Effect of Silkworm Pupa Oil on Hydrochloric Acid/Ethanol-Induced Gastric Ulcer. AB - BACKGROUND: Silkworm pupa is a traditional Chinese food that is rich in various saturated and unsaturated fatty acids. Unsaturated fatty acids have a certain protective effect on oxidative damage. The present study used an animal model to determine the protective effect of silkworm pupa oil on hydrochloric acid/ethanol induced gastric ulcer. RESULTS: Silkworm pupa oil is rich in unsaturated fatty acids, including palmitoleic acid 63.4 g.kg-1 , oleic acid 249.1 g.kg-1 , linoleic acid 47.0 g.kg-1 , and linolenic acid 337.8 g.kg-1 , whereas unsaturated fatty acid content is 700 g.kg-1 . Compared to the gastric ulcer control group, high and low doses of pupa oil reduced the gastric ulcer area and gastric secretion, whereas gastric pH increased. It also increased serum antioxidant SOD, CAT, GSH-Px levels, SST, and VIP levels and reduced serum IL-6, IL-12, TNF-alpha, and IFN-gamma, MTL, and GT levels. RT-qPCR and western blot analyses indicated that silkworm pupa oil significantly increases CAT, GSH-Px, EGF, EGFR, VEGF, eNOS, Cu/Zn-SOD, Mn-SOD, and IkappaB-alpha expression and lowers NF-kappaB, Bcl 2, COX-2, and iNOS expression. CONCLUSIONS: Silkworm pupa oil treatment reduces oxidative damage and inflammation in mice, and high-dose silkworm pupa oil is superior to low-dose silkworm pupa oil, following ranitidine. This article is protected by copyright. All rights reserved. PMID- 30479042 TI - Trends in use of echocardiography in hospitalized patients with syncope. AB - PURPOSE: We sought to assess the trends in use, predictors of echocardiography, and its impact on in-hospital mortality in patients admitted with syncope using a large national database. METHODS: Utilizing the Nationwide Inpatient Sample (NIS) database from 2001 to 2014, we identified adult patients (>18 years) with a primary discharge diagnosis of syncope and use of echocardiogram was ascertained. RESULTS: A total of 3 174 619 patients with a primary discharge diagnosis of syncope were identified, of which 184 167 (5.8%) underwent an echocardiogram. The rate of syncope hospitalization remained constant between 2001 and 2009 (1.1/1000 US population) but has since decreased steadily to about 0.5/1000 US population in 2014. After adjusting for patient and hospital characteristics, the rate of echocardiogram use increased significantly from 5.1% in 2001 to 6.8% in 2014 (2.7% relative increase per year [Ptrend = 0.024]). Predictors of use were cardiac disorders, hypertension, diabetes, peripheral vascular disease, and renal failure. After adjusting for baseline risk, use of echocardiography was not associated with in-hospital mortality (OR = 0.827, P = 0.155), but was associated with a 14.6% increase in adjusted length of stay and a 22.6% increase in adjusted hospital cost compared to no echocardiography use (both P < 0.001). CONCLUSIONS: The admission rates for syncope are decreasing and use of echocardiography in hospitalized patients with syncope is appropriately low. Given the lack of any favorable impact on mortality and the association with increased costs, there is a continued need to emphasize evidence-based use of echocardiography in patients presenting with syncope. PMID- 30479043 TI - Transdiagnostic school-based intervention for adolescents with early persistent psychiatric symptoms: An initial single-group effect study. AB - AIM: Mental health intervention programs for adolescents generally focus on specific symptoms, such as anxiety or depression. Psychiatric symptoms in adolescence are often heterogeneous, transient and shift over time. These characteristics require a transdiagnostic approach with emphasis on positive psychological development. This study aimed to examine the feasibility and effectiveness of Mastermind, a novel transdiagnostic intervention targeting general underlying mechanisms of psychiatric symptoms in adolescents. METHODS: Adolescents were screened for psychiatric symptoms with the Strengths and Difficulties Scale in a school-based program in two consecutive years. Adolescents were eligible for the intervention when they had psychiatric symptoms at both screening assessments. Participants received an 8 weeks program containing elements of empowerment and attention bias modification. Psychiatric symptoms were assessed before the start of the intervention, immediately after the intervention and at 6-month follow-up. RESULTS: A total of 241 adolescents were eligible for the intervention, of whom 80 participated (mean age 12.5 years). Generalized Estimating Equations, adjusted for gender and educational level, showed a decrease of negative attention bias, psychotic, anxiety, depression and behavioural symptoms immediately after intervention. The effects remained at follow-up. Overall risk for psychiatric disorders, distress and low self-esteem had decreased at follow-up. CONCLUSIONS: A simple two-step school based screening can identify adolescents with persistent psychiatric symptoms. The Mastermind transdiagnostic group intervention may be effective to reduce psychiatric symptoms, enhance self-esteem and lower the risk for developing psychiatric disorders. PMID- 30479044 TI - Topical silymarin administration for prevention of acute radiodermatitis in breast cancer patients: A randomized, double-blind, placebo-controlled clinical trial. AB - Radiation-induced dermatitis is one of the most common side effects of radiotherapy. Silymarin, a flavonoid extracted from the Silybum marianum, exhibits antioxidant and anti-inflammatory activities. The purpose of this study was to investigate the efficacy of silymarin gel in prevention of radiodermatitis in patients with breast cancer. During this randomized, double-blinded, placebo controlled clinical trial, the preventive effect of silymarin 1% gel was assessed in comparison with placebo, on radiodermatitis occurrence. Forty patients randomly received silymarin gel or placebo formulation on chest wall skin following modified radical mastectomy, once daily starting at the first day of radiotherapy for 5 weeks. Radiodermatitis severity was assessed weekly based on Radiation Therapy Oncology Group (RTOG) and National Cancer Institute Common Terminology for Adverse Events (NCI-CTCAE) criteria radiodermatits grading scale for 5 weeks. The median NCI-CTCAE and RTOG scores were significantly lower in silymarin group at the end of the third to fifth weeks (p value < 0.05). The scores increased significantly in both placebo and silymarin groups during radiotherapy, but there was a delay in radiodermatitis development and progression in silymarin group. Prophylactic administration of silymarin gel could significantly reduce the severity of radiodermatitis and delay its occurrence after 5 weeks of application. PMID- 30479045 TI - Separation of nine novel triterpene saponins from Camellia japonica seeds using high-performance countercurrent chromatography and reversed-phase high performance liquid chromatography. AB - INTRODUCTION: Camellia japonica L. (Theaceae) is an evergreen shrub, which is cultivated as a popular ornamental tree in Korea, China, and Japan and its seeds have been used as a source of cooking oil, in cosmetics and as a traditional medicine. Intensive phytochemical works have revealed that oleanane-type saponins are the characteristic compounds of the seeds of C. japonica. OBJECTIVE: The purpose of the present study is to isolate and determine oleanane-type saponins from C. japonica using high-performance countercurrent chromatography (HPCCC) coupled with reversed-phase high-performance liquid chromatography (RP-HPLC) and spectroscopic evidences, respectively. METHODOLOGY: HPLC electrospray ionisation quadrupole time-of-flight mass spectrometry (ESI-Q-TOF-MS) was applied to profile the saponin composition of an enriched saponin extract of C. japonica seeds. The enriched saponin extract was separated by HPCCC using a dichloromethane/methanol/isopropanol/water (9:6:1:4, v/v/v/v) system and RP-HPLC. The structures of the isolates were determined utilising ESI-Q-TOF-MS, one dimensional and two-dimensional NMR and optical rotation. RESULTS: HPCCC on enriched saponin extract of C. japonica yielded four saponin fractions in the order of the number of sugars attached to the triterpene aglycone, and preparative RP-HPLC on each saponin fraction led to the isolation of nine novel saponins, namely camoreoside A-I, along with six known ones. CONCLUSIONS: This study indicates that combination of HPLC-ESI-Q-TOF-MS analysis and HPCCC coupled with RP-HPLC are excellent tools for discovering saponins from natural sources. PMID- 30479047 TI - Automated Optimization of XCMS Parameters for Improved Peak Picking of LC/MS Data using the Coefficient of Variation and Parameter Sweeping for Untargeted Metabolomics. AB - Accurate peak picking and further processing is a current challenge in the analysis of untargeted metabolomics using liquid chromatography/mass spectrometry data. The optimization of these processes is crucial to obtain proper results. This study investigated and optimized the detection of peaks by XCMS, a widely used R package for peak picking and processing of high-resolution LC-MS metabolomics data by their coefficient of variation using neat standard solutions of drug like compounds. The obtained results were additionally verified by using fortified pooled plasma samples. Settings of the mass spectrometer were optimized by recommendations in literature to enable a reliable detection of the investigated analytes. XCMS parameters were evaluated using a comprehensive parameter sweeping approach. The optimization steps were statistically evaluated and further visualized after principal component analysis (PCA). Concerning the lower concentrated solution in methanol samples, the optimization of both mass spectrometer and XCMS parameters improved the median coefficient of variation from 24 % to 7 %, retention time fluctuation from 9.3 s to 0.54 s, and fluctuation of the mass to charge ratio (m/z) from m/z 0.00095 to m/z 0.00028. The number of parent compounds and their related species annotated by CAMERA increased from 88 to 113 while the total amount of features decreased from 3282 to 428. Optimized MS such as increased resolution led to a higher specificity of peak picking. PCA supported these findings by showing the best clustering of samples after optimization of both mass spectrometer and XCMS parameters. The results implied that peak picking needs to be individually adapted for the experimental set up. Reducing unwanted variation in the data set was most successful after combining high resolving power with strict peak picking settings. PMID- 30479046 TI - Second primary cancer after female breast cancer: Familial risks and cause of death. AB - BACKGROUND: With continuous increases in survival rates following breast cancer (BC) diagnosis, the challenge of multiple primary cancers has become an issue. The data on familial risk of SPCs after BC diagnosis and the related mortality in BC patients are scarce. METHODS: A total of 87 752 female BC patients were followed for SPC diagnoses and records of death. Relative risks (RRs) of SPC in BC patients who had first-degree relatives (parents or siblings) affected by the same cancer were compared to the patients without family history. Causes of death were compared between patients with and without SPC. RESULTS: After a median follow-up of 5 years, 14 952 BC patients developed SPCs, among which 10 280 (68.8%) had first-degree relatives diagnosed with cancer. Familial risks were significant for 14 site-specific SPCs, and the highest risk was for second ovarian cancer (RR = 6.28, 95%CI: 4.50-8.75), compared to those without family history (1.49, 1.34-1.65). In patients with SPC, SPC was the main cause of death, including diverse cancers and BC in approximately equal proportions. CONCLUSIONS: Family history contributed to the excess number of patients with SPCs, and SPC was the leading cause of death in patients with SPC. Taking family history at diagnosis of BC may provide warning signs with regard to possible subsequent SPCs and may offer possibilities for counseling, intervention and management. PMID- 30479048 TI - Alkyl Radical Carbonylation Using Organosilicates via Visible-Light Photoredox Catalysis. AB - Primary, secondary and tertiary alkyl radicals, formed by photocatalyzed oxidation of organosilicates, can be involved efficiently in radical carbonylation with carbon monoxide (CO), which leads to a variety of unsymmetrical ketones. This work constitutes the first example of radical carbonylation under a photooxidative regime. PMID- 30479049 TI - Transfemoral aortic valve replacement for severe aortic valve regurgitation in a patient with a pulsatile-flow biventricular assist device. AB - Severe aortic regurgitation (AR) is a rare but significant complication of ventricular assist device therapy. Experience with transcatheter aortic valve replacement (TAVR) in this setting of patients is very limited, while the scarcely reported cases exclusively refer to TAVR under continuous-flow left ventricular assist devices. Here, we present the first successful TAVR while running a pulsatile-flow biventricular assist device (PF-BiVAD). Clinical data were collected based on the patient's electronic medical records after the patient's consent was obtained. We describe the case of a 57-year-old man in whom a PF-BiVAD (EXCOR, Berlin Heart, Berlin, Germany) had been initially inserted after fulminant myocarditis with subsequent severe dilated cardiomyopathy as bridge-to-transplantation therapy. Over the following 2 years, the patient developed severe de novo AR under PF-BiVAD therapy. This, along with progressive cardiac decompensation, led to the decision for TAVR by our heart team as a minimal invasive approach for severe AR. TAVR using two Edwards SAPIEN 3 bioprostheses as a valve-in-valve procedure resulted in a significant reduction of AR from severe to mild, with trace paravalvular leakage and without significant pressure gradients. The patient underwent total orthotopic heart transplantation afterwards. This is the first report of successful TAVR in a patient with severe de novo AR while running a PF-BiVAD. PMID- 30479050 TI - Silicone in breastmilk from a breast implant: The hottest issue in Korea. PMID- 30479051 TI - Probing effects of the number and positions of -OCH3 and -CN substituents on color tuning of Ir (III) complex derivatives through a joint study of computation and experiment. AB - We performed a joint theoretical and experimental study on sixteen Ir (III) complexes bearing a similar molecular platform of bis(2-phenylbenzothiozolato N,C2') iridium(III) (acetylacetonate) by grafting -OCH3 groups and/or -CN groups on different positions of the C-related arene moiety of the C^N ligand (C-ring). Our results reveal that the introduction of -CN renders an overall drop in the FMO energy levels while a reverse increase is observed for -OCH3. The ortho- and para-sites of the C-ring are more effective substitution positions to modulate the HOMO energy level due to the fact that the electronic density of HOMO mainly locates at them while the meta-site would induce a stronger impact on LUMO since the electronic density of LUMO mainly distributes over the position. Utilizing the synergistic effects of the substituents and the substituted positions, a wide color-tuning range from 479 nm to 637 nm was achieved, which covers nearly the whole window of visible spectrum. In particular, the tri-substituted Ir35mo4cn complex (lambdaem max = 637 nm) may be a potential candidate for high efficiency red OLEDs materials due to its greatly enhanced absorption processes, relatively higher 3MLCT (%), lower DeltaES1-T1, enlarged separation between 3MLCT/pi-pi* and 3MC d-d states, and good hole and particle-transporting performances. Finally, six representative complexes were synthesized and their spectra were determined, which confirm the reliability of our computational strategy. PMID- 30479052 TI - Lokivetmab therapy for pruritus in a dog with cutaneous mastocytosis. AB - BACKGROUND: Cutaneous mastocytosis (CM) is a rare disease of dogs characterized by rash, pruritus and proliferation of mast cells in the skin. Oral H1 antihistamines are recommended as the treatment to control pruritus. HYPOTHESIS/OBJECTIVE: To describe the effective treatment of pruritus associated with CM with lokivetmab in one dog. ANIMAL: A 4-year-old, spayed female cross bred dog presented with severely pruritic, erythematous to pigmented macules and papules involving the ventral abdomen, interdigital skin, perivulval area and both pinnae; the pruritus had been unresponsive to treatment with antihistamines, prednisone and ciclosporin. METHODS AND MATERIALS: Complete blood count and serum biochemistry, abdominal ultrasound, blood smear and skin cytological evaluation, PCR, histopathological and immunohistochemical examination of skin biopsies. RESULTS: Skin cytological evaluation revealed high numbers of uniform, heavily granulated mast cells; histopathological findings showed focal dermal proliferations of well-differentiated, uniform mast cells consistent with a low grade mast cell tumour (MCT). Clinical staging revealed that the disease was confined to the skin. Mutations of c-kit exon 8 and 11 were not detected. Treatment was initiated with anti-canine-interleukin (IL)-31 monoclonal antibody lokivetmab; antihistamines were continued. The dog's pruritus resolved within seven days and was maintained in remission over 15 months with once monthly lokivetmab injections; the skin lesions improved but did not resolve. CONCLUSION AND CLINICAL IMPORTANCE: Lokivetmab treatment was effective in resolving and maintaining pruritus remission in this dog with widespread cutaneous mast cell disease. Whether CM in dogs represent a separate entity that should be distinguished from a low-grade MCT requires further investigation. PMID- 30479053 TI - Design, synthesis, and molecular docking study of benzothiazolotriazine derivatives for anticonvulsant potential. AB - A series of newer benzothiazolotriazine derivatives (4a-k) was designed, synthesized, and characterized as anticonvulsant agents against the two classically used MES and scPTZ animal models. The synthesized derivatives were tested in vivo in both the animal models, followed by a neurotoxicity study by the rotarod method. Compound 4e, 8-chloro-4-(2-chlorocyclohexa-1,5-dien-1-yl)-2 ((4-methoxybenzyl)thio)-10aH-benzo[4,5]thiazolo[3,2a][1,3,5]triazine was found most promising among the series in both the animal models, with no neurotoxicity. From this it may be confirmed that the presence of a methoxy (OCH3 ) group at the lipophilic aryl ring was showing high anticonvulsant potency. In the molecular modeling study, compound 4e (docking score = -8.70) showed important hydrogen bond interaction with the amino acids LYS 329, SER 137, GLY 136 and pi-pi interactions with PHE 189 at the active site of GABA-AT. These derivatives can be further explored for the development of newer/novel anticonvulsant agents. PMID- 30479054 TI - Novel DRAQ5TM/SYTOX(r) Blue Based Flow Cytometric Strategy to Identify and Characterize Stem Cells in Human Breast Milk. AB - BACKGROUND: Human breast milk could be an important stem cell source for the development of newborn and preterm infants, but quantitative data on the stem cell content in breast milk at various gestational stages are needed to determine the clinical value of breast milk as a source of stem cells. Breast milk also contains milk fat globules, lipid droplets of different sizes, debris and dead cells and these components hamper flow cytometry analysis of human breast milk samples. METHODS: Here, we originally used standard protocols for flow cytometry to characterize cell populations in human breast milk but failed to discriminate between cells and noncellular components. We then applied a centrifugation protocol to separate cream and skim milk from the cell-containing pellet and used a novel staining protocol with DRAQ5TM and SYTOX(r) blue dye as well as antibodies to characterize cells within the pellet fraction. RESULTS: Flow cytometry analysis identified viable DRAQ5TM+ /SYTOX(r) Blue- cells and determined the content of CD11b+ monocytes and TRA-1-81+ putative stem cells in human breast milk samples. CONCLUSIONS: Hence, we developed a novel and reliable flow cytometry based-approach to quantify subpopulation of cells in human breast milk with a high content of milk fat globules, lipid droplets, and particles. This approach will improve the identification and quantification of breast milk cells and allow standardizing the flow cytometry-based evaluation of the stem cell content. (c) 2018 International Clinical Cytometry Society. PMID- 30479055 TI - Bridging Surface Charge and Catalytic Activity of Defective Carbon Electrocatalyst. AB - Electrocatalysis is dominated by reaction at the solid-liquid-gas interface, and the surface properties of electrocatalysts determine the electrochemical behavior. The surface charge (electronic properties) of active sites on catalysts can significantly modulate the adsorption and desorption of intermediates and tune the electrocatalysis. However, there is no direct evidence to bridge the surface charge and catalytic activity of active sites. In this work, we controllably created defects (active sites) on HOPG (highly oriented pyrolytic graphite) surface and broke the intrinsic sp2-hybridization of graphite by plasma, which induces the localization of surface charge onto defective active sites, as proved by scanning ion conductance microscopy (SICM) and Kelvin probe force microscopy (KPFM). The electrochemical test revealed the significantly enhanced intrinsic activity by the localized surface charge with a volcano relationship. The DFT calculation confirmed the relationship between the surface charge and the catalytic activity. This work correlates surface charge and catalytic activity, which provides the insight into the electrocatalytic behavior and would guide the design of advanced electrocatalysts for various reactions. PMID- 30479056 TI - Evaluating a shortened interpretation criterion for intraoperative parathyroid hormone monitoring in patients with primary hyperparathyroidism: A 5-minutes criterion in primary hyperparathyroidism and intraoperative algorithm. AB - BACKGROUND: Most criteria require a parathyroid hormone (PTH) decline of >=50% within 10 minutes after excision of the gland during surgery for primary hyperparathyroidism. The aim was to evaluate a model allowing earlier prediction of cure. METHODS: One thousand eighteen patients with primary hyperparathyroidism were included. A >=50% decline from baseline within 10 minutes after excision intraoperatively predicted complete removal of hypersecreting tissue. The data were reanalyzed regarding a criterion, requiring a >=50% decline after 5 minutes. Based on the data and the present literature, an algorithm was created. RESULTS: Assay predicted cure in 854 patients (true-positive; 83.89%) after 10 minutes (false-positive [FP] in 13 patients; 1.52%). Nevertheless, only 14 (1.83%) showed persisting disease. According to the "5 minutes" criterion, 723 patients (71.02%) showed a >=50% decline from baseline within 5 minutes and 10 (1.38%) patients had a FP decline (sensitivity 0.75, specificity 0.86). CONCLUSION: Using a modified criterion, surgery can be discontinued 5 minutes earlier in 71%. PMID- 30479058 TI - The cohesin complex in mammalian meiosis. AB - Cohesin is an evolutionary conserved multi-protein complex that plays a pivotal role in chromosome dynamics. It plays a role both in sister chromatid cohesion and in establishing higher order chromosome architecture, in somatic and germ cells. Notably, the cohesin complex in meiosis differs from that in mitosis. In mammalian meiosis, distinct types of cohesin complexes are produced by altering the combination of meiosis-specific subunits. The meiosis-specific subunits endow the cohesin complex with specific functions for numerous meiosis-associated chromosomal events, such as chromosome axis formation, homologue association, meiotic recombination and centromeric cohesion for sister kinetochore geometry. This review mainly focuses on the cohesin complex in mammalian meiosis, pointing out the differences in its roles from those in mitosis. Further, common and divergent aspects of the meiosis-specific cohesin complex between mammals and other organisms are discussed. PMID- 30479057 TI - Characteristics and Outcomes of Patients with Acute Liver Failure Admitted to Australian and New Zealand Intensive Care Units. AB - BACKGROUND: Knowledge about patients with Acute Liver Failure (ALF) in Australia and New Zealand (ANZ) is lacking. We hypothesised that the pattern of disease would be similar to previous studies and that, despite low transplantation rates, mortality would be comparable. METHODS: We obtained data from the ANZ Intensive Care Society Adult Patient Database and the ANZ Liver Transplant Registry for ten years commencing 2005 and analysed for patient outcomes. RESULTS: During the study period, 1 022 698 adults were admitted to intensive care units (ICUs) across ANZ, of which 723 had ALF. The estimated annual incidence of ALF over this period was 3.4/million people and increased over time (p=0.001). ALF patients had high illness severity (APACHE III 79.8 vs. 50.1 in non-ALF patients; p<0.0001), and were more likely to be younger, female, pregnant and immunosuppressed. ALF was an independent predictor of mortality (OR 1.5 (1.26-1.79); p<0.0001). At less than 23%, the use of liver transplantation was low, but the mortality of 39% was similar to previous studies. CONCLUSIONS: ALF is a rare but increasing diagnosis in ANZ ICUs. Low transplantation rates in ANZ for ALF do not appear to be associated with higher mortality rates than reported in the literature. This article is protected by copyright. All rights reserved. PMID- 30479059 TI - CXXC5: A novel regulator and coordinator of TGF-beta, BMP and Wnt signaling. AB - CXXC5 is a member of the CXXC-type zinc-finger protein family. Proteins in this family play a pivotal role in epigenetic regulation by binding to unmethylated CpG islands in gene promoters through their characteristic CXXC domain. CXXC5 is a short protein (322 amino acids in length) that does not have any catalytic domain, but is able to bind to DNA and act as a transcription factor and epigenetic factor through protein-protein interactions. Intriguingly, increasing evidence indicates that expression of the CXXC5 gene is controlled by multiple signaling pathways and a variety of transcription factors, positioning CXXC5 as an important signal integrator. In addition, CXXC5 is capable of regulating various signal transduction processes, including the TGF-beta, Wnt and ATM-p53 pathways, thereby acting as a novel and crucial signaling coordinator. CXXC5 plays an important role in embryonic development and adult tissue homeostasis by regulating cell proliferation, differentiation and apoptosis. In keeping with these functions, aberrant expression or altered activity of CXXC5 has been shown to be involved in several human diseases including tumourigenesis. This review summarizes the current understanding of CXXC5 as a transcription factor and signaling regulator and coordinator. PMID- 30479060 TI - Comparison of the efficacy and safety of povidone-iodine foam dressing (Betafoam), hydrocellular foam dressing (Allevyn), and petrolatum gauze for split thickness skin graft donor site dressing. AB - We evaluated the efficacy and safety of a povidone-iodine (PVP-I) foam dressing (Betafoam) for donor site dressing versus a hydrocellular foam dressing (Allevyn) and petrolatum gauze. This prospective Phase 4 study was conducted between March 2016 and April 2017 at eight sites in Korea. A total of 106 consenting patients (aged >= 19 years, scheduled for split-thickness skin graft) were randomised 1:1:1 to PVP-I foam, hydrocellular, or petrolatum gauze dressings for up to 28 days after donor site collection. We assessed time to complete epithelialisation, proportion with complete epithelialisation at Day 14, and wound infection. Epithelialisation time was the shortest with PVP-I foam dressing (12.74 +/- 3.51 days) versus hydrocellular foam dressing (16.61 +/- 4.45 days; P = 0.0003) and petrolatum gauze (15.06 +/- 4.26 days, P = 0.0205). At Day 14, 83.87% of PVP-I foam dressing donor sites had complete epithelialisation, versus 36.36% of hydrocellular foam dressing donor sites (P = 0.0001) and 55.88% of petrolatum gauze donor sites (P = 0.0146). There were no wound infections. Incidence rates of adverse events were comparable across groups (P = 0.1940). PVP-I foam dressing required less time to complete epithelialisation and had a good safety profile. PMID- 30479061 TI - Male Sex Increases Mortality in Patients Presenting with Ventricular Tachyarrhythmias. AB - OBJECTIVES: The study sought to assess the impact of male sex on survival in patients presenting with ventricular tachyarrhythmias. METHODS: All consecutive patients surviving ventricular tachycardia (VT) and ventricular fibrillation (VF) on admission from 2002 to 2016 were included and stratified according to sex differences by propensity score matching. The primary prognostic endpoint was all cause mortality at 30 months. Secondary endpoints were all-cause mortality at 30 days, at index hospitalization, after discharge, the composite of recurrent ventricular tachyarrhythmias and appropriate ICD interrogation, and finally rehospitalization related to ventricular tachyarrhythmias. RESULTS: A total of 784 (392 males and 392 females) patients were included. The rate of VT and VF was similar in both groups (VT: male 65% vs. female 62%; VF: male 35% vs. female 38%). Male sex was independently associated with the primary endpoint of all cause mortality at 30 months (31% vs. 23%; HR = 1.432; 95% CI 1.089- 1.883; p=0.010) as well as with and the secondary endpoint of all-cause mortality at index hospitalization (mortality rate 31% vs. 23%; log-rank p=0.010; HR = 1.432; 95% CI 1.089- 1.883; p=0.010; mortality rate 10% vs. 15%; HR=1.685; 95% CI 1.117 2.542; p=0.013). No differences in further secondary endpoints were found. Sex differences of the primary endpoint were predominantly observed in patients with VT at index (mortality rate 28% versus 20%; HR=1.512; 95% CI 1.040-2.189; p=0.028), without an implantable cardioverter defibrillator (ICD) and with left ventricular ejection fraction (LVEF) >=35% (log-rank values, p<0.05). CONCLUSION: Males presenting with ventricular tachyarrhythmias on admission were associated with higher all-cause mortality at 30 months and all-cause mortality at index hospitalization. This article is protected by copyright. All rights reserved. PMID- 30479062 TI - Reduced SIRT1/AMPK in Amyotrophic Lateral Sclerosis Patient-Derived Mesenchymal Stem Cells can be restored by resveratrol. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neuron system. Our previous study has shown that bone marrow mesenchymal stem cells (BM-MSCs) from ALS patients have functional limitations in releasing neurotrophic factors and exhibit the senescence phenotype. In this study, we examined SIRT1/AMPK activities and identified significant decreases in the ALS-MSCs compared to normal healthy control originated BM-MSCs. This decline was restored by pre-treatment with resveratrol (RSV), measured using quantitative PCR, NAD/NADH assay, and immunoblot analysis. Neuro-progenitor markers were increased in RSV treated ALS-MSCs (RSV/ALS-MSCs). The differentiated ALS-MSCs exhibited a cell body and dendritic shape similar to neurons. RSV/ALS-MSCs showed significantly increased differentiation rate as compared to the untreated differentiated ALS-MSCs (ALS-dMSCs). The neurite numbers and lengths were also significantly increased. This was confirmed with immunoblot analysis using neuron specific markers such as nestin, NF-M, Tuj-1, and Map-2 in RSV/ALS-dMSCs. Thus, this study shows that ALS-MSCs showed down-regulation of AMPK/SIRT1 signaling, which was recovered by treatment with RSV. This data suggest that RSV can be one of candidate agents for improving therapeutic efficacy of ALS patients' originated MSCs. PMID- 30479063 TI - Surgery vs. radiotherapy for locally advanced hypopharyngeal cancer in the contemporary era: A population-based study. AB - OBJECTIVES: To compare overall survival (OS) in locally advanced hypopharyngeal cancer treated with surgery or definitive chemoradiotherapy in the contemporary era. METHODS: From 2010 to 2015, data for patients diagnosed with hypopharyngeal cancer (T2-T4aM0) and treated with total pharyngectomy with lymph node dissection (surgery group) or definitive radiotherapy and chemotherapy (chemoradiotherapy group) was retrieved from the SEER database. Multivariate analyses were performed in each subgroup divided according to T category (T2-3 or T4a). RESULTS: The number of patients in the surgery and chemoradiotherapy groups was 209 and 648, respectively. Among them, the number of T4a patients was 111 and 126 in each group. Three-year OS rate in the surgery and chemoradiotherapy groups was 37.9% and 44.1%, respectively (P = 0.178). The 3-year OS rate for the T2-3 patients was 46.5% and 48.7% (P = 0.598), and the 3-year OS rate for the T4a patients was 29.9% and 26.1% in the surgery and chemoradiotherapy groups, respectively (P = 0.439). On multivariate analysis, the chemoradiotherapy group was not inferior to the surgery group in T2-T4a patients (Hazard ratio [HR] for the chemoradiotherapy group 0.889, 95% confidence interval [CI] 0.699-1.129, P = 0.334), in T2-3 patients (HR 0.932, 95% CI 0.699-1.297, P = 0.675), and in T4a patients (HR 0.880, 95% CI 0.617-1.256, P = 0.481). CONCLUSIONS: Chemoradiotherapy for locally advanced hypophagyngeal cancer showed a comparable OS rate to surgery. For patients with T4a category cancer with high possibility of preserving the laryngopharyngeal function, chemoradiotherapy may be a promising alternative treatment. PMID- 30479064 TI - The challenge of defining "ultra-high-risk" neuroblastoma. AB - Given the biological and clinical heterogeneity of neuroblastoma, risk stratification is vital to determining appropriate treatment. Historically, most patients with high-risk neuroblastoma (HR-NBL) have been treated uniformly without further stratification. Attempts have been made to identify factors that can be used to risk stratify these patients and to characterize an "ultra-high risk" (UHR) subpopulation with particularly poor outcome. However, among published data, there is a lack of consensus in the definition of the UHR population and heterogeneity in the endpoints and statistical methods used. This review summarizes our current understanding of stratification of HR-NBL and discusses the complex issues in defining UHR neuroblastoma. PMID- 30479065 TI - Evaluation of Surgical Wound Healing in Orthopedic Patients with Impaired Tissue Integrity According to Nursing Outcomes Classification. AB - PURPOSE: To assess the surgical wound (SW) healing in orthopedic patients with Impaired tissue integrity according to the Nursing Outcomes Classification (NOC). METHODS: A prospective longitudinal study performed with 24 patients. Data collection was performed through an instrument containing the NOC indicators. FINDINGS: The indicators skin approximation, drainage, surrounding skin erythema, periwound edema, increased skin temperature, and foul wound odor presented a statistically significant increase when compared the means between the first and the last day of evaluation. CONCLUSION: The NOC indicators allowed to monitor the SW healing indicating an improvement. IMPLICATIONS FOR NURSING PRACTICE: The NOC can favor an earlier identification of the degree of commitment for each patient and enables implementation of care to achieve target outcomes. PMID- 30479066 TI - A protocol to transfer a fed-batch platform process into semi-perfusion mode: The benefit of automated small scale bioreactors compared to shake flasks as scale down model. AB - Continuous processes such as perfusion processes can offer advantages compared to fed-batch or batch processes in bio-processing: improved product quality (e.g. for labile products), increased product yield and cost savings. In this work, a semi-perfusion process was established in shake flasks and transferred to an automated small scale bioreactor by daily media exchange via centrifugation based on an existing fed-batch process platform. At first development of a suitable medium and feed composition, the glucose concentration required by the cells and the cell specific perfusion rate (CSPR) were conducted in shake flasks as the conventional scale down system. This lead to an optimized process with a three fold higher titer of 10 g/L monoclonal antibody (mAb) compared to the standard fed-batch. To proof the suitability and benefit as a small scale model, the established semi-perfusion process was transferred to an automated small scale bioreactor with improved pH and dissolved oxygen (DO) control. The average specific productivity improved from 24.16 pg/(c*d) in the fed-batch process and 36.04 pg/c*d in the semi-perfusion shake flask to 38.88 pg/(c*d) in the semi perfusion process performed in the controlled small scale bioreactor, thus illustrating the benefits resulting from the applied semi-perfusion approach, especially in combination with controlled DO and pH settings. This article is protected by copyright. All rights reserved. PMID- 30479067 TI - Longitudinal interprofessional student-led clinics - a formula for implementation. PMID- 30479068 TI - Association of proximal elements of social disadvantage with children's language development at 2 years: an analysis of data from the Children in Focus (CiF) sample from the ALSPAC birth cohort. AB - BACKGROUND: An association between social disadvantage and early language development is commonly reported in the literature, but less attention has been paid to the way that different aspects of social disadvantage affect both expressive and receptive language in the first 2 years of life. AIMS: To examine the contributions of gender, parental report of early language skills and proximal social variables (the amount of stimulation in the home, the resources available to the child and the attitudes/emotional status of the primary carer and the support available to him/her) controlling for distal social variables (family income and maternal education) to children's expressive and receptive language development at 2 years in a community ascertained population cohort. METHODS & PROCEDURES: Data from 1314 children in the Children in Focus (CiF) sample from the Avon Longitudinal Study of Parents and Children (ALSPAC) were analyzed. Multivariable regression models identified the contribution of proximal (what parents do with their children) measures of social disadvantage adjusting for more distal (e.g., family income and material wealth) measures as well as early language development at 15 months to the development of verbal comprehension, expressive vocabulary and expressive grammar (word combinations) at 2 years of age. OUTCOME & RESULTS: In the final multivariable models gender, earlier language and proximal social factors, co-varying for distal factors predicted 36% of the variance for expressive vocabulary, 22% for receptive language and 27% for word combinations at 2 years. Language development at 15 months remained a significant predictor of outcomes at 24 months. Environmental factors were associated with both expressive scales but the picture was rather more mixed for receptive language suggesting that there may be different mechanisms underlying the different processes. CONCLUSIONS & IMPLICATIONS: This study supports the argument that social advantage makes a strong contribution to children's language development in the early years. The results suggest that what parents/carers do with their children is critical even when structural aspects of social disadvantage such as family income and housing have been taken into consideration although this relationship varies for different aspects of language. This has the potential to inform the targeting of public health interventions focusing on early language and pre-literacy skills on the one hand and home learning environments on the other and, potentially, the two in combination. PMID- 30479069 TI - Persistence and stochasticity are key determinants of genetic diversity in plants associated with banded iron formation inselbergs. AB - The high species endemism characteristic of many of the world's terrestrial island systems provides a model for studying evolutionary patterns and processes, yet there has been no synthesis of studies to provide a systematic evaluation of terrestrial island systems in this context. The banded iron formations (BIFs) of south-western Australia are ancient terrestrial island formations occurring within a mosaic of alluvial clay soils, sandplains and occasional granite outcropping, across an old, gently undulating, highly weathered, plateau. Notably, these BIFs display exceptionally high beta plant diversity. Here, we address the determinants and consequences of genetic diversity for BIF-associated plant species through a comprehensive review of all studies on species distribution modelling, phylogenetics, phylogeography, population genetics, life history traits and ecology. The taxa studied are predominantly narrowly endemic to individual or a few BIF ranges, but some have more regional distributions occurring both on and off BIFs. We compared genetic data for these BIF-endemic species to other localised species globally to assess whether the unique history and ancestry of BIF landscapes has driven distinct genetic responses in plants restricted to this habitat. We also assessed the influence of life-history parameters on patterns of genetic diversity. We found that BIF-endemic species display similar patterns of genetic diversity and structure to other species with localised distributions. Despite often highly restricted distributions, large effective population size or clonal reproduction appears to provide these BIF endemic species with ecological and evolutionary resilience to environmental stochasticity. We conclude that persistence and stochasticity are key determinants of genetic diversity and its spatial structure within BIF-associated plant species, and that these are key evolutionary processes that should be considered in understanding the biogeography of inselbergs worldwide. PMID- 30479071 TI - Identification of the novel HLA-B*49:01:01:04 allele in a Saudi individual. AB - HLA-B*49:01:01:04 differs from HLA-B*49:01:01:01 by a single nucleotide substitution (G?A) at position 3627. This article is protected by copyright. All rights reserved. PMID- 30479070 TI - Exposure to antazoline-naphazoline eye drops during pregnancy and the risk of congenital malformations: a Danish nationwide cohort study. AB - PURPOSE: To investigate whether exposure to antazoline-naphazoline eye drops in the first trimester of pregnancy was associated with an increased risk of malformations in humans. METHODS: All women giving live birth between 1997 and 2011 in Denmark were included in this nationwide cohort study. All women redeeming at least one prescription of antazoline-naphazoline eye drops during the first 84 days of pregnancy were identified. Logistic regression was used to estimate the odds ratios of malformations among exposed offspring compared to non exposed offspring. RESULTS: We identified 977 706 births between 1997 and 2011. A total of 3061 women (0.32%) were exposed to antazoline-naphazoline eye drops in the first trimester of pregnancy. The rate of congenital malformations was 3.0% (n = 93) in exposed offspring and 3.5% (n = 33 594) in unexposed offspring. First trimester exposure to antazoline-naphazoline was not associated with major congenital malformations overall (odds ratio: 0.88, 95% confidence interval: 0.71 1.09) or with any specific major malformation. The number of redeemed prescriptions was unchanged during all trimesters of pregnancy as compared to before and after pregnancy (p < 0.05). CONCLUSION: Exposure to antazoline naphazoline eye drops in the first trimester of pregnancy appears not to be associated with increased teratogenic risk. PMID- 30479072 TI - Anti-TPO IgE Autoantibody in Chronic Urticaria: Is It Clinically Relevant? PMID- 30479073 TI - Mechanisms by Which Atopic Dermatitis Predisposes to Food Allergy and the Atopic March. AB - The Atopic march denotes the progression from atopic dermatitis (AD) to the development of other allergic disorders such as immunoglobulin (Ig) E-mediated food allergy, allergic rhinitis and asthma in later childhood. There is increasing evidence from prospective birth cohort studies that early-onset AD is a risk factor for other allergic diseases or is found in strong association with them. Animal studies now provide mechanistic insights into the pathways that may be responsible for triggering the progression from the skin barrier dysfunction seen in AD to epicutaneous sensitization, food allergy and allergic airway disorders. Recent large randomized controlled trials have demonstrated the efficacy of early interventions targeted at AD and food allergy prevention. These show great promise for research into future strategies aimed at prevention of the atopic march. PMID- 30479074 TI - Biomarkers for Recurrent Wheezing and Asthma in Preschool Children. AB - Wheezing is one of the characteristic symptoms of asthma, but all preschool children with wheezing are not diagnosed with asthma. Preschool children are not cooperative enough to participate in spirometry and invasive tests. Thus, there is no conventional method to diagnose asthma in preschool children. We reviewed studies on non-invasive biomarkers for assessing asthma in preschool children. Specimens that can be easily obtained by non-invasive methods are blood, exhaled breath and urine. Eosinophils, eosinophil cationic protein and eosinophil-derived neurotoxin (EDN) in blood are helpful in evaluating eosinophilic inflammation of the airways. Exhaled breath contains nitric oxide, volatile organic compounds, various cytokines and mediators as analytical components. Fraction of exhaled nitric oxide has been used to assess the degree of eosinophil inflammation and has been standardized in school-age children and adults, but not yet in preschool children. Exhaled breath condensate (EBC) pH and various cytokines/mediators that are detected in EBC seem to be promising biomarkers for assessing asthma, but need more standardization and validation. There are several biomarkers useful for assessing asthma, but none are ideal. Some biomarkers need standardized methods of obtaining samples from uncooperative preschool children for clinical use and require sufficient validation. Recently, another activated eosinophil marker, serum EDN, has shown promising results as a biomarker for recurrent wheezing and asthma in preschool children. PMID- 30479075 TI - Causal Relationship Between Anti-TPO IgE and Chronic Urticaria by In Vitro and In Vivo Tests. AB - PURPOSE: Immunoglobulin (Ig) E autoantibodies against thyroid antigens such as thyroid peroxidase (TPO) have been demonstrated in chronic spontaneous urticaria (CSU) patients in higher frequency than healthy subjects. However, if these IgE autoantibodies can trigger urticaria is still a matter of study. The aim of this study was to investigate the relationship between concomitant IgE autoantibodies against thyroid antigens in CSU. METHODS: Patients with CSU, healthy subjects and patients with autoimmune thyroid disease (ATD) were recruited. Total IgE and specific anti-TPO IgE and IgG were assessed in all subjects. The basophil activation test and skin tests with TPO were performed to demonstrate whether this antigen could selectively induce urticaria reaction in subjects with positive anti-TPO IgE. RESULTS: Anti-TPO IgE was present in all 3 groups (CSU: 34.0%, ATD: 16.6%, healthy subjects: 8.1%). Anti-TPO IgE levels were higher in CSU patients, whereas anti-TPO IgG were higher in ATD patients. After exposure to TPO, CD203c expression from patients with CSU and anti-TPO IgE significantly increased in comparison to the other groups; 33.0% vs. 14.0% in ATD patients and 9.0% in control subjects (P < 0.05). Skin reactions with TPO were higher in patients with CSU according to the intradermal (CSU: 18.0%, ATD: 3.3%, control: 8.0%) and skin prick tests (12.0%, 0%, 0%, respectively). Passive transfer of anti-TPO IgE from a CSU patient to the skin of control subjects without anti-TPO IgE induced a positive skin reaction. CONCLUSIONS: Anti-TPO IgE is not a specific biomarker for CSU. However, IgE against TPO plays a pathogenic role in inducing effector cell activation and skin exacerbation in some patients with CSU. PMID- 30479076 TI - Characteristics of Adult Severe Refractory Asthma in Korea Analyzed From the Severe Asthma Registry. AB - PURPOSE: Although mild to moderate asthma is much more common, the morbidity and mortality of severe asthma are much higher. This study was performed to identify and analyze the clinical characteristics of severe asthma in Korea. METHODS: We registered patients with severe refractory asthma into the Severe Asthma Registry supported by the Severe Asthma Work Group of the Korean Academy of Asthma, Allergy and Clinical Immunology. Patients were enrolled since 2010 from the 15 university hospitals nationwide in Korea. Severe asthma was defined according to modified European Respiratory Society/American Thoracic Society criteria. Information on demographics, medical history, pulmonary function tests and skin prick tests was collected; the clinical characteristics of severe asthmatics were analyzed from the collected data. RESULTS: A total of 489 patients were enrolled with a mean age of 62.3; 45% are male. Sixty percent of patients received Global Initiative for Asthma step 4 treatment, and 30% received step 5 treatment. The most common comorbidities were allergic rhinitis (58.7%). Aspirin hypersensitivity was observed in 14.0%. Approximately half (53.9%) are non smokers. Atopy was proven in 38.5% of the patients. Regarding asthma medications, inhaled corticosteroids and long-acting beta-agonist combination inhalers were most commonly prescribed (96.5%), followed by leukotriene antagonists (71.0%). A recombinant anti-immunoglobulin E monoclonal antibody (omalizumab) has been used in 1.8% of the patients. The mean forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and FEV1/FVC were 78.7%, 67.5% and 67.9% of predicted values, respectively. The mean Asthma Control Test and quality of life questionnaire scores were 16.5 out of 25 and 59.5 out of 85, respectively. CONCLUSIONS: The baseline characteristics of severe asthma patients in the Korea Severe Asthma Registry were analyzed and reported for the first time. With this cohort, further prospective studies should be performed to search for ways to improve management of severe refractory asthma. PMID- 30479077 TI - Adaptation and Validation of the Korean Version of the Urticaria Control Test and Its Correlation With Salivary Cortisone. AB - PURPOSE: Frequent changes in chronic urticaria (CU) activity over time can cause psychological stress, which also serves as a trigger of CU. To measure the control status of CU, the Urticaria Control Test (UCT) was developed in Germany. This study aimed to investigate the validity, reliability and responsiveness to changes in CU for the Korean version of the UCT (K-UCT) and its relation with salivary cortisol and cortisone levels. METHODS: Linguistic adaptation of the UCT into Korean was conducted. A total of 96 CU patients were enrolled, and 80 of them completed the study. The K-UCT and other outcome scores for CU were measured and repeated after 4 weeks of treatment. Control status was classified by physicians into well-controlled, partly-controlled, and uncontrolled CU. Salivary cortisol and cortisone were measured by liquid chromatography-tandem mass spectrometry. RESULTS: Excellent internal consistency and intra-class reliability were obtained. Strong correlations between the K-UCT and disease severity, reflected in the Urticaria Activity Score (UAS)/global assessment of urticaria control by physicians/patient assessment of symptom severity/CU-specific quality of life were noted. K-UCT scores >=12 were found to be optimal for determining well-controlled CU (sensitivity, 75.0%; specificity, 758%; area under the curve, 0.824). Perceived stress scale scores were significantly correlated with the UAS and the K-UCT. Salivary cortisone levels were significantly correlated with K-UCT (r = 0.308, P = 0.009) and differed significantly according to control status determined by a K-UCT >=12. CONCLUSIONS: This study demonstrated that the K-UCT can be a valid instrument with which to gauge CU control status in Korean patients. Further studies are needed to validate salivary cortisone as a biomarker for CU control. PMID- 30479078 TI - Comparison of Long-term Efficacy of Subcutaneous Immunotherapy in Pediatric and Adult Patients With Allergic Rhinitis. AB - PURPOSE: Data comparing the long-term efficacy and safety of subcutaneous immunotherapy (SCIT) using house dust mite (HDM) in children and adults with allergic rhinitis (AR) are limited. This study aimed to compare the long-term effects of HDM-SCIT in a cohort of Chinese pediatric and adult patients with AR. METHODS: A total of 124 pediatric and adult AR patients received HDM-SCIT for 3 years, with 118 patients being followed-up for 2 years. Prior to treatment (baseline), at the end of the 3-year treatment periods (third year) and 2 years after the discontinuation of treatment (fifth year), all patients were evaluated for total nasal symptom scores (TNSS), daily medication score (DMS), total combined score (TCS; symptoms [nasal + ocular] + DMS) and quality of life (QoL). Safety was assessed according to adverse events reported. RESULTS: After 3-year treatment, HDM-SCIT significantly improved symptoms and QoL scores at the end of the third and fifth years in both groups. Better improvements were observed in the third and fifth years based on baseline, in children compared to adults (TNSSDelta3: 6.66 vs. 5.41, P = 0.011; TCSDelta3: 4.30 vs. 3.83, P = 0.027 and TNSSDelta5: 6.16 vs. 4.86, P = 0.037; TCSDelta5: 4.11 vs. 3.62, P = 0.044).Shorter duration of AR history before SCIT (<10 vs. >=10 years) resulted in better improvements at the end of the third and fifth years (TCSDelta3: 4.12 vs. 3.13, P = 0.036; TCSDelta5: 3.90 vs. 3.09, P = 0.033). HDM-SCIT was safe and comparable in both children and adults with AR. CONCLUSIONS: Children with AR may achieve better long-term efficacy of HDM-SCIT than adults with AR. PMID- 30479079 TI - Association Between Epithelial Cytokines and Clinical Phenotypes of Elderly Asthma. AB - PURPOSE: Asthma in the elderly has different clinical features including more severe phenotypes with higher comorbidities. Epithelial cells are known to initiate innate/adaptive immune responses in asthmatic airways. We investigated clinical features and epithelial derived cytokine levels in elderly asthmatics compared to non-elderly asthmatics in a cross-sectional cohort of adult asthmatics in order to further understand its pathogenic mechanisms. METHODS: A total of 1,452 adult asthmatics were enrolled from a single tertiary hospital and were classified into 2 groups: 234 elderly (>= 60 years at initial diagnosis) and 1,218 non-elderly (< 60 years at initial diagnosis) asthmatics. Asthma-related clinical parameters were compared between the 2 groups. Serum levels of epithelial cell-derived cytokines including interleukin (IL)-31, IL-33, IL-8, eotaxin-2, transforming growth factor beta 1 (TGF-beta1) and periostin were measured by enzyme-linked immunosorbent assay. RESULTS: Significantly higher prevalence rates of late-onset asthma (onset age >= 40 years) and severe asthma, as well as the lower rate of atopy, blood/sputum eosinophil counts, total immunoglobulin E and eosinophil cationic protein levels were noted in elderly asthmatics compared to non-elderly asthmatics (P < 0.05, respectively). The forced expiratory volume in 1 second (FEV1, % predicted) level tended to be lower in elderly asthmatics (P = 0.07). In addition, serum IL-33 and IL-31 levels were significantly lower in elderly asthmatics, while no differences were found in the serum level of IL-8, eotaxin-2, TGF-beta1 or periostin. Among elderly asthmatics, subjects with severe asthma had lower FEV1 (% predicted) value, but showed significantly higher serum levels of eotaxin-2 and TGF-beta1, than those with non severe asthma (P < 0.05 for each). CONCLUSIONS: These findings suggest that age related changes of epithelial cell-derived cytokines may affect clinical phenotypes and severity of elderly asthma: decreased levels of IL-33 and IL-31 may contribute to less Th2 phenotype, while increased levels of eotaxin-2 and TGF beta1 may contribute to severity. PMID- 30479080 TI - Prevalence and Clinical Features of Drug Reactions With Eosinophilia and Systemic Symptoms Syndrome Caused by Antituberculosis Drugs: A Retrospective Cohort Study. AB - PURPOSE: Although there have been reported cases of drug reactions with eosinophilia and systemic symptoms (DRESS) syndrome caused by antituberculosis drugs, there has been no research to examine its prevalence. This study assessed the prevalence and clinical characteristics of DRESS syndrome caused by antituberculosis drugs. METHODS: The electronic medical records of a cohort consisting of adult patients diagnosed with tuberculosis between July 2006 and June 2010 were reviewed and retrospectively inspected. We searched the surveillance system for adverse drug reactions and the electronic medical records to identify patients who reported severe cutaneous adverse reactions to antituberculosis drugs. These patients were then re-assessed using a European Registry of Severe Cutaneous Adverse Reactions to Drugs and Collection of Biological Samples (RegiSCAR) scoring system. Clinical characteristics, including the symptoms and latency of DRESS syndrome, the therapeutic dosage and period of steroids, and the final duration of tuberculosis therapy, were examined. RESULTS: Of the 1,253 adult patients with tuberculosis receiving antituberculosis drugs, 15 were identified as potential cases of DRESS syndrome (prevalence of 1.2%). Ethambutol was the most frequently used drug (53.5%), followed by rifampicin (26.7%), pyrazinamide (20.0%), streptomycin (13.3%), and isoniazid (6.7%). The median latency after day 1 of antituberculosis medication was 42 days. The median daily dose of steroids, expressed in prednisone-equivalent units, was 33-mg/day, and the median dosing period was 14 days. The duration of tuberculosis treatment was 76 days longer than the standard treatment period of 180 days. There was a significant difference in the peak eosinophil counts of DRESS syndrome patients according to RegiSCAR scores. Moreover, there was a significant quantitative correlation between the RegiSCAR score and peak eosinophil count. A negative correlation was also found between the RegiSCAR score and latency. CONCLUSIONS: This study confirmed the prevalence of DRESS syndrome in a cohort of adult patients with tuberculosis. PMID- 30479081 TI - Different Biological Pathways Are Up-regulated in the Elderly With Asthma: Sputum Transcriptomic Analysis. AB - BACKGROUND: Elderly asthma (EA) is increasing, but the pathogenesis is unclear. This study aimed to identify EA-related biological pathways by analyzing genome wide gene expression profiles in sputum cells. METHODS: A total of 3,156 gene probes with significantly differential expressions between EA and healthy elderly controls were used for a hierarchical clustering of genes to identify gene clusters. Gene set enrichment analysis provided biological information, with replication from Gene Expression Omnibus expression profiles. RESULTS: Fifty-five EA patients and 10 elderly control subjects were enrolled. Two distinct gene clusters were found. Cluster 1 (n = 35) showed a lower eosinophil proportion in sputum and less severe airway obstruction compared to cluster 2 (n = 20). The replication data set also identified 2 gene clusters (clusters 1' and 2'). Among 5 gene sets significantly enriched in cluster 1 and 3 gene sets significantly enriched in cluster 2, we confirmed that 2 were significantly enriched in the replication data set (OXIDATIVE_PHOSPHORYLATION gene set in cluster 1 and EPITHELIAL MESENCHYMAL TRANSITION gene set in cluster 2'). CONCLUSIONS: The findings of 2 distinct gene clusters in EA and different biological pathways in each gene cluster suggest 2 different pathogenesis mechanisms underlying EA. PMID- 30479082 TI - Mugwort Pollen-Related Food Allergy: Lipid Transfer Protein Sensitization and Correlation With the Severity of Allergic Reactions in a Chinese Population. AB - PURPOSE: Little is known about the importance of lipid transfer protein (LTP) sensitization in China. In this study, we investigated the relationship between LTP sensitization and the severity of clinical symptoms in a population of patients with mugwort pollen-related food allergy. METHODS: Food-induced symptoms were evaluated in 148 patients with mugwort pollen allergy by a standardized questionnaire. Specific immunoglobulin E (IgE) to Art v 1, Art v 3, Pru p 3, Ara h 9 and Cor a 8 were quantified by ImmunoCAP. Immunoblotting of peach extracts were performed with sera from peach-allergic patients. RESULTS: In total, 72% (107/148) of the study population experienced food allergy. Forty-eight percent (51/107) of patients with mugwort pollen-related food allergy experienced at least 1 episode of food-induced anaphylaxis. Food allergy correlated with IgE reactivity to Art v 3, but not to Art v 1. Sensitization to Pru p 3, Ara h 9 or Cor a 8 was prevalent (80%, 69 or 63%, respectively) among individuals with food allergy. Food allergic patients with systemic reactions (SR) had higher values for Pru p 3, Ara h 9 and Cor a 8 than patients with oral allergy syndrome (OAS). Furthermore, the strong IgE reactivity detected in immunoblots of peach extracts indicated that Pru p 3 was the major allergen and was more prevalent in patients with SR than in patients with OAS (100% vs. 55%). CONCLUSIONS: LTPs are major food allergens for mugwort pollen-related food allergy in China, and may contribute to SR. PMID- 30479083 TI - Effects of Ser47-Point Mutation on Conformation Structure and Allergenicity of the Allergen of Der p 2, a Major House Dust Mite Allergen. AB - PURPOSE: Hypoallergenic recombinant Der p 2 has been produced by various genetic manipulations, but mutation of a naturally polymorphic amino acid residue known to affect IgE binding has not been studied. This study aimed to determine the effect of a point mutation (S47W) of residue 47 of Der p 2 on its structure and immunoglobulin (Ig) E binding. Its ability to induce pro-inflammatory responses and to induce blocking IgG antibody was also determined. METHODS: S47 of recombinant Der p 2.0110, one of the predominant variants in Bangkok, was mutated to W (S47W). S47W secreted from Pichia pastoris was examined for secondary structure and for the formation of a hydrophobic cavity by 8-Anilino-1 naphthalenesulfonic acid (ANS) staining. Monoclonal and human IgE-antibody binding was determined by enzyme-linked immunosorbent assay. Allergen-induced degranulation by human epsilon receptor expressed-rat basophil was determined. Stimulation of the pro-inflammatory cytokine interleukin (IL)-8 release from human bronchial epithelial (BEAS2B) cells and inhibition of IgE binding to the wild type allergen by S47W-induced IgG were determined. RESULTS: S47W reduced secondary structure and failed to bind the hydrophobic ANS ligand as well as a monoclonal antibody known to be dependent on the nature of the side chain of residue 114 in an adjacent loop. It could also not stimulate IL-8 release from BEAS2B cells. IgE from house dust mite (HDM)-allergic Thais bound S47W with 100 fold weaker avidity, whereas IgE of HDM-allergic Australians did not. S47W still induced basophil degranulation, although requiring higher concentrations for some subjects. Anti-S47W antiserum-immunized mice blocked the binding of human IgE to wild type Der p 2. CONCLUSIONS: The mutant S47W had altered structure and reduced ability to stimulate pro-inflammatory responses and to bind IgE, but retained its ability to induce blocking antibodies. It thus represents a hypoallergen produced by a single mutation of a non-solvent-accessible amino acid. PMID- 30479084 TI - Pollen/Fruit Syndrome: Clinical Relevance of the Cypress Pollen Allergenic Gibberellin-Regulated Protein. AB - A pollen/food-associated syndrome (PFAS) has been described between peach and cypress pollen. Cross-reactive allergens were characterized which belong to the Gibberellin-regulated protein (GRP) family, BP14 in cypress pollen and Pru p 7 in peach. GRP are small cationic protein with anti-microbial properties. A patient suffering from a peach/cypress syndrome was explored clinically and biologically using 2 types of immunoglobulin E (IgE) multiarray microchip, immunoblots and a basophil activation test to assess the clinical relevance of various extracts and purified allergens from fruits or cypress pollen. In addition to PR10 sensitization, the patient showed specific IgE to Pru p 7, BP14 and allergen from pomegranate. These last 3 allergens and allergenic sources are able to induce ex vivo basophil activation characterized by the monitoring of the expression of CD63 and CD203c, both cell surface markers correlated with a basophil mediator release. Up to 100% of cells expressed CD203c at 50 ng/mL of BP14 protein. In contrast, snakin-1, a GRP from potato sharing 82% sequence identity with Pru p 7 did not activate patient's basophils. These results strongly suggest that, like Pru p 7, BP14 is a clinically relevant allergenic GRP from pollen. Allergen members of this newly described protein family are good candidates for PFAS where no cross-reactive allergens have been characterized. PMID- 30479085 TI - Significance of elevated SCC-Ag level on tumor recurrence and patient survival in patients with squamous-cell carcinoma of uterine cervix following definitive chemoradiotherapy: a multi-institutional analysis. AB - OBJECTIVE: There is no definitive guideline for the significance and cut-off value of squamous-cell carcinoma antigen (SCC-Ag) in cervical cancer. Thus, we analyzed the significance and optimal cut-off value of SCC-Ag for predicting tumor recurrence and patient survival in squamous-cell carcinoma of uterine cervix. METHODS: From January 2010 to October 2016, we enrolled 304 cervical cancer patients with squamous-cell carcinoma staging International Federation of Gynecology and Obstetrics (FIGO) Ib-IVa and treated with definitive chemoradiotherapy (CRT) followed by intra-cavitary radiotherapy (ICR). The cut off value of SCC-Ag level for tumor recurrence was calculated using the receiver operating characteristic (ROC) curve. The recurrence-free survival (RFS) and overall survival (OS) were assessed using Kaplan-Meier method to estimate the significance of SCC-Ag level. RESULTS: The optimal cut-off value of SCC-Ag level for predicting tumor recurrence was calculated and set at 4.0 ng/mL in the ROC curve. After a median follow-up period of 36.5 months, the 3-year RFS (56.6% vs. 80.2%, p<0.001) and OS (72.1% vs. 86.8%, p=0.005) were significantly lower in SCC Ag >=4 ng/mL arm than in <4 ng/mL arm. The 3-year locoregional recurrence (17.6% vs. 7.0%, p=0.012), distant metastasis (20.4% vs. 6.9%, p=0.002), and para-aortic recurrence (9.4% vs. 2.1%, p=0.012) rates were significantly higher in SCC-Ag >=4 ng/mL arm than in SCC-Ag <4 ng/mL arm. CONCLUSION: Pre-treatment SCC-Ag level higher than 4 ng/mL may be a useful predictor of tumor recurrence in patients with squamous-cell carcinoma of uterine cervix treated with definitive CRT and ICR. PMID- 30479086 TI - Factors influencing decision-making around opportunistic salpingectomy: a nationwide survey. AB - OBJECTIVE: To explore current practice and influencing factors on adoption of the opportunistic salpingectomy (OS), particularly regarding the decision making, to eventually enhance the development and implementation of clear guidelines. METHODS: This nationwide cross-sectional survey study was conducted in all hospitals in the Netherlands. An anonymous online survey was sent to gynecologists with special interest in gynecological oncology, gynecological endoscopy or urogynecology and all Dutch gynecology trainees. The survey mainly focused on current practice regarding OS and identification of influencing factors on the level of innovation, organization, healthcare professional and individual patient. RESULTS: The response rate was 348 out of 597 gynecologists (58.3%) and 142 out of 340 trainees (41.8%). Current practice of discussing and performing the OS varied widely, with ovarian cancer (OC) risk reduction as most important supportive factor on innovation level. Supportive factors on the level of organization and healthcare provider were; working in a non-training hospital, knowledge of current literature and extensive work experience (in years and annual number of hysterectomies). On individual patient level, a vaginal approach of hysterectomy, negative family history for OC and the presence of firm adhesions were suppressive factors for the OS. CONCLUSION: In this study we evaluated the current practice regarding the opportunistic salpingectomy in the Netherlands and identified influencing factors on different levels to raise awareness and attribute to development of a targeted implementation strategy, on both national and international level. PMID- 30479087 TI - Incorporation of paclitaxel-based hyperthermic intraperitoneal chemotherapy in patients with advanced-stage ovarian cancer treated with neoadjuvant chemotherapy followed by interval debulking surgery: a protocol-based pilot study. AB - OBJECTIVES: We conducted a protocol-based cohort study to evaluate the outcomes of interval debulking surgery (IDS) followed by paclitaxel-based hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of advanced-stage ovarian cancer. METHODS: From October 2015 to May 2018, 65 patients with stages IIIC-IV ovarian cancer were treated according to the study protocol. HIPEC was performed with paclitaxel (175 mg/m2) for 90 minutes, only in cases of optimal cytoreduction. RESULTS: Of 65 patients, 40 (61.5%) patients underwent neoadjuvant chemotherapy (NAC), 34 (52.3%) patients had a high tumor burden with a Fagotti score >=8 at diagnostic laparoscopy, and 6 (9.2%) had definite stage IV metastasis and/or poor performance status before NAC. Twenty-seven (41.5%) patients underwent IDS followed by HIPEC. The mean duration of IDS with HIPEC was 543.8 (range, 277.0-915.0) minutes. Grade III/IV perioperative complications occurred in 7.4% (n=2)/3.7% (n=1) of patients and no cases of mortality were reported within 30 days postoperatively. The median progression-free survival was 21.3 months, and the median overall survival was not reached for those who received HIPEC. CONCLUSIONS: According to our study protocol, IDS followed by paclitaxel-based HIPEC as a first-line treatment appears to be feasible and safe for the treatment of advanced-stage ovarian cancer. Further evaluations of this procedure are required to assess its survival benefits. PMID- 30479088 TI - The detrimental effect of adopting interval debulking surgery in advanced stage low-grade serous ovarian cancer. AB - OBJECTIVE: To examine outcomes of patients having treatments for newly diagnosed advanced stage low-grade serous ovarian cancer (LGSC). METHODS: We conducted a retrospective case series of women affected by advanced stage (stage IIIB or more) LGSC undergoing surgery in a single oncologic center between January 2000 and December 2017. Survival outcomes were assessed using Kaplan-Meier and Cox models. RESULTS: Data of 72 patients were retrieved. Primary cytoreductive surgery was attempted in 68 (94.4%) patients: 19 (27.9%) had residual disease (RD) >1 cm after primary surgery. Interval debulking surgery (IDS) was attempted in 15 of these 19 (78.9%) patients and the remaining 4 patients having not primary debulking surgery. Twelve out of 19 (63.1%) patients having IDS had RD. After a mean (+/-standard deviation) follow-up was 61.6 (+/-37.2) months, 50 (69.4%) and 22 (30.5%) patients recurred and died of disease, respectively. Via multivariate analysis, non-optimal cytoreduction (hazard ratio [HR]=2.79; 95% confidence interval [CI]=1.16-6.70; p=0.021) and International Federation of Obstetrics and Gynecologists (FIGO) stage IV (HR=3.15; 95% CI=1.29-7.66; p=0.011) were associated with worse disease-free survival. Via multivariate analysis, absence of significant comorbidities (HR=0.56; 95% CI=0.29-1.10; p=0.093) and primary instead of IDS (HR=2.95; 95% CI=1.12-7.74; p=0.027) were independently associated with an improved overall survival. CONCLUSION: LGSC is at high risk of early recurrence. However, owing to the indolent nature of the disease, the majority of patients are long-term survivors. Further prospective studies and innovative treatment modalities are warranted to improve patients care. PMID- 30479089 TI - Association of pretreatment thrombocytosis with prognosis in ovarian cancer: a systematic review and meta-analysis. AB - OBJECTIVE: To investigate the association between pre-treatment thrombocytosis and prognosis in patients with ovarian cancer (OC). METHODS: PubMed, EMBASE, and the Cochrane Library were searched for articles regarding the prognosis of OC patients with pre-treatment thrombocytosis by the end of March 2018. Pooled estimates for overall survival (OS) and progression-free survival (PFS) events were calculated as hazard ratios (HRs) either on a fixed or random effect model by Stata 13.0 software. Funnel plot and Egger's test were applied to evaluate publication bias and sensitivity analyses were undertaken to estimate the strength of outcomes. RESULTS: Eleven studies that met the inclusion criteria were enrolled, including a total of 4,953 patients. Pooled results showed that pre-treatment thrombocytosis was significantly associated with OS (HR=1.722; 95% confidence interval [CI]=1.437-2.064) and PFS (HR=1.452; 95% CI=1.323-1.593) in the cohort. Significant correlation was found in OS and PFS between pre-treatment thrombocytosis and both epithelial OC (all stages and differentiation degrees of OC) and advanced epithelial OC (III or IV) by subgroup analyses, which were performed according to publication year, country, case numbers, OC category, International Federation of Gynecology and Obstetrics stage, and cut-off value. However, subgroup analyses indicated no significant correlation between pre treatment thrombocytosis and OS for patients with high-grade serous (poorly differentiated or undifferentiated) OC (HR=1.220; 95% CI=0.946-1.573; p=0.125). Egger's test demonstrated no obvious publication bias in the articles enrolled in this study (OS: p=0.226; PFS: p=0.071). CONCLUSION: Pre-treatment thrombocytosis might be taken as an independent prognostic indicator for patients with OC. PMID- 30479090 TI - The age-adjusted Charlson comorbidity index as a predictor of survival in surgically treated vulvar cancer patients. AB - OBJECTIVE: To evaluate the impact of age-adjusted Charlson comorbidity index (ACCI) in predicting disease-free survival (DFS), overall survival (OS), and cancer-specific survival (CSS) among surgically treated patients with vulvar carcinoma. The secondary aim is to evaluate its impact as a predictor of the pattern of recurrence. METHODS: We retrospectively evaluated data of patients that underwent surgical treatment for vulvar cancer from 1998 to 2016. ACCI at the time of primary surgery was evaluated and patients were classified as low (ACCI 0-1), intermediate (ACCI 2-3), and high risk (>3). DFS, OS and CSS were analyzed using the Kaplan-Meir and the Cox proportional hazard models. Logistic regression model was used to assess predictors of distant and local recurrence. RESULTS: Seventy-eight patients were included in the study. Twelve were classified as low, 36 as intermediate, and 30 as high risk according to their ACCI. Using multivariate analysis, ACCI class was an independent predictor of worse DFS (hazard ratio [HR]=3.04; 95% confidence interval [CI]=1.54-5.99; p<0.001), OS (HR=5.25; 95% CI=1.63-16.89; p=0.005) and CSS (HR=3.79; 95% CI=1.13 12.78; p=0.03). Positive nodal status (odds ratio=8.46; 95% CI=2.13-33.58; p=0.002) was the only parameter correlated with distant recurrence at logistic regression. CONCLUSION: ACCI could be a useful tool in predicting prognosis in surgically treated vulvar cancer patients. Prospective multicenter trials assessing the role of ACCI in vulvar cancer patients are warranted. PMID- 30479091 TI - Prognostic factors of synchronous endometrial and ovarian endometrioid carcinoma. AB - OBJECTIVE: Gynecologists occasionally encounter synchronous endometrial and ovarian endometrioid carcinoma (SEO-EC) patients who show favorable prognosis than locally advanced or metastatic disease patients. This study aimed to elucidate prognostic factors of SEO-EC and identify patients who have a sufficiently low risk of recurrence without receiving adjuvant chemotherapy. METHODS: We retrospectively reviewed 46 patients with pathologically confirmed SEO-EC who underwent surgery at the National Cancer Center Hospital between 1997 and 2016. Immunohistochemical evaluation of DNA mismatch repair (MMR) protein expression were performed for both endometrial and ovarian tumors. Patient outcomes were analyzed according to clinicopathologic factors. RESULTS: From the multivariate analysis, cervical stromal invasion indicated a worse prognosis for progression-free survival (hazard ratio [HR]=6.85; 95% confidence interval [CI]=1.50-31.1) and overall survival (HR=6.95; 95% CI=1.15-41.8). Lymph node metastasis and peritoneal dissemination did not significantly affect survival. MMR deficiency was observed in 13 patients (28.3%), with both endometrial and ovarian tumors showing the same MMR expression status. MMR deficiency was not significantly associated with survival. Of 23 patients with lesions confined to only the uterine body and adnexa, only 2 had recurrence in the group receiving adjuvant therapy, while none of the 10 patients who did not receive adjuvant therapy had recurrence. CONCLUSION: SEO-EC patients with tumors localized to the uterine body and adnexa lesions had a low risk for recurrence and may not require adjuvant therapy. SEO-EC may have prognostic factors different from those of endometrial and ovarian cancer. PMID- 30479092 TI - A novel prediction score for predicting the baseline risk of recurrence of stage I-II endometrial carcinoma. AB - OBJECTIVE: To develop and validate a 3-year recurrence prediction score (RPS) system for predicting the baseline risk of recurrence of stage I-II endometrial carcinoma. METHODS: We reviewed 427 patients with International Federation of Gynecology and Obstetrics staging I-II endometrial carcinoma underwent surgery without any adjuvant therapy from 2005 to 2013. The patients were divided into 2 groups: the test cohort (n=251) comprising those who underwent surgery in odd numbered years, and the validation cohort (n=176) comprising those who underwent surgery in even-numbered years. Multivariate analysis was performed using 7 candidate predictors to identify the risk factors for 3-year recurrence-free interval (RFI) in the test cohort. Each risk factor was scored based on logistic regression analyses of the test data set, and the sum of the risk factor scores was defined as the RPS system. We then applied the system in the validation cohort. RESULTS: Multivariate analysis revealed that the significant risk factors were age >=60 years, pathological type II, positive cervical stromal invasion, and positive peritoneal cytology. In the test cohort, the 3-year RFI rates were 100%, 95.8%, 79.9%, and 33.3% for RPSs of 0, 1, 2, and 3, respectively. In the validation cohort, the 3-year RFI was significantly higher in the low-RPS group (RPS 0 or 1) than in the high-RPS group (RPS 2 or 3) (95.2% vs. 79.9%, p<0.01). CONCLUSIONS: The RPS system shows significant reproducibility for predicting the baseline risk of recurrence. The system could potentially impact the choice of adjuvant therapy for stage I-II endometrial carcinoma. PMID- 30479093 TI - Efficacy and dosimetry analysis of image-guided radioactive 125I seed implantation as salvage treatment for pelvic recurrent cervical cancer after external beam radiotherapy. AB - OBJECTIVE: To investigate the efficacy of image-guided radioactive 125I seed (IGRIS) implantation for pelvic recurrent cervical cancer (PRCC) after external beam radiotherapy (EBRT), and analyze the influence of clinical and dosimetric factors on efficacy. METHODS: From July 2005 to October 2015, 36 patients with PRCC received IGRIS. We evaluated local progression-free survival (LPFS) and overall survival (OS). RESULTS: The median follow up was 11.5 months. The 1- and 2-year LPFS rate was 34.9% and 20%, respectively. The multivariate analysis indicated recurrence site (central or pelvic wall) (hazard ratio [HR]=0.294; 95% confidence interval [CI]=0.121-0.718), lesion volume (HR=2.898; 95% CI=1.139 7.372), D 90 (HR=0.332; 95% CI=0.130-0.850) were the independent factors affecting LPFS. The 1- and 2-year OS rate was 52.0% and 19.6%, respectively. The multivariate analysis suggested pathological type (HR=9.713; 95% CI=2.136-44.176) and recurrence site (HR=0.358; 95% CI=0.136-0.940) were the independent factors affecting OS. The dosimetric parameters of 33 patients mainly included D90 (128.5+/-47.4 Gy), D100 (50.4+/-23.7 Gy) and V100 (86.7%+/-12.9%). When D90 >=105 Gy or D100 >=55 Gy or V100 >=91%, LPFS was extended significantly, but no significant difference for OS. The 79.2% of 24 patients with local pain were suffering from pain downgraded after radioactive 125I seed implantation. CONCLUSION: IGRIS implantation could be a safe and effective salvage treatment for PRCC after EBRT, which could markedly release the pain. Recurrence site, tumor volume and dose were the main factors affected efficacy. Compared with central recurrence, it was more suitable for patients with pelvic wall recurrent cervical cancer after EBRT. PMID- 30479094 TI - Current state and outlook for drug repositioning anticipated in the field of ovarian cancer. AB - Ovarian cancer is the seventh most common cancer and the eighth most common cause of cancer mortality in women. Although standard chemotherapy is the established treatment for ovarian cancer, the prognosis remains poor, and it is highly anticipated that new drugs will be developed. New drugs, such as humanized anti vascular endothelial growth factor monoclonal antibodies and poly ADP-ribose polymerase inhibitors, are expected to improve clinical outcomes of ovarian cancer. However, long-term, costly research is required to develop such new drugs, and soaring national healthcare costs are becoming a concern worldwide. In this social context, drug repositioning, wherein existing drugs are used to develop drugs with new indications for other diseases, has recently gained attention. Because trials have already confirmed the safety in humans and the pharmacokinetics of such drugs, the development period is shorter than the conventional development of a new drug, thereby reducing costs. This review discusses the available basic experimental and clinical data on drugs used for other types of cancer for which drug repositioning is anticipated to repurpose the drug for the treatment of ovarian cancer. These include statins, which are used to treat dyslipidemia; bisphosphonate, which is used to treat osteoporosis; metformin, which is used to treat diabetes; non-steroidal anti-inflammatory drugs; ivermectin, an antiparasitic agent; and itraconazole, an anti-fungal agent. These drugs will play an important role in future drug repositioning strategies for ovarian cancer. Furthermore, drug repositioning is anticipated to extend not only to ovarian cancer treatment but also to ovarian cancer prevention. PMID- 30479095 TI - Optimal cutoff age for predicting prognosis associated with serous epithelial ovarian cancer: what is the best age cutoff? AB - OBJECTIVE: Elderly age is one of the poor prognostic factors in epithelial ovarian cancer (EOC), but the optimal age cut-off is not known. The present study sought to identify the ideal age cutoff that represents a negative prognostic factor in EOC, considering the geriatric assessment. METHODS: Hazard ratios (HRs) with p-values were calculated using all possible age cutoffs with stage, histology, grade, optimality and comorbidities as covariates in multivariate Cox regression model. The trends of p-value and HR by age cutoff were further evaluated in a subgroup of histology and in The Cancer Genome Atlas (TCGA) dataset. In addition, propensity score-matching analysis using the identified age cutoff was performed. RESULTS: An age of 66 years was shown to be the most significant cutoff for defining old age with independent prognostic power (HR=1.45; 95% confidence interval=1.04-2.03; p=0.027). This result was also observed with the analyses of serous histology subgroup and with the analysis of a TCGA dataset with serous EOC. In survival analysis, patients aged >=66 years had significantly worse overall survival compared with younger individuals (56 months vs. 87 months; p=0.006), even following propensity score matching (57 vs. 78 months; p=0.038). CONCLUSION: An age of 66 years is the best cutoff to define elderly age in serous EOC patients considering the geriatric assessment, and this information can be used in the administration of individualized therapies in elderly EOC patients. PMID- 30479096 TI - Serum calcium is a novel parameter to assess metabolic syndrome in endometrial carcinoma. AB - OBJECTIVES: To investigate the distribution of serum calcium and the relationship between serum calcium and serum metabolic parameters in endometrial carcinoma (EC) patients. METHODS: Retrospective assessment of patients diagnosed with endometrial cancer from Peking University People's Hospital from 2004 to 2009. Clinical characteristics as well as pretreatment serum calcium, albumin, fasting plasma glucose (FPG), serum triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and total cholesterol (TC) value were extracted from patient records. Serum calcium was corrected for albumin. Unpaired t test and analysis of covariance were used to compare serum calcium among categorical variables. Simple correlation analyses and partial correlation analyses were used to assess the associations between serum calcium and continuous variables. RESULTS: Two-hundred twenty patients were included in this study. After adjusting for confounders, postmenopausal patients had higher total serum calcium (p=0.002) and albumin-corrected serum calcium (p=0.012) than premenopausal patients, endometrioid endometrial carcinoma (EEC) patients had higher total serum calcium than non-endometrioid endometrial carcinoma (NEEC) patients (p=0.037). Significant positive correlations were found between total serum calcium and FPG (p=0.017), TG (p=0.043), HDL (p=0.042), LDL (p<0.001), and TC (p<0.001) after adjusting for multiple variables, and the corrected serum calcium showed no significant correlation with metabolic parameters. CONCLUSION: Total serum calcium might be a more sensitive parameter for metabolic syndrome in endometrioid endometrial cancer patients than lipids. PMID- 30479097 TI - The prognostic significance of estrogen and progesterone receptors in grade I and II endometrioid endometrial adenocarcinoma: hormone receptors in risk stratification. AB - OBJECTIVES: Although patients with grade I and II endometrioid endometrial adenocarcinoma (EEA) are considered with good prognosis, among them 15%-25% died in 5 years. It is still unknown whether integrating estrogen receptor (ER) and progesterone receptor (PR) into clinical risk stratification can help select high risk patients with grade I-II EEA. This study was to investigate the prognostic value of ER and PR double negativity (ER/PR loss) in grade I-II EEA, and the association between ER/PR loss and The Cancer Genome Atlas (TCGA) classification. METHODS: ER and PR were assessed by immunohistochemistry on hysterectomy specimens of 903 patients with grade I-II EEA. ER and PR negativity were determined when <1% tumor nuclei were stained. Gene expression data were obtained from the TCGA research network. RESULTS: Compared with ER or PR positive patients (n=868), patients with ER/PR loss (n=35) had deeper myometrial infiltration (p=0.012), severer FIGO stage (p=0.004), and higher rate of pelvic lymph node metastasis (p=0.020). In univariate analysis, ER/PR loss correlated with a shorter progression-free survival (PFS; hazard ratio [HR]=5.25; 95% confidence interval [CI]=2.21-12.52) and overall survival (OS; HR=7.59; 95% CI=2.55-22.60). In multivariate analysis, ER/PR loss independently predicted poor PFS (HR=3.77; 95% CI=1.60-10.14) and OS (HR=5.56; 95% CI=1.37-22.55) for all patients, and poor PFS for patients in stage IA (n=695; HR=5.54; 95% CI=1.28-23.89) and stage II-IV (n=129; HR=5.77; 95% CI=1.57-21.27). No association was found between ER/PR loss and TCGA classification. CONCLUSION: Integrating ER/PR evaluation into clinical risk stratification may improve prognosis for grade I-II EEA patients. PMID- 30479098 TI - Peritoneal cancer index in ovarian cancer. PMID- 30479099 TI - Tailoring radicality in early cervical cancer: how far can we go? AB - Today, the patient who is diagnosed with early cervical cancer is offered a variety of treatments apart from standard therapy. Patients can be treated with a less radical hysterectomy (RH) regarding parametrectomy, a trachelectomy either vaginal or abdominal, and this can be performed through a minimal invasive or open procedure. All this in combination with nerve sparing and/or sentinel node technique. Level 1 evidence for the oncological safety of all these modifications is only available from 3 randomized controlled trials (RCTs). Two RCTs on more or less radical parametrectomy both showed that oncological safety was not compromised by doing less radical surgery. Because of the heterogeneity of the patient population and the high frequency of adjuvant radiotherapy, the true impact of surgical radicality cannot be assessed. Regarding the issue of oncological safety of fertility sparing treatments, case-control and retrospective case series suggest that trachelectomy is safe as long as the tumor diameter does not exceed 2 cm. Recently, both a RCT and 2 case-control studies showed a survival benefit for open surgery compared to minimally invasive surgery, whereas many previous case-control and retrospective case series on this subject did not show impaired oncological safety. In a case-control study the survival benefit for open surgery was restricted to the group of patients with a tumor diameter more than 2 cm. Although modifications of the traditional open RH seem safe for tumors with a diameter less than 2 cm, ongoing prospective RCTs and observational studies should give the final answer. PMID- 30479100 TI - Opportunistic salpingectomy in the Netherlands. PMID- 30479101 TI - Challenges of being a hospital nurse manager in the Volta region of Ghana: a qualitative study. AB - AIM: To explore the challenges facing hospital nurse managers (HNMs) in selected hospitals in the Volta region of Ghana. METHOD: The study, which had an exploratory qualitative design, involved the recruitment of 12 HNMs from six public hospitals in the Volta region of Ghana. Purposive sampling was used and data were collected through semi-structured interviews. The conventional content analysis approach was adopted for data analysis. FINDINGS: The study revealed several managerial challenges of being HNMs in performing their roles. These include: a lack of managerial preparedness, clear job descriptions and support; interference by other managers; and inadequate nursing staff and material resources. All these compromised the quality of nursing care. Participants found their role tedious and stressful, but also regard it as an opportunity to learn new ideas. CONCLUSION: HNMs face several challenges that negatively affect their performance. There is a need for succession planning, career development and mentoring programmes to strengthen HNMs' leadership and management skills to help them provide high-quality nursing care. PMID- 30479102 TI - Role of peer support for people with a spinal cord injury. AB - : Spinal cord injuries can result in significant physiological and psychological challenges for patients. Nurses have an important role in the rehabilitation of people with a spinal cord injury, as does the provision of peer support by people who are 'living well' after experiencing a spinal cord injury. AIM: To explore peer support and whether it can have an effective role in a multidisciplinary team approach to supporting a patient with a spinal cord injury. METHOD: This was an independent evaluation that used an online survey, a focus group and telephone interviews to elicit the views of respondents about the Spinal Injury Association (SIA) peer support service in England and Wales. There were four groups of respondents: people with a spinal cord injury; their family and friends; peer support officers; and nurse specialists and other healthcare practitioners. FINDINGS: It was identified that peer support officers were valued for their ability to provide a positive role model for people with a spinal cord injury. Healthcare practitioners involved in the care of people with a spinal cord injury also appreciated the training and support they received from peer support officers. CONCLUSION: This evaluation demonstrated that peer support officers were regarded as an important element of a multidisciplinary team approach to managing the care of those who had experienced a spinal cord injury. Peer support officers were also considered a valuable source of information and education, particularly for healthcare practitioners working in settings where spinal cord injury was not a common presentation. PMID- 30479103 TI - ? AB - Incidence of cancer recti (CR)in Ukraine constitutes 38 in 100 thousands of population.There are two main trends in surgical treatment of precancerous states and early stageCR: radical rectal resection and local transanal excision of the affection zone. After asingle-port procedure introduction into laparoscopic surgery the alternative method ofrectal tumors resection have had evolved - a transanal minimally invasive surgery withsingle-port (TAMIS). In the clinic the TAMIS procedure was applied in 3 patients foradenomatous rectal polyps. Operative intervention was done using transanal videoen'doscopic excision of villous rectal tumor. First experience of application of TAMIS wit'nessed the method efficacy, its relatively low cost and low risk of complications occur'rence. Application of this adopted procedure contributes for improvement of the treat'ment results in rectal tumors. PMID- 30479104 TI - ? AB - Immediate and late results of the combined gastrectomy (CG) performance in 719patients, suffering locally-spread gastric cancer (LSGC), were analyzed. Additionalresection of adjacent organs was performed in 165 observations. In early postoperativeperiod complications in 116 (16.1%) patients have had occurred, including surgicalcomplications - in 77.7%, and nonsurgical - in 22.3%. Lethality in 30 postoperativedays have constituted 11.1%. The patients' postoperative life time was at average (22.9+/- 1.67) mo, mediana- 9.3 mo; indices of 3-year and 5-year survival - (18.9 +/- 1.72)and (12.9 +/- 1.51)%,accordingly. Essential difference in favor of subtotal distal gastricresection was established, basing on comparison data between this procedure and CG.The data obtained witnessed the expediency of combined operative interventions, whathave had widened possibilities of the patients' radical treatment for LSGC. PMID- 30479105 TI - ? AB - Detailed statistic alanalysis of the treatment results in patients, who have had sufferedgastroduodenal ulcer hemorrhage, in The Gastro-Intestinal Hemorrhage Centre, wasperformed. Application of exteriorization procedure, using original method of doublesticking and out sticking of the needle bilaterally from ulcerative defect, for duodenalulcer, complicated by hemorrhage, have had guaranteed mechanical squeezing of theperiulcer zone vessels and effective removal of the ulcer out side the gut lumen. Thishave had promoted improvement of the patients' treatment results. PMID- 30479107 TI - ? AB - Results of examination and treatment in 256 patients, suffering an acute ileus (AI), wereanalyzed. Differentiation-diagnostic program was elaborated, what have permitted toestablish a correct diagnosis in 98.4% patients. Higher informativity of ultrasonograph'ic investigation, permitting to verify the diagnosis on early stage of the disease and toestimate conservative treatment efficacy, accordingly, in 94.4 and 87.8% patients, wasestablished while doing comparative analysis of ultrasonographic and radiological diag'nostic methods. PMID- 30479106 TI - ? AB - The covered perforation of gastroduodenal ulcer constitutes certain difficulties in diag'nosis, causing distortion of clinical symptoms. The diagnosis is usually established withdelay. In the clinic during 7 years in 24 patients the covered perforative aperture of gas'troduodenal ulcer was revealed, constituting 6.8% of total number of perforative ulcers.Pneumoperitoneum was not established. After pneumogastroscopy in 3 patients with afree gas revealed, they were operated on. After analyzing of dynamics in rest of patientstheir state degradation and the peritoneal symptoms occurrence was noted, what havehad demanded performance of operative intervention. Lethality was 4.1%. PMID- 30479108 TI - ? AB - The investigation objective was to estimate the peritoneal adhesions formation risk inchildren with phenotypic signs of the connective tissues dysplasia (CTD-syndrome).On the first stage the formalized phenotypic clinical signs were estimated in accor'dance to chi2 Pearson criteria (p<0.05). On the second stage a prognostic value of genet'ic polymorphism of N-arylacetyltransferase-2 (NAT2) gene for determination of riskfor the occurrence of postoperative adhesive process in abdominal cavity, using themethod of allele-specific amplification of NAT2 allele with the help of polymerase chainreaction (PCR), was determined. In accordance to results of investigation, obtained inchildren with CTD-syndrome a genetic polymorphism NAT2 was revealed rather morefrequently, responsible for "rapid acetylation", they constitute the risk group for theadhesion ileus occurrence, in them complex prophylactic measure must be undertak'en, beginning from intraoperative stage. PMID- 30479109 TI - ? AB - Lethality, morbidity, survival indices and metabolic consequences of total pancreatec'tomy (TP), performed in patients, suffering pancreatic tumors, were analyzed. Therewere retrospectively analyzed 35 TP operations, including 5- urgent, 30 - elective,performed in a single center. General lethality have constituted 20% (7 patients died),and after elective TP - 6.7% (2 died). Complications rate after elective TP have consti'tuted 40%; survival mediana-18 mo; indices of a 3-year survival - 40%, and a 5-year one - 13.3%. Most frequently revealed metabolic changes after TP - pancreaticexocrine insufficiency, pancreatogenic diabetes, changes in a lipid metabolism inhepatocytes. Our experience witnesses expediency of TP introduction into surgicalpractice in specialized centers of Ukraine with results, which are matching a worldwide. PMID- 30479110 TI - ? AB - Examination and treatment of 70 patients, suffering an acute necrotic pancreatitits, wasconducted. Content of presepsin, procalcitonin, S-reactive protein and interleukin-6(IL-6) in the patients' blood plasma was determined, and bacteriological investiga'tions, contrast-enhanced CT were conducted as well. Positive results of bacteriologi'cal investigations were noted in 43 patients. Level of presepsin and procalcitonin inpatients, suffering purulent-septic complications, in 3 - 4 times exceeded such in asterile pancreonecrosis. Presersin level,exceeding over 632 pg/ml, have permitted toconfirm the presence of local and systemic infection with high specificity and sensitivi'ty, and this have exceeded diagnostic possibilities of the procalcitonin content determi'nation. High level of IL-6 and S-reactive protein is characteristic for the systemicinflammatory response syndrome (SIRS) of infective and noninfective origin. PMID- 30479111 TI - ? AB - Analyzed the results of surgical treatment of 132 patients, including 68 - for cancer ofthe pancreatic head (in 46 - with jaundice) and 64 - chronic pancreatitis (CP) with aprimary lesion of the pancreatic head (16 - with jaundice). The distribution of patientsinto groups was carried out with a maximum value of classification functions calculatedby special formulas. Next studied indicators of endothelial dysfunction for differentialdiagnosis. A certain threshold of VEGF = 346 pg / ml, in which the patients were divid'ed into groups: SP and cancer on the pancreatic head. It was even more accurate indi'cator threshold VEGF = 248 pg / ml. To predict the severity of the pathological process,along with the use of diagnostic data, using the method of classification trees.Pancreatoduodenal resection for Whipple was performed in 23 patients, for Traverso-Longmire - in 8, subtotal right sided pancreatectomy for Fortner - in 3, hepaticoje'junostomy by Roux - in 8, duodenopreserving resection for Beger - in 6, her Berneseoption - in 7, operation Frey - in 51. In 26 (19.7%) patients, minimally invasive inter'vention for removal of bile were spread through the final primary pathological processand severe general state. Postoperative complications occurred in 18 (13.6%) patients,died 3 (2.3%). PMID- 30479112 TI - ? AB - The investigation objective was to improve the immediate results of surgical treatmentof the aortal valve failure, applying minimization of operative trauma and, accordingly,rapid functional rehabilitation of patients. The aortal valve prosthesis, using minimallyinvasive access, was conducted in 44 patients. There was proved, that conduction ofministernotomy for strict indications is effective and have significant advantages, com'paring with classic median sternotomy, because it provides minimal surgical trauma,preservation of the thoracic cage frame, and better cosmetic effect. PMID- 30479113 TI - ? AB - Impact of the autologous cells transplantation in complex of treatment of complicatedarterial form of thoracic outlet syndrome was estimated. In accordance to the proce'dure proposed 18 patients were operated on, in 16 patients a standard decompressiveand reconstructive operative interventions were performed. The proposed procedureapplication have promoted improvement of the patients' treatment results due to opti'mization of microcirculation and angiogenesis. PMID- 30479114 TI - ? AB - Results of treatment of 71 patients, suffering an acute idiopathic deep veins thrombo'sis (DVT) of lower extremities,were analyzed. In 32 (45.1%) patients rivaroxaban wasapplied, in 39 (54.9%) - varfarin. The term of anticoagulant therapy was determined inaccordance to the D-dimers level. Recurrence of the DVT, of massive hemorrhage orpulmonary thromboembolism in the follow-up groups were absent. In 29 (74.4%)patientsa constant dose of varfarin was lined up during minimal recommended period.For reduction of the DVT occurrence risk a rivaroxaban may serve as an alternative tovarfarin. PMID- 30479115 TI - ? AB - Dynamical sonoelastography with technology of acoustic radiation force imaging (ARFI)and estimation of the shear wave elastography(SWE) were applied in 78 patients, suf'fering venous thrombosis (VTH), while presence of floating proximal part of thrombus.Empirical border index SWE is adduced, its value constitutes 2.5 m/s. Basing on theinvestigations results data, three categories of the VTH embologenic risk were estab'lished: high (SWE up to 2 m/s), middle (SWE 2 - 3 m/s), low (SWE over 3 m/s), whatpredicts the treatment tactics. Dynamical sonoelastography with ARFI technology andthe SWE estimation permits to reveal embologenic forms of VTH objectively and tochoose adequate tactics of the patients' treatment. PMID- 30479116 TI - ? AB - Retrospective analysis of the multispiral computer tomography results was conductedin 52 children, suffering portal hypertension (PH). Three types (A, V, S) of thesplenomesenterial confluence (SMC) structure were delineated. Basing on anatomicalpeculiarities of SMC, possibility of the mesocaval shunting (MCSH) performance inaccordance to procedures of side-to-side or of a N-like MCSH (N-MCSH) in aSMC types A and S is nearly similar; in a SMC types V the possibility of N- MCSH per'formance is exceeding that of MCSH in a side-to-side fashion. Decompression prop'erties and changes in portohepatic perfusion (PHP) after application of MCSH in vari'ous SMC types were analyzed. The greatest decompression and preservation of PHP inSMC types V and S were achieved after performance of MCSH in a side-to-side fash'ion. In a SMC type A the essential difference of these indices in various kinds of MCSHwas not observed. PMID- 30479117 TI - ? AB - Results of treatment of 276 patients, suffering the lower renalis calyx (LRC) calculi, hav'ing size (1.14 +/- 0.35) sm, were analyzed. Depending on acuteness of infundibulo-pelvic angle (IPA) the examined persons were divided on groups with blunt (n=118) andacute (n=158) IPA; 8 anatomic parameters of the LRC were in total determined. Therewas established, that extracorporal shock-wave lithotripsy, in accordance to the cal'culated index of a LRC calculis elimination, is expedient to apply in a bigger IPA, lesserinfundibulo-lumbar angle, lesser length of the LRC neck; transcutaneousnephrolithotripsy is effective not depending from a calculi dimensions, length of theLRC neck, value of IPA and infundibulo-lumbar angle. PMID- 30479118 TI - Electrically and optically tunable responses in graphene/ transition metal dichalcogenide heterostructures. AB - Heterostructures involving layered two dimensional (2D) transitional metal dichalcogenides (TMDCs) are not only fundamentally interesting to explore emerging properties at atomically thin limit, but also technically important to achieve novel optoelectronic devices. However, achieving tunable optoelectronic properties and clarifying interlayer processes (charge transfer, energy transfer) in 2D heterostructures remain to be part of the key challenges so far. Here, by fabricating heterostructures of graphene and monolayer TMDCs (n-type MoS2 and p type WSe2), we demonstrate both electrically and optically tunable response from the heterostructure, revealing the critical interface process between graphene and TMDCs. In MoS2/graphene heterostructure, electron transfer from MoS2 to graphene is observed and gate-tunable interface relaxation induces the electrically controlled photoluminescence (PL). While in WSe2/graphene heterostructure, gate tunable electron transfer from graphene to WSe2 is observed and the PL is tuned by carrier density, which can be controlled by the gate voltage. The interlayer process can also be modulated by laser intensity, which enables photo-induced doping on graphene and optically tunable electrical characteristics of graphene. Combining the tunable Fermi level of graphene and strong light-matter interaction of monolayer TMDCs, our demonstrations are important to the design of multifunctional and efficient optoelectronic devices with graphene/TMDCs heterostructures. PMID- 30479119 TI - Persulfate activation on crystallographic manganese oxides: Mechanism of singlet oxygen evolution for nonradical selective degradation of aqueous contaminants. AB - Minerals and transitional metal oxides of earth-abundant elements are desirable catalysts for in situ chemical oxidation in environmental remediation. However, catalytic activation of peroxydisulfate (PDS) by manganese oxides was barely investigated. In this study, one-dimension manganese dioxides (alpha- and beta MnO2) were discovered as effective PDS activators among the diverse manganese oxides for selective degradation of organic contaminants. Compared with other chemical states and crystallographic structures of manganese oxide, beta-MnO2 nanorods exhibited the highest phenol degradation rate (0.044 min-1, 180 min) by activating PDS. A comprehensive study was conducted utilizing electron paramagnetic resonance, chemical probes, radical scavengers, and different solvents to identity the reactive oxygen species (ROS). Singlet oxygen (1O2) was unveiled to be the primary ROS, which was generated by direct oxidation or recombination of superoxide ions and radicals from a metastable manganese intermediate at neutral pH. The study dedicates to the first mechanistic study into PDS activation over manganese oxides and provides a novel catalytic system for selective removal of organic contaminants in wastewater. PMID- 30479120 TI - Long-Circulating Amphiphilic Doxorubicin for Tumor Mitochondria-Specific Targeting. AB - The mitochondria have emerged as a novel target for cancer chemotherapy primarily due to their central roles in energy metabolism and apoptosis regulation. Here we report a new molecular approach to achieve high levels of tumor- and mitochondria selective delivery of the anticancer drug doxorubicin. This is achieved by molecular engineering which functionalizes doxorubicin with a hydrophobic lipid tail conju-gated by a solubility-promoting polyethylene glycol polymer (amphiphilic Doxorubicin or amph-DOX). In vivo, the amphiphile conjugated to doxorubicin exhibits a dual function: i) it binds avidly to serum albumin and hijacks albumin's circulating and transporting pathways, resulting in prolonged circulation in blood, increased accumulation in tumor, and reduced exposure to the heart; ii) it also redirects doxorubicin to mi-tochondria by altering the drug molecule's intracellular sorting and transportation routes. Efficient mito chondrial targeting with amph-DOX causes a significant increase of reactive oxygen species (ROS) levels in tumor cells, resulting in markedly improved antitumor efficacy than the unmodified doxorubicin. Am-phiphilic modification provides a simple strategy to simultaneously increase the efficacy and safety of doxorubicin in cancer chemotherapy. PMID- 30479121 TI - MALDI-MSI of Immunotherapy: Mapping the EGFR-Targeting Antibody Cetuximab in 3D Colon Cancer Cell Cultures. AB - Immunotherapies are treatments that use a patient's immune system to combat disease. One important type of immunotherapy employed in cancer treatments is the delivery of monoclonal antibodies to block growth receptors. In this manuscript, we develop a methodology that enables accurate and simple evaluation of antibody type drug delivery using MALDI-MSI. To overcome the mass range limitation that prevents the detection of large therapeutic antibodies, we used in situ reduction and alkylation to break disulfide bonds to generate smaller fragments. These smaller fragments are more readily ionized and detected by MALDI-MSI without losing spatial information of the parent drug. As a proof of concept study, we evaluated the distribution of cetuximab in 3D colon cell cultures. Cetuximab is a monoclonal antibody that binds to the extracellular domain of epidermal growth factor receptor (EGFR), which is often overexpressed in colorectal cancer (CRC) and mediates cell differentiation, proliferation, migration, and angiogenesis. Cetuximab directly inhibits tumor growth and metastasis, and induces apoptosis. By performing on-tissue reduction followed by MALDI-MSI analysis, we successfully mapped the time-dependent penetration and distribution of cetuximab in spheroids derived from two different colon cancer cell lines (HT-29 and DLD-1). The localization patterns were further confirmed with IF staining of the drug. Changes in other biomolecules following drug treatment were also observed including the elevation of ATP in spheroids. The developed method was also been applied to map cetuximab distribution in patient-derived colorectal tumor organoids (CTOs). Overall, we believe this powerful label-free approach will be useful to visualize the heterogeneous distribution of antibody drugs in tissues and tumors, and help to monitor and optimize their use in the clinic. PMID- 30479122 TI - QM-Mechanism-Based Hierarchical High-Throughput in silico Screening Catalyst Design for Ammonia Synthesis. AB - We propose and test a hierarchical high-throughput screening (HHTS) approach to catalyst design for complex catalytic reaction systems that is based on quantum mechanics (QM) derived full reaction networks with QM rate constants, but simplified to examine only the reaction steps likely to be rate-determining. We illustrate this approach by applying it to determine the optimum dopants (our of 35 candidates) to improve the turn-over-frequency (TOF) for the Fe-based Haber Bosch ammonia-synthesis process. We start from the QM-based free-energy reaction network for this reaction over Fe(111) which contains the 26 most important surface configurations and 17 transition states at operating conditions of temperature and pressure, from which we select the key reaction steps that might become rate-determining for the alloy. These are arranged hierarchically by decreasing free-energy reaction barriers. We then extract from the full reaction network a reduced set of reaction rates required to quickly predict the effect of the catalyst changes on each barrier. This allows us to test new candidates with only 1% of the effort for a full calculation. Thus we were able to quickly screen 34 candidate dopants to select a small subset (Rh, Pt, Pd, Cu) that satisfy all criteria, including stability. Then from these four candidates expected to increase the TOF for NH3 production, we selected the best candidate (Rh) for a more complete free-energy and kinetic analysis (10 times the effort for HHTS but still 10% of the effort for a complete analysis of the full reaction network). We predict that Rh doping of Fe will increase the TOF for NH3 synthesis by a factor of ~3.3 times compared to Fe(111), in excellent agreement with our HHTS predictions, validating this approach. PMID- 30479123 TI - Ambimodal Dipolar/Diels-Alder Cycloaddition Transition States Involving Proton Transfers. AB - Quantum mechanical computations and molecular dynamics simulations have been used to elucidate the factors that control reaction outcomes in ambimodal transition states leading to both dipolar and Diels-Alder cycloaddition products, which can interconvert via alpha-ketol rearrangements. The dipolar cycloaddition pathways were found to be disadvantaged due to the persistence of charge separation after the second C-C formation en route to the dipolar cycloaddition adducts. Structural modifications that result in the stabilization of the charge-separated species lead to an increase in the amount of dipolar cycloadducts formed. PMID- 30479124 TI - Mapping the Substrate Recognition Pathway in Cytochrome P450. AB - Cytochrome P450s are ubiquitous metalloenzymes involved in the metabolism and detoxification of foreign components via catalysis of the hydroxylation reactions of a vast array of organic substrates. However, the mechanism underlying the pharmaceutically critical process of substrate access to the catalytic center of cytochrome P450 is a long standing puzzle, further complicated by the crystallographic evidences of closed catalytic center in both substrate-free and substrate-bound cytochrome P450. Here we address a crucial question whether the conformational heterogeneity prevalent in cytochrome P450 translates to heterogeneous pathways for substrate access to the catalytic center of this metalloenzymes. By atomistically capturing the full process of spontaneous substrate association from bulk solvent to the occluded catalytic center of an archetypal system P450cam in multi-microsecond-long continuous unbiased molecular dynamics simulations, we here demonstrate that the substrate recognition in P450cam always occurs through a single well-defined dominant pathway. The simulated final bound pose resulting from these unguided simulations is in striking resemblance with crystallographic bound pose. Each individual binding trajectory reveals that the substrate, initially placed at random location in bulk solvent, spontaneously lands on a single key channel on protein-surface of P450cam and resides there for an uncharacteristically long period, before correctly identifying the occluded target-binding cavity. Surprisingly, the passage of substrate to the closed catalytic center is not accompanied by any large-scale opening in protein. Rather, the unbiased simulated trajectories (~57 microsecond) and underlying Markov state model, in combination with free-energy analysis, unequivocally show that the substrate recognition process in P450cam needs a substrate-induced side-chain displacement coupled with a complex array of dynamical interconversions of multiple metastable substrate conformations. Further, the work reconciles multiple precedent experimental and theoretical observations on P450cam and establishes a comprehensive view of substrate recognition in cytochrome P450 that only occurs via substrate-induced structural rearrangements. PMID- 30479125 TI - Aqueous synthesis of lead halide perovskite nanocrystals with high water stability and bright photoluminescence. AB - Lead halide perovskites nanocrystals (NCs) have attracted intense attentions because of their excellent optoelectronic properties. The ionic nature of halide perovskites makes them highly vulnerable to water. Encapsulation of perovskite NCs with inorganic or organic materials have been reported to enhance the stability, however they often suffer from large aggregation size, low water solubility and difficulty for further surface functionalization. Here, we report a facile aqueous process to synthesize water-soluble CsPbBr3/Cs4PbBr6 NCs with the assistance of fluorocarbon agent, which features a novel mechanism of the perovskite crystallization at oil/water interface and direct perovskite NCs/fluorocarbon agent self-assembly in aqueous environment. The products exhibit a high absolute photoluminescence quantum yield (PLQY) of ~80% in water with the photoluminescence lasting for weeks. Through successive ionic layer adsorption and reaction (SILAR), BaSO4 was further applied to encapsulate the NCs, and greatly enhanced their stability in phosphate buffered saline solutions. The high stability in water and saline solution, high PLQY and tunable emission wavelength, together with the successful demonstration of brain tissue labelling and photoluminescence under X-ray excitation, make our perovskite NCs a promising choice for X-ray fluorescent bio-labels. PMID- 30479126 TI - Designing Lithium-sulfur Batteries with High-loading Cathodes at a Lean Electrolyte condition. AB - Developing lithium-sulfur cells with a high-loading cathode at a lean-electrolyte condition is the key to bringing the lithium-sulfur technology into the energy storage market. However, it has proven extremely challenging to develop a cell that simultaneously satisfies the above-mentioned metrics while also displaying high electrochemical efficiency and stability. Here, we present a concept of constructing a conductive cathode substrate with a low surface area and optimized nanoporosity (i.e., limited micropores in the porous matrix) that enables achieving a high sulfur loading of 13 mg cm-2 and a high sulfur content of 75 wt.% with an extremely low electrolyte/sulfur ratio of just 4.0 MUL mg-1. The high-loading nanocomposite cathodes demonstrate high areal capacities of 9.3 mAh cm-2, high energy densities of 18.6 mWh cm-2, and superior cyclability with excellent capacity retention of 85% after 200 cycles. These values are higher than the benchmarks set up for developing future commercial lithium-sulfur cells (i.e., areal capacity of > 2 - 4 mAh cm-2, energy density of > 8 - 13 mWh cm-2, and a long cycle life of 200 cycles with a capacity retention of 80%). The cathode design further exhibits high rate capability from C/20 to 1C rates and great potential to attain ultrahigh sulfur loading and content of 17 mg cm-2 and 80 wt.%. The key nanostructural feature that enables realizing fast charge transport is the low surface area and limited microporosity that avoid the fast consumption of the electrolyte during cell cycling. PMID- 30479127 TI - Chalcopyrite ZnSnSb2: A Promising Thermoelectric Material. AB - Ternary compounds with a tetragonal chalcopyrite structure such as CuGaTe2 are promising thermoelectric (TE) materials. (zT = 1.4 [Plirdpring et al., Adv. Mater. 2012, 24, 3622]). It has been demonstrated in a various chalcopyrite systems including compounds with quaternary chalcopyrite-like structures that the lattice parameter ratio c/a being exactly 2.00 to have a pseudo-cubic structure is key to increase the degeneracy at the valence band edge and ultimately achieve high thermoelectric performance. (Zhang et al., Adv. Mater. 2014, 26, 3848). Considering the fact that ZnSnSb2 with a chalcopyrite structure is reported to have c/a close to 2.00, it is expected to have multiple valence bands leading to a high p-type zT. However, there are no complete investigations on the high temperature TE properties of ZnSnSb2 mainly due to the difficulty of obtaining a single-phase ZnSnSb2. In the present study, pure ZnSnSb2 samples with no impurities are synthesized successfully using a Sn flux-based method and TE properties are characterized up to 585 K. Transport properties and the thermal analysis indicate that the structure of ZnSnSb2 remains chalcopyrite with no order-disorder transition and clearly show that ZnSnSb2 can be made to exhibit a high zT in the low-to-mid temperature range through further optimization. PMID- 30479128 TI - Nicotinamide-Containing Di- and Trinucleotides as Chemical Tools for Studies of NAD-Capped RNAs. AB - We report the chemical synthesis of a set of nicotinamide adenine dinucleotide (NAD) cap analogues containing chemical modifications that reduce their susceptibility to NAD-RNA-degrading enzymes. These analogues can be incorporated into transcripts in a similar way as NAD. Biochemical characterization of RNAs carrying these caps with DXO, NudC, and Nudt12 enzymes led to the identification of compounds that can be instrumental in unraveling so far unaddressed biological aspects of NAD-RNAs. PMID- 30479129 TI - Phthalate release from plastic fragments and degradation in seawater. AB - Plastic debris in the environment contain plasticizers, such as phthalates (PAEs), that can be released during plastic aging. Here, two common plastic materials, i.e., an insulation layer of electric cables (polyvinylchloride, PVC cables) and plastic garbage bag (polyethylene, PE-bags), were incubated in natural seawater under laboratory conditions, and the PAE migration to the seawater phase was studied with varying light and bacterial conditions over a 90 day time course. Free PAEs diluted in seawater were also studied for bacterial degradation. Our results showed that, within the first month of incubation, both plastic materials significantly leached out PAEs in surrounding water. We found that di-isobutyl phthalate (DiBP) and di-n-butyl phthalate (DnBP) were the main PAEs released from the PE-bags, with the highest values of 83.4 +/- 12.5 and 120.1 +/- 18.0 ng g-1 of plastic, respectively. Furthermore, dimethyl phthalate (DMP) and diethyl phthalate (DEP) were the main PAEs released from PVC-cables, with mass fractions as high as 9.5 +/- 1.4 and 68.9 +/- 10.3 ng g-1, respectively. Additionally, we found that light and bacterial exposure increased the total amount of PAEs released from PVC-cables by a factor of up to 5, whereas they had no influence in the case of PE-bags. PMID- 30479130 TI - Toxicant deposition and transport in alveolus: a classical density functional prediction. AB - The deposition and transport of toxicants on pulmonary surfactant is an important process in human health and medical care. We have introduced classical density functional theory (CDFT) to provide insight into this process. Nine typical toxicants in PM2.5 were considered, and their free energy and structural information have been examined. The free energy profile indicates that PbO, As2O3 and CdO are the 3 toxicants most easily deposited in the pulmonary alveolus, which is consistent with survey data. CuO appears to be the easiest toxicant to transport through the surfactant. Structural analysis indicates that the toxicants tend to pass through the surfactant with rotation. The configuration of the pulmonary surfactant was examined by extending our previous work to polymer systems, and it appears that both the configurational entropy and the direct interaction between the surfactant and the toxicant dominate the configuration of the pulmonary surfactant. PMID- 30479131 TI - Carbene-Catalyzed [4 + 2] Annulation of 2 H-Azirine-2-carboxaldehydes with Ketones via Azolium Aza-Dienolate Intermediate. AB - A new carbene-catalyzed [4 + 2] annulation of 2 H-azirine-2-carbaldehydes with ketones was developed, thus providing the 2,3-dihydro-6 H-1,3-oxazin-6-one core structures with broad scope and good to excellent yields. Notably, the azolium aza-dienolates generated from the addition of NHCs to 2 H-azirines are first uncovered. PMID- 30479132 TI - Synthesis of Quinolinone Alkaloids via Aryne Insertions into Unsymmetric Imides in Flow. AB - A general strategy for the synthesis of 3,4-dioxygenated quinolin-2-one natural products is reported. The key step is a regioselective insertion of arynes into unsymmetric imides. When performed in continuous flow, the reaction proceeds within minutes, while lower yields and longer reaction times are observed in batch. The resulting N-acylated 2-aminobenzophenones were transformed to (+/-) peniprequinolone, (+/-)-aflaquinolones E and F, (+/-)-6-deoxyaflaquinolone E, (+/ )-quinolinones A and B, and (+/-)-aniduquinolone C in 1-3 steps. PMID- 30479133 TI - Structural Characterization of Methylenedianiline Regioisomers by Ion Mobility Mass Spectrometry and Tandem Mass Spectrometry: IV. 3-Ring and 4-Ring Isomers. AB - Matrix assisted laser desorption/ionization-mass spectrometry (MALDI-MS) is used to characterize methylenedianiline (MDA) 3-ring and 4-ring species. Building on our previous MALDI-MS 2-ring MDA isomer study, here we compare 3-ring and 4-ring electrospray ionization (ESI) and MALDI results. In ESI, 3-ring and 4-ring MDAs each form one single [M+H]+ parent ion. Whereas in MALDI, each MDA multimer forms three unique precursor ions: [M+H]+, [M.]+, and [M-H]+. In this study, 3-ring and 4-ring MDA precursors are characterized to identify the unique fragment ions formed and their respective fragmentation pathways. In addition to the three possible precursors, the 3-ring and 4-ring species are higher-order oligomer precursors in polyurethane (PUR) production and thus provides additional insight into the polymeric behavior of these PUR hard block precursors. The combination of ion mobility-mass spectrometry (IM-MS) and tandem mass spectrometry (MS/MS) allow the structural characterization of these larger MDA multimers. PMID- 30479134 TI - Three-Dimensional Chestnut-like Architecture Assembled from NaTi3O6(OH).2H2O@N Doped Carbon Nanosheets with Enhanced Sodium Storage Properties. AB - The application of sodium titanates anodes of low cost, feasible operate voltage and non-toxicity were severely hindered by the inferior cycling stability and poor rate capability. Here, three-dimensional chestnut-like NaTi3O6(OH).2H2O@N doped carbon nanospheres (NTOH @CN) with loose crystal structure were prepared by self-sacrificed template method. The nanospheres were composed of nanosheets and linked with nanowires, which interweaved to construct a meshwork structure. The growth mechanism of unique 3D NTOH @CN nanospheres was investigated by tracking the synthesis pro-cess of different hydrothermal durations. The rate performances of 3D NTOH @CN were superior to that of NaTi3O6(OH).2H2O irregular spheres assembled from nanosheets (3D-NTOH) and NaTi3O6(OH).2H2O nanosheets (2D-NTOH). Excellent cycle and rate performance were obtained due to the open crystal structure, unique 3D nanosphere morphology with short diffusion paths, N-doped carbon surrounding and the solid solution reaction. In addition, the re-action mechanism, morphology change and dynamics research during the sodium insertion/desertion process have been carefully studied. Based on varied ex-situ analysis, the irreversible metallic titanium formation and the excellent structur al stability of nanospheres morphology has been evidenced. And the pseudocapacitive phenomenon was also detected and effectively enhanced Na+ ions storage capability. The systematical and comprehensive study provide a holograph for the design and synthesis of sodium titanates nanostructure. PMID- 30479135 TI - Topographical Features of Graphene-Oxide-Functionalized Substrates Modulate Cancer and Healthy Cell Adhesion Based on the Cell Tissue of Origin. AB - Graphene-derived materials, such as graphene oxide (GO), have been widely explored for biomedical and biological applications, including cancer research. Despite some recent works proving that GO inhibits the migration and invasion of different cancer cells, so far most of these in vitro studies have been conducted using GO sheets dispersed in solution or as a planar film. On the contrary, little is known about cellular activities, such as cell viability, adhesion, and spreading, when cancer cells interface with GO functionalized hydrogel-based surfaces, biomechanically and structurally more similar to the tumor environment. Here, we evaluate the interactions of human breast cancer cells (MDA-MB-231) with alginate (Alg)/GO hydrogel-based substrates, and compare them with a cancer cell line from human osteosarcoma (HOS) and healthy murine fibroblasts (3T3). We observed that GO addition selectively inhibits malignant breast cancer cell adhesion efficiency and spreading area, while promotes HOS and 3T3 adhesive processes. Furthermore, we did not observe the same results over Alg substrates with GO nanosheets dispersed in the medium, without embedment into the Alg. This suggests that cancer (MDA-MB-231 and HOS) and healthy (3T3) cell adhesion efficacy does not depend on the cellular tumoral nature and it is driven by the topographical cues provided by the GO-based substrates, whose physical-mechanical characteristics better mimic those of the cell native tissue. We envision that this study can provide a rational for future design and use of graphene-based nanomaterials for cancer research by deepening the knowledge of graphene-cancer cell specific interactions. PMID- 30479136 TI - Validation and reproducibility of cardiovascular 4D-flow MRI from two vendors using 2 * 2 parallel imaging acceleration in pulsatile flow phantom and in vivo with and without respiratory gating. AB - BACKGROUND: 4D-flow magnetic resonance imaging (MRI) is increasingly used. PURPOSE: To validate 4D-flow sequences in phantom and in vivo, comparing volume flow and kinetic energy (KE) head-to-head, with and without respiratory gating. MATERIAL AND METHODS: Achieva dStream (Philips Healthcare) and MAGNETOM Aera (Siemens Healthcare) 1.5-T scanners were used. Phantom validation measured pulsatile, three-dimensional flow with 4D-flow MRI and laser particle imaging velocimetry (PIV) as reference standard. Ten healthy participants underwent three cardiac MRI examinations each, consisting of cine-imaging, 2D-flow (aorta, pulmonary artery), and 2 * 2 accelerated 4D-flow with (Resp+) and without (Resp-) respiratory gating. Examinations were acquired consecutively on both scanners and one examination repeated within two weeks. Volume flow in the great vessels was compared between 2D- and 4D-flow. KE were calculated for all time phases and voxels in the left ventricle. RESULTS: Phantom results showed high accuracy and precision for both scanners. In vivo, higher accuracy and precision ( P < 0.001) was found for volume flow for the Aera prototype with Resp+ (-3.7 +/- 10.4 mL, r = 0.89) compared to the Achieva product sequence (-17.8 +/- 18.6 mL, r = 0.56). 4D-flow Resp- on Aera had somewhat larger bias (-9.3 +/- 9.6 mL, r = 0.90) compared to Resp+ ( P = 0.005). KE measurements showed larger differences between scanners on the same day compared to the same scanner at different days. CONCLUSION: Sequence-specific in vivo validation of 4D-flow is needed before clinical use. 4D-flow with the Aera prototype sequence with a clinically acceptable acquisition time (<10 min) showed acceptable bias in healthy controls to be considered for clinical use. Intra-individual KE comparisons should use the same sequence. PMID- 30479137 TI - Cross-species evidence of interplay between neural connectivity at the micro- and macroscale of connectome organization in human, mouse and rat brain. AB - The mammalian brain describes a multi-scale system. At the microscale, axonal, dendritic and synaptic elements ensure neuron-to-neuron communication, and at the macroscale, large-scale projections form the anatomical wiring for communication between cortical areas. While it is clear that both levels of neural organization play a crucial role in brain functioning, their interaction is not extensively studied. Connectome studies of the mammalian brain in cat, macaque and human have recently shown regions with larger and more complex pyramidal cells to have more macroscale corticocortical connections. Here, we aimed to further validate these cross-scale findings in the human, mouse and rat brain. We combined neuron reconstructions from the NeuroMorpho.org neuroarchitecture database with macroscale connectivity data derived from connectome mapping by means of tract tracing (rat, mouse) and in vivo diffusion MRI (human). Across these three mammalian species we show cortical variation in neural organization to be associated to features of macroscale connectivity, with cortical variation in neuronal complexity explaining significant proportions of cortical variation in the number of white matter projections of cortical areas. Our findings converge on the notion of a relationship between features of micro- and macroscale neural connectivity to form a central aspect of mammalian neural architecture. PMID- 30479138 TI - The Modern Hospital Bed: A 'Prescription for Recovery and Wellness'. PMID- 30479139 TI - What to Expect in the Third Edition of ST72. PMID- 30479140 TI - Staying Ahead of 'Enormous and Evolving' Cyberthreats Requires End-to-End Collaboration. PMID- 30479145 TI - The Roundup A compilation of items about healthcare technology news, regulations, and AAMI initiatives. PMID- 30479143 TI - Ten Questions With ... PMID- 30479141 TI - Overcoming Subject Matter Snobbery: Knowing that You Don't Know Everything. PMID- 30479146 TI - Precision Tracking. PMID- 30479147 TI - Device Integration Specialists Are Needed to Fill Vital Support Gap. PMID- 30479148 TI - Seek and You Shall Find? PMID- 30479149 TI - Keeping Track of All the Moving Pieces. PMID- 30479150 TI - Multigas Monitors: Overview and Preventive Maintenance Essentials. PMID- 30479151 TI - Frequency and Duration of Infusion Pump Alarms: Establishing National Benchmarks. AB - Reduction of clinical alarms is a priority due to alarm fatigue and the high incidence of nonactionable alarms, especially those generated from physiological monitors. However, research on infusion pump alarm types and frequencies is limited. The purpose of this study was to establish a baseline for infusion pump alarm frequencies and duration in the hospital setting. Frequency and duration of alarms across 29 hospitals using 11,410 infusion pumps revealed 987,240 alarms associated with 568,164 infusions during a consecutive 60-day period. Pump alarms accounted for only 0.8% of infusion time, with an average of 1.74 alarms per delivery and 0.18 alarms per hour. Average alarm duration was 0:02:38 (h:min:s), with 60% of alarms being addressed within 0:01:08. The most frequent alarms were keep vein open (33.77%), hold expired (27.18%), and downstream occlusion (22.94%). The medical/surgical and intensive care unit (ICU) care areas had the highest number of alarms (41.66% and 39.70% of total alarms, respectively), but pediatrics/neonatal ICU had the highest frequency of alarms per delivery (4.91). Intravenous fluids accounted for 47.16% of total alarms, with an average of 3.03 alarms per delivery, whereas parenteral nutrition and propofol had 6.77 and 6.74 average alarms per delivery, respectively. A higher average number of alarms per delivery occurred on Saturdays (1.74) and Sundays (1.73) compared with weekdays. Infusion pump alarm data collected and analyzed were sufficient to establish a reasonable baseline of infusion pump alarm types and relative frequencies for the device. PMID- 30479152 TI - A Holistic and Collaborative Approach to Audible Alarm Design. PMID- 30479154 TI - A Roundtable Discussion: Improving the 'Alarm Problem' Will Require Much More Than Just Reducing the Number of Alarms. PMID- 30479155 TI - A Life Cycle Approach to Medical Device Cybersecurity. PMID- 30479156 TI - Medical Equipment and Healthcare Technology: Health Vision 2050. AB - To address the demands of worldwide demographic and epidemiologic changes and globalization, as well as their effects on population health, the Ministry of Health in Oman developed a long-term plan for its health system called Health Vision 2050. The plan was shaped by international consultants, who sought to augment the vision with up-to-date evidence and achieve alignment with international standards. The Health Vision 2050 main document was anchored by 24 separate strategic studies covering different dimensions and pillars of the health system, one of which was the strategic study of medical equipment and healthcare technology (MEHT). This study analyzed the current status of MEHT, highlighted the achievements and bottlenecks, anticipated future challenges, and determined the future vision through pragmatic, contextualized, and actionable objectives and strategies that will provide a platform for comprehensive MEHT planning. Of note, pharmacological technologies, pharmaceutical drugs, and information technology have not been covered under the scope of this vision. By shedding light on this important strategic study about MEHT, the aim of this article is to assist other countries that are seeking to improve their MEHT based on the latest international guidelines and standards. PMID- 30479157 TI - New ACMQ Management to Help Make VIP->Growth a Reality. PMID- 30479158 TI - Toxigenic V. cholerae, V. parahaemolyticus, and V. vulnificus in oysters from the Gulf of Mexico and sold in Mexico City. AB - Oysters can accumulate potentially pathogenic bacteria, such as Vibrio cholerae, V. parahaemolyticus, and V. vulnificus. The aim of this study was to detect the presence of these Vibrio species and their toxigenic variants in oysters from the Gulf of Mexico sold in Mexico City. Oyster samples were studied using traditional culture and molecular polymerase chain reaction analysis. V. cholerae was present in 30.4% of the samples and its toxigenic variant chxA+ in 26.1%. It was isolated only in deshelled oysters, mainly in the dry season. V. parahaemolyticus was present in 95.7% of the samples and the toxigenic variant was found in 17.4%. V. vulnificus was identified in 60.9% of the samples, 38% of which corresponded to the environmental genotype and 21.7% to the clinical genotype, mainly in the cold season. Consumption of the oysters analyzed poses health risks due to the presence of Vibrio species, especially in deshelled oysters. PMID- 30479159 TI - Effects of cognitive behavioral therapy on people living with HIV and depression: A systematic review and meta-analysis. AB - The aim of this review is to examine the efficacy of cognitive behavioral therapy (CBT) on people living with HIV (PLWH) and depression. A literature search from five electronic databases was conducted, and articles published until July 2017 were collected. The inclusion criteria included randomized controlled trials (RCTs) of CBT that were conducted among PLWH with clinically relevant depression. Comprehensive Meta-Analysis 2 was used to obtain pooled results. Seven RCTs, with a total sample size of 388 participants, met the inclusion criteria. Compared with the control group, the CBT group had statistically significant, short-term improvements in depression (g = -0.486, 95% CI [-0.969 to -0.003], P = 0.048). A significant reduction in viral load was also observed at the long-term follow-up (g = -0.306, 95% CI [-0.573 to -0.040], P = 0.024), but no improvements were found in CD4. Results of this meta-analysis showed that CBT is effective in reducing depression symptoms in PLWH with comorbid depression for a short period of time. However, the findings of this review may not be generalized in the clinical field due to the small number of involved studies and the limited study sample. Thus, more robust and adequately powered studies are needed to further explore CBT interventions in PLWH with depression. PMID- 30479160 TI - Biogenic synthesis of AgNPs using Artemisia oliveriana extract and their biological activities for an effective treatment of lung cancer. AB - Silver nanoparticles (AgNPs) were synthesized using Artemisia oliveriana extract, and their physicochemical characteristics were studied. The antioxidant and antimicrobial activities of the AgNPs, as well as their anticancer effects on the lung cancer cell line (A549), using 1,1-diphenyl-2-picrylhydrazyl (DPPH), MIC and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) techniques respectively demonstrated that the synthesized AgNPs mainly affected the gram positive bacteria rather than the gram-negative bacteria, and exhibited significant cellular toxicity on the A549 cell line. Further, the cellular uptake of the AgNPs results indicated that the AgNPs accumulated within the cell. Moreover, their impact on the expression of apoptotic genes including Bax, Bcl-2, caspase-3 (CASP3), caspase-9 (CASP9) and miR-192 using real-time PCR demonstrated substantial increase in the expression of all mentioned genes (p<.001). Finally, the apoptotic effects of the AgNPs through DNA fragmentation test, flow cytometry and cell cycle analysis indicated the induction of apoptosis in the A549 cell line. The results revealed that the AgNPs synthesized using A. oliveriana extract have potential biological applications. PMID- 30479161 TI - Current understanding of the mixed pain concept: a brief narrative review. AB - Despite having been referenced in the literature for over a decade, the term 'mixed pain' has never been formally defined. The strict binary classification of pain as being either purely neuropathic or nociceptive once left a good proportion of patients unclassified; even the recent adoption of 'nociplastic pain' in the IASP Terminology leaves out patients who present clinically with a substantial overlap of nociceptive and neuropathic symptoms. For these patients, the term 'mixed pain' is increasingly recognized and accepted by clinicians. Thus, an independent group of international multidisciplinary clinicians convened a series of informal discussions to consolidate knowledge and articulate all that is known (or, more accurately, thought to be known) and all that is not known about mixed pain. To inform the group's discussions, a MEDLINE search for the Medical Subject Heading 'mixed pain' was performed via PubMed. The search strategy encompassed clinical trial articles and reviews from January 1990 to the present. Clinically relevant articles were selected and reviewed. This paper summarizes the group's consensus on several key aspects of the mixed pain concept, envisioned to serve as a foundation for future attempts at generating a mechanistic and/or clinical definition of mixed pain. A definition would have important implications for the development of recommendations or guidelines for diagnosis and treatment of mixed pain. PMID- 30479162 TI - STAT3-activated lncRNA LUCAT1 drives cell proliferation, migration and invasion in hepatoblastoma through regulating miR-301b/STAT3 axis. AB - Hepatoblastoma usually occurs in infant or toddlers. Nowadays, long non-coding RNAs (lncRNAs) have been widely studied in various human cancers. However, the role of lncRNAs in hepatoblastoma still needs to be elucidated. This study aimed to investigate the biological role of a certain lncRNA in hepatoblastoma. According to the TCGA data, upregulation of lncRNA LUCAT1 was closely associated with the poor overall survival of hepatoblastoma patients. Next, the expression patterns of LUCAT1 in hepatoblastoma tissues and cell lines were detected with qRT-PCR. The results revealed that LUCAT1 was highly expressed in hepatoblastoma tissues and cell lines. To identify the biological function of LUCAT1 in hepatoblastoma, loss-of function assays were carried out. Knockdown of LUCAT1 inhibited cell proliferation, migration and invasion but reversed epithelial mesenchymal transition (EMT) phenotype into MET. Next, we investigated the molecular mechanism of LUCAT1. STAT3 was found to be a transcription activator of LUCAT1. Further mechanism investigation revealed that LUCAT1 increased STAT3 expression through competitively binding to miR-301b. In conclusion, LUCAT1 was activated by STAT3 and promoted cell proliferation, migration and invasion in hepatoblastoma through modulating miR-301b/STAT3 axis. PMID- 30479163 TI - Moderate versus deep sedation in adults undergoing colonoscopy: Systematic review and meta-analysis. AB - Objective To perform a systematic review and meta-analysis comparing effectiveness and safety of moderate and deep sedation during colonoscopy. Research design and methods We searched MEDLINE, EMBASE, CENTRAL and google scholar in May 2017 and updated in March 2018 to identify all randomized controlled trials that compared the effectiveness and safety of moderate and deep sedation during colonoscopy. The quality of studies was assessed using the "Risk of bias" tool. The primary endpoints were defined as patient satisfaction, physician satisfaction, incidence of recall, and incidence of desaturation. Recovery time was also evaluated. Review Manager and Comprehensive Meta-Analysis software were used for statistical analysis. Results A total of 919 patients from three studies were included in the final analysis. The combined analysis did not reveal any differences in patient satisfaction between moderate and deep sedation (RR =0.94; 95%CI: 0.86 to 1.04; Pchi2 = 0.06; I2 = 65%; number needed to treat to harm [NNTH] = 15.6; 95%CI: NNTH 7.8 to infinity to number needed to treat to benefit [NNTB] = 3078.0), physician satisfaction (RR =0.35; 95%CI: 0.02 to 6.95; Pchi2 < 0.001; I2 = 100%; NNTB =1.6; 95%CI: NNTB 1.5 to NNTB 1.8), incidence of recall (RR =5.82; 95%CI: 0.51 to 66.48; Pchi2 = 0.11; I2 = 60%; NNTH =11.0; 95%CI: NNTH 7.5 to NNTH 20.5), or recovery time (mean difference = -6.77; 95%CI: 16.21 to 2.67; Pchi2 < 0.001; I2 = 99%). However, incidence of desaturation was higher in the deep group than in the moderate group (RR =0.18; 95%CI: 0.01 to 0.99; Pchi2 = 0.48; I2 = 0%; NNTB =56.7; 95%CI: NNTB 31.6 to NNTB 273.1). Conclusions Moderate sedation showed comparable safety and effectiveness to deep sedation with respect to patient satisfaction, physician satisfaction, incidence of recall, and recovery time. PMID- 30479164 TI - Association between neurodegenerative diseases and pneumonia: a retrospective population-based study. AB - PURPOSE: The association between pneumonia and neurodegenerative diseases (NDs) has never been reported in detail. We address this relationship with reference to a general population. METHODS: Using Taiwan's National Health Insurance Research Database to identify a pneumonia cohort (including the typical and atypical), we established an ND cohort of 19,062 patients and a non-ND cohort of 76,227 people. In both cohorts, the risk of pneumonia was measured using multivariable Cox proportional hazards models. RESULTS: The adjusted hazard ratio (aHR) [95% confidence interval (CI)] for the pneumonia cohort was 2.10 (1.96-2.24), regardless of age, sex, comorbidities, or drug use in the ND cohort. The [aHR (95% CI)] for adults aged 20-49 years was [2.08 (1.58-2.75)]; men [2.20 (2.01 2.40)]. However, the older subjects [3.41 (2.99-3.88)] were at greatest risk of pneumonia, if the aged 20-49 years as reference. For the ND and non-ND cohorts, those with comorbidities (with the exception of hyperlipidemia) had higher risk; aHR (95% CI) is [2.35 (2.30-2.52)]. The [aHR (95% CI)] for without comorbidities is [3.28 (2.52-4.26)]. No significant difference was observed in incidence of pneumonia between those who were and were not using statin medications; the aHR (95% CI) was 1.03 (0.93-1.14). CONCLUSION: The ND cohort had a higher risk of pneumonia, regardless of age, sex, comorbidities, or statin use. The risk of pneumonia was higher in elderly and male patients in the ND cohort. PMID- 30479165 TI - Metal ion concentrations after metal-on-metal hip arthroplasty are not correlated with habitual physical activity levels. AB - INTRODUCTION:: Metal-on-metal (MoM) hip arthroplasties have shown high clinical failure rates with many patients at risk for a revision and under surveillance for high metal ion concentrations. Implant wear releasing such ions is assumed to be a function of use, i.e. the patient's physical activity. This study aimed to assess whether habitual physical activity levels of MoM patients are correlated with metal ion concentrations and are higher in patients with high (at risk) than in patients with low (safe) metal ion concentrations. METHODS:: A cohort study was conducted of patients with any type of MoM hip prosthesis. Metal ion concentrations were determined using ICP-MS. Habitual physical activity of subjects was measured in daily living using an acceleration-based activity monitor. Outcome consisted of quantitative and qualitative activity parameters. RESULTS:: In total, 62 patients were included. Mean age at surgery was 60.8 +/- 9.3 years and follow-up was 6.3 +/- 1.4 years. Cobalt concentrations were highly elevated overall (112.4 +/- 137.9 nmol/L) and significantly more in bilateral (184.8 +/- 106.5 nmol/L) than in unilateral cases (87.8 +/- 139.4 nmol/L). No correlations were found between physical activity parameters and metal ion concentrations. Subgroup analysis of patients with low versus high cobalt concentration showed no significant differences in habitual physical activity. DISCUSSION:: No correlation was found between physical activity levels and metal ion concentrations. Implant use by normal habitual activities of daily living seems not to influence metal ion concentrations. PMID- 30479166 TI - Free-Roaming Cat (Felis Catus) Management and Welfare Policies in Two University Campuses in Beirut, Lebanon: Strengths, Weaknesses, and Opportunities. AB - Little information has been reported about the welfare and management of free roaming animals in Middle Eastern countries. Here we describe a case study of free-roaming cat (Felis catus) management policies in two universities in Beirut, Lebanon whereby cats are immensely valued for their presence and the benefits they bring to students and employees. Guided by concern for animal welfare, the innovative, humane approaches by the universities include arranging adoptions, discouraging pet abandonment, food provision, health monitoring, nurturing a social responsibility consciousness among young people, formal endorsement of animal rights and humane treatment in student conduct expectations, sterilization, and veterinary care. The policies serve as blueprint for universities and other institutions across the globe to adopt proactive approaches to free-roaming cat management as well take responsibility for the welfare of all animals on campus (rather than only for ethical conduct in use of animals in scientific research). They also inspire students, as the next generation, to safeguard animals and the environment. PMID- 30479167 TI - The Portico transcatheter aortic valve for the treatment of severe aortic stenosis. AB - The Portico TAVI system (Abbott Vascular, Santa Clara, CA, USA) has been specifically designed to mitigate some of the complications associated with first generation valves. Most of the data generated from randomized studies comparing transcatheter aortic valve implantation with surgery stem from reported experiences with first generation transcatheter heart valve devices. The aim of this review is to describe the repositionable and retrievable Portico system and its implantation technique, coupled with our single-center experience and to provide a review of the clinical results reported so far in the literature. PMID- 30479168 TI - Vitamin D deficiency is associated with dyslipidemia: a cross-sectional study in 3,788 subjects. AB - BACKGROUND: Previously we reported severe vitamin D deficiency in a large-scale cohort in Tangshan area in northern China. However, whether vitamin D deficiency is associated with cardiovascular risk factors has not been systematic examined in the cohort. OBJECTIVE: We aimed to determine the correlation between serum vitamin D status and lipid levels in circulation via an observational study. METHODS: Serum 25-hydroxyvitamin D [25(OH)D] was measured. Based on the measurement the subjects were classified into quintiles. Dyslipidemia was defined as having one of the following: elevated serum total cholesterol, LDL cholesterol, triglycerides, or decreased HDL cholesterol, under lipid-control treatment. RESULTS: The study was conducted in a total of 3788 adults in northern China during their routine health examinations. When the highest quintile of the 25(OH)D level was set as reference, the risk of having dyslipidemia increased progressively across the highest to the lowest 25(OH)D with the ORs of 1 (reference), 1.232 (95% CI, 1.005-1.509), 1.235 (95% CI, 1.007-1.513), 1.403 (95% CI, 1.143-1.735) and 1.494 (95% CI, 1.217-1.833), respectively (Ptrend< 0.0001) after adjustment for age. This trend was unchanged after further adjustment for several potential confounders. In linear regression analysis, we found an inverse significant correlation between 25(OH)D and triglycerides (beta coefficient= 0.077, p < 0.05), and LDL cholesterol (beta coefficient=-0.245, p < 0.05), and positive correlation with HDL cholesterol (beta coefficient =0.038, p = 0.018). CONCLUSION: Vitamin D deficiency is found to be associated with dyslipidemia in a cohort of 3788 subjects. Specifically, serum 25(OH)D is inversely correlated with LDL cholesterol and triglycerides levels, and positively correlated with HDL cholesterol level. PMID- 30479169 TI - A cost-effectiveness analysis of endoscopic eradication therapy (EET) for management of dysplasia arising in patients with Barrett's esophagus in the United Kingdom. AB - BACKGROUND AND AIMS: Endoscopic eradication therapy (EET) is the first line approach for treating Barrett's Esophagus (BE) related neoplasia globally. The British Society of Gastroenterology (BSG) recommend EET with combined endoscopic resection (ER) for visible dysplasia followed by endoscopic ablation in patients with both low and high grade dysplasia (LGD and HGD). The aim of this study is to perform a cost-effectiveness analysis for EET for treatment of all grades of dysplasia in BE patients. METHODS: A Markov cohort model with a lifetime time horizon was used to undertake a cost effectiveness analysis. A hypothetical cohort of United Kingdom (UK) patients diagnosed with BE entered the model. Patients in the treatment arm with LGD and HGD received EET and patients with non dysplastic BE (NDBE) received endoscopic surveillance only. In the comparator arm, patients with LGD, HGD and NDBE received endoscopic surveillance only. A UK National Health Service (NHS) perspective was adopted and the incremental cost effectiveness ratio (ICER) was calculated. Sensitivity analysis was conducted on key input parameters. RESULTS: EET for patients with LGD and HGD arising in BE is cost-effective compared to endoscopic surveillance alone (lifetime ICER L3,006 per QALY gained). The results show that as the time horizon increases, the treatment becomes more cost-effective. The five year financial impact to the UK NHS of introducing EET is L7.1m. CONCLUSIONS: EET for patients with low and high grade BE dysplasia, following updated guidelines from the BSG has been shown to be cost-effective for patients with BE in the UK. PMID- 30479170 TI - Life style habits, biochemical factors and their interaction in the prediction of incident hypertension during 21-year follow-up. AB - BACKGROUND: Hypertension is a global health threat and major cardiovascular risk. Various risk-prediction models for incident hypertension have been developed but not many of them have studied the risk-predictive value of life style factors in combination with cardiovascular biomarkers during long-term period of over 10 years. METHODS: We examined differences in several classical variables for 299 subjects in OPERA (Oulu Project Elucidating Risk of Atherosclerosis) cohort in subjects with no or new hypertension during a follow-up period of 21 years. Effect of both various life style habits and biomarkers were investigated. RESULTS: Baseline blood pressure, being overweight and smoking actively were independent predictors of new hypertension in majority of multivariate models during long-term follow-up of 21 years in subjects without previous hypertension. Increased high-sensitive C-reactive protein (hsCRP) level (> 3 mg/L) was the strongest predictor of incident hypertension in univariate model. Subjects with two or all three of main risk factors (being overweight, smoking actively and having high hsCRP) had 4-fold risk for incident hypertension. CONCLUSIONS: Smoking, overweight and increased hsCRP level had risk-predictive value in incident hypertension prediction during long-term follow-up of 21 years. Assessment and measurement of these parameters could be used in help of detecting high risk subjects and primary prevention of hypertension very early on. In addition, the study shows that blood pressure at the middle-age should be followed and treated intensively to prevent hypertension in the older age. KEY MESSAGES: Baseline blood pressure, being overweight and smoking actively are independent predictors of new hypertension during a long-term follow-up of 21 years. Having two or all three risk factors (smoking actively, body mass index over 25 kg/m2, high-sensitive C-reactive protein (hsCRP) level over 3 mg/L) indicates a 4-fold risk for incident hypertension within 21-year follow-up. PMID- 30479171 TI - Pharmacokinetic drug evaluation of CVT-301 for the treatment of Parkinson's disease. AB - INTRODUCTION: Levodopa (LD) in combination with a decarboxylase inhibitor is a mainstay and the most effective therapeutic agent in the treatment of Parkinson's disease (PD). Unfortunately, during chronic treatment with this agent, ON-OFF phenomena and dyskinesia appear. Despite the many medical treatment options available, unpredictable OFF episodes can still occur and be severe and disabling. A rescue therapy that provides a rapid and predictable ON response for patients with OFF periods would be of great value for such patients. Areas covered: CVT-301 is a self-administered dry powder aerosol inhaled formulation of LD that is being developed as a self-administered treatment for OFF periods. The PK profile of CVT-301, the efficacy and the safety highlighted in randomized clinical trials will be reviewed. Expert opinion: CVT 301 may offer several potential advantages including increased systemic bioavailability through pulmonary absorption, rapid onset of action, avoidance of first-pass drug metabolism and less plasma level variability. PMID- 30479172 TI - Pharmacokinetic drug evaluation of letermovir prophylaxis for cytomegalovirus in hematopoietic stem cell transplantation. AB - INTRODUCTION: Letermovir is a new antiviral approved to prevent cytomegalovirus infection in hematopoietic stem cell transplant recipients. It has a distinct mechanism of action as it acts as a terminase complex inhibitor, and shows some advantages compared to the current treatment options for cytomegalovirus infection. Areas covered: This review focuses on the efficacy, safety, pharmacokinetics, pharmacodynamics and drug-drug interactions of letermovir. Expert opinion: Letermovir is a new antiviral to prevent cytomegalovirus infection. Unlike the currently used polymerase inhibitors, it has a distinct mechanism of action with better safety, limited resistance and no cross resistance. Although a lot of research on pharmacokinetics and drug-drug interactions has already been performed, it might be useful to clarify the effect of letermovir on voriconazole exposure, the drug-drug interaction between caspofungine and letermovir and the effect of statins on letermovir exposure. Also, the lack of an exposure-response relationship should be confirmed in large real-life post-marketing studies in order to be able to lower the intravenous dose of letermovir. PMID- 30479173 TI - Current developments in lantibiotic discovery for treating Clostridium difficile infection. AB - INTRODUCTION: Clostridium difficile is a major cause of healthcare-associated diarrhea linked to the misuse of antimicrobials and the corresponding deleterious impact they have on the protective microbiota of the gut. Resistance to agents used to treat C. difficile including metronizadole and vancomycin has been reported highlighting the need for novel agents. Lantibiotics represent a novel class of agents that many studies have highlighted as effective against C. difficile. Areas covered: In this review lantibiotics including nisin, actagardine, mersacidin, NAI-107 and MU-1140 that exhibit good activity against C.difficile, all of which are currently in the preclinical phase of investigation are discussed. The lantibiotic NVB302, which has completed phase I clinical trials for the treatment of C. difficile, is also described. Expert opinion: Lantibiotics represent promising candidates for the treatment of C. difficile infections due to their novel mode of action, which is thought to decrease the potential of resistance developing and the fact they often possess a less deleterious effect on the protective gut microbiota when compared to traditional agents. They are also extremely amenable to bioengineering approaches and the incorporation of synthetic biology to produce more potent variants. PMID- 30479174 TI - Cost-effectiveness of sorafenib versus best supportive care in advanced hepatocellular carcinoma in Egypt. AB - BACKGROUND: In light of constrained budgets and the need to fund efficient treatment options, this study set out to assess the cost-effectiveness of sorafenib as a first-line treatment of hepatocellular carcinoma (HCC) compared to best supportive care (BSC) from the military hospital perspective in Egypt. METHODS: A decision analytic Markov model simulated disease progression with clinical parameters and utility values derived from published data. Data on direct medical costs were collected from the local health care system or payer. Costs and effects were discounted at 3.5% annually and reported in USD using purchasing power parity adjustments. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Mortality occurred less frequently in the sorafenib group (sorafenib group: 99.96%, BSC group: 99.99%). The total quality adjusted life years (QALYs) of the sorafenib cohort were estimated to be 46.24 compared with 42.27 for the BSC cohort, which resulted in an incremental gain of 3.96 QALYs. The total costs for the sorafenib and BSC cohorts were USD 4,229,940 and USD 3,092,886, respectively (incremental cost = $1,137,054), resulting in an incremental cost-effectiveness ratio (ICER) of USD 286,776 per QALY gained for the sorafenib cohort. One-way sensitivity analyses that addressed the uncertainty of the BSC estimates indicated that the progression-free survival for BSC and utility value of progression had the greatest effects on the results. CONCLUSION: This study concluded that sorafenib does offer increased survival and quality of life at an increased cost but at an ICER that exceeds the nationally accepted cost-effectiveness threshold. Our findings support health care decision-making of the efficient allocation of health care system resources to improve the health of the Egyptian population. Whether sorafenib is cost-effective in specific subgroups with additional risk factors needs to be addressed in future studies. PMID- 30479175 TI - An update on diagnosis and therapy of metabolic myopathies. AB - INTRODUCTION: Metabolic myopathies are a heterogeneous group of disorders characterized by inherited defects of enzymatic pathways involved in muscle fiber energetics. Diagnosing metabolic myopathies requires a thoroughly taken individual and family history, a meticulous neurologic exam, exercise tests, blood and urine tests, needle-electromyography, nerve-conduction studies, muscle biopsy, targeted genetic tests, or next-generation sequencing. There is limited evidence from the literature to guide treatment of metabolic myopathies. Treatment is largely limited to non-invasive/invasive symptomatic measures. However, promising results have been achieved with enzyme replacement therapy in Pompe disease (GSD-II). Primary coenzyme-Q deficiency responds favorably to coenzyme-Q supplementation. MNGIE responds to allogeneic hematopoietic stem cell transplantation, orthotopic liver transplantation, and carrier erythrocyte entrapped thymidine phosphorylase enzyme therapy. MADD may respond to riboflavin. Areas covered: This review aims to summarize and discuss recent findings and new insights concerning diagnosis and treatment of metabolic myopathies. Expert commentary: Except for GSD-II, coenzyme-Q deficiency, and MNGIE, treatment of metabolic myopathies is usually palliative and supportive (non-invasive or invasive). Non-invasive symptomatic treatment includes physiotherapy, diet, administration of drugs, conservative orthopedic measures, and respiratory non invasive support. Important is the avoidance of triggers for episodic forms of fatty acid oxidation disorders. Invasive measures include orthopedic surgery and invasive mechanical ventilation. PMID- 30479176 TI - The effect of saddle height and saddle position changes from pedal on muscles and joints behaviors in ergometer: A parametric study. AB - The physical activities such as pedaling can affect the lower limb muscles strength and rehabilitation. Improper pedaling can cause injury. In this study, we would investigate the effects of saddle place (saddle position and saddle height) on the behavior of muscles and joints. Moreover, we would try to reveal the relationship between the muscles activity (Act) and the joints reaction forces ( F) and saddle position and saddle height. To this end, the pedaling conditions are obtained from the biomechanical model of the human movement system presented in AnyBody software. The variations in 12 muscles Act and total, normal and shear F of ankle, knee and hip joints are studied for the various saddle places in the pedaling feasible range. The relationships of those muscles Act and joints F are predicted by the response surface method. The results indicate that the muscles and the joints behavior changes for various saddle position and saddle height. The maximum and the minimum of the total response are acquired in the ankle and hip joints, respectively. In contrast to the ankle and hip joints, the knee shear response is greater than the normal response. The predictive models of the muscles Act and the joints F (the regression coefficients ( R2) are 0.60-0.95 and 0.76-0.97, respectively) indicate their nonlinear behavior with saddle position and saddle height variations. Studying the muscles and joints behavior in different pedaling condition can be helpful for the suitable saddle placement in order for rehabilitation, muscles soreness reduction, and joints disorder treatment. PMID- 30479177 TI - Non-steroidal anti-inflammatory drugs use, knowledge, and behaviours around their use and misuse in Irish collegiate student-athletes. AB - OBJECTIVES: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used by athletes to treat injuries but are also reportedly misused as performance or recovery aids. This study aimed to investigate NSAIDs use, knowledge, and behaviour regarding use and misuse of NSAIDs in Irish student-athletes. METHODS: One hundred and forty-nine (21.2+/-3.5 years) student-athletes completed an anonymous, validated questionnaire online. Descriptive statistics were used to summarize the data. Univariate and multivariate regression analysis was utilised to examine whether associated factors could predict NSAIDs misuse. RESULTS: Ninety-four percent of respondents reported using NSAIDs in the past, 63.8% used NSAIDs previously before or after completion and/or practice, 13.9% took more than the recommended dosage and this was higher (22.9%) for over-the-counter NSAIDs. More than half were unsure of NSAIDs side-effects. Misuse of NSAIDs was more common in respondents who had more favourable attitudes to the benefits of NSAIDs (OR=4.83, 95% CI=1.18-19.61), high reported stress (OR=1.73, 95% CI=0.58 1.73) or greater behavioural intention to use NSAIDs (OR=1.89, 95% CI=0.90-4.53). High perceived athletic identity also significantly predicted behavioural intention (p=0.01). CONCLUSION: Education strategies to improve student-athletes' knowledge of appropriate use and side-effects of NSAIDs is recommended, particularly for those with high levels of stress and athletic identity. PMID- 30479178 TI - Virtual Screening of a Natural Compound Library at Orthosteric and Allosteric Binding Sites of the Neurotensin Receptor. AB - Molecular dynamics (MD) simulation using the AMBER force field has been performed on the neurotensin receptor, a class A type G-protein coupled receptor in its activated conformation co-crystallized with the non-peptide agonists. For structure-based hit molecule identification via natural chemical compound library, orthosteric sites on neurotensin receptor have been mapped by docking using AutoDock4.0 and Vina with the known agonists and antagonists SR48692, SR142948, ML301 and ML314 of the receptor. Furthermore, clustering analysis on the MD trajectories by SIMULAID has been performed to filter receptor conformations for the allosteric binders from the Otava natural compound library. Comparative mappings of contrasting binding region patterns have been done between the crystal structure orthosteric sites as well as the binding regions in the SIMULAID-based cluster center conformations from MD trajectories with the FTmap server using the small organic molecule fragments as the probes. The distinct binding region in the cluster-based conformations in the extra-cellular region of the receptor has been identified for targeted docking by Otava natural chemical compound library using AutoDock4.0 and Vina docking suites to obtain putative allosteric binders. A group of compounds from the Otava library has been identified as showing high free energy in both AutoDock4.0 and Vina docking suites. Biophysical assessments on the natural compound computational hit molecules will be done to identify lead structures from the hit molecules. PMID- 30479179 TI - Evaluation of frailty status among older people living in urban communities by Edmonton Frail Scale in Wuhu, China: a cross-sectional study. AB - BACKGROUND: There are few studies that have explored the factors that are associated with frailty among older people in China. OBJECTIVE: To investigate the frailty status of older people living in urban communities and to examine the sociodemographic factors that are associated with their frailty status in China. DESIGN: Cross-sectional study. METHODS: We used convenience sampling to recruit the participants (aged 60 and above) from four communities in an urban area of Wuhu City, Anhui Province, China. Participants completed a questionnaire which included the Edmonton Frail Scale (EFS) and sociodemographic factors. Logistic regression models were used to examine the association between sociodemographic factors and frailty status among older Chinese people. RESULTS: Of 306 participants, the percentage of participants with a robust score (0-4) on the EFS was 71.9%, 14.1% had an apparently vulnerable score (5-6), and 14.0% had a frail score (7-17). Among all participants, 64.4% had adequate social support and 54.9% self-reported having a good health status. Age, chronic disease status and marital status were significantly associated with frailty. However, no significant associations were observed according to gender, education level, smoking, alcohol drinking and medication use. CONCLUSIONS: There are high percentage of frail older Chinese adults in urban area. The present study findings could provide better understanding of the factors associated with frailty status of this population. Early screening for frailty using a simple scale such as the Edmonton Frail Scale should be undertaken in health settings in China. Impact statement: Nurses should be encouraged to undertake early screening for frailty using the EFS in clinical practice in China. PMID- 30479181 TI - 2018 SPP Fall Abstracts. PMID- 30479180 TI - Food insecurity, mental distress and suicidal ideation in rural Africa: Evidence from Nigeria, Uganda and Ghana. AB - BACKGROUND:: In sub-Saharan Africa, mental and substance-related disorders account for 19% of all years lived with disability, yet the intersection between poverty and mental distress is poorly understood since most psychiatric research is conducted in high-income countries. AIMS:: To examine the prevalence of and associations between food insecurity, mental distress and suicidal ideation in three rural village clusters in sub-Saharan Africa. METHOD:: Cross-sectional multivariate analysis of sociodemographic variables associated with mental distress and suicidal ideation in three countries. The sample included 1,142 individuals from three rural village clusters in Nigeria ( n = 380), Uganda ( n = 380) and Ghana ( n = 382). Food insecurity was measured based on the number of months in the previous year that the respondent's family reported being 'unable to eat two square meals per day'. Mental distress was assessed using the Kessler non-specific psychological distress scale (K6) and suicidal ideation was measured using an item from PRIME-MD. Other sociodemographic variables included gender, age, literacy and occupation. RESULTS:: The prevalence of individuals with moderate or severe mental distress in Nigeria, Uganda and Ghana were higher than previously reported in the literature: 35.5%, 30.8% and 30.4%, respectively, and suicidal ideation rates were 29.7%, 21.3% and 10.9%. No differences were observed in mental distress between men and women in any of the sites. Being a farmer (vs student or other) was protective for mental distress in two sites (Uganda and Ghana) but no other social indicators, such as age, gender, literacy and food insecurity, were significantly associated with mental distress. Risk for suicidal ideation differed across sites: it was associated with food insecurity in Nigeria, female gender in Uganda, and older age in Uganda. CONCLUSIONS:: Mental distress and suicidal ideation were highly prevalent in three settings of extreme poverty across all groups, in ways that were not always consistent with the global literature. These findings suggest that more research is needed in to better understand the social etiology of mental distress in sub-Saharan Africa. PMID- 30479182 TI - Introductory paragraph. PMID- 30479183 TI - Drug-drug interactions in patients receiving hematopoietic stem cell transplantation. AB - INTRODUCTION: Recipients of hematopoietic stem cell transplantation (HSCT) are exposed to numerous drugs in both pre- and post-transplantation period, which creates an opportunity for drug-drug interactions (DDIs); if clinically relevant DDIs happen, the risk of adverse treatment outcomes is increased. Areas covered: This review is focused on DDIs in recipients of HSCT that were observed and published as clinical trials, case series or case reports. Relevant publications were found by the systematic search of the following online databases: MEDLINE, SCOPUS, EBSCO, and SCINDEX. Expert opinion: The most important DDIs involve cytostatic or immunosuppressant drug on one side, and antimicrobial drugs on the other. The majority of clinically relevant interactions have pharmacokinetic character, involving drug metabolizing enzymes in the liver. Antifungal azoles inhibit metabolism of many cytostatic and immunosuppressant drugs at cytochromes and increase their plasma concentrations. Macrolide antibiotics and fluoroqunolones should be avoided in HSCT recipients, as they have much larger potential for drug-drug interactions than other antibiotic groups. HSCT recipients increasingly receive new immunomodulating drugs, and further observational studies are needed to reveal unsuspected drug-drug interactions with clinical relevance. PMID- 30479184 TI - Commentary on Some Recent Theses Relevant to Combating Aging: December 2018. AB - Theses reviewed in this issue include "A Thromboresistant Cell-Derived Biomaterial Modification for Vascular Grafts", "Actomyosin mediated tension orchestrates thermogenic programs in adipocytes", "Age-Associated Changes in Intrathymic B Cell Population in Mice", "Endoplasmic Reticulum Stress is Transmissible among Cells of the Central Nervous System", "Evaluation of Early Tumor Angiogenesis Using Ultrasound Acoustic Angiography", and "Interactions Between Amyloid-Beta and Microglial Cells". PMID- 30479185 TI - Phone-based interventions to control gestational weight gain: a systematic review on features and effects. AB - OBJECTIVE: The aim of this study was to summarize the evidence regarding the effects and the features of phone-based interventions to control gestational weight gain (GWG). METHODS: We included studies that evaluated the effects of phone-based interventions on controlling GWG. The characteristics of studies, effects, and features of interventions were extracted. RESULTS: A total of 12 studies met the inclusion criteria. Outcomes were categorized into three groups (GWG control, proportion of women returning to pre-pregnancy weight, and proportion of women who exceeded the Institute of Medicine recommendations for GWG). Although most studies (66%) showed a statistically significant positive effect of phone-based interventions on the GWG control, the effects on the other outcome categories were found to be inconsistent. While the included studies used phone call and short messaging service (SMS), no study used the other functions of telephones and mobile phones such as video call, internet access, social networks, and smartphone applications. Regarding the functionalities, phone calls were used to provide guidance for healthy weight gain and communication with healthcare providers. SMS provided reminders, educational materials, and guidance. CONCLUSION: Phone-based interventions can help pregnant women control GWG by providing guidance, reminders, and educational materials. When these interventions use multiple functionalities, they are more effective in controlling GWG. PMID- 30479186 TI - Prevalence and clinical significances of red cell alloimmunization and red cell bound immunoglobulin G in polytransfused patients with thalassemias. AB - The study was to determine the prevalence and clinical significances of red blood cell (RBC)-bound IgG as detected by flow cytometry in polytransfused patients with thalassemias. Relationship of the presence of RBC-bound IgG with RBC alloimmunization was also evaluated. This study included 59 polytransfused patients with beta-thalassemia disease. We studied the frequency of RBC autoantibodies and alloimmunization. Direct Coombs test and flow cytometry were performed to detect the presence of RBC autoantibodies while RBC alloantibodies were detected by antibody screening and identification assays. Eight (13.6%) and 34 (57.6%) patients were found a positive direct Coombs test and flow cytometry, respectively. Twenty (33.9%) patients developed RBC alloantibodies. The four most frequent RBC alloantibodies were anti-E (55%), anti-Mia (40%), anti-Di(a) (25%) and anti-c (15%), respectively. There was no significant difference in the presence of RBC-bound IgG between polytransfused with thalassemia patients who developed RBC alloimmunization (13 of 20; 65%) and those without RBC alloantibodies (21 of 39; 53.8%), p = 0.412. Splenectomy and increased transfusion requirement were significantly associated with the presence of RBC bound IgG but not with RBC alloantibody formation. The overall frequency of RBC alloantibody formation in polytransfused patients with thalassemias was 33.9%. The most common RBC alloantibody was anti-E. RBC autoantibody formation was more frequently detected by flow cytometry (57.6%) than by direct Coombs test (13.6%). Splenectomy was significantly associated with the development of autoreactive RBC bound IgG antibodies in the polytransfused patients with thalassemias. The presence of the anti-RBC autoantibodies may cause an increase of transfusion requirement. PMID- 30479187 TI - Risk factors for hospitalizations and readmissions among individuals with sickle cell disease: results of a U.S. survey study. AB - OBJECTIVE: Hospital admissions are significant events in the care of individuals with sickle cell disease (SCD) due to associated costs and potential for quality of life compromise. METHODS: This cross-sectional cohort study evaluated risk factors for admissions and readmissions between October 2014 and March 2016 in adults with SCD (n = 201) and caregivers of children with SCD (n = 330) at six centres across the U.S. Survey items assessed social determinants of health (e.g. educational attainment, difficulty paying bills), depressive symptoms, social support, health literacy, spirituality, missed clinic appointments, and outcomes hospital admissions and 30-day readmissions in the previous year. RESULTS: A majority of adults (64%) and almost half of children (reported by caregivers: 43%) were admitted, and fewer readmitted (adults: 28%; children: 9%). The most common reason for hospitalization was uncontrolled pain (admission: adults: 84%, children: 69%; readmissions: adults: 83%, children: 69%). Children were less likely to have admissions/readmissions than adults (Admissions: OR: 0.35, 95% CI: [0.23,0.52]); Readmissions: 0.23 [0.13,0.41]). For all participants, missing appointments were associated with admissions (1.66 [1.07, 2.58]) and readmissions (2.68 [1.28, 6.29]), as were depressive symptoms (admissions: 1.36 [1.16,1.59]; readmissions: 1.24 [1.04, 1.49]). In adults, difficulty paying bills was associated with more admissions, (3.11 [1.47,6.62]) readmissions (3.7 [1.76,7.79]), and higher spirituality was associated with fewer readmissions (0.39 [0.18,0.81]). DISCUSSION: Missing appointments was significantly associated with admissions and readmissions. Findings confirm that age, mental health, financial insecurity, spirituality, and clinic attendance are all modifiable factors that are associated with admissions and readmissions; addressing them could reduce hospitalizations. PMID- 30479188 TI - Concussion reporting and perceived knowledge of professional fighters. AB - OBJECTIVE: For concussions to be effectively managed in sports, they need to be correctly identified and reported. The extent to which professional athletes correctly recognize concussions, and their willingness to report symptoms, is not yet well understood. Given the risk of head injuries leading to concussions across combat sports, insight into professional fighters' knowledge and reporting of concussive symptoms is essential to improve concussion management. METHOD: To investigate understanding and reporting patterns of concussions sustained while training or competing, 257 fighters completed a self-report questionnaire assessing self-perception of concussion knowledge, trust of ringside medical providers, and reported number of previous head injuries. Fighting history, including number of knockouts, was obtained from self-report (amateur) and published (professional) records. RESULTS: Significant gaps in fighters' perceived knowledge of concussion symptoms and long-term effects of multiple concussions emerged. Approximately 40% of fighters reported returning to training or competition the same day a head injury was sustained, while 21% of fighters endorsed concealing symptoms of head injury from medical providers and coaches. CONCLUSIONS: Confusion surrounding terms used to describe head injuries amongst fighters (e.g., concussions, knockouts), coupled with limited understanding of concussive symptoms and a desire to return to competition, likely contributes to significant underreporting of symptoms. Key terms: concussion; sports-related concussions; psychological aspects of sport; boxing; martial arts. PMID- 30479189 TI - Toxic effects of subacute inhalation exposure to trichloroethylene on serum lipid profile, glucose and biochemical parameters in Sprague-Dawley rats. AB - The current study evaluated the inhalation toxicity of trichloroethylene (TCE) at 0, 10, 100, 250 and 400 ppm in Sprague-Dawley rats for 10 day period, because the subacute inhalation toxicity of TCE on serum lipid profile, glucose and some biochemical parameters has not been previously reported. TCE vapors were generated using the dynamic generation system based on evaporation method in the exposure chamber. On the basis of the results, mean serum low-density lipoprotein (LDL) and albumin (ALB) decreased significantly in all the groups exposed to TCE compared with the control group (p < .005), but there was a significant increase for parameters: fasting blood glucose (FBG) and alkaline phosphatase (ALP) (p < .005). Rats exposed to 400 ppm TCE showed a significant decrease in serum cholesterol (CHOL) and protein (Pr) compared with the control group (p < .005). A negative relationship was found between triglycerides (TG), very low density lipoprotein (VLDL), CHOL, LDL, Pr, ALB and urea levels and the subacute exposure to concentrations of TCE (R2 = -0.26, p < .05), but there was a direct correlation for parameters FBG, ALP and alanine aminotransferase (ALT) (R2 = 0.42, p < .05). In conclusion, studies with Sprague-Dawley rats demonstrated that subacute inhalation exposure to TCE (>= 100 PPM) is associated with biochemical and lipotoxicity in the form of decreased serum ALB and LDL and raised ALP and glucose levels. The present study also provides additional evidence relating to decreased serum CHOL and Pr after subacute inhalation exposure to 400 ppm TCE. PMID- 30479190 TI - Efficacy and safety of bispecific T-cell engager (BiTE) antibody blinatumomab for the treatment of relapsed/refractory acute lymphoblastic leukemia and non Hodgkin's lymphoma: a systemic review and meta-analysis. AB - OBJECTIVES: Multiple clinical trials have been conducted to investigate the therapeutic effects of blinatumomab on acute lymphoblastic leukemia (ALL) and non Hodgkin's lymphoma (NHL). We did a meta-analysis including 8 clinical trials to verify the efficacy and safety of blinatumomab in patients with relapsed/refractory ALL and NHL. METHODS: We searched and investigated all relevant publications from PubMed, Web of Science, Embase, and ClinicalTrials.gov. The primary endpoint was complete remission (CR). The secondary end points were the minimal residual disease (MRD) response, and the adverse effects including cytokine release syndrome (CRS) and grade >= 3 neurological events. RESULTS: Our study showed that the pooled CR rate was 0.45 (95% CI: 0.37-0.53) in ALL and 0.20 (0.12-0.27) in NHL respectively. The pooled CR rate is higher in ALL patients with BM blasts <50% than that of patients with BM blasts >=50% (0.75 versus 0.33). A history of allo-HSCT has no effect on the CR rate. The pooled MRD response rate was 0.42 (95% CI: 0.29-0.54) in ALL. For adverse effects, the pooled occurrence rate of grade >=3 CRS was 0.04 (95% CI: 0.01-0.06), and the pooled occurrence rate of grade >= 3 neurological events was 0.12 (95% CI: 0.08-0.16). DISCUSSION: Blinatumomab is effective in treating relapsed/refractory ALL and NHL. ALL patients manifested better therapeutic response than NHL patients and a reduced tumor load favored the clinical response. For adverse effects, severe CRS and neurological events did not happen very often. CONCLUSION: Blinatumomab shows valid therapeutic effects and limited adverse response in treating relapsed/refractory ALL and NHL in our meta analysis. PMID- 30479191 TI - Involvement of miRNA polymorphism in mucositis development in childhood acute lymphoblastic leukemia treatment. AB - AIM: Mucositis, linked to methotrexate, daunorubicin or cyclophosphamide, is a frequent childhood acute lymphoblastic leukemia (ALL) therapy side effect. miRNAs regulate the expression of pharmacokinetic/pharmacodynamic pathway genes. SNPs in miRNAs could affect their levels or function, and affect their pharmacokinetic/pharmacodynamic pathway target genes. Our aim was to determine the association between miRNA genetic variants targeting mucositis-related genes and mucositis-developing risk. PATIENTS & METHODS: We analyzed 160 SNPs in 179 Spanish children with B-cell precursor ALL homogeneously treated with LAL/SHOP protocols. RESULTS: We identified three SNPs in miR-4268, miR-4751 and miR-3117 associated with mucositis, diarrhea and vomiting, respectively. CONCLUSION: The effect of these SNPs on genes related to drug pharmacokinetics/pharmacodynamics could explain mucositis, diarrhea and vomiting development during ALL therapy. PMID- 30479192 TI - Correlates of Early Sexual Debut Among Sexually Active Youth in Ghana. AB - Using the 2014 Ghana Demographic and Health Survey, this study explores the correlates of early sexual debut among 2,746 (males = 670 and females = 2,076) sexually active youth aged 15 to 24 years in Ghana. The results indicate that males aged 15 to 19 years (odds ratio [ OR] = 8.84, p < .001) and who had basic education ( OR = 3.17, p < .001) were significantly more likely to initiate sexual debut early. Urban males who had used modern contraceptive ( OR = 0.35, p < .001) were significantly less likely to initiate early sexual debut. Meanwhile, females aged 15 to 19 years ( OR = 4.26, p < .001); who had used modern contraceptive ( OR = 1.99, p < .001); with no formal ( OR = 2.90, p < .001) or basic ( OR = 3.12, p < .001) education; with partial access to media ( OR = 1.58, p < .01); and from the Akans ( OR = 1.73, p < .001), Ewes ( OR = 1.92, p < .001), and other ethnic groups ( OR = 1.63, p < .001) were significantly more likely to initiate early sexual debut. However, employed females living in rural areas ( OR = 0.70, p < .01) and those with average ( OR = 0.54, p < .01) or rich ( OR = 0.51, p < .01) household living in urban areas were significantly less likely to initiate early sexual debut. Interventions and policies targeting those living in both rural and urban areas are therefore needed for adolescent males and females in their early teens before they start engaging in sexual intercourse. PMID- 30479193 TI - Building Global Health Capacity at a Minority-Serving Institution in the Bronx: The Potential Role of PhotoVoice and the Geo-Social Pathway Framework in This Endeavor. AB - Global health training programs for undergraduate students are expanding in the United States, which includes Minority-Serving Institutions (MSIs), but capacity building is needed at MSIs to develop career pathways into the field, especially for those institutions that serve low-income students who live in communities with high health disparities. Often, global health pathways begin by building a global lens through the examination of local health issues coupled with international educational experiences. This approach is limited for students who come from low-income settings with limited funding for international experiences, and as a result, may not see the feasibility of a global health career. However, there may be opportunity in harnessing student motivations and participatory research methods to build interest in a global health career. This article outlines the course, Fundamentals of Global Health, offered at a public MSI in the Bronx. The course was grounded in the Geo-Social Pathway Framework and utilized PhotoVoice to engage students in individual research projects. A constant comparison method was used to analyze papers, photos, reflections, and presentations in order to identify themes. Analysis of course materials submitted by students suggests that they were motivated to examine health disparities using PhotoVoice and that they focused their research projects on their family and community health disparities, or aligned with educational or professional goals to address their community health needs. This course model may inform future training in global health for students at MSIs, but community-based participatory research priority funding is needed to sustain global health at these key institutions. PMID- 30479194 TI - Changes in Psychosocial Factors and Physical Activity Among Finnish Working-Age Men in the Adventures of Joe Finn Campaign. AB - This study evaluated changes in psychosocial factors and self-reported physical activity (PA) among the sample of Finnish men who underwent the fitness tests during the national health campaign. Another aim was to examine whether the fitness test feedback was a meaningful experience for PA change. Baseline data were collected in 2011 by fitness test and questionnaire. Men who had low/moderate fitness along with overweight ( n = 361) were recruited to the postcampaign study in 2014. Data were analyzed with nonparametric tests, logistic regression analysis, and content analysis. The postcampaign survey was completed by 102 men. Positive PA change was associated with high goals, planning skills, and self-efficacy for PA. One fourth of men recalled that they had surprisingly poor fitness at baseline. This experience was not related to positive PA change. A fitness test may awake motivation, but promotion of self-efficacy and self regulatory skills is needed to support concrete behavior change. PMID- 30479195 TI - Cost-Effectiveness of Niraparib and Olaparib as Maintenance Therapy for Patients with Platinum-Sensitive Recurrent Ovarian Cancer. AB - BACKGROUND: The recent approval of olaparib and niraparib as maintenance therapy can significantly affect the management of ovarian cancer. Clinical benefits, however, come with trade-offs in adverse events and costs. OBJECTIVE: To evaluate the cost-effectiveness of new ovarian cancer poly-ADP ribose polymerase (PARP) inhibitor therapies, olaparib and niraparib, as maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer. METHODS: A decision tree model was constructed to evaluate the costs and effectiveness of olaparib and niraparib compared with placebo from a U.S. health care sector perspective. Costs included drug costs and costs of disease monitoring and management of adverse events throughout the treatment course. Costs were estimated from RED BOOK, Medicare reimbursement rates, and the literature and reported in 2017 U.S. dollars. Clinical effectiveness was measured in progression-free survival (PFS) life-years based on clinical trial results (NCT00753545, NCT01874353, and NCT01847274). The incremental cost-effectiveness ratio (ICER) was computed by dividing the incremental cost by the incremental effectiveness. RESULTS: At base case, niraparib was the more effective treatment option with slightly higher PFS, followed by olaparib. The ICERs for niraparib and olaparib compared with common baseline placebo were $235K and $287K per PFS life-year, respectively, with olaparib extended-dominated by niraparib. Both drugs were associated with lower ICERs in patients with a gBRCA mutation than in patients without a gBRCA mutation. One-way sensitivity analysis suggested that drug prices and PFS could affect ICERs significantly, but the ICERs remained above $100K per PFS life-year within the plausible ranges of all parameters. Probabilistic sensitivity analysis suggested that niraparib was associated with higher net benefits compared with placebo only when willingness-to-pay (WTP) values were above $210K per PFS life year thresholds. CONCLUSIONS: PARP inhibitors niraparib and olaparib will extend PFS in platinum-sensitive recurrent ovarian cancer patients but are also associated with high drug acquisition costs. The base case ICERs were around or above $250K per PFS life-year in this model. No formal cost-effectiveness WTP threshold for health technology assessment exists in the United States. At a reference WTP of $100K per PFS life-year, the PARP inhibitors may not be cost effective options. DISCLOSURES: This study was unfunded. The authors have nothing to disclose. PMID- 30479196 TI - Lessons Learned from Using Global Outcome Measures to Assess Community Pharmacy Performance. AB - INTRODUCTION: As value-based and alternative payment models proliferate, there is growing interest in measuring pharmacy performance. However, little research has explored the development and implementation of systems to measure pharmacy performance. Additionally, systems that currently exist rely on process and surrogate outcome measures that are not always relevant to patients and payers. PROGRAM DESCRIPTION: This article describes the process used to design and implement a performance measurement program for a group of enhanced services pharmacies in North Carolina. This program was successful in measuring quality based on medication adherence, hospitalizations, emergency department visits, and total cost of medical care for nearly all North Carolina pharmacies. Measures were scored and combined into a single 11-point composite pharmacy performance score. To demonstrate the measures, we compared performance scores for enhanced services pharmacies (n = 119) to other North Carolina pharmacies (n = 1,616) during the baseline measurement period (March 1, 2015-May 31, 2015). Adherence measure scores for enhanced services pharmacies exceeded those of other pharmacies (P values < 0.0001-0.003), but total scores were not significantly different, with enhanced services pharmacy mean total scores of 6.54 vs. 6.29 for all other pharmacies (P = 0.115). OBSERVATIONS: The program described provides an example of a composite performance measurement system that can be used to support alternative pharmacy payment models and shows that case-mix adjustment is possible for broad outcomes such as those used in this program. The measures used for the program depend on timely feeds of medical claims. Payers and pharmacy networks implementing a similar program may need to explore alternative structure or process measures. IMPLICATIONS: As pharmacy payment models evolve, there may be value in collaboration between academics, pharmacists, and payers to bring different areas of expertise and perspectives into the performance measurement process. This program demonstrates that global outcome measurement is possible over a broad set of pharmacies and invites additional research to explore the validity of this and other methods to measure pharmacy quality and performance. DISCLOSURES: The program described in this article was supported by Funding Opportunity Number 1C12013003897 from the U.S Department of Health and Human Services, Centers for Medicare & Medicaid Services. The contents provided are solely the responsibility of the authors and do not necessarily represent the official views of HHS or any of its agencies. Community Care of North Carolina received the grant and subcontracted with the UNC Eshelman School of Pharmacy to carry out this project. Shasky, Pfeiffenberger, and Trygstad are employed by Community Care of North Carolina. Urick and Ferreri are employed by the UNC Eshelman School of Pharmacy. Farley was employed by the UNC Eshelman School of Pharmacy during data collection for this project and reports consulting fees from UCB Pharmaceutical Company unrelated to this project. Pfeiffenberger reports membership on the Pharmacy Quality Alliance (PQA) task force on pharmacy level measures; Trygstad is a PQA board member; Urick is a member of a scientific advisory committee for PQA. PMID- 30479197 TI - Cost-Effectiveness of Targeted Pharmacotherapy for Moderate to Severe Plaque Psoriasis. AB - BACKGROUND: Newer classes of targeted drugs for moderate to severe plaque psoriasis are more effective and more expensive than older classes, posing a difficult and potentially costly decision about whether to use them as initial targeted treatments. OBJECTIVE: To estimate the clinical and economic outcomes of initial targeted treatment for the following drugs: adalimumab, etanercept, and infliximab (TNFalpha inhibitors); apremilast (PDE4 inhibitor); ustekinumab (IL 12/23 inhibitor); and ixekizumab, secukinumab, and brodalumab (IL-17 inhibitors). METHODS: We developed a Markov model to simulate patient outcomes as measured by quality-adjusted life-years (QALYs) and health care costs over a 10-year period. We assumed that patients who fail initial targeted treatment either proceed to subsequent therapy or discontinue targeted treatment. Effectiveness estimates for initial treatment were defined as improvement in Psoriasis Area and Severity Index (PASI) from baseline and derived from a 2018 network meta-analysis. Wholesale acquisition drug costs were discounted by a class-specific, empirically derived rebate percentage off of 2016 costs. We conducted one-way and probabilistic sensitivity analyses to assess uncertainty in results. RESULTS: The incremental benefits compared with no targeted treatment were, in descending order: ixekizumab 1.68 QALYs (95% credible range [CR] = 1.11-2.02), brodalumab 1.64 QALYs (95% CR = 1.08-1.98), secukinumab 1.51 QALYs (95% CR = 1.00-1.83), ustekinumab 1.43 QALYs (95% CR=0.94-1.74), infliximab 1.27 QALYs (95% CR = 0.89 1.55), adalimumab 1.15 QALYs (95% CR = 0.76-1.44), etanercept 0.97 QALYs (95% CR = 0.61-1.25), and apremilast 0.87 QALYs (95% CR = 0.52-1.17). Costs of care without targeted treatment totaled $66,451, and costs of targeted treatment ranged from $137,080 (apremilast) to $255,422 (ustekinumab). Probabilistic sensitivity analysis results indicated that infliximab and apremilast are likely to be the most cost-effective initial treatments at willingness-to-pay thresholds around $100,000 per QALY, while IL-17 drugs are more likely to be cost-effective at thresholds approaching $150,000 per QALY. Acquisition cost of the initial targeted drug and utility of clinical response were the most influential parameters. CONCLUSIONS: Our findings suggest that initial targeted treatment with IL-17 inhibitors is the most effective treatment strategy for plaque psoriasis patients who have failed methotrexate and phototherapy. Apremilast, brodalumab, infliximab, ixekizumab, and secukinumab are cost-effective at different willingness-to-pay thresholds. Additional research is needed on whether the effectiveness of targeted agents changes when used after previously targeted agents. DISCLOSURES: Funding for this study was contributed by the Institute for Clinical and Economic Review (ICER). Ollendorf, Chapman, Pearson, and Kumar are current employees, and Loos and Liu are former employees, of ICER, an independent organization that evaluates the evidence on the value of health care interventions, which is funded by grants from the Laura and John Arnold Foundation, Blue Shield of California Foundation, and the California HealthCare Foundation. ICER's annual policy summit is supported by dues from Aetna, AHIP, Anthem, Alnylam, AstraZeneca, Blue Shield of California, Cambia Health Solutions and MedSavvy, CVS Caremark, Editas, Express Scripts, Genentech, GlaxoSmithKline, Harvard Pilgrim Health Care, Health Care Service Corporation, OmedaRx, United Healthcare, Johnson & Johnson, Kaiser Permanente, Premera Blue Cross, Merck, National Pharmaceutical Council, Takeda, Pfizer, Novartis, Lilly, Humana, Prime Therapeutics, Sanofi, and Spark Therapeutics. Linder owns stock in Amgen, Biogen, and Eli Lilly; has contingent value rights in Sanofi Genzyme (related to alemtuzumab for multiple sclerosis); has received grant support from Astellas Pharma not related to this study and Clintrex, which was supported by AstraZeneca on an unrelated topic; and has received an honorarium from the Society of Healthcare Epidemiology of America (SHEA) as part of the SHEA Antimicrobial Stewardship Research Workshop Planning Committee, an educational activity supported by Merck. No other authors have potential conflicts of interest. PMID- 30479198 TI - Sustaining Ambulatory Comprehensive Medication Management Practices: Perspectives from a Minnesota Pharmacist Collaborative. AB - INTRODUCTION: In a time of evolving health care landscapes, pharmacists who provide comprehensive medication management (CMM) need to demonstrate financial and quality value to sustain their practice. Minnesota CMM programs started providing services in 1998, before recognition or reimbursement existed, and continue practices today. This long history lends itself well to the development of best practices for sustaining CMM practices. PROGRAM DESCRIPTION: The Health Systems for Integrated Medication Management (HAIMM) represents 13 Minnesota health systems, including 90 pharmacists and 121 clinics across the state. Pharmacist representatives from each of the participating health systems were polled to determine commonly implemented sustainability strategies. Common trends were identified, and the group was surveyed for important considerations on implementation of each strategy. OBSERVATIONS: Poll results of strategies for CMM practice sustainability were placed into 2 categories: fiscal and quality-based initiatives. Each strategy was discussed to determine implementation options and lessons learned from the collaborative. IMPLICATIONS: Numerous strategies were identified to ensure CMM practice sustainability. HAIMM's programs found it best to use a mixture of fiscal and quality-based strategies to sustain their practices. DISCLOSURES: No outside funding supported this study. The authors have no conflicts of interest to declare. The information within this article should not be construed as legal advice, and the Health-Systems Alliance for Integrated Medication Management (HAIMM) disclaims all liability of action or lack of action resulting from use of this content. Readers should obtain legal and/or professional advice from a licensed professional within their state. PMID- 30479199 TI - Coverage of Novel Therapeutic Agents by Medicare Prescription Drug Plans Following FDA Approval. AB - BACKGROUND: Regulatory approval of novel therapies by the FDA does not guarantee insurance coverage requisite for most clinical use. In the United States, the largest health insurance payer is the Centers for Medicare & Medicaid Services (CMS), which provides Part D prescription drug benefits to over 43 million Americans. While the FDA and CMS have implemented policies to improve the availability of novel therapies to patients, the time required to secure Medicare prescription drug benefit coverage-and accompanying restrictions-has not been previously described. OBJECTIVE: To characterize Medicare prescription drug plan coverage of novel therapeutic agents approved by the FDA between 2006 and 2012. METHODS: This is a cross-sectional study of drug coverage using Medicare Part D prescription drug benefit plan data from 2007 to 2015. Drug coverage was defined as inclusion of a drug on a plan formulary, evaluated at 1 and 3 years after FDA approval. For covered drugs, coverage was categorized as unrestrictive or restrictive, which was defined as requiring step therapy or prior authorization. Median coverage was estimated at 1 and 3 years after FDA approval, overall, and compared with a number of drug characteristics, including year of approval, CMS protected class status, biologics versus small molecules, therapeutic area, orphan drug status, FDA priority review, and FDA-accelerated approval. RESULTS: Among 144 novel therapeutic agents approved by the FDA between 2006 and 2012, 14% (20 of 144) were biologics; 40% (57 of 144) were included in a CMS-protected class; 31% (45 of 144) were approved under an orphan drug designation; 42% (60 of 144) received priority review; and 11% (16 of 144) received accelerated approval. The proportion of novel therapeutics covered by at least 1 Medicare prescription drug plan was 90% (129 of 144) and 97% (140 of 144) at 1 year and 3 years after approval, respectively. At 3 years after approval, 28% (40 of 144) of novel therapeutics were covered by all plans. Novel therapeutic agents were covered by a median of 61% (interquartile range [IQR] = 39%-90%) of plans at 1 year and 79% (IQR = 57%-100%) at 3 years (P < 0.001). When novel therapeutics were covered, many plans restricted coverage through prior authorization or step therapy requirements. The median proportion of unrestrictive coverage was 29% (IQR = 13% 54%) at 3 years. Several drug characteristics, including therapeutic area, FDA priority review, FDA-accelerated approval, and CMS-protected drug class, were associated with higher rates of coverage, whereas year of approval, drug type, and orphan drug status were not. CONCLUSIONS: Most Medicare prescription drug plans covered the majority of novel therapeutics in the year following FDA approval, although access was often restricted through prior authorization or step therapy and was dependent on plan choice. DISCLOSURES: Funding for this study was contributed by a student research grant awarded to Shaw and provided by the Yale School of Medicine Office of Student Research under National Institutes of Health training grant award T35DK104689. Ross reports research grants to Yale University from the U.S. Food and Drug Administration (U01FD005938, U01FD004585), Medtronic, Johnson & Johnson, Centers for Medicare & Medicaid Services (HHSM-500 2013-13018I), Blue Cross-Blue Shield Association, Laura and John Arnold Foundation, Agency for Healthcare Research and Quality (R01HS022882), and National Institutes of Health (R01HS025164), unrelated to this study. Dhruva has nothing to disclose. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. PMID- 30479200 TI - Incident-to Billing for Pharmacists. AB - The inclusion of pharmacists on care teams has been shown to improve clinical and economic health outcomes. However, a significant barrier to the widespread incorporation of pharmacists into care teams is the ability to financially support the salary of the pharmacist. A mechanism to improve the ability of pharmacists to generate clinical revenue already exists in the form of incident to billing, although there remains considerable uncertainty regarding the criteria for incident-to billing and specifically how pharmacists can use this model to capture revenue for clinical services. In this article, we discuss incident-to billing criteria as it pertains to outpatient clinics, common misconceptions related to incident-to billing, and how clinical pharmacists may use this mechanism to generate revenue for the clinical services they provide. DISCLOSURES: This work was not supported by any funding source. The authors have no relevant conflicts of interest to disclose. PMID- 30479201 TI - Discrepancies Between FDA-Required Labeling and Evidence that Payers Cite in Drug Coverage Policies. AB - BACKGROUND: FDA-required labeling summarizes certain data that the FDA relies on in its drug approval process. However, when determining coverage of specialty drugs, health care payers may consider dissimilar evidence. OBJECTIVE: To compare evidence cited by the largest U.S. commercial payers in their specialty drug coverage policies with evidence featured in the labeling of the indicated drugs. METHODS: We used the Tufts Medical Center Specialty Drug Evidence and Coverage Database (SPEC)-a database of specialty drug coverage policies issued by 17 of the 20 largest U.S. commercial health care payers-to identify coverage policies for drugs indicated for multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, and non-small cell lung cancer (NSCLC). These disease categories were selected because each was represented by multiple drugs. For each drug, we identified endpoints included in the clinical studies presented in the FDA-required labeling. Using SPEC, we identified randomized controlled trials (RCTs) and other clinical studies that at least 1 payer cited in its coverage policies for the included drugs. We reviewed the full text of each study to identify the endpoints reported. We categorized endpoints as identical to endpoints in the FDA-required labeling of the drugs; similar (e.g., a different measurement scale was used to evaluate the same endpoint); and different (the endpoint was not featured in the FDA-required labeling). RESULTS: We included 41 drugs and reviewed 348 studies (246 RCTs and 102 other clinical studies). Of 2,237 endpoints, 63% were categorized as identical, 26% as similar, and 12% as different. Rheumatoid arthritis was the indication with the largest proportion of endpoints categorized as identical (74% of endpoints in the RCTs cited by payers; 59% of endpoints in the other clinical studies cited by payers). NSCLC was the indication with the largest proportion of endpoints categorized as different (33% of end-points in the RCTs cited by payers; 37% of endpoints in the other clinical studies cited by payers). CONCLUSIONS: Payers often report reviewing clinical evidence that goes beyond information included in FDA-required labeling. Our findings suggest that the FDA should continue engaging with the manufacturer and payer communities to appropriately facilitate communication of information necessary to allow for informed coverage decisions. DISCLOSURES: This study was funded by an unrestricted grant from the Pharmaceutical Research and Manufacturers of America. The authors work with The Center for the Evaluation of Value and Risk in Health, which is partially supported through the CEA Registry Sponsorship program; the CEA Registry has received funding from the National Science Foundation, National Library of Medicine, Agency for Healthcare Research and Quality, Centers for Disease Control and Prevention, and a variety of pharmaceutical and device companies that subscribe to the data. Chambers reports personal fees from Health Advances, Ernst & Young, Magellan Health, Summit Therapeutics, and Sanofi-Aventis, unrelated to this study. Neumann reports past advisory board work with Amgen, Avexis, Axovant, Bayer, Bluebird, Congressional Budget Office, Janssen, Merck, Novo Nordisk, Pacira, Paratek, and Sage; consulting work for Boston Health Economics, GSK, Precision Health Economics, Veritech, and Vertex; speaker fees from AbbVie, Celgene, and Roche; and grants from the Alzheimer's Association, Amgen, Gates, Lundbeck, NIH, NPC, and Sage, all unrelated to this study. The other authors have nothing to disclose. PMID- 30479202 TI - Clinical Utility of Pharmacogenetic Testing and a Clinical Decision Support Tool to Enhance the Identification of Drug Therapy Problems Through Medication Therapy Management in Polypharmacy Patients. AB - BACKGROUND: In polypharmacy patients, medication therapy management (MTM) services provide a comprehensive review of current medications and future treatment goals. Pharmacogenetics (PGx) may further optimize the identification of potential drug therapy problems (DTPs); however, the clinical utility of PGx information with a clinical decision support tool (CDST) in an MTM setting in identifying DTPs has not been systematically assessed. OBJECTIVE: To assess the clinical utility of an MTM service enhanced by pharmacogenetic test results and a clinical decision support tool. METHODS: This study was a post hoc analysis of the data obtained from an open-label, randomized, observational trial. Polypharmacy patients eligible for MTM service were randomly assigned to 3 intervention arms: standard MTM (SMTM), MTM incorporating CDST (CMTM), and CMTM further enhanced by PGx test results of CYP450 and VKORC1 enzymes (PGxMTM). Allocation for this post hoc analysis was based on patient adherence to the research protocol and completion of a PGx test. The number of DTPs per patient was compared across the 3 arms using analysis of variance. In addition, the frequency of serious DTPs as a categorical variable (grade 3 or above vs. lower grade) was compared across the 3 arms between PGx driven and non-PGx driven DTP recommendations. Statistical significance was tested using the chi-square test. The level of agreement between the DTP seriousness and the acceptance made by prescribers was presented as Cohen's kappa coefficient. RESULTS: Numbers of patients after cohort reallocation based on completion of PGx testing were 104, 180, and 58 for the SMTM, CMTM, and PGxMTM arms, respectively. On average, 3.08 DTPs were identified for each patient, which was nearly identical across all 3 arms. Blinded clinical pharmacists considered seriousness (grade 3 or 4) in 31% of the PGx-related DTPs in comparison with 4.9% of the non-PGx DTPs (P < 0.001). The more serious (i.e., grade 3 or above) DTP recommendations were more likely to be accepted by prescribers with the odds ratios of 1.95 (P = 0.05) and 2.39 (P = 0.15), when the analysis was performed for all DTPs and DTPs from the PGxMTM arm only, respectively. CONCLUSIONS: MTM enhanced by PGx testing and the clinical decision support tool did not increase the number of DTPs identified. However, PGx testing and the decision support software helps pharmacists determine more serious DTPs, and resulting subsequent recommendations were more readily accepted by a prescriber. Future study of the patient safety outcomes and overall health care costs associated with the utility of the decision support is warranted. DISCLOSURES: No funding was received for conducting the post hoc analysis presented in this study. Magness is employed by Magellan Health, which received funding from Genelex for costs to administrate the medication management program. The open-label randomized trial was sponsored by Genelex (Clinicaltrials.gov ID number NCT02428660). PGx tests were provided and laboratory analysis was performed by Genelex. Valerie Baron is an employee of YouScript, which created the clinical decision support tool used in this study and formerly was part of Genelex. The other authors have nothing to disclose. PMID- 30479203 TI - State Approaches to Therapeutic Interchange in Community Pharmacy Settings: Legislative and Regulatory Authority. AB - Therapeutic interchange is the act of switching a prescribed drug for another drug in the same therapeutic class that is believed to be therapeutically similar but may be chemically different. Therapeutic interchange is different from generic substitution in that it does not occur between therapeutically equivalent products; instead, products are substituted for those that are likely to have a substantially equivalent therapeutic effect generally at a lower cost. Therapeutic interchange is common in institutional settings across the United States but rarely occurs in community pharmacy settings without a pharmacist first contacting the original prescriber and requesting a new prescription in order to facilitate a change. As of 2018, Arkansas, Idaho, and Kentucky have passed laws to enable therapeutic interchange in community pharmacy settings. In general, these laws require the original prescriber to opt-in to allow therapeutic interchange, and the pharmacist generally must leverage the formulary of the patient's health plan to guide decision making within the same therapeutic class. These 3 states require that the pharmacist notify the original prescriber of any interchange in order to ensure a complete and accurate medication record. When appropriately structured, state laws enabling therapeutic interchange in community pharmacy settings allow pharmacists to use their medication expertise to save valuable time and enhance patient care while reducing health care costs. DISCLOSURES: No funding supported the writing of this article. The authors have nothing to disclose. PMID- 30479205 TI - The role of mitochondria in systemic lupus erythematosus: A glimpse of various pathogenetic mechanisms. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is a polysystem autoimmune disease that adversely affects human health. Various organ can be affected, including the kidney or brain. Traditional treatment methods for SLE primarily rely on glucocorticoids and immunosuppressors. Unfortunately, these therapeutic agents cannot prevent a high recurrence rate after SLE remission. Therefore, novel therapeutic targets are urgently required. METHODS: A systematic search of the published literature regarding the abnormal structure and function of mitochondria in SLE and therapies targeting mitochondria was performed in several databases. RESULTS: Accumulating evidence indicates that mitochondrial dysfunction plays important roles in the pathogenesis of SLE, including influencing mitochondrial DNA damage, mitochondrial dynamics change, abnormal mitochondrial biogenesis and energy metabolism, mitophagy, oxidative stress, inflammatory reactions, apoptosis and NETosis. Further investigation of mitochondrial pathophysiological roles will result in further clarification of SLE. Specific lupus-induced organ damage also exhibits characteristic mitochondrial changes. CONCLUSION: This review aimed to summarize the current research on the role of mitochondrial dysfunction in SLE, which will necessarily provide potential novel therapeutic targets for SLE. PMID- 30479206 TI - Treatment of hypertension induced albuminuria. AB - Regardless of having similar antihypertensive effect, different antihypertensive drug classes have different effect on albuminuria.Patients with albuminuria will usually need more than one drug to achieve blood pressure control, particularly if the aim is also to reduce albuminuria.Albuminuria is independently associated with cardiovascular and renal risk regardless of diabetes status. The recent ESC/ESH guidelines listed microalbuminuria among the hypertension-mediated organ damages. Albumin-to-creatinine ratio was suggested to be included in the routine workup for evaluation of every hypertensive patient and changes in albuminuria were considered to have moderate prognostic value. Because of its specific effects on renal hemodynamic and glomerular structure, the ACEIs and ARBsshould be prescribed in maximum tolerated doses. The MRAscan be considered in uncontrolled hypertensive patients. The CCBscan be used in addition to the RAAS blockade. Data on antialbuminuric effect of the new CCBs generation (T-type and N type channel blockers) is promising and they might be preferential CCBs when available. In the case of resistant hypertension thiazide or thiazide-like diuretic has to be added into the combination with RAAS blockers and other antihypertensive drugs. Low-salt intake has to be recommended for all hypertensive patients, particularly those with albuminuria. A multifactorial and early antialbuminuric approach should be started early even when albuminuria values are below the cut-off value for microalbuminuria. PMID- 30479207 TI - Treatment of Hypertension Induced Target Organ Damage in Children and Adolescents. AB - High blood pressure in children and adolescents may have adverse impact on the heart, the vessels, the kidney, and the central nervous system causing early functional or structural changes. The most prevalent subclinical hypertensive target organ damage in children and adolescents is left ventricular hypertrophy, and echocardiographic assessment of left ventricular mass is suggested in all hypertensive children. There is evolving evidence that antihypertensive treatment in children and adolescents could lead to regression of target organ damage, emphasizing also the importance of adequate blood pressure control. Assessment of subclinical organ damage could guide clinical decisions from diagnosis with regard to intensity of non-pharmacological treatment, time to wait for initiation of pharmacological treatment, and choice of drug. Longitudinal studies are needed to relate the effectiveness of antihypertensive treatment and blood pressure targets in childhood with future cardiovascular or renal events. This review summarizes evidence on the associations of hypertension with target organ damage in children and adolescents and the role of antihypertensive therapy on the regression of target organ damage in the pediatric age group. PMID- 30479208 TI - Treatment of hypertension to prevent atrial fibrillation. AB - Atrial fibrillation (AF) and hypertension (HT) are expected to rapidly rise worldwide in the next few years. Important improvements in AF therapy are hampered by pro-arrhythmic and bleeding risks of current medications. Prevention of AF is an important matter as it will not only prevent the disease but also medications side effects, and it is likely to be cost effective. HT is a major contributor to AF. As a modifiable risk factor, its treatment might reduce new onset AF, and recurrent AF after cardioversion or ablation as well. We review here the effect of HT treatment to prevent AF. Renin-angiotensin system (RAS) blockers prevent new-onset AF in patients at high cardiovascular risk, and especially so in heart failure patients. Evidence is less strong among hypertensive patients, except in the presence of left ventricular hypertrophy or if at high cardiovascular risk. In such circumstances, losartan or valsartan were more effective than atenolol or amlodipine. After medical or electrical cardioversion, RAS blockers favourably affect AF recurrence and this class of drug should figure among the prescribed antihypertensive medications. Last, the addition of renal denervation to pulmonary vein isolation may provide even further therapeutic opportunities in patients with refractory HT and AF. PMID- 30479209 TI - pNitro-Tyr-PseAAC: Predict nitrotyrosine sites in proteins by incorporating five features into Chou's general PseAAC. AB - BACKGROUND: Closely related to causes of various diseases such as rheumatoid arthritis, septic shock, and coeliac disease; tyrosine nitration is considered as one of the most important post-translational modification in proteins. Inside a cell, protein modifications occur accurately by the action of sophisticated cellular machinery. Specific enzymes present in endoplasmic reticulum accomplish this task. The identification of potential tyrosine residues in a protein primary sequence, which can be nitrated, is a challenging task. METHODS: To counter the prevailing, laborious and time-consuming experimental approaches, a novel computational model is introduced in the present study. Based on data collected from experimentally verified tyrosine nitration sites feature vectors are formed. Later, an adaptive training algorithm is used to train a back propagation neural network for prediction purposes. To objectively measure the accuracy of the proposed model, rigorous verification and validation tests are carried out. RESULTS: Through verification and validation, a promising accuracy of 88%, a sensitivity of 85%, a specificity of 89.18% and Mathew's Correlation Coefficient of 0.627 is achieved. CONCLUSION: It is concluded that the proposed computational model provides the foundation for further investigation and be used for the identification of nitrotyrosine sites in proteins. PMID- 30479210 TI - Pituitary adenylyl cyclase activating polypeptide (PACAP) signaling and the cell cycle machinery in neurodegenerative diseases. AB - Pituitary adenylyl cyclase activating polypeptide (PACAP) is a neuropeptide with great neuroprotective effects and remarkable therapeutic potential. PACAP activates several cellular pathways to exert its protective effects. Emerging evidence shows that PACAP can modify the levels and activity of cell cycle components involved in neurodegeneration to protect neurons from death. Cell cycle is a highly-regulated process that controls the balance between proliferation, differentiation and death of every cell in the body. Aberrant expression and function of components of the cell cycle machinery have been linked to neurodegenerative diseases, in which different types of neuronal cells become dysfunctional and dye in response to toxic insults. Since neurons are post mitotic cells, re-entry into the cell cycle has been shown to be pathological and contribute to the process of neurodegeneration. Moreover, an increasing number of studies highlights the importance of the role of cell cycle components outside the cell cycle, and their involvement in neurodegenerative disorders. Here, we discuss the pleiotropic effects of PACAP on cell cycle machinery and the implication for the treatment of neurodegenerative diseases. PMID- 30479211 TI - Nanotherapeutics for the treatment of cancer and arthritis. AB - Nanotechnology is gaining significant attention worldwide for the treatment of complex disease such as AIDS (acquired immune deficiency syndrome), cancer and rheumatoid arthritis. Nanomedicine is the application of nanotechnology used for diagnosis and treatment for the disease that includes the preservation and improvement of human health by covering an area such as drug delivery using nanocarriers, nanotheranostics and nanovaccinology. The present article provides an insight on several aspects of nanomedicine such as usages of multiple type of nanocarriers, their status, advantages and disadvantages with reference to cancer and rheumatoid arthritis. An extensive search was performed on bibliographic database for research article on nanotechnology and nanomedicine along with looking deeply into the aspects of these diseases, and how all of them are co related. We further combined all the necessary information from various published articles and briefed to provide the current status. Nanomedicine confers a unique technology against complex diseases which includes early diagnosis, prevention, and personalized therapy. The most common nanocarriers used globally are liposomes, polymeric nanoparticles, dendrimers, metallic nanoparticles, magnetic nanoparticles, solid lipid nanoparticles, polymeric micelles and nanotubes among others. Nanocarriers are used to deliver drugs and biomolecules like proteins, antibody fragments, DNA fragments, and RNA fragments as the base of cancer biomarkers. PMID- 30479212 TI - Removal of Pharmaceutical Contaminants in Wastewater using Nanomaterials: A Comprehensive Review. AB - BACKGROUND: The limitless presence of pharmaceutical contaminants in discharged wastewater has emerged as a threat to aquatic species and humans. Their presence in drinking water has although raised substantial concerns, very little is known about the fate and ecological impacts of these pollutants. As a result, these pollutants are inevitably introduced to our food chain at trace concentrations. Unfortunately, the conventional wastewater treatment techniques are unable to treat pharmaceuticals completely with practical limitations. The focus has now been shifted towards nanotechnology for the successful remediation of these persistent pollutants. Thus, the current review specifically focuses on providing readers brief yet sharp insights into applications of various nanomaterials for the removal of pharmaceutical contaminants. METHODS: An exhaustive collection of bibliographic database was done with articles having high impact and citations in relevant research domains. An in-depth analysis of screened papers was done through standard tools. Studies were categorized according to the use of nanoscale materials as nano-adsorbents (graphene, carbon nanotubes), nano photocatalysts (metal, metal oxide), nano-filtration, and ozonation for promising alternative technologies for the efficient removal of recalcitrant contaminants. RESULTS: A total of 365 research articles were selected. The contemporary advancements in the field of nanomaterials for drinking and wastewater treatment have been thoroughly analyzed along with their future perspectives. CONCLUSION: The recommendations provided in this article will be useful to adopt novel strategies for on-site removal of the emerging contaminants in pharmaceutical effluents and related industries. PMID- 30479213 TI - Expression Profile of Endoglin in Different Grades of Endometrial Cancer. AB - BACKGROUND: Endoglin is a marker of active, proliferating endothelial cells of blood vessels. In many cancers, it is present in both peripheral vessels and vessels located inside tumor. Endoglin is more specific and sensitive compared to other tumor angiogenesis markers. It is suggested that endoglin can be considered a reliable marker of disease outcome. OBJECTIVE: The aim of the study was to assess the expression of endoglin and to determine its potential usefulness as a complementary molecular marker of endometrial cancer. METHOD: The study included 60 women who underwent hysterectomy: 45 with endometrioid endometrial cancer (study group) and 15 without neoplastic changes (control group). The study group was further divided according to the degree of histological differentiation: G1, 17; G2, 15; and G3, 13. The expression of endoglin was determined immunohistochemically with mouse anti-Endoglin monoclonal antibody. The obtained reactions were evaluated using light microscopy. RESULTS: Analysis of endoglin expression in endothelium showed that it reached 145% of the control. In G2, we observed that the endoglin level decreased and was similar to the control, while in G3 it increased and was even higher than in G1. In cancer cells, endoglin expression increased with the degree of histological differentiation. CONCLUSION: Endoglin can be considered a valuable complementary molecular marker, allowing to visualize the advancement of the cancer process, including endometrial cancer. PMID- 30479214 TI - Differential Expression of Sumoylation Enzymes SAE1, UBA2, UBC9, PIAS1 and RanBP2 in Major Ocular Tissues of Mouse Eye. AB - It is now well established that protein sumoylation is an important mechanism to regulate multiple cellular processes including gene transcription, chromatin structure, cell proliferation and differentiation, as well as pathogenesis. In the vertebrate eye, we and other have previously shown that sumoylation can regulate differentiation of major ocular tissues including retina and lens. However, the expression patterns of the three types of sumoylation enzymes, the activating enzymes SAE1 and UBA2, the conjugating enzyme UBC9, and the ligating enzymes such as RanBP2 and PIAS1 have not be well studied in the ocular tissues. In the present study, using QRT-PCR and western blot analysis, we have determined the differentiation expression patterns of the above three types of enzymes, and the obtained results lay down a foundation for further exploration of sumoylation functions in vertebrate eye. PMID- 30479215 TI - Inhibition of the ATPase domain of human topoisomerase IIa on HepG2 cells by 1, 2 benzenedicarboxylic acid, mono (2-ethylhexyl) ester: molecular docking and dynamics simulations. AB - BACKGROUND: The major attention has been received by the natural products in the prevention of diseases due to their pharmacological role. OBJECTIVE: The major focus of the study was to search for highly potential anti-cancer compounds from marine Streptomyces sp. VITJS4 (NCIM No. 5574). METHOD: Cytotoxic assay was examined by MTT assay on HepG2 cells. Bioassay-guided fractionation of the ethyl acetate extract from the fermented broth led to the isolation of the compound. The lead compound structure was elucidated by combined NMR and MS analysis, and the absolute configuration was assigned by extensive spectroscopic analysis. RESULTS: On the basis of spectroscopic data, the compound was identified as 1, 2 benzenedicarboxylic acid, mono 2-ethylhexyl (BMEH). The compound exhibited in vitro anticancer potential against liver (HepG2) cancer cells. Based on the flow cytometric analysis, it was evident that the BMEH was also effective in arresting the cell cycle at G1 phase. Further, the Western blotting analysis confirmed the down-regulation of Bcl-2 family proteins, and activation of caspase-9 and 3. The molecular dynamics simulation was performed to reveal the activity of the compound over a time period of 10ns. From the molecular dynamics studies, it was found that the stability and compactness were attained by the protein by means of the compound interaction. CONCLUSION: This study highlights our collaborative efforts to ascertain lead molecules from marine actinomycete. This is the first and foremost report to prove the mechanistic studies of the purified compound 1, 2-benzene dicarboxylic acid, mono(2-ethylhexyl) ester isolated from marine Streptomyces sp.VITJS4 against HepG2 cells. PMID- 30479216 TI - Insilico structure modeling and molecular docking analysis of phosphoribosyl pyrophosphate amidotransferase (PPAT) with antifolate inhibitors. AB - Cancer remains the one most serious disease worldwide. Robust metabolism is hallmark of the cancer. PPAT (phosphoribosyl pyrophosphate amidotransferase) catalyzes the first committed step of de novo purine biosynthesis. Hence PPAT, the key regulatory spot in De novo purine nucleotide biosynthesis is an attractive and credible drug target for leukemia and other cancer therapeutics. In the present study detailed computational analysis has been performed for PPAT protein the key enzyme in de novo purine biosynthesis is inhibited by many folate derivatives, hence we aimed to investigate and gauge the inhibitory effect of antifolate derivatives; lomexterol (LTX) methotrexate (LTX), and pipretixin (PTX) with human PPAT to effectively capture and inhibit De novo purine biosynthesis pathway. Sequence to structure computational approaches followed by molecular docking experiments were performed to gain insight into the inhibitory mode, binding orientation and binding affinities of selected antifolate derivatives against important structural features of PPAT. Results indicated strong affinity of antifolate inhibitors for the conserved active site of PPAT molecule encompassing number of hydrophobic, hydrogen bonding, Vander waals and electrostatic interactions. Conclusively, the strong physical interaction of selected antifolate inhibitors with human PPAT suggests the selective inhibition of De novo purine biosynthesis pathway by antifolate derivatives towards cancer therapeutics. PMID- 30479217 TI - Evolving Mechanistic Concepts Of Epileptiform Synchronization And Their Relevance In Curing Focal Epileptic Disorders. AB - The synchronized activity of neuronal networks under physiological conditions is mirrored by specific oscillatory patterns of the EEG that are associated with different behavioral states and cognitive functions. Excessive synchronization can however lead to focal epileptiform activity characterized by interictal and ictal discharges in epileptic patients and animal models. This review focusses on studies that have addressed epileptiform synchronization in temporal lobe regions by employing in vitro and in vivo recording techniques. First, we consider the role of ionotropic and metabotropic excitatory glutamatergic transmission in seizure generation as well as the paradoxical role of GABAA signaling in initiating and perhaps maintaining focal seizure activity. Second, we address non synaptic mechanisms (which include voltage-gated ionic currents and gap junctions) in the generation of epileptiform synchronization. For each mechanism, we discuss the action of anti-epileptic drugs that are presumably modulating excitatory or inhibitory signaling and voltage-gated currents to prevent seizures in epileptic patients. These findings provide insights into the mechanisms of seizure initiation and maintenance thus leading to the development of specific pharmacological treatments for focal epileptic disorders. PMID- 30479218 TI - Current drugs and potential future neuroprotective compounds for Parkinson's disease. AB - The research progress of understanding the etiology and pathogenesis of Parkinson's disease (PD) has yet lead to the development of some clinical approaches intended to treat cognitive and behavioral symptoms, such as memory and perception disorders. Despite the major advances in different genetic causes and risk factors for PD, which share common pathways to cell dysfunction and death, there is not yet a complete model of PD that can be used to accurately predict the effect of drugs on disease progression. Clinical trials are also important to test any novel neuro-protective agent, and recently there have been great advances in the use of anti-inflammatory drugs and plant flavonoid antioxidants to protect against specific neuronal degeneration and its interference with lipid and cholesterol metabolism. The increasing knowledge of the molecular events underlying the degenerative process of PD has stimulated research to identify natural compounds capable of halting or slowing the progress of neural deterioration. Polyphenols and flavonoids, which play a neuroprotective role in a wide array of in vitro and in vivo models of neurological disorders, emerged from among the multi-target bio-agents found mainly in plants and microorganisms. This review presents a detailed overview of the multimodal activities of neuroprotective bio-agents tested so far, emphasizing their neurorescue/neuroregenerative activity. The brain-penetrating property of bio agents may make these compounds an important class of natural drugs for the treatment of neurodegenerative diseases. Although there are numerous studies demonstrating beneficial effects in the laboratory by identifying critical molecular targets, the clinical efficacy of these neuroprotective treatments remains to be proven accurately. PMID- 30479219 TI - Long Noncoding RNA:Function and Mechanism on Differentiation of Mesenchymal Stem Cells and Embryonic Stem Cells. AB - BACKGROUND: Long suspected as transcriptional noise, recently recognized, long non-coding RNAs (lncRNAs) are emerging as an indicator, biomarker and therapy target in the physiologic and pathologic process. Mesenchymal stem cells and embryonic stem cells are important source for normal and therapeutic tissue repair. However, the mechanism of stem cell differentiation is not completed understood. Research on lncRNAs may provide novel insights into the mechanism of differentiation process of the stem cell which is important for the application of stem cell therapy. The lncRNAs field is still very young, new insights into lncRNAs function are emerging to a greater understanding of biological processes. OBJECTIVE: In this review, we summarize the recent researches studying lncRNAs and illustrate how they act in the differentiation of the mesenchymal stem cells and embryonic stem cells, and discuss some future directions in this field. RESULTS: Numerous lncRNAs were differentially expressed during differentiation of mesenchymal stem cells and embryonic stem cells. LncRNAs were able to regulate the differentiation processes through epigenetic regulation, transcription regulation and post-transcription regulation.. CONCLUSION: LncRNAs are involved in the differentiation process of mesenchymal stem cells and embryonic stem cells, and they could become promising indicator, biomarker and therapeutic targets in the physiologic and pathologic process. However, the mechanisms of the role of lncRNAs still require further investigation. PMID- 30479220 TI - Induction of Apoptosis by pierisin-6 in HPV positive HeLa and HepG2 Cancer Cells is mediated by the caspase-3 dependent mitochondrial pathway. AB - OBJECTIVE: To explore the cytotoxic and apoptotic activity of the pierisin-6 protein in HPV HeLa and HepG2 cell lines. METHODS: In this study, isolation and purification of cytotoxic prierisin-6 from the larvae of Pieris napi by affinity column chromatography techniques.Characterization of full-length mRNA of pierisin 6 gene was performed using 3'/5' RACE PCR. The quantitative RT-PCR used to study the developmental stage-specific expression of pierisin-6 mRNA. The most effective concentration of pierisin-6 protein was determined by measuring cell proliferation. Apoptosis was assessed using AO/Et-Br, Propidium Iodide and Rhodamine 123 assays, whereas protein levels of caspase 3, cytochrome C were evaluated by ELISA method. Pierisin-6 induced cell cycle arrest was determined using Propidium iodide by FACS. RESULTS: In this study, Pierisin-6, a novel apoptotic protein was found to have cytotoxicity against HeLa at IC50 of 2.02 ng/ml and HepG2 human cancer cell lines. Flow cytometry analysis confirms an increased percentage of apoptotic cells in sub G1 phase and cell cycle arrest at S phase. Alteration in the transmembrane potential of mitochondria, Cytochrome c released from mitochondrial membrane, and caspase substrate assay demonstrated the cleavage of Ac-DEVD-pNA signifying the activation of Caspase-3. These findings suggested that Pierisin-6 significantly induce apoptosis in HeLa and HepG2 cells and is attributed mainly through a mitochondrial pathway by activation of caspases. The developmental and stage-specific expression of pierisin-6 mRNA was one thousand-fold increased from second to third instar larvae and gradually declined before pupation. CONCLUSION: Pierisin-6 represents a promising therapeutic approach for liver cancer patients. PMID- 30479222 TI - Cryopreservation Of Orchids - A Review. AB - BACKGROUND: The orchids are one of the beautiful creations of nature which stand apart from any other assemblage of flowering plants. They are highly evolutionary and ecologically significant group of plants that have effectively occupied almost every habitat on the earth. Indiscriminate collections and extermination of their natural habitats have threatened many species of orchids with extinction, resulting into severe reduction of their genetic resources in nature. It is necessary to adopt sound scientific protocols for preservation of orchid species. METHOD: This cost effective technique provides large storage time for the conservation of germplasm. Presently, efforts have been made to explore various cryopreservation techniques utilized so far and factors affecting the longevity of the propagules (in vivo and in vitro) while cryopreserving them. The sample to be cryopreserved are freeze-preserved in two ways, a) stepwise at two different subzero temperatures and b) in rapid method the samples are placed directly in the liquid nitrogen. RESULTS: The orchid seeds and pollen are the most suitable propagules for cryopreservation of orchids due to their minute size and less space requirement. CONCLUSION: Among the tissues (such as seeds, pollen, protocorms etc.) seeds are the most reliable. The present article reviews the cryopreservation techniques and factors effecting the cryopreservation, for in vitro conservation of orchid genepool. PMID- 30479221 TI - Synthesis of 3-Arylaminopropenone Linked 2-Arylbenzo[d]imidazo[2,1-b]thiazole Conjugates as Anticancer and Apoptotic Inducing Agents. AB - A new series of 3-arylaminopropenone linked 2-arylbenzo[d]imidazo[2,1-b]thiazole conjugates (4a-z) were synthesized and screened for cytotoxic activity against four human cancer cell lines. These conjugates showed moderate to good antiproliferative activity in the range of 1.6 - 48.5 uM. Some conjugates like 4e, 4f, 4g, 4k, 4m, 4r and 4t exhibited good antiproliferative activity and the insights of structure activity relationships were developed. Among them, conjugate 4e showed significant potential particularly against HeLa cell line with IC50 value 1.6 uM. Flow cytometry analysis indicates that conjugate 4e induce cell cycle arrest at G1 phase. In addition, the mechanism of cell growth inhibition and apoptotic induction by this conjugate was investigated in HeLa cancer cells using cell-based assays, including wound healing assay and Hoechst staining. Moreover, conjugate 4e led to collapse of mitochondrial membrane potential (DPsim) and increased levels of reactive oxygen species (ROS) were noted. PMID- 30479223 TI - Recent Patents, Formulation Techniques, Classification and Characterization of Liposomes. AB - BACKGROUND: During past decades' liposomes have emerged as efficient carriers for drugs, diagnostics, vaccines, nutrients and other bioactive agents. Liposomes, the spherical vesicles consisting of phospholipids bilayer have the ability to encapsulate both lipophilic and hydrophilic drugs. Extensive studies have been done in the past for investigating a number of drugs and genes for controlled release with liposomal formulation. Liposomes have also been investigated for their use in cancer treatment. Liposomes offer various advantages because of their biocompatible, biodegradable, nontoxic and non-immunogenic nature. METHODS: Liposomes are having cell-specific targeting with important applications in the fields of nanotechnology like cancer therapy, diagnosis, gene delivery, cosmetics, agriculture and in food technology. They are prepared by various methods like sonication method, ethanol injection method, lipid film hydration method, micro-emulsion method. CONCLUSION: This review will provide an overview of classification, the various formulation methods, characterization, patented formulations and applications of liposomes with future prospects. PMID- 30479224 TI - Mitochondria-Targeted Drugs. AB - BACKGROUND: Targeting of drugs to the subcellular compartments represents one of the modern trends in molecular pharmacology. The approach for targeting mitochondria was developed nearly 50 years ago, but only in the last decade has it started to become widely used for delivering drugs. A number of pathologies are associated with mitochondrial dysfunction, including cardiovascular, neurological, inflammatory and metabolic conditions. OBJECTIVE: This mini-review aims to highlight the role of mitochondria in pathophysiological conditions and diseases, to classify and summarize our knowledge about targeting mitochondria and to review the most important preclinical and clinical data relating to the antioxidant lipophilic cations MitoQ and SkQ1. METHODS: Review of available information in the PubMed and ClinicalTrials databases (US National Library of Medicine) with no limiting period. RESULTS AND CONCLUSION: Mitochondria play an important role in the pathogenesis of many diseases and possibly in aging. Both MitoQ and SkQ1 have shown many beneficial features in animal models and in a few completed clinical trials. More clinical trials and research efforts are needed to understand the signaling pathways influenced by these compounds. The antioxidant lipophilic cations have great potential for the treatment of a wide range of pathologies. PMID- 30479225 TI - Pleural effusion as an indicator of short term mortality in acute pulmonary embolism. AB - Introduction: Pulmonary embolism (PE) is known as one of the major causes of cardiovascular morbidity and mortality. Identification of high risk patients for short term and long-term mortality is crucial. The purpose of this study is to demonstrate the prognostic importance of simplified pulmonary embolism severity index (sPESI), radiological investigations and comorbidities in terms of short term mortality by simultaneous assessment of sPESI score, pulmonary computed tomography (CT) angiography findings and underlying comorbidities in patients diagnosed with acute pulmonary embolism. Materials and Methods: We retrospectively evaluated 570 patients diagnosed with acute PE confirmed by computer tomography pulmonary angiography (CTPA). Comorbidities were recorded, pulmonary embolism severity index scores were calculated and CTPA data were evaluated as predictors for short-term mortality. Result: The study population consisted of 570 patients, 292 (51.2%) patients were female and 74 patients (12.9%) died within 30 days due to PE diagnosis. In univariate analysis male gender (p= 0.031), congestive heart failure (CHF)(p< 0.029), main pulmonary artery involvement (p= 0.045), presence of pleural effusion (p= 0.001) and pericardial effusion (p= 0.004) at time of diagnosis and high risk sPESI group (p< 0.001) had a significant influence on mortality. In the multivariate analysis, pleural effusions (HR, 1.67; CI, 1.05-2.66; p< 0.030) and sPESI high risk group (HR, 9.56; CI, 4.71-19.43; p< 0.001) were remained significant and independent prognostic factors for survival. Conclusions: The present study underlined that presence of pleural effusion at the time of diagnosis in patients with massive pulmonary embolism and a high sPESI score in other patients were significant predictors of short-term mortality. PMID- 30479226 TI - Body surface area: a new anthropometric measurement for obstructive sleep apnea syndrome. AB - Introduction: We aimed to explore the possibility of using body surface area (BSA) as a new anthropometric measurement in evaluation of OSAS. Materials and Methods: Obesity was defined as having a BMI >= 30 kg/m2. BSA were calculated using the Mosteller and Boyd formulas. Totaly 426 (306 male) cases were included in this study. Result: The mean BMI was 33.0 kg/m2. The mean BSA was 2.06 m2 and 2.11 m2 respectively. BMI, AHI, oxygen desaturation, ODI and oxygen saturation were found different between the groups. Both BMI and BSA correlated positively with AHI, oxygen desaturation and ODI and negatively with oxygen saturation. There was no difference between BMI and BSA in mild cases in both gender. However, in moderate and severe cases, BMI and BSA were higher in males. We dedected that BSA and BMI display similar sensitivity and specificity values for the prediction of severe OSAS. Conclusions: To the best of our knowledge, this is the first study to examine the potential association between BSA and the severity of OSAS. As a result, we determined that BSA correlated with polisomnographic parameters as BMI. In severe OSAS BSA can be used as a predictor parameter like BMI. PMID- 30479227 TI - General features of patients with Pulmonary Langerhans Cell Histiocytosis followed in our instution. AB - Introduction: Pulmonary Langerhans Cell Histiocytosis (PLCH) is a rare disease affecting young smokers. It is more common between the ages of 20-40 and equals the male/female ratio. Lung biopsy is the most useful methods for diagnosis. The first treatment is to quit smoking. Corticosteroids or chemotherapeutic agents can be used in severe progressive cases despite of quiting smoking. The patients with PLCH followed in our clinic were assessed with general clinical features in the light of the literature. Materials and Methods: We retrospectively evaluated patients with PLCH in our clinic between January 1999 and June 2017. Result: The female and male distribution of the 21 patients was 11/10. The average age was 35.04 +/- 11.78 years. All patients were active smokers at the time of admission. The most common symptom was dyspnea. The most common finding in the pulmonary function tests was obstructive ventilatory defect. The DLCO value of the 70% patient in the carbonmonooxid diffusion test was below 80%. The most common pathologic findings detected in high-resolution chest tomography (HRCT) were cystic lesions involving bilateral upper and middle areas. There were 3 (14%) patients with pneumothorax at the time of admission and 6 (28.5%) patients with pneumothorax history before. The most common diagnostic method was open lung biopsy. All the patients quit cigarette after the diagnosis. There were 6 patients using steroid therapy, 1 patient receiving steroid and bosentan therapy, and 1 patient made pleurectomy due to recurrent pneumothorax. Lung transplantation was done to patient who received combined bosentan treatment with steroids. Conclusions: PLCH is a rare disease and should be considered in young, smokers with spontaneous pneumothorax and cystic lung disease in the differential diagnosis. As more diffusions are affected in patients, respiratory functions for follow-up should be evaluated with diffusion tests. It is essential to quit smoking in therapy. PMID- 30479228 TI - [Causes of mediastinal/hilar granulomatous lymphadenitis]. AB - Introduction: Granulomatous lung disease (GLD) is caused by a wide range of conditions and it is challenge for pulmonologist. A detailed history of exposures is fundamental in GDL and has been found pivotal to reach a precise diagnosis. Materials and Methods: Between September 2014 and December 2016, the distribution of patients diagnosed with granulomatous lymphadenitis in the mediastinal/hilar lymph nodes by endobronchial ultrasound (EBUS) or mediastinoscopy was analyzed. To be listed as 'confident', a diagnosis of sarcoidosis required compatible histological, radiological and clinical findings in conjunction with negative cultures. Infectious entities listed as 'confident' had either microorganisms in tissue section, positive culture, positive serology or positive antigen detection in a consistent clinical pathological setting. Result: Granulomatous lymphadenitis was detected in 110 patients. The included 110 cases consisted of 70.9% women and median age of 53 (range 44-61) years. The final diagnosis of the patients was accepted to be sarcoidosis in 79 (71.8%), sarcoid like granulomas in 7 (6.4%), tuberculosis in 4 (3.6%), silicosis in 4 (3.6%), drug-associated granuloma in 2 (1.8%), hypersensitivity pneumonitis in 1 (0.9%), Chron disease in 1 (0.9%), unspecified in 12 (10.9%). Three patients were classified as tuberculosis based on culture. Conclusions: In this study, we found that the most common cause of granulomatous lymphadenitis was sarcoidosis. Contrary to expectations, the number of patients diagnosed with tuberculosis was very low. PMID- 30479229 TI - [Frequency of restless legs syndrome and relationship between depression, anxiety and sleep quality among medical school students]. AB - Introduction: We aimed to investigate the relationship between frequency of restless legs syndrome (RLS), depression, anxiety and sleep quality among medical school students. Materials and Methods: We applied a questionnaire to medical school students. This questionnaire includes some questions about demographic features of participants, questions related with RLS diagnosis, the pittsburgh sleep quality index (PSQI), beck-depression-scale (BDS), beck-anxiety scale (BAS) to all subjects. Participants diagnosed with RLS asked to response some additional questions related with RLS severity rating scale. All results compared between RLS diagnosed and healthy subjects. Result: A total of 402 medical school students, of whom 55.2% (n= 22) were female, were participated into this study. The ratio of subjects diagnosed as RLS was 16.9% (n= 68). The ratio of RLS diagnosed participants in female students was 18.0% (n= 40) and in male students was 15.6% (n= 28). Of 169 participants who got a poor sleep quality, 36 subjects (21.3%) was diagnosed as RLS. On the other hand, of 233 participants who got a good sleep quality, 32 subjects (13.7%) was diagnosed as RLS (p= 0.004). Score for the RLS severity ranging scale for participants who were diagnosed as RLS was positively correlated with both BDS and BAS scores (p= 0.002, r= 0.372 ve p< 0.001, r= 0.506, respectively). Conclusions: In this study, the rate of RLS in medical school students were higher than the rate presented in the literature. Additionaly, participants who were diagnosed as RLS in our study had worse sleep quality than healthy subjects. Moreover, RLS may be associated with some psychological mood disorders. PMID- 30479230 TI - [Smoking prevalence of elementary school students in Manisa]. AB - Introduction: In this study it is aimed to evaluate the prevalence of smoking, factors affecting smoking status, and the attitudes of the elementary school students towards the smoking prohibition law which was approved in July 2009, in city. Materials and Methods: The universe of this descriptive study was 6th-7th 8th class, 8236 urban and 4937 semi-urban, total 13.173 elementary schools students in city center. Study population was determined on the basis of a previous study in which the smoking trial prevalence was found 17.5%, 831 students in 6 urban 3 semi-urban, total 9 schools were chosen randomly. A questionnaire was prepared investigating smoking status, the effects of smoking and family history. Among the 9 chosen schools, the questionnaire was applied to 615 students. SPSS 14.0 statistical package was used. Result: Forty-seven percentages of the students were female. Prevalence of smoking trial was found 23.5% (16% in urban, 35% in semi-urban schools) while the prevalence of smoking was 7.1% (1.7% in urban, 15.7% in semi-urban schools). Mean age of first smoking trial was 10.04 +/- 2.3. The smoking prohibition law was supported by 86.6% of the students, the warnings on the cigarette package was thought to be effective by 43.3% students and 35.2% of the students were exposed to passive smoke. Male gender, social status, education level of the family, smoker family member or close friends were found to be important risk factors for smoking prevalence of the students. Conclusions: The early onset of smoking should guide the smoking struggle be concentrated in elementary school especially in semi-urban areas where the smoking prevalence is high. PMID- 30479231 TI - [Culture proven extra pulmonary tuberculosis: drug susceptibility and genetic profile analysis]. AB - Introduction: Tuberculosis is seen generally in the lungs. Besides, all organs in the body can be affected by tuberculosis. Diagnosis of extra pulmonary tuberculosis (EPTB) is more difficult than pulmonary tuberculosis (PTB). Although, the isolation of Mycobacterium tuberculosis is gold standard of diagnosis of EPTB, the rate of bacteriologic isolation is low especially in EPTB. If M. tuberculosis is detected, it gives some information about the epidemiological features of the disease and drug susceptibility. Materials and Methods: In this study, extra pulmonary samples isolated M. tuberculosis in mycobacteriology laboratory were evaluated between 2009-2016. The identification of the genotype of isolated bacteria and drug sensitivity tests were conducted. Spoligotyping was accomplished using a standard technique as described previously. Result: During the study period, M. tuberculosis were cultured in 171 extra pulmonary samples of 165 patients (75 male, 90 female, mean age: 53.35 +/- 19.92). Initial direct microscopically examination was revealed M. tuberculosis in 44 patients. There were more than one extra pulmonary organ involvement in six patients. The most common EPTB forms were lymph node TB in 60 patients, pleural tuberculosis in 32 patients and bone tuberculosis in 25 patients. Immunosuppression was detected in 44 (%26.6) patients. Among these, seven patients were infected with HIV. In 21 of 175 samples, drug resistance was detected. Rifampicin resistance in 7 samples, high level isoniazid resistance in 11 samples and rifampicin plus isoniazid resistance (multiply drug resistance) in 6 samples were demonstrated. One hundred thirty-five clinical isolates were cultured from tuberculosis patient's different samples, of which the genetic profile was determined by using Spoligotyping. The major Spoligotypes were T (n= 62; 45.9%), LAM7-TUR (ST41) (n= 11; 8.1%) and H1 (n= 9; 6%) genotypes. Conclusions: The most common EPTB form was lymph node tuberculosis in culture proven patients. In these patients group, multiply drug resistance rate was low (3.6%). Spoligotypes T (45.9%) was detected as most common genetic profile. PMID- 30479232 TI - [Postintubation tracheal stenosis]. AB - Postintubation tracheal stenosis (PITS) is an iatrogenic complication seen increasingly often as the number of intensive care unit (ICU) bed multiply, the indications for endotracheal intubation expand and disease awareness rises. PITS has a clinical severity spectrum ranging from asymptomatic cases to patients requiring urgent interventional procedures. It should therefore always be considered in the differential diagnosis in patients with a history of intubation who present with the complaint of difficult breathing. The golden standart for diagnosis is fiberoptic/rigid bronchoscopy. Even though tracheal resection and end-to-end anastomosis (TRA) is the preferred traetment, in some selected cases and in the patients who are not candidates for surgery, bronchoscopic interventions can be life saving, temporizing until surgery is possible and even be curative. PMID- 30479233 TI - [Aggressive skin metastasis in lung cancer]. AB - A fifty seven year old male patient was admitted to our clinic because of complaints of cough and sputum. Computed tomography revealed by a 36x25 mm mass on the lateral of the 7th left rib, a 50x52 mm mass on the right main bronchus, growing 40x34 mm lymph nodes on the carina and paratracheal, 60x42 mm mass on the right adrenal and extensive bone metastasis. Squamous cell carcinoma was diagnosed by performed bronchoscopic biopsy. Scalp dermal biopsy was taken upon detection of extensive lesions on the skin.Scalp biopsy was reported squamous cell carcinoma infiltration.The last time when was given radiotherapy to footwell metastasis, the patient was fever and hypotension, we were accepted intensive care unit. In this article, we aimed to discuss rarely aggressive skin metastasis in a squamous cell carcinoma, a type of lung cancerin the light of current literature data. PMID- 30479234 TI - [From carbonmonoxide intoxication to organ donation; organ protective mechanic ventilation in severe pulmonary damage]. AB - Organ donation is a matter of concern in critically ill patients who need intensive care after carbonmonoxide (CO) intoxication. A 26-year-old female patient was unconscious after having spent 20 minutes in the bathroom with a water heater (70% butane and 30% propane mixture). In the CT of the patient with Glasgow Coma Scale (GCS) 3, ventricular system was erased, white-gray matter separation was lost and fissures were observed as erased. Torax CT showed conspicuous areas showing air bronchograms in both lung bases and posterior areas and diffuse frosted glass densities in other areas. In a patient with no improvement in consciousness; apnea test, neurological examination and CT angiography showed that there was no blood flow in the brain and brain death was confirmed. On the second day of hospitalization, the relatives gave their approval for the donation. It may also be advantageous to use oxygen at high concentrations in carbonmonoxide poisoning as it may allow recruitment of closed alveoli. Successful kidney, heart, lung, liver and pancreas transplants from donors exposed to CO have been reported. Carbonmonoxide intoxication may be appropriate for transplantation for patients who are waiting for organs of brain death cases where the organ preservation is well done. Although carbonmonoxide intoxication has failed in the literature, it shows that there is no definite contraindication. PMID- 30479236 TI - Sternal diastasis; computerized tomography findings. PMID- 30479235 TI - Extracorporeal carbondioxide removal (ECCO2R): case series and review of literature. AB - Introduction: Ventilation treatment has proven success in acute respiratory distress syndrome (ARDS), while it still remains a challenge to utilize it with lower tidal volumes especially in subjects with respiratory acidosis. The concept of supporting conventional ventilation with extracorporeal carbondioxide removal (ECCO2R) may contribute in adjusting respiratory acidosis consequent to tidal volume reduction in protective ventilation setting. This method allows an easier management of ARDS due to its less invasive approach. As shown by recent studies, ECCO2R can be preferred in subjects with exacerbation of chronic obstructive pulmonary disease (COPD) who are unresponsive to non-invasive ventilation (NIV). One of the most important aspects of this can be stated as the reduced rate of endotracheal intubation. Materials and Methods: Subjects that were admitted to intensive care unit between March 2014 to November 2015 due to hypercapnic respiratory failure were treated using ECCO2R. Result: Over the study period, five patients received ECCO2R therapy. All subjects were managed with ECCO2R (Hemolung, A Lung Inc., Pittsburgh, USA) via a 15.5 FG percutaneously inserted cannula. Conclusions: We observed that ECCO2R is a promising method in the management of patients having COPD and can be used to protect lungs in patients with ARDS. PMID- 30479237 TI - Enlarged lymph node or what else? A rare case of pulmonary artery aneurysm. PMID- 30479238 TI - Pulmonary tuberculosis developed in sarcoidosis patients. PMID- 30479240 TI - Co-authoring: creating mental health information, about, for and with older people. PMID- 30479239 TI - Answer: Pulmonary tuberculosis in sarcoidosis patients: two cases. PMID- 30479241 TI - Non-pharmacological interventions for depression/anxiety in older adults with physical comorbidities affecting functioning: systematic review and meta analysis. AB - : ABSTRACTObjective:To review the effectiveness of non-pharmacological interventions in older adults with depression or anxiety and comorbidities affecting functioning. DESIGN: Systematic review and meta-analysis of randomized controlled trials, including searches of 10 databases (inception-Jul 2017). SETTING: Home/community. PARTICIPANTS: People aged 60 and over experiencing functional difficulties from physical or cognitive comorbidities and have symptoms or a diagnosis of depression and/or anxiety. INTERVENTIONS: Non pharmacological interventions targeted at depression/anxiety. MEASUREMENTS: We extracted outcome data on depressive symptoms, quality of life, functioning, and service use. We used random effects meta-analysis to pool study data where possible. Two authors assessed the risk of bias using the Cochrane Risk of Bias tool. RESULTS: We identified 14 eligible trials including 2099 randomized participants and two subgroup analyses. Problem-solving therapy (PST) reduced short-term clinician-rated depressive symptoms (n = 5 trials, mean difference in Hamilton Depression Rating Scale score -4.94 [95% CI -7.90 to -1.98]) but not remission, with limited evidence for effects on functioning and quality of life. There was limited high-quality evidence for other intervention types. Collaborative care did not appear to affect depressive symptoms, functioning, or quality of life; and had mixed evidence for effects upon remission. No intervention consistently affected service use, but trials were limited by small sample sizes and short follow-up periods. No anxiety interventions were identified. CONCLUSION: PST may reduce depressive symptoms post-intervention in older people with depression and functional impairments. Collaborative care appears to have few effects in this population. Future research needs to assess cost-effectiveness, long-term outcomes, and anxiety interventions for this population. PMID- 30479242 TI - Partnership for mental health development in Sub-Saharan Africa (PaM-D): a collaborative initiative for research and capacity building. AB - : AimsIn low- and middle-income countries (LMIC) in general and sub-Sahara African (SSA) countries in particular, there is both a large treatment gap for mental disorders and a relative paucity of empirical evidence about how to fill this gap. This is more so for severe mental disorders, such as psychosis, which impose an additional vulnerability for human rights abuse on its sufferers. A major factor for the lack of evidence is the few numbers of active mental health (MH) researchers on the continent and the distance between the little evidence generated and the policy-making process. METHODS: The Partnership for Mental Health Development in Africa (PaM-D) aimed to bring together diverse MH stakeholders in SSA, working collaboratively with colleagues from the global north, to create an infrastructure to develop MH research capacity in SSA, advance global MH science by conducting innovative public health-relevant MH research in the region and work to link research to policy development. Participating SSA countries were Ghana, Kenya, Liberia, Nigeria and South Africa. The research component of PaM-D focused on the development and assessment of a collaborative shared care (CSC) program between traditional and faith healers (T&FHs) and biomedical providers for the treatment of psychotic disorders, as a way of improving the outcome of persons suffering from these conditions. The capacity building component aimed to develop research capacity and appreciation of the value of research in a broad range of stakeholders through bespoke workshops and fellowships targeting specific skill-sets as well as mentoring for early career researchers. RESULTS: In the research component of PaM-D, a series of formative studies were implemented to inform the development of an intervention package consisting of the essential features of a CSC for psychosis implemented by primary care providers and T&FHs. A cluster randomised controlled trial was next designed to test the effectiveness of this package on the outcome of psychosis. In the capacity-building component, 35 early and mid-career researchers participated in the training workshops and several established mentor mentee relationships with senior PaM-D members. At the end of the funding period, 60 papers have been published and 21 successful grant applications made. CONCLUSION: The success of PaM-D in energising young researchers and implementing a cutting-edge research program attests to the importance of partnership among researchers in the global south working with those from the north in developing MH research and service in LMIC. PMID- 30479243 TI - The waiting list is an inadequate benchmark for estimating the effectiveness of psychotherapy for depression. PMID- 30479244 TI - Human Stampedes: An Updated Review of Current Literature. AB - Human stampedes are a major cause of mortality in mass gatherings, but they have received limited scientific attention. While the number of publications has increased, there is no recent review of new study results. This study compiles and reviews available literature on stampedes, their prevention, preparedness, and response.A search for peer-reviewed and grey literature in PubMed (National Center for Biotechnology Information, National Institutes of Health; Bethesda, Maryland USA), Google Scholar (Google Inc.; Mountain View, California USA), Web of Science (Thomson Reuters; New York, New York USA), the World Health Organization Library Database (WHOLIS; World Health Organization; Geneva, Switzerland), and ReliefWeb (UN Office for the Coordination of Humanitarian Affairs; Geneva, Switzerland) was conducted, and papers were selected according to pre-defined eligibility criteria. Included items were read and results were compiled and summarized. A total of 64 publications were included, of which, 34 were published between 2013-2016. The most studied events were Germany's Love Parade stampede in 2010 (Duisburg, Germany; n = 6) and the United Kingdom (UK) Hillsborough Stadium stampede in 1989 (Sheffield, England; n = 4). Conflicting definitions of human stampedes were found. The common belief that they result from an irrational and panicking crowd has progressively been replaced by studies suggesting that successive systemic failures are main underlying causes. There is a lack of systematic reporting, making news reports often the only source available. Prevention measures are mainly related to crowd management and venue design, but their effectiveness has not been studied. Drills are recommended in the preparedness phase to improve coordination and communication. Delay in decisions, poor triage, or loss of medical records are common problems in the response, which may worsen the outcome.Stampedes are complex phenomenon that remain incompletely understood, hampering formulation of evidence-based strategies for their prevention and management. Documentation comes mostly from high-profile events and findings are difficult to extrapolate to other settings. More research from different disciplines is warranted to address these gaps in order to prevent and mitigate future events. A start would be to decide on a common definition of stampedes.Moitinho de Almeida M, von Schreeb J. Human stampedes: an updated review of current literature. Prehosp Disaster Med. PMID- 30479245 TI - The Angolan Pandemic Rapid Response Team: An Assessment, Improvement, and Development Analysis of the First Self-sufficient African National Response Team Curriculum. AB - OBJECTIVE: The purpose of this study was to assess, through participant self assessment, the effectiveness of a rapid response team curriculum based on the World Health Organization (WHO) Ebola Virus Disease Consolidated Preparedness Checklist, Revision 1. METHODS: A pre-and-post survey for the purpose of process improvement assessment involving 44 individuals was conducted in Angola. The survey was conducted before and after a 6-day training workshop held in Luanda, Angola, in December 2017. A paired t-test was used to identify any significant change on six 7-point Likert scale questions with alpha <.05 (95% CI). RESULTS: Two of the 6 questions, "I feel confident the team can effectively work together to accomplish its assigned goals and objectives during a suspected contagious hemorrhagic fever disease outbreak" and "I understand basic pandemic response concepts" changed significantly from the presurvey to the postsurvey. The 4 remaining questions had near statistical significant change or an upward trend. CONCLUSION: This Angolan rapid response team training curriculum based on WHO guidelines, After Action Reports, and internationally accepted standard operating procedures provides the nation of Angola with the confidence to rapidly respond at the national level to a highly infectious contagion in the region. (Disaster Med Public Health Preparedness. 2018;page 1 of 5). PMID- 30479246 TI - AGING AND HEALTH TECHNOLOGY ASSESSMENT: AN IDEA WHOSE TIME HAS COME. AB - OBJECTIVES: With the increase in technologies to support an aging population, health technology assessment (HTA) of aging-related technologies warrants special consideration. At Health Technology Assessment international (HTAi) 2016 and HTAi 2017, an international panel explored interests in HTA focused on aging. METHODS: Panelists from five countries shared the state of aging and HTA in their countries. Opportunities were provided for participants to discuss and rate the themes identified by the panelists. RESULTS: In 2016, the highest ranked themes were: (i) identifying unmet needs of older adults that could be met by technology how can HTA help?; (ii) differences in assessment of aging-related technologies what is the scope?; and (iii) involvement of older adults and caregivers. These themes became the starting point for discussion in 2017, for which the highest ranked themes were: (i) identification of challenges in HTA and aging; and (ii) approaches to advancing effectiveness of HTA for aging. CONCLUSION: These discussions allowed for examination of future directions for HTA and aging: engagement of older adults to inform the agenda of HTA and the broader public policy enterprise; a systems approach to thinking about needs of older persons should support the type and level of care desired by the individual rather than the health institutions, and HTA should reflect these desires when evaluating technological aides; and there is potential for health information systems and "big data" to support HTA activities that assess usability of technologies for older adults. We hope to build on the momentum of this community to continue exploring opportunities for aging and HTA. PMID- 30479248 TI - A Prospective Comparison of Quick Sequential Organ Failure Assessment, Systemic Inflammatory Response Syndrome Criteria, Universal Vital Assessment, and Modified Early Warning Score to Predict Mortality in Patients with Suspected Infection in Gabon. AB - The quick sequential organ failure assessment (qSOFA) score has been proposed for risk stratification of emergency room patients with suspected infection. Its use of simple bedside observations makes qSOFA an attractive option for resource limited regions. We prospectively assessed the predictive ability of qSOFA compared with systemic inflammatory response syndrome (SIRS), universal vital assessment (UVA), and modified early warning score (MEWS) in a resource-limited setting in Lambarene, Gabon. In addition, we evaluated different adaptations of qSOFA and UVA in this cohort and an external validation cohort from Malawi. We included 279 cases, including 183 with an ad hoc (suspected) infectious disease diagnosis. Overall mortality was 5%. In patients with an infection, oxygen saturation, mental status, HIV status, and all four risk stratification score results differed significantly between survivors and non-survivors. The UVA score performed best in predicting mortality in patients with suspected infection, with an area under the receiving operator curve (AUROC) of 0.90 (95% confidence interval [CI]: 0.78-1.0, P < 0.0001), outperforming qSOFA (AUROC 0.77; 95% CI: 0.63-0.91, P = 0.0003), MEWS (AUROC 0.72; 95% CI: 0.58-0.87, P = 0.01), and SIRS (AUROC 0.70; 95% CI: 0.52-0.88, P = 0.03). An amalgamated qSOFA score applying the UVA thresholds for blood pressure and respiratory rate improved predictive ability in Gabon (AUROC 0.82; 95% CI: 0.68-0.96) but performed poorly in a different cohort from Malawi (AUROC 0.58; 95% CI: 0.51-0.64). In conclusion, UVA had the best predictive ability, but multicenter studies are needed to validate the qSOFA and UVA scores in various settings and assess their impact on patient outcome. PMID- 30479247 TI - Potential Biological Control of Schistosomiasis by Fishes in the Lower Senegal River Basin. AB - More than 200 million people in sub-Saharan Africa are infected with schistosome parasites. Transmission of schistosomiasis occurs when people come into contact with larval schistosomes emitted from freshwater snails in the aquatic environment. Thus, controlling snails through augmenting or restoring their natural enemies, such as native predators and competitors, could offer sustainable control for this human disease. Fishes may reduce schistosomiasis transmission directly, by preying on snails or parasites, or indirectly, by competing with snails for food or by reducing availability of macrophyte habitat (i.e., aquatic plants) where snails feed and reproduce. To identify fishes that might serve as native biological control agents for schistosomiasis in the lower Senegal River basin-one of the highest transmission areas for human schistosomiasis globally-we surveyed the freshwater fish that inhabit shallow, nearshore habitats and conducted multivariate analyses with quantitative diet data for each of the fish species encountered. Ten of the 16 fish species we encountered exhibited diets that may result in direct (predation) and/or indirect (food competition and habitat removal) control of snails. Fish abundance was low, suggesting limited effects on schistosomiasis transmission by the contemporary fish community in the lower Senegal River basin in the wild. Here, we highlight some native species-such as tilapia, West African lungfish, and freshwater prawns that could be aquacultured for local-scale biological control of schistosomiasis transmission. PMID- 30479249 TI - Impact of Small Intestine Bacterial Overgrowth on Response to a Nutritional Intervention in Bangladeshi Children from an Urban Community. AB - Small intestine bacterial overgrowth (SIBO) is prevalent among children living in low-income settings, leading to impaired growth and development. The aim of this study was to assess linear and ponderal growth parameters between malnourished SIBO-positive and SIBO-negative children aged 12-18 months who prospectively underwent a nutritional intervention. A glucose hydrogen breath test to detect SIBO was performed in 194 stunted (length-for-age Z score [LAZ] < -2 standard deviations) or at-risk of stunting (LAZ score between < -1 and -2 standard deviations) children. Participants received nutritional supplementation (egg and milk) in addition to their regular family meals 6 days per week for 90 days. Small intestine bacterial overgrowth was defined as a >= 12-ppm rise in breath hydrogen over the patient's baseline during the 3-hour test. Small intestine bacterial overgrowth status before intervention was forced into a multivariable linear regression model to examine its effects on anthropometric changes in response to the intervention. Sociodemographic data at enrollment was analyzed through multivariable logistic regression in an attempt to predict SIBO positivity. Overall, 14.9% (29/194) children were diagnosed with SIBO before the nutritional intervention. No statistically significant difference was observed among SIBO-positive and SIBO-negative groups in terms of their response to the nutritional intervention (SIBO-positive coefficient [95% CI], P-value for ?LAZ 0.003 [-0.14, 0.13], 0.96; ?weight-for-age Z score -0.05 [-0.20, 0.09], 0.46; and ?weight-for-length Z score -0.10 [-0.31, 0.10], 0.33). This study demonstrated that a noteworthy proportion of malnourished children living in a disadvantaged urban community were SIBO positive; however, it failed to reveal an association between SIBO status and response to nutritional intervention. PMID- 30479250 TI - The Conservative Treatment of Traumatic Thoracolumbar Vertebral Fractures. AB - BACKGROUND: The conservative treatment of traumatic thoracolumbar vertebral fractures is often not clearly defined. METHODS: This review is based on articles retrieved by a systematic search in the PubMed and Web of Science databases for publications up to February 2018 dealing with the conservative treatment of traumatic thoracolumbar vertebral fractures. The search initially yielded 3345 hits, of which 35 were suitable for use in this review. RESULTS: It can be concluded from the available original clinical research on the subject, including three randomized controlled trials (RCTs), that the primary diagnostic evaluation should be with plain x-rays, in the standing position if possible. If a fracture is suspected on the plain films, computed tomography (CT) is indicated. Magnetic resonance imaging (MRI) is additionally advisable if there is a burst fracture. The spinal deformity resulting from the fracture should be quantified in terms of the Cobb angle. The choice of a conservative or operative treatment strategy is based on the primary stability of the fracture, the degree of deformity, the presence or absence of disc injury, and the patient's clinical state. Our analysis of the three RCTs implies that early functional therapy without a corset should be performed, although treatment in a corset may be appropriate to control pain. Follow-up x-rays should be obtained after mobilization and at one week, three weeks, six weeks, and twelve weeks. CONCLUSION: Further comparative studies of the indications for surgery and specific conservative treatment modalities would be desirable. PMID- 30479251 TI - Obesity Surgery and the Treatment of Metabolic Diseases. AB - BACKGROUND: 3.9% of men and 5.2% of women in Germany suffer from second-degree obesity (body mass index [BMI] >= 35 to <40 kg/m2), and 6.5 million persons suffer from diabetes. Obesity surgery has become established as a further treatment option alongside lifestyle changes and pharmacotherapy. METHODS: The guideline was created by a multidisciplinary panel of experts on the basis of publications retrieved by a systematic literature search. It was subjected to a formal consensus process and tested in public consultation. RESULTS: The therapeutic aims of surgery for obesity and/or metabolic disease are to improve the quality of life and to prolong life by countering the life-shortening effect of obesity and its comorbidities. These interventions are superior to conservative treatments and are indicated when optimal non-surgical multimodal treatment has been tried without benefit, in patients with BMI >= 40 kg/m2, or else in patients with BMI >= 35 kg/m2 who also have one or more of the accompanying illnesses that are associated with obesity. A primary indication without any prior trial of conservative treatment exists if the patient has a BMI >= 50 kg/m2, if conservative treatment is considered unlikely to help, or if especially severe comorbidities and sequelae of obesity are present that make any delay of surgical treatment inadvisable. Metabolic surgery for type 2 diabetes is indicated (with varying recommendation grades) for patients with BMI >= 30 kg/m2, and as a primary indication for patients with BMI >= 40 kg/m2. The currently established standard operations are gastric banding, sleeve gastrectomy, proximal Roux-en-Y gastric bypass, omega-loop gastric bypass, and biliopancreatic diversion. CONCLUSION: No single standard technique can be recommended in all cases. In the presence of an appropriate indication, the various surgical treatment options for obesity and/or metabolic disease should be discussed with the patient. PMID- 30479252 TI - Adhesions and Abdominal Pain: Ileal Perforation by a Sharp Ingested Foreign Body With Mechanical Erosion at the Base of the Appendix. PMID- 30479253 TI - Monitoring Sterile Pacemaker Implants. PMID- 30479254 TI - In Reply. PMID- 30479255 TI - New Classification. PMID- 30479257 TI - Tuberculous Tenosynovitis. PMID- 30479256 TI - In Reply. PMID- 30479258 TI - Crazy Paving Pattern. PMID- 30479259 TI - 6 Blind Men, an Elephant, and the Peer-Review Process. PMID- 30479260 TI - The Effect of Presentation Mode and Production Type on Word Memory for Hearing Impaired Signers. AB - BACKGROUND: Production effect (PE) is a memory phenomenon referring to better memory for produced (vocalized) than for non-produced (silently read) items. Reading aloud was found to improve verbal memory for normal-hearing individuals, as well as for cochlear implant users, studying visually and aurally presented material. PURPOSE: The present study tested the effect of presentation mode (written or signed) and production type (vocalization or signing) on word memory in a group of hearing impaired young adults, sign-language users. RESEARCH DESIGN: A PE paradigm was used, in which participants learned lexical items by two presentation modes, written or signed. We evaluated the efficacy of two types of productions: vocalization and signing, using a free recall test. STUDY SAMPLE: Twenty hearing-impaired young adults, Israeli sign language (ISL) users, participated in the study, ten individuals who mainly use manual communication (MC) (ISL as a first language), and ten who mainly use total communication (TC). DATA COLLECTION AND ANALYSIS: For each condition, we calculated the proportion of study words recalled. A mixed-design analysis of variance was conducted, with learning condition (written-vocalize, written-signed, and manual-signed) and production type (production and no-production) as within-subject variables, and group (MC and TC) as a between-subject variable. RESULTS: Production benefit was documented across all learning conditions, with better memory for produced over non-produced words. Recall rates were higher when learning written words relative to signed words. Production by signing yielded better memory relative to vocalizing. CONCLUSIONS: The results are explained in light of the encoding distinctiveness account, namely, the larger the number of unique encoding processes involved at study, the better the memory benefit. PMID- 30479261 TI - Speech Recognition in Noise in Adults and Children Who Speak English or Chinese as Their First Language. AB - BACKGROUND: Speech recognition of individuals who are listening to a nonnative language is significantly degraded in the presence of background noise and may be influenced by proficiency, age of acquisition, language experience, and daily use of the nonnative language. PURPOSE: The purpose of this study is to examine and compare speech recognition in noise performance across test conditions with varying signal-to-noise ratios (SNRs) as well as the presence of vocal and spatial cues in listeners who speak American English as a native language or Mandarin Chinese as a native language. Self-rated English proficiency and experience were collected for native Mandarin Chinese speakers to determine its relationship to performance on the test measures. RESEARCH DESIGN: A cross sectional repeated measures design was used for the study. STUDY SAMPLE: Four groups of participants were included in the study. The adult groups consisted of 25 adults who speak native English and 25 adults who speak native Mandarin Chinese with English as an additional language. The pediatric groups consisted of 16 children who speak native English and 16 children who speak native Mandarin Chinese with English as an additional language. DATA COLLECTION AND ANALYSES: Percent correct speech recognition in noise was assessed at three SNRs (-3, 0, +3 dB) using the adult or pediatric versions of the AzBio sentence test. The Listening in Spatialized Noise-Sentence (LiSN-S) test was used to determine the effect of providing spatial and vocal cues on the speech recognition in noise performance of the groups of participants. The data for each age group and test measure were analyzed with a repeated measures analysis of variance. Correlation analyses were performed to examine relationships between English proficiency and experience on performance across the speech recognition test conditions. RESULTS: Analysis of the data from the adult or pediatric AzBio sentence test identified a significant effect of native language for adults but no significant effect for children. The higher SNRs yielded better performance for all listeners. On the LiSN-S test, results for the adult and pediatric groups were similar and showed significantly better performance for the native English speakers in every test condition. The demographic and language characteristics that most affected speech recognition performance across the test measures included the length of time the person lived in the United States, the age of English acquisition, the number of minutes per day English was spoken by the participant, and the self-rated English proficiency. CONCLUSIONS: The findings in this study highlight the importance and benefit of higher SNRs as well as the provision of vocal and spatial cues for improving speech recognition performance in noise of adult and pediatric listeners who speak Mandarin Chinese as a native language. PMID- 30479262 TI - Psychometric Properties of the Turkish Version of the Satisfaction with Amplification in Daily Living Questionnaire in Hearing Aid Users. AB - BACKGROUND: Assessing hearing aid satisfaction is important for hearing aid adaptation in individuals who have hearing loss. Each user should be compared to oneself during the adaptation of the hearing aid and the determination of the satisfaction level, because, each user has their own demands and expectations. Therefore, the survey evaluations which reveal the personal preferences and expectations gain importance in the determination of the benefit and satisfaction rate for hearing aid users. PURPOSE: The purpose of this study was to evaluate the reliability of the Turkish version of the Satisfaction with Amplification in Daily Living (TSADL) among hearing aid users. RESEARCH DESIGN: The original Satisfaction with Amplification in Daily Living (SADL) questionnaire was translated from English to the TSADL. Linguistic adaptation attempted to ensure equivalency, both grammatically and idiomatically, and was assessed by investigators related to the field. STUDY SAMPLE: One hundred and sixty hearing aid users with sensorineural hearing loss, aged 18 to 90 yr (54.51 +/- 18.21), who had been using a hearing aid regularly for more than 6 mo participated in the study; seventy three (45.10%) were male and 87 (54.30%) were female. DATA COLLECTION: Participants completed the TSADL twice, 3 mo apart (long enough to forget their replies in the first application but short enough to prevent any changes to the measured properties). RESULTS: When factor analysis of the questionnaire was performed, subdimension factor loadings were found to range from 0.744 to 0.854 for "Positive Effect," 0.62 to 0.985 for "Personal Image," and 0.903 to 0.913 for "Adverse Features"; the factor loading of "Service and Cost" was 0.983. Because all factor loadings were above 0.30, no items were excluded from the Turkish version of the questionnaire. Although the TSADL retained the original four factors, because of differences in Turkish social structures and perspectives, questions #12 and #15 revealed an association between the "Service and Cost" and "Positive Effects" subdimensions. CONCLUSIONS: The SADL-TR scale can be reliably used in clinical studies to rapidly assess patient satisfaction, compare satisfaction levels, determine normative satisfaction level, compare various amplifications, and gather administrative outcome data. PMID- 30479263 TI - Auditory P300 in Noise in Younger and Older Adults. AB - BACKGROUND: Older adults often report difficulty hearing in background noise which is not completely attributable to peripheral hearing loss. Although age related declines in cognition and hearing in background noise occur, the underlying age-related changes in processing of auditory stimuli in background noise has yet to be fully understood. The auditory P300 has the potential to elucidate the effects of age on auditory and cognitive processing of stimuli in background noise, but additional research is warranted. PURPOSE: The purpose of this study was to investigate age-related differences in cognitive processing of auditory stimuli by evoking the auditory P300 at multiple signal-to-noise ratios (SNRs). RESEARCH DESIGN: A two-group, repeated measures study design was used. STUDY SAMPLE: A convenience sample of 35 participants, 15 older adults (mean age of 66.4 yr) and 20 younger adults (mean age of 21.1 yr), participated in the study. All participants had negative otologic and neurological histories. DATA COLLECTION AND ANALYSIS: The auditory P300 was evoked using an oddball paradigm with 500 (frequent) and 1000 Hz (target) tonal stimuli in quiet and in the presence of background noise at +20, +10, and 0 SNRs. P300 amplitudes and latencies were measured in each condition for every participant. Repeated measures analyses of variance were conducted for the amplitude and latency measures of the P300 for each group. RESULTS: Results from this study demonstrated P300 latencies were significantly longer in older adults in noise at the most challenging condition (0 SNR) compared with the quiet condition and between the +10 SNR and 0 SNR conditions. Although older adults had significantly longer P300 latencies compared with younger adults, no significant group by listening condition interaction existed. No significant P300 amplitude differences were found for group, noise, or group * listening condition interactions. CONCLUSIONS: Results provide evidence that auditory cortical processing, regardless of age, is poorer at more difficult SNRs. However, results also demonstrate that older adults perform significantly poorer than younger adults. This supports the notion that some degree of age-related decline in synchronous firing and rate of transmission of the auditory cortical neurons contributing to the auditory P300 exists. Studies are needed to further understand the impact of noise on auditory cortical processing across populations. PMID- 30479264 TI - Teaching Counseling Skills in Audiology Graduate Programs: Clinical Supervisors' Perceptions and Practices. AB - BACKGROUND: Counseling is a critical component within audiological service delivery. Partnering with patients to support them in learning to effectively cope with their hearing challenges is a key component in achieving desired outcomes. Even though there is agreement on the foundational role counseling plays in audiology service delivery, counseling instruction varies among audiology training programs. PURPOSE: The purpose of this study was to investigate the perspectives and practices of supervisors in audiology graduate training programs related to mentoring students in the acquisition of counseling skills. RESEARCH DESIGN: A cross-sectional design was used; participants completed a self-report survey. STUDY SAMPLE: The survey was sent to 323 clinical supervisors in AuD graduate programs in the United States. DATA COLLECTION AND ANALYSIS: Completed surveys were received from 205 supervisors. Responses were analyzed using descriptive statistics to identify practice trends. RESULTS: Participants reported their perceptions about importance of teaching counseling skills to audiology students, their confidence in teaching skills, their self efficacy for supporting student learning, how they provide feedback to students, and challenges they encounter. Most participants reported their program requires a counseling course (88%; n = 176). Most of the participants reported confidence in teaching counseling skills; however, fewer reported being very or extremely confident in teaching students how to talk with clients about their emotions (53%; n = 109) and explaining the rationale behind specific counseling strategies (47%; n = 97). Participants with more years of supervisory experience had statistically significantly higher self-ratings for teaching confidence and self efficacy for supporting student learning in counseling than those with fewer years of experience. CONCLUSIONS: Audiology supervisors in AuD programs believe counseling is important to teach to students; however, they report variability in use of methods for providing feedback, evaluating student performance, and in their self-efficacy for supporting student learning. Future audiologists would benefit from a more systematic approach within graduate training for teaching counseling skills. PMID- 30479265 TI - A Large-Scale Examination of Veterans with Normal Pure-Tone Hearing Thresholds within the Department of Veterans Affairs. AB - BACKGROUND: Department of Veterans Affairs (VA) audiologists have anecdotally reported examining numerous Veterans with normal pure-tone thresholds; however, the prevalence of these patients within the VA is unknown. The VA audiological data repository provides an ideal dataset to examine this group of Veterans. Knowing the prevalence of normal-hearing Veterans within the VA system is the first step to understanding the underlying referral patterns and clinical complaints of Veterans. Data repositories which capture data from both normal and impaired populations provide an indispensable view into hearing health care which can help to improve diagnosis and treatment of Veterans' hearing difficulties. PURPOSE: Using the VA audiological data repository, this study aimed to (1) determine the prevalence of normal hearing thresholds among Veterans seeking hearing health care within the VA health care system and (2) determine the prevalence of abnormal clinical audiology test results among Veterans with normal hearing thresholds. RESEARCH DESIGN: This study was a large-scale retrospective, descriptive observational analysis of uploaded audiological records from the VA Denver Acquisition and Logistics Center audiological data repository encompassing visits that took place between April 1991 and June 2015. STUDY SAMPLE: At the time of data extraction, there were 3,641,326 audiological records in the repository, with 2,322,771 unique individual records. The study sample was further restricted to include only individuals with normal hearing (n = 235,091), which was defined as pure-tone thresholds better than, or equal to, 25 dB HL at octave frequencies from 250 to 8000 Hz, bilaterally. Patients ranged from 19 to 90+ years of age. DATA COLLECTION AND ANALYSIS: We describe the data using frequencies and percentages for categorical variables and means and standard deviations for continuous variables. In addition to hearing thresholds, the occurrence of abnormal results on other tests in the audiological test battery is also reported. We estimate the prevalence of normal hearing among all Veterans with records in the VA audiological data repository. RESULTS: Veterans with normal hearing were on average 37 yr old. The prevalence of Veterans with normal hearing thresholds visiting VA audiology clinics in the current hearing repository dataset was 10.12%. Overall, 41% of Veterans with normal pure-tone thresholds had other clinically abnormal audiological test results; for example, contralateral acoustic reflex thresholds (31.7%) and tympanometry (21.5%) had the highest rate of abnormal test results. CONCLUSIONS: Approximately one in ten Veterans seeking care within the VA healthcare system, and reported to the VA audiological data repository, has normal pure-tone hearing thresholds. This may be an underestimate of the true underlying prevalence of normal-hearing Veterans seeking audiology services at the VA because records with normal results were not consistently submitted to the repository. In addition, 41% of Veterans with normal pure-tone thresholds nonetheless presented with other audiological abnormalities. This study suggests that future work directed toward understanding referral patterns and clinical complaints of individuals who present to VA audiology clinics with normal hearing thresholds may be fruitful in the cause of improving diagnosis and treatment of Veterans' hearing difficulties. PMID- 30479266 TI - Problems and Life Effects Experienced by Tinnitus Research Study Volunteers: An Exploratory Study Using the ICF Classification. AB - BACKGROUND: Tinnitus is one of the most distressing hearing-related symptoms. It is often associated with a range of physiological and psychological complications, such as depression, anxiety, and insomnia. Hence, approaching tinnitus from a biopsychological perspective may be more appropriate than from purely a biomedical model. OBJECTIVE: The present study was aimed at determining the relationship between tinnitus and the problems and life effects experienced by UK-based tinnitus research study volunteers. Open-ended questions were used. Responses were classified using the International Classification of Functioning, Disability and Health (ICF) framework to understand the impact of tinnitus in a multidimensional manner using a biopsychosocial perspective. RESEARCH DESIGN: A cross-sectional survey design was used. STUDY SAMPLE: Study sample included a sample of 240 adults with tinnitus who were interested in undertaking an Internet based intervention for tinnitus. DATA COLLECTION AND ANALYSIS: The data were collated using two open-ended questions. The first focused on problems related to having tinnitus and the second to life effects as a result of tinnitus. Responses were analyzed using a simplified content analysis approach to link concepts to ICF categories in accordance with established linking rules. A Wilcoxon signed rank test was performed to compare the number of responses between the two questions. RESULTS: There were 764 responses related to problems identified, 797 responses associated with life effects due to tinnitus, and 37 responses that did not fit into any ICF category. No significant differences were observed in the number of responses between the two questions. In addition, no significant association between the number of responses reported and demographic variables was found. Most of the problems and life effects experienced by tinnitus sufferers were related to body function, followed by activity limitations, and participation restrictions. Only a few responses were related to environmental and personal factors. The most frequent responses related to body function involved "emotional functions" (b152), "sleep functions" (b134), "hearing functions" (b230), "sustaining attention" (b1400), and "energy level" (b1300). For activity limitations and participation restrictions they were "communicating with-receiving-spoken messages" (d310), "socialization" (d9205), "handling stress and other psychological demands" (d240), and "recreation and leisure" (d920). The most frequently occurring responses related to environmental factors were "sound intensity" (e2500), "sound quality" (e2501), and "general products and technology for communication" (e1250). "Coping styles" was the most frequently occurring personal factor. CONCLUSIONS: The study highlights the use of open-ended questions in gathering useful information about the impact of tinnitus. The responses coded to ICF show that tinnitus impacts many domains, not only particularly body function, but also activity limitations and participation restrictions. The results demonstrate the heterogeneous nature of the impact of tinnitus on people affected. PMID- 30479267 TI - The Relationship between Random Gap Detection and Hearing in Noise Test Performances. AB - BACKGROUND: Temporal acoustic cues are particularly important for speech understanding, and past research has inferred a relationship between temporal resolution and speech recognition in noise ability. A temporal resolution disorder is thought to affect speech understanding abilities because persons would not be able to accurately encode these frequency transitions, creating speech discrimination errors even in the presence of normal pure-tone hearing. PURPOSE: The primary purpose was to investigate the relationship between temporal resolution as measured by the Random Gap Detection Test (RGDT) and speech recognition in noise performance as measured by the Hearing in Noise Test (HINT) in adults with normal audiometric thresholds. The second purpose was to examine the relationship between temporal resolution and spatial release from masking. RESEARCH DESIGN: The HINT and RGDT protocols were administered under headphones according to the guidelines specified by the developers. The HINT uses an adaptive protocol to determine the signal-to-noise ratio where the participant recognizes 50% of the sentences. For HINT conditions, the target sentences were presented at 0 degrees and the steady-state speech-shaped noise and a four talker babble (4TB) was presented at 0 degrees , +90 degrees , or -90 degrees for noise front, noise right, and noise left conditions, respectively. The RGDT is used to evaluate temporal resolution by determining the smallest time interval between two matching stimuli that can be detected by the participant. The RGDT threshold is the shortest time interval where the participant detects a gap. Tonal (0.5, 1, 2, and 4 kHz) and click stimuli random gap subtests were presented at 60 dB HL. Tonal subtests were presented in a random order to minimize presentation order effects. STUDY SAMPLE: Twenty-one young, native English speaking participants with normal pure-tone thresholds (<=25 dB HL for 500-4000 Hz) participated in this study. The average age of the participants was 20.2 years (SD = 0.66). DATA COLLECTION AND ANALYSIS: Spearman rho correlation coefficients were conducted using SPSS 22 (IBM Corp., Armonk, NY) to determine the relationships between HINT and RGDT thresholds and derived measures (spatial advantage and composite scores). Nonparametric testing was used because of the ordinal nature of RGDT data. RESULTS: Moderate negative correlations (p < 0.05) were found between eight RGDT and HINT threshold measures and a moderate positive correlation (p < 0.05) was found between RGDT click thresholds and HINT 4TB spatial advantage. This suggests that as temporal resolution abilities worsened, speech recognition in noise performance improved. These correlations were not statistically significant after the p value reflected the Bonferroni correction for multiple comparisons. CONCLUSION: The results of the present study imply that the RGDT and HINT use different temporal processes. Performance on the RGDT cannot be predicted from HINT thresholds or vice versa. PMID- 30479270 TI - Augmented reality powers a cognitive assistant for the blind. AB - To restore vision for the blind, several prosthetic approaches have been explored that convey raw images to the brain. So far, these schemes all suffer from a lack of bandwidth. An alternate approach would restore vision at the cognitive level, bypassing the need to convey sensory data. A wearable computer captures video and other data, extracts important scene knowledge, and conveys that to the user in compact form. Here, we implement an intuitive user interface for such a device using augmented reality: each object in the environment has a voice and communicates with the user on command. With minimal training, this system supports many aspects of visual cognition: obstacle avoidance, scene understanding, formation and recall of spatial memories, navigation. Blind subjects can traverse an unfamiliar multi-story building on their first attempt. To spur further development in this domain, we developed an open-source environment for standardized benchmarking of visual assistive devices. PMID- 30479272 TI - Managing a sustainable deep-sea 'blue economy' requires knowledge of what actually lives there. AB - Ensuring that the wealth of resources contained in our oceans are managed and developed in a sustainable manner is a priority for the emerging 'blue economy'. However, modern ecosystem-based management approaches do not translate well to regions where we know almost nothing about the individual species found in the ecosystem. Here, we propose a new taxon-focused approach to deep-sea conservation that includes regulatory oversight to set targets for the delivery of taxonomic data. For example, a five-year plan to deliver taxonomic and genomic knowledge on a thousand species in regions of the ocean earmarked for industrial activity is an achievable target. High-throughput, integrative taxonomy can, therefore, provide the data that is needed to monitor various ecosystem services (such as the natural history, connectivity, value and function of species) and to help break the regulatory deadlock of high-seas conservation. PMID- 30479273 TI - Spatiotemporally controlled genetic perturbation for efficient large-scale studies of cell non-autonomous effects. AB - Studies in genetic model organisms have revealed much about the development and pathology of complex tissues. Most have focused on cell-intrinsic gene functions and mechanisms. Much less is known about how transformed, or otherwise functionally disrupted, cells interact with healthy ones towards a favorable or pathological outcome. This is largely due to technical limitations. We developed new genetic tools in Drosophila melanogaster that permit efficient multiplexed gain- and loss-of-function genetic perturbations with separable spatial and temporal control. Importantly, our novel tool-set is independent of the commonly used GAL4/UAS system, freeing the latter for additional, non-autonomous, genetic manipulations; and is built into a single strain, allowing one-generation interrogation of non-autonomous effects. Altogether, our design opens up efficient genome-wide screens on any deleterious phenotype, once plasmid or genome engineering is used to place the desired miRNA(s) or ORF(s) into our genotype. Specifically, we developed tools to study extrinsic effects on neural tumor growth but the strategy presented has endless applications within and beyond neurobiology, and in other model organisms. PMID- 30479271 TI - Translation attenuation by minocycline enhances longevity and proteostasis in old post-stress-responsive organisms. AB - : Aging impairs the activation of stress signaling pathways (SSPs), preventing the induction of longevity mechanisms late in life. Here, we show that the antibiotic minocycline increases lifespan and reduces protein aggregation even in old, SSP-deficient Caenorhabditis elegans by targeting cytoplasmic ribosomes, preferentially attenuating translation of highly translated mRNAs. In contrast to most other longevity paradigms, minocycline inhibits rather than activates all major SSPs and extends lifespan in mutants deficient in the activation of SSPs, lysosomal or autophagic pathways. We propose that minocycline lowers the concentration of newly synthesized aggregation-prone proteins, resulting in a relative increase in protein-folding capacity without the necessity to induce protein-folding pathways. Our study suggests that in old individuals with incapacitated SSPs or autophagic pathways, pharmacological attenuation of cytoplasmic translation is a promising strategy to reduce protein aggregation. Altogether, it provides a geroprotecive mechanism for the many beneficial effects of tetracyclines in models of neurodegenerative disease. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter). PMID- 30479276 TI - Message from the Editor. PMID- 30479274 TI - Selective agonist of TRPML2 reveals direct role in chemokine release from innate immune cells. AB - Cytokines and chemokines are produced and secreted by a broad range of immune cells including macrophages. Remarkably, little is known about how these inflammatory mediators are released from the various immune cells. Here, the endolysosomal cation channel TRPML2 is shown to play a direct role in chemokine trafficking and secretion from murine macrophages. To demonstrate acute and direct involvement of TRPML2 in these processes, the first isoform-selective TRPML2 channel agonist was generated, ML2-SA1. ML2-SA1 was not only found to directly stimulate release of the chemokine CCL2 from macrophages but also to stimulate macrophage migration, thus mimicking CCL2 function. Endogenous TRPML2 is expressed in early/recycling endosomes as demonstrated by endolysosomal patch clamp experimentation and ML2-SA1 promotes trafficking through early/recycling endosomes, suggesting CCL2 being transported and secreted via this pathway. These data provide a direct link between TRPML2 activation, CCL2 release and stimulation of macrophage migration in the innate immune response. PMID- 30479275 TI - Molecular basis for activation of lecithin:cholesterol acyltransferase by a compound that increases HDL cholesterol. AB - Lecithin:cholesterol acyltransferase (LCAT) and LCAT-activating compounds are being investigated as treatments for coronary heart disease (CHD) and familial LCAT deficiency (FLD). Herein we report the crystal structure of human LCAT in complex with a potent piperidinylpyrazolopyridine activator and an acyl intermediate-like inhibitor, revealing LCAT in an active conformation. Unlike other LCAT activators, the piperidinylpyrazolopyridine activator binds exclusively to the membrane-binding domain (MBD). Functional studies indicate that the compound does not modulate the affinity of LCAT for HDL, but instead stabilizes residues in the MBD and facilitates channeling of substrates into the active site. By demonstrating that these activators increase the activity of an FLD variant, we show that compounds targeting the MBD have therapeutic potential. Our data better define the substrate binding site of LCAT and pave the way for rational design of LCAT agonists and improved biotherapeutics for augmenting or restoring reverse cholesterol transport in CHD and FLD patients. PMID- 30479277 TI - Radiation Therapy Patient Education Review and a Case Study Using the Virtual Environment for Radiotherapy Training System. AB - INTRODUCTION: The emergence of modern learning environments for radiation therapy (RT) education offers innovative opportunities for RT patients. This article presents a descriptive review of the current state of practice for two recently available tools, the "Virtual Environment for Radiotherapy Training" (VERT) and the "Patient Education And Radiotherapy Learning" (PEARL) systems. Subsequently, a case study summarizes the instructional design and development of an RT breast cancer patient education program, with the intention of providing a blueprint for further patient education initiatives that incorporate VERT. METHODS: A total of 278 articles were identified for the descriptive review, using academic databases and a grey literature search. After screening for descriptive accounts of patient education interventions using VERT or PEARL, five full articles were retrieved and coded using a data extraction protocol. This information was used to inform the subsequent development of a breast cancer education program using a three step development model, encompassing (1) consultation process and literature review; (2) program content and instructional process; and (3) program evaluation plan. The VERT integration process within the second stage is the focus of the case study presented. RESULTS: The literature search found that methods for the design, delivery, and evaluation of the education programs varied across studies. Positive impacts of VERT and PEARL in patient education have been demonstrated. The development of the 1-hour education program was based on comprehensive, evidence-based learner literature and was designed with the intention of specifically engaging learners with the three-dimensional VERT system. In particular, the VERT integration process aimed to exploit VERT's range of visualization features and draw upon the multidisciplinary nature of radiation cancer care. DISCUSSION: VERT and PEARL offer innovative education opportunities and have been justly recognized as valuable tools for RT patient education. When aligned to an educational framework, rich visual displays offered by VERT and PEARL have the potential to support patient education programs and exploit the advantages of a virtual RT environment. With the increasing accessibility of these tools, the data presented in this article offer information for educators interested in development and evaluation of future patient education programs. Feasibility and economic aspects need to be addressed within local departments, and further research is required to ascertain specific capability of VERT and PEARL in supporting psychological and health-related patient outcomes. PMID- 30479278 TI - The Radiation Therapist and the Patient: Epiphanies, Stories, and Social Media. PMID- 30479279 TI - Letter to the Editor. PMID- 30479280 TI - Response to Letter to the Editor. PMID- 30479281 TI - Opportunity Is Knocking: The Need to Responsively and Responsibly Integrate Therapeutic MRI into Radiation Therapy. PMID- 30479282 TI - Building a Magnetic Resonance Imaging Safety Culture from the Ground Up. AB - Magnetic resonance imaging (MRI) uses a strong magnetic field to generate diagnostic images. This magnetic field has the potential to cause serious and even fatal injuries to patients undergoing scans and to personnel in the area. Ensuring awareness of MRI hazards and safety procedures through a formalized education and training program is integral in creating an MRI safety culture that protects patients and staff from harm. The aim of our project was to develop an accessible and interprofessional electronic e-module learning series to instill an MRI safety culture throughout the entire hospital. This is the first such program in Canada. A simplified e-search was conducted using key search terms "mri: safety, education, safety training." Very few articles were found that fulfilled our needs in helping us build an MRI safety program. In concert with an e-search we reached out to similar institutions and, through informal discussions, we confirmed the lack of a formalized, transferable safety program within Canada. This led to the creation of an interprofessional working team at our institution composed of key stakeholders: educators, clinical and technical experts from radiation therapy, medical imaging, the research institute, medical radiation physics, nursing, and radiation oncology. This team collaborated on the development of three education modules tailored for specific audiences based on classification as Non-MR Personnel, Level 1 MR Personnel, or Level 2 MR Personnel as defined by the American College of Radiology guidelines. All modules were 10 to 20 minutes in length with interactive engagement activities throughout as well as a final summative evaluation to test for comprehension. Knowledge of the existence of the MRI unit is only one facet of creating an MRI safety culture. By increasing the awareness of the hazards of MRI to all personnel throughout the hospital, the risk of harm to patients and staff may be decreased. PMID- 30479283 TI - Patterns of Practice in Canadian Radiation Treatment Centres: Results of a National Survey. AB - PURPOSE: Radiation therapy has changed rapidly over the past decade due to the application of technological advances. A survey was conducted of radiation treatment centres in Canada to establish current patterns of practice across the country. Areas of inquiry included treatment techniques and image verification, as well as roles and responsibilities of radiation therapists (RTs). METHODS AND MATERIALS: In January 2016, a survey was sent to managers of the 46 radiation treatment centres in Canada. This survey sought information on a range of staffing and practice variables for the fiscal year 2014/2015. RESULTS: Of the 46 centres contacted, 37 centres responded, representing an 80.4% response rate. Survey results showed that the use of volumetric arc therapy and intensity modulated radiation therapy is common across Canada for several anatomic sites, as well as the use of daily pretreatment image verification. A high degree of variability exists for imaging modality (two dimensional vs. three dimensional) for some sites, including brain, head and neck, and lung. RTs' responsibilities have expanded uniformly across the country, with RTs involved in organ-at-risk contouring and on-treatment image approval at the majority of centres. Despite this role expansion, specialty roles in areas of quality and applications expertise are still rare. CONCLUSIONS: Radiation therapy in Canada has transitioned to high-technology treatment techniques with relative consistency across the country. There is, however, variation in the imaging modality used for daily verification. Canada may benefit from consensus guidelines on the application of three-dimensional imaging for treatment verification. While RTs have expanded their responsibilities, role definition for RTs working in supervisory or supporting positions has not kept pace at many centres and it is unclear if RTs are supported in their expanded accountabilities. PMID- 30479284 TI - Message de la redactrice en chef. PMID- 30479285 TI - Utilising the Virtual Environment for Radiotherapy Training System to Support Undergraduate Teaching of IMRT, VMAT, DCAT Treatment Planning, and QA Concepts. AB - The use of three-dimensional virtual reality technologies in education has been widely reported in the literature. The goal of this article is to review how the virtual environment for radiotherapy training (VERT) can be utilised to support the teaching of intensity-modulated radiotherapy (IMRT), volumetric-modulated arc therapy, and dynamic conformal arc therapy techniques. Utilising Pinnacle v14 (Philips Radiation Oncology Systems, Madison, WI) and Monaco v 5.10 (Elekta CMS, Maryland Heights, MO), we exported IMRT, volumetric-modulated arc therapy, and dynamic conformal arc therapy treatment plans to VERT. Quality assurance (QA) plans were also exported from the Monaco planning software to demonstrate theoretical concepts and virtual plan delivery using the ArcCHECK phantom (Sun Nuclear Corp, Melbourne, FL) and solid water IMRT phantom. Several VERT features were utilised to critically evaluate dose coverage and organ at risk sparing on inverse treatment plans. The display of gantry and multileaf collimator motion and fluence maps could be a useful feature in the education of treatment planning concepts. QA could be delivered on VERT to demonstrate patient-specific QA concepts in a virtual environment. Anecdotal evidence shows that the use of VERT for collaborative plan evaluation sessions is likely to engage the students and improve their ability to evaluate treatment plans. VERT can be utilised to reinforce understanding of treatment plan evaluation skills, QA, and treatment delivery of inverse plans in educational environments. PMID- 30479286 TI - Patient Acceptance of Half-dose Vs. Half-time Molecular Breast Imaging. AB - OBJECTIVE: A number of strategies have been implemented at our institution to allow reductions in the administered dose or imaging time for molecular breast imaging (MBI). In this work, we examine patient opinions of whether dose reduction or time reduction is preferred. METHODS: Sixty female volunteers were randomized to undergo MBI at either half-dose (150 MBq Tc-99m sestamibi; images acquired for 10 minutes per view) or half-time (300 MBq Tc-99m sestamibi; images acquired for 5 minutes per view). A survey was then performed to assess patient comfort and examination preferences. Survey responses were compared between groups using Fisher's exact test. RESULTS: No differences were observed between groups regarding opinions of radiation dose, duration of examination, examination comfort, and willingness to undergo MBI in the future. Of those who responded, most women (39/55 [70%]) indicated a preference for the examination type they underwent, either half-dose or half-time MBI, rather than the other protocol. CONCLUSIONS: Survey findings support that MBI, whether performed at half-time or half-dose, is well accepted by patients. PMID- 30479287 TI - Effect of Topical Anesthetic Cream on Pain During Periareolar Injection of Technetium Tc99m Sulfur Colloid for Sentinel Lymph Node Biopsy in Breast Cancer: A Randomized Control Trial. AB - BACKGROUND: Injection of Tc99m to localize nodes for sentinel lymph node biopsy is reported by patients as very painful. The purpose of this study was to determine if anesthetic cream reduces pain associated with periareolar injection of Tc99m and to help elucidate conflicting literature regarding the efficacy of anesthetic cream for this procedure. METHODS: A randomized, double-blind, placebo controlled methodology was used for adult females with breast cancer undergoing periareolar injection of Tc99m for sentinel lymph node biopsy. Pain levels were compared using anesthetic cream (2.5% lidocaine/2.5% prilocaine) vs. placebo. Patient exclusion criteria included use of opioids or adjuvant pain medication or injecting Tc99m the day before surgery. The Numerical Rating Scale was used to assess pain levels immediately after the injections. RESULTS: Comparing 23 experimental and 26 control patients, there was no significant difference between the experimental (median = 4) and the control group (median = 5) on level of pain experienced U= 0.492, P > .05. CONCLUSIONS: The experimental group had a slightly lower median pain score; however, there was no statistically significant difference between those who used the cream compared with those who used a placebo, supporting the conclusion that anesthetic cream does not reduce pain during Tc99m injections. This study adds to the current literature to provide a stronger position that there is no benefit to using anesthetic cream for this procedure. PMID- 30479288 TI - Examining the Prevalence of Compassion Fatigue and Burnout in Radiation Therapists Caring for Palliative Cancer Patients. AB - OBJECTIVE: Radiation therapists (RTs) play an important role in caring for patients undergoing radiotherapy for palliative intent. RTs are in a primary position to provide emotional support to their patients and, as a result, compassion fatigue (CF) and burnout can develop. The purpose of this study was to investigate the prevalence of CF and burnout in RTs providing care to palliative cancer patients, the various intrinsic and extrinsic factors that influence how RTs provide care to this specific patient population, and to determine if RTs feel supported through education and resources. METHODS: RTs at a single radiation therapy centre who have direct patient contact comprising greater than 50% of their clinical practice were invited to complete a self-administered electronic questionnaire. The questionnaire consisted of demographic questions; the Professional Quality of Life Compassion Satisfaction and Fatigue Questionnaire to assess for CF and burnout; and additional questions to assess possible factors affecting CF and burnout among subgroups. Descriptive statistics were used for data analysis. RESULTS: A total of 42 survey responses were received resulting in a 32% response rate. Responses indicated RTs have a high level of compassion satisfaction and low burnout and secondary traumatic stress. However, it was observed that lack of resources to assist dying patients and their family members as well as a fast-paced work environment and the need for education to support staff in coping with CF and burnout were potential stressors. CONCLUSION: This study found that RTs do not experience above average levels of CF and burnout. However, intrinsic factors such as high patient load, a fast-paced clinical environment, and patients' age had the most impact emotionally on staff providing care to this specific patient population. PMID- 30479289 TI - Treating Too Lightly? Radiation Therapists' Experiences of Workplace Violence When Providing Care to Cancer Patients and Their Families. AB - INTRODUCTION: Workplace violence (WPV) is defined as any act in which a person is abused, threatened, intimidated, or assaulted during their employment. Despite an absence of published evidence, radiation therapists (RTs) are considered a "low risk" profession for WPV. The aim of this research was to determine the incidence, severity, and impact of WPV on RTs perpetrated by patients and/or their caregivers. MATERIALS AND METHODS: A cross-sectional online questionnaire, based on established components of WPV, was distributed via e-mail to all RTs in a large, urban cancer clinic. The questionnaire was divided into the five categories of WPV and asked about the frequency, severity, perpetrator, location, and impact of WPV. RESULTS: Seventy-eight responses were received from a department of 165 RTs (47% response rate). Fifty-nine RTs reported experiencing at least one verbal abuse event during their career. Twenty-five reported experiencing a verbal threat at least once, 46 reported at least one occasion of harassing behaviour, and 18 experienced a threatening action at least once. Five RTs reported suffering from at least one physical assault. The majority of this WPV took place on the treatment unit, with the patient as the perpetrator, and was not reported by the RT. High numbers of RTs reported suffering from stress (35), frustration (34), and anxiety (29) as a consequence of WPV. CONCLUSIONS: The close, longitudinal relationship between RTs and cancer patients puts RTs at considerable risk of experiencing multiple WPV events during their career. WPV is infrequently reported by RTs, perhaps linked to the belief that excellent patient care requires you to accept and excuse poor behaviour by patients. Prevention programs and de-escalation training are needed for RTs, but short-term measures such as shift or unit changes may prevent multiple WPV exposures which are associated with an increased risk of emotional and psychological sequelae. PMID- 30479290 TI - Building Foundations for Indigenous Cultural Competence: An Institution's Journey Toward "Closing the Gap". PMID- 30479291 TI - Radiation Therapists' Perceptions of Advanced Practice in Alberta. AB - OBJECTIVES: The purpose of this study was to describe radiation therapists' (RTs) perceptions of advanced practice (AP) and determine perceived barriers and benefits to the role. METHODS: A descriptive cross-sectional electronic survey of Albertan RTs was conducted from October to November 2016. The Canadian Association of Medical Radiation Technologists database was used to identify participants, and a modified Dillman methodology was used for survey distribution. RESULTS: The survey response rate was 29.3% (56/191). Most respondents had a Bachelor's degree (58.9%, 33/56) and 10 or more years of experience (60.7%, 34/56). Respondents included individuals in management/education positions (22.6%, 12/53) and clinical practitioners (58.5%, 31/53). Respondents reported high agreement with a number of definition components of AP, including a requirement for at least 5-year experience (90.5% +/- 17.6%). Respondents viewed increased knowledge in specialty areas (97.7%, 43/44), job satisfaction (88.6%, 39/44), enhanced patient care due to collaborative practice (88.6%, 39/44), and increased continuity of care (86.4%, 38/44) as benefits. Respondents highly agreed that AP would benefit patients in Alberta (83.2% +/- 23.7%); there was less personal interest in becoming advanced practitioners (58.3% +/-35.7%). Insufficient directives, guidance, and training were seen as personal (93.6%, 45/47) and professional (91.3%, 42/46) barriers to AP. CONCLUSIONS: Overall, Albertan RTs agree with the components of AP proposed by the Canadian Association of Medical Radiation Technologists as well as the benefits of creating the position. There is an urgent need to provide clear guidance and directives to RTs with regard to AP practice parameters and training requirements in order for successful implementation. PMID- 30479292 TI - Assessing the Psychological Impact of Daily Bowel Preparation on Prostate Patients Who Receive Radiation Therapy. AB - PURPOSE: Evidence has shown that the prostate moves depending on filling of the rectum and, to a lesser extent, the bladder; many radiation therapy departments have adopted standardized bladder filling/rectal emptying protocols for radiotherapy treatment. Daily treatments may be delayed until appropriate volumes are attained; the resultant psychological impact of these delays on patients is unknown. The purpose of this study was to determine levels of anxiety, depression, distress, and bother related to bowel preparation for prostate cancer patients undergoing radiation therapy treatment. METHODS: A prospective cohort analysis of prostate cancer patients undergoing external beam radiation therapy was completed. Patients were assigned to one of three groups; Group A was standard of care, Group B was standard of care plus increased educational information regarding bowel preparation, Group C was standard of care plus increased educational information regarding bowel preparation plus an anti flatulent medication. Hospital Anxiety and Depression Scale, Distress Thermometer, and a Bowel Status Bother survey were completed by participants at the start of theircourse of radiation treatment, mid-way through, and at the end. Analysis of variance testing was completed to determine differences in mean scores between the three groups. RESULTS: Mean age of patients (N = 30) was 66 years; 50% of the participants had a university education; 80% were married. Anxiety levels decreased over time in all groups (P = .039) with no difference between groups (P = 0.447). Depression levels across time for each group remained low (P = .577). Overall distress levels associated with bowel preparation were low among each group, and no significant differences were reported (P = .978). All groups reported high rates of quality of life. CONCLUSIONS: Findings from this study indicate that collectively across three groups and over time, there were low levels of anxiety, depression, and distress from bowel preparation. Amount, timing, quality, and approach to educational information are important factors to ensure patients feel prepared for their radiation therapy treatments. PMID- 30479293 TI - The Utility of Penile Bulb Contouring to Localise the Prostate Apex as Compared to Urethrography. AB - PURPOSE: High-precision radiotherapy relies on accurate anatomic localisation. Urethrography is often used to localise the prostatic apex. However, urethrography is an invasive localisation procedure and may introduce a systemic error. The penile bulb (PB) is contoured to minimise the risk of erectile dysfunction. The purpose of this study is to assess the value of using the PB, as an alternative to urethrography, to localise the prostate. METHODS AND MATERIALS: The PB was localised on 10 patients treated with simplified intensity-modulated arc radiotherapy at computed tomography simulation during treatment weeks 1 and 7. All patients underwent placement of fiducial markers. Urethrography was used only at simulation. Distances from the superior PB contour to the inferior prostate contour, the apex fiducial marker, and to the inferior prostate contour were obtained as well. The PB was contoured by two observers independently. Agreement coefficients and analysis of variance were used to assess reliability between rates and consistency of measurements over time. RESULTS: The PB-apex distance was greater than or equal to the urethrogram-apex distance in 24/30 (80%) measurements, and the median difference was 3 mm and was consistent between raters. The greatest variation in PB-IM distance between weeks was 6 mm, the median was 3 mm, and the agreements of measurements between weeks for raters 1 and 2 were 0.79 and 0.69, respectively. These differences were not statistically different and were consistent with the computed tomography slice thickness. CONCLUSIONS: The PB can be used to identify the prostate apex and can be reliably contoured between observers. Measurements are consistent between patients and through the duration of treatment. The PB distance measurements support studies indicating that urethrography causes a shift of the prostate superiorly. The distance from the PB to prostate apex remains stable during treatment for individual patients but varies between patients. PMID- 30479294 TI - The Performance of Radiographic Criteria for Bone Malignancy When Applied to Computed Tomography and Magnetic Resonance Imaging. AB - BACKGROUND: The conventional radiologic features that differentiate benign from malignant bone lesions were originally described using radiography (x-ray [XR]). When evaluating sectional imaging studies such as magnetic resonance imaging (MRI) and computed tomography (CT), one may apply these principles to identify malignant bone lesions. The aim of this study was to evaluate the performances of these radiographic features for detecting malignity when applied to CT and MRI. MATERIALS AND METHODS: This retrospective study was approved by our institutional ethical board. Thirty-nine patients with histopathologic proof of a high-grade bone malignancy and preoperative imaging data obtained with a minimum of two different modalities were included in the study. Four radiologists reviewed the images and scored the lesions for distinctness of margins, presence and type of periosteal reaction, matrix mineralization, and presence of soft tissue mass. The average score for each modality was then tested for accuracy with regard to the histopathology. RESULTS: When lesion margins were considered, XR was the best modality to detect a high-grade malignancy. MRI, especially postcontrast T1 weighted sequence, was the least helpful in this regard. There was no significant difference between CT and XR and between CT and MRI. When the periosteal reaction was considered, XR was the best modality to detect the malignant type of periosteal reaction. In this regard, MRI and CT were misleading; either by not detecting or undergrading periosteal reaction. MRI was the best modality to detect soft tissue mass. CONCLUSION: Conventional imaging criteria for bone malignancy can be misleading when applied to MRI or CT. When cross-sectional imaging features contradict those from XR, the latter should be the guide for clinical management. PMID- 30479295 TI - Diffusion-weighted Magnetic Resonance Imaging in Non-traumatic Vertebral Collapse: A Relook Into Its Utility in Making the Diagnosis in a Population Where Infections of Spine Are a Common Cause. AB - AIM: Magnetic resonance imaging (MRI) is the imaging investigation of choice in vertebral collapse. In this study, we considered various MRI features and appearance based on morphological features, signal intensity, contrast enhancement characteristics, and diffusion-weighted imaging (DWI) of various types of non-traumatic vertebral collapse for differentiating benign from malignant causes and its role in differentiating cases of infectious causes of vertebral collapse from malignant causes. MATERIALS AND METHODS: Between November 2014 to November 2016 a total of 100 consecutive patients from the MRI centre of JN Medical College and Hospital, Aligarh, were evaluated for the study. Inclusion criteria included patients presenting with backache, limb weakness, and fever who had undergone radiography of the spine that showed features of collapse. All patients underwent MRI on a 1.5 T MR Scanner. Coronal, sagittal and axial spine images were obtained using T1 weighted, T2 weighted, short tau inversion recovery, T1 postcontrast, and DWI sequences. RESULTS: In our study, we found different causes of non-traumatic vertebral collapse that were broadly categorized as benign or malignant. The benign causes were further sub categorized into osteoporotic or infectious based on morphological features, signal intensity characteristics, and DWI. However, on DWI, the patients with infective collapse showed mean apparent diffusion coefficient values of 884 * 10 6 mm2/s ranging between 700 and 1,100 * 10-6 mm2/s between those of malignant and benign osteoporotic collapse, with significant overlap. The statistical difference between the malignant and infective cases, as well as between osteoporotic and infective cases, was not found to be statistically significant (P > .05). CONCLUSION: MRI plays a key role in establishing the cause of vertebral collapse, classifying it as either benign or malignant. DWI, although described in various studies as highly sensitive in differentiating benign osteoporotic and malignant collapse, was found to be good in differentiating only osteoporotic from malignant collapse, with the infectious cases proving to be a grey zone with significant overlap of quantitative diffusion findings. PMID- 30479296 TI - Internationalising Research Methods Teaching of Undergraduate Health Professionals. AB - OBJECTIVE: The project aims were: (1) identifying the pedagogical impact of collaborative student experience on student understanding of research methods and (2) evaluating the perceived value of providing students with an international perspective on their professional practice. METHODS: Student cohorts from year 1 of the University of Liverpool (UoL) (n = 80) and year 2 of the Royal Melbourne Institute of Technology University (RMIT) (n = 128) undergraduate Medical Radiation Science degree programmes participated in the intervention as part of their teaching. Students were tasked with designing, deploying, and analysing data from survey-based research projects and invited to provide feedback via an anonymous and voluntary online survey (UoL students) or an equivalent paper-based survey (RMIT students), comprising both quantitative (Likert) and qualitative (open) questions. RESULTS: Responses were received from 83% of RMIT and 31% of UoL students. Over 42% of respondents enjoyed the opportunity to interact with overseas peers, while 14.7% did not; 40% of respondents felt the intervention helped in their understanding of research methods, whilst 28% indicated it had not. The main positive themes were learning the research process, team working skills, networking opportunities, and understanding cultural differences. Interpreting data were invaluable; only a minority valued the engagement with their overseas counterparts. There was poor engagement with social media. CONCLUSIONS: Students reported clear value of the innovation for learning research skills and process. The extent of research skills learning supports changes in research activity and culture in the past 10 years. With internationalisation becoming increasingly important in today's health care economy, the degree to which the students identified this aspect of the research as a key learning point highlights the benefits of the active approach. The negative appraisal of the social media support was interpreted as a response to the platform (WhatsApp) and privacy issues with sharing phone numbers. PMID- 30479297 TI - Infection, Disease & Health for today, tomorrow, and the future. PMID- 30479298 TI - Twitter and Middle East respiratory syndrome, South Korea, 2015: A multi-lingual study. AB - BACKGROUND: Different linguo-cultural communities might react to an outbreak differently. The 2015 South Korean MERS outbreak presented an opportunity for us to compare tweets responding to the same outbreak in different languages. METHODS: We obtained a 1% sample through Twitter streaming application programming interface from June 1 to 30, 2015. We identified MERS-related tweets with keywords such as 'MERS' and its translation in five different languages. We translated non-English tweets into English for statistical comparison. RESULTS: We retrieved MERS-related Twitter data in five languages: Korean (N = 21,823), English (N = 4024), Thai (N = 2084), Japanese (N = 1334) and Indonesian (N = 1256). Categories of randomly selected user profiles (p < 0.001) and the top 30 sources of retweets (p < 0.001) differed between the five language corpora. Among the randomly selected user profiles, K-pop fans ranged from 4% in the Korean corpus to 70% in the Thai corpus; media ranged from 0% (Thai) to 14% (Indonesian); political advocates ranged from 0% (Thai) to 19% (Japanese); medical professionals ranged from 0% (Thai) to 7% (English). Among the top 30 sources of retweets for each corpus (150 in total), 70 (46.7%) were media; 29 (19.3%) were K-pop fans; 7 (4.7%) were political; 9 (6%) were medical; and 35 (23.3%) were categorized as 'Others'. We performed chi-square feature selection and identified the top 20 keywords that were most unique to each corpus. CONCLUSION: Different linguo-cultural communities exist on Twitter and they might react to the same outbreak differently. Understanding audiences' unique Twitter cultures will allow public health agencies to develop appropriate Twitter health communication strategies. PMID- 30479299 TI - Epidemiological and clinical features of imported malaria at the three main hospitals of the Friuli-Venezia Giulia Region, Italy. AB - BACKGROUND: Imported malaria cases continue to occur in non-endemic regions among travellers returning from tropical and subtropical countries. At particular risk of acquiring malaria is the group of travellers identified as immigrants who return to their home country with the specific intent of visiting friends or relatives (VFRs) and who commonly believe they are immune to malaria and fail to seek pre-travel advice. Our aim was to review the current trends of imported malaria in the three main hospitals of the Friuli-Venezia Giulia region (FVG), North Eastern Italy, focusing in particular on patient characteristics and laboratory findings. METHODS: In this retrospective study, we examined all malaria cases among patients admitted from January 2010 through December 2014 to the emergency department of the three main hospitals located in FVG. RESULTS: During the 5-year study period from 2010 to 2014, there were a total of 140 patients with a diagnosis of suspected malaria and who received microscopic confirmation of malaria. The most common species identified was P. falciparum, in 96 of 140 cases (69%), followed by P. vivax (13%), P. ovale (4%), P. malariae (4%), and mixed infection (4%). The most common reason for travel was VFRs (54%), followed by work (17%), and recent immigration (15%). Moreover, 78% of all patients took no chemoprophylaxis, 80 (79%) of whom were foreigners. Notably, the percentage of Italian travellers who took chemoprophylaxis was only 20% (8 of 39 Italian cases), and the regimen was appropriate in only four cases. Parasitaemia greater than 5% was observed in 11 cases (10%), all due to P. falciparum infection. CONCLUSIONS: We highlight that VFRs have the highest proportion of malaria morbidity and the importance of improving patient management in this category. These data are useful for establishing appropriate malaria prevention measures and recommendations for international travellers. PMID- 30479300 TI - Contextual factors associated with consistent condom use and condom self-efficacy amongst African asylum seekers and refugees in Hong Kong. AB - BACKGROUND: Hong Kong has no systematic domestic policies committed to the rights of asylum-seekers and refugees (ASRs). This study explores the sexual health behaviours and social inequities amongst African ASRs in Hong Kong. METHODS: A cross-sectional survey of African ASRs was conducted through three local non governmental organizations in 2013. A logistic model was used to test the interactions and relationship between the respondents' consistent condom use and contextual antecedents, socio-demographic factors, psychosocial factors and condom self-efficacy (CSE) score. RESULTS: 371 adult African ASRs were recruited. In the previous month, 35% and 38% of participants consistently had used condoms with regular and casual sexual partners respectively. However, less than 50% perceived no risk of HIV/STIs and less than 60% reported not knowing how to access sexual health screening. Consistent condom use was less likely among African ASRs who were married (adjusted odds ratio (aOR) = 0.10), used recreational drugs (aOR = 0.11) or were unsure of their sexual orientation (aOR = 0.05) and was positively associated with higher CSE scores (aOR = 1.09) Pre migration determinants and lifestyle determinants accounted for most of the variance in the model. CONCLUSION: The inconsistent condom use makes African ASRs vulnerable to HIV/STIs. Tailored interventions are needed to address the associated determinants and inequities amongst African ASRs living in Hong Kong. PMID- 30479301 TI - Evaluation of stainless steel surgical instruments subjected to multiple use/processing. AB - BACKGROUND: To determine the effect of multiple use and processing cycles on instrument quality over the life of stainless steel, complex designed clinical surgical instruments. METHODS: Steam sterilised surgical instruments due to be discarded from Australian hospitals, because of loss of functionality, were assessed for contaminating protein and bacteria using the bicinchoninic acid protein assay and microbial culture, respectively. Biofilm presence and instrument damage were visually confirmed by scanning electron microscopy (SEM). Instruments were categorised into hinged/serrated, screw, cannulated, flexible, and irregular surfaced (but not hinged) according to their design. RESULTS: Protein contamination ranged from 24 MUg on the new screw to 3,756,046 MUg contaminating a discarded forceps. The more complex the instrument design the higher the protein contamination. All samples were culture negative, however, biofilm was visually confirmed on 4/8 instruments tested using SEM. SEM also detected soil, holes or black stains on all the instruments. CONCLUSION: "Ready to use" surgical instruments that underwent multiple uses and processing cycles were contaminated with high amounts of protein, and microscopy revealed the presence of soil, structural damage, black stains and biofilm. While less affected new but multiply processed screws also showed soil and biofilm contamination. These findings highlight the need for further research into determining what is the "life" of stainless steel instruments and development of standard criteria for evaluating when to "retire" an instrument. PMID- 30479302 TI - Knowledge, practices & attitude toward antibiotics use and bacterial resistance in Jordan: A cross-sectional study. AB - BACKGROUND: Antimicrobial resistance represents a significant public health problem worldwide. Irrational use of antibiotics is the main driving factor for the evolution of antimicrobials-resistant organisms. The aim of this study is to evaluate the areas of defects in the knowledge and practices of the community about antibiotic use. METHODS: A cross-sectional study on a sample of 1060 randomly-selected adults residing in the North of Jordan using a pre-validated questionnaire to evaluate knowledge, practices and attitude toward antimicrobial use and misuse, as well as to assess knowledge about antimicrobial resistance. RESULTS: Of all respondents, 41% (n = 437) stated that they have received oral antibiotics in the past two months, of which 38% acquired the antibiotics without a prescription. 32% of those who received antibiotics did not complete the recommended course of treatment. 39-54% of the sample population believe in common misconceptions/malpractices of antibiotics use. The majority (70%) of the respondents have not known about the term "antimicrobials resistance". Although people with higher education and higher income were generally more knowledgeable about appropriate antibiotics use and antimicrobial resistance, responses to some of the most important aspects in the assessment of knowledge showed no statistical difference between the different groups. CONCLUSIONS: Our data revealed major defects in the public knowledge about appropriate antibiotics use, as well as lack of awareness on "antimicrobial resistance" problem. Awareness about appropriate antibiotic use and the serious consequences of antibiotic misuse should reach everyone in the community regardless of their educational or economic status. PMID- 30479303 TI - Clinical management of drug-resistant bacteria in Australian hospitals: An online survey of doctors' opinions. AB - BACKGROUND: To gain a better understanding of clinical practice for the treatment of common drug-resistant infections. METHODS: A web-based anonymous survey was developed to gain a better understanding of clinical practice of patients infected with drug-resistant bloodstream infections (BSI). The survey instrument was a questionnaire requesting doctors to provide their opinion on the most likely choice of an antibiotic, dose and route of administration for patients infected with a drug-resistant Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa or Enterococcus faecium. RESULTS: All of the survey participants (n = 28) were hospital-based doctors. Choice of therapy for drug resistant E. coli and K. pneumoniae was uniform across survey participants. However, optimal treatment of ceftazidime-resistant P. aeruginosa and VRE was less clear. CONCLUSION: The survey adds to the limited body of evidence in this clinical area and can be a useful tool for health economists in determining the additional cost of treating patients with drug-resistant infections. PMID- 30479304 TI - Pricing for safety and quality in healthcare: A discussion paper. AB - INTRODUCTION: Increasingly, over the past decade, there has been a global shift in healthcare away from fixed "fee for service" payment mechanisms towards value based reimbursement models rewarding safety and quality patient outcomes. Curbing the burgeoning costs of healthcare while incentivising higher quality and safer patient care are key drivers of this approach. At face value, this is clearly a worthwhile endeavour. However, there is a lack of conclusive evidence to support the effectiveness of such schemes where they have been introduced internationally. For this reason, Australia has largely been an observer of the shift in payment modalities that are occurring in other countries such as the United States and the United Kingdom. METHOD: This paper presents an overview of current Australian practice in pricing for safety and quality in Healthcare. Recommendations are provided to help infection control professionals prepare for the upcoming introduction of funding reforms aimed at reducing complications acquired in Australian public hospitals. CONCLUSION: The implications for infection control professionals are wide-ranging. This will be a period of significant adjustment for the public health system in Australia. PMID- 30479305 TI - How much do superbugs cost Australian hospitals? An evidence-based open-access tool. AB - Drug resistant "superbugs" are on the rise and pose a considerable threat. Little is known of their impact on health outcomes and costs to health services at a country-level. Local and relevant estimates that are realistic and derived with a transparent method can stimulate and inform policy responses. We describe an innovative online open-access tool, ResImpact that provides estimates of the national cost of common drug-resistant infections in Australia. Users are able to modify the proportion of five resistant organisms and be presented with an estimate of the associated healthcare costs. By translating complex economic data into a practical and user-friendly output, policy makers and other health professionals can improve their policy response for the Australian healthcare system. PMID- 30479306 TI - Successfully clearing discharged patients of methicillin-resistant Staphylococcus aureus: Opportunities for the prevention and containment of antimicrobial resistance. AB - BACKGROUND: Australian hospitals routinely screen for multi-resistant organisms (MRO) to prevent the spread of healthcare-associated infection. The results of positive MRSA screening typically include: informing patient of their MRSA, single accommodation and contact precautions within the health care facility. These actions are associated with both negative and positive psychosocial effects, but also bring economic and human resource costs. MRSA clearance, however, is a less routine practice, and it is typically conducted only while patients are admitted. This paper reports the results of a study implementing a MRSA clearance program that included giving patients the opportunity to continue the clearance swabbing regime once discharged from hospital. METHODS: Retrospective cohort study of MRSA clearance between 2013 and 2016 at a private hospital in Australia. RESULTS: The MRSA clearance program was successful in increasing the MRSA clearance rate from 0 patients in 2013 to 13% (n12) in 2014, 11% (n10) in 2015, and 18% (n14) in 2016. CONCLUSION: Allowing patients to continuing participation in MRSA clearance following discharge has increased the clearance rate of MRSA. Clearing patients of MRSAs is advantageous to patients, the health system and society, reducing health economic costs and the negative psychosocial effects associated with contact precautions. PMID- 30479307 TI - Joint consensus on the use of OCT in coronary bifurcation lesions by European and Japanese bifurcation clubs. AB - Coronary artery bifurcation lesions comprise approximately 15-20% of all PCI and constitute a complex lesion subgroup. Intravascular optical coherence tomography (OCT) is a promising adjunctive tool for guiding coronary bifurcation with its unrivalled high resolution. Compared to angiography, intravascular OCT has a clear advantage to depict ostial lesion(s) in bifurcation without misleading 2 dimensional appearance of the conventional angiography such as overlap and foreshortening. In addition, OCT has the ability of reconstructing a bifurcation in three dimension and assessing the side branch ostium from 3D reconstruction of main vessel pullback, which can be applied to ensure the optimal recrossing position of the wire after main vessel stenting. Recently, on-line co registration of OCT and angiography became widely available and helps the operator to position a stent in precise landing zones reducing the risk of geographic miss. Despite these technological advancements, the currently available clinical data are mainly based on observational studies with a small number of patients and there are few evidence from randomized trials. The joint working group of the European and the Japanese Bifurcation Club reviewed all the available literatures regarding OCT use in bifurcation lesions and provides recommendation on OCT guiding of coronary intervention in bifurcation lesions. PMID- 30479308 TI - Impact of implant depth on hydrodynamic function with the ACURATE neo transcatheter heart valve following valve-in-valve transcatheter aortic valve replacement in Mitroflow bioprosthetic valves: an ex-vivo bench study. AB - AIMS: We assessed impact of implant depth on hydrodynamic function following valve-in-valve(VIV) transcatheter aortic valve replacement(TAVR) using the ACURATE neo (Boston Scientific Corporation, Natick, MA) transcatheter heart valve(THV) through an ex-vivo bench study. METHODS AND RESULTS: Multiple implantation depths were tested at incremental depths of 2mm using a small size ACURATE neo valve for VIV TAVR in 19mm, 21mm, 23mm, and 25mm Mitroflow(Sorin Group Canada Inc, Burnaby, BC) bioprosthetic valves. Multimodality imaging and hydrodynamic evaluation was performed at each implantation depth. A low implantation was associated with higher transvalvular gradients. The highest transvalvular gradient was observed at -10mm depth for 19mm(40.0+/-0.5mmHg), -8mm for 21mm(15.3+/-0.2mmHg), -6mm for 23mm(14.7+/-0.3mmHg) and -8mm for 25mm(8.4+/ 0.2mmHg) surgical valves. The lowest transvalvular gradient was observed at 0mm depth for the 19mm(14.9+/-0.2mmHg)/21mm(7.2+/-0.1mmHg), and +2mm depth for the 23mm(5.7+/-0.1mmHg)/25mm(5.8+/-0.1mmHg) surgical valves. At low implantation there was worse leaflet pin-wheeling and also evidence of THV leaflet interaction with those of the surgical valve that impaired leaflet coaptation resulting in a high regurgitant fraction(42.5% in the 21mm and 83.3% in the 23mm surgical valve at -10mm depths). CONCLUSIONS: A high implant is desirable to facilitate favourable hydrodynamic function when performing VIV TAVR using the ACURATE neo THV for Mitroflow aortic bioprosthesis sized <= 25mm. In a 19mm Mitroflow valve, positioning the upper crown of the ACURATE neo above the posts of the surgical valve facilitates favourable transvalvular gradients. Low implantation results in higher transvalvular gradients, worse pin-wheeling and THV leaflet dysfunction can be severe due to interaction with the surgical valve. PMID- 30479309 TI - Management of Incomplete Surgical Left Atrial Appendage Exclusion. PMID- 30479310 TI - Frictional characteristics of nano-confined water mediated hole-doped single layer graphene on silica surface. AB - We have investigated the frictional properties of single-layer graphene (SLG) coated rough silica substrate under the influence of nano-confined hydration layer underneath SLG. Through the friction and surface potential measurements by atomic force microscopy (AFM), we found polygonal features in AFM images of SLG protected silica surface that exhibit simultaneously larger friction and higher surface potential as compared to their surrounding areas due to water layers confined under SLG. Nano-confined water layers at the SLG-silica interface can induce the hole-doping effect in SLG, resulting in a more positively-charged and hydrophilic surface that favors adsorption of ambient water molecules. Therefore, during friction measurements, nanoscale capillary bridges can form within the interstices of AFM probe-SLG contact, leading to larger adhesion and friction. The friction forces were found to respectively have negative and positive dependence on the sliding velocity inside and outside the polygonal regions due to different surface wettability. Hence, it is possible to manipulate the frictional properties of SLG-coated silica by the amount of hydration layer confined underneath SLG. Our results may find applications in friction control for future nano-devices. PMID- 30479311 TI - Quantitative measurement of contact area and electron transport across platinum nanocontacts for scanning probe microscopy and electrical nanodevices. AB - Conductive modes of atomic force microscopy are widely used to characterize the electronic properties of materials, and in such measurements, contact size is typically determined from current flow. Conversely, in nanodevice applications, the current flow is predicted from the estimated contact size. In both cases, it is very common to relate the contact size and current flow using well-established ballistic electron transport theory. Here we performed 19 electromechanical tests of platinum nanocontacts with in situ transmission electron microscopy to measure contact size and conductance. We also used molecular dynamics simulations of matched nanocontacts to investigate the nature of contact on the atomic scale. Together, these tests show that the ballistic transport equations under-predict the contact size by more than an order of magnitude. The measurements suggest that the low conductance of the contact cannot be explained by the scattering of electrons at defects nor by patchy contact due to surface roughness; instead, the lower-than-expected contact conductance is attributed to approximately a monolayer of insulating surface species on the platinum. Surprisingly, the low conductance persists throughout loading and even after significant sliding of the contact in vacuum. We apply tunneling theory and extract best-fit barrier parameters that describe the properties of this surface layer. The implications of this investigation are that electron transport in device-relevant platinum nanocontacts can be significantly limited by the presence and persistence of surface species, resulting in current flow that is better described by tunneling theory than ballistic electron transport, even for cleaned pure-platinum surfaces and even after loading and sliding in vacuum. PMID- 30479312 TI - Optimal trajectory generation for time-to-contact based aerial robotic perching. AB - Many biological organisms (e.g. insects, birds, and mammals) rely on the perception of an informational variable called time-to-contact (TTC) to control their motion for various tasks such as avoiding obstacles, landing, or interception. TTC, defined as the required time to contact an object if the current velocity is maintained, has been recently leveraged for robot motion control in various tasks. However, most existing robotic applications of TTC simply control the TTC to be constant or constantly decreasing, without fully exploring the applicability for TTC. In this paper, we propose two-stage TTC based strategies and apply them to aerial robotic perching. With the proposed strategies, we can generate reference trajectories for TTC to realize the non zero contact velocity required by perching, which is impossible for constant or constantly decreasing TTC strategy, but of critical importance for robust perching performance. We conduct simulations to verify the superiority of the proposed strategies in terms of shorter time for perching and satisfying more constraints. Further, with properly designed controllers, we perform experiments on a palm-size quadcopter to track the planned reference trajectories and realize aerial robotic perching. The research presented in this paper can be readily applied to the control of flying robot for perching with visual feedback, and can inspire more alternative forms of TTC based planning and control for robotic applications. PMID- 30479313 TI - Training bioinspired sensors to classify flows. AB - We consider the inverse problem of classifying flow patterns from local sensory measurements. This problem is inspired by the ability of various aquatic organisms to respond to ambient flow signals, and is relevant for translating these abilities to underwater robotic vehicles. In Colvert, Alsalman and Kanso, B&B (2018), we trained neural networks to classify vortical flows by relying on a single flow sensor that measures a 'time history' of the local vorticity. Here, we systematically investigate the effects of distinct types of sensors on the accuracy of flow classification. We consider four types of sensors-vorticity, flow velocities parallel and transverse to the direction of flow propagation, and flow speed-and show that the networks trained using transverse velocity outperform other networks, even when subjected to aggressive data corruption. We then train the network to classify flow patterns instantaneously, using a spatially-distributed array of sensors and a single 'one time' sensory measurement. The network, based on a handful of spatially-distributed sensors, exhibits remarkable accuracy in flow classification. These results lay the groundwork for developing learning algorithms for the dynamic deployment of sensory arrays in unsteady flows. PMID- 30479314 TI - Electronic textiles based on aligned electrospun belt-like cellulose acetate nanofibers and graphene sheets: portable, scalable and eco-friendly strain sensor. AB - Recently, there has been strong interest in flexible and wearable electronics to meet the technological demands of modern society. Environmentally-friendly and scalable electronic textiles is a key area that is still significantly underdeveloped. Here, we describe a novel strain sensor composed of aligned cellulose acetate (CA) nanofibers with belt-like morphology and a reduced graphene oxide (RGO) layer. The unique spatial alignment, microstructure and wettability of CA nanofibrous membranes facilitate their close contact with deposited GO colloids. After a portable and fast hot-press process within 700 s at 150 degrees C, the GO on CA membrane can be facilely reduced to a conductive RGO layer. Moreover, the connection among contiguous CA nanofibers and the interaction between the GO and CA substrate were both highly enhanced, resulting in superior mechanical strength with Young's modulus of 1.3 GPa and small sheet resistance lower than 10 kOmega. Therefore, the conductive RGO/CA membrane was successfully utilized as a strain sensor in a broad deformation range and with versatile deformation types. Moreover, the distinctive mechanical strength under different stretch angles endowed the well-aligned RGO/CA film with intriguing sensitivity against stress direction. Such a cost-effective and environmentally friendly method can be easily extended to the scalable production of graphene based flexible electronic textiles. PMID- 30479315 TI - Mosquitoes modulate leg dynamics at takeoff to accommodate surface roughness. AB - Insects perform takeoffs from a nearly unquantifiable number of surface permutations and many use their legs to initiate upward movement prior to the onset of wingbeats, including the mosquito. In this study we examine the unprovoked pre-takeoff mechanics of Aedes aegypti mosquitoes from two surfaces of contrasting roughness, one with roughness similar to polished glass and the other comparable to the human forearm. Using high-speed videography, we find mosquitos exhibit two distinct leg actions prior to takeoff, the widely observed push and a previously undocumented leg-strike, where one of the rearmost legs is raised and strikes the ground. Across 106 takeoff sequences we observe a greater incidence of leg-strikes from the smoother surface, and rationalize this observation by comparing the characteristic size of surface features on the mosquito tarsi and each test surface. Measurements of pre-takeoff kinematics reveal both strategies remain under the mechanosensory detection threshold of mammalian hair and produce nearly identical vertical body velocities. Lastly, we develop a model that explicates the measured leg velocity of striking legs utilized by mosquitoes, 0.59 m s-1. PMID- 30479316 TI - Low-temperature one-pot synthesis of WS2 nanoflakes as electrocatalyst for hydrogen evolution reaction. AB - Transition metal dichalcogenides have unique physicochemical properties. Herein, a low-temperature facile method is demonstrated to synthesize ultrathin tungsten disulfide nanoflakes. They are loosely stacked between layers with highly exposed edges, which provide lots of active sites for electrochemical applications. The by-product of crystalline carbon improves their conductivity, which also enhances their performance in hydrogen evolution reaction. PMID- 30479317 TI - One-step synthesis and deposition of ZnFe2O4 related composite films via SPPS route for photodegradation application. AB - Binary spinel-type metal oxides (AB2O4) related materials, including ferrites (AFe2O4), are attractive photocatalysts thanks to their excellent visible light response for the photodegradation of organic pollutants. Currently, these materials are synthesized via conventional chemical routes suffering from long preparation duration and multistep. Moreover, the photocatalysts are obtained as nano-powders from conventional chemical routes would introduce another drawback for their recycling and reuse. From an industrial perspective, it is desirable to develop an efficient and facile synthesis process to produce photocatalysts in a non-dispersible form. Herein, we demonstrate that the solution precursor plasma spray (SPPS) process is a single-step method for depositing photocatalytically active zinc ferrite-based films within several minutes. The influence of the precursor ratio on the microstructures and phase compositions of the ZnFe2O4 films was investigated by XRD and Raman analyses. In addition, two optimized ZnFe2O4 films were prepared by increasing the ZnO loading and tailoring injection pattern of the precursor solution. The surface morphologies and optical bandgap were also determined by SEM and UV-visible spectroscopy. The photocatalytic activities of the ZnFe2O4 films were evaluated through the degradation of the Orange II dye and of tetracycline hydrochloride under UV or visible light irradiation. The results show that compositional ratios and composition distribution of the ZnFe2O4 films prepared via SPPS played a key role on the photocatalytic activity. The SPPS route was demonstrated to be a promising method for the synthesis and the deposition of metal oxide (i.e. perovskite type and spinel type) films within a single-step for functional applications. PMID- 30479318 TI - Are patients aware of potential risks of weight reduction surgery? An internet based survey. AB - Background/Aim: Obesity has become a global health care problem. In Saudi Arabia, up to 75% of adults are reportedly overweight. Morbid obesity has been associated with an increased risk of many comorbidities and mortality. Bariatric surgery is currently considered the most effective treatment option for morbid obesity. However, there are many concerns regarding the short and long-term complications of weight reduction surgery. It is unclear whether the general population is adequately aware of these risks. Therefore, we aimed to assess awareness of the general population of bariatric surgery complications. Although effective, bariatric surgery has been associated with many acute complications, reported in a range of 0.3% to 8% of operations. Patients and Methods: We performed a cross sectional study between July and August of 2017 in Jeddah, Saudi Arabia. We used a 26-item, Arabic, electronically distributed questionnaire, to examine public awareness of the acute complications of bariatric surgery. Hypothesis testing was used to examine associations. Results: In total, 624 questionnaires were completed electronically. Mean age of participants was 25 (+/-13.2) and 66% were females. Of the surveyed population, 64% reported being aware of acute complications of bariatric surgery. Participants who had previously undergone a bariatric operation had a higher degree of awareness when compared to those who had not undergone a bariatric operation before (80.4% vs. 61.3%, P < 0.001). Females had higher awareness compared to males (70.8% vs. 52.1%, P < 0.001). Awareness of complications was not statistically different when stratified by level of education (P = 0.131) but occupation predicted awareness (P = 0.007). Conclusion: Two-thirds of the general population appears to be aware of the potential acute complications associated with bariatric surgery. Furthermore, awareness seems to be higher in females, individuals who had previously undergone weight reduction surgery, and health care workers. PMID- 30479319 TI - Major bleeding risk of endoscopic sphincterotomy versus endoscopic papillary balloon dilatation in hemodialysis patients. AB - Background/Aims: Endoscopic sphincterotomy (EST) and endoscopic papillary balloon dilatation (EPBD) are used for therapeutic endoscopic retrograde cholangiopancreatography (ERCP). The postprocedure bleeding rate for EPBD is low in the normal population; however, this bleeding rate in a group of patients prone to bleeding, such as patients with end-stage renal disease, is not well established. We therefore evaluated the post-EST and post-EPBD bleeding rate among hemodialysis (HD) patients based on data from Taiwan's National Health Insurance Research Database (NHIRD). Patients and Methods: The NHIRD entries for a population of 2 million were screened for patients who had a catastrophic illness card for HD between 1st January 2004 and 31st December 2011 and these patients were enrolled as research subjects. The rates of major gastrointestinal tract bleeding events appearing within 14 days after EST or EPBD were compared between HD and non-HD patients. Results: A total of 3561 patients, over 18 years of age and without liver cirrhosis or hematologic diseases, underwent 3826 EST and 280 EPBD procedures during the 8 calendar years selected for our analysis. The total post-ERCP major bleeding rate was much higher in HD than in non-HD patients (8.64% vs. 2.16%, P < 0.0001). The rate of postprocedure major bleeding events was lower for non-HD patients who underwent EPBD than those who underwent EST (0.75% vs. 2.26%; P = 0.049), whereas the postprocedure major bleeding event rates were similar in HD patients who underwent either EPBD or EST (8.70% vs. 8.33%; P = 0.484). Conclusion: Post-ERCP, post-EST, and post-EPBD major bleeding rates were all higher in HD patients in this study. EPBD resulted in lower postprocedure major bleeding events than EST in the non-HD population, but it failed to provide the reduction in bleeding events needed to perform endoscopic hemostasis in HD patients. PMID- 30479320 TI - Outcome of biliary atresia among Saudi children: A tertiary care center experience. AB - Background/Aims: Data from Western countries indicate that biliary atresia (BA) is the leading cause of end-stage liver disease in children and the most common indication for liver transplantation (LT) in the pediatric population. There is no data on the epidemiology and outcome of BA in Saudi Arabia. The main objective of our study was to understand the clinical and epidemiological characteristics and outcome of BA in the Saudi population. Patients and Methods: We retrospectively reviewed the database of infantile cholestasis cases that presented to our center from 2008 to 2015 and identified BA cases. Data on clinical, biochemical, imaging, and histopathological characteristics were collected by chart review. The two primary study outcomes were (1) successful Kasai portoenterostomy (KPE) defined as resolution of jaundice (total serum bilirubin <20 MUmol/L) and (2) survival with native liver. Results: Over the study period, we evaluated 450 cases of infantile cholestasis. In all, 21 cases (11 males) were diagnosed with BA (4.7%). BA cases were first seen by pediatric gastroenterologists at a median age of 65 days. KPE was performed in 12 cases at a median age of 73 days. Successful KPE was achieved in four cases (33%). Five of the remaining eight cases had LT and three died before LT. Nine of the 21 BA cases were denied KPE and had primary LT at median 8 months of age. The native liver 4-year survival rate was 14.3% and the overall survival rate was 81%. Conclusion: BA is an uncommon cause of infantile cholestasis in Saudi Arabia. Our study provides a snapshot of the epidemiology of BA in Saudi Arabia that is characterized by late referral to pediatric gastroenterologists and poor outcome without LT. PMID- 30479321 TI - Findings during screening colonoscopies in a Middle Eastern cohort. AB - Background/Aims: Colorectal cancer is the most common cancer in males and the third most common cancer in females. We aim to determine the polyp and adenoma prevalence in a cohort of patients who underwent opportunistic screening colonoscopies. Patients and Methods: A retrospective cohort study was conducted using an endoscopic reporting database of individuals seen at three tertiary care hospitals (two public hospitals and one private) in Riyadh, Saudi Arabia. Consecutive patients who were 45 years of age and older and underwent opportunistic screening colonoscopies between November 2016 and October 2017 were included. We excluded those with a history of colon cancer or colonic resection for any reason, inflammatory bowel disease, gastrointestinal bleeding, or anemia. Results: Around 1180 patients were included in the study with a mean age of 58.6 years (SD = 7.3), with males representing 53.6% and an overall cecal intubation rate of 92.4%. Masses were found in 1.6% of the study population (50% in the sigmoid or rectosigmoid, 37.5% in the rectum). The polyp detection rate in colonoscopies was 24.8% and the adenoma detection rate was 16.8%. The histology of removed polyps was tubular adenomas in 56.6%, hyperplastic polyps in 32.7%, tubulovillous adenomas in 8.2%, and villous adenomas in 2.5%. The majority of the polyps were in the sigmoid colon (28.3%) and rectum (22.0%), followed by the ascending colon (11.2%) and cecum (10.3%), then the transverse colon and descending colon (9.4% each), and multiple locations in the remainder. Conclusion: The prevalence of polyps and adenomas in this cohort is less than that reported in the Western populations. PMID- 30479322 TI - Association between hypokalemia and small bowel capsule endoscopy completion rates in patients in South China: A prospective single-center study. AB - Background/Aims: Approximately 20-30% of small bowel capsule endoscopies (SBCEs) do not reach the cecum at the completion of the examination. We aimed to determine whether hypokalemia influences the completion rate and small bowel transit time (SBTT) of SBCE. Patients and Methods: From January to December 2017, 112 patients (18-75 years old) who underwent SBCE were assessed consecutively for enrolment in our study. On the day of the procedure, a blood test was performed prior to capsule ingestion. The completion rate, gastric transit time (GTT), SBTT, and diagnostic yield were recorded for each SBCE. Results: The SBCE completion rate was lower in the hypokalemia group than that in the normal potassium group (55.6% (15/27) vs. 76.5% (65/85), P = 0.036). The median GTT was 55.5 +/- 47.1 min in the hypokalemia group and 46.7 +/- 44.5 min in the normal potassium group (P > 0.05). The median SBTT was 412.8 +/- 123.3 min in the hypokalemia group and 367.3 +/- 172.5 min in the normal potassium group (P > 0.05). The diagnostic yields of the hypokalemia and normal potassium groups were 74.1% and 78.8%, respectively (P = 1.00). Conclusion: Hypokalemia may decrease the SBCE completion rate. Physicians should consider the possibility of hypokalemia after bowel preparation because this condition is not rare. Potassium deficiencies should be rectified prior to performing SBCE procedures to increase the SBCE completion rate. PMID- 30479323 TI - Appraisal of Basic-Hemostatic Markers in Lung Cancer Patients During Follow-Up Care After Radiotherapy Treatment. AB - BACKGROUND The aim of this paper was to investigate the association between clinicopathological factors and the coagulation test in lung cancer patients during follow-up care after treatment. MATERIAL AND METHODS Ninety-five medical patients with histologically proven advanced lung carcinoma (LC) who had undergone radiotherapy were prospectively reviewed between January 2014 and December 2016. The study investigated the relationship between the biochemical results, the disease stage, and the survival rate in lung cancer patients. Post treatment coagulation-based D-dimer (DD), fibrinogen (Fib), and complete blood count (CBC) were evaluated during the follow-up over a period of 2 years after treatment or until the patient's death. RESULTS An increase of D-dimer generates an increased chance of early death by approximately 0.03% per 1 D-dimer unit. In cases when the difference in the D-dimer concentration equals 1000, the risk of an early death increases by (1.00031000-1)*100%=35%. CONCLUSIONS High levels of D dimer are associated with an advanced form of disease with metastasis and higher risk of early death in lung cancer patients. PMID- 30479324 TI - Double dative bond between divalent carbon(0) and uranium. AB - Dative bonds between p- and d-block atoms are common but species containing a double dative bond, which donate two-electron pairs to the same acceptor, are far less common. The synthesis of complexes between UCl4 and carbodiphosphoranes (CDP), which formally possess double dative bonds Cl4U?CDP, is reported in this paper. Single-crystal X-ray diffraction shows that the uranium-carbon distances are in the range of bond lengths for uranium-carbon double bonds. A bonding analysis suggests that the molecules are uranium-carbone complexes featuring divalent carbon(0) ligands rather than uranium-carbene species. The complexes represent rare examples with a double dative bond in f-block chemistry. Our study not only introduces the concept of double dative bonds between carbones and f block elements but also opens an avenue for the construction of other complexes with double dative bonds, thus providing new opportunities for the applications of f-block compounds. PMID- 30479326 TI - Passive directional sub-ambient daytime radiative cooling. AB - Demonstrations of passive daytime radiative cooling have primarily relied on complex and costly spectrally selective nanophotonic structures with high emissivity in the transparent atmospheric spectral window and high reflectivity in the solar spectrum. Here, we show a directional approach to passive radiative cooling that exploits the angular confinement of solar irradiation in the sky to achieve sub-ambient cooling during the day regardless of the emitter properties in the solar spectrum. We experimentally demonstrate this approach using a setup comprising a polished aluminum disk that reflects direct solar irradiation and a white infrared-transparent polyethylene convection cover that minimizes diffuse solar irradiation. Measurements performed around solar noon show a minimum temperature of 6 degrees C below ambient temperature and maximum cooling power of 45 W m-2. Our passive cooling approach, realized using commonly available low cost materials, could improve the performance of existing cooling systems and enable next-generation thermal management and refrigeration solutions. PMID- 30479325 TI - Expansive microbial metabolic versatility and biodiversity in dynamic Guaymas Basin hydrothermal sediments. AB - Microbes in Guaymas Basin (Gulf of California) hydrothermal sediments thrive on hydrocarbons and sulfur and experience steep, fluctuating temperature and chemical gradients. The functional capacities of communities inhabiting this dynamic habitat are largely unknown. Here, we reconstructed 551 genomes from hydrothermally influenced, and nearby cold sediments belonging to 56 phyla (40 uncultured). These genomes comprise 22 unique lineages, including five new candidate phyla. In contrast to findings from cold hydrocarbon seeps, hydrothermal-associated communities are more diverse and archaea dominate over bacteria. Genome-based metabolic inferences provide first insights into the ecological niches of these uncultured microbes, including methane cycling in new Crenarchaeota and alkane utilization in ANME-1. These communities are shaped by a high biodiversity, partitioning among nitrogen and sulfur pathways and redundancy in core carbon-processing pathways. The dynamic sediments select for distinctive microbial communities that stand out by expansive biodiversity, and open up new physiological perspectives into hydrothermal ecosystem function. PMID- 30479327 TI - Colossal tunability in high frequency magnetoelectric voltage tunable inductors. AB - The electrical modulation of magnetization through the magnetoelectric effect provides a great opportunity for developing a new generation of tunable electrical components. Magnetoelectric voltage tunable inductors (VTIs) are designed to maximize the electric field control of permeability. In order to meet the need for power electronics, VTIs operating at high frequency with large tunability and low loss are required. Here we demonstrate magnetoelectric VTIs that exhibit remarkable high inductance tunability of over 750% up to 10 MHz, completely covering the frequency range of state-of-the-art power electronics. This breakthrough is achieved based on a concept of magnetocrystalline anisotropy (MCA) cancellation, predicted in a solid solution of nickel ferrite and cobalt ferrite through first-principles calculations. Phase field model simulations are employed to observe the domain-level strain-mediated coupling between magnetization and polarization. The model reveals small MCA facilitates the magnetic domain rotation, resulting in larger permeability sensitivity and inductance tunability. PMID- 30479328 TI - Cross-species interference of gene expression. AB - Microbes can contribute to protection of animals and plants against diseases. A recent study reveals a mechanism by which a bacterium controls fungal infection in wheat, involving secretion of a metabolite that affects histone acetyltransferase activity of a plant pathogenic fungus. PMID- 30479329 TI - Understanding dynamics of coherent Ising machines through simulation of large scale 2D Ising models. AB - Many problems in mathematics, statistical mechanics, and computer science are computationally hard but can often be mapped onto a ground-state-search problem of the Ising model and approximately solved by artificial spin-networks of coupled degenerate optical parametric oscillators (DOPOs) in coherent Ising machines. To better understand their working principle and optimize their performance, we analyze the dynamics during the ground state search of 2D Ising models with up to 1936 mutually coupled DOPOs. For regular as well as frustrated and disordered 2D lattices, the machine finds the correct solution within just a few milliseconds. We determine that calculation performance is limited by freeze out effects and can be improved by controlling the DOPO dynamics, which allows to optimize performance of coherent Ising machines in various tasks. Comparisons with Monte Carlo simulations reveal that coherent Ising machines behave like low temperature spin systems, thus making them suitable for optimization tasks. PMID- 30479330 TI - Seasonal energy exchange in sea ice retreat regions contributes to differences in projected Arctic warming. AB - Rapid and, in many cases, unprecedented Arctic climate changes are having far reaching impacts on natural and human systems. Despite state-of-the-art climate models capturing the rapid nature of Arctic climate change, termed Arctic amplification, they significantly disagree on its magnitude. Using a regional, process-oriented surface energy budget analysis, we argue that differences in seasonal energy exchanges in sea ice retreat regions via increased absorption and storage of sunlight in summer and increased upward surface turbulent fluxes in fall/winter contribute to the inter-model spread. Models able to more widely disperse energy drawn from the surface in sea ice retreat regions warm more, suggesting that differences in the local Arctic atmospheric circulation response contribute to the inter-model spread. We find that the principle mechanisms driving the inter-model spread in Arctic amplification operate locally on regional scales, requiring an improved understanding of atmosphere-ocean-sea ice interactions in sea ice retreat regions to reduce the spread. PMID- 30479331 TI - A CRISPR-Cas9-triggered strand displacement amplification method for ultrasensitive DNA detection. AB - Although polymerase chain reaction (PCR) is the most widely used method for DNA amplification, the requirement of thermocycling limits its non-laboratory applications. Isothermal DNA amplification techniques are hence valuable for on site diagnostic applications in place of traditional PCR. Here we describe a true isothermal approach for amplifying and detecting double-stranded DNA based on a CRISPR-Cas9-triggered nicking endonuclease-mediated Strand Displacement Amplification method (namely CRISDA). CRISDA takes advantage of the high sensitivity/specificity and unique conformational rearrangements of CRISPR effectors in recognizing the target DNA. In combination with a peptide nucleic acid (PNA) invasion-mediated endpoint measurement, the method exhibits attomolar sensitivity and single-nucleotide specificity in detection of various DNA targets under a complex sample background. Additionally, by integrating the technique with a Cas9-mediated target enrichment approach, CRISDA exhibits sub-attomolar sensitivity. In summary, CRISDA is a powerful isothermal tool for ultrasensitive and specific detection of nucleic acids in point-of-care diagnostics and field analyses. PMID- 30479333 TI - Imaging antiferromagnetic antiphase domain boundaries using magnetic Bragg diffraction phase contrast. AB - Manipulating magnetic domains is essential for many technological applications. Recent breakthroughs in Antiferromagnetic Spintronics brought up novel concepts for electronic device development. Imaging antiferromagnetic domains is of key importance to this field. Unfortunately, some of the basic domain types, such as antiphase domains, cannot be imaged by conventional techniques. Herein, we present a new domain projection imaging technique based on the localization of domain boundaries by resonant magnetic diffraction of coherent X rays. Contrast arises from reduction of the scattered intensity at the domain boundaries due to destructive interference effects. We demonstrate this approach by imaging antiphase domains in a collinear antiferromagnet Fe2Mo3O8, and observe evidence of domain wall interaction with a structural defect. This technique does not involve any numerical algorithms. It is fast, sensitive, produces large-scale images in a single-exposure measurement, and is applicable to a variety of magnetic domain types. PMID- 30479332 TI - Slx5-Slx8 ubiquitin ligase targets active pools of the Yen1 nuclease to limit crossover formation. AB - The repair of double-stranded DNA breaks (DSBs) by homologous recombination involves the formation of branched intermediates that can lead to crossovers following nucleolytic resolution. The nucleases Mus81-Mms4 and Yen1 are tightly controlled during the cell cycle to limit the extent of crossover formation and preserve genome integrity. Here we show that Yen1 is further regulated by sumoylation and ubiquitination. In vivo, Yen1 becomes sumoylated under conditions of DNA damage by the redundant activities of Siz1 and Siz2 SUMO ligases. Yen1 is also a substrate of the Slx5-Slx8 ubiquitin ligase. Loss of Slx5-Slx8 stabilizes the sumoylated fraction, attenuates Yen1 degradation at the G1/S transition, and results in persistent localization of Yen1 in nuclear foci. Slx5-Slx8-dependent ubiquitination of Yen1 occurs mainly at K714 and mutation of this lysine increases crossover formation during DSB repair and suppresses chromosome segregation defects in a mus81? background. PMID- 30479335 TI - Differentiation between enamines and tautomerizable imines in the oxidation reaction with TEMPO. AB - Enamine and imine represent two of the most common reaction intermediates in syntheses, and the imine intermediates containing alpha-hydrogen often exhibit the similar reactivity to enamines due to their rapid tautomerization to enamine tautomers. Herein, we report that the minor structural difference between the enamine and the enamine tautomer derived from imine tautomerization results in the different chemo- and regioselectivity in the reaction of cyclohexanones, amines and TEMPO: the reaction of primary amines furnishes the formal oxygen 1,2 migration product, alpha-amino-enones, while the reaction of secondary amines under similar conditions generates exclusively arylamines via consecutive dehydrogenation on the cyclohexyl rings. The 18O-labeling experiment for alpha amino-enone formation revealed that TEMPO served as oxygen transfer reagent. Experimental and computational studies of reaction mechanisms revealed that the difference in chemo- and regioselectivity could be ascribed to the flexible imine enamine tautomerization of the imine intermediate containing an alpha-hydrogen. PMID- 30479334 TI - PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance. AB - Engineered oncolytic viruses are used clinically to destroy cancer cells and have the ability to boost anticancer immunity. Phosphatase and tensin homolog deleted on chromosome 10 loss is common across a broad range of malignancies, and is implicated in immune escape. The N-terminally extended isoform, phosphatase and tensin homolog deleted on chromosome 10 alpha (PTENalpha), regulates cellular functions including protein kinase B signaling and mitochondrial adenosine triphosphate production. Here we constructed HSV-P10, a replicating, PTENalpha expressing oncolytic herpesvirus, and demonstrate that it inhibits PI3K/AKT signaling, increases cellular adenosine triphosphate secretion, and reduces programmed death-ligand 1 expression in infected tumor cells, thus priming an adaptive immune response and overcoming tumor immune escape. A single dose of HSV P10 resulted in long term survivors in mice bearing intracranial tumors, priming anticancer T-cell immunity leading to tumor rejection. This implicates HSV-P10 as an oncolytic and immune stimulating therapeutic for anticancer therapy. PMID- 30479336 TI - Vasculogenic mimicry formation in EBV-associated epithelial malignancies. AB - Epstein-Barr virus (EBV)-associated epithelial cancers, including nasopharyngeal carcinoma (NPC) and approximately 10% of gastric cancers, termed EBVaGC, represent 80% of all EBV-related malignancies. However, the exact role of EBV in epithelial cancers remains elusive. Here, we report that EBV functions in vasculogenic mimicry (VM). Epithelial cancer cells infected with EBV develop tumor vascular networks that correlate with tumor growth, which is different from endothelial-derived angiogenic vessels and is VEGF-independent. Mechanistically, activation of the PI3K/AKT/mTOR/HIF-1alpha signaling cascade, which is partly mediated by LMP2A, is responsible for EBV-induced VM formation. Both xenografts and clinical samples of NPC and EBVaGC exhibit VM histologically, which are correlated with AKT and HIF-1alpha activation. Furthermore, although anti-VEGF monotherapy shows limited effects, potent synergistic antitumor activities are achieved by combination therapy with VEGF and HIF-1alpha-targeted agents. Our findings suggest that EBV creates plasticity in epithelial cells to express endothelial phenotype and provides a novel EBV-targeted antitumor strategy. PMID- 30479337 TI - MFF-dependent mitochondrial fission regulates presynaptic release and axon branching by limiting axonal mitochondria size. AB - Neurons display extreme degrees of polarization, including compartment-specific organelle morphology. In cortical, long-range projecting, pyramidal neurons (PNs), dendritic mitochondria are long and tubular whereas axonal mitochondria display uniformly short length. Here we explored the functional significance of maintaining small mitochondria for axonal development in vitro and in vivo. We report that the Drp1 'receptor' Mitochondrial fission factor (MFF) is required for determining the size of mitochondria entering the axon and then for maintenance of their size along the distal portions of the axon without affecting their trafficking properties, presynaptic capture, membrane potential or ability to generate ATP. Strikingly, this increase in presynaptic mitochondrial size upon MFF downregulation augments their capacity for Ca2+ ([Ca2+]m) uptake during neurotransmission, leading to reduced presynaptic [Ca2+]c accumulation, decreased presynaptic release and terminal axon branching. Our results uncover a novel mechanism controlling neurotransmitter release and axon branching through fission dependent regulation of presynaptic mitochondrial size. PMID- 30479338 TI - Pd(OAc)2-catalyzed asymmetric hydrogenation of sterically hindered N-tosylimines. AB - Asymmetric hydrogenation of sterically hindered substrates still constitutes a long-standing challenge in the area of asymmetric catalysis. Herein, an efficient palladium acetate (an inexpensive Pd salt with low toxicity) catalyzed asymmetric hydrogenation of sterically hindered N-tosylimines is realized with high catalytic activities (S/C up to 5000) and excellent enantioselectivities (ee up to 99.9%). Quantum chemical calculations suggest that uniformly high enantioselectivities are observed due to the structurally different S- and R reaction pathways. PMID- 30479339 TI - Geometric phase magnetometry using a solid-state spin. AB - A key challenge of magnetometry lies in the simultaneous optimization of magnetic field sensitivity and maximum field range. In interferometry-based magnetometry, a quantum two-level system acquires a dynamic phase in response to an applied magnetic field. However, due to the 2pi periodicity of the phase, increasing the coherent interrogation time to improve sensitivity reduces field range. Here we introduce a route towards both large magnetic field range and high sensitivity via measurements of the geometric phase acquired by a quantum two-level system. We experimentally demonstrate geometric-phase magnetometry using the electronic spin associated with the nitrogen vacancy (NV) color center in diamond. Our approach enables unwrapping of the 2pi phase ambiguity, enhancing field range by 400 times. We also find additional sensitivity improvement in the nonadiabatic regime, and study how geometric-phase decoherence depends on adiabaticity. Our results show that the geometric phase can be a versatile tool for quantum sensing applications. PMID- 30479340 TI - Efficient solar-driven electrocatalytic CO2 reduction in a redox-medium-assisted system. AB - Solar-driven electrochemical carbon dioxide (CO2) reduction is capable of producing value-added chemicals and represents a potential route to alleviate carbon footprint in the global environment. However, the ever-changing sunlight illumination presents a substantial impediment of maintaining high electrocatalytic efficiency and stability for practical applications. Inspired by green plant photosynthesis with separate light reaction and (dark) carbon fixation steps, herein, we developed a redox-medium-assisted system that proceeds water oxidation with a nickel-iron hydroxide electrode under light illumination and stores the reduction energy using a zinc/zincate redox, which can be controllably released to spontaneously reduce CO2 into carbon monoxide (CO) with a gold nanocatalyst in dark condition. This redox-medium-assisted system enables a record-high solar-to-CO photoconversion efficiency of 15.6% under 1-sun intensity, and an outstanding electric energy efficiency of 63%. Furthermore, it allows a unique tuning capability of the solar-to-CO efficiency and selectivity by the current density applied during the carbon fixation. PMID- 30479341 TI - Ancient Fennoscandian genomes reveal origin and spread of Siberian ancestry in Europe. AB - European population history has been shaped by migrations of people, and their subsequent admixture. Recently, ancient DNA has brought new insights into European migration events linked to the advent of agriculture, and possibly to the spread of Indo-European languages. However, little is known about the ancient population history of north-eastern Europe, in particular about populations speaking Uralic languages, such as Finns and Saami. Here we analyse ancient genomic data from 11 individuals from Finland and north-western Russia. We show that the genetic makeup of northern Europe was shaped by migrations from Siberia that began at least 3500 years ago. This Siberian ancestry was subsequently admixed into many modern populations in the region, particularly into populations speaking Uralic languages today. Additionally, we show that ancestors of modern Saami inhabited a larger territory during the Iron Age, which adds to the historical and linguistic information about the population history of Finland. PMID- 30479342 TI - Human milk oligosaccharides, milk microbiome and infant gut microbiome modulate neonatal rotavirus infection. AB - Neonatal rotavirus infections are predominantly asymptomatic. While an association with gastrointestinal symptoms has been described in some settings, factors influencing differences in clinical presentation are not well understood. Using multidisciplinary approaches, we show that a complex interplay between human milk oligosaccharides (HMOs), milk microbiome, and infant gut microbiome impacts neonatal rotavirus infections. Validating in vitro studies where HMOs are not decoy receptors for neonatal strain G10P[11], population studies show significantly higher levels of Lacto-N-tetraose (LNT), 2'-fucosyllactose (2'FL), and 6'-siallylactose (6'SL) in milk from mothers of rotavirus-positive neonates with gastrointestinal symptoms. Further, these HMOs correlate with abundance of Enterobacter/Klebsiella in maternal milk and infant stool. Specific HMOs also improve the infectivity of a neonatal strain-derived rotavirus vaccine. This study provides molecular and translational insight into host factors influencing neonatal rotavirus infections and identifies maternal components that could promote the performance of live, attenuated rotavirus vaccines. PMID- 30479343 TI - Clearance of maternal barriers by paternal miR159 to initiate endosperm nuclear division in Arabidopsis. AB - Sperm entry triggers central cell division during seed development, but what factors besides the genome are inherited from sperm, and the mechanism by which paternal factors regulate early division events, are not understood. Here we show that sperm-transmitted miR159 promotes endosperm nuclear division by repressing central cell-transmitted miR159 targets. Disruption of paternal miR159 causes approximately half of the seeds to abort as a result of defective endosperm nuclear divisions. In wild-type plants, MYB33 and MYB65, two miR159 targets, are highly expressed in the central cell before fertilization, but both are rapidly abolished after fertilization. In contrast, loss of paternal miR159 leads to retention of MYB33 and MYB65 in the central cell after fertilization. Furthermore, ectopic expression of a miR159-resistant version of MYB33 (mMYB33) in the endosperm significantly inhibits initiation of endosperm nuclear division. Collectively, these results show that paternal miR159 inhibits its maternal targets to promote endosperm nuclear division, thus uncovering a previously unknown paternal effect on seed development. PMID- 30479345 TI - Hysteresis control of epithelial-mesenchymal transition dynamics conveys a distinct program with enhanced metastatic ability. AB - Epithelial-mesenchymal transition (EMT) have been extensively characterized in development and cancer, and its dynamics have been modeled as a non-linear process. However, less is known about how such dynamics may affect its biological impact. Here, we use mathematical modeling and experimental analysis of the TGF beta-induced EMT to reveal a non-linear hysteretic response of E-cadherin repression tightly controlled by the strength of the miR-200s/ZEBs negative feedback loop. Hysteretic EMT conveys memory state, ensures rapid and robust cellular response and enables EMT to persist long after withdrawal of stimuli. Importantly, while both hysteretic and non-hysteretic EMT confer similar morphological changes and invasive potential of cancer cells, only hysteretic EMT enhances lung metastatic colonization efficiency. Cells that undergo hysteretic EMT differentially express subsets of stem cell and extracellular matrix related genes with significant clinical prognosis value. These findings illustrate distinct biological impact of EMT depending on the dynamics of the transition. PMID- 30479344 TI - Macrophage-derived netrin-1 promotes abdominal aortic aneurysm formation by activating MMP3 in vascular smooth muscle cells. AB - Abdominal aortic aneurysms (AAA) are characterized by extensive extracellular matrix (ECM) fragmentation and inflammation. However, the mechanisms by which these events are coupled thereby fueling focal vascular damage are undefined. Here we report through single-cell RNA-sequencing of diseased aorta that the neuronal guidance cue netrin-1 can act at the interface of macrophage-driven injury and ECM degradation. Netrin-1 expression peaks in human and murine aneurysmal macrophages. Targeted deletion of netrin-1 in macrophages protects mice from developing AAA. Through its receptor neogenin-1, netrin-1 induces a robust intracellular calcium flux necessary for the transcriptional regulation and persistent catalytic activation of matrix metalloproteinase-3 (MMP3) by vascular smooth muscle cells. Deficiency in MMP3 reduces ECM damage and the susceptibility of mice to develop AAA. Here, we establish netrin-1 as a major signal that mediates the dynamic crosstalk between inflammation and chronic erosion of the ECM in AAA. PMID- 30479347 TI - Single cell RNA-sequencing identifies a metabolic aspect of apoptosis in Rbf mutant. AB - The function of Retinoblastoma tumor suppressor (pRB) is greatly influenced by the cellular context, therefore the consequences of pRB inactivation are cell type-specific. Here we employ single cell RNA-sequencing (scRNA-seq) to profile the impact of an Rbf mutation during Drosophila eye development. First, we build a catalogue of 11,500 wild type eye disc cells containing major known cell types. We find a transcriptional switch occurring in differentiating photoreceptors at the time of axonogenesis. Next, we map a cell landscape of Rbf mutant and identify a mutant-specific cell population that shows intracellular acidification due to increase in glycolytic activity. Genetic experiments demonstrate that such metabolic changes, restricted to this unique Rbf mutant population, sensitize cells to apoptosis and define the pattern of cell death in Rbf mutant eye disc. Thus, these results illustrate how scRNA-seq can be applied to dissect mutant phenotypes. PMID- 30479346 TI - Dual HLA B*42 and B*81-reactive T cell receptors recognize more diverse HIV-1 Gag escape variants. AB - Some closely related human leukocyte antigen (HLA) alleles are associated with variable clinical outcomes following HIV-1 infection despite presenting the same viral epitopes. Mechanisms underlying these differences remain unclear but may be due to intrinsic characteristics of the HLA alleles or responding T cell repertoires. Here we examine CD8+ T cell responses against the immunodominant HIV 1 Gag epitope TL9 (TPQDLNTML180-188) in the context of the protective allele B*81:01 and the less protective allele B*42:01. We observe a population of dual reactive T cells that recognize TL9 presented by both B*81:01 and B*42:01 in individuals lacking one allele. The presence of dual-reactive T cells is associated with lower plasma viremia, suggesting a clinical benefit. In B*42:01 expressing individuals, the dual-reactive phenotype defines public T cell receptor (TCR) clones that recognize a wider range of TL9 escape variants, consistent with enhanced control of viral infection through containment of HIV-1 sequence adaptation. PMID- 30479348 TI - TRIM28 protects TRIM24 from SPOP-mediated degradation and promotes prostate cancer progression. AB - TRIM24 is an effector substrate of the E3 ubiquitin ligase adaptor SPOP and becomes stabilized in prostate cancer (PCa) with SPOP mutations. However, how TRIM24 protein is regulated in the vast majority of SPOP-wildtype PCa is unknown. Here we report TRIM28 as a critical upstream regulator of TRIM24. TRIM28 protein interacts with TRIM24 to prevent its ubiquitination and degradation by SPOP. Further, TRIM28 facilitates TRIM24 occupancy on the chromatin and, like TRIM24, augments AR signaling. TRIM28 promotes PCa cell proliferation in vitro and xenograft tumor growth in vivo. Importantly, TRIM28 is upregulated in aggressive PCa and associated with elevated levels of TRIM24 and worse clinical outcome. TRIM24 and AR coactivated gene signature of SPOP-mutant PCa is similarly activated in human PCa with high TRIM28 expression. Taken together, this study provides a novel mechanism to broad TRIM24 protein stabilization and establishes TRIM28 as a promising therapeutic target. PMID- 30479349 TI - A Convenient Non-harm Cervical Spondylosis Intelligent Identity method based on Machine Learning. AB - Cervical spondylosis (CS), a most common orthopedic diseases, is mainly identified by the doctor's judgment from the clinical symptoms and cervical change provided by expensive instruments in hospital. Owing to the development of the surface electromyography (sEMG) technique and artificial intelligence, we proposed a convenient non-harm CS intelligent identify method EasiCNCSII, including the sEMG data acquisition and the CS identification. Faced with the limit testable muscles, the data acquisition method are proposed to conveniently and effectively collect data based on the tendons theory and CS etiology. Faced with high-dimension and the weak availability of the data, the 3-tier model EasiAI is developed to intelligently identify CS. The common features and new features are extracted from raw sEMG data in first tier. The EasiRF is proposed in second tier to further reduce the data dimension, improving the performance. A classification model based on gradient boosted regression tree is developed in third tier to identify CS. Compared with 4 common machine learning classification models, the EasiCNCSII achieves best performance of 91.02% in mean accuracy, 97.14% in mean sensitivity, 81.43% in mean specificity, 0.95 in mean AUC. PMID- 30479350 TI - Architecture and subunit arrangement of the complete Saccharomyces cerevisiae COMPASS complex. AB - Methylation of histone H3 lysine 4 (H3K4) is catalyzed by the multi-component COMPASS or COMPASS-like complex, which is highly conserved from yeast to human, and plays essential roles in gene expression and transcription, cell cycle progression, and DNA repair. Here we present a cryo-EM map of the complete S. cerevisiae COMPASS complex. Through tag or Fab labeling strategy combined with cryo-EM 3D reconstruction and cross-linking and mass spectrometry (XL-MS) analysis, we uncovered new information on the subunit arrangement: Cps50, Cps35, and Cps30 were determined to group together to form the face region in the head of the complex, and Cps40 and the N-terminal portion of Set1 reside on the top of the head. Our map reveals the location of the active center and a canyon in the back of the head. Together, our study provides the first snapshot of the complete architecture of yeast COMPASS and a picture of its subunit interaction network, which could facilitate our understanding of the COMPASS machinery and its functionality. PMID- 30479351 TI - Gradient and scattering forces of anti-reflection-coated spheres in an aplanatic beam. AB - Anti-reflection coatings (ARCs) enable one to trap high dielectric spheres that may not be trappable otherwise. Through rigorously calculating the gradient and scattering forces, we directly showed that the improved trapping performance is due to the reduction in scattering force, which originates from the suppression of backscattering by ARC. We further applied ray optics and wave scattering theories to thoroughly understand the underlying mechanism, from which, we inferred that ARC only works for spherical particles trapped near the focus of an aplanatic beam, and it works much better for large spheres. For this reason, in contradiction to our intuition, large ARC-coated spheres are sometimes more trappable than their smaller counter parts. Surprisingly, we discovered a scattering force free zone for a large ARC-coated sphere located near the focus of an aplanatic beam. Our work provides a quantitative study of ARC-coated spheres and bridges the gap between the existing experiments and current conceptual understandings. PMID- 30479352 TI - Ambient Air Pollution Exposures and Newly Diagnosed Pulmonary Tuberculosis in Jinan, China: A Time Series Study. AB - Few epidemiological studies have evaluated the effects of air pollution on the risk of pulmonary tuberculosis (TB). We investigated the associations of ambient air pollutants (particulate matter with aerodynamic diameter <2.5 MUm (PM2.5), sulfur dioxide (SO2),nitrogen dioxide (NO2), ozone (O3), and carbon monoxide (CO)) in relation to the risk of pulmonary TB in a cohort of Chinese TB patient in Jinan city from 2011 to 2015. A total of 9344 newly diagnosed pulmonary TB cases were included. Poisson regression model was employed to estimate the risk of air pollution and daily diagnosed pulmonary TB. Four different air pollution exposure windows (3, 6, 9, and 12 months) before TB diagnoses were calculated from the daily concentration of air pollution. In overall analysis, we did not find strong evidence for an association between continuous exposures to most ambient air pollutants and risk for pulmonary TB. However, in categorical analysis, we observed statistically significant overall associations between pulmonary TB risk and PM2.5 (3 month exposure window: RR = 1.228, 95%CI: 1.091 1.381) as well as CO (3 month exposure window: RR = 1.169, 95%CI: 1.028-1.329; 9 month exposure window: RR = 1.442, 95%CI: 1.028-2.024) exposures. Moreover, subgroup analyses suggested that most of the air pollutants (PM2.5, SO2, O3, and CO) were significantly associated with increased risk of TB among the males, the females, the <60 years, and the smear negative cases. The dominant statistically significant associations were detected at 3-month exposure window of air pollution before the diagnosis of TB. Our results detected positive associations between ambient PM2.5, CO exposures and the risk of newly diagnosed pulmonary TB in China. The suggestive evidence that the 3 month air pollution exposure window was associated with increased TB risk warrants further investigation. PMID- 30479353 TI - Radiopaque Fully Degradable Nanocomposites for Coronary Stents. AB - Bioresorbable scaffolds (BRS) were introduced to overcome limitations of current metallic drug-eluting stents and poly-L-lactide (PLLA) has been used in the fabrication of BRS due to its biodegradability and biocompatibility. However, such polymers have weaker mechanical properties as compared to metals, limiting their use in BRS. We hypothesized that nanofillers can be used to enhance the mechanical properties considerably in PLLA. To this end, polymer-matrix composites consisting of PLLA reinforced with 5-20 wt% barium sulfate (BaSO4) nanofillers as a potential BRS material was evaluated. Stearic-acid (SA) modified BaSO4 nanofillers were used to examine the effect of functionalization. Rigid nanofillers improved the tensile modulus and strength of PLLA (60% and 110% respectively), while the use of SA-BaSO4 caused a significant increase (~110%) in the elongation at break. Enhancement in mechanical properties is attributed to functionalization which decreased the agglomeration of the nanofillers and improved dispersion. The nanocomposites were also radiopaque. Finite element analysis (FEA) showed that scaffold fabricated from the novel nanocomposite material has improved scaffolding ability, specifically that the strut thickness could be decreased compared to the conventional PLLA scaffold. In conclusion, BaSO4/PLLA-based nanocomposites could potentially be used as materials for BRS with improved mechanical and radiopaque properties. PMID- 30479354 TI - beta-diversity decreases with increasing trophic rank in plant - arthropod food chains on lake islands. AB - Contrasting trophic theories of island biogeography try to link spatial patterns in species distribution and richness with dietary preferences, arguing that the spatial turnover of species among habitat patches changes with trophic rank causing a systematic change in the proportion of plants, herbivores, and predators across habitats of different size. Here we test these predictions using quantitative surveys of plants, spiders, and herbivores as well as of omnivorous and predatory ground beetles on undisturbed Polish lake islands. We found decreased proportions of predators and habitat generalists on larger islands. Environmental niches and niche overlap were highest in predators. Variability in environmental niche width among species increased at higher trophic levels. Our results confirm models that predict a decrease in spatial species turnover (beta diversity) with increasing trophic level. We speculate that the major trigger for these differences is a reduced dispersal ability in plants at basal trophic ranks when compared to higher trophic levels. PMID- 30479356 TI - Genome-wide DNA methylation changes in CD19+ B cells from relapsing-remitting multiple sclerosis patients. AB - Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system. The inflammatory process in MS is driven by both T and B cells and current therapies are targeted to each of these cell types. Epigenetic mechanisms may provide a valuable link between genes and environment. DNA methylation is the best studied epigenetic mechanism and is recognized as a potential contributor to MS risk. The objective of this study was to identify DNA methylation changes associated with MS in CD19+ B-cells. We performed an epigenome-wide association analysis of DNA methylation in the CD19+ B-cells from 24 patients with relapsing-remitting MS on various treatments and 24 healthy controls using Illumina 450 K arrays. A large differentially methylated region (DMR) was observed at the lymphotoxin alpha (LTA) locus. This region was hypermethylated and contains 19 differentially methylated positions (DMPs) spanning 860 bp, all of which are located within the transcriptional start site. We also observed smaller DMRs at 4 MS-associated genes: SLC44A2, LTBR, CARD11 and CXCR5. These preliminary findings suggest that B-cell specific DNA-methylation may be associated with MS risk or response to therapy, specifically at the LTA locus. Development of B-cell specific epigenetic therapies is an attractive new avenue of research in MS treatment. Further studies are now required to validate these findings and understand their functional significance. PMID- 30479355 TI - Phylogenetic and mutational analyses of human LEUTX, a homeobox gene implicated in embryogenesis. AB - Recently, human PAIRED-LIKE homeobox transcription factor (TF) genes were discovered whose expression is limited to the period of embryo genome activation up to the 8-cell stage. One of these TFs is LEUTX, but its importance for human embryogenesis is still subject to debate. We confirmed that human LEUTX acts as a TAATCC-targeting transcriptional activator, like other K50-type PAIRED-LIKE TFs. Phylogenetic comparisons revealed that Leutx proteins are conserved across Placentalia and comprise two conserved domains, the homeodomain, and a Leutx specific domain containing putative transcriptional activation motifs (9aaTAD). Examination of human genotype resources revealed 116 allelic variants in LEUTX. Twenty-four variants potentially affect function, but they occur only heterozygously at low frequency. One variant affects a DNA-specificity determining residue, mutationally reachable by a one-base transition. In vitro and in silico experiments showed that this LEUTX mutation (alanine to valine at position 54 in the homeodomain) results in a transactivational loss-of-function to a minimal TAATCC-containing promoter and a 36 bp motif enriched in genes involved in embryo genome activation. A compensatory change in residue 47 restores function. The results support the notion that human LEUTX functions as a transcriptional activator important for human embryogenesis. PMID- 30479358 TI - Multiple physical aspects during the flow and heat transfer analysis of Carreau fluid with nanoparticles. AB - The current work is concerned with the two-dimensional boundary layer flow of a non-Newtonian fluid in the presence of nanoparticles. The heat and mass transfer mechanism for Carreau nanofluid flow due to a radially stretching/shrinking sheet is further investigated in this article. The governing physical situation is modelled in the form of partial differential equations and are simplified to a system of non-linear ordinary differential equations by employing dimensionless variables. Numerical simulations for non-dimensional velocity, temperature and concentration fields has been performed with the assistance of built-in Matlab solver bvp4c routine. One significant computational outcome of this study is the existence of multiple numerical solutions for the flow fields. The impacts of various developing parameters, for instance, Weissenberg number, power-law index, shrinking parameter, suction parameter, Prandtl number, Schmidt number, Brownian motion and thermophoresis parameter on the velocity, temperature and nanoparticles concentration are visualized through tables and graphical experiment. The numerical results demonstrate that the rates of heat and mass transfer are raised by higher Weissenberg number for first solution and an inverse is seen for second solution. Moreover, an increasing trend is seen in nanofluids temperature for both solutions with greater values of thermophoresis parameter. In addition, the numerical results obtained by the applied technique are validated with existing literature and found to be in an excellent agreement. PMID- 30479357 TI - Partitioning beta diversity in a tropical karst seasonal rainforest in Southern China. AB - Both deterministic and stochastic processes have been linked to forest community assembly; however, their contribution to beta diversity has not been properly explored, and no studies to date have investigated their impacts on sparse depleted soils in forests that contain widespread exposed limestone karst. We found that the pairwise differences in species composition between quadrates was determined by a balanced variation in abundance, whereby the individuals of some species at one site were substituted by an equivalent number of individuals of different species at another site. Both the total beta diversity and its balanced variation in abundance declined with increasing sampling grain size. Our research indicated that environmental differences exert a strong influence on beta diversity, particularly total beta diversity and its balanced abundance variation in larger grain sizes. It was evident that deterministic and stochastic processes worked together, and that deterministic processes were more important than stochastic processes in the regulation of beta diversity in this heterogeneous tropical karst seasonal rainforest of Southern China. However, in future research a functional trait based approach will be required to tease out the relative degree of deterministic and stochastic processes toward an assessment of the temporal changes in species composition. PMID- 30479359 TI - Accurate and efficient data acquisition methods for high-resolution angle resolved photoemission microscopy. AB - Angle-resolved photoemission spectroscopy (ARPES) is a powerful experimental technique in materials science, as it can directly probe electronic states inside solids in energy (E) and momentum (k) space. As an advanced technique, spatially resolved ARPES using a well-focused light source (high-resolution ARPES microscopy) has recently attracted growing interests because of its capability to obtain local electronic information at micro- or nano-metric length scales. However, there exist several technical challenges to guarantee high precision in determining translational and rotational positions in reasonable measurement time. Here we present two methods of obtaining k-space mapping and real-space imaging in high-resolution ARPES microscopy. One method is for k-space mapping measurements that enables us to keep a target position on a sample surface during sample rotation by compensating rotation-induced displacements (tracing acquisition method). Another method is for real-space imaging measurements that significantly reduces total acquisition time (scanning acquisition method). We provide several examples of these methods that clearly indicate higher accuracy in k-space mapping as well as higher efficiency in real-space imaging, and thus improved throughput of high-resolution APRES microscopy. PMID- 30479360 TI - Clinical Utility of Intraoperative Tympanomastoidectomy Assessment Using a Surgical Microscope Integrated with an Optical Coherence Tomography. AB - Significant technical and optical advances are required for intraoperative optical coherence tomography (OCT) to be utilized during otological surgeries. Integrating OCT with surgical microscopy makes it possible to evaluate soft tissue in real-time and at a high resolution. Herein, we describe an augmented reality, intraoperative OCT/microscope system with an extended working distance of 280 mm, providing more space for surgical manipulation than conventional techniques. We initially performed ex vivo experiments to evaluate system performance. In addition, we validated the system by performing preliminary clinical assessments of tympanomastoidectomy outcomes in six patients with chronic otitis media. The system evaluated residual inflammation in the region-of interest of the mastoid bone. Most importantly, the system intraoperatively revealed the connection between the graft and the remnant tympanic membrane. The extended working distance allows otological surgeons to evaluate the status of both the mastoid bone and tympanic membrane during manipulation, affording full intraoperative imaging. PMID- 30479361 TI - Cisplatin treatment induces attention deficits and impairs synaptic integrity in the prefrontal cortex in mice. AB - Patients treated for cancer frequently experience chemobrain, characterized by impaired memory and reduced attention. These deficits often persist after treatment, and no preventive or curative interventions exist. In mice, we assessed the effect of cisplatin chemotherapy on attention using the 5-choice serial reaction time task and on synaptic integrity. We also assessed the capacity of mesenchymal stem cells to normalize the characteristics of chemobrain. Mice were trained in the 5-choice serial reaction time task. After reaching advancement criteria at a 4-second stimulus time, they were treated with cisplatin followed by nasal administration of mesenchymal stem cells. Cisplatin reduced the percentage of correct responses due to an increase in omissions, indicating attention deficits. Mesenchymal stem cell treatment reversed these cisplatin-induced deficits in attention. Cisplatin also induced abnormalities in markers of synaptic integrity in the prefrontal cortex. Specifically, cisplatin decreased expression of the global presynaptic marker synaptophysin and the glutamatergic presynaptic marker vGlut2. Expression of the presynaptic GABAergic marker vGAT increased. Nasal mesenchymal stem cell administration normalized these markers of synaptic integrity. In conclusion, cisplatin induces long lasting attention deficits that are associated with decreased synaptic integrity in the prefrontal cortex. Nasal administration of mesenchymal stem cells reversed these behavioural and structural deficits. PMID- 30479362 TI - Comparative assessment shows the reliability of chloroplast genome assembly using RNA-seq. AB - Chloroplast genomes (cp genomes) are widely used in comparative genomics, population genetics, and phylogenetic studies. Obtaining chloroplast genomes from RNA-Seq data seems feasible due to the almost full transcription of cpDNA. However, the reliability of chloroplast genomes assembled from RNA-Seq instead of genomic DNA libraries remains to be thoroughly verified. In this study, we assembled chloroplast genomes for three Erysimum (Brassicaceae) species from three RNA-Seq replicas and from one genomic library of each species, using a streamlined bioinformatics protocol. We compared these assembled genomes, confirming that assembled cp genomes from RNA-Seq data were highly similar to each other and to those from genomic libraries in terms of overall structure, size, and composition. Although post-transcriptional modifications, such as RNA editing, may introduce variations in the RNA-seq data, the assembly of cp genomes from RNA-seq appeared to be reliable. Moreover, RNA-Seq assembly was less sensitive to sources of error such as the recovery of nuclear plastid DNAs (NUPTs). Although some precautions should be taken when producing reference genomes in non-model plants, we conclude that assembling cp genomes from RNA-Seq data is a fast, accurate, and reliable strategy. PMID- 30479363 TI - Aging of stimulus-driven and goal-directed attentional processes in young immigrants with long-term high altitude exposure in Tibet: An ERP study. AB - High altitude (HA) exposure reduces the behavioral response to visual attention and the neural basis is still largely unclear. The present study explored the stimulus-driven and goal-directed factors that are hidden within this attentional behavior impairment via a visual search paradigm in young immigrants in Tibet by recording event-related potential (ERPs). We found that HA explosure significantly slowed the stimulus-driven behaviors instead of the goal-directed behaviors. Furthermore, the P1, N1, and P3 amplitudes collectively indicated the poor efficiency of entire attention behaviors, in which the P3 magnitude of resources allocation was negatively correlated with the attentional behavior response. And the P3 scalp distribution suggested a compensation for insufficient resources of sensory processing only in the goal-directed behaviors. Together, the present study made the point on how stimulus-driven and goal-directed attentional behaviors changed as a result of chronic HA environment exposure, which is similar to aging. PMID- 30479364 TI - A prostate derived commensal Staphylococcus epidermidis strain prevents and ameliorates induction of chronic prostatitis by UPEC infection. AB - Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) is a common syndrome with limited therapies and an unknown etiology. Previously, our laboratory has defined a potential role for pathogenic infection in disease onset. Intra urethral infection with a uropathogenic Escherichia coli strain isolated from a CP/CPPS patient, CP1, induces prostatic inflammation and tactile allodynia in mice. We have also demonstrated that a prostate specific Staphylococcus epidermidis bacterial isolate, NPI (non-pain inducing), from a healthy subject reduces pain and inflammation in an experimental autoimmune prostatitis (EAP) murine model. Here we focus on the interplay between these human isolates in the context of prostatitis development and resolution. NOD/ShiLtJ mice were inoculated with either NP1 or CP1, or combinations of both. Infection with CP1 induced pelvic tactile allodynia after 7 days, while NPI instillation alone induced no such response. Instillation with NPI 7 days following CP1 infection resolved pelvic tactile allodynia and prophylactic instillation 7 days prior to CPI infection prevented its onset. Prophylactic NPI instillation also prevented CP1 colonization of both prostate and bladder tissues. In vitro analyses revealed that CP1 and NPI do not directly inhibit the growth or invasive potential of one another. Immunological analyses revealed that specific markers associated with CP1-induced pelvic allodynia were decreased upon NPI treatment or repressed by prophylactic colonization. This study demonstrates that a commensal bacterial isolate can inhibit the colonization, pain responses, and immunological activation to uropathogenic bacteria, emphasizing the power of a healthy prostatic microflora in controlling health and disease. PMID- 30479365 TI - PT symmetry protected non-Hermitian topological systems. AB - We study PT symmetry protected topological phase in non-Hermitian 1D and 2D systems. We show that topological phase exist in non-Hermitian PT symmetric systems for both gapped and gapless systems and discuss appearance of exceptional points. We apply our formalism to a complex extension of the SSH model, topological semimetals and nodal superconductors. PMID- 30479366 TI - Flavonoids are identified from the extract of Scutellariae Radix to suppress inflammatory-induced angiogenic responses in cultured RAW 264.7 macrophages. AB - Scutellariae Radix (SR), also named Huangqin in China, is the dried root of Scutellaria baicalensis Georgi. Historically, the usage of SR was targeted to against inflammation. In fact, chronic inflammation has a close relationship with hypoxia and abnormal angiogenesis in tumor cells. Hence, we would like to probe the water extract of SR in suppressing the inflammation-induced angiogenesis. Prior to determine the pharmaceutical values of SR, the first step is to analysis the chemical compositions of SR according to China Pharmacopeia (2015). From the results, the amount of baicalin was 12.6% by weight. Furthermore, the anti angiogenic properties of SR water extract were evaluated in lipopolysaccharide (LPS) pre-treated cultured macrophage RAW 264.7 cells by detecting the inflammatory markers, i.e. Cox-2, cytokine and iNOS, as well as the translocation activity of NFkappaB and angiogenic biomarker, i.e. VEGF. This herbal extract was capable of declining both inflammatory and angiogenic hallmarks in a concentration-dependent manner. Moreover, the SR-derived flavonoids, i.e. baicalin, baicalein, wogonin and wogonoside, were shown to be active chemicals in the anti-inflammatory-induced angiogenesis. Therefore, the inflammation-induced angiogenesis is believed to be suppressed by SR water extract, or its major ingredients. These results shed light in the benefiting role of SR in the inflammation-induced angiogenesis in vitro. PMID- 30479367 TI - Mouse LIMR3/CD300f is a negative regulator of the antimicrobial activity of neutrophils. AB - Leukocyte mono-immunoglobulin-like receptor (LMIR)/CD300 proteins comprise a family of immunoglobulin-like receptors that are widely expressed on the immune cell surface in humans and mice. In general, LMIR3/CD300f suppresses the inflammatory response, but it can occasionally promote it. However, the precise roles of LMIR3 in the function of neutrophils remain to be elucidated. In the present study, we investigated LMIR3 expression in mature and immature neutrophils, and evaluated the effects of LMIR3 deficiency in mouse neutrophils. Our results indicated that bone marrow (BM) neutrophils expressed LMIR3 on their cell surface during cell maturation and that surface LMIR3 expression increased in response to Pseudomonas aeruginosa infection in a TLR4/MyD88-dependent manner. LMIR3-knockout (KO) neutrophils displayed significantly increased hypochlorous acid production, and elastase release, as well as significantly augmented cytotoxic activity against P. aeruginosa and Candida albicans; meanwhile, inhibitors of elastase and myeloperoxidase offset this enhanced antimicrobial activity. Furthermore, LMIR3-KO mice were significantly more resistant to Pseudomonas peritonitis and systemic candidiasis, although this may not be entirely due to the enhanced activity of neutrophils. These results demonstrate that LMIR3/CD300f deficiency augments the antimicrobial activity of mouse neutrophils. PMID- 30479368 TI - Integrin targeting of glyphosate and its cell adhesion modulation effects on osteoblastic MC3T3-E1 cells revealed by label-free optical biosensing. AB - This study is a discovery of interesting and far reaching properties of the world leading herbicide active ingredient glyphosate. Here we demonstrate the cell adhesion-modifying characteristics of glyphosate affecting cellular interactions via Arg-Gly-Asp (RGD)-dependent integrins. This conclusion was supported by the observations that a glyphosate surface coating induced integrin-specific cell adhesion, while glyphosate in solution inhibited cell adhesion on an RGD displaying surface. A sensitive, real-time, label-free, whole cell approach was used to monitor the cell adhesion kinetic processes with excellent data quality. The half maximal inhibitory concentration (IC50) for glyphosate was determined to be 0.47 +/- 0.07% (20.6 mM) in serum-free conditions. A three-dimensional dissociation constant of 0.352 mM was calculated for the binding between RGD specific integrins in intact MC3T3-E1 cells and soluble glyphosate by measuring its competition for RGD-motifs binding, while the affinity of those RGD-specific integrins to the RGD-motifs was 5.97 uM. The integrin-targeted affinity of glyphosate was proven using competitive binding assays to recombinant receptor alphavbeta3. The present study shows not only ligand-binding properties of glyphosate, but also illustrates its remarkable biomimetic power in the case of cell adhesion. PMID- 30479370 TI - Isolation, identification, structural elucidation and bioactivity of Heneicos-1 ene from Coriandrum sativum L. foliage. AB - Coriander foliage is a distinctive spice employed on a daily basis in curry and other Indian traditional food preparations mainly for the unique flavour attributes and health benefits. Radical scavenging activity has been demonstrated previously for coriander foliage. However, specific molecules responsible were not identified. A new molecule was isolated via chromatographic technique, and its structure was established by employing multinuclei and multidimensional NMR and HRMS techniques. The identified molecule Heneicos-1-ene was also screened for radical scavenging activity and antimicrobial activity, wherein it displayed radical scavenging activity of 89.6 +/- 0.62% at 200 ppm, and also exhibited substantial antimicrobial activity against E. coli and Salmonella typhi. PMID- 30479369 TI - Antrodia cinnamomea induces autophagic cell death via the CHOP/TRB3/Akt/mTOR pathway in colorectal cancer cells. AB - Antrodia cinnamomea, a well-known traditional medicine used in Taiwan, is a potent anticancer drug for colorectal cancer, but the upstream molecular mechanism of its anticancer effects remains unclear. In this study, A. cinnamomea extracts showed cytotoxicity in HCT116, HT29, SW480, Caco-2 and, Colo205 colorectal cancer cells. Whole-genome expression profiling of A. cinnamomea extracts in HCT116 cells was performed. A. cinnamomea extracts upregulated the expression of the endoplasmic reticulum stress marker CHOP and its downstream gene TRB3. Moreover, dephosphorylation of Akt and mTOR as well as autophagic cell death were observed. Gene expression and autophagic cell death were reversed by the knockdown of CHOP and TRB3. Autophagy inhibition but not apoptosis inhibition reversed A. cinnamomea-induced cell death. Finally, we demonstrated that A. cinnamomea extracts significantly suppressed HCT116 tumour growth in nude mice. Our findings suggest that autophagic cell death via the CHOP/TRB3/Akt/mTOR pathway may represent a new mechanism of anti-colorectal cancer action by A. cinnamomea. A. cinnamomea is a new CHOP activator and potential drug that can be used in colorectal cancer treatment. PMID- 30479371 TI - Kinesin Family of Proteins Kif11 and Kif21B Act as Inhibitory Constraints of Excitatory Synaptic Transmission Through Distinct Mechanisms. AB - Despite our understanding of the functions of the kinesin family of motor proteins (Kifs) in neurons, their specific roles in neuronal communication are less understood. To address this, by carrying out RNAi-mediated loss of function studies, we assessed the necessity of 18 Kifs in excitatory synaptic transmission in mouse primary hippocampal neurons prepared from both sexes. Our measurements of excitatory post-synaptic currents (EPSCs) have identified 7 Kifs that were found to be not critical and 11 Kifs that are essential for synaptic transmission by impacting either frequency or amplitude or both components of EPSCs. Intriguingly we found that knockdown of mitotic Kif4A and Kif11 and post-mitotic Kif21B resulted in an increase in EPSCs suggesting that they function as inhibitory constraints on synaptic transmission. Furthermore, Kifs (11, 21B, 13B) with distinct effects on synaptic transmission are expressed in the same hippocampal neuron. Mechanistically, unlike Kif21B, Kif11 requires the activity of pre-synaptic NMDARs. In addition, we find that Kif11 knockdown enhanced dendritic arborization, synapse number, expression of synaptic vesicle proteins synaptophysin and active zone protein Piccolo. Moreover, expression of Piccolo constrained Kif11 function in synaptic transmission. Together these results suggest that neurons are able to utilize specific Kifs as tools for calibrating synaptic function. These studies bring novel insights into the biology of Kifs and functioning of neural circuits. PMID- 30479372 TI - Kruppel-like factor 8 regulates VEGFA expression and angiogenesis in hepatocellular carcinoma. AB - Tumor angiogenesis plays a critical role in hepatocellular carcinoma (HCC) development and progression, but its mechanism is unclear. Kruppel-like factor 8 (KLF8) is a transcription factor that plays an important role in HCC progression. Here, we investigated the role of KLF8 in angiogenesis in HCC and its possible mechanism. Immunohistochemistry, quantitative RT-PCR, western blotting, promoter reporter assays, chromatin immunoprecipitation (ChIP), and chicken chorioallantoic membrane (CAM) and nude mouse tumor models were used to show that the mRNA and protein expression levels of KLF8 and VEGFA are highly correlated in HCC tissue samples. The up-regulation of KLF8 increased VEGFA protein levels and induced VEGFA promoter activity by binding to the CACCC region of the VEGFA promoter. In addition, KLF8 regulated HIF-1alpha and Focal adhesion kinase (FAK) expression. The PI3K/AKT inhibitor LY294002 inhibited KLF8-induced VEGFA expression, whereas PI3K/AKT signaling pathway proteins, such as P-PDK1(Ser241) and P-AKT(Thr308), were decreased significantly. KLF8-overexpressing HCC cells had a higher potential for inducing angiogenesis. Thus, our results indicate that KLF8 may induce angiogenesis in HCC by binding to the CACCC region of the VEGFA promoter to induce VEGFA promoter activity and through FAK to activate PI3K/AKT signaling to regulate HIF-1alpha expression levels. PMID- 30479373 TI - Copper and other heavy metals in grapes: a pilot study tracing influential factors and evaluating potential risks in China. AB - In this study, grapes (Vitis vinifera L.) were systematically sampled across the main grape-producing areas in a nationwide survey of China. Grapes from special regions, such as heavy metal polluted areas (e-waste dismantling area) and pesticide free areas (courtyard) were also collected to make a comparison. Grape skins and pulps were separated to evaluate influence of accumulation behavior, environmental transport and water cleaning efficiency to heavy metals. Levels of copper in grape skins (5.02 +/- 3.18 MUg/g) were higher than in pulps (3.74 +/- 1.48 MUg/g). Only high level of copper in two grape skins (sampled from an e waste dismantling area) showed obvious decrease during water clean-up procedure, indicating the influence of air deposition. Statistical analysis showed no significant difference in the copper levels of grapes from markets, courtyards and e-waste dismantling areas. Concentrations and sources of chromium (Cr), manganese (Mn), nickel (Ni), cadmium (Cd), lead (Pb) and arsenic (As) were also analyzed. Higher levels of these heavy metals were observed in grape skins than pulps. Finally, we evaluated the risk of ingesting heavy metal through grapes using the estimated daily intake (EDI). No health risk was found by consuming grapes according to the data from this study. PMID- 30479375 TI - Protein trafficking through TIGER domains. PMID- 30479374 TI - Addendum: Exercise-dependent formation of new junctions that promote STIM1-Orai1 assembly in skeletal muscle. PMID- 30479376 TI - Sorting it out at the Golgi. PMID- 30479377 TI - Prostate-specific markers to identify rare prostate cancer cells in liquid biopsies. AB - Despite improvements in early detection and advances in treatment, patients with prostate cancer continue to die from their disease. Minimal residual disease after primary definitive treatment can lead to relapse and distant metastases, and increasing evidence suggests that circulating tumour cells (CTCs) and bone marrow-derived disseminated tumour cells (BM-DTCs) can offer clinically relevant biological insights into prostate cancer dissemination and metastasis. Using epithelial markers to accurately detect CTCs and BM-DTCs is associated with difficulties, and prostate-specific markers are needed for the detection of these cells using rare cell assays. Putative prostate-specific markers have been identified, and an optimized strategy for staining rare cancer cells from liquid biopsies using these markers is required. The ideal prostate-specific marker will be expressed on every CTC or BM-DTC throughout disease progression (giving high sensitivity) and will not be expressed on non-prostate-cancer cells in the sample (giving high specificity). Some markers might not be specific enough to the prostate to be used as individual markers of prostate cancer cells, whereas others could be truly prostate-specific and would make ideal markers for use in rare cell assays. The goal of future studies is to use sensitive and specific prostate markers to consistently and reliably identify rare cancer cells. PMID- 30479378 TI - Integrating molecular nuclear imaging in clinical research to improve anticancer therapy. AB - Effective patient selection before or early during treatment is important to increasing the therapeutic benefits of anticancer treatments. This selection process is often predicated on biomarkers, predominantly biospecimen biomarkers derived from blood or tumour tissue; however, such biomarkers provide limited information about the true extent of disease or about the characteristics of different, potentially heterogeneous tumours present in an individual patient. Molecular imaging can also produce quantitative outputs; such imaging biomarkers can help to fill these knowledge gaps by providing complementary information on tumour characteristics, including heterogeneity and the microenvironment, as well as on pharmacokinetic parameters, drug-target engagement and responses to treatment. This integrative approach could therefore streamline biomarker and drug development, although a range of issues need to be overcome in order to enable a broader use of molecular imaging in clinical trials. In this Perspective article, we outline the multistage process of developing novel molecular imaging biomarkers. We discuss the challenges that have restricted the use of molecular imaging in clinical oncology research to date and outline future opportunities in this area. PMID- 30479379 TI - Models of immune selection for multi-locus antigenic diversity of pathogens. AB - It is well accepted that pathogens can evade recognition and elimination by the host immune system by varying their antigenic targets. Thus, it has become a truism that host immunity is a major driver and determinant of the antigenic diversity of pathogens. However, it remains puzzling how host immunity selects for antigenic diversity at the level of the pathogen population, given that hosts have acquired immune responses to multiple antigens of most pathogens - sometimes through multiple effectors of both humoral and cellular immunity. In this Opinion article, we address this puzzle and the related question of why pathogens often have diversity at multiple antigenic loci. Here, we describe five hypotheses to explain the polymorphism of multiple antigens in a single pathogen species and highlight research relevant to our current models of thinking about multi-locus antigenic diversity. PMID- 30479381 TI - Clinical epigenetics: seizing opportunities for translation. AB - Biomarker discovery and validation are necessary for improving the prediction of clinical outcomes and patient monitoring. Despite considerable interest in biomarker discovery and development, improvements in the range and quality of biomarkers are still needed. The main challenge is how to integrate preclinical data to obtain a reliable biomarker that can be measured with acceptable costs in routine clinical practice. Epigenetic alterations are already being incorporated as valuable candidates in the biomarker field. Furthermore, their reversible nature offers a promising opportunity to ameliorate disease symptoms by using epigenetic-based therapy. Thus, beyond helping to understand disease biology, clinical epigenetics is being incorporated into patient management in oncology, as well as being explored for clinical applicability for other human pathologies such as neurological and infectious diseases and immune system disorders. PMID- 30479380 TI - Author Correction: Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. AB - In the version of this article originally published, an author was missing from the author list. Alexander J. Lazar should have been included between Jorge M. Blando and James P. Allison. The author has been added to the list, and the author contributions section has been updated to include Alexander J. Lazar's contribution to the study. The error has been corrected in the print, PDF and HTML versions of the manuscript. PMID- 30479382 TI - Lineage tracking reveals dynamic relationships of T cells in colorectal cancer. AB - T cells are key elements of cancer immunotherapy1 but certain fundamental properties, such as the development and migration of T cells within tumours, remain unknown. The enormous T cell receptor (TCR) repertoire, which is required for the recognition of foreign and self-antigens2, could serve as lineage tags to track these T cells in tumours3. Here we obtained transcriptomes of 11,138 single T cells from 12 patients with colorectal cancer, and developed single T cell analysis by RNA sequencing and TCR tracking (STARTRAC) indices to quantitatively analyse the dynamic relationships among 20 identified T cell subsets with distinct functions and clonalities. Although both CD8+ effector and 'exhausted' T cells exhibited high clonal expansion, they were independently connected with tumour-resident CD8+ effector memory cells, implicating a TCR-based fate decision. Of the CD4+ T cells, most tumour-infiltrating T regulatory (Treg) cells showed clonal exclusivity, whereas certain Treg cell clones were developmentally linked to several T helper (TH) cell clones. Notably, we identified two IFNG+ TH1 like cell clusters in tumours that were associated with distinct IFNgamma regulating transcription factors -the GZMK+ effector memory T cells, which were associated with EOMES and RUNX3, and CXCL13+BHLHE40+ TH1-like cell clusters, which were associated with BHLHE40. Only CXCL13+BHLHE40+ TH1-like cells were preferentially enriched in patients with microsatellite-instable tumours, and this might explain their favourable responses to immune-checkpoint blockade. Furthermore, IGFLR1 was highly expressed in both CXCL13+BHLHE40+ TH1-like cells and CD8+ exhausted T cells and possessed co-stimulatory functions. Our integrated STARTRAC analyses provide a powerful approach to dissect the T cell properties in colorectal cancer comprehensively, and could provide insights into the dynamic relationships of T cells in other cancers. PMID- 30479383 TI - Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome. AB - The proteasome is an ATP-dependent, 2.5-megadalton machine responsible for selective protein degradation in eukaryotic cells. Here we present cryo-EM structures of the substrate-engaged human proteasome in seven conformational states at 2.8-3.6 A resolution, captured during breakdown of a polyubiquitylated protein. These structures visualize a continuum of dynamic substrate-proteasome interactions from ubiquitin recognition to substrate translocation, during which ATP hydrolysis sequentially navigates through all six ATPases. Three principal modes of coordinated hydrolysis are observed, featuring hydrolytic events in two oppositely positioned ATPases, in two adjacent ATPases, and in one ATPase at a time. These hydrolytic modes regulate deubiquitylation, translocation initiation and processive unfolding of substrates, respectively. ATP hydrolysis powers a hinge-like motion in each ATPase that regulates its substrate interaction. Synchronization of ATP binding, ADP release and ATP hydrolysis in three adjacent ATPases drives rigid-body rotations of substrate-bound ATPases that are propagated unidirectionally in the ATPase ring and unfold the substrate. PMID- 30479384 TI - Rhythms found in skin. PMID- 30479385 TI - Inflammation linked to Takotsubo. PMID- 30479386 TI - Hypertriglyceridaemia - REDUCE-IT with icosapent ethyl. PMID- 30479387 TI - Dapagliflozin DECLAREd safe. PMID- 30479388 TI - First sun-dimming experiment will test a way to cool Earth. PMID- 30479389 TI - The secret laws of success and status. PMID- 30479391 TI - First law of leadership: be human first, scientist second. PMID- 30479390 TI - Juggling research and family life: h onest reflections from scientist dads. PMID- 30479392 TI - From the archive. PMID- 30479393 TI - Emergence and spread of resistant N. meningitidis implicated in invasive meningococcal diseases during the past decade (2008-2017). AB - Neisseria meningitidis is one of the most crucial causes of bacterial meningitis worldwide. The incidence of meningitis due to N. meningitidis greatly changes from one geographical area to the other: 500,000-1,200,000 invasive meningococcal diseases occur each year, with 50,000-135,000 deaths. Once the diagnosis of bacterial meningitis is made, parenteral antibiotic treatment is started as soon as possible. A preventive treatment can also be proposed for those subjects at risk of exposure. Globally, resistance to antibiotics used in the treatment of prophylaxis of meningococcal disease is relatively rare. Penicillin is becoming less useful in the treatment of invasive meningococcal diseases because meningococcal isolates are increasingly less susceptible to this antibiotic. Meningococcal strains less susceptible to ceftriaxone or ciprofloxacin are rare. In addition, resistance to rifampicin is not a current concern as resistant isolates are rarely reported. In conclusion, the emergence of new meningococcal strains with decreasing susceptibility during the last decade should not be ignored, as this could be a worrying phenomenon in the future and justifies a judicious epidemiological survey on a continuous basis. PMID- 30479394 TI - Geninthiocins C and D from Streptomyces as 35-membered macrocyclic thiopeptides with modified tail moiety. AB - Geninthiocin is a thiopeptide with 35-membered macrocyclic core moiety. It has potent anti-Gram-positive (G+) bacteria activity. Herein, we reported two new congeners (2-3) of geninthiocin (geninthiocin A, 1) from Streptomyces sp. CPCC 200267, and designated them as geninthiocins C and D, whose structures were determined by NMR. Geninthiocins A, C and D had the same 35-membered macrocyclic core moiety, but possessed a -Dha-Dha-NH2, -Dha-Ala-NH2, and -NH2 tail, respectively. Besides, the Ala residue in geninthiocin C was determined as L- configuration by C3 Marfey's method. In vitro assays indicated that geninthiocins C-D showed no antibacterial activity, in contrast to the potent anti-G+ bacteria activity displayed by geninthiocin A. Therefore, the -Dha-Dha-NH2 tail of geninthiocin A played an important role in its potent activity against G+ bacteria. PMID- 30479395 TI - Identification, molecular characterization, and structural analysis of the blaNDM 1 gene/enzyme from NDM-1-producing Klebsiella pneumoniae isolates. AB - NDM-1 comprises a carbapenemase that was first detected in 2008 in New Delhi, India. Since then, NDM-1-producing Klebsiella pneumoniae strains have been reported in many countries and usually associated with intra and inter-hospital dissemination, along with travel-related epidemiological links. In South America, Brazil represents the largest reservoir of NMD-1-producing K. pneumoniae. Here, we focused on the detection and molecular/structural characterization of the blaNDM-1 resistance gene/enzyme from 24 K. pneumoniae clinical isolates in the Midwest region of Brazil. Antimicrobial susceptibility assays showed that all isolates are resistant to carbapenems. Molecular typing of the isolates revealed seven clonal groups among the K. pneumoniae isolates, which may indicate intra or inter-hospital dissemination. Moreover, the blaNDM-1 gene was detected in all 24 K. pneumoniae isolates and the full blaNDM-1 gene was cloned. Bioinformatics analysis showed that the NDM-1 enzyme sequence found in our isolates is highly conserved when compared to other NDM-1 enzymes. In addition, molecular docking studies indicate that the NDM-1 identified binds to different carbapenems through hydrogen and zinc coordination bonds. In summary, we present the molecular characterization of NDM-1-producing K. pneumoniae strains isolated from different hospitals, also providing atomic level insights into molecular complexes NDM 1/carbapenem antibiotics. PMID- 30479397 TI - The Invisible Carbon Footprint as a hidden impact of peatland degradation inducing marine carbonate dissolution in Sumatra, Indonesia. AB - In Indonesia, land use change (LUC) in the form of peatland degradation induces carbon loss through direct CO2 emissions, but also via soil leaching of which circa 50% is decomposed and emitted as CO2 from the rivers. However, the fate of the remaining exported leached carbon is uncertain. Here, we show that the majority of this carbon is respired in the estuaries and emitted to the atmosphere. However, a portion is adsorbed into the marine carbon pool where it favors CaCO3 dissolution and can therefore be seen as the invisible carbon footprint. We conclude that the effects of LUC stretch beyond the terrestrial realm and are not limited to CO2 emissions, but also affect marine ecosystems. Considering the ecological and economical importance of these ecosystems, it is important that this so far invisible carbon footprint, as well as the aquatic and marine CO2 emissions, are included in climate mitigation strategies. PMID- 30479396 TI - NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation. AB - Neurofibromatosis type 1 (NF1) is an autosomal genetic disorder. Patients with NF1 are associated with mono-allelic loss of the tumor suppressor gene NF1 in their germline, which predisposes them to develop a wide array of benign lesions. Intriguingly, recent sequencing efforts revealed that the NF1 gene is frequently mutated in multiple malignant tumors not typically associated with NF1 patients, suggesting that NF1 heterozygosity is refractory to at least some cancer types. In two orthogonal mouse models representing NF1- and non-NF1-related tumors, we discover that an Nf1+/- microenvironment accelerates the formation of benign tumors but impairs further progression to malignancy. Analysis of benign and malignant tumors commonly associated with NF1 patients, as well as those with high NF1 gene mutation frequency, reveals an antagonistic role for NF1 heterozygosity in tumor initiation and malignant transformation and helps to reconciliate the role of the NF1 gene in both NF1 and non-NF1 patient contexts. PMID- 30479399 TI - Low Temperature Bonding by Infiltrating Sn3.5Ag Solder into Porous Ag Sheet for High Temperature Die Attachment in Power Device Packaging. AB - We have proposed a high temperature die attach method with porous Ag sheet as an interlayer for power device packaging. Sn-3.5Ag solder paste can infiltrate into the porous Ag sheet through capillary forces and Sn can react with the porous Ag sheet and Ag metallizations at the interfaces to form Ag3Sn after reflow at 260 degrees C for 10 min. The large specific surface area and the high diffusion rates between Ag and Sn accelerate the Sn consumption in the porous Ag structure, thus significantly reducing the processing time. The difference of the melting points of the die attach material before and after reflow could be expanded as large as 259 degrees C. The bondlines show good electrical and thermal conductivities. Furthermore, the average shear strength of the bondlines at 300 degrees C is higher than 20 MPa. The porous Ag skeleton remained in the bondline would contribute greatly to the heat dissipation and the electrical signal transmission in power devices. PMID- 30479398 TI - Megadomains and superloops form dynamically but are dispensable for X-chromosome inactivation and gene escape. AB - The mammalian inactive X-chromosome (Xi) is structurally distinct from all other chromosomes and serves as a model for how the 3D genome is organized. The Xi shows weakened topologically associated domains and is instead organized into megadomains and superloops directed by the noncoding loci, Dxz4 and Firre. Their functional significance is presently unclear, though one study suggests that they permit Xi genes to escape silencing. Here, we find that megadomains do not precede Xist expression or Xi gene silencing. Deleting Dxz4 disrupts the sharp megadomain border, whereas deleting Firre weakens intra-megadomain interactions. However, deleting Dxz4 and/or Firre has no impact on Xi silencing and gene escape. Nor does it affect Xi nuclear localization, stability, or H3K27 methylation. Additionally, ectopic integration of Dxz4 and Xist is not sufficient to form megadomains on autosomes. We conclude that Dxz4 and megadomains are dispensable for Xi silencing and escape from X-inactivation. PMID- 30479401 TI - Analytic estimation of transition between instantaneous eigenstates of quantum two-level system. AB - Transition amplitudes between instantaneous eigenstates of a quantum two-level system are evaluated analytically on the basis of a new parametrization of its evolution operator, which has recently been proposed to construct exact solutions. In particular, the condition under which the transitions are suppressed is examined analytically. It is shown that the analytic expression of the transition amplitude enables us, not only to confirm the adiabatic theorem, but also to derive the necessary and sufficient condition for quantum two-level system to remain in one of the instantaneous eigenstates. PMID- 30479400 TI - Distinct contributions of tensile and shear stress on E-cadherin levels during morphogenesis. AB - During epithelial morphogenesis, cell contacts (junctions) are constantly remodeled by mechanical forces that work against adhesive forces. E-cadherin complexes play a pivotal role in this process by providing persistent cell adhesion and by transmitting mechanical tension. In this context, it is unclear how mechanical forces affect E-cadherin adhesion and junction dynamics. During Drosophila embryo axis elongation, Myosin-II activity in the apico-medial and junctional cortex generates mechanical forces to drive junction remodeling. Here we report that the ratio between Vinculin and E-cadherin intensities acts as a ratiometric readout for these mechanical forces (load) at E-cadherin complexes. Medial Myosin-II loads E-cadherin complexes on all junctions, exerts tensile forces, and increases levels of E-cadherin. Junctional Myosin-II, on the other hand, biases the distribution of load between junctions of the same cell, exerts shear forces, and decreases the levels of E-cadherin. This work suggests distinct effects of tensile versus shear stresses on E-cadherin adhesion. PMID- 30479402 TI - Measurement and Design Heterogeneity in Perceived Message Effectiveness Studies: A Call for Research. PMID- 30479403 TI - Perceived Message Effectiveness Meets the Requirements of a Reliable, Valid, and Efficient Measure of Persuasiveness. PMID- 30479404 TI - When Home is Still Unsafe: From Family Reunification to Foster Care Reentry. AB - Reuniting children with their families is the preferred outcome of foster care, yet many children reunited with their families reenter foster care. This study examined how parental substance abuse and mental health problems, and the time allotted for reunification, are associated with reentry risk. We used a complete cohort of children who entered the Texas foster care system in fiscal years 2008 2009 to identify the risk of foster care reentry within five years of reunification using selection-adjusted multi-level survival analysis. Approximately 16% of reunified children reentered care within 5 years. Substance abuse and mental health problems predicted higher rates of reentry. Reunification after 12 months was associated with increased reentry risk overall, but not among children commonly exempted from federal permanency timelines. Permanency guidelines that restrict the length of time to achieve reunification may have the unintended consequence of pushing reunification before maltreatment risks have been resolved. PMID- 30479405 TI - Person Perception from Face and Voice. PMID- 30479406 TI - The Role of Memory Traces Quality in Directed Forgetting: A Comparison of Young and Older Participants. AB - A reduced directed-forgetting (DF) effect in normal aging has frequently been observed with the item method. These results were interpreted as age-related difficulties in inhibiting the processing of irrelevant information. However, since the performance of older adults is usually lower on items to remember, the age effect on DF abilities could also be interpreted as reflecting memory problems. Consequently, the present study aimed at investigating the influence of memory traces quality on the magnitude of the DF effects in normal aging. We predicted that increasing the quality of memory traces (by increasing presentation times at encoding) would be associated with attenuated DF effects in older participants due to the increased difficulty of inhibiting highly activated memory traces. A classical item-method DF paradigm was administered to 48 young and 48 older participants under short and long encoding conditions. Memory performance for information to memorize and to suppress was assessed with recall and recognition procedures, as well as with a Remember/Know/Guess (RKG) paradigm. The results indicated that, when memory traces are equated between groups, DF effects observed with the recall, recognition and RKG procedures are of similar amplitude in both groups (all ps>0.05). This suggests that the decreased DF effect previously observed in older adults might not actually depend on their inhibitory abilities but may rather reflect quantitative and qualitative differences in episodic memory functioning. PMID- 30479408 TI - Greater Cognitive Effort for Better Learning: Tailoring an Instructional Design for Learners with Different Levels of Knowledge and Motivation. AB - The capacity limitation of working memory is a widely recognised determinant of human learning. A cognitive load exceeding the capacity hampers learning. Cognitive load can be controlled by tailoring an instructional design to levels of learner prior knowledge. However, such as design does not necessarily motivate to use the available capacity for better learning. The present review examines literatures on the effects of instructional design, motivation, emotional state, and expertise level on cognitive load and cognitive effort, which ultimately affect working memory performance and learning. This examination suggests further studies on the effects of motivation and negative emotional states on the use of working memory. Prospective findings would help better explain and predict individual differences in the use of working memory for cognitive learning and task performance. PMID- 30479407 TI - Better Neuronal Efficiency After Emotional Competences Training: An fMRI Study. AB - Earlier studies demonstrated that adult emotional competences (EC) can be improved through relatively brief training. This increase has been investigated, thus far, using self-reported questionnaires and behavioral data. The aim of the present study was to evaluate the cerebral correlates underlying improvement in EC. An experimental group received an EC training and a control group received brief sessions of drama improvisation. Participants viewed negative, positive, and neutral pictures while attempting to decrease, increase, or not modulate their emotional reactions. Subjective reactions were assessed via on-line ratings. After the intervention, the training group showed less cerebral activity as compared to the control group within different regions related to emotional regulation and attention including prefrontal regions and the bilateral inferior parietal lobule, the right precentral gyrus and the intraparietal sulcus. These results suggest increased neural efficiency in the training group as a result of emotional competencies training. PMID- 30479409 TI - 'Some' Effects of Age, Task, Task Content and Working Memory on Scalar Implicature Processing. AB - In three experiments, we investigated the effect of age, task, task content and working memory (WM) on scalar implicature processing. We found that three-year olds still often interpret the scalar term 'some' logically (some being compatible with all), but five-year-olds and especially seven-year-olds are highly competent pragmatic reasoners. Additionally we found that not only the nature of the task but also the specific task content influences the number of pragmatic answers: an Action-Based-Task (ABT) leads to more pragmatic answers than a metalinguistic Truth-Value Judgment Task (TVJT) that, in turn, leads to more pragmatic answers than a different TVJT that includes more cognitive content. Finally, we found no effect of WM in both five-year-olds and seven-year olds. Children with a high WM capacity did not provide significantly more pragmatic answers than children with a low WM capacity. PMID- 30479410 TI - More Money, More Trust? Target and Observer Differences in the Effectiveness of Financial Overcompensation to Restore Trust. AB - Recent research revealed that despite its financial costs, overcompensation is not more effective to restore trust in the perpetrator than equal compensation. In a lab experiment (N = 115), we compared the effects of these compensation sizes for both targets of the compensation and non-involved observers. It was revealed that overcompensation did not yield superior outcomes than equal compensation. Specifically, for targets overcompensation resulted in lower levels of trust than equal compensation, while for observers equal compensation and overcompensation resulted in similar levels of trust. This finding suggests that overcompensation is not a cost-effective trust repair strategy, neither for the targets nor for third party observers. Other implications are discussed as well. PMID- 30479411 TI - Experts' Misinterpretation of Box Plots - a Dual Processing Approach. AB - Recent studies have shown that students often misinterpret the area of the box in box plots as representing the frequency or proportion of observations in that interval, while it actually represents density. This misinterpretation has been shown to be based on the saliency of this area and can be explained by heuristic reasoning as defined by dual process theories. In this study we tested whether expert users of box plots also display this misinterpretation and show signs of the same heuristic reasoning as found in students. Using a reaction time test, we found signs of heuristic reasoning in experts, both with respect to accuracy and reaction times. If even experts have difficulty interpreting box plots, one can question whether these are an appropriate form of representation to use when reporting data and deserve the prominent place they currently have in the statistics curriculum. PMID- 30479413 TI - Some Differences in Some: Examining Variability in the Interpretation of Scalars Using Latent Class Analysis. AB - The present study investigated people's understanding of underinformative sentences like 'Some oaks are trees'. Specifically, the scalar term 'some' can be interpreted pragmatically, Not all oaks are trees, or logically, some and possibly all oaks are trees. The aim of this study was to capture the interindividual variability in the interpretation of such sentences. In two experiments, participants provided truth value judgments for 20 underinformative sentences on which a latent class analysis was performed. The results revealed three latent classes: a consistent pragmatic group, a consistent logical group and an inconsistent group. Furthermore, we examined whether this interindividual variability could be explained by text characteristics, response times, cognitive abilities and personality traits. The results showed that only participants' response times to the underinformative sentences could predict class membership. Specifically, the slower participants responded, the more likely they were to interpret underinformative sentences consistently pragmatic or inconsistent instead of consistently logical. PMID- 30479414 TI - Measuring Gratitude: A Comparative Validation of the Dutch Gratitude Questionnaire (GQ6) and Short Gratitude, Resentment, and Appreciation Test (SGRAT). AB - The aim of this article was to validate and compare the Dutch translations of the Gratitude Questionnaire (GQ6) and the Short Gratitude, Resentment, and Appreciation Test (SGRAT) in an adult general population sample. In an online survey, 706 respondents (M age = 44, SD age = 14) completed Dutch versions of the GQ6, the SGRAT, the Satisfaction With Life Scale (SWLS) and the Positive Affect and Negative Affect Schedule (PANAS). At six week follow-up, 440 (62%) of them (M age = 46, SD age = 14) again completed the GQ6-NL and SGRAT-NL. Parallel analyses, exploratory factor analyses and confirmatory factor analyses revealed and confirmed one factor for the GQ6-NL, and three factors for the SGRAT-NL. Internal consistency indices of the GQ6-NL and of the SGRAT-NL were satisfactory. Both questionnaires demonstrated good test-retest reliability. Regression analyses showed, for the total scores on both gratitude questionnaires, positive associations with the SWLS and the Positive Affect Scale, and negative associations with the Negative Affect Scale. The results support the validity of the Dutch GQ6 and SGRAT. These questionnaires can be used to conduct further research of the grateful disposition in Dutch speaking individuals and groups. PMID- 30479415 TI - Explaining Entrepreneurial Status and Success from Personality: An Individual Level Application of the Entrepreneurial Orientation Framework. AB - Entrepreneurial orientation is defined as an organization's strategy, describing its innovativeness, proactivity, risk taking, autonomy and competitiveness. We argue that this concept can be translated to the individual level as a constellation of five personality traits that characterize entrepreneurs. We examine the usefulness of these five traits in explaining entrepreneurial status and success. Our results show that entrepreneurs score higher than non entrepreneurs on innovativeness, proactivity, and risk taking. In addition, latent growth curve modeling revealed that the individual EO traits were related to objective venture performance, albeit only after introducing venture life cycle as a moderator. In line with a differentiation perspective, risk taking, innovativeness, need for achievement, and need for autonomy were positively related to revenue and number of employees when venture life cycle was high. In line with a situation strength perspective, need for autonomy was positively related with growth in number of employees when venture life cycle was low. We conclude that individual entrepreneurial orientation offers a useful framework to understanding entrepreneurship once situational factors, such as venture life cycle, are taken into consideration. PMID- 30479416 TI - Tasteful Brands: Products of Brands Perceived to be Warm and Competent Taste Subjectively Better. AB - Using survey and experimental data, the present research examines the effect of brand perception on experienced taste. The content of brand perception can be organized along the two social perception dimensions of warmth and competence. We use these two dimensions to systematically investigate the influence of brand perception on experienced taste and consumer behavior toward food products. The brand's perceived warmth and competence independently influenced taste, both when it was measured as a belief and as an embodied experience following consumption. Taste mediated the link between brand's warmth and competence perceptions and three consumer behavioral tendencies crucial for the marketing success of brands: buying intentions, brand loyalty, and support for the brand. PMID- 30479417 TI - Validation and Psychometric Properties of the French Versions of the Environmental Reward Observation Scale and of the Reward Probability Index. AB - Background: Low levels of environmental rewards have been related to depression on a number of occasions in the scientific literature. Two scales have been created to assess environmental rewards: the Environmental Reward Observation Scale (EROS) and the Reward Probability Index (RPI). This study aims to validate the French versions of these two scales. Method: 466 non-clinical adults completed an online survey assessing environmental rewards, depression, anxiety, activation, avoidance and behavioural systems. Confirmatory factor analyses were performed to assess the factorial structures of the French EROS and RPI. Results: A one-factor solution for the EROS and a two-factor solution for the RPI best fitted the data. High levels of internal consistency were found for both the EROS and the RPI. Convergent validity was also examined, revealing that high environmental rewards appear to be related to activation and behavioural activation system. Conclusion: The French versions of the EROS and the RPI appear to be reliable assessments of environmental rewards. PMID- 30479418 TI - Exploratory Study of Depressed Adolescents' Life Narratives. AB - Objective: The aim of this study was to explore the life stories of depressive adolescents and compare them with non-clinical adolescents' life stories. Methods: For this purpose, we compared 20 life stories of hospitalized adolescents suffering from major depressive episode with 40 life stories of adolescents attending school divided into two groups: 20 non-depressed and 20 depressed adolescents. Results: Results showed that life stories differed as a function of psychopathology. Depressed hospitalized adolescents spoke about their disease and defined themselves by their depression. The depressed adolescents in school concentrated on schooling and school achievements, while the non-depressed group defined themselves by their family, friends and inclusion in a peer group. Conclusion: These analyses allowed us to highlight specific themes mentioned by each of the three groups of adolescents. Although life stories are personal and unique, analysis of such stories allows us to better understand the daily reality of depressive adolescents and the relationships between the life events they experience, daily stressors, depression and how they construct their personal history. PMID- 30479419 TI - The Effect of Fearful Expressions on Multiple Face Tracking. AB - How does the visual system realize dynamic tracking? This topic has become popular within cognitive science in recent years. The classical theory argues that multiple object tracking is accomplished via pre-attention visual indexes as part of a cognitively impenetrable low-level visual system. The present research aimed to investigate whether and how tracking processes are influenced by facial expressions that convey abundant social information about one's mental state and situated environment. The results showed that participants tracked fearful faces more effectively than neutral faces. However, this advantage was only present under the low-attentional load condition, and distractor face emotion did not impact tracking performance. These findings imply that visual tracking is not driven entirely by low-level vision and encapsulated by high-level representations; rather, that facial expressions, a kind of social information, are able to influence dynamic tracking. Furthermore, the effect of fearful expressions on multiple face tracking is mediated by the availability of attentional resources. PMID- 30479420 TI - Mindfulness-Based Cognitive Therapy for Trichotillomania: A Bayesian Case-Control Study. AB - Over the last years, mindfulness-based interventions combined with habit reversal training have been demonstrated to be particularly suitable for addressing trichotillomania. However, because these studies always combined mindfulness training to habit reversal without including either a mindfulness or habit reversal condition alone, it is still unclear whether clinical benefits are the consequences of mindfulness or merely result from habit reversal training. The primary purpose of the present study was thus to examine whether a mindfulness training procedure without habit reversal could alleviate trichotillomania. Using a Bayesian probabilistic approach for single-case design, client's hair loss severity and level of mindfulness were compared to a normative sample (n = 15) before treatment, after treatment, and at six-month follow-up. Improvement in mindfulness first occurred, and that beneficial effect then transferred to hair pulling. Indeed, as compared to the normative sample, the client exhibited, from baseline to post-treatment, an improvement in mindfulness. Although a marginal trend to improvement was already evidenced at post-treatment, the mindfulness program only had a significant beneficial effect transferred to hair-loss severity at six-month follow-up. Although it remains particularly difficult to infer generalization from one client, the data from the present case study are the first to suggest that mindfulness training per se might be a suitable clinical intervention for trichotillomania. PMID- 30479422 TI - Reliability and Validity Evidence of Scores on the French Version of the Questionnaire about Interpersonal Difficulties for Adolescents. AB - This study examined the reliability and validity evidence drawn from the scores of the French version of the Questionnaire about Interpersonal Difficulties for Adolescents (QIDA) in a sample of 957 adolescents (48.5% boys) ranging in age from 11 to 18 years (M = 14.48, SD = 1.85). A principal axis factoring (PAF) and confirmatory factor analyses (CFA) were performed to determine the fit of the factor structure of scores on the QIDA. PAF and CFA replicated the previously identified correlated five-factor structure of the QIDA: Assertiveness, Heterosexual Relationships, Public Speaking, Family Relationships, and Close Friendships. The QIDA yielded acceptable reliability scores for French adolescents. Validity evidence of QIDA was also established through correlations with scores on the School Anxiety Inventory and the Social Anxiety Scale for Adolescents. Most of the correlations were positive and exceeded the established criteria of statistical significance, but the magnitude of these varied according to the scales of the QIDA. Results supported the reliability and validity evidence drawn from the scores of the French version of the QIDA. PMID- 30479421 TI - Organizational Justice and Perceived Organizational Support: Impact on Negative Work-Home Interference and Well-being Outcomes. AB - It is well established that negative work-home interference (NegWHI) impacts upon several work attitudes and behaviors. In the interests of both organizational effectiveness and employee well-being, it is important to identify concepts related to NegWHI and investigate their effects on well-being outcomes. This study examines the mediating role of (1) perceived organizational support (POS) in the relationship between organizational justice (OJ) and NegWHI; and (2) NegWHI in the relationships between POS and four well-being outcomes. A total of 509 employees of a Belgian hospital were surveyed. Data were analyzed using structural equation modeling and the bootstrapping method. Results showed that POS partially mediates the relationships between distributive and passive procedural justice and NegWHI, and fully mediates the relationship between the other justice dimensions and NegWHI. NegWHI partially mediates the relationships between POS and both job satisfaction and intention to quit, and fully mediates the relationship between POS and job strain. Furthermore, POS is positively related to job engagement. This study showed that organizations can help employees to better manage their work and family lives and reduce the impact of NegWHI by enhancing employees' feeling that they are supported by their organization. In order to increase POS, organizations need to promote justice in the workplace. PMID- 30479423 TI - The Effects of Aging on the Components of Auditory - Verbal Short-Term Memory. AB - This study aimed at exploring the effects of aging on the multiple components of the auditory-verbal short-term memory (STM). Participants of 45-54, 55-64, 65-74 and 75-84 years of age were presented STM tasks assessing short-term retention of order and item information, and of phonological and lexical-semantic information separately. Because older participants often present reduced hearing levels, we sought to control for an effect of hearing status on performance on STM tasks. Participants' hearing thresholds were measured with a pure-tone audiometer. The results showed age-related effects on all STM components. However, after hearing status was controlled for in analyses of covariance, the age-related differences became non-significant for all STM processes. The fact that age-related hearing loss may in large part explain decreases in performance on STM tasks with aging is discussed. PMID- 30479424 TI - Direct and Indirect Effects of Young Adults' Relationship Status on Life Satisfaction through Loneliness and Perceived Social Support. AB - This study examined the indirect effects of relationship status (single vs. in a relationship) on life satisfaction through social and emotional (romantic and family) loneliness and perceived social support from significant others, family, and friends. Five hundred and fifty three Polish young adults (335 females and 218 males), ranging in age from 20-30 years (M = 23.42), completed the Polish versions of the Satisfaction With Life Scale, the Social and Emotional Loneliness Scale for Adults, and the Multidimensional Scale of Perceived Social Support. The results indicated that single individuals reported significantly lower satisfaction with life and social support from a significant other, but higher romantic and social loneliness, and higher family support compared to participants in a relationship. A path analysis revealed no direct effect of relationship status on satisfaction with life. However, there were significant indirect effects from relationship status to life satisfaction though romantic, family, and social loneliness, and through perceived social support from significant others and from family. Therefore, singlehood may be deleterious to life satisfaction because of the higher loneliness and lower social support from a significant other. PMID- 30479426 TI - The Factor Structure, Predictors, and Percentile Norms of the Center for Epidemiologic Studies Depression (CES-D) Scale in the Dutch-speaking Adult Population of Belgium. AB - The Center of Epidemiologic Studies Depression Scale (CES-D) is a commonly used self-report scale to measure depressive symptoms in the general population. In the present study, the Dutch version of the CES-D was administered to a sample of 837 Dutch-speaking adults of Belgium to examine the factor structure of the scale. Using confirmatory factory analysis (CFA), four first-order models and two second-order models were tested, and the second-order factor model with three pairs of correlated error terms provided the best fit to the data. Second, five socio-demographic variables (age, gender, education level, relation status, and family history of depression) were included as covariates to the second-order factor model to explore the associations between background characteristics and the latent factor depression using a multiple indicators and multiple causes (MIMIC) approach. Age had a significantly negative effect on depression, but the effect was not substantial. Female gender, lower education level, being single or widowed, and having a family history of depression were found to be significant predictors of higher levels of depression symptomatology. Finally, percentile norms on the CES-D raw scores were provided for subgroups of gender by education level for the general Dutch-speaking adult population of Belgium. PMID- 30479427 TI - Measures of Implicit Gender Attitudes May Exaggerate Differences in Underlying Associations among Chinese Urban and Rural Women. AB - The oppression of women in rural China is more severe than in urban China, not only because the two areas differ in terms of social hierarchy, but also because urban women are more likely to fight against their subordination, which is endorsed by conventional social views on gender. To independently assess these relationships, we applied the Quadruple Process model to measure the processes underlying implicit gender attitudes in a sample of urban and rural females. The results indicated that the urban women had higher in-group favoritism than did the rural women. Application of the Quad model, however, showed that pro-women associations were similarly activated among urban and rural women, but that women in rural settings more effectively inhibited activated associations. Differences in inhibition, rather than in activated associations, appear to account for the less favorable attitudes among rural women. Thus, the differences in attitudinal responses among urban and rural women exaggerate the differences in underlying evaluative associations with respect to gender and conceal differences in self regulating the expression of those associations. PMID- 30479429 TI - Attachment Styles, Perceived Stress and Social Support in a Malaysian Young Adults Sample. AB - The purpose of this research was to examine the validity of an adult attachment style questionnaire, to understand the relationships between the type of attachment style in relation to self-perceived stress and social support, and to investigate the influence of gender, ethnicity and religion on the above constructs. The participants were 308 university students from Malaysia. A demographic questionnaire and three self-report inventories were administrated in this study. The data indicated that the Relationship Scales Questionnaire (RSQ) is a multidimensional construct with nine factors: "dismissing," "preoccupied with romance," "preoccupied with close relationships," "fearful," "preoccupied with dependency," "secure emotional," "comfortable depending," "preoccupied with mistrust" and "mutual secure." Different attachment styles were positively or negatively correlated at a significant level with perceived stress and social support. Attachment styles were explained by 20 and 33% of the total variance in self-perceived stress and perceived social support, respectively. There were significant gender, ethnic and religious differences in attachment styles, perceived stress and social support. PMID- 30479428 TI - Validation of the Marijuana Effect Expectancies Questionnaire (MEEQ) in a Non Clinical French-Speaking Adolescent Sample. AB - Teenagers commonly use cannabis. Expectancies related to the effects of cannabis play an important role in its consumption and are frequently measured with the Marijuana Effect Expectancies Questionnaire (MEEQ). This study aims to assess the psychometric properties (factor structure, internal consistency reliability, criterion validity) of the French MEEQ. A sample of 1,343 non-clinical teenagers (14-18 years) were recruited to answer a self-report questionnaire; 877 of them responded twice (one-year interval). A four-factor structure was obtained: Cognitive Impairment and Negative, Relaxation and Social Facilitation, Perceptual Enhancement and Craving and Negative Behavioral Effect Expectancies. It is concluded that the French MEEQ constitutes an appropriate tool to measure cannabis effect expectancies among adolescents. PMID- 30479430 TI - A Validation of the French Version of the Attitudes to Aging Questionnaire (AAQ): Factor Structure, Reliability and Validity. AB - Introduction: The Attitudes to Aging Questionnaire (AAQ) was developed to measure attitudes toward the aging process as a personal experience from the perspective of older people. The present study aimed to validate the French version of the AAQ. Participants and methods: This study examined factor structure, acceptability, reliability and validity of the AAQ's French version in 238 Belgian adults aged 60 years or older. In addition, participants provided information on demographics, self-perception of their mental and physical health (single items), quality of life (WHOQOL-OLD) and social desirability (DS-36). Results: Exploratory Factor Analysis produced a three-factor solution accounting for 36.9% of the variance. No floor or ceiling effects were found. The internal consistency, measured by Cronbach's alpha coefficients for the AAQ subscales were 0.62 (Physical Change), 0.74 (Psychological Growth), and 0.75 (Psychosocial Loss). A priori expected associations were found between AAQ subscales, self reported health and quality of life, indicating good convergent validity. The scale also showed a good ability to discriminate between people with lower and higher education levels, supporting adequate known-groups validity. Finally, we confirmed the need to control for social desirability biases when assessing self reported attitudes toward one's own aging. Conclusion: The data support the usefulness of the French version of the AAQ for the assessment of attitudes toward their own aging in older people. PMID- 30479431 TI - The Impeding Role of Self-Critical Perfectionism on Therapeutic Alliance During Treatment and Eating Disorder Symptoms at Follow-up in Patients with an Eating Disorder. AB - This study examines the impeding role of self-critical perfectionism at onset of treatment on therapeutic alliance during treatment and eating disorder symptoms at follow-up in patients with an eating disorder. Participants were 53 female patients with a mean age of 21.1 years treated for an eating disorder in a specialized inpatient treatment unit. Self-critical perfectionism was assessed at admission, therapeutic alliance was assessed during treatment (after three months of treatment), and eating disorder symptoms were assessed at admission, after three months and one year later. Self-critical perfectionism negatively related to treatment alliance with the therapist. Although self-critical perfectionism was not directly predictive of subsequent changes in eating disorder symptoms, it was indirectly related to less reduction in body dissatisfaction through the therapeutic alliance. These results point to the importance of self-critical perfectionism in the therapeutic alliance and in changes in body image problems. Treatment implications are discussed. PMID- 30479432 TI - When School and Family Convey Different Cultural Messages: The Experience of Turkish Minority Group Members in France. AB - The present studies aim to compare the cultural values promoted by the French educational system and the Turkish families living in France to their youngsters. Because of their collectivist background Turkish immigrants may convey less individualistic values to their children compared to French parents and teachers. However, Turkish students may become more individualistic as they are socialized in the school system. In study 1 (N = 119), French school teachers, French parents, and Turkish-origin parents had to resolve six dilemmas by choosing either an individualistic or a collectivistic response-option. As expected, French teachers emphasized individualism more than Turkish parents, but not more than French parents. In Study 2 (N = 159), similar dilemmas were presented to French and Turkish-origin pupils. In elementary school, Turkish children were less individualistic than French-born children, but this gap was reduced in high school. PMID- 30479433 TI - Observer-Rated Alexithymia and its Relationship with the Five-Factor-Model of Personality. AB - Studies examining the relationship between alexithymia and personality exclusively employed self-report measures of alexithymia. In the present study, we examined the relationship of both observer-rated and self-reported alexithymia with the Big Five personality dimensions. We administered the Toronto Structured Interview for Alexithymia (TSIA) as an interview-based measure of alexithymia and, in addition, two self-report questionnaires, the 20-item Toronto Alexithymia Scale (TAS-20) and the Bermond-Vorst Alexithymia Questionnaire (BVAQ). Fifty-one university students were interviewed and completed the alexithymia scales and the NEO Five-Factor Inventory. In contrast to TAS-20 and BVAQ, the Difficulty identifying feelings (DIF) scale of the TSIA was found to be unrelated to neuroticism, suggesting that the frequently reported association between DIF and neuroticism could be due to the use of self-report scales. In contrast, the affective dimension of alexithymia, measured by the BVAQ, was even negatively related with neuroticism. Thus, a paucity of fantasy and little emotional arousal goes together with increased emotional stability. Furthermore, we revealed negative correlations between interview-based alexithymia scores and openness to experience and agreeableness, which cross-validated the self-report findings. Finally, extraversion and conscientiousness each showed only one negative correlation, namely with subscales of the BVAQ. Taken together, our findings show that on the basis of interviews there is no evidence for a relation of DIF with neuroticism, while associations of alexithymia with low openness to experience and low agreeableness emerged irrespective of assessment approach. The relations of alexithymia with personality are discussed in the light of different measurement approaches. PMID- 30479434 TI - The Pursuit of Self-Esteem and Its Motivational Implications. AB - Although recent studies have found contingent self-esteem (CSE) to be negatively related to individuals' well-being, research concerning its implications for motivation and engagement is scarce. In two studies, we investigated the relation between CSE, motivation, and engagement in achievement-related situations. A first cross-sectional study among second year high school students (N = 641; 54.1% female) confirmed the hypothesized motivational ambiguity associated with academic CSE. Beyond the contribution of academic self-esteem, academic CSE was positively related to behavioral and emotional engagement, but also to emotional disaffection and test anxiety. These associations could partially be explained by motivational quality, as CSE was also positively related to both autonomous and controlled types of motivation. In a second experimental study among university students (N = 72; 70.8% female), who participated in a tangram puzzle task under varying feedback circumstances, global CSE related to more tension, while predicting less behavioral task perseverance. These effects were not moderated by the type of feedback provided (i.e., positive vs. negative). Theoretical and practical implications of these results are discussed. PMID- 30479435 TI - Where Do the Cultural Differences in Dynamics of Controlling Parenting Lie? Adolescents as Active Agents in the Perception of and Coping with Parental Behavior. AB - There is ongoing debate about the universal or culture-specific role of controlling parenting in children's and adolescents' development. This study addressed the possibility of cultural variability in how controlling parenting practices are perceived and dealt with. Specifically, we examined Belgian (N = 341) and Chinese (N = 316) adolescents' perceptions of and reactions towards a vignette depicting parental guilt-induction, relative to generally controlling and autonomy supportive vignettes. Whereas Belgian adolescents perceived guilt induction to be as controlling as generally controlling parental behavior, Chinese adolescents' perception of guilt-induction as controlling was more moderate. Belgian and Chinese adolescents also showed some similarities and differences in their responses to the feelings of need frustration following from the controlling practices, with compulsive compliance for instance being more common in Chinese adolescents. Discussion focuses on cross-cultural similarities and differences in dynamics of controlling parenting. PMID- 30479436 TI - The Portuguese Validation of the Basic Psychological Need Satisfaction and Frustration Scale: Concurrent and Longitudinal Relations to Well-being and Ill being. AB - This research comprises two studies based on Self Determination Theory. In Study 1, we translate and examine the factor structure of the Basic Psychological Needs Satisfaction and Frustration Scale (BPNSFS; Chen, Vansteenkiste et al., 2015) in a sample of Portuguese undergraduate students. Further, in Study 2 we used an independent longitudinal sample of 12th grade students to inspect whether the six subscales differently predict adjustment over time. Confirmatory factor analysis showed that a six-factor solution best fitted the BPNSFS data. Subsequent structural equation modelling indicated that the dimensions of need satisfaction and need frustration predicted unique variance in participants' well-being and ill-being over time, even after controlling for reciprocal and baseline effects. Taken together the findings support the 6-factor multidimensional structure of the BPNSFS and provide extensive support for the distinction between the satisfaction and frustration dimensions of needs, suggesting that they should be measured and interpreted as relatively distinct motivational constructs. PMID- 30479437 TI - Future Time Perspective Connectedness to a Career: The Contextual Effects of Classroom Knowledge Building. AB - Professor Willy Lens has provided inspiration through his scholarship and mentorship for research in Future Time Perspective (FTP) theory. The traditional conceptualization of FTP consists of hierarchically organized psychological constructs that define individual differences in perceptions of the future across varying levels of specificity. The levels of specificity create a nested variable structure that is often described in a top-down fashion, from domain-general to context-specific. In the current study, relations among measures of connectedness, an FTP construct regarding concern for and planfulness about the future, are examined at three levels of specificity: domain-general, domain specific, and context-specific. We examine interactions between domain-specific and domain-general levels of FTP. A sample of 3962 undergraduate engineering majors (mean age 20) from a large research university in the southwestern United States of America were surveyed. Hierarchical linear modeling was used to examine the hypothesis that aggregate classroom levels of student knowledge building moderate relations in the nested connectedness variable structure. At the student level of analysis measures of students' domain-general, domain-specific, and context-specific connectedness were significantly and positively related. At the classroom level of analysis, results indicated that higher levels of aggregate classroom knowledge building shifted the direction of relations suggesting that in more engaging classroom contexts perceived value of learning for reaching a future goal may shape how students plan for future careers (domain-specific FTP). Implications for FTP theory are discussed. PMID- 30479438 TI - Understanding Students' Instrumental Goals, Motivation Deficits and Achievement: Through the Lens of a Latent Profile Analysis. AB - Building on the future oriented and regulated nature of instrumental goals, Lens and colleagues developed a 2 (proximal-distal) x 2 (internal-external) motivational framework. The current study aimed to test this framework from a person-centred perspective, while equally taking into account students' lack of motivation as to extend the empirical and theoretical borders of the model. Latent Profile Analyses were used to test the viability of two to five motivational profiles among Japanese second-year students (N = 781). A solution with three latent subgroups fitted the sample best, explaining 6% to 62% of the variance in the measured variables. The profiles were labelled "low future oriented motivational profile", "average motivated profile", and "highly motivated profile". The highly motivated subgroup reported the most adaptive pattern of motivation and highest levels of deep level learning, while few differences were found for surface learning and GPA. Theoretical and practical implications are discussed. PMID- 30479439 TI - Achievement Goals and their Underlying Goal Motivation: Does it Matter Why Sport Participants Pursue their Goals? AB - This study examined whether the good or bad outcomes associated with mastery approach (MAP) and performance-approach (PAP) goals depend on the extent to which they are motivated by autonomous or controlled motivation. A sample of 515 undergraduate students who participated in sport completed measures of achievement goals, motivation of achievement goals, perceived goal attainment, sport satisfaction, and both positive and negative affect. Results of moderated regression analyses revealed that the positive relations of both MAP and PAP goals with perceived goal attainment were stronger for athletes pursuing these goals with high level of autonomous goal motivation. Also, the positive relations between PAP goals and both sport satisfaction and positive affect were stronger at high levels of autonomous goal motivation and controlled goal motivation. The shape of all these significant interactions was consistent with tenets of Self Determination Theory as controlled goal motivation was negatively associated with positive affect and sport satisfaction and positively associated with negative affect. Overall, these findings demonstrated the importance of considering goal motivation in order to better understand the conditions under which achievement goals are associated with better experiential and performance outcomes in the lives of sport participants. PMID- 30479440 TI - Building on the Enriched Hierarchical Model of Achievement Motivation: Autonomous and Controlling Reasons Underlying Mastery Goals. AB - Two motivational theories - the Achievement Goal Theory and Self-Determination Theory - have recently been combined to explain students' motivation, making it possible to study the "what" and the "why" of learners' achievement strivings. The present study built on this approach by (a) investigating whether the distinction between autonomous or volitional and controlling or pressuring reasons can be meaningfully applied to the adoption of mastery-avoidance goals, (b) investigating the concurrent and prospectiverelations between mastery avoidance goals and their underlying reasons and learning strategies when mastery approach goals and their underlying reasons were also considered, and by (c) incorporating psychological need experiences as an explanatory variable in the relation between achievement motives (i.e., the motive to succeed and motive to avoid failure) and both mastery goals and their underlying reasons. In two Turkish university students samples (N = 226, Mage = 22.36; N = 331, Mage = 19.5), autonomous and controlling reasons appeared applicable to mastery avoidance goals and regression and path analysis further showed that mastery avoidance goals and their underlying autonomous reasons fail to predicted learning strategies over and above the pursuit of mastery-approach goals and their underlying reasons. Finally, need experiences were established as mediators between achievement motives and both mastery goals and their underlying reasons. PMID- 30479441 TI - Intrapersonal Achievement Goals and Underlying Reasons among Long Distance Runners: Their Relation with Race Experience, Self-Talk, and Running Time. AB - In a sample of long distance runners, we examined the role of type of intrapersonal achievement goals (i.e., approach versus avoidance) and type of underlying reasons (i.e., autonomous and controlled), assessed prior to the race, as predictors of both pre-race (e.g., race appraisals) and post-race (e.g., flow experience) outcomes. Of 221 (62.4% males) runners, 111 reported pursuing an intrapersonal-approach goal (i.e., doing better than before) as their dominant or preferred achievement goal for the race, while 86 prioritized intrapersonal avoidance goals (i.e., avoiding to perform worse than before). Regression and path analyses showed that the type of achievement goals predicted none of the outcomes except for running time, with approach goals predicting better performance when compared to avoidance goals. Path analyses revealed that autonomous reasons underlying intrapersonal goal pursuit related positively to pre-race challenge appraisals, performance and, via need satisfaction, to flow experience. Interestingly, controlled reasons positively related to pre-race threat appraisals and positively predicted both positive and negative self-talk, with both yielding opposing relations with flow. These findings complement past research on the intersection between the Achievement Goal Approach and Self Determination Theory and highlight the value of studying the reasons underlying intrapersonal achievement goals. PMID- 30479442 TI - A Tribute to Dr. Willy Lens. AB - Dr. Willy Lens, born on December 10th, 1943, passed away on August 29th, 2014. With his passing, the motivation community has lost a seminal member, a mentor, and a friend. Dr. Lens - a Fellow of the Association for Psychological Science and Founding Fellow of the American Educational Research Association - made fundamental contributions to the study of motivation both through his own work and through his caring and thoughtful mentorship of a large community of scholars. With this tribute, we want to honor Dr. Willy Lens' significance to psychology and education as well as his positive influence, both personally and professionally, on the lives of dozens of scholars. With his contagious enthusiasm and caring mentorship, Willy was an example for our academic community and with this tribute we express our gratitude for the privilege to have collaborated with him. PMID- 30479443 TI - Emerging Trends and Future Directions for the Field of Motivation Psychology: A Special Issue in Honor of Prof. Dr. Willy Lens. AB - This special issue is devoted to Prof. Dr. W. Lens, who passed away end of August 2014 while he was vacationing. The special issue is meant to honor Willy's intellectual contribution to the field of motivation psychology and his enthusiastic and devoted mentorship, which has spurred many of us to study motivation-related topics. In line with Willy's interest and extensive network, the special issue brings together scholars from diverse theoretical perspectives (i.e., Achievement Goal Theory, Future Time Perspective Theory, and Self Determination Theory) and diverse cultural backgrounds (i.e., China, Peru, Greece, Portugal, Belgium, US, Australia, Canada). We introduce the special issue by highlighting four emerging trends that characterize contemporary motivation psychology and that were central to Willy's work: (a) multiperspectivism (i.e., a reliance on multiple motivational frameworks); (b) the diversity of motives and goals that underlie behavior (i.e., motivational heterogeneity); (c) interest in motives for non-participation; and (d) the issue of universalism versus relativism (i.e., the question whether there exist universal motivational processes or whether these processes are contingent upon sociodemographic, personality-based, and contextual factors). Each of the eight contributions in the special issue touch upon one or more of these emerging themes, which are critically discussed in conjunction with a number of directions for future research. PMID- 30479444 TI - Servant Leadership, Organisational Citizenship Behavior and Creativity: The Mediating Role of Team-Member Exchange. AB - Using a multi-source field study design with 184 unique triads of employees supervisor dyads, this paper examines whether servant leaders install a serving attitude among employees. That is, servant leaders aim to encourage employees to take responsibility, to cooperate and to create high quality interactions with each other (team-member exchange; TMX). We hypothesise that servant leadership will have an influence on Organisational Citizenship Behavior (OCB) and creativity through team-member exchange. Two facets of OCB are distinguished: organisational citizenship behaviour towards individuals (OCBI), on the one hand, and taking up extra tasks that benefit the organisation (OCBO), on the other hand. The results show that servant leadership is positively related to team member exchange, and that team-member exchange is positively related to OCBI, OCBO and creativity. The bootstrapping estimates indicated significant indirect effects of servant leadership on the three target variables through team-member exchange. The study's findings add to the body of literature on servant leadership, OCB and creativity at the workplace, and underline the importance of creating favourable working conditions that foster positive and high quality team member exchange. This study also broadens our understanding on the importance of co-workers on the relation between servant leadership and organizational citizenship behavior (OCB) and creativity. PMID- 30479445 TI - Assessing Energy Intake in Daily Life: Signal-Contingent Smartphone Application Versus Event-Contingent Paper and Pencil Estimated Diet Diary. AB - Objectives: Investigating between-meal snack intake and its associated determinants such as emotions and stress presents challenges because both vary from moment to moment throughout the day. A smartphone application (app), was developed to map momentary between-meal snack intake and its associated determinants in the context of daily life. The aim of this study was to compare energy intake reported with the signal-contingent app and reported with an event contingent paper and pencil diet diary. Methods: In a counterbalanced, cross sectional design, adults (N = 46) from the general population reported between meal snack intake during four consecutive days with the app and four consecutive days with a paper and pencil diet diary. A 10-day interval was applied between the two reporting periods. Multilevel regression analyses were conducted to compare both instruments on reported momentary and daily energy intake from snacks. Results: Results showed no significant difference (B = 11.84, p = .14) in momentary energy intake from snacks between the two instruments. However, a significant difference (B = -105.89, p < .01) was found on energy intake from total daily snack consumption. Conclusions: As at momentary level both instruments were comparable in assessing energy intake, research purposes will largely determine the sampling procedure of choice. When momentary associations across time are the interest of study, a signal-contingent sampling procedure may be a suitable method. Since the compared instruments differed on two main features (i.e. the sampling procedure and the device used) it is difficult to disentangle which instrument was the most accurate in assessing daily energy intake. PMID- 30479446 TI - The Effect of Corrective Feedback on Performance in Basic Cognitive Tasks: An Analysis of RT Components. AB - The current work examines the effect of trial-by-trial feedback about correct and error responding on performance in two basic cognitive tasks: a classic Stroop task (n = 40) and a color-word matching task (n = 30). Standard measures of both RT and accuracy were examined in addition to measures obtained from fitting the ex-Gaussian distributional model to the correct RTs. For both tasks, RTs were faster in blocks of trials with feedback than in blocks without feedback, but this difference was not significant. On the other hand, with respect to the distributional analyses, providing feedback served to significantly reduce the size of the tails of the RT distributions. Such results suggest that, for conditions in which accuracy is fairly high, the effect of corrective feedback might either be to reduce the tendency to double-check before responding or to decrease the amount of attentional lapsing. PMID- 30479447 TI - The Development of Symbolic and Non-Symbolic Number Line Estimations: Three Developmental Accounts Contrasted Within Cross-Sectional and Longitudinal Data. AB - Three theoretical accounts have been put forward for the development of children's response patterns on number line estimation tasks: the log-to-linear representational shift, the two-linear-to-linear transformation and the proportion judgment account. These three accounts have not been contrasted, however, within one study, using one single criterion to determine which model provides the best fit. The present study contrasted these three accounts by examining first, second and sixth graders with a symbolic and non-symbolic number line estimation task (Experiment 1). In addition, first and second graders were tested again one year later (Experiment 2). In case of symbolic estimations, the proportion judgment account described the data best. Most young children's non symbolic estimation patterns were best described by a logarithmic model (within the log-to-lin account), whereas those of most older children were best described by the simple power model (within the proportion judgment account). PMID- 30479450 TI - What Do You Believe In? French Translation of the FAD-Plus to Assess Beliefs in Free Will and Determinism and Their Relationship with Religious Practices and Personality Traits. AB - The influence of (dis)belief in free will on prosocial behaviors and sense of control has attracted considerable interest over the last few years. The provision of relevant research tools to assess beliefs in free will and determinism for the community thus becomes a central endeavour. However, no relevant validated questionnaires are currently available to the French language community. Therefore, the present study was aimed at providing a valid French translation of the FAD-plus (Paulhus & Carey, 2011), a questionnaire built to assess people's beliefs in Free will and Determinism. Exploratory factor analysis of the data obtained in Sample 1 revealed a four factor model. Confirmatory factor analyses on the basis of Sample 2 data were conducted to compare the theoretical model advanced by Paulhus and Carey's versus the model obtained in Sample 1. With only but a few modifications as compared to the original questionnaire, the questionnaire that we here propose appears to constitute a reliable tool for the French language community. We also examined the relationship between beliefs in free will, determinism and religious practices. We found that the more people are engaged in religious practices, the more they believe in determinism and in the inevitability of their future. PMID- 30479448 TI - Psychometric Properties of the BIS/BAS Scales and the SPSRQ in Flemish Adolescents. AB - Objective: Gray's Reinforcement Sensitivity Theory (RST) is a frequently used model of personality that is relevant to the period of adolescence. However, the psychometric properties of the most frequently used questionnaires to measure the RST-constructs, namely the Behavioural Inhibition System and Behavioural Activation System Scales (BIS/BAS Scales) and the Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSRQ), are rarely examined in samples of adolescents. Therefore, the goal of the present study was to examine the two factor structure, reliability and convergent validity of the BIS/BAS Scales and SPSRQ in a Flemish adolescent community sample. Method: A sample of 579 adolescents (39.5% boys; 14-19 years) was recruited. The proposed two-factor structure was assessed using Exploratory Structural Equation Modeling. Reliability was evaluated using internal consistency and construct validity was examined with the correlations between the two questionnaires and with the Temperament and Character Inventory-short form (TCI-SF). Results: After the removal of problematic items, and the addition of correlated errors, all indices indicated a good fit for the two-factor structure of the modified BIS/BAS Scales. For the modified SPSRQ, three fit indices indicated a good model fit, while a fourth fit index was slightly below the cut-off score of an adequate model fit. Internal consistency of both questionnaires was sufficient. In general, the associations with scales of the TCI-SF were as expected, with positive correlations between BIS-related scales, and between BAS-related scales of all three instruments. Discussion: In Flemish adolescents, the use of a two-factor model to analyze data gathered with the modified BIS/BAS Scales or modified SPSRQ seems appropriate. PMID- 30479451 TI - A French Translation of the Pleasure Arousal Dominance (PAD) Semantic Differential Scale for the Measure of Affect and Drive. AB - Multivariate studies have repeatedly confirmed that three basic dimensions of human emotional behavior, called pleasure (P), arousal (A) and dominance (D) are persistent in organizing human judgments for a wide range of perceptual and symbolic stimuli. The Mehrabian and Russell's PAD semantic differential scale is a well-established tool to measure these categories, but no standardized French translation is available for research. The aim of this study was to validate a French version of the PAD. For this purpose, (1) Mehrabian and Russell's PAD was translated through a process of translations and back-translations and (2) this French PAD was tested in a population of 111 French-speaking adults on 21 images of the International Affective Picture System (IAPS). A confirmatory factor analysis revealed the expected three-factor structure; the French PAD also distributed the images in the affective space according to the expected boomerang shape. The present version of PAD is thus a valid French translation of Mehrabian and Russell's original PAD. PMID- 30479452 TI - Identity Statuses throughout Adolescence and Emerging Adulthood: A Large-Scale Study into Gender, Age, and Contextual Differences. AB - Identity formation constitutes a core developmental task during adolescence and emerging adulthood. However, it remains unclear how identity formation may vary across age, gender, and context (education vs. employment) in these developmental periods. The present study used a recently developed model to examine identity statuses or types in a sample of 7,906 Flemish individuals (14-30 years old; 64% female). As expected, achievement, foreclosure, moratorium, carefree diffusion, troubled diffusion, and an undifferentiated status emerged through cluster analysis. Women were overrepresented in the moratorium status (characterized by high exploration), whereas men were mainly situated in foreclosure and carefree diffusion statuses (both characterized by low exploration, but individuals in foreclosure having strong identity commitments as well). Individuals in the carefree and troubled diffusion statuses, which represent the least adaptive statuses, were youngest. High school students were overrepresented in the diffusion statuses and college students were mostly present in achievement (representing the most mature status) and moratorium. Finally, employed individuals were overrepresented in foreclosure, whereas unemployed individuals were mainly situated in troubled diffusion. In sum, the present study systematically examined relationships between empirically-identified identity statuses and socio-demographic variables in a large-scale sample, generating important information on age, gender, and contextual differences in identity. PMID- 30479453 TI - Exploring Acceptability and Feasibility of Evidence-Based Practice in Child Welfare Settings: A Pilot Study with Attachment-Based Family Therapy. AB - The Flemish Child Welfare System (CWS) is in great need of a shared empirically informed clinical strategy for working with depressed adolescents and their families. Many evidence-based practices (EBP) exist, but little is known as to whether they can be successfully imported in the CWS. Therefore, the current study explores the implementation of a particular EBP, Attachment-Based Family Therapy (ABFT), in home-based services of the Flemish CWS in Belgium. Specifically, the study focused on (1) the acceptability of ABFT by counselors and whether negative attitudes about EBP can be changed (n = 73 counselors), and (2) the feasibility of implementing ABFT (n = 43 adolescents, 11-17 years old, 72% female) by exploring initial effectiveness. The results suggest that (1) initial negative attitudes of counselors towards ABFT were significantly more positive after attending training and discussions about ABFT, and that (2) ABFT could be used by counselors to successfully reduce adolescent depressive symptoms. Future research should include a control group to draw stronger causal conclusions. Strengths and limitations of the study's design and implications for further dissemination are discussed. PMID- 30479454 TI - Terminating a Child's Life? Religious, Moral, Cognitive, and Emotional Factors Underlying Non-Acceptance of Child Euthanasia. AB - Is opposition to child euthanasia motivated only by ideology, or also by other personality characteristics and individual differences? In Belgium, the first country to legalize child euthanasia (in 2014), we investigated religious, moral, emotional, and cognitive factors underlying the (dis)approval of this legalization (N = 213). Disapproval was associated with religiousness, collectivistic morality (loyalty and purity), and prosocial dispositions, in terms of emotional empathy and behavioral generosity, but not values (care and fairness). It was also associated with low flexibility in existential issues and a high endorsement of slippery slope arguments, but not necessarily low openness to experience. A regression analysis showed that in addition to religiousness, low flexibility in existential issues and high empathy and generosity distinctly predicted opposition to child euthanasia. Whereas most of the findings parallel those previously reported for adult euthanasia, the role of prosocial inclinations in predicting moral opposition seems to be specific to child euthanasia. PMID- 30479456 TI - ESTIMATION OF A MONOTONE DENSITY IN S-SAMPLE BIASED SAMPLING MODELS. AB - We study the nonparametric estimation of a decreasing density function g 0 in a general s-sample biased sampling model with weight (or bias) functions wi for i = 1, ..., s. The determination of the monotone maximum likelihood estimator gn and its asymptotic distribution, except for the case when s = 1, has been long missing in the literature due to certain non-standard structures of the likelihood function, such as non-separability and a lack of strictly positive second order derivatives of the negative of the log-likelihood function. The existence, uniqueness, self-characterization, consistency of gn and its asymptotic distribution at a fixed point are established in this article. To overcome the barriers caused by non-standard likelihood structures, for instance, we show the tightness of gn via a purely analytic argument instead of an intrinsic geometric one and propose an indirect approach to attain the n -rate of convergence of the linear functional ? wi gn. PMID- 30479455 TI - Selective formation of heteroaryl thioethers via a phosphonium ion coupling reaction. AB - Heteroaryl thioethers, comprised of pyridines and diazines, are an important class of compounds with relevance to medicinal chemistry. Metal-catalyzed cross couplings and SNAr are traditionally used to form C-S bonds in these systems but are limited by available halogenated precursors. An alternative approach is presented where pyridines and diazines are transformed into heterocyclic phosphonium salts and then C-S bonds are formed by adding thiolate nucleophiles. The process is 4-selective for pyridines, simple to execute and can be used to make derivatives of complex pharmaceuticals. PMID- 30479457 TI - Language unifies relational coding: The roles of label acquisition and accessibility in making flexible relational judgments. AB - Language is likely structuring spatial judgments, but how it achieves this is not clear. We examined the development of relative, spatial judgments across verbal and nonverbal tasks of above, below, right and left in children between the ages of 5 and 10 years. We found that the verbal ability to make above/below judgments preceded verbal right/left judgments and all nonverbal judgments. We also found that only when the labels were accessed - as opposed to only having been acquired - did children's nonverbal performance improve. Our findings further indicate that accessing the correct term was not needed for enhanced performance. The results suggest that accessing language unifies different instantiations of a relation into a single representation. PMID- 30479458 TI - Acoustic Actuation of in situ Fabricated Artificial Cilia. AB - We present on-chip acoustic actuation of in situ fabricated artificial cilia. Arrays of cilia structures are UV polymerized inside a microfluidic channel using a photocurable polyethylene glycol (PEG) polymer solution and photomasks. During polymerization, cilia structures are attached to a silane treated glass surface inside the microchannel. Then, the cilia structures are actuated using acoustic vibrations at 4.6 kHz generated by piezo transducers. As a demonstration of a practical application, DI water and fluorescein dye solutions are mixed inside a microfluidic channel. Using pulses of acoustic excitations, and locally fabricated cilia structures within a certain region of the microchannel, a waveform of mixing behavior is obtained. This result illustrates one potential application wherein researchers can achieve spatiotemporal control of biological microenvironments in cell stimulation studies. These acoustically actuated, in situ fabricated, cilia structures can be used in many on-chip applications in biological, chemical and engineering studies. PMID- 30479459 TI - Increased susceptibility of aging gastric mucosa to injury and delayed healing: Clinical implications. AB - In this editorial we comment on the article by Fukushi K et al published in the recent issue of the World Journal of Gastroenterology 2018; 24(34): 3908-3918. We focus specifically on the mechanisms of the anti-thrombotic action of aspirin, gastric mucosal injury and aging-related increased susceptibility of gastric mucosa to injury. Aspirin is widely used not only for the management of acute and chronic pain and arthritis, but also importantly for the primary and secondary prevention of cardiovascular events such as myocardial infarcts and strokes. Clinical trials have consistently shown that antiplatelet therapy with long term, low dose aspirin (LDA) - 75 to 325 mg daily, dramatically reduces the risk of non fatal myocardial infarcts, stroke and mortality in patients with established arterial diseases. However, such treatment considerably increases the risk of gastrointestinal (GI) ulcerations and serious bleeding by > 2-4 fold, especially in aging individuals. This risk is further increased in patients using LDA together with other antiplatelet agents, other nonsteroidal anti-inflammatory agents (NSAIDs) and/or alcohol, or in patients with Helicobacter pylori (H. pylori) infection. Previous studies by our group and others have demonstrated prominent structural and functional abnormalities in gastric mucosa of aging individuals (which we refer to as aging gastric mucosa or "aging gastropathy") compared to the gastric mucosa of younger individuals. Aging gastric mucosa has impaired mucosal defense, increased susceptibility to injury by a variety of noxious agents such as aspirin, other NSAIDs and ethanol, and delayed and impaired healing of injury. The mechanism underlying these abnormalities of aging gastric mucosa include reduced mucosal blood flow causing hypoxia, upregulation of PTEN, activation of pro-apoptotic caspase-3 and caspase-9, and reduced survivin (anti-apoptosis protein), importin-alpha (nuclear transport protein), vascular endothelial growth factor, and nerve growth factor. The decision regarding initiation of a long-term LDA therapy should be made after a careful consideration of both cardiovascular and GI risk factors. The latter include a previous history of GI bleeding and/or ulcers, age >= 70, male gender, concurrent use of other NSAIDs, alcohol consumption and H. pylori infection. Furthermore, the incidence of GI ulcers and bleeding can be reduced in patients on long term LDA treatment by several measures. Clinicians treating such patients should test for and eradicate H. pylori, instruct patients to avoid alcohol and non-aspirin NSAIDs, including cyclooxygenase-2-selective NSAIDs, and prescribe proton pump inhibitors in patients on LDA therapy. In the future, clinicians may be able to prescribe one of several potential new drugs, which include aspirin associated with phosphatidylcholine (PL2200), which retains all property of aspirin but reduces by approximately 50% LDA-induced GI ulcerations. PMID- 30479460 TI - Liver as a target of human immunodeficiency virus infection. AB - Liver injury is a characteristic feature of human immunodeficiency virus (HIV) infection, which is the second most common cause of mortality in HIV-infected patients. Now it is recognized that liver plays a key role in HIV infection pathogenesis. Antiretroviral therapy (ART), which suppresses HIV infection in permissive immune cells, is less effective in hepatocytes, thereby making these cells a silent reservoir of HIV infection. In addition to direct hepatotoxic effects of HIV, certain ART treatment modalities provide hepatotoxic effects. The exact mechanisms of HIV-triggered chronic hepatitis progression are not elucidated, but the liver is adversely affected by HIV-infection and liver cells are prominently involved in HIV-elicited injury. These effects are potentiated by second hits like alcohol. Here, we will focus on the incidence of HIV, clinical evidence of HIV-related liver damage, interactions between HIV and liver cells and the role of alcohol and co-infection with hepatotropic viruses in liver inflammation and fibrosis progression. PMID- 30479461 TI - CXC family of chemokines as prognostic or predictive biomarkers and possible drug targets in colorectal cancer. AB - Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women, worldwide. In the early stages of the disease, biomarkers predicting early relapse would improve survival rates. In metastatic patients, the use of predictive biomarkers could potentially result in more personalized treatments and better outcomes. The CXC family of chemokines (CXCL1 to 17) are small (8 to 10 kDa) secreted proteins that attract neutrophils and lymphocytes. These chemokines signal through chemokine receptors (CXCR) 1 to 8. Several studies have reported that these chemokines and receptors have a role in either the promotion or inhibition of cancer, depending on their capacity to suppress or stimulate the action of the immune system, respectively. In general terms, activation of the CXCR1/CXCR2 pathway or the CXCR4/CXCR7 pathway is associated with tumor aggressiveness and poor prognosis; therefore, the specific inhibition of these receptors is a possible therapeutic strategy. On the other hand, the lesser known CXCR3 and CXCR5 axes are generally considered to be tumor suppressor signaling pathways, and their stimulation has been suggested as a way to fight cancer. These pathways have been studied in tumor tissues (using immunohistochemistry or measuring mRNA levels) or serum [using enzyme-linked immuno sorbent assay (ELISA) or multiplexing techniques], among other sample types. Common variants in genes encoding for the CXC chemokines have also been investigated as possible biomarkers of the disease. This review summarizes the most recent findings on the role of CXC chemokines and their receptors in CRC and discusses their possible value as prognostic or predictive biomarkers as well as the possibility of targeting them as a therapeutic strategy. PMID- 30479462 TI - Gut microbiota in common elderly diseases affecting activities of daily living. AB - Gut microbiota are involved in the development or prevention of various diseases such as type 2 diabetes, fatty liver, and malignancy such as colorectal cancer, breast cancer and hepatocellular carcinoma. Alzheimer's disease, osteoporosis, sarcopenia, atherosclerotic stroke and cardiovascular disease are major diseases associated with decreased activities of daily living (ADL), especially in elderly people. Recent analyses have revealed the importance of gut microbiota in the control of these diseases. The composition or diversity of these microbiota is different between patients with these conditions and healthy controls, and administration of probiotics or prebiotics has been shown effective in the treatment of these diseases. Gut microbiota may affect distant organs through mechanisms that include regulating the absorption of nutrients and/or the production of microbial metabolites, regulating and interacting with the systemic immune system, and translocating bacteria/bacterial products through disrupted mucosal barriers. Thus, the gut microbiota may be important regulators in the development of diseases that affect ADL. Although adequate exercise and proper diet are important for preventing these diseases, their combination with interventions that manipulate the composition and/or diversity of gut microbiota could be a promising strategy for maintaining health condition and preserving ADL. This review thus summarizes current understanding of the role of gut microbiota in the development or prevention of diseases closely associated with the maintenance of ADL. PMID- 30479463 TI - Yiguanjian decoction enhances fetal liver stem/progenitor cell-mediated repair of liver cirrhosis through regulation of macrophage activation state. AB - AIM: To investigate whether Yiguanjian decoction (YGJ) has an anti-liver cirrhotic effect and whether it regulates hepatic stem cell differentiation. METHODS: A rat model of liver cirrhosis was established via subcutaneous injection of carbon tetrachloride (CCl4) for 8 wk. From the beginning of the ninth week, the rats received 2-acetylaminofluorene (2-AAF) by oral gavage and a DLK-1+ fetal liver stem/progenitor cell (FLSPC) transplant or an FLSPC transplant in combination with YGJ treatment for 4 wk. In vitro, lipopolysaccharide (LPS) activated macrophages were co-cultured with WB-F344 cells, and the differentiation of WB-F344 cells was observed in the presence and absence of YGJ treatment. RESULTS: FLSPC transplantation improved liver function and histopathology, and inhibited the activation of the non-canonical Wnt signaling pathway, while activating the canonical Wnt signaling pathway. YGJ enhanced the therapeutic effects of FLSPCs and also promoted the liver regeneration differentiation of FLSPCs into hepatocytes. In vitro, LPS-activated macrophages promoted the differentiation of WB-F344 cells into myofibroblasts, and the canonical Wnt signaling was inhibited while the non-canonical Wnt signaling was activated in WB-F344 cells. YGJ suppressed the activation of macrophages and then inhibited non-canonical Wnt signaling and promoted canonical Wnt signaling. CONCLUSION: YGJ enhances FLSPC-mediated repair of liver cirrhosis through regulation of macrophage activation state, and YGJ in combination with stem cell transplantation may be a suitable treatment for end-stage liver cirrhosis. PMID- 30479464 TI - Ubiquitin-like modifier activating enzyme 2 promotes cell migration and invasion through Wnt/beta-catenin signaling in gastric cancer. AB - AIM: To investigate the function and mechanism of ubiquitin-like modifier activating enzyme 2 (Uba2) in progression of gastric cancer (GC) cells. METHODS: Uba2 level in patients with GC was analyzed by Western blotting and immunohistochemistry. MTT and colony formation assays were performed to examine cell proliferation. Flow cytometry was used for cell cycle analysis. Wound healing and Transwell assays were conducted to examine the effects of Uba2 on migration and invasion. Expression levels of cell cycle-related proteins, epithelial-mesenchymal transition (EMT) biomarkers, and involvement of the Wnt/beta-catenin pathway was assessed by Western blotting. Activation of the Wnt/beta-catenin pathway was confirmed by luciferase assay. RESULTS: Uba2 expression was higher in GC than in normal tissues. Increased Uba2 expression was correlated with tissue differentiation, Lauren's classification, vascular invasion, and TNM stage, as determined by the analysis of 100 GC cases (P < 0.05). Knock-down of Uba2 inhibited GC cell proliferation, induced cell cycle arrest, and altered expression of cyclin D1, P21, P27, and Bcl-2, while up regulation of Uba2 showed the opposite effects. The wound healing and Transwell assays showed that Uba2 promoted GC cell migration and invasion. Western blotting revealed alterations in EMT biomarkers, suggesting the role of Uba2 in EMT. Furthermore, the luciferase reporter assay indicated the involvement of the Wnt/beta-catenin signaling pathway as a possible modulator of Uba2 oncogenic functions. CONCLUSION: Uba2 plays a vital role in GC cell migration and invasion, possibly by regulating the Wnt/beta-catenin signaling pathway and EMT. PMID- 30479465 TI - Mode of delivery by an ulcerative colitis mother in a case of twins: Immunological differences in cord blood and placenta. AB - AIM: To understand the effects of delivery mode on the immune cells frequency and function in cord blood and placenta. METHODS: We evaluated immunological differences in cord blood and placental tissues for a case of twins one of which delivered vaginally while the other delivered by caesarian section (C-section). Cord blood mononuclear cells were isolated and placenta tissues were processed for cell isolation. Immune phenotyping was performed by flow cytometry methods following staining for T cells, natural killer (NK) cells, monocytes, neutrophils and CD71+ erythroid cells in both cord blood and placenta tissues. In addition, fetal calprotectin of twins was measured 12 wk after birth. RESULTS: We found lower percentages of immune cells (e.g. T cells, monocytes and neutrophils) in the cord blood of C-section delivered compared to vaginally delivered newborn. In contrast, percentages of monocytes and neutrophils were > 2 folds higher in the placental tissues of C-section delivered newborn. More importantly, we observed lower percentages of CD71+ erythroid cells in both cord blood and placental tissues of C-section delivered case. Lower CD71+ erythroid cells were associated with a more pro-inflammatory milieu at the fetomaternal interface reflected by higher expression of inhibitory receptors on CD4+ T cells, higher frequency of monocytes and neutrophils. Furthermore, type of delivery impacted the gene expression profile in CD71+ erythroid cells. Finally, we found that C-section delivered child had > 20-fold higher FCP in his fecal sample at 12 wk of age. CONCLUSION: Mode of delivery impacted immune cells profile in cord blood/placenta. In particular frequency of immunosuppressive CD71+ erythroid cells was reduced in C-section delivered newborn. PMID- 30479466 TI - Increased end-stage renal disease risk in patients with inflammatory bowel disease: A nationwide population-based study. AB - AIM: To estimate the risk of end-stage renal disease (ESRD) in patients with inflammatory bowel disease (IBD). METHODS: From January 2010 to December 2013, patients with Crohn's disease (CD) and ulcerative colitis (UC) were identified, based on both the International Classification of Diseases, 10th revision (ICD 10) and the rare, intractable disease registration program codes from the National Health Insurance (NHI) database in South Korea. We compared 38812 patients with IBD to age- and sex-matched non-IBD controls with a ratio of 1:3. Patients newly diagnosed with ESRD were identified with the ICD-10 code. RESULTS: During a mean follow-up of 4.9 years, ESRD was detected in 79 (0.2%) patients with IBD and 166 (0.1%) controls. The incidence of ESRD in patients with IBD was 0.42 per 1000 person-years. Patients with IBD had a significantly higher risk of ESRD than controls [adjusted hazard ratio (HR) = 3.03; 95% confidence interval (CI): 1.77-5.20; P < 0.001]. The incidences (per 1000 person-years) of ESRD were 0.51 in patients with CD and 0.13 in controls, respectively (adjusted HR = 6.33; 95%CI: 2.75-14.56; P < 0.001). In contrast, the incidence of ESRD was similar between the UC and control groups (0.37 vs 0.37 per 1000 person-years; adjusted HR = 2.01; 95%CI: 0.90-4.51; P = 0.089). CONCLUSION: The risk of ESRD was elevated in patients with CD, but not UC. Patients with CD should be monitored carefully for signs of renal insufficiency. PMID- 30479467 TI - Prediction of colorectal tumor grade and invasion depth through narrow-band imaging scoring. AB - AIM: To determine the usefulness of assigning narrow-band imaging (NBI) scores for predicting tumor grade and invasion depth in colorectal tumors. METHODS: A total of 161 colorectal lesions were analyzed from 138 patients who underwent endoscopic or surgical resection after conventional colonoscopy and magnifying endoscopy with NBI. The relationships between the surface and vascular patterns of the lesions, as visualized with NBI, and the tumor grade and depth of submucosa (SM) invasion were determined histopathologically. Scores were assigned to distinct features of the surface microstructures of tubular and papillary-type lesions. Using a multivariate analysis, a model was developed for predicting the tumor grade and depth of invasion based on NBI-finding scores. RESULTS: NBI findings that correlated with a high tumor grade were associated with the "regular/irregular" (P < 0.0001) surface patterns and the "avascular area" pattern (P = 0.0600). The vascular patterns of "disrupted vessels" (P = 0.0714) and "thick vessels" (P = 0.0133) but none of the surface patterns were associated with a depth of invasion of >= 1000 MUm. In our model, a total NBI-finding score >= 1 was indicative of a high tumor grade (sensitivity: 0.97; specificity: 0.24), and a total NBI-finding score >= 9 (sensitivity: 0.56; specificity: 1.0) was predictive of a SM invasion depth >= 1000 MUm. Scores less than these cutoff values signified adenomas and a SM invasion depth < 1000 MUm, respectively. Associations were also noted between selected NBI findings and tumor tissue architecture and histopathology. CONCLUSION: Our multivariate statistical model for predicting tumor grades and invasion depths from NBI-finding scores may help standardize the diagnosis of colorectal lesions and inform therapeutic strategies. PMID- 30479468 TI - Burden and outcomes for complex perianal fistulas in Crohn's disease: Systematic review. AB - AIM: To systematically review the literature on epidemiology, disease burden, and treatment outcomes for Crohn's disease (CD) patients with complex perianal fistulas. METHODS: PubMed, Embase, and Cochrane were searched for relevant articles (published 2000-November 2016) and congress abstracts (published 2011 November 2016). RESULTS: Of 535 records reviewed, 62 relevant sources were identified (mostly small observational studies). The cumulative incidence of complex perianal fistulas in CD from two referral-centre studies was 12%-14% (follow-up time, 12 years in one study; not reported in the second study). Complex perianal fistulas result in greatly diminished quality of life; up to 59% of patients are at risk of faecal incontinence. Treatments include combinations of medical and surgical interventions and expanded allogeneic adipose-derived stem cells. High proportions of patients experience lack of or inadequate response to treatment (failure and relapse rates, respectively: medical, 12%-73% and 0%-41%; surgical: 0%-100% and 11%-20%; combined medical/surgical: 0%-80% and 0%-50%; stem cells: 29%-47% and not reported). Few studies (1 of infliximab; 3 of surgical interventions) have been conducted in treatment-refractory patients, a population with high unmet needs. Limited data exist on the clinical value of anti-tumour necrosis factor-alpha dose escalation in patients with complex perianal fistulas in CD. CONCLUSION: Complex perianal fistulas in CD pose substantial clinical and humanistic burden. There is a need for effective treatments, especially for patients refractory to anti-tumour necrosis factor alpha agents, as evidenced by high failure and relapse rates. PMID- 30479471 TI - Degradation of Paracetamol and Its Oxidation Products in Surface Water by Electrochemical Oxidation. AB - Paracetamol and its toxic transformation products have been found in surface water, wastewater, and drinking water. Effective methods to degrade these products must be found to reduce their detrimental effects on microorganisms in aquatic systems and minimize the concern on human health. Thus, this study looked into the electrochemical oxidation of paracetamol and its oxidation products on surface water, and results were compared with those of paracetamol synthetic solution oxidation. Degradation of paracetamol was conducted using a stainless steel electrode cell, a pH of 3, and direct current densities of 5.7 mA/cm2 (6 V) and 7.6 mA/cm2 (12 V). For both current densities applied, the pharmaceutical and its oxidation products observed by high-performance liquid chromatography with diode-array detection (HPLC-DAD) at 254 nm were totally degraded. Faster degradation of paracetamol was observed at a higher current density. Indeed, 95% of paracetamol was oxidized in only 15 min at the 7.6 mA/cm2 current density. In comparison to the paracetamol synthetic solution's oxidation, degradation of paracetamol was faster in the surface water than the synthetic solution, at 5.7 mA/cm2. Nevertheless, at 7.6 mA/cm2, total degradation of paracetamol in surface water was delayed up to 40 min, versus 7.5 min in the synthetic solution. Three oxidation products, observed by HPLC-DAD at 254 nm, were fully oxidized. In comparison with the paracetamol synthetic solution, degradation of the oxidation products in surface water was faster than in synthetic solutions for both current densities. Furthermore, the 7.6 mA/cm2 current density resulted in faster degradation of oxidation products. Results obtained from this work are promising for practical applications because short reaction times and low current densities are needed for degradation of paracetamol and its oxidation products. These densities can be potentially supplied by photovoltaic cells. PMID- 30479469 TI - Phenotypic Features of Central Sensitization. AB - Purpose: The current manuscript reviews approaches for phenotyping central sensitization (CS). Methods: The manuscript covers the concept of diagnostic phenotyping, use of endophenotypes, biomarkers, and symptom clusters. Specifically, the components of CS that include general sensory sensitivity (assessed by quantitative sensory testing) and a symptom cluster denoting sleep difficulties, pain, affect, cognitive difficulties, and low energy (S.P.A.C.E.). Results: Each of the assessment domains are described with reference to CS and their presence in chronic overlapping pain conditions (COPCs) - conditions likely influenced by CS. Conclusions: COPCs likely represent clinical diagnostic phenotypes of CS. Components of CS can also be assessed using QST or self-report instruments designed to assess single elements of CS or more general composite indices. PMID- 30479470 TI - Children's Conversational Memory Regarding a Minor Transgression and a Subsequent Interview. AB - Children's memories for their conversations are commonly explored in child abuse cases. In two studies, we examined conversational recall in 154 4- to 9-year-old children's reports of an interaction with a stranger, some of whom were complicit in a transgression and were admonished to keep it a secret. Immediately afterwards, all children were interviewed about their interaction. One week later, children were asked recall questions about their interaction with the stranger, their conversations with the stranger, and their conversations with the interviewer. Overall, interaction recall questions elicited few details about children's conversations, whereas conversation recall questions were effective in doing so. Accuracy was high in response to both the interaction and conversation recall questions, with no differences observed. Questions explicitly inquiring about coaching elicited higher error rates, as well as apparent attempts to maintain secrecy. Source errors were rare. Conversation recall questions elicited new transgression disclosures among a substantial percentage of children. The results provide tentative support for the use of recall questions in eliciting conversational information from children. PMID- 30479473 TI - Exercise testing and adipokine levels for the evaluation of overweight and obesity in children. AB - BACKGROUND: Childhood obesity poses a global health threat. We investigated the association of the cardiopulmonary exercise testing indexes with adipokines levels and insulin resistance along with the beneficial effect of physical exercise on insulin resistance in children. MATERIAL AND METHODS: Thirty-two obese, 21 overweight, and 30 normal-weight children participated in the current study, with mean age 11.98 (+/-1.95), 10.91 (+/-1.72), and 11.35 (+/-2.21) years, respectively. All children were clinically healthy. The children and their parents provided data on physical activity, while spirometry and maximal cardiopulmonary exercise testing were performed for the functional evaluation of the respiratory status of the study population. RESULTS: Leptin levels were significantly lower in normal-weight children compared to the obese ones (p <0.001). Maximum quantity of oxygen (VO2max) differences were statistically significant between the three groups (p =0.025 for normal weight vs overweight, and p =0.001 for normal vs obese children). Leptin levels were inversely related to VO2max in obese children (p =0.009, r =-0.491). Homeostatic model assessment of insulin resistance (HOMA-IR) was statistically significantly lower among children that were more physically active (p =0.042). Leptin was significantly related to body mass index among obese children (r =-0.582, p <0.001). CONCLUSIONS: Leptin is significantly inversely related to VO2max in obese children. This study, however, allows further assumptions for adipokines and childhood obesity, along with the possible role of leptin as an additional obesity index in relation with cardiopulmonary function. HIPPOKRATIA 2017, 21(3): 124-129. PMID- 30479472 TI - Understanding neonatal hypoxic-ischemic encephalopathy with metabolomics. AB - BACKGROUND: Hypoxic-ischemic encephalopathy (HIE), a serious complication of perinatal asphyxia, is commonly associated with an unfavorable outcome. In-depth research is important not only for the interpretation of the underlying biological alternations but may also provide the basis for the development of novel diagnostic and therapeutic tools. The application of metabolomics in perinatal asphyxia/HIE is a relatively new approach. METHODS: We performed a narrative, non-systematic review in the literature of metabolomic studies involving newborn animals and humans exposed to hypoxia-ischemia or developing perinatal asphyxia/HIE. RESULTS: Fifteen animal studies, nine studies in human neonates, and two review articles were evaluated. Changes in the metabolomic profile of newborn animals exposed to hypoxia-ischemia and of asphyxiated neonates with HIE are presented in relation to the underlying pathophysiology. The clinical relevance of these findings is further discussed in a comprehensible to the bedside clinician manner. CONCLUSIONS: Metabolomics may provide an explanation for the various metabolic alternations occurring in perinatal asphyxia/HIE, elucidate the biological background of the applied therapeutic interventions and promote the development of novel diagnostic-prognostic biomarkers of the disease. HIPPOKRATIA 2017, 21(3): 115-123. PMID- 30479474 TI - Caregiver's perception of epilepsy treatment, quality of life and comorbidities in an international cohort of CDKL5 patients. AB - OBJECTIVE: CDKL5 is a genetic condition associated with drug-resistant epilepsy and intellectual disability. There is limited information on its natural history. We investigated the natural history, complications, and the effectiveness of current treatment strategies. METHODS: This study was conducted in conjunction with the CDKL5-UK Charity, with patients recruited from the USA and Europe. Online questionnaires were completed by parents/carers and included information relating to demographics, growth, development, epilepsy, comorbid conditions, and efficacy and side effects of antiepileptic treatments. RESULTS: Thirty-nine of the 44 patients were female. Median age was five years (range five months to 31 years), and all had a history of epilepsy. All patients had developmental delay, with 4/21 able to run and 4/22 able to climb. Gastrointestinal problems were reported in 31/43. Cardiac arrhythmia was seen in 11/29. Over one-quarter of the patients had tried ten or more antiepileptic medications. Vigabatrin was reportedly the most effective AED (antiepileptic drug) in 12/23; clobazam (most effective in 6/14); sodium valproate (most effective in 5/27), and levetiracetam (most effective in 3/27). VNS (Vagal Nerve Stimulator) was reported to be effective in 9/12. One year after VNS insertion, 9/12 reported improved (QoL), and there were improvements in mood, school achievement and concentration in (9/11). The ketogenic diet was considered effective and to have improved QoL in (12/23). CONCLUSION: Vigabatrin appears to be more effective than other AEDs. VNS and ketogenic diet are also relatively effective. Gastrointestinal and cardiovascular system complications are common. The results may help to guide management of epilepsy in CDKL5. It highlights a possible link between CDKL5 and potentially treatable life-threatening complications such as cardiac arrhythmia. More research in this area may help us develop a more systematic approach to treating these patients. HIPPOKRATIA 2017, 21(3): 130-135. PMID- 30479475 TI - Matrix metalloproteinases in ureteropelvic junction obstruction. AB - BACKGROUND: Management of ureteropelvic junction obstruction (UPJO) remains controversial. The aim of the present study was to measure the levels of matrix metalloproteinases (MMPs) in UPJO patients who were planned to undergo surgery and thus clarify if MMPs levels could serve as potential biomarkers of surgical obstruction in UPJO. METHODS: Serum samples of infants with UPJO diagnosis were compared to serum samples of healthy age-matched controls. MMP2 and MMP9 were quantified using enzyme-linked immunosorbent assay (ELISA). RESULTS: A total of 17 infants with UPJO diagnosis, and median age 1.5 months, were prospectively recruited. MMP9 levels were significantly decreased in the serum samples of UPJO infants compared to controls (p =0.037). Also MMP2 values were higher in UPJO infants compared to controls, but the difference was not statistically significant (p =0.206). CONCLUSIONS: This study found decreased concentrations of MMP9 in infants with obstructive hydronephrosis. However, the results should be tested in larger population samples and even be evaluated simultaneously with urine samples in order to delineate the ability of MMPs to serve as obstruction biomarkers. HIPPOKRATIA 2017, 21(3): 136-139. PMID- 30479477 TI - Daily dose of itraconazole 100 mg to treat allergic bronchopulmonary aspergillosis (ABPA) related eosinophilia: a case report. AB - BACKGROUND: Itraconazole can be used in the treatment of allergic bronchopulmonary aspergillosis (ABPA), as add-on therapy to antiasthmatic medications. Description of the case: The case of an 83-year-old male with asthma, newly diagnosed with ABPA, is presented. A daily itraconazole dose of 100 mg managed to efficiently control eosinophilia and reduce his total IgE count, while these laboratory findings relapsed three months after stopping itraconazole. When the dose was reduced to 100 mg of itraconazole every other day, it was proved insufficient to control eosinophilia. Moreover, one year later, he is being efficiently treated with 100 mg itraconazole daily. CONCLUSIONS: The dose of itraconazole 100 mg can effectively treat some cases of ABPA with asthma. HIPPOKRATIA 2017, 21(3): 144-146. PMID- 30479476 TI - The effects of S-adenosyl-L-methionine-vitamin B complex on mild and moderate depressive symptoms. AB - BACKGROUND: S-adenosyl-L-methionine (SAMe) acts as a methyl donor, with dopamine, norepinephrine, and serotonin elevating properties, with potential antidepressant effects. In this study, we evaluated the efficacy of SAMe-vitamin B complex supplement for improving mild and moderate depressive symptoms. SUBJECTS AND METHODS: The study included 60 patients diagnosed with depression, with mild or moderate depressive symptoms, randomly allocated into two groups. The study group was treated with SAMe-vitamin B complex while the control group was administered a placebo, once daily for three months. The severity of depressive symptoms was measured by the Hamilton Depression rating scale (HAMD17). We measured the symptoms' severity with the Clinical Global Impression-Severity scale (CGI-S), and the improvement or worsening after treatment with the Clinical Global Impression-Improvement scale (CGI-I). RESULTS: The mean HAMD17 score at zero point refers to moderate depressive symptoms in both groups. We found a statistically significant difference between the two groups regarding the mean HAMD17 and CGI-S scores at three months (p <0.001) and a significant difference within the study group without an influence by the age or gender. Mean CGI-I score in the study group at three months showed minimally or much improvement while no change or minimal worsening was observed in the control group with significant differences between the groups (p <0.001). CONCLUSION: Three months of supplementation with SAMe-vitamin B complex is effective for the treatment of mild to moderate depressive symptoms. HIPPOKRATIA 2017, 21(3): 140-143. PMID- 30479478 TI - Nasopharyngeal angiofibroma in an adult with Proteus syndrome. First reported case. AB - BACKGROUND: Proteus Syndrome (PS) is a rare hamartoneoplastic disorder consisting of a disproportionate and asymmetric overgrowth of body parts, leading to severe body and face disfigurement. Individuals with PS frequently need to undergo a number of surgical procedures including Otolaryngology interventions. Their peculiar anatomy turns even the most straightforward intervention to a challenging one. CASE DESCRIPTION: A 31-year-old adult male with PS presented with recurrent epistaxis and nasal obstruction. A nasal mass was found during the physical examination, which was surgically removed under general anesthesia. Histology revealed juvenile angiofibroma. CONCLUSION: This is the first reported case of a patient with PS presenting with juvenile nasopharyngeal angiofibroma. Although vascular malformations may appear in these patients, juvenile nasopharyngeal angiofibroma should be taken under consideration when PS patients present with recurrent epistaxis. HIPPOKRATIA 2017, 21(3): 147-149. PMID- 30479479 TI - Isolated sphenochoanal polyp: report of three cases. AB - BACKGROUND: Choanal polyps constitute 3-6 % of all nasal polyps and are lesions which usually originate from the mucosa of the maxillary sinus and have a solitary growth pattern. Polyps originating from the sphenoid sinus are rarely seen and are known as sphenochoanal polyps. Surgical treatment of the sphenochoanal polyps is its complete excision together with the pedicle and the portion inside the sphenoid sinus. CASES REPORT: We report the cases of three patients who were referred to the ENT outpatient department for a persistent unilateral nasal obstruction that was resistant to medical treatment. After their clinical and endoscopic examination and imaging evaluation, these patients underwent endoscopic excision of the sphenochoanal polyps which in histopathology were proven to be inflammatory polyps. CONCLUSION: Although rarely seen sphenochoanal polyps must be kept in mind in the differential diagnosis of unilateral sphenoid sinus and posterior nasal cavity masses. HIPPOKRATIA 2017, 21(3): 150-153. PMID- 30479480 TI - Thyroid transcription factor-1 expression in invasive and non-invasive urothelial carcinomas. AB - BACKGROUND: Thyroid transcription factor-1 (TTF-1) has been considered a sensitive marker for thyroid and lung tumors. Recent data have shown that a wide range of neoplasms may express TTF-1. CASE SERIES: We performed an immunohistochemical study in a case series of 42 urothelial carcinomas (UCs) on tissue microarrays sections, in order to investigate how often UCs express the TTF-1 protein and the diagnostic utility of this marker. In addition, we sought to determine by immunohistochemistry if there is an association between TTF-1 expression and the expression of specific basal-like or luminal markers. Five out of the 42 cases (11.9 %) were positive for TTF-1. Three positive tumors concerned non-invasive papillary UCs. There was no association between TTF-1 expression and tumor grade (chi2, p =0.419), stage (chi2, p =0.550) or cytokeratin 5/6 (chi2, p =0.330), cytokeratin 20 (chi2, p =0.995) and estrogen receptors expression (chi2, p =0.268). CONCLUSIONS: UCs may show TTF-1 expression and pathologists should be aware of this phenomenon in order to avoid misdiagnosis, notably in metastatic disease. HIPPOKRATIA 2017, 21(3): 154-157. PMID- 30479481 TI - Endovascular treatment of an axillary artery pseudoaneurysm following shoulder arthroplasty. PMID- 30479482 TI - Subjective visual vertical in patients with benign positional paroxysmal vertigo. PMID- 30479483 TI - Syncope in a patient with tortuous right common carotid artery. PMID- 30479484 TI - Adverse Human Health Impacts in the Anthropocene. AB - This commentary presents a summarized discussion of key findings and relevant ideas from previously published study, index analysis, and human health risk model application for evaluating ambient air-heavy metal contamination in Chemical Valley Sarnia (CVS). The CVS study provides previously unavailable data in the CVS area which evaluates the adverse effects on air quality due to nearby anthropogenic activities. The study provided an assessment of environmental pollutants, finding that carcinogenic and non-carcinogenic substances are present in trace quantities. The main findings of the study suggest that chronic exposure of humans to several contaminants identified in the area studied may lead to carcinogenic health effects, including cancer (such as nephroblastomatosis) as well as non-carcinogenic health effects, such as damage to the tracheobronchial tree. Children were found to have a significantly higher risk, that is, a higher hazard index: a value used to measure non-carcinogenic health risk from heavy metals identified in air samples collected during the research period from 2014 to 2017. This study quantified the influence of environmental contaminants, relative to human exposures and the consequence of developing nephroblastomatosis in the human population. PMID- 30479485 TI - Scurvy is Back. AB - Background and objective: Scurvy, caused by vitamin C deficiency, first described by Hippocrates, is known to many as 'The Pirates' Disease'. Although a disease rarely acknowledged in modern medicine, we present 2 cases of elderly gentlemen found to have scurvy, who improved significantly on treatment. Methods: This study presents a case report of 2 patients undergoing rehabilitation at Karin Grech Hospital in Malta, noted to have signs and symptoms of vitamin C deficiency. Vitamin C levels were found to be low and thus supplementation was administered. Results: After a few weeks, a significant improvement was noted in level of frailty, mood, bleeding tendency, and gum health. Conclusions: The modern doctor must keep this ancient disease in mind, as it presents insidiously with debilitating repercussions, particularly in older people who are at a higher risk. It is easily treatable once detected. PMID- 30479486 TI - Perioperative Enteral Nutrition After Left Ventricular Assist Device Implantation. AB - Objective: We assessed what predicts nutritional adequacy at day 14 following implantation of left ventricular assist device (LVAD). Method: We retrospectively reviewed the cases of 97 adult patients who underwent LVAD implantation at our institution from June 2011 to June 2016. We divided the patients into two groups based on the administered enteral nutrition (EN) calories on post-operative day (POD) 14: the EN calories of group SEN (sufficient enteral nutrition) were >80% of their total target calories, or the EN calories of group IEN (insufficient enteral nutrition) were <80% of their total target calories. We compared the two groups in terms of the perioperative factors within 1 week after surgery. Results: Groups SEN and IEN consisted of 53 and 44 patients, respectively. The mean doses of adrenaline and noradrenaline, mean central venous pressure (CVP), duration of nitric oxide administration, and mean residual gastric volume during 1 week after surgery in group SEN were significantly lower than those in group IEN (P < .05). In multivariate analysis, higher CVP during 1 week after surgery was identified as an independent risk factor for delayed EN on POD14 (odds ratio, 1.40; 95% confidence interval, 1.11-1.66; P = .0037). Total bilirubin, occurrence of acute kidney injury, and mixed venous blood saturation during 1 week after surgery were not significant predictors for EN on POD14. Conclusions: Increased CVP within 1 week after LVAD implantation was an independent factor for reduced EN feeding. PMID- 30479488 TI - Context-Sensitive Computational Mechanisms of Decision Making. AB - Real-world information is primarily sensory in nature, and understandably people attach value to the sensory information to prepare for appropriate behavioral responses. This review presents research from value-based, perceptual, and social decision-making domains, so far studied using isolated paradigms and their corresponding computational models. For example, in perceptual decision making, the sensory evidence accumulation rather than value computation becomes central to choice behavior. Furthermore, we identify cross-linkages between the perceptual and value-based domains to help us better understand generic processes pertaining to individual decision making. The purpose of this review is 2-fold. First, we identify the need for integrated study of different domains of decision making. Second, given that both our perception and valuation are influenced by the surrounding context, we suggest the integration of different types of information in decision making could be done by studying contextual influences in decision making. Future research needs to attempt toward a system-level understanding of various subprocesses involved in decision making. PMID- 30479487 TI - Salt an Essential Nutrient: Advances in Understanding Salt Taste Detection Using Drosophila as a Model System. AB - Taste modalities are conserved in insects and mammals. Sweet gustatory signals evoke attractive behaviors while bitter gustatory information drive aversive behaviors. Salt (NaCl) is an essential nutrient required for various physiological processes, including electrolyte homeostasis, neuronal activity, nutrient absorption, and muscle contraction. Not only mammals, even in Drosophila melanogaster, the detection of NaCl induces two different behaviors: Low concentrations of NaCl act as an attractant, whereas high concentrations act as repellant. The fruit fly is an excellent model system for studying the underlying mechanisms of salt taste due to its relatively simple neuroanatomical organization of the brain and peripheral taste system, the availability of powerful genetic tools and transgenic strains. In this review, we have revisited the literature and the information provided by various laboratories using invertebrate model system Drosophila that has helped us to understand NaCl salt taste so far. We hope that this compiled information from Drosophila will be of general significance and interest for forthcoming studies of the structure, function, and behavioral role of NaCl-sensitive (low and high concentrations) gustatory circuitry for understanding NaCl salt taste in all animals. PMID- 30479489 TI - Oligodendroglia Are Particularly Vulnerable to Oxidative Damage After Neurotrauma In Vivo. AB - In the paper "Oligodendroglia are particularly vulnerable to oxidative damage after neurotrauma in vivo," we determined the extent of oxidative damage to specific cellular subpopulations and structures within regions vulnerable to secondary degeneration and assessed the effect this had on oligodendroglial function. Comparative assessment of oxidative damage demonstrated selective vulnerability of oligodendroglia, specifically oligodendrocyte progenitor cells (OPCs) to DNA oxidation in vivo. Immunohistochemical fate mapping along the oligodendroglial lineage showed a transient susceptibility of these cells to DNA oxidation, protein nitration, and lipid peroxidation, with mature oligodendrocytes derived immediately after injury more vulnerable to DNA oxidation than their counterparts existing at the time of injury or later derived. In situ hybridization demonstrated a reduction in myelin regulatory factor (MyRF) messenger RNA (mRNA) fluorescence in newly derived mature oligodendrocytes, suggesting a compromise in the production and maintenance of the myelin sheath in these cells. The data imply a deficit in the normal differentiation of OPCs to myelinating oligodendrocytes, associated with a transient increase in oxidative damage, which may contribute to the dysmyelinating phenotype seen at chronic time points after injury. Identifying and understanding the sources of this oxidative damage is integral for the development of therapeutic interventions for neurotrauma. PMID- 30479490 TI - Unique Biology and Single-Channel Properties of GluN2A- and GluN2C-Containing Triheteromeric N-Methyl-D-Aspartate Receptors. AB - Triheteromeric N-methyl-D-aspartate receptors (NMDARs) are assemblies of two different types of GluN2 subunits that endow receptors with properties distinct from their diheteromeric counterparts. Previous studies show an abundance of triheteromeric NMDARs across the central nervous system (CNS), making them an important receptor population to investigate and potential drug target. A recent study by Bhattacharya et al. (1) demonstrated the prevalence of GluN1/GluN2A/GluN2C triheteromeric NMDARs in cerebellar granule cells (CGCs), (2) suggested that GluN2C subunits seldom express as diheteromers, (3) suggested that GluN2A subunits are the preferred partners for GluN2C to functionally express at the cell surface, and (4) revealed unique single-channel properties of these triheteromeric assemblies, which may enable these cells to perform unique tasks. Taken together, this work demonstrates the physiological existence of GluN1/GluN2A/GluN2C receptors in the CGCs. PMID- 30479491 TI - An Unusual Mass of Posterior Mediastinum: A Case of Retrotracheal Parathyroid Adenoma Presenting With Primary Hyperparathyroidism. AB - Although parathyroid ectopy in the mediastinum has been the subject of several publications, its location in the posterior mediastinum is very rarely reported. We report a case of a 69-year-old patient who presented with clinical symptoms of malignant hypercalcemia due to a retrotracheal mediastinal parathyroid adenoma. The surgical excision leads to a quick normalisation of the phosphocalcic balance with improvement of the clinical symptoms. Ectopic hypersecreting parathyroid adenoma with life-threatening hypercalcemia should prompt radiological assessment and appropriate surgical management to prevent further clinical complications. PMID- 30479492 TI - Comment to Empirical Therapy for Chronic Suppurative Otitis Media. AB - Chronic suppurative otitis media is an inflammatory condition characterized by disruption of tympanic membrane and aural discharge. It is one of the most incidental conditions in head and neck. There has been a substantial debate about the therapeutic approach for some decades now. From review of past medical literature, it was evident that culture and sensitivity is essential in eradicating the causative organism. However, the cost-effectiveness is a major concern for low-income population. Due to such concern, empirical therapy has proved to be a suitable therapeutic approach since commonly found organisms are highly sensitive to routine antibiotics. PMID- 30479493 TI - The Incidence of Muscle Abnormalities in Broiler Breast Meat - A Review. AB - The dramatic improvements in the growth rate and breast muscle size and yield in broilers through the intensive genetic selection, and the improvement in nutrition and management over the past 50 years have introduced serious abnormalities that influenced the quality of breast meat. The abnormalities include pale-soft-exudative (PSE) conditions, deep pectoral muscle (DPM) myopathy, spaghetti meat (SM), white striping (WS), and woody breast (WB) that have serious negative implications to the broiler meat industry. The incidences of PSE and DPM have been known for several decades, and their prevalence, etiology and economic impact have been well discussed. However, other abnormalities such as SM, WS and WB conditions have been reported just for few years although these conditions have been known for some time. The newly emerging quality issues in broilers are mainly associated with the Pectoralis major muscles, and the incidences have been increased dramatically in some regions of the world in recent years. As high as 90% of the broilers are affected by the abnormalities, which are expected to cause from $200 million to $1 billion economic losses to the U.S. poultry industry per year. So, this review mainly discusses the histopathological characteristics and biochemical changes in the breast muscles with the emphasis on the newly emerging abnormalities (SM, WS, and WB) although other abnormalities are also discussed. The impacts of the anomalies on the nutritional, functional, mechanical and sensory quality of the meat and their implications to the poultry industry are discussed. PMID- 30479495 TI - Effects of Fat Reduction on the Stability, Microstructure, Rheological and Color Characteristics of White-Brined Cheese Emulsion with Different Emulsifying Salt Amounts. AB - Cheese emulsion is an intermediate product for the production of cheese powder and needs to be stable, homogeneous and pumpable characteristics to convey to the spray drier. This study was conducted to evaluate the effects of fat reduction and emulsifying salt (ES) amount in cheese emulsion systems on the physicochemical characteristics. Reduced-fat (RF) and full-fat (FF) white-brined cheese emulsions were produced with different dry matters (DM; 15%-25% excluding ES) and ES concentrations (0%-3% based on cheese weight). Stable cheese emulsion was obtained at lower DM in RF cheese emulsion than that of FF cheese emulsion. Reduction in the amount of ES resulted in instability of both emulsions. Apparent viscosity with pseudoplastic flow behavior significantly increased with the decrease of fat content in stable cheese emulsions. Microstructure of emulsions appeared to be related to the fat content, stability and degree of emulsification. Reduction of fat content caused to get less lightness and more greenness in color, whereas yellowness was significantly decreased by increase in the amount of ES. In conclusion, fat reduction resulted in higher viscosities of cheese emulsion due to inducing the increment of protein, and the addition amount of ES considered as very important factor to produce stable cheese emulsion without protein precipitation or cream separation. Therefore, for preparation of RF cheese emulsion using a variety of white-brined cheese, lower amounts of DM would be suggested in this study to obtain homogenous droplets in the atomizing process of spray drying. PMID- 30479494 TI - Prevalence, Serotype Diversity, Genotype and Antibiotic Resistance of Listeria monocytogenes Isolated from Carcasses and Human in Korea. AB - This study investigated the prevalence of Listeria monocytogenes in slaughterhouses, and determined serovars and genotypes, and antibiotic resistance of the isolates obtained from slaughterhouses and humans in Korea. Two hundred ninety samples were collected from feces (n=136), carcasses [n=140 (cattle: n=61, swine: n=79)], and washing water (n=14) in nine slaughterhouses. Eleven human isolates were obtained from hospitals and the Korea Center for Disease Control and Prevention. Listeria monocytogenes was enriched and identified, using polymerase chain reaction (PCR) and 16S rRNA sequencing. Serovars and presence of virulence genes were determined, and genetic correlations among the isolates were evaluated by the restriction digest patterns of AscI. Antibiotic resistance of L. monocytogenes isolates were examined against 12 different antibiotics. Of 290 slaughterhouse samples, 15 (5.17%) carcass samples were L. monocytogenes positive. Most L. monocytogenes isolates possessed all the virulence genes, while polymorphisms in the actA gene were found between carcass and human isolates. Serovars 1/2a (33.3%) and 1/2b (46.7%) were the most frequent in carcass isolates. Genetic correlations among the isolates from carcass and clinical isolates were grouped within serotypes, but there were low geographical correlations. Most L. monocytogenes isolates were antibiotic resistant, and some strains showed resistance to more than four antibiotics. These results indicate that L. monocytogenes are isolated from carcass and human in Korea, and they showed high risk serotypes and antibiotic resistance. Therefore, intensive attentions are necessary to be aware for the risk of L. monocytogenes in Korea. PMID- 30479496 TI - Comparative Genome Analysis and Evaluation of Probiotic Characteristics of Lactobacillus plantarum Strain JDFM LP11. AB - In the current study, the probiotic potential of approximately 250 strains of lactic acid bacteria (LAB) isolated from piglet fecal samples were investigated; among them Lactobacillus plantarum strain JDFM LP11, which possesses significant probiotic potential, with enhanced acid/bile tolerance, attachment to porcine intestinal epithelial cells (IPEC-J2), and antimicrobial activity. The genetic characteristics of strain JDFM LP11 were explored by performing whole genome sequencing (WGS) using a PacBio system. The circular draft genome have a total length of 3,206,883 bp and a total of 3,021 coding sequences were identified. Phylogenetically, three genes, possibly related to survival and metabolic activity in the porcine host, were identified. These genes encode p60, lichenan permease IIC component, and protein TsgA, which are a putative endopeptidase, a component of the phosphotransferase system (PTS), and a major facilitator in the gut environment, respectively. Our findings suggest that understanding the functional and genetic characteristics of L. plantarum strain JDFM LP11, with its candidate genes for gut health, could provide new opportunities and insights into applications in the animal food and feed additive industries. PMID- 30479497 TI - Evaluation of Cudrania tricuspidata Leaves on Antioxidant Activities and Physicochemical Properties of Pork Patties. AB - Characterization and utilization of the bioactive compounds from natural resources is one of the most concerns to maintain quality properties of foods, especially to prevent the oxidation of lipids in meat products. Phytochemical components and antioxidant activities of Cudrania tricuspidata (CT) leaves extracted using various solvents and their effects on physicochemical properties of pork patties during refrigerated storage were measured. The combined solvents of 80% ethanol, 80% methanol and pure double-distilled (dd)-water obtained the higher total phenolic compounds, flavonoids content, and antioxidant activities as compared to the pure solvent alone. Among the individual antioxidant components, catechin was the predominant polyphenol in CT leaves in all extracts. The addition of CT leaves extracts into pork patties showed high antioxidant activities since thiobarbituric acid-reactive substances (TBARS) values of added CT extracts were lower than those of the control (p<0.05). In conclusion, CT leaf phytochemical components displayed antioxidant activity that varied with the extract solvent used. CT extracts were superior to control in retarding lipid oxidation of pork patties, which was evident as reduced TBARS and peroxide values (POV). PMID- 30479498 TI - Effect of Egg Albumen, Vegetable Oil, Corn Bran, and Cooking Methods on Quality Characteristics of Chicken Nuggets Using Response Surface Methodology. AB - Response surface methodology was used to study the effect of egg albumen (5-15 g), vegetable oil (5-15 g), and corn bran (5-15 g) on sensory and textural (firmness and toughness) quality of chicken nuggets cooked by the oven, steam, and microwave methods. The egg albumen and vegetable oil had a positive linear effect but corn bran had a negative linear effect at p<0.01 on sensory overall acceptability scores of nuggets. Firmness and toughness scores were increased significantly (p<0.01) with the increase in corn bran level in the formulation. The optimum level of egg albumen, vegetable oil, and corn bran were obtained and validated. Cooking methods also affected the sensory and textural quality of nuggets. Steam cooked nuggets had higher values of sensory scores than oven and microwave cooked nuggets. Oven cooked nuggets showed higher values of firmness and toughness than steam and microwave cooked nuggets. Results of this study suggest that emulsion based meat products can be enriched with dietary fiber source like corn bran without compromising the sensory and textural quality of the products. PMID- 30479499 TI - Quality and Lactic Acid Bacteria Diversity of Pork Salami Containing Kimchi Powder. AB - We investigated the quality properties and bacteria diversity of pork salami containing homemade kimchi powder (KP). Pork salamis were manufactured with commercial starter culture (control), and 1% KP (KP1), 3% KP (KP3), and 5% KP (KP5). The salami was fermented and aged for 2 days and 56 days, respectively. The pH and AW values of salamis with KP were significantly lower than that of the control (p<0.05). The 2-thiobarbituric acid reactive substance values of all salamis with KP increased but were below 0.2 mg MDA/kg. Salamis with KP, decreased the L* value, but increased the a* and b* values (p<0.05). The Lactobacillus count was significantly higher in the salamis with KP than in the control by day 14 (p<0.05). The number of Leuconostoc was higher in salamis with KP than in the control and was the highest in salamis in KP1. The KP1 protected lipid oxidation and showed low TBARS value of pork salami compared to the control. This study demonstrates that KP can improve pork salami properties and can serve as a potential natural compounds for fermented meat prodcuts like Metzgerei. PMID- 30479500 TI - Effect of Buckwheat (Fagopyrum esculentum) Powder on the Physicochemical and Sensory Properties of Emulsion-type Sausage. AB - Various amounts of buckwheat powder (0%, 1%, 2%, and 3%) were added to emulsion type pork sausages. The effects of buckwheat powder on the physicochemical characteristics of the emulsion type sausages, including proximate composition, cooking yield, viscosity, pH, instrumental color, texture profile analysis (TPA), and sensory evaluation, were determined. Increased levels of added buckwheat powder led to higher moisture (p<0.05), ash content (p<0.05 or >0.05), and cooking yield (p<0.05). However, the protein and fat contents of the sausage samples were lower (p<0.05) with higher levels of added buckwheat powder. The instrumental color and pH values were affected by the addition of buckwheat powder, which has a pH of 6.1 and associated color coordinates of L*=75.0, a*=1.3, and b*=8.7. Meat batter with 3% buckwheat powder was shown the highest (p<0.05) viscosity indicating great formation of emulsion. There were no significant differences in the TPA among the treated samples. The viscosity value increased with increasing cooking yield in the batter (r2=0.7283) i.e. the correlation coefficient between the two measurements was very high and positive. For sensory traits except for tenderness, the highest scores (p<0.05) was detected on sausages with 3% added buckwheat powder by a panel. These results suggest that the addition of 3% buckwheat powder to emulsion-type sausages produces a more beneficial meat product, with a lower fat content, greater formation of emulsion and no adverse effects on sensory properties. PMID- 30479501 TI - Effect of Ground Chopi (Zanthoxylum piperitum) on Physicochemical Traits and Microbial Community of Chicken Summer Sausage during Manufacture. AB - Changes in microbial community and physicochemical traits of chicken summer sausage made from spent layer thigh added with different level (0%, 0.1%, 0.3%, and 0.5% w/w) of ground chopi (Zanthoxylum piperitum) during manufacture were analyzed. The microbial community was profiled and analyzed by sequencing 16S rRNA gene using Illumina MiSeq. Samples were taken from raw sausage batter, after 15 h of fermentation, 8 h of cooking including cooling down, and 7 d of drying. The final pH of the sausage was reduced by the addition of ground chopi. However, no clear effect on water activity was observed. Ground chopi inhibited the development of red curing color after fermentation as it exhibited antimicrobial effect. However, the effect on species richness and microbial composition after cooking was unclear. Ground chopi delayed lipid oxidation during manufacture and the effect was dependent on the addition level. Fermentation reduced the species richness with a dominancy of lactic acid bacteria. The profile of microbiota in the raw batter was different from other stages, while the closest relationship was observed after cooking and drying. Proteobacteria was predominant, followed by Firmicutes and Bacteroidetes in raw samples. Firmicutes became dominating after fermentation and so forth, whereas other predominant phylum decreased. At genus level, unclassified Lactobacillales was the most abundant group found after fermentation and so forth. Therefore, the overall microbial composition aspects were mainly controlled during fermentation by the abundance of lactic acid bacteria, while bacterial counts and lipid oxidation were controlled by cooking and the addition of ground chopi. PMID- 30479502 TI - Comparison of Meat Quality Characteristics of Wet- and Dry-aging Pork Belly and Shoulder Blade. AB - The physicochemical characteristics and oxidative stability of wet-aged and dry aged pork cuts were investigated at different aging periods (1, 7, 14 and 21 d). Samples were assigned into four groups in terms of shoulder blade-wet aging (SW), shoulder blade-dry aging (SD), belly-wet aging (BW), and belly-dry aging (BD). SD showed significantly higher pH at 21 d of aging than the other samples. Wet-aged cuts had significantly higher released water (RW) %, lightness (L*) and shear force compared to the dry-aged meats. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis showed greater degradation of proteins for dry-aged cuts than the wet-aged cuts. At the end of aging, wet-aged cuts showed significantly lower thiobarbituric acid-reactive substances (TBARS) value than the dry-aged samples, indicating higher oxidative stability for wet-aged pork cuts. However, dry-aging led to higher degradation of proteins resulting in increased water-holding capacity (WHC) and decreased shear force value. PMID- 30479503 TI - Effects of Deep Freezing Temperature for Long-term Storage on Quality Characteristics and Freshness of Lamb Meat. AB - This study investigated the effects of deep freezing and storage temperature (-50 degrees C, -60 degrees C, and -80 degrees C) on the quality and freshness of lamb. To compare the qualities of deep frozen and stored lamb, fresh control and normal freezing conditions (-18 degrees C) were adopted. As quality and freshness parameters, drip loss (thawing loss and cooking loss), water-holding capacity (WHC), texture profile analysis (TPA), thiobarbituric acid reactive substances (TBARS), and total volatile basic nitrogen (TVBN) were evaluated during 5 months of storage. Temperature influenced the drip loss and WHC, and deep freezing minimized the moisture loss during frozen storage compared to the normal freezing condition. Lamb frozen and stored at deep freezing temperature showed better tenderness than that stored in normal freezing conditions. In particular, lamb frozen at lower than -60 degrees C exhibited fresh lamb-like tenderness. Regardless of temperature, evidence of lipid oxidation was not found in any frozen lamb after 5 months, while TVBN was dependent on the applied temperature. Therefore, this study demonstrated that deep freezing could potentially be used to maintain freshness of lamb for 5 months. From the quality and economic aspects, the freezing and storage condition of -60 degrees C is estimated as the optimum condition for frozen lamb. PMID- 30479504 TI - Effects of Pre-cooking Methods on Quality Characteristics of Reheated Marinated Pork Loin. AB - We evaluated the effects of pre-cooking methods on the quality of reheated marinated pork loin. Frozen marinated pork loins cooked using various methods (boiling, grilling, pan frying, infrared cooking, and superheated steam cooking) were reheated in a microwave, and their pH, color, cooking loss, re-heating loss, total loss, thiobarbituric acid reactive substance (TBARS) value, sensory properties, and shear force were determined. Although all parameters varied with different cooking methods, lightness values and TBARS values showed the tendency to decrease and increase, respectively, after reheating. Superheated steam-cooked samples showed the lowest values of cooking loss, total loss, TBARS value, and shear force (p<0.05) and the highest lightness, redness, and yellowssness values and juiciness, chewiness, and overall acceptability scores (p<0.05). These results show that pre-cooking with superheated steam maintains the quality characteristics of marinated pork loin upon reheating. Therefore, pre-cooking with superheated steam may be beneficial for the commercial distribution of frozen cooked marinated pork loin. PMID- 30479505 TI - Quality Characteristics of Functional Fermented Sausages Added with Encapsulated Probiotic Bifidobacterium longum KACC 91563. AB - The present study aimed at evaluating the utilization possibility of encapsulated probiotic Bifidobacterium longum for production of functional fermented sausages. The B. longum isolated from the feces samples of healthy Korean infants encapsulated with glycerol as a cryprotectant was used for fermented sausages production as a functional bacterial ingredient, and its effect was also compared with those inoculated with commercial starter culture (CSC). Results showed that most inoculated encapsulated B. longum (initial count, 5.88 Log CFU/g) could survive after 4 days fermentation (5.40 Log CFU/g), and approximately a half (2.83 Log CFU/g) of them survived in the products after 22 days of ripening. The products inoculated with encapsulated B. longum presented the lowest lipid oxidation level, while had higher total unsaturated fatty acid content and more desirable n-6/n-3 fatty acids than those inoculated with CSC or non-inoculated control. Moreover, the odor and taste scores in the samples made with B. longum were comparable to those in the treatment with CSC. The inoculation with the B. longum had no effects on the biogenic amine contents as well as did not cause defects in color or texture of the final products. Thus, the encapsulation could preserve the probiotic B. longum in the meat mixture, and the encapsulated B. longum could be used as a functional ingredient for production of healthier fermented meat products. PMID- 30479506 TI - Physicochemical Properties of Liquid Infant Formula Stored at Different Temperatures. AB - Changes in the physicochemical properties of ready-to-feed liquid infant formula (LIF) stored at different temperatures (10, 20, 30, and 40 degrees C) for 6 mon, focusing on 5-hydroxymethylfurfural (HMF) content, color, pH, fat globule size distribution, and rheological properties were determined. The HMF content increased with storage time, and LIF stored at 40 degrees C had a higher HMF content than that of LIF stored at 10 degrees C. The lightness (L*) decreased while redness (a*) and yellowness (b*) increased with increasing HMF content. The fat globule size and pH of LIF stored at 10 degrees C did not change. However, in the case of LIF stored at 30 degrees C and 40 degrees C, the fat globule size increased and the pH decreased during storage for 6 mon. LIF stored at 40 degrees C had a higher apparent viscosity (etaa,10) than that of LIF stored at 10 degrees C, and the shear-thinning behavior of LIF stored at higher temperature was stronger than that of LIF stored at low temperature. The physicochemical changes of LIF during storage were accelerated by Maillard reaction (MR) at higher storage temperatures. Therefore, even if LIF is aseptically manufactured, we recommend that sterilized LIF should be stored at low temperature in order to minimize quality changes during storage. PMID- 30479508 TI - Utilization of the Crust from Dry-aged Beef to Enhance Flavor of Beef Patties. AB - The crust that inevitably forms on dry-aged beef is usually trimmed and discarded before sale. The aim of this study was to explore methods for utilizing this crust in processed meat products. Four sirloins were dry-aged for 28 d at 4C (75% relative humidity). The crust obtained from the surface of the sirloins after completion of dry aging was lyophilized. Patties were prepared without added crust (control) or with 5% w/w crust, aerobically packaged, and stored at 4C for 7 d. Electronic nose analysis indicated that the volatile profile differed significantly between the patties with and without crust. Compared to the control patties, patties containing crust had higher flavor, tenderness, juiciness, and acceptability scores in a sensory panel evaluation (all p<0.05). In addition, patties with crust were less hard, gummy, and chewy than the control patties after 3 and 7 d of storage (all p<0.05). The number of total aerobic bacteria was higher in raw patties with crust than in the control patties during the storage (p<0.05). However, no pathogens were detected. 2-Thiobarbituric acid reactive substance values of patties containing crust were significantly lower than those of control patties after 2 and 6 d of storage (both p<0.05). Thus, crust from dry aged beef can enhance the flavor by providing beefy and palatable flavor without a long period of dry aging. PMID- 30479507 TI - Isolation and Characterization of an Anti-listerial Bacteriocin from Leuconostoc lactis SD501. AB - Although bacteriocins with anti-listerial activity have been isolated from a wide variety of lactic acid bacteria, little is known about those from Leuconostoc lactis, a heterofermentative bacterium that produces diacetyl and exopolysaccharides in dairy foods. In this study, an anti-listerial bacteriocin was isolated from Leuc. lactis SD501 and characterized. It was particularly potent against Listeria monocytogenes and also inhibited Enterococcus faecalis. Anti-listerial activity reached a maximum during the early stationary phase and then decreased gradually. The anti-listerial substance was sensitive to proteinase K and alpha-chymotrypsin, confirming its proteinaceous nature. Its activity remained stable at pH values ranging from 1 to 10. In addition, it was strongly resistant to high temperatures, retaining its activity even after incubation for 15 min at 121C. The apparent molecular mass of the partially purified anti-listerial bacteriocin was approximately 7 kDa. The characteristics of the SD501 bacteriocin, including its small molecular size (<10 kDa), strong anti-listerial activity, wide pH stability and good thermostability, indicate its classification as a Class IIa bacteriocin. PMID- 30479509 TI - The Effects of Natural Antioxidants on Protein Oxidation, Lipid Oxidation, Color, and Sensory Attributes of Beef Patties during Cold Storage at 4C. AB - This study aimed to investigate the use of golden thread extract (GTE), clove extract (CE), and commercially available nitrite for retarding lipid and protein oxidation and for maintaining color stability and sensory attributes in beef patties stored at 4C. GTE, CE, and nitrite treatment samples were found to be efficient in retarding lipid oxidation as all three treatments resulted in low thiobarbituric acid reactive substance (TBARS) content (p<0.05). By using GTE, CE, and nitrite into beef patties, protein oxidation was not developed. Incorporation of GTE and CE into beef patties maintained color stability by protecting against the decrease of L*, a*, b*, chroma, and hue angle values and exhibited significant influence on sensory characteristics, including color and odor of beef patties (p<0.05). Compared to commercially available nitrite, GTE and CE were more effective as antioxidants for inhibiting lipid oxidation, and preserving color stability of fresh beef patties. The study indicated that GTE and CE could be utilized efficiently to extend the shelf life of beef patties. PMID- 30479510 TI - Risk Assessment for Salmonellosis in Chicken in South Korea: The Effect of Salmonella Concentration in Chicken at Retail. AB - Salmonellosis caused by chicken consumption has been a critical issue in food safety worldwide, including in Korea. The probability of illness from consumption of chicken was simulated in study, based on the recipe of Dakgalbi, a commonly eaten chicken dish in Korea. Additionally, the processing stage at slaughterhouses to decrease Salmonella concentration in broilers was modeled to explore its effect on the likelihood of illness. A Monte Carlo simulation model was created using @RISK. Prevalence of Salmonella in chickens at the retail stage was found to be predominantly important in determining the probability of illness. Other than the prevalence, cooking temperature was found to have the largest impact on the probability of illness. The results also demonstrated that, although chlorination is a powerful tool for decreasing the Salmonella concentration in chicken, this effect did not last long and was negated by the following stages. This study analyzes the effects of variables of the retail-to table pathway on the likelihood of salmonellosis in broiler consumption, and also evaluates the processing step used to decrease the contamination level of Salmonella in broilers at slaughterhouses. According to the results, we suggest that methods to decrease the contamination level of Salmonella such as chlorination had little effect on decreasing the probability of illness. Overall, these results suggest that preventing contamination of broiler with Salmonella must be a top priority and that methods to reduce the concentration of Salmonella in broilers at slaughterhouses hardly contribute to safe consumption of Salmonella-contaminated chicken. PMID- 30479511 TI - Prevalence of Antibiotic Residues and Antibiotic Resistance in Isolates of Chicken Meat in Korea. AB - The aim of study was to investigate the correlation between the level of 17 antibiotic residues and 6 antibiotic resistances of Escherichia coli isolates in chicken meats. A total of 58 chicken meats were collected from retail grocery stores in five provinces in Korea. The total detection rate of antibiotic residues was 45% (26 out of 58). Ten out of 17 antibiotics were detected in chicken meats. None of the antibiotics exceeded the maximum residue level (MRLs) in chicken established by the Ministry of Food and Drug Safety (MFDS). The most detected antibiotics were amoxicillin (15.5%), followed by enrofloxacin (12.1%) and sulfamethoxazole (10.3%). In a total of 58 chicken meats, 51 E. coli strains were isolated. E. coli isolates showed the highest resistance to ampicillin (75%), followed by tetracycline (69%), ciprofloxacin (65%), trimethoprim/ sulfamethoxazole (41%), ceftiofur (22%), and amoxicillin/clavulanic acid (12%). The results of study showed basic information on relationship between antibiotic residue and resistance for 6 compounds in 13 chicken samples. Further investigation on the antibiotic resistance patterns of various bacteria species is needed to improve food safety. PMID- 30479512 TI - Antimicrobial Activity of a Bacteriocin Produced by Enterococcus faecalis KT11 against Some Pathogens and Antibiotic-Resistant Bacteria. AB - In this study, the antimicrobial activity of a bacteriocin produced by Enterococcus faecalis KT11, isolated from traditional Kargi Tulum cheese, was determined, and bacteriocin KT11 was partially characterized. The results showed that bacteriocin KT11 was antagonistically effective against various Gram positive and Gram-negative test bacteria, including vancomycin- and/or methicillin-resistant bacteria. The activity of bacteriocin KT11 was completely abolished after treatment with proteolytic enzymes (proteinase K, alpha chymotrypsin, protease and trypsin), which demonstrates the proteinaceous nature of this bacteriocin. Additionally, bacteriocin KT11 remained stable at pH values ranging from 2 to 11 and after autoclaving at 121C for 30 min. In addition, the activity of bacteriocin KT11 was stable after treatment with several surfactants (EDTA, SDS, Triton X-100, Tween 80 and urea) and organic solvents (chloroform, propanol, methanol, ethyl alcohol, acetone, hexane and ethyl ether). Cell-free supernatant of E. faecalis KT11 was subjected to ammonium sulfate precipitation and then desalted by using a 3.5-kDa cut-off dialysis membrane. The bacteriocin activity was determined to be 711 AU/mL in the dialysate. After tricine-SDS-PAGE analysis, one peptide band, which had a molecular weight of ~3.5 kDa, exhibited antimicrobial activity. Because the bacteriocin KT11, isolated from E. faecalis KT11, exhibits a broad antimicrobial spectrum, heat stability and stability over a wide pH range, this bacteriocin can be used as a potential bio-preservative in foods. Additionally, bacteriocin KT11 alone or in combination with conventional antibiotics may provide a therapeutic option for the treatment of multidrug resistant clinical pathogens after further in vivo studies. PMID- 30479513 TI - The Influence of Hen Aging on Eggshell Ultrastructure and Shell Mineral Components. AB - The eggshell, which is a complex and highly ordered structure, is very important factor for food safety and egg marketing. This study investigated the changes in eggshell structure and shell components in relationship to hen age. For this study, we examined the histological change of the endometrium of the 30-, 60-, and 72-wk-old commercial layers, and analyzed the ultrastructure and ionic composition of their eggshells. The results showed that histological deformation, fibrosis, atrophy and elimination of micro-villi in the uterus endometrium were found through microscopic observation that was associated with increasing hen age. Concentration of blood-ion components such as Ca2+, Na+, K+, and Cl- ions did not change with age. Along with the results from the ultrastructure analysis of the eggshell, the palisade layer ratio and the density of mammillary knobs were significantly decreased in older hens. In addition, the type B mammillary knobs were frequently observed with increasing hen age. In the mineral element assay from the eggshell, Ca2+, S2-, and Co2+ significantly decreased with increasing hen age, whereas Na+, K+, and V2+ significantly increased. Therefore, the damages of endometrial tissue inhibit the processes of ion transmission and the crystallization of eggshell formation, resulting in a large and non-uniform mammillary knob formation. This means the conditions of endometrial cells affect the formation of the eggshell structure. In conclusion, hen aging causes the weakness of the eggshell and degrades the eggshell quality. PMID- 30479514 TI - Effects of Intensive Alfalfa Feeding on Meat Quality and Fatty Acid Profile of Korean Native Black Goats. AB - The aim of this study was to determine meat quality characteristics and fatty acid composition of Korean native black goats (KNBG) finished on intensive feeding of alfalfa (ALF) and conventional feeding of commercial concentrate pellets (CCP) with low-energy common grasses. Ten KNBG (12 months old) were divided into two groups and subjected to either ALF or CCP treatments. The goats were slaughtered after 6 months of feeding with experimental diets to investigate meat quality characteristics and fatty acid compositions of longissimus lumborum muscle. There were no significant differences in proximate chemical composition, collagen, or myoglobin content between ALF and CCP groups of goats. Meat color, water-holding capacity, or tenderness was not significantly different between the two groups either. However, proportions of monounsaturated fatty acids and polyunsaturated fatty acids were significantly (p<0.05) different between the two groups. The proportion of oleic acid was significantly (p<0.05) higher in ALF goat whereas proportion of linoleic and arachidonic acids were significantly (p<0.05) higher in CCP goat. Results suggest that KNBG finished with intensive feeding of alfalfa could produce goat meat with desirable fatty acids for human diets. PMID- 30479515 TI - The Dry-aging and Heating Effects on Protein Characteristics of Beef Longissiumus Dorsi. AB - The aim of this study was to investigate the effects of dry-aging (DA) and the cooking process on the myofibril protein functionalities and in vitro digestibility of proteins in beef loin. Six sirloins from beef were dry-aged for 28 d, and the control group (n=6) was analyzed 2 d postmortem for this study. Dimensional changes (reduction of thickness and surface shrinkage) after cooking were significantly greater in the control group than the DA group, whereas the shear force of the DA group was significantly lower than that of the control. Effect of cooking on aggregation, hydrophobicity, and in vitro digestibility were significantly higher in the DA group than in the control. After cooking, the protein in DA sirloins was more oxidized than in the control samples. According to the sodium dodecyl sulfate-polyacrylamide gel electrophoresis result, the low molecular weight bands (below 17 kDa) increased in the DA group, finding that the protein characteristics of dry-aged beef was affected by cooking. PMID- 30479516 TI - Nondestructive Estimation of Lean Meat Yield of South Korean Pig Carcasses Using Machine Vision Technique. AB - In this paper, we report the development of a nondestructive prediction model for lean meat percentage (LMP) in Korean pig carcasses and in the major cuts using a machine vision technique. A popular vision system in the meat industry, the VCS2000 was installed in a modern Korean slaughterhouse, and the images of half carcasses were captured using three cameras from 175 selected pork carcasses (86 castrated males and 89 females). The imaged carcasses were divided into calibration (n=135) and validation (n=39) sets and a multilinear regression (MLR) analysis was utilized to develop the prediction equation from the calibration set. The efficiency of the prediction equation was then evaluated by an independent validation set. We found that the prediction equation-developed to estimate LMP in whole carcasses based on six variables-was characterized by a coefficient of determination (Rv 2 ) value of 0.77 (root-mean square error [RMSEV] of 2.12%). In addition, the predicted LMP values for the major cuts: ham, belly, and shoulder exhibited Rv 2 values>=0.8 (0.73 for loin parts) with low RMSEV values. However, lower accuracy (Rv (2) =0.67) was achieved for tenderloin cuts. These results indicate that the LMP in Korean pig carcasses and major cuts can be predicted successfully using the VCS2000-based prediction equation developed here. The ultimate advantages of this technique are compatibility and speed, as the VCS2000 imaging system can be installed in any slaughterhouse with minor modifications to facilitate the on-line and real-time prediction of LMP in pig carcasses. PMID- 30479517 TI - Comparison of Physicochemical Properties between Standard and Sow Pork. AB - This study was conducted to investigate the dressing percentage and physicochemical characteristics, such as fatty acid composition, water holding capacity (WHC), shear force, meat color, cooking loss, and sensory evaluation, of experimental pork obtained from a total of 12 standard pigs and sows. The water content of tenderloin (73.38%) was the highest in standard pork (p<0.05). A statistically significant difference in crude protein content was shown between standard pork and sow pork (p<0.05). There were significant differences between standard pork and sow pork in shear forces of loin and tenderloin (p<0.01). There was a significant difference in WHC between standard pork and sow pork in loin, tenderloin, and hind legs (p<0.05). The CIE L* and CIE b* values of standard loin were significantly higher than those of sow loin (p<0.05). The CIE a* values of sow loin were significantly higher than those of standard loin (p<0.05). The contents of arachidonic acid for standard pork and sow pork were 0.33% and 0.84%, respectively (p<0.05). However, there was no difference in the total content of unsaturated fatty acid between the two groups. There were no significant differences between standard pork and sow pork after sensory evaluation, except for color and tenderness. The overall acceptability of standard pork was significantly higher than that of sow pork (p<0.05). PMID- 30479518 TI - Effects of Natural Between-Days Variation in Sleep on Elite Athletes' Psychomotor Vigilance and Sport-Specific Measures of Performance. AB - Performance capacity in athletes depends on the ability to recover from past exercise. While evidence suggests that athletic performance decreases following (partial) sleep deprivation and increases following sleep extension, it is unclear to which extent natural variation in sleep impacts performance. Sleep quantity and, for the first time, sleep stages were assessed among 98 elite athletes on three non-consecutive nights within a 7-day monitoring period, along with performance tests that were taken on standardized times each following morning. Performance assessment included psychomotor performance (10-minute psychomotor vigilance task) and sport-specific tests of fine (e.g., accuracy) and gross motor skills (e.g., endurance, power). Mixed-effects models were employed to assess the effect of sleep quantity (total sleep time (TST), sleep onset latency (SOL), wake after sleep onset, sleep efficiency) and sleep stage duration (light, deep, REM) on performance. Average TST was 7:30 +/- 1:05 hours, with a mean variation of 57 minutes across days. Longer TSTs were associated with faster reaction times (p = 0.04). Analyses indicated small and inconsistent effects of sleep quantity (TST, SOL) and sleep staging (light sleep) on gross motor performance, and no effects on fine motor skill performance. Results indicate that natural variation in sleep quantity impacts psychomotor vigilance to a greater extent than athletic performance. Small or absent effects can be a consequence of the rather small variation in non-manipulated sleep. It is suggested that one night of compromised sleep may not be immediately problematic, but that more extreme sleep loss or accumulated sleep debt may have more severe consequences. PMID- 30479519 TI - The Addition of Transcutaneous Electrical Nerve Stimulation with Roller Massage Alone or in Combination Did Not Increase Pain Tolerance or Range of Motion. AB - Roller massage (RM) can be painful and induce muscle activity during application. Acute increases in pain pressure threshold (PPT) and range of motion (ROM) have been previously reported following RM. It is unclear whether the RM-induced increases in PPT and ROM can be attributed to changes in neural or muscle responses. To help determine if neural pain pathways are affected by roller massage, transcutaneous electrical nerve stimulation (TENS) was utilized as a form of electroanalgesia during RM with PPT and ROM tested on the affected and contralateral quadriceps. The purpose of this study was to evaluate in both quadriceps, the effect of brief intense TENS on PPT and ROM following unilateral RM of the quadriceps. A randomized within subjects' design was used to examine local and non-local effects of TENS and roller massage versus a control condition (rolling without TENS application). Four 30s bouts of roller massage of the dominant quadriceps were implemented with 30s of rest. The researcher applied the RM using a constant pressure device with approximately 70% of the maximum tolerable load. Perceived pain was monitored using a visual analog scale (VAS) during RM. Ipsilateral and contralateral quadriceps ROM and PPT were measured immediately following RM. Significant main effects for time showed increased PPT and ROM in both the treated and contralateral quadriceps, with no significant main effects for intervention or interactions for intervention and time. Moderate to large effect sizes and minimal clinically important differences (MCID) were detected when comparing baseline to pre- and post-tests respectively. VAS scores were significantly (main effect for intervention) and near significantly (interactions) reduced with MCID when TENS was applied during rolling. The addition of TENS to rolling did not increase PPT or ROM in the affected or contralateral quadriceps, likely due to a repeated testing effect. PMID- 30479520 TI - The Post-Exercise Inflammatory Response to Repeated-Sprint Running in Hypoxia. AB - This study investigated the acute inflammatory response to a repeat-sprint training session in hypoxia. Eleven amateur team-sport athletes completed a repeat-sprint training in hypoxia (RSH) protocol (4 sets of 4x4-s running sprints) in both normoxia and normobaric hypoxia (FiO2 0.145 to simulate an altitude of 3000 m) on separate days. Participants provided venous blood samples prior to (PRE), immediately after (POST), and 3 h after (3 h) completion of the protocol, and capillary blood lactate samples were taken upon arrival, at PRE, and at POST. Distance was recorded for each sprint. Venous blood samples were analysed to determine plasma concentrations of cytokines IL-1beta, IL-1ra, IL-6, IL-8, IL-10, and TNFalpha. There was no interaction or main effect of condition for any cytokine (p > 0.05). However, time effects indicated that IL-10 was decreased by an average of 19% across the two experimental trials at 3 h compared to POST (p = 0.04), IL-6 increased by 55% from PRE to POST (p = 0.03) then decreased by 43% from POST to 3 h (p = 0.02), and IL-8 decreased by 30% from PRE to POST (p = 0.04) and was further reduced at 3 h compared to POST (by an additional 23%; p = 0.02). A time * condition interaction (p = 0.03) indicated that lactate was higher in hypoxia. There was no interaction effect or effect of condition for sprint distance (p > 0.05). These results suggest that team-sport athletes can perform a RSH session without increasing inflammation when compared to the same training session performed in normoxia. PMID- 30479521 TI - Establishing the Reliability and Limits of Meaningful Change of Lower Limb Strength and Power Measures during Seated Leg Press in Elite Soccer Players. AB - Measurement of lower limb strength, power and asymmetries of soccer players is important for monitoring physical development and injury risk. The aim of the present study was to establish the reliability and limits of meaningful change of single and double leg maximal strength, power and bilateral imbalance measures in elite soccer players using a pneumatic resistance based seated leg press. Thirteen participants undertook an incremental resistance leg press test on three separate testing days within a seven day period. Paired t-tests established no significant differences (p > 0.156) between consecutive tests, whilst 'good' reliability (intraclass correlation coefficient-ICC >0.762) and acceptable typical percentage errors (< 6.9%) were observed for maximal resistance, velocity and force pushed as well as average and peak power outputs. Imbalance variables accounting for left and right leg average power output across all repetitions were established as the most reliable imbalance variables, with 'good' reliability (ICC > 0.874) and absolute typical error values of 2.1%. Imbalance variables calculated using peak power output or average power output from the last 4 repetitions resulted in weaker reliability (ICC < 0.657) and significant differences between tests, and therefore were considered less suitable for applied use. Subsequently, to better inform the practitioner, limits of meaningful change were calculated for all strength, power and imbalance variables. The current study shows that lower limb strength, and power output variables and average imbalance measures of soccer players assessed through a seated leg press protocol show acceptable levels of reliability, and provides practitioners with limits of meaningful change around parameters to better evaluate test results. PMID- 30479522 TI - Youth Australian Footballers Experience Similar Impact Forces to the Head as Junior- and Senior-League Players: A Prospective Study of Kinematic Measurements. AB - The aims of this study were to investigate the frequency, magnitude, and distribution of head impacts sustained by youth AF players over a season of games and report subjective descriptions on the mechanism-of-injury and sign and symptoms experienced. A prospective observational cohort study with participants (n = 19) (age range 13-14 yr., mean +/- SD 13.9 +/- 0.3 yr.) wearing a wireless impact measuring device behind their right ear over the mastoid process prior to game participation. Participants completed an individual post-game logbook providing feedback responses on recalling having a direct hit to their head with another player or the surface. Players experienced a mean (SD) of 5 (+/-4) impacts per-player per-game. The peak linear rotation (PLA) median, (95th percentiles) were 15.2g (45.8g). The median (95th percentile) peak rotational acceleration (PRA) were 183,117 deg/s2 (594,272 deg/s2). Median (95th percentile) Head Impact Telemetry Severity profile were 15.1 (46.1) and Risk Weighted Exposure Combined Probability were 0.0012 (0.7062). Twelve participants reported sustaining a head impact. Players reporting a head impact had a faster mean impact duration (t(25) = 2.4; p = 0.0025) and had a lower median PLA(g) (F(23,2) = 845.5; p = 0.0012) than those who did not report a head impact. These results show similar measurements to the older junior- (aged 17-19) and senior-league (20+) players. Furthermore, players who reported sustaining a direct or indirect impact during games had similar measurements to those who did not, thus highlighting the difficulty of concussion recognition, at least with youth. Future research may need to establish the relationship between concussion-like symptoms in the absence of an impact and in relation to concussion evaluation assessments such as the King-Devick and SCAT5. PMID- 30479524 TI - Positional Differences in the Most Demanding Passages of Play in Football Competition. AB - The aim of this investigation was to determine the position and duration specific activity of the most demanding passages of play in football players. Global positioning system data were collected from twenty-three football players across a competitive season. A total of 605 individual match files were analysed. Players were categorised based on positional groups; full-back (FB), central defender (CD), midfielder (MF), wide midfielders (WMF) and forwards (FW). The most demanding passage of a match play was analysed using a rolling average method, where maximal values were calculated for four different time durations (1', 3', 5' and 10') using distance (m.min-1), high metabolic load distance (HMLD) and average metabolic power (AMP) as variables of interest. Using distance as the criterion variable, MF and WMF positions covered greater distance, and fewer sprinting meters (>7.0 m.s-1, m.min-1). With HMLD as the criterion variable, the values for WMF and MF positions were higher than the CD and FW positions. The MF and WMF positions performed more high-intensity accelerations and decelerations when the criterion variable was AMP. These results provide an understanding of the most demanding passages of play to inform training practices for specific football playing positions. PMID- 30479523 TI - Monitoring Heart Rate Variability Before and After a Marathon in an Elite Wheelchair Athlete: A Case Study. AB - The purpose of this study was to analyze heart rate variability (HRV) oscillations before and after a marathon which involved trans-meridian air travel and substantial time zone differences in a professional wheelchair athlete with Charcot-Marie-Tooth (CMT) disease. The natural logarithm of the root mean square difference between adjacent normal R-R intervals (Ln rMSSD) was measured daily on the days before, including and following the race. Relative to baseline, small ( 3.8 - -4.6%) reductions in LnRMSSD were observed following relocation and on race day, indicating only minor effects of travel on cardiac-autonomic activity. On the morning following the marathon, a 23.1% reduction in Ln rMSSD was observed, which returned to baseline by 48 h. The race time set by the athlete was the world-leading time in his class. This case study showed that Ln rMSSD responses to marathon in an elite wheelchair athlete with CMT was similar to those previously reported among unrestricted endurance athletes. PMID- 30479525 TI - Bioelectrical Impedance Vector Analysis (BIVA) and Body Mass Changes in an Ultra Endurance Triathlon Event. AB - This study aimed to provide the first description of the whole-body bioimpedance vector of nine non-professional triathletes, and to assess body mass (BM) and vector variations evoked by an ultra-endurance triathlon event. Anthropometric and bioelectrical assessments were performed before (PRE), after (POST), and 48 hours following the race (POST48h). Bioimpedance vector analysis (BIVA) showed triathletes' vectors placed to the left of the major axis and mostly outside the 50% tolerance ellipse of the reference population. Vector migration in POST indicated dehydration, paralleled by a decrease in BM (p = 0.0001). Increased hydration status from POST to POST48h was suggested by a reversed vector migration and increased BM (p = 0.0001). Compared to PRE, POST48h values reflected fluid retention by changes in BIVA, while BM was still lower (p = 0.0001). Racing time was positively related to basal resistance -R/h- (r = 0.68; p = 0.04) and bioimpedance -Z/h- (r = 0.68; p = 0.045). Besides, basal R/h and Z/h were positively related to PRE-to-POST changes of R/h and Z/h (r = 0.80; p = 0.009). PRE-to-POST changes of R/h and Z/h were positively related to racing time (r = 0.80, p = 0.01) and internal workload (r = 0.80, p <= 0.02). Notwithstanding the lack of significant correlation between BM and bioelectrical parameters, the vector's behavior was explained from a multifactorial perspective (including BM variations) by using multiple regression analysis. On the other hand, BM changes were not related to racing time, internal workload or energy deficit (ranges: r = - 0.46 to 0.65; p = 0.06 to 0.98). In conclusion, these triathletes exhibit a specific bioelectrical distribution. Furthermore, vector migration was consistent with fluid loss induced by the event. Finally, vector analysis seems to provide additional information about hydration changes 48h after the event in comparison with BM alone. PMID- 30479526 TI - The Effects of Exercise Training and High Triglyceride Diet in an Estrogen Depleted Rat Model: The Role of the Heme Oxygenase System and Inflammatory Processes in Cardiovascular Risk. AB - Cardiovascular morbidity and mortality of premenopausal women are significantly lower compared to men of similar age. However, this protective effect evidently decreases after the onset of menopause. We hypothesized that physical exercise could be a potential therapeutic strategy to improve inflammatory processes and cardiovascular antioxidant homeostasis, which can be affected by the loss of estrogen and the adverse environmental factors, such as overnutrition. Ovariectomized (OVX, n= 40) and sham-operated (SO, n= 40) female Wistar rats were randomized to exercising (R) and non-exercising (NR) groups. Feeding parameters were chosen to make a standard chow (CTRL) or a high triglyceride diet (HT) for 12 weeks. Aortic and cardiac heme oxygenase (HO) activity and HO-1 concentrations significantly decreased in all of the NR OVX and SO HT groups. However, the 12 week physical exercise was found to improve HO-1 values. Plasma IL-6 concentrations were higher in the NR OVX animals and rats fed HT diet compared to SO CTRL rats. TNF-alpha concentrations were significantly higher in the NR OVX groups. 12 weeks of exercise significantly reduced the concentrations of both TNF alpha and IL-6 compared to the NR counterparts. The activity of myeloperoxidase enzyme (MPO) was significantly increased as a result of OVX and HT diet, however voluntary wheel-running exercise restored the elevated values. Our results show that estrogen deficiency and HT diet caused a significant decrease in the activity and concentration of HO enzyme, as well as the concentrations of TNF alpha, IL-6, and the activity of MPO. However, 12 weeks of voluntary wheel running exercise is a potential non-pharmacological therapy to ameliorate these disturbances, which determine the life expectancy of postmenopausal women. PMID- 30479527 TI - Biomechanical Effects of Ball Position on Address Position Variables of Elite Golfers. AB - The purpose of this study was to investigate address position variables in response to changes in ball position in golfers. Eleven male professional golfers were instructed to perform their golf swing. A three-dimensional motion analysis system, with eight infrared cameras and two force platforms, was used to capture the address positions. A golf ball has a diameter of 4.27 cm, and a radius of 2.14 cm. Even small movements of ball position in the mediolateral (M-L) and anteroposterior (A-P) directions significantly changed the address position. When the ball was moved to the left, the shoulder rotation and club-face aim rotated toward the left of the target, and the left vertical ground reaction force increased. When the ball was moved to the right, the opposite findings were observed. When the ball was moved closer, the trunk, hip, knee, ankle, and absolute arm angle extended; the lie angle of the golf club increased; and the center of pressure moved toward the posterior direction. These changes were reversed when the ball was moved further away. The M-L ball position critically changed the address positions of the upper extremities in the horizontal plane, and the A-P ball position critically changed the angles of whole body parts in the sagittal plane. Furthermore, club-head kinematics at impact such as club-face aim, club path, and angle of attack were significantly changed in the M-L ball position; and club-head speed and angle of attack were significantly changed in the A-P ball position. This in-depth understanding of the address position in association with the ball position could provide valuable data for swing coaches when finding a golfer's optimal address position. PMID- 30479528 TI - Effect of Post-Exercise Massage on Passive Muscle Stiffness Measured Using Myotonometry - A Double-Blind Study. AB - It is commonly believed that massage can reduce muscle stiffness and is desirable for recovery from exercise. However, the effect massage on muscle stiffness following eccentric exercises is currently unknown. This study aimed to examine the effect of post-exercise massage on passive muscle stiffness over a five-day period. A randomised cross-over study design was adopted. After 40 minutes of downhill running, 18 male recreational runners had one leg received a 16-minute massage and the contralateral leg received a 16-minute sham ultrasound treatment. Passive stiffness for four leg muscles (rectus femoris, biceps femoris, tibialis anterior, and gastrocnemius) was assessed using myotonometry at baseline, immediately post-run, post-treatment, 24, 48, 72, and 96 hours post-run. A 2 (treatment) * 7 (time) mixed ANOVA was conducted with a robust procedure on the myotonometry data of each leg muscle to examine the effect of treatment on stiffness. Passive stiffness for all muscles changed over time but no treatment effect was found. Stiffness increased at 24 hours post-run and remained elevated from baseline levels for up to 96 hours across all four muscles. Significant treatment * time interaction was only found in the tibialis anterior but no post hoc differences were identified. Passive stiffness of major leg muscles increased after a bout of unaccustomed eccentric exercise and remained elevated for up to four days post-exercise. Compared with the placebo treatment, post-exercise massage had no beneficial effect in alleviating altered muscle stiffness in major leg muscles. PMID- 30479530 TI - Influence of Different Loads on Force-Time Characteristics during Back Squats. AB - The deceleration sub-phase during the back squat (BSQ) makes it difficult to stimulate the muscles throughout the full range of motion, and it has only been reported for one load during BSQ. The purpose of this study was to investigate whether a deceleration sub-phase occurs during BSQ with different loads and to assess the influence of load on the deceleration sub-phase duration and negative impulse during the deceleration sub-phase. Sixteen healthy men (mean +/- standard deviation: age: 25 +/- 3 years; height: 1.73 +/- 0.07 m; mass: 83.2 +/- 16.1 kg; BSQ one repetition maximum (1RM): 163.8 +/- 36.6 kg; BSQ 1RM/body weight: 2.0 +/- 0.4) who had performed resistance training for at least 1 year were recruited for this study. The subjects performed parallel BSQ with 0%, 12%, 27%, 42%, 56%, 71%, and 85% of each 1RM on a force plate in a random order. The deceleration sub phase duration and negative impulse during the deceleration sub-phase were calculated from force-time data. The absolute durations of the deceleration sub phase were not significantly different according to load except for 27% 1RM and 85% 1RM (p = 0.01). However, as the load increased from 12 to 85% 1RM, the relative duration of the deceleration sub-phase decreased (p < 0.05). The negative impulse during the deceleration sub-phase also increased from 0 to 42% 1RM (p < 0.05). A deceleration sub-phase occurs regardless of the load (0%-85% 1RM), and a large portion of the deceleration sub-phase occupied the concentric phase, with low-moderate loads, and a large amount of negative impulse occurred during the short deceleration sub-phase with a high load. PMID- 30479529 TI - Training Quantification and Periodization during Live High Train High at 2100 M in Elite Runners: An Observational Cohort Case Study. AB - The questionable efficacy of Live High Train High altitude training (LHTH) is compounded by minimal training quantification in many studies. We sought to quantify the training load (TL) periodization in a cohort of elite runners completing LHTH immediately prior to competition. Eight elite runners (6 males, 2 females) with a VO2peak of 70 +/- 4 mL.kg-1.min-1 were monitored during 4 weeks of sea-level training, then 3-4 weeks LHTH in preparation for sea-level races following descent to sea-level. TL was calculated using the session rating of perceived exertion (sRPE) method, whereby duration of each training session was multiplied by its sRPE, then summated to give weekly TL. Performance was assessed in competition at sea-level before, and within 8 days of completing LHTH, with runners competing in 800 m (n = 1, 1500 m/mile (n = 6) and half-marathon (n = 1). Haemoglobin mass (Hbmass) via CO rebreathing and running economy (RE) were assessed pre and post LHTH. Weekly TL during the first 2 weeks at altitude increased by 75% from preceding sea-level training (p = 0.0004, d = 1.65). During the final week at altitude, TL was reduced by 43% compared to the previous weeks (p = 0.002; d = 1.85). The ratio of weekly TL to weekly training volume increased by 17% at altitude (p = 0.009; d = 0.91) compared to prior sea-level training. Hbmass increased by 5% from pre- to post-LHTH (p = 0.006, d = 0.20). Seven athletes achieved lifetime personal best performances within 8 days post-altitude (overall improvement 1.1 +/- 0.7%, p = 0.2, d = 0.05). Specific periodization of training, including large increases in training load upon arrival to altitude (due to increased training volume and greater stress of training in hypoxia) and tapering, were observed during LHTH in elite runners prior to personal best performances. Periodization should be individualized and align with timing of competition post-altitude. PMID- 30479531 TI - Maximum Strength Development and Volume-Load during Concurrent High Intensity Intermittent Training Plus Strength or Strength-Only Training. AB - The purpose of this study was to compare maximal strength gains during strength training (ST) and concurrent training (CT) consisting of high-intensity intermittent training plus strength training over the course of a 12-week intervention. A secondary purpose was to examine the relationship between strength training volume and strength gain in both groups. Nineteen recreationally active males were divided into CT (n = 11) and ST (n = 8) groups. The CT group performed repeated 1 min efforts at 100% of maximal aerobic speed interspersed by 1 min of passive recovery until accumulating a total running distance of 5km followed by a strength session (consisting of three sets of seven exercises with loads of 8-12 repetition maximum) twice weekly for a period of 12 weeks. The ST group performed only strength training sessions during the same 12 week period. Strength training total volume-load (Sigma repetitions x load) for the upper- and lower-body was computed, while maximal strength (1RM) was evaluated at baseline, week 8, and week 12. Lower-body volume-load over 12 weeks was not different between groups. Absolute 1RM increased in both groups at week 8 and week 12, while 1RM relative to body mass increased in both groups at week 8, but only ST increased relative maximum strength between week 8 and week 12. There was a statistically significant correlation between strength training lower-body volume-load and maximum strength change between baseline and week 8 for the CT group (r = 0.656), while no significant correlations were found for the ST group. In summary, executing high-intensity intermittent exercise twice a week before strength training did not impair maximal strength after 8 weeks, however, only ST demonstrated an increase in relative strength after 12 weeks. PMID- 30479532 TI - Heart Rate-Index Estimates Oxygen Uptake, Energy Expenditure and Aerobic Fitness in Rugby Players. AB - The purpose of the study was to verify the suitability of heart rate-index (HRindex) in predicting submaximal oxygen consumption (VO2), energy expenditure (EE) and maximal oxygen consumption (VO2max) during treadmill running in rugby players. Fifteen professional rugby players (99.8 +/- 12.7 kg, 1.85 +/- 0.09 m) performed a running incremental test while VO2 (breath-by-breath) and heart rate (HR) were measured. HRindex was calculated (actual HR/resting HR) to predict submaximal and maximal VO2 ({[(HRindex x 6)-5.0] x (3.5 body weight)}) and EE. Measured and predicted VO2 and EE were compared by two-way RM-ANOVA (method, speed), correlation and Bland-Altman analysis. Measured and predicted VO2max were compared by paired t-test, correlation and Bland-Altman analysis. Submaximal VO2 and EE significantly increased (baseline VO2: 8.1 +/- 1.6 ml.kg-1.min-1 VO2max: 46.8 +/- 4.3 ml.kg-1.min-1, baseline EE: 0.03 +/- 0.01 kcal.kg-1.min-1, peak EE: 0.23 +/- 0.03 kcal.kg-1.min-1) as a function of speed (p < 0.001 and p < 0.001 for VO2 and EE respectively) yet measured and predicted values at equal treadmill speeds were not significantly different (p = 0.17; p = 0.16) and highly correlated (r = 0.95; r = 0.94). The Bland-Altman analysis confirmed a non significant bias between measured and estimated VO2 (measured: 40.3 +/- 10.7, estimated: 40.7 +/- 10.1 ml.kg-1.min-1, bias = 1.35 ml.kg-1.min-1, z = 1.12, precision = 3.39 ml.kg-1.min-1) and EE (measured: 20.0 +/- 0.05 kcal.kg-1.min-1, estimated: 20.0 +/- 0.05 kcal.kg-1.min-1, bias = 0.00 kcal.kg-1.min-1, z = 0.04, precision = 0.02 kcal.kg-1.min-1). Estimated and predicted VO2max were not statistically different (p = 0.91), highly correlated (r = 0.96), and showed a non-significant bias (bias = 0.17, z = 0.22, precision = 1.29 ml.kg-1.min-1). HRindex is a valid field method to track VO2, EE and VO2max during running in rugby players. PMID- 30479533 TI - Effects of Exercise-Induced Fatigue on Lower Extremity Joint Mechanics, Stiffness, and Energy Absorption during Landings. AB - The aim of this study was to determine the effects of two fatigue protocols on lower-limb joint mechanics, stiffness and energy absorption during drop landings. Fifteen male athletes completed landing tasks before and after two fatigue protocols (constant speed running [R-FP] and repeated shuttle sprint plus vertical jump [SJ-FP]). Sagittal plane lower-limb kinematics and ground reaction forces were recorded. Compared with R-FP, SJ-FP required significantly less intervention time to produce a fatigue state. The ranges of motion (RoM) of the hip were significantly greater when the athletes were fatigued for both protocols. Knee RoM significantly increased after SJ-FP but not after R-FP (p > 0.05), whereas the RoM of the ankle was significantly greater after R-FP but lower after SJ-FP. When fatigued, the first peak knee extension moment was significantly greater in R-FP but lower in SJ-FP; the second peak ankle plantar flexion moment was lower, regardless of protocols. After fatigue, vertical, hip, and knee stiffness was lower, and more energy was absorbed at the hip and knee for both protocols. Hip and knee extensors played a crucial role in altering movement control strategies to maintain similar impact forces and to dissipate more energy through a flexed landing posture when fatigued compared to when non fatigued. Furthermore, SJ-FP seems to be a more efficient method to induce fatigue due to less intervention time than R-FP. PMID- 30479534 TI - The Risk Factors of Hamstring Strain Injury Induced by High-Speed Running. AB - Hamstring strain injury is a multifactorial and complex problem involving interactions among various factors. Information about risk factors for this injury is inconsistent among studies because the strong effects of confounding factors and injury situations are often ignored. We investigated the relationship between hamstring strain induced by high-speed running and intrinsic risk factors, including hip muscle morphology and function, by excluding the influences of confounding factors. Sixty-one male track and field athletes (age, 19.6 +/- 1.1 years; 95% confidence interval, 19.3-19.9) who often performed high speed running were monitored throughout one season. Before the season, we measured hip and knee strength, muscle thickness of the gluteus maximus and biceps femoris, and hip and knee joint range of motion (ROM). We also obtained information about each athlete's history of hamstring injury by questionnaire. Eighteen athletes sustained hamstring strain injuries induced by high-speed running. Eighteen uninjured athletes who had the same profile of confounding factors as the injured athletes were selected as controls. Previously injured athletes had a significantly higher injury rate than uninjured athletes (p < .05; odds ratio, 2.85). No other measurements had a significant relationship with the occurrence of injury. However, passive hip ROM (flexion and extension) tended to be larger in the injured than control group. A history of hamstring strain was a strong risk factor for hamstring strain injury, and it may affect other factors. Therefore, the risk factors for hamstring strain injury should be investigated by eliminating the impact of a history of hamstring strain. PMID- 30479535 TI - Validation of a French Version of the Psychological Characteristics of Developing Excellence Questionnaire (MacNamara & Collins, ): A Situated Approach to Talent Development. AB - This study sought to validate the psychometric properties of a French-language version of the Psychological Characteristics of Developing Excellence Questionnaire (PCDEQ). Data were gathered from 305 athletes in French-speaking Switzerland (mean age: 16.6 yr, SD: 2.9). Translation of the PCDEQ followed established guidelines and included a standardized back-translation process. The psychometric properties were examined by descriptive statistics, Cronbach's alphas for internal reliability, confirmatory factor analysis, intraclass correlations and a paired t-test for test-retest reliability. The results provided evidence of validity of the French version of the PCDEQ. Two items were excluded for low factor loading, and the re-specified model was improved and confirmed the six-dimensional structure with acceptable fit using most criteria (chi2/df), RMSEA, SRMR, TFI, CFI). Cronbach's alpha also indicated that internal reliability was adequate for validation. Given the adequate psychometric properties, the French-version PCDEQ can be used with confidence for monitoring and designing interventions to enable aspiring athletes or artists to develop the psychological skills and characteristics that can act as important catalysts for their development. PMID- 30479536 TI - Decline in Match Running Performance in Football is affected by an Increase in Game Interruptions. AB - This study quantified the contribution of game interruptions to the fatigue related declines in match running performance over the course of a football match. Using a semi-automatic multiple camera system, the running activity of 792 individual German Bundesliga performances was divided into pre-defined 15-minute intervals and subsequently analysed under two prerequisites: with (effective playing time) and without (total playing time) consideration of game interruptions. Results showed a significant decline in effective playing time over the course of a match, from 66.3% of the total playing time in the first 15 minutes to 55.9% in the final 15 minutes of a match. Under consideration of the total playing time, match running performances decreased by 24.2% on average; considering the effective playing time, they decreased on average by only 10.2%. It can, therefore, be concluded that more than half (57.9%) of the commonly reported decline in match running performance cannot be assigned to physical fatigue, but rather to an increase in game interruptions as the game progresses. In conclusion, this study demonstrated for the first time that the decline in players' match running performance during football matches is substantially amplified by a proven increase in game interruptions, indicating that there may be a tendency among practitioners to overestimate fatigue-induced performance declines. PMID- 30479537 TI - Cardiometabolic and Muscular Fatigue Responses to Different CrossFit(r) Workouts. AB - CrossFit(r) consists of workouts of the day (WODs) in which different exercises are conducted at high intensity with minimal or no rest periods. This study sought to quantify exercise intensity and muscular fatigue in the three CrossFit(r) session modalities: gymnastics (G), metabolic conditioning (M) and weightlifting (W). Thirty two, young, strength-trained, healthy men completed the three WODs: G ("Cindy"), M (double skip rope jumps) and W (power cleans). The variables measured in the sessions were: mean heart rate (HR), rate of perceived exertion (RPE), blood lactate [lactate], and jump height (H), average power (AP) and maximum take-off velocity (Vmax) in a counter movement jump test. In all three WODs, elevated HR values (>=90% of the theoretical HRmax) were recorded at the time points mid-session and end-session. Mean RPEs were 17.6 +/- 1.6 (G WOD), 16.0 +/- 2.3 (M WOD), and 15.7 +/- 2.0 (W WOD). Postexercise [lactate] was higher than 10 mmol.L-1 for the three WODs. Following the G ("Cindy") and W (power cleans) WODs, respectively, significant muscular power losses were observed in H (7.3% and 8.1%), Vmax (13.8% and 3.3%), AP relative (4.6% and 8.3%) and AP total (4.2% and 8.2%) while losses in the M WOD were not significant (p > 0.05). A vigorous intensity of exercise was noted in all three WODs, with greater mean HRs detected in the "Cindy" and skip rope WODs than power clean WOD. Muscular fatigue was produced in response to the "Cindy" and power clean WODs but not the skip rope WOD. PMID- 30479539 TI - There Is No Such Thing as an International Elite Under-9 Soccer Player. PMID- 30479538 TI - Reducing Glycemic Indicators with Moderate Intensity Stepping of Varied, Short Durations in People with Pre-Diabetes. AB - Investigate the effects of short duration stair climbing/descending at a self selected pace on post-prandial glucose responses in adults. Thirty participants (10 female) completed 4 oral glucose tolerance tests on separate days. Following glucose consumption, participants underwent seated rest (control) or walked up/down 21 stairs at a self-selected comfortable pace for 10, 3, and 1min in randomized order. Blood glucose was measured by capillary sampling from finger sticks every 15min until values for all trials converged. Area under the curve (AUC) was calculated by trapezoidal rule. In addition, cardiometabolic measurements were taken during stair exercise with a mobile metabolic cart. Results are presented as mean (SD) unless stated otherwise. All stair-climbing trials reduced peak (30min) postprandial blood glucose levels compared to the control [(1 min = 12(31), p = 0.026; 3 min = -15(25), p = 0.003; 10 min = 35(32) mg/dL, p < 0.001]. At 45min, there were significant reductions only for the 3 and 10 min trials [13(29) and 23(31) mg/dL, p = 0.023 and < 0.001 respectively], but not the 1 min trial [6(33) mg/dL, p = 0.317]. There were significant differences in AUC compared to the control only for the 3 and 10min trials [502 (1141) and 866 (1123) mg/dL.min-1, p = 0.023 and < 0.000] but not for the 1min trial [353 (1265) mg/dL.min-1, p = 0.110]. Median (interquartile range) RPEs reported for the 1, 3, and 10min trials were 1.0 (1.5), 2.0(2), and 3.0 (2.0) respectively, while VO2 was n/a, 54(12), and 59(13)% of peak, respectively. Total metabolic cost was 1.4 (0.5), 4.0 (1.0), and 11.9 (2.1) L O2, respectively. A single 1min bout of low-moderate intensity stair stepping can significantly lower peak glucose concentration, with longer bouts being more effective. PMID- 30479540 TI - Changes in Cortisol and Immunoglobulin a Concentrations in Referees during a Professional Football Match. PMID- 30479541 TI - ? PMID- 30479542 TI - Status and use of pesticides in forage crops in India. AB - The Indian livestock population is huge. Most (99%) of the livestock owners still follow traditional animal husbandry practices and graze their livestock, especially small ruminants, on natural pastures where no pesticides are used. In order to feed the ever-increasing livestock population, efforts are being made to increase quality fodder productivity from limited land resources. In such situations, pesticides play an important role by minimizing the loss of green fodder due to disease and pest attack. In countries such as Canada, Israel, the UK, and other European countries, pesticides have been registered for forage crops; in India, however, although pesticides have been registered for cultivable grain, horticultural and cash crops, etc., there are no registration guidelines or authenticated information regarding pesticide use with regard to forage crops. Hence, there is a need to take necessary steps in this direction, keeping in view the importance of fodder and livestock in the country. In this review, detailed aspects of the status and use of pesticides in forage crops in India are discussed. PMID- 30479543 TI - Action mechanism of bleaching herbicide cyclopyrimorate, a novel homogentisate solanesyltransferase inhibitor. AB - The action mechanism of cyclopyrimorate, a novel herbicide for weed control in rice fields, was investigated. Cyclopyrimorate caused bleaching symptoms in Arabidopsis thaliana similar to those caused by existing carotenoid biosynthesis inhibitors, mesotrione and norflurazon. However, cyclopyrimorate treatment resulted in significant accumulation of homogentisate and a reduction in the level of plastoquinone. A metabolite of cyclopyrimorate, des-morpholinocarbonyl cyclopyrimorate (DMC), was detected in plants. These data suggested that cyclopyrimorate and/or DMC inhibit homogentisate solanesyltransferase (HST), a downstream enzyme of 4-hydroxyphenylpyruvate dioxygenase in the plastoquinone biosynthesis pathway. In vitro assays showed that A. thaliana HST was strongly inhibited by DMC and weakly by cyclopyrimorate, whereas other commercial bleaching herbicides did not inhibit HST. DMC derivatives showed a positive correlation between HST inhibition and in vivo bleaching activities. These results indicate that the target site of cyclopyrimorate and DMC is HST, a novel target site of commercial herbicides. PMID- 30479544 TI - Biosynthesis of (2-nitroethyl)benzene and (Z)- and (E)-(2-nitroethenyl)benzenes from (Z)- and (E)-phenylacetaldoximes and phenylacetonitrile; defense allomone of Eutrichodesmus elegans and Eutrichodesmus armatus (Polydesmida: Haplodesmidae). AB - The defense allomones of two haplodesmid millipedes, Eutrichodesmus elegans and E. armatus (Polydesmida: Haplodesmidae), are known as a mixture of the following three nitro compounds: (2-nitroethyl)benzene and (Z)- and (E)-(2 nitroethenyl)benzenes. Administrations of a mixture of 2H-labeled (Z)- and (E) phenylacetaldoximes and of 2H-labeled phenylacetonitrile as precursors resulted in the same production of three 2H-labeled nitro compounds, [2' nitroethyl][2,3,4,5,6-2H5]benzene and [(Z)- and (E)-2'-nitroethenyl][2,3,4,5,6 2H5]benzenes, in both species. Oxime administration at an appropriate dose resulted in the production of three nitro compounds with similar natural ratios more effectively than nitrile administration. Conversion from oximes to nitrile and vice versa was evidenced during administration. Occurrences of three precursors (Z- and E-oximes and nitrile) were detected sporadically in millipede extracts by selected ion chromatography. PMID- 30479545 TI - The influence of Brassica rapa var. perviridis growth conditions on the uptake and translocation of pesticides. AB - We cultivated Brassica rapa var. perviridis in soil mixed with four pesticides (fenobucarb, procymidone, flutolanil, and tolclofos-methyl) at different temperatures, day lengths, and soil water contents. We compared plants' uptake and translocation abilities of the pesticides as affected by growth conditions. The root concentration factor (RCF) of pesticides tended to increase with rising temperature; however, but the influence of temperature on the transpiration stream concentration factor (TSCF) differed for each pesticide. The RCFs and TSCFs of pesticides were high for short days. The soil water content had little or no effect on the uptake and translocation of pesticides. These results showed that it is necessary to consider growth conditions, especially the temperature and day length in plant uptake models for these pesticides. PMID- 30479546 TI - Effects of environmental factors on the herbicidal activity and phytotoxicity of ipfencarbazone. AB - Ipfencarbazone exhibits excellent herbicidal activity against Echinochloa spp. and is safe for transplanted rice at a dose of 250 g a.i./ha. However, the effect of various environmental factors on its activity has not been verified. The present study evaluated the factors affecting the herbicidal activity of ipfencarbazone against Echinochloa spp. and its phytotoxicity to transplanted rice. The herbicidal activity and phytotoxicity of ipfencarbazone were barely affected by temperature, soil texture, water leakage, or flooding water depth. When an overflow was conducted artificially 6 hr after application, the herbicidal activity was stable. Furthermore, ipfencarbazone completely inhibited the emergence of Echinochloa spp. for 56 days regardless of the soil texture, water leakage and overflow conditions. When the period between application and reflooding was within 24 hr of herbicide application, the phytotoxicity of ipfencarbazone on transplanted rice was slight. These results suggest that ipfencarbazone shows stable efficacy in practical use. PMID- 30479547 TI - Activation of cell proliferation in Arabidopsis root meristem by isoprothiolane. AB - A plant growth regulating agent "Fuji-one" has been used to control non-parasitic damping-off (Murenae disease) of rice seedlings. Its active ingredient, isoprothiolane (diisopropyl 1,3-dithiolan-2-ylidenemalonate, IPT), enhances root elongation of rice and Arabidopsis. To understand the mechanisms of IPT's effect on root development, its effect on Arabidopsis root cells was investigated histologically. IPT at a lower concentration (12.5 ug/mL) had no effect on root cell elongation, whereas it enhanced cell division in the root meristem. Histological analysis using phytohormone-related mutants indicated that jasmonic acid and ethylene were involved in the enhanced cell division. In contrast, IPT at a higher concentration (75 ug/mL) suppressed both cell elongation and cell division, in which jasmonic acid and ethylene were not involved. In addition, root hair formation was suppressed by treatment with IPT. These analyses demonstrated that IPT (12.5 ug/mL) enhanced root elongation by activating cell division in a jasmonic acid- and ethylene-dependent manner. PMID- 30479548 TI - Insecticidal properties of pyripyropene A, a microbial secondary metabolite, against agricultural pests. AB - We previously reported the strong insecticidal activity of a microbial secondary metabolite, pyripyropene A (PP-A), against aphids. Pyripyropenes (PPs) have been known to show weak feeding inhibition against lepidopteran pests, but their strong aphicidal activities were first reported in our former study. Here we investigated the details of the insecticidal property of PP-A. Our biological evaluation of PP-A found that it shows high insecticidal activities against some sucking pests, such as whiteflies, as well as aphids, and preferable biological profiles as agricultural insecticides. Furthermore, PP-A controlled aphids well under field conditions. PMID- 30479549 TI - Nicotinic acetylcholine receptor alpha6 subunit mutation (G275V) found in a spinosad-resistant strain of the flower thrips, Frankliniella intonsa (Thysanoptera: Thripidae). AB - The flower thrips Frankliniella intonsa strain showing resistance to spinosad was established in the laboratory. The resistant strain showed an LC50 value of 1398.7 mg/L in a leaf dipping/contact assay. The LC50 value was ca. 280 times higher than that of the most susceptible strain. An insecticidal assay using synergists suggested no involvement of degradation enzymes, such as cytochrome P450, glutathione S-transferase, and carboxyl esterase, in the resistance. Glycine at amino acid position 275 of the nicotinic acetylcholine receptor (nAChR) alpha6 subunit was mutated to valine in the resistant strain. These results suggest that spinosad resistance in F. intonsa is conferred by the reduced sensitivity of nAChR. PMID- 30479550 TI - Comparison of soil sorption parameters of pesticides measured by batch and centrifugation methods using an andosol. AB - We compared the soil sorption coefficient (K d) measured by batch and centrifugation methods using a Japanese andosol and ten pesticides. Although the K d values measured by both methods increased with time, those obtained via the batch method tended to be higher during the test period. The difference in K d values between the two methods affected pesticide concentrations estimated in the soil solution, and the results estimated using K d values obtained via the batch method underestimated the observed trends. PMID- 30479551 TI - Anti-plant viral activity of peptaibols, trichorzins HA II, HA V, and HA VI, isolated from Trichoderma harzianum HK-61. AB - Three peptaibols, trichorzins HA II (1), HA V (2), and HA VI (3), were isolated from okara fermented with Trichoderma harzianum HK-61 as anti-plant viral agents. Their structures were confirmed by spectroscopic and chemical methods. At micro molar concentrations, the trichorzins inhibited infections by Cucumber mosaic virus in the cowpea plant Vigna sesquipedalis. PMID- 30479552 TI - Management of melanin biosynthesis dehydratase inhibitor (MBI-D)-resistance in Pyricularia oryzae using a non-MBI-D fungicidal application program for nursery boxes and a diclocymet and ferimzone mixture for field foliar applications. AB - We compared the risk of reselecting melanin biosynthesis dehydratase inhibitor (MBI-D)-resistant Pyricularia oryzae isolates between two treatment programs, a nursery box application of diclocymet and a rotational program in which nursery boxes received a non-MBI-D fungicide application and then later, in the field, a foliar application of a diclocymet and ferimzone mixture. Both were effective against panicle blast. However, the latter prevented the reselection of MBI-D resistant isolates more effectively than the former. PMID- 30479553 TI - Root uptake and translocation of 14C-heptachlor and its degradation products in soil by zucchini and tomato seedlings. AB - To investigate root uptake and translocation of heptachlor and its degradates (cis-heptachlor epoxide and 1-hydroxychlordene) in soil, zucchini and tomato seedlings were transplanted to soil approximately four months after treatment with 14C-heptachlor. The results indicated that a relation between the root concentration factor and the log P ow did not follow Briggs' theory, probably due to the contribution of plant metabolism. It also appeared that a compound with a lower log P ow tends to show higher mobility from root to shoot. PMID- 30479554 TI - Studies on the behavior and ecotoxicity of pesticides and their transformation products in a river. AB - To clarify the properties of pesticide transformation products (TPs) for which the risk to aquatic organisms should be evaluated, I monitored the concentrations of paddy pesticides and their TPs in the Sakura River, Japan, during the rice growing season in 2007-2010. I also conducted algal growth inhibition tests of herbicides and their TPs using a diatom and a green alga and acute toxicity tests of insecticides and their TPs using a caddisfly and a daphnid. Moreover, on the basis of the results of pesticide monitoring and toxicity tests, I attempted to evaluate the risk of these compounds to the riverine organisms as well as the risk of mixtures of insecticides and their TPs for caddisflies and cladocerans. The TPs were detected in the river water depending on the half-lives of the parent compounds and of the TPs in water and soil. The toxicities of the parent compound and its TPs may be related to their hydrophobicities and chemical structures. Some toxic and persistent TPs that formed rapidly in water and soil posed a risk to the organisms over a long period. The physicochemical properties and chemical structures of a parent compound and its TPs can be key factors in evaluating the pesticide TP risk to aquatic organisms in rivers. PMID- 30479555 TI - Development and diffusion of practical technologies for pesticide residue analysis. AB - We often encounter difficulties in analyzing pesticide residues in food, since the residue level to be measured is infinitesimal but the food samples may contain a variety of matrices, including interferences, for chromatographic analysis. Thus it is important to find out the key points to be checked in the extraction, purification, and determination steps of analysis. We have attempted to develop practical technologies for the analysis of pesticide residues in raw agricultural commodities based on the following studies: The effect of processing and cooking on pesticide residue levels in several crop samples (rice, wheat, soybean, and sesame) was investigated. The processing factor is useful to estimate the amount of exposure to each pesticide residue for risk assessment and is helpful in setting the maximum residue limits of processed foods. In addition, residue levels in the peel and pulp of watermelon, melon, and kiwi fruit samples were examined to confirm the differences in the distribution of residues. As a basic study, the effect of water-soaking pretreatment of powdered dry cereal on extraction efficiency was examined, and an optimal time for water-soaking was found. A recent study examined the ability of several new types of solid-phase extraction columns to remove matrices in brown rice samples and verified the effective purification method for each sample. PMID- 30479557 TI - Trends and determinants of complementary feeding practices in Tanzania, 2004 2016. AB - Background: Following the successful implementation of the Millennium Development Goals (MDGs) strategy in Tanzania, improvements in child health indicators were observed. However, it remains unclear whether complementary feeding practices have improved given the renewed global agenda on child nutrition. This study investigated trends and socioeconomic and health service factors of complementary feeding practices in Tanzania for the period spanning from 2004 to2016. Methods: The study was based on the Tanzania Demographic and Health Survey data for the years 2004-2005 (n = 2480), 2010 (n = 2275) and 2015-2016 (n = 2949) to estimate the trends in complementary feeding practices. Multivariate logistic regression models that adjusted for year of the survey, clustering and sampling weights were used to investigate the association between the modifiable study factors (socioeconomic and health service factors) and complementary feeding practices among children aged 6-23 months in Tanzania. Results: Over the study period, minimum dietary diversity (MDD) and minimum acceptable diet (MAD) have worsened from 46% (95% confidence interval [95% CI] 41.5-50.7%) in 2004-2005 to 30% (95% CI 25.7-32.9%) in 2015-2016 and 16.9% (95% CI 14.9-18.9%) in 2004-2005 to 6.0% (95% CI 4.9-7.1%) in 2015-2016, respectively. Minimum meal frequency (MMF) remained unchanged, 37% in 2004-2005 and 2015-2016. The introduction of solid, semi-solid and soft foods improved from 79% (95% CI 74.5-83.9%) in 2004-2005 to 87% (95% CI 83.7-90.9%) in 2015-2016. Multivariate analyses revealed that higher maternal education and household wealth, mother's employment, health facility birthing and postnatal care (PNC) visit were associated with MDD, MAD and MMF. Traditional birth attendant-assisted births and PNC visits were associated with the introduction of complementary foods. In contrast, birthing in the health facility was associated with the delayed introduction of complementary foods. Conclusion: Between 2004 and 2016, the prevalence and determinants of complementary feeding practices varied in Tanzania. Improving complementary feeding practices is feasible in Tanzania given the renewed focus on child nutrition in the country. Child nutrition policy interventions should target all mothers, particularly mothers from low socioeconomic background and those with limited access to health services to maximise results. PMID- 30479558 TI - Geographic Information Science and the Analysis of Place and Health. AB - The representation of place is a key theoretical advancement that Geographic Information Science can offer to improve the understanding of environmental determinants of health, but developing robust computational representations of place requires a substantial departure from conventional notions of geographic representation in Geographic Information Systems (GIS). Unlike conventional GIS representations based on either objects or locations, we suggest place representation should incorporate dynamic subjective, experiential, and relational aspects of place, as the influence of place on health behavior concerns not only the features that can be objectively observed at a particular location but also the environmental perceptions of the individual, as molded by biological, social, and experiential characteristics. In addition, assessments of environmental exposures on health outcomes should focus on individuals' time activity patterns and microenvironment profiles, which form a potentially unique personalized exposure environment for each individual. Addressing these representational challenges via collaborative research has the potential to advance both Geographic Information Science and health research. PMID- 30479556 TI - Toxoplasma gondii seroprevalence among pregnant women attending antenatal clinic in Northern Tanzania. AB - Background: Acute Toxoplasma gondii infection during pregnancy represents a risk for congenital disease, especially among women without previous exposure to infection. There is, however, a paucity of information about the epidemiology of T. gondii infection in pregnant women in Tanzania. This study aimed to determine the seroprevalence of T. gondii infection and associated demographic, clinical, and behavioral risk factors in pregnant women attending ante-natal clinic (ANC) at Kilimanjaro Christian Medical Center (KCMC), a referral medical center in Northern Tanzania. Methods: A hospital-based cross-sectional study was carried out from 1 February to 30 April 2017. Data on maternal demographic characteristics, obstetric history, knowledge, and practices related to T. gondii infection were collected from 254 pregnant women attending antenatal care at KCMC. A sample of 4 mL of blood was collected from each participant and sera prepared from each sample. Serum samples were tested for the presence of specific T. gondii IgG and IgM antibodies by indirect Enzyme-Linked Immunosorbent Assay (ELISA). DNA was extracted from whole blood for polymerase chain reaction (PCR) testing, targeting the DNA sequence coding for the Internal Transcribed Spacer 1 (ITS1). Results: The overall T. gondii seroprevalence, including both IgM- and IgG-positive individuals, was 44.5%. Of the 254 tested women, 102 and 23 were seropositive for T. gondii-specific IgG and IgM antibodies respectively and 113 individuals had antibodies of either or both classes. All IgM-positive samples were also tested by PCR, and all were negative. The majority (90%) of the women surveyed had never heard about toxoplasmosis. Consumption of raw vegetables [aOR = 0. 344; 95% CI 0.151-0.784; p = 0.011] and having regular contact with soil [aOR = 0.482; 95% CI 0.268-0.8681; p = 0.015] were both associated with T. gondii antibody status. Inverse relationships with probability of T. gondii exposure were observed, such that these practices were associated with reduced probability of antibody detection. Conclusion: Based on serology results, we report widespread exposure to T. gondii infection among pregnant women attending ANC in KCMC. The complex interaction of risk factors for T. gondii infection needs to be studied in larger longitudinal studies. PMID- 30479559 TI - An analysis of qualitative and mixed methods abstracts from Japanese, UK and US primary care conferences. AB - Background: As research in family medicine covers varied topics, multiple methodologies such as qualitative research (QR) and mixed methods research (MMR) are crucial. However, we do not know about the difference in the proportion of QR or MMR between Japan, the UK and the US. This knowledge is needed to shape future research within countries with developing primary care such as Japan and other Asian countries. This study aims to describe the use of QR and MMR in Japanese primary care and compare this to the UK and US; then to make informed recommendations for primary care research. Methods: A repeated cross-sectional study (2012-2016) based on the abstracts submitted to the annual conferences of the Japanese Primary Care Association in Japan, the Royal College of General Practitioners in the UK, and the North American Primary Care Research Group in the US and other North American countries. The proportions of QR/MMR among all the posters and paper presentations for each of these three conferences were assessed. Also examined were trends and types of qualitative techniques for all three countries and participants/settings for Japan. Results: There were 1080 abstracts for Japan, 575 for UK and 3614 for US conferences. QR/MMR proportions were 7.5%, 15.1% and 28.1%, respectively. Japan's proportion was lower than that of UK and US (p < 0.001). The proportion was increasing over time for the UK (p = 0.02). Steps for coding and analyses was most popular for Japan, thematic analysis for the UK and grounded theory for the US. Primary care doctors and hospitals were the commonest contexts for Japan. Conclusions: QR and MMR were not as popular in primary care in Japan compared to the UK and the US, whereas their use was increasing in the UK. Approaches, participants and settings may differ among these countries. Education and promotion of QR/MMR and multi-disciplinary collaborations need to be recommended in Japan with developing primary care. PMID- 30479560 TI - Neonatal nasogastric tube feeding in a low-resource African setting - using ergonomics methods to explore quality and safety issues in task sharing. AB - Background: Sharing tasks with lower cadre workers may help ease the burden of work on the constrained nursing workforce in low- and middle-income countries but the quality and safety issues associated with shifting tasks are rarely critically evaluated. This research explored this gap using a Human Factors and Ergonomics (HFE) method as a novel approach to address this gap and inform task sharing policies in neonatal care settings in Kenya. Methods: We used Hierarchical Task Analysis (HTA) and the Systematic Human Error Reduction and Prediction Approach (SHERPA) to analyse and identify the nature and significance of potential errors of nasogastric tube (NGT) feeding in a neonatal setting and to gain a preliminary understanding of informal task sharing. Results: A total of 47 end tasks were identified from the HTA. Sharing, supervision and risk levels of these tasks reported by subject matter experts (SMEs) varied broadly. More than half of the tasks (58.3%) were shared with mothers, of these, 31.7% (13/41) and 68.3% were assigned a medium and low level of risk by the majority (>=4) of SMEs respectively. Few tasks were reported as 'often missed' by the majority of SMEs. SHERPA analysis suggested omission was the commonest type of error, however, due to the low risk nature, omission would potentially result in minor consequences. Training and provision of checklists for NGT feeding were the key approaches for remedying most errors. By extension these strategies could support safer task shifting. Conclusion: Inclusion of mothers and casual workers in care provided to sick infants is reported by SMEs in the Kenyan neonatal settings. Ergonomics methods proved useful in working with Kenyan SMEs to identify possible errors and the training and supervision needs for safer task-sharing. PMID- 30479561 TI - Effects on nurses' quality of working life and on patients' quality of life of an educational intervention to strengthen humanistic practice among hemodialysis nurses in Switzerland: a protocol for a mixed-methods cluster randomized controlled trial. AB - Background: Humanistic nursing practice constitutes the cornerstone of the nursing profession. However, according to some authors, such practice tends to fade over time in favour of non-humanistic behaviours. To contrast this tendency, an educational intervention (EI) based on Watson's Theory of Human Caring was developed and tested in two pilot studies involving, respectively, rehabilitation nurses in Quebec (Canada) and haemodialysis (HD) nurses in Switzerland. In light of the positive results obtained in these, another study is being undertaken to examine more in depth the EI's effects on both HD nurses and patients in French Switzerland. The EI is expected to have positive effects on quality of nurse patient relationship (NPR), team cohesion, nurse quality of working life (QoWL), and patient quality of life (QoL). Methods/design: The study described in this protocol will use a mixed-method cluster randomised controlled trial design. For the quantitative component, nurse and patient data will be collected through questionnaires. The accessible population of 135 nurses and 430 patients will be clustered into 10 HD units. These units will be randomised into an experimental group (EG) and a waiting-list control group (WLCG). Measurements will be taken at baseline (pre-intervention) and repeatedly over time (post-intervention): immediately at EI completion and six and 12 months thereafter. For the qualitative portion of the study, 18 semi-structured interviews will be conducted with EG nurses picked at random two months after EI completion to explore perceived changes in nurse humanistic practice. Qualitative data will be analysed through the relational caring inquiry method, a phenomenological approach. Descriptive and inferential statistics will be computed from the quantitative data. Discussion: The study described in this protocol will determine if and how the proposed EI promotes humanistic nursing practice and how this practice affects quality of NPR, nurse QoWL, and patient QoL. Moreover, it will lay the groundwork for offering the EI to nurses in other healthcare sectors. Trial registration: This clinical study was registered with ClinicalTrials.gov [NCT03283891, 14/09/2017]. PMID- 30479562 TI - Impact of a person-centered intervention for patients with head and neck cancer: a qualitative exploration. AB - Background: People affected by head and neck cancer (HNC) experience a variety of multifaceted health-related problems during the treatment process, based on both the disease and side effects, several years after the treatment is complete. This study investigated a person-centred intervention using transition theory as a framework. Aim: Thus, the aim of the present study was to explore patients' experience of the transition and person centred care from diagnosis to the end of the treatment period. Methods: Interviews were conducted with 12 persons included in the person-centred intervention group. The patients were recruited from a randomised controlled study. We used a directed deductive content analysis as an analysis method. Results: There was a distinct transition between being a healthy person to being diagnosed with a serious disease. The majority of the participants felt that the diagnosis had put their lives in the balance; they felt both healthy and sick at the same time, and all participants described that their symptoms and side effects were the worst possible and totally unexpected. Of great importance was the health-care plan, comprising self-management goals which were formed in partnership between the patient and the nurse. The participants experienced that their interaction and engagement with lay persons and healthcare professionals supported a gradual acceptance of the situation and a sense of relief with a kind of awareness of the disease. Conclusion: The intervention played a significant role in promoting a healthy transition. Person centredness and transition theory can help healthcare professionals to be more confident and resourceful in supporting people affected by HNC. PMID- 30479563 TI - miR-144/451 cluster plays an oncogenic role in esophageal cancer by inhibiting cell invasion. AB - Background: miRNA clusters are widely expressed across species, accumulating evidence has illustrated that miRNA cluster functioned more efficiently than single miRNA in cancer oncogenesis. It is likely that miRNA clusters are more stable and reliable than individual miRNA to be biomarkers for diagnosis and therapy. We previously found low expression of miR-144/451 was closely related with the risk for esophageal cancer. Researches on miR-144/451 cluster were mostly focused on individual miRNA but not the whole cluster, the regulatory mechanism of miRNA cluster were largely unknown. Methods: In present study, we firstly analysed biological functions of individual miRNAs of miR-144/451 in ECa9706 transfected with miRNA mimics. We further analysed the biological function of the whole cluster in stable transgenic cell overexpressing miR 144/451. We then performed genome-wide mRNA microarray to detect differentially expressed gene profiles in stable transgenic cells. Results: Overexpression of miR-144-3p promoted early apoptosis of ECa9706 and inhibited cell migration, cell invasion and cell proliferation. miR-144-5p and miR-451a inhibited cell proliferation, at the same time, miR-451a inhibited cell migration. Overexpression of miR-144/451 leads to the arrest cell cycle from S to G2 and G2 to M,while the invasion ability was obviously inhibited. We further observed c Myc, p-ERK were downregulated in cells overexpressing miR-144/451, while p53 was up-regulated. The downstream effectors of c-Myc, MMP9 and p-cdc2 were downregulated in miR-144/451 stable transgenic cell. miR-144/451 may or partly inhibited cell cycles and invasion of ECa9706 through inhibiting ERK/c-Myc signaling pathway. Conclusion: Collectively, we analysed the function of miR 144/451 cluster from individual to overall level. miR-144/451 cluster played proto oncogene role in esophageal cancer by inhibiting cell invasion. PMID- 30479564 TI - Mifepristone inhibits non-small cell lung carcinoma cellular escape from DNA damaging cisplatin. AB - Background: Lung cancer is the leading cause of cancer deaths in the world. The major histopathological subtype of lung cancer is non-small cell lung cancer (NSCLC). Platinum-based therapy is the standard of care for patients with advanced stage NSCLC. However, even with treatment, most patients will die of this disease within 5 years and most of these deaths are due to recurrence. One strategy to inhibit recurrence is to use cytostatic compounds following courses of lethal chemotherapy. We have shown in various cancer cell types that mifepristone (MF), an anti-progestin/anti-glucocorticoid, is a powerful cytostatic anti-cancer agent. Thus, in this work we tested the hypothesis that MF should be efficacious in inducing cytostasis and preventing repopulation of NSCLC following cisplatin (CDDP) therapy. Methods: We established an in vitro approach wherein human NSCLC cells with different genetic backgrounds and sensitivities to CDDP (A549 and H23) were exposed to rounds of lethal concentrations of CDDP for 1 h followed or not by MF monotherapy. Every 2 days, cell number, cell viability, and colony-forming ability of viable cells were studied. Results: CDDP killed the majority of cells, yet there were remnant cells escaping CDDP lethality and repopulating the culture, as evidenced by the improved clonogenic survival of viable cells. In contrast, when cells exposed to CDDP where further treated with MF following CDDP removal, their number and clonogenic capacity were reduced drastically. Conclusion: This study reports that there is repopulation of NSCLC cells following a lethal concentration of CDDP monotherapy, that NSCLC cells are sensitive to the growth inhibition properties of MF, and that MF abrogates the repopulation of NSCLC cells following CDDP therapy. Our study supports further evaluating MF as an adjuvant therapy for NSCLC. PMID- 30479565 TI - The miR-199a-3p regulates the radioresistance of esophageal cancer cells via targeting the AK4 gene. AB - Background: MiRNAs was recognized as vital regulators involved in cancer development. Radioresistance remains a major obstacle for effective treatment of cancers. The mechanisms on the miRNA-mediated radioresistance of cancers are still poorly understood. The main subject of this study is to find new miRNA biomarker that regulates the radioresistance of esophageal cancer (EC). Methods: The cumulative dose of radiation assays were used to screen the EC radioresistant cell lines. Wound-healing and invasion assays were used to characterize the properties of these cell lines. The following survival fraction experiments were performed to test the effects of miR-199a-3p and AK4 in the radioresistance of EC. In addition, we used the luciferase reporter assays to identify the putative underlying mechanism that relates to the miR-199a-3p regulated radio-resistance. Results: We found that the AK4 gene is one of the targets of miR-199a-3p, which promotes the radioresistance of EC cells. The following experiments by force reversal of the miR-199a-3p or AK4 levels confirmed the relationship of miR-199a 3p and AK4 with the radioresistance of EC cells. In addition, the activities of several signaling pathway were drastically altered by the forced changes of the miR-199a-3p level in EC cells. Conclusion: Taken together, we found that miR-199a 3p can be potentially used as a biomarker for the EC radioresistance. Moreover, these results provides new insights into the mechanism on the radioresistance of EC cells, and also might guide the clinical therapy of EC. PMID- 30479566 TI - Increased activated regulatory T cell subsets and aging Treg-like cells in multiple myeloma and monoclonal gammopathy of undetermined significance: a case control study. AB - Background: Accumulating evidence have indicated that regulatory T cells (Tregs) play an essential role in T cell-mediated immune response and development of multiple myeloma (MM). CD4+FoxP3+ T cells are composed of three phenotypically and functionally distinct subpopulations: CD45RA+FoxP3lo resting Tregs (rTregs), CD45RA-FoxP3hi activated Tregs (aTregs) and CD45RA-FoxP3lo non-suppressive T cells (non-Tregs). We aimed to clarify the frequency and function of these three subpopulations in newly diagnosed multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS) patients. In addition, CD28-CD4+FoxP3+ Treg-like cell is a senescent regulatory T cell subset with partial suppressive function, which could be impaired during myelomagenesis. Methods: we examined 20 patients with MGUS, 26 patients with newly diagnosed MM and 18 healthy volunteers. Flow cytometric analysis in peripheral blood and bone marrow was performed for frequency study. The immunosuppressive function of Treg subsets was assessed by their ability to suppress the proliferation of responder cells in co-culture. Concentration of cytokine from the culture supernatants of proliferation assay was measured using ELISA. Results: The proportion of activated Tregs in CD4+ T cells was significantly higher in MGUS and MM patients than healthy controls (P = 0.01, P < 0.001) in both PB and BM; while the proportion of rTregs in MGUS, MM patients was significantly lower than that of controls (P = 0.02, P < 0.01) only in BM. There was no significant difference in frequencies of non-Tregs from MGUS to MM patients with normal controls (P = 0.14, P = 0.88). Significant increase in PB and BM Treg-like cells was observed in MGUS and MM cohort compared with healthy controls (P < 0.01, P < 0.01). Treg-like cells in MM patients were significantly higher than those in MGUS patients (P < 0.01). The inhibition rate of aTreg in bone marrow of MM patients was significantly higher than that of rTreg (P < 0.01), while the inhibition rate of non-Treg was significantly lower than that of rTreg cells (P < 0.01). Functional assays revealed the suppressive and secretory abilities of three Treg subsets were intact in MM patients. Conclusions: In summary, aTregs and aging Treg-like cells were quantitatively altered in MGUS and MM patients, which might be associated with disease progression and prognosis. PMID- 30479567 TI - A novel non-sulphamoylated 2-methoxyestradiol derivative causes detachment of breast cancer cells by rapid disassembly of focal adhesions. AB - Background: 2-Methoxyestradiol (2ME2) is an estradiol metabolite with well documented antiproliferative properties in many cancer cell lines. However, it is rapidly metabolised in vivo which limits its clinical application. Therefore, more stable derivatives with potentially improved clinical features have been designed by our group. Here we describe an estrone-like derivative of 2ME2, namely EE-15-one, that unlike other derivatives which induce cell cycle arrest, induces a rapid loss of cell-substrate adhesion through the inactivation and disassembly of focal adhesions. Methods: To assess the effect of 2-ethyl-estra 1,3,5 (10),15-tetraen-3-ol-17-one (EE-15-one) on breast cancer cell lines, cell survival was quantified. The effect of EE-15-one on cell attachment was assessed by measuring cell adhesion and cell rounding via light microscopy. Effects on focal adhesion dynamics and actin cytoskeleton organisation were visualised by immunofluorescence while focal adhesion signalling was assessed by western blot. Cell death was quantified using a lactate dehydrogenase activity (LDH) assay. To investigate specificity towards cell-substrate over cell-cell contact inhibition, EE-15-one effects on 3D cell cultures were assessed. Results: Cell survival assays show an almost complete loss of cells within 24 h of EE-15-one exposure in contrast to published sulphamoylated 2ME2 derivatives. Cell loss is linked to rapid detachment and adhesion inhibition. Focal adhesion size and number are rapidly diminished while actin fibres became severed and disappeared within 2 h post exposure. These changes were not due to cell necrosis as LDH activity only slightly increased after 24 h. Cells grown in cell-cell adhesion dependent spheroids did not respond to EE-15-one exposure suggesting that EE-15-one specifically inhibits cell-substrate adhesions but not cell-cell adhesions and does not directly impact the actin cytoskeleton. Conclusion: We show that a novel 2ME2 derivative, EE-15-one, induces rapid loss of focal adhesion function leading to cell-substrate detachment through interference with integrin-based cell substrate adhesions, but not cadherin dependent cell-cell adhesions. Therefore, EE-15-one is the first 2ME2 derivative that has an alternative mode of action to the antimitotic activity of 2ME2. As such EE-15-one shows potential as a lead compound for further development as an inhibitor of cell-substrate adhesion which is essential for metastatic dissemination. PMID- 30479568 TI - Thyroid stimulating hormone suppression time on cardiac function of patients with differentiated thyroid carcinoma. AB - Background: This study was to investigate the influence of thyroid stimulating hormone (TSH) suppression time on the cardiac function of differentiated thyroid carcinoma (DTC) patients. Methods: 105 DTC patients were divided into strict TSH suppression group (model group, TSH <= 0.1 mU/L) and general TSH suppression group (control group, TSH > 0.1 mU/L). According to the suppression time, these two groups were respectively divided into three groups: group within half a year, group between half a year and a year and group more than a year. Gated myocardial perfusion imaging was applied to observe differences of left ventricle (LV) myocardial perfusion, LV diastolic and systolic function and LV systolic synchrony in every group. Results: The left ventricular diastolic function, systolic synchrony and myocardial perfusion level of model group decreased with prolonged suppression time. The values of left ventricular EF, PFR and BPM in patients less than half a year were higher than those in 6 months to 1 year for control group. Conclusion: Thyroid stimulating hormone suppression can influence the cardiac function of patients and with the prolongation of suppression time, regardless of the level of TSH suppression, the possibility of cardiac function depression in patients will increase. TSH may lower the risk of cardiovascular disease in high-risk patients than those in TSH patients with moderate or low risk. The drugs improving cardiac function should be used cooperatively in different suppression period to decrease the occurrence rate of cardiac adverse reactions. PMID- 30479569 TI - Identification of RPL5 and RPL10 as novel diagnostic biomarkers of Atypical teratoid/rhabdoid tumors. AB - Background: Rhabdoid tumors (RTs) are aggressive tumors that occur most frequently in children under 2 years old, which often invade kidney (KRTs) and Center Nervous System, named Atypical teratoid/rhabdoid tumors (AT/RTs). RTs often progress fast and lead to a high lethality. RTs have a low incidence, we can hardly accumulate enough samples to elicit the diagnosis. More importantly, histologically, RTs present a host of neural, epithelial, mesenchymal, or ependymal patterns, which makes them rather variable and difficult to diagnose. Molecularly, RTs are diagnosed mainly on the lack of SMARCB1/INI1 protein expression, which, on the one hand, accounts for 75% of RTs, on the other hand, loss of expression of SMARCB1 is not exclusive to RTs. So, there is a need to find more accurate diagnose markers of RTs. Methods: In this study, we analyzed 109 samples including AT/RT, KRT and corresponding normal samples downloaded form NCBI GEO database. First, we identified the differentially expressed lncRNAs and PCGs in AT/RT, KRT and corresponding normal samples. Second, we evaluated the co expression relationship between lncRNA and PCG, and defined four types of the dysregulated PCG-lncRNA pairs. Third, we compared the differentially expressed genes, the dysregulated PCG-lncRNA pairs and commonly known cancer genes, we get potential diagnostic markers. Then, the potential diagnostic markers were subjected to Receiver operating characteristic (ROC) analysis to assess the diagnostic accuracy. Importantly, differential expression of the marker genes in different tumors was shown to distinguish AT/RT and KRT from other pediatric tumors specifically. Results: We compared the expression profiles between 47 AT/RTs, 31 KRTs, 8 normal brain samples, and 23 normal kidney samples. After applying a stringent set of criteria on the gene expression profiles, we identified 3667 PCGs and 81 lncRNAs differentially expressed in AT/RT, 3809 PCGs and 34 lncRNAs differentially expressed in KRT tissues. Next, we compared the three sets(AT/RT versus control brain samples, KRT versus control kidney samples, and AT/RT versus KRT) of differentially expressed lncRNAs and PCGs, 491 PCGs and 2 lncRNAs appeared in all three sets. We examined the correlation of the expression levels of these genes in the 'three-set overlap' group and identified four types of dysregulated lncRNAs and PCGs. By compared these genes to the well known cancer driver genes, 19 PCGs were selected as potential candidates of diagnostic markers. Filtered with the number of the corresponding co-expressed lncRNA (namely "degree"), eight PCGs with more than five lncRNAs in the 'three set overlap' group were selected as candidate diagnostic markers. Among them, RPL5 and RPL10 exhibited high sensitivity and specificity in diagnosis of AT/RT and KRT. However, when these two genes were used to distinguish AT/RT and KRT from other pediatric tumors, only AT/RT can be distinguished from medulloblastoma. Conclusions: Our study mined existing GEO datasets for novel diagnostic markers associated with Rhabdoid tumors, and identified RPL5 and RPL10 as potential diagnostic markers for AT/RT. These two biomarkers may be used as supplementary biomarkers to canonical diagnostic tools such as biopsy and immunohistochemistry. PMID- 30479570 TI - Polymorphisms of TGFBR1, TLR4 are associated with prognosis of gastric cancer in a Chinese population. AB - Background: Helicobacter pylori (H. pylori)-induced gastric cancer is an intricate progression of immune response against H. pylori infection. IL-16, TGF beta1 and TLR4 pathways were the mediators involved in the immune response. We hypothesized that genetic variations in genes of these pathways have potential susceptibility to gastric cancer risk, and predict clinical outcomes of patients. Methods: To investigate the susceptibility and prognostic value of genetic variations of IL-16, TGFBR1 and TLR4 pathways to gastric cancer, we performed a case-control study combined a retrospective study in a Chinese population. Genotyping for all polymorphisms was based on the Sequenom's MassARRAY platform, and H. pylori infection was determined by using an immunogold testing kit. Results: We found rs10512263 CC genotype was found to be a decreased risk of gastric cancer (CC vs. TT: adjusted OR = 0.54, 95% CI 0.31-0.97); however, rs334348 GG genotype was associated with increased risk of gastric cancer (GG vs. AA: adjusted OR = 1.51, 95% CI 1.05-2.18). We found that carriers harboring rs1927911 A allele (GA/AA) or rs10512263 C allele (CT/CC) have unfavorable survival time than none carriers (rs1927911: GA/AA vs. GG: adjusted HR = 1.27, 95% CI 1.00-1.63; rs10512263: CT/CC vs. TT: adjusted HR = 1.29, 95% CI 1.02-1.63) and that individuals harboring both two minor alleles (rs1927911 GA/AA and rs10512263 CT/CC) suffered a significant unfavorable survival (adjusted HR = 1.64, 95% CI 1.17-2.31). Conclusion: In short, we concluded that two polymorphisms (rs334348, rs10512263) in TGFBR1 were associated with risk of gastric cancer, and that TLR4 rs1927911 and TGFBR1 rs10512263 were associated with clinical outcomes of gastric cancer patients. PMID- 30479572 TI - Circulating natural antibodies to inflammatory cytokines are potential biomarkers for atherosclerosis. AB - Background: Inflammatory cytokines contribute to the development of atherosclerosis. Natural antibodies in the circulation have protective effects on common diseases including atherosclerosis-related conditions. Purpose: The present study aimed to investigate the possible involvement of circulating IgG antibodies against inflammatory cytokines in atherosclerosis. Methods: A total of 220 patients with diagnosis of atherosclerosis and 200 healthy controls were recruited. Seven linear peptide antigens were used to develop an enzyme-linked immunosorbent assay in-house for detection of plasma IgG antibodies against interleukin 1beta (fragments IL1beta-1 and IL1beta-2), IL6, IL8, tumor necrosis factor alpha (fragments TNFalpha-1 and TNFalpha-2) and IL1alpha. Results: Atherosclerotic patients had an increase in the levels of circulating IgG to TNFalpha-1(adjusted r2 = 0.038, p < 0.001) and IL1alpha (adjusted r2 = 0.025, p = 0.002) compared with control subjects. Female patients mainly contributed to increased anti-TNFalpha-1 IgG levels (adjusted r2 = 0.073, p < 0.001) and anti IL1alpha IgG levels (adjusted r2 = 0.044, p = 0.003). In addition, female patients showed higher anti-IL1beta-2 IgG levels than controls (adjusted r2 = 0.023, p = 0.026). There was no significant change of circulating IgG antibodies to other cytokines. ROC curve analysis showed an AUC of 0.564 for anti-TNFalpha-1 IgG assay with 22.8% sensitivity against a specificity of 90.0%, and an AUC of 0.539 for anti-IL1alpha IgG assay with 17.8% sensitivity against a specificity of 90.0%; the anti-IL1beta-2 IgG assay had an AUC of 0.580 with 26.3% sensitivity against a specificity of 89.8% in female patients. There was no correlation between plasma IgG levels and carotid intima-media thickness. Conclusion: Natural antibodies to inflammatory cytokines may be potential biomarkers for atherosclerosis. PMID- 30479571 TI - MicroRNA-133b/EGFR axis regulates esophageal squamous cell carcinoma metastases by suppressing anoikis resistance and anchorage-independent growth. AB - Background: Anoikis resistance has been demonstrated to facilitate distant metastases of cancers. MicroRNA-133b (miR-133b) is found to be down-regulated in various tumors, including esophageal squamous cell carcinoma (ESCC), and closely correlates with the malignant phenotype of ESCC. This study aimed to evaluate the roles of miR-133b in metastases of ESCC via regulating anoikis. Methods: The expression of miR-133b and related molecules were detected in ESCC tissues and cells. The target relationship between miR-133b and epidermal growth factor receptor (EGFR) was verified by dual luciferase reporter assay. Cell proliferation was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Anoikis and anchorage-independent growth were assessed by anoikis assay and soft agar assay. Migration and invasion were evaluated by scratch and transwell assays. The expressions of related molecules were detected by reverse transcription-quantitative polymerase chain reaction and western blotting. The in vivo results were determined by tumor xenografts in nude mice. Results: MiR-133b level was decreased in ESCC tissues and cells, which negatively correlated with EGFR, integrin beta4 (ITGB4), and phosphorylated focal adhesion kinase levels. Moreover, miR-133b down-regulated EGFR expression in ESCC cells. Overexpression of miR-133b inhibited the anoikis resistance, migration, invasion and epithelial-mesenchymal transition of ESCC cells via targeting EGFR. Finally, miR-133b overexpression suppressed tumor growth and lung metastases of ESCC in vivo. ITGB4/FAK/growth factor receptor-bound protein 2 (Grb2), protein kinase B (AKT), and extracellular signal-regulated kinase (ERK) pathways were involved in the regulatory mechanisms of miR-133b/EGFR axis in ESCC metastases in vitro and in vivo. Conclusions: The results suggested that miR-133b/EGFR axis regulated metastases of ESCC by affecting anoikis resistance via ITGB4/FAK/Grb2, AKT, and ERK pathways. PMID- 30479573 TI - Key factors identified by proteomic analysis in maize (Zea mays L.) seedlings' response to long-term exposure to different phosphate levels. AB - Background: Maize seedlings are constantly exposed to inorganic phosphate (Pi) limited environments. To understand how maize cope with low Pi (LP) and high Pi (HP) conditions, physiological and global proteomic analysis of QXN233 genotype were performed under the long-term Pi starvation and supplementation. Methods: We investigated the physiological response of QXN233 genotype to LP and HP conditions and detected the changes in ion fluxes by non-invasive micro-test technology and gene expression by quantitative real-time polymerase chain reaction. QXN233 was further assessed using vermiculite assay, and then proteins were isolated and identified by nano-liquid chromatography-mass spectrometry. Results: A negative relationship was observed between Na+ and Pi, and Na+ efflux was enhanced under HP condition. Furthermore, a total of 681 and 1374 were identified in the leaves and roots, respectively, which were mostly involved in metabolism, ion transport, and stress response. Importantly, several key Pi transporters were identified for breeding potential. Several ion transporters demonstrated an elaborate interplay between Pi and other ions, together contributing to the growth of QXN233 seedlings. Conclusion: The results from this study provide insights into the response of maize seedlings to long-term Pi exposure. PMID- 30479575 TI - Minor ailments, major problems: a critical appraisal of Rafferty et al. (2017). PMID- 30479574 TI - Cost-effectiveness analysis of secukinumab versus other biologics and apremilast in the treatment of active Psoriatic arthritis: a Finnish perspective. AB - Objective: To study cost-effectiveness of an interleukin (IL)-17A inhibitor secukinumab, with other biologics and apremilast in patients with Psoriatic arthritis (PsA) from payer perspective in Finland. Methods: In this semi-Markov model, subcutaneous (SC) secukinumab was compared with SC treatments etanercept and its biosimilar, certolizumab pegol, adalimumab and its biosimilar, golimumab, ustekinumab, intravenous (IV) treatment infliximab, as well as oral non-biologic apremilast. Patients without prior exposure (naive) to biologics and without moderate to severe psoriasis were considered for secukinumab 150 mg group. Secukinumab 300 mg group included naive patients with moderate to severe psoriasis and all patients with prior biologic exposure. The PsA Response Criteria (PsARC) at 12-week was primary criteria for treatment response. Other clinical as well as cost related model inputs were derived from relevant clinical trials as well as Finnish publications. The key model outcomes were quality adjusted life years and incremental cost-effectiveness ratio. An annual 3% discount rate was applied to all future costs and benefits. Model input variations were assessed through sensitivity analyses and alternative scenario analyses. Results: For a lifetime horizon (60 years), secukinumab 150 mg dominated all branded SC biologics and apremilast with highest QALY of 8.01 and lowest lifetime cost of ?187,776, while it was cost-effective against IV infliximab among biologic-naive patients without moderate to severe psoriasis. Secukinumab 300 mg was cost-effective against all branded SC biologics and apremilast and dominated IV infliximab among biologic-naive patients with moderate to severe psoriasis, while it was cost-effective in biologic experienced patients. With the one-way sensitivity analysis, PsARC response, drug acquisition cost, and health assessment questionnaire score were the most important parameters affecting the outcomes. Across all treatment groups, patients on secukinumab were most likely to achieve highest net monetary benefit than other competitors in probabilistic sensitivity analysis. With alternative scenario analysis, results largely remained unchanged. Conclusions: Secukinumab is a cost effective treatment for PsA patients from a Finnish payer's perspective. PMID- 30479576 TI - Cost-effectiveness of strategies to prevent road traffic injuries in eastern sub Saharan Africa and Southeast Asia: new results from WHO-CHOICE. AB - Background: Road safety has been receiving increased attention through the United Nations Decade of Action on Road Safety, and is also now specifically addressed in the sustainable development goals 3.6 and 11.2. In an effort to enhance the response to Road Traffic Injuries (RTIs), this paper aims to examine the cost effectiveness of proven preventive interventions and forms part of an update of the WHO-CHOICE programme. Methods: Generalized cost-effectiveness analysis (GCEA) approach was used for our analysis. GCEA applies a null reference case, in which the effects of currently implemented interventions are subtracted from current rates of burden, in order to identify the most efficient package of interventions. A population model was used to arrive at estimates of intervention effectiveness. All heath system costs required to deliver the intervention, regardless of payer, were included. Interventions are considered to be implemented for 100 years. The analysis was undertaken for eastern sub-Saharan Africa and Southeast Asia. Results: In Southeast Asia, among individual interventions, drink driving legislation and its enforcement via random breath testing of drivers at roadside checkpoints, at 80% coverage, was found to be the most cost-effective intervention. Moreover, the combination of "speed limits + random breath testing + motorcycle helmet use", at 90% coverage, was found to be the most cost-effective package. In eastern sub-Saharan Africa, enforcement of speed limits via mobile/handheld cameras, at 80% coverage, was found to be the most cost-effective single intervention. The combination of "seatbelt use + motorcycle helmet use + speed limits + random breath testing" at 90% coverage was found to be the most cost-effective intervention package. Conclusion: This study presents updated estimates on cost-effectiveness of practical, evidence-based strategies that countries can use to address the burden of RTIs. The combination of individual interventions that enforces simultaneously multiple road safety measures are proving to be the most cost-effective scenarios. It is important to note, however, that, in addition to enacting and enforcing legislation on the risk factors highlighted as part of this paper, countries need to have a coordinated, multi-faceted strategy to improve road safety. PMID- 30479577 TI - The acceptance and willingness to pay (WTP) for hypothetical dengue vaccine in Penang, Malaysia: a contingent valuation study. AB - Background: Malaysia has been experiencing an escalation in dengue cases since the past 5 years. As the dengue vaccine pipeline continues to develop steadily with strong public interests, this study had been sought to elicit the acceptance and the willingness to pay (WTP) for hypothetical dengue vaccine in Malaysia. Methods: This study adopted the cross-sectional, contingent valuation study that involved 400 respondents in Penang, Malaysia. The double-bounded dichotomous choice via bidding game approach was employed to elicit the WTP value for two hypothetical 3-doses dengue vaccines (Vaccines A and B with 5- and 10-years' protection, respectively against dengue). A univariate logistic regression model was employed to assess the key determinants of vaccine acceptance, while the mean WTP value and its associated factors were measured by using the parametric two part model (TPM). Results: Dengue vaccine appeared to be highly acceptable (88.4%) among the population in Penang, Malaysia. Respondents who were of Chinese ethnicity (OR 0.36, p = 0.017), with higher dengue knowledge score (OR 1.43, p = 0.016), and higher vaccination attitude score (OR 1.91, p < 0.001) were more likely to accept the vaccine. The first step logit estimation from TPM displayed that pensioners (OR 2.37, p = 0.036), respondents who were self-employed or working in the private sector (OR 1.21, p = 0.002), respondents with higher education level (OR 2.09-3.29, p < 0.05), and those who accepted the vaccine (OR 3.23, p = 0.001) were more likely to pay for the vaccine. The adjusted mean WTP value for the vaccine was MYR39.21 (USD9.45) per dose. Next, the second-stage regression from TPM revealed the key factors that significantly affected the WTP value, which were composed of age, gender, occupation, household income, dengue prevention practice, and protection duration of the vaccine. The pensioners and those with better dengue prevention practice were willing to pay more for the vaccines. Additionally, all the respondents elicited a higher WTP amount toward the vaccine with longer protection duration (Vaccine B). Conclusion: Strong acceptance toward dengue vaccine reflects the high value of the vaccine in Malaysia. The WTP estimates offer quantification of the private benefit in reducing occurrences of the disease. Besides, the people's preferences-based WTP value for the vaccine tends to complement scientific decision-making and prioritization in the management of dengue in the country. PMID- 30479578 TI - Costs and savings associated with a pharmacists prescribing for minor ailments program in Saskatchewan. PMID- 30479580 TI - Enhancing radiotherapy effect in breast cancer with nanoparticles: A review. AB - Amongst all efforts for improving oncological management outcomes, nanoparticles enhanced radiation for breast cancer patient's treatment is a novel approach that has grown interest for research in the last decade. Multiple preclinical data has been published, from all around the globe; however, clinical evidence is still insufficient for implementing the method in routine practice and in disease specific management. Gold nanoparticles (AuNP), which may be among the most studed materials, account for the majority of available data; however, some new materials have also been used in preclinical settings. Without any safety data available at the moment to support an active use, dosimetric in vitro and in vivo information seems to be consistent with a very promising and hopeful panorama for clinical applications. This review evaluates existing dosimetric data in breast cancer tissue, and a probable future impact in treatment choices and patient outcomes, as further investigation is required in a clinical setting. PMID- 30479579 TI - Anti-inflammatory Activity of Tocotrienols in Age-related Pathologies: A SASPected Involvement of Cellular Senescence. AB - Tocotrienols (T3) have been shown to represent a very important part of the vitamin E family since they have opened new opportunities to prevent or treat a multitude of age-related chronic diseases. The beneficial effects of T3 include the amelioration of lipid profile, the promotion of Nrf2 mediated cytoprotective activity and the suppression of inflammation. All these effects may be the consequence of the ability of T3 to target multiple pathways. We here propose that these effects may be the result of a single target of T3, namely senescent cells. Indeed, T3 may act by a direct suppression of the senescence-associated secretory phenotype (SASP) produced by senescent cells, mediated by inhibition of NF-kB and mTOR, or may potentially remove the origin of the SASP trough senolysis (selective death of senescent cells). Further studies addressed to investigate the impact of T3 on cellular senescence "in vitro" as well as in experimental models of age-related diseases "in vivo" are clearly encouraged. PMID- 30479582 TI - Predicting the HILIC Retention Behavior of the N-Linked Glycopeptides Produced by Trypsin Digestion of Immunoglobulin Gs (IgGs). AB - The prediction of the retention behavior/time would facilitate the identification and characterization of glycoproteins, particularly the analytical challenges, such as the characterization of low-abundance glycoforms. This task is essential in the biotherapeutics industry, where the type and amount of glycosylation on recombinant IgG alter the efficacy, function, and immunogenicity. Models exist for the prediction of the hydrophilic interaction liquid chromatography retention of peptides and glycans. Here, we have devised a unified model to predict the retention behavior of glycopeptides from human IgGs and applied this to the analysis of glycopeptides from rabbit IgGs. The combined model is capable of accurately predicting the retention of native IgG glycopeptides on 2 completely different liquid chromatography-mass spectrometry systems. PMID- 30479581 TI - Feasibility of intensity-modulated radiotherapy to treat gastric cancer. AB - Aim: To present a proposed gastric cancer intensity-modulated radiotherapy (IMRT) treatment planning protocol for an institution that have not introduced volumetric modulated arc therapy in clinical practice. A secondary aim was to determine the impact of 2DkV set-up corrections on target coverage and organ at risk (OAR). Methods and Materials: Twenty consecutive patients were treated with a specially-designed non-coplanar 7-field IMRT technique. The isocenter-shift method was used to estimate the impact of 2DkV-based set-up corrections on the original base plan (BP) coverage. An alternative plan was simulated (SP) by taking into account isocenter shifts. The SP and BP were compared using dose volume histogram (DVH) plots calculated for the internal target volume (ITV) and OARs. Results: Both plans delivered a similar mean dose to the ITV (100.32 vs. 100.40%), with no significant differences between the plans in internal target coverage (5.37 vs. 4.96%). Similarly, no significant differences were observed between the maximal dose to the spinal cord (67.70 and 67.09%, respectively) and volume received 50% of the prescribed dose of: the liver (62.11 vs. 59.84%), the right (17.62 vs. 18.58%) and left kidney (29.40 vs. 30.48%). Set-up margins (SM) were computed as 7.80 mm, 10.17 mm and 6.71 mm in the left-right, cranio-caudal and anterior-posterior directions, respectively. Conclusion: Presented IMRT protocol (OAR dose constraints with selected SM verified by 2DkV verification) for stomach treatment provided optimal dose distribution for the target and the critical organs. Comparison of DVH for the base and the modified plan (which considered set-up uncertainties) showed no significant differences. PMID- 30479583 TI - Differential analysis of quantitative proteome and acetyl-proteome profiling between premenopausal and postmenopausal ovarian tissues. AB - Background: Natural menopause is always accompanied by specific signs and symptoms, suggesting physiological changes in this peoriod. However, no systematic study has assessed the changes at molecular level in the ovaries during the menopausal transition so far. This study integrated quantitative proteome and acetyl-proteome to comprehensively uncover the changes of ovarian protein and protein-acetylation profiles in this transitional period. The findings would provide novel insights into the biology of menopause and help relieve and treat the associated signs and symptoms, further improving the women's health care. Methods: Freshly thawed ovarian tissue samples obtained from premenopausal and postmenopausal women were assessed with Tandem Mass Tags for the quantitative analysis of the global profile and acetyl-proteomes by 2 dimensional separation and LC-MS/MS. Results: Comprehensively, 4210 types of protein, with 3551 types quantifiable were detected. 3047 acetylated sites in 1583 types of protein with 2256 quantifiable in 1248 proteins were detected. By comparing the global and acetylated proteome profiles for postmenopausal women and premenopausal women, 151 types of proteins were found upregulated and 65 were downregulated, along with 23 acetylated sites upregulated and 220 sites downregulated. For Immune response, the complement and coagulation cascades plus the citrate cycle and cellular detoxification were found to be significantly enhanced, while the extracellular structure and matrix organization, ECM-receptor interactions plus the infections were markedly suppressed. In addition, the amino acids around the acetylated sites were enriched by motif analysis, which can help us uncover amino acid sequence and search for the specific target in the subsequent study. Conclusion: Global and acetylated proteome Profiles in ovary differ between the premenopausal and postmenopausal groups. These proteomic-level changes may offer some potential biological markers to identify the pathological changes in ovary and help relieve and treat the associated signs and symptoms, and ultimately improve women's health care. PMID- 30479584 TI - Correction to: Quantitative phosphoproteomic analysis reveals reciprocal activation of receptor tyrosine kinases between cancer epithelial cells and stromal fibroblasts. AB - [This corrects the article DOI: 10.1186/s12014-018-9197-x.]. PMID- 30479585 TI - Green Platinum Nanoparticles Interaction With HEK293 Cells: Cellular Toxicity, Apoptosis, and Genetic Damage. AB - Metal nanoparticles are widely used in industry, agriculture, textiles, drugs, and so on. The adverse effect of green platinum nanoparticles on human embryonic kidney (HEK293) cells is not well established. In the current study, green platinum nanoparticles were synthesized using leaf extract of Azadirachta indica L. Green platinum nanoparticles were characterized by dynamic light scattering and transmission electron microscope. The cytotoxicity of green platinum nanoparticle was observed in HEK293 cells by applying 3-(4,5-dimethylthiazol-2 yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and Neutral red uptake (NRU) assays. Cell viability of the cells was decreased in a concentration and duration-dependent manner. Generation of reactive oxygen species (ROS) in HEK293 cells due to green platinum nanoparticles was examined using fluorescent dye 2,7-dichlorofluorescein diacetate (DCFDA), and ROS was increased according to exposure pattern. The cytotoxicity of HEK293 cells was correlated with increased caspase 3, depolarization of mitochondrial membrane potential, and DNA fragmentation. The abovementioned finding confirmed that mitochondria play an important role in genotoxicity and cytotoxicity induced by nanoparticles in HEK293 cells. Further, we determined other oxidative stress biomarkers, lipid peroxide (LPO) and glutathione (GSH); LPO was increased and GSH was decreased in HEK293 cells. It is also important to indicate that HEK293 cells appear to be more susceptible to green platinum nanoparticles exposure after 24 hours. This result provides a dose- and time-dependent apoptosis and genotoxicity of green nanoparticles on HEK293 cells. PMID- 30479586 TI - 2,3,7,8-Tetrachlorodibenzo-p-Dioxin and TGF-beta3 Mediated-Mouse Embryonic Palatal Mesenchymal Cells. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a well-known environmental teratogenic agent for cleft palate. But transforming growth factor beta3 (TGF beta3) is an essential growth factor for palatogenesis. This study is to clarify effects of TCDD and TGF-beta3 in mouse embryonic palatal mesenchymal (MEPM) cells. The result showed that with increase of TCDD (0.5 nM-10 nM), the expression of TGF-beta3 increased, but after 10 nM TCDD, the expression of TGF beta3 reduced. The viabilities of MEPM cells decreased in 10 nM TCDD-treated group. But the viabilities increased in 10 ng/mL TGF-beta3-treated group, or the viabilities were between that of them in combination of 10 nM TCDD and 10 ng/mL TGF-beta3-treated group. This phenomenon was the same as the motilities. In addition, we found that the expression of phosphorylated Smad2/3 and Smad7 was increased by 10 nM TCDD, 10 ng/mL TGF-beta3, or combination of 10 nM TCDD and 10 ng/mL TGF-beta3 induced, but the expression of Smad4 was decreased. These data revealed that the TGF-beta/Smad signaling pathway affected TCDD and TGF-beta3 in MEPM cells. PMID- 30479588 TI - Evidence of a Dose Threshold for Radiation-Induced Leukemia. AB - In 1958, Neil Wald presented data on the incidence of leukemia among the Hiroshima atomic bomb survivors. These data, which suggested a dose-response threshold for radiation-induced leukemia, were included in the first UNSCEAR report (1958). However, this evidence of a threshold was not recognized. It was obfuscated and concealed. In 2010, Zbigniew Jaworowski identified these data as evidence of radiation hormesis. A letter to the editor in 2014 and 2 articles in 2014 and 2015 presented a graph of these UNSCEAR 1958 data, which revealed a threshold at about 500 mSv. Since the blood-forming stem cells of bone marrow are more radiosensitive than most other cell types, it is reasonable to expect thresholds for inducing other types of cancer by ionizing radiation-their thresholds are likely higher than 500 mSv. A careful examination of the Wald data reveals the suprisingly low incidence of radiogenic leukemia, only 0.5% of the survivors who were in the high radiation zone. Many articles on radiation risk have been published since 2015 by other authors, but none makes reference to this evidence of a threshold, either to challenge or endorse it. In this commentary, the author addresses the comments from a colleague. PMID- 30479587 TI - Sodium Dichloroacetate Pharmacological Effect as Related to Na-K-2Cl Cotransporter Inhibition in Rats. AB - The study objective was to investigate a possible sodium dichloroacetate (DCA) pharmacological mechanism causing an increase in diuresis in rats. The aim was to define characteristics of 24-hour urinary Na+, K+, Cl-, Ca2+, and Mg2+ excretion in Wistar male rats and to evaluate effect of a single-dose DCA and repeated DCA dosage on diuresis. Six control and 6 DCA-treated male rats aged 5 to weeks after a single DCA dose and repeated dosage were tested. The single DCA dose treatment caused a significantly higher 24-hour diuresis when compared to control (P < .05), and it was related to increased Cl-, Na+, and K+ urine excretion and a significant increase in Ca2+ and Mg2+ excretion (P < .05); after the repeated 4 week DCA dosage, the diuresis was not increased, but the excretion of the Na+, Cl , Ca2+, and Mg2+ ions was significantly higher. Kidney immunohistochemistry has revealed that DCA continuous treatment results in an increase in the size of Henle loop thick ascending limb epithelial cells (P < .001). The study results show a significantly reduced RNA expression of Na-K-2Cl co-transporter (NKCC1) in thymus of 4-week DCA-treated rats (P < .03). The study data have indicated a possible mechanism of such pharmacological effect to be NKCC inhibition. PMID- 30479590 TI - Critical Care Testing in the New Millennium - The Integration of Point of Care Testing. PMID- 30479589 TI - Biological Effects of Continuous Low-Dose-Rate Irradiation in Silkworms and Mice: Growth Promotion and Tumor Transplantability. AB - A previous study showed that continuous low-dose-rate irradiation promoted the growth of silkworm larvae. This study aimed to confirm that finding, determine the optimal dose rate for growth promotion, and compare low- and high-dose-rate irradiation in silkworms, while also investigating the effects of the radiation emitting sheet on growth and tumor transplantability in mice. Silkworm eggs were placed on low-dose-emitting sheets with 4 different dose rates (gamma-ray rate: 1.7 -22.4 MUSv/hour) or on control sheets. The other groups of silkworm larvae received single whole-body X-irradiation (0.1-50 Gy), and subsequent body weight changes were monitored. Starting at 3 weeks old, Balb/c mice were bred on the same sheets, and body weight change was measured. Seven weeks later, the mice were used to investigate the transplantability of EMT6 tumor cells cultured in vitro. The silkworms bred on the 13.4- and 22.4-MUSv/hour sheets became larger than the control. Single 50-Gy irradiation suppressed the growth of silkworms. An increase in the time to EMT6 tumor development was observed in low-dose-rate irradiated mice. This study confirmed growth promotion of silkworms by continuous low-dose radiation and demonstrated growth suppression at a high dose rate. Growth promotion was not observed in mice; further studies using higher dose-rate sheets may be warranted. PMID- 30479591 TI - The Essential Role of Information Management in Point-of-Care/Critical Care Testing. AB - Laboratory medicine is undergoing tremendous change in recent years driven primarily by technology, regulations, reimbursement, and market forces. In this paradigm shift, the laboratory is under tremendous pressure to adapt to new requirements for critical care testing. Indeed, laboratories have entered the information age where chemical data is being extracted from specimens in totally automated fashion. In the past, laboratory data has played a more historical role in the care of critically ill patients, arriving at the bedside too late to be of significant use in the active, ongoing care of the patient. However, today's physicians taking care of critically ill patients now require that laboratory results are made available in real-time and, if possible, at the patient's pont of-care. Many new testing point-of-care testing devices have been developed to address this need however often laboratories implement such distributed devices with little or no attention to the information technology requirements. In fact, as little as 10 percent of point-of-care testing is actually managed by the central laboratory computer hence critically importance results are not found on the patient's electronic medical record. In addition, the billing and management data for point-of-care testing is often handled manually with no plans to interface point-of-care devices to the laboratory billing and management systems. Because of recent improvements of information handling and interface capability, such shortcomings in data management are no longer acceptable. Indeed, the demands for laboratories to utilize information technology are such that those laboratories with no overall plan for data management of critical care testing will probably not survive this market driven paradigm. We present a discussion of the various approaches to computerization of point-of-care testing including the advantages and the disadvantages of each approach. PMID- 30479593 TI - The Value of Blood Lactate Measurements in ICU: An Evaluation of the Role in the Management of Patients on Haemofiltration. AB - In response to clinical demand some point-of-care analysers now provide blood lactate measurements in critical care. Recent literature has raised concerns about the value and interpretation of these measurements. Two particular concerns relate to over-interpretation of lactate rises as equating tissue hypoxia and also the failure to recognise the contribution from inotropic support. We undertook this study to evaluate blood lactate measurements in intensive care unit (ICU) patients in the assessment of response to, and requirements for, haemofiltration (HF) with lactate replacement fluid and to evaluate influences from hepatic failure and from inotropic supportive therapy. Haemofiltration is a convenient renal replacement therapy widely used in intensive care management as an alternative to haemodialysis. Mainly used for the treatment of acute renal failure the process involves removal by filtration of fluid, electrolytes, metabolites and other substances and simultaneous replacement of essential fluid and electrolytes as well as a buffer, usually in the form of lactate (sodium salt). There is controversy about whether lactate replacement may be harmful to the patient and, if so, when it would be appropriate to use a lactate-free fluid at greater expense. Serial blood lactate with simultaneous blood gas measurements were recorded in 27 patients requiring HF for acute renal failure. At baseline all patients had base deficits of >5mmol/L and 14 (52%) had blood lactates of >3.5mmol/L. Lactate 'tolerance' was monitored by peak changes in these parameters during the procedure. There was a worsening of base deficit in only three of the patients in whom lactate rises exceeded 10 mmol/L at some stage during HF with one survivor. A further twelve patients with rises of blood lactate greater than 5 mmol/L improved their base deficit (+1 to +17) with 8 (67%) survivors. Of the remaining twelve patients with improved base deficit (+2 to +20), 10(83%) survived. The influence on 'lactate tolerance' in patients with co-incidental liver disease and those on inotropic support was studied. In these groups lactate tolerance was compromised, particularly those on adrenaline support. Patients with initial blood lactate measurements of >10mmol/l and large base deficits were also lactate intolerant. The data suggest that rises in blood lactate during HF signal harm if accompanied by inadequate improvement in base deficit. Blood lactate and simultaneous acid-base response measurements during HF help to assign correct buffer replacement and should be performed on all patients. PMID- 30479592 TI - Microchips, Microarrays, Biochips and Nanochips - Personal Laboratories for the 21st Century. PMID- 30479594 TI - Recommendation on Reporting Results for Blood Glucose (From an IFCC Stage 1 Document) IFCC Scientific Division Working Group on Selective Electrodes. PMID- 30479595 TI - IFCC Professional Scientific Exchange Programme Expression of CD85, a Killer-Cell Inhibitory Receptor (KIR) Molecule on T Cells in B-Chronic Lymphocytic Leukemia (B-CLL). PMID- 30479596 TI - Foreword from the Editor-in-Chief. PMID- 30479597 TI - Laboratory Medicine: Meeting the Needs of Mediterranean Nations. PMID- 30479598 TI - Communicable Diseases in the Mediterranean Region. AB - Communicable diseases still pose a health hazard and are a major cause of death in many parts of the world. Tuberculosis is one of the top 10 causes of death worldwide with an annual burden of 1.7 million. Global deaths in 2016 for other communicable diseases included 1.34 million from hepatitis; 1.0 million from HIV related causes; and almost half a million from malaria. Outbreaks of vaccine preventable diseases like polio, measles, rubella and other life-threatening diseases also pose a significant threat to various communities around the world. In this paper, we shed some light on the epidemiology of communicable diseases in the Mediterranean Region and conclude that socioeconomic differences between the north and the south Mediterranean lead to differences in the epidemiology of communicable diseases. PMID- 30479599 TI - Are Medical Laboratories Ready for the Diagnosis of Parasitic Diseases? AB - Economic instability, destabilisation with armed conflagration, religious and ethnic conflicts are the most important driving factors for migrations towards Europe. Mediterranean countries are important route for refugees who emigrate from the Middle East, Africa and Asia. Viral, bacterial, parasitic and fungal diseases carried by these refugees constitute a significant health risk in Mediterranean countries. Parasitic diseases, such as intestinal parasites, pediculosis, scabies, lymphatic filariasis, schistosomiasis, malaria and leishmaniasis, which may reach the Mediterranean region trough migrations, were briefly reviewed and the precautions to be taken were mentioned. It is of utmost importance that laboratories in the Mediterranean countries pay particular attention to parasitic infections, especially by using experienced staff and appropriate diagnostic methods in combating such infections. The diagnosis and screening of all these infections among the refugees can be done by some basic parasitological laboratory methods such as direct methods for stool samples (direct wet smear, concentration methods, permanent stains, special stains), methods for blood samples (thick and thin blood films, blood concentration procedures), direct methods for urogenital specimens, serological methods, molecular methods and rapid diagnosis kits. These methods can be easily learned by laboratory employees. We suggest that migratory related infections study group should be established in Mediterranean countries, which should inform each other by sharing their findings and observations with officials in congresses and symposiums, and should cooperate on this issue and prepare training and workshop programs and health education programs in these countries should be updated about the health and risk factors of refugees. PMID- 30479600 TI - Travel, Migration and Emerging Infectious Diseases. AB - Emerging infectious diseases (EID) threaten public health and are sustained by increasing global commerce, travel and disruption of ecological systems. Travelers could play a role in importing EIDs and could be a sentinel of major epidemics. In connection with the extension of poverty, urbanization, extensive livestock rearing and globalization, we could be exposed to a third epidemiological transition characterized by zoonotic diseases and infections with multidrug-resistant bacteria. The risk appears low for emerging infectious diseases, or very low for high-risk emerging infectious diseases, but higher for multidrug-resistant enterobacteriaceae carriage with possibly limited consequences. The role played by migrants is weaker than imagined. Immigrants don't play the role of sentinel epidemic so far. They could play a role in importing multidrug-resistant enterobacteriaceae, but it is poorly evaluated. PMID- 30479601 TI - Is the Profession of Laboratory Medicine Uniform Across the North Mediterranean Countries? AB - Harmonization of the postgraduate training of both Clinical Scientists and Physicians, in Laboratory Medicine (LM) has been a goal for many years, for the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) and the Union Europeenne de Medecins Specialistes (UEMS), Section of Laboratory Medicine/Medical Biopathology. This was based on the concept of free movement of people within the European Union. Much has been achieved within the respective European organizations in the development of curricula that will harmonize the postgraduate training at least within the European Union (EU). Advances in the area of diagnostics and the need for particular expertise in distinct areas have led to the emergence of laboratory scientists and physicians specialized in hematology (including transfusion medicine), clinical biochemistry, immunology, and microbiology. However, the training and specialization is varying and practice is of laboratory medicine is polyvalent in some countries and single specialties in others countries. Moreover, these advances have led to the involvement of non-medical scientists in the clinical laboratories. However, the training and the roles of Medical Doctors and Clinical Scientists in a Clinical laboratory, differ from country to country. These differences still remain today throughout Europe and even within the EU. PMID- 30479602 TI - EFLM Project "Exchange of Practical Knowledge and Skills in Laboratory Medicine" EFLMLabX. AB - Background: In many laboratories/institutions of the European Federation for Clinical Chemistry and Laboratory Medicine (EFLM) there is a need to acquire additional practical knowledge and skills in different fields of Laboratory Medicine (LM).Until now, there were no possibilities, in official and open ways, to find the link to such additional but very important education, which may be obtained in other laboratories in the country or abroad. The aim of this EFLM project is to create and operate a network of medical laboratories willing and able to offer practical training in various fields/aspects of Laboratory Medicine. Methods: We conducted the survey among EFLM members, with the aim to identify the EFLM members' needs and possibilities to offer different practical training in laboratories in the country or abroad. We created the EFLMLabX website portal within the main EFLM website for offering, searching the practices and establishing direct contacts between applicants and providers institutions. Results: According to the very positive survey results (146 responses) about needs (128) and interest to offer different practices (87) on the field of LM, that we have obtained from EFLM National Societies (28) in 2015, we noted a great interest for training and exchange of practical knowledge and skills in LM amongst EFLM countries. In January 2018 we have launched EFLMLabX portal. Since now we have already 13 providers/partners institutions, from 10 different countries, which offer 17 different practice positions. Four practices are already ongoing and two were already finished. Conclusions: With this project, according to obtained higher level of knowledge/experience on different field of laboratory diagnostics of general professional population (of EuSpLM), better networks between professionals, experts, and scientists we will gain higher general quality of our profession. PMID- 30479603 TI - Economic Evaluation as a Tool in Emerging Technology Assessment. AB - Medical technologies are part of health technologies and they include medical devices (MD) and in vitro diagnostics (IVD). They have become a vital part of modern healthcare. Framework for introduction of new technology in the healthcare system includes a few steps: analytical and clinical accuracy assessment, clinical utility determination and economic evaluation. In addition, payers are interested whether new technology is adequate for reimbursement. There are fairly enough specific guidelines for implementation of economic methods at the early stage of IVD development. Searching the available literature in this field, this paper discusses the economic evaluations of emerging medical technologies with focus on point of care testing (POCT) and genetic testing. Results of POCT economy studies depend on investigated perspective (payers, policy makers or society), used effectiveness values (utility, effectiveness or consequence estimated as monetary value) and understanding of clinical pathway. There is a need for better understanding of the care pathway, resource utilisation and how they change with the introduction of POCT. Introduction of genetic testing before drug therapy was recommended with the aim to improve treatment benefit and to reduce costs of adverse drug reaction. Clinical utility and cost-effectiveness analyses should be considered for novel genetic testing - guided treatments. Most of the studies considering genetic testing - guided treatments showed that those combinations were cost-saving or cost-effective compared to standard care. For medical tehnology there is no universal guidance for outcomes measurement, cost calculation, performance requirements, use of a certain type of economic studies and economic thresholds. PMID- 30479604 TI - Who or What is SHERLOCK? AB - Background: Polymerase chain reaction (PCR) is the most commonly used method for detecting nucleic acids. However, PCR requires specialized and expensive equipment, as well as specially trained personnel. Recently, new innovative diagnostic methods have been developed to detect nucleic acids using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene editing technology. Objective: This manuscript reviews the newly emerging diagnostic methods that exploit the CRISPR technology. Results: The programmable endonuclease properties of CRISPR have been harnessed for use in diagnostic testing.Specific High-sensitivity Enzymatic Reporter un-LOCKing (SHERLOCK) and DNA Endonuclease Targeted CRISPR Trans Reporter (DETECTR) are diagnostic tools that can be used to detect specific RNA/DNA at low attomolar concentrations. Heating Unextracted Diagnostic Samples to Obliterate Nuclease (HUDSON), is a process of heat and chemical reduction that allows for direct detection of nucleotides in body fluids.HUDSON and SHERLOCK can be combined to detect RNA/DNA directly from urine, saliva, serum, plasma, and whole blood with limited sample preparation or equipment with results in 1 to 2 hours. In addition, a lateral flow readout has been developed to facilitate assay detection. Conclusions: Potential uses of this emerging technology are numerous due to the analytical sensitivity and specificity, simplicity, speed, and flexibility. PMID- 30479605 TI - Advancement in POCT Molecular Testing: The Multiplex PCR POCT Devices for Infectious Diseases. AB - Rapid and accurate diagnostic tests are very important for the global control of infectious diseases. The point of care diagnosis has become a promising strategy in recent years. Different kind of point of care testing devices has been introduced into the market in the last decade. These devices must provide a low cost, robust, sensitive, specific, and practical analysis in order to replace the conventional clinical laboratory diagnostic test algorithms when needed. The successful implementation of point of care diagnostics has a potential to increase the strength of infectious diseases surveillance programs. Finally, the rapid progress in point of care diagnosis can stimulate a shift from a centralized diagnostic model to a decentralized patient-centered approach. PMID- 30479606 TI - New Solutions for the Sample Transport and Results Delivery: A Digital Lab. AB - The consolidation of laboratories, the evolution to integrated care network as well as an environment of consumerization are disrupting laboratory services and operations. The switch to SMART (Speed Metrics Automation Remote Technologies) digital laboratories based health ecosystems depends on several prerequisites for successes. Intelligent processes, integration of big data and real-time data management, automation, blockchain, Internet of things and enhancement of user experiences are key element of the smart digital laboratory. Safety, security and cost-effectiveness are pillars for the credibility and transferability of such smart digital laboratory environment. This transforming ecosystem will also trigger novel human - machine interfaces and we will be the gatekeepers for this new "click to brick" ecosystem. PMID- 30479607 TI - Next Generation Sequencing: From Research Area to Clinical Practice. AB - Translating the power of high-throughput sequencing technologies from research area into clinical medicine is one of the major goal for several researchers and health-care providers. One of the important advantages of these technologies is that they can be successfully used in a numerous range of clinical applications. The efficiency of sequencing, that can now be achieved, is leading impressive progress in the diagnostics of common and rare genetic disorders, inherited forms of cancer, prenatal testing or infectious diseases, to cite some examples. Despite several challenges and limitations still remain to overcome, the high throughput sequencing technologies are leading to real and unprecedented benefits for the medical care of patients. PMID- 30479608 TI - miRNA and Other Non-Coding RNAs as Promising Diagnostic Markers. AB - Since the discovery of non-coding RNAs (ncRNAs) a new area has emerged in the field of biomarkers. NcRNAs are RNA molecules of different sizes that are transcribed as independent genes or as part of protein coding genes and are not translated, therefore they do not produce proteins. They have been classified according to their size and function and include microRNAs (miRNAs), piwiRNAs (piRNAs), snoRNAs and long non-coding RNAs (lncRNAs). These non-coding RNAs are present in different cell compartments participating in multiple cell functions, but they have also been identified in biological fluids, also known as cell-free or circulating ncRNAs, where they can be detected in exosomes, bound on lipoproteins as well as free circulating molecules. The role of circulating ncRNAs is still under investigation but are believed to be paracrine or endocrine messengers to systematically deliver signals between cells and tissues. Detecting ncRNAs in biological fluids has opened a new field in Clinical Chemistry utilizing them as biomarkers of diseases or prognostic markers for different pathological conditions. Herein, the different types of ncRNAs and their potential in the field of diagnostics are outlined. PMID- 30479609 TI - NGS for Metabolic Disease Diagnosis. PMID- 30479610 TI - Reflections on the Mentor-Mentee Relationship: A Symbiosis. PMID- 30479611 TI - Inter-Laboratory Exchange of Knowledge and Technology Around our Sea - A Lab Surfing Project. PMID- 30479612 TI - Corrigendum: Carbapenem-Resistant E. cloacae in Southwest China: Molecular Analysis of Resistance and Risk Factors for Infections Caused by NDM-1-Producers. AB - [This corrects the article DOI: 10.3389/fmicb.2018.00658.]. PMID- 30479613 TI - Corrigendum: Characterization of ML-005, a Novel Metaproteomics-Derived Esterase. AB - [This corrects the article DOI: 10.3389/fmicb.2018.01925.]. PMID- 30479614 TI - Intravitreal injection of the synthetic peptide LyeTx I b, derived from a spider toxin, into the rabbit eye is safe and prevents neovascularization in a chorio allantoic membrane model. AB - Background: The great diversity of molecules found in spider venoms include amino acids, polyamines, proteins and peptides, among others. Some of these compounds can interact with different neuronal receptors and ion channels including those present in the ocular system. To study potential toxicity and safety of intravitreal injection in rabbits of LyeTx I b, a synthetic peptide derived from the toxin LyeTx I found in venom from the spider Lycosa eritrognatha and to evaluate the angiogenic activity on a CAM model. Methods: ARPE-19 cells were treated with LyeTx I b (0.36; 0.54; 0.72; 2.89; 4.34 or 9.06 MUM). In this study, New Zealand rabbits were used. LyeTx I b (2.89 MUM) labeled with FITC dissolved in PBS, or only PBS, were injected into vitreous humor. Electroretinogram (ERG) was recorded 1 day before injection and at 7, 14 and 28 days post-injection. Clinical examination of the retina was conducted through tonometer and eye fundus after ERG. Eyes were enucleated and retinas were prepared for histology in order to assess retinal structure. CAMs were exposed to LyeTx I b (0.54; 0.72; 2.17 or 2.89 MUM). Results: ARPE-19 cells exposed to LyeTx I b showed cell viability at the same levels of the control. The fluorescence of LyeTx I b labeled with FITC indicated its retinal localization. Our findings indicate ERG responses from rats injected in the eye with LyeTx I b were very similar to the corresponding responses of those animals injected only with vehicle. Clinical examination found no alterations of intraocular pressure or retinal integrity. No histological damage in retinal layers was observed. CAM presented reduced neovascularization when exposed to LyeTx I b. Conclusions: Intravitreal injection of LyeTx I b is safe for use in the rabbit eye and prevents neovascularization in the CAM model, at Bevacizumab levels. These findings support intravitreal LyeTx I b as a good candidate to develop future alternative treatment for the retina in neovascularization diseases. PMID- 30479615 TI - Acute and late toxicities in localized prostate cancer patients treated with low dose 125I brachytherapy (110 Gy) in combination with external beam radiation therapy versus brachytherapy alone (160 Gy). AB - Purpose: The aim of this analysis was to compare acute and late toxicities between low-dose-rate brachytherapy (LDR-BT) (110 Gy) in combination with 45 Gy in 25 fractions external beam radiation therapy (EBRT) and LDR-BT (160 Gy) alone for localized prostate cancer. Material and methods: One hundred five consecutive patients with localized prostate cancer treated from May 2014 to May 2017 were included in this retrospective analysis. Sixty patients received combination therapy and 45 patients received BT monotherapy. The LDR-BT procedure was performed using 125I seeds. Results: The median follow-up time was 28 months in both groups. Three-year effect rates were overall survival: 100% in both groups. The biochemical failure rate was 2.3% in the combination group and 0% in the monotherapy group (p = 0.373). No patients died during the study period. In both groups, almost all the patients experienced acute urethritis. There was a significant difference between the combination therapy group (8.3%) and BT monotherapy group (11.1%) in late genitourinary (GU) toxicities >= grade 2 (p = 0.035). Only 2 patients (3.3%) in the combination therapy group developed late >= grade 2 rectal hemorrhage. There were no significant differences between two groups in hematuria >= grade 2 (p = 0.068) or rectal hemorrhage >= grade 2 (p = 0.206). Conclusions: To our knowledge, this is the first report to compare the GU and gastrointestinal toxicities between the combination therapy and BT monotherapy (160 Gy) for localized prostate cancer. Unexpectedly, there were more late GU toxicities (except for hematuria) in the BT monotherapy group. PMID- 30479616 TI - Predicting pubic arch interference in permanent prostate brachytherapy based on the specific parameters derived from nuclear magnetic resonance imaging. AB - Purpose: The aim of this study was to establish a more reliable method to predict pubic arch interference (PAI) before permanent prostate brachytherapy. Material and methods: We retrospectively analyzed the nuclear magnetic resonance imaging (MRI) results of forty patients with prostate cancer, who were treated with permanent implantation of 125I seeds (permanent brachytherapy). We measured and calculated six parameters based on the MRI results: 1. The prostate volume (PV); 2. The angle of the pubic arch (AoPA); 3. The angle of PAI (AoPAI, pubic symphysis level); 4. The height of PAI (hPAI, pubic symphysis level); 5. The maximum angle of PAI (AoPAIMax); 6. The maximum height of PAI (hPAIMax). We then tested which parameters could accurately predict PAI through receiver operating characteristic (ROC) curve analysis. Results: The results of this study demonstrated that AoPAI, hPAI, hPAIMax, and AoPAIMax could predict PAI. Out of forty cases in our research, 10 cases were with PAI and 30 cases without PAI during the operation. The areas under the ROC curve for PV, AoPA, AoPAI (pubic symphysis level), hPAI (pubic symphysis level), AoPAIMax, and hPAIMax were 0.592, 0.567, 0.957, 0.940, 0.927, and 0.877, respectively. The AoPAI (pubic symphysis level), hPAI (pubic symphysis level), AoPAIMax, and hPAIMax were statistically correlated with PAI. The boundary values were 26.32 degrees , 1.13 cm, 28.37 degrees , and 1.51 cm, respectively. Conclusions: This new method derived from MRI has predictive value, as AoPAI, hPAI, hPAIMax, and AoPAIMax could predict PAI. Taking other factors into consideration, we suggest the use of AoPAI as a novel and very reliable predictor of PAI. PMID- 30479617 TI - The analysis of the long-term outcomes in elderly women treated for locally advanced cervical cancer. AB - Purpose: Locally advanced cervical cancer (LACC) should be treated with a combination of external irradiation and brachytherapy with concurrent chemotherapy. However, as cervical carcinoma cells can disperse by way of the lymphatic system to either pelvic or para-aortic nodes, planning the extent of radiation requires precise information about the spread of the disease to the lymph nodes, especially to the para-aortic area. Material and methods: All of the 75 women included in our study underwent chemoradiotherapy, which started with brachytherapy. Out of them, 54 have undergone radical hysterectomy with lymphadenectomy followed by chemoradiation. We have retrospectively analyzed the 5-year overall survival (OS) rates relative to the lymph node involvement, the type of lymphadenectomy performed (pelvic, para-aortic, or both), the size of the tumor (> or < 4 cm), the histological type, grading, and the age of patients. Results: We observed significant differences in the OS rates relative to the age of the patients with LACC. We noted significant differences in the OS rates related to para-aortic lymphadenectomy and presence of lymph node metastases. Conclusions: Para-aortic lymphadenectomy seems to have a positive influence on long-term outcomes in the LACC patients, and elderly patients may benefit more from applied therapy. PMID- 30479618 TI - Comparison of impact of target delineation of computed tomography- and magnetic resonance imaging-guided brachytherapy on dose distribution in cervical cancer. AB - Purpose: The dose distributions obtained from three imaging approaches for target delineation in cervical cancer using high-dose-rate (HDR) brachytherapy were investigated. Material and methods: Ten cervical cancer patients receiving four fractions of HDR brachytherapy were enrolled. Based on different imaging approaches, three brachytherapy plans were developed for each patient: with the high-risk clinical target volume (HRCTV) delineated on magnetic resonance (MRI) images for every fraction (approach A; MRI-only); on MRI for the first fraction and computed tomography (CT) images for the subsequent fractions (approach B; MRI1st/CT); and on CT images for all fractions (approach C; CT-only). The volume, height, width at point A, width at maximum level, and dosimetric parameters (D100, D98, D95, and D90 of the HRCTV; and D0.1cc, D1cc, and D2cc of all organs at risk, or organ at risk - OAR: bladder, rectum, sigmoid colon, and bowel) provided by each approach were compared. Results: The mean HRCTV volume, width, and height obtained from approach C (CT-only) were overestimated compared to those from approaches A (MRI-only) and B (MRI1st/CT). The doses to the HRCTV for approaches A and B were similar. However, the HRCTV doses for approach C were significantly lower than those for approaches A and B for all parameters (D95 D100). As to the OAR, the three approaches showed no differences. Conclusions: A combination of MRI and CT is a safe alternative approach for cervical cancer HDR brachytherapy. The technique provides comparable dosimetric outcomes to MRI-based planning, while being more cost-effective. PMID- 30479619 TI - High-dose-rate interstitial brachytherapy in recurrent head and neck cancer: an effective salvage option. AB - Purpose: High-dose-rate (HDR) interstitial brachytherapy has an established role in head and neck malignancies and offers good survival rates; however, there is scant data on improved local control (LC) and treatment-related complications in recurrent cases. We present our results in patients with recurrent head and neck cancers treated with HDR interstitial brachytherapy. Material and methods: Twenty five patients with recurrent head and neck cancers were treated with HDR interstitial brachytherapy using Iridium 192 between 2009 and 2016. Of these, 75% received radical brachytherapy, and 25% received external beam radiation therapy (EBRT) followed by brachytherapy boost. Treatment sites included oral cavity (15/25) and oropharynx (10/25). Median dose of 4.5 Gy was administered twice per day, with median total brachytherapy dose of 40.5 Gy in radical and 27 Gy for EBRT cases. Results: With median follow-up of 25 months, 4 local recurrences were observed within first year of follow-up. Two-year local control and overall survival outcomes for the entire group were 75% and 68%, respectively. Local control rate with radical BRT vs. BRT as a boost following EBRT was found to be significant (2-year LCR 62% vs. 85%; p < 0.02). Dosimetric assessment revealed D90 - 4.08 Gy, V100 - 94.1%, V150 - 24.7%, and V200 - 10.1%. Xerostomia, altered taste, and dysphagia were the major complications commonly grade 1 and 2. Grade 3 toxicity was only 2%. Pre-treatment volume > 85 cc had a negative impact on overall survival (26 months vs. 12 months; p = 0.02), and interval time between primary and recurrence more than 15 months had an impact on the local control rate (p < 0.01). Conclusions: Results of HDR interstitial brachytherapy have shown acceptable local control and overall survival rates along with tolerable toxicities and morbidity in recurrent head and neck cancers. PMID- 30479620 TI - Interstitial brachytherapy in soft tissue sarcoma: a 5 years institutional experience with Cobalt 60-based high-dose-rate brachytherapy system. AB - Purpose: Soft tissue sarcoma (STS) is rare but aggressive neoplasm. Interstitial brachytherapy (ISBT) alone or combined with external beam radiotherapy (EBRT) as post-operative treatment improves loco-regional (LRC) and distant control. Material and methods: Out of twenty-nine non-metastatic STS (lower limb 64%) patients (median age 37 yrs), treated with surgery and post-operative ISBT during February 2011 - December 2016, 27 patients with > 6 months follow-up were analyzed. Spindle cell sarcoma was the commonest (24%) histology. Eleven patients (44%) received EBRT (45-50 Gy), where ISBT was used as boost (16-20 Gy). Fourteen patients (56%) received ISBT alone (4 Gy per fractio). Treatment was done with a 60 Cobalt (60Co) source high-dose-rate system. Results: With a median follow-up of 20 months (17-51 months), LRC rate was 85.7% (with EBRT 90.5% and ISBT 83.2% alone). Median disease-free survival (DFS) was 39.7 +/-3.9 months (32-47.2 months). Median loco-regional failure-free survival (LRRFS) was 43.8 +/-3.6 months (36.8-50.9 months). Distant failure-free survival (DFFS) was 18 months (15.5-26.6 months). Overall survival was 42.4 +/-3.4 months (35.7-48.1 months). Tumor grade was a significant factor for DFFS. Total radiation dose (including EBRT) has significant influence on DFS and LRRFS. 14.8% patients developed >= grade 2 late toxicity (skin atrophy, hypo-pigmentation, and telangiectasia). Conclusions: Combination of surgery and ISBT with/out EBRT improves local and distant control with acceptable late toxicities. 60Co-based ISBT is safe and gives a good outcome. PMID- 30479621 TI - Image-guided interstitial high-dose-rate brachytherapy in the treatment of metastatic esophageal squamous cell carcinoma. AB - Purpose: To evaluate the efficacy of computed tomography (CT)- and magnetic resonance imaging (MRI)-guided interstitial high-dose-rate brachytherapy (HDR IBT = IBT) in patients with metastatic esophageal squamous cell carcinoma. Material and methods: Eleven patients with 21 unresectable metastases of histologically proven esophageal squamous cell carcinoma were included in this retrospective study. Fourteen visceral and 7 lung metastases were treated with image-guided (CT or open MRI guidance) IBT using a 192Iridium source (single fraction irradiation). Clinical and imaging follow-up were performed every 3 months after treatment. Primary endpoint was local tumor control (LTC) and safety. Furthermore, we analyzed safety, progression-free survival (PFS), and overall survival (OS). Results: The median diameter of the target lesions was 2.2 cm (range: 0.7-6.8 cm), treated with a median D100 of 20.1 Gy (range: 10-25 Gy). During a median follow-up of 6.3 months (range: 3-21.8 months), three patients displayed local recurrences, resulting in LTC of 85.7%. Median PFS was 3.4 months and median OS after IBT was 13.7 months. No severe adverse events (grade 3+) requiring hospitalization or invasive intervention were recorded. Conclusions: Image-guided IBT is a safe and effective treatment in patients with metastasized esophageal squamous cell carcinoma. PMID- 30479622 TI - Single fraction computed tomography-guided high-dose-rate brachytherapy or stereotactic body radiotherapy for primary and metastatic lung tumors? AB - Purpose: To provide a pilot dosimetric study of computed tomography (CT)-guided high-dose-rate (HDR) brachytherapy (BRT) and stereotactic body radiotherapy (SBRT) for primary and metastatic lung lesions. Material and methods: For nine lung primary and metastasis patients, 3D image-based BRT plan using a single virtual catheter was planned for 34 Gy in single fraction to the gross tumor volume (GTV) + 3 mm margin to account for tumor deformation. These plans were compared to margin-based (MB-) and robustness optimized (RO-) SBRT, assuming the same tumor deformation under real-time tumor tracking. Consistent dose calculation was ensured for both BRT and SBRT plans using the same class of collapsed cone convolution superposition algorithm. Plan quality metrics were compared by Friedman tests and Wilcoxon t-tests. Results and Conclusions: Brachytherapy plans showed significant higher GTV mean dose compared to MB- and RO-SBRT (122.2 Gy vs. 50.4 and 44.7 Gy, p < 0.05), and better dose gradient index (R50) = 2.9 vs. 4.3 and 8.4 for MB- and RO-SBRT, respectively. Dose constraints per the RTOG 0915 protocol were achieved for all critical organs except chest wall in BRT. All other dose-volume histograms (DVH) metrics are comparable between BRT and SBRT. Treatment delivery time of BRT and SBRT plans significantly increased and decreased with increasing GTV size, respectively. SBRT using advanced MLC tracking technique and non-coplanar VMAT can achieve comparable dosimetric quality to HDR BRT. Whether or not, the significantly higher GTV dose can increase killing of radioresistant tumor cells and offset the effect of tumor reoxygenation in single fraction BRT, requires further clinical investigation. PMID- 30479623 TI - A systematic review of treating recurrent head and neck cancer: a reintroduction of brachytherapy with or without surgery. AB - Purpose: To review brachytherapy use in recurrent head and neck carcinoma (RHNC) with focus on its efficacy and complication rates. Material and methods: A literature search of PubMed, Ovid, Google Scholar, and Scopus was conducted from 1990 to 2017. Publications describing treatment of RHNC with brachytherapy with or without surgery were included. The focus of this review is on oncologic outcomes and the safety of brachytherapy in the recurrent setting. Results: Thirty studies involving RHNC treatment with brachytherapy were reviewed. Brachytherapy as adjunctive treatment to surgical resection appears to be associated with an improved local regional control and overall survival, when compared with the published rates for re-irradiation utilizing external beam radiotherapy (RT) or brachytherapy alone. Safety data remains variable with different isotopes and dose rates with implantable brachytherapy demonstrating a tolerable side effect profile. Conclusions: Although surgery remains a mainstay treatment for RHNC, intraoperative interstitial brachytherapy delivery as adjunctive therapy may improve the treatment outcome and may be associated with fewer complication rates as compared to reirradiation using external beam radiotherapy. Further investigations are required to elucidate the role of brachytherapy for RHNC. PMID- 30479624 TI - Experimental study of pelvic perioperative brachytherapy with iodine 125 seeds (I 125) in an animal model. AB - Purpose: The aim of this study is to investigate the feasibility of perioperative I-125 low-dose-rate brachytherapy mesh implantation in pelvic locations in an animal model, before applying it clinically. Material and methods: The animal model was the Romanov adult ewe. Non-radioactive dummy I-125 seeds were implanted by laparotomy in the pelvic area. Forty-five dummy seeds were placed on a 10 cm2 polyglactin mesh to obtain a dose of 160 Gy at 5 mm from the center of each seed. Three CT scans were performed at day 15, day 70, and day 180 after surgery to check the positioning of the mesh for eventual seed migration according to bony landmarks and to perform a 3D theoretical dosimetric study. The experimental study design was based on Simon's minimax plan with a preliminary analysis of 10 ewes to validate the protocol and a second series of 7 ewes. Results: After the first step, 9 of 10 ewes were investigated. For 8 of 9 animals, the 160 Gy isodose line volume was within 10%, showing feasibility of the procedure and allowing 7 more to be added. At the end of the study, 16 of 17 animals were examined. No seeds loss was observed. The volume difference of the 160 Gy isodose line was within 10% in 13 of 16 ewes between the three CT scans. Twelve out of 16 had a coordinate deviation less than or equal to 10 mm on the three axes between the first and the third scans. Conclusions: These results show the technical feasibility of the pelvic mesh implantation in ewes. A phase I study for patients with locally advanced or recurrent pelvic tumors amenable to surgery, in combination with surgical resection should be possible. PMID- 30479625 TI - Inversely designed, 3D-printed personalized template-guided interstitial brachytherapy for vaginal tumors. AB - Purpose: In this paper, we report cases of two patients with vaginal tumor who underwent interstitial brachytherapy (ISBT), using three-dimensional (3D)-printed personalized templates designed inversely from computed tomography (CT) or magnetic resonance (MR) images. Material and methods: Patient 1 presenting with vaginal vault recurrence was planned to receive whole pelvis external beam radiotherapy (EBRT) followed by ISBT. The tumor invaded the paracolpium; thus, we planned to administer ISBT to include the tumor and vaginal membrane. A template was designed with holes for plastic needle applicator insertion considering the appropriate direction based on pre-treatment medical images. Patient 2 presenting with vaginal cancer was scheduled to receive EBRT and ISBT because of a paracolpium invasion. Before ISBT, MR imaging was performed with vaginal cylinder inserted in the patient's vagina. By measuring the length of the tumor manually and projecting the tumor orthogonally to a plane parallel to the bottom surface of the cylinder applicator, a template was designed. Computer-aided design software was used for planning both templates. Polycarbonate/acrylonitrile butadiene-styrene resin was selected as material of the templates. Results: Patient 1 received 4-fraction ISBT one week apart. A mean of 10 applicators were inserted through the holes of the template in an average of 9 minutes (range, 5 15 minutes). All applicators were inserted toward the planned directions. Median minimum dose covering 90% (D90%) of the clinical target volume (CTV) was 634 cGy. Patient 2 underwent three-fraction irradiation twice daily at 6-hour interval. All applicators were inserted through the inside of the template. The median D90% of the CTV was 703 cGy. No grade 3 or higher toxicity were found in both series. Conclusions: 3D-printed templates designed using medical images are useful, especially for ISBT of vaginal tumors. Further verification of clinical indications, design of templates, and manufacturing process are needed. PMID- 30479626 TI - An automated dose verification software for brachytherapy. AB - Purpose: To report an implementation method and the results of independent brachytherapy dose verification software (DVS). Material and methods: The DVS was developed based on Visual C++ and adopted a modular structure design. The DICOM RT files exported from a treatment planning system (TPS) were automatically loaded into the DVS. The DVS used the TG-43 formalism for dose calculation. A total of 15 cervical cancer patients who underwent brachytherapy were retrospectively selected to test the DVS. Dosimetric parameters and gamma analysis (0.1 cm, 5%) were used to evaluate the dose differences between the DVS and the TPS. Results: Compared with the TPS dose, the gamma pass rates of the dose calculated by the DVS were higher than 98%. For the clinical target volume (CTV), the dosimetric differences were less than 0.63% for D90% and D100%. For the bladder, rectum, and sigmoid, the agreement of D0.1cc, D1cc, and D2cc were within a 0.78% level. Conclusions: With minimal human-computer interactions, the DVS can verify the accuracy of doses calculated by the TPS. PMID- 30479627 TI - Transitional cell carcinoma of endometrium: a case report of rare pure form. AB - Transitional cell carcinoma is a very rare histological subtype of endometrial cancer, with only 18 cases described in literature. Ovary represents the most common site where it accounts for 2% of all ovarian cancers. Due to the rarity of this disease, current management is controversial and includes various approaches, mostly described in the adjuvant setting, both radiotherapy and chemotherapy alone or in combination. Here, we report a case of a 65-year-old patient who underwent adjuvant vaginal brachytherapy for an endometrial transitional cell carcinoma. The patient was treated with radical total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO), without lymph-node sampling, and adjuvant endocavitary brachytherapy delivering 30 Gy in 5 fractions in consecutive days. Treatment tolerance was excellent, with only G1 genitourinary acute toxicity and no other adverse events reported. In this experience, the choice of brachytherapy alone resulted in excellent local control outcomes. However, the patient developed a distant recurrence after 43 months and chemotherapy was applied. More research is required to determine the most effective treatment for this rare histological subtype, and in particular, the role of chemotherapy and radiotherapy combinations. PMID- 30479628 TI - Dose coverage comparison between "interstitial catheter-only" and "hybrid intracavitary-interstitial brachytherapy" for early stage squamous cell carcinoma of the buccal mucosa. AB - Purpose: When squamous cell carcinoma of the buccal mucosa (BSCC) extends surrounding anatomical sites such as gingiva, retromolar triangle, or hard palate, it might be challenging to ensure adequate tumor coverage by sole interstitial brachytherapy due to the complexity of catheter implantation. By combining interstitial catheters with an enoral placed, individually assembled "oral spacer plus embedded catheters" device (hybrid of intracavitary interstitial brachytherapy), it should be easier to deliver the necessary tumoricidal dose to irregular-shaped tumor volumes (clinical target volume - CTV) with improved conformity. The purpose of this analysis was to compare the dose distribution created by the hybrid of intracavitary-interstitial brachytherapy (HBT) with the dose distribution of an interstitial catheter only-approach, based on the interstitial catheters used for HBT (ISBT-only) by evaluating respective treatment plans (HBT plan vs. ISBT-only plan) for the treatment of early stage BSCC. Material and methods: A retrospective analysis was performed for patients with localized BSCC treated between April 2013 and October 2017. All patients received sole HBT without additional external beam radiation therapy or planned neck dissection. Dosimetric parameters taken into account for comparison between actual HBT and virtual ISBT-only were CTV D90, CTV V100, CTV V150, CTV V200, mandible D2cc, and mucosal surface D2cc. Results: Dosimetrically, HBT showed a trend toward better CTV D90 compared to ISBT-only. In addition, HBT demonstrated statistically better CTV V100 coverage compared to ISBT-only. There was no statistically significant difference with respect to CTV V150, CTV V200, and mucosal surface D2cc, while a trend was seen in better mandible D0.1cc between HBT and ISBT-only. Conclusions: The HBT approach appears to enable improved dose coverage of irregular-shaped enoral tumor volumes compared to ISBT-only for patients with early stage BSCC. PMID- 30479629 TI - Eligibility of monoclonal antibody-based therapy for patients with severe asthma: a Canadian cross-sectional perspective. AB - Background: Based on immunologic phenotypes underlying asthma, use of monoclonal antibody based therapies is becoming the new standard of care for severe, corticosteroid refractory clinical symptoms. Patients may qualify for one or more of these targeted treatments, based on clinical characteristics and approved indications. However, the statistics are not well characterized, particularly in the Canadian population. Methods: The objective of this observational study was to identify and describe the proportion of patients with severe asthma who were eligible for targeting IgE, IL-5, or both pathways of immunomodulation. We reviewed a cross-sectional cohort of patients in a Canadian Allergy and Immunology referral practice. We also compared demographic and clinical characteristics of each group. Results: Of the 128 patients with severe asthma, 84 (66%) were eligible for omalizumab, 100 (78%) for mepolizumab, 52 (41%) for reslizumab, and 68 (53%) for benralizumab. Overlap in treatment eligibility varied; 68 (53%) patients were eligible for both omalizumab and mepolizumab, 47 (37%) were eligible for omalizumab and benralizumab, and 37 (29%) were eligible for all four medications. Patient demographics and clinical characteristics were similar, and levels of serum biomarkers varied based on locally approved prescribing criteria. Conclusion: In this severe asthma population from a Canadian Allergist's practice, one-third of individuals qualified for all currently available biologics. 41-78% were eligible for at least one mAb. Patients were most likely to be eligible for mepolizumab. Objective assessments to determine asthma phenotype, along with further characterization of safety profiles will lead to further advances in asthma management. PMID- 30479630 TI - Prevalence of allergic and nonallergic rhinitis in a rural area of northern China based on sensitization to specific aeroallergens. AB - Background: Most epidemiologic studies reporting prevalence of allergic rhinitis (AR) and nonallergic rhinitis (NAR) have assessed solely self-reported prevalence, without confirmation by objective measures. Furthermore, reports of prevalence of NAR in Chinese subjects are scarce. Thus, we aimed to explore the prevalence and risk factors of AR and NAR in a Chinese, based on both clinical manifestation and allergic status. Methods: We conducted a population-based cross sectional survey, involving 1084 local residents from a rural area of Beijing, China. Participants were enrolled using a stratified two-stage cluster sampling method. All adult participants or the guardians of children completed standardized questionnaires to provide relevant demographic and clinical information. Skin prick tests were also performed to determine sensitization to specific aeroallergens. AR/NAR was classified according to Allergic Rhinitis and its Impact on Asthma criteria. Results: Prevalence of self-reported AR was 46.80%. Based on SPT results, the confirmed standardized prevalence of AR and NAR were 16.78% and 24.60%, respectively. Severity scores for nasal itching, sneezing, rhinorrhea and congestion were significantly higher in subjects with AR, than subjects with NAR (P < 0.05 for all). The three most common aeroallergens in self-reported AR group were Blattella germanica (16.6%), Dermatophagoides farinae (14.6%), and Dermatophagoides pteronyssinus (13.9%). Family history of AR and atopic dermatitis were significantly associated with AR (adjusted OR: 4.97 and 2.69, respectively), whereas family history of AR and asthma were significantly associated with NAR (adjusted OR: 3.53 and 2.45, respectively). Similarly, comorbid asthma, CRS, and atopic dermatitis were significant risk factors for both AR and NAR. Conclusions: Combination of standardized questionnaires and specific allergen tests may provide more accurate estimates of prevalence of AR and NAR and associated risk factors. PMID- 30479631 TI - The diagnosis of hereditary angioedema with C1 inhibitor deficiency: a survey of Canadian physicians and laboratories. AB - Background: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is an autosomal dominant disease resulting in random and unpredictable attacks of swelling. The swelling in C1-INH-HAE is a result of impaired regulation of bradykinin production. The fact that the array of tests needed to diagnose HAE is not always available to the treating physicians is challenging for them and their patients. Methods: The data for this article were extracted from two distinct surveys. The first survey was conducted among HAE treating physicians and aimed to determine the availability and utilization of the various assays performed to help the diagnosis of C1-INH-HAE. The second survey was conducted with the various laboratories across Canada that performs the assays used in the diagnosis of HAE. The aim of this survey was to determine the availability and profile of the various assays used in the diagnosis of C1-INH-HAE in Canada, thereby ultimately bringing a rational basis for the biological testing. Results: C1-INH functional assay was widely available in Canada (93%), but was only offered by a small numbers of hospitals meaning that there could be longer delays in the analysis of these samples that may explain why the physicians expressed a lower level of confidence in this assay (59%). Antigenic C1-INH was available to the vast majority of the physicians treating C1-INH-HAE (93%) and was considered reliable by 96% of the respondents. Antigenic C4 was found available to all Canadian physicians and, although with limited specificity, was considered very reliable by all the participants. This study revealed that 81% of physicians were able to order the antigenic C1q and the confidence in this assay was moderate (70%). Concerning genetic testing, the survey revealed that most of the CHAEN members never had to or couldn't order this test. Conclusion: This study highlights the need for improved education and knowledge exchange, about biological assays available to Canadian physicians and their performance in proper diagnosis of C1-INH-HAE to improve confidence and access to relevant tests. PMID- 30479633 TI - Editorial. PMID- 30479632 TI - In Vitro and In Vivo Models for Assessing the Host Response to Biomaterials. AB - The foreign body response (FBR) occurs ubiquitously to essentially all non biological materials that are implanted into higher organisms. The FBR is characterized by inflammation followed by fibrosis and is mediated largely by macrophages. While many current medical devices tolerate the FBR, the FBR is responsible for many asceptic device failures and is hindering advancements of new devices that rely on device-host communication to function. To this end, in vitro and in vivo models are critical to studying how a biomaterial, via its chemistry and properties, affect the FBR. This short review highlights the main in vitro and in vivo models that are used to study the FBR. In vitro models that capture macrophage interrogation of a biomaterial and evaluation of macrophage attachment, polarization and fusion are described. In vivo models using rodents, which provide a relatively simple model of the complex FBR process, and human relevant nonhuman primate models are described. Collectively, the combination of in vitro and in vivo models will help advance our fundmental understanding of the FBR and enable new biomaterials to be developed that can effectively modulate the FBR to achieve a desire device-host outcome. PMID- 30479634 TI - Ultrasound surveillance in twin pregnancy: An update for practitioners. AB - Ultrasound has revolutionised the management of multiple pregnancies and their complications. Increasing frequency of twin pregnancies mandates familiarity of all clinicians with the relevant pathologies and evidence-based surveillance and management protocols for their care. In this review, we summarise the latest evidence relating to ultrasound surveillance of twin pregnancies including first trimester assessment and screening, growth surveillance and the detection and management of the complications of monochorionic pregnancies including twin-to twin-transfusion syndrome, selective fetal growth restriction, twin reversed arterial perfusion sequence and conjoined twinning. PMID- 30479635 TI - Charting the practical dimensions of understaffing from a managerial perspective: The everyday shape of the UK's sonographer shortage. AB - Introduction: Across the last two decades, ultrasound services in many healthcare sectors have become increasingly pressurised as a consequence of upsurging demand and difficulties in recruiting viable clinicians. Indeed by 2013, the UK government's Migration Advisory Committee had listed sonography as an official 'shortage specialty'. Comparatively little research has to date, however, explored the impacts of this situation upon the departments themselves, and the individuals working therein. The core purpose of this study is, thus, to lend qualitative depth to current understandings of the frontline situation in the UK's ultrasound units, many of which are understaffed, from the perspective of their managers. Methods: Using a thematic analysis informed by a Straussian model of Grounded Theory, N = 20 extended accounts provided by ultrasound department leads in public (n = 18) and private (n = 2) units were explored. Results: Four global themes emerged from the analysis of which the first two (the broadly sociological matters) are described in this paper. Theme 1 addresses how a lack of staff in the broader ultrasound economy has created a troublesome migratory system in contemporary UK ultrasound. Theme 2 addresses how this economy works chiefly to the advantage of the most junior and the most senior clinicians, often leaving mid-career professionals in the borderline impossible situation of having to concurrently occupy both junior and senior roles. Conclusions: The findings ideally open up debate on some key practical contingencies of the UK's sonographer shortage, and reflect upon literature regarding the nuanced aspects of a shifting healthcare workplace constitution. PMID- 30479636 TI - Reliability and differences in quadriceps femoris muscle morphology using ultrasonography: The effects of body position and rest time. AB - Introduction: The purpose of this investigation was to: (1) to determine the reliability of rectus femoris muscle cross-sectional area and echo intensity obtained using panoramic ultrasound imaging during seated and supine lying positions before and after a 5-minute rest period and (2) to determine the influence of body position and rest period on the magnitude of rectus femoris muscle cross-sectional area and echo intensity measurements. Methods: A total of 23 males and females (age = 21.5 +/- 1.9 years) visited the laboratory on two separate occasions. During each visit, panoramic ultrasound images of the rectus femoris were obtained in both a seated and a supine position before (T1) and after a 5-minute (T2) rest period to quantify any potential changes in either muscle cross-sectional area and/or echo intensity. Results: None of the muscle cross-sectional area or echo intensity measurements exhibited systematic variability, and the ICCs were 0.98-0.99 and 0.88-0.91, and the coefficients of variation were <= 3.9% and <= 8.2% for muscle cross-sectional area and echo intensity, respectively. Our results indicated that muscle cross-sectional area was greater in the seated than supine position, whereas echo intensity was greater in the supine position. Further, echo intensity increased in the seated position from T1 to T2. Conclusion: Both rectus femoris muscle cross-sectional area and echo intensity may be reliably measured in either a seated or supine lying position before or after a 5-minute rest period. Aside from echo intensity in the seated position, rest period had no influence on the magnitude of muscle cross-sectional area or echo intensity. Comparison of muscle cross-sectional area values that are obtained in different body positions is ill-advised. PMID- 30479637 TI - Ultrasound-guided fine-needle aspiration cytology of lesions in the head and neck performed without local anaesthesia - An analysis of pain perception. AB - Introduction: Ultrasound-guided fine-needle aspiration cytology is commonly carried out in the head and neck. The aim was to examine the amount of pain experienced by patients undergoing this procedure carried out without the use of local anaesthetic. Methods: A questionnaire was given to 109 consecutive patients undergoing ultrasound-guided fine-needle aspiration cytology containing a visual analogue scale. Patients were asked to mark with a vertical line on the 100 mm horizontal scale amount of pain they experienced during the biopsy. The pain was subsequently categorised as 'no pain', 'mild pain', 'moderate pain' or 'severe pain' based on previous pain studies. Results: Hundred patients completed the visual analogue scale section of the questionnaire satisfactorily. Twenty-one patients experienced no pain, 62 experienced mild pain and 17 experienced moderate pain. No patients experienced severe pain. Further analysis showed that females had significantly higher visual analogue scale scores (Mann-Whitney test: U = 925.5, z = 2.211, P = 0.027). Patients who were aware that they were going to have a biopsy had significantly lower visual analogue scale scores than those who were not aware (Mann-Whitney test: U = 859.5, z = 2.263, P = 0.024). Conclusions: Ultrasound-guided fine-needle aspiration cytology is generally a well-tolerated procedure with pain scores being higher in females. It is advised that patients are told by the referring clinician the need for biopsy as this reduces the amount of pain experienced. PMID- 30479638 TI - A comparison of ultrasound with magnetic resonance imaging in the assessment of fetal biometry and weight in the second trimester of pregnancy: An observer agreement and variability study. AB - Objective: To compare the intra and interobserver variability of ultrasound and magnetic resonance imaging in the assessment of common fetal biometry and estimated fetal weight in the second trimester. Methods: Retrospective measurements on preselected image planes were performed independently by two pairs of observers for contemporaneous ultrasound and magnetic resonance imaging studies of the same fetus. Four common fetal measurements (biparietal diameter, head circumference, abdominal circumference and femur length) and an estimated fetal weight were analysed for 44 'low risk' cases. Comparisons included, intra class correlation coefficients, systematic error in the mean differences and the random error. Results: The ultrasound inter- and intraobserver agreements for ultrasound were good, except intraobserver abdominal circumference (intra-class correlation coefficient = 0.880, poor), significant increases in error was seen with larger abdominal circumference sizes. Magnetic resonance imaging produced good/excellent intraobserver agreement with higher intra-class correlation coefficients than ultrasound. Good interobserver agreement was found for both modalities except for the biparietal diameter (magnetic resonance imaging intra class correlation coefficient = 0.942, moderate). Systematic errors between modalities were seen for the biparietal diameter, femur length and estimated fetal weight (mean percentage error = +2.5%, -5.4% and -8.7%, respectively, p < 0.05). Random error was above 5% for ultrasound intraobserver abdominal circumference, femur length and estimated fetal weight and magnetic resonance imaging interobserver biparietal diameter, abdominal circumference, femur length and estimated fetal weight (magnetic resonance imaging estimated fetal weight error >10%). Conclusion: Ultrasound remains the modality of choice when estimating fetal weight, however with increasing application of fetal magnetic resonance imaging a method of assessing fetal weight is desirable. Both methods are subject to random error and operator dependence. Assessment of calliper placement variations may be an objective method detecting larger than expected errors in fetal measurements. PMID- 30479639 TI - Accuracy of ultrasound-guided versus palpation-based carpometacarpal joint injections: A randomized pilot study in cadavers. AB - Objective: To determine the accuracy of ultrasound guidance compared to palpation in performing carpometacarpal joint injections in cadavers. Design: In all, 36 carpometacarpal joints were randomized to either ultrasound-guided or palpation based injections, with 1 cc of blue latex solution injected into each joint. The specimens were then dissected and the distribution of the latex was assessed by two independent, blinded raters. Injection accuracy was evaluated on a four-point quartile rating scale of 1-4, corresponding to the amount of the latex solution within the joint (1 = 0-25%, 2 = 26-50%, 3 = 51-75%, 4 = 76-100%). Inter-rater reliability was a secondary measure. Results: The mean rating of accuracy was 2.1 for both palpation-based and ultrasound-guided injections. There was no statistically significant difference in accuracy between the two injectors. Chi square analysis testing differences in accuracy for the two conditions was not statistically significant. The Cronbach's alpha for rater 2 was 0.74, which represents an acceptable level of reliability. A Friedman's Chi-square for the two raters was 2.3 (p = 0.13), indicating no significant difference between raters. Conclusion: Ultrasound guidance did not improve the accuracy of carpometacarpal joint injections in cadavers. However, the high inter-rater reliability attests to the value of the novel assessment scale. PMID- 30479640 TI - Isolated hydatid cyst of thyroid: An unusual case. AB - Introduction: Hydatid cystic disease is a parasitic infestation that is mostly caused by Echinococcus granulosus, which is common in sheep-rearing areas of the Mediterranean, Middle East, Australia, New Zealand, South Africa, and South America. Canines are the definitive hosts, and herbivores (e.g. sheep, horses, deer) or humans are intermediate hosts. Ingested eggs from animal feces hatch in the gut and release oncospheres (immature forms of the parasite enclosed in an embryonic envelope). Case report: A very rare case of isolated, thyroidal, hydatic cyst is presented. Conclusion: Non-vascular cysts may be seen on ultrasonographic examination that are not specific for hydatid disease. Clinical and laboratory findings are therefore important. Definitive diagnosis is based on histopathological findings. Treatment is surgical and antiparasitic drugs are required after surgery. PMID- 30479641 TI - Effects of chocolate containing Leuconostoc mesenteroides strain NTM048 on immune function: a randomized, double-blind, placebo-controlled trial. AB - Background: Previous reports showed that oral administration of Leuconostoc mesenteroides strain NTM048 increases IgA levels and CD4+ T cell population in feces and mice, respectively, as revealed by flow cytometric analysis of splenocytes. This study aimed to evaluate the effect of chocolate supplemented with L. mesenteroides strain NTM048 (> 1.00 * 109 CFU/day, NTM048) on the immune parameters of healthy subjects, using a randomized, placebo-controlled, double blinded study design. Methods: Participants (mean age: 46.3 years) ingested 28 g of test food daily, at a time of their own choice, for 4 weeks. The immunological parameters of all participants were evaluated two times (pre- and post- ingestion). At the end of the study, various immunological parameters of the participants were measured and scoring of immunological vigor (SIV) was performed using a comprehensive algorithm. Results: Ingestion of NTM048-supplemented chocolate significantly improved SIV in the NTM048 group (18.6 +/- 1.6) compared to that in the placebo group (17.8 +/- 2.0) after 4 weeks (p = 0.049). Several immunological parameters (CD8+T cells, CD8+CD28+ T cells, and memory T cells) were significantly elevated in the NTM048 group as compared to the placebo group (all p < 0.05). In addition, T cell proliferation index at post-ingestion significantly increased compared with that at pre-ingestion in the NTM048 (p = 0.017) and placebo groups (p = 0.037), although no differences were observed between the two groups. Conclusion: Our results suggest that ingestion of chocolate supplemented with NTM048 is effective against the age-related decline in T cell-related immune functions. Trial registration: UMIN Clinical Trials Registry UMIN000021989. Registered 19 April 2016, https://upload.umin.ac.jp/cgi open-bin/ctr_e/ctr_view.cgi?recptno=R000025321. PMID- 30479643 TI - ? AB - Efficacy of the ureteric stricture (UC) treatment, using energy of the Holmium (in 55%patients) and the diode (in 45%) lasers was analyzed. In 37 (77%) patient spositiveresults were achieved already after one session, in 4 (8.3%) - one more session wasperformed in terms up to 3 mo after the first one, in 3 (6.3%) - two sessions were per'formed. Positive results were achieved in total in 91.6% patients. Application of laserenergy in treatment of UC is effective and not dependent from the energy kind and con'stitutes a perspective method of the patient's endoscopic treatment. PMID- 30479642 TI - Different age-independent effects of nutraceutical combinations on endothelium mediated coronary flow reserve. AB - Background: Some components of Nutraceuticals (NUT) such as red yeast rice and Morus alba have demonstrated positive effects on the endothelial function in hypercholesterolemic subjects. Our aim was to compare the effects of two different NUT combinations on cold pressure test (CPT) derived coronary flow reserve (CFR) assessed by transthoracic echo-Doppler. Results: In a randomized, single-blind study, 28 consecutive patients with a variety of cardiovascular risk factors received NUT A (LopiGLIK(r): berberine, red yeast rice powder, and leaf extract of Morus alba) or B (Armolipid Plus(r): policosanol, red yeast rice, berberine, astaxantine, folic acidandcoenzyme Q10). An echo-Doppler exam with evaluation of CFR was performed at baseline, 2 h (acute test) and 30 days after daily NUT assumption. Blood sampling for metabolic profile and platelet aggregometry was performed at baseline and after 30 days of daily NUT assumption. CFR was not significantly modified at the acute test. After 30 days, CFR improved with NUT A (p < 0.0001), because of the increase of hyperemic flow velocity (p = 0.007), but not with NUT B. CFR was comparable between the two groups at baseline but became significantly higher after 30 days in NUT A (p < 0.02), with a higher CFR percent variation versus baseline (p = 0.008). Total cholesterol and LDL cholesterol were reduced with both NUT A (p < 0.001 and p < 0.002, respectively) and B (both p < 0.02), whereas platelet aggregation did not significantly change. In the pooled group of patients, after adjusting for age and percent changes of systolic blood pressure, heart rate, LDL-cholesterol and glycemia, NUT A - but not NUT B - was independently associated with CFR changes (beta = 0.599, p = 0.003). Conclusions: LopiGLIK(r) improved endothelial-derived CFR, independently of the beneficial effects exerted on the lipid profile. These findings can have clinical reflections on the prevention of age-related inflammatory diseases including coronary artery disease. Trial registration: (NUTRENDO)"(ClinicalTrials.gov, NCT02969070). PMID- 30479644 TI - Body size regulation by maturation steroid hormones: a Drosophila perspective. AB - The mechanism that determines the specific body size of an animal is a fundamental biological question that remains largely unanswered. This aspect is now beginning to be understood in insect models, particularly in Drosophila melanogaster, with studies highlighting the importance of nutrient-responsive growth signaling pathways involving insulin/insulin-like growth factor signaling (IIS) and target of rapamycin (TOR) (IIS/TOR). These pathways operate in animals, from insects to mammals, adjusting the growth rate in response to the nutritional condition of the organism. Organismal growth is closely coupled with the process of developmental maturation mediated by maturation steroid hormones, which is influenced greatly by environmental and nutritional conditions. Recent Drosophila studies have been revealing the mechanisms responsible for this phenomenon. In this review, I summarize some important findings about the steroid hormone regulation of Drosophila body growth, calling attention to the influence of developmental nutritional conditions on animal size determination. PMID- 30479645 TI - Physiological predictors of reproductive performance in the European Starling (Sturnus vulgaris). AB - Background: It is widely assumed that variation in fitness components has a physiological basis that might underlie selection on trade-offs, but the mechanisms driving decreased survival and future fecundity remain elusive. Here, we assessed whether physiological variables are related to workload ability or immediate fitness consequences and if they mediate future survival or reproductive success. We used data on 13 physiological variables measured in 93 female European starlings (Sturnus vulgaris) at two breeding stages (incubation, chick-rearing), for first-and second-broods over two years (152 observations). Results: There was little co-variation among the physiological variables, either in incubating or chick-rearing birds, but some systematic physiological differences between the two stages. Chick-rearing birds had lower hematocrit and plasma creatine kinase but higher hemoglobin, triglyceride and uric acid levels. Only plasma corticosterone was repeatable between incubation and chick-rearing. We assessed relationships between incubation or chick-rearing physiology and measures of workload, current productivity, future fecundity or survival in a univariate manner, and found very few significant relationships. Thus, we next explored the utility of multivariate analysis (principal components analysis, Mahalanobis distance) to account for potentially complex physiological integration, but still found no clear associations. Conclusions: This implies either that a) birds maintained physiological variables within a homeostatic range that did not affect their performance, b) there are relatively few links between physiology and performance, or, more likely, c) that the complexity of these relationships exceeds our ability to measure it. Variability in ecological context may complicate the relationship between physiology and behavior. We thus urge caution regarding the over-interpretation of isolated significant findings, based on single traits in single years, in the literature. PMID- 30479646 TI - Morphological and biochemical characterization of the cutaneous poison glands in toads (Rhinella marina group) from different environments. AB - Background: Amphibian defence against predators and microorganisms is directly related to cutaneous glands that produce a huge number of different toxins. These glands are distributed throughout the body but can form accumulations in specific regions. When grouped in low numbers, poison glands form structures similar to warts, quite common in the dorsal skin of bufonids (toads). When accumulated in large numbers, the glands constitute protuberant structures known as macroglands, among which the parotoids are the most common ones. This work aimed at the morphological and biochemical characterization of the poison glands composing different glandular accumulations in four species of toads belonging to group Rhinella marina (R. icterica, R. marina, R. schneideri and R. jimi). These species constitute a good model since they possess other glandular accumulations together with the dorsal warts and the parotoids and inhabit environments with different degrees of water availability. Results: We have observed that the toads skin has three types of poison glands that can be differentiated from each other through the morphology and the chemical content of their secretion product. The distribution of these different glands throughout the body is peculiar to each toad species, except for the parotoids and the other macroglands, which are composed of an exclusive gland type that is usually different from that composing the dorsal warts. Each type of poison gland presents histochemical and biochemical peculiarities, mainly regarding protein components. Conclusions: The distribution, morphology and chemical composition of the different types of poison glands, indicate that they may have different defensive functions in each toad species. PMID- 30479647 TI - Intermittent administration of a fasting-mimicking diet intervenes in diabetes progression, restores beta cells and reconstructs gut microbiota in mice. AB - Fasting and especially intermittent fasting have been shown to be an effective intervention in many diseases, such as obesity and diabetes. The fasting mimicking diet (FMD) has recently been found to ameliorate metabolic disorders. To investigate the effect of a new type of low-protein low-carbohydrate FMD on diabetes, we tested an FMD in db/db mice, a genetic model of type 2 diabetes. The diet was administered every other week for a total of 8 weeks. The intermittent FMD normalized blood glucose levels in db/db mice, with significant improvements in insulin sensitivity and beta cell function. The FMD also reduced hepatic steatosis in the mice. Deterioration of pancreatic islets and the loss of beta cells in the diabetic mice were prevented by the FMD. The expression of beta cell progenitor marker Ngn3 was increased by the FMD. In addition, the FMD led to the reconstruction of gut microbiota. Intermittent application of the FMD increased the genera of Parabacteroides and Blautia while reducing Prevotellaceae, Alistipes and Ruminococcaceae. The changes in these bacteria were also correlated with the fasting blood glucose levels of the mice. Furthermore, intermittent FMD was able to reduce fasting blood glucose level and increase beta cells in STZ induced type 1 diabetic mouse model. In conclusion, our study provides evidence that the intermittent application of an FMD is able to effectively intervene in the progression of diabetes in mice. PMID- 30479650 TI - Patterns of breastfeeding practices among infants and young children in Abu Dhabi, United Arab Emirates. AB - Background: Despite the ongoing efforts to improve infant feeding practices, low rates of breastfeeding and early introduction of complementary feeding have been reported in many countries. Systematic documentation of breastfeeding practices in the United Arab Emirates (UAE) is needed in order to directing successful strategies. The aim of this study was to evaluate breastfeeding practices among mothers in Abu Dhabi, UAE, using the World Health Organization (WHO) infant and young child feeding indicators. Methods: In this cross-sectional study, mothers of children below the age of two were recruited from the community and health centers located in different areas in Abu Dhabi. Following informed consent, a structured questionnaire including WHO-indicators was used for in-person interviews on sociodemographics and breastfeeding. Exclusive breastfeeding (EBF) was calculated as the percentage of babies 0 - < 6 months of age who had been exclusively breastfed in the last 24 h. Results: A total of 1822 mothers participated in the study; 95.6% (1741/1822) of mothers initiated breastfeeding and 59.8% (1089/1822) initiated breastfeeding within the first hour. Exclusive breastfeeding among infants 0-6 months was 44.3% (362/818). Although the median duration of "any breastfeeding" was 12 months (95% CI 11.2, 12.7), the median duration of EBF was 3 months (95% CI 2.8, 3.3). Most of the children (894/1004, 89%) aged 6 months and above were receiving complementary feeding, but 21.7% (218/1004) of them had had an early introduction of complementary feeding, i.e. before 6 months of age. Using "the WHO infant and young child feeding indicators" as standard for comparative evaluation, breastfeeding initiation was rated "good", the proportion of children being exclusively breastfed until 6 months was rated "fair" and the duration of EBF was considered "poor". Conclusions: According to the WHO infant feeding indicators the breastfeeding practices were suboptimal in several aspects with a low proportion of children being exclusively breastfed, short breastfeeding duration and early introduction of complementary feeding, despite high socioeconomic status. These findings suggest that there is a need to understand potential barriers towards breastfeeding in order to develop appropriate strategies to promote and support breastfeeding in Abu Dhabi. PMID- 30479648 TI - Trimethylamine N-oxide, a gut microbiota-dependent metabolite of choline, is positively associated with the risk of primary liver cancer: a case-control study. AB - Background: Evidence has suggested a potential link exists between trimethylamine N-oxide (TMAO), a choline-derived metabolite produced by gut microbiota, and some cancers, but little is known for primary liver cancer (PLC). Methods: A case control study was designed including 671 newly diagnosed PLC patients and 671 control subjects frequency-matched by age (+/-5 years) and sex, in Guangdong province, China. High-performance liquid chromatography with online electrospray ionization tandem mass spectrometry (HPLC-MS/MS) was used to measure serum TMAO and choline. The associations between these biomarkers and PLC risk were evaluated using logistic regression models. Results: Serum TMAO concentrations were greater in the PLC group than the control group (P = 0.002). Logistic regression analysis showed that the sex- and age-adjusted odds ratio (OR) and (95% confidence interval [CI]) was 3.43 (2.42-4.86) when comparing the top and bottom quartiles (Q4 vs Q1). After further adjusting for more selected confounders, the OR (95% CI) remained significant but was attenuated to 2.85 (1.59-5.11) (Q4 vs Q1). The multivariable-adjusted ORs (95% CIs) across quartiles of choline were 0.35-0.15 (P -trend < 0.001). Conclusion: Higher serum levels of TMAO were associated with increased PLC risk. The association was stronger in those with lower serum levels of choline. Additional large prospective studies are required to confirm these findings. Trial registration: This study was registered at clinicaltrials.gov as NCT 03297255. PMID- 30479651 TI - LBP rs2232618 polymorphism contributes to risk of sepsis after trauma. AB - Background: Previous study revealed that rs2232618 polymorphism (Phe436Leu) within LBP gene is a functional variant and associated with susceptibility of sepsis in traumatic patients. Our aim was to confirm the reported association by enlarging the population sample size and perform a meta-analysis to find additional evidence. Methods: Traumatic patients from Southwest (n = 1296) and Southeast (n = 445) of China were enrolled in our study. After genotyping, the relationship between rs2232618 and the risk of sepsis was analyzed. Furthermore, we proceeded with a comprehensive literature search and meta-analysis to determine whether the rs2232618 polymorphism conferred susceptibility to sepsis. Results: Significance correlation was observed between rs2232618 and risk of sepsis in Southwest patients (P = 0.002 for the dominant model, P = 0.006 for the recessive model). The association was confirmed in Southeast cohort (P = 0.005 for the dominant model) and overall combined cohorts (P = 4.5 * 10-4, P = 0.041 for the dominant and recessive model). Multiple logistical regression analyses suggested that rs2232618 polymorphism was related to higher risk of sepsis (OR = 1.77, 95% CI = 1.26-2.48, P = 0.001 in Southwest patients; OR = 2.11, 95% CI = 1.24-3.58, P = 0.006 in Southeast cohort; OR = 1.54, 95% CI = 1.34-2.08, P = 0.006 in overall cohort). Furthermore, meta-analysis of four studies (including the present study) confirmed that rs2232618 within LBP increased the risk of sepsis (OR = 1.75, P < 0.001 for the dominant model; OR = 6.08, P = 0.003 for the recessive model; OR = 2.72, P < 0.001 for the allelic model). Conclusions: The results from our replication study and meta-analysis provided firm evidence that rs2232618T allele significantly increased the risk of sepsis. PMID- 30479649 TI - The protective effect of neonatal oral administration of oleanolic acid against the subsequent development of fructose-induced metabolic dysfunction in male and female rats. AB - Background: Consumption of fructose-rich diets has been implicated in the increasing global prevalence of metabolic syndrome (MetS). Interventions during periods of early ontogenic developmental plasticity can cause epigenetic changes which program metabolism for positive or negative health benefits later in life. The phytochemical oleanolic acid (OA) possesses anti-diabetic and anti-obesity effects. We investigated the potential protective effects of neonatal administration of OA on the subsequent development of high fructose diet-induced metabolic dysfunction in rats. Method: Male and female (N = 112) suckling rats were randomly assigned to four groups and administered orally: distilled water (DW), oleanolic acid (OA; 60 mg/kg), high-fructose solution (HF; 20% w/v) or OA + HF for 7 days. The rats were weaned onto normal commercial rat chow up to day 55. From day 56, half of the rats in each treatment group were continued on plain water and the rest on a high fructose solution as drinking fluid for 8 weeks. On day 110, the rats were subjected to an oral glucose tolerance test and then euthanased on day 112. Tissue and blood samples were collected to determine the effects of the treatments on visceral fat pad mass, fasting plasma levels of cholesterol, insulin, glucose, triglycerides, insulin resistance (HOMA-IR) and glucose tolerance. Results: Rats which consumed fructose as neonates and then later as adults (HF + F) and those which consumed fructose only in adulthood (DW + F) had significant increases in terminal body mass (females only), visceral fat mass (males and females), serum triglycerides (females only), epididymal fat (males only), fasting plasma glucose (males and females), impaired glucose metabolism (females only), beta-cell dysfunction and insulin resistance (males and females) compared to the other treatment groups (P < 0.05). There were no differences in fasting serum cholesterol levels across all treatment groups in both male and female rats (P > 0.05). Conclusion: We conclude that neonatal oral administration of OA during the critical window of developmental plasticity protected against the development of health outcomes associated with fructose induced metabolic disorders in the rats. PMID- 30479652 TI - Vacuum-assisted closure (VAC(r)) systems and microbiological isolation of infected wounds. AB - Background: Negative pressure wound therapy is now largely used to treat infected wounds. The prevention and reduction of healthcare-associated infections is a high priority for any Department of Health and great efforts are spent to improve infection control systems. It is assumed that vacuum-assisted closure (VAC(r)) dressings should be watertight and that all the secretions are gathered in a single container but there is no consistent data on air leakage and possible dispersion of bacteria from the machine. Methods: We have conducted a prospective experimental study on 10 patients with diagnosis of wound infection to verify whether the filtration process is microbiologically efficient. We compared the bacteria population present in the wound to the one present in the air discharged by the VAC(r) machine. Results: This study shows that the contamination of the VAC(r) machine is considerably lower than the environment or wound contamination. Conclusions: Negative pressure wound therapy system does not represent a risk factor for healthcare-associated infections. PMID- 30479653 TI - Three cases of resuscitative endovascular balloon occlusion of the aorta (REBOA) in austere pre-hospital environment-technical and methodological aspects. AB - Background: The present paper describes three cases where ER-REBOA(r) was used with partial aorta occlusion (AO), by performing a partial resuscitative endovascular balloon occlusion of the aorta or pREBOA, in an austere pre-hospital military environment.In addition, because no specific REBOA algorithm for pre hospital environment exists yet, this paper seeks to fill this gap, proposing a new pragmatic REBOA algorithm. Methods: Belgian Special Operations Surgical Team applied REBOA in three patients according to a decisional algorithm, based on the MIST acronym used for trauma patients. Only 3 ml, in the first instance, was inflated in the balloon to get AO. The balloon was then progressively deflated, and reperfusion was tracked through changes of end-tidal carbon dioxide (EtCO2). Results: Systolic blood pressure (SBP) before ER-REBOA(r) placement was not higher than 60 mmHg. However, within the first 5 min after AO, SBP improved in all three cases. Due to the aortic compliance, a self-made pREBOA was progressively achieved while proximal SBP was raising with intravenous fluid infusion. Afterwards, during deflation, a steep inflection point was observed in SBP and EtCO2. Conclusions: ER-REBOA(r) is suitable for use in an austere pre hospital environment. The MIST acronym can be helpful to select the patients for which it could be beneficial. REBOA can also be performed with pREBOA in a dynamic approach, inflating only 3 mL in the balloon and using the aortic compliance. Furthermore, while proximal SBP can be convenient to follow the occlusion, EtCO2 can be seen as an easy and interesting marker to follow the reperfusion. PMID- 30479655 TI - Predicting the potential global distribution of diosgenin-contained Dioscorea species. AB - Background: Diosgenin, mainly extracted from wild diosgenin-contained Dioscorea species, is a well-known starting material of steroidal and contraceptive drugs. However, due to large market demand and increasingly ecological damage, wild Dioscorea species resources available have been gradually declining. Therefore, identification of new potential ecological distribution of diosgenin-contained Dioscorea species is necessary for diosgenin production. Methods: In this study, a large occurrence dataset (1808 data points) of diosgenin-contained Dioscorea species was obtained from Eastern Asia, Southern North America and Southern Africa. Along with the data for six critical environmental parameters and one soil factor, Geographic Information System for Global Medicinal Plant was applied to predict the potential suitable distribution of Dioscorea species. Results: The results showed that the potential distribution of these Dioscorea species covered a wide field, and that new ecological suitability areas were mainly distributed in the central region of South America, the southern part of the European and coastal region of Oceania. Jackknife test indicated that annual precipitation and annual mean radiation were the important climatic factors controlling the distribution of Dioscorea species. Conclusions: The suitable areas and critical climatic factors will serve as a useful guide for diosgenin-contained Dioscorea species conservation and cultivation in ecological suitable areas. PMID- 30479654 TI - A preliminary review of studies on adaptogens: comparison of their bioactivity in TCM with that of ginseng-like herbs used worldwide. AB - Modern studies have shown that adaptogens can non-specifically enhance the resistance of human body under a wide range of external stress conditions with a multi-targeted and multi-channel network-like manner, especially by affect the immune-neuro-endocrine system and the hypothalamic-pituitary-adrenal axis. This review article draws the attention to the relationships of adaptogens, tonics from traditional Chinese medicine (TCM) and ginseng-like herbs worldwide, which all have similar plant sources and clinical applications. To clarify the sources and pharmacological mechanisms of these plant-originated adaptogens, which will provide useful information for the utilization of adaptogens to improve the human health. Meanwhile, the TCMs and the world-wide ginseng-like herbs from each region's ethnopharmacology will be beneficial modernization and globalization. PMID- 30479656 TI - Human papilloma virus E1-specific T cell immune response is associated with the prognosis of cervical cancer patients with squamous cell carcinoma. AB - Background: Cervical cancer is attributable to human papilloma virus (HPV) infection in the majority cases. E1, an HPV derived-protein, plays an important role in the initiation and development of cervical cancer. Our study aims to investigate the HPV E1-specific T cell response in patients with cervical squamous cell carcinoma (CSCC). Methods: A total of 66 CSCC patients with FIGO stage IIB-IIIB and 60 healthy controls were enrolled. Enzyme-Linked ImmunoSpot (ELISPOT) assays was used to measure the HPV E1-specific T cell response in the peripheral blood of these patients before treatment. The patients were treated with chemotherapy and/or radiotherapy and followed up clinically for three years. The relationship between the T cell response, various clinical characteristics and the prognosis were studied with univariate analysis, multivariate analysis and survival curve analysis. Results: The frequency of HPV E1-specific T cell response in peripheral blood of cervical cancer patients was 59.09%, with mean response intensity 24.56 SFC/106 PBMCs. The frequency and intensity of HPV E1 specific T cell response in patients were higher than healthy controls(p < 0.001; p = 0.009). The intensity of HPV E1-specific T cell responses were higher in the stage IIB patients and patients with no pelvic lymph node metastasis (p = 0.038; p = 0.044). Univariate analysis showed that HPV E1 specific T cell response was associated with progression-free survival (PFS) and overall survival (OS) (PFS: p = 0.021; OS: p = 0.004). Multivariate analysis showed that HPV E1-specific T cell response was an independent prognostic factor influencing PFS and OS among all the factors included in our study (PFS: HR = 7.252, 95%CI = 1.690-31.126, p = 0.008; OS: HR = 7.499, 95%CI = 1.661-33.856, p = 0.009). The survival curves showed that the rate of PFS and OS in patients with HPV E1 specific T cell response was significantly higher than those who did not response. Conclusions: Our study demonstrated that the level of HPV E1-specific T cell response was correlated with the survival of advanced patients with CSCC. Patients who displayed no HPV E1-specific T cell response were more likely to be those with poor prognosis. PMID- 30479657 TI - The long-term effects of a prevention program on the number of critical incidents and sick leave days. AB - Background: This study explores the effectiveness of refresher training sessions of an intervention program at reducing the employees' risk of injury due to patient violence in forensic psychiatric hospital. Methods: The original safety intervention program that consisted of a 3 days' workshop was conducted in the maximum-security ward of a psychiatric hospital in Israel. Ever since the original intervention, annual refreshers were conducted highlighting one of the safety elements covered in the original intervention. The study examines the effect of the intervention program along with the refreshers over a period of 10 years in four wards. Results: Analysis of the data demonstrates that beyond the initial reduction following the original intervention, refreshers seem to have an additional positive long-term effect, reducing both the number of violent incidents and the number of actual employee injuries in forensic psychiatric hospital. Conclusions: We conclude that such an intervention program followed by refresher training would promote employees' wellbeing. A healthy work environment is part of management's commitment to improve employee wellbeing at the workplace. PMID- 30479658 TI - Direct medical costs for patients with schizophrenia: a 4-year cohort study from health insurance claims data in Guangzhou city, Southern China. AB - Background: Schizophrenia is one of the leading public health issues in psychiatry and imposes a heavy financial burden on the healthcare systems. This study aims to report the direct medical costs and the associated factors for patients with schizophrenia in Guangzhou city, Southern China. Methods: This was a retrospective 4-year cohort study. Data were obtained from urban health insurance claims databases of Guangzhou city, which contains patients' sociodemographic characteristics, direct medical costs of inpatient and outpatient care. The study cohort (including all the reimbursement claims submitted for schizophrenia inpatient care during November 2010 and October 2014) was identified using the International Classification of Diseases Tenth version (F20). Their outpatient care information was merged from outpatient claims database. Descriptive analysis and the multivariate regression analysis based on Generalized Estimating Equations model were conducted. Results: A total of 2971 patients were identified in the baseline. The cohort had a mean age of 50.3 years old, 60.6% were male, and 67.0% received medical treatment in the tertiary hospitals. The average annual length of stay was 254.7 days. The average annual total direct medical costs per patient was 41,972.4 Chinese Yuan (CNY) ($6852.5). The inpatient costs remained as the key component of total medical costs. The Urban Employee Basic Medical Insurance enrollees with schizophrenia had higher average costs for hospitalization (CNY42,375.1) than the Urban Resident Basic Medical Insurance enrollees (CNY40,917.3), and had higher reimbursement rate (85.8% and 61.5%). The non-medication treatment costs accounted for the biggest proportion of inpatient costs for both schemes (55.8% and 64.7%). Regression analysis suggested that insurance type, age, hospital levels, and length of stay were significantly associated with inpatient costs of schizophrenia. Conclusions: The direct annual medical costs of schizophrenia were high and varied by types of insurance in urban China. The findings of this study provide vital information to understand the burden of schizophrenia in China. Results of this study can help decision-makers assess the financial impact of schizophrenia. PMID- 30479659 TI - In vitro culture expansion impairs chondrogenic differentiation and the therapeutic effect of mesenchymal stem cells by regulating the unfolded protein response. AB - In vitro expansion of mesenchymal stem cells (MSCs) has been implicated in loss of multipotency, leading to impaired chondrogenic potential and an eventual therapeutic effect, as reported in our previous study. However, the precise regulatory mechanism is still unclear. Here, we demonstrate that endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) were involved in transformation of MSCs induced by in vitro culture based on the comparative profiling of in vitro cultured bone marrow MSCs at passage 3 (P3 BMSCs) vs. fresh P0 BMSCs by microarray analysis. Indeed, RT-PCR and Western blot analysis showed significantly lower expression levels of three key UPR-related molecules, ATF4, ATF6 and XBP1, in P3 BMSCs than P0 BMSCs. Further, we found that UPR suppression by 4-phenylbutyrate (4-PBA) reduced the chondrogenic potential of P0 BMSCs and further cartilage regeneration. Conversely, UPR induction by tunicamycin (TM) enhanced the chondrogenic differentiation of P3 BMSCs and the therapeutic effect on cartilage repair. Thus, the decline in the chondrogenic potential of stem cells after in vitro culture and expansion may be due to changes in ER stress and the UPR pathway. PMID- 30479661 TI - Developing fast enzyme recycling strategy through elucidating enzyme adsorption kinetics on alkali and acid pretreated corn stover. AB - Background: Although various pre-treatment methods have been developed to disrupt the structure of lignocellulosic biomass, high dosage of cellulases is still required to hydrolyze lignocellulose to fermentable sugars. Enzyme recycling via recycling unhydrolyzed solids after enzymatic hydrolysis is a promising strategy to reduce enzyme loading for production of cellulosic ethanol. Results: To develop effective enzyme recycling method via recycling unhydrolyzed solids, this work investigated both enzymatic hydrolysis kinetics and enzyme adsorption kinetics on dilute acid and dilute alkali pre-treated corn stover (CS). It was found that most of the hydrolysable biomass was hydrolyzed in the first 24 h and about 40% and 55% of the enzymes were adsorbed on unhydrolyzed solids for dilute alkali-CS and dilute acid-CS, respectively, at 24 h of enzymatic hydrolysis. Lignin played a significant role in such adsorption and lignin materials derived from dilute acid-CS and dilute alkali-CS possessed different enzyme adsorption properties. Enzyme recycling was performed by recycling unhydrolyzed solids after 24 h enzymatic hydrolysis for five successive rounds, and successfully reduced 40% and 50% of the enzyme loadings for hydrolysis of dilute alkali-CS and for hydrolysis of dilute acid-CS, respectively. Conclusions: This study presents that the enzymes adsorbed on the unhydrolyzed solids after short-time hydrolysis could be recycled effectively for efficient enzymatic hydrolysis. Lignin derived from dilute acid-CS has higher enzyme adsorption capacity than the lignin derived from dilute alkali-CS, which led to more enzymes recycled. By applying the enzyme recycling strategy developed in this study, the enzyme dosage needed for effective cellulose hydrolysis can be significantly reduced. PMID- 30479660 TI - Clostridium acetobutylicum grows vegetatively in a biofilm rich in heteropolysaccharides and cytoplasmic proteins. AB - Background: Biofilms are cell communities wherein cells are embedded in a self produced extracellular polymeric substances (EPS). The biofilm of Clostridium acetobutylicum confers the cells superior phenotypes and has been extensively exploited to produce a variety of liquid biofuels and bulk chemicals. However, little has been known about the physiology of C. acetobutylicum in biofilm as well as the composition and biosynthesis of the EPS. Thus, this study is focused on revealing the cell physiology and EPS composition of C. acetobutylicum biofilm. Results: Here, we revealed a novel lifestyle of C. acetobutylicum in biofilm: elimination of sporulation and vegetative growth. Extracellular polymeric substances and wire-like structures were also observed in the biofilm. Furthermore, for the first time, the biofilm polysaccharides and proteins were isolated and characterized. The biofilm contained three heteropolysaccharides. The major fraction consisted of predominantly glucose, mannose and aminoglucose. Also, a great variety of proteins including many non-classically secreted proteins moonlighting as adhesins were found considerably present in the biofilm, with GroEL, a S-layer protein and rubrerythrin being the most abundant ones. Conclusions: This study evidenced that vegetative C. acetobutylicum cells rather than commonly assumed spore-forming cells were essentially the solvent-forming cells. The abundant non-classically secreted moonlighting proteins might be important for the biofilm formation. This study provides the first physiological and molecular insights into C. acetobutylicum biofilm which should be valuable for understanding and development of the biofilm-based processes. PMID- 30479662 TI - Real-time adsorption and action of expansin on cellulose. AB - Background: Biological pretreatment is an environmentally safe method for disrupting recalcitrant structures of lignocellulose and thereby improving their hydrolysis efficiency. Expansin and expansin-like proteins act synergistically with cellulases during hydrolysis. A systematic analysis of the adsorption behavior and mechanism of action of expansin family proteins can provide a basis for the development of highly efficient pretreatment methods for cellulosic substrates using expansins. Results: Adsorption of Bacillus subtilis expansin (BsEXLX1) onto cellulose film under different conditions was monitored in real time using a quartz crystal microbalance with dissipation. A model was established to describe the adsorption of BsEXLX1 onto the film. High temperatures increased the initial adsorption rate while reducing the maximum amount of BsEXLX1 adsorbed onto the cellulose. Non-ionic surfactants (polyethylene glycol 4000 and Tween 80) at low concentrations enhanced BsEXLX1 adsorption; whereas, high concentrations had the opposite effect. However, sodium dodecyl sulfate inhibited adsorption at both low and high concentrations. We also investigated the structural changes of cellulose upon BsEXLX1 adsorption and found that BsEXLX1 adsorption decreased the crystallinity index, disrupted hydrogen bonding, and increased the surface area of cellulose, indicating greater accessibility of the substrate to the protein. Conclusions: These results increase our understanding of the interaction between expansin and cellulose, and provide evidence for expansin treatment as a promising strategy to enhance enzymatic hydrolysis of lignocellulose. PMID- 30479663 TI - Dual expression of plastidial GPAT1 and LPAT1 regulates triacylglycerol production and the fatty acid profile in Phaeodactylum tricornutum. AB - Background: Metabolic engineering has emerged as a potential strategy for improving microalgal lipid content through targeted changes to lipid metabolic networks. However, the intricate nature of lipogenesis has impeded metabolic engineering. Therefore, it is very important to identify the crucial metabolic nodes and develop strategies to exploit multiple genes for transgenesis. In an attempt to unravel the microalgal triacylglycerol (TAG) pathway, we overexpressed two key lipogenic genes, glycerol-3-phosphate acyltransferase (GPAT1) and lysophosphatidic acid acyltransferase (LPAT1), in oleaginous Phaeodactylum tricornutum and determined their roles in microalgal lipogenesis. Results: Engineered P. tricornutum strains showed enhanced growth and photosynthetic efficiency compared with that of the wild-type during the growth phase of the cultivation period. However, both the cell types reached stationary phase on day 7. Overexpression of GPAT1 and LPAT1 increased the TAG content by 2.3-fold under nitrogen-replete conditions without compromising cell growth, and they also orchestrated the expression of other key genes involved in TAG synthesis. The transgenic expression of GPAT1 and LPAT1 influenced the expression of malic enzyme and glucose 6-phosphate dehydrogenase, which enhanced the levels of lipogenic NADPH in the transgenic lines. In addition, GPAT1 and LPAT1 preferred C16 over C18 at the sn-2 position of the glycerol backbone. Conclusion: Overexpression of GPAT1 together with LPAT1 significantly enhanced lipid content without affecting growth and photosynthetic efficiency, and they orchestrated the expression of other key photosynthetic and lipogenic genes. The lipid profile for elevated fatty acid content (C16-CoA) demonstrated the involvement of the prokaryotic TAG pathway in marine diatoms. The results suggested that engineering dual metabolic nodes should be possible in microalgal lipid metabolism. This study also provides the first demonstration of the role of the prokaryotic TAG biosynthetic pathway in lipid overproduction and indicates that the fatty acid profile can be tailored to improve lipid production. PMID- 30479664 TI - Advances and challenges in the management of advanced fibrosis in nonalcoholic steatohepatitis. AB - Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common type of chronic liver disease worldwide. From the spectrum of NAFLD, it is nonalcoholic steatohepatitis (NASH) that predominantly predisposes patients to higher risk for development of cirrhosis and hepatocellular carcinoma. There is growing evidence that the risk of progression to cirrhosis and hepatocellular carcinoma is not uniform among all patients with NASH. In fact, NASH patients with increasing numbers of metabolic diseases such as diabetes, hypertension, visceral obesity and dyslipidemia are at a higher risk of mortality. Additionally, patients with higher stage of liver fibrosis are also at increased risk of mortality. In this context, NASH patients with fibrosis are in the most urgent need of treatment. Also, the first line of treatment for NASH is lifestyle modification with diet and exercise. Nevertheless, the efficacy of lifestyle modification is quite limited. Additionally, vitamin E and pioglitazone may be considered for subset of patients with NASH. There are various medications targeting one or more steps in the pathogenesis of NASH being developed. These drug regimens either alone or in combination, may provide potential treatment option for patients with NASH. PMID- 30479666 TI - Antibiotic prophylaxis in foot and ankle surgery: a systematic review of the literature. AB - Background: With the advent of bacterial resistance, it is important now more than ever to evaluate use of antibiotic chemoprophylaxis in foot and ankle surgery. Within this area of the body there may be less dissection, surgery time with smaller incisions and importantly smaller sizes of implanted fixation as compared to other bone and joint procedures. Our objective was to systematically evaluate the quality of evidence behind existing guidelines. Methodology: A systematic literature search was performed: MEDLINE, CINHAL, EMBASE and the Cochrane library from 1990 up to March 2018. To avoid omitting any studies on the subject, Google Scholar was also used. The inclusion criterion were studies exploring perioperative antibiotic use, postoperative infection rates in elective foot and ankle surgery and studies associated with this subject evaluating antibiotic use in clean elective foot and ankle surgery. The exclusion criterion being studies upon contaminated or dirty surgery or those which were inclusive of procedures proximal to the foot and ankle. Results: Overall 11 studies met the inclusion criteria. From the grading of evidence, 2 level one and 4 level two studies were recognised. These studies ranked relatively highly in comparison to 5 studies that were graded as level three and level four tiers of evidence. Results of SSI rates found within this systematic review ranged from 0% to 9.4% of overall postoperative infections encountered after foot and ankle surgery in the studies analysed. Conclusion: Whilst fragmented, aspects of antibiotic chemoprophylaxis are established fields in elective surgery with a growing body of evidence. Evidence for antibiotic use however, specifically within elective foot and ankle surgery, is lacking. This systematic review is a seminal paper which delivers an impression of the most influential literature within the field of foot and ankle surgery, with the aim being to entice conclusions and guide future research. PMID- 30479665 TI - Rapid detection of papillary thyroid carcinoma by fluorescence imaging using a gamma-glutamyltranspeptidase-specific probe: a pilot study. AB - Background: Nodular lesions of the thyroid gland, including papillary thyroid carcinoma (PTC), may be difficult to diagnose by imaging, such as in ultrasonic echo testing, or by needle biopsy. Definitive diagnosis is made by pathological examination but takes several days. A more rapid and simple method to clarify whether thyroid nodular lesions are benign or malignant is needed. Fluorescence imaging with gamma-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG) uses gamma glutamyltranspeptidase (GGT), a cell-surface enzyme, to hydrolyze the gamma glutamyl peptide and transfer the gamma-glutamyl group. GGT is overexpressed in several cancers, such as breast, lung, and liver cancers. This imaging method is rapid and useful for detecting such cancers. In this study, we tried to develop a rapid fluorescence detection method for clinical samples of thyroid cancer, especially papillary carcinoma. Methods: Fluorescence imaging with gGlu-HMRG was performed to detect PTC using 23 surgically resected clinical samples. A portable imaging device conveniently captured white-light images and fluorescence images with blue excitation light. Hematoxylin-eosin (HE) staining was used to evaluate which fluorescent regions coincided with cancer, and immunohistochemical examination was used to detect GGT expression. Results: All 16 PTC samples exhibited fluorescence after topical application of gGlu-HMRG, whereas the normal sections of each sample showed no fluorescence. HE staining revealed that each fluorescent region corresponded to a region with carcinoma. The PTC samples also exhibited GGT expression, as confirmed by immunohistochemistry. Conclusions: All PTC samples were detected by fluorescence imaging with gGlu-HMRG. Thus, fluorescence imaging with gGlu-HMRG is a rapid, simple, and powerful detection tool for PTC. PMID- 30479667 TI - Validation of a weight bearing ankle equinus value in older adults with diabetes. AB - Background: Accurate measurement of ankle joint dorsiflexion is clinically important as a restriction has been linked to many foot and ankle pathologies, as well as increased ulcer risk and delayed ulcer healing in people with diabetes. Use of the reliable weight bearing (WB) Lunge test is limited as normal and restricted ranges for WB ankle joint dorsiflexion are not identified. Additionally the extent of WB dorsiflexion restriction that results in clinically adverse outcomes is unclear. Therefore the aim of this investigation is to validate a proposed weight bearing equinus value (dorsiflexion < 30 degrees ) in unimpaired cohorts, and secondly to investigate any clinical effects this degree of ankle dorsiflexion restriction has on forefoot plantar pressure variables in older adults with diabetes. Methods: Ankle dorsiflexion was measured using a Lunge test with the knee extended in young adults without diabetes (YA) and older adults with diabetes (DA). In-shoe and barefoot plantar pressure was recorded for the DA group. Spearman's correlation was calculated to determine any association between the presence of ankle equinus and plantar pressure variables in the DA group. DA group differences in people with and without an equinus were examined. Results: A weight bearing equinus of < 30 degrees , assessed in a lunge using an inclinometer placed on the anterior tibia, falls within the restricted range in young unimpaired cohorts. In the DA group this degree of ankle restriction had a fair and significant association with elevated barefoot forefoot peak pressure (r = 0.274, p = 0.005) and pressure-time integrals (r = 0.321, p = .001). The DA equinus group had significantly higher barefoot peak pressure (mean kPa (SD): 787.1 (246.7) vs 652.0 (304.5), p = 0.025) and pressure-time integrals (mean kPa (SD): 97.8 (41.6) vs 80.4 (30.5), p = 0.017) than the DA non equinus group. Conclusions: We support a preliminary weight bearing ankle equinus value of < 30 degrees . This value represents a restricted range in young adults and is correlated with increased forefoot plantar pressure variables in older adults with diabetes. Mean population weight bearing ankle dorsiflexion data presented here for older adults with diabetes, will allow use of the more functional Lunge test with knee extended in research and clinical practice. PMID- 30479668 TI - Neck circumference is associated with non-traditional cardiovascular risk factors in individuals at low-to-moderate cardiovascular risk: cross-sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - Background: Neck circumference (NC) is associated with traditional cardiovascular risk factors (CVRF), but its usefulness to identify earlier atherogenic risk has been scarcely examined. Associations of NC with non-traditional CVRF were investigated in participants at low-to-moderate risk from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Methods: 807 individuals (35-54 years) without obesity, diabetes or cardiovascular disease was stratified into quartiles of NC (cut-off for men: 36.5; 37.9 and 39.5 cm; women: 31.4; 32.5 and 34 cm) and traditional and non-traditional risk factors (lipoprotein subfractions by Vertical Auto Profile, adiponectin, leptin, E-selectin) were compared across groups. In linear regression models, associations of NC with non-traditional risk factors were tested for the entire sample and for low-risk group (<= 2 CVRF). Results: In both sexes, BMI, waist circumference, systolic and diastolic blood pressure, fasting and 2-h plasma glucose, HOMA-IR, triglycerides, leptin, E selectin, small dense LDL-cholesterol, IDL-cholesterol, VLDL3-cholesterol and TG/HDL ratio increased significantly, while HDL2-cholesterol and HDL3-cholesterol decreased across NC quartiles. In linear regression models, a direct association [beta(95% CI)] of NC with leptin [(0.155 (0.068-0.242); 0.147 (0.075-0.220)], E selectin [(0.105 (0.032-0.177); 0.073 (0.006 to 0.140)] and small-dense LDL [(1.866 (0.641-3.091); 2.372 (1.391-3.353)] and an inverse association with HDL2 cholesterol [(- 0.519 (- 0.773 to - 0.266); - 0.815 (- 1.115 to 0.515)] adjusted for age were detected for men and women, respectively. Conclusion: Our findings indicate that measurement of NC may be useful for an earlier identification of unfavorable atherogenic metabolic profile in middle-aged individuals at lower cardiovascular risk level. PMID- 30479669 TI - Hypoglycemia incidence and awareness among insulin-treated patients with diabetes: the HAT study in Brazil. AB - Background: Hypoglycemia affects patient safety and glycemic control during insulin treatment of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM). The Hypoglycemia Assessment Tool study in Brazil aimed to determine the proportion of patients experiencing hypoglycemic events and to characterize patient awareness and fear about hypoglycemia, among insulin-treated T1DM or T2DM patients. Methods: This was a non-interventional, multicenter study, with a 6-month retrospective and a 4-week prospective evaluation of hypoglycemic events. Patients completed a questionnaire at baseline and at the end of the study, and also a patient diary. The answers 'occasionally' and 'never' to the question 'Do you have symptoms when you have a low sugar level?' denoted impaired hypoglycemia awareness. Fear was reported on a 10-point scale, from 'not afraid at all' to 'absolutely terrified'. Results: From 679 included patients, 321 with T1DM and 293 T2DM, median age of 33.0 and 62.0 years, 59% and 56% were female, and median diabetes duration was 15.0 and 15.0 years, respectively. Median time of insulin use was 14.0 and 6.0 years. During the prospective period, 91.7% T1DM and 61.8% T2DM patients had at least one hypoglycemic event. In the same period, 54.0% T1DM and 27.4% T2DM patients had nocturnal hypoglycemia, 20.6% T1DM and 10.6% T2DM patients had asymptomatic hypoglycemia, and severe events occurred in 20.0% and 10.3%, respectively. At baseline, 21.4% T1DM and 34.3% T2DM had hypoglycemia unawareness. The mean score of hypoglycemia fear was 5.9 +/- 3.1 in T1DM and 5.4 +/- 3.9 in T2DM. The most common attitude after hypoglycemic events were to increase calorie intake (60.3%) and blood glucose monitoring (58.0%) and to reduce or skip insulin doses (30.8%). Conclusions: Referred episodes of hypoglycemia were high, in both T1DM and T2DM insulin users. Patient attitudes after hypoglycemia, such as reduction in insulin and increase in calorie intake, can affect diabetes management. These findings may support clinicians in tailoring diabetes education and insulin treatment for patients with diabetes, in order to improve their glycemic control while reducing the risk of hypoglycemic events. PMID- 30479670 TI - Population attributable fractions for Type 2 diabetes: an examination of multiple risk factors including symptoms of depression and anxiety. AB - Background: Population attributable fractions (PAFs) are frequently used to quantify the proportion of Type 2 diabetes cases due to single risk factors, an approach which may result in an overestimation of their individual contributions. This study aimed to examine Type 2 diabetes incidence associated with multiple risk factor combinations, including the metabolic syndrome, behavioural factors, and specifically, depression and anxiety. Methods: Using data from the population based HUNT cohort, we examined incident diabetes in 36,161 Norwegian adults from 1995 to 2008. PAFs were calculated using Miettinen's case-based formula, using relative risks estimated from multivariate regression models. Results: Overall, the studied risk factors accounted for 50.5% of new diabetes cases (78.2% in men and 47.0% in women). Individuals exposed to both behavioural and metabolic factors were at highest risk of diabetes onset (PAF = 22.9%). Baseline anxiety and depression contributed a further 13.6% of new cases to this combination. Men appeared to be particularly vulnerable to the interaction between metabolic, behavioural and psychological risk factors. Conclusion: This study highlights the importance of risk factor clustering in diabetes onset, and is the first that we know of to quantify the excess fraction of incident diabetes associated with psychological risk factor interactions. PMID- 30479671 TI - Use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in older patients with ER positive HER2-negative breast cancer: Young International Society of Geriatric Oncology review paper. AB - The current standard of care for the management of estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer has been redefined by the introduction of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Although adults aged 65 years and older account for the majority of patients with breast cancer, limited data are available about the age specific dosing, tolerability, and benefit of CDK4/6 inhibitors in this growing population. Older adults are under-represented in clinical trials and as a result, clinicians are forced to extrapolate from findings in younger and healthier patients when making treatment decisions for older patients. In this article, we review the limited age-specific evidence on the efficacy, toxicity, and quality of life (QoL) outcomes associated with the use of CDK4/6 inhibitors in older adults. We also describe ongoing trials evaluating CDK4/6 inhibitors in the older population and highlight that only a minority of adjuvant and metastatic trials of CDK4/6 inhibitors in the general breast cancer population includes geriatric assessments. Finally, we propose potential strategies to help guide decision making for fit and unfit older patients based on disease endocrine sensitivity, the need for rapid response and geriatric assessment. PMID- 30479672 TI - Assessing response to neo-adjuvant therapy in locally advanced rectal cancer using Intra-voxel Incoherent Motion modelling by DWI data and Standardized Index of Shape from DCE-MRI. AB - Background: Our aim was to investigate preoperative chemoradiation therapy (pCRT) response in locally advanced rectal cancer (LARC) comparing standardized index of shape (SIS) obtained from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with intravoxel-incoherent-motion-modelling-derived parameters by diffusion-weighted imaging (DWI). Materials and methods: Eighty-eight patients with LARC were subjected to MRI before and after pCRT. Apparent diffusion coefficient (ADC), tissue diffusion (Dt), pseudodiffusion (Dp) and perfusion fraction (f) were calculated and percentage changes ?ADC, ?Dt, ?Dp, ?f were computed. SIS was derived comparing DCE-MRI pre- and post-pCRT. Nonparametric tests and receiver operating characteristic (ROC) curves were performed. Results: A total of 52 patients were classified as responders (tumour regression grade; TRG ? 2) and 36 as not-responders (TRG > 3). Mann-Whitney U test showed statistically significant differences in SIS, ?ADC and ?Dt between responders and not-responders and between complete responders (19 patients with TRG = 1) versus incomplete responders. The best parameters to discriminate responders by nonresponders were SIS and ?ADC, with an accuracy of 91% and 82% (cutoffs of 5.2% and 18.7%, respectively); the best parameters to detect pathological complete responders were SIS, ?f and ?Dp with an accuracy of 78% (cutoffs of 38.5%, 60.0% and 83.0%, respectively). No increase of performance was observed by combining linearly each possible couple of parameters or combining all parameters. Conclusion: SIS allows assessment of preoperative treatment response with high accuracy guiding the surgeon versus more or less conservative treatment. DWI-derived parameters reached less accuracy compared with SIS and combining linearly DCE- and DWI-derived parameters; no increase of accuracy was obtained. PMID- 30479673 TI - Relationship between a three-month physical conditioning "posture-balance motricity and health education" (PBM-HE) program on postural and balance capacities of sedentary older adults: influence of initial motor profile. AB - Background: The aims of this study were (i) to define the relationship between a physical reconditioning cycle using balance exercises and muscular-articular stress and the balance capabilities of sedentary older adults and (ii) to assess whether older adults with weaker equilibrium abilities have a significantly limited progression. Our sample consisted of 338 people (263 women, 75 men) with an age, weight and height of 74.4 years (+/- 8.6), 67 kg (+/- 13.6) and 161.4 cm (+/- 8) and with a body mass index of 25.6 (+/- 4.3). The functional evaluations consisted of individual motor profile tests, monopodal eyes open and eyes closed for 30 s, a Timed Up and Go test (TUG) and stabilometric measurements on hard ground with eyes open for a duration of 25.6 s. The physical repackaging protocol was based on the 12-week Posture-Balance-Motricity and Health Education (PBM-ES) method with two 90-min weekly group sessions. Results: The evolution of the "posture" and "balance" variables was significantly associated with the equilibration capacities (p < 0.001). For unipedal stance with open eyes on the dominant and non-dominant sides, respectively, the progressions were significant for the profiles of middle (OR: 4.78 and 2.42) and low levels (OR: 4.34 and 1.66). Eyes-closed progressions were non-significant for the low-level balance profiles. For the COP Surface and Length variables, compared to those with high levels of balance, respectively, the progressions were significant for the middle (OR: 1.41 and 2.98) and low-level (OR: 2.91 and 3.28) profiles. Conclusions: After a 3-month bi-weekly PBM-HE program, we observed that sedentary older adults with the lowest initial level of balance progressed significantly more than high level individuals, but only for basic motor abilities. It turns out that even among the most deconditioned people and older adults, very significant progress can be made. This increase requires an individualized training content focused on initial mobilizable capacities. PMID- 30479674 TI - Phonon and heat transport control using pillar-based phononic crystals. AB - Phononic crystals have been studied for the past decades as a tool to control the propagation of acoustic and mechanical waves. Recently, researchers proposed that nanosized phononic crystals can also control heat conduction and improve the thermoelectric efficiency of silicon by phonon dispersion engineering. In this review, we focus on recent theoretical and experimental advances in phonon and thermal transport engineering using pillar-based phononic crystals. First, we explain the principles of the phonon dispersion engineering and summarize early proof-of-concept experiments. Next, we review recent simulations of thermal transport in pillar-based phononic crystals and seek to uncover the origin of the observed reduction in the thermal conductivity. Finally, we discuss first experimental attempts to observe the predicted thermal conductivity reduction and suggest the directions for future research. PMID- 30479675 TI - Voids and compositional inhomogeneities in Cu(In,Ga)Se2 thin films: evolution during growth and impact on solar cell performance. AB - Structural defects such as voids and compositional inhomogeneities may affect the performance of Cu(In,Ga)Se2 (CIGS) solar cells. We analyzed the morphology and elemental distributions in co-evaporated CIGS thin films at the different stages of the CIGS growth by energy-dispersive x-ray spectroscopy in a transmission electron microscope. Accumulation of Cu-Se phases was found at crevices and at grain boundaries after the Cu-rich intermediate stage of the CIGS deposition sequence. It was found, that voids are caused by Cu out-diffusion from crevices and GBs during the final deposition stage. The Cu inhomogeneities lead to non uniform diffusivities of In and Ga, resulting in lateral inhomogeneities of the In and Ga distribution. Two and three-dimensional simulations were used to investigate the impact of the inhomogeneities and voids on the solar cell performance. A significant impact of voids was found, indicating that the unpassivated voids reduce the open-circuit voltage and fill factor due to the introduction of free surfaces with high recombination velocities close to the CIGS/CdS junction. We thus suggest that voids, and possibly inhomogeneities, limit the efficiency of solar cells based on three-stage co-evaporated CIGS thin films. Passivation of the voids' internal surface may reduce their detrimental effects. PMID- 30479676 TI - MHC-identical and transgenic cynomolgus macaques for preclinical studies. AB - Cynomolgus macaques are useful experimental animals that are physiologically and genetically close to humans. We have developed two kinds of experimental usage of cynomolgus macaque: transplantation and disease models. First, we identified certain major histocompatibility complex (MHC) haplotypes including homozygotes and heterozygotes in cynomolgus macaques native to the Philippines, because they have less polymorphism in the MHC than that in other origins such as Vietnam and Indonesia. As a preclinical model of the induced pluripotent stem cell (iPSC) stock project, we established iPSCs from various types of MHC homozygous macaques, which were transplanted into compatible MHC heterozygous macaques, the iPSC stock project was experimentally shown to be effective. Second, to obtain disease models of cynomolgus macaques for studies on regenerative medicine including cell therapies, we established two kinds of genetic technology to modify cynomolgus macaques: transgenic technology and gene editing technology using CRISPR-Cas9. We will establish disease models, such as Alzheimer's disease and progeria (Werner syndrome). In future, we will distribute the MHC-identical cynomolgus monkeys and genetically modified macaques to researchers, especially those engaging in regenerative medicine. PMID- 30479677 TI - Dependent layering of venous refluxed contrast: A sign of critically low cardiac output. AB - Mortality associated with cardiogenic shock can reach 80%. Although most often diagnosed clinically, the hemodynamics of cardiogenic shock may manifest on contrast-enhanced computed tomography as dependent layering of contrast within the inferior vena cava (IVC), a finding referred to as the "IVC level sign." Herein we present 2 cases of the IVC level sign. Swift recognition of the IVC level sign and awareness of its dire prognostic implications is essential for achieving the best patient outcomes. PMID- 30479678 TI - Meconium pseudocyst presenting as massive ascites in a new-born. AB - Meconium pseudocyst (MPC) is a rare but well-known surgical condition due to prenatal bowel perforation. A case of MPC secondary to prenatal bowel perforation is presented. Massive ascites requiring peritoneal drainage and disappearance of prenatal intraperitoneal calcifications have not been previously reported in MPC. MPC may present at birth with large ascites requiring peritoneal drainage to establish breathing and ventilation. Absence of prenatal intra-abdominal calcifications does not rule out MPC. PMID- 30479679 TI - Methicillin-resistant Staphylococcal aureus patellar tendon abscess and septic prepatellar bursitis in an injection drug user. AB - We report a case of intratendinous patellar abscess and prepatellar septic bursitis following direct inoculation in a 26-year-old male injection drug user. The patient presented with 2 days of progressive knee pain, swelling, and erythema. Computed tomography demonstrated an enlarged patellar tendon with central low attenuation. Ultrasonography revealed a complex intratendinous fluid collection concerning for abscess. Aspiration of this fluid collection yielded grossly purulent fluid which grew methicillin-resistant staphylococcal aureus. The patient subsequently underwent operative debridement which revealed an intratendinous patellar abscess with extension to involve the prepatellar bursa. This case report demonstrates typical, though nonspecific, radiographic findings of abscess in an atypical location and highlights the importance of clinical history in diagnosing musculoskeletal disorders, particularly in the absence of traditional types of traumatic injury. PMID- 30479680 TI - Bilateral renal artery stenosis treated with drug-eluting balloon angioplasty in unique treatment. AB - Renal artery stenosis commonly manifests with hypertension refractory to medical treatment. We report a case of renal artery stenosis occurring in a 19-year-old female patient who presented with extremely high blood pressure and bilateral renal stenosis at the duplex ultrasound. Renal angiography confirmed the bilateral and irregular stenosis due to fibromuscular dysplasia, associated to extent collaterals suppling the poststenotic right renal artery. Therefore, angioplasty with drug-eluting balloon was performed in order to obtain a good vessel patency and to improve patency in the long term follow-up. After the endovascular treatment the blood pressure improved markedly, maintaining this result at 12 months follow-up at clinical examination and duplex ultrasound. PMID- 30479681 TI - Percutaneous transhepatic use of rigid bronchial forceps as bailout in difficult biliary stent retrieval. AB - Endoscopic retrieval of embedded, proximally migrated, or fractured plastic biliary stents may be technically challenging and sometimes unsuccessful. Percutaneous transhepatic techniques have previously been described to assist in such challenging cases. Here in, we describe a difficult case in which all commonly described endoscopic and percutaneous techniques failed to retrieve a proximally migrated, fractured, and looped plastic biliary stent. We finally successfully retrieved the plastic forceps after off-label utilization of rigid bronchial forceps via a percutaneous transhepatic approach. We describe the technique utilized in detail and this appears to be the first description of this off-label use in this challenging scenario. PMID- 30479682 TI - Transcatheter arterial embolization for initial hemostasis in a hemodynamically unstable patient with mesenteric hemorrhage: A case report. AB - Surgical treatment of mesenteric injuries is necessary to control hemorrhage, manage bowel injuries, and evaluate bowel perfusion. It has recently been suggested that some patients can be managed with transcatheter arterial embolization (TAE) for initial hemostasis. We present a hemodynamically unstable patient who was initially managed by TAE for traumatic mesenteric hemorrhage. A 60-year-old man was injured in a motor vehicle accident and transported to our facility. On arrival, the patient was hemodynamically stable, and had abdominal pain. Physical examination revealed a seatbelt sign on the lower abdomen. A contrast-enhanced computed tomography (CT) scan showed intra-abdominal hemorrhage, mesenteric hematoma, and a giant-pseudoaneurysm, but no intra abdominal free air or changes in the appearance of the bowel wall. After the CT scan, his vital signs deteriorated and surgical intervention was considered, but TAE was performed to control the hemorrhage. After TAE, the patient was hemodynamically stable and had no abdominal tenderness. A follow-up CT scan was performed 2 days later which showed partial necrosis of the transverse colon and some free air. Resection of the injured transverse colon with primary anastomosis was performed. The patient improved and was discharged 35 days after injury. TAE can be effective as the initial hemostatic procedure in patients with traumatic mesenteric hemorrhage. PMID- 30479683 TI - Current and future impact of clinical gastrointestinal research on patient care in diabetes mellitus. AB - The worldwide rise in the prevalence of obesity supports the need for an increased interaction between ongoing clinical research in the allied fields of gastrointestinal medicine/surgery and diabetes mellitus. There have been a number of clinically-relevant advances in diabetes, obesity, and metabolic syndrome emanating from gastroenterological research. Gastric emptying is a significant factor in the development of upper gastrointestinal symptoms. However, it is not the only mechanism whereby such symptoms occur in patients with diabetes. Disorders of intrinsic pacing are involved in the control of stomach motility in patients with gastroparesis; on the other hand, there is limited impact of glycemic control on gastric emptying in patients with established diabetic gastroparesis. Upper gastrointestinal functions related to emptying and satiations are significantly associated with weight gain in obesity. Medications used in the treatment of diabetes or metabolic syndrome, particularly those related to pancreatic hormones and incretins affect upper gastrointestinal tract function and reduce hyperglycemia and facilitate weight loss. The degree of gastric emptying delay is significantly correlated with the weight loss in response to liraglutide, a glucagon-like peptide-1 analog. Network meta-analysis shows that liraglutide is one of the two most efficacious medical treatments of obesity, the other being the combination treatment phentermine-topiramate. Interventional therapies for the joint management of obesity and diabetes mellitus include newer endoscopic procedures, which require long-term follow-up and bariatric surgical procedure for which long-term follow up shows advantages for individuals with diabetes. Newer bariatric procedures are presently undergoing clinical evaluation. On the horizon, combination therapies, in part directed at gastrointestinal functions, appear promising for these indications. Ongoing and future gastroenterological research when translated to care of individuals with diabetes mellitus should provide additional options to improve their clinical outcomes. PMID- 30479684 TI - Unhealthy eating habits around sleep and sleep duration: To eat or fast? AB - Traditionally, breakfast skipping (BS), and recently late-night dinner eating (LNDE), have attracted attention in public health because they can predispose to cardiometabolic conditions such as obesity and type 2 diabetes. Intriguingly, it has become evident that short duration of sleep elicits similar health risks. As LNDE, BS, and short sleep can be closely related and can aggravate each other, these three should not be considered separately. In this context, LNDE (or its equivalents, snacking or heavy alcohol consumption after dinner) and BS may be representative unhealthy eating habits around sleep (UEHAS). While it is important to take energy in the early morning for physical and intellectual activities, attaining a fasting state is essential for metabolic homeostasis. Our previous UEHAS studies have shown that BS without LNDE, i.e., BS alone, is not associated with obesity and diabetes, suggesting the possibility that BS or taking a very low energy breakfast, which could yield fasting for a while, may prevent obesity and diabetes in people with inevitable LNDE. Further studies considering UEHAS and short sleep simultaneously are needed to elucidate the effects of these unhealthy lifestyles on cardiometabolic diseases. PMID- 30479685 TI - Circadian rhythms of hormone secretion and obesity. AB - The adipose tissue homeostasis is profoundly affected by circadian rhythms of corticosteroid secretion and chronic loss of hormonal oscillations is associated with obesity. How adipose tissue differentially responds to pulsatile vs continuous presence of glucocorticoids is poorly defined. To address this question, Bahrami-Nejad et al studied differentiation of pre-adipocytes, containing endogenously tagged CCAAT/enhancer binding protein and peroxisome proliferator-activated receptor (PPAR) gamma (key regulators of adipocyte differentiation), in response to corticosteroids that were delivered either in an oscillatory fashion or continuously. The authors show that the bi-stable state of differentiation of pre-adipocytes and adipocytes was regulated by a combination of fast and slow positive feedback networks, that determined unique threshold of PPARgamma in these cells. Evidently, pre-adipocytes used the fast feedback loop to reject differentiation cues of oscillating pulses of glucocorticoids and failed to differentiate into fat cells. In contrast, when glucocorticoids were delivered continuously, precursor cells exploited the slow feedback loop to embark on a path of maximal differentiation. This differential differentiation response of pre-adipocytes to pulsatile vs continuous exposure to glucocorticoids was corroborated in vivo. Thus, mice receiving non-oscillating doses of exogenous glucocorticoids, for 21 d, elicited excessive accumulation of visceral and subcutaneous fat. These data shed new light on the mechanisms of obesity caused by putative misalignment of circadian secretion of glucocorticoids or their persistently high levels due to chronic stress or Cushing's disease. PMID- 30479687 TI - Antigen-armed antibodies against B-cell malignancies. PMID- 30479688 TI - B2M, JAK2 and MET in the genetic landscape of immunotolerance in lung cancer. PMID- 30479686 TI - Use of sodium bicarbonate and blood gas monitoring in diabetic ketoacidosis: A review. AB - Diabetic ketoacidosis (DKA) is a severe and too-common complication of uncontrolled diabetes mellitus. Acidosis is one of the fundamental disruptions stemming from the disease process, the complications of which are potentially lethal. Hydration and insulin administration have been the cornerstones of DKA therapy; however, adjunctive treatments such as the use of sodium bicarbonate and protocols that include serial monitoring with blood gas analysis have been much more controversial. There is substantial literature available regarding the use of exogenous sodium bicarbonate in mild to moderately severe acidosis; the bulk of the data argue against significant benefit in important clinical outcomes and suggest possible adverse effects with the use of bicarbonate. However, there is scant data to support or refute the role of bicarbonate therapy in very severe acidosis. Arterial blood gas (ABG) assessment is an element of some treatment protocols, including society guidelines, for DKA. We review the evidence supporting these recommendations. In addition, we review the data supporting some less cumbersome tests, including venous blood gas assessment and routine chemistries. It remains unclear that measurement of blood gas pH, via arterial or venous sampling, impacts management of the patient substantially enough to warrant the testing, especially if sodium bicarbonate administration is not being considered. There are special circumstances when serial ABG monitoring and/or sodium bicarbonate infusion are necessary, which we also review. Additional studies are needed to determine the utility of these interventions in patients with severe DKA and pH less than 7.0. PMID- 30479689 TI - Precision virotherapies: Coming soon. PMID- 30479690 TI - Should we measure clonal circulating plasma cells in light chain amyloidosis? PMID- 30479691 TI - Aberrant glycosylation in colorectal cancer with genomic and epigenomic alterations. PMID- 30479692 TI - Third party, umbilical cord blood derived regulatory T-cells for prevention of graft versus host disease in allogeneic hematopoietic stem cell transplantation: feasibility, safety and immune reconstitution. AB - Incubation of umbilical cord blood (UCB) derived regulatory T-cells (Tregs) with fucosyltransferase enzyme improves their ability to home to the target tissue to prevent graft vs. host disease (GVHD). We report results of 5 patients (Double UCB Transplant, n=2; Peripheral Blood Matched Unrelated Donor Transplant, n=3) who received UCB-Tregs (Dose level = 1*106/kg), infused one day prior to the donor graft. All patients received their designated UCB-Treg dose without any infusion reaction. The ratio of conventional T-cells in donor graft was at least 10 times higher than infused UCB-Tregs (ratio range, 12-356). All patients engrafted at median of 13 days (range, 8-17 days). One patient died due to brain hemorrhage on day 45. A bi-modal increase of plasma IL-10 level occurred on day 7 and day 21 and notably, plasma IL-2 level dropped significantly in all patients at Day 7. All evaluable patients developed >=grade II acute GVHD and at 1 year follow up, all were alive and without evidence of disease relapse. No increase in the chronic GVHD biomarkers (REG3a and Elafin) was observed at day 7. At the time of last follow up, all evaluable patients were off immune-suppression. Stage 2 of this clinical trial examining UCB-Treg at dose level= 1*107/kg is currently underway. PMID- 30479693 TI - Prognostic significance of tumor genotypes and CD8+ infiltrates in stage I-III colorectal cancer. AB - Background: We explored the clinical significance of tumor genotypes and immunophenotypes in non-metastatic colorectal cancer (CRC). Methods: In primary tumors (paraffin blocks) from 412 CRC patients treated with adjuvant chemotherapy, we examined pathogenic mutations (panel NGS; 347 informative); mismatch repair (MMR) immunophenotype (360 informative); and CD8+ lymphocyte density (high - low; 412 informative). The primary outcome measure was disease free survival (DFS). Results: We evaluated 1713 pathogenic mutations (median: 3 per tumor; range 0-49); 118/412 (28.6%) tumors exhibited high CD8+ density; and, 40/360 (11.1%) were MMR-deficient. Compared to MMR-proficient, MMR-deficient tumors exhibited higher CD8+ density (chi-square, p<0.001) and higher pathogenic mutation numbers (p=0.003). High CD8+ density was an independent favorable prognosticator (HR=0.49, 95%CI 0.29-0.84, Wald's p=0.010). Pathogenic BRCA1 and ARID1A mutations were inversely associated with each other (p<0.001), were not associated with MMR-deficiency or CD8+ density, but both independently predicted for unfavorable DFS (HR=1.98, 95%CI 1.12-3.48, p=0.018 and HR=1.99, 95%CI 1.11 3.54, p=0.020, respectively). Conclusion: In non-metastatic CRC, high CD8+ lymphocyte density confers a favorable prognosis and may be developed as a single marker in routine diagnostics. The unfavorable prognostic effect of pathogenic BRCA1 and ARID1A mutations is a novel observation that, if further validated, may improve treatment selection. PMID- 30479695 TI - Expression of neuropilin-1 is linked to glioma associated microglia and macrophages and correlates with unfavorable prognosis in high grade gliomas. AB - High grade gliomas, including glioblastoma (GB), are devastating malignancies with very poor prognosis. Over the course of the last decade, there has been a failure to develop new treatments for GB. Reasons for this failure include the lack of validation of novel molecular targets, which are often characterized in animal models and directly transposed to human trials. Here we build on our previous findings, which describe how the multi-functional co-receptor Neuropilin 1 (NRP1) signals through glioma associated microglia/macrophages (GAMS) to promote murine glioma, and investigate NRP1 expression in human glioma. Clinical and gene expression data were obtained via The Cancer Genome Atlas (TCGA), and analyzed using R statistical software. Additionally, CIBERSORT in silico deconvolution was used to determine fractions of immune cell sub-populations within the gene expression datasets. We find that NRP1 expression is correlated with poor prognosis, glioma grade, and associates with the mesenchymal GB subtype. In human GB, NRP1 expression is highly correlated with markers of monocytes/macrophages, as well as genes that contribute to the pro-tumorigenic phenotype of these cells. PMID- 30479694 TI - DVL1 and DVL3 differentially localize to CYP19A1 promoters and regulate aromatase mRNA in breast cancer cells. AB - The CYP19A1 gene encodes aromatase, an enzyme that converts androgens into estrogens and consequently directly contributes to both the depletion of androgens and the synthesis of estrogens in several organs. Aromatase is critical for diverse biological processes such as proliferation, regulation of fat metabolism and hormone signaling. Additionally, it is also overexpressed in diverse cancers and drives hormone-dependent tumor progression and increases 17 beta-estradiol (E2) within tumors and the tumor microenvironment. Although the inhibition of E2 production via aromatase inhibitors represents a major therapeutic paradigm in clinical oncology, fundamental questions regarding how cancer cells gain the capacity to overexpress aromatase remain unanswered. Multiple tissue-specific CYP19A1 promoters are known to be aberrantly active in tumors, yet how this occurs is unclear. Here, for the first time, we report that Dishevelled (DVL) proteins, which are key mediators of Wnt signaling, regulate aromatase expression in multiple breast cancer cell lines. We also report that DVL enters the nucleus and localizes to at least two different CYP19A1 promoters (pII and I.4) previously reported to drive overexpression in breast tumors and to a very distal CYP19A1 placental promoter (I.1) that remains poorly characterized. We go on to demonstrate that DVL-1 and DVL-3 loss of function leads to differential changes in various aromatase transcripts and in E2 production. The report, herein, uncovers a new regulator of CYP19A1 transcription and for the first time demonstrates that DVL, a critical mediator of WNT signaling, contributes to aberrant breast cancer-associated estrogen production. PMID- 30479696 TI - Clinical associations of mucin 1 in human lung cancer and precancerous lesions. AB - Mucin 1 (MUC1) is a cell membrane glycoprotein overexpressed in non-small cell lung cancer (NSCLC) and has been implicated in carcinogenesis of premalignant lung lesions. Thus, MUC1 has been a target of interest for vaccine strategies for lung cancer treatment and prevention. Here, we assessed MUC1 expression by immunohistochemistry using tumor samples from patients with biopsy-proven NSCLC. Levels of expression in areas of dysplasia, metaplasia, adenocarcinoma in situ, and carcinoma within the same tissue sample were characterized independently on a scale of 0-3 for paired comparison. We also assessed clinical data for correlations with MUC1 expression. Our analysis included 16 samples from patients with squamous lesions and 19 from patients with adenocarcinoma lesions. Among squamous lesions, MUC1 expression score was significantly increased in dysplastic compared with metaplastic areas (mean difference = 0.83, 95% confidence interval [CI], 0.21-infinity; P = 0.021). MUC1 expression was also increased among areas of squamous cell carcinoma versus dysplastic areas (mean difference = 0.44, 95% CI, -0.006-infinity; P = 0.052). In the adenocarcinoma lesions, MUC1 expression was increased in adenocarcinoma versus adenocarcinoma in situ, although not significantly (mean difference = 0.20, 95% CI, -0.055-infinity; P = 0.094). The increase in MUC1 expression with the progression of premalignant lung lesions to invasive carcinoma in patients with NSCLC supports MUC1 as a possible therapeutic target for the prevention and treatment of lung cancer. PMID- 30479697 TI - Loss of TXNIP enhances peritoneal metastasis and can be abrogated by dual TORC1/2 inhibition. AB - Peritoneal metastasis (PM) is a debilitating consequence of multiple cancers. As cancer cells lose tonic signaling related to attachment dependence, critical morphologic shifts result in alteration of the transcriptome. Identifying key genes associated with this transformation may lead to targeted therapies for this devastating complication. TC71, CHLA9, PANC1, YOU and HEYA8 cell lines were grown as tumor spheroids in polyHEMA coated plates. Temporal profiling of transcriptomic alterations over 72 hrs was used to develop a comprehensive PM model. We identified transcriptomic outliers using Gaussian mixtures model clustering to identify drivers of spheroid formation. Outliers were validated in The Cancer Genome Atlas (TCGA) and an ovarian tissue microarray (TMA) and by modulation in ovarian cancer models in vitro and in peritoneal xenograft models. Outlier analysis of PM genes identified the gene TXNIP and the TORC signaling as central to PM. Ovarian cancer spheroids isolated from patient ascites had significantly higher TXNIP than their attached counterparts (p = 0.047). TXNIP levels predicted progression-free (log-rank p = 0.026) survival in stage 1/2 ovarian cancer and overall survival (log rank p = 0.047) in stage 3/4 ovarian cancer. In vitro, TXNIP silencing was associated with increased mTOR signaling and enhanced spheroid development which could be overcome by TAK228, a TORC1/2 inhibitor. Similarly, in vivo peritoneal xenograft models of carcinomatosis were prevented by TAK228. PM is driven by TXNIP-associated TORC1/2 signaling. This work provides the first evidence that TORC1/2 inhibition may prevent PM. PMID- 30479700 TI - Karyotypic description of the stingless bee Meliponaquinquefasciata Lepeletier, 1836 (Hymenoptera, Meliponini) with emphasis on the presence of B chromosomes. AB - Stingless bees are distributed widely in the tropics, where they are major pollinators of several plant species. In this study, the karyotype of Meliponaquinquefasciata Lepeletier, 1836 was analysed, with emphasis on the presence of B chromosomes. Post-defecating larvae were analysed using Giemsa staining, the C-banding technique, sequential staining with fluorochromes, and FISH. The chromosome number ranged from 2n = 18 to 22 (females) and from n = 9 to 13 (males) due to the presence of 0-4 B chromosomes. This result demonstrates that M.quinquefasciata has the same chromosomal number as other Melipona Illiger, 1806 species. Considering the A complement, heterochromatin was located only in the pericentromeric region of pair 1. Staining with chromomycin A3 (CMA3) and labelling with rDNA probe, indicated that this region corresponded to the nucleolus organising region. The B chromosomes of M.quinquefasciata could be found in individuals from different localities, they were completely heterochromatic (C-banding) and uniformly stained by 4',6-diamidino-2 phenylindole (DAPI). Variations in the number of B chromosomes were detected between cells of the same individual, between individuals of the same colony, and between colonies from different localities. PMID- 30479699 TI - EpCAMhigh and EpCAMlow circulating tumor cells in metastatic prostate and breast cancer patients. AB - The presence of high expressing epithelial cell adhesion molecule (EpCAMhigh) circulating tumor cells (CTC) enumerated by CellSearch(r) in blood of cancer patients is strongly associated with poor prognosis. This raises the question about the presence and relation with clinical outcome of low EpCAM expressing CTC (EpCAMlow CTC). In the EU-FP7 CTC-Trap program, we investigated the presence of EpCAMhigh and EpCAMlow CTC using CellSearch, followed by microfiltration of the EpCAMhigh CTC depleted blood. Blood samples of 108 castration-resistant prostate cancer patients and 22 metastatic breast cancer patients were processed at six participating sites, using protocols and tools developed in the CTC-Trap program. Of the prostate cancer patients, 53% had >=5 EpCAMhigh CTC and 28% had >=5 EpCAMlow CTC. For breast cancer patients, 32% had >=5 EpCAMhigh CTC and 36% had >=5 EpCAMlow CTC. 70% of prostate cancer patients and 64% of breast cancer patients had in total >=5 EpCAMhigh and/or EpCAMlow CTC, increasing the number of patients in whom CTC are detected. Castration-resistant prostate cancer patients with >=5 EpCAMhigh CTC had shorter overall survival versus those with <5 EpCAMhigh CTC (p = 0.000). However, presence of EpCAMlow CTC had no relation with overall survival. This emphasizes the importance to demonstrate the relation with clinical outcome when presence of CTC identified with different technologies are reported, as different CTC subpopulations can have different relations with clinical outcome. PMID- 30479698 TI - A phase 2 trial of neoadjuvant metformin in combination with trastuzumab and chemotherapy in women with early HER2-positive breast cancer: the METTEN study. AB - The METTEN study assessed the efficacy, tolerability, and safety of adding metformin to neoadjuvant chemotherapy plus trastuzumab in early HER2-positive breast cancer (BC). Women with primary, non-metastatic HER2-positive BC were randomized (1:1) to receive metformin (850 mg twice-daily) for 24 weeks concurrently with 12 cycles of weekly paclitaxel plus trastuzumab, followed by four cycles of 3-weekly FE75C plus trastuzumab (arm A), or equivalent regimen without metformin (arm B), followed by surgery. Primary endpoint was the rate of pathological complete response (pCR) in the per-protocol efficacy population. pCR rate was numerically higher in the metformin-containing arm A (19 of 29 patients [65.5%, 95% CI: 47.3-80.1]) than in arm B (17 of 29 patients [58.6%, 95% CI: 40.7 74.5]; OR 1.34 [95% CI: 0.46-3.89], P = 0.589). The rate of breast-conserving surgery was 79.3% and 58.6% in arm A and B (P = 0.089), respectively. Blood metformin concentrations (6.2 MUmol/L, 95% CI: 3.6-8.8) were within the therapeutic range. Seventy-six percent of patients completed the metformin containing regimen; 13% of patients in arm A dropped out because of metformin related gastrointestinal symptoms. The most common adverse events (AEs) of grade >=3 were neutropenia in both arms and diarrhea in arm A. None of the serious AEs was deemed to be metformin-related. Addition of anti-diabetic doses of metformin to a complex neoadjuvant regimen was well tolerated and safe. Because the study was underpowered relative to its primary endpoint, the efficacy data should be interpreted with caution. PMID- 30479701 TI - Latent profiles of physical and psychological outcomes of bereaved parents in China who lost their only child. AB - Background: Along with the implementation of the one-child policy in China, a special group of bereaved parents called 'shiduer' (), meaning parents bereaved by the loss of their only child, emerged. Although previous research has examined the physical and psychological health of this population, individual differences in physical and psychological outcomes are still not well understood. Objective: This study aimed to identify heterogenous subgroups of Chinese bereaved parents who lost their only child based on the physical and psychological health of this population as well as the predictive factors of each subgroup. Method: Latent profile analysis was used to explore underlying patterns of physical and psychological indicators including subjective physical health, negative psychological outcomes (i.e. depression, post-traumatic stress disorder and prolonged grief disorder) and positive psychological outcomes (i.e. post traumatic growth) among a sample of Chinese bereaved parents who lost their only child (N = 536). A three-step approach was used to examine the effects of covariates including quality of spousal relationship and recruitment channels on psychological and physical outcomes. Results: A three-profile model identified severity-based groupings of a 'resilient' subgroup (n = 153), a 'coping' subgroup (n = 338) and a 'dysfunctional' subgroup (n = 45). Less satisfaction with spousal relationship and recruitment from institutions in the community and online self help groups (vs. offline support groups) are associated with the membership of the 'coping' or 'dysfunctional' subgroup compared to the 'resilient' subgroup. Conclusions: There is heterogeneity regarding the physical and psychological health of Chinese parents after losing their only child. The predictive effects of the quality of spousal relationship and the recruitment channels could provide directions for professional intervention. PMID- 30479702 TI - Similarity in symptom patterns of posttraumatic stress among disaster-survivors: a three-step latent profile analysis. AB - Background: Individuals express symptoms of posttraumatic stress in various ways, noted for example in the many symptom combinations in the diagnostic manuals. Studies aiming to examine differences of symptom presentations by extracting latent classes or profiles indicate both the presence of subtypes with differing symptomatology and subtypes distinguished by severity levels. Few studies have examined subtype associations with long-term outcomes. Objective: The current study aimed to apply latent profile analysis on posttraumatic stress (PTS) in a highly homogenous sample of Swedish tourists exposed to the 2004 Southeast Asia tsunami and to examine if classes differed in their long-term outcome. Methods: An latent profile analysis was conducted using self-report data collected one year after the disaster from 1638 highly exposed survivors that endorsed >= 1 symptom of PTS. Associations were examined between the classes and predictors of PTS (loss of a relative or friend, subjective life threat) and levels of PTS at a three-year follow up. Results: The latent profile analysis indicated four classes: minimal, low, moderate, and severe symptoms. The classes were distinguished mainly by their levels of PTS. Loss of a relative or friend and subjective life threat were associated with a higher likelihood of belonging to any other class than the minimal class. The severity level of the classes at one year were predictive of PTS severity at the three-year follow-up. Conclusions: Homogeneous profiles of posttraumatic stress differing mainly in symptom severity were found in this sample of disaster survivors. Profile diversity may be related to sample variation and unmeasured confounders rather than reflect qualitatively different disorders. PMID- 30479703 TI - Non-profit drug research and development: the case study of Genethon. AB - Non-profit drug research and development (R&D) has the potential to deliver innovative treatments at affordable prices. Using the case study methodology, we discuss some ethical and economic issues, including the possible impact of non profit companies on innovation efforts from for-profit firms. Like other non profits, Genethon is willing to adopt an ethical attitude toward their donors by pricing their products affordably. It remains to be seen if the approach to internalize the marketing authorization, manufacturing and distribution activities prove to be efficient and sustainable. Also, the firm faces an ethical dilemma because lower prices of innovative drugs can dry the for-profit R&D in the area and prevent patient access to future innovations. PMID- 30479704 TI - Targeted Screening for Predominant CYP1B1 Mutations in Primary Congenital Glaucoma. PMID- 30479705 TI - Visual and Refractive Outcomes and Tomographic Changes after Femtosecond Laser assisted Intrastromal Corneal Ring Segment Implantation in Patients with Keratoconus. AB - Purpose: To evaluate the visual, refractive, and tomography changes after femtosecond laser-assisted intrastromal corneal ring segment (ICRS; Intacs(r) SK) implantation in patients with keratoconus. Methods: In this prospective interventional case series, Intacs SK ICRSs were inserted using a femtosecond laser into eyes with stage I-IV keratoconus. Visual, refractive, and corneal tomography changes, along with surgical complications, were analyzed 1 week, 2 months, and 6 months postoperatively. Results: The study evaluated 71 eyes of 52 patients (mean age: 27.5 years). Six months postoperatively, the spherical equivalent, mean sphere, and mean cylinder were decreased by 2.07, 1.47, and 1.13 diopters (D), respectively. The mean preoperative uncorrected distance visual acuity (UDVA) increased from 0.87 +/- 0.26 to 0.46 +/- 0.19 LogMAR and the mean preoperative corrected distance visual acuity (CDVA) increased from 0.55 +/- 0.21 to 0.28 +/- 0.17 LogMAR (P < 0.001). Flat and steep keratometry decreased by a mean corneal power in the 3-mm zone, and mean anterior elevation decreased by 0.91 D, 2.52 D, and 1.03 microns (P < 0.001), respectively. Among all eyes, 93.0% gained one or more lines of CDVA. Mean internal anterior chamber depth decreased from 3.25 +/- 0.33 to 3.14 +/- 0.45 mm (P = 0.001), and mean irregularity in the 3-mm zone decreased from 5.63 +/- 1.71 to 5.24 +/- 1.82 (P = 0.006). However, mean posterior elevation and irregularity in the 5-mm zone did not change significantly. Conclusion: Implantation of one or two Intacs SK segments is safe and effective to treat keratoconus, leading to significant improvement in UDVA, CDVA, and refractive error. PMID- 30479706 TI - Ex vivo Caprine Model to Study Virulence Factors in Keratitis. AB - Purpose: To develop an infectious keratitis model using caprine (goat) corneas and to investigate the expression of virulence factors during infection. Methods: Goat eyes were surface-sterilized and dissected, and the corneas were placed on an agarose-gelatin solid support (0.5% in phosphate-buffered saline) in a 12-well culture plate containing 10% fetal bovine serum-supplemented culture medium for 3 weeks. Cell viability tests (trypan blue and MTT) were performed on the cultured corneas. Corneas were infected with Pseudomonas aeruginosa and Fusarium solani separately. Infection progression was observed via histological analysis and hematoxylin and eosin (H-E) staining. For Pseudomonas-infected corneas, expression of eight virulence genes (exoS, exoT, exoY, alpR, prpL, lasA, lasB, and algD) was determined via quantitative real-time PCR (qRT-PCR) at 48-h and 72 h time-points. For Fusarium-infected corneas, expression of five proteases (C7Z0E6, C7ZFW9, C7Z7U2, C7ZNV5, and C7YY94) was quantified via qRT-PCR at 2, 4, and 8 days after infection. Protease from infected corneas was detected via gelatin zymography. Results: Goat corneas with a viable epithelium could be maintained for 15 days. Pseudomonas infection progressed rapidly, and complete corneal degradation was observed on day 4 after infection. Fusarium infection progressed more slowly. Histological analysis and H-E staining of Fusarium infected cornea revealed mycelia penetrating all layers of the cornea. qRT-PCR revealed expression of all eight virulence factors, and statistically significant difference in expression of prpL and alpR in Pseudomonas-infected corneas. Expression of C7ZNV5 was highest in Fusarium-infected corneas. Conclusion: Goat corneas can be used to evaluate the expression of virulence factors involved in Pseudomonas and Fusarium infection. PMID- 30479707 TI - Real Time Polymerase Chain Reaction for Hepatitis B Screening in Donor Corneas in the Central Eye Bank of Iran. AB - Purpose: The aim of this study was to report the results of the use of real-time polymerase chain reaction (PCR) for the diagnosis of hepatitis B virus (HBV) infection in cornea donors at the Central Eye Bank of Iran. Methods: Between 2014 and 2016, all cornea donors that had negative screening serologic results for hepatitis B (HB) surface antigen, HB surface antibody (Ab), hepatitis C virus Ab, human immune deficiency virus Ab, human T-cell leukemia virus Ab, and syphilis, and positive serology for HB core Ab were subjected to real-time PCR with a detection limit of 400 IU/mL to identify HBV DNA. Positive results for HBV DNA were considered occult HBV infections in these donors. Results: Over the 3-year period, 122 out of 10448 cornea donors had negative screening serologic tests outside of HB core Ab. Of which, 90 cases were subjected to real-time PCR. Occult HBV was detected in 11 cases (12.2%), resulting in the rejection of the corresponding corneas. The remaining 79 cases (87.8%) had negative results for HBV DNA and the corresponding corneas were used for transplantation. Conclusion: Implementation of PCR for the detection of occult HBV in cornea donors is necessary to not only increase the security level of cornea donation but also minimize the rejection rate of donors that have isolated HB core Ab reactivity. PMID- 30479708 TI - Association of FOXE3-p.Ala170Ala and PITX3-p.Ile95Ile Polymorphisms with Congenital Cataract and Microphthalmia. AB - Purpose: To investigate the association of FOXE3-p.Ala170Ala (rs34082359) and PITX3-p.Ile95Ile (rs2281983) polymorphisms with congenital cataract and microphthalmia in a western Indian population. Methods: FOXE3-p.Ala170Ala (c.510C>T) and PITX3-p.Ile95Ile (c.285C>T) polymorphisms were genotyped in 561 subjects consisting of 242 cases with congenital cataract, 52 with microphthalmia, and 267 controls using polymerase chain reaction-restriction fragment length polymorphism. Approximately 10% of samples were randomly sequenced for each single nucleotide polymorphism to confirm the genotypes. The prediction of mRNA secondary structure for polymorphism FOXE3-p.Ala170Ala and PITX3-p.Ile95Ile was performed. Results: A significantly high frequency of T allele and a borderline significance in the frequency of TT genotype of FOXE3 p.Ala170Ala was observed in microphthalmia cases, as compared to controls [T allele: OR: [CI] = 1.8 [1.15-2.72], P = 0.0115; TT: OR [CI] = 2.9 [1.14-7.16], P = 0.0291). The frequency of CC genotype was significantly low in microphthalmia cases when compared to controls (CC: OR [CI] = 0.5 [0.24-0.86, P = 0.0150). There was no significant difference in the allele and genotype frequencies of PITX3 p.Ile95Ile between cases and controls. A slight free energy change was observed in the secondary structure of mRNA between the FOXE3-p.Ala170Ala C-allele ( 917.60 kcal/mol) and T-allele (-916.80 kcal/mol) and between PITX3-p.Ile95Ile C allele (-659.80 kcal/mol) and T-allele (-658.40 kcal/mol). Conclusion: The present findings indicate that FOXE3-p.Ala170Ala 'T' allele and 'TT' genotype could be predisposing factors for microphthalmia while 'CC' genotype might play a protective role against it. A reduction in the free energy change associated with FOXE3-p.Ala170Ala 'T' allele could further contribute towards disease risk. PMID- 30479709 TI - P.Gly61Glu and P.Arg368His Mutations in CYP1B1 that Cause Congenital Glaucoma may be Relatively Frequent in Certain Regions of Gilan Province, Iran. AB - Purpose: To perform a population-based screening of four CYP1B1 mutations p.Gly61Glu, p.Arg368His, p.Arg390His, and p.Arg469Trp-in the province of Gilan, Iran. Previous studies have shown that CYP1B1 is a cause of disease in approximately 70% of Iranian patients with primary congenital glaucoma (PCG), and that these four mutations constitute the majority of CYP1B1 mutated alleles. The carrier frequencies may even justify premarital screenings. Methods: DNA was extracted from the blood samples of 700 individuals recruited in a population based epidemiology study in Gilan. Screenings were performed using polymerase chain reaction protocols based on restriction fragment length polymorphism or the amplification-refractory mutation system. For confirmation, the DNA of individuals with mutations was sequenced using the Sanger protocol. Results: Five individuals carried the p.Gly61Glu mutation, and seven carried the p.Arg368His mutation. The p.Arg390His and p.Arg469Trp mutations were not observed in any of the 700 individuals screened. The mutations were not geographically randomly distributed in Gilan; four of the p.Gly61Glu-harboring individuals were from Talesh, and six of the p.Arg368His-harboring individuals were from the eastern regions of Gilan. Conclusion: The frequency of individuals who carry either p.Gly61Glu or p.Arg368His is relatively high in Gilan, and notably high in certain localities within Gilan. We suggest further screenings be performed to definitively assess the need for implementing measures to encourage screening for p.Gly61Glu and p.Arg368His before marriage in Talesh and the eastern regions of Gilan, respectively. Finally, our assessment showed that regional frequencies of CYP1B1 mutations do not necessarily mirror national frequencies. PMID- 30479710 TI - Factors Associated with Conjunctival Erosions after Ahmed Glaucoma Valve Implantation. AB - Purpose: To investigate the frequency of conjunctival erosions in a series of patients who underwent Ahmed valve implantation in a tertiary referral center and to study risk factors associated with the conjunctival erosions. Methods: This is a single-center, retrospective case-control study of all patients who underwent Ahmed valve implantation between October 2006 and July 2016 at the Kresge Eye Institute in Detroit, Michigan. The series consisted of 306 eyes (277 patients) that underwent Ahmed valve implantation. The rate of conjunctival erosions was determined. Univariate, bivariate, and Cox-proportional hazard analyses were performed to identify factors associated with conjunctival erosions. Results: During the study period, 23 erosions occurred in 306 eyes (7.52%). Aphakia was significantly more common in eyes with erosions (P < 0.05). Aphakia (P = 0.02), uveitic glaucoma (P = 0.03), and longer post-operative use of topical steroids (P < 0.04) significantly increased the risk of erosions based on the Cox model. There were similar rates of erosions with each type of patch graft. No conjunctival erosion was observed after using the modified scleral tunnel method (n = 10). Conclusions: The overall erosion rate was 7.52% in our series. Uveitic glaucoma, aphakia, and longer post-operative use of topical steroids were significantly associated with conjunctival erosions. PMID- 30479712 TI - Comparison of Retinal and Choroidal Involvement in Sarcoidosis-related Chorioretinitis Using Fluorescein and Indocyanine Green Angiography. AB - Purpose: To compare the involvement of the retina with that of the choroid in ocular sarcoidosis (OS) using dual fluorescein angiography (FA)/indocyanine green angiography (ICGA). Methods: A retrospective study of 23 patients with the diagnosis of OS was performed. Angiographic signs were quantified following the established FA/ICGA scoring system for uveitis. Results: The choroid was predominantly involved in 19 (82.6%) patients or 87% (40/46) of the eyes, and the retina in 2 (8.7%) patients or 13% (6/46) of the eyes. The mean angiographic score was 7.15 +/- 4.5 for the retina (FA) compared to 14.02 +/- 4.86 for the choroid (ICGA) (P < 0.0001). In 13% (3/23) of patients, FA did not show retinal inflammation, whereas ICGA was strongly positive, revealing occult choroidal lesions. Conclusion: The choroid is preferentially involved in OS, for which ICGA is the examination of choice. There is a risk of underestimating the global ocular involvement and of missing choroidal involvement if only FA is used. FA/ICGA scoring system allows for quantitative assessment of inflammation in the posterior uvea that occurs in OS; therefore, the system can be useful to quantitatively monitor outcomes in clinical trials. PMID- 30479711 TI - Protective Effects of 17beta-Estradiol on Benzo(e) pyrene[B(e)P]-induced Toxicity in ARPE-19 cells. AB - Purpose: The aim of this study was to examine the effect of 17beta-estradiol on Benzo(e)pyrene [B(e)P]-induced toxicity in ARPE-19 cells. Methods: We pretreated ARPE-19 cells with 20 nM and 40 nM 17beta-estradiol for 6 hours, followed by addition of 300 MUM B(e)P for additional 24 hours. Cell viability was measured using Trypan blue dye-exclusion assay. JC-1 assay was performed to measure mitochondrial membrane potential (DeltaPsim). For a quantitative estimation of cell death, apoptotic markers such as caspase-3/7, caspase-9, and caspase-12 were measured. Results: Our results demonstrated that when treated with B(e)P, the viability and DeltaPsim of ARPE-19 cells declined by 25% and 63%, respectively (P < 0.05). However, pretreating with 17beta-estradiol increased the viability of ARPE-19 cells by 21% (20 nM) and 10% (40 nM) (P < 0.05). Furthermore, the significantly reduced DeltaPsim in betaE+B(e)P treated cells ARPE-19 cells was restored by pre-treatment with 17beta-estradiol- DeltaPsim was increased by 177% (20 nM) and 158% (40 nM) (P < 0.05). We further observed a significant up regulation in the activity of Caspases-3/7, -9, and -12 in B(e)P-treated ARPE-19 cells. However, 17beta-estradiol treatment significantly reduced the activity of all apoptotic markers (P < 0.05). Conclusion: In conclusion, our results demonstrate that 17beta-estradiol protects ARPE-19 cells against B(e)P-induced toxicity by decreasing apoptosis, preventing cell death, and restoring mitochondrial membrane potential. PMID- 30479713 TI - Glial Cells and Retinal Nerve Fibers Morphology in the Optic Nerves of Streptozotocin-induced Hyperglycemic Rats. AB - Purpose: This study analyzes the structures of optic nerve elements, i.e., glial cells and nerve fibers, in an STZ-induced hyperglycemic animal model. Morphological changes in glial elements of the optic nerve in hyperglycemic and normoglycemic animals were compared. Methods: Transmission electron microscopy, histochemistry, immunohistochemistry, and morphometry were used in this study. Results: Hyperglycemia increased the numbers of inner mesaxons and axons with degenerative profiles. Furthermore, it led to both an increase in the amount of debris and in the numbers of secondary lysosomic vesicles in glial cytoplasm. Hyperglycemia also led to a decrease in glial fibrillary acidic protein expression and an increase in periodic acid-Schiff-positive deposits in the optic nerves of hyperglycemic animals. Conclusion: We conclude that the damage to the structural elements observed in our animal models contributes to the pathogenesis of optic neuropathy in the early stages of diabetes. PMID- 30479714 TI - Sympathetic Ophthalmia: Experience from a Tertiary Care Center in Northern India. AB - Purpose: To describe our clinical experience with sympathetic ophthalmia (SO) at a tertiary eye care center in north India. Methods: In this retrospective case series, analysis of the clinical features and visual outcomes of patients diagnosed with SO between March 2012 and March 2016 were performed. Results: Ten male and four female patients (median age, 15.5 years) with SO following penetrating trauma (10 patients) or ocular surgery (four patients) were included. SO developed 2 weeks to 3 years after the insult. Mean presenting visual acuity of the sympathizing eyes was 1.086 (LogMAR). Anterior chamber reaction was documented in all eyes in which it could be assessed (14 sympathizing eyes; five exciting eyes). Neurosensory detachment was seen in 10 of 14 patients (71.5%). Five patients (35.7%) were managed with oral steroids alone, whereas nine (64.3%) were treated with intravenous pulse dexamethasone followed by oral steroids. Inflammation recurred in three patients during steroid tapering, necessitating restarting of steroid therapy with or without additional immunosuppressants. At the last follow-up, all 14 patients were in remission with low-dose oral steroids; seven patients were also on immunosuppressants. At the final follow-up, 12 of 14 (85.7%) sympathizing eyes achieved 20/40 or better visual acuity and three exciting eyes achieved at least 6/24 visual acuity. Conclusion: Although SO is a potentially blinding disorder, early detection and individualized treatment allow most patients achieve good final visual acuity. PMID- 30479715 TI - Traumatic Ptosis: Evaluation of Etiology, Management and Prognosis. AB - Introduction: To investigate whether a systematic approach to subgrouping traumatic ptosis according to etiology can allow for better tailoring of prognosis and treatment. Methods: Retrospective chart review of patients with trauma-related blepharoptosis managed by Oculoplastic surgery specialists at an academic medical center from January 1995 to November 2015. Injury mechanism, eyelid position and function, interventions, and outcomes were reviewed. Results: Of 648 patients treated for blepharoptosis, 55 (8.5%) were traumatic. Careful review revealed 4 subcategories of traumatic ptosis cases: aponeurotic (n = 16), myogenic (n = 18), neurogenic (n = 7), and mechanical (n = 14). Margin reflex distance (MRD1) at presentation was significantly worse for the myogenic subtype (-0.59 mm, SD +/-2.09, P = 0.046). The aponeurotic subtype had the best average levator function at presentation (14.29 mm, SD +/-2.05), while myogenic had the worst (8.41 mm, SD +/-4.94) (P = 0.004). Thirty-five (63.6%) patients were managed surgically. Final MRD1 was significantly different for each subtype (P = 0.163), with aponeurotic 2.63 mm (SD +/-1.01), myogenic 1.29 mm (SD +/-2.24), neurogenic 1.79 mm (SD +/-2.48), and mechanical 2.31 mm (SD +/-1.18). There was a significant increase in MRD1 from presentation to final follow up across all groups (P < 0.05). Conclusion: Traumatic ptosis is heterogenous. Systematically evaluating traumatic ptosis cases by trauma mechanism can guide decisions about prognosis and management. Two-thirds of cases were treated surgically, with most patients responding well to conjunctiva-Muller resection or external levator advancement. While all subgroups demonstrated improvement in MRD1 at final follow up, aponeurotic cases had the best prognosis, while myogenic fared the worst and required the longest for maximal recovery. PMID- 30479716 TI - Peripapillary Retinal Nerve Fiber Layer Thickness in Normal Iranian Children Measured with Optical Coherence Tomography. AB - Purpose: This study aimed to measure the peripapillary retinal nerve fiber layer (RNFL) thickness using spectral-domain optical coherence tomography (SD-OCT) in normal Iranian children aged below 18 years. Methods: Peripapillary RNFL imaging was performed in the right eye of normal Iranian children aged below 18 years using Spectralis SD-OCT (Heidelberg Engineering; Vista, CA). The effects of age, gender, cup-to-disc ratio, and spherical equivalent (SE) on global and sectoral RNFL thicknesses were evaluated. Results: A total of 115 eyes were imaged. Approximately 51 (44.3%) of the cases were female children. The mean age was 12.44 +/- 2.52 years. The SE of refractive error was 0.39 +/- 1.38 diopters (range: -3.00 to +4.5 D). The RNFL thickness measurements in the superior, inferior, nasal, and temporal quadrants were 129.25 +/- 14.52, 128.16 +/- 13.46, 76.76 +/- 10.58, and 69.58 +/- 9.94 MUm, respectively. The global RNFL thickness was 101.01 +/- 7.74 MUm. In both univariate and multiple regression analyses, SE was the only determinant of RNFL thickness (all P values < 0.05). Conclusion: OCT analysis can effectively measure RNFL thickness in children, and SE is the only determinant of RNFL thickness in normal Iranian patients aged below 18 years. PMID- 30479717 TI - The Prevalence of Lower Eyelid Fornix Fat Prolapse: A Diagnostic Measure of Involutional Entropion. AB - Purpose: In our experience, lower lid involutional entropion is commonly associated with inferior fornix fat prolapse and non-eversion of the tarsal plate. We aimed to assess the prevalence of this sign as an early diagnostic indicator of lower lid involutional entropion in symptomatic and control groups. Methods: Prospective, comparative, observational case series. Fornix fat prolapse and failure of tarsal eversion in patients with involutional entropion were studied. Fornix fat prolapse was assessed by pulling the lower lid margin to the inferior orbital rim and comparing the meniscus of the protruding fat. The absence of tarsal eversion and lid laxity were also assessed. Patients were reassessed following correction using radiofrequency entropion surgery. Results: Sixty eyes of 50 Caucasian patients with involutional entropion underwent entropion correction. Fornix fat prolapse was found preoperatively in 83.3% (50 eyes), with complete reversal of fat prolapse in 76% (38 eyes) over a mean follow up of 18.9 months, after successful surgery (P < 0.01). None of the 100 eyes (50 patients) in the control group showed fornix fat prolapse or absence of lower lid tarsal eversion (P < 0.01). Conclusion: There is high prevalence of fornix fat prolapse and failure of tarsal eversion (BB sign) in involutional entropion, with reversal after successful eyelid surgery. The absence of fornix fat prolapse in normal controls suggests that this is an important, underlying anatomical etiology, with diagnostic and prognostic value. PMID- 30479718 TI - Awareness of Eye Health and Diseases among the Population of the Hilly Region of Nepal. AB - Purpose: To collect information regarding awareness and knowledge of eye health and diseases among the population of the hilly region of Nepal. Methods: In a population-based survey, 1834 participants were enrolled in to the study. Field procedures included the development of a survey questionnaire, field orientation, pretesting, and household data collection. Association between knowledge of eye diseases was derived using the Chi-square test and odds ratios with a 95% confidence interval. A P value of <=0.05 was considered significant. Results: Most participants were 31-40 years old (33.4%), female (51.1%), of upper caste (43.4%), Hindus (83.3%), received secondary level of education (34.4%), and involved in agriculture (48.6%). Awareness of cataract, night blindness, glaucoma, strabismus, and systemic diseases was 74.6%, 53.4%, 17.4%, 70.8%, and 46.5%, respectively. Knowledge regarding these diseases among those aware was 39.1%, 72.2%, 50.9%, and 92.3%, respectively. Awareness of cataract was significantly higher (88.4%) among higher caste groups (P < 0.001; OR, 4.29; 95% CI, 3.34-5.54), followed by business as an occupation (88.2%; P = 0.001; OR, 2.65; 95% CI, 1.44-4.9). Awareness of night blindness was significantly higher among students (72.6%; P < 0.001; OR, 2.46; 95% CI, 1.65-3.67). Conclusion: There was a general lack of awareness and knowledge of common eye diseases. Improved awareness and knowledge are required for the prevention, early treatment, and access to eye care. PMID- 30479721 TI - The Evolution of Glaucoma Drainage Implants. AB - The modern glaucoma drainage implant era was initiated with implantation of a plate posterior to the limbus connected to the anterior chamber by a long silicone tube. Non-restrictive (Molteno and Baerveldt implants) and flow restrictive (Ahmed Glaucoma Valve) implants were developed. With increased clinical experience, variables influencing success and failure of glaucoma drainage implant surgery were better understood. In an iterative process, complications were reduced and indications for drainage implant surgery were broadened. Growth of utilization of glaucoma drainage implants has dramatically increased in recent years. Glaucoma drainage implants have improved the prognosis for surgical success for refractory glaucoma, and have a well-established role in the surgical treatment of glaucoma. PMID- 30479722 TI - Regressing Conjunctival Nevus in a Child. AB - Purpose: To report a case exhibiting drastic regression of a conjunctival nevus in a child. Case Report: Spontaneous regression of conjunctival nevus is uncommon. We report the case of a nine-year-old Caucasian boy presenting a conjunctival-pigmented lesion situated at the plica semilunaris that underwent a significant reduction in size and color over a period of 15 months. Conclusion: Conjunctival nevus in children is common but regression is rare, especially at the plica. This information could form an important part of the consent process when choosing between observation and surgical excision in the management of a small conjunctival lesion with no suspicious clinical features; since the latter invasive treatment involves risks such as infection, scarring and the possible risk of general anesthesia in children. PMID- 30479723 TI - Burkholderia Cepacia Endophthalmitis: An Unusual Presentation. AB - Purpose: To report three cases of Burkholderia cepacia endophthalmitis following uneventful phacoemulsification surgery. Case Report: Three cases presented with blurriness of vision 2 to 3 weeks following phacoemulsification. Vitreous culture confirmed the diagnosis. Pars plana vitrectomy with intravitreal injection of vancomycin (1 mg/0.1 ml) and ceftazidime (2.25 mg/0.1 ml) was performed. Despite several modalities of treatment, 2 cases did not respond to intravitreal antibiotics and vitrectomy. The first case ended up with phthisis bulbi and the second case underwent evisceration. One case improved after intravitreal injection of the first dose of antibiotic. Conclusion: B. cepacia endophthalmitis is rare and difficult to treat. More studies are necessary to understand the course and outcome of the infection. PMID- 30479720 TI - An Update on Optical Coherence Tomography Angiography in Diabetic Retinopathy. AB - Optical coherence tomography angiography (OCTA) is a novel non-invasive imaging modality for 3-dimensional visualization of retinal and optic nerve capillary networks. In this article, a comprehensive review of relevant original articles in the PubMed database was performed using the search terms "diabetic retinopathy," "diabetic macular edema," "diabetes mellitus," and "optical coherence tomography angiography." OCTA was found to detect microvascular changes early in diabetes mellitus, even before they become clinically evident. Morphological and qualitative assessment of vascular changes can help to determine the pathophysiological processes, activity, treatment, and follow-up of diabetic retinopathy (DR). Vessel density and foveal avascular zone are the most investigated quantified indices shown to be early predictors of DR, correlated to DR severity and visual function, and useful in predicting response to treatment. OCTA has shown to be a promising alternative to fluorescein angiography in the management of DR. Further studies are warranted to determine the role of OCTA in the routine clinical management of DR. PMID- 30479719 TI - Negative Regulators of Angiogenesis, Ocular Vascular Homeostasis, and Pathogenesis and Treatment of Exudative AMD. AB - Angiogenesis, the formation of new blood vessels from pre-existing capillaries, is very tightly regulated and normally does not occur except during developmental and reparative processes. This tight regulation is maintained by a balanced production of positive and negative regulators, and alterations under pathological conditions such as retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration can lead to growth of new and abnormal blood vessels. Although the role of proangiogenic factors such as vascular endothelial growth factor has been extensively studied, little is known about the roles of negative regulators of angiogenesis in the pathogenesis of these diseases. Here, we will discuss the role of thrombospondin-1 (TSP1), one of the first known endogenous inhibitors of angiogenesis, in ocular vascular homeostasis, and how its alterations may contribute to the pathogenesis of age-related macular degeneration and choroidal neovascularization. We will also discuss its potential utility as a therapeutic target for treatment of ocular diseases with a neovascular component. PMID- 30479724 TI - Optic Nerve Cysticercosis at the Orbital Apex Presenting as Optic Neuritis. AB - Purpose: To describe an unusual presentation of ocular cysticercosis and highlight the role of imaging in diagnosis. Case Report: A 33-year-old female presented with loss of vision in her right eye and features suggesting optic neuritis. Magnetic resonance imaging (MRI) of the brain and orbits revealed a cystic lesion with peripheral rim enhancement in the optic nerve substance at the orbital apex. An enzyme-linked immunosorbent assay test for cysticercosis further established the diagnosis as optic nerve cysticercosis. She was treated with oral albendazole and steroids, resulting in remarkable improvement in visual acuity and resolution of the lesion. Conclusion: A high index of clinical suspicion along with appropriate imaging methods can help diagnose rare presentations of ocular cysticercosis. With timely management, successful outcomes can be obtained. PMID- 30479725 TI - Bilateral Proptosis in a Child: A Rare Presentation of Acute Lymphoblastic Leukemia. AB - Purpose: Acute lymphoblastic leukemia (ALL), a common hematological malignancy observed in children, typically presents with fever, pallor, easy bruising, hepatosplenomegaly and lymphadenopathy. However, when ALL manifests with unusual signs and the blood counts and peripheral smears are normal, it causes a diagnostic dilemma. Case Report: We report a 5-year-old boy who presented with bilateral proptosis as the initial manifestation of ALL. He presented with fever and bilateral knee pain attributed to a fall while playing. There was a history of progressive bilateral proptosis for a 3-month period not associated with any other complaints such as fever, eye pain, redness, or tearing. Thyroid function tests were normal. Blood counts acquired upon proptosis presentation were normal. When he presented to us three months later, blood counts revealed a pancytopenia but the peripheral smear showed no abnormal cells. Magnetic resonance imaging of the brain and orbits was normal. Bone marrow aspirate flow cytometry confirmed the diagnosis of B cell acute lymphoblastic lymphoma. Conclusion: Ophthalmologists should be aware of the unusual ophthalmologic manifestations of acute leukemia, as they may precede overt leukemia and cause diagnostic dilemmas. Knowledge about the rare and isolated extramedullary manifestations of ALL facilitates early diagnosis and thereby improves prognosis. PMID- 30479726 TI - Multiple Pit Defects of Unknown Etiology in a Foldable Hydrophobic Intraocular Lens. PMID- 30479727 TI - Resolution of Photoreceptor Layer Damage in Multiple Evanescent White Dot Syndrome. PMID- 30479728 TI - Evolution of a Retinal Hemorrhage. PMID- 30479729 TI - Intraocular Pressure after Myopic Photorefractive Keratectomy. PMID- 30479730 TI - Author's Reply. PMID- 30479731 TI - Patterns of Uveitis at a Tertiary Referral Center in Northeastern Iran. PMID- 30479732 TI - Author's Reply. PMID- 30479733 TI - Intranasal administration of exosomes derived from mesenchymal stem cells ameliorates autistic-like behaviors of BTBR mice. AB - Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by three core symptoms that include social interaction deficits, cognitive inflexibility, and communication disorders. They have been steadily increasing in children over the past several years, with no effective treatment. BTBR T+tf/J (BTBR) mice are an accepted model of evaluating autistic-like behaviors as they present all core symptoms of ASD. We have previously shown that transplantation of human bone marrow mesenchymal stem cells (MSC) to the lateral ventricles of BTBR mice results in long lasting improvement in their autistic behavioral phenotypes. Recent studies point exosomes as the main mediators of the therapeutic effect of MSC. Here, we tested whether treatment with the exosomes secreted from MSC (MSC-exo) will show similar beneficial effects. We found that intranasal administration of MSC-exo increased male to male social interaction and reduced repetitive behaviors. Moreover, the treatment led to increases of male to female ultrasonic vocalizations and significant improvement in maternal behaviors of pup retrieval. No negative symptoms were detected following MSC-exo intranasal treatments in BTBR or healthy C57BL mice. The marked beneficial effects of the exosomes in BTBR mice may translate to a novel, non-invasive, and therapeutic strategy to reduce the symptoms of ASD. PMID- 30479735 TI - Topological Sensitivity in the Recognition of Disoriented Figures. AB - A previous study by the author found that discrimination latencies for figure pairs with the same topological structure (isomorphic pairs) were longer than for pairs with different topological structures (nonisomorphic pairs). These results suggest that topological sensitivity occurs during figure recognition. However, sameness was judged in terms of both shape and orientation. Using this criterion, faster discrimination of nonisomorphic pairs may have arisen from the detection of differences in the corresponding locations of the paired figures, which is not a topological property. The current study examined whether topological sensitivity occurs even when identity judgments are based on the sameness of shapes, irrespective of their orientation, where the sameness of location is not ensured. The current results suggested the involvement of topological sensitivity, indicating that processing of structural properties (invariant features) of a figure may be prioritized over processing of superficial features, such as location, length, and angles, in figure recognition. PMID- 30479734 TI - Color, Music, and Emotion: Bach to the Blues. AB - When people make cross-modal matches from classical music to colors, they choose colors whose emotional associations fit the emotional associations of the music, supporting the emotional mediation hypothesis. We further explored this result with a large, diverse sample of 34 musical excerpts from different genres, including Blues, Salsa, Heavy metal, and many others, a broad sample of 10 emotion-related rating scales, and a large range of 15 rated music-perceptual features. We found systematic music-to-color associations between perceptual features of the music and perceptual dimensions of the colors chosen as going best/worst with the music (e.g., loud, punchy, distorted music was generally associated with darker, redder, more saturated colors). However, these associations were also consistent with emotional mediation (e.g., agitated sounding music was associated with agitated-looking colors). Indeed, partialling out the variance due to emotional content eliminated all significant cross-modal correlations between lower level perceptual features. Parallel factor analysis (Parafac, a type of factor analysis that encompasses individual differences) revealed two latent affective factors- arousal and valence -which mediated lower level correspondences in music-to-color associations. Participants thus appear to match music to colors primarily in terms of common, mediating emotional associations. PMID- 30479736 TI - Utilization of neonatal medication error prevention strategies: a clinical practice survey of Australian and New Zealand neonatal units. AB - Background: Medication errors are common in neonatal care and can lead to significant harm. We sought to explore utilization of various medication error prevention strategies across Australian and New Zealand neonatal units (NNUs) through a clinical practice survey. Methods: An electronic survey was distributed in October 2016 to relevant staff at each of the 29 level III NNUs identified as members of the Australian and New Zealand Neonatal Network (ANZNN). The survey contained questions relating to a range of medication error prevention strategies identified from a previous systematic review on the topic. The evaluated interventions targeted different aspects of the medication-use process including prescribing, evaluation/checking of orders by clinical pharmacists, transmission, preparation and dispensing of orders, storage of medications, and medication administration. Results: From the 20 respondents, the evidence-based strategies most commonly utilized were use of smart pumps (n = 18; 90%), and ward-based clinical pharmacists (n = 17; 85%). Interventions least commonly utilized included barcode scanning with medication administration (n = 0; 0%), electronic prescribing and clinical decision support (n = 1; 5%), and dedicated medication administration nurse (n = 2; 10%). The total number of evidence-based medication error prevention strategies utilized in each NNU ranged from 2 to 10 (median = 7), 10 of 16 strategies were utilized by less than 50% of NNUs. Conclusion: While evidence supports utilization of a number of medication error prevention strategies, these appear inconsistently utilized across current practice settings. PMID- 30479737 TI - Clinical practice guidelines for older people with multimorbidity and life limiting illness: what are the implications for deprescribing? AB - Background: The aim of this study was (1) to apply the current United Kingdom (UK) National Institute for Health and Care Excellence (NICE) clinical practice guidelines to a hypothetical older patient with multimorbidity and life-limiting illness; (2) consider how treatment choices could be influenced by NICE guidance specifically related to multimorbidity; and, (3) ascertain if such clinical practice guidelines describe how and when medication should be reviewed, reduced and stopped. Methods: Based upon common long-term conditions in older people, a hypothetical older patient was constructed. Relevant NICE guidelines were applied to the hypothetical patient to determine what medication should be initiated in three treatment models: a new patient model, a treatment-resistant model, and a last-line model. Medication complexity for each model was assessed according to the medication regimen complexity index (MRCI). Results: The majority of the guidelines recommended the initiation of medication in the hypothetical patient; if the initial treatment approach was unsuccessful, each guideline advocated the use of more medication, with the regimen becoming increasingly complex. In the new patient model, 4 separate medications (9 dosage units) would be initiated per day; for the treatment-resistant model, 6 separate medications (15 dosage units); and, for the last-line model, 11 separate medications (20 dosage units). None of the guidelines used for the hypothetical patient discussed approaches to stopping medication. Conclusions: In a UK context, disease-specific clinical practice guidelines routinely advocate the initiation of medication to manage long-term conditions, with medication regimens becoming increasingly complex through the different steps of care. There is often a lack of information regarding specific treatment recommendations for older people with life-limiting illness and multimorbidity. While guidelines frequently explain how and when a medication should be initiated, there is often no information concerning when and how the medications should be reduced or stopped. PMID- 30479738 TI - Pharmacovigilance of medicines for rare and ultrarare diseases. AB - The assessment of the safety of medicines for rare diseases during the development phase is often limited by the few data available from small numbers of patients. This also applies to a lesser extent during the postmarketing phase of the lifecycle of a medicine. By using all available sources of data for rare diseases drugs, and by carefully assessing these data, the most informed safety profile can be obtained. This should also allow a clear view of data that are not available at any given time point and facilitates planning of strategies to obtain data through appropriate postmarketing risk management. Although it is not always easy, there are possibilities to increase the speed by which data in the postmarketing period can be generated by better use of data from ongoing formal clinical trials, by early planning of drug or disease registries and leveraging the power of both disease patient support groups, which are often well established, and networks to facilitate international research, specifically in rare diseases. The future may offer approaches using personal medical monitoring data tools and 'big data' to further facilitate the availability of information and to determine the effectiveness and safety profiles of drugs used for rare diseases and thus allow the benefit/risk of these drugs to be optimized. These issues will be discussed here. PMID- 30479740 TI - Strategies to promote public engagement around deprescribing. AB - Many seniors remain unaware that certain medications may be harmful, despite high rates of polypharmacy and inappropriate medication use among community-dwelling older adults. Patient education is an effective method for reducing the use of inappropriate medications. Increasing public awareness and engagement is essential for promoting shared decision-making to deprescribe. The Canadian Deprescribing Network was created to address the lack of a systematic pan Canadian initiative to implement deprescribing among older Canadians. The Canadian Deprescribing Network deliberately included patient advocates in its organization from the outset, in order to ensure a key strategic focus on public awareness and education. In this paper, we present the processes and activities rolled out by the Canadian Deprescribing Network as a blueprint model for engaging the public on deprescribing. Embedded within the structure of the network, the subcommittee on public awareness and engagement implements an action plan that includes needs assessments, population surveys, focus groups, deprescribing fairs, national stakeholders' meetings, public lectures and monthly exchanges with community champions and seniors' organizations. Educational materials and online media have been developed based on the answers to the questions: what information do seniors need about deprescribing? who should this information be delivered to? who needs to deliver the message? and how should seniors be engaged in deprescribing? In conjunction with seniors' organizations, members of the Network have iteratively refined key deprescribing messages, disseminated information about deprescribing, engaged the press and created a grass roots-driven public awareness and education campaign across Canada. Over 3000 seniors and seniors' organizations are involved, with over 25,000 educational tools being distributed across the country. PMID- 30479739 TI - Principle of rational prescribing and deprescribing in older adults with multiple chronic conditions. AB - Although the majority of older adults in the developed world live with multiple chronic conditions (MCCs), the task of selecting optimal treatment regimens is still fraught with difficulty. Older adults with MCCs may derive less benefit from prescribed medications than healthier patients as a result of the competing risk of several possible outcomes including, but not limited to, death before a benefit can be accrued. In addition, these patients may be at increased risk of medication-related harms in the form of adverse effects and significant burdens of treatment. At present, the balance of these benefits and harms is often uncertain, given that older adults with MCCs are often excluded from clinical trials. In this review, we propose a framework to consider patients' own priorities to achieve optimal treatment regimens. To begin, the practicing clinician needs information on the patient's goals, what the patient is willing and able to do to achieve these goals, an estimate of the patient's clinical trajectory, and what the patient is actually taking. We then describe how to integrate this information to understand what matters most to the patient in the context of an array of potential tradeoffs. Finally, we propose conducting serial therapeutic trials of prescribing and deprescribing, with success measured as progress towards the patient's own health outcome goals. The process described in this manuscript is truly an iterative process, which should be repeated regularly to account for changes in the patient's priorities and clinical status. With this process, we aim to achieve optimal prescribing, that is, treatment regimens that maximize benefits that matter to the patient and minimize burdens and potential harms. PMID- 30479741 TI - Significant drug-drug interaction between warfarin and nafcillin. AB - Nafcillin, a beta-lactam semisynthetic penicillin, is highly resistant to penicillinase and is similar to other penicillins except that it is primarily metabolized in the liver. It is believed that nafcillin causes CYP3A4 enzyme induction which decreases warfarin's half-life. The onset of CYP3A4 induction by nafcillin occurs within the first 7 days, but maximal effects may take up to 2 weeks. Once nafcillin is discontinued, the effects persist for several weeks. A 79-year-old male with a history of atrial fibrillation and a 53-year-old male with a history of recurrent venous thromboembolism required significantly higher weekly warfarin doses during courses of nafcillin therapy. Both patients required a 2.5-3.5-fold increase from their baseline weekly warfarin dose to achieve therapeutic international normalized ratios (INRs) while on nafcillin. Traditional protocol-driven warfarin management can result in suboptimal anticoagulation in patients on warfarin and nafcillin. PMID- 30479742 TI - (+)-JQ1 attenuated LPS-induced microglial inflammation via MAPK/NFkappaB signaling. AB - Background: Microglia activation is a crucial event in neurodegenerative disease. The depression of microglial inflammatory response is considered a promising therapeutic strategy. NFkappaB signaling, including IKK/IkappaB phosphotylation, p65 nucelus relocalization and NFkappaB-related genes transcription are prevalent accepted to play important role in microglial activation. (+)-JQ1, a BRD4 inhibitor firstly discovered as an anti-tumor agent, was later confirmed to be an anti-inflammatory compound. However, its anti-inflammatory effect in microglia and central neural system remains unclear. Results: In the current work, microglial BV2 cells were applied and treatment with lipopolysaccharide (LPS) to induce inflammation and later administered with (+)-JQ1. In parallel, LPS and (+) JQ1 was intracerebroventricular injected in IL-1beta-luc transgenic mice, followed by fluorescence evaluation and brain tissue collection. Results showed that (+)-JQ1 treatment could significantly reduce LPS induced transcription of inflammatory cytokines both in vitro and in vivo. (+)-JQ1 could inhibit LPS induced MAPK but not PI3K signaling phosphorylation, NFkappaB relocalization and transcription activity. In animal experiments, (+)-JQ1 postponed LPS induced microglial and astrocytes activation, which was also dependent on MAPK/NFkappaB signaling. Conclusions: Thus, our data demonstrated that (+)-JQ1 could inhibit LPS induced microglia associated neuroinflammation, via the attenuation of MAPK/NFkappaB signaling. PMID- 30479743 TI - Early aggressive intervention for infantile atopic dermatitis to prevent development of food allergy: a multicenter, investigator-blinded, randomized, parallel group controlled trial (PACI Study)-protocol for a randomized controlled trial. AB - Background: Atopic dermatitis is the first clinical manifestation of the atopic march, with the highest incidence in the first year of life. Those affected often go on to develop other allergic diseases including food allergy, asthma, and allergic rhinitis. Recent evidence suggests that sensitization to foods may occur through a defective skin barrier which is common in atopic dermatitis in early life. We hypothesize that therapeutic aggressive intervention to treat new onset atopic dermatitis may prevent the development of later allergen sensitization, and associated food allergy, asthma, and allergic rhinitis. Methods: This study is a multi-center, pragmatic, two-parallel group, assessor-blind, superiority, individually randomized controlled trial. Atopic dermatitis infants (N = 650) 7 13 weeks old who develop an itchy rash within the previous 28 days are randomly assigned to the aggressive treatment or the conventional treatment in a 1:1 ratio. The primary outcome is oral food challenge-proven IgE-mediated hen's egg allergy at the age of 28 weeks. Discussion: This is a novel pragmatic RCT study to examine the efficacy of early aggressive treatment for atopic dermatitis to prevent later food allergy. If our hypothesis is correct, we hope that such a strategy might impact on disease prevention in countries where food allergy is common, and that our results might reduce the frequency and associated costs of all food allergies as well as hens egg food allergy. Long-term follow and other similar studies will help to determine whether such a strategy will reduce the burden of other allergic diseases such as asthma and allergic rhinitis.Trial registration UMIN-CTR: UMIN000028043. PMID- 30479744 TI - Current evidence for spinal X-ray use in the chiropractic profession: a narrative review. AB - The use of routine spinal X-rays within chiropractic has a contentious history. Elements of the profession advocate for the need for routine spinal X-rays to improve patient management, whereas other chiropractors advocate using spinal X rays only when endorsed by current imaging guidelines. This review aims to summarise the current evidence for the use of spinal X-ray in chiropractic practice, with consideration of the related risks and benefits. Current evidence supports the use of spinal X-rays only in the diagnosis of trauma and spondyloarthropathy, and in the assessment of progressive spinal structural deformities such as adolescent idiopathic scoliosis. MRI is indicated to diagnose serious pathology such as cancer or infection, and to assess the need for surgical management in radiculopathy and spinal stenosis. Strong evidence demonstrates risks of imaging such as excessive radiation exposure, overdiagnosis, subsequent low-value investigation and treatment procedures, and increased costs. In most cases the potential benefits from routine imaging, including spinal X-rays, do not outweigh the potential harms. The use of spinal X rays should not be routinely performed in chiropractic practice, and should be guided by clinical guidelines and clinician judgement. PMID- 30479745 TI - Cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a Mainzer-Saldino syndrome diagnosis. AB - Background: Mainzer-Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. The main characteristics of MZSDS are short limbs, mild narrow thorax, blindness, and renal failure. Thus far, variants in two genes are associated with MZSDS: IFT140, and IFT172. In this study, we describe a 1-year-old girl presenting with mild skeletal abnormalities, Leber congenital amaurosis, and bilateral hearing difficulties. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses. Methods: We performed diagnostic whole-exome sequencing (WES) analysis to determine the genetic cause of the disease and analyzed two gene panels, containing all currently known genes in vision disorders, and in hearing impairment. Upon detection of the likely causative variants, ciliary phenotyping was performed in patient urine-derived renal epithelial cells (URECs) and rescue experiments were performed in CRISPR/Cas9 derived Ift140 knock out cells to determine the pathogenicity of the detected variants in vitro. Cilium morphology, cilium length, and intraflagellar transport (IFT) were evaluated by immunocytochemistry. Results: Diagnostic WES revealed two novel compound heterozygous variants in IFT140, encoding IFT140. Thorough investigation of WES data did not reveal any variants in candidate genes associated with hearing impairment. Patient-derived URECs revealed an accumulation of IFT-B protein IFT88 at the ciliary tip in 41% of the cells indicative of impaired retrograde IFT, while this was absent in cilia from control URECs. Furthermore, transfection of CRISPR/Cas9-derived Ift140 knock out cells with an IFT140 construct containing the patient mutation p.Tyr923Asp resulted in a significantly higher percentage of IFT88 tip accumulation than transfection with the wild-type IFT140 construct. Conclusions: By combining the clinical, genetic, and functional data from this study, we could conclude that the patient has SRTD9, also called Mainzer-Saldino syndrome, caused by variants in IFT140. We suggest the possibility that variants in IFT140 may underlie hearing impairment. Moreover, we show that urine provides an excellent source to obtain patient-derived cells in a non-invasive manner to study the pathogenicity of variants detected by genetic testing. PMID- 30479746 TI - Predictors of chronic prescription opioid use after orthopedic surgery: derivation of a clinical prediction rule. AB - Background: Prescription opioid use at high doses or over extended periods of time is associated with adverse outcomes, including dependency and abuse. The aim of this study was to identify mediating variables that predict chronic opioid use, defined as three or more prescriptions after orthopedic surgery. Methods: Individuals were ages between 18 and 50 years and undergoing arthroscopic hip surgery between 2004 and 2013. Two categories of chronic opioid use were calculated based on individuals (1) having three or more unique opioid prescriptions within 2 years and (2) still receiving opioid prescriptions > 1 year after surgery. Univariate elationships were identified for each predictor variable, then significant variables (P > 0.15) were entered into a multivariate logistic regression model to identify the most parsimonious group of predictor variables for each chronic opioid use classification. Likelihood ratios were derived from the most robust groups of variables. Results: There were 1642 participants (mean age 32.5 years, SD 8.2, 54.1% male). Nine predictor variables met the criteria after bivariate analysis for potential inclusion in each multivariate model. Eight variables: socioeconomic status (from enlisted rank family), prior use of opioid medication, prior use of non-opioid pain medication, high health-seeking behavior before surgery, a preoperative diagnosis of insomnia, mental health disorder, or substance abuse were all predictive of chronic opioid use in the final model (seven variables for three or more opioid prescriptions; four variables for opioid use still at 1 year; all< 0.05). Post test probability of having three or more opioid prescriptions was 93.7% if five of seven variables were present, and the probability of still using opioids after 1 year was 69.6% if three of four variables were present. Conclusion: A combination of variables significantly predicted chronic opioid use in this cohort. Most of these variables were mediators, indicating that modifying them may be feasible, and the potential focus of interventions to decrease the risk of chronic opioid use, or at minimum better inform opioid prescribing decisions. This clinical prediction rule needs further validation. PMID- 30479747 TI - Priority-setting, the Indian way. PMID- 30479748 TI - Global birth prevalence and mortality from inborn errors of metabolism: a systematic analysis of the evidence. AB - Background: Inborn errors of metabolism (IEM) are a group of over 500 heterogeneous disorders resulting from a defect in functioning of an intermediate metabolic pathway. Individually rare, their cumulative incidence is thought to be high, but it has not yet been estimated globally. Although outcomes can often be good if recognised early, IEM carry a high fatality rate if not diagnosed. As a result, IEM may contribute significantly to the burden of non-communicable childhood morbidity. Methods: We conducted a systematic literature review of birth prevalence and case fatality of IEM globally, with search dates set from 1980 to 2017. Using random-effects meta-analysis, we estimated birth prevalence of separate classes of IEM and all-cause IEM, split by geographical region. We also estimated levels of parental consanguinity in IEM cases and global case fatality rates and resultant child deaths from all-cause IEM. Findings: 49 studies met our selection criteria. We estimate the global birth prevalence of all-cause IEM to be 50.9 per 100 000 live births (95% confidence intervals (CI) = 43.4-58.4). Regional pooled birth prevalence rates showed the highest rates of IEM to be in the Eastern Mediterranean region (75.7 per 100 000 live births, 95% CI = 50.0-101.4), correlating with a higher observed rate of parental consanguinity in studies from this area. We estimate case fatality rates to be 33% or higher in low- and middle-income countries (LMICs), resulting in a minimum of 23 529 deaths from IEM per year globally (95% CI = 20 382-27 427), accounting for 0.4% of all child deaths worldwide. Conclusions: IEM represent a significant cause of global child morbidity and mortality, comprising a notable proportion of child deaths currently not delineated in global modelling efforts. Our data highlight the need for policy focus on enhanced laboratory capacity for screening and diagnosis, community interventions to tackle parental consanguinity, and increased awareness and knowledge regarding management of IEM, particularly in LMICs. PMID- 30479749 TI - Burden of suicide presented as one of the leading causes of death: uncover facts or misrepresent statistics? AB - Background: Suicide is a relatively rare incident. Nevertheless, parts of the literature on intentional self-harm behaviour state that suicide is one of the leading causes of death. We aimed to assess the evidence behind the statement that suicide is a leading cause of death across all ages, with reference to the methods of ranking causes of death. Methods: Two sets of data were used: For the European Union (EU) we used cause specific mortality statistics from the European Statistical Office (Eurostat) for the data-year 2014, and globally and for the WHO European Region we used data from Global Health Estimates (GHE) 2015. We used different sets of rules to select mutually exclusive leading underlying causes of mortality for Europe (EU28). We also present lists with estimates of leading causes of death globally, and for the WHO European Region based on the GHE 2015. Results: In 2014, 1.2% of all reported deaths in the Europe Union (EU28) were due to suicide, and 1.4% globally (2015) according to the WHO estimates. In Europe, suicide was ranked as number 11 and 15 in the two different ranking lists we used, and according to GHE-2015, suicide was ranked as the 17th leading cause globally, and number 14 in the WHO European Region. Looking at the differences by sex, suicide for males was ranked as the ninth and the tenth leading cause of death in two ranking lists for the European Union. For females, suicide was number 13 in the first and 23 in the second list, respectively. Conclusions: Different cause lists and rules for ranking produce different leading causes of mortality. The quality of data can also affect the ranking. Our rankings suggested that suicide was not among the ten leading causes of death in Europe or globally. To ensure that ranking causes of death is not driven by political motives and funding considerations, standard methods and official tabulation lists should be used. The rankings do not necessarily present the causes of mortality of greatest public health importance. PMID- 30479750 TI - Association between antibiotic consumption and the rate of carbapenem-resistant Gram-negative bacteria from China based on 153 tertiary hospitals data in 2014. AB - Background: This study aimed to investigate the relationship between the rate of carbapenem-resistant Gram-negative bacteria and antibiotic consumption intensity in 153 tertiary hospitals from China in 2014. Methods: A retrospective study using national surveillance data from 2014 was conducted. Data on the annual consumption of each antibiotic, as well as the rate of carbapenem-resistant Gram negative bacteria, were collected from each participating hospital, and the correlation between antibiotic consumption and carbapenem- resistant rate was analyzed. Results: The overall antibiotic consumption intensity among the hospitals varied between 23.93 and 86.80 defined daily dosages (DDDs) per 100 patient-days (median, 46.30 DDDs per 100 patient-days). Cephalosporins were the most commonly used antibiotic, followed by quinolones, penicillins, and carbapenems, and the rate of carbapenem-resistant Gram-negative bacteria from each hospital varied. The correlations between carbapenem consumption intensity and rate of carbapenem resistance revealed correlation factors of 0.271 for Escherichia coli (p < 0.01), 0.427 for Klebsiella pneumoniae (p < 0.01), 0.463 for Pseudomonas aeruginosa (p < 0.01), and 0.331 for Acinetobacter baumannii (p < 0.01). Conclusions: A significant relationship existed between the carbapenem consumption and the rates of carbapenem-resistant gram negative bacilli. Rational use of carbapenems should be implemented to address the issue of carbapenem resistance in hospitals. PMID- 30479751 TI - Emergence of high drug resistant bacterial isolates from patients with health care associated infections at Jimma University medical center: a cross sectional study. AB - Background: The rates of resistant microorganisms which complicate the management of healthcare associated infections (HAIs) are increasing worldwide and getting more serious in developing countries. The objective of this study was to describe microbiological features and resistance profiles of bacterial pathogens of HAIs in Jimma University Medical Center (JUMC) in Ethiopia. Methods: Institution based cross sectional study was carried out on hospitalized patients from May to September, 2016 in JUMC. Different clinical specimens were collected from patients who were suspected to hospital acquired infections. The specimens were processed to identify bacterial etiologies following standard microbiological methods. Antibacterial susceptibility was determined in vitro by Kirby-Bauer disk diffusion method following Clinical and Laboratory Standards Institute guidelines. Results: Overall, 126 bacterial etiologies were isolated from 118 patients who had HAIs. Of these, 100 (79.4%) were gram negative and the remaining were gram positive. The most common isolates were Escherichia coli 31(24.6%), Klebsiella species 30(23.8%) and Staphylococcus aureus 26 (20.6%). Of 126 bacterial isolates, 38 (30.2%), 52 (41.3%), and 24 (19%) were multidrug-resistant (MDR, resistant to at least one agent in three or more antimicrobial categories), extensively drug resistant (XDR, resistant to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories), pan-drug resistant (PDR, resistant to all antibiotic classes) respectively. More than half of isolated gram-negative rods (51%) were positive for extended spectrum beta-lactamase (ESBL) and/or AmpC; and 25% of gram negative isolates were also resistant to carbapenem antibiotics. Conclusions: The pattern of drug resistant bacteria in patients with healthcare associated infection at JUMC is alarming. This calls for coordinated efforts from all stakeholders to prevent HAIs and drug resistance in the study setting. PMID- 30479752 TI - Urinary tract infection caused by a small colony variant form of capnophilic Escherichia coli leading to misidentification and non-reactions in antimicrobial susceptibility tests. AB - Background: Small colony and capnophilic variant cases have been separately reported, but there has been no reports of their simultaneous presence in one isolate. We report a case of Escherichia coli with coexpressed small colony and capnophilic phenotypes causing misidentification in automated biochemical kits and non-reactions in antimicrobial susceptibility test cards. Case presentation: An 86-year-old woman developed urinary tract infection from a strain of Escherichia coli with SCV and capnophilic phenotypes in co-existence. This strain did not grow without the presence of CO2, and therefore proper identification from automated system was not possible. 16 s rRNA sequencing and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was able to identify the bacteria. Conclusion: As these strains do not grow on culture parameters defined by CLSI or on automated systems, proper identification using alternative methods are necessary. PMID- 30479753 TI - Investigation of a Carbapenemase-producing Acinetobacter baumannii outbreak using whole genome sequencing versus a standard epidemiologic investigation. AB - Background: The standard epidemiologic investigation of outbreaks typically relies on spatiotemporal data and pulsed-field gel electrophoresis (PFGE), but whole genome sequencing (WGS) is becoming increasingly used. This investigation aimed to characterize a carbapenemase-producing Acinetobacter baumannii (CPAb) nosocomial outbreak using WGS compared to a standard outbreak investigation. Methods: The CPAb outbreak occurred in a single center between 2012 and 2014. The standard investigation used spatiotemporal data and PFGE to generate a chain of transmission. A separate WGS investigation generated a chain of transmission based solely on WGS and date of sampling and was blinded to all other spatiotemporal data and PFGE. Core single nucleotide variant (SNV) phylogenetic analysis was performed on WGS data generated using the Illumina MiSeq platform. The chains of transmission were compared quantitatively and qualitatively to assess the concordance between both methods. Results: 28 colonized and infected cases were included. Of the 27 transmission events identified using the standard investigation, 12 (44%) were identical to the transmission events using WGS. WGS identified several transmission events that had not been detected by traditional method, and numerous transmission events that had occurred on different hospital wards than suspected by standard methods. The average number (standard deviation [SD]) of SNVs per transmission events was 1.63 (SD, 1.31) by traditional method and 0.63 (SD, 0.79) by WGS (p = 0.001) All isolates harbored the rare carbapenemase bla OXA-237. Conclusions: The traditional and WGS investigations had moderate concordance. When used alongside epidemiologic data and clinical information, WGS could help improve the mapping of transmission events. PMID- 30479754 TI - Nudge to better care - blood cultures and catheter-related bloodstream infections in Germany at two points in time (2006, 2015). AB - Background: Blood cultures (BCs) are the gold standard for diagnosing sepsis and are prerequisite for a targeted antibiotic treatment and essential for patient outcomes. Aim of the study was to analyze the frequency of BCs, the rate of central line-associated bloodstream infections (CLABSIs) and to study the association between both parameters on intensive care units in Germany over time. Methods: Cross-sectional studies at two points in time (2006, 2015) on ICUs participating in the German hospital infection surveillance system. CLABSIs were defined according to the Center for Disease Control and Prevention (CDC). Univariable and multivariable analyses were performed using generalized linear models. Results: A total of 639 ICUs participated in 2006 or 2015 and 90 ICUs ("core group") in both years. Overall, 2,427,921 patient days from 644,575 patients were analyzed. In the ICU core group the frequency of BCs per 1000 patient days doubled from 57.8 (interquartile range [IQR] 29.8-101.2; 2006) to 128.2 (IQR 71.6-183.2; 2015). In the same time, the pooled median CLABSI rate decreased from 0.8 (IQR 0-1.9; 2006) per 1000 central-line catheter days to 0.2 (IQR 0-0.9; 2015). Conclusions: From 2006 to 2015 the frequency of BCs increased on ICUs in Germany and is now within the recommended 100 to 200 BCs sets per 1000 patient days. PMID- 30479755 TI - In vitro and in vivo bactericidal activity of ceftazidime-avibactam against Carbapenemase-producing Klebsiella pneumoniae. AB - Background: In recent years, the incidence of carbapenem-resistant Enterobacteriaceae (CRE) infections has increased rapidly. Since the CRE strain is usually resistant to most of antimicrobial agents, patients with this infection are often accompanied by a high mortality. Therefore, it instigates a severe challenge the clinical management of infection. In this study, we study the in vitro and in vivo bactericidal activity of ceftazidime-avibactam administrated either alone or in combination with aztreonam against KPC or NDM carbapenemase-producing Klebsiella pneumoniae, and explore a new clinical therapeutic regimen for infections induced by their resistant strains. Methods: The microdilution broth method was performed to analyze the minimal inhibitory concentration (MIC). The time-kill curve assay of ceftazidime-avibactam at various concentrations was conducted in 16 strains of KPC-2 and 1 strain of OXA 232 carbapenemase-producing Klebsiella pneumoniae. The in vitro synergistic bactericidal effect of ceftazidime-avibactam combined with aztreonam was determined by checkerboard assay on 28 strains of NDM and 2 strains of NDM coupled with KPC carbapenemase-producing Klebsiella pneumoniae. According to calculating grade, the drugs with synergistic bactericidal effect were selected as an inhibitory concentration index. The in vitro bactericidal tests of ceftazidime-avibactam combined with aztreonam were implemented on 12 strains among them. Effect of ceftazidime-avibactam antibiotic against KPC carbapenemase producing K. pneumoniae strain Y8 Infection was performed in the mouse model. Results: The time-kill assays revealed that ceftazidime-avibactam at various concentrations of 2MIC, 4MIC and 8MIC showed significant bactericidal efficiency to the resistant bacteria strains. However, in 28 strains of NDM and 2 strains of NDM coupled with KPC carbapenemase- producing Klebsiella pneumoniae, only 7 strains appeared the susceptibility to ceftazidime-avibactam treatment, MIC50 and MIC90 were 64 mg/L and 256 mg/L, respectively. Antimicrobial susceptibility testing of ceftazidime-avibactam combined with aztreonam disclosed the synergism of two drugs in 90% (27/30) strains, an additive efficiency in 3.3% (1/30) strains, and irrelevant effects in 6.6% (2/30) strains. No antagonism was found. The subsequent bactericidal tests also confirmed the results mentioned above. Therapeutic efficacy of Ceftazidime-Avibactam against K. pneumoniae strain Y8 infection in mouse indicated 70% of infection group mice died within 4 days, and all mice in this group died within 13 days. Bacterial load testing results showed that there was no significant difference in the amount of bacteria in the blood between the infected group and the treatment group. However, the spleen and liver of treatment group mice showed lower CFU counts, as compare with infected group, indicating that ceftazidime-avibactam has a significant effect on the bacteria and led to a certain therapeutic efficacy. Conclusion: This study indicated ceftazidime-avibactam therapy occupied significant bactericidal effects against KPC-2 and OXA-232 carbapenemase-producing Klebsiella pneumoniae. While combined with aztreonam, the stronger synergistic bactericidal effects against NDM carbapenemase-producing Klebsiella pneumoniae were achieved. PMID- 30479756 TI - Independent control of harmonic amplitudes and phases via a time-domain digital coding metasurface. AB - Harmonic manipulations are important for applications such as wireless communications, radar detection and biological monitoring. A general approach to tailor the harmonics involves the use of additional amplifiers and phase shifters for the precise control of harmonic amplitudes and phases after the mixing process; however, this approach leads to issues of high cost and system integration. Metasurfaces composed of a periodic array of subwavelength resonators provide additional degrees of freedom to realize customized responses to incident light and highlight the possibility for nonlinear control by taking advantage of time-domain properties. Here, we designed and experimentally characterized a reflective time-domain digital coding metasurface, with independent control of the harmonic amplitude and phase. As the reflection coefficient is dynamically modulated in a predefined way, a large conversion rate is observed from the carrier signal to the harmonic components, with magnitudes and phases that can be accurately and separately engineered. In addition, by encoding the reflection phases of the meta-atoms, beam scanning for multiple harmonics can be implemented via different digital coding sequences, thus removing the need for intricate phase-shift networks. This work paves the way for efficient harmonic control for applications in communications, radar, and related areas. PMID- 30479759 TI - Covert infrared image encoding through imprinted plasmonic cavities. AB - Functional surfaces that can control light across the electromagnetic spectrum are highly desirable. Plasmonic nanostructures can assume this role by exhibiting dimension-tunable resonances that span multiple electromagnetic regimes. However, changing these structural parameters often impacts the higher-order resonances and spectral features in lower-wavelength domains. In this study, we discuss a cavity-coupled plasmonic system with resonances that are tunable across the 3-5 or 8-14 MUm infrared bands while retaining near-invariant spectral properties in the visible domain. This result is accomplished by regime-dependent resonance mechanisms and their dependence on independent structural parameters. Through the identification and constraint of key parameters, we demonstrate multispectral data encoding, where images, viewable in the infrared spectral domain, appear as uniform areas of color in the visible domain-effectively hiding the information. Fabricated by large area nanoimprint lithography and compatible with flexible surfaces, the proposed system can produce multifunctional coatings for thermal management, camouflage, and anti-counterfeiting. PMID- 30479758 TI - High-fidelity multimode fibre-based endoscopy for deep brain in vivo imaging. AB - Progress in neuroscience relies on new techniques for investigating the complex dynamics of neuronal networks. An ongoing challenge is to achieve minimally invasive and high-resolution observations of neuronal activity in vivo inside deep brain areas. Recently introduced methods for holographic control of light propagation in complex media enable the use of a hair-thin multimode optical fibre as an ultranarrow imaging tool. Compared to endoscopes based on graded index lenses or fibre bundles, this new approach offers a footprint reduction exceeding an order of magnitude, combined with a significant enhancement in resolution. We designed a compact and high-speed system for fluorescent imaging at the tip of a fibre, achieving a resolution of 1.18 +/- 0.04 um across a 50-um field of view, yielding 7-kilopixel images at a rate of 3.5 frames/s. Furthermore, we demonstrate in vivo observations of cell bodies and processes of inhibitory neurons within deep layers of the visual cortex and hippocampus of anaesthetised mice. This study paves the way for modern microscopy to be applied deep inside tissues of living animal models while exerting a minimal impact on their structural and functional properties. PMID- 30479757 TI - In vivo theranostics with near-infrared-emitting carbon dots-highly efficient photothermal therapy based on passive targeting after intravenous administration. AB - Carbon dots that exhibit near-infrared fluorescence (NIR CDs) are considered emerging nanomaterials for advanced biomedical applications with low toxicity and superior photostability and targeting compared to currently used photoluminescence agents. Despite progress in the synthesis of NIR CDs, there remains a key obstacle to using them as an in vivo theranostic agent. This work demonstrates that the newly developed sulfur and nitrogen codoped NIR CDs are highly efficient in photothermal therapy (PTT) in mouse models (conversion efficiency of 59%) and can be readily visualized by photoluminescence and photoacoustic imaging. The real theranostic potential of NIR CDs is enhanced by their unique biodistribution and targeting. Contrary to all other nanomaterials that have been tested in biomedicine, they are excreted through the body's renal filtration system. Moreover, after intravenous injection, NIR CDs are accumulated in tumor tissue via passive targeting, without any active species such as antibodies. Due to their accumulation in tumor tissue without the need for intratumor injection, high photothermal conversion, excellent optical and photoacoustic imaging performance, and renal excretion, the developed CDs are suitable for transfer to clinical biomedical practice. PMID- 30479760 TI - High Resected Gastric Volume and poorly controlled DM2 in laparoscopic sleeve gastrectomy. AB - Background: Our aim is to evaluate the effects of High Resected Gastric Volume(HRGV) on poorly Type 2 Diabetes Mellitus(DM2) after Laparoscopic Sleeve Gastrectomy(LSG). Methods: 256 patients were divided into two groups according to the RGV: < 1500 mL(Group A: 131 pts) and > 1500 mL(Group B: 147 pts). % excess body mass index loss (%EBMIL), Fasting Blood Glucose (FBG), HbA1c, C peptide were assessed before surgery and at the 3rd day, 6th,12th,24th,36th month after LSG. Results: A significant difference in %EBMIL between the two groups at 24 and 36 months was found. RGV was not significantly associated with DM2 in the multivariate logistic regression. FBG levels showed no differences between the two groups. A significant decrease of Hb1Ac at 6 and 12 months was found in group B. The C-peptide level showed a significant reduction at 6 and 12 months in group B. Conclusion: The HRGV may play a role in the regulation of the glucose metabolism in the first year after LSG without influence in poorly DM2 control. Further studies are needed to confirm these findings. PMID- 30479761 TI - Epidemiology of salivary gland tumours in an Eastern Caribbean nation: A retrospective study. AB - Objective: The epidemiology of the salivary glands tumour is not well documented in the Caribbean countries. Therefore, the aim of this study is to determine the local trend of salivary gland tumours with a review of current diagnostic techniques. Design & Methods: Retrospective data was collected from the electronic database at the Pathology department of the San Fernando Teaching Hospital between the periods January 2005 to June 2015. All patients who underwent primary resection of either the parotid, submandibular or minor salivary glands for diagnosed tumour cytologically or suspected tumour were included in this study. The clinical and histopathological data were then collected and analyzed. Results: A total of 85 surgeries were performed for suspected or diagnosed neoplasia, 54 parotidectomies, 26 submandibular gland and 5 minor salivary gland excisions. The benign neoplastic lesions, pleomorphic adenoma and Warthin's tumour, were the most common 53 (62.4%) of all the resections performed, followed by non-neoplastic lesions 25 (29.4%) such as sialadenitis, cysts or normal glands. Malignant neoplasms made up the minority with only 7 cases whereby mucoepidermoid carcinoma was the most common malignant neoplasm found followed by squamous cell carcinoma. Conclusion: Parotid gland remains the most frequent site of salivary gland tumours (80%), with pleomorphic adenoma being the most common benign tumour. Triple assessment is still required to manage these cases adequately with stress on preoperative tissue diagnosis FNAB vs USS guided core biopsy. PMID- 30479762 TI - Effect of vitamin C and vitamin E on lung contusion: A randomized clinical trial study. AB - : There is association between lung contusion (lC) and a progressive inflammatory response. The protective effect of vitamin C and vitamin E, as strong free radical scavengers on favourite outcome of (LC) in animal models, has been confirmed. Design: to evaluate the effect of vitamins, E and C on arterial blood gas (ABG) and ICU stay, in (LC), with injury severity score (ISS) 18 +/- 2, due to blunt chest trauma. Methods: This study was a randomized, double-blind, placebo-controlled clinical trial. Patients with (ISS) 18 +/- 2 blunt chest trauma, who meet criteria, participated in the study. A total of 80 patients from Feb 2015 to Jun2018and were randomly divided into 4 groups. Patients received intravenous vitamin E (1000IU mg), was (group I); intravenous vitamin C (500) (group II). Vitamin C + vitamin E = (group III), and intravenous distilled water = (control group) or (group IV). ABG, serum cortisol, and CRP levels were determined at baseline, 24 h and 48 h after the intervention. Results: a significant decrease in ICU stay in group III compared to other groups (p < 0.001). Co-administration of vitamin C and vitamin E showed significant increases pH (values to reference range from acidemia"), oxygen pressure, and oxygen saturation in group III compared to other groups (p < 0.001). A significant decrease in carbon dioxide pressure was also detected after receiving vitamin C and vitamin E in group III, compared to other groups (p < 0.001). There was no significant difference cortisol and CRP levels between groups after the intervention. Conclusion: Co-administration of vitamin C and vitamin E, improve the ABG parameters and reduce ICU stay. PMID- 30479763 TI - Marginal resection of solitary plasmacytoma in the anterior region of the mandible and dental implant rehabilitation: Report of an unusual case. AB - Introduction: Plasmacytoma describes a neoplastic proliferation of plasma cells affecting different groups of patients according to location, and may demonstrate heterogeneous tumor progression and survival rate. The present article describes a case of solitary plasmacytoma in the mandible. Presentation of case: A 57-year old male smoker was referred to the oral and maxillofacial service with extensive injury, approximately 4-5 cm in size, involving the anterior inferior region of mandible. After confirming diagnosis of plasmacytoma through incisional biopsy, because it was a recurrent lesion, excision of the lesion was performed through marginal resection of the mandible under general anesthesia. During the same surgical procedure, a 2.4-mm system fixation plate was placed to mitigate the risk for pathological fracture of the mandible. In a second surgery, a region in the base of the mandible was rehabilitated using implants and prosthesis. Conclusion: The patient is currently undergoing clinical and radiological follow up of 2 years with success. PMID- 30479764 TI - Idiopathic granulomatous mastitis: A retrospective cohort study between 44 patients with different treatment modalities. AB - Background: Idiopathic granulomatous mastitis (IGM) is an uncommon benign chronic inflammatory disease which can clinically and radiographically mimic abscess or breast cancer. Definitive diagnosis was made by histopathology and exclusion of an identifying etiology. Optimal treatment has not been yet established. The aim of this study was to report and describe the clinical signs, radiological findings, managements, clinical course, and clinical outcomes after treatment of IGM. Method: We retrospectively studied IGM medical records of 44 patients in our institute collected from March 1990 to October 2016. The patient characteristics, clinical presentations, radiological findings, microbiological workups, tissue pathology, treatment modalities, outcomes, and follow-up data were reviewed and analyzed. The success rate, recurrence rate and time-to-healing were compared focusing on the treatment modalities to find the proper treatments for IGM patient. Results: Forty-four patients were diagnosed as IGM. The median follow-up time was 20.73 months ranging from 1.26 to 118.8 months while the median time of the diagnosis was 21 days ranging from 2 to 246 days. Due to the follow-up period, only thirty-nine patient data were used for the analysis. In the first setting, 30 patients were treated by surgery, 6 patients were treated by using steroid while other 3 patients were treated by other different treatments. Only 25 from 39 patients (64.10%) were cured by the first modality. The overall median time-to-healing was 84 days while the medians of time-to-healing treated by surgery, steroid and the rest were 75, 114.5, and 238 days respectively. The surgical treatment had the shortest time-to-healing but not statistically significant (p = 0.23). Thirteen patients out of twenty-five (52%) had wound complications after performing an excision. Lastly, five patients out of thirty nine (12.82%) had recurrence. Conclusion: IGM is an uncommon benign disease which is hardly distinguished from malignancy. There is not a significant difference among treatment modalities in term of time-to-healing and recurrence of disease. The result shows that surgery is outperformed by the shortest healing time. However, the surgical treatment must be chosen with careful due to high rate of wound complications. Multimodality treatment is recommended as the proper treatments for IGM patient. PMID- 30479767 TI - Chilaiditi's sign, a cause of pseudo-pneumoperitoneum: A case report. AB - The differentiation between a pseudo-pneumoperitoneum and true pneumoperitoneum on an initial chest radiograph is challenging but essential to clinical practice. The former is managed conservatively whereas the latter may require surgical intervention. Chilaiditi's sign describes a rare incidental radiological finding of gas filled bowel interpositioned between the right hemi-diaphragm and the liver, which is visible on a plain abdominal or chest radiograph. It is often misdiagnosed as a pneumoperitoneum. Correct diagnosis of Chilaiditi's sign in an asymptomatic patient can prevent unnecessary procedures. We have reported one incidental chest radiograph with Chilaiditi's sign in a patient presenting and treated for pneumonia. The report aims to illustrate the diagnostic dilemma experienced by clinicians in distinguishing a true versus pseudo-pneumoperitoneum on a chest radiograph. PMID- 30479765 TI - Effect of diets supplemented with linseed alone or combined with vitamin E and selenium or with plant extracts, on Longissimus thoracis transcriptome in growing finishing Italian Large White pigs. AB - Background: Supplementing farm animals diet with functional ingredients may improve the nutritional quality of meat products. Diet composition has been also demonstrated to influence the gene expression with effect on biological processes and pathways. However, the knowledge on the effect of nutrients at the molecular level is scant. In particular, studies on the effects of antioxidants and polyphenols dietary supplementation have been investigated mainly in rodents, and only scarcely in farm animals so far. RNA-Seq with next-generation sequencing is increasingly the method of choice for studying changes in the transcriptome and it has been recently employed also in pig nutrigenomics studies to identify diet induced changes in gene expression. The present study aimed to investigate the effect of diets enriched with functional ingredients (linseed, vitamin E and plant extracts) on the transcriptome of pig Longissimus thoracis to elucidate the role of these compounds in influencing genes involved in muscle physiology and metabolism compared to a standard diet. Results: Eight hundred ninety-three significant differentially expressed genes (DEGs) (FDR adjusted P-value <= 0.05) were detected by RNA-Seq analysis in the three diet comparisons (D2-D1, D3-D1, D4 D1). The functional analysis of DEGs showed that the diet enriched with n-3 PUFA from linseed (D2) mostly downregulated genes in pathways and biological processes (BPs) related to muscle development, contraction, and glycogen metabolism compared to the standard diet. The diet supplemented with linseed and vitamin E/Selenium (D3) showed to mostly downregulate genes linked to oxidative phosphorylation. Only few genes involved in extracellular matrix (ECM) organization were upregulated by the D3. Finally, the comparison D4-D1 showed that the diet supplemented with linseed and plant extracts (D4) upregulated the majority of genes compared to D1 that were involved in a complex network of pathways and BPs all connected by hub genes. In particular, IGF2 was a hub gene connecting protein metabolism, ECM organization, immune system and lipid biosynthesis pathways. Conclusion: The supplementation of pig diet with n-3 PUFA from linseed, antioxidants and plant-derived polyphenols can influence the expression of a relevant number of genes in Longissimus thoracis muscle that are involved in a variety of biochemical pathways linked to muscle function and metabolism. PMID- 30479766 TI - Barriers and enablers in the use of respite interventions by caregivers of people with dementia: an integrative review. AB - Background: Due to the increase in the number of people with dementia, relatives often provide in-home care. This care constitutes a cornerstone of the healthcare system, and maintaining these caregivers' well-being is therefore of paramount importance. Although respite interventions are generally considered an effective support system, they tend to be underutilized. The aim of this integrative literature review is to highlight the factors that promote and impede the use of respite interventions. Methods: Searches were conducted on the PubMed and CINAHL databases for studies of respite interventions from 1980 to 2016, and they yielded 51 articles of relevance. Results: Analysis of these articles revealed modifiable and immutable factors that influence the use of respite. The most cited topic categories in the literature were attributes of respite services and workload managed by caregivers, which is characterized by the onset of burden. Conclusion: The factors promoting or impeding the use of respite interventions identified by our analysis highlight the need to adapt respite service attributes and use caregivers' skills to foster the partnership between healthcare teams and caregivers and to ensure the accompanying dyad's quality and safety. PMID- 30479768 TI - The fine spatial and temporal control of ultrasonic neuromodulation is a necessary condition for discerning the accompanying subjective feelings, but is it sufficient? PMID- 30479770 TI - The significance of non-occupational asbestos exposure in women with mesothelioma. AB - Malignant mesothelioma is a rare and aggressive pleural or peritoneal tumour almost always caused by exposure to asbestos fibres. Exposure to asbestos can cause malignant mesothelioma 30-40 years after exposure. A description of sources of exposure is important for prevention and possible financial compensation. Three women with cases of histologically confirmed malignant mesothelioma diagnosed from non-occupational asbestos exposure are described. Patients were contacted for an interview to assess their exposure history to asbestos. All three cases had mixed exposure histories related to secondary, environmental contamination, and domestic exposure. This case series highlight how ubiquitous asbestos is in the environment and how diverse the exposures may be. It is anticipated that a significant number of cases of non-occupational mesothelioma will be seen in many countries for several decades given the extent of asbestos containing materials. PMID- 30479771 TI - Effectiveness of benralizumab for allergic and eosinophilic predominant asthma following negative initial results with omalizumab. AB - A 64-year-old woman, who had presented with a 30-year history of refractory asthma, and been treated with anti-allergic drug therapy, inhaled corticosteroids, a long-acting beta-agonist, and a long-acting muscarinic antagonist. She had been characterized as an allergic, eosinophilic asthmatic. Although omalizumab was tried initially, it was found to be insufficient. We began treatment with benralizumab. The asthma symptom control and sinusitis were improved immediately. Benralizumab was effective for overlapping patient population following negative initial results with omalizumab. PMID- 30479769 TI - Philadelphia chromosome positive AML arising from JAK2-positive myelofibrosis. AB - Background: A feature of myeloproliferative neoplasia is transforming to more aggressive and malignant myeloid neoplasia, including acute myeloid leukemia. Different pathogenesis mechanisms participate in transformation, including transformation of existing potential preleukemic clones, since JAK2-mutant myeloproliferative neoplasms often transform to JAK2 wild-type acute myeloid leukemia. Case presentation: Here, we present an 80 year old man with a JAK2 V617F mutant primary myelofibrosis. After 10 months the disease transform into a Philadelphia chromosome positive acute myeloid leukemia, detecting the cytogenetic aberration; t(9;22)(q34;q22) encoding the rare BCR-ABL1 fusion gene; e6a2. The patient had treatment response to tyrosine kinases, illustrating the potential benefits of such approach in treating these patients subset. Conclusion: The case illustrates the potential of leukemic transformation to Philadelphia chromosome positive myeloid malignancies from potential existing preleukemic clones, and the awareness of such an evolution among patients with myeloproliferative neoplasms. Tyrosine kinases have potential effect also in patients presenting without chronic myeloid leukemia and with rare BCR-ABL1 fusion transcripts, and should probably be a part of the treatment approach. PMID- 30479772 TI - Conducting trials on corticosteroid dosing for respiratory failure in the last paradise. AB - It is interesting to find that Japanese clinicians continue to hesitate to change their practice even after accumulating evidence for the inefficacy of high-dose corticosteroid for ARDS in the Letters to the Editor discussion. Given the widespread use of the therapy even for other categories of acute hypoxemic respiratory failure with diffuse alveolar damage represented by acute exacerbation of interstitial pneumonia, Japan is the last part of the world in which efficacy of corticosteroid dosing (including pulse therapy) is assessed in those patients if they wish to continue this trend. PMID- 30479773 TI - Comments on unresponsive decompression illness case. AB - We have read the case report about a decompression sickness that was unresponsive to hyperbaric oxygen treatment in your journal. Presented case is intriguing; however, we think there are some contradictive issues in the discussion of the case. In this letter, we aim to comment on these issues that may raise further question. Bubble formation plays a very important role for decompression sickness, but proposed mechanism is incorrect as nitrogen does not change state during decompression. Use of terminology for diving-related diseases and comments on properties of helium may cause misunderstandings. Also importance of history of the dive in evaluating an accident should be emphasized. PMID- 30479774 TI - A protocol to prospectively assess risk factors for medial tibial stress syndrome in distance runners. AB - Background: Medial tibial stress syndrome (MTSS) is a lower leg injury with a reported incidence rate of up to 35% in active individuals. Although numerous prospective studies have tried to identify risk factors for developing MTSS, managing the syndrome remains difficult. One risk factor yet to be extensively explored in MTSS development is reduced lower leg girth. Further investigation of reduced lower leg girth is required due to the important role lower leg musculature plays in attenuating ground reaction forces during the gait cycle. Therefore, the primary aim of this study is to ascertain whether lower leg muscle morphology and function contribute to the development of MTSS. Our ultimate aim is to identify potential risk factors for MTSS that can be targeted in future studies to better manage the injury or, preferably, prevent individuals developing MTSS. Methods: This study will be prospective in design and will recruit asymptomatic distance runners. All participants will be tested at base line and participants will have their training data longitudinally tracked over the following 12 months to assess any individuals who develop MTSS symptoms. At base line, outcome measures will include bilateral measures of lower limb anthropometry; cross sectional area (CSA) and thickness of the tibialis anterior, peroneals, flexor digitorum longus, flexor hallucis longus and thickness of soleus, medial and lateral head of gastrocnemius. Tibial bone speed of sound, ankle dorsiflexion range of motion, strength of the six previously described muscles, foot alignment and ankle plantar flexor endurance will also be assessed. Participants will also complete a treadmill running protocol where three dimensional kinematics, plantar pressure distribution and electromyography data will be collected. Discussion: This study will aim to identify characteristics of individuals who develop MTSS and, in turn, identify modifiable risk factors that can be targeted to prevent individuals developing this injury. PMID- 30479776 TI - Generic prescription drug price increases: which products will be affected by proposed anti-gouging legislation? AB - Background: In the United States (U.S.), large price increases for selected generic drugs have elicited public outrage. Recent legislative proposals aim to increase price transparency and identify outlier drug "price spikes." It is unknown how many and what types of products would be highlighted by such efforts. Methods: IQVIA Health Incorporated's National Sales PerspectivesTM provided sales, use and price data for all generic prescription products (unique molecule manufacturer-formulation combinations) sold in the U.S. We estimated annual prescription price levels and changes between 2013 and 2014. We identify drugs with annual prescription price increases in excess of the medical consumer price index (CPI), and in excess of 15% or 20%, per legislative proposals. We reported annualized inflation-adjusted mean, standard deviation (SD), median, and 95th percentile prescription price increases and percentage of products exceeding the growth in the medical CPI. We fitted logistic regression models to identify characteristics of drugs associated with each category of price increase. Results: We analyzed data for 6,182 generic products. The mean inflation-adjusted price increase among all generic products was 38% (SD 1,053%), the median, 2%; the 95th percentile, 135%; and the mean price level, $29.69 (SD $378.44). Approximately half of all products experienced price increases in excess of the growth in the medical CPI; 28% had price increases greater than 15% and 23% had price increases greater than 20%. Drugs exceeding outlier thresholds exhibited lower baseline price levels than the mean price level observed among all generic drugs. The most consistent characteristic predicting whether a product would exceed "price spike" thresholds proposed in legislation is the being supplied by only one manufacturer. Conclusions: "Price spikes" among generic drugs in 2014 were more common than newspaper stories and legislative hearings suggest. While the cross-sectional association between an indicator of being sold by only a single manufacturer and the probability of meeting specific price growth thresholds is suggestive of an economically intuitive causal story, future work should delve more deeply into whether decreases in generic competition explain the dramatic price increases that have captured the public's attention in recent years. PMID- 30479777 TI - Ovarian cancer in a former asbestos textile factory worker: a case report. AB - Background: The International Agency for Research on Cancer (IARC) defined that asbestos is a group 1 substance that causes lung cancer, mesothelioma (pleura and peritoneum), laryngeal cancer, and ovarian cancer in humans. Many studies on lung cancer, and mesothelioma caused by asbestos exposure have been conducted, but there was no case report of ovarian cancer due to asbestos exposure in Korea. We describe a case of ovarian cancer caused by asbestos exposure in a worker who worked at an asbestos textile factory for 3 years and 7 months in the late 1970s. Case presentation: A 57-year-old woman visited the hospital because she had difficulty urinating. Ovarian cancer was suspected in radiologic examination, and exploratory laparotomy was performed. She was diagnosed with epithelial ovarian cancer. The patient did not undergo postoperative chemotherapy and recovered. She joined the asbestos factory in March 1976 and engaged in asbestos textile twisting and spinning for 1 year, 2 years and 7 months respectively. In addition, she lived near the asbestos factory for more than 20 years. There was no other specificity or family history. Conclusion: Considering the patient's occupational and environmental history, it is estimated that she had been exposed to asbestos significantly, so we determined that ovarian cancer in the patient is highly correlated with the occupational exposure of asbestos and environmental exposure is a possible cause as well. Social devices are needed to prevent further exposure to asbestos. It is also necessary to recognize that ovarian cancer can occur in workers who have previously been exposed to asbestos, and the education and social compensation for those workers are needed. PMID- 30479778 TI - Changes of hemodynamic and cerebral oxygenation after exercise in normobaric and hypobaric hypoxia: associations with acute mountain sickness. AB - Objective: Normobaric (NH) and hypobaric hypoxia (HH) are associated with acute mountain sickness (AMS) and cognitive dysfunction. Only few variables, like heart rate-variability, are correlated with AMS. However, prediction of AMS remains difficult. We therefore designed an expedition-study with healthy volunteers in NH/HH to investigate additional non-invasive hemodynamic variables associated with AMS. Methods: Eleven healthy subjects were examined in NH (FiO2 13.1%; equivalent of 3.883 m a.s.l; duration 4 h) and HH (3.883 m a.s.l.; duration 24 h) before and after an exercise of 120 min. Changes in parameters of electrical cardiometry (cardiac index (CI), left-ventricular ejection time (LVET), stroke volume (SV), index of contractility (ICON)), near-infrared spectroscopy (cerebral oxygenation, rScO2), Lake-Louise-Score (LLS) and cognitive function tests were assessed. One-Way-ANOVA, Wilcoxon matched-pairs test, Spearman's-correlation analysis and Student's t-test were performed. Results: HH increased heart rate (HR), mean arterial pressure (MAP) and CI and decreased LVET, SV and ICON, whereas NH increased HR and decreased LVET. In both NH and HH cerebral oxygenation decreased and LLS increased significantly. After 24 h in HH, 6 of 11 subjects (54.6%) developed AMS. LLS remained increased until 24 h in HH, whereas cognitive function remained unaltered. In HH, HR and LLS were inversely correlated (r = - 0.692; p < 0.05). More importantly, the rScO2-decrease after exercise in NH significantly correlated with LLS after 24 h in HH (r = - 0.971; p < 0.01) and rScO2 correlated significantly with HR (r = 0.802; p < 0.01), CI (r = 0.682; p < 0.05) and SV (r = 0.709; p < 0.05) after exercise in HH. Conclusions: Both acute NH and HH altered hemodynamic and cerebral oxygenation and induced AMS. Subjects, who adapted their CI had higher rScO2 and lower LLS. Furthermore, rScO2 after exercise under normobaric conditions was associated with AMS at high altitudes. PMID- 30479775 TI - Exercise as 'precision medicine' for insulin resistance and its progression to type 2 diabetes: a research review. AB - Type 2 diabetes and obesity epidemics are in effect in the United States and the two pathologies are linked. In accordance with the growing appreciation that 'exercise is medicine,' it is intuitive to suggest that exercise can play an important role in the prevention and/or treatment of these conditions. However, if exercise is to truly be considered as a viable alternative to conventional healthcare prevention/treatment strategies involving pharmaceuticals, it must be prescribed with similar scrutiny. Indeed, it seems reasonable to posit that the recent initiative calling for 'precision medicine' in the US standard healthcare system should also be applied in the exercise setting. In this narrative review, we consider a number of explanations that have been forwarded regarding the pathological progression to type 2 diabetes both with and without the concurrent influence of overweight/obesity. Our goal is to provide insight regarding exercise strategies that might be useful as 'precision medicine' to prevent/treat this disease. Although the etiology of type 2 diabetes is complex and cause/consequence characteristics of associated dysfunctions have been debated, it is well established that impaired insulin action plays a critical early role. Consequently, an exercise strategy to prevent/treat this disease should be geared toward improving insulin sensitivity both from an acute and chronic standpoint. However, research suggests that a chronic improvement in insulin sensitivity only manifests when weight loss accompanies an exercise intervention. This has resonance because ectopic fat accumulation appears to represent a central component of disease progression regardless of whether obesity is also part of the equation. The cause/consequence characteristics of the relationship between insulin resistance, pathological fat deposition and/or mobilsation, elevated and/or poorly-distributed lipid within myocytes and an impaired capacity to use lipid as fuel remains to be clarified as does the role of muscle mitochondria in the metabolic decline. Until these issues are resolved, a multidimensional exercise strategy (e.g., aerobic exercise at a range of intensities and resistance training for muscular hypertrophy) could provide the best alternative for prevention/treatment. PMID- 30479780 TI - Schistosomiasis in a Scottish school group after freshwater swimming in Uganda: the need to raise awareness. AB - Introduction: Schistosomiasis, a travel-related trematode infection, can cause a range of symptoms with potentially life-threatening complications. In this report, we describe an outbreak of schistosomiasis in a Scottish school group that had travelled to Uganda. We discuss the requirement for robust and accurate pre-travel advice, and the importance of raising awareness in travellers, particularly due to the asymptomatic nature of the disease. In addition, we highlight the need to submit a serum sample for laboratory testing on return from endemic regions where freshwater exposure has occurred. Case presentation: A Scottish school group consisting of 19 individuals visited Uganda during July 2016 with one positive symptomatic case identified on return to the UK. As three of the individuals were not Scottish residents, their data were excluded from this report. Freshwater exposure was noted from taking part in activities which included swimming in the Nile. The Scottish Parasite Diagnostic and Reference Laboratory performed serology testing using sera from 16 Scottish residents to detect IgG towards Schistosoma egg antigens. Thirteen were positive despite only one case being symptomatic. Conclusion: The high positivity rate raised several issues. These included the lack of a robust risk assessment by the travel company organizing the trip, the lack of awareness of schistosomiasis by some individuals, the lack of appropriate and accurate pre-travel advice, and the asymptomatic nature of the infection. This report provides supportive evidence to strengthen the need for improvements to prevent largely asymptomatic cases being missed in future. PMID- 30479779 TI - The chromosome-level quality genome provides insights into the evolution of the biosynthesis genes for aroma compounds of Osmanthus fragrans. AB - Sweet osmanthus (Osmanthus fragrans) is a very popular ornamental tree species throughout Southeast Asia and USA particularly for its extremely fragrant aroma. We constructed a chromosome-level reference genome of O. fragrans to assist in studies of the evolution, genetic diversity, and molecular mechanism of aroma development. A total of over 118 Gb of polished reads was produced from HiSeq (45.1 Gb) and PacBio Sequel (73.35 Gb), giving 100* depth coverage for long reads. The combination of Illumina-short reads, PacBio-long reads, and Hi-C data produced the final chromosome quality genome of O. fragrans with a genome size of 727 Mb and a heterozygosity of 1.45 %. The genome was annotated using de novo and homology comparison and further refined with transcriptome data. The genome of O. fragrans was predicted to have 45,542 genes, of which 95.68 % were functionally annotated. Genome annotation found 49.35 % as the repetitive sequences, with long terminal repeats (LTR) being the richest (28.94 %). Genome evolution analysis indicated the evidence of whole-genome duplication 15 million years ago, which contributed to the current content of 45,242 genes. Metabolic analysis revealed that linalool, a monoterpene is the main aroma compound. Based on the genome and transcriptome, we further demonstrated the direct connection between terpene synthases (TPSs) and the rich aromatic molecules in O. fragrans. We identified three new flower-specific TPS genes, of which the expression coincided with the production of linalool. Our results suggest that the high number of TPS genes and the flower tissue- and stage-specific TPS genes expressions might drive the strong unique aroma production of O. fragrans. PMID- 30479781 TI - Two male siblings with a novel LRBA mutation presenting with different findings of IPEX syndrome. AB - Introduction: LPS-responsive beige-like anchor (LRBA) protein deficiency is a disease of immune dysregulation with autoimmunity affecting various systems. Case Presentation: Two male siblings with a novel LRBA mutation had different primary findings at admission: the younger sibling had chronic early-onset diarrhoea and the elder one had autoimmune haemolytic anaemia. During long-term follow-up for IPEX phenotype, both developed hypogammaglobulinaemia, enteropathy and lung involvement. The patients partially responded to immunosuppressive therapies. A homozygous c.2496C>A, p.Cys832Ter (p.C832*) mutation in the LRBA gene causing a premature stop codon was detected. After molecular diagnosis, abatacept, as a target-specific molecule, was used with promising results. Conclusion: LRBA deficiency is a recently defined defect, with variable presentations in different patients; a single, definitive treatment option is thus not yet available. PMID- 30479782 TI - Case report: A fatal case of cryptococcosis in an immunocompetent patient due to Cryptococcus deuterogattii (AFLP6/VGII). AB - Introduction: Cryptococcosis in immunocompetent adults is a rare disease in Europe, mostly induced by members of the Cryptococcus gattii species complex. The diagnosis can be challenging due to its rarity, unspecific symptoms and long symptomless latency. Case presentation: A 49-year-old woman with a three weeks history of headache was admitted to the hospital due to discrete ataxia and impaired vision. Cranial magnetic resonance imaging (MRI) showed a contrast enhancing mass in the cerebellum. Further investigations detected a slight leukocytosis and a single subpleural nodule in the right inferior lung lobe. The cerebral lesion was surgically removed, and a direct frozen section only showed an unspecific inflammation. In the course of her admission she developed non treatable cerebral edema and died ten days after surgical intervention. Histopathological examination of the surgical specimen and postmortem evaluation of the lung and the cerebrum demonstrated fungal elements. Molecular identification of the fungal elements in formalin-fixed paraffin-embedded tissue lead to the diagnosis of cryptococcosis induced by C. gattii sensu lato. Molecular genetic analysis identified the involved cryptococcal species as genotype AFLP6/VGII, recently described as Cryptococcus deuterogattii, which is known to be endemic to the west-coast of Canada and the USA. Additional heteroanamnestic information revealed that she had spent her holidays on Vancouver Island, Canada, two years before disease onset, indicating that infection during this stay seems to be plausible. Conclusion: Cryptococcosis due to C. deuterogattii is a rarely encountered fungal disease in Europe, not particularly associated with immunodeficiency, and infection is likely to be contracted in endemic areas. Due to its rarity, long symptomless latency, unspecific symptoms and misleading radiological features the diagnosis can be challenging. Physicians need to be aware of this differential diagnosis in immunocompetent patients, as early adequate therapy can be lifesaving. PMID- 30479783 TI - Transcranial magnetic stimulation for diplopia in a patient with spinocerebellar ataxia type 6: a case report. AB - Background: In Patients with spinocerebellar ataxia type 6 (SCA6) are often treated by transcranial magnetic stimulation (TMS) over the motor cortex and cerebellum. However, few reports have examined effective therapeutic modalities for diplopia in SCA6 patients. In the current case, we applied single-pulse TMS over the motor cortex and cerebellum to improve ataxia, and observed an unexpected improvement of diplopia. Case presentation: A 62-year-old Japanese male with spinocerebellar ataxia type 6 (SCA6) was admitted to our hospital for exacerbation of ataxia. We administered single-pulse transcranial magnetic stimulation (TMS) over the hand motor area and the cerebellum with a circular coil to reduce ataxia. After the initiation of TMS, since diplopia unexpectedly improved, we started a quantitative assessment of diplopia by counting the number of fixation spots that he observed in his visual field. This assessment suggested that TMS had an immediate and cumulative effect on diplopia. We also delivered more localized stimulation only over the motor cortex with a Figure-8 coil, and diplopia improved immediately. Additionally, we administered a sham stimulation before the real stimulation over the motor cortex and the cerebellum. The sham stimulation improved diplopia, and greater improvement was observed with subsequent real stimulation. We also used a Hess chart examination and video recordings of binocular gross appearance to elucidate the changes in ocular movement objectively. However, these examinations did not reveal any obvious oculomotor changes. Conclusions: We applied single-pulse TMS to a SCA6 patient with diplopia, which improved without any adverse effects. TMS may have potential for the treatment of diplopia in SCA6 patients. PMID- 30479784 TI - The Role of Self-Transcendence and Cognitive Processes in the Response Expectancy Effect. AB - Neuropsychological assessment is known to be influenced by expectancy effects, which can either enhance (placebo) or diminish (nocebo) cognitive performance. Research suggests that the response expectancy effect is influenced by various individual and situational factors and that the placebo effect results in an increase in monitoring processes as measured indirectly. However, the impact on monitoring processes has not yet been studied by direct measures such as Judgement Of Learning (JOL). This study aimed to investigate the response expectancy effect on various neuropsychological tasks, including a task that directly assesses monitoring capacities (JOL). In addition to determining which cognitive functions are influenced by the expectancy effect, this study examined the moderating role of the self-transcendence dimension of personality. Eighty healthy subjects were exposed to three bogus conditions presented as allegedly having a positive, negative, or no impact on cognitive capacities. Then they completed, in random order, three blocks of tasks (executive, attentional, and memory), one in each condition. Results showed an effect of negative instructions on flexibility (poorer performance) and memory (better performance) scores. Furthermore, positive instructions led to better explicit monitoring capacities (JOL) than the neutral condition. These effects were moderated by self transcendence, as only participants with moderate or high self-transcendence exhibited these effects. Overall, our results showed that the response expectancy effect emerges from a combination of individual and cognitive factors. PMID- 30479785 TI - A Factorial Validation of Parental Mediation Strategies with Regard to Internet Use. AB - This study investigated the strategies which parents employ in order to mediate their adolescent child's internet use, thereby including the perspectives from the mother, the father and an adolescent child aged 13 to 18. Data from 357 families (n = 1071) were analyzed. Parental mediation strategies were inductively derived from a wide range of concrete mediation practices. Factor analysis yielded the same six factor solution for each informant, resulting in the identification of six distinct parental mediation strategies. Differences occurred between the three informants in terms of the quantity of mediation taking place. Parental mediation was predicted by the child's age, but less by the parents' age and the child's gender. PMID- 30479786 TI - Factor Structure of the Affective Style Questionnaire in Flemish Adolescents. AB - Emotion regulation plays an important role in both healthy and problematic adolescent psychological functioning. Emotion regulation tendencies can be assessed with the Affective Style Questionnaire (ASQ; Hofmann & Kashdan, 2010), but its validity in Dutch speaking adolescents has not been investigated so far. Two methods, namely traditional confirmatory factor analysis (CFA) and the recently developed exploratory structural equations modeling (ESEM), were compared to examine the dimensional structure of the ASQ in a Flemish adolescent sample (N = 1,601). Although, as expected, the ESEM-model fit the data better than the CFA-model, the fit indices indicated that both models did not have an acceptable fit. With a shortened version of the ASQ, model fit improved substantially, but only the ESEM solution provided a good fit. The ESEM results support the use of the adapted ASQ to effectively assess the affective styles of concealing, adjusting and tolerating in Dutch-speaking adolescents. PMID- 30479787 TI - Perpetrator as a Potential Victim. Does Threatened Retaliation from the Victim Reduce Obedience towards Authority? AB - In an experiment conducted within the Milgram paradigm, it was examined whether obedience towards an authority would be reduced in conditions in which the teacher had grounds to fear revenge from the learner. A comparison was made of the behaviour of participants in classic conditions and in conditions in which they were told that following the first part of the experiment, there would be an alteration of roles: the teacher would become the learner. It turned out that the level of compliance was the same in both groups. The dominant behaviour, regardless of whether the participant expects a change of roles or not, is total obedience. PMID- 30479788 TI - Implicit Belittlements Call for Implicit Measures: Emotional Reactions to Youth Paternalistic Stereotypes. AB - Age discrimination at work can potentially affect every worker. Indeed, like 'old' workers, young ones hired in their first job elicit the idea that they have quite interesting social abilities but lack of competence, which constitutes a case of paternalistic stereotypes (Fiske, Cuddy, Glick, & Xu, 2002). Generally, the negative (incompetence) facet of such stereotypes is not blatantly expressed, but is subtly conveyed behind an apparently positive discourse. Consequently, it is considered as being generally under-detected, while harmful. In this paper, we examine whether paternalistic stereotyping's under-detection is real or if it is due to the use of inadequate measures. Based on a study showing that targets feel that something is wrong (Dardenne, Dumont, & Bollier 2007), we rely on affective measures to investigate whether the detection of the subtly conveyed negative facet of paternalistic stereotypes calls for subtle, implicit measures. In Study 1, explicit self-reports of targets' affective states after a meeting with a paternalistic boss revealed mainly positive affect. In Study 2, an implicit emotional measure however revealed the presence of a negative affective state. The last Study, using a more ecological affective measure, demonstrates that paternalistic stereotypes trigger an ambivalent affective reaction. Altogether, the three studies suggest that the negative facet of paternalistic stereotypes is not as under-detected as we thought. PMID- 30479789 TI - The Effect of Central Executive Load on Fourth and Sixth Graders' Use of Arithmetic Strategies. AB - In the present study, we set out to investigate whether and how central executive load constrains the strategies that children use during arithmetic processing. Using a dual-task paradigm accompanied by the choice/no-choice method, we tested 233 children (115 6th graders, 118 4th graders). Results showed that the impact of central executive load on reaction times and accuracy scores related to strategy use increased with the magnitude of the demands of the central executive, with central executive load playing an important role in strategy use. Sixth graders performed better than 4th graders in the application of appropriate strategies. Children's adaptability with respect to strategy choice was affected by the type and magnitude of the central executive load; children showed better adaptability under the no-load condition and the inconsistent/low load condition than under conditions with greater load. Grade level affected children's adaptability with respect to strategy choice, with 6th graders exhibiting significantly better performance than 4th graders. These results confirm that the development of central executive skills contributes to children's overall strategy use and adaptability. These findings have important implications for understanding the category specificity of central executive working memory in arithmetic cognition and the mechanisms of strategy development in childhood. PMID- 30479790 TI - Insights into the Belgian Linguistic Conflict from a (Social) Psychological Perspective: Introduction to the Special Issue. PMID- 30479791 TI - Principled Disagreements: Adhesion to Intergroup Justice Standards in the Context of the Belgian Linguistic Conflict. AB - According to the "Waffle" model of the Belgian Linguistic Conflict (Klein et al., 2012), this conflict centres around two main dimensions: One concerns the use of language across the territory and the second concerns the distribution of resources between the two main linguistic communities, Dutch-speakers and French speakers. The model suggests that the two groups adhere to different justice principles regarding these issues and that these disagreements are a function of the intensity of the conflict. With respect to the first dimension, Dutch speakers are expected to adhere more to a principle of linguistic territoriality than French-speakers who should be more in favor of a free choice of one's idiom across the territory. With respect to the second dimension, the model posits that Dutch-speakers will adhere more to an equity principle whereas French-speakers should adhere more to a need principle. We tested these hypotheses in the context of a large-scale survey involving two waves: in May 2011 in the middle of a political crisis, and in June 2014, when the conflict was appeased. The pattern of "disagreements" in a subsample that participated in both waves of the survey (N = 378) is consistent with the Waffle model and, as expected, more severe at the heart of the conflict (in 2011) than after pacification (in 2014). However, differences were driven mostly by supporters of the Flemish nationalist party N VA. Moreover, endorsement of principles on both dimensions are predictive of separatist attitudes in the Dutch-speaking sample whereas only the first dimension plays a role for the French speaking sample. PMID- 30479792 TI - Attitudes Towards World War II Collaboration in Belgium: Effects on Political Positioning Towards the Amnesty Issue in the Two Main Linguistic Communities. AB - It is a known fact that some Belgians collaborated with the Nazi occupier during WWII. However, according to a popular myth, collaboration was widespread in Flanders, whereas Walloons bravely resisted. Of course, historical reality is much more nuanced, but this oversimplification has largely resurfaced in political debates surrounding the Belgian linguistic conflict. Demands for amnesty for former collaborators addressed by Flemish nationalist parties are a case in point. We conducted two studies in order to investigate Belgians' attitudes towards this political issue in the two linguistic communities. In 2012, a first survey (N = 521; 315 French-speakers (FS) and 206 Dutch-speakers (DS)) showed that WWII collaboration was morally condemned, and attitudes towards amnesty were predominantly negative, in both groups. However, DS tended to support amnesty more than FS. This effect of Linguistic Group on Support for Amnesty was mediated by Judgments of Morality of collaboration, and this mediation was moderated by Linguistic identification. In 2015, a second survey (N = 774; 476 FS and 298 DS) confirmed these results. Moreover, judgments about the Unfairness of the repression of collaboration also mediated the effect of Linguistic Group on Support for Amnesty. These results suggest that differences in political position-taking regarding the granting of amnesty between DS and FS are, at least partly, due to different attitudes towards collaboration and to the membership to a linguistic community. PMID- 30479793 TI - The Structure of Prejudice and Its Relation to Party Preferences in Belgium: Flanders and Wallonia Compared. AB - We test two assumptions of the generalized prejudice literature. First, that the structure of generalized prejudice (i.e. how prejudices are interrelated) is dependent on the intergroup context. Second, that different types of prejudice have similar political consequences and run via the generalized prejudice component. We perform these tests in the two main regions of Belgium - Flanders and Wallonia - and investigate the influence of differences in the history of immigration, experience of the linguistic and autonomy conflict, and the separate party system and political discourse (i.e. the societal and intergroup context) on these premises. We make use of the Belgian Election Panel (BEP) data that included measures of prejudice toward multiple target groups (immigrants, Flemings, Walloons, homosexuals, and Jews) and voting propensities for the main political parties. Our results show that, regardless of the differences in intergroup experiences, the structure of prejudice is identical in Flanders and Wallonia. Flemings are, however, more tolerant toward homosexuals and immigrants than Walloons. The political context and the set of potential political outlets does play an important moderating role in the translation of prejudices to party preferences: While negative attitudes toward the other regional group seem to divide the electorate in Flanders, it does not affect voting intentions in Wallonia. Anti-immigrant prejudice is crucial in both regions, but affects voters in different ways at the right-side of the political spectrum. PMID- 30479794 TI - Walloons as General or Specific Others? A Comparison of anti-Walloon and anti immigrant Attitudes in Flanders. AB - This study attempts to shed light on the structure, the prevalence and the determinants of anti-Walloon attitudes in Flanders. For this purpose, we contrast anti-Walloon prejudice with prejudice against a relatively well-understood and archetypical out-group, namely immigrants. Our theoretical approach draws on insights from two paradigms of intergroup relations: the Group-Focused Enmity approach stressing that specific prejudices have a strong common denominator, and the Differentiated Threat model arguing that specific prejudices are contingent on the context of intergroup relations as well as the involved types of threat. To assess the (dis)similarities in anti-Walloon and anti-immigrant prejudice, we use the Flemish dataset of the Belgian National Election Study (BNES) 2010. Comparable measurement instruments for both forms of prejudice are analyzed by means of structural equation modeling. Our results reveal a nuanced picture regarding the similarities and differences between anti-Walloon and anti immigrant attitudes in Flanders. One the one hand, anti-Walloon and anti immigration attitudes are strongly correlated and rooted in economic threat perceptions. On the other hand, anti-Walloon attitudes are less outspoken in the Flemish population than anti-immigrant attitudes, are less founded on cultural threat perceptions and are more closely linked to feelings of identification with the Flemish in-group. PMID- 30479795 TI - Collective Victimhood and Ingroup Identity Jointly Shape Intergroup Relations, Even in a Non-violent Conflict: The Case of the Belgians. AB - Collective victimhood is the belief that one's own group has been intentionally and undeservingly harmed by another group (Bar-Tal, Chernyak-Hai, Schori, & Gundar, 2009). While previous research has established the link between collective victimhood and negative intergroup behaviors, the underlying mechanism is virtually unexplored. In the current study, we test the idea that intergroup emotions play an important role, particularly for those group members who are highly identified. Whereas previous research has primarily studied collective victimhood in violent contexts, the current study focuses on its role in the intergroup relations in Belgium, known as a non-violent conflict between French and Dutch speakers. The associations between collective victimhood, intergroup emotions, and action tendencies were studied in an online survey. The sample consisted of both French-speaking and Dutch-speaking Belgians (Ntotal = 1774). Structural equation modeling showed that collective victimhood was negatively related to intergroup affiliative emotions (i.e., sympathy) and positively to intergroup distancing emotions (i.e., anger). In addition, these relationships were stronger for participants who strongly identified with their ingroup. Furthermore, intergroup affiliative emotions positively predicted fostering contact with outgroup members, and negatively predicted the tendencies to exclude and take revenge on the outgroup; intergroup distancing emotions positively predicted outgroup exclusion and revenge, and negatively predicted fostering contact with them. The established associations were no different between the linguistic groups. Our results confirm that collective victimhood, and the emotions associated, can help to understand intergroup conflict in non-violent contexts, in addition to violent ones. PMID- 30479796 TI - An Insiders' Outside Perspective on the Flemish-Walloon Conflict: The Role of Identification and Disidentification for the German-Speaking Minority. AB - In this study we analyzed the opinions of citizens of the German-speaking minority in Belgium on the linguistic conflict between the Walloons and the Flemish, as well as their attitudes towards these linguistic communities. We were especially interested in the effects of identification with the local community and disidentification with Belgium. We distributed a survey questionnaire in Eupen, the capital of the German-speaking community, and received replies from 129 inhabitants. Results showed that identification with the German-speaking community was associated with positive attitudes towards the German-speaking community and with demands for more autonomy of the community within the federal Belgian state. Disidentification with Belgium was not positively correlated with these constructive and positive outcomes, but with negative perceptions of all three Belgian communities, the perception of strong conflicts among these communities, and demands for the separation of the Belgian federal state into independent regions. The results are in line with previous research on these processes and point to unique, positive aspects of a strong local identity. PMID- 30479797 TI - Intergroup Reconciliation between Flemings and Walloons: The Predictive Value of Cognitive Style, Authoritarian Ideology, and Intergroup Emotions. AB - Testifying to the gap in fundamental research on positive intergroup outcomes, we investigated reconciliation attitudes in a non-violent intergroup context (i.e., the linguistic conflict in Belgium). By incorporating both important predictors of negative outgroup attitudes (i.e., individual differences in rigid cognitive styles and authoritarian ideologies), and important predictors of reconciliation (i.e., intergroup emotions), we aimed to contribute to a more comprehensive theoretical framework for the analysis of intergroup relations. We recruited one Flemish (N = 310) and one Walloon (N = 365) undergraduate students sample to test the proposed model. Structural equation analyses with maximum likelihood estimation were conducted using the Lavaan package. In both samples, similar patterns were found. More in particular, the need for cognitive closure appeared to be the basic predictor of right-wing attitudes (i.e., right-wing authoritarianism and social dominance orientation) and essentialist thinking, which were then associated with less outgroup empathy and trust, and more outgroup anger. Furthermore, outgroup trust and empathy were positively related to reconciliation. Interestingly, some differences between the Flemish and Walloon sample were found, such as the direct effects of need for closure and social dominance orientation in the first sample, and the non-significant effects of essentialism in the latter sample. Considering the ongoing public and political debate about the linguistic conflict in Belgium, these findings shed a new light on how individual differences relate to specific outgroup emotions, and how these are associated with important intergroup outcomes in the face of intergroup conflict. PMID- 30479799 TI - Body Dissatisfaction Revisited: On the Importance of Implicit Beliefs about Actual and Ideal Body Image. AB - Body dissatisfaction (i.e., a negative attitude towards one's own physical appearance) is assumed to originate from a perceived discrepancy between the actual physical appearance (i.e., actual body image) and the desired ideal state of the body (i.e., ideal body image). We assessed implicit beliefs about these two aspects of the body image independently using two Relational Responding Tasks (RRT) in a sample of participants who were either low or high in explicitly reported body dissatisfaction. As hypothesized, differences in body dissatisfaction exerted a differential influence on the two RRT scores. The implicit belief that one is thin was less pronounced in participants who were strongly dissatisfied with their body relative to participants who were more satisfied with their body. The implicit desire to be thin (i.e., thin ideal body image), in contrast, tended to be more pronounced in participants who exhibited a high degree of body dissatisfaction as compared to participants who exhibited a low degree of body dissatisfaction. Hierarchical regression analyses also revealed that the RRT scores were predictive of self-reported body dissatisfaction, even over and above the predictive validity of some (but not all) explicit predictors of body dissatisfaction that were included in the present study. More generally, these findings contribute to the empirical validation of the RRT as a measure of implicit beliefs in the context of body dissatisfaction. PMID- 30479800 TI - Job Insecurity and Innovative Work Behaviour: A Psychological Contract Perspective. AB - Innovation is considered to be of crucial importance for organisational survival and growth, and in this respect employees play a leading role, as they are the ones who develop innovative ideas. At the same time, the struggle for organisational survival and growth gives rise to perceptions of job insecurity. To date, few studies have explored how employees' innovative work behaviour (IWB) is influenced by the perceived threat of job loss (i.e. job insecurity). As both job insecurity and IWB are increasingly salient in light of organisational change and competition, the present study examines the relationship between job insecurity and IWB, as well as the role of psychological contract breach in explaining this relationship. We hypothesized a negative relation between job insecurity and innovative work behaviour, with psychological contract breach as a mediator in this relationship. Participants were 190 employees from an industrial organisation that had faced restructuring and downsizing for several years. Contrary to our predictions, no direct association was found between job insecurity and the two sub-dimensions of innovative work behaviour (i.e., idea generation and idea implementation). Indirect relationships, however, were found between job insecurity and the two types of IWB through psychological contract breach. Surprisingly, psychological contract breach was positively related to idea generation and idea implementation. These findings shed new light on the relationship between job insecurity and IWB. PMID- 30479801 TI - Self-Compassion Scale: IRT Psychometric Analysis, Validation, and Factor Structure - Slovak Translation. AB - The present study verifies the psychometric properties of the Slovak version of the Self-Compassion Scale through item response theory, factor-analysis, validity analyses and norm development. The surveyed sample consisted of 1,181 participants (34% men and 66% women) with a mean age of 30.30 years (SD = 12.40). Two general factors (Self-compassionate responding and Self-uncompassionate responding) were identified, whereas there was no support for a single general factor of the scale and six subscales. The results of the factor analysis were supported by an independent sample of 676 participants. Therefore, the use of total score for the whole scale would be inappropriate. In Slovak language the Self-Compassion Scale should be used in the form of two general subscales (Self compassionate responding and Self-uncompassionate responding). In line with our theoretical assumptions, we obtained relatively high Spearman's correlation coefficients between the Self-Compassion Scale and related external variables, demonstrating construct validity for the scale. To sum up, the Slovak translation of The Self-Compassion Scale is a reliable and valid instrument that measures Self-compassionate responding and Self-uncompassionate responding. PMID- 30479802 TI - Correction: Identity Statuses Throughout Adolescence and Emerging Adulthood: A Large-scale Study into Gender, Age, and Contextual Differences. AB - [This corrects the article on p. 32 in vol. 57.]. PMID- 30479803 TI - Association between Non-Suicidal Self-Injury, Parents and Peers Related Loneliness, and Attitude Towards Aloneness in Flemish Adolescents: An Empirical Note. AB - Loneliness and attitude towards aloneness have been shown to be associated to depression, anxiety, and other psychiatric disorders in adolescents and they may also increase the vulnerability to Non-Suicidal Self-Injury (NSSI). Therefore, the present study investigated the association between lifetime prevalence and functions of NSSI, parent- and peer-related loneliness, and attitude towards aloneness (positive and negative). Data regarding NSSI, loneliness, and attitude towards aloneness were collected from a sample of 401 high school students from three different high schools located in the Dutch-speaking part of Belgium. Lifetime prevalence of NSSI was found to be 16.5%. Females reported a higher lifetime prevalence of NSSI than males. Higher mean scores for parent-, peer related loneliness, and positive attitude (i.e., affinity) towards aloneness was observed in adolescents with lifetime NSSI as compared to adolescents without a history of NSSI. Finally, a positive correlation between self-related (i.e., automatic) functions of NSSI and parent- and peer-related loneliness and a positive attitude towards aloneness was also observed. PMID- 30479804 TI - Can Cancellara Really be a Flandrien? Ethno-Cultural Identity Representation Predicts Regional Exclusivity of a Historically Contested Cycling Term. AB - In Flanders the term flandrien refers to cyclists who display a strong work ethic, great perseverance, are powerful and who perform best in adverse weather conditions. Until the 1960s, only leading cyclists originating from the province of West- and East-Flanders were considered as flandriens. After 1960, the media extended the use of this term to Belgian cyclists in general and even to international cyclists. The present study examined whether Flemish citizens agree with this generalization considering that the term flandrien still plays a highly symbolical role in the public discourse on Flemish identity. First, the main aim was to investigate whether having an ethno-cultural identity representation of the Flemish identity is positively related to perceived regional exclusivity of the term flandrien. Second, this study explored whether Flemish identification moderates this relation (i.e. this relation is only expected for high identifiers) and also predicts Flemings' regional exclusivity of the term. Results revealed that the more Flemings endorse an ethno-cultural identity representation the more they consider a flandrien as an exclusively Flemish cyclist, and the less they will include international cyclists in their consideration of a flandrien. Flemish identification did not moderate this relation but did predict the consideration of a flandrien as a Flemish cyclist. These findings indicate that the current interpretation of the historical cycling term flandrien is influenced by cultural conceptualizations of Flemish identity. PMID- 30479805 TI - Letter from the New Editor. PMID- 30479806 TI - Validation of the Young Schema Questionnaire-Short Form in a Flemish Community Sample. AB - The Young Schema Questionnaire (YSQ, Young, 1994) was developed to assess Early Maladaptive Schemas (EMS), which account for the dysfunctional beliefs in individuals with personality disorders or maladaptive personality traits. This study aims to investigate the factor structure, the reliability and the validity of the original YSQ - Short Form (Young & Brown, 1998; YSQ-SF, 15 EMS) as well as an extension including 16 EMS, based on the 16 factor structure of the YSQL2 (Young & Brown, 1998) in a community sample. The sample consisted of 672 participants (51% females; M age-total = 44.34; SD age-total = 16.24). Results show evidence for both the 15 and 16 factor solution of the YSQ-SF with good internal consistency coefficients for the different scales. Significant gender differences were observed for Self-Sacrifice (females higher) and Entitlement (men higher), along with different patterns of correlations between age and Insufficient Self-Control (r = -.19), Enmeshment (r = -0.16) and Self-Sacrifice (r = .13). Furthermore, Big Five personality traits were significantly associated with several schema scales. In sum, we can conclude that both the YSQ-SF15 and 16 are valid instruments to assess EMS among a Flemish community sample. However, given the unique additive value of the 16th EMS (Social Undesirability) in predicting lower scores on Extraversion and Openness, the use of the YSQ-SF16 could be favored. PMID- 30479807 TI - The Influence of Grit on Life Satisfaction: Self-Esteem as a Mediator. AB - Improving people's life satisfaction has become an important goal for many individuals and societies. In this study we investigate how grit influences life satisfaction. We propose that individuals' self-esteem mediates the relationship between grit and life satisfaction. Study 1, with a sample of 243 employees enrolled in a business training course, found that an individual's grit was positively related to life satisfaction and that self-esteem fully mediated this relationship. In Study 2, with 218 full-time employees, self-efficacy, self control, and self-consciousness were included as mediators, but they did not exceed the power of self-esteem in explaining the relationship between grit and life satisfaction. Implications, limitations and future research directions are discussed. PMID- 30479808 TI - The Delicate Balance to Adjustment: A Qualitative Approach of Student's Transition to the First Year at University. AB - First year experience in higher education has been extensively investigated in the literature. Yet, two limitations can be identified out of the literature. The majority of the studies focused on single factor analysis, restraining the multifactorial understanding of adjustment's determinants. Moreover, the temporal unfolding of the first year at the university has mainly been disregarded, limiting the dynamic framing of adjustment process. To overcome these limitations, the current study used a longitudinal qualitative design in order to grasp the dynamic complexity of adjustment process. Semi-structured interviews were conducted in two steps with 17 freshmen from Science department. The aims were to unfold the constructs at play in student's adjustment process and the dynamic interplay between them over time. The analyses were grounded into Nicholson's theoretical framework of transition cycle and the material was analyzed through thematic and sequential analysis. Four themes (readiness, reaching personal drives, fighting an overwhelming program and becoming a self regulated learner) and four different events (starting up, click, exhaustion and deficiencies accumulation) were identified in the material disclosing the dynamic nature of adjustment process. An overall reflection on the findings is proposed in the conclusion. PMID- 30479809 TI - Subjective Memory Complaints in Portuguese Young Adults: Contributions from the Adaptation of the Prospective and Retrospective Memory Questionnaire. AB - Self-report instruments that allow to characterize the frequency of daily memory failures are essential for a comprehensive assessment of memory functioning. In this context, we aimed to provide preliminary evidence of validity and reliability for the European Portuguese adaptation of the Prospective and Retrospective Memory Questionnaire (PRMQ). A total of 1052 healthy participants completed an online survey with the PRMQ. The exploration of the construct validity suggested the tripartite model with a general memory, a prospective memory, and a retrospective memory factors to have the best adjustment to the data. Measurement invariance across age and sex groups was also verified. The questionnaire revealed good convergent validity with a general self-report measure of memory (0.778 < r < 0.853), and satisfactory values of internal consistency (0.779 < Cronbach's alpha < 0.887) and of test-retest reliability (0.815 < r < 0.852). There were no prominent effects of sex and age in the PRMQ scores. Although the sample encompassed mainly younger and highly educated adults, this study presented the first evidence of validity and reliability for the European Portuguese version of the questionnaire. PMID- 30479810 TI - How does Conditional Regard Impact Well-being and Eagerness to Learn? An Experimental Study. AB - Conditional regard refers to regard dependent upon the receiver's fulfillment of certain expectations. Using an experimental design, we examined the effect of conditional negative and positive regard on well-being and eagerness to learn in university freshmen (N = 131). Participants experienced either failure or success followed by conditional vs. unconditional regard. As expected, success and failure had opposite effects on well-being and eagerness to learn. More importantly, there was an increase in positive affect following success in the context of conditional regard, but not in the context of unconditional regard. Additionally, the decrease in positive affect following failure was more pronounced when accompanied by conditional as compared to unconditional regard. Conditional regard thus magnified the impact of success versus failure on students' emotional experiences. PMID- 30479811 TI - The Impact of Language Switching Frequency on Attentional and Executive Functioning in Proficient Bilingual Adults. AB - Bilingual advantages in executive functions are well documented (see Bialystok, 2009; Dong & Li, 2015, for a review), but the specific aspects of bilingualism that underlie these advantages are unclear. The few studies conducted up until now on this subject (e.g., Hartanto & Yang, 2016; Prior & Gollan, 2011; Verreyt, Woumans, Vandelanotte, Szmalec, & Duyck, 2016) have suggested that the frequency of language switching may partially mediate this advantage. We further investigate the impact of oral language-switching frequency on the development of alerting, response inhibition and cognitive flexibility skills in proficient bilinguals. Two groups of proficient bilingual adults (21 low-frequency language switchers and 21 high-frequency language switchers), matched for age, gender, second-language proficiency and socio-cultural status, participated in the study. Tasks assessing alerting, response inhibition and cognitive flexibility were administered. Our results revealed that high-frequency language switchers responded more quickly in the task assessing cognitive flexibility. No group effect was found on the tasks assessing alerting and response inhibition. These results suggest that language-switching frequency is likely an underlying factor in the enhanced cognitive flexibility of proficient bilinguals. PMID- 30479813 TI - Science and Society, Part IV: Psychologist Paul Eelen "Not a Single Football Player will Believe that he is Determined by the Ball". AB - This manuscript is part of a special issue to commemorate professor Paul Eelen, who passed away on August 21, 2016. Paul was a clinically oriented scientist, for whom learning principles (Pavlovian or operant) were more than salivary responses and lever presses. His expertise in learning psychology and his enthusiasm to translate this knowledge to clinical practice inspired many inside and outside academia. Several of his original writings were in the Dutch language. Instead of editing a special issue with contributions of colleagues and friends, we decided to translate a selection of his manuscripts to English to allow wide access to his original insights and opinions. Even though the manuscripts were written more than two decades ago, their content is surprisingly contemporary. The present manuscript presents a translation of an interview with Paul Eelen by the University of Leuven student magazine Veto. First published as: Wetenschap en maatschappij deel vijf: de psycholoog Paul Eelen. "Geen enkele voetballer zal geloven dat hij gedetermineerd is door de bal". Interview in Veto Magazine, April 3 2000, 26, pp. 8-9. Interviewed by: Diederik Vandendriessche and Yves Dejaegere. PMID- 30479814 TI - The Broken Achilles Heel of Behavior Therapy: A Couple of Reflections on the Function Analysis. AB - This manuscript is part of a special issue to commemorate professor Paul Eelen, who passed away on August 21, 2016. Paul was a clinically oriented scientist, for whom learning principles (Pavlovian or operant) were more than salivary responses and lever presses. His expertise in learning psychology and his enthusiasm to translate this knowledge to clinical practice inspired many inside and outside academia. Several of his original writings were in the Dutch language. Instead of editing a special issue with contributions of colleagues and friends, we decided to translate a selection of his manuscripts to English to allow wide access to his original insights and opinions. Even though the manuscripts were written more than two decades ago, their content is surprisingly contemporary. This manuscript was originally published in 1992 and discusses functional analysis as the Achilles heel of cognitive-behavioural therapy (CBT). Functional analysis is that part of CBT where insight in learning principles feeds into clinical case conceptualisation. Even though functional analysis was self-evident for first generation behaviour therapists, its importance has been overlooked since long. It is striking to see how modern CBT-approaches again incorporate functional assessment. First published as: Eelen, P., & Van den Bergh, O. (1992). De gebroken achillespees van de gedragstherapie: enkele bedenkingen bij de functieanalyse. Psychotherapeutisch Paspoort, 2, 25-34. PMID- 30479812 TI - Why Humans Fail in Solving the Monty Hall Dilemma: A Systematic Review. AB - The Monty Hall dilemma (MHD) is a difficult brain teaser. We present a systematic review of literature published between January 2000 and February 2018 addressing why humans systematically fail to react optimally to the MHD or fail to understand it. Based on a sequential analysis of the phases in the MHD, we first review causes in each of these phases that may prohibit humans to react optimally and to fully understand the problem. Next, we address the question whether humans' performance, in terms of choice behaviour and (probability) understanding, can be improved. Finally, we discuss individual differences related to people's suboptimal performance. This review provides novel insights by means of its holistic approach of the MHD: At each phase, there are reasons to expect that people respond suboptimally. Given that the occurrence of only one cause is sufficient, it is not surprising that suboptimal responses are so widespread and people rarely understand the MHD. PMID- 30479815 TI - The Therapist as Conditioned Stimulus. AB - This manuscript is part of a special issue to commemorate professor Paul Eelen, who passed away on August 21, 2016. Paul was a clinically oriented scientist, for whom learning principles (Pavlovian or operant) were more than salivary responses and lever presses. His expertise in learning psychology and his enthusiasm to translate this knowledge to clinical practice inspired many inside and outside academia. Several of his original writings were in the Dutch language. Instead of editing a special issue with contributions of colleagues and friends, we decided to translate a selection of his manuscripts to English to allow wide access to his original insights and opinions. Even though the manuscripts were written more than two decades ago, their content is surprisingly contemporary. This manuscript was originally published in 1989 as part of an edited book on the therapeutic relation. In this chapter, Paul Eelen takes a critical position against the dominance of the client-centered approach. He presents the therapeutic relation as a behavioural interaction between the patient and his therapist which is subject to laws of learning. This is exemplified by an in-depth analysis of the therapist as a conditioned stimulus. First published as: Eelen, P., Depreeuw, E., & Van den Bergh, O. (1989). De therapeut als geconditioneerde stimulus. In H. Vertommen, G. Cluckers, & G. Lietaer (Eds.), De relatie in therapie (pp. 147 165). Leuven: Universitaire Pers Leuven. PMID- 30479816 TI - Behaviour Therapy and Behaviour Modification Background and Development. AB - This manuscript is part of a special issue to commemorate professor Paul Eelen, who passed away on August 21, 2016. Paul was a clinically oriented scientist, for whom learning principles (Pavlovian or operant) were more than salivary responses and lever presses. His expertise in learning psychology and his enthusiasm to translate this knowledge to clinical practice inspired many inside and outside academia. Several of his original writings were in the Dutch language. Instead of editing a special issue with contributions of colleagues and friends, we decided to translate a selection of his manuscripts to English to allow wide access to his original insights and opinions. Even though the manuscripts were written more than two decades ago, their content is surprisingly contemporary. This manuscript is a transcription of a lecture that was published in 1980. It was Paul Eelen's first public presentation after a two-year study in the United States, which has inspired much of his later thinking. The text can be viewed as a manifesto for behaviour therapy as it was then advancing in Belgium and the Netherlands. This presentation was given as the introduction to the L.A.P.P. seminar day held October 27, 1980, which was themed: Behaviour modification. The lecture was published as: Eelen, P. (1980). Gedragstherapie en gedragsmodificatie: Achtergronden. Leuvens Bulletin L. A. P. P., 39, 1-19. PMID- 30479817 TI - Classical Conditioning: Classical Yet Modern. AB - This manuscript is part of a special issue to commemorate professor Paul Eelen, who passed away on August 21, 2016. Paul was a clinically oriented scientist, for whom learning principles (Pavlovian or operant) were more than salivary responses and lever presses. His expertise in learning psychology and his enthusiasm to translate this knowledge to clinical practice inspired many inside and outside academia. Several of his original writings were in the Dutch language. Instead of editing a special issue with contributions of colleagues and friends, we decided to translate a selection of his manuscripts to English to allow wide access to his original insights and opinions. Even though the manuscripts were written more than two decades ago, their content is surprisingly contemporary. The present manuscript was originally published as part of a Liber Amicorum for Paul Eelen's own supervisor, prof. Joseph Nuttin. In this chapter, Paul Eelen presents a modern view on Pavlovian learning. It appeared in 1980, at the heyday of cognitive psychology which initially dismissed conditioning. Paul Eelen's perseverance in presenting learning principles as key to study human behaviour has proven correct and ahead of time. First published as: Eelen, P. (1980). Klassieke conditionering: Klassiek en toch modern. In Liber Amicorum, Prof. J. R. Nuttin, Gedrag, dynamische relatie en betekeniswereld (pp. 321-343). Leuven: Universitaire Pers Leuven. PMID- 30479818 TI - Paul Eelen: Reflections on Life and Work. AB - This manuscript is part of a special issue to commemorate professor Paul Eelen, who passed away on August 21, 2016. Paul was a clinically oriented scientist, for whom learning principles (Pavlovian or operant) were more than salivary responses and lever presses. His expertise in learning psychology and his enthusiasm to translate this knowledge to clinical practice inspired many inside and outside academia. Several of his original writings were in the Dutch language. Instead of editing a special issue with contributions of colleagues and friends, we decided to translate a selection of his manuscripts to English to allow wide access to his original insights and opinions. Even though the manuscripts were written more than two decades ago, their content is surprisingly contemporary. This introductory article presents a reflection on Paul's career and legacy and introduces the selected manuscripts that are part of this special issue. PMID- 30479819 TI - Executive Function, Chaos and Temperament: Specificities in Preschoolers with Externalizing Behaviors. AB - Various factors may contribute to the emergence of externalizing behavior (EB) problems in the preschool period. At the child level, temperament and executive function (EF) seem to play an important role, as well as environmental variables such as household chaos. In this study, we examined the profiles of 49 EB preschoolers compared to 49 typically developing (TD) preschoolers matched on age and gender. To evaluate the behavioral aspect of EB, we asked teachers and parents to fill out questionnaires, but we also used an observational paradigm. We assessed executive functions using attention, inhibition, flexibility and working memory tests. Finally, we used questionnaires to assess household chaos and child temperament. Results showed that children rated by parents as presenting EB were also assessed so by teachers and exhibited more agitation in our observational paradigm. As expected, EB children also presented weaker performance than the TD children in all EF tasks, except those measuring attention, and showed a larger reaction-time variability. Parents of the EB group reported a more chaotic environment at home. Finally, we found that child temperament (i.e., emotionality) also plays a role in group belonging. This study shows that EB children already exhibit specific characteristics by the time they are of preschool age, not only in the behavioral sphere, but also in the cognitive and environmental areas. However, despite all the differences between the two groups, a discriminant analysis showed that EF capacities have a weak power for EB diagnosis. PMID- 30479820 TI - Different Clinical Presentations in Eating Disorder Patients with Non-Suicidal Self-Injury Based on the Co-Occurrence of Borderline Personality Disorder. AB - Non-suicidal self-injury (NSSI) and borderline personality disorder (BPD) features are common in patients with eating disorders (ED), yet little is known regarding the clinical presentation of ED patients who present with NSSI with and without BPD. The current study compared self-injurious, female ED inpatients with (n = 98; NSSI+BPD) and without BPD (n = 45; NSSI-only) on different self-reported clinical features. Results suggest that ED patients with NSSI+BPD differ from those with NSSI-only with regard to frequency of suicidal ideation, alcohol, drug or medication abuse, internalizing/externalizing psychopathology, interpersonal problems, and coping strategies, with the NSSI+BPD group demonstrating more impairment in each of these domains. Despite these differences in clinical presentation, however, groups did not differ in NSSI features. In sum, while self injurious ED patients may present with similar NSSI behavior regardless of BPD diagnosis, those with NSS+BPD represent a group with much higher clinical complexity and greater treatment needs. PMID- 30479821 TI - Moral Judgments Depend on Information Presentation: Evidence for Recency and Transfer Effects. AB - Moral judgements are crucial for social life and rely on the analysis of the agent's intention and the outcome of the agent's action. The current study examines to the influence of how the information is presented on moral judgement. The first experiment investigated the effects of the order in which intention and outcome information was presented. The results showed that participants relied more on the last presented information, suggesting a recency effect. The second experiment required participants to make two types of judgments (wrongness vs. punishment) and manipulated the order of the requested two types of judgments. Results showed an asymmetrical transfer effect whereby punishment judgements, but not wrongness judgements were affected by the order of presentation. This asymmetrical transfer effect was likely linked to the ambiguity of the punishment judgement. Altogether, the study showed that the order in which information was presented and the order in which one was asked to think about the wrongness of an action or the punishment that the action deserves were two factors that should be irrelevant, but actually influenced moral judgements. The influence of these factors was mostly observed during the most difficult judgements, precisely in situations where human decision is called upon, such as in court trials. PMID- 30479822 TI - Understanding Long-term Outcome from the Patients' Perspective: A Mixed Methods Naturalistic Study on Inpatient Psychotherapy. AB - Objective: The complex phenomenon of psychotherapy outcome requires further conceptual and methodological developments that facilitate clinically meaningful research findings. In this study, we rely on an idiosyncratic and process oriented understanding of treatment effects in order to investigate long-term outcome. A conceptual model of long-term outcome is presented that comprises both a taxonomy of change and explanatory factors. Method: A mixed methods naturalistic study was conducted in an inpatient psychotherapy setting. Long-term quantitative outcome data are complemented with a data-driven thematic analysis of interviews with 22 participants, five to six years after ending inpatient psychotherapy. Results: Long-term outcome findings show improved well-being for the majority of former patients and this until five to six years after treatment. From the patients' perspectives, long-term changes can be situated on different interrelated existential levels: reconnection to others and (the meaning of) life, a revelation, an altered self, life changes, and altered expectations and ideas about recovery and treatment. The complex interplay of the person, the therapy centre, the outside world and the evolution over time helped explain the experienced changes and individual differences. Conclusion: The findings support the value of an idiosyncratic and process-oriented understanding of outcome and recovery as well as substantiate the importance of multiple methods and perspectives when studying the effects of psychotherapy. PMID- 30479823 TI - Social Support, Adjustment, and Psychological Distress of Help-Seeking Expatriates. AB - The present study aimed to explore the interrelations between support processes, adjustment, and psychological distress within a sample of help-seeking expatriates. Specifically, we examined (1) the association between expatriates' cross-cultural adjustment (i.e., work, interaction and general adjustment) and levels of psychological distress (i.e., depression, anxiety and stress), (2) the association between expatriates' perceptions of socioemotional and instrumental support availability and their level of cross-cultural adjustment, and (3) the moderating role of expatriates' socioemotional and instrumental support needs in the latter association. Findings showed that lower levels of expatriates' work adjustment were associated with higher levels of psychological distress. Further, perceived availability of socioemotional support was positively linked to expatriates' interaction and work adjustment. Finally, instrumental support needs moderated the relationship between instrumental support availability and general adjustment such that higher levels of instrumental support availability were associated with better general adjustment, but only for expatriates reporting high needs for instrumental support. Our study represents a novel contribution to the expatriate literature by shedding light on expatriates' vulnerability for psychological distress and understanding the type of social support that is considered most beneficial for help-seeking expatriates. Suggestions are made for clinical interventions for expatriates in need of support. PMID- 30479824 TI - Correction to: Medical treatment of dystonia. AB - [This corrects the article DOI: 10.1186/s40734-016-0047-6.]. PMID- 30479825 TI - Association of CYP2D6 polymorphisms and extrapyramidal symptoms in schizophrenia patients receiving risperidone: a retrospective study. AB - Background: Risperidone is mainly metabolized by cytochrome P450 (CYP) 2D6 in the liver. The gene encoding CYP2D6 is highly polymorphic. The average steady-state plasma concentration of risperidone active moiety is higher in the CYP2D6 intermediate metabolizers (IMs) compared with that in the extensive metabolizers (EMs). An association between drug-induced extrapyramidal symptoms scale (DIEPSS) score and CYP2D6 polymorphisms has not been reported to date. This study investigates the association of CYP2D6 polymorphisms with the severity of extrapyramidal symptoms in schizophrenia patients receiving risperidone therapy. Methods: Schizophrenia patients undergoing risperidone treatment were recruited for the study in the Kobe University Hospital. We evaluated extrapyramidal symptoms of schizophrenia using the DIEPSS. CYP2D6*10 and CYP2D6*14 were analyzed using TaqMan(r) assays, and CYP2D6*5 was analyzed using the long-PCR method. Patients with CYP2D6*1/*5, *1/*14, *5/*10, *10/*10, and *10/*14 were classified as IMs, and patients with CYP2D6*1/*1 and *1/*10 were classified as EMs. Patients with CYP2D6*5/*5, *5/*14, and *14/*14 were classified as poor metabolizers (PMs). Results: A total of 22 patients were included in the study. No patients were classified as PMs. The dose of risperidone (mg/day) was not significantly different between EMs (n = 15) and IMs (n = 7) (median with the interquartile range: 4.0 (2.0-6.0) vs. 4.0 (2.0-7.0) mg, p = 0.31). The age and disease duration of schizophrenia were not significantly different between the EMs and IMs. The DIEPSS score in the IMs was significantly higher than that in the EMs (median with the interquartile range: 5.0 (3.5-6.5) vs. 0.0 (0.0-3.0), p < 0.001). The multiple regression analysis showed that CYP2D6 IMs is a significant risk factor for the DIEPSS (p < 0.05). Conclusion: Special attentions should be paid to the onset of extrapyramidal symptoms in schizophrenia patients identified as CYP2D6 IM undergoing risperidone therapy. PMID- 30479826 TI - "Before I die I want to ...": An experience of death education among university students of social service and psychology. AB - The censorship of death and dying has removed the "memento mori" practices, and in order to reintroduce this practice, some "Before I die" projects have been increasingly implemented. Running in parallel, in the syllabi of social service and psychology students, some experiences of death education has commenced. This study illustrates the results of a qualitative research conducted on the "Before I die I want to ..." Polaroid(r) Project (BIDIWT), which is divided into two phases. The first phase entails an analysis of the wishes collected from the United States, Japan, India, and Italy. The second phase refers to the analysis of the captions of the BIDIWT realized from two groups of undergraduates, with regard to the effect of such experience on their religiosity, representation of death, and fear of death. PMID- 30479827 TI - Caroli's-type ductal plate malformation and a portosystemic shunt in a 4-month old kitten. AB - Case summary: A 4-month-old neutered male Russian Blue kitten had a 4 week history of hypersalivation and failure to thrive. In addition, there was a 2 week history of soft tissue swelling on the ventral abdomen, which had failed to improve with antimicrobial therapy. There were no significant physical examination or neurological deficits on examination; however, the cat had a quiet demeanour for its age. Postprandial bile acids were increased (32 umol/l; reference interval <25 umol/l). An abdominal CT scan revealed changes consistent with an extrahepatic portosystemic shunt and inflammation of fat of the ventral abdominal body wall. Surgical biopsy and culture of the subcutaneous swelling identified non-infectious steatitis. Ten weeks following initial presentation, surgical exploration, liver biopsy and ligation of the portosystemic shunt were performed. Liver biopsy was submitted to the Anatomical Pathology Laboratory of Cornell University Animal Health Diagnostic Center, New York, USA. Histopathology revealed a ductal plate malformation (Caroli's type), as well as changes consistent with a portosystemic shunt. Relevance and novel information: Ductal plate malformations are rarely described in the veterinary literature. To our knowledge this is the first reported case of Caroli's-type malformation in a cat. There are no biochemical changes that allow for differentiation of ductal plate malformations from other hepatopathies. Liver biopsy is required for a definitive diagnosis. PMID- 30479828 TI - Social cognitive determinants of exercise behavior in the context of behavior modeling: a mixed method approach. AB - Research has shown that persuasive technologies aimed at behavior change will be more effective if behavioral determinants are targeted. However, research on the determinants of bodyweight exercise performance in the context of behavior modeling in fitness apps is scarce. To bridge this gap, we conducted an empirical study among 659 participants resident in North America using social cognitive theory as a framework to uncover the determinants of the performance of bodyweight exercise behavior. To contextualize our study, we modeled, in a hypothetical context, two popular bodyweight exercise behaviors - push ups and squats - featured in most fitness apps on the market using a virtual coach (aka behavior model). Our social cognitive model shows that users' perceived self efficacy (betaT = 0.23, p < 0.001) and perceived social support (betaT = 0.23, p < 0.001) are the strongest determinants of bodyweight exercise behavior, followed by outcome expectation (betaT = 0.11, p < 0.05). However, users' perceived self regulation (betaT = -0.07, p = n.s.) turns out to be a non-determinant of bodyweight exercise behavior. Comparatively, our model shows that perceived self efficacy has a stronger direct effect on exercise behavior for men (beta = 0.31, p < 0.001) than for women (beta = 0.10, p = n.s.). In contrast, perceived social support has a stronger direct effect on exercise behavior for women (beta = 0.15, p < 0.05) than for men (beta = -0.01, p = n.s.). Based on these findings and qualitative analysis of participants' comments, we provide a set of guidelines for the design of persuasive technologies for promoting regular exercise behavior. PMID- 30479829 TI - Co-production and evaluation of an e-learning resource to improve African Caribbean families' knowledge about schizophrenia and engagement with services: a pilot randomised controlled trial protocol. AB - Background: A higher proportion of African-Caribbean people in the UK are diagnosed with schizophrenia spectrum disorders than other ethnic groups. High levels of shame and stigma at individual and community levels contribute to delayed access to care, potentially increasing the duration of untreated psychosis and so worsening outcomes. Inferior access, more coercive care, and worse outcomes have created a 'circle of fear' of mental health services within African-Caribbean communities. This further discourages early engagement with statutory services and increases the burden of care for families living with schizophrenia.Providing tailored and relevant information about psychosis (psychoeducation) has the potential for improving outcomes for patients and families. However, there are no culturally appropriate psychoeducation programmes for African-Caribbeans in the UK. We aim to determine whether an e-learning resource, co-produced with African-Caribbean stakeholders to improve knowledge about psychoses, would be culturally acceptable and accessible to members of this population. Methods: A pilot randomised controlled trial of the feasibility of co producing and testing a novel e-learning resource to improve knowledge about and attitudes towards schizophrenia in African-Caribbean families. We will seek to recruit 40 participants, aged >= 16 years, either to receive the intervention or as controls. They will self-refer or be referred via inpatient and wellbeing services, family and carers' forums, statutory community mental health teams, and voluntary sector/non-governmental agencies (NGOs). Participants will complete the Ca-KAP, ASMI, and SF-12. Acceptability will be explored qualitatively via focus groups and individual semi-structured interviews. Discussion: The proposed trial will demonstrate the feasibility of conducting a fully powered RCT to evaluate the efficacy of an e-learning resource about schizophrenia with African-Caribbean families. Qualitative work will explore the intervention's accessibility and barriers/facilitators to participation, including attitudes to randomisation. These data will facilitate further refinement of the intervention. Trial registration: ISRCTN11394005, retrospectively registered 20/03/2018. PMID- 30479830 TI - "Family planning in Rwanda is not seen as population control, but rather as a way to empower the people": examining Rwanda's success in family planning from the perspective of public and private stakeholders. AB - Background: Rwanda has made significant strides in improving the health of its people, including increasing access to and use of family planning. Contraceptive use has increased from 17% to 53% in just one decade, from 2005 to 2015. Methods: The data consist of 13 in-depth interviews conducted with family planning program experts in Rwanda to better understand the mechanisms for success, elucidate remaining challenges, speculate on the future of the program, and discuss potential applicability for translating aspects of the program in other settings. Results: All respondents first noted the positive aspects of government will, leadership, and management of the family planning program when asked to describe the reasons for success. The challenges that loomed the largest for the program were service accessibility for rural Rwandans, adolescent access to and use of contraceptives, opposition from religious institutions, as well as inadequate human resources and funding. These challenges were openly acknowledged and are in the process of being addressed. Conclusion: The importance of government leadership and focus in the success of Rwanda's family planning program was prominent. All positive aspects of the program are based upon the strong foundation the government has built and nurtured. Since innovation is welcomed and program evaluation is considered essential, the outlook for Rwanda's family planning program is favorable. The issues that remain are common and persistent challenges for family planning programs. Other nations could learn tangible practices from Rwanda's success and follow Rwanda's efforts to mitigate the remaining challenges. PMID- 30479831 TI - A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release. AB - The clinical use of genetically modified T-cell therapies has led to unprecedented response rates in leukemia and lymphoma patients treated with anti CD19 chimeric antigen receptor (CAR)-T. Despite this clinical success, FDA approved T-cell therapies are currently limited to B-cell malignancies, and challenges remain with managing cytokine-related toxicities. We have designed a novel antibody-T-cell receptor (AbTCR) platform where we combined the Fab domain of an antibody with the gamma and delta chains of the TCR as the effector domain. We demonstrate the ability of anti-CD19-AbTCR-T cells to trigger antigen-specific cytokine production, degranulation, and killing of CD19-positive cancer cells in vitro and in xenograft mouse models. By using the same anti-CD19 binding moiety on an AbTCR compared to a CAR platform, we demonstrate that AbTCR activates cytotoxic T-cell responses with a similar dose-response as CD28/CD3zeta CAR, yet does so with less cytokine release and results in T cells with a less exhausted phenotype. Moreover, in comparative studies with the clinically validated CD137 (4-1BB)-based CAR, CTL019, our anti-CD19-AbTCR shows less cytokine release and comparable tumor inhibition in a patient-derived xenograft leukemia model. PMID- 30479832 TI - Opportunities and challenges in public and community engagement: the connected for cognitive health in later life (CHILL) project. AB - Plain English summary: Two goals of public health research are to understand what causes disease and ill health, and what can be done to prevent it. To develop appropriate and effective actions, we need to know what resources are available to communities, and what are the beliefs and values that influence behaviour. This means that research needs to be carried out close to the people it affects, to better understand context and environment, as well as people's understandings and interpretations of health and health risk.Connected for Cognitive Health in Later Life (CHILL) was a project developed to test whether engaging local residents in research might be a good way of firstly: raising awareness of research findings in the community; and secondly, affecting mid-life behaviours in favour of ageing well and reducing risk of dementia. We investigated perceptions of ageing and how to age 'well' in a town whose population health is ranked worse than the regional average. Project activities involved: identifying and engaging with stakeholders; conducting 'mini' street interviews; holding community workshops; and taking part in a large community event.This paper describes the process of carrying out the research, and presents a flavour of some of the information captured on context and local understanding of dementia risk. It then goes on to discuss in more depth some of the challenges in attempting to involve people in shaping research and intervention development, before offering some conclusions and suggested next steps for researchers. Abstract: Background Identifying risk of disease and ill health, and developing prevention strategies, are key objectives in public health research. However, poor understanding of the impact of local context, including cultural and ethnic differences, challenges our ability to develop actions that are acceptable and meaningful to local communities. This suggests a need for research embedded in sub-populations, seeking to better understand context, understanding and interpretation of health and health risk. Methods Against a backdrop of wide inequalities in health, the Connected for Cognitive Health In Later Life (CHILL) project began work in a locality with worse than regional average health outcomes aiming to co-develop a project investigating perceptions of ageing and how to age 'well'. Another goal was to test the potential for using Community Based Participatory Research (CBPR) as a way of communicating research knowledge, raising awareness and understanding amongst community members of mid-life risk factors for developing dementia. A four-part scoping study was embarked on, including: stakeholder identification and engagement; street interviews; community workshops; and a wider public engagement event. Results Whilst the project was able to stimulate interest, gain involvement from a small group of residents, and successfully engage members of the public, it was not possible, within the relatively short timescale of the scoping project, to achieve the depth of community involvement necessary to co-design and seek additional funding for collaborative research activities. Conclusions A number of challenges were encountered in scoping CBPR on this particular topic and location. Potential explanations include lack of 'readiness' or 'capacity' amongst the local population, and a very limited timescale for the scoping research to adapt and respond to this. This has significant implications in terms of time and effort necessary to build infrastructure to support research partnerships if researchers wish to engage successfully with members of the public on population health in the future. PMID- 30479833 TI - New insights into structural features and optimal detection of circulating tumor DNA determined by single-strand DNA analysis. AB - Circulating cell-free DNA (cfDNA) has received increasing interest as an apparent breakthrough approach in diagnostics, personalized medicine, and tumor biology. However, the structural features of cfDNA are poorly characterized. Specifically, the literature has discrepancies with regards to cfDNA size profile. We performed a blinded study of the distribution of cfDNA fragment sizes in cancer patient plasma (n = 11), by various ultra-deep-sequencing approaches and quantitative PCR (Q-PCR). Whole-genome sequencing of single-stranded DNA library preparation (SSP S) revealed that nearly half of the total cfDNA fragment number are below 120 nucleotides, which are not readily detectable by standard double-stranded DNA library preparation (DSP) protocols. Fractional size distribution of cancer patient circulating DNA was very similar using both SSP-S-based or Q-PCR-based methods also revealing that high molecular weight (over 350 bp) cfDNA is a minor component (~2%). These extra small detected cfDNA fragments may mostly result from nicks occurring in blood circulation in one or both DNA strands, which are subsequently revealed through the denaturation step of the SSP and Q-PCR procedures. Detailed analysis of the data suggested that most of the detectable cfDNA in blood has a nucleosome footprint (~10-bp periodicity repeats). The nucleosome is thus the most stabilizing structure of DNA in the circulation. cfDNA molecules, which are initially packed in chromatin, are released from cells and are then dynamically degraded in blood both within and between nucleosomes or transcription factor-associated subcomplexes. While this study provides new insights into cfDNA size profiles harmonizing sequencing and Q-PCR findings, our data validate the use of a specific Q-PCR method and SSP-S for obtaining an optimal qualitative and quantitative analytical signal. PMID- 30479834 TI - A pilot study of the clinical evidence for the methodology for prevention of oral mucositis during cancer chemotherapy by measuring salivary excretion of 5 fluorouracil. AB - Objective to re-examine measures to prevent oral mucositis caused by drugs in head and neck cancer patients during cancer treatment by measuring salivary excretion of 5-fluorouracil. Saliva, blood, and urine were simultaneously collected from oral cancer patients and breast cancer patient at the point in time of before, during, and after the administration of 5-FU, then the 5-FU levels of the samples were quantitatively analysed using LC-MS/MS. In all patients, the 5-FU levels in saliva and serum peaked at 30 min to 3 h after the start of 5-FU treatment, and high levels were maintained throughout the administration of the drug. With regard to urinary 5-FU levels, they remained high from 3 to 120 h after the start of 5-FU treatment. After the completion of 5 FU treatment, even though it not appeared in the patients' serum and urine promptly, 5-FU was detected in saliva at 12 h after the completion of 5-FU treatment in one oral cancer patient and at 48 h after the completion of 5-FU treatment in the breast cancer patient. It was suggested that the level of hydration after the completion of chemotherapy may be involved in the differences in 5-FU excretion. PMID- 30479836 TI - Multimodal imaging of retinal metastasis masquerading as an acute retinal necrosis. AB - Background: To report the multimodal imaging and histology of a case of metastatic esophageal cancer with vitreoretinal involvement resembling acute retinal necrosis (ARN) in a patient receiving systemic chemotherapy. Case presentation: A 69-year-old Japanese man with a history of stage 4 esophageal carcinoma, treated with three cycles of 5-fluorouracil (5-FU) and cisplatin (CDDP) chemotherapy as well as 30 sessions of radiation therapy, presented with new onset of blurry vision in the right eye (OD). Visual acuity was 20/200 OD. Fundus examination OD revealed 2+ nuclear cataract, veil-like vitreous opacity, a tractional retinal detachment, and white retinal lesions in the macula and periphery masquerading as an ARN. Due to the poor view and uncertainty regarding diagnosis, combined cataract extraction and 25 gauge pars plana vitrectomy was performed. Polymerase chain reaction and cytologic analysis were performed on the vitreous samples, which was negative for all infectious entities but positive for poorly differentiated malignant cells. The vitreous biopsy was consistent with the primary endoscopic esophageal biopsy. Ultra-wide view fundus imaging revealed multifocal white intraretinal lesions in the macula and periphery. Optical coherence tomography through these white opacities displayed hyper-reflective inner retinal lesions with no choroidal involvement, suggestive of retinal metastasis. Observation and palliative support was continued until the patient passed away 3 months after diagnosis. Conclusion: Retinal metastasis may mimic infectious syndromes such as ARN and are associated with a very poor prognosis. Outside of the retina, no further central nervous system metastasis was found. 5 FU is known to cross the blood-brain-barrier but may be inadequate in preventing retinal metastasis. PMID- 30479837 TI - Multilevel critical stenosis with minimal functional deficits: a case of cervical spondylotic myelopathy. AB - Introduction: We present a case of a previously asymptomatic and highly functional individual whose critical degenerative stenosis was exacerbated by recent trauma (motor vehicle accident), resulting in cervical spondylotic myelopathy. Case presentation: A 57-year-old African-American man with no significant past medical history presented to the Orthopaedic Surgery outpatient clinic with mild neck discomfort, stiffness, and bilateral hand numbness 4 days after being involved in a motor vehicle accident. He ambulated without assistive devices and displayed a tandem gait pattern with normal cadence. He was minimally tender to palpation at the posterior cervical midline and paraspinal musculature with motor and sensory function intact bilaterally. Reflexes were hypoactive at C5, C6, C7, L4, and S1 bilaterally with positive Babinski signs bilaterally. Imaging revealed degenerative changes, spinal stenosis, and cord compression. The patient eventually underwent posterior cervical decompression and fusion from the C3 to the C6 level, with the only reported complication being transient loss of somatosensory evoked potential (SSEP) signals intra-operatively. In the postoperative period, the patient complained of stiffness in his left shoulder, elbow, and hand, as well as left hand palmar numbness and an inability to make a full fist. His complaints were managed with medication and physical therapy. Discussion: This case report highlights the point that stenosis that occurs slowly over time is often well compensated, and patients are commonly asymptomatic at first glance. Often times, acute events tip patients from being asymptomatic to symptomatic, generally warranting invasive intervention to prevent further insults from causing permanent damage. PMID- 30479835 TI - Transcriptomic profiling of tantalum metal implant osseointegration in osteopenic patients. AB - Objectives: The long-term success of dental implants is established by literature. Although clinically well defined, the complex genetic pathways underlying osseointegration have not yet been fully elucidated. Furthermore, patients with osteopenia/osteoporosis are considered to present as higher risk for implant failure. Porous tantalum trabecular metal (PTTM), an open-cell porous biomaterial, is suggested to present enhanced biocompatibility and osteoconductivity. The goal of this study was to evaluate the expression patterns of a panel of genes closely associated with osteogenesis and wound healing in osteopenic patients receiving either traditional titanium (Ti) or PTTM cylinders to assess the pathway of genes activation in the early phases of osseointegration. Material and methods: Implant cylinders made of Ti and PTTM were placed in osteopenic volunteers. At 2- and 4 weeks of healing, one Ti and one PTTM cylinder were removed from each subject for RT-PCR analysis using osteogenesis PCR array. Results: Compared to Ti, PTTM-associated bone displayed upregulation of bone matrix proteins, BMP/TGF tisuperfamily, soluble ligand and integrin receptors, growth factors, and collagen genes at one or both time points. Histologically, PTTM implants displayed more robust osteogenesis deposition and maturity when compared to Ti implants from the same patient. Conclusions: Our results indicate that PTTM properties could induce an earlier activation of genes associated with osteogenesis in osteopenic patients suggesting that PTTM implants may attenuate the relative risk of placing dental implants in this population. PMID- 30479838 TI - A randomized double-blind, placebo-controlled, cross-over trial assessing the effect of tadalafil (Cialis) on the cardiovascular response in men with complete spinal cord injury above the sixth thoracic level: A Pilot Study. AB - Study design: Double-blind, randomized cross-over placebo-controlled pilot study. Objectives: To determine the effects of tadalafil on systolic blood pressure (SBP), heart rate (HR), and dizziness of men with American Spinal Injury Association Impairment Scale-A (AIS-A) spinal cord injury (SCI) between cervical 4 (C4) and thoracic-5 (T5) levels. Setting: Outpatient rehabilitation clinic. Design: Double-blind, randomized cross-over placebo-controlled pilot study. Methods: 20 males with AIS-A SCI, C4-T5 received either tadalafil 20 mg or placebo for the first arm, and then were crossed-over after 1 week to the second arm. SBP, HR, and Visual Analogue Scale (VAS) for dizziness upon sitting up from lying were measured at baseline and again 1, 2, 4, 12, 22, 29, and 36 h post dose administration. The change in each outcome measure (SBP, HR, VAS dizziness) was observed from pre-dose to each time point. A change in VAS dizziness of 2 cm or greater (scale 0-10 cm) was considered positive. Results: SBP did not change significantly in either group. However, HR increased significantly in the tadalafil group at several time points (12 h p < 0.05, 22 h p <0.05, 29 h p <0.01, and 36 h p <0.05), with no change in the placebo group. The VAS dizziness significantly increased (range 2-6 cm changes) at some time point in 1/4 of the subjects after tadalafil, but not in the placebo group; all reports of dizziness were at 12 h or later. Conclusions: Tadalafil use in people with SCI above T6 is safe with respect to not causing hypotension; hemodynamic changes that occurred 12-36 h post administration were compensated for by elevations in HR. Sponsorship: The Manitoba Medical Services Foundation and the Health Sciences Centre Foundation. PMID- 30479839 TI - Apigenin suppresses the stem cell-like properties of triple-negative breast cancer cells by inhibiting YAP/TAZ activity. AB - Triple-negative breast cancer (TNBC) remains a clinical challenge because of the absence of effective therapeutic targets. In TNBC, overexpression of YAP and TAZ correlates with bioactivities of cancer stem cells (CSCs), high histological grade, resistance to chemotherapy, and metastasis. Thus, YAP/TAZ may serve as potential therapeutic targets in TNBC. To identify YAP/TAZ inhibitors, in previous experiments, we screened a library of natural compounds by using YAP/TAZ luciferase reporter assay and identified apigenin as a potential inhibitor. In this study, we demonstrated that apigenin significantly suppressed the proliferation and migration of TNBC cells. Furthermore, we demonstrated that apigenin inhibited stemness features of TNBC cells in both in vitro and in vivo assays. Our mechanism study demonstrated that apigenin decreased YAP/TAZ activity and the expression of target genes, such as CTGF and CYR61, in TNBC cells. We also showed that apigenin disrupted the YAP/TAZ-TEADs protein-protein interaction and decreased expression of TAZ sensitized TNBC cells to apigenin treatment. Collectively, our studies suggest that apigenin is a promising therapeutic agent for the treatment of TNBC patients with high YAP/TAZ activity. PMID- 30479840 TI - Survival of midbrain dopamine neurons depends on the Bcl2 factor Mcl1. AB - Mitochondria-dependent apoptosis plays an important role in the embryonic development of the midbrain dopaminergic system as well as in Parkinson's disease. Central to mitochondria-dependent apoptosis is the Bcl2 family of apoptosis-regulating proteins. However, it was unclear which Bcl2 proteins are important for the survival of dopaminergic neurons. Here, we identify Mcl1 as a critical Bcl2 pro-survival factor in midbrain dopaminergic neurons. Using a chemical biology approach to inhibit various components of the apoptotic machinery in the dopaminergic MN9D cell line or the control neuroblastoma N2A cell line, we find that functional inhibition of Mcl1 with the high affinity small molecule inhibitor UMI-77 results in a rapid and dose-dependent loss of viability, selectively in dopaminergic cells. In-depth analysis of the apoptotic signaling pathway reveals that chemical inhibition of Mcl1 results in the activation of Bax, activation of cleaved caspase-3 and finally cell death. The dependence of mouse dopaminergic midbrain neurons on Mcl1 was confirmed using ex vivo slice cultures from Pitx3GFP/+ and wildtype mice. In mouse dopaminergic midbrain neurons positive for the midbrain dopaminergic marker Pitx3, or tyrosine hydroxylase, UMI-77 treatment caused a dramatic increase in cleaved caspase 3, indicating that Mcl1 activity is required for basal neuronal survival. Overall, our results suggest that Mcl1 is of critical importance to dopaminergic neurons and is a weak link in the chain controlling cellular survival. Boosting the pro survival function of Mcl1 should be pursued as a therapeutic approach to augment the resilience of midbrain dopaminergic neurons to apoptotic stress in Parkinson's disease. PMID- 30479841 TI - A novel therapeutic anticancer property of raw garlic extract via injection but not ingestion. AB - Prior studies suggest a possibility that the anticancer property of garlic is more effective only when exposed directly to cancer cells than absorbed first by the normal epithelial cells of the gastrointestinal tract wall. We tested this possibility in two mouse models of highly aggressive malignancies that cannot yet be cured by conventional therapies: sarcoma 180- and EL4-induced lethal ascites. Daily oral gavages of raw garlic extract (RGE; equivalent to 100 mg wet weight) for 21 days failed to offer any meaningful effect in the mice with malignancies. However, the daily injection of the same amounts of the same materials for 21 days completely cured all the mice of cancer. This novel anticancer activity of RGE was present entirely in the size fraction of the molecules smaller than 3000 Dalton rather than the larger molecules and was completely partitioned into the organic phase rather than into the aqueous phase. One half of the anticancer activity was inactivated by heating at 100 degrees C for 10 min, suggesting that multiple components were concertedly involved. In a direct comparison, the RGE was significantly more effective in killing the cultured cancer cells in vitro than the extracts from other 21 raw vegetables and fruits. In cell culture, RGE killed a wide variety of different cancer cells regardless of species of origin and cell types. Cancer cells generally are well known to be defective in many common metabolic pathways present in their normal cell counterpart for processing normal nutrients. The metabolism of these otherwise normal nutrients could be stalled in the cancer cells and become cytotoxic. The most-effective way of treating cancer by RGE may be the direct injection instead of eating the cooked garlic. PMID- 30479842 TI - A needs assessment for simulation-based training of emergency medical providers in Nebraska, USA. AB - Background: Training emergency medical services (EMS) workforce is challenging in rural and remote settings. Moreover, critical access hospitals (CAHs) struggle to ensure continuing medical education for their emergency department (ED) staff. This project collected information from EMS and ED providers across Nebraska to identify gaps in their skills, knowledge, and abilities and thus inform curriculum development for the mobile simulation-based training program. Methods: The needs assessment used a three-step process: (1) four facilitated focus group sessions were conducted in distinct geographical locations across Nebraska to identify participants' perceived training gaps; (2) based on the findings from the focus group, a needs assessment survey was constructed and sent to all EMS and ED staff in Nebraska; and (3) 1395 surveys were completed and analyzed. Results: Thematic areas of training gaps included cardiopulmonary conditions, diabetes management, mass casualty incidents (MCI), maternal health and child delivery, patient assessment, pediatric care (PC), and respiratory emergency care. Gaps in non-clinical skills were related to crisis management such as maintaining effective teamwork. Participants frequently identified cardiopulmonary care, PC, and MCI as highly needed trainings. Other needs included life support-related retaining courses, sessions informing protocol updates, the availability of retraining tailored for rural areas, substance use related emergencies, and farming-related injuries. Conclusion: EMS and ED staff identified several skill gaps and training needs in the provision of emergency services in rural communities. These results allow for the development of customized training curricula and, with the help of an on-site simulation-based program, can identify gaps in health professionals' skills, knowledge, and abilities and thus help them respond to acute healthcare needs of rural communities. PMID- 30479843 TI - The evidence behind the use of platelet-rich plasma (PRP) in scar management: a literature review. AB - Introduction: Autologous platelet-based concentrates represent increasingly popular adjuncts to a variety of medical, surgical and aesthetic interventions. Their beneficial potential rests on the ability to deliver a high concentration of growth factors to the target tissues. There are currently no reports in the literature appraising the evidence behind the use of platelet-rich plasma (PRP) in scar management. Methods: A detailed English literature review was conducted using PubMed Medline, Embase and Web of Science; the manuscripts were appraised and classified according to the Joanna Briggs Institute Levels of evidence. The results are presented in descending order of evidence separately for atrophic, keloid, surgical and traumatic scars. Discussion: On the basis of level 1 evidence currently available, it appears that PRP can improve the quality of atrophic acne scars treated with ablative fractional CO2 laser and decrease the duration of laser-related side effects including oedema and erythema. Regarding surgical scars, the current data suggest that PRP may improve wound healing and early scar quality; furthermore, incorporation of PRP in fat-grafting procedures undertaken in conjunction with non-ablative, fractional laser can contribute to better wound healing as well as a significant improvement in texture, colour and contour in traumatic scar resurfacing. There are no high level studies at present to support the incorporation of autologous platelet-based concentrates in the management of keloid scars. Conclusion: PRP is a promising adjunct in scar management practice. Further research with long-term follow-up is warranted to delineate the value of this modality in different subtypes of scars. PMID- 30479844 TI - Effects of Resveratrol and Morin on Insoluble Tau in Tau Transgenic Mice. AB - Tauopathies are neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal dementia (FTD), in which tau protein aggregates within neurons. An effective treatment is lacking and is urgently needed. We evaluated two structurally similar natural compounds, morin and resveratrol, for treating tauopathy in JNPL3 P301L mutant human tau overexpressing mice. Rotarod tests were performed to determine effects on motor function. After treatment from age 11 to 14 months, brains of 26 mice were collected to quantify aggregated hyperphosphorylated tau by Thioflavin T and immunohistochemistry (IHC) and to quantify total tau (HT7 antibody) and hyperphosphorylated tau (AT8 antibody) in homogenates and a fraction enriched for paired helical filaments. Resveratrol reduced the level of total hyperphosphorylated tau in IHC sections (p=0.036), and morin exhibited a tendency to do so (p=0.29), while the two drugs tended to increase the proportion of solubilizable tau that was hyperphosphorylated, as detected in blots. Neither resveratrol nor morin affected motor function. One explanation of these results is that the drugs might interrupt a late stage in tau aggregation, after small aggregates have formed but before further aggregation has occurred. Further animal studies would be informative to explore the possible efficacy of morin or resveratrol for treating tauopathies. PMID- 30479845 TI - 2D:4D Ratio Differs in Ischemic Stroke: A Single Center Experience. AB - Background: The index to ring finger length (2D:4D) ratio is a proxy biomarker for prenatal exposure of sex hormones. Sex hormones are associated with the pathogenesis of ischemic stroke. The purpose of the study was to demonstrate the association between 2D:4D and ischemic stroke. Methodology: This study retrospectively reviewed the data of 100 patients with first ever ischemic stroke between September, 2016 and June, 2017. The lengths of index finger and ring finger of both hands were measured using electronic calipers and calculated for 2D:4D ratios. Receive operating characteristic (ROC) mode was used to detect predicting performance of 2D:4D ratios for ischemic stroke. Results: 2D:4D ratios in ischemic stroke patients were higher than controls in both hands (P < 0.05), except right 2D:4D ratio in females. The ROC analyses showed that the area under the curve (AUC) were 0.635 (95%CI: 0.527-0.743) for left 2D:4D ratio, and 0.647 for right (95%CI: 0.539-0.755) (P < 0.05). The AUC of left and right 2D:4D ratio in male were 0.667 (95%CI: 0.514-0.820) and 0.670 (95%CI: 0.519-0.822) (P < 0.05). In female, no significance were found in ROC analysis. And there were no correlation between 2D:4D value and stroke severity (P > 0.05). Conclusions: The current study indicated that the diagnostic value of 2D:4D ratio was limited in ischemic stroke. Further research is required to explore the role of it in screening ischemic stroke. PMID- 30479846 TI - Tuberous Sclerosis Complex: Clinical Spectrum and Epilepsy: A Retrospective Chart Review Study. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant genetic neurocutaneous disorder, with heterogeneous manifestations. We aimed to review the clinical presentation of TSC and its association with epilepsy among Saudi population. This was a retrospective chart review study of 88 patients diagnosed with TSC with or without epilepsy. In 38.6% of patients, symptoms began before 1 year of age. The most frequent initial manifestations of TSC were new onset of seizures (68.2%), skin manifestations (46.6%) and development delay (23.9%). During the evolution of the disease 65.9% had epilepsy, 17% facial angiofibromas, 13.6% Shagreen patch, 18.2% heart rhabdomyomas and 12.5% retinal hamartomas. The genetic study for TSC diagnosis was done for 44 patients, 42 (95,4%) of them were genetically confirmed, for whom 13 patients had TSC1 mutation (29.5%), 29 patients were carrying TSC2 gene mutation (65.9%), Genetic test for TSC 1 and TSC 2 were negative for 2 patients (4.5%) despite positive gene mutation in their relative with TSC. The most common manifestations were central nervous system (predominantly epilepsy) and dermatological manifestations. Most of the patients develop epilepsy with multiple seizure types. TSC 2 mutation is more common than TSC 1 mutation. PMID- 30479848 TI - Frailty as an Outcome Predictor After Ankle Fractures: Where Are We Now? PMID- 30479847 TI - Galphas signaling controls intramembranous ossification during cranial bone development by regulating both Hedgehog and Wnt/beta-catenin signaling. AB - How osteoblast cells are induced is a central question for understanding skeletal formation. Abnormal osteoblast differentiation leads to a broad range of devastating craniofacial diseases. Here we have investigated intramembranous ossification during cranial bone development in mouse models of skeletal genetic diseases that exhibit craniofacial bone defects. The GNAS gene encodes Galphas that transduces GPCR signaling. GNAS activation or loss-of-function mutations in humans cause fibrous dysplasia (FD) or progressive osseous heteroplasia (POH) that shows craniofacial hyperostosis or craniosynostosis, respectively. We find here that, while Hh ligand-dependent Hh signaling is essential for endochondral ossification, it is dispensable for intramembranous ossification, where Galphas regulates Hh signaling in a ligand-independent manner. We further show that Galphas controls intramembranous ossification by regulating both Hh and Wnt/beta catenin signaling. In addition, Galphas activation in the developing cranial bone leads to reduced ossification but increased cartilage presence due to reduced cartilage dissolution, not cell fate switch. Small molecule inhibitors of Hh and Wnt signaling can effectively ameliorate cranial bone phenotypes in mice caused by loss or gain of Gnas function mutations, respectively. Our work shows that studies of genetic diseases provide invaluable insights in both pathological bone defects and normal bone development, understanding both leads to better diagnosis and therapeutic treatment of bone diseases. PMID- 30479850 TI - Admitting Service Affects Cost and Length of Stay of Hip Fracture Patients. AB - Introduction: The purpose of this study was to analyze the effect of the admitting service on cost of care for hip fracture patients by comparing the cost difference between patients admitted to the medicine service versus those admitted to a surgical service. Methods: A 2-year cohort of patients 55 years or older who were admitted to a single level 1 trauma center with an operative hip fracture were included. Patient demographics, comorbidities, admitting service, complications, and hospital length of stay were recorded for each patient. Cost of hospitalization, discharge disposition, and 30-day readmissions were collected. Patients who were admitted to the medicine service (medicine cohort) were compared to those admitted to a surgery service (surgery cohort). Multivariate regression models controlling for age, Charlson comorbidity index (CCI), and American Society of Anesthesiology (ASA) scores were used to evaluate hospitalization costs with a P value of <.05 as significant. Results: Two hundred twenty-five hip fracture patients were included; 143 (63.6%) patients were admitted to a surgical service, while 82 (36.4%) were admitted to the medicine service. Patients admitted to medicine service had greater CCI and ASA scores, longer lengths of stay, and more complications than those patients admitted to surgery service. Linear regression model controlling for age, CCI, ASA score, and time to surgery demonstrates that patients admitted to a surgical service will have 2.0-day (95% confidence interval [CI]: 0.561-3.503; P = .007) shorter admissions with a US$4215 reduction in cost (95% CI: US$314-US$8116; P = .034) compared to patients admitted to the medicine service. Discussions: In our urban safety net hospital, hip fracture patients admitted to medicine service had longer lengths of stay and higher total hospitalization costs than patients who were admitted to surgery service. Conclusions: This study highlights that the admitting service should be an area of focus for hospitals when developing programs to provide effective and cost-conscious care to hip fracture patients. PMID- 30479849 TI - Charlson Comorbidity Index Predicts 5-Year Survivorship of Surgically Treated Hip Fracture Patients. AB - Introduction: This study aims to assess the correlation of the age-adjusted Charlson comorbidity index (ACCI) with 5-year mortality in a surgically treated hip fracture population. Materials and Methods: A retrospective analysis was performed on 1057 patients aged 60 years and above who underwent surgery for hip fracture with a minimum of 5-year follow-up (92.2% 5-year follow-up rate) in a tertiary hospital. Manual review of patients' electronic hospital records was performed to record demographic data, comorbidities, and length of stay. Mortality data were extracted from the hospital's electronic medical records and corroborated with the National Electronic Health Record. Results: Of the 1057 patients, 283 (26.8%) were male. The majority of patients were 80 years of age and above (42.5%), with the oldest patient operated on age 102 with a mean age of 77.8 (8.6) years. Four hundred eighteen (39.5%) patients sustained extracapsular intertrochanteric fractures. The mean follow-up duration was 8 years and 3 days with an overall survivorship of 37.2%. A multiple regression model constructed with ACCI, age, gender, and fracture pattern demonstrated satisfactory predictive ability with a concordance statistic of 0.68. Patients with a higher ACCI category (>=6) had an increased 5-year mortality rate (41.8%) with an odds ratio of 13.6 (6.7-31.8, P < .001) compared to those with an ACCI category of 3 and below (89.3%). Discussion: The study demonstrates that ACCI correlated with 5 year mortality after surgical treatment of hip fracture. This information is pertinent in the counseling of patients with regard to their midterm survival following hip fracture surgery and may inform policy makers of the varied midterm survival rates in patients with differing ACCI scores and educate the allocation of health-care resources. Conclusion: The ACCI correlates with 5-year mortality after surgical treatment of hip fracture. PMID- 30479851 TI - Artificial intelligence and melanoma diagnosis: ignoring human nature may lead to false predictions. PMID- 30479852 TI - Subclinical oral involvement in patients with endemic pemphigus foliaceus. AB - Background: We have described a variant of endemic pemphigus foliaceus (EPF) in El Bagre area known as pemphigus Abreu-Manu. Our previous study suggested that Colombian EPF seemed to react with various plakin family proteins, such as desmoplakins, envoplakin, periplakin BP230, MYZAP, ARVCF, p0071 as well as desmoglein 1. Objectives: To explore whether patients affected by a new variant of endemic pemphigus foliaceus (El Bagre-EPF) demonstrated oral involvement. Materials and Methods: A case-control study was done by searching for oral changes in 45 patients affected by El Bagre-EPF, as well as 45 epidemiologically matched controls from the endemic area matched by demographics, oral hygiene habits, comorbidities, smoking habits, place of residence, age, sex, and work activity. Oral biopsies were taken and evaluated via hematoxylin and eosin staining, direct immunofluorescence, indirect immunofluorescence, confocal microscopy, and immunohistochemistry. Results: Radicular pieces and loss of teeth were seen in in 43 of the 45 El Bagre-EPF patients and 20 of the 45 controls (P < 0.001) (confidence interval [CI] 98%). Hematoxylin and eosin staining showed 23 of 45 El Bagre-EPF patients had corneal/subcorneal blistering and lymphohistiocytic infiltrates under the basement membrane zone and around the salivary glands, the periodontal ligament, and the neurovascular bundles in all cell junction structures in the oral cavity; these findings were not seen in the controls (P < 0.001) (CI 98%). The direct immunofluorescence, indirect immunofluorescence, confocal microscopy, and microarray staining displayed autoantibodies to the salivary glands, including their serous acini and the excretory duct cell junctions, the periodontal ligament, the neurovascular bundles and their cell junctions, striated muscle and their cell junctions, neuroreceptors, and connective tissue cell junctions. The autoantibodies were polyclonal. IgA autoantibodies were found in neuroreceptors in the glands and were positive in 41 of 45 patients and 3 of 45 controls. Conclusions: Patients affected by El Bagre-EPF have some oral anomalies and an immune response, primarily to cell junctions. The intrinsic oral mucosal immune system, including IgA and secretory IgA, play an important role in this autoimmunity. Our data contradict the hypothesis that pemphigus foliaceus does not affect the oral mucosa due to the desmoglein 1-desmoglein 3 compensation. PMID- 30479854 TI - Potential applications of topical oxygen therapy in dermatology. AB - Background: Topical oxygen therapy is a cosmetic procedure that is becoming more and more popular in dermatology; however, only a few articles on this topic are present in the literature. In this work we report our group experience with oxygen therapy as an adjuvant treatment in various dermatological conditions. Methods: Four studies were conducted. In the first study we used vehiculated oxygen therapy for diseases that cause hair loss. In the second study oxygen was used in the treatment of mild acne. In the third study moderate acne was treated with topical oxygen. In the fourth study chronic dermatological conditions such as psoriasis and atopic dermatitis were treated with this procedure. Results: In studies 1 and 2 the outcomes in groups who used topical oxygen therapy as an adjuvant treatment were better than in the groups that did not use it. Studies 3 and 4 also showed very good results, but no control groups were present in the study. Conclusion: Topical oxygen therapy was useful in the treatment of hair loss conditions, mild and moderate acne, and in chronic cutaneous diseases, showing effectiveness as a support therapy in all of these conditions. Further and larger studies should be conducted to better evaluate its effectiveness in dermatological conditions. PMID- 30479853 TI - The potential roles of herpesvirus and cytomegalovirus in the exacerbation of pemphigus vulgaris. AB - Background: Among exogenous etiologies, the critical role of microbial agents such as herpesviruses (HSV1/2) and cytomegalovirus (CMV) in triggering and flaring autoimmune conditions such as pemphigus vulgaris (PV) has been recently discovered. Objectives: The present study aimed to investigate the plausible role of these viruses in the exacerbation of PV using serological and molecular methods. Patients/Methods: Sixty patients with PV (30 with relapse type and 30 with remission type) were recruited for the purpose of this case-control study. Skin, mucosal, and throat specimens were obtained and examined for viruses by reverse transcriptase polymerase chain reaction. To determine the immunoglobulin G (IgG) titer, enzyme-linked immunosorbent assay was used. Results: Desmoglein1 specific IgG was positive in 56.7% of patients with the relapse form and in 20.0% of those with the remission form indicating a significant difference across the 2 groups (P = 0.003), but the rate of positivity for desmoglein3-specific IgG in the relapse and remission types was 76.7% and 63.3%, respectively, with no significant difference (P = 0.260). There was no difference in the mean levels of HSV-IgG and CMV-IgG in the relapse and remission groups. HSV and CMV positivity in PV patients was independent of the site of the samples. Using the multivariable linear regression model, the level of CMV-IgG in PV patients was directly affected by female sex and advanced ages. Conclusions: Our study could not demonstrate the role of HSV1/2 and CMV as triggering factors for PV exacerbation. Further studies are needed to evaluate the potential role of these viruses in PV exacerbation especially considering demographic variables. PMID- 30479856 TI - Onychoscopy: an observational study in 237 patients from the Kashmir Valley of North India. AB - Background: Nail disorders comprise approximately 10% of all dermatological conditions. Because diagnosis is not always possible by clinical means alone, additional diagnostic procedures may be required at times. Dermoscopy of nails (onychoscopy) has shown promising results in diagnosing various nail disorders and also avoids time-consuming investigations such as culture and biopsy. Objective: To study the dermoscopic features of various nail disorders to determine the correlation between KOH examination and onychoscopic patterns in patients with the clinical suspicion of onychomycosis, and to differentiate benign pigmented lesions from malignant ones. Methods: An open, observational and cross-sectional study of 237 patients was conducted. All patients underwent clinical examination and the affected nails were examined with a dermatoscope. The onychoscopic patterns were identified and recorded. Results: The study included 237 patients with the following diagnoses: 81 onychomycosis, 63 psoriasis, 27 lichen planus, 30 longitudinal melanonychia, 24 connective tissue disorders, 5 onychophagia and nail tics, 3 subungual verrucae, 2 glomus tumor, 1 Darier disease, and 1 enchondroma. The most common onychoscopic findings were spiked pattern in cases of onychomycosis, dilated and tortuous capillaries in cases of psoriasis, longitudinal streaks and nail fragmentation in cases of lichen planus, and enlarged capillaries in cases of connective tissue diseases. Limitations: The study was only observational and did not compare the results to biopsy and culture. Conclusions: Onychoscopy may be used as an important diagnostic tool when evaluating nail disorders. It should be used to aid in the diagnosis of various nail disorders and to avoid unnecessary and time-consuming investigations. PMID- 30479857 TI - A case of unilateral inflamed plaques with comedones of the face. PMID- 30479855 TI - New trends in botulinum toxin use in dermatology. AB - Background: Recent studies have highlighted new botulinum neurotoxin (BoNT) applications in the field of dermatology. Objective: To review current knowledge of BoNT use in dermatology. Methods: The literature of the last 5 five years has been reviewed. Results: We describe interesting protocols of BoNT treatment for hyperhidrosis (HH), hypertrophic scars and keloids, Raynaud phenomenon, facial flushing, oily skin, psoriasis, Hailey-Hailey disease, and cutaneous lesions like painful lesions and periorbital syringomas. Conclusions: Several skin conditions eligible for BoNT treatment have been described. After the wide application for HH treatment, scars as well as vascular and inflammatory skin disorders, oily skin and cutaneous lesions represent fields of application of BoNT. PMID- 30479858 TI - Human papillomavirus in skin tags: a case series. PMID- 30479859 TI - Chronic recurrent multifocal osteomyelitis with psoriatic skin manifestations in a 12-year-old female. PMID- 30479860 TI - Differentiation of pityriasis rubra pilaris from plaque psoriasis by dermoscopy. AB - Background: Diagnosing and differentiating pityriasis rubra pilaris (PRP) from other disorders can be a challenging task. Although histopathology remains the gold standard, it may not be feasible at times, especially in children. Being noninvasive, dermoscopy can be of great diagnostic importance in such a scenario. Dermoscopy overcomes the refractive properties of stratum corneum by interface medium or cross-polarization enabling easier visualization of lesions. Objective: To study the dermoscopic features of PRP and compare them with dermoscopic features of psoriasis. Patients and Methods: Retrospective observational analysis of dermoscopic characteristics of 28 patients with PRP (16) and psoriasis (12). Polarized dermoscopy at 10* magnification was performed and photographs were captured by Apple iPhone 7. The selection of dermoscopic variables was based on preexisting literature on the dermoscopic patterns of the 2 entities. Results: The most frequent dermoscopic criteria of PRP were the presence of a central hair (16/16; 100%), follicular plugs (11/16; 68.7%), and perifollicular yellow/orange halos (9/16; 56.2%). No vascular structures were seen in our cases of PRP. Psoriasis was characterized by regularly distributed dotted vessels (12/12; 100%) and white scales (8/12; 66.6%). Conclusions: Round-to-oval yellowish areas surrounding a central hair with or without follicular plugs represents the most frequent dermoscopic pattern of PRP. PMID- 30479861 TI - Dermoscopy features of acquired reactive perforating collagenosis: a case series. PMID- 30479863 TI - Basal cell carcinoma: variation in invasion depth by subtype, sex, and anatomic site in 4,565 cases. AB - Background: The depth of invasion by basal cell carcinoma (BCC) subtypes varies. Objective: To investigate BCC invasion depth variation by subtype and anatomic site. Method: A prospective consecutive case series of excised BCC from 2009 to 2014 in a single Australian clinic. Results: Descending mean depths for a total of 4,565 BCC cases by subtype were as follows: nodulocystic, 1.9 mm (n = 84, 95% CI: 1.70-2.03, P = 0.66); nodular, 1.6 mm (n = 947, 95% CI: 1.53-1.63, P < 0.0001); aggressive, 1.5 mm (n = 925, 95% CI: 1.44-1.59, P < 0.0001); superficial combined with nodular, 0.9 mm (n = 1,081, 95% CI: 0.83-0.90, P < 0.0001); and superficial, 0.3 mm (n = 1,528, 95% CI: 0.32-0.36, P < 0.0001). Deeper invasion was associated with increased chronic sunlight exposed sites. The deepest aggressive BCCs occurred on the neck with a mean depth of 1.8 mm (n = 46, 95% CI: 1.47-2.21). Conclusion: We found significant differences in the depth of invasion for BCCs by sex, subtype, and anatomic site. For BCC with characteristics matching this study, overall adequate microscopic excision depths are proposed: superficial, 1.0 mm; superficial combined with nodular, 2.0 mm; nodular, 3.0 mm; and aggressive, 3.0 mm. PMID- 30479862 TI - Clinicopathologically problematic melanocytic tumors: a case-based review. AB - Background: In spite of recent advances in the histopathological and molecular diagnosis of melanocytic neoplasms, a certain proportion of these lesions remain a daunting challenge for both the clinician and the pathologist. Objectives: To emphasize the importance of close collaboration between clinicians and pathologists in case of problematic melanocytic lesions. Patients: We report and discuss 5 problematic scenarios of melanocytic lesions, including tumoral melanosis, nevoid melanoma, lentiginous melanoma, spitzoid melanoma and BAPoma that may pose diagnostic difficulties in our practice. Conclusions: Clinico dermoscopic-pathological correlation, with incorporation of all the available data, in problematic melanocytic skin neoplasms is of paramount importance for accurate diagnosis. PMID- 30479864 TI - Challenging clinical diagnosis of 2 lesions on the back: dermoscopy gives the clue. PMID- 30479865 TI - A tiny facial pigmented macule: overcoming the diagnostic challenge. PMID- 30479866 TI - Impact of clinical and personal data in the dermoscopic differentiation between early melanoma and atypical nevi. AB - Background: Differential diagnosis of clinically atypical nevi (aN) and early melanomas (eMM) still represents a challenge even for experienced dermoscopists, as dermoscopy alone is not sufficient to adequately differentiate these equivocal melanocytic skin lesions (MSLs). Objectives: The objectives of this study were to investigate what were the most relevant parameters for noninvasive differential diagnosis between eMM and aN among clinical, personal, and dermoscopic data and to evaluate their impact as risk factors for malignancy. Methods: This was a retrospective study performed on 450 MSLs excised from 2014 to 2016 with a suspicion of malignancy. Dermoscopic standardized images of the 450 MSLs (300 aN and 150 eMM) were collected and evaluated. Patients' personal data (ie, age, gender, body site, maximum diameter) were also recorded. Dermoscopic evaluations were performed by 5 different experts in dermoscopy blinded to histopathological diagnosis. Fleiss' kappa was calculated to measure concordance level between experts in the description of dermoscopic parameters for each MSL. The power of the studied variables in discriminating malignant from benign lesions was also investigated through F-statistics. Results: The variables age and maximum diameter supplied the highest discriminant power (F = 253 and 227, respectively). Atypical network, blue white veil and white shiny streaks were the most significant dermoscopic patterns suggestive of malignancy (F = 110, 104 and 99.5, respectively). Shiny white streaks was the only dermoscopic parameter to obtain satisfactory concordance value. Gender was not a discriminant factor. The specific statistical weight of clinical and personal data (ie, "patient's age" and "lesion diameter") surpassed those of atypical dermoscopic features. Conclusions: The objective clinical and personal data collected here could supply a fundamental contribution in the correct diagnosis of equivocal MSLs and should be included in diagnostic algorithms along with significant dermoscopic features (ie, atypical network, blue-white veil, and shiny white streaks). PMID- 30479867 TI - Early dermoscopic sign of folliculotropism in patients with mycosis fungoides. PMID- 30479869 TI - A white-bluish plaque with rapid growth after palpation. PMID- 30479868 TI - Degree of differentiation of cutaneous squamous cell carcinoma: a comparison between a Swedish cohort of organ transplant recipients and immunocompetent patients. AB - Background: Organ transplant recipients (OTRs) have a very high risk of developing cutaneous squamous cell carcinoma (cSCC). Immunosuppressed OTRs may have a higher proportion of poorly differentiated cSCC than non-OTRs. Objectives: The aim of this study was to investigate the degree of differentiation of cSCCs in OTRs compared with immunocompetent individuals. Patients/Methods: Data from the Swedish Cancer Registry were crosschecked with data from the Transplant registry of the Transplant Institute at Sahlgrenska University Hospital in Gothenburg, Sweden. All OTRs with a diagnosis of cSCC, basosquamous carcinoma, and/or cSCC in situ established at the Department of Dermatology, Sahlgrenska University Hospital, during 2002-2015 were included. The control group consisted of non-OTRs with the same diagnoses during the same time period. Results: During 2002-2015, 82 OTRs diagnosed with 515 tumors and 883 non-OTRs with 1,247 tumors were included. OTRs developed 0.47 tumors/year vs 0.10 tumors/year for non-OTRs, but no significant differences were observed in the degree of tumor differentiation of invasive cSCCs between OTRs and non-OTRs (P = 0.4). The distribution of poorly, moderately, and well-differentiated invasive cSCCs among OTRs and non-OTRs were 8.5% vs 12.5%, 22.1% vs 29.9%, and 69.4% vs 57.6%, respectively. Conclusions: OTRs do not develop a higher proportion of poorly differentiated cSCCs than non-OTRs. PMID- 30479870 TI - Dermoscopic findings of perifollicular pigmentation associated with vandetanib. PMID- 30479871 TI - Health Economics and Outcomes Research of Wound Care: Overview of Methodology. AB - Objective: To provide an overview of comparative effectiveness research (CER) methodology and discuss the challenges of health economics and outcomes research (HEOR) in wound care. Approach: Narrative description of HEOR methodology with supporting references. Results: With the increasing costs of clinical trials, the use of observational studies in a real-world setting will be essential. Wound care clinicians should understand the importance of proper methods for conducting CER studies. Propensity score methods and marginal structural modeling can create a "quasi-randomized" environment for measuring wound closure and can help drive informed decision-making. In wound care, a paucity of HEOR information is available with great reluctance to use this information by payers, the Food and Drug Administration, the Centers for Medicare & Medicaid Services, and other agencies. Furthermore, a limited amount of high-quality retrospective data to measure wound care outcomes exist. The U.S. Wound Registry is one of few data sources that accurately reports on outcomes for all wound types and is a Qualified Clinical Data Registry. Innovation and Conclusions: Several CER approaches in observational studies provide sufficiently detailed information to help decision-makers make informed choices about wound care products regarding efficacy in the real-world setting. Using CER and cost-effectiveness studies succinctly needs to be incorporated if progress is to be made in improving wound care outcomes and reducing cost. PMID- 30479874 TI - Erratum. AB - [This corrects the article on p. 20 in vol. 7.]. PMID- 30479872 TI - Early vs. late MRD response- and risk-based treatment intensification of childhood acute lymphoblastic leukemia: a prospective pilot study from Saudi Arabia. AB - Background: Refinement of risk-based treatment stratification by minimal residual disease (MRD) at different time points has improved outcomes of childhood acute lymphoblastic leukemia (ALL). In this prospective study we evaluated effects of such stratification, including intensification of therapy based on response assessment at day-15 and MRD at day-29 of induction to test if treatment intensification would improve outcomes. Methods: 241 patients, 1-14 years old, newly diagnosed with ALL, were recruited and stratified by risk and MRD response into three treatment Arms (A, B, or C). Arm A was modified from COG AALL0331, B from AALL0232, and C from AALL0232 and AALL0434. Assignments were according to NCI risk, phenotype, rapid vs. slow early response (SER), steroid pretreatment, MLL rearrangement (MLLR), CNS3, and testicular involvement. Patients on Arm A had treatment intensified early based on day-15 marrow results or late based on end of-induction MRD. Results: 5-year OS, EFS, and CIR were 89.5% +/- 4.0%, 87.6% +/- 4.3%, and 7.1% +/- 3.5%. No significant difference was found by B- vs. T cell phenotype. 5-year OS, EFS, and CIR for B-cell ALL were 90.5% +/- 2.4%, 88.7% +/- 2.6%, and 6.4% +/- 2.0%. Outcomes for patients with t(1;19)/TCF3-PBX1 and MLLR were significantly (p <= 0.05) worse than for other patients. MRD level at end-of induction associated with outcomes, but association with a specific MRD value at end-of-induction varied significantly by NCI-risk group. Late treatment intensification based on end-of-induction MRD significantly improved survival outcomes for NCI-SR patients, however, patients with NCI-HR and positive MRD at end-of-induction had significantly inferior outcomes despite intensification. MRD transitions between day-15 and day-29 of induction associated with differences for OS and EFS. Conclusions: Arm switching to a more intensive protocol had mixed results. Assigning patients by end-of-induction MRD-risk alone did not reflect response kinetics of the different NCI-risk groups. Although late treatment intensification improved outcomes of NCI-SR patients with positive MRD at end-of induction, further refinement is needed to improve outcomes of NCI-HR with SER. Integration of NCI-risk group with specific MRD value and time point allows more refined treatment stratification.Trial Registration Protocols were approved by King Abdullah International Medical Research Center and Ethics Review Committee RC08053J. PMID- 30479873 TI - Intravitreal Trimethoprim and Sulfamethoxazole Toxicity to the Retina of Albino Rabbits. AB - Purpose: To evaluate retinal toxicity of intravitreal trimethoprim sulfamethoxazole (TMP-SMX) in an albino rabbit model. Methods: Albino rabbits (N = 10) were treated in the right eye with the maximum intravitreal dose of TMP-SMX mixture (1600 MUg/8000 MUg /0.1 mL), while 0.1 mL saline was injected into the vitreous of the left eye. Clinical examination and electrophysiological (electroretinogram [ERG] and visual evoked potentials [VEPs]) testing were conducted before injection, 3 days, 1, 2, and 4 weeks postinjection. Retinal structure and expression of glial fibrillary acidic protein (GFAP) were assessed from histology and immunocytochemistry respectively at the end of the follow-up period. Results: Clinical examination was normal throughout the follow-up period. ERG responses from the experimental eyes were similar to those recorded from the control eyes, but the sum of oscillatory potentials decreased in the experimental eyes at 2 weeks postinjection. The VEP responses, elicited by stimulation of the experimental eyes, were abnormal having reduced amplitude and prolonged implicit time. Histological damage in the experimental eyes was expressed by thickness reduction of whole, outer, and inner nuclear layers. GFAP was expressed in retinal Muller cells of all experimental eyes, but none of control eyes. Conclusions: A single intravitreal injection of TMP-SMX mixture (1600 MUg/8000 MUg, respectively) causes functional and structural damage to the inner retina and retinal output. Signs of retinal stress were also evident by GFAP expression in retinal Muller cells of all experimental eyes. Therefore, the use of TMP-SMX via intravitreal administration should be done with caution. Translational Relevance: These findings highlight the risk of retinal toxicity after intravitreal injection of trimethoprim-sulfamethoxazole and emphasize that this treatment should be carefully considered. PMID- 30479875 TI - Erratum. AB - [This corrects the article on p. 28 in vol. 7, PMID: 30356944.]. PMID- 30479876 TI - Prevalence and Determinants Associated With Spectacle-Wear Compliance in Aphakic Infants. AB - Purpose: We assess the prevalence of spectacle wear and the factors associated with compliance among aphakic infants with congenital cataracts who underwent lens extraction in South China. Methods: Infants aged 3 months to 3 years were enrolled from among participants in the Childhood Cataract Program of the Chinese Ministry of Health (CCPMOH). The prevalence and potential determinants of spectacle-wearing compliance were identified from interviews with the infants' caregivers. Results: Among 192 infant caregivers, the mean (SD) age of the infants was 1.89 (0.50) years, and 57% were males. Compliance was 30.9% in the 3 month- to 1-year-old age group, 78.0% in the 1- to 2-year-old age group, and 87.0% in the 2- to 3-year-old age group. The following two factors were associated with spectacle-wearing compliance: softness of the spectacles frame (beta = 1.273, P = 0.002, odds ratio [OR] = 3.6, 95% confidence interval [CI] = 1.6-8.0) and communication with other caregivers regarding the spectacle-wearing experience (beta = -2.955, P = 0.034, OR = 0.1, 95% CI = 0-0.8). Conclusions: Compliance with spectacle wear was low during the earlier stage, but increased with time in aphakic infants. However, overall compliance should be improved. Therefore, efficient strategies aimed at improving spectacle-wearing compliance are needed. Translational Relevance: These findings reveal the low spectacle wearing compliance in aphakic infants and support useful information to improve compliance. PMID- 30479877 TI - Rho-Kinase Inhibition Reduces Myofibroblast Differentiation and Proliferation of Scleral Fibroblasts Induced by Transforming Growth Factor beta and Experimental Glaucoma. AB - Purpose: We evaluated prevention of transforming growth factor beta (TGFbeta) induced transdifferentiation of cultured scleral fibroblasts to myofibroblasts by rho-associated protein kinase (ROCK) inhibitors. Additionally, we tested whether local delivery of ROCK inhibitors reduced scleral fibroblast proliferation in response to chronic intraocular pressure (IOP) elevation. Methods: Primary human peripapillary sclera (PPS) fibroblasts were cultured and treated with TGFbeta to induce myofibroblast transdifferentiation, as determined by immunoblot assessment of alpha smooth muscle actin (SMA) levels and collagen gel contraction. Cells were treated with the ROCK inhibitors Y27632, fasudil, and H1152 before TGFbeta treatment. ROCK activity in TGFbeta-treated fibroblasts and sclera from ocular hypertensive mice was assessed by measuring phosphorylation of the ROCK substrate MYPT1 at Thr696. Fibroblast proliferation following IOP elevation and ROCK inhibitor treatment was assessed by an enzyme-linked immunosorbent (ELISA) assay. Results: ROCK inhibitors H1152 (10MUM), Y27632 (10 MUM), and fasudil (5MUM) reduced SMA expression 72%, 85%, and 68%, respectively. Collagen gel contraction was reduced by 36% (P < 0.001), 27% (P = 0.0003), and 33% (P = 0.0019) following treatment with fasudil (25 MUM), Y27632 (10 MUM), and H1152 (10MUM). ROCK activity induced by TGFbeta rose 4.74 +/- 1.9 times over control at 4 hours (P = 0.0004) and 2.4 +/- 0.47-fold (P = 0.0016) in sclera after IOP elevation. Proliferation of scleral fibroblasts after chronic IOP elevation was reduced 77% by Y27632 (P = 0.001) and 84% by fasudil (P = 0.0049). Conclusions: ROCK inhibitors reduce TGFbeta-induced myofibroblast transdifferentiation and glaucoma induced scleral cell proliferation. Translational Relevance: These findings suggest altered fibroblast activity promoted by ROCK inhibitors could modify scleral biomechanics and be relevant to glaucoma treatment. PMID- 30479879 TI - Erratum. AB - [This corrects the article on p. 6 in vol. 3.]. PMID- 30479878 TI - Noninvasive Assessment of Retinal Blood Flow Using a Novel Handheld Laser Speckle Contrast Imager. AB - Purpose: We assessed the image quality and reproducibility of blood flow measurements from a novel handheld laser speckle imager in handheld and stabilized use cases. Methods: Eleven dilated human subjects were imaged with the XyCAM Handheld Retinal Imager investigational device (XyCAM HRI) in the handheld and stabilized use case in nine consecutive imaging sessions. Subjects then underwent standard color fundus photography using a Topcon TRC 50DX. The vessel to-background contrast of the XyCAM HRI red-free photo was compared to the fundus photograph, while the coefficient of variation of blood flow measurements in specific arteries and veins also was determined. Results: Vessel-to-background contrast was statistically greater in the handheld use case when compared to the standard color fundus photographs (P = 0.01). Estimates of mean blood flow velocity (BFV) were highly correlated between the stabilized and handheld use case (r 2 = 0.96). Peak velocity estimates in arteries were significantly higher than those in veins (P < 0.05). Conclusions: The XyCAM HRI prototype can acquire fundus photographs with the same or better level of clarity as color fundus photographs, and reproducibly acquire functional blood flow information in the handheld use case. Translational Relevance: To our knowledge, this is the first human study of a handheld laser speckle retinal imaging device. Determination of retinal blood flow has applications to ophthalmic and systemic disease and a portable handheld retinal imager that determines blood flow may be widely adopted at the point of care. PMID- 30479881 TI - Greenhouse gas flux with reflooding of a drained salt marsh soil. AB - Salt marshes are highly effective carbon (C) sinks and bury more C per square meter annually than any other ecosystem. Reclamation and anthropogenic impacts, however, have resulted in extensive losses of salt marshes. Carbon credits can be generated and sold by restoring marshes, but only if C sequestration and net reductions in greenhouse gases (GHG) are reliably quantified. Restored marshes, however, may exhibit different patterns of GHG emissions than natural marshes and it is possible that they could temporarily become sources of N2O even in the usually N-limited estuarine environment. Research on short-term GHG flux following salt marsh restoration is limited to studies of two restored marshes which examined GHG flux more than six months after the return of tidal flooding. Here we report on a laboratory experiment in which soil cores collected from a drained agricultural marsh on the St. Lawrence Estuary were flooded with estuary water. Gas flux measurements immediately after flooding revealed small increases in N2O and CH4, but a large decline in CO2 yielding, from a climatic perspective, a net cooling effect over the observation period. In addition to restoring the land's capacity to sequester C once a marsh develops, returning tidal flooding thus appears to have the added benefit of stemming large ongoing C losses. With more than 400 km2 of undeveloped dykeland, Eastern Canada is well positioned to restore large sections of marsh and contribute to reducing atmospheric CO2 concentrations. PMID- 30479880 TI - Measuring the Contrast Sensitivity Function Using the qCSF Method With 10 Digits. AB - Purpose: The Bayesian adaptive quick contrast sensitivity function (qCSF) method with a 10-letter identification task provides an efficient CSF assessment. However, large populations are unfamiliar with letters and cannot benefit from this test. To overcome the barrier, we conducted this study. Method: A new font for digits (0~9) was created. The digits were then filtered with a raised cosine filter, rescaled to different sizes to cover spatial frequencies from 0.5 to 16 cycles per degree (cpd), and used as stimuli in a 10-alternative forced choice (10AFC) digit identification task. With the 10AFC digit identification task, the CSFs of five young and five old observers were measured using the qCSF and Psi methods. The estimates from the latter served as reference. Results: The new digit font showed significantly improved similarity structure, Levene's test, F(1, 88) = 6.36, P = 0.014. With the 10-digit identification task, the CSFs obtained with the qCSF method matched well with those obtained with the Psi method (root mean square error [RMSE] = 0.053 log10 units). With approximately 30 trials, the precision of the qCSF method reached 0.1 log10 units. With approximately 75 trials, the precision of the CSFs obtained with the qCSF was comparable to that of the CSFs measured by the Psi method in 150 trials. Conclusions: The qCSF with the 10 digit identification task is validated for both young and old observers. Translational Relevance: The qCSF method with the 10 digit identification task provides an efficient and precise CSF test especially for people who are unfamiliar with letters. PMID- 30479882 TI - Toxicity of Melaleuca alternifolia essential oil to the mitochondrion and NAD+/NADH dehydrogenase in Tribolium confusum. AB - Background: In our previous study, Melaleuca alternifolia essential oil (EO) was considered to have an insecticidal effect by acting on the mitochondrial respiratory chain in insects. However, the mode of action is not fully understood. Methods: In this study, we investigated the insecticidal efficacy of the M. alternifolia EO against another major stored-product pest, Tribolium confusum Jacquelin du Val. Rarefaction and vacuolization of the mitochondrial matrix were evident in oil-fumigated T. confusum adults. Results: Alterations to the mitochondria confirmed the insecticidal effect of the M. alternifolia EO. Furthermore, comparative transcriptome analysis of T. confusum using RNA-seq indicated that most of the differentially expressed genes were involved in insecticide detoxification and mitochondrial function. The biochemical analysis showed that the intracellular NAD+/NADH ratio is involved in the differential effect of the M. alternifolia EO. Discussion: These results led us to conclude that NAD+/NADH dehydrogenase may be the prime target site for the M. alternifolia EO in insects, leading to blocking of the mitochondrial respiratory chain. PMID- 30479883 TI - The relationship between social rank and spatial learning in pheasants, Phasianus colchicus: cause or consequence? AB - Individual differences in performances on cognitive tasks have been found to differ according to social rank across multiple species. However, it is not clear whether an individual's cognitive performance is flexible and the result of their current social rank, modulated by social interactions (social state dependent hypothesis), or if it is determined prior to the formation of the social hierarchy and indeed influences an individual's rank (prior attributes hypothesis). We separated these two hypotheses by measuring learning performance of male pheasants, Phasianus colchicus, on a spatial discrimination task as chicks and again as adults. We inferred adult male social rank from observing agonistic interactions while housed in captive multi-male multi-female groups. Learning performance of adult males was assayed after social rank had been standardised; by housing single males with two or four females. We predicted that if cognitive abilities determine social rank formation we would observe: consistency between chick and adult performances on the cognitive task and chick performance would predict adult social rank. We found that learning performances were consistent from chicks to adults for task accuracy, but not for speed of learning and chick learning performances were not related to adult social rank. Therefore, we could not support the prior attributes hypothesis of cognitive abilities aiding social rank formation. Instead, we found that individual differences in learning performances of adults were predicted by the number of females a male was housed with; males housed with four females had higher levels of learning performance than males housed with two females; and their most recent recording of captive social rank, even though learning performance was assayed while males were in a standardized, non-competitive environment. This does not support the hypothesis that direct social pressures are causing the inter individual variation in learning performances that we observe. Instead, our results suggest that there may be carry-over effects of aggressive social interactions on learning performance. Consequently, whether early life spatial learning performances influence social rank is unclear but these performances are modulated by the current social environment and a male's most recent social rank. PMID- 30479885 TI - beadplexr: reproducible and automated analysis of multiplex bead assays. AB - Multiplex bead assays are an extension of the commonly used sandwich ELISA. The advantage over ELISA is that they make simultaneous evaluation of several analytes possible. Several commercial assay systems, where the beads are acquired on a standard flow cytometer, exist. These assay systems come with their own software tool for analysis and evaluation of the concentration of the analyzed analytes. However, these tools are either tied to particular commercial software or impose other limitations to their licenses, such as the number of events which can be analyzed. In addition, all these solutions are 'point and click' which potentially obscures the steps taken in the analysis. Here we present beadplexer, an open-source R-package for the reproducible analysis of multiplex bead assay data. The package makes it possible to automatically identify bead clusters, and provides functionality to easily fit a standard curve and calculate the concentrations of the analyzed analytes. beadplexer is available from CRAN and from https://gitlab.com/ustervbo/beadplexr. PMID- 30479884 TI - Serotonin 5-HT1A receptor binding and self-transcendence in healthy control subjects-a replication study using Bayesian hypothesis testing. AB - Objective: A putative relationship between markers for the serotonin system and the personality scale self-transcendence (ST) and its subscale spiritual acceptance (SA) has been demonstrated in a previous PET study of 5-HT1A receptor binding in healthy control subjects. The results could however not be replicated in a subsequent PET study at an independent centre. In this study, we performed a replication of our original study in a larger sample using Bayesian hypothesis testing to evaluate relative evidence both for and against this hypothesis. Methods: Regional 5-HT1A receptor binding potential (BPND) was examined in 50 healthy male subjects using PET with the radioligand [11C]WAY100635. 5 HT1Aavailability was calculated using the simplified reference tissue model (SRTM) yielding regional BPND. ST and SA were measured using the Temperament and Character Inventory (TCI) questionnaire. Correlations between ST/SA scores and 5 HT1ABPND in frontal cortex, hippocampus and raphe nuclei were examined by calculation of default correlation Bayes factors (BFs) and replication BFs. Results: There were no significant correlations between 5-HT1A receptor binding and ST/SA scores. Rather, five of six replication BFs provided moderate to strong evidence for no association between 5-HT1A availability and ST/SA, while the remaining BF provided only weak evidence. Conclusion: We could not replicate our previous findings of an association between 5-HT1A availability and the personality trait ST/SA. Rather, the Bayesian analysis provided evidence for a lack of correlation. Further research should focus on whether other components of the serotonin system may be related to ST or SA. This study also illustrates how Bayesian hypothesis testing allows for greater flexibility and more informative conclusions than traditional p-values, suggesting that this approach may be advantageous for analysis of molecular imaging data. PMID- 30479886 TI - Ecological divergence of burying beetles into the forest canopy. AB - Closely related species with overlapping geographic ranges encounter a significant challenge: they share many ecological traits and preferences but must partition resources to coexist. In Ontario, potentially eleven species of carrion beetles (Coleoptera: Silphidae) live together and require vertebrate carrion for reproduction. Their reliance on an ephemeral and uncommon resource that is unpredictable in space and time is thought to create intense intra- and interspecific competition. Evidence suggests that burying beetle species reduce competition by partitioning carrion for breeding across different habitats, temperatures, and seasons. Here, we test predictions of an alternative axis for partitioning carrion: vertical partitioning between the ground and forest canopy. We conducted a survey of carrion beetles from May to July 2016 at the Queen's University Biological Station across 50 randomly generated points using baited lethal traps at zero and six metres. Ground traps yielded more species and individuals compared to those in the canopy, and the number of individuals and species caught increased through the season in both trap types. Ground and canopy traps were accurately distinguished by the presence or absence of three species: ground traps contained more Nicrophorus orbicollis and Necrophila americana, while canopy traps contained more Nicrophorus pustulatus. We trapped 253 N. pustulatus in the canopy, but only 60 on the ground. N. pustulatus is thought to be rare across its geographic range, but our results suggest it is uniquely common in canopy habitats, demonstrating a vertical partitioning of habitat and resources. Our results are consistent with N. pustulatus having diverged into canopy habitats as a strategy to coexist with closely related sympatric species when competing for similar resources. We still, however, do not know the traits that allow N. pustulatus to flourish in the canopy, exactly how N. pustulatus uses canopy resources for breeding, or the factors that restrict the expansion of other burying beetles into this habitat. PMID- 30479887 TI - Enhancement of a protocol purifying T1 lipase through molecular approach. AB - T1 Lipase is a thermostable secretary protein of Geobacillus zalihae strain previously expressed in a prokaryotic system and purified using three-step purification: affinity 1, affinity 2, and ion exchange chromatography (IEX). This approach is time consuming and offers low purity and recovery yield. In order to enhance the purification strategy of T1 lipase, affinity 2 was removed so that after affinity 1, the cleaved Glutathione S-transferase (GST) and matured T1 lipase could be directly separated through IEX. Therefore, a rational design of GST isoelectric point (pI) was implemented by prediction using ExPASy software in order to enhance the differences of pI values between GST and matured T1 lipase. Site-directed mutagenesis at two locations flanking the downstream region of GST sequences (H215R and G213R) was successfully performed. Double point mutations changed the charge on GST from 6.10 to 6.53. The purified lipase from the new construct GST tag mutant-T1 was successfully purified using two steps of purification with 6,849 U/mg of lipase specific activity, 33% yield, and a 44 fold increase in purification. Hence, the increment of the pI values in the GST tag fusion T1 lipase resulted in a successful direct separation through IEX and lead to successful purification. PMID- 30479888 TI - Optimizing the trainable B-COSFIRE filter for retinal blood vessel segmentation. AB - Segmentation of the retinal blood vessels using filtering techniques is a widely used step in the development of an automated system for diagnostic retinal image analysis. This paper optimized the blood vessel segmentation, by extending the trainable B-COSFIRE filter via identification of more optimal parameters. The filter parameters are introduced using an optimization procedure to three public datasets (STARE, DRIVE, and CHASE-DB1). The suggested approach considers analyzing thresholding parameters selection followed by application of background artifacts removal techniques. The approach results are better than the other state of the art methods used for vessel segmentation. ANOVA analysis technique is also used to identify the most significant parameters that are impacting the performance results (p-value ! 0.05). The proposed enhancement has improved the vessel segmentation accuracy in DRIVE, STARE and CHASE-DB1 to 95.47, 95.30 and 95.30, respectively. PMID- 30479889 TI - A new microvertebrate assemblage from the Mussentuchit Member, Cedar Mountain Formation: insights into the paleobiodiversity and paleobiogeography of early Late Cretaceous ecosystems in western North America. AB - The vertebrate fauna of the Late Cretaceous Mussentuchit Member of the Cedar Mountain Formation has been studied for nearly three decades, yet the fossil-rich unit continues to produce new information about life in western North America approximately 97 million years ago. Here we report on the composition of the Cliffs of Insanity (COI) microvertebrate locality, a newly sampled site containing perhaps one of the densest concentrations of microvertebrate fossils yet discovered in the Mussentuchit Member. The COI locality preserves osteichthyan, lissamphibian, testudinatan, mesoeucrocodylian, dinosaurian, metatherian, and trace fossil remains and is among the most taxonomically rich microvertebrate localities in the Mussentuchit Member. To better refine taxonomic identifications of isolated theropod dinosaur teeth, we used quantitative analyses of taxonomically comprehensive databases of theropod tooth measurements, adding new data on theropod tooth morphodiversity in this poorly understood interval. We further provide the first descriptions of tyrannosauroid premaxillary teeth and document the earliest North American record of adocid remains, extending the appearance of this ancestrally Asian clade by 5 million years in western North America and supporting studies of pre-Cenomaninan Laurasian faunal exchange across Beringia. The overabundance of mesoeucrocodylian remains at the COI locality produces a comparatively low measure of relative biodiversity when compared to other microvertebrate sites in the Mussentuchit Member using both raw and subsampling methods. Much more microvertebrate research is necessary to understand the roles of changing ecology and taphonomy that may be linked to transgression of the Western Interior Seaway or microhabitat variation. PMID- 30479890 TI - Honey bee viruses in Serbian colonies of different strength. AB - Protection of honey bees is of great economic importance because of their role in pollination. Crucial steps towards this goal are epidemiological surveys of pathogens connected with honey bee losses. In this study deformed wing virus (DWV), chronic bee paralysis virus (CBPV), acute bee paralysis virus (ABPV) and sacbrood virus (SBV) were investigated in colonies of different strength located in five regions of Serbia. The relationship between colony strength and virus occurrence/infection intensity were assessed as well as the genetic relationship between virus sequences from Serbia and worldwide. Real-time RT-PCR analyses detected at least one virus in 87.33% of colonies. Single infection was found in 28.67% colonies (21.33%, 4.00%, 2.67% and 0.67% in cases of DWV, ABPV, SBV and CBPV, respectively). In the majority of colonies (58.66%) more than one virus was found. The most prevalent was DWV (74%), followed by ABPV, SBV and CBPV (49.30%, 24.00% and 6.70%, respectively). Except for DWV, the prevalence of the remaining three viruses significantly varied between the regions. No significant differences were found between colony strength and either (i) the prevalence of DWV, ABPV, SBV, CBPV and their combinations, or (ii) DWV infection levels. The sequences of honey bee viruses obtained from bees in Serbia were 93-99% identical with those deposited in GenBank. PMID- 30479891 TI - MTBseq: a comprehensive pipeline for whole genome sequence analysis of Mycobacterium tuberculosis complex isolates. AB - Analyzing whole-genome sequencing data of Mycobacterium tuberculosis complex (MTBC) isolates in a standardized workflow enables both comprehensive antibiotic resistance profiling and outbreak surveillance with highest resolution up to the identification of recent transmission chains. Here, we present MTBseq, a bioinformatics pipeline for next-generation genome sequence data analysis of MTBC isolates. Employing a reference mapping based workflow, MTBseq reports detected variant positions annotated with known association to antibiotic resistance and performs a lineage classification based on phylogenetic single nucleotide polymorphisms (SNPs). When comparing multiple datasets, MTBseq provides a joint list of variants and a FASTA alignment of SNP positions for use in phylogenomic analysis, and identifies groups of related isolates. The pipeline is customizable, expandable and can be used on a desktop computer or laptop without any internet connection, ensuring mobile usage and data security. MTBseq and accompanying documentation is available from https://github.com/ngs fzb/MTBseq_source. PMID- 30479893 TI - Soil moisture dynamics under two rainfall frequency treatments drive early spring CO2 gas exchange of lichen-dominated biocrusts in central Spain. AB - Background: Biocrusts, communities dominated by mosses, lichens, cyanobacteria, and other microorganisms, largely affect the carbon cycle of drylands. As poikilohydric organisms, their activity time is often limited to short hydration events. The photosynthetic and respiratory response of biocrusts to hydration events is not only determined by the overall amount of available water, but also by the frequency and size of individual rainfall pulses. Methods: We experimentally assessed the carbon exchange of a biocrust community dominated by the lichen Diploschistes diacapsis in central Spain. We compared the effect of two simulated precipitation patterns providing the same overall amount of water, but with different pulse sizes and frequency (high frequency: five mm/day vs. low frequency: 15 mm/3 days), on net/gross photosynthesis and dark respiration. Results: Radiation and soil temperature, together with the watering treatment, affected the rates of net and gross photosynthesis, as well as dark respiration. On average, the low frequency treatment showed a 46% +/- 3% (mean +/- 1 SE) lower rate of net photosynthesis, a 13% +/- 7% lower rate of dark respiration, and a 24% +/- 8% lower rate of gross photosynthesis. However, on the days when samples of both treatments were watered, no differences between their carbon fluxes were observed. The carbon flux response of D. diacapsis was modulated by the environmental conditions and was particularly dependent on the antecedent soil moisture. Discussion: In line with other studies, we found a synergetic effect of individual pulse size, frequency, environmental conditions, and antecedent moisture on the carbon exchange fluxes of biocrusts. However, most studies on this subject were conducted in summer and they obtained results different from ours, so we conclude that there is a need for long-term experiments of manipulated precipitation impacts on the carbon exchange of biocrusts. This will enable a more complete assessment of the impacts of climate change-induced alterations in precipitation patterns on biocrust communities. PMID- 30479892 TI - Integration of phylogenomics and molecular modeling reveals lineage-specific diversification of toxins in scorpions. AB - Scorpions have evolved a variety of toxins with a plethora of biological targets, but characterizing their evolution has been limited by the lack of a comprehensive phylogenetic hypothesis of scorpion relationships grounded in modern, genome-scale datasets. Disagreements over scorpion higher-level systematics have also incurred challenges to previous interpretations of venom families as ancestral or derived. To redress these gaps, we assessed the phylogenomic relationships of scorpions using the most comprehensive taxonomic sampling to date. We surveyed genomic resources for the incidence of calcins (a type of calcium channel toxin), which were previously known only from 16 scorpion species. Here, we show that calcins are diverse, but phylogenetically restricted only to parvorder Iurida, one of the two basal branches of scorpions. The other branch of scorpions, Buthida, bear the related LKTx toxins (absent in Iurida), but lack calcins entirely. Analysis of sequences and molecular models demonstrates remarkable phylogenetic inertia within both calcins and LKTx genes. These results provide the first synapomorphies (shared derived traits) for the recently redefined clades Buthida and Iurida, constituting the only known case of such traits defined from the morphology of molecules. PMID- 30479894 TI - The most complete enantiornithine from North America and a phylogenetic analysis of the Avisauridae. AB - The most complete known North American enantiornithine was collected in 1992 but never formally described. The so-called "Kaiparowits avisaurid" remains one of the most exceptional Late Cretaceous enantiornithine fossils. We recognize this specimen as a new taxon, Mirarce eatoni (gen. et sp. nov.), and provide a complete anatomical description. We maintain that the specimen is referable to the Avisauridae, a clade previously only known in North America from isolated tarsometatarsi. Information from this specimen helps to clarify evolutionary trends within the Enantiornithes. Its large body size supports previously observed trends toward larger body mass in the Late Cretaceous. However, trends toward increased fusion of compound elements across the clade as a whole are weak compared to the Ornithuromorpha. The new specimen reveals for the first time the presence of remige papillae in the enantiornithines, indicating this feature was evolved in parallel to dromaeosaurids and derived ornithuromorphs. Although morphology of the pygostyle and (to a lesser degree) the coracoid and manus appear to remain fairly static during the 65 million years plus of enantiornithine evolution, by the end of the Mesozoic at least some enantiornithine birds had evolved several features convergent with the Neornithes including a deeply keeled sternum, a narrow furcula with a short hypocleidium, and ulnar quill knobs-all features that indicate refinement of the flight apparatus and increased aerial abilities. We conduct the first cladistic analysis to include all purported avisuarid enantiornithines, recovering an Avisauridae consisting of a dichotomy between North and South American taxa. Based on morphological observations and supported by cladistic analysis, we demonstrate Avisaurus to be paraphyletic and erect a new genus for "A. gloriae," Gettyia gen. nov. PMID- 30479895 TI - Characteristics of the complete mitochondrial genome of Suhpalacsa longialata (Neuroptera, Ascalaphidae) and its phylogenetic implications. AB - The owlflies (Family Ascalaphidae) belong to the Neuroptera but are often mistaken as dragonflies because of morphological characters. To date, only three mitochondrial genomes of Ascalaphidae, namely Libelloides macaronius; Ascaloptynx appendiculatus; Ascalohybris subjacens, are published in GenBank, meaning that they are greatly under-represented in comparison with the 430 described species reported in this family. In this study, we sequenced and described the complete mitochondrial genome of Suhpalacsa longialata (Neuroptera, Ascalaphidae). The total length of the S. longialata mitogenome was 15,911 bp, which is the longest known to date among the available family members of Ascalaphidae. However, the size of each gene was similar to the other three Ascalaphidae species. The S. longialata mitogenome included a transposition of tRNACys and tRNATrp genes and formed an unusual gene arrangement tRNACys-tRNATrp-tRNATyr (CWY). It is likely that the transposition occurred by a duplication of both genes followed by random loss of partial duplicated genes. The nucleotide composition of the S. longialata mitogenome was as follows: A = 41.0%, T = 33.8%, C = 15.5%, G = 9.7%. Both Bayesian inference and ML analyses strongly supported S. longialata as a sister clade to (Ascalohybris subjacens + L. macaronius), and indicated that Ascalaphidae is not monophyletic. PMID- 30479898 TI - A general pattern of the species abundance distribution. AB - Since the 1970s, species abundance distributions (SADs) have been one of the most fundamental issues in ecology and have frequently been investigated and reviewed. However, there was surprisingly little consensus. This study focuses on three essential questions. (1) Is there a general pattern of SAD that no community can violate it? (2) If it exists, what does it look like? (3) Why is it like this? The frequency distributions of 19,833 SADs from eight datasets (including eleven taxonomic groups from terrestrial, aquatic, and marine ecosystems) suggest that a general pattern of SAD might exist. According to two hypotheses (the finiteness of the total energy and the causality from the entropy to the diversity), this study assumes that the general pattern of SAD is approximately consistent with Zipf's law, which means that Zipf's law might be more easily to observe when one investigates any SAD. In the future, this conjecture not only needs to be tested (or supported) by more and more datasets, but also depends on how well it is explained from different angles of theories. PMID- 30479897 TI - Family-based whole-exome sequencing identifies novel loss-of-function mutations of FBN1 for Marfan syndrome. AB - Background: Marfan syndrome (MFS) is an inherited connective tissue disorder affecting the ocular, skeletal and cardiovascular systems. Previous studies of MFS have demonstrated the association between genetic defects and clinical manifestations. Our purpose was to investigate the role of novel genetic variants in determining MFS clinical phenotypes. Methods: We sequenced the whole exome of 19 individuals derived from three Han Chinese families. The sequencing data were analyzed by a standard pipeline. Variants were further filtered against the public database and an in-house database. Then, we performed pedigree analysis under different inheritance patterns according to American College of Medical Genetics guidelines. Results were confirmed by Sanger sequencing. Results: Two novel loss-of-function indels (c.5027_5028insTGTCCTCC, p.D1677Vfs*8; c.5856delG, p.S1953Lfs*27) and one nonsense variant (c.8034C>A, p.Y2678*) of FBN1 were identified in Family 1, Family 2 and Family 3, respectively. All affected members carried pathogenic mutations, whereas other unaffected family members or control individuals did not. These different kinds of loss of function (LOF) variants of FBN1 were located in the cbEGF region and a conserved domain across species and were not reported previously. Conclusions: Our study extended and strengthened the vital role of FBN1 LOF mutations in the pathogenesis of MFS with an autosomal dominant inheritance pattern. We confirm that genetic testing by next-generation sequencing of blood DNA can be fundamental in helping clinicians conduct mutation based pre- and postnatal screening, genetic diagnosis and clinical management for MFS. PMID- 30479896 TI - Do mothers also "manipulate" grandparental care? AB - Paternity uncertainty has proven to be a robust ultimate hypothesis for predicting the higher investment in grandchildren observed among maternal grandparents compared to that of the paternal grandparents. Yet the proximate mechanisms for generating such preferred biases in grandparental investment remain unclear. Here we address two different questions for better understanding the proximate mechanisms leading to the observed bias in grandparental investments: (i) is there a larger emphasis on resemblance descriptions (between grandchildren and grandparent) among daughters than among sons, and (ii) do mothers really believe that their offspring more resemble their parents, that is, the children's grandparents, than fathers do? From questioning grandparents, we find that daughters more often and more intensely than sons express opinions about grandchild-grandparent resemblance. Moreover, daughters also seem to believe that their children more resemble their grandmother than sons do. The latter is, however, not the case for beliefs about children's resemblance to grandfathers. In sum, our results suggest that even in a population of Norwegians, strongly influenced by ideas concerning gender equality, there exist a sexual bias among parents in opinions and descriptions about grandchild grandparent resemblance. This resemblance bias, which echoes that of mothers biasing resemblance descriptions of newborns to putative fathers, does not seem to represent a conscious manipulation. Yet it could be instrumental for influencing grandparental investments. We believe that a "manipulative mother hypothesis" might parsimoniously account for many of the results relating to biased alloparenting hitherto not entirely explained by "the paternity uncertainty hypothesis." PMID- 30479899 TI - Intake of supplementary food during pregnancy and lactation and its association with child nutrition in Timor Leste. AB - Abstract: There is little evidence on maternal consumption of supplementary food on nutritional status of children. The objectives of this study were to measure the prevalence and determinants of supplementary food intake during pregnancy and lactation, and their association with nutritional status of under-five children in Timor Leste. Methods: Cross-sectional data from Timor Leste Demographic and Health Survey on 5,993 mother (15-49 years) child dyads (<5 years) were included in the analysis. Self-reported intake of supplementary food intake was the explanatory variable. Child's nutritional status was assessed by stunting, wasting, and underweight and categorized according to WHO recommendations. Results: The prevalence of taking supplementary food during pregnancy and lactation was, respectively, 29.1% (95% CI [27.2-31.0]) 31.0% (95% CI [29.1 33.0]), and that of taking iron supplement during pregnancy was close to three fifths (63.1%, 95% CI [60.9-65.3]). The odds of taking supplementary food during pregnancy and lactation were lower among those in the younger age groups and higher among urban residents. Compared with mothers who had supplementary food during pregnancy and lactation, those did not have had respectively 1.36 (OR = 1.360, 95% CI [1.191-2.072]) and 1.15 times (OR = 1.152, 95% CI [1.019-1.754]) higher odds of having stunted, and 1.30 (OR = 1.307, 95% CI [1.108-1.853]) and 1.43 (OR = 1.426, 95% CI [1.140-1.863]) times higher odds of having underweight children. Those who had none of the supplements had respectively 1.67 (OR = 1.674, 95% CI [1.118-2.087]) and 1.63 (OR = 1.631, 95% CI [1.130-2.144]) times higher odds of having stunted and underweight children. Conclusion: A great majority of the mothers in Timor Leste are not taking supplementary food during pregnancy and lactation. We found a positive relationship between supplementary food intake during pregnancy and lactation with stunting and wasting among under five children. PMID- 30479901 TI - A taxonomic reassessment of Piramys auffenbergi, a neglected turtle from the late Miocene of Piram Island, Gujarat, India. AB - Background: Piramys auffenbergi was described as an emydine turtle based on a well-preserved skull retrieved from late Miocene deposits exposed on Piram Island, India. The description and figures provided in the original publication are vague and do not support assignment to Emydinae. This taxon has mostly been ignored by subsequent authors. Material and Methods: We reexamine the holotype specimen, provide an extensive description and diagnosis for Piramys auffenbergi, and include this taxon in a global character-taxon matrix for Pleurodira. Results: The presence of a processus trochlearis pterygoidei conclusively shows pleurodiran affinities for Piramys auffenbergi. Inclusion of this taxon in a phylogenetic analysis retrieves it within Stereogenyini closely related to the Asian taxa Shweboemys pilgrimi and Brontochelys gaffneyi. Discussion: Our reexamination of the holotype of Piramys auffenbergi confidently rejects the original assessment of this taxon as an emydine testudinoid and conclusively shows affinities with the pleurodiran clade Stereogenyini instead. Even though most taxa from this lineage are thought to be coastal turtles, all Asian stereogenyines were collected from continental deposits, suggesting a more diverse paleoecology for the group. PMID- 30479900 TI - Relationship between vertical and horizontal force-velocity-power profiles in various sports and levels of practice. AB - This study aimed (i) to explore the relationship between vertical (jumping) and horizontal (sprinting) force-velocity-power (FVP) mechanical profiles in a large range of sports and levels of practice, and (ii) to provide a large database to serve as a reference of the FVP profile for all sports and levels tested. A total of 553 participants (333 men, 220 women) from 14 sport disciplines and all levels of practice participated in this study. Participants performed squat jumps (SJ) against multiple external loads (vertical) and linear 30-40 m sprints (horizontal). The vertical and horizontal FVP profile (i.e., theoretical maximal values of force (F 0), velocity (v 0), and power (P max)) as well as main performance variables (unloaded SJ height in jumping and 20-m sprint time) were measured. Correlations coefficient between the same mechanical variables obtained from the vertical and horizontal modalities ranged from -0.12 to 0.58 for F 0, 0.31 to 0.71 for v 0, -0.10 to 0.67 for P max, and -0.92 to -0.23 for the performance variables (i.e, SJ height and sprint time). Overall, results showed a decrease in the magnitude of the correlations for higher-level athletes. The low correlations generally observed between jumping and sprinting mechanical outputs suggest that both tasks provide distinctive information regarding the FVP profile of lower-body muscles. Therefore, we recommend the assessment of the FVP profile both in jumping and sprinting to gain a deeper insight into the maximal mechanical capacities of lower-body muscles, especially at high and elite levels. PMID- 30479902 TI - An emerging viral pathogen truncates population age structure in a European amphibian and may reduce population viability. AB - Infectious diseases can alter the demography of their host populations, reducing their viability even in the absence of mass mortality. Amphibians are the most threatened group of vertebrates globally, and emerging infectious diseases play a large role in their continued population declines. Viruses belonging to the genus Ranavirus are responsible for one of the deadliest and most widespread of these diseases. To date, no work has used individual level data to investigate how ranaviruses affect population demographic structure. We used skeletochronology and morphology to evaluate the impact of ranaviruses on the age structure of populations of the European common frog (Rana temporaria) in the UK. We compared ecologically similar populations that differed most notably in their historical presence or absence of ranavirosis (the acute syndrome caused by ranavirus infection). Our results suggest that ranavirosis may truncate the age structure of R. temporaria populations. One potential explanation for such a shift might be increased adult mortality and subsequent shifts in the life history of younger age classes that increase reproductive output earlier in life. Additionally, we constructed population projection models which indicated that such increased adult mortality could heighten the vulnerability of frog populations to stochastic environmental challenges. PMID- 30479903 TI - Influencing factors and health risk assessment of microcystins in the Yongjiang river (China) by Monte Carlo simulation. AB - The Yongjiang river is a large, shallow, hyper-trophic, freshwater river in Guangxi, China. To investigate the presence of microcystin-RR, microcystin-LR, and microcystin-YR (MC-RR, MC-LR, and MC-YR) in the Yongjiang river and describe their correlation with environmental factors, as well as, assess health risk using Monte Carlo simulation, 90 water samples were collected at three sample points from March to December 2017. Results showed that during the monitoring period, total concentrations of MC-RR (TMC-RR), MC-YR (TMC-YR), and MC-LR (TMC LR) varied from 0.0224 to 0.3783 MUg/L, 0.0329 to 0.1433 MUg/L, and 0.0341 to 0.2663 MUg/L, respectively. Total phosphorus (TP) content appeared to be related to TMC-LR and the total concentrations of microcystins (TMCs), while pH and total nitrogen (TN)/TP ratio appeared to be related to TMC-RR and TMC-YR, respectively. Using the professional health risk assessment software @Risk7.5, the risks of dietary intake of microcystins (MCs), including the carcinogenic risk and non carcinogenic risk, were evaluated. It was found that the carcinogenic risk of MC RR from drinking water was higher than MC-LR and MC-YR, and the presence of MCs would lead to high potential health risks, especially in children. The carcinogenic risk of MC-RR to children was >1 * 10-4, the maximum allowance level recommended by the US Environmental Protection Agency; as for adults, it was >5 * 10-5, the maximum allowance level recommended by the International Commission on Radiological Protection. The non-carcinogenic hazard index (HI) of MC-RR, MC-YR, and MC-LR increased successively, indicating that MC-LR was more hazardous to human health than MC-YR and MC-RR, but its HI was <1. This suggests that MCs pose less risk to health. However, it is necessary to strengthen the protection and monitoring of drinking water source for effective control of water pollution and safeguarding of human health. PMID- 30479904 TI - Do fish get wasted? Assessing the influence of effluents on parasitic infection of wild fish. AB - Many ecosystems are influenced simultaneously by multiple stressors. One important environmental stressor is aquatic pollution via wastewater treatment plant (WWTP) effluents. WWTP effluents may contribute to eutrophication or contain anthropogenic contaminants that directly and/or indirectly influence aquatic wildlife. Both eutrophication and exposure to anthropogenic contaminants may affect the dynamics of fish-parasite systems. With this in mind, we studied the impact of WWTP effluents on infection of brown trout by the parasite Tetracapsuloides bryosalmonae, the causative agent of proliferative kidney disease (PKD). PKD is associated with the long-term decline of wild brown trout (Salmo trutta) populations in Switzerland. We investigated PKD infection of brown trout at two adjacent sites (~400 m apart) of a Swiss river. The sites are similar in terms of ecology except that one site receives WWTP effluents. We evaluated the hypothesis that fish inhabiting the effluent site will show greater susceptibility to PKD in terms of prevalence and disease outcome. We assessed susceptibility by (i) infection prevalence, (ii) parasite intensity, (iii) host health in terms of pathology, and (iv) estimated apparent survival rate. At different time points during the study, significant differences between sites concerning all measured parameters were found, thus providing evidence of the influence of effluents on parasitic infection of fish in our study system. However, from these findings we cannot determine if the effluent has a direct influence on the fish host via altering its ability to manage the parasite, or indirectly on the parasite or the invertebrate host via increasing bryozoa (the invertebrate host) reproduction. On a final note, the WWTP adhered to all national guidelines and the effluent only resulted in a minor water quality reduction assessed via standardized methods in this study. Thus, we provide evidence that even a subtle decrease in water quality, resulting in small-scale pollution can have consequences for wildlife. PMID- 30479905 TI - Microsatellite loci development and population genetics in Neotropical fish Curimata mivartii (Characiformes: Curimatidae). AB - The Curimatidae family plays an ecological role in the recycling and distribution of nutrients and constitutes a major food source for several commercially important fishes. Curimata mivartii, a member of this family, is considered a short-distance migratory species (<=100 km), categorized by the International Union for Conservation of Nature as a near threatened species, based on its declining population densities and habitat disturbance and fragmentation. Since population genetics and species-specific molecular tools remain unknown for all members of the Curimatidae family, this study developed a set of microsatellite loci and studied the population genetics of C. mivartii in the lower section of the Colombian Magdalena-Cauca basin. The results showed high levels of genetic diversity and evidence of gene flow even between locations separated over 350 km. This information provides a baseline for designing conservation and management programs for C.mivartii and constitutes the first study of population genetics in Curimatidae. PMID- 30479906 TI - Skin bacterial diversity is higher on lizards than sympatric frogs in tropical Australia. AB - Animal skin acts as a barrier between the organism and its environment and provides the first line of defense against invading pathogens. Thus, skin surfaces harbor communities of microbes that are interacting with both the host and its environment. Amphibian skin bacteria form distinct communities closely tied to their host species, but few studies have compared bacterial communities between amphibians and other, non-amphibian sympatric animals. Notably, skin microbes on reptiles have gained little attention. We used next-generation sequencing technology to describe bacterial communities on the skin of three lizard species and compared them to bacteria on six cohabiting frog species in the Northern Territory of Australia. We found bacterial communities had higher richness and diversity on lizards than frogs, with different community composition between reptiles and amphibians and among species. Core bacteria on the three lizard species overlapped by over 100 operational taxonomic units. The bacterial communities were similar within species of frogs and lizards, but the communities tended to be more similar between lizard species than between frog species and when comparing lizards with frogs. The diverse bacteria found on lizards invites further questions on how and how well reptiles interact with microorganisms through their scaly skin. PMID- 30479907 TI - Effects of sex and joint action on voluntary activation. AB - The current study tested the hypothesis that voluntary activation during maximal voluntary contraction (MVC) conditionally depends on sex and joint action. Twenty eight healthy adults (14 of each sex) performed knee extensor MVC and plantar flexor MVC at extended and flexed knee positions. Voluntary activation during MVC was assessed using a twitch interpolation technique. The voluntary activation during plantar flexor MVC at the extended knee position was significantly lower (P = 0.020, 95% confidence interval 1.4 to 14.6, Cohen's d for between-subject design = 0.94) in women (88.3% +/- 10.0%) than in men (96.2% +/- 6.6%). In contrast, no significant sex differences were shown in the voluntary activation during knee extensor MVC (93.7% +/- 5.9% (women) vs. 95.0% +/- 3.9% (men)) and during plantar flexor MVC at the flexed knee position (90.4% +/- 12.2% (women) vs. 96.8% +/- 5.6% (men)). The voluntary activation during knee extensor MVC was significantly higher (P = 0.001, 95% confidence interval 2.1 to 8.8, Cohen's d for within-subject design = 0.69) than that during plantar flexor MVC at the extended knee position in women, whereas the corresponding difference was not observed in men. The results revealed that the existence of sex difference in the voluntary activation during MVC depends on joint action and joint angle. PMID- 30479908 TI - Saccades and handedness interact to affect scene memory. AB - Repetitive saccades benefit memory when executed before retrieval, with greatest effects for episodic memory in consistent-handers. Questions remain including how saccades affect scene memory, an important visual component of episodic memory. The present study tested how repetitive saccades affect working and recognition memory for novel scenes. Handedness direction (left-right) and degree (strong/consistent vs. mixed/inconsistent) was measured by raw and absolute laterality quotients respectively from an 8-question handedness inventory completed by 111 adults. Each then performed either 30 s of repetitive horizontal saccades or fixation before or after tasks of scene working memory and scene recognition. Regression with criterion variables of overall percent correct accuracy and d-prime sensitivity showed that when saccades were made before working memory, there was better overall accuracy as a function of increased direction but not degree of handedness. Subjects who made saccades before working memory also performed worse during subsequent recognition memory, while subjects who fixated or made saccades after the working memory task performed better. Saccades made before recognition resulted in recognition accuracy that was better (Cohen's d = 0.3729), but not significantly different from fixation before recognition. The results demonstrate saccades and handedness interact to affect scene memory with larger effects on encoding than recognition. Saccades before scene encoding in working memory are detrimental to short- and long-term memory, especially for those who are not consistently right-handed, while saccade execution before scene recognition does not appear to benefit recognition accuracy. The findings are discussed with respect to theories of interhemispheric interaction and control of visuospatial attention. PMID- 30479909 TI - Recommended nitrogen fertilization enhances soil carbon sequestration in China's monsoonal temperate zone. AB - China consumes more than one-third of the world's nitrogen (N) fertilizer, and an increasing amount of N fertilizer has been applied over the past decades. Although N fertilization can increase the carbon sequestration potentials of cropland in China, the quantitative effects of different N fertilizer application levels on soil carbon changes have not been evaluated. Therefore, a 12-year cultivation experiment was conducted under three N fertilizer application levels (no N fertilizer input, the recommended N fertilizer input after soil testing, and the estimated additional fertilizer input) to estimate the effect of N addition on soil carbon changes in the root layer (0-80 cm) and non-root layer (80-200 cm) using a within-study meta-analysis method. The results showed significant declines in the soil inorganic carbon (SIC) in the root layers and significant growth in the SIC in the non-root layers under N fertilizer input. The soil organic carbon (SOC) in the root layers and the non-root layer significantly decreased under all the treatments. In addition, the recommended N fertilizer application level significantly increased the SOC and soil total carbon stocks compared with the future N fertilizer application level and no N input, while the future N fertilization significantly decreased the SIC and soil total carbon compared with no N input. The results suggest that N fertilization can rearrange the soil carbon distribution over the entire soil profile, and the recommended N fertilization rather than excess N input can increase the soil carbon stock, which suggests that the national soil testing program in China can improve the soil carbon sequestration potential. PMID- 30479911 TI - Enhanced Melanoma-Targeted Therapy by "Fru-Blocked" Phenyboronic Acid-Modified Multiphase Antimetastatic Micellar Nanoparticles. AB - Metastasis remains the main driver of mortality in patients suffering from cancer because of the refractoriness resulting from the multi-phase metastatic cascade. Herein, a multifunctional self-delivering PBA-LMWH-TOS nanoparticle (PLT NP) is established that acts as both nanocarrier and anti-metastatic agent with effects on most hematogenous metastases of cancers. The hydrophilic segment (low molecular weight heparin, LMWH) inhibits the interactions between tumor cells and platelets. The hydrophobic segment (d-alpha-tocopheryl succinate, TOS) could inhibit the expression of matrix metalloproteinase-9 (MMP-9) in B16F10 cells which is first reported in this article. Surprisingly, even the blank NPs showed excellent anti-metastatic capacity in three mouse models by acting on different phases of the metastatic cascade. Moreover, the overexpression of sialic acid (SA) residues on tumor cells is implicated in the malignant and metastatic phenotypes of cancers. Thus, these 3-aminophenylboronic acid (PBA)-modified doxorubicin (DOX)-loaded NPs offer an efficient approach for the treatment of both solid melanomas and metastases. Furthermore, a simple pH-sensitive "Fructose (Fru)-blocking" coping strategy is established to reduce the NP distribution in normal tissues and distinctly increases the accumulation in melanoma tumors. These micellar NPs consisting of biocompatible materials offer a promising approach for the clinical therapy of highly invasive solid tumors and metastases. PMID- 30479910 TI - Direct CVD Growth of Graphene on Technologically Important Dielectric and Semiconducting Substrates. AB - To fabricate graphene based electronic and optoelectronic devices, it is highly desirable to develop a variety of metal-catalyst free chemical vapor deposition (CVD) techniques for direct synthesis of graphene on dielectric and semiconducting substrates. This will help to avoid metallic impurities, high costs, time consuming processes, and defect-inducing graphene transfer processes. Direct CVD growth of graphene on dielectric substrates is usually difficult to accomplish due to their low surface energy. However, a low-temperature plasma enhanced CVD technique could help to solve this problem. Here, the recent progress of metal-catalyst free direct CVD growth of graphene on technologically important dielectric (SiO2, ZrO2, HfO2, h-BN, Al2O3, Si3N4, quartz, MgO, SrTiO3, TiO2, etc.) and semiconducting (Si, Ge, GaN, and SiC) substrates is reviewed. High and low temperature direct CVD growth of graphene on these substrates including growth mechanism and morphology is discussed. Detailed discussions are also presented for Si and Ge substrates, which are necessary for next generation graphene/Si/Ge based hybrid electronic devices. Finally, the technology development of the metal-catalyst free direct CVD growth of graphene on these substrates is concluded, with future outlooks. PMID- 30479912 TI - A Sensitive and Wide Coverage Ambient Mass Spectrometry Imaging Method for Functional Metabolites Based Molecular Histology. AB - Histological examination with a deep link between functional metabolites and tissue structure and biofunctions will provide important in situ biochemical information, and then essentially reveal what has happened in tissue at the molecular level. However, due to the complexity and heterogeneity of tissue samples and the large number of metabolites, it is still a challenge to globally map the diverse metabolites, especially for those low-abundance functional ones. Here, a sensitive air flow-assisted desorption electrospray ionization mass spectrometry imaging method for the mapping of a broad range of metabolites is presented. It exhibits properties characteristic of wide coverage, high sensitivity, wide dynamic range, rapid analysis procedure, and high specificity for tissue metabolites imaging. More than 1500 metabolites, including cholines, polyamines, amino acids, carnitines, nucleosides, nucleotides, nitrogen bases, organic acids, carbohydrates, cholesterol sulfate, cholic acid, lipids, etc., can be visualized in an untargeted analysis. The distribution of metabolites shows good spatial match with tissue histological structure and biofunctions in heterogeneous rat kidney, rat brain, and human esophageal cancer tissue. This method possesses the ability to globally showcase the molecular processes in tissue, and provide an insightful way for structural and functional molecular recognition in histological examination, even for intraoperative decision-making. PMID- 30479913 TI - Designing Magnetic Anisotropy through Strain Doping. AB - The coupling between a material's lattice and its underlying spin state links structural deformation to magnetic properties; however, traditional strain engineering does not allow the continuous, post-synthesis control of lattice symmetry needed to fully utilize this fundamental coupling in device design. Uniaxial lattice expansion induced by post-synthesis low energy helium ion implantation is shown to provide a means of bypassing these limitations. Magnetocrystalline energy calculations can be used a priori to estimate the predictive design of a material's preferred magnetic spin orientation. The efficacy of this approach is experimentally confirmed in a spinel CoFe2O4 model system where the epitaxial film's magnetic easy axis is continuously manipulated between the out-of-plane (oop) and in-plane (ip) directions as lattice tetragonality moves from ip to oop with increasing strain doping. Macroscopically gradual and microscopically abrupt changes to preferential spin orientation are demonstrated by combining ion irradiation with simple beam masking and lithographic procedures. The ability to design magnetic spin orientations across multiple length scales in a single crystal wafer using only crystal symmetry considerations provides a clear path toward the rational design of spin transfer, magnetoelectric, and skyrmion-based applications where magnetocrystalline energy must be dictated across multiple length scales. PMID- 30479914 TI - 3D Self-Architectured Steam Electrode Enabled Efficient and Durable Hydrogen Production in a Proton-Conducting Solid Oxide Electrolysis Cell at Temperatures Lower Than 600 degrees C. AB - Hydrogen production via water electrolysis using solid oxide electrolysis cells (SOECs) has attracted considerable attention because of its favorable thermodynamics and kinetics. It is considered as the most efficient and low-cost option for hydrogen production from renewable energies. By using proton conducting electrolyte (H-SOECs), the operating temperature can be reduced from beyond 800 to 600 degrees C or even lower due to its higher conductivity and lower activation energy. Technical barriers associated with the conventional oxygen-ion conducting SOECs (O-SOECs), that is, hydrogen separation and electrode instability that is primarily due to the Ni oxidation at high steam concentration and delamination associated with oxygen evolution, can be remarkably mitigated. Here, a self-architectured ultraporous (SAUP) 3D steam electrode is developed for efficient H-SOECs below 600 degrees C. At 600 degrees C, the electrolysis current density reaches 2.02 A cm-2 at 1.6 V. Instead of fast degradation in most O-SOECs, performance enhancement is observed during electrolysis at an applied voltage of 1.6 V at 500 degrees C for over 75 h, attributed to the "bridging" effect originating from reorganization of the steam electrode. The H-SOEC with SAUP steam electrode demonstrates excellent performance, promising a new prospective for next-generation steam electrolysis at reduced temperatures. PMID- 30479915 TI - One-Step Method for Instant Generation of Advanced Allogeneic NK Cells. AB - Conventional combinatorial anticancer therapy has shown promising outcomes; still, a significant interest in developing new methods to reinforce and possibly merge chemotherapy and immunotherapy persists. Here, a new one-step method that immediately modifies immune cells into a targeted form of chemoimmunotherapy through spontaneous and rapid incorporation of hydrophobized antibody-drug conjugates (ADCs) on the surface of immune cells is presented. Therapeutic objectives of this approach include targeted delivery of a potent chemotherapeutic agent to avoid adverse effects, enhancing the mobilization of infused immune cells toward tumor sites, and preserving the intense cytotoxic activities of immune cells against tumor cells. The embedding of hydrophobized ADCs on the immune cell membrane using the strategy in this study provides noninvasive, nontoxic, and homogenous modifications that transiently arm immune cells with highly potent cytotoxic drugs targeted toward cancer cells. The resulting surface-engineered immune cells with ADCs significantly suppress the tumor growth and drive the eradication of target cancer cells through combinatorial anticancer effects. This novel strategy allows convenient and timely preparation of advanced chemoimmunotherapy on a single immune cell to treat various types of cancer. PMID- 30479917 TI - Superior Stability and Efficiency Over 20% Perovskite Solar Cells Achieved by a Novel Molecularly Engineered Rutin-AgNPs/Thiophene Copolymer. AB - Perovskite solar cells (PSCs) with efficiencies greater than 20% have been realized mostly with expensive spiro-MeOTAD hole-transporting material. PSCs are demonstrated that achieve stabilized efficiencies exceeding 20% with straightforward low-cost molecularly engineered copolymer poly(1-(4-hexylphenyl) 2,5-di(thiophen-2-yl)-1H-pyrrole) (PHPT-py) based on Rutin-silver nanoparticles (AgNPs) as the hole extraction layer. The Rutin-AgNPs additive enables the creation of compact, highly conformal PHPT-py layers that facilitate rapid carrier extraction and collection. The spiro-MeOTAD-based PSCs show comparable efficiency, although their operational stability is poor. This instability originated from potential-induced degradation of the spiro-MeOTAD/Au contact. The addition of conductive Rutin-AgNPs into PHPT-py layer allows PSCs to retain >97% of their initial efficiency up to 60 d without encapsulation under relative humidity. The PHPT-py/ Rutin-AgNPs-based devices surpass the stability of spiro MeOTAD-based PSCs and potentially reduce the fabrication cost of PSCs. PMID- 30479918 TI - Double-Shelled Phosphorus and Nitrogen Codoped Carbon Nanospheres as Efficient Polysulfide Mediator for High-Performance Lithium-Sulfur Batteries. AB - Lithium-sulfur batteries are regarded as very promising energy storage devices due to their high energy density, low cost, and environmental friendliness; however, their insulating properties and the instability of sulfur-based electrodes impede the practical applications of Li-S batteries. Here, a versatile strategy to synthesize double-shelled nitrogen and phosphorus codoped carbon spheres (NPDSCS) as an efficient sulfur host for Li-S batteries is reported. With strong trapping, good affinity, high adsorption for polysulfides, and the bifunctional catalyzing for sulfur redox processes, the developed NPDSCS cathodes with a high S loading of 72.4% exhibit large specific discharge capacity of 1326 mAh g-1 at 0.1C, high Coulombic efficiency, good rate capability, and excellent cycling performance with a reversible capacity of 814 mAh g-1 at 1C after 500 cycles. PMID- 30479919 TI - Backward Phase Matching for Second Harmonic Generation in Negative-Index Conformal Surface Plasmonic Metamaterials. AB - Backward phase matching, which describes counterpropagating fundamental and harmonic waves in a negative-index medium, is one of the most intriguing phenomena in nonlinear metamaterials. Predicted theoretically decades ago, however, it is still a challenging task to be applied for efficient second harmonic (SH) generation in a nonlinear metamaterial with ultrathin geometry and ultralow loss. Here, a negative-index spoof plasmonic metamaterial is reported, which is composed of an ultrathin symmetrical corrugated metallic strips loaded with nonlinear active devices. The simulated and measured power spectra and surface near-field distributions show that a peak SH signal can be generated at the backward phase-matched frequency point in a 120 degrees curved surface with high efficiency, thanks to the ultrathin flexible geometry, significant confinement effect, and large propagation length of the spoof surface plasmons. The results open new technological challenges from nano- and micro-nonlinear photonics to science and engineering of compact, broadband, and efficient frequency-mixing metamaterials and electromagnetic devices. PMID- 30479920 TI - Metal-to-Semiconductor Transition and Electronic Dimensionality Reduction of Ca2N Electride under Pressure. AB - The discovery of electrides, in particular, inorganic electrides where electrons substitute anions, has inspired striking interests in the systems that exhibit unusual electronic and catalytic properties. So far, however, the experimental studies of such systems are largely restricted to ambient conditions, unable to understand their interactions between electron localizations and geometrical modifications under external stimuli, e.g., pressure. Here, pressure-induced structural and electronic evolutions of Ca2N by in situ synchrotron X-ray diffraction and electrical resistance measurements, and density functional theory calculations with particle swarm optimization algorithms are reported. Experiments and computation are combined to reveal that under compression, Ca2N undergoes structural transforms from R 3- m symmetry to I 4- 2d phase via an intermediate Fd 3- m phase, and then to Cc phase, accompanied by the reductions of electronic dimensionality from 2D, 1D to 0D. Electrical resistance measurements support a metal-to-semiconductor transition in Ca2N because of the reorganizations of confined electrons under pressure, also validated by the calculation. The results demonstrate unexplored experimental evidence for a pressure-induced metal-to-semiconductor switching in Ca2N and offer a possible strategy for producing new electrides under moderate pressure. PMID- 30479921 TI - Antifouling Super Water Absorbent Supramolecular Polymer Hydrogel as an Artificial Vitreous Body. AB - Recently, there has been a high expectation that high water absorbent hydrogels can be developed as an artificial vitreous body. However, the drawbacks associated with in vivo instability, biofouling, uncontrollable in situ reaction time, and injection-induced precrosslinked fragmentation preclude their genuine use as vitreous substitutes. Here, a supramolecular binary copolymer hydrogel termed as PNAGA-PCBAA by copolymerization of N-acryloyl glycinamide (NAGA) and carboxybetaine acrylamide (CBAA) is prepared. This PNAGA-PCBAA hydrogel physically crosslinked by dual amide hydrogen bonds of NAGA exhibits an ultralow solid content (1.6, 98.4 wt% water content), and shear-thinning behavior, body temperature extrudability/self-healability, rapid network recoverability, and very close key parameters (modulus, antifouling/antifibrosis, light transmittance, refractive index, ultrastability) to human vitreous body. It is demonstrated that the hydrogel can be readily injected by a 22G needle into the rabbits' eyes where the gelling network is rapidly recovered. After 16 weeks postoperation, the hydrogel acts as a very stable vitreous substitute without affecting the structure of soft tissues in eye, or eliciting adverse effects. This supramolecular binary copolymer hydrogel finds a broad application in ophthalmic fields as not only a self-recoverable permanent vitreous substitute, but also transient intraocular filling for prevention of inner tissues in postsurgical eyes. PMID- 30479916 TI - Regulation of Inflammatory Cytokines for Spinal Cord Injury Repair Through Local Delivery of Therapeutic Agents. AB - The balance of inflammation is critical to the repair of spinal cord injury (SCI), which is one of the most devastating traumas in human beings. Inflammatory cytokines, the direct mediators of local inflammation, have differential influences on the repair of the injured spinal cord. Some inflammatory cytokines are demonstrated beneficial to spinal cord repair in SCI models, while some detrimental. Various animal researches have revealed that local delivery of therapeutic agents efficiently regulates inflammatory cytokines and promotes repair from SCI. Quite a few clinical studies have also shown the promotion of repair from SCI through regulation of inflammatory cytokines. However, local delivery of a single agent affects only a part of the inflammatory cytokines that need to be regulated. Meanwhile, different individuals have differential profiles of inflammatory cytokines. Therefore, future studies may aim to develop personalized strategies of locally delivered therapeutic agent cocktails for effective and precise regulation of inflammation, and substantial functional recovery from SCI. PMID- 30479922 TI - Stiffness-Independent Toughening of Beams through Coaxial Interfaces. AB - To be of engineering relevance, it is essential for stiff and strong materials to possess also high toughness. However, as these properties are typically mutually exclusive, they are rarely found in nature and synthetic replications are extremely limited. Here, an elegant albeit simple physical principle that enables ligaments in cellular networks to possess these mechanical properties simultaneously is presented. The underlying architecture consists of multiple, coaxially aligned layers separated by interfaces that prevent crack propagation, hence increasing the energy required for complete rupture. The results show that the fracture strain and toughness can be increased by over 100%, when compared to conventional reference struts, while fully maintaining the density, stiffness, and strength. The bioinspired and highly versatile approach is scale-independent under the absence of shear, applicable to various geometries, and complementary to existing approaches. It can, therefore, significantly improve safety and reduce cost and environmental impact in numerous applications, such as packaging, sports equipment, and transportation. PMID- 30479923 TI - Silicon-Enhanced Adipogenesis and Angiogenesis for Vascularized Adipose Tissue Engineering. AB - The enhancement of adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and sufficient vascularization remain great challenges for the successful reconstruction of engineered adipose tissue. Here, the bioactive effects of silicon (Si) ions on adipogenic differentiation of human BMSCs (HBMSCs) and the stimulation of vascularization during adipose tissue regeneration are reported. The results show that Si ions can enhance adipogenic differentiation of HBMSCs through the stimulation of the expression of adipogenic differentiation switches such as peroxisome proliferator-activated receptor gamma and CCAAT/enhancer-binding protein alpha. Furthermore, Si ions can enhance both angiogenesis and adipogenesis, and inhibit dedifferentiation of cocultured adipocytes by regulating the interactions between HBMSC-derived adipocytes and human umbilical vein endothelial cells, in which the promotion of the expression of insulin-like growth factor 1 and vascular endothelial growth factor plays vital roles. The in vivo studies further demonstrate that the designed composite hydrogel with the ability to release bioactive Si ions clearly stimulates neovascularization and adipose tissue regeneration. The study suggests that Si ions released from biomaterials are important chemical cues for adipogenic differentiation and biomaterials with the ability to release Si ions can be designed for adipose tissue engineering. PMID- 30479924 TI - Flexible Asymmetric Supercapacitors with Ultrahigh Energy Density through Synergistic Design of Electrodes. AB - Despite being among the most researched energy storage devices, supercapacitors have often suffered from their relatively low operating voltage and energy density, which greatly limit their practical applications. In this work, asymmetric supercapacitors (ASCs) are developed by synergistically designing carbon nanotube composite electrodes with 3D porous structures. The resultant ASC devices exhibit an extended operating voltage of 1.8 V, much higher than that of symmetric supercapacitors (<=1.0 V). Significantly, the obtained ASC devices deliver ultrahigh volumetric energy density as high as 19.8 mWh cm-3 (corresponding to an areal energy density of 198 uWh cm-2), which is the highest value among reported ASC devices. In addition, the ASC devices not only possess outstanding cycling stability and long self-discharging time, but also exhibit excellent mechanical flexibility under any bending states, even over 5000 bending cycles. The demonstrated flexible ASC devices with high performance are promising to be used as power sources for next-generation portable and wearable electronics. PMID- 30479926 TI - Superlubricity of Graphite Sliding against Graphene Nanoflake under Ultrahigh Contact Pressure. AB - Superlubricity of graphite sliding against graphene can be easily attained at the nanoscale when it forms the incommensurate contact under a low contact pressure. However, the achievement of superlubricity under an ultrahigh contact pressure (>1 GPa), which has more applications in the lubrication of micromachine and nanomachine, remains unclear. Here, this problem is addressed and the robust superlubricity of graphite is obtained under ultrahigh contact pressures of up to 2.52 GPa, by the formation of transferred graphene nanoflakes on a silicon tip. The friction coefficient becomes as low as 0.0003, a state that is attributed to the extremely low shear strength of the graphene/graphite interface in the incommensurate contact. When the pressure exceeds some threshold, the superlubricity state collapses suddenly with the friction coefficient increasing ~10 times. The failure of superlubricity originates from the delamination of the topmost graphene layers on graphite under ultrahigh contact pressures, which requires the tip to provide additional exfoliation energies during the sliding process. The results demonstrate that the superlubricity of graphite sliding against graphene can exist stably under ultrahigh contact pressure, which would appear to accelerate its application in nanoscale lubrication. PMID- 30479927 TI - Nanoporous Films and Nanostructure Arrays Created by Selective Dissolution of Water-Soluble Materials. AB - Highly porous thin films and nanostructure arrays are created by a simple process of selective dissolution of a water-soluble material, Sr3Al2O6. Heteroepitaxial nanocomposite films with self-separated phases of a target material and Sr3Al2O6 are first prepared by physical vapor deposition. NiO, ZnO, and Ni1- x Mg x O are used as the target materials. Only the Sr3Al2O6 phase in each nanocomposite film is selectively dissolved by dipping the film in water for 30 s at room temperature. This gentle and fast method minimizes damage to the remaining target materials and side reactions that can generate impurity phases. The morphologies and dimensions of the pores and nanostructures are controlled by the relative wettability of the separated phases on the growth substrates. The supercapacitor properties of the porous NiO films are enhanced compared to plain NiO films. The method can also be used to prepare porous films or nanostructure arrays of other oxides, metals, chalcogenides, and nitrides, as well as films or nanostructures with single-crystalline, polycrystalline, or amorphous nature. PMID- 30479925 TI - Biotransporting Biocatalytic Reactors toward Therapeutic Nanofactories. AB - Drug-delivery systems (DDSs), in which drug encapsulation in nanoparticles enables targeted delivery of therapeutic agents and their release at specific disease sites, are important because they improve drug efficacy and help to decrease side effects. Although significant progress has been made in the development of DDSs for the treatment of a wide range of diseases, new approaches that increase the scope and effectiveness of such systems are still needed. Concepts such as nanoreactors and nanofactories are therefore attracting much attention. Nanoreactors, which basically consist of vesicle-encapsulated enzymes, provide prodrug conversion to therapeutic agents rather than simple drug delivery. Nanofactories are an extension of this concept and combine the features of nanoreactors and delivery carriers. Here, the required features of nanofactories are discussed and an overview of current strategies for the design and fabrication of different types of nanoreactors, i.e., systems based on lipid or polymer vesicles, capsules, mesoporous silica, viral capsids, and hydrogels, and their respective advantages and shortcomings, is provided. In vivo applications of biocatalytic reactors in the treatment of cancer, glaucoma, neuropathic pain, and alcohol intoxication are also discussed. Finally, the prospects for further progress in this important and promising field are outlined. PMID- 30479928 TI - Development of Biocompatible HA Hydrogels Embedded with a New Synthetic Peptide Promoting Cellular Migration for Advanced Wound Care Management. AB - In the past few years, there have been many efforts underway to develop effective wound healing treatments for traumatic injuries. In particular, wound-healing peptides (WHPs) and peptide-grafted dressings hold great promise for novel therapeutic strategies for wound management. This study reports a topical formulation of a new synthetic WHP (REGRT, REG) embedded in a hyaluronic acid (HA)-based hydrogel dressing for the enhancement of acute excisional wound repair. The copper-free click chemistry is utilized to form biocompatible HA hydrogels by cross-linking dibenzocyclooctyl-functionalized HA with 4-arm poly(ethylene glycol) (PEG) azide. The HA hydrogels are grafted with the REG peptide, a functional derivative of erythroid differentiation regulator1, displaying potent cell motility-stimulating ability, thus sustainably releasing physiologically active peptides for a prolonged period. Combined with the traditional wound healing benefits of HA, the HA hydrogel embedded REG (REG HAgel) accelerates re-epithelialization in skin wound healing, particularly by promoting migration of fibroblasts, keratinocytes, and endothelial cells. REG HAgels improve not only rate, but quality of wound healing with higher collagen deposition and more microvascular formation while being nontoxic. The peptide grafted HA hydrogel system can be considered as a promising new wound dressing formulation strategy for the treatment of different types of wounds with combinations of various natural and synthetic WHPs. PMID- 30479930 TI - TiS2 as an Advanced Conversion Electrode for Sodium-Ion Batteries with Ultra-High Capacity and Long-Cycle Life. AB - Titanium disulfide (TiS2) is investigated as an advanced conversion electrode for sodium (Na)-ion batteries (NIB) in an ether-based electrolyte (NaPF6/glyme (DME)). The as-prepared TiS2 demonstrates a high reversible capacity of 1040 mA h g-1 at 0.2 A g-1 with the capacity contribution of 521 mA h g-1 in the voltage region below 1.0 V (vs Na/Na+), remarkable initial coulombic efficiency of 95.9% and superior rate capability of 621 mA h g-1 at 40 A g-1. The high conductivity of the Ti-based compounds and nanosized particles generated by chemical conversion reactions could minimize the entropic barrier for the reversible conversion, resulting in high reversibility and ultrafast charge/discharge ability of the electrode. Moreover, with its strong ability to adsorb soluble polysulfide intermediates, the as-prepared TiS2 electrode exhibits superior cycling stability over 9000 cycles, serving as a stable and ultra-high capacity conversion electrode for NIBs. PMID- 30479929 TI - Distinct Iron Deposition Profiles of Liver Zones in Various Models with Iron Homeostasis Disorders. AB - Determination of iron accumulation is crucial in diagnosing the occurrence and progression of many liver- and iron-related diseases. Thus far, little is known about the profiles of iron deposition in different liver zones, particularly under conditions with disordered iron homeostasis. Here, uneven iron distribution in livers of patients with hereditary hemochromatosis (HH) is uncovered, showing the region with the highest iron concentration near the entrance site of the portal vein and hepatic artery in contrast to the sites with the lowest iron concentration close to the distal edge. Distinct iron distribution profiles are also found throughout liver zones in wild-type mice and various mouse models with iron metabolism disorders, including hemochromatosis (Hfe-/- ), iron deficiency, and inflammation. Of note, similar findings observed in HH patients are further demonstrated in Hfe-/- mice. Moreover, the zones with greater iron accumulation appear to be more sensitive to iron changes, e.g., there is iron increase upon iron overload and iron loss in response to iron deficiency. Mechanistic investigation manifests that these differential iron changes in liver zones are subjected to the regulation by the hepcidin-ferroportin axis. Additionally, the data corroborate the reliability of magnetic resonance imaging (MRI) in recognizing the differential iron deposition profiles among liver zones. PMID- 30479931 TI - Light-Controllable Digital Coding Metasurfaces. AB - Since the advent of digital coding metamaterials, a new paradigm is unfolded to sample, compute and program electromagnetic waves in real time with one physical configuration. However, one inconvenient truth is that actively tunable building blocks such as diodes, varactors, and biased lines must be individually controlled by a computer-assisted field programmable gate array and physically connected by electrical wires to the power suppliers. This issue becomes more formidable when more elements are needed for more advanced and multitasked metadevices and metasystems. Here, a remote-mode metasurface is proposed and realized that is addressed and tuned by illuminating light. By tuning the intensity of light-emitting diode light, a digital coding metasurface composed of such light-addressable elements enables dynamically reconfigurable radiation beams in a control-circuitry-free way. Experimental demonstration is validated at microwave frequencies. The proposed dynamical remote-tuning metasurface paves a way for constructing unprecedented digital metasurfaces in a noncontact remote fashion. PMID- 30479932 TI - Ultrathin 2D Cobalt Zeolite-Imidazole Framework Nanosheets for Electrocatalytic Oxygen Evolution. AB - 2D layered materials, including metal-di-chalcogenides and transition metal layered double hydroxides, among others, are intensively studied because of new properties that emerge from their 2D confinement, which are attractive for advanced applications. Herein, 2D cobalt ion (Co2+) and benzimidazole (bIm) based zeolite-imidazole framework nanosheets, ZIF-9(III), are reported as exceptionally efficient electrocatalysts for the oxygen evolution reaction (OER). Specifically, liquid-phase ultrasonication is applied to exfoliate a [Co4(bIm)16] zeolite imidazole framework (ZIF), named as ZIF-9(III) phase, into nanoscale sheets. ZIF 9(III) is selectively prepared through simple mechanical grinding of cobalt nitrate and benzimidazole in the presence of a small amount of ethanol. The resultant exfoliated nanosheets exhibit significantly higher OER activity in alkaline conditions than the corresponding bulk phases ZIF-9 and ZIF-9(III). The electrochemical and physicochemical characterization data support the assignment of the OER activity of the exfoliated nanosheet derived material to nitrogen coordinated cobalt oxyhydroxide N4CoOOH sites, following a mechanism known for Co porphyrin and related systems. Thus, exfoliated 2D nanosheets hold promise as potential alternatives to commercial noble metal electrocatalysts for the OER. PMID- 30479933 TI - Injectable and Spatially Patterned Microporous Annealed Particle (MAP) Hydrogels for Tissue Repair Applications. AB - Spatially patterned hydrogels are becoming increasingly popular in the field of regenerative medicine and tissue repair because of their ability to guide cell infiltration and migration. However, postfabrication technologies are usually required to spatially pattern a hydrogel, making these hydrogels difficult to translate into the clinic. Here, an injectable spatially patterned hydrogel is reported using hyaluronic acid (HA)-based particle hydrogels. These particle hydrogels are sequentially loaded into a syringe to form a pattern and, once injected, they maintain the pattern. The applicability of this hydrogel in a wound healing skin model, a subcutaneous implant model, as well as a stroke brain model is examined and distinct patterning in all models tested is shown. This injectable and spatially patterned hydrogel can be used to create physical or biochemical gradients. Further, this design can better match the scaffold properties within the physical location of the tissue (e.g., wound border vs wound center). This allows for better design features within the material that promote repair and regeneration. PMID- 30479934 TI - Hand-Driven Gyroscopic Hybrid Nanogenerator for Recharging Portable Devices. AB - With the rise of portable and wearable electronics, a fast-charging, long-lasting power solution is needed; thus, there are attempts to harvest energy from the ambient environment. Mechanical energy harvesting through piezoelectric and triboelectric nanogenerators (PENG and TENG) is a promising approach due to their light weight, low cost, and high-power density in comparison to other technologies. Both types of generators are capable of charging portable and smart devices on their own by converting mechanical energy into electricity. However, most previous methods have excessive input conditions, such as high rpm and input frequency, that can be only applied with other actuators. Here, a hand-held gyroscopic generator is presented that uses the gyroscopic principle to reach a rotation rate above 8000 rpm with only hand input. The generator comprises a rotating flywheel inside a casing. Both the flywheel and casing have a TENG, and with a hybrid generator, electrical power is produced from rotation, vibration, and centrifugal force during operation. The device shows a consistent open circuit voltage (V OC) of 90 V and a closed-circuit current (I CC) of 11 uA with a frequency of 200 Hz. As a stand-alone device, this generator can power portable sensors and smartphones through hand rotation. PMID- 30479936 TI - Low Temperature Fabrication for High Performance Flexible CsPbI2Br Perovskite Solar Cells. AB - All-inorganic CsPbX3-based perovskites, such as CsPbI2Br, show much better thermal and illumination stability than their organic-inorganic hybrid counterparts. However, fabrication of high-quality CsPbI2Br perovskite film normally requires annealing at a high temperature (>250 degrees C) that is not compatible with the plastic substrate. In this work, a Lewis base adduct-promoted growth process that makes it possible to fabricate high quality CsPbI2Br perovskite films at low temperature is promoted. The mechanism is attributed to synthesized dimethyl sulfoxide (DMSO) adducts which allow a low activation energy route to form CsPbI2Br perovskite films during the thermal annealing treatment. A power conversion efficiency (PCE) of 13.54% is achieved. As far as it is known, this is the highest efficiency for the CsPbI2Br solar cells fabricated at low temperature (120 degrees C). In addition, the method enables fabrication of flexible CsPbI2Br PSCs with PCE as high as 11.73%. Surprisingly, the bare devices without any encapsulation maintain 70% of their original PCEs after being stored in ambient air for 700 h. This work provides an approach for preparing other high performance CsPbX3-based perovskite solar cells (PSCs) at low temperature, particularly for flexible ones. PMID- 30479935 TI - 3D Printing Fiber Electrodes for an All-Fiber Integrated Electronic Device via Hybridization of an Asymmetric Supercapacitor and a Temperature Sensor. AB - Wearable fiber-shaped electronic devices have drawn abundant attention in scientific research fields, and tremendous efforts are dedicated to the development of various fiber-shaped devices that possess sufficient flexibility. However, most studies suffer from persistent limitations in fabrication cost, efficiency, the preparation procedure, and scalability that impede their practical application in flexible and wearable fields. In this study, a simple, low-cost 3D printing method capable of high manufacturing efficiency, scalability, and complexity capability to fabricate a fiber-shaped integrated device that combines printed fiber-shaped temperature sensors (FTSs) with printed fiber-shaped asymmetric supercapacitors (FASCs) is developed. The FASCs device can provide stable output power to FTSs. Moreover, the temperature responsivity of the integrated device is 1.95% degrees C-1. PMID- 30479937 TI - Flash-Induced Stretchable Cu Conductor via Multiscale-Interfacial Couplings. AB - Herein, a novel stretchable Cu conductor with excellent conductivity and stretchability is reported via the flash-induced multiscale tuning of Cu and an elastomer interface. Microscale randomly wrinkled Cu (amplitude of ~5 um and wavelength of ~45 um) is formed on a polymer substrate through a single pulse of a millisecond flash light, enabling the elongation of Cu to exceed 20% regardless of the stretching direction. The nanoscale interlocked interface between the Cu nanoparticles (NPs) and the elastomer increases the adhesion force of Cu, which contributes to a significant improvement of the Cu stability and stretchability under harsh yielding stress. Simultaneously, the flash-induced photoreduction of CuO NPs and subsequent Cu NP welding lead to outstanding conductivity (~37 kS cm 1) of the buckled elastic electrode. The 3D structure of randomly wrinkled Cu is modeled by finite element analysis simulations to show that the flash-activated stretchable Cu conductors can endure strain over 20% in all directions. Finally, the wrinkled Cu is utilized for wireless near-field communication on the skin of human wrist. PMID- 30479938 TI - Biodegradable 2D Fe-Al Hydroxide for Nanocatalytic Tumor-Dynamic Therapy with Tumor Specificity. AB - Therapeutic nanocatalysis has emerged as an intriguing strategy for efficient cancer-specific therapy, but the traditional inorganic nanocatalysts suffer from low catalytic efficiency and difficulty in biodegradation, hindering their further clinical translation. Herein, a tumor microenvironment-triggered, biodegradable and biocompatible nanocatalyst employing 2D hydroxide nanosheet is presented, and is shown to have high catalytic capacity to efficiently produce abundant hydroxyl radicals under the tumor microenvironment and consequently kill tumor cells selectively. A polyethylene glycol (PEG)-conjugated Fe2+-containing hydroxide nanosheet is successfully constructed via a facile but efficient bottom up approach that concurrently realizes nanosheet synthesis and PEGylation. Importantly, the nanosheets are featured with high catalytic activity to disproportionate H2O2 in tumors, and consequently generate abundant hydroxyl radicals at a high reaction rate under tumorous acidic condition; the highly toxic hydroxyl radicals, as a result, cause the death of tumor cells in vitro and suppress the tumor growth in vivo without the use of any supplementary toxic agent, only with the biocompatible nanocatalysts. Meanwhile, the desirable biodegradation and biocompatibility of the hydroxide nanosheet render a high degree of safety to the organism. Therefore, this work provides the first paradigm of biodegradable 2D nanocatalytic platform with concurrently high catalytic-therapeutic performance and biosafety for efficient tumor-specific treatment. PMID- 30479939 TI - Reversible Mechanochromic Delayed Fluorescence in 2D Metal-Organic Micro/Nanosheets: Switching Singlet-Triplet States through Transformation between Exciplex and Excimer. AB - Mechanochromic luminescent materials have attracted much attention and present a variety of applications in information security, data recording, and storage devices. However, most of these smart luminescent systems are based on typical fluorescence and/or phosphorescence mechanisms; the mechanochromic delayed fluorescence (MCDF) materials involving switching singlet and triplet states are rarely studied to date. Herein, new 2D layered metal-organic micro/nanosheets, [Cd(9-AC)2(BIM)2] (named as MCDF-1; 9-AC = anthracene-9-carboxylate and BIM = benzimidazole) and its solvate form containing interlayer CH3CN (named as MCDF 2), which exhibit reversible mechanochromic delayed fluorescence characteristics, are presented. With applying the mechanical force, the luminescent center of MCDF 1 can be converted from 9-AC/BIM exciplex to 9-AC/9-AC excimer, resulting in alternations of delayed fluorescence. Such luminescent change can be further recovered by CH3CN fumigation, accompanied by the structural transformation from MCDF-1 to MCDF-2. Furthermore, the force-responsive process also refers to the energy redistribution between singlet and triplet states as inferred by both temperature-dependent photophysics and theoretical calculations. Therefore, this work not only develops new 2D micro/nanosheets as MCDF materials, but also supplies a singlet-triplet energy switching mechanism on their reversible mechanochromic process. PMID- 30479940 TI - Control of Interface Defects for Efficient and Stable Quasi-2D Perovskite Light Emitting Diodes Using Nickel Oxide Hole Injection Layer. AB - Metal halide perovskites (MHPs) have emerged as promising materials for light emitting diodes owing to their narrow emission spectrum and wide range of color tunability. However, the low exciton binding energy in MHPs leads to a competition between the trap-mediated nonradiative recombination and the bimolecular radiative recombination. Here, efficient and stable green emissive perovskite light-emitting diodes (PeLEDs) with an external quantum efficiency of 14.6% are demonstrated through compositional, dimensional, and interfacial modulations of MHPs. The interfacial energetics and optoelectronic properties of the perovskite layer grown on a nickel oxide (NiO x ) and poly(3,4 ethylenedioxythiophene):polystyrene sulfonate hole injection interfaces are investigated. The better interface formed between the NiO x /perovskite layers in terms of lower density of traps/defects, as well as more balanced charge carriers in the perovskite layer leading to high recombination yield of carriers are the main reasons for significantly improved device efficiency, photostability of perovskite, and operational stability of PeLEDs. PMID- 30479941 TI - A Facile Approach to Improve Interchain Packing Order and Charge Mobilities by Self-Assembly of Conjugated Polymers on Water. AB - Development of facile and economic approaches for assembling organic semiconductors into more ordered structures toward high charge mobilities is highly demanding for the fabrication of organic circuits. Here a simple and facile approach is reported to prepare conjugated polymer thin films with improved crystallinities and charge mobilities by self-assembling semiconducting polymers on water. The formation of polymer thin films with more ordered structures is attributed to coffee ring effect induced by solvent-evaporation on water, and the hydrophobic nature of conjugated polymers that forces the polymer chains to pack densely and orderly on water surface. This approach is applicable to typical semiconducting polymers, and charge mobilities of their thin films are boosted remarkably. Finally, this new method can be utilized to easily fabricate the array of field-effect transistors with high charge mobilities in an economic way. PMID- 30479942 TI - Palate ulcer, uvular destruction and nasal septal perforation caused by Sporothrix brasiliensis in an HIV-infected patient. AB - Sporotrichosis is a human and animal disease caused by dimorphic pathogenic species of the genus Sporothrix. We report a dramatic presentation of Sporothrix brasiliensis infection, with destruction of the nasal septum, soft palate, and uvula of an HIV-infected woman. She was successfully treated with amphotericin B deoxycholate followed by itraconazole. Sporotrichosis remains a neglected opportunistic infection in patients with AIDS and awareness of this potentially fatal infection is of utmost importance. PMID- 30479943 TI - Urinary capillariosis in a free-ranging Marsican brown bear (Ursus arctos marsicanus). AB - Extraintestinal nematodes have been seldom investigated in the brown bear (Ursus arctos). In this study, a case of urinary capillariosis and bladder associated lesions is reported in a deceased free-ranging Marsican brown bear (Ursus arctos marsicanus) from Central Italy. Gross lesions in the urinary bladder consisted of scattered foci of mucosal hyperemia, while at histological examination mild cystitis was observed. At microscopic examination of urine and bladder lavage fluid, capillariid adult female nematodes and eggs were found, suspected of belonging to the genus Pearsonema based on their location in the urinary bladder. This is the first report of Pearsonema infection and associated bladder lesions in a brown bear. PMID- 30479945 TI - Intracolonic cardiac pacemaker: A case of device migration with colon perforation out of a subcutaneous epifascial pocket. PMID- 30479944 TI - Genetic diversity of Toxoplasma gondii isolates obtained from free-living wild birds rescued in Southeastern Brazil. AB - Recent studies carried out in Brazil have shown that strains from the same Toxoplasma gondii genotype can infect humans, domestic animals (dogs and cats) and animals slaughtered for human consumption (pigs, sheep, goats, and chickens), suggesting a common infection route. However, little is known about the importance of free-living wild birds within this epidemiological context. The objective of this work was to isolate, genotype, and evaluate the virulence for mice of new isolates of T. gondii obtained from free-living wild birds from the state of Minas Gerais, Southeastern Brazil. From August 2016 to June 2017, T. gondii was isolated from the hearts and brains collected from 6 out of 45 free living wild birds, namely, a roadside hawk (Rupornis magnirostris), a campo flicker (Colaptes campestris), a southern caracara (Caracara plancus) and a tropical screech-owl (Megascops choliba), all rescued in Belo Horizonte. One isolate was obtained from a toco toucan (Ramphastos toco), rescued in Cristiano Otoni, and another was obtained from southern caracara, rescued in Santa Luzia. Five different genotypes were identified by PCR-RFLP. A unique genotype was shared in two different isolates obtained from a southern caracara and a toco toucan. This genotype has never been previously described in any other host or place. Three isolates were classified as of intermediary virulence and three isolates as avirulent for mice. The combined analysis of alleles ROP18/ROP5 (a serine/threonine kinase, and a polymorphic pseudokinase, respectively) was effective in determining the virulence of five of all the isolates with the exception of that from R. magnirostris. Atypical isolates of T. gondii obtained from free-living wild birds rescued in the state of Minas Gerais share the same genotypes of strains that infect humans, domestic animals, and animals slaughtered for human consumption. PMID- 30479946 TI - Severe coronary artery spasm repeatedly induced after left pulmonary vein isolation in patient with atrial fibrillation. PMID- 30479947 TI - Implantation of a leadless pacemaker in a pediatric patient with congenital heart disease. PMID- 30479948 TI - Polymorphic ventricular tachycardia associated with an episode of reflex syncope: Is this the needle in the haystack? PMID- 30479949 TI - A unique triadin exon deletion causing a null phenotype. PMID- 30479950 TI - Wolff-Parkinson-White syndrome due to a left atrial appendage-to-left ventricular connection: A case of a successful pathway elimination from inside of the left atrial appendage. PMID- 30479951 TI - Cardioneuroablation in ictal asystole-New treatment method. PMID- 30479952 TI - Cyclical sinus bradycardia and atrioventricular block induced by ticagrelor. PMID- 30479953 TI - Expanding the electrical phenotype of NKX2-5 mutations: Ventricular tachycardia, atrial fibrillation, and complete heart block within one family. PMID- 30479954 TI - Damage to the left internal mammary artery during anterior epicardial access for ventricular tachycardia ablation. PMID- 30479955 TI - Multiple atrial tachycardias after orthotopic heart transplantation: A case report and literature review. PMID- 30479956 TI - Adenosine-sensitive atrial tachycardia originating from the anterior mitral annulus. PMID- 30479957 TI - Respiratory rate trending as a cause for atrial lead noise: A first report in an implantable cardioverter-defibrillator patient. PMID- 30479958 TI - Atypical flutter following lung transplantation involving recipient-to-donor tissue connections. PMID- 30479959 TI - A pseudo-sinus rhythm due to bigeminal ectopy with the focus in the right superior pulmonary vein. PMID- 30479960 TI - Case report: Mycobacterium bovis orchitis post intravesical Bacillus Calmette Guerin. AB - Bacillus Calmette-Guerin (BCG) therapy is a common adjunctive therapy for superficial bladder carcinoma but there has been noted to be complications from this treatment ranging from general disseminated infections to osteomuscular involvement. We report a case regarding a 63 year old gentleman who presented with right testicular swelling and pain and later found to have evidence consistent with Mycobacterium bovis orchitis. We also detail a literature review regarding genitourinary infections secondary to BCG therapy and discussion regarding current testing modalities. PMID- 30479961 TI - A case report of serotype W135 Neisseria meningitidis epiglottitis in the United States and review of twelve adult cases of meningococcal epiglottitis. PMID- 30479962 TI - Campylobacter fetus spondylodiscitis: A case report and review of the literature. AB - Campylobacter are common zoonotic food borne pathogens but infrequent causes of disseminated human infection. Campylobacter fetus is an unusual cause of human infection and spondylodiscitis. We describe a case of C. fetus infection in a 72 year-old woman who presented with indolent onset lumbar spondylodiscitis. The literature is reviewed and the presentation of spondylodiscitis is contrasted with the usual aggressive nature of bacteremia with this pathogen. PMID- 30479963 TI - Roseomonas mucosa bacteremia in a neutropenic child: A case report and literature review. AB - Roseomonas species is rarely found to be pathogenic to humans and there are few clinical cases that have been described in the literature. We report a case of Roseomonas mucosa bacteremia that involved a 9-year-old Japanese boy who was in a condition of febrile neutropenia caused by chemotherapy for cerebellar medulloblastoma. Conventional phenotyping failed to identify the organism; however, genetic analysis using 16S rDNA sequencing confirmed the pathogen to be R. mucosa. The patient recovered following treatment by meropenem without any complications. A literature review of pediatric cases of Roseomonas bacteremia identified 12 other documented cases, and these revealed that a common clinical situation for the infection is an immunocompromised state with malignancy and/or an indwelling intravenous catheter. Because of the low number of cases, the overall picture of Roseomonas bacteremia in children remains to be elucidated; however, the prognosis of the infection appears to be satisfactory. PMID- 30479964 TI - Hypercalcemia due to parathyroid hormone-related peptide secreted by neuroendocrine dedifferentiated prostate cancer. PMID- 30479965 TI - Concomitant perinephric Castleman disease and renal cell carcinoma initially suspected to be metastasis: A case report and 24 months follow up. PMID- 30479966 TI - Conservative management of hostile bladders with intravesical botulinum toxin for successful renal transplantation. PMID- 30479967 TI - Urinary tract infection with rare pathogen Raoultella Planticola: A post operative case and review. PMID- 30479969 TI - Tolerance of Tithonia diversifolia and Chromolaena odorata in heavy metal simulated-polluted soils and three selected dumpsites. AB - Soil heavy metals pollution is of global concern in view of their flow through the food chain. The convectional, physical, and chemical approaches to remediate polluted soils are usually expensive and not eco-friendly. Phytoextraction is a promising alternative because of the cost effectiveness and eco-friendliness. Therefore, this study was designed to determine the abilities of Chromolaena odorata (Co) and Tithonia diversifolia (Td) to extract heavy metals from polluted soil. Soil analysis was done in part per million (ppm) before Td and Co were grown separately on sixty soil samples of 6.5 kg each collected from 3 selected dumpsites in Irese, New Stadium, and a control site (Ijare), Akure in Ondo State. Three replicates of the soil samples collected from Ijare were simulated with 10 g/kg each of cadmium (Cd), zinc (Zn), iron (Fe), copper (Cu) and lead (Pb) and used in assessing the phytoextraction capabilities of Co and Td. Two grams per kilogram of each of the heavy metals were mixed together and used in simulating three soil samples collected from Ijare and phytoextraction capabilities of Co and Td assessed. A control experiment using soil sample from Ijare was also set up in three replicates for Co and Td. Soil analyses were also carried out after the experiment in ppm. Plant biomass was assessed. Heavy metal contents in roots, shoots and soil samples were analyzed after harvest to determine the bioaccumulation (BF). Data obtained were subjected to one way Analysis of Variance at alpha0.05. The most contaminated soil sample before and after the experiment was obtained in soil sample (mg/kg) from OD with Cd = 0.08 and 0.071, Zn = 1.92 and 1.85, Fe = 8.44 and 6.94, Cu = 3.04 and 2.54 and Pb = 1.4 and 0.93 respectively. The highest fresh and dry weights (g) for Td and Co were recorded in the plants grown in the control soil. The fresh weight (g) for Td and Co shoots and roots were 110.58 and 52.90; and 48.41 and 7.18 respectively. The dry weights (mg) for Td and Co shoots and roots were 20.56 and 4.68; and 16.66 and 0.36 respectively. Uptake of heavy metals in T. diversifolia and C. odorata tissues (ppm) were Cd (0.43 and 0.06), Zn (6.57 and 3.8), Cu (3.93 and 2.21), Pb (2.37 and 1.94) and Fe (55.15 and 32.82) respectively. This study showed Tithonia diversifolia and C. odorata were capable of reducing heavy metals in polluted soils. Thus the plants are good candidates for the phytoextraction of heavy metals from polluted soils. PMID- 30479968 TI - Is oxidative stress of adipocytes a cause or a consequence of the metabolic syndrome? AB - Metabolic syndrome is accompanied by oxidative stress in animals and humans. The main source of ROS in experimental metabolic syndrome is NADPH oxidase and possibly adipocyte mitochondria. It is now documented that oxidative stress induces insulin resistance of adipocytes and increases secretion of leptin, MCP 1, IL-6, and TNF-alpha by adipocytes. It was established that oxidative stress induces a decrease in adiponectin production by adipocytes. It has also been shown that obesity itself can induce oxidative stress. Oxidative stress can cause an alteration of intracellular signaling in adipocytes that apparently leads to the formation of insulin resistance of adipocytes. Chronic stress, glucocorticoids, mineralocorticoids, angiotensin-II, TNF-alpha also play an important role in the pathogenesis of oxidative stress of adipocytes. Oxidative stress is not only a consequence of metabolic syndrome, but also a reason and a foundational link in the pathogenesis of the metabolic syndrome. PMID- 30479970 TI - Hip hemi-arthroplasty for neck of femur fracture: What is the current evidence? AB - This editorial reviews and summarises the current evidence (meta-analyses and Cochrane reviews) relating to the use of hip hemi-arthroplasty for neck of femur fractures. Regarding the optimal surgical approach, two recent meta-analyses have found that posterior approaches are associated with: higher rates of dislocation compared to lateral and anterior approaches; and higher rates of re-operation compared to lateral approaches. Posterior approaches should therefore be avoided when performing hip hemi-arthroplasty procedures. Assessing the optimal prosthesis head component, three recent meta-analyses and one Cochrane review have found that while unipolar hemi-arthroplasty can be associated with increased rates of acetabular erosion at short-term follow-up (up to 1 year), there is no significant difference between the unipolar hemi-arthroplasty and bipolar hemi arthroplasty for surgical outcome, complication profile, functional outcome and acetabular erosion rates at longer-term follow-up (2 to 4 years). With bipolar hemi-arthroplasty being the more expensive prosthesis, unipolar hemi-arthroplasty is the recommended option. With regards to the optimal femoral stem insertion technique, three recent meta-analyses and one Cochrane Review have found that, while cemented hip hemi-arthroplasties are associated with a longer operative time compared to uncemented Hip Hemi-arthroplasties, cemented prostheses have lower rates of implant-related complications (particularly peri-prosthetic femoral fracture) and improved post-operative outcome regarding residual thigh pain and mobility. With no significant difference found between the two techniques for medical complications and mortality, cemented hip hemi arthroplasty would appear to be the superior technique. On the topic of wound closure, one recent meta-analysis has found that, while staples can result in a quicker closure time, there is no significant difference in post-operative infections rates or wound healing outcomes when comparing staples to sutures. Therefore, either suture or staple wound closure techniques appear equally appropriate for hip hemi-arthroplasty procedures. PMID- 30479971 TI - Biomechanics of posterior shoulder instability - current knowledge and literature review. AB - Posterior instability of the shoulder is a rare condition and represents about 10% of shoulder instability. It has become more frequently recognized in the last year, even though it is more difficult to diagnose than anterior shoulder instability. As this form of shoulder pathology is somewhat rare, biomechanical knowledge is limited. The purpose of our study was to perform an extensive literature search, including PubMed and Medline, and to give an overview of the current knowledge on the biomechanics of posterior shoulder instability. The PubMed/Medline databases were utilized, and all articles related to posterior shoulder instability and biomechanics were included to form a comprehensive compilation of current knowledge. A total of 93 articles were deemed relevant according to our inclusion and exclusion criteria. As expected with any newly acknowledged pathology, biomechanical studies on posterior shoulder instability remain limited in the literature. Current biomechanical models are performed in a static manner, which limits their translation for explaining a dynamic pathology. Newer models should incorporate dynamic stabilization of both the rotator cuff and scapulothoracic joint. There is a current lack of knowledge with regards to the pathomechanism of posterior shoulder instability, with no consensus on appropriate treatment regimens. Further investigation is therefore required at both basic science and clinical levels. PMID- 30479972 TI - Recently highlighted nutraceuticals for preventive management of osteoarthritis. AB - Osteoarthritis (OA) is a chronic degenerative disease of articular cartilage with limited treatment options. This reality encourages clinicians to suggest preventive measures to delay and contain the outbreak of the pathological conditions. Articular cartilage and synovium suffering from OA are characterised by an inflammatory state and by significant oxidative stress, responsible for pain, swelling and loss of mobility in the advanced stages. This review will focus on the ability of olive oil to exert positive effects on the entire joint to reduce pro-inflammatory cytokine release and increase lubricin synthesis, olive leaf extract, since it maintains lubrication by stimulating high molecular weight hyaluronan synthesis in synovial cells, curcumin, which delays the start of pathological cartilage breakdown, sanguinarine, which downregulates catabolic proteases, vitamin D for its capacity to influence the oxidative and pro inflammatory environment, and carnosic acid as an inducer of heme oxygenase-1, which helps preserve cartilage degeneration. These molecules, considered as natural dietary supplements, appear like a cutting-edge answer to this tough health problem, playing a major role in controlling homeostatic balance loss and slowing down the pathology progression. Natural or food-derived molecules that are able to exert potential therapeutic effects are known as "nutraceutical", resulting from the combination of the words "nutrition" and "pharmaceutical". These compounds have gained popularity due to their easy availability, which represents a huge advantage for food and pharmaceutical industries. In addition, the chronic nature of OA implies the use of pharmacological compounds with proven long-term safety, especially because current treatments like nonsteroidal anti inflammatory drugs and analgesics improve pain relief but have no effect on degenerative progression and can also cause serious side effects. PMID- 30479973 TI - Should antibiotics be administered before arthroscopic knee surgery? A systematic review of the literature. AB - AIM: To explore the current evidence surrounding the administration of prophylactic antibiotics for arthroscopic knee surgery. METHODS: Databases were searched from inception through May of 2018 for studies examining prophylactic antibiotic use and efficacy in knee arthroscopy. Studies with patient data were further assessed for types of arthroscopic procedures performed, number of patients in the study, use of antibiotics, and outcomes with the intention of performing a pooled analysis. Data pertaining to "deep tissue infection" or "septic arthritis" were included in our analysis. Reported data on superficial infection were not included in our data analysis. For the pooled analysis, a relative risk ratio was calculated and chi2 tests were used to assess for statistical significance between rates of infection amongst the various patient groups. Post hoc power analyses were performed to compute the statistical power obtained from our sample sizes. Number needed to treat analyses were performed for statistically significant differences by dividing 1 by the difference between the infection rates of the antibiotic and no antibiotic groups. An alpha value of 0.05 was used for our analysis. Study heterogeneity was assessed by Cochrane's Q test as well as calculation of the I 2 value. RESULTS: A total of 49682 patients who underwent knee arthroscopy for a diverse set of procedures across 19 studies met inclusion critera for pooled analysis. For those not undergoing graft procedures, there were 27 cases of post-operative septic arthritis in 34487 patients (0.08%) who received prophylactic antibiotics and 16 cases in 10911 (0.15%) who received none [risk ratio (RR) = 0.53, 95% confidence interval (CI): 0.29-0.99, P = 0.05]. A sub-group analysis in which bony procedures were excluded was performed which found no significant difference in infection rates between patients that received prophylactic antibiotics and patients that did not (P > 0.05). All anterior cruciate ligament reconstruction studies used prophylactic antibiotics, but two studies investigating the effect of soaking the graft in vancomycin in addition to standard intravenous (IV) prophylaxis were combined for analysis. There were 19 cases in 1095 patients (1.74%) who received IV antibioitics alone and no infections in 2034 patients who received IV antibiotics and had a vancomycin soaked graft (RR = 0.01, 95%CI: 0.001-0.229, P < 0.01). CONCLUSION: Prophylactic antibiotics are effective in preventing septic arthritis following simple knee arthroscopy. In procedures involving graft implantation, graft soaking reduces the rate of infection. PMID- 30479975 TI - Promptly reporting of critical laboratory values in pediatrics: A work in progress. AB - In the 21st century, the determination of alert thresholds remains the most challenging and controversial issue in clinical pediatrics. Pre-analytical, analytical, and post-analytical matters will consolidate or undermine the fate of any laboratory process. Pre-analytical issues need to be cleared off before the laboratory physician can dispatch the result to the pediatrician in charge. Once it is cleared off, the classification of essential laboratory results is paramount. It is more than an academic exercise and may be subdivided in the order of priority we handle it to inform promptly and safely the primary physicians. Currently, we are applying new modes of making sure relevant information is transmitted without interrupting the standard workflow of the primary physicians in charge for the child, who eventually need a fast line of action for results that may be life-threatening. PMID- 30479976 TI - Human milk banking can be an innovative approach for developing countries. PMID- 30479974 TI - Analysis of a ten step protocol to decrease postoperative spinal wound infections. AB - AIM: To define a ten-step protocol that reduced the incidence of surgical site infection in the spine surgery practice of the senior author and evaluate the support for each step based on current literature. METHODS: In response to unexplained increased infection rates at our institution following spine surgery, a ten-step protocol was implemented: (1) preoperative glycemic management based on hemoglobin A1c (HbA1c); (2) skin site preoperative preparation with 2% chlorhexidine gluconate disposable cloths; (3) limit operating room traffic; (4) cut the number of personnel in the room to the minimum required; (5) absolutely no flash sterilization of equipment; (6) double-gloving with frequent changing of outer gloves; (7) local application of vancomycin powder; (8) re-dosing antibiotic every 4 h for prolonged procedures and extending postoperative coverage to 72 h for high-risk patients; (9) irrigation of subcutaneous tissue with diluted povidone-iodine solution after deep fascial closure; and (10) use of DuraPrep skin preparation at the end of a case before skin closure. Through an extensive literature review, the current data available for each of the ten steps was evaluated. RESULTS: Use of vancomycin powder in surgical wounds, routine irrigation of surgical site, and frequent changing of surgical gloves are strongly supported by the literature. Preoperative skin preparation with chlorhexidine wipes is similarly supported. The majority of current literature supports control of HbA1c preoperatively to reduce risk of infection. Limiting the use of flash sterilization is supported, but has not been evaluated in spine specific surgery. Limiting OR traffic and number of personnel in the OR are supported although without level 1 evidence. Prolonged use of antibiotics postoperatively is not supported by the literature. Intraoperative use of DuraPrep prior to skin closure is not yet explored. CONCLUSION: The ten-step protocol defined herein has significantly helped in decreasing surgical site infection rate. Several of the steps have already been shown in the literature to have significant effect on infection rates. As several measures are required to prevent infection, instituting a standard protocol for all the described steps appears beneficial. PMID- 30479977 TI - Waterpipe tobacco smoking: A reality or hidden iceberg for Iranian women. PMID- 30479978 TI - Intensity-specific effects of acute exercise on human memory function: considerations for the timing of exercise and the type of memory. AB - Background: The purpose of this review was to evaluate whether acute exercise intensities have unique effects on memory function, and whether this is influenced by memory type as well as the temporality of the acute exercise bout. Methods: A systematic review was employed, using several databases (PubMed, PsychInfo,Sports Discus, Google Scholar, Embase). Results: In total, 9 articles met the study criteria. All 9 studies evaluated either working memory capacity or episodic-related memory function. The main findings across these studies were 1) when acute exercise occurs before the memory task, high-intensity exercise may be less favorable for working memory but may favor episodic memory; 2) when acute exercise occurs during the memory task, high-intensity exercise may be less favorable for working memory capacity; and 3) high-intensity exercise may not associate with long-term memory function when it occurs shortly after memory encoding. Conclusion: The relationship between acute exercise and memory is complex and may vary based on the intensity of exercise, the temporality of exercise, and the memory type evaluated. PMID- 30479979 TI - Legislation for patient information leaflets in Iran: Focus on lay-friendliness. AB - Background: Patient information leaflet (PIL) which accompanies medicinal products and informs patients about dosage, side effects, etc., is known as a tool which empowers patients to be more involved in making decisions related to their medications and health. In recent years, policy makers have paid much attention to PIL and its lay-friendliness i.e. being clear,explicit, and easy to read and understand. In various countries, PIL is known as a legal genre and must be prepared in understandable language. The present study aimed to situate PIL within its institutional context and investigate the importance is given to the lay-friendliness of PIL in Iran. Methods: In this observational study, official website of Food and Drug Administration of the Islamic Republic of Iran (IFDA) was consulted. Iran's rules and regulations, legal requirements,linked to PIL production and translation were introduced and discussed in relation to lay friendliness.. Results: Limited legislation relevant for the production and translation of lay-friendly PIL was found. The IFDA has not issued any documents or guidelines which exclusively concern lay- friendliness of PIL. Any methods which can assess lay-friendliness in original and translated PILs were not observed. Conclusion: The IFDA, the authoritative body in charge of legislation concerning PIL, has given limited importance to the language used in PIL and its lay-friendliness, witnessed by the limited legislation which is relevant for the production and translation of easy-to-understand PIL. It is not clear that how the IFDA assesses quality and lay-friendliness of original and translated PILs. PMID- 30479980 TI - Assessment of contrast perception of obstacles in a tunnel entrance. AB - Background: The purpose of this study was to assess the contrast perception of obstacles in a tunnel entrance which was placed in Ilam Province, Iran. Methods: An obstacle with the reflection coefficient of 20% was mounted at the entrance of thetunnel and then, the car was placed near the tunnel entrance and the intrinsic luminance of the road (Lr,intrinsic) and obstacle (Lo,intrinsic) were measured inside the car using the luminance meter. Results: Intrinsic luminance of obstacle and road at the entrance of the tunnel were measured as 41 and 17 cd/m2, respectively. The contrast perception of obstacle in deriver's eyes and in the safe stopping distance (SSD) from the tunnel entrance was determined as 2.79 cd/m2. At the entrance of the studied tunnel, the contrast perception of obstacles with the reflection coefficient of 20% was lower than the minimum contrast perception (28%) recommended by International Commission on Illumination. Conclusion: The main conclusion that can be drawn from it, is that this obstacle in the SSD from the tunnel entrance cannot be conceived by the drivers, which may lead to higher rate of road traffic crashes. PMID- 30479981 TI - Cognitive determinants of self-care behaviors among patients with heart failure: A path analysis. AB - Background: Heart failure (HF) is a common clinical syndrome resulting from any structural or functional cardiac disorder that impairs the ability of ventricles to fill with or eject blood.Our aim in this study was to examine the possible direct/indirect effects of health belief model(HBM) constructs on self-care behaviors among HF patients. Methods: A secondary analysis was conducted on an HBM-based data set collected from 180 patients with HF who were recruited from a heart hospital in Tehran, Iran, during a prospective experimental study in 2008. A regression-based path analysis was conducted to examine the relationships between HBM constructs (as independent variables) and self-care behaviors (as dependent variable). Results: A conceptual path model was identified for the cognitive determinants of self-care behaviors among HF patients. Knowledge (beta = 0.399), perceived barriers (beta = 0.315) and susceptibility (beta = 0.165) had direct effects on self-care (R2 = 0.512, P < 0.001). Perceived benefits, self efficacy, severity and threat, locus of control and cues to action had indirect effects on self-care through the first three variables. Conclusion: HBM was found to be helpful in understanding direct and indirect associations between the cognitive determinants and self-care behaviors among HF patients. Based on this challenging path analysis, HF patients' knowledge and perceived barriers and susceptibility are suggested as the most core categories while designing HF educational programs. Better understanding on such associations may lead nurses and health practitioners in designing properly informed stage-specific educational interventions aiming to foster self-care behaviors among HF patients. PMID- 30479982 TI - Fruit and vegetable consumption among adults in Namibia: analysis of a nationally representative population. AB - Background: Prevalence of F&V consumption in Namibia is not known. In this study we aimed to address this gap by using nationally representative data with the objectives of measuring the prevalence of adequate F&V consumption among adult men and women and their socio demographic determinants. Methods: This study is based on data from Namibia Demographic and Health Survey (NDHS2013). Sample population were 14 185 men and women aged between 15 and 49 years.Amount of fruit and vegetable consumption was measured by self-reported frequencies and was defined as adequate (at least 5 servings/day) according to World Health Organization (WHO)guidelines. Results: Overall, only 4.3% (3.8-4.9%) of the men and women reported consuming at least 5 servings of F&V a day, with the percentage being slightly higher among women (4.8%,95% CI=3.7-6.2) compared with men (4.2%, 95% CI=3.6-4.8). In the multivariable analysis,education level and household wealth status appeared to be the only factors associated with adequate F&V intake. Men and women who had primary level education had higher odds of eating at least 5 servings of F&V a day compared with those who had no education. Regarding wealth status, men and women from non-poor households had respectively 2.13 times(OR=2.13, 95% CI=1.01-4.48) and 2.2 times (OR=2.19, 95% CI=1.56-3.38) higher odds of eating at least 5 servings of F&V a day. Conclusion: Only a small proportion of the men and women consumed adequate amount of F&V on daily basis. Having primary level education and non-poor household wealth status were positively associated with adequate amount of F&V intake. PMID- 30479983 TI - Does long sleep duration increase risk of metabolic syndrome in Azar cohort study population? AB - Background: We decided to assess the correlation between metabolic syndrome (MetS) risks,sleep and napping duration in Azar cohort population according to the increasing incidence of MetS in the world and inconsistence results about sleep duration and MetS. Methods: In this cross-sectional study, MetS and sleep habits of 14916 subjects (35-70 years old) who inhabited in Shabestar city were determined by ATPIII and Pittsburg questionnaire respectively. Inclusion criteria were subjects with 35-70 years old and living in Shabestar for at least 9 months of the year. Results: According to the results, age, living place, body mass index, hypnotic drug use, sleep and napping duration and TV time were the risk factors of MetS. In this regard, long sleep duration (>9 h/24 h), napping (0.25-2 h/day), hypnotic drug use and watching TV (2 h/day)increased the risk of MetS by 1.18 (1.05-1.33), 1.16(1.07-1.26), 1.35(1.13-1.60), and 1.13(1.04-1.23) respectively. Conclusion: According to these results, it appears that proper education for improvement of sleep habit is necessary to reduce incidence of MetS and its consequences. However, there is need for more longitudinal researches and using objective method of sleep habits evaluation for more precise results. PMID- 30479984 TI - Evaluation of occupational exposure to different levels of mixed organic solvents and cognitive function in the painting unit of an automotive industry. AB - Background: The cognitive function could be affected following exposure to organic solvents.The purpose of this study was to examine the cognitive performance of workers exposed to different levels of organic solvents in a painting unit of an automotive industry. Methods: This case-control study was conducted, in 2017, on 121 and 111 workers from the painting and assembly units of an automotive industry as the case and control groups,respectively. Exposure of workers to organic solvents were determined according to National Institute for Occupational Safety and Health (NIOSH) method. The cognitive performance of the studied population was evaluated by the computerized tests. Results: The obtained scores of the N-Back in 1 and 2 blocks and the simple reaction time tests(SRTTs) were significantly differed in the exposed group (p<0.05). No significant difference was observed between case and control groups in the Stroop test score (p> 0.05). Moreover, a significant relationship between the hazard quotient and the cognitive function test scores were observed except the Stroop test. Conclusion: Exposure to organic solvents affect the cognitive functions even below the Occupational Exposure Limits (OELs). Moreover, workers with high exposure levels of organic solvents had highest risk of poor memory and reaction time. PMID- 30479985 TI - Development and psychometric evaluation of an emotional growth questionnaire for university students. AB - Background: Despite the importance of emotional growth promotion among students, there is still a lack of standard emotional growth tools to evaluate the concept while developing interventional programs. The aim of present study was to devise and provide a valid and reliable instrument for measuring students' emotional growth. Methods: This study was conducted from 2016 to 2017 among university students. A questionnaire containing 79 items was made using focus group discussions with students and studying relevant texts. Exploratory factor analysis (EFA) (n = 188) was used to determine the construct validity of the questionnaire. Confirmatory factor analysis (CFA) (n = 38) was performed to assess the validity of the model. Reliability (n = 56) and repeatability (n = 31) of the questionnaire were assessed. Results: A 4-factor (positive identity, self esteem, effective communication and motivation)and 21-item solution was found as the best solution, which explained 63.5% of total variancebetween the items. The results of CFA approved the validity of the model (CFI = 0.914, RMSEA= 0.070). Cronbach alpha (0.93) and Intra class correlation coefficient (0.91) approved the reliability and repeatability of questionnaire. Conclusion: The 21 items questionnaire seems to be a valid and reliable instrument to measure emotional growth among university students. PMID- 30479986 TI - Improving safe street-crossing behaviors among primary school students: a randomized controlled trial. AB - Background: Child pedestrian injury is a global public health concern. Our aim in the present study was to investigate the effects of active learning-based educational intervention on street-crossing behavior among male primary school students in Mehriz county, Iran. Methods: In this randomized controlled trial, 90 first grade elementary school students(experiment = 50, control group = 48) participated. The "ASSURE Model" was applied to design the template of this active learning-based educational program, which was implemented for the experiment group in eight sessions. Behaviors of the students about ''looking for vehicles on the street'', "being cautious of dangers'' and ''crossing from safe places'' were observed and documented in actual traffic environments before, 1 week, and 6 months after intervention. Results: One week and 6 months after the intervention, the experiment group's performance in all 3 behaviors were significantly improved (P < 0.001). Distraction-adjusted differences in the mean scores of behaviors between the experiment (Mean = 2.62) and control (Mean = 3.19)groups before and 6 months after intervention (Mean in experiment groups = 6.3, Mean in control group = 4.24) were also statistically significant (P < 0.001). Conclusion: Our educational intervention was found to be helpful in promoting the street crossing behaviors of primary school-aged children. School healthcare professionals may apply active learning education as the core category of their interventional programs to promote street-crossing behaviors among primary school students. PMID- 30479987 TI - Evaluation of cardiovascular risk factors in women referring to health centers in Tabriz, Iran, 2017. AB - Background: Cardiovascular disease (CVD) is the leading cause of mortality among men and women around the world. The aim of this study was to investigate major cardiovascular risk factors in women living in the Tabriz petrochemical region, Iran during spring 2017. Methods: In this cross-sectional study, a sample of 152 women aged 30-55 years was selected from who attended health center in Tabriz, Iran. Anthropometric measurements, blood pressure,daily dietary intakes and fasting serum lipid profile, oxidized LDL (ox-LDL) and high sensitivity C reactive protein (hs-CRP) were evaluated. Results: The prevalence of overweight, general and abdominal obesity (based on Body mass index [BMI] and waist circumference [WC]) was 34.2%, 52.6%, and 73.7%, respectively. Eleven point two percent and 4.6% of women had pre-hypertension based on systolic blood pressure (SBP)and diastolic blood pressure (DBP). High serum triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and low high density lipoprotein cholesterol (HDL-C)were determined in 32.5%, 25.7%, 17.8% and 56.6% of subjects, respectively. The median of serum ox-LDL concentration was 3181.5 ng/L. Sixty-five point eight percent of participants hadhigh hs-CRP levels. In the multiple-adjusted quintile regression analysis, significant relationships were found between serum ox-LDL and age (B = 96.7, P = 0.003) and between serum hs-CRP with diastolic blood pressure (B = 0.1, P = 0.083) and TG (B = 0.01, P = 0.088). Conclusion: The high prevalence of cardiovascular risk factors in the studied women warrants more public health attention. The results also suggest that aging was associated with high serumox-LDL and increased serum hs-CRP levels, which may reflect enhanced DBP and serum TG. PMID- 30479988 TI - WOMEN IN SURGERY - an overview of the evolving trends in Nigeria. AB - Background: Since 1974 when the first Nigerian female surgeon was produced, an increasing number of Nigerian females have qualified as surgeons and more are in the various residency training programmes in Nigeria to become surgeons. Aim: To document the evolving trend of Nigerian females training as surgeons and their contribution to the surgical workforce. Methodology: A questionnaire based survey of Nigerian females who are qualified surgeons and those in the surgical training programmes from June 2016 - September 2017. Results: Sixty questionnaires were sent out, and 54(90%) responded, with 49(91%) completely answering the questionnaire. The age range of the respondents was between 29 -72 years, with a mean age of 37.5 +/- 6.2 years. Twelve (22.2%) were registrars, 18(33.3%) were senior registrars, and 24(44.4%) were specialists. One respondent (1.85%) had an academic professorial chair. The reasons for the preferred choice of subspecialty included: genuine interest 44(89.8%), availability of mentors 20(40.8%), the availability of a structured programme 14(28.62%), lifestyle friendly programmes 7(14.3%), remuneration 6(12.2%), and the duration of the training 1(2.2%). Thirty three (67.4%) were married, 11(22.5%) were single and 5(10.2%) were divorced. Twenty six (78.8%) gave birth to children during their surgical training programmes, while 12(36.4%) and 5(15.2%) gave birth to children before and after their programmes respectively. Twelve (37.5%) of the respondents who gave birth during training, had disruption in their training. Four (8.2%) of the respondents, made a career switch from Surgery. Conclusion: The evolving interest of female doctors in Surgery in Nigeria as highlighted in this study is a welcome development and should be encouraged and sustained by mentoring of aspiring female surgeons even from the medical schools. PMID- 30479989 TI - MISSILE AND BLAST INJURIES IN NIGERIA - THE SOUTHEAST EXPERIENCE. AB - Background: Missile injuries occupy a large segment of injuries treated in Southeast Nigeria, accounting for a significant proportion of morbidity and mortality. However, blast injuries are uncommon in this region. This study became necessary as a result of the rising spate of violence in various parts of Nigeria, particularly in the Northeast and in the Niger Delta regions, as well as the ever-present fear of kidnappers, armed robbers and occasionally, trigger happy security agents. Aim: To determine the types of missile and blast injuries in Southeast region, the circumstances that led to them, the management of the patients, and the outcome. Design of this study: This is a collaborative, retrospective multi-centre study. Setting: 1. Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra State. 2. Imo State University Teaching Hospital, Orlu, Imo State 3. Abia State University Teaching Hospital Aba, Abia State. 4. Federal Medical Centre, Owerri, Imo State. 5. University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu State, all in the Southeast of Nigeria. Methodology: Patients who were treated for missile or blast injuries in the last five years in each of the collaborating institutions were studied to determine the pattern of such injuries, causes, management options and outcome. Results: Four thousand, two hundred and sixteen (4,216) patients were admitted with missile and blast injuries in the collaborating Institutions in a period of five years. Majority of the injuries (4,177{99.1%}) were from gunshots, mainly to the limbs. The 39 (0.9%) cases of blast injuries were from land mines, hand grenades, and the Biafran type of improvised explosive device, popularly known as "Ogbunigwe". Seven hundred and seventy-two (18.3%) of the patients signed against medical advice and went to traditional bone-setters. Of the remaining 3,444 patients, 3,432 (99.7%) had good outcome. However, there were a total of 12 (0.4%) deaths, four from fulminant sepsis; eight from unknown causes. Conclusion: Missile injuries account for a significant proportion of injuries treated in the Southeast of Nigeria; only a few were blast injuries. The outcome of management of the affected patients was satisfactory. PMID- 30479990 TI - PAEDIATRIC OTORHINOLARYNGOLOGICAL PRESENTATION OF HALITOSIS IN A DEVELOPING COUNTRY. AB - Background: Halitosis is a common medico social symptom among children. Aim: To determine the clinical, epidemiological patterns, aetiology and psycho-social issues of halitosis among children in a tertiary hospital in Nigeria. Methodology: This was a prospective hospital based study of children with complaints of halitosis. The study was carried out in Ear, Nose & throat Department, Ekiti State University Teaching Hospital, Ado Ekiti over a period of two years, (October 2015 to September 2017). Consent was obtained from the parents/guardian. Data was obtained by using pretested interviewer assisted questionnaire.All the data obtained were collated and analyzed by using SPSS version 16.0. Ethical clearance was obtained from the ethical committee of the institution. Results: The prevalence of halitosis in this study was 6.8% and there were 58.5% males and 41.5% females with a male to female ratio of 1.5:1. Their age ranged from 1 year - 18 years with a mean of 9.48 +/- 5.84 SD years.Sources of referral for the otorhinolaryngology, head and neck care were mainly from general practitioners (52.3%) and from pediatricians (24.6%). Halitosis was noticed by family members in 50.8% and from family friends in 23.1%. Nasal and throat diseases in 49.2% and 29.2% respectively were the commonest otorhinolaryngology, head and neck disorders that were responsible for halitosis. The major causes were rhinosinusitis in 24.6%, impacted nasal foreign body in 23.1% and adenotonsillar hypertrophy in 18.5%. Associated disabilities in children and family with halitosis include social withdrawal in 35.4%, low social interaction in 32.3% and depression in 29.2%. Acute halitosis (<3/12) accounted for 50.8% while chronic halitosis (>3/12) accounted for 49.2%. In all, fifty four (83.1%) of the patients were successfully treated. Conclusion: Bad breath is a common ear, nose and throat symptom in children it is commonly due to nasal and pharyngeal diseases which are amenable to treatment. PMID- 30479991 TI - TREATMENT OUTCOME OF SHORT DENTAL IMPLANTS. AB - Background: Bone resorption following tooth loss and proximity of the alveolar crest to vital structures such as the maxillary sinus and the inferior dental canal can be a limitation to tooth replacement with an implant. The placement of short dental implants may reduce the need for bone augmentation as bone augmentation increases the cost of providing dental implant treatment. Aim: To assess the treatment outcome and survival rate of short implants used for single and multiple teeth replacement after one year of loading and restoration. Methodology: This study included 26 patients aged 21 to 70 years with a mean of 47.24 SD +/- 14.51 years that received 55 short dental implants (Bicon system, Boston, USA) for single and multiple teeth replacement at the Restorative Dentistry Clinic of Lagos University Teaching Hospital, Nigeria between 2012 and 2016. Demographic data such as age, sex, location of implant, length of implant, placement technique and type of restoration (crown or bridge) were obtained from the patients' hospital records. Patients were recalled three months, six months and one year after implant placement and restoration to assess clinically for implant mobility, pain, suppuration, gingival recession and inflammation around the implant retained restorations. Marginal bone loss and peri-implant radiolucency were evaluated using periapical radiograph. Results: Survival rate of short implants placed in this study was 96.4%. None of the surviving implants showed a marginal bone loss greater than 1.5mm one year after placement. None of the surviving and functional implant restoration demonstrated mobility, suppuration or peri-implant radiolucency during the review period. The 8mm implants demonstrated a statistically significantly higher survival rate compared with the 6mm implants (p=0.039). A significantly higher percentage of failure was recorded among the implants placed in the lower premolar region (p=0.001). Conclusion: This study has shown that the use of short implants is a viable option in teeth replacement especially when the alveolar bone height is less than 10mm. PMID- 30479992 TI - TRAUMATIC CORNEAL LACERATION IN NORTHWESTERN NIGERIA. AB - Background: Corneal laceration is a partial or full thickness corneal injury resulting from direct or indirect ocular trauma. Cornea laceration generally leads to the development of corneal opacity which is a significant cause of blindness worldwide, particularly in developing countries where facility for corneal transplant is not readily available. Clinical outcomes depend on causes, the part of cornea involved, and availability of skilled human resource and presence of corneal transplant services. Aim: To assess the presentation, causes, and outcome of management of traumatic cornea laceration among patients at Federal Medical Centre (FMC), Birnin Kebbi, Kebbi, Nigeria. Methodology: A one year, retrospective review of all patients with traumatic corneal laceration who presented to eye clinic of Federal Medical Centre (FMC) Birnin Kebbi, Nigeria between November 2013 and October 2014. Information retrieved from the patient records included patient's bio data, clinical features, presenting visual acuity (VA), agents of injury, surgical intervention and visual outcome after treatment. The data obtained were analyzed with SPSS version 16. Results: Thirty two cases of traumatic corneal laceration presented during the study period. The age of study participants ranged from 2 years to 47 years with a mean of 15.28+12.46. 16 (50%) were children less than ten years old. There were 21(65.6%) males and 11(34.4%) females with male/female ratio of 1.9:1 and 20 (62%) cases of corneal lacerations occurred at home. Majority of injuries were inflicted with sticks in 9 (28.1%) cases followed by motor bike accidents in 6(18.8%). The left eye was mostly affected 18 (56.2%). Thirteen patients (40%) presented within 24 hours of injury while 16 (50%) presented within a week while one (3.1%) reported after two weeks. Presenting visual acuities in 28(90.6%) ranged from 6/12 to hand movement and no light perception in 3(9.4%). Associated injuries included uveal prolapsed 28(87.5), cataract 15(46.9%), vitreous haemorrhage 6(18.8%) and retinal detachment 1(3.1%). All the patients had examination under anesthesia and cornea repair carried out within 36-48 hours of admission in 28(87.5%) cases and within 7 days in the remaining 4 (12.5%) patients. One (3.2%) patient developed endophthalmitis. After 6weeks follow up, visual accuity of 6/60 and better were achieved in 9 eyes. There was a statistically significant correlation between the presenting visual acuity and visual outcome. However, no relationships exist statistically between age, sex, and agent of injury. The site of injury also shows statistical association with the visual acuity at six weeks follow up. Conclusion: from this study, we observed that traumatic corneal lacerations were significant causes of ocular morbidity especially in children; public eye-health education is recommended as a preventive measure. PMID- 30479993 TI - PROFESSIONAL EXPERIENCES, TRAINING ATTITUDES AND EXPECTATIONS OF RESIDENTS IN DENTISTRY: A NATIONWIDE SURVEY. AB - Background: Worldwide, it has been acknowledged that feedback from students and trainees is important for evaluation of training. However, there is limited data on the professional experiences, expectations and attitude of residents in dentistry to their training. Aim: This study aimed to analyse the professional experiences, expectations, and attitudes of dentistry residents to training in Nigeria. Design of the study: Cross-sectional study. Setting: All the accredited Nigerian Teaching Hospitals with dental surgeons undergoing residency training in any of the 10 specialties examined in West Africa. Methodology: The study was conducted through a self- administered closed anonymous 46-items questionnaire adapted from that used for general surgery residents in the United States of America. The collected data included various aspects of the technical, human and professional domains of the expectations, attitudes and perceptions of dental residents to their training. Data from the questionnaires were collated and entered into Microsoft Excel version 10, 2002 (Microsoft, Redmond, WA, USA) and processed using STATA software (StataCorp LLC, Texas, USA). Categorical variables were calculated as proportions and percentages with 95% corresponding intervals. chi2 - test was used to analyse the association between selected demographic characteristics and some of the responses. Fischer's exact test was done where necessary. Statistical significance was set at p<=0.05 and tests were two- sided. Results: Nigeria has 11 accredited training institutions for residency in dentistry, of which 214 residents participated representing 93% of the estimated total. Most were males (133, 65.2%) with male to female ratio of 1.9:1. Residents aged between 30-34 years of age made up 41.5% while 77.4% were married. Close to one third (31.8%) were residents in oral and maxillofacial surgery. Residents expressed low level of satisfaction with the quality of residency training (64, 30.3%; 95% CI 24.5-36.9) and believe that they had appropriate level of operating skill from their training (96, 45.3%; 95% CI 38.6-52.1). Few agreed that the training programme had adequate support structures for struggling residents (64, 30.3%; 95% CI 24.5-36.9) but many (105, 65.2%; 95% CI 57.5-72.2) felt the residency programme took too long. More males (31.8%) than females (14.9%) expressed satisfaction with the level of didactic teaching during the residency programme with statistically significant difference (p=0.032). Orthodontic residents expressed the greatest approval (54.5%) for the support structures put by the training programme for struggling residents, while the least were in oral medicine (12.5%) with high statistically significant difference (p=0.014). The level of support from faculty/departmental member to struggling resident was felt to be most adequate by those who had passed the primaries exam (69.5%) with statistically significant difference from other residents (p= 0.021). Conclusion: Overall, this study showed that Nigerian dentistry residents had low level of satisfaction with the quality of their training indicating the need for a holistic review of the training curriculum and conduct of trainers. There is need to reinforce motivating and tackle demotivating factors identified in this study to improve the response of dentistry residents to their training as these would improve the value of competency assessments undertaken by the postgraduate colleges while sustaining interest in the profession for the interest of the wider society. PMID- 30479994 TI - Mucocele of appendix with an elevated carcinoembryonic antigen: A case report. AB - Mucocele of the appendix is an uncommon disease in which there is cystic dilatation of the appendix caused by mucus secretion and usually associated with benign or malignant causes. Preoperative diagnosis is difficult as the patient presents with non-specific clinical symptoms. We report a case of mucocele of the appendix with elevated serum carcinoembryonic antigen (CEA) - a condition sparsely reported in literature. Patient presented with pain in the right iliac fossa for 7 months. On exploration, a cystic mass of the appendix without perforation was found in right iliac fossa. There was no lymph nodes enlargement. Appendicectomy was performed with subsequent normalization of CEA level and histopathology confirmed the diagnosis of mucinous neoplasm of the appendix. Patient is feeling well after one year of follow up. PMID- 30479995 TI - MINIMAL INVASIVE SURGICAL APPROACH IN THEMANAGEMENT OF COMMINUTED CROWN-ROOT FRACTURE- A CASE REPORT. AB - Comminuted root fractures have a questionable prognosis and present with limited treatment options. In the following case, a comminuted crown root fracture in relation to maxillary left central incisor was managed with a minimally invasive surgical approach. The procedure involved repairing the multiple fracture lines in the root with Biodentine following the endodontic therapy and root resection. The patient was found to be asymptomatic at the end of a follow up period of ten months. PMID- 30479996 TI - Peer-Reviewed Abstracts of Scientific Paper Presentation at The 57th Annual Conference Of The West African College Of Surgeons at Ougadougou, Burkina Faso 26th February - 4th March 2017. PMID- 30479997 TI - WOMEN IN SURGERY. PMID- 30479998 TI - Efficacy of Semiannual Single Fixed Low-Dose Rituximab Therapy in Steroid Dependent Minimal Change Nephrotic Syndrome: A Case Series. AB - The frequency of using rituximab to treat refractory nephrotic syndrome has recently been increasing, and the conventional dose of rituximab used to treat it, 375 mg/m2 body surface area once weekly for 4 weeks, has been modelled on the chemotherapy regimen for B-cell non-Hodgkin's lymphoma. The dose and intervals of rituximab in refractory nephrotic syndrome remain controversial. Clear lymphoma cell hyperplasia is seen in lymphoma patients, but not in nephrotic syndrome patients. Since we thought that it might be possible to reduce the dose of rituximab if only used for the purpose of depleting CD20-positive B cells in nephrotic patients' peripheral blood, we tried semiannually with a single fixed rituximab dose of 100 mg/body, and a complete remission was attained in 3 cases without treatment with prednisolone or cyclosporine. Our report strongly suggests considering appropriate dose and interval of rituximab therapy in the treatment of steroid-dependent nephrotic syndrome. PMID- 30479999 TI - Randomised controlled trial of cognitive behavioural therapy in COPD. AB - Anxiety is an important comorbidity in chronic obstructive pulmonary disease (COPD). We investigated if cognitive behavioural therapy (CBT), delivered by respiratory nurses, reduced symptoms of anxiety and was cost-effective. Patients with COPD and anxiety were randomised to CBT or self-help leaflets. Anxiety, depression and quality of life were measured at baseline, 3, 6 and 12 months. A cost-effectiveness analysis was conducted from a National Health Service hospital perspective and quality-adjusted life-years estimated using the EuroQol-5D questionnaire. In total, 279 patients were recruited. Group mean change from baseline to 3 months in the Hospital Anxiety and Depression Anxiety Subscale was 3.4 (95% CI 2.62-4.17, p<0.001) for the CBT group and 1.88 (95% CI 1.19-2.55, p<0.001) in the leaflet group. The CBT group was superior to leaflets at 3 months (mean difference in the Hospital Anxiety and Depression Anxiety Subscale was 1.52, 95% CI 0.49-2.54, p=0.003). Importantly, the CBT intervention was more cost effective than leaflets at 12 months, significantly lowering hospital admissions and attendance at emergency departments. CBT delivered by respiratory nurses is a clinically and cost-effective treatment for anxiety in patients with COPD relative to self-help leaflets. PMID- 30480000 TI - Distal respiratory tract viral infections in young children trigger a marked increase in alveolar mast cells. AB - Viral infections predispose to the development of childhood asthma, a disease associated with increased lung mast cells (MCs). This study investigated whether viral lower respiratory tract infections (LRTIs) can already evoke a MC response during childhood. Lung tissue from young children who died following LRTIs were processed for immunohistochemical identification of MCs. Children who died from nonrespiratory causes served as controls. MCs were examined in relation to sensitisation in infant mice exposed to allergen during influenza A infection. Increased numbers of MCs were observed in the alveolar parenchyma of children infected with LRTIs (median (range) 12.5 (0-78) MCs per mm2) compared to controls (0.63 (0-4) MCs per mm2, p=0.0005). The alveolar MC expansion was associated with a higher proportion of CD34+ tryptase+ progenitors (controls: 0% (0-1%); LRTIs: 0.9% (0-3%) CD34+ MCs (p=0.01)) and an increased expression of the vascular cell adhesion molecule (VCAM)-1 (controls: 0.2 (0.07-0.3); LRTIs: 0.3 (0.02-2) VCAM-1 per mm2 (p=0.04)). Similarly, infant mice infected with H1N1 alone or together with house dust mite (HDM) developed an increase in alveolar MCs (saline: 0.4 (0.3-0.5); HDM: 0.6 (0.4-0.9); H1N1: 1.4 (0.4-2.0); HDM+H1N1: 2.2 (1.2-4.4) MCs per mm2 (p<0.0001)). Alveolar MCs continued to increase and remained significantly higher into adulthood when exposed to H1N1+HDM (day 36: 2.2 (1.2 4.4); day 57: 4.6 (1.6-15) MCs per mm2 (p=0.01)) but not when infected with H1N1 alone. Our data demonstrate that distal viral infections in young children evoke a rapid accumulation of alveolar MCs. Apart from revealing a novel immune response to distal infections, our data may have important implications for the link between viral infections during early childhood and subsequent asthma development. PMID- 30480001 TI - Pulmonary vascular pruning in smokers with bronchiectasis. AB - There are few studies looking at the pulmonary circulation in subjects with bronchiectasis. We aimed to evaluate the intraparenchymal pulmonary vascular structure, using noncontrast chest computed tomography (CT), and its clinical implications in smokers with radiographic bronchiectasis. Visual bronchiectasis scoring and quantitative assessment of the intraparenchymal pulmonary vasculature were performed on CT scans from 486 smokers. Clinical, lung function and 6-min walk test (6MWT) data were also collected. The ratio of blood vessel volume in vessels <5 mm2 in cross-section (BV5) to total blood vessel volume (TBV) was used as measure of vascular pruning, with lower values indicating more pruning. Whole lung and lobar BV5/TBV values were determined, and regression analyses were used to assess the differences in BV5/TBV between subjects with and without bronchiectasis. 155 (31.9%) smokers had bronchiectasis, which was, on average, mild in severity. Compared to subjects without bronchiectasis, those with lower lobe bronchiectasis had greater vascular pruning in adjusted models. Among subjects with bronchiectasis, those with vascular pruning had lower forced expiratory volume in 1 s and 6MWT distance compared to those without vascular pruning. Smokers with mild radiographic bronchiectasis appear to have pruning of the distal pulmonary vasculature and this pruning is associated with measures of disease severity. PMID- 30480002 TI - A Perplexing Case of Pituitary Apoplexy Masquerading as Recurrent Meningitis. AB - In this article, we present an exceptional case of pituitary apoplexy in which a patient presented with meningeal symptoms of headache, stiff neck, and nausea rather than the classical findings of ophthalmoplegia and/or vision loss. The patient has had 2 similar presentations with cerebrospinal fluid showing neutrophilic pleocytosis, as well as a computed tomography scan showing a prominent pituitary gland. On current presentation, the patient's vital signs were stable and the physical examination was remarkable for nuchal rigidity. Magnetic resonance imaging of the head revealed an expansile pituitary gland lesion measuring 2.0 * 1.7 * 1.5 cm with upward displacement of the overlying optic chiasm. Cerebrospinal fluid showed neutrophilic pleocytosis, low glucose, high protein content, and negative bacterial and fungal cultures. Surgical decompression subsequently revealed findings consistent with pituitary apoplexy. This is the first known case in which a patient had recurrent episodes of meningitis due to pituitary apoplexy in the absence of a clinical deterioration. Early identification of apoplexy masquerading as meningitis will allow early surgical intervention, if necessary, to prevent complications, recurrence, and morbidity. As such, the presence of sterile meningitis in patients with a known pituitary adenoma should be considered for prompt surgical evaluation. PMID- 30480003 TI - A Rare Case of Macrophage Activation Syndrome Presenting as the First Manifestation of Systemic Lupus Erythematosus. AB - Macrophage activation syndrome (MAS) itself is a rare, potentially life threatening complication of a rheumatic disease, mostly seen in juvenile idiopathic arthritis. It infrequently occurs in systemic lupus erythematosus (SLE), and it is extremely rare to be the first presentation of SLE. In a study of 511 patients with SLE, 7 cases (1.4%) of MAS were identified. In all the cases, MAS was simultaneous to the presentation of SLE in this article, we report a case of a patient with MAS who presented with fever, rash, and high ferritin level up to 16911 ng/mL. A high degree of suspicion is required that high fever and rash can be clues to MAS. Early diagnosis is necessary since mortality rates remain high for untreated cases. PMID- 30480004 TI - Iatrogenic Paradoxical Stroke in a Patient With Catheter-Associated Thrombosis and Systemic-to-Pulmonary Venous Shunt. AB - Paradoxical embolism occurs when thrombotic material traverses a right-to-left shunt. We describe the first case of paradoxical stroke resulting from manipulation of a disused chemotherapy port. Contrast studies revealed that the mechanism was systemic-to-pulmonary venous shunt, in which systemic veins drain into the left atrium via collaterals. Chronically thrombosed central venous catheters may result in venous stenosis and shunt formation, exposing patients to risks of paradoxical stroke, acute coronary syndrome, hypoxemia, and other complications. This case highlights the life-threatening complications that may result from neglect of an implantable central venous catheter. Preventative measures are to promptly recognize and treat catheter-related thrombosis and to remove unneeded catheters. PMID- 30480005 TI - Crescendo Transient Ischemic Attacks Due to Basilar Coccidioidal Meningitis With Coccidioma. AB - Coccidioidal meningitis typically presents with symptoms that may include headache, altered mental status including personality changes, fever, nausea, vomiting, gait abnormalities, and focal neurological deficits. This is a case of coccidioidal meningitis that initially presented as 4 consecutive crescendo cerebrovascular transient ischemic attacks with focal neurological deficits that resolved within minutes. Imaging showed a left basilar coccidioma. Follow-up at 4 months showed treatment response to conservative therapy of fluconazole 1000 mg with a dexamethasone taper. Crescendo cerebrovascular transient ischemic attacks are a unique initial presentation of coccidioidal meningitis. PMID- 30480006 TI - Incidence, Presentation, and Treatment of Pediatric and Adolescent Meniscal Root Injuries. AB - Background: Despite the increasing incidence of sports-related knee injuries in youth athletes, few studies have reported on the diagnosis and treatment of pediatric and adolescent meniscal root injuries. Purpose: To describe traumatic posterior meniscal root injuries in a pediatric and adolescent population and compare the presentation of meniscal root injuries versus that of nonroot injuries. Study Design: Cohort study; Level of evidence, 3. Methods: A study was conducted of all knee arthroscopies performed on consecutive patients treated in a pediatric sports practice from March 2012 through February 2015. All patients who were younger than 20 years at the time of their injury and who underwent an arthroscopy with meniscal injury were included. Patients with discoid lateral meniscus, atraumatic meniscal cysts, partial-thickness meniscal root injuries (LaPrade type 1), and recurrent root tears were excluded. A comparative analysis of root and nonroot injuries was performed. Results: A total of 314 patients had surgery for meniscal injury (mean patient age, 16.0 years; range, 10.5-19.6 years). Of these patients, 58 (18.5%) posterior meniscal root injuries were identified. The root injuries were more likely to have joint line tenderness on preliminary physical examination compared with nonroot injuries (96.5% vs 58.6%, respectively; P < .001). Root injuries rarely occurred in isolation compared with nonroot meniscal tears (6.9% vs 17.6%; P = .021) and were frequently treated in combination with anterior cruciate ligament (ACL) injuries (86.2%). Lateral root injuries occurred more often in conjunction with ACL injuries compared with medial root injuries (84.8% vs 22.2%; P < .001). On review of preoperative imaging, meniscal extrusion occurred more often in root injuries than in nonroot injuries (32.8% vs 3.5%; P < .0001) and was uncommonly seen in the skeletally immature patient. Extrusion was seen more often in medial than lateral root tears (66.7% vs 21.7%; P = .008). A majority of patients (57/58) underwent transosseous suture repair of the meniscal root. Conclusion: When treating a pediatric or adolescent patient for a traumatic meniscal tear, a surgeon may expect to see a posterior meniscal root injury in as many as 1 in 6 patients. When treated for an ACL, contact, or multiligament injury or meniscal extrusion, a pediatric or adolescent patient may demonstrate a meniscal root avulsion or complex meniscal tear. These data provide practitioners with an improved ability to identify and treat meniscal root injuries that otherwise lead to rapid cartilage degeneration. PMID- 30480007 TI - Nonarthroplasty Surgical Treatment Options for Massive, Irreparable Rotator Cuff Tears. AB - Massive, irreparable rotator cuff tears (MIRCTs) provide a significant dilemma for orthopaedic surgeons. One treatment option for MIRCTs is reverse total shoulder arthroplasty. However, other methods of treating these massive tears have been developed. A search of the current literature on nonoperative management, arthroscopic debridement, partial repair, superior capsular reconstruction (SCR), graft interposition, balloon spacer arthroplasty, trapezius transfer, and latissimus dorsi transfer for MIRCTs was performed. Studies that described each surgical technique and reported on clinical outcomes were included in this review. Arthroscopic debridement may provide pain relief by removing damaged rotator cuff tissue, but no functional repair is performed. Partial repair has been suggested as a technique to restore shoulder functionality by repairing as much of the rotator cuff tendon as possible. This technique has demonstrated improved clinical outcomes but also fails at a significantly high rate. SCR has recently gained interest as a method to prohibit superior humeral head translation and has been met with encouraging early clinical outcomes. Graft interposition bridges the gap between the retracted tendon and humerus. Balloon spacer arthroplasty has also been recently proposed and acts to prohibit humeral head migration by placing a biodegradable saline-filled spacer between the humeral head and acromion; it has been shown to provide good clinical outcomes. Both trapezius and latissimus dorsi transfer techniques involve transferring the tendon of these respective muscles to the greater tuberosity of the humerus; these 2 techniques have shown promising restoration in shoulder function, especially in a younger, active population. Arthroscopic debridement, partial repair, SCR, graft interposition, balloon spacer arthroplasty, trapezius transfer, and latissimus dorsi transfer have all been shown to improve clinical outcomes for patients presenting with MIRCTs. Randomized controlled trials are necessary for confirming the efficacy of these procedures and to determine when each is indicated based on specific patient and anatomic factors. PMID- 30480008 TI - Poor Readability of AOSSM Patient Education Resources and Opportunities for Improvement. AB - Background: Appropriate education on the disease processes associated with orthopaedic pathology can affect patient expectations and functional outcome. Hypothesis: Patient education resources from the American Orthopaedic Society for Sports Medicine (AOSSM) are too complex for comprehension by the average orthopaedic patient. Study Design: Cross-sectional study. Methods: Patient education resources provided by the AOSSM were analyzed with software that provided 10 readability scores as well as opportunities for improving readability. The readability scores were compared with the recommended eighth grade reading level. Results: A total of 39 patient education resources were identified and evaluated. The mean +/- SD reading grade-level scores were as follows: Coleman-Liau Index, 12.5 +/- 1.11; New Dale-Chall Readability Formula, 10.9 +/- 1.37; Flesch-Kincaid Grade Level, 9.9 +/- 1.06; FORCAST Readability Formula, 11.4 +/- 0.51; Fry Readability Formula, 12.8 +/- 2.79; Gunning Fog Index, 11.9 +/- 1.37; Raygor Readability Index, 13.1 +/- 2.37; Simple Measure of Gobbledygook, 12.3 +/- 0.90; Automated Readability Index, 11.2 +/- 1.18; and New Automated Readability Index, 10.6 +/- 1.27. After averaging the reading grade level scores, only 1 patient education resource was found to be written at an 8th to 9th-grade level, and 14 (36%) were written above a 12th-grade level. All scores were significantly different from the eighth-grade level (P < .0065). The percentage of complex words and long words were 19.6% +/- 2.67% and 41.4% +/- 3.18%, respectively. Conclusion: Patient education resources provided by the AOSSM are at a significantly higher reading level than recommended. Simple changes can drastically improve these scores to increase health literacy and possibly outcome. PMID- 30480009 TI - Do Prophylactic Knee Braces Protect the Knee Against Impacts or Tibial Moments? An In Vitro Multisensory Study. AB - Background: Knee braces are prescribed by physicians to protect the knee from various loading conditions during sports or after surgery, even though the effect of bracing for various loading scenarios remains unclear. Purpose: To extensively investigate whether bracing protects the knee against impacts from the lateral, medial, anterior, or posterior directions at different heights as well as against tibial moments. Study Design: Controlled laboratory study. Methods: Eight limb specimens were exposed to (1) subcritical impacts from the medial, lateral, anterior, and posterior directions at 3 heights (center of the joint line and 100 mm inferior and superior) and (2) internal/external torques. Using a prophylactic brace, both scenarios were conducted under braced and unbraced conditions with moderate muscle loads and intact soft tissue. The change in anterior cruciate ligament (ACL) strain, joint acceleration in the tibial and femoral bones (for impacts only), and joint kinematics were recorded and analyzed. Results: Bracing reduced joint acceleration for medial and lateral center impacts. The ACL strain change was decreased for medial superior impacts and increased for anterior inferior impacts. Impacts from the posterior direction had substantially less effect on the ACL strain change and joint acceleration than anterior impacts. Bracing had no effect on the ACL strain change or kinematics under internal or external moments. Conclusion: Our results indicate that the effect of bracing during impacts depends on the direction and height of the impact and is partly positive, negative, or neutral and that soft tissue absorbs impact energy. An effect during internal or external torque was not detected. Clinical Relevance: Bracing in contact sports with many lateral or medial impacts might be beneficial, whereas athletes who play sports with rotational moments on the knee or anterior impacts may be safer without a brace. PMID- 30480010 TI - 10-Year Epidemiology of Ankle Injuries in Men's and Women's Collegiate Basketball. AB - Background: Ankle injury is the most common injury in men's and women's basketball, regardless of the level of competition. Purpose: To use the National Collegiate Athletic Association (NCAA) Injury Surveillance Program/System (ISP/ISS) to review the 10-year epidemiology of ankle injuries in men's and women's collegiate basketball players. Study Design: Descriptive epidemiology study. Methods: The NCAA ISP was queried for men's and women's collegiate basketball ankle injury data from the 2004 through 2014 academic years. Ankle injury rates were calculated based on injuries per athlete-exposure (AE). Injury proportion ratios (IPRs) were determined by comparing variables between sexes. Activity and position of injury were also studied. Results: Over the 10-year study period, most ankle injuries in collegiate basketball occurred in the preseason (female, 1.45/1000 AEs; male, 2.00/1000 AEs), were contact related (female, 50.4%; male, 57.6%), were treated conservatively (female, 98.5%; male, 99.3%), and were new injuries (female, 78.0%; male, 78.9%), resulting in a time loss of less than 7 days (female, 62.7%; male, 65.2%). The most common injury types were lateral ligament complex tears (female, 83.5%; male, 80.0%), deltoid ligament tears (female, 5.6%; male, 7.2%), and high ankle sprains (female, 7.1%; male, 7.0%). Guards experienced the highest rate of ankle injuries in competition (female, 50.1%; male, 43.3%), and rebounding was found to be the most common activity during an injury (female, 30.3%; male, 34.4%). The rate of ankle injuries was significantly lower in women than in men (IPR, 0.81 [95% CI, 0.75 0.88]). Conclusion: This study found that most ankle injuries in collegiate basketball occurred during the preseason, were contact related, were treated conservatively, and were new injuries that resulted in a time loss of less than 7 days. PMID- 30480011 TI - Efficacy of Fresh Osteochondral Allograft Transplantation in the Knee for Adults 40 Years and Older. AB - Background: Osteochondral allograft (OCA) transplantation has become a standard therapy for cartilage restoration in young patients. Purpose: To determine the efficacy of fresh OCA transplantation for focal cartilage lesions in patients aged >=40 years compared with a group of patients aged <=39 years. Study Design: Cohort study; Level of evidence, 3. Methods: A database was used to identify patients who underwent fresh OCA transplantation in the knee in a single-surgeon practice over a 10-year period and who completed baseline patient-reported outcome (PRO) questionnaires, including the International Knee Documentation Committee (IKDC); Knee injury and Osteoarthritis Outcome Score (KOOS) subscales of Pain, Symptoms, Activities of Daily Living, Quality of Life (QOL), and Sports & Recreation; and Veterans RAND 12-Item Health Survey (VR-12). Patients who completed the same PRO measures at a minimum 12-month follow-up were categorized into 2 groups based on age at surgery and were observed longitudinally. Mixed model regression was used to predict longitudinal growth curves for each PRO score while controlling for confounding patient and surgical variables. Results: The study group consisted of 38 patients with a mean age of 52.32 years (range, 40-69 years) and mean final follow-up of 44.47 +/- 24.32 months. The control group consisted of 42 patients with a mean age of 27.19 years (range, 15-39 years) and mean final follow-up of 33.75 +/- 19.53 months. A statistically significant improvement from baseline to final follow-up was seen for the IKDC score and all 5 KOOS subscores in both the study and the control groups (P < .01 in 10 of 12 comparisons and P < .05 for the other 2 comparisons). Maximum improvements were seen in the KOOS QOL and Sports & Recreation subscores for both groups. There was no statistically significant difference between groups in the change from baseline to final follow-up or in differences at any time point in model-based longitudinal projections for any PRO score through 5 years. Conclusion: There was a significant improvement of outcomes for both groups, with no statistically significant difference between groups over longitudinal follow up. The efficacy of fresh OCA transplantation in adults aged >=40 years with a focal chondral lesion and without osteoarthritis is similar to that of younger adults, and benefits are greatest for the KOOS QOL and Sports & Recreation subscales, which reflect functional outcomes. PMID- 30480012 TI - An Evaluation of the Rotator Cuff Repair Research Pipeline. AB - Background: We conducted a study of recommendations from the American Academy of Orthopaedic Surgeons (AAOS) guideline, "Optimizing the Management of Rotator Cuff Problems." Using these recommendations, we conducted searches of clinical trial registries and bibliographic databases to note the extent to which new research has been undertaken to address areas of deficiency. Hypothesis: Newly conducted research regarding rotator cuff repair and injury is available that will fill knowledge gaps identified by the AAOS guideline. Study Design: Cross-sectional study. Methods: For each recommendation in the AAOS guideline, we created PICO (participants, intervention, comparator, outcome) questions and search strings. Searches were conducted of ClinicalTrials.gov, the World Health Organization's International Clinical Trials Registry Platform, MEDLINE via PubMed, and EMBASE to locate studies undertaken after the final literature search performed by the AAOS work group. Results: We located 210 newly registered trials and 448 published studies that are relevant to the recommendations made in the rotator cuff guideline. The majority of the recommendations have been addressed by relevant registered trials or published studies. Of the 448 published studies, 185 directly addressed the guideline recommendations. Additionally, 71% of the 185 published studies directly addressing the recommendations were randomized trials or systematic reviews/meta-analyses. The most important finding of our study was that the recommendations in the AAOS rotator cuff guideline have been adequately addressed. Conclusion: Orthopaedic researchers have adequately addressed knowledge gaps regarding rotator cuff repair treatment and management options. As such, the AAOS may consider a guideline update to ensure that recommendations reflect current findings in orthopaedic literature. PMID- 30480014 TI - Optimal Angle of the Bone Tunnel for Avoiding Axillary Nerve Injuries During Arthroscopic Transosseous Rotator Cuff Repair: A Magnetic Resonance Imaging-Based Simulation Study. AB - Background: Axillary nerve injury and suture cutout through the roof of the tunnel are potential complications of arthroscopic transosseous rotator cuff repair (ATORCR). Purpose: To determine a safe angle of drilling for the bone tunnel during ATORCR such that the axillary nerve is not at risk. The thickness of the bone bridge over the tunnel for different angles of drilling was also determined. Study Design: Descriptive laboratory study. Methods: The drilling of a straight tunnel was simulated on 30 magnetic resonance imaging (MRI) scans in the oblique coronal plane by drawing a straight line that passed at a "safe distance" of 5 mm from the axillary nerve and emerging at the medial border of the insertion of the rotator cuff on the greater tuberosity. The angle made by this line with the horizontal axis of the humerus was measured on 3 MRI sections: anterior (passing just posterior to the lateral lip of the bicipital groove), middle (at the most lateral point of the proximal humerus), and posterior (an equal number of cuts away from the middle section as between anterior and middle). The thickness of the overlying bone roof was measured for this line as well as for simulation lines drawn at 50 degrees , 55 degrees , 60 degrees , and 65 degrees with the horizontal axis. A "safe limit," defined as the mean - 2SD, was also calculated. Results: The axillary nerve was found to be safe, with a safety margin of 5 mm, at drill angles of less than 61.1 degrees and 60.3 degrees in the posterior and middle sections, respectively. The safe limit value for thickness of the overlying bone roof for the tunnel drilled at 60 degrees was 5.0 mm in the posterior section (mean, 8.2 +/- 0.3 mm) and 5.5 mm in the middle section (mean, 8.1 +/- 0.2 mm). In the anterior section, the minimum safe angle was 57.7 degrees , and the mean thickness of the bone roof for the 55 degrees angle was 6.3 +/- 0.2 mm (safe limit, 3.7 mm). Conclusion: Straight bone tunnels in ATORCR surgery should be drilled at an angle of 60 degrees to the horizontal axis of the humerus or 30 degrees to the humeral shaft to ensure the safety of the axillary nerve while at the same time ensuring adequate thickness of the overlying bone roof. The anterior tunnel close to the bicipital groove should be drilled cautiously at 55 degrees to the horizontal axis or 35 degrees to the humeral shaft. Clinical Relevance: The findings of the present study will help the surgeon choose the best angle for drilling tunnels during ATORCR surgery to avoid axillary nerve injuries as well as suture cut-through without the need for any proprietary device. PMID- 30480013 TI - Anterior Shoulder Instability: A Systematic Review of the Quality and Quantity of the Current Literature for Surgical Treatment. AB - Background: Anterior shoulder instability is the most common sequela of shoulder dislocation and can result in repeated dislocations or subluxation of the glenohumeral joint. Anterior shoulder instability can be treated conservatively or surgically with several procedures. Purpose: To date, arthroscopic Bankart is the most common surgical procedure for the treatment of anterior shoulder instability. No previous studies have compared all anterior shoulder surgical procedures. In this study, the authors performed a systematic review of journal articles describing all surgical procedures for anterior shoulder instability to determine the scientific evidence and level of recommendation. Study Design: Systematic review; Level of evidence, 4. Method: A comprehensive literature search was conducted (July 19, 2016) with 4 reputed databases: PubMed, EMBASE, the Cochrane databases, and Web of Science. The articles found in the literature search were screened by 2 reviewers on the basis of their titles, abstracts, and full text. Data were extracted from relevant studies, and potentially relevant records were selected for full-text review. Included articles were classified according to their scientific quality (level of evidence, 1-5). The studies were then combined for each surgical procedure, and a grade of recommendation was assigned for each procedure: grade A, treatment recommendation based on level 1 evidence studies; B, based on level 2 or 3 evidence studies; C, based on level 4 or 5 evidence and could represent conflicting results; or I, insufficient evidence to recommend a treatment. As such, the grade of recommendation provides a summary score for the quality and quantity of available literature to support the surgical procedures reviewed here. Results: The systematic literature review generated 11,281 articles. After screening, 655 articles were included. Results revealed 31 surgical procedures for shoulder instability following dislocation: 10 surgical procedures were given an A or B recommendation; 11, a C recommendation; and 10, an I recommendation. Conclusion: This review identified many surgical procedures to treat anterior shoulder instability. Ten of these surgical procedures had an abundant amount of published articles to describe their safety and efficacy. Arthroscopic Bankart and open Bankart were the most commonly reported procedures that cite satisfactory postoperative outcomes and limited complications. Publications on the other surgical procedures were less common. Surgeons should be careful when recommending surgery, and they should choose the appropriate surgical procedure based on evidence-based literature. PMID- 30480016 TI - Etiology, Diagnosis, and Treatment of Dynamic Nerve Compression Syndromes of the Elbow Among High-Level Pitchers: A Review of 7 Cases. AB - Background: Dynamic compressive neuropathies around the elbow are a rare entity described by a relatively small body of literature, mostly consisting of single case reports. No standardized diagnostic protocols have been described to date. To the authors' knowledge, this study represents the largest case series of dynamic compressive neuropathies in the upper extremity. Purpose: To identify various etiologies of dynamic compressive neuropathies around the elbow, devise a systematic diagnostic protocol, and review treatment options. Study Design: Case series; Level of evidence, 4. Methods: A retrospective review was conducted of patients who presented to a single practice between 2013 and 2017 and were diagnosed with a dynamic compressive neuropathy around the elbow. Results: A total of 7 patients were identified, with a mean follow-up of 2 years. All patients were high-level pitchers. One patient was a minor league pitcher; 4 patients were National Collegiate Athletic Association athletes; and 2 patients were high school athletes. All patients underwent a systematic diagnostic workup. The diagnosis was established with dynamic nerve conduction testing. Three etiologies for dynamic nerve compression around the elbow were identified: 1 case of lateral antebrachial cutaneous nerve compression by the biceps tendon, 3 cases of ulnar nerve compression by an anconeus epitrochlearis muscle, and 3 cases of posterior interosseous nerve compression at the arcade of Frohse with hypertrophic extensor carpi radialis brevis and extensor digitorum communis muscles. Two patients were treated conservatively, while 5 patients required surgery. All patients were able to return to pitching. Conclusion: Dynamic compressive neuropathies around the elbow are rare entities that present unique diagnostic challenges to the treating clinician. In this cohort, all patients were young throwing athletes. Physical examination of the patient frequently lacks typical findings of chronic nerve entrapment syndromes. Dynamic nerve conduction studies establish the diagnosis, and treatment often requires surgical decompression to achieve complete resolution of symptoms. PMID- 30480015 TI - The Impact of Depression on Patient Outcomes in Hip Arthroscopic Surgery. AB - Background: Mental health impairments have been shown to negatively affect preoperative self-reported function in patients with various musculoskeletal disorders, including those with femoroacetabular impingement. Hypothesis: Those with symptoms of depression will have lower self-reported function, more pain, and less satisfaction on initial assessment and at 2-year follow-up than those without symptoms of depression. Study Design: Cohort study; Level of evidence, 3. Methods: Patients who were enrolled in a multicenter hip arthroscopic surgery registry and had 2-year outcome data available were included in the study. Patients completed the 12-item International Hip Outcome Tool (iHOT-12), visual analog scale (VAS) for pain, and 12-item Short-Form Health Survey (SF-12) when consenting for surgery. At 2-year follow-up, patients were emailed the iHOT, the VAS, and a rating scale of surgical satisfaction. Initial SF-12 mental component summary (MCS) scores <46.5 and <=36 were used to qualify symptoms of depression and severe depression, respectively, as previously described and validated. Repeated-measures analysis of variance was performed to compare preoperative and 2-year postoperative iHOT-12, VAS, and satisfaction scores between those with and without symptoms of depression. Results: A total of 781 patients achieved the approximate 2-year milestone (mean follow-up, 735 +/- 68 days), with 651 (83%) having 2-year outcome data available. There were 434 (67%) female and 217 (33%) male patients, with a mean age of 35.8 +/- 13.0 years and a mean body mass index of 25.4 +/- 8.8 kg/m2. The most common procedures were femoroplasty (83%), followed by synovectomy (80%), labral repair (76%), acetabuloplasty (58%), acetabular chondroplasty (56%), femoral chondroplasty (23%), and labral reconstruction (19%). The mean initial SF-12 MCS score was 51.5 +/- 10.3, with cutoff scores indicating symptoms of depression and severe depression in 181 (28%) and 71 (11%) patients, respectively. Patients with symptoms of depression scored significantly (P < .05) lower on the initial iHOT-12 and VAS and 2-year follow-up iHOT-12, VAS, and rating scale of surgical satisfaction. Conclusion: A large number of patients who underwent hip arthroscopic surgery presented with symptoms of depression, which negatively affected self-reported function, pain levels, and satisfaction on initial assessment and at 2-year follow-up. Surgeons who perform hip arthroscopic surgery may need to identify the symptoms of depression and be aware of the impact that depression can have on surgical outcomes. PMID- 30480017 TI - The Cliff Sign: A New Radiographic Sign of Hip Instability. AB - Background: The preoperative diagnosis of hip microinstability is challenging. Although physical examination maneuvers and magnetic resonance imaging findings associated with microinstability have been described, there are limited reports of radiographic features. In patients with microinstability, we observed a high incidence of a steep drop-off on the lateral edge of the femoral head, which we have named the "cliff sign." Purpose: (1) To determine the relationship of the cliff sign and associated measurements with intraoperative microinstability and (2) to determine the interobserver reliability of these measurements. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: A total of 115 consecutive patients who underwent hip arthroscopy were identified. Patients with prior hip surgery, Legg-Calve-Perthes disease, fractures, pigmented villonodular synovitis, or synovial chondromatosis were excluded, resulting in the inclusion of 96 patients in the study. A perfect circle around the femoral head was created on anteroposterior pelvis radiographs. If the lateral femoral head did not completely fill the perfect circle, it was considered a positive cliff sign. Five additional measurements relating to the cliff sign were calculated. The diagnosis of microinstability was made intraoperatively by the (1) amount of traction required to distract the hip, (2) lack of hip reduction after initial traction release following joint venting, or (3) intraoperative findings consistent with hip microinstability. Continuous variables were analyzed through use of unpaired t tests and discrete variables with Fisher exact tests. Interobserver reliability (n = 3) was determined for each measurement. Results: Overall, 89% (39/44) of patients with microinstability had a cliff sign, compared with 27% of patients (14/52) without instability (P < .0001). Conversely, 74% of patients with a cliff sign had microinstability, while only 12% of patients without a cliff sign had instability (P < .0001). In women younger than 32 years with a cliff sign, 100% (20/20) were diagnosed with instability. No differences were found in any of the 5 additional measurements. Excellent interobserver reliability was found for the presence of a cliff sign and the cliff angle measurement. Conclusion: We have identified a radiographic finding, the cliff sign, that is associated with the intraoperative diagnosis of hip microinstability and has excellent interobserver reliability. Results showed that 100% of young women with a cliff sign had intraoperative microinstability. The cliff sign may be useful in the preoperative diagnosis of hip microinstability. PMID- 30480018 TI - Differences in the Mechanism of Head Impacts Measured Between Men's and Women's Intercollegiate Lacrosse Athletes. AB - Background: Lacrosse is a rapidly growing sport in the United States. Comparing the magnitude and frequency of head impact mechanisms between sexes will provide data for injury prevention techniques and risk reduction of head injuries. Purpose: To compare sex-specific differences in the magnitude and frequency of head impact mechanisms in National Collegiate Athletic Association (NCAA) Division III intercollegiate lacrosse athletes. Study Design: Cohort study; Level of evidence, 2. Methods: A total of 31 NCAA Division III intercollegiate lacrosse athletes (16 men [mean age, 21 +/- 1 years; mean height, 179.70 +/- 5.82 cm; mean weight, 80.71 +/- 6.33 kg] and 15 women [mean age, 20 +/- 1 years; mean height, 165.43 +/- 5.25 cm; mean weight, 64.08 +/- 7.59 kg]) voluntarily participated in this study. Participants wore xPatch sensors at every event during the 2015 spring season. Sensors recorded the magnitude, frequency, and location of head impacts over 10g. Linear (g) and rotational (deg/s2) acceleration determined impact magnitudes. We calculated incidence rates (IRs; per 1000 athlete-exposures [AEs]) and incidence rate ratios (IRRs) with 95% CIs to determine frequency differences. Film footage from each event was synchronized with the time of each head impact for verification and mechanism coding. Sex and impact mechanism served as the independent variables. Results: A significant interaction was found between impact mechanism and sex (P < .001) and main effects for impact mechanism (P < .001) and sex (P < .001). The most common mechanism in men's lacrosse was head to body (IR, 970.55/1000 AEs [95% CI, 266.14-331.98]), and in women's lacrosse, stick to head (IR, 289.87/1000 AEs [95% CI, 124.32-184.55]) was most common. Only 9 of 419 impermissible head impacts in men's lacrosse games were classed as penalties (2%); 7 of 25 impermissible head impacts in women's lacrosse games were called as penalties (28%). Conclusion: The impact mechanisms of head to body in men's lacrosse and stick to head in women's lacrosse are penalties but occur frequently, suggesting that a focus on stressing rule enforcement is warranted. Because mechanism and sex affect the magnitude of head impacts, proper offensive and defensive techniques against opponents should be encouraged to reduce head impacts. PMID- 30480019 TI - Patient-Specific Parameters Associated With Traction in Primary and Revision Hip Arthroscopic Surgery. AB - Background: Distraction of the hip joint is a necessary step during hip arthroscopic surgery. The force of traction needed to distract the hip is not routinely measured, and little is known about which patient factors may influence this force. Purpose: To quantify the force of traction required for adequate distraction of the hip during arthroscopic surgery and explore the relationship between hip joint stiffness and patient-specific demographics, flexibility, and anatomy. Study Design: Case series; Level of evidence, 4. Methods: A total of 101 patients (61 female) undergoing primary hip arthroscopic surgery were prospectively enrolled. A load cell attached to the traction boot continuously measured traction force. Fluoroscopic images were obtained before and after traction to measure joint displacement. The stiffness coefficient was calculated as the force of traction divided by joint displacement. Relationships between the stiffness coefficient and patient demographics and clinical parameters were investigated using a univariable regression model. The regression analysis was repeated separately by patient sex. Variables significant at P < .05 were included in a multivariable regression model. Results: The instantaneous peak force averaged 80 +/- 18 kilogram-force (kgf), after which the force required to maintain distraction decreased to 57 +/- 13 kgf. In univariable regression analysis, patient sex, alpha angle, hamstring flexibility, and Beighton hypermobility score were each correlated to stiffness. However, patient sex was the only significant variable in the multivariable regression model. Intrasex analysis demonstrated that increased hamstring flexibility correlated with decreased final holding stiffness in male patients and that higher Beighton scores correlated with decreased maximal stiffness in female patients. Conclusion: Male patients undergoing primary arthroscopic surgery have greater stiffness to hip distraction during arthroscopic surgery compared with female patients. In male patients, stiffness increased with decreasing hamstring flexibility. In female patients, increased Beighton scores corresponded to decreased stiffness. The presence of a labral tear was not correlated with stiffness to distraction. These data may be used to identify patients in whom a specific focus on capsular repair and/or plication may be warranted. PMID- 30480020 TI - Advanced Patellar Tendinopathy Is Associated With Increased Rates of Bone Patellar Tendon-Bone Autograft Failure at Early Follow-up After Anterior Cruciate Ligament Reconstruction. AB - Background: Revision anterior cruciate ligament (ACL) reconstruction can be potentially devastating for a patient. As such, it is important to identify prognostic factors that place patients at an increased risk for graft failure. There are no data on the effects of patellar tendinopathy on failure of ACL reconstruction when using a bone-patellar tendon-bone (BPTB) autograft. Purpose/Hypothesis: The purpose of this study was to investigate the association of patellar tendinopathy with the risk of graft failure in primary ACL reconstruction when using a BPTB autograft. The hypothesis was that patellar tendinopathy would result in higher rates of graft failure when using a BPTB autograft for primary ACL reconstruction. Study Design: Cohort study; Level of evidence, 3. Methods: All patients undergoing ACL reconstruction at a single institution from 2005 to 2015 were examined. A total of 168 patients undergoing primary ACL reconstruction with a BPTB autograft were identified. Patients' magnetic resonance imaging scans were reviewed for the presence and grade of patellar tendinopathy by 2 musculoskeletal fellowship-trained radiologists; both were blinded to the aim of the study, patient demographics, surgical details, and outcomes. Patients were divided into 2 groups: failure (defined as presence of symptomatic laxity or graft insufficiency) and success of the ACL graft. Statistical analyses were run to examine the association of patellar tendinopathy with failure of ACL reconstruction using a BPTB autograft. Results: At a mean follow-up of 18 months, there were 7 (4.2%) patients with graft failure. Moderate or severe patellar tendinopathy was associated with ACL graft failure (P = .011). Age, sex, and side of reconstruction were not associated with the risk of graft failure, although the majority of patients who failed were younger than 20 years. The use of patellar tendons with moderate to severe tendinopathy was associated with a relative risk of ruptures of 6.1 (95% CI, 1.37-27.34) as compared with autograft tendons without tendinopathy. Conclusion: Moderate or severe patellar tendinopathy significantly increases the risk of graft failure when using a BPTB autograft for primary ACL reconstruction. Patellar tendinopathy should be considered when determining the optimal graft choice for patients undergoing primary ACL reconstruction with autograft tendons. PMID- 30480021 TI - Arthroscopic Anatomic Glenoid Reconstruction: Analysis of the Learning Curve. AB - Background: Anatomic glenoid reconstruction involves the use of distal tibial allograft for bony augmentation of the glenoid surface. An all-arthroscopic approach was recently described to avoid damage to the subscapularis tendon and preserve the capsule and labrum. Purpose: To explore and compare change in surgical time between 2 proposed methods used for the treatment of anterior shoulder instability-arthroscopic anatomic glenoid reconstruction (AAGR) and arthroscopic Latarjet (AL)-over successive procedures. We also compared graft positioning on the anterior glenoid surface between the 2 methods. Study Design: Cohort study; Level of evidence, 3. Methods: This was a single-surgeon retrospective review of 54 cases of surgically treated recurrent anterior shoulder instability: 27 had AAGR with distal tibial allograft, while the other 27 had AL. AAGR with the distal tibial allograft was the primary choice for the treatment of anterior shoulder instability; however, AL was performed when tibial allograft was not available from the bone bank. Thus, there was an overlapping period for those 2 procedures. Procedure start and end times were recorded, and duration was calculated. Postoperative 3-dimensional computed tomography scans were reviewed, and graft position was judged to be in the lower third (desired position), middle third, or upper third of the anterior glenoid surface. To assess learning, these data were organized in chronological order of surgery, and each surgical cohort was divided into 3 chronological clusters of 9 patients each. Learning was assessed through change in operative time over successive clusters, change in variability of operative time among clusters, and change in graft positioning among clusters. Statistical analysis comprised a 2-tailed independent-sample t test and the Levene test for equality of variance. Results: Our study found that AAGR was significantly faster to perform than AL in the early (P = .001), middle (P = .001), and late (P = .05) clusters of each cohort. Duration of surgery did not significantly improve across clusters within each cohort (P = .15-.79). There were no significant changes in the variability of surgical time in the AAGR group (P = .09) or the AL group (P = .13). Desired positioning of the bone graft on the anterior glenoid surface (lower third) was identified more commonly in the AAGR cohort. Conclusion: AAGR is faster to learn and perform than AL for the treatment of recurrent anterior shoulder instability with significant glenoid bone loss. The current study found higher rates of desired graft positioning for AAGR clusters. PMID- 30480023 TI - Effects of Ulnar Collateral Ligament Reconstruction on Pitch Selection in Major League Baseball Pitchers. AB - Background: Ulnar collateral ligament (UCL) injuries represent one of the most common impairments to the throwing arm of professional pitchers. Return to play and postoperative performance metrics have been studied extensively, but pitch selection before and after surgery has not been evaluated. Purpose/Hypothesis: This study aimed to characterize the effects of UCL reconstruction on pitch selection in Major League Baseball (MLB) pitchers. We hypothesized that pitchers will throw fewer fastballs and a greater percentage of off-speed pitches after undergoing UCL reconstruction. Study Design: Retrospective cohort study; Level of evidence, 3. Methods: Using publicly available data, we evaluated MLB pitchers who underwent UCL reconstruction between 2003 and 2014. Pitching data were collected for the 2 seasons before UCL reconstruction as well as the first 2 seasons after reconstruction; the data consisted of the total number of pitches thrown and the percentage of fastballs, curveballs, changeups, and sliders. Repeated-measures analysis of variance was used with post hoc least significant difference pairwise t tests to evaluate for statistical significance at P < .05. Results: Overall, 87 pitchers (mean age, 28.2 +/- 3.5 years) met all inclusion and exclusion criteria. There was a statistically significant difference in the total number of pitches thrown before and after surgery (P < .01) as well as in the percentage of fastballs thrown before and after surgery (P = .02). There was also a statistically significant increase in the use of curveballs between 1 and 2 years postoperatively (7.5% and 8.8%, respectively; P = .01). No other findings were statistically significant. Conclusion: Pitchers who underwent UCL reconstruction were shown to have a statistically significant decline in the percentage of fastballs thrown postoperatively as compared with before injury, with a compensatory trend toward an increased use of curveballs and sliders. PMID- 30480022 TI - Anterior Cruciate Ligament Reconstruction Using a Bone-Patellar Tendon-Bone Graft With and Without a Ligament Augmentation Device: A 25-Year Follow-up of a Prospective Randomized Controlled Trial. AB - Background: Various grafts and ligament augmentation devices (LADs) have been used in the search for optimal reconstruction of the anterior cruciate ligament (ACL). Purpose: To compare 25-year follow-up results after ACL reconstruction using a bone-patellar tendon-bone (BPTB) graft with or without the Kennedy LAD. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: One hundred patients undergoing ACL reconstruction between 1991 and 1993 were randomized into 2 groups: reconstruction using a BPTB graft alone (BPTB group, 51 patients) or a BPTB graft with the Kennedy LAD (LAD group, 49 patients). The 25 year follow-up evaluation included a clinical knee examination, patient-reported outcome measures, and an assessment of radiological osteoarthritis (OA) according to the Ahlback classification. Additional outcomes were reruptures and knee arthroplasty. Results: Ninety-three patients (93%) were available for the follow up evaluation: 48 patients in the BPTB group and 45 in the LAD group. Through telephone calls, 26 patients were excluded from further investigation because of reruptures and arthroplasty in the knee of interest; 67 patients were further investigated. A total of 43 of 44 (98%) and 42 of 44 (95%) patients had negative or 1+ Lachman and pivot-shift test results, respectively. The mean Lysholm score was 85 for the BPTB group and 83 for the LAD group. All mean Knee injury and Osteoarthritis Outcome Score (KOOS) subscale values were >=73. There were no statistically significant differences between groups in any of these outcomes or regarding the Tegner score, radiological classification of OA, or number of ACL reruptures. Signs of radiological OA were detected in all patients, and severe radiological OA (Ahlback grade III, IV, or V) was detected in 32% of patients in the BPTB group and 21% of patients in the LAD group (P = .37). There were 12 patients in the BPTB group and 7 in the LAD group who had documented reruptures (P = .40). One patient in the BPTB group and 6 in the LAD group underwent knee arthroplasty (P = .054). Conclusion: In the present study, there were no statistically significant differences between groups in any of the outcomes. After 25 years, 19% of patients had reruptures, 27% had severe radiological OA, and 7% underwent knee arthroplasty. PMID- 30480024 TI - Efficacy of a Virtual Arthroscopic Simulator for Orthopaedic Surgery Residents by Year in Training. AB - Background: Virtual reality arthroscopic simulators are an attractive option for resident training and are increasingly used across training programs. However, no study has analyzed the utility of simulators for trainees based on their level of training/postgraduate year (PGY). Purpose/Hypothesis: The primary aim of this study was to determine the utility of the ArthroS arthroscopic simulator for orthopaedic trainees based on their level of training. We hypothesized that residents at all levels would show similar improvements in performance after completion of the training modules. Study Design: Descriptive laboratory study. Methods: Eighteen orthopaedic surgery residents performed diagnostic knee and shoulder tasks on the ArthroS simulator. Participants completed a series of training modules and then repeated the diagnostic tasks. Correlation coefficients (r 2) were calculated for improvements in the mean composite score (based on the Imperial Global Arthroscopy Rating Scale [IGARS]) as a function of PGY. Results: The mean improvement in the composite score for participants as a whole was 11.2 +/- 10.0 points (P = .0003) for the knee simulator and 14.9 +/- 10.9 points (P = .0352) for the shoulder simulator. When broken down by PGY, all groups showed improvement, with greater improvements seen for junior-level residents in the knee simulator and greater improvements seen for senior-level residents in the shoulder simulator. Analysis of variance for the score improvement variable among the different PGY groups yielded an f value of 1.640 (P = .2258) for the knee simulator data and an f value of 0.2292 (P = .917) for the shoulder simulator data. The correlation coefficient (r 2) was -0.866 for the knee score improvement and 0.887 for the shoulder score improvement. Conclusion: Residents training on a virtual arthroscopic simulator made significant improvements in both knee and shoulder arthroscopic surgery skills. Clinical Relevance: The current study adds to mounting evidence supporting virtual arthroscopic simulator-based training for orthopaedic residents. Most significantly, this study also provides a baseline for evidence-based targeted use of arthroscopic simulators based on resident training level. PMID- 30480025 TI - Risk Factors for Concomitant Collateral Ligament Injuries in Children and Adolescents With Anterior Cruciate Ligament Tears. AB - Background: Risk factors for concomitant ligament injuries (CLIs) of the lateral collateral ligament (LCL) and medial collateral ligament (MCL) in children and adolescents with anterior cruciate ligament (ACL) tears are unknown. Purpose: To determine whether body mass index (BMI), sex, age, and injury mechanism are associated with CLIs in children and adolescents with ACL tears and whether CLIs are associated with meniscal and chondral injuries and a delay to surgery. Study Design: Cohort study; Level of evidence, 3. Methods: We reviewed the records of patients aged <=18 years with ACL tears from 2009 through 2013 for sex, age, height, weight, CLI, injury mechanism, intra-articular injury, and time to surgery. Patients were assigned to groups according to the presence of a CLI (CLI group) compared with the presence of an isolated ACL tear (ACL group). BMI was categorized as underweight, normal weight, or overweight/obese. The older group was defined as age >=14 years for girls and >=16 years for boys. Logistic regression, Mann-Whitney U tests, and chi-square tests were performed (alpha = 0.05). Results: We included 509 patients (267 girls) with a mean age of 15 years (range, 6-18 years) at the time of injury. There were 396 patients (78%) in the ACL group and 113 patients (22%) in the CLI group (90 with MCL, 11 with LCL, and 12 with both MCL and LCL injuries). Groups had similar proportions of overweight/obese patients (P = .619) and girls (P = .104). Older age (odds ratio [OR], 2.0 [95% CI, 1.3-3.3]) and contact injuries (OR, 2.2 [95% CI, 1.4-3.4]) were associated with CLIs. The CLI group had a higher proportion of chondral injuries (P = .001) but not meniscal injuries (P = .295) and presented to surgery earlier than the ACL group (P = .002). Conclusion: Older age and contact injuries were associated with CLIs in children and adolescents with ACL tears, whereas BMI category and sex were not. CLIs were associated with a higher proportion of chondral injuries but not meniscal injuries and were not associated with a delay to surgery. PMID- 30480026 TI - Periventricular nodular heterotopia in 22q11.2 deletion and frontal lobe migration. AB - Objective: We aimed to delineate the distribution of periventricular nodular heterotopia (PNH) in patients with 22q11.2 microdeletion syndrome (22q11.2DS) and place this in the context of other genetic forms of PNH. Methods: We retrospectively analyzed brain imaging and postmortem data available for adult patients with 22q11.2DS. We included only those with good quality MRI data (n = 29) in addition to two patients with PNH identified through postmortem studies. We also reviewed the pattern of PNH in all genetic conditions reported with this phenotype. Results: Of the total seven patients (M = 4, F = 3; age: 19-61 years) identified to have PNH, six had a history of seizures, six had schizophrenia, six had variable levels of intellectual disability, and two had obsessive compulsive disorder. In all seven patients, the nodules were located over the dorsal pole of the frontal horn of the lateral ventricles. The nodules were small, noncontiguous, and ranged in number from 1 to 10 per individual. Our review identified 37 genetic conditions associated with PNH. With the cases reported here, 22q11.2DS becomes the fifth most commonly reported genetic condition, and the third most common copy number variation, associated with PNH. Interpretation: The neuropsychiatric manifestations in our patients with PNH support other data indicating abnormal neurodevelopment as part of the pathogenesis of 22q11.2DS.The location and cellular characteristics of PNH in 22q11.2DS overlaps with a group of migrating postnatal interneurons termed Arc cells, although more research is needed to confirm that PNH in 22q11.2DS represents Arc cells arrested in their migratory pathway. PMID- 30480027 TI - Clinical and infarction patterns of PFO-related cryptogenic strokes and a prediction model. AB - Objectives: The higher than expected PFO rate in CS patients has raised concerns that paradoxical embolism maybe the pathophysiologic mechanism for strokes. However, only a small proportion of pathogenic PFOs cause CS. Therefore, accurate recognition of patients with pathogenic PFOs among all CS patients could guide clinical decision making in selecting the most appropriate treatment. The aim of this study was to devise a new algorithm to stratify cryptogenic stroke (CS) patients into pathogenic patent foramen ovale (p-PFO)- and non-p-PFO-related patients. Methods: A total of 1201 patients with acute ischemic stroke were recruited from two different medical centers, and 253 CS patients were identified. Of the 253 patients, 111 were diagnosed with PFO using contrast transcranial Doppler. Data on medical histories, neuroimaging and laboratory tests were compared in CS patients with or without PFO. Results: Compared with PFO-negative CS patients, PFO-positive CS patients showed younger onset age, lower incidence of hypertension and dyslipidemia, characteristic infarction pattern in magnetic resonance imaging and specifically altered platelet activity and coagulation function. Based on the above information, we constructed a PFO judgment formula (Hr-PFOJ) by means of feature weight estimation and predictive performance evaluation to predict pathogenic PFO in CS patients with a sensitivity of 76.3% and a specificity of 66.5%. Interpretations: Hr-PFOJ judgment formula is a useful screening tool for identification of patients with pathogenic PFO who may benefit from PFO-related treatment. PMID- 30480028 TI - A phase I study of TAS-205 in patients with Duchenne muscular dystrophy. AB - Objective: Currently, the only approved standard Duchenne muscular dystrophy (DMD) treatment in Japan is oral steroids, which have various disadvantages. Previous work has suggested that hematopoietic-type prostaglandin D synthase (HPGDS), involved in production of the inflammatory mediator prostaglandin D2 (PGD2), might have a role in DMD pathology. We therefore investigated the safety, pharmacokinetics (PK), and pharmacodynamics of a highly selective HPGDS inhibitor (TAS-205) in Japanese patients with genetically confirmed DMD. Methods: This was a double-blind, randomized, placebo-controlled phase I study to evaluate the use of single or 7-day repeated doses of TAS-205 administered orally. The urinary excretion of PGD2 metabolites was also assessed. Results: The PK analysis set included 15 and 14 patients in the single- and repeated-dose periods, respectively; the pharmacodynamics set and the safety set included 21 and 19 patients in each period, respectively. The PK of TAS-205 were linear in the dose range studied (1.67-13.33 mg/kg/dose) and the plasma concentration of TAS-205 reached steady state by Day 4. TAS-205 dose-dependently decreased the urinary excretion of tetranor-prostaglandin D metabolite at each measurement time point and did not affect the urinary excretion of tetranor-prostaglandin E metabolite. No clinically significant adverse events were reported after TAS-205 single or repeated administration. Interpretation: We confirmed the safety and tolerability of TAS-205 in this study. TAS-205 decreased the total urinary excretion of PGD2 metabolites in a dose-dependent manner, suggesting that TAS-205 might be a therapeutic option to treat DMD patients. PMID- 30480029 TI - Evaluating the cerebral correlates of survival in amyotrophic lateral sclerosis. AB - Objective: To evaluate cerebral degenerative changes in ALS and their correlates with survival using 3D texture analysis. Methods: A total of 157 participants were included in this analysis from four neuroimaging studies. Voxel-wise texture analysis on T1-weighted brain magnetic resonance images (MRIs) was conducted between patients and controls. Patients were divided into long- and short survivors using the median survival of the cohort. Neuroanatomical differences between the two survival groups were also investigated. Results: Whole-brain analysis revealed significant changes in image texture (FDR P < 0.05) bilaterally in the motor cortex, corticospinal tract (CST), insula, basal ganglia, hippocampus, and frontal regions including subcortical white matter. The texture of the CST correlated (P < 0.05) with finger- and foot-tapping rate, measures of upper motor neuron function. Patients with a survival below the media of 19.5 months demonstrated texture change (FDR P < 0.05) in the motor cortex, CST, basal ganglia, and the hippocampus, a distribution which corresponds to stage 4 of the distribution TDP-43 pathology in ALS. Patients with longer survival exhibited texture changes restricted to motor regions, including the motor cortex and the CST. Interpretation: Widespread gray and white matter pathology is evident in ALS, as revealed by texture analysis of conventional T1-weighted MRI. Length of survival in patients with ALS is associated with the spatial extent of cerebral degeneration. PMID- 30480030 TI - Native ancestry is associated with optic neuritis and age of onset in hispanics with multiple sclerosis. AB - Background and Objective: Hispanics with multiple sclerosis (MS) present younger and more often with optic neuritis (ON) as compared to Whites in the western United States. Regional differences related to Hispanic genetic admixture could be responsible. We investigated the association between global genetic ancestry and ON and age at onset of MS in Hispanics. Methods: Data were obtained for 1033 self-identified Hispanics with MS from four MS-based registries from four academic institutions across the United States January 2016-April 2017. Multivariate regression models, utilizing genetic ancestry estimates for Native American (NA), African, and European ancestry, were used to assess the relationship between genetic ancestry and ON presentation and age of MS onset, defined as age at first symptom. Results: Genetic ancestry and ON proportions varied by region where NA ancestry and ON proportions were highest among Hispanics in the southwestern United States (40% vs. 19% overall for NA and 38% vs. 25% overall for ON). A strong inverse correlation was observed between NA and European ancestry (r = -0.83). ON presentation was associated with younger age of onset (OR: 0.98; 95% CI: 0.96-0.99; P = 7.80 * 10-03) and increased NA ancestry (OR: 2.35 for the highest versus the lowest quartile of NA ancestry; 95% CI: 1.35 4.10; P = 2.60 * 10-03). Younger age of onset was found to be associated with a higher proportion NA (Beta: -5.58; P = 3.49 * 10-02) and African ancestry (Beta: 10.07; P = 1.39 * 10-03). Interpretation: Ethnic differences associated with genetic admixture could influence clinical presentation in Hispanics with MS; underscoring the importance of considering genetic substructure in future clinical, genetic, and epigenetic studies in Hispanics. PMID- 30480031 TI - Deep brain stimulation in five patients with severe disorders of consciousness. AB - Objective: The efficacy of deep brain stimulation in disorders of consciousness remains inconclusive. We investigated bilateral 30-Hz low-frequency stimulation designed to overdrive neuronal activity by dual pallido-thalamic targeting, using the Coma Recovery Scale Revised (CRS-R) to assess conscious behavior. Methods: We conducted a prospective, single center, observational 11-month pilot study comprising four phases: baseline (2 months); surgery and titration (1 month); blind, random, crossover, 1.5-month ON and OFF periods; and unblinded, 5-month stimulation ON. Five adult patients were included: one unresponsive-wakefulness syndrome male (traumatic brain injury); and four patients in a minimally conscious state, one male (traumatic brain injury) and three females (two hemorrhagic strokes and one traumatic brain injury). Primary outcome measures focused on CRS-R scores. Secondary outcome measures focused notably on baseline brain metabolism and variation in activity (stimulation ON - baseline) using normalized fluorodeoxyglucose positron emission tomography maps. Statistical analysis used random-effect models. Results: The two male patients (one minimally conscious and one unresponsive wakefulness syndrome) showed improved mean CRS-R scores (stimulation ON vs. baseline), in auditory, visual and oromotor/verbal subscores, and visual subscores respectively. The metabolism of the medial cortices (low at baseline in all five patients) increased specifically in the two responders. Interpretation: Our findings show there were robust but limited individual clinical benefits, mainly in visual and auditory processes. Overall modifications seem linked to the modulation of thalamo-cortico-basal and tegmental loops activating default mode network cortices. Specifically, in the two responders there was an increase in medial cortex activity related to internal awareness. PMID- 30480032 TI - Autophagic vacuolar myopathy is a common feature of CLN3 disease. AB - Objective: The neuronal ceroid lipofuscinoses (NCL) are genetic degenerative disorders of brain and retina. NCL with juvenile onset (JNCL) is genetically heterogeneous but most frequently caused by mutations of CLN3. Classical juvenile CLN3 includes a rare protracted form, which has previously been linked to autophagic vacuolar myopathy (AVM). Our study investigates the association of AVM with classic, non-protracted CLN3. Methods: Evaluation of skeletal muscle biopsies from three, non-related patients with classic, non-protracted and one patient with protracted CLN3 disease by histology, immunohistochemistry, electron microscopy, and Sanger sequencing of the coding region of the CLN3 gene. Results: We identified a novel heterozygous CLN3 mutation (c.1056+34C>A) in one of our patients with classic, non-protracted CLN3 disease. The skeletal muscle of all CLN3 patients was homogeneously affected by an AVM characterized by autophagic vacuoles with sarcolemmal features and characteristic lysosomal pathology. Interpretation: Our observations show that AVM is not an exceptional phenomenon restricted to protracted CLN3 but rather a common feature in CLN3 myopathology. Therefore, CLN3 myopathology should be included in the diagnostic spectrum of autophagic vacuolar myopathies. PMID- 30480034 TI - Regulatory B cells in myasthenia gravis are differentially affected by therapies. AB - We analyzed the number and functionality of regulatory B (Breg) cells in well defined myasthenia gravis patients. We first showed a decreased number of circulating CD19+ CD24++ CD38++ Breg cells and an altered functionality of Breg cells in untreated myasthenia gravis patients. Next, we demonstrated that the proportion of circulating Breg cells was restored in myasthenia gravis patients after thymectomy, probably as Breg cells could be sequestered in the myasthenia gravis thymus. In contrast, corticosteroid treatments did not restore and decreased even more the proportion of Breg cells in myasthenia gravis patients. These results clearly demonstrated that two distinct immunomodulatory therapies affect differentially Breg cells. PMID- 30480033 TI - Cervical skin denervation associates with alpha-synuclein aggregates in Parkinson disease. AB - Objective: Autonomic nervous system is involved at the onset of Parkinson disease (PD), and alpha-synuclein (alpha-Syn) and its phosphorylated form (p-alphaSyn) have been detected in dermal autonomic nerve fibers of PD. We assessed disease specific conformation variant of alpha-Syn immunoreactivity in cutaneous nerves and characterized skin denervation patterns in PD and atypical parkinsonism (AP). Methods: We enrolled 49 subjects, 19 with PD, 17 age-matched healthy controls, and 13 with AP. The manifestations of disease were rated on clinical scales. Skin biopsies from ankle, thigh, and neck were analyzed by immunofluorescence for p alphaSyn, 5G4 as a conformation specific antibody to pathogenic alpha-Syn and PGP9.5 as axonal marker. Intraepidermal nerve fiber density was measured in all anatomical sites as marker of neurodegeneration. Thirteen of the 19 PD underwent a 1 year follow-up visit plus skin biopsies. Results: PD subjects displayed more severe cervical skin denervation (P < 0.03), which correlated to disease duration and worsened between initial and follow-up examination (P < 0.001). p-alphaSyn and 5G4 were equally sensitive and specific for the diagnosis of PD (area under the ROC was 0.839 for p-alphaSyn and 0.886 for 5G4). PD and AP with possible alpha-synucleinopathies share the features of marked cervical denervation and the presence of 5G4. In contrast AP with possible tauopathies were normal. Interpretation: Conformational specific forms of alpha-Syn are detectable in skin biopsy by immunofluorescence in PD, with a promising diagnostic efficiency similar to p-alphaSyn. Cervical cutaneous denervation correlates with disease duration and increases over time standing out as a potential biomarker of PD progression. PMID- 30480035 TI - A novel KIF5A gene variant causes spastic paraplegia and cerebellar ataxia. AB - Mutations in the kinesin family member 5A (KIF5A) gene are mainly associated with autosomal dominant spastic paraplegia 10 (SPG10). The additional complicated symptoms of SPG10 commonly include a wide spectrum. However, cerebellar ataxia is only noticed in a very few patients. Herein, we described a large autosomal dominant family, in which the affected individuals presented with progressive spastic paraparesis and marked cerebellar ataxia. Exome sequencing revealed that a novel variant in the KIF5A gene might be responsible for the phenotype. The obvious cerebellar ataxia indicated that the KIF5A gene should be included in the expanding gene list for spasticity-ataxia spectrum. PMID- 30480036 TI - Immune checkpoint inhibitors in the onset of myasthenia gravis with hyperCKemia. AB - Immune checkpoint inhibitors sometimes cause neuromuscular adverse events. Although a few cases of myasthenia gravis with hyperCKemia triggered by immune checkpoint inhibitors have been described, conclusive evidence remains limited. We conducted a systematic review of published cases of myasthenia gravis with hyperCKemia related to immune checkpoint inhibitors. Moreover, we tested anti striational antibodies in the case of myasthenia gravis with myositis after nivolumab administration. We located 17 published case reports. Anti-striational antibodies were tested in six cases and five cases were positive. Our systematic analyses revealed poor prognosis in myasthenia gravis combined hyperCKemia with immune checkpoint inhibitors. PMID- 30480037 TI - Cerebral autoinflammatory disease treated with anakinra. AB - Interest in autoimmune encephalitis has been growing since the discovery of various autoimmune antibodies, such as N-methyl D-aspartate receptors antibody and leucine-rich glioma-inactivated 1 antibody. However, in contrast to autoimmune encephalitis associated with dysregulated adaptive immunity in the brain, the question of whether innate immunity-mediated autoinflammatory diseases exist in the brain has drawn much attention. Herein, we report a patient with microglia-dominant acute autoinflammatory encephalitis successfully treated with anakinra, an including interleukin-1 receptor blocker. In comparison to systemic autoinflammatory disease, we term this encephalitis cerebral autoinflammatory disease. Cerebral autoinflammatory disease could suggest new conceptual approaches to patients previously diagnosed with an unspecified encephalitis. PMID- 30480040 TI - "A Two Glass of Wine Shift": Dominant Discourses and the Social Organization of Nurses' Substance Use. AB - We undertook an institutional ethnography utilizing the expert knowledge of nurses who have experienced substance-use problems to discover: (a) What are the discourses embedded in the talk among nurses in their everyday work worlds that socially organize their substance-use practices and (b) how do those discourses manage these activities? Data collection included interviews, researcher reflexivity, and texts that were critically analyzed with a focus on institutional features. Analysis revealed dominant moralistic and individuated discourses in nurses' workplace talk that socially organized their substance-use practices, subordinated and silenced experiences of work stress, and erased employers' roles in managing working conditions. Conclusions included that nurses used substances in ways that enabled them to remain silent and keep working. Nurses' education did not prepare them regarding nurses' substance-use problems or managing emotional labor. Nurses viewed alcohol as an acceptable and encouraged coping strategy for nurses to manage emotional distress. PMID- 30480039 TI - Noninvasive continuous optical monitoring of absolute cerebral blood flow in critically ill adults. AB - We investigate a scheme for noninvasive continuous monitoring of absolute cerebral blood flow (CBF) in adult human patients based on a combination of time resolved dynamic contrast-enhanced near-infrared spectroscopy (DCE-NIRS) and diffuse correlation spectroscopy (DCS) with semi-infinite head model of photon propogation. Continuous CBF is obtained via calibration of the DCS blood flow index (BFI) with absolute CBF obtained by intermittent intravenous injections of the optical contrast agent indocyanine green. A calibration coefficient ( gamma ) for the CBF is thus determined, permitting conversion of DCS BFI to absolute blood flow units at all other times. A study of patients with acute brain injury ( N=7 ) is carried out to ascertain the stability of gamma . The patient-averaged DCS calibration coefficient across multiple monitoring days and multiple patients was determined, and good agreement between the two calibration coefficients measured at different times during single monitoring days was found. The patient averaged calibration coefficient of 1.24*109 (mL/100 g/min)/(cm2/s) was applied to previously measured DCS BFI from similar brain-injured patients; in this case, absolute CBF was underestimated compared with XeCT, an effect we show is primarily due to use of semi-infinite homogeneous models of the head. PMID- 30480041 TI - Nurses' Perspectives on Lean Redesigns to Patient Flow and Inpatient Discharge Process Efficiency. AB - As hospitals around the world increasingly face pressure to improve efficiency, "Lean" process improvement has become a popular approach to improving patient flow. In this article, we examine nurses' perspectives on the implementation of Lean redesigns to the inpatient discharge process. We found that nurses experienced competing demands and tensions related to their time and professional roles and responsibilities as a result of Lean. Four main themes included (a) addressing the needs of individual patients, while still maintaining overall patient flow; (b) meeting discharge efficiency targets while also achieving high patient satisfaction scores; (c) "wasting time" to save time; and (d) the "real" work of providing clinical care versus the "Lean" work of process improvement. Our findings highlight the importance of soliciting hospital nurses' perspectives when implementing Lean process improvements to improve efficiency and patient flow. PMID- 30480043 TI - When Colonoscopy Fails... Refer, Repeat, and Succeed. PMID- 30480038 TI - Clinical application of advanced MR methods in children: points to consider. AB - The application of both functional MRI and diffusion MR tractography prior to a neurosurgical operation is well established in adults, but less so in children, for several reasons. For this review, we have identified several aspects (task design, subject preparation, actual scanning session, data processing, interpretation of results, and decision-making) where pediatric peculiarities should be taken into account. Further, we not only systematically identify common issues, but also provide solutions, based on our experience as well as a review of the pertinent literature. The aim is to provide the clinician as well as the imaging scientist with information that helps to plan, conduct, and interpret such a clinically-indicated exam in a way that maximizes benefit for, and minimizes the burden on the individual child. PMID- 30480042 TI - Training Neurodegenerative Disease Support Group Leaders: A New Support Group Functioning Scale. AB - Support group leaders play pivotal roles in maintaining healthy community support groups; however, these leaders also have personal support needs and typically lack formal training in managing complex behaviors of neurodegenerative disorders. A support group well-being questionnaire, assessing support group functioning, was developed and piloted among participants of an educational training program designed for support group leaders of various neurodegenerative disorder-specific support groups. An exploratory factor analysis evaluated the questionnaire's psychometric properties and identified a reliable single factor five-item solution, which was titled the Support Group Functioning Scale (SGFS). Preliminary interpretation guidelines were proposed. Development of this scale is a first step in identifying support group leaders' needs as they provide frontline assistance to caregivers and individuals with neurodegenerative illnesses. This tool shows promise as an efficient way to identify support groups in need of assistance and to assess the impact of trainings on support group functioning. Further validation of the scale is needed. PMID- 30480044 TI - Benign Pharyngoesophageal Strictures: Increasingly Encountered and Still a Challenge. PMID- 30480045 TI - High Efficacy of Repeating Colonoscopy by an Advanced Endoscopist after an Incomplete Colonoscopy. AB - Background and Aims: This study aims to evaluate the role of an advanced endoscopist to study the entire colon after an incomplete colonoscopy. Methods: All patients with an elective incomplete colonoscopy performed under deep sedation in our department between January 2010 and October 2016 were included. Patients with a colonic stenosis, an inadequate bowel preparation, or a colonoscopy performed without deep sedation were excluded. Included patients were followed up to evaluate if and what type of subsequent examinations (colonoscopy by an advanced endoscopist, single-balloon enteroscopy [SBE], and/or CT colonography) was performed to complete the study of the entire colon. Lesions found during these subsequent examinations were also recorded. Results: Ninety three patients had an incomplete colonoscopy, with no diagnosis of colorectal cancer (CRC) and a high-risk polyp rate of 5.4% (n = 5). Seventy-seven patients with incomplete colonoscopies underwent subsequent examinations, namely CT colonography in 45.5% (n = 35), colonoscopy by an advanced endoscopist in 53.2% (n = 41), and SBE in 13% (n = 10). In the 49 patients who performed either colonoscopy (n = 39) or SBE (n = 10) by an advanced endoscopist, the cecal intubation rate was 100%, and high-risk polyps were found in 26.5% (n = 13) and CRC in 4.1%. CT colonography revealed findings consistent with polyps and CRC in 22.9% (n = 8) and 2.9% (n = 1) of the cases, respectively. Colonoscopy was further repeated in 6 patients with suspected polyps in CT colonography, confirming the initial diagnosis in 5 patients. Conclusions: Colonoscopy by an advanced endoscopist achieved cecal intubation in all patients, representing a good choice after an incomplete colonoscopy. PMID- 30480046 TI - Endoscopic Dilation of Pharyngoesophageal Strictures: There Are More Dimensions than a Diameter. AB - Background/Aims: Dysphagia due to benign pharyngoesophageal strictures (PES) often requires repeated dilations; however, a uniform definition for the therapeutic efficacy of this technique has not been yet established. We aimed to assess the overall efficacy of endoscopic dilation of pharyngoesophageal anastomotic or post-radiotherapy (post-RT) strictures. Methods: The data of 48 patients with post-RT (n = 29) or anastomotic PES (n = 19) submitted to endoscopic dilation during a 3-year period were retrospectively assessed. The Kochman criteria were used to determine refractoriness and recurrence. Patients were asked to answer a questionnaire determining prospectively the dilation program efficacy as (a) dysphagia improvement, (b) dysphagia resolution, (c) need for further dilations, or (d) percutaneous endoscopic gastrostomy (PEG) during the previous 6 months. Need for additional therapy was considered an inefficacy criterion. Results: The median number of dilations per patient was 4 (total of 296 dilations) with a median follow-up of 29 months. The mean predilation dysphagia Mellow-Pinkas score was 3 and the initial stenosis diameter was 7 mm. Fifteen and 29% of patients presented with the Kochman criteria for refractory and recurrent strictures, respectively. Moreover, 96 and 60% showed dysphagia improvement and resolution, respectively. Seventy-five-percent did not require dilations during 6 months, and 89% did not require PEG. From the patients' perspective, overall efficacy was achieved in 58% of cases. Nine additional therapies were required. Number of dilations (OR 0.7), stricture diameter (OR 2.2), and nonrecurrence criteria (OR 14.2) appeared as significant predictors of overall efficacy, whereas refractory stenosis criteria did not. Conclusions: Endoscopic dilation seems to be effective for patients with dysphagia after RT or surgery, especially when assessed as patient perception of improvement. Narrow strictures, recurrent ones, and strictures requiring a higher number of dilations may predict worse outcomes. Key Message: Health professionals should establish well-defined efficacy criteria for dilations and base their decision beyond exclusively objective measurements. PMID- 30480047 TI - Optimizing the Risk Assessment in Upper Gastrointestinal Bleeding: Comparison of 5 Scores Predicting 7 Outcomes. AB - Introduction: Although different scores have been suggested to predict outcomes in the setting of upper gastrointestinal bleeding (UGIB), few comparative studies between simplified versions of older scores and recent scores have been published. We aimed to evaluate the accuracy of pre- (PreRS) and postendoscopic Rockall scores (PostRS), the Glasgow-Blatchford score (GBS) and its simplified version (sGBS), as well as the AIMS65 score in predicting different clinical outcomes. Methods: In this retrospective study, PreRS, PostRS, GBS, sGBS, and AIMS65 score were calculated, and then, areas under the receiver operating characteristic curve were used to evaluate the performance of each score to predict blood transfusion, endoscopic therapy, surgery, admission to intensive/intermediate care unit, length of hospital stay, as well as 30-day rebleeding or mortality. Results: PreRS, PostRS, GBS, and sGBS were calculated for all the 433 included patients, but AIMS65 calculation was only possible for 315 patients. Only the PreRS and PostRS were able to fairly predict 30-day mortality. The GBS and sGBS were good in predicting blood transfusion and reasonable in predicting surgery. None of the studied scores were good in predicting the need for endoscopic therapy, admission to intensive/intermediate care unit, length of hospital stay, and 30-day rebleeding. Conclusions: Owing to the identified limitations, none of the 5 studied scores could be singly used to predict all the clinically relevant outcomes in the setting of UGIB. The sGBS was as precise as the GBS in predicting blood transfusion and surgery. The PreRS and PostRS were the only scores that could predict 30-day mortality. An algorithm using the PreRS and the sGBS as an initial approach to patients with UGIB is presented and suggested. PMID- 30480049 TI - Distant Thromboembolic Disease Diagnosed by Endoscopic Ultrasound in Pancreatic Cancer: A Case Series. AB - Thrombosis and cancer have a very well-known association. Pancreatic cancer has the highest risk for thrombotic events amongst gastrointestinal cancers and is a leading direct cause of death in cancer patients. We assessed the role of endoscopic ultrasound (EUS) in identifying distant thrombotic events in pancreatic cancer patients. We performed a retrospective review of all EUS cases for pancreatic cancer in two centers and assessed all remotely located thrombotic events diagnosed. In a period of 6 months, a total of 55 EUS for pancreatic neoplasm were performed and the following thrombotic events were identified in 4 patients (7.3%): pulmonary thromboembolism (75%) and vena cava thrombosis (25%). The authors present these 4 cases of thrombotic disease identified by EUS, 50% of them previously missed by noninvasive imaging. EUS evaluation is not seldom limited to the targeted lesion prior identified in other imaging studies. Vascular thrombus can be an incidental finding on EUS. If untreated, pulmonary embolism has a high overall mortality. This series underlines the importance of a systematic, station approach EUS technique, namely in the mediastinum, regardless of the clinical indication. PMID- 30480048 TI - Ultrasonography in Gastroenterology: The Need for Training. AB - The use of ultrasonography (US) as an imaging modality in medicine has spread across almost every clinical specialty. This diffusion is based on the simplicity, accessibility, portability and affordability of the technique producing real-time high-resolution images using non-ionising radiation. On the other hand, this trend also extended the technique to settings other than healthcare, such as public facilities, private houses or remote sites. This tendency can be observed worldwide, from developing countries to prestigious medical schools and tertiary referral hospitals. Furthermore, point-of-care US (POCUS), i.e., US executed at the patient's bedside to obtain real-time objective information with diagnostic and clinical monitoring purposes or to guide invasive procedures, has been incorporated in many specialties. In gastroenterology, despite the essential role of endoscopy, clinical practice is highly dependent on non-endoscopic imaging techniques. However, as in other specialties, the indications of US in gastroenterology have been increasing steadily, covering a broad range of conditions. In response to the generalised employment of US by non radiologists, institutions such as the European Federation of Societies for Ultrasound in Medicine and Biology and the Royal College of Radiologists issued recommendations to ensure high-quality practice. These theoretical and practical requisites include performing a certain number of examinations and mandatory skills in order to achieve certification to execute unsupervised US. Therefore, there is a need for modern gastroenterology to include US as a basic skill in its clinical practice. To ensure the provision of high-quality US, adequate instruction of future specialists should be guaranteed by the gastroenterology departments and required in the residency training programme. PMID- 30480050 TI - Common Variable Immunodeficiency-Associated Inflammatory Enteropathy: The New Era of Biological Therapy. AB - Common variable immunodeficiency (CVID) is the most frequent form of immunodeficiency in adults. Clinical manifestations are heterogeneous with an increased susceptibility to infections and inflammatory conditions, namely autoimmune diseases, such as inflammatory bowel disease. We present the clinical case of a Caucasian female patient, 21 years old, with a past medical history of CVID, with multiple visits to the emergency department due to abdominal pain in the lower quadrants and diarrhea. Her biochemical analysis showed elevated inflammatory parameters. Stool cultures and parasitological examination of feces were negative. Ileocolonoscopy revealed lymphoid nodular hyperplasia of the terminal ileum, and the small bowel capsule endoscopy demonstrated edema and multiple pleomorphic ulcers (Lewis score = 1,104). CVID-associated inflammatory enteropathy was suspected. Budesonide 9 mg/day was started, but no positive clinical response was observed. It was decided to initiate biological therapy with infliximab. The patient's condition is currently clinically improved with no complications due to biological therapy. PMID- 30480051 TI - Increased Gastric Retention Capacity, Assessed by Scintigraphy, after APC Treatment of Dilated Gastrojejunal Anastomosis. AB - Background: Weight regain occurs in about 20% of patients after Roux-en-Y gastric bypass (RYGB). Studies have reported that in most cases this regain is associated with dilatation of the gastrojejunal anastomosis. To correct this dilatation, one of the methods used is the application of argon plasma coagulation (APC). Case: The authors report the case of a 39-year-old woman submitted to RYGB who had weight regain. In the endoscopic evaluation, the patient presented with dilatation of the gastrojejunal anastomosis, for which treatment with APC and an adjusted diet was proposed. After 3 sessions of APC, the patient presented with a reduction of the anastomosis diameter, weight loss, and increased satiety to food, with an increased gastric emptying time evidenced by scintigraphy. Conclusion: APC proved to be a safe and efficacious method. PMID- 30480052 TI - Peroral Endoscopic Myotomy with Water Pump-Assisted Submucosal Tunnel Creation. PMID- 30480053 TI - Challenging Lumen-Apposing Metal Stent Removal after Successful Drainage of a Pancreatic Pseudocyst. PMID- 30480054 TI - An Incidental Subepithelial Cecal Lesion. PMID- 30480055 TI - Jejunal Lipoma, an Uncommon Cause of Gastrointestinal Bleeding. PMID- 30480056 TI - Refractory Chronic Pouchitis and Autoimmune Hemolytic Anemia Successfully Treated with Vedolizumab. PMID- 30480057 TI - Evaluation of ADCratio on liver MRI diffusion to discriminate benign versus malignant solid liver lesions. AB - PURPOSE: The aim of this project is to investigate the usefulness of the absolute liver lesion ADC value and ratio of Apparent diffusion coefficient (ADC) values of a liver lesion and liver parenchyma to discriminate between a benign and malignant lesion. METHODS: Liver MRI scans performed between January 2009 and June 2015 were retrospectively analysed. Scans were performed on either a 1.5 T or 3 T MRI unit. The type of liver lesion (benign or malignant) was determined by its radiological appearance, histology result and clinical management. Lesions with undetermined diagnosis or MRI studies degraded by artifacts were excluded. Liver cysts were also excluded from the analysis. ADC value of a lesion and liver parenchyma was measured and ADCratio was calculated. The values were analysed using independent samples t-test Results:Data set contained 39 benign lesions and 36 malignant lesions. Mean ADC value for benign lesions was 1678, and the mean value for malignant lesions was 1097 with a statistically significant difference of p < 0.001. All lesions with ADC value below 955 were malignant, while all lesions with ADC value above 1880 were benign. ADC value of 1260 was identified as the best available cut-off value for differentiating benign and malignant lesions, achieving sensitivity of 92%, specificity of 80% and an overall accuracy of 89%. The mean lesion to liver ADCratio for benign lesions was 1.3467 and for malignant lesions was 0.9038 with a statistically significant difference of p < 0.001. All lesions with ADCratio measuring <0.9 were malignant while lesions with ADCratio>1.5 were benign. ADCratio of 1.1 was identified statistically as the best available cut-off value for differentiating benign from malignant lesions, with sensitivity of 82%, specificity of 86% and an overall accuracy of 92%. CONCLUSION: Our dataset indicates that lesion to background liver ADCratio is superior in discriminating between benign and malignant focal lesions compared to absolute ADC values of the hepatic lesions. PMID- 30480058 TI - MR Imaging of hypoxic ischemic encephalopathy - Distribution Patterns and ADC value correlations. AB - Background and purpose: Neonatal hypoxic-ischemic encephalopathy causes hypoxic brain injury. Due to differences in brain maturity at time of insult, severity of hypotension and duration of insult, there are four distinct patterns of brain injury. Magnetic resonance imaging is the most sensitive modality for evaluating these patterns of brain injury. Additional role of Diffusion weighted imaging and ADC values can be useful in the evaluation of such cases. We conducted this study to analyse the usefulness of ADC values in the brain tissue affected by hypoxic ischemic injury. Materials and Methods: We conducted a prospective study of all the patients referred to our department for magnetic resonance scanning of brain with history of hypoxic ischemic encephalopathy and clinical features cerebral palsy. 23 Cases with imaging manifestations of hypoxic ischemic encephalopathy were included in the study. We studied distribution patterns of HIE in our cases and calculated the ADC values of involved as well as normal grey and white matter. Further, sensitivity, specificity, predictive values, and likelihood ratios for each dichotomized diffusion and ADC values were obtained Wilson Score method. Results: The most common distribution pattern in our study was involvement of peri-rolandic area (15 cases, 65%). ADC values were significantly (p < 0.005) increased in abnormal white matter. No significant changes (p = 0.8) were seen in ADC values of normal and abnormal grey matter. Conclusions: Due to significant increase in ADC values of affected white matter, ADC value can be used as a marker to detect chronic sequel of hypoxic ischaemic brain injury. Another observation was the perirolandic brain tissue being most common area of involvement in the cases with cerebral palsy. PMID- 30480059 TI - Acquisition, Maintenance, and Therapeutic Use of a Simple Motor Skill. AB - Operant conditioning of the spinal stretch reflex (SSR) or its electrical analog, the H-reflex, is a valuable experimental paradigm for studying the acquisition and maintenance of a simple motor skill. The CNS substrate of this skill consists of brain and spinal cord plasticity that operates as a hierarchy-the learning experience induces plasticity in the brain that guides and maintains plasticity in the spinal cord. This is apparent in the two components of the skill acquisition: task-dependent adaptation, reflecting brain plasticity; and long term change, reflecting gradual development of spinal plasticity. The inferior olive, cerebellum, sensorimotor cortex, and corticospinal tract (CST) are essential components of this hierarchy. The neuronal and synaptic mechanisms of the spinal plasticity are under study. Because acquisition of this skill changes the spinal cord, it can affect other skills, such as locomotion. Thus, it enables investigation of how the highly plastic spinal cord supports the acquisition and maintenance of a broad repertoire of motor skills throughout life. These studies have resulted in the negotiated equilibrium model of spinal cord function, which reconciles the spinal cord's long-recognized reliability as the final common pathway for behaviors with its recently recognized ongoing plasticity. In accord with this model, appropriate H-reflex conditioning in a person with spasticity due to an incomplete spinal cord injury can trigger wider beneficial plasticity that markedly improves walking. H-reflex operant conditioning appears to provide a valuable new method for enhancing functional recovery in people with spinal cord injury and possibly other disorders as well. PMID- 30480062 TI - Non-volant small mammal data from fragmented forests in Terengganu State. AB - This data article is about non-volant small mammal (squirrel, rat and tree shrew) capture from fragmented forest understories within sub-urban areas of Setiu (Peladang Agro Resort and Setiu Wetland Research Station) and inhabited areas of Hulu Terengganu (Saok and Lasir waterfalls) that are situated in Terengganu State, Peninsular Malaysia. Fruits like banana and oil palm were individually placed into each cage before the cages were fastened onto three to five meter height tree branches. The traps were also spatially distributed about ten meters from each other. Under this installation, fifty baited traps were used during the twenty-four nights of sample collection. All animals caught were distinguished by morphology and released at the same location it was caught. The understory data comprise of seven non-volant mammal species from family groups Sciuridae, Muridae and Tupaiidae. Overall, Callosciurus notatus (n = 17, 39%) were dominant in the capture pool from all sites. Comparatively, Sundascriurus tenuis (n = 2, 4%) and Rattus rattus (n = 4, 9.3%) were restricted to Saok Waterfalls and Setiu Wetland. Banana and oil palm fruits did not attract any small mammals during the Lasir Waterfall (Hulu Terengganu) survey. All data were interpret into Shannon, Simpson, Margalef, Menhinik and Evenness indices to individually or collectively distinguish small mammal variety in Terengganu State. PMID- 30480060 TI - Unconscious Psychological Treatments for Physiological Survival Circuits. AB - The idea of targeting unconscious or implicit processes in psychological treatments is not new, but until recently it has not been easy to manipulate these processes without also engaging consciousness. Here we review how this is possible, using various modern cognitive neuroscience methods including a technique known as Decoded Neural-Reinforcement. We discuss the general advantages of this approach, such as how it can facilitate double-blind placebo controlled studies, and minimize premature patient dropouts in the treatment of fear. We also speculate how this may generalize to other similar physiological survival processes. PMID- 30480063 TI - Dataset on quality and physiological changes of raspberry fruit during their development and under auxin in-vitro assay. AB - The data presented in this article are related to the research article entitled "Expression of two indole-3-acetic acid (IAA)-amido synthetase (GH3) genes during fruit development of raspberry (Rubus idaeus Heritage)" (Bernales et al., In press). This data article describes the relation of all size variables between them and with the weight showing an increasing trend between length and weight and an inverse relation of fruit firmness and ethylene production during development. In addition, IAA treatment during auxin in-vitro assay showed no significant changes in firmness, a significant increase of ethylene and respiratory production. PMID- 30480061 TI - Glucocorticoids affect bone mineral density and bone remodelling in OVX sheep: A pilot study. AB - The aim of this study was to validate the combination of ovariectomy and glucocorticoid treatment in sheep as a large animal model for osteoporosis by measuring the concentration of specific biomarkers in the blood of the sheep and measuring bone loss over five months. Aged Merino ewes were randomly allocated into four groups: control, ovariectomy (OVX), and two OVX groups receiving glucocorticoids-one group once-monthly for five months (OVXG), and the other for two months followed by no treatment for three months (OVXG2). Parameters measured were biochemical markers of bone turnover, areal bone mineral density, volumetric bone mineral density, and total and trabecular bone parameters. Ovariectomy increased the concentrations of bone resorption marker C-terminal telopeptides of type 1 collagen (CTx-1) and bone turnover marker serum osteocalcin (OC) concentrations in the OVX group compared to control sheep. The combination of ovariectomy and glucocorticoid treatment increased the concentrations of CTx-1 and decreased serum OC concentrations in the OVXG group compared to OVXG2. Femur and lumbar spine bone density were lower in experimentally treated groups when compared with the control group. Total and trabecular vBMD in the proximal tibia were significantly lower in the treatment groups when compared with the control group. A significant negative correlation between femoral bone density and CTx-1 was found. The results of this study suggest that the combination of OVX and glucocorticoids induces bone loss in a short period of time in sheep. PMID- 30480064 TI - Pooled cross-sectional sample data of the 2015, 2016, 2017 National Health Interview Surveys for studying the determinants of health care market and labor market outcomes in post Affordable Care Act USA. AB - This data article contains health care market and labor market outcome measures along with their determinants for individuals in the civilian non institutionalized population of the United States. The underlying source data is the anonymized person's level publically released versions of the 2015, 2016 and 2017 National Health Interview Surveys (NHIS). The included Health care market outcomes are "Access to health care", "Usage of Health care", and "Level of Expenditure on health care"; while the labor market outcomes are "Employment Status"," Full-time participation Status", and "Level of hours spent working". Together, these outcome measures describe the intensive and extensive margins of individual's Health care demand and labor supply in the United States. Although the original paper [4] focused on investigating the relative influence of inter generational co-residence on these outcomes for the year 2015 and 2016, this full data set includes additional information for the year 2017 allowing one to investigate further interesting aspects of the US health care market and labor market for the period post Affordable Care Act. The determinant factors covered in the data include not only socio- economic and demographic characteristics but also key policy variables such as "Extended coverage status" and "Flexible account coverage status". PMID- 30480065 TI - Data on physico-chemical, performance, combustion and emission characteristics of Persea Americana Biodiesel and its blends on direct-injection, compression ignition engines. AB - This data article is based on research work which examines the potential of Persea americana (Avocado) plant oil biodiesel and its blends as viable alternative to the environmentally degrading and virtually unsustainable fossil fuel (diesel) in direct-injection, compression-ignition engines. The Avocado biodiesel was synthesized by a single-process, methanol-catalyzed transesterification reaction under optimum conditions. The cold flow and critical properties of the produced biodiesel and its blends were analyzed by using America standard for testing materials (ASTM) procedures. Data on performance and combustion characteristics of the biodiesel and its blends on test engine HR178FA/FAE Single Cylinder, 4-Stroke, air-cooled, direct-injection, compression ignition diesel engine at various engine loads of 0%, 20%, 40%, 60%, 80% and 100% are provided. The emission and smoke opacity characteristics were measured by a nova 7460 exhaust gas analyzer and AVL 437 smoke meter respectively. PMID- 30480066 TI - Analysis of data for comorbidity and survival in out-of-hospital cardiac arrest. AB - The data presented in this article is supplementary to the research article titled "Comorbidity and survival in out-of-hospital cardiac arrest" (Hirlekar et al., 2018). The data contains information of how Charlson Comorbidity Index (CCI) is calculated and coded from ICD-10 codes. Multivariable logistic regression was used in the analysis of association between comorbidity and return of spontaneous circulation. We present baseline characteristics of patients found in VF/VT. All patients with non-missing data on all baseline variables are analyzed separately. We compare the baseline characteristics of patients with and without complete data set. Analysis of when comorbidity was identified in relation to outcome is also shown. PMID- 30480067 TI - Dataset on the evaluation of chemical and mechanical properties of steel rods from local steel plants and collapsed building sites. AB - The quality of steel rods used in structural applications has been subjected to continuous scrutiny by researchers in Nigeria. In this data article, the experimental data on the chemical and mechanical properties of steel rods from collapsed building sites and local steel plants have been reported. The chemical composition consisting of carbon, manganese, silicon, sulphur, phosphorus among other elements were recorded using an optical emission spectrometer. Some of the main elements were used to evaluate the carbon equivalent value and the results are reported in this article. The yield strength, ultimate tensile strength and percentage elongation were also presented as obtained from the universal testing machine. The hardness values of the steel rod samples were also presented. PMID- 30480068 TI - Dataset on ammonia, nitrous oxide, methane, and carbon dioxide fluxes from two soils fertilized amended with treated and non-treated cattle slurry. AB - The current data article presents a set of fluxes of ammonia (NH3), nitrous oxide (N2O), methane (CH4), and carbon dioxide (CO2) measured from two different soils under a Mediterranean double-cropping system (oat in autumn/winter followed by maize in spring/summer). The two soils were fertilized using four different treatments: (i) Injection of raw cattle slurry (100 mm depth), (ii) application of raw cattle slurry followed by soil incorporation (20 mm depth), (iii) band application of acidified (pH=5.5) cattle slurry followed by soil incorporation (20 mm depth), and (iv) band application of acidified (pH=5.5) cattle slurry without soil incorporation. A non-amended soil was also considered as control treatment. The data presented here were obtained over a three years experiment between 2012 and 2015. Fluxes were measured in a period between slurry applications to soil (before plant seeding) till crop harvest. The data presented here are supporting the research article "Band application of acidified slurry as an alternative to slurry injection in a Mediterranean double-cropping system: Agronomic effect and gaseous emissions" (Fangueiro et al., 2018). PMID- 30480069 TI - Data relating to the transcriptomes of human lung epithelial cells exposed to radon-emitting rock, tobacco smoke or cannabis smoke. AB - Presented herein are RNA expression data linked to the exposure of human lung epithelial cells to either low dose radon-emitting rock, tobacco smoke or cannabis smoke. Two cell lines were used, one representing a 'normal' lung epithelial cell (BEAS-2B, derived from immortilized bronchial epithelial cells from a cadaver) and one representing a 'cancerous' lung epithelial cell (NCI H1975, derived from a primary lung adenocarcinoma from a non-smoker). Control cells were cultured under standard conditions. Test cells were either (a) continuously cultured in the presence of pulverized uranium-containing rock emitting 38 Bq/m3 radon, or (b) exposed five days a week, to a 1:10,000 dilution of either tobacco or cannabis smoke from one cigarette. RNA was extracted from the cells at various time-points over a period of 1-17 weeks (7-140 days). cDNA libraries were prepared from the RNA, and the libraries were sequenced. Raw, aligned sequencing data, from 38 biosamples, are available through a public repository. Differential gene expression data, relating to control and test samples from various time-points, are linked to this article. Detailed analyses relating to these data can be found in the article "Human lung epithelial cells cultured in the presence of radon-emitting rock experience gene expression changes similar to those associated with tobacco smoke exposure" [1]. PMID- 30480070 TI - Data on microbiological quality of raw cow milk in East Azerbaijan province, Iran. AB - Microbial contamination of milk can lead to undesirable effects on texture, color, odor, or flavor that result in shorter shelf life. It may also cause serious illnesses in consumers if it contains over than standard limit of these parameters. In this data, we evaluate the total bacterial count (TBC) and somatic cell count (SCC) of raw milk in East Azerbaijan province using BactoScan and Fossomatic equipment, respectively. According to the 30 points selected in the province map, the 10,800 samples were collected during a one-year period. Microbiological results in this data show heavy contaminations of milk samples with TBC indicator (73.6%), while SCC in only 6.4% samples were over the recommended levels by the Iranian standard. Therefore, it is necessary to take attention in order to control of these microbial parameters especially TBC during of milk production to avoid the potential risk of high microbial contamination. PMID- 30480071 TI - Sunspot data and human longevity. AB - Solar energy at birth and human lifespan, Journal of Photochemistry & Photobiology B 186 (2018)59-68. This paper uses National Center for Health Statistics (NCHS) death data collected from 1979- 2013, inclusive, and average monthly solar intensity as measured by sunspot number collected from the National Oceanic and Atmospheric Administration (NOAA) from 1900-2013, inclusive. PMID- 30480072 TI - Data on chemical composition of alkaloids of Plumula nelumbinis and antioxidant activity from thirteen habitats in China. AB - Plumula nelumbinis is widely consumed as tea for its pharmacological properties, which is related to its chemical composition, so the identification of the major compounds of P. nelumbinis is valuable. The data described in this article is supported by the research article entitled "Chemical composition of alkaloids of Plumula nelumbinis and their antioxidant activity from different habitats in China" (Tian et al., 2018). Included are the MS-MS Spectrograms of seven alkaloid standards and thirty alkaloids identified in the P. nelumbinis, which is based on ultra-performance liquid chromatography electrospray ionization quadrupole time of-flight mass spectrometry method. Also included are the total alkaloids content and the antioxidant activity of total alkaloid in P. nelumbinis from 13 habitats in China, which was accomplished with three different antioxidant assays. PMID- 30480073 TI - Dataset on seed details of wheat genotypes, solution treatments to measure seedling emergence force and the relation between seedling force and strain. AB - The seed details (weight, vigor) and germination rate of 16 wheat (Triticum aestivum) genotypes in a non-limiting conditions were measured. The dataset presents seed germination rate and seed vigor of 16 wheat genotypes. The dataset also presents the concentrations of the cations to create solution treatments of various sodium adsorption ratio (SAR) and ionic strength (I). Finally, dataset presented a figure of the experimental design to measure seedling emergence force of wheat genotypes. The image of the setup and the relation between strain and force have been presented here to convert the strain of the beam into seedling emergence force. This dataset has been used in research work titled 'Greater emergence force and hypocotyl cross sectional area may improve wheat seedling emergence in sodic conditions' (Anzooman et al., 2018) [1]. PMID- 30480074 TI - Data on characterization and validation of assays for ultrasensitive quantitative detection of small molecules: Determination of free thyroxine with magnetic and interferometric methods. AB - The presented data refer to optimization and quantitative characterization of a rapid lateral flow assay based on high-affinity bifunctional ligand and magnetic nanolabels, which was developed for detection of small molecules of thyroid hormones. The results were obtained by several techniques, including the magnetic particle quantification method, spectral-correlation interferometry and spectral phase interferometry, dynamic light scattering, enzyme linked immunosorbent assay. The long-term stability of "antibody - magnetic nanoparticle" conjugates is shown. The assay specificity is confirmed, and verification of successful combination of magnetic particles and antibodies is demonstrated. The kinetic and equilibrium dissociation constants are determined for interactions between thyroxine and monoclonal antibodies. The obtained data could be used for design of other platforms for detection of small molecules. PMID- 30480075 TI - Data from a photovoltaic system using fuzzy logic and the P&O algorithm under sudden changes in solar irradiance and operating temperature. AB - This article presents the data of a PV system using fuzzy logic and the perturb and observe (P&O) algorithm, under sudden changes in the solar irradiance and the operating temperature of a PV module. The mathematical modeling of the PV module, the dc-dc converter and the fuzzy and P&O controllers were discussed in our previous work entitled "Fuzzy logic based MPPT controller for a PV System" (Algarin et al., 2017) [1]. Data are presented for six cases with different operating conditions: in the first case the two controllers were evaluated for standard test conditions with constant solar irradiance of 1000 W/m2 and constant temperature of 25 degrees C. In the remaining five cases sudden increases and decreases were made in the operating conditions of the PV module. Finally, the theoretical data of the PV system are presented, which can be used as a reference to analyze the data obtained with the two controllers in the six cases. Data are provided in Supplementary material in Tables 1-7. PMID- 30480077 TI - Development of an objective water security index and assessment of its association with quality of life in urban areas of developing countries. AB - A composite metric assessing water security's physical dimension at the micro/ community level is lacking but is essential for setting priorities for program and policy implementations. We prepared an objective index (OI) of water security to measure the physical dimension using a model centered on household water-use behavior in developing countries' urban areas. A cross-sectional household survey (n = 1500) with multi-stage cluster design was conducted from December 2015 to February 2016 in the Kathmandu Valley, which has faced long-term, severe water shortage. A structured questionnaire probed socio-demographic characteristics, water sources, frequency and quantity of water use, cost related to water, etc. A 15-item water insecurity scale was used to measure subjective and experiential dimension of water insecurity. The World Health Organization Quality of Life - BREF was used to measure quality of life (QoL). The QoL has been considered as proxy of well-being in this study. The OI measured differential water security within small cities, the utility's service areas for instance, and identified area-specific key dimensions that need improvement. Overall, the OI and its key dimensions can be useful measures to design water-scarcity averting programs and policies, specific to a particular community's needs. The increased OI values were significantly and positively associated with better physical and psychological health and better social relationship domains of QoL suggesting health implications of water security. PMID- 30480076 TI - The Tumor Suppressor SASH1 Interacts With the Signal Adaptor CRKL to Inhibit Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer. AB - Background & Aims: The tumor-suppressor sterile alpha motif- and Src-homology 3 domain containing 1 (SASH1) has clinical relevance in colorectal carcinoma and is associated specifically with metachronous metastasis. We sought to identify the molecular mechanisms linking decreased SASH1 expression with distant metastasis formation. Methods: SASH1-deficient, SASH1-depleted, or SASH1-overexpressing HCT116 colon cancer cells were generated by the Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated 9-method, RNA interference, and transient plasmid transfection, respectively. Epithelial-mesenchymal transition (EMT) was analyzed by quantitative reverse-transcription polymerase chain reaction, immunoblotting, immunofluorescence microscopy, migration/invasion assays, and 3-dimensional cell culture. Yeast 2-hybrid assays and co immunoprecipitation/mass-spectrometry showed V-Crk avian sarcoma virus CT10 oncogene homolog-like (CRKL) as a novel interaction partner of SASH1, further confirmed by domain mapping, site-directed mutagenesis, co-immunoprecipitation, and dynamic mass redistribution assays. CRKL-deficient cells were generated in parental or SASH1-deficient cells. Metastatic capacity was analyzed with an orthotopic mouse model. Expression and significance of SASH1 and CRKL for survival and response to chemotherapy was assessed in patient samples from our department and The Cancer Genome Atlas data set. Results: SASH1 expression is down-regulated during cytokine-induced EMT in cell lines from colorectal, pancreatic, or hepatocellular cancer, mediated by the putative SASH1 promoter. Deficiency or knock-down of SASH1 induces EMT, leading to an aggressive, invasive phenotype with increased chemoresistance. SASH1 counteracts EMT through interaction with the oncoprotein CRKL, inhibiting CRKL-mediated activation of SRC kinase, which is crucially required for EMT. SASH1-deficient cells form significantly more metastases in vivo, depending entirely on CRKL. Patient tumor samples show significantly decreased SASH1 and increased CRKL expression, associated with significantly decreased overall survival. Patients with increased CRKL expression show significantly worse response to adjuvant chemotherapy. Conclusions: We propose SASH1 as an inhibitor of CRKL-mediated SRC signaling, introducing a potentially druggable mechanism counteracting chemoresistance and metastasis formation. PMID- 30480078 TI - Which activities count? Using experimental data to understand conceptualizations of physical activity. AB - US health surveys consistently report that men and those with higher socioeconomic status (SES) engage in more physical activity than women and lower SES counterparts, using questions that ask about physical activity during leisure time. However, social characteristics such as gender and SES shape understandings of and access to leisure-based physical activity as well as other domains where healthy activity is available - namely house work, care work, and paid work. Thus, the physical activity of US adults may look different when what counts as physical activity expands beyond leisure activity. The current study uses Amazon's Mechanical Turk platform to conduct a 2-by-2-by-2 factorial experiment that crosses three types of physical activities: leisure, house or care work, and paid work. We find that physical activity questions that prime respondents - that is, ask respondents - to consider house/care work or paid work lead to increased minutes reported of physical activity compared to not priming for physical activity, while asking about leisure is no different from having no physical activity primed. The effect on reported physical activity of priming with house/care work is stronger for women than men, demonstrating support for gendered specialization of time spent in the house and care work domain. The effects on reported physical activity of priming with house/care work and paid work are stronger for those with less education compared to more education, consistent with socioeconomic divisions in access to physical activity in house/care work and employment. This study highlights the contingence of our understanding of the physical activity of US adults on both its measurement in surveys and the social forces which shape understanding of and access to physical activity. PMID- 30480080 TI - A very light lunch: Interoceptive deficits and food aversion at onset in a case of behavioral variant frontotemporal dementia. AB - Introduction: Patients affected by the behavioral variant frontotemporal dementia (bvFTD) frequently experience, at a delayed onset, abnormal eating behavior involving increased food intake. Although delusional food-related symptoms have attracted much attention, the behavioral and neural features of food aversion manifestations in bvFTD remain poorly documented. Methods: We describe the rare case of a patient with bvFTD presenting with lack of interoception for swallowing and digestion, coupled with a dramatic food aversion at onset. We also compared his MRI scan to 84 healthy individuals using a voxel-based morphometry approach. Results: We found gray matter density reductions involving the postcentral gyrus bilaterally, insulae, and right medial orbitofrontal cortex. Discussion: Our results shed new light on the behavioral and neuroanatomical features of food aversion and interoception deficits in bvFTD, suggesting that besides orbitofrontal cortex, also a distributed system associated with interoception might play a role in such behavioral manifestation. PMID- 30480079 TI - Fusion of deep learning models of MRI scans, Mini-Mental State Examination, and logical memory test enhances diagnosis of mild cognitive impairment. AB - Introduction: Our aim was to investigate if the accuracy of diagnosing mild cognitive impairment (MCI) using the Mini-Mental State Examination (MMSE) and logical memory (LM) test could be enhanced by adding MRI data. Methods: Data of individuals with normal cognition and MCI were obtained from the National Alzheimer Coordinating Center database (n = 386). Deep learning models trained on MRI slices were combined to generate a fused MRI model using different voting techniques to predict normal cognition versus MCI. Two multilayer perceptron (MLP) models were developed with MMSE and LM test results. Finally, the fused MRI model and the MLP models were combined using majority voting. Results: The fusion model was superior to the individual models alone and achieved an overall accuracy of 90.9%. Discussion: This study is a proof of principle that multimodal fusion of models developed using MRI scans, MMSE, and LM test data is feasible and can better predict MCI. PMID- 30480081 TI - Alzheimer's disease: 3-Dimensional MRI texture for prediction of conversion from mild cognitive impairment. AB - Introduction: Currently, there are no tools that can accurately predict which patients with mild cognitive impairment (MCI) will progress to Alzheimer's disease (AD). Texture analysis uses image processing and statistical methods to identify patterns in voxel intensities that cannot be appreciated by visual inspection. Our main objective was to determine whether MRI texture could be used to predict conversion of MCI to AD. Methods: A method of 3-dimensional, whole brain texture analysis was used to compute texture features from T1-weighted MR images. To assess predictive value, texture changes were compared between MCI converters and nonconverters over a 3-year observation period. A predictive model using texture and clinical factors was used to predict conversion of patients with MCI to AD. This model was then tested on ten randomly selected test groups from the data set. Results: Texture features were found to be significantly different between normal controls (n = 225), patients with MCI (n = 382), and patients with AD (n = 183). A subset of the patients with MCI were used to compare between MCI converters (n = 98) and nonconverters (n = 106). A composite model including texture features, APOE-epsilon4 genotype, Mini-Mental Status Examination score, sex, and hippocampal occupancy resulted in an area under curve of 0.905. Application of the composite model to ten randomly selected test groups (nonconverters = 26, converters = 24) predicted MCI conversion with a mean accuracy of 76.2%. Discussion: Early texture changes are detected in patients with MCI who eventually progress to AD dementia. Therefore, whole-brain 3D texture analysis has the potential to predict progression of patients with MCI to AD. PMID- 30480082 TI - A randomized, double-blind, placebo-controlled trial of resveratrol with glucose and malate (RGM) to slow the progression of Alzheimer's disease: A pilot study. AB - Introduction: Human studies on low-dose resveratrol are scarce. This study aims to evaluate the safety, tolerability, and efficacy of an oral preparation of resveratrol, glucose, and malate (RGM) in slowing the progression of Alzheimer's disease (AD). Methods: Thirty-nine subjects with mild to moderate AD who were free of life-threatening disease and who did not have contraindications to the use of the study product were screened. Progression of AD was measured by change in the cognitive portion of the Alzheimer's Disease Assessment Scale-cognitive subscale. Secondary outcomes included Clinician's Global Impression of Change, Mini-Mental State Examination, Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale, and Neuropsychiatric Inventory. 15 mL of the following preparation per dose, i.e., 5 g dextrose, 5 g malate, and 5 mg resveratrol, or matching placebo was ingested with an 8 oz glass of commercial unsweetened grape juice twice a day for 1 year. Group differences in the rate of change in the outcome measures were examined using generalized estimating equations. Results: The treatment and control groups were similar on all of the screening variables. At 12 months, change scores on Alzheimer's Disease Assessment Scale-cognitive subscale, Mini-Mental State Examination, Alzheimer's Disease Cooperative Study Activities of Daily Living Scale, or Neuropsychiatric Inventory all showed less deterioration in the treatment than the control group; however, none of the change scores reached statistical significance. The most common AE were falls, all in the control group. None of the falls were deemed to be study related. Conclusion: Low-dose oral resveratrol is safe and well tolerated. Interpretation of the effects on clinical outcomes trajectories remains uncertain. A larger study is required to determine whether low-dose resveratrol may be beneficial. Trial Registration: ClinicalTrials.gov (NCT00678431), Registered 05/15/2008. PMID- 30480083 TI - Evaluation of a guideline directed medical therapy titration program in patients with heart failure with reduced ejection fraction. AB - Introduction: Heart failure is associated with recurrent hospitalizations and high mortality. Guideline directed medical treatment (GDMT), including beta blockers (BBs), angiotensin converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs) and aldosterone antagonists (AAs) has shown to improve outcomes. Current guidelines recommend the use of these medication classes at maximally tolerated dosages. Despite the evidence, < 25% of patients with heart failure with reduced left ventricular ejection fraction (HFrEF) are on the appropriate medical regimen titrated to the target doses. As such, we sought to assess the utility of a focused GDMT clinic to reduce this gap. Methods: We conducted a retrospective chart review through existing patient data in a single center teaching hospital of patients referred to a focused GDMT clinic primarily staffed with heart failure trained nurse specialists, physician assistants and cardiologists. Management guidelines were developed with protocols for the initiation and uptitration of all therapeutic agents considered as GDMT.Our primary objective was to determine whether enrollment into a dedicated nursing led guideline directed medical therapy clinic would increase the proportion of patients with heart failure with reduced ejection fraction on appropriate medications as well as medication dosages in patients, the percentage of patients on the following medications and percentage at target doses: Renin-Angiotensin Aldosterone System Blockers, Evidence Based Beta Blockers, and Aldosterone Antagonists. Our secondary objective was to determine if there was any clinical benefit on objective measures including renal function, hospital admissions, mortality and implantable defibrillator shocks. Results: Between October 2015 and March 2017, 63 patients were identified by requisition forms, in which 61 were able to be identified based on legibility of identifying information. Mean duration of follow up was 264.44 +/- 162.68 days over 7 +/- 3.94 days. Mean ejection fraction was 21.8 +/- 7.3%. New onset cardiomyopathies (diagnosed within 30 days) compiled 21% of the patient population while those with demonstrated cardiomyopathies (> 90 days) compiled 48% of the patient population. Patients with NYHA class III heart failure compiled 65% of the patient population.There was a statistically significant increase in the mean number of GDMT at any dose (2.31 +/- 0.76 to 2.74 +/- 0.66; p < 0.001) and mean number of GDMT at target doses (0.54 +/- 0.79 to 1.52 +/- 1.1; p < 0.001). Percentage of the population that were on no target doses at initial visit was 62% which was reduced to 18% after intervention.Clinical improvement was reflected in significant improvement in ejection fraction from 21.8 +/- 7.8% to 36.2 +/- 14.3% (p < 0.001). Increases in sodium and chloride were statistically small but significant. There a significant reduction in heart failure hospitalizations in comparison to a year prior to after the initial encounter in the clinic (p < 0.001). Conclusion: This pilot study showed that a nurse directed GDMT titration program successfully increased the number of GDMT that patients were able to tolerate in a timely fashion, all the while enhancing ejection fraction, sodium and chloride levels, with a reduction in rehospitalization rates. PMID- 30480084 TI - Age-related changes in four-dimensional CMR-derived atrioventricular junction velocities and displacements: Implications for the identification of altered annular dynamics for ventricular function assessment. AB - Background: We determined the age-related changes in atrioventricular junction (AVJ) velocities and displacements by feature tracking cardiovascular magnetic resonance (FT-CMR) in a healthy community-based population. We also investigated the importance of age-matching for the identification of altered AVJ dynamics. Methods: FT-CMR was performed in 230 controls (18-78 years) and in two patient groups each consisting of 40 subjects (group 1: 23-55 years, group 2: 56-80 years). AVJ dynamic parameters, including systolic velocity Sm, early diastolic velocity Em, late diastolic velocity Am, maximal systolic excursion MAPSE and the new parameter sweep surface area velocity SSAV were measured. Results: Increasing age in the control group was significantly associated with reductions in Sm, Em, MAPSE (r = -0.40, -0.76, -0.34, all P < 0.001) and an increase in Am (r = 0.45, P < 0.001). For patient group 1, the selection of an age-unmatched control group (56-76 years) underestimated the number of patients with abnormal AVJ dynamics during systole and early diastole (38% vs. 70% for Sm; 20% vs. 60% for Em; 35% vs. 50% for MAPSE). In contrast, for patient group 2, the number of patients with systolic and early diastolic AVJ dynamic abnormalities was overestimated (88% vs. 63% for Sm; 90% vs. 68% for Em; 73% vs. 58% for MAPSE) when compared with age unmatched controls (24-55 years). Fifty-percent (20/40) of the sub-group of patients with normal left ventricular ejection fraction exhibited abnormal systolic Sm or MAPSE measurements. Conclusions: Significant correlations exist between age and AVJ dynamics. Age matching is important for evaluating AVJ long axis function. PMID- 30480085 TI - Adults with congenital heart disease overestimate their physical activity level. AB - Background: Physical activity reduces the risk of acquired cardiovascular disease, which is of great importance in patients with congenital heart disease (CHD). There are diverging data whether physical activity level (PAL) differs between patients with CHD and controls. Furthermore, it is unknown if PAL can be reliably assessed in patients with CHD using self-reported instruments. Methods: Seventy-five patients with CHD (mean age 37.5 +/- 15.5 years, women n = 29 [38.7%]) and 42 age and sex matched controls completed the International Physical Activity Questionnaire (IPAQ) and carried the activity monitor Actiheart over 4 days. Time spent at >=3 METS >=21.4 min/day, i.e. reaching the WHO recommendation for PAL to promote health, was used as the outcome measure. Data on PAL obtained from IPAQ were compared with Actiheart. Results: The proportion of individuals reaching target PAL according to IPAQ was similar in patients with CHD and controls (70.7%vs.76.2%, p = 0.52) as well as between patients with simple and complex lesions. There was an overall difference between IPAQ and Actiheart in detecting recommended PAL (72.6%vs.51.3%, p < 0.001). In a subgroup analysis, this difference was also detected in patients but was borderline for controls. The negative predictive value for IPAQ in detecting insufficient PAL was higher in patients than in controls (73%vs.40%). Conclusions: The proportion of persons reaching sufficient PAL to promote health was similar in patients and controls. The self-reported instrument overestimated PAL in relation to objective measurements. However, with a high negative predictive value, IPAQ is a potentially useful tool for detecting patients with insufficient PAL. PMID- 30480086 TI - Risk factors of levodopa-induced dyskinesia in Parkinson's disease: results from the PPMI cohort. AB - Levodopa-induced dyskinesias (LID) negatively impact on the quality of life of patients with Parkinson's disease (PD). We assessed the risk factors for LID in a cohort of de-novo PD patients enrolled in the Parkinson's Progression Markers Initiative (PPMI). This retrospective cohort study included all PD patients enrolled in the PPMI cohort. Main outcome was the incidence rate of dyskinesia, defined as the first time the patient reported a non-zero score in the item "Time spent with dyskinesia" of the MDS-UPDRS part IV. Predictive value for LID development was assessed for clinical and demographical features, dopamine transporter imaging (DaTscan) pattern, cerebrospinal fluid (CSF) biomarkers (Abeta42, total tau, phosphorylated tau, total alpha synuclein) and genetic risk score for PD. Overall, data from 423 PD patients were analyzed. The cumulative incidence rate of LID was 27.4% (95% CI = 23.2-32.0%), with a mean onset time of 5.81 years from PD diagnosis. Multivariate Cox regression analysis showed several factors predicting LID development, including female gender (HR = 1.61, 95% CI = 1.05-2.47), being not completely functional independent as measured by the modified Schwab & England ADL scale (HR = 1.81, 95% CI = 0.98-3.38), higher MDS UPDRS part III score (HR = 1.03, 95% CI = 1.00-1.05), postural instability gait disturbances or intermediate phenotypes (HR = 1.95, 95% CI = 1.28-2.96), higher DaTscan caudate asymmetry index (HR = 1.02, 95% CI = 1.00-1.03), higher polygenic genetic risk score (HR = 1.39, 95% CI = 1.08-1.78), and an anxiety trait (HR = 1.02, 95% CI = 1.00-1.04). In PD patients, cumulative levodopa exposure, female gender, severity of motor and functional impairment, non-tremor dominant clinical phenotype, genetic risk score, anxiety, and marked caudate asymmetric pattern at DaTscan at baseline represent independent risk factors for developing LID. PMID- 30480087 TI - 24-hour levodopa-carbidopa intestinal gel may reduce troublesome dyskinesia in advanced Parkinson's disease. AB - Levodopa-carbidopa intestinal gel (LCIG) is effective for the control of motor fluctuations in Parkinson's disease (PD). The objective of this study is to report the reduction of dyskinesias after transitioning from 16 to 24-h/day LCIG infusion. From a cohort of 74 PD patients treated with LCIG for motor fluctuations, we identified 12 patients that were treated with 24-h per day infusion with the aim to control troublesome daytime dyskinesia. Clinical, demographic, dyskinesia rating scales were evaluated. Daytime dyskinesia was reduced in 75% (9/12) patients following treatment with 24-h therapy, including 7 who were compared with 16-h therapy and 2 that were transitioned from oral dopaminergic therapy to 24-h LCIG. Combining the data from all 12 subjects, troublesome dyskinesias were reduced during 24-h LCIG; UPDRS 4.1 (time spent with dyskinesias) mean change was -1.5 +/- 0.75, p = 0.010 (Wilcoxon signed-rank test) and UPDRS 4.2 (functional impact of dyskinesias) mean change was -1.7 +/- 0.90, p = 0.016, without changing their UPDRS part 3 "ON" scores (p = 0.138) or H&Y (p = 0.157). In 5 patients, improvement in dyskinesia occurred despite an overall increase in the total daily levodopa dose. None of the patients had worsening of dyskinesia after a median follow-up of 28 months. 24-h per day infusion of LCIG may be a useful strategy in the management of troublesome dyskinesias in PD patients with disabling dyskinesias resistant to attempts to optimise 16-hours per day therapy. We postulate that this may be due to a pharmacodynamic as opposed to pharmacokinetic mechanism. PMID- 30480088 TI - Retained free energy as a driving force for phase transformation during rapid solidification of stainless steel alloys in microgravity. AB - Ternary Fe-Cr-Ni stainless steel alloys often exhibit a multi-step transformation known as double recalescence where primary ferrite converts to austenite during rapid solidification processes such as casting and welding. In addition to the volume free energy associated with undercooling between the phases, the free energy driving the transformation comes from two additional sources that are retained within the metastable solid-one from the primary phase undercooling and one from melt shear. A new physical model is proposed based on accumulation of defects, such as dislocations or tilt boundaries, and lattice strain. A dimensionless analysis technique shows that the free energy associated with metastable solidification is conserved and the contribution from melt shear can be predicted based on a modification of the Read-Shockley dislocation energy equation. With these additional terms the incubation time between nucleation events becomes inversely proportional to the total free energy squared for bulk diffusion and cubed for grain boundary diffusion mechanisms. In the case of the ferrous alloys studied, the grain boundary mechanism provides a better fit and when the model is applied the delay time behavior collapses to a single master curve for the entire alloy family. PMID- 30480089 TI - A Difficult Challenge for the Clinical Laboratory: Accessing and Interpreting Manufacturer Cross-Reactivity Data for Immunoassays Used in Urine Drug Testing. AB - Urine drug testing by immunoassay is widely used to detect nonmedical drug use and to monitor patients prescribed controlled substances. A key attribute of urine drug testing immunoassays is cross-reactivity, namely the response of various compounds compared to the target of the assay. In this report, we analyzed the variability in how manufacturer cross-reactivity data are summarized in package inserts for commercially available amphetamines, benzodiazepines, and opiates immunoassays, 3 broad drug classes commonly included in routine drug testing panels. Specifically, we determined the number of compounds tested for cross-reactivity, manner in which cross-reactivity is measured, concentration units used, how often compounds known to be cross-reactive with marketed urine drug testing immunoassays prior to 2010 were tested, availability of the package insert online, and how often cross-reactivity on "designer drugs" was found in the package inserts. There was wide variability in the number of compounds tested (both positive and negative), with the highest number of tested compounds generally found in point-of-care urine drug testing applications. Most package inserts used ng/mL as the concentration units and expressed cross-reactivity in terms of equivalent concentrations to the assay calibrator. Approximately 50% of package inserts were directly available online. Cross-reactivity data were sparse with respect to "off-target" drugs known to be cross-reactive prior to 2010 (an example being quinolone antibiotics and opiates immunoassays) and designer drugs. The present study indicates lack of consistency in cross-reactivity information in package inserts, complicating the interpretation of urine drug testing results. We use 3 example clinical cases to illustrate practical challenges accessing and interpreting cross-reactivity data. PMID- 30480090 TI - Voltage control of unidirectional anisotropy in ferromagnet-multiferroic system. AB - Demonstration of ultralow energy switching mechanisms is imperative for continued improvements in computing devices. Ferroelectric (FE) and multiferroic (MF) order and their manipulation promise an ideal combination of state variables to reach attojoule range for logic and memory (i.e., ~30* lower switching energy than nanoelectronics). In BiFeO3 (BFO), the coupling between the antiferromagnetic (AFM) and FE order is robust at room temperature, scalable in voltage, stabilized by the FE order, and can be integrated into a fabrication process for a beyond CMOS (complementary metal-oxide semiconductor) era. The presence of the AFM order and a canted magnetic moment in this system causes exchange interaction with a ferromagnet such as Co0.9Fe0.1 or La0.7Sr0.3MnO3. Previous research has shown that exchange coupling (uniaxial anisotropy) can be controlled with an electric field. However, voltage modulation of unidirectional anisotropy, which is preferred for logic and memory technologies, has not yet been demonstrated. Here, we present evidence for electric field control of exchange bias of laterally scaled spin valves that is exchange coupled to BFO at room temperature. We show that the exchange bias in this bilayer is robust, electrically controlled, and reversible. We anticipate that magnetoelectricity at these scaled dimensions provides a powerful pathway for computing beyond modern nanoelectronics by enabling a new class of nonvolatile, ultralow energy computing elements. PMID- 30480091 TI - Stretchable organic optoelectronic sensorimotor synapse. AB - Emulation of human sensory and motor functions becomes a core technology in bioinspired electronics for next-generation electronic prosthetics and neurologically inspired robotics. An electronic synapse functionalized with an artificial sensory receptor and an artificial motor unit can be a fundamental element of bioinspired soft electronics. Here, we report an organic optoelectronic sensorimotor synapse that uses an organic optoelectronic synapse and a neuromuscular system based on a stretchable organic nanowire synaptic transistor (s-ONWST). The voltage pulses of a self-powered photodetector triggered by optical signals drive the s-ONWST, and resultant informative synaptic outputs are used not only for optical wireless communication of human machine interfaces but also for light-interactive actuation of an artificial muscle actuator in the same way that a biological muscle fiber contracts. Our organic optoelectronic sensorimotor synapse suggests a promising strategy toward developing bioinspired soft electronics, neurologically inspired robotics, and electronic prostheses. PMID- 30480092 TI - Multifunctional wafer-scale graphene membranes for fast ultrafiltration and high permeation gas separation. AB - Reliable and large-scale manufacturing routes for perforated graphene membranes in separation and filtration remain challenging. We introduce two manufacturing pathways for the fabrication of highly porous, perforated graphene membranes with sub-100-nm pores, suitable for ultrafiltration and as a two-dimensional (2D) scaffold for synthesizing ultrathin, gas-selective polymers. The two complementary processes-bottom up and top down-enable perforated graphene membranes with desired layer number and allow ultrafiltration applications with liquid permeances up to 5.55 * 10-8 m3 s-1 Pa-1 m-2. Moreover, thin-film polymers fabricated via vapor-liquid interfacial polymerization on these perforated graphene membranes constitute gas-selective polyimide graphene membranes as thin as 20 nm with superior permeances. The methods of controlled, simple, and reliable graphene perforation on wafer scale along with vapor-liquid polymerization allow the expansion of current 2D membrane technology to high performance ultrafiltration and 2D material reinforced, gas-selective thin-film polymers. PMID- 30480093 TI - Mosaics of topological defects in micropatterned liquid crystal textures. AB - Topological defects in the orientational order that appear in thin slabs of a nematic liquid crystal, as seen in the standard schlieren texture, behave as a random quasi-two-dimensional system with strong optical birefringence. We present an approach to creating and controlling the defects using air pillars, trapped by micropatterned holes in the silicon substrate. The defects are stabilized and positioned by the arrayed air pillars into regular two-dimensional lattices. We explore the effects of hole shape, lattice symmetry, and surface treatment on the resulting lattices of defects and explain their arrangements by application of topological rules. Last, we show the formation of detailed kaleidoscopic textures after the system is cooled down across the nematic-smectic A phase transition, frustrating the defects and surrounding structures with the equal-layer spacing condition of the smectic phase. PMID- 30480094 TI - Ultrathin ZSM-5 zeolite nanosheet laminated membrane for high-flux desalination of concentrated brines. AB - The tremendous potential of zeolite membranes for efficient molecular separation via size-exclusion effects is highly desired by the energy and chemical industries, but its practical realization has been hindered by nonselective permeation through intercrystalline spaces and high resistance to intracrystalline diffusion in the conventional zeolite membranes of randomly oriented polycrystalline structures. Here, we report the synthesis of ZSM-5 zeolite nanosheets with very large aspect ratios and nanometer-scale thickness in the preferred straight channel direction. We used these ZSM-5 nanosheets to fabricate ultrathin (<500 nm) laminated membranes on macroporous alumina substrates by a simple dip-coating process and subsequent consolidation via vapor phase crystallization. This ultrathin b-oriented ZSM-5 membrane has demonstrated extraordinary water flux combined with high salt rejection in pervaporation desalination for brines containing up to 24 weight % of dissolved NaCl. The ZSM-5 nanosheets may also offer opportunities to developing high-performance battery ion separators, catalysts, adsorbents, and thin-film sensors. PMID- 30480096 TI - Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways. AB - Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder caused by loss-of-function mutations in PKD1 or PKD2. Increased glycolysis is a prominent feature of the disease, but how it impacts on other metabolic pathways is unknown. Here, we present an analysis of mouse Pkd1 mutant cells and kidneys to investigate the metabolic reprogramming of this pathology. We show that loss of Pkd1 leads to profound metabolic changes that affect glycolysis, mitochondrial metabolism, and fatty acid synthesis (FAS). We find that Pkd1-mutant cells preferentially use glutamine to fuel the TCA cycle and to sustain FAS. Interfering with either glutamine uptake or FAS retards cell growth and survival. We also find that glutamine is diverted to asparagine via asparagine synthetase (ASNS). Transcriptional profiling of PKD1-mutant human kidneys confirmed these alterations. We find that silencing of Asns is lethal in Pkd1-mutant cells when combined with glucose deprivation, suggesting therapeutic approaches for ADPKD. PMID- 30480095 TI - Superhydrophobic lab-on-chip measures secretome protonation state and provides a personalized risk assessment of sporadic tumour. AB - Secretome of primary cultures is an accessible source of biological markers compared to more complex and less decipherable mixtures such as serum or plasma. The protonation state (PS) of secretome reflects the metabolism of cells and can be used for cancer early detection. Here, we demonstrate a superhydrophobic organic electrochemical device that measures PS in a drop of secretome derived from liquid biopsies. Using data from the sensor and principal component analysis (PCA), we developed algorithms able to efficiently discriminate tumour patients from non-tumour patients. We then validated the results using mass spectrometry and biochemical analysis of samples. For the 36 patients across three independent cohorts, the method identified tumour patients with high sensitivity and identification as high as 100% (no false positives) with declared subjects at risk, for sporadic cancer onset, by intermediate values of PS. This assay could impact on cancer risk management, individual's diagnosis and/or help clarify risk in healthy populations. PMID- 30480098 TI - Mycorrhizal fungi mediate the direction and strength of plant-soil feedbacks differently between arbuscular mycorrhizal and ectomycorrhizal communities. AB - Plants influence their soil environment, which affects the next generation of seedlings that can be established. While research has shown that such plant-soil feedbacks occur in the presence of mycorrhizal fungi, it remains unclear when and how mycorrhizal fungi mediate the direction and strength of feedbacks in tree communities. Here we show that arbuscular mycorrhizal and ectomycorrhizal fungal guilds mediate plant-soil feedbacks differently to influence large-scale patterns such as tree species coexistence and succession. When seedlings are grown under the same mycorrhizal type forest, arbuscular mycorrhizal plant species exhibit negative or neutral feedbacks and ectomycorrhizal plant species do neutral or positive feedbacks. In contrast, positive and neutral feedbacks dominate when seedlings are grown in associations within the same versus different mycorrhizal types. Thus, ectomycorrhizal communities show more positive feedbacks than arbuscular mycorrhizal communities, potentially explaining why most temperate forests are ectomycorrhizal. PMID- 30480097 TI - An improved genome assembly for Larimichthys crocea reveals hepcidin gene expansion with diversified regulation and function. AB - Larimichthys crocea (large yellow croaker) is a type of perciform fish well known for its peculiar physiological properties and economic value. Here, we constructed an improved version of the L. crocea genome assembly, which contained 26,100 protein-coding genes. Twenty-four pseudo-chromosomes of L. crocea were also reconstructed, comprising 90% of the genome assembly. This improved assembly revealed several expansions in gene families associated with olfactory detection, detoxification, and innate immunity. Specifically, six hepcidin genes (LcHamps) were identified in L. crocea, possibly resulting from lineage-specific gene duplication. All LcHamps possessed similar genomic structures and functional domains, but varied substantially with respect to expression pattern, transcriptional regulation, and biological function. LcHamp1 was associated specifically with iron metabolism, while LcHamp2s were functionally diverse, involving in antibacterial activity, antiviral activity, and regulation of intracellular iron metabolism. This functional diversity among gene copies may have allowed L. crocea to adapt to diverse environmental conditions. PMID- 30480099 TI - In vivo multiphoton microscopy detects longitudinal metabolic changes associated with delayed skin wound healing. AB - Chronic wounds are difficult to diagnose and characterize due to a lack of quantitative biomarkers. Label-free multiphoton microscopy has emerged as a useful imaging modality capable of quantifying changes in cellular metabolism using an optical redox ratio of FAD/(NADH+FAD) autofluorescence. However, the utility of an optical redox ratio for long-term in vivo monitoring of tissue metabolism has not been robustly evaluated. In this study, we demonstrate how multiphoton microscopy can be used to monitor changes in the metabolism of individual full-thickness skin wounds in vivo. 3D optical redox ratio maps and NADH fluorescence lifetime images identify differences between diabetic and control mice during the re-epithelialization of wounds. These metabolic changes are associated with a transient increase in keratinocyte proliferation at the wound edge. Our study demonstrates that high-resolution, non-invasive autofluorescence imaging can be performed in vivo and that optical redox ratios can serve as quantitative optical biomarkers of impaired wound healing. PMID- 30480100 TI - Big bottlenecks in cardiovascular tissue engineering. AB - Although tissue engineering using human-induced pluripotent stem cells is a promising approach for treatment of cardiovascular diseases, some limiting factors include the survival, electrical integration, maturity, scalability, and immune response of three-dimensional (3D) engineered tissues. Here we discuss these important roadblocks facing the tissue engineering field and suggest potential approaches to overcome these challenges. PMID- 30480102 TI - Slow recovery from a disease epidemic in the spotted hyena, a keystone social carnivore. AB - Predicting the impact of disease epidemics on wildlife populations is one of the twenty-first century's main conservation challenges. The long-term demographic responses of wildlife populations to epidemics and the life history and social traits modulating these responses are generally unknown, particularly for K selected social species. Here we develop a stage-structured matrix population model to provide a long-term projection of demographic responses by a keystone social predator, the spotted hyena, to a virulent epidemic of canine distemper virus (CDV) in the Serengeti ecosystem in 1993/1994 and predict the recovery time for the population following the epidemic. Using two decades of longitudinal data from 625 known hyenas, we demonstrate that although the reduction in population size was moderate, i.e., the population showed high ecological 'resistance' to the novel CDV genotype present, recovery was slow. Interestingly, high-ranking females accelerated the population's recovery, thereby lessening the impact of the epidemic on the population. PMID- 30480101 TI - Neuronal coding of multiscale temporal features in communication sequences within the bat auditory cortex. AB - Experimental evidence supports that cortical oscillations represent multiscale temporal modulations existent in natural stimuli, yet little is known about the processing of these multiple timescales at a neuronal level. Here, using extracellular recordings from the auditory cortex (AC) of awake bats (Carollia perspicillata), we show the existence of three neuronal types which represent different levels of the temporal structure of conspecific vocalizations, and therefore constitute direct evidence of multiscale temporal processing of naturalistic stimuli by neurons in the AC. These neuronal subpopulations synchronize differently to local-field potentials, particularly in theta- and high frequency bands, and are informative to a different degree in terms of their spike rate. Interestingly, we also observed that both low and high frequency cortical oscillations can be highly informative about the listened calls. Our results suggest that multiscale neuronal processing allows for the precise and non-redundant representation of natural vocalizations in the AC. PMID- 30480103 TI - A high therapeutic efficacy of polymeric prodrug nano-assembly for a combination of photodynamic therapy and chemotherapy. AB - Combination of photodynamic therapy and chemotherapy has been emerging as a new strategy for cancer treatment. Conventional photosensitizer tends to aggregate in aqueous media, which causes fluorescence quenching, reduces reactive oxygen species (ROS) production, and limits its clinical application to photodynamic therapy. Traditional nanoparticle drug delivery system for chemotherapy also has its disadvantages, such as low drug loading content, drug leakage, and off-target toxicity for normal tissues. Here, we developed a reduction-sensitive co-delivery micelles TB@PMP for combinational therapy, which composed of entrapping a red aggregation-induced emission fluorogen (AIEgen) for photodynamic therapy and PMP that contains a reduction-sensitive paclitaxel polymeric prodrug for chemotherapy. AIEgen photosensitizer illustrates a much improved photostability and ROS production efficiency in aggregate state and PMP loads a high dose of paclitaxel and carries a smart stimuli-triggered drug release property. This co delivery system provides a better option that replaces AIEgen photosensitizer for cancer diagnosis and therapy. PMID- 30480105 TI - Welcome to Innovation in Aging. PMID- 30480104 TI - Cooperative interaction among BMAL1, HSF1, and p53 protects mammalian cells from UV stress. AB - The circadian clock allows physiological systems to adapt to their changing environment by synchronizing their timings in response to external stimuli. Previously, we reported clock-controlled adaptive responses to heat-shock and oxidative stress and showed how the circadian clock interacts with BMAL1 and HSF1. Here, we present a similar clock-controlled adaptation to UV damage. In response to UV irradiation, HSF1 and tumor suppressor p53 regulate the expression of the clock gene Per2 in a time-dependent manner. UV irradiation first activates the HSF1 pathway, which subsequently activates the p53 pathway. Importantly, BMAL1 regulates both HSF1 and p53 through the BMAL1-HSF1 interaction to synchronize the cellular clock. Based on these findings and transcriptome analysis, we propose that the circadian clock protects cells against the UV stress through sequential and hierarchical interactions between the circadian clock, the heat shock response, and a tumor suppressive mechanism. PMID- 30480106 TI - Association of Hospital Admission Risk Profile Score with Mortality in Hospitalized Older Adults. AB - Objectives: To evaluate the association of the Hospital Admission Risk Profile (HARP) score with mortality after discharge in a population of hospitalized older adults. Design: Retrospective cohort study. Participants: Hospitalized patients aged 70 years or older. Measurements: Patient age at the time of admission, modified Folstein Mini-Mental Status Exam score, and self-reported instrumental activities of daily living 2 weeks prior to admission were used to calculate a HARP score. The primary outcome assessed was overall mortality up to 365 days after hospital discharge. Cox proportional hazard analyses evaluated the association between HARP score and mortality adjusting for age, sex, and comorbidities associated with increased mortality. Results: Of the 474 patients, 165 (34.8%) had a low HARP score, 177 (37.4%) had an intermediate, and 132 (27.8%) had a high score. HARP score was not associated with differences in 30 day readmission rates. High HARP score patients had higher mortality when compared to patients with low HARP scores at all time frames (30 days: 12.9% vs 1.8%, p < .05; 90 days: 19.7% vs 4.8%, p < .05; 365 days: 34.8% vs 16.9%, p < .05). In fully adjusted Cox proportional models, patients with high HARP scores had a 3.5 times higher odds of mortality when compared to low HARP score patients. Conclusion: The HARP score is a simple and easy to use instrument that identifies patients at increased risk for mortality after hospital discharge. Early identification of patients at increased risk for mortality has the potential to help guide treatment decisions following hospital discharge and provides additional information to providers and patients for shared decision making and may help in clarifying and achieving patient and family goals of care. PMID- 30480107 TI - Body Composition and Physical Function in Older Adults with Various Comorbidities. AB - Background: Lower muscle and higher fat mass are characteristics of older adults; their physical function is also characterized by slower gait speed and weaker strength. However, the association between specific body composition and physical function is unclear. Methods: We examined the association between body composition and physical performance using combined cross-sectional data of 1,821 participants from 13 clinical studies at Wake Forest University that used a consistent battery of tests. All participants were >=60 years old and had one of the following conditions: healthy, osteoarthritis, coronary artery disease, obesity, heart failure, at elevated risk for disability, renal transplantation candidates, heart failure with preserved ejection fraction, moderate self reported disability, hypertension, diabetes, or coronary artery disease, at high risk for cardiovascular disease. Data at enrollment from each study using uniform tools including body mass index (BMI), dual energy x-ray absorptiometry, physical performance assessment using 4 m walk speed, five chair rise time, handgrip strength, short physical performance battery (17), and Pepper Assessment Tool for Disability were analyzed. Results: Increased BMI was associated with slower walk speed, lower short physical performance battery, and higher Pepper Assessment Tool for Disability score. Increased percentage of body fat was associated with slower walk speed, lower hand grip strength, lower short physical performance battery scores, and higher Pepper Assessment Tool for Disability scores. Percent appendicular lean mass was associated with faster walk speed, higher handgrip strength, higher short physical performance battery, and lower Pepper Assessment Tool for Disability score. There were no significant discrepancies in relationship between body composition and physical function by gender except gender and BMI on chair-rise time. Conclusions: Higher BMI and percent body fat were associated with poor physical function while percent appendicular lean mass was associated with better physical function. There was no significant discrepancy in the by gender. PMID- 30480108 TI - "When I Said I Wanted to Die at Home I Didn't Mean a Nursing Home": Care Trajectories at the End of Life. AB - Background and Objectives: Little is known regarding the care trajectories older adults experience at the end of life (EOL). We drew on a structural/institutional life course perspective to examine the trajectories evident among older adults transitioning through the Canadian formal long-term care system. The sequence of care transitions as well as the impact of social location, social and economic resources, and health-related factors on these trajectories were examined. Research Design and Methods: To identify EOL care trajectories, we used administrative data collected on older adults (aged 65+) who received publicly subsidized long-term care services (e.g., nursing home and home and community based care) in one health region in British Columbia, Canada from January 1, 2008 through December 31, 2011 and who died by March 31, 2012 (n = 11,816). Multinomial logistic regression analyses assessed the impact of selected covariates on these trajectories. Results: The majority of those studied (65.4%) died outside of acute hospital settings. The most common trajectories involved transitions from home care to nursing home/residential care to non-hospital death (39.5%) and transitions from in-home care to hospital death (22.4%). These and other trajectories were shaped by social structural factors, access to social and economic resources, as well as health status and prior hospitalizations. Discussion and Implications: Despite calls for minimizing hospital-based deaths and maximizing home-based deaths, older LTC recipients often experience EOL care trajectories that end in death in a nursing home care setting. Our findings point to the value of a structural/institutional life course perspective in informing an understanding of who experiences this and other major EOL care trajectories. In doing so, they also provide direction for policy and practice designed to address inequalities and enhance the quality of EOL care. PMID- 30480109 TI - Advance Care Planning: Contemporary Issues and Future Directions. AB - Advance care planning (ACP) is widely considered an essential step toward achieving end-of-life care that is consistent with the preferences of dying patients and their families. ACP comprises a living will and a durable power of attorney for health care (DPAHC); these tools enable patients to articulate and convey their treatment preferences when they are still cognitively intact. In this article, we describe the strengths, weaknesses, and correlates of ACP in the United States, with attention to race and socioeconomic disparities therein. We then discuss other public policies and community programs designed to increase both the number of older adults who articulate their preferences for end-of-life care, and efficacy of ACP for ensuring that patients' end-of-life treatment preferences are met. We describe the characteristics, strengths, and limitations of Physician Orders for Life Sustaining Treatment (POLSTs), and describe community programs, educational interventions, and public policies aimed toward increasing the prevalence and efficacy of end-of-life preparations. A key policy advance in the early 2010s has been Medicare coverage of one doctor-patient consultation session regarding end-of-life issues; we highlight the potentials and possible pitfalls of this policy. We conclude by identifying areas for future research, and highlighting practices from other nations that may help improve quality of end-of-life care in the United States. PMID- 30480110 TI - The Role of Social Support in Elder Financial Exploitation Using a Community Sample. AB - Background and Objective: Social support is known to be an important protective factor against elder financial exploitation (FE), yet few empirical studies have examined the relationship between FE and distinct components of social support. Perceived social support, social network size, and interactions with close network members (positive and negative) were measured separately and tested as potential predictors of FE. Research Design and Methods: Three hundred and ninety five community-dwelling adults aged 60 and older were recruited to complete a 90 minute survey and interview. We used OLS regression to examine the role of social support in FE. Other risk factors associated with FE including dependency, poor physical health, depression, cognition, and demographic characteristics were included as potential predictors. Results: Negative interactions with close network members predicted FE, and remained predictive when all other variables and social support factors were included in the model. Other social support factors were not unique predictors of FE. Discussion and Implications: Negative social interactions with close network members are important to assess and consider in FE prevention and intervention programs; relationships between social interactions and other risk factors warrant further attention. PMID- 30480111 TI - A Question of Trust: Does Mistrust or Perceived Discrimination Account for Race Disparities in Advance Directive Completion? AB - Background and Objectives: Advance directive completion is associated with end-of life quality indicators such as dying at home and receiving hospice care. Black older adults are less likely to complete advance directives than their white counterparts. The underlying reasons for these race disparities are not well understood. Research Design and Methods: In two related studies, data from the Health and Retirement Study were used to examine whether mistrust in health care providers and/or perceived discrimination accounted for lower rates of advance directive completion by black older adults in the United States. Odds of advance directive completion were modeled using logistic regression and multiple measures of trust in health care providers and both medical and nonmedical perceived discriminatory treatment. Results: In Study 1 (n = 699), controlling for medical mistrust did not reduce the gap between black and white participants' odds of possessing advance directives. In Study 2 (n = 2,736), higher percentages of black participants reported experiencing medical and nonmedical discriminatory treatment. However, none of the measures of discrimination accounted for black participants' lower odds of possessing advance directives. Discussion and Implications: These results call into question the common assertion that mistrust in medical providers or the health care system contributes to lower rates of advance care planning by black older adults. Future research should examine the potential relationships between advance directive completion and other dimensions of discrimination. PMID- 30480112 TI - Conceptualizing Productive Engagement in a System Dynamics Framework. AB - Gerontologists have argued that the growing human capital of the aging population can be better marshaled as a resource for families, communities, and society at large. Additionally, this active, purposeful engagement can produce positive outcomes for older adults themselves. In this manuscript, we propose that existing conceptual frameworks articulating antecedents and outcomes of productive engagement, including working, volunteering, and caregiving can be improved using a system dynamics (SD) approach. Through a series of five unstructured group model-building sessions, experts from gerontology and systems science developed a qualitative SD model of the productive engagement of older adults. The model illustrates the reciprocal and dynamic nature of the stocks of human capital of older adults, social capital of older adults, and family resources; the engagement of older adults in productive activities; and the social and organizational variables that affect the flow and depletion of these stocks. Given this is the first attempt to develop a SD model for productive engagement in later life, the model is preliminary and heuristic. However, it offers a new approach to advancing theory and research on productive engagement in later life. Further, it can guide the development of mathematical models to estimate the effects of changes in any part of this system. PMID- 30480113 TI - Some Things I Have Learned About Aging by Studying the Life Course. AB - "Aging" and the "life course" are distinct but complementary phenomena that inform one another. Building on this insight, this essay conveys some lessons the author has learned about aging by studying the life course. These include that (1) age is a salient dimension of individual identity and social organization; (2) a reconfigured life course brings reconfigured aging; (3) old age is a highly precarious phase of life; (4) difference and inequality are not the same, but both can accumulate over time; (5) aging is gendered; (6) aging is interpersonal, and "independence" is an illusion; (7) "choice" and "responsibility" can be dirty words; (8) much of aging is in the mind-it is imagined and anticipated; and (9) history leaves its footprints on aging, and the future of aging is already here. These lessons culminate in a final insight: that to understand personal aging, gerontologists must look beyond the personal, for much of the relevant action is to be found in social experience. PMID- 30480114 TI - Marriage, Cohabitation, and Divorce in Later Life. AB - Older adults are at the forefront of family change as a declining share experiences lifelong marriage and rates of cohabitation and divorce in later life continue to rise. The goal of this article is to review recent scholarship on marriage, cohabitation, and divorce among older adults and identify directions for future research. The varied family experiences characterizing the later life course demonstrate the importance of moving beyond marital status to capture additional dimensions of the marital biography, including transitions, timing, duration, and sequencing. Cohabitation operates as an alternative to marriage for older adults and is increasingly replacing remarriage following divorce or widowhood. The gray divorce rate has doubled in recent decades as older adults abandon marriage in favor of unmarried partnerships or singlehood. The retreat from marriage among older adults raises important questions about the ramifications of family change for health and well-being as well as access to caregivers given that spouses historically have been the primary source of care. PMID- 30480115 TI - Aging and Disability Among Hispanics in the United States: Current Knowledge and Future Directions. AB - Background and Objectives: Hispanics are the most rapidly aging minority population in the United States. Our objective is to provide a summary of current knowledge regarding disability among Hispanics, and to propose an agenda for future research. Research Design and Methods: A literature review was conducted to identify major areas of research. A life course perspective and the Hispanic Paradox were used as frameworks for the literature review and for identifying future areas of research. Results: Four research areas were identified: (1) Ethnic disparities in disability; (2) Heterogeneity of the U.S. older Hispanic population; (3) Risk factors for disability; and (4) Disabled life expectancy. Older Hispanics are more likely than non-Hispanic whites to be disabled or to become disabled. Disability varied by country of origin, nativity, age of migration, and duration in the United States. Important risk factors for disability included chronic health conditions, depression, and cognitive impairment. Protective factors included positive affect and physical activity. Older Hispanics have longer life expectancy than non-Hispanic whites but spend a greater proportion of old age disabled. Future research should continue to monitor trends in disability as younger generations of Hispanics reach old age. Attention needs to be given to regional variation within the United States for disability prevalence, early-life risk factors, and factors that may contribute to variation in disabled life expectancy. There is also an urgent need for interventions that can effectively prevent or delay the onset of disability in older Hispanics. Discussion and Implications: Considerable research has examined disability among older Hispanics, but continued research is needed. It is important that research findings be used to inform public policies that can address the burden of disability for older Hispanic populations. PMID- 30480116 TI - Innovative Models for High-Risk Patients Use Care Coordination and Palliative Supports to Reduce End-of-life Utilization and Spending. AB - Background and Objectives: Care coordination and palliative care supports are associated with reduced anxiety, fewer hospital admissions, and improved quality of life for patients and their families. Early palliative care can result in savings in the end-of-life period, but there is limited evidence that larger scale models can improve both utilization and the cost of care. Three models that received Health Care Innovation Awards from the Centers for Medicare & Medicaid Services aimed to improve quality of care and reduce cost through the use of innovative care coordination models. This study explores the total cost of care and selected utilization outcomes at the end-of-life for these innovative models, each of which enrolled adults with multiple chronic conditions and featured care coordination with advance care planning as a component of palliative care. These included a comprehensive at-home supportive care model for persons predicted to die within a year and two models offering advance care planning in nursing facilities and during care transitions. Research Design and Methods: We used regression models to assess model impacts on costs and utilization for high-risk Medicare beneficiaries participating in the comprehensive supportive care model (N = 3,339) and the two care transition models (N = 587 and N = 277) who died during the study period (2013-2016), relative to a set of matched comparison patients. Results: Comparing participants in each model who died during the study period to matched comparators, two of the three models were associated with significantly lower costs in the last 90 days of life ($2,122 and $4,606 per person), and the third model showed nonsignificant differences. Two of the three models encouraged early hospice entry in the last 30 days of life. For the comprehensive at-home supportive care model, we observed aggregate savings of nearly $19 million over the study period. One care transition model showed aggregate savings of over $500,000 during the same period. Potential drivers of these cost savings include improved patient safety, timeliness of care, and caregiver support. Discussion and Implications: Two of the three models achieved significant lower Medicare costs than a comparison group and the same two models also sustained their models beyond the Centers for Medicare & Medicaid Services award period. These findings show promise for achieving palliative care goals as part of care coordination innovation. PMID- 30480117 TI - Onset of Multiple Chronic Conditions and Depressive Symptoms: A Life Events Perspective. AB - Background: While the association between depressive symptoms and chronic illness has been the subject of many studies, little is known about whether depressive symptoms differ as a function of the illnesses people have as they transition to living with multiple chronic conditions. Methods: Self-reports of five diagnosed chronic conditions (arthritis, diabetes, heart disease, hypertension, and pulmonary disease) and depressive symptoms were provided by 3,396 people participating in three waves of the ORANJ BOWLSM research panel. Longitudinal multilevel modeling was used to examine the effects that transitioning to having a diagnosis of multiple chronic conditions has on depressive symptoms. Results: Between 2006 and 2014, controlling for age, gender, income, race, and a lifetime diagnosis of depression, people who transitioned to having a diagnosis of multiple chronic conditions had significantly higher levels of depressive symptoms than people who did not make this transition. The diagnosis of arthritis, diabetes, heart disease, and pulmonary disease, but not hypertension had independent effects, increasing depressive symptoms. Conclusions: Having a diagnosis of multiple chronic conditions leads to increases in depressive symptoms, but not all illnesses have the same effect. Findings highlight the need for clinicians to be aware of mental health risks in patients diagnosed with multiple chronic conditions, particularly those with a diagnosis of arthritis, diabetes, heart disease, and pulmonary disease. Clinical care providers should take account of these findings, encouraging psychosocial supports for older adults who develop multiple chronic conditions to minimize the negative psychological impact of illness diagnosis. PMID- 30480118 TI - Grandparenting in the United States. AB - Grandparenting varies enormously in the United States and here we discuss that growing diversity. Relying on exchange and reciprocity, feminist, and political economic theoretical perspectives, we begin by exploring the increasing need for grandchild care and assistance in the United States and the dearth of federal and employer supports for working families. Assessing the impact of sociodemographic trends, notably the rise in single parenting and the increase in employment among grandparents, we assess the intensification of grandparenting. Then we turn to issues related to proximity, examining the pleasures and challenges of coresidential, custodial, long distance, and transnational grandparenting. Finally, we turn to the impact of grandparenting on the emotional, physical, and financial wellbeing of grandparents. PMID- 30480119 TI - Does Comprehensive Culture Change Adoption via the Household Model Enhance Nursing Home Residents' Psychosocial Well-being? AB - Background and Objectives: Several studies suggest that to substantially improve residents' psychosocial well-being, traditional-model nursing homes should redesign themselves as small, homelike "households" along with comprehensively adopting other aspects of "culture change," a set of reforms meant to improve residents' quality of life. But this evidence mainly comes from qualitative studies. This comparative, observational study tested quantitatively whether residents in a household-model nursing home that had comprehensively adopted culture change reforms displayed greater positive affect, increased cognitive engagement, more extensive social interactions with staff and greater use of the environment than did residents at partial culture-change-adopting facilities with traditional, institutional environments. Research Design and Methods: Household model residents were matched on clinical and demographic factors with residents at two institutional control facilities that had partially adopted culture change and were observed for 8 hours each. To provide potentially converging evidence, aides and nurses were also observed. Finally, a culture change implementation assessment was conducted. Results: The implementation assessment showed that the household-model home had implemented culture change beyond national norms, whereas the control facilities were U.S.-typical partial adopters. It also revealed that household-model staff cared for residents in a more person-centered manner. Observation analyses revealed that household-model residents spent less time idle and less time stationary at wheelchair hubs. Moreover, although household-model residents did not spend the most time in the dining area overall, they spent the greatest percentage of time there talking with staff, displaying positive affect, and displaying active engagement. Finally, household-model residents and staff spent the most time in task-oriented interactions, including personal care. Discussion and Implications: These results suggest that the intended psychosocial benefits materialize in household-model facilities, particularly in the dining area and in resident-staff relationships. The findings raise the possibility that facilities may be able to achieve these outcomes without entirely redesigning their environment. PMID- 30480120 TI - Precarity, Inequality, and the Problem of Agency in the Study of the Life Course. AB - Although long neglected, the themes of inequality and the differentiating consequences of structurally organized constraints and opportunities for individuals have recently become a major theme of scholars in aging and life course studies. Beyond the evidence of intracohort patterns of cumulative dis/advantage in health and resources, recent societal trends of increasing inequality have added another dimension of theoretical interest and practical urgency to these concerns. These trends have been noteworthy both for the dramatic increase and for their planetary breadth, affecting Asia and Europe as well as America. Both researchers and popular writers have observed the growing importance of the precariat, an emerging subpopulation with tenuous connection to the primary economy encompasses individuals of every age. At the same time, individual agency and related concepts such as "choice" and "decision-making" continue regularly to appear as featured terms in studies of life course and related fields. Such concepts accord a strong explanatory force to the individual, and continue to be widely accepted as unproblematic and legitimate. This article examines the relevance of these two domains of life-course scholarship in analyzing an urgent contemporary problem-struggles associated with the "transition to adulthood" and the situation of young adults. Young people confronting this transition have been the focus of both the celebration of agency and of the growing attention on inequality and adversity and its effects on vulnerable periods and key transitions in the life course. Their situation provides an opportunity to resolve some of the tensions between perspectives that emphasize agency and those that emphasize inequality. PMID- 30480121 TI - Preventing Late-Life Depression: Lessons in Intervention Development From Goa, India. AB - We describe the development of an intervention strategy for the indicated prevention of depression in older adults living in Goa, India. Of particular novelty, the intervention is deliverable by lay health counselors and is grounded in problem solving therapy for primary care and brief behavioral treatment for insomnia. We have named the intervention "DIL" (the Hindi word for "heart" and an acronym for "depression in late life.") Additional DIL strategies include psychoeducation in self-management of co-occurring medical disorders such as diabetes mellitus, together with assistance in navigation to needed social and economic resources. We present the results of a preliminary open-trial case series involving 21 participants with subsyndromal symptoms of depression, demonstrating feasibility, acceptability, and benefit to participants. We then present the design of a larger confirmatory trial into which 181 participants have been enrolled. "DIL" is a novel and large depression prevention trial conducted with lay health counselors in a low-resource country. Its results are likely to have implications for depression prevention in older adults in other low- and middle-income countries and to inform contemporary models of the staging of depressive illness in later life. PMID- 30480122 TI - Arab American Cognitive Aging: Opportunities for Advancing Research on Alzheimer's Disease Disparities. AB - Background and Objectives: This article highlights the dearth of and need for research on Arab American cognitive aging. We propose that studying cognitive health issues among older Arab Americans provides an innovative opportunity to advance knowledge about causes and consequences of Alzheimer's disease (AD) disparities and refine understanding of factors linked to immigrant health in the United States. Research Design and Methods: Demographic information is provided on Arab Americans, who are on the cusp of being recognized by the U.S. government as a distinct ethnic group separate from whites. In the tradition of minority aging, we present a broad review of specific issues in the contemporary case of Arab Americans. Results: We detail how including Arab Americans provides unique information on the importance of: (i) extending racial/ethnic group comparisons; (ii) linking social experiences to late-life cognitive health; and (iii) incorporating ethnic factors related to immigration and religion in the study of AD disparities. Discussion and Implications: Studying Arab American cognitive aging provides an innovative opportunity to more fully delineate factors that create and sustain health disparities, with special insights into both causes and consequences. PMID- 30480124 TI - Program Abstracts from the 21st International Association of Gerontology and Geriatrics (IAGG) World Congress. PMID- 30480125 TI - Index of Participants. PMID- 30480123 TI - Age of Migration and the Incidence of Cognitive Impairment: A Cohort Study of Elder Mexican-Americans. AB - Background and Objectives: To explore nativity and age of migration differentials in the incidence of cognitive impairment among older Mexican-Americans. Research Design and Methods: We employ maximum-likelihood discrete time hazard models to estimate risk ratios of cognitive impairment in a sample of 2,708 Mexican Americans 65 and older who were cognitively healthy at baseline over a follow-up period of up to 20 years. Results: Late-life immigrant women have a 46% higher risk of cognitive impairment compared to U.S.-born Mexican-American women. Conversely, midlife immigrant men have a 29% lower risk of cognitive impairment compared to U.S.-born Mexican-American men. The incidence of cognitive impairment did not differ for early-life and midlife immigrant women relative to U.S.-born women or for early- and late-life immigrant men compared to U.S.-born men. Discussion and Implications: Differences in cognitive impairment risk between U.S.-born and foreign-born Mexican-American subgroups may be partly due to health selectivity. Cognitive impairment is more prevalent among immigrant groups which may result in a higher burden on family members and/or high dependency on public resources. Programs are needed that can detect decline at earlier stages and reduce the risk for cognitive impairment among older immigrants entering their last decades of life. PMID- 30480126 TI - Cross-national Differences in Intergenerational Family Relations: The Influence of Public Policy Arrangements. AB - Focusing mostly on Europe, this overview reveals how the research on cross national differences in intergenerational family relations has moved from basic descriptions to a focus on understanding how support exchanges are shaped by macro-level processes. A key issue concerns generational interdependence, the extent to which public policy arrangements impose reliance on older and younger family members or enable individual autonomy. Real theoretical progress is visible in three areas of research. The first pertains to analyses at the micro level of how family members actually respond to the incentives that different macro contexts provide. The generosity or restrictedness of public provisions variably releases or necessitates normative obligations in interdependent family relationships. The second area of progress involves analyses of the implications of specific policies rather than policy packages for gender and socioeconomic inequality. The third area of progress is a more nuanced view on the familialism individualism divide. These three areas provide inspiring examples for future investigations. PMID- 30480127 TI - Translating Basic Research on the Aging Family to Caregiving Intervention: The Case of Within-Family Differences. AB - Since its inception, the field of gerontology has sought to establish optimal connections between the scientific activities of researchers and the real-world concerns of practitioners and clinicians. The concept of translational research has emerged in recent years as a model for bridging the gap between science and service. This article provides an example of how basic research findings can be translated to provide guidance for intervention in the area of family caregiving. We review findings from an innovative program of research on within-family differences, which extends theory and research from the developmental psychological study of children to the family in later life. The within-family difference perspective focuses on how the individual parent-child dyads in a particular family differ from and are affected by other dyads. Basic research on this topic has revealed the extent of parental favoritism in later life, factors related to parental differential treatment of offspring, and the consequences of such favoritism and treatment on sibling relationship quality and psychological well-being. Four examples are provided of ways in which attention to within family differences research could enhance caregiving interventions. PMID- 30480128 TI - Nonpharmacological Management of Behavioral and Psychological Symptoms of Dementia: What Works, in What Circumstances, and Why? AB - Objective: Behavioral and psychological symptoms of dementia (BPSD) refer to the often distressing, noncognitive symptoms of dementia. BPSD appear in up to 90% of persons with dementia and can cause serious complications. Reducing the use of antipsychotic medications to treat BPSD is an international priority. This review addresses the following questions: What nonpharmacological interventions work to manage BPSD? And, in what circumstances do they work and why? Method: A realist review was conducted to identify and explain the interactions among context, mechanism, and outcome. We searched electronic databases for empirical studies that reported a formal evaluation of nonpharmacological interventions to decrease BPSD. Results: Seventy-four articles met the inclusion criteria. Three mechanisms emerged as necessary for sustained effective outcomes: the caring environment, care skill development and maintenance, and individualization of care. We offer hypotheses about how different contexts account for the success, failure, or partial success of these mechanisms within the interventions. Discussion: Nonpharmacological interventions for BPSD should include consideration of both the physical and the social environment, ongoing education/training and support for care providers, and individualized approaches that promote self-determination and continued opportunities for meaning and purpose for persons with dementia. PMID- 30480129 TI - Factors Predicting Decisions About Technology Adoption Among Older Adults. AB - Background and Objectives: Numerous technology applications are available that have the potential to improve the quality of life (QoL) of older adults. However, older adults are less likely to adopt new and emerging technologies and reap the potential benefits. This study examines factors that influence older adults' decisions about the adoption of new technology. Research Design and Methods: Fifty-two older adults participated in a mixed-method procedure, which entailed: (1) observing presentations detailing nine differing technologies, (2) assessing the technologies using tailored questionnaires, and (3) participating in focus group discussions. Participants were assigned into one of seven groups separated by age (65-74, 75+) and language (English, Spanish). The outcome was willingness to adopt technology. Predictors included self-assessed abilities (e.g., numeric ability), computer/Internet skills and knowledge, technology readiness, age, language, and technology ratings (e.g., perceived value). Analyses included Spearman's rho, t-tests, and regression analysis. Focus group discussions were examined for supportive examples. Results: Self-assessed abilities and computer/Internet skills were predictive of willingness to adopt technologies although the relationship varied according to the technology examined. Technology readiness, age, and language group showed weak associations with the outcome. Of the technology ratings, perceived value, confidence in ability to learn the technology, and the perceived impact on QoL were the most robust predictors of willingness to adopt technology. Discussion and Implications: Findings indicate that various stakeholders in technology adoption among older adults must be cognizant of a technology's functionality and complexity as well as the characteristics and abilities of older adults. However, certain factors such as perceptions about the value of the technology and potential impact on QoL are also critically important to decisions regarding technology adoption among older people. PMID- 30480132 TI - Closing the Capacity-Ability Gap: Using Technology to Support Aging With Disability. AB - There is a critical need to develop supports for older adults who have a wide range of abilities, including those aging with long-term impairments. Without appropriate support, many individuals will be functioning below optimal levels and will face participation barriers. Technology holds great promise to provide individualized support for a wide range of abilities and for a variety of domains. To ensure technology interventions are designed well and meet research documented user requirements, we need more specific, actionable models to provide guidance for those developing and designing interventions. In this paper, we present the TechSAge Aging and Disability Model to bridge models from the aging and disability literatures and to disambiguate the population of individuals aging into disability from those aging with disability (i.e., pre-existing impairments). We also present the TechSAge Technology Intervention Model to support aging with pre-existing impairments, which provides direction and touch points for technology interventions. These models reflect the complex and dynamic interaction between age-related changes and an individual's prior capabilities and limitations. We describe the need for these models with respect to filling a gap in the disability and aging literature by highlighting the importance of differentiating between age-related changes and long-term impairments when designing interventions. We also show the need for quantitative and qualitative data to refine the models given complexities of the current state of the literature and survey data. The TechSAge Technology Intervention Model can be used to drive and inform technology redesign and development. PMID- 30480131 TI - Bridging the Gap After Physical Therapy: Clinical-Community Linkages With Older Adult Physical Activity Programs. AB - Background and Objectives: Many barriers exist to older adult participation in physical activity, despite known benefits. Referrals from physical therapists (PTs) through clinical-community linkages offer novel, promising opportunities to increase older adult engagement in appropriate community-based physical activity programs. We assessed the capacity of PTs to participate in such linkages. Research Design and Methods: We collected qualitative data using semistructured phone interviews (n = 30) with PTs across 14 states. We conducted thematic analysis using a priori themes based on the 2008 Bridging Model of Etz and colleagues: capacity to assess patient risk, ability to provide brief counseling, capacity and ability to refer, and awareness of community resources. Results: Risk assessment and counseling were already part of routine practice for our respondents, but counseling could be further facilitated if PTs had more skills to engage less-motivated patients. PTs expressed a desire to refer their patients to community programs; however, barriers to referrals included lack of knowledge of and trust in community programs, and limited infrastructure for communicating with potential partners. Discussion and Implications: PTs have the capacity to develop patient referral linkages with community-based physical activity programs. PT session length and content facilitates patient risk assessment and behavioral counseling. Integrating motivational techniques can help PTs engage less-motivated patients in physical activity. Systemic improvements should include innovations in communication infrastructure, identifying clinic-level champions, and in-person outreach initiated by organizations that deliver community physical activity programs. PMID- 30480133 TI - Exploring Older Adults' Video Game Use in the PRISM Computer System. AB - Background and Objective: As part of the PRISM (Personal Reminder Information & Social Management) randomized field trial, a large group of older adults (N = 150) received a computer system in their home that presented them with the opportunity to play eleven different video games. While researchers have often assessed older adults' gaming preferences and habits through survey data and focus groups, this trial represented a unique opportunity to study gaming behavior "in the wild" over an entire year. Research Design and Methods: We present an exploration of game usage data, individual differences in game preferences and gaming habits, and individual difference predictors of game use. Results: Although few individual difference variables consistently predicted game use and preferences, there were clear favorites among the different games, and results demonstrate that given the opportunity and training many older adults may become active and long-term gamers. Discussion and Implications: Findings have implications for designing video games that older adults enjoy, supporting enjoyable and meaningful interactions with video games across the life span, and for designing cognitive, social, and health interventions involving games. PMID- 30480134 TI - Validity and Reliability of the Major Depression Inventory for Persons With Dual Sensory Loss. AB - Background and Objectives: Research has shown that dual sensory loss is a risk factor for depression in older adults. However, validated measures of depression for people with dual sensory loss are lacking. The purpose of the present study was to investigate the construct validity and reliability of the Major Depression Inventory for use among elderly persons with acquired dual sensory loss. Research Design and Methods: A cross-sectional questionnaire survey was conducted in a national sample of people >=50 years of age with functional acquired dual sensory loss. Of the invited participants, 302 (66%) returned the questionnaire and 207 complete cases were included for analysis. Rasch models and graphical log-linear Rasch models were used for item analysis. Lack of differential item functioning was tested relative to severity of vision and hearing impairment, mode of questionnaire completion, age, sex, comorbidity, instrumental activities of daily living, social position, and cohabitation status. Results: The 10-item Major Depression Inventory did not fit the Rasch model. An 8-item version, excluding the items "feeling sad" and "sleep problems," fit a graphical log-linear Rasch model. No evidence of differential item functioning was discovered, thus the 8 item Major Depression Inventory was measurement invariant across severity of impairments and mode of completing the questionnaire. The overall reliability was 0.81 and ranged from acceptable to good for all subgroups of participants, except males with severe hearing impairment and low functional status. Consequently, the 8-item version of the Major Depression Inventory was considered construct valid and reliable within the frame of reference. Discussion and Implications: An 8 item version of the Major Depression Inventory can be used to screen for depressive symptoms in elderly persons with acquired dual sensory loss. PMID- 30480135 TI - Mobility and Vitality Lifestyle Program (MOVE UP): A Community Health Worker Intervention for Older Adults With Obesity to Improve Weight, Health, and Physical Function. AB - Background and Objectives: Obesity rates in adults >=65 years have increased more than other age groups in the last decade, elevating risk for chronic disease and poor physical function, particularly in underserved racial and ethnic minorities. Effective, sustainable lifestyle interventions are needed to help community-based older adults prevent or delay mobility disability. Design, baseline recruitment, and implementation features of the Mobility and Vitality Lifestyle Program (MOVE UP) study are reported. Research Design and Methods: MOVE UP aimed to recruit 26 intervention sites in underserved areas around Allegheny County, Pennsylvania and train a similar number of community health workers to deliver a manualized intervention to groups of approximately 12 participants in each location. We adapted a 13-month healthy aging/weight management intervention aligned with several evidence-based lifestyle modification programs. A nonrandomized, pre-post design was used to measure intervention impact on physical function performance, the primary study endpoint. Secondary outcomes included weight, self-reported physical activity and dietary changes, exercise self-efficacy, health status, health-related quality of life, and accelerometry in a subsample. Results: Of 58 community-based organizations approached, nearly half engaged with MOVE UP. Facilities included neighborhood community centers (25%), YMCAs (25%), senior service centers (20%), libraries (18%), senior living residences (6%), and churches (6%). Of 24 site-based cohorts with baseline data completed through November 2017, 21 community health workers were recruited and trained to implement the standardized intervention, and 287 participants were enrolled (mean age 68 years, 89% female, 33% African American, other, or more than one race). Discussion and Implications: The MOVE UP translational recruitment, training, and intervention approach is feasible and could be generalizable to diverse aging individuals with obesity and a variety of baseline medical conditions. Additional data regarding strategies for program sustainability considering program cost, organizational capacity, and other adaptations will inform public health dissemination efforts. PMID- 30480137 TI - Investigating the Avoidability of Hospitalizations of Long Stay Nursing Home Residents: Opportunities for Improvement. AB - Background and Objectives: To examine the relationship between hospital diagnoses associated with hospital transfers of long stay nursing home residents, ratings of avoidability of transfer, and RN-identified quality improvement opportunities. Research Design and Methods: Prospective clinical demonstration project, named OPTIMISTIC, with trained RNs embedded in nursing homes that performed root cause analyses for 1,931 transfers to the hospital between November 2014 and July 2016. OPTIMISTIC RNs also rated whether transfers were avoidable, identified quality improvement opportunities, and recorded hospital diagnoses. Resident characteristics were obtained from Minimum Data Set assessments. Relationships between six hospital diagnoses commonly considered "potentially avoidable" and OPTIMISTIC RN root cause analysis findings were examined. Facilities were participating in the OPTIMISTIC demonstration project designed to reduce hospital transfers during the study period. Results: Twenty-five percent of acute transfers associated with six common diagnoses were considered definitely or probably avoidable by project RNs versus 22% of transfers associated with other diagnoses. The most common quality improvement opportunity identified for transfers rated as avoidable was that the condition could have been managed safely if appropriate resources were available, a factor cited in 45% of transfers associated with any of the six diagnoses. Problems with communication among stakeholders were the most commonly noted area for improvement (48%) for transfers associated with other diagnoses. Many other areas for quality improvement were noted, including earlier detection of change in status and the need for understanding patient preferences or a palliative care plan. Discussion and Implications: Although some nursing home transfers may later be deemed potentially avoidable based on post-transfer hospital diagnosis from Medicare claims data, OPTIMISTIC nurses caring for these residents at time of transfer categorized the majority of these transfers as unavoidable irrespective of the hospital diagnosis. Multiple quality improvement opportunities were identified associated with these hospital transfers, whether the transfer was considered potentially avoidable or unavoidable. PMID- 30480136 TI - Effects of Sequential Participation in Evidence-Based Health and Wellness Programs Among Older Adults. AB - Background and Objectives: Evidence suggests participation in evidence-based programs by older adults is effective, yet most studies focus on participation in a single evidence-based program, leaving repeated participation insufficiently understood. We aimed to compare participation in multiple evidence-based programs (repeaters) versus a single evidence-based program (nonrepeaters). Research Design and Methods: Secondary data analysis was conducted on pre-post longitudinal data targeting older adults participating in evidence-based program(s) in Texas (2013-2016). Surveys included sociodemographic and health related indicators (e.g., self-rated health, health behaviors, and falls-risks). Mixed-effects models examined pre-post changes in health-related indicators. Results: Of the 734 study-eligible participants, 145 (20%) participated in two or more evidence-based programs. The participants' average age was 74 years, and the majority was female (80%), non-Hispanic White (79%), or lived in urban or large rural cities/towns (79%). At baseline, repeaters reported less depressive symptomology (p = .049), fewer chronic conditions (p = .048), and less concern of falling (p = .030) than nonrepeaters. Repeaters had better workshop attendance and completion rates (p < .001). Compared to nonrepeaters, repeaters showed significantly-better improvements in communication with physicians (p = .013). Discussion and Implications: Study findings suggest potential benefits of participation in multiple evidence-based program workshops, but repeaters may have different health profiles than nonrepeaters in natural settings. Future evaluations should consider participants' past participations in evidence-based programs. Further research is needed to build more comprehensive evidence about the incremental benefits of participation in multiple evidence-based programs. PMID- 30480139 TI - Erratum: A Comprehensive Analysis of Morbidity Life Expectancies Among Older Hispanic Subgroups in the United States: Variation by Nativity and Country of Origin. AB - [This corrects the article DOI: 10.1093/geroni/igy014.][This corrects the article DOI: 10.1093/geroni/igy014.]. PMID- 30480138 TI - Exploration of Perceived Psychosocial Benefits of Senior Companion Program Participation Among Urban-Dwelling, Low-Income Older Adult Women Volunteers. AB - Background: As the older adult population increases, it is imperative to increase older adults' opportunities for social involvement, thus maintaining their important roles and contributions to society. While there are known health related benefits of volunteerism among older adults, a dearth of information exists on the perceived benefits of volunteerism among low-income and ethnic minority older adults. Purpose: To understand the perceived psychosocial benefits of volunteering in the Senior Companion Program and to present findings of focus groups conducted with urban-dwelling, low-income older adult women volunteers. Design and Methods: Inductive content analysis and the Dedoose qualitative data analysis software were used for analyzing data obtained from 59 older adult women Senior Companions who participated in nine focus groups. Results: Content analyses of the focus group transcripts identified four major themes: (1) Reducing social isolation; (2) Improving quality of life; (3) Finding purpose and meaning; and (4) Increasing understanding of aging. The majority of our participants (81%) were African American women, with a mean age of 70 years. Approximately 83.1% had completed high school and 62.7% lived below the poverty line. Discussion and Implications: Findings provided data rich in descriptions of positive psychosocial outcomes, finding meaning and purpose, and a better understanding of aging in urban-dwelling, low-income older women volunteers. The findings also provide support for the need for policies and programs that promote civic engagement in this population. PMID- 30480140 TI - Valuation of Life Among Old and Very Old Adults: Comparison Between Germany and Japan. AB - Background and Objectives: Valuation of life (VOL) represents a construct capturing individuals' active attachment to their life. The majority of studies on VOL were conducted in North America and Europe where personal autonomy and independence are highly valued, leaving open the question about the relevance of this construct in interdependence-oriented cultures. Using a framework of cross cultural and life-span theories, the present study compared levels and predictors of VOL between the young-old and old-old individuals from Germany and Japan. Research Design and Methods: Two hundred fifty-seven Germans and 248 Japanese, matched by age, gender, education, and IADL, answered a 5-item VOL scale and shared information on sociodemographic, social, and health resources. Results: Germans' VOL levels were higher than in Japanese participants. Both culture- and age-moderated predictions of VOL: education was significant only in the young-old Japanese, and close social partners mattered in the old-old, not in the young old. Health determined VOL irrespective of culture and age. Discussion and Implications: The findings suggest that cultural values and aging processes should be considered to better understand how individuals value their life and to help older adults to feel that his/her life is meaningful and worth living. PMID- 30480141 TI - Loneliness and Anxiety About Aging in Adult Day Care Centers and Continuing Care Retirement Communities. AB - Background and Objectives: The present study compares how 2 settings: adult day care centers (ADCCs) and continuing care retirement communities (CCRCs) fare with regard to loneliness and anxiety about aging. Loneliness is a highly prevalent and distressing subjective experience of inadequate social relations, which has negative effects on health and well-being. Anxiety about aging is defined as worries brought up by imagining the negative consequences and losses associated with old age. The study also examines whether anxiety about aging accounts for differences in loneliness between the 2 settings. This study took place in Israel, where ADCCs are funded by the National Insurance Institute of Israel and CCRCs tend to be funded by private income and wealth. Despite notable differences between the settings, a common goal of both is to reduce loneliness among older adults. Research Design and Methods: A cross-sectional design of 4 ADCCs and 4 CCRCs (N = 456). Results: Compared with CCRC residents, older adults in ADCCs reported higher levels of loneliness (Mean [SD] = 1.46 [0.60], Mean [SD] = 1.78 [0.80], respectively, t [df]= -5.10 [448], p < .001) and higher levels of anxiety about aging (Mean [SD] = 2.96 [0.88], Mean [SD] = 3.27 [0.99], respectively, t [df] = -3.42 [440], p < .001). Anxiety about aging partially accounted for the differences between the 2 settings in levels of loneliness (B = 0.03, 95% confidence interval [CI]: 0.0037-0.0651). Discussion and Implications: Although it is not possible to determine causality from this cross-sectional design, it is possible that CCRCs provide a better social outlet for older adults than ADCCs. PMID- 30480143 TI - Randomized Controlled Trial of Exercise to Improve Walking Energetics in Older Adults. AB - Background and Objectives: Mobility limitation is common and has been linked to high energetic requirements of daily activities, including walking. The study objective was to determine whether two separate forms of exercise could reduce the energy cost of walking and secondary outcomes related to activity and participation domains among older adults with mobility limitation. Research Design and Methods: Community-dwelling older adults with self-reported mobility limitation (n = 72) were randomized to 12 weeks of twice-weekly, group-based, instructor-led timing and coordination, aerobic walking, or stretching and relaxation (active control) programs. The primary outcome was the energy cost of walking (mL O2/kg/m), assessed by a 5-minute treadmill walking test (0.8 m/s). Secondary outcomes were fatigability, physical activity, endurance, physical function, and life-space. Baseline-adjusted ANCOVAs were used to determine mean differences between exercise and control groups at 12 and 24 weeks. Results: Exercise session attendance was high: 86% for timing and coordination, 81% for aerobic walking, and 90% for stretching and relaxation. At 12 weeks, timing and coordination reduced the mean energy cost of walking by 15% versus stretching and relaxation (p = .008). Among those with high baseline cost, timing and coordination reduced mean energy cost by 20% versus stretching and relaxation (p = .055). Reductions were sustained at 24 weeks. Aerobic walking had no effect on the energy cost of walking at 12 or 24 weeks. At 12 weeks, there was a trend toward faster gait speed (by 0.1 m/s) in timing and coordination versus stretching and relaxation (p = .074). Fatigability, physical activity, endurance, physical function, and life-space did not change with timing and coordination or aerobic walking versus stretching and relaxation at 12 or 24 weeks. Discussion and Implications: Twelve weeks of timing and coordination, but not aerobic walking, reduced the energy cost of walking among older adults with mobility limitation, particularly among those with high baseline energy cost; reductions in energy cost were sustained following training cessation. Timing and coordination also led to a trend toward faster gait speed. PMID- 30480144 TI - From a Bird's Eye View: Whole Social Networks in Adult Day Care Centers and Continuing Care Retirement Communities. AB - Background and Objectives: The present study describes whole social networks in 4 adult day care centers (ADCCs) and 4 continuing care retirement communities (CCRCs) in Israel. Method: Each respondent received a list of names of all individuals receiving services in the respective ADCC or CCRC and was asked to indicate whom he/she knows from the list. We derived whole social network properties and used hierarchical cluster analysis to group network settings. We further examined the ability of the social network data to classify respondents as members of either an ADCC or a CCRC. Results: Many social network properties were more favorable in CCRCs than in ADCCs. A striking finding of the present study is that one can classify with a relatively high degree of accuracy a respondent as belonging to an ADCC or a CCRC, simply based on his or her social properties (specifically, number of people who know the participant and are known by the participant). Implications: Despite some similarities between CCRCs and ADCCs, CCRCs likely allow for more inclusive and active social relations. This information should be valuable to administrators and care providers. PMID- 30480142 TI - Population Health Solutions for Assessing Cognitive Impairment in Geriatric Patients. AB - In December 2017, the National Academy of Neuropsychology convened an interorganizational Summit on Population Health Solutions for Assessing Cognitive Impairment in Geriatric Patients in Denver, Colorado. The Summit brought together representatives of a broad range of stakeholders invested in the care of older adults to focus on the topic of cognitive health and aging. Summit participants specifically examined questions of who should be screened for cognitive impairment and how they should be screened in medical settings. This is important in the context of an acute illness given that the presence of cognitive impairment can have significant implications for care and for the management of concomitant diseases as well as pose a major risk factor for dementia. Participants arrived at general principles to guide future screening approaches in medical populations and identified knowledge gaps to direct future research. Key learning points of the summit included: recognizing the importance of educating patients and healthcare providers about the value of assessing current and baseline cognition;emphasizing that any screening tool must be appropriately normalized and validated in the population in which it is used to obtain accurate information, including considerations of language, cultural factors, and education; andrecognizing the great potential, with appropriate caveats, of electronic health records to augment cognitive screening and tracking of changes in cognitive health over time. PMID- 30480145 TI - Care Recipient Concerns About Being a Burden and Unmet Needs for Care. AB - Background: Disabled older adults' needs for help with daily activities sometimes go unmet with potentially long-term negative consequences for health and well being. Objectives: To examine the relationship between care recipient unmet needs and (1) concerns about being a burden; (2) perceptions of caregiver burden; and (3) and caregiver self-reports of burden in community-dwelling care recipient caregiver dyads. Research Design and Methods: Telephone surveys with 196 linked caregiver-care recipient dyads from the 2017 Pittsburgh Regional Caregiver Survey. Of 376 caregivers who gave initial permission to contact the recipient (February-July), 262 caregivers were recontacted and gave permission to attempt a care recipient survey (September-October; n = 196 completed; 74.8% response rate). In addition to the burden measures, we controlled for several covariates, including disability level, receipt of paid help, and care recipient and caregiver sociodemographics. Results: Slightly more than one fourth (27.2%) of care recipients were "very concerned" about being a burden, and 43.6% were "somewhat concerned." Care recipient concerns about being a burden (exp(B) = 1.71, 95% confidence interval [CI] exp(B) [1.15, 2.54]); and caregiver self reported burden (exp(B) = 1.82, 95% CI exp(B) [1.17, 2.85]) were independent predictors of more care recipient unmet needs. Recipient perceptions of caregiver burden were not independently predictive. Care recipients with higher disability levels, those without paid help, and those whose caregiver was not a spouse/child also reported more unmet needs. The impact of burden on unmet needs was stronger for instrumental activities of daily living/mobility needs than for activities of daily living needs. Discussion and Implications: Potential interventions to reduce unmet needs should take a dyadic approach, focusing on reducing both care recipient perceptions of being a burden and caregiver experienced burden. PMID- 30480146 TI - Uses and Gratifications Sought From Mobile Phones and Loneliness Among Japanese Midlife and Older Adults: A Mediation Analysis. AB - Background and Objectives: Mobile phone use is increasing among older adults, yet few studies have examined how the various purposes for which mobile phones are used affect loneliness and through what mechanisms. This study aims to address the gap by examining if different uses and gratifications of mobile phone are associated with loneliness and whether there is a mediation effect through face to-face social interaction. Research Design and Methods: Participants included 1,318 mobile phone users drawn from a national probability sample of Japanese middle-aged (65% aged 40-64 years) and older adults (35% aged 65 years or older) in 2011. Ordinary Least Squares regression and mediation analyses were used. Results: Regression analyses revealed that using a mobile phone for sociability purposes was associated with decreased loneliness (b = -0.10, p < .001), while using it for the purposes of entertainment/passing time was associated with increased loneliness (b = 0.04, p < .01); some effects varied by age and mobile phone feature use. Further, sociability was associated with increased face-to face social interaction, which was, in turn, associated with reduced loneliness. Passing time, however, was related to reduced face-to-face interaction and, in turn, an increased sense of loneliness. Discussion and Implications: Although it is not possible to determine causality from this cross-sectional design, it is possible that the various purposes for which mobile phones are used (specifically sociability and passing time) partially affect loneliness through their effects on either increasing or decreasing face-to-face social interaction. Recommendations for enhancing positive and reducing negative effects of mobile phone usage are discussed. PMID- 30480147 TI - Validity of a Novel, Clinically Relevant Measure to Differentiate Functional Power and Movement Velocity and Discriminate Fall History Among Older Adults: A Pilot Investigation. AB - Background and Objectives: Lower-body muscular power and movement velocity (MV) are associated with balance and physical function. The Tendo power analyzer (Tendo) is a portable device that calculates functional lower body power (FLBP) and MV. This reliable (Cronbach's alpha = .98) method is validated against motion capture analysis of functional lower body sit-to-stand power and velocity (r = .76). However, the Tendo has not been utilized in discrimination or prediction of falls. We determined the discriminant validity of FLBP and MV among older adults based on the history of falls. These results lay the framework for longitudinal research in FLBP and MV in fall prediction/prevention. Research Design and Methods: Cross-sectional investigation examining differences between FLBP and MV during 5 sit-to-stands of 98 community-dwelling older adults (aged 77.5 years, 61% female) classified by the history of fall (no = 59, yes = 39). Participants completed 5 consecutive sit-to-stands (60-second rest between each) with FLBP and MV measured by the Tendo. Multivariate analysis of variance modeling determined between-group differences in functional lower body sit-to-stand average velocity, peak velocity, relative average power, and relative peak power. Binary and forward conditional logistic regression models determined the ability of each measure to discriminate fall history. Results: FLBP and MV were significantly lower in older adults with a fall history (p < .05). Relative average power and peak power were 15% and 16% lower and average and peak velocity were 18% and 14% slower, respectively among fallers. Logistic regression indicated average velocity was the best discriminator of fall history (p < .05). Discussion and Implications: The Tendo detects differences in FLBP and MV during a sit-to-stand while discriminating fall history. Future longitudinal studies should determine efficacy in fall prediction and applicability toward clinically relevant interventions for fall prevention. PMID- 30480148 TI - Longevity's Purposes. PMID- 30480149 TI - Coming Out of "Retirement"-Predictors of Driving Resumption Among Older Drivers. AB - Background and Objectives: Predictors and consequences of driving cessation in older adults have been studied extensively. This study sought to establish the extent to which former drivers resume driving and identify associated factors. Research Design and Methods: Descriptive analysis of the 2011-2015 National Health and Aging Trends Study data (Round 1: n = 6,680; Round 5: n = 3,409) characterized the extent of driving resumption through 2015 by baseline driving status (driver, former driver, never driver). Weighted multivariate logistic regression and multilevel longitudinal models examined predictors of driving resumption. Results: Among drivers who stopped driving during the study, 17%-28% resumed driving. Age, vehicle ownership, stroke, hospitalization, memory, and perceived transportation barriers were associated with resumption in regression analysis. In multilevel analysis stratified by baseline driving status, poor word recall (OR = 0.62; 95% CI = 0.40, 0.95) and use of public transportation (OR = 9.74; 95% CI = 1.54, 61.77) were significantly associated with driving resumption for baseline drivers, while use of taxi (OR < 0.001; 95% CI = <0.001, 0.02) was negatively associated with resumption for baseline former drivers. Discussion and Implications: This study highlights several factors associated with driving resumption. Uncertainty about the underlying causes for resumption remains, so results should be interpreted with caution. However, predictive factors may help to identify individuals in need of additional mobility transition counseling. Ongoing transportation assessment may be warranted among former drivers. PMID- 30480150 TI - Program Abstracts from the GSA 2018 Annual Scientific Meeting "The Purposes of Longer Lives". PMID- 30480151 TI - Index Participants. PMID- 30480152 TI - Why did the Japanese Government take so long to approve the intrauterine contraceptive device? AB - While the majority of East Asian countries embraced the modern intrauterine device (IUD) during the 1960s, the sale and distribution of the IUD in Japan was not authorized until 1974. In this paper, I address why the Japanese Government took so long to permit the use of the IUD. Firstly, I examine scientific debates in Japan during the early 1950s on the efficacy of the IUD and associated health risks, to illustrate how the Government's conservative attitude was fostered by a co-constitutive relationship between health officials and leading obstetrician gynaecologists who believed that the IUD was dangerous and likely to induce abortion. I also trace the Japanese Government's rapidly changing attitude through the 1960s, and analyse the influential interaction between national policy making and the enthusiastic response of a small number of Japanese doctors to the transnational movement to curb population growth in developing countries. I argue that the specific ways in which biomedical discourse was shaped by the sociopolitical position of doctors in relation to the Government's health administration explains the Japanese Government's resistance to use of the IUD. However, I also note that the Government's dramatic change in attitude was influenced directly by transnational reproductive politics. This paper will enhance the history of reproductive politics in post-war Japan, which has tended to focus on the politics surrounding abortion and the contraceptive pill. PMID- 30480153 TI - The Egg Rumour by Ellamae Cieslik. PMID- 30480154 TI - Calcium mobilization is responsible for Thapsigargin induced Epstein Barr virus lytic reactivation in in vitro immortalized lymphoblstoid cell lines. AB - The latent state is a critical component of all herpesvirus infections, and its regulation remains one of the most active areas of Epstein-Barr Virus (EBV) research. In particular, identifying environmental factors that trigger EBV reactivation into a virus-productive state has become a central goal in EBV latency research. Recently, a category of chemicals known as inducers of the endoplasmic reticulum unfolded protein response (UPR) have been shown to trigger EBV lytic reactivation in various established EBV-associated lymphoma cell lines. This has led to the recent belief that UPR is a universal cellular signaling pathway that directly triggers EBV lytic reactivation irrespective of cell type. We tested the potency of several widely used UPR inducers for EBV lytic reactivation on virus-immortalized primary lymphoblastoid cell lines (LCLs) in vitro. We found that, with the exception of Thapsigargin (Tg), UPR inducers did not trigger significant increases in BZLF1 transcripts or changes in the numbers of EBV genomic copies/cell in our panel of primary LCLs. Further investigation revealed that induction of lytic reactivation by Tg appeared to be due to its ability to trigger intracellular Ca2+ mobilization rather than its ability to induce UPR, based on our observations in which UPR induction alone was not sufficient to trigger the EBV lytic cycle in our LCLs. EBV immortalized LCLs have rarely been included in the majority of the lytic reactivation studies yet the characteristics of latent infection in LCLs should resemble those of proliferating B cells in clinically encountered lymphoproliferative diseases. Based on these observations, we propose an alternative mechanism of action for Tg in triggering EBV lytic reactivation in LCLs, and suggest that the proposed use of any chemical inducers of UPR for a purpose of oncolytic/lytic induction therapy needs to be fully evaluated pre-clinically in a panel of LCLs. PMID- 30480155 TI - Influence of flooding and soil properties on the genetic diversity and distribution of indigenous soybean-nodulating bradyrhizobia in the Philippines. AB - One of the strategies that is commonly used in the Philippines to improve the production of soybean is by inoculation. However, this technique often fails mainly due to the lack of information about the indigenous soybean rhizobia in the Philippines soil. In this study, the diversity of indigenous bradyrhizobia collected from the non-flooded and flooded soil conditions at 11 locations in the country was investigated using a local soybean cultivar as the host plant. The genetic variation among the 424 isolates was detected through Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) treatment and sequence analysis for 16S rRNA gene, 16S-23S rRNA internal transcribed spacer (ITS) region and rpoB housekeeping gene. All the isolates were classified under the Bradyrhizobium species namely B. elkanii, B. diazoefficiens, B. japonicum, B. yuanmingense and a considerable proportion of the isolates were clustered under Bradyrhizobium sp. The isolates which were classified under Bradyrhizobium sp. were thought to be endemic to Philippines soil as evidenced by their nucleotide divergence against the known rhizobia and the historical absence of rhizobia inoculation in the collection sites. The major influence on the distribution and diversity of soybean bradyrhizobia is attributed to the difference in the flooding period, followed by soil properties such as pH, soil type, and nutrient content. As determined, it is proposed that the major micro-symbiont of soybean in the Philippines are B. elkanii for non-flooded soils, then B. diazoefficiens and B. japonicum for flooded soils. PMID- 30480156 TI - Access to improved water and sanitation in sub-Saharan Africa in a quarter century. AB - The realization of the scale, magnitude, and complexity of the water and sanitation problem at the global level has compelled international agencies and national governments to increase their resolve to face the challenge. There is extensive evidence on the independent effects of urbanicity (rural-urban environment) and wealth status on access to water and sanitation services in sub Saharan Africa. However, our understanding of the joint effect of urbanicity and wealth on access to water and sanitation services across spatio-temporal scales is nascent. In this study, a pooled regression analysis of the compositional and contextual factors that systematically vary with access to water and sanitation services over a 25-year time period in fifteen countries across sub-Saharan Africa (SSA) was carried out. On the whole, substantial improvements have been made in providing access to improved water sources in SSA from 1990 to 2015 unlike access to sanitation facilities over the same period. Households were 28.2 percent and 125.2 percent more likely to have access to improved water sources in 2000-2005 and 2010-2015 respectively, than in 1990-1995. Urban rich households were 329 percent more likely to have access to improved water sources compared with the urban poor. Although access to improved sanitation facilities increased from 69 percent in 1990-1995 and 74 percent in 2000-2005 it declined significantly to 53 percent in 2010-2015. Urban rich households were 227 percent more likely to have access to improved sanitation facilities compared with urban poor households. These results were mediated and attenuated by biosocial, socio cultural and contextual factors and underscore the fact that the challenge of access to water and sanitation in sub-Saharan Africa is not merely scientific and technical but interwoven with environment, culture, economics and human behaviour necessitating the need for interdisciplinary research and policy interventions. PMID- 30480158 TI - Reuse of fly ash and bottom ash in mortars with improved thermal conductivity performance for buildings. AB - An approach towards effective utilization of fly ash and bottom ash in the construction of energy efficient buildings has been presented in this paper. Two masonry mortar grades MM3 and MM5 were considered for trial mix. Portland pozzolana cement with substitution of sand by fly ash and bottom ash separately in different substitution ratios (SR) were adopted for preparation of test samples. Fly ash and bottom ash with lime dust and marble dust combinations were also tested as sand free mortars. 28 days compressive strength, apparent porosity, bulk density and thermal conductivity parameters were evaluated for all such samples. By analysing the test results, it was observed that all the SR combinations satisfied the minimum masonry mortar grade MM0.7, as per IS 2250. Both the MM3 and MM5 grade mortars could be produced at 60% SR by fly ash, and corresponding reductions in thermal conductivity values were 69%, and 54% respectively, while compared with conventional mortar. Sand less mortar for both the grades resulted around 57% reductions in corresponding thermal conductivity values. Overall heat transfer co-efficient (U-value) for both side plastered and rendered brick masonry wall panel was found to be reduced by 15.58%, while comparison made between conventional mix of MM5 grade and corresponding 50% fly ash substituted mix. Thus such ash blended mortar mix appears to be advantageous in building envelop application for lowering the overall cooling/heating demand of building, besides utilizing the coal ash up to largest extent and saving natural mineral sand from depletion. PMID- 30480157 TI - Novel inverse agonists for the orphan G protein-coupled receptor 6. AB - The orphan G protein-coupled receptor 6 (GPR6) displays unique promise as a therapeutic target for the treatment of neuropsychiatric disorders due to its high expression in the striatopallidal neurons of the basal ganglia. GPR6, along with closely related orphan receptors GPR3 and GPR12, are phylogenetically related to CB1 and CB2 cannabinoid receptors. In the current study, we performed concentration-response studies on the effects of three different classes of cannabinoids: endogenous, phyto-, and synthetic, on both GPR6-mediated cAMP accumulation and beta-arrestin2 recruitment. In addition, structure-activity relationship studies were conducted on cannabidiol (CBD), a recently discovered inverse agonist for GPR6. We have identified four additional cannabinoids, cannabidavarin (CBDV), WIN55212-2, SR141716A and SR144528, that exert inverse agonism on GPR6. Furthermore, we have discovered that these cannabinoids exhibit functional selectivity toward the beta-arrestin2 recruitment pathway. These novel, functionally selective inverse agonists for GPR6 can be used as research tools and potentially developed into therapeutic agents. PMID- 30480159 TI - Fabrication and microstructure of quartz ceramics with orderly-arranged carbon filler. AB - Ceramics with tailored pore structure are showing potential applications in some special fields. For fabricating quartz ceramics with orderly-arranged carbon filler, a combination of 3D printing, vacuum suction filtration and sintering was explored to fabricate quartz ceramics with highly-ordered and well-connected big pore channels. The spatial lattice structure in the polylactic acid (PLA) template fabricated by 3D printing together with raw material ratio and sintering temperature has great effect on the properties and pore structure of the porous quartz ceramics. To demonstrate the technical feasibility for fabricating quartz ceramics with orderly-arranged filler, carbon powder was taken as an example and fully filled in the big pore channels of the porous quartz ceramics via vacuum impregnation method. By choosing the quartz ceramics with only highly-ordered and well-connected big pore channels as substrate, quartz ceramics with orderly arranged carbon filler were successfully obtained. PMID- 30480160 TI - Chemotactic behavior of egg mitochondria in response to sperm fusion in mice. AB - Mitochondria are the powerhouses of eukaryotic cells and their positioning contributes to fertilization and early developmental processes. We report that sperm fusion triggers Ca2+ oscillations and mitochondrial movement toward fused sperm (mitochondrial chemotaxis) in mouse eggs. Mitochondria functioned in Ca2+ storage and were colocalized with endoplasmic reticulum (ER) during Ca2+ oscillations. Mitochondria then moved toward the fused sperm. Sperm extracts lacking nuclei induced Ca2+ oscillations, but did not promote mitochondrial chemotaxis. Our results suggest that sperm fusion motivates Ca2+ oscillation independent mitochondrial chemotaxis. This phenomenon indicates that egg mitochondria interact with sperm materials, presumably nuclear substances, and their network tethers egg and sperm nuclei at the early stage of zygote formation. PMID- 30480162 TI - Validation of a claims-based algorithm identifying eligible study subjects in the ADAPTABLE pragmatic clinical trial. AB - Objective: Validate an algorithm that uses administrative claims data to identify eligible study subjects for the ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-Term Effectiveness) pragmatic clinical trial (PCT). Materials and methods: This study used medical records from a random sample of patients identified as eligible for the ADAPTABLE trial. The inclusion criteria for ADAPTABLE were a history of acute myocardial infarction (AMI) or percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), or other coronary artery disease (CAD), plus at least one of several risk enrichment factors. Exclusion criteria included a history of bleeding disorders or aspirin allergy. Using a claims-based algorithm, based on International Classification of Diseases, 9th Edition, Clinical Modification (ICD-9-CM) and 10th Edition (ICD-10) codes and Current Procedural Terminology (CPT) codes, we identified patients eligible for the PCT. The primary outcome was the positive predictive value (PPV) of the identification algorithm: the proportion of sampled patients whose medical records confirmed their ADAPTABLE study eligibility. Exact 95% confidence limits for binomial random variables were calculated for the PPV estimates. Results: Of the 185 patients whose medical records were reviewed, 168 (90.8%; 95% Confidence Interval: 85.7%, 94.6%) were confirmed study eligible. This proportion did not differ between patients identified with codes for AMI and patients identified with codes for PCI or CABG. Conclusion: The estimated PPV was similar to those in claims-based identification of drug safety surveillance events, indicating that administrative claims data can accurately identify study eligible subjects for pragmatic clinical trials. PMID- 30480161 TI - Detection of local and remote cellular damage caused by spinal cord and peripheral nerve injury using a heat shock signaling reporter system. AB - Spinal cord and peripheral nerve injury results in extensive damage to the locally injured cells as well as distant cells that are functionally connected to them. Both primary and secondary damage can cause a broad range of clinical abnormalities, including neuropathic pain and cognitive and memory dysfunction. However, the mechanisms underlying these abnormalities remain unclear, awaiting new methods to identify affected cells to enable examination of their molecular, cellular and physiological characteristics. Here, we report that both primary and secondary damage to cells in mouse models of spinal cord and peripheral nerve injury can be detected in vivo using a novel fluorescent reporter system based on the immediate stress response via activation of Heat Shock Factor 1. We also provide evidence for altered electrophysiological properties of reporter-positive secondarily-injured neurons. The comprehensive identification of injured, but surviving cells located both close and at distant locations from the injury site in vivo will provide a way to study their pathophysiology and possibly prevention of their further deterioration. PMID- 30480163 TI - Recruitment of precarious families in an interventional study: Lessons from the French "Fruits and vegetables at home" (FLAM) trial. AB - Background: The FLAM study was set up in order to assess the effectiveness of FV vouchers allowed to low-income households, on their FV consumption. The aim of the present study was to investigate issues associated with conducting interventional trials in disadvantaged populations using the FLAM study as an example of reaching target populations and recruitment difficulties. Methods: Families were recruited in Saint-Denis city (North Paris suburb), via social and municipal structures. Main interest variables in the study (food consumptions) were collected using face-to-face food interviews, either at home or municipal facilities. A qualitative analysis was performed among people who refused to participate in order to understand the barriers to participation. Results: A total of 95 parents-child pairs were included from May 2015 to May 2016. The families were mostly in precarious situation (63.3%), and most of parents were unemployed (71.3%). Almost the two third of children and 79.4% of parents were small consumers of FV (less than 3.5 servings per day). Several reasons for non participation were reported including time constraints, understanding and mistrust issues. Conclusions: Though using facilitating strategies, we recruited fewer participants than expected. The population finally included was mainly made of precarious families with a low consumption of FV. These results highlight the importance of identifying effective facilitating strategies to improve recruitment in disadvantaged populations. Trial registration: ClinicalTrial.gov no. NCT02461238, on June 3, 2015, retrospectively registered. PMID- 30480165 TI - Pachymetry-induced exacerbation of map-dot-fingerprint dystrophy. PMID- 30480164 TI - Recruiting under-represented populations into psychiatric research: Results from the help for hoarding study. AB - This study compares the effectiveness of approaches used to recruit a diverse sample for a randomized clinical trial for Hoarding Disorder (HD) in the San Francisco Bay Area. Of the 632 individuals who inquired about the study, 313 were randomized and 231 completed treatment. Most participants heard about the study via flyering (N = 161), followed by advocacy groups (N = 113), word of mouth (N = 84), health care professionals (N = 78), online (N = 68), and media (N = 11). However, those that heard about the study via advertising methods, such as flyers, were less likely to complete the study, p = .01, while those recruited via advocacy groups were most likely to be randomized, p = .03. No source proved more effective in recruiting underrepresented groups such as men, p = .60; non whites, p = .49; or Hispanics, p = .97. Advertising recruited the youngest individuals, p < 0.001, and word of mouth was most likely to recruit unemployed, disabled, or retired individuals, p = .01. Thus, results suggest an ongoing multimodal approach is likely to be most effective in both soliciting and retaining a diverse sample. Future studies should compare recruitment methods across greater geographical regions too, as well as in terms of financial and human costs. PMID- 30480166 TI - Jerome H. Siegel, MD. PMID- 30480167 TI - Effects of PCL, PEG and PLGA polymers on curcumin release from calcium phosphate matrix for in vitro and in vivo bone regeneration. AB - Calcium phosphate materials are widely used as bone-like scaffolds or coating for metallic hip and knee implants due to their excellent biocompatibility, compositional similarity to natural bone and controllable bioresorbability. Local delivery of drugs or osteogenic factors from scaffolds and implants are required over a desired period of time for an effectual treatment of various musculoskeletal disorders. Curcumin, an antioxidant and anti-inflammatory molecule, enhances osteoblastc activity in addition to its anti-osteoclastic activity. However, due to its poor solubility and high intestinal liver metabolism, it showed limited oral efficacy in various preclinical and clinical studies. To enhance its bioavailability and to provide higher release, we have used poly (epsilon-caprolactone) (PCL), poly ethylene glycol (PEG) and poly lactide co glycolide (PLGA) as the polymeric system to enable continuous release of curcumin from the hydroxyapatite matrix for 22 days. Additionally, curcumin was incorporated in plasma sprayed hydroxyapatite coated Ti6Al4V substrate to study in vitro cell material interaction using human fetal osteoblast (hFOB) cells for load bearing implants. MTT cell viability assay and morphological characterization by FESEM showed highest cell viability with samples coated with curcumin-PCL-PEG. Finally, 3D printed interconnected macro porous beta-TCP scaffolds were prepared and curcumin-PCL-PEG was loaded to assess the effects of curcumin on in vivo bone regeneration. The presence of curcumin in TCP results in enhanced bone formation after 6 weeks. Complete mineralized bone formation increased from 29.6 % to 44.9% in curcumin-coated scaffolds compared to pure TCP. Results show that local release of curcumin can be designed for both load bearing or non-load bearing implants with the aid of polymers, which can be considered an excellent candidate for wound healing and tissue regeneration applications in bone tissue engineering. PMID- 30480168 TI - Takotsubo Cardiomyopathy following Head and Neck Oncologic Surgery: A Case Report. PMID- 30480170 TI - Presenting OTO Open. PMID- 30480169 TI - Management and Outcome of Rhinosinusitis in Nigeria. AB - Objective: The aim of this study is to present the management and outcome of treatment of rhinosinusitis in Nigeria. Study Design: A retrospective review of the case notes of patients with rhinosinusitis between January 2009 and December 2014. Setting: Study at the University of Ilorin Teaching Hospital, Nigeria, using retrieved case notes after ethical approval was received. Subjects and Methods: The information retrieved included sociodemographic data, clinical presentation, duration, endoscopic examination, and other clinical management protocols with follow-up. All information was entered into SPSS version 20 and analyzed descriptively, and results are presented in tables and figure. Results: A total of 5618 patients were seen in the ear, nose, and throat clinic over the 6 year period. Of the patients, 445 had rhinosinusitis, and only 410 had complete data for analysis. Patient age ranged from 2 to 75 years (mean +/- SD, 31.8 +/- 1.2 years). The male to female ratio was 1.2:1. The duration of symptoms varied from 3 days to 10 years, with 78.7% having symptoms between 3 and 120 months. About 82.4% had nasal discharge, 51.3% had sneezing, 78.9% had alternating nasal obstruction, and 49.3% had nasal itch. Of the patients, 61.4% had a predisposition, of which 30.9% were allergic, 23.3% were infective, and 7.2% were vasomotor. Ethmoidal-maxillary sinuses were commonly affected radiologically. About 63% of patients had medical treatment, and only 28.7% had surgical intervention, of which 37% were scheduled for surgical treatment and 7.3% refused. Improved symptoms were noticed in 72.6% of patients, and 1.4% reported no improvement. Conclusion: Rhinosinusitis is still common, affecting active males economically with more chronic cases and more allergic predisposition. Early medical management is still effective, and endoscopic sinus surgery is now a better surgical option with better outcome in 72.6%. PMID- 30480171 TI - NSQIP as a Predictor of Length of Stay in Patients Undergoing Free Flap Reconstruction. AB - Objective: The National Surgical Quality Improvement Program (NSQIP) calculator was created to improve outcomes and guide cost-effective care in surgery. Patients with head and neck cancer (HNC) undergo ablative and free flap reconstructive surgery with prolonged postoperative courses. Methods: A case series with chart review was performed on 50 consecutive patients with HNC undergoing ablative and reconstructive free flap surgery from October 2014 to March 2016 at a tertiary care center. Comorbidities and intraoperative and postoperative variables were collected. Predicted length of stay was tabulated with the NSQIP calculator. Results: Thirty-five patients (70%) were male. The mean (SD) age was 67.2 (13.4) years. The mean (SD) length of stay (LOS) was 13.5 (10.3) days. The mean (SD) NSQIP-predicted LOS was 10.3 (2.2) days (P = .027). Discussion: The NSQIP calculator may be an inadequate predictor for LOS in patients with HNC undergoing free flap surgery. Additional study is necessary to determine the accuracy of this tool in this patient population. Implications for Practice: Head and neck surgeons performing free flap reconstructive surgery following tumor ablation may find that the NSQIP risk calculator underestimates the LOS in this population. PMID- 30480172 TI - Novel Mobile App Allows for Fast and Validated Intraoperative Assessment of Otolaryngology Residents. AB - Evaluation of resident operative skills is challenging in the fast-paced operating room environment and limited by lack of validated assessment metrics. We describe a smartphone-based app that enables rapid assessment of operative skills. Accreditation Council for Graduate Medical Education (ACGME) otolaryngology taxonomy surgical procedures (n = 593) were uploaded to the software platform. The app was piloted over 1 month. Outcomes included (1) completion of evaluation, (2) time spent completing the evaluation, and (3) quantification of case complexity, operative autonomy, and performance. During the study, 12 of 12 procedures, corresponding to 3 paired evaluated by the resident/attending dyad. Mean +/- SD time of evaluation completion was 98.0 +/- 24.2 and 123.0 +/- 14.0 seconds for the resident and attending, respectively. Mean time between resident and attending evaluation completion was 27.9 +/- 26.8 seconds. Resident and attending scores for case complexity, operative autonomy, and performance were strongly correlated (P < .0001). Rapid evaluation of resident intraoperative performance is feasible using smartphone-based technology. PMID- 30480173 TI - Ultrasound-Guided Needle Biopsy for Diagnosis of Advanced-Stage Malignancies of the Upper Aerodigestive Tract. AB - Objective: Traditionally, direct laryngoscopy confirms stage and tissue diagnosis prior to treatment planning. Patients who are frail or have tenuous airway anatomy may incur risks while undergoing anesthesia. Further, direct laryngoscopy is scheduled after initial examination, introducing diagnosis delay. This study investigates the impact of ultrasound examination with guided needle biopsy compared with traditional operative biopsy. Study Design: Case series. Setting: Tertiary head and neck clinic. Subjects and Methods: The records of patients at the Veterans Affairs Medical Center Memphis and Regional One Health who had supraglottic, oropharyngeal, and hypopharyngeal cancer that was diagnosed by ultrasound needle biopsy were reviewed from 2011 to 2016. Demographics, stage, biopsy results, and treatment were abstracted. Results: Seventeen patients who underwent ultrasound-guided needle biopsy of the primary site were included. Average age was 63 years old, and 65% of patients were stage T4 (11/17). Needle biopsy yielded malignant cells in 76% (13/17). Eleven patients were included in subsequent analysis because 6 patients underwent needle biopsy only. Fisher exact test showed no difference between the 2 methods (P = .27). Sensitivity was 86% and specificity was 100%. Seven patients had a median potential delay in diagnosis of 10 days. Conclusions: Ultrasound can be used effectively to obtain a tissue diagnosis, circumventing an operative biopsy. Moreover, ultrasound may provide additional imaging details to support accurate staging. This strategy may prove worthwhile to cut costs and reduce delay to staging, reduce risk for those with contraindications to anesthesia, and increase staging accuracy via enhanced imaging details. PMID- 30480174 TI - EKG Electrode as a Tactile Locator of Stoma after Decannulation: A Pilot Study. AB - Objective: We aimed to evaluate the use of an electrocardiogram (EKG) electrode over decannulation dressings covering the stoma to improve speech intelligibility and volume and reduce air escape by facilitating identification of the "sweet spot" of the dressing. No objective data exist for patient outcomes with use of the EKG electrode dressing. Methods: This prospective study included head and neck oncology patients at a tertiary hospital who received a tracheostomy. A standard tracheostomy decannulation dressing was placed followed by an EKG electrode. A speech pathologist evaluated speech volume via sound-level meter and captured speech intelligibility for random sentence-level speech. A blinded reviewer scored speech samples for intelligibility. Patients completed a 4 question satisfaction survey. Results: Four patients completed the study. Based on the survey, the patients favored the button, with the lowest scores being 8.5 out of 10. Speech understanding was 48.5% without the button and 83% with the button. Normal speech volume was 73.75 dB without the button and 77.75 dB with the button. Loud speech volume was 80.75 dB without the button and 87 dB with the button. Discussion: This pilot study shows objective benefits of the EKG button as well as improved patient satisfaction. Inexpensive and low maintenance, the EKG electrode provides better occlusion of stoma dressing with easier localization. Implications for Practice: Dissemination of our results will aim to improve quality and patient outcomes following decannulation. PMID- 30480175 TI - An Extubation Protocol for Angioedema. AB - Angioedema-nonpitting edema of the mucous membranes and skin-most commonly occurs as a complication from the use of angiotensin-converting enzyme inhibitors. At our institution, the otolaryngology department has incorporated the use of the endotracheal tube cuff-leak test and bedside direct laryngoscopy to aid in timing for extubation of angioedema patients. Prospective data collection of patients presenting to the emergency department with angioedema was performed. Of 76 patients with angioedema, 9 required fiberoptic intubation. Intubation was performed at a median of 73 hours (range, 44-118). An endotracheal tube cuff-leak test was performed in 7 patients prior to extubation, and bedside direct laryngoscopy was also performed in 3 of these 7 patients to document resolution of laryngeal edema. The use of the endotracheal tube cuff-leak test and bedside direct laryngoscopy is an easy and inexpensive method to help determine eligibility for extubation in patients intubated for angioedema. PMID- 30480176 TI - From Morbidity and Mortality to Quality Improvement: Effects of a Structured and Interactive Otolaryngology Conference. AB - Objective: Measure the effects of a structured morbidity and mortality conference format on the attitudes of resident and faculty participants. Study Design: Prospective cohort study. Setting: Otorhinolaryngology-head and neck surgery residency training program. Subjects and Methods: Two changes were implemented to the structure of our morbidity and mortality conference: (1) we adopted a recently described presentation framework called situation-background-assessment recommendation and (2) appointed a faculty moderator to lead the conference. Surveys were distributed to residents and faculty before and after these modifications were implemented to measure changes in attitude of conference attendees. Results: After implementing the above changes to the morbidity and mortality conference, participant engagement increased from "moderately engaged" to "extremely engaged" (P < .01). Among both faculty and residents, the perceived educational value of conference also improved from "moderately educational" to "extremely educational" (P < .01). Finally in the attending cohort, the impact on future patient care increased from "no change" to "greatly enhanced" (P < .01). Conclusion: By implementing the situation-background-assessment-recommendation framework and appointing a faculty moderator to morbidity and mortality conference, participants reported significantly enhanced engagement during the conference, increased educational value of the session, and a positive impact on future patient care. PMID- 30480177 TI - Free Flap Anastomosis Leak after Implantable Doppler Removal. PMID- 30480178 TI - Patient Safety and Quality Improvement Education in Otolaryngology Residency: Preliminary Look at a Module-Based Approach. AB - Since publication of the Institute of Medicine's report To Err Is Human in 1999, patient safety and health care quality have become hot topics in the parlance of modern medical care. The Accreditation Council for Graduate Medical Education now requires integration of these topics into resident education, with evidence of trainee involvement in Patient Safety and Quality Improvement (PSQI) projects. Research in other disciplines indicates that interactive, experiential learning leads to the highest quality PSQI education. Otolaryngology as a field has been slow to adopt these changes into its residency curricula due to competing educational demands and lack of faculty expertise. The author reports preliminary experience with integration of an online module-based curriculum that addresses both of these issues. PMID- 30480180 TI - Cholesterol Granuloma of the Thyroid Mimicking Malignancy. PMID- 30480179 TI - The Incidental Thyroid Lesion in Parathyroid Disease Management. AB - Objective: The incidental thyroid lesion is a common finding during general imaging studies. Their management has been the subject of numerous studies and recommendations. Parathyroid disease workup necessitates imaging investigation of the adjacent thyroid gland and therefore provides a unique window to the perioperative management of thyroid incidentaloma. The specific prevalence of incidental thyroid lesions in the context of parathyroid disease is unknown. We seek to investigate its prevalence during parathyroid workup and surgery and to ascertain if there was a change in management of these patients. Study Design: Five-year retrospective database review. Setting: Tertiary care medical center. Subjects and Methods: The source and indication for referral, preoperative investigation findings, and management of the incidental thyroid lesions were examined. The actual procedure performed and final pathology results were assessed. Results: A total of 98 patients and 106 operations, including revision surgeries, were identified. There were 21 incidental thyroid lesions (21.4%) detected, whereby 15 patients underwent fine-needle aspirations and 12 subsequently had diagnostic hemithyroidectomies. This decision was made preoperatively in 5 patients and intraoperatively in 7 patients at the time of parathyroid surgery. Along with other pathologies, there were 7 patients with micropapillary thyroid carcinoma identified. Conclusions: In our series, the prevalence of incidental thyroid lesion and thyroid malignancy is comparable to the general population. The management of the initial parathyroid disease in our patients was altered by the imaging and cytological findings of these thyroid lesions. This has implications on perioperative counseling of the thyroid and parathyroid disease. PMID- 30480181 TI - Intravascular Papillary Endothelial Hyperplasia of the Neck: A Case Report. PMID- 30480182 TI - Third Branchial Cleft Cyst with Mycobacterium Infection. PMID- 30480184 TI - Human Papillomavirus Subtype 16 and the Pathologic Characteristics of Laryngeal Cancer. AB - Objective: Laryngeal cancer is the most common type of cancer in the head and neck. Human papillomavirus (HPV) represents a group of >150 related viruses. Infection with certain types of HPV can cause some types of cancer. This study aimed to evaluate the sociodemographic and histopathologic characters of squamous cell carcinoma of the larynx and its relationship to HPV subtype 16 (HPV-16). Study design: Cross-sectional. Setting: Tertiary university hospitals at 5 districts in Egypt (Minia, Cairo, Giza, Qaluobia, and Bani Seuif). Subjects and Methods: This cross-sectional study was conducted on 50 adult patients with laryngeal cancer who were admitted at 5 tertiary care hospitals in Egypt from January 2014 through December 2014. All patients were subjected to a comprehensive preoperative assessment, histopathologic assessments of tumor biopsies, and immunohistochemical staining for HPV-16. Results: HPV-16 immunostaining was positive in 9 patients (18%). A significant correlation between HPV-16 immunoreactivity and tumor grade (P < .001) was detected, with no significant correlation between HPV-16 immunoreactivity and other clinical and pathologic variables. Conclusion: The frequency of HPV-16 in laryngeal carcinoma is 18%, and there is significant correlation between HPV-16 and tumor grade. PMID- 30480183 TI - Pediatric Trainees Managing a Difficult Airway: Comparison of Laryngeal Mask Airway, Direct, and Video-Assisted Laryngoscopy. AB - Objective: Difficult airway management is a key skill required by all pediatric physicians, yet training on multiple modalities is lacking. The objective of this study was to compare the rate of, and time to, successful advanced infant airway placement with direct laryngoscopy, video-assisted laryngoscopy, and laryngeal mask airway (LMA) in a difficult airway simulator. This study is the first to compare the success with 3 methods for difficult airway management among pediatric trainees. Study Design: Randomized crossover pilot study. Setting: Tertiary academic medical center. Methods: Twenty-two pediatric residents, interns, and medical students were tested. Participants were provided 1 training session by faculty using a normal infant manikin. Subjects then performed all 3 of the aforementioned advanced airway modalities in a randomized order on a difficult airway model of a Robin sequence. Success was defined as confirmed endotracheal intubation or correct LMA placement by the testing instructor in <=120 seconds. Results: Direct laryngoscopy demonstrated a significantly higher placement success rate (77.3%) than video-assisted laryngoscopy (36.4%, P = .0117) and LMA (31.8%, P = .0039). Video-assisted laryngoscopy required a significantly longer amount of time during successful intubations (84.8 seconds; 95% CI, 59.4-110.1) versus direct laryngoscopy (44.9 seconds; 95% CI, 33.8-55.9) and LMA placement (36.6 seconds; 95% CI, 24.7-48.4). Conclusions: Pediatric trainees demonstrated significantly higher success using direct laryngoscopy in a difficult airway simulator model. However, given the potential lifesaving implications of advanced airway adjuncts, including video-assisted laryngoscopy and LMA placement, more extensive training on adjunctive airway management techniques may be useful for trainees. PMID- 30480185 TI - True Tracheal Bronchus. PMID- 30480186 TI - Androgen Receptor Expression in Primary Nonsquamous Cell Rare-Variant Carcinomas of the Head and Neck. AB - Objective: Androgen receptor (AR) is a diagnostic immunohistochemical marker for salivary gland duct carcinoma (SDC), but other nonsquamous cell head and neck carcinomas (NSCCs) may also express it. The aim of this preliminary study was to investigate the immunohistochemical expression of AR in rare head and neck NSCCs. Study Design: Retrospective analysis of histologic records. Setting: A large community hospital. Subjects and Methods: Twenty-seven patients with NSCC were selected (21 men, 6 women; average age, 69 years). Exclusion criteria were histologically confirmed primary and metastatic head and neck squamous cell carcinomas and thyroid carcinomas. AR immunohistochemistry was done on formalin fixed, paraffin-embedded tissue blocks. Results: Variable AR expression was found in 5 of 27 (25%) cases of NSCC. All 7 patients with SDC showed intense and extensive positive immunoreactivity. Of 27 NSCC tumors, 15 (56%) had negative staining. Conclusion: In the head and neck, expression of AR is not limited to SDCs; other NSCCs also express it. When surgery or radiotherapy is not appropriate for recurrent or metastatic head and neck NSCC, palliative chemotherapy offers poor results. Antiandrogen therapy is well tolerated and is much less toxic than chemotherapy. Since androgen deprivation therapy has been used against SDCs, this therapy may theoretically be used in a small subset of head and neck NSCCs. PMID- 30480187 TI - Mediastinal Foreign Body Presenting as Biphasic Stridor and Hoarseness. PMID- 30480188 TI - Progressive Facial Paralysis Caused by Heterotopic Ossification of the Stylohyoid Ligament. PMID- 30480189 TI - Giant Parotid Carcinosarcoma Arising in a Pleomorphic Adenoma: Facial Nerve Preservation by Retrograde Dissection. PMID- 30480191 TI - Two-Year Sustained Benefit of an Absorbable Implant for the Treatment of NVC. PMID- 30480190 TI - Patterns of Upper Airway Obstruction on Drug-Induced Sleep Endoscopy in Patients with Sleep-Disordered Breathing with AHI <5. AB - Objective: To describe the patterns of upper airway obstruction in patients with sleep-disordered breathing with apnea-hypopnea index (AHI) <5 using drug-induced sleep endoscopy (DISE). Study Design: Retrospective study. Setting: Tertiary care center. Subjects and Methods: Inclusion of patients with sleep-disordered breathing with AHI <5 on polysomnography who underwent DISE. Patients <18 years of age were excluded. DISE findings were reported with the VOTEL classification system: the level of collapse was described as occurring at the velum, oropharynx, tongue base, epiglottis, and the lingual tonsils. The degree of collapse was reported as complete, partial, or none. The pattern of the obstruction was described as anteroposterior, lateral, or concentric when applicable. Results: A total of 54 patients with sleep-disordered breathing with AHI <5 underwent DISE. Ages ranged from 19 to 65 years. DISE was performed alone in 7% (n = 4) of patients and in conjunction with surgery in 93% (n = 50) of patients. The velum was the most frequent site of upper airway obstruction (85%, n = 46), followed by base of tongue (63%, n = 34), epiglottis (39%, n = 21), lingual tonsils (35%, n = 19), and oropharynx (31%, n = 17). Eighty-three percent (n = 45) of patients had multiple levels of upper airway obstruction, and 15% (n = 8) had a single level of upper airway obstruction. Conclusion: Patients with sleep-disordered breathing with AHI <5 have significant upper airway obstruction as seen on DISE. DISE findings indicate that a majority of these patients have multiple levels of upper airway obstruction, which can lead to significant symptoms. PMID- 30480192 TI - Invasive Sino-orbital-skull Base Aspergillosis Progressing from Aspergillus Ball of Maxillary Sinus: A Case Report. PMID- 30480193 TI - Does Surgical Volume Influence the Need for Second Surgery? A Pilot Study. AB - Objective: To examine outcomes of pediatric thyroidectomy in the context of training background, institution, and experience of the surgeon. Study Design: Case series with chart review. Setting: A tertiary academic medical center and a pediatric hospital. Subjects and Methods: Eighty-one thyroidectomy patients younger than 18 years. Outcomes were major complications (recurrent laryngeal nerve injury, permanent hypocalcemia, and wound infection), length of stay (LOS), and need for repeat surgery. Results: Eighty-one patients, 39 from the University of Nebraska Medical Center and 42 from the Children's Hospital and Medical Center Omaha, were identified over a 12-year time period. No difference was found in surgeon training (otolaryngology/head and neck surgery vs general/pediatric surgery) for complications (1 vs 1, odds ratio [OR] = 0.76, 95% confidence interval [CI] = [0.05, 13.1]), LOS >1 day (5 vs 13, OR = 0.39, 95% CI = [0.13, 1.24]), or need for second surgery (4 vs 7, OR = 1.47, 95% CI = [0.39, 5.49]). Higher surgeon volume (>=12 surgeries) was found to be significant for decreased need for second surgery (3 vs 8, OR = 6.67, 95% CI = [1.57, 27.17]). Patients of higher-volume surgeons were 4.2 times more likely to stay in the hospital 1 day or less compared with those patients operated on by surgeons with less experience (7 vs 11, 95% CI = [1.59, 15.0]). Conclusions: Need for second surgery in pediatric thyroidectomy may be predicted by surgical volume. PMID- 30480194 TI - Online Teaching Tool for Sinus Surgery: Trends toward Mobile and Global Education. AB - Objective: Online resources may provide an ideal forum for expert presentation of surgical techniques. The purpose of this study was to investigate utilization patterns of a sinus surgery website, SinusVideos.com, to gain insight into the needs of viewers. Study Design: Retrospective analysis. Setting: Surgical teaching website. Subjects and Methods: The website's anonymized analytic database was queried from 2009 to 2014. Quantified data included user demographics, geographic location, viewing device, page visits, and time spent on the website. Results: A total of 428,691 website pages were viewed during the study period. Growth in viewership was observed each successive year since the site was launched. The mean time spent viewing webpages was 96.1 seconds for desktop computer users, 98.0 for tablet users, and 103.8 for mobile users. The percentage of mobile devices used to view the site increased significantly between 2009 and 2014 (2.1% vs 25.4%, respectively; P < .0001). The website's viewership expanded globally, with a significant increase in site views from outside North America over this same period (18.4% vs 51.7%, P < .0001). Conclusion: The observed increase in global participation and mobile device usage may reflect new areas of growth for surgical education. PMID- 30480195 TI - Pulmonary Function of Patients with Chronic Rhinosinusitis and the Impact of Endoscopic Sinus Surgery. AB - Objective: The aim of this study was to compare pulmonary function tests (PFTs) among control subjects and patients with chronic rhinosinusitis (CRS) and to investigate the outcomes of endoscopic sinus surgery (ESS) on PFTs among patients with CRS. Study Design: Prospective study conducted from June 2015 to June 2016. Setting: Tertiary referral hospital. Subjects and Methods: The study is based on 2 groups: adult control subjects (group 1, n = 25) and adult patients with medically resistant CRS (group 2, n = 25). PFTs were used to compare the lower airway condition between the groups. Another comparison in PFTs was made among patients with CRS at 1 week preoperatively and 1 month postoperatively to evaluate the effectiveness of ESS. Results: In group 1, all subjects had an FEV1/FVC ratio >=80% (forced expiratory volume in 1 second / forced vital capacity) with a mean of 0.84 +/- 0.07, as compared with group 2, from 61% to 70% for 5 (20%) patients, 71% to 79% for 10 (40%), and >=80% for 10 (40%). FEV1/FVC was significantly lower in group 2 than group 1 (P = .04). At 1 month postoperatively, the FEV1/FVC values of group 2 was from 61% to 70% for 2 (8%) patients, 71% to 79% for 13 (52%), and >=80% for 10 (40%). The mean FEV1/FVC was 0.9 +/- 0.50, and these values were significantly higher (P = .02) when compared with preoperative values. Conclusion: This study provides objective evidence that patients with CRS may have nonmanifest lower airway affection when compared with control subjects and that ESS is efficacious in the improvement of such affection. PMID- 30480196 TI - Neurovestibular Symptoms in Astronauts Immediately after Space Shuttle and International Space Station Missions. AB - Objectives: (1) To assess vestibular changes and related sensorimotor difficulties, especially instability of posture and gait, among astronauts immediately after they return from space and to compare the effects experienced after short- and long-duration space missions. (2) To determine whether any difficulties experienced were severe enough to impair the astronauts' ability to leave the spacecraft in the event of an emergency. Study Design: Prospective cohort study. Setting: National Aeronautics and Space Administration's Kennedy Space Center and Johnson Space Center. Subjects and Methods: Fourteen crewmembers of 3 Space Shuttle missions that lasted about 1 week and 18 crewmembers of 8 International Space Station missions that lasted about 6 months were given brief vestibular examinations 1 to 5 hours after landing. These examinations focused on the presence of vestibular and motor coordination difficulties, as well as motion sickness and motion sensations. Standardized tests included the observation of abnormal eye movements, finger-to-nose pointing, standing up from a seated position, postural stability, and tandem gait. Results: Unsteady walking and postural instabilities were observed after short- and long-duration missions. Motion sickness symptoms were observed after long-duration missions but not after short-duration missions. The symptom most frequently reported by the astronauts was an exaggerated perceived motion associated with sudden head movements during reentry and after landing. Conclusion: The severity of the observed abnormalities would limit the ability of crewmembers during the first 5 hours after landing and increase the time required to leave the spacecraft during this period. PMID- 30480198 TI - Cochlear Implantation of a Patient with Definitive Neurosarcoidosis. PMID- 30480197 TI - Wrist Motion Variation between Novices and Experienced Surgeons Performing Simulated Airway Surgery. AB - Objective: To determine whether wrist motion measured by a smartphone application can be used as a performance metric for a simulated airway procedure requiring both wrist and finger dexterity. We hypothesized that this accelerometer application could detect differences between novices and experienced surgeons performing simulated cricothyrotomy. Setting: Academic medical center. Study Design: Prospective pilot cohort study. Methods: Voluntary surgeons and nonsurgeons were recruited. After viewing a training video, smartphones with accelerometer applications were attached to both wrists while subjects performed a cricothyrotomy on a validated task trainer. Procedure time and motion parameters, including average resultant acceleration (ARA), total resultant acceleration (TRA), and suprathreshold acceleration events (STAEs), were collected for dominant and nondominant hands. Subjects were stratified by prior experience. Blinded experts scored each performance using Objective Structured Assessment of Technical Skills (OSATS), and t tests were used to compare performance. Results: Thirty subjects were enrolled. Median age was 26 years, and 20 subjects were male. In the dominant hand, significant differences were seen between novice and experienced surgeons in TRA (P = .005) and procedure time (P = .006), while no significant differences were seen in STAEs (P = .42) and ARA (P = .33). In the nondominant hand, all variables were significantly different between the 2 groups: STAEs (P = .012), ARA (P = .007), TRA (P = .004), and procedure time (P = .006). Conclusions: Wrist motion measured by a low-cost smartphone application can distinguish between novice and experienced surgeons performing simulated airway surgery. This tool provides cost-effective and objective performance feedback. PMID- 30480199 TI - Tympanometric Patterns of Children with Allergic Rhinitis Treated at a Tertiary Health Institution. AB - Objectives: To determine the prevalence of otitis media with effusion (OME) and compare patterns of tympanogram between children with and without allergic rhinitis in Ibadan, Nigeria. Study Design: A case-control study of children (2-7 years) with AR from May 2015 to March 2016. Setting: Tertiary hospital. Subjects and Methods: Consecutive 86 children with AR and 86 healthy controls (nonallergic) participated in the study. A structured questionnaire was administered to parents or caregivers of the participants to obtain relevant sociodemographic and clinical information. Diagnosis of AR was by symptomatology and nasal cytology. Both groups had ear, nose, and throat examination and tympanometric evaluation. OME was diagnosed according to Jerger's tympanometric patterns. Results: The mean +/- SD ages of cases and controls were 3.80 +/- 1.72 and 3.78 +/- 1.71 years, respectively. All cases presented with watery nasal discharge, bouts of sneezing, and nasal itching. The duration of AR symptoms was 18 +/- 13 months. Among cases and controls, Jerger's type A tympanogram was the most common pattern, while type C was the least common. Thirty-nine (45.3%) children with AR had OME, as compared with 8 (9.3%) controls, and the difference was statistically significant (P < .001; odds ratio = 8.090; 95% CI = 3.48 18.79). Conclusion: Prevalence of OME was significantly high among children with AR. Jerger's type B and C tympanograms were more common among children with AR than the healthy pediatric population. This background information supports the need for routine tympanometric evaluation of children with AR. PMID- 30480200 TI - Middle Eastern Rhinoplasty: Relationship of the Nasal Spine and Caudal Septum to Tip Projection and Columellar-Labial Angle. AB - Objective: To measure the anterior nasal spine length (ANSL) and septal caudal extension (SCE), as well as assess the strength of association between these variables and tip projection in the Middle Eastern nose. Our secondary aim was to assess if columellar-labial angle (CLA) or columellar-spinal angle (CSA) vary as a function of ANSL and/or SCE. Study Design/Setting: Prospective single institutional study. Subjects: Middle Eastern primary rhinoplasty patients without nasal trauma or prior endonasal surgical history. Methods: Photographic and intraoperative caliper measurements were used to determine Goode ratio (GR), CLA, CSA, ANSL, and SCE. Associations between numeric variables were examined with scatterplots, including use of LOWESS curves and Pearson correlation coefficients. Linear regression models were used for predicting quantitative variables (GR, CLA, CSA). Logistic regression models were used for predicting overprojection status based on GR. Results: In total, 102 patients met inclusion criteria (82 females, 20 males). Mean ANSL and SCE were 8.6 mm and 14.9 mm, respectively; ANSL and SCE had a strong positive association with each other. SCE and ANSL were found to have low predictability for GR, CLA, or CSA. Conclusion: Determinations of projection status using the GR method do not appear to be related to ANSL or SCE values in our Middle Eastern study group. Relationships of absolute columellar-labial or columellar-spinal angles are likely more complex than isolated value implications of SCE or ANSL. PMID- 30480201 TI - Fungus Ball of the Middle Ear: A Case Study. PMID- 30480202 TI - Myospherulosis following Rhinoplasty. PMID- 30480203 TI - Open Access: Is There a Predator at the Door? PMID- 30480204 TI - Image-Based 3-Dimensional Characterization of Laryngotracheal Stenosis in Children. AB - Objectives: Describe a technique for the description and classification of laryngotracheal stenosis in children using 3-dimensional reconstructions of the airway from computed tomography (CT) scans. Study Design: Cross-sectional. Setting: Academic tertiary care children's hospital. Subjects and Methods: Three dimensional models of the subglottic airway lumen were created using CT scans from 54 children undergoing imaging for indications other than airway disease. The base lumen models were deformed in software to simulate subglottic airway segments with 0%, 25%, 50%, and 75% stenoses for each subject. Statistical analysis of the airway geometry was performed using metrics extracted from the lumen centerlines. The centerline analysis was used to develop a system for subglottic stenosis assessment and classification from patient-specific airway imaging. Results: The scaled hydraulic diameter gradient metric derived from intersectional changes in the lumen can be used to accurately classify and quantitate subglottic stenosis in the airway based on CT scan imaging. Classification is most accurate in the clinically relevant 25% to 75% range of stenosis. Conclusions: Laryngotracheal stenosis is a complex diagnosis requiring an understanding of the airway lumen configuration, anatomical distortions of the airway framework, and alterations of respiratory aerodynamics. Using image-based airway models, we have developed a metric that accurately captures subglottis patency. While not intended to replace endoscopic evaluation and existing staging systems for laryngotracheal stenosis, further development of these techniques will facilitate future studies of upper airway computational fluid dynamics and the clinical evaluation of airway disease. PMID- 30480205 TI - Unilateral Pulsatile Tinnitus Associated with an Internal Carotid Artery Eustachian Tube Dehiscence. PMID- 30480206 TI - Laryngeal Fracture following Violent Sneeze: Management and Biomechanical Analysis. PMID- 30480207 TI - Head and Neck Squamous Cell Carcinoma in Western Uganda: Disease of Uncertainty and Poor Prognosis. AB - Objectives: Patients with head and neck squamous cell carcinoma (HNSCC) have symptoms that masquerade as benign conditions, resulting in late presentations. The objective is to describe characteristics and stages of patients with HNSCC and document their prognosis from clinical experience in western Uganda. Study Design: Cross-sectional study with clinical follow-up. Setting: Mbarara Regional Referral Hospital. Subjects and Methods: Fifty-one participants were recruited from February to July 2016. A questionnaire was used for patient characteristics, and staging, serologic studies, biopsy for histopathology, and immunohistochemistry were investigated. Staging was subclassified as early (stage I and II) and late (stage III and IV). Analysis was done with Fisher's exact test. Results: Of 51 participants, 44 (86.5%) were male; the group had a mean age of 57.7 years, and 41 (80.1%) presented with late stage. Of 10 participants who presented with early stage, 6 (60%) had laryngeal HNSCC. The pharynx was ranked as the highest subsite (n = 19, 37.3%), followed by the oral cavity (n = 9, 17.6%), the larynx (n = 9, 17.6%), an unknown primary (n = 8, 15.7%), and sinonasal area (n = 6, 11.8%). Tobacco smoking, alcohol consumption, and prior use of traditional remedy were common characteristics among participants. Moderate differentiation was the most common grade (n = 23, 45.1%). Helicobacter pylori, Epstein-Barr virus, human immunodeficiency virus, and human papilloma virus type 16 were identified among 51 participants. However, none could afford referral for radiotherapy; hence, 1-year survival was 4%. Conclusion: The majority of our patients with HNSCC present at late stage, and the prognosis is poor. There is great need for preventative community-based education and early screening services to save our population. PMID- 30480208 TI - An Alternative Method of Endoscopic Intrasphenoidal Vidian Neurectomy. AB - Objective: To develop an easy surgical approach to facilitate clinical management. Study Design: A novel transnasal endoscopic 3-step surgical method for vidian neurectomy was designed and tried in 91 cases with a mild-to-severe degree of allergic and nonallergic rhinitis refractory to routine medical therapy. Setting: Endoscopic vidian neurectomy requires accurate localization of the vidian canal. However, it is not easy to localize during surgery because of its deep location and the complex anatomy of the pterygopalatine fossa. Subjects and Methods: This technique consists of 3 steps, including transnasal endoscopic perforation of the anterior wall of the sphenoidal sinus as the first step and removal of the anterior wall until the exposure of the vidian canal in the junction between the anterior wall and the floor of the sphenoid sinus as the second step. The last step is the accurate resection and cauterization of the vidian nerve. In some cases in which the sphenoid sinus developed well with a big lateral space, an extended procedure of posterior ethmoidectomy was included to allow good exposure of the vidian canal. Results: Using this technique, successful endoscopic vidian neurectomy in this series of patients was confirmed by both histology and Schirmer test, showing its distinct advantages of easy localization of the vidian canal and less risk of injury to the nerve and vessel bundles within the pterygopalatine fossa. Conclusion: Taken together, this novel 3-step procedure of endoscopic vidian neurectomy plus an extended procedure guarantees good exposure of the vidian canal and therefore accurate vidian neurectomy. PMID- 30480209 TI - The Bifurcated Frontal Sinus. AB - Objectives: Frontal sinus anatomy is complex, and multiple variations of ethmoid pneumatization have been described that affect the frontal outflow tract. In addition, the lumen proper of the frontal sinus may exist as 2 separate parallel cavities that share an ipsilateral outflow tract. This variant has not been previously described and may have implications for surgical management. Study Design: Case series. Setting: Tertiary rhinology practice. Subjects and Methods: Cases with radiographic and intraoperative findings of separate parallel tracts within a unilateral frontal sinus were identified from a consecutive series of 186 patients who underwent endoscopic sinus surgery between May 2015 and July 2016. Data were recorded including sinusitis phenotype, coexisting frontal cells, and extent of surgery. Results: Ten patients (5.4%) were identified with computed tomography scans demonstrating bifurcation of the frontal sinus into distinct medial and lateral lumens. All cases were treated with Draf 2a or 2b frontal sinusotomy with partial removal of the common wall to create a unified ipsilateral frontal ostium. Eleven sides had a coexisting ipsilateral agger nasi cell, 7 had a supra-agger cell, 8 had a suprabullar cell, and 1 had a frontal septal cell. There were no significant complications. Conclusion: The bifurcated frontal sinus is an anatomic variant that the surgeon should recognize to optimize surgical outcomes. Failure to do so may result in incomplete clearance of the sinus and residual disease. The bifurcated sinus may occur with other types of frontal sinus cells and may be safely treated with endoscopic techniques. PMID- 30480210 TI - Expanding the Capacity of Otolaryngologists in Kenya through Mobile Technology. AB - Objective: To determine if reliable, objective audiologic data can be obtained by nonotolaryngology and nonaudiology practitioners using novel mobile technology in an effort to expand the capacity for early identification and treatment of disabling hearing loss in the developing world. Study Design: Cross-sectional, proof-of-concept pilot study. Setting: Screenings took place during an annual 2 week otolaryngology surgical mission in October 2016 in semirural Malindi, Kenya. Subject and Methods: Eighty-seven patients (174 total ears) were included from 2 deaf schools (n = 12 and 9), a nondeaf school (n = 9), a tuberculosis ward (n = 8), and a walk-in otology clinic at a local hospital (n = 49). An automated, tablet-based, language-independent, clinically validated, play audiometry system and wireless otoscopic endoscopy via an iPhone or laptop platform was administered by Kenyan community health workers (CHWs) and nursing staff. Results: Various degrees of hearing loss and otologic pathology were identified, including 1 child presumed to be deaf who was found to have unilaterally normal hearing. Other pathology included 2 active perforations, 2 healed perforations, 2 middle ear effusions, and 1 cholesteatoma. CHWs and nursing staff demonstrated proficiency performing audiograms and endoscopy. Patients screened in a deaf school were more likely to complete an unreliable audiogram than patients screened in other settings (P < .01). Conclusion: This study demonstrates the feasibility of a non-otolaryngology-based hearing screening program. This may become an important tool in reducing the impact of hearing loss and otologic pathology in areas bereft of otolaryngologists and audiologists by allowing CHWs to gather important patient data prior to otolaryngologic evaluation. PMID- 30480211 TI - Congenital Mastoidal Cholesteatoma in an 87-Year-Old Woman Treated by Watchful Waiting. PMID- 30480212 TI - Interdisciplinary Crisis Resource Management Training: How Do Otolaryngology Residents Compare? A Survey Study. AB - Objective: Emergent medical crises, such as acute airway obstruction, are often managed by interdisciplinary teams. However, resident training in crisis resource management traditionally occurs in silos. Our objective was to compare the current state of interdisciplinary crisis resource management (IDCRM) training of otolaryngology residents with other disciplines. Methods: A survey study examining (1) the frequency with which residents are involved in interdisciplinary crises, (2) the current state of interdisciplinary training, and (3) the desired training was conducted targeting Canadian residents in the following disciplines: otolaryngology, anesthesiology, emergency medicine, general surgery, obstetrics and gynecology, internal medicine, pediatric emergency medicine, and pediatric/neonatal intensive care. Results: A total of 474 surveys were completed (response rate, 12%). On average, residents were involved in 13 interdisciplinary crises per year. Only 8% of otolaryngology residents had access to IDCRM training, as opposed to 66% of anesthesiology residents. Otolaryngology residents reported receiving an average of 0.3 hours per year of interdisciplinary training, as compared with 5.4 hours per year for pediatric emergency medicine residents. Ninety-six percent of residents desired more IDCRM training, with 95% reporting a preference for simulation-based training. Discussion: Residents reported participating in crises managed by interdisciplinary teams. There is strong interest in IDCRM and crisis resource management training; however, it is not uniformly available across Canadian residency programs. Despite their pivotal role in managing critical emergencies such as acute airway obstruction, otolaryngology residents received the least training. Implication: IDCRM should be explicitly taught since it reflects reality and may positively affect patient outcomes. PMID- 30480213 TI - Randomized Controlled Pilot Study of Video Self-assessment for Resident Mastoidectomy Training. AB - A prospective randomized controlled pilot study was performed to determine if video self-assessment improves competency in mastoidectomy and to assess interrater agreement between expert and resident evaluations of recorded mastoidectomy. Sixteen otolaryngology residents were recorded while performing cadaveric mastoidectomy and randomized into video self-assessment and control groups. All residents performed a second recorded mastoidectomy. Performance was evaluated by blinded experts with a validated assessment scale. Video self assessment did not lead to greater skill improvement between the first and second mastoidectomy. Interrater agreement was fair to substantial between the expert evaluators and between resident self-evaluations by recall and video review. Agreement between experts and residents was only slight to fair; residents consistently rated their performance higher than experts (P < .05). In conclusion, 1 session of video self-review did not lead to improved competence in mastoidectomy over standard practice. While experts agree on assessments, residents may overestimate their competency in performing cadaveric mastoidectomy. PMID- 30480214 TI - Design and Study of a Next-Generation Computer-Assisted System for Transoral Laser Microsurgery. AB - Objective: To present a new computer-assisted system for improved usability, intuitiveness, efficiency, and controllability in transoral laser microsurgery (TLM). Study Design: Pilot technology feasibility study. Setting: A dedicated room with a simulated TLM surgical setup: surgical microscope, surgical laser system, instruments, ex vivo pig larynxes, and computer-assisted system. Subjects and Methods: The computer-assisted laser microsurgery (CALM) system consists of a novel motorized laser micromanipulator and a tablet- and stylus-based control interface. The system setup includes the Leica 2 surgical microscope and the DEKA HiScan Surgical laser system. The system was validated through a first-of-its kind observational study with 57 international surgeons with varied experience in TLM. The subjects performed real surgical tasks on ex vivo pig larynxes in a simulated TLM scenario. The qualitative aspects were established with a newly devised questionnaire assessing the usability, efficiency, and suitability of the system. Results: The surgeons evaluated the CALM system with an average score of 6.29 (out of 7) in ease of use and ease of learning, while an average score of 5.96 was assigned for controllability and safety. A score of 1.51 indicated reduced workload for the subjects. Of 57 subjects, 41 stated that the CALM system allows better surgical quality than the existing TLM systems. Conclusions: The CALM system augments the usability, controllability, and efficiency in TLM. It enhances the ergonomics and accuracy beyond the current state of the art, potentially improving the surgical safety and quality. The system offers the intraoperative automated scanning of customized long incisions achieving uniform resections at the surgical site. PMID- 30480215 TI - Treatment Receipt and Outcomes of Self-Reported Voice Problems in the US Population Aged >=65 Years. AB - Objectives: (1) Characterize the US population aged >=65 years with self-reported voice problems, (2) describe voice treatment characteristics in this group, and (3) identify factors associated with self-reported voice improvement. Study Design: Retrospective cohort study. Setting: Population-based cross-sectional US national survey sample. Subjects and Methods: We identified a cohort of adults aged >=65 years from the 2012 National Health Interview Survey, a population based US national survey. Descriptive and multivariable regression analyses were performed. Results: The prevalence of self-reported voice problems in this cohort was 10%. Of those, 44% reported voice problems for >1 month. The strongest predictor of reporting voice improvement was receipt of voice treatment (odds ratio, 3.50; 95% confidence interval, 1.36-9.00), after adjusting for sex, age, race, education, and health status. Eleven percent reported voice treatment, which included 20% of those with moderate or worse voice problem severity. Female sex and worse health status were associated with reporting voice treatment. Among those with voice treatment, 38% reported "better," 33% "same," and 29% "worse" voice symptoms over the past year, compared to 17%, 67%, and 16%, respectively, among those without treatment. Health status influenced likelihood of reporting voice improvement but not universally. Conclusions: We observed a significant self-reported burden of voice problems in the US population aged >=65 years. Most are untreated and thus not well represented in the current literature. Vocal improvement was strongly associated with treatment. Further investigation is needed to clarify patient and treatment characteristics most associated with vocal improvement. PMID- 30480216 TI - Electronic Cigarette Awareness, Use, and Perceptions among Cancer Patients. AB - Objective: Electronic cigarettes (e-cigs) are an emerging trend, yet little is known about their use in the cancer population. The objectives of this study were (1) to describe characteristics of e-cig use among cancer patients, (2) to define e-cig advertising exposure, and (3) to characterize perceptions of traditional cigarettes versus e-cigs. Study Design: Cross-sectional study. Setting: Comprehensive cancer center. Subjects and Methods: Inpatient, current smokers with a cancer diagnosis. E-cig exposure and use were defined using descriptive statistics. Wilcoxon rank test was used to compare perceptions between e-cigs and traditional cigarettes. Results: A total of 979 patients were enrolled in the study; 39 cancer patients were identified. Most cancer patients were women (59%), with an average age of 53.3 years. Of the patients, 46.2% reported e-cig use, most of which (88.9%) was "experimental or occasional." The primary reason for e cig use was to aid smoking cessation (66.7%), alternative use in nonsmoking areas (22.2%), and "less risky" cigarette replacement (5.6%). The most common sources for e-cig information were TV (76.9%), stores (48.7%), friends (35.9%), family (30.8%), and newspapers or magazines (12.8%). Compared with cigarettes, e-cigs were viewed as posing a reduced health risk (P < .001) and conferring a less negative social impression (P < .001). They were also viewed as less likely to satisfy nicotine cravings (P = .002), to relieve boredom (P = .0005), to have a calming effect (P < .001), and as tasting pleasant (P = .006). Conclusions: E-cig use and advertising exposure are common among cancer patients. E-cig use is perceived as healthier and more socially acceptable but less likely to produce a number of desired consequences of cigarette use. PMID- 30480217 TI - ENT Outreach in Africa: Rules of Engagement. AB - To address inequality of access to ear, nose, and throat (ENT) care, there must be significant and sustained investment in education and training of surgeons, audiologists, speech therapists, clinical officers, anesthetists, and specialized nurses engaged in ENT in sub-Saharan Africa and other developing nations. Outreach by ENT surgeons from developed countries is essential if we are to address the critical lack of access to ENT care in SSA. However, it should be based on mutual respect, shared values, aspirations, a desire to create a durable and sustainable impact, and internationally accepted best practice. In this article, we propose rules of engagement for outreach projects in SSA and other developing countries to optimize their contributions by making them useful, sustainable, productive, and developmental. These proposed rules of engagement are based on our personal experiences and observations-good and bad-of outreach activities in our countries. PMID- 30480218 TI - Thyroid Cancer and Iodine Deficiency Status: A 10-Year Review at a Single Cancer Center in Tanzania. AB - Objective: To highlight the magnitude and distribution of thyroid cancer at the largest cancer center in Tanzania and to correlate patient region of residence with regions of dietary iodine adequacy and deficiency in the country. Study Design: A retrospective cross-sectional chart review to characterize patients with thyroid cancer and regions of residence. Setting: Ocean Road Cancer Institute (ORCI), the largest cancer center in Tanzania. Subjects and Methods: Subjects had histologically confirmed thyroid cancer and no history of cancer treatment. Between January 2006 and April 2016, the cases of 139 consecutive patients with thyroid cancer at ORCI were retrospectively reviewed. Patients were grouped into those from iodine-adequate and iodine-deficient regions, based on the Tanzania demographic and health survey. Results: Patients' median age was 47 years (range, 17-73 years), and the male:female ratio was 1:5. The number of people with thyroid cancer seen at ORCI increased steadily during the study period, with no significant difference between papillary (46%) and follicular (45%) diagnoses. Nonpapillary cancers occurred more frequently among males and patients >=45 years of age, but these did not reach statistical significance. Seventy-five percent of all thyroid cancers were from areas of iodine deficiency, and this was similar in papillary and follicular cancer subtypes. Conclusion: The incidence of differentiated thyroid cancer is increasing at the largest cancer center in Tanzania, whereby papillary and follicular subtypes were significantly higher in regions with long-standing dietary iodine deficiency. PMID- 30480219 TI - Fast thermoresponsive optical membrane using hydrogels embedded in macroporous silicon. AB - We have fabricated a temperature-sensitive hydrogel through copolymerization of N isopropylacrylamide (NIPAAm) and Acrylamide (AAm) inside a macroporous silicon structure and demonstrated fast thermal response compared to its bulk structure. The presented method allows physical arrangement of micro-sized hydrogels within a predefined arrayed structure. Static and dynamic temperature responses of the fabricated structure are successfully demonstrated through optical transmission measurement. The measured temporal response reveals that presented structure can allow fast response time of the implemented hydrogels. Furthermore, spatial thermo-distribution pattern can be observed through pixel-like, arrayed macropores, which indicates a potential for addressing individual or single channel hydrogel sensors or actuators through temperature stimulation. PMID- 30480220 TI - Editorial Seminars in MSK Radiology. PMID- 30480221 TI - Leadership Development for Hospital Physicians. PMID- 30480222 TI - DUO: an innovative multidrug delivery system. PMID- 30480223 TI - DNA Methylation and Chromatin: Role(s) of Methyl-CpG-Binding Protein ZBTB38. AB - DNA methylation plays an essential role in the control of gene expression during early stages of development as well as in disease. Although many transcription factors are sensitive to this modification of the DNA, we still do not clearly understand how it contributes to the establishment of proper gene expression patterns. We discuss here the recent findings regarding the biological and molecular function(s) of the transcription factor ZBTB38 that binds methylated DNA sequences in vitro and in cells. We speculate how these findings may help understand the role of DNA methylation and DNA methylation-sensitive transcription factors in mammalian cells. PMID- 30480224 TI - Whole-Day Gait Monitoring in Patients with Alzheimer's Disease: A Relationship between Attention and Gait Cycle. AB - Background: Gait impairment in patients with Alzheimer's disease (AD) and its relationship with cognitive function has been described, but reports of gait analysis in AD in daily living are limited. Objective: To investigate whether gait pattern of patients with AD in daily living is associated with cognitive function. Methods: Gait was recorded in 24 patients with AD and 9 healthy controls (HC) for 24 hours by using a portable gait rhythmogram. Mean gait cycle and gait acceleration were compared between the AD and HC groups. For the AD group, these gait metrics were assessed for correlations with cognitive function, as determined by the Mini Mental State Examination and Wechsler Memory Scale Revised (WMS-R). Results: Although both gait parameters were not different between the patients with AD and HC, gait cycle in patients with AD was positively correlated with attention/concentration scores on the WMS-R (r = 0.578), and not with memory function. Patients with AD with attention scores as high as HC displayed a longer gait cycle than both HC (p = 0.048) and patients with AD with lower attention scores (p = 0.011). The patients with AD with lower attention scores showed a similar gait cycle with HC (p = 0.994). Conclusion: Patients with AD with impaired attentional function walk with faster gait cycle comparable to HC in daily living walking, which was unexpected based on previous gait analysis in clinical settings. This result probably reflects diminished consciousness to either the environment or instability of gait in the patients with AD with impaired attention. PMID- 30480225 TI - When New Technology is an Answer for Old Problems: The Use of Videoconferencing in Cognitive Aging Assessment. AB - People living with cognitive impairment and dementia require regular screening of their symptomatology and needs. Brief cognitive screening is crucial for assessing these conditions. Such screening can give health professionals a snapshot of the patient's cognitive abilities and help in their monitoring and adaptation. An appropriate administration of brief cognitive screening using telemedicine technology, such as videoconference, can improve access to care and treatment planning. Moreover, the burden that rural and underserved communities often suffer because of limited access to specialty mental health services is also of concern. Herein, in this review, we describe the existing and relevant research regarding the administration of neuropsychological instruments via videoconferencing, and suggest methodological improvements for further studies. To date, only a handful of scientific studies have been published documenting the feasibility and acceptability of videoconferencing among older people and health professionals. Varying in their assessment tools, the studies demonstrate the reliability of cognitive testing and clinical diagnosis of dementia via videoconferencing, as noted by the associations between results of several cognitive tests using it as compared to face-to-face interviews. Further research is required to replicate findings and bring new solutions for their adaptation to a wide range of individuals, health professionals, areas of practice and settings. PMID- 30480226 TI - Aluminum Should Now Be Considered a Primary Etiological Factor in Alzheimer's Disease. AB - In this paper, I have summarized the experimental and largely clinical evidence that implicates aluminum as a primary etiological factor in Alzheimer's disease. The unequivocal neurotoxicity of aluminum must mean that when brain burdens of aluminum exceed toxic thresholds that it is inevitable that aluminum contributes toward disease. Aluminum acts as a catalyst for an earlier onset of Alzheimer's disease in individuals with or without concomitant predispositions, genetic or otherwise. Alzheimer's disease is not an inevitable consequence of aging in the absence of a brain burden of aluminum. PMID- 30480228 TI - The GABA-Working Memory Relationship in Alzheimer's Disease. AB - Alzheimer's disease (AD) is a highly debilitating neurodegenerative disease with no cure to date. Emerging evidence indicates aberrations of the primary inhibitory neurotransmitter GABA in the frontal, parietal and temporal cortices, and hippocampal regions of the AD brains. GABA levels have been reported to predict working memory (WM) load capacity in the healthy young population. Since working memory is impaired in AD, it opens an active area of research to investigate the influence of GABA on WM performance in AD. Advancements in neuroimaging techniques and signal processing tools can aid in neurochemical profiling of GABA in AD as well as facilitate in probing the role of GABA in AD specific impairments of working memory. PMID- 30480229 TI - Survival Curves and Behavioral Profiles of Female 3xTg-AD Mice Surviving to 18 Months of Age as Compared to Mice with Normal Aging. AB - New evidence reveals a high degree of heterogeneity in Alzheimer's disease (AD) clinical and temporal patterns, supporting the existence of several subgroups of patients. Prognosticators of end-of-life dementia specific to elderly patients are necessary to address this heterogeneity. Among 3xTg-AD mice, a widely-used model for AD, a very small number of animals overcome advanced neuropathological stages of disease beyond 18 months of age. They are usually females, which reach longevity in spite of worse neuropathological status as compared to males (the morbidity/mortality paradox). We posit that 3xTg-AD long-term survivors could serve to model end-of-life dementia but also aware about the mortality selection bias. In the present study, we performed behavioral and functional phenotype in long-term survivors, 18-month-old female 3xTg-AD mice and age-matched wildtype undergoing normal aging. Animals were followed up until natural death to correlate survival with phenotype assessments. Strong similarity of their behavioral profiles in all the variables analyzed (e.g. reflexes, sensorimotor functions, locomotion, exploration, emotionality, and anxiety-like behaviors) was found, with the exception of memory impairment, which was a salient trait in old 3xTg-AD survivors. The two groups showed similar mean life expectancy and had behavioral correlates among lifespan, neophobia and long-term memory in common, with some distinctions in 3xTg-AD, supporting recent studies in end-of-life patients. In spite of the small sample size, this brief report presents an interesting scenario to further study heterogeneity and survival in Alzheimer's disease. 3xTg-AD survivors may be a model to gain insight into the frailty/survival paradigm in normal and pathological aging. PMID- 30480227 TI - Overview and Current Status of Alzheimer's Disease in Bangladesh. AB - Alzheimer's disease (AD) is a complex neurological disorder with economic, social, and medical burdens which is acknowledged as leading cause of dementia marked by the accumulation and aggregation of amyloid-beta peptide and phosphorylated tau (p-tau) protein and concomitant dementia, neuron loss and brain atrophy. AD is the most prevalent neurodegenerative brain disorder with sporadic etiology, except for a small fraction of cases with familial inheritance where familial forms of AD are correlated to mutations in three functionally related genes: the amyloid-beta protein precursor and presenilins 1 and 2, two key gamma-secretase components. The common clinical features of AD are memory impairment that interrupts daily life, difficulty in accomplishing usual tasks, confusion with time or place, trouble understanding visual images and spatial relationships. Age is the most significant risk factor for AD, whereas other risk factors correlated with AD are hypercholesterolemia, hypertension, atherosclerosis, coronary heart disease, smoking, obesity, and diabetes. Despite decades of research, there is no satisfying therapy which will terminate the advancement of AD by acting on the origin of the disease process, whereas currently available therapeutics only provide symptomatic relief but fail to attain a definite cure and prevention. This review also represents the current status of AD in Bangladesh. PMID- 30480231 TI - Interictal Epileptiform Activity in the Foramen Ovale Electrodes of a Frontotemporal Dementia Patient. AB - Frontotemporal dementia (FTD) is a frequent cause of cognitive decline. While epilepsy is an important comorbidity of Alzheimer's disease, we lack studies on its presence in FTD. We report on an FTD patient with transient, short-term changes of behavior and cognitive performance suggesting non-convulsive epilepsy. Video-EEG recording with foramen ovale (FO) electrodes revealed mesio-temporal epileptiform potentials, undetectable by scalp leads. We also found beta spindles in the FO electrodes, not described in the literature. We conclude that video-EEG monitoring with FO electrodes might usefully complement the assessment of dementia-associated epilepsy opening new perspectives in dementia-research. PMID- 30480230 TI - Imaging Biomarkers in Alzheimer's Disease: A Practical Guide for Clinicians. AB - Although recent developments in imaging biomarkers have revolutionized the diagnosis of Alzheimer's disease at early stages, the utility of most of these techniques in clinical setting remains unclear. The aim of this review is to provide a clear stepwise algorithm on using multitier imaging biomarkers for the diagnosis of Alzheimer's disease to be used by clinicians and radiologists for day-to-day practice. We summarized the role of most common imaging techniques and their appropriate clinical use based on current consensus guidelines and recommendations with brief sections on acquisition and analysis techniques for each imaging modality. Structural imaging, preferably MRI or alternatively high resolution CT, is the essential first tier of imaging. It improves the accuracy of clinical diagnosis and excludes other potential pathologies. When the results of clinical examination and structural imaging, assessed by dementia expert, are still inconclusive, functional imaging can be used as a more advanced option. PET with ligands such as amyloid tracers and 18F-fluorodeoxyglucose can improve the sensitivity and specificity of diagnosis particularly at the early stages of the disease. There are, however, limitations in using these techniques in wider community due to a combination of lack of facilities and expertise to interpret the findings. The role of some of the more recent imaging techniques including tau imaging, functional MRI, or diffusion tensor imaging in clinical practice, remains to be established in the ongoing and future studies. PMID- 30480232 TI - Methylation Profiling RIN3 and MEF2C Identifies Epigenetic Marks Associated with Sporadic Early Onset Alzheimer's Disease. AB - A number of genetic loci associate with early onset Alzheimer's disease (EOAD); however, the drivers of this disease remains enigmatic. Genome wide association and in vivo modeling have shown that loss-of-function, e.g., ABCA7, reduced levels of SIRT1 and MEFF2C, or increased levels of PTK2beta confer risk or link to the pathogenies. It is known that DNA methylation can profoundly affect gene expression and can impact on the composition of the proteome; therefore, the aim of this study is to assess if genes associated with sporadic EOAD (sEOAD) are differentially methylated. Epi-profiles of DNA extracted from blood and cortex were compared using a pyrosequencing platform. We identified significant group wide hypomethylation in AD blood when compared to controls for 7 CpGs located within the 3'UTR of RIN3 (CpG1 p = 0.019, CpG2 p = 0.018, CpG3 p = 0.012, CpG4 p = 0.009, CpG5 p = 0.002, CpG6 p = 0.018, and CpG7 p = 0.013, respectively; AD/Control n = 22/26; Male/Female n = 27/21). Observed effects were not gender specific. No group wide significant differences were found in the promoter methylation of PTK2beta, ABCA7, SIRT1, or MEF2C, genes known to associate with late onset AD. A rare and significant difference in methylation was observed for one CpG located upstream of the MEF2C promoter in one AD individual only (22% reduction in methylation, p = 2.0E-10; Control n = 26, AD n = 25, Male/Female n = 29/22). It is plausible aberrant methylation may mark sEOAD in blood and may manifest in some individuals as rare epi-variants for genes linked to sEOAD. PMID- 30480233 TI - Perfusion-Phase [18F]THK5351 Tau-PET Imaging as a Surrogate Marker for Neurodegeneration. AB - We aimed to test if early, perfusion phase tau-PET imaging with [18F]THK5351 might substitute for [18F]FDG PET information on neurodegeneration, as has been previously shown for amyloid-tracers. A patient with cognitive impairment and positive amyloid-PET was examined by [18F]THK5351 tau-PET and [18F]FDG PET. The pattern of early phase of [18F]THK5351 uptake was compared to [18F]FDG visually and by the dice similarity coefficient. Visual inspection of axial slices and stereotactic-surface projection indicated a striking agreement between combined 0 2 min p.i. perfusion images of [18F]THK5351 and standard [18F]FDG 30-60 min p.i. A two-phase protocol of [18F]THK5351 PET might give information on neurodegeneration and tau pathology in a single session. PMID- 30480235 TI - Optimal Cut-Off Value for Locus Coeruleus-to-Pons Intensity Ratio as Clinical Biomarker for Alzheimer's Disease: A Pilot Study. AB - Background: Studies using neuromelanin-sensitive-MRI have established the locus coeruleus (LC)-to-pons intensity ratio as a biomarker for diagnosis of Parkinson's and Alzheimer's diseases. More detailed analysis is needed for exploiting the highest clinical potential of this technique. Objective: The aim is to determine the location of the highest LC-to-pons ratio within the LC and develop an easy-to-use tool for clinical application. Methods: Ten patients diagnosed with various stages of Alzheimer's disease (74.1+/-3.9 years, range 68 80, 7 females) and ten healthy elderly subjects (72.4+/-3.1 years, range 68-77, 5 females) participated in the study. Five subsequent slices with a thickness of 2.5 millimeters were analyzed using the image analysis tool FSL, starting with the first slice below inferior colliculus. The outcome variable was the intensity ratio between maximum values of LC and adjacent pontine region. Results: The section located 10 millimeters below the inferior colliculus has the highest potential in differentiating between healthy controls and patients, with the intensity-ratio difference between groups of 12.3% and effect size of 1.577. For the cut-off value of 1.09, the sensitivity and specificity values were 100% and 80%, respectively. Conclusion: We consider the method a promising clinical tool to aid AD diagnosis workup. PMID- 30480236 TI - Differential Effect of APOE Alleles on Brain Glucose Metabolism in Targeted Replacement Mice: An [18F]FDG-MUPET Study. AB - Background: The Apolipoprotein E (ApoE) alleles E2, E3, and E4 are known to differentially modulate cerebral glucose metabolism and the risk for Alzheimer's disease (AD) via both amyloid-beta (Abeta)-dependent and independent mechanisms. Objective: We investigated the influence of ApoE on cerebral glucose metabolism in humanized APOE Targeted Replacement (TR) mice at ages that precede the comparison of Abeta parenchymal deposits in APOE4-TR mice. Methods: Fludeoxyglucose ([18F]FDG) positron emission tomography (PET) measures were performed longitudinally in homozygous APOE-TR mice (APOE2, APOE3, APOE4; n = 10 for each group) at 3, 5, 11, and 15 months. Results were quantified using standard uptake values and analyzed statistically using a linear mixed effects model. Levels of the Abeta40 and Abeta42 peptides were quantified ex vivo using enzyme-linked immunosorbent assay (ELISA) at 15 months in the same animals. Results: APOE2 mice (versus APOE3) showed a significant increase in glucose metabolism starting at 6 months, peaking at 9 months. No evidence of hypometabolism was apparent in any region or time point for APOE4 mice, which instead displayed a hypermetabolism at 15 months. Whole brain soluble Abeta40 and Abeta42 levels were not significantly different between genotypes at 15 months. Conclusions: Introduction of human APOE alleles E2 and E4 is sufficient to produce alterations in brain glucose metabolism in comparison to the control allele E3, without a concomitant alteration in Abeta40 and Abeta42 levels. These results suggest novel Abeta-independent metabolic phenotypes conferred by E2 and E4 alleles and have important implications for preclinical studies using TR-mice. PMID- 30480237 TI - The Effects of Mindfulness on Older Adults with Mild Cognitive Impairment. AB - Background: The current lack of an effective cure for dementia would exacerbate its prevalence and incidence globally. Growing evidence has linked mindfulness to cognitive and psychological improvements that could be relevant for mild cognitive impairment (MCI). Objective: To investigate whether mindfulness practice can improve health outcomes of MCI. Methods: The study is the first longitudinal mixed-methods observational study with a one-year follow-up period, that customized an eight-week group-based mindfulness training program for older adults with MCI (n = 14). Measures included cognitive function, psychological health, trait mindfulness, adherence to mindfulness practice, and everyday activities functioning as assessed at pre-intervention, post-intervention, and one-year follow-up. Repeated measures ANOVAs, Pearson's correlation analyses, and Mann-Whitney U tests were performed. Results: The MCI participants showed significant improvements in cognitive function (p < 0.05) and trait mindfulness (p < 0.05) after completing the intervention. Between program intervention and one-year follow-up (59 weeks), positive correlations were found between their cognitive function (p < 0.05) and everyday activities functioning (p < 0.05) with the duration of mindfulness meditation; and between trait mindfulness and the level of informal mindfulness practice (p < 0.05). Those who meditated more during these 59 weeks, showed greater improvements in cognitive function (p < 0.05) and everyday activities functioning (p < 0.05), with large effect sizes at the one-year follow-up. Qualitative findings will be reported separately. Conclusion: Long-term mindfulness practice may be associated with cognitive and functional improvements for older adults with MCI. Mindfulness training could be a potential efficacious non-pharmacological therapeutic intervention for MCI. PMID- 30480234 TI - Genetic, Transcriptome, Proteomic, and Epidemiological Evidence for Blood-Brain Barrier Disruption and Polymicrobial Brain Invasion as Determinant Factors in Alzheimer's Disease. AB - Diverse pathogens are detected in Alzheimer's disease (AD) brains. A bioinformatics survey showed that AD genome-wide association study (GWAS) genes (localized in bone marrow, immune locations and microglia) relate to multiple host/pathogen interactomes (Candida albicans, Cryptococcus neoformans, Bornavirus, Borrelia burgdorferri, cytomegalovirus, Ebola virus, HSV-1, HERV-W, HIV-1, Epstein-Barr, hepatitis C, influenza, Chlamydia pneumoniae, Porphyrymonas gingivalis, Helicobacter pylori, Toxoplasma gondii, Trypanosoma cruzi). These interactomes also relate to the AD hippocampal transcriptome and to plaque or tangle proteins. Upregulated AD hippocampal genes match those upregulated by multiple bacteria, viruses, fungi, or protozoa in immunocompetent cells. AD genes are enriched in GWAS datasets reflecting pathogen diversity, suggesting selection for pathogen resistance, as supported by the old age of AD patients, implying resistance to earlier infections. APOE4 is concentrated in regions of high parasitic burden and protects against childhood tropical infections and hepatitis C. Immune/inflammatory gain of function applies to APOE4, CR1, and TREM2 variants. AD genes are also expressed in the blood-brain barrier (BBB), which is disrupted by AD risk factors (age, alcohol, aluminum, concussion, cerebral hypoperfusion, diabetes, homocysteine, hypercholesterolemia, hypertension, obesity, pesticides, pollution, physical inactivity, sleep disruption, smoking) and by pathogens, directly or via olfactory routes to basal-forebrain BBB control centers. The BBB benefits from statins, NSAIDs, estrogen, melatonin, memantine, and the Mediterranean diet. Polymicrobial involvement is supported by upregulation of bacterial, viral, and fungal sensors/defenders in the AD brain, blood, or cerebrospinal fluid. AD serum amyloid-beta autoantibodies may attenuate its antimicrobial effects favoring microbial survival and cerebral invasion leading to activation of neurodestructive immune/inflammatory processes, which may also be augmented by age-related immunosenescence. AD may thus respond to antibiotic, antifungal, or antiviral therapy. PMID- 30480238 TI - Efficacy and Safety of the Immunization with DNA for Alzheimer's Disease in Animal Models: A Systematic Review from Literature. AB - Background: Alzheimer's disease (AD) is a neurodegenerative disease that does not have a proven cure; however, one of the most promising strategies for its treatment has been DNA vaccines. Objective: The present review is aimed to report the new developments of the efficacy and safety of DNA vaccines for AD in animal models. Method: The method PRISMA was used for this review. The article search was made in the electronic databases PubMed, LILACS, and Scopus using the descriptors ''Alzheimer disease" and ''Vaccine, DNA". Articles published between January 2001 and September 2017 in English, Portuguese, and Spanish were included. Results: Upon the consensus, the researchers identified 28 original articles. The studies showed satisfying results as for the decrease of amyloid plaques in mouse, rabbits, and monkeys brains using mostly the DNA Abeta42 vaccine, AV-1955, and AdPEDI-(Abeta1-6)11, mainly with a gene gun. In addition to a reduction in tau by the first DNA vaccine (AV-1980D) targeting this protein. The use of adjuvants and boosters also had positive results as they increased the destruction of the amyloid plaques and induced an anti-inflammatory response profile without side effects. Conclusion: The results of DNA vaccines targeting the amyloid-beta and the tau protein with or without adjuvants and boosters were promising in reducing amyloid plaques and tau protein without side effects in animals. Although there are many vaccines being tested in animals, few reach clinical trials. Thus, as a future perspective, we suggest that clinical studies should be conducted with vaccines that have been promising in animal models (e.g., DNA Abeta42 vaccine, AV-1955, and AdPEDI-(Abeta1-6)11). PMID- 30480239 TI - Midlife Work-Related Stress is Associated with Late-Life Gray Matter Volume Atrophy. AB - Background: Work-related stress has been associated with an increased dementia risk. However, less is known about the mechanisms that underlie these associations. Objective: The goal is to examine associations between midlife work related stress and late-life structural brain alterations. Methods: The Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study participants were randomly selected from independent population-based surveys (mean age 50) in Finland. MRI measurements included gray matter (GM) volume, white matter lesions (WML) and medial temporal atrophy (MTA) (1st re-examination, n = 102); and GM volume, hippocampal volume, WML volume, cortical thickness, and MTA (2nd re examination, n = 64). Work-related stress comprised a score from two questions administered in midlife. Results: Higher levels of midlife work-related stress were associated with lower GM volume (beta= -0.077, p = 0.033) at the first re examination, even after adjusting for several confounders. No significant associations were found with MTA, WML, or MRI measurements at the second re examination. Conclusion: Previously shown associations of midlife work-related stress with dementia risk may be at least partly explained by associations with lower GM volume in late-life. The lack of associations at the second re examination may indicate a critical time window for the effects of midlife work related stress, and/or selective survival/participation. PMID- 30480240 TI - A Possibility of Simultaneous Treatment with the Multicomponent Drug, Ninjin'yoeito, for Anorexia, Apathy, and Cognitive Dysfunction in Frail Alzheimer's Disease Patients: An Open-Label Pilot Study. AB - A recent classification analysis of neuropsychiatric symptoms in patients with Alzheimer's disease (AD) revealed a distinct cluster with apathy and eating problems including anorexia that exhibits frailty. The apathy and frailty are risk factors in the disease progresses. However, there is currently no effective drug for treating both anorexia and apathy in AD. Here, we conducted an open label pilot study to determine whether ninjin'yoeito (NYT, TJ-108), a multicomponent drug, is effective for improving anorexia and apathy in patients with AD, and consequently their cognitive function. Trials were conducted at three sites in Japan. Twenty patients [4 men and 16 women, average age = 82.6+/ 7.7 (mean+/-SD) years old], including 19 AD and 1 mixed dementia with anorexia/apathy, were examined. NYT (6-9 g/day) was administered for 12 weeks. The changes in scores for "anorexia" using the Neuropsychiatric Inventory (NPI) subcategory for eating disturbance (primary outcome measure), NPI including "apathy", the vitality index, Mini-Mental State Examination (MMSE), and physical and blood nutrition indices were evaluated at baseline (week 0), and weeks 4, 8 and 12. After week 4, significant improvements were observed in the scores for "anorexia" and "apathy" by NPI and meal ingestion amount. Vitality index and MMSE score were significantly improved by week 12. We propose that NYT, a multicomponent drug with several effects including dopamine modulation, is a new type dementia therapeutic agent with low risk of adverse reactions that can improve simultaneously anorexia/apathy, as well as cognitive dysfunction in frail AD patients. PMID- 30480241 TI - Deletion of Alzheimer's Disease Risk Gene ABCA7 Alters White Adipose Tissue Development and Leptin Levels. AB - ATP-binding cassette A7 (ABCA7) is a genetic risk factor for late-onset Alzheimer's disease (AD). It belongs to a group of transporter genes that specializes in regulating lipid transport in the periphery as well as in the brain. ABCA7 has been implicated in a number of roles relating to AD pathology, including phagocytic clearance of amyloid-beta peptides. We have discovered that deletion of ABCA7 in mouse causes a dramatic reduction in white adipose tissue (WAT) in female mice. WAT is important in AD context because it is the primary producer of leptin, which is a hormone that is known to modulate AD neuropathology. WAT in male Abca7-/- mice was not altered. The pathological link between ABCA7 and WAT that impacts on AD is unknown. Our transcription analysis revealed that lipin-1 expression was significantly upregulated in female Abca7-/- mice, indicating that ABCA7 affects WAT development. The circulating leptin level was significantly reduced in female Abca7-/- mice without any change in WAT leptin mRNA or protein expression, indicating that ABCA7 does not affect leptin production, but alters the circulating leptin level indirectly by affecting WAT development. Insulin is a key hormone that regulates WAT development, i.e., adipogenesis, and it was significantly reduced in female Abca7-/- mice. These data when put together suggest that ABCA7 plays a role in regulating WAT development and consequently circulating leptin levels, which are known to modulate AD neuropathology. PMID- 30480242 TI - Validation of the English Version of the Multimodal Assessment of Capacities in Severe Dementia (MAC-SD): A Cognitive and Functional Scale for Use in Severe Dementia. AB - Background: Most existing screening instruments that assess cognition and functioning in dementia suffer from floor effects, limiting their utility in severely demented patients. In 2015, the first author devised a new instrument, The Multimodal Assessment of Capacities in Severe Dementia (MAC-SD), to address this need. The MAC-SD Spanish version proved reliable, valid, and useful for evaluating patients with severe dementia. Objective: This report presents the results of a field trial of the English version of the MAC-SD in a U.S. population. Methods: The MAC-SD was administered to 40 participants with severe dementia along with gold standard measures of cognition and functioning in dementia (the Severe Mini-Mental State Exam, the Severe Impairment Battery, the Global Deterioration Scale, and the Barthel Index of Activities of Daily Living). Data analysis was performed to determine floor effects, reliability, validity, sensitivity to change, and clinical usefulness. Results: The MAC-SD showed no significant floor effects, acceptable reliability, convergent validity with control measures, internal validity, and known groups validity. Of participants who scored the lowest possible on control measures, MAC-SD scores ranged widely. The MAC-SD was highly sensitive to change, and was able to detect changes not seen on control measures. Conclusions: The MAC-SD English version is reliable and valid for use in the cognitive and functional assessment of patients with severe dementia. It gives more detailed information than control instruments about the cognitive and functional abilities of patients with the most severe dementia, and is able to detect changes in these patients not shown by control measures. PMID- 30480244 TI - Studies on Copper and Abeta1-16-Induced Conformational Changes in CAG/CTG Trinucleotide Repeats Sequence. AB - DNA conformation and stability are critical for the normal cell functions, which control many cellular processes in life, such as replication, transcription, DNA repair, etc. The accumulation of amyloid-beta peptide (Abeta) and Copper (Cu) are the etiological factors for neurodegenerative diseases and hypothesized that they can cause DNA instability. In the current investigation, we studied copper and Abeta1-16 induced conformation and stability changes in CAG/CTG sequences and found alterations from B-DNA to altered B-conformation. Further, the interaction of the copper and Abeta1-16 with CAG/CTG sequences was studied by molecular docking modeling and results indicated that the interaction of copper and Abeta1 16 was through the hydrogen bond formation between adenine, guanine, and cytocine. This study illustrates the role of the copper and Abeta1-16 in modulating the DNA conformation and stability. PMID- 30480243 TI - Prion Protein PRNP: A New Player in Innate Immunity? The Abeta Connection. AB - The prion protein PRNP has been centrally implicated in the transmissible spongiform encephalopathies (TSEs), but its normal physiological role remains obscure. We highlight emerging evidence that PRNP displays antimicrobial activity, inhibiting the replication of multiple viruses, and also interacts directly with Alzheimer's disease (AD) amyloid-beta (Abeta) peptide whose own antimicrobial role is now increasingly secure. PRNP and Abeta share share membrane-penetrating, nucleic acid binding, and antiviral properties with classical antimicrobial peptides such as LL-37. We discuss findings that binding of abnormal nucleic acids to PRNP leads to oligomerization of the protein, and suggest that this may be an entrapment and sequestration process that contributes to its antimicrobial activity. Some antimicrobial peptides are known to be exploited by infectious agents, and we cover evidence that PRNP is usurped by herpes simplex virus (HSV-1) that has evolved a virus-encoded 'anti PRNP'.unction. These findings suggest that PRNP, like LL-37 and Abeta, is likely to be a component of the innate immune system, with implications for the pathoetiology of both AD and TSE. PMID- 30480245 TI - Increased All-Cause Mortality by Antipsychotic Drugs: Updated Review and Meta Analysis in Dementia and General Mental Health Care. AB - It is almost ten years since the Banerjee 2009 report established that inappropriate prescribing of antipsychotics in the elderly was occurring in the UK and such patients had an 85% increased risk of adverse events and greater mortality. This report was a critical analysis addressing the outcomes of treatment practices for dementia in UK patients and globally, aimed at reducing prescribing of antipsychotic drugs for dementia. Since 2009, many significant studies worldwide (including several more recent large retrospective studies) provide more extensive longitudinal data for the adverse impacts of antipsychotic drugs in dementia. We have used the data in these studies including from over 380,000 dementia patients, with 85,069 prescribed antipsychotic agents as well as from 359,235 non-dementia antipsychotic drug users to provide an up-dated meta analysis. This is the first meta-analysis to include evidence from general mental health studies showing that antipsychotic drugs precipitate excessive mortality across the spectrum. Prescribing of antipsychotic drugs for dementia or for other mental health care should be avoided and alternative means sought for handling behavioral disorders of such patients. PMID- 30480247 TI - Atomic Force Microscopy Analysis of EPPS-Driven Degradation and Reformation of Amyloid-beta Aggregates. AB - Amyloid-beta (Abeta) peptides can be aggregated into beta-sheet rich fibrils or plaques and deposited on the extracellular matrix of brain tissues, which is a hallmark of Alzheimer's disease. Several drug candidates have been designed to retard the progression of the neurodegenerative disorder or to eliminate toxic Abeta aggregates. Recently, 4-(2-Hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS) has emerged as a promising drug candidates for elimination of toxic Abeta aggregates. However, the effect of EPPS on the degradation of Abeta aggregates such as fibrils has not yet been fully elucidated. In this article, we investigate the EPPS-driven degradative behavior of Abeta aggregates at the molecular level by using high-resolution atomic force microscopy. We synthesized Abeta fibrils and observed degradation of fibrils following treatment with various concentrations (1-50 mM) of EPPS for various time periods. We found that degradation of Abeta fibrils by EPPS increased as a function of concentration and treatment duration. Intriguingly, we also found regeneration of Abeta aggregates with larger sizes than original aggregates at high concentrations (10 and 50 mM) of EPPS. This might be attributed to a shorter lag phase that facilitates reformation of Abeta aggregates in the absence of clearance system. PMID- 30480246 TI - The Bri2 and Bri3 BRICHOS Domains Interact Differently with Abeta42 and Alzheimer Amyloid Plaques. AB - Alzheimer's disease (AD) is the most common form of dementia and there is no successful treatment available. Evidence suggests that fibril formation of the amyloid beta-peptide (Abeta) is a major underlying cause of AD, and treatment strategies that reduce the toxic effects of Abeta amyloid are sought for. The BRICHOS domain is found in several proteins, including Bri2 (also called integral membrane protein 2B (ITM2B)), mutants of which are associated with amyloid and neurodegeneration, and Bri3 (ITM2C). We have used mouse hippocampal neurons and brain tissues from mice and humans and show Bri3 deposits dispersed on AD plaques. In contrast to what has been shown for Bri2, Bri3 immunoreactivity is decreased in AD brain homogenates compared to controls. Both Bri2 and Bri3 BRICHOS domains interact with Abeta40 and Abeta42 present in neurons and reduce Abeta42 amyloid fibril formation in vitro, but Bri3 BRICHOS is less efficient. These results indicate that Bri2 and Bri3 BRICHOS have different roles in relation to Abeta aggregation. PMID- 30480248 TI - Cognitive Decline: Not Always Alzheimer's Disease. AB - A 66-year-old woman presented with slowly progressive cognitive decline. MRI showed bi-frontotemporal atrophy, but the 14.3.3 protein was not present in cerebrospinal fluid. Electroencephalogram was irrelevant. Interview with relatives led doctors to search for a genetic cause and confirmed the diagnosis of Gerstmann-Straussler-Scheinker syndrome. PMID- 30480249 TI - Melatonin Effects on EEG Activity During Sleep Onset in Mild-to-Moderate Alzheimer's Disease: A Pilot Study. AB - There is evidence demonstrating that 5-mg of fast-release melatonin significantly reduces nocturnal sleep onset in patients with mild-to-moderate Alzheimer's disease (AD). However, the physiological mechanism that could promote sleep installation by melatonin in patients with AD is still poorly understood. The present pilot study was designed to analyze the effects of melatonin on cortical activity during the sleep onset period (SOP) in eight mild-to-moderate AD patients treated with 5-mg of fast-release melatonin. Electroencephalographic recordings were obtained from C3-A1, C4-A2, F7-T3, F8-T4, F3-F4, and O1-O2. The relative power (RP), interhemispheric, intrahemispheric, and fronto-posterior correlations of six electroencephalographic bands were calculated and compared between two conditions: placebo and melatonin. Results show that at F7-T3, F3-F4, and C3-A1, melatonin induced an increase of the RP of the delta band. Likewise, in F7-T3, melatonin induced a decrease of the RP in the alpha1 band. Similarly, results show a lower interhemispheric correlation between the F7-T3 and F8-T4 derivations in the alpha1 band compared to the placebo condition. We conclude that the short sleep onset related to melatonin intake in AD patients was associated with a lower RP of the alpha1, a higher RP of the delta band (mainly in the left hemisphere) and a decreased interhemispheric EEG coupling in the alpha1 band. The possible role of the GABAergic neurotransmission as well as of the cascade of neurochemical events that melatonin triggers on sleep onset are discussed. PMID- 30480250 TI - Long-Term Non-Invasive Treatment via Intranasal Administration of Nerve Growth Factor Protects the Human Brain in Frontotemporal Dementia associated with Corticobasal Syndrome: A Pilot Study. AB - Background: Nerve growth factor (NGF) is known for playing a critical protective role on a number of brain neurons in mammals, including humans. NGF can be delivered to the CNS via nasal route and has a neuroprotective action in case of neurodegenerative diseases. Objective: The aim of this study is to investigate for the first time whether purified NGF can play a neuroprotective role on human brain neurons affected by neurodegenerative diseases when administered via nasal route. Methods: Two female patients, both affected by frontotemporal dementia (FTD) associated with corticobasal syndrome (CBS) at different stages of disease progression, received a daily intranasal NGF spray for one year. Clinical/neurological aspects were observed over time. The follow-up study was performed using 18 FDG PET. Results: This case study seems to demonstrate that IN NGF slows down the common decline caused by FTD/CBS. Conclusions: These findings suggest the potential neuroprotective role of IN-NGF administered in case of neurodegenerative diseases. PMID- 30480252 TI - Cognitive Functioning Differences Between Physically Active and Sedentary Older Adults. AB - Older adults engaging in regular physical activity can help create a buffer toward cognitive decline. The main aim of this study was to assess the effects of physical activity and cognitive functioning on a sample of young-old and old-old physically active adults and young-old and old-old sedentary adults. Cognitive functioning was examined using the digit span test, Wisconsin card sorting task. The National Task Group-Early Detection Screen for Dementia measure was used explore the relationship between scores and physical activity and sedentary adults. Findings from the study showed partial support for physical activity has a positive relationship with cognitive functioning. The results found Young-old adults did better on the DST than all other groups regardless of being sedentary or physically active. Young-old physically active adults, however, did better on the DST latency measure than sedentary adults while old-old physically active adults did worse on the DST latency measure compared with old-old sedentary adults. The results also found that Physically active adults had a better score on the NTG-EDSD measure compared to the sedentary adults. Findings showed no significant differences for the WCST. Future research exploring the relationship between physical activity and cognitive functioning should do so by having more control over the extraneous variables. PMID- 30480251 TI - Neonatal Neurodegeneration in Alzheimer's Disease Transgenic Mouse Model. AB - Alzheimer's disease (AD) is a progressive disorder characterized by a variety of molecular pathologies causing cortical dementia with a prominent memory deficit. Formation of the pathology, which begins decades before the diagnosis of the disease, is highly correlated with the clinical symptoms. Several proteomics studies were performed using animal models to monitor the alterations of the brain tissue proteome at different stages of AD. However, proteome changes in the brain regions of newborn transgenic mouse model have not been investigated yet. To this end, we analyzed protein expression alterations in cortex, hippocampus and cerebellum of transgenic mice carrying five familial AD mutations (5XFAD) at neonatal day-1. Our results indicate a remarkable difference in protein expression profile of newborn 5XFAD brain with region specific variations. Additionally, the proteins, which show similar expression alteration pattern in postmortem human AD brains, were determined. Bioinformatics analysis showed that the molecular alterations were mostly related to the cell morphology, cellular assembly and organization, and neuroinflammation. Moreover, morphological analysis revealed that there is an increase in neurite number of 5XFAD mouse neurons in vitro. We suggest that, molecular alterations in the AD brain exist even at birth, and perhaps the disease is silenced until older ages when the brain becomes vulnerable. PMID- 30480253 TI - Human Brain Single Nucleotide Polymorphism: Validation of DNA Sequencing. AB - Genetic factors may be involved in the onset of neurodegenerative diseases like Alzheimer's disease. In the case of the familial type, the disease is due to an inherited mutation at specific sites in three genes. Also, there are some genetic risk factors that facilitate the development of sporadic Alzheimer's disease. All of these genetic analyses were performed using blood samples as a source of DNA. However, the presence of somatic mutations in the brain can be identified only using brain samples. In this review, we comment on a method that correctly identifies single nucleotide variations in the human brain and that can be used to validate high-through sequencing techniques. This method involves selective enrichment of the DNA population bearing the nucleotide variations, thereby facilitating posterior validation of the data by Sanger's sequencing. PMID- 30480254 TI - Aripiprazole for the Treatment of Inappropriate Sexual Behavior: Case Report of an Alzheimer's Disease Patient Known as Heterosexual with Recently Shifted Sexual Orientation to Same Gender. AB - Although inappropriate sexual behavior in dementia is not common, it can be extremely troublesome for healthcare professionals and caregivers as well as patients themselves. There is paucity of data in the literature for the management of these behaviors, but the limited available data suggest efficiency of some commonly used treatment modalities. Herein, we present a 74-year old Alzheimer's disease (AD) patient, known to be heterosexual throughout her past life, presenting with a recent display of same-sex inappropriate sexual behavior six years after the initial diagnosis of her disease. This new clinical picture of hypersexuality responded well to aripiprazole and her symptoms gradually diminished and eventually disappeared after onset of medication. This report also constitutes the first reported case of an AD patient in the published literature presenting with hypersexuality of shifted sexual orientation during the course of the disease. PMID- 30480255 TI - No Relationship of Anti-Androgens to Alzheimer's Disease or Cognitive Disorder in the MedWatch Database. AB - Background: Two large studies suggest that risk is not increased. But other studies have found increased risk of Alzheimer's disease and impaired cognition. Objective: To determine whether androgen deprivation therapy increases the risk of impaired cognition or Alzheimer's disease in men with prostate cancer. Methods: We used data from MedWatch, the Food and Drug Administration (FDA) Safety Information and Adverse Event Reporting Program. Machine-readable data from MedWatch, including adverse drug reaction reports from manufacturers, are part of a public database. We used the online tool OpenVigil 2.1 to query the database. OpenVigil calculates proportional reporting ratios (PRRs) from adverse drug reaction reports to determine whether the combination of drug and adverse event are related. For example, PRR = 2 indicates that the adverse reaction is two times more frequent in users of the drug than in the general population. Results: We analyzed adverse event reporting data for these androgen-deprivation drugs: The luteinizing hormone releasing hormone (LHRH) agonists leuprolide, goserelin triptorelin, histrelin; the anti-androgens flutamide, nilutamide, enzalutamide, and bicalutamide; the LHRH antagonist degarelix; the CYP17 inhibitor abiraterone; the anti-fungal ketoconazole, which is also an anti androgen administered to men with advanced prostate cancer. Conclusion: Our analysis of FDA MedWatch adverse event data reports does not support the idea that androgen deprivation therapy per se is associated with Alzheimer's disease or cognitive dysfunction. Perhaps the prostate cancer itself, or the stress it imposes on the man who has it, may be detrimental to mood and intellect, increasing susceptibility to Alzheimer's disease and cognitive disorder. PMID- 30480256 TI - RNA-Sequencing Reveals Similarities and Differences in Gene Expression in Vulnerable Brain Tissues of Alzheimer's and Parkinson's Diseases. AB - Background: Neuropathological changes of Alzheimer's disease (AD) and Parkinson's disease (PD) can coexist in the same sample, suggesting possible common degenerative mechanisms. Objective: The objective of this study was to use RNA sequencing to compare gene expression in AD and PD vulnerable brain regions and search for co-expressed genes. Methods: Total RNA was isolated from AD/CTL frontal cortex and PD/CTL ventral midbrain. Sequencing libraries were prepared, multiplex paired-end RNA sequencing was carried out, and bioinformatics analyses of gene expression used both publicly available (tophat2/bowtie2/Cufflinks) and commercial (Qlucore Omics Explorer) algorithms. Results: Both AD (frontal cortex, n = 10) and PD (ventral midbrain, n = 14) samples showed extensive heterogeneity of gene expression. Hierarchical clustering of heatmaps revealed two gene populations (AD, 376 genes; PD, 351 genes) that separated AD or PD from control samples at false-discovery rates (q) of <5% and fold changes of at least 1.3 (AD) or 1.5 (PD). 10,124 genes were co-expressed in our AD and PD samples. A very small group of these genes (n = 23) showed both low variances (<150; variance = standard deviation squared) and reduced expressions (>1.5-fold under-expression) in both AD and PD. Ingenuity Pathways Analyses (IPA, Qiagen) revealed loss of NAD biosynthesis and salvage as the major canonical pathway significantly altered in both AD and PD. Conclusions: AD and PD in vulnerable brain regions appear to arise from and result in independent molecular genetic abnormalities, but we identified several under-expressed genes with potential to treat both diseases. NAD supplementation shows particular promise. PMID- 30480258 TI - The Assessment of Cerebrovascular Response to a Language Task from the Addenbrooke's Cognitive Examination in Cognitive Impairment: A Feasibility Functional Transcranial Doppler Ultrasonography Study. AB - Background: The incidence of dementia is predicted to rise rapidly, but sensitive diagnostic tests remain elusive. Changes in cerebral blood flow velocity (CBFv) can occur at an early stage of cognitive decline, and can be measured by transcranial Doppler ultrasonography (TCD). Objective: The aim of this study was to characterize the CBFv changes that occur in healthy older adults (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD), in response to a language task from the Addenbrooke's cognitive examination (ACE-III). Methods: Participants underwent bilateral TCD, continuous heart rate (ECG), end-tidal CO2 (capnography, ETCO2), and beat-to-beat blood pressure (Finometer, MAP), monitoring, during a 5-minute baseline, followed by cognitive tasks from the ACE III. Data are presented for a language task (repeating words and phrases aloud), as peak percentage change in CBFv, HR, MAP, and ETCO2 from a normalized baseline. Results: 30 participants (mean age 73.2 years, 20% female) were recruited; HC (n = 10), MCI (n = 10), AD (n = 10). Language scores did not differ between groups (p = 0.16). Peak percentage change in CBFv differed between groups with the language task (HC: 15.9 (7.5)%, MCI: 6.7 (4.5)%, AD: 0.1 (7.1)%; p < 0.005). However, changes in MAP (HC: 7.9 (4.6)%, MCI: -0.1 (0.9)%, AD: 0.9 (4.4)%; p < 0.005), HR (HC: 8.8 (8.2)%, MCI: 0.7 (4.3)%, AD: -0.5 (5.6)%; p = 0.005), and ETCO2 (HC: -0.9 (3.2)%, MCI: 0.9 (3.2)%, AD: -5.2 (5.7)%; p = 0.006), also occurred. Conclusions: TCD measured CBFv changes to a language task from the ACE III was feasible in a cognitively impaired population, further work is required in a larger population. PMID- 30480259 TI - Pathological Increases in Neuronal Hyperactivity in Selective Cholinergic and Noradrenergic Pathways May Limit the Efficacy of Amyloid-beta-Based Interventions in Mild Cognitive Impairment and Alzheimer's Disease. AB - In spite of compelling evidence linking amyloid-beta (Abeta) disturbances to the pathophysiology of Alzheimer's disease (AD), Abeta-based treatments have consistently failed to produce any beneficial effects both in mild cognitive impairment (MCI) and AD, even with successful reductions of toxic aggregated and soluble Abeta species. Before abandoning both the hypothesis and approach, there is a need to examine some overlooked factors that may have contributed to the lack of efficacy, such as the potential drug-induced increases in neuronal hyperactivity leading to adverse cognitive effects. In particular, we posit that selective cholinergic and noradrenergic pathways will be especially vulnerable to this adverse effect. If confirmed, this idea could help identify a potentially preventable and treatable obstacle for enhancing the efficacy of therapeutic agents in MCI and AD. PMID- 30480257 TI - Innate Immune and Fungal Model of Alzheimer's Disease. AB - Various fungi and bacteria can colonize in the brain and produce physical alterations seen in Alzheimer's disease (AD). Environmental and genetic factors affect the occurrence of fungal colonization, and how fungi can grow, enter the brain, and interact with the innate immune system. The essence of AD development is the defeat of the innate immune system, whether through vulnerable patient health status or treatment that suppresses inflammation by suppressing the innate immune system. External and mechanical factors that lead to inflammation are a door for pathogenic opportunity. Current research associates the presence of fungi in the etiology of AD and is shown in cerebral tissue at autopsy. From the time of the discovery of AD, much speculation exists for an infective cause. Identifying any AD disease organism is obscured by processes that can take place over years. Amyloid protein deposits are generally considered to be evidence of an intrinsic response to stress or imbalance, but instead amyloid may be evidence of the innate immune response which exists to destroy fungal colonization through structural interference and cytotoxicity. Fungi can remain ensconced for a long time in niches or inside cells, and it is the harboring of fungi that leads to repeated reinfection and slow wider colonization that eventually leads to a grave outcome. Although many fungi and bacteria are associated with AD affected tissues, discussion here focuses on Candida albicans as the archetype of human fungal pathology because of its wide proliferation as a commensal fungus, extensive published research, numerous fungal morphologies, and majority proliferation in AD tissues. PMID- 30480260 TI - Pharmacokinetics in Rat of P8, a Peptide Drug Candidate for the Treatment of Alzheimer's Disease: Stability and Delivery to the Brain. AB - Strategies to achieve a therapy for Alzheimer's disease (AD) aimed at reducing the effects of amyloid-beta (Abeta) have largely involved inhibiting or modifying the activities of the beta- or gamma-secretases or by the use of monoclonal antibodies (MAb). We previously offered the potential for a new, early and effective approach for the treatment of AD by a strategy that does not target the secretases. We showed that a family of peptides containing the DEEEDEEL sequence and another independent peptide, all derived from the amino terminus of PS-1, are each capable of markedly reducing the production of Abeta in vitro and in mThy1 hAPP transgenic mice. These peptides gave a strong and specific binding with the ectodomain of amyloid-beta protein precursor (AbetaPP) and did not affect the catalytic activities of beta- or gamma-secretase, or the level of AbetaPP. Critical to the development of any therapeutic for AD is the requirement that it is stable and can be delivered to the brain. We report here data on the metabolic stability and delivery to the rat brain of our lead candidate P8 by intravenous (IV), intranasal (IN), and subcutaneous (SC) administration. Pharmacokinetics (PK) of P8 in rat plasma and CSF following a single dose of P8 demonstrate that SC administration gives better absorption compared to IN and is the delivery method of choice for the further development of P8 as a clinical candidate. PMID- 30480261 TI - Should the Treatment of Amyloidosis Be Personified? Molecular Mechanism of Amyloid Formation by Abeta Peptide and Its Fragments. AB - Abeta40 and Abeta42 peptides are believed to be associated with Alzheimer's disease. Aggregates (plaques) of Abeta fibrils are found in the brains of humans affected with this disease. The mechanism of formation of Abeta fibrils has not been studied completely, which hinders the development of a correct strategy for therapeutic prevention of this neurodegenerative disorder. It has been found that the most toxic samples upon generation of fibrils are different oligomeric formations. Based on different research methods used for studying amyloidogenesis of Abeta40 and Abeta42 peptides and its amyloidogenic fragments, we have proposed a new mechanism of formation of amyloid fibrils. In accord with this mechanism, the main building unit for fibril generation is a ring-like oligomer. Association of ring-like oligomers results in the formation of fibrils of different morphologies. Our model implies that to prevent development of Alzheimer's disease a therapeutic intervention is required at the earliest stages of amyloidogenesis-at the stage of formation of ring-like oligomers. Therefore, the possibility of a personified approach for prevention not only of Alzheimer's disease development but also of other neurodegenerative diseases associated with the formation of fibrils is argued. PMID- 30480262 TI - Cognitive Improvement in Healthy Older Adults Can Parallel That of Younger Adults Following Lifestyle Modification: Support for Cognitive Reserve During Aging. AB - Executive function was assayed following a nutritional supplementation in healthy adults using the Trail Making Test. Comparison with published normative scores demonstrated that cohorts from 35-74 years of age displayed similar relative improvement compared to their own baseline performance. These findings support early, pro-active lifestyle modifications to maintain cognitive performance during aging and further demonstrate the persistence of cognitive reserve in healthy older adults. PMID- 30480263 TI - A "Model-on-Demand" Methodology For Energy Intake Estimation to Improve Gestational Weight Control Interventions. AB - Energy intake underreporting is a frequent concern in weight control interventions. In prior work, a series of estimation approaches were developed to better understand the issue of underreporting of energy intake; among these is an approach based on semi-physical identification principles that adjusts energy intake self-reports by obtaining a functional relationship for the extent of underreporting. In this paper, this global modeling approach is extended, and for comparison purposes, a local modeling approach based on the concept of Model-on Demand (MoD) is developed. The local approach displays comparable performance, but involves reduced engineering e ort and demands less a priori information. Cross-validation is utilized to evaluate both approaches, which in practice serves as the basis for selecting parsimonious yet accurate models. The effectiveness of the enhanced global and MoD local estimation methods is evaluated with data obtained from Healthy Mom Zone, a novel gestational weight intervention study focused on the needs of obese and overweight women. PMID- 30480264 TI - Vitamin B12 transports modified RNA into E. coli and S. Typhimurium cells. AB - Specifically designed, antisense oligonucleotides are promising candidates for antibacterial drugs. They suppress the correct expression of bacterial genes by complementary binding to essential sequences of bacterial DNA or RNA. The main obstacle in fully utilizing their potential as therapeutic agents comes from the fact that bacteria do not uptake oligonucleotides from their environment. Herein, we report that vitamin B12 can transport oligonucleotides into Escherichia coli and Salmonella typhimurium cells. 5'-Aminocobalamin with an alkyne linker and azide-modified oligonucleotides enabled the synthesis of vitamin B12-2'OMeRNA conjugates using an efficient "click" methodology. Inhibition of protein expression in E. coli and S. Typhimurium cells indicates an unprecedented transport of 2'OMeRNA oligomers into bacterial cells via the vitamin B12 delivery pathway. PMID- 30480265 TI - Kinetic arrest of front transformation to gain access to the bulk glass transition in ultrathin films of vapour-deposited glasses. AB - Physical vapour deposition has emerged as the technique to obtain glasses of unbeatable stability. However, vapour deposited glasses exhibit a different transformation mechanism to ordinary glasses produced from liquid. Vapour deposited glasses of different thermodynamic stability, from ultrastable to those similar to ordinary glasses, transform into the liquid state via front propagation starting at the most mobile surfaces/interfaces, at least for the first stages of the transformation, eventually dynamiting the high thermal stability achieved for some of these glasses. A previous study showed that it was possible to avoid this transformation front by capping the films with a higher Tg material. We show here fast calorimetry measurements on TPD and IMC vapour deposited glasses capped respectively with TCTA and TPD. This capped configuration is very effective in suppressing the heterogeneous transformation of the stable glasses into the supercooled liquid and shifts the devitrification temperature to much higher values, where the bulk homogeneous mechanism becomes active. This approach may be useful to further study the bulk glass transition in thin films. PMID- 30480266 TI - Ligand-mediated reversal of the oxidation state dependent ROS scavenging and enzyme mimicking activity of ceria nanoparticles. AB - Nanoceria is considered as a potent antioxidant (free radical scavenger) and its enzymatic activity is reported to be a function of the oxidation state of surface cerium ions. Here we demonstrate phosphine ligand-dependent enzymatic activity of nanoceria irrespective of its as-synthesized oxidation state. PMID- 30480267 TI - Multi-colour bipolar electrochemiluminescence for heavy metal ion detection. AB - We report a new approach to heavy metal ion detection based on bipolar electrochemiluminescence (BP-ECL), which is simple and low cost yet highly sensitive. By using potential-resolved multicolour electrochemiluminescence (3D ECL) as the sensor readout, both qualitative and quantitative information on the sample is obtained. PMID- 30480268 TI - A comparative study of the structure, stability and energetic performance of 5,5' bitetrazole-1,1'-diolate based energetic ionic salts: future high energy density materials. AB - Developing novel energetic materials of high detonation performance and low sensitivity is one of the primary objectives related to explosive research. By employing ab initio calculations, a series of energetic ionic salts based on 5,5' bitetrazole-1,1'-diolate (BTO) were thoroughly investigated to understand the structure-property-performance interrelationship. The physicochemical and detonation characteristics of these energetic ionic salts including structural, electronic, vibrational and performance parameters (heats of formation, detonation pressures, and detonation velocities) were discussed in detail. The strong intermolecular hydrogen bonding environment between the BTO2- anion and various cations is mainly responsible for prominent detonation performance and enhanced molecular stability. Such strong intermolecular hydrogen bonds are observed in hydrazine and hydroxylammonium cations compared to other cations. To predict an accurate band gap, electronic band structures of the studied energetic ionic salts (EIS) were calculated using the HSE06 hybrid functional and they are found to be wide band gap insulators with a bandwidth ranging from 4.33-5.05 eV. Careful inspection of various EIS revealed that the hydroxylammonium and hydrazine cations produce the highest density relative to other cations when combined with the BTO anion. The detonation characteristics of BTO2- are computed using EXPLO5 code. In particular, HA-BTO and TKX-50 exhibit high detonation pressure (38.85 and 40.23 GPa) and detonation velocities (9.94 and 9.91 km s-1), superior to those of traditional nitrogen-rich energetic materials with moderate sensitivities. These results highlight the importance of hydrogen bonding interactions in designing energetic salts for next-generation explosives, propellants, and pyrotechnics. PMID- 30480270 TI - Comparison of different machine learning models for the prediction of forces in copper and silicon dioxide. AB - Recently, the machine learning (ML) force field has emerged as a powerful atomic simulation approach because of its high accuracy and low computational cost. However, there have been relatively fewer applications to multicomponent materials. In this study, we construct and compare ML force fields for both an elemental material (Cu) and binary material (SiO2) with varied inputs and regression models. The atomic environments are described by structural fingerprints that take into account the bond angle, and then, different ML techniques, including linear regression, a neural network and a mixture model method, are used to learn the structure-force relationship. We found that using angular structural fingerprints and a mixture model method significantly improves the accuracy of ML force fields. Additionally, we discuss an effective structural fingerprint auto-selection method based on the least absolute shrinkage and selection operator and the genetic algorithm. The atomic simulations conducted for ML force fields are in excellent agreement with ab initio calculations. As a result of the simulation with our ML force field for the structural and vibrational properties of amorphous SiO2, simulated annealing with a slow cooling rate improved the ring statistics in the amorphous structure and the phonon density of states. PMID- 30480271 TI - An ionic liquid-functionalized amphiphilic Janus material as a Pickering interfacial catalyst for asymmetric sulfoxidation in water. AB - Ionic liquid-functionalized amphiphilic Janus chiral salen TiIV catalysts were prepared by partial hydrophobic modification of silica with a chiral salen TiIV complex through an imidazolium ionic liquid (IL) linker. By optimizing their hydrophobic/hydrophilic balance, the IL-functionalized JNP materials exhibited excellent interfacial activity, significantly accelerating asymmetric sulfoxidation in water through the formation of stable Pickering emulsions. Moreover, catalyst recovery was readily achieved using centrifugation. PMID- 30480272 TI - Semi-solid-state aluminium-air batteries with electrolytes composed of aluminium chloride hydroxide with various hydrophobic additives. AB - Semi-solid-state Al-air batteries with solid electrolytes prepared by mixing AlCl3.6H2O and various hydrophobic additives were prepared and tested. All of the prepared Al-air batteries exhibited higher current 48 hours after battery preparation. This might be due to a decrease in battery resistance as AlCl3.6H2O melted and penetrated into the air cathode as a result of its hygroscopic property. Among the batteries tested, when commercial vaseline and butyl methyl imidazolium hexafluorophosphate were mixed with AlCl3.6H2O and used as the solid electrolyte, the prepared Al-air battery exhibited a stable high current and electrochemical property. PMID- 30480275 TI - Imaging of intracellular-specific microRNA in tumor cells by symmetric exponential amplification-assisted fluorescence in situ hybridization. AB - We report a symmetric exponential amplification-assisted fluorescence in situ hybridization (SEXPAR-FISH) strategy for imaging intracellular-specific microRNAs (miRNAs) in cells. The strategy eliminates the risk of cell loss and miRNA leakage, and low-abundant intracellular miR-27a in cells can be imaged in only 2 h without compromising sensitivity and specificity. PMID- 30480276 TI - Nickel-catalysed decarbonylative borylation of aroyl fluorides. AB - The first Ni(cod)2/PPh3 catalyst system has been established for decarbonylative borylation of aroyl fluorides with bis(pinacolato)diboron. A wide range of functional groups in the substrates were well tolerated. The ease of access of the starting aroyl fluorides indicates that these results might become an alternative to the existing decarbonylation events. PMID- 30480278 TI - Influence of humidity and iron(iii) on photodegradation of atmospheric secondary organic aerosol particles. AB - The absorption of solar actinic radiation by atmospheric secondary organic aerosol (SOA) particles drives condensed-phase photochemical processes, which lead to particle mass loss by the production of CO, CO2, hydrocarbons, and various oxygenated volatile organic compounds (OVOCs). We examined the influence of relative humidity (RH) and Fe(iii) content on the OVOC release and subsequent mass loss from secondary organic aerosol material (SOM) during UV irradiation. The samples were generated in a flow tube reactor from the oxidation of d limonene by ozone. The SOM was collected with a Micro Orifice Uniform Deposit Impactor (MOUDI) on CaF2 windows. To selected samples, a variable amount of FeCl3 was added before irradiation. The resulting SOM samples, with or without added FeCl3, were irradiated with a 305 nm light-emitting diode and the release of several OVOCs, including acetic acid, acetone, formic acid and acetaldehyde, was measured with a Proton Transfer Reaction Time-of-Flight Mass Spectrometer (PTR ToF-MS). The release of OVOCs from photodegradation of SOM at typical ambient mid values of RH (30-70%) was 2-4 times higher than under dry conditions. The release of OVOCs was slightly enhanced in the presence of low concentrations of iron (0.04 Fe molar ratio) but it was suppressed at higher concentrations (0.50 Fe molar ratio) of iron indicating the existence of a complicated radical chemistry driving the photodegradation of SOM. Our findings suggest that the presence of iron in atmospheric aerosol particles will either increase or decrease release of OVOCs due to the photodegradation of SOM depending on whether the relative iron concentration is low or high, respectively. At atmospherically relevant RH conditions, the expected fractional mass loss induced by these photochemical processes from limonene SOA particles would be between 2 and 4% of particle mass per hour. Therefore, photodegradation is an important aging mechanism for this type of SOA. PMID- 30480279 TI - Comment on "Investigations on HONO formation from photolysis of adsorbed HNO3 on quartz glass surfaces" by S. Laufs and J. Kleffmann, Phys. Chem. Chem. Phys., 2016, 18, 9616. AB - Laufs and Kleffmann observed that HNO3 surface photolysis rates resemble that of HNO3 in the gas phase after depositing HNO3 in air at ~50% relative humidity onto quartz glass surfaces. They questioned the dry HNO3 coverage (1.1 * 1014 molecules per cm2 after depositing ~15 mTorr HNO3 on silica at 0% humidity) used to derive our previously published HNO3 near-UV surface absorption cross sections. We directly determined the HNO3 coverage on a quartz surface using a quartz crystal microbalance (QCM). A similar HNO3 monolayer coverage obtained by QCM confirms that our estimated HNO3 coverage is reasonable. We also obtained an NO2 quantum yield from the 308 nm HNO3 photolysis on fused silica. In this Comment, we provide an explanation of the variance in HNO3 surface photolysis rates by clarifying the effects arising from important differences in the HNO3 coverage on quartz/silica in the presence of humidity versus those in the absence of humidity. PMID- 30480280 TI - Understanding the temperature effect on transport dynamics and structures in polyamide reverse osmosis system via molecular dynamics simulations. AB - The structures and transport dynamics of water and salt ions in polyamide (PA) reverse osmosis (RO) membranes as well as the temperature effects on the RO process were systematically investigated using a fully atomistic simulation method. By comparing the experimental data of the commercial membrane FT-30 and the available MD simulation results, the reliability of our PA RO model was validated. In addition, the groups on the polymer chains that preferentially participated in the coordination shells of salt ions were determined. Moreover, we found that the self-diffusion coefficients of both ions reduced by two orders of magnitude due to interactions between the ions and the polymer chains. Furthermore, NEMD simulations showed that the temperature has both positive and negative effects on the water flux. Although increasing the temperature can enhance the mobility of water molecule, it also can reduce the size of water clusters, which hampers an increase in the water flux. The decrease in size of the largest water clusters can partly explain the decrease in water flux when salt ions exist in the membrane. The current work provides a comprehensive understanding of the structure and transport behaviour of water and salt ions in the RO membranes. PMID- 30480281 TI - Bioorthogonal release of sulfonamides and mutually orthogonal liberation of two drugs. AB - Sulfonamide derivatives have been used in pharmaceutics for decades. Here we report a new approach to release sulfonamides efficiently using a bioorthogonal reaction of sulfonyl sydnonimines and dibenzoazacyclooctyne (DIBAC). The second order rate constant of the cycloaddition reaction can be up to 0.62 M-1 s-1, and the reactants are highly stable under physiological conditions. Most significantly, we also discovered the mutual orthogonality between the sydnonimine-DIBAC and benzonorbornadiene-tetrazine cycloaddition pairs, which can be used for selective and simultaneous liberation of sulfonamide and primary amine drugs. PMID- 30480283 TI - Bronze alloys with tin surface sites for selective electrochemical reduction of CO2. AB - Low concentration tin bronze alloys show high selectivity for CO2 electroreduction to CO, while high concentration tin bronze alloys show high selectivity for formate. The tin surface sites appear to control selectivity by influencing the binding characteristics toward the first reaction intermediate on copper-based alloys. PMID- 30480284 TI - Self-passivated ultra-thin SnS layers via mechanical exfoliation and post oxidation. AB - Remarkable optical/electrical features are expected in two-dimensional group-IV monochalcogenides (MXs; M = Sn/Ge and X = S/Se) with a uniquely distorted layered structure. The lone pair electrons in the group-IV atoms are the origin of this structural distortion, while they also cause a strong interlayer force and high chemical reactivity. The fabrication of chemically stable few-to-monolayer MX has been a significant challenge. We have observed that, once the SnS surface is oxidized, the SnOx top layer works as a passivation layer for the SnS layer underneath. In this work, the SnOx/SnS hetero-structure is studied structurally, optically, and electrically. When tape-exfoliated bulk SnS is oxygen-annealed under a reduced pressure at 10 Pa, surface oxidation and SnS sublimation proceed simultaneously, resulting in a monolayer-thick SnS layer with the SnOx passivation layer. The field-effect transistor of nine-layer SnS prepared via mechanical exfoliation exhibits a p-type characteristic because of intrinsic Sn vacancies, whereas ambipolar behavior is observed for the monolayer-thick SnS obtained via oxygen annealing probably owing to the additional n-type doping by S vacancies. This work on monolayer-thick SnS fabrication can be applied to other unstable lone pair analogues and can facilitate future research on MXs. PMID- 30480287 TI - Cancer diagnosis: from tumor to liquid biopsy and beyond. AB - Technological advancements in research on circulating biomarkers from patient derived blood have enabled a less invasive means of diagnosing non-hematologic cancers. Considered a more practical way of real-time patient monitoring than traditional tumor biopsy, liquid biopsy markers including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA) and extracellular vesicles (EVs) and exosomes certainly have the potential to change the dynamics of cancer management and treatment. Liquid biopsy essentially presents a snapshot of the disease from the primary and/or distant tumor locations and can be utilized for repeated sampling of tumor markers to adjust therapy according to the patient's response to treatment, also known as personalized or precision treatment. In this review, we discuss the research progress in this field with respect to each of the liquid biopsy markers ranging from CTCs, EVs to ctDNA. First, we highlight key CTC technologies that have been commercialized and extensively employed for patient sample analysis. Next, we present some recent developments with regards to exosome and ctDNA research. We then conclude with some future perspectives on the areas of research for these biomarkers. Taken together, we believe these non invasive capabilities and their potential for diagnostic development can influence treatment selections and aid precision cancer therapies. PMID- 30480288 TI - Intaglio-type random silver networks as the cathodes for efficient full-solution processed flexible quantum-dot light-emitting diodes. AB - Flexible quantum-dot light-emitting diodes (FQLEDs) hold great promise as a leading display and lighting technology due to their light weight, low-cost, and saturated emission color. However, there remain many challenges in the development of high quality electrodes on flexible substrates for device fabrication and operation. In this work, we present a robust flexible transparent conductive film with embedded random Ag networks in the PET substrate (named PRAN). The PRAN composite film exhibits an average transmittance of 85%, and the sheet resistance reaches near 5.3 Omega sq-1 without any obvious change after bending 3000 times, indicating excellent flexibility of this type of conductive film. A highly conductive poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) layer was employed to smooth the surface of the PRAN electrode. Consequently, FQLEDs based on these flexible electrodes are successfully fabricated and the peak power efficiencies of 42.3, 101.9, and 6.4 lm W-1 are achieved for the red, green and blue devices, respectively. To the best of our knowledge, these are the best efficiencies for the FQLEDs reported to date. These results lay the foundation of the realization of ITO-free, high-efficiency FQLEDs for use in flexible lighting and display applications. PMID- 30480289 TI - Colloidal LaPO4:Gd3+ nanocrystals: X-ray induced single line UV emission. AB - Colloidal solutions of nearly monodisperse 5 nm LaPO4:Gd3+ nanocrystals are shown to strongly emit UV radiation upon excitation with tungsten Kalpha radiation (59.3 keV) or vacuum UV radiation (160 nm). The UV emission of the particles consists mainly of a single line at 311 nm corresponding to the 6P7/2-8S7/2 transition of Gd3+. The highest emission intensity is observed for LaPO4 nanocrystals with a Gd3+ concentration of 20%. Since the absorption cross section of biomaterials is low for X-rays but high for 311 nm radiation, the UV emission of particles embedded in the biological tissue can only affect the direct vicinity of the particles. Nanocrystals of LaPO4:Gd3+ could, therefore, be interesting for biomedical applications such as strongly localized drug release by X-ray triggered UV uncaging reactions. PMID- 30480291 TI - Structural characterization of heterogeneous RhAu nanoparticles from a microwave assisted synthesis. AB - A microwave assisted method was used to synthesize RhAu nanoparticles (NPs). Characterization, based upon transmission electron microscopy (TEM), energy dispersive spectroscopy, and powder X-ray diffraction, provided the evidence of monomodal alloy NPs with a mean size distribution between 3 and 5 nm, depending upon the composition. Extended X-ray adsorption fine-structure spectroscopy (EXAFS) also showed evidence of alloying, but the coordination numbers of Rh and Au indicated significant segregation between the metals. More problematic were the low coordination numbers for Rh; values of ca. 9 indicate NPs smaller than 2 nm, significantly smaller than those observed with TEM. Additionally, no single particle structural models were able to reproduce the experimental EXAFS data. Resolution of this discrepancy was achieved with high resolution aberration corrected scanning TEM imaging which showed the presence of ultra-small (<2 nm) pure Rh clusters and larger (~3-5 nm) segregated particles with Au-rich cores and Rh-decorated shells. A heterogeneous model with a mixture of ultrasmall pure Rh clusters and larger segregated Rh/Au NPs was able to explain the experimental measurements of the NPs over the range of compositions measured. The combination of density functional theory, EXAFS, and TEM allowed us to quantify the heterogeneity in the RhAu NPs. It was only through this combination of theoretical and experimental techniques that resulted in a bimodal distribution of particle sizes that was able to explain all of the experimental characterization data. PMID- 30480292 TI - Reliable and quantitative SERS detection of dopamine levels in human blood plasma using a plasmonic Au/Ag nanocluster substrate. AB - Accurate and rapid blood-based detection of dopamine levels can aid in the diagnosis and monitoring of diseases related to dopaminergic dysfunction. For the sensitive detection of dopamine levels in human blood plasma (i.e., plasma dopamine levels), a silver-plated Au bimetallic nanocluster (so called plasmonic Au/Ag nanocluster) was prepared as a surface-enhanced Raman scattering (SERS) substrate by the combination of electrodeposition and electroless plating methods. The plasmonic effect of the Au/Ag nanocluster substrate was optimized by controlling the particle morphology, packing density, and interparticle distance, showing the best performance in its SERS activity. The lowest detection limit of dopamine was ~10-11 M. A linear standard curve was obtained by plotting the log scale of dopamine concentration (log C) versus Raman intensity at 1152 cm-1. The optimized SERS substrate quantified the plasma dopamine levels of patients with antipsychotic drug-induced Parkinsonism (n = 15) as 3.24 * 10-9 M and healthy control subjects (n = 15) as 2.31 * 10-8 M. Patients with drug-induced Parkinsonism had ~86% lower plasma dopamine concentration than healthy subjects (two-tailed p-value = 0.000002), indicating a clear separation between the groups. Our study provides the first report on the quantitative SERS detection of dopamine levels in human blood plasma with Parkinsonism. The results highlight the potential clinical utility of the optimized SERS technique in screening clinical populations with dopaminergic dysfunction, i.e., differentiating between healthy subjects and patients with Parkinsonism. PMID- 30480294 TI - Synthesis of highly stable red-emissive carbon polymer dots by modulated polymerization: from the mechanism to application in intracellular pH imaging. AB - Great efforts have been made to develop facile and efficient methods to prepare carbonaceous nanostructures with long-wavelength emission. Herein, we report a low-temperature aqueous strategy to synthesize red-emissive carbon polymer dots (R-CPDs) through the regulation of oxidative polymerization of p-phenylenediamine at 80 degrees C. The morphology, chemical composition and photophysical properties of the R-CPDs are characterized and analyzed in detail, thereby elucidating their photoluminescence origins from the surface state and crosslink enhanced emission effect. The resulting R-CPDs possess unique features including high pH-sensitivity within pH 4-6 and a wide-range tunable solvent-color effect (lambdaem 528-600 nm). Moreover, the R-CPDs show high stability in physiological media with high salinity, and good resistance to photobleaching. In addition to their favorable biocompatibility, the R-CPDs are applied for monitoring the pH fluctuation in HeLa cells. This study not only provides a unique red emissive carbonaceous nanomaterial for cellular imaging and multicolor applications, but also presents a novel perspective for the construction of long-wavelength emission carbon-based nanomaterials by simple and controllable strategies. PMID- 30480295 TI - Investigating the breakdown of the nerve agent simulant methyl paraoxon and chemical warfare agents GB and VX using nitrogen containing bases. AB - A range of nitrogen containing bases was tested for the hydrolysis of a nerve agent simulant, methyl paraoxon (MP), and the chemical warfare agents, GB and VX. The product distribution was found to be highly dependant on the basicity of the base and the quantity of water used for the hydrolysis. This study is important in the design of decontamination technology, which often involve mimics of CWAs. PMID- 30480298 TI - Correction: Physical crosslinking of hyaluronic acid in the presence of phospholipids in an aqueous nano-environment. AB - Correction for 'Physical crosslinking of hyaluronic acid in the presence of phospholipids in an aqueous nano-environment' by Piotr Beldowski et al., Soft Matter, 2018, DOI: 10.1039/c8sm01388h. PMID- 30480299 TI - Adhesion strategies of Dictyostelium discoideum- a force spectroscopy study. AB - Biological adhesion is essential for all motile cells and generally limits locomotion to suitably functionalized substrates displaying a compatible surface chemistry. However, organisms that face vastly varying environmental challenges require a different strategy. The model organism Dictyostelium discoideum (D.d.), a slime mould dwelling in the soil, faces the challenge of overcoming variable chemistry by employing the fundamental forces of colloid science. To understand the origin of D.d. adhesion, we realized and modified a variety of conditions for the amoeba comprising the absence and presence of the specific adhesion protein Substrate Adhesion A (sadA), glycolytic degradation, ionic strength, surface hydrophobicity and strength of van der Waals interactions by generating tailored model substrates. By employing AFM-based single cell force spectroscopy we could show that experimental force curves upon retraction exhibit two regimes. The first part up to the critical adhesion force can be described in terms of a continuum model, while the second regime of the curve beyond the critical adhesion force is governed by stochastic unbinding of individual binding partners and bond clusters. We found that D.d. relies on adhesive interactions based on EDL-DLVO (Electrical Double Layer-Derjaguin-Landau-Verwey-Overbeek) forces and contributions from the glycocalix and specialized adhesion molecules like sadA. This versatile mechanism allows the cells to adhere to a large variety of natural surfaces under various conditions. PMID- 30480300 TI - 3D self-supported Ni(PO3)2-MoO3 nanorods anchored on nickel foam for highly efficient overall water splitting. AB - Electrolyzing water as a sustainable energy source is a promising and appealing method to resolve the environmental crisis. Developing efficient and stable bifunctional electrocatalysts for the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER) is crucial and challenging in the overall water splitting process. Herein, we report the synthesis of Ni(PO3)2-MoO3 nanorods anchored on nickel foam (Ni(PO3)2-MoO3/NF) within a two-step strategy and their application as a bifunctional water splitting electrocatalyst. The results show that the optimal Ni(PO3)2-MoO3/NF electrodes exhibit superior catalytic activity with robust durability and ultralow overpotentials of 86 mV for HER and 234 mV for OER to achieve 10 mA cm-2 (eta10) in alkaline solution. The favorable performance of the obtained catalyst is attributed mainly to the synergetic effect between Ni(PO3)2 and MoO3, as well as the self-supporting porous conductive substrate. As a result, the integrated Ni(PO3)2-MoO3/NF electrodes deliver eta10 at a small potential of 1.47 V for overall water splitting, highlighting a promising application as a bifunctional electrocatalyst. PMID- 30480310 TI - Self-assembly of granular spheres under one-dimensional vibration. AB - The self-assembly of uniform granular spheres is related to the fundamentals of granular matter such as the transitions of phases, order/disorder and jamming states. This paper presents a DEM (discrete element method) study of the continuous self-assembly of uniform granular spheres from random close packing (RCP) to partially and nearly fully ordered packings under one-dimensional (1D) sinusoidal vibration without other interventions. The effects of the vibration amplitude and frequency are investigated in a wide range. The structures of the packings are characterized in terms of packing fraction and other microscopic structural parameters, including the coordination number, bond-orientational orders, and, in particular, ordered clusters, by adaptive common neighbor analysis (a-CNA). It is shown that 1D vibrations can also lead to the self assembly of uniform granular spheres with packing fractions exceeding the RCP limit, and FCC (face centered cubic) and HCP (hexagonal close packed) structures coexist in the self-assembled packings while their total fraction can reach nearly 100%. The structures of these packings can be better correlated with the vibration velocity amplitude rather than the commonly used vibration intensity. The dynamics of such self-assembly is also preliminarily analyzed. Our study not only presents the conditions for the self-assembly of uniform granular spheres under 1D vibration, but also characterizes the order-disorder transitions during the process, which can improve our understanding of the fundamentals of granular materials and jamming states. PMID- 30480311 TI - Displacement chemistry-based nanopore analysis of nucleic acids in complicated matrices. AB - To overcome the effect of other components of complicated biological samples on nanopore stochastic sensing, displacement chemical reaction was utilized to selectively extract the target nucleic acid from whole blood. Given its simplicity and high sensitivity for detecting nucleic acids, our developed displacement chemistry-based nanopore sensing strategy offers the potential for fieldable/point-of-care diagnostic applications. PMID- 30480312 TI - Immunohisto(cyto)chemistry: an old time classic tool driving modern oncological therapies. AB - In the era of precision medicine immunohistochemistry (IHC) and immunocytochemistry (ICC) share some of the highlights in personalized treatment. Survival data obtained from clinical trials shape the cut-offs and IHC scoring that serve as recommendations for patient selection both for targeted and conventional therapies. Assessment of Estrogen and Progesterone Receptors along with HER2 status has been among the first approved immunostaining assays revolutionizing breast cancer treatment. Similarly, ALK positivity predicts the efficacy of ALK inhibitors in patients with non-small cell lung cancer (NSCLC). In recent years, Programmed Death Ligand 1 (PD-L1) IHC assays have been approved as companion or complimentary diagnostic tools predicting the response to checkpoint inhibitors. Anti-PD-L1 and anti-PD-1 monoclonal antibodies have inaugurated a new period in the treatment of advanced cancers, but the path to approval of these biomarkers is filled with immunohistochemical challenges. The latter brings to the fore the significance of molecular pathology as a hub between basic and clinical research. Besides, novel markers are translated into routine practice, suggesting that we are at the beginning of a new exciting period. Unraveling the molecular mechanisms involved in cellular homeostasis unfolds biomarkers with greater specificity and sensitivity. The introduction of GL13 (SenTraGor(r)) for the detection of senescent cells in archival material, the implementation of key players of stress response pathways and the development of compounds detecting common mutant P53 isoforms in dictating oncological treatments are paradigms for precision oncology. PMID- 30480314 TI - Administrative databases to monitor the prevalence of cerebral palsy. PMID- 30480313 TI - Phenotypic biomarkers of climatic impacts on declining insect populations: a key role for decadal drought, thermal buffering and amplification effects and host plant dynamics. AB - 1.Widespread population declines have been reported for diverse Mediterranean butterflies over the last three decades, and have been significantly associated to increased global change impacts. The specific landscape and climatic drivers of these declines remain uncertain for most declining species. 2.Here we analyse whether plastic phenotypic traits of a model butterfly species (Pieris napi) perform as reliable biomarkers of vulnerability to extreme temperature impacts in natural populations, showing contrasting trends in thermally exposed and thermally buffered populations. 3.We also examine whether improved descriptions of thermal exposure of insect populations can be achieved by combining multiple information sources (i.e. integrating measurements of habitat thermal buffering, habitat thermal amplification, host plant transpiration, and experimental assessments of thermal death time (TDT), thermal avoidance behaviour (TAB) and thermally induced trait plasticity). These integrative analyses are conducted in two demographically declining and two non-declining populations of P. napi. 4.The results show that plastic phenotypic traits (butterfly body mass and wing size) are reliable biomarkers of population vulnerability to extreme thermal conditions. Butterfly wing size is strongly reduced only in thermally exposed populations during summer drought periods. Lab rearing of these populations documented reduced wing size due to significant negative effects of increased temperatures affecting larval growth. We conclude that these thermal biomarkers are indicative of the population vulnerability to increasing global warming impacts, showing contrasting trends in thermally exposed and buffered populations. 5.Thermal effects in host plant microsites significantly differ between populations, with stressful thermal conditions only effectively ameliorated in mid-elevation populations. In lowland populations we observe a six fold reduction in vegetation thermal buffering effects, and larval growth occurs in these populations at significantly higher temperatures. Lowland populations show reduced host plant quality (C/N ratio), reduced leaf transpiration rates and complete aboveground plant senescence during the peak of summer drought. Amplified host plant temperatures are observed in open microsites, reaching thermal thresholds that can affect larval survival. 6.Overall, our results suggest that butterfly population vulnerability to long-term drought periods is associated to multiple co-occurring and interrelated ecological factors, including limited vegetation thermal buffering effects at lowland sites, significant drought impacts on host plant transpiration and amplified leaf surface temperature, as well as reduced leaf quality linked to the seasonal advance of plant phenology. Our results also identify multi-annual summer droughts affecting larval growing periods as a key driver of the recently reported butterfly population declines in the Mediterranean biome. This article is protected by copyright. All rights reserved. PMID- 30480315 TI - Multiple sclerosis epidemiology in Finland: regional differences and high incidence. AB - OBJECTIVES: Studies on the east-west gradient of multiple sclerosis (MS) are scarce. In Finland, epidemiological differences have been only partially elucidated, but the MS risk is high, and it has been claimed that the occurrence follows a longitudinal gradient. In this register-based study, we updated the MS epidemiology in southwest Finland (SwF) and compared it to the easternmost hospital district, North Karelia (NK), for which no previous data exist. MATERIAL AND METHODS: Patients with ICD-10 code G35 were identified from hospital district administrative data. Patient records were reviewed to include only cases with a definitive diagnosis. Incidence period covered 5 years (2012-2016) and the prevalence date was December 31, 2016. Results were standardized using the direct method. RESULTS: 1184 persons had MS in SwF and 253 persons in NK at the end of 2016. The prevalence was 280/100,000 (95% Cl 264-296) in SwF and 168/100,000 (95% Cl 148-190) in NK (age-standardized for the European standard population 2013). During the incidence period, 211 new MS diagnoses were made in SwF and 49 in NK. The annual age-standardized (ESP 2013) incidence was 12.1/100,000 person-years (95% Cl 10.5-13.8) in SwF and 8.6/100,000 person-years (95% Cl 6.4-11.2) in NK in the age group 10-69 years. CONCLUSIONS: There are regional differences in MS epidemiology in Finland, possibly related to demographic, social and genetic circumstances but the retrospective nature and limited sample size of this study might introduce some uncertainty to the calculations. SwF is a region with a globally very high risk for MS. This article is protected by copyright. All rights reserved. PMID- 30480316 TI - Coping style and cortisol levels in infancy predict hair cortisol following new group formation in captive rhesus macaques (Macaca mulatta). AB - Social instability in primate groups has been used as a model to understand how social stress affects human populations. While it is well established that individual cercopithecines have different temperaments or personalities, little is known about how temperament mediates the experience of social instability in large, naturalistic groups. Here, we report findings from a study tracking a newly formed group of captive rhesus macaques (Macaca mulatta). We examine whether inter-individual differences in temperament during infancy affect physiological responses to new group formation years later, measured through hair cortisol 9 months after the group was formed. Our results show that early life measures of temperament characteristics predict later-life hypothalamic-pituitary adrenal activity following new group formation, though not always in the directions we predicted. Individuals with higher blood cortisol concentrations in response to a novel stressor and lower blood cortisol concentrations following a Dexamethasone Suppression Test in infancy had lower hair cortisol values following new group formation later in life. Individuals characterized in infancy as more emotional or more active exhibited lower hair cortisol profiles 9 months after group formation. We suggest that these two temperament characteristics, emotionality and activity, may represent two different mechanisms leading to low hair cortisol values. That is, the physiological measure of low hair cortisol may have two different meanings depending on temperament characteristics of the individual. Our results demonstrate that temperament and physiological responsiveness measures in infancy can predict individual responses to a new group formation years later. PMID- 30480317 TI - Risk factors for suicide in depression in Finland: first-hospitalized patients followed up to 24 years. AB - OBJECTIVE: To examine longitudinally risk factors for suicide in depression, and gender differences in risk factors and suicide methods. METHOD: We linked data from (a) The Finnish Hospital Discharge Register, (b) the Census Register of Statistics Finland, and (c) Statistics Finland's register on causes of deaths. All 56 826 first-hospitalized patients (25 188 men, 31 638 women) in Finland in 1991-2011 with a principal diagnosis of depressive disorder were followed up until death (2587 suicides) or end of the year 2014 (maximum 24 years). RESULTS: Clinical characteristics (severe depression adjusted hazard ratio [AHR] 1.19 [95% CI 1.08-1.30]; psychotic depression AHR 1.45 [1.30-1.62]; and co-morbid alcohol dependence AHR 1.26 [1.13-1.41]), male gender (AHR 2.07 [1.91-2.24]), higher socioeconomic status and living alone at first hospitalization were long-term predictors of suicide deaths. Highest risk was associated with previous suicide attempts (cumulative probability 15.4% [13.7-17.3%] in men, 8.5% [7.3-9.7%] in women). Gender differences in risk factors were modest, but in lethal methods prominent. CONCLUSION: Sociodemographic and clinical characteristics at first hospitalization predict suicide in the long term. Inpatients with previous suicide attempts constitute a high-risk group. Despite some gender differences in risk factors, those in lethal methods may better explain gender disparity in risk. This article is protected by copyright. All rights reserved. PMID- 30480318 TI - Treatment of benign pigmented lesions using a novel Dermal Cooling System. AB - Benign pigmented lesions are among the most common dermatologic diagnoses that patients seek treatments for. Treatment modalities range from cryotherapy to light and laser-based technologies. These treatments have been shown to be effective, yet may lead to dyschromia or significant downtime. Therefore, we report the first clinical experience with a novel Dermal Cooling System that provides localized and controlled freezing to benign pigmented lesions. Twenty patients seeking treatment for benign pigmented lesions were treated with the Dermal Cooling System at the laser and cosmetic dermatology clinic at the University of California, San Diego. Photographs were captured at baseline and follow-up visits. Two blinded investigators reviewed and graded the photographs. Most patients experienced improvement after 1 month following the first treatment. Macular or slightly raised lesions responded best. Treatment side effects were transient, lasted a maximum of 3 days, and included erythema, swelling, itching, and darkening. There was no observed long-term dyschromia. The novel Dermal Cooling System shows promise in the treatment of flat to slightly raised benign pigmented lesions with little-to-no downtime. Further clinical experience is necessary to continue to optimize treatment parameters. Lasers Surg. Med. (c) 2018 Wiley Periodicals, Inc. PMID- 30480319 TI - Recurrent hyponatremia in a young adult woman with anorexia nervosa and the effects of insufficient communication. AB - This is the case of an 18-year-old young adult woman with anorexia nervosa (AN) who presented to the emergency department with complications from AN and was found to be hyponatremic. The hyponatremia was prioritized and corrected with fluids on hospital day one. The consulting adolescent medicine team recommended the primary inpatient medical team initiate the malnutrition protocol. Nephrology recommended fluid restriction. Despite initiation of this protocol and emphasis on protocol adherence with the primary team, patient, and family, the hyponatremia recurred. Retrospectively, there were three factors that led to her recurrent hyponatremia: inconsistencies in protocol adherence across medical clinical providers, lack of knowledge regarding the importance of adherence to the malnutrition protocol, and suboptimal communication between medical clinical providers. A multidisciplinary team experienced in the care of patients with AN may enhance inpatient treatment of this condition. A multidisciplinary team experienced in AN will have a better understanding of the complexities of AN, skill in protocol implementation, understand the importance of protocol adherence, and be more likely to clearly communicate the plan of care to the patient/family. These skills can lead to improved care quality, decreased risk of adverse outcomes, and likely decreased medical costs. PMID- 30480320 TI - Clinical benefit of using a multifractional Er:YAG laser combined with a spatially modulated ablative (SMA) module for the treatment of striae distensae: A prospective pilot study in 20 patients. AB - BACKGROUND AND OBJECTIVE: Striae distensae (SD) are cutaneous lesions that often occur on the breasts, abdomen, hips, and thighs. The aim of this study is to evaluate the effectiveness of a new technique using a non-invasive Er:YAG laser combined with Spatially Modulated Ablation (SMA) module for the treatment of SD. STUDY DESIGN/MATERIALS AND METHODS: This prospective pilot clinical study included 20 patients with skin phototypes I to IV who are affected by SD. The Er:YAG 2940 nm laser with SMA module was used in scanning mode with fluences of 2.3 J/cm2 , frequency of 3 Hz, and pulse duration of 0.3 milliseconds. The laser beam is split into several microspots and penetrates only by 50 MUm in the epidermis thickness. This technology induces also the generation of acoustic waves to stimulate tissue regeneration. Each patient underwent six laser sessions. An objective and subjective assessment of SD were used. All adverse events were reported. RESULTS: Most patients reported good improvement and expressed their satisfaction with the treatment. Cutometric analysis showed significant improvement in skin elasticity at the end of study. Moreover, ultrasound analysis revealed an increase in dermal thickness (P < 0.01). POSAS scores decreased significantly at 3 and 6 months, reflecting improved skin quality. The average recovery time was 5 days, with no adverse effects reported. CONCLUSION: Using Er:YAG laser (2,940 nm) with SMA technology to treat SD resulted in improved volume and textural appearance without side effects. The elasticity and thickness of the dermis also improved. The Er:YAG laser with SMA module may be considered as a novel and effective technique to treat SD lesions with minimal time recovery. Lasers Surg. Med. (c) 2018 Wiley Periodicals, Inc. PMID- 30480321 TI - Identifying a male clinical cutoff on the Eating Disorder Examination Questionnaire (EDE-Q). AB - OBJECTIVE: Evidence suggests that eating disorders (EDs) may be under-detected in males. Commonly used measures of EDs such as the Eating Disorder Examination Questionnaire (EDE-Q) were initially developed within female samples, raising concern regarding the extent to which these instruments may be appropriate for detecting EDs in males. The current study used receiver operating characteristic curve analysis to (a) examine the accuracy of the EDE-Q global score in correctly classifying males with and without clinically significant ED pathology, and (b) establish the optimal EDE-Q global clinical cutoff for males. METHOD: Participants were a clinical sample of 245 male ED patients and a control sample of 205 male undergraduates. RESULTS: Eating Disorder Examination-Questionnaire global scores demonstrated moderate-high accuracy in predicting ED status (area under the curve = 0.85, 95% CI: 0.82-0.89). The optimal cutoff of 1.68 yielded a sensitivity of 0.77 and specificity of 0.77. DISCUSSION: Overall, results provide preliminary support for the discriminant validity of EDE-Q scores among males. However, concerns remain regarding the measure's ability to comprehensively assess domains of disordered eating most relevant to males. Therefore, careful attention to the possibility for measurement bias and continued evaluation of the scale in males is encouraged. PMID- 30480322 TI - Treatment of poikiloderma of Civatte using a redesigned pulsed dye laser with a 15 mm diameter treatment spot. AB - OBJECTIVES: The pulsed-dye laser has long been a gold standard in the treatment of poikiloderma of Civatte. Recent advances in pulsed dye laser technology enable output energies 50% higher, enabling beam diameters of up to 15 mm with clinically relevant fluences. In this study, we investigate this new laser for treatment of this condition. MATERIALS AND METHODS: Twenty subjects were enrolled in the study. A total of four treatments were administered at monthly intervals. Blinded assessment of digital, cross-polarized photographs taken at baseline and two months following the last treatment was performed by blinded physician raters using an 11-point clearance scale. Subject reported pain scores immediately following treatment and side effects at all visits were recorded by the investigator. RESULTS: Seventeen subjects completed the study. Blinded reviewers correctly identified the baseline photo in 48 of 51 cases (94%). All three reviewers mis-identified the same subjects. The blinded reviewers scored 14 out of the 17 subjects with an improvement greater than 40% and 10 out of the 17 subjects greater than 50%. Average improvement was 49% for all 17 subjects. Side effects were limited to mild edema, and mild to moderate erythema and purpura. Pain scores averaged 3.5 on using an 11-point scale. CONCLUSION: This study demonstrates the safety and effectiveness of a new pulsed-dye laser with a 15 mm spot and 50% higher fluences for the treatment of poikiloderma of Civatte. Lasers Surg. Med. (c) 2018 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc. PMID- 30480323 TI - Tocilizumab for thyroid eye disease. AB - BACKGROUND: Thyroid eye disease (TED) is an autoimmune disorder that constitutes a major clinical and therapeutic challenge. Current treatment options for moderate-to-severe TED include immunotherapy, orbital radiotherapy and decompression surgery. Limited drugs of proven efficacy are available for the treatment of people with TED. Given the role in the pathogenesis of TED of interleukin (IL)-6 expression in adipocytes, fibroblasts and macrophages, the proposed theory is that inhibition of IL-6 by tocilizumab may be an effective treatment in TED by directly reducing the inflammatory response. In addition, there is an unmet need for a new treatment that can modify the natural course of the disease and reduce the incidence of late complications that can occur as a result of fibrosis following inflammation. OBJECTIVES: To investigate the efficacy and harms of tocilizumab for the treatment of people with TED. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 6); MEDLINE Ovid; Embase Ovid; LILACS BIREME; OpenGrey; the ISRCTN registry; ClinicalTrials.gov; the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and the EU Clinical Trials Register. The date of the search was 31 July 2018. SELECTION CRITERIA: We searched for trials of tocilizumab administered by intravenous infusion using any dosage regimen, compared with placebo or intravenous glucocorticoid therapy for people with TED. DATA COLLECTION AND ANALYSIS: We planned to use standard methods recommended by Cochrane. The primary outcome was change in TED score (as defined by investigators). Secondary outcomes included measurement of the following parameters: change in proptosis, change in extraocular motility, change in palpebral aperture measurements, number of relapses, development of optic neuropathy and change in quality of life score. We planned to measure these outcomes at three months (range two to six months) and 12 months (range six to 18 months) post-treatment. Adverse outcomes included any adverse effects identified in the trials at any time point. MAIN RESULTS: No studies met the inclusion criteria of this review. We found one randomised, placebo-controlled, double masked study (NCT01297699). This study plans to evaluate the efficacy and harms of tocilizumab administration in people with moderate-to-severe or sight threatening graves' ophthalmopathy (GO), that had not responded adequately to treatment with intravenous corticosteroid pulses. It was completed in December 2015 and will be assessed for inclusion in the review when data become available. AUTHORS' CONCLUSIONS: There is currently no evidence from randomised controlled trials evaluating the efficacy and harms of tocilizumab for the treatment of people with TED. PMID- 30480324 TI - Community-based supplementary feeding for food insecure, vulnerable and malnourished populations - an overview of systematic reviews. AB - BACKGROUND: Supplementary feeding may help food insecure and vulnerable people by optimising the nutritional value and adequacy of the diet, improving quality of life and improving various health parameters of disadvantaged families. In low- and middle-income countries (LMIC), the problems supplementary feeding aims to address are entangled with poverty and deprivation, the programmes are expensive and delivery is complicated. OBJECTIVES: 1. To summarise the evidence from systematic reviews of supplementary feeding for food insecure, vulnerable and malnourished populations, including children under five years of age, school-aged children, pregnant and lactating women, people with HIV or tuberculosis (or both), and older populations.2. To describe and explore the effects of supplementary feeding given to people in these groups, and to describe the range of outcomes between reviews and range of effects in the different groups. METHODS: In January 2017, we searched the Cochrane Database of Systematic Reviews, MEDLINE, Embase and nine other databases. We included systematic reviews evaluating community-based supplementary feeding, and concerning food insecure, vulnerable and malnourished populations. Two review authors independently undertook selection of systematic reviews, data extraction and 'Risk of bias' assessment. We assessed review quality using the AMSTAR tool, and used GRADEpro 'Summary of findings' tables from each review to indicate the certainty of the evidence for the main comparisons. We summarised review findings in the text and reported the data for each outcome in additional tables. We also used forest plots to display results graphically. MAIN RESULTS: This overview included eight systematic reviews (with last search dates between May 2006 and February 2016). Seven were Cochrane Reviews evaluating interventions in pregnant women; children (aged from birth to five years) from LMIC; disadvantaged infants and young children (aged three months to five years); children with moderate acute malnutrition (MAM); disadvantaged school children; adults and children who were HIV positive or with active tuberculosis (with or without HIV). One was a non Cochrane systematic review in older people with Alzheimer's disease. These reviews included 95 trials relevant to this overview, with the majority (74%) of participants from LMIC.The number of included participants varied between 91 and 7940 adults, and 271 and more than 12,595 children. Trials included a wide array of nutritional interventions that varied in duration, frequency and format, with micronutrients often reported as cointerventions. Follow-up ranged from six weeks to two years; three trials investigated outcomes at four to 17 years of age. All reviews were rated as high quality (AMSTAR score between eight and 11). The GRADE certainty ratings ranged from very low to moderate for individual comparisons, with the evidence often comprising only one or two small trials, thereby resulting in many underpowered analyses (too small to detect small but important differences). The main outcome categories reported across reviews were death, anthropometry (adults and children) and other markers of nutritional status, disease-related outcomes, neurocognitive development and psychosocial outcomes, and adverse events.Mortality data were limited and underpowered in meta-analysis in all populations (children with MAM, in children with HIV, and in adults with tuberculosis) with the exception of balanced energy and protein supplementation in pregnancy, which may have reduced the risk of stillbirth (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.39 to 0.94; 5 trials, 3408 women). Supplementation in pregnancy also improved infant birth weight (mean difference (MD) 40.96 g, 95% CI 4.66 to 77.26; 11 trials, 5385 participants) and reduced risk of infants born small-for-gestational age (RR 0.79, 95% CI 0.69 to 0.90; 7 trials, 4408 participants). These effects did not translate into demonstrable long-term benefits for children in terms of growth and neurocognitive development in the one to two trials reporting on longer-term outcomes. In one study (505 participants), high-protein supplementation was associated with increased risk of small-for-gestational age babies.Effects on growth in children were mixed. In children under five years of age from LMIC, one review found that supplementary feeding had a little or no effect on child growth; however, a more recent review in a similar population found that those who received food supplementation gained an average of 0.12 kg more in weight (MD 0.12 kg, 95% CI 0.05 to 0.18; 9 trials, 1057 participants) and 0.27 cm more in height (MD 0.27 cm, 95% CI 0.07 to 0.48; 9 trials, 1463 participants) than those who were not supplemented. Supplementary food was generally more effective for younger children (younger than two years of age) and for those who were poorer or less well-nourished. In children with MAM, the provision of specially formulated food improved their weight, weight-for height z scores and other key outcomes such as recovery rate (by 29%), as well as reducing the number of participants dropping out (by 70%). In LMIC, school meals seemed to lead to small benefits for children, including improvements in weight z scores, especially in children from lower-income countries, height z scores, cognition or intelligence quotient tests, and maths and spelling performance.Supplementary feeding in adults who were HIV positive increased the daily energy and protein intake compared to nutritional counselling alone. Supplementation led to an initial improvement in weight gain or body mass index but did not seem to confer long-term benefit.In adults with tuberculosis, one small trial found a significant benefit on treatment completion and sputum conversion rate. There were also significant but modest benefits in terms of weight gain (up to 2.60 kg) during active tuberculosis.The one study included in the Alzheimer's disease review found that three months of daily oral nutritional supplements improved nutritional outcomes in the intervention group.There was little or no evidence regarding people's quality of life, adherence to treatment, attendance at clinic or the costs of supplementary feeding programmes. AUTHORS' CONCLUSIONS: Considering the current evidence base included, supplementary food effects are modest at best, with inconsistent and limited mortality evidence. The trials reflected in the reviews mostly reported on short-term outcomes and across the whole of the supplementation trial literature it appears important outcomes, such as quality of life and cost of programmes, are not systematically reported or summarised. PMID- 30480325 TI - Validity of Indirect Ultrasound Findings in Acute Anterior Cruciate Ligament Ruptures. AB - OBJECTIVES: Ultrasound (US) is increasingly being used as an extension of the physical examination on the sidelines, in training rooms, and in clinics. Anterior cruciate ligament (ACL) injury in sport is common, but the literature on US findings after acute ACL rupture is limited. Three indirect US findings of ACL rupture have been described, and this study assessed the validity of these indirect signs. METHODS: Patients with an acute knee injury (<6 weeks) underwent US examinations to determine whether there was evidence of a femoral notch sign, posterior cruciate ligament wave sign, or capsular protrusion sign. Ultrasound findings were compared to magnetic resonance imaging. RESULTS: Sixty-nine patients were included (53 with ACL tears and 16 control patients). The posterior cruciate ligament sign had the highest sensitivity (84.9%), and the notch sign had the highest specificity (93.8%). If 2 or 3 of the signs were positive, the sensitivity was 86.8%, and the specificity was 87.5%. CONCLUSIONS: A US examination is an easy-to-perform and noninvasive test, and the 3 indirect signs of an acute ACL tear had high positive predictive values ranging from 91.8% to 96.8%. PMID- 30480326 TI - A Rare Case of an Arteriovenous Malformation Scar Pregnancy Treated With a Combined and Conservative Approach. PMID- 30480327 TI - Re: "TAC-302 promotes neurite outgrowth of isolated peripheral neurons and prevents bladder denervation related bladder dysfunctions following bladder outlet obstruction in rats" and "Therapeutic effect of TAC-302, a cyclohexenoic fatty alcohol derivative, on bladder denervation-related storage and voiding dysfunctions in rats". PMID- 30480328 TI - HER2 protein overexpression in non-amplified ductal carcinoma in situ: quality issue or transcription mechanisms gone awry? AB - we read with interest the recent report by Hui et al. entitled 'Discordant HER2 immunohistochemical expression and gene amplification in ductal carcinoma in situ - evaluating HER2 in synchronous in situ and invasive carcinoma'.1 This study compares HER2 immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) between admixed synchronous in situ and invasive carcinomas exhibiting an equivocal 2+ HER2 IHC score in the invasive component. This article is protected by copyright. All rights reserved. PMID- 30480329 TI - Molecular and Histological Characteristics of Bovine Caudal Nucleus Pulposus by Combined Changes in Hydrostatic and Osmotic Pressures in vitro. AB - Intervertebral disc degeneration is ubiquitous among aging patients, and altered matrix homeostasis is one of the key features of this condition. Physicochemical stresses have a significant impact on matrix homeostasis as they lead to progressive degeneration and may be associated with spinal pain and dysfunction. Thus, it is important to understand the cellular and matrix characteristics of nucleus pulposus in response to these stresses, which include hydrostatic and osmotic pressures during alternate loading conditions. We hypothesized that a combination of changes in hydrostatic pressure and in osmotic pressure that mimic normal, daily spinal stress would stimulate anabolic function, whereas a non realistic combination of those stresses would stimulate catabolic function in nucleus pulposus cells. We examined the effects of these combined stresses, represented by 12 systematic conditions, on the metabolic activities of enzymatically isolated bovine caudal nucleus pulposus in vitro. We measured the gene expression of extracellular matrix (ECM) molecules and proliferating cell nuclear antigen (PCNA) and evaluated the quality of the matrix and the capability of cell proliferation immunohistologically. Combined cyclic hydrostatic pressure at 0.5 MPa, 0.5 Hz and high osmotic pressure at 450 mOsm upregulated the aggrecan core protein and collagen type-II gene expression significantly (p < 0.05), and showed trends of upregulation of chondroitin sulfate N acetylgalactosaminyltransferase 1, matrix metalloproteinase-13, and PCNA. ECM, however, contained empty spaces at a high osmotic pressure with and without hydrostatic pressure. Since ECM has highly specialized physicochemical properties, homeostasis should involve not only phenotypic cellular behavior but also turnover of ECM. This article is protected by copyright. All rights reserved. PMID- 30480330 TI - Pharmacokinetics and pharmacodynamics of 3 dosages of oestriol after continuous vaginal ring administration for 21 days in healthy, postmenopausal women. AB - AIM: Evaluation of the oestriol pharmacokinetics, pharmacodynamics and safety in healthy, postmenopausal women under treatment with a vaginal ring with continuous delivery rates of 0.125 (Test 1), 0.250 (Test 2) or 0.500 mg/day (Test 3) for 21 days. METHODS: Thirty-one subjects received a single application of Test 1, 2 or 3. The oestriol plasma concentration was determined by LC-MS/MS. The FSH, LH and SHBG serum concentrations, maturation value (MV) and vaginal pH were assessed to describe the pharmacodynamics. Adverse events, local tolerability and endometrial thickness (ET) were evaluated to determine safety. RESULTS: The 90% CI of the coefficient/slope beta was 0.5997 %-1.174 % for AUC0-tlast , 0.5838 %-1.115 % for AUC0-infinity and 0.2408 %-0.943 % for Cmax . Dose-proportionality could not be rejected for AUC, but a deviation from proportionality was statistically significant for Cmax . The FSH and LH curves showed a decrease that was more pronounced with higher delivery rates; however, SHBG did not presented this behavior. A treatment effect on MV and vaginal pH was comparable for all formulations. All products showed increase in MV (70-80%) and the distribution of parabasal, intermediate and superficial cells showed a shift towards superficial cells. The vaginal pH values markedly decreased under treatment. The effect on ET was no dose-dependent. CONCLUSION: All formulations released sufficient amounts of oestriol to trigger the maximum local effect. However, there was no difference between formulations regarding surrogate parameters for clinical efficacy. A dose dependency; however, was clearly demonstrated for FSH and LH. The product was well tolerated and safe. PMID- 30480331 TI - Mind your teeth-The relationship between mastication and cognition. AB - This article explores the multifactorial relationship between mastication and cognition, with a focus on dementia. Older persons, especially those with dementia, are at great risk of suffering from oral health problems such as orofacial pain and loss of natural teeth. A possible explanation could be that the cognitive and motor impairments resulting from dementia cause a decrease in self-care and as such, a worsening of oral health. An alternative explanation is that cognition and oral health influence each other. Animal studies show that a decrease in masticatory activity, for example, due to a soft diet or loss of teeth, causes memory loss and neuronal degeneration. The relationship between mastication and cognition has also been researched in human studies, but a cause effect relationship has not been proven. It is likely that multiple factors play a role in this relationship, such as self-care, nutrition, stress and pain. PMID- 30480332 TI - Trajectories of social support in adults with type 2 diabetes: Associations with depressive symptoms and functional disability. AB - OBJECTIVES: Little is known about temporal trajectories of social support in adults with type 2 diabetes (T2D) and how they are associated with diabetes related outcomes. This study identified and explored different trajectories of social support in a community sample of adults with T2D, as well as the extent to which different trajectories were prospectively associated with depressive symptoms and functional disability. METHODS: Data came from five annual waves of the Evaluation of Diabetes Treatment study (N=1,077). Social support, depressive symptoms, and functional disability were assessed via self-report. Separate analyses were conducted to examine the associations between social support trajectories, depressive symptoms, and functional disability, adjusting for demographic characteristics, diabetes-related covariates, and baseline depressive symptoms and functional disability. RESULTS: Latent class growth modeling identified four distinct social support trajectories. Trajectory Groups 1 and 2 were comprised participants with persistently low and persistently moderate-low social support, respectively. Trajectory Groups 3 and 4 included participants with persistently moderate-high and persistently high social support, respectively. People with persistently low social support reported higher functional disability relative to those with persistently moderate-high and persistently high social support. CONCLUSIONS: The findings of the present study indicate that temporal patterns of social support are a predictor of future functional disability among adults with T2D. PMID- 30480333 TI - Medical leadership competencies: A comparative study of physicians in public and private sector hospitals in India. AB - PURPOSE: Indian health care system comprising of public and private sectors needs enhancement of medical leadership capacity to face the growing challenges. Hence, this study was designed to evaluate medical leadership competencies of public and private sector doctors. FINDINGS: A survey questionnaire was developed to assess "self-assessed proficiency levels" as well as "perceived importance of competency levels," to which 532 doctors responded-290 (54.5%) from private sector and 242 (45.5%) from public sector hospitals. Statistically significant "leadership competency gap" was observed for all 30 leadership competencies in both sectors, more so in public sector. The 10 most deficient competencies were mainly in the NHS-MLCF domains of "working with others," "managing services," and "setting direction." The most low-rated competency among public sector doctors was "knowledge of HR, procurement, financial, and contract management" while "ability to influence key decision makers who determine future government policies" was most deficient among private sector physicians. Further, deficiencies related to "time and stress management" and "conducting need analysis, identifying and prioritizing requirements" were confined to public and private sector doctors, respectively. CONCLUSIONS: This study, first from India, highlights a critical need for medical leadership development programs in both sectors for enhancement of medical leadership capacity in the country. PMID- 30480334 TI - Assessment of the Placental Cord Insertion Using 3-Dimensional Ultrasound at the Time of the Structural Fetal Survey. AB - OBJECTIVES: The influence of placental morphologic characteristics on pregnancy outcomes is poorly understood. Our objective was to evaluate the relationship of the distance of the placental cord insertion from the placental edge (PCI-D) with associated placental characteristics as well as birth outcomes. METHODS: We performed a retrospective cohort study of nulliparous women with singleton gestations undergoing obstetric ultrasound examinations between 14 and 23 weeks' gestation with a cervical length of greater than 3.0 cm who delivered between 24 and 42 weeks. A 3-dimensional volume of the placenta was evaluated. The PCI-D was obtained with Virtual Organ computer-aided analysis software (GE Healthcare, Milwaukee, WI). Generalized linear regression and generalized additive models were fitted to explore the associations between the PCI-D in relation to demographic and clinical characteristics. RESULTS: A total of 216 pregnancies were included in the analysis. The PCI-D did not correlate with maternal age, gestational age at delivery, mode of delivery, or 5-minute Apgar score. Although not statistically significant, the birth weight z score (P = .09) was associated with a longer PCI-D, and gravidity was associated with a shorter PCI-D (P = .10). A low-lying placenta or placenta previa was associated with a longer PCI-D (P = .03). CONCLUSIONS: The PCI-D is associated with a low placental position in the second trimester. These data are helpful for understanding placental development. The PCI-D may be associated with pregnancy-related factors such as birth weight and multigravidity. More research is required to evaluate the effects of pregnancy-related factors on the PCI-D and the effect of the PCI-D on pregnancy outcomes. PMID- 30480335 TI - Biomimetic Proteoglycans can Molecularly Engineer Early Osteoarthritic Cartilage in vivo. AB - Biomimetic proteoglycans (BPGs) have the potential to treat osteoarthritis (OA) given that these molecules mimic the structure and properties of natural proteoglycans, which are significantly reduced in OA. We examined the effects of BPGs injected into the intra-articular space in an in vivo OA rabbit knee model and evaluated the effect on histological response, joint friction, and BPG distribution and retention. Rabbits underwent ACL transection to create an arthritic state after 5 weeks. OA rabbits were treated with BPGs or Euflexxa(r) (hyaluronic acid) intra-articular injections. Non-OA rabbits were injected similarly with BPGs; contralateral joints served as controls. The progression of OA and response to injections were evaluated using Mankin and gross grading systems indicating that mild OA was achieved in operated joints. The coefficient of friction (COF) of the intact knee joints were measured using a custom pendulum friction apparatus, showing that OA joints and OA + Euflexxa(r) joints demonstrated increased COF than non-operated controls, while BPG-injected non-OA and OA + BPGs were not significantly different from non-OA controls. Injected fluorescently labeled BPGs demonstrated that BPGs diffused into cartilage with localization in the pericellular region. This article is protected by copyright. All rights reserved. PMID- 30480336 TI - A tribute to a true conservation innovator, Brad McRae, 1966-2017. PMID- 30480337 TI - Bedside Neurolysis for Palliative Care of Critically Ill Patients With Pancreatic Cancer. PMID- 30480338 TI - Is the longitudinal deformation of the left ventricle affected by vitamin D deficiency in nondiabetics? A 2D speckle-tracking echocardiographic study. AB - OBJECTIVES: Vitamin D deficiency with its high global prevalence is associated with some pathological changes in the myocardium. The aim of our study was to assess the longitudinal deformation of the left ventricular (LV) myocardium in subjects with vitamin D deficiency. METHODS: This cross-sectional study recruited 98 consecutive nondiabetic subjects (45 subjects with vitamin D deficiency and 53 subjects without vitamin D deficiency) without significant epicardial coronary artery stenosis. The longitudinal subendocardial deformation indices of the LV myocardium were evaluated with 2D speckle-tracking echocardiography. RESULTS: The end-systolic strain, the systolic strain rate, and the early and late diastolic strain rates were not statistically significantly different between the subjects with and without vitamin D deficiency. CONCLUSIONS: The global longitudinal subendocardial deformations of the LV, including the systolic strain rate and the systolic and diastolic strain rates, as evaluated with 2D speckle-tracking echocardiography were not statistically significantly correlated with the presence or absence of vitamin D deficiency. PMID- 30480339 TI - Impaired bone healing following treatment of established nonunion correlates with serum cytokine expression. AB - Delayed union and nonunion are a significant concern in long bone fractures and spinal fusions. Treatment of nonunion often entails multiple revision surgeries that further increase the financial, physical, and emotional burden on patients. The optimal treatment strategy for nonunions remains unclear in many cases, and the risk of complications after revision procedures remains high. This is in part due to our limited understanding of the biological mechanisms that inhibit proper bone healing and lead to nonunion. And yet, few preclinical models directly investigate how healing is impacted after establishment of nonunion, with most instead primarily focusing on treatment immediately after a fresh bone injury. Here, we utilized a critical size femoral defect model in rats where treatment was delayed 8 weeks post-injury, at which time nonunion was established. In this study, acute and delayed treatments with bone morphogenetic protein-2 (BMP-2) were assessed. We found that delayed treatment resulted in decreased bone formation and reduced mechanical strength compared to acute treatment, even when BMP-2 dose was increased by 2.5 times the acute treatment dose. Interestingly, serum cytokine analysis at 12 weeks post-treatment revealed signs of chronic immune dysregulation after delayed treatment. In particular, non-responders (rats that did not exhibit defect bridging) demonstrated higher overall expression of inflammatory cytokines, including TNFalpha and IL-1beta, compared to responders. These findings suggest that re-establishing long-term immune homeostasis may be critical for successful bone healing, particularly after nonunion. This article is protected by copyright. All rights reserved. PMID- 30480340 TI - Increased mortality and hospital readmission risk in patients with dementia and a history of cardiovascular disease: results from a nationwide registry linkage study. AB - OBJECTIVE: To evaluate the impact of cardiovascular disease (CVD) on mortality and readmission risk in patients with dementia. METHODS: Prospective hospital based cohort of 59,194 patients with dementia admitted to hospital or visiting a day-clinic between 2000 through 2010. Patients were divided in those with and without a history of CVD (i.e. previous admission for CVD; coronary heart disease, heart failure, stroke, atrial fibrillation or other CVD). Absolute mortality risks (ARs), median survival times and hazard ratios (adjusted for age, sex and comorbidity) were calculated. RESULTS: Three-year ARs and HRs were higher and survival times were shorter among patients visiting a day-clinic with a history of CVD than in those without. The differences were less pronounced for inpatients. Readmission risk was further increased in the presence of CVD in both day clinic and inpatients. CONCLUSION: Clinicians need to be more aware of worse prognosis of the population with CVD and dementia. PMID- 30480341 TI - Clinicopathologic and Ultrasound Variables Associated With a Heavy Axillary Nodal Tumor Burden in Invasive Breast Carcinoma. AB - OBJECTIVES: To identify clinicopathologic and ultrasound (US) variables that were associated with a heavy nodal tumor burden, which was defined as 3 or more lymph nodes involved with metastasis to the axilla after invasive breast carcinoma. METHODS: With ethical approval, 621 patients with a pathologic diagnosis of invasive breast carcinoma were retrospectively analyzed for clinical, pathologic, and US data. Pathologic findings were ascertained by the final paraffin pathologic analysis. Ultrasound characteristics were evaluated on the basis of the American College of Radiology's Breast Imaging Reporting and Data System (BI RADS). Univariate and multivariate logistic regression analyses were used to assess the clinicopathologic and US variables that were associated with a heavy nodal tumor burden at the axilla. RESULTS: There were 107 cases (17.2%) of invasive breast carcinoma with a heavy tumor burden at the axilla. The independent clinicopathologic variables for a heavy tumor burden at the axilla included a tumor size of 2 to 5 cm (odds ratio [OR], 1.86; P = .036), the presence of lymphovascular invasion (OR, 23.52; P < .001), the presence of papillary invasion (OR, 2.93; P = .043), and a non-triple-negative subtype (OR, 2.34; P = .04). The independent US features of breast tumors that were associated with a heavy tumor burden at the axilla included BI-RADS category 5 (OR, 5.50; P = .024) and a posterior acoustic shadow (OR, 1.94; P = .024). CONCLUSIONS: A large tumor size, lymphovascular invasion, papillary invasion, and a non-triple negative subtype on the pathologic analysis as well as BI-RADS category 5 and a posterior acoustic shadow on a US assessment were associated with a heavy nodal tumor burden at the axilla. These US characteristics of the primary breast carcinoma might provide additional information to axillary US for the prediction of axillary nodal tumor loads. PMID- 30480342 TI - Availability of health workforce in urban and rural areas in relation to Canadian seniors. AB - Geographic imbalances in health human resources exist in a health care system when the composition, level, or use of health care providers does not lead to the same optimal health-system goals in all regions. This can lead to inequitable distribution of health care services, particularly for rural and remote populations. This study aims to determine to what extent the distribution of regulated health professionals and seniors in urban and rural areas of the Canadian jurisdictions is different from one another and from the national average. Data used in this study are for the 2016 calendar year. Information about physicians was obtained from the Canadian Institute for Health Information (CIHI) Scott's Medical Database. The data for nurses (nurse practitioners, registered nurses, and licensed practical nurses) were also sourced from CIHI, Health Workforce Database. Geographic information is based on the postal code of physicians' preferred mailing address, and the residence in the case of nurses and the population. Using the Statistical Area Classification from Statistics Canada, each physician and nurse was assigned to either an urban metropolitan, urban non-metropolitan, or rural/remote area. Findings indicate that there were twice as many nurses per 1000 seniors in urban Canada than in rural Canada. However, this gap was threefold in the case of physicians. Provinces with the largest and lowest gap and international comparisons are also provided. Three broad strategies are offered for policymakers in order to mitigate this health workforce imbalance and reduce the regional shortage of nurses and physicians. PMID- 30480343 TI - The effects of different periods of co-administration of oral and long-acting injectable aripiprazole: A propensity score analysis. AB - OBJECTIVE: Long-acting injectable (LAI) aripiprazole is recommended to be combined with oral aripiprazole for 2 weeks after its introduction. However, we often experience patients who require more than 2 weeks of combined use. Therefore, differences in combination periods need to be examined. METHODS: This was a case-control study. We surveyed prescription profiles for oral aripiprazole administration in conjunction with LAI aripiprazole introduction and assessed the clinical course during a 12-week follow-up period. RESULTS: Among 121 patients, 58 (47.9%) were administered both oral and LAI aripiprazole for more than 2 weeks. Although there was no significant difference in treatment failure (defined as psychiatric hospitalization or discontinuation of LAI aripiprazole from any cause) between the two groups, the group that was administered oral aripiprazole for more than 2 weeks received less additional benzodiazepines compared with that of the 2 weeks group (adjusted odds ratio, 0.055; 95% confidence interval [0.0060, 0.50]; p < 0.01). CONCLUSIONS: Our data support a flexible co administration period for oral and LAI aripiprazole in consideration of the pharmacokinetics, but further studies are needed. PMID- 30480344 TI - Antibodies@MOFs: An In Vitro Protective Coating for Preparation and Storage of Biopharmaceuticals. AB - Antibodies have emerged as a fast-growing category of biopharmaceuticals that have been widely applied in scientific research, medical diagnosis, and disease treatment. However, many antibodies and other biopharmaceuticals display inferior biophysical properties, such as low stability and a propensity to undergo aggregation. Enhancing the stability of biopharmaceuticals is essential for their wide applications. Here, a facile in vitro protective coating strategy based on metal-organic frameworks (MOFs) is proposed to efficiently protect antibodies against perturbation environments and quickly recover them from the MOFs before usage, which avoids introducing protective additives into the body, which may cause biosafety risks. The protected antibodies exhibit extraordinary thermal, chemical, and mechanical stabilities, and they can survive for long-term storage (>3 weeks) under severe temperature variation (4 <-> 50 degrees C) at a fast ramp rate (25 degrees C min-1 ). More importantly, the encapsulated antibodies can be easily released as quickly as 10 s with high efficiency (~100%) to completely remove the MOFs before use. This study paves a new avenue for the facile preparation and storage of biopharmaceuticals represented by antibodies under ambient or perturbation conditions, which may greatly broaden and promote the applications of both MOFs and biopharmaceuticals. PMID- 30480345 TI - Standards for the management of cancer-related pain across Europe. A position paper from the EFIC Task Force on Cancer Pain. AB - BACKGROUND AND OBJECTIVE: Pain is a common symptom in patients that survive cancer and in those that live with progressive advanced disease. Evidence from meta-analyses suggests that pain remains poorly controlled for a large proportion of patients; barriers to good management include poor assessment of pain, inadequate support for patient self-management, and late or inadequate access to strong opioid analgesia in those with advanced disease. METHODS: The European Pain Federation (EFIC) established a Task Force in 2017 which convened a European group of experts, drawn from a diverse range of relevant clinical disciplines, to prepare a position paper on appropriate standards for management of cancer related pain. The expert panel reviewed the available literature and made recommendations using the GRADE system to combine quality of evidence with strength of recommendation. The panel took into account the desirable and undesirable effects of the management recommendation, including the cost and inconvenience of each when deciding the recommendation. RESULTS AND CONCLUSIONS: The 10 standards presented are aimed to improve cancer pain management and reduce variation in practice across Europe. The Task Force believes that adoption of these standards by all 37 countries will promote the quality of care of patients with cancer related pain and reduce unnecessary suffering. This article is protected by copyright. All rights reserved. PMID- 30480346 TI - Hot Off the Press: A Systematic Review And Meta-analysis of Ketamine as an Alternative to Opioids for Acute Pain in the Emergency Department. AB - Ketamine has been studied as an alternative to opioids for acute pain in the emergency department setting. This review compares the effectives of intravenous ketamine at a dose of <0.5mg/kg to opioids for acute pain in adult patients. Measurements were taken within 60 minutes of administration. Ketamine was found to have similar effectiveness to opioids. Increased, but short-lived, side effects were seen with ketamine. PMID- 30480347 TI - High Prevalence and Endemism of Trypanosomatids on a Small Caribbean Island. AB - We describe the monoxenous trypanosomatids parasitizing true bugs and flies on the island of Curacao. Out of 248 examined true bugs belonging to 17 species, 93 individuals were found to be infected (overall 38% prevalence) by at least one trypanosomatid species (referred to as typing units; TUs). Out of 80 flies, six were infected. All detected trypanosomatids were compared based on their 18S rRNA sequences with TUs parasitizing bugs and flies described from mainland South America, allowing us to assess their diversity and distribution. Besides Leptomonas pyrrhocoris and Leptomonas seymouri, two known species of the subfamily Leishmaniinae, our analysis revealed six new TUs falling into the groups 'jaculum', Blastocrithidia and Herpetomonas. Moreover, two new members of the genus Phytomonas and three new TUs belonging to the monophyletic group designated as 'new clade 2' sensu Tyc et al. (2013) were isolated. The detected trypanosomatids were characterized by moderate diversity (13 TUs) species richness. Out of nine and four TUs from the heteropteran and dipteran hosts, respectively, 11 TUs have not been encountered before. Although a sampling bias may partially affect the comparison between trypanosomatid communities on Curacao and the mainland, the high proportion of unique TUs from the former location suggests that the prominent role of islands in increasing the global diversity of macroscopic organisms may also extend to their protistan parasites. This article is protected by copyright. All rights reserved. PMID- 30480348 TI - Multi-tissue integration of transcriptomic and specialized metabolite profiling provides tools for assessing the common bean (Phaseolus vulgaris) metabolome. AB - Common bean (Phaseolus vulgaris L.) is an important legume species with a rich natural diversity of landraces which originated from the wild forms following multiple independent domestication events. After the publication of its genome, several resources for this relevant crop have been made available; a comprehensive characterization of specialized metabolism in P. vulgaris, however, is still lacking. In this work, we used a metabolomics approach based on liquid chromatography-mass spectrometry (LC-MS) to dissect the chemical composition at a tissue-specific level in several accessions of common bean belonging to different gene pools. Using a combination of literature search, mass spectral interpretation, 13 C-labeling, and correlation analyses, we were able to assign chemical classes and/or putative structures for approximately 39% of all measured metabolites. Additionally, we integrated this information with transcriptomics data and phylogenetic inference from multiple legume species to reconstruct the possible metabolic pathways and identify sets of candidate genes involved in the biosynthesis of specialized metabolites. A particular focus was given to flavonoids, triterpenoid saponins and hydroxycinnamates, as they represent metabolites involved in important ecological interactions and are also associated to several health-promoting benefits when integrated into the human diet. The data are presented here in the form of an accessible resource which we hope will set grounds for further studies of specialized metabolism in Legumes. This article is protected by copyright. All rights reserved. PMID- 30480349 TI - A hydrostable cathode material based on the layered P2@P3 composite with revealed redox behavior of Cu for high-rate and long cycling sodium-ion batteries. AB - Viewing from the perspective of sustainable development, the low-cost layered oxides without Ni or Co are considered to be the most promising type of cathode materials for future sodium-ion batteries. The atmospheric and electrochemical corrosion occurring at the interfaces of layered cathodes, however, results in serious degradation of both the capacity and cycle life. A P2@P3 layered oxide composite induced by Zn doping, which only consists of cheap transition metals with high rate and long cycling performance represents a promising cathode for sodium-ion batteries. The P2@P3 biphase synergetic property in this composite is well revealed not only in electrochemical performance but also its humidity resistance. The results indicate partial Zn substitutes in Na0.78Cu0.33 xZnxMn0.67O2 composite can effectively promote and control biphase formation for improving the structural/electrochemical stability as well as the ionic diffusion coefficient. Based on in situ synchrotron X-ray diffraction coupled with Electron Energy-Loss spectroscopy, X-ray photoelectron spectroscopy, and X-ray absorption near-edge spectroscopy, a possible way of Cu2+/3+ redox reaction has been revealed in this material, and the mechanism of Na0.78Cu0.33-xZnxMn0.67O2 composite is proposed to be a solid solution and two-phase mechanism. PMID- 30480350 TI - Blue Light Induced Carbene Transfer Reactions of Diazoalkanes. AB - Carbenes are very important reactive intermediates to access a variety of complex molecules and possess widespread application in organic synthesis or drug discovery. Typically, their chemistry is accessed by the use of transition metal catalysts. Herein, we describe the application of low energy blue light for the photochemical generation of carbenes from donor-acceptor diazoalkanes. This catalyst-free and operationally simple approach enables highly efficient cyclopropenation reactions with alkynes and rearrangement of sulfides under mild reaction conditions, which can be utilized under both batch and continuous-flow conditions. PMID- 30480351 TI - Synthetic Polyester from Plant Oil Feedstock by Functionalizing Polymerization. AB - Catalytic functionalization/polymerization of castor oil-derived undecenol yields an aliphatic polyester in a single step under mild conditions. The key to selective formation of linear high melting polyester is highly active carbonylation catalysts that at the same time do not undergo strong isomerization. PMID- 30480352 TI - Zn-Ion Hybrid Micro-Supercapacitors with Ultrahigh Areal Energy Density and Long Term Durability. AB - On-chip micro-supercapacitors (MSCs), as promising power candidates for microdevices, typically exhibit high power density, large charge/discharge rates, and long cycling lifetimes. However, as for most reported MSCs, the unsatisfactory areal energy density (<10 uWh cm-2 ) still hinders their practical applications. Herein, a new-type Zn-ion hybrid MSC with ultrahigh areal energy density and long-term durability is demonstrated. Benefiting from fast ion adsorption/desorption on the capacitor-type activated-carbon cathode and reversible Zn stripping/plating on the battery-type electrodeposited Zn-nanosheet anode, the fabricated Zn-ion hybrid MSCs exhibit remarkable areal capacitance of 1297 mF cm-2 at 0.16 mA cm-2 (259.4 F g-1 at a current density of 0.05 A g-1 ), landmark areal energy density (115.4 uWh cm-2 at 0.16 mW cm-2 ), and a superb cycling stability without noticeable decay after 10 000 cycles. This work will inspire the fabrication and development of new high-performance microenergy devices based on novel device design. PMID- 30480353 TI - The effect of two exercise modalities on skeletal muscle capillary ultrastructure in individuals with type 2 diabetes. AB - Type 2 diabetes is associated with microvascular dysfunction, but little is known about how capillary ultrastructure is affected by exercise training. To investigate the effect of two types of exercise training on skeletal muscle capillary ultrastructure and capillarization in individuals with type 2 diabetes, 21 individuals with type 2 diabetes were allocated (randomized controlled trial) to 11 weeks of aerobic exercise training consisting of either moderate-intensity endurance training (END; n=10), or low-volume high-intensity interval training (HIIT; n=11). Skeletal muscle biopsies (m vastus lateralis) were obtained before and after the training intervention. At baseline, there was no difference in capillarization, capillary structure and exercise hyperaemia between the two groups. After the training intervention, capillary-to-fiber ratio increased by 8+/-3% in the END group (P<0.05) and was unchanged in the HIIT group with no difference between groups. Endothelium thickness increased (P<0.05), basement membrane thickness decreased (P<0.05) and the capillary lumen tended (P=0.07) to increase in the END group, whereas these structural indicators were unchanged after HIIT. In contrast, skeletal muscle endothelial nitric oxide synthase (eNOS) increased after HIIT (P<0.05), but not END, whereas there was no change in vascular endothelial growth factor (VEGF), superoxide dismutase (SOD)-2 or NADPH oxidase after both training protocols. In contrast to END training, HIIT did not alter capillarization or capillary structure in individuals with type 2 diabetes. In conclusion, HIIT appears to be a less effective strategy to treat capillary rarefaction and reduce basement thickening in type 2 diabetes. This article is protected by copyright. All rights reserved. PMID- 30480354 TI - Assessing the referral of clients with respiratory symptoms to general physicians: a survey of community pharmacists in Beirut. AB - OBJECTIVES: The main objective of this study was to assess the ability of community pharmacists practicing in Beirut to identify red flag respiratory symptoms, and therefore to adequately refer clients to a general physician when warranted. Secondary objectives included determining whether demographic factors affect the odds of referral, and to qualify degree of agreement of community pharmacists with a panel of expert physicians. METHODS: In this cross-sectional study, pharmacies were randomly selected and invited to complete a self administered survey, each containing 10 clinical vignettes that combined different characteristics (age group, gender, presenting symptom, duration of symptoms). Bivariate and multivariate logistic regressions were used to inspect predictors of referral, correct referral and under-referral. KEY FINDINGS: A total of 214 pharmacies were visited and 141 (65.9%) responded. Pharmacists were more likely to refer female patients (P = 0.035) and patients who presented with a longer duration of symptoms (P < 0.001). Correct referral was higher in pharmacies that were more than 20 min away from the nearest hospital (P = 0.013) and with clients who presented with haemoptysis (P < 0.001), dyspnoea (P < 0.001) or wheezing (P < 0.027), while it was lower with female patients (P < 0.001). Under-referral was higher in pharmacies that served more than 500 clients weekly (P = 0.048) and in patients presenting for dry cough (P < 0.001) or productive cough (P < 0.001). CONCLUSION: This study has shown that there is a need for further investigation into the practices of community pharmacists of Beirut. An action plan may be advised to alleviate the burden of patients who might currently be under-referred and experience morbidity as a result. PMID- 30480355 TI - Solid Phase Synthesis and Self-Assembly of Higher-Order siRNAs and their Bioconjugates. AB - New methods for the synthesis of higher-order siRNA motifs and their bioconjugates have recently gained widespread attention in the development of new and improved gene therapeutics. Our efforts aim to produce new chemical tools and protocols for the generation of modified siRNAs that screen for important oncogene targets as well as silence their activity for effective gene therapy in cancer models. More specifically, we have developed an efficient solution-phase synthesis for the production of a ribouridine branchpoint synthon that can be effectively incorporated by solid phase synthesis within higher-order RNA structures, including those adopting V-, and Y- and >-< shape RNA templates. Self assembly of complementary RNA to the template strands produced higher-order siRNA nanostructures that were characterized by a combination of PAGE, DLS and TEM techniques. In an effort to extend the repertoire of functionally diverse siRNAs, we have also developed solid phase bioconjugation strategies for incorporating bio-active probes such as fatty acid appendages and fluorescent reporters. Taken together, these methods highlight the ability to generate higher-order siRNAs and their bioconjugates for exploring the influence of modified siRNA structure on anti-cancer activity. This article is protected by copyright. All rights reserved. PMID- 30480356 TI - Synthesis, anticancer activity and cytotoxicity of 7-O-beta-D-galactosyl-PEG epothilone B. AB - Epothilone, the macrolide compound produced by Sorangium cellulosum, has antitumor activity. Its anti-tumor mechanism is similar to that of paclitaxel, which promotes the polymerization of tubulin and induces apoptosis. Herein, 7-O beta-D-galactosyl-PEG-epothilone B 6 was synthesized. It showed that the toxicity of the synthesized compound was 1/182 of the epothilone B. In addition, compound 6 also had significant anticancer activity under the action of enzyme. This article is protected by copyright. All rights reserved. PMID- 30480357 TI - A Tunneling Dielectric Layer Free Floating Gate Nonvolatile Memory Employing Type I Core-Shell Quantum Dots as Discrete Charge-Trapping/Tunneling Centers. AB - A nonvolatile memory with a floating gate structure is fabricated using ZnSe@ZnS core-shell quantum dots as discrete charge-trapping/tunneling centers. Systematical investigation reveals that the spontaneous recovery of the trapped charges in the ZnSe core can be effectively avoided by the type-I energy band structure of the quantum dots. The surface oleic acid ligand surrounding the quantum dots can also play a role of energy barrier to prevent unintentional charge recovery. The device based on the quantum dots demonstrates a large memory window, stable retention, and good endurance. What is more, integrating charge trapping and tunneling components into one quantum dot, which is solution synthesizable and processible, can largely simplify the processing of the floating gate nonvolatile memory. This research reveals the promising application potential of type-I core-shell nanoparticles as the discrete charge trapping/tunneling centers in nonvolatile memory in terms of performance, cost, and flexibility. PMID- 30480358 TI - Simultaneous Increase in Brightness and Singlet Oxygen Generation of an Organic Photosensitizer by Nanocrystallization. AB - Efficient organic photosensitizers are attractive for cancer cell ablation in photodynamic therapy. Bright fluorescent photosensitizers are highly desirable for simultaneous imaging and therapy. However, due to fundamental competition between emission and singlet oxygen generation, design attempts to increase singlet oxygen generation almost always leads to the loss of fluorescence. Herein, it is shown for the first time that nanocrystallization enables a simultaneous and significant increase in the brightness and singlet oxygen generation of an organic photosensitizer. Spectroscopic studies show simultaneous enhancement in the visible light absorption and fluorescence after nanocrystallization. The enhanced absorption of visible light in nanocrystals is found to translate directly to the enhanced singlet oxygen production, which shows a higher ability to kill HeLa cells as compared to their amorphous counterpart. PMID- 30480359 TI - Synthesis of P-Doped and NiCo-Hybridized Graphene-Based Fibers for Flexible Asymmetrical Solid-State Micro-Energy Storage Device. AB - Fiber supercapacitors (FSCs) are promising energy storage devices in portable and wearable smart electronics. Currently, a major challenge for FSCs is simultaneously achieving high volumetric energy and power densities. Herein, the microscale fiber electrode is designed by using carbon fibers as substrates and capillary channels as microreactors to space-confined hydrothermal assembling. As P-doped graphene oxide/carbon fiber (PGO/CF) and NiCo2 O4 -based graphene oxide/carbon fiber (NCGO/CF) electrodes are successfully prepared, their unique hybrid structures exhibit a satisfactory electrochemical performance. An all solid-state PGO/CF//NCGO/CF flexible asymmetric fiber supercapacitor (AFSC) based on the PGO/CF as the negative electrode, NCGO/CF hybrid electrode as the positive electrode, and poly(vinyl alcohol)/potassium hydroxide as the electrolyte is successfully assembled. The AFSC device delivers a higher volumetric energy density of 36.77 mW h cm-3 at a power density of 142.5 mW cm-3 . In addition, a double reference electrode system is adopted to analyze and reduce the IR drop, as well as effectively matching negative and positive electrodes, which is conducive for the optimization and improvement of energy density. For the AFSC device, its better flexibility and electrochemical properties create a promising potential for high-performance micro-supercapacitors. Furthermore, the introduction of the double reference electrode system provides an interesting method for the study on the electrochemical performances of two-electrode systems. PMID- 30480360 TI - Prognostic role of Rab27A and Rab27B expression in patients with non-small cell lung carcinoma. AB - BACKGROUND: Rab27A and Rab27B are the major components of vesicle fusion and trafficking in exosome secretion and play important roles in tumor progression and metastasis. In addition, Rab27A and Rab27B are associated with tumor prognosis. This study investigated the prognostic roles of Rab27A and Rab27B expression in patients with non-small cell lung cancer (NSCLC). METHODS: Rab27A and Rab27B expression was assessed in 133 cases of NSCLC by immunohistochemistry. We evaluated the correlations between Rab27A and Rab27B expression and clinicopathological data and determined their prognostic role in NSCLC. RESULTS: Rab27A and Rab27B expression were significantly related to patient gender (P = 0.007 and 0.002, respectively) and histologic type (P = 0.009 and < 0.001, respectively), but not to patient age, smoking history, surgical method, or tumor node metastasis stage. The multivariate Cox proportional hazards regression model verified that high Rab27B expression is a prognostic factor for unfavorable disease-specific survival (hazard ratio 2.680, 95% confidence interval 1.116 6.437; P = 0.027) in squamous cell carcinoma (SQCC). Kaplan-Meier analysis revealed significantly poorer prognosis in SQCC patients with high Rab27B expression compared to patients with low Rab27B expression (P = 0.030). CONCLUSION: High Rab27B expression could be an unfavorable prognostic factor in patients with SQCC of the lung. PMID- 30480361 TI - The 7th Sino-German Frontiers of Chemistry Symposium - Learning from Nature. AB - Bilateral Symposium: The Technical University, Institute for Advanced Studies, hosted the 7th Sino-German Frontiers of Chemistry Symposium from September 2 to September 6, 2018. This event, co-organized by the Chinese Chemical Society (CCS) and the Gesellschaft Deutscher Chemiker (German Chemical Society), featured excellent talks by the invited early-career chemists of both countries and offered ample opportunities for discussions and making friends among the participants. PMID- 30480362 TI - CD146-Mediated Acquisition of Stemness Phenotype Enhances Tumor Invasion and Metastasis after EGFR-TKI Resistance in Lung Cancer. AB - INTRODUCTION: Tumors are more likely to metastasize after development of resistance to EGFR TKIs. CD146 is a multi-functional molecule and is implicated in tumor invasion and metastasis; however, its role in lung cancer has not been clearly established. OBJECTIVE: Here we aimed to explore the relationship between CD146-pathway and stem cell phenotype after EGFR-TKI resistance in lung cancer. METHODS: EGFR-TKI resistance cell lines were established by exposing parental cells to Erlotinib/Gefitinib. CD146 level was measured by western blot, RT-PCR and immunocytochemistry fluorescent. Cell migration was examined by transwell assay and scratch assay. Stemness phenotype genes were evaluated by RT-PCR and stem cell phenotype was observed by microsphere formation assay. RESULTS: CD146 and stemness phenotype genes were increased while beta-catenin was decreased in acquired EGFR-TKI resistance cell lines. CD146 over-expression induced up regulation of stemness related genes and inversely correlated with beta-catenin expression, which further increased the migration capability of the resistance cancer cells. CD146 knockdown suppressed cell migration and stemness phenotype. CONCLUSIONS: CD146 molecule contributes to the stemness phenotype and migration in EGFR-TKI resistance cells. CD146 might be a potential therapeutic target for EGFR-TKI resistance lung cancer or metastasis prevention. This article is protected by copyright. All rights reserved. PMID- 30480363 TI - Utility of peripheral blood smear in rapid diagnosis of Pertussis. PMID- 30480364 TI - Sodium Ion Batteries using Ionic Liquids as Electrolytes. AB - Sodium ion batteries have been developed using ionic liquids as electrolytes. Sodium is superior to lithium as a raw material for mass production of large scale batteries for energy storage due to its abundance and even distribution across the earth. Ionic liquids are non-volatile and non-flammable, which improved the safety of the batteries remarkably. In addition, operation temperatures were extended to higher values, improving the performance of the batteries by facilitating the reaction at the electrode and mass transfer. Binary systems of sodium and quaternary ammonium salts, such as 1-ethyl-3 methylimidazolium and N-methyl-N-propylpyrrolidinium bis(fluorosulfonyl)amide, were employed as electrolytes for sodium ion batteries. A series of positive and negative electrode materials were examined to be combined with these ionic liquid electrolytes. A 27 Ah full cell was fabricated employing sodium chromite (NaCrO2 ) and hard carbon as positive and negative electrode materials, respectively. The gravimetric energy density obtained for the battery was 75 Wh kg-1 and its volumetric energy density was 125 Wh L-1 . The capacity retention after 500 cycles was 87 %. Further improvement of the cell performance and energy density is expected on development of suitable electrode materials and optimization of the cell design. PMID- 30480365 TI - Developing 1D Sb-Embedded Carbon Nanorods to Improve Efficiency and Stability of Inverted Planar Perovskite Solar Cells. AB - To overcome the zigzag pathway transport of the electron diffusion process and eliminate the surface trap states of phenyl-C61-butyric acid methyl ester (PCBM) nanofilms in inverted perovskite solar cells, novel 1D N-type doped carbon nanorods (CNRs) are developed by a stibonium (Sb) auxiliary ball milling method and introduced into the PCBM film to prepare the PCBM:Sb-CNRs hybrid transport layer. In this way, the N-type doped Sb-CNRs can extend the built-in electric field between CH3 NH3 PbI3 and PCBM to facilitate the separation of electron/hole pairs. The discontinuous band with the built-in potential in the PCBM/Sb-CNRs heterojunction can boost interfacial charge redistribution and promote electrons diffusion from PCBM to electrode through 1D Sb-CNRs network. As a result, the high device efficiency of 19.26% with enhanced air stability and little hysteresis are achieved. This work demonstrates a simple strategy to improve the efficiency and stability of perovskite photovoltaic devices using low-cost carbon nanomaterials. PMID- 30480366 TI - Encapsulating Au-Fe3O4 Nanodots into AIE active Supramolecular Assemblies: Ambient Visible light Harvesting "Dip-Strip" Photocatalyst for C-C /C-N Bond Formation Reactions. AB - The present study demonstrates the development of supramolecular porous ensemble consisting of hetero-oligophenylene derivative 6 and Au-Fe3O4 nanodots. Supramolecular assemblies of AIE active hetero-oligophenylene derivative 6 served as reactors for the generation of Au-Fe3O4 nanodots. The as prepared supramolecular ensemble functioned as an efficient recyclable photocatalytic system for C(sp2)-H bond activation of anilines for the construction of quinoline carboxylates. Interestingly, the 'dip catalyst' prepared by depositing PTh-co PANI-6: Au-Fe3O4 nanodots on a filter paper which served as a recyclable strip (upto 10 cycles) for C-C/C-N bond formation reaction. PMID- 30480367 TI - Application of endoscopic ultrasound-guided-fine needle aspiration combined with cyst fluid analysis for the diagnosis of mediastinal cystic lesions. AB - BACKGROUND: Mediastinal cystic lesions account for approximately 15-20% of all mediastinal masses and are difficult to differentiate because of similar imaging manifestation. The aim of this study was to differentiate mediastinum cystic lesions through endoscopic ultrasound-guided-fine needle aspiration (EUS-FNA) and parameters from cyst-fluid analysis. METHODS: Over a period of eight years, 37 patients suspected with mediastinal cystic lesions were assessed. Cyst fluid was collected via EUS-FNA and further examined using cytological and biochemical techniques. Definitive diagnosis was established based on cytology, surgical pathology, and/or clinical follow-up. RESULTS: Based on the final pathological reports or long-term follow-up, 19 patients were diagnosed with benign cysts, 14 with benign or malignant tumors, 2 with tuberculosis, 1 with an abscess, and 1 with a pancreatic pseudocyst. Computed tomography or magnetic resonance imaging mistakenly distinguished eight cases as solid masses (27.03%), but EUS revealed cystic characteristics. Carcinoembryonic antigen and lactate dehydrogenase (LDH) were evaluated from the cyst fluid obtained by EUS-FNA. There was no statistically significant difference in carcinoembryonic antigen values between benign and malignant cysts; however the average LDH value in the malignancy group was significantly higher than in the benign group. CONCLUSION: EUS-FNA showed great potential for differentiating mediastinal lesions by combining imaging manifestation and cytological examination. The elevated LDH value from cyst fluid chemical analysis could be used as an auxiliary indicator for diagnosing malignancy. PMID- 30480368 TI - Fixed-dose combination pharmacologic therapy to improve hypertension control worldwide: Clinical perspective and policy implications. PMID- 30480369 TI - Synthesis and Magnetic Properties of (Pyrrolidin-1-oxyl)-(Nitronyl Nitroxide)/(Iminonitroxide)-Dyads. AB - Unlike extensively studied diradicals linked by pi-conjugated systems, only a few studies have investigated weakly coupled diradicals linked by an sp3 carbon atom. Herein, we prepared pyrrolidin-1-oxyl-(nitronyl nitroxide)-dyad 5 and pyrrolidin 1-oxyl-iminonitroxide-dyad 6. From the observed temperature dependence of the magnetic susceptibility, 5 and 6 were determined to be in singlet ground states with 2Jintra/kB = -35.2 K and -13.6 K, respectively. From these results and theoretical calculations of related diradicals, the spin-polarization model counting the small spin density of the sp3 carbon atom was shown to be used as a spin-prediction model. PMID- 30480370 TI - Nurse-led brief sleep education intervention aimed at parents of school-aged children with neurodevelopmental and mental health disorders: Results from a pilot study. AB - PURPOSE: To test the effects of a single-session parent sleep educational intervention, led by a pediatric nurse, on sleep in a group of school-aged children attending a National Health Service mental health clinic in Murcia, Spain. DESIGN AND METHODS: Parents/caregivers of 26 children (mean age = 8.58 years; standard deviation = 0.58; 80.8% male) with neurodevelopmental or mental health disorders (84.6% pervasive developmental disorder), and with a suspicion of a behavioral sleep problem, participated in a 45-min group educational session about healthy sleep practices, supplemented by a written handout. The main outcome measures were derived from items of the Pediatric Sleep Questionnaire and included an insomnia composite score, a daytime sleepiness composite score, average sleep onset latency, and sleep duration on both weekdays and weekends. Outcome variables were assessed before and 3 months after the intervention. RESULTS: After the educational intervention, the insomnia and daytime composite scores decreased significantly (ps < 0.03). Weekday and weekend sleep duration significantly increased ( ps < 0.01). No statistically significant difference was observed in sleep onset latency before and after the intervention. PRACTICE IMPLICATIONS: A brief and relatively inexpensive single sleep educational session can positively impact sleep in children with neurodevelopmental and mental health disorders. Thus, this intervention meets the characteristics of a successful "entry level" treatment in a stepped-care approach. The stepped-care model places nurses in a pivotal position to ensure that their patients will receive the least complex and most accessible intervention, from which they are likely to get some benefit, and that a sizeable number of patients who need treatment may receive it. Thus, it is important for nurses in all types of practice settings to have an understanding of healthy sleep patterns, as well as sleep disorders in children. Pediatric nurses, regardless of their setting, are in a unique position to screen children and adolescents for sleep behavior problems or sleep disorders, to educate families about healthy sleep practices, provide guidance and feedback, and recommend referral to pediatric specialized care for more complex assessment and management. PMID- 30480371 TI - Air-assisted liquid-liquid extraction coupled with dispersive liquid-liquid microextraction and a drying step for extraction and preconcentration of some phthalate esters from edible oils prior to their determination by GC. AB - In this work, a new, cheap, simple, fast and low organic solvent consuming procedure is proposed for isolation, enrichment and gas chromatographic determination of some phthalate esters in edible oils. The method is based on a combination of air - assisted liquid-liquid extraction and dispersive liquid liquid microextraction followed by a drying step under N2 gas. Several experimental parameters affecting both extraction and preconcentration steps were investigated and optimized. Under the optimum conditions for the proposed method, wide linear ranges (0.05-800 MUg L-1 ) and low detection limits (0.007-0.023 MUg L-1 ) were observed. The ranges of enrichment factors and extraction recoveries were 68-340 and 14-68%, respectively. Eventually, the target analytes were successfully determined in different edible oils using the proposed method. This article is protected by copyright. All rights reserved. PMID- 30480372 TI - Flow cytometry identification of nonhemopoietic neoplasms during routine immunophenotyping. AB - INTRODUCTION: Nonhemopoietic neoplasms (NHNs) may be encountered during routine flow cytometry (FC) immunophenotyping. The clue of their presence mainly relies on detection of CD45-negative (CD45-) cells with altered scatter parameters. METHODS: In this study, we evaluated a monoclonal antibody combination conceived to characterize the CD45- population by FC, suspected of belonging to NHNs, when present. The panel included CD45 for leucocytes identification, CD326 (clones BerEP4 and HEA-125) to mark epithelial cells, CD33 to identify myeloid cells, CD138 to trace plasma cells and CD56 useful in the identification of neuroendocrine tumours. 7AAD vital dye was used to gate out dead cells. Results were correlated with cytomorphology and confirmed by histological data, if available. RESULTS: Among 9422 specimens submitted for routine FC investigation, 47 samples that included fine-needle aspirates, bone marrow aspirates, tissue biopsies and body fluids had a detectable CD45- population and a sufficient cell amount to be further investigated. FC revealed the presence of CD326-positive epithelial cells in 38 specimens; altered scatter parameters and variable reactivity to the other antigens tested allowed to suspect NHNs in the remaining nine samples. The presence of NHNs was confirmed in all cases by morphology. CONCLUSIONS: The current results show that when CD45- cells with altered scatter parameters were detected, cytometrists involved in leukaemia/lymphoma diagnosis may require further FC investigations to rapidly identify NHNs in different specimens, thus reducing the time of the immunohistochemical diagnostic workup to reach a final diagnosis. PMID- 30480373 TI - Neonatal and infant diagnostic HIV-PCR uptake and associations during three sequential policy periods in Cape Town, South Africa: a longitudinal analysis. AB - INTRODUCTION: To strengthen the early infant diagnosis (EID) programmes and timeously identify and treat HIV-infected infants, birth HIV-PCR for some/all infants has been recommended in the Western Cape, South Africa since 2014. Operational data on the implementation of such programmes in low- and middle income countries are limited. METHODS: Utilizing the electronic records platform at primary care facilities, we developed an electronic register which consolidated obstetric and HIV-related data, allowing us to track a cohort of HIV infected/exposed mother/infant dyads longitudinally from antenatal care through delivery to infant HIV-PCR. We assessed guideline implementation and impact on EID of three sequential EID policies in a referral chain of facilities in Cape Town (primary-tertiary care). Birth HIV-PCR was indicated in period 1 if symptomatic; period 2 if meeting high-risk criteria for transmission; and period 3 for all HIV-exposed neonates. RESULTS: We enrolled 2012 HIV-exposed infants; 89.2% had at least one HIV-PCR at any point. The majority of birth tests were performed in hospital versus primary care regardless of policy period. Almost half of all infants (47.9%) had at least one high-risk criterion for vertical infection; of these, 39.7% had a birth test. Infants with more risk factors were more likely to have birth EID. Receipt of a birth HIV-PCR significantly reduced the likelihood of receiving a follow-up test at six to ten weeks, even after adjusting for potential confounders (aOR 0.18 (0.12 to 0.26)). The proportion of infants tested at six to ten weeks old dropped from 92.9% (period 1) to 80.2% in period 3 and those receiving birth HIV-PCR increased, peaking at 67.4% during period 3. The proportion of positive birth tests was highest (2.9%) when birth tests were restricted to infants meeting high-risk criteria, with a low proportion positive for the first time at six to ten weeks. During period 3, the proportion positive at six to ten weeks was high (2.4%), highlighting the importance of follow-up to detect intrapartum and early postpartum infections. CONCLUSIONS: Over all policy periods, EID guidelines were incompletely implemented across all levels of care but especially in primary care. Birth HIV PCR reduced return for follow-up testing, such follow-up testing is critical for the effectiveness of the programme. PMID- 30480374 TI - Multiple Ether-Functionalized Phosphonium Ionic Liquids as Highly Fluid Electrolytes. AB - Ionic liquids (ILs) are promising electrolytes, although their often high viscosity remains a serious drawback. The latter can be addressed by the introduction of multiple ether functionalization. Based on the highly atom efficient synthesis of tris(2-ethoxyethyl) phosphine, several new phosphonium ionic liquids were prepared, which allows studying the influence of the ether side chains. Their most important physicochemical properties have been determined and will be interpreted using established approaches like ionicity, hole theory, and the Walden plot. There is striking evidence that the properties of phosphonium ionic liquids with the methanesulfonate anion are dominated by aggregation, whereas the two triple ether functionalized ILs with the highest fluidity show almost ideal behavior with other factors being dominant. It is furthermore found that the deviation from ideality is not significantly changed upon introduction of the ether side chains, although a very beneficial impact on the fluidity of ILs is observed. Multiple ether functionalization therefore proves as a powerful tool to overcome the disadvantages of phosphonium ionic liquids with large cations. PMID- 30480375 TI - Determination of the binding mechanism of histone deacetylase inhibitors. AB - This article places its focus on methods and tools enabling the elucidation of the mechanism by which ligands, small molecule inhibitors or substrates, interact with zinc containing bacterial or human members of the histone deacetylase family (HDACs). These methods include biochemical and biophysical approaches and can be subdivided into equilibrium and kinetic methods. More information about the exact mode of action can be obtained by combining these methods with specific mutant variants of the enzymes and/or series of structural similar ligands. All available equilibrium and kinetic data including additional information from 3D structures of HDAC-ligand complexes can be beneficially combined in a data analysis procedure called Integrated Global Fit analysis eventually providing the most likely binding mechanism. This article is protected by copyright. All rights reserved. PMID- 30480376 TI - Characterization and regulation of MT1-MMP cell surface-associated activity. AB - Quantitative assessment of MT1-MMP cell surface-associated proteolytic activity remains undefined. Presently, MT1-MMP was stably expressed and a cell-based FRET assay developed to quantify activity towards synthetic collagen-model triple helices. To estimate the importance of cell surface localization and specific structural domains on MT1-MMP proteolysis, activity measurements were performed using a series of membrane-anchored MT1-MMP mutants and compared directly with those of soluble MT1-MMP. MT1-MMP activity (kcat /KM ) on the cell surface was 4.8-fold lower compared with soluble MT1-MMP, with the effect largely manifested in kcat . Deletion of the MT1-MMP cytoplasmic tail enhanced cell surface activity, with both kcat and KM values affected, while deletion of the hemopexin like domain negatively impacted KM and increased kcat . Overall, cell surface localization of MT1-MMP restricts substrate binding and protein coupled motions (based on changes in both kcat and KM ) for catalysis. Comparison of soluble and cell surface-bound MT2-MMP revealed 12.9-fold lower activity on the cell surface. The cell-based assay was utilized for small molecule and triple-helical transition state analog MMP inhibitors, which were found to function similarly in solution and at the cell surface. These studies provide the first quantitative assessments of MT1-MMP activity and inhibition in the native cellular environment of the enzyme. This article is protected by copyright. All rights reserved. PMID- 30480377 TI - Response for letter "Be cautious in comparing the seroprevalence of hepatitis E detected at different years in different countries". PMID- 30480378 TI - Carbon-ion radiotherapy for HCC-A potential tool to fulfil an unmet gap in the treatment algorithms? PMID- 30480379 TI - How to reduce mortality of bacterascites-That is the question. PMID- 30480380 TI - Multimodal Cancer Theranosis Using Hyaluronate-Conjugated Molybdenum Disulfide. AB - Among various 2D nanomaterials, molybdenum disulfide (MoS2 ) exhibits unique visible photoluminescence with high absorption at the near-infrared (NIR) range. Despite these optical properties, the efforts to use MoS2 nanomaterials for optical imaging and photothermal therapy are hampered by their instability and low intracellular delivery efficiency. Multifunctional MoS2 conjugated with hyaluronate (HA) for cancer theranosis is reported herein. HA facilitates the delivery of MoS2 to tumor cells by the HA-receptor mediated endocytosis. In BALB/c nude mice inoculated with a colorectal cancer cell line of HCT116, HA-MoS2 conjugates appear to be accumulated in the primary tumor at a content more than that in the liver and kidney. The disulfide bonding between MoS2 and thiolated HA seems to degrade in the cytoplasm, releasing MoS2 sheets in stacks and enhancing luminescence efficiency. The HA-MoS2 conjugates are readily detected via photoacoustic imaging as well as upconversion and downconversion fluorescence imaging. With NIR light illumination, HA-MoS2 conjugates enable highly effective photothermal tumor ablation. All these results confirm the promising potential of HA-MoS2 conjugates for cancer theranosis. PMID- 30480381 TI - Gold Nanoparticles with Antibiotic-Metallopolymers toward Broad-Spectrum Antibacterial Effects. AB - Bacterial infection has evolved into one of the most dangerous global health crises. Designing potent antimicrobial agents that can combat drug-resistant bacteria is essential for treating bacterial infections. In this paper, a strategy to graft metallopolymer-antibiotic bioconjugates on gold nanoparticles is developed as an antibacterial agent to fight against different bacterial strains. Thus, these nanoparticle conjugates combine various components in one system to display enhanced bactericidal efficacy, in which small sized nanoparticles provide high surface area for bacteria to contact, cationic metallopolymers interact with the negatively charged bacterial membranes, and the beta-lactam antibiotics' sterilzation capabilities are improved via evading intracellular enzymolysis by beta-lactamase. This nanoparticle-based antibiotic metallopolymer system exhibits an excellent broad-spectrum antibacterial effect, particularly for Gram-negative bacteria, due to the synergistic effect of multicomponents on the interaction with bacteria. PMID- 30480383 TI - Target-Mediated Drug Disposition Model for Bispecific Antibodies: Properties, Approximation and Optimal Dosing Strategy. AB - Bispecific antibodies (BsAb) bind to two different targets, and create two binary and one ternary complex (TC). These molecules have shown promise as immuno oncology drugs, and the TC is considered the pharmacologically active species that drives their pharmacodynamic effect. Here we have presented a general target mediated drug disposition model for these BsAbs, which bind to two different targets on different cell membranes. The model includes four different binding events for BsAb, turnover of the targets, and internalization of the complexes. In addition, a quasi-equilibrium approximation with decreased number of binding parameters and, if necessary, reduced internalization parameters is presented. The model is further used to investigate the kinetics of BsAb and TC concentrations. Our analysis shows that larger doses of BsAbs may delay the build up of the TC. Consequently, a method to compute the optimal dosing strategy of BsAb, which will immediately create and maintain maximal possible TC concentration, is presented. This article is protected by copyright. All rights reserved. PMID- 30480382 TI - Association between breast cancer and thyroid cancer: A study based on 13 978 patients with breast cancer. AB - BACKGROUND: Thyroid cancer (TC) is one of the most commonly seen secondary malignancy in breast cancer (BC) survivors. MATERIALS AND METHODS: A retrospective study was conducted in BC patients in our center from 1999 to 2013. Patients were divided into BC-TC group and BC-alone group. RESULTS: In total, 13 978 BC patients were identified, among whom 247 (1.8%) had TC. The standardized incidence ratio (SIR) of TC was 4.48 compared with Chinese females, and up to 98.0% of cases were thyroid papillary carcinomas. A family history of malignancy was the only independent risk factor (odds ratio = 1.457, P = 0.025) for development of TC in patients with BC. We also identified inferior survival in patients with synchronous versus metachronous BC-TC (P = 0.016). Synchronous BC TC (risk ratio = 5.597, P = 0.018) was an independent prognostic factor for inferior RFS. CONCLUSIONS: We observed high co-occurrence of TC in patients with BC. There might be different mechanisms behind synchronous and metachronous BC TC. PMID- 30480384 TI - Induction of smell through transethmoid electrical stimulation of the olfactory bulb. AB - BACKGROUND: Anosmia has an estimated prevalence of 5% of the general population. Outside of inflammatory causes, therapeutic options are limited despite research advances. Bypassing peripheral neuronal damage through central stimulation is a potential therapeutic option that has shown success in other sensory systems, most notably with hearing. We performed a pilot study to determine the feasibility of inducing smell through artificial electrical stimulation of the olfactory bulbs in humans. METHODS: Subjects with a history of sinus surgery, including total ethmoidectomy, with intact ability to smell were enrolled. The ability to smell was confirmed with a 40-item smell identification test. Awake subjects underwent nasal endoscopy and either a monopolar or bipolar electrode was positioned at 3 areas along the lateral lamella of the cribriform plate within the ethmoid sinus cavity. A graded stimulation current of 1-20 mA at 3.17 Hz was administered while cortical evoked potential (CEP) recordings were collected. Subjective responses of perceived smell along with reports of discomfort were recorded. Subjects with artificially induced smell underwent repeat stimulation after medically induced anosmia. RESULTS: Five subjects (age, 43-72 years) were enrolled. Three subjects reported smell perception smell with electrical stimulation. This was reproducible after inducing anosmia, but CEP recordings could not provide objective support. All subjects tolerated the study with minimal discomfort. CONCLUSION: This is the first report of induced smell through transethmoid electrical stimulation of the olfactory bulb. These results provide a proof of concept for efforts in development of an olfactory implant system. PMID- 30480385 TI - Replacement of the descending thoracic aorta after stent-graft failure. AB - Open surgery after failed endovascular aortic repair remains an important therapy. The potential modes of stent-graft failure include: type I endoleaks; progression of the aortic disease at the landing zones or proximal/distal to them persistent false lumen perfusion in post-dissection aneurysms; retrograde aortic dissection; stent-graft infection; and stent-graft collapse, fracture, or dislocation. The mortality associated with those procedures can be up to 20% depending on the complexity of the operation and the comorbidities of the patient, especially the presence of graft infection. In this video tutorial we present the case of a young patient with a 7-cm pseudoaneurysm of the descending thoracic aorta following aortic coarctation repair. Initial stent-graft therapy failed due to type I endoleak. Open surgery with stent-graft explantation and replacement of the descending thoracic aorta was performed. The details of the operation are shown in the step-by-step video. PMID- 30480386 TI - Completely thoracoscopic superior segmentectomy of the right lower lobe. AB - Minimally invasive pulmonary segmentectomy allows adequate oncologic treatment in selected cases while preserving lung parenchyma and minimizing perioperative morbidity and length of hospital stay. Although several variations of minimally invasive pulmonary segmentectomy have been described, I favor a fully thoracoscopic multiport approach that allows direct access to the segmental structures, and is straightforward and versatile enough to allow adaptation (such as conversion to lobectomy in the case of positive margins) if there are unexpected intraoperative findings. Key aspects of the procedure include proper patient positioning, appropriate positioning of operating trocars, standardized technique to expose and dissect the segmental vein, bronchus, and artery, and accurate division of the intersegmental plane and fissure. PMID- 30480387 TI - Beating heart porcine high-fidelity simulator for the training of edge-to-edge mitral valve repair. AB - Transcatheter treatment of structural heart disease is becoming an everyday reality for an increasing number of surgeons, and effective training modalities for basic guide-wire skills, catheter handling, and periprocedural imaging are of growing relevance. In this video tutorial we present a beating-heart porcine model used as a high-fidelity training simulator for transcatheter cardiac valve procedures. We demonstrate a complete transcatheter edge-to-edge mitral valve repair procedure, including periprocedural imaging, clip deployment, and quality control. Various mitral valve pathologies can be simulated, including the demonstrated leaflet prolapse. Trainees practice clip navigation within the left atrium, transmitral passage, and clip orientation as well as grasping mitral valve leaflets to treat mitral regurgitation. Periprocedural imaging is achieved via epicardial echocardiography and left ventricular cardioscopy, and these imaging modalities are also relied on to guide surgeons during the simulations, as required. The beating heart model enables realistic demonstration of the hemodynamic consequences of valve repair, and we believe that this simulator represents a valuable adjunct to surgical training. PMID- 30480388 TI - Uniportal VATS approach for treatment of empyema: Challenges and recommendations. AB - The uniportal VATS approach is now taking the lead in the practice of thoracic surgery and is transforming the way we operate. We describe here how to perform a uniportal VATS debridement and decortication, with a special focus on tips and tricks for getting inside an empyema pouch and identifying the optimal plane of cleavage for decortication. PMID- 30480389 TI - Muscle-sparing extrapleural repair of neonatal aortic coarctation. AB - The goal of surgical treatment of aortic coarctation is to relieve the pressure gradient on the aorta and to allow for subsequent growth of the repaired aorta. In this regard, coarctation resection and extended end-to-end anastomosis has become the surgical gold standard. Early and long-term results have been reported to be excellent. In this tutorial, we present our technique for correction of aortic coarctation using a muscle-sparing, extrapleural approach. PMID- 30480390 TI - [Safety in shipping: the role of the human factor.] AB - OBJECTIVES: The main aim of this paper is to examine the role of human factors in the safety of ship transport (shipping). METHODS: Particularly, we analyzed the personal, psychosocial and organizational factor that intervene in this context and the consequences on the safety performance and workers' well-being. RESULTS: In this review, some shipping accidents and their causes are presented and a particular attention will be paid to human error, fatigue and stress, non technical skills and perception of safety. CONCLUSIONS: In the final part of the paper the safety performance and its antecedents in the context of shipping will be extensively examined. PMID- 30480391 TI - [The Italian version of the "Claustrophobia Questionnaire": validation study and perspectives of use for the occupational physician.] AB - OBJECTIVES: Aim of our study was to adapt the Claustrophobia Questionnaire (CLQ) to the Italian context. METHODS: In our study, a sample of 50 claustrophobic patients was compared to 50 healthy people (control group). All of them answered the Claustrophobia Questionnaire and the Stait-Trait Anxiety Inventory Form Y1 and Y2, as well as demographic questions. RESULTS: As it was theoretically expected, our results confirmed the two-factor structure and showed that the Italian version of the CLQ has good psychometric properties. Indeed, it was observed that claustrophobic patients scored higher in claustrophobia than those from the control group. CONCLUSIONS: In conclusion, the Italian version of the CLQ is a reliable and valid instrument to assess claustrophobic fear. PMID- 30480392 TI - [The study of psycho-social well being in the educational contexts toward the Va.RP tool: a study case.] AB - OBJECTIVES: The organizational well-being construct has become a theme with broad scientific and law debate, pertaining prevention and protection measures concerning work-related stress, both for assessment and intervention on psychosocial risks. This paper focuses on a case study identified in a specific organizational context of a upper middle school. METHODS: Starting from a research-intervention perspective, this paper was primarily based on the use of the "Psychosocial Risk Assessment" (Va.RP) Italian tool, in shape for medium organizations, Va.RP-M, in a further form specially remodeled for organizational school contexts. Some of the dimensions measured by the instrument are: the role, transparency of information, support, the relationship between work vs. private life, the perception of organizational and managerial aspects. In addition to this instrument, it was made a board regarding the "practical solutions" deemed most relevant according to the critical organizational received by workers, closing with a request for comments and suggestions on initiatives in order to prevent work-related stress. RESULTS: The results show an emerging dissatisfaction primarily related to the dimensions of perceived lack of organizational justice, role, career advancement, leadership and work flexibility. As for "practical solutions" suggested, respondents identify priorities for high salient specific actions. CONCLUSIONS: Overall, it is confirmed as the face and prevent work-related stress is a process that must involve all stakeholders comprised into the organization, with a particular concern in promoting a strength of organizational management, to improve the well being in partcular in classroom settings. Teachers emerge as a figure of multiparty function experienced in the psychosocial dynamics considered. PMID- 30480393 TI - Potentiation of muscle strength by focal vibratory stimulation on quadriceps femoris. AB - OBJECTIVES: Several studies have investigated the effects of focal vibration on muscle strength. Non-univocal results have been found. The aim of this study was to evaluate the effect of prolonged focal vibratory stimulation on quadriceps muscle strength at two different frequencies (80 and 300 Hz). The evaluation of muscle strength was performed at different intervals of time after the end of the vibratory stimulation in order to quantify the long-term effects and their trends over time. METHODS: Twenty-seven healthy volunteers were divided into three groups, a control group (no treatment) and two groups treated with vibratory stimulation (80 or 300 Hz) of relaxed quadriceps femoris bilaterally, once a day (30 min) for 5 consecutive days. The quadriceps' strength was measured through an isokinetic dynamometer, before and at three time intervals after the treatment, with a follow-up period of 4 weeks. The outcome measure was the Peak Torque (PT, Nm) of the quadriceps femoris produced by extension movement at three defined angular velocities and during isometric contraction. RESULTS: No changes in PT were observed in the control group over time, while PT increased in the treated groups. No significant difference in PT behavior was observed between these two groups. PTs recorded before and after the treatment were markedly different, and the increase in the PT persisted until the follow-up at 4 weeks, for all angular velocities tested. CONCLUSIONS: Prolonged vibratory stimulation of the quadriceps femoris, both at 80 and at 300 Hz, leads to an increase in muscle strength. The vibration effect does not appear to fade at the end of treatment, but persists at the follow up, suggesting a likely underlying plastic process. The results of the current study suggest that 30-min per day, 5 day focal vibratory treatment can be helpful during the clinical practice to regain muscular strength. It does not require patient's effort during the treatment, requires a little time, its effects are long-lasting, and there are no known adverse effects. PMID- 30480394 TI - [Regeneration and rehabilitation. Plastic surgery practice in a rehabilitation centre.] AB - OBJECTIVES: Regenerative Surgery aims at the restoration of the loss of structures and functions of the body using four innovative approaches: physical energies, biomaterials, cell products and stem cells. METHODS: The Authors provide an overview of their experience with Regenerative Surgery procedures at the Plastic Surgery Unit of the University of Pavia, Istituti Clinici Scientifici Salvatore Maugeri, in a 10 years period, from 2007 to 2017, for the treatment of extensive acute soft tissue loss, chronic ulcers, disabling scars and degenerative pathologies with different aethiology. RESULTS: Regenerative Surgery is a well-established and effective practice in a modern Plastic Surgery Unit. CONCLUSIONS: Regenerative methods are effectively used both as exclusive options in case of absolute contraindication to traditional surgery and as alternative to the latter in order to provide the same outcome with less invasiveness or in combination with minor traditional surgical procedures to reduce the overall surgical burden. PMID- 30480395 TI - [Physical activity, tool for the prevention and management of chronic diseases]. AB - OBJECTIVES: Physical activity is a key element in the prevention, treatment and rehabilitation of many diseases. METHODS: In the context of an adequate lifestyle, its practice amplifies the health benefits and increases the fitness, and furthermore counteracts the development and progression of chronic non communicable diseases, modulating many risk factors. Its function is important in all life cycles and helps to keep the functional capabilities and independence even with aging. RESULTS: While inadequate physical activity (due to a sedentary lifestyle) is currently the fourth leading cause of mortality in developed countries, being one of the main public health issues, strong scientific evidences show that a regular and sufficient dose of physical activity reduces by about 30% the risk of premature death, cardiovascular disease and stroke, type II diabetes, colon and breast cancer, depression. CONCLUSIONS: Several guidelines and recommendations define the type, intensity, frequency and duration of physical activity, and many lifestyle preventative interventions prove its effectiveness and sustainability. Although so far a minority of the population actually adheres to the recommendations, the epidemiological strenght of lifestyle-oriented programs is considerable: quitting sedentariness, even low doses of physical activity are protective for health and reduce by about 22 % the risk of premature death. Physical activity is also an important therapeutic tool for patients with cardiovascular diseases, hypertension, diabetes II, cancer, chronic obstructive pulmonary diseases; an appropriate dosage reduces the risk of recurrence and disease progression, improves the control of clinical parameters and increases the patient's quality of life. PMID- 30480396 TI - ? AB - Connection of the cytokins profile with experimental hepatic encephalopathy (HE) inrats was studied. Investigation was conducted on 20 laboratory rats, in which HE wassimulated, using SCl4 injection. The interleukins (IL) level, including, IL-1beta, IL-4, IL-10 and interferon gamma(IFN-gamma), was determined using immunoassay method with the help of polyclonal antibodies. Enhancement of the proinflammatory IL-1beta and INF gammacontent in the rats blood serum while induced HE by 57.9 and 39.5% accordingly (p <0.05), comparing with such in a control and the compensation enhancement of the anti'inflammatory IL-4 and IL-10 level by 34.6 and 75.9% (p < 0.05) was established. Theresults obtained confirms the cytokins role in pathogenesis of HE, determination of theirlevel constitutes significant criterion for the posttransplantation complications prog'nostication. Inflammation and profile of cytokins constitute the main target in therapy ofHE in patients, suffering liver cirrhosis PMID- 30480397 TI - ? AB - Dynamics of the posttraumatic spasticity syndrome, a key component of spinal trauma,was investigated on simulation model of the open penetrating spinal cord (SC) traumaon adult male rats of aWistarline after half transection of the SC cross'section with itsdurable compression by biocompatible foreign body. Squeezing of the injured SC byforeign body potentiates formation of spasticity syndrome, and do not influence orrestricts a severe pain syndrome occurrence. Reduction of the SC squeezing due tothe foreign body elongation and reduction of its volume was accompanied by trustwor'thy rising of functional activity and the spasticity reduction in paretic extremity. Changesin activity of efferent chain of the movement system while formation of spasticity syn'drome in simulated trauma have occurred in both parts of SC ' in the injured one and inintact one as well, its severity did not correlate with presence of foreign body in zone oftrauma. PMID- 30480398 TI - ? AB - Possibilities of application of preparations, containing biologically active substances(BAS) of fetoplacental origin, in systemic therapy of the wounds, were analyzed.Comparison of morphological characteristics of the cold wounds while application ofplacental extract (PE) and cryopreserved serum of the cord blood (CPSCB) was done.The pronounced stimulating impact on the wounds healing due to improvement ofmicrocirculation in tissues, bordering upon the cryodestruction zone, the local immuneprocesses stimulation, activation of the granulation tissue and epithelial wound defectformation were noted. Therapeutic effect of CPSCB is more significant than that of PE.The data obtained serve as a background for the BAS of fetoplacental origin applicationin complex treatment of the wounds. PMID- 30480399 TI - ? PMID- 30480400 TI - ? PMID- 30480401 TI - ? AB - The genetic diversity of 13 Vincetoxicum Wolf species distributed in Ukraine was investigated using 4 of the 8 nuclear microsatellite markers, previously developed for Vincetoxicum atratum from Japan. The number of alleles ranged from 8 to 25. The expected heterozygosities were 0,690-0,938 and observed ones ranged from 0,205 to 0,806. In general, the level of genetic variation in studied representatives of the genus Vincetoxicum from Ukraine proved to be comparable with that of Vincetoxicum atratum. The microsatellite loci Vinc5, Vinc104, Vinc123, Vinc124 can be successfully used to assess intra- and interspecific polymorphisms of species of the genus Vincetoxicum Wolf in Ukraine. PMID- 30480403 TI - Mutagenesis testing using the LacZ reporter activity of the reparation gene mus209 in Drosophila melanogaster. AB - We studied a set of Drosophila melanogaster strains that could be potentially suitable for testing a variety of mutagenic factors. Their genomes contained insertions of the enhancer trap P{lacW} in which the activity of the LacZ reporter is under the control of the reparation genes' regulatory region. We demonstrated that the beta-galactosidase reporter, which is encoded by insertion of P{lacW} element in the gene mus209, is induced by irradiation in the cells of the salivary glands and wing imaginal discs. Despite the fact that the reporting coloration is not associated with the dose of radiation treatment, we found that the induction threshold of the reporter is different for these tissues. Thus, coloration in salivary glands is detectable after the dose of 200 rad and above, whereas the imaginal discs get colored with 500 rad and above. Thereby, multiple thresholds for induction of the reporter in the various tissues allow approximating the received dose. PMID- 30480404 TI - ? AB - The formation of different types of the artifacts in the amplification reaction with using different classes of the molecular-genetic markers (Indel and SSR) was studied. It was shown that DNA heteroduplexes formed during amplification of heterozygous samples, as fragments of target genes and microsatellite loci. During the electrophoresis in native polyacrylamide gel of the amplification products of homozygous samples for microsatellite loci it was revealed specific additional fragments that do not belong to the class of heteroduplex DNA. It was supposed, that the additional fragments belong to a special type of homoduplex DNA - non-linear homoduplexes. The analysis revealed that the formation of a non linear homoduplex DNA takes place on the 20-25 cycle of the PCR, both at the amplification of the individual samples, and individual DNA fragments that was cut out from the gel. PMID- 30480405 TI - ? AB - Genetic control of dark color of glumes was studied in Triticum spelta L. var. caeruleum accessions using gliadins as genetic markers. F2 and BC1 plants from crosses between the spelt accessions and common wheat varieties with white glumes served as the material for the investigation. Analysis of segregation for glume colour fitted the monogenic control of the character. Using electrophoretical analysis of gliadin of seeds from the hybrid plants it was revealed that in the T. spelta var. caeruleum accessions the allele Gli-A1j* is linked to the allele for dark (black) glumes at the Rg-A1 locus. PMID- 30480406 TI - ? AB - Molecular-genetic study of C-590T polymorphic locus of IL-4 gene in 31 children with recurrent episodes of acute obstructive bronchitis and 50 people who constituted the control population-based group has been carried out. It is proved that the presence of this polymorphic locus leads to three-fold increase of the risk of acute obstructive bronchitis recurrent episodes. PMID- 30480408 TI - ? AB - In the article the data on the distribution of CYP21A2 gene mutations (gene deletion/conversion, c.290-13C>A/G, E110Vfs, I172N, cluster of mutations I236N, V237E, M239K, V281L, Q318X, R356W) among Ukrainian patients with congenital adrenal hyperplasia of different clinical phenotypes are presented. The most common mutation in the studied group (n = 27) is the CYP21A2 gene deletion/conversion. Possible patterns of the studied mutations distribution in different populations of the world and the patients' genotype - phenotype association are discussed. PMID- 30480407 TI - Bcl1 polymorphism of glucocorticoid receptor gene in patients with bronchial asthma with obesity. AB - The objective of this investigation was to analyze possible association between BclI polymorphism of glucocorticoid receptor gene and obesity in patients with bronchial asthma (BA). The study involved 188 patients with bronchial asthma and 95 apparently healthy adult individuals. Generally accepted assessments and examinations for BA diagnosis, and anthropometric, molecular-genetic and statistic methods of investigation were used in the research. It was found out that the patients with BA demonstrated higher body mass index (BMI) and higher ratio of fat centralization much more often, than the control group. Genotypes distribution for BclI polymorphism in patients with BA showed a statistically significant difference between patients with different BMI unlike the control group. Comparison of genotype frequency for BclI polymorphism in glucocorticoid receptor gene in individuals with different ratio of fat centralization in the control group and in the patients with BA separately showed statistically significant differences in the distribution of gene allelic variations only among the patients with BA. It was demonstrated that G/G genotype in the patients with visceral obesity was associated with BA. PMID- 30480409 TI - Reduction of radiation-induced nitrative stress in leucocytes and kidney cells of rats upon administration of polyphenolic complex concentrates from red wine. AB - The research has shown that exposure to ionizing radiation at the dose of 30 cGy leads to the activation of NO-synthase way of nitrogen oxide synthesis, as well as to the accumulation of its stable metabolites and 3'-nitrotyrosine modified proteins in rat peripheral blood leucocytes and the renal cortical layer. NO synthase activity was preserved at the control value through the consumption of red wine natural polyphenolic complex concentrates by the irradiated animals. The content of proteins modified by tyrosine nitration decreased in the early period of post-radiation exposure due to the influence of the investigated concentrate. Thus the ability of red wine natural polyphenolic complex concentrates to prevent adverse changes in L-arginine/NO system and, therefore, inhibit the development of nitrative stress induced by low doses of ionizing radiation has been proved experimentally. PMID- 30480410 TI - ? AB - Expression of Tlr2, Muc2, Defa genes in rat duodenal upon long-term gastric hypacidity (hypochlorhydria) and with multiprobiotic correction was investigated. Increasing of Tlr2, Muc2, Defa expression on the background of the intensification of lipid peroxidation in rat duodenal villus and crypt epithelial cells upon gastric hypoacidity was shown. The mRNAs patterns of genes mentioned above were shown to decrease or approach to control values as well as the level of lipid peroxidation products under the treatment of hypoacidic rats with the multiprobiotic. The data obtained may indicate involvement of genes Tlr2, Muc2, Defa in development of inflammation in the duodenum due to dysbiotic changes under conditions of prolonged hypochlorhydria. PMID- 30480411 TI - ? AB - In this study there were investigated the changes in surface marker CD44 in human erythrocytes exposed to cryoprotective media, as well as the impact of oxidative modification of membrane-cytoskeleton proteins on the CD44 characteristics under the changed physico-chemical parameters of the cellular environment. Glycerol, DMSO, sucrose, and PEG-1500 were shown to cause a decrease in CD44 expression level and amount of CD44-positive cells during prolonged exposure erythrocytes with them. That may reflect subtle adjustments in the system of protein-protein interactions in erythrocyte membrane-cytoskeleton complex, which may affect the stability of cells during cryopreservation. Extracellular substances (sucrose and PEG-1500) exhibited a more pronounced effect on the CD44 in erythrocytes in comparison with the examined substances of endocellular type. Modification of membrane-cytoskeleton proteins with oxidizing bifunctional reagent diamide enhanced the identified tendencies. PMID- 30480412 TI - ? AB - It was shown phenotypic changes in the root system of seedlings Arabidopsis thaliana in transgenic lines with overexpression and suppressed gene expression of serine-threonine protein kinase KIN10 in conditions of energy shortage and under normal conditions. The normal growth and development of KIN10 overexpressing plants with in energy deficiency conditions were detected. The significant inhibition of the plant development under normal conditions for these plant lines was obsereved. The levels of KIN10 gene expression under normal conditions in different organs A. thaliana, particularly in the roots, stems, leaves and flowers were analyzed. The highest level expression of the gene was fixed in the leaves. PMID- 30480413 TI - Colocalization of USP1 and RN domain of Bcr-Abl oncoprotein in terms of cronic myeloid leukemia cell rearrangements. AB - The development of chronic myeloid leukemia (CML) is the result of a reciprocal translocation between chromosomes 9 and 22 due to the emergence of Philadelphia chromosome. The product of this mutation is a hybrid oncoprotein Bcr-Abl. According to the results of mass spectrometric analysis, USP1 protein was identified as a potential candidate for interaction with the PH domain Bcr-Abl oncoprotein. Due to the deubiquitination properties, USP1 protein can prevent proteasomal degradation of Bcr-Abl oncoprotein in a cell and, consequently, contribute to its accumulation, and the progression of the disease. In this work, creating the genetic constructs, we detected the USP1 protein localization in the cell. Also, a nuclear colocalization of USP1 protein with PH domain of Bcr-Abl oncoprotein in HEK293T cells was shown. The results are important for understanding the implications of the Philadelphia chromosome emergence, and the development of new methods for CML treatment, since the recent techniques are not always effective due to the emergence of numerous mutations that cause drug resistance and relapse of the disease. PMID- 30480414 TI - Differential expression of a cysteine proteinase and cystatin pair as side-by side fusion forms in Escherichia coli. AB - As a basic study, the fusion expressions of two functionally related proteins were described. The side by side fusion construction, expression, purification and functional characterization of Arabidopsis papain-like cysteine proteinase (CP) and cysteine proteinase inhibitor (CPI) were successfully carried out by using an Escherichia coli expression system without affecting the recombinant bacterial growth. The purification products of two different fused constructs designated as "R1: H2N-maltose binding protein-CPI-CP-COOH and R2: H2N-maltose binding protein-CP-CPI-COOH" showed inverse enzymatic/inhibitory activities, in vitro. Analysis of the constructs by using computational tools revealed that the arrangement of CP/CPI pair in fusion forms might be the important criteria for proper tertiary organization, structural folding and functional property. The overall results showed that the C-terminally located molecule could be the active folded structure in each fusion construct. The achievements of the present work may be utilized in a specific protein engineering application such as manufacturing the novel switchable expression systems in the future. PMID- 30480415 TI - ? AB - Using bioinformatics analysis, the homologues of the genes Sr33 and Sr35 were identifed in the genomes of Triticum aestivum, Hordeum vulgare and Triticum urartu. It is known that these genes provide resistance to hightly virulent wheat stem rust races (Ug99). To identify important for resistance amino acid sites, the comparison of the founded homologues with the Sr33 and Sr35 protein sequences was performed. It was found that the sequences S5DMA6 and E9P785 are the closest homologues of RGA1e protein - a product of the Sr33 gene, and the sequences M7YFA9 (CNL-C) and F2E9R2 are the homologues of CNL9 - a product of the gene Sr35. It is assumed that the homologues of the genes Sr33 and Sr35, which derived from the wild relatives of wheat and barley, can provide resistance to various forms of a stem rust and can be used in the future breeding programs for wheat improvement. PMID- 30480416 TI - ? AB - The mechanisms of diabetes-associated impairment of cellular immune defense and its regulation by vitamin D3 are not fully elucidated. The study was devoted to investigating the functional state of T-cell immunity as well as humoral immune activity in response to artificial immunization in experimental diabetes and after prolonged administration of vitamin D3. It was established that diabetes is characterized by a 2.3 times decrease in blood serum 25OHD3 content. Vitamin D3 deficiency was accompanied by the failures in proliferative activity of T lymphocytes and alterations of the regulatory (CD4+-postive lymphocytes) and cytotoxic (CD8+-positive lymphocytes) cell subpopulations. It was found an increase in the content of phosphorylated p65 subunit of nuclear factor kappaB in total lysates of spleen T lymphocytes and its enhanced translocation to the nucleus. In addition, it was shown intensification of humoral IgG response to administration of recombinant diphtheria toxin subunit B. Revealed impairments in the cellular link of the immune system were associated with an increase in splenocytes apoptosis, which was detected by Annexin V-GFP ability to bind phosphatidyl serine that is specifically located on the outer surface of plasmalemma in apoptosis. Prolonged vitamin D3 treatment (within 2 months) in a dose of 20 IU/animal leads to normalization of the proliferative activity and the ratio of T-cell subpopulations, reduces the formation of phosphorylated subunit of NF-kappaB - p65 and contributes to a balanced secretion of IgG against artificial antigen. These changes were accompanied by a decrease in apoptotic events in the total population of splenocytes. Our findings suggest an important role of vitamin D3 in the regulation of the immune system abnormalities related to type 1 diabetes. PMID- 30480417 TI - ? AB - This study is an attempt to elucidate of agmatine effects upon leukocyte apoptosis in experimental diabetes mellitus (EDM). We demonstrated the increase in numbers of the leukocytes with both early and late signs of apoptosis at diabetes. Further changes in the morphofunctional state of the leukocytes include the increased amount of fragmented DNA, elevated apoptotic index and violated ratio of p53 to Bcl-2 proteins. Agmatine has been shown to exert direct corrective effects on leukocyte apoptosis: the content of r53 and Bcl-2 proteins was normalized, apoptotic index was decreased, the process of nuclear DNA degradation was ceased, while the amount of cells with early and late signs of apoptosis was diminished. PMID- 30480418 TI - ? AB - The polyphasic taxonomic analysis of the strain-antagonist of phytopathogenic bacteria and micromycetes was carried. It was found that the combination of culture-morphological, physiological and biochemical properties allowed to attribute the strain to the group Bacillus subtilis. It was shown that fatty acids of the cell walls of the strain were represented mainly by branched derivatives of iso- and anti iso- C15:0 and C17:0 fatty acids (85%) which was typical for the Bacillus amyloliquefaciens species. After molecular genetic analysis of the nucleotide sequence of the 16S rRNA gene and studying the profile of polymorphic nucleotides the strain was attributed to subspecies Bacillus amyloliquefaciens subsp. plantarum. PMID- 30480419 TI - Regulation of leucogenesis by extracellular ubiquitin in rodents after chemically induced inhibition. AB - To study the influence of intraperitoneally injected extracellular ubiquitin on regeneration of leucopoiesis calculation of nuclear cell count in bone marrow and peripheral blood smearsstained withazure-eosin was performed. In the first, control group of animals inhibition of haematopoiesis achieved by means of 100 mg/kg cyclophosphamide LD50 50-200 mg/kg injection. Bone marrow and peripheral blood samples from the first group of rats had been taken at 24, 48, 72, 96 and 168 h points after injection of cytostatic. Animals of the second, test group were injected by 200 MUg/ml ubiquitin 72 h later after cytostatic injection. Our experiments revealed that ubiquitin makes corrections in regeneration of leucopoiesis and leads to normalisation of the process. Ubiquitin regulates stem cell activity, normalizes the release of functional cells into bloodstream, supposedly retains progenitor cells in zones of differentiation and maturation, and restores the nuclear cell ratio in PB and BM. We suppose that obtained results are important for elucidation of new pathways of ubiquitinylation and give us possibilities to find new therapeutics for regeneration of leucopoiesis that is very essential for treatment of radiated bone marrow and chemotherapeutic side effects in cancer patients. PMID- 30480420 TI - A case of prenatal detection of a de novo unbalanced complex chromosomal rearrangement involving four chromosomes. AB - Complex chromosomal rearrangements are rarely observed prenatally. Genetic counceling of CCR carriers is complicated, especially in cases of de novo origin of the rearrangement. Here we present a new case of a de novo CCR involving four chromosomes observed in amniotic fluid cells of the fetus at 17 weeks of gestation. The rearrangement was characterized as an apparently balanced four-way translocation t(1;11;7;13)(~p21;~q13.5;~q32;~q22)dn by conventional cytogenetic studies. However, array-based comparative genomic hybridization revealed 5 submicroscopic heterozygous interstitial deletions on chromosome 1, 11, 7, 13 with a total loss of 21.1 Mb of genetic material in regions close to those, designated as breakpoints by conventional cytogenetic analysis. The described case clearly illustrates that high-resolution molecular genetic analysis should be combined with conventional cytogenetic techniques to exclude subtle chromosomal abnormalities in CCR cases detected prenatally. PMID- 30480421 TI - ? AB - In the previous cytogenetic study of new human stem cell line 4BL at the 205th passage we observed the ploidy of chromosomal set and regular aberrations. To investigate the nature of monosomy of certain chromosomes the array CGH and FISH analyses have been used. The aberrations of chromosomes have been identified in all the cases of monosomies previously revealed by G-banding. The largest changes of the DNA balance have been detected in the chromosomes 2, 4, 10, 13 and 17. The probable cause of the monosomies of chromosomes 4, 10, 13 and 17 is massive loss of the genetic material. The monosomy of the second chromosome pair is caused by significant transformation one of the homologs in a type of numerous duplications and formation of der(2)t(2;?)(q21;?). Due to application of array CGH the regions of the structural aberrations of the chromosomes 2, 4, 10, 13 and 17 have been concretized, what permitted to perform their clarifying identification by multicolored FISH method. The results obtained by us confirm the hypothesis about coordinated appearance of the deletions and duplications and their stabilization impact on the transformed chromosomes. PMID- 30480422 TI - Microbially Synthesized Repeats of Mussel Foot Protein Display Enhanced Underwater Adhesion. AB - Mussels strongly adhere to a variety of surfaces by secreting byssal threads that contain mussel foot proteins (Mfps). Recombinant production of Mfps presents an attractive route for preparing advanced adhesive materials. Using synthetic biology strategies, we synthesized Mfp5 together with Mfp5 oligomers containing two or three consecutive, covalently-linked Mfp5 sequences named Mfp5(2) and Mfp5(3). The force and work of adhesion of these proteins were measured underwater with a colloidal probe mounted on an atomic force microscope and the adsorption was measured with a quartz crystal microbalance. We found positive correlations between Mfp5 molecular weight and underwater adhesive properties, including force of adhesion, work of adhesion, protein layer thickness, and recovery distance. DOPA-modified Mfp5(3) displayed a high force of adhesion (201 +/- 36 nN MUm-1) and a high work of adhesion (68 +/- 21 fJ MUm-1) for a cure time of 200 s, which are higher than those of previously reported Mfp-mimetic adhesives. Results presented in this study highlight the power of synthetic biology in producing biocompatible and highly adhesive Mfp-based materials. PMID- 30480423 TI - Self-Supported FeCo2S4 Nanotube Arrays as Binder-Free Cathode for Lithium-Sulfur Batteries. AB - Inhibiting shuttle effect, buffering volume expansion and improving utilization of sulfur have been the three strategic points for developing a high-performance lithium-sulphur (Li-S) battery. Driven by this background, a flexible sulfur host material composed of FeCo2S4 nanotube arrays grown on the surface of carbon cloth is designed for binder-free cathode of the Li-S battery through two-step hydrothermal methods. Among the rest, the interconnected carbon fiber skeleton of the composite electrode ensures the basic electrical conductivity, whereas the FeCo2S4 nanotube arrays not only boost the electron and electrolyte transfer but also inhibit the dissolution of polysulfide due to their strong chemical adsorption. Meanwhile, the hollow structures of those arrays can provide a large inner space to accommodate volume expansion of sulfur. More significantly, the developed composite electrode also reveals a catalytic action for accelerating the reaction kinetic of the Li-S battery. As a result, the FeCo2S4/CC@S electrode delivers a high discharge capacity of 1384 mA h g-1 at the current density of 0.1 C and simultaneously exhibits a stable Coulomb efficiency of about 98%. PMID- 30480424 TI - Fabrication of Metal Nanostructures on DNA Templates. AB - Metal nanoarchitectures fabrication based on DNA assembly has attracted a good deal of attention. DNA nanotechnology enables precise organization of nanoscale objects with extraordinary structural programmability. The spatial addressability of DNA nanostructures and sequence-dependent recognition allow functional elements to be precisely positioned; thus novel functional materials that are difficult to produce using conventional methods could be fabricated. This review focuses on the recent development of the fabrication strategies towards manipulating the shape and morphology of metal nanoparticles and nanoassemblies based on the rational design of DNA structures. DNA-mediated metallization, including DNA-templated conductive nanowire fabrication and sequence-selective metal deposition, etc., is briefly introduced. The modifications of metal nanoparticles (NPs) with DNA and subsequent construction of heterogeneous metal nanoarchitectures are highlighted. Importantly, DNA-assembled dynamic metal nanostructures that are responsive to different stimuli are also discussed as they allow the design of smart and dynamic materials. Meanwhile, the prospects and challenges of these shape-and morphology-controlled strategies are summarized. PMID- 30480425 TI - Hierarchically Porous Co-MOF-74 Hollow Nanorods for Enhanced Dynamic CO2 Separation. AB - Metal-organic frameworks (MOFs) with coordinatively unsaturated (open) metal sites have been intensively investigated in gas separations because their active sites can selectively interact with targeted molecules such as CO2. Although such MOFs have shown to exhibit exceptional CO!2 uptake capacity at equilibrium, the dynamic separation behavior is often not satisfactory to be considered in practical applications. Herein we report a facile and efficient self-sacrifice template strategy based on the nanoscale Kirkendall effect to form novel Co-MOF 74 hollow nanorods enabling adsorption/desorption of gas molecules in a facilitated manner. The time-dependent microscopic and diffraction examinations were performed to elucidate the formation mechanism of Co-MOF-74 hollow nanorods and to obtain insights into the factors critical to maintaining the rod-like morphology. Such nanostructured MOF exhibited much sharper CO2 molecular separation behavior than conventional MOF bulk crystals under a dynamic flow condition, owing to its enhanced adsorption kinetics through the shortened diffusion distance. Such enhanced dynamic molecular separation behavior was further confirmed by chromatographic separations where a significant peak narrowing was demonstrated. PMID- 30480426 TI - Wafer-Scale Multilayer Fabrication for Silk Fibroin-Based Microelectronics. AB - Silk fibroin is an excellent candidate for biomedical implantable devices because of its biocompatibility, controllable biodegradability, solution processability, flexibility, and transparency. Thus, fibroin has been widely explored in biomedical applications as biodegradable films as well as functional microstructures. Although there exists a large number of patterning methods for fibroin thin films, multilayer micropatterning of fibroin films interleaved with metal layers still remains a challenge. Herein, we report a new wafer-scale multilayer microfabrication process named AMoS (Aluminum hard mask on silk fibroin) which is capable of micropatterning multiple layers composed of both fibroin and inorganic materials (e.g., metal, and dielectrics) with high precision microscale alignment. To the best of our knowledge, our AMoS process is the first demonstration of wafer-scale multilayer processing of both silk fibroin and metal micropatterns. In the AMoS process, aluminum deposited on fibroin is first micropatterned using the conventional ultraviolet (UV) photolithography, and the patterned aluminum layer is then used as a mask to pattern fibroin underneath. We demonstrate the versatility of our fabrication process by fabricating fibroin microstructures with different dimensions, passive electronic components composed of both fibroin and metal layers, and functional fibroin microstructures for drug delivery. Furthermore, since one of the crucial advantages of fibroin is biocompatibility, we assess the biocompatibility of our fabrication process through the culture of highly-susceptible primary neurons. Because the AMoS process utilizes the conventional UV photolithography, the principal advantages of our process are multilayer fabrication with high precision alignment, high-resolution, wafer-scale large area processing, no requirement for chemical modification of the protein, and high throughput and thus low cost, all of which have not been feasible with silk fibroin. Therefore, the proposed fabrication method is a promising candidate for batch fabrication of functional fibroin microelectronics (e.g., memristors and organic thin film transistors) for next-generation implantable biomedical applications. PMID- 30480427 TI - Dendrimer Heparan Sulfate Glycomimetics: Potent Heparanase Inhibitors for Anticancer Therapy. AB - Heparanase is a mammalian endoglycosidase that cleaves heparan sulfate (HS) polysaccharides and contributes to remodelling of the extracellular matrix and regulation of HS-binding protein bioavailabilities. Heparanase is upregulated in malignant cancers and inflammation, aiding cell migration and the release of signaling molecules. It is established as a highly druggable extracellular target for anticancer therapy, but current compounds have limitations, because of cost, production complexity, or off-target effects. Here, we report the synthesis of a novel, targeted library of single-entity glycomimetic clusters capped with simple sulfated saccharides. Several dendrimer HS glycomimetics display low nM IC50 potency for heparanase inhibition equivalent to comparator compounds in clinical development, and potently inhibit metastasis and growth of human myeloma tumor cells in a mouse xenograft model. Importantly, they lack anticoagulant activity and cytotoxicity, and also inhibit angiogenesis. They provide a new candidate class for anticancer and wider therapeutic applications, which could benefit from targeted heparanase inhibition. PMID- 30480428 TI - Striatal, hippocampal and cortical networks are differentially responsive to the M4- and M1-muscarinic acetylcholine receptor mediated effects of xanomeline. AB - Preclinical and clinical data suggest that muscarinic acetylcholine receptor activation may be therapeutically beneficial for the treatment of schizophrenia and Alzheimer's diseases. This is best exemplified by clinical observations with xanomeline, whose efficacy is thought to be mediated through co-activation of the M1and the M4 muscarinic acetylcholine receptors (mAChRs). Here we examined the impact of treatment with xanomeline and compared it to selective M1 and M4 mAChR activators on in vivo intracellular signaling cascades in mice, including 3'-5' cyclic adenosine monophosphate-response element binding protein (CREB) phosphorylation and inositol phosphate-1 (IP1) accumulation, in striatum, hippocampus and prefrontal cortex. We additionally assessed the effects of xanomeline on hippocampal electrophysiological signatures in rats, using ex vivo recordings from CA1 as well as in vivo hippocampal theta. As expected, xanomeline's effects across these readouts were consistent with activation of both M1 and M4 mAChRs, however, differences were observed across different brain regions suggesting non-uniform activation of these receptor subtypes in the central nervous system. Interestingly, despite near equal in vitro potency at the M1 and the M4 mAChRs, during in vivo assays xanomeline produced M4-like effects at significantly lower brain exposures than those at which M1-like effects were observed. Our results raise the possibility that clinical efficacy observed with xanomeline was, in part, driven through its non-uniform activation of mAChR subtypes in the central nervous system and, at lower doses, through preferential agonism of the M4 mAChR. PMID- 30480429 TI - Thermal Reshaping Dynamics of Gold Nanorods: Influence of Size, Shape, and Local Environment. AB - The thermal reshaping of gold nanorods in a polymer matrix is an important phenomenon for many potential applications. However, a fundamental understanding of the various mechanisms that govern the nanorod reshaping dynamics is still lacking. Here we provide evidence for a phenomenological model of the gold nanorod shape transformation based on the measurements and detailed analysis of the time-resolved thermal reshaping for a variety of gold nanorods having different geometries (aspect ratio, volume, diameter) in a crosslinked epoxy matrix at application relevant temperatures (120-220 oC). Our analysis suggests that a) the nanorod reshaping dynamics consist of two temporal regimes that are governed by different phenomena, and b) the ultimate amount of reshaping at a given temperature depends strongly on the initial particle geometry and the mechanical stiffness of its surroundings. At short times the shape transformation is dominated by a curvature-induced surface diffusion process in which the activation energy for diffusion depends on curvature. At long times, however, the surrounding environment plays a key role in slowing the diffusion and stabilizing the nanorod shape. We show that the long time behavior can be well described using a modified surface diffusion model that takes into account the slowing of atomic diffusivity as a result of external forces arising from mechanical constraints. The ability to tune both the final shape and the reshaping dynamics in nanocomposites opens up new possibilities in tailoring the optical properties of these materials. PMID- 30480430 TI - Phospho-Tau Impairs Nuclear-Cytoplasmic Transport. AB - Aggregation of hyperphosphorylated tau is the hallmark of several tauopathies, including Alzheimer's disease (AD). Although the mechanism underlying tau associated neuronal damage remains unclear, it is believed that tau hyperphosphorylation is one of the key features in disease progression. A recent study demonstrates that hyperphosphorylated tau (P-tau) interacts with components of the nuclear pore complex (NPC) to impair nuclear-cytoplasmic transport and contribute to tau-induced neurotoxicity. The NPC thus represents a point of convergence between pathological tau and neuronal dysfunction in AD. PMID- 30480431 TI - Ultralarge Area Sub-10-nm Plasmonic Nanogap Array by Block Copolymer Self Assembly for Reliable High Sensitivity SERS. AB - Effective surface enhancement of Raman scattering (SERS) requires strong near field enhancement as well as effective light collection of plasmonic structures. To this end, plasmonic nanoparticle (NP) arrays with narrow gaps or sharp tips have been suggested as desirable structures. We present highly dense and uniform Au nanoscale gap array enabled by the customized design of NP shape and arrangement employing block copolymer self-assembly. Block copolymer self assembly in thin film offers uniform hexagonal packed nanopost template arrays over the entire surface of 2 in. wafer. Conventional evaporative metal deposition over the nanotemplate surface allows precise geometric control and positional arrangement of metal NPs, constituting tunable, strong plasmonic near-field enhancement particularly at the "hot spots" near interparticular nanoscale gaps. Underlying field distribution has been investigated by a finite-difference time domain simulation. In the detection of thiophenol, our Au nanogap array shows a remarkable enhancement of Raman intensity greater than ~104 a standard deviation as small as 12.3 % compared to planar Au thin film. In addition, Adenine biomolecules can be detected as low as a detection limit of 100 nM. Our approach proposes highly sensitive and reliable SERS based on a scalable, low-cost bottom up strategy. PMID- 30480432 TI - CellFy-A Cell-Based Fragment Screen against C-Type Lectins. AB - Fragment-based drug discovery is a powerful complement to conventional high throughput screening, especially for diffi-cult targets. Screening low molecular weight fragments usual-ly requires highly sensitive biophysical methods due to the generally low affinity of the identified ligands. Here, we de-veloped a cell based fragment screening assay (cellFy) that allows sensitive identification of fragment hits in a physio-logically more relevant environment in contrast to isolated target screenings in solution. For this a fluorescently labelled multivalent reporter was employed, enabling direct measure-ment of displacement by low molecular weight fragments without requiring enzymatic reactions or receptor activation. We applied this technique to identify hits against two chal lenging targets of the C-type lectin receptor (CLR) family: Dendritic Cell Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN) and Langerin. Both recep-tors are involved in pathogen recognition and initiation of an immune response, which renders them attractive targets for immune modulation. Due to their shallow and hydrophilic primary binding site, hit identification for CLRs is challeng-ing and drug-like ligands for CLRs are sparse. Screening of a fragment library followed by hit validation identified several promising candidates for further fragment evolution for DC-SIGN. Additionally, a multiplexed assay format was developed for simultaneous screening against multiple CLRs allowing a selectivity counterscreening. Overall, this sensitive cell-based fragment screening assay provides a powerful tool for rapid identification of bioactive fragments, even for difficult targets. PMID- 30480433 TI - Gly-His-Thr-Asp-Amide, an Insulin-Activating Peptide from the Human Pancreas Is a Strong Cu(II) but a Weak Zn(II) Chelator. AB - The Cu(II) and Zn(II) binding abilities of Gly-His-Thr-Asp-amide (GHTD-am), a tetrapeptide coreleased from the pancreas along with insulin, were studied using UV-vis and circular dichroism spectroscopies, potentiometry, and calorimetry. GHTD-am is a very strong Cu(II) chelator, forming a three-nitrogen complex with a conditional affinity constant C K at pH 7.4 of 4.5 * 1012 M-1. The fourth coordination site can be occupied by a solvent molecule or a ternary ligand, such as imidazole, with C K on the order of several hundred reciprocal molar. The Zn(II) binding ability of GHTD-am is relatively weak, with C K values at pH 7.4 of 3.0 * 104 and 2.0 * 103 M-1 for the first and second GHTD-am molecule coordinated, respectively. These results are discussed in light of the modes of interactions of Zn(II) and Cu(II) ions with insulin. A direct effect of GHTD-am on the Zn(II) interactions with insulin is unlikely, but its Cu(II) complex may have a biological relevance because of its high affinity and ability to form ternary complexes. PMID- 30480434 TI - Random formation of G-quadruplexes in human telomere overhangs leads to a kinetic folding pattern with targetable vacant G-tracts. AB - G-quadruplexes formed in the 3? telomere overhang (~200 nucleotides) have shown to regulate biological functions of human telomeres. The mechanism governing the population pattern of multiple telomeric G-quadruplexes is yet to be elucidated inside the telomeric overhang in a time window shorter than thermodynamic equilibrium. Using a single-molecule force ramping assay, we quantified G quadruplex populations in telomere overhangs in a full physiological range of 99 to 291 nucleotides. We found that G-quadruplexes randomly form in these overhangs within seconds, which leads to a population governed by a kinetic, rather than thermodynamic, folding pattern. The kinetic folding gives rise to vacant G-tracts between G-quadruplexes. By targeting these vacant G-tracts using complementary DNA fragments, we demonstrated that binding to the telomeric G-quadruplexes becomes more efficient and specific for telomestatin derivatives. PMID- 30480435 TI - High Throughput/High Precision Sampling of Single Cells into ICP-MS for Elucidating Cellular Nanoparticles. AB - In single cell analysis with ICP-MS, it is highly important to ensure precise single cell sampling into ICP. For this purpose, a simple configured pressure resistant MicroCross interface is developed for high throughput/high precision microdroplet generation and single cell encapsulation. Aqueous cell suspension is ejected and sheared into droplets by tangent-flowing hexanol-continuous phases in the flow-focusing geometry of MicroCross, wherein to precisely trap a single cell into a droplet, with an extremely low probability of <0.005% for a single droplet encapsulating two cells. MicroCross interface is coupled with time-resolved ICP MS (TRA-ICP-MS) for quantifying nanoparticles in single MCF-7 cells. At the optimal conditions, sufficient temporal-spatial resolution of the microdroplets is achieved facilitating high-throughput sampling of single cells into ICP. For solving the serious carbon deposition on the sampling cone and the unstable plasma torch caused by incomplete oxidation of hexanol phase in ICP, dimethyl carbonate (DMC) is for the first time used as a superb oxygen compensation reagent, which ensures adequate oxidation of hexanol, effectively eliminates the carbon deposition and maintains a stable plasma. The single cell analysis results indicated a remarkable discrepancy of the number of nanoparticles among the individual cells, falling into a range of 130-584 per MCF-7 cell in the case of AuNPs. PMID- 30480436 TI - Enhanced Red Emission in Er3+-Sensitized NaLuF4 Upconversion Crystals via Energy Trapping. AB - Luminescence efficiency of trivalent lanthanide-doped upconversion (UC) materials is significantly limited by luminescence concentration quenching. In this work, red UC emission is dramatically enhanced in Er3+-sensitized NaLuF4 UC crystals through energy trapping under multiple excitation wavelengths. Cross-relaxation quenching and the energy migration to internal lattice defects are simultaneously suppressed by confining the excitation energy in the Er3+ activator after introducing the Tm3+ or Ho3+ energy trapping center. The enhanced red UC emission (Er3+: 660 nm) mainly comes from the effective excitation energy confinement by Tm3+ and Ho3+ trapping centers through an easy energy transfer between Er3+ and Tm3+/Ho3+: 4I11/2 (Er3+) -> 3H5 (Tm3+) -> 4I13/2 (Er3+) and 4I11/2 (Er3+) -> 5I6 (Ho3+) -> 4I13/2 (Er3+). It is found that the confining efficiency of excitation energy in Er3+-sensitized NaLuF4 crystals is higher than that in Yb3+/Er3+ cosensitized NaLuF4 crystals, and the luminescence efficiency of Er3+-sensitized NaLuF4 crystals is much higher than that of Er3+-based host sensitization UC crystals (NaErF4). Moreover, Er3+-sensitized UC particles can be efficiently excited by three different wavelengths (808, 980, and 1532 nm), indicating huge advantages for applications in bioimaging, anticounterfeiting, and solar cells. PMID- 30480438 TI - 3d Transition Metals for C-H Activation. AB - C-H activation has surfaced as an increasingly powerful tool for molecular sciences, with notable applications to material sciences, crop protection, drug discovery, and pharmaceutical industries, among others. Despite major advances, the vast majority of these C-H functionalizations required precious 4d or 5d transition metal catalysts. Given the cost-effective and sustainable nature of earth-abundant first row transition metals, the development of less toxic, inexpensive 3d metal catalysts for C-H activation has gained considerable recent momentum as a significantly more environmentally-benign and economically attractive alternative. Herein, we provide a comprehensive overview on first row transition metal catalysts for C-H activation until summer 2018. PMID- 30480437 TI - Synergistic Effect between Different Coordination Geometries of Lanthanides and Various Coordination Modes of 2-Picolinic Acid Ligands Tuning Three Types of Rare 3d-4f Heterometallic Tungstoantimonates. AB - Three types of N-heterocyclic aromatic acid decorated 3d-4f heterometallic Keggin type tungstoantimonates: Na4[Ln(H2O)5]2[Fe4(H2O)2(pic)4(B-beta-SbW9O33)2].26H2O [Ln3+ = La3+ (1), Pr3+ (2), Nd3+ (3), Sm3+ (4), Eu3+ (5)], Na6H4[Fe2W4O9(H2O)2(Hpic)4 (B-beta SbW9O33)2][Ln(H2O)8]2[Fe4W2O7(H2O)4(pic)2(Hpic)2(B-beta-SbW9O33)2].38H2O [Ln3+ = Gd3+ (6), Dy3+ (7)], and Na2H2{[Ln(H2O)6]2[Fe4(H2O)2(Hpic)2(pic)2(B-beta SbW9O33)2]}2.44H2O [Ln3+ = Ho3+ (8), Er3+ (9), Hpic = 2-picolinic acid] have been prepared. 1-5 comprise a quadripic-inserted Krebs-type [Fe4(H2O)2(pic)4(B-beta SbW9O33)2]10- moiety supported by two [Ln(H2O)5]3+ groups on both sides where it can be considered that four pic ligands replace eight aqua ligands located on the original Krebs-type [Fe4(H2O)10(B-beta-SbW9O33)2]10- fragment to form the [Fe4(H2O)2(pic)4(B-beta-SbW9O33)2]10- moiety. Remarkably, the quadripic-inserted subunits are further concatenated through the coordination role of the pic ligands to create a 3-D heterometallic framework. In contrast, the molecular units of 6-7 contain two kinds of non-Krebs-type quadripic-inserted [Fe2W4O9(H2O)2(Hpic)4(B-beta-SbW9O33)2]6- and {[Ln(H2O)8]2[Fe4W2O7(H2O)4(pic)2(Hpic)2(B-beta-SbW9O33)2]}4- moieties. The molecular units of 8-9 contain two identical quadripic-inserted Krebs-type {[Ln(H2O)6]2[Fe4(H2O)2(Hpic)2(pic)2(B-beta-SbW9O33)2]}2- moieties, and both display a 1-D heterometallic double chain. For all we know, 1-9 stand for the first 3d-4f heterometallic tungstoantimonate hybrids functionalized by pic ligands. Particularly, the solid-state NIR photoluminescence (PL) spectrum in the range of 800-1450 nm of 3 and the solid-state visible PL spectra in the range of 500-750 nm of 4, 5, 7, and 8 at room temperature display the featured fluorescence emission bands stemming from Ln3+ cations. In the PL emission procedures of 5 and 7, energy transfer from [B-beta-SbW9O33]9- fragments and pic ligands to Ln3+ ions has been observed. Additionally, the correlated color temperatures of 4, 5, 7, and 8 are indexed to 2731, 2020, 4557, and 1685 K, respectively. PMID- 30480439 TI - Bond Order Conservation Principle and Peculiarities of the Metal-Metal Bonding. AB - Pauling's principles developed later in the bond valence model (BVM) are fundamental in description of bonding in ionic solids and surface phenomena on metals, but applicability of these principles to the metal-metal bonds in the bulk compounds was demonstrated only recently, with a spotlight on the bond valence-bond length correlations. This work is focused on the bond order conservation in cluster compounds and determination of empiric bond valence parameters for the metal-metal bonds, which ensure very simple and reasonably accurate bonding analysis, with zero cost, in any complex cluster compound. Such peculiarities of cluster compounds as matrix effect and nonuniform distribution of the ionic charges (bond valence sums) on the ligands around metal clusters, as well as other important examples of the BVM application to compounds with metal metal bonds, are discussed. PMID- 30480440 TI - Facile Preparation of Amorphous Fe-Co-Ni Hydroxide Arrays: A Highly Efficient Integrated Electrode for Water Oxidation. AB - Facile and fast synthesis of functional materials with high catalytic activity is highly demanded to meet the industrial production and applications such as electrolysis. In this study, Ni foam is employed as the current collector and Ni source, which is dipped into the mixture of Fe and Co metal ions solution at room temperature for several minutes, to in situ grow Fe-Co-Ni hydroxide arrays and construct the three-dimensional integrated electrode. This short-time preparation at room temperature is beneficial to avoid the rapid growth of the generated primary nanocrystallites and cause intimate interactions between Fe, Co, and Ni atoms. The obtained self-supported and vertically aligned Fe-Co-Ni hydroxides present an amorphous phase, which exhibit high activity with low overpotentials of 212 mV at 10 mA cm-2 and 319 mV at 100 mA cm-2, associated with a small Tafel slope of 52 mV dec-1 toward the oxygen evolution reaction. PMID- 30480442 TI - Chemometric Approaches for Developing Infrared Nanosensors to Image Anthracyclines. AB - Generation, identification, and validation of optical probes to image molecular targets in a biological milieu remains a challenge. Synthetic molecular recognition approaches leveraging the intrinsic near-infrared fluorescence of single-walled carbon nanotubes is a promising approach for long-term biochemical imaging in tissues. However, generation of nanosensors for selective imaging of molecular targets requires a heuristic approach. Here, we present a chemometric platform for rapidly screening libraries of candidate single-walled carbon nanotube nanosensors against biochemical analytes to quantify fluorescence response to small molecules including vitamins, neurotransmitters, and chemotherapeutics. We further show this approach can be leveraged to identify biochemical analytes that selectively modulate the intrinsic near-infrared fluorescence of candidate nanosensors. Chemometric analysis thus enables identification of nanosensor-analyte 'hits' and also nanosensor fluorescence signaling modalities such as wavelength-shifts that are optimal for translation to biological imaging. Through this approach, we identify and characterize a nanosensor for the chemotherapeutic anthracycline doxorubicin, which provides an up to 17 nm fluorescence red-shift and exhibits an 8 uM limit of detection, compatible with peak circulatory concentrations of doxorubicin common in therapeutic administration. We demonstrate selectivity of this nanosensor over dacarbazine, a chemotherapeutic commonly co-injected with DOX. Lastly, we demonstrate nanosensor tissue compatibility for imaging of doxorubicin in muscle tissue by incorporating nanosensors into the mouse hindlimb and measuring nanosensor response to exogenous DOX administration. Our results motivate chemometric approaches to nanosensor discovery for chronic imaging of drug partitioning into tissues and towards real-time monitoring of drug accumulation. PMID- 30480441 TI - Stable Indium-Pyridylcarboxylate Framework: Selective Gas Capture and Sensing of Fe3+ Ion in Water. AB - By employing a pyridyl-decorated dicarboxylic acid ligand, 3-(2',5' dicarboxylphenyl)pyridine acid (H2dcpy), a three-dimensional In3+-based metal organic framework, H3O[In3(dcpy)4(OH)2].3DMF.4H2O (1), with a good chemical stability toward acid and base has been synthesized. The compound 1 shows an uncommon (3,8)-connected tfz-d; UO3 topological net based on linear In3(COO)4(OH)2 clusters and also contains one-dimensional open channels. Particularly, 1 contains two types of dcpy2- linkers, in which the pyridyl group in one participates in coordination with the In3+ ion, whereas that in the other is uncoordinated but hangs in the inner sides of the channels as functionalized sites. Gas adsorption experiments demonstrate that 1 is able to selectively adsorb C2H2, C2H4, and CO2 over CH4. Simultaneously, 1 shows a highly selective and sensitive fluorescence detection toward Fe3+ ion in water with good recyclability. PMID- 30480443 TI - Highly Potent 17beta-HSD2 Inhibitors with a Promising Pharmacokinetic Profile for Targeted Osteoporosis Therapy. AB - Intracellular elevation of E2 levels in bone by inhibition of 17beta hydroxysteroid dehydrogenase type 2 (17beta-HSD2) without affecting systemic E2 levels is an attractive approach for a targeted therapy against osteoporosis, a disease which is characterized by loss of bone mineral density. Previously identified inhibitor A shows high potency on human and mouse 17beta-HSD2, but poor pharmacokinetic properties when applied perorally in mice. A combinatorial chemistry approach was utilized to synthesize truncated derivatives of A, leading to highly potent compounds with activities in the low nanomolar to picomolar range. Compound 33, comparable to A in terms of inhibitor potency against both human and mouse enzymes, displays high in vitro metabolic stability in human and mouse liver S9 fraction as well as low toxicity and moderate hepatic CYP inhibition. Thus, compound 33 showed a highly improved peroral pharmacokinetic profile in comparison to A, making 33 a promising candidate for further development. PMID- 30480444 TI - Identification of 5-(2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4 amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model. AB - We herein report the structural optimization and structure-activity relationship (SAR) studies of 5-(2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives as a new class of receptor-interacting protein kinase 1 (RIPK1) inhibitors. Among all the obtained RIPK1 inhibitors, 1-(5-{4-amino-7-ethyl-7H pyrrolo[2,3-d]pyrimidin-5-yl}-2,3-dihydro-1H-indol-1-yl)-2-[3 (trifluoromethoxy)phenyl]ethan-1-one (22b) is the most active one. This compound potently inhibited RIPK1 with a binding affinity (KD) of 0.004 MUM and an enzymatic IC50 value of 0.011 MUM, and also showed good kinase selectivity. It could efficiently protect cells from necroptosis and attenuate the necrotic cell death of vascular endothelial cells induced by tumor cells both in vitro and in vivo. Importantly, Compound 22b exhibited excellent anti-metastasis activity in the experimental B16 melanoma lung metastasis model. It also displayed favorable pharmacokinetic properties. Collectively, 22b could be a promising agent for preventing tumor metastasis. PMID- 30480445 TI - Correction to Constant-pH Molecular Dynamics Simulations for Large Biomolecular Systems. PMID- 30480447 TI - Correction to "DFT Provides Insight into the Additive-Free Conversion of Aqueous Methanol to Dihydrogen Catalyzed by [Ru(trop2dad)]: Importance of the (Electronic) Flexibility of the Diazadiene Moiety". PMID- 30480448 TI - Probing Amino Acid Interaction with a Polystyrene Nanoparticle Surface Using Saturation-Transfer Difference (STD)-NMR. AB - The interaction between individual amino acids and the surface of carboxylate modified polystyrene nanoparticles in solution was studied using Saturation Transfer Difference (STD)-Nuclear Magnetic Resonance (NMR). Individual amino acids were screened for nanoparticle binding using an STD-NMR experiment at a fixed saturation time, and STD buildup curves were measured for those amino acids that exhibited significant STD difference signals in the initial screening. The strongest STD effects were measured for protons of aromatic side chains, with relatively weaker effects observed for protons in long-chain aliphatic and positively charged side chains. This indicates that there are several modes of binding to these polystyrene nanoparticles: electrostatic attraction between the negatively charged surface of the carboxylate-modified polystyrene nanoparticle and positively charged amino acids, hydrophobic effects between long aliphatic side chains and the nanoparticle surface, and pi-pi interactions between aromatic amino acids and aromatic groups in styrene. This information can be used in future studies to predict and understand interactions between nanoparticle surfaces and specific amino acid residues in small peptides and proteins. PMID- 30480449 TI - Correction to "Sublimation Entropy and Dissociation Constants Prediction by Quantitative Evaluation of Molecular Mobility in Crystals". PMID- 30480450 TI - Micellar Radii Description for Phase Behavior and Viscosity Modeling of Aqueous Surfactant Solutions and Microemulsions. AB - The study of surfactant solutions and microemulsions is relevant for many industrial applications that include oil recovery, environmental remediation, and detergency. Understanding the coupled nature of microstructure, phase behavior, and rheology can help in the design of these applications. The microstructure of surfactant solutions and microemulsion determines equilibrium properties including phase composition and viscosity. Modeling microemulsion phase behavior by explicitly defining the shape and size of micelles allows for the consistent estimation of phase viscosity. We define a coupled microstructure-phase behavior viscosity model by considering a 2D lattice where micelles are assumed elliptical. We also define equivalent 3D models where micelles are assumed to be oblate and prolate spheroids. The compositional dependence of the micellar radii is defined such that the oil-internal-bicontinuous-water-internal structural transitions are consistent with experimental observations. The model offers physical insights by modeling the transition between oil-internal-bicontinuous water-internal regions in ternary diagrams as critical events, which are then tied to the unusual behavior observed in viscosity and scattering. PMID- 30480451 TI - Investigating Interfacial Effects on Surface Nanobubbles Without Pinning Using Molecular Dynamics Simulation. AB - We investigated how the stability of aqueous argon surface nanobubbles on hydrophobic surfaces depends on gas adsorption, solid-gas interaction energy, and the bulk gas concentration using molecular dynamics simulation with the SPC-E water solvent. We observed stable surface nanobubbles without surface pinning sites for longer than 160nsec, contrary to previous finding using monoatomic Lennard-Jones solvent. In addition, the hydrophobicity of substrate plays an effect to reduce the requirement degree of oversaturation on water bulk. We found that gas enrichment layer, gas adsorption monolayer on the hydrophobic substrate, and water hydrogen bonding near the interface are likely necessary conditions for nanobubble stability. We concluded that gas nanobubble stability does not necessarily require three phase pinning sites. PMID- 30480452 TI - 200+ Protein Concentrations in Healthy Human Blood Plasma: Targeted Quantitative SRM SIS Screening of Chromosomes 18, 13, Y and the Mitochondrial Chromosome Encoded Proteome. AB - This work continues the series of the quantitative measurements of the proteins encoded by different chromosomes in the blood plasma of a healthy person. Selected Reaction Monitoring with Stable Isotope-labeled peptide Standards (SRM SIS) and a gene-centric approach, which is the basis for the implementation of the international Chromosome-centric Human Proteome Project (C-HPP), were applied for the quantitative measurement of proteins in human blood plasma. Analyses were carried out in the frame of C-HPP for each protein-coding gene of the four human chromosomes: 18, 13, Y and mitochondrial. Concentrations of proteins encoded by 667 genes were measured in 54 blood plasma samples of the volunteers, which health conditions were consistent with requirements to the astronauts. The gene list included 276, 329, 47 and 15 genes of chromosomes 18, 13, and Y and the mitochondrial chromosome, respectively. Only 205 proteins (30.7%) were detected in the samples. Of them, 84, 106, 10 and 5 belonged to chromosomes 18, 13, and Y and the mitochondrial chromosome, respectively. Each detected protein was found in at least one of the samples analyzed. The SRM SIS raw data are available in the ProteomeXchange repository (PXD004374, PASS01192). PMID- 30480453 TI - Mechanoregulation of cancer-associated fibroblasts phenotype in 3D interpenetrating hydrogel networks. AB - Tumor stromal residing cancer-associated fibroblasts (CAFs) are significant accomplices in the growth and development of malignant neoplasm. As cancer progresses, the stroma undergoes a dramatic remodeling and stiffening of its extracellular matrix (ECM). However, exactly how these biomechanical changes influence CAF behavior and the functional paracrine crosstalk with the neighboring tumor cells in a 3-dimensional (3D) microenvironment remains elusive. Herein, a collagen and alginate interpenetrating network (CoAl-IPN) hydrogel system was employed as a 3D in vitro surrogate of the cancerous breast tissue stromal niche. In this study, the mechanical properties of the CoAl-IPN were precisely fine-tuned with Young's Modulus (E) of ~108 and 898 Pa. The results revealed that the 3D polymeric network mechanics and microstructure are critical biophysical determinants of human breast CAFs (b-CAFs) morphology, phenotype and paracrine dialogue with MDA-MB-231 tumoroids. A compliant hydrogel network favors b-CAFs spreading, nuclear translocation of YAP/TAZ mechano-signaling protein and upregulation of CAF hallmark transcripts. Conversely, a rigid and highly crosslinked hydrogel network imposed a "physical entrapment" effect on the b-CAFs that limits its spreading and phenotype in a manner that effectively muted its pro-tumorigenic paracrine activity. Collectively, the CoAl-IPN 3D culture system has proven to be a versatile platform in defining the 3D biophysical parameters that could either promote or restrain the pro-tumorigenic activity of b-CAFs and sheds critical mechano-mediated insights into the phenotypic plasticity and corresponding specific bioactivity of b-CAFs in the 3D microenvironment. PMID- 30480454 TI - A Bottom-Up Approach to Solution-Processed, Atomically Precise Graphitic Cylinders on Graphite. AB - Extended carbon nanostructures, such as carbon nanotubes (CNTs), exhibit remarkable properties but are difficult to synthesize uniformly. Herein, we present a new class of carbon nanomaterials constructed via the bottom-up self assembly of cylindrical, atomically precise small molecules. Guided by supramolecular design principles and circle packing theory, we have designed and synthesized a fluorinated nanohoop that, in the solid state, self-assembles into nanotube-like arrays with channel diameters of precisely 1.63 nm. A mild solution casting technique is then used to construct vertical "forests" of these arrays on a highly ordered pyrolytic graphite (HOPG) surface through epitaxial growth. Furthermore, we show that a basic property of nanohoops, fluorescence, is readily transferred to the bulk phase, implying that the properties of these materials can be directly altered via precise functionalization of their nanohoop building blocks. The strategy presented is expected to have broader applications in the development of new graphitic nanomaterials with pi-rich cavities reminiscent of CNTs. PMID- 30480456 TI - Asymmetric Synthesis of Fmoc-Protected beta-Hydroxy and beta-Methoxy Amino Acids via a Sharpless Aminohydroxylation Reaction Using FmocNHCl. AB - An efficient asymmetric synthesis of l- threo-beta-hydroxyasparagine and l- threo beta-methoxyaspartate that are suitably protected for Fmoc solid phase peptide synthesis is described. The key step in these syntheses was a Sharpless asymmetric aminohydroxylation reaction under basic conditions using N chlorofluorenyl carbamate (FmocNHCl), a readily prepared and storable nitrogen source. PMID- 30480455 TI - Experimental Identification of Critical Condition for Drastically Enhancing Thermoelectric Power Factor of Two-Dimensional Layered Materials. AB - Nanostructuring is an extremely promising path to high-performance thermoelectrics. Favorable improvements in thermal conductivity are attainable in many material systems, and theoretical work points to large improvements in electronic properties. However, realization of the electronic benefits in practical materials has been elusive experimentally. A key challenge is that experimental identification of the quantum confinement length, below which the thermoelectric power factor is significantly enhanced, remains elusive due to lack of simultaneous control of size and carrier density. Here we investigate gate-tunable and temperature-dependent thermoelectric transport in gamma-phase indium selenide (gamma-InSe, n-type semiconductor) samples with thickness varying from 7 to 29 nm. This allows us to properly map out dimension and doping space. Combining theoretical and experimental studies, we reveal that the sharper pre edge of the conduction-band density of states arising from quantum confinement gives rise to an enhancement of the Seebeck coefficient and the power factor in the thinner InSe samples. Most importantly, we experimentally identify the role of the competition between quantum confinement length and thermal de Broglie wavelength in the enhancement of power factor. Our results provide an important and general experimental guideline for optimizing the power factor and improving the thermoelectric performance of two-dimensional layered semiconductors. PMID- 30480457 TI - Formal Synthesis of (+)-Phomactin A. AB - A concise formal synthesis of (+)-phomactin A has been achieved. The key features of this synthetic strategy involve a one-pot Prins/Conia-ene cyclization protocol for the construction of the highly functionalized 1-oxadeclin core (AB ring) and a late-stage direct gamma-hydroxylation of enone for the installation of the C ring. PMID- 30480458 TI - Comparison of recovery of mobility and self-efficacy after total knee arthroplasty based on two different protocols: A prospective cohort study. AB - Objectives; The purpose of this study was to compare the recovery of mobility and self-efficacy following total knee arthroplasty (TKA) between the 5-day and the 28-day protocol. This prospective cohort study was carried out at two hospitals. Methods; In total, 104 patients who underwent TKA were enrolled. The primary outcomes measured were Life Space Assessment (LSA) for mobility and modified-Gait Efficacy Scale (mGES) for self-efficacy. Knee Society Score (KSS) was used to estimate the functional outcomes. These assessments were performed in all patients preoperatively, and at 1, 3, and 6 months postoperatively. After calculating the propensity score using covariates, such as patient characteristics, LSA, mGES, and KSS at baseline, propensity score adjusted multivariate analysis of covariance (MANCOVA) was performed. Results; MANCOVA revealed significant differences in LSA and mGES, but not in KSS, between the two protocols. The adjusted means of LSA and mGES in the 28-day protocol were significantly greater than those in the 5-day protocol in all the postoperative assessments. Conclusions; Mobility and self-efficacy were greater following the 28-day protocol than the 5-day protocol after TKA. Our findings suggest that the modified treatment procedure for improving mobility and self-efficacy is necessary to introduce the early discharge protocol in Japan. PMID- 30480459 TI - Geraniol and linalool anticandidal activity, genotoxic potential and embryotoxic effect on zebrafish. AB - AIM: Geraniol and linalool are major constituents of the essential oils of medicinal plants. MATERIALS & METHODS: Antifungal activity of geraniol and linalool were evaluated against five Candida species. The genotoxicity of these compounds was evaluated by the cytokinesis-block micronucleus test, and the embryotoxic assays use zebrafish model. RESULTS: Geraniol and linalool inhibited Candida growth, but geraniol was more effective. The geraniol at concentration of 800 MUg/ml and the linalool at concentration of 125 MUg/ml significantly increased chromosome damage. Geraniol was more toxic to zebrafish embryo than linalool: LC50 values were 31.3 and 193.3 MUg/ml, respectively. CONCLUSION: Geraniol and linalool have anticandidal activity, but they also exert genotoxic and embryotoxic effects at the highest tested concentrations. PMID- 30480460 TI - Effect of Polyethylene Glycol Surface Charge Functionalization of SWCNT on the in vitro and in vivo Nanotoxicity and Biodistribution Monitored Noninvasively using MRI. AB - The current study evaluated in vitro and in vivo toxicity of carboxyl or amine PEG surface functionalization of single walled carbon nanotubes (SWCNTs). Assessments of cytotoxicity, genotoxicity, immunotoxicity and oxidative stress were performed in vitro and in vivo (in a one-month follow-up study). The SWCNT biodistribution was investigated using noninvasive MRI. Results confirmed the enhanced biocompatibility of PEG-functionalized SWCNTs compared to non functionalized materials with significant decreases (p < 0.05) in the percentage of cell viability and increases in ROS generation, mitochondrial membrane potential, cell apoptosis, oxidative stress generation and oxidative DNA damage in vitro. PEG-functionalized SWCNTs with amine terminals were found to induce prominent increases in ROS generation, mitochondrial membrane potential, and oxidative stress compared to carboxy functionalization. No significant difference in the biodistribution of either functionalized SWCNTs was observed in MRI. In vivo assessments revealed a statistically significant increase (p < 0.05) in oxidative stress as early as 24 h in serum and liver; however, all values normalized at 2 weeks' investigation time point. DNA damage was minimal with either PEG-COOH or PEG-NH2 functionalized SWCNTs after two weeks' exposure. The negatively charged SWCNTs caused lesser DNA damage compared to positively charged samples. Carboxy-functionalized SWCNTs did not caused substantial changes in inflammatory mediators and were found to be significantly safer than non functionalized SWCNTs and may pave the way for novel biomedical applications in cancer diagnosis and therapy. PMID- 30480461 TI - Triple GLP-1/GIP/glucagon receptor agonists, a potential novel treatment strategy in Alzheimer's disease. PMID- 30480462 TI - High-fructose in drinking water initiates activation of inflammatory cytokines and testicular degeneration in rat. AB - The increased consumption of high-fructose in diet may contribute to high prevalence of metabolic syndrome in the world. The influence of high-fructose diet on male reproductive system has been poorly documented. In this study, we investigated the effects of dietary high-fructose on the expression of inflammatory cytokines in association with certain testicular proteins and sex hormones in the testis of rats. Fructose was given to the rats as 20% solution (7.8 mg/kg) in drinking water for 15 weeks. Dietary high-fructose caused testicular degeneration, also decreased testicular concentration of testosterone and right testis absolute weight. This dietary intervention increased iNOS and TNF-alpha mRNAs as well as iNOS, NF-kappaB and p-NF-kappabeta proteins, but decreased IL-10 and IL-6 mRNAs expressions, in testicular samples of rats. Moreover, testicular TNF-alpha, IL-1beta, and iNOS and plasma IL-1beta levels were significantly increased in rats fed with fructose. A marked increase in the expression level of IGF-1R protein was considered in testicular tissue of fructose-treated rats. The expression intensities of c-kit, claudin-1 and pan cadherin were comparable in seminiferous tubules of control and fructose-treated rats. In conclusion, high-fructose intake of rats leads to activation of inflammatory cytokines, which is accompanied by testicular degeneration. These changes could be responsible for hormonal dysfunction with low intra-testicular testosterone level, which could be relevant to male infertility. PMID- 30480463 TI - The stronger one-sided relative hypoperfusion, the more pronounced ipsilateral spatial attentional bias in patients with asymptomatic carotid stenosis. AB - Patients with asymptomatic, high-grade internal carotid artery stenosis often suffer from subtle cognitive impairments with unclear underlying neuro-cognitive mechanisms. Thus, we hypothesized that stenosis-related unilateral cerebral hypoperfusion leads to an ipsilateral attentional bias; 22 patients with asymptomatic, one-sided high-grade carotid stenosis and 24 age-matched healthy controls underwent pseudo-continuous arterial spin labeling to assess brain perfusion in the territory of the carotid arteries. Furthermore, a parametric assessment of attention functions was carried out on the basis of the computational Theory of Visual Attention. Both patients' perfusion and spatial attention were significantly more lateralized than those of healthy controls. Critically, both asymmetry indices were significantly correlated in patients, i.e. the stronger one-sided relative hypoperfusion, the stronger ipsilateral bias of attention. This association was specifically pronounced in parietal cortices and independent of white matter hyperintensities as a surrogate for cerebrovascular brain damage. Results provide evidence for a link between lateralized hypoperfusion and lateralized attentional weighting in asymptomatic, high-grade carotid stenosis. Data suggest that lateralized hypoperfusion with simultaneous spatial attentional bias might serve as a potential therapeutic target in one-sided carotid stenosis. PMID- 30480464 TI - Stress and anxiety among mothers of premature infants in a Malaysian neonatal intensive care unit. AB - OBJECTIVE: This study aims to determine maternal stress and anxiety as perceived by mothers whose premature infants were admitted to the neonatal intensive care unit (NICU) and to identify maternal stress and its relationship with maternal and infant characteristics and anxiety. BACKGROUND: Vulnerable premature infants commonly require special care in the NICUs. In most cases, prolonged hospitalization results in stress and anxiety for the mothers. METHODS: A non probability convenience survey was used in a public hospital, with 180 mothers completing the 26-item Perceived Stress Scale (PSS) and a 40-item State-Trait Anxiety Inventory (STAI). RESULTS: 56.5% of mothers had high levels of stress, 85.5% of mothers had a high level of state-anxiety and 67.8% of mothers had a high level of trait-anxiety. The stress experienced by these mothers had a significant relationship with anxiety, and was found to be associated with state and trait anxiety levels, but not with maternal and infant characteristics. CONCLUSION: Mothers in this setting revealed high levels of stress and anxiety during their premature infants' NICU admission. An immediate interventional programme focusing on relieving mothers' anxiety and stress is needed to prevent maternal stress and anxiety at an early stage. PMID- 30480465 TI - Abnormal uterine bleeding in adolescents: ultrasound evaluation of uterine volume. AB - OBJECTIVE: To evaluate ultrasonographic measurements of internal genitalia in girls suffering from abnormal uterine bleeding (AUB) and to compare the appearances with those of healthy girls. DESIGN Prospective case - control study. METHODS: One hundred and five not sexually active adolescent girls were enrolled 67 patients were suffering from AUB and there were 38 healthy peers. The groups did not differ in chronological age, or in postmenarcheal age. All girls underwent assessment of their history, clinical data and transabdominal pelvic ultrasound to evaluate their uterus and ovaries. In order to avoid the impact of endometrium cycle fluctuations, the uterine volume was calculated including and excluding its thickness. RESULTS: The uterine volume among the girls suffering from AUB was significantly larger than in the control group. The mean uterine volume including endometrium in the study and control groups was 63.2 +/- 24.8 and 47.8 +/- 17.5 cm3, respectively (p=.001), and excluding the endometrium was 34.7 +/- 13.1 and 29.1 +/- 13.8 cm3 (p=.043). We did not find any significant difference in ovarian volume between the groups. CONCLUSIONS: The girls in the AUB group have significantly larger uterine volume than healthy girls. This finding does not depend on endometrial thickness. PMID- 30480466 TI - The dual-therapy COMBO stent: a rationale for a light dual antiplatelet therapy treatment. AB - The COMBO stent is a new, sirolimus-eluting bioresorbable polymer, bioengineered stent. This technology combines the advantages of second-generation drug-eluting stents with the endothelial progenitor cell capture technology mediated by the anti-CD34 antibody coating on the COMBO luminal surface. This dual technology should improve vessel endothelium regeneration and may lay the biological basis for a short dual antiplatelet therapy course. As new evidence is adding on the safety and efficacy of this stent compared with first- and second-generation drug eluting stents and across a variety of patient populations, aim of this review is to summarize available clinical experience and future perspective with this device. PMID- 30480467 TI - Longitudinal study of functional brain network reorganization in clinically isolated syndrome. AB - BACKGROUND:: There is a lack of longitudinal studies exploring the topological organization of functional brain networks at the early stages of multiple sclerosis (MS). OBJECTIVE:: This study aims to assess potential brain functional reorganization at rest in patients with CIS (PwCIS) after 1 year of evolution and to characterize the dynamics of functional brain networks at the early stage of the disease. METHODS:: We prospectively included 41 PwCIS and 19 matched healthy controls (HCs). They were scanned at baseline and after 1 year. Using graph theory, topological metrics were calculated for each region. Hub disruption index was computed for each metric. RESULTS:: Hub disruption indexes of degree and betweenness centrality were negative at baseline in patients ( p < 0.05), suggesting brain reorganization. After 1 year, hub disruption indexes for degree and betweenness centrality were still negative ( p < 0.00001), but such reorganization appeared more pronounced than at baseline. Different brain regions were driving these alterations. No global efficiency differences were observed between PwCIS and HCs either at baseline or at 1 year. CONCLUSION:: Dynamic changes in functional brain networks appear at the early stages of MS and are associated with the maintenance of normal global efficiency in the brain, suggesting a compensatory effect. PMID- 30480468 TI - Incense Smoke Exposure Augments Systemic Oxidative Stress, Inflammation and Endothelial Dysfunction in Male Albino Rats. AB - Incense smoke is reported to increase cardiovascular disease (CVD) risk in exposed individuals. However, the mechanism underlying the toxic effect of incense smoke on cardiovascular system is unclear. To test this, we chronically exposed male albino rats to two different types of Arabian incense smoke and studied their effects on oxidative stress, inflammation and endothelial function. Rats exposed to either of incense smoke showed a significant increase in malondialdehyde (MDA) and a significant decline in superoxide dismutase (SOD) and reduced glutathione (GSH). Endothelial functional marker, nitric oxide (NO) was significantly decreased while endothelin-1 was significantly increased in rats exposed to both the incense types. Incense smoke exposure also led to a significant increase in chemokines and inflammatory mediators including monocyte chemoattractant protein-1 (MCP-1), granulocyte-macrophage-colony stimulating factor (GM-CSF), regulated on activation normal T cell expressed and secreted (RANTES), interleukin-4 (IL-4), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-alpha). Besides, incense smoke exposed rats demonstrated a significant increase in the expression of intercellular adhesion molecule-1 (ICAM 1), vascular cell adhesion molecules-1 (VCAM-1), and E-selectin. Importantly, cessation of incense smoke exposure for 30 days led to a significant reversal in the levels of all the studied markers. Collectively, this study describes oxidative stress, endothelial dysfunction and inflammation as possible underlying mechanisms in the toxic effects of incense smoke on increased CVD risk in incense smoke exposed individuals. Findings also underscore that the avoiding incense smoke exposure may have beneficial health effects. PMID- 30480470 TI - Corrigendum. PMID- 30480469 TI - Multidrug-Resistant Salmonella enterica Isolated from Food Animal and Foodstuff May Also Be Less Susceptible to Heavy Metals. AB - Salmonella enterica is a foodborne pathogen showing increasing multidrug resistance (MDR). We characterized the antimicrobial resistance (AMR) genotype using microarrays in a panel of 105 nontyphoidal S. enterica isolated from food animals and foodstuff. Nineteen isolates were chosen on the basis of their MDR and virulence for determination of heavy metal susceptibilities and screened by polymerase chain reaction for heavy metal resistance genes. Whole-genome sequencing (WGS) was performed on three isolates carrying clinically important AMR genes and the cdtB toxin gene to detect other heavy metal resistance mechanisms, and conjugation assays were performed to evaluate transfer of AMR/toxin genes with heavy metal resistance genes. AMR genotyping results showed isolates harbored between 1 and 12 mobile AMR genes, with 58% being classified as MDR. The tested subset of isolates showed reduced susceptibility to zinc (78%), copper (68%), silver (63%), arsenic (47%), and tellurite (26%); phenotypes that could be attributed to zitB (n = 32%), pcoA/pcoD (n = 32%), tcrB (n = 16%), arsB (n = 16%), silA/silE (n = 42%), and terF (n = 26%) genes. WGS confirmed the presence of other heavy metal resistance genes such as copA, cusA, and czcD. Isolates often harbored multiple heavy metal resistance genes. Two strains (Sal25 and Sal368) were able to conjugate with Escherichia coli J53 at a relatively high frequency (~10-4 colony-forming units per recipient). Transformants selected in the presence of copper harbored either an IncHI2 (J53/Sal25 transconjugant) or IncF (J53/Sal368 transconjugant) plasmid with decreased susceptibilities to tellurite, zinc, copper, cobalt, arsenic, lead, mercury, and silver. blaCTX-M-1 and mcr-1 genes were also transferred to one transconjugant, and tet(M) and blaTEM-1 genes to the other. This work shows the presence of a diversity of AMR genes in this zoonotic pathogen, and suggests that heavy metals may contribute to selection of clinically important ones through the food chain, such as the plasmid-mediated colistin resistance gene mcr-1. PMID- 30480471 TI - Patisiran, an RNAi therapeutic for the treatment of hereditary transthyretin mediated amyloidosis. AB - Hereditary transthyretin-mediated amyloidosis is a rapidly progressive, heterogeneous disease caused by the accumulation of misfolded transthyretin protein as amyloid fibrils at multiple sites, and is characterized by peripheral sensorimotor neuropathy, autonomic neuropathy and/or cardiomyopathy. Current treatment options have limited efficacy and often do not prevent disease progression. Patisiran is a novel RNA interference therapeutic that specifically reduces production of both wild-type and mutant transthyretin protein. In Phase II, III and long-term extension studies in patients with hereditary transthyretin mediated amyloidosis, patisiran has consistently slowed or improved progression of neuropathy. In addition, the Phase III trial demonstrated significant improvements in quality of life measures and indicators of cardiomyopathy. Here, we highlight efficacy and safety data from the patisiran clinical trial programme. PMID- 30480472 TI - Population subdivision and the frequency of aflatoxigenic isolates in Aspergillus flavus in the United States. AB - Consumption of food contaminated with aflatoxin, from crops infected by Aspergillus flavus, is associated with acute toxicosis, cancer, and stunted growth. While such contamination is more common in the lower latitudes of the United States, it is unclear if this pattern is associated with differences in the relative frequencies of aflatoxigenic individuals of A. flavus. To determine if the frequency of aflatoxin-producing ability of A. flavus increases as latitude decreases, we sampled 281 isolates from field soils in two north-south transects in the U.S. and tested them for aflatoxin production. We also genotyped 161 isolates using 10 microsatellite markers to assess population structure. While the population density of A. flavus was highest at lower latitudes, there was no difference in the frequency of aflatoxigenic A. flavus isolates in relation to latitude. We found that the U.S. population of A. flavus is subdivided into two genetically differentiated subpopulations that are not associated with chemotype or geographic origin of isolates. The two populations differ markedly in allelic and genotypic diversity. The less diverse population is more abundant and may represent a clonal lineage derived from the more diverse population. Overall, increased aflatoxin contamination in lower latitudes may be explained partially by differences in population density of A. flavus, not genetic population structure. PMID- 30480473 TI - Analysis of Defense-Related Gene Expression in Citrus Hybrids Infected by Xylella fastidiosa. AB - Resistance to Xylella fastidiosa was evaluated in 264 hybrids of crosses between Murcott tangor (Citrus reticulata x Citrus sinensis) and Pera sweet orange (C. sinensis) under field conditions. Uninfected hybrids were grafted with buds collected from Pera sweet orange plants infected with X. fastidiosa, forming a plant with two scions (i.e., hybrid branches and Pera sweet orange branches). From these plants, we chose ten genotypes with three biological replicates. We evaluated gene expression, bacterial multiplication and citrus variedated chlorosis (CVC) symptom development in both scions. Xylella fastidiosa was not detected in most hybrid scions and none showed disease symptoms. In contrast, all Pera sweet orange scions were infected with X. fastidiosa and expressed symptoms of CVC. We quantified the expression of twelve defense-related genes by qPCR comparing resistant to susceptible scions. We suggest that some of these genes are involved in resistance of the hybrids to X. fastidiosa, since their expression was significantly higher in the resistant hybrid scions than in tolerant hybrids and scions originated from CVC symptomatic Pera sweet orange buds. However, we note that these data should be interpreted carefully, as the plant genotypes tested are related but necessarily distinct (hybrids of C. reticulata and C. sinensis, in relation to a C. sinensis control). A principal component analysis (PCoA) revealed a relationship between the expression of these genes and hybrid scions, and between scions that originated from infected buds and the presence of the bacteria and plant symptoms. Multi-year field trials are necessary to develop plant resistance to X. fastidiosa. While the experimental design used here had limitations, it allowed us to identify a set of genes potentially involved in Citrus sp. resistance to this pathogen. Future work on the role of these genes in plant defenses to X. fastidiosa infection is necessary to confirm their importance in the displayed resistance phenotype. PMID- 30480475 TI - Letter to the Editor for the article "Flat-head positioning increases cerebral blood flow in anterior circulation acute ischemic stroke: A cluster randomized phase IIb trial". PMID- 30480474 TI - BIM deletion polymorphism accounts for lack of favorable outcome in Japanese females with follicular lymphoma. AB - Deletion polymorphism of BCL-2-like protein 11 (BIM) is specifically found in East Asia. To explain some epidemiological discrepancies between Asian and Western countries, we analyzed a silent single nucleotide polymorphism (SNP) in exon 5 (c465C > T) and a deletion site (2903 bp) in intron 2 in 77 patients with follicular lymphoma by the Q-invader method using PCR. In females, 5-year progression-free survivals (PFS) were 20.0% in the BIM deletion group, 66.7% in the SNP group and 81.5% in the wild-type (WT) group (p = .0012). In the WT group, 5-year PFS was 40.4% in males (p = .0448 vs. female PFS). This tendency was strengthened in patients receiving rituximab (26.9% vs. 84.2%, p = .006). Superior PFS in the WT females in Japan was comparable with the results of cohort studies in the United States and Sweden. Favorable prognosis in Japanese females may be masked by the BIM deletion polymorphism. PMID- 30480476 TI - Low flow in the left atrial appendage assessed by transesophageal echocardiography is associated with increased stroke severity-Results of a single center cross-sectional study. AB - BACKGROUND: About 25% of strokes are thought to be cryptogenic. There is growing evidence that most of these cryptogenic strokes are thromboembolic and caused by an undetected atrial fibrillation. Measured slow flow in the left atrial appendage has been proposed to be an indicator for the thromboembolic risk since it is possibly associated with undetected atrial fibrillation. METHODS: We evaluated all patients (n = 909; mean of 62 years, 39% female) admitted with an ischemic stroke (84%) or transient ischemic attack to our university medical center who underwent transesophageal echocardiography examination 2012-2014. Baseline characteristics, cardio-/neurovascular risk factors, electrocardiogram monitoring data, National Institute of Health Stroke Scale values, the localization of the stroke, as well as transesophageal echocardiography findings were analyzed. RESULTS: Stroke severity measured by the National Institute of Health Stroke Scale in patients with a low flow in the left atrial appendage was significantly higher than in patients without left atrial appendage low flow (p < 0.001). There was a threshold phenomenon in flow velocity at about 60 cm/s above which no significant change in National Institute of Health Stroke Scale values could be observed. These patients were significantly different concerning incidence of heart failure (10.6% vs. 2.3%; p < 0.001) and atrial fibrillation (32.2% vs. 8.8%; p < 0.001). However, threshold phenomenon of left atrial appendage flow was unchanged when excluding atrial fibrillation and heart failure patients. CONCLUSIONS: A low flow in the left atrial appendage was associated with clinically elevated stroke severity and could be indicated as an independent stroke risk factor. Further prospective studies are warranted to evaluate beneficial effects of therapeutic options in these patients also in the assumed absence of atrial fibrillation. PMID- 30480477 TI - Placement effects of inertial measurement units on contact identification in wheelchair racing. AB - Inertial measurement units (IMUs) provide a practical solution for attaining key performance data for wheelchair sports. The effects of IMU placement position on the identification of propulsion characteristics are unknown. The aim of this study was to determine the variability in the reliability of cycle time measurements (time between hand contacts) across IMU locations on the chair frame (axle housings), and wheels (axle, push rim, outer rim), on both the left and right sides (n = 8). Contacts were defined by spikes in the resultant acceleration data, corresponding to impact between the hands and push rim, and verified against motion capture. Five elite wheelchair racing athletes propelled at racing speeds on a treadmill. Excellent inter-rater Intraclass Correlation Coefficient values indicated high reliability and repeatability for both motion capture and IMU signal analysis approaches (R = 0.997, p < 0.001 and R = 0.990, p < 0.001, respectively). The best results were (as determined by the best between method agreement) were observed for IMUs located on the frame. Detection reliability was positively associated with signal-to-noise ratio of the acceleration data. The IMU assessment approach facilitates an automated processing capability, which is an improvement to the currently used video analysis. PMID- 30480478 TI - Does Breathing Wood Smoke Make the Flu Worse? Sex Might Matter. PMID- 30480479 TI - Phytophthora infestans sporangia produced in culture and on tomato leaflet lesions show marked differences in indirect germination rates, aggressiveness, and global transcription profiles. AB - Sporangia of Phytophthora infestans from pure cultures on agar plates are typically used in lab studies, whereas sporangia from leaflet lesions drive natural infections and epidemics. Multiple assays were performed to determine if sporangia from these two sources are equivalent. Sporangia from plate cultures showed much lower rates of indirect germination and produced much less disease in field and moist-chamber tests. This difference in aggressiveness was observed whether the sporangia had been previously incubated at 4 C (to induce indirect germination) or at 21 C (to prevent indirect germination). Furthermore, lesions caused by sporangia from plates produced much less sporulation. RNA-Seq analysis revealed that thousands of the >17,000 P. infestans genes with an RPKM >1 (reads per kilobase of exon model per million mapped reads >1) were differentially expressed in sporangia obtained from plate cultures of two independent field isolates compared to sporangia of those isolates from leaflet lesions. Among the significant differentially expressed genes (DEGs), putative RxLR effectors were over-represented, with almost half of the 355 effectors with RPKM>1 being up- or down-regulated. DEGs of both isolates included nine flagellar-associated genes, and all were down-regulated in plate sporangia. Ten elicitin genes were also detected as DEGs in both isolates, and nine (including INF1) were up-regulated in plate sporangia. These results corroborate previous observations that sporangia produced from plates and leaflets sometimes yield different experimental results and suggest hypotheses for potential mechanisms. We caution that use of plate sporangia in assays may not always produce results reflective of natural infections and epidemics. PMID- 30480480 TI - Convergent evolution of effector protease recognition by Arabidopsis and barley. AB - The Pseudomonas syringae cysteine protease AvrPphB activates the Arabidopsis resistance protein RPS5 by cleaving a second host protein, PBS1. AvrPphB induces defense responses in other plant species, but the genes and mechanisms mediating AvrPphB recognition in those species have not been defined. Here, we show that AvrPphB induces defense responses in diverse barley cultivars. We show also that barley contains two PBS1 orthologs, that their products are cleaved by AvrPphB, and that the barley AvrPphB response maps to a single locus containing a nucleotide-binding leucine-rich repeat (NLR) gene, which we termed AvrPphB Resistance 1 (Pbr1). Transient co-expression of PBR1 with wild-type AvrPphB, but not a protease inactive mutant, triggered defense responses, indicating that PBR1 detects AvrPphB protease activity. Additionally, PBR1 co-immunoprecipitated with barley and N. benthamiana PBS1 proteins, suggesting mechanistic similarity to detection by RPS5. Lastly, we determined that wheat cultivars also recognize AvrPphB protease activity and contain two putative Pbr1 orthologs. Phylogenetic analyses showed however that Pbr1 is not orthologous to RPS5. Our results indicate that the ability to recognize AvrPphB evolved convergently, and imply that selection to guard PBS1-like proteins occurs across species. Also, these results suggest that PBS1-based decoys may be used to engineer protease effector recognition-based resistance in barley and wheat. . PMID- 30480481 TI - Direct regulation of the EFR-dependent immune response by Arabidopsis TCP transcription factors. AB - One layer of the innate immune system allows plants to recognize pathogen associated molecular patterns (PAMPS), activating a defense response known as PAMP-triggered immunity (PTI). Maintaining an active immune response, however, comes at the cost of plant growth and development; accordingly, optimization of the balance between defense and development is critical to plant fitness. The TCP transcription factor family consists of well-characterized transcriptional regulators of plant development and morphogenesis. The three closely-related class I TCPs TCP8, TCP14, and TCP15 have also been implicated in the regulation of effector-triggered immunity, but there has been no previous characterization of PTI-related phenotypes. To identify TCP targets involved in PTI, we screened a PAMP-induced gene promoter library in a yeast one-hybrid assay and identified interactions of these three TCPs with the EFR promoter. The direct interactions between TCP8 and EFR were confirmed to require an intact TCP binding-site in planta. A tcp8 tcp14 tcp15 triple mutant was impaired in EFR-dependent PTI and exhibited reduced levels of PATHOGENESIS-RELATED PROTEIN 2 and induction of EFR expression after elicitation with elf18, but also increased production of ROS relative to Col-0. Our data support an increasingly complex role for TCPs at a nexus of plant development and defense. PMID- 30480482 TI - Renal dysfunction and cardiogenic shock complicating acute coronary syndromes. PMID- 30480483 TI - Systemic arterial hypertension but not IGF-I treatment stimulates cardiomyocyte enlargement in neonatal lambs. AB - Although cardiomyocyte terminal differentiation is nearly complete at birth in sheep, as in humans, very limited postnatal expansion of myocyte number may occur. The capacity of newborn cardiomyocytes to respond to growth stimulation by proliferation is poorly understood. Our objective was to test this growth response in newborn lambs with two stimuli shown to be potent inducers of cardiomyocyte growth in fetuses and adults: increased systolic load (Load) and insulin-like growth factor I (IGF-I). Vascular catheters and an inflatable aortic occluder were implanted in lambs. Hearts were collected for analysis at 18 days of age after a 7-day experiment and compared with control hearts. Load hearts, but not IGF-I hearts, were heavier ( P = 0.001) because of increased mass of the left ventricle (LV), septum, and left atrium (40-50%, P = 0.004). Terminal differentiation and cell cycle activity were not different between groups. Myocyte length was 7% greater in Load lamb hearts ( P < 0.05), and binucleated myocytes, which comprise ~90% of LV cells, were 25% larger in volume ( P = 0.03). Myocyte number per gram of myocardium was decreased in all ventricles of Load lambs ( P = 0.01). Cells from the IGF-I group were not different by any comparison. These results suggest that the newborn sheep LV responds to systolic stress with cardiomyocyte hypertrophy, not proliferation. Furthermore, IGF-I is ineffective at stimulating cardiomyocyte proliferation at this age (despite effectiveness when administered before birth). Thus, to expand cardiomyocyte number in the newborn heart, therapies other than systolic pressure load and IGF I treatment need to be developed. PMID- 30480484 TI - Can Solitary Pulmonary Nodules Be Accurately Characterized with Diffusion weighted MRI? PMID- 30480485 TI - MRI of Recurrent Glioblastoma: Reliability and Reality. PMID- 30480486 TI - Editor's Recognition Awards. PMID- 30480487 TI - Autologous Blood Patch Injection versus Hydrogel Plug in CT-guided Lung Biopsy: A Prospective Randomized Trial. AB - Purpose To compare the effect of autologous blood patch injection (ABPI) with that of a hydrogel plug on the rate of pneumothorax at CT-guided percutaneous lung biopsy. Materials and Methods In this prospective randomized controlled trial ( https://ClinicalTrials.gov , NCT02224924), a noninferiority design was used for ABPI, with a 10% noninferiority margin when compared with the hydrogel plug, with the primary outcome of pneumothorax rate within 2 hours of biopsy. A type I error rate of 0.05 and 90% power were specified with a target study population of 552 participants (276 in each arm). From October 2014 to February 2017, all potential study participants referred for CT-guided lung biopsy (n = 2052) were assessed for enrollment. Results The data safety monitoring board recommended the trial be closed to accrual after an interim analysis met prespecified criteria for early stopping based on noninferiority. The final study group consisted of 453 participants who were randomly assigned to the ABPI (n = 226) or hydrogel plug (n = 227) arms. Of these, 407 underwent lung biopsy. Pneumothorax rates within 2 hours of biopsy were 21% (42 of 199) and 29% (60 of 208); chest tube rates were 9% (18 of 199) and 13% (27 of 208); and delayed pneumothorax rates within 2 weeks after biopsy were 1.4% (three of 199) and 1.5% (three of 208) in the ABPI and hydrogel plug arms, respectively. Conclusion Autologous blood patch injection is noninferior to a hydrogel plug regarding the rate of pneumothorax after CT-guided percutaneous lung biopsy. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 30480488 TI - Interreader Variability of Dynamic Contrast-enhanced MRI of Recurrent Glioblastoma: The Multicenter ACRIN 6677/RTOG 0625 Study. AB - Purpose To evaluate factors contributing to interreader variation (IRV) in parameters measured at dynamic contrast material-enhanced (DCE) MRI in patients with glioblastoma who were participating in a multicenter trial. Materials and Methods A total of 18 patients (mean age, 57 years +/- 13 [standard deviation]; 10 men) who volunteered for the advanced imaging arm of ACRIN 6677, a substudy of the RTOG 0625 clinical trial for recurrent glioblastoma treatment, underwent analyzable DCE MRI at one of four centers. The 78 imaging studies were analyzed centrally to derive the volume transfer constant (Ktrans) for gadolinium between blood plasma and tissue extravascular extracellular space, fractional volume of the extracellular extravascular space (ve), and initial area under the gadolinium concentration curve (IAUGC). Two independently trained teams consisting of a neuroradiologist and a technologist segmented the enhancing tumor on three dimensional spoiled gradient-recalled acquisition in the steady-state images. Mean and median parameter values in the enhancing tumor were extracted after registering segmentations to parameter maps. The effect of imaging time relative to treatment, map quality, imager magnet and sequence, average tumor volume, and reader variability in tumor volume on IRV was studied by using intraclass correlation coefficients (ICCs) and linear mixed models. Results Mean interreader variations (+/- standard deviation) (difference as a percentage of the mean) for mean and median IAUGC, mean and median Ktrans, and median ve were 18% +/- 24, 17% +/- 23, 27% +/- 34, 16% +/- 27, and 27% +/- 34, respectively. ICCs for these metrics ranged from 0.90 to 1.0 for baseline and from 0.48 to 0.76 for posttreatment examinations. Variability in reader-derived tumor volume was significantly related to IRV for all parameters. Conclusion Differences in reader tumor segmentations are a significant source of interreader variation for all dynamic contrast-enhanced MRI parameters. (c) RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Wolf in this issue. PMID- 30480489 TI - Detection of Colorectal Hepatic Metastases Is Superior at Standard Radiation Dose CT versus Reduced Dose CT. AB - Purpose To evaluate colorectal cancer hepatic metastasis detection and characterization between reduced radiation dose (RD) and standard dose (SD) contrast material-enhanced CT of the abdomen and to qualitatively compare between filtered back projection (FBP) and iterative reconstruction algorithms. Materials and Methods In this prospective study (from May 2017 through November 2017), 52 adults with biopsy-proven colorectal cancer and suspected hepatic metastases at baseline CT underwent two portal venous phase CT scans: SD and RD in the same breath hold. Three radiologists, blinded to examination details, performed detection and characterization of 2-15-mm lesions on the SD FBP and RD adaptive statistical iterative reconstruction (ASIR)-V 60% series images. Readers assessed overall image quality and lesions between SD FBP and seven different iterative reconstructions. Two nonblinded consensus reviewers established the reference standard using the picture archiving and communication system lesion marks of each reader, multiple comparison examinations, and clinical data. Results RD CT resulted in a mean dose reduction of 54% compared with SD. Of the 260 lesions (233 metastatic, 27 benign), 212 (82%; 95% confidence interval [CI]: 76%, 86%) were detected with RD CT, whereas 252 (97%; 95% CI: 94%, 99%) were detected with SD (P < .001); per-lesion sensitivity was 79% (95% CI: 74%, 84%) and 94% (95% CI: 90%, 96%) (P < .001), respectively. Mean qualitative scores ranked SD images as higher quality than RD series images, and ASIR-V ranked higher than ASIR and Veo 3.0. Conclusion CT evaluation of colorectal liver metastases is compromised with modest radiation dose reduction, and the use of iterative reconstructions could not maintain observer performance. (c) RSNA, 2018. PMID- 30480491 TI - Shear-Wave Elastography of Benign versus Malignant Musculoskeletal Soft-Tissue Masses: Comparison with Conventional US and MRI. AB - Purpose To examine if shear-wave elastography (SWE) improves the accuracy of diagnosing soft-tissue masses as benign or malignant compared with US alone or in combination with MRI. Materials and Methods Two hundred six consecutive adult participants (mean age, 57.7 years; range, 18-91 years), including 89 men (median age, 56.0 years; range, 21-91 years) and 117 women (median age, 59.1 years; range, 18-88 years), who were referred for biopsy of a soft-tissue mass were prospectively recruited from December 2015 through March 2017. Participants underwent B-mode US, MRI, and SWE prior to biopsy. Three musculoskeletal radiologists independently reviewed US images alone, followed by US and MRI images together, and classified lesions as benign, probably benign, probably malignant, or malignant. For SWE, the area under the receiver operating characteristic (ROC) curve (AUC) was calculated for transverse shear-wave velocity (SWV). Multivariable logistic regression was used to investigate the association between SWE and malignancy alongside individual demographic and imaging variables. Results At histologic examination, 79 of 206 (38%) participants had malignant lesions. SWV showed good diagnostic accuracy for lesions classified as benign or probably benign by US alone (AUC = 0.87 [95% confidence interval {CI}: 0.79, 0.95]). SWV did not provide substantive diagnostic information for lesions classified as probably malignant or malignant, whether the classification was made with or without MRI. However, multivariable modeling indicated that diagnostic accuracy may vary by lesion position (interaction P = .02; superficial, odds ratio [OR] = 17.7 [95% CI: 1.50, 207], P = .02; deep/mixed, OR = 0.24 [95% CI: 0.07, 0.86], P = .03) and participant age (interaction P = .01; eg, age 43 years, OR = 0.72 [95% CI: 0.15, 3.5], P = .69; age 72 years, OR = 0.08 [95% CI: 0.02, 0.37], P = .001). Conclusion Shear-wave elastography can increase accuracy of soft-tissue lesion diagnosis in conjunction with US. However, a single cut-off may not be universally applicable with diagnostic accuracy that is affected by lesion position and patient age. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 30480490 TI - The RSNA Pediatric Bone Age Machine Learning Challenge. AB - Purpose The Radiological Society of North America (RSNA) Pediatric Bone Age Machine Learning Challenge was created to show an application of machine learning (ML) and artificial intelligence (AI) in medical imaging, promote collaboration to catalyze AI model creation, and identify innovators in medical imaging. Materials and Methods The goal of this challenge was to solicit individuals and teams to create an algorithm or model using ML techniques that would accurately determine skeletal age in a curated data set of pediatric hand radiographs. The primary evaluation measure was the mean absolute distance (MAD) in months, which was calculated as the mean of the absolute values of the difference between the model estimates and those of the reference standard, bone age. Results A data set consisting of 14 236 hand radiographs (12 611 training set, 1425 validation set, 200 test set) was made available to registered challenge participants. A total of 260 individuals or teams registered on the Challenge website. A total of 105 submissions were uploaded from 48 unique users during the training, validation, and test phases. Almost all methods used deep neural network techniques based on one or more convolutional neural networks (CNNs). The best five results based on MAD were 4.2, 4.4, 4.4, 4.5, and 4.5 months, respectively. Conclusion The RSNA Pediatric Bone Age Machine Learning Challenge showed how a coordinated approach to solving a medical imaging problem can be successfully conducted. Future ML challenges will catalyze collaboration and development of ML tools and methods that can potentially improve diagnostic accuracy and patient care. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 30480492 TI - Fluorine 18-FDG PET/CT and Diffusion-weighted MRI for Malignant versus Benign Pulmonary Lesions: A Meta-Analysis. AB - Purpose To perform a meta-analysis of the literature to compare the diagnostic performance of fluorine 18 fluorodeoxyglucose PET/CT and diffusion-weighted (DW) MRI in the differentiation of malignant and benign pulmonary nodules and masses. Materials and Methods Published English-language studies on the diagnostic accuracy of PET/CT and/or DW MRI in the characterization of pulmonary lesions were searched in relevant databases through December 2017. The primary focus was on studies in which joint DW MRI and PET/CT were performed in the entire study population, to reduce interstudy heterogeneity. For DW MRI, lesion-to-spinal cord signal intensity ratio and apparent diffusion coefficient were evaluated; for PET/CT, maximum standard uptake value was evaluated. The pooled sensitivities, specificities, diagnostic odds ratios, and areas under the receiver operating characteristic curve (AUCs) for PET/CT and DW MRI were determined along with 95% confidence intervals (CIs). Results Thirty-seven studies met the inclusion criteria, with a total of 4224 participants and 4463 lesions (3090 malignant lesions [69.2%]). In the primary analysis of joint DW MRI and PET/CT studies (n = 6), DW MRI had a pooled sensitivity and specificity of 83% (95% CI: 75%, 89%) and 91% (95% CI: 80%, 96%), respectively, compared with 78% (95% CI: 70%, 84%) (P = .01 vs DW MRI) and 81% (95% CI: 72%, 88%) (P = .056 vs DW MRI) for PET/CT. DW MRI yielded an AUC of 0.93 (95% CI: 0.90, 0.95), versus 0.86 (95% CI: 0.83, 0.89) for PET/CT (P = .001). The diagnostic odds ratio of DW MRI (50 [95% CI: 19, 132]) was superior to that of PET/CT (15 [95% CI: 7, 32]) (P = .006). Conclusion The diagnostic performance of diffusion-weighted MRI is comparable or superior to that of fluorine 18 fluorodeoxyglucose PET/CT in the differentiation of malignant and benign pulmonary lesions. (c) RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Schiebler in this issue. PMID- 30480493 TI - Building Simulation Exercise Capacity in Latin America to Manage Public Health Emergencies. AB - Simulation exercises, whether discussion- or operations-based, are an essential component of public health emergency preparedness and response-so much so that the ability to conduct exercises is included as a key indicator for measurement of emergency response operations in the Joint External Evaluation and as a requirement of the International Health Regulations. Exercises allow ministry of health partners to actually practice and demonstrate their learned capacities and show progress toward those global health security goals. In recent years, the general technique in the global health security arena has been for external partners to design, facilitate, and evaluate public health emergency exercises for ministry of health partners. However, in 2017, the Centers for Disease Control and Prevention (CDC) Global Response Preparedness Team (GRPT) piloted regional training for ministry of health representatives from 4 countries in Latin America to build their internal capacity to design, facilitate, and evaluate simulation exercises using the US Homeland Security Exercise Evaluation Program (HSEEP). Using this program as the source material, the team modified the content for application to an international audience, facilitated it as a 4-day workshop, and designed an evaluation protocol to measure participants' satisfaction with the course as well as their ability to apply concepts learned in their day-to-day jobs. Representatives of 3 of the 4 ministries of health that attended the workshop designed exercises to implement in their home countries, with 2 having completed the facilitation and evaluation of their exercises at the time of this publication. PMID- 30480495 TI - US Global Health Security Investments Improve Capacities for Infectious Disease Emergencies. PMID- 30480494 TI - Building Global Health Security Capacity: The Role for Implementation Science. PMID- 30480496 TI - Building Laboratory-Based Arbovirus Sentinel Surveillance Capacity During an Ongoing Dengue Outbreak, Burkina Faso, 2017. AB - In West Africa, identification of nonmalarial acute febrile illness (AFI) etiologic pathogens is challenging, given limited epidemiologic surveillance and laboratory testing, including for AFI caused by arboviruses. Consequently, public health action to prevent, detect, and respond to outbreaks is constrained, as experienced during dengue outbreaks in several African countries. We describe the successful implementation of laboratory-based arbovirus sentinel surveillance during a dengue outbreak in Burkina Faso during fall 2017. We describe implementation, surveillance methods, and associated costs of enhanced surveillance during an outbreak response as an effort to build capacity to better understand the burden of disease caused by arboviruses in Burkina Faso. The system improved on existing routine surveillance through an improved case report form, systematic testing of specimens, and linking patient information with laboratory results through a data management system. Lessons learned will improve arbovirus surveillance in Burkina Faso and will contribute to enhancing global health security in the region. Elements critical to the success of this intervention include responding to a specific and urgent request by the government of Burkina Faso and building on existing systems and infrastructure already supported by CDC's global health security program. PMID- 30480497 TI - Use of the Staged Development Tool for Assessing, Planning, and Measuring Progress in the Development of National Public Health Institutes. AB - The Staged Development Tool (SDT) was created to help national public health institutes (NPHIs) assess their current capacity and develop roadmaps for achieving a higher level of functioning. This article discusses the current use of the SDT by national public health institutes to establish baseline capacity and inform strategic planning and its proposed use in a 3-step sequence for measuring the impact of capacity-building interventions over time. The article also includes descriptions of how national public health institutes have been using the SDT to assess their baseline capacity in management issues and core public health functions. The first use of the SDT by a national public health institute provides essential baseline information on their capacities and levels of functioning and plans for addressing gaps. By repeating the SDT after time for the plans to be implemented, the SDT can be used to evaluate changes in capacity and the effectiveness of the interventions made. Because the SDT is built to be complementary to existing assessments and public health strengthening tools and guidelines, implementing the SDT provides concrete, complementary information that can help countries achieve global health security goals and address current and future threats to public health. PMID- 30480498 TI - Factors Influencing Community Event-based Surveillance: Lessons Learned from Pilot Implementation in Vietnam. AB - Community event-based surveillance aims to enhance the early detection of emerging public health threats and thus build health security. The Ministry of Health of Vietnam launched a community event-based surveillance pilot program in 6 provinces to improve the early warning functions of the existing surveillance system. An evaluation of the pilot program took place in 2017 and 2018. Data from this evaluation were analyzed to determine which factors were associated with increased detection and reporting. Results show that a number of small, local events were detected and reported through community event-based surveillance, supporting the notion that it would also facilitate the rapid detection and reporting of potentially larger events or outbreaks. The study showed the value of supportive supervision and monitoring to sustain community health worker reporting and the importance of conducting evaluations for community event-based surveillance programs to identify barriers to effective implementation. PMID- 30480499 TI - Strengthening Global Health Security Through Africa's First Absolute Post Master's Fellowship Program in Field Epidemiology in Uganda. AB - Uganda is prone to epidemics of deadly infectious diseases and other public health emergencies. Though significant progress has been made in response to emergencies during the past 2 decades, system weaknesses still exist, including lack of a robust workforce with competencies to identify, investigate, and control disease outbreaks at the source. These deficiencies hamper global health security broadly. To address need for a highly competent workforce to combat infectious diseases, the Uganda Ministry of Health established the Public Health Fellowship Program (PHFP), the advanced-level Field Epidemiology Training Program (FETP), closely modeled after the CDC's Epidemic Intelligence Service (EIS) program. The 2-year, full-time, non-degree granting program is the first absolute post-master's FETP in Africa for mid-career public health professionals. Fellows gain competencies in 7 main domains, which are demonstrated by deliverables, while learning through service delivery 80% of the time in the ministry of health. During 2015-2017, PHFP enrolled 3 cohorts of 31 fellows. By January 2018, PHFP had graduated 2 cohorts (2015 and 2016) of 19 fellows. Fellows were placed in 17 priority areas of the ministry of health. They completed 153 projects (including 60 outbreak investigations, 12 refugee assessments, 40 surveillance projects, and 31 applied epidemiologic studies), of which 49 involved potential bioterrorism agents or epidemic-prone diseases. They made 132 conference presentations, prepared 40 manuscripts for peer-reviewed publication (17 published as of December 2017), and produced 3 case studies. Many of these projects have resulted in public health interventions that led to improvements in disease control and surveillance systems. The program has produced 19 issues of ministry of health bulletins. One year after graduation, graduates have been placed in key public health decision-making positions. Within 3 years, PHFP has strengthened global health security through improvement in public health emergency response; identification, investigation and control of outbreaks at their sources; and documentation and dissemination of findings to inform decision making by relevant stakeholders. PMID- 30480500 TI - Institutionalizing One Health: From Assessment to Action. AB - A One Health approach is critical to strengthening health security at country, regional, and global levels. However, operationally its uptake remains limited. Recent momentum in assessing capacity to effectively prevent, detect, and respond to disease threats has resulted in identification of gaps that require dedicated action. This article highlights relevant tools, standards, and guidance to assist countries and institutions in meeting the collective vision articulated at the 2018 Prince Mahidol Award Conference on "Making the World Safe from the Threats of Emerging Infectious Diseases." Taking stock of assessment findings, resources, priorities, and implementation initiatives across human and animal health, environment and disaster risk reduction sectors can help expand participation in global health security, target risk drivers, and form synergies for collective action and shared gains for both emerging and endemic disease challenges. In addition to health security gains, a multisectoral, One Health approach can drive benefits for wider health sector and global development goals. PMID- 30480501 TI - Strengthening Healthcare Facilities Through Water, Sanitation, and Hygiene (WASH) Improvements: A Pilot Evaluation of "WASH FIT" in Togo. AB - Water, sanitation, and hygiene (WASH) services in healthcare facilities are essential to ensure quality health care and to facilitate infection, prevention, and control practices. They are critical to responding to outbreaks and preventing healthcare-associated infections and, therefore, critical to global health security. Many healthcare facilities in low- and middle-income settings have limited WASH services. One tool to address this issue is the World Health Organization (WHO) and United Nations Children's Fund (UNICEF) Water and Sanitation for Health Facility Improvement Tool, or "WASH FIT." WASH FIT is a continuous improvement tool based on key WHO environmental health and infection, prevention, and control standards. While using WASH FIT, internal teams regularly perform self-assessments at their facilities, using up to 65 WASH indicators to develop and implement an improvement plan. The Ministry of Health and Social Protection (MSPS) in Togo, with support from WHO and the US Centers for Disease Control and Prevention (CDC), piloted this tool in 3 healthcare facilities. The pilot included facility assessments at 3 time points and in-depth interviews and document review 7 months after initiating WASH FIT. Facilities made improvements without significant external financial or material support. On average, pilot facilities improved from 18% of total indicators meeting standards at baseline to 44% after 7 months. Examples included improved drinking water supply, medical waste segregation, and increased soap at handwashing stations. Participants reported improvements in staff and patient satisfaction, hand hygiene, and occupational safety. Findings suggest that WASH FIT, coupled with training and supervision, may help facilities improve WASH services and practices, thus contributing to global health security. Based on these findings, the Togolese MSPS plans to scale up nationwide. Les services d'eau, d'assainissement, et d'hygiene (WASH) dans les etablissements de sante sont essentiels pour assurer des soins de qualite et faciliter les pratiques de prevention et controle des infections. Ils sont essentiels pour repondre aux epidemies et prevenir les infections associees aux soins de sante, et donc a la securite sanitaire mondiale. De nombreux pays a revenu faible ou intermediaire ont des services WASH limites dans les etablissements de soins. Un outil recemment publie pour remedier cette situation est l'outil WASH FIT [Water and Sanitation for Health Facility Improvement Tool] de l'Organisation mondiale de la Sante (OMS) et le Fonds des Nations Unies (UNICEF) pour l'amelioration de l'eau et l'assainissement dans les formations sanitaires. WASH FIT est un outil d'amelioration continue base sur les normes de l'OMS en matiere de sante environnementale et de prevention et controle des infections. Lors de l'utilisation de WASH FIT, les equipes internes effectuent regulierement des auto-evaluations dans leurs installations en utilisant jusqu'a 65 indicateurs pour elaborer et mettre en oeuvre leur plan d'amelioration. Le ministere de la Sante et de la Protection Sociale (MSPS) du Togo, avec le soutien de l'OMS et les Centres pour le controle et la prevention des maladies (CDC), a fait un pilotage de cet outil dans 3 centres de sante. Ce pilotage comprenait 3 evaluations dans chaque formation sanitaire, des interviews approfondies, et une revue documentaire, 7 mois apres l'initiation du WASH FIT. Les formations sanitaires ont realise des progres, sans aide financiere ou materielle exterieure. En moyenne, les formations sanitaires sont passees de 18% des indicateurs atteignant les standards au depart, a 44% apres 7 mois. Les exemples incluent l'approvisionnement en eau potable, le tri des dechets medicaux, et le savon aux points de lavage des mains. Les participants ont signale des ameliorations dans la satisfaction du personnel et des patients, l'hygiene des mains, et la securite au travail. Les resultats indiquent que WASH FIT, associe a la formation et a la supervision, pourrait etre un outil pour aider les formations sanitaires a ameliorer les services et pratiques WASH, contribuant ainsi a la securite sanitaire mondiale. Sur la base de ces resultats, le MSPS prevoit une extension a l'echelle nationale. PMID- 30480502 TI - Law and the JEE: Lessons for IHR Implementation. AB - In an increasingly globalized world, countries face infectious disease threats and public health emergencies that transcend borders, making health security of paramount importance. Legal frameworks, at both the international and national levels, can empower governments to strengthen public health and preparedness systems to better detect and respond to infectious disease threats and public health emergencies. The development of the International Health Regulations (IHR) (2005) and the Global Health Security Agenda (GHSA), and the resulting Joint External Evaluation (JEE), are examples of coordinated global efforts to build capacity to prevent, detect, and respond to the international spread of disease. This article uses 3 case studies to describe a role for law in IHR implementation. It highlights the Centers for Disease Control and Prevention's (CDC's) Global Health Security Public Health Law Project and describes how legal mapping data and the resources developed are being used by countries to strengthen health systems and support IHR implementation. PMID- 30480503 TI - Global Health Security Implementation: Expanding the Evidence Base. PMID- 30480504 TI - A Cross-Cutting Approach to Surveillance and Laboratory Capacity as a Platform to Improve Health Security in Uganda. AB - Global health security depends on effective surveillance for infectious diseases. In Uganda, resources are inadequate to support collection and reporting of data necessary for an effective and responsive surveillance system. We used a cross cutting approach to improve surveillance and laboratory capacity in Uganda by leveraging an existing pediatric inpatient malaria sentinel surveillance system to collect data on expanded causes of illness, facilitate development of real time surveillance, and provide data on antimicrobial resistance. Capacity for blood culture collection was established, along with options for serologic testing for select zoonotic conditions, including arboviral infection, brucellosis, and leptospirosis. Detailed demographic, clinical, and laboratory data for all admissions were captured through a web-based system accessible at participating hospitals, laboratories, and the Uganda Public Health Emergency Operations Center. Between July 2016 and December 2017, the expanded system was activated in pediatric wards of 6 regional government hospitals. During that time, patient data were collected from 30,500 pediatric admissions, half of whom were febrile but lacked evidence of malaria. More than 5,000 blood cultures were performed; 4% yielded bacterial pathogens, and another 4% yielded likely contaminants. Several WHO antimicrobial resistance priority pathogens were identified, some with multidrug-resistant phenotypes, including Acinetobacter spp., Citrobacter spp., Escherichia coli, Staphylococcus aureus, and typhoidal and nontyphoidal Salmonella spp. Leptospirosis and arboviral infections (alphaviruses and flaviviruses) were documented. The lessons learned and early results from the development of this multisectoral surveillance system provide the knowledge, infrastructure, and workforce capacity to serve as a foundation to enhance the capacity to detect, report, and rapidly respond to wide-ranging public health concerns in Uganda. PMID- 30480505 TI - Establishment of a Sentinel Laboratory-Based Antimicrobial Resistance Surveillance Network in Ethiopia. AB - In 2014, as part of the Global Health Security Agenda, Ethiopia was provided the technical and financial resources needed to prioritize antimicrobial resistance (AMR) in the national public health sphere. Under the direction of a multi stakeholder working group, AMR surveillance was launched in July 2017 at 4 sentinel sites across the country. The AMR surveillance initiative in Ethiopia represents one of the first systematic efforts to prospectively collect, analyze, and report national-level microbiology results from a network of hospitals and public health laboratories in the country. Baseline readiness assessments were conducted to identify potential challenges to implementation to be addressed through capacity-building efforts. As part of these efforts, the working group leveraged existing resources, initiated laboratory capacity building through mentorship, and established infrastructure and systems for quality assurance, data management, and improved coordination. As a result, AMR surveillance data are being reported and analyzed for use; data from more than 1,700 patients were collected between July 2017 and March 2018. The critical challenges and effective solutions identified through surveillance planning and implementation have provided lessons to help guide successful AMR surveillance in other settings. Ultimately, the surveillance infrastructure, laboratory expertise, and communication frameworks built specifically for AMR surveillance in Ethiopia can be extended for use with other infectious diseases and potential public health emergencies. Thus, building AMR surveillance in Ethiopia has illustrated how laying the foundation for a specific public health initiative can develop capacity for core public health functions with potential benefit. PMID- 30480506 TI - Assessing the Surveillance System for Priority Zoonotic Diseases in the Democratic Republic of the Congo, 2017. AB - High-functioning communicable disease surveillance systems are critical for public health preparedness. Countries that cannot quickly detect and contain diseases are a risk to the global community. The ability of all countries to comply with the International Health Regulations is paramount for global health security. Zoonotic diseases can be particularly dangerous for humans. We conducted a surveillance system assessment of institutional and individual capacity in Kinshasa and Haut Katanga provinces in the Democratic Republic of the Congo for nationally identified priority zoonotic diseases (eg, viral hemorrhagic fever [VHF], yellow fever, rabies, monkeypox, and influenza monitored through acute respiratory infections). Data were collected from 79 health workers responsible for disease surveillance at 2 provincial health offices, 9 health zone offices, 9 general reference hospitals, and 18 health centers and communities. A set of questionnaires was used to assess health worker training in disease surveillance methods; knowledge of case definitions; availability of materials and tools to support timely case detection, reporting, and data interpretation; timeliness and completeness of reporting; and supervision from health authorities. We found that health workers either had not been recently or ever trained in surveillance methods and that their knowledge of case definitions was low. Timeliness and completeness of weekly notification of epidemic-prone diseases was generally well performed, but the lack of available standardized reporting forms and archive of completed forms affected the quality of data collected. Lessons learned from our assessment can be used for targeted strengthening efforts to improve global health security. PMID- 30480507 TI - Development of a Costed National Action Plan for Health Security in Pakistan: Lessons Learned. AB - In order to assess progress toward achieving compliance with the International Health Regulations (2005), member states may voluntarily request a Joint External Evaluation (JEE). Pakistan was the first country in the WHO Eastern Mediterranean Region to volunteer for and complete a JEE to establish the baseline of the country's public health capacity across multiple sectors covering 19 technical areas. It subsequently developed a post-JEE costed National Action Plan for Health Security (NAPHS). The process for developing the costed NAPHS was based on objectives and activities related to the 3 to 5 priority actions for each of the 19 JEE technical areas. Four key lessons were learned during the process of developing the NAPHS. First, multisectoral coordination at both federal and provincial levels is important in a devolved health system, where provinces are autonomous from a public health sector standpoint. Second, the development of a costed NAPHS requires engagement and investment of the country's own resources for sustainability as well as donor coordination among national and international donors and partners. Engagement from the ministries of Finance, Planning and Development, and Foreign Affairs and from WHO was also important. Third, development of predefined goals, targets, and indicators aligned with the JEE as part of the NAPHS process proved to be critical, as they can be used to monitor progress toward implementation of the NAPHS and provide data for repeat JEEs. Lastly, several challenges were identified related to the NAPHS process and costing tool, which need to be addressed by WHO and partners to help countries develop their plans. PMID- 30480508 TI - Lack of T-cell-mediated IL-2 and TNFalpha production is linked to decreased CD58 expression in intestinal tissue during acute simian immunodeficiency virus infection. AB - For an effective T-cell activation and response, co-stimulation is required in addition to the antigen-specific signal from their antigen receptors. The CD2/CD58 interaction is considered as one of the most important T-cell co stimulatory pathways for T-cell activation and proliferation, and its role in regulating intestinal T-cell function in acute and chronic SIV -infected macaques is poorly documented. Here, we demonstrated a significant reduction of CD58 expression in both T- and B-cell populations during acute SIV infection along with high plasma viral load and a loss of intestinal CD4+ T cells compared to SIV uninfected control macaques. The reduction of CD58 expression in T cells was correlated with the reduced expression of T-cell-mediated IL-2 and TNFalpha production. Together, these results indicate that reduction in the CD2/CD58 interaction pathway in mucosal lymphocytes might play a crucial role in mucosal T cell dysfunction during acute SIV/HIV infection. PMID- 30480509 TI - Detection of deep fungal infections: a polyphasic approach. AB - PURPOSE: Tissue samples from patients with suspicion of deep or subcutaneous fungal infections were analysed at the Portuguese Reference Mycology Laboratory according to a proposed diagnostic approach, which aims to constitute a rapid and accurate diagnosis for these fungal infections. METHODOLOGY: Forty-six tissue biopsy samples were analysed over a period of 26 months, using a diagnostic approach that includes culture, panfungal PCR and Aspergillus-directed PCR.Results/Key findings. Overall, 23 samples were reported as negative while the remaining 23 were reported as positive for fungi (PCR, culture and/or histology). PCR showed an estimated detection limit of 12 pg DNA ul-1. From the 46 samples, 30 were negative for fungal DNA while 16 gave positive results. From these, 12 cases were detected by panfungal PCR and six cases by PCR directed toward Aspergillus. In 61 % of the cases, there was concordance between molecular and cultural methods. Aetiological agents identified were Candida albicans, C. glabrata, C. tropicalis, Trichosporon montevideense, Alternaria spp., Exophiala sp., Trichoderma sp., Histoplasma spp., Aspergillus fumigatus, Trichophyton rubrum and Paracoccidioides brasiliensis. CONCLUSION: Our results showed that the proposed polyphasic approach appears to be a useful strategy in the detection of fungi from tissue samples, allowing a better prognosis. In further studies, the inclusion of a higher number of samples and the implementation of more genus specific PCRs will certainly contribute to an increase in the specificity and sensitivity of this method. PMID- 30480510 TI - Erythrobacter zhengii sp. nov., a bacterium isolated from deep-sea sediment. AB - A Gram-stain-negative, strictly aerobic, rod-shaped bacterium, designated V18T, was isolated from a deep-sea sediment sample collected from the Pacific Ocean and subjected to a polyphasic taxonomic investigation. Cells of strain V18T grew in medium containing 0-10.0 % (w/v) NaCl (optimum 1.0 %), at pH 5.5-9.0 (optimum 6.5 7.0) and at 10-40 degrees C (optimum 30-37 degrees C). Aesculin and Tweens 20, 40, 60 and 80 were hydrolysed. The isolate contained carotenoid-like pigments and lacked bacteriochlorophyll a. Strain V18T was closely related to members of the genus Erythrobacter, namely Erythrobacter odishensis JA747T (98.9 % 16S rRNA gene sequence similarity), E. westpacificensis JLT2008T (98.8 %), E. gangjinensis K7 2T (97.7 %), E. aquimixticola JSSK-14T (97.6 %), E. marinus KCTC 23554T (97.4 %), E. atlanticus s21-N3T (97.3 %), E. arachoides RC4-10-4T (97.2 %), E. citreus RE35F/1T (97.1 %) and E. luteus KA37T (97.0 %), and exhibited less than 97.0 % sequence similarity with the type strains of other species with validly published names. Phylogenetic analyses revealed that strain V18T clustered with E. odishensis JA747T and formed an independent lineage. The average nucleotide identity and in silico DNA-DNA hybridization values between strain V18T and the type strains of Erythrobacter species were 70.5-83.4 % and 18.4-26.1 %, respectively. Strain V18T contained ubiquinone 10 (Q-10) as the sole respiratory quinone. The major fatty acids (>10 %) were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c), summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and C16 : 0. The major polar lipids were sphingoglycolipid (SGL), diphosphatidylglycerol (DPG), phosphatidyglycerol (PG), phosphatidylethanolamine (PE) and one unidentified lipid (L1). The DNA G+C content was 62.6 mol%. According to the phenotypic, chemotaxonomic and phylogenetic data, strain V18T represents a novel species of the genus Erythrobacter, for which the name Erythrobacter zhengii is proposed. The type strain is V18T (=KCTC 62389T=MCCC 1K03475T). PMID- 30480511 TI - Notification that new names of prokaryotes, new combinations, and new taxonomic opinions have appeared in volume 68, part 11 of the IJSEM. PMID- 30480512 TI - Nanoparticle-Based Drug Delivery Systems for Enhanced Tumor-Targeting Treatment. AB - The encapsulation of targeting agents into nanoscale drug delivery systems (DDS) for cancer therapy has received considerable attention in recent years. The thriving area of cancer nanotechnology provides a unique and comprehensive anticancer approach through early diagnosis, prediction, prevention, and personalized medical therapy, preferentially vital in target-specific drug curative strategies. In this review, the concept of cancer nanotechnology and its areas of specialty are introduced, followed by a detailed presentation of specific targeting methods and various nanoparticle (NP) drug delivery systems. The technical bottleneck attached to the clinical translation and nanotoxicity issues is emphasized for future breakthroughs, that will boost drug efficacy to a higher level with the assistance of nanotechnology. PMID- 30480513 TI - Enhanced Endocytic and pH-Sensitive Poly(malic acid) Micelles for Antitumor Drug Delivery. AB - Poly(beta-benzyl malate) (PBM), a derivative of poly(beta-malic acid) (PMLA), is a potential antitumor drug carrier due to its desirable biocompatibility and nontoxicity. In this study, micelles based on PBM-PEG polymers were prepared, which possessed several key features, including (i) micelle formation via self assembly with a size of approximately 100 nm, (ii) pi-pi stacking interactions between the polymer chains and between the polymer and the drug, improving the stability of micelles and drug loading capacity (drug loading rate increased to 20 wt%), (iii) the cell penetrating peptide (TAT) was shielded by a long PEG chain before reaching the tumor site and exposed to tumor tissue, and (iv) high efficiency tumor uptake via exposure to TAT. At the site of a tumor, the extracellular pH level caused cleavage of the hydrazine bond, which led to the exposure of TAT on the polymeric micelles, thus enhancing cellular internalization. Then, the polymeric micelles disintegrated and DOX was released in response to the acidic pH in the lysosomal and endosomal compartments within the tumor cells. Both in vitro and in vivo efficacy studies indicated that this pH-sensitive PBM polymeric micelle is a promising antitumor drug carrier. PMID- 30480514 TI - Folate-Modified Liposomes Loaded with Telmisartan Enhance Anti-Atherosclerotic Potency for Advanced Atherosclerosis in ApoE-/- Mice. AB - For the effective inhibition of atherosclerotic plaque rupture, there is an urgent need to develop a carrier which can specifically deliver the therapeutic agents to atherosclerotic lesions. Since the representative hallmark of plaques in advanced atherosclerosis is the large number of macrophages which highly upregulate folate receptor beta (FR-beta), we herein investigated the potential of folate-modified liposomes (FA-P-LP) as the carrier for active targeting of atherosclerotic plaques. In vitro cellular uptake tests, FA-P-LP exhibited an enhanced uptake in activated RAW264.7 macrophages with high expression of FR beta, whereas this enhanced effect was dramatically diminished when the cells were pretreated with excess amount of free folate, indicating that FA-P-LP were mainly taken up by the receptor-mediated endocytosis. From the in vivo distribution assay, it was confirmly demonstrated that FA-P-LP significantly accumulated in atherosclerotic lesions and were co-localized with macrophages within plaques. Thereafter, we utilized the FA-P-LP to deliver an angiotensin receptor blocker (ARB), telmisartan (Tel), to macrophages in atherosclerotic plaques and evaluated their therapeutic effects on plaque destabilization. After 12 weeks treatment in ApoE-/- mice with established atherosclerosis, FA-P-LP/Tel exerted a marked improvement in key advanced plaque properties without affecting the plasma lipid level and blood pressure. These beneficial effects include the regression of atherosclerotic plaques possibly attributing to the enhanced cellular cholesterol efflux and reduced macrophage infiltration, an increase in the protective collagen layer overlying lesions resulting from suppression of collagenase activity and decrease in matrix 2/9 (MMP 2/9) expression, suppression of oxidative stress, and a reduction in plaque necrosis and calcification. Thus, administration of Tel in a targeted liposome could stabilize the advanced atherosclerotic lesions independent of lipid lowering and blood pressure decrease. In conclusion, FA-P-LP could effectively home to the atherosclerotic lesion through the active targeting mechanism after systemic administration, indicating their high potential as the carrier for atherosclerosis therapy. Together, the FA-P-LP/Tel would be considered as a promising nanotherapeutic approach to prevent plaque rupture, providing an alternative regimen for clinical treatment of advanced atherosclerosis. PMID- 30480515 TI - Naturally-Derived PHA-L Protein Nanoparticle as a Radioprotector Through Activation of Toll-Like Receptor 5. AB - High energy ray in medical diagnosis and therapy can benefit to patients, but can also cause the significant damages to biomolecules such as DNA, as well as free radical generation, inevitably leading to numerous side effects. Small molecular radioprotectors provide an effective route to preserve the healthy tissue and whole body from ionizing radiation, but always have a short circulation time in body. Inorganic nanoparticles show major protection effect but their heavy metal components considerably jeopardize translational promise due to suboptimal biocompatibility. Herein, we report a novel protein nanoparticle that can overcome limitations of both small molecular and inorganic nanoparticle radioprotectors and can be used as a radioprotector with spontaneous biocompatibility, outstanding pharmacokinetics and improvement on survival rate under exposure to gamma-ray irradiation. PHA-L protein nanoparticle serves to clear excessive reactive oxygen species in vivo, prevents radiation-induced hematopoietic and gastrointestinal damages and boosts the survival rate of irradiated mice to ~70%. A detailed study of the mechanism shows PHA-L protein nanoparticle can target and activate the toll-like receptor 5 in vitro and in vivo, and thus protect irradiated cells by immune response. Importantly, the PHA L protein nanoparticle can perform highly efficient clearance while eliciting negligible toxicological response. PMID- 30480516 TI - Electrospun Bilayer Composite Vascular Graft with an Inner Layer Modified by Polyethylene Glycol and Haparin to Regenerate the Blood Vessel. AB - In this study, we prepared a composite vascular graft with two layers. The inner layer, which was comprised of degradable Poly(lactic-co-glycolic acid) (PLGA)/Collagen (PC) nanofibers modified by mesoporous silica nanoparticles (MSN), was grafted with polyethylene glycol (PEG) and heparin to promote cell proliferation and to improve blood compatibility. The outer layer was comprised of polyurethane (PU) nanofibers in order to provide mechanical support. The growth and proliferation of human umbilical vein endothelial cells (HUVECs) in the inner layer was significant, and blood compatibility testing showed that the inner layer had good blood compatibility. The MSN-PEG-Heparin on the fiber surface was observed in vitro during the degradation of the inner layer. After 60 days, the weight of fiber membrane decreased by 92.4%. The inner layer did not cause an inflammatory reaction during the degradation process in vivo and there was uniform cellular growth on the PC/MSN-PEG-Heparin fiber membrane. Composite grafts implanted into the rabbit carotid artery were evaluated for 8 weeks by H&E and immunohistochemical staining, demonstrating that a monolayer of endothelium (CD31-labeled) and smooth muscle (alphaSMA-labeled) regenerated on the composite graft. Our results demonstrate that the composite graft, with a functional inner layer, has potential to be used for small-caliber blood vessels with long-term patency. PMID- 30480517 TI - A Synergistically Enhanced T1 and T2-Weighted Magnetic Resonance/Near-Infrared Contrast Agent of Gd-Doping Fe3O4@Fluorescence PEGylated Nanoparticles for Multimodality Imaging of Hepatocarcinoma. AB - In recent years, multimodal imaging nanoprobes with high resolution and high sensitivity capabilities have attracted considerable interest because they could offer complementary diagnostic information that would lead to a more precise diagnosis. Herein, the facile fabrication of Gd-doping magnetic nanoparticles conjugated with the PEGylated fluorescence probe Cy5.5 and the tumor-penetrating peptide RGERPPR (R) has been demonstrated for tri-modality targeted T1 and T2 weighted magnetic resonance (MR) and the near-infrared (NIR) fluorescence imaging of hepatocarcinoma-bearing mice. The obtained R-GdMFs nanoparticles with a rational design are water-dispersible, have long-term stability, and have controllable magnetic delivery and excellent biocompatibility with no impact on the cell and major organ functions, as was confirmed by MTT and LDH assay, ROS measurements and H&E staining. Relaxivity measurements show a better T1 relaxivity (r1) of 16.49 mM-1 s-1 and a T2 relaxivity (r2) of 141.98 mM-1 s-1 by mutual enhancement, which realized enhanced T1 and T2-weighted in vitro and in vivo MR imaging, which accumulated in the tumor region due to the mediation of the tumor-penetrating peptide. Meanwhile, the in vivo NIR fluorescence imaging results also revealed that the R-GdMFs could be significantly targeting the tumor tissue with bright NIR fluorescence imaging, which would lead to a more precise diagnosis. These findings indicated that as-synthesized R-GdMFs nanoparticles could be used as a platform for synergistically enhanced T1 and T2-weighted MR/NIR fluorescence multimodality imaging in various biomedical systems. PMID- 30480518 TI - Real-Time Imaging Tracking of a Dual Fluorescent Vaccine Delivery System Based on Ovalbumin Loaded Zinc Phthalocyanine-Incorporated Copolymer Nanoparticles. AB - The vaccine delivery process plays a significant role for antigen-specific immune responses, which directly determines the effect of immunotherapy. It is crucial to reveal the real-time process of the vaccine release and the status of the implanted carrier in vivo. Herein, a dual fluorescent vaccine delivery system was monitored with the rhodamine-ovalbumin loaded zinc phthalocyanine conjugated nanoparticles (PHA-OVA NPs) to explore the vaccine delivery process. The PHA-OVA NPs showed a sustained release of ovalbumin in vitro and could significantly enhance the uptake of antigen by dendritic cells (DCs). The PHA-OVA NPs could also upregulate the levels of costimulatory molecules on the surface of DCs, suggesting an enhanced ability of the antigen delivery system to promote antigen presentation to antigen-special T cells compared to soluble antigen. The fates of the ovalbumin and the PHA NPs were tracked simultaneously in vivo using the multispectral fluorescence imaging system and the results showed that the antigen was carried to the lymphoid organs by the delivery vehicle. The multispectral fluorescence imaging provided an innovative method to track the vaccine delivery process simultaneously. PMID- 30480519 TI - Co-Delivery of RUNX2-Targeting miRNAs and shRNAs Using Nanoparticles Composed of Dexamethasone and PEI Induces Chondrogenesis of Human Mesenchymal Stem Cells. AB - RNA interference (RNAi) plays important roles, and microRNAs (miRNAs) are used as biomarkers and targets in cell therapies. In this study, we fabricated miRNAs and short hairpin RNAs (shRNAs) targeting the osteogenic RUNX2 gene to induce chondrogenesis of human mesenchymal stem cells (hMSCs). pDNA harboring these miRNAs and shRNAs was complexed with nanoparticles composed of dexamethasone and tetramethlyrhodamine-labeled branched polyethyleneimine (RDtNPs). The miRNAs and shRNAs reduced RUNX2 expression in hMSCs at early (12 h) and late (72 h) time points, respectively. Co-delivery of miRNAs and shRNAs resulted in rapid and sustained RUNX2 silencing. Moreover, dexamethasone in the nanoparticles enhanced chondrogenic differentiation. Gene and protein expression of RUNX2 was lower in hMSCs transfected with RDtNPs complexed with pDNA harboring miRNAs plus shRNAs for 72 h than in control hMSCs. Moreover, delivery of these miRNAs and shRNAs increased gene and protein expression of chondrogenic SOX9. These changes in expression facilitated the chondrogenic differentiation of hMSCs, as demonstrated by analysis of markers related to mature chondrocytes. Furthermore, histological and immunohistological analyses detected specific extracellular matrix and cartilage-related proteins in cultures of hMSCs transfected with these miRNAs and shRNAs. PMID- 30480520 TI - Hyaluronic Acid-Functionalized Gadolinium Doped Iron Oxide Nanoparticles for Atherosclerosis-Targeted Mr Imaging. AB - Magnetic resonance imaging (MRI) contrast agents (CTs) with both positive (T1) and negative (T2) contrast abilities have attracted considerable interests due to their complementary diagnostic information for more precise diagnosis. In this study, gadolinium-doped oxide nanoparticles functionalized by hyaluronic acid (HA GdIO NPs) were synthesized for atherosclerosis-targeting T1-T2 dual-model MR imaging. The results showed that the HA-GdIO NPs exhibited high magnetic susceptibility and good biocompatibility. After being coated with HA, the HA-GdIO NPs specifically accumulated in the atherosclerosis plaques through targeting CD44-overpression macrophages which played a central role in development of atherosclerotic plaques. Furthermore, the HA-GdIO NPs can provide enhanced T1 and T2 dual phase contrast effects in vitro and in vivo, particularly in the vascular regions of mice. This work may provide a promising idea to construct MRI contrast agents with both effective and targeted contrast abilities for biomedical applications. PMID- 30480522 TI - Novel Carbon Dots-Derived from Radix Puerariae Carbonisata Significantly Improve the Solubility and Bioavailability of Baicalin. AB - Baicalin (BA) has gained considerable attention in recent years for its multiple pharmacological activities. However, its optimum pharmaceutical potential has been limited by its poor solubility in water. In this study, for the first time, we discovered that novel water-soluble carbon dots (CDs, named RPC-CDs) from aqueous extracts of Radix Puerariae Carbonisata (RPC). The chemical composition and morphological features of the RPC-CDs we obtained were characterized using various spectroscopies and transmission electron microscopy and the CDs have a low toxicity against RAW 264.7 cells by the CCK-8 assay. Most importantly, the RPC-CDs were able to greatly increase the solubility of baicalin in water, which could be related to the glucuronide structure of baicalin. Moreover, the result of indirect competitive enzyme-linked immunosorbent assays (icELISA) indicated that the area under the baicalin concentration-time curve value of baicalin-RPC CDs (BA-CDs) was 1.7-fold greater than those of a baicalin suspension liquid (BA control) after oral administration at a dose of 72 mg/kg. This study not only provides evidence to support further investigation of the considerable potential of carbon dots, but also offers support for the future clinical application of baicalin. PMID- 30480521 TI - Multiwalled Carbon Nanotubes Prevent Tumor Metastasis Through Switching M2 Polarized Macrophages to M1 via TLR4 Activation. AB - Targeting tumor-associated macrophages (TAMs) has emerged as a novel therapeutic strategy for cancer metastasis. Here, we investigated whether carboxylated multiwalled carbon nanotubes (MWCNTs-COOH) prevent tumor metastasis through regulating macrophage polarization. In Lewis lung carcinoma (LLC) or B16F10 melanoma-bearing mice, intratracheal instillation of MWCNTs-COOH significantly reduced metastatic burden in the lungs. MWCNTs-COOH promoted the expression of M1 markers (iNOS and CXCR10) and inhibited the expression of M2 markers (CD206 and Arg-1) along with an increased expression of Th1 cytokines (TNF-alpha and IL-12) and decreased expression of Th2 cytokines (TGF-beta and IL-10). Such changes were accompanied with TLR4 mRNA and protein elevation. Importantly, macrophage depletion in mice lungs reversed the anti-metastatic effects of MWCNTs-COOH. In vitro, MWCNTs-COOH switched IL-4/13-treated macrophages to the M1 phenotype and thus prevented the migration and invasion of LLC cells, accompanied by the upregulation of toll-like receptor (TLR)-4/NF-kappaB p65 signaling. Moreover, TAK 242 (resatorvid), a specific TLR4 inhibitor, reversed the effects of MWCNTs-COOH on macrophage polarization. In summary, MWCNTs-COOH effectively prevent tumor metastasis through skewing M2-polarized macrophages to M1 via activating TLR4/NF kappaB signaling. Thus, targeting TAMs by MWCNTs-COOH is a potential therapeutic approach against tumor metastasis. PMID- 30480523 TI - Modeling and Bias-Robust Estimation of the Acoustic Release of Chemotherapeutics from Liposomes. AB - This paper models the acoustic drug release of chemotherapeutics from liposomes using a kinetic model that accounts for systematic biases affecting the drug delivery process. An optimal stochastic filter is then proposed to provide robust estimates of the percent drug released. Optimality is guaranteed by accurately identifying the underlying statistical noise characteristics in experimental data. The estimator also quantifies the bias in the release, exhibited by the experimental data. Drug release is experimentally measured as a change in fluorescence upon the application of ultrasound. First, a first-order kinetic model is proposed to model the release, which is aided by a bias term to account for the fact that full release is not achieved under the conditions explored in this study. The noise structure affecting the process dynamics and the measurement process is then identified in terms of the statistical covariance of the measured quantities. The identified covariance magnitudes are then utilized to estimate the dynamics of drug release as well as the bias term. The identified a priori knowledge is used to implement an optimal Kalman filter, which was initially tested in a simulation environment. The experimental datasets are then fed into the filter to estimate the state and identify the bias. Experiments span a number of ultrasonic power densities for liposomes. The results suggest that the proposed algorithm, the optimal Kalman filter, performs well in modeling acoustically activated drug release from liposomes. PMID- 30480524 TI - Changing the Way of Entrance: Highly Efficient Transfer of mRNA and siRNA via Fusogenic Nano-Carriers. AB - Transferring nucleic acids into mammalian cells heavily influences life science for decades. While first applications mainly dealt with DNA transfer for various purposes as e.g., plasmid encoded protein expression or generation of mutant strains, subsequent applications additionally transferred RNA molecules of mainly small lengths for specific knockdown (RNAi) or site-specific genome modification (gRNA). Significant improvements in full length mRNA generation and extension of mRNA lifetimes additionally allows their use for transient expression in latest times. For all of these types of nucleic acids the most common cell incorporation method is based on complexation and subsequent endosomal uptake. This so-called lipofection can be used theoretically for almost any mammalian cell type and a tremendous number of different product compositions exist in order to deal with drawbacks as transfer efficiency, cell type selectivity, endosomal degradation, slow uptake and cytotoxicity. In contrast, new methods transfer complexed RNA molecules directly into the cytoplasm using liposomal nano-carriers that fuse with cellular plasma membranes immediately upon contact to free functional nucleic acids directly into the cytoplasm. Here, we compare both methods in detail with special focus on robustness, short- and long-term cytotoxicity, efficiency and functionality for various types of transferred RNA. Our data clearly indicate that direct RNA incorporation via fusogenic nano-carriers circumvents most endosomal uptake-based challenges, making it to a most promising alternative for nucleic acid transfer. PMID- 30480525 TI - Co-Delivery of Rose Bengal and Doxorubicin Nanoparticles for Combination Photodynamic and Chemo-Therapy. AB - Carboxymethyl chitosan (CMCS) is applied as a nanodelivery system carrier for sustained intracellular release of rose bengal (RB) and doxorubicin (DOX) to achieve combinational drug treatments. An integral analytical method was used to characterize the structure of CMCS-RB, the amount of RB and DOX, the average particle size, the zeta potential, and the morphology, including Fourier transform infrared (FTIR), nuclear magnetic resonance (1H NMR), ultraviolet visible spectroscopy (UV-Vis), scanning electron microscope (SEM), laser particle size analyzer and transmission electron microscopy (TEM). The results revealed that the maximum encapsulation efficiency and loading capacity of DOX into the CMCS-RB-DOX nanoparticles was 13.38% and 53.18%, respectively. The content of RB in the CMCS-RB prodrug was 11.25%. The release of RB and DOX under different conditions was investigated through dynamic dialysis. CCK-8 assay were used to study the inhibitory effect on normal cells and Cal-27 oral cancer cells. The cytotoxicity results of CMCS-RB-DOX nanoparticles showed excellent photosensitizer properties and strong efficacy of photodynamic therapy (PDT). PMID- 30480526 TI - Ciliary Mechanism of Regulating Hedgehog and Wnt/beta-Catenin Signaling Modulates Ultraviolet B Irradiation-Induced Photodamage in HaCaT Cells. AB - Skin undergoes photoaging, typically characterized by UV-damage lesions with matrix degradation and inflammatory changes. This process involves Hedgehog (Hh) signaling and the canonical Wnt pathway. Recently, primary cilia-microtubule based organelles-have been implicated in the transduction of Hh and Wnt signaling. However, their role in photoaging remained unclear. In this study, we have shown that UVB causes both upregulation of MMPs and proinflammatory cytokines, as well as cilia formation in HaCaT cells, and that these changes can be attenuated by ciliogenesis inhibitor HPI-4 and anti-inflammatory PD98059 treatment. These cellular processes involved downregulation of transcriptional activity of components of Hh signaling, Gli1 and Gli2, as well as the turnover of p-beta-catenin in canonical Wnt signaling, indicating the ciliary mechanism in photoaging. Our data demonstrate for the first time that pharmaceutical targeting of the primary cilia might have therapeutic benefits in the treatment of photoaging. PMID- 30480527 TI - A Novel Peptide Aptamer to Detect Plasmodium falciparum Lactate Dehydrogenase. AB - Alternative antibody (aptamer)-based biosensors are attracting increasing attention owing to advantages such as simplicity and low cost, which are beneficial for point-of-care diagnosis, particularly where resources are limited. In this study based on in silico modeling predictions made with Autodock Vina, the binding affinity of an optimized novel peptide (Pf_P1: KITTTDEEVEGIFD) was altered compared to that of the original epitope peptide (P1: KITDEEVEGIFDC). The binding energy of Pf_P1 implies that it has stronger interactions with Plasmodium falciparum lactate dehydrogenase (LDH) than with human LDH. Fluorescence-linked immunosorbent assay (FLISA) demonstrated significant interactions (P < 0.05) between the Pf_P1 peptide and P. falciparum LDH at 35.7 nmol. A peptide- and antibody-linked sandwich FLISA was able to detect at least 100 infected red blood cells (RBC)/MUL significantly (P < 0.001). The clinical diagnostic performance of peptide- and antibody-linked sandwich FLISA was evaluated using blood samples from patients infected by P. falciparum with parasitemia values of 151 to 128,636. All positive samples exhibited higher fluorescence than normal samples did. In conclusion, in silico modeling was used to efficiently design a Plasmodium LDH epitope-derived peptide aptamer to function as an alternative to antibodies in immunoassays. PMID- 30480528 TI - ERRATUM Mechanism of Nanotization-Mediated Improvement in the Efficacy of Caffeine Against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonism (Journal of Biomedical Nanotechnology, Vol. 11(12), pp. 2211-2222 (2015)). PMID- 30480529 TI - Changes in Peritoneal Transport and Peritoneal Damage in Japanese Patients Undergoing Peritoneal Dialysis Using Neutral-pH Dialysate: A Retrospective Cohort Study at Two Centers. AB - The effects of medium- or long-term use of neutral-pH dialysate on peritoneal transport and peritoneal damage have not been sufficiently researched.We retrospectively evaluated time-dependent changes in the dialysate-to-plasma ratio of creatinine (D/P Cr) and biomarkers of peritoneal damage in the effluent of 65 patients who underwent peritoneal dialysis (PD) with neutral-pH dialysate, including 48 who underwent medium-term PD (>=3 years) and 17 who underwent long term PD (>=5 years).Patients who underwent medium-term PD initially had a D/P Cr of 0.59 (range: 0.53 - 0.74), nonsignificantly changing to 0.65 (range: 0.55 - 0.73), 0.67 (range: 0.56 - 0.74), and 0.67 (range: 0.62 - 0.72) after 1, 2, and 3 years respectively (p = 0.30, p = 0.26, and p = 0.19). Patients who underwent long-term PD initially had a D/P Cr of 0.57 (range: 0.52 - 0.62), nonsignificantly changing to 0.61 (range: 0.52 - 0.69), 0.64 (range: 0.54 - 0.67), 0.62 (range: 0.57 - 0.66), 0.65 (range: 0.50 - 0.72), and 0.61 (range: 0.48 - 0.7) after 1, 2, 3, 4, and 5 years respectively (p = 0.49, p = 0.31, p = 0.24, p = 0.23, and p = 0.46). After 3 years, a significant increase in effluent hyaluronan (HA) from 90 ng/mL initially (range: 66 - 121 ng/mL) to 144 ng/ mL (range: 116 - 216 ng/mL) was observed (p = 0.04).No significant change in D/P Cr was observed in patients who underwent PD with neutral-pH dialysate. However, effluent HA, which is a biomarker for peritoneal damage, increased. In patients using neutral-pH dialysate, D/P Cr cannot be a biomarker for determining PD discontinuation within 5 years, but effluent HA might be useful. PMID- 30480530 TI - Maintaining Peritoneal Dialysis Adequacy: The Process of Incremental Prescription. AB - Urea kinetics (weekly Kt/V) greater than 1.7 generally define adequate peritoneal dialysis (PD). Adequacy of PD depends on residual renal function and PD clearance. Preserving residual renal function and peritoneal membrane characteristics helps to maintain PD adequacy.The dose of PD can be augmented by increasing the total dialysate volume. Greater volume can be achieved by increasing either the fill volume per exchange or the number of exchanges. Increased time on dialysis can be achieved by keeping PD fluid in the peritoneal cavity at all times. Increasing the convective force enhances solute removal with ultrafiltration.Incremental PD is used during urgent starts and in patients who are newly starting or who have been on PD. Urgent starts require use of frequent low-volume exchanges to avoid leaks at surgical sites. The dialysate volume can be gradually increased provided that no leakage occurs, up to approximately 2 L per exchange on day 14 for an average-size adult. New-start patients require only 1 - 2 exchanges daily if they still have residual renal function. Incremental PD retains patients on PD as residual renal function wanes and peritoneal membrane characteristics change because of dextrose exposure, infection, and inflammation.Use of a cycler permits patients to achieve adequacy by increasing the volume per cycle and the number of cycles per treatment. Using a non-dextrose based solution, such as icodextrin, allows patients to achieve adequate ultrafiltration with less dextrose exposure.Adequate dialysis can be achieved by manipulating the dialysate dwell volume and the frequency of exchanges, and by optimizing ultrafiltration. PMID- 30480531 TI - Comparison of Various Scaling Parameters and Energy Expenditure in Peritoneal Dialysis Patients. AB - Peritoneal dialysis (PD) dosing is determined by urea clearance scaled to total body water (TBW). However, studies delivering greater peritoneal Kt/V urea have failed to demonstrate improved survival. Body surface area (BSA) has been suggested as an alternative scaling factor. Cellular metabolism generates toxins, and thus total energy expenditure (TEE) might be a preferable scaling factor. Because TEE is cumbersome to determine, we set out to determine the association of anthropomorphic scaling factors with TEE.The TEE was determined using the Recent Physical Activity Questionnaire combined with resting energy expenditure by validated equations that use doubly labelled isotopic water and body composition by multi-frequency bioimpedance.In 148 adult PD patients [97 men (65.5%)], mean age was 60.6 +/- 20.6 years, and median PD treatment duration was 9.1 months (range: 3.5 - 25.2 months). Mean weight in the group was 73.6 +/- 16.7 kg, body mass index (BMI) was 26.0 +/- 4.9 kg/m2, and BSA was 1.86 +/- 0.24 m2. The mean TEE was 1974 +/- 414 kcal daily, and it correlated with BMI (men: r = 0.48, p < 0.001; women r = 0.36, p = 0.018), BSA (men: r = 0.56; women: r = 0.63; both p < 0.001), and TBW (men: r = 0.62; women: r = 0.65; both p < 0.001). Skeletal muscle mass correlated with BMI (men: r = 0.48; women: r = 0.50), BSA (men: r = 0.72; women: r = 0.63), and TBW (men: r = 0.98; women: r = 0.99), all p < 0.001.Comparing scaling factors, correlations with TEE were stronger for TBW and BSA than for BMI. Skeletal muscle mass was most strongly associated with TBW. Our study did not demonstrate any advantage for BSA compared with TBW as a scaling factor to adjust the dose of PD. PMID- 30480532 TI - Prevention of Peritoneal Dialysis Drop-Out. AB - Compared with hemodialysis (HD), peritoneal dialysis (PD) is associated with reduced cost and improved quality of life. But despite those benefits, PD represents a small percentage of the renal replacement therapy performed. Although a number of factors contribute to that situation, peritoneal drop-out is a complex issue that leads to as much as a 35% annual transition from PD to in center HD. The reasons for drop-out are multifaceted and include contributions from the patient or caregiver, health care regulatory systems, and factors intrinsic to the PD modality. In this review, we focus on specific causes of PD drop-out and on prevention and intervention strategies that can improve success and duration on PD. PMID- 30480533 TI - Accuracy of a Newly-Introduced Oscillometric Device for the Estimation of Arterial Stiffness Indices in Patients on Peritoneal Dialysis: A Preliminary Validation Study. AB - The aim of the present study was to compare the aortic systolic blood pressure (aSBP), heart-rate-adjusted augmentation index (AIx75), and pulse wave velocity (PWV) obtained using the Mobil-O-Graph (IEM, Stolberg, Germany) and SphygmoCor (AtCor, Sydney, Australia) devices in patients receiving peritoneal dialysis (PD).After a 10-minute rest in the supine position, the Mobil-O-Graph and SphygmoCor devices were applied in randomized order in 27 consecutive PD patients. The agreement between the measurements produced by the Mobil-O-Graph and SphygmoCor devices was explored using Bland-Altman analysis.The Mobil-O-Graph derived aSBP, AIx75, and PWV did not differ from the same measurements obtained with SphygmoCor (aSBP: 120.5 +/- 18.2 mmHg vs. 124.4 +/- 19.0 mmHg, p = 0.438; AIx75: 27.0% +/- 12.4% vs. 24.5% +/- 10.6%, p = 0.428; PWV: 9.5 +/- 2.1 m/s vs. 10.1 +/- 3.1 m/s, p = 0.397). The slight difference in the estimation of aSBP is possibly explained by the difference in brachial SBP used for the calibration of the devices (131.0 +/- 20.6 mmHg vs. 134.5 +/- 19.7 mmHg, p = 0.525). Mobil-O Graph-derived measurements correlated strongly with paired measurements obtained with the SphygmoCor device. Bland-Altman plots showed no evidence of asymmetry and a wide range of agreement between the two devices.Our study shows acceptable agreement between Mobil-O-Graph and SphygmoCor in the estimation of arterial stiffness indices in PD patients. Accordingly, the Mobil-O-Graph device accurately performs aortic ambulatory blood pressure monitoring in this population. PMID- 30480534 TI - Telehealth in Peritoneal Dialysis: Review of Patient Management. AB - Telehealth encompasses a broad variety of technologies and tactics to deliver virtual medical, health, and education services. Telemedicine is the use of electronic communications for the exchange of medical information from one site to another to improve a patient's clinical health status.Several studies show that, by providing better patient oversight and communication, telehealth in PD enhances patient care, outcomes, quality of care, and satisfaction. Associated benefits include increased patient retention to home dialysis, reduced use of hospital services, and reduced costs of care.The sustainability of telehealth had been limited by reimbursement and regulatory restrictions. The Centers for Medicare and Medicaid Services (CMS) limited services related to end-stage renal disease by providing reimbursement for telehealth only in rural areas or counties outside of a metropolitan statistical area. Moreover, the dialysis facility and the patient's home were not approved as originating sites. However, effective January 1, 2019, those restrictions will be lifted. Telehealth will require that home dialysis patients be established with 3 initial face-to-face monthly clinical assessments without the use of telehealth; after those initial 3 months, a face-to-face visit at least once every 3 consecutive months will be required. Claims can be submitted using designated Current Procedural Terminology codes and modifiers.The actual extension of telehealth to home dialysis patients will depend on the details of forthcoming CMS regulations. PMID- 30480535 TI - Experience Managing Adult Patients on Continuous Ambulatory Peritoneal Dialysis in Bangladesh. AB - Continuous ambulatory peritoneal dialysis (CAPD) is becoming increasingly known to the patients of Bangladesh, and patient numbers are increasing. Here, we report our experience and clinical outcomes in this field.Our analysis included all CAPD patients managed in a tertiary care hospital in Bangladesh between 2003 and 2015. All patients received a Tenckhoff double-cuff catheter by mini laparotomy, and twin bags were used in most patients. In acute cases, regular exchanges were started manually with small-volume dwells the same or the next day.During the study period, 500 patients (mean age: 62 +/- 18 years; 62% men; 86% percent with diabetes) were managed. Selection of CAPD was made by choice (47%) or for hemodynamic instability (32%), remote residence (17%), or poor vascular access (4%). Total duration of follow-up was 9364 patient-months (range: 1 - 78 months). The peritonitis rate was 1 episode in 30 patient-months. Fewer than 5% of patients required catheter removal. Similarly, the percentages of catheter tip migration and fluid leak were at the lower end. Patient survival was 68%, 48%, 38%, 22%, and 8% at 1, 2, 3, 5, and 7 years. Deaths were mostly attributable to vascular events.In a population with predominantly diabetic patients, CAPD was shown to be a viable mode of renal replacement therapy. The rates of peritonitis and catheter-related complications were low. Survival in the initial years can be considered acceptable. PMID- 30480536 TI - A Case in Which Renal Function and Peritoneal Function Were Maintained for Ten Years by Proactive Combination Therapy with Peritoneal Dialysis and Hemodialysis. AB - To avoid loss of residual renal function (RRF) and to enhance solute clearance, we sometimes, from the initiation of peritoneal dialysis (PD) therapy, combine PD with hemodialysis (HD) that removes little or no fluid. In one typical valuable case, a 51-year-old woman with diabetic nephropathy who selected combined PD and HD therapy as her first dialysis method has continued on that therapy for 10 years. Her dialysis schedule consists of 5 PD days and 1 HD day without fluid removal weekly. Because this combination therapy was proactively started at dialysis initiation, good fluid control could be kept with urinary excretion and PD ultrafiltration. Stable peritoneal equilibration test data indicate that peritoneal resting might be expected to be beneficial for the preservation of peritoneal function. This case demonstrates that proactive combination therapy can be extremely useful for preserving both RRF and peritoneal function, indicating a good prognosis. PMID- 30480537 TI - Neisseria mucosa Peritonitis in the Setting of a Migrated Intrauterine Device. AB - Peritonitis is a major complication in peritoneal dialysis (PD) patients, often requiring a switch to hemodialysis (HD). Common sources of bacterial peritonitis are touch contamination and PD catheter-related infection. Intra-abdominal pathology is a less common cause of peritonitis in PD patients, and rarely is Neisseria mucosa the causative organism.We present an uncommon case of N. mucosa peritonitis in a 30-year-old African American female patient treated with nocturnal intermittent PD. The infection occurred in the setting of a translocated intrauterine contraceptive device (IUCD) in the infrahepatic region because of transmural migration. Our patient underwent laparoscopic removal of the IUCD and received empiric intraperitoneal (IP) vancomycin and intravenous ceftriaxone. After the isolate was identified as N. mucosa, her regimen was changed to IP ceftriaxone for a total of 21 days. Cell count after completion of antibiotics showed resolution of the peritonitis. The PD catheter was salvaged and transition to HD was avoided. PMID- 30480538 TI - When Love Hurts, It Leaves No Options! An Unusual Case of Pasteurella Peritoneal Dialysis Peritonitis Causing Severe Intra-abdominal Adhesions Preventing a Future Peritoneal Dialysis Option. AB - A 67-year-old white man with a history of end-stage renal disease receiving peritoneal dialysis (PD) presented with acute onset of vomiting, chills, and abdominal pain. He was diagnosed with PD-associated peritonitis secondary to Pasteurella. After failure of 3 weeks of antibiotic treatment, catheter loss occurred. On follow-up, the patient was found to have extensive intra-abdominal adhesions precluding placement of a new PD catheter. PMID- 30480539 TI - Better Healing of the Exit Site with Negative-Pressure Wound Therapy. AB - Exit-site infection poses a risk for peritonitis and can shorten peritoneal dialysis (PD) vintage. A loose fit of the skin around the catheter at the exit site can push bacteria surrounding the catheter into the subcutaneous tunnel. Negative-pressure wound therapy (NPWT) has been used to hasten healing of the wound after an operation or to treat pressure ulcers. We hypothesized that NPWT could speed the healing of the exit site and tighten the fit of the skin around the catheter. Using a V.A.C. Therapy system [vacuum-assisted closure (KCI, San Antonio, TX, U.S.A.)], NPWT was therefore applied in 9 patients for 1 - 2 weeks after the PD catheter insertion operation. Results in those patients were compared with results in patients who did not receive NPWT.The healed exit site was classified as either tightly fitted (when the skin was tightly connected around the PD catheter) or loosely fitted (when the skin was not tightly connected around the catheter). The relevant data were retrieved from the medical record and analyzed retrospectively.Patients who received NPWT had a tight exit site after 1 - 2 weeks. Those who did not receive NPWT did not have a tight exit site after 1 - 2 weeks. No bleeding was observed in patients receiving NPWT. Bleeding from the exit site after the catheter insertion operation was observed in 3 patients not receiving NPWT.Because we use a fine trocar to make the subcutaneous catheter tunnel, bleeding from the vasculature can often be observed. That bleeding could be minimized with the application of NPWT. Negative pressure could also hasten wound healing and result in a tight fit of the skin around the catheter within in 1 - 2 weeks compared with the 1 month typically required with the use of conventional film dressings.Negative-pressure wound therapy is beneficial for creating a tight fit of the skin to the catheter within 1 - 2 weeks and might reduce the number of exit-site and tunnel infections, which could result in a reduction in the peritonitis rate. PMID- 30480540 TI - Is It Safe to Initiate Peritoneal Dialysis Treatment Immediately After Percutaneous Catheter Placement? AB - In this retrospective study, the safety of initiating peritoneal dialysis (PD) immediately after percutaneous PD catheter insertion was evaluated. Patients who underwent peritoneal catheter insertion and then immediately began dialysis treatment were included in the study. Patient age, sex, treatment modalities, and method of catheter insertion were recorded.Acute PD was performed in 33 patients (age: 57.7 +/- 16.7 years; 21 men, 12 women). Catheters were inserted percutaneously in 28 patients and surgically in 5 patients. The PD modalities used were continuous ambulatory PD in 18 patients, automated PD in 11 patients, and both modalities in 4 patients. Acute PD was started within 24 hours of catheter insertion. Leaks occurred in 8 patients who had catheters inserted percutaneously (28.5%). Peritonitis occurred in 1 patient. No complications were observed in 24 patients. Leaks were fully resolved for patients kept in a supine position, with fill volumes reduced to 500 mL - 700 mL and the dwell period decreased to 60 minutes from 120 minutes. Leaks were not observed in the patients when the fill volume was increased by 200 mL and the dwell period was increased by 30 minutes every 2 days to reach 1300 mL and 180 minutes by the 7th day.Immediate-start dialysis after percutaneous peritoneal catheter insertion seems safe when performed in a supine position with low-volume exchanges and short dwell times. PMID- 30480541 TI - A Rare Complication During Percutaneous Peritoneal Dialysis Catheter Insertion: Intravesical Placement. AB - Peritoneal dialysis (PD) is one of the treatment options for patients with end stage renal failure. To start PD treatment, a catheter must be placed for access to the abdominal cavity, and it can be placed using surgical, laparoscopic, or percutaneous methods. However, complications can develop during catheter placement.In the present case report, we describe a patient in whom treatment was pursued after an unusual complication rarely mentioned in the literature: a dialysis catheter accidentally inserted percutaneously into the bladder. Under ultrasonography guidance, the catheter was pulled from the urinary bladder and pushed into the intra-abdominal cavity. No complications resulted from the procedure, and the patient proceeded to PD treatment. This case is, to our knowledge, the only such report in the literature. PMID- 30480542 TI - Treatment of a Dialysate Leak by Simultaneous Catheter Removal and Replacement in a Patient Undergoing Continuous Ambulatory Peritoneal Dialysis. AB - Continuous ambulatory peritoneal dialysis (PD) is one of the treatment methods used for end-stage renal failure. When mechanical complications occur with this treatment method, methods such as tomographic peritoneography, abdominal scintigraphy, and magnetic resonance peritoneography are used to uncover the problem. Here, we report the detection by tomographic peritoneography of a subcutaneous dialysate leak in a patient undergoing PD. The PD catheter was subsequently removed, and a new catheter was inserted. The patient then restarted continuous ambulatory PD without any problem. PMID- 30480543 TI - Percutaneous screws CT guided to fix sacroiliac joint in tile C pelvic injury. Outcomes at 5 years of follow-up. AB - INTRODUCTION: The treatment of the sacroiliac joint (SIJ) vertical instability is a matter of current discussions and remains controversial. The aim of our study is the evaluation of the surgical management of SIJ vertical instability involving the use of cannulated screws introduced under CT guidance and local anesthesia. MATERIALS AND METHODS: In the set time frame of 7 years, 96 poly trauma patients with Tile's type C fracture of the pelvis with vertical instability of the SIJ were treated. The average distance between the two stumps was 73.4 mm (range: 43-100 mm). All patients were treated with anterior stabilization and subsequent stabilization with cannulated screws (Asnis(r) Stryker(r) 6 mm, an average length of 70 mm; range from 55 to 85 mm) of the sacroiliac fracture. The clinical and radiological follow-up was performed with follow-up plain radiograph and Majeed score (from 1 to 60 months after injury). RESULTS: The consolidation of pelvic fractures was obtained after an average of 63 days. The average Majeed score was as follows: 96 points at 1 month, 84 points at 3 months, 62 points at 6 months, 44 points at 12 months, 42 points at 24 months, 32 points at 36 months, 28 points at 48 months and 28 points at 60 months. Complications were as follows: not fatal deep vein thrombosis in five cases, skin infection at the entry point of the screws in six cases, screw breakage in one case and loosening of the screws in one case. Radiological evidence of fracture consolidation was achieved on average at 63 days. Forty seven patients managed to get back to their pre-trauma employment at the end of the convalescence period. CONCLUSIONS: Our results suggest that the stabilization of SI Tile type C fracture/dislocations with CT-guided percutaneous cannulated screws is a valid and feasible management option and associated with a low complication rate. PMID- 30480544 TI - Post-traumatic massive hand lymphedema fully cured by vascularized lymph node flap transfer. AB - Post-traumatic localized hand lymphedema is a rare situation and its diagnosis may be difficult, causing lack of care leading to failure of care. Our case study is of two young women with massive post-traumatic hand lymphedema who were treated for algodystrophy for 2 years, and whose bandages and physiotherapy were unsuccessful. Major social and psychological consequences due to difficulty with diagnosis and management resulting in inappropriate tests and therapeutic treatment were prescribed due to these issues. Noncontrast magnetic resonance lymphography revealed complete lymphatic vessel blockage in the hand and wrist. A vascularized lymph node flap harvested at the groin level was transferred to the elbow level 1 month after local dermolipectomy. These procedures resulted in the restoration of lymphatic flow. Both patients were definitely cured, and they returned to normal life within 6 months after surgery. Lymph node flap transfer associated with dermolipectomy may cure massive localized lymphedema in selected cases. PMID- 30480545 TI - Posterior versus direct anterior approach in total hip arthroplasty: difference in patient-reported outcomes measured with the Forgotten Joint Score-12. AB - INTRODUCTION: When the postoperative outcome of primary total hip arthroplasty (THA) was compared with the direct anterior approach (DAA) and the posterior approach (PA), there was no significant difference of the clinical outcome at 6 months to 1 year after surgery in many studies. This study was performed to compare the medium-term outcome of THA via the DAA or PA and clarify which approach achieves better quality of life (QOL). METHODS: We investigated 61 hips receiving primary THA (30 via DAA and 31 via PA), using hip function scores such as the Harris Hip Score (HHS) and patient-reported outcomes such as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Japanese Orthopaedic Association Hip Disease Evaluation Questionnaire (JHEQ), and the Forgotten Joint Score-12 (FJS). RESULTS: The mean duration of postoperative follow-up was 36.8 months in the DAA group and 40.5 months in the PA group. There was no difference in preoperative or postoperative HHS between the two groups. Although there was no difference of postoperative WOMAC and JHEQ, the postoperative FJS-12 score was significantly higher in the DAA group than in the PA group (75.2 +/- 15.9 versus 60.1 +/- 24.4, p = 0.01). CONCLUSION: When forgetting the artificial joint in daily life is the target, better QOL can be achieved by performing THA via the DAA. PMID- 30480546 TI - Piezo's membrane footprint and its contribution to mechanosensitivity. AB - Piezo1 is an ion channel that gates open when mechanical force is applied to a cell membrane, thus allowing cells to detect and respond to mechanical stimulation. Molecular structures of Piezo1 reveal a large ion channel with an unusually curved shape. This study analyzes how such a curved ion channel interacts energetically with the cell membrane. Through membrane mechanical calculations, we show that Piezo1 deforms the membrane shape outside the perimeter of the channel into a curved 'membrane footprint'. This membrane footprint amplifies the sensitivity of Piezo1 to changes in membrane tension, rendering it exquisitely responsive. We assert that the shape of the Piezo channel is an elegant example of molecular form evolved to optimize a specific function, in this case tension sensitivity. Furthermore, the predicted influence of the membrane footprint on Piezo gating is consistent with the demonstrated importance of membrane-cytoskeletal attachments to Piezo gating. PMID- 30480548 TI - Natural variation in sugar tolerance associates with changes in signaling and mitochondrial ribosome biogenesis. AB - How dietary selection impacts genome evolution to define the optimal range of nutrient intake is a poorly understood question with medical relevance. We have addressed this question by analyzing Drosophila simulans and sechellia, recently diverged species with differential diet choice. D. sechellia larvae, specialized to a nutrient scarce diet, did not survive on sugar rich conditions, while the generalist species D. simulans was sugar tolerant. Sugar tolerance in D. simulans was a tradeoff for performance on low energy diet and was associated with global reprogramming of metabolic gene expression. Hybridization and phenotype-based introgression revealed the genomic regions of D. simulans that were sufficient for sugar tolerance. These regions included genes that are involved in mitochondrial ribosome biogenesis and intracellular signaling, such as PPP1R15/Gadd34 and SERCA, which contributed to sugar tolerance. In conclusion, genomic variation affecting genes involved in global metabolic control defines the optimal range for dietary macronutrient composition. PMID- 30480547 TI - Variance adaptation in navigational decision making. AB - Sensory systems relay information about the world to the brain, which enacts behaviors through motor outputs. To maximize information transmission, sensory systems discard redundant information through adaptation to the mean and variance of the environment. The behavioral consequences of sensory adaptation to environmental variance have been largely unexplored. Here, we study how larval fruit flies adapt sensory-motor computations underlying navigation to changes in the variance of visual and olfactory inputs. We show that variance adaptation can be characterized by rescaling of the sensory input and that for both visual and olfactory inputs, the temporal dynamics of adaptation are consistent with optimal variance estimation. In multisensory contexts, larvae adapt independently to variance in each sense, and portions of the navigational pathway encoding mixed odor and light signals are also capable of variance adaptation. Our results suggest multiplication as a mechanism for odor-light integration. PMID- 30480549 TI - Single-dose radiotherapy disables tumor cell homologous recombination via ischemia/reperfusion injury. AB - Tumor cure with conventional fractionated radiotherapy is 65%, dependent on tumor cell-autonomous gradual buildup of DNA double strand break (DSB) misrepair. Here we report single dose radiotherapy (SDRT), a disruptive technique that ablates >90% of human cancers, operates a distinct dual-target mechanism, linking acid sphingomyelinase (ASMase)-mediated microvascular perfusion defects to DNA unrepair in tumor cells to confer tumor cell lethality. ASMase-mediated microcirculatory vasoconstriction post-SDRT conferred an ischemic stress response within parenchymal tumor cells, with reactive oxygen species triggering the evolutionarily conserved SUMO Stress Response, specifically depleting chromatin associated free SUMO3. Whereas SUMO3, but not SUMO2, was indispensible for homology-directed repair (HDR) of DSBs, HDR loss-of-function post-SDRT yielded DSB unrepair, chromosomal aberrations and tumor clonogen demise. Vasoconstriction blockade with the endothelin-1 inhibitor BQ-123, or ROS scavenging post-SDRT using peroxiredoxin-6 overexpression or the SOD-mimetic tempol, prevented chromatin SUMO3 depletion, HDR loss-of-function and SDRT tumor ablation. We also provide evidence of mouse to human translation of this biology in a randomized clinical trial, showing 24Gy SDRT, but not 3x9Gy fractionation, coupled early tumor ischemia/reperfusion to human cancer ablation. The SDRT biology provides opportunities for mechanism-based selective tumor radiosensitization via accessing SDRT/ASMase signaling, as current studies indicate this pathway is tractable to pharmacologic intervention. PMID- 30480550 TI - Select panicogenic drugs and stimuli induce consistent increases in tail skin flushes and decreases in core body temperature. AB - Panic attacks (PAs) are episodes of intense fear or discomfort that are accompanied by a variety of both psychological and somatic symptoms. Panic induction in preclinical models (e.g. rats) has largely been assayed through flight and avoidance behavioral tests and cardiorespiratory activity. Yet, the literature pertaining to PAs shows that thermal sensations (hot flushes/heat sensations and chills) are also a common symptom during PAs in humans. Considering that temperature alterations are objectively measurable in rodents, we hypothesized that select panicogenic drugs and stimuli induce consistent changes in thermoregulation related to hot flushes and chills. Specifically, we challenged male rats with intraperitoneal injections of the GABAergic inverse agonist FG-7142; the alpha2 adrenoceptor antagonist yohimbine; the serotonin agonist D-fenfluramine, and 20% CO2 (an interoceptive homeostatic challenge). We assayed core body temperature and tail skin temperature using implanted radiotelemetry probes and tail thermistors/thermal imaging camera, respectively, and found that all challenges elicited rapid, high-amplitude (~7-9 degrees C) increase in tail skin temperature and delayed decreases (~1-3 degrees C) in core body temperature. We propose that thermal sensations such as these may be an additional indicator of a panic response in rodents and humans, as these panicogenic compounds or stimuli are known to precipitate PAs in persons with panic disorder. PMID- 30480551 TI - Further pharmacological comparison of D-methamphetamine and L-methamphetamine in rats: abuse-related behavioral and physiological indices. AB - Previous preclinical research suggests that L-methamphetamine (L-MA) has potential therapeutic utility to treat psychostimulant abuse. This study examined potential abuse-related and adverse physiological effects of D-MA and L-MA alone and in combination in rats, as these effects had not been previously characterized. Potential abuse-related effects were examined in locomotor sensitization and conditioned place preference paradigms. Body temperature was monitored to assess the physiological effects of these drugs or drug combinations. In the locomotor study, D-MA induced locomotor sensitization to both D-MA and L-MA. L-MA induced locomotor sensitization only to D-MA. Responses to a combination of L-MA and D-MA were not differentially affected by L-MA or D MA conditioning. In the conditioned place preference study, D-MA and L-MA each induced significant place preference. L-MA did not attenuate D-MA-induced place preference. In the body temperature study, D-MA induced hyperthermia and L-MA induced hypothermia. In combination, L-MA did not affect D-MA-induced hyperthermia. These data suggest that L-MA alone produces less abuse-related and adverse physiological effects than D-MA, but modulates and is modulated by concurrent and subsequent D-MA exposure, which may enhance the abuse liability of both drugs. These findings should be considered when L-MA is proposed for replacement therapy. PMID- 30480552 TI - Evaluating the potential of kit-based 68Ga-ubiquicidin formulation in diagnosis of infection: a pilot study68Ga. AB - OBJECTIVE: The aim was to evaluate the diagnostic potential of Ga-ubiquicidin positron-emission tomography/computed tomography (PET/CT) in imaging patients with infection. MATERIALS AND METHODS: Ga-NOTA-ubiquicidin (Ga-UBI) was prepared by addition of freshly eluted Ga-chloride from Ge/Ga generator into the NOTA ubiquicidin vial and incubated at room for 15 min at 90 degrees C. After compounding of the radiopharmaceutical, quality control using instant thin-layer chromatography, culture and endotoxin estimation was performed. Patients with suspected infection associated with diabetic foot, cellulitis and fracture were selected for the pilot study investigation to evaluate the ability of the tracer Ga-UBI in localization at infection sites. The PET/CT findings were compared with other diagnosis like microbial culture reports and bone scintigraphy to evaluate true positives or negatives in the study. RESULTS: The current study demonstrated the potential of kit-based Ga-UBI in localization of infection sites in most of the patients proven positive for infection on culture tests and bone scintigraphy. The kit could offer radiolabeling yield more than 95% in 15 min incubation at 90 degrees C. Quality control rendered the kit as a clinical grade preparation with endotoxin content less than 10 EU/ml and sterility up to 14 days of culture incubation. Eight of 10 patients underwent culture test and showed positive results. Two patients had undergone three-phase bone scan as an indirect sign of active infection. Ga-UBI PET/CT showed tracer localization in four of eight culture-positive patients. Tracer localization was observed in one of two patients whose culture reports were not available. Ga-UBI failed to identify infection in four patients with culture-positive results. CONCLUSION: The present study concluded that Ga-UBI prepared using NOTA-UBI kit is a potential agent in targeting infections associated with disease conditions including diabetic foot, cellulitis and fracture. The patient selection holds significance in accurate diagnosis using Ga-UBI PET/CT. PMID- 30480553 TI - Negligible Risk of Acute Renal Failure Among Hospitalized Patients After Contrast Enhanced Imaging With Iodinated Versus Gadolinium-Based Agents. AB - INTRODUCTION: The potential adverse renal outcome among patients undergoing iodine-based contrast-enhanced computerized tomography (CT) has been questioned recently, given the caution undertaken in patients' selection, hydration protocols, and the low radiocontrast volume, used with advanced imaging equipment. MATERIALS AND METHODS: This study is a retrospective assessment of renal outcome in 12,580 hospitalized patients undergoing contrast-enhanced CT, compared with 754 patients subjected to gadolinium-based magnetic resonance imaging, with subsequent propensity matching for clinical characteristics and potential risk factors. RESULTS: The risk of postcontrast acute kidney injury (PC AKI) was found to be negligible as compared with patients undergoing enhanced magnetic resonance imaging studies, before and after propensity matching (8% vs 7.3% rate of AKI in the nonmatched iodine-based contrast agents [IBCAs] and gadolinium-based contrast agents [GBCAs], respectively, P = 0.3, and 7% in the matched IBCA group, P = 0.9), including comparisons among subgroups with well defined risk factors such as chronic renal failure, diabetes, older age, and hypertension. However, lower systolic blood pressure before imaging was associated with higher risk to develop PC-AKI after IBCA administration but not with GBCA (for systolic blood pressure lower than 110 mm Hg, odds ratio for AKI after IBCA was 1.49; 95% confidence interval, 1.16-1.88, and after GBCA; odds ratio, 0.12; 95% confidence interval, 0.003-0.73). CONCLUSIONS: With the current precautions undertaken, the real-life risk of PC-AKI among inpatients undergoing CT is insignificant. Possible reasons for the diverse impact of blood pressure on the propensity to develop acute kidney failure after iodine-based but not gadolinium-based enhancement imaging are discussed. PMID- 30480554 TI - Glymphatic Pathway of Gadolinium-Based Contrast Agents Through the Brain: Overlooked and Misinterpreted. AB - BACKGROUND: The "glymphatic system" (GS), a brain-wide network of cerebrospinal fluid microcirculation, supplies a pathway through and out of the central nervous system (CNS); malfunction of the system is implicated in a variety of neurological disorders. In this exploratory study, we analyzed the potential of a new imaging approach that we coined delayed T2-weighted gadolinium-enhanced imaging to visualize the GS in vivo. METHODS: Heavily T2-weighted fluid attenuated inversion recovery (hT2w-FLAIR) magnetic resonance imaging was obtained before, and 3 hours and 24 hours after intravenous gadolinium-based contrast agent (GBCA) application in 33 neurologically healthy patients and 7 patients with an impaired blood-brain barrier (BBB) due to cerebral metastases. Signal intensity (SI) was determined in various cerebral fluid spaces, and white matter hyperintensities were quantified by applying the Fazekas scoring system. FINDINGS: Delayed hT2w-FLAIR showed GBCA entry into the CNS via the choroid plexus and the ciliary body, with GBCA drainage along perineural sheaths of cranial nerves and along perivascular spaces of penetrating cortical arteries. In all patients and all sites, a significant SI increase was found for the 3 hours and 24 hours time points compared with baseline. Although no significant difference in SI was found between neurologically healthy patients and patients with an impaired BBB, a significant positive correlation between Fazekas scoring system and SI increase in the perivascular spaces 3 hours post injection was shown. INTERPRETATION: Delayed T2-weighted gadolinium-enhanced imaging can visualize the GBCA pathway into and through the GS. Presence of GBCAs within the GS might be regarded as part of the natural excretion process and should not be mixed up with gadolinium deposition. Rather, the correlation found between deep white matter hyperintensities, an imaging sign of vascular dementia, and GS functioning demonstrated feasibility to exploit the pathway of GBCAs through the GS for diagnostic purposes. PMID- 30480555 TI - Celiac ganglia: can they be misinterpreted on multimodal 68Ga-PSMA-11 PET/MR? AB - OBJECTIVE: The objective of this study was to investigate the morphologic features and Ga-prostate-specific membrane antigen (PSMA)-11 avidity of celiac ganglia (CG) on multimodal PET/MRI. MATERIALS AND METHODS: Ga-PSMA-11 whole-body PET/MR examinations in 120 patients, referred for staging or follow-up of prostate cancer, were retrospectively reviewed to investigate the radiotracer uptake [maximum standardized uptake value (SUVmax)] and morphologic features (size, shape, location) of CG. Nodular, oval and longitudinal nodular, thick or with oval parts shapes of CG were regarded as mistakable with lymph nodes, whereas linear and longitudinal shapes were considered as not mistakable. RESULTS: On MR scans, CG were visible in 98% (117/120) on both sides and in two patients only on the left side. Mistakable CG shape was detected in 69% (83/120) of patients on both or at least one side. The left CG were thicker (4+/-1.4 mm; range: 1.5-7.5 mm) than the right ones (3+/-1.3 mm; range: 0.5-7 mm). Mean SUVmax was 2.51+/-1.17 (range: 0.02-5.48) in the left CG and 2.23+/-1.22 (range: 0.02 5.91) in the right CG. Increased Ga-PSMA-11 uptake, SUVmax at least 2, was detected in 75% (90/120), and both - erroneous shape and elevated Ga-PSMA-ligand uptake - was observed in 55% (66/120) of all patients on both sides or at least one side. CONCLUSION: Frequently observed, the nodular, oval and longitudinal (nodular, thick or with oval parts) shape of CG, especially of the thicker left CG, on MR scans may cause mistaking them for lymph nodes, even abnormal or metastatic. On whole-body PET/MRI, evident and sometimes high Ga-PSMA-11 uptake in CG increases the risk of a misinterpretation of them as metastases.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/. PMID- 30480556 TI - Advances in neuroblastoma therapy. AB - PURPOSE OF REVIEW: Our understanding of the biologic basis of neuroblastoma, the genetic heterogeneity of this malignancy and the role of host factors has expanded significantly in recent years. In this review, we highlight current and future risk-based treatment approaches and discuss the opportunities and challenges of selecting optimal therapies for specific patient subsets. RECENT FINDINGS: Significant progress has been made in understanding neuroblastoma predisposition and new approaches have been taken to treatment of this disease. Although survival remains poor for patients with high-risk neuroblastoma, current era therapy has improved outcomes. Integration of new prognostic markers into neuroblastoma classification systems will allow more precise risk classification and refined treatment assignment. Promising treatments that include targeted therapies as well as immunotherapeutics are being evaluated in clinical trials, and new predictive biomarkers are being developed. SUMMARY: As our understanding of neuroblastoma biology deepens, our approaches to therapy for this disease continue to evolve. Improved risk stratification and the use of predictive biomarkers will aid in treatment selection for patients with neuroblastoma, and it is expected that future treatments will be associated with greater efficacy and less toxicity. PMID- 30480557 TI - Influenza: annual seasonal severity. AB - PURPOSE OF REVIEW: Influenza remains a major cause of morbidity and mortality. The 2017-2018 season was one of the most severe in the past decade. The exact factors determining the severity of a particular influenza season are complex and often poorly understood. RECENT FINDINGS: Factors impacting annual influenza severity include characteristics of the specific virus, influenza vaccination, and antiviral use. Although viral virulence factors are important in this context and our knowledge of these is growing, there is a complex interplay between expression of these factors and their impact on a particular patient population. Vaccination has demonstrated efficacy in preventing disease, but vaccination rates remain sub-optimal and vaccine effectiveness can vary significantly between influenza strains and patient populations. Finally, while antiviral treatment is available and has shown benefits, many patients with influenza do not receive treatment. SUMMARY: Strides have been made in recent years towards understanding the many factors that contribute to the severity of any particular influenza season. Obvious areas for improvement include improved vaccination rates and antiviral use. Additionally, a more complete understanding of reasons for poor strain and population-specific vaccine effectiveness may help reduce the severity of future influenza seasons. PMID- 30480558 TI - Pattern Recognition Receptor-reactivity Screening of Liver Transplant Patients: Potential for Personalized and Precise Organ Matching to Reduce Risks of Ischemia reperfusion Injury. AB - OBJECTIVE AND BACKGROUND: Pattern recognition receptors (PRRs) on immune and parenchymal cells can detect danger-associated molecular patterns (DAMPs) released from cells damaged during ischemia-reperfusion injury (IRI), in heart attack or stroke settings, but also as an unavoidable consequence of solid organ transplantation. Despite IRI being a significant clinical problem across all solid organ transplants, there are limited therapeutics and patient-specific diagnostics currently available. METHODS: We screened portal blood samples obtained from 67 human liver transplant recipients both pre- [portal vein (PV) sample] and post-(liver flush; LF) reperfusion for their ability to activate a panel of PRRs, and analyzed this reactivity in relation to biopsy-proven IRI. RESULTS: PV samples from IRI+ orthotopic liver transplantation (OLT) patients (n = 35) decreased activation of hTLR4- and hTLR9-transfected cells, whereas PV from IRI- patients (n = 32) primarily increased hTLR7 and hNOD2 activation. LF samples from OLT-IRI patients significantly increased activation of hTLR4 and hTLR9 over IRI- LF. In addition, the change from baseline reactivity to hTLR4/9/NOD2 was significantly higher in IRI+ than IRI- OLT patients. CONCLUSIONS: These results demonstrate that TLR4/7/9 and NOD2 are involved in either promoting or attenuating hepatic IRI, and suggest a diagnostic screening of portal blood for reactivity to these PRRs might prove useful for prediction and/or therapeutic intervention in OLT patients before transplantation. PMID- 30480559 TI - Impact of the Primary Tumor Location on the Prognosis for Colon Cancer: Adjustment for Bias Could Lead to Other Conclusions. PMID- 30480560 TI - Microsatellite Instability as a Predictive Biomarker for Adjuvant Chemotherapy in Gastric Cancer: Are we There Yet? PMID- 30480561 TI - Editorial: Leadership in American Surgery: Women are Rising to the Top. PMID- 30480562 TI - To Treat, or Not to Treat, That is the Question: Biomarker-guided Adjuvant Chemotherapy for Stage II and III Gastric Cancer. PMID- 30480563 TI - Quality Measures in Surgical Palliative Care: Adapting Existing Palliative Care Measures to Improve Care for Seriously Ill Surgical Patients. PMID- 30480564 TI - When Things Go Wrong: The Surgeon as Second Victim. PMID- 30480565 TI - Regarding Manuscript "Impact of Centralized Management of Bariatric Surgery Complications on 90-day Mortality". PMID- 30480566 TI - Pancreatic Hormone Responses to Mixed Meal Test in New-onset Prediabetes/Diabetes After Non-necrotizing Acute Pancreatitis. AB - AIM: To investigate the pancreatic hormone responses to mixed meal test, in particular changes in insulin secretion, insulin sensitivity, and their interrelationship, in individuals with new-onset prediabetes or diabetes after non-necrotizing acute pancreatitis (NODAP) compared with healthy controls. METHODS: Twenty-nine individuals with NODAP and 29 age-and sex-matched healthy controls were recruited. All participants (after fasting for at least 8 h) were given 12 oz. of BOOST drink and blood samples were collected before and after stimulation to measure insulin, C-peptide, glucagon, and pancreatic polypeptide. Indices of insulin sensitivity (HOMA-IS, 1/fasting insulin, Raynaud, and Matsuda) and insulin secretion (HOMA-beta, Stumvoll, insulinogenic index 30' and 60') were calculated. Repeated measures analyses were conducted in the unadjusted and adjusted models. RESULTS: Insulin and C-peptide levels were significantly higher in individuals with NODAP compared with controls during mixed meal test in both the unadjusted (P=0.001 for both) and adjusted (P=0.004 and P=0.006, respectively) models. HOMA-IS (P=0.005), 1/fasting insulin (P=0.018), Raynaud index (P=0.018), and Matsuda index (P=0.021) were significantly lower in individuals with NODAP, whereas HOMA-beta (P=0.028) and Stumvoll index (P=0.013) were significantly higher. Glucagon and pancreatic polypeptide levels did not differ significantly between NODAP and controls during mixed meal test in both the unadjusted (P=0.345 and P=0.206, respectively) and adjusted (P=0.359 and P=0.158, respectively) models. CONCLUSIONS: Decreased insulin sensitivity, beta cell compensation, and no significant change in postprandial levels of glucagon and pancreatic polypeptide characterize NODAP. The above findings may help develop an evidence-based protocol with a view to optimize control of glucose homeostasis in NODAP. PMID- 30480567 TI - Gastroesophageal Reflux Treatment With Proton Pump Inhibitors in Patients With Hypertension. PMID- 30480568 TI - Drug nonadherence is a common but often overlooked cause of hypertensive urgency and emergency at the emergency department. AB - OBJECTIVES: Over 70% of patients who visit the emergency department with a hypertensive emergency or a hypertensive urgency have previously been diagnosed with hypertension. Drug nonadherence is assumed to play an important role in development of hypertensive urgency and hypertensive emergency, but exact numbers are lacking. We aimed to retrospectively compare characteristics of patients with hypertensive urgency and hypertensive emergency and to prospectively quantify the attribution of drug nonadherence. METHODS: We retrospectively analysed clinical data including information on nonadherence obtained by treating physicians of patients with SBP at least 180 mmHg and DBP at least 110 mmHg visiting the emergency department between 2012 and 2015. We prospectively studied drug adherence among patients admitted to the emergency department with severely elevated BP by measuring plasma drug levels using liquid chromatography tandem mass spectrometry from September 2016 to March 2017. RESULTS: Of the 1163 patients retrospectively analysed, 257 (22.0%) met the criteria for hypertensive urgency and 356 (30.6%) for hypertensive emergency. Mean SBP (SD) was 203 (19) mmHg and mean DBP 121 (12) mmHg. Mean age was 60.1 (14.6) years; 55.1% were men. In 6.3% of patients with hypertensive urgency or hypertensive emergency, nonadherence was recorded as an attributing factor. Of the 59 patients prospectively analysed, 18 (30.5%) were nonadherent for at least one of the prescribed antihypertensive drugs. CONCLUSION: Hypertensive urgency and hypertensive emergency are common health problems resulting in frequent emergency department admissions. Workup of patients with a hypertensive urgency or hypertensive emergency should include an assessment of drug adherence to optimize treatment strategy. PMID- 30480569 TI - Introduction by the Guest Editor: Ronald Barr. PMID- 30480570 TI - Cancer Burden in Adolescents and Young Adults: A Review of Epidemiological Evidence. AB - Cancer burden in adolescents and young adults (AYAs) is expressed through a large proportion of the quality of life lost on individual level and also causes losses to the society in terms of a decreased productivity and social structure. A specific cancer spectrum and distinctive needs of AYA patients require targeted studies and cancer control measures. Incidence is intermediate between that for children and for older adults, and two-thirds of the AYA cancers affect women. Cancers of the breast and cervix uteri, representing a large portion of the burden, are amenable to prevention. Survival is relatively high, but it is lower in AYA patients with certain cancers that are common in childhood or older adulthood. Tailored cancer care with centralized multidisciplinary provision improves the outcome, as demonstrated by survival of leukemia patients. Mortality is decreasing in high-income countries for the cancers that contribute to the burden most, but lack of progress is seen for some rarer subtypes, such as brain tumors and sarcomas of the bone and soft tissue. There is unacceptable lack of information on cancer burden in low-income countries in which the outcomes for AYA patients are likely dreadful. Investment is required to establish cancer registration system and appropriate cancer care delivery in these settings. PMID- 30480571 TI - Adolescent and Young Adult Cancer Biology. AB - Adolescent and young adult (AYA) patients with cancer have not attained the same improvements in overall survival as either younger children or older adults. One possible reason for this disparity may be that the AYA cancers exhibit unique biologic characteristics, resulting in differences in clinical and treatment resistance behaviors. Our current understanding of the unique biological/genomic characteristics of AYA cancers is limited. However, there has been some progress that has provided clues about the biology of AYA cancers. We here review the latest findings in the area of AYA cancer biology and discuss what is required to advance the field for the more effective treatment of this patient population. PMID- 30480572 TI - Modifiable Risk Factors for the Development of Breast Cancer in Young Women. AB - INTRODUCTION: Breast cancer is the most common malignancy among adolescents and young adults (AYAs) women aged 15 to 39 years at diagnosis. An improved understanding of modifiable factors that mitigate the risks of the development of breast cancer may allow for future strategies to reduce the incidence of AYA breast cancer. METHOD: A literature review was conducted to report upon associations between modifiable lifestyle factors and breast cancer risk. RESULTS: Higher levels of physical activity, lower red meat intake, and higher intake of plants appear to decrease the risk of developing AYA breast cancer, whereas associations between obesity and AYA breast cancer risk were less straightforward. CONCLUSIONS: Further research, ideally in large prospective trials, is needed to truly understand modifiable risk factors for the development of AYA breast cancer. PMID- 30480573 TI - Lymphoma in Adolescents and Young Adults: Current Perspectives. AB - Lymphomas in adolescents and young adults represent approximately one quarter of all cancers in this age group. Historically, adolescent and young adult cancer patients represent a unique population with diverging issues surrounding psychosocial hardships/barriers, economics, and lack of standardization of therapeutic approaches.Furthermore, the biologic differences within the adolescent and young adult population seen in various lymphoma subtypes likely play a role in overall outcomes for this group. Without an organized approach to clinical and translational research for adolescent and young adult patients within specialized treatment centers, this population may continue to experience inferior results. Here we look at the current perspectives of adolescent and young adult lymphomas with respect to disease biology, clinical characteristics, treatment, and prognosis of this unique lymphoma population. PMID- 30480575 TI - Dynamics and Challenges of Clinical Trials in Adolescents and Young Adults With Cancer. AB - Inclusion in cancer clinical trials is considered the optimal standard of care, offering improved patient experience and progressive survival gains for subsequent generations of patients. Adolescent and young adult (AYA) patients are underrepresented in cancer research; consequently, improvements in outcomes for AYAs lag behind their pediatric and adult counterparts. Despite international evidence of underrepresentation in research, systematically tested interventions to improve recruitment for AYAs do not exist, and recruitment rates for AYAs continue to be lower than those for children. We review recruitment of AYAs into trials and discuss barriers and facilitators. PMID- 30480574 TI - Challenges of Clinical Management of Adolescent and Young Adults With Bone and Soft Tissue Sarcoma. AB - Clinical management of adolescents and young adults with bone and soft tissue sarcomas is quite challenging, mainly because of different chemotherapy approaches adopted by pediatric and adult oncologists and tumor-associated factors related to this peculiar age group. Overcoming these barriers is essential for adolescent and young adult patients, whose survival and long-term physical effects are worse than their pediatric counterparts. Nowadays, constant efforts from international collaborations between pediatric and adult oncologists of sarcoma groups have optioned in converging toward a common therapeutic strategy, while improving quality of treatment, as well as research advances dedicated to this at-risk age group of patients with sarcomas. PMID- 30480576 TI - Models of Care-There Is More Than One Way to Deliver. AB - Adolescents and young adults (AYAs) with cancer constitute a particular group of patients with unique features, whose needs during and after treatment are poorly met. A standardized model of care for them has yet to be established, as neither the pediatric nor the adult oncology systems seamlessly fit their needs. Regardless of the setting in which they are treated, their health care providers should be aware of the impact that the disease and its treatments have on these especially vulnerable patients. Simple ways of improving the AYA experience should be considered: reducing isolation through connections with peers, adapting the staff's approach to the emotional and developmental needs of this age group, and modifying the hospital environment making it more age appropriate. Commitment of national governments is valuable; building and sharing international experience will accelerate advances in clinical care, education, and research. Further progress in the care of AYA cancer patients is still needed to improve their outcomes. PMID- 30480577 TI - Psychosocial Support in Adolescents and Young Adults With Cancer. AB - Various forms of psychosocial support have been suggested in working with adolescents and young adults (AYAs) as they attempt to cope with cancer, including peer-based interventions, individual psychoeducational counseling, and skill-based interventions. More recently, modern electronic applications created technology-based ways to deliver information and support and have grown in popularity to satisfy AYA needs for information and support. Such support should be offered routinely rather than in a response to a crisis. This article focuses on psychosocial interventions for AYAs aged 15 to 39 years with cancer at diagnosis, during treatment, and shortly after. PMID- 30480580 TI - Dietary fat and risk of type 2 diabetes. AB - PURPOSE OF REVIEW: Nutrition recommendations emphasize that not only dietary fat quantity but also fat quality plays a role in the prevention of type 2 diabetes (T2D). The aim of this review is to summarize the evidence for dietary fat and risk of T2D, to highlight recent findings and point out future research directions. RECENT FINDINGS: Total fat intake was not associated with risk of T2D, whereas the findings on fatty acids (FAs) and risk of T2D were controversial. Recent findings suggested that FAs from the same classes (e.g. omega-6 FAs) but different sources might be differently associated with the risk of T2D, with indication for an association with lower risk of T2D for plant-based and higher risk/no association for animal-based FAs. In addition, differences between populations from different geographic areas might exist, but no interaction effects for fat intake and genetic predisposition were observed regarding T2D risk. The simultaneous investigation of different fats and dietary patterns can provide important and meaningful insights into these associations. SUMMARY: The evidence for the association between dietary fat intake and risk of T2D is not conclusive yet. To strengthen the evidence, the complexity of the different associations of dietary fats should be considered in well conducted future studies. PMID- 30480579 TI - Palliative Care in Adolescents and Young Adults With Cancer-Why Do Adolescents Need Special Attention? AB - Meeting shortfalls in the provision of care to adolescents and young adults with cancer has focused largely on improving outcomes and psychosocial support. A significant percentage of adolescents and young adults with cancer will die of disease because of initial poor prognosis conditions or disease relapse. In adults, progress has been made in the concept of an integrated cancer/palliative care service. In pediatric oncology, the application of this philosophy of care has lagged behind somewhat. In the case of adolescents, particularly those with advanced cancer, the palliative care needs, in a broader sense than only end-of life care, are often not adequately met, irrespective of whether treatment is delivered in a pediatric or adult cancer service. There are a number of age specific aspects to palliative and supportive care for adolescents. Complex interactions between clinicians, parents, and patients potentially limit the young person's ability to influence care planning. The wide variation in real or perceived competency at this age, the developmental challenges in relation to behavior, communication, and coping strategy all require particular professional expertise that is not always available. PMID- 30480581 TI - Effects of exercise on HDL functionality. AB - PURPOSE OF REVIEW: Low HDL-cholesterol (HDL-C) levels are a strong predictor of cardiovascular disease risk and can be improved with regular exercise. However, raising HDL-C levels pharmacologically has not shown convincing clinical benefits. Thus, research has recently focused on identifying therapies that improve HDL function, with exercise representing such a potential therapy. The purpose of this review is to summarize the effects of exercise interventions on HDL function. RECENT FINDINGS: The effects of exercise and lifestyle interventions on the primary atheroprotective functions of HDL are reviewed, namely, cholesterol efflux, antioxidative, and anti-inflammatory properties. Differences in study design, study population, and assays are discussed to aid in the interpretation of the reviewed studies. SUMMARY: There is mixed evidence that regular aerobic exercise improves cholesterol efflux capacity, with recent research suggesting an exercise dose threshold needs to be exceeded to produce beneficial effects. There is preliminary evidence that exercise improves the antioxidative and anti-inflammatory properties of HDL. Although exercise represents a potential therapeutic approach to improve HDL function, the heterogeneity and/or lack of findings warrants more and larger studies to determine what HDL function(s) are most responsive to regular exercise and what dose of exercise elicits the greatest improvements in HDL functionality. PMID- 30480582 TI - Is pericardial effusion a negative prognostic marker? Meta-analysis of outcomes of pericardial effusion. AB - BACKGROUND: The prognostic relevance and the prevalence of pericardial effusion in several diseases are not well established. The aim of this meta-analysis is to summarize the available evidence related to pericardial effusion prevalence and outcomes according to the cause. METHODS: Articles investigating the prognosis of pericardial effusion were identified by literature search. Twenty-three studies were finally included (17 022 patients). All-cause mortality was the primary end point. Secondary end-point was the prevalence of pericardial effusion in most common diseases related to this clinical condition. RESULTS: The pooled prevalence of pericardial effusion was 19.5% [95% confidence interval (CI): 14.3 26]. After a mean follow-up of 36 +/- 23 months, the risk of death was higher in pericardial effusion patients [hazard ratio (HR) 1.59, 95% CI 1.37-1.85, P < 0.0001]. Stratifying for the main disease, pericardial effusion is associated with unfavourable outcome in all available subgroups: pulmonary arterial hypertension HR 1.53 (95% CI: 1.22-1.92; P < 0.0001), chronic heart failure (CHF) HR 1.53 (95% CI: 1.22-1.92; P < 0.0001), myocardial infarction HR 2.65 (95% CI: 1.4-4.99; P = 0.003) and malignancies HR 1.75 (95% CI: 1.09-2.81, P = 0.021). The lack of data concerning the idiopathic pericardial effusion does not permit a secure risk assessment but the average incidence of mortality is 14.5% (95% CI: 7.7-25.6). CONCLUSION: Pericardial effusion should be considered a marker of the severity of the underlying disease, whereas for idiopathic pericardial effusion the correlation with poor prognosis is less clear. PMID- 30480583 TI - Strategies for access to affordable hepatitis C testing and treatment in Asia. AB - PURPOSE OF REVIEW: With increasing availability of generic direct-acting antivirals (DAAs) and associated price reductions, various governments, multilateral institutions, and donors have started providing testing and treatment for hepatitis C virus (HCV) infection. More data on the quality of these generic medicines and on cost-effectiveness of their use are becoming widely available. This review seeks to describe some of the treatment programs for HCV that are evolving in Cambodia, India, Indonesia, Malaysia, Myanmar, and Thailand. RECENT FINDINGS: The quality of multiple generic DAAs has been shown to be bioequivalent to innovator formulations, with generic versions achieving high cure rates in real-world settings. Although published materials are limited, there is expanding experience with local pilot and national treatment programs which are largely being funded by national governments and other institutions. SUMMARY: Countries and other public health stakeholders are recognizing the need to scale up HCV diagnosis and treatment programs using generic DAAs. However, local pilot or national treatment programs need to be massively expanded to eliminate HCV in high-burden areas. PMID- 30480584 TI - Civil society demand for accountability to achieve the 90-90-90 targets: lessons from Eastern and Southern Africa. AB - PURPOSE OF REVIEW: Civil society demand for accountability has long been a critical component of the AIDS response. In the age of 90-90-90 HIV treatment goals, civil society advocacy has continued, but often in new forms. In particular, civil society accountability at the intersection of national policy and global health financing has taken on increasing importance, but has not been well documented. RECENT FINDINGS: Civil society demand for accountability is a key to addressing both the insufficient progress toward '90-90-90' HIV treatment goals and the gap in democracy in HIV policymaking particularly prevalent in the context of internationally financed HIV programming. Civil society can serve three vital functions for accountability: unlocking decision-making processes monopolized by powerful funders through North-South networks; challenging dominant ideas that justify status-quo policies; and 'venue shifting' to institutionalize new, more open spaces for policymaking. SUMMARY: The functions of civil society demand for accountability have played key roles in improving the AIDS response in several countries in East and Southern Africa. Dramatically scaling-up capacity for civil society advocacy is necessary in the near term to achieve global HIV goals. PMID- 30480585 TI - A rare mutation of retinoic acid receptor-beta associated with lethal neonatal Matthew-Wood syndrome. PMID- 30480578 TI - Oncofertility: Meeting the Fertility Goals of Adolescents and Young Adults With Cancer. AB - Adolescents and young adults aged 15 to 39 years who are diagnosed with cancer (AYA survivors) undergo a range of therapies for cancer cure but subsequently may be at risk of treatment-related infertility, and for female AYA survivors, adverse pregnancy outcomes. Future fertility is important to AYA survivors. Meeting their fertility goals requires awareness of this importance, knowledge of cancer treatment-related fertility risks, appropriate fertility counseling on these risks, and access to fertility care. Epidemiologic and dissemination and implementation research are needed to estimate more precise risks of traditional and novel cancer therapies on fertility and pregnancy outcomes and improve the delivery of fertility care. PMID- 30480586 TI - Approaching Unusual Pediatric Distal Humerus Fracture Patterns. AB - Pediatric distal humerus fractures are common, and numerous variations can occur depending on patient's age, position of the extremity at the time of injury, and energy of impact. Classic injury patterns include the flexion/extension supracondylar humerus, medial epicondyle, lateral condyle, and the transphyseal distal humerus. We describe our treatment philosophy for pediatric elbow fractures and how these principles were applied to some unusual fractures that presented to our institution. PMID- 30480587 TI - Predicting Discharge Disposition After Shoulder Arthroplasty in the United States. AB - INTRODUCTION: Postdischarge management for shoulder replacement continues to be performed on a case-by-case basis, with no uniform guidelines dictating management. The goal of this study was to develop a nomogram to preoperatively predict a patient's discharge disposition after elective shoulder arthroplasty. METHODS: Patients who underwent elective shoulder arthroplasty between 2012 and 2015 were identified in the National Surgical Quality Improvement Program database. A multivariable logistic regression model was used to identify risk factors for discharge to a postacute care facility, and these results were used to create a predictive nomogram. RESULTS: From 2012 to 2015, 8,363 procedures were identified. In our cohort, 962 patients (11.5%) were discharged to a postacute care facility, and 7,492 patients (88.5%) were discharged home. Preoperative functional status, followed by American Society of Anesthesiologists Class and age, had the strongest predictive value for discharge disposition after shoulder arthroplasty. DISCUSSION: Discharge disposition can be predicted using a nomogram with commonly identified preoperative and intraoperative variables. LEVEL OF EVIDENCE: Level III, retrospective cohort design, observational study. PMID- 30480588 TI - Venous Thromboembolism After Shoulder Arthoplasty and Arthroscopy. AB - Venous thromboembolism (VTE) in the orthopaedic literature largely focuses on lower extremity trauma and arthroplasty, with relatively few investigations of VTE after shoulder surgery. Because the rate of shoulder surgery, especially arthroplasty, continues to expand, it is important for practicing surgeons to understand the magnitude of risk, potential consequences, and prevention methods with regard to VTE. VTE after shoulder surgery has been a topic of increasing interest over the past decade, and the purpose of this review is to examine the recent literature on pathophysiology, risk factors, incidence, diagnosis, sequelae, prevention, treatment, and current recommendations regarding VTE after shoulder surgery. PMID- 30480589 TI - Challenges to Orthopaedic Resident Education. AB - Orthopaedic resident educators confront many important issues. This may be the most challenging time yet for orthopaedic education. A survey of program directors and chairs aimed to identify the major challenges in orthopaedic education. Many issues were identified, and the following four major themes emerged: (1) loss of professionalism, (2) too much emphasis on procedures, (3) lack of clinical experience, and (4) challenges with external oversight. Professionalism in taking care of patients may be compromised by work-hour limitations and affected by generational differences. Limitations to progressive, graduated responsibility include internal and external factors, resulting in a lack of opportunity. Overemphasis on case volume fosters a training environment where technical skill is seen as most important and can detract from teaching the basic principles of being a doctor, including shared decision making. This paper explores these major challenges to orthopaedic resident education in 2018. Substantial changes will be required to address these challenges, but better understanding of the issues they face should help educators identify, minimize, or ideally avoid threats to optimal resident education. PMID- 30480590 TI - Eosinophilic colitis and colonic eosinophilia. AB - PURPOSE OF REVIEW: Eosinophilic colitis is a rare condition, with a prevalence rate in the USA of 2-3/100 000 persons (0.003%), but diagnosed in 0.1% of biopsies in those colonoscoped for diarrhoea. Secondary colonic eosinophilia is more common and associated with systemic, colonic and infectious diseases. In this review, the latest advances in diagnosis, treatment and prognosis are summarized and discussed. RECENT FINDINGS: What constitutes a 'normal' count of eosinophils is poorly documented but there are recent studies that establish normal colonic eosinophil ranges as well as distinguishing histological and clinical findings in primary eosinophilic colitis and secondary colonic eosinophilia in children and adults. Primary eosinophilic colitis is rare, relatively straightforward to diagnose, but may be difficult to treat. Colonic eosinophilia may be overt in parasite infection and connective tissue disease. More subtle, secondary colonic eosinophilia is a useful biomarker for gastrointestinal diseases, such as inflammatory bowel disease, colonic spirochaetosis and collagenous colitis, but the eosinophilia may more often be overlooked. A limited number of drugs are also known to cause left sided colonic eosinophilia such as clopidogrel, ibuprofen and oestroprogestinic agents. SUMMARY: Advances in our understanding of primary eosinophilic colitis and secondary colonic eosinophilia is progressing and if present, colonic eosinophilia should point the clinician and pathologist to a list of differential diagnoses worth considering to direct optimal management. PMID- 30480591 TI - Detection of Calcified Aortic Plaques in an Apolipoprotein E Animal Model Using a Human Computed Tomography System for Ultra-High-resolution Imaging: A Feasibility Study. AB - PURPOSE: The purpose of this study was to prospectively evaluate the feasibility of detecting calcified aortic plaques in apolipoprotein E knockout (ApoE-KO) mice using a state-of-the-art human computed tomography (CT) system. MATERIALS AND METHODS: Eleven ApoE-KO and 9 wild-type mice, all male, were examined in this study. After intraperitoneal injection of 6.6% ketamine all mice underwent 2 ultra-high-resolution CT protocols on a third-generation dual-source CT system at 120 kVp and 130 kVp tube voltage, both performed with a tube current time product of 1300 mAs. Images (0.4 mm) with an increment of 0.2 mm were reconstructed using an iterative reconstruction algorithm. Calcium detectability and scores (Agatston, volume, mass) were determined with a dedicated human calcium scoring software (CaScoring). After the CT examination, a calcium quantification assay of the aortae was performed to determine the aortic calcium content of each mouse. The CT scan time ranged between 40 and 48 seconds. All mice survived the procedure. RESULTS: Calcified plaques could be detected in 8 of 11 ApoE-KO mice. Quantification of calcium levels showed significant differences between those with morphologic calcium plaques detected in CT and those without (3.44+/-1.6 MUg Ca/mg vs. 0.33+/-0.35 MUg Ca/mg; P<0.05). The receiver-operating characteristics analysis revealed a total calcium cut-off value of 0.71 MUg Ca/mg for the detection using calcium score algorithms (specificity: 100% and sensitivity: 90%). CONCLUSION: Using a state-of-the-art human CT protocol and an in-human established calcium scoring system allows for the detection and quantification of calcified aortic plaques in ApoE-KO mice. These results may facilitate preclinical imaging for translational and longitudinal atherosclerotic research studies. PMID- 30480592 TI - Asthma, obesity and targeted interventions: an update. AB - PURPOSE OF REVIEW: Obese asthma is now widely recognized as a phenotype of difficult asthma that is common and less responsive to traditional asthma treatments, so identifying specific treatments is increasingly important. RECENT FINDINGS: Obesity can lead to asthma through a complex relationship of causes including mechanical, inflammatory, metabolic and genetic factors. Exercise programmes including pulmonary rehabilitation, weight loss via dietary restriction, exercise and bariatric surgery, or combinations of all of these can improve quality of life, symptoms, and exercise capacity, with reductions in medication use and exacerbations, and represent tailored treatment for this phenotype of severe difficult to treat asthmatic patients. SUMMARY: Exercise programmes and pulmonary rehabilitation, weight loss programmes targeting 5-10% weight loss and bariatric surgery are effective treatments for the obese asthma phenotype. PMID- 30480593 TI - JBJS Open Access. PMID- 30480594 TI - Safety of Overlapping Inpatient Orthopaedic Surgery: A Multicenter Study. AB - BACKGROUND: Although overlapping surgery is used to maximize efficiency, more empirical data are needed to guide patient safety. We conducted a retrospective cohort study to evaluate the safety of overlapping inpatient orthopaedic surgery, as judged by the occurrence of perioperative complications. METHODS: All inpatient orthopaedic surgical procedures performed at 5 academic institutions from January 1, 2015, to December 31, 2015, were included. Overlapping surgery was defined as 2 skin incisions open simultaneously for 1 surgeon. In comparing patients who underwent overlapping surgery with those who underwent non overlapping surgery, the primary outcome was the occurrence of a perioperative complication within 30 days of the surgical procedure, and secondary outcomes included all-cause 30-day readmission, length of stay, and mortality. To determine if there was an association between overlapping surgery and a perioperative complication, we tested for non-inferiority of overlapping surgery, assuming a null hypothesis of an increased risk of 50%. We used an inverse probability of treatment weighted regression model adjusted for institution, procedure type, demographic characteristics (age, sex, race, comorbidities), admission type, admission severity of illness, and clustering by surgeon. RESULTS: Among 14,135 cases, the frequency of overlapping surgery was 40%. The frequencies of perioperative complications were 1% in the overlapping surgery group and 2% in the non-overlapping surgery group. The overlapping surgery group was non-inferior to the non-overlapping surgery group (odds ratio [OR], 0.61 [90% confidence interval (CI), 0.45 to 0.83]; p < 0.001), with reduced odds of perioperative complications (OR, 0.61 [95% CI, 0.43 to 0.88]; p = 0.009). For secondary outcomes, there was a significantly lower chance of all-cause 30-day readmission in the overlapping surgery group (OR, 0.67 [95% CI, 0.52 to 0.87]; p = 0.003) and shorter length of stay (e, 0.94 [95% CI, 0.89 to 0.99]; p = 0.012). There was no difference in mortality. CONCLUSIONS: Our results suggest that overlapping inpatient orthopaedic surgery does not introduce additional perioperative risk for the complications that we evaluated. The suitability of this practice should be determined by individual surgeons on a case-by-case basis with appropriate informed consent. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 30480595 TI - Open Reduction and Tunneled Suspensory Device Fixation Compared with Nonoperative Treatment for Type-III and Type-IV Acromioclavicular Joint Dislocations: The ACORN Prospective, Randomized Controlled Trial. AB - BACKGROUND: Nonoperative management of complete acromioclavicular (AC) joint dislocation has yielded reasonable results, although patients may report dissatisfaction with the outcome. The purpose of this prospective, randomized, controlled trial was to compare patient outcome following nonoperative care versus operative treatment with open reduction and tunneled suspension device (ORTSD) fixation for acute, type-III or IV disruptions of the AC joint. METHODS: Sixty patients aged 16 to 35 years with an acute type-III or IV disruption of the AC joint were randomized to receive ORTSD fixation or nonoperative treatment, following a power analysis to determine sample size. Functional outcomes were assessed with use of the Disabilities of the Arm, Shoulder and Hand (DASH) as the primary outcome measure and the Oxford Shoulder Scores (OSS) and Short Form (SF 12) as secondary outcome measures at 6 weeks, 3 months, 6 months, and 1 year after treatment. Reduction was evaluated with use of radiographs. Any complications were noted at each assessment. The economic implication of each treatment was evaluated. RESULTS: ORTSD and nonoperative groups were similar with regard to demographics at baseline. The mean degree of radiographic displacement was significantly less in patients following ORTSD fixation (1.75 mm) compared with patients who received nonoperative treatment (10.61 mm, p < 0.0001). At 1 year postoperatively, the mean DASH score was 4.67 in the nonoperative treatment group and 5.63 in the ORTSD group, and the mean OSS was 45.72 and 45.63, respectively. Patients managed with ORTSD fixation had inferior DASH scores at 6 weeks (p < 0.01). There were 5 patients who experienced failed nonoperative treatment and subsequently underwent a surgical procedure. ORTSD fixation (L3,359.73) was associated with significantly higher costs than nonoperative treatment (L796.22, p < 0.0001). CONCLUSIONS: ORTSD fixation confers no functional benefit over nonoperative treatment at 1 year following type-III or IV disruptions of the AC joint. Although patients managed nonoperatively generally recovered faster, a substantial group of patients remained dissatisfied following nonoperative treatment and required delayed surgical reconstruction. We were unable to identify any demographic or injury-related factors that predicted a poorer outcome in these patients. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 30480596 TI - The Effect of Time During the Academic Year or Resident Training Level on Complication Rates After Lower-Extremity Orthopaedic Trauma Procedures. AB - BACKGROUND: Few studies have evaluated the effect of resident participation on morbidity and mortality after orthopaedic trauma surgery. The goal of this study was to evaluate whether complications after orthopaedic trauma procedures involving residents correlate with the level of resident training and the timing in the academic year. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for all patients who underwent operative fixation of proximal femoral fractures, femoral shaft fractures, and tibial shaft fractures from 2005 to 2012. A total of 1,851 cases with resident involvement were identified, and complication rates were calculated and analyzed with respect to resident level of training (postgraduate year [PGY] 1 through 6) and the academic quarter in which the procedure took place. RESULTS: The composite complication rates in the first academic quarter for serious adverse events (10.96%), any adverse events (18.57%), and surgical complications (9.62%) did not significantly differ from those during the remainder of the year (11.40%, 17.81%, and 7.19%, respectively). The rates of any adverse event were significantly higher for senior-level residents (quarter 1, 20.58%; quarter 2, 20.05%) than for junior residents (quarter 1, 11.76%; quarter 2, 12.44%) during the first half of the academic year (quarter 1, p = 0.044; quarter 2, p = 0.024). CONCLUSIONS: This evaluation of the composite complication rates found no "July effect" in lower-extremity orthopaedic trauma surgery. There was evidence for a July effect for superficial surgical site infections, in that there was a significantly higher rate in the first academic quarter. Senior residents may benefit from more oversight or instruction during the first portion of the academic year. PMID- 30480597 TI - The Stability of the Porous Tantalum Components Used in Revision THA to Treat Severe Acetabular Defects: A Radiostereometric Analysis Study. AB - BACKGROUND: The acetabular components used in revision total hip arthroplasty (THA) to treat severe acetabular bone defects have high rates of re-revision at mid to long-term follow-up. Early translation of acetabular components used in revision THA is a good predictor of later loosening, and radiostereometric analysis (RSA) is the most sensitive method to measure migration. The objectives of the present study were to use RSA to compare the migration of the porous tantalum acetabular components used to treat severe bone defects with the previously established acceptable proximal translation threshold of <=1 mm within 2 years, and to determine the effect on migration of the addition of inferior screws through the component into the ischium or pubis. METHODS: RSA was utilized to measure the migration of 55 porous tantalum components used to treat severe acetabular defects (28 Paprosky IIIA, 27 Paprosky IIIB; 21 hips with pelvic discontinuity) at a mean follow-up of 4 years (range, 2 to 12 years). RESULTS: Forty-eight of the 55 components migrated less than the threshold that predicts later loosening (>1 mm) and 50 had not been re-revised at the time of the latest follow-up. Seven components, none of which had inferior screw fixation, exceeded the translation threshold. Of these, 6 were implanted to treat pelvic discontinuity. Of those 6 components, 5 were re-revised for loosening related to patient symptoms. At 2 years, the absolute median proximal translation of components with inferior screw fixation was |0.3| mm (range, |0.1| to |0.9| mm), compared with |0.4| mm (range, |0.03| to |16.4| mm) for those without inferior screws (p = 0.04). CONCLUSIONS: As measured with use of RSA, the majority of porous tantalum acetabular components used in a revision THA to treat severe acetabular defects had acceptable early migration. This predicts good long-term survivorship of these components. The use of inferior screws further improved acetabular component fixation. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 30480598 TI - Clinical and Radiographic Outcomes of a Posteriorly Augmented Glenoid Component in Anatomic Total Shoulder Arthroplasty for Primary Osteoarthritis with Posterior Glenoid Bone Loss. AB - BACKGROUND: The primary objectives of this study were to evaluate the ability of a posteriorly stepped augmented glenoid component, used in patients with primary glenohumeral osteoarthritis with B2 or B3 glenoid morphology, to correct preoperative retroversion and humeral head subluxation and to identify factors associated with radiographic radiolucency and patient-reported clinical outcomes. METHODS: We identified 71 shoulders with B2 or B3 glenoid morphology that underwent anatomic total shoulder arthroplasty with use of a posteriorly stepped augmented glenoid component and with a preoperative 3-dimensional computed tomography (3D-CT) scan and a minimum of 2 years of clinical and radiographic follow-up. The Penn Shoulder Score (PSS), shoulder range of motion, glenoid center-peg osteolysis, and postoperative version and humeral head subluxation were the main outcome variables of interest. RESULTS: Follow-up was a median of 2.4 years (range, 1.9 to 5.7 years); the mean patient age at treatment was 65 +/- 7 years (range, 51 to 80 years). PSS, range of motion, humeral head centering, and glenoid version were significantly improved among all patients (p < 0.0001). Patients with persistent posterior subluxation of the humeral head postoperatively had worse preoperative fatty infiltration of the teres minor and greater postoperative component retroversion (p < 0.05). Patients with center-peg osteolysis had more preoperative joint-line medialization and posterior glenoid bone loss (p < 0.05). Patients with more preoperative humeral head posterior subluxation had a lower PSS, adjusting for confounders (p < 0.05). CONCLUSIONS: Posteriorly stepped augmented glenoid components can improve pathologic retroversion and posterior subluxation of the humeral head in B2 and B3 glenoids, with significant improvements found in clinical outcome scores at a minimum of 2 years of follow-up in the vast majority of patients. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 30480599 TI - Clinical and MRI Outcomes of Fresh Osteochondral Allograft Transplantation After Failed Cartilage Repair Surgery in the Knee. AB - BACKGROUND: Fresh osteochondral allograft transplantation is an appealing option to address a failed cartilage repair surgical procedure, given the ability to treat large lesions and to address the subchondral osseous changes commonly seen in the revision setting. We hypothesized that osteochondral allograft transplantation after failed cartilage repair would result in low failure rates and improved function and that improved graft incorporation on postoperative magnetic resonance imaging (MRI) would correlate with a superior clinical outcome. METHODS: A retrospective review of prospectively collected data was used to identify 43 patients treated with fresh osteochondral allograft transplantation after a previous cartilage repair surgical procedure and having a minimum follow-up of 2 years. Clinical outcomes were evaluated using the Short Form-36 (SF-36) score, International Knee Documentation Committee (IKDC) Subjective Knee Score, Marx Activity Scale, Knee Outcome Survey-Activities of Daily Living (KOS-ADL) Questionnaire, Cincinnati Sports Activity Score, and Cincinnati Overall Symptom Assessment. Postoperative MRI scans were obtained at a mean time of 19.7 months and were independently reviewed by a musculoskeletal radiologist using the Osteochondral Allograft MRI Scoring System (OCAMRISS). RESULTS: At a mean 3.5-year follow-up after osteochondral allograft transplantation, significant improvements (p < 0.05) in SF-36 Physical Function, SF-36 Pain, KOS-ADL, IKDC Subjective Knee Score, and Cincinnati Overall Symptom Assessment were seen. Over 90% of grafts remained in situ at the time of the latest follow-up, although 17 knees (40%) underwent reoperation, the majority for arthroscopic debridement or manipulation for stiffness. Body mass index (BMI) of >30 kg/m was associated with worse clinical outcomes. The mean total OCAMRISS score demonstrated poorer allograft integration in patients with graft failure, but the total score did not meaningfully correlate with clinical outcome scores. However, better individual articular cartilage appearance and osseous integration subscores were associated with better clinical outcome scores. CONCLUSIONS: Significant improvements in pain and function were seen following fresh osteochondral allograft transplantation after failed cartilage repair, with an overall graft survival rate of >90%. Patients with greater bone and cartilage incorporation on MRI had superior clinical outcomes, although persistent osseous edema was frequently seen. We concluded that osteochondral allograft transplantation is an effective salvage treatment after failed cartilage repair and recommend further evaluation of techniques to optimize graft integration. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 30480600 TI - Computer-Assisted Virtual Surgical Technology Versus Three-Dimensional Printing Technology in Preoperative Planning for Displaced Three and Four-Part Fractures of the Proximal End of the Humerus. AB - BACKGROUND: This study aimed to determine the difference between computer assisted virtual surgical technology and 3-dimensional (3D) printing technology in preoperative planning for proximal humeral fractures. METHODS: Between February 2009 and October 2015, 131 patients with 3 and 4-part proximal humeral fractures were divided into 3 groups on the basis of the preoperative planning method: conventional (n = 53), virtual surgical (n = 46), and 3D printing (n = 32). Fracture characteristics and intraoperative realization of preoperative planning (reduction shape and implant choices) were evaluated. Postoperative functional outcomes were assessed using the American Shoulder and Elbow Surgeons, Constant-Murley, and Short Form-36 (SF-36) scoring systems and shoulder range of motion; postoperative radiographic outcomes were assessed with respect to the loss of the neck-shaft angle (NSA) and loss of humeral head height (HHH). RESULTS: Excellent sensitivity, specificity, and accuracy for fracture characteristics were seen in all 3 groups. The correlations for NSA (p = 0.033) and HHH (p = 0.035) were higher in the virtual surgical group than in the 3D printing group. The lengths of the medial support screws in the actual choices were shorter than those in the preoperative plan for the 3D printing group, but a similar pattern was not seen in the virtual surgical group. Compared with the conventional method, the virtual surgical and 3D printing methods of preoperative planning resulted in shorter operative time, less blood loss, and fewer fluoroscopic images. The functional outcomes in both the 3D printing and virtual surgical groups were better than those in the conventional group. The virtual surgical method was faster than the 3D printing method, as suggested by a shorter time to surgery (2.5 compared with 4.6 days; p < 0.001), a shorter time for preoperative planning (30.4 compared with 262.4 minutes; p < 0.001), and a decreased duration of hospital stay (10.9 compared with 14.6 days; p < 0.001). CONCLUSIONS: The clinical outcomes in both the virtual surgical and 3D printing groups were better than those in the conventional group. However, computer assisted virtual surgical technology is more convenient and efficient, considering the shorter time for preoperative planning. In addition, it has improved correlation with preoperative planning. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 30480602 TI - In Younger Patients with End-Stage Knee Osteoarthritis, Computer-Assisted Versus Conventional Total Knee Arthroplasty Did Not Improve Function at 15 Years. PMID- 30480601 TI - Minimally Invasive Versus Open Repair for Acute Achilles Tendon Rupture: Meta Analysis Showing Reduced Complications, with Similar Outcomes, After Minimally Invasive Surgery. AB - BACKGROUND: There is no consensus on the optimal technique for repairing an acute Achilles tendon rupture. The purpose of this meta-analysis was to compare the complications, subjective outcomes, and functional results between minimally invasive surgery and open repair of an Achilles tendon rupture. METHODS: A systematic literature search of MEDLINE/PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), EBSCOhost, and ClinicalTrials.gov was performed. Eligible studies were randomized controlled trials (RCTs) comparing minimally invasive surgery and open repair of acute Achilles tendon ruptures. A meta analysis was performed, while bias and the quality of the evidence were rated according to the Cochrane Database questionnaire and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. The meta-analysis was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines. RESULTS: Eight studies, with 182 patients treated with minimally invasive surgery and 176 treated with open repair, were included. The meta-analysis showed a significantly decreased risk ratio (RR) of 0.21 (95% confidence interval [CI] = 0.10 to 0.40, p = 0.00001) for overall complications and 0.15 (95% CI = 0.05 to 0.46, p = 0.0009) for wound infection after minimally invasive surgery. Patients treated with minimally invasive surgery were more likely to report good or excellent subjective results (RR = 1.18, 95% CI = 1.04 to 1.33, p = 0.009). No differences between groups were found with respect to reruptures, sural nerve injury, return to preinjury activity level, time to return to work, or ankle range of motion. The overall quality of evidence was generally low because of a substantial risk of bias, heterogeneity, indirectness of outcome reporting, and evaluation of a limited number of patients. CONCLUSIONS: There was a significantly decreased risk of postoperative complications, especially wound infection, when acute Achilles tendon rupture was treated with minimally invasive surgery compared with open surgery. Patients treated with minimally invasive surgery were significantly more likely to report a good or excellent subjective outcome. Current evidence is associated with high heterogeneity and a considerable risk of bias. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 30480603 TI - Reporting of Near-Infrared Spectroscopy Did Not Reduce Risk for Cerebral Desaturation Events in Patients Having Arthroscopic Shoulder Surgery in the Beach Chair Position. PMID- 30480604 TI - Robotic Technology in Orthopaedic Surgery. PMID- 30480605 TI - What's New in Orthopaedic Rehabilitation. PMID- 30480606 TI - The Michigan Arthroplasty Registry Collaborative Quality Initiative Experience: Improving the Quality of Care in Michigan. AB - The Michigan Arthroplasty Registry Collaborative Quality Initiative (MARCQI) is a regional quality improvement effort that is focused on hip and knee arthroplasty. From its inception in 2012, MARCQI has grown to include data from 66 hospitals and surgery centers, and contains over 209,000 fully abstracted cases in its database. Using high-quality risk-standardized outcomes data, MARCQI drives quality improvement through a collaborative and nonpunitive structure. Quality improvement initiatives have included transfusion reduction, infection prevention, venous thromboembolism reduction, and reduction of discharge to nursing homes. In addition, MARCQI focuses on postmarket surveillance of implants by computing revision-risk estimates based on the cases that were registered prior to the end of 2016. This paper describes the impact of MARCQI on the quality of hip and knee arthroplasty care in the state of Michigan since its inception in 2012, and it briefly summarizes the recently released 5-year report. PMID- 30480607 TI - The Historical Development of Value-Based Care: How We Got Here. AB - The original architects of Medicare modeled the payment system on the existing fee-for-service (FFS) structure that historically dominated the health-insurance market. Under the FFS paradigm, health-care expenditures experienced an exponential rise. In response, the managed care and capitation models of health care delivery were developed. However, changes in Medicare reimbursement, along with an increasing volume of orthopaedic procedures and escalating implant costs, call into question the cost-effectiveness of this service line. The success of the Medicare Acute Care Episode (ACE) Demonstration Project proved the feasibility of value-based care and ushered in a new era of bundled payment initiatives. PMID- 30480608 TI - Fresh Osteochondral Allograft Transplantation Is an Effective Salvage Strategy for Revision of Failed Cartilage Repair: Commentary on an article by Tim Wang, MD, et al.: "Clinical and MRI Outcomes of Fresh Osteochondral Allograft Transplantation After Failed Cartilage Repair Surgery in the Knee". PMID- 30480609 TI - Preoperative Planning in Fracture Surgery: The End of Colored Pens and Tracing Paper?: Commentary on an article by Yanxi Chen, MD, PhD, et al.: "Computer Assisted Virtual Surgical Technology Versus Three-Dimensional Printing Technology in Preoperative Planning for Displaced Three and Four-Part Fractures of the Proximal End of the Humerus". PMID- 30480610 TI - Clarifying Role Expectations and Practice Standards Using a Clinical Nurse Leader Professional Practice Model Illustration. AB - BACKGROUND: Despite evidence of the positive impact of the clinical nurse leader (CNL) role, implementation of supplemental nursing roles has proven to be challenging due to unclear role explanations and organizational unfamiliarity. PROBLEM: Nurses practice in a dynamic environment and need to cope with the rapid pace of change in practice roles. Outside of the preparation of the CNL, many nursing professionals are not educated or prepared on the essential aspects the CNL role. APPROACH: A graphic illustration was developed to facilitate discussion and provide insight into the CNL role, with the aim of creating consensus on the CNL role functions and expectations. OUTCOMES: Following the implementation of the CNL practice model illustration, participants reported a significant improvement in their understanding and importance of the CNL role. CONCLUSIONS: Professional practice model illustrations may be beneficial in developing a consensus of practice. PMID- 30480611 TI - Manifestations of High-Reliability Principles on Hospital Units With Varying Safety Profiles: A Qualitative Analysis. AB - BACKGROUND: To prevent patient harm, health care organizations are adopting practices from other complex work environments known as high-reliability organizations (HRO). PURPOSE: The purpose was to explore differences in manifestations of HRO principles on hospital units with high and low safety performance. METHODS: Focus groups were conducted on units scoring high or low on safety measures. Themes were identified using a grounded theory approach, and responses were compared using qualitative thematic analysis. RESULTS: High performers indicated proactive responses to safety issues and expressed understanding of systems-based errors, while low performers were more reactive and often focused on individual education to address issues. Both groups experienced communication challenges, although they employed different methods of speaking up. CONCLUSION: Some HRO principles were present in the language used by our participants. High performers exhibited greater manifestations of HRO, although HRO alone was insufficient to describe our results. Mindful organizing, which expands on HRO, was a better fit. PMID- 30480612 TI - Barriers to Integrating Research Into Clinical Nursing Practice. AB - BACKGROUND: Using research findings in clinical practice is a cornerstone in improving the quality of care, but nurses face different barriers in doing so. PURPOSE: The purpose was to explore barriers to research utilization in clinical practice as perceived by nurses. METHOD: A cross-sectional survey was done using a convenience sampling method in a single specialist hospital in Saudi Arabia. The Barriers to Research Utilization questionnaire was used to collect data. RESULTS: The mean overall score (out of 4) for the Barriers questionnaire was 2.67 (SD = 0.47). The 3 most reported barriers were lack of time, physician cooperation, and other staff support. Nurses working in pediatric and maternity units reported more barriers. CONCLUSION: Clinical setting factors are those most perceived by nurses as barriers to integrating research into practice. Reforms in the clinical areas should take place to overcome these barriers. PMID- 30480613 TI - Nursing Documentation of Postoperative Pain Management: A Documentary Analysis. AB - BACKGROUND: Although proper documentation of pain for postoperative patients is essential to promote patient health outcomes, there is limited examination of nurses' documentation of pain management. PURPOSE: The purpose of this study was to qualitatively analyze nursing documentation of pain management among postoperative patients in Jordan. METHOD: A documentary analysis method was used. A purposive sample of 80 medical records were reviewed, and a total of 720 nursing records were analyzed. RESULTS: The analysis revealed that nurses' documentation of pain management was limited, vague, incomplete, and largely dependent on their subjective evaluation. Many of the documented goals were broad, not specific, not measurable, and with no time frame. CONCLUSIONS: Documentation patterns revealed a lack of proactive and systematic approach to pain assessment and management. Furthermore, there was little documented evidence of efforts to evaluate the effectiveness of pain management interventions. Findings have important implications for standardizing documentation of pain assessment, intervention, and evaluation. PMID- 30480614 TI - Blended Facilitation as an Effective Implementation Strategy for Quality Improvement and Research in Nursing Homes. AB - BACKGROUND: Blended facilitation, which leverages the complementary skills and expertise of external and internal facilitators, is a powerful strategy that nursing stakeholders and researchers may use to improve implementation of quality improvement (QI) innovations and research performed in nursing homes. PROBLEM: Nursing homes present myriad challenges (eg, time constraints, top-down flow of communication, high staff turnover) to QI implementation and research. APPROACH: This methods article describes the theory and practical application of blended facilitation and its components (external facilitation, internal facilitation, relationship building, and skill building), using examples from a mixed QI and research intervention in Veterans Health Administration nursing homes. CONCLUSIONS: Blended facilitation invites nursing home stakeholders to be equal partners in QI and research processes. Its intentional use may overcome many existing barriers to QI and research performed in nursing homes and, by strengthening relationships between researchers and stakeholders, may accelerate implementation of innovative care practices. PMID- 30480615 TI - Grounded Running Reduces Musculoskeletal Loading. AB - PURPOSE: Recent observations demonstrate that a sizeable proportion of the recreational running population runs at rather slow speeds and does not always show a clear flight phase. This study determined the key biomechanical and physiological characteristics of this running pattern, i.e. grounded running (GR), and compared these characteristics with slow aerial running (SAR) and reference data on walking at the same slow running speed. METHODS: Thirty male subjects performed instructed GR and SAR at 2.10 m.s on a treadmill. Ground reaction forces, tibial accelerations and metabolic rate were measured to estimate general musculoskeletal loading (external power and maximal vertical ground reaction force), impact intensity (vertical instantaneous loading rate and tibial acceleration) and energy expenditure. More explicit measures of muscular loading (muscle stresses and peak eccentric power) were calculated based on a representative subsample, in which detailed kinematics and kinetics were recorded. We hypothesized that all measures would be lower for the GR condition. RESULTS: Subjects successfully altered their running pattern upon a simple instruction towards a GR pattern by increasing their duty factor from 41.5% to 51.2%. As hypothesized, impact intensity, general measures for musculoskeletal and the more explicit measures for muscular loading decreased by up to 35.0%, 20.3% and 34.0% respectively compared to SAR. Contrary to our hypothesis, metabolic rate showed an increase of 4.8%. CONCLUSION: Changing running style from SAR to GR reduces musculoskeletal loading without lowering the metabolic energy requirements. As such, GR might be beneficial for most runners as it has the potential to reduce the risk of running related injuries while remaining a moderate-to-vigorous form of physical activity, contributing to fulfillment of the recommendations concerning physical activity and public health. PMID- 30480616 TI - From Total Volume to Sequence Maps-Sophisticated Accelerometer Data Analysis. AB - PURPOSE: To date, epidemiological studies have focused on the potential health effects of total volume of physical activity (PA) or sedentary behaviour (SB). However, two persons may have the same volume of PA or SB but accumulated in a completely different sequence. The pattern of accumulating PA and SB might be more important for health effects than the total volume. Therefore the aim was to develop a sophisticated algorithm translating accelerometer data into detailed sequence maps considering how PA and SB are accumulated throughout the day. METHODS: We developed a novel algorithm to convert accelerometer counts into a sequence map based on behaviour states defined by a combination of intensity (SB, light, moderate, and vigorous intensity) and duration (sporadic accumulation or in bouts of different duration). Additionally, hierarchical cluster analysis was applied to identify clusters of children with similar behavioural sequence maps. RESULTS: Clustering resulted in seven clusters of children with similar PA and SB sequence maps: an average cluster (33% of children); a cluster with relatively more SB, light and moderate PA in bouts (SB and PA bouters, 31%); a cluster characterized by more sporadic SB and light PA (light activity breakers, 26%); and four smaller clusters with 7% of the children or less. CONCLUSION: This novel algorithm is a next step in more sophisticated analyses of accelerometer data considering how PA and SB are accumulated throughout the day. The next step is identifying whether specific patterns of accumulating PA and SB are associated with improved health outcomes. PMID- 30480617 TI - Quantifying Brain White Matter Microstructure of People with Lateral Ankle Sprain. AB - PURPOSE: This study aimed to quantify differences in white matter microstructure and static postural control in individuals with and without a previous history of a lateral ankle sprain. METHODS: Ten participants with a history of a lateral ankle sprain and 10 controls performed 3, 20-second trials of single-leg static balance on a force platform under an eyes-open condition. Resultant sample entropy (SampEn) was used to assess static postural control performance. To assess white matter microstructure, fractional anisotropy (FA) of the superior cerebellar peduncles and corticospinal tracts was quantified using diffusion tensor imaging (DTI). In the case of statistically significant differences in FA, component diffusivities were evaluated, including mean diffusivity, radial diffusivity (RD), and axial diffusivity (AD). RESULTS: Significant differences between participants with and without a history of lateral ankle sprains were observed in superior cerebellar peduncle FA and RD. Participants with a history of lateral ankle sprains had significantly lower FA in the superior cerebellar peduncle compared to controls. Participants with a history of lateral ankle sprains also demonstrated higher RD values in the superior peduncle compared to control. Finally, participants with a history of lateral ankle sprains had lower resultant SampEn values compared to controls. CONCLUSION: Findings suggest that microstructural changes in white matter tracts governing postural control, may be biomarkers of central nervous system dysfunction in individuals with a lateral ankle sprain history. PMID- 30480619 TI - Predicting treatment outcome for anxiety disorders with or without comorbid depression using clinical, imaging and (epi)genetic data. AB - PURPOSE OF REVIEW: The present review complements previous reviews on prediction research in anxiety disorders with a focus on clinical, imaging and genetic as well as epigenetic factors and aims to provide recommendations for the design of future integrative studies in adults as well as children. RECENT FINDINGS: Clinical factors predicting worse outcome such as a diagnosis of social anxiety disorder, comorbid depression and certain cognitive, behavioral and personality traits as well as low socioeconomic status were confirmed in large clinical studies. Imaging factors focusing on the fear and anxiety network were repeatedly described as predicting therapy response in small exploratory studies. The plethora of candidate gene studies has now been complemented by large genome-wide association studies and small epigenetic investigations with the need for replication in larger samples. SUMMARY: The present status of research on predictors for therapy response in anxiety disorders, in particular on imaging and genetic factors, is still fragmentary. Some clinical factors for poorer outcome, though, have been consistently replicated and should be considered in the revision of therapy guidelines. There is a definite need for large integrative studies at the national and international level integrating multiple levels of biomarkers at different stages of development. PMID- 30480620 TI - Molecular and immunohistochemical analyses of uveal melanoma patient cohort. AB - Uveal melanoma is a rare form of melanoma and the most frequent primary eye malignancy in adults. The major molecular alterations underlying uveal melanoma pathogenesis affect mainly the GNAQ, GNA11, SF3B1, and BAP1 genes. In this study, we somatically genotyped 31 Brazilian uveal melanomas for BRAF, GNA11, GNAQ, SF3B1, and BAP1 gene mutations and assessed BRCA2 and p53 protein expression. GNAQ and GNA11 mutations were detected in 60%, and SF3B1 mutation rate was 30%. p53 Immunostaining was markedly positive in 5/31, and 3/31 samples showed negative BRCA2 expression. This study supports the importance of these key genes in uveal melanoma tumorigenesis; p53 and BRCA pathways seem to play a role in a subset of patients, possibly heralding unfavorable prognosis. PMID- 30480621 TI - What has changed in the epidemiology of skin melanoma in central Italy during the past 20 years? AB - The aim was to evaluate changes in skin melanoma incidence and mortality at a population level in central Italy over the past two decades. Skin melanoma incidence rate from 1994 to 2014, were retrieved from the Umbrian Cancer Registry (about 900 000 inhabitants). Changes from 1994-1999 to 2010-2014 in tumour and patient characteristics- sex, age (0-44, 45-64, >=65 years), site (head and neck, trunk, limbs), morphology (superficial spreading, nodular, other), thickness (<=1, 1-2, 2-4, >4) and stage I-II, III-IV were evaluated. Trends in age standardized incidence and mortality rates were evaluated as annual percent change. During the past two decades, melanoma incidence significantly increased in both sexes (+6%/year amng men and +4%/year among women) and in all ages (0-44 years: +4.7 and +4.3; 45-64 years: +6.1 and +4.4; >=65 years: +6.6 and +1.7), morphologies, except nodular, and stages. Mortality was stable among men and women. In the area, incidence increased for thin and thick melanoma, showing a true increase, whereas mortality did not increase. Therefore, although improvements in treatment and downstaging effect of early diagnosis have to be considered, a certain degree of overdiagnosis cannot be ruled out. PMID- 30480622 TI - MiR-135b is a novel oncogenic factor in cutaneous melanoma by targeting LATS2. AB - Melanoma develops from pigment-producing melanocytes in the epidermis, and is the most common type of skin cancer. Because of the lack of effective therapies, the median survival of patients developing metastatic melanoma is less the 1 year. In this paper, we studied the oncogenic role of miR-135b in melanoma cells. We compared the miR-135b levels in 20 melanoma tissues in reference to their corresponding nontumor regions. Next, we studied the impact of miR-135b or its inhibitor on cell proliferation, migration, or apoptosis in either primary melanocytes or the melanoma cell line, respectively. Finally, we validated large tumor suppressor kinase 2 (LATS2) as the downstream target of miR-135b in a luciferase reporter assay, western blotting analysis, and knockdown study in primary melanocytes. MiR-135b expression was significantly upregulated in melanoma tissue. Overexpressing miR-135b in primary melanocytes promoted cell proliferation and migration. In contrast, inhibition of miR-135b expression suppressed the growth and metastasis of A-375 cells and enhanced cell apoptosis. LATS2 was confirmed as the target of miR-135b. Knockdown of LATS2 in melanocytes also promoted cell growth, but not cell invasion potential. Our findings showed miR-135b as a novel oncogene in melanoma tumorigenesis. The oncogenic mechanism may involve the downregulation of LATS2. PMID- 30480623 TI - Neonatal Teratoma: Craniofacial Treatment. AB - Teratomas are rare congenital neoplasms. Head and neck locations of the tumor are uncommon with combined intracranial and extracranial extensions being even more rare. The authors present a case of teratoma involving the temporal, buccal, maxillary, orbital and extending to the intracranial regions, which was successfully managed by surgical resection. PMID- 30480624 TI - Bone Flap Technique With Piezosurgery for Impacted Teeth Extraction and Bone Cysts Removal Without Additional Fixation. AB - To explore a new surgical approach for impacted teeth extraction and cystectomy using piezosurgery that provides proper bone healing in normal anatomical structure without additional fixation and graft materials.In cases with intact and relatively thicker vestibular compact bone, a bone flap design was used with converging osteotomy lines made with piezosurgery tips which allow proper stabilization after enucleation or extraction.Procedure was performed in 10 patients with 9 to 36 months follow-up resulted in satisfactory healing without any complications.Comparing to traditional techniques, effective enucleation and accelerated bone regeneration are achieved, with reduced risk of complications, operation time, and costs. PMID- 30480625 TI - Anatomical Variation in Morphometry and Morphology of the Foramen Magnum and Occipital Condyle in Dried Adult Skulls. AB - BACKGROUND: The foramen magnum (FM) is the largest opening and is outlet through which medulla oblongata and spinal cord along with meninges, vertebral arteries, anterior and posterior spinal arteries, tectorial membrane, alar ligaments, and spinal branch of the accessory nerve. Occipital condyle (OC) is an important part of craniovertebral or craniocervical junction located anterolaterally on either side of the FM. The objective of the study was to assess variations of FM and OC in Ethiopian dried adult skulls. METHODS: Observation-based descriptive study design was employed. The study was undertaken in 54 FM and 108 OC of 54 adult Ethiopian skulls. The morphometry of FM and OC were determined using a sliding vernier caliper. RESULTS: The mean values of anteroposterior and transverse diameters of the FM were 35.19 and 30.17 mm, respectively, and the mean area of the FM was 853.36 mm. The shapes of FM were determined as round in 22.2%, oval in 18.5%, egg like in 20.4%, triangular in 3.7%, pentagonal in 11.1%, hexagonal in 7.4%, irregular in 13%, and rectangular in 3.7% of the cases. The mean length of right and left OC was 25.69 and 26.96 mm, respectively, and the mean widths of the right and left OC were 12.76 and 13.04 mm, respectively. CONCLUSION: Our study identified various shapes of FM and diameter. The anteroposterior diameter is greater than the transverse diameter. The morphometric study of OC confirmed the length of left side is significantly greater than the right side. PMID- 30480626 TI - Karapandzic Flap: A Useful Option for Reconstruction of Lower Lip. AB - Lip carcinoma is a common cancer of the head and neck region and it more commonly affects the lower lip (>90%). Out of all the carcinomas affecting the lower lip, squamous cell carcinoma accounts for 95% of the patients. Reconstruction of lower lip is a challenging task, as it requires taking into consideration the restoration of function as well as aesthetics. In this study, a patient for whom successful reconstruction of lower lip defect was done using the Karapandzic flap was presented. PMID- 30480627 TI - Comparison of the Clinical Outcomes of Buccal Advancement Flap Versus Platelet Rich Fibrin Application for the Immediate Closure of Acute Oroantral Communications. AB - The aim of this study was to compare the clinical outcomes of buccal advancement flap surgery to platelet-rich fibrin (PRF) application for the closure of acute oroantral communications (AOACs). In 36 patients, following the extractions of posterior maxillary teeth, AOACs which were larger than 3 mm diameter were detected. In group A, PRF clots were used in 21 patients and group B, classic buccal advancement flap was used in 15 patients. Baseline variables such as pain, the analgesic doses are taken, and swelling was assessed preoperatively. These were also examined on postoperative days 1, 2, 3, and 7, and patients were seen again in the 3rd week. In group A, statistically significant reduction was examined (P < 0.05) in pain and the analgesic doses are taken (sum of 1st, 2nd, 3rd, and 7th days on days 1 and 2) (PRF). The swelling was also significantly less in group A (P < 0.05). The mean duration did not differ between the groups (P > 0.05). In conclusion, both methods were successful for the immediate closure of AOACs. However, a lesser amount of pain and no swelling observed with the use of PRF clots for the immediate closure of AOACs compared to buccal advancement flap surgery. PMID- 30480628 TI - Masseter-to-Facial Nerve Transfer for Reanimation of a Patient With Long-Term Facial Paralysis. AB - Facial paralysis is a condition caused by a wide variety of etiologies, including neurologic, congenital, infectious, neoplastic, systemic, and iatrogenic causes. A patient suffering from long-term facial paralysis, with minimal innervation detected through electroneurography, who was successfully reanimated by performing a masseter-to-facial nerve transfer, was presented in this study. Facial paralysis had been caused after resection of an acquired middle ear cholesteatoma more than 5 years before. PMID- 30480629 TI - Tympanogram Findings in Hemodialysis Patients. AB - BACKGROUND: The aim of this study is to investigate whether changes in cerebrospinal fluid (CSF) pressure during the hemodialysis (HD) treatment are reflected on tympanometric measurements. METHODS: The study was performed on 24 HD patients. The static compliance and absorbance values of the patients before and after HD were measured using a wideband tympanometry. The tympanogram tests were performed immediately before and at the end of the HD session. RESULTS: The static compliance values of the patients after HD were significantly lower than those before HD. This decrease significantly correlated with the adequacy of dialysis determined by urea reduction rate and Kt/V. The absorbance values showed a decrease in the band 343 and 727 Hz, but no significant difference was found in other frequencies. The static admittance and absorbance values were influenced by the HD process. DISCUSSION: This influence might be due to the increase in CSF pressure as a result of the removal of urea from blood during HD session. PMID- 30480630 TI - Distraction Osteogenesis of Fibula Graft for Mandibular Reconstruction Following Ameloblastoma Ablation. AB - BACKGROUND: Resection of maxillofacial may cause a series of complications such as loss of facial deformity, dysfunction, and psychological distress. Mandibular reconstruction following resection still remains difficult. METHODS: A 18-year old male patient with mandibular ameloblastoma was admitted in the hospital of stomatology. The tumor was dissected and the defect was reconstructed using vascularized fibula graft. One year later, distraction osteogenesis (DO) was performed on the fibula graft to augment the alveolar bone for dental implants. Panoramic radiographs, computed tomography, and clinical photographs were taken. Five months after completion of distraction, the distraction device was removed. RESULTS: Panoramic radiographs, computed tomography, and clinical photographs showed the good healing after fibula graft for mandibular reconstruction following ameloblastoma ablation and satisfied alveolar bone with good width and height for dental implants after DO. CONCLUSIONS: This report suggests that DO of fibula graft following mandibular reconstruction was an efficient method to augment the alveolar bone for dental implants. PMID- 30480631 TI - Review of "Interventions to Reduce Intraoperative Costs: A Systematic Review" by Childers CP, Showen A, Nuckols T, Maggard-Gibbons M in Ann Surg 268:48-57, 2018. PMID- 30480632 TI - The Precise Midline Positioning Instrument for Le Fort I Osteotomy. AB - To reduce the deviations in the horizontal direction of posterior maxilla during the maxilla Le Fort I osteotomy, the authors develop and validate the precise midline positioning instrument for Le Fort I osteotomy, which can guide the precise relocation of the truncated maxillary bone segment. The patent application for the precise midline positioning instrument for Le Fort I osteotomy is already submitted (patent no: 201711245533.6, China). The accuracy of Le Fort I osteotomy can be improved significantly, because of the amplification effect of this patent on the rotation/micro-movement of the posterior maxilla in all directions to achieve the precise movement and pairing of the maxillary bone segment. And this method is simple, efficient, and laborsaving. PMID- 30480633 TI - Sensory Changes in Periocular Skin After Upper Eyelid Surgery. AB - The aim of this interventional, prospective study is to estimate the change in periocular cutaneous sensation after upper eyelid surgery. The trial included 48 eyes of 24 patients undergoing upper eyelid blepharoplasty or upper eyelid blepharoplasty and blepharoptosis repair. Eyelid sensation was measured using a Cochet-Bonnet filament-type esthesiometer at 4 predetermined anatomical locations in the upper eyelid. The mean esthesiometry reading was calculated at the preoperative visit (4.06 cm), at 2-week postoperative visit (4.38 cm), and at final postoperative visit (4.52 cm). Paired t test showed no significant difference in sensation measurement at second visit compared with baseline (P = 0.205) or at final visit compared with baseline (P = 0.092). Paired t test showed no correlation between type of surgery and change in sensation. Sex and age did not influence change in sensation. In 40 of 42 eyelids, (95.24%), patients reported no reduction in subjective eyelid sensation. The authors conclude that eyelid sensation was not compromised objectively or subjectively by upper eyelid skin incision surgery. Surgeons can reassure patients contemplating surgery that it is very unlikely that cutaneous sensation will be damaged. PMID- 30480634 TI - A Step-by-Step Procedure for Bone Regeneration Using Calcium Phosphate Scaffolds: From Site Preparation to Graft Placement. AB - Hydroxyapatite (HA) is the main mineral component of bone and teeth. HA is often used as a bone substitute and especially in its granular form it is osteoconductive and osseointegrating as shown by many investigations in animals and humans. HA granules are used for filling bone defects, but they have poor handling qualities and retention at the surgical site, leading to graft voids between the granules and bone tissue and resulting in mechanical instability. Furthermore HA implantation is not constantly followed by favorable results, especially when it is carried out for augmentation of the alveolar ridge. This article offers a protocol for bone reconstruction and predictable implant treatment outcomes. We provide a step-by-step description of both the recipient site and composite graft preparations using coralline HA granules (CHAG) and homologous fibrin glue (HFG). In the present study, 20 randomly selected patients (12 women and 8 men) underwent bone regeneration using CHAG-HFG before a dental implant procedure. Radiographic imaging, physical examination, and histological analysis were performed during a 2-year period. Biopsies were obtained at second stage surgery before implant insertion using a 2.8-mm trephine bur. A morphological study of 20 bioptic human specimens was performed. Our results demonstrate that this surgical protocol for the preparation of the recipient site associated with a mixture of coralline HA granules with homologous fibrin glue provides reliable bone regeneration, thus reducing failures and minimizing risks of postoperative morbidity. PMID- 30480635 TI - Transoral Robotic Surgery With Transoral Retropharyngeal Lymph Node Dissection in Patients With Tonsillar Cancer: Anatomical Points, Surgical Techniques, and Clinical Usefulness. AB - OBJECTIVE: The purpose of this study was to evaluate the clinical usefulness of TORS and transoral robotic retropharyngeal lymph node (RPLN) dissection in tonsillar cancer patients with suspicious RPLN metastasis. METHODS: From April 2008 to March 2014, 71 patients with tonsillar cancer underwent transoral robotic surgery and standard neck dissection at the Yonsei Head and Neck Cancer Center. RESULTS: Three patients underwent transoral robotic ropharyngectomy with transoral robotic RPLN dissection because of suspicious RPLN metastasis. The mean age of the patients was 42 years (range, 31-50 years). There were no cases of wound infection or serious complications related to wound healing. Mild nasal regurgitation was observed during an oral diet immediately after surgery, but all patients spontaneously resolved without surgical treatment. There was no significant bleeding due to great vessel injury during surgery or swallowing difficulty due to cranial nerve IX injury. CONCLUSION: Although the oncologic stability and usefulness of this technique should be confirmed based on large scale research, RPLN can be easily accessed and resected through our approach with less morbidity compared to the conventional surgical approach. In addition, because RPLN metastasis can be performed pathologically based on obtained specimens, it will be helpful to explore whether to perform adjuvant radiation. PMID- 30480636 TI - Suturing a Vomer Flap to the Hard Palate Through a Hole When the Nasal Lining is Not Available. AB - The nasal lining by suturing a vomer flap onto the bony ridge of the cleft through a hole was repaired.A 16-month-old girl had an incomplete bilateral posterior cleft palate. While incising the periosteum and elevating the nasal mucosa from the cleft edge of the right side, the mucosa was sheared and a buttonhole was made, and as a result, the nasal lining could not be coapted. A vomer flap to close the nasal lining was applied. On the left side, the nasal mucosa from the cleft margin was sutured to the vomer flap. On the right side, where no nasal lining was available, 2 holes were drilled 5 mm lateral to each bony cleft margin, and the vomer flap was sutured to the palate with 4-0 vicryl through the holes. The elevated bilateral mucoperiosteal flaps were brought together to the midline and sutured to the anterior triangular flap in a V-Y pushback fashion.This method could be used to cover the nasal lining when nasal mucosa is not available. PMID- 30480637 TI - Trans-Oral Robotic Surgery of Submandibular Gland Removal with Preservation of Sublingual Gland and Wharton's Duct. AB - In surgical removal of a submandibular gland, trans-cervical approach has esthetic problem and existing trans-oral approaches are extensively invasive. The authors have used trans-oral robotic surgery to remove the submandibular gland with preservation of the sublingual gland and the Wharton's duct, and hereby report the case and discuss our preliminary experiences. PMID- 30480638 TI - Intraoral Endoscopic Ligation of Maxillary Artery in the Infratemporal Fossa. AB - Ligation of the sphenopalatine and posterior nasal arteries is indicated for posterior epistaxis as initial treatment or when conservative measures fail. In some patients, a transnasal approach or its alternative transantral approach are not possible due to tumor filling the nasal corridor, pterygopalatine fossa, or maxillary sinus. Aim of this study was to evaluate feasibility of endoscopically assisted transoral approach for the ligation of the maxillary artery (MA). Six fresh cadaver specimens (12 sides), previously prepared with intravascular injections of colored latex, were dissected. A combined transnasal and transoral approach exposed the MA from the deep belly of the temporalis muscle laterally to its terminal branches medially. Anatomical relationships of the MA with the deep belly of the temporalis muscle and the lower head of the lateral pterygoid muscle, and feasibility of access to the MA via a transoral approach were assessed. In all specimens, the MA was found at the point where horizontal fibers of the lower head of the lateral pterygoid muscle cross the vertical fibers of the deep belly of the temporalis muscle. In 5 specimens, the artery ran anteriorly and laterally to lower head of the lateral pterygoid muscle, and in 1 specimen, it ran posteriorly and medially to this muscle, diving between its fibers. The modified endoscopically assisted transoral approach is feasible to ligate the MA. It can be used for proximal vascular control in cases when transnasal and transantral approaches are not viable. PMID- 30480640 TI - Leveraging pragmatic clinical trial design to advance phosphate management in end stage renal disease. AB - PURPOSE OF REVIEW: Phosphate lowering toward the normal range is advocated and widely practiced in patients with end-stage renal disease receiving dialysis. This approach is guided by basic science data and large observational studies that have demonstrated a consistent association between hyperphosphatemia and adverse events, including cardiovascular morbidity and all-cause mortality. There has never been a clinical trial to assess the efficacy of phosphate lowering in maintenance dialysis recipients. RECENT FINDINGS: Despite several trials comparing the effect of different phosphate-binding agents on biochemical targets, no trial has evaluated whether targeting normophosphatemia using phosphate binders mediates better patient outcomes. Recent work has highlighted the feasibility of conducting a randomized trial comparing two strategies for phosphate control. We believe that this research question is optimally suited to a pragmatic trial design. SUMMARY: There is a pressing need for a well-designed randomized controlled trial to evaluate whether intensive phosphate lowering confers improved cardiovascular outcomes in patients receiving maintenance dialysis. We propose a broad framework for such a trial using the principles of pragmatic trial design. The ultimate objective of such a trial will be to provide patients and clinicians with reliable and broadly applicable information on whether reducing serum phosphate toward the normal range improves patient important outcomes. PMID- 30480641 TI - Natural killer cells as modulators of alloimmune responses. AB - PURPOSE OF REVIEW: Natural killer (NK) cells are effector cells of the innate immune system that can lyse target cells without prior sensitization and are important in host defense to virally infected and transformed cells. Although the concept of 'missing-self' would suggest NK cells could target foreign allografts, the prevailing dogma has been that NK cells are not active participants in the rejection of solid organ allografts. This review summarizes recent studies that challenge this conclusion and instead suggest NK cells are important in outcomes posttransplant. RECENT FINDINGS: NK cells expressing specific cell surface receptors may promote graft damage and rejection. However, recent studies suggest some NK cell subsets have tolerogenic or immunoregulatory potential and promote graft stability, suggesting a dichotomous role for NK cells after transplant. Furthermore, NK cells respond to cells infected with cytomegalovirus and Epstein Barr virus, and studies suggest some NK cells have immune memory. SUMMARY: Our understanding of the role of NK cells posttransplant has evolved from 'no role' to the current idea that NK cells may have 'complex interactions' that impact graft outcomes. Additional studies, using cutting edge techniques to comprehensively analyze the phenotypic and functional subsets of NK cells in transplant recipients, are clearly necessary. PMID- 30480642 TI - Effector B cells in cardiac allograft vasculopathy. AB - PURPOSE OF REVIEW: B cells have recently emerged as important immune players in solid organ rejection, especially in cardiac allograft vasculopathy (CAV), a chronic form of rejection following heart transplantation. B cells can exert either regulatory or effector functions. This review will provide an update on effector B cells in CAV. RECENT FINDINGS: Independent studies reported the abundance of B cells in graft infiltrates during CAV, especially around coronary arteries. Infiltrates comprise CD20+ CD27+ memory B cells together with differentiated CD20-CD138+ plasma cells, which are almost always associated with T cells and macrophages. The structure of some of these infiltrates evokes that of germinal centers, suggesting the generation of tertiary lymphoid organs in the graft. Remarkably, B-cell infiltrates are most often detected in the absence of circulating donor human leukocyte antigen-specific antibodies, strongly suggesting that the two components are unrelated. Characterization of B-cell clones isolated from explanted human cardiac graft infiltrates revealed the prevalence of polyreactive B innate, B1-like B cells. Accumulating evidence suggests that these cells act primarily as antigen-presenting cells in situ. Additional effector functions, such as local antibody secretion and pro inflammatory cytokine production, promoting T-cell polarization, macrophage activation and fibrosis are also considered. SUMMARY: Converging observations made through animal and human studies add substantial support for an effector B cell role in the pathophysiology of CAV. On the basis of these collective findings, a therapeutic strategy targeting B cells could reasonably be envisaged to prevent or treat this complication. PMID- 30480643 TI - Xenogeneic transplantation and tolerance in the era of CRISPR-Cas9. AB - PURPOSE OF REVIEW: The use of genetically modified donor pigs has been integral to recent major advances in xenograft survival in preclinical nonhuman primate models. CRISPR-Cas9 gene editing technology has dramatically accelerated the development of multimodified pigs. This review examines the current and projected impact of CRISPR-Cas9-mediated donor modification on preventing rejection and potentially promoting tolerance of porcine xenografts. RECENT FINDINGS: CRISPR Cas9 has been used to engineer several genetic modifications relevant to xenotransplantation into pigs, including glycosyltransferase knockouts (GGTA1, CMAH, beta4GALNT2, A3GALT2 and combinations thereof), other knockouts (SLA-I, ULBP1, PERV and GHR), and one knock-in (anti-CD2 monoclonal antibody transgene knocked into GGTA1). Although the use of these pigs as donors in preclinical nonhuman primate models has been limited to a single study to date, in-vitro analysis of their cells has provided invaluable information. For example, deletion of three of the glycosyltransferases progressively decreased the binding and cytotoxicity of preexisting immunoglobulin G and immunoglobulin M in human sera, suggesting that this 'triple-knockout' pig could be a platform for clinical xenotransplantation. SUMMARY: CRISPR-Cas9 enables the rapid generation of gene edited pigs containing multiple tailored genetic modifications that are anticipated to have a positive impact on the efficacy and safety of pig-to-human xenotransplantation. PMID- 30480644 TI - Epithelioid Trophoblastic Tumor: Expanding the Clinicopathologic Spectrum of a Rare Malignancy. AB - Epithelioid trophoblastic tumor is a malignancy derived from the chorionic laeve type intermediate trophoblast with sufficient rarity that the vast majority of literature on the topic exists in the form of case reports and small series. Classically, it is regarded as a well-circumscribed tumor with an expansile growth pattern that occurs in reproductive-aged women, usually after a normal pregnancy. However, we recently encountered a case of epithelioid trophoblastic tumor with aggressive spread throughout the abdomen and pelvis in a 68-yr-old female presenting 30 yr after her last delivery. Although to our knowledge this is the first report in a postmenopausal patient to be confirmed by molecular analysis of short tandem repeats, there are multiple similar case reports spanning a variety of clinical settings that deviate from the original description. We therefore sought to synthesize the clinicopathologic data among the available reports in the English literature, with emphasis on pathologic findings. While the overarching themes are largely unchanged, this series of 77 patients reveals a broader spectrum of disease and highlights frequent misdiagnosis. Here we present a clinicopathologic update on this rare entity, with emphasis on a practical approach to diagnosis. PMID- 30480645 TI - Multiple Epidermolytic Acanthomas: Rare Vulval Lesions Which May be Mistaken for Viral Warts. AB - Epidermolytic acanthoma is a rare benign lesion that most often presents as a solitary or multiple small papular lesions on the trunk, face, limbs or external male genitalia. Only a small number of cases have been reported occurring on the vulva and clinically and histologically they may mimic and be misdiagnosed as viral warts. We report 2 cases of multiple epidermolytic acanthomas localized to the vulva. Molecular tests (in situ hybridization and polymerase chain reaction) showed no evidence of human papillomavirus infection and p16 staining was negative. We stress the need for pathologists to consider epidermolytic acanthoma in the differential diagnosis of multiple vulval lesions resembling viral warts. PMID- 30480646 TI - Intratumoral Heterogeneity Accounts for Apparent Progression of Noninvasive Serous Tumors to Invasive Low-grade Serous Carcinoma: A Study of 30 Low-grade Serous Tumors of the Ovary in 18 Patients With Peritoneal Carcinomatosis. AB - Noninvasive ovarian low-grade serous tumors [atypical proliferative serous tumor (APST)/serous borderline tumor] appear to progress to invasive low-grade serous carcinoma (LGSC) at a low but regular rate. The underlying biology of this phenomenon is unknown. We studied 18 patients with 30 ovarian tumors (12 bilateral), including APST, noninvasive LGSC and invasive LGSC, who also had low grade serous carcinomatosis. Tumors were evaluated for microinvasion (usual eosinophilic cell type), microinvasive carcinoma (<5 mm invasion of micropapillary nests), and overt carcinoma (>=5 mm invasion of micropapillary nests). Tumors were evaluated based on the original numerical order of sections under the hypothetical scenarios in which sampling was stopped at 1 section/cm and 2 sections/cm. Sampling based on 1 section/cm of greatest tumor dimension identified invasion of any type in 21 tumors (70%). Among these 21 tumors, 10 had microinvasive carcinoma, and 11 overt carcinoma. Sampling based on 2 sections/cm identified microinvasive carcinoma in 9 tumors and overt carcinoma in 14 tumors. With increased sampling from 1 to 2 sections/cm, the diagnosis in 3 tumors would have changed from microinvasive carcinoma to overt carcinoma, and in an additional 2 tumors from APST to APST with microinvasive carcinoma. Sampling based on >2 sections/cm changed the diagnosis in 1 additional case of APST with microinvasive carcinoma to overt carcinoma. These findings support that undetected (unsampled) occult invasion in the primary ovarian tumors is a likely explanation for some cases of apparent progression of noninvasive low-grade serous ovarian tumors to invasive LGSC. To minimize undetected occult invasion, consideration of sampling noninvasive low-grade ovarian serous tumors with at least 2 sections/cm of maximum tumor diameter may be warranted. The eosinophilic cell type of microinvasion, or microinvasive carcinoma, regardless of size, should prompt further sampling to identify overt carcinoma. The eosinophilic type of microinvasion was never seen alone in this cohort and by itself may be biologically insignificant. PMID- 30480647 TI - Ovarian Endometrioid Carcinoma Misdiagnosed as Mucinous Carcinoma: An Underrecognized Problem. AB - Primary mucinous carcinoma of the ovary is uncommon, and while numerous studies have focused on improving our ability to distinguish these tumors from gastrointestinal metastases, recent data suggest that up to one fifth are still misdiagnosed with a previously underrecognized culprit: endometrioid carcinoma. Using an index case of an ovarian endometrioid carcinoma with mucinous differentiation masquerading as a mucinous carcinoma, we sought to identify the most efficient biomarker combination that could distinguish these 2 histotypes. Eight immunohistochemical markers were assessed on tissue microarrays from 183 endometrioid carcinomas, 77 mucinous carcinomas, and 72 mucinous borderline tumors. Recursive partitioning revealed a simple 2-marker panel consisting of PR and vimentin. The combination of PR absence and vimentin absence could predict mucinous tumors with a sensitivity of 95.1%, a specificity of 96.7%, and an overall accuracy of 96.0%. Additional marker combinations did not improve accuracy. The 5-yr ovarian cancer-specific survival for mucinous carcinoma was significantly worse than endometrioid carcinoma (70% vs. 86%, respectively, P=0.02). Our proposed 2-marker algorithm allows diagnostic distinction between mucinous and endometrioid ovarian carcinomas when morphology is not straightforward. Given key differences in the underlying biology and clinical behavior of these 2 histotypes, improved diagnostic precision is essential for guiding appropriate management and treatment. PMID- 30480648 TI - Establishing a Culture of Patient Safety, Quality, and Service in Plastic Surgery: Integrating the Fractal Model. AB - PROBLEM: There are obstacles to effective nationwide implementation of a culture of patient safety. Plastic surgery faces unique challenges in this area because quality measures are not as well-established as in other fields. Plastic surgery may also require emphasis on patient-reported outcomes as a quality-of-life specialty with distinct concomitant analytical methods. APPROACH: We devised a dynamic framework, based on our 3-year experience using a Comprehensive Unit Based Safety Program-a formal quality improvement committee structure, literature review, and work from The Johns Hopkins Armstrong Institute for Patient Safety and Quality. This framework is specific and exportable to the field of plastic surgery. Monthly patient safety, quality, and service committee meetings encourage multilevel participation in a bottom-up fashion, while connecting with other departments and entities in Johns Hopkins Medicine. Our model focuses our work in the following four domains: (1) safety, (2) external measures, (3) patient experience, and (4) value. Our framework identifies and communicates clear goals, creates necessary infrastructure, identifies opportunities and needs, uses robust performance to develop and implement interventions, and includes analytics to track improvement plans and results. OUTCOMES: We have gradually implemented this quality improvement structure into the Johns Hopkins Department of Plastic and Reconstructive Surgery successfully since 2012. Outcomes have improved in externally reported measures of patient safety, quality, and service. We have demonstrated exemplary National Surgical Quality Improvement Program performance for morbidity, return to operating room, and readmission rates. Patient satisfaction surveys show improvement related to the high-level patient experience. PMID- 30480649 TI - OD, OS, and OU: Talking in Code? PMID- 30480650 TI - UDI2Claims: Planning a Pilot Project to Transmit Identifiers for Implanted Devices to the Insurance Claim. AB - BACKGROUND: In response to problems with the current postmarket surveillance of medical devices, the U.S. Food and Drug Administration mandated device labelers to include a unique device identifier (UDI), composed of a device identifier (DI) and production identifier. Including the DI in insurance claims could be a potent method to monitor implanted devices, yet implementation has lagged because of questions of benefit and operational concerns. METHODS: To illustrate the potential benefit of including DIs in claims, rates of 90-day adverse events after implantation using an electronic health record (EHR) were compared with the EHR plus claims, which capture utilization outside that EHR's health system. To explore operations, we planned a pilot project to transmit the DI of implanted devices from the point of care to the claim at two provider/payer pairs. RESULTS: By querying claims plus EHR, estimated rates of patients with potential adverse events were as much as 3.75 times higher. For our pilot, our multistakeholder team identified and resolved the following five challenges: (1) capturing the DI at the point of care; (2) selecting a location for the DI on the claim form; (3) transmitting the DI to the claim form; (4) analyzing the claim forms received by the payer; and (5) verifying the quality of the transmitted information. CONCLUSIONS: Including DIs on claims could allow more complete data capture of adverse events for implanted devices than the EHR data. We overcame challenges in transmitting the DI to the claim with attention to planning and multistakeholder involvement. PMID- 30480651 TI - Eyes and Ears on Patient Safety: Sources of Notifications About the Health, Performance, and Conduct of Health Practitioners. AB - OBJECTIVE: The aim of the study was to describe the sources of notifications of concern ("notifications") regarding the health, performance, and conduct of health practitioners from 14 registered professions in Australia. METHODS: This retrospective cohort study analyzed 43,256 notifications lodged with the Australian Health Practitioner Regulation Agency and the Health Professional Councils Authority between 2011 and 2016. We used descriptive statistical analysis to describe the characteristics of these notifications, including their source, issue and domain, and subject. RESULTS: Patients and their relatives lodged more than three-quarters (78%) of notifications regarding clinical performance, including diagnosis, treatment, and communication. Fellow practitioners were a common source of notifications about advertising and titles. Self-reports commonly related to health impairments, such as mental illness or substance use. Other agencies played a role in reporting concerns about prescribing or supply of medicines. CONCLUSIONS: Various actors in the healthcare system play different roles in sketching the picture of healthcare quality and safety that notifications present to regulators. Improved understanding of which sources are most likely to raise which concerns may enhance regulators' ability to identify and respond to patient safety risks. PMID- 30480652 TI - Ammonia Inhalation Does Not Increase Deadlift 1-Repetition Maximum in College Aged Male and Female Weight Lifters. AB - Vigil, JN, Sabatini, PL, Hill, LC, Swain, DP, and Branch, JD. Ammonia inhalation does not increase deadlift 1-repetition maximum in college-aged male and female weight lifters. J Strength Cond Res 32(12): 3392-3397, 2018-Ammonia inhalant use by powerlifters and weight lifters is a prevalent practice with little research support for improved performance. The purpose of this study was to investigate the effects of ammonia as a stimulant on athletic performance during a deadlift 1 repetition maximum (1RM) absolute strength test. Subjects (men: n = 10, mean +/- SD age = 21 +/- 1 year, mass = 72.5 +/- 6.8 kg; and women: n = 10, age = 22 +/- 5 years, mass = 66.2 +/- 8.1 kg) were required to have at least 2 years of resistance training experience while lacking a history of asthma, lightheadedness, fainting, anaphylaxis, sickle cell traits, and other respiratory disorders. After a baseline 1RM test, subjects were paired by 1RM performance and gender, then randomly assigned in a counterbalanced treatment order to control (water) or ammonia trials after a minimum 72-hour recovery period for another 1RM test involving attempts at 100.0, 102.5, 105.0, and 107.5% of the established 1RM value. Testing was then repeated after the minimum rest period for the remaining trial. Results revealed the expected gender main effect for absolute deadlift 1RM (93.0 +/- 29.5 [women]; 152.0 +/- 29.5 kg [men]; p < 0.001), but no trial main effect (p = 0.874) or gender by trial interaction effect (baseline = 93.0 +/- 15.3, 151.8 +/- 42.3 kg; water = 92.0 +/- 12.5, 150.9 +/- 37.8 kg; ammonia = 92.5 +/- 16.4, 153.4 +/- 37.9 kg) for women and men, respectively (p = 0.559). Within the limitations of this study, there is no support for the practice of ammonia inhalation to improve deadlift 1RM in training or competition. PMID- 30480653 TI - The Activity Profile of Elite Male Amateur Boxing After the 2013 Rule Changes. AB - Davis, P, Connorton, AJ, Driver, S, Anderson, S, and Waldock, R. The activity profile of elite male amateur boxing after the 2013 rule changes. J Strength Cond Res 32(12): 3450-3455, 2018-An activity profile of competitive elite amateur boxing after the rule changes in 2013 was created from video footage to allow identification of the technical and tactical demands as well as differences between winners and losers. The study analyzed 50 World Championship bouts involving 60 male boxers (mean +/- SD) of age: 23.5 +/- 2.8 years, height: 176.2 +/- 12.2 cm, and body mass: 71.7 +/- 16.2 kg. The results establish that boxing at this level requires the ability to maintain an activity rate of ~1.55 actions per second, consisting of ~21 punches, ~3.6 defensive movements, and ~56 vertical hip movements all per-minute. Winners had a higher amount of straight punches and straight punches lead hand in round 1 (both p < 0.043) along with total punches landed in round 3 (p = 0.030). They also had a lower ratio of punches thrown to punches landed in round 3 and air punches as a percentage of missed in round 2 and 3 (both p < 0.015). The results suggest that a winning strategy must include the straight punch technique from both lead and rear hands and the ability to increase punching accuracy over subsequent rounds. Tactically, boxing has become long range with straight punches, increased defense and movement around the ring, in contrast to short-range hooks as seen pre-2013. These changes should be considered when creating new training strategies. PMID- 30480654 TI - Reliability and Sensitivity of Neuromuscular and Perceptual Fatigue Measures in Collegiate Men's Basketball: Retraction. PMID- 30480655 TI - The Lack of Electromyography Normalization May Limit the Conclusions in: Traditional vs. Suspended Push-up Muscle Activation in Athletes and Sedentary Women. PMID- 30480656 TI - Response to Effects of Reactiv "Maximum Beta-Hydroxy Beta-Methylbutyrate" on Body Mass and Performance in Elite Male Rugby Players. PMID- 30480657 TI - Physical Fitness Performance of Young Professional Soccer Players Does not Change During Several Training Seasons in a Spanish Elite Reserve Team: Club Study, 1996 2013: Erratum. PMID- 30480658 TI - Methodological Flaws in Aubry, RL, Power, GA, and Burr, JF. An Assessment of Running Power as a Training Metric for Elite and Recreational Runners. J Strength Cond Res 32: 2258-2264, 2018. PMID- 30480659 TI - Authors' Response. PMID- 30480660 TI - Genome-wide polyadenylation site mapping datasets in the rice blast fungus Magnaporthe oryzae. AB - Polyadenylation plays an important role in gene regulation, thus affecting a wide variety of biological processes. In the rice blast fungus Magnaporthe oryzae the cleavage factor I protein Rpb35 is required for pre-mRNA polyadenylation and fungal virulence. Here we present the bioinformatic approach and output data related to a global survey of polyadenylation site usage in M. oryzae wild-type and Deltarbp35 strains under a variety of nutrient conditions, some of which simulate the conditions experienced by the fungus during part of its infection cycle. PMID- 30480661 TI - Comprehensive geological dataset describing a crystalline rock mass for hydraulic stimulation experiments. AB - High-resolution 3D geological models are crucial for underground development projects and corresponding numerical simulations with applications in e.g., tunneling, hydrocarbon exploration, geothermal exploitation and mining. Most geological models are based on sparse geological data sampled pointwise or along lines (e.g., boreholes), leading to oversimplified model geometries. In the framework of a hydraulic stimulation experiment in crystalline rock at the Grimsel Test Site, we collected geological data in 15 boreholes using a variety of methods to characterize a decameter-scale rock volume. The experiment aims to identify and understand relevant thermo-hydro-mechanical-seismic coupled rock mass responses during high-pressure fluid injections. Prior to fluid injections, we characterized the rock mass using geological, hydraulic and geophysical prospecting. The combination of methods allowed for compilation of a deterministic 3D geological analog that includes five shear zones, fracture density information and fracture locations. The model may serve as a decameter scale analog of crystalline basement rocks, which are often targeted for enhanced geothermal systems. In this contribution, we summarize the geological data and the resulting geological interpretation. PMID- 30480662 TI - Transcriptomic study of Herpes simplex virus type-1 using full-length sequencing techniques. AB - Herpes simplex virus type-1 (HSV-1) is a human pathogenic member of the Alphaherpesvirinae subfamily of herpesviruses. The HSV-1 genome is a large double stranded DNA specifying about 85 protein coding genes. The latest surveys have demonstrated that the HSV-1 transcriptome is much more complex than it had been thought before. Here, we provide a long-read sequencing dataset, which was generated by using the RSII and Sequel systems from Pacific Biosciences (PacBio), as well as MinION sequencing system from Oxford Nanopore Technologies (ONT). This dataset contains 39,096 reads of inserts (ROIs) mapped to the HSV-1 genome (X14112) in RSII sequencing, while Sequel sequencing yielded 77,851 ROIs. The MinION cDNA sequencing altogether resulted in 158,653 reads, while the direct RNA seq produced 16,516 reads. This dataset can be utilized for the identification of novel HSV RNAs and transcripts isoforms, as well as for the comparison of the quality and length of the sequencing reads derived from the currently available long-read sequencing platforms. The various library preparation approaches can also be compared with each other. PMID- 30480663 TI - Unified field studies of the algae testbed public-private partnership as the benchmark for algae agronomics. AB - National scale agronomic projections are an important input for assessing potential benefits of algae cultivation on the future of innovative agriculture. The Algae Testbed Public-Private Partnership was established with the goal of investigating open pond algae cultivation across different geographic, climatic, seasonal, and operational conditions while setting the benchmark for quality data collection, analysis, and dissemination. Identical algae cultivation systems and data analysis methodologies were established at testbed sites across the continental United States and Hawaii. Within this framework, the Unified Field Studies were designed for algae cultivation during all 4 seasons across the testbed network. With increasingly diverse algae research and development, and field deployment strategies, the challenges associated with data collection, quality, and dissemination increase dramatically. The dataset presented here is the complete, curated, climatic, cultivation, harvest, and biomass composition data for each season at each site. These data enable others to do in-depth cultivation, harvest, techno-economic, life cycle, resource, and predictive growth modelling analysis, as well as development of crop protection strategies throughout the algae cultivation industry. PMID- 30480664 TI - In-vivo probabilistic atlas of human thalamic nuclei based on diffusion- weighted magnetic resonance imaging. AB - The thalamic nuclei are involved in many neurodegenerative diseases and therefore, their identification is of key importance in numerous clinical treatments. Automated segmentation of thalamic subparts is currently achieved by exploring diffusion-weighted magnetic resonance imaging (DW-MRI), but in absence of such data, atlas-based segmentation can be used as an alternative. Currently, there is a limited number of available digital atlases of the thalamus. Moreover, all atlases are created using a few subjects only, thus are prone to errors due to the inter-subject variability of the thalamic morphology. In this work, we present a probabilistic atlas of anatomical subparts of the thalamus built upon a relatively large dataset where the individual thalamic parcellation was done by employing a recently proposed automatic diffusion-based clustering method. Our analyses, comparing the segmentation performance between the atlas-based and the clustering method, demonstrate the ability of the provided atlas to substitute the automated diffusion-based subdivision in the individual space when the DW-MRI is not available. PMID- 30480665 TI - Overview and experience of the YODA Project with clinical trial data sharing after 5 years. AB - The Yale University Open Data Access (YODA) Project has facilitated access to clinical trial data since 2013. The purpose of this article is to provide an overview of the Project, describe key decisions that were made when establishing data sharing policies, and suggest how our experience and the experiences of our first two data generator partners, Medtronic, Inc. and Johnson & Johnson, can be used to enhance other ongoing or future initiatives. PMID- 30480666 TI - Columbia Open Health Data, clinical concept prevalence and co-occurrence from electronic health records. AB - Columbia Open Health Data (COHD) is a publicly accessible database of electronic health record (EHR) prevalence and co-occurrence frequencies between conditions, drugs, procedures, and demographics. COHD was derived from Columbia University Irving Medical Center's Observational Health Data Sciences and Informatics (OHDSI) database. The lifetime dataset, derived from all records, contains 36,578 single concepts (11,952 conditions, 12,334 drugs, and 10,816 procedures) and 32,788,901 concept pairs from 5,364,781 patients. The 5-year dataset, derived from records from 2013-2017, contains 29,964 single concepts (10,159 conditions, 10,264 drugs, and 8,270 procedures) and 15,927,195 concept pairs from 1,790,431 patients. Exclusion of rare concepts (count <= 10) and Poisson randomization enable data sharing by eliminating risks to patient privacy. EHR prevalences are informative of healthcare consumption rates. Analysis of co-occurrence frequencies via relative frequency analysis and observed-expected frequency ratio are informative of associations between clinical concepts, useful for biomedical research tasks such as drug repurposing and pharmacovigilance. COHD is publicly accessible through a web application-programming interface (API) and downloadable from the Figshare repository. The code is available on GitHub. PMID- 30480667 TI - Predicting the mutations generated by repair of Cas9-induced double-strand breaks. AB - The DNA mutation produced by cellular repair of a CRISPR-Cas9-generated double strand break determines its phenotypic effect. It is known that the mutational outcomes are not random, but depend on DNA sequence at the targeted location. Here we systematically study the influence of flanking DNA sequence on repair outcome by measuring the edits generated by >40,000 guide RNAs (gRNAs) in synthetic constructs. We performed the experiments in a range of genetic backgrounds and using alternative CRISPR-Cas9 reagents. In total, we gathered data for >109 mutational outcomes. The majority of reproducible mutations are insertions of a single base, short deletions or longer microhomology-mediated deletions. Each gRNA has an individual cell-line-dependent bias toward particular outcomes. We uncover sequence determinants of the mutations produced and use these to derive a predictor of Cas9 editing outcomes. Improved understanding of sequence repair will allow better design of gene editing experiments. PMID- 30480668 TI - Erratum: Welcome to Innovation in Aging. AB - [This corrects the article DOI: 10.1093/geroni/igx001.][This corrects the article DOI: 10.1093/geroni/igx001.]. PMID- 30480669 TI - Correction to: Hepatology, Medicine and Policy: Articles with DOIs 10.1186/s41124 016-0014-8, 10.1186/s41124-016-0013-9 and 10.1186/s41124-016-0012-x. AB - [This corrects the article DOI: 10.1186/s41124-016-0012-x.][This corrects the article DOI: 10.1186/s41124-016-0013-9.][This corrects the article DOI: 10.1186/s41124-016-0014-8.]. PMID- 30480670 TI - New ferrocene-based 2-thio-imidazol-4-ones and their copper complexes. Synthesis and cytotoxicity. AB - Synthesis, characterization (HRMS, NMR, EPR, XANES, UV-Vis spectroscopy, and electrochemistry), DNA and BSA binding and in vitro biological screening of two new ferrocene-incorporated thiohydantoin derivatives (5 and 6) and their copper coordination compounds are reported. The ferrocene-based thiohydantoin derivatives were prepared by copper-catalyzed azide alkyne cycloaddition reactions between alkynyl ferrocenes and 5-(Z)-3-(2-azidoethyl)-2-(methylthio)-5 (pyridin-2-ylmethylene)-1H-imidazol-4H-one. Alkynyl ferrocenes necessary for these syntheses were prepared by new procedures. Intermolecular redox reactions between the ferrocene fragment and copper(+2) coordinated ions were studied by different methods to determine the mechanism and kinetic constants of redox processes. Ferrocene-containing imidazolones (5 and 6) and their copper complexes were also tested for their in vitro cytotoxic activity against MCF-7 and A-549 carcinoma cells, and also against the noncancerous cell line Hek-293. The results showed modest cytotoxicity against the subjected cancer cell line compared with cisplatin. The ability of the obtained compounds to cause DNA degradation and cell apoptosis was investigated, and the distribution of cytosol/pellets was studied by AAS. PMID- 30480671 TI - N,N-Dialkylbenzimidazol-2-ylidene platinum complexes - effects of alkyl residues and ancillary cis-ligands on anticancer activity. AB - Eleven complexes of [(1,3-dialkylbenzimidazol-2-ylidene)LnCl3-n]Pt(n-1)+, with Ln = DMSO (8), Ph3P (9), (Ph3P)2 (10), and alkyl = Me (a), Et (b), Bu (c), octyl (d), were synthesised and tested for cellular accumulation, cytotoxicity, interference with the tumour cell cycle, and interaction with DNA. The delocalised lipophilic cationic bisphosphane complexes 10 were on average found to be more cytotoxic in MTT assays against a panel of seven cancer cell lines than the neutral DMSO and monophosphane complexes 8 and 9. The uptake of complexes 10, at least into HCT116 colon carcinoma cells, was also significantly greater than that of analogues 8 and 9. Their cytotoxicities did not differ significantly with the N-alkyl side chain length. The complexes that were most active, with sub-micromolar IC50 (72 h) values against HCT116wt cells, that is 8b, 9b, 10a-c, worked by a mode of action that was dependent on the functional p53, yet were still far more active than cisplatin in both of the HCT116wt and HCT116-/- variants. In detailed binding analyses 8c, 9c and 10a-c showed a lower affinity to DNA and different binding modes when compared to cisplatin, preferably forming mono-adducts with DNA and distorting it to a lower extent. Also, unlike cisplatin, they arrested the HCT116 cells of both variants predominantly in the G1 phase. PMID- 30480672 TI - Pattern recognition of toxic metal ions using a single-probe thiocoumarin array. AB - Pattern recognition methods such as linear discriminant analysis and principal component analysis are useful tools for the identification of analytes such as metal ions. These typically use a number of distinct molecular probes that exhibit cross-reactivity. Here we report a single molecule that demonstrates varying response in different solvents, therefore enabling the combination of probe and solvent to generate the required array diversity. Seven toxic metal ions were introduced as aqueous samples, and PCA and LDA techniques applied. The array could correctly identify all metals in pure water samples, all metals in doped lake-water samples. Further, we have explored the limit of detection of the system for two metal ions, Cu(ii) and Hg(ii), confirming the promise of the system as a candidate to identify toxic metals in environmental water sources. PMID- 30480673 TI - The capricious nature of iodine catenation in I2 excess, perovskite-derived hybrid Pt(iv) compounds. AB - Perovskite-derived hybrid platinum iodides with the general formula A2PtIVI6 (A = formamidinium FA and guanidinium GUA) accommodate excess I2 to yield hydrogen bond-stabilized compounds where the I2 forms catenates with I- anions on the PtI6 octahedra. PMID- 30480674 TI - One-pot synthesis of highly sintering- and coking-resistant Ni nanoparticles encapsulated in dendritic mesoporous SiO2 for methane dry reforming. AB - We present a one-pot method for the encapsulation of small Ni particles into a dendritic SiO2 skeleton. Such confined Ni particles are robust against metal particle sintering and preferentially grow amorphous carbon instead of graphitized carbon, which maintain high activity and stability towards methane dry reforming at 700 degrees C for 200 h. PMID- 30480675 TI - Luminescent materials of lanthanoid complexes hosted in zeolites. AB - Herein we highlight our systematic efforts to develop luminescent hybrid materials by modifying zeolites with lanthanoid complexes, and studies conducted by other groups are also included where it is necessary. Four main approaches were employed to modify zeolites with lanthanoid complexes to produce luminescent hybrid materials: inside functions, closure of the pore opening with an organic sensitizer, inside-outside double functions, and embedding the hybrid materials within matrices. Our emphasis is especially placed on understanding the influence of microenvironments of the void spaces on the luminescence performances of the encapsulated lanthanoid complexes, which has important implications for optimizing the luminescence of the resulting hybrid materials, and potential application as luminescent sensors. PMID- 30480676 TI - Double-excitation manifold's effect on exciton transfer dynamics and the efficiency of coherent light harvesting. AB - The efficiency of natural light harvesting systems is largely determined by their ability to transfer excitations from the antenna to the energy trapping center before recombination. The exciton diffusion length similarly limits organic photovoltaics and demands bulk heterojunction architectures. Dark state protection, achieved by coherent coupling between subunits within the antenna, can significantly reduce radiative recombination and enhance the efficiency of energy trapping. In this work we extend the dark state concept to the double excitation manifold by studying the dynamical flow of excitations. We show that the lowest double-excitation state carries minimal oscillator strength, but relaxation to this state from higher lying double excitations can be relatively rapid such that the lowest double excitation state can act as a dynamical dark state protecting excitation from radiative recombination. This mechanism is sensitive to topology and operates differently for chain and ring structures, while becoming more pronounced in both geometries when the size of the antenna increases. When the exciton-exciton annihilation (EEA) mechanism is considered, the double-excitation population is quickly depleted and the dynamics change dramatically. However the efficiency and output power are still significantly different from those calculated using the single-excitation manifold alone, justifying the necessity of considering the double-excitation manifold. Remarkably, in certain scenarios, EEA can even increase the overall light harvesting efficiency by bringing population down from the double-excitation dark states to the single-excitation manifold. PMID- 30480677 TI - Single photon ionization time-of-flight mass spectrometry with a windowless RF discharge lamp for high temporal resolution monitoring of the initial stage of methanol-to-olefins reaction. AB - Methanol-to-olefins (MTO) is a very important industrial catalysis technique for the production of light olefins, which is of great economic value and strategic significance. However, it is a great challenge for the traditional analytical methods to obtain the real-time information of product variation during MTO reaction process, which is vital for the conversion process research and mechanism explanation. In this study, a single photon ionization time-of-flight mass spectrometry (SPI-TOFMS) based on a windowless RF-discharge (WLRF) lamp was developed for real-time measurement of catalytic product during the initial stage of MTO reaction. The vacuum ultraviolet (VUV) photon energy was easily adjusted by changing the discharge gas. Argon (Ar) gas was eventually adopted as the discharge gas, since it produces photons with appropriate energy of 11.6 eV and 11.8 eV for ionization of light olefin molecules. The detection sensitivities of ethylene and propylene were largely improved to a substantially similar level with limits of detection (LODs) down to 16.98 and 9.64 ppbv, respectively. The initial stage of MTO reaction was real-time monitored with a high temporal resolution of 0.5 s, revealing that ethylene was the first olefin product followed by propylene. The successful application of WLRF-SPI-TOFMS in the monitoring of MTO catalytic process indicated broad application prospects of this instrument in the industrial reaction process monitoring. PMID- 30480678 TI - Photo-triggered conversion of hydrophilic fluorescent biomimetic nanostructures for cell imaging. AB - Fluorescent nanoarchitectures, such as hydrophobic micelles and hydrophilic vesicles decorated with fluorescent carbon nanoparticles, were fabricated from one fatty acid by means of photo-triggering. The biomimetic nanostructures, like cell membrane structures, have applications in fluorescence imaging in both the cell cytoplasm and nucleus. Besides, hydrophobic micelles can be used as very stable fluorescent inks. PMID- 30480679 TI - Recent advances in nucleophile-triggered CO2-incorporated cyclization leading to heterocycles. AB - Carbon dioxide (CO2) has emerged as a sustainable, feasible, abundant one-carbon synthon and displays great potential in the synthesis of heterocycles such as lactones, lactams, and 2-oxazolidinones, which are privileged motifs in pharmaceutical chemistry demonstrating bioactivities. Although the fixation of CO2 is restricted due to its thermodynamic stability and kinetic inertness, multiple breakthroughs have been realized in annulation chemistry. This review concentrates on the advances made in the last five years in CO2-incorporated cyclization triggered by N-, O-, and C-nucleophiles. Three transformation modes of CO2 including carboxylative cyclization, carbonylative cyclization, and reductive cyclization have been summarized. Moreover, typical mechanisms and significant applications of these reactions are also described. PMID- 30480680 TI - Tracking mitochondrial 1O2-ROS production through a differential mitochondria nucleoli fluorescent probe. AB - The dual-emissive fluorescent probe described here enabled dynamic tracking of singlet oxygen (1O2)-ROS species production and localization dynamics between the mitochondria and nucleoli in the presence of agents perturbing the mitochondrial membrane potential and under a photodynamic (PDT) system. Local structural information during the probe-1O2 interaction was followed by spectrally resolved confocal microscopy. PMID- 30480681 TI - Solving the Schrodinger equation of hydrogen molecules with the free-complement variational theory: essentially exact potential curves and vibrational levels of the ground and excited states of the Sigma symmetry. AB - The Schrodinger equation of hydrogen molecules was solved essentially exactly and systematically for calculating the potential energy curves of the electronic ground and excited states of the 1Sigmag, 1Sigmau, 3Sigmag, and 3Sigmau symmetries. The basic theory is the variational free complement theory, which is an exact general theory for solving the Schrodinger equation of atoms and molecules. The results are essentially exact with the absolute energies being correct beyond MU-hartree digits. Furthermore, all of the present wave functions satisfy correct orthogonalities and Hamiltonian-orthogonalities to each other at every nuclear distance along the potential curve, which makes systematic analyses and discussions possible among all the calculated electronic states. It is noteworthy that these conditions were not satisfied in many of the accurate calculations of H2 reported so far. Based on the present essentially exact potential curves, we calculated and analyzed the vibrational energy levels associated with all the electronic states. Among them, the excited states having double-well potentials showed some interesting features of the vibrational states. These results are worthy of future investigations in astronomical studies. PMID- 30480682 TI - Si(bzimpy)2 - a hexacoordinate silicon pincer complex for electron transport and electroluminescence. AB - A neutral hexacoordinate silicon complex containing two 2,6-bis(benzimidazol-2' yl)pyridine (bzimpy) ligands has been synthesized and explored as a potential electron transport layer and electroluminescent layer in organic electronic devices. The air and water stable complex is fluorescent in solution with a lambdamax = 510 nm and a QY = 57%. Thin films grown via thermal evaporation also fluoresce and possess an average electron mobility of 6.3 * 10-5 cm2 V-1 s-1. An ITO/Si(bzimpy)2/Al device exhibits electroluminescence with lambdamax = 560 nm. PMID- 30480683 TI - Interlayer expansion of 2D MoS2 nanosheets for highly improved photothermal therapy of tumors in vitro and in vivo. AB - Interlayer-expanded MoS2 (E-MoS2) nanosheets with an interlayer spacing of 0.94 nm are demonstrated to show an high photothermal conversion efficiency of ~62%. More importantly, such biocompatible E-MoS2 nanosheets show highly improved photothermal therapy (PTT) of tumors in vitro and in vivo under near-infrared light irradiation. PMID- 30480684 TI - A label-free immunosensor for the detection of nuclear matrix protein-22 based on a chrysanthemum-like Co-MOFs/CuAu NWs nanocomposite. AB - In this study, a new, simple, and label-free electrochemical immunosensor was presented for the detection of nuclear matrix protein-22 (NMP-22). In order to accurately monitor very small amounts of NMP-22, it was advantageous to use highly efficient nanomaterials as signals. For this reason, we synthesized a chrysanthemum-like nanocomposite (Co-MOFs/CuAu NWs), using Co-based metal-organic frameworks (Co-MOFs) as carriers and copper gold nanowires (CuAu NWs) wrapped around their surface, which was applied for modifying a glassy carbon electrode (GCE). The Co-MOFs/CuAu NWs possessed outstanding catalytic capabilities, which served as signal materials and simultaneously carried the anti-NMP-22 antibody (Ab). When different concentrations of the NMP-22 antigen (Ag) were specifically attached to the immunosensor, the current responses decreased by varying degrees. The designed biosensor used the principle to establish a linear regression equation and achieve an accurate quantification of NMP-22. After optimization, the NMP-22 sensor exhibited a good linear response over a concentration range from 0.1 pg mL-1 to 1 ng mL-1, with a lower detection limit of 33 fg mL-1 (based on S/N = 3). The proposed biosensor demonstrated the advantages of ultra sensitivity, high specificity and acceptable reproducibility, suggesting that the proposed strategy has the potential for the quantification of NMP-22 in human urine samples. Moreover, the novel nanocomposite Co-MOFs/CuAu NWs are promising materials for electrochemical sensors to detect other biomolecules. PMID- 30480685 TI - Single molecule magnetic behaviour in lanthanide naphthalenesulfonate complexes. AB - The use of 2-naphthalenesulfonate (NAS) ligand in lanthanide chemistry afforded a family of isostructural mononuclear lanthanide complexes with the formula [Ln(NAS)2(H2O)6](NAS).3H2O [Ln = Tb (1), Dy (2), Er (3), Yb (4)]. Crystallographic studies determined a square antiprismatic geometry (D4d) for the Ln centre and crystallization in an unprecedented chiral space group. The latter was further confirmed by the observation of Cotton effects in single crystal circular dichroism (CD) spectra. Static and dynamic magnetic measurements identified weak intermolecular dipolar interactions in 2, and such effects can be waived by dilution, which was noted by the detection of zero-field single molecule magnet (SMM) behaviour and hysteresis loop in a magnetically diluted sample (5). Compounds 2-4 exhibit SMM behaviours with energy barriers of 53, 32, and 45 K, respectively. To the best of our knowledge, these complexes are the first examples of pure 4f sulfonate-based SMMs. PMID- 30480686 TI - OFF/ON switching of circularly polarized luminescence by oxophilic interaction of homochiral sulfoxide-containing o-OPEs with metal cations. AB - Here we describe a new class of CPL switches based on oxophilic interactions between chiral sulfoxide-containing ortho-phenylene ethynylene (o-OPE) foldamers and cationic metals. These systems represent a unique case combining high glum values (up to 0.7 * 10-2) and high quantum yields in both folded ON and unfolded OFF CPL states. PMID- 30480687 TI - Unexpected wavelength dependency of the photocatalytic CO2 reduction performance of the well-known (bpy)Re(CO)3Cl complex. AB - The selective photocatalytic reduction of CO2 to CO has often been accomplished using complexes incorporating the Re(CO)3Cl fragment. We now discovered that the photocatalytic performance of the well-known parent compound (bpy)Re(CO)3Cl (bpy = 2,2'-bipyridine) surprisingly depends on the illumination wavelengths: the turnover numbers (TONs) measured using various cut-off filters showed an increased photocatalytic activity when irradiated with visible light with wavelengths longer than 450 nm - even if the compound hardly absorbs light in this wavelength region. Therefore, catalytic, spectroscopic and theoretical investigations were performed to explain this exceptional effect. PMID- 30480688 TI - A mitochondria-targeted nitric oxide donor triggered by superoxide radical to alleviate myocardial ischemia/reperfusion injury. AB - A novel mitochondria-targeted superoxide-responsive nitric oxide donor was developed by incorporation of diphenylphosphinyl and triphenylphosphonium groups into diazeniumdiolate, enabling remarkable protection against ischemia/reperfusion injury in H9c2 cells and isolated rat hearts. PMID- 30480690 TI - A capping agent dissolution method for the synthesis of metal nanosponges and their catalytic activity towards nitroarene reduction under mild conditions. AB - We report a general strategy for the synthesis of metal nanosponges (M = Ag, Au, Pt, Pd, and Cu) using a capping agent dissolution method where addition of water to the M@BNHx nanocomposite affords the metal nanosponges. The B-H bond of the BNHx polymer gets hydrolysed upon addition of water and produces hydrogen gas bubbles which act as dynamic templates leading to the formation of nanosponges. The rate of B-H bond hydrolysis has a direct impact on the final nanostructure of the materials. The metal nanosponges were characterized using powder XRD, electron microscopy, XPS, and BET surface area analyzer techniques. The porous structure of these nanosponges offers a large number of accessible surface sites for catalytic reactions. The catalytic activity of these metal nanosponges has been demonstrated for the reduction of 4-nitrophenol where palladium exhibits the highest catalytic activity (k = 0.314 min-1). The catalytic activity of palladium nanosponge was verified for the tandem dehydrogenation of ammonia borane and the hydrogenation of nitroarenes to arylamines in methanol at room temperature. The reduction of various substituted nitroarenes was proven to be functional group tolerant except for a few halogenated nitroarenes (X = Br and I) and >99% conversion was noted within 30-60 min with high turnover frequencies (TOF) at low catalyst loading (0.1 mol%). The catalyst could be easily separated out from the reaction mixture via centrifugation and was recyclable over several cycles, retaining its porous structure. PMID- 30480689 TI - Interaction of monohydrogensulfide with a family of fluorescent pyridoxal-based Zn(ii) receptors. AB - H2S and its conjugate base HS- have recently gained increasing attention for their reactivity with bioinorganic targets. However, so far, stable adducts of bioinorganic compounds with H2S/HS- are still scarce due to the propensity of sulfide to form insoluble metal sulfides. In this work, we studied the reactivity of HS- with a family of fluorescent zinc complexes via a variety of spectroscopic techniques. The complexes selected for this study feature a pyridoxal moiety with different substituent groups on the ligand framework. Interaction of the complexes under investigation with HS- results in the displacement of the coordinated ligand from the Zn center with the concomitant precipitation of ZnS in the case of complexes 1 and 3, whereas for complex 2 our data points to the coordination of HS- to the metal center likely assisted by hydrogen bonding with the OH of the pyridoxal moiety. In the presence of HS-, the fluorescence emission of complex 2 is enhanced, whereas the fluorescence emission of complexes 1 and 3 is quenched. The results highlight the potential of complex 2 to be implemented as a HS- fluorescent sensor via a coordinative-based approach. PMID- 30480691 TI - Strain-controlled high harmonic generation with Dirac fermions in silicene. AB - Two-dimensional (2D) materials with zero band gap exhibit remarkable electronic properties with wide tunability. High harmonic generation (HHG) in such materials offers unique platforms to develop novel optoelectronic devices at the nanoscale, as well as to investigate strong-field and ultrafast nonlinear behaviour of massless Dirac fermions. However, control of HHG by modulating the electronic structures of materials has remained largely unexplored to date. Here we report controllable HHG by tuning the electronic structures via mechanical engineering. Using an ab initio approach based on time-dependent density-functional theory (TDDFT), we show that the HHG process is sensitive to the modulation of band structures of monolayer silicene while preserving the Dirac cones under biaxial and uniaxial strains, which can lead to significant enhancement of harmonic intensity up to an order of magnitude. With the additional advantage of silicene in compatibility and integration into the current silicon-based electronic industry, this study may open a new avenue to develop efficient solid-state optoelectronic nano-devices, and provide a valuable tool to understand the strong field and mechanically induced ultrafast nonlinear response of Dirac carriers in 2D materials. PMID- 30480692 TI - Tetrazastannoles versus distannadiazanes - a question of the tin(ii) source. AB - Various tin(ii) compounds such as Mes*2Sn (Mes* = 2,4,6-tri-tert-butylphenyl), Sn[N(SiMe3)2]2 and TerSnCl (Ter = 2,6-bis(2,4,6-trimethylphenyl)phenyl) could be readily oxidised by organic azides to release N2, forming nitrogen-tin compounds. Depending on the used Sn(ii) compound, the reactions with two equivalents of azide led to the formation of tetrazastannoles (R2N4SnR'2) or cyclo distannadiazanes [R2Sn(MU-NR')]2. The reactivity was independent of the electronic situation of the organic azide. Additionally, Mes*2Sn formed an amido azido compound of the type R(R')Sn(N(SiMe3)2)N3 in the presence of Me3SiN3. Presumably, the corresponding tetrazastannole was formed in the first step followed by a ring opening reaction. The same holds true for the reaction of Sn[N(SiMe3)2]2 with Me3SiN3 while TerSnCl showed no reaction in the presence of Me3SiN3, even after prolonged heating. PMID- 30480693 TI - Modifying methylalumoxane via alkyl exchange. AB - Methylalumoxane (MAO) ionizes highly selectively in the presence of octamethyltrisiloxane (OMTS) to generate [Me2Al.OMTS]+ [(MeAlO)16(Me3Al)6Me]-. We can take advantage of this transformation to examine the reactivity of a key component of MAO using electrospray ionization mass spectrometry (ESI-MS), and here we describe the reactivity of this pair of ions with other trialkyl aluminum (R3Al) components. Using continuous injection methods, we found Et3Al to exchange much faster and extensively at room temperature in fluorobenzene (t1/2 ~2 s, up to 25 exchanges of Me for Et) than iBu3Al (t1/2 ~40 s, up to 11 exchanges) or Oct3Al (t1/2 ~200 s, up to 7 exchanges). The exchanges are reversible and the methyl groups on the cation are also observed to exchange with the added R3Al species. These results point to the reactive components of MAO having a structure that deviates significantly from the cage-like motifs studied to date. PMID- 30480694 TI - Highly self-diffused Sn doping in alpha-Fe2O3 nanorod photoanodes initiated from beta-FeOOH nanorod/FTO by hydrogen treatment for solar water oxidation. AB - In this study, we present an advanced strategy of low-temperature hydrogen annealing combined with high- temperature quenching in air for activating alpha Fe2O3 nanorod photoanodes to boost the photoelectrochemical performance. We report that various low-temperature annealing conditions (340, 360, 380, and 400 degrees C) under hydrogen gas flow convert beta-FeOOH into magnetite (Fe3O4) as well as introduce Sn4+ diffusion from FTO substrates to its surface. Furthermore, high-temperature quenching (800 degrees C) resulted in the phase change of magnetite (Fe3O4) into hematite (alpha-Fe2O3) and self Sn4+ doping into the hematite lattice. Thus, the hydrogen-assisted thermally activated hematite photoanode achieved a photocurrent density of 1.35 mA cm-2 at 1.23 V vs. RHE and 1.91 mA cm-2 at 1.4 V vs. RHE, which is 70% and 80% higher than that of directly quenched hematite at 800 degrees C. These combined two step strategies provide new insight into high Sn-self doping for alpha-Fe2O3 photoanodes and allow for further development of more efficient solar water oxidation systems. PMID- 30480695 TI - Modular functionalization of crystalline graphene by recombinant proteins: a nanoplatform for probing biomolecules. AB - Graphene, as well as other two-dimensional materials, is a promising candidate for use in bioimaging, therapeutic drug delivery, and bio-sensing applications. Here, we developed a protocol to functionalize graphene with recombinant proteins using genetically encoded SpyTag-SpyCatcher chemistry. SpyTag forms a covalent isopeptide bond with its genetically encoded partner SpyCatcher through spontaneous amidation under physiological conditions. The functionalization protocol developed is based on the use of short proteins as a linker, where two graphene-binding-peptides (GBPs) are attached to both ends of SpyTag (referred to as GStG), followed by the covalent conjugation with SpyCatcher-fusion proteins. The proposed method enables the decoration of crystalline graphene with various proteins, such as fluorescent proteins and affibody molecules that bind to cancerous cells. This scheme, which takes advantage of the cleanness of single crystal graphene and the robustness of SpyTag-SpyCatcher chemistry, provides a versatile platform on which to study the biomolecule-surface and cell-substrate interactions and, indeed, may lead to a new way of designing biomedical devices. The interaction between peptides and graphene was clearly shown using molecular dynamics simulation and proven using specially designed experiments. PMID- 30480696 TI - Metallic MoS2 nanosheets: multifunctional electrocatalyst for the ORR, OER and Li O2 batteries. AB - Lithium-oxygen batteries (LOBs) possess the highest theoretical specific density among all types of lithium batteries, making them ideal candidates to replace the current Li ion batteries for next-generation electric vehicle applications. However, designing highly active catalysts with high electronic conductivities to kinetically accelerate the sluggish oxygen reduction/evolution reactions (ORR/OER) is still a big challenge. This work was dedicated to developing two dimensional (2D) trigonal phase MoS2 (1T-MoS2) nanosheets as a highly active electrocatalyst for LOBs for the first time. Metallic 1T-MoS2 prepared via in situ liquid-redox intercalation and exfoliation was hybridized with functionalized carbon nanotubes (CNTs) to form freestanding, binder-free oxygen electrodes. The 1T-MoS2/CNT electrode exhibited excellent electrochemical performances with a high reversible capacity of 500 mA h g-1 at a current density of 200 mA g-1 for more than 100 cycles owing to the catalytically active surfaces of 1T-MoS2 accessible by Li+ ions and O2. Density functional theory (DFT) calculations identified the catalytically active basal planes in 1T-MoS2 during the ORR as well as the initial ORR path during LOB cycles. The results based on the rotational ring disk electrode (RRDE) experiments also supported the findings from the DFT calculations, where the 1T-MoS2 basal planes are active for both the ORR and OER, not the semiconducting hexagonal MoS2 (2H-MoS2) whose edges are only electrocatalytically active. This study sheds light on the use of metallic 1T MoS2 as a multifunctional oxygen electrocatalyst for LOB applications with enhanced ORR and OER activities. PMID- 30480697 TI - A 3D conductive network of porous carbon nanoparticles interconnected with carbon nanotubes as the sulfur host for long cycle life lithium-sulfur batteries. AB - Constructing an interlinked three-dimensional conductive carbon structure as a sulfur host is considered to be an effective strategy for suppressing the capacity decay over long-term cycling and improving the rate performance of lithium-sulfur (Li-S) batteries, because it can not only facilitate rapid electronic and ionic transportation in the cathode, but also be conducive to confine lithium polysulfide (LiPS) dissolution and shuttling. In this report, we designed a novel 3D conductive network structure (CNTs/Co-NC), which is composed of Co-NC (cobalt embedded in an N-doped porous carbon composite) derived from ZIF 67 polyhedra and inserted carbon nanotubes (CNTs), and applied it as a sulfur host for Li-S batteries. The CNT/Co-NC network structure is firstly prepared via the in situ nucleation of small ZIF-67 crystals on the surface of CNTs and eventually grown into CNT/ZIF-67 hybrid materials; after subsequent carbonization and infiltration of sulfur procedures, the S@CNT/Co-NC cathode is obtained. Li-S batteries based on the S@CNT/Co-NC cathode show an improved rate capability of 772.6 mA h g-1 at the 2 C rate, enhanced long cycling stability under a large current density with a low capacity decay rate of ~0.067% per cycle at the 0.5 C rate after 500 cycles and ~0.072% per cycle at the 1 C rate after 700 cycles and an excellent coulombic efficiency of about 95% up to 500 cycles at 0.5 C and 91% up to 700 cycles at 1 C. The superior performance of S@CNTs/Co-NC should be ascribed to the rapid charge transfer, excellent electron conductivity, improved adsorption capability for LiPSs and enhanced redox kinetics of this 3D conductive network structure. PMID- 30480698 TI - Process-induced cell wall permeability modulates the in vitro starch digestion kinetics of common bean cotyledon cells. AB - The presence of cell walls entrapping starch granules in common bean cotyledons, prevailing after thermal processing and mechanical disintegration, has been identified as the main reason for their (s)low in vitro starch digestibility. Nevertheless, it is unknown if the role of cell walls on starch digestion changes as processing conditions (e.g. time) are modified. In this study, it was hypothesised that cell wall permeability would be differently affected depending on thermal process intensity, giving origin to distinct in vitro starch digestion kinetic profiles. Cotyledon cells were isolated from common beans by applying processing conditions normally found at the household level (95 degrees C and times between 30 and 180 min (palatable range)). Isolated cells were characterised and subsequently subjected to in vitro simulated digestion. Microstructural properties, the starch gelatinisation degree, and the total starch content were similar among samples. In contrast, a higher diffusion of fluorescently labelled pancreatic alpha-amylase inside the cells was evident as processing time increased. From the kinetic analysis of digestion products, it was determined that longer lag phases and slower reaction rate constants were present in samples with a lower degree of process-induced cell wall permeability. The qualitative analysis of the remaining pellets showed that cellular integrity was maintained throughout in vitro digestion. A mechanism for the in vitro starch digestion of isolated common bean cotyledon cells as well as an alternative kinetic model to describe this process were proposed. Overall, our work demonstrated that the in vitro starch digestion kinetics of common bean cotyledon cells can be modulated by influencing cell wall permeability through thermal processing time. PMID- 30480699 TI - Elevated air humidity increases UV mediated leaf and DNA damage in pea (Pisum sativum) due to reduced flavonoid content and antioxidant power. AB - Growth in high relative air humidity (RH, >85%) affects plant morphology and causes diminished response to stomatal closing signals. Many greenhouses are prone to high RH conditions, which may negatively affect production and post harvest quality. UV radiation induces stomatal closure in several species, and facilitates disease control. We hypothesised that UV exposure may trigger stomatal closure in pea plants (Pisum sativum) grown in high RH, thereby restoring stomatal function. The effects of UV exposure were tested on plants grown in moderate (60%) or high (90%) RH. UV exposure occurred at night, according to a disease control protocol. Lower stomatal conductance rates were found in UV-exposed plants, though UV exposure did not improve the rate of response to closing stimuli or desiccation tolerance. UV-exposed plants showed leaf curling, chlorosis, necrosis, and DNA damage measured by the presence of cyclobutane pyrimidine dimers (CPD), all of which were significantly greater in high RH plants. These plants also had lower total flavonoid content than moderate RH plants, and UV-exposed plants had less than controls. Plants exposed to UV had a higher content of cuticular layer uronic compounds than control plants. However, high RH plants had a higher relative amount of cuticular waxes, but decreased proteins and uronic compounds. Plants grown in high RH had reduced foliar antioxidant power compared to moderate RH. These results indicate that high RH plants were more susceptible to UV-induced damage than moderate RH plants due to reduced flavonoid content and oxidative stress defence. PMID- 30480700 TI - Signatures of consolidated superparamagnetic and spin-glass behavior in magnetite silver core-shell nanoparticles. AB - A detailed investigation of magnetization relaxation for silver-coated magnetite nanostructures with three different types of magnetic behavior in a single particle is presented. Magnetite nanoparticles of diameter ~6.5 nm synthesized via single-phase emulsion were further coated with a silver shell of thickness ~2 nm. The synthesized nanoparticles are found to be efficiently photoluminescent. The coating of silver generates a magnetically disordered spin layer at the interface of the magnetic core and the non-magnetic shell. This intermediate layer plays a significant role in the dynamical magnetic response of nanoparticles under an external magnetic field. We present detailed magnetic measurements such as field- and temperature-dependent dc magnetization with zero field-cooled and field-cooled protocols, ac susceptibility and time decay of magnetization relaxation along with their analysis using various formalisms viz. Neel-Arrhenius, Vogel-Fulcher and power law models. The relaxation analysis suggests the consolidated presence of two characteristic relaxation times corresponding to the superparamagnetic and spin-glass behavior of silver-coated magnetite nanoparticles. PMID- 30480701 TI - Metalation behavior of a bis-saturated NHC ligand with a flexible m-xylyl linker. AB - Saturated N-heterocyclic carbenes have unique ligand properties that differ even from their unsaturated analogs. While the unsaturated version has been extensively used in multidentate ligand scaffolds, the incorporation of the saturated version is less common. Here we report the straightforward synthesis of a new bis-saturated N-heterocyclic carbene ligand wherein the carbene moieties are linked by a flexible meta-xylyl unit. Carbene metal complexes of the proligand can be generated by direct metalation, transmetallation or base assisted metalation all of which lead to monodentate coordination modes of silver or iridium. Attempts at direct metalation using zirconium tetrakis-dimethylamide did not lead to complex formation but to the chloroform adduct or amide addition product. As yet, a method to generate pincer complexes from this ligand has not been found. The flexible nature of the xylyl linker as well as the higher sigma bacisity and pi-acidity are postulated to contribute to these results. PMID- 30480702 TI - A Time to Press Reset and Regenerate Cardiac Stem Cell Biology. PMID- 30480703 TI - Penetrance of the ABCA4 p.Asn1868Ile Allele in Stargardt Disease. PMID- 30480704 TI - Author Response: Penetrance of the ABCA4 p.Asn1868Ile Allele in Stargardt Disease. PMID- 30480705 TI - Morphologic, Biomechanical, and Compositional Features of the Internal Limiting Membrane in Pathologic Myopic Foveoschisis. AB - Purpose: To investigate alterations in the morphologic, compositional, and biomechanical properties of the internal limiting membrane (ILM) in pathologic myopic foveoschisis (MF) eyes. Methods: ILM specimens were peeled from 61 eyes with MF and 56 eyes with stage III/IV idiopathic macular hole (IMH) as a control. Samples were analyzed for transmission electron microscopy (TEM), scanning electron microscopy, immunofluorescence, Western blotting, and atomic force microscopy. ILM characteristics were compared between the two groups. Results: TEM findings revealed that thickness of the MF ILMs significantly decreased compared with that of IMH ILMs (0.753 +/- 0.215 vs. 1.894 +/- 0.247 MUm; P < 0.0001). The vitreal side stiffness of the MF ILMs was markedly higher than that of the IMH ILMs (3.520 +/- 0.803 vs. 0.879 +/- 0.230 MPa, P < 0.0001). Comparing with the IMH group, collagen IV exhibited decreased concentration and different immunofluorescence distribution in ILMs of MF eyes, so also protein alpha3 (IV), alpha4 (IV), and alpha5 (IV). The immunofluorescence staining results showed that astrocytes were observed in none of the IMH eyes and in 12 of 16 MF eyes (75%, P < 0.0001). Conclusions: These alterations in the MF ILMs appear to be associated with Muller cell and astrocyte reactive gliosis. The present findings contribute to a more in-depth understanding of the pathogenesis of MF. PMID- 30480707 TI - Incorrect Data in Figures. PMID- 30480706 TI - IL-1 and TGF-beta Modulation of Epithelial Basement Membrane Components Perlecan and Nidogen Production by Corneal Stromal Cells. AB - Purpose: To determine whether (1) the in vitro expression of epithelial basement membrane components nidogen-1, nidogen-2, and perlecan by keratocytes, corneal fibroblasts, and myofibroblasts is modulated by cytokines/growth factors, and (2) perlecan protein is produced by stromal cells after photorefractive keratectomy. Methods: Marker-verified rabbit keratocytes, corneal fibroblasts, myofibroblasts were stimulated with TGF-beta1, IL-1alpha, IL-1beta, TGF-beta3, platelet-derived growth factor (PDGF)-AA, or PDGF-AB. Real-time quantitative RT-PCR was used to detect expression of nidogen-1, nidogen-2, and perlecan mRNAs. Western blotting evaluated changes in protein expression. Immunohistochemistry was performed on rabbit corneas for perlecan, alpha-smooth muscle actin, keratocan, vimentin, and CD45 at time points from 1 day to 1 month after photorefractive keratectomy (PRK). Results: IL-1alpha or -1beta significantly upregulated perlecan mRNA expression in keratocytes. TGF-beta1 or -beta3 markedly downregulated nidogen-1 or -2 mRNA expression in keratocytes. None of these cytokines had significant effects on nidogen-1, -2, or perlecan mRNA expression in corneal fibroblasts or myofibroblasts. IL-1alpha significantly upregulated, while TGF-beta1 significantly downregulated, perlecan protein expression in keratocytes. Perlecan protein expression was upregulated in anterior stromal cells at 1 and 2 days after -4.5 or -9 diopters (D) PRK, but the subepithelial localization of perlecan became disrupted at 7 days and later time points in -9-D PRK corneas when myofibroblasts populated the anterior stroma. Conclusions: IL-1 and TGF-beta1 have opposing effects on perlecan and nidogen expression by keratocytes in vitro. Proximate participation of keratocytes is likely needed to regenerate normal epithelial basement membrane after corneal injury. PMID- 30480708 TI - Unclear Sentence and Incorrect Number in Figure. PMID- 30480710 TI - Opioid-Related Problems Increasing Among Older Adults. PMID- 30480709 TI - Preventing Maltreatment of Children. PMID- 30480711 TI - Declining Numbers of Rural US Hospitals. PMID- 30480712 TI - New NIH-DoD Limb Loss Registry. PMID- 30480714 TI - Curbing Surprise Medical Bills Can Be a Window Into Cost Control. PMID- 30480715 TI - The Production of Drug Plants in the United States. PMID- 30480716 TI - Trends in Telemedicine Use in a Large Commercially Insured Population, 2005-2017. PMID- 30480717 TI - Trends in First Gabapentin and Pregabalin Prescriptions in Primary Care in the United Kingdom, 1993-2017. PMID- 30480718 TI - Cardiac Outcomes After Treatment for Depression in Patients With Acute Coronary Syndrome. PMID- 30480719 TI - Baseline Genotype Testing to Assess Drug Resistance Before Beginning HIV Treatment. PMID- 30480720 TI - Cardiac Outcomes After Treatment for Depression in Patients With Acute Coronary Syndrome. PMID- 30480721 TI - Cardiac Outcomes After Treatment for Depression in Patients With Acute Coronary Syndrome. PMID- 30480722 TI - Baseline Genotype Testing to Assess Drug Resistance Before Beginning HIV Treatment-Reply. PMID- 30480723 TI - Cardiac Outcomes After Treatment for Depression in Patients With Acute Coronary Syndrome-Reply. PMID- 30480725 TI - Behavior Therapy for Cognitive Decline. PMID- 30480724 TI - Vaccine Prevents Active Tuberculosis. PMID- 30480726 TI - High-Dose Folic Acid Does Not Prevent Preeclampsia. PMID- 30480727 TI - Artificial Pancreas Improves Glycemic Control. PMID- 30480728 TI - Hypertension Drug Fails to Slow Cognitive Decline. PMID- 30480730 TI - Interventions to Prevent Child Maltreatment. PMID- 30480729 TI - Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial. AB - Importance: Current treatments for long-term prophylaxis in hereditary angioedema have limitations. Objective: To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks. Design, Setting, and Participants: Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized. Interventions: Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments. Main Outcome and Measures: Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period. Results: Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4 week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were 1.49 (95% CI, -1.90 to -1.08; P < .001); -1.44 (95% CI, -1.84 to -1.04; P < .001); and -1.71 (95% CI, -2.09 to -1.33; P < .001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab). Conclusions and Relevance: Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy. Trial Registration: EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805. PMID- 30480732 TI - Seeing the Present Through the Past: History, Empathy, and Medical Education. PMID- 30480734 TI - Primary Care Interventions to Prevent Child Maltreatment: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. AB - Importance: Child maltreatment, also referred to as child abuse and neglect, can result in lifelong negative consequences. Objective: To update the evidence on interventions provided in or referable from primary care to prevent child maltreatment for the US Preventive Services Task Force. Data Sources: PubMed, Cochrane Library, EMBASE, and trial registries through December 18, 2017; references; experts; literature surveillance through July 17, 2018. Study Selection: English-language fair- and good-quality randomized clinical trials that (1) included children with no known exposure to maltreatment and no signs or symptoms of current or past maltreatment, (2) evaluated interventions feasible in a primary care setting or that could result from a referral from primary care, and (3) reported abuse or neglect outcomes or proxies for abuse or neglect (eg, injury with a specificity for abuse, visits to the emergency department, hospitalization). Data Extraction and Synthesis: Two reviewers independently assessed titles/abstracts, full-text articles, and study quality; a third resolved conflicts when needed. When at least 3 similar trials were available, random-effects meta-analyses were conducted. Main Outcomes and Measures: Direct measures (including reports to child protective services and removal of the child from the home) or proxy measures of abuse or neglect; behavioral, emotional, mental, or physical well-being; and harms. Results: Twenty-two trials (33 publications) were included (N = 11 132). No significant association was found between interventions and reports to child protective services within 1 year of intervention completion (10.6% vs 11.9%; pooled odds ratio [OR], 0.94 [95% CI, 0.72-1.23]; 10 trials [n = 2444]) or removal of the child from the home within 1 to 3 years of follow-up (3.5% vs 3.7%; pooled OR, 1.09 [95% CI, 0.16-7.28]; 4 trials [n = 609]). No statistically significant associations were observed between interventions and outcomes for emergency department visits in the short term (<2 years), hospitalizations, child development, school performance, and prevention of death. Nonsignificant results from single trials led to a conclusion of insufficient evidence for injuries, failure to thrive, failure to immunize, school attendance, and other measures of abuse or neglect. Inconsistent results led to a conclusion of insufficient evidence for long-term (>=2 years) outcomes for reports to child protective services (ORs range from 0.48 to 1.13; 3 trials [n = 1690]), emergency department visits (1 of 2 trials reported significant differences) and internalizing and externalizing behavior symptoms (3 of 6 trials reported reductions in behavior difficulties). No eligible trials on harms of interventions were identified. Conclusions and Relevance: Interventions provided in or referable from primary care did not consistently prevent child maltreatment. No evidence on harms is available. PMID- 30480735 TI - Interventions to Prevent Child Maltreatment: US Preventive Services Task Force Recommendation Statement. AB - Importance: In 2016, approximately 676 000 children in the United States experienced maltreatment (abuse, neglect, or both), with 75% of these children experiencing neglect, 18% experiencing physical abuse, and 8% experiencing sexual abuse. Approximately 14% of abused children experienced multiple forms of maltreatment, and more than 1700 children died as a result of maltreatment. Objective: To update the US Preventive Services Task Force (USPSTF) 2013 recommendation on primary care interventions to prevent child maltreatment. Evidence Review: The USPSTF commissioned a review of the evidence on primary care interventions to prevent maltreatment in children and adolescents without signs or symptoms of maltreatment. Findings: The USPSTF found limited and inconsistent evidence on the benefits of primary care interventions, including home visitation programs, to prevent child maltreatment and found no evidence related to the harms of such interventions. The USPSTF concludes that the evidence is insufficient to assess the balance of benefits and harms of primary care interventions to prevent child maltreatment. The level of certainty of the magnitude of the benefits and harms of these interventions is low. Conclusions and Recommendation: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of primary care interventions to prevent child maltreatment. (I statement). PMID- 30480736 TI - Mystery Myelitis in Children. PMID- 30480737 TI - Unvaccinated Children. PMID- 30480738 TI - Letter to the Editor: Challenges to the Common Clinical Paradigm for Diagnosis of Glaucomatous Damage With OCT and Visual Fields. PMID- 30480739 TI - Author Response: Challenges to the Common Clinical Paradigm for Diagnosis of Glaucomatous Damage With OCT and Visual Fields. PMID- 30480740 TI - No Relation Between the Severity of Corneal Nerve, Epithelial, and Keratocyte Cell Morphology With Measures of Dry Eye Disease in Type 1 Diabetes. AB - Purpose: Patients with diabetes have a propensity to develop dry eye symptoms (DES), with reduced tear secretion and corneal sensitivity. The underlying pathologic basis of DES was explored in patients with Type 1 diabetes. Methods: Forty-two patients with Type 1 diabetes mellitus (T1DM) (age: 49.21 +/- 2.53 years, duration of diabetes: 29.98 +/- 2.64 years) and 25 control subjects (age: 48.70 +/- 2.84 years) underwent assessment of DES using a validated dry eye questionnaire, and tear stability and tear production were assessed using tear breakup time (TBUT) and Schirmer's test, respectively. Corneal confocal microscopy was undertaken to quantify corneal nerve fiber density (CNFD), branch density (CNBD), fiber length (CNFL), keratocyte density (KD), and corneal epithelial basal cell (CEBC) density and area. Results: The prevalence of DES was significantly higher (P = 0.03), and TBUT (P = 0.006), corneal sensation (P < 0.0001), CNFD (P = 0.001), CNBD (P = 0.001), CNFL (P = 0.003), and KD (P = 0.04) were significantly lower in patients with T1DM compared to control subjects. However, these measures did not differ significantly between T1DM patients with and without dry eye. There was no correlation between DES and TBUT or corneal nerve keratocyte and CEBC morphology. Conclusions: DES and TBUT are significantly increased in patients with T1DM, but are not related to corneal nerve, basal epithelial, or keratocyte cell morphology. PMID- 30480741 TI - Altered Signaling Pathways in Aniridia-Related Keratopathy. AB - Purpose: To study the Notch1, Wnt/beta-catenin, sonic hedgehog (SHH), and mammalian target of rapamycin (mTOR) cell signaling pathways in naive and surgically treated corneas of aniridia cases with advanced aniridia-related keratopathy (ARK). Methods: Two naive corneal buttons from patients with advanced ARK submitted to penetrating keratoplasty for the first time, one corneal button from an ARK patient that had undergone a keratolimbal allograft (KLAL), two corneal buttons from ARK patients who had previously undergone centered or decentered transplantation, and two adult healthy control corneas were processed for immunohistochemistry in this descriptive study. Antibodies specific against elements of the Notch1 (Notch1; Dlk1; Numb), Wnt/beta-catenin (Wnt5a; Wnt7a; beta catenin), SHH (glioma-associated oncogene homolog [Gli1]; Hes1), and mTOR (mTOR1; ribosomal protein S6 [rpS6]) signaling pathways were used as well as antibodies against PAX6 and keratin 13 (Krt13). Results: All ARK corneas presented signs of conjunctivalization and analogous signaling pathway changes in the subepithelial pannus and epithelium, with decreased detection of the Notch1 signaling pathway and an increased presence of the Notch1 inhibitors Numb and Dlk1. Increased detections of Wnt/beta-catenin (enhanced presence of Wnt5a, Wnt7a, and beta catenin), SHH (detection of Gli1 and Hes1), and mTOR (identification of mTOR and rpS6) signaling pathways were found in the subepithelial pannus and epithelium of all ARK corneas, when compared with normal controls. Conclusions: The similarity in pathway alterations found in all ARK corneas, irrespective of limbal stem cell transplantation, further supports the discussion on the role of host-specific factors and limbal stem cell deficiency in ARK. PMID- 30480742 TI - Genome-Wide Association Study to Identify a New Susceptibility Locus for Central Serous Chorioretinopathy in the Japanese Population. AB - Purpose: Central serous chorioretinopathy (CSC) is a retinal disorder that often affects the vision of middle-aged people yet the molecular mechanisms of CSC remain unknown. This study was conducted to identify genetic factors influencing individual differences in susceptibility to CSC. Methods: A two-stage genome-wide association study (GWAS) was conducted with a total of 320 unrelated Japanese idiopathic CSC cases and 3245 population-based controls. In a discovery stage, 137 unrelated Japanese idiopathic CSC cases and 1174 population-based controls were subjected to GWAS, followed by a replication study using an additional 183 individuals with idiopathic CSC and 2071 population-based volunteers. The results of the discovery and replication stages were combined to conduct a meta-analysis. Results: In the two-stage GWAS, rs11865049 located at SLC7A5 in chromosome 16q24.2 was identified as a novel disease susceptibility locus for CSC, as evident from the discovery and replication results using meta-analysis (combined P = 9.71 * 10-9, odds ratio = 2.10). Conclusions: The results of the present study demonstrated that SLC7A5 might be the potential candidate gene associated with CSC, indicating a previously unidentified molecular mechanism of CSC. PMID- 30480743 TI - A Controlled Impact of Optic Nerve as a New Model of Traumatic Optic Neuropathy in Mouse. AB - Purpose: Traumatic optic neuropathy (TON) is the most feared visual consequence of head and ocular trauma in both military and civilian communities, for which standard treatment does not exist. Animal models are critical for the development of novel TON therapies as well as the understanding of TON pathophysiology. However, the models currently used for TON have some limitations regarding consistency and mirroring the exact pathological progression of TON in closed ocular trauma. In this study, we modified the model of controlled cortical impact and adapted it for studying TON. Methods: We defined new standardized procedures to induce TON in mice, wherein the optic nerve is reproducibly exposed to a graded controlled impact of known velocity to produce a graded deficit in retinal ganglion cell (RGC) electrophysiological functions. Results: The key results of validating this newly modified model, "controlled orbital impact (COI)," included (1) the injury parameters (velocity as well as contusion depth and time), which were quantifiable and manageable to generate a wide range of TON severities; (2) a reproducible endpoint of diminished positive scotopic threshold response (pSTR) has been achieved without the interference of surgical variability and destruction of surrounding tissues; (3) the contralateral eyes showed no significant difference to the eyes of naive mice, allowing them to be used as an internal control to minimize interindividual variability among mice; and (4) the occurrence of injury-associated mortality and/or ocular comorbidity was rare. Conclusions: Taken together, this model overcomes some limitations of prior TON mouse models and provides an innovative platform to identify therapeutic targets for neuroprotection and/or neurorestoration following traumatic ocular injury. PMID- 30480744 TI - Bioinformatics Analysis of Weighted Genes in Diabetic Retinopathy. AB - Purpose: Intricate signaling networks and transcriptional regulators translate pathogen recognition into defense responses. The aim of this study was to identify the weighted genes involved in diabetic retinopathy (DR) in different rodent models of diabetes. Methods: We performed a gene coexpression analysis of publicly available microarray data, namely, the GSE19122 dataset from the Gene Expression Omnibus database. We conducted gene coexpression analysis on the microarray data to identify modules of functionally related coexpressed genes that are differentially expressed in different rodent models. We leveraged a richly curated expression dataset and used weighted gene coexpression network analysis to construct an undirected network. We screened 30 genes in the most closely related module. A protein-protein interaction network was constructed for the genes in the most related module using the Search Tool for the Retrieval of Interacting Genes. Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed for the 30 genes. Results: Five visual perception-related genes (Pde6g, Guca1a, Rho, Sag, and Prph2) were significantly upregulated. Based on the competing endogenous RNA hypothesis, a link between the long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and visual perception-related mRNAs was constructed using bioinformatics tools. Six potential microRNAs (miR-155-5p, miR 1a-3p, miR-122-5p, miR-223-3p, miR-125b-5p, and miR-124-3p) were also screened. Conclusions: MALAT1 might play important roles in DR by regulating Sag and Guca1a through miR-124-3p and regulating Pde6g through miR-125b-5p. PMID- 30480745 TI - ? PMID- 30480746 TI - [Psittacosis - a forgotten diagnosis in Sweden?] AB - Psittacosis, parrot fever, is an infectious disease caused by Chlamydophila psittaci, a common pathogen among birds. The clinical course ranges from a mild flu-like illness to severe disease that requires intensive care in humans. We report three cases of severe pneumonia where C. psittaci was unexpectedly detected during routine validation of a new C. psittaci PCR assay. Psittacosis is a notifiable disease in Sweden and national statistics show that 96% of Swedish psittacosis cases were identified in five of the 24 microbiological laboratories available in the country. These five laboratories perform PCR for C. psittaci routinely in panels with other atypical pneumonia agents and/or Legionella, suggesting that psittacosis is an underdiagnosed infection in Sweden. PMID- 30480747 TI - [Laboratory diagnosis of rare diseases]. AB - Psittacosis (parrot fever) is underdiagnosed in Sweden, possibly due to lack of awareness, and the fact that only five out of 24 clinical microbiology laboratories routinely perform the PCR test for Chlamydia psittaci. The test has shown 100% sensitivity and 100% sensitivity for the pathogen in samples from the lower part of the respiratory tract which caters for a high predictive value in patients with symptoms and signs of community-acquired atypical pneumonias, provided optimal patient selection. Knowledge and awareness of treatable rare diseases amongst healthcare personnel combined with conveniently available cost effective diagnostic techniques is essential for improvements in the handling of rare diseases. PMID- 30480748 TI - The association of thyroid-stimulating hormone (TSH) and free thyroxine (fT4) concentration levels with carbohydrate and lipid metabolism in obese and overweight teenagers. AB - INTRODUCTION: Obesity has increased rapidly among children and adolescents during the last 30 years. Pediatric patients with a BMI >85th centile are more often diagnosed with increased TSH levels than children with proper body weight. MATERIALS AND METHODS: The data of 961 overweight and obese children, aged 13, recruited in four cities in Poland as part of PoZdro!, a two-year prophylactic program, were analysed to observe the relationship between serum TSH and fT4 concentration and carbohydrate and lipid metabolism parameters, as well as anthropometric parameters. RESULTS: TSH concentration in the study group was positively correlated, whereas fT4 concentration was negatively correlated with WHR and WHtR values, fasting serum glucose concentrations and 1-hour glucose concentration, fasting serum insulin concentrations, 1-hour and 2-hour insulin concentration, ALT serum activity, as well as total cholesterol, LDL cholesterol and triglycerides serum concentrations. An increased risk of metabolic syndrome was diagnosed already in patients with TSH concentrations >2.5 mUI/L. CONCLUSIONS: TSH concentration in the upper half of the current reference range (>2.50 mIU/L) is associated with an increased risk of lipid and carbohydrate metabolism disorders and therefore increased chances of developing metabolic syndrome. It seems advisable to regularly monitor thyroid function in overweight and obese pediatric patients. PMID- 30480749 TI - Adropin in women with polycystic ovary syndrome. AB - INTRODUCTION: Women with polycystic ovary syndrome (PCOS) frequently develop metabolic complications. Among the new markers responsible for metabolic disorders, adropin seems to be of the great significance. MATERIAL AND METHODS: 134 women aged 17-45 years were enrolled. PCOS group consisted of 73 women, diagnosed on the basis of ESHRE-ASRM criteria. All PCOS women presented phenotype A of PCOS. Control group consisted of 61 women with regular menstrual cycles, matched for nutritional status. All women underwent anamnesis, physical examination, anthropometric measurements, abdominal ultrasonography, and dual energy X-ray absorptiometry (DXA). Serum adropin levels were determined by ELISA. Biochemical (fasting glucose and insulin, oral glucose tolerance test, lipid and SHBG) and hormonal (testosterone, androstenedione, LH, FSH and estradiol) measurements were performed. Insulin resistance indices (HOMA, QUICKI, Matsuda) and free androgen index (FAI) were calculated according to the standard formula. Statistical significance was defined by p<=0.05. RESULTS: Serum adropin levels were lower in PCOS group, but the results were not statistically significant. Positive correlations among adropin and androstenedione levels were observed in PCOS group. CONCLUSIONS: Serum adropin levels were lower in women with PCOS compared with controls, but the results were not statistically significant. Therefore, more studies including adropin are needed to clarify this association. PMID- 30480750 TI - Comparison of adipose tissue derived genes in endogenous Cushing's syndrome versus diet-induced obesity. AB - INTRODUCTION: Dysregulation of adipokine secretion and action are characteristic features of obesity that is a main clinical feature of Cushing's syndrome (CS). We have investigated whether endogenous glucocorticoid excess influences adipose tissue derived gene expression. MATERIAL AND METHODS: mRNA expression of adipokines; adiponectin, resistin, tumor necrosis factor-?, interleukin-6 (IL-6), angiotensinogen (AGT), plasminogen activator inhibitor type 1, retinol binding protein 4, visfatin, cystatin C was assessed by quantitative real-time RT-PCR in visceral adipose tissue removed during abdominal surgery of eight patients with CS, and six control patients. RESULTS: We did not find any significant difference in the investigated genes, however, the almost significant overexpression of AGT and underexpression of IL-6 might be noteworthy (p=0.06 in both cases). CONCLUSIONS: No significant differences were found in the expression of the investigated genes known as cardiometabolic risk factors. This indicates that there are no major differences between endogenous hypercortisolism or diet induced obesity regarding the expression of adipokines involved in cardiometabolic disorders. However, the difference in AGT and IL-6 expression might be included in pathways affecting fat distribution in CS. PMID- 30480751 TI - Subclinical hyperthyroidism in the course of autonomous nodules - clinical evaluation. AB - : Introduction Subclinical hyperthyroidism (SCH) also known as mildly symptomatic has recently been diagnosed more frequently. One of the main endogenous causes of this disorder is autonomously functioning thyroid nodule (AFTN). Despite the fact that it is usually asymptomatic SCH entails repercussions on the cardiovascular system and bone as well as carries a risk of progression to overt hyperthyroidism with a typical clinical picture. Treatment is still controversial and its benefits are widely debated in literature. The method applied in the study was a retrospective analysis of medical records with particular account of medical history, physical examination and additional tests obtained during the process of diagnostic and therapeutic procedures. PATIENTS: We selected a group of 49 patients (10.6% of all subjects with hyperthyroidism), 41 women (83.7%) with AFTN at the stage SCH treated in the Outpatient Endocrinological Clinic and the Department of Endocrinology of the Medical University of Lublin over a three-year long period. RESULTS: Forty-one patients (83.7%) suffered from typical symptoms of hyperthyroidism; only eight patients (16.3%) were asymptomatic. The most frequently reported symptom in women was tachycardia (51.2%) and anxiety in men (50%). The type of thyrostatic drugs and the length of therapy did not affect the outcome of Iodine-131 therapy. In the vast majority of the patients (87.8%) radioidodine therapy was effective where 30 patients (61.2%) reached euthyreosis and 13 patients (22.5%) developed hypothyroidism. CONCLUSIONS: Most patients with SCH in the course of AFTN suffered from typical symptoms of overt hyperthyroidism; only every sixth patient was asymptomatic. PMID- 30480752 TI - The influence of hypothyroidism and substitution treatment on thyroid hormone conversion ratios and rT3 concentration in patients with end-stage renal failure. AB - The increasing number of patients with end-stage renal disease (ESRD) requires seeking new opportunities to improve their quality of life not only because of kidney disease, but also due to other disturbances, such as thyroid hormone disorders. The aim of the study The objective of the study was to evaluate the influence of coexisting hypothyroidism and thyroid hormone therapy in patients with ESRD on thyroid hormone conversion ratios and rT3 concentration. Material and methods The study involved 85 patients aged 26 to 87 years, with a mean age of 59,62+/-15,45 years. Four groups of patients were examined: G1 group - 25 persons without RF and hypothyroidism, G2 - 26 patients with ESRD treated with hemodialysis (HD), G3-12 patients with ESRD treated with HD and newly diagnosed hypothyroidism and G4 -22 HD patients with hypothyroidism were treated with thyroid hormones substitution. The concentrations of TSH, T4, T3, fT4, fT3 and rT3 were measured and the fT3/fT4, T3/T4, rT3/T4/and rT3/fT3 conversion ratios were calculated. Concentrations of protein, hsCRP, Hg, and blood gases were also checked; anion gap was calculated. Results: Patients from group G1 through G2 to G3 were older (ptrend=0,002), with lower Hb level (ptrend<0,001), with lower pH (ptrend<0,001), with increased anion gap (ptrend<0,013) and CRP concentrations (ptrend<0,001), and decreased total protein level (ptrend<0,001). There were increased TSH values (ptrend<0,001) lower and lower T4 (ptrend=0,024), fT3 (ptrend<0,001), T3 (ptrend<0,001) and rT3 (ptrend=0,008) levels. rT3/T3 ratio didn't change, rT3/T4 ratio tended to decrease (ptrend=0,065) similarly to T3/T4 ratio (ptrend=0,063), and fT3/fT4 ratio was also decreased (ptrend=0,005). It seems that the treatment of thyroid disease in patients with renal failure, treated with hemodialysis is not associated with change of rT3 and conversion factors levels. Conclusions: The concentration of rT3 in HD patients in relation to healthy persons tends to decrease, and hypothyroidism increases this tendency in these patients. Hormone substitution treatment does not eliminate the influence of RF on inhibition of rT3 production. In patients with ESRD, hypothyroidism additionally reduces the conversion of thyroid hormones examined by fT3/fT4 and less extent T3/T4 ratios. PMID- 30480753 TI - Protocol-directed sedation versus non-protocol-directed sedation in mechanically ventilated intensive care adults and children. AB - BACKGROUND: The sedation needs of critically ill patients have been recognized as a core component of critical care that is vital to assist recovery and ensure humane treatment. Evidence suggests that sedation requirements are not always optimally managed. Suboptimal sedation, both under- and over-sedation, have been linked to short-term (e.g. length of stay) and long-term (e.g. psychological recovery) outcomes. Strategies to improve sedation assessment and management have been proposed. This review was originally published in 2015 and updated in 2018. OBJECTIVES: To assess the effects of protocol-directed sedation management compared to usual care on the duration of mechanical ventilation, intensive care unit (ICU) and hospital mortality and other patient outcomes in mechanically ventilated ICU adults and children. SEARCH METHODS: We used the standard search strategy of the Cochrane Anaesthesia, Critical and Emergency Care Group (ACE). We searched the Cochrane Central Register of Controlled trials (CENTRAL) (December 2017), MEDLINE (OvidSP) (2013 to December 2017), Embase (OvidSP) (2013 to December 2017), CINAHL (BIREME host) (2013 to December 2017), LILACS (2013 to December 2017), trial registries and reference lists of articles. (The original search was run in November 2013). SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-randomized controlled trials conducted in ICUs comparing management with and without protocol-directed sedation in intensive care adults and children. DATA COLLECTION AND ANALYSIS: Two authors screened the titles and abstracts and then full-text reports identified from our electronic search. We assessed seven domains of potential risk of bias for the included studies. We examined clinical, methodological and statistical heterogeneity and used the random-effects model for meta-analysis where we considered it appropriate. We calculated the mean difference (MD) for duration of mechanical ventilation and risk ratio (RR) for mortality across studies, with 95% confidence intervals (CIs). MAIN RESULTS: We included four studies with a total of 3323 participants (864 adults and 2459 paediatrics) in this update. Three studies were single-centre, patient-level RCTs and one study was a multicentre cluster-RCT. The settings were in metropolitan centres and included general, mixed medical surgical, medical only and a range of paediatric units. All four included studies compared the use of protocol-directed sedation, specifically protocols delivered by nurses, with usual care. We rated the risk of selection bias due to random sequence generation low for two studies and unclear for two studies. The risk of bias was highly variable across the domains and studies, with the risk of selection and performance bias generally rated high and the risk of detection and attrition bias generally rated low.When comparing protocol-directed sedation with usual care, there was no clear evidence of difference in duration of mechanical ventilation in hours for the entire duration of the first ICU stay for each patient (MD -28.15 hours, 95% CI -69.15 to 12.84; I2 = 85%; 4 studies; adjusted sample 2210 participants; low-quality evidence). There was no clear evidence of difference in ICU mortality (RR 0.77, 95% CI 0.39 to 1.50; I2 = 67%; 2 studies; 513 participants; low-quality evidence), or hospital mortality (RR 0.90, 95% CI 0.72 to 1.13; I2 = 10%; 3 studies; adjusted sample 2088 participants; low-quality evidence). There was no clear evidence of difference in ICU length of stay (MD 1.70 days, 95% CI-3.71 to 0.31; I2 = 82%; 4 studies; adjusted sample of 2123 participants; low-quality of evidence), however there was evidence of a significant reduction in hospital length of stay (MD -3.09 days, 95% CI -5.08 to 1.10; I2 = 2%; 3 studies; adjusted sample of 1922 participants; moderate-quality evidence). There was no clear evidence of difference in the incidence of self extubation (RR 0.88, 95% CI 0.55 to 1.42; I2 = 0%; 2 studies; adjusted sample of 1687 participants; high-quality evidence), or incidence of tracheostomy (RR 0.67, 95% CI 0.35 to 1.30; I2 = 66%; 3 studies; adjusted sample of 2008 participants; low-quality evidence). Only one study examined incidence of reintubation, therefore we could not pool data; there was no clear evidence of difference (RR 0.65, 95% CI 0.35 to 1.24; 1 study; 321 participants; low-quality evidence). AUTHORS' CONCLUSIONS: There is currently limited evidence from RCTs evaluating the effectiveness of protocol-directed sedation on patient outcomes. The four included RCTs reported conflicting results and heterogeneity limited the interpretation of results for the primary outcomes of duration of mechanical ventilation and mortality. Further studies, taking into account differing contextual characteristics, are necessary to inform future practice. Methodological strategies to reduce the risk of bias need to be considered in future studies. PMID- 30480754 TI - Moxibustion for alleviating side effects of chemotherapy or radiotherapy in people with cancer. AB - BACKGROUND: Moxibustion, a common treatment in traditional Chinese medicine, involves burning herbal preparations containing Artemisia vulgaris on or above the skin at acupuncture points. Its intended effect is to enhance body function, and it could reduce the side effects of chemotherapy or radiotherapy and improve quality of life (QoL) in people with cancer. OBJECTIVES: To assess the effects of moxibustion for alleviating side effects associated with chemotherapy, radiotherapy or both in people with cancer. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE via Ovid, Embase via Ovid and AMED (Allied and Complementary Medicine Database) from their inception to February 2018. We also searched databases in China including the Chinese BioMedical Literature Database (CBM), Chinese Medical Current Contents (CMCC), TCMonline, Chinese Dissertation Database (CDDB), China Medical Academic Conference (CMAC) and Index to Chinese Periodical Literature from inception to August 2017. Registries for clinical trials and other resources were also searched. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing moxibustion treatment, including moxa cone and moxa stick, versus sham, no treatment or conventional treatment. DATA COLLECTION AND ANALYSIS: Two review authors (HWZ and FC) independently extracted data on study design, participants, treatment and control intervention, and outcome measures, and they also assessed risk of bias in the included studies. We performed meta analyses, expressing dichotomous outcomes as risk ratios (RR) and continuous outcomes as mean differences (MD), with 95% confidence intervals (CI). MAIN RESULTS: We included 29 RCTs involving 2569 participants. Five RCTs compared moxibustion versus no treatment, 15 compared moxibustion plus conventional treatment versus conventional treatment, one compared moxibustion versus sham moxibustion, and eight compared moxibustion versus conventional medicine. The overall risk of bias was high in 18 studies and unclear in 11 studies. Studies measured outcomes in various ways, and we could rarely pool data.Moxibustion versus no treatment: low-certainty evidence from single small studies suggested that moxibustion was associated with higher white blood cell counts (MD 1.77 * 109/L; 95% CI 0.76 to 2.78; 80 participants, low-certainty evidence) and higher serum haemoglobin concentrations (MD 1.33 g/L; 95% CI 0.59 to 2.07; 66 participants, low-certainty evidence) in people with cancer, during or after chemotherapy/radiotherapy, compared with no treatment. There was no evidence of an effect on leukopenia (RR 0.50, 95% CI 0.10 to 2.56; 72 participants, low certainty evidence) between study groups. The effects on immune function (CD3, CD4, and CD8 counts) were inconsistent.Moxibustion versus sham moxibustion: low certainty evidence from one study (50 participants) suggested that moxibustion improved QoL (measured as the score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30)) compared with sham treatment (MD 14.88 points; 95% CI 4.83 to 24.93). Low-certainty evidence from this study also showed reductions in symptom scores for nausea and vomiting (MD -38.57 points, 95% CI -48.67 to -28.47) and diarrhoea (MD -13.81, 95% CI -27.52 to -0.10), and higher mean white blood cell count (MD 1.72 * 109/L, 95% CI 0.97 to 2.47), serum haemoglobin (MD 2.06 g/L, 95% CI 1.26 to 2.86) and platelets (MD 210.79 * 109/L, 95% CI 167.02 to 254.56) when compared with sham moxibustion.Moxibustion versus conventional medicines: low-certainty evidence from one study (90 participants) suggested that moxibustion improved WBC count eight days after treatment ended compared with conventional medicines (MD 0.40 * 109/L; 95% CI 0.15 to 0.65). Low-certainty evidence from two studies (235 participants) suggested moxibustion improved serum haemoglobin concentrations compared with conventional medicines (MD 10.28 g/L; 95% CI 4.51 to 16.05).Moxibustion plus conventional treatment versus conventional treatment alone: low-certainty evidence showed that moxibustion plus conventional treatment was associated with lower incidence and severity of leukopenia (WHO grade 3 to 4) (RR 0.14, 95% CI 0.01 to 2.64; 1 study, 56 participants), higher QoL scores on the EORTC QLQ-C30 (MD 8.85 points, 95% CI 4.25 to 13.46; 3 studies, 134 participants, I2 = 26%), lower symptom scores for nausea and vomiting (RR 0.43, 95% CI 0.25 to 0.74; 7 studies, 801participants; I2 = 19%), higher white blood cell counts (data not pooled due to heterogeneity), higher serum haemoglobin (MD 3.97 g/L, 95% CI 1.40 to 6.53; 2 studies, 142 participants, I2 = 0%). There was no difference in platelet counts between the two groups (MD 13.48 * 109/L; 95% CI -16.00 to 42.95; 2 studies, 142 participants; I2 = 34%).Most included studies did not report related adverse events, such as burning or allergic reactions. AUTHORS' CONCLUSIONS: Limited, low-certainty evidence suggests that moxibustion treatment may help to reduce the haematological and gastrointestinal toxicities of chemotherapy or radiotherapy, improving QoL in people with cancer; however, the evidence is not conclusive, and we cannot rule out benefits or risks with this treatment. High-quality studies that report adverse effects are needed. PMID- 30480755 TI - Timing of dornase alfa inhalation for cystic fibrosis. AB - BACKGROUND: Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. This is an update of a previously published Cochrane Review. OBJECTIVES: To determine whether the timing of dornase alfa inhalation (in relation to airway clearance techniques or morning versus evening inhalation) has an impact on objective and subjective measures of clinical efficacy in people with cystic fibrosis. SEARCH METHODS: Relevant randomised and quasi-randomised controlled trials were identified from the Cochrane Cystic Fibrosis Trials Register, Physiotherapy Evidence Database (PEDro), clinical trial registries and international cystic fibrosis conference proceedings.Date of the most recent search: 06 June 2018. SELECTION CRITERIA: Any trial of dornase alfa in people with cystic fibrosis where timing of inhalation was the randomised element in the trial with either: inhalation before compared to after airway clearance techniques; or morning compared to evening inhalation. DATA COLLECTION AND ANALYSIS: Both authors independently selected trials, assessed risk of bias and extracted data with disagreements resolved by discussion. Relevant data were extracted and, where possible, meta-analysed. MAIN RESULTS: We identified 115 trial reports representing 55 trials, of which five trials (providing data on 122 participants) met our inclusion criteria. All five trials used a cross-over design. Intervention periods ranged from two to eight weeks. Four trials (98 participants) compared dornase alfa inhalation before versus after airway clearance techniques. Inhalation after instead of before airway clearance did not significantly change forced expiratory volume at one second (very-low quality evidence). Similarly, forced vital capacity (low-quality evidence) and quality of life (very-low quality evidence) were not significantly affected; forced expiratory flow at 25% was significantly worse with dornase alfa inhalation after airway clearance, mean difference -0.17 litres (95% confidence interval -0.28 to -0.05), based on the pooled data from two small trials in children (7 to 19 years) with well-preserved lung function. All other secondary outcomes were statistically non-significant.In one trial (25 participants), morning versus evening inhalation had no impact on lung function or symptoms (low quality evidence). AUTHORS' CONCLUSIONS: The current evidence derived from a small number of participants does not indicate that inhalation of dornase alfa after airway clearance techniques is more or less effective than the traditional recommendation to inhale nebulised dornase alfa 30 minutes prior to airway clearance techniques, for most outcomes. For children with well-preserved lung function, inhalation before airway clearance may be more beneficial for small airway function than inhalation after. However, this result relied on a measure with high variability and trials with variable follow-up. In the absence of strong evidence to indicate that one timing regimen is better than another, the timing of dornase alfa inhalation can be largely based on pragmatic reasons or individual preference with respect to the time of airway clearance and time of day. Further research is warranted. PMID- 30480756 TI - Interventions during pregnancy to prevent preterm birth: an overview of Cochrane systematic reviews. AB - BACKGROUND: Preterm birth (PTB) is a major factor contributing to global rates of neonatal death and to longer-term health problems for surviving infants. Both the World Health Organization and the United Nations consider prevention of PTB as central to improving health care for pregnant women and newborn babies. Current preventative clinical strategies show varied efficacy in different populations of pregnant women, frustrating women and health providers alike, while researchers call for better understanding of the underlying mechanisms that lead to PTB. OBJECTIVES: We aimed to summarise all evidence for interventions relevant to the prevention of PTB as reported in Cochrane systematic reviews (SRs). We intended to highlight promising interventions and to identify SRs in need of an update. METHODS: We searched the Cochrane Database of Systematic Reviews (2 November 2017) with key words to capture any Cochrane SR that prespecified or reported a PTB outcome. Inclusion criteria focused on pregnant women without signs of preterm labour or ruptured amniotic membranes. We included reviews of interventions for pregnant women irrespective of their risk status. We followed standard Cochrane methods.We applied GRADE criteria to evaluate the quality of SR evidence. We assigned graphic icons to classify the effectiveness of interventions as: clear evidence of benefit; clear evidence of harm; clear evidence of no effect or equivalence; possible benefit; possible harm; or unknown benefit or harm. We defined clear evidence of benefit and clear evidence of harm to be GRADE moderate- or high-quality evidence with a confidence interval (CI) that does not cross the line of no effect. Clear evidence of no effect or equivalence is GRADE moderate- or high-quality evidence with a narrow CI crossing the line of no effect. Possible benefit and possible harm refer to GRADE low quality evidence with a clear effect (CI does not cross the line of no effect) or GRADE moderate- or high-quality evidence with a wide CI. Unknown harm or benefit refers to GRADE low- or very low-quality evidence with a wide CI. MAIN RESULTS: We included 83 SRs; 70 had outcome data. Below we highlight key results from a subset of 36 SRs of interventions intended to prevent PTB. OUTCOME: preterm birthClear evidence of benefitFour SRs reported clear evidence of benefit to prevent specific populations of pregnant women from giving birth early, including midwife-led continuity models of care versus other models of care for all women; screening for lower genital tract infections for pregnant women less than 37 weeks' gestation and without signs of labour, bleeding or infection; and zinc supplementation for pregnant women without systemic illness. Cervical cerclage showed clear benefit for women with singleton pregnancy and high risk of PTB only.Clear evidence of harmNo included SR reported clear evidence of harm.No effect or equivalenceFor pregnant women at high risk of PTB, bedrest for women with singleton pregnancy and antibiotic prophylaxis during the second and third trimester were of no effect or equivalent to a comparator.Possible benefitFour SRs found possible benefit in: group antenatal care for all pregnant women; antibiotics for pregnant women with asymptomatic bacteriuria; pharmacological interventions for smoking cessation for pregnant women who smoke; and vitamin D supplements alone for women without pre-existing conditions such as diabetes.Possible harmOne SR reported possible harm (increased risk of PTB) with intramuscular progesterone, but this finding is only relevant to women with multiple pregnancy and high risk of PTB. Another review found possible harm with vitamin D, calcium and other minerals for pregnant women without pre-existing conditions. OUTCOME: perinatal deathClear evidence of benefitTwo SRs reported clear evidence of benefit to reduce pregnant women's risk of perinatal death: midwife-led continuity models of care for all pregnant women; and fetal and umbilical Doppler for high-risk pregnant women.Clear evidence of harmNo included SR reported clear evidence of harm.No effect or equivalenceFor pregnant women at high risk of PTB, antibiotic prophylaxis during the second and third trimester was of no effect or equivalent to a comparator.Possible benefitOne SR reported possible benefit with cervical cerclage for women with singleton pregnancy and high risk of PTB.Possible harmOne SR reported possible harm associated with a reduced schedule of antenatal visits for pregnant women at low risk of pregnancy complications; importantly, these women already received antenatal care in settings with limited resources. OUTCOMES: preterm birth and perinatal deathUnknown benefit or harmFor pregnant women at high risk of PTB for any reason including multiple pregnancy, home uterine monitoring was of unknown benefit or harm. For pregnant women at high risk due to multiple pregnancy: bedrest, prophylactic oral betamimetics, vaginal progesterone and cervical cerclage were all of unknown benefit or harm. AUTHORS' CONCLUSIONS: Implications for practiceThe overview serves as a map and guide to all current evidence relevant to PTB prevention published in the Cochrane Library. Of 70 SRs with outcome data, we identified 36 reviews of interventions with the aim of preventing PTB. Just four of these SRs had evidence of clear benefit to women, with an additional four SRs reporting possible benefit. No SR reported clear harm, which is an important finding for women and health providers alike.The overview summarises no evidence for the clinically important interventions of cervical pessary, cervical length assessment and vaginal progesterone because these Cochrane Reviews were not current. These are active areas for PTB research.The graphic icons we assigned to SR effect estimates do not constitute clinical guidance or an endorsement of specific interventions for pregnant women. It remains critical for pregnant women and their healthcare providers to carefully consider whether specific strategies to prevent PTB will be of benefit for individual women, or for specific populations of women.Implications for researchFormal consensus work is needed to establish standard language for overviews of reviews and to define the limits of their interpretation.Clinicians, researchers and funders must address the lack of evidence for interventions relevant to women at high risk of PTB due to multiple pregnancy. PMID- 30480757 TI - Acupuncture for hypertension. AB - BACKGROUND: Elevated blood pressure (hypertension) affects about one billion people worldwide. It is important as it is a major risk factor for stroke and myocardial infarction. However, it remains a challenge for the medical profession as many people with hypertension have blood pressure (BP) that is not well controlled. According to Traditional Chinese Medicine theory, acupuncture has the potential to lower BP. OBJECTIVES: To assess the effectiveness and safety of acupuncture for lowering blood pressure in adults with primary hypertension. SEARCH METHODS: We searched the Hypertension Group Specialised Register (February 2017); the Cochrane Central Register of Controlled Trials (CENTRAL) 2017, Issue 2; MEDLINE (February 2017); Embase (February 2017), China National Knowledge Infrastructure (CNKI) (January 2015), VIP Database (January 2015), the World Health Organisation Clinical Trials Registry Platform (February 2017)and ClinicalTrials.gov (February 2017). There were no language restrictions. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) that compared the clinical effects of an acupuncture intervention (acupuncture used alone or add-on) with no treatment, a sham acupuncture or an antihypertensive drug in adults with primary hypertension. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies according to inclusion and exclusion criteria. They extracted data and assessed the risk of bias of each trial, and telephoned or emailed the authors of the studies to ask for missing information. A third review author resolved disagreements. Outcomes included change in systolic blood pressure (SBP), change in diastolic blood pressure (DBP), withdrawal due to adverse effects, and any adverse events. We calculated pooled mean differences (MD) with 95% confidence intervals (CI) for continuous outcomes using a fixed-effect or random-effects model where appropriate. MAIN RESULTS: Twenty-two RCTs (1744 people) met our inclusion criteria. The RCTs were of variable methodological quality (most at high risk of bias because of lack of blinding). There was no evidence for a sustained BP lowering effect of acupuncture; only one trial investigated a sustained effect and found no BP lowering effect at three and six months after acupuncture. Four sham acupuncture controlled trials provided very low quality evidence that acupuncture had a short term (one to 24 hours) effect on SBP (change) -3.4 mmHg (-6.0 to -0.9) and DBP 1.9 mmHg (95% CI -3.6 to -0.3). Pooled analysis of eight trials comparing acupuncture with angiotensin-converting enzyme inhibitors and seven trials comparing acupuncture to calcium antagonists suggested that acupuncture lowered short-term BP better than the antihypertensive drugs. However, because of the very high risk of bias in these trials, we think that this is most likely a reflection of bias and not a true effect. As a result, we did not report these results in the 'Summary of findings' table. Safety of acupuncture could not be assessed as only eight trials reported adverse events. AUTHORS' CONCLUSIONS: At present, there is no evidence for the sustained BP lowering effect of acupuncture that is required for the management of chronically elevated BP. The short-term effects of acupuncture are uncertain due to the very low quality of evidence. The larger effect shown in non-sham acupuncture controlled trials most likely reflects bias and is not a true effect. Future RCTs must use sham acupuncture controls and assess whether there is a BP lowering effect of acupuncture that lasts at least seven days. PMID- 30480758 TI - Omega-3 fatty acids for dialysis vascular access outcomes in patients with chronic kidney disease. AB - BACKGROUND: Maintaining long-term vascular access patency is necessary for high quality haemodialysis (HD) treatment of patients with the terminal and most serious stage of chronic kidney disease (CKD) - end-stage kidney disease (ESKD). Oral supplementation with omega-3 fatty acids (omega-3FA) may help to prevent blockage of the vascular access by reducing the risk of thrombosis and stenosis. OBJECTIVES: To evaluate the efficacy and safety of omega-3FA supplementation versus placebo or no treatment for maintaining vascular access patency in ESKD patients undergoing HD. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 23 July 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) of omega-3 fatty acids versus placebo that assessed the patency of arteriovenous fistula (AVF) or arteriovenous graft (AVG) types of vascular access in ESKD patients. DATA COLLECTION AND ANALYSIS: We assessed the risk of bias of each eligible study using the Cochrane Risk of Bias tool and made separate overall risk of bias judgments for the efficacy and safety outcomes. The certainty of evidence was assessed using the GRADE approach. The primary efficacy outcome was loss of vascular patency and the primary safety outcomes were occurrences of serious adverse events (e.g. death, hospitalisation, cardiovascular events, major bleeding). Secondary outcomes were the occurrence of non-serious adverse events (e.g. minor bleeding, gastrointestinal events and other adverse events). Efficacy effects were reported as risk ratios (RR) and safety effects as risk differences (RD) with 95% confidence intervals (CI). Studies were pooled separately by type of vascular access using a random-effects model. MAIN RESULTS: Five studies (833 participants) were included; one was a very small pilot study of 7 participants. All studies compared oral omega-3FA supplements against placebo. Four studies enrolled participants with arteriovenous grafts (AVGs), and the other had participants with arteriovenous fistulas (AVFs). The risk of bias for both efficacy and safety outcomes was unclear for all studies, due mainly to incomplete reporting for allocation concealment and incompleteness of study follow-up.In AVF patients, omega-3FA supplementation probably makes little or no difference to the 12-month risk of patency loss (1 study, 536 participants: RR 1.01, 95% CI 0.84 to 1.21; moderate certainty evidence), risk of death (1 study, 567 participants: RD 0.00, 95% CI -0.03 to 0.02; moderate certainty evidence) and risk of hospitalisation (1 study, 567 participants: RD 0.00, 95% CI -0.08 to 0.08; low certainty evidence). There was no information on cardiovascular events and major bleeding.In AVG patients, it is very uncertain whether omega-3FA supplementation reduces the risk of patency loss within 6 months (2 studies, 41 participants: RR 0.91, 95% CI 0.36 to 2.28; very low certainty evidence) or 12 months (2 studies, 220 participants: RR 0.59, 95% CI 0.27 to 1.31; very low certainty evidence). omega-3FA supplementation may make little or no difference to the risk of death within 6 to 12 months in AVG patients (4 studies, 261 participants: RD 0.01, 95% CI -0.05 to 0.07; low certainty evidence). It is very uncertain if omega-3FA supplementation increases the risk of hospitalisation (3 studies, 65 participants: RD 0.08, 95% CI -0.11 to 0.28; very low certainty evidence), changes the risk of cardiovascular events (4 studies, 261 participants: RD -0.02, 95% CI -0.11 to 0.07; very low certainty evidence), or increases the risk of major bleeding (3 studies, 65 participants: RD 0.08, 95% CI -0.11 to 0.28; very low certainty evidence) within 6 to 12 months in AVG patients. There may be an increase in the risk of mild gastrointestinal adverse reactions (3 studies, 65 participants: RD 0.25, 95% CI 0.07 to 0.43; low certainty evidence) such as a sensation of bloatedness, gas or a fishy aftertaste. AUTHORS' CONCLUSIONS: In CKD patients with an AVF, there is moderate certainty that omega-3FA supplementation makes little or no difference to preventing patency loss; and in patients with an AVG, it is very uncertain that omega-3FA supplementation prevents patency loss within 12 months. PMID- 30480759 TI - Phonics training for English-speaking poor readers. AB - BACKGROUND: The reading skills of 16% of children fall below the mean range for their age, and 5% of children have significant and severe reading problems. Phonics training is one of the most common reading treatments used with poor readers, particularly children. OBJECTIVES: To measure the effect of phonics training and explore the impact of various factors, such as training duration and training group size, that might moderate the effect of phonics training on literacy-related skills in English-speaking poor readers. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, 12 other databases, and three trials registers up to May 2018. We also searched reference lists of included studies and contacted experts in the field to identify additional studies. SELECTION CRITERIA: We included studies that used randomisation, quasi-randomisation, or minimisation to allocate participants to a phonics intervention group (phonics training only or phonics training plus one other literacy-related skill) or a control group (no training or non-literacy training). Participants were English speaking poor readers with word reading one standard deviation below the appropriate level for their age (children, adolescents, and adults) or one grade or year below the appropriate level (children only), for no known reason. Participants had no known comorbid developmental disorder, or physical, neurological, or emotional problem. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 14 studies with 923 participants in this review. Studies took place in Australia, Canada, the UK, and the USA. Six of the 14 included studies were funded by government agencies and one was funded by a university grant. The rest were funded by charitable foundations or trusts. Each study compared phonics training alone, or in conjunction with one other reading-related skill, to either no training (i.e. treatment as usual) or alterative training (e.g. maths). Participants were English-speaking children or adolescents, of low and middle socioeconomic status, whose reading was one year, one grade, or one standard deviation below the level expected for their age or grade for no known reason. Phonics training varied between studies in intensity (up to four hours per week), duration (up to seven months), training group size (individual and small groups), and delivery (human and computer). We measured the effect of phonics training on seven primary outcomes (mixed/regular word reading accuracy, non-word reading accuracy, irregular word reading accuracy, mixed/regular word reading fluency, non-word reading fluency, reading comprehension, and spelling). We judged all studies to be at low risk of bias for most risk criteria, and used the GRADE approach to assess the quality of the evidence.There was low-quality evidence that phonics training may have improved poor readers' accuracy for reading real and novel words that follow the letter-sound rules (standardised mean difference (SMD) 0.51, 95% confidence interval (CI) 0.13 to 0.90; 11 studies, 701 participants), and their accuracy for reading words that did not follow these rules (SMD 0.67, 95% CI 0.26 to 1.07; 10 studies, 682 participants). There was moderate-quality evidence that phonics training probably improved English speaking poor readers' fluency for reading words that followed the letter-sounds rules (SMD 0.45, 95% CI 0.19 to 0.72; 4 studies, 224 participants), and non-word reading fluency (SMD 0.39, 95% CI 0.10 to 0.68; 3 studies, 188 participants), as well as their accuracy for reading words that did not follow these rules (SMD 0.84, 95% CI 0.30 to 1.39; 4 studies, 294 participants). In addition, there was low-quality evidence that phonics training may have improved poor readers' spelling (SMD 0.47, 95% CI -0.07 to 1.01; 3 studies, 158 participants), but only slightly improve their reading comprehension (SMD 0.28, 95% CI -0.07 to 0.62; 5 studies, 343 participants). AUTHORS' CONCLUSIONS: Phonics training appears to be effective for improving literacy-related skills, particularly reading fluency of words and non-words, and accuracy of reading irregular words. More studies are needed to improve the precision of outcomes, including word and non-word reading accuracy, reading comprehension, spelling, letter-sound knowledge, and phonological output. More data are also needed to determine if phonics training in English-speaking poor readers is moderated by factors such as training type, intensity, duration, group size, or administrator. PMID- 30480760 TI - Cognitive behavioural therapy plus standard care versus standard care plus other psychosocial treatments for people with schizophrenia. AB - BACKGROUND: Cognitive behavioural therapy (CBT) is a psychosocial treatment that aims to help individuals re-evaluate their appraisals of their experiences that can affect their level of distress and problematic behaviour. CBT is now recommended by the National Institute for Health and Care Excellence (NICE) as an add-on treatment for people with a diagnosis of schizophrenia. Other psychosocial therapies that are often less expensive are also available as an add-on treatment for people with schizophrenia. This review is also part of a family of Cochrane Reviews on CBT for people with schizophrenia. OBJECTIVES: To assess the effects of CBT compared with other psychosocial therapies as add-on treatments for people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study Based Register of Trials (latest 6 March, 2017). This register is compiled by systematic searches of major resources (including AMED, BIOSIS CINAHL, Embase, MEDLINE, PsycINFO, PubMed, and registries of clinical trials) and their monthly updates, handsearches, grey literature, and conference proceedings, with no language, date, document type, or publication status limitations for inclusion of records into the register. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) involving people with schizophrenia who were randomly allocated to receive, in addition to their standard care, either CBT or any other psychosocial therapy. Outcomes of interest included relapse, global state, mental state, adverse events, social functioning, quality of life and satisfaction with treatment. We included trials meeting our inclusion criteria and reporting useable data. DATA COLLECTION AND ANALYSIS: We reliably screened references and selected trials. Review authors, working independently, assessed trials for methodological quality and extracted data from included studies. We analysed dichotomous data on an intention-to-treat basis and continuous data with 60% completion rate. Where possible, for binary data we calculated risk ratio (RR), for continuous data we calculated mean difference (MD), all with 95% confidence intervals (CIs). We used a fixed-effect model for analyses unless there was unexplained high heterogeneity. We assessed risk of bias for the included studies and used the GRADE approach to produce a 'Summary of findings' table for our main outcomes of interest. MAIN RESULTS: The review now includes 36 trials with 3542 participants, comparing CBT with a range of other psychosocial therapies that we classified as either active (A) (n = 14) or non active (NA) (n = 14). Trials were often small and at high or unclear risk of bias. When CBT was compared with other psychosocial therapies, no difference in long-term relapse was observed (RR 1.05, 95% CI 0.85 to 1.29; participants = 375; studies = 5, low quality evidence). Clinically important change in global state data were not available but data for rehospitalisation were reported. Results showed no clear difference in long term rehospitalisation (RR 0.96, 95% CI 0.82 to 1.14; participants = 943; studies = 8, low-quality evidence) nor in long term mental state (RR 0.82, 95% CI 0.67 to 1.01; participants = 249; studies = 4, low-quality evidence). No long-term differences were observed for death (RR 1.57, 95% CI 0.62 to 3.98; participants = 627; studies = 6, low-quality evidence). Only average endpoint scale scores were available for social functioning and quality of life. Social functioning scores were similar between groups (long term Social Functioning Scale (SFS): MD 8.80, 95% CI -4.07 to 21.67; participants = 65; studies = 1, very low-quality evidence), and quality of life scores were also similar (medium term Modular System for Quality of Life (MSQOL): MD -4.50, 95% CI -15.66 to 6.66; participants = 64; studies = 1, very low-quality evidence). There was a modest but clear difference favouring CBT for satisfaction with treatment - measured as leaving the study early (RR 0.86, 95% CI 0.75 to 0.99; participants = 2392; studies = 26, low quality evidence). AUTHORS' CONCLUSIONS: Evidence based on data from randomised controlled trials indicates there is no clear and convincing advantage for cognitive behavioural therapy over other - and sometimes much less sophisticated and expensive - psychosocial therapies for people with schizophrenia. It should be noted that although much research has been carried out in this area, the quality of evidence available is mostly low or of very low quality. Good quality research is needed before firm conclusions can be made. PMID- 30480761 TI - Mefloquine for preventing malaria in pregnant women. AB - BACKGROUND: The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine for malaria for all women who live in moderate to high malaria transmission areas in Africa. However, parasite resistance to sulfadoxine-pyrimethamine has been increasing steadily in some areas of the region. Moreover, HIV-infected women on cotrimoxazole prophylaxis cannot receive sulfadoxine-pyrimethamine because of potential drug interactions. Thus, there is an urgent need to identify alternative drugs for prevention of malaria in pregnancy. One such candidate is mefloquine. OBJECTIVES: To assess the effects of mefloquine for preventing malaria in pregnant women, specifically, to evaluate:* the efficacy, safety, and tolerability of mefloquine for preventing malaria in pregnant women; and* the impact of HIV status, gravidity, and use of insecticide-treated nets on the effects of mefloquine. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, Latin American Caribbean Health Sciences Literature (LILACS), the Malaria in Pregnancy Library, and two trial registers up to 31 January 2018. In addition, we checked references and contacted study authors to identify additional studies, unpublished data, confidential reports, and raw data from published trials. SELECTION CRITERIA: Randomized and quasi randomized controlled trials comparing mefloquine IPT or mefloquine prophylaxis against placebo, no treatment, or an alternative drug regimen. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all records identified by the search strategy, applied inclusion criteria, assessed risk of bias, and extracted data. We contacted trial authors to ask for additional information when required. Dichotomous outcomes were compared using risk ratios (RRs), count outcomes as incidence rate ratios (IRRs), and continuous outcomes using mean differences (MDs). We have presented all measures of effect with 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach for the following main outcomes of analysis: maternal peripheral parasitaemia at delivery, clinical malaria episodes during pregnancy, placental malaria, maternal anaemia at delivery, low birth weight, spontaneous abortions and stillbirths, dizziness, and vomiting. MAIN RESULTS: Six trials conducted between 1987 and 2013 from Thailand (1), Benin (3), Gabon (1), Tanzania (1), Mozambique (2), and Kenya (1) that included 8192 pregnant women met our inclusion criteria.Two trials (with 6350 HIV-uninfected pregnant women) compared two IPTp doses of mefloquine with two IPTp doses of sulfadoxine-pyrimethamine. Two other trials involving 1363 HIV infected women compared three IPTp doses of mefloquine plus cotrimoxazole with cotrimoxazole. One trial in 140 HIV-infected women compared three doses of IPTp mefloquine with cotrimoxazole. Finally, one trial enrolling 339 of unknown HIV status compared mefloquine prophylaxis with placebo.Study participants included women of all gravidities and of all ages (four trials) or > 18 years (two trials). Gestational age at recruitment was > 20 weeks (one trial), between 16 and 28 weeks (three trials), or <= 28 weeks (two trials). Two of the six trials blinded participants and personnel, and only one had low risk of detection bias for safety outcomes.When compared with sulfadoxine-pyrimethamine, IPTp-mefloquine results in a 35% reduction in maternal peripheral parasitaemia at delivery (RR 0.65, 95% CI 0.48 to 0.86; 5455 participants, 2 studies; high-certainty evidence) but may have little or no effect on placental malaria infections (RR 1.04, 95% CI 0.58 to 1.86; 4668 participants, 2 studies; low-certainty evidence). Mefloquine results in little or no difference in the incidence of clinical malaria episodes during pregnancy (incidence rate ratio (IRR) 0.83, 95% CI 0.65 to 1.05, 2 studies; high-certainty evidence). Mefloquine decreased maternal anaemia at delivery (RR 0.84, 95% CI 0.76 to 0.94; 5469 participants, 2 studies; moderate certainty evidence). Data show little or no difference in the proportions of low birth weight infants (RR 0.95, 95% CI 0.78 to 1.17; 5641 participants, 2 studies; high-certainty evidence) and in stillbirth and spontaneous abortion rates (RR 1.20, 95% CI 0.91 to 1.58; 6219 participants, 2 studies; I2 statistic = 0%; moderate-certainty evidence). IPTp-mefloquine increased drug-related vomiting (RR 4.76, 95% CI 4.13 to 5.49; 6272 participants, 2 studies; high-certainty evidence) and dizziness (RR 4.21, 95% CI 3.36 to 5.27; participants = 6272, 2 studies; moderate-certainty evidence).When compared with cotrimoxazole, IPTp-mefloquine plus cotrimoxazole probably results in a 48% reduction in maternal peripheral parasitaemia at delivery (RR 0.52, 95% CI 0.30 to 0.93; 989 participants, 2 studies; moderate-certainty evidence) and a 72% reduction in placental malaria (RR 0.28, 95% CI 0.14 to 0.57; 977 participants, 2 studies; moderate-certainty evidence) but has little or no effect on the incidence of clinical malaria episodes during pregnancy (IRR 0.76, 95% CI 0.33 to 1.76, 1 study; high-certainty evidence) and probably no effect on maternal anaemia at delivery (RR 0.94, 95% CI 0.73 to 1.20; 1197 participants, 2 studies; moderate-certainty evidence), low birth weight rates (RR 1.20, 95% CI 0.89 to 1.60; 1220 participants, 2 studies; moderate-certainty evidence), and rates of spontaneous abortion and stillbirth (RR 1.12, 95% CI 0.42 to 2.98; 1347 participants, 2 studies; very low-certainty evidence). Mefloquine was associated with higher risks of drug-related vomiting (RR 7.95, 95% CI 4.79 to 13.18; 1055 participants, one study; high-certainty evidence) and dizziness (RR 3.94, 95% CI 2.85 to 5.46; 1055 participants, 1 study; high-certainty evidence). AUTHORS' CONCLUSIONS: Mefloquine was more efficacious than sulfadoxine-pyrimethamine in HIV-uninfected women or daily cotrimoxazole prophylaxis in HIV-infected pregnant women for prevention of malaria infection and was associated with lower risk of maternal anaemia, no adverse effects on pregnancy outcomes (such as stillbirths and abortions), and no effects on low birth weight and prematurity. However, the high proportion of mefloquine-related adverse events constitutes an important barrier to its effectiveness for malaria preventive treatment in pregnant women. PMID- 30480762 TI - Full publication of results initially presented in abstracts. AB - BACKGROUND: Abstracts of presentations at scientific meetings are usually available only in conference proceedings. If subsequent full publication of results reported in these abstracts is based on the magnitude or direction of the results, publication bias may result. Publication bias creates problems for those conducting systematic reviews or relying on the published literature for evidence about health and social care. OBJECTIVES: To systematically review reports of studies that have examined the proportion of meeting abstracts and other summaries that are subsequently published in full, the time between meeting presentation and full publication, and factors associated with full publication. SEARCH METHODS: We searched MEDLINE, Embase, the Cochrane Library, Science Citation Index, reference lists, and author files. The most recent search was done in February 2016 for this substantial update to our earlier Cochrane Methodology Review (published in 2007). SELECTION CRITERIA: We included reports of methodology research that examined the proportion of biomedical results initially presented as abstracts or in summary form that were subsequently published. Searches for full publications had to be at least two years after meeting presentation. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and assessed risk of bias. We calculated the proportion of abstracts published in full using a random-effects model. Dichotomous variables were analyzed using risk ratio (RR), with multivariable models taking into account various characteristics of the reports. We assessed time to publication using Kaplan-Meier survival analyses. MAIN RESULTS: Combining data from 425 reports (307,028 abstracts) resulted in an overall full publication proportion of 37.3% (95% confidence interval (CI), 35.3% to 39.3%) with varying lengths of follow-up. This is significantly lower than that found in our 2007 review (44.5%. 95% CI, 43.9% to 45.1%). Using a survival analyses to estimate the proportion of abstracts that would be published in full by 10 years produced proportions of 46.4% for all studies; 68.7% for randomized and controlled trials and 44.9% for other studies. Three hundred and fifty-three reports were at high risk of bias on one or more items, but only 32 reports were considered at high risk of bias overall.Forty-five reports (15,783 abstracts) with 'positive' results (defined as any 'significant' result) showed an association with full publication (RR = 1.31; 95% CI 1.23 to 1.40), as did 'positive' results defined as a result favoring the experimental treatment (RR =1.17; 95% CI 1.07 to 1.28) in 34 reports (8794 abstracts). Results emanating from randomized or controlled trials showed the same pattern for both definitions (RR = 1.21; 95% CI 1.10 to 1.32 (15 reports and 2616 abstracts) and RR = 1.17; 95% CI, 1.04 to 1.32 (13 reports and 2307 abstracts), respectively.Other factors associated with full publication include oral presentation (RR = 1.46; 95% CI 1.40 to 1.52; studied in 143 reports with 115,910 abstracts); acceptance for meeting presentation (RR = 1.65; 95% CI 1.48 to 1.85; 22 reports with 22,319 abstracts); randomized trial design (RR = 1.51; 95% CI 1.36 to 1.67; 47 reports with 28,928 abstracts); and basic research (RR = 0.78; 95% CI 0.74 to 0.82; 92 reports with 97,372 abstracts). Abstracts originating at an academic setting were associated with full publication (RR = 1.60; 95% CI 1.34 to 1.92; 34 reports with 16,913 abstracts), as were those considered to be of higher quality (RR = 1.46; 95% CI 1.23 to 1.73; 12 reports with 3364 abstracts), or having high impact (RR = 1.60; 95% CI 1.41 to 1.82; 11 reports with 6982 abstracts). Sensitivity analyses excluding reports that were abstracts themselves or classified as having a high risk of bias did not change these findings in any important way.In considering the reports of the methodology research that we included in this review, we found that reports published in English or from a native English-speaking country found significantly higher proportions of studies published in full, but that there was no association with year of report publication. The findings correspond to a proportion of abstracts published in full of 31.9% for all reports, 40.5% for reports in English, 42.9% for reports from native English-speaking countries, and 52.2% for both these covariates combined. AUTHORS' CONCLUSIONS: More than half of results from abstracts, and almost a third of randomized trial results initially presented as abstracts fail to be published in full and this problem does not appear to be decreasing over time. Publication bias is present in that 'positive' results were more frequently published than 'not positive' results. Reports of methodology research written in English showed that a higher proportion of abstracts had been published in full, as did those from native English-speaking countries, suggesting that studies from non-native English-speaking countries may be underrepresented in the scientific literature. After the considerable work involved in adding in the more than 300 additional studies found by the February 2016 searches, we chose not to update the search again because additional searches are unlikely to change these overall conclusions in any important way. PMID- 30480763 TI - Phosphodiesterase inhibitors for lower urinary tract symptoms consistent with benign prostatic hyperplasia. AB - BACKGROUND: Benign prostatic hyperplasia (BPH) refers to non-malignant enlargement of the prostate gland that may cause bothersome lower urinary tract symptoms (LUTS). Alpha-blockers (ABs) and 5-alpha reductase inhibitors (5-ARIs) are the mainstay of medical treatment. Recently, phosphodiesterase inhibitors (PDEIs) that so far have been used mainly to treat erectile dysfunction were introduced to treat male LUTS. OBJECTIVES: To assess the effects of PDEIs compared to placebo and other standard of care drugs (ABs and 5-ARIs) in men with LUTS consistent with BPH. SEARCH METHODS: We conducted a systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Web of Science, and clinical trials registries of the World Health Organization (WHO) and the National Institutes of Health (NIH) (updated 2 August 2018). We performed citation tracking and handsearching of abstracts and conference proceedings. We also contacted study authors to ask for additional information. SELECTION CRITERIA: We considered for inclusion in this systematic review randomised controlled trials (RCTs) comparing PDEIs versus placebo, ABs, or 5-ARIs for at least four weeks in men with BPH-LUTS. DATA COLLECTION AND ANALYSIS: Three review authors independently screened the literature and extracted data. Primary outcomes were effects on urinary symptoms as assessed by the International Prostate Symptom Score (IPSS-total; score ranging from 0 to 35, with higher values reflecting more symptoms), urinary bother as assessed by the Benign Prostatic Hyperplasia Impact Index (BPHII; score ranging from 0 to 13, with higher values reflecting more bother), and adverse events (AEs). We used GRADE to rate the quality of evidence. We considered short-term (up to 12 weeks) and long term (12 weeks or longer) results separately. MAIN RESULTS: We included a total of 16 randomised trials in this review. The results for primary outcomes are as follows.PDEI versus placebo: PDEIs may result in a small improvement in IPSS total score (mean difference (MD) 1.89 lower, 95% confidence interval (CI) 2.27 lower to 1.50 lower; n = 4293; low-quality evidence) compared to placebo, and may reduce the BPHII score slightly (MD 0.52 lower, 95% CI 0.71 lower to 0.33 lower; n = 3646; low-quality evidence). Rates of AEs may be increased (risk ratio (RR) 1.42, 95% CI 1.21 to 1.67; n = 4386; low-quality evidence). This corresponds to 95 more AEs per 1000 participants (95% CI 47 more to 151 more per 1000). Study results were limited to a treatment duration of six to 12 weeks.PDEI versus AB: PDEIs and ABs probably provide similar improvement in IPSS-total score (MD 0.22 higher, 95% CI 0.49 lower to 0.93 higher; n = 933; moderate-quality evidence) and may have a similar effect on BPHII score (MD 0.03 higher, 95% CI 1.10 lower to 1.16 higher; n = 550; low-quality evidence) and AEs (RR 1.35, 95% CI 0.80 to 2.30; n = 936; low-quality evidence). This corresponds to 71 more AEs per 1000 participants (95% CI 41 fewer to 264 more per 1000). Study results were limited to a treatment duration of six to 12 weeks.PDEI and AB versus AB alone: the combination of PDEI and AB may provide a small improvement in IPSS-total score (MD 2.56 lower, 95% CI 3.92 lower to 1.19 lower; n = 193; low-quality evidence) compared to AB alone. We found no evidence for BPHII scores. AEs may be increased (RR 2.81, 95% CI 1.53 to 5.17; n = 194; moderate-quality evidence). This corresponds to 235 more AEs per 1000 participants (95% CI 69 more to 542 more per 1000). Study results were limited to treatment duration of four to 12 weeks.PDEI and AB versus PDEI alone: the combination of PDEI and AB may provide a small improvement in IPSS-total (MD 2.4 lower, 95% CI 6.47 lower to 1.67 higher; n = 40; low-quality evidence) compared to PDEI alone. We found no data on BPHII or AEs. Study results were limited to a treatment duration of four weeks.PDEI and 5 ARI versus 5-ARI alone: in the short term (up to 12 weeks), the combination of PDEI and 5-ARI probably results in a small improvement in IPSS-total score (MD 1.40 lower, 95% CI 2.24 lower to 0.56 lower; n = 695; moderate-quality evidence) compared to 5-ARI alone. We found no evidence on BPHII scores or AEs. In the long term (13 to 26 weeks), the combination of PDEI and 5-ARI likely results in a small reduction in IPSS-total score (MD 1.00 less, 95% CI 1.83 lower to 0.17 lower; n = 695; moderate-quality evidence). We found no evidence about effects on BPHII scores. There may be no difference in rates of AEs (RR 1.07, 95% CI 0.84 to 1.36; n = 695; low-quality evidence). This corresponds to 19 more AEs per 1000 participants (95% CI 43 fewer to 98 more per 1000).We found no trials comparing other combinations of treatments or comparing different PDEI agents. AUTHORS' CONCLUSIONS: Compared to placebo, PDEI likely leads to a small reduction in IPSS total and BPHII sores, with a possible increase in AEs. There may be no differences between PDEI and AB with regards to improvement in IPSS-total, BPHII, and incidence of AEs. There appears to be no added benefit of PDEI combined with AB compared to PDEI or AB alone or PDEI combined with 5-ARI compared to ARI alone with regards to urinary symptoms. Most evidence was limited to short-term treatment up to 12 weeks and of moderate or low certainty. PMID- 30480764 TI - Corticosteroids for septic arthritis in children. AB - BACKGROUND: Septic arthritis is an acute infection of the joints characterised by erosive disruption of the articular space. It is the most common non-degenerative articular disease in developing countries. The most vulnerable population for septic arthritis includes infants and preschoolers, especially boys. Septic arthritis disproportionately affects populations of low socioeconomic status. Systemic corticosteroids and antibiotic therapy may be beneficial for treatment of septic arthritis. Even if the joint infection is eradicated by antibiotic treatment, the inflammatory process may produce residual joint damage and sequelae. OBJECTIVES: To determine the benefits and harms of corticosteroids as adjunctive therapy in children with a diagnosis of septic arthritis. SEARCH METHODS: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, Latin American Caribbean Health Sciences Literature (LILACS), the World Health Organization (WHO) trials portal (www.who.int/ictrp/en/), ClinicalTrials.gov (www.ClinicalTrials.gov), and Google Scholar. We searched all databases from their inception to 17 April 2018, with no restrictions on language of publication. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with patients from two months to 18 years of age with a diagnosis of septic arthritis who were receiving corticosteroids in addition to antibiotic therapy or as an adjuvant to other therapies such as surgical drainage, intra-articular puncture, arthroscopic irrigation, or debridement. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility, data extraction, and evaluation of risk of bias. We considered as major outcomes the presence of pain, activities of daily living, normal physical joint function, days of antibiotic treatment, length of hospital stay, and numbers of total and serious adverse events. We used standard methodological procedures expected by Cochrane. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created a 'Summary of findings' table. MAIN RESULTS: We included two RCTs involving a total of 149 children between three months and 18 years of age who were receiving antibiotics for septic arthritis. The most commonly affected joints were hips and knees. These studies were performed in Costa Rica and Israel. In both studies, dexamethasone administered intravenously (ranging from 0.15 to 0.2 mg/kg/dose every six to eight hours) during four days was the corticosteroid, and the comparator was placebo. Trials excluded patients with any degree of immunodeficiency or immunosuppression. The longest follow-up was one year. Trials did not report activities of daily living nor length of hospital stay. Both studies used adequate processes for randomisation, allocation concealment, and blinding, and review authors judged them to have low risk of selection and performance bias. Losses to follow-up were substantive in both studies, and we judged them to have high risk of attrition bias and of selective outcome reporting. We graded all outcomes as low quality due to concerns about study limitations and imprecision.The risk ratio (RR) for absence of pain at 12 months of follow-up was 1.33, favouring corticosteroids (95% confidence interval (CI) 1.03 to 1.72; P = 0.03; number needed to treat for an additional beneficial outcome (NNTB) = 13, 95% CI 6 to 139; absolute risk difference 24%, 95% CI 5% to 43%).The RR for normal function of the affected joint at 12 months of follow-up was 1.32, favouring corticosteroids (95% CI 1.12 to 1.57; P = 0.001; NNTB = 13, 95% CI 7 to 33; absolute risk difference 24%, 95% CI 11% to 37%).We found a reduction in the number of days of intravenous antibiotic treatment favouring corticosteroids (mean difference (MD) -2.77, 95% CI -4.16 to -1.39) based on two trials with 149 participants.Researchers did not report length of hospital stay. One trial (49 participants) reported that treatment with dexamethasone was associated with a shorter duration of IV antibiotic treatment, leading to a shorter hospital stay, and although duration of hospitalisation was a primary outcome of the study, study authors did not provide data on the duration of hospitalisation. We downgraded the quality by one level for concerns about study limitations (high risk of attrition bias and selective reporting), and by another level for imprecision.In one trial of 49 participants, researchers followed 29 children for 12 months, and parents reported that no children demonstrated adverse effects of the intervention. AUTHORS' CONCLUSIONS: Evidence for corticosteroids as adjunctive therapy in children with a diagnosis of septic arthritis is of low quality and is derived from the findings of two trials (N = 149). Corticosteroids may increase the proportion of patients without pain and the proportion of patients with normal function of the affected joint at 12 months, and may also reduce the number of days of antibiotic treatment. However, we cannot draw strong conclusions based upon these trial results. Additional randomised clinical trials in children with relevant outcomes are needed. PMID- 30480765 TI - Aneuploid acute myeloid leukemia exhibits a signature of genomic alterations in the cell cycle and protein degradation machinery. AB - BACKGROUND: Aneuploidy occurs in more than 20% of acute myeloid leukemia (AML) cases and correlates with an adverse prognosis. METHODS: To understand the molecular bases of aneuploid acute myeloid leukemia (A-AML), this study examined the genomic profile in 42 A-AML cases and 35 euploid acute myeloid leukemia (E AML) cases. RESULTS: A-AML was characterized by increased genomic complexity based on exonic variants (an average of 26 somatic mutations per sample vs 15 for E-AML). The integration of exome, copy number, and gene expression data revealed alterations in genes involved in DNA repair (eg, SLX4IP, RINT1, HINT1, and ATR) and the cell cycle (eg, MCM2, MCM4, MCM5, MCM7, MCM8, MCM10, UBE2C, USP37, CK2, CK3, CK4, BUB1B, NUSAP1, and E2F) in A-AML, which was associated with a 3-gene signature defined by PLK1 and CDC20 upregulation and RAD50 downregulation and with structural or functional silencing of the p53 transcriptional program. Moreover, A-AML was enriched for alterations in the protein ubiquitination and degradation pathway (eg, increased levels of UHRF1 and UBE2C and decreased UBA3 expression), response to reactive oxygen species, energy metabolism, and biosynthetic processes, which may help in facing the unbalanced protein load. E AML was associated with BCOR/BCORL1 mutations and HOX gene overexpression. CONCLUSIONS: These findings indicate that aneuploidy-related and leukemia specific alterations cooperate to tolerate an abnormal chromosome number in AML, and they point to the mitotic and protein degradation machineries as potential therapeutic targets. PMID- 30480766 TI - Ezetimibe for the prevention of cardiovascular disease and all-cause mortality events. AB - BACKGROUND: Cardiovascular disease (CVD) remains an important cause of mortality and morbidity, and high levels of blood cholesterol are thought to be the major modifiable risk factors for CVD. The use of statins is the preferred treatment strategy for the prevention of CVD, but some people at high-risk for CVD are intolerant to statin therapy or unable to achieve their treatment goals with the maximal recommended doses of statin. Ezetimibe is a selective cholesterol absorption inhibitor, whether it has a positive effect on CVD events remains uncertain. Results from clinical studies are inconsistent and a thorough evaluation of its efficacy and safety for the prevention of CVD and mortality is necessary. OBJECTIVES: To assess the efficacy and safety of ezetimibe for the prevention of CVD and all-cause mortality. SEARCH METHODS: We searched the CENTRAL, MEDLINE, Embase and Web of Science on 27 June 2018, and two clinical trial registry platforms on 11 July 2018. We checked reference lists from primary studies and review articles for additional studies. No language restrictions were applied. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared ezetimibe versus placebo or ezetimibe plus other lipid-modifying drugs versus other lipid-modifying drugs alone in adults, with or without CVD, and which had a follow-up of at least 12 months. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted data, assessed risk of bias and contacted trialists to obtain missing data. We performed statistical analyses according to the Cochrane Handbook for Systematic Reviews of Interventions and used the GRADE to assess the quality of evidence. MAIN RESULTS: We included 26 RCTs randomising 23,499 participants. All included studies assessed effects of ezetimibe plus other lipid-modifying drugs compared with other lipid-modifying drugs alone or plus placebo. Our findings were driven by the largest study (IMPROVE-IT), which had weights ranging from 41.5% to 98.4% in the different meta-analyses.Ezetimibe with statins probably reduces the risk of major adverse cardiovascular events compared with statins alone (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.90 to 0.98; a decrease from 284/1000 to 267/1000, 95% CI 256 to 278; 21,727 participants; 10 studies; moderate-quality evidence). Trials reporting all-cause mortality used ezetimibe with statin or fenofibrate and found they have little or no effect on this outcome (RR 0.98, 95% CI 0.91 to 1.05; 21,222 participants; 8 studies; high-quality evidence). Adding ezetimibe to statins probably reduces the risk of non-fatal myocardial infarction (MI) (RR 0.88, 95% CI 0.81 to 0.95; a decrease from 105/1000 to 92/1000, 95% CI 85 to 100; 21,145 participants; 6 studies; moderate-quality evidence) and non fatal stroke (RR 0.83, 95% CI 0.71 to 0.97; a decrease 32/1000 to 27/1000, 95% CI 23 to 31; 21,205 participants; 6 studies; moderate-quality evidence). Trials reporting cardiovascular mortality added ezetimibe to statin or fenofibrate, probably having little or no effect on this outcome (RR 1.00, 95% CI 0.89 to 1.12; 19457 participants; 6 studies; moderate-quality evidence). The need for coronary revascularisation might be reduced by adding ezetimibe to statin (RR 0.94, 95% CI 0.89 to 0.99; a decrease from 196/1000 to 184/1000, 95% 175 to 194; 21,323 participants; 7 studies); however, no difference in coronary revascularisation rate was observed when a sensitivity analysis was limited to studies with a low risk of bias.In terms of safety, adding ezetimibe to statins may make little or no difference in the risk of hepatopathy (RR 1.14, 95% CI 0.96 to 1.35; 20,687 participants; 4 studies; low-quality evidence). It is uncertain whether ezetimibe increase or decrease the risk of myopathy (RR 1.31, 95% CI 0.72 to 2.38; 20,581 participants; 3 studies; very low-quality evidence) and rhabdomyolysis, given the wide CIs and low event rate. Little or no difference in the risk of cancer, gallbladder-related disease and discontinuation due to adverse events were observed between treatment groups. For serum lipids, adding ezetimibe to statin or fenofibrate might further reduce the low-density lipoprotein cholesterol (LDL-C), total cholesterol and triglyceride levels and likely increase the high-density lipoprotein cholesterol levels; however, substantial heterogeneity was detected in most analyses.None of the included studies reported on health-related quality of life. AUTHORS' CONCLUSIONS: Moderate- to high-quality evidence suggests that ezetimibe has modest beneficial effects on the risk of CVD endpoints, primarily driven by a reduction in non fatal MI and non-fatal stroke, but it has little or no effect on clinical fatal endpoints. The cardiovascular benefit of ezetimibe might involve the reduction of LDL-C, total cholesterol and triglycerides. There is insufficient evidence to determine whether ezetimibe increases the risk of adverse events due to the low and very low quality of the evidence. The evidence for beneficial effects was mainly obtained from individuals with established atherosclerotic cardiovascular disease (ASCVD, predominantly with acute coronary syndrome) administered ezetimibe plus statins. However, there is limited evidence regarding the role of ezetimibe in primary prevention and the effects of ezetimibe monotherapy in the prevention of CVD, and these topics thus requires further investigation. PMID- 30480767 TI - Gene therapy for sickle cell disease. AB - BACKGROUND: Sickle cell disease encompasses a group of genetic disorders characterized by the presence of at least one hemoglobin S (Hb S) allele, and a second abnormal allele that could allow abnormal hemoglobin polymerisation leading to a symptomatic disorder.Autosomal recessive disorders (such as sickle cell disease) are good candidates for gene therapy because a normal phenotype can be restored in diseased cells with only a single normal copy of the mutant gene. This is an update of a previously published Cochrane Review. OBJECTIVES: The objectives of this review are:- to determine whether gene therapy can improve survival and prevent symptoms and complications associated with sickle cell disease;- to examine the risks of gene therapy against the potential long-term gain for people with sickle cell disease. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises of references identified from comprehensive electronic database searches and searching relevant journals and abstract books of conference proceedings. We also searched online trial registries,Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 19 July 2018. SELECTION CRITERIA: All randomised or quasi-randomised clinical trials (including any relevant phase 1, 2 or 3 trials) of gene therapy for all individuals with sickle cell disease, regardless of age or setting. DATA COLLECTION AND ANALYSIS: No trials of gene therapy for sickle cell disease were found. MAIN RESULTS: No trials of gene therapy for sickle cell disease were reported. AUTHORS' CONCLUSIONS: No randomised or quasi-randomised clinical trials of gene therapy for sickle cell disease were reported. Thus, no objective conclusions or recommendations in practice can be made on gene therapy for sickle cell disease. This systematic review has identified the need for well-designed, randomised controlled trials to assess the benefits and risks of gene therapy for sickle cell disease. PMID- 30480768 TI - First-line drugs inhibiting the renin angiotensin system versus other first-line antihypertensive drug classes for hypertension. AB - BACKGROUND: This is the first update of a Cochrane Review first published in 2015. Renin angiotensin system (RAS) inhibitors include angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and renin inhibitors. They are widely prescribed for treatment of hypertension, especially for people with diabetes because of postulated advantages for reducing diabetic nephropathy and cardiovascular morbidity and mortality. Despite widespread use for hypertension, the efficacy and safety of RAS inhibitors compared to other antihypertensive drug classes remains unclear. OBJECTIVES: To evaluate the benefits and harms of first-line RAS inhibitors compared to other first-line antihypertensive drugs in people with hypertension. SEARCH METHODS: The Cochrane Hypertension Group Information Specialist searched the following databases for randomized controlled trials up to November 2017: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. SELECTION CRITERIA: We included randomized, active-controlled, double-blinded studies (RCTs) with at least six months follow-up in people with elevated blood pressure (>= 130/85 mmHg), which compared first-line RAS inhibitors with other first-line antihypertensive drug classes and reported morbidity and mortality or blood pressure outcomes. We excluded people with proven secondary hypertension. DATA COLLECTION AND ANALYSIS: Two authors independently selected the included trials, evaluated the risks of bias and entered the data for analysis. MAIN RESULTS: This update includes three new RCTs, totaling 45 in all, involving 66,625 participants, with a mean age of 66 years. Much of the evidence for our key outcomes is dominated by a small number of large RCTs at low risk for most sources of bias. Imbalances in the added second-line antihypertensive drugs in some of the studies were important enough for us to downgrade the quality of the evidence.Primary outcomes were all cause death, fatal and non-fatal stroke, fatal and non-fatal myocardial infarction (MI), fatal and non-fatal congestive heart failure (CHF) requiring hospitalizations, total cardiovascular (CV) events (fatal and non-fatal stroke, fatal and non-fatal MI and fatal and non-fatal CHF requiring hospitalization), and end-stage renal failure (ESRF). Secondary outcomes were systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR).Compared with first-line calcium channel blockers (CCBs), we found moderate-certainty evidence that first-line RAS inhibitors decreased heart failure (HF) (35,143 participants in 5 RCTs, risk ratio (RR) 0.83, 95% confidence interval (CI) 0.77 to 0.90, absolute risk reduction (ARR) 1.2%), and that they increased stroke (34,673 participants in 4 RCTs, RR 1.19, 95% CI 1.08 to 1.32, absolute risk increase (ARI) 0.7%). Moderate-certainty evidence showed that first-line RAS inhibitors and first-line CCBs did not differ for all-cause death (35,226 participants in 5 RCTs, RR 1.03, 95% CI 0.98 to 1.09); total CV events (35,223 participants in 6 RCTs, RR 0.98, 95% CI 0.93 to 1.02); and total MI (35,043 participants in 5 RCTs, RR 1.01, 95% CI 0.93 to 1.09). Low-certainty evidence suggests they did not differ for ESRF (19,551 participants in 4 RCTs, RR 0.88, 95% CI 0.74 to 1.05).Compared with first-line thiazides, we found moderate-certainty evidence that first-line RAS inhibitors increased HF (24,309 participants in 1 RCT, RR 1.19, 95% CI 1.07 to 1.31, ARI 1.0%), and increased stroke (24,309 participants in 1 RCT, RR 1.14, 95% CI 1.02 to 1.28, ARI 0.6%). Moderate-certainty evidence showed that first-line RAS inhibitors and first-line thiazides did not differ for all-cause death (24,309 participants in 1 RCT, RR 1.00, 95% CI 0.94 to 1.07); total CV events (24,379 participants in 2 RCTs, RR 1.05, 95% CI 1.00 to 1.11); and total MI (24,379 participants in 2 RCTs, RR 0.93, 95% CI 0.86 to 1.01). Low certainty evidence suggests they did not differ for ESRF (24,309 participants in 1 RCT, RR 1.10, 95% CI 0.88 to 1.37).Compared with first-line beta-blockers, low certainty evidence suggests that first-line RAS inhibitors decreased total CV events (9239 participants in 2 RCTs, RR 0.88, 95% CI 0.80 to 0.98, ARR 1.7%), and decreased stroke (9193 participants in 1 RCT, RR 0.75, 95% CI 0.63 to 0.88, ARR 1.7% ). Low-certainty evidence suggests that first-line RAS inhibitors and first line beta-blockers did not differ for all-cause death (9193 participants in 1 RCT, RR 0.89, 95% CI 0.78 to 1.01); HF (9193 participants in 1 RCT, RR 0.95, 95% CI 0.76 to 1.18); and total MI (9239 participants in 2 RCTs, RR 1.05, 95% CI 0.86 to 1.27).Blood pressure comparisons between first-line RAS inhibitors and other first-line classes showed either no differences or small differences that did not necessarily correlate with the differences in the morbidity outcomes.There is no information about non-fatal serious adverse events, as none of the trials reported this outcome. AUTHORS' CONCLUSIONS: All-cause death is similar for first line RAS inhibitors and first-line CCBs, thiazides and beta-blockers. There are, however, differences for some morbidity outcomes. First-line thiazides caused less HF and stroke than first-line RAS inhibitors. First-line CCBs increased HF but decreased stroke compared to first-line RAS inhibitors. The magnitude of the increase in HF exceeded the decrease in stroke. Low-quality evidence suggests that first-line RAS inhibitors reduced stroke and total CV events compared to first-line beta-blockers. The small differences in effect on blood pressure between the different classes of drugs did not correlate with the differences in the morbidity outcomes. PMID- 30480769 TI - In vitro maturation in subfertile women with polycystic ovarian syndrome undergoing assisted reproduction. AB - BACKGROUND: Polycystic ovarian syndrome (PCOS) occurs in 4% to 7% of all women of reproductive age and 50% of women presenting with subfertility. Subfertility affects 15% to 20% of couples trying to conceive. A significant proportion of these women ultimately need assisted reproductive technology (ART). In vitro fertilisation (IVF) is one of the assisted reproduction techniques employed to raise the chances of achieving a pregnancy. For the standard IVF technique, stimulating follicle development and growth before oocyte retrieval is essential, for which a large number of different methods combining gonadotrophins with a gonadotrophin-releasing hormone (GnRH) agonist or antagonist are used. In women with PCOS, the supra-physiological doses of gonadotrophins used for controlled ovarian hyperstimulation (COH) often result in an exaggerated ovarian response, characterised by the development of a large cohort of follicles of uneven quality, retrieval of immature oocytes, and increased risk of ovarian hyperstimulation syndrome (OHSS). A potentially effective intervention for women with PCOS-related subfertility involves earlier retrieval of immature oocytes at the germinal-vesicle stage followed by in vitro maturation (IVM). So far, the only data available have derived from observational studies and non-randomised clinical trials. OBJECTIVES: To assess the effectiveness and safety of IVM followed by IVF or ICSI versus conventional IVF or ICSI among women with PCOS undergoing assisted reproduction. SEARCH METHODS: This is the second update of this review. We performed the search on 17 April 2018.The search was designed with the help of the Cochrane Gynaecology and Fertility Group Information Specialist, for all published and unpublished randomised controlled trials (RCTs).We searched the the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL via the Cochrane Central Register of Studies Online, MEDLINE, Embase, CINAHL, and the trial registers for ongoing and registered trials and the Open Grey database for grey literature from Europe. We made further searches in the National Institute for Health and Care Excellence (NICE) fertility assessment and treatment guidelines. We handsearched reference lists of relevant systematic reviews and RCTs, together with PubMed and Google for any recent trials that have not yet been indexed in the major databases. SELECTION CRITERIA: All RCTs on the intention to perform IVM before IVF or ICSI compared with conventional IVF or ICSI for subfertile women with PCOS, irrespective of language and country of origin. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, extracted data from studies, and attempted to contact the authors of studies for which data were missing. Our primary outcomes were live birth per woman randomised and miscarriage. We performed statistical analysis using Review Manager 5. We assessed evidence quality using GRADE methods. MAIN RESULTS: We found two RCTs suitable for inclusion in the review and six ongoing trials that have not yet reported results. Both included studies were published as abstracts in international conferences.Both studies were at unclear or high risk of bias for most of the seven domains assessed. Common problems were unclear reporting of study methods and lack of blinding. The main limitations in the overall quality of the evidence were high risk of bias and serious imprecision.There were no data on the primary outcomes of this review, namely live birth per woman randomised and miscarriage.Both studies reported clinical pregnancy rate: there was evidence of an effect between IVM and IVF, favouring the former (odds ratio 3.10, 95% confidence interval 1.06 to 9.00; 71 participants; 2 studies; I2 = 0%; very low quality evidence). The incidence of OHSS was zero in both studies in both groups.There were no data for the other outcomes specified in this review. AUTHORS' CONCLUSIONS: Though promising data on the in vitro maturation (IVM) technique have been published, unfortunately there is still no evidence from properly conducted randomised controlled trials upon which to base any practice recommendations regarding IVM before in vitro fertilisation (IVF) or intracytoplasmic sperm injection for women with polycystic ovarian syndrome. Regarding our secondary outcomes, very low-quality evidence showed that clinical pregnancy was higher with IVM when compared to IVF, whereas the incidence of ovarian hyperstimulation syndrome was zero in both studies in both groups. We are awaiting the results of six ongoing trials and eagerly anticipate further evidence from good-quality trials in the field. PMID- 30480770 TI - Strategies to improve the implementation of workplace-based policies or practices targeting tobacco, alcohol, diet, physical activity and obesity. AB - BACKGROUND: Given the substantial period of time adults spend in their workplaces each day, these provide an opportune setting for interventions addressing modifiable behavioural risk factors for chronic disease. Previous reviews of trials of workplace-based interventions suggest they can be effective in modifying a range of risk factors including diet, physical activity, obesity, risky alcohol use and tobacco use. However, such interventions are often poorly implemented in workplaces, limiting their impact on employee health. Identifying strategies that are effective in improving the implementation of workplace-based interventions has the potential to improve their effects on health outcomes. OBJECTIVES: To assess the effects of strategies for improving the implementation of workplace-based policies or practices targeting diet, physical activity, obesity, tobacco use and alcohol use.Secondary objectives were to assess the impact of such strategies on employee health behaviours, including dietary intake, physical activity, weight status, and alcohol and tobacco use; evaluate their cost-effectiveness; and identify any unintended adverse effects of implementation strategies on workplaces or workplace staff. SEARCH METHODS: We searched the following electronic databases on 31 August 2017: CENTRAL; MEDLINE; MEDLINE In Process; the Campbell Library; PsycINFO; Education Resource Information Center (ERIC); Cumulative Index to Nursing and Allied Health Literature (CINAHL); and Scopus. We also handsearched all publications between August 2012 and September 2017 in two speciality journals: Implementation Science and Journal of Translational Behavioral Medicine. We conducted searches up to September 2017 in Dissertations and Theses, the WHO International Clinical Trials Registry Platform, and the US National Institutes of Health Registry. We screened the reference lists of included trials and contacted authors to identify other potentially relevant trials. We also consulted experts in the field to identify other relevant research. SELECTION CRITERIA: Implementation strategies were defined as strategies specifically employed to improve the implementation of health interventions into routine practice within specific settings. We included any trial with a parallel control group (randomised or non-randomised) and conducted at any scale that compared strategies to support implementation of workplace policies or practices targeting diet, physical activity, obesity, risky alcohol use or tobacco use versus no intervention (i.e. wait-list, usual practice or minimal support control) or another implementation strategy. Implementation strategies could include those identified by the Effective Practice and Organisation of Care (EPOC) taxonomy such as quality improvement initiatives and education and training, as well as other strategies. Implementation interventions could target policies or practices directly instituted in the workplace environment, as well as workplace-instituted efforts encouraging the use of external health promotion services (e.g. gym membership subsidies). DATA COLLECTION AND ANALYSIS: Review authors working in pairs independently performed citation screening, data extraction and 'Risk of bias' assessment, resolving disagreements via consensus or a third reviewer. We narratively synthesised findings for all included trials by first describing trial characteristics, participants, interventions and outcomes. We then described the effect size of the outcome measure for policy or practice implementation. We performed meta analysis of implementation outcomes for trials of comparable design and outcome. MAIN RESULTS: We included six trials, four of which took place in the USA. Four trials employed randomised controlled trial (RCT) designs. Trials were conducted in workplaces from the manufacturing, industrial and services-based sectors. The sample sizes of workplaces ranged from 12 to 114. Workplace policies and practices targeted included: healthy catering policies; point-of-purchase nutrition labelling; environmental supports for healthy eating and physical activity; tobacco control policies; weight management programmes; and adherence to guidelines for staff health promotion. All implementation interventions utilised multiple implementation strategies, the most common of which were educational meetings, tailored interventions and local consensus processes. Four trials compared an implementation strategy intervention with a no intervention control, one trial compared different implementation interventions, and one three arm trial compared two implementation strategies with each other and a control. Four trials reported a single implementation outcome, whilst the other two reported multiple outcomes. Investigators assessed outcomes using surveys, audits and environmental observations. We judged most trials to be at high risk of performance and detection bias and at unclear risk of reporting and attrition bias.Of the five trials comparing implementation strategies with a no intervention control, pooled analysis was possible for three RCTs reporting continuous score-based measures of implementation outcomes. The meta-analysis found no difference in standardised effects (standardised mean difference (SMD) 0.01, 95% CI -0.32 to 0.30; 164 participants; 3 studies; low certainty evidence), suggesting no benefit of implementation support in improving policy or practice implementation, relative to control. Findings for other continuous or dichotomous implementation outcomes reported across these five trials were mixed. For the two non-randomised trials examining comparative effectiveness, both reported improvements in implementation, favouring the more intensive implementation group (very low certainty evidence). Three trials examined the impact of implementation strategies on employee health behaviours, reporting mixed effects for diet and weight status (very low certainty evidence) and no effect for physical activity (very low certainty evidence) or tobacco use (low certainty evidence). One trial reported an increase in absolute workplace costs for health promotion in the implementation group (low certainty evidence). None of the included trials assessed adverse consequences. Limitations of the review included the small number of trials identified and the lack of consistent terminology applied in the implementation science field, which may have resulted in us overlooking potentially relevant trials in the search. AUTHORS' CONCLUSIONS: Available evidence regarding the effectiveness of implementation strategies for improving implementation of health-promoting policies and practices in the workplace setting is sparse and inconsistent. Low certainty evidence suggests that such strategies may make little or no difference on measures of implementation fidelity or different employee health behaviour outcomes. It is also unclear if such strategies are cost-effective or have potential unintended adverse consequences. The limited number of trials identified suggests implementation research in the workplace setting is in its infancy, warranting further research to guide evidence translation in this setting. PMID- 30480771 TI - Survival differences with immediate versus delayed chemotherapy for asymptomatic incurable metastatic colorectal cancer. AB - BACKGROUND: For patients with asymptomatic, incurable, metastatic colorectal cancer, palliative, systemic treatment can be started immediately, or can be delayed until disease-related symptoms occur. How the potential survival benefit of starting palliative, systemic treatment immediately after diagnosis weighs up against the potential side effects is currently under debate, and was investigated in this review. OBJECTIVES: To assess the effects of immediate versus delayed chemotherapy, with or without targeted therapy, on overall survival, toxicity, quality of life, progression-free survival, and compliance with chemotherapy for individuals with asymptomatic, metastatic, incurable colorectal cancer. SEARCH METHODS: We searched CENTRAL; 2018, Issue 8, MEDLINE Ovid, Embase Ovid, PsycINFO, the World Health Organization International Clinical Trials Registry Platform, and Clinicaltrials.gov, from inception to 23 August 2018. We did not apply limitations based on language or date of publication. We searched the reference lists of all included studies to identify trials that may not have been identified from the electronic searches. SELECTION CRITERIA: Randomised controlled trials evaluating immediate versus delayed chemotherapy in persons with asymptomatic, metastatic, incurable colorectal cancer. DATA COLLECTION AND ANALYSIS: We applied standard methodological procedures, according to the recommendations of Cochrane and Cochrane Colorectal Cancer. Two review authors independently reviewed the studies identified by literature searches, selected relevant trials, extracted data, and assessed risk of bias of the included studies. We used the Cochrane tool to assess risk of bias, Review Manager 5 software for meta-analysis, GRADE methods to evaluate the quality of the evidence, and GRADEpro GDT software to develop a 'Summary of findings' table. MAIN RESULTS: We included three randomised controlled trials (351 participants) investigating immediate versus delayed chemotherapy in people diagnosed with asymptomatic, metastatic, incurable colorectal cancer. Giving immediate versus delayed chemotherapy may make little or no difference to overall survival (hazard ratio (HR) 1.17, 95% confidence interval (CI) 0.93 to 1.46; 3 studies, 351 persons; low-quality evidence). For toxicity, giving immediate versus delayed chemotherapy may make little or no difference to the risk of grade 3 or 4 nausea and vomiting (risk ratio (RR) 0.84, 95% CI 0.31 to 2.25; 2 studies, 140 persons; very low-quality evidence), stomatitis (RR 1.10, 95% CI 0.47 to 2.55; 2 studies, 140 persons; very low-quality evidence), or diarrhoea (RR 0.69, 95% CI 0.34 to 1.40; 2 studies, 140 persons, very low-quality evidence). We are uncertain whether delayed chemotherapy made a difference to quality of life (very low quality evidence), progression-free survival (low-quality evidence), or compliance with chemotherapy (low-quality evidence), as we had insufficient data to pool for these outcomes. AUTHORS' CONCLUSIONS: Based on a limited number of trials, very sparse data, and uncertainty of the evidence, this review was unable to establish whether there was a difference in overall survival or other clinically relevant outcomes, between immediate or delayed chemotherapy in persons with metastatic, incurable, colorectal cancer. The results should be interpreted with caution. PMID- 30480772 TI - Fecal transplantation for treatment of inflammatory bowel disease. AB - BACKGROUND: Inflammatory bowel disease (IBD) is a chronic, relapsing disease of the gastrointestinal tract that is thought to be associated with a complex interplay between microbes and the immune system, leading to an abnormal inflammatory response in genetically susceptible individuals. Dysbiosis, characterized by the alteration of the composition of the resident commensal bacteria in a host compared to healthy individuals, is thought to play a major role in the pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD), two subtypes of IBD. There is growing interest to correct the underlying dysbiosis through the use of fecal microbiota transplantation (FMT) for the treatment of IBD. OBJECTIVES: The objective of this systematic review was to assess the efficacy and safety of FMT for the treatment of IBD. SEARCH METHODS: We searched the MEDLINE, Embase, Cochrane Library, and Cochrane IBD Group Specialized Register databases from inception to 19 March 2018. We also searched ClinicalTrials.gov, ISRCTN metaRegister of Controlled Trials, and the Conference Proceedings Citation Index. SELECTION CRITERIA: Only randomized trials or non randomized studies with a control arm were considered for inclusion. Adults or pediatric participants with UC or CD were eligible for inclusion. Eligible interventions were FMT defined as the administration of fecal material containing distal gut microbiota from a healthy donor to the gastrointestinal tract of a someone with UC or CD. The comparison group included participants who did not receive FMT and were given placebo, autologous FMT, or no intervention. DATA COLLECTION AND ANALYSIS: Two authors independently screened the titles and extracted data from the included studies. We used the Cochrane risk of bias tool to assess study bias. The primary outcomes were induction of clinical remission, clinical relapse, and serious adverse events. Secondary outcomes included clinical response, endoscopic remission and endoscopic response, quality of life scores, laboratory measures of inflammation, withdrawals, and microbiome outcomes. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes and the mean difference and 95% CI for continuous outcomes. Random-effects meta-analysis models were used to synthesize effect sizes across trials. The overall certainty of the evidence supporting the primary and selected secondary outcomes was rated using the GRADE criteria. MAIN RESULTS: Four studies with a total of 277 participants were included. These studies assessed the efficacy of FMT for treatment of UC in adults; no eligible trials were found for the treatment of CD. Most participants had mild to moderate UC. Two studies were conducted in Australia, one study was conducted in Canada, and another in the Netherlands. Three of the included studies administered FMT via the rectal route and one study administered FMT via the nasoduodenal route. Three studies were rated as low risk of bias. One study (abstract publication) was rated as unclear risk of bias. Combined results from four studies (277 participants) suggest that FMT increases rates of clinical remission by two-fold in patients with UC compared to controls. At 8 weeks, 37% (52/140) of FMT participants achieved remission compared to 18% (24/137) of control participants (RR 2.03, 95 % CI, 1.07 to 3.86; I2 = 50%; low certainty evidence). One study reported data on relapse at 12 weeks among participants who achieved remission. None of the FMT participants (0/7) relapsed at 12 weeks compared to 20% of control participants (RR 0.28, 95% CI 0.02 to 4.98, 17 participants, very low certainty evidence). It is unclear whether there is a difference in serious adverse event rates between the intervention and control groups. Seven per cent (10/140) of FMT participants had a serious adverse event compared to 5% (7/137) of control participants (RR 1.40, 95% CI 0.55 to 3.58; 4 studies; I2 = 0%; low certainty evidence). Serious adverse events included worsening of UC necessitating intravenous steroids or surgery; infection such as Clostridium difficile and cytomegalovirus, small bowel perforation and pneumonia. Adverse events were reported by two studies and the pooled data did not show any difference between the study groups. Seventy-eight per cent (50/64) of FMT participants had an adverse event compared to 75% (49/65) of control participants (RR 1.03, 95% CI 0.81 to 1.31; I2 = 31%; moderate certainty evidence). Common adverse events included abdominal pain, nausea, flatulence, bloating, upper respiratory tract infection, headaches, dizziness, and fever. Four studies reported on clinical response at 8 weeks. Forty-nine per cent (68/140) of FMT participants had a clinical response compared to 28% (38/137) of control participants (RR 1.70, 95% CI 0.98 to 2.95, I2 = 50%, low certainty evidence). Endoscopic remission at 8 weeks was reported by three studies and the combined results favored FMT over the control group. Thirty per cent (35/117) of FMT participants achieved endoscopic remission compared to 10% (11/112) of control participants (RR 2.96, 95 % CI 1.60 to 5.48, I2 = 0%; low certainty evidence). AUTHORS' CONCLUSIONS: Fecal microbiota transplantation may increase the proportion of participants achieving clinical remission in UC. However, the number of identified studies was small and the quality of evidence was low. There is uncertainty about the rate of serious adverse events. As a result, no solid conclusions can be drawn at this time. Additional high-quality studies are needed to further define the optimal parameters of FMT in terms of route, frequency, volume, preparation, type of donor and the type and disease severity. No studies assessed efficacy of FMT for induction of remission in CD or in pediatric participants. In addition, no studies assessed long-term maintenance of remission in UC or CD. Future studies are needed to address the therapeutic benefit of FMT in CD and the long-term FMT-mediated maintenance of remission in UC or CD. PMID- 30480773 TI - Omega-3 fatty acid addition during pregnancy. AB - BACKGROUND: Higher intakes of foods containing omega-3 long-chain polyunsaturated fatty acids (LCPUFA), such as fish, during pregnancy have been associated with longer gestations and improved perinatal outcomes. This is an update of a review that was first published in 2006. OBJECTIVES: To assess the effects of omega-3 LCPUFA, as supplements or as dietary additions, during pregnancy on maternal, perinatal, and neonatal outcomes and longer-term outcomes for mother and child. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (16 August 2018), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing omega 3 fatty acids (as supplements or as foods, stand-alone interventions, or with a co-intervention) during pregnancy with placebo or no omega-3, and studies or study arms directly comparing omega-3 LCPUFA doses or types. Trials published in abstract form were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data, assessed risk of bias in trials and assessed quality of evidence for prespecified birth/infant, maternal, child/adult and health service outcomes using the GRADE approach. MAIN RESULTS: In this update, we included 70 RCTs (involving 19,927 women at low, mixed or high risk of poor pregnancy outcomes) which compared omega 3 LCPUFA interventions (supplements and food) compared with placebo or no omega 3. Overall study-level risk of bias was mixed, with selection and performance bias mostly at low risk, but there was high risk of attrition bias in some trials. Most trials were conducted in upper-middle or high-income countries; and nearly half the trials included women at increased/high risk for factors which might increase the risk of adverse maternal and birth outcomes.Preterm birth < 37 weeks (13.4% versus 11.9%; risk ratio (RR) 0.89, 95% confidence interval (CI) 0.81 to 0.97; 26 RCTs, 10,304 participants; high-quality evidence) and early preterm birth < 34 weeks (4.6% versus 2.7%; RR 0.58, 95% CI 0.44 to 0.77; 9 RCTs, 5204 participants; high-quality evidence) were both lower in women who received omega-3 LCPUFA compared with no omega-3. Prolonged gestation > 42 weeks was probably increased from 1.6% to 2.6% in women who received omega-3 LCPUFA compared with no omega-3 (RR 1.61 95% CI 1.11 to 2.33; 5141 participants; 6 RCTs; moderate-quality evidence).For infants, there was a possibly reduced risk of perinatal death (RR 0.75, 95% CI 0.54 to 1.03; 10 RCTs, 7416 participants; moderate-quality evidence: 62/3715 versus 83/3701 infants) and possibly fewer neonatal care admissions (RR 0.92, 95% CI 0.83 to 1.03; 9 RCTs, 6920 participants; moderate-quality evidence - 483/3475 infants versus 519/3445 infants). There was a reduced risk of low birthweight (LBW) babies (15.6% versus 14%; RR 0.90, 95% CI 0.82 to 0.99; 15 trials, 8449 participants; high-quality evidence); but a possible small increase in large-for-gestational age (LGA) babies (RR 1.15, 95% CI 0.97 to 1.36; 6 RCTs, 3722 participants; moderate-quality evidence, for omega-3 LCPUFA compared with no omega-3. Little or no difference in small-for-gestational age or intrauterine growth restriction (RR 1.01, 95% CI 0.90 to 1.13; 8 RCTs, 6907 participants; moderate-quality evidence) was seen.For the maternal outcomes, there is insufficient evidence to determine the effects of omega-3 on induction post-term (average RR 0.82, 95% CI 0.22 to 2.98; 3 trials, 2900 participants; low-quality evidence), maternal serious adverse events (RR 1.04, 95% CI 0.40 to 2.72; 2 trials, 2690 participants; low-quality evidence), maternal admission to intensive care (RR 0.56, 95% CI 0.12 to 2.63; 2 trials, 2458 participants; low-quality evidence), or postnatal depression (average RR 0.99, 95% CI 0.56 to 1.77; 2 trials, 2431 participants; low-quality evidence). Mean gestational length was greater in women who received omega-3 LCPUFA (mean difference (MD) 1.67 days, 95% CI 0.95 to 2.39; 41 trials, 12,517 participants; moderate-quality evidence), and pre-eclampsia may possibly be reduced with omega 3 LCPUFA (RR 0.84, 95% CI 0.69 to 1.01; 20 trials, 8306 participants; low-quality evidence).For the child/adult outcomes, very few differences between antenatal omega-3 LCPUFA supplementation and no omega-3 were observed in cognition, IQ, vision, other neurodevelopment and growth outcomes, language and behaviour (mostly low-quality to very low-quality evidence). The effect of omega-3 LCPUFA on body mass index at 19 years (MD 0, 95% CI -0.83 to 0.83; 1 trial, 243 participants; very low-quality evidence) was uncertain. No data were reported for development of diabetes in the children of study participants. AUTHORS' CONCLUSIONS: In the overall analysis, preterm birth < 37 weeks and early preterm birth < 34 weeks were reduced in women receiving omega-3 LCPUFA compared with no omega-3. There was a possibly reduced risk of perinatal death and of neonatal care admission, a reduced risk of LBW babies; and possibly a small increased risk of LGA babies with omega-3 LCPUFA.For our GRADE quality assessments, we assessed most of the important perinatal outcomes as high-quality (e.g. preterm birth) or moderate-quality evidence (e.g. perinatal death). For the other outcome domains (maternal, child/adult and health service outcomes) GRADE ratings ranged from moderate to very low, with over half rated as low. Reasons for downgrading across the domain were mostly due to design limitations and imprecision.Omega-3 LCPUFA supplementation during pregnancy is an effective strategy for reducing the incidence of preterm birth, although it probably increases the incidence of post term pregnancies. More studies comparing omega-3 LCPUFA and placebo (to establish causality in relation to preterm birth) are not needed at this stage. A further 23 ongoing trials are still to report on over 5000 women, so no more RCTs are needed that compare omega-3 LCPUFA against placebo or no intervention. However, further follow-up of completed trials is needed to assess longer-term outcomes for mother and child, to improve understanding of metabolic, growth and neurodevelopment pathways in particular, and to establish if, and how, outcomes vary by different types of omega-3 LCPUFA, timing and doses; or by characteristics of women. PMID- 30480774 TI - Probiotics for treating eczema. AB - BACKGROUND: Eczema is a common chronic skin condition. Probiotics have been proposed as an effective treatment for eczema; their use is increasing, as numerous clinical trials are under way. This is an update of a Cochrane Review first published in 2008, which suggested that probiotics may not be an effective treatment for eczema but identified areas in which evidence was lacking. OBJECTIVES: To assess the effects of probiotics for treating patients of all ages with eczema. SEARCH METHODS: We updated our searches of the following databases to January 2017: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, the Global Resource of Eczema Trials (GREAT) database, MEDLINE, Embase, PsycINFO, the Allied and Complementary Medicine Database (AMED), and Latin American Caribbean Health Sciences Literature (LILACS). We searched five trials registers and checked the reference lists of included studies and relevant reviews for further references to relevant randomised controlled trials (RCTs). We also handsearched a number of conference proceedings. We updated the searches of the main databases in January 2018 and of trials registries in March 2018, but we have not yet incorporated these results into the review. SELECTION CRITERIA: Randomised controlled trials of probiotics (live orally ingested micro-organisms) compared with no treatment, placebo, or other active intervention with no probiotics for the treatment of eczema diagnosed by a doctor. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane. We recorded adverse events from the included studies and from a separate adverse events search conducted for the first review. We formally assessed reporting bias by preparing funnel plots, and we performed trial sequential analysis for the first primary outcome - eczema symptoms at the end of active treatment.We used GRADE to assess the quality of the evidence for each outcome (in italic font). MAIN RESULTS: We included 39 randomised controlled trials involving 2599 randomised participants. We included participants of either gender, aged from the first year of life through to 55 years (only six studies assessed adults), who had mild to severe eczema. Trials were undertaken in primary and secondary healthcare settings, mainly in Europe or Asia. Duration of treatment ranged from four weeks to six months, and duration of follow-up after end of treatment ranged from zero to 36 months. We selected no standard dose: researchers used a variety of doses and concentrations of probiotics. The probiotics used were bacteria of the Lactobacillus and Bifidobacteria species, which were taken alone or combined with other probiotics, and were given with or without prebiotics. Comparators were no treatment, placebo, and other treatments with no probiotics.For all results described in this abstract, the comparator was no probiotics. Active treatment ranged from six weeks to three months for all of the following results, apart from the investigator-rated eczema severity outcome, for which the upper limit of active treatment was 16 weeks. With regard to score, the higher the score, the more severe were the symptoms. All key results reported in this abstract were measured at the end of active treatment, except for adverse events, which were measured during the active treatment period.Probiotics probably make little or no difference in participant- or parent-rated symptoms of eczema (13 trials; 754 participants): symptom severity on a scale from 0 to 20 was 0.44 points lower after probiotic treatment (95% confidence interval (CI) -1.22 to 0.33; moderate quality evidence). Trial sequential analysis shows that target sample sizes of 258 and 456, which are necessary to demonstrate a minimum mean difference of -2 and -1.5, respectively, with 90% power, have been exceeded, suggesting that further trials with similar probiotic strains for this outcome at the end of active treatment may be futile.We found no evidence suggesting that probiotics make a difference in QoL for patients with eczema (six studies; 552 participants; standardised mean difference (SMD) 0.03, 95% CI -0.36 to 0.42; low-quality evidence) when measured by the participant or the parent using validated disease specific QoL instruments.Probiotics may slightly reduce investigator-rated eczema severity scores (24 trials; 1596 participants). On a scale of 0 to 103 for total Severity Scoring of Atopic Dermatitis (SCORAD), a score combining investigator rated eczema severity score and participant scoring for eczema symptoms of itch and sleep loss was 3.91 points lower after probiotic treatment than after no probiotic treatment (95% CI -5.86 to -1.96; low-quality evidence). The minimum clinically important difference for SCORAD has been estimated to be 8.7 points.We noted significant to extreme levels of unexplainable heterogeneity between the results of individual studies. We judged most studies to be at unclear risk of bias; six studies had high attrition bias, and nine were at low risk of bias overall.We found no evidence to show that probiotics make a difference in the risk of adverse events during active treatment (risk ratio (RR) 1.54, 95% CI 0.90 to 2.63; seven trials; 402 participants; low-quality evidence). Studies in our review that reported adverse effects described gastrointestinal symptoms. AUTHORS' CONCLUSIONS: Evidence suggests that, compared with no probiotic, currently available probiotic strains probably make little or no difference in improving patient-rated eczema symptoms. Probiotics may make little or no difference in QoL for people with eczema nor in investigator-rated eczema severity score (combined with participant scoring for eczema symptoms of itch and sleep loss); for the latter, the observed effect was small and of uncertain clinical significance. Therefore, use of probiotics for the treatment of eczema is currently not evidence-based. This update found no evidence of increased adverse effects with probiotic use during studies, but a separate adverse events search from the first review revealed that probiotic treatment carries a small risk of adverse events.Results show significant, unexplainable heterogeneity between individual trial results. Only a small number of studies measured some outcomes.Future studies should better measure QoL scores and adverse events, and should report on new probiotics. Researchers should also consider studying subgroups of patients (e.g. patients with atopy or food allergies, adults) and standardising doses/concentrations of probiotics given. PMID- 30480775 TI - Prevalence of nonfounder BRCA1/2 mutations in Ashkenazi Jewish patients presenting for genetic testing at a hereditary breast and ovarian cancer center. AB - BACKGROUND: Genetic assessment in Ashkenazi Jewish (AJ) patients often is limited to BRCA1/2 founder mutation testing. With access to time-efficient and cost efficient multigene panel testing, some advocate expanding genetic testing in this population. However, to the best of the authors' knowledge, rates of nonfounder BRCA1/2 mutations and mutations in cancer-associated genes other than BRCA1/2 among AJ are not known. In the current study, the authors sought to assess the prevalence of mutations other than BRCA1/2 founder mutations among AJ patients undergoing genetic assessment. METHODS: The authors reviewed the medical records for all AJ patients who underwent genetic assessment at a single institution between June 2013 and December 2016. Mutations were categorized as 1) BRCA1/2 AJ founder mutations (BRCA1 185delAG, BRCA1 5382insC, or BRCA2 6174delT); 2) nonfounder BRCA1/2 mutations; or 3) mutations in non-BRCA1/2 cancer-associated genes. RESULTS: A total of 732 AJ patients underwent genetic assessment. Of these, 371 patients (51%) had a personal history of breast or ovarian cancer, 540 patients (73.8%) had a family history of breast cancer, and 132 patients (18%) had a family history of ovarian cancer. In the study population, 101 patients (13.8%) were found to have a pathogenic mutation, 78 patients (10.7%) had a BRCA1/2 founder mutation, 3 patients (0.4%) had a nonfounder BRCA1/2 mutation, and 20 patients (2.7%) had a mutation in a non-BRCA1/2 cancer-associated gene. Non-BRCA1/2 cancer-associated genes harboring mutations included RAD51D, TP53, mutS homolog 6 (MSH6), checkpoint kinase 2 (CHEK2), adenomatous polyposis coli (APC), and Fanconi anemia group C protein (FANCC). CONCLUSIONS: Among AJ patients found to have a pathogenic mutation on genetic assessment, approximately 22.8% had a mutation that would be missed with BRCA1/2 AJ founder mutation testing. Comprehensive multigene panel sequencing can provide clinically relevant genetic information for AJ patients and should be considered for genetic assessment in this population. PMID- 30480776 TI - Adverse side effects of dexamethasone in surgical patients. AB - BACKGROUND: In the perioperative period, dexamethasone is widely and effectively used for prophylaxis of postoperative nausea and vomiting (PONV), for pain management, and to facilitate early discharge after ambulatory surgery.Long-term treatment with steroids has many side effects, such as adrenal insufficiency, increased infection risk, hyperglycaemia, high blood pressure, osteoporosis, and development of diabetes mellitus. However, whether a single steroid load during surgery has negative effects during the postoperative period has not yet been studied. OBJECTIVES: To assess the effects of a steroid load of dexamethasone on postoperative systemic or wound infection, delayed wound healing, and blood glucose change in adult surgical patients (with planned subgroup analysis of patients with and without diabetes). SEARCH METHODS: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library, and the Web of Science for relevant articles on 29 January 2018. We searched without language or date restriction two clinical trial registries to identify ongoing studies, and we handsearched the reference lists of relevant publications to identify all eligible trials. SELECTION CRITERIA: We searched for randomized controlled trials comparing an incidental steroid load of dexamethasone versus a control intervention for adult patients undergoing surgery. We required that studies include a follow-up of 30 days for proper assessment of the number of postoperative infections, delayed wound healing, and the glycaemic response. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for eligibility, extracted data from relevant studies, and assessed all included studies for bias. We resolved differences by discussion and pooled included studies in a meta-analysis. We calculated Peto odds ratios (ORs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes. Our primary outcomes were postoperative systemic or wound infection, delayed wound healing, and glycaemic response within 24 hours. We created a funnel plot for the primary outcome postoperative (wound or systemic) infection. We used GRADE to assess the quality of evidence for each outcome. MAIN RESULTS: We included in the meta-analysis 37 studies that included adults undergoing a large variety of surgical procedures (i.e. abdominal surgery, cardiac surgery, neurosurgery, and orthopaedic surgery). We excluded one previously included study, as this study was recently retracted. Age range of participants was 18 to 80 years. There is probably little or no difference in the risk of postoperative (wound or systemic) infection with dexamethasone compared with no treatment, placebo, or active control (ramosetron, ondansetron, or tropisetron) (Peto OR 1.01, 95% confidence interval (CI) 0.80 to 1.27; 4603 participants, 26 studies; I2 = 32%; moderate-quality evidence). The effects of dexamethasone on delayed wound healing are unclear because the wide confidence interval includes both meaningful benefit and harm (Peto OR 0.99, 95% CI 0.28 to 3.43; 1072 participants, eight studies; I2 = 0%; low-quality evidence). Dexamethasone may produce a mild increase in glucose levels among participants without diabetes during the first 12 hours after surgery (MD 13 mg/dL, 95% CI 6 to 21; 10 studies; 595 participants; I2 = 50%; low-quality evidence). We identified two studies reporting on glycaemic response after dexamethasone in participants with diabetes within 24 hours after surgery (MD 32 mg/dL, 95% CI 15 to 49; 74 participants; I2 = 0%; very low-quality evidence). AUTHORS' CONCLUSIONS: A single dose of dexamethasone probably does not increase the risk for postoperative infection. It is uncertain whether dexamethasone has an effect on delayed wound healing in the general surgical population owing to imprecision in trial results. Participants with increased risk for delayed wound healing (e.g. participants with diabetes, those taking immunosuppressive drugs) were not included in the randomized studies reporting on delayed wound healing included in this meta-analysis; therefore our findings should be extrapolated to the clinical setting with caution. Furthermore, one has to keep in mind that dexamethasone induces a mild increase in glucose. For patients with diabetes, very limited evidence suggests a more pronounced increase in glucose. Whether this influences wound healing in a clinically relevant way remains to be established. Once assessed, the two studies awaiting classification and three that are ongoing may alter the conclusions of this review. PMID- 30480777 TI - Safety and survival outcomes for bloodless transplantation in patients with myeloma. AB - High-dose therapy (HDT) and autologous stem cell transplantation (ASCT) are established components in the treatment of multiple myeloma; however, undergoing transplantation usually requires hematopoietic support, which poses a challenge among patients who are unwilling to receive blood products. Most transplant centers decline HDT/ASCT to these patients because of safety concerns. Here, the authors' institutional data on safety, engraftment parameters, and survival outcomes after bloodless ASCT (BL-ASCT) are examined among patients with myeloma. This retrospective case-control study included patients who underwent BL-ASCT and Transfusion-supported ASCT (TS-ASCT) at Emory University Hospital between August 2006 and August 2016. In total, 24 patients who underwent BL-ASCT and 70 who underwent TS-ASCT were included. The median time for neutrophil engraftment, platelet engraftment and the median length of hospital stay all were equivalent for both groups. There were no transplant-related cardiovascular complications or mortality in either the BL-ASCT group or the TS-ASCT group. The median progression-free survival was 36 months and 44 months in the BL-ASCT and TS-ASCT groups, respectively (P = .277), and the median OS was not reached in either group at a median follow-up of 59 months after ASCT (P = .627). There was no transplant-related mortality at the 100-day or 1-year mark in either group. BL ASCT is safe and feasible; transplant-related mortality, cardiovascular and hematologic complications are similar to those associated with TS-ASCT. Furthermore, BL-ASCT can yield similar engraftment and survival parameters comparable to those observed with TS-ASCT. PMID- 30480778 TI - Anti-angiogenic therapy for high-grade glioma. AB - BACKGROUND: This is an updated version of the original Cochrane Review published in September 2014. The most common primary brain tumours in adults are gliomas. Gliomas span a spectrum from low to high grade and are graded pathologically on a scale of one to four according to the World Health Organization (WHO) classification. High-grade glioma (HGG) carries a poor prognosis. Grade IV glioma is known as glioblastoma and carries a median survival in treated patients of about 15 months. Glioblastomas are rich in blood vessels (i.e. highly vascular) and also rich in a protein known as vascular endothelial growth factor (VEGF) that promotes new blood vessel formation (the process of angiogenesis). Anti angiogenic agents inhibit the process of new blood vessel formation and promote regression of existing vessels. Several anti-angiogenic agents have been investigated in clinical trials, both in newly diagnosed and recurrent HGG, showing preliminary promising results. This review was undertaken to report on the benefits and harms associated with the use of anti-angiogenic agents in the treatment of HGGs. OBJECTIVES: To evaluate the efficacy and toxicity of anti angiogenic therapy in people with high-grade glioma (HGG). The intervention can be used in two broad groups: at first diagnosis as part of 'adjuvant' therapy, or in the setting of recurrent disease. SEARCH METHODS: We conducted updated searches to identify published and unpublished randomised controlled trials (RCTs), including the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 9), MEDLINE and Embase to October 2018. We handsearched proceedings of relevant oncology conferences up to 2018. We also searched trial registries for ongoing studies. SELECTION CRITERIA: RCTs evaluating the use of anti angiogenic therapy to treat HGG versus the same therapy without anti-angiogenic therapy. DATA COLLECTION AND ANALYSIS: Review authors screened the search results and reviewed the abstracts of potentially relevant articles before retrieving the full text of eligible articles. MAIN RESULTS: After a comprehensive literature search, we identified 11 eligible RCTs (3743 participants), of which 7 were included in the original review (2987 participants). There was significant design heterogeneity in the included studies, especially in the response assessment criteria used. All eligible studies were restricted to glioblastomas and there were no eligible studies evaluating other HGGs. Ten studies were available as fully published peer-reviewed manuscripts, and one study was available in abstract form. The overall risk of bias in included studies was low. This risk was based upon low rates of selection bias, detection bias, attrition bias and reporting bias. The 11 studies included in this review did not show an improvement in overall survival with the addition of anti-angiogenic therapy (pooled hazard ratio (HR) of 0.95, 95% confidence interval (CI) 0.88 to 1.02; P = 0.16; 11 studies, 3743 participants; high-certainty evidence). However, pooled analysis from 10 studies (3595 participants) showed improvement in progression free survival with the addition of anti-angiogenic therapy (HR 0.73, 95% CI 0.68 to 0.79; P < 0.00001; high-certainty evidence).We carried out additional analyses of overall survival and progression-free survival according to treatment setting and for anti-angiogenic therapy combined with chemotherapy compared to chemotherapy alone. Pooled analysis of overall survival in either the adjuvant or recurrent setting did not show an improvement (HR 0.93, 95% CI 0.86 to 1.02; P = 0.12; 8 studies, 2833 participants; high-certainty evidence and HR 0.99, 95% CI 0.85 to 1.16; P = 0.90; 3 studies, 910 participants; moderate-certainty evidence, respectively). Pooled analysis of overall survival for anti-angiogenic therapy combined with chemotherapy compared to chemotherapy also did not clearly show an improvement (HR 0.92, 95% CI 0.85 to 1.00; P = 0.05; 11 studies, 3506 participants; low-certainty evidence). The progression-free survival in the subgroups all showed findings that demonstrated improvements in progression-free survival with the addition of anti-angiogenic therapy. Pooled analysis of progression-free survival in both the adjuvant and recurrent setting showed an improvement (HR 0.75, 95% CI 0.69 to 0.82; P < 0.00001; 8 studies, 2833 participants; high-certainty evidence and HR 0.64, 95% CI 0.54 to 0.76; P < 0.00001; 2 studies, 762 participants; moderate-certainty evidence, respectively). Pooled analysis of progression-free survival for anti-angiogenic therapy combined with chemotherapy compared to chemotherapy alone showed an improvement (HR 0.72, 95% CI 0.66 to 0.77; P < 0.00001; 10 studies, 3464 participants). Similar to trials of anti-angiogenic therapies in other solid tumours, adverse events related to this class of therapy included hypertension and proteinuria, poor wound healing, and the potential for thromboembolic events, although generally, the rate of grade 3 and 4 adverse events was low (< 14.1%) and in keeping with the literature. The impact of anti-angiogenic therapy on quality of life varied between studies. AUTHORS' CONCLUSIONS: The use of anti-angiogenic therapy does not significantly improve overall survival in newly diagnosed people with glioblastoma. Thus, there is insufficient evidence to support the use of anti angiogenic therapy for people with newly diagnosed glioblastoma at this time. Overall there is a lack of evidence of a survival advantage for anti-angiogenic therapy over chemotherapy in recurrent glioblastoma. When considering the combination anti-angiogenic therapy with chemotherapy compared with the same chemotherapy alone, there may possibly be a small improvement in overall survival. While there is strong evidence that bevacizumab (an anti-angiogenic drug) prolongs progression-free survival in newly diagnosed and recurrent glioblastoma, the impact of this on quality of life and net clinical benefit for patients remains unclear. Not addressed here is whether subsets of people with glioblastoma may benefit from anti-angiogenic therapies, nor their utility in other HGG histologies. PMID- 30480779 TI - Cellular physiology controls photoautotrophic production of 1,2-propanediol from pools of CO2 and glycogen. AB - Synechocystis sp. PCC 6803 PG is a cyanobacterial strain capable of synthesizing 1,2-propanediol from carbon dioxide via a heterologous three-step pathway and a methylglyoxal synthase originating from E. coli as initial enzyme. The production window is restricted to the late growth and stationary phase and is apparently coupled to glycogen turn-over. To understand the underlying principle of the carbon partitioning between the Calvin-Benson-Bassham (CBB) cycle and glycogen in the context of 1,2-propanediol production, experiments utilizing 13 C labeled carbon dioxide (CO2 ) have been conducted. Carbon fluxes and partitioning between biomass, storage compounds, and product have been monitored under permanent illumination as well as under dark conditions. About one-quarter of the carbon incorporated into 1,2-propanediol originated from glycogen, while the rest was derived from CO2 fixed in the CBB cycle during product formation. Furthermore, 1,2-propanediol synthesis was depending on the availability of photosynthetic active radiation and glycogen catabolism. We postulate that the regulation of the methylglyoxal synthase from E. coli conflicts with the heterologous reactions leading to 1,2-propanediol in Synechocystis sp. PCC 6803 PG. Additionally, homology comparison of the genomic sequence to genes encoding for the methylglyoxal bypass in E. coli suggested the existence of such a pathway also in Synechocystis sp. PCC 6803. These findings are critical for all heterologous pathways coupled to the CBB cycle intermediate dihydroxyacetone phosphate via a methylglyoxal synthase and reveal possible engineering targets for rational strain optimization. This article is protected by copyright. All rights reserved. PMID- 30480781 TI - Patient experience further underscores the importance of infection prevention. PMID- 30480780 TI - WITHDRAWN: Psychotherapy for depression among incurable cancer patients. AB - BACKGROUND: The most common psychiatric diagnosis among cancer patients is depression; this diagnosis is even more common among patients with advanced cancer. Psychotherapy is a patient-preferred and promising strategy for treating depression among cancer patients. Several systematic reviews have investigated the effectiveness of psychological treatment for depression among cancer patients. However, the findings are conflicting, and no review has focused on depression among patients with incurable cancer. OBJECTIVES: To investigate the effects of psychotherapy for treating depression among patients with advanced cancer by conducting a systematic review of randomized controlled trials (RCTs). SEARCH METHODS: We searched the Cochrane Pain, Palliative and Supportive Care Group Register, The Cochrane Controlled Trials Register, MEDLINE, EMBASE, CINAHL, and PsycINFO databases in September 2005. SELECTION CRITERIA: All relevant RCTs comparing any kind of psychotherapy with conventional treatment for adult patients with advanced cancer were eligible for inclusion. Two independent review authors identified relevant studies. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the original reports using standardized data extraction forms. Two independent review authors also assessed the methodological quality of the selected studies according to the recommendations of a previous systematic review of psychological therapies for cancer patients that utilized ten internal validity indicators. The primary outcome was the standardized mean difference (SMD) of change between the baseline and immediate post-treatment scores. MAIN RESULTS: We identified a total of ten RCTs (total of 780 participants); data from six studies were used for meta-analyses (292 patients in the psychotherapy arm and 225 patients in the control arm). Among these six studies, four studies used supportive psychotherapy, one adopted cognitive behavioural therapy, and one adopted problem-solving therapy. When compared with treatment as usual, psychotherapy was associated with a significant decrease in depression score (SMD = -0.44, 95% confidence interval [CI] = -0.08 to -0.80). None of the studies focused on patients with clinically diagnosed depression. AUTHORS' CONCLUSIONS: Evidence from RCTs of moderate quality suggest that psychotherapy is useful for treating depressive states in advanced cancer patients. However, no evidence supports the effectiveness of psychotherapy for patients with clinically diagnosed depression. PMID- 30480783 TI - A Collaborative Approach to Creating a Perioperative Nursing Recruitment and Retention Strategy. PMID- 30480782 TI - Results of the 2018 AORN Salary and Compensation Survey. AB - AORN conducted its 16th annual compensation survey for perioperative nurses in June 2018. A multiple regression model was used to examine how several variables, including job title, education level, certification, experience, and geographic region, affect perioperative nurse compensation. Comparisons between the 2018 data and data from previous years are presented. The effects of other forms of compensation (eg, on-call compensation, overtime, bonuses, shift differentials, benefits) on total compensation also are examined. Additional analyses explore the current state of the nursing shortage and the sources of job satisfaction and dissatisfaction. PMID- 30480785 TI - Decreasing Surgical Procedure-Related Infections Using Culture, Collaboration, and Communication. PMID- 30480784 TI - Did You Know? PMID- 30480786 TI - Improving Efficiency and Standardization in a Robotics Program: A Quality Improvement Project. AB - After an evaluation of the growing robotics program at Christiana Care Health System in Newark, Delaware, perioperative leaders identified needs related to a lack of instrument set standardization and inconsistent workflow processes; these deficiencies were causing higher-than-anticipated turnaround time (ie, 59 minutes) and an excessive inventory of sterilized robotic instruments. A workgroup was created to review the results of the evaluation and develop solutions for the robotic surgery program. Goals included a 40-minute procedure turnaround time and a 35% reduction in sterilized robotic instrument set inventory one year after project initiation. By developing a team training program, improving operational efficiencies, and improving standardization, the robotics program achieved a 10-minute TAT reduction and a 54% reduction in sterilized robotic instrument inventory. Personnel considered the project to be a huge success because it laid the groundwork for improving efficiency and standardization in Christiana Care Health System's robotics program. PMID- 30480787 TI - Guideline Implementation: Safe Patient Handling and Movement: 1.8 www.aornjournal.org/content/cme. AB - Physical stressors that occur with patient and equipment handling in the OR (eg, moving or lifting patients, carrying heavy instrument sets, prolonged standing) can contribute to musculoskeletal disorders for perioperative personnel. In addition to increasing patient safety, safe patient handling and movement (SPHM) programs have been shown to reduce the risk and severity of injuries, workers' compensation costs, and personnel fatigue and to increase health care workers' morale and quality of life. The AORN "Guideline for safe patient handling and movement" provides guidance for implementing an SPHM program. This article discusses key takeaways from the guideline, including forming an interdisciplinary team to oversee the SPHM program, selecting safe patient handling technologies and equipment, and assessing the unique needs of each patient to develop an individualized plan for SPHM. Perioperative RNs should review the complete guideline for additional information and for guidance when writing and updating policies and procedures. PMID- 30480789 TI - Aneurysm clipping. PMID- 30480788 TI - Decreasing Surgical Site Infections by Developing a High Reliability Culture. AB - Today's fast-paced and complex perioperative setting requires a collaborative and mindful approach to implementing evidence-based practices and preventing patient harm. Recent changes in the health care landscape coupled with the potential harm caused by surgical site infections require a shift in culture in which all members of the perioperative team have zero tolerance for preventable harm. This article discusses high-reliability organizations and examples of ways in which perioperative teams can apply the principles of high reliability to the prevention of surgical site infections. Characteristics of high-reliability organizations include mindfulness, collaboration, standardization, and use of a structured model to implement evidence into practice. By understanding and applying these concepts and others described in this article, members of a multidisciplinary team should be more prepared to ensure that all staff members are following evidence-based practices during every patient encounter. PMID- 30480791 TI - Tsugawa Y, Jena AB, Orav EJ, et al. Age and sex of surgeons and mortality of older surgical patients: observational study. BMJ. 2018;361:k1343. https://doi.org/10.1136/bmj.k1343. PMID- 30480790 TI - Clinical Issues-December 2018: 1.5 www.aornjournal.org/content/cme. PMID- 30480792 TI - Guideline for transmission-based precautions. PMID- 30480794 TI - The Key to Safety: Generosity. PMID- 30480793 TI - Remote Video Auditing to Verify OR Cleaning: A Quality Improvement Project. AB - There are many sources of contamination in the perioperative environment. Patient experience can be negatively affected by the presence of environmental contamination, especially if it is the cause of a surgical site infection. Perioperative and environmental services staff members and leaders are tasked with ensuring a clean and safe environment for their patients while maintaining an awareness of time and budgetary constraints. In addition, leaders are responsible for the competency of their staff members and must address performance issues when needed. New technological advances designed to streamline monitoring and reporting processes related to OR cleanliness are available for use. This article describes the quality improvement project that one multifacility organization completed related to the use of remote video auditing and the positive effect it had on the organization's environmental contamination. PMID- 30480795 TI - Delayed Recognition of a Positive Blood Culture. PMID- 30480797 TI - The Importance of Leak Testing Flexible Endoscopes: 1.6 www.aornjournal.org/content/cme. AB - Leak testing is a vital processing step that detects fluid invasion in an endoscope. Endoscopes that are inadequately leak tested can pose a risk for transmission of infection or injury to patients. If not detected, fluid invasion of an endoscope can damage the endoscope and increase repair costs. This article presents evidence to support leak testing, provides recommendations for correct leak testing, explains reasons for leak-testing failures, and discusses a case scenario with a failed leak test and the approach that facility personnel took to improve the quality and consistency of leak testing their endoscopes. PMID- 30480798 TI - Protecting Patients From Surgical Smoke. PMID- 30480799 TI - Sterile Technique. PMID- 30480800 TI - Altered plasma proteins released from platelets and endothelial cells are associated with human patent ductus arteriosus. AB - Patent ductus arteriosus is the third most common congenital heart disease and resulted from the persistence of ductal patency after birth. Ductus arteriosus closure involves functional and structural remodeling, controlled by many factors. The changes in plasma protein levels associated with PDA closure are not known. Here we for the first time demonstrate six key differential plasma proteins in human patent ductus arteriosus patients using proteomic technology and present a model to illustrate the constriction and closure of ductus arteriosus. Differentially expressed proteins were analyzed by using isobaric tags for relative and absolute quantification and validated by enzyme-linked immunosorbent assay in new samples. The proteomic data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier PXD008568. We found 74 upregulated and 98 downregulated proteins in the plasma of patients with PDA. Five decreased proteins (platelet factor 4, fibrinogen, von Willebrand factor, collagen, and mannose binding lectin associated serine protease-2) and one increased protein (fibronectin) may increase the risk of patent ductus arteriosus. Those proteins are closely related to platelet activation and coagulation cascades, complement mannan-binding lectin, and other systemic signaling pathways. Our findings for the first time indicate that the differential proteins involved in different pathways may play key roles in the nonclosure of the ductus arteriosus in humans and may be developed as biomarkers for diagnosis. All those findings may be served as the basis of understanding the etiology and pathogenesis of patent ductus arteriosus. PMID- 30480801 TI - MicroRNA-99b suppresses human cervical cancer cell activity by inhibiting the PI3K/AKT/mTOR signaling pathway. AB - Cervical cancer is common cancer among women with high morbidity. MicroRNAs (miRs) are involved in the progression and development of cervical cancer. This study aimed to explore the effect of miR-99b-5p (miR-99b) on invasion and migration in cervical cancer through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway. The microarray-based analysis was used to screen out differentially expressed miRNAs. Expression of miR-99b, PI3K, AKT, mTOR, and ribosomal protein S6 kinase (p70S6K) was determined in both cervical cancer tissues and paracancerous tissues. Next, alteration of miR-99b expression in cervical cancer was conducted to evaluate levels of PI3K, AKT, mTOR, p70S6K matrix metallopeptidase 2, epithelial cell adhesion molecule, and intercellular adhesion molecule 1, as well as the effect of miR-99b on cell proliferation, invasion, migration, cell cycle distribution, and apoptosis. The results demonstrated that miR-99b expression was decreased and levels of PI3K, AKT, mTOR, and p70S6K were elevated in cervical cancer tissues. More important, overexpressed miR-99b repressed the PI3K/AKT/mTOR signaling pathway, inhibited cell proliferation, invasion, and migration, blocked cell cycle entry, and promoted apoptosis in cervical cancer. These results indicate that miR-99b attenuates the migration and invasion of human cervical cancer cells through downregulation of the PI3K/AKT/mTOR signaling pathway, which provides a therapeutic approach for cervical cancer treatment. PMID- 30480802 TI - Home sweet suboxic home: remarkable hypoxia tolerance in two demersal fish species in the Gulf of California. PMID- 30480803 TI - Cell fate regulation by reticulon-4 in human prostate cancers. AB - Reticulon-4 (RTN4), a reticulon family protein localized in the endoplasmic reticulum, is reported to be involved in multiple physiological processes like neuroendocrine secretion and membrane trafficking in neuroendocrine cells. Previous studies have presented a great potential of RTN4 for the treatment of autoimmune-mediated demyelinating diseases and spinal cord injury regeneration. While interaction with Bcl-2 and Bcl-2-like family in apoptosis modulation implicated its possible role in various human cancers. However, the investigation of this gene in prostate cancer is mainly ignored. Here in our current study, we focused on its role in prostate cancer and found that RTN4 DNA copy numbers were higher in prostate cancer than normal prostate gland while its RNA and protein expressions were relatively lower. Chromosomal neighbor gene EML6 had similar expression patterns with RTN4 in prostate cancer tissues and cell lines, and further research found that they could be both targeted by miR-148a-3p. Lentivirus-mediated RTN4 overexpression potently inhibited DU145 and LNCaP cells proliferation. Cell cycle was blocked in G2/M phase and significant cell senescence was observed in RTN4 overexpressed prostate cancer cells. Finally, interaction networks in the normal prostate gland and cancer tissues further revealed that RTN4 maybe phosphorylated by MAPKAPK2 and FYN at tyrosine 591 and serine 107, respectively. All these results implied that RTN4 might somehow participate in prostate tumor progression, and this elicits possibility to develop or identify selective agents targeting RTN4 for prostate cancer therapy. PMID- 30480804 TI - Preparation of adriamycin gelatin microsphere-loaded decellularized periosteum that is cytotoxic to human osteosarcoma cells. AB - The purpose of this study was to develop a novel approach to treat bone osteosarcoma using a multipurpose scaffold aiming for local drug delivery. The slowly releasing microspheres was designed to deliver the chemotherapy drug adriamycin (ADM) and a decellularized (D) periosteum scaffold (which is known to be able to promote bone regeneration) was used to carry these microspheres. D periosteum was obtained by physical and chemical decellularization. Histological results showed that the cellular components were effectively removed. The D periosteum showed an excellent cytocompatibility and the ability to promote adhesion and growth of fibroblasts. Two kinds of slowly releasing microspheres, adriamycin gelatin microspheres (ADM-GMS) and adriamycin poly (dl-lactide-co glycolide) gelatin microspheres (ADM-PLGA-GMS), were prepared and anchored to D periosteum, resulting in two types of drug-releasing regenerative scaffolds. The effectiveness of these two scaffolds in killing human osteosarcoma cells was tested by evaluating cell viability overtime of the cancer cells cultured with the scaffolds. In summary, a gelatin/decellularized periosteum-based biologic scaffold material was designed aiming for local delivery of chemotherapy drugs for osteosarcoma, with the results showing ability of the scaffolds in sustaining release of the cancer drug and in suppressing growth of the cancer cells in vitro. PMID- 30480805 TI - National trends in contralateral prophylactic mastectomy in women with locally advanced breast cancer. AB - BACKGROUND AND OBJECTIVES: Women with unilateral early-stage breast cancer are increasingly choosing contralateral prophylactic mastectomy (CPM) despite the absence of survival benefits and increased risk of surgical complications. Data are lacking on whether this trend extends to women with clinically locally advanced nonmetastatic (cT4M0) cancer. This study aims to estimate national CPM trends in women with unilateral cT4M0 breast cancer. METHODS: Women aged >= 18 years, who underwent mastectomy during 2004 to 2014 for unilateral cT4M0 breast cancer were identified using the National Cancer Database and grouped as all locally advanced (T4), chest wall invasion, skin nodule/ulceration, or both (T4abc), and inflammatory (T4d) cancer. Poisson regression for trends and logistic modeling for predictors of CPM were performed. RESULTS: Of 23 943 women, 41% had T4abc disease and 35% T4d. Cumulative CPM rates were 15%, 23%, and 18%, for the T4abc, T4d, and all T4 groups, respectively. Trend analysis revealed a significant upsurge in CPM demonstrating 12% annual growth for T4abc tumors, 8% for T4d and 9% for all T4 (all P < 0.001). CONCLUSIONS: Increasing numbers of women with unilateral cT4M0 breast cancer are undergoing CPM. This rising trend warrants further research to understand stakeholders' preferences in surgical decision-making for women with locally advanced breast cancer. PMID- 30480806 TI - c-Met inhibition is required for the celecoxib-attenuated stemness property of human colorectal cancer cells. AB - Cyclooxygenase-2 (COX-2) is frequently overexpressed and enhances colorectal cancer (CRC) tumorigenesis, including cancer stem cell (CSC) regulation. Accordingly, nonsteroidal anti-inflammatory drugs (NSAIDs), inhibiting COX-1/2 activity, are viewed as potential drugs for CRC treatment. Accumulated evidence indicates that celecoxib has the most potency for antitumor growth among NSAIDs and the underlying mechanism is only partly dependent on COX-2 inhibition. However, the potency of these NSAIDs on CSC inhibition is still not known. In this study, we found that among these NSAIDs, celecoxib has the most potency for CSC inhibition of CRC cells, largely correlating to inhibition of c-Met, not COX 2. Further analysis reveals that c-Met activity was required for basal CSC property. Silence of c-Met blocked whereas overexpression of c-Met enhanced the celecoxib-inhibited CSC property. Collectively, these results not only first elucidate the mechanism underlying celecoxib-inhibited CSC but also indicate c Met as a critical factor for the CSC property of CRC cells. PMID- 30480807 TI - Inhibition of miR-124 improves neonatal necrotizing enterocolitis via an MYPT1 and TLR9 signal regulation mechanism. AB - BACKGROUNDS: Necrotizing enterocolitis (NEC) was one of the main causes of morbidity and mortality in neonates. Our objective was to detect the mechanism of miR-124 in small bowel tissues of NEC. METHODS: Hematoxylin and eosin (H&E) staining was used to detect the repair of the damaged tissues in rat NEC model. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to evaluate the cell apoptosis level in intestinal tissue. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the messenger RNA (mRNA) expression level of miR-124, Rho-associated coiled-coil-containing protein kinase 1 (ROCK1), myosin phosphatase target subunit 1 (MYPT1), and Toll like receptor 9 (TLR9) in NEC tissues and IEC-6 cells. Luciferase reporter assay was used to verify whether ROCK1 is a direct target of miR-124. RESULTS: miR-124 was overexpressed in the NEC tissues, while ROCK1 and MYPT1 was downregulated in the NEC tissues. Inhibition of miR-124, suppressed the intestinal cell apoptosis and promoted the expression of ROCK1 and MYPT1. What is more, overexpression of miR-124 could inhibit the expression of ROCK1, TLR9, and MYPT1. Luciferase assay confirmed that miR-124 can regulate the transcriptional activity of ROCK1 through binding its 3'-UTR region. CONCLUSION: miR-124 was a promoter of NEC, which promotes the intestine cell apoptosis and inflammatory cell infiltration through the inhibition of TLR9 expression by targeting ROCK1. PMID- 30480808 TI - Cholinergic activity regulates the secretome of epicardial adipose tissue: Association with atrial fibrillation. AB - Botulinum toxin injection on epicardial fat, which inhibits acetylcholine (ACh) release, reduced the presence of atrial fibrillation (AF) in patients after heart surgery. Thus, we wanted to study the profile of the released proteins of epicardial adipose tissue (EAT) under cholinergic activity (ACh treatment) and their value as AF predictors. Biopsies, explants, or primary cultures were obtained from the EAT of 85 patients that underwent open heart surgery. The quantification of muscarinic receptors (mAChR) by real-time polymerase chain reaction or western blot showed their expression in EAT. Moreover, mAChR Type 3 was upregulated after adipogenesis induction (p < 0.05). Cholinergic fibers in EAT were detected by vesicular ACh transporter levels and/or acetylcholinesterase activity. ACh treatment modified the released proteins by EAT, which were identified by nano-high-performance liquid chromatography and TripleTOF analysis. These differentially released proteins were involved in cell structure, inflammation, or detoxification. After testing the plasma levels of alpha defensin 3 (inflammation-involved protein) of patients who underwent open heart surgery ( n = 24), we observed differential levels between the patients who developed or did not develop postsurgery AF (1.58 +/- 1.61 ng/ml vs. 6.2 +/- 5.6 ng/ml; p < 0.005). The cholinergic activity on EAT might suggest a new mechanism for studying the interplay among EAT, autonomic nervous system dysfunction, and AF. PMID- 30480809 TI - Patients with multiple needs for healthcare and priority to the worse off. AB - There is a growing body of literature which suggests that decisions about healthcare priority setting should take into account the extent to which patients are worse off. However, such decisions are often based on how badly off patients are with respect to the condition targeted by the treatment whose priority is under consideration (condition-specific severity). In this paper I argue that giving priority to the worse off in terms of condition-specific severity does not reflect the morally relevant sense of being worse off. I conclude that an account of giving priority to the worse off relevant for healthcare priority setting should take into account how badly off patients are when all of their conditions are considered (holistic severity). PMID- 30480810 TI - The possible role of bacteria, viruses, and parasites in initiation and exacerbation of irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is a prolonged and disabling functional gastrointestinal disorder with the incidence rate of 18% in the world. IBS could seriously affect lifetime of patients and cause high economic burden on the community. The pathophysiology of the IBS is hardly understood, whereas several possible mechanisms, such as visceral hypersensitivity, irregular gut motility, abnormal brain-gut relations, and the role of infectious agents, are implicated in initiation and development of this syndrome. Different studies demonstrated an alteration in B-lymphocytes, mast cells (MC), T-lymphocytes, and cytokine concentrations in intestinal mucosa or systemic circulation that are likely to contribute to the formation of the IBS. Therefore, IBS could be developed in those with genetic predisposition. Infections' role in initiation and exacerbation of IBS has been investigated by quite several clinical studies; moreover, the possible role of some pathogens in development and exacerbation of this disease has been described. It appears that the main obligatory pathogens correspond with the IBS disease, Clostridium difficile, Escherichia coli, Mycobacterium avium subspecies paratuberculosis, Campylobacter concisus, Campylobacter jejuni, Chlamydia trachomatis, Helicobacter pylori, Pseudomonas aeruginosa, Salmonella spp, Shigella spp, and viruses, particularly noroviruses. A number of pathogenic parasites (Blastocystis, Dientamoeba fragilis, and Giardia lamblia) may also be involved in the progression and exacerbation of the disease. Based on the current knowledge, the current study concludes that the most common bacterial, viral, and parasitic pathogens may be involved in the development and progression of IBS. PMID- 30480811 TI - Specific prognostic factors in hepatitis B virus-related and non-hepatitis B virus-related intrahepatic cholangiocarcinoma after macroscopic curative resection. AB - BACKGROUND: The hepatitis B virus (HBV)-related intrahepatic cholangiocarcinoma (iCCA) was recognized as a unique subtype of iCCA, within particular features in demography, clinicopathology, and genealogy. However, how they predict prognosis, in particular, for HBV- and non-HBV-related iCCA is still unclear. METHODS: Demographic, clinicopathologic, and genetic features were retrospectively collected and reviewed to determine the specific prognostic factors, precisely predicting the overall survival (OS) in HBV-related (n = 119) and non-HBV-related ( n = 149) iCCA patients, respectively. RESULTS: In HBV-related iCCA, TP53 mutation, vascular invasion, extrahepatic metastasis, and serum levels of alpha fetoprotein (AFP) were independent prognostic factors for OS. In non-HBV-related iCCA, RAS/ RAF mutation and lymphatic metastasis independently predicted the OS of patients. Tumor differentiation and serum levels of CA19-9 were significantly associated with OS in both HBV- and non-HBV-related iCCA patients. In a subset analysis, TP53 and RAS/RAF mutations were consistently related to poorer outcome in HBV- and non-HBV-related iCCA, respectively. CONCLUSIONS: The HBV- and non-HBV related iCCA have different prognostic factors for the OS. PMID- 30480812 TI - Decolonizing "Community" in Community Psychology. AB - This article endeavors to craft pathways that disrupt dominant modes of knowledge production and imagine nonhierarchical epistemic possibilities in teaching community psychology. The first section of the article discusses how the decolonial turn inspires new ways of advancing the critical social justice agenda of community psychology. Drawing upon decolonial frameworks and allied critical theories, I outline how coloniality is entrenched in the ways we theorize, research, and teach about "communities"-and the importance of decolonizing the construct of community in community psychology. The second section presents three vignettes capturing student responses to endeavors in the classroom to dismantle notions of community-as-Other. I interpret these vignettes through a decolonial perspective in order to highlight how colonial discourses of community can be produced and potentially maintained in the classroom context. The third section outlines some pedagogical and curricular recommendations as a possible pathway toward decolonizing notions of community. I conclude with some questions/provocations geared toward advancing decolonial and liberatory praxis in community psychology. PMID- 30480813 TI - Skin disorders are prominent features in primary immunodeficiency diseases: a systematic overview of current data. AB - Primary immunodeficiency diseases (PIDs) are characterized by an increased risk of infections, autoimmunity, autoinflammation, malignancy and allergic disorders. Skin disorders are also common clinical features in PIDs and may be among the presenting manifestations. Recognition of specific PID-associated skin conditions in combination with other clinical features as described in the currently used warning signs could raise suspicion of an underlying PID. We aimed to provide a systematically obtained overview of skin disorders and their prevalence in PIDs. Secondary, the prevalence of Staphylococcus (S.) aureus-associated skin disorders and atopy were reviewed, as these are the most prominent skin features in PIDs. A systematic search was performed in Embase, Medline, Web of Science, Cochrane and Google Scholar (up to May 9th 2018). All original observational and experimental human studies that address the presence of skin disorders in PIDs were selected. We rated study quality using the Institute of Health Economics Quality Appraisal Checklist for Case Series Studies. Sixty-seven articles (5030 patients) were included. Study quality ranged from 18.2-88.5%. A broad spectrum of skin disorders was reported in 30 PIDs, mostly in single studies with a low number of included patients. An overview of associated PIDs per skin disorder was generated. Data on S. aureus-associated skin disorders and atopy in PIDs were limited. In conclusion, skin disorders are prominent features in PIDs. Through clustering of PIDs per skin disorder, we provide a support tool to use in clinical practice that should raise awareness of PIDs based on presenting skin manifestations. This article is protected by copyright. All rights reserved. PMID- 30480814 TI - Effects of nebulized N--acetylcystein on the expression of HMGB1 and RAGE in rats with hyperoxia--induced lung injury. AB - OBJECTIVE: To investigate the role of high mobility group box 1 (HMGB1) and receptor for advanced glycation end product (RAGE) in the lungs of hyperoxia induced rats and the effect of N--acetlycystein (NAC). METHODS: A model of hyperoxic lung injury was established, rats in the NAC intervention, and control, hyperoxia group were given nebulized NAC aerosol, nebulized same volume of saline once a day for 7 consecutive days, respectively. Wet/dry ( W/ D) ratio of the lungs was determined to evaluate the edema of the lung tissues. Conventional hematoxylin-eosin (HE) staining was used to observe the pathological changes of lung tissues. Immunohistochemical staining was used to investigate the expression of HMGB1 and RAGE in the lung tissues. Quantitative reverse-transcription polymerase chain reaction and western blot analysis were used to measured the changes in the messenger RNA (mRNA) and protein expression of HMGB1 and RAGE, respectively. RESULTS: Weight gain of the rats in the hyperoxia group was significantly slower than that in the control group and intervention group (p < 0.05). HE staining results showed lung tissues in the hyperoxia group were severely damaged compared with control group. W/D ratio in hyperoxia group was significantly higher than that in control group and intervention group (p < 0.05). Protein and mRNA expression of HMGB1 and RAGE in the hyperoxia group were significantly higher than control group and intervention group (p < 0.05). CONCLUSION: HMGB1 and RAGE were involved in the pathogenesis of hyperoxia-induced lung injury, inhalation of NAC might alleviate hyperoxia-induced lung injury by regulating the expression of HMGB1 and RAGE. PMID- 30480815 TI - Embryo quality, and not chromosome nondiploidy, affects mitochondrial DNA content in mouse blastocysts. AB - It has been shown recently that there is premature mitochondria biosynthesis in blastocysts from older women whose egg or embryo quality is poor and that aneuploid blastocysts also have a high number of mitochondrial DNA (mtDNA) copies. Whether nondiploidy/aneuploidy or reduced egg or embryo quality causes premature mitochondrial biosynthesis is not known. This study constructed haploid, diploid, triploid, and tetraploid blastocysts by parthenogenetic activation, intracytoplasmic sperm injection with one or two sperm heads, blastomere electrofusion, respectively, and generated reduced cytoplasm quality embryos from diabetic mouse and in vitro fertilization of aged oocytes, and examined whether nondiploidy or reduced cytoplasm quality causes premature mitochondrial biosynthesis. MtDNA numbers of each blastocyst from different models were tested by absolute quantitative real-time polymerase chain reaction. It was found that mtDNA content in preimplantation embryos was not associated with their chromosome ploidy, while mtDNA copy numbers in embryos with suboptimal quality were increased. Therefore, it might be the reduced cytoplasmic quality, and not chromosome nondiploidy, that causes premature mitochondria biosynthesis in blastocysts. PMID- 30480816 TI - Knockdown of NEAT1 repressed the malignant progression of glioma through sponging miR-107 and inhibiting CDK14. AB - Aberrant expressions of long noncoding RNAs (lncRNAs) contribute to carcinogenesis via regulating tumor suppressors or oncogenes. LncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been recognized as an oncogene to promote tumor progression of many cancers. However, the function of NEAT1 in glioma remains poorly discovered. Currently, we focused on the role of NEAT1 in glioma. Here, we found that NEAT1 was greatly upregulated in glioma cells compared with normal human astrocytes (NHAs). Meanwhile, miR-107 was significantly downregulated in glioma cell lines. Then, we observed that knockdown of NEAT1 suppressed the growth and invasion of glioma cells including U251 and SW1783 cells. Reversely, overexpression of NEAT1 dramatically induced glioma cell survival, increased cell colony formation, and promoted cell invasion ability. Subsequently, bioinformatics analysis was performed to predict the correlation between NEAT1 and miR-107. Moreover, it was revealed that NEAT1 could modulate miR-107 via serving as an endogenous sponge of miR-107. The direct binding correlation between NEAT1 and miR-107 was validated in our study. In addition, cyclin dependent kinase 14 (CDK14) was predicted as an messenger RNA target of miR-107 and the association between them was confirmed in our research. Moreover, we implied that NEAT1 demonstrated its biological functions via regulating miR-107 and CDK14 in vivo. In summary, our findings indicated that NEAT1/miR-107/CDK14 axis participated in glioma development. NEAT1 could act as a significant prognostic biomarker in glioma progression. PMID- 30480817 TI - miR-142-3p as tumor suppressor miRNA in the regulation of tumorigenicity, invasion and migration of human breast cancer by targeting Bach-1 expression. AB - BACKGROUND: Breast cancer is the most common type of cancer among women, and despite improved treatments, it remains a major challenge. However, improved mechanistic insight may lead to novel therapeutic strategies. miR-142-3p belongs to the miR-142 family and is involved in pathogenesis and metastasis of various types of malignancies by targeting several important messenger RNAs (mRNAs) including Bach-1. This is especially true for breast cancer, where Bach-1 is involved in the metastatic spread by deregulation of metastasis-associated genes. METHODS: In this study, we collected 24 breast cancer tissues with 24 adjusted normal tissues to measure the expression levels of miR-142-3p and Bach-1 mRNA using quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and IHC. miR-142-3p targeting of Bach-1 expression in MCF-7 and MDA-MB-468 breast cancer cells was evaluated using bioinformatics, qRT-PCR and western blot analyses. The cellular proliferation, invasion, and migration were assessed by MTT, transwell matrigel and wound healing assay and the EMT-associated proteins C X-C chemokine receptor type 4 (CXCR-4), matrix metalloproteinase-9 (MMP9), and vascular endothelial growth factor receptor (VEGFR) were analyzed by western blot analysis. Also, the expression levels of tumor suppressors including miR-330, miR 145, and miR-34a were estimated by qRT-PCR. RESULTS: Analysis of paired specimens of primary malignant and normal tissues showed that miR-142-3p was downregulated, while Bach-1 mRNA and protein both were overexpressed in the breast cancer tumors. This inverse relationship was confirmed by cell line experiments demonstrating that miR-142-3p expression reduced Bach-1 mRNA levels. Furthermore, replacement of miR-142-3p could inhibit the proliferation, invasion, and migration in breast cancer potentially by targeting of Bach-1 mRNA and subsequent inhibition of CXCR4, MMP9, and VEGFR protein expressions. In addition, induction of miR-142-3p could upregulate tumor suppressor miRNAs, including miR-330, miR 145, and miR34a. CONCLUSION: For the first time, our results revealed that miR 142-3p could target Bach-1in breast cancer cells leading to the reduction of EMT related proteins and reduced cell proliferation, invasion, and migration. The results also demonstrated that miR-142-3p could regulate important tumor suppressor miRNAs in breast cancer cells. In conclusion, our results suggest that miR-142-3p could be a good candidate for the targeted therapy of breast cancer, especially for the invasive type. PMID- 30480818 TI - AnatomyNet: Deep Learning for Fast and Fully Automated Whole-volume Segmentation of Head and Neck Anatomy. AB - PURPOSE: Radiation therapy (RT) is a common treatment option for head and neck (HaN) cancer. An important step involved in RT planning is the delineation of organs-at-risks (OARs) based on HaN computed tomography (CT). However, manually delineating OARs is time-consuming as each slice of CT images needs to be individually examined and a typical CT consists of hundreds of slices. Automating OARs segmentation has the benefit of both reducing the time and improving the quality of RT planning. Existing anatomy auto-segmentation algorithms use primarily atlas-based methods, which require sophisticated atlas creation and cannot adequately account for anatomy variations among patients. In this work, we propose an end-to-end, atlas-free 3D convolutional deep learning framework for fast and fully automated whole-volume HaN anatomy segmentation. METHODS: Our deep learning model, called AnatomyNet, segments OARs from head and neck CT images in an end-to-end fashion, receiving whole-volume HaN CT images as input and generating masks of all OARs of interest in one shot. AnatomyNet is built upon the popular 3D U-net architecture, but extends it in three important ways: 1) a new encoding scheme to allow auto-segmentation on whole-volume CT images instead of local patches or subsets of slices, 2) incorporating 3D squeezeand-excitation residual blocks in encoding layers for better feature representation, and 3) a new loss function combining Dice scores and focal loss to facilitate the training of the neural model. These features are designed to address two main challenges in deep-learning-based HaN segmentation: a) segmenting small anatomies (i.e., optic chiasm and optic nerves) occupying only a few slices, and b) training with inconsistent data annotations with missing ground truth for some anatomical structures. RESULTS: We collected 261 HaN CT images to train AnatomyNet, and used MICCAI Head and Neck Auto Segmentation Challenge 2015 as a benchmark dataset to evaluate the performance of AnatomyNet. The objective is to segment nine anatomies: brain stem, chiasm, mandible, optic nerve left, optic nerve right, parotid gland left, parotid gland right, submandibular gland left, and submandibular gland right. Compared to previous state-of-the-art results from the MICCAI 2015 competition, AnatomyNet increases Dice similarity coefficient by 3.3% on average. AnatomyNet takes about 0.12 seconds to fully segment a head and neck CT image of dimension 178*302*225, significantly faster than previous methods. In addition, the model is able to process whole-volume CT images and delineate all OARs in one pass, requiring little pre- or post-processing. CONCLUSION: Deep learning models offer a feasible solution to the problem of delineating OARs from CT images. We demonstrate that our proposed model can improve segmentation accuracy and simplify the auto-segmentation pipeline. With this method, it is possible to delineate OARs of a head and neck CT within a fraction of a second. This article is protected by copyright. All rights reserved. PMID- 30480819 TI - Redefining the signaling pathways from pluripotency to pancreas development: In vitro beta-cell differentiation. AB - Pancreatic beta-cells are destroyed by the immune system, in type 1 diabetes (T1D) and are impaired by glucose insensitivity in type 2 diabetes (T2D). Islet cells transplantation is a promising therapeutic approach based on in vitro differentiation of pluripotent stem cells (PSCs) to insulin-producing cells (IPCs). According to evolutionary stages in beta-cell development, there are several distinct checkpoints; each one has a unique characteristic, including definitive endoderm (DE), primitive gut (PG), posterior foregut (PF), pancreatic epithelium (PE), endocrine precursor (EP), and immature beta-cells up to functional beta-cells. A better understanding of the gene regulatory networks (GRN) and associated transcription factors in each specific developmental stage, guarantees the achievement of the next successful checkpoints and ensures an efficient beta-cell differentiation procedure. The new findings in signaling pathways, related to the development of the pancreas are discussed here, including Wnt, Activin/Nodal, FGF, BMP, retinoic acid (RA), sonic hedgehog (Shh), Notch, and downstream regulators, required for beta-cell commitment. We also summarized different approaches in the IPCs protocol to conceptually define a standardized system, leading to the creation of a reproducible method for beta cell differentiation. To normalize blood glucose level in diabetic mice, the replacement therapy in the early differentiation stage, such as EP stages was associated with better outcome when compared with the fully differentiated beta cells' graft. PMID- 30480820 TI - Even if the fetus is not a person, abortion is immoral: The impairment argument. AB - Much of the debate about the ethics of abortion has centered on whether the fetus is a person. In an attempt to sidestep this complex issue, I argue that, even if the fetus is not a person, abortion is immoral. To arrive at this conclusion, I argue that giving a fetus fetal alcohol syndrome is immoral, and that if this is so, then killing the fetus is immoral. Roughly, this is because killing the fetus impairs it more than giving it fetal alcohol syndrome. Since abortion (in most cases) amounts to killing the fetus, this means that abortion (in most cases) is immoral. I defend the premises of this argument against a plethora of objections, concluding that they either do not work, or commit their proponent to a controversial position. PMID- 30480821 TI - The role of trust in global health research collaborations. AB - Collaborations in global health research are on the rise because they enhance productivity, facilitate capacity building, accelerate output and make tackling big, multifactorial research questions possible. In this paper, I examine the concepts of trust and reliance in scientific collaborations in general, but also in the particular context of collaborations in global health research between high-income countries and low-and-middle income countries (LMIC). I propose and defend the argument that given the particular characteristics of collaborations and demands of trust relationships, reliance is a better relational mode for successful collaborations. Although reliance can be difficult to establish in situations where asymmetry of power exists, trust should not be the only relational mode available to LMIC researchers because of the type of vulnerability it introduces to the relationship. I conclude that the promotion of good collaborations requires addressing the power imbalances between partners, and establishing an even playing field in global health research. PMID- 30480822 TI - A novel multidimensional signature predicts prognosis in hepatocellular carcinoma patients. AB - The abnormal expression of microRNAs (miRNAs) or protein-coding genes (PCGs) have been found to be associated with the prognosis of hepatocellular carcinoma (HCC) patients. Using bioinformatics analysis methods including Cox's proportional hazards regression analysis, the random survival forest algorithm, Kaplan-Meier, and receiver operating characteristic (ROC) curve analysis, we mined the gene expression profiles of 469 HCC patients from The Cancer Genome Atlas (n = 379) and Gene Expression Omnibus (GSE14520; n = 90) public database. We selected a signature comprising one protein-coding gene (PCG; DNA polymerase MU) and three miRNAs (hsa-miR-149-5p, hsa-miR-424-5p, hsa-miR-579-5p) with highest accurate prediction (area under the ROC curve [AUC] = 0.72; n = 189) from the training data set. The signature stratified patients into high- and low-risk groups with significantly different survival (median 27.9 vs. 55.2 months, log-rank test, p < 0.001) in the training data set, and its risk stratification ability were validated in the test data set (median 47.4 vs. 84.4 months, log-rank test, p = 0.03) and an independent data set (median 31.0 vs. 46.0 months, log-rank test, p = 0.01). Multivariable Cox regression analysis showed that the signature was an independent prognostic factor. And the signature was proved to have a better survival prediction power than tumor-node-metastasis (TNM) stage (AUC signature = 0.72/0.64/0.62 vs. AUC TNM = 0.65/0.61/0.61; p < 0.05). Moreover, we validated the expression of these prognostic genes from the PCG-miRNA signature in Huh-7 cell by real-time polymerase chain reaction. In conclusion, we found a signature that can predict survival of HCC patients and serve as a prognostic marker for HCC. PMID- 30480823 TI - The effects of social exclusion on processing of social information - A cognitive psychology perspective. AB - In this article, we review the research investigating the effects of social exclusion on processing of social information. We look into this topic from the point of view of cognitive psychology aiming to provide a systematic description of the effects of exclusion on workings of different cognitive mechanisms involved in social information processing. We focus on four lines of inquiry. First, we present the research on the effects of exclusion on memory for social information. Second, we review studies, which have investigated how exclusion changes the way people view and evaluate their social environment. Third, we look into the research which has investigated whether exclusion modulates early social information processing at the perceptual level. Finally, we discuss the research on the effects of exclusion on attentional processes. Importantly, we also present gaps in our understanding on these issues and provide suggestions as to how future research could provide a more detailed view on how exclusion modulates social information processing. PMID- 30480824 TI - Effective biosynthesis of benzoyl-pyrrothine dithiolopyrrolone antibiotic by cinnamic acid-precursor addition in culture of Saccharothrix algeriensis NRRL B 24137. AB - Dithiolopyrrolone antibiotics, produced by several microorganisms, are known for their strong antimicrobial and antitumor activities. Among of this microorganisms, Saccharothrix algeriensis NRRL B-24137, a rare actinobacterium, has the abillity to produce several dithiolopyrrolones derivatives depending on precursors added in the culture medium. After 10 days of strain fermentation on semi-synthetic medium supplemented with cinnamic acid and HPLC purification, biosynthesis of benzoyl-pyrrothine dithiolopyrrolone was evidenced through complete spectroscopic (UV-visible and 1H and 13C NMR) and spectrometric (EI-MS) analyses. The pure molecule showed appreciable minimum inhibitory concentration values against several Gram-positive bacteria and filamentous fungi. This article is protected by copyright. All rights reserved. PMID- 30480825 TI - A novel power supply system for puborectails-like artificial anal sphincter. AB - Puborectails-like artificial anal sphincter (PAAS) is an innovative new type of artificial anal sphincter (AAS). It overcomes many drawbacks and inadequacies of various previous AASs, and it has successfully been implanted to proceed vivo test for almost 3 weeks. During vivo-test, PAAS shows its ability to retain continence with low risk of ischemia necrosis, and somehow truly helps to remodel rectal perception. However, there are still many defects that influence the long term implantation of PAAS, especially in power supply system (PSS). This article presents a new designed PSS includes a new transcutaneous energy transfer (TET) system, a heat reduction system, and a safety usage system. The new PSS reduces the total size of PAAS by at least 30%. New designed TET system can satisfy Qi standard, and render a power of 3w to fulfill the requirement of fast charging and normal use of PAAS at the distance of 15.5mm when frequency of TET system is 110kHz, which previous TET system can hardly achieve. Heat reduction system helps to reduce the heat generated during TET charging. It can reduce heat by 40% during the same period of time of TET charging. Safety usage system helps the user control PAAS more properly which can reduce the rate of failure of PAAS system. This article is protected by copyright. All rights reserved. PMID- 30480826 TI - Volatile compounds other than CO2 emitted by different microorganisms promote distinct post-transcriptionally regulated responses in plants. AB - A "box-in-box" co-cultivation system was used to investigate plant responses to microbial volatile compounds (VCs), and to evaluate the contributions of organic and inorganic VCs (VOCs and VICs, respectively) to these responses. Arabidopsis plants were exposed to VCs emitted by adjacent Alternaria alternata and Penicillium aurantiogriseum cultures, with and without charcoal filtration. No VOCs were detected in the headspace of growth chambers containing fungal cultures with charcoal filters. However, these growth chambers exhibited elevated CO2 and bioactive CO and NO headspace concentrations. Independently of charcoal filtration, VCs from both fungal phytopathogens promoted growth and distinct developmental changes. Plants cultured at CO2 levels observed in growth boxes containing fungal cultures were identical to those cultured at ambient CO2 . Plants exposed to charcoal-filtered fungal VCs, non-filtered VCs, or super elevated CO2 levels exhibited transcriptional changes resembling those induced by increased irradiance. Thus, in the "box-in-box" system, (a) fungal VICs other than CO2 and/or VOCs not detected by our analytical systems strongly influence the plants' responses to fungal VCs, (b) different microorganisms release VCs with distinct action potentials, (c) transcriptional changes in VC-exposed plants are mainly due to enhanced photosynthesis signaling, and (d) regulation of some plant responses to fungal VCs is primarily post-transcriptional. PMID- 30480827 TI - Distinct Lipid Transfer Proteins display different IgE-binding activities that are affected by fatty acid binding. PMID- 30480828 TI - Trends in liver cancer mortality in the United States: Dual burden among foreign- and US-born persons. AB - BACKGROUND: Since the mid-1980s, the burden of liver cancer in the United States has doubled, with 31,411 new cases and 24,698 deaths occurring in 2014. Foreign born individuals may be more likely to die of liver cancer than individuals in the general US-born population because of higher rates of hepatitis B infection, a low socioeconomic position, and language barriers that limit the receipt of early cancer detection and effective treatment. METHODS: To determine whether liver cancer mortality rates were higher among foreign-born individuals versus US born individuals in the United States, population-based cancer mortality data were obtained from the National Center for Health Statistics of the Centers for Disease Control and Prevention. Annual population estimates were obtained from the US Census Bureau's American Community Survey. Age-adjusted mortality rates and rate ratios (RRs) for liver cancer stratified by birth place were calculated, and the average annual percent change (AAPC) was used to evaluate trends. RESULTS: A total of 198,557 deaths from liver and intrahepatic bile duct cancer were recorded during 2005-2014, and 16% occurred among foreign-born individuals. Overall, foreign-born individuals had a 24% higher risk of liver cancer mortality than US-born individuals (RR, 1.24; 95% confidence interval [CI], 1.22-1.25). Foreign-born individuals did not have any significant changes in liver cancer mortality rates overall, but among US-born individuals, liver cancer mortality rates significantly increased (AAPC, 2.7; 95% CI, 2.1-3.3). CONCLUSIONS: Efforts that address the major risk factors for liver cancer are needed to help to alleviate the health disparities observed among foreign-born individuals and reverse the increasing trend observed in the US-born population. PMID- 30480829 TI - Double standards in body evaluation? How identifying with a body stimulus influences ratings in women with anorexia nervosa and bulimia nervosa. AB - OBJECTIVE: Women with eating disorders (ED) evaluate their own body more negatively than do women without ED. However, it is unclear whether this negative rating is due to objective bodily features or different standards for one's own body and others' bodies. Therefore, the purpose of this study was to examine whether women with ED apply double standards when rating bodies by disentangling the objective features of one's own body from the feelings of ownership. METHOD: We presented n = 34 women with anorexia nervosa, n = 31 women with bulimia nervosa, and n = 114 healthy controls with pictures of thin, average-weight, overweight, athletic, and hypermuscular bodies. Identity was manipulated by showing each body once with the participant's own face and once with the face of another woman. Participants were instructed to report their emotional state according to valence and arousal and to rate body attractiveness, body fat, and muscle mass. RESULTS: Women with anorexia nervosa and bulimia nervosa displayed greater self-deprecating double standards in body fat rating than did women without ED, as quantified by the difference between the ratings of the same body with one's own versus another woman's face. Double standards reflected in valence, arousal and attractiveness ratings were significantly more pronounced in women with anorexia nervosa than in women without ED. DISCUSSION: The double standards found may be due to an activation of dysfunctional self-related body schemata, which distort body evaluation depending on identity. Double standards related to body fat were characteristic for women with ED, but not for women without ED. PMID- 30480830 TI - Warning labels on fashion images: Short- and longer-term effects on body dissatisfaction, eating disorder symptoms, and eating behavior. AB - OBJECTIVE: Fashion warning labels that caution readers about digitally altered images have been recommended and adopted by several countries to prevent body dissatisfaction and eating disorders. This study investigated the short- and longer-term influence of fashion warning labels on affect, body dissatisfaction, eating disorder symptoms, and snack consumption using a randomized-controlled experiment. METHOD: Female undergraduates (n = 118) were randomized to view and rate responses to fashion images either with or without a warning label. They then consumed snacks and completed questionnaires. Sixty-four participants (54%) completed follow-up online surveys asking them to view and rate new fashion images with or without warning labels once per week for 4 weeks. Primary outcomes were affect, body dissatisfaction, eating disorder symptoms, and kilocalories consumed. RESULTS: Overall, fashion warning labels had no short-term effects on affect, body dissatisfaction, or kilocalories consumed in the lab. However, individuals who reported engaging in restrictive eating consumed fewer kilocalories when exposed to advertisements with warning labels (M = 170.33, SD = 120.78) versus no labels (M = 286.46, SD = 166.30), p = .008. Warning labels also had no protective effects after repeated exposure over 4 weeks on affect or eating disorder symptoms, and significantly increased appearance orientation (p = .001). DISCUSSION: Warning labels on media images are unlikely to be an effective policy tool to prevent negative affect, body dissatisfaction, and eating disorder symptoms, and, in some cases, may exacerbate these concerns. PMID- 30480831 TI - Acoustic Radiation Force Impulse Imaging With Virtual Touch Tissue Quantification Enables Characterization of Mild Hypoxic-Ischemic Brain Damage in Neonatal Rats. AB - OBJECTIVES: The aim of this study was to investigate whether the measurement of brain tissue stiffness using acoustic radiation force impulse (ARFI) elastography with virtual touch tissue quantification can improve the early detection of neonatal hypoxic-ischemic brain damage in rats. METHODS: Seven-day-old Sprague Dawley rats were randomly assigned to 3 groups: the mild asphyxia (n = 30), moderate asphyxia (n = 30), and sham control (n = 10) groups. Rats in the mild and moderate asphyxia groups were exposed to 8% oxygen (hypoxia) for 30 and 60 minutes, respectively, at 1 hour after ligation of the right common carotid artery. An ultrasound diagnostic instrument was used to obtain 2-dimensional ultrasound images, and ARFI with virtual touch tissue quantification was used to measure shear wave velocity preoperatively and at 12, 24, 48, and 72 hours postoperatively. Hematoxylin-eosin staining was used to evaluate brain damage. RESULTS: Two-dimensional ultrasound imaging detected swelling and increased echogenicity at 48 to 72 hours in the mild asphyxia group and at 24 to 72 hours in the moderate asphyxia group. The shear wave velocity substantially increased from 0.65 +/- 0.04 m/s preoperatively to 0.78 +/- 0.07 m/s at 72 hours in the moderate asphyxia group and from 0.64 +/- 0.04 m/s preoperatively to 0.70 +/- 0.03 m/s at 72 hours in the mild asphyxia group. The changes in the shear wave velocity coincided with the histopathologic changes in the brain, which included neuronal demyelination, hyperplasia, and necrosis; edema around vascular structures; and hemorrhage in the ependymal and periventricular areas. CONCLUSION: Shear wave velocity data obtained with the virtual touch tissue quantification technique may be used for early diagnosis of neonatal hypoxic ischemic brain damage. PMID- 30480832 TI - The Identity Objection to the future-like-ours argument. AB - Some critics of Don Marquis's 'future-like-ours' anti-abortion argument launch what has been called the Identity Objection. The upshot of this objection is that under a psychological theory of personal identity, a non-sentient fetus lacks precisely what Marquis believes gives it a right to life - a future like ours. However, Eric Vogelstein, in a recent article, has argued that under this theory of personal identity a non-sentient fetus, in fact, has a future like ours, which he believes dissolves the Identity Objection. But Vogelstein is mistaken. Even if he is correct that there is a sense in which a non-sentient fetus has a future of value under a psychological theory of personal identity, the sense in which it has one is importantly different from the sense in which we have one, meaning that, under such a theory, a non-sentient fetus does not have a future like ours. PMID- 30480833 TI - Use of Shear Wave Elastography in the Sonographic Triage of Thyroid Nodules: Feasibility Study in a Series of Lesions Already Selected for Fine Needle Aspiration. AB - OBJECTIVES: The aim of this study was to evaluate the application of shear wave elastography (SWE) in the routine management of thyroid nodules, as a possible additional tool to the standard sonographic triage. METHODS: A total of 248 consecutive patients scheduled for ultrasound-guided thyroid fine-needle aspiration were included in the study. The presence of a pure colloid lesion was an exclusion criterion. Absolute and relative SWE stiffness measurements on color coded elastograms, expressed in kilopascals and meters per second, were correlated with radiologic and pathologic features. RESULTS: SWE values in thyroid nodules were significantly higher than normal thyroid tissue (P = .0001), proving the different elastic properties of the pathologic tissues. Regarding the radiologic characteristics of the nodules, SWE highest values were associated with the largest lesions (P = .0105) but independent from sonographic and Doppler findings. The SWE elasticity was not influenced by the characteristics of the biopsy smears. The final correlation between the SWE results and the pathologic diagnoses showed a trend in stiffness from tender tumors (follicular adenoma) to papillary thyroid carcinoma (P = .016). CONCLUSIONS: SWE allows the identification of nodules within normal parenchyma; however, the present study does not confirm the potential role in differentiating between benign and malignant thyroid nodules. PMID- 30480834 TI - Social comparisons in eating disorder recovery: Using PhotoVoice to capture the sociocultural influences on women's recovery. AB - OBJECTIVE: This qualitative study draws on a photo-elicitation method ("PhotoVoice") and semistructured interviews to examine the role of social comparison during the eating disorder (ED) recovery process. METHOD: Thirty U.S. women in self-defined recovery, ages 18-35, used photography to capture personally meaningful social and cultural influences on their recovery, including factors supporting, and hindering their recovery process. Participants then shared these photographs with the research team, and described them in detail. RESULTS: Photographs and interviews were examined for social comparisons using thematic analysis, and two broad categories emerged: recovery-promoting and recovery-hindering comparisons. Across the 30 interviews, participants reported 143 recovery hindering comparisons and 100 recovery promoting comparisons. The vast majority of comparisons involved friends and media personalities, and took place in vivo or on social media platforms. The presence of "upward" and "downward" food and body comparisons that both support and hinder recovery suggests that social comparisons during the recovery process are more nuanced than previously known. DISCUSSION: The classically ascribed uses of comparison in social comparison theory do not appear to hold for women in ED recovery. Comparisons should be encouraged in treatment and interventions if and only if the comparisons are meant to support the recovery process. PMID- 30480835 TI - A beta-binomial mixed-effects model approach for analysing longitudinal discrete and bounded outcomes. AB - Patient-reported outcomes (PROs) are currently being increasingly used as primary outcome measures in observational and experimental studies since they inform clinicians and researchers about the health-status of patients and generate data to facilitate improved care. PROs usually appear as discrete and bounded with U, J, or inverse J shapes, and hence, exponential family members offer inadequate distributional fits. The beta-binomial distribution has been proposed in the literature to fit PROs. However, the fact that the beta-binomial distribution does not belong to the exponential family limits its applicability in the regression model context, and classical estimation approaches are not straightforward. Moreover, PROs are usually measured in a longitudinal framework in which individuals are followed up for a certain period. Hence, each individual obtains several scores of the PRO over time, which leads to the repeated measures and defines the correlation structure in the data. In this work, we have developed and proposed an estimation procedure for the analysis of correlated discrete and bounded outcomes, particularly PROs, by a beta-binomial mixed effects model. Additionally, we have implemented the methodology in the PROreg package in R. Because there are similar approaches in the literature to address the same issue, this work also incorporates a comparison study between our proposal and alternative methodologies commonly implemented in R and shows the superior performance of our estimation procedure. This paper was motivated by the analysis of the health-status of patients with chronic obstructive pulmonary disease, where the main objective is the assessment of risk factors that may affect the evolution of the disease. The application of the proposed approach in the study leads to clinically relevant results. PMID- 30480836 TI - The joint contribution of physical activity, insomnia symptoms and smoking to the cost of short-term sickness absence. AB - Physical inactivity has been associated with both insomnia symptoms and smoking. Further, they are all independently associated with increased sickness absence (SA) from work. However, joint contribution of either physical activity (PA) with insomnia symptoms or with smoking to SA and, especially, their direct cost for the employer, are poorly understood. Therefore, we aimed to examine these joint associations with short-term (<15 days) SA cost. The Helsinki Health Study is a cohort of midlife employees of the City of Helsinki, Finland (baseline n=8960, response rate 67%). During 2000-2002 the participants were mailed a survey questionnaire that gathered information on health behaviour and sociodemographic characteristics. SA, salary, and time of employment were followed up through the employer's personnel register between 2002-2016 for those with a written consent to the use of their register data (78% of the participants). Individual salary data were used to calculate the direct cost of short-term SA. Data were analysed with a two-part model. Inactive participants with frequent insomnia symptoms had 2526? (95% CI 1736?-3915?) higher cost of short-term SA than vigorously active participants without insomnia symptoms. Furthermore, inactive smokers had 4166? (95% CI 2737?-5595?) higher cost for the employer over the follow-up than vigorously active non-smokers. In conclusion, this study showed that PA and insomnia symptoms as well as PA and smoking are jointly associated with short term SA cost. The results emphasize encouraging employers to improve work environments so that they promote active lifestyle, good sleep and non-smoking in order to reduce the cost of SA. This article is protected by copyright. All rights reserved. PMID- 30480837 TI - Spx, the central regulator of the heat- and oxidative stress response in B. subtilis, can repress transcription of translation-related genes. AB - Spx is a Bacillus subtilis transcription factor that interacts with the alpha subunits of RNA polymerase. It can activate the thiol stress response regulon and interfere with the activation of many developmental processes. Here, we show that Spx is a central player orchestrating the heat shock response by up-regulating relevant stress response genes as revealed by comparative transcriptomic experiments. Moreover, these experiments revealed the potential of Spx to inhibit transcription of translation-related genes. By in vivo and in vitro experiments, we confirmed that Spx can inhibit transcription from rRNA. This inhibition depended mostly on UP elements and the alpha subunits of RNA polymerase. However, the concurrent up-regulation activity of stress genes by Spx, but not the inhibition of translation related genes, was essential for mediating stress response and antibiotic tolerance under the applied stress conditions. The observed inhibitory activity might be compensated in vivo by additional stress response processes interfering with translation. Nevertheless, the impact of Spx on limiting translation becomes apparent under conditions with high cellular Spx levels. Interestingly, we observed a subpopulation of stationary phase cells that contains raised Spx levels, which may contribute to growth inhibition and a persister-like behaviour of this subpopulation during outgrowth. This article is protected by copyright. All rights reserved. PMID- 30480838 TI - Gene expression profiling of human tissue-resident immune cells: Comparing blood and liver. AB - In this study, we describe a method to reliably characterize intrahepatic leukocyte populations using flow cytometry and next-generation RNA sequencing on fresh human liver biopsies. Over the last decades, immune responses of viral hepatitis patients, and of other liver diseases, have been incompletely characterized. Most studies include peripheral blood samples only, foregoing the possibility to investigate the site of inflammation directly. Here, we show that with an optimized protocol that combines cell sorting and RNA sequencing, we can perform a side by side comparison of both intrahepatic and peripheral immune cells. Using core liver biopsies from chronic hepatitis B virus patients, we show that the expression levels of IFN-stimulated genes and leukocyte-specific genes are markedly different in the liver compartment as compared to the peripheral blood. These observations emphasize the need to sample the liver directly. The variation of gene expression profiles in these chronic hepatitis B patients was considerable, despite the uniform treatment with nucleotide analogs and absence of liver inflammation in these patients. Finally, we show that this method can provide a detailed characterization of previously undetected liver-specific effects of novel candidate therapeutic compounds. PMID- 30480839 TI - Nonlithium Metal-Sulfur Batteries: Steps Toward a Leap. AB - Present mobile devices, transportation tools, and renewable energy technologies are more dependent on newly developed battery chemistries than ever before. Intrinsic properties, such as safety, high energy density, and cheapness, are the main objectives of rechargeable batteries that have driven their overall technological progress over the past several decades. Unfortunately, it is extremely hard to achieve all these merits simultaneously at present. Alternatively, exploration of the most suitable batteries to meet the specific requirements of an individual application tends to be a more reasonable and easier choice now and in the near future. Based on this concept, here, a range of promising alternatives to lithium-sulfur batteries that are constructed with non Li metal anodes (e.g., Na, K, Mg, Ca, and Al) and sulfur cathodes are discussed. The systems governed by these new chemistries offer high versatility in meeting the specific requirements of various applications, which is directly linked with the broad choice in battery chemistries, materials, and systems. Herein, the operating principles, materials, and remaining issues for each targeted battery characteristics are comprehensively reviewed. By doing so, it is hoped that their design strategies are illustrated and light is shed on the future exploration of new metal-sulfur batteries and advanced materials. PMID- 30480840 TI - Correlation of Conventional Ultrasound Characteristics of Breast Tumors With Axillary Lymph Node Metastasis and Ki-67 Expression in Patients With Breast Cancer. AB - OBJECTIVES: To explore the association between the ultrasound (US) characteristics of breast tumors with axillary lymph node metastasis (ALNM) and Ki-67 expression in patients with breast cancer. METHODS: In total, 527 consecutive patients with breast cancer who had undergone US examinations and curative surgery with axillary lymph node evaluations were included. The size, shape, aspect ratio, margin, internal echo, internal calcification, posterior echo attenuation, lymphatic hilar structure, cortical thickness, and blood flow of the axillary lymph nodes or primary breast lesions were observed with conventional US. Pathologic prognostic factors, including the histologic type of the tumor, histologic grade, estrogen and progesterone receptor status, lymph node status, and Ki-67 expression were determined. A logistic regression model was used to evaluate whether the US characteristics of primary breast lesions were associated with ALNM and Ki-67 expression. RESULTS: The maximum tumor diameter (odds ratio [OR], 1.54; 95% confidence interval [CI], 1.05-2.27; P = .028), tumor margin (OR, 2.89; 95% CI, 1.69-4.94; P < .001), internal echo (OR, 2.17; 95% CI, 1.47-3.20; P < .001), and Ki-67 status (OR, 3.57; 95% CI, 2.29 5.58; P < .001) had significant value as independent predictors of ALNM. Only the internal echo (OR, 1.95; 95% CI, 1.28-2.95; P = .002) of breast cancer was an independent predictor of the Ki-67 status. The heterogeneity in the internal echo indicated faster cancer cell proliferation and was associated with a worse prognosis in patients with breast carcinoma. CONCLUSIONS: Certain conventional US characteristics may be useful predictors of ALNM and the Ki-67 status in patients with breast cancer. PMID- 30480841 TI - Sustainability Index (S-Index): A tool for use in the evaluation and planning of institutional animal collections. AB - Maintaining sustainable living collections is at the core of every zoo's and aquarium's mission. In spite of increasing awareness of sustainability challenges, few practical applications to support collection sustainability have been developed. In addition, much of the onus to address issues regarding collection sustainability has fallen to regional zoo associations, rather than on individual collection managers, creating a "tragedy of the commons." Responsibility for sustainability, however, ultimately defaults to each individual institution; as active participants in an association and the population management system, other institutions are the most reliable source of animals. Each collection manager must ensure that their collection contributes to association-wide sustainability. With this in mind, a sustainability index tool, S-Index, has been developed using basic demographic concepts and novel metrics for institutional collection evaluation. Furthermore, combining S-Index data across facilities allows the evaluation of the sustainability of individual taxa or taxonomic groups within the Association. An S-Index analysis of 27 Association of Zoos and Aquariums member avian collections over ten years demonstrates the use of this analytical tool. PMID- 30480842 TI - Obesity and eating disorders: Articles from the International Journal of Eating Disorders 2017-2018. AB - OBJECTIVE: This virtual issue of the International Journal of Eating Disorders (IJED) is presented in conjunction with The Obesity Society (TOS) to coincide with Obesity Week held in Nashville, TN November 11-15, 2018. METHODS: We present selected articles published in IJED in 2017-2018 that are relevant to scholars who focus on obesity, eating disorders (EDs), or both areas of inquiry. DISCUSSION: We hope to promote discussion and collaboration between the obesity and ED fields, and stimulate additional work, including submissions to IJED. PMID- 30480843 TI - Membrane-enriched solute carrier family 2 member 1 (SLC2A1/GLUT1) in psoriatic keratinocytes confers sensitivity to 2-deoxy-D-glucose (2-DG) treatment. AB - Psoriasis is a common chronic disease with accelerated epidermal cell growth. Solute carrier family 2 member 1 (SLC2A1), also named GLUT1, transports glucose and its analogues into cells. With elevated membrane-bound GLUT1, psoriatic keratinocytes uptake more glucose with increased glucose metabolism. Competition between glucose and its analogues can serve as a strategy to inhibit glycolysis as well as proliferation. In this study, we investigated the expression patterns of GLUT1 in keratinocytes in the human psoriasis vulgaris and imiquimod-induced psoriasis model, and determined that the glucose metabolism inhibitor 2 deoxyglucose (2-DG) can relieve the psoriatic lesions. We found membrane-enriched GLUT1 in psoriasis keratinocytes, which suggested some potential for glucose metabolic target therapy based on the glycolytic microenvironment. Furthermore, 2 DG was able to relieve the psoriatic lesions in an in vivo animal model which provides a new possible therapeutic strategy. This article is protected by copyright. All rights reserved. PMID- 30480844 TI - Guselkumab in the treatment of severe Hidradenitis suppurativa. AB - Hidradenitis suppurativa (HS) is a chronic skin disease characterized by auto inflammation resulting in abscesses, nodules, fistula and scaring in the affected areas. It is known as one of the most life restricting diseases in dermatology with highly negative effects regarding the DLQI. Despite the uprising therapeutic approaches available for HS, there is still a need for more effective medications to treat this auto-inflammational disease. This article is protected by copyright. All rights reserved. PMID- 30480845 TI - A review of zoo-based cognitive research using touchscreen interfaces. AB - In the past few decades, there has been an increase in the number of zoo-based touchscreen studies of animal cognition around the world. Such studies have contributed to the field of comparative cognition despite the fact research has only been performed at a relatively small number of institutions and with a narrow range of species. Nonetheless, zoo-based touchscreen studies are increasingly recognized as both having the potential to be enriching for captive animals by providing them with opportunities for choice, as well as potentially being a tool with which to measure changes in welfare. Zoo-based touchscreen research on public display also has the potential to impact zoo visitors; encouraging them not only learn more about the cognitive abilities of animals, but also potentially promoting increased respect for these species. Given the lack of a comprehensive review of this scope of specialized research, and the broad potential impacts on animals and programs, here we discuss the history, implementation, and potential outcomes of touchscreen research in zoo settings. PMID- 30480846 TI - Resistance against Ralstonia solanacearum in tomato depends on methionine cycle and gamma-aminobutyric acid metabolic pathways. AB - Bacterial wilt (BW) caused by Ralstonia solanacearum is a complex and destructive disease affecting over 200 plant species. To investigate the interaction of R. solanacearum and its host tomato (Solanum lycopersicum) plants, a comparative proteomic analysis was conducted in tomato stems inoculated with high and mild aggressiveness of R. solanacearum isolates, RsH and RsM. The results indicated a significant alteration of the methionine cycle (MTC) and downregulation of gamma aminobutyric acid (GABA) biosynthesis. Furthermore, transcriptome profiling of two key tissues (stem and root) at three stages (0, 3 and 5dpi) after inoculation with RsH in resistant and susceptible tomato plants is presented, transcript profiles of MTC and GABA pathways were analyzed. Subsequently, the MTC associated genes, SAMS2, SAHH1, MS1, and GABA biosynthesis related genes, GAD2 and SSADH1, were knocked-down by virus-induced gene silencing(VIGS), followed by analysis of .plants defense responses upon R. solanacearum RsM and RsH infection. These results showed that silencing of SAHH1, MS1, and GAD2 in tomato leads to decreased resistance against R. solanacearum. In summary, the infection assays, proteomic and transcriptomic data described in this study indicate that both MTC and GABA biosynthesis play important roles in pathogenic interaction between R. solanacearum and tomato plants. This article is protected by copyright. All rights reserved. PMID- 30480847 TI - The role of myeloid-derived suppressor cells in chronic infectious diseases and the current methodology available for their study. AB - An effective pathogen has the ability to evade the immune response. The strategies used to achieve this may be based on the direct action of virulence factors or on the induction of host factors. Myeloid-derived suppressor cells (MDSCs) are immune cells with an incredible ability to suppress the inflammatory response, which makes them excellent targets to be exploited by pathogenic bacteria, viruses, or parasites. In this review, we describe the origin and suppressive mechanisms of MDSCs, as well as their role in chronic bacterial, viral, and parasitic infections, where their expansion seems to be essential in the chronicity of the disease. We also analyze the disadvantages of current MDSC depletion strategies and the different in vitro generation methods, which can be useful tools for the deeper study of these cells in the context of microbial infections. PMID- 30480848 TI - Messages from the auricle - limiting progression of heart failure with preserved ejection fraction through transcutaneous nerve stimulation of nerves in the external ear. PMID- 30480849 TI - [All]-S,S-dioxide Oligo-Thienylenevinylenes: Synthesis and Structural/Electronic Shapes From Their Molecular Force Fields. AB - Oligo-S,S-dioxothienylenevinylenes have been prepared by transferring oxygens to the sulfur atoms using the HOF*CH3CN complex. Their photophysical properteis are presented in comparison with their thiophenevinylene congeners together with their vibrational properties and molecular force fields permiting the interpretation of the alteration of aromaticity and inter-ring exocyclic pi conjugation in this series. PMID- 30480850 TI - The Chemistry of Nucleation: In situ Pair Distribution Function analysis of secondary building units during UiO-66 MOF formation. AB - The concept of Secondary Building Units (SBUs) is central to all science on metal organic frameworks (MOFs), and it is widely used to design new MOF materials. However, the presence of SBUs during MOF formation remains controversial, and the formation mechanism of MOFs remains unclear due to limited information about the evolution of prenucleation cluster structures. Here in situ Pair Distribution Function (PDF) analysis was used to probe UiO-66 formation under solvothermal conditions. The expected SBU - a hexanuclear zirconium cluster - is present in the metal salt precursor solution. Addition of organic ligands results in a disordered structure with correlations up to 23 A resembling crystalline UiO-66. Heating leads to fast cluster aggregation, and further growth and ordering results in the crystalline product. Thus, SBUs are present already at room temperature and act as building blocks for MOF formation. The proposed formation steps provide insight for further development of MOF synthesis. PMID- 30480851 TI - Multifractal and Lacunarity Analyses of Microvascular Morphology in Eyes with Diabetic Retinopathy: A Projection Artifact Resolved Optical Coherence Tomography Angiography Study. AB - OBJECTIVE: To evaluate the degree of microvascular impairment in diabetic retinopathy using multifractal and lacunarity analyses and to compare the diagnostic ability between traditional Euclidean measures (fovea avascular zone area and vessel density) and fractal geometric features. METHODS: This retrospective cross-sectional study included a total of 143 eyes of 94 patients with different stages of diabetic retinopathy. The retinal microvasculature was imaged by projection removed optical coherence tomography angiography. We examined the degree of association between fractal metrics of the retinal microvasculature and diabetic retinopathy severity. The area under the receiver operating characteristic curve was used to estimate the diagnostic performance. RESULTS: With increasing diabetic retinopathy severity, the multifractal spectrum shifted towards the left bottom and exhibited less left skewness and asymmetry. The vessel density, multifractal features and lacunarity measured from the deep capillary plexus were strongly associated with diabetic retinopathy severity. The multifractal feature D5 showed the highest diagnostic ability. The combination of multifractal features further improved the discriminating power. CONCLUSIONS: Multifractal and lacunarity analyses can be potentially valuable tools for assessment of microvascular impairments in diabetic retinopathy. Multifractal geometric parameters exhibit a better discriminatory performance than Euclidean measures, particularly for detection of the early stages of diabetic retinopathy. This article is protected by copyright. All rights reserved. PMID- 30480852 TI - Causal parenthood and the ethics of gamete donation. AB - According to the causal theory of parenthood, people incur parental obligations by causing children to exist. Proponents of the causal theory often argue that gamete donors have special obligations to their genetic offspring. In response, many defenders of current gamete donation practices would reject the causal theory. In particular, they may invoke the 'too many parents problem': many people who causally contribute to the existence of children - for instance, fertility doctors - do not thereby incur parental obligations. This article argues that the conclusions commonly drawn by causal theorists, and by their critics, are premature. Causal theorists have a promising response to the too many parents problem. This response, however, defuses the moral concern that many causal theorists have raised about gamete donation. A similar point, it is argued, applies to Rivka Weinberg's 'Hazmat Theory'. PMID- 30480853 TI - Facile Synthesis and Topological Transformation of Multicomponent Miktoarm Star Copolymers. AB - Multicomponent miktoarm stars (MMSs) comprising at least three kinds of chemically different arm segments are extremely important due to their great potential as multiphase materials to elucidate composition/topology-dependent properties and applications. At present, a "core first" route gives ABC stars, "coupling onto" and combinatorial methods afford ABC and ABCD stars, and modular and iterative approaches enable facile synthesis of MMSs with five or more components. Meanwhile, the introduction of stimuli-labile linkages and couplable groups into star polymers further enriches the family of smart materials. Upon external stimuli, linking reaction, or postpolymerization modification, miktoarm stars are potentially converted into other architectural polymers such as linear, tadpole-like, graft, and dendrimer-like polymers via cleavage and rearrangement in the chain structure. This feature article aims to systematically summarize the synthetic methods and versatile topological transitions of ABC, ABCD, and ABCDE stars. The advantages and limitations of each approach are highlighted, and the future considerations on developments and challenges are discussed. PMID- 30480854 TI - Adjunctive virtual reality for procedural pain management of burn patients during dressing change or physical therapy: A systematic review and meta-analysis of randomized controlled trials. AB - Dressing change and physical therapy are extremely painful procedures for burn patients. Adjunctive virtual reality therapy reportedly reduces pain when added to analgesics, but a summary analysis of the data has yet to be performed. We conducted this systematic review and meta-analysis of randomized controlled trials to verify the pain-reducing efficacy of virtual reality among burn patients undergoing dressing change or physical therapy. We searched MEDLINE (via PubMed), EMBASE (via OVID), and the Cochrane Central Register of Controlled Trials (via OVID) for relevant trials based on predetermined eligibility criteria from database establishment to February 2018. Two reviewers screened citations and extracted data independently. The quality of the included studies was evaluated according to the Cochrane Handbook, whereas statistical heterogeneity was assessed using chi-square tests and I2 statistics. Review Manager 5.3 was used for statistical analysis. Thirteen randomized controlled trials with 362 patients who underwent 627 burn dressing change or physical therapy sessions were included. The additional use of virtual reality significantly reduced pain intensity, time spent thinking about pain, and unpleasantness, and was more fun compared with that of using analgesics alone. Virtual reality is an effective pain reduction measurement added to analgesics for burn patients undergoing dressing change or physical therapy. However, multicenter, parallel group design randomized controlled trials are still required. PMID- 30480855 TI - The Morbidity of Subthreshold Pediatric Bipolar Disorder: A Systematic Literature Review and Meta-Analysis. AB - OBJECTIVE: Evaluate the morbidity of subthreshold pediatric bipolar (BP) disorder. METHODS: We performed a systematic literature search in November 2017 and included studies examining the morbidity of pediatric subthreshold BP. Extracted outcomes included functional impairment, severity of mood symptoms, psychiatric comorbidities, suicidal ideation and behaviors, and mental health treatment. We used meta-analysis to compute the pooled standardized mean difference (SMD) for continuous measures and the pooled risk ratio (RR) for binary measures between two paired groups: subthreshold pediatric BP vs. controls, and subthreshold pediatric BP vs. pediatric BP-I. RESULTS: Eleven papers, consisting of seven datasets, were included. We compared subthreshold pediatric BP (N=244) to non-Bipolar controls (N=1125) and subthreshold pediatric BP (N=643) to pediatric BP-I (N=942). Subthreshold pediatric BP was associated with greater functional impairment (SMD=0.61, CI 0.25-0.97), greater severity of mood symptomatology (mania: SMD=1.88, CI 1.38-2.38; depression: SMD=0.66, CI 0.52 0.80), higher rates of disruptive behavior (RR=1.75, CI 1.17-2.62), mood (RR=1.78, CI 1.29-2.79) and substance use (RR=2.27, CI 1.23-4.21) disorders, and higher rates of suicidal ideation and attempts (RR=7.66, CI 1.71-34.33) compared to controls. Pediatric BP-I was associated with greater functional impairment, greater severity of manic symptoms, higher rates of suicidal ideation and attempts, and higher rates of mental health treatment compared to subthreshold pediatric BP. There were no differences between full and subthreshold cases in the severity of depressive symptoms or rates of comorbid disorders. CONCLUSIONS: Subthreshold pediatric BP disorder is an identifiable morbid condition associated with significant functional impairment including psychiatric comorbidities and high rates of suicidality. This article is protected by copyright. All rights reserved. PMID- 30480856 TI - Autonomic Behavior in Lipase-active Oil Droplets. AB - Developing self-fueled micro-reactor droplets with programmable autonomic behaviors provides a step towards smart liquid dispersions comprising motile microscale objects. Here we prepare aqueous suspensions of lipase-coated oil globules comprising a mixture of a triglyceride substrate (tributyrin, 1,2,3 tributylglycerol) and a low-density oil (polydimethylsiloxane, PDMS), and describe a range of active behaviors based on controlled enzyme-mediated consumption of individual droplets under non-equilibrium conditions. Encapsulation of the lipase-coated lipid/PDMS droplets into a model protocell as energy-rich sub-compartments is demonstrated as an internalized mechanism for activating protocell buoyancy. Taken together, our results highlight opportunities for the regulation of autonomic behavior in enzyme-powered oil droplets, and provide a new platform for increasing the functionality and energization of synthetic protocells. PMID- 30480857 TI - Supramolecular Capsules: Strong versus Weak Chalcogen Bonding. AB - Resorcin[4]arene cavitands containing either 2,1,3-benzotelluradiazole or 2,1,3 benzothiadiazole motifs were dimerized to supramolecular capsules by chalcogen bonding. Their respective behavior varied depending on the interaction strength of the chalcogen bonds with Te forming strong interactions and S weak interactions. The tremendous strength of multiple 2Te-2N square interactions led to formation of a chalcogen-bonded dimeric capsule in all solvents, as shown by X ray crystal structures with 16 short Te???N distances (<=2.9 A) and confirmed by native electrospray ionization mass spectrometry (ESI-MS). With the S cavitand, solvent-dependent crystallization resulted in different arrangements: either a shifted 2S-2N square-bonded capsule or an interlocked 1D polymer with an infinite pi-pi stacking array. The association constant to form the dimeric capsule in [D8 ]THF at 283 K, solely based on weak 2S-2N square interactions, was determined as Ka =786 m-1 . PMID- 30480858 TI - Buprenorphine: Therapeutic potential beyond substance abuse. AB - Discussion of buprenorphine and its potential utility for the treatment of inflammatory disorders. PMID- 30480859 TI - Taming Radical Intermediates for the Construction of Enantioenriched Trifluoromethylated Quaternary Carbon Centers. AB - We demonstrate the construction of trifluoromethylated quaternary carbon centers via an asymmetric radical transformation. Enantioenriched trifluoromethylated oxindoles were accessed through the use of a hypervalent iodine-based trifluoromethyl transfer reagent in combination with a magnesium Lewis acid catalyst and PyBOX-type ligands to achieve up to 99% ee and excellent chemical yields. Mechanistic studies were performed by experimental and computational methods and suggest a single electron transfer induced SN2-type mechanism. This is thereby the first report on the construction of enantioenriched trifluoromethylated carbon centers using hypervalent iodine-based reagents proposing such a reaction pathway. PMID- 30480861 TI - New Roles for Photoexcited Eosin Y in Photochemical Reactions. AB - Neutral eosin Y-derived photoexcited states have been found to serve as photoacids and direct hydrogen atom transfer (HAT) catalysts in the activation of glycals and C-H bonds, respectively. These studies pave the way for further use of eosin Y in photochemical synthesis. PMID- 30480860 TI - Predictors of response to synchronized transcranial magnetic stimulation for major depressive disorder. AB - BACKGROUND: Synchronized transcranial magnetic stimulation (sTMS) is a new modality to reduce symptoms of major depressive disorder (MDD). sTMS uses rotating neodymium magnets to deliver low-field stimulation matched to the individual alpha frequency (IAF). A previous multisite study showed that sTMS significantly reduced MDD symptoms in the per-protocol sample. To this end, we evaluated clinical features associated with optimal sTMS outcomes. METHODS: Using the per-protocol sample (n = 120) from the parent sham-controlled trial, we performed univariate and stepwise linear regression to identify predictors of response after 6 weeks of sTMS. A subsample (n = 83) that entered a 4-week open/active continuation phase also was examined. Candidate variables included age, sex, comorbid anxiety, number of failed antidepressants in the current depressive episode, MDD severity (17-item Hamilton Depression Rating Scale; HAMD17), anxiety symptom severity (HAMD17 anxiety/somatization factor), and IAF. RESULTS: We found that greater baseline depressive (p < 0.001) and anxiety (p < 0.001) symptom severity were associated with better response to active sTMS, whereas fewer failed antidepressant trials predicted superior response to sham (p < 0.001). MDD severity and antidepressant resistance predicted outcomes in open/active phase sTMS; lower IAF predicted poorer response in participants who received 10 weeks of active sTMS (p = 0.001). CONCLUSIONS: Participants with greater severity of depression and higher anxiety had superior responses to active sTMS, whereas treatment naive individuals exhibited a greater response to sham. These results lend support to the primary efficacy findings, and support further investigation of sTMS as a therapeutic noninvasive brain stimulation modality. PMID- 30480862 TI - Quantitative Evaluation of Infrared Absorbance Spectra - Lorentz Profile versus Lorentz Oscillator. AB - We present the theoretical basis for a profound upgrade of the method of absorbance band fitting ("band deconvolution"), which requires only minute changes in the code of corresponding spectrometer software. This upgrade is based on a (re-)connection of the damped harmonic oscillator model ("Lorentz oscillator") and the Lorentz profile used for band fitting. Based on this reconnection, we provide a proper extension to multiple oscillators. As a result, band fitting allows directly obtaining all oscillator parameters with very good accuracy, at least for the not too strong oscillators present in organic and biological matter. Accordingly, this could be the initial spark to open the way to a long-awaited paradigm shift in infrared spectroscopy: Away from a mere oscillator position-based, towards an also intensity-based quantitative interpretation of spectra. As an extra, absorbance band fitting ("Poor Man's Dispersion Analysis"), allows to obtain the index of refraction function in one go. PMID- 30480864 TI - Spotlights are papers selected by editors published in peer-reviewed journals that may be more regionally specific or appearing in languages other than English. PMID- 30480863 TI - Catalytic Atropenantioselective Heteroannulation between Isocyanoacetates and Alkynyl Ketones: Synthesis of Enantioenriched Axially Chiral 3-Arylpyrroles. AB - We report herein the first examples of catalytic enantioselective synthesis of axially chiral 3-arylpyrroles. Reaction of alpha-isocyanoacetates with beta-aryl alpha,beta-alkynic ketones in the presence of silver oxide and a phosphine ligand derived from Cinchona alkaloid occurred chemoselectively to afford enantioenriched 3-arylpyrroles in high yields with excellent enantiomeric excesses. The pyrrole ring was de novo constructed in this process. PMID- 30480865 TI - The Minamata Convention on Mercury and the role for the environmental sciences community. PMID- 30480866 TI - Electrochemical Pseudocapacitors Based on Ternary Nanocomposite of Conductive Polymer/Graphene/Metal Oxide: An Introduction and Review to it in Recent Studies. AB - This review gives an overview of the synthesis, surface and electrochemical investigations over ternary nanocomposite of conductive polymers in the development of new supercapacitors. They utilize both Faradaic and non-Faradaic procedures to store charge, leading to higher specific capacitance and energy density, higher cell voltage, longer life cycle and moderated power density. Owing to a unique combination of features such as superb electrical conductivity, corrosion resistance in aqueous electrolytes, highly modifiable nanostructures, long cycle life and the large theoretical specific-surface area, the use of ternary nanocomposites as a supercapacitor electrode material has become the focus of a significant amount of current scientific researches in the field of energy storage devices. In these nanocomposites, graphene not only can be utilized to provide a substrate for growing nanostructured polymers in a polymer carbon nanocomposite structure in order to overcome the insulating nature of conductive polymers at dedoped states, but also is capable of providing a platform for the decoration of metal oxide nanoparticles to avoid their agglomeration. In this regard, synthesis, characterization and performance of different ternary nanocomposites of conductive polymer/graphene/metal oxide are discussed in detail. These remarkable results demonstrate the exciting commercial potential for high performance, environmentally friendly and low-cost electrical energy storage devices based on ternary nanocomposite of conductive polymer/graphene/metal oxide. PMID- 30480867 TI - Sexual dimorphism modifies habitat-associated divergence: Evidence from beach and creek breeding sockeye salmon. AB - Studies of parallel or convergent evolution (the repeated, independent evolution of similar traits in similar habitats) rarely explicitly quantify the extent of parallelism (i.e., variation in the direction and/or magnitude of divergence) between the sexes; instead they often investigate both sexes together or exclude one sex. However, differences in male and female patterns of divergence could contribute to overall variation in the extent of parallelism among ecotype pairs, especially in sexually dimorphic traits. Failing to properly attribute such variation could lead to underestimates of the importance of environmental variation in shaping phenotypes. We investigate the extent of parallelism in the body shape of male and female beach and creek spawning sockeye salmon (Oncorhynchus nerka) from two lake systems in western Alaska that were colonized independently after the last ice age. Although both sexes showed some degree of parallelism, patterns of beach-creek body shape divergence vary between the sexes and between lake systems. Phenotypic change vector analyses revealed highly parallel aspects of divergence between males from different lake systems (males from beaches had deeper bodies than males from creeks) but weaker parallelism in females, and high parallelism between the sexes in one lake system but not the other. Body shape also had population-specific components, which were mostly, but not entirely, explained by environmental variation in the form of creek depth. Our results highlight the importance of explicitly considering the extent of parallelism between the sexes, and environmental variation among sites within habitat types. This article is protected by copyright. All rights reserved. PMID- 30480868 TI - Increase of scabies in Germany and development of resistant mites? Evidence and consequences. AB - Scabies has been diagnosed surprisingly frequently in Germany in recent years, and the use of acaricides has risen markedly. Present figures indicate an increase in the prevalence/incidence of scabies, but do not prove or quantify it for the following reasons: (a) scabies is not a notifiable disease in Germany; (b) the diagnosis is not always confirmed lege artis by means of light microscopy or dermatoscopy (which may lead to a comparatively high proportion of false positive diagnoses due to the low overall prevalence of scabies); (c) repeated treatments of the same patient and treatment of contact persons are included in the total number of prescriptions. Therefore, there are no valid data on disease occurrence, either in the current situation or from previous periods. Observations of ineffective treatment with permethrin have led to speculations that Sarcoptes mites are developing resistance to this drug. However, there is little evidence for this assumption. We discuss risk groups (children, elderly people in need of care, health personnel treating migrants in nursing institutions, refugees, sexually active young adults) and evaluate their possible contribution, albeit in the absence of evidence. None of the groups would be solely responsible for an increased frequency. We have compiled recommendations on how the management of scabies could be improved, and present a way of differentiating permethrin resistance from application errors and/or lack of compliance. The goal is to solve the epidemiological and parasitological questions mentioned above. PMID- 30480869 TI - Transplanting livers from HCV-infected donors into HCV-negative recipients: Promise but mind the pitfalls. AB - A major consequence of the opioid epidemic has been a marked increase in the number of hepatitis C virus (HCV)-infected deceased donors. Although many HCV positive patients waitlisted for a liver transplant (LT) remain HCV-viremic prior to transplant, this number is decreasing. Utilization of livers from HCV-infected donors mirrors that of HCV-negative donors, and are largely transplanted into HCV viremic recipients. This article is protected by copyright. All rights reserved. PMID- 30480870 TI - Water in rechargeable multivalent-ion batteries: an electrochemical Pandora's box. AB - Multivalent-ion batteries built on water-based electrolytes represent energy storage at suitable price-points, competitive performance and enhanced safety. However, to comply with modern energy-density requirements, the battery must be reversible within an operating voltage window greater than 1.23V or the electrochemical stability limits of free water. Taking advantage of its powerful solvation and catalytic activities, adding water in electrolyte preparations can unlock a wider gamut of liquid mixtures as compared to strictly non-aqueous systems. However, a point-by-point sweep of all potential formulations is arduous and ineffective without some form of systematic rationalization. The present review consolidates recent progress, pitfalls, limits and insights critical to expediting aqueous electrolyte designs which boost multivalent-ion battery outputs. PMID- 30480871 TI - Vaginal progesterone, oral progesterone, 17-OHPC, cerclage and pessary for preventing preterm birth in at risk singleton pregnancies: an updated systematic review and network meta-analysis. AB - BACKGROUND: Recent progesterone trials call for an update of previous syntheses of interventions to prevent preterm birth. OBJECTIVES: To compare the relative effects of different types and routes of administration of progesterone, cerclage and pessary at preventing preterm birth in at-risk women overall and in specific populations. SEARCH STRATEGY: We searched Medline, EMBASE, CINAHL, Cochrane CENTRAL, and Web of Science up to January 1st , 2018. SELECTION CRITERIA: We included randomised trials of progesterone, cerclage or pessary for preventing preterm birth in at-risk singleton pregnancies. DATA COLLECTION AND ANALYSIS: We used a piloted data extraction form and performed Bayesian random-effects network meta-analyses with 95% Credibility Intervals (CrI), as well as pairwise meta analyses, rating the quality of the evidence using GRADE. MAIN RESULTS: We included 40 trials (11,311 women). In at-risk women overall, vaginal progesterone reduced preterm birth <34 (OR 0.43, 95% CrI 0.20-0.81) and <37 weeks (OR 0.51, 95% CrI 0.34-0.74), and neonatal death (OR 0.41, 95% CrI 0.20-0.83). In women with a previous preterm birth, vaginal progesterone reduced preterm birth <34 (OR 0.29, 95% CI 0.12-0.68) and <37 weeks (OR 0.43, 95% CrI 0.23-0.74), while 17alpha hydroxyprogesterone caproate reduced preterm birth <37 weeks (OR 0.53, 95% CrI 0.27-0.95) and neonatal death (OR 0.39, 95% CI 0.16-0.95). In women with a short cervix (<=25 mm), vaginal progesterone reduced preterm birth <34 weeks (OR 0.45, 95% CI 0.24-0.84). CONCLUSIONS: Vaginal progesterone was the only intervention with consistent effectiveness for preventing preterm birth in singleton at-risk pregnancies overall and in those with a previous preterm birth. This article is protected by copyright. All rights reserved. PMID- 30480872 TI - Calcific Metamorphosis Of The Pulp Following Extrusive Luxation. AB - BACKGROUND/AIM: The literature on the pathogenesis of extrusive dental luxation has been focused on periodontal tissue responses, with little attention given to the pulp. The aim of this study was to evaluate the response of dental pulp of teeth following extrusive luxation in a rat model. MATERIAL AND METHODS: The maxillary right central incisors of 30 rats were extensively luxated and repositioned after 5 minutes. The animals were euthanized after 7, 15, and 30 days to provide three groups: I, II and III, respectively (n=10). Histological sections were stained with H and E for histomorphometric analysis of the odontoblast layer, reparative dentin deposition, Hertwig's epithelial root sheath, pulp necrosis, and periapical inflammatory infiltrate. RESULTS: In most cases, new vascular formation occured in association with reparative dentin deposition on the root walls and within the pulp. In some cases, dentin deposition occupied the entire pulp space over time, with no other types of non odontogenic hard tissues being observed. Pulp necrosis with the presence of periapical inflammatory infiltrate was also observed in a few cases. No statistical differences were observed among the studied groups. CONCLUSIONS: Following extrusive luxation, calcific metamorphosis of the pulp is very likely to occur. This article is protected by copyright. All rights reserved. PMID- 30480873 TI - Interactive effects of age and hydration state on human thermoregulatory function during exercise in hot-dry conditions. AB - AIM: Aging and hypohydration independently attenuate heat dissipation during exercise; however, the interactive effects of these factors remain unclear. We assessed the hypothesis that aging suppresses hypohydration-induced reductions in whole-body heat loss during exercise in the heat. METHODS: On two occasions, eight young (mean [SD]: 24 [4] years) and eight middle-aged (59 [5] years) men performed 30-min bouts of light (heat production of 175 W.m-2 ) and moderate (275 W.m-2 ) cycling (separated by 15-min rest) in the heat (40 degrees C, 15% relative humidity) when euhydrated and hypohydrated (~4% reduction in body mass). Heat production and whole-body net heat exchange (evaporative heat loss + dry heat gain) were measured via indirect and direct calorimetry (respectively) and heat storage was calculated via their temporal summation. RESULTS: Net heat exchange was reduced, while heat storage was elevated, in the middle-aged men during moderate exercise when euhydrated (both P<=0.01). In the young, evaporative heat loss was attenuated in the hypohydrated vs euhydrated condition during light (199+/-6 vs 211+/-10 W.m-2 ; P<=0.01) and moderate (287+/-15 vs 307+/-13 W.m-2 ; P<=0.01) exercise, but was similar in the middle-aged men, averaging 223+/-6 and 299+/-15 W.m-2 , respectively, across conditions (both P>=0.32). Heat storage was thereby exacerbated by hypohydration in the young (both P<0.01) but not the middle-aged (both P>=0.32) during both exercise bouts and, as a result, was similar between groups when hypohydrated (both P>=0.50). CONCLUSION: Hypohydration attenuates heat loss via sweating in young but not middle-aged men, indicating that aging impairs one's ability to mitigate further sweat-induced fluid loss during hypohydration. This article is protected by copyright. All rights reserved. PMID- 30480874 TI - Patient reported outcome measures in forty-three patients undergoing endoscopic middle ear surgery. AB - 1.PROMs are a useful technique to assess patient experience of middle ear surgery 2.Endoscopic ear surgery patients report better scar discomfort score 3.Endoscopic and open ear surgery patients report equivalent pain scores 4.Endoscopic and open ear surgery patients report equivalent overall patient experience This article is protected by copyright. All rights reserved. PMID- 30480875 TI - Reinforce the interface of Ni-rich LiNi0.8Co0.1Mn0.1O2 cathode material for lithium-ion batteries under high operating voltage through Ce. AB - Nickel-rich cathode material is one of the most promising cathode materials for high-energy lithium-ion batteries. However, the structure stability, thermodynamic stability, cycle and rate performances of Ni-rich materials still need to be further improved. In this research, rare earth element Ce is employed to reinforce the interface of Ni-rich cathode material both internally and externally. It has been determined that high valence state Ce4+ can easily cause the oxidization of Ni2+ to Ni3+ when being doped into the material due to its strong oxidation performance, thus reducing Li+/Ni2+ mixing degree. Besides, the inert Ce3+-ions in transition metal slabs with the strong Ce-O bond can maintain the layered structure at high delithiation state. Further, when the calcination temperature during synthesis is above 500C, a CeO2 coating layer will form, which can protect the electrode from the erosion of electrolyte and alleviate the increasing resistance during cycling. The modified Ni-rich materials fabricated with an erosion-resisting CeO2 layer outside and stronger Ce-O bond inside with reduced Li+/Ni2+ mixing degree exhibit excellent electrochemical properties, especially under high operating voltage, i.e., the 50th capacity retention at 0.2 C within 2.75-4.5V has been improved from 89.8% to 99.2% after the modification. PMID- 30480876 TI - Implementation of a depression screening protocol among respiratory insufficiency patients. AB - INTRODUCTION: Unnoticed and untreated depression is prevalent among patients with chronic respiratory insufficiency. Comorbid depression causes suffering and worsens patients' outcomes. OBJECTIVES: The objective of this evaluation was to assess preliminary outcomes of a depression screening protocol among chronic respiratory insufficiency patients at a tertiary care pulmonary outpatient clinic. METHODS: In the depression screening protocol, the patients filled the Depression Scale (DEPS) questionnaire. Patients whose scores suggested depression were offered the opportunity of a further evaluation of mood at a psychiatric outpatient clinic. The outcomes of the protocol were evaluated retrospectively from the patient records. RESULTS: During the period of evaluation, 238 patients visited the outpatient clinic. DEPS was administered to 176 patients (74%), of whom 60 (34%) scored >=9 (out of 30), thus exceeding the cut-off for referral. However, only 13 patients were referred, as the remainder declined the referral. Finally, seven patients were evaluated at the psychiatric clinic, and they all were deemed depressive. Symptoms of depression were most prevalent among patients with a long smoking history, refractory dyspnoea, and a history of depression. CONCLUSION: Depression screening was positive in a third of the patients. The depression screening protocol improved the detection of depression symptoms, but the effects on the patients' treatment and clinical course were small. Rather than referring patients to a psychiatric unit, the evaluation and management of depression should be undertaken at the pulmonary unit. This article is protected by copyright. All rights reserved. PMID- 30480877 TI - Hypothalamic-pituitary-adrenal axis differentially responses to morning and evening psychological stress in healthy subjects. AB - AIM: The hypothalamic-pituitary-adrenal (HPA) axis responds to changing environmental demands including psychological stressors. The aim of the present study was to assess whether the time of day effects on the acute response of HPA axis activity to acute psychological stress. METHOD: We studied 27 healthy young subjects. The subjects were participated two experiments as follows. In the first experiment, subjects were instructed to keep their regular sleep schedule for 2 weeks which were measured by using a wrist-worn activity monitor. Afterward, to evaluate a diurnal rhythm of salivary cortisol, eight saliva samples were collected during waking period every 2 hours from when the subjects woke up. In the second experiment, the subjects were randomly assigned to two groups. The Trier Social Stress Test (TSST) was performed either in the morning (n = 14) or in the evening (n = 13). We measured diurnal rhythm of salivary cortisol and stress response of salivary cortisol and heart rate by the TSST. Morning and evening tests were started at 2 hours and 10 hours after woke up, respectively. RESULTS: All subjects showed a normal diurnal rhythm of salivary cortisol concentration, with a peak in the morning immediately after awaking and a minimum in the evening. The salivary cortisol response after the TSST was significantly increased from the prestress level in the morning but not in the evening. CONCLUSION: The HPA response to acute psychological stress was more pronounced in the morning than in the evening, correlating with the circadian regulation of cortisol synthesis. PMID- 30480878 TI - Platelet miR-28 expression level and thrombocytosis in MPN patients. PMID- 30480879 TI - 3D Microfibrous Scaffolds Selectively Promotes Proliferation and Glial Differentiation of Adult Neural Stem Cells: A Platform to Tune Cellular Behavior in Neural Tissue Engineering. AB - Biomaterials are essential for the development of innovative biomedical and therapeutic applications. Biomaterials-based scaffolds can influence directed cell differentiation to improve cell-based strategies. Using a novel microfluidics approach, poly (epsilon-caprolactone) (PCL), is used to fabricate microfibers with varying diameters (3-40 um) and topographies (straight and wavy). Multipotent adult rat hippocampal stem/progenitor cells (AHPCs) are cultured on 3D aligned PCL microfibrous scaffolds to investigate their ability to differentiate into neurons, astrocytes, and oligodendrocytes. The results indicate that the PCL microfibers significantly enhance proliferation of the AHPCs compared to control, 2D planar substrates. While the AHPCs maintained their multipotent differentiation capacity when cultured on the PCL scaffolds, there is a significant and dramatic increase in immunolabeling for astrocyte and oligodendrocyte differentiation when compared with growth on planar surfaces. Our results show a 3.5-fold increase in proliferation and 23.4-fold increase in astrocyte differentiation for cells on microfibers. Transplantation of neural stem/progenitor cells within a PCL microfiber scaffold may provide important biological and topographic cues that facilitate the survival, selective differentiation, and integration of transplanted cells to improve therapeutic strategies. PMID- 30480880 TI - Should ACA risk adjustment be more like Medicare Advantage? AB - Insurers may think Medicare has a better risk-adjustment structure than the exchanges. Good luck convincing Congress. PMID- 30480882 TI - Zika outbreak puts focus back on fight over abortion access. AB - Zika's impact on infants may shift the terms of debate about abortion access. PMID- 30480881 TI - Why a Chinese billionaire is now the biggest investor in CHS. AB - During the time Tianqiao Chen and Wellington were buying big into CHS this year, the company's stock was trading for less than $20 a share. It closed Friday at $10.21 after trading a year ago for $60 a share. PMID- 30480883 TI - The 100 Most Influential People in Healthcare. PMID- 30480884 TI - Obama, Tyson lead Modern Healthcare's 100 Most Influential People in Healthcare. PMID- 30480885 TI - A helping hand for insurers. AB - Major consulting firms and a growing list of niche advisers are competing aggressively to help major insurers use big data to identify high-risk patients and manage their costs. PMID- 30480886 TI - FLOTUS-a 'most influential' we forgot. AB - This column is a mea culpa. In this week's issue of Modern Healthcare, we highlight the leaders whom our readers and the editorial staff consider the most influential people in healthcare. PMID- 30480887 TI - Community health centers using innovation to address the opioid addiction epidemic. AB - Long before the nationwide epidemic of opioid addiction made headlines, community health centers across the country were witnessing it and confronting it on their doorsteps. PMID- 30480888 TI - Startup betting on 'liquid biopsy' to match cancer patients with trials. PMID- 30480890 TI - Largest healthcare management consulting firms: Ranked by 2015 total healthcare revenue ($ in millions). PMID- 30480889 TI - 'We asked what services ... could be better performed at centers of excellence throughout the system'. AB - After becoming CEO of the near bankrupt Mount Sinai Medical Center in New York City in 2003, Dr. Kenneth Davis led a notable financial turnaround with the help of a board filled with some of New York City's wealthiest businessmen. Now, as head of a financially robust system that includes seven hospitals, 7,100 employed physicians and a sprawling network of practices and ambulatory centers that stretches from Westchester County to Florida, he is attempting to lead Mount Sinai into the new era of population health management and affordable care. Modern Healthcare Editor Merrill Goozner asked him about key elements in that transition. This is an edited transcript. PMID- 30480892 TI - Changes loom as most-popular Medigap plans face extinction. PMID- 30480891 TI - Will Trump embrace controversial House GOP health proposals?. AB - The plan, which lacks details and numbers, would make big changes in Medicare and Medicaid. PMID- 30480894 TI - Tax credit boosts healthcare services in remote areas of Hawaii. AB - The Lana'i Community Health Center, which treats about half of the island's 3,200 residents, will accommodate an additional 600 to 800 patients every year. PMID- 30480893 TI - Health systems with insurance operations have tough 2015. AB - The Affordable Care Act encourages health systems to take risk through insurance operations. But recent financial results show that the payoff won't be immediate. PMID- 30480895 TI - The Other Victims of Gun Violence. Part I: The Nurse. AB - Earlier this month, patients torn apart by bullets sprayed in an Orlando nightclub arrived by the dozens at the area's sole Level 1 trauma center. Clinicians who routinely handle the worst injuries in healthcare were in tears as they described the experience. In the months before the horrific Orlando shooting, Modern Healthcare was exploring the toll on those whose job it is to repair the carnage from guns in a workplace that rarely slows down to take stock of the emotional toll on employees. Here are their stories. PMID- 30480896 TI - Beyond the EHR money pit: After investing big in health records, systems still face growing IT needs for upgrades, analytics and patient engagement. AB - Demands for constant upgrades to already-installed electronic health record systems are slowing investment in other important digital technologies like telehealth, remote patient monitoring and online billing. PMID- 30480897 TI - EHR safety goes to court. AB - A recently filed lawsuit alleging a faulty electronic health record system caused patient harm may be among the first in a wave of such cases, even though most experts say the latest EHR systems are better designed than older models. PMID- 30480898 TI - CMS proposal on Part B drugs deserves support. AB - Medicare's first step in reining in the skyrocketing cost of specialty drugs deserves support--something it has not received from hospitals, doctors, politicians or, of course, the pharmaceutical industry, which benefits the most from the status quo. PMID- 30480899 TI - MACRA likely to accelerate consolidation; will the regulatory framework support it? AB - It took 17 years and more than a dozen acts of Congress before the Medicare sustainable growth-rate formula was replaced by the Medicare Access and CHIP Reauthorization Act in April 2015. PMID- 30480901 TI - Largest healthcare law firms: Ranked by number of healthcare lawyers employed in 2015. PMID- 30480900 TI - 'This is not about gun control...this is about public health'. AB - Dr. Andrew Gurman, a hand surgeon from Hollidaysburg, Pa., became the 171st president of the American Medical Association earlier this month. He sat down with Modern Healthcare Managing Editor Gregg Blesch to discuss the major policy decisions made at the AMA's recently concluded annual meeting. The following is an edited transcript. PMID- 30480902 TI - A study of factors contributing to the aggravation of gambling disorder. AB - While many Japanese nationals are considered to have problems with pachinko and pachisuro (Japanese slot machines), the factors contributing to the process by which gambling disorder-is aggravated remain unclear. Therefore, the aim of this study was to establish baseline data for measures to prevent the further escalation of this gambling disorder; To elucidate the contributing factors, a self-administered questionnaire was distributed to pathological gamblers. The survey items were composed of the following basic attributes; scores on the South Oaks Gambling Screen (SOGS); gambling motivation; matters arising, after gambling behavior; remedies for excessive gambling; the Kessler 6 (K6); the CAGE (Cut down, Annoyed, Guilty, Eye opener) questionnaire; and the 8-item Family Adaptability and Cohesion Evaluation Scale at Kwansei Gakuin IV (FACESKGIV-8). The results of hierarchical multiple regression analysis using SOGS scores as the dependent variable indicated that the variables determined to contribute to the aggravation of gambling addiction were age, sex, past employment experience in the service sector, obtaining money as a motivation for gambling, and seeing limits as a remedy for excessive gambling. Because gamblers tend to fixate on money and experience increasing difficulty devoting attention to other matters as gambling problems grow more serious, the results of this study suggest the need to provide environments that will enable affected individuals to reflect on their own style of gambling at the stage at which their gambling behavior begins to exceed the scope of their own revenue. PMID- 30480903 TI - Impact of Flushing Response on the Relationship between Alcohol Consumption and Gamma-glutamyl Transpeptidase: the KOBE study. AB - Individuals with an inactive acetaldehyde dehydrogenase 2 have an. elevated level of serum acetaldehyde after drinking alcohol, and this may cause an alcohol flushing response with symptoms such as facial flushing, tachycardia, headache, and nausea. Recent studies have suggested that the flushing response influences the association between alcohol consumption and various health-related outcomes. In the present study, we investigated the impact of the flushing response on the relationship between alcohol consumption and serum y -GTP levels in Japanese drinkers. We conducted a cross-sectional study of 521 Japanese drinkers (260 men and 261 'vomen) to examine the impact of the alcohol flushing response on the relationship between alcohol consumption and serum y -GTP levels. The subjects were divided into three groups according to the amount .of daily alcohol consumption. (low, <20 g; moderate, 20-39 g;. and high, >40 g). Multiple adjustments were performed with linear regression models to examine the association between daily alcohol consumption and serum y-GTP levels, adjusting for potential con- founders including the flushing response. We found that the proportion of flushers was significantly lower in the high alcohol consumption group than in the low consumption group. The results of a multivariable analysis showed that,serum y -GTP levels were significantly higher in the moderate and high consumption groups than in the low consumption group after. adjusting for all potential confounders other than the flushing response. In addition, the association between serum y -GTP levels and alcohol consumption was unchanged after adjusting for the presence of the flushing response. In conclusion, serum y -GTP levels increased with increasing alcohol-consumption regardless of the flushing response. Screening for heavy drinkers using serum y-GTP levels was very important to prevent alcohol-related diseases or health problems in health examination. PMID- 30480904 TI - Evaluation of the relationship between internet addiction and interpersonal relationships in university studentsin Japan. AB - With the popularization of the internet, internet addiction among the youth has received a lot of attention in recent years. While.the internet is an effective tool for: communication, the youth, who find real-life communication difficult, reportedly overuse,this aspect of the internet However, this is more of an impression based on clinical cases, with few factual findings. Therefore, the aim of this research was to study the reality of internet addiction -among university students and to examine the multilateral relationship between internet addiction and interpersonal relationships. We conducted a questibnnaire stirvey among 221 uriiversity students, analyzing the level of internet addiction, relevant interpersonal relationships, personal "charcteristics, and other factors associated with internet use. We found that the number of students who were dependent on the internet was 10 (4.7%) and the number of students with a tendency toward dependency was 98 (45.6%). In interpersonal relationships, internet addiction was significantly correlated with parental overprotection, a sense of contentment from the present parent-child rela- tionship, relationships with friends, number of friends, and availability of free time. In personal characteristics, internet addiction was significantly correlated with social skills and feelings of self-esteem. In other factors, internet addiction was significantly correlated with typing on a message board, video browsing, online gaming, use of a personal computer, desire to escape, distraction, pleasure, and connecting with others. Furthermore, we conducted a multiple regression analysis to consider the effects of these three aspects associated with internet addiction. The results suggest that internet addictionl is promoted by parental overprotection, low self-esteem, having few friends, and passive internet service usage. Thus, education is required to promote careful use of the internet to prevent internet addiction from escalating. Further, it is important to understand and support interpersonal relationships to prevent internet addiction from making life worse. PMID- 30480905 TI - Development of group psychotherapy focused on emotion for Substance Use Disorders: Serigaya Collaboration for Open heart Project (SCOP). AB - Previous researches suggest that addressing alexithymia and emotional dysregulation in patients with alcohol and drug addiction is important. However, interventions focused on emotional problems in Substance Use Disorder (SUD) patients are rare in Japanese hospital settings. In 2014, we developed and implemented an intervention called the Serigaya Collaboration for Open heart Project (SCOP) for those SUD inpatients who have difficulty recognizing and expressing their emotions. The SCOP consists of a series of emotion-focused group psychotherapies provided by psychologist, occupational therapist, and nurse. The purpose of this preliminary study is to assess the efficacy of.SCOP in SUD patients. A total of 65 inpatients (37 alcohol and 28 drug use disorder) participated in the research. Thirty-two patients consented to receive the SCOP intervention concurrently with treatment as usual (TAU), while the rest of the patients (n = 33) received only TAU. TAU consists of cognitive-behavioral group therapy, psychoeducational group sessions, occupational therapy, and on-site self help group attendances. Based on medical records, we assessed retrospectively the 6 months prognosis after discharge. A comparison was made between the SCOP and TAU groups in terms of treatment retention, attendance at self-help group meetings, -and alcohol or drug relapse. No dif- ference in post-discharge treatment retention was observed between the groups. The SCOP group had more self help group attendees and fewer patients with alcohol or drug relapse than the TAU group. Although our present study is retrospective in design, our preliminary findings suggest that the SCOP intervention which focuses on emotions may be effective in encouraging SUD patients to join self-help groups, and helped prevent alcohol or drug relapses. PMID- 30480906 TI - Mechanism and management of alcohol-induced asthma. AB - The purpose of the present review is to explain the mechanism of alcohol-induced asthma in Japanese. An oral ethanol provocation test was performed in Japanese asthmatics to measure pulmonary function, blood ethanol, acetaldehyde and histamine. Acetaldehyde dehydrogenase 2 (ALDH2) genotype was determined by polymerase chain reaction (PCR) and ethanol patch test. Human bronchi and mast cells were stimulated with acetaldehyde in vitro. Approximately half of the asthmatic subjects developed bronchoconstriction with concomitant increases in blood acetaldehyde and histamine, which was associated with genetically reduced ALDH2 activities. In vitro acetaldehyde stimulation induced bronchoconstriction and degranulation of human mast cells. Collectively, as a metabolite of alcohol, the elevation of acetaldehyde following alcohol consumption induces airway mast cells to release histamine, which result in exacerbation of asthma in susceptible population. PMID- 30480907 TI - Still without Sales Restriction? Fatal Caffeine Toxicity A case report. AB - Caffeine-containing drinks are popular daily beverages worldwide and highly concentrated caffeine in the form of tablets is easily obtainable in local chemists. It is common to detect caffeine in toxicological screens in autopsy cases, but we always have to take in account that caffeine itself possesses toxicity which may sometimes lead to death The case was a 44-year-old woman who was found dead in her room one day in June. Empty packages of 'Estaron Mocha 12(r), accounting for 14 tablets, were found at the scene. The autopsy showed nothing remarkable suggesting external forces, apart from white granules in her stomach. Toxicological analysis revealed 127 mg/L of caffeine concentration in the deceased's blood, which was considered to be fatal. Caffeine intoxication cases have been reported from many countries. Some are caused by accidental overtake of energy drinks, and many others are caused by intentional intake of caffeine tablets. We think that some restrictions will be effective to prevent this kind of death. PMID- 30480908 TI - An autopsy case of caffeine intoxication related by energy drink. AB - An autopsy case of caffeine intoxication related to the consumption of caffeinated products, such as energy drinks and caffeine contained drugs, was reported. Case report: A male in his early twenties was working a night shift job. After work one morning he came home and was not feeling well. He was vomiting a great deal and could not move, so his family had him lay down to rest. That afternoon they discovered his death. Although the decedent was examined by postmortem computed tomography, his cause of death could not be determined. A forensic autopsy was performed to investigate his cause of death. Autopsy findings: There were no obvious injuries on his whole body. Only slight brain edema and congestion of other organs were observed, but no significant lesions were found in his organs. A yellowish granular substance was observed in the stomach, duodenum, and small intestine. Alcohol concentration was 0.01mg/ml in the blood and urine. GC-MS and LC-MS/MS analyses did not detect any chemical substance except caffeine from his blood and urine. By LC-MS/MS analysis, the caffeine level (p g/mL) was 182, 71, and 10700 in the blood, urine, and gastric contents, respectively. Results and discussion: The fatal level of caffeine in blood has been reported as >100 u g/ mL. Thus, the cause of death was diagnosed as caffeine intoxication. It was revealed that he had consumed many energy drinks to stay awake and alert. Because he had a history of feeling ill and vomiting, it is suspected that he had an excessive intake of caffeine. Energy drinks, unlike most medicines, are able to be consumed repeatedly, and caffeine intoxication is a possible result. The reporting of this case will enlighten the danger of repetitious and chronic consumption of caffeinated products, such as energy drinks and caffeine contained drugs. PMID- 30480909 TI - Autopsy of a patient with alcoholic suffering from cardiopulmonary arrest at the hospital. AB - A 48-year-old Japanese woman with >10 years history of alcoholic had been falling repeatedly during 1 week before her death. She complained of nausea and did not eat or drink for 2 days. Thereafter, she became drowsy and she was transferred to the hospital. On arrival at the hospital, she had cardiopulmonary arrest and died soon after. Although blood tests showed metabolic ketoacidosis, a hemorrhagic lesion was also found in the brain by computed tomography. To determine the cause of death,. a forensic autopsy was performed on the next day. At autopsy, cerebral contusion, skull fracture, and subdural hemorrhage caused.by the head injury received after falling were found. Histological examination showed fatty changes and Mallory bodies in the liver. There was a marked increase in ketone bodies, especially beta -hydroxybutyrate, in postmortem blood examination. Therefore, the cause of death was diagnosed as alcoholic ketoacidosis. Accurate diagnosis of mild trauma and metabolic disease is difficult by postmortem computed tomography; therefore, autopsy is required for sudden death. In this case, the cause of death and accompanying traumatic lesions that were compatible with her history was clarified by autopsy. Furthermore, because the blood was taken at the time of cardiopulmonary arrest, we.obtained reliable data from the terminal stage of alcoholic ketoacidosis. This case demonstrates the physiological and pathological changes in sudden death of a patient with alcoholic. PMID- 30480910 TI - The profile of persons with alcohol and drug problems in Spain From "Proyecto Hombre Observatory Report 2014". AB - This article is an extension of a presentation with the same title given at the Japanese Alcohol, Nicotine & Drug Addiction Conference in Kobe on October 13th 2015: Firstly, a brief overview of support activities and services within Proyecto Hombre is given outlining the advanced assistance programs for supporting and treating addiction. problems. Secondly, it lays out the profile of persons with alcohol and drug problems as taken from "Proyecto Hombre Observatory Report 2014" vhich has informed the reality of adult users' life situation based on a series of indicators from the EuropASI, while they were being treated at Proyecto Hombre 27 Centers in Spain between 1 January, 2014 and 31 December, 2014. The sample consists of 1941 people treated during 2014 after application of the criteria for validation of the questionnaire. The profiles so obtained enable the design of treatment programs according to their specific situation in Proyecto Hombre. In order to allow some guidance to Japanese investigators and social workers regarding the design of treatments programs based on current user situation, this article draws attention to general sociodemographic data as well as data notable for its variation by gender and also by substance, and draws limited conclusions based on these. PMID- 30480911 TI - ? AB - A comparative cytological analysis of intra- and intertissular cytomictic interactions in early micro-sporogenesis of mono- and dicotyledonous plants was performed by the example of the two cellular systems - microsporocytes and tapetum. It is found that cytomixis is the component of intratissular interactions mainly. In the tapetum cells cytomixis is notable for structural and temporary taxon specific features. The nuclear migration in microsporocytes is confined mainly to zygotene-pachytene meiotic stages and characterized by a certain synchronism with cytomixis at the tapetum. Intertissular cytomictic interactions (tapetum - microsporocytes) were found in the monocot anthers only. Intertissular interactions are likely to reflect the intensification of competitive relations between the tapetum and microsporocytes for area in the process of anther tissue differentiation. Polyploid tapetum nucleus and syncytia being powerful acceptors are able to compete with microsporocytes and direct the chromatin translocation to their favor. The absence of intertissular interactions in dicots probably reflects a better balance between the processes of differentiation at somatic and generative tissues into microsporangium compared to monocots. PMID- 30480912 TI - ? AB - Precise chromosome segregation is vital for speciation and hybrid formation. The aim of the work was to study the chromosomes behaviour and inheritance of maternal and paternal genomes in Arabidopsis regenerants de-rived from in vitro cultured cells on the medium with PFFA. The Arabidopsis thaliana model hybrid between Columbia and Landsberg erecta ecotypes was developed, which chromosomes were easy to distinguish using the 12 SSLP selected markers. Also, the influence of PFFA on the callus formation and regeneration of plants was analysed. 20 regenerated plants cultured with PFFA were derived, three of which were shown to loss the heterozygosity in six loci by DNA markers analysis. Different models are certainly required to understand how and when the mechanisms leading to proper chromosome segregation are established in species and hybrids. PMID- 30480914 TI - ? AB - Types of aerenchyma formation in adventive roots of wild plant S. latifolium L. are described for the first time. Specific cell divisions and patterns of cell growth in the inner and outer root cortex at the initial stages of aerenchyma formation are highlighted in detail. Destructive processes in cells occurred under aerenchyma formation are considered in the view of known stages of programmed cell death in plants. PMID- 30480913 TI - ? AB - The anatomical research of the vegetative organs of the cytoplasmatic hybrid in vitro plants containing the Brassica napus nucleus and the Lesquerella fendleri chloroplasts had been conducted in comparison to the parental forms. It was found, that the anatomical structure of the cybrid had been similar to rapeseed. Anomalous changes in the epithelial, parenchymal and connective tissue of the leaf, stalk, stem, and root of the cybrid were detected. The appearance of the anatomical defects can be explained by nuclear-cytoplasmatic incompatibility which is the cause of low adaptability of the cybrid to in vivo conditions and takes place due to alien chloroplast gene expression in the remote species. PMID- 30480915 TI - ? AB - The anabolic effects require brief exposures to higher than average PTH concentrations. The catabolic effects result from pathological conditions in which parathyroid glands secrete too much hormone continuously at a sustained level. The aim of the present study was observance of intermittent (I-PTH) and continuous (C-PTH) PTH 1-34 administration influence on bovine chondrogenic progenitor cells (CPC) differentiation. Alcian blue was used to determine proteoglycan accumulation in CPC monolayer cultures. Thus in plates containing CPCs in C-PTH media chondrogenic differentiation was indicated by intensive proteoglycan accumulation in extracellular matrix. CPCs monolayer cultured in osteogenic media were subjected to Alizarin Red staining for matrix mineralization detection. Intense staining was revealed in I-PTH cells in comparison with C-PTH plates. The data obtained by monolayer cultures histological staining were confirmed by PCR analysis. PMID- 30480917 TI - Association of polymorphisms in intron 2 of FGFR2 and breast cancer risk in Shinese women. AB - Recent genome-wide association studies (GWAS) demonstrated that genetic variation in intron 2 of fibroblast growth factor receptor 2 (FGFR2) was a novel risk for breast cancer. We investigated whether two SNPs rs1219648 and rs2981582 in intron 2 of FGFR2 were associated with the risk of breast cancer in Chinese women. A total of 340 female breast cancer patients and 400 normal age-matched controls were recruited. Two SNPs were genotyped using matrix-assisted laser desorption/ionization mass spectrometry. The two SNPs rs1219648 and rs2981582 showed no association with the risk of breast cancer. A subgroup analysis by menopausal status demonstrated that the distribution of rs2981582 T alleles, including CT and TT genotypes, was significantly higher in premenopausal patients compared with postmenopausal patients. The TT genotype in rs2981582 was more strongly associated with ER-positive than with ER-negative tumors by ER status analysis. Analysis by haplotypes showed that no haplotypes associated with breast cancer. The results showed no association between two SNPs, rs1219648 and rs2981582 and breast cancer risk, although in a stratified analysis rs2981582 strongly associated with premenopausal and ER-positive breast cancer patients in Chinese women. PMID- 30480916 TI - ? AB - The aim of the study was to evaluate the association between the angiotensin converting enzyme ACE I/D (rs4340) polymorphism and DNA damage in pati-ents with essential hypertension (EH). The I/D polymorphism of ACE was determined by polymerase chain reaction in 170 male hypertensive patients and 64 normotensive blood donors. We used flow cytometry to determine the levels of cell death, micronuclei and accumulation of peripheral blood leukocytes in G1/G0, S, G2/M phases of the cell cycle. Additionally, the whole blood samples were incubated in vitro at 4 oC for 24 h to investigate the genotype effects on the susceptibility of cells to DNA damage. We found lower frequency of cells in DNA synthesis S phase and higher levels of micronuclei in the hypertensive compared to normotensive group (p<0.05); increased formation of micronuclei was seen due to elevated micronuclei fre-quencies in patients with the ACE II genotype (p < 0.05), but not in ID or DD genotype carriers. Incubation of whole blood samples of normotensive individuals lead to the most active cell death (p < 0.05) and micronuclei formation (p > 0.05) in the II genotype carriers too. However, hypertensive patients displayed different cellular response to incubation-induced DNA damages in the ACE I/D genotype groups; after incubation, the frequencies of micronuclei were significantly higher in the DD genotype carriers (p < 0.05). To conclude, the study suggests that the ACE I/D polymorphism may contribute to mechanisms and intensity of DNA damages in hypertensive and normotensive individuals. PMID- 30480918 TI - ? AB - The effect of the low temperature (4 oC) on the orga-nization of actin filaments (microfilaments) of cells of different growth zones of the root of Arabidopsis thaliana (L.) have been studied. It was found that cold treatment inhibits growth of the main root and gives its morphology, causing a large number of deformed (ectopic) root hairs in the zone of differentiation. The temporal relationship of the disorientation and the organization of actin filaments and the detected changes of growth and morphology of roots under conditions of cold factor is shown. It has been found that the most sensitive to the cold are actin filaments of root hairs, meristematic cells, cells of elongation zone, and all epidermal cells of the root zones of A. thaliana. PMID- 30480919 TI - ? AB - In this study we presented data on the production of branched root hairs in the seedlings of A. thaliana under progressive water deficit. The overall production of branched hairs was quite high under stress conditions and amounted to 8,27 %. On the contrary, this form of root hairs was almost absent in the control group (0,27 %). The highest number of branched hairs was produced at the beginning of the stress action. Branched root hairs are quite uniform structures in the sense of their morphology. To solve the question how the branched hairs grow, the structure of actin cytoskeleton was explored. This structure was different in the root hair and in its branch, which is an indication that the hair stops its growth at the moment when the branching starts. We have also characterized the production of branched root hairs in hormonal mutants of Arabidopsis and found the involvement of auxin in this process. PMID- 30480920 TI - ? AB - The aim of this study was to examine association between IFNL4 gene ss469415590 and treatment efficiency in group of Ukrainian PEG-interferon/ribavirin-treated chronic hepatitis C patients. Study group consisted of 92 unrelated hepatitis C virus genotype 1 mono-infected patients: case group - 29 patients with late or absent virological response; control group - 63 patients with sustained virological response. Study material was genomic DNA. Genotyping was performed using amplification-refractory mutation system PCR. Statistical analysis was performed using GenePop and OpenEpi statistical packages. Obtained results show that ss469415590 DeltaG/DeltaG genotype is associated with poor virological response (OR = 3.62; CI 95%: 1.12-11.67) in PEG-interferon/ribavirin-treated chronic hepatitis C patients from Ukraine. PMID- 30480982 TI - Histomorphometric evaluation of seminiferous tubules and stereological assessment of germ cells in testes following administration of aqueous leaf-extract of Lawsonia inermis on aluminium-induced oxidative stress in adult Wistar rats. AB - OBJECTIVES: This study aimed to investigate the 'Cytoprotective effect of Lawsonia inermis aqueous leaf-extract on aluminium-induced Oxidative stress in Histomorphometric of the Seminiferous tubule and Stereology of Germ Cells of adult male Wistar rats', assessing its effect on the Histomorphometry of the Seminiferous tubule and Stereology of Germ Cells. METHODS: Thirty-five adult male Wistar rats, weighing between 100-196g, and fifteen mice of the same weight range were used. Lawsonia inermis extracts and aluminum chloride (AlCl3) were administered for a period of three (3) weeks, with Five (5) rats per group. Group 1 (control), received rat pellets and distilled water. Group 2 received 60mg/kg/d aqueous extract. Group 3 received 0.5mg/kg/d of AlCl3. Group 4 received 0.5mg/kg/d of AlCl3 and 60mg/kg/d of aqueous extract orally. Group 5 received 0.5mg/kg/d of AlCl3 and 75mg/kg/d of aqueous extract orally. Group 6 received 0.5mg/kg/d of AlCl3 and 100mg/kg/d of aqueous extract orally. Group 7 received 0.5mg/k/d of AlCl3 and 5mg/Kg/d of ascorbic acid orally. Twenty-four hours after the last administration, the animals were weighed, sedated with chloroform and blood was collected. The testes were removed and weighed. RESULTS: There were statistically significant changes in the percentage of seminiferous tubular and seminiferous ductal diameter within the experimental animals in all the groups (p<0.05). Stereological findings revealed increase in spermatogonia, primary spermatocytes, round Spermatids and elongated spematids, spermatozoa, Sertoli cells population of the control rats while the rats given 0.5mg of aluminum chloride per kg of body weight had the lowest value (p<0.05). CONCLUSION: In this study, we demonstrated the affected histomorphometry of the seminiferous tubule and stereology of germ cells in testes, where stress impacts were most felt and subsequently translated into drastic reproductive dysfunction and distortion of spermatogenesis. PMID- 30480989 TI - N-type Ionic-Organic Electronic Ratchets for Energy Harvesting. AB - Ionic-organic ratchets are three terminal electronic devices with an asymmetric conductivity of the active layer that makes them capable of generating useful DC electrical power by converting electromagnetic noise signals available in any environment. In this work we demonstrate for the first time an n-type ionic organic ratchet which can generate a current of up to 7.29 uA and power up to 12.5 uW that exceed values reported for many of the presently state-of-the-art, p type organic electronic ratchets. We show that n-type ratchets require elimination of electron traps at the SiO2 surface, which is not required in p type devices. This can be achieved by using a trap-free passivation layer such as BCB, where the traditional silane treatment is insufficient. Chemical doping is employed to further reduce/fill electron traps in the channel, and increase carrier concentration and mobilities. Scanning kelvin probe force microscopy studies provide evidence of a pn-like rectifying junction in the n-type ratchets fabricated in this work, which inherently differs from the rectification mechanism of previous ionic-organic p-type ratchets. PMID- 30480990 TI - A New Insight into the Anchoring Mechanism of Polysulfides inside Nanoporous Covalent Organic Frameworks for Lithium-Sulfur Batteries. AB - The application prospects of lithium-sulfur (Li-S) batteries are constrained by many challenges, especially the shuttle effect of lithium polysulfides (Li2Sx). Recently, microporous covalent organic framework (COF) materials have been used to anchor-electrodes in lithium-sulfur (Li-S) batteries, because of its preferable characteristics, such as self-design ability, suitable pore size and various active groups. In order to identify the ideal anchoring materials that can effectively restrain the shuttle of Li2Sx species, the anchoring mechanism between COF materials and Li2Sx species should be investigated in depth. Therefore, we systematically investigated the anchoring mechanism between specific COF nanomaterials (consist of Boron, Oxygen atoms and Benzene group) and Li2Sx (x=1, 2, 4, 6, 8) species on the surface and inside the pore using the density functional theory methods with van der Waals interactions. The detailed analysis of the adsorption energy, difference charge density, charge transfer and atomic density of states can be used to determine that the COF nanomaterials, with the structure of boroxine connecting to benzene groups and boroxine groups not constructed at the corner of the structure, can effectively anchor Li2Sx series. Accordingly, this study provides the theoretical basis for the molecular scale design of ideal anchoring materials, which can be useful to improve the performance of the Li-S batteries. PMID- 30480991 TI - Detection and Imaging of Hydrogen Sulfide in Lysosome of Living Cells with an Activatable Fluorescence Quantum Dots. AB - The simple, sensitive and specific detection of hydrogen sulfide (H2S) is of great importance due to its crucial role in food safety, environmental pollution, and various pathological and physiological processes. Here, we reported an activatable fluorescence nanoprobe-based quantum dots (QDs) for sensitive and selective monitoring of H2S in red wine, environmental water samples, and lysosome of live cancer cells. The nanoprobe was prepared through a strong electrostatic interaction between thioglycolic acid stabilized CdTe QDs and p amino thiophenol capped silver nanoparticles (AgNPs) that resulted in the formation of the assembled nanostructure, called QDs/AgNPs nanocomplexes. The initial fluorescence of QDs was effective quenched by the AgNPs due to the inner filter effect. Upon interaction with H2S, the strong etching ability of H2S to AgNPs could trigger the disassembly of QDs/AgNPs nanocomplexes, and generate Ag2S on the surface of QDs, achieving a shell-core Ag2S/CdTe QDs with remarkable fluorescence as a result of the termination of inner filter effect. The aqueous solution studies displayed that the assembled QDs/AgNPs nanoprobe was sensitive to detect H2S, with a detection limit of 15 nM. In addition, this assembled QDs/AgNPs nanoprobe showed a high specificity toward H2S over other anions and biologically relevant species. The subsequent fluorescence imaging studies demonstrated that the assembled QDs/AgNPs nanoprobe exhibited high ability to enter into cellular lysosome and in situ generated an enhancement fluorescence, which was used for endogenous H2S detection in lysosome of living cancer cells. This proposed nanoprobe revealed a more simple, rapid, time-saving, low-cost, sensitive and selective for monitoring of H2S in further environmental pollution, food safety, and clinical diagnosis of H2S-related diseases. PMID- 30480992 TI - Nanoparticle formulation of moxifloxacin and intramuscular route of delivery improve antibiotic pharmacokinetics and treatment of pneumonic tularemia in a mouse model. AB - Francisella tularensis causes a serious and often fatal infection, tularemia. We compared the efficacy of moxifloxacin formulated as free drug vs. disulfide snap top mesoporous silica nanoparticles (MSNs) in a mouse model of pneumonic tularemia. We found that MSN-formulated moxifloxacin was more effective than free drug and that the intramuscular and subcutaneous routes were markedly more effective than the intravenous route. Measurement of tissue silica levels and fluorescent flow cytometry assessment of colocalization of MSNs with infected cells revealed that the enhanced efficacy of MSNs and the intramuscular route of delivery was not due to better delivery of MSNs to infected tissues or cells. However, moxifloxacin blood levels demonstrated that the nanoparticle formulation and intramuscular route provided the longest half-life and longest time above the minimal inhibitory concentration. Thus, improved pharmacokinetics are responsible for the greater efficacy of nanoparticle formulation and intramuscular delivery compared with free drug and intravenous delivery. PMID- 30480994 TI - Micro-patterned cell orientation of cyanobacterial liquid-crystalline hydrogels. AB - Control of cell extension direction is crucial for the regeneration of tissues, which are generally composed of oriented molecules. The scaffolds of highly oriented liquid crystalline polymer chains were fabricated by casting cyanobacterial mega-saccharides, sacran, on parallel-aligned micrometer bars of polystyrene (PS). Polarized microscopy revealed that the orientation was in transverse direction to the longitudinal axes of the PS bars. Swelling behavior of the micro-patterned hydrogels was dependent on the distance between the PS bars. The mechanical properties of these scaffolds were dependent on the structural orientation; additionally, the Young's moduli in the transverse direction were higher than those in the parallel direction to the major axes of the PS bars. Further, fibroblast L929 cells were cultivated on the oriented scaffolds to be aligned along the orientation axis. L929 cells cultured on these scaffolds exhibited uniaxial elongation. PMID- 30480993 TI - Dual role of magnetic nanoparticles as intracellular hotspots and extracellular matrix disruptors triggered by magnetic hyperthermia in 3D cell culture models. AB - Magnetic hyperthermia is a promising therapy for the localized treatment of cancer based on the exposure of magnetic nanoparticles to an external alternating magnetic field. In order to evaluate some of the mechanisms involved in the cellular damage caused by this treatment, two different 3D cell culture models were prepared using collagen, which is the most abundant protein of the extracellular matrix. The same amount of nanoparticles was added to cells either before or after their incorporation to the 3D structure. Therefore, in one model, particles were located only inside cells (In model), while the other one had particles both inside and outside cells (In&Out model). In the In&Out model, the hyperthermia treatment facilitated the migration of the particles from the outer areas of the 3D structure to the inner parts, achieving a faster homogeneous distribution throughout the whole structure and allowing the particles to gain access to the inner cells. The cell death mechanism activated by the magnetic hyperthermia treatment was different in both models. Necrosis was observed in the In model while apoptosis in the In&Out model 24 hours after the hyperthermia application. This was clearly correlated with the amount of nanoparticles located inside the cells. Thus, the combination of both 3D models allowed us to demonstrate two different roles of the magnetic particles during the hyperthermia treatment: i) The modulation of the cell death mechanism depending on the amount of intracellular particles, and ii) The disruption of the collagen matrix caused by the extracellular nanoparticles. PMID- 30480995 TI - Methylene Blue-Fortified Molybdenum Trioxide Nanoparticles: Harnessing Radical Scavenging Property. AB - Hybrid nanosystem with impeccable cellular imaging and antioxidant functionality is demonstrated. The microwave-irradiation derived molybdenum trioxide nanoparticles (MoO3 NPs) were surface functionalized with cationic dye molecule, methylene blue (MB), which enables superior UV-visible absorbance and fluorescence emission wavelengths potential for bioimaging. Radical scavenging property of the pristine MoO3 NPs and MoO3-MB NPs were studied in vivo using Caenorhabditis elegans as model system. Heat shock induced oxidative stress in the C. elegans was significantly resolved by the MoO3-MB NPs, in agreement with in vitro radical scavenging study by electron paramagnetic resonance spectroscopy. Hybrid nanostructures of MoO3-MB demonstrate synergistic benefits in the intracellular imaging with intrinsic biocompatibility and antioxidant behavior, which can facilitate application as advanced healthcare materials toward bioimaging and clinical therapeutics. PMID- 30480996 TI - Tailoring Copper Foam with Silver Dendrite Catalysts for Highly Selective Carbon Dioxide Conversion into Carbon Monoxide. AB - The present study outlines the important steps to bring electrochemical conversion of carbon dioxide (CO2) closer to commercial viability by using a large-scale metallic foam electrode as highly conductive catalyst scaffold. Due to its versatility, it was possible to specifically tailor three-dimensional copper foam through coating with silver dendrite catalysts by electrodeposition. The requirements of high yield CO2 conversion to carbon monoxide (CO) were met by tuning the deposition parameters towards a homogeneous coverage of the copper foam with nanosized dendrites, which additionally featured crystallographic surface orientations favoring CO production. The presented results evidence that Ag dendrites, owing a high density of planes with stepped (220) surface sites, paired with the superior active surface area of the copper foam can significantly foster the CO productivity. In a continuous flow-cell reactor set-up, CO faradaic efficiencies reaching from 85 % to 96 % for a wide range of low applied cathode potentials (< 1.0 VRHE) along with high CO current densities up to 27 mA/cm2 were achieved, far outperforming other tested scaffold materials. Overall, this research provides new strategic guidelines for the fabrication of efficient and versatile cathodes for CO2 conversion compatible with large-scale integrated prototype devices. PMID- 30480997 TI - Aluminum (oxy) Hydroxide Nanorods Activate an Early Immune Response in Pseudomonas aeruginosa Vaccine. AB - Bacterial vaccines have been widely used to prevent infectious diseases, especially in veterinary medicine. Although there are many reports on bacterin adjuvants, only a few contain innovations in bacterin adjuvants. Taking this into consideration, in this study, we designed and synthesized a new aluminum (oxy) hydroxide (AlOOH) nanorod (Al-NR) with a diameter of 200 +/- 80 nm and a length of 1.1 +/- 0.6 MUm. Using whole-Pseudomonas aeruginosa PAO1 as antigens, we showed that the bacterial antigens of P. aeruginosa PAO1 adsorbed on the Al-NRs induced a quick and stronger antigen-specific antibody response than those of the other control groups, especially in the early stage of immunization. Furthermore, the level of antigen-specific IgG was approximately 4-fold higher than that of the no adjuvant group and 2.5-fold higher than those of other adjuvant groups in the first week after the initial immunization. The potent adjuvant activity of the Al-NRs was attributed to the rapid presentation of antigen adsorbed on them by APCs. Additionally, Al-NRs induced a milder local inflammation than the other adjuvants. In short, we confirmed that Al-NRs, enhancing both humoral and cellular immune responses, are a potentially promising vaccine adjuvant delivery system for inhibiting the whole-pseudomonas aeruginosa infection. PMID- 30480998 TI - Nuclear and Electron Magnetic Resonance Spectroscopies of Atomically Precise Gold Nanoclusters. AB - Atomically precise gold nanoclusters display properties that are unseen in larger nanoparticles. When the number of gold atoms is sufficiently small, the clusters exhibit molecular properties. Their study requires extensive use of classic molecular physical chemistry and, thus, methods such as vibrational spectroscopies, electrochemistry, density functional theory and molecular dynamics calculations, and of course nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopies. NMR and EPR studies have been mostly carried out on the benchmark, stable molecules Au25(SR)18, Au38(SR)24, Au102(SR)44, and Au144(SR)60 (where SR = thiolate). In this Account, we showcase examples primarily taken from our previous and ongoing NMR and EPR studies, which we hope will trigger further interest in the use of these sensitive, though often underutilized, techniques. Indeed, 1D and 2D NMR spectra of pure, atomically precise clusters can be very detailed and informative. Molecular clusters are molecules and, thus, have discrete energy levels and undergo stepwise oxidation or reduction. The effect of the charge state on the chemical shifts and line shapes is a function of the ligand type (ligands differ due to specific bonds with different Au atom types) and the position of the chemical group along the ligand backbone: for groups near the Au core, they can be very dramatic. Ligand-protected gold clusters are hard-soft molecules where a hard metal core is surrounded by a dynamic molecular layer. The latter provides a nanoenvironment that interfaces the cluster core with the surrounding environment and can be permeated by molecules and ions. NMR spectroscopy is especially useful to assess its structure. For example, the data show that whereas long alkanethiolates form bundles, shorter chains exhibit more conformational freedom and are quite folded. NMR spectroscopy allows studying diastereotopic effects and provides information on possible hydrogen bonds of ligands with sulfur or surface gold atoms. EPR spectroscopy is a very precise technique to check and characterize the magnetic state of gold clusters or clusters doped with foreign metal atoms. Electron nuclear double resonance (ENDOR) provides a powerful tool to assess the interaction of an unpaired electron with nuclei, as we showed for 197Au and 1H. It can be used as a sensitive probe of the spin-density distribution in nanoclusters: for example, it showed that the singly occupied molecular orbital may span outside the Au core by nearly 6 A. Solid-state EPR spectroscopy has provided compelling evidence that the specific ligands and the crystallinity degree are very important factors in determining the interactions between clusters in the solid state. Depending on the condition, paramagnetic, superparamagnetic, ferromagnetic, or antiferromagnetic behavior can be observed. Time-resolved EPR was successfully tested to determine the efficiency of singlet oxygen generation via sensitization of Au25 clusters. This Account thus demonstrates some of the remarkable insights that can be gained into the properties of atomically precise clusters through detailed NMR and EPR studies. PMID- 30481000 TI - Orientation of human Microprocessor on primary microRNAs. AB - Single-stranded microRNAs (miRNAs) regulate gene expression by triggering mRNA degradation and/or inhibiting mRNA translation. miRNAs play important roles in various critical cellular processes and are associated with numerous human diseases, including cancer and neurodegenerative diseases. miRNA sequences are embedded in the primary precursor RNAs (pri-miRNAs) that are initially processed by the Microprocessor complex in the nucleus. Microprocessor can orient itself on pri-miRNAs in two ways: one orientation results in subsequent miRNA production and the other leads to cleavage of the miRNA sequence. Therefore, orienting Microprocessor on pri-miRNAs is a fundamental mechanism to determine the accuracy and efficiency of pri-miRNA processing and, in turn, miRNA production. Multiple mechanisms controlling Microprocessor orientation on pri-miRNAs, involving both cis-acting RNA elements and trans-acting factors, have recently been revealed. In this review, we discuss these exciting mechanisms and consider potential unknown mechanisms that might regulate Microprocessor orientation on pri-miRNAs. PMID- 30480999 TI - Nitric Oxide Detector Based on WO3-1wt%In2O3-1wt%Nb2O5 with State-of-the-Art Selectivity and ppb-Level Sensitivity. AB - Fast, sensitive, and precise detection of nitric oxide (NO) is critical to many applications in environmental monitoring and early disease diagnosis via respiratory testing. An effective detection system requires a sensor to detect NO gas at the parts per billion (ppb) level, and this system should possess a high degree of anti-interference selectivity. To achieve these targets, a series of gas sensor thin films based on intrinsic WO3, one-additive-doped WO3 (prepared by doping In2O3 or Nb2O5), and two-additive-doped WO3 (synthesized by doping with In2O3 and Nb2O5) oxides were successfully grown. By analyzing the properties of sensitivity, selectivity, responsiveness, and recovery time of the gas sensors, we found that WO3-1wt%In2O3-1wt%Nb2O5 has overwhelming advantages over intrinsic WO3, WO3-In2O3, and WO3-Nb2O5. A sensing response value of 2.4 was observed for NO concentrations as low as 20 ppb from the WO3-1wt%In2O3-1wt%Nb2O5 sensor. With 100 ppb NO gas, the WO3-1wt%In2O3-1wt%Nb2O5 sensor achieved a high response of 56.1 at 70 degrees C, which is a state-of-the-art performance for NO detection at low working temperature settings. WO3-1wt%In2O3-1wt%Nb2O5 also yields significantly improved selectivity and stability over intrinsic WO3, WO3-In2O3, and WO3-Nb2O5. Studies on the sensing mechanism show that the grain size, rather than the n-n heterostructure effect, plays a dominant role in the observed results. By decreasing the grain size so that it is close to the thickness of the space-charge layer, the sensing response is enhanced. Although room remains to further improve the sensing properties, the performance of WO3-1wt%In2O3 1wt%Nb2O5 is sufficient for implementation in low-content NO detection devices. PMID- 30481001 TI - Recent Developments in Carbon Sensors for At-Source Electroanalysis. AB - Our understanding of the world around us has been greatly enhanced by our ability to detect and quantify analytes in the environment and in biology. It is highly beneficial to perform analysis at the site of interest as many situations do not afford the luxury of time required for samples to be collected and sent off for analysis. Some processes necessitate immediate detection to facilitate rapid action. As an example, harmful environmental phenomena can result from dynamic events such as the recent spate of tropical cyclones in the Caribbean and Southeastern region of the United States. These storms have mobilized nutrients, facilitating large-scale algal blooms that are damaging to marine ecosystems and human health. The rapid delivery of analytical information during such events is the key to quickly mitigating detrimental effects. Another example is analytically monitoring the quality of drinking water in the context of avoiding residential crises such as in Flint, MI where residents were exposed to high levels of Pb. Other examples include monitoring airborne workplace hazards with smart wearable devices and point-of-care (POC) diagnostics for monitoring health. An excellent, low-cost and portable approach to measurements at the location of interest is electroanalysis. Specifically, carbon-based electrochemical sensors offer a versatile, chemically functional, and (bio)compatible platform for detecting a variety of analytes. Carbon is utilized in many forms including graphene, composites and fibers. Using carbon-based sensors, scientists are creating novel electroanalytical devices that are greatly improving the speed and quality of at-source detection. PMID- 30481002 TI - Giant Unilamellar Vesicle Microarrays for Cell Function Study. AB - Giant unilamellar vesicles (GUVs) are widely used as artificial cell models which contribute to elucidate fundamental questions on origin of life and cell functions. Herein, the GUV microarrays were developed using a point-to-plane electrode system combined with microcontact stripping technique. The biomolecules (DNA, etc.) were selectively encapsulated only inside patterned GUVs. The GUV arrays were used to investigate species mass transport across cell membranes. The release of carboxyfluorescein from GUVs showed a melittin concentration dependent manner. The diffusion coefficient were 0.37 * 10-11, 0.36 * 10-11, 0.54 * 10-11, 1.10 * 10-11, 1.74 * 10-11, 2.31 * 10-11, and 3.62 * 10-11 m2/s for 0, 0.5, 1.0, 2.0, 3.0, 4.0, and 5.0 MUM melittin, respectively. The GUV arrays were also a good platform for cell metabolism investigation. Horseradish peroxidase (HRP) loaded GUV microarrays were used to mimic internal metabolism by exposing them to the substrates of H2O2 and o-PD to yield fluorescent 2,3-diaminophenazine (2,3 DAP).The proposed GUV arrays have great potential in cell function studies. PMID- 30481003 TI - Near-Field Coupled Integrable Two-Dimensional InSe Photosensor on Optical Fiber. AB - Two-dimensional (2D) van der Waals layered materials possess innate advantages as integrable sensors, due to their thinness, flexibility and sensitivity. They can be seamlessly integrated onto surfaces with different geometries where detection of near-field signal is desired. In this study, we develop a device transfer technique to integrate 2D devices onto an arbitrary smooth surface. Such technique utilizes a sacrificial polymer underlayer and achieves clean and non destructive full device transfer. For demonstration, we transferred a complete 2D multilayer InSe photodetector device onto a stripped optical fiber. Due to the extreme vicinity of the 2D photodetector with the fiber core, the device can effectively couple with the evanescent field and accurately detect information transmitted inside the optical fiber. In addition, these super thin flexible device assemblies can be integrated onto the fibers themselves to non-invasively monitor the optical fiber performance. The demonstration of optically coupled, conformal 2D devices on substrates of different form factors can enable a variety of near-field optical and sensing applications. PMID- 30481004 TI - Synthetic biology approaches in immunology. AB - Breakthroughs in gene synthesis has allowed synthetic biologists the ability to design any DNA sequence of interest, enabling the possibility to create complex systems inside cells with novel functions to tackle problems in immunology. Synthetic immunology of mammalian cells expressing natural or synthetic genes can guide and induce immune responses in patients. Through recent developments in engineering chimeric receptors, it is now feasible to customize control over engineered cells to target the disease sites with specificity. These cells can avoid immune rejection if derived from expandable cell types (e.g. stem cells or T cells) and then can be grown in abundance before implantation. However, safety concerns of engineered cells in circulation necessitates the development of a wide range of mechanisms to kill cells after their therapeutic life ends. This therapeutic effect is still predominantly the secretion of therapeutic proteins but novel therapeutic interventions have been explored by synthetic biologists. In the pursuit of engineering new cell functions for synthetic immunology, it is possible that many problems previously thought intractable may actually be possible. PMID- 30481005 TI - Relating Organic Fouling in Membrane Distillation to Intermolecular Adhesion Forces and Interfacial Surface Energies. AB - This study investigates the fouling mechanisms in membrane distillation, focusing on the impact of foulant type and membrane surface chemistry. Interaction forces between a surface- functionalized particle probe simulating a range of organic foulants and model surfaces, modified with different surface energy materials, were measured by atomic force microscopy (AFM). The measured interaction forces were compared to those calculated based on the experimentally determined surface energy components of the particle probe, model surface, and medium (i.e., water). Surfaces with low interfacial energy exhibited high attractive interaction forces with organic foulants, implying a higher fouling potential. In contrast, hydrophilic surfaces (i.e., surfaces with high interfacial energy) showed the lowest attractive forces with all types of foulants. We further performed fouling experiments with alginate, humic acid, and mineral oil in direct contact membrane distillation using polyvinylidene fluoride membranes modified with various materials to control membrane surface energy. The observed fouling behavior was compared to the interaction force data to better understand the underlying fouling mechanisms. A remarkable correlation was obtained between the evaluated interaction force data and the fouling behavior of the membranes with different surface energy. Membranes with low surface energy were fouled by hydrophobic, low surface tension foulants via "attractive" and subsequent "adsorptive" interaction mechanisms. Furthermore, such membranes have a higher fouling potential than membranes with high or ultralow surface energy. PMID- 30481006 TI - Response to Comment on "Application of Struvite Alters the Antibiotic Resistome in Soil, Rhizosphere, and Phyllosphere". PMID- 30481007 TI - Inverse Design of a Catalyst for Aqueous CO/CO2 Conversion Informed by the NiII Iminothiolate Complex. AB - A computational inverse design method suitable to assist the development and optimization of molecular catalysts is introduced. Catalysts are obtained by continuous optimization of "alchemical" candidates in the vicinity of a reference catalyst with well-defined reaction intermediates and rate-limiting step. A NiII iminoalkoxylate catalyst for aqueous CO/CO2 conversion is found with improved performance relative to a NiII-iminothiolate reference complex, previously reported as a biomimetic synthetic model of CO dehydroxygenase. Similar energies of other intermediates and transition states along the reaction mechanism show improved scaling relations relative to the reference catalyst. The linear combination of atomic potential tight-binding model Hamiltonian and the limited search of synthetically viable changes in the reference structure enable efficient minimization of the energy barrier for the rate-limiting step (i.e., formation of [LNiII(COOH)]-), bypassing the exponential scaling problem of high throughput screening techniques. The reported findings demonstrate an inverse design method that could also be implemented with multiple descriptors, including reaction barriers and thermodynamic parameters for reversible reactivity. PMID- 30481008 TI - SO2F2 Mediated Oxidative Dehydrogenation and Dehydration of Alcohols to Alkynes. AB - Direct synthesis of alkynes from inexpensive, abundant alcohols was achieved in high yields (greater than 40 examples, up to 95% yield) through a SO2F2-promoted dehydration and dehydrogenation. This straightforward transformation of sp3-sp3 (C-C) bonds to sp-sp (C-C) bonds requires only inexpensive and readily available reagents (no transition metals) under mild condition. The crude alkynes are sufficiently free of impurities to permit direct use in further transformations as illustrated by regioselective Huisgen alkyne-azide cycloaddition reactions with PhN3 to give 1,4-substituted 1,2,3-traiazoles (16 examples, up to 92% yield) and Sonogashira couplings (10 examples, up to 77% yield). PMID- 30481009 TI - An Improved Strategy for Fluorescent Tagging of Membrane Proteins for Overexpression and Purification in Mammalian Cells. AB - An essential prerequisite for in vitro biochemical or structural studies is a construct that is amenable to high level expression and purification and is biochemically "well-behaved". In the field of membrane protein research, the use of green fluorescent protein (GFP) to monitor and optimize the heterologous expression in different hosts has radically changed the ease of streamlining and multiplexing the testing of a large number of candidate constructs. This is achieved by genetically fusing the fluorescent proteins to the N- or C-terminus of the proteins of interest to act as reporters which can then be followed by methods such as microscopy, spectroscopy, or in-gel fluorescence. Nonetheless, a systematic study on the effect of GFP and its spectral variants on the expression and yields of recombinant membrane proteins is lacking. In this study, we genetically appended four common fluorescent protein tags, namely, mEGFP, mVenus, mCerulean, and mCherry, to the N- or C-terminus of different membrane proteins and assessed their expression in mammalian cells by fluorescence-detection size exclusion chromatography (FSEC) and protein purification. We find that, of the four fluorescent proteins, tagging with mVenus systematically results in higher expression levels that translates to higher yields in preparative purifications, thus making a case for switching to this yellow spectral variant as a better fusion tag. PMID- 30481010 TI - Comparative Binding Analysis of N- Acetylneuraminic Acid in Bovine Serum Albumin and Human alpha-1 Acid Glycoprotein. AB - In this present study focus that determination of biologically significant N Acetylneuraminic acid (NANA) drug binding interaction mechanism between bovine serum albumin (BSA) and human alpha-1 acid glycoprotein (HAG) using various optical spectroscopy and computational methods. The steady state fluorescence spectroscopy result suggests that the fluorescence intensity of BSA, HAG was quenched by NANA drug in a static mode of quenching. Further time- resolved emission spectroscopy measurements confirm that mode of quenching mechanism of NANA drug in BSA and HAG system. The FT-IR, excitation -emission matrix analysis confirms the presence of NANA drug in HAG, BSA system and fluorescence resonance energy transfer analysis calculation shows that the NANA drug energy transfer between HAG, BSA system. The molecular docking result shows good binding affinity in both protein complex and further molecular dynamics simulations and charge distribution analysis were performed to understand more insight binding interaction mechanism of NANA drug in HAG, BSA complex. PMID- 30481011 TI - Partitioning of PAHs between Crude Oil Micro Droplets, Water and Copepod Biomass in Oil-in-Seawater Dispersions of Different Crude Oils. AB - The impact of oil micro-droplets on the partitioning of polycyclic aromatic hydrocarbons (PAHs) between water and marine zooplankton was evaluated. The experimental approach allowed direct comparison of crude oil dispersions (containing both micro oil droplets and water soluble fraction; WSF) with the corresponding WSF (without oil droplets). Dispersion concentration and oil type have an impact on the PAH composition of WSFs and therefore affects dispersion bioavailability. Higher T-PAH body residues were observed in copepods treated with dispersions compared to the corresponding WSFs. PAHs with Log Kow 3-4.5 displayed comparable accumulation factors between treatments, however, accumulation factors for less soluble PAHs (Log Kow=4.5-6) was higher for the WSF than for the dispersions suggesting low bioavailability for components contained in oil droplets. The higher PAH body residue in dispersion exposures is assumed to result mainly from copepods grazing on oil droplets, which offers an alternative uptake route to passive diffusion. To a large degree this route is controlled by the filtration rates of the copepods, which may be inversely related to droplet concentration. PMID- 30481012 TI - Conformational 2-Fold Interpenetrated Uranyl Supramolecular Isomers Based on (6,3) Sheet Topology: Structure, Luminescence, and Ion Exchange. AB - Six new 2-fold interpenetrated uranyl coordination polymers with two distinct types of (6,3)-net layers, (H3O)[(UO2)(L)].H2O (1), (Hbipy)[(UO2)(L)].H2O (2), (Hbib)[(UO2)(L)].H2O (3), (H2dib)[(UO2)2(L)2].H2O (4), [Zn(H2O)6][(UO2)2(L)2].5H2O (5), and (NH4)[(UO2)(L)].H2O (6), (bipy = 2,2' bipyridine, bib = 4,4'-di(1 H-imidazol-1-yl)-1,1'-biphenyl, and dib = 1,4-di(1 H imidazol-1-yl)benzene), were hydrothermally prepared from a tripodal polycarboxylate ligand, tri(4-carboxyphenyl)phenylsilane (H3L), with different N bearing organic templates as the stacking templates and charge compensators. Structural analyses indicate that these compounds comprise two sets of conformational supramolecular isomers because of the same framework compositions but different conformations of the carboxylate ligands. The solid-state emission spectra of compounds 1-6 were recorded. Ion-exchange studies revealed that the ammonia hydrate in 6 can be selectively substituted by alkali metal cations with appropriate ionic radii, and that the resulting structures remain stable, as demonstrated by crystallographic characterization. PMID- 30481013 TI - Alkaline and Earth Alkaline Energetic Materials Based on a Versatile and Multifunctional 1-Aminotetrazol-5-one Ligand. AB - In our effort to seek for the "green" energetic coordination polymers (CPs), a versatile and multifunctional 1-amino-tetrazol-5-one ligand was synthesized and its complexes with a series of alkaline and earth alkaline metals were prepared and comprehensively characterized. A broad range of differently shaped 1D, 2D, and 3D supramolecular structures for the prepared energetic compounds were found, where each metal was bound in a specific and characteristic fashion. All prepared CPs show very good thermostability, with decomposition temperatures above 236 degrees C and remarkable insensitivity to mechanical impact and friction (impact sensitivity > 40 J, friction sensitivity > 360 N). In terms of detonation performance, our CPs were calculated to have detonation velocities in the range of 6.8-8.1 km.s-1 and detonation pressures in the range of 16.5-24.5 GPa. Upon their combustion, new materials show a range of characteristic flame colors (from yellow to blue), making these compounds as promising components for various "green" pyrotechnic formulations. PMID- 30481014 TI - Highly Efficient and Robust Photocatalytic Systems for CO2 Reduction Consisting of a Cu(I) Photosensitizer and Mn(I) Catalysts. AB - The development of highly efficient, selective, and durable photocatalytic CO2 reduction systems that only use earth-abundant elements is key for both solving global warming and tackling the shortage of energy and carbon resources. Here, we successfully developed CO2 reduction photocatalysts using [Cu2(P2bph)2]2+ (CuPS) (P2bph = 4,7-diphenyl-2,9-di(diphenylphosphinotetramethylene)-1,10 phenanthroline) as a redox photosensitizer and fac-Mn(X2bpy)(CO)3Br (Mn(4X)) (X2bpy = 4,4'-X2-2,2'-bipyridine (X = -H and -OMe) or Mn(6mes) (6mes = 6,6' (mesityl)2-2,2'-bipyridne)) as the catalyst. The most efficient photocatalysis was achieved by Mn(4OMe): The total quantum yield of CO2 reduction products was 57%, the turnover number based on the Mn catalyst was over 1300, and the selectivity of CO2 reduction was 95%. Electronic and steric effects of the substituents (X) in the Mn complexes largely affected both the photocatalytic efficiency and the product selectivity. For example, the highest selectivity of CO formation was achieved by using Mn(6mes) (selectivity SCO = 96.6%), whereas the photocatalytic system using Mn(4H) yielded HCOOH as the main product ( SHCOOH = 74.6%) with CO and H2 as minor products ( SCO = 23.7%, SH2 = 1.7%). In these photocatalytic reactions, CuPS played its role as an efficient and very durable redox photosensitizer, while remaining stable in the reaction solution even after a turnover number of 200 had been reached (the catalyst used had a turnover number of over 1000). PMID- 30481015 TI - Synthesis, Structure, and Properties of the Layered Oxide Chalcogenides Sr2CuO2Cu2S2 and Sr2CuO2Cu2Se2. AB - The structures of two new oxide chalcogenide phases, Sr2CuO2Cu2S2 and Sr2CuO2Cu2Se2, are reported, both of which contain infinite CuO2 planes containing Cu2+ and which have Cu+ ions in the sulfide or selenide layers. Powder neutron diffraction measurements show that Sr2CuO2Cu2Se2 exhibits long-range magnetic ordering with a magnetic structure based on antiferromagnetic interactions between nearest-neighbor Cu2+ ions, leading to a ?2 a * ?2 a * 2 c expansion of the nuclear cell. The ordered moment of 0.39(6) MUB on the Cu2+ ions at 1.7 K is consistent with the value predicted by density functional theory calculations. The compounds are structurally related to the cuprate superconductors and may also be considered as analogues of the parent phases of this class of superconductor such as Sr2CuO2Cl2 or La2CuO4. In the present case, however, the top of the chalcogenide-based valence band is very close to the vacant Cu2+ 3d states of the conduction band, leading to relatively high measured conductivity. PMID- 30481017 TI - Insights into the mechanisms of pyrazinamide resistance of three pyrazinamidase mutants N11K, P69T and D126N. AB - In an effort to discover the mechanism of resistance offered by Mycobacterium tuberculosis (Mtb) toward the pyrazinamide (PZA) drug, an extensive molecular dynamics strategy was employed. PZA is a first-line prodrug that effectively cuts the therapy time by 33% (from 9 to 6 months). Pyrazinamidase enzyme (PZase), encoded by the pncA gene, is responsible for the activation of prodrug PZA into pyrazinoic acid (POA). POA is toxic and potently inhibit the growth of latent Mtb even at low pH. PZA resistance is caused by three genes pncA, rpsA, and panD. Among them, pncA gene contributes 72 to 99% to the resistance. Hence, the present study focused on the novel mutations N11K, P69T, and D126N in pncA gene. In the present study, the possible mechanism of these three mutations was studied through molecular dynamics simulation and docking techniques. Our in-depth analysis and results are in strong agreement with our experimental observation. The binding pocket analysis showed that mutations decrease the volume of the active site and hinder the correct orientation of PZA drug in the active site. Moreover, the Patchdock score was found low as compared to WT showing the disturbance of shape complementarity between PZase and PZA drug. These mutations were found to disturb the position of the Fe2+ ion. Among the mutations, D126N allosterically disturbed the position of the Fe2+ ion. MMGBSA analyses showed that these mutations decrease the binding affinity toward the PZA drug. In conclusion, mutations N11K, P69T, and D126N result in weak binding affinity with PZA also cause significant structural deformations that leading to PZA resistance. This study provides useful information that mutations in other than active parts may also cause proteins folding and ligand displacement effect, altering the biological functions. PMID- 30481016 TI - Heteroleptic Copper(I) Complexes Prepared from Phenanthroline and Bis-Phosphine Ligands: Rationalization of the Photophysical and Electrochemical Properties. AB - The electronic and structural properties of ten heteroleptic [Cu(NN)(PP)]+ complexes have been investigated. NN indicates 1,10-phenanthroline (phen) or 4,7 diphenyl-1,10-phenanthroline (Bphen); each of these ligands is combined with five PP bis-phosphine chelators, i.e., bis(diphenylphosphino)methane (dppm), 1,2 bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)benzene (dppb), and bis[(2-diphenylphosphino)phenyl] ether (POP). All complexes are mononuclear, apart from those based on dppm, which are dinuclear. Experimental data-also taken from the literature and including electrochemical properties, X-ray crystal structures, UV-vis absorption spectra in CH2Cl2, luminescence spectra and lifetimes in solution, in PMMA, and as powders-have been rationalized with the support of density functional theory calculations. Temperature dependent studies (78-358 K) have been performed for selected complexes to assess thermally activated delayed fluorescence. The main findings are (i) dependence of the ground-state geometry on the crystallization conditions, with the same complex often yielding different crystal structures; (ii) simple model compounds with imposed C2 v symmetry ([Cu(phen)(PX3)2]+; X = H or CH3) are capable of modeling structural parameters as a function of the P-Cu-P bite angle, which plays a key role in dictating the overall structure of [Cu(NN)(PP)]+ complexes; (iii) as the P-Cu-P angle increases, the energy of the metal-to-ligand charge transfer absorption bands linearly increases; (iv) the former correlation does not hold for emission spectra, which are red-shifted for the weaker luminophores; (v) the larger the number of intramolecular pi interactions within the complex in the ground state, the higher the luminescence quantum yield, underpinning a geometry locking effect that limits the structural flattening of the excited state. This work provides a general framework to rationalize the structure-property relationships of [Cu(NN)(PP)]+, a class of compounds of increasing relevance for electroluminescent devices, photoredox catalysis, and solar-to-fuels conversion, which so far have been investigated in an unsystematic fashion, eluding a comprehensive understanding. PMID- 30481018 TI - Effects of Single Nucleotide Polymorphisms on the binding of afatinib to EGFR: a potential patient stratification factor revealed by modelling studies. AB - The anticancer drug afatinib has been found to be more effective at inhibiting the oncogenic EGFR mutant exon 19 deletion (19del) over the oncogenic EGFR mutant L858R. The underlying mechanism has been hypothesized to result from differences in structural constraints introduced by the mutations and stabilizing interactions afforded by a buried water molecule in 19del (Kannan S. et al. Scientific Reports 2017, 7: 1540). The COSMIC cancer database is mined for EGFR sequences to discover that several mutations in the form of Single Nucleotide Polymorphisms (SNPs) line this hydration cavity. In this work, the effects of these SNPs on the affinity of afatinib for EGFRWT and oncogenic mutants EGFRL858R and EGFR19del were studied using Free Energy Perturbation and Thermodynamic Integration calculations. The simulations reveal that several SNPs have significant effects on the affinity of afatinib for the mutant EGFRs carrying the SNPs and may thus have clinical implications relating to emergence of resistance to afatinib, thus potentially impacting the choice of EGFR inhibitors in the clinic. PMID- 30481019 TI - Automatic Construction of the Initial Orbitals for Efficient Generalized Valence Bond Calculations of Large Systems. AB - We propose an efficient general strategy for generating initial orbitals for generalized valence bond (GVB) calculations which makes routine black-box GVB calculations on large systems feasible. Two schemes are proposed, depending on whether the restricted Hartree-Fock (RHF) wavefunction is stable (scheme I) or not (scheme II). In both schemes, the first step is the construction of active occupied orbitals and active virtual orbitals. In scheme I, active occupied orbitals are composed of the valence orbitals (the inner core orbitals are excluded) and the active virtual orbitals are obtained from the original virtual space by requiring its maximum overlap with the virtual orbital space of the same system at a minimal basis set. In scheme II, active occupied orbitals and active virtual orbitals are obtained from the set of unrestricted natural orbitals (UNOs), which are transformed from two sets of unrestricted HF spatial orbitals. In the next step, the active occupied orbitals and active virtual ones are separately transformed to localized orbitals. Localized occupied and virtual orbital pairs are formed using the Kuhn-Munkres (KM) algorithm and are used as the initial guess for the GVB orbitals. The optimized GVB wavefunction is obtained using the second-order self-consistent-field algorithm in the GAMESS program. With this procedure, GVB energies have been obtained for the lowest singlet and triplet states of polyacenes (up to decacene with 96 pairs) and the singlet ground state of two di-copper-oxygen-ammonia complexes. We have also calculated the singlet-triplet gaps for some polyacenes and the relative energy between two di-copper-oxygen-ammonia complexes with the block-correlated second order perturbation theory based on the GVB reference. PMID- 30481020 TI - Comparative Assessment of Scoring Functions: The CASF-2016 Update. AB - In structure-based drug design, scoring functions are often employed to evaluate protein-ligand interactions. A variety of scoring functions have been developed so far, and thus some objective benchmarks are desired for assessing their strength and weakness. The comparative assessment of scoring functions (CASF) benchmark developed by us provides an answer to this demand. CASF is designed as a "scoring benchmark", where the scoring process is decoupled from the docking process to depict the performance of scoring function more precisely. Here, we describe the latest update of this benchmark, i.e. CASF-2016. Each scoring function is still evaluated by four metrics, including "scoring power", "ranking power", "docking power", and "screening power". Nevertheless, the evaluation methods have been improved considerably in several aspects. A new test set is compiled, which consists of 285 protein-ligand complexes with high-quality crystal structures and reliable binding constants. A panel of 25 scoring functions are tested on CASF-2016 as demonstration. Our results reveal that the performance of current scoring functions is more promising in terms of docking power than scoring, ranking, and screening power. Scoring power is somewhat correlated with ranking power, so are docking power and screening power. The results obtained on CASF-2016 may provide valuable guidance for the end users to make smart choices among available scoring functions. Moreover, CASF is created as an open-access benchmark so that other researchers can utilize it to test a wider range of scoring functions. The complete CASF-2016 benchmark will be released on the PDBbind-CN web server (http://www.pdbbind-cn.org/casf.asp/) once this article is published. PMID- 30481021 TI - A Quasi-Atomic Analysis of Three-Center Two-Electron Zr-H-Si Interactions. AB - A comprehensive analysis of the bonding structure of the disilyl zirconocene amide cation {Cp2Zr[N(SiHMe2)2]}+ is conducted by application of an intrinsic orbital localization method that yields quasi-atomic orbitals (QUAOs). An emphasis is placed on describing a previously characterized three-center two electron interaction between zirconium, hydrogen, and silicon that presents structural and spectroscopic features similar to that of agostic bonds. Expressions of the first order density matrix in terms of the QUAOs yields bonds orders (BOs), kinetic bond orders (KBOs), and the extent of transfer of charge that are useful to determine the electronic nature of the Zr-H-Si bond. The interactions between the QUAOs demonstrate the importance of vicinal interactions in the stabilization of the molecule. In addition, the evolution of the QUAOs during reactions with Lewis bases reveals the role of the Zr-H-Si interaction in facilitating the reaction. PMID- 30481022 TI - Molecular Insight into Fatty Acids Adsorption on Bare and Hydrated (111) Fluorite Surface. AB - The adsorption of fatty acids with various chain structures on the (111) fluorite surface is investigated using density functional theory including a correction for dispersive interactions. In the case of the acidic form, we observe that the molecular form is preferred over the dissociated one and the molecule adsorbs on a surface calcium atom with an energy of -78.2 kJ mol 1. Also, we show that the carboxylate anion adsorbs on the surface under two possible configurations, a double-monodentate one or a single-monodentate one, the double-monodentate being favored. At both 0 K and 300 K, the chain length does not affect the geometry of the carboxyl group, but it strongly impacts the global geometry of the molecule adsorption on the fluorite surface: the "flat" adsorption mode, i.e. when the molecule is parallel to the surface, is favored when the number of carbon atoms is equal or higher to 6, due to dispersion forces. However, when the molecule is in hydrated conditions, the chain folds up on itself to reduce the interactions with water, while the carboxylate group adsorbs in single-monodentate configuration. In aqueous conditions, the chain length does not impact anymore the adsorption energies, the vertical adsorption mode being always favored. . PMID- 30481023 TI - The Oscillatory Photoelectron Signal of N-Methylmorpholine as a Test Case for the Algebraic-Diagrammatic Construction Method of Second Order. AB - Motivated by recent progress in the application of time-resolved photoelectron spectroscopy (TRPES) to molecular Rydberg states, we report herein a detailed assessment of the performance of the second-order algebraic diagrammatic construction (ADC(2)) method in the simulation of their TRPES spectra. As the test case, we employ the tertiary aliphatic amine N -methylmorpholine (NMM), which is notable for the fact that the signal of its 3s state exhibits long-lived oscillations along the electron binding energy axis. The relaxation process of photoexcited NMM is simulated via the Born-Oppenheimer molecular dynamics method, and the resulting TRPES spectrum is generated basing on ionization energies and approximate Dyson orbital norms calculated with the continuum orbital technique. On the whole, the simulated TRPES spectrum achieves satisfactory agreement with experiment, which suggests that the ADC(2) method provides a realistic description of the potential energy surfaces of the relevant excited and ionized states. In particular, the simulations reproduce the fine oscillatory structure of the signal of the 3s state, and provide evidence to the effect that it results from a coherent vibrational wavepacket evolving along the deformation modes of the six-membered ring. However, it is found that ADC(2) underestimates of electron binding energies by up to a few tenths of an electronvolt. The case of NMM demonstrates the usefulness of ADC(2) as a tool to aid the interpretation of the TRPES spectra of large organic molecules. PMID- 30481024 TI - Theoretical Investigation of Transcriptional Bursting: A Multi-State Approach. AB - Variability in gene expression causes genetically identical cells to exhibit different phenotypes. One probable cause of this variability is transcriptional bursting, where the synthesis of RNA molecules randomly alternates with periods of silence in the transfer of genetic information. Yet, the molecular mechanisms behind this variability remain unclear. Experiments indicate that multiple biochemical states might be involved in the production of RNA molecules. Stimulated by these observations, we developed a theoretical framework to investigate the mechanisms of transcriptional bursting. It is based on a multi state stochastic approach that provides a full quantitative description of the dynamic properties in the system. We found that the degree of stochastic fluctuations during transcription directly correlates with the number of biochemical states. This explains experimentally observed variability and fluctuations in the quantities of the produced RNA molecules. The procedure to estimate the number of relevant biochemical states participating in the transcription is outlined and applied for analysis of experimental results. We also developed a general dynamic phase diagram for the transcription process. The presented theoretical method clarifies physical-chemical aspects of the transcriptional bursting and presents a minimal chemical-kinetic description of the process. PMID- 30481025 TI - Oscillating picoNewton Force Manipulation on Single-Molecule Enzymatic Conformational and Reaction Dynamics. AB - Oscillation force has been demonstrated in theoretical studies as a critical role in unraveling the comprehensive enzymatic dynamics and address its regulation on enzyme activity. Utilizing the imposed external mechanical oscillation force by our newly developed magnetic tweezers coupled single-molecule photon-stamping imaging spectroscopic microscope, we experimentally studied a millisecond scale oscillation force manipulation on single Horseradish Peroxidase (HRP) enzymatic conformational and reaction dynamics. We have studied the enzymatic reaction dynamics and found that the enzyme activity changes under the real-time oscillatory force manipulation. Moreover, the oscillation force shows the capability of manipulating the enzyme active-site conformational state as well as the nascent-formed product's interaction with the active site of the enzyme, which impacts on the product release pathways. Specifically, we have identified there are two product releasing pathways, the solvation-mediated diffusion releasing pathway and the spilling-out releasing pathway. We have observed that the spilling-out pathway can be significantly perturbed by the oscillatory force manipulation. Our correlated interpretation of enzymatic conformational and reaction dynamics provides a new insight into the comprehensive understanding of the complex conformational dynamics evolved in an enzymatic reaction. Technically, we have also demonstrated a novel approach capable of unfolding an enzyme under an enzymatic reaction condition in real time, and furthermore, by using an oscillatory mechanical weak pN force to manipulate enzyme conformations, and the enzyme thermal fluctuation is fully maintained. The real-time in situ fluorescence probe at the enzymatic active site reports the active site conformational dynamics through each enzymatic reaction turnovers. PMID- 30481026 TI - Synthesis of Functionalized Chromene and Chroman Derivatives via Cesium Carbonate Promoted Formal [4 + 2] Annulation of 2'-Hydroxychalcones with Allenoates. AB - A new strategy has been established for the synthesis of functionalized chromene and chroman derivatives via a Cs2CO3-catalyzed domino addition of 2' hydroxychalcone derivatives with allenoates, which can serve as a general avenue for the construction of multi-replaced chromene derivatives. Chemoselectivity of this synthesis was found to depend on substitu-ents on substrates. Good to excellent yields were achieved under simple and mild conditions at the room temperature. PMID- 30481027 TI - Novel Tetrazole-containing Analogs of Itraconazole as Potent Anti-angiogenic Agents with Reduced CYP3A4 Inhibition. AB - Itraconazole has been found to possess potent anti-angiogenic activity, exhibiting promising antitumor activity in several human clinical studies. The wider use of itraconazole in the treatment of cancer, however, has been limited by its potent inhibition of the drug metabolizing enzyme CYP3A4. In an effort to eliminate the CYP3A4 inhibition while retaining its anti-angiogenic activity, we designed and synthesized a series of derivatives in which the 1, 2, 4-triazole ring is replaced with various azoles and non-azoles. Among these analogs, 15n with tetrazole in place of 1, 2, 4-triazole exhibited optimal inhibition of HUVEC proliferation with an IC50 of 73 nM without significant effect on CYP3A4 (EC50 > 20 uM). Similar to itraconazole, 15n induced Nieman-Pick C phenotype (NPC phenotype) and blocked AMPK/mTOR signaling. These results suggest that 15n is a promising angiogenesis inhibitor that can be used in combination with most other known anticancer drugs. PMID- 30481028 TI - Finding Order in the Disordered Hydration Shell of Rapidly Exchanging Water Molecules around the Heaviest Alkali Cs+ and Fr. AB - We report the structural and dynamical characterization of the intrinsically disordered hydration shells of the heaviest alkali ions, Cs+ and Fr+, obtained in ab initio molecular dynamics simulations. The knowledge of solvation and complexion properties of short-lived Fr+ is very limited and mostly based on extrapolations from the smaller alkali metal ions. To this end, we provide a critical insight into Fr+ solvation, demonstrating an extreme example of disordered solvation with no distinction between the ion-bound and solvent-bound states of water based on the ion-water distance. However, these two states are distinguished through distance-solvent rearrangement correlation, where either coordination number or electric field is employed to treat solvent rearrangement. Utilizing reaction rate theory, we find that the water exchange timescale for Fr+ (2.1-2.3 ps) is unexpectedly slower than for Cs+ (0.5-1.2 ps), because Fr+ experiences stronger nonequilibrium solvent effects. This study provides a new perspective on weak and hydrophobic solvation. PMID- 30481029 TI - Unique diversity of sting-related toxins based on transcriptomic and proteomic analysis of the jellyfish Cyanea capillata and Nemopilema nomurai (Cnidaria: Scyphozoa). AB - The scyphozoan jellyfish Cyanea capillata and Nemopilema nomurai are common blooming species in China. They possess heterogeneous nematocysts and produce various types of venom that can elicit diverse sting symptoms in humans. However, the differences in venom composition between the two species remain unclear. In this study, a combined transcriptomic and proteomic approach was used to identify and compare putative toxins in penetrant nematocysts isolated from C. capillata and N. nomurai. A total of 53 and 69 putative toxins were identified in C. capillata nematocyst venom (CnV) and N. nomurai nematocyst venom (NnV), respectively. These sting-related toxins from both CnV and NnV could be grouped into 10 functional categories, including proteinases, phospholipases, neurotoxins, cysteine-rich secretory proteins (CRISPs), lectins, pore-forming toxins (PFTs), protease inhibitors, ion channel inhibitors, insecticidal components and other toxins, but the constituent ratio of each toxin category varied between CnV and NnV. Metalloproteinases, proteases and pore-forming toxins were predominant in NnV, representing 27.5 %, 18.8 % and 8.7 % of the identified venom proteins, respectively, while phospholipases, neurotoxins and proteases were the top three identified venom proteins in CnV, accounting for 22.6 %, 17.0 % and 11.3 %, respectively. Our findings provide comprehensive information on the molecular diversity of toxins from two common blooming and stinging species of jellyfish in China. Furthermore, the results reveal a possible relationship between venom composition and sting consequences, guiding the development of effective treatments for different jellyfish stings. PMID- 30481030 TI - Locating Exceptional Points on Multidimensional Complex-Valued Potential Energy Surfaces. AB - We present a method for locating non-Hermitian degeneracies, called exceptional points (EPs), and minimum-energy EPs between molecular resonances using the complex absorbing potential equation-of-motion coupled cluster (CAP-EOM-CC) method. EPs are the complex-valued analogue of conical intersections (CIs) and have a similar impact on nonadiabatic processes between resonances as CIs have on non-radiative transitions between bound states. The use of analytic gradients enables applications to multidimensional problems. We demonstrate that the CAP EOM-CC method in the singles and doubles approximation (CAP-EOM-CCSD) yields crossings of the correct dimensionality. Results are presented for hydrogen cyanide and chloroethylene, for which the location of the crossings of anionic resonances is crucial for understanding the dissociative electron attachment process. PMID- 30481031 TI - TKO6: A Peptide Standard to Assess Interference for Unit-Resolved Isobaric Labeling Platforms. AB - Protein abundance profiling using isobaric labeling is a well-established quantitative mass spectrometry technique. However, ratio distortion resulting from co-isolated and co-fragmented ions - commonly referred to as interference - remains a drawback of this technique. Tribrid mass spectrometers, such as the Orbitrap Fusion and the Orbitrap Fusion Lumos with a triple mass analyzer configuration, facilitate methods (namely SPS-MS3) that can help alleviate interference. However, few standards are available to measure interference and thereby aid in method development. Here we introduce the TKO6 standard that assesses ion interference and is designed specifically for data acquired at low (unit) mass resolution. We use TKO6 to compare interference in MS2 versus MS3 based quantitation methods, data acquisition methods of different lengths, and ion trap-based TMT reporter ion analysis (IT-MS3) with conventional Orbitrap based analysis (OT-MS3). We show that the TKO6 standard is a valuable tool for assessing quantification accuracy in isobaric tag-based analyses. PMID- 30481032 TI - Synthesis of Cyclopenta[ b]piperazinones via an Azaoxyallyl Cation. AB - A new and efficient reaction sequence between 2-furylcarbinols, anilines, and alpha-haloamides has been developed to afford highly functionalized cyclopenta[ b]piperazinones. This transformation was accomplished through an aza-Piancatelli cyclization/azaoxyallyl cation trapping with a complete control of the diastereoselectivity. PMID- 30481033 TI - Organocatalytic Enantioselective Synthesis of alpha-Fluoro-beta-amino Acid Derivatives. AB - Asymmetric cyclocondensation of N-sulfonylimines with fluoroacetic acid promoted by isothiourea catalyst HBTM-2 generates 3-fluoro-beta-lactams with high enantio- and diastereoselectivity. These reactive compounds are opened with alcohols or amines to produce the corresponding alpha-fluoro-beta-amino acid derivatives in moderate yields. PMID- 30481034 TI - Data-independent acquisition mass spectrometry to quantify protein levels in FFPE tumor biopsies for molecular diagnostics. AB - Mass spectrometry-based protein quantitation is currently used to measure therapeutically relevant protein biomarkers in CAP/CLIA setting to predict likely responses of known therapies. Selected reaction monitoring (SRM) is the method of choice due to its outstanding analytical performance. However, data-independent acquisition (DIA) is now emerging as a proteome-scale clinical assay. We evaluated the ability of DIA to profile the patient-specific proteomes of sample limited tumor biopsies and to quantify proteins of interest in a targeted fashion using formalin-fixed, paraffin-embedded (FFPE) tumor biopsies (n=12) selected from our clinical laboratory. DIA analysis on the tumor biopsies provided 3,713 quantifiable proteins including actionable biomarkers currently in clinical use, successfully separated two gastric cancers from colorectal cancer specimen solely based on global proteomic profiles, and identified subtype-specific proteins with prognostic or diagnostic value. We demonstrate the potential use of DIA-based quantitation to inform therapeutic decision-making using TUBB3, for which clinical cut-off expression levels have been established by SRM. Comparative analysis of DIA-based proteomic profiles and mRNA expression levels found positively and negatively correlated protein-gene pairs, a finding consistent with previously reported results from fresh-frozen tumor tissues. PMID- 30481035 TI - A Concerted Synchronous [2+2] Cycloreversion Repair Catalyzed by Two Electrons. AB - The current understanding of photoenzyme catalyzed [2+2] cycloreversion repair of cyclobutane pyramidine dimer (CPD) is that a photogenerated electron from the photolyase enzyme catalyzes the repair. This one-electron catalyzed repair is a sequential two-bond breaking cycloreversion of the cyclobutane center and involves a negative ion radical as an intermediate. Here, by resonantly capturing two exogenous low energy electrons (LEEs) into the molecular field of a CPD, we show that the concerted synchronous two-bond breaking reaction, which is intermediate-free, and hence a safe repair, is feasible through two-electron catalysis. PMID- 30481036 TI - Femtosecond direct laser induced assembly of monolayer of Gold Nanostructures with tunable surface plasmon resonance and high performance LSPR and SERS Sensing. AB - We show Femtosecond direct laser induced assembly of gold nanostructures with plasmon resonance band variable as a function of laser irradiation in a wide range of visible wavelengths. A system of 2-photon lithography is used to achieve site-selectively controlled dewetting of thin gold film into nanostructures where size and shape are highly depending on the laser power. Simultaneous measurements of Localized Surface Plasmon Resonance (LSPR) and Surface Enhanced Raman Scattering (SERS) in the presence of various concentrations of trans-1,2-Bis(4 pyridyl) ethylene (BPE) as target molecule are performed in order to highlight the relationship between structural dimensions, plasmonic effect, and detection activity. The resulting gold NPs exhibit high sensitivity as both LSPR and SERS sensors and allow the detection of picomolar concentrations of BPE with a SERS Enhancement Factor (SEF) of 1.33*109 and a linear detection range between 10-3 and 10-12 M. PMID- 30481037 TI - Conductance Spectroscopy of Exfoliated Thin Flakes of NbxBi2Se3. AB - We study unconventional superconductivity in exfoliated single crystals of a promising 3D topological superconductor candidate, Nb-doped Bi2Se3 through differential conductance spectroscopy and magneto-transport. The strong anisotropy of the critical field along the out- of-plane direction suggests that the thin exfoliated flakes are in the quasi-2D limit. Normal metal-superconductor (NS) contacts with either high or low transparencies made by deposit- ing gold leads onto Nb-doped Bi2Se3 flakes both show significant enhancement in zero bias conductance and coherence dips at the superconducting energy gap. Such behavior is inconsistent with conventional Blonder-Tinkham-Klapwijk theory. Instead, we discuss how our results are consistent with p-wave pairing symmetry, supporting the possibility of topological superconductivity in Nb-doped Bi2Se3. PMID- 30481038 TI - Visible-Light Photocatalyzed Deoxygenation of N-Heterocyclic N-Oxides. AB - A scalable and operationally simple method is described that allows for the chemoselective deoxygenation of a wide range of N-heterocyclic N-oxides (a total of 36 examples). This visible-light-induced protocol features the use of only commercially available reagents, room-temperature conditions, and unprecedented chemoselective removal of the oxygen atom in a quinoline N-oxide in the presence of a pyridine N-oxide in the same molecule through the judicious selection of a photocatalyst. PMID- 30481039 TI - Palladium-Catalyzed Chemoselective Protodecarboxylation of Polyenoic Acids. AB - Conditions for the first palladium-catalyzed chemoselective protodecarboxylation of polyenoic acids to give the desired polyenes in good yields are presented. The reactions proceed under mild conditions using either a Pd(0) or Pd(II) catalyst and tolerate a variety of aryl and aliphatic substitutions. Unique aspects of the reaction include the requirement of phosphines, water, and a polyene adjacent to the carboxylic acid. PMID- 30481040 TI - Nonlinear Holographic All-Dielectric Metasurfaces. AB - Nonlinear holographic metasurfaces have been intensively studied due to their potentials in practical applications. So far, nonlinear holographic metasurfaces have only been realized with plasmonic nanoantennas, suffering from high absorption loss and low damage threshold. Herein we propose and experimentally demonstrate a novel mechanism for nonlinear holographic metasurfaces. In contrast with conventional studies, the all-dielectric metasurface is composed of C-shaped Si nanoantennas. The incident laser is enhanced by their fundamental resonance, whereas the generated third-harmonic generation (THG) signals are redistributed to the air gap region via the higher order resonance, significantly reducing the absorption loss at short wavelength and resulting in an enhancement factor as high as 230. After introducing abrupt phase changes from 0 to 2pi to the C elements, high-efficiency cyan and blue THG holograms have been experimentally generated with the Si metasurface for the very first time. This research shall shed light on the advances of nonlinear all-dielectric metasurfaces. PMID- 30481041 TI - DMAKO-20 as a new multi-target anticancer prodrug activated by the tumor specific CYP1B1 enzyme. AB - In order to reduce the pervasive toxicity of natural shikonin, alkannin and their synthetic analogues and to enhance the selectivity of these chemotherapeutics towards cancer cells, a novel 5,8-dimethyl alkannin oxime derivative (DMAKO-20) was designed, synthesized and evaluated for its strong antitumor activity both in vitro and in vivo. It showed potent growth inhibitory effects against HCT-15, HCT 116 and K562 cells (IC50 < 1MUM), moderate anti-proliferative activity towards MDA-MB-231, HepG2, PANC, Bel7402 and MGC803 cancer cells (IC50 < 10MUM), and was nontoxic to the human normal VEC and HSF cells. In vivo efficacy studies demonstrated that DMAKO-20 (10 mg/kg, i.v. on every the other day, 8 times in 14 days) resulted in 59.3% reduction in HCT-15 xenograft volume. It was as effective as the toxic antimetabolite 5-FU but revealed neither toxicity nor death in mice. The mechanistic investigations indicated that DMAKO-20 underwent the tumor specific CYP1B1-catalyzed bioactivation to afford nitric oxide and active naphthoquinone mono-oximes, which exhibited combined anticancer effects. It was defined as a representative of the "Multi-target Anticancer Prodrugs Activated by Specific Enzymes in cancer cells". The produced active metabolites exerted anticancer effects by the direct nucleophilic alkylation and the induction of the apoptosis of cancer cells through activation of the mitochondrial pathway. The discovery of DMAKO-20 and the illustration of its molecular mechanisms may provide a new strategy to overcome the non-selective toxicity of the current chemotherapeutics. PMID- 30481042 TI - Short-term low calorie diet remodels skeletal muscle lipid profile and metabolic gene expression in obese adults. AB - Diet intervention in obese adults is the first strategy to induce weight loss and to improve insulin sensitivity. We hypothesized that improvements in insulin sensitivity after weight loss from a short-term dietary intervention tracks with alterations in expression of metabolic genes and abundance of specific lipid species. Eight obese, insulin resistant, non-diabetic adults were recruited to participate in a three-week low calorie diet intervention cohort study (1,000 kcal/day). Fasting blood samples and vastus lateralis skeletal muscle biopsies were obtained before and after the dietary intervention. Clinical chemistry and measures of insulin sensitivity were determined. Unbiased microarray gene expression and targeted lipidomic analysis of skeletal muscle was performed. Body weight was reduced, insulin sensitivity (HOMA-IR) was enhanced, and serum insulin concentration and blood lipid (triglyceride, cholesterol, LDL and HDL) levels were improved after dietary intervention. Gene set enrichment analysis of skeletal muscle revealed that oxidative phosphorylation was among the most enriched pathways identified after dietary intervention. mRNA expression of PDK4 and MLYCD increased, while SCD1 decreased in skeletal muscle after dietary intervention. Dietary intervention altered the intramuscular lipid profile of skeletal muscle, with changes in content of phosphatidylcholine and triglyceride species among the pronounced.Short-term diet intervention and weight loss in obese adults alters metabolic gene expression and reduces specific phosphatidylcholine and triglyceride species in skeletal muscle, concomitant with improvements in clinical outcomes and enhanced insulin sensitivity. PMID- 30481043 TI - Probing Mitochondrial Permeability Transition Pore Activity in Nucleated Cells and Platelets by High-Throughput Screening Assays Suggests Involvement of Protein Phosphatase 2B in Mitochondrial Dynamics. AB - Mitochondrial permeability transition pore (mPTP) formation is well documented in isolated mitochondria. However, convincing detection of mPTP in whole cells remains elusive. In this study, we describe a high-throughput assay for Ca2+ activated mPTP opening in platelets using HyperCyt flow cytometry. In addition, we demonstrate that in several nucleated cells, using multiple approaches, the detection of cyclophilin D-dependent mPTP opening is highly challenging. Results with the mitochondrial-targeted Ca2+-sensing green fluorescent protein (mito Case12) suggest the involvement of protein phosphatase 2B (PP2B; calcineurin) in regulating mitochondrial dynamics. Our results highlight the danger of relying on cyclosporine A alone as a pharmacological tool, and the need for comprehensive studies of mPTP in the cell. PMID- 30481044 TI - Clinically Meaningful Improvement After Treatment of Cartilage Defects of the Knee With Osteochondral Grafts. AB - BACKGROUND:: Mosaicplasty and fresh osteochondral allograft transplantation (OCA) are popular cartilage restoration techniques that involve the single-stage implantation of viable, mature hyaline cartilage-bone dowels into chondral lesions of the knee. Recently, there has been greater focus on what represents a clinically relevant change in outcomes reporting, and commonly applied metrics for measuring clinical significance include the minimal clinically important difference (MCID) and substantial clinical benefit (SCB). PURPOSE:: To define the MCID and SCB after mosaicplasty or OCA for the International Knee Documentation Committee (IKDC) subjective form and Knee Outcome Survey-Activities of Daily Living (KOS-ADL) and to determine patient factors that are predictive of achieving the MCID and SCB after mosaicplasty or OCA. STUDY DESIGN:: Cohort study (diagnosis); Level of evidence, 3. METHODS:: An institutional cartilage registry was reviewed to identify patients who underwent mosaicplasty or OCA. The decision to perform either mosaicplasty or OCA was generally based on chondral defect size. The IKDC and KOS-ADL were administered preoperatively and at a minimum of 2 years postoperatively. Patient responses to the outcome measures were aggregated, and the MCID and SCB of these outcome scores were calculated with anchor-based methods. Multivariate analysis adjusted for age and sex was performed to identify patient factors predictive of achieving the MCID and SCB. RESULTS:: Of the 372 eligible patients, 151 (41%) were lost to follow-up, 46 (12%) had incomplete preoperative outcome scores and 2 were treated with OCA of the tibia and therefore excluded. In total, 173 knees were analyzed (n = 173 patients; mean age, 33.0 years; 37% female). Seventy-five (43%) and 98 (57%) knees were treated with mosaicplasty and OCA, respectively. The mean +/- SD MCIDs for the IKDC and KOS-ADL were 17 +/- 3.9 and 10 +/- 3.7, respectively. The SCBs for the IKDC and KOS-ADL were 30 +/- 6.9 and 17 +/- 3.9, respectively. Univariate analysis demonstrated no association between procedure (mosaicplasty or OCA) and likelihood of achieving the MCID or SCB. In the multivariate analysis, lower preoperative IKDC and KOS-ADL scores, higher preoperative Marx Activity Rating Scale scores, lower preoperative 36-Item Short Form Health Survey pain scores, and a history of <=1 prior ipsilateral knee surgical procedure were predictive of achieving the MCID and/or SCB. CONCLUSION:: These values can be used to define a clinically meaningful improvement for future outcome studies. For surgeons considering mosaicplasty or OCA for their patients, these results can help guide clinical decision making and manage patient expectations before surgery. PMID- 30481045 TI - Predictors of 5-Year Citation Rate in the Orthopaedic Sports Medicine Literature. AB - BACKGROUND:: The citation rate of a research published article is an indicator of its quality and impact and contributes to the journal's impact factor. Within the orthopaedic sports medicine literature, predictors of citation rates have not been previously described. PURPOSE:: To identify characteristics of published articles that predict 5-year citation rates of studies in the orthopaedic sports medicine literature. STUDY DESIGN:: Cross-sectional study. METHODS:: Research articles published in The American Journal of Sports Medicine (AJSM), Arthroscopy: The Journal of Arthroscopic and Related Surgery, and Knee Surgery, Sports Traumatology, Arthroscopy (KSSTA) from 2012 were analyzed. Extracted characteristics of published articles included journal, author number, origin of study, first author degree, subject of study, study type, sample size, number of references and institutions, conflicts of interest, level of evidence, and 5-year citation rates. Multivariate logistic regression was used to determine predictors of greater than the mean number of citations at 5 years. RESULTS:: A total of 825 published articles ( AJSM, n = 313; Arthroscopy, n = 173; KSSTA, n = 339) were included in the final analysis. The mean number of 5-year citations was 23.2 (95% CI, 21.6-24.9; range, 1.0-260.0). AJSM had a significantly greater citation rate (32.4) than Arthroscopy (21.7) and KSSTA (15.2) ( P < .001 for both). Arthroscopy had a greater citation rate than KSSTA ( P = .008). Independent predictors of greater than the mean number of citations at 5 years were published articles in AJSM (odds ratio [OR], 5.17; 95% CI, 2.81-9.52; P < .0001), published articles of North American origin (OR, 1.79; 95% CI, 1.25-2.58; P = .002), and published articles regarding the hip (OR, 2.68; 95% CI, 1.08-6.67; P = .035). CONCLUSION:: Published articles in AJSM, those from North America, and those examining the hip were independent predictors of greater citation rates at 5 years. PMID- 30481046 TI - Hip Arthroscopic Surgery in Borderline Developmental Dysplastic Hips: A Systematic Review. AB - BACKGROUND:: It remains controversial whether hip arthroscopic surgery should be applied to patients with a borderline developmental dysplastic hip (BDDH). PURPOSE:: To review the outcomes of hip arthroscopic surgery for a BDDH and which factors influence these outcomes. STUDY DESIGN:: Systematic review. METHODS:: PubMed, Embase, and the Cochrane Library were searched through March 2018 for studies reporting the outcomes of primary hip arthroscopic surgery in patients with a BDDH. Inclusion in the review was based on the definition of a BDDH, patient-reported outcomes, and duration of follow-up. The primary outcome was the modified Harris Hip Score (mHHS). The failure rate, visual analog scale, satisfaction score, and patient-reported outcomes such as the Hip disability and Osteoarthritis Outcome Score were defined as secondary outcomes. RESULTS:: Nine studies with 425 patients who underwent hip arthroscopic surgery were included in this review. The mean follow-up times ranged from 25.4 to 28.8 months across the studies. A significant improvement was obtained in the mHHS, with a mean score of 61.8 preoperatively to 82.8 postoperatively; all other patient-reported outcomes also improved significantly, except the 12-Item Short Form Health Survey mental component summary. The overall failure rate was 14.1%, and the mean reoperation rate was 8.5%. The rate of conversion to total hip arthroplasty ranged from 4.4% to 26.0%, and the rate of conversion to periacetabular osteotomy was 4.0%. Combined defects such as cartilage damage, hip osteoarthritis, ligamentum teres tears, and femoroacetabular impingement could influence the outcomes after arthroscopic surgery in BDDHs. CONCLUSION:: Hip arthroscopic surgery was demonstrated to be a promising approach for BDDHs, but the outcomes could be influenced by multiple risk factors. A higher level of evidence is still needed to support current findings. PMID- 30481047 TI - Comparison of F18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography and Dynamic Contrast-Enhanced Magnetic Resonance Imaging as Markers of Graft Viability in Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND:: F18-fluorodeoxyglucose positron emission tomography/computed tomography (F18-FDG PET/CT) can be used to assess changes in the metabolism of an anterior cruciate ligament (ACL) graft as it is undergoing "ligamentization." Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is the preferred modality for noninvasive assessment of graft structure and graft vascularity. PURPOSE:: To compare the use of F18-FDG PET/CT and DCE-MRI to assess ligamentization within the ACL graft and correlate the results with clinical tests. STUDY DESIGN:: Case series; Level of evidence, 4. METHODS:: Among 30 recruited patients, 27 patients (3 females and 24 males) completed 2 follow-up assessments at a mean of 125 +/- 22 days and 259 +/- 38 days after arthroscopic ACL reconstruction. At both assessments, anterior drawer test, Lachman test, and Lysholm scoring (LS) were conducted. Images from F18-FDG PET/CT and MRI were analyzed qualitatively and quantitatively (maximum standardized uptake value [SUVmax], SUVmax ratio to the contralateral side [SUVmax CL], normalized enhancement [NE]) in 3 zones: femoral, intra-articular (IA), and tibial. Of the 27 recruited patients, 1 patient had reinjury due to a fall. Therefore, 26 patients were considered for the final analysis. RESULTS:: A significant improvement ( P = .0001) was found in median LS, from 78.5 (range, 62-90) to 94.5 (range, 84-100), at the second follow-up. All grafts were found to be viable on PET/CT and vascularized on MRI. All grafts were seen as continuous on MRI, with exception of 1 graft at the second follow-up. Dynamic MRI identified single vessel supply to all of the grafts at the first follow-up and multiple-vessel supply in 10 patients at the second follow-up. Reduction in the median SUVmax, SUVmax CL, and NE at second follow-up was seen in all 3 zones. Only SUVmax CL in the IA zone showed a significant reduction ( P = .032); patients with excellent LS at the second follow-up showed significantly higher reduction ( P = .005) than patients with good LS. NE in the IA zone was correlated (0.39; P = .048) with LS only at the first follow-up, whereas SUVmax CL (-0.52; P = .006) and SUVmax ( 0.49, P = .010) in the IA zone negatively correlated with LS at the second follow up only. No correlation was observed between PET/CT and MRI parameters. CONCLUSION:: Glucose metabolism and vascularity in the graft tissue can be used to assess ligamentization of ACL graft. A viable and vascularized graft at first follow-up is associated with good to excellent final outcome, regardless of LS at this stage. Since no correlation was observed between PET/CT and MRI parameters, they may be assessing different domains of the same process. Higher NE in the IA zone at the first follow-up and lower SUVmax CL in the same region at second follow-up are associated with better outcome. PMID- 30481048 TI - Photopolymerizable Injectable Cartilage Mimetic Hydrogel for the Treatment of Focal Chondral Lesions: A Proof of Concept Study in a Rabbit Animal Model. AB - BACKGROUND:: In this study, we investigate the in vitro and in vivo chondrogenic capacity of a novel photopolymerizable cartilage mimetic hydrogel, enhanced with extracellular matrix analogs, for cartilage regeneration. PURPOSE:: To (1) determine whether mesenchymal stem cells (MSCs) embedded in a novel cartilage mimetic hydrogel support in vitro chondrogenesis, (2) demonstrate that the proposed hydrogel can be delivered in situ in a critical chondral defect in a rabbit model, and (3) determine whether the hydrogel with or without MSCs supports in vivo chondrogenesis in a critical chondral defect. STUDY DESIGN:: Controlled laboratory study. METHODS:: Rabbit bone marrow-derived MSCs were isolated, expanded, encapsulated in the hydrogel, and cultured in chondrogenic differentiation medium for 9 weeks. Compressive modulus was evaluated at day 1 and at weeks 3, 6, and 9. Chondrogenic differentiation was investigated via quantitative polymerase reaction, safranin-O staining, and immunofluorescence. In vivo, a 3 mm-wide * 2-mm-deep chondral defect was created bilaterally on the knee trochlea of 10 rabbits. Each animal had 1 defect randomly assigned to be treated with hydrogel with or without MSCs, and the contralateral knee was left untreated. Hence, each rabbit served as its own matched control. Three groups were established: group A, hydrogel (n = 5); group B, hydrogel with MSCs (n = 5); and group C, control (n = 10). Repair tissue was evaluated at 6 months after intervention. RESULTS:: In vitro, chondrogenesis and the degradable behavior of the hydrogel by MSCs were confirmed. In vivo, the hydrogel could be delivered intraoperatively in a sterile manner. Overall, the hydrogel group had the highest scores on the modified O'Driscoll scoring system (group A, 17.4 +/- 4.7; group B, 13 +/- 3; group C, 16.7 +/- 2.9) ( P = .11) and showed higher safranin-O staining (group A, 49.4% +/- 20%; group B, 25.8% +/- 16.4%; group C, 36.9% +/- 25.2%) ( P = .27), although significance was not detected for either parameter. CONCLUSION:: This study provides the first evidence of the ability to photopolymerize this novel hydrogel in situ and assess its ability to provide chondrogenic cues for cartilage repair in a small animal model. In vitro chondrogenesis was evident when MSCs were encapsulated in the hydrogel. CLINICAL RELEVANCE:: Cartilage mimetic hydrogel may offer a tissue engineering approach for the treatment of osteochondral lesions. PMID- 30481049 TI - Quality of Cryopreserved Peripheral Blood Mononuclear Cells Recovered from the Hepatitis/AIDS Biobank. AB - BACKGROUND: Peripheral blood mononuclear cells (PBMCs) count among the most important samples in a biobank, and the quality of cryopreserved PBMCs is crucial for further research. This study evaluated the quality of PBMCs recovered from the Beijing Capital Medical University Hepatitis/AIDS Biobank after 2-11 years of cryopreservation. MATERIALS AND METHODS: A total of 87 PBMC samples with different cryopreservation times (2006, 2007, 2013, and 2015) were thawed, and the cell number and cell viability were determined by acridine orange/propidium iodide staining. Then, DNA was extracted from the cryopreserved PBMCs and assessed for quantity on an ultramicrospectrophotometer. RESULTS: The median cell viability rate was 73.58% for the 87 PBMC samples cryopreserved for 2-11 years. A rate of 80.98% was obtained for PBMCs collected in 2006, a value higher than those of other cryopreservation times (2007, 2013, and 2015). Similarly, more live and total cells were obtained in PBMCs cryopreserved since 2006 compared with other cryopreservation times (since 2007, 2013, and 2015, respectively). Nonparametric Spearman correlation analysis indicated positive associations of cell viability with live (r = 0.578, p < 0.0001) and total (r = 0.338, p = 0.0003) cell numbers. Meanwhile, DNA amounts increased with total cell number. Statistical analysis showed that 3.69 MUg DNA was obtained from ~1 * 106 cells. CONCLUSION: Cryopreservation time (2-11 years) has negligible effects on the quality of PBMCs. Meanwhile, the cell number is positively correlated with cell viability. PMID- 30481050 TI - Female Soccer Players With Anterior Cruciate Ligament Reconstruction Have a Higher Risk of New Knee Injuries and Quit Soccer to a Higher Degree Than Knee Healthy Controls. AB - BACKGROUND:: Many patients with anterior cruciate ligament (ACL) reconstruction who return to sport suffer new ACL injuries or quit sports soon after returning. PURPOSE:: To prospectively follow a cohort of female soccer players with primary unilateral ACL reconstruction and matched knee-healthy controls from the same soccer teams to compare (1) the rate of new traumatic and nontraumatic knee injuries and other injuries, (2) the proportion of players who quit soccer, and (3) player-reported activity level and satisfaction with activity level and knee function. STUDY DESIGN:: Cohort study; Level of evidence, 2. METHODS:: A total of 117 active female soccer players (mean +/- SD age, 19.9 +/- 2.5 years) 18.9 +/- 8.7 months after ACL reconstruction and 119 knee-healthy female soccer players (19.5 +/- 2.5 years) matched from the same teams were prospectively followed for 2 years for new knee injuries, other injuries, soccer playing level, activity level according to the Tegner Activity Scale, and satisfaction with activity level and knee function. RESULTS:: Players with ACL reconstruction had a higher rate of new ACL injuries (n = 29 vs 8; 19 vs 4 per 100 player years; rate ratio [RR], 4.82; 95% CI, 2.20-10.54; P < .001), other traumatic knee injuries (29 vs 16 per 100 player years; RR, 1.84; 95% CI, 1.16-2.93; P < .01), and nontraumatic knee injuries (33 vs 9 per 100 player years; RR, 3.62; 95% CI, 2.11-6.21; P < .001) as compared with controls. There was no difference in the rate of other (not knee) injuries (43 vs 48 per 100 player years; RR, 0.90; 95% CI, 0.65-1.23; P = .494). During the 2-year follow-up, 72 (62%) players with ACL reconstruction quit soccer, as opposed to 43 (36%) controls ( P = .001). The median Tegner Activity Scale score decreased in both groups ( P < .001) but more for the ACL reconstructed group ( P < .015). CONCLUSION:: Female soccer players with ACL reconstruction had nearly a 5-fold-higher rate of new ACL injuries and a 2- to 4 fold-higher rate of other new knee injuries, quit soccer to a higher degree, and reduced their activity level to a greater extent as compared with knee-healthy controls. PMID- 30481051 TI - Detection and Molecular Characterization of Methicillin-Resistant Staphylococcus aureus Isolated from Bulk Tank Milk of Cows, Sheep, and Goats. AB - This study is aimed at detecting and characterizing methicillin-resistant Staphylococcus aureus (MRSA) from bulk tank milk samples of cows, sheep, and goats collected from dairy farms in the Czech Republic. All MRSA isolates were identified using PCR detection of the Staphylococcus aureus-specific fragment SA442 and mecA gene. The staphylococcal chromosomal cassettes mec (SCCmec), spa, and multilocus sequence types (MLST) were determined. The presence of genes encoding enterotoxins (ses), Panton-Valentine leukocidin (pvl), exfoliative toxins A, B (eta, etb), and toxic shock syndrome toxin (tst) were assessed. To differentiate human and animal origin, the presence of staphylokinase (sak) gene, phiSa3 prophage, and susceptibility to tetracycline was tested. Out of 49 bulk tank milk samples examined, 14 (28.6%) were MRSA-positive. Eleven positive samples came from cow's milk (38%) and the remaining three from goat's milk (33%). All samples of ewe's milk were negative. In MRSA isolates three sequence types containing seven spa types were identified. Twelve isolates (85.7%) belonged to ST398 spa types t011/SCCmec IVa, t011/SCCmec V, t034/SCCmec V, t1456/SCCmec IVa, t1255/SCCmec V, and t2346/SCCmec V. Another two isolates belonged to ST5/t3598/SCCmec IVa and ST8/t064/SCCmec IVNT. In six isolates, one or more ses genes (seb, sed, seg, sei, and sej) were confirmed. One isolate from cow's milk harbored the tst gene. Another two isolates (ST398/t1456/SCCmec IVa and ST5/t3598/SCCmec IVa) harbored the sak gene and phiSa3 prophage, and the latter was the only tetracycline-susceptible isolate in this study. However, none of the isolates was positive for pvl or eta, etb. These results suggest that there is the wide geographical spread of ST398 across different regions of the Czech Republic with no host preference among dairy cattle and goats. Therefore, when evaluating the occupational and foodborne risks, MRSA carriage and infection should be taken into account. PMID- 30481052 TI - miR-3666 inhibits lung cancer cell proliferation, migration and invasion by targeting BPTF. AB - Our previous study suggested that BPTF overexpression was observed in lung adenocarcinoma, and closely associated with advanced clinical stage, more metastatic lymph nodes, present distant metastasis, low histological grade and poor prognosis. Down-regulation of BPTF inhibited lung adenocarcinoma cells proliferation and promoted lung adenocarcinoma cells apoptosis. The purpose of this study is to identify valuable microRNAs (miRNAs), which target BPTF to modulate lung adenocarcinoma cells proliferation. In our results, we found that miR-3666 was notably reduced in lung adenocarcinoma tissues and cell lines. By using miR-3666 mimics, cells proliferation, migration, and invasion were suppressed by miR-3666 overexpression, while were enhanced by reduction of miR 3666. Moreover, bioinformatics analysis using Targetscan database and miRanda software suggested a putative targeting site in BPTF 3'-UTR. Furthermore, we verified that miR-3666 directly targeted to 3'-UTR of BPTF by luciferase reporter assay. Overexpression of miR-3666 negatively regulated protein expression of BPTF by western blot. Finally, PI3K/AKT and EMT was demonstrated to be inhibited by miR-3666 overexpression in lung cancer cells. In conclusion, our data indicate that miR-3666 might play an essential role in cell proliferation, migration and invasion by targeting BPTF and partly inhibited PI3K/AKT and EMT signaling pathways in human lung cancers. PMID- 30481053 TI - Hypothesis: Muon Radiation Dose and Marine Megafaunal Extinction at the End Pliocene Supernova. AB - Considerable data and analysis support the detection of one or more supernovae (SNe) at a distance of about 50 pc, ~2.6 million years ago. This is possibly related to the extinction event around that time and is a member of a series of explosions that formed the Local Bubble in the interstellar medium. We build on previous work, and propagate the muon flux from SN-initiated cosmic rays from the surface to the depths of the ocean. We find that the radiation dose from the muons will exceed the total present surface dose from all sources at depths up to 1 km and will persist for at least the lifetime of marine megafauna. It is reasonable to hypothesize that this increase in radiation load may have contributed to a newly documented marine megafaunal extinction at that time. PMID- 30481054 TI - Salmonella Prevalence and Antimicrobial Drug Resistance in Dual-Purpose Cattle Operations in the Eastern Region of Zulia State, Venezuela. AB - To evaluate the Salmonella prevalence and its antimicrobial susceptibility in dual-purpose cattle farms, fecal (n = 3964; from cows and calves) and environmental samples (n = 334; personnel, feed, and water sources) were collected over a 1-year period at six farms in the eastern region of Zulia State, Venezuela. Salmonella detection was carried out using standard microbiological culture methods. From 453 isolated Salmonella, antimicrobial susceptibility was tested using a panel of 10 antibiotics by the disk diffusion test method. Overall, the prevalence of Salmonella at the farm was 10.4% (n = 410/3964), being positive for Salmonella in at least in one sample. Salmonella was found in 11% (222/2009) of cows and 9.7% (188/1937) of calves. The prevalence of environmental samples was 10.78% (36/334), where water sources and milkers' hands showed higher occurrence (p < 0.01). Among the Salmonella isolates recovered, 10.2% displayed resistance to tetracyclines, aminoglycosides, cephalosporins, penicillins, sulfonamides, quinolones and fluoroquinolones. Overall, multidrug resistance was 9.1%, and the most common combination was cephalothin-gentamicin-tetracycline, followed by gentamicin-norfloxacin-tetracycline. Over the course of this study, it was found that 100% of the evaluated farms had cattle shedding Salmonella and that the surrounding farm environments were contaminated, which contributed to the cycling of the pathogen at the farms and further contamination of the milk. However, only a low percentage of isolates exhibited significant antimicrobial resistance. PMID- 30481055 TI - Functional BCL-2 rs2279115 Promoter Noncoding Variant Contributes to Glioma Predisposition, Especially in Males. AB - As a crucial oncogene, B cell lymphoma-2 (BCL-2) could promote cancer cell survival by inhibiting apoptosis via suppressing activation of proapoptotic proteins, such as BAX and BAK. There is a functional rs2279115 genetic polymorphism locating in BCL-2 promoter and deregulating BCL-2 expression. However, it is still largely undefined how BCL-2 rs2279115 promoter noncoding genetic variant is involved in glioma development. We examined the association between BCL-2 rs2279115 and glioma risk using a case-control approach. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression adjusted by age and sex. Our results demonstrated that BCL-2 rs2279115 was significantly associated with glioma risk. The odd of individuals harboring A allele (CA + AA genotype) was 0.50 (95% CI = 0.39-0.64, p = 1.0 * 10-7) compared with CC genotype carriers. Stratification analyses by sex elucidated that BCL-2 rs2279115 was significantly associated with glioma risk in males (OR = 0.41, 95% CI = 0.30-0.58, p = 1.0 * 10-7), but not in females (p > 0.05). In summary, our results indicate that the functional BCL-2 rs2279115 genetic variant contributes to glioma predisposition and suggest prevalent involvement of regulatory genetic variations in glioma development. PMID- 30481056 TI - DNA Repair Signaling of Huntingtin: The Next Link Between Late-Onset Neurodegenerative Disease and Oxidative DNA Damage. AB - A new hypothesis for the mechanism of Huntington's disease (HD) is driven by a small molecule lead that may connect age-associated reactive oxygen stress, oxidative DNA damage, and mitochondrial dysfunction. These pathways have also recently been defined in genome-wide association studies of cytosine-adenine guanine-expansion polyglutamine neurodegenerative diseases, including HD and the spinocerebellar ataxias. We discuss how N6-furfuryladenine (N6FFA) nucleotide salvage and role as a kinase neosubstrate may have important mechanistic implications for both HD and familial Parkinson's disease. N6FFA highlights a mechanism of how energy dysregulation and protein misfolding in neurodegeneration may be the effect of age-associated reactive oxygen species damage to DNA and part of a feedback loop augmenting with aging. PMID- 30481057 TI - Underappreciated Roles of the Translocase of the Outer and Inner Mitochondrial Membrane Protein Complexes in Human Disease. AB - Mitochondria are critical for cellular survival, and for their proper functioning, translocation of ~1500 proteins across the mitochondrial membranes is required. The translocase of the outer (TOMM) and inner mitochondrial membrane (TIMM) complexes are major components of this translocation machinery. Through specific processes, preproteins and other molecules are imported, translocated, and directed to specific mitochondrial compartments for their function. In this study, we review the association of subunits of these complexes with human disease. Pathogenic mutations have been identified in the TIMM8A (DDP) and DNAJC19 (TIMM14) genes and are linked to Mohr-Tranebjaerg syndrome and dilated cardiomyopathy syndrome (with and without ataxia), respectively. Polymorphisms in TOMM40 have been associated with Alzheimer's disease, frontotemporal lobar degeneration, Parkinson's disease with dementia, dementia with Lewy bodies, nonpathological cognitive aging, and various cardiovascular-related traits. Furthermore, reduced protein expression levels of several complex subunits have been associated with Parkinson's disease, Meniere's disease, and cardiovascular disorders. However, increased mRNA and protein levels of complex subunits are found in cancers. This review highlights the importance of the mitochondrial import machinery in human disease and stresses the need for further studies. Ultimately, this knowledge may prove to be critical for the development of therapeutic modalities for these conditions. PMID- 30481058 TI - Antimicrobial Resistance in Fecal Escherichia coli and Salmonella enterica from Dairy Calves: A Systematic Review. AB - The discovery of antibiotics brought with it many advances in the health and well being of humans and animals; however, in recent years development of antimicrobial resistance (AMR) has increasingly become a concern. Much of the antibiotic use on dairy farms is for disease management in mature cattle, and AMR in fecal organisms is relatively rare in this group. However, young dairy calves often carry high levels of AMR in their fecal Escherichia coli and Salmonella enterica, which could provide a potential reservoir of AMR genes on dairy farms. To develop practical and effective antibiotic stewardship policies for dairy calf rearing, it is vital to have a solid understanding of the current state of knowledge regarding AMR in these animals. A systematic review process was used to summarize the current scientific literature regarding AMR in fecal S. enterica and E. coli and associations between management practices and AMR prevalence in dairy calves in the United States and Canada. Seven online databases were searched for literature published from 1997 to 2018. Multiple studies indicated an association between preweaned calves and increased risk of fecal shedding of resistant bacteria, compared to other animal groups on dairy farms. There also was evidence, although less consistent, of an impact of antibiotic treatment, antibiotic-containing milk replacer feeding, and feeding nonsalable or waste milk (WM) on the presence of AMR bacteria. Overall, the research summarized in this systematic review highlights the need for continued research on the impact of management practices, including antibiotic use, WM feeding, and disease prevention practices in reducing AMR in E. coli and S. enterica in dairy calves. In addition, few data were available on physiological and microbiological factors that may contribute to the high relative populations of resistant bacteria in young calves, suggesting another valuable area of future research. PMID- 30481059 TI - Antibiotic Resistance of Lactobacillus spp. and Streptococcus thermophilus Isolated from Chinese Fermented Milk Products. AB - The aim of the present study was to investigate the phenotypic and genotypic antimicrobial resistance and the transferability of resistance markers in 87 lactic acid bacterial strains recovered from fermented milk products obtained from different areas of China. The isolates were identified as 21 Lactobacillus bulgaricus, 8 Lactobacillus casei, 6 Lactobacillus rhamnosus, 3 Lactobacillus paracasei, 2 Lactobacillus acidophilus, and 47 Streptococcus thermophilus strains. High levels of intrinsic resistance were revealed among the tested species. The following resistance genes were detected in strains isolated from fermented milk products: tet(M) in two L. bulgaricus and two S. thermophilus isolates, strA and strB in nine and seven S. thermophilus isolates, respectively; sul1 in six L. bulgaricus and seven S. thermophilus isolates, sul2 in one S. thermophilus isolate, aac(6')-aph(2") in two L. bulgaricus isolates, and aph(3") II and aph(3")-III in one S. thermophilus and two L. bulgaricus isolates, respectively. Transfer of the monitored antibiotic resistance genes was not observed in the filter mating assays of this study. To our knowledge, the strA, strB, sul1, sul2, and aph(3")-II genes in S. thermophilus, and the sul1 and aac(6')-aph(2") genes in L. bulgaricus were identified for the first time. These results indicate the potential risks posed by lactic acid bacteria (LAB) in fermented milk products in expanding the antibiotic resistance gene reservoir and transferring antibiotic resistance genes among bacteria. Further investigations are required to identify the potential sources of contamination and the dissemination routes of antibiotic resistance genes among LAB in fermented milk products. PMID- 30481060 TI - Antibody Responses to Salmonella in Pigs from Weaning Up to Marketing and Presence of Salmonella at Slaughter. AB - Salmonella is estimated to be one of the leading causes of enteric illness worldwide. Human salmonellosis is most frequently related to contaminated food products, particularly those of animal origin, such as pork. Pigs are often asymptomatic carriers of Salmonella, highlighting the importance of identifying high-prevalence farms and effective detection methods. The objectives of this study were to investigate Salmonella antibody responses and their association with on-farm shedding and Salmonella isolation at slaughter. Fourteen groups of pigs from eight farrowing sources were followed from birth to slaughter (totaling 796 pigs). Information about farm management was collected through a questionnaire. Blood and fecal samples were collected four times at different stages of production, and palatine tonsils/submandibular lymph nodes were obtained at slaughter. Sera were tested for Salmonella antibodies by enzyme linked immunosorbent assay, and fecal/tissue samples were cultured for Salmonella. Data were analyzed using a mixed-effect multivariable modeling method with farm, litter, and pig as random effects. Salmonella seropositivity rates were 20.3%, 5.8%, 15.9%, and 37.3% at weaning, at the end of nursery, at end of grower, and at end of finisher, respectively. Salmonella seropositivity and shedding increased with age (p < 0.05), and pigs shedding Salmonella were more likely to test seropositive (p = 0.02). Antibody response and shedding on-farm had no significant association with isolation of Salmonella from tissues harvested at slaughter. The variation in Salmonella seropositivity due to farm was 28.9% of total variation. These findings indicate that on-farm intervention may be a more effective approach to control Salmonella and to reduce the presence of Salmonella at slaughter. Additionally, the observation that some pigs in this study were Salmonella-negative throughout production and at slaughter is promising with regard to food safety, and studies are needed to explore the genotypes of those pigs. PMID- 30481061 TI - Vitamin E supplementation and caloric restriction promotes regulation of insulin secretion and glycemic homeostasis by different mechanisms in rats. AB - Vitamin E and caloric restriction have antioxidant effects in mammals. The aim of this study was to evaluate effects of vitamin E supplementation and caloric restriction upon insulin secretion and glucose homeostasis in rats. Male Wistar rats were distributed among the following groups: C, control group fed ad libitum; R, food quantity reduction of 40%; CV, control group supplemented with vitamin E [30 mg.kg-1.day-1]; and RV, food-restricted group supplemented with vitamin E. The experiments ran for 21 days. Glucose tolerance and insulin sensitivity was higher in the CV, R, and RV groups. Insulin secretion stimulated with different glucose concentrations was lower in the R and RV groups, compared with C and CV. In the presence of glucose and secretagogues, insulin secretion was higher in the CV group and was lower in the R and RV groups. An increase in insulin receptor occurred in the fat pad and muscle tissue of groups CV, R, and RV. Levels of hepatic insulin receptor and phospho-Akt protein were higher in groups R and RV, compared with C and CV, while muscle phospho-Akt was increased in the CV group. There was a reduction in hepatic RNA levels of the hepatocyte growth factor gene and insulin degrading enzyme in the R group, and increased levels of insulin degrading enzyme in the CV and RV groups. Thus, vitamin E supplementation and caloric restriction modulate insulin secretion by different mechanisms to maintain glucose homeostasis. PMID- 30481062 TI - Extended structure of pleiotropic DNA repair-promoting protein PprA from Deinococcus radiodurans. AB - Pleiotropic protein promoting DNA repair A (PprA) is a key protein facilitating the extreme radiation resistance of Deinococcus radiodurans. PprA is a unique protein to the genus Deinococcus and exists as an oligomer ranging from a tetramer to an ~100-mer depending on protein concentrations. Here, the X-ray crystal structure of PprA was determined to clarify how PprA confers radiation resistance. The tertiary structure of dimeric PprA was elucidated by using mutants obtained with random and site-directed mutagenesis methods (W183R and A139R); these mutants have disabled DNA binding and polymerization functions. Because the mutant A139R and W183R proteins have dimeric assemblies with 2 different interfaces (Interfaces 1 and 2), the linear and oligomerized PprA model was constructed as a left-handed face-to-face periodic screw structure. In addition, the linear structure in solution was confirmed by small-angle scattering experiments. The site-directed mutational analysis identified essential basic amino acids for DNA binding. These analytical data support the hypothesis that a complex assembly of PprA molecules, which are extended and have a screw structure, surrounds and stretches the DNA strand, acting as a novel guide to colocalize the DNA strands for efficient DNA repairs.-Adachi, M., Shimizu, R., Shibazaki, C., Satoh, K., Fujiwara, S., Arai, S., Narumi, I., Kuroki, R. Extended structure of pleiotropic DNA repair-promoting protein PprA from Deinococcus radiodurans. PMID- 30481063 TI - Quality of life in Japanese couples during the transition to parenthood. AB - OBJECTIVE: This study aimed to examine the quality of life (QOL) in Japanese couples during the transition to parenthood with their first child. BACKGROUND: Relevant literature suggests that the health status of women drop during pregnancy and the postpartum period. However, less is known about their partner's well-being during the transition to parenthood and little research has addressed the relationship between couples' QOL across multiple domains. METHOD: Participants included 9216 married Japanese men and women, including 3729 couples, who were expecting or raising their first child under the age of three. They independently completed questionnaires on baseline demographics and on WHOQOL-BREF. RESULTS: Men showed higher scores for psychological QOL, while women had higher scores for social and environment QOL. A significant interaction between gender and stage of transition to parenthood was found. The moderating effect of age between the stage and QOL was found for men on the physical and psychological domains. Couples' QOL scores were weakly to moderately correlated. CONCLUSION: Findings suggest that both men and women had lower QOL, with the exception of women's physical QOL, after childbirth, but they showed different trends during the transition to parenthood across different domains of QOL. PMID- 30481064 TI - Women's experiences of positive postnatal partner support. AB - OBJECTIVE: To explore women's experiences of support from their partners in the first year and a half post-baby and identify the particular attitudes and behaviours they considered helpful. BACKGROUND: Becoming a mother brings major life changes that impact on maternal mental health. Partner support can have a protective effect during this transition period, although there is currently a gap in the research regarding specific examples of partner support that women find helpful. METHODS: Six mothers who self-identified as receiving positive partner support took part in semi-structured interviews. Data were analysed using Interpretative Phenomenological Analysis. RESULTS: Three superordinate themes emerged: role navigation, emotional support and teamwork. Role navigation included an attitude of respect and appreciation of the mother role, as well as a shift in the father's priorities to include the whole family. Specific behaviours such as communicating with the mother in an empathic way, offering praise and demonstrating reliability and a willingness to help were seen as emotionally supportive. Teamwork included notions of fairness and equality. CONCLUSION: The present study extends upon previous research by providing clear examples of what women consider helpful from their partners, including an attitude of respect, placing family first, contributing fairly to household responsibilities, flexibility during the changing stages of child development, and facilitating personal time for mothers. These findings may assist to support new parents through the often difficult transition to parenthood. PMID- 30481065 TI - Long Noncoding RNA SOX2OT Accelerates the Carcinogenesis of Wilms' Tumor Through ceRNA Through miR-363/FOXP4 Axis. AB - Increasing literature supports the vital functions of long noncoding RNAs (lncRNAs) in human cancers. However, the biological function and regulatory mechanisms of lncRNAs in Wilms' tumor are still elusive. The aim of this study is to investigate the clinical significance and pathological role of lncRNA SOX2OT in Wilms' tumor progression. SOX2OT was identified to be upregulated in Wilms' tumor tissue and cells. In vitro, SOX2OT knockdown suppressed Wilms' tumor cells (SK-NEP-1, G-401) proliferation and invasion, and triggered apoptosis. In vivo xenograft assays and SOX2OT knockdown significantly inhibited Wilms' tumor growth. With the help of bioinformatics analysis and luciferase assay, SOX2OT was validated to harbor miR-363, acting as miRNA sponge or competing endogenous RNA. Furthermore, FOXP4 was validated to be the target protein of miR-363. Western blot and reverse transcription-polymerase chain reaction confirmed that SOX2OT was positively correlated with FOXP4 protein through sponging miR-363, forming a negative cascade regulation. In conclusion, our study realizes that SOX2OT acted as oncogene in the tumorigenesis of Wilms' tumor, suggesting the SOX2OT/miR 363/FOXP4 pathway in Wilms' tumor. PMID- 30481066 TI - Electrically stimulated acupuncture increases renal blood flow through exosome carried miR-181. AB - Acupuncture with low-frequency electrical stimulation (Acu/LFES) can prevent muscle atrophy by increasing muscle protein anabolism in mouse models of chronic kidney disease. During the treatment of muscle wasting, we found that Acu/LFES on the gastrocnemius muscle of the leg enhances renal blood flow. We also found that Acu/LFES increases exosome abundance and alters exosome-associated microRNA expression in the circulation. When exosome secretion was blocked using GW4869, the Acu/LFES-induced increase in renal blood flow was limited. This provided evidence that the increased renal blood flow is exosome mediated. To identify how exosomes regulate renal blood flow, we performed microRNA deep sequencing in exosomes isolated from treated and untreated mouse serum and found that the 34 microRNAs are altered by Acu/LFES. In particular, miR-181d-5p is increased in the serum exosome of Acu/LFES-treated mice. In silico searching suggested that miR 181d-5p could target angiotensinogen. Using a luciferase reporter assay, we demonstrated that miR-181 directly inhibits angiotensinogen. When Acu/LFES treated muscle was excised and incubated in culture medium, we found that the amount of exosomes and miR-181d-5p was increased in the medium providing evidence that Acu/LFES can increase miR-181 secretion. We conclude that Acu/LFES on leg hindlimb increases miR-181 in serum exosome leading to increased renal blood flow. This study provides important new insights about the mechanism(s) by which acupuncture may regulation of muscle-organ cross talk through exosome-derived microRNA. PMID- 30481067 TI - Multiphoton imaging reveals axial differences in metabolic autofluorescence signals along the kidney proximal tubule. AB - Kidney proximal tubules (PTs) are densely packed with mitochondria, and defects in mitochondrial function are implicated in many kidney diseases. However, little is known about intrinsic mitochondrial function within PT cells. Here, using intravital multiphoton microscopy and live slices of mouse kidney cortex, we show that autofluorescence signals provide important functional readouts of redox state and substrate metabolism and that there are striking axial differences in signals along the PT. Mitochondrial NAD(P)H intensity was similar in both PT segment (S)1 and S2 and was sensitive to changes in respiratory chain (RC) redox state, whereas cytosolic NAD(P)H intensity was significantly higher in S2. Mitochondrial NAD(P)H increased in response to lactate and butyrate but decreased in response to glutamine and glutamate. Cytosolic NAD(P)H was sensitive to lactate and pyruvate and decreased dramatically in S2 in response to inhibition of glucose metabolism. Mitochondrial flavoprotein (FP) intensity was markedly higher in S2 than in S1 but was insensitive to changes in RC redox state. Mitochondrial FP signal increased in response to palmitate but decreased in response to glutamine and glutamate. Fluorescence lifetime decays were similar in both S1 and S2, suggesting that intensity differences are explained by differences in abundance of the same molecular species. Expression levels of known fluorescent mitochondrial FPs were higher in S2 than S1. In summary, substantial metabolic information can be obtained in kidney tissue using a label free live imaging approach, and our findings suggest that metabolism is tailored to the specialized functions of S1 and S2 PT segments. PMID- 30481068 TI - Wild Boar: A Reservoir of Foodborne Zoonoses. AB - Wild boar populations around the world have increased dramatically over past decades. Climate change, generating milder winters with less snow, may affect their spread into northern regions. Wild boars can serve as reservoirs for a number of bacteria, viruses, and parasites, which are transmissible to humans and domestic animals through direct interaction with wild boars, through contaminated food or indirectly through contaminated environment. Disease transmission between wild boars, domestic animals, and humans is an increasing threat to human and animal health, especially in areas with high wild boar densities. This article reviews important foodborne zoonoses, including bacterial diseases (brucellosis, salmonellosis, tuberculosis, and yersiniosis), parasitic diseases (toxoplasmosis and trichinellosis), and the viral hepatitis E. The focus is on the prevalence of these diseases and the causative microbes in wild boars. The role of wild boars in transmitting these pathogens to humans and livestock is also briefly discussed. PMID- 30481069 TI - Evaluating the efficacy of sample collection approaches and DNA metabarcoding for identifying the diversity of plants utilized by nectivorous bats. AB - In this study, we evaluated the efficacy of sample collection approaches and DNA metabarcoding to identify plants utilized by nectivorous bats. Samples included guano collected from beneath bat roosts and pollen-swabs from bat fur, both of which were subjected to DNA metabarcoding and visual identification of pollen (microscopy) to measure plant diversity. Our objectives were to determine whether DNA metabarcoding could detect likely food plants of nectivorous bats, whether sample types would produce different estimates of plant diversity, and to compare results of DNA metabarcoding to visual identification. Visual identification found that 99% of pollen was from Agave, which is thought to be the bats' main food source. The dominant taxon found by metabarcoding was also Agavoideae, but a broader diversity of plant species was also detected, many of which are likely "by-catch" from the broader environment. Metabarcoding outcomes differed between sample types, likely because pollen-swabs measured the plant species visited by bats and guano samples measured all items consumed in the bat's diet, even those that were not pollen or nectar. Overall, metabarcoding is a powerful, high throughput tool to understand bat ecology and species interactions, but careful analysis of results is necessary to derive accurate ecological conclusions. PMID- 30481070 TI - Loaded dice: A game theory analysis of drunk driving laws in Brazil. AB - OBJECTIVE: The aim of the study was to evaluate whether the current legislation would encourage drunk drivers to refrain from taking a breathalyzer and thus avoid jail time. METHOD: Brazilian traffic laws currently have 3 possible punishments for drivers suspected of driving under the influence: A fine and suspension of license for 12 months if the breathalyzer result is under 0.3 mg/L (by law; a result up to 0.33 mg/L would receive the same punishment due to a later regulatory document) but positive; the same punishment for refusal to take a breathalyzer test; and up to 3 years of jail time and license cancellation if over 0.3 mg/L. Analysis was done using decision tree analysis as well as game theory to evaluate the rational choice for drunk drivers according to possible financial loss. RESULTS: The authors have found that the rational choice for a drunk driver is not taking the breathalyzer test to avoid heavier penalties. This, in turn, contributes to the inefficacy of the law. CONCLUSION: The authors have also calculated that the fine for refusing should be around 2.5 times higher so that the economic equilibrium would shift toward encouraging drivers to take the test. This should also be accompanied by other incentives to promote safe behavior while driving. PMID- 30481071 TI - Prevalence and Characteristics of Methicillin-Resistant Staphylococcus aureus Isolates in Pigs and Pig Farmers in Korea. AB - In this study, we investigated the prevalence and characteristics of methicillin resistant Staphylococcus aureus (MRSA) isolates from pigs and pig farmers in Korea. A total of 1245 nasal swabs were collected from pigs and farmers at 53 pig farms in nine provinces from 2012 to 2016. The prevalence of MRSA was 7.9% (88/1119) in pigs and 16.7% (21/126) in farmers. Among 119 farmers working on conventional farms, 21 (17.6%) tested positive for MRSA. However, no MRSA was detected in either pigs or farmers at four organic farms. The individual pig level prevalence of MRSA differed between age groups, with the percentage of positive samples being highest in weaners (17.3%), followed by growers (9.0%), piglets (6.5%), finishers (4.4%), and sows (0%). Two different lineages of MRSA were detected among the 109 isolates from pigs and farmers: (1) livestock associated types of MRSA belonging to 27 isolates of ST541-t034-V, 24 isolates of ST398-t571-V, 17 isolates of ST398-t034 variant (G420A)-V, and one isolate of ST541-t8588-V; and (2) community-associated types of MRSA belonging to 21 isolates of ST188-t189-IV, 14 isolates of ST72-t324-IV, three isolates of ST72 t664-IV, one isolate of ST72-t148-IV, and one isolate of ST72-t5440-IV. Identical genotypes were detected in both pigs and farmers at six farms. New MRSA clones were isolated from pigs (ST398-t034 (G420A)-V, ST188-t189-IV, and ST398-t571-V) and pig farmers (ST541-t8588-V and ST72-t5440-IV). The prevalence of MRSA was also correlated with antibiotic usage, and the clones showed diversification between pigs and farmers. Ultimately, the increased frequency and diversification of livestock-associated MRSA could be a potential threat to public health in Korea. To our knowledge, this is the first study to report the prevalence and characteristics of MRSA in pigs and pig farmers in Korea. PMID- 30481072 TI - HIF1alpha-siRNA and gemcitabine combination-based GE-11 peptide antibody-targeted nanomedicine for enhanced therapeutic efficacy in pancreatic cancers. AB - Pancreatic cancer is one of the deadliest cancers across the world with an average 5-year survival rate of less than <6%. In this study, gemcitabine (GEM) and HIF1alpha-siRNA loaded GE-11 peptide conjugated liposome was successfully prepared and evaluated for its antitumor efficacy in pancreatic cancer cells. The GE11 increased the targeting specificity of liposome carrier and increased the intracellular concentrations in the cancer cells. Furthermore, synergistic combination of GEM and HIF1a-siRNA exhibited remarkable improvement in the declining of cancer cell proliferations. siRNA could effectively decrease the expression of HIF1a gene in the cancer cells. Importantly, GE-11 peptide conjugated GEM/siRNA-loaded liposomes (GE-GML/siRNA) increased the total amount of apoptosis cells with higher proportion of cells in late apoptosis phase. GE GML induced remarkable apoptosis of cancer cells and induced chromatin condensation and nuclear fragmentation which are considered to be typical features of apoptosis and cell death. GE-GML/siRNA showed a significant reduction in the tumor burden suggesting the superior anticancer efficacy of this formulation. GE-GML/siRNA showed 4-fold reduction in tumor compared to control and 2-fold reduction compared to GE-GML, respectively. Overall, present work lays foundation for the combination of GEM and HIF1a-siRNA loaded in a targeted nanocarrier system as a unique therapeutic option in pancreatic cancer treatment. PMID- 30481073 TI - miR-21 Contributes to Human Amniotic Membrane-Derived Mesenchymal Stem Cell Growth and Human Amniotic Membrane-Derived Mesenchymal Stem Cell-Induced Immunoregulation. AB - BACKGROUND: Human amniotic membrane-derived mesenchymal stem cells (hAM-MSCs) are considered a new and favorable source of stem cells for cell replacement-based therapy. Some microRNAs (miRNAs) have been reported to participate in the regulation of immune responses. Our aim was to investigate the effects of miR-21 on the biological characteristics, immunoregulatory properties, and potential mechanisms of hAM-MSCs. METHODS: hAM-MSCs were isolated from the placental amnion membrane of a newborn. Cell proliferation, cell cycle, apoptosis, and expressions of cell surface markers were measured by CCK-8 and flow cytometric assays in hAM MSCs. The expression of mesenchymal-specific antigens vimentin and stage-specific embryonic antigen-4 (SSEA-4) were identified by immunofluorescence staining. Tumor necrosis factor alpha (TNF-alpha), monocyte chemotactic protein-1 (MCP-1), and interleukin-10 (IL-10) expressions in the cocultured supernatant of hAM-MSCs and peripheral blood mononuclear cells (PBMC) were detected via enzyme-linked immunosorbent assays (ELISA). RESULTS: Flow cytometric analyses revealed that the positive expression rates of the cell surface markers CD29, CD44, CD73, and CD90 in hAM-MSCs were 97.3%, 96.3%, 97.8%, and 98.2%, respectively, while the rates of CD34 and CD45 expression were only 0.6% and 0.84%, respectively. The immunofluorescent staining results showed that vimentin and SSEA-4 were positive in hAM-MSCs. CCK-8 assays revealed that miR-21 overexpression significantly promoted hAM-MSC proliferation. Cell cycle analyses revealed that the number of hAM-MSCs-miR-21 cells during the synthesis phase (S phase) was significantly increased. miR-21 overexpression also significantly inhibited apoptosis in hAM MSCs. The ELISA analyses revealed that miR-21 overexpression enhanced the inhibitory effect of hAM-MSCs on the secretion of TNF-alpha and MCP-1 as well as the promotive effect on the secretion of IL-10 in PBMC cocultured with miR-21-hAM MSCs. In addition, miR-21 downregulation reduced the inhibitory effect of hAM MSCs on the secretion of TNF-alpha, MCP-1, and the promotive effect on the secretion of IL-10 in PBMC cocultured with anti-miR-21-hAM-MSCs. CONCLUSIONS: Our data showed that miR-21 promoted hAM-MSCs proliferation, inhibited apoptosis, and was involved in controlling the immunoregulatory capacity of hAM-MSCs. PMID- 30481074 TI - Sovereign Rules and Rearrangements: Banning Methadone in Occupied Crimea. AB - In 2014, Russian authorities in occupied Crimea shut down all medication-assisted treatment (MAT) programs for patients with opioid use disorder. These closures dramatically enacted a new political order. As the sovereign occupiers in Crimea advanced new constellations of citizenship and statehood, so the very concept of "right to health" was re-tooled. Social imaginations of drug use helped single out MAT patients as a population whose "right to health," protected by the state, would be artificially restricted. Here, I argue that such acts of medical disenfranchisement should be understood as contemporary acts of statecraft. PMID- 30481075 TI - Role of Pannexin and adenosine triphosphate (ATP) following myocardial ischemia/reperfusion. AB - OBJECTIVES: The purinergic system has not been investigated in detail following ischemia/reperfusion (I/R) injury in the heart. In the present study we focus on both release and response to extracellular adenosine triphosphate (ATP). Pannexin (Panx) channels have been shown to be involved in ATP release from myocytes and can activate P2X1 and P2Y2 receptors on the coronary artery. DESIGN: We applied a well characterized I/R model in rats, with 24 hours of reperfusion. Panx expression in the myocardial tissue was measured with quantitative polymerase chain reaction (qPCR) and flow cytometry. ATP release was detected in situ using luminescence and the vascular response to nucleotides determined in a wire myograph. RESULTS: Here we show that Panx expression is increased after experimental myocardial I/R, leading to an increase in extracellular ATP release, which could be inhibited by probenecid. Functional studies revealed that the P2Y2 receptor dependent contraction is reduced in the coronary artery after I/R, which might be a response to the increased ATP levels. CONCLUSION: We therefore, conclude that the regulation of the arterial purinergic system minimizes coronary contractions following ischemia. PMID- 30481076 TI - Exercise as a therapeutic approach to improve blood pressure in patients with peripheral arterial disease: current literature and future directions. AB - INTRODUCTION: Patients with symptomatic peripheral artery disease (PAD) exhibit reduced functional capacity and increased mortality due to cardiovascular disease. Although exercise has been a cornerstone for clinical treatment to improve walking capacity in patients with symptomatic PAD, its effects on cardiovascular parameters have been poorly explored. Areas covered: This review examines the role of exercise in improving blood pressure in patients with symptomatic PAD and summarizes the current evidence on the acute (single bout of exercise) and chronic effects of walking and resistance exercise on blood pressure and its determinants. Expert commentary: In patients with symptomatic PAD, exercise promotes acute and chronic reductions in blood pressure. These effects were observed particularly after walking and resistance exercise. Future studies are necessary to investigate the effects of other exercise modalities, especially non-painful exercises, on cardiovascular function in patients with symptomatic PAD. PMID- 30481077 TI - Cytogenetic analysis of adult T-Cell leukemia/lymphoma: evaluation of a Caribbean cohort. PMID- 30481078 TI - Estimation of radiation dose-reduction factor for cerium oxide nanoparticles in MRC-5 human lung fibroblastic cells and MCF-7 breast-cancer cells. AB - In the current study, radiation dose-reduction factor (DRF) of nanoceria or cerium oxide nanoparticles (CONPs) in MRC-5 Human Lung Fibroblastic Cells and MCF 7 Breast-Cancer Cells was estimated. Characterization of CONPs was determined using scanner electron microscope (SEM), energy dispersive spectroscopy (EDS), transmission electron microscopy (TEM) and spectrophotometer. Then, six plans were designed with different radiation dose values on planning target value. The obtained MRC-5 and MCF-7 cells were treated with non-toxic concentrations of CONPs and then exposed. Finally, cell viability (%) of the cell lines was determined using MTT assay. The findings showed that CONPs have no significant radioprotective effect against 10 cGy radiation dose value. Nevertheless, 70 MUM CONPs resulted in a significant radioprotection against 100, 200, 300, 400 and 500 cGy radiation dose values compared with the control group in MRC-5 cells. For all radiation dose values, mean cell viability (%) of MCF-7 had not increased significantly at the presence of nanoceria compared with control group. According to the findings, it was revealed that the use of CONPs have a significant radioprotective effect on normal lung cells, while they do not provide any protection for MCF-7 cancer cells. These properties can help to increase therapeutic ratio of radiotherapy. PMID- 30481079 TI - Cause of Death in Follicular Lymphoma in the First Decade of the Rituximab Era: A Pooled Analysis of French and US Cohorts. AB - PURPOSE: Although the life expectancy of patients with follicular lymphoma (FL) has increased, little is known of their causes of death (CODs) in the rituximab era. PATIENTS AND METHODS: We pooled two cohorts of newly diagnosed patients with FL grade 1-3A. Patients were enrolled between 2001 and 2013 in two French referral institutions (N = 734; median follow-up 89 months) and 2002 and 2012 in the University of Iowa and Mayo Clinic Specialized Program of Research Excellence (SPORE; N = 920; median follow-up 84 months). COD was classified as being a result of lymphoma, other malignancy, treatment related, or all other causes. RESULTS: Ten-year overall survival was comparable in the French (80%) and US (77%) cohorts. We were able to classify COD in 248 (88%) of 283 decedents. In the overall cohort, lymphoma was the most common COD, with a cumulative incidence of 10.3% at 10 years, followed by treatment-related mortality (3.0%), other malignancy (2.9%), other causes (2.2%), and unknown (3.0%). The 10-year cumulative incidence of death as a result of lymphoma or treatment was higher than death as a result of all other causes for each age group (including patients >= 70 years of age at diagnosis [25.4% v 16.6%]) Follicular Lymphoma International Prognostic Index score 3 to 5 (27.4% v 5.2%), but not Follicular Lymphoma International Prognostic Index score 0 to 1 (4.0% v 3.7%); for patients who failed to achieve event-free survival within 24 months from diagnosis (36.1% v 7.0%), but not for patients who achieved event-free survival within 24 months of diagnosis (6.7% v 5.7%); and for patients with a history of transformed FL (45.9% v 4.7%), but not among patients without (8.1% v 6.2%). Overall, 77 of 140 deaths as a result of lymphoma occurred in patients whose FL transformed after diagnosis. CONCLUSION: Despite the improvement in overall survival in patients with FL in the rituximab era, their leading COD remains lymphoma, especially after disease transformation. Treatment-related mortality also represents a concern, which supports the need for less-toxic therapies. PMID- 30481080 TI - Fertility experiences in women reporting endometriosis: findings from the Understanding Fertility Management in Contemporary Australia survey. AB - PURPOSE: To examine the fertility experiences of women reporting and not reporting endometriosis in a population-based survey. MATERIALS AND METHODS: A cross-sectional survey among a community sample of 1543 women in Australia. Data were analysed to compare fertility management between women who did and did not report endometriosis. Factors associated with unintended pregnancy, infertility diagnosis, time to conception and live birth were identified through multivariable analyses. RESULTS: While individual contraceptive use did not differ by endometriosis status, avoiding pregnancy was less important to women reporting endometriosis (50.5%) than to others (68.7%; p < .001). Women reporting endometriosis were approximately three times more likely to report an infertility diagnosis-the majority (39.7%) of which were 'unexplained female or male infertility'-(p < .001) and six times more likely to report taking longer than 12 months to conceive than those who did not report endometriosis (p < .001). Although more women reporting a diagnosis of endometriosis also reported never having been pregnant (11.9%) than those who did not report a diagnosis (6.0%), this difference was not statistically significant (p = .060). There were also no endometriosis-associated differences in women's reports of unintended pregnancy, abortion, having been pregnant, or having had a live birth. CONCLUSIONS: Our findings counter the common assertion that women with endometriosis are unlikely to conceive, and support the need for health care and information that addresses all aspects of fertility management (not just infertility) for women with endometriosis. PMID- 30481081 TI - Dose-response relation between serum total cholesterol levels and overall cancer risk: evidence from 12 prospective studies involving 1,926,275 participants. AB - This study aimed to clarify the association between serum total cholesterol (TC) levels and overall cancer risk. Study-specific relative risks (RR) and 95% confidence intervals (CI) were pooled using a random-effects model, and dose response relation was also evaluated. Twelve prospective studies were identified with a total of 1,926,275 participants and 13,1676 cases. High levels of serum TC showed an inverse association with overall cancer risk (RR for the highest versus the lowest category: 0.87, 95% CI: 0.83 ~ 0.90; I2 = 52.5%). A linear dose response relation between serum TC levels and overall cancer risk was found (p = .004 for Wald test; I2 = 49.6%), and the pooled RR was 0.92 (95% CI: 0.89 ~ 0.94) for 3 mmol/L, 0.86 (95% CI: 0.81 ~ 0.90) for 5 mmol/L, 0.80 (95% CI: 0.74 ~ 0.87) for 7 mmol/L. Our dose-response meta-analysis of 12 prospective studies indicated that higher serum TC levels were significantly associated with reduced cancer risk. PMID- 30481082 TI - Challenges in the Polyene- and Azole-Based Pharmacotherapy of Ocular Fungal Infections. AB - Polyenes and azoles constitute 2 major drug classes in the antifungal armamentarium used to treat fungal infections of the eye such as fungal keratitis, endophthalmitis, conjunctivitis, and blepharitis. These classes of drugs have come to occupy an important niche in ophthalmic antifungal therapy due to their broad spectrum of activity against a variety of filamentous and yeast like fungi. Natamycin suspension (Natacyn(r)), a polyene antifungal drug, is currently the only US FDA-approved formulation for treating ophthalmic fungal infections, whereas the other polyene and azole antifungals such as amphotericin B, fluconazole, itraconazole, ketoconazole, miconazole, voriconazole, and posaconazole are routinely used off-label in the clinical setting. Despite potent antifungal activity, the clinical utility of these agents in ophthalmic infections has been challenged by their physicochemical properties, the unique ocular anatomy and physiology, selective antifungal activity, ocular and systemic toxicity, emergence of resistance and cross-resistance, and absence of reliable techniques for developing a robust in vitro-in vivo correlation. This review discusses the aforementioned challenges and the common approaches undertaken to circumnavigate the difficulties associated with the polyene- and azole-based pharmacotherapy of ophthalmic fungal infections. PMID- 30481083 TI - Differentiating factors in treatment-free remission trials: impact of study design on results and clinical applications. AB - For patients with chronic myeloid leukemia in chronic phase with sustained deep molecular responses on long-term tyrosine kinase inhibitor (TKI) therapy, treatment-free remission (TFR) feasibility has been established. TFR is now a treatment goal for patients meeting specific criteria; NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines(r)) for CML have developed criteria for attempting TFR outside clinical trials, and TFR was added to the US Food and Drug Administration-approved nilotinib label. Importantly, TFR studies vary in design and characteristics of participating patients. We discuss key study design elements to consider when assessing results from TFR trials, including criteria for attempting TFR, characteristics of enrolled patients, use of a consolidation phase (whereby patients continue TKI treatment on study before attempting TFR), and criteria for restarting TKI therapy. Finally, we review the criteria outlined in the NCCN Guidelines(r) for TFR outside clinical trials and compare to criteria used in TFR studies. PMID- 30481084 TI - Effects of Stimulus-Related Variables on Mental States Recognition in Huntington'S Disease. AB - BACKGROUND: Cognitive abnormalities in Huntington's Disease (HD) can involve the specific impairment of the social perspective taking as well as difficulties in recognizing others' mental state many years before the onset of motor symptoms. AIMS: At the scope of assessing how the difficulties in mental state recognition might be an HD early sign before motor symptoms appear, our study was aimed to investigate how the recognition of others' mental states in HD subjects is moderated by different stimulus related features (gender, difficulty (low, medium, high) and valence (positive, negative, neutral) of the mental states that are to be recognized). METHODS: Subjects with pre-manifest (n = 20) and manifest (n = 40) HD performed the revised "Reading the Mind in the Eyes Test" and were compared with age-matched healthy controls (HC, 40 subjects per cohort). RESULTS: Our results highlight an early impairment in mental state recognition preceding manifest HD symptoms and a deterioration of these abilities with HD progression. Moreover, we found in HD pre-manifest subjects an impairment concerning the recognition of negative and neutral mental states, as well as of mental states with moderate recognition difficulty. Finally, we found that participant gender did not influence the performance in recognizing others' mental states, while all participants recognized mental states displayed by females more accurately than those displayed by males. CONCLUSIONS: We conclude that difficulties in the recognition of complex mental states can be considered as an early sign of HD, before evident behavioral manifestations, and peculiar features of the stimulus influence it. PMID- 30481085 TI - Breast Cancer Research in the Caribbean: Analysis of Reports From 1975 to 2017. AB - PURPOSE: Breast cancer is among the leading causes of death resulting from cancer in Caribbean women. Studies examining exogenous and genetically predetermined endogenous risk factors are critical to define breast cancer susceptibility in Caribbean women. The purpose of this systematic review is to assess the existing scientific literature in the last 42 years (1975 to 2017) to describe the body of research generated for the population of this region and determine future research directions. METHODS: We selected published research articles using a combination of definite keyword searches in PubMed. Only articles presenting the Caribbean population as the focus of their research objectives were included in this analysis. RESULTS: Studies on breast cancer in the Caribbean are limited. A majority of publications on Caribbean populations were descriptive, focusing on cancer trends and clinicopathologic factors. High incidence and mortality rates for breast cancer are reported for the region, and there seem to be some differences between countries in the frequency of cases according to age at presentation. A limited number of epidemiologic, behavioral, and genetic and molecular studies were conducted in more recent years. CONCLUSION: A regional strategy for cancer registration is needed for the Caribbean to address possible underestimates of breast cancer incidence. Furthermore, behavioral, molecular, genetic, and epidemiologic investigations of breast cancer are critical to address the concerns related to currently described high incidence and mortality rates in the Caribbean. PMID- 30481086 TI - Initiating Advance Care Planning in Primary Care: A Model for Success. AB - BACKGROUND: Primary care physicians recognize the importance of advance care planning (ACP) conversations and report lack of training and time in the office to start them. Previous efforts have shown that ACP is a low-risk high-value intervention for older patients and those with life-limiting illness. OBJECTIVE: To measure the impact of physician coaching and staff training with registered nurse (RN) support and electronic medical record (EMR) enhancements on the initiation of 2000 ACP conversations in primary care. METHODS: Employing VitalTalk(r) physician coaching, Respecting Choices(r) "Last Steps" ACP facilitator training, support provided by an ACP nurse liaison and EMR customization, the intervention was introduced into 36 primary care practices with an additional EMR tool adopted by 12 of the 36. RESULTS: There was an increase from zero at baseline in the number of ACP conversations and a leveling out of new ACP initiated each month. A total of 7200 ACP conversations were initiated for 31 months in 36 primary care practices, and 29% of conversations had advance directives scanned into the EMR during a 10-month review period. Most ACP conversations were initiated by RN care managers. In 2017, there were 7589 more ACP conversations initiated. DISCUSSION/CONCLUSION: By combining two complementary, evidenced-based curricula, providing support of a nurse liaison and designing a summary and alert in the EMR, this program exceeded its goal to initiate 2000 ACP conversations in primary care. Other health systems might consider a similar multicomponent intervention to increase ACP. PMID- 30481087 TI - Idealhalers Versus Realhalers: Is It Possible to Bypass Deposition in the Upper Respiratory Tract? AB - This review discusses how advances in formulation and device design can be utilized to dramatically improve lung targeting and dose consistency relative to current marketed dry powder inhalers (DPIs). Central to the review is the development of engineered particles that effectively bypass deposition in the upper respiratory tract (URT). This not only reduces the potential for off-target effects but it also reduces variability in dose delivery to the lungs resulting from anatomical differences in the soft tissue in the mouth and throat. Low density porous particles are able to largely bypass URT deposition due to the fact that both the primary particles and their agglomerates are respirable. The low-density particles also exhibit dose delivery to the lungs that is largely independent of inspiratory flow rate across a range of flow rates that most subjects achieve with portable DPIs. Coupling this with delivery devices that are breath actuated, simple to operate (open-inhale-close), and have adherence tracking capability enables drug delivery that is largely independent of how a subject inhales, with a user experience that is close to that of an "idealhaler." PMID- 30481089 TI - The Importance of Being Acceptable - Psychiatric Staffs' Talk about Women Patients in Forensic Care. AB - Currently, women comprise about ten percent of those sentenced to psychiatric forensic clinics in Sweden. Those who are sentenced to forensic care because of offending and violent behaviour have already taken a step away from the usually expected female behaviour. On the other hand, there are many women in forensic care who have not committed crimes, but who instead self-harm. Studies have identified a gender bias in diagnosing and care in psychiatric settings, but there are few studies conducted on women in forensic care. The present study therefore examined how the situation of women patients and female norms are expressed in the staff's talk about these women during verbal handovers and ward rounds at a forensic clinic in Sweden. The aim was to explore how psychiatric staff, in a context of verbal handovers and ward rounds, talk about women who have been committed to forensic psychiatric care, and what consequences this might have for the care of the patients. The content of speech was examined using audio recordings and a method of analysis that was inspired by thematic analysis. The analysis identified that the staff talked about the women in a way that indicates that they expected the women to follow the rules and take responsibility for their bodies in order to be regarded as acceptable patients. PMID- 30481088 TI - Promoter haplotypes of the corticotropin-releasing hormone encoding gene modulate the physiological stress response in vitro and in vivo. AB - The corticotropin-releasing hormone (CRH) is a neuropeptide mediating stress responses. CRH exerts effects via the hypothalamus pituitary adrenal axis as well as immediate effects on the sympathetic-adrenal-medullary system. Genetic variants of the CRH promoter were previously found to be associated with altered CRH promoter activity and physiological reactions. Functional characterization of three CRH promoter haplotypes have been performed in vitro using a reporter gene assay under different stimulation conditions. Furthermore, 232 healthy subjects were genotyped and the influence of CRH haplotypes on basal parameters such as post-awakening cortisol and blood pressure as well as on stress reactivity measured after socially evaluated cold pressor test (SeCPT) was investigated. In vitro, CRH haplotype 2 showed the highest promoter activity under baseline conditions and after forskolin stimulation compared with other haplotypes. Forskolin treatment resulted in a two fold increase of haplotype 2 promoter activity compared with the baseline condition. Cell line-dependent promoter activation was found after hydrocortisone treatment. In vivo, CRH haplotype 2 carriers showed significant higher baseline blood pressure (p = .002) and blood pressure after SeCPT (p < .001), but did not differ in cortisol levels. This study provides converging evidence for the importance of CRH promoter variants on physiological stress response parameters. PMID- 30481090 TI - New tools of the trade: parsing out the role of radiotherapy for early-stage diffuse large B-cell lymphoma. PMID- 30481091 TI - Comparative cytogenetics of four species of Thrichomys (Rodentia: Echimyidae). AB - Thrichomys Trouessart, 1880 is a genus of echimyid rodents endemic to South America, distributed from northeastern Brazil to Paraguay and Bolivia. Although all the recognized species of this genus have already been karyotyped, detailed comparative cytogenetic analyses have not been performed yet. We karyologically analyzed four species of Thrichomys from different Brazilian states. Our analyses included GTG- and CBG-banding, silver-staining of the nucleolar organizer regions (Ag-NORs) and fluorescent in situ hybridization (FISH) with telomeric and 45S rDNA probes. Comparative GTG-banding suggested that the interspecific variation may result from Robertsonian rearrangements, pericentric and paracentric inversions, centromere repositioning, and heterochromatin variation. FISH with a telomeric probe showed interspecies variation in interstitial telomeric sequences (ITs) distribution. Our results represent the most complete data on the cytogenetics of Thrichomys reported to date and give an insight into the chromosome evolution of this genus. PMID- 30481092 TI - Determination of Spontaneous Dicentric Frequencies and Establishment of Dose response Curves after Expose of Human Peripheral Blood Lymphocytes to Low and High Dose Rate 60Co Gamma Rays - The Basis for Cytogenetic Biodosimetry in Vietnam. AB - PURPOSE: The purposes of this study are to investigate spontaneous dicentric frequencies and dose response curves of dicentrics induced by gamma 60Co for replenishing the data sets used for biodosimetry in Vietnam. MATERIALS AND METHODS: 104 healthy donor blood samples were collected for chromosome aberrations background study, 03 healthy donor blood samples were used for generating the dose response curves at 1.96 mGy/min and 275 mGy/min. Blood collection, in vitro irradiation, cell culture and harvest, slide preparation and metaphase scoring were performed according to IAEA standard protocol (2011). Blind exposed samples were scored for verifying each curve. RESULTS: The dicentric, fragment and chromatid break frequencies in 106310 metaphases of 104 donors were 0.023% +/- 0.005%, 0.045% +/- 0.007% and 0.101% +/- 0.011%, respectively. The dose response curve for low dose rate was y = C + (0.0137 +/- 0.0055)D + (0.0912 +/- 0.0142)D2 and for high dose rate was y = C + (0.0337 +/- 0.0046)D + (0.0539 +/- 0.0031)D2, where both of them were verified. CONCLUSION: The data of this study were established for biological dose assessment in cases with low LET of accidental or occupational radiation exposures in the dose range of 0.1 - 5.0 Gy. PMID- 30481093 TI - Analysis of interleukin 23 and 7G10 interactions for computational design of lead antibodies against immune-mediated inflammatory diseases. AB - Wealth of structural data on theurapeutic targets in complex with monoclonal antibodies (mAbs) and advances in molecular modeling algorithms present exciting opportunities in the field of novel biologic design. Interleukin 23 (IL23), a well-known drug target for autoimmune diseases, in complex with mAb 7G10 offers prospect to design potent lead antibodies by traversing the complete epitope paratope interface. Herein, key interactions aiding antibody-based neutralization in IL23-7G10 complex are resolute through PyMOL, LigPlot+, Antibody i-Patch, DiscoTope and FoldX. Six amino acids Ser31, Val33, Asn55, Lys59 in heavy chain and His34, Ser93 in light chain are subjected to in silico mutagenesis with residues Met, Trp, Ile, Leu and Arg. A set of 431 mutant macromolecules are outlined. Binding affinities of these molecules with IL23 are estimated through protein-protein docking by employing ZDOCK, ClusPro and RosettaDock. Subsequently, the macromolecules revealed comparable result with 7G10 are cross validated through binding free-energy calculations by applying Molecular Mechanics/Poisson Boltzman Surface Area method in CHARMM. Thirty nine designed theoretical antibodies showed improved outcome in all evaluations; from these, top 10 molecules showed at least nine unit better binding affinity compared to the known mAb. These molecules have the potential to act as lead antibodies. Subsequent molecular dynamics simulations too favored prospective of best ranked molecule to have therapeutic implications in autoimmune and inflammatory diseases. Abbreviations: IL23: interleukin 23; IL17: interleukin17; Ab: antibody; Ag: antigen; mAbs: monoclonal antibodies; STAT3: signal transducer and activator of transcription 3; STAT4: signal transducer and activator of transcription 4; PDB: protein databank; MM/PBSA: molecular mechanics Poisson-Boltzmann surface area; Ag-Ab: antigen- antibody complex; SPC/E: extended simple point charge; SD: steepest descents; PME: particle mesh ewald; dG: binding free energies; Fv: variable fragment. PMID- 30481094 TI - A definite measure of occupancy exposures, seeking with non-radiolabeled in vivo 5-HT2A receptor occupancy and in vitro free fractions. AB - Unbound drug concentration in the brain would be the true exposure responsible for specific target occupancy. Drug exposures from preclinical are total concentrations of those over/underestimate the clinical dose projection. With the application of mass spectrometry, the current work proposes a definite measure of test drug exposures at serotonin-2A occupancy. The 5-HT2A occupancy of antagonist in the rat brain has determined with non-radiolabeled tracer MDL-100,907 at an optimized dose (3 ug/kg) and treatment time (30 min). Equilibrium dialysis method determines the in vitro free fraction of the test antagonist in untreated rat brain homogenates and plasma. Drug-free fractions derived the unbound concentration (EC50) in plasma and brain at test doses. The corresponding binding affinities (Ki) correlated with the unbound concentrations. Except for quetiapine, the ED50 values in the dose-occupancy curves of antagonists are close and ranged from 1 to 3 mg/kg. The test drug quetiapine, eplivanserin, and clozapine showed high free fractions in plasma, but for ketanserin and olanzapine, the brain free fraction was higher. The correlation between the unbound EC50 of the antagonists and corresponding Ki values was good (r2=0.828). The improved EC50 accuracy with unbound concentrations was 10-250 folds in plasma and 10-170 folds in the brain. Further, the free fractions (fu, plasma/fu, brain) of test drugs had shown a correlation of ~83% with brain permeability (Ctotal brain/Ctotal plasma), a limiting factor. Thus, correlating the occupancy with unbound exposure and pharmacology would result in an accurate measurement of drug potency and optimizes in selecting the clinical dose. PMID- 30481095 TI - Effect of Cultural, Folk, and Religious Beliefs and Practices on Delays in Diagnosis of Ovarian Cancer in African American Women. AB - BACKGROUND: Certain cultural, folk, and religious beliefs that are more common among African Americans (AAs) have been associated with later-stage breast cancer. It is unknown if these beliefs are similarly associated with delays in diagnosis of ovarian cancer. METHODS: Data from a multicenter case-control study of ovarian cancer in AA women were used to examine associations between cultural/folk beliefs and religious practices and stage at diagnosis and symptom duration before diagnosis. Associations between cultural/folk beliefs or religious practices and stage at diagnosis were assessed with logistic regression analyses, and associations with symptom duration with linear regression analyses. RESULTS: Agreement with several of the cultural/folk belief statements was high (e.g., 40% agreed that "if a person prays about cancer, God will heal it without medical treatments"), and ~90% of women expressed moderate to high levels of religiosity/spirituality. Higher levels of religiosity/spirituality were associated with a twofold increase in the odds of stage III-IV ovarian cancer, whereas agreement with the cultural/folk belief statements was not associated with stage. Symptom duration before diagnosis was not consistently associated with cultural/folk beliefs or religiosity/spirituality. CONCLUSIONS: Women who reported stronger religious beliefs or practices had increased odds of higher stage ovarian cancer. Inaccurate cultural/folk beliefs about cancer treament were not associated with stage; however, these beliefs were highly prevalent in our population and could impact patient treatment decisions. Our findings suggest opportunities for health education interventions, especially working with churches, and improved doctor-patient communication. PMID- 30481096 TI - Body Image, Attractiveness, and Sexuality Among Women: The Influence of Experience and Social Context. PMID- 30481097 TI - Breastfeeding Greater Than 6 Months Is Associated with Smaller Maternal Waist Circumference Up To One Decade After Delivery. AB - BACKGROUND: Abdominal obesity is an important indicator of cardiometabolic dysfunction in later life. Prior studies have observed an inverse association between breastfeeding and maternal waist circumference (WC) in the years after pregnancy, but this may be due to bias resulting from systematic differences in women who do and do not breastfeed. MATERIALS AND METHODS: A total of 678 women enrolled in the Pregnancy Outcomes and Community Health (POUCH) cohort also participated in the POUCHmoms Study 7-15 years after delivery. Multivariable linear regression models and propensity scores were used to assess the relationship between WC measured at follow-up and self-reported history of breastfeeding duration of >6 months versus <=6 months. RESULTS: After a mean follow-up period of 11.0 (standard deviation = 1.4) years, breastfeeding was significantly associated with smaller WC. A threshold effect was detected for women who reported breastfeeding >6 months; their adjusted mean WC was 3.5 cm (95% confidence interval [CI]: -5.7 to -1.2) smaller compared with women who breastfed <=6 months. The use of two propensity score approaches, weighted and matched, produced similar results; adjusted mean WC difference was -3.6 cm (95% CI: -5.6 to -1.6) and -3.1 cm (95% CI: -5.5 to -0.7), respectively. CONCLUSIONS: This study extends conventional observational study methods to incorporate propensity score approaches that make it possible to separate the study design from the study analysis to account for systematic differences in women who did and did not breastfeed. After reducing potential bias, breastfeeding for greater than 6 months was independently associated with smaller WC in the decade after delivery. PMID- 30481098 TI - Multilevel Predictors of Continued Adherence to Breast Cancer Screening Among Women Ages 50-74 Years in a Screening Population. AB - BACKGROUND: U.S. women of ages 50-74 years are recommended to receive screening mammography at least biennially. Our objective was to evaluate multilevel predictors of nonadherence among screened women, as these are not well known. MATERIALS AND METHODS: A cohort study was conducted among women of ages 50-74 years with a screening mammogram in 2011 with a negative finding (Breast Imaging Reporting and Data System 1 or 2) within Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium research centers. We evaluated the association between woman-level factors, radiology facility, and PROSPR research center, and nonadherence to breast cancer screening guidelines, defined as not receiving breast imaging within 27 months of an index screening mammogram. Multilevel mixed-effects logistic regression was used to calculate odds ratios and 95% confidence intervals. RESULTS: Nonadherence to guideline recommended screening interval was 15.5% among 51,241 women with a screening mammogram. Non-Hispanic Asian/Pacific Islander women, women of other races, heavier women, and women of ages 50-59 years had a greater odds of nonadherence. There was no association with ZIP code median income. Nonadherence varied by research center and radiology facility (variance = 0.10, standard error = 0.03). Adjusted radiology facility nonadherence rates ranged from 10.0% to 26.5%. One research center evaluated radiology facility communication practices for screening reminders and scheduling, but these were not associated with nonadherence. CONCLUSIONS: Breast cancer screening interval nonadherence rates in screened women varied across radiology facilities even after adjustment for woman level characteristics and research center. Future studies should investigate other characteristics of facilities, practices, and health systems to determine factors integral to increasing continued adherence to breast cancer screening. PMID- 30481099 TI - Situational Contexts and Risk Factors Associated with Incapacitated and Nonincapacitated Sexual Assaults Among College Women. AB - BACKGROUND: Research has documented multilevel risk factors associated with experiencing incapacitated sexual assault among undergraduate women. Less is known about multilevel risk factors associated with nonincapacitated sexual assault. This study examines and compares the different settings, coercion methods, and relationships in which incapacitated and nonincapacitated sexual assaults occur among undergraduate women. MATERIALS AND METHODS: Our sample included 253 undergraduate women who reported experiencing sexual assault during college on a population-based survey of randomly selected students at two colleges in New York City in 2016 (N = 1671, response rate = 67%). We examined event-level data on their most significant sexual assault incident since entering college. Using multivariable statistical analysis, we identified situational contexts associated with incapacitated and nonincapacitated assault incidents adjusting for binge drinking, illicit drug use, and other confounding sociodemographic and psychosocial variables. RESULTS: Almost half (47%) of women who experienced sexual assault reported being incapacitated due to alcohol or drugs during the most significant incident. Being at a party before the event and "acquaintance" perpetrators were associated with incapacitated sexual assault after adjusting for binge drinking and other confounders. Meeting a perpetrator through an Internet dating app or indicating the perpetrator was an intimate partner were each associated with nonincapacitated assault incidents. Perpetrator use of physical force and verbal coercion were also associated with nonincapacitated assault incident. CONCLUSIONS: The different situational contexts associated with incapacitated and nonincapacitated sexual assaults have important implications for the design of prevention strategies that will effectively target the diverse risk environments in which campus sexual assault occurs. PMID- 30481100 TI - Product review: avelumab, an anti-PD-L1 antibody. AB - Although immunotherapies have been employed for many decades, immune checkpoint inhibitors have only recently entered the oncologic landscape. Avelumab is a fully human monoclonal antibody that blocks the interaction between PD-L1 on tumor cells and PD-1 on T cells, thereby inhibiting immunosuppression in the tumor microenvironment and reducing tumor growth. Most early clinical trials of avelumab as monotherapy and in combination regimens were part of the international JAVELIN clinical trial program, which included more than 7000 patients in more than 30 trials with at least 15 tumor types. Avelumab has been approved by the U.S. FDA for the treatment of metastatic Merkel cell carcinoma and metastatic urothelial carcinoma that has progressed during or following treatment with a platinum-based regimen. Its acceptable safety profile and ability to induce durable responses in otherwise deadly tumors provide the rationale for its use in other tumor types and in combination with other therapies. PMID- 30481101 TI - Do the Oncological and Surgical Outcomes of Young and Older Women Differ in the Treatment of Colorectal Cancer? AB - BACKGROUND: The present study aimed to compare the surgical and oncological outcomes between young and older women with colorectal cancer (CRC). MATERIALS AND METHODS: This retrospective study included 1815 women with CRC between 2010 and 2014. Participants were divided into a young group (under the age of 65 years) and an old group (65 years and older). The surgical and oncological outcomes were compared between the two groups using univariate and multivariate analyses. RESULTS: Around 45.1% (N = 819) patients were the older group. The old group had a higher comorbidity rate and a lower proportion of receiving postoperative chemotherapy. The old group also had a significantly higher blood loss (190 +/- 611 mL vs. 145 +/- 200 mL, p = 0.027) and a higher rate of intraoperative transfusion (5.4% vs. 3.0%, p = 0.011). They were found to develop more complications after surgery (11.7% vs. 7.8%, p = 0.015). The overall survival (OS) of the old group was lower than that of the young group (5-year OS rates: 72.8% vs. 83.8%, p < 0.001; adjusted hazard ratio: 1.86, 95% confidence interval: 1.49-2.33). However, the cancer-specific survival (CSS) was not significantly different between the old and young groups (5-year CSS rates: 84.7% vs. 84.9%, p = 0.076). CONCLUSIONS: Older women with CRC had poorer OS than young women with CRC, but had similar CSS. Therefore, the management of comorbidities along with cancer treatment may be important in older women with CRC. PMID- 30481102 TI - A Review of Pregnancy-Associated Breast Cancer: Diagnosis, Local and Systemic Treatment, and Prognosis. AB - The incidence of pregnancy-associated breast cancer (PABC) increases as more women choose to delay childbearing and the population-based incidence of breast cancer rises. Reliably and safely staging PABC is necessary to choose between starting with local or systemic therapy. With regard to local therapy, both lumpectomy and mastectomy can be considered depending on gestational age and the stage at diagnosis. By mirroring nonpregnant treatment regimens as much as possible, chemotherapy may improve long-term oncologic outcomes while allowing for surgical downstaging during pregnancy. Delaying treatment due to misconceptions regarding risk of local and systemic therapy most certainly worsens oncologic outcomes, and most neonatal morbidity is related to gestational age at delivery and not in utero exposures. Pregnancy itself was once considered an independent risk factor for worse outcome, but the prognosis of these patients is not significantly different than nonpregnant counterparts of a similar age. PMID- 30481103 TI - The Association Between Parity and Subsequent Cardiovascular Disease in Women: The Atherosclerosis Risk in Communities Study. AB - BACKGROUND: Previous studies are inconclusive on the relationship between parity and cardiovascular disease (CVD), with few evaluating multiple cardiovascular outcomes. It is also unclear if any relationship between parity and CVD is independent of breastfeeding. We examined the associations between parity and cardiovascular outcomes, including breastfeeding adjustment. MATERIALS AND METHODS: Data were from 8,583 White and African American women, 45-64 years of age, in the Atherosclerosis Risk in Communities Study. Coronary heart disease (CHD), myocardial infarction (MI), heart failure, and strokes were ascertained from 1987 to 2016 by annual interviews and hospital surveillance. Parity and breastfeeding were self-reported. Cox proportional hazards regression estimated hazard ratios (HR) for the association between parity and cardiovascular outcomes, adjusting for baseline sociodemographic, clinical and lifestyle factors, and breastfeeding. RESULTS: Women reported no pregnancies (6.0%), or having 0 (1.6%), 1-2 (36.2%), 3-4 (36.4%), or 5+ (19.7%) live births. During 30 years follow-up, there were 1,352 CHDs, 843 MIs, 750 strokes, and 1,618 heart failure events. Compared with women with 1-2 prior births, those with prior pregnancies and no live births had greater incident CHD (HR = 1.64, 95% confidence interval 1.14-2.42) and heart failure risk (1.46, 1.04-2.05), after adjustment for baseline characteristics. Women with 5+ births had greater risk of CHD (1.29, 1.10-1.52) and hospitalized MI (1.38, 1.13-1.69), after adjustment for baseline characteristics and breastfeeding. CONCLUSIONS: In a diverse U.S. cohort, a history of 5+ live births is associated with CHD risk, specifically, MI, independent of breastfeeding. Having a prior pregnancy and no live birth is associated with greater CHD and heart failure risk. PMID- 30481104 TI - Epidemiologic challenges in norovirus vaccine development. AB - Norovirus is the leading cause of acute gastroenteritis (AGE) worldwide. In the United States norovirus is estimated to cause 19-21 million illnesses, 1.7-1.9 million outpatient visits, 56,000-71,000 hospitalizations, and 570-800 deaths annually. Through direct costs and loss of productivity, norovirus disease cost the US economy more than $5.5 billion annually. Due to the lack of available therapies to treat norovirus infections and their highly infectious nature, preventing norovirus illness through vaccination is an appealing strategy. Currently, several norovirus vaccines are in development, including five vaccines in preclinical trials, an oral monovalent vaccine (Vaxart, Inc.) that recently completed a phase IB clinical trial, and a bivalent intramuscular vaccine (Takeda Pharmaceutical Company Limited) in a phase IIB clinical trial. However, no norovirus vaccines are currently available on the market. In this commentary we aim to describe some of the barriers faced in norovirus vaccine development, particularly focusing on vaccine effectiveness and defining the target population. PMID- 30481105 TI - 30-Day Outcomes of Laparoscopic Versus Open Total Proctocolectomy with Ileoanal Anastomosis in Children and Young Adults: A Combined Analysis of the National Surgical Quality Improvement Project Pediatric and Adult Databases. AB - BACKGROUND: Studies comparing pediatric laparoscopic and open total proctocolectomy with ileoanal anastomosis (TPC-IAA) are limited in size and number. This study utilized the adult and pediatric databases of the National Surgical Quality Improvement Project (NSQIP) to evaluate 30-day outcomes of these two techniques. MATERIALS AND METHODS: Patients younger than 21 years who underwent TPC-IAA from 2012 to 2016 were identified in both NSQIP databases. Simple and multivariate logistic regression was used to compare risk of reoperation, readmission, and postoperative occurrences between laparoscopic and open groups. Cox regression was used to evaluate length of stay (LOS). RESULTS: A total of 440 cases were identified, of which 421 (95.7%) were elective. Median age in the elective group was 15.8 years (interquartile range 13-18). Diagnoses included inflammatory bowel disease (47%), benign neoplasm (42%), and Hirschsprung disease (6%). The laparoscopic group (67.5%, n = 139) had shorter median postoperative LOS (6 versus 8 days, P < .001) and decreased incidence of pulmonary complications (risk ratio [RR] 0.09; CI: 0.01-0.80, P = .031) and superficial surgical site infections (SSI) (RR 0.30; 95% CI: 0.10-0.88, P = .028). Median operative time was shorter (4.6 versus 5.1 hours, P = .013) and risk of organ space SSI was lower (RR = 0.11, 95% CI: 0.01-0.80, P = .037) in the open group (n = 282). Rates of 30-day readmission and reoperation were similar between groups. CONCLUSIONS: In the first study to utilize data from both the pediatric and adult NSQIP databases, resulting in the largest pediatric sample of TPC-IAA to date, we found that 67.5% of elective cases were performed laparoscopically, the highest reported in a multi-institutional pediatric study, indicating increasing comfort with advanced laparoscopic techniques among pediatric surgeons. The laparoscopic approach resulted in shorter postoperative LOS and decreased risk of superficial SSI, whereas the open approach was associated with shorter operative time and lower risk of organ space SSI. PMID- 30481106 TI - Safety, immunogenicity, and lot-to-lot consistency of live attenuated varicella vaccine in 1-3 years old children: a double-blind, randomized phase III trial. AB - The study was to evaluate the safety, immunogenicity and lot-to-lot consistency of live attenuated varicella vaccine in Chinese population aged 1-3 years. The double-blind, randomized phase III trial was conducted in Henan Province, China. In total, 1197 subjects were included in this study. Subjects were randomly assigned into four groups in a 2:2:2:1 ratio to receive one of the three lots of commercial scale (CS) vaccine or the licensed pilot scale (LPS) vaccine. Seroconversion rate and neutralizing antibody titers (NATb) were assessed at day 0 pre-vaccination and at day 30 post-vaccination. Safety data were recorded for 30 days post-vaccination. After vaccination, the geometric mean titers (GMTs) of the three CS groups were 25.04 (95% confidence interval [CI], 22.85 to 27.44), 24.47 (95% CI, 22.35 to 26.78) and 25.88 (95% CI, 23.61 to 28.36), respectively (P = 0.6928). The ratio of GMTs adjusted for covariates of each pair of lots were all between 0.67 to 1.50 in susceptible subjects. The difference of seroconversion rate between pooled CS group and LPS group was 3.82 (95% CI, 0.55 to 8.81). Meanwhile, the percentage of solicited local, systemic and unsolicited adverse reactions showed no difference across the four groups, and most of the adverse reactions were mild or moderate in intensity. The CS group was comparable to the LPS group in safety and immunogenicity. The consistency of three consecutive CS lots was reliable. Moreover, the CS group was non-inferior to the LPS group. PMID- 30481108 TI - 'I also want to be vaccinated!' - adolescent boys' awareness and thoughts, perceived benefits, information sources, and intention to be vaccinated against Human papillomavirus (HPV). AB - This study investigates boys' awareness and thoughts about human papillomavirus (HPV) and HPV vaccination, perceived benefits of vaccinating men, information sources and intention to be vaccinated against HPV. We used a qualitative approach and interviews were conducted with 31 upper secondary school male students. Two main themes 1) Promotion of equal health and 2) Increased knowledge facilitates the decision about HPV vaccination emerged from the analysis. The informants believed that it was important and fair to protect boys and girls equally against HPV. If HPV vaccination could prevent both girls and boys against an HPV-related disease, there was nothing to question or to discuss. It was not a matter of sex; it was a matter of equal rights. Moreover, an important reason for vaccinating boys was to prevent the transmission of the virus. However, the boys felt unsure and stated that they needed to know more. The school nurse and the school health were considered suitable both for distributing information and for providing the vaccinations. In conclusion, the participants were in favor of introducing HPV vaccination also for boys in the national vaccination program. Sex-neutral HPV vaccinations were viewed both as a way to stop the virus transmission and a means to promote equal health for the entire population. PMID- 30481107 TI - Ethnic Minority Status and Experiences of Infertility in Female Veterans. AB - BACKGROUND: In the general population, infertility is increasingly prevalent in ethnic minority women; these women suffer longer and are less likely to access care. There is a paucity of data regarding the issue of race and infertility in the growing female military veteran population. MATERIALS AND METHODS: This cross sectional observational study involved computer-assisted telephone interviews of 1,004 Veterans Administration (VA)-enrolled women aged <=52 years. RESULTS: Racial minority veterans were more likely than white veterans to self-report infertility (24% vs. 18%), equally likely to report infertility evaluation (52% vs. 52%), and less likely to report receiving infertility treatment (31% vs. 63%). Differences in self-reported infertility (odds ratios [OR]: 1.50, 95% confidence interval [CI]: 1.02-2.22) and infertility treatment (OR: 0.32, 95% CI: 0.13-0.81) were retained after controlling for age, income, marital status, education, insurance, history of pelvic inflammatory disease, and lifetime sexual assault. While racial minority veterans were equally as likely as white veterans to be evaluated for infertility, white and racial minority groups reported different reasons for not seeking evaluation. CONCLUSIONS: Consistent with civilian studies, our data suggest that racial minority VA-enrolled female veterans are more likely to self-report infertility and less likely to receive infertility treatment. Future research should investigate whether these findings are consistent nationwide and regardless of VA enrollment, and if minority veterans have unique barriers to care. A better understanding of how the VA might improve awareness of infertility evaluation and treatment options, especially for racial minority veterans, is needed. PMID- 30481109 TI - LncRNA TATDN1 contributes to the cisplatin resistance of non-small cell lung cancer through TATDN1/miR-451/TRIM66 axis. AB - BACKGROUND: Chemoresistance has been considered to be a major obstacle for cancer therapy clinically. Long non-coding RNAs (LncRNAs) are asscociated with the development, prognosis and drug-resistance of non-small cell lung cancer (NSCLC). Whereas, the regulatory mechanism of lncRNA TATDN1 in the cisplatin resistance of NSCLC is still not clear. METHODS: The expression of TATDN1, miR-451 and TRIM66 in NSCLC tissues and cell lines were detected by qRT-PCR or western blot. Immunohistochemistry (IHC) assay was performed for the detection of TATDN1 expression profile. 88 patients who underwent cisplatin treatment were followed up to 60-months for the analysis of survival rate. MTT and Flow cytometry analysis were performed for the assessment of cell survival rate, proliferation and apoptosis. Bioinformatics, Dual-Luciferase reporter were employed to analyze the interaction among TATDN1, miR-451 and TRIM66. Xenograft tumor model was constructed to verify the role of TATDN1 in NSCLC treated with cisplatin (DDP) in vivo. RESULTS: TATDN1 and TRIM66 was significantly upregulated while miR-451 was downregulated in NSCLC tissues and cell lines, especially in DDP-resistant tumor tissues and cells. Survival rates of NSCLC patients with low TATDN1 expression were improved following DDP chemotherapy. TATDN1 upregulated TRIM66 expression via sponge for miR-451. Moreover, TATDN1 knockdown improved DDP-sensitivity in NSCLC patients by regulation of miR-451/TRIM66 axis. Finally, knockdown of TATDN1 improved the sensitivity of NSCLC to DDP in vivo. CONCLUSIONS: TATDN1 enhanced the DDP-tolerance of NSCLC cells by upregulating TRIM66 expression via sponging miR-451, hinting a novel regulatory pathway of chemoresistance in DDP-tolerant NSCLC cells and providing a potential therapeutic target for NSCLC patients with DDP-reistance. PMID- 30481110 TI - Immunogenicity and safety of intramuscular versus subcutaneous administration of a combined measles, mumps, rubella, and varicella vaccine to children 12 to 18 months of age. AB - This randomized trial conducted in France compared intramuscular (IM) and subcutaneous (SC) administration of two doses of a measles, mumps, rubella, and varicella (MMRV) combination vaccine (ProQuad(r)) administered one month apart to 405 children 12-18 months of age (NCT00402831). The 2-dose regimen of MMRV administered IM was shown to be as immunogenic as the 2-dose regimen administered SC for all antigens 6 weeks post-vaccination for the subjects who were initially seronegative for measles, mumps, rubella, or varicella (lower bounds of the two sided 95% CIs for the difference in response rates for all antigens greater than 10% [range -2.1 for varicella to -3.0 for mumps]). The antibody response rates for all vaccine antigens 6 weeks after the second dose of MMRV were > 99% in both the IM and SC groups. Fewer subjects in the IM group experienced injection-site AEs compared with the SC group (17.8% and 28.6% post-dose 1, and 20.4% and 29.5% post-dose 2, respectively). From Day 0 to Day 4 post-dose 2, fewer subjects reported erythema and swelling in the IM group than in the SC group (15.4% and 27.0%, and 6.0% and 12.5%, respectively). In both groups, most injection-site AEs started during the first four days after vaccination; their intensity was mainly mild or <=2.5 cm. The rates of fever were comparable between the two groups after each dose of MMRV. In conclusion, two doses of the MMRV vaccine were highly immunogenic and well tolerated when administered either SC or IM. ClinicalTrials.gov Identifier: NCT00402831. PMID- 30481111 TI - Injury rates and characteristics in recreational, elite student and professional dancers: A systematic review. AB - The purpose of this study was to systematically review the literature and synthesise the evidence on injury rates and characteristics in recreational, elite student, and professional dancers. Five online databases were searched from inception to January 2018 and screened by two independent reviewers. Primary research studies were eligible for inclusion if they reported injury rates in recreational, elite student, and/or professional dancers of any genre and measured individual dance exposure at the hour, event, or day level. Sixteen studies were included, with only three studies incorporating recreational dancers. Reported injury incidence rates were less than 5 injuries per 1,000 dance hours, however substantially different definitions and methods for measuring injury and dance exposure were used. Based on the current evidence there is not an identifiable difference in injury rate or characteristics between recreational, elite student, and professional dancers. However, there remains a lack of high quality comprehensive data available across levels and genres of dance participation, and greater focus on consistency and completeness of reporting in dance injury research is still required. PMID- 30481112 TI - A Geometrically Exact Model for Soft Continuum Robots: The Finite Element Deformation Space Formulation. AB - Mathematical modeling of soft robots is complicated by the description of the continuously deformable three-dimensional shape that they assume when subjected to external loads. In this article we present the deformation space formulation for soft robots dynamics, developed using a finite element approach. Starting from the Cosserat rod theory formulated on a Lie group, we derive a discrete model using a helicoidal shape function for the spatial discretization and a geometric scheme for the time integration of the robot shape configuration. The main motivation behind this work is the derivation of accurate and computational efficient models for soft robots. The model takes into account bending, torsion, shear, and axial deformations due to general external loading conditions. It is validated through analytic and experimental benchmark. The results demonstrate that the model matches experimental positions with errors <1% of the robot length. The computer implementation of the model results in SimSOFT, a dynamic simulation environment for design, analysis, and control of soft robots. PMID- 30481113 TI - Self-Other Agreement in Personality Reports: A Meta-Analytic Comparison of Self- and Informant-Report Means. AB - Self-report questionnaires are the most commonly used personality assessment despite longstanding concerns that self-report responses may be distorted by self protecting motives and response biases. In a large-scale meta-analysis ( N = 33,033; k = 152 samples), we compared the means of self- and informant reports of the same target's Big Five personality traits to examine the discrepancies in two rating sources and whether people see themselves more positively than they are seen by others. Inconsistent with a general self-enhancement effect, results showed that self-report means generally did not differ from informant-report means (average delta = -.038). Moderate mean differences were found only when we compared self-reports with stranger reports, suggesting that people are critical of unacquainted targets. We discuss implications of these findings for personality assessment and other fields in which self-enhancement motives are relevant. PMID- 30481114 TI - No Room to "Lean In": A Qualitative Study on Gendered Barriers to Promotion and Leadership. AB - INTRODUCTION: The gender gap in professorship and leadership roles persists in academic medicine, whereas reasons for these disparities remain unclear. MATERIALS AND METHODS: Open-ended text responses to a 2013 faculty engagement survey were analyzed by using the grounded theory and consensual qualitative analysis techniques. The authors grouped 491 faculty's text responses into descriptive codes and three themes: (1) No Obstacles, (2) Barriers to Success, and (3) Concerns Regarding Processes. Demographics of codes were compared by using chi-square analysis. RESULTS: Male faculty identified barriers that included negative views of leadership or leaders. Female faculty, especially those in clinical roles, expressed barriers related to role overload, including that the demands of their current positions prevented advancement or addition of further roles, no matter how desirable further roles may be. Women also shared that considerable self-promotion was required to receive acknowledgement of their work and support by leadership. CONCLUSION: A proposed framework depicts male and female faculty's concerns on a continuum. No Obstacle and Process Concerns were relatively gender neutral, whereas large gender disparities occurred within the Barriers to Success theme. Women's barriers largely revolved around internal obstacles (I can't do any more), and men's barriers largely revolved around external factors (leaders are impeding my progress). Resources are needed to mitigate work overload specifically for female faculty, and to ensure that all faculty are both engaged in advanced career opportunities and encouraged to pursue leadership positions. PMID- 30481115 TI - Handling Stress and Sample Storage Are Associated with Weaker Complement-Mediated Bactericidal Ability in Birds but Not Bats. AB - Variation in immune defense influences infectious disease dynamics within and among species. Understanding how variation in immunity drives pathogen transmission among species is especially important for animals that are reservoir hosts for zoonotic pathogens. Bats, in particular, have a propensity to host serious viral zoonoses without developing clinical disease themselves. The immunological adaptations that allow bats to host viruses without disease may be related to their adaptations for flight (e.g., in metabolism and mediation of oxidative stress). A number of analyses report greater richness of zoonotic pathogens in bats than in other taxa, such as birds (i.e., mostly volant vertebrates) and rodents (i.e., nonvolant small mammals), but immunological comparisons between bats and these other taxa are rare. To examine interspecific differences in bacterial killing ability (BKA), a functional measure of overall constitutive innate immunity, we use a phylogenetic meta-analysis to compare how BKA responds to the acute stress of capture and to storage time of frozen samples across the orders Aves and Chiroptera. After adjusting for host phylogeny, sample size, and total microbe colony-forming units, we find preliminary evidence that the constitutive innate immune defense of bats may be more resilient to handling stress and storage time than that of birds. This pattern was also similar when we analyzed the proportion of nonnegative and positive effect sizes per species, using phylogenetic comparative methods. We discuss potential physiological and evolutionary mechanisms by which complement proteins may differ between species orders and suggest future avenues for comparative field studies of immunity between sympatric bats, birds, and rodents in particular. PMID- 30481116 TI - How Individual Variation in Host Tolerance Affects Competence to Transmit Parasites. AB - Tolerance, or the maintenance of host health or fitness at a given parasite burden, has often been studied in evolutionary and medical contexts, particularly with respect to effects on the evolution of parasite virulence and individual patient outcomes. These bodies of work have provided insight about tolerance for evolutionary phenomena (e.g., virulence) and individual health (e.g., recovering from an infection). However, due to the specific motivations of that work, few studies have considered the ecological ramifications of variation in tolerance, namely, how variation in forms of tolerance could mediate parasite movement through populations and even community-level disease dynamics. Tolerance is most commonly regarded as the relationship between host fitness and parasite burden. However, few if any studies have actually quantified host fitness, instead utilizing proxies of fitness as the response variables to be regressed against parasite burden. Here, we address how attention to the effects of parasite burden on traits that are relevant to host competence (i.e., the ability to amplify parasites to levels transmissible to other hosts/vectors) will enhance our understanding of disease dynamics in nature. We also provide several forms of guidance for how to overcome the challenges of quantifying tolerance in wild organisms. PMID- 30481117 TI - Discovery platform for inhibitors of IgH gene enhancer activity. AB - Immunoglobulin heavy chain (IgH) translocations are common and early oncogenic events in B cell and plasma cell malignancies including B cell non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). IgH translocations bring oncogenes into close proximity with potent enhancer elements within the IgH locus, leading to oncogene up-regulation. As IgH enhancer activity is tightly controlled by B cell lineage-specific signaling and transcriptional networks, we hypothesized that IgH enhancers are potentially druggable targets/elements. To test this, we developed a molecular imaging-based high-throughput screening platform for discovering inhibitors of IgH enhancer-driven transcriptional activity. As proof of concept, we identified a low micromolar potency molecule (compound 30666) that inhibited immunoglobulin production by MM cells and blocked expression of an array of IgH translocation-induced oncogenes (CCND1, FGFR3/MMSET, and MYC) in MM and NHL cell lines. Prolonged exposure to 30666 significantly reduced the viability of IgH translocation-positive NHL and MM cells, but was less effective against cells lacking IgH translocations. Compound 30666 exhibited suitable pharmacological properties, including metabolic stability in liver microsomes and oral bioavailability in mice, and demonstrated preclinical anti-MM activity in a plasmacytoma mouse model. Our work suggests that IgH enhancers are attractive and potentially druggable targets for IgH translocation driven malignancies. PMID- 30481118 TI - Staphylococcus aureus Infecting and Colonizing Experimental Animals, Macaques, in a Research Animal Facility. AB - An outbreak of methicillin-resistant Staphylococcus aureus (MRSA) infections on the skin and soft tissues of experimental macaques in the vivarium of The Rockefeller University, New York, triggered this observational and interventional study. We screened 14 macaques in the colony (samples from head, nares, and rectum) and their housing (40 environmental surfaces) four times in 1 year, for S. aureus colonization or contamination, while implementing enhanced decolonization and decontamination procedures. A total of 114 isolates of S. aureus were recovered and characterized (antibiograms, spa typing, multilocus sequence typing, pulsed-field gel electrophoresis [PFGE], mecA, Panton-Valentine Leukocidin, and arginine catabolic mobile element). Based on these results, six strains of S. aureus were identified: two MRSA strains (t16708/ST3862/PFGE-A, t16709/ST3862/PFGE-C) and one methicillin-sensitive S. aureus (t8397/ST3884/PFGE D) were characterized for the first time in this study; strains belonging to spa types t189 and t4167 have been identified in primates in previous studies. None of these strains was common to the neighboring New York City human community. Thus, it seems probable that the animals were already colonized upon arrival to the University. We suggest screening primates for S. aureus carriage upon arrival to University vivaria and possible implementation of extensive decolonization procedures before any surgical interventions. PMID- 30481119 TI - Making discoveries in immunology. PMID- 30481120 TI - Correlates of Recent HIV Testing Among Transgender Women in Greater Kuala Lumpur, Malaysia. AB - PURPOSE: In Malaysia, an estimated 9.7%-12.4% of transgender women (TW) are HIV positive, with higher estimates among those engaged in sex work. According to the 90-90-90 Joint United Nations Programme on HIV/AIDS strategy, HIV testing is the first crucial step in curbing the HIV epidemic. This study examines correlates of recent HIV testing among TW in Greater Kuala Lumpur, Malaysia. METHODS: TW (N = 199) in Greater Kuala Lumpur completed a survey on healthcare access and utilization, including HIV testing history. Bivariate logistic regression and penalized multivariate logistic regression were used to explore correlates of HIV testing in the last 12 months. RESULTS: Overall, 41.7% of TW reported having ever been tested for HIV. Among participants who were HIV negative or not sure of their HIV status (n = 187), only 18.7% (n = 35) had been tested for HIV in the last 12 months. The multivariate analysis indicated that having a primary care provider (PCP), being 26-40 years of age, and having higher mental health functioning were positively associated with recent HIV testing. Active amphetamine use and previous depression diagnosis were also associated with recent HIV testing. CONCLUSION: HIV testing is the first step in linking individuals to prevention and treatment interventions. Our findings suggest that having a PCP can improve engagement in HIV testing. Moreover, PCPs can serve as a valuable link to HIV treatment and prevention services. Current interventions that target social and behavioral risk factors for HIV, on their own, may be insufficient at engaging all HIV-vulnerable TW. PMID- 30481122 TI - Reporting of Cosmesis in Head and Neck Reconstruction: A Systematic Review. AB - OBJECTIVE: To identify the method and rate at which cosmesis is reported after reconstruction from head and neck surgery among adults. DATA SOURCES: A medical librarian implemented search strategies in multiple databases for head and neck reconstruction, outcome assessment/patient satisfaction, and cosmesis/appearance. REVIEW METHODS: Inclusion and exclusion criteria were designed to capture studies examining adults undergoing reconstruction after head and neck cancer surgery with assessment of postoperative cosmesis. The primary outcome was the method to assess cosmesis. Secondary outcomes were types of instruments used and the rate at which results were reported. Validated instruments used in these studies were compared and critically assessed. RESULTS: The search identified 4405 abstracts, and 239 studies met inclusion and exclusion criteria. Of these, 43% (n = 103) used a scale or questionnaire to quantify the cosmetic outcome: 28% (n = 66), a visual analog, Likert, or other scale; 13% (n = 30), a patient questionnaire; and 3% (n = 7), both. Of the 103 studies that used an instrument, 14% (n = 14, 6% overall) used a validated instrument. The most common validated instrument was the University of Washington Quality of Life (UWQOL) questionnaire (4%, n = 9). The most highly rated instruments were the UWQOL and the Derriford Appearance Scale. CONCLUSIONS: Reporting of cosmetic outcomes after head and neck cancer reconstruction is heterogeneous. Most studies did not report patient feedback, and a minority used a validated instrument to quantify outcomes. To reduce bias, improve reliability, and decrease heterogeneity, we recommend the UWQOL to study cosmetic outcomes after head and neck reconstruction. PMID- 30481121 TI - Understanding Patients' Perspectives and Information Needs Following a Positive Home Human Papillomavirus Self-Sampling Kit Result. AB - OBJECTIVE: We explored patient perspectives after a positive human papillomavirus (HPV) self-sampling result to describe experiences and information needs for this home-based screening modality. MATERIALS AND METHODS: We recruited women who tested high-risk (hr) HPV positive during a pragmatic trial evaluating mailed hrHPV self-sampling kits as an outreach strategy for women overdue for Pap screening in a U.S. integrated health care system. Telephone interviews were conducted from 2014 to 2017. Five independent coders analyzed transcripts using iterative content analysis. RESULTS: Forty-six women (61% of invited; median age 55.5 years) completed a semistructured interview. Six themes emerged: (1) convenience of home-based screening, (2) intense feelings and emotions after receiving positive kit results, (3) importance of seeing provider and discussing kit results, (4) information seeking from various sources, (5) confusion about purpose and meaning of HPV versus Pap tests, and (6) concern that HPV self sampling is inaccurate when the subsequent Pap test is normal. CONCLUSIONS: Although women liked the kit's convenience, discussion about discordant home HPV and in-clinic Pap results led them to question the accuracy of HPV self-sampling. Patient-provider communication around home HPV kits is more complex than for reflex or cotesting because clinician-collected Pap results are unknown at the time of the positive kit result. Patients need education about differences between HPV and Pap tests and how they are used for screening and follow-up. To reassure patients and keep them interested in self-sampling, education should be provided at multiple time points during the screening process. PMID- 30481123 TI - Health Care Costs and Cost-effectiveness in Laryngotracheal Stenosis. AB - OBJECTIVE: Laryngotracheal stenosis (LTS) is resource-intensive disease. The cost effectiveness of LTS treatments has not been adequately explored. We aimed to conduct a cost-effectiveness analysis comparing open reconstruction (cricotracheal/tracheal resection [CTR/TR]) with endoscopic dilation in the treatment of LTS. STUDY DESIGN: Retrospective cohort. SETTING: Tertiary referral center (2013-2017). SUBJECTS AND METHODS: Thirty-four LTS patients were recruited. Annual costs were derived from the Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University. Cost-effectiveness analysis compared CTR/TR versus endoscopic dilation at a willingness-to-pay threshold of $50,000 per quality-adjusted life year (QALY) over 5- and 10-year time horizons. The incremental cost-effectiveness ratio (ICER) was calculated with deterministic analysis and tested for sensitivity with univariate and probabilistic sensitivity analysis. RESULTS: Mean LTS costs were $4080.09 (SE, $569.29) annually for related health care visits. The major risk factor for increased cost was etiology of stenosis. As compared with idiopathic patients, patients with intubation related stenosis had significantly higher annual costs ($5286.56 vs $2873.62, P = .03). The cost of CTR/TR was $8583.91 (SE, $2263.22). Over a 5-year time horizon, CTR/TR gained $896 per QALY over serial dilations and was cost-effective. Over a 10-year time horizon, CTR/TR dominated dilations with a lower cost and higher QALY. CONCLUSION: The cost of treatment for LTS is significant. Patients with intubation-related stenosis have significantly higher annual costs than do idiopathic patients. CTR/TR contributes significantly to cost in LTS but is cost effective versus endoscopic dilations for appropriately selected patients over a 5- and 10-year horizon. PMID- 30481124 TI - Ruling engines and diffraction gratings before Rowland: the work of Lewis Rutherfurd and William Rogers. AB - Diffraction gratings are famously associated with Henry Rowland of Johns Hopkins University but there were precursors. Although gratings were first made and used in Europe, reliable machines for ruling gratings were developed in the USA, and two men, Lewis Rutherfurd and William Rogers, tackled the problem before Rowland. Rutherfurd, a wealthy independent astronomer, designed and built the first screw operated engine for ruling diffraction gratings, the fore-runner of almost all subsequent ruling engines. With it he and his assistant D. C. Chapman ruled many gratings which he generously distributed to practising scientists, thereby materially advancing the science of spectroscopy. Rogers was a Harvard astronomer who developed an interest in the ruling of fine lines on glass that led him to construct a ruling engine with which he investigated the causes of the errors in the rulings he had examined. He continued to seek improvements with a second engine designed for ruling diffraction gratings. He ceased developing this engine when Rowland's excellent gratings began to be available, concentrating instead on related problems to which he could apply the knowledge and skills he had gained, but his investigations assisted Rowland and other later ruling engine builders. This paper brings together what is known about the ruling engines of Rutherfurd and Rogers, their development, the gratings they produced, their quality and the work that was done with them, and assesses and compares their achievements and the impacts of the work of these two men. PMID- 30481126 TI - The religion of the young Isaac Newton. PMID- 30481125 TI - Comparison of Microbiota Variation in Korean Healthy Adolescents with Adults Suggests Notable Maturity Differences. AB - Comparative studies of microbiome variation in world populations and different developmental stages of organisms are essential to decipher the linkages among microbiome, health, and disease. Notably, the gut microbiota are believed to mature in early life. In this context, we compared the gut microbiota diversity in Korean adolescent healthy samples (KAHSs) to healthy Korean adults (HKAs) as well as the Human Microbiome Project healthy samples (HMPHSs), the latter being one of the largest adult cohorts, based on organismal composition, alpha- and beta-diversities, function/pathway prediction analysis, and co-occurrence networks. We found that the gut microbiota compositions, including the ratios of firmicutes to bacteroidetes, between KAHSs and HMPHSs were different, and the diversities of KAHSs were less than those of HMPHSs. The predicted functions, for example, secondary bile acid synthesis and insulin signaling of KAHSs and HMPHSs, were also significantly different. Genus-level networks showed that co occurrences among different taxa more frequently happened in HMPHSs than in KAHSs. Even though both KAHSs and HMPHSs represent healthy microbiomes, comparisons showed substantial differences, likely implicating different diets, environments, and demographics. Interestingly, we observed lower microbial diversities and less frequent co-occurrences among different taxa in KAHSs than adult HMPHSs and HKAs. These new findings collectively suggest that the adolescent gut microbiota in the present Korean sample did not reach the extent of maturity of adult microbiota diversity. In all, further population studies of microbiome variation across geographies and developmental stages are warranted, and should usefully inform future diagnostics and therapeutics innovation targeting the microbiome. PMID- 30481128 TI - Examining the unresolved conundrum of Traditional Birth Attendants' involvement in maternal and child health care delivery in Ghana. AB - Traditional Birth Attendants (TBAs) have been a critical human resource in maternal health care delivery in Ghana. However, following the World Health Organization's directive for countries to discontinue using TBAs, the government of Ghana has since emphasized the use of skilled birth attendants. This policy shift created tensions between TBAs and Community Health Nurses. We examine this conundrum in this paper. We find that despite the ban, TBAs still attend a significant number of births - a situation which has produced intense contestations and continuous jostling for "functioning space" and clients between TBAs and nurses. We recommend a consensus-based partnership approach that promotes cultural competence and is sensitive to contextual cultural practices that underpin pregnancy and childbirth. PMID- 30481127 TI - Role of Ultrasound-Guided Fine-Needle Aspiration Cytology of Omentum in Diagnosis of Abdominal Tuberculosis. AB - AIM: To evaluate the efficacy of ultrasound-guided (USG) fine-needle aspiration cytology examination (FNAC) of the omentum in the diagnosis of abdominal tuberculosis (TB). METHODS: Retrospective review was conducted of data from patients who presented with clinically suspected peritoneal TB between June 2016 and April 2018. We included patients in whom imaging showed omental thickening with or without ascites. Additional features that were assessed on imaging included ascites, the presence of mesenteric or retroperitoneal adenopathy, ileocecal thickening, and involvement of solid abdominal organs. Ultrasound guided FNAC of the omentum was performed using a 22-gauge needle. The cytologic assessment was done for granulomatous inflammation, bacilli on Zeihl-Neelson stain, and for other pathology if any. RESULTS: During the study period, 35 omental FNACs were done. Of these patients, malignancy was reported in eight (22.8%). Of the remaining 27 patients, positive results for TB were reported in 19 patients (70.4%). In these 19 patients with positive FNAC, the median age was 33 years (range 10-63 years), with eight males (42.1%). Ascites was present in 14 (73.7%), abdominal lymphadenopathy was present in 9 (47.4%), ileocecal thickening and involvement of solid abdominal organs were reported in 3 (15.8%) and 4 (21%) patients, respectively. Granulomatous inflammation was reported in 17 (89.5%) and acid-fast bacilli in 10 (57.6%) patients. The Genexpert analysis was done in two patients, with a positive result in one patient. CONCLUSION: Ultrasound-guided FNAC of the omentum is helpful to diagnose abdominal TB in patients having omental thickening with or without other abnormal findings. PMID- 30481129 TI - On the impact of ethanol on the rejection and transfer mechanism during ultrafiltration of a charged macromolecule in water/ethanol. AB - Ultrafiltration (UF) is a sustainable membrane separation technique. It could be useful for the concentration/purification of bio-sourced molecules that are extracted either by pure ethanol or by water/ethanol mixtures. Nevertheless, the process optimization requires an in-depth understanding of the transfer mechanisms of solute through membranes, especially for charged solutes, that are nowadays not sufficiently documented. Previous studies achieved in aqueous media have shown that the rejection of charged solutes by an UF membrane involves at least three mechanisms: convection, diffusion and electrostatic interactions. The present study aims at a systematic analysis of the transfer mechanisms of a model protein (lysozyme) in water/ethanol mixtures (100/0-70/30 v/v) during UF by a zirconia inorganic membrane. The influence of the pH varying in the 4-9 range and of the ionic strength (I) is also discussed. The ionic strength I can be adjusted by addition of an indifferent electrolyte (NaCl) only aiming at the screening of the electrostatic interactions or by addition of a selectively adsorbed electrolyte(KH2PO4) that is able to change the isoelectric pH of the protein and thus to modulate the electrostatic interactions in a different way when compared to NaCl. Of course, both salts have an impact on the protein rejection in UF. The results are analysed using the CDE model previously developed in our group to explain the behaviour of a single protein during UF in water and accounting for convection, diffusion and electrophoretic migration. The applicability of the CDE model in water/ethanol mixtures up to 70/30 v/v is finally shown. PMID- 30481130 TI - New species and records of Coryneum from China. AB - Following the abandonment of dual nomenclature and the implementation of single name nomenclature for pleomorphic fungi, Coryneum was considered to have priority over Pseudovalsa and was recommended for use. Currently, Coryneum is the only genus in the family Coryneaceae (Diaporthales). However, DNA sequence data are lacking for most Coryneum species, and no detailed phylogenetic analyses of the genus are yet available. In the present study, fresh Coryneum samples were collected from chestnut (Castanea) and oak (Quercus) trees in China and morphologically compared with accepted Coryneum species. Based on morphological characteristics, they were identified as one known species, Coryneum castaneicola, and three novel species described here as C. gigasporum, C. sinense, and C. suttonii. Conidial dimensions and host association were considered major characters for species distinction. The previously unknown sexual morph of C. castaneicola is reported and described. A phylogenetic analysis of nuc rDNA internal transcribed spacer (ITS1-5.8S-ITS2 = ITS) and large subunit (28S) sequence data of a representative matrix of Diaporthales confirmed Coryneaceae to represent a monophyletic clade. A phylogenetic analysis of a combined sequence matrix containing the ITS-28S rDNA, the translation elongation factor 1-alpha (TEF1alpha), and the second largest subunit of the RNA polymerase II (RPB2) of the four Chinese and four additional European Coryneum species was performed, confirming the distinctness of these novel species. PMID- 30481131 TI - Revision of pyrophilous taxa of Pholiota described from North America reveals four species-P. brunnescens, P. castanea, P. highlandensis, and P. molesta. AB - A systematic reevaluation of North American pyrophilous or "burn-loving" species of Pholiota is presented based on molecular and morphological examination of type and historical collections. Confusion surrounds application of the names P. brunnescens, P. carbonaria, P. castanea, P. fulvozonata, P. highlandensis, P. molesta, and P. subsaponacea, with multiple names applied to a single species and multiple species described more than once. Molecular annotations using nuc rDNA ITS1-5.8S-ITS2 (internal transcribed spacer [ITS] barcode) and RPB2 (RNA polymerase II second largest subunit) are used to aid in application of these names in a phylogenetic context. Based on ITS molecular annotations of 13 types, the following heterotypic synonymies are proposed: P. highlandensis (syn. P. carbonaria and P. fulvozonata); P. molesta (syn. P. subsaponacea); and P. brunnescens (syn. P. luteobadia). In addition, we observed that the species P. castanea, known previously only from the type collection in Tennessee, is found commonly on burned sites near the Gulf Coast and other southeast regions of the United States. Overall, the pyrophilous trait is evolutionarily derived in Pholiota. Endophytic and endolichenic stages were deduced for P. highlandensis, the most widely distributed of the pyrophilous Pholiota. As a result, we introduce the "body snatchers" hypothesis that explains the maintenance of some pyrophilous fungi in ecosystems as endophytes and/or endolichenic fungi. Photographs, taxonomic descriptions, and a dichotomous key to pyrophilous species of Pholiota that occur in North America are presented. PMID- 30481132 TI - Two Lactarius species (subgenus Plinthogalus) in ectomycorrhizal association with tropical Quercus trees in eastern Mexico. AB - Two species of Lactarius are documented from fragments of tropical lowland oak forest in central Veracruz. Lactarius trichodermoides, described here as new, was found in association with Quercus sapotifolia and Lactarius subplinthogalus with Quercus glaucescens. Both Lactarius species were identified morphologically and supported by phylogenetic analyses of nuc rDNA internal transcribed spacers (ITS1 5.8S-ITS2) and D1-D2 domains of nuc 28S rDNA sequences. Confirmation of mycobionts in ectomycorrhizal (ECM) associations was verified by molecular identification of ECM root tips. Detailed macroscopic and microscopic descriptions and photographs and illustrations of basidiomes and ectomycorrhizas are presented. The new binomial Lactarius chiangmaiensis is proposed for L. subplinthogalus var. chiangmaiensis. PMID- 30481133 TI - The relationship between smoking and dysmenorrhea: A meta-analysis. AB - Many studies have investigated the potential association between smoking and dysmenorrhea. However, results from such studies have been inconsistent. In this study, we assessed the association between smoking and dysmenorrhea by meta analysis. We performed a systematic search of the international databases, including PubMed, Scopus, Web of Science, EBSCO and Google Scholar by the MeSH heading and/or additional terms to obtain relevant studies published from 1990 until 2017. I2 statistics were used to assess heterogeneity. Pooled effects size was obtained using a random effects model. Subgroup analyses were also conducted. Data were analyzed through Stata software version 12 (Stata Corp, College Station, TX, USA). A total of fourteen studies were included in meta-analysis. A significant positive association was observed between current smoking and dysmenorrhea in both the unadjusted (odds ratio [OR] = 1.60; 95 percent confidence interval [CI]: 1.35, 1.85) and adjusted models (AOR = 1.44; 95 percent CI: 1.18, 1.69). Also, the association between current smoking and primary dysmenorrhea was significant only in the unadjusted model (OR = 1.53; 95 percent CI: 1.21, 1.85). The pooled effects size showed a significant association between smoking and dysmenorrhea in the fourteen eligible studies. This provides a new approach for prevention from dysmenorrhea in females for policymakers. PMID- 30481134 TI - Use of Telehealth Screening to Detect Diabetic Retinopathy and Other Ocular Findings in Primary Care Settings. AB - PURPOSE: To determine the incidence of diabetic retinopathy (DR) and other ocular findings in previously diagnosed diabetes using telehealth retinal screening with nonmydriatic fundus photography (nFP) in primary care physicians' offices. METHODS: A retrospective study based on electronic chart review was performed. All diabetic patients who participated in the Wills Eye Hospital (WEH) telehealth retinal screening program from July 1, 2012 to February 20, 2017 were included. In addition to evaluation of DR, other eye pathologies of the retina were detected using nFP. RESULTS: Overall, 9,946 diabetics participated in the WEH telehealth screening system. After exclusion of missing or unreadable images, 15,180 eyes of 7,624 (76.7%) patients were eligible for final analysis. A total of 1,269 (16.6%) patients were noted to have DR changes in at least one eye. Of those, 475 (37.4%) had mild nonproliferative DR (NPDR) in the more severely affected eye, 712 (56.1%) had moderate NPDR, 33 (2.6%) had severe NPDR, 19 (1.5%) had proliferative DR, and 30 (2.4%) have received pan-retinal photocoagulation previously. In addition, there was evidence of diabetic macular edema detectable on nFP in 34 eyes of 29 patients. Other ocular findings included hypertensive retinopathy (709, 9.3%), increased or asymmetric cup-to-disc ratio (562, 7.4%), age-related cataract (379, 5.0%), cotton-wool spots (221, 2.9%), choroidal nevus (74, 1.0%), age-related macular degeneration (AMD) (66, 0.9%), and epiretinal membrane (48, 0.6%). Patients with hypertensive retinopathy, glaucomatous findings, cataract, or AMD were significantly older (p < 0.001) than those without these ocular pathologies. CONCLUSION: The WEH Telehealth Screening Program identified DR in approximately one out of six patients and other ocular pathologies in over 25% of the diabetic population that received screenings in Philadelphia area primary care offices. Given the importance of early detection and routine eye care to prevent vision loss for DR patients, these findings have a significant impact. PMID- 30481135 TI - Marasas et al. 1984 "Toxigenic Fusarium Species: Identity and Mycotoxicology" revisited. AB - This study was conducted to determine the species identity and mycotoxin potential of 158 Fusarium strains originally archived in the South African Medical Research Council's Mycotoxigenic Fungal Collection (MRC) that were reported to comprise 17 morphologically distinct species in the classic 1984 compilation by Marasas et al., Toxigenic Fusarium Species: Identity and Mycotoxicology. Maximum likelihood and maximum parsimony molecular phylogenetic analyses of single and multilocus DNA sequence data indicated that the strains represented 46 genealogically exclusive phylogenetically distinct species distributed among eight species complexes. Moreover, the phylogenetic data revealed that 80/158 strains were received under a name that is not accepted today (ex F. moniliforme) or classified under a different species name. In addition, gas chromatography-mass spectrometry (GC-MS) and/or high-performance liquid chromatography-mass spectrometry (HPLC-MS)-based mycotoxin analyses were conducted to determine which toxins the strains could produce in liquid and/or solid cultures. All of the trichothecene toxin-producing fusaria were nested within the F. sambucinum (FSAMSC) or F. incarnatum-equiseti (FIESC) species complexes. Consistent with this finding, GC-MS analyses detected trichothecenes in agmatine-containing broth or rice culture extracts of all 13 FSAMSC and 10/12 FIESC species tested. Species in six and seven of the eight species complexes were able to produce moniliformin and beauvericin, respectively, whereas B-type fumonisins were only detected in extracts of cracked maize kernel cultures of three species in the F. fujikuroi (FFSC) species complex. PMID- 30481136 TI - In vitro selection of ecologically adapted ectomycorrhizal fungi through production of fungal biomass and metabolites for use in reclamation of biotite mine tailings. AB - Mineral weathering plays an important role in poor-nutrient environments such as mine spoils and tailings. Ectomycorrhizal (ECM) fungi are able to enhance mineral weathering through different mechanisms, thereby increasing the availability of minerals and nutrients to plants. Six ECM fungi (Cadophora finlandia, Cenococcum geophilum, Hebeloma crustuliniforme, Lactarius aurantiosordidus, Paxillus involutes, and Tricholoma scalpturatum) were tested here for their tolerance to biotite-quartz-rich mine tailings. Either solid- or liquid-medium methods were used for in vitro selection of ECM fungi for their ability to grow on mine tailings. ECM fungi were selected based on their mycelial radial growth and metabolite production (ergosterol and low-molecular-mass organic acids, LMMOAs). We found a strong correlation between fungal ergosterol content and mycelial radial growth using the solid-medium method. However, the liquid-medium method was more appropriate for ergosterol synthesis and permitted direct measurement of organic acid production. We found that LMMOAs were exuded by ECM fungi, which solubilized mine tailings for their own growth and nutrition. Finally, we concluded that the ECM fungi C. finlandia and T. scalpturatum are the species most tolerant to tailings and could potentially improve the survival rate, growth, and health of white spruce seedlings planted on biotite mine spoils and tailings. PMID- 30481137 TI - Social Networks and Sugar-Sweetened Beverage Consumption in a Pediatric Urban Academic Practice. AB - Increased sugar-sweetened beverage (SSB) consumption is linked to childhood obesity. The risk of increased SSB consumption is multifactorial. Limited studies have examined children's SSB consumption and social networks. In order to examine the association between SSB consumption and SSB preferences of a child's social network, a cross-sectional survey was administered to patients aged 8-17 years from June to September 2016. In a questionnaire, subjects completed a beverage consumption recall, identified people important to them along with each person's favorite beverage, and answered questions about habits, environment, and attitudes. Subjects with higher SSB consumption (>16 fl oz) were compared to subjects with lower SSB consumption (<=16 fl oz). 202 surveyed: 55% female, 53% Hispanic, 45% Black, 28% overweight or obese. Children drank an average of 3 cups/day of SSBs, range of 0-15 cups/day. Social networks included caregiver, relative, and friend. Subjects with higher SSB consumption (n = 96) were compared to those with lower SSB consumption (n = 106). We found children with higher SSB consumption had higher odds of reporting a higher number of people in their immediate social networks who prefer SSB, adjusted for habits, environment, and attitudes (aOR 1.41; 95% CI: 1.02-1.99; p < 0.05). Children are more likely to have higher SSB consumption if they list people in their immediate social network who prefer SSB as their favorite drink. Further research is required to explore the influence of social networks on health behaviors of children. PMID- 30481138 TI - Content validation of a questionnaire measuring basic perinatal depression knowledge. AB - Perinatal depression (PND) screening is encouraged in healthcare settings. We aimed to develop and content validate a basic PND knowledge questionnaire for use among pharmacists and potentially other primary healthcare professionals (HCPs). A six-item questionnaire was developed. Twenty-five perinatal mental health experts were invited to participate in content validation by completing the questionnaire and assessing its content validity. A content validity index (CVI) score above 0.8 was indicative of content validity. Expert comments may inform items' deletion or revision. Between November 2016 and February 2017, ten experts participated. For five out of six items, the CVI score was 0.9 or 1.0. Two experts selected "I think none are correct" for one item regarding the onset of postpartum depression. Comments reflected the lack of consensus in the literature surrounding onset periods and prevalence rates and informed minor modifications to three of six questions and seven of 24 response options. The CVI for the questionnaire was 0.83.Content validation of a questionnaire measuring basic PND knowledge resulted in modifications. Comments about PND onset and prevalence indicated the need for consistency when defining and measuring these constructs. This questionnaire may be used among pharmacists and other HCPs. PMID- 30481139 TI - Identifying risk and protective factors related to depressive symptoms among Northern Plains American Indian women cancer survivors. AB - Cancer is the leading cause of death among American Indian and Alaska Native (AIAN) women, and depressive symptoms have been linked to higher mortality, but research on depressive symptoms among AIAN cancer patients has been scant. The purpose of this exploratory study was, using the Framework of Historical Oppression, Resilience, and Transcendence, to examine risk and protective factors related to depressive symptoms in American Indian (AI) women cancer survivors. We examined the relationships of adverse childhood experiences (ACE), perceived health status, resilience, and social support with depressive symptoms in Northern Plains AI women cancer survivors. We used a cross-sectional design with purposive sampling of 73 female cancer survivors (aged 18 years or older) between June 2014 and February 2015. Hierarchical multiple regression was used to test three sets of variables in relation to depressive symptoms: (1) sociodemographics, (2) risk factors (ACE and perceived health), and (3) protective factors (psychological resilience and social support). Approximately 47 percent of participants had probable depressive symptoms. Depressive symptoms were inversely associated with perceived health, psychological resilience, and social support. These results support bolstering existing social support among AI cancer patients and survivors as well as prevention and intervention efforts that strengthen resilience. PMID- 30481140 TI - The Use of Tools and Checklists to Assess the Risk of Child Sexual Exploitation: Lessons from UK Practice. AB - Tools to assess the risk of becoming a victim of child sexual exploitation (CSE) have been developed by UK CSE practitioners based on their professional experiences, with little evidence underpinning their development, and no evaluation/validation. Little is known about how they are used in practice. This paper summarizes two studies. The first study consisted of a rapid review to identify factors associated with increased or decreased risk of vulnerability to becoming a victim of CSE and the assessment of 10 tools being used in the UK. The second study undertook interviews and online survey with professionals across multi-agencies to establish the use of tools. Results illustrate the context and processes in which the tools are being used and identify concerns regarding their ability to identify and protect children. PMID- 30481141 TI - Sleep Hygiene Mediates, but Does Not Moderate, Associations Between Temperament and Sleep Quality in University Students. AB - Although there are theoretical reasons to expect associations among temperament, sleep hygiene behaviors (SHB), and global sleep quality (GSQ), these relations have not yet been examined despite their potential impact on undergraduate student well-being. The present study was conducted to (1) examine relations between temperament and GSQ in university students broadly recruited, (2) document associations between SHB and temperament in this sample, and (3) to determine whether associations among temperament, SHB, and GSQ were best explained by mediation or moderation models. One hundred fifty-two university students completed questionnaires that inquired about temperament, SHB, and GSQ. Correlations revealed that poorer SHB and GSQ were associated reduced effortful control; poorer SHB was also associated with increased negative affect (SHB and GSQ were unrelated to extraversion and orienting sensitivity). Mediation models assessing relations amongst temperament, SHB, and GSQ indicated that negative affect and effortful control may predispose university students to engage in fewer SHB, negatively impacting GSQ; variability in SHB did not moderate the impact of temperament on GSQ. Additional research is needed to confirm and extend these findings, with the ultimate goal of improving undergraduate GSQ (a) by reducing negative affect and increasing effortful control or (b) by improving SHB that are uniquely associated with these temperament profiles. PMID- 30481142 TI - Report of the Fifth Zebrafish Research Conference of China. AB - The fifth zebrafish research conference of China was held from October 29 to November 1, 2017, at Wuzhen, China, a beautiful small town that is close to Shanghai. The organizing committee, composed of Tao P. Zhong, Ruilin Zhang, Jie He, Xu Wang, Weijun Pan, Ying Cao, Yao Zu, Qiu Jiang, and Jiulin Du, organized enthusiastically and successfully the 4-day meeting. A total of 646 attendees from 110 academic and corporate institutions, mainly from China and also United States, Germany, Sweden, Singapore, Taiwan, and Japan, presented and discussed their recent research progresses. The packed meeting program included keynote and plenary presentations, concurrent oral talks, and poster sessions. The meeting also invited established investigators to present their research achievements in the fields of development and genetics using other model systems. The conference was a great success and revealed how important the zebrafish has become as a model system for developmental biology, functional genomics, tissue regeneration, and biomedicine. PMID- 30481143 TI - Clinical Significance of B7-H3 Expression During the Progression of Hepatitis B Virus Infection. AB - B7-H3, one of the costimulatory members participating in checkpoint pathway, has been shown to be upregulated after hepatitis B virus (HBV) infection. To further explore the clinical significance of dynamic B7-H3 expression during the progression of HBV infection, we systematically investigated the expression pattern of B7-H3 and the correlation of B7-H3 expression with the ratio of T lymphocyte subsets and clinical parameters at different stages in the course of the disease. Flow cytometry and enzyme-linked immunosorbent assay data showed that soluble form of B7-H3 (sB7-H3) was positively correlated with the frequency of Treg cells in acute hepatitis B (AHB), chronic hepatitis B (CHB), and hepatocellular carcinoma patients with HBV infection (HBV-HCC). Membrane form of B7-H3 (mB7-H3) expressed on Treg cells and monocytes was positively correlated with the frequency of Treg cells in CHB. SB7-H3 had relationship with mB7-H3 expressed on Treg cells and monocytes at different stages during HBV infection, except for HBV-HCC. MB7-H3 expressed on Treg cells was positively correlated with that on monocytes in AHB, CHB, HBV-liver cirrhosis, and HBV-HCC. The B7-H3 expression was positively correlated with aspartate aminotransferase and alanine aminotransferase levels in CHB and sB7-H3 level was higher in late tumor/node/metastasis (TNM) stage in HCC. Higher mB7-H3 expression was associated with greater tumor size, later TNM stage, and worse prognosis in HBV-HCC indicated by immunohistochemistry. Taken together, these results suggested that B7-H3 might contribute to the progression of HBV infection by triggering inhibitory signals in effector T cells and it was closely associated with the progression and poor prognosis during HBV infection. B7-H3 could be utilized as a potential clinical indicator and a potential target for therapeutic strategies against HBV infection. PMID- 30481144 TI - Antecedent and Consequence of Nurse Engagement. AB - This study explores the mediating effect of work engagement on the relationship between transformational leadership (TFL) and nurses' job performance, along with the moderating effect of conscientiousness on work engagement within the TFL/performance relationship. Survey data were collected from 234 supervisor subordinate dyads at a regional hospital in Taiwan, and linear regression modeling performed to examine the hypotheses. TFL was found to be positively correlated with nurses' job performance; and the motivation mechanism of work engagement did mediate the relationship between TFL and job performance, but only when nurses' conscientiousness was high. As such, the results provide new insights into both how, and why, TFL can enhance nurses' job performance: specifically, that their work engagement and conscientiousness are key determinants of how the TFL/job performance relationship operates. PMID- 30481145 TI - Validation of the Arabic and Tunisian Arabic version of the KINDL questionnaires for children with diabetes type 1. AB - AIM: We aimed to validate the Arabic and Tunisian Arabic versions of diabetes- specific quality of life (QOL) instrument KINDL-R Diabetes Module for Tunisian children population with type 1 diabetes. PATIENTS AND METHODS: This a cross sectional study to validate Arabic and Tunisian KINDL QOL instrument that we translate in literary and dialectal Arabic. Both forward and backward translations from the German version of KINDL QOL into Arabic version were performed. Our project received a GPED grant in August 2014. After the face validity of the Arabic version was established, it was then pilot-tested. Finally, the validity and reliability of the final version of the Arabic KINDL questionnaire were evaluated. RESULTS: The KINDL-R Diabetes Module (DM) questionnaire of QOL was given to 212 persons : 108 children (aged 3-17 years) with T1DM and 104 parents. The Cronbach's alpha coefficients of the overall items and the main domains was about 0.7. The mean total score of the KINDL-R DM was 69,56 A +/- 14,01 in children aged 7-13 years, 59.93A+/- 15.17 in children aged 13-17 years and 56.6A+/- 9.9 in parents (higher scores indicate better QOL). The parents reported lower diabetes-specific HRQOL than the children themselves (p < 0.01).Emotional score was correlated to environment (p = 0,03). Self-esteem was reported to environment (p = 0,02) and mother's instruction level's (p = 0,014). CONCLUSIONS: The KINDL-R Diabetes Module (DM) of QOL in literary and dialectal Arabic have sufficient acceptability, reliability and validity so as to be used for the purposes of a comparative in Tunisian and Arabic populations. PMID- 30481146 TI - Prevalence of Severe Fever with Thrombocytopenia Syndrome Virus in Ticks Collected from National Parks in Korea. AB - Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral disease in East Asian countries, including China, Japan, and the Republic of Korea (ROK). The causative agent of SFTS is the SFTS virus (SFTSV), which is transmitted by ticks. To investigate the prevalence of SFTSV in the ROK, a total of 9744 ticks were collected from vegetation in five national parks between July and November 2015. Of the collected adult and nymph ticks, Haemaphysalis longicornis (68.44%) was the most abundant, followed by Haemaphysalis flava (29.66%), Ixodes nipponensis (1.56%), and Amblyomma testudinarium (0.34%). Collected larval ticks were of the genera Haemaphysalis (99.61%) and Ixodes (0.39%). One-step RT-PCR and nested PCR were used to detect SFTSV-specific genes from each individual adult and nymph tick and pooled larval ticks. SFTSV was detected in 4.77% (48/1006) in H. longicornis, 1.15% (5/436) in H. flava, 0% (0/23) in I. nipponensis, and 20% (1/5) in A. testudinarium. The infection rate of SFTSV in adult and nymph ticks was 3.61%. The prevalence of SFTSV in adult and nymph ticks was relatively high, compared with previous reports. In larval ticks, the minimum infection rate was 0.31%. SFTSV was detected in ticks collected from both trail and nontrail areas in the national parks, and up to 800 meters above sea level. The sequences obtained showed 99.4-99.7% homology with SFTS virus S segment sequences from Chinese and Japanese ticks. PMID- 30481148 TI - It Takes a Village to Raise a Journal. PMID- 30481147 TI - Effect of trail C1595T variant and gene expression on the pathogenesis of non small cell lung cancer. AB - It is known that disorders in apoptosis function play an important role in the pathogenesis of many types of cancer, including lung cancer. Tumor necrosis factor related apoptosis inducing ligand (TRAIL), a type II transmembrane protein, is a death ligand capable of inducing apoptosis by activating distinctive death receptor. Our purpose in this study is to investigate the gene polymorphisms in TRAIL molecular pathway and TRAIL gene expression levels in non small cell lung cancer (NSCLC) patients in terms of pathogenesis and prognosis of the disease. In this study, TRAIL C1595T polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism analysis in 158 patients with NSCLC and 98 healthy individuals. Surgically resected tissues were examined and classified histopathologically. In addition, TRAIL gene expression levels in tumor tissue and tumor surrounding tissue samples of 48 patients with NSCLC were determined using real-time polymerase chain reaction. TRAIL gene expression levels of NSCLC patients were detected significantly 28.8 fold decrease in the tumor tissue group compared to the control group (p=0.026). When patients were compared to tumor stage, expression of TRAIL gene in advanced tumor stage was found to be significantly 7.86 fold higher than early tumor stage [p=0.028]. No significant relationship was found between NSCLC predisposition and prognostic parameters of NSCLC with TRAIL genotypes, but the frequency of TRAIL gene 1595 CT genotype was observed to be lower in the patients compared to the other genotypes, and the difference was found to be very close to statistical significance (p=0.07). It can be suggested that TRAIL may play an important role in the development of NSCLC and may be an effective prognostic factor in tumor progression.: It is known that disorders in apoptosis function play an important role in the pathogenesis of many types of cancer, including lung cancer. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a type II transmembrane protein, is a death ligand capable of inducing apoptosis by activating distinctive death receptor. Our purpose in this study is to investigate the gene polymorphisms in TRAIL molecular pathway and TRAIL gene expression levels in non-small cell lung cancer (NSCLC) patients in terms of pathogenesis and prognosis of the disease. PMID- 30481149 TI - Orderly display of limb lead ECGs raises Chinese intern's diagnostic accuracy when determining frontal plane QRS axis. AB - BACKGROUND: There is limited information on whether the orderly display of limb lead ECGs (electrocardiograms) can facilitate students to determine frontal plane QRS complex wave electrical axis. OBJECTIVES: The study investigated whether the orderly display of limb lead ECGs can raise Chinese undergraduate intern's diagnostic accuracy when determining frontal plane axis. DESIGN: A total of 147 fifth-year undergraduate interns aged between 21 and 25 years were randomly arranged into 2 groups: one group was given classically displayed ECGs of limb leads while the other group was given orderly displayed ECGs of limb leads. They were then taught to determine frontal plane axis with one of the above displays. The intern's diagnostic accuracy and time used were measured. RESULTS: After teaching, the orderly display can more effectively raise diagnostic accuracy when determining axis as compared to the classical display (76.65 +/- 23.16% vs. 68.88 +/- 23.21%, P < 0.05), although diagnostic accuracy in axis determination was improved in both groups as compared to the axis determination at baseline (all P < 0.05). CONCLUSIONS: Orderly display of limb lead ECGs may raise Chinese intern's diagnostic accuracy when determining frontal plane axis. PMID- 30481150 TI - Significance of bacteriophages in fermented soybeans: A review. AB - Bacteriophages are ubiquitous and have been reported to have been found in many food products. Their presence is important as they have the ability to interact with their bacterial host in food matrices. Fermented soybean products, one of the most widely consumed ethnic foods among Asian people, are prepared naturally and include Japanese Natto, Indian Kinema, Korean Chongkukjang and Thai Thua Nao. This review highlights bacteriophages which have been isolated from fermented soybean products and also includes an overview of their diversity, occurrence as well as their significance. PMID- 30481151 TI - Addison's disease in antiphospholipid syndrome: a rare complication. AB - Addison's disease (AD) is the most common endocrine manifestation of antiphospholipid syndrome (APS), but it remains a very rare complication of the syndrome. It is caused by adrenal venous thrombosis and consequent hemorrhagic infarction or by spontaneous (without thrombosis) adrenal hemorrhage, usually occurring after surgery or anticoagulant therapy. We present a clinical case of a 36-year-old female patient with a previous diagnosis of APS. She presented with multiple thrombotic events, including spontaneous abortions. During evaluation by the third episode of abortion, a CT imaging revealed an adrenal hematoma, but the patient was discharged without further investigation. A few weeks later, she presented in the emergency department with manifestations suggestive of adrenal insufficiency. Based on that assumption, she started therapy with glucocorticoids, with significant clinical improvement. After stabilization, additional investigation confirmed AD and excluded other etiologies; she also started mineralocorticoid replacement. This case illustrates a rare complication of APS that, if misdiagnosed, may be life threatening. A high index of suspicion is necessary for its diagnosis, and prompt treatment is crucial to reduce the morbidity and mortality potentially associated. Learning points: AD is a rare but life-threatening complication of APS. It is important to look for AD in patients with APS and a suggestive clinical scenario. APS must be excluded in patients with primary adrenal insufficiency and adrenal imaging revealing thrombosis/hemorrhage. Glucocorticoid therapy should be promptly initiated when AD is suspected. Mineralocorticoid replacement must be started when there is confirmed aldosterone deficiency. Hypertension is a common feature of APS; in patients with APS and AD, replacement therapy with glucocorticoids and mineralocorticoids may jeopardize hypertension management. PMID- 30481152 TI - LHX3 deficiency presenting in the United States with severe developmental delay in a child of Syrian refugee parents. AB - In this case report, we present a novel mutation in Lim-homeodomain (LIM-HD) transcription factor, LHX3, manifesting as combined pituitary hormone deficiency (CPHD). This female patient was originally diagnosed in Egypt during infancy with Diamond Blackfan Anemia (DBA) requiring several blood transfusions. Around 10 months of age, she was diagnosed and treated for central hypothyroidism. It was not until she came to the United States around two-and-a-half years of age that she was diagnosed and treated for growth hormone deficiency. Her response to growth hormone replacement on linear growth and muscle tone were impressive. She still suffers from severe global development delay likely due to delay in treatment of congenital central hypothyroidism followed by poor access to reliable thyroid medications. Her diagnosis of DBA was not confirmed after genetic testing in the United States and her hemoglobin normalized with hormone replacement therapies. We will review the patient's clinical course as well as a review of LHX3 mutations and the associated phenotype. Learning points: Describe an unusual presentation of undertreated pituitary hormone deficiencies in early life Combined pituitary hormone deficiency due to a novel mutation in pituitary transcription factor, LHX3 Describe the clinical phenotype of combined pituitary hormone deficiency due to LHX3 mutations. PMID- 30481153 TI - Utilisation of gonadotrophin-releasing hormone (GnRH) analogue to differentiate ovarian from adrenal hyperandrogenism in postmenopausal women. AB - Postmenopausal hyperandrogenism is a relatively rare diagnosis resulting from excess androgen production from the adrenals or ovaries. The exclusion of malignant causes is a priority. Laboratory tests and imaging are utilised to help differentiate the source of excess androgens. We report two cases of postmenopausal hyperandrogenism in women aged 75 and 67 years. Both cases presented with clinical features suggestive of hyperandrogenism which had developed gradually over the previous 2 years. Laboratory investigations confirmed a significant elevation in their serum testosterone levels. In both cases, imaging did not reveal any abnormality of the adrenals or ovaries. To help differentiate an adrenal vs ovarian source a single-dose GnRH analogue was given with measurement of testosterone and gonadotrophin levels pre and post. The reduction in gonadotrophins achieved by the GnRH analogue resulted in suppression of testosterone levels which suggested an ovarian source. Both patients proceeded to bilateral oophorectomy. Histology revealed a benign hilus cell tumour in one case and a benign Leydig cell tumour in the other. Learning points: A key part of the work-up of postmenopausal hyperandrogenism is to differentiate between an adrenal or an ovarian source of excess androgens; Imaging may not identify small ovarian tumours or hyperthecosis and may also identify incidental adrenal masses which are non-functioning; Current guidelines suggest ovarian and adrenal venous sampling when imaging is inconclusive but this requires technical expertise and has a high failure rate; GnRH analogue use can successfully confirm ovarian source and should be considered as a diagnostic tool in this setting. PMID- 30481154 TI - Bone microarchitecture and volumetric bone density impairment in young male adults with childhood-onset growth hormone deficiency. AB - CONTEXT: Adult growth hormone deficiency (AGHD) is characterized by low bone density and increased risk of fracture. Bone microarchitecture is insufficiently evaluated in patients with childhood-onset AGHD (CO AGHD). OBJECTIVE: To assess volumetric bone density (vBMD) and bone microarchitecture in CO AGHD in early adulthood after cessation of recombinant growth hormone (rhGH) treatment. DESIGN AND SUBJECTS: Case-control study in a major academic medical center in Beijing, including twenty young male adults with CO AGHD and thirty age- and weight matched non-athletic healthy men. High-resolution peripheral quantitative computerized tomography (HR-pQCT) of distal radius and tibia was performed. OUTCOMES: The main outcomes were vBMD and morphometry parameters from HR-pQCT. RESULTS: Compared with healthy controls, CO AGHD group had significantly decreased insulin like growth factor 1 (IGF-1) level and IGF-1 SDS (p<0.001). beta-CTX and alkaline phosphatase levels in CO AGHD group were significantly increased (p<0.001). CO AGHD group had significantly decreased total vBMD, cortical vBMD, trabecular vBMD, cortical area, cortical thickness as well as trabecular thickness and trabecular bone volume fraction of both tibia and radius (p<0.001). CO AGHD patients had an 8.4 kg decrease in grip strength and a significantly decrease in creatinine levels (p=0.001). At both tibia and radius, by finite element analysis, bone stiffness and failure load of the CO AGHD patients were significantly decreased (p<0.001). After adjusting for age, BMI and serum levels of testosterone and free thyroxin, serum IGF-1 level was a positive predictor for total vBMD, cortical vBMD, cortical area, trabecular vBMD, bone stiffness and failure load of both tibia and distal radius in all subjects. CONCLUSIONS: Young adult male patients with childhood-onset adult growth hormone deficiency who are no longer receiving growth hormone replacement have prominently impaired volumetric bone density and bone microarchitecture, and lower estimated bone strength. PMID- 30481155 TI - Plasma steroid metabolome profiling for the diagnosis of adrenocortical carcinoma. AB - OBJECTIVE: Current workup for the pre-operative distinction between frequent adrenocortical adenomas (ACA) and rare but aggressive adrenocortical carcinomas (ACC) combines imaging and biochemical testing. We here investigated the potential of plasma steroid hormone profiling by liquid chromatography tandem mass spectrometry (LC-MS/MS) for the diagnosis of malignancy in adrenocortical tumours. DESIGN: Retrospective cohort study of prospectively collected EDTA plasma samples in a single tertiary reference center. METHODS: Steroid hormone profiling by liquid chromatography tandem mass spectrometry (LC-MS/MS) in random plasma samples and logistic regression modelling. RESULTS: 15 steroid hormones were quantified in 66 ACA (29 males; M) and 42 ACC (15 M) plasma samples. Significantly higher abundances in ACC vs. ACA were observed for 11 deoxycorticosterone, progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, DHEA, DHEAS and estradiol (all p<0.05). Maximal areas under the curve (AUC) for discrimination between ACA and ACC for single analytes were only 0.76 (estradiol) and 0.77 (progesterone), respectively. Logistic regression modelling enabled the discovery of diagnostic signatures composed of six specific steroids for male and female patients with AUC of 0.95 and 0.94, respectively. Positive predictive values in males and females were 92% and 96%, negative predictive values 90 and 86%, respectively. CONCLUSION: This study in a large adrenal tumour patient cohort demonstrates the value of plasma steroid hormone profiling for diagnosis of ACC. Application of LC-MS/MS analysis and of our model may facilitate diagnosis of malignancy in non-expert centers. We propose to continuously evaluate and improve diagnostic accuracy of LC-MS/MS-profiling by applying machine learning algorithms to prospectively obtained steroid hormone profiles. PMID- 30481156 TI - Germline and somatic mosaicism in a family with Multiple Endocrine Neoplasia type 1 (MEN1) syndrome. AB - CONTEXT: Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the tumor suppressor gene MEN1 and can be diagnosed based on clinical, familial and/or genetic criteria. We present a family in which we found both germline and somatic mosaicism for MEN1. Family description: In our proband we diagnosed MEN1. The mutation was not detected in her parents (DNA extracted from leucocytes). When her brother was found to harbor the same MEN1 mutation as our proband and, around the same time, their father was diagnosed with a neuroendocrine carcinoma, this tumour was investigated for the MEN1 mutation as well. In the histologic biopsy of this tumour the same MEN1 mutation was detected as previously found in his children. Re-analysis of his blood using multiplex ligation-dependent probe amplification (MLPA) showed a minimal, but consistently decreased signal for the MEN1 specific MLPA-probes. The deletion was confirmed in his son by high resolution array analysis. Based on the array data we concluded that the deletion was limited to the MEN1 gene and that the father had both germline and somatic mosaicism for MEN1. CONCLUSIONS: To our knowledge this is the first reported family with combined germline and somatic mosaicism for MEN1. This study illustrates that germline mosaicism is important to consider in apparently sporadic de novo MEN1 mutations, because of its particular importance for genetic counseling, specifically when evaluating the risk for family members and when considering the possibility of somatic mosaicism in the parent with germline mosaicism. PMID- 30481157 TI - MECHANISMS IN ENDOCRINOLOGY: Does circadian and ultradian glucocorticoid exposure affect the brain? AB - Glucocorticoids are a class of systematically secreted hormones, vital for mammalian life, which are intensively investigated for more than 80 years. They regulate multiple body processes like metabolism, fluid homeostasis, immune and stress system responsivity, as well as brain function. Glucocorticoids have a complex rhythm by which they are released to circulation from the adrenal cortex. The hormone exhibits a circadian variation, with high hormonal levels being secreted just prior and during the active part of the day, and progressively lower and lower amounts being released during the inactive part of it. Underlying this diurnal variation there is a more dynamic, ultradian rhythm composed of frequent episodes of glucocorticoid secretion (hormonal pulses). Accumulating evidence from observational, in silico, in vitro and in vivo, preclinical and clinical studies suggest that both aspects of glucocorticoid rhythmicity are preserved among mammalian species and are important for brain function. The central nervous system is exposed to both aspects of the hormonal rhythm, and has developed mechanisms able to perceive them, and translate them to differential cellular events, genomic and non-genomic. Thus, glucocorticoid rhythmicity regulates various physiological neural and glial processes, under baseline and stressful conditions, and hormonal dysrhythmicity has been associated with cognitive and behavioural defects. This raises a number of clinical implications concerning (i) glucocorticoid involvement in neuropsychiatric disease, and (ii) improving the therapeutic efficacy or expanding the role of glucocorticoid-based treatments in such conditions. PMID- 30481159 TI - HDAC inhibitors impair Fshb subunit expression in murine gonadotrope cells. AB - Fertility is dependent on follicle-stimulating hormone (FSH), a product of gonadotrope cells of the anterior pituitary gland. Hypothalamic gonadotropin releasing hormone (GnRH) and intra-pituitary activins are regarded as the primary drivers of FSH synthesis and secretion. Both stimulate expression of the FSH beta subunit gene (Fshb), although the underlying mechanisms of GnRH action are poorly described relative to those of the activins. There is currently no consensus on how GnRH regulates Fshb transcription, as results vary across species and between in vivo and in vitro approaches. One of the more fully developed models suggests that the murine Fshb promoter is tonically repressed by histone deacetylases (HDACs) and that GnRH relieves this repression, at least in immortalized murine gonadotrope-like cells (LbetaT2 and alphaT3-1). In contrast, we observed that the class I/II HDAC inhibitor trichostatin A (TSA) robustly inhibited basal, activin A-, and GnRH-induced Fshb mRNA expression in LbetaT2 cells and in primary murine pituitary cultures. Similar results were obtained with the class I specific HDAC inhibitor, entinostat, whereas two class II specific inhibitors, MC1568 and TMP269, had no effects on Fshb expression. Collectively, these data suggest that class I HDACs are positive, not negative, regulators of Fshb expression in vitro and that, contrary to earlier reports, GnRH may not stimulate Fshb by inhibiting HDAC-mediated repression of the gene. PMID- 30481158 TI - VALIDATION OF A CLINICOPATHOLOGICALSCORE FOR THE PREDICTION OF POST-SURGICAL EVOLUTION OF PITUITARY ADENOMA: RETROSPECTIVE ANALYSIS ON 566 PATIENTS FROM A TERTIARY CARE CENTRE. AB - A clinicopathological score has been proposed by Trouillas et al. to predict the evolution of pituitary adenomas. Aim of our study was to perform an independent external validation of this score and identify other potential predictor of post surgical outcome. The study sample included 566 patients with pituitary adenomas, specifically 253 FSH/LH-secreting, 147 GH-secreting, 85 PRL-secreting, 72 ACTH secreting and 9 TSH-secreting tumours with at least 3-year post-surgical follow up. In 437 cases, pituitary adenomas were non-invasive, with low (grade 1a, 378 cases) or high (grade 1b, 59 cases) proliferative activity. In 129 cases, tumours were invasive, with low (grade 2a, 87 cas-es) or high (grade 2b, 42 cases) proliferative activity. During the follow-up (mean 5.8 years), 60 pa-tients developed disease recurrence or progression, with a total of 130 patients with pituitary disease at last follow-up. Univariate analysis demonstrated a significantly higher risk of disease persistence and recurrence/progression in patients with PRL-, ACTH- and FSH/LH-secreting tumours as com-pared to those with somatotroph tumours, and in those with high proliferative activity (grade 1b and 2b) or >1 cm diameter. Multivariate analysis confirmed tumour type and grade to be independent predictors of disease free-survival. Tumour invasion, Ki-67 and tumour type were the only independent prognostic factors of disease-free survival. Our data confirmed the validity of Trouillas' score, being tumour type and grade independent pre-dictors of disease evolution. Therefore, we recommend to always consider both features, together with tumour histological subtype, in the clinical setting to early identify patients at higher risk of recurrence. PMID- 30481160 TI - Depressive symptoms, burnout, and declining medical career interest among undergraduate pre-medical students. AB - Objectives: To investigate the relationship between mental health issues and medical career interest among undergraduate premedical students, and to explore whether this association varies by gender. Methods: A longitudinal survey of freshman and sophomore premedical students at Indiana University was conducted during the 2015-16 academic year. Survey data were collected from 390 respondents via an online questionnaire (response rate=14%) in September 2015, and 292 of these respondents participated in the follow-up survey in April 2016 (retention rate=75%). Multi-level regression models were used to estimate the associations among depressive symptoms, burnout, and medical career interest. Results: Respondents who experienced more depressive symptoms (beta = -.07, z =-2.49, p =.013) and higher levels of burnout (beta = -.50, z =-3.98, p <.001) reported significant reductions in medical career interest over the study period. These associations remained consistent after controlling for socio-demographic characteristics and prior academic achievement. Depressive symptoms were associated with steeper declines in medical career interest among women compared to men (beta = -.09, z =-2.01, p =.045), though the relationship between burnout and medical career interest did not significantly vary by gender. Conclusions: Results provide evidence that premeds who experience more depressive symptoms and higher levels of burnout become less interested in entering the medical profession. The negative association between depressive symptoms and medical career interest was even more pronounced among premedical women compared to men. Findings suggest that colleges and universities in the United States should implement programs aimed at safeguarding the mental health of premedical students. PMID- 30481161 TI - Transcriptional expressions of Chromobox 1/2/3/6/8 as independent indicators for survivals in hepatocellular carcinoma patients. AB - Chromobox (CBX) proteins are important components of epigenetic regulation complexes known to play key roles in hepatocellular carcinoma (HCC). Little is known about the function of distinct CBXs in HCC. To address this issue, the study investigated the roles of CBXs in the prognosis of HCC using ONCOMINE, UALCAN, Human Protein Atlas, Kaplan-Meier Plotter, c-BioPortal databases. Over expressions of 8 CBXs members were found to be significantly associated with clinical cancer stages and pathological tumor grades in HCC patients. Besides, higher mRNA expressions of CBX1/2/3/6/8 were found to be significantly associated with shorter overall survival (OS) in HCC patients, while higher mRNA expression of CBX7 was associated with favorable OS. Multivariate analysis also showed that high mRNA expressions of CBX1/2/3/6/8 were independent prognostic factors for shorter OS of HCC patients. Moreover, high mutation rate of CBXs (51%) was also observed in HCC patients, and genetic alteration in CBXs was associated with shorter OS and disease-free survival (DFS) in HCC patients. Taken together, these results indicated that CBX1/2/3/6/8 could be prognostic biomarkers for survivals of HCC patients. PMID- 30481162 TI - Splicing factor SRSF1 promotes gliomagenesis via oncogenic splice-switching of MYO1B. AB - Abnormal alternative splicing (AS) caused by alterations of splicing factors contributes to tumor progression. Serine/arginine splicing factor 1 (SRSF1) has emerged as a key oncodriver in numerous solid tumors, leaving its roles and mechanisms largely obscure in glioma. Herein we demonstrated that SRSF1 was increased in glioma tissues and cell lines. Moreover, its expression was correlated positively with tumor grade and Ki-67 index, but inversely with patients' survival. Using RNA-seq, we comprehensively screened and identified multiple SRSF1-affected AS events. Motif analysis revealed a position-dependent modulation of AS by SRSF1 in glioma. Functionally, we verified that SRSF1 promoted cell proliferation, survival and invasion by specifically switching the AS of myosin IB (MYO1B) gene and facilitating the expression of the oncogenic and membrane-localized isoform, MYO1B-fl. Strikingly, MYO1B splicing was dysregulated in parallel with SRSF1 expression in gliomas, and predicted the poor prognosis of the patients. Further investigation revealed that SRSF1-guided AS of MYO1B gene increased the tumorigenic potentials of glioma cells through the PDK1/AKT and PAK/LIMK pathways. Taken together, we identify SRSF1 as an important oncodriver, which integrates the AS controlling of MYO1B into promotion of gliomagenesis, and represents a potential prognostic biomarker and target for glioma therapy. PMID- 30481163 TI - A Simple and Innovative Repair Technique for Full-Thickness Defects of Lower Lip. PMID- 30481164 TI - Atypical Fibroxanthoma Invading Parietal Bone. PMID- 30481165 TI - Klotho Protein Protects Human Keratinocytes from UVB-Induced Damage Possibly by Reducing Expression and Nuclear Translocation of NF-kappaB. AB - BACKGROUND UV-related skin disease such as actinic keratosis is a major concern in public health. In view of the cell injury induced by UVB, Klotho protein it is an ideal therapy to eliminate UVB-induced cell damages and the associated signaling pathways. MATERIAL AND METHODS To gain insights into the potential role of Klotho and the underlying molecular mechanism, we constructed a Klotho overexpress HaCaT cell line and assessed the protection against UVB insults. The effects of exposure to UVB radiation on the human keratinocyte HaCaT cells, including cell growth, apoptosis, and changes of selected biomarkers, were measured by CCK-8, flow cytometry, Quantitative real-time PCR, and Western blot analysis. RESULTS We found that enhanced NF-kappaB activity was accompanied by decreased expression of the anti-aging protein Klotho upon UVB stimulation, which was further confirmed with in vivo experiments. Overexpression of Klotho was able to considerably alleviate the UVB-induced damages to cells and reversed the UVB caused biomarker changes to a great extent, which was comparable to the effects of administration of NF-kappaB inhibitor PDTC, suggesting the inhibition of nuclear translocation and DNA-binding activity of NF-kappaB. Furthermore, Klotho overexpression was proved to decrease the nuclear expression of NF-kappaB as much as the treatment with PDTC, which provides support for the direct regulation of NF-kappaB by Klotho. CONCLUSIONS Collectively, our work provides new insight into the potential role of Klotho in the context of UVB-induced injuries in human keratinocytes, as well as providing the basis for future study of new therapies against UV-related skin disease. PMID- 30481166 TI - Long-distance communication: Looping of human papillomavirus genomes regulates expression of viral oncogenes. AB - High-risk human papillomaviruses (HPVs) are a major cause of cancers. HPVs infect epithelial cells, and viral oncogenes disrupt several cellular processes, including cell division, differentiation, and apoptosis. Expression of these oncogenes is relatively low in undifferentiated epithelial cells but increases in differentiating cells by unknown mechanisms. In a new study, Parish and colleagues unveil how two cellular proteins, CCCTC-binding factor (CTCF) and Yin Yang 1 (YY1), mediate looping of the HPV18 genome, which regulates expression of viral oncogenes in both dividing and differentiating epithelial cells. PMID- 30481167 TI - Correction: Drosophila species learn dialects through communal living. AB - [This corrects the article DOI: 10.1371/journal.pgen.1007430.]. PMID- 30481168 TI - Modeling craniofacial development reveals spatiotemporal constraints on robust patterning of the mandibular arch. AB - How does pattern formation occur accurately when confronted with tissue growth and stochastic fluctuations (noise) in gene expression? Dorso-ventral (D-V) patterning of the mandibular arch specifies upper versus lower jaw skeletal elements through a combination of Bone morphogenetic protein (Bmp), Endothelin-1 (Edn1), and Notch signaling, and this system is highly robust. We combine NanoString experiments of early D-V gene expression with live imaging of arch development in zebrafish to construct a computational model of the D-V mandibular patterning network. The model recapitulates published genetic perturbations in arch development. Patterning is most sensitive to changes in Bmp signaling, and the temporal order of gene expression modulates the response of the patterning network to noise. Thus, our integrated systems biology approach reveals non intuitive features of the complex signaling system crucial for craniofacial development, including novel insights into roles of gene expression timing and stochasticity in signaling and gene regulation. PMID- 30481169 TI - Genome-wide CRISPR screens for Shiga toxins and ricin reveal Golgi proteins critical for glycosylation. AB - Glycosylation is a fundamental modification of proteins and membrane lipids. Toxins that utilize glycans as their receptors have served as powerful tools to identify key players in glycosylation processes. Here, we carried out Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9-mediated genome wide loss-of-function screens using two related bacterial toxins, Shiga-like toxins (Stxs) 1 and 2, which use a specific glycolipid, globotriaosylceramide (Gb3), as receptors, and the plant toxin ricin, which recognizes a broad range of glycans. The Stxs screens identified major glycosyltransferases (GTs) and transporters involved in Gb3 biosynthesis, while the ricin screen identified GTs and transporters involved in N-linked protein glycosylation and fucosylation. The screens also identified lysosomal-associated protein transmembrane 4 alpha (LAPTM4A), a poorly characterized four-pass membrane protein, as a factor specifically required for Stxs. Mass spectrometry analysis of glycolipids and their precursors demonstrates that LAPTM4A knockout (KO) cells lack Gb3 biosynthesis. This requirement of LAPTM4A for Gb3 synthesis is not shared by its homolog lysosomal-associated protein transmembrane 4 beta (LAPTM4B), and switching the domains between them determined that the second luminal domain of LAPTM4A is required, potentially acting as a specific "activator" for the GT that synthesizes Gb3. These screens also revealed two Golgi proteins, Transmembrane protein 165 (TMEM165) and Transmembrane 9 superfamily member 2 (TM9SF2), as shared factors required for both Stxs and ricin. TMEM165 KO and TM9SF2 KO cells both showed a reduction in not only Gb3 but also other glycosphingolipids, suggesting that they are required for maintaining proper levels of glycosylation in general in the Golgi. In addition, TM9SF2 KO cells also showed defective endosomal trafficking. These studies reveal key Golgi proteins critical for regulating glycosylation and glycolipid synthesis and provide novel therapeutic targets for blocking Stxs and ricin toxicity. PMID- 30481170 TI - A Bayesian mixture modelling approach for spatial proteomics. AB - Analysis of the spatial sub-cellular distribution of proteins is of vital importance to fully understand context specific protein function. Some proteins can be found with a single location within a cell, but up to half of proteins may reside in multiple locations, can dynamically re-localise, or reside within an unknown functional compartment. These considerations lead to uncertainty in associating a protein to a single location. Currently, mass spectrometry (MS) based spatial proteomics relies on supervised machine learning algorithms to assign proteins to sub-cellular locations based on common gradient profiles. However, such methods fail to quantify uncertainty associated with sub-cellular class assignment. Here we reformulate the framework on which we perform statistical analysis. We propose a Bayesian generative classifier based on Gaussian mixture models to assign proteins probabilistically to sub-cellular niches, thus proteins have a probability distribution over sub-cellular locations, with Bayesian computation performed using the expectation-maximisation (EM) algorithm, as well as Markov-chain Monte-Carlo (MCMC). Our methodology allows proteome-wide uncertainty quantification, thus adding a further layer to the analysis of spatial proteomics. Our framework is flexible, allowing many different systems to be analysed and reveals new modelling opportunities for spatial proteomics. We find our methods perform competitively with current state of-the art machine learning methods, whilst simultaneously providing more information. We highlight several examples where classification based on the support vector machine is unable to make any conclusions, while uncertainty quantification using our approach provides biologically intriguing results. To our knowledge this is the first Bayesian model of MS-based spatial proteomics data. PMID- 30481171 TI - RNA3DCNN: Local and global quality assessments of RNA 3D structures using 3D deep convolutional neural networks. AB - Quality assessment is essential for the computational prediction and design of RNA tertiary structures. To date, several knowledge-based statistical potentials have been proposed and proved to be effective in identifying native and near native RNA structures. All these potentials are based on the inverse Boltzmann formula, while differing in the choice of the geometrical descriptor, reference state, and training dataset. Via an approach that diverges completely from the conventional statistical potentials, our work explored the power of a 3D convolutional neural network (CNN)-based approach as a quality evaluator for RNA 3D structures, which used a 3D grid representation of the structure as input without extracting features manually. The RNA structures were evaluated by examining each nucleotide, so our method can also provide local quality assessment. Two sets of training samples were built. The first one included 1 million samples generated by high-temperature molecular dynamics (MD) simulations and the second one included 1 million samples generated by Monte Carlo (MC) structure prediction. Both MD and MC procedures were performed for a non redundant set of 414 RNAs. For two training datasets (one including only MD training samples and the other including both MD and MC training samples), we trained two neural networks, named RNA3DCNN_MD and RNA3DCNN_MDMC, respectively. The former is suitable for assessing near-native structures, while the latter is suitable for assessing structures covering large structural space. We tested the performance of our method and made comparisons with four other traditional scoring functions. On two of three test datasets, our method performed similarly to the state-of-the-art traditional scoring function, and on the third test dataset, our method was far superior to other scoring functions. Our method can be downloaded from https://github.com/lijunRNA/RNA3DCNN. PMID- 30481173 TI - Machine learning in population health: Opportunities and threats. AB - Abraham D. Flaxman and Theo Vos of the Institute for Health Metrics and Evaluation, University of Washington, discuss near-term applications for ML in population health and name their priorities for ongoing ML development. PMID- 30481172 TI - Development and validation of machine learning models to identify high-risk surgical patients using automatically curated electronic health record data (Pythia): A retrospective, single-site study. AB - BACKGROUND: Pythia is an automated, clinically curated surgical data pipeline and repository housing all surgical patient electronic health record (EHR) data from a large, quaternary, multisite health institute for data science initiatives. In an effort to better identify high-risk surgical patients from complex data, a machine learning project trained on Pythia was built to predict postoperative complication risk. METHODS AND FINDINGS: A curated data repository of surgical outcomes was created using automated SQL and R code that extracted and processed patient clinical and surgical data across 37 million clinical encounters from the EHRs. A total of 194 clinical features including patient demographics (e.g., age, sex, race), smoking status, medications, comorbidities, procedure information, and proxies for surgical complexity were constructed and aggregated. A cohort of 66,370 patients that had undergone 99,755 invasive procedural encounters between January 1, 2014, and January 31, 2017, was studied further for the purpose of predicting postoperative complications. The average complication and 30-day postoperative mortality rates of this cohort were 16.0% and 0.51%, respectively. Least absolute shrinkage and selection operator (lasso) penalized logistic regression, random forest models, and extreme gradient boosted decision trees were trained on this surgical cohort with cross-validation on 14 specific postoperative outcome groupings. Resulting models had area under the receiver operator characteristic curve (AUC) values ranging between 0.747 and 0.924, calculated on an out-of-sample test set from the last 5 months of data. Lasso penalized regression was identified as a high-performing model, providing clinically interpretable actionable insights. Highest and lowest performing lasso models predicted postoperative shock and genitourinary outcomes with AUCs of 0.924 (95% CI: 0.901, 0.946) and 0.780 (95% CI: 0.752, 0.810), respectively. A calculator requiring input of 9 data fields was created to produce a risk assessment for the 14 groupings of postoperative outcomes. A high-risk threshold (15% risk of any complication) was determined to identify high-risk surgical patients. The model sensitivity was 76%, with a specificity of 76%. Compared to heuristics that identify high-risk patients developed by clinical experts and the ACS NSQIP calculator, this tool performed superiorly, providing an improved approach for clinicians to estimate postoperative risk for patients. Limitations of this study include the missingness of data that were removed for analysis. CONCLUSIONS: Extracting and curating a large, local institution's EHR data for machine learning purposes resulted in models with strong predictive performance. These models can be used in clinical settings as decision support tools for identification of high-risk patients as well as patient evaluation and care management. Further work is necessary to evaluate the impact of the Pythia risk calculator within the clinical workflow on postoperative outcomes and to optimize this data flow for future machine learning efforts. PMID- 30481174 TI - A new method for modelling biological invasions from early spread data accounting for anthropogenic dispersal. AB - Biological invasions are one of the major causes of biodiversity loss worldwide. In spite of human aided (anthropogenic) dispersal being the key element in the spread of invasive species, no framework published so far accounts for its peculiar characteristics, such as very rapid dispersal and independence from the existing species distribution. We present a new method for modelling biological invasions using historical spatio-temporal records. This method first discriminates between data points of anthropogenic origin and those originating from natural dispersal, then estimates the natural dispersal kernel. We use the expectation-maximisation algorithm for the first step; we then use Ripley's K function as a spatial similarity metric to estimate the dispersal kernel. This is done accounting for habitat suitability and providing estimates of the inference precision. Tests on simulated data show good accuracy and precision for this method, even in the presence of challenging, but realistic, limitations of data in the invasion time series, such as gaps in the survey times and low number of records. We also provide a real case application of our method using the case of Litoria frogs in New Zealand. This method is widely applicable across the field of biological invasions, epidemics and climate change induced range shifts and provides a valuable contribution to the management of such issues. Functions to implement this methodology are made available as the R package Biolinv (https://cran.r-project.org/package=Biolinv). PMID- 30481175 TI - Religiosity predicts negative attitudes towards science and lower levels of science literacy. AB - Past research suggests that religion and science may conflict on which is a better tool for explaining the world. This conflict implies that religiosity might negatively impact both attitudes toward science and science knowledge. However, past research has focused mostly on religious affiliation and has not consistently identified such a relation using a general religiosity measure that assesses religious beliefs and religious practice. Using two large, nationally representative datasets as well as two original datasets, and controlling for relevant demographic variables, four studies (N = 9,205) showed that general measures of religiosity are negatively associated with science knowledge, a relation that was partially mediated by an association between religiosity and negative attitudes toward science. Study 2 also showed that parents' reports about their religiosity and its role in their children's upbringing predicted, some 20 years later, their children's attitudes toward science. The studies are correlational but the longitudinal relations in Study 2 suggests that religiosity might undermine science literacy. PMID- 30481176 TI - Deep-learning-assisted diagnosis for knee magnetic resonance imaging: Development and retrospective validation of MRNet. AB - BACKGROUND: Magnetic resonance imaging (MRI) of the knee is the preferred method for diagnosing knee injuries. However, interpretation of knee MRI is time intensive and subject to diagnostic error and variability. An automated system for interpreting knee MRI could prioritize high-risk patients and assist clinicians in making diagnoses. Deep learning methods, in being able to automatically learn layers of features, are well suited for modeling the complex relationships between medical images and their interpretations. In this study we developed a deep learning model for detecting general abnormalities and specific diagnoses (anterior cruciate ligament [ACL] tears and meniscal tears) on knee MRI exams. We then measured the effect of providing the model's predictions to clinical experts during interpretation. METHODS AND FINDINGS: Our dataset consisted of 1,370 knee MRI exams performed at Stanford University Medical Center between January 1, 2001, and December 31, 2012 (mean age 38.0 years; 569 [41.5%] female patients). The majority vote of 3 musculoskeletal radiologists established reference standard labels on an internal validation set of 120 exams. We developed MRNet, a convolutional neural network for classifying MRI series and combined predictions from 3 series per exam using logistic regression. In detecting abnormalities, ACL tears, and meniscal tears, this model achieved area under the receiver operating characteristic curve (AUC) values of 0.937 (95% CI 0.895, 0.980), 0.965 (95% CI 0.938, 0.993), and 0.847 (95% CI 0.780, 0.914), respectively, on the internal validation set. We also obtained a public dataset of 917 exams with sagittal T1-weighted series and labels for ACL injury from Clinical Hospital Centre Rijeka, Croatia. On the external validation set of 183 exams, the MRNet trained on Stanford sagittal T2-weighted series achieved an AUC of 0.824 (95% CI 0.757, 0.892) in the detection of ACL injuries with no additional training, while an MRNet trained on the rest of the external data achieved an AUC of 0.911 (95% CI 0.864, 0.958). We additionally measured the specificity, sensitivity, and accuracy of 9 clinical experts (7 board-certified general radiologists and 2 orthopedic surgeons) on the internal validation set both with and without model assistance. Using a 2-sided Pearson's chi-squared test with adjustment for multiple comparisons, we found no significant differences between the performance of the model and that of unassisted general radiologists in detecting abnormalities. General radiologists achieved significantly higher sensitivity in detecting ACL tears (p-value = 0.002; q-value = 0.019) and significantly higher specificity in detecting meniscal tears (p value = 0.003; q-value = 0.019). Using a 1-tailed t test on the change in performance metrics, we found that providing model predictions significantly increased clinical experts' specificity in identifying ACL tears (p-value < 0.001; q-value = 0.006). The primary limitations of our study include lack of surgical ground truth and the small size of the panel of clinical experts. CONCLUSIONS: Our deep learning model can rapidly generate accurate clinical pathology classifications of knee MRI exams from both internal and external datasets. Moreover, our results support the assertion that deep learning models can improve the performance of clinical experts during medical imaging interpretation. Further research is needed to validate the model prospectively and to determine its utility in the clinical setting. PMID- 30481178 TI - VDR polymorphism, gene expression and vitamin D levels in leprosy patients from North Indian population. AB - BACKGROUND: Leprosy is a chronic infectious disease caused by Mycobacterium leprae and mainly affects skin, peripheral nerves. Vitamin D receptor (VDR) gene polymorphism has been found to be associated with leprosy. Vitamin D has been shown to control several host immunomodulating properties through VDR gene. Vitamin D deficiency was also found to be linked to an increased risk for several infections and metabolic diseases. OBJECTIVE: In the present study, we investigated the association of VDR gene polymorphism, mRNA gene expression of VDR and the vitamin D levels with leprosy and its reactional states. METHODOLOGY: A total of 305 leprosy patients consisting of tuberculoid (TT), borderline tuberculoid (BT), borderline lepromatous (BL), lepromatous leprosy (LL), as well as 200 healthy controls were enrolled in the study. We identified single nucleotide polymorphisms (SNPs) of VDR Taq1, Fok1 and Apa1, as well as the expression of VDR mRNA gene using PCR-based restriction fragment length polymorphism (RFLP) analysis and real-time PCR respectively. We also performed ELISA to measure vitamin D levels. RESULT: We observed that SNP of VDR gene (Fok1 and Taq1) are associated with the leprosy disease. The allelic frequency distribution of T and t allele (p = 0.0037), F and f allele (p = 0.0024) was significantly higher in leprosy patients and healthy controls. ff genotype of Fok1 was found to be associated with leprosy patients [p = 0.0004; OR (95% CI) 3.148 (1.662-5.965)]. The recessive model of Fok1 genotype was also found to be significantly associated in leprosy patients in comparison to healthy controls [p = 0.00004; OR (95% CI) 2.85 (1.56-5.22)]. Leprosy patients are significantly associated with t-F-a haplotype. Further, VDR gene expression was found to be lower in non-reaction group compared to that of reaction group of leprosy and healthy controls. Paradoxically, we noted no difference in the levels of vitamin D between leprosy patients and healthy controls. CONCLUSION: Blood levels of vitamin D do not play any role in clinical manifestations of any forms of leprosy. ff genotype of Fok1 and tt genotype of Taq1 was found to be associated with leprosy per se. Association of t-F-a haplotype with leprosy was found to be significant and could be used as a genetic marker to identify individuals at high risk for developing leprosy. VDR gene expression was lower in TT/BT and BL/LL groups of leprosy in comparison to that of healthy controls. PMID- 30481177 TI - A metabolome-wide characterization of the diabetic phenotype in ZDF rats and its reversal by pioglitazone. AB - Type 2 diabetes (T2D) is a complex metabolic disease associated with alterations in glucose, lipid and protein metabolism. In order to characterize the biochemical phenotype of the Zucker diabetic fatty (ZDF) rat, the most common animal model for the study of T2D, and the impact of the insulin sensitizer pioglitazone, a global, mass spectrometry-based analysis of the metabolome was conducted. Overall, 420 metabolites in serum, 443 in the liver and 603 in the intestine were identified at study end. In comparison to two control groups, obese diabetic ZDF rats showed characteristic metabolic signatures that included hyperglycemia, elevated beta-oxidation, dyslipidemia-featured by an increase in saturated and monounsaturated fatty acids and a decrease of medium chain and of polyunsaturated fatty acids in serum-and decreased amino acid levels, consistent with their utilization in hepatic gluconeogenesis. A 13-week treatment with the PPARgamma agonist pioglitazone reversed most of these signatures: Pioglitazone improved glycemic control and the fatty acid profile, elevated amino acid levels in the liver, but decreased branched chain amino acids in serum. The hitherto most comprehensive metabolic profiling study identified a biochemical blueprint for the ZDF diabetic model and captured the impact of genetic, nutritional and pharmacological perturbations. The in-depth characterization on the molecular level deepens the understanding and further validates the ZDF rat as a suitable preclinical model of diabetes in humans. PMID- 30481179 TI - Deletion of Pr72 causes cardiac developmental defects in Zebrafish. AB - The alpha regulator subunit B'' of protein phosphatase 2 (PPP2R3A), a regulatory subunit of protein phosphatase 2A (PP2A), was reported to present a special subcellular localization in cardiomyocytes and elevate in non-ischemia failing hearts. PPP2R3A has two transcriptions PR72 and PR130. PR72 acts as a negative regulator of the Wnt signaling cascade, while the Wnt signaling cascade plays a pivotal role in cardiac development. And PR130 was found to be involved in cardiac development of zebrafish in our previous study. Thus, to investigate the function of PR72 in heart, two stable pr72 knockout (KO) zebrafish lines were generated using Transcription Activator-Like Effector Nuclease (TALEN) technology. Homozygous pr72 KO fish struggled to survive to adulthood and exhibited cardiac developmental defects, including enlarged ventricular chambers, reduced cardiomyocytes and decreased cardiac function. And the defective sarcomere ultrastructure that affected mitochondria, I bands, Z lines, and intercalated disks was also observed. Furthermore, the abnormal heart looping was detected in mutants which could be rescued by injection with wild type pr72 mRNA. Additionally, it was found that Wnt effectors were elevated in mutants. Those indicated that deletion of pr72 in zebrafish interrupted cardiac development, probably through activation of the Wnt pathway. PMID- 30481180 TI - Mobile detection of autism through machine learning on home video: A development and prospective validation study. AB - BACKGROUND: The standard approaches to diagnosing autism spectrum disorder (ASD) evaluate between 20 and 100 behaviors and take several hours to complete. This has in part contributed to long wait times for a diagnosis and subsequent delays in access to therapy. We hypothesize that the use of machine learning analysis on home video can speed the diagnosis without compromising accuracy. We have analyzed item-level records from 2 standard diagnostic instruments to construct machine learning classifiers optimized for sparsity, interpretability, and accuracy. In the present study, we prospectively test whether the features from these optimized models can be extracted by blinded nonexpert raters from 3-minute home videos of children with and without ASD to arrive at a rapid and accurate machine learning autism classification. METHODS AND FINDINGS: We created a mobile web portal for video raters to assess 30 behavioral features (e.g., eye contact, social smile) that are used by 8 independent machine learning models for identifying ASD, each with >94% accuracy in cross-validation testing and subsequent independent validation from previous work. We then collected 116 short home videos of children with autism (mean age = 4 years 10 months, SD = 2 years 3 months) and 46 videos of typically developing children (mean age = 2 years 11 months, SD = 1 year 2 months). Three raters blind to the diagnosis independently measured each of the 30 features from the 8 models, with a median time to completion of 4 minutes. Although several models (consisting of alternating decision trees, support vector machine [SVM], logistic regression (LR), radial kernel, and linear SVM) performed well, a sparse 5-feature LR classifier (LR5) yielded the highest accuracy (area under the curve [AUC]: 92% [95% CI 88%-97%]) across all ages tested. We used a prospectively collected independent validation set of 66 videos (33 ASD and 33 non-ASD) and 3 independent rater measurements to validate the outcome, achieving lower but comparable accuracy (AUC: 89% [95% CI 81%-95%]). Finally, we applied LR to the 162-video-feature matrix to construct an 8-feature model, which achieved 0.93 AUC (95% CI 0.90-0.97) on the held-out test set and 0.86 on the validation set of 66 videos. Validation on children with an existing diagnosis limited the ability to generalize the performance to undiagnosed populations. CONCLUSIONS: These results support the hypothesis that feature tagging of home videos for machine learning classification of autism can yield accurate outcomes in short time frames, using mobile devices. Further work will be needed to confirm that this approach can accelerate autism diagnosis at scale. PMID- 30481181 TI - Mitochondrial genome annotation and phylogenetic placement of Oreochromis andersonii and O. macrochir among the cichlids of southern Africa. AB - Genetic characterization of southern African cichlids has not received much attention. Here, we describe the mitogenome sequences and phylogenetic positioning of Oreochromis andersonii and O. macrochir among the African cichlids. The complete mitochondrial DNA sequences were determined for O. andersonii and O. macrochir, two important aquaculture and fisheries species endemic to southern Africa. The complete mitogenome sequence lengths were 16642 bp and 16644 bp for O. andersonii and O. macrochir respectively. The general structural organization follows that of other teleost species with 13 protein coding genes, 2 rRNAs, 22 tRNAs and a non-coding control region. Phylogenetic placement of the two species among other African cichlids was performed using Maximum Likelihood (ML) and Bayesian Markov-Chain-Monte-Carlo (MCMC). The consensus trees confirmed the relative positions of the two cichlid species with O. andersonii being very closely related to O. mossambicus and O. macrochir showing a close relation to both species. Among the 13 mitochondrial DNA protein coding genes ND6 may have evolved more rapidly and COIII was the most conserved. There are signs that ND6 may have been subjected to positive selection in order for these cichlid lineages to diversify and adapt to new environments. More work is needed to characterize the southern Africa cichlids as they are important species for capture fisheries, aquaculture development and understanding biogeographic history of African cichlids. Bio-conservation of some endangered cichlids is also essential due to the threat by invasive species. PMID- 30481182 TI - Antibody responses to Zika virus proteins in pregnant and non-pregnant macaques. AB - The specificity of the antibody response against Zika virus (ZIKV) is not well characterized. This is due, in part, to the antigenic similarity between ZIKV and closely related dengue virus (DENV) serotypes. Since these and other similar viruses co-circulate, are spread by the same mosquito species, and can cause similar acute clinical syndromes, it is difficult to disentangle ZIKV-specific antibody responses from responses to closely-related arboviruses in humans. Here we use high-density peptide microarrays to profile anti-ZIKV antibody reactivity in pregnant and non-pregnant macaque monkeys with known exposure histories and compare these results to reactivity following DENV infection. We also compare cross-reactive binding of ZIKV-immune sera to the full proteomes of 28 arboviruses. We independently confirm a purported ZIKV-specific IgG antibody response targeting ZIKV nonstructural protein 2B (NS2B) that was recently reported in ZIKV-infected people and we show that antibody reactivity in pregnant animals can be detected as late as 127 days post-infection (dpi). However, we also show that these responses wane over time, sometimes rapidly, and in one case the response was elicited following DENV infection in a previously ZIKV-exposed animal. These results suggest epidemiologic studies assessing seroprevalence of ZIKV immunity using linear epitope-based strategies will remain challenging to interpret due to susceptibility to false positive results. However, the method used here demonstrates the potential for rapid profiling of proteome-wide antibody responses to a myriad of neglected diseases simultaneously and may be especially useful for distinguishing antibody reactivity among closely related pathogens. PMID- 30481184 TI - From humanitarian aid to humanization: When outgroup, but not ingroup, helping increases humanization. AB - Dehumanization and infrahumanization involve decreasing the humanity attributed to others. Despite the existence of a large body of work on these topics, little is known about how to increase outgroup humanization. Across two experiments, we examined the effects of intergroup and intragroup helping on dehumanization and infrahumanization. In Study 1, we showed that news of an outgroup helping the ingroup after a natural disaster reduced infrahumanization, but not dehumanization. Reduced infrahumanization emerged regardless of the amount of aid given by the outgroup. By contrast, learning about ingroup helping the outgroup following a natural disaster did not decrease dehumanization or infrahumanization, regardless of amount of aid offered by the ingroup. Study 2 replicated and extended these findings by demonstrating that only intergroup helping by the outgroup to the ingroup reduced dehumanization. Intragroup helping, by either the ingroup or outgroup had no influence on outgroup perceptions. We report all measures, manipulations, and exclusions in each study. Implications of recent research on intergroup helping as a means to outgroup humanization are considered. PMID- 30481183 TI - Psychological advocacy towards healing (PATH): A randomized controlled trial of a psychological intervention in a domestic violence service setting. AB - BACKGROUND: Experience of domestic violence and abuse (DVA) is associated with mental illness. Advocacy has little effect on mental health outcomes of female DVA survivors and there is uncertainty about the effectiveness of psychological interventions for this population. OBJECTIVE: To test effectiveness of a psychological intervention delivered by advocates to DVA survivors. DESIGN, MASKING, SETTING, PARTICIPANTS: Pragmatic parallel group individually randomized controlled trial of normal DVA advocacy vs. advocacy + psychological intervention. Statistician and researchers blinded to group assignment. Setting: specialist DVA agencies; two UK cities. Participants: Women aged 16 years and older accessing DVA services. INTERVENTION: Eight specialist psychological advocacy (SPA) sessions with two follow up sessions. MEASUREMENTS: Primary outcomes at 12 months: depression symptoms (PHQ-9) and psychological distress (CORE-OM). Primary analysis: intention to treat linear (logistic) regression model for continuous (binary) outcomes. RESULTS: 263 women recruited (78 in shelter/refuge, 185 in community), 2 withdrew (1 community, control group; 1 intervention, refuge group), 1 was excluded from the study for protocol violation (community, control group), 130 in intervention and 130 in control groups. Recruitment ended June 2013. 12-month follow up: 64%. At 12-month follow up greater improvement in mental health of women in the intervention group. Difference in average CORE-OM score between intervention and control groups: -3.3 points (95% CI -5.5 to -1.2). Difference in average PHQ-9 score between intervention and control group: -2.2 (95% CI -4.1 to -0.3). At 12 months, 35% of the intervention group and 55% of the control group were above the CORE-OM 2clinical threshold (OR 0.32, 95% CI 0.16 to 0.64); 29% of the intervention group and 46% of the control group were above the PHQ-9 clinical threshold (OR 0.41, 95% CI 0.21 to 0.81). LIMITATIONS: 64% retention at 12 months. CONCLUSIONS: An eight-session psychological intervention delivered by DVA advocates produced clinically relevant improvement in mental health outcomes compared with normal advocacy care. TRIAL REGISTRATION: ISRCTN registry ISRCTN58561170 Original Research 3675/3750. PMID- 30481185 TI - Women's experiences of a randomised controlled trial of a specialist psychological advocacy intervention following domestic violence: A nested qualitative study. AB - BACKGROUND: Women's experience of domestic violence and abuse (DVA) is associated with mental illness which may not be addressed by domestic violence advocacy. The study aimed to compare the experiences of women receiving a psychological intervention with women receiving usual advocacy in a randomized controlled trial (PATH: Psychological Advocacy Towards Healing), to illuminate the trial results by exploring women's experiences of benefits and difficulties. METHODS: A qualitative study nested within the PATH trial, based in two DVA agencies in the UK. A purposive sample of thirty-one intervention and usual care participants were interviewed up to three interviews over a year. Thematic analysis was carried out, incorporating concepts from the Trans-Theoretical Model of change. FINDINGS: The PATH trial reports a clinically relevant improvement in mental health outcomes for women receiving the intervention compared to usual advocacy. The qualitative study reveals which elements of the intervention were beneficial or problematic, which outcomes were most meaningful and relevant to participants and highlights reasons for variations in adherence. Women valued the educational, psychological and emotional elements of the intervention, they felt safe to explore repressed emotions for the first time and experienced a reduction in self blame, improved sense of identity and greater self-esteem. They also incorporated new skills and self-help techniques to enable sustainable change. Women receiving usual advocacy reported un-met needs for psychological and emotional support. Adherence was affected by women's 'psychological 'readiness' to engage, the competing demands of practical issues such as housing insecurity, legal proceedings or the availability of child care, and breaks in the continuity of professional care. CONCLUSIONS: Continuity and regularity of sessions with a trained specialist worker was key to women's recovery. Individual assessment of 'readiness' would optimise the timing of delivery to maximise adherence and benefit. PMID- 30481187 TI - In-vivo and numerical analysis of the eigenmodes produced by a multi-level Tic Tac-Toe head transmit array for 7 Tesla MRI. AB - Radio-frequency (RF) field inhomogeneities and higher levels of specific absorption rate (SAR) still present great challenges in ultrahigh-field (UHF) MRI. In this study, an in-depth analysis of the eigenmodes of a 20-channel transmit Tic-Tac-Toe (TTT) RF array for 7T neuro MRI is presented. The eigenmodes were calculated for five different Z levels (along the static magnetic field direction) of the coil. Four eigenmodes were obtained for each Z level (composed of 4 excitation ports), and they were named based on the characteristics of their field distributions: quadrature, opposite-phase, anti-quadrature, and zero-phase. Corresponding finite-difference time-domain (FDTD) simulations were performed and experimental B1+ field maps were acquired using a homogeneous spherical phantom and human head (in-vivo). The quadrature mode is the most efficient and it excites the central brain regions; the opposite-phase mode excites the brain peripheral regions; anti-quadrature mode excites the head periphery; and the zero phase mode excites cerebellum and temporal lobes. Using this RF array, up to five eigenmodes (from five different Z levels) can be simultaneously excited. The superposition of these modes has the potential to produce homogeneous excitation with full brain coverage and low levels of SAR at 7T MRI. PMID- 30481186 TI - Enhancing the prediction of acute kidney injury risk after percutaneous coronary intervention using machine learning techniques: A retrospective cohort study. AB - BACKGROUND: The current acute kidney injury (AKI) risk prediction model for patients undergoing percutaneous coronary intervention (PCI) from the American College of Cardiology (ACC) National Cardiovascular Data Registry (NCDR) employed regression techniques. This study aimed to evaluate whether models using machine learning techniques could significantly improve AKI risk prediction after PCI. METHODS AND FINDINGS: We used the same cohort and candidate variables used to develop the current NCDR CathPCI Registry AKI model, including 947,091 patients who underwent PCI procedures between June 1, 2009, and June 30, 2011. The mean age of these patients was 64.8 years, and 32.8% were women, with a total of 69,826 (7.4%) AKI events. We replicated the current AKI model as the baseline model and compared it with a series of new models. Temporal validation was performed using data from 970,869 patients undergoing PCIs between July 1, 2016, and March 31, 2017, with a mean age of 65.7 years; 31.9% were women, and 72,954 (7.5%) had AKI events. Each model was derived by implementing one of two strategies for preprocessing candidate variables (preselecting and transforming candidate variables or using all candidate variables in their original forms), one of three variable-selection methods (stepwise backward selection, lasso regularization, or permutation-based selection), and one of two methods to model the relationship between variables and outcome (logistic regression or gradient descent boosting). The cohort was divided into different training (70%) and test (30%) sets using 100 different random splits, and the performance of the models was evaluated internally in the test sets. The best model, according to the internal evaluation, was derived by using all available candidate variables in their original form, permutation-based variable selection, and gradient descent boosting. Compared with the baseline model that uses 11 variables, the best model used 13 variables and achieved a significantly better area under the receiver operating characteristic curve (AUC) of 0.752 (95% confidence interval [CI] 0.749 0.754) versus 0.711 (95% CI 0.708-0.714), a significantly better Brier score of 0.0617 (95% CI 0.0615-0.0618) versus 0.0636 (95% CI 0.0634-0.0638), and a better calibration slope of observed versus predicted rate of 1.008 (95% CI 0.988-1.028) versus 1.036 (95% CI 1.015-1.056). The best model also had a significantly wider predictive range (25.3% versus 21.6%, p < 0.001) and was more accurate in stratifying AKI risk for patients. Evaluated on a more contemporary CathPCI cohort (July 1, 2015-March 31, 2017), the best model consistently achieved significantly better performance than the baseline model in AUC (0.785 versus 0.753), Brier score (0.0610 versus 0.0627), calibration slope (1.003 versus 1.062), and predictive range (29.4% versus 26.2%). The current study does not address implementation for risk calculation at the point of care, and potential challenges include the availability and accessibility of the predictors. CONCLUSIONS: Machine learning techniques and data-driven approaches resulted in improved prediction of AKI risk after PCI. The results support the potential of these techniques for improving risk prediction models and identification of patients who may benefit from risk-mitigation strategies. PMID- 30481188 TI - Workload measurement for molecular genetics laboratory: A survey study. AB - Genetic testing availability in the health care system is rapidly increasing, along with the diffusion of next-generation sequencing (NGS) into diagnostics. These issues make imperative the knowledge-drive optimization of testing in the clinical setting. Time estimations of wet laboratory procedure in Italian molecular laboratories offering genetic diagnosis were evaluated to provide data suitable to adjust efficiency and optimize health policies and costs. A survey was undertaken by the Italian Society of Human Genetics (SIGU). Forty-two laboratories participated. For most molecular techniques, the most time-consuming steps are those requiring an intensive manual intervention or in which the human bias can affect the global process time-performances. For NGS, for which the study surveyed also the interpretation time, the latter represented the step that requiring longer times. We report the first survey describing the hands-on times requested for different molecular diagnostics procedures, including NGS. The analysis of this survey suggests the need of some improvements to optimize some analytical processes, such as the implementation of laboratory information management systems to minimize manual procedures in pre-analytical steps which may affect accuracy that represents the major challenge to be faced in the future setting of molecular genetics laboratory. PMID- 30481190 TI - Furious snarling: Teeth-exposure and anxiety-related attentional bias towards angry faces. AB - Dot-probe studies consistently show that high trait anxious individuals have an attentional bias towards threatening faces. However, little is known about the influence of perceptual confounds of specific emotional expressions on this effect. Teeth-exposure was recently recognized as an important factor for the occurrence of attentional bias towards angry faces in a closely related paradigm (the face-in-the-crowd paradigm). Therefore, we investigated the effect of exposed teeth on attentional bias towards angry faces in the dot-probe task. Participants (N = 74) were asked to classify probe stimuli that were preceded by two simultaneously presented face cues, one angry and the other neutral. Half of the angry faces had exposed teeth, the other half had concealed teeth. Afterwards, participants completed the trait anxiety scale of the STAI. For angry faces with non-exposed teeth, we found the expected positive correlation (r = .441) of trait anxiety with the attentional bias score (reaction times for probes replacing the neutral face minus reaction times for probes replacing the angry face). However, we found no influence of trait anxiety on attentional bias towards angry faces with exposed teeth. These results suggest that natural low level stimulus confounds of emotional faces like exposed teeth can affect the manifestation of anxiety-related attentional biases towards angry faces in the dot-probe task. PMID- 30481189 TI - Relationships between intensity, duration, cumulative dose, and timing of smoking with age at menopause: A pooled analysis of individual data from 17 observational studies. AB - BACKGROUND: Cigarette smoking is associated with earlier menopause, but the impact of being a former smoker and any dose-response relationships on the degree of smoking and age at menopause have been less clear. If the toxic impact of cigarette smoking on ovarian function is irreversible, we hypothesized that even former smokers might experience earlier menopause, and variations in intensity, duration, cumulative dose, and age at start/quit of smoking might have varying impacts on the risk of experiencing earlier menopause. METHODS AND FINDINGS: A total of 207,231 and 27,580 postmenopausal women were included in the cross sectional and prospective analyses, respectively. They were from 17 studies in 7 countries (Australia, Denmark, France, Japan, Sweden, United Kingdom, United States) that contributed data to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). Information on smoking status, cigarettes smoked per day (intensity), smoking duration, pack-years (cumulative dose), age started, and years since quitting smoking was collected at baseline. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CIs) for the associations between each smoking measure and categorised age at menopause (<40 (premature), 40-44 (early), 45-49, 50-51 (reference), and >=52 years). The association with current and former smokers was analysed separately. Sensitivity analyses and two-step meta-analyses were also conducted to test the results. The Bayesian information criterion (BIC) was used to compare the fit of the models of smoking measures. Overall, 1.9% and 7.3% of women experienced premature and early menopause, respectively. Compared with never smokers, current smokers had around twice the risk of experiencing premature (RRR 2.05; 95% CI 1.73-2.44) (p < 0.001) and early menopause (1.80; 1.66-1.95) (p < 0.001). The corresponding RRRs in former smokers were attenuated to 1.13 (1.04 1.23; p = 0.006) and 1.15 (1.05-1.27; p = 0.005). In both current and former smokers, dose-response relationships were observed, i.e., higher intensity, longer duration, higher cumulative dose, earlier age at start smoking, and shorter time since quitting smoking were significantly associated with higher risk of premature and early menopause, as well as earlier menopause at 45-49 years. Duration of smoking was a strong predictor of age at natural menopause. Among current smokers with duration of 15-20 years, the risk was markedly higher for premature (15.58; 11.29-19.86; p < 0.001) and early (6.55; 5.04-8.52; p < 0.001) menopause. Also, current smokers with 11-15 pack-years had over 4-fold (4.35; 2.78-5.92; p < 0.001) and 3-fold (3.01; 2.15-4.21; p < 0.001) risk of premature and early menopause, respectively. Smokers who had quit smoking for more than 10 years had similar risk as never smokers (1.04; 0.98-1.10; p = 0.176). A limitation of the study is the measurement errors that may have arisen due to recall bias. CONCLUSIONS: The probability of earlier menopause is positively associated with intensity, duration, cumulative dose, and earlier initiation of smoking. Smoking duration is a much stronger predictor of premature and early menopause than others. Our findings highlight the clear benefits for women of early smoking cessation to lower their excess risk of earlier menopause. PMID- 30481191 TI - Impact of Bacillus spp. spores and gentamicin on the gastrointestinal microbiota of suckling and newly weaned piglets. AB - Administrating antibiotics to young piglets may have short- and long-term consequences on the gut microbiota. We hypothesised that these consequences may be alleviated by concurrent probiotic administration. The study objective was to investigate the effect of administrating gentamicin and a mixture of Bacillus (B.) licheniformis, B. subtilis and B. amyloliquefaeceans spores on the gut microbiota of piglets pre- and post-weaning. Twenty-four sows and their litters were randomly allocated to four treatment groups receiving; a) Bacillus spore mixture (six B. subtilis, two B. amyloliquefaeceans, and one B. licheniformis) fed to sows and piglets (PRO); b) gentamicin (5 mg per day) administered to piglets on day 4, 5, and 6 of age (AB); c) Bacillus spore mixture fed to sows and piglets, and gentamicin to piglets (PRO+AB); or d) no administration of probiotics or antibiotics (CTRL). Faecal and digesta samples were collected repeatedly during the study. Selected samples were subjected to 16S rRNA gene sequencing, culture counts, and organic acid, biogenic amine and tissue gene expression analysis. Treatment had a significant effect on the faecal microbial community composition on day 28 and 42, and colonic community on day 28. Faecal species richness (observed and estimated) and Shannon index, and colonic species richness, were higher in AB compared to PRO piglets on day 28, and were not significantly different from day 42. PRO piglets had the highest faecal concentration of iso-butyric acid on day 7 and a higher butyric acid concentration compared to CTRL piglets. We conclude that gentamicin and Bacillus spores influence the gut microbial diversity of piglets, although administration of gentamicin did not result in dysbiosis as hypothesised. PMID- 30481193 TI - S-maup: Statistical test to measure the sensitivity to the modifiable areal unit problem. AB - This work presents a nonparametric statistical test, S-maup, to measure the sensitivity of a spatially intensive variable to the effects of the Modifiable Areal Unit Problem (MAUP). To the best of our knowledge, S-maup is the first statistic of its type and focuses on determining how much the distribution of the variable, at its highest level of spatial disaggregation, will change when it is spatially aggregated. Through a computational experiment, we obtain the basis for the design of the statistical test under the null hypothesis of non-sensitivity to MAUP. We performed an exhaustive simulation study for approaching the empirical distribution of the statistical test, obtaining its critical values, and computing its power and size. The results indicate that, in general, both the statistical size and power improve with increasing sample size. Finally, for illustrative purposes, an empirical application is made using the Mincer equation in South Africa, where starting from 206 municipalities, the S-maup statistic is used to find the maximum level of spatial aggregation that avoids the negative consequences of the MAUP. PMID- 30481192 TI - The association of employment status with ideal cardiovascular health factors and behaviors among Hispanic/Latino adults: Findings from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). AB - BACKGROUND: The American Heart Association's 2020 Impact Goals propose to improve cardiovascular health (CVH) and reduce deaths from cardiovascular diseases and stroke in the US. Targeted health promotion efforts in workplaces and communities are needed to achieve these population-level changes. The present study examined the sex-specific cross-sectional associations between employment status and ideal CVH among Hispanics/Latinos, and whether these associations were modified by age (i.e., younger adults [aged 18-44] compared to middle-aged and older adults [aged 45-74]). METHODS: This study included 4,797 males and 7,043 females (aged 18-74) from the Hispanic Community Health Study / Study of Latinos. Employment status was categorized as employed full-time (FT), employed part-time (PT), employed (FT or PT) and homemakers, homemakers only, and unemployed. CVH metrics, operationalized as 'ideal' versus 'less than ideal,' included health factors (i.e., blood pressure, cholesterol, and fasting glucose) and health behaviors (i.e., body mass index, smoking, physical activity [PA], and diet). A total CVH score was derived based on the seven CVH metrics, and dichotomized as ideal vs. less than ideal (score of 11-14 vs. 0-10). Survey-based generalized linear regression models with Gaussian binomial distribution were used to estimate adjusted prevalence differences (APDs) and their 95% confidence intervals (CIs) for the associations between employment status (with employed FT as referent) and ideal CVH (total score and each metric), adjusting for socio-demographic characteristics. Effect modification by age was examined. RESULTS: Among males, compared to their employed FT counterparts, those who were employed PT had a higher prevalence of ideal CVH score (APD = 6.8, 95% CI = 1.7, 11.8), ideal BMI (APD = 8.5, 95% CI = 3.0, 14.0), and ideal PA (APD = 4.8, 95% CI = 0.9, 8.7). Age modified the associations of employment type with ideal CVH score and ideal BMI, i.e., younger males who were employed PT had a higher prevalence of ideal CVH score and ideal BMI. Among females, employment status was not associated with ideal CVH score. Compared to females employed FT, females who were homemakers had a lower prevalence of ideal (non-) smoking (APD = -4.7, 95% CI = -8.5, -1.0) and ideal PA (APD = -7.9, 95% CI = -12.7, -3.0), and females who were unemployed had a lower prevalence of ideal PA (APD = -10.4, 95% CI = -16.7, -4.1). Age modified the associations of employment type with ideal fasting glucose and ideal PA, i.e., middle-aged and older females who were homemakers or unemployed had a lower prevalence of ideal fasting glucose and ideal PA. CONCLUSIONS: Hispanic/Latino males who were employed PT had the most favorable CVH profiles but these associations were mostly driven by better CVH (total score and metrics) among younger males. Hispanic/Latino females who were homemakers or unemployed had lower rates of ideal CVH metrics. PMID- 30481194 TI - Temporal understanding of human mobility: A multi-time scale analysis. AB - The recent availability of digital traces generated by cellphone calls has significantly increased the scientific understanding of human mobility. Until now, however, based on low time resolution measurements, previous works have ignored to study human mobility under various time scales due to sparse and irregular calls, particularly in the era of mobile Internet. In this paper, we introduced Mobile Flow Records, flow-level data access records of online activity of smartphone users, to explore human mobility. Mobile Flow Records collect high resolution information of large populations. By exploiting this kind of data, we show the models and statistics of human mobility at a large-scale (3,542,235 individuals) and finer-granularity (7.5min). Next, we investigated statistical variations and biases of mobility models caused by different time scales (from 7.5min to 32h), and found that the time scale does influence the mobility model, which indicates a deep coupling of human mobility and time. We further show that mobility behaviors like transportation modes contribute to the diversity of human mobility, by exploring several novel and refined features (e.g., motion speed, duration, and trajectory distance). Particularly, we point out that 2-hour sampling adopted in previous works is insufficient to study detailed motion behaviors. Our work not only offers a macroscopic and microscopic view of spatial temporal human mobility, but also applies previously unavailable features, both of which are beneficial to the studies on phenomena driven by human mobility. PMID- 30481195 TI - Surgical treatment of primary solitary fibrous tumors involving the pelvic ring. AB - The surgical treatment of primary solitary fibrous tumors (SFT) involving the pelvic ring has not been reported previously. In this study, we aimed to evaluate the efficacy of surgical treatment for this disease. From 2009 to 2015, 13 patients underwent tumor resection at our hospital, with an average age of 49.5 years (27-68 years). Four patients underwent en bloc resection, and 9 patients underwent piecemeal resections. A Chi-square test was used to compare the postoperative recurrence rates between the en bloc resection and the piecemeal resection groups (p = 0.68), and no significant difference was found between the benign and malignant solitary fibrous tumor groups (p = 0.44). The 5-year survival rate of the patients in this study was 83.3%, and the 5-year progression free survival rate was 63.5%. The progression-free survival rate was not significantly different between the en bloc resection and piecemeal resection groups (p = 0.97). Piecemeal resection can also achieve acceptable local control, particularly for patients with sacral tumors, as they may achieve even better postoperative function with sacral nerve preservation. Recurrence and metastasis occur relatively late in the course of this disease. Therefore, long-term follow up is required. PMID- 30481196 TI - Injury prevalence and safety habits of boda boda drivers in Moshi, Tanzania: A mixed methods study. AB - BACKGROUND: Traffic crashes are a major cause of global morbidity and mortality disproportionately affecting low- and middle-income countries (LMICs). Motorcycle taxi (boda boda) drivers are particularly vulnerable because they are exposed to traffic risks with limited safety equipment. This study aims to characterize injury prevalence and safety habits among boda boda drivers, as well as ways to improve road traffic safety in LMICs. METHODS: A cross-sectional mixed methods study was conducted with 300 boda boda drivers between 24 March and 3 April 2014 in urban Moshi, Tanzania. A convenience sample of participants was drawn from 25 of 58 registered boda boda stands and 2 of 31 unregistered stands. Data were analyzed using R, and content thematic analysis was performed and agreed upon by three investigators. Logistic regression models were used to evaluate the association between boda boda characteristics and injury risk. RESULTS: In total, 300 drivers participated, of whom 148 (49.3%) had experienced a crash during their lifetime, and 114 (77.0%) sustained at least one injury. Only 27 of those injured (23.4%) were hospitalized. Of all participants, 220 (73.3%) reported consistent helmet usage, despite 285 participants (95.0%) agreeing that helmet usage reduces injury severity. From the 280 helmets observed, 231 (82.5%) were either damaged or fit improperly. Having a cracked helmet was associated with higher risk of being involved in a traffic crash. Owning a helmet with a proper fit was associated with reduced risk for a traffic crash (OR = 0.06) and road traffic injuries (OR = 0.07). A thematic analysis of boda boda drivers' suggestions to increase road safety identified four intervention areas: 1) roadway infrastructure and traffic regulation, 2) road user attitudes and safe driving behaviors, 3) education and training, and 4) law enforcement. CONCLUSION: Our study demonstrates boda boda drivers' safety behaviors and identifies four intervention areas that can be leveraged to increase overall road traffic safety. Unfortunately, while boda boda drivers are aware of ways to improve safety, adherence to safety habits remains low. Successful multi-sectoral interventions are needed to improve road safety for boda boda drivers in Tanzania. PMID- 30481197 TI - Measuring and understanding social-emotional behaviors in preschoolers from rural Pakistan. AB - The Strengths and Difficulties Questionnaire (SDQ) is widely-used to measure symptoms of common childhood behavioral problems that may lead to mental health difficulties. In a sample of 1,302 highly-disadvantaged mothers and their preschoolers, we evaluated the factor structure and reliability of the parent report version of the SDQ in rural Pakistan. Confirmatory factor analyses suggested that the original structure of the SDQ was not appropriate for our data. We created conceptually- and empirically-coherent measures of children's externalizing behavior problems and prosocial skills. Child and family correlates of social-emotional behaviors were similar to those found in other countries, supporting the validity of our new composites. Girls and children with more siblings had fewer externalizing behavior problems and more prosocial behaviors at four years. Further, maternal depressive symptoms and food insecurity were uniquely linked to more externalizing behavior problems at four years. In contrast, maternal education, home environment quality, and social-emotional skills at two years were associated with more prosocial behaviors at four years. PMID- 30481198 TI - Percentage fractions of urinary di(2-ethylhexyl) phthalate metabolites: Association with obesity and insulin resistance in Korean girls. AB - OBJECTIVE: We assessed the associations of percentage fractions of urinary di(2 ethylhexyl) phthalate (DEHP) metabolites with obesity and insulin resistance in Korean girls. METHODS: In total, 137 girls, aged 6 to 13 years (65 overweight cases and 72 controls), were recruited. Anthropometric indices and the homeostatic model assessment of insulin resistance (HOMA-IR) index were determined. Four major urinary DEHP metabolites were analyzed in spot urine samples by gas chromatography-tandem mass spectrometry, including mono(2 ethylhexyl) phthalate, mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2 ethyl-5-oxohexyl) phthalate (MEOHP), and mono(2-ethyl-5-carboxypentyl) phthalate. RESULTS: There were no significant differences in the urinary concentrations of the DEHP metabolites between the overweight and control groups. The percentage fraction of MEHHP (MEHHP%) among all DEHP metabolites was significantly higher in the overweight prepubertal girls than in the controls (P = 0.035). MEHHP% was positively associated with the body mass index percentile, waist circumference, body fat percentage, and HOMA-IR index in the prepubertal girls. After adjusting for covariates, the prepubertal girls in a higher MEHHP% quartile were found to have a higher odds ratio for central obesity than those in a lower quartile (odds ratios: 5.05 for quartile 3; 7.30 for quartile 4). The relative rate of MEHHP oxidation to MEOHP was negatively associated with the body mass index percentile and waist circumference in the prepubertal girls. However, no such association was observed in the pubertal girls. CONCLUSIONS: MEHHP% was positively associated with obesity and insulin resistance in prepubertal girls. Further studies are necessary to elucidate the causal links between altered phthalate metabolism and increased susceptibility to insulin resistance in children. PMID- 30481199 TI - Proficiency in pole handling during Nordic walking influences exercise effectiveness in middle-aged and older adults. AB - Nordic walking (NW) is a total body version of walking increasingly used as a health-promoting activity by middle-aged and older adults. The present study examined the relationship between force exerted through the pole and physiological response during NW. In this non-randomized exercise trial, 17 participants comprising 8 middle-aged and older recreationally trained Nordic walkers (NWrec: 63.7 +/- 8.1 years) and 9 experienced NW instructors (NWinstr: 57.5 +/- 7.8 years) underwent outdoor ordinary walking (OW) and NW bouts as fast as possible for 12 minutes. Walking distance, speed, heart rate (HR), energy expenditure (METs and J/kg/m) and upper and lower limb muscle activities using surface electromyogram (EMG) were assessed. A pole with a built-in load cell measured force applied to the pole with peak pole force, pole contact time, % of pole contact time with respect to the gait cycle, and pole impulse derived. We conducted two-way analysis of covariance adjusted for age and BMI. There was a significant group and walking type interaction for walking distance and speed (P = 0.04), METs (P < 0.01), and HR (P = 0.04) with higher values in the NWinstr group during NW than OW. As expected, upper limb EMG activities increased (P < 0.01) with NW in both groups. All pole force measures were significantly higher in NWinstr than NWrec (P <= 0.01). Change in walking distance and speed were correlated with pole peak force (r = 0.67, P < 0.01) and pole impulse (r = 0.63, P = 0.01). Similarly, change in METs was associated with peak pole force (r = 0.66, P < 0.01) and pole impulse (r = 0.56, P = 0.02). These results indicate that planting the pole on the ground more forcefully and for longer periods to derive a driving force in NW enhances the effectiveness of the exercise and potentially the health-derived benefits. PMID- 30481200 TI - Equal division of parental care enhances nestling development in the Blackcap. AB - Because parental care is costly, conflict between mates over their roles in reproduction seems unavoidable unless they both benefit from parental labour split equally between partners. In the current paper we analyse the division of parental investment in the Blackcap (Sylvia atricapilla), a species that experiences high nest predation. We show that both sexes invest in the incubation of eggs as well as feeding and brooding nestlings at a similar level. We also found that pairs which divided feeding duties more equally produced nestlings that grew faster. Faster nestling development enables earlier fledging in case of predation attempts at the end of nesting period. Thus parents who more evenly participate in provisioning may benefit from higher breeding success. Our findings suggest that in species under high risk of nest predation disparity in parental investment may not provide much benefit to parent's residual reproductive value and that equality in parental duties constitutes a winning strategy. PMID- 30481201 TI - Comparing individual-level clinical data from antenatal records with routine health information systems indicators for antenatal care in the West Bank: A cross-sectional study. AB - BACKGROUND: In most low- and middle-income settings, national aggregate health data is the most consistently available source for policy-making and international comparisons. In the West Bank, the paper-based health information system with manual aggregations is transitioning to an individual-level data eRegistry for maternal and child health at the point-of-care. The aim of this study was to explore beforehand how routine health information systems indicators for antenatal care can change with the introduction of the eRegistry. METHODS: Data were collected from clinical antenatal paper records of pregnancy enrollments for 2015 from 17 primary healthcare clinics, selected by probability sampling from five districts in the West Bank. We used the individual-level data from clinical records to generate routinely reported health systems indicators. We weighted the data to produce population-level estimates, and compared these indicators with aggregate routine health information systems reports. RESULTS: Antenatal anemia screening at 36 weeks was 20% according to the clinical records data, compared to 52% in the routine reports. The clinical records data showed considerably higher incidences of key maternal conditions compared to the routine reports, including fundal height discrepancy (20% vs. 0.01%); Rh-negative blood group (6.8% vs. 1.4%); anemia with hemoglobin<9.5 g/dl (6% vs. 0.6%); and malpresentation at term (1.3% vs. 0.03%). Only about a sixth of cases with these conditions were referred according to guidelines to designated referral clinics. CONCLUSIONS: Differences between indicators from the clinical records data and routine health information systems reports can be attributed to human error, inconsistent denominators, and complexities of data processes. Key health systems indicators were prone to underestimations since their registration was dependent on referral of pregnant women. With a transition to individual-level data, as in the eRegistry under implementation, the public health authorities will be able to generate reliable health systems indicators reflective of the population's health status. PMID- 30481202 TI - Analysis of genetic diversity and structure in a worldwide walnut (Juglans regia L.) germplasm using SSR markers. AB - Persian or English walnut (Juglans regia L.), the walnut species cultivated for nut production, is one of the oldest food sources known and is grown worldwide in temperate areas. France is the 7th leading producer as of 2016 with 39 kt. Deciphering walnut genetic diversity and structure is important for efficient management and use of genetic resources. In this work, 253 worldwide accessions from the INRA walnut germplasm collection, containing English walnut and several related species, were genotyped using 13 SSR (Single Sequence Repeat) markers selected from the literature to assess diversity and structure. Genetic diversity parameters showed a deficiency of heterozygotes and, for several SSRs, allele specificities among the accessions tested. Principal Coordinate Analysis (PCoA) showed the 253 accessions clustered in largely in agreement with the existing botanical classification of the genus. Among the 217 J. regia accessions, two main clusters, accessions from Eastern Europe and Asia, and accessions from Western Europe and America, were identified using STRUCTURE software. This was confirmed by Principal Coordinate Analysis and supported by Neighbor-Joining tree construction using DARwin software. Moreover, a substructure was found within the two clusters, mainly according to geographical origin. A core collection containing 50 accessions was selected using the maximum length sub-tree method and prior knowledge about their phenotype. The present study constitutes a preliminary population genetics overview of INRA walnut genetic resources collection using SSR markers. The resulting estimations of genetic diversity and structure are useful for germplasm management and for future walnut breeding programs. PMID- 30481204 TI - A new method for evaluating the impacts of semantic similarity measures on the annotation of gene sets. AB - MOTIVATION: The recent revolution in new sequencing technologies, as a part of the continuous process of adopting new innovative protocols has strongly impacted the interpretation of relations between phenotype and genotype. Thus, understanding the resulting gene sets has become a bottleneck that needs to be addressed. Automatic methods have been proposed to facilitate the interpretation of gene sets. While statistical functional enrichment analyses are currently well known, they tend to focus on well-known genes and to ignore new information from less-studied genes. To address such issues, applying semantic similarity measures is logical if the knowledge source used to annotate the gene sets is hierarchically structured. In this work, we propose a new method for analyzing the impact of different semantic similarity measures on gene set annotations. RESULTS: We evaluated the impact of each measure by taking into consideration the two following features that correspond to relevant criteria for a "good" synthetic gene set annotation: (i) the number of annotation terms has to be drastically reduced and the representative terms must be retained while annotating the gene set, and (ii) the number of genes described by the selected terms should be as large as possible. Thus, we analyzed nine semantic similarity measures to identify the best possible compromise between both features while maintaining a sufficient level of details. Using Gene Ontology to annotate the gene sets, we obtained better results with node-based measures that use the terms' characteristics than with measures based on edges that link the terms. The annotation of the gene sets achieved with the node-based measures did not exhibit major differences regardless of the characteristics of terms used. PMID- 30481205 TI - A deep learning model for the detection of both advanced and early glaucoma using fundus photography. AB - PURPOSE: To build a deep learning model to diagnose glaucoma using fundus photography. DESIGN: Cross sectional case study Subjects, Participants and Controls: A total of 1,542 photos (786 normal controls, 467 advanced glaucoma and 289 early glaucoma patients) were obtained by fundus photography. METHOD: The whole dataset of 1,542 images were split into 754 training, 324 validation and 464 test datasets. These datasets were used to construct simple logistic classification and convolutional neural network using Tensorflow. The same datasets were used to fine tune pre-trained GoogleNet Inception v3 model. RESULTS: The simple logistic classification model showed a training accuracy of 82.9%, validation accuracy of 79.9% and test accuracy of 77.2%. Convolutional neural network achieved accuracy and area under the receiver operating characteristic curve (AUROC) of 92.2% and 0.98 on the training data, 88.6% and 0.95 on the validation data, and 87.9% and 0.94 on the test data. Transfer learned GoogleNet Inception v3 model achieved accuracy and AUROC of 99.7% and 0.99 on training data, 87.7% and 0.95 on validation data, and 84.5% and 0.93 on test data. CONCLUSION: Both advanced and early glaucoma could be correctly detected via machine learning, using only fundus photographs. Our new model that is trained using convolutional neural network is more efficient for the diagnosis of early glaucoma than previously published models. PMID- 30481203 TI - Comparison of the antifibrotic effects of the pan-histone deacetylase-inhibitor panobinostat versus the IPF-drug pirfenidone in fibroblasts from patients with idiopathic pulmonary fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with a poor prognosis. Pirfenidone is the first antifibrotic agent to be approved for IPF-treatment as it is able to slow down disease progression. However, there is no curative treatment other than lung transplantation. Because epigenetic alterations are associated with IPF, histone deacetylase (HDAC)-inhibitors have recently been proven to attenuate fibrotic remodeling in vitro and in vivo. This study compared the effects of pirfenidone with the pan-HDAC-inhibitor panobinostat/LBH589, a FDA-approved drug for the treatment of multiple myeloma, head-to-head on survival, fibrotic activity and proliferation of primary IPF fibroblasts in vitro. METHODS: Primary fibroblasts from six IPF-patients were incubated for 24h with vehicle (0.25% DMSO), panobinostat (LBH589, 85 nM) or pirfenidone (2.7 mM), followed by assessment of proliferation and expression analyses for profibrotic and anti-apoptosis genes, as well as for ER stress and apoptosis-markers. In addition, the expression status of all HDAC enzymes was examined. RESULTS: Treatment of IPF-fibroblasts with panobinostat or pirfenidone resulted in a downregulated expression of various extracellular matrix (ECM) associated genes, as compared to vehicle-treated cells. In agreement, both drugs decreased protein level of phosphorylated (p)-STAT3, a transcription factor mediating profibrotic responses, in treated IPF-fibroblasts. Further, an increase in histone acetylation was observed in response to both treatments, but was much more pronounced and excessive in panobinostat-treated IPF-fibroblasts. Panobinostat, but not pirfenidone, led to a significant suppression of proliferation in IPF-fibroblasts, as indicated by WST1- and BrdU assay and markedly diminished levels of cyclin-D1 and p-histone H3. Furthermore, panobinostat-treatment enhanced alpha-tubulin-acetylation, decreased the expression of survival-related genes Bcl-XL and BIRC5/survivin, and was associated with induction of ER stress and apoptosis in IPF-fibroblasts. In contrast, pirfenidone-treatment maintained Bcl-XL expression, and was neither associated with ER stress-induction nor any apoptotic signaling. Pirfenidone also led to increased expression of HDAC6 and sirtuin-2, and enhanced alpha-tubulin deacetylation. But in line with its ability to increase histone acetylation, pirfenidone reduced the expression of HDAC enzymes HDAC1, -2 and -9. CONCLUSIONS: We conclude that, beside other antifibrotic mechanisms, pirfenidone reduces profibrotic signaling also through STAT3 inactivation and weak epigenetic alterations in IPF-fibroblasts, and permits survival of (altered) fibroblasts. The pan-HDAC-inhibitor panobinostat reduces profibrotic phenotypes while inducing cell cycle arrest and apoptosis in IPF-fibroblasts, thus indicating more efficiency than pirfenidone in inactivating IPF-fibroblasts. We therefore believe that HDAC-inhibitors such as panobinostat can present a novel therapeutic strategy for IPF. PMID- 30481206 TI - Optimizing evacuation efficiency under emergency with consideration of social fairness based on a cell transmission model. AB - Traffic assignment and management objectives are considered as two significant parts in developing the emergency evacuation plan, which can directly influence the evacuation performance and efficiency. From the perspective of disaster response operators, the evacuation objective frequently is to minimize the total evacuation time to reduce losses, which may lead to an unreasonable and unfair phenomenon where people in highest risk areas may be forced to sacrifice their priorities of evacuation to improve the system evacuation efficiency. In this paper, considering both efficiency and social fairness in emergency evacuation, a weight function consisting of risk evaluation index as variable and the emphasis degree of managers on social fairness principle as coefficient was initially proposed and embedded in system optimal (SO) objective function. Combining the weight function and other constraints based on an extended cell transmission model (CTM), the linear program (LP) model was established to realize the simulation of dynamic traffic assignment in emergency evacuation. Employing this model, the impact of the management strategy of balancing both efficiency and social fairness on evacuation results was studied in the "Tianjin Explosions" case. In the end, the conclusion of "balancing social fairness is valuable during evacuation" was obtained. PMID- 30481208 TI - Prediction of findings at screening colonoscopy using a machine learning algorithm based on complete blood counts (ColonFlag). AB - Adenomatous polyps are a common precursor lesion for colorectal cancer. ColonFlag is a machine- learning-based algorithm that uses basic patient information and complete blood cell counts (CBC) to identify individuals at elevated risk of colorectal cancer for intensified screening. The purpose of this study was to determine whether ColonFlag is also able to predict the presence of high risk adenomatous polyps at colonoscopy. This study was conducted at a large colon cancer screening center in Calgary, Alberta. The study population included asymptomatic individuals between the ages of 50 and 75 who underwent a screening colonoscopy between January 2013 and June 2015. All subjects had at least one CBC result within the year prior to colonoscopy. Based on age, sex, red blood cell parameters, inflammatory cells and platelets, the ColonFlag algorithm generated a score from 0 to 100. We compared the ability of the ColonFlag test result to discriminate between individuals who were found to have a high risk polyp and those with a normal colonoscopy. Among the 17,676 individuals who underwent a screening colonoscopy there were 1,014 found to have a high risk precancerous lesion (5.7%) and 60 were found to have colorectal cancer (0.3%). At a specificity of 95%, the odds ratio for a positive ColonFlag was 2.0 for those with an advanced precancerous lesion compared with those with a normal colonoscopy. The odds ratio did not vary according to patient subgroup, colorectal cancer location or stage. ColonFlag is a passive test that can use routine blood test results to help identify individuals at elevated risk for high risk precancerous polyps as well as frank colorectal cancer. These individuals may be targeted in an effort to achieve greater compliance with conventional screening tests. PMID- 30481207 TI - Multiple configurations of EGFR exon 20 resistance mutations after first- and third-generation EGFR TKI treatment affect treatment options in NSCLC. AB - After sequential treatment with first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), EGFR-mutant non-small cell lung cancers frequently harbor multiple resistance mutations in exon 20 of EGFR including T790M, mediating resistance to first-generation TKIs, and at codons 792, 796, or 797 mediating resistance to third-generation TKIs. However, whether these resistance mutations are in cis or trans has therapeutic implications for patients. We analyzed a cohort of 29 patients with NSCLC harboring EGFR mutations at codons 792, 796, or 797 to establish the configuration of these mutations. We performed hybrid capture-based, next-generation sequencing on formalin-fixed paraffin-embedded biopsy tissue or liquid biopsy. 27 samples had both a T790M mutation and a mutation at codons 792, 796, or 797. In all of these cases, the mutations were found in the cis configuration; the trans configuration was not observed. Two patients' samples harbored a mutation at codon 797 but no T790M mutation. In these two cases, longitudinal analysis showed earlier biopsies harbored EGFR T790M, which was undetectable following osimertinib treatment. Treatment of one these patients with both first- and third-generation EGFR TKIs resulted in a mixed response. Here we describe multiple configurations of EGFR T790M and third generation TKI resistance mutations at codons 792, 796, and 797. These mutations are most commonly found in cis, which confers resistance to all current EGFR TKIs. We also describe two patients that exhibited T790M loss with acquisition of a mutation at codon 797. In addition, one of these patients, with an EGFR C797S in a lung biopsy was subsequently found to have EGFR C797N in a later biopsy of pleural fluid, highlighting the dynamic multiclonal nature of advanced NSCLC. PMID- 30481209 TI - Evaluation of a call center to assess post-discharge maternal and early neonatal outcomes of facility-based childbirth in Uttar Pradesh, India. AB - BACKGROUND: Maternal and neonatal outcomes in the immediate post-delivery period are critical indicators of quality of care. Data on childbirth outcomes in low income settings usually require home visits, which can be constrained by cost and access. We report on the use of a call center to measure post-discharge outcomes within a multi-site improvement study of facility-based childbirth in Uttar Pradesh, India. METHODS: Of women delivering at study sites eligible for inclusion, 97.9% (n = 157,689) consented to follow-up. All consenting women delivering at study facilities were eligible to receive a phone call between days eight and 42 post-partum to obtain outcomes for the seven-day period after birth. Women unable to be contacted via phone were visited at home. Outcomes, including maternal and early neonatal mortality and maternal morbidity, were ascertained using a standardized script developed from validated survey questions. Data Quality Assurance (DQA) included accuracy (double coding of calls) and validity (consistency between two calls to the same household). Regression models were used to identify factors associated with inconsistency. FINDINGS: Over 23 months, outcomes were obtained by the call center for 98.0% (154,494/157,689) consenting women and their neonates. 87.9% of call center-obtained outcomes were captured by phone call alone and 12.1% required the assistance of a field worker. An additional 1.7% were obtained only by a field worker, 0.3% were lost-to-follow up, and only 0.1% retracted consent. The call center captured outcomes with a median of 1 call (IQR 1-2). DQA found 98.0% accuracy; data validation demonstrated 93.7% consistency between the first and second call. In a regression model, significant predictors of inconsistency included cases with adverse outcomes (p<0.001), and different respondents on the first and validation call (p<0.001). CONCLUSIONS: In areas with widespread mobile cell phone access and coverage, a call center is a viable and efficient approach for measurement of post-discharge childbirth outcomes. PMID- 30481210 TI - Serum concentration of anti-Cytomegalovirus IgG and ischaemic stroke in patients with advanced HIV infection in Malawi. AB - BACKGROUND: Studies in high-income settings have shown association between Cytomegalovirus (CMV) infection and adverse cardiovascular outcome, especially in HIV infection. We aimed to study the association between serum concentration of anti-CMV IgG and ischaemic stroke in HIV-infected Malawians. METHODS: Our sample was derived from a case-control stroke study in Malawi. Serum concentration of anti-CMV IgG was measured using enzyme-linked immunosorbent assay. Multivariable logistic regression was used to study the association between high concentrations of anti-CMV IgG (above the third tertile) and ischaemic stroke while adjusting for cardiovascular risk factors. RESULTS: Overall, 139 HIV-positive adults (48.2% women; 48 ischaemic stroke cases and 91 controls; median age: 45 years) were included. The median CD4+ count was 136 and 401 cell/mm3 (IQR: [75-278] and [230 533]) in cases and controls, respectively. High concentration of anti-CMV IgG was associated with ischaemic stroke in the univariable model (OR = 2.56 [1.23-5.34]) but not after adjusting for duration of antiretroviral therapy (ART), CD4+ count, and other cardiovascular risk factors (OR = 0.94 [0.29-3.08]). Low CD4+ count was an independent predictor of stroke. There was a negative correlation between serum concentration of anti-CMV IgG and CD4+ count (rho = -0.30, p < 0.001). CONCLUSIONS: High concentration of anti-CMV IgG is not independently associated with ischaemic stroke in HIV-infected Malawians. Larger cohort studies are needed to further investigate the role of humoral response to CMV in the pathophysiology of HIV-associated stroke. PMID- 30481211 TI - Reactivation of latent HIV-1 in vitro using an ethanolic extract from Euphorbia umbellata (Euphorbiaceae) latex. AB - Euphorbia umbellata (E. umbellata) belongs to Euphorbiaceae family, popularly known as Janauba, and its latex contains a combination of phorbol esters with biological activities described to different cellular protein kinase C (PKC) isoforms. Here, we identified deoxi-phorbol esters present in E. umbellata latex alcoholic extract that are able to increase HIV transcription and reactivate virus from latency models. This activity is probably mediated by NF-kB activation followed by nuclear translocation and binding to the HIV LTR promoter. In addition, E. umbellata latex extract induced the production of pro inflammatory cytokines in vitro in human PBMC cultures. This latex extract also activates latent virus in human PBMCs isolated from HIV positive patients as well as latent SIV in non-human primate primary CD4+ T lymphocytes. Together, these results indicate that the phorbol esters present in E. umbellata latex are promising candidate compounds for future clinical trials for shock and kill therapies to promote HIV cure and eradication. PMID- 30481212 TI - Qualitative evaluation of coronary atherosclerosis in a large cohort of young and middle-aged Dutch tissue donors implies that coronary thrombo-embolic manifestations are stochastic. AB - BACKGROUND AND AIMS: With the intention to gain support for the hypothesis that incident ischemic complications of atherosclerotic disease involve a stochastic aspect, we performed a histological, qualitative evaluation of the epidemiology of coronary atherosclerotic disease in a cohort of aortic valve donors. PATIENTS AND METHODS: Donors (n = 695, median age 54, range 11-65 years) were dichotomized into a non-cardiovascular (non-CVD) and a cardiovascular disease death (CVD) group. Consecutive 5 mm proximal left coronary artery segments were Movat stained, and the atherosclerotic burden for each segment was graded (revised AHA classification). RESULTS: Non-CVD and CVD groups showed steep increase of atherosclerosis severity beyond the age of 40, resulting in an endemic presence of advanced atherosclerosis in men over 40 and women over 50 years. In fact, only 19% of the non-CVD and 6% of the CVD donors over 40 years were classified with a normal LCA or a so called non-progressive lesion type. Fibrous calcified plaques (FCP), the consolidated remnants of earlier ruptured lesions, dominated in both non-CVD and CVD donors. Estimates of the atherosclerosis burden (i.e. average lesion grade, proportion of FCPs, and average number of FCPs per cross-section) were all higher in the CVD group (p<1.10-16, p<0.0001, and p<0.05, respectively). CONCLUSIONS: Dominance of consolidated FCP lesions in males over 40 and females over 50 years, show that plaque ruptures in the left coronary artery are common. However, the majority of these ruptures remain asymptomatic. This implies that the atherosclerotic process is repetitive. A relative difference in disease burden between CVD and non-CVD donors supports the concept that complications of atherosclerotic disease involve a stochastic element. PMID- 30481213 TI - Forecasting the incidence of salmonellosis in seniors in Canada: A trend analysis and the potential impact of the demographic shift. AB - Salmonella infections remain an important public health issue in Canada and worldwide. Although the majority of Salmonella cases are self-limiting, some will lead to severe symptoms and occasionally severe invasive infections, especially in vulnerable populations such as seniors. This study was performed to assess temporal trends of Salmonella cases in seniors over 15 years (2014-2028) and assess possible impact of demographic shift on national incidence; taking into account of trends in other age groups. The numbers of reported Salmonella cases in seniors (60 years and over) in eight provinces and territories for a period of fifteen years were analysed (1998-2013) using a time-adjusted Poisson regression model. With the demographic changes predicted in the age-structure of the population and in the absence of any targeted interventions, our analysis showed the incidence of Salmonella cases in seniors could increase by 16% by 2028 and the multi-provincial incidence could increase by 5.3%. As a result, the age distribution amongst the Salmonella cases is expected to change with a higher proportion of cases in seniors and a smaller proportion in children (0-4 years old). Over the next decades, cases of infection, hospitalizations and deaths associated with Salmonella in seniors could represent a challenge to public health due to an aging population in Canada. As life expectancy increases in Canada, identification of unique risk factors and targeted prevention in seniors should be pursued to reduce the impact of the demographic shift on disease incidence. PMID- 30481214 TI - A model investigating environmental factors that play a role in female fecundity or birth rate. AB - OBJECTIVE: Over 12% of women in the United States have reduced fertility and/or fecundity. Environmental factors, such as temperature, and socioeconomic factors have been implicated in reducing female fecundity. The purpose of this study is to investigate the effect of environmental factors coupled with socioeconomic factors on birth rate at the country-level. We use birth rate as a proxy for female fecundity. This will enable us to identify the most important factors affecting female fecundity. METHODS: Using country-specific data from 182 countries, we constructed a regression model of the effects of environmental and socioeconomic factors on birth rate at the country-level. Our model assesses the role of temperature, Gross Domestic Product (GDP) per capita, fine air particulate matter (PM 2.5), and prevalence of male and female Body Mass Index (BMI) > = 25 (age-standardized) on birth rate per country. Because many of these factors are inter-dependent, we include all possible two-way interaction terms to assess the role of individual factors and interactions between multiple factors in the model. RESULTS: In the full regression model, we found that GDP per capita along with 5 interaction terms were significant after adjusting for multiple testing. Female BMI was only nominally significant. GDP per capita was independently associated with birth rate (adjusted p-value <0.001). Prevalence of BMI > = 25 age-standardized in males and females were also significant when interacting with air pollution or GDP on female fecundity (birth rate). Temperature did not affect birth rate either independently or as an interaction unless BMI was removed from the model. CONCLUSION: A country's economic wealth was the most significant factor in predicting birth rate in a statistical model that includes environmental and socioeconomic variables. This is important for future studies investigating environmental factors involved in increasing or decreasing female fecundity. PMID- 30481215 TI - Remodeling the endoplasmic reticulum proteostasis network restores proteostasis of pathogenic GABAA receptors. AB - Biogenesis of membrane proteins is controlled by the protein homeostasis (proteostasis) network. We have been focusing on protein quality control of gamma aminobutyric acid type A (GABAA) receptors, the major inhibitory neurotransmitter gated ion channels in mammalian central nervous system. Proteostasis deficiency in GABAA receptors causes loss of their surface expression and thus function on the plasma membrane, leading to epilepsy and other neurological diseases. One well-characterized example is the A322D mutation in the alpha1 subunit that causes its extensive misfolding and expedited degradation in the endoplasmic reticulum (ER), resulting in autosomal dominant juvenile myoclonic epilepsy. We aimed to correct misfolding of the alpha1(A322D) subunits in the ER as an approach to restore their functional surface expression. Here, we showed that application of BIX, a specific, potent ER resident HSP70 family protein BiP activator, significantly increases the surface expression of the mutant receptors in human HEK293T cells and neuronal SH-SY5Y cells. BIX attenuates the degradation of alpha1(A322D) and enhances their forward trafficking and function. Furthermore, because BiP is one major target of the two unfolded protein response (UPR) pathways: ATF6 and IRE1, we continued to demonstrate that modest activations of the ATF6 pathway and IRE1 pathway genetically enhance the plasma membrane trafficking of the alpha1(A322D) protein in HEK293T cells. Our results underlie the potential of regulating the ER proteostasis network to correct loss of-function protein conformational diseases. PMID- 30481217 TI - Correction: Aspergillus endocarditis: Diagnostic criteria and predictors of outcome, A retrospective cohort study. AB - [This corrects the article DOI: 10.1371/journal.pone.0201459.]. PMID- 30481216 TI - Does the melatonin receptor 1B gene polymorphism have a role in postoperative delirium? AB - INTRODUCTION: Patients undergoing cardiac surgery are at high risk for postoperative delirium, which is associated with longer hospital and intensive care lengths of stays, increased morbidity and mortality. Because sleep disturbances are common in delirium, melatonin has been an area of interest in the treatment of delirium. The rs10830963 single nucleotide polymorphism of the melatonin receptor 1B gene can cause pathological dysfunction of this receptor and is associated with delayed morning offset of melatonin. We hypothesized patients undergoing aortic cardiac surgery who have the risk genotype of a melatonin receptor 1B polymorphism would have a higher incidence of postoperative delirium. METHODS: Ninety-eight patients undergoing aortic root or valve surgery underwent analysis for melatonin receptor 1B single nucleotide polymorphism, rs10830963. Using a validated method, CHART-DEL, all charts were retrospectively reviewed and scored for the presence of delirium while blinded to the results of the melatonin receptor 1B gene polymorphism. RESULTS: Genotyping for melatonin receptor 1B polymorphism was acceptable in 76 subjects of European descent of which 18 (23.7%) had delirium. Four of seven subjects with the risk genotype had delirium versus only 20.3% of subjects without the risk genotype. This carried an odds ratio of 5.2 (1.0, 26.1), p = 0.050. CONCLUSION: This observation suggests a role of the risk genotype of a melatonin receptor 1B polymorphism in the development of postoperative delirium. These hypotheses generating results warrant further prospective studies in a larger cohort group with delirium, circadian rhythm and melatonin assessments. PMID- 30481218 TI - Deep analysis of Loop L1 HVRs1-4 region of the hexon gene of adenovirus field strains isolated in Poland. AB - BACKGROUND: To date, studies on loop L1 HVRs1-4 region of the hexon gene in fowl adenovirus genome (FAdVs) lack comprehensive molecular data. In this study detailed prospectively obtained sequences from field adenovirus strains, NVRI, Poland have been analyzed. METHODS: Overall hundred and thirty seven adenovirus strains were collected, evaluated, and examined of hyper variable loop L1 region HVRs1-4 of the hexon gene for the presence of similarity, mutations, tertiary structure, and spinal conformation. RESULTS: Sequences were characterized, and divided for five species and seven types, FAdV-A-E/FAdV-1/2/4/5/7/8a/8b/11. The presence of predicted tertiary structure depending on type/species were determined. Analysis of specific selected sequences: GQMTN 1/A, 7/E, and 8b/E, GQMTT 2/11/D, GQLSN 4/C, GQMTH 5/B, and GQMSN 8a/E in examined HVRs1-4 Loop L1 region of hexon gene compared to tertiary structure indicated that this visibly conservative region represents the antigenic binging activity. CONCLUSION: This is the first molecular study on tertiary structure on HVRs1-4 region in adenovirus genome conducted in Poland. Analysis indicated specific sequence in Loop L1 HVR1-4 region which is strictly responsible for antibodies binding. This information could assist during the process connected with specific preventive strategies based on their molecular genome investigation and new facilitate studies. This study will help to better understand the mechanisms of pathogenicity of adenovirus strains provide a guide for disease control in birds. PMID- 30481219 TI - Correction: Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue. AB - [This corrects the article DOI: 10.1371/journal.pone.0145937.]. PMID- 30481220 TI - Fake science: The impact of pseudo-psychological demonstrations on people's beliefs in psychological principles. AB - Magicians use deception to create effects that allow us to experience the impossible. More recently, magicians have started to contextualize these tricks in psychological demonstrations. We investigated whether witnessing a magic demonstration alters people's beliefs in these pseudo-psychological principles. In the classroom, a magician claimed to use psychological skills to read a volunteer's thoughts. After this demonstration, participants reported higher beliefs that an individual can 1) read a person's mind by evaluating micro expressions, psychological profiles and muscle activities, and 2) effectively prime a person's behaviour through subtle suggestions. Whether he was presented as a magician or psychologist did not influence people's beliefs about how the demonstration was achieved, nor did it influence their beliefs in pseudo psychological principles. Our results demonstrate that pseudo-psychological demonstrations can have a significant impact on perpetuating false beliefs in scientific principles and raise important questions about the wider impact of scientific misinformation. PMID- 30481221 TI - An integrated characterization of Picea abies industrial bark regarding chemical composition, thermal properties and polar extracts activity. AB - The present work determines the chemical and thermal characteristics as well as the phytochemical and antioxidant potential of the polar extractives of the Picea abies bark from an industrial mill, their wood and bark components and also different bark fractions obtained by mechanical fractionation (fine B1, Phi<0.180 mm, medium B3, 0.450 < Phi<0.850 mm and coarse B6, 2 < Phi<10 mm). The aim is to increase the knowledge on the Picea abies bark to better determine possible uses other than burning for energy production and to test an initial size reduction process to achieve fractions with different characteristics. Compared to wood, bark presented similar lignin (27%), higher mineral (3.9% vs 0.4%) and extractives (20.3% vs 3.8%) and lower polysaccharides (48% vs 71%) contents. Regarding bark fractions the fines showed higher ash (6.3%), extractives (25%) and lignin (29%) than the coarse fraction (3.9%, 19% and 25% respectively). Polysaccharide contents increased with particle size of the bark fractions (38% vs 52% for B1 and B6) but showed the same relative composition. The phytochemical profile of ethanol and water extracts presented higher contents for bark than wood of total phenols (2x higher), flavonoids (3x higher) and tannins (4-10x higher) with an increasing tendency with particle size. Bark antioxidant activity was higher than that of wood for ferric-reducing antioxidant power (FRAP, 10 vs 6 mmolFe2+/gExt for the ethanol extract) and free radical scavenging activity (DPPH, 6 vs 18 mg/L IC50 for the ethanol extract) methods. The different bark fractions antioxidant activity was very similar. Bark thermal properties showed a much lower volatiles to fixed carbon ratio (V/FC) than wood (3.1 vs 5.2) although the same higher heating value (20.3 MJ/kg). The fractions were quite similar. Bark presented chemical features that point to their possible upgrade, whether by taking advantage of the high extractives with bioactive compounds or the production potential for hemicellulose-derived oligomers with possible use in nutraceutical and pharmaceutical industries. PMID- 30481222 TI - Combining species distribution modeling and field surveys to reappraise the geographic distribution and conservation status of the threatened thin-spined porcupine (Chaetomys subspinosus). AB - The threatened thin-spined porcupine (Chaetomys subspinosus), a forest-specialist endemic to the Brazilian Atlantic forest, was rarely detected in the wild during the 20th century. Previous geographic distribution assessments were carried out nearly three decades ago and were based on interview data. We performed extensive field surveys (based on active search and interviews), a literature review, and species distribution modeling to predict and validate a more reliable picture of its geographic distribution and environmental suitability gradient. We identified the main predictors of species' incidence, its conservation status, and pinpointed key areas for species conservation. Our results indicated that C. subspinosus is distributed continuously in the Atlantic forest from southeastern Espirito Santo to central-eastern Sergipe state, totaling 104,326 km2 of occurrence area, although only 3,299 km2 (13.3%) is currently represented by native forests (species habitat). C. subspinosus was absent or at least so rare that it was not detected in more than half of the locations sampled by interviews (53.5%). Our results suggest that populations are sensitive to climatic conditions and habitat loss, becoming abruptly rarer when the remaining forest cover reaches less than 10% area within a region (~ 5,000 km2 scale). This result indicates that the high deforestation level of the Atlantic forest is already close to the limit of regional species resistance. Bahia state still harbors the bulk of the remaining forest with high climatic suitability, and generally under low levels of legal protection. Herein we highlight priority areas and research gaps that could guide decision makers to promote conservation strategies for this threatened species. PMID- 30481223 TI - Correction: CaSTLe - Classification of single cells by transfer learning: Harnessing the power of publicly available single cell RNA sequencing experiments to annotate new experiments. AB - [This corrects the article DOI: 10.1371/journal.pone.0205499.]. PMID- 30481224 TI - Correction: Excess direct hospital cost of treating adult patients with ventilator associated respiratory infection (VARI) in Vietnam. AB - [This corrects the article DOI: 10.1371/journal.pone.0206760.]. PMID- 30481225 TI - Selection of appropriate reference genes for RT-qPCR analysis in Propylea japonica (Coleoptera: Coccinellidae). AB - Reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) is a reliable technique commonly used in molecular biology to analyze RNA expression. The selection of suitable reference genes for data normalization is a precondition for credible measurements of gene expression levels using RT-qPCR. Propylea japonica is one of the most common pests of many crop systems throughout East Asia, and has often been used in the testing of non-target impacts during environmental risk assessments of genetically engineered plants. The present study assessed the suitability of nine frequently used reference genes for comparisons of P. japonica gene expression. Expression stability was compared across developmental stages, sex, a range of tissues, and following exposure to different temperatures. Data were analyzed using RefFinder, which integrated the results obtained using NormFinder, geNorm, BestKeeper, and the DeltaCt method. This led to the identification of unique sets of reference genes for each experimental condition: ribosomal protein S18 (RPS18) and elongation factor 1 alpha (EF1A) for developmental stage comparisons, RPS18 and EF1A for sex comparisons, EF1A and ribosomal protein L4 for tissue comparisons, and RPS18 and EF1A for analyses of temperature-mediated effects. These reference genes will help to enhance the accuracy of RT-qPCR analyses of P. japonica gene expression. This work represents an initial move towards building a standardized system for RT-qPCR analysis of P. japonica, providing a basis for the ecological risk assessment of RNAi-based insect control products. PMID- 30481226 TI - An introduced plant affects aquatic-derived carbon in the diets of riparian birds. AB - Non-native plants can impact riparian ecosystem function through diverse terrestrial and aquatic pathways, with cascading effects on food webs. Invasion mediated vegetation changes can depress terrestrial arthropod communities and alter arthropod flux across the aquatic-terrestrial interface. We investigated the effects of a non-native woody plant, Robinia neomexicana, on insect contributions to riparian songbird diets. This plant was introduced over 100 years ago to the Clear Creek drainage in northwestern Colorado (USA) from its native range, which extends into southern Colorado. We used stable isotope analysis of insects and avian feces to 1) assess whether the relative contributions of aquatic- and terrestrial-derived arthropod prey differed between reference sites and sites invaded by R. neomexicana, and 2) quantify the amount of aquatic- and terrestrial-derived resources consumed by an insectivorous songbird assemblage. Two species of insectivorous songbirds consumed more aquatic insects in invaded sites compared to reference sites. This change in terrestrial- and aquatic-derived prey in bird diets in response to a near-range plant invasion suggests that the introduction of novel species from more distant native ranges could produce similar or stronger effects. Overall, the songbird community consumed approximately 34% aquatic resources, which highlights the importance of these subsidies to riparian consumers. Our investigation of insect subsidies demonstrates how introduced species can indirectly affect food webs and provides insight into the plasticity of riparian consumer responses. PMID- 30481227 TI - Musical practice as an enhancer of cognitive function in healthy aging - A systematic review and meta-analysis. AB - Aging is accompanied by cognitive decline, although recent research indicates that the rate of decline depends on multiple lifestyle factors. One of such factors is musical practice, an activity that involves several sensory and motor systems and a wide range of high-level cognitive processes. This paper describes the first systematic review and meta-analysis, to our knowledge, of the impact of musical practice on healthy neurocognitive aging. The inclusion criteria for the review required that studies were empirical works in English or Spanish that they explored the effects of musical practice on older people; they included an assessment of cognitive functions and/or an assessment of brain status; and they included a sample of participants aged 59 years or older with no cognitive impairment or brain damage. This review led to the selection of 13 studies: 9 correlational studies involving older musicians and non-musicians and 4 experimental studies involving short-term musical training programs. The results of the meta-analysis showed cognitive and cerebral benefits of musical practice, both in domain-specific functions (auditory perception) and in other rather domain-general functions. Moreover, these benefits seem to protect cognitive domains that usually decline with aging and boost other domains that do not decline with aging. The origin of these benefits may reside, simultaneously, in the specific training of many of these cognitive functions during musical practice (specific training mechanism), in the improvement of compensatory cognitive processes (specific compensatory mechanism), and in the preservation of general functions with a global influence on others, such as perceptual capacity, processing speed, inhibition and attention (general compensatory mechanism). Therefore, musical practice seems to be a promising tool to reduce the impact of cognitive problems associated to aging. PMID- 30481228 TI - A new plan quality objective function for determining optimal collimator combinations in prostate cancer treatment with stereotactic body radiation therapy using CyberKnife. AB - Stereotactic body radiation therapy with CyberKnife for prostate cancer has long treatment times compared with conventional radiotherapy. This arises the need for designing treatment plans with short execution times. We propose an objective function for plan quality evaluation, which was used to determine an optimal combination between small and large collimators based on short treatment times and clinically acceptable dose distributions. Data from 11 prostate cancer patients were used. For each patient, 20 plans were created based on all combinations between one small (? 10-25 mm) and one large (? 35-60 mm) Iris collimator size. The objective function was assigned to each combination as a penalty, such that plans with low penalties were considered superior. This function considered the achievement of dosimetric planning goals, tumor control probability, normal tissue complication probability, relative seriality parameter, and treatment time. Two methods were used to determine the optimal combination. First, we constructed heat maps representing the mean penalty values and standard deviations of the plans created for each collimator combination. The combination giving a plan with the smallest mean penalty and standard deviation was considered optimal. Second, we created two groups of superior plans: group A plans were selected by histogram analysis and group B plans were selected by choosing the plan with the lowest penalty from each patient. In both groups, the most used small and large collimators were assumed to represent the optimal combination. The optimal combinations obtained from the heat maps included the 25 mm as a small collimator, giving small/large collimator sizes of 25/35, 25/40, 25/50, and 25/60 mm. The superior-group analysis indicated that 25/50 mm was the optimal combination. The optimal Iris combination for prostate cancer treatment using CyberKnife was determined to be a collimator size between 25 mm (small) and 50 mm (large). PMID- 30481230 TI - Kidney injury by cyclosporine A is aggravated in heme oxygenase-1 deficient mice and involves regulation of microRNAs. AB - Cyclosporine A (CsA), a widely used immunosuppressive drug, exerts nephrotoxic activities, as demonstrated by increased tubulointerstitial fibrosis, inflammation and podocyte damage. Recently, a number of microRNAs expressed in the kidney have been reported to be elevated during renal damage. Our aim was to investigate the effect of CsA on selected microRNAs in the mouse kidney after CsA treatment. Moreover, as heme oxygenase-1 (HO-1, encoded by the Hmox1 gene) was shown to play a protective role during kidney disorders, we assessed whether HO-1 deficiency in vivo influences the CsA-regulated microRNAs' expression. We have observed that the pro-fibrotic miR-21 and pro-apoptotic miR-34a expression was upregulated in kidneys of HO-1 deficient mice and it was further enhanced by CsA. Concomitantly, the level of anti-fibrotic microRNAs, belonging to miR-29 and miR 200 families, was down-regulated after CsA treatment. Generally, Hmox1 knock-out (Hmox1-/-) animals were more susceptible to CsA treatment, as the mortality rate was 4 out of 9 Hmox1-/- mice, and increased fibrosis (Tgfb2, Pai1), inflammation (Il6) and apoptosis (Cdkn1a-p21) were noticed in the HO-1 deficient kidneys. In summary, our data demonstrate that CsA induces significant changes in the expression of renal microRNAs and emphasize HO-1 deficiency as an important factor contributing to the CsA-mediated renal toxicity. PMID- 30481231 TI - Foot and Ankle Injuries in Soccer. AB - The ankle is one of the most commonly injured joints in soccer and represents a significant cost to the healthcare system. The ligaments that stabilize the ankle joint determine its biomechanics-alterations of which result from various soccer related injuries. Acute sprains are among the most common injury in soccer players and are generally treated conservatively, with emphasis placed on secondary prevention to reduce the risk for future sprains and progression to chronic ankle instability. Repetitive ankle injuries in soccer players may cause chronic ankle instability, which includes both mechanical ligamentous laxity and functional changes. Chronic ankle pathology often requires surgery to repair ligamentous damage and remove soft-tissue or osseous impingement. Proper initial treatment, rehabilitation, and secondary prevention of ankle injuries can limit the amount of time lost from play and avoid negative long-term sequelae (eg, osteochondral lesions, arthritis). On the other hand, high ankle sprains portend a poorer prognosis and a longer recovery. These injuries will typically require surgical stabilization. Impingement-like syndromes of the ankle can undergo an initial trial of conservative treatment; when this fails, however, soccer players respond favorably to arthroscopic debridement of the lesions causing impingement. Finally, other pathologies (eg, stress fractures) are highly encouraged to be treated with surgical stabilization in elite soccer players. PMID- 30481229 TI - Association between number of children and carotid intima-media thickness in Bangladesh. AB - Previous studies on the association between number of children and carotid intima media thickness (cIMT) were limited to Western populations. Pregnancy in women is associated with physiologic changes that may influence the risk of cardiovascular disease. Comparing the association between number of children and cIMT in men and women can provide insights on whether the association may be due to pregnancy. We investigated the association between number of children and cIMT among 718 female (mean age 37.5 years) and 417 male participants (mean age 41.3 years), randomly selected from the Health Effect of Arsenic Longitudinal Study (HEALS), a population-based cohort study in Bangladesh. Multivariate linear regression was used to assess the association and to control for education attainment, history of diabetes, age, smoking, betel use, BMI, systolic blood pressure, and diastolic blood pressure. The average number of children was 4.43 for women and 3.74 for men. There were no nulliparous women. We observed a positive association between number of children and cIMT in women. Mean cIMT increased by 4.5 MUm (95% CI, 0.8 8.1) per increment of one birth (P = 0.02). Compared to women with two children, cIMT in women with 4 children and >=5 children was 23.6MUm (95%CI, 2.6-44.7; P = 0.03) and 25.1 MUm (95%CI, 3.5-46.6; P = 0.02) greater, respectively. The association was not modified by BMI, SBP, betel use or age. Data in men showed no evidence of association (P = 0.4). The finding suggests a role of high parity in atherosclerosis in women of a low-income, high parity population. PMID- 30481232 TI - Geniculate Artery Injury During Primary Total Knee Arthroplasty. AB - Major arterial injury associated with total knee arthroplasty (TKA) is a rare and potentially devastating complication. However, the rate of injury to smaller periarticular vessels and the clinical significance of such an injury have not been well investigated. The purpose of this study is to describe the rate and outcomes of geniculate artery (GA) injury, the time at which injury occurs, and any associations with tourniquet use. From November 2015 to February 2016, 3 surgeons at a single institution performed 100 consecutive primary TKAs and documented the presence or absence and the timing of GA injury. The data were then retrospectively reviewed. All TKAs had no prior surgery on the operative extremity. Other variables collected included tourniquet use, tranexamic acid (TXA) administration, intraoperative blood loss, postoperative drain output, and blood transfusion. The overall rate of GA injury was 38%, with lateral inferior and middle GA injury in 31% and 15% of TKAs, respectively. Most of the injuries were visualized during bone cuts or meniscectomy. The rate of overall or isolated GA injury was not significantly different (P > .05) with either use of intravenous (84 patients) or topical (14 patients) TXA administration. Comparing selective tourniquet use (only during cementation) vs routine use showed no differences in GA injury rate (P = .37), blood loss (P = .07), or drain output (P = .46). There is a relatively high rate of GA injury, with injury to the lateral GA occurring more often than the middle GA. Routine or selective tourniquet use does not affect the rate of injury. PMID- 30481233 TI - Hip and Core Muscle Injuries in Soccer. AB - Soccer is the most popular sport in the world and has the fourth highest number of sports injuries. Hip and groin injuries account for 14% of soccer injuries and can be difficult to recognize and treat as they often require a high level of suspicion and advanced imaging. Groin pain can be separated into 3 categories: (1) defined clinical entities for groin pain (adductor-related, iliopsoas related, inguinal-related [sports hernias/athletic pubalgia], and pubic-related groin pain), (2) hip-related groin pain (hip morphologic abnormalities, labral tears, and chondral injuries), and (3) other causes of groin pain. Conservative approaches are typically the first line of treatment, but operative intervention has been reported to result in higher rates of return to sport in athletes with hip-related and inguinal-related groin pain injuries. In patients with concurrent hip-related and inguinal-related groin pain, the failure to recognize the relationship and treat both conditions may result in lower rates of return to sport. Preseason screening programs can identify high-risk athletes, who may benefit from a targeted prevention program. Further study on exercise therapy, early surgical intervention, and potential biologic intervention are needed to determine the most effective methods of preventing groin injuries in athletes. PMID- 30481234 TI - Knee Injuries in Elite Level Soccer Players. AB - As one of the most popular sports in the world, soccer injury rates involving the knee continue to rise. An alarming trend of knee injuries, including increased anterior cruciate ligament ruptures, underscores the need to review our current understanding of these injuries in soccer players. This article includes a critical review of the epidemiology of knee injuries in soccer, anterior cruciate ligament and other ligamentous injuries, cartilage and meniscal injury, post traumatic osteoarthritis, as well as current prevention initiatives. PMID- 30481235 TI - Medical Complications and Outcomes After Total Shoulder Arthroplasty: A Nationwide Analysis. AB - There is a paucity of evidence describing the types and rates of postoperative complications following total shoulder arthroplasty (TSA). We sought to analyze the complications following TSA and determine their effects on described outcome measures. Using discharge data from the weighted Nationwide Inpatient Sample from 2006 to 2010, patients who underwent primary TSA were identified. The prevalence of specific complications was identified using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes. The data from this database represent events occurring during admission, prior to discharge. The associations between patient characteristics, complications, and outcomes of TSA were evaluated. The specific outcomes analyzed in this study were mortality and length of stay (LOS). A total of 125,766 patients were identified. The rate of complication after TSA was 6.7% (8457 patients). The most frequent complications were respiratory, renal, and cardiac, occurring in 2.9%, 0.8%, and 0.8% of cases, respectively. Increasing age and total number of preoperative comorbidities significantly increased the likelihood of having a complication. The prevalence of postoperative shock and central nervous system, cardiac, vascular, and respiratory complications was significantly higher in patients who suffered postoperative mortality (88 patients; 0.07% mortality rate) than in those who survived surgery (P < 0.0001). In terms of LOS, shock and infectious and vascular complications most significantly increased the length of hospitalization. Postoperative complications following TSA are not uncommon and occur in >6% of patients. Older patients and certain comorbidities are associated with complications after surgery. These complications are associated with postoperative mortality and increased LOS. PMID- 30481236 TI - Patient Preferences in Office-Based Orthopedic Care: A Prospective Evaluation. AB - Patient satisfaction has become a topic of interest within orthopedics as the landscape of provider reimbursement continues to evolve to reward value of care. Online internet physician rating sites are becoming increasingly popular ways for patients to subjectively express their provider experience. Understanding what patients value during their episode of care is important in the modern healthcare environment. The purpose of this study is to determine what preferences, if any, patients have when selecting their physician and how they experience care in an outpatient orthopedic setting. A prospective survey was electronically administered to 212 patients in an adult reconstruction clinic. One hundred ninety-six patients (92.5%) completed the survey. Demographic questions regarding age, sex, ethnicity, and prior adult reconstruction surgical history were obtained. When patients were asked how much time they would like the doctor to spend with them on a routine visit, the most common answer was 10 to 15 minutes (41.3%), with only 10.2% patients desiring >20 minutes. The majority of patients (83.1%) believe >=30 minutes is too long to wait to see their surgeon. Less than half of patients (41.8%) stated that they would feel as though they were receiving below average care if seen only by a nurse practitioner or physician's assistant at a postoperative visit. Patients reported no significant age, gender, or ethnicity preferences for their physician. Recommendations from friends or other physicians was the most common (66.4%) way for patients to find their physicians, while 12.2% utilized online rating sites during their search. Optimizing patient experiences in the office may include keeping wait times to <30 minutes and educating patients on the roles of physician extenders. More work needs to be done to further elucidate variables influencing the subjective patient experience with their orthopedic care. PMID- 30481237 TI - Soccer or Football Medicine? Global Sports Medicine for a Global Game. PMID- 30481238 TI - The Effect of Playing Position on Injury Risk in Male Soccer Players: Systematic Review of the Literature and Risk Considerations for Each Playing Position. AB - Soccer (football) is a complex contact sport with a substantial risk of injury. As injury surveillance is the first step of the injury prevention paradigm, soccer epidemiology is well reported in the existing literature, but less is known about the actual role of player position on the general injury risk. The goal of this study is to present the existing evidence regarding the influence of player's position on general injury risk in male soccer. A systematic review of the Medline database was carried out. Only English written studies on male soccer and citing playing position as a possible determinant of injury risk were included. One hundred and two full texts were evaluated for eligibility, and 11 studies were selected for the qualitative synthesis. Of the 11 studies included in the systematic review, 5 didn't find any significant correlation with between player's position and general injury risk, while the remaining 6 studies found player's position to be correlated with injury risk, with mixed findings depending on each study. The most consistent finding was a tendency for goalkeepers (GKs) to sustain less injuries compared to outfield players. When considering only the studies reporting just the match injury risk, forwards seemed to be at higher risk, even if there wasn't a complete agreement. Few studies have evaluated a possible effect of playing position on general injury risk in male soccer. There is no agreement if weather or not different playing positions are associated to a higher injury risk. GKs seem to be at lower risk of injury when compared to outfield players. PMID- 30481239 TI - The In Vivo Impact of Leukocyte Injections on Normal Rat Achilles Tendons: Potential Detriment to Tendon Morphology, Cellularity, and Vascularity. AB - In this study, we determine the in vivo effects of injecting sub-populations of leukocytes into normal rat Achilles tendons via a controlled laboratory study. Allogenic monocytes, granulocytes, or plasma were injected into 24 healthy rat Achilles tendons. Treated and contralateral un-treated control tendons then assessed for cellularity, histologic morphology, and vascularity after 7 and 14 days. Significant increases of 221% and 249% in cellularity (P = 0.014) were seen on day 14 within Achilles tendons injected with granulocytes as compared to plasma and monocytes, respectively. Also, significant improvement in morphology (P = 0.029) between days 7 and 14 was seen for the granulocyte injected Achilles tendons. Significant increases in cellularity after an injection of granulocytes, compared to monocytes and plasma, corresponds to a significant increase in inflammation within the tissue, suggesting that leukocyte-rich platelet-rich plasma (PRP) preparations are proinflammatory and potentially catabolic when injected into tendon tissue. The concentration and composition of white blood cells within PRP preparations is variable and needs to be better understood in order to optimize clinical utility of PRP injections. PMID- 30481240 TI - The PASTA Bridge--A Repair Technique for Partial Articular-Sided Rotator Cuff Tears: A Biomechanical Evaluation of Construct Strength. AB - Partial articular-sided supraspinatus tendon avulsion (PASTA) tears are a common clinical problem that can require surgical intervention to reduce patient symptoms. Currently, no consensus has been reached regarding the optimal repair technique. The PASTA Bridge technique was developed by the senior author to address these types of lesions. A controlled laboratory study was performed comparing the PASTA Bridge with a standard transtendon rotator cuff repair to confirm its biomechanical efficacy. A 50% articular-sided partial tear of the supraspinatus tendon was created on 6 matched pairs of fresh-frozen cadaveric shoulders. For each matched pair, 1 humerus received a PASTA Bridge repair, whereas the contralateral side received a repair using a single suture anchor with a horizontal mattress suture. The ultimate load, yield load, and stiffness were determined from the load-displacement results for each sample. Video tracking software was used to determine the cyclic displacement of each sample at the articular margin and the repair site. Strain at the margin and repair site was then calculated using this collected data. There were no significant differences between the 2 repairs in ultimate load (P = .577), strain at the repair site (P = .355), or strain at the margin (P = .801). No instance of failure was due to the PASTA Bridge construct itself. The results of this study have established that the PASTA Bridge is biomechanically equivalent to the transtendon repair technique. The PASTA Bridge is technically easy, percutaneous, reproducible, and is associated with fewer risks. PMID- 30481241 TI - The Three H's: Head, Heart, and Heat Considerations in Soccer. AB - Soccer requires significant physical conditioning and endurance, as well as the physicality required for contact play. In order to keep athletes safe, it is important that coaches, medical staff, and the players themselves are educated on the most common dangers to their health that they may encounter on a soccer pitch. This article aims to review the current literature and recommendations on concussion, cardiovascular considerations, and heat-related illness as they relate to competitive soccer, with a goal of educating all those who help to keep athletes healthy and competing to their full potential. PMID- 30481242 TI - Upper Extremity Injuries in Soccer. AB - Upper limb injuries in soccer represent only a marginal portion of injuries, however this is mainly true for outfield players. Goalkeepers are reported to have up to 5 times more upper extremity injuries, many of them requiring substantial time-loss for treatment and rehabilitation. The most common upper extremity injury locations are the shoulder/clavicle followed by the hand/finger/thumb, elbow, wrist, forearm, and upper arm. The mechanism of injury, presentation, physical examination, and imaging features all play a significant role in reaching the correct diagnosis. Taking to consideration the position the player plays and his demands will also enable tailoring the optimal treatment plan that allows timely and safe return to play. This article discusses common upper extremity injuries observed in soccer players, focusing on proper diagnosis and optimal management. PMID- 30481243 TI - Use of Musculoskeletal Ultrasound and Regenerative Therapies in Soccer. AB - Improvements in ultrasound technology have increased the popularity and use of ultrasound as a diagnostic and therapeutic modality for many soccer-related musculoskeletal (MSK) injuries. As a dynamic imaging modality, ultrasound offers increased accuracy and efficacy with minimally invasive procedures, such as guided injections, percutaneous tenotomy, and regenerative therapies, in the clinical setting. Emerging evidence indicates that regenerative therapies, such as platelet-rich-plasma (PRP), mesenchymal stem cells, and amniotic products, are a promising treatment for many MSK injuries and are gaining popularity among professional athletes. PRP is a safe treatment for a number of MSK conditions and has been included in the standard of care. However, conflicting evidence on return-to-play timeframes and efficacy in certain MSK conditions have led to inconsistent recommendations on indications for use, dose, and timing of treatment. Mesenchymal stem cell therapy, while promising, lacks high-level evidence of efficacy despite its increasing use among athletes. Currently, no data are available regarding the outcome of the use of amniotic products for the treatment of injuries in athletes. Furthermore, preparation of many regenerative therapies eclipses the concept of minimal manipulation and is subject to US Food and Drug Administration phase I to III trials. High-level research on regenerative medicine therapies should be continuously conducted to establish their clinical efficacy and safety data. PMID- 30481244 TI - 3 steps we can take to address childhood adversity. PMID- 30481245 TI - Childhood adversity and lifelong health: From research to action. AB - Childhood adversity is a significant root cause of chronic illness and early death. Prevention, mitigation, and Tx of toxic stressors must be part of our paradigm of care. PMID- 30481246 TI - MSK injury? Make splinting choices based on the evidence. AB - Which devices do-and don't-have evidence to support their use when it comes to injuries like carpal tunnel syndrome, "tennis elbow," or an ankle sprain? Read on. PMID- 30481247 TI - How could improved provider communication have improved the care this patient received? PMID- 30481248 TI - Progressive discoloration over the right shoulder. AB - The discolored patch on our patient's shoulder was nothing new-but when it grew in size and developed hypertrichosis, it prompted a closer investigation. PMID- 30481249 TI - Should you reassess your patient's asthma diagnosis? AB - Asthma may not be a permanent diagnosis in adults. A study finds that up to one third of adults with physician-diagnosed asthma no longer had it after 5 years. PMID- 30481250 TI - A closer look at an ezetimibe discussion. PMID- 30481251 TI - Disagreement over a Case Report Dx. PMID- 30481252 TI - What medical therapies work for gastroparesis? PMID- 30481253 TI - Obstructive sleep apnea: A better Dx model for primary care. AB - This study identified a method that provides a truer assessment of disease probability than has been achieved with history and physical exam evaluation. PMID- 30481254 TI - Adult foot fractures: A guide. AB - This review can help you refine your approach to the diagnosis and management of adult foot fractures, while offering guidance on when to pursue advanced imaging. PMID- 30481255 TI - Primary hyperparathyroidism: Labs to order, Tx to consider. AB - Unexplained kidney stones, osteoporosis, or certain subtle clues may point to hyperparathyroidism. These tests and imaging options can help you to be sure. PMID- 30481256 TI - Persistent erythematous papulonodular rash. AB - The rash on our patient's abdomen was not itchy or painful, but it had persisted for more than a year and continued to spread. A biopsy confirmed our suspicions. PMID- 30481257 TI - SkeletalVis: An exploration and meta-analysis data portal of cross-species skeletal transcriptomics data. AB - Motivation: Skeletal diseases are prevalent in society, but improved molecular understanding is required to formulate new therapeutic strategies. Large and increasing quantities of available skeletal transcriptomics experiments give the potential for mechanistic insight of both fundamental skeletal biology and skeletal disease. However, no current repository provides access to processed, readily interpretable analysis of this data. To address this, we have developed SkeletalVis, an exploration portal for skeletal gene expression experiments. Results: The SkeletalVis data portal provides an exploration and comparison platform for analysed skeletal transcriptomics data. It currently hosts 287 analysed experiments with 739 perturbation responses with comprehensive downstream analysis. We demonstrate its utility in identifying both known and novel relationships between skeletal expression signatures. SkeletalVis provides users with a platform to explore the wealth of available expression data, develop consensus signatures and the ability to compare gene signatures from new experiments to the analysed data to facilitate meta-analysis. Availability: The SkeletalVis data portal is freely accessible at http://phenome.manchester.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30481258 TI - An Equivariant Bayesian Convolutional Network predicts recombination hotspots and accurately resolves binding motifs. AB - Motivation: Convolutional neural networks (CNNs) have been tremendously successful in many contexts, particularly where training data is abundant and signal-to-noise ratios are large. However, when predicting noisily observed phenotypes from DNA sequence, each training instance is only weakly informative, and the amount of training data is often fundamentally limited, emphasizing the need for methods that make optimal use of training data and any structure inherent in the process. Results: Here we show how to combine equivariant networks, a general mathematical framework for handling exact symmetries in CNNs, with Bayesian dropout, a version of MC dropout suggested by a reinterpretation of dropout as a variational Bayesian approximation, to develop a model that exhibits exact reverse-complement symmetry and is more resistant to overtraining. We find that this model combines improved prediction consistency with better predictive accuracy compared to standard CNN implementations and state-of-art motif finders. We use our network to predict recombination hotspots from sequence, and identify binding motifs for the recombination-initiation protein PRDM9 previously unobserved in this data, which were recently validated by high-resolution assays. The network achieves a predictive accuracy comparable to that attainable by a direct assay of the H3K4me3 histone mark, a proxy for PRDM9 binding. Availability: https://github.com/luntergroup/EquivariantNetworks. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30481259 TI - EpistasisRank and EpistasisKatz: interaction network centrality methods that integrate prior knowledge networks. AB - Motivation: An important challenge in gene expression analysis is to improve hub gene selection to enrich for biological relevance or improve classification accuracy for a given phenotype. In order to incorporate phenotypic context into co-expression, we recently developed an epistasis-expression network centrality method that blends the importance of gene-gene interactions (epistasis) and main effects of genes. Further blending of prior knowledge from functional interactions has the potential to enrich for relevant genes and stabilize classification. Results: We develop two new expression-epistasis centrality methods that incorporate interaction prior knowledge. The first extends our SNPrank (EpistasisRank) method by incorporating a gene-wise prior knowledge vector. This prior knowledge vector informs the centrality algorithm of the inclination of a gene to be involved in interactions by incorporating functional interaction information from the Integrative Multi-species Prediction (IMP) database. The second method extends Katz centrality to expression-epistasis networks (EpistasisKatz), extends the Katz bias to be a gene-wise vector of main effects and extends the Katz attenuation constant prefactor to be a prior knowledge vector for interactions. Using independent microarray studies of major depressive disorder, we find that including prior knowledge in network centrality feature selection stabilizes the training classification and reduces overfitting. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30481260 TI - Atorvastatin protects cardiac progenitor cells from hypoxia-induced cell growth inhibition via MEG3/miR-22/HMGB1 pathway. AB - Heart failure (HF) induced by ischemia myocardial infarction (MI) is one of the major causes of morbidity and mortality all around the world. Atorvastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, has been demonstrated to benefit patients with ischemic or non-ischemic-induced HF, but the mechanism is still poorly understood. Increasing evidence indicates that lncRNAs play important role in variety of human disease. However, the role and underlying molecular mechanisms remain largely unclear. In our work, we applied 0.5% O2 to generate a hypoxia cardiac progenitor cell (CPC) model. Then, CCK8 and EdU assays were employed to investigate the role of atorvastatin in hypoxia CPC cell model. We found that hypoxia inhibits CPC viability and proliferation through modulating MEG3 expression, while atorvastatin application can protect CPCs from hypoxia induced injury through inhibiting MEG3 expression. Then, we demonstrated that repression of MEG3 inhibited the hypoxia-induced injury of CPCs and overexpression of MEG3 inhibited the protective effect of atorvastatin in the hypoxia-induced injury of CPCs. Furthermore, our study illustrated that atorvastatin played its role in CPC viability and proliferation by modulating the expression of HMGB1 through the MEG3/miR-22 pathway. Our study, for the first time, uncovered the molecular mechanism of atorvastatin's protective role in cardiomyocytes under hypoxia condition, which may provide an exploitable target in developing effective therapy drugs for MI patients. PMID- 30481261 TI - Evidenced-Based Approach to Abdominoplasty Update. AB - The following publication was compiled as an evidence-based update for plastic surgeons performing abdominoplasty from a review of the published literature on that subject between January 2014 and February 2017. It is an overview of various aspects of abdominoplasty including preoperative patient assessment, variations and advances in both surgical and anesthetic technique, patient safety, and outcomes. It is intended to serve as an adjunct to previously published evidence based reviews of abdominoplasty. PMID- 30481262 TI - PhastWeb: a web interface for evolutionary conservation scoring of multiple sequence alignments using phastCons and phyloP. AB - Summary: The Phylogenetic Analysis with Space/Time models (PHAST) package is a widely used software package for comparative genomics that has been freely available for download since 2002. Here we introduce a web interface (phastWeb) that makes it possible to use two of the most popular programs in PHAST, phastCons and phyloP, without downloading and installing the PHAST software. This interface allows users to upload a sequence alignment and either upload a corresponding phylogeny or have one estimated from the alignment. After processing, users can visualize alignments and conservation scores as genome browser tracks and download estimated tree models and raw scores for further analysis. Altogether, this resource makes key features of the PHAST package conveniently available to a broad audience. Availability: PhastWeb is freely available on the web at http://compgen.cshl.edu/phastweb/. The website provides instructions as well as examples. PMID- 30481263 TI - Organ-Specific, Age-Dependent Associations of Steady-State Pressures and Pulsatile Pressure Wave Components with End-Organ Measures. AB - Background: The contribution of steady-state pressures and the forward (Pf) and backward (reflected) (Pb) wave pressure components of pulse pressure (PP) to risk prediction have produced contrasting results. We hypothesized that the independent contribution of steady-state pressures (mean arterial pressure [MAP]), Pf and Pb to cardiovascular damage is organ-specific and age-dependent. Methods: In 1384 black South Africans from a community sample, we identified independent relations between MAP, Pf or Pb (applanation tonometry and SphygmoCor software) and either left ventricular mass index (LVMI) (n=997)(echocardiography), carotid intima media thickness (IMT)(n=804) (B-mode ultrasound), or aortic pulse wave velocity (PWV)(n=1217). Results: Independent of risk factors, relations between Pf and IMT were noted in those over 50 years of age (p<0.02), whilst in those less than 50 years of age, MAP (p<0.005) was independently associated with IMT. Pb failed to show independent relations with IMT at any age (p>0.37) In contrast, independent relations between Pb and LVMI were noted in those less than (p<0.0001), and greater than (p<0.02) 50 years of age, whilst MAP was not independently associated with LVMI at any age (p>0.07) and Pf tended to show significant relations only in the elderly (p=0.05). Moreover, whilst MAP (p<0.005) and Pb (p<0.01) showed independent relations with PWV at any age, Pf failed to show independent relations (p>0.10). Conclusion: Independent of confounders, steady-state and aortic forward and backward wave pressures show associations with end organ measures that are organ specific and age-dependent. PMID- 30481264 TI - Cannabinoids, Chemical Senses, and Regulation of Feeding Behavior. AB - The herb Cannabis sativa has been traditionally used in many cultures and all over the world for thousands of years as medicine and recreation. However, because it was brought to the Western world in the late 19th century, its use has been a source of controversy with respect to its physiological effects as well as the generation of specific behaviors. In this regard, the CB1 receptor represents the most relevant target molecule of cannabinoid components on nervous system and whole-body energy homeostasis. Thus, the promotion of CB1 signaling can increase appetite and stimulate feeding, whereas blockade of CB1 suppresses hunger and induces hypophagia. Taste and flavor are sensory experiences involving the oral perception of food-derived chemicals and drive a primal sense of acceptable or unacceptable for what is sampled. Therefore, research within the last decades focused on deciphering the effect of cannabinoids on the chemical senses involved in food perception and consequently in the pattern of feeding. In this review, we summarize the data on the effect of cannabinoids on chemical senses and their influences on food intake control and feeding behavior. PMID- 30481265 TI - Antibody Persistence at the Population Level 5 Years After Mass Vaccination With Meningococcal Serogroup A Conjugate Vaccine (PsA-TT) in Burkina Faso: Need for a Booster Campaign? AB - Background: In Burkina Faso, serogroup A meningococcal (NmA) conjugate vaccine (PsA-TT, MenAfriVac) was introduced through a mass campaign in children and adults in December 2010. Similar to a serological survey in 2011, we followed population-level antibody persistence for 5 years after the campaign and estimated time of return to previously-published pre-vaccination levels. Methods: We conducted 2 cross-sectional surveys in 2013 and early 2016, including representative samples (N = 600) of the general population of Bobo-Dioulasso, Burkina Faso. Serum bactericidal antibody titers (rabbit complement) were measured against NmA reference strain F8236 (SBA-ref), NmA strain 3125 (SBA 3125), and NmA-specific immunoglobulin G (IgG) concentrations. Results: During the 2016 survey, in different age groups between 6 and 29 years, the relative changes in geometric means compared to 2011 values were greater among younger age groups. They were between -87% and -43% for SBA-ref; -99% and -78% for SBA-3125; and -89% and -63% for IgG. In linear extrapolation of age-specific geometric means from 2013 to 2016, among children aged 1-4 years at the time of the PsA-TT campaign, a return to pre-vaccination levels should be expected after 12, 8, and 6 years, respectively, according to SBA-ref, SBA-3125, and IgG. Among older individuals, complete return to baseline is expected at the earliest after 11 years (SBA-ref and SBA-3125) or 9 years (IgG). Conclusions: Based on SBA-3125, a booster campaign after 8 years would be required to sustain direct immune protection for children aged 1-4 years during the PsA-TT campaign. Antibodies persisted longer in older age groups. PMID- 30481266 TI - Computational modeling reveals MAP3K8 as mediator of resistance to vemurafenib in thyroid cancer stem cells. AB - Motivation: Val600Glu (V600E) mutation is the most common BRAF mutation detected in thyroid cancer. Hence, recent research efforts have been performed trying to explore several inhibitors of the V600E mutation-containing BRAF kinase as potential therapeutic options in thyroid cancer refractory to standard interventions. Among them, vemurafenib is a selective BRAF inhibitor approved by FDA for clinical practice. Unfortunately, vemurafenib often displays limited efficacy in poorly differentiated and anaplastic thyroid carcinomas probably because of intrinsic and/or acquired resistance mechanisms. In this view, cancer stem cells may represent a possible mechanism of resistance to vemurafenib, due to their self-renewal and chemo resistance properties. Results: We present a computational framework to suggest new potential targets to overcome drug resistance. It has been validated with an in vitro model based upon a spheroid forming method able to isolate thyroid cancer stem cells that may mimic resistance to vemurafenib. Indeed, vemurafenib did not inhibit cell proliferation of BRAF V600E thyroid cancer stem cells, but rather stimulated cell proliferation along with a paradoxical overactivation of ERK and AKT pathways. The computational model identified a fundamental role of mitogen-activated protein kinase 8 (MAP3K8), a serine/threonine kinase expressed in thyroid cancer stem cells, in mediating this drug resistance. To confirm model prediction, we set a suitable in vitro experiment revealing that the treatment with MAP3K8 inhibitor restored the effect of vemurafenib in terms of both DNA fragmentation and PARP cleavage (apoptosis) in thyroid cancer stem cells. Moreover, MAP3K8 expression levels may be a useful marker to predict the response to vemurafenib. Availability: The model is available in GitHub repository visiting the following URL: https://github.com/francescopappalardo/MAP3K8-Thyroid-Spheres-V-3.0. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30481268 TI - Towards risk-adapted perioperative treatment of gastroesophageal cancer. PMID- 30481267 TI - A seven-Gene Signature assay improves prognostic risk stratification of perioperative chemotherapy treated gastroesophageal cancer patients from the MAGIC trial. AB - Background: Following neoadjuvant chemotherapy for operable gastroesophageal cancer, lymph node metastasis is the only validated prognostic variable; however, within lymph node groups there is still heterogeneity with risk of relapse. We hypothesized that gene profiles from neoadjuvant chemotherapy treated resection specimens from gastroesophageal cancer patients can be used to define prognostic risk groups to identify patients at risk for relapse. Patients and methods: The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial (n = 202 with high quality RNA) samples treated with perioperative chemotherapy were profiled for a custom gastric cancer gene panel using the NanoString platform. Genes associated with overall survival (OS) were identified using penalized and standard Cox regression, followed by generation of risk scores and development of a NanoString biomarker assay to stratify patients into risk groups associated with OS. An independent dataset served as a validation cohort. Results: Regression and clustering analysis of MAGIC patients defined a seven Gene Signature and two risk groups with different OS [hazard ratio (HR) 5.1; P < 0.0001]. The median OS of high- and low-risk groups were 10.2 [95% confidence interval (CI) of 6.5 and 13.2 months] and 80.9 months (CI: 43.0 months and not assessable), respectively. Risk groups were independently prognostic of lymph node metastasis by multivariate analysis (HR 3.6 in node positive group, P = 0.02; HR 3.6 in high-risk group, P = 0.0002), and not prognostic in surgery only patients (n = 118; log rank P = 0.2). A validation cohort independently confirmed these findings. Conclusions: These results suggest that gene-based risk groups can independently predict prognosis in gastroesophageal cancer patients treated with neoadjuvant chemotherapy. This signature and associated assay may help risk stratify these patients for post-surgery chemotherapy in future perioperative chemotherapy-based clinical trials. PMID- 30481269 TI - The effect of pre-existing immunity on virus detection and immune responses in a phase II randomized trial of a Russian-backbone live attenuated influenza vaccine in Bangladeshi children. AB - Background: In a 2012 phase II clinical trial (NCT01625689), 300 Bangladeshi children aged 24 to 59 months with no prior influenza vaccine exposure were randomized to receive a single dose of intra-nasally administered trivalent Russian-backbone live attenuated influenza vaccine (LAIV) or placebo. Protocol defined analyses, presented in the companion manuscript, demonstrate decreased viral detection and immunogenicity for A/H1N1pdm09 relative to the A/H3N2 and B strains. This post-hoc analysis of the trial data aims to investigate the LAIV strain differences by testing the hypothesis that pre-existing immunity may influence viral recovery and immune responses after LAIV receipt. Methods: We used logistic regressions to evaluate the relations between markers of pre existing immunity (i.e., hemagglutination inhibition (HAI), microneutralization, and IgA and IgG antibodies) and LAIV viral recovery in the week post-vaccination. We then tested for potential effect modification by baseline HAI titers (i.e., <10 versus >=10) and week 1 viral recovery on the LAIV-induced serum and mucosal immune responses measured between days 0 and 21 post-vaccination. Results: Higher levels of pre-existing immunity to influenza A/H3N2 and B were strongly associated with strain-specific prevention of viral shedding upon LAIV receipt. While evidence of LAIV immunogenicity was observed for all three strains, the magnitudes of immune responses were most pronounced in children with no evidence of pre-existing HAI and in those with detectable virus. Conclusion: The results provide evidence for a bidirectional association between viral replication and immunity and underscore the importance of accounting for pre-existing immunity when evaluating virologic and immunologic responses to LAIVs. PMID- 30481270 TI - Patient reported outcomes (PROs) as a Routine Measure for Cancer Inpatients - the Final Missing Piece of the Puzzle? PMID- 30481271 TI - Functional imaging in echocardiography can sometimes replace direct structure visualization. PMID- 30481272 TI - Immunogenicity and viral shedding of Russian-backbone seasonal trivalent, live attenuated influenza vaccine in a phase II randomized placebo-controlled trial among pre-school aged children in urban Bangladesh. AB - Introduction: We evaluated Russian-backbone, live-attenuated influenza vaccine (LAIV) for immunogenicity and viral shedding in a phase 2, randomized, placebo controlled trial among Bangladeshi children. Materials and Methods: Healthy children received a single, intranasal dose of LAIV containing the 2011-2012 WHO recommended formulation or placebo (clinicaltrials.gov # NCT01625689). A/H1N1 and A/H3N2 concentrations were >=106.5 EID50/dose and influenza B was >=106 EID50/dose. Nasopharyngeal wash (NPW) specimens were collected on days 0, 2, 4, and 7. RTPCR and sequencing identified influenza virus (vaccine or wild-type). On days 0 and 21, blood specimens were collected to assess serum immunogenicity using hemagglutination inhibition, microneutralization, IgA/IgG ELISAs; and NPW specimens were collected to assess mucosal immunogenicity using kinetic IgA ELISA. Results: Three-hundred children aged 24-59 months were enrolled in the immunogenicity and viral shedding analyses. Among children receiving LAIV, 45% and 67% shed A/H3N2 and B vaccine strains, respectively. No child shed A/H1N1 vaccine strains. There were significantly higher day 21 geometric mean titers (GMTs) for the LAIV as compared to the placebo groups in all immunoassays for A/H3N2 and B (Log10 titer p<0.0001, GMT Ratio >2.0). Among immunoassays for A/H1N1, only the mucosal IgA GMT was significantly higher than placebo at day 21 (Log10 titer p=0.0465). Conclusion: Children vaccinated with LAIV had serum and mucosal antibody responses to A/H3N2 and B, but only mucosal IgA response to A/H1N1. Many children shed A/H3N2 and B vaccine strains, but none shed A/H1N1. More research is needed to determine the reason for decreased LAIV A/H1N1 immunogenicity and virus shedding. PMID- 30481273 TI - Prevalence and determinants of QuantiFERON-diagnosed tuberculosis infection in 9,810 Mongolian schoolchildren. AB - Background: There is controversy regarding the potential influence of vitamin D deficiency, exposure to environmental tobacco smoke, BCG vaccination, season and body habitus on susceptibility to Mycobacterium tuberculosis (MTB) infection. Methods: We conducted a cross-sectional analysis to identify determinants of a positive QuantiFERON(r)-TB Gold (QFT) assay result in children aged 6-13 years attending 18 schools in Ulaanbaatar, Mongolia. Data relating to potential risk factors for MTB infection were collected by questionnaire, physical examination and determination of serum 25-hydroxyvitamin D (25[OH]D) concentrations. Risk ratios were calculated using generalized estimating equations with adjustment for potential confounders, and population attributable fractions (PAFs) were calculated for modifiable risk factors identified. Results: 946/9,810 (9.6%) participants had a positive QFT result. QFT-positivity was independently associated with household exposure to pulmonary TB (adjusted risk ratio [aRR] 4.75, 95% CI 4.13-5.46, P<0.001; PAF 13.1%, 95% CI 11.1%-15.0%), vitamin D deficiency (aRR 1.23, 95% CI 1.08-1.40, P=0.002; PAF 5.7%, 1.9%-9.3%), exposure to environmental tobacco smoke (one indoor smoker, aRR 1.19, 95% CI 1.04-1.35; two or more indoor smokers, aRR 1.30, 95% CI 1.02-1.64; P for trend, 0.006; PAF 7.2%, 95% CI 2.2%-12.0%) and increasing age (aRR per additional year 1.14, 95% CI 1.10-1.19, P<0.001). No statistically significant independent association was seen for presence of a BCG scar, season of sampling or body mass index. Conclusions: Our findings underline the importance of contact tracing in TB exposed households as a strategy to identify MTB-infected children. Vitamin D deficiency and exposure to environmental tobacco smoke may be modifiable risk factors for MTB infection. PMID- 30481274 TI - The answer lies in the third dimension. PMID- 30481276 TI - Mapping of Corneal Layer Thicknesses With Polarization-Sensitive Optical Coherence Tomography Using a Conical Scan Pattern. AB - Purpose: We demonstrate segmentation and mapping of corneal layers (epithelium, Bowman's layer, and stroma) across the entire cornea (limbus to limbus), using additional contrast provided by polarization-sensitive optical coherence tomography (PS-OCT) and analyze the reproducibility of the procedure. Methods: A custom built PS-OCT system operating at 1045 nm central wavelength with conical scanning was used for image acquisition. Conical scanning allows for almost perpendicular beam incidence on the corneal surface and provides good signal quality over the entire field of view. Epithelium, Bowman's layer, and stroma were segmented using the additional contrast provided by PS-OCT. Thickness maps were computed and analyzed in sectors. Both eyes of 20 healthy volunteers were imaged at least three times to test this method and to quantify reproducibility. Results: Thickness maps of the epithelium show significant (P < 0.001) superior thinning and an inferior thickening. Bowman's layer appears homogeneous within the central 7 to 8 mm diameter of the cornea and gets thinner toward the periphery until this layer disappears between 4 and 5.5 mm eccentricity from the center. Intersubject variations of the measured thicknesses of epithelium (coefficient of variation [CV] ~8%), Bowman's layer (CV~25%), and stroma (CV~10%) were observed. Very good reproducibility of thickness measurements of epithelium (CV < 3%), Bowman's layer (CV < 5%), and stroma (CV < 2%) was found. Furthermore, a significant correlation (P < 0.001) between layer thicknesses of the right and left eyes of the same subject was found. Conclusions: PS-OCT with conical scanning is a feasible approach for determining thickness maps of corneal layers on a large field of view with high reproducibility. PMID- 30481275 TI - Reproductive factors, exogenous hormone use and risk of B-cell non-Hodgkin lymphoma in a cohort of women from the European Prospective Investigation into Cancer and Nutrition. AB - The role of hormonal factors in lymphoid neoplasms etiology remains unclear. Previous studies have yielded conflicting results, been underpowered to assess many lymphoma subtypes, or lacked detailed information on relevant exposures. Within the European Prospective Investigation into Cancer and Nutrition cohort, we analyzed comprehensive data collected at baseline (1992-2000) on reproductive factors and exogenous hormone use among 343,458 women, including 1,427 incident B cell non-Hodgkin lymphomas (NHL) and its major subtypes identified after a mean follow-up of 14 years (through 2015). We estimated hazard ratios and 95% confidence intervals using multivariable proportional hazards modeling. Overall, we observed no statistically significant associations between parity, age at first birth, breastfeeding, oral contraceptive use or ever use of postmenopausal hormone therapy and risk of B-cell NHL or its subtypes. Women who had a surgical menopause had a 51% higher risk of B-cell NHL (based on 67 cases) compared with natural menopause (hazard ratio=1.51, 95% confidence interval=1.17, 1.94). Given that this result may be due to chance, our results provide little support for the hypothesis that sex hormones play a role in lymphomagenesis. PMID- 30481279 TI - Scanning Acoustic Microscopy Comparison of Descemet's Membrane Normal Tissue and Tissue With Fuchs' Endothelial Dystrophy. AB - Purpose: To describe the application of scanning acoustic microscopy in the GHz range (GHz-SAM) for qualitative imaging and quantitative characterization of the micromechanical properties of the Descemet's membrane and endothelial cells of cornea tissue. Methods: Investigated were samples of a normal tissue and a tissue with Fuchs' endothelial dystrophy (FECD, cornea Guttata). Descemet's membranes were fixed on glass substrates and imaged utilizing a focused acoustic lens operating at a center frequency of 1 GHz. Results: GHz-SAM data, based on the well-established V(z) technique, revealed discrepancies in the velocity of the propagation of Rayleigh surface acoustic waves (RSAW). RSAW were found to be slower in glass substrates with FECD samples than in the same glass substrates (soda-lime) with normal Descemet membrane, which indicates lower shear and bulk moduli of elasticity in tissues affected by FECD. Conclusions: Noninvasive/nondestructive GHz-SAM, is utilized in this study for the imaging and characterization of Descemet membranes, fixated on glass substrates. V(z) signatures containing sufficient oscillations were obtained for the system of Descemet membranes on glass substrates. The observed variation in the microelastic properties indicates potential for further investigations with GHz SAM based on the V(z) technique. PMID- 30481278 TI - Pulses of Melanopsin-Directed Contrast Produce Highly Reproducible Pupil Responses That Are Insensitive to a Change in Background Radiance. AB - Purpose: To measure the pupil response to pulses of melanopsin-directed contrast, and compare this response to those evoked by cone-directed contrast and spectrally narrowband stimuli. Methods: Three-second unipolar pulses were used to elicit pupil responses in human subjects across three sessions. Thirty subjects were studied in session 1, and most returned for sessions 2 and 3. The stimuli of primary interest were "silent substitution" cone- and melanopsin-directed modulations. Red and blue narrowband pulses delivered using the post-illumination pupil response (PIPR) paradigm were also studied. Sessions 1 and 2 were identical, whereas session 3 involved modulations around higher radiance backgrounds. The pupil responses were fit by a model whose parameters described response amplitude and temporal shape. Results: Group average pupil responses for all stimuli overlapped extensively across sessions 1 and 2, indicating high reproducibility. Model fits indicate that the response to melanopsin-directed contrast is prolonged relative to that elicited by cone-directed contrast. The group average cone- and melanopsin-directed pupil responses from session 3 were highly similar to those from sessions 1 and 2, suggesting that these responses are insensitive to background radiance over the range studied. The increase in radiance enhanced persistent pupil constriction to blue light. Conclusions: The group average pupil response to stimuli designed through silent substitution provides a reliable probe of the function of a melanopsin-mediated system in humans. As disruption of the melanopsin system may relate to clinical pathology, the reproducibility of response suggests that silent substitution pupillometry can test if melanopsin signals differ between clinical groups. PMID- 30481277 TI - Sex Effects on Gene Expression in Lacrimal Glands of Mouse Models of Sjogren Syndrome. AB - Purpose: Sjogren syndrome is an autoimmune disease that occurs primarily in women, and is associated with lacrimal gland inflammation and aqueous-deficient dry eye. We hypothesize that sex-associated differences in lacrimal gland gene expression are very important in promoting lymphocyte accumulation in this tissue and contribute to the onset, progression, and/or severity of the inflammatory disease process. To test our hypothesis, we explored the nature and extent of sex related differences in gene expression in autoimmune lacrimal glands. Methods: Lacrimal glands were collected from age-matched, adult, male and female MRL/MpJ Tnfrsf6lpr (MRL/lpr) and nonobese diabetic/LtJ (NOD) mice. Glands were processed for the analysis of differentially expressed mRNAs by using CodeLink Bioarrays and Affymetrix GeneChips. Data were evaluated with bioinformatics and statistical software. Results: Our results show that sex significantly influences the expression of thousands of genes in lacrimal glands of MRL/lpr and NOD mice. The immune nature of this glandular response is very dependent on the Sjogren syndrome model. Lacrimal glands of female, as compared with male, MRL/lpr mice contain a significant increase in the expression of genes related to inflammatory responses, antigen processing, and chemokine pathways. In contrast, it is the lacrimal tissue of NOD males, and not females, that presents with a significantly greater expression of immune-related genes. Conclusions: These data support our hypothesis that sex-related differences in gene expression contribute to lacrimal gland disease in Sjogren syndrome. Our findings also suggest that factors in the lacrimal gland microenvironment are critically important in mediating these sex associated immune effects. PMID- 30481281 TI - Adrenal and Glucocorticoid Effects on the Circadian Rhythm of Murine Intraocular Pressure. AB - Purpose: Intraocular pressure (IOP) fluctuates with a robust circadian rhythm, which is synchronized to organismal rhythmicity through the master circadian clock located in the suprachiasmatic nuclei. The mechanisms maintaining circadian synchrony between the suprachiasmatic nuclei and IOP rhythms are presently unknown. The purpose of this study was to evaluate the necessity and sufficiency of adrenal and glucocorticoid function for the entrainment of iris-ciliary body (iris-CB) and IOP circadian rhythms in mice. Methods: Iris-CB complexes were dissected from C57Bl/6J mice that were kept in 12-hour light/dark cycles at 3 hour intervals, and their core clock gene (Per1, Per2, and Bmal1) and glucocorticoid receptor mRNA expression were quantified. Iris-CB complexes from period2::luciferase mice were dissected and cultured to measure in vitro rhythmicity. To determine the phase-shifting effect of glucocorticoids on the iris-CB, dexamethasone or vehicle was added to the cultured tissues at defined circadian phases. The diurnal IOP rhythms of adrenalectomized or sham-operated mice under the 12-hour light/dark cycles were also measured. Results: In iris-CB complexes, glucocorticoid receptor mRNA expression remained stable throughout the day, whereas the mRNA of core clock genes showed a robust circadian rhythmicity. Dexamethasone significantly induced phase-delays when administered between circadian time 8 (CT8) to CT12 and phase-advance when given between CT16 to CT20. Adrenalectomy abolished circadian IOP rhythmicity, particularly diminishing nocturnal IOP elevation compared with sham-operated mice. Conclusions: Glucocorticoids are sufficient for phase shifting the circadian clock in iris-CB. Intact adrenal function is required for manifest circadian rhythms of IOP in mice. Taken together, these data are consistent with the hypothesis that glucocorticoids mediate circadian entrainment of IOP to the master circadian oscillator. PMID- 30481282 TI - Subcellular locations of potential cell wall proteins in plants: predictors, databases and cross-referencing. AB - The cell wall is the most striking feature that distinguishes plant cells from animal cells. It plays an essential role in cell shape, stability, growth and protection. Despite being present in small amounts, cell wall proteins (CWPs) are crucial components of the cell wall. The cell wall proteome generally consists of sensu stricto CWPs, apoplast proteins and extracellular secreted proteins. Currently, there is a need for the bioinformatics analysis of a tremendous number of protein sequences that have been generated from genomic, transcriptomic and proteomics research. Compared with intracellular proteins, the location prediction of CWPs is challenging because many aspects of these proteins have not been experimentally characterized, and there are no CWP-trained, specific predictors available. By introducing the biological relevance (particularly molecular aspects) of the cell wall and CWPs, we critically evaluated the accuracy of 16 state-of-the-art predictors and classical predictors for the prediction of CWPs using an independent database of Arabidopsis and rice proteins. All experimentally verified CWPs and non-CWPs were retrieved from the UniProt Knowledgebase. Based on the evaluation, we currently recommend the predictors mGOASVM, HybridGO-Loc and FUEL-mLoc for CWPs. Furthermore, we outlined the public databases that can be used to cross-reference the subcellular location of CWPs. We illustrate a flowchart of the subcellular location prediction and a cross-reference of possible CWPs. Finally, we discuss challenges and perspectives in the bioinformatics analysis of CWPs. It is hoped that this article will provide practical guidance regarding CWPs for nonspecialists and provide insight for bioinformatics experts to develop computational tools for CWPs. PMID- 30481280 TI - Association of Microaneurysms on Adaptive Optics Scanning Laser Ophthalmoscopy With Surrounding Neuroretinal Pathology and Visual Function in Diabetes. AB - Purpose: We evaluate diabetic microaneurysm (MA) features on high-resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) and their correlations with visual acuity (VA) and local retinal pathology on spectral domain optical coherence tomography (SDOCT). Methods: Diabetic participants underwent VA testing and AOSLO and SDOCT imaging of MAs. AOSLO images were graded for MA dimension, wall hyperreflectivity (WH), intraluminal hyperreflectivity (IH), and perfusion pattern. SDOCTs centered on each MA were graded for disorganization of the retinal inner layers (DRIL) and other neuroretinal pathology. Results: We imaged 109 MAs (30 eyes). Multivariate modeling, including statistically significant covariates from bivariate analyses, associated WH with greater MA size (P = 0.001) and DRIL (P = 0.04). IH was associated with perfusion (P = 0.003) and MA visibility on photographs (P = 0.0001), and larger MA size with partial perfusion (P = 0.03), MA ring signs (P = 0.0002), and photographic visibility (P = 0.01). Multivariate modeling revealed an association of WH and VA with DRIL. Conclusions: AOSLO imaging demonstrates associations of hyperreflective MA walls with MA size and adjacent DRIL, as well as the presence of DRIL with lower VA. This study identifies a correlation between vascular and neural pathology associated with VA decline. Further studies of MA structure and neuroretinal disorganization may enable novel approaches to assess anatomic and functional outcomes in the diabetic eye. PMID- 30481283 TI - BlendMol: Advanced Macromolecular Visualization in Blender. AB - Summary: Programs such as VMD and PyMOL are excellent tools for analyzing macromolecular structures, but they do not implement many of the advanced rendering techniques common in the film and video-game industries. In contrast, the open-source program Blender is a general-purpose tool for industry-standard rendering/visualization, but its user interface is poorly suited for rigorous scientific analysis. We present BlendMol, a Blender plugin that imports VMD or PyMOL scenes into Blender. BlendMol-generated images are well-suited for use in manuscripts, outreach programs, websites, and classes. Availability and Implementation: BlendMol is available free of charge from http://durrantlab.com/blendmol/. It is written in Python. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30481284 TI - Prostacyclin synthesis and prostacyclin receptor expression in the porcine corpus luteum: evidence for a luteotropic role in vitro. AB - The prostacyclin (prostaglandin I2) signaling system is an essential regulator of vascular homeostasis. Since the corpus luteum is a highly vascularized gland, prostacyclin seems to be crucial for luteal development and function. Although progress has been made in understanding the luteotropic action of prostacyclin in mammals, its role in the porcine corpus luteum remains to be determined. Therefore, studies were conducted to (1) determine profiles of prostacyclin synthase expression and prostacyclin metabolite concentration, as well as prostacyclin G-protein-coupled receptor expression in porcine luteal tissue on days 2 to 16 of the estrous cycle and days 10 to 30 of pregnancy using real-time PCR, western blot, or enzyme immunoassay; and (2) examine the effect of prostacyclin on progesterone synthesis in vitro. To accomplish the second aim, luteal cells were treated with prostacyclin analogs, iloprost and carbaprostacyclin, in the presence or absence of prostacyclin receptor antagonists. The mRNA expression of cytochrome P450 family 11 subfamily A member 1 and hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1 was analyzed using real-time PCR, while progesterone concentration in culture medium was assessed by radioimmunoassay.Dynamic changes of prostacyclin synthase and prostacyclin receptor expression were observed in porcine luteal tissue during the estrous cycle and early pregnancy. Moreover, prostacyclin stimulated progesterone production and this effect was abolished by the addition of prostacyclin receptor antagonists. Our findings provide strong evidence that prostacyclin and its signaling system are present in corpus luteum of the pig and may directly promote luteotropic activity through upregulation of progesterone synthesis. PMID- 30481285 TI - Biallelic variants in FBXL3 cause intellectual disability, delayed motor development and short stature. AB - FBXL3 (F-Box and Leucine Rich Repeat Protein 3) encodes a protein that contains an F-box and several tandem leucine-rich repeats (LRR) domains. FBXL3 is part of the SCF (Skp1-Cullin-F box protein) ubiquitin ligase complex that binds and leads to phosphorylation dependent degradation of the central clock protein cryptochromes (CRY1 and CRY2) by the proteasome and its absence causes circadian phenotypes in mice and behavioral problems. No FBXL3 related phenotypes have been described in humans. By a combination of exome sequencing and homozygosity mapping, we analyzed two consanguineous families with intellectual disability and identified homozygous LoF (loss-of-function) variants in FBXL3. In the first family, from Pakistan, an FBXL3 frameshift variant (NM_012158.2:c.885delT:p.(Leu295Phefs*25)) was the only segregating variant in five affected individuals in two family loops (LOD score: 3.12). In the second family, from Lebanon, we identified a nonsense variant (NM_012158.2:c.445C>T:p.(Arg149*). In a third patient from Italy, a likely deleterious non-synonymous variant (NM_012158.2:c.1072T>C:p.(Cys358Arg)) was identified in homozygosity. Protein 3D modeling predicted that the Cys358Arg change influences the binding with CRY2 by destabilizing the structure of the FBXL3, suggesting that this variant is also likely to be LoF. The eight affected individuals from the three families presented with a similar phenotype that included intellectual disability, developmental delay, short stature and mild facial dysmorphism, mainly large nose with a bulbous tip. The phenotypic similarity and the segregation analysis suggest that FBXL3 biallelic, loss-of function variants link this gene with syndromic autosomal recessive developmental delay/intellectual disability. PMID- 30481286 TI - Specific inhibition of myostatin activation is beneficial in mouse models of SMA therapy. AB - Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by loss of alpha-motor neurons, leading to profound skeletal muscle atrophy. Patients also suffer from decreased bone mineral density and increased fracture risk. The majority of treatments for SMA, approved or in clinic trials, focus on addressing the underlying cause of disease, insufficient production of full-length SMN protein. While restoration of SMN has resulted in improvements in functional measures, significant deficits remain in both mice and SMA patients following treatment. Motor function in SMA patients may be additionally improved by targeting skeletal muscle to reduce atrophy and improve muscle strength. Inhibition of myostatin, a negative regulator of muscle mass, offers a promising approach to increase muscle function in SMA patients. Here we demonstrate that muSRK-015P, a monoclonal antibody which specifically inhibits myostatin activation, effectively increases muscle mass and function in two variants of the pharmacological mouse model of SMA in which pharmacologic restoration of SMN has taken place either 1 or 24 days after birth to reflect early or later therapeutic intervention. Additionally, muSRK-015P treatment improves the cortical and trabecular bone phenotypes in these mice. These data indicate that preventing myostatin activation has therapeutic potential in addressing muscle and bone deficiencies in SMA patients. An optimized variant of SRK-015P, SRK-015, is currently in clinical development for treatment of SMA. PMID- 30481287 TI - OPTIMA: A Phase II Dose and Volume De-Escalation Trial for Human Papillomavirus Positive Oropharyngeal Cancer. AB - Background: Patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) were assigned to dose and volume de-escalated radiotherapy (RT) or chemoradiotherapy (CRT) based on response to induction chemotherapy in an effort to limit treatment related toxicity while preserving efficacy. Patients and Methods: Patients were classified as low-risk (<=T3, <=N2B, <=10 pack-year history [PYH]) or high-risk (T4 or >=N2C or > 10 PYH). After 3 cycles of carboplatin/nab-paclitaxel, response was assessed using Response Evaluation Criteria in Solid Tumors 1.1. Low-risk patients with >=50% response received 50 Gray (Gy) RT (RT50) while low-risk patients with 30-50% response or high-risk patients with >=50% response received 45Gy CRT (CRT45). Patients with lesser response received standard-of-care 75Gy CRT (CRT75). RT/CRT was limited to the first echelon of uninvolved nodes. The primary endpoint was 2-year progression-free survival (PFS) compared to a historic control of 85%. Secondary endpoints included overall survival (OS) and toxicity. Results: Sixty-two patients (28 low-risk/34 high-risk) were enrolled. Of low-risk patients, 71% received RT50 while 21% received CRT45. Of high-risk patients, 71% received CRT45. With a median follow-up of 29 months, 2-year PFS and OS were 95% and 100% for low-risk patients and 94% and 97% for high-risk patients, respectively. The overall 2-year PFS was 94.5% and within the 11% non inferiority margin for the historic control. Grade 3+ mucositis occurred in 30%, 63%, and 91% of the RT50, CRT45, and CRT75 groups, respectively (p=0.004). Rates of any PEG-tube use were 0%, 31%, and 82% for RT50, CRT45, and CRT75 groups, respectively (p<0.0001). Conclusions: Induction chemotherapy with response and risk-stratified dose and volume de-escalated RT/CRT for HPV+ OPSCC is associated with favorable oncologic outcomes and reduced acute and chronic toxicity. Further evaluation of induction-based de-escalation in large multicenter studies is justified. Trial Registration: Clinical trials.gov identifier: NCT02258659. PMID- 30481288 TI - Deforestation Impacts Network Co-occurrence Patterns of Microbial Communities in Amazon Soils. AB - Co-occurrence networks allow for the identification of potential associations among species, which may be important for understanding community assembly and ecosystem functions. We employed this strategy to examine prokaryotic co occurrence patterns in the Amazon soils and the response of these patterns to land use change to pasture, with the hypothesis that altered microbial composition due to deforestation will mirror the co-occurrence patterns across prokaryotic taxa. In this study, we calculated Spearman correlations between operational taxonomic units (OTUs) as determined by 16S rRNA gene sequencing, and only robust correlations were considered for network construction (-0.80 >= rho >= 0.80, adjusted P <0.01). The constructed network represents distinct forest and pasture components, with altered compositional and topological features. A comparative analysis between two representative modules of these contrasting ecosystems revealed novel information regarding changes to metabolic pathways related to nitrogen cycling. Our results showed that soil physicochemical properties such as temperature, C/N and H++Al3+ had a significant impact on prokaryotic communities, with alterations to network topologies. Taken together, changes in co-occurrence patterns and physicochemical properties may contribute to ecosystem processes including nitrification and denitrification, two important biogeochemical processes occurring in tropical forest systems. PMID- 30481289 TI - Dppa3 is critical for Lin28a-regulated ES cells naive-primed state conversion. AB - Lin28a is a pluripotent factor that promotes somatic cell reprogramming. Unlike other pluripotent factors, Lin28a expression is transient and accumulated in primed embryonic stem (ES) cells, but its exact function and mechanism in the conversion of ES cells from naive to primed state remain unclear. Here, we present evidence for Dppa3, a protein originally known for its role in germ cell development, as a downstream target of Lin28a in naive-primed conversion. Using rescue experiment we demonstrate that Dppa3 functions predominantly downstream of Lin28a during naive-primed state conversion. Higher level of Lin28a prevents let 7 maturation and results in Dnmt3a/b (target of let-7) upregulation, which in turn induces hypermethylation of the Dppa3 promoter. Dppa3 demarcates naive versus primed pluripotency states. These results emphasize that Lin28a plays an important role during the naive-primed state conversion of ES cells, which is partially mediated by a Lin28a-let-7-Dnmt3a/b-Dppa3 axis. PMID- 30481290 TI - New Guidelines and Position papers in the European Journal of Cardio-Thoracic Surgery. PMID- 30481291 TI - Erratum to: 'Ninety-day hospital costs for anatomic lung resections' [Eur J Cardiothorac Surg 2018; doi:10.1093/ejcts/ezy296]. PMID- 30481292 TI - Does the 'non-intubated' anaesthetic technique offer any advantage for patients undergoing pulmonary lobectomy? AB - A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was: Do patients undergoing pulmonary lobectomy using the non-intubated anaesthetic technique have superior clinical outcomes? Altogether, 324 papers were found using the reported search, of which 5 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. The non-intubated anaesthetic technique can be safely used in patients undergoing video-assisted thoracic surgery lobectomy. Low conversion rates to intubation are reported, and conversion has been safely managed with no associated morbidity or mortality reported. The technique has not been shown to impact on the incidence of postoperative complications. However, studies consistently demonstrate improved postoperative outcomes in terms of recovery from anaesthesia permitting earlier oral intake and mobilization which is associated with a reduced length of hospital stay. PMID- 30481293 TI - The fate of the downstream aorta after open aortic repair for acute DeBakey type I aortic dissection: total arch replacement with elephant trunk technique versus non-total arch replacement. AB - OBJECTIVES: The aim of this study was to evaluate the fate of the downstream aorta following open aortic repair for acute DeBakey type I aortic dissection comparing total arch replacement (TAR) with the elephant trunk (ET) technique versus non-total arch replacement (non-TAR). METHODS: From October 1999 to December 2016, 267 patients underwent open repair for acute DeBakey type I aortic dissection. A tear-oriented strategy was mainly used to determine the extent of graft replacement. Hospital mortality was 10.0% (12/120 patients) in the TAR group and 17.0% (25/147 patients) in the non-TAR group (P = 0.070). Late outcomes were compared in 230 hospital survivors (TAR: n = 108 and non-TAR: n = 122). Mean follow-up was 6.5 +/- 4.6 years. The aortic diameters were measured at 4 levels, across 6 time points using computed tomography. RESULTS: Freedom from additional aortic surgery for distal dilation was significantly better in the TAR group than the non-TAR group (TAR: 97.5 +/- 1.8% at 5 years and non-TAR: 88.2 +/- 3.4% at 5 years, P = 0.045). Freedom from a distal aortic event was also significantly better in the TAR group compared with the non-TAR group (TAR: 97.2 +/- 1.6% at 5 years and non-TAR: 80.7 +/- 4.2% at 5 years, P = 0.013). In the non-TAR group, the aortic arch diameter significantly increased (P < 0.001). Significant aortic remodelling occurred at the proximal descending aorta in the TAR with ET group (P < 0.001). CONCLUSIONS: The TAR with ET reduced the need for additional distal aortic repair compared to non-TAR. TAR with ET prevented unfavourable aortic growth in both the aortic arch and the proximal descending aorta. PMID- 30481294 TI - Enhanced axonal Neuregulin-1 type-III signaling ameliorates neurophysiology and hypomyelination in a Charcot-Marie-Tooth type 1B mouse model. AB - Charcot-Marie-Tooth neuropathies (CMTs) are a group of genetic disorders that affect the peripheral nervous system (PNS) with heterogeneous pathogenesis and no available treatment. Axonal Neuregulin 1 type III (Nrg1TIII) drives peripheral nerve myelination by activating downstream signaling pathways such as PI3K/Akt and MAPK/Erk that converge on master transcriptional regulators of myelin genes, such as Krox20. We reasoned that modulating Nrg1TIII activity may constitute a general therapeutic strategy to treat CMTs that are characterized by reduced levels of myelination. Here, we show that genetic overexpression of Nrg1TIII ameliorates neurophysiological and morphological parameters in a mouse model of demyelinating CMT1B, without exacerbating the toxic gain of function that underlies the neuropathy. Intriguingly, the mechanism appears not to be related to Krox20 or myelin gene upregulation, but rather to a beneficial rebalancing in the stoichiometry of myelin lipids and proteins. Finally, we provide proof of principle that stimulating Nrg1TIII signaling, by pharmacological suppression of the Nrg1TIII inhibitor TACE/ADAM17, also ameliorates the neuropathy. Thus, modulation of Nrg1TIII by TACE/ADAM17 inhibition may represent a general treatment for hypomyelinating neuropathies. PMID- 30481295 TI - Facilitators and Barriers to Implementation of a Peer Support Intervention for Patients with Chronic Pain: A Qualitative Study. AB - Objective: Pain self-management information and support, delivered by peers, are a potentially useful approach to help patients who are struggling to manage their chronic pain. Before implementation into clinical settings, it is important to understand factors that may influence the success of implementation. The purpose of this study was to explore facilitators and barriers to implementation of peer support for chronic pain. Design: Semistructured interviews were conducted with clinicians who provide care to patients with chronic pain, regarding their perceptions of the proposed peer support intervention. Setting: A single US Veterans Affairs Medical Center. Subjects: Using maximum variation sampling, 15 providers were interviewed (11 women, four men). Clinicians' disciplines included primary care, physical therapy, nursing, clinical psychology, social work, and pharmacy. Results: Findings indicated that clinicians 1) had an overall positive perception of the intervention; 2) had specific intervention outcomes they wanted for patients; 3) anticipated that the intervention could positively influence their role; 4) anticipated barriers to intervention participation and maintenance; and 5) had concerns regarding peer coach selection. Findings are discussed in the context of the Consolidated Framework for Implementation Research. Conclusions: Understanding clinician perceptions of a peer support intervention is critical for successful implementation. The feedback collected in this study will facilitate implementation of the intervention on a broader scale, allowing more patients to benefit. PMID- 30481296 TI - The genome of the tegu lizard Salvator merianae: combining Illumina, PacBio, and optical mapping data to generate a highly contiguous assembly. AB - Background: Reptiles are a species-rich group with great phenotypic and life history diversity, but are highly underrepresented among the vertebrate species with sequenced genomes. Results: Here, we report a high-quality genome assembly of the tegu lizard Salvator merianae, the first lacertid with a sequenced genome. We combined 74X Illumina short read, 29.8X PacBio long read and optical mapping data to generate a high-quality assembly with a scaffold N50 value of 55.4 Mb. The contig N50 value of this assembly is 521 Kb, making it the most contiguous reptile assembly so far. We show that the tegu assembly has the highest completeness of coding genes and conserved non-exonic elements (CNEs) compared to other reptiles. Furthermore, the tegu assembly has the highest number of evolutionarily conserved CNE pairs, corroborating a high assembly contiguity in intergenic regions. Like in other reptiles, Long Interspersed Nuclear Elements (LINEs) comprise the most abundant transposon class. We used transcriptomic data, homology- and de novo gene predictions to annotate 22,413 coding genes, of which 16,995 (76%) likely have human orthologs as inferred by CESAR-derived gene mappings. Finally, we generated a multiple genome alignment comprising 10 squamates and 7 other amniote species and identified conserved regions that are under evolutionary constraint. Conserved non-exonic elements cover 38 Mb (1.8%) of the tegu genome, with 3.3 Mb in these elements being squamate-specific. In contrast to placental mammal-specific CNEs, very few of these squamate-specific CNEs (<20 Kb) overlap transposons, highlighting a difference in how lineage specific CNEs originated in these two clades. Conclusions: The tegu lizard genome together with the multiple genome alignment and comprehensive conserved element datasets provide a valuable resource for comparative genomic studies of reptiles and other amniotes. PMID- 30481297 TI - Effects of lespedeza condensed tannins alone or with monensin, soybean oil, and coconut oil on feed intake, growth, digestion, ruminal methane emission, and heat energy by yearling Alpine doelings. AB - Fifty-four Alpine doelings (initial body weight and age of 31.7 +/- 0.38 kg and 306 +/- 1.9 d, respectively) were allocated to nine treatments individually fed for ad libitum intake of 25% concentrate and 75% forage diets (dry matter basis). Alfalfa was the forage in the Control diet. Other diets contained Sericea lespedeza as the forage, with 1.25% dry matter of quebracho extract included in the concentrate fraction for a dietary condensed tannin level of 8.4%. Lespedeza treatments were no additive (L) and inclusion of monensin (I) at 22 mg/kg dry matter (L-I), soybean oil at 3% (L-S), coconut oil at 3% (L-N), I and 3% soybean oil (L-I-S), I and 3% coconut oil (L-I-N), 1.5% soybean oil and 1.5% coconut oil (L-S-N), and I, 1.5% soybean oil, and 1.5% coconut oil (L-I-S-N). The experiment was 12 wk with two 6-wk periods. Gas exchange was determined in wk 6 and 12, and other measures occurred in wk 5 and 11. The Control diet offered averaged 2.67% nitrogen, 43.8% neutral detergent fiber, and 8.8% acid detergent lignin, and the L diet offered averaged 2.03% nitrogen, 42.8% neutral detergent fiber, and 13.2% acid detergent lignin. There were no treatment * period interactions for digestibilities (P >= 0.770) or methane emission (P >= 0.324). There were differences (P < 0.001) between the Control treatment and diets with lespedeza in intake of dry matter (1.46, 1.23, 1.30, 1.18, 1.32, 1.10, 1.02, 1.20, and 1.01 kg/d; SEM = 0.059), digestibility of organic matter (57.4, 50.9, 51.8, 52.7, 50.3, 52.1, 52.1, 51.9, and 49.8%; SEM = 1.42), and digestibility of nitrogen (59.1, 31.2, 32.5, 37.1, 31.6, 38.3, 30.4, 38.4, and 34.1% for Control, L, L-I, L S, L-N, L-I-S, L-I-N, L-S-N, and L-I-S-N, respectively; SEM = 2.21). Ruminal methane emission was less (P < 0.001) for diets with lespedeza than for the Control in MJ/d (1.36, 0.76, 0.84, 0.71, 0.71, 0.66, 0.65, 0.68, and 0.68; SEM = 0.048) and relative to intake of gross energy (5.92, 3.27, 3.49, 3.19, 2.84, 2.91, 3.20, 3.20, and 3.27%; SEM = 0.165) and digestible energy (11.19, 6.98, 7.40, 6.38, 5.90, 5.69, 6.37, 6.38, and 6.70% for Control, L, L-I, L-S, L-N, L-I S, L-I-N, L-S-N, and L-I-S-N, respectively; SEM = 0.400). In conclusion, the magnitude of effect of condensed tannins from lespedeza and quebracho extract on ruminal methane emission by Alpine doelings did not diminish over time and was not markedly influenced by dietary inclusion of monensin, soybean oil, or coconut oil. PMID- 30481298 TI - Current status of interventional cardiac electrophysiology training in ESC member countries: an EHRA Young EP Report. PMID- 30481299 TI - Evaluation of procalcitonin accuracy for the distinction between Gram-negative and Gram-positive bacterial sepsis in burn patients. AB - Background: Sepsis is the main cause of death in burns. Early institution of antimicrobial therapy is crucial to optimize outcomes but superfluous therapy increases adverse events, microbial resistance and costs. Blood cultures are the gold standard for diagnosis but can take 48-72 hours. Biomarkers are used to help sepsis diagnosis and distinction between Gram-negative and Gram-positive bacterial cause. The aim of this work is to evaluate procalcitonin (PCT) accuracy for this distinction in burn patients. Methods: Retrospective observational study of adult septic burn patients with >= 15% TBSA admitted from January 2011 to December 2014 at a Burn Unit in Portugal. A statistical analysis was done, evaluating the correlation between PCT levels on the day of the first positive blood culture and microbiological data for Gram-negative and Grand-positive bacteria. Patients with mixed bacterial and fungal blood cultures were excluded. Data were summarized by quartiles statistics. Results: Blood cultures were positive in 189 patients: 75 (39.7%) showed growth for Gram-negative and 114 (60.3%) for Gram-positive bacteria. Patients with Gram-negative bacteria have significantly higher PCT levels. ROC curve analysis showed accuracy for Gram negative discrimination with AUC = 0.687. Most elevated levels were related to non-fermentative Gram-negative bacteria and by Klebsiella pneumoniae and other Enterobacteriaceae. Conclusion: PCT levels were significantly higher in burn patients with Gram-negative sepsis comparing to patients with Gram-positive sepsis and controls. The determination of PCT levels may help the choice of empirical antimicrobial therapy while microbiological culture results are not available, despite not fully ensuring the desirable degree of precision. PMID- 30481300 TI - Sarcolemmal Complement Membrane Attack Complex Deposits During Acute Rejection of Myofibers in Nonhuman Primates. AB - We have previously studied in nonhuman primates several aspects of the acute rejection of myofibers, including the histological characteristics, the mechanisms of myofiber elimination by the T cells, and the development of anti donor antibodies. Here, we report the participation of the complement membrane attack complex (MAC) in this context. We used muscle sections of macaques from experiments of allogeneic muscle precursor cell transplantation with confirmed rejection of the graft-derived myofibers. Sections were stained with hematoxylin and eosin, alizarin red and for immunodetection of MAC, CD8, CD4, C3, C4d, and immunoglobulins. The prominent finding was the presence of sarcolemmal MAC (sMAC) deposits in biopsies with ongoing acute rejection or with recent acute rejection. The numbers of sMAC-positive myofibers were variable, being higher when there was an intense lymphocyte infiltration. Few sMAC-positive myofibers were necrotic or had evidence of sarcolemma permeation. The immunodetection of C3, C4d, and immunoglobulins did not provide significant elements. In conclusion, sMAC deposits were related to myofiber rejection. The fact that the vast majority of sMAC-positive myofibers had no signs of necrosis or sarcolemmal permeation suggests that MAC would not be harmful to myofibers by itself. PMID- 30481301 TI - Ventricular substrate identification using close-coupled paced electrogram feature analysis. AB - Aims: Substrate based catheter ablation strategies are widely employed for treatment of scar-related ventricular tachycardia (VT). We analysed intracardiac electrograms (EGMs) from close-coupled paced extrastimuli extracted from the EnSite Precision mapping system. We sought to characterize EGM responses of ventricular myocardium to varying coupling intervals from the right ventricular apex (RVA) in both healthy individuals and patients presenting with VT for catheter ablation. Methods and results: Extrastimuli were delivered from the RVA after estimation of the ventricular effective refractory period. Electrograms were recorded from high-density mapping catheters in the left ventricle and exported for analysis to MATLAB. Observational data were collected from 14 patients with ischaemic VT (mean age 72.4 +/- 6.3 years, one female) and five controls (mean age 59.4 +/- 7.4 years, one female). These derived data were used to inform an interventional strategy on a further 10 patients (mean age 64.7 +/- 10.0 years; two female). Significant differences were observed in EGM duration (ED) and latency (LT) at all coupling intervals between VT patients and controls. Significant increases in ED and LT with decreased RVA coupling interval were observed at VT isthmuses. Abnormal responses derived from control subject data were used to classify four types of ventricular EGM response. Targeting sites with abnormal LT and ED significantly reduced VT inducibility (5/14 derivation patients to 0/10 intervention patients; P = 0.03). Conclusion: Paced electrogram feature analysis is a novel tool to characterize the ischaemic substrate. Association with VT isthmuses and early ablation results suggest a possible role in substrate ablation for ischaemic VT. PMID- 30481302 TI - Impact of a streamlined rotational system for the management of acute aortic syndrome: sharing is caring. AB - OBJECTIVES: Acute type A aortic dissection is an emergency associated with up to 30% of hospital mortality. It has been established that outcomes are improved with specialist aortic team care in high-volume centres. Most centres are limited to a small number of aortic specialists, thus making it logistically impractical to have a dedicated 24/7 single-centre service. In 2011, a rotational 24/7 service between 3 centres covering a geographical location was introduced including 24/7 access to a dissection 'Hotline'. METHODS: We analysed data since 2003 from a prospectively collected database. A total of 227 patients underwent surgery for acute aortic syndrome between 2003 and 2017. The results on outcomes were compared before and after the initiation of the dissection hotline and 24/7 dedicated service. RESULTS: We identified 128 patients from the pre-rotational group and 99 patients from the post-rotational group. Both groups were well matched in terms of demographics and comorbidities. In the post-rotational group, there was an increase in arch surgery (11.8% vs 20.2%, P: 0.07). The introduction of the rotational service reduced 30-day mortality (20% vs 8%, P: 0.010). The introduction of the service improved the overall long-term survival [P: 0.04, hazard ratio 1.86; confidence interval (1.03-3.38)] in the multivariable analysis. There was no difference between the groups in postoperative complications. There was an increase in the median length of hospital stay in the post-rotational group (13 days vs 20 days, P: 0.014). CONCLUSIONS: A streamlined aortic dissection service allows for centralized care. This provides the referring centres with 24/7 access to an experienced aortic team and may improve patient outcomes. PMID- 30481303 TI - Endothelial cells exposed to phosphate and indoxyl sulphate promote vascular calcification through interleukin-8 secretion. AB - Background: Vascular calcification (VC) is amplified during chronic kidney disease, partly due to uraemic toxins such as inorganic phosphate (Pi) and indoxyl sulphate (IS) that trigger osteogenic differentiation of vascular smooth muscle cells (VSMCs). These toxins also alter endothelial cell (EC) functions but whether this contributes to VC is unknown. Here, we hypothesized that ECs exposed to Pi and IS promote VSMC calcification. Methods: Human umbilical vein ECs were treated with Pi, IS or both, and then the conditioned media [endothelial cell conditioned medium (EC-CM)] was collected. Human aortic SMCs (HASMCs) were exposed to the same toxins, with or without EC-CM, and then calcification and osteogenic differentiation were evaluated. Procalcifying factors secreted from ECs in response to Pi and IS were screened. Rat aortic rings were isolated to assess Pi+IS-induced calcification at the tissue level. Results: Pi and Pi+IS induced HASMCs calcification, which was significantly exacerbated by EC-CM. Pi+IS induced the expression and secretion of interleukin-8 (IL-8) from ECs. While IL-8 treatment of HASMCs stimulated the Pi+IS-induced calcification in a concentration dependent manner, IL-8 neutralizing antibody, IL-8 receptors antagonist or silencing IL-8 gene expression in ECs before collecting EC-CM significantly prevented the EC-CM procalcifying effect. IL-8 did not promote the Pi+IS-induced osteogenic differentiation of HASMCs but prevented the induction of osteopontin (OPN), a potent calcification inhibitor. In rat aortic rings, IS also promoted Pi induced calcification and stimulated the expression of IL-8 homologues. Interestingly, in the Pi+IS condition, IL-8 receptor antagonist lifted the inhibition of OPN expression and partially prevented aortic calcification. Conclusion: These results highlight a novel role of IL-8, whose contribution to VC in the uraemic state results at least from interaction between ECs and VSMCs. PMID- 30481304 TI - Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the kelch domain substrate-recognition surface and enhance RAS-MAPK signaling. AB - Noonan syndrome (NS), the most common RASopathy, is caused by mutations affecting signaling through RAS and the MAPK cascade. Recently, genome scanning has discovered novel genes implicated in NS, whose function in RAS-MAPK signaling remains obscure, suggesting the existence of unrecognized circuits contributing to signal modulation in this pathway. Among these genes, LZTR1 encodes a functionally poorly characterized member of the BTB/POZ protein superfamily. Two classes of germline LZTR1 mutations underlie dominant and recessive forms of NS, while constitutional monoallelic, mostly inactivating, mutations in the same gene cause schwannomatosis, a cancer-prone disorder clinically distinct from NS. Here we show that dominant NS-causing LZTR1 mutations do not affect significantly protein stability and subcellular localization. We provide the first evidence that these mutations, but not the missense changes occurring as biallelic mutations in recessive NS, enhance stimulus-dependent RAS-MAPK signaling, which is triggered, at least in part, by an increased RAS protein pool. Moreover, we document that dominant NS-causing mutations do not perturb binding of LZTR1 to CUL3, a scaffold coordinating the assembly of a multimeric complex catalyzing protein ubiquitination, but are predicted to affect the surface of the Kelch domain mediating substrate binding to the complex. Collectively, our data suggest a model in which LZTR1 contributes to the ubiquitination of protein(s) functioning as positive modulator(s) of the RAS-MAPK signaling pathway. In this model, LZTR1 mutations are predicted to variably impair binding of these substrates to the multi-component ligase complex and their efficient ubiquitination and degradation, resulting in MAPK signaling upregulation. PMID- 30481305 TI - Factors associated with older people's emergency department attendance towards the end of life: a systematic review. AB - Background: Emergency department (ED) attendance for older people towards the end of life is common and increasing, despite most preferring home-based care. We aimed to review the factors associated with older people's ED attendance towards the end of life. Methods: Systematic review using Medline, Embase, PsychINFO, CINAHL and Web of Science from inception to March 2017. Included studies quantitatively examined factors associated with ED attendance for people aged >=65 years within the last year of life. We assessed study quality using the QualSyst tool and determined evidence strength based on quality, quantity and consistency. We narratively synthesized the quantitative findings. Results: Of 3824 publications identified, 21 were included, combining data from 1 565 187 participants. 17/21 studies were from the USA and 19/21 used routinely collected data. We identified 47 factors and 21 were included in the final model. We found high strength evidence for associations between ED attendance and palliative/hospice care (adjusted effect estimate range: 0.1-0.94); non-white ethnicity (1.03-2.16); male gender (1.04-1.83, except 0.70 in one sub-sample) and rural areas (0.98-1.79). The final model included socio-demographic, illness and service factors, with largest effect sizes for service factors. Conclusions: In this synthesis, receiving palliative care was associated with lower ED attendance in the last year of life for older adults. This has implications for service models for older people nearing the end of life. However, there is limited evidence from European countries and none from low or middle-income countries, which warrants further research. PMID- 30481306 TI - Multivariate genomic predictions for age at puberty in tropically adapted beef heifers. AB - Heifers that have an earlier age at puberty often have greater lifetime productivity. Age at puberty is moderately heritable so selection should effectively reduce the number of days to puberty, and improve heifer productivity and profitability as a result. However, recording age at puberty is intensive, requiring repeat ovarian scanning to determine age at first corpus luteum (AGECL). Genomic selection has been proposed as a strategy to select for earlier age at puberty, however large reference populations of cows with AGECL records and genotypes would be required to generate accurate genomic estimated breeding values (GEBV) for this trait. Reproductive maturity score (RMS) is a proxy trait for age at puberty for implementation in northern Australia beef herds, where large scale recording of AGECL is not feasible. RMS assigns a score of 0-5 from a single ovarian scan to describe ovarian maturity at approximately 600 days. Here we use multivariate genomic prediction to evaluate the value of a large RMS data set to improve accuracy of GEBV for age at puberty (AGECL). There were 882 Brahman and 990 Tropical Composite heifers with AGECL phenotypes, and an independent set of 974 Brahman, 1798 Santa Gertrudis, and 910 Droughtmaster heifers with RMS phenotypes. All animals had 728,785 real or imputed SNP genotypes. The correlation of AGECL and RMS (h2 = 0.23) was estimated as -0.83 using the genomic information. This result also demonstrates that using genomic information it is possible to estimate genetic correlations between traits collected on different animals in different herds, with minimal or unknown pedigree linkage between them. Inclusion of heifers with RMS in the multi-trait model improved the accuracy of genomic evaluations for AGECL. Accuracy of RMS GEBV generally did not improve by adding heifers with AGECL phenotypes into the reference population. These results suggest that RMS and AGECL may be used together in a multi-trait prediction model to increase the accuracy of prediction for age at puberty in tropically adapted beef cattle. PMID- 30481307 TI - Polymorphisms in TLR4 and TNFA and Risk of Mycobacterium tuberculosis Infection and Development of Active Disease in Contacts of Tuberculosis Cases in Brazil: A Prospective Cohort Study. AB - Background: The role of genetic polymorphisms in latent tuberculosis (TB) infection and progression to active TB is not fully understood. Methods: We tested the single nucleotide polymorphisms (SNPs) rs5743708 (TLR2), rs4986791 (TLR4), rs361525 (TNFA), rs2430561 (IFNG) rs1143627 (IL1B) as risk factors for tuberculin skin test (TST) conversion or development of active TB in contacts of active TB cases. Contacts of microbiologically confirmed pulmonary TB cases were initially screened for longitudinal evaluation up to 24 months, with clinical examination and serial TST, between 1998 and 2004 at a referral center in Brazil. Data and biospecimens were collected from 526 individuals who were contacts of 177 active TB index cases. TST conversion was defined as induration >=5mm after a negative TST result (0 mm) at baseline or month 4 visit. Independent associations were tested using logistic regression models. Results: Among the 526 contacts, 60 had TST conversion and 44 developed active TB during follow-up. Multivariable regression analysis demonstrated that male sex (OR: 2.3, 95%CI: 1.1-4.6), as well as SNPs in TLR4 genes (OR: 62.8, 95%CI: 7.5-525.3) and TNFA (OR: 4.2, 95%CI: 1.9 9.5) were independently associated with TST conversion. Moreover, a positive TST at baseline (OR: 4.7, 95%CI: 2.3-9.7) and SNPs in TLR4 (OR: 6.5, 95%CI: 1.1-36.7) and TNFA (OR: 12.4, 95%CI:5.1-30.1) were independently associated with incident TB. Conclusions: SNPs in TLR4 and TNFA predicted both TST conversion and active TB among contacts of TB cases in Brazil. PMID- 30481308 TI - The tuberization signal StSP6A represses flower bud development in potato. AB - Potato (Solanum tuberosum L.) can reproduce sexually through flowering and asexually through tuberization. While tuberization has been thoroughly studied, little research has been done on potato flowering. Flower bud development in the strictly short-day tuberizing S. tuberosum group Andigena is impaired under short day conditions. This impaired development may indicate that tuberization negatively influences flowering. The aim of this research was to determine how tuberization affects flower bud development. To find out whether the absence of tubers improves flowering we prevented tuberization by: (1) grafting potato scions onto wild potato rootstocks, which were unable to form tubers; (2) removing stolons, the underground structures on which tubers form; (3) using plants that were silenced in the tuberization signal StSP6A. Additionally, transgenic plants with increased StSP6A expression were used to determine if flower bud development was impaired. The absence of a tuber-sink alone did not accelerate flower bud development, nor did it allow more plants to reach anthesis (open flowering stage) or have more open flowers. Interestingly, reducing StSP6A expression improved flower bud development, and increasing expression impaired it. Our results show that flower bud development in potato is repressed by the tuberization signal StSP6A, and not by competition with the underground tuber sink. PMID- 30481309 TI - Outcomes of different rehabilitative procedures in patients with pulmonary atresia, ventricular septal defect and major aortopulmonary collateral arteries. AB - OBJECTIVES: The objective of this study was to compare our clinical outcomes of the central shunt and the right ventricle-pulmonary artery (RV-PA) connection in patients with pulmonary atresia, ventricular septal defect and the major aortopulmonary collateral arteries. METHODS: From November 2009 to October 2017, a total of 157 consecutive patients with pulmonary atresia, ventricular septal defect, the major aortopulmonary collateral arteries and the hypoplastic PAs who underwent palliative surgery were included. Seventy patients underwent the central shunt (the central shunt group) and 87 patients underwent the RV-PA connection (the RV-PA group). Propensity score matching was used to create 2 cohorts with similar baseline characteristics: 56 central shunt patients were one to-one-matched with 56 RV-PA connection patients. The early and late outcomes were compared. RESULTS: The median duration of follow-up was 18 months in the central shunt group and 22 months in the RV-PA group (P = 0.10). The probability of complete repair was significantly lower in the central shunt group as compared with the RV-PA group (P = 0.048). The Kaplan-Meier estimates of complete repair rates were 47.2 +/- 10.0% after 3 years and 56.0 +/- 11.6% after 5 years in the central shunt group, which were lower as compared with 62.3 +/- 7.6% after 3 years and 74.5 +/- 7.2% after 5 years in the RV-PA group. The increase in the mean McGoon ratio and the mean Nakata index were significantly lower in the central shunt group than those in the RV-PA group (0.57 +/- 0.52 vs 1.02 +/- 0.44, P = 0.036; 98.2 +/- 35.1 mm2/m2 vs 176.9 +/- 85.4 mm2/m2, P = 0.025, respectively). The in-hospital morbidity and mortality after complete repair were similar between 2 groups. CONCLUSIONS: Compared with the central shunt, the RV-PA connection appears to be a more effective palliative procedure to improve the probability of complete repair and PA growth in patients with pulmonary atresia, ventricular septal defect and the major aortopulmonary collateral arteries, in whom primary repair is not feasible. PMID- 30481310 TI - An AGAMOUS MADS-box gene, SlMBP3, regulates the velocity of placenta liquefaction and seed formation in tomato. AB - AGAMOUS (AG) MADS-box transcription factors have been shown to play crucial roles in floral organ and fruit development in angiosperms. Here, a tomato AG MADS-box gene, SlMBP3, was isolated. SlMBP3 is preferentially expressed in flowers and early fruit developmental stages in wild type (WT), Nr and rin mutants. Its transcripts are notably accumulated in pistils, decreased in abundance during seed and placental development and increased again during flower development. SlMBP3-RNAi tomato plants displayed fleshy placenta without jelly and extremely malformed seeds with no seed coat while SlMBP3-overexpressing plants exhibited advanced placenta liquefaction and larger seeds. Physiological feature studies showed that enzymatic activities related to cell wall modification, and the contents of cell wall components and pigments were dramatically altered in SlMBP3 RNAi placentas compared with WT. Alteration of these physiological features was also observed in SlMBP3-overexpressing placentas. Moreover, the lignin content of mature seeds in SlMBP3-RNAi lines was markedly lower than that in WT. RNA-seq and qRT-PCR analysis revealed that genes involved in seed development and the biosynthesis of cell wall modification related enzymes, gibberellin (GA), indole 3-acetic acid (Aux/IAA) and abscisic acid (ABA) were downregulated in SlMBP3-RNAi lines. These results demonstrate that SlMBP3 regulates placenta and seed development in tomato. PMID- 30481311 TI - Commentary: Multicenter Study of Pipeline Flex for Intracranial Aneurysms. PMID- 30481312 TI - Construction and characterization of ribonuclease H2 knockout NIH3T3 cells. AB - Ribonuclease H (RNase H) specifically hydrolyzes the 5'-phosphodiester bonds of the RNA of RNA/DNA hybrid. Both type 1 and 2 RNases H act on the RNA strand of the hybrid, while only type 2 acts on the single ribonucleotide embedded in DNA duplex. In this study, to explore the role of mammalian type 2 RNase H (RNase H2) in cells, we constructed the RNase H2 knockout NIH3T3 cells (KO cells) by CRISPR/Cas9 system. KO cells hydrolyzed RNA strands in RNA/DNA hybrid, but not single ribonucleotides in DNA duplex, while wild-type NIH3T3 cells (WT cells) hydrolyzed both. Genomic DNA in the KO cells was more heavily hydrolyzed than in the WT cells by the alkaline or RNase H2 treatment, suggesting that the KO cells contained more ribonucleotides in genomic DNA than the WT cells. The growth rate of the KO cells was 60% of that of the WT cells. Expression of interferon stimulated genes (ISGs) in the KO cells was not markedly elevated compared to the WT cells. These results suggest that in NIH3T3 cells, RNase H2 is crucial for suppressing the accumulation of ribonucleotides in genomic DNA but not for the expression of ISGs. PMID- 30481313 TI - The role of dialysis in the pathogenesis and treatment of dementia. PMID- 30481314 TI - Spruce and beech as local determinants of forest fungal community structure in litter, humus and mineral soil. AB - Beech forests reaches its native distribution limit in SE Norway, but is expected to expand substantially northwards due to climate warming. This may potentially result in a fundamental transformation of contemporary Northern European forests, with tentative effects on the associated belowground fungi. Fungal communities mediate vital ecosystem processes such as ecosystem productivity and carbon sequestration in boreal forests. To investigate how soil fungi is affected by the vegetation transition from spruce to beech forest, we sampled litter, humus and mineral soil in a forest landscape dominated by beech, spruce or a mixture of these. The fungal communities in the soil samples were analyzed by DNA metabarcoding of the rDNA ITS2 region. Although soil layers were the most important structuring gradient, we found clear differences in fungal species composition between spruce and beech plots. The differences in fungal community composition were most evident in the litter and least in the mineral soil. Decomposers, most notably Mycena, dominated the litter layer while various mycorrhizal fungi dominated the humus and mineral layers. Some ectomycorrhizal taxa, such as Cenoccocum and Russula, were more abundant in spruce forests. Differences in fungal community composition between forest types can potentially have large impacts on carbon sequestration rates. PMID- 30481316 TI - Atrial fibrillation: the era of scientific breakthrough. PMID- 30481315 TI - Merging genotypes: graft union formation and scion/rootstock interactions. AB - Grafting has been utilized for at least the past 7000 years. However, historically grafting has been developed by growers without particular interest beyond the agronomical and ornamental effects, thus knowledge about grafting has remained largely empirical. Much of the commercial production of fruit, and increasingly vegetables, relies upon grafting with rootstocks to provide resistance to soil borne pathogens and abiotic stresses as well as to influence scion growth and performance. Although there is considerable agronomic knowledge about the use and selection of rootstocks for many species, we know little of the molecular mechanisms underlying rootstock adaptation to different soil environments and rootstock conferred modification of scion phenotypes. Furthermore, the processes involved in the formation of the graft union and graft compatibility are poorly understood despite over one hundred years of scientific study. In this review, we provide an overview of what is known about grafting and the mechanisms underlying rootstock/scion interactions. We highlight recent studies that have advanced our understanding of graft union formation and outline subjects for further development. PMID- 30481317 TI - Corrigendum to: Safety and efficiency of porous-tip contact-force catheter for drug-refractory symptomatic paroxysmal atrial fibrillation ablation: results from the SMART SF trial. PMID- 30481318 TI - An ultra-high affinity ligand of HIV-1 TAR reveals the RNA structure recognized by P-TEFb. AB - The HIV-1 trans-activator protein Tat binds the trans-activation response element (TAR) to facilitate recruitment of the super elongation complex (SEC) to enhance transcription of the integrated pro-viral genome. The Tat-TAR interaction is critical for viral replication and the emergence of the virus from the latent state, therefore, inhibiting this interaction has long been pursued to discover new anti-viral or latency reversal agents. However, discovering active compounds that directly target RNA with high affinity and selectivity remains a significant challenge; limiting pre-clinical development. Here, we report the rational design of a macrocyclic peptide mimic of the arginine rich motif of Tat, which binds to TAR with low pM affinity and 100-fold selectivity against closely homologous RNAs. Despite these unprecedented binding properties, the new ligand (JB181) only moderately inhibits Tat-dependent reactivation in cells and recruitment of positive transcription elongation factor (P-TEFb) to TAR. The NMR structure of the JB181-TAR complex revealed that the ligand induces a structure in the TAR loop that closely mimics the P-TEFb/Tat1:57/AFF4/TAR complex. These results strongly suggest that high-affinity ligands which bind the UCU bulge are not likely to inhibit recruitment of the SEC and suggest that targeting of the TAR loop will be an essential feature of effective Tat inhibitors. PMID- 30481319 TI - Clinical and Radiological Follow-up of Intraneural Perineuriomas. AB - BACKGROUND: Management of intraneural perineuriomas remains controversial, largely due to the lack of knowledge regarding the natural history of these lesions. OBJECTIVE: To describe the typical radiological growth pattern of intraneural perineuriomas and to determine how the pattern of growth relates to clinical progression. METHODS: We performed a retrospective review of the magnetic resonance imaging (MRI) studies and serial clinical examinations of a cohort of patients with biopsy-proven intraneural perineuriomas who had 2 MRI studies at least 2 yr apart. The outcome of interest was radiological growth in length or width of the intraneural perineurioma. Radiological growth was tested for association with clinical progression. RESULTS: Twenty patients were included in the study. By width, the lesions were on average larger on repeat imaging (P = .009). By absolute length, the lesions were on average longer on repeat imaging (P = .02). By lesion:landmark ratio, there was no difference in length of the lesions between sequential images (P = .09), with 10 (50%) lesions being shorter and 7 (35%) showing no change. No lesions grew to involve a new nerve or division of a nerve on sequential imaging. None of the variables tested were associated with clinical progression. CONCLUSION: We found that intraneural perineuriomas only rarely grow in length, do not grow to involve new nerves or nerve divisions, and growth does not correlate with clinical progression. These findings have significant ramifications for management of these tumors. PMID- 30481320 TI - Interventions Targeting Smoking Cessation for Patients with Chronic Pain: An Evidence synthesis. AB - Introduction: Smoking is a risk factor for chronic pain conditions. Epidemiological evidence suggests that smoking cessation may be an important treatment target in people with chronic pain. The aim of this study was to examine the effectiveness of smoking cessation interventions in people with chronic pain. Methods: We systematically searched for clinical trials investigating the effectiveness of smoking cessation interventions for people with chronic pain, compared to any control comparator. Primary outcomes were pain and physical function. Secondary outcomes were smoking status, quality of life, psychological and cognitive function, and adverse events. We assessed risk of bias using the Cochrane Risk of Bias criteria, and the quality of evidence with GRADE. Results: Searches retrieved 3,845 records and identified two trials for inclusion (total n=99 participants). There was low quality evidence of no effect of smoking cessation programs on pain and very low quality evidence of no effect on function at short term follow-up. There was conflicting evidence on the effect of smoking cessation interventions for changing the smoking status, and number of cigarettes consumed per day. There was no effect on depression and anxiety. Conclusion: Current evidence does not indicate clinically important effects of smoking cessation interventions in people with chronic pain. There is a need for high quality trials in this area. Implications: Our review highlights an important evidence gap. We found only two studies investigating smoking cessation programs for chronic pain conditions providing very low to low quality evidence. PMID- 30481321 TI - A Clinical Rule for Preoperative Prediction of BRAF Mutation Status in Craniopharyngiomas. AB - BACKGROUND: Papillary craniopharyngiomas are characterized by BRAFV600E mutations. Targeted therapy can elicit a dramatic radiographic regression of these tumors. Therefore, prediction of BRAF mutation status before definitive surgery could enable neoadjuvant treatment strategies. OBJECTIVE: To establish preoperative prediction criteria to identify patients with a BRAF mutant craniopharyngioma. METHODS: Sixty-four patients with craniopharyngioma were included in this study. We determined BRAF mutation status by targeted sequencing. After scoring interobserver variability between presurgical clinical data and radiographic features, we established a diagnostic rule for BRAF mutation in our discovery cohort. We then validated the rule in an independent cohort. RESULTS: The BRAFV600E mutation was detected in 12 of 42 patients in the discovery cohort. There were no patients under age 18 with BRAF mutation. Calcification was rare in tumors with BRAF mutation (P < .001), and 92% of them were supradiaphragmatic in location. Combining these 3 features-older than 18 years, absence of calcification, and supradiaphragmatic tumor location-we established a rule for predicting BRAF mutation. In cases where all 3 criteria were fulfilled, the sensitivity and specificity for the presence of BRAF mutation were 83% and 93%, respectively. In the validation cohort (n = 22), the sensitivity was 100% and specificity was 89%. CONCLUSION: We propose predictive criteria for a BRAF mutation in craniopharyngioma using preoperative clinical and radiographic data. This rule may be useful in identifying patients who could potentially benefit from neoadjuvant BRAFV600E-targeted systemic therapies. PMID- 30481322 TI - Nocturnal enuresis in children is associated with differences in autonomic control. AB - Study Objectives: To assess the relationship between urine osmolality, cardiovascular parameters, and nocturnal enuresis in a population of children undergoing polysomnographic assessment. Methods: This prospective observational study included consecutive children aged 5-17 years presenting for overnight polysomnography. Children were evaluated using continuous ambulatory blood pressure monitoring to assess heart rate and blood pressure. Urine samples were collected throughout the night to determine urine sodium excretion and osmolality. Comparisons of results were made between children with and without a history of nocturnal enuresis. Results: A total of 61 children were included for analysis; 13 had a history of nocturnal enuresis. Children with nocturnal enuresis had greater disruption in respiratory parameters including higher apnea hypopnea index (mean difference 12.2+/-8.8 events/h, p<0.05), attributable to more central respiratory events (mean difference 5.4+/-4.9, p<0.05), and higher variability in both oxygen and carbon dioxide parameters compared to those without nocturnal enuresis. Sleep parameters, urine osmolality, and blood pressure did not differ between groups. Children with nocturnal enuresis showed an increase, rather than a decrease, in heart rate across the night (+5.4+/-19.1 vs. -6.0+/-14.8 beats/min, p < 0.05). Conclusions: Children with a history of nocturnal enuresis have greater respiratory abnormalities, no differences in urine osmolality or blood pressure, and loss of normal heart rate decrease across the night. This pattern suggests that autonomic control, rather than renal or hemodynamic abnormalities, may contribute to the pathophysiology of nocturnal enuresis. PMID- 30481323 TI - Self-incompatibility in Papaver Pollen: Programmed Cell Death in an Acidic Environment. AB - Self-Incompatibility (SI) is a genetically controlled mechanism that prevents self-fertilisation and thus encourages outbreeding and genetic diversity. During pollination, most SI systems utilise cell-cell recognition to reject incompatible pollen. Mechanistically, one of the best-studied SI systems is that of Papaver rhoeas (poppy), which involves the interaction between the two S-determinants, a stigma-expressed secreted protein (PrsS) and a pollen-expressed plasma-membrane localised protein (PrpS). This interaction is the critical step in determining acceptance of compatible pollen or rejection of incompatible pollen. Cognate PrpS PrsS interaction triggers a signalling network causing rapid growth arrest and eventually programmed cell death (PCD) in incompatible pollen. In this review, we provide an overview of recent advances in our understanding of the major components involved in the SI-induced PCD (SI-PCD). In particular, we focus on the importance of SI-induced intracellular acidification and consequences for protein function, and the regulation of soluble inorganic pyrophosphatase (Pr p26.1) activity by post-translational modification. We also discuss attempts at the identification of protease(s) involved in the SI-PCD process. Finally, we outline future opportunities made possible by the functional transfer of the P. rhoeas SI system to Arabidopsis. PMID- 30481324 TI - A canopy conundrum: can wind-induced movement help to increase crop productivity by relieving photosynthetic limitations? AB - Wind-induced movement is a ubiquitous occurrence for all plants grown in natural or agricultural settings and in the context of high, damaging wind speeds it has been well studied. However, the impact of lower wind speeds (that do not cause any damage) on mode of movement, light transmission and photosynthetic properties has, surprisingly, not been fully explored. This is likely to be influenced by biomechanical properties and architectural features of the plant and canopy. A limited number of eco-physiological studies have indicated that movement in wind has the potential to alter light distribution within canopies, improving canopy productivity by relieving photosynthetic limitations. Given the current interest in canopy photosynthesis is timely to consider such movement in terms of crop yield progress. This opinion article sets out the background to wind-induced crop movement and argues that plant biomechanical properties may have a role in the optimisation of whole canopy photosynthesis via established physiological processes. We discuss how this could be achieved using canopy models. PMID- 30481325 TI - The evolution of root branching: increasing the level of plasticity. AB - Plant roots and root systems are indispensable for water and nutrient foraging and as such a major evolutionary achievement for plants to cope with dry land conditions. The ability of roots to branch contributes substantially to their capacity to explore the soil for water and nutrients, and led about 400 Mya to the successful colonization of land by plants, eventually even in arid regions. During this colonization, different forms of root branching evolved, reinforcing step by step the phenotypic plasticity of the root system. Whereas the lycophytes, the most ancient land plants with roots, are only branching at the root tip, ferns are able to form roots laterally in a fixed pattern along the main root. Finally, roots of seed plants show the highest phenotypic plasticity, because lateral roots can possibly, dependent on internal and/or external signals, be produced at almost any position along the main root. The competence to form lateral roots is in seed plants based on the presence of internal cell files with stem cell-like features. Despite the dissimilarities between the different clades, a number of genetic modules seem to be co-opted in order to acquire root branching capacity. In this review, starting from the lateral root pathways in seed plants, we review root branching in the different land plant lineages and discuss the hitherto described genetic modules that contribute to their root branching capacity. As such, we try to get insight into how land plants have acquired an increasing root branching plasticity during evolution that contributed to the successful colonization of our planet by seed plants. PMID- 30481326 TI - Combined Adipose-Derived Mesenchymal Stem Cells and Low-Energy Extracorporeal Shock Wave Therapy Protect the Brain From Brain Death-Induced Injury in Rat. AB - This study tested the hypothesis that combined adipose-derived mesenchymal stem cell (ADMSC) and low-energy extracorporeal shock wave (ECSW) therapy could protect brain from brain death (BD)-induced injury. Adult male Sprague Dawley rats were categorized into group 1 (sham control), group 2 (BD), group 3 (BD + ECSW [0.15 mJ/mm2/300 impulses] applied to the skull surface 3 hours after BD induction), group 4 (BD + ADMSC [1.2 * 106 cell] by intravenous injection 3 hours after BD induction) and group 5 (BD + ECSW + ADMSC). By 6 hours after BD induction, circulating/spleen levels of immune cells (CD3/CD4+, CD8/CD4+, Treg+) and circulating levels of inflammatory cells (MPO/Ly6G/CD11a/b) and soluble mediators (TNF-alpha/IL-6) were lowest in group 1 and significantly progressively reduced from groups 2 to 5 (all p < 0.0001). Brain protein expressions of inflammatory (TNF-alpha/NF-kappaB/MMP-9/IL-1beta), apoptotic (caspase 3/PARP/mitochondrial-BAX), oxidative stress/DNA-damage (NOX-1/NOX-2/oxidized protein/gamma-H2AX) biomarkers exhibited an identical pattern, whereas anti oxidant (SIRT1/SIRT3) and mitochondrial-integrity (mitochondrial-cytochrome-C) biomarkers exhibited an opposite pattern to inflammatory biomarkers among the 5 groups (all p < 0.0001). The cellular expressions of inflammatory/brain-edema (F4/80/CD14+/GFAP/AQP4) biomarkers exhibited an identical pattern to inflammation among the 5 groups (all p < 0.0001). In conclusion, ECSW-ADMSC therapy is superior to either alone for attenuating brain from BD-induced damage. PMID- 30481327 TI - A UDP-glucosyltransferase PpUGT85A2 responsible for peach volatile glycosylation. AB - The monoterpene linalool is a major contributor to aroma and flavor in peach (Prunus persica) fruit. It accumulates during fruit ripening, where up to ~40% of the compound is present in a nonvolatile glycosylated form, which affects flavor quality and consumer perception by retronasal perception during tasting. Despite the importance of this sequestration to flavor, the UDP-glycosyltransferase (UGT) responsible for linalool glycosylation has not been identified in peach. UGT gene expression during peach fruit ripening and among different peach cultivars was analyzed using RNA-Seq and transcripts correlated with linalyl-beta-D-glucoside were selected as candidates for functional analysis. Kinetic resolution of a racemic mixture R, S-linalool was shown for PpUGT85A2, with a slight preference for S-(+)-linalool. PpUGT85A2 was shown to catalyze synthesis of linalyl-beta-D glucoside in vitro, although did not exhibit the highest enzyme activity between tested substrates. Subcellular localization of PpUGT85A2 in the cytoplasm and nucleus was detected. Application of linalool to peach leaf disks promoted PpUGT85A2 expression and linalyl-beta-D-glucoside generation. Transient expression in peach fruit and stable over-expression in tobacco and Arabidopsis resulted in significant accumulation of linalyl-beta-D-glucoside in vivo. Taken together, the results indicate that PpUGT85A2 expression is a major control point predicting linalyl-beta-D-glucoside content. PMID- 30481328 TI - Role of the uS9/yS16 C-terminal tail in translation initiation and elongation in Saccharomyces cerevisiae. AB - The small ribosomal subunit protein uS9 (formerly called rpS16 in Saccharomyces cerevisiae), has a long protruding C-terminal tail (CTT) that extends towards the mRNA cleft of the ribosome. The last C-terminal residue of uS9 is an invariably conserved, positively charged Arg that is believed to enhance interaction of the negatively charged initiator tRNA with the ribosome when the tRNA is base-paired to the AUG codon in the P-site. In order to more fully characterize the role of the uS9 CTT in eukaryotic translation, we tested how truncations, extensions and substitutions within the CTT affect initiation and elongation processes in Saccharomyces cerevisiae. We found that uS9 C-terminal residues are critical for efficient recruitment of the eIF2*GTP*Met-tRNAiMet ternary complex to the ribosome and for its proper response to the presence of an AUG codon in the P site during the scanning phase of initiation. These residues also regulate hydrolysis of the GTP in the eIF2*GTP*Met-tRNAiMet complex to GDP and Pi. In addition, our data show that uS9 CTT modulates elongation fidelity. Therefore, we propose that uS9 CTT is critical for proper control of the complex interplay of events surrounding accommodation of initiator and elongator tRNAs in the P- and A sites of the ribosome. PMID- 30481329 TI - Associations Among Sleep Latency, Subjective Pain, and Thermal Pain Sensitivity in Gynecologic Cancer. AB - Objective.: Pain is common among women with gynecologic cancer and contributes to depressed mood, sleep disturbances, and likelihood of future chronic pain. Little is known about how psychosocial factors are associated with central sensitization of pain in gynecologic cancer. This study examined relations among depressive symptoms, sleep, subjective pain, and aftersensation pain (a proxy for central sensitization of pain) in gynecologic cancer. Participants were 42 women (mean age [SD] = 59.60 [10.11] years) enrolled in a randomized clinical trial examining psychological intervention effects on sleep, pain, mood, and stress hormones/cytokines in gynecologic cancer. Six to eight weeks after surgery, participants completed an assessment of depressive symptoms, sleep, and subjective pain and a temporal summation of pain protocol via quantitative sensory testing (QST). Controlling for recent chemotherapy, history of chronic pain, and analgesic medication use, regression analyses revealed that longer sleep onset latency (SOL; B = 3.112, P = 0.039, bias-corrected and accelerated (BCa) 95% confidence interval [CI] = 0.371 to 6.014) and greater sensory pain ( B = 0.695, P = 0.023, BCa 95% CI = 0.085 to 1.210) were associated with greater aftersensation pain at 15 seconds. Greater sensory pain scores were associated with greater aftersensation pain at 30 seconds ( B = 0.286, P = 0.045, BCa 95% CI = 0.008 to 0.513). Depression was not associated with aftersensation pain. The overall models accounted for 44.5% and 40.4% of the variance in aftersensation pain at 15 and 30 seconds, respectively. Longer SOL and higher subjective sensory pain were related to greater aftersensation of experimentally induced pain in women postsurgery for gynecologic cancers. Interventions that improve sleep and subjective sensory pain during the perisurgical period may reduce risk for central sensitization of pain. PMID- 30481330 TI - Corrigendum to: Metal tolerance protein MTP6 affects mitochondrial iron and manganese homeostasis in cucumber. PMID- 30481332 TI - Inhibition of Monoacylglycerol Lipase Reduces the Reinstatement of Methamphetamine-Seeking and Anxiety-Like Behaviors in Methamphetamine Self Administered Rats. AB - Background: Methamphetamine is a highly addictive psychostimulant with reinforcing properties. Our laboratory previously found that Delta8 tetrahydrocannabinol, an exogenous cannabinoid, suppressed the reinstatement of methamphetamine-seeking behavior. The purpose of this study was to determine whether the elevation of endocannabinoids modulates the reinstatement of methamphetamine-seeking behavior and emotional changes in methamphetamine self administered rats. Methods: Rats were tested for the reinstatement of methamphetamine-seeking behavior following methamphetamine self-administration and extinction. The elevated plus-maze test was performed in methamphetamine self administered rats during withdrawal. We investigated the effects of JZL184 and URB597, 2 inhibitors of endocannabinoid hydrolysis, on the reinstatement of methamphetamine-seeking and anxiety-like behaviors. Results: JZL184 (32 and 40 mg/kg, i.p.), an inhibitor of monoacylglycerol lipase, significantly attenuated both the cue- and stress-induced reinstatement of methamphetamine-seeking behavior. Furthermore, URB597 (3.2 and 10 mg/kg, i.p.), an inhibitor of fatty acid amide hydrolase, attenuated only cue-induced reinstatement. AM251, a cannabinoid CB1 receptor antagonist, antagonized the attenuation of cue-induced reinstatement by JZL184 but not URB597. Neither JZL184 nor URB597 reinstated methamphetamine-seeking behavior when administered alone. In the elevated plus maze test, rats that were in withdrawal from methamphetamine self-administration spent less time in the open arms. JZL184 ameliorated the decrease in time spent in the open arms. Conclusion: We showed that JZL184 reduced both the cue- and stress-induced reinstatement of methamphetamine-seeking and anxiety-like behaviors in rats that had self-administered methamphetamine. It was suggested that a decrease in 2-arachidonoylglycerol in the brain could drive the reinstatement of methamphetamine-seeking and anxiety-like behaviors. PMID- 30481331 TI - Characterization and Levels of Expression of Sensory Neuron Membrane Proteins in the Adult Citrus Fruit Fly (Diptera: Tephritidae). AB - Sensory neuron membrane proteins (SNMPs) play an important role in insect chemoreception; however, the SNMPs for Bactrocera minax (Enderlein) (Diptera: Tephritidae), an economically important pest of citrus, remain uncharacterized. Here, we report on the molecular characterization of SNMPs (BminSNMP1 and BminSNMP2) from adult B. minax. The open-reading frames of BminSNMP1 and BminSNMP2 were 1,608 and 1,647 nucleotides, encoding proteins of 535 and 557 amino acid residues, respectively. Phylogenetic analysis showed that the two BminSNMPs belonged to two distinct subgroups, indicating the possibility of their contrasting function in insect chemoreception. Real-time PCR results showed that BminSNMP1 was expressed primarily in the antennae of males and females, where levels of expression were similar at different developmental stages of females, but lower in 1- and 5-d-old males than in 15- and 20-d-old males. In both sexes, BminSNMP2 was expressed at high levels in antennae and in nonolfactory tissues, especially in legs, where levels were higher than in other nonolfactory tissues. We found highest levels of expression of BminSNMP2 in antennae of both sexes in 30-d-old adults, while in legs of both sexes, highest levels of expression were detected in 1- and 30-d-old adults. We discuss the possible physiological functions of BminSNMPs based on our findings. PMID- 30481333 TI - Treating Chronic Insomnia in Postmenopausal Women: A Randomized Clinical Trial Comparing Cognitive-Behavioral Therapy for Insomnia (CBTI), Sleep Restriction Therapy, and Sleep Hygiene Education. AB - Study objectives: Insomnia is a leading cause of disability in postmenopausal women. Multicomponent cognitive-behavioral therapy for insomnia (CBTI) is a first line treatment for chronic insomnia, but support for its efficacy in treating menopause-related insomnia is scarce. The present study evaluated whether CBTI is an efficacious treatment for menopause-related chronic insomnia, and whether sleep restriction therapy (SRT)-a single component of CBTI-is equally effective compared to CBTI. Methods: Single-site, randomized controlled trial. 150 postmenopausal women (56.44+/-5.64 years) with chronic DSM-5 insomnia disorder related to menopause were randomized to 3 treatment conditions: sleep hygiene education (SHE), SRT, or CBTI. Blinded assessments were performed at baseline, posttreatment, and 6 months after treatment. The Insomnia Severity Index (ISI) and sleep diaries served as primary outcomes. Results: From baseline to posttreatment, ISI decreased 7.70 points in the CBTI group (p<.001), 6.56 points in the SRT group (p<.001), and 1.12 in the SHE group (p=.01). Although average sleep duration increased in all groups by 6-month follow-up, CBTI patients obtained 40-43 more minutes of nightly sleep than those who received SHE or SRT. Remission rates in the CBTI (54-84%) and SRT (38-57%) groups were higher than SHE patients (4-33%) at posttreatment and 6-month follow-up. CBTI patients were generally more likely to remit than SRT patients. Conclusions: CBTI and SRT effectively treat menopause-related insomnia disorder and are superior to sleep hygiene education. Response to CBTI and SRT are similar, but CBTI outperforms SRT in improving sleep maintenance, which may increase likelihood of remission. PMID- 30481334 TI - Ribosomal DNA loci derived from Brachypodium stacei are switched off for major parts of the life cycle of Brachypodium hybridum. AB - Nucleolar dominance (ND) is an epigenetic phenomenon that occurs in some plant and animal allopolyploids and hybrids, whereby only one ancestral set of 35S rRNA genes retains the ability to form the nucleolus, whilst the rDNA loci derived from the other progenitor are transcriptionally silenced. Since there is substantial evidence that ND is regulated developmentally, this study focusses upon the establishment and/or maintenance of ND during different stages of development in the model grass allotetraploid, Brachypodium hybridum. Fluorescence in situ hybridisation with a 25S rDNA probe to 3-D cells shows that ND is present not only in root meristematic and differentiated cells of this species, but is also present in male meiocytes at prophase I, tetrads of microspores and different embryonic tissues. The inactive state of B. stacei originated rDNA loci is confirmed by silver staining method. We show that only B. distachyon-derived 35S rDNA loci form a nucleolus/nucleoli in the aforementioned tissues, whereas B. stacei-like loci remain highly condensed and thus transcriptionally suppressed. The establishment of ND during earlier stages of B. hybridum embryo development cannot be ruled out. However, our proposal of gradual pseudogenisation of B. stacei-like loci in the evolution of the allotetraploid seems to be more likely. PMID- 30481335 TI - Responses of broiler chickens to Eimeria challenge when fed a nucleotide-rich yeast extract. AB - Nucleotide-rich yeast extract (YN) was investigated for effects on growth performance, jejunal physiology, and cecal microbial activity in Eimeria challenged broiler chickens. A total of 360-day-old male chicks (Ross * Ross 708) were placed on floor pens and provided a corn-soybean meal-based diet without or with YN (500 g/MT; n = 12). On d 10, 6 replicates per diet were orally administered with 1 mL of E. acervulina and E. maxima sporulated oocysts and the rest (non-challenged control) were administered with 1 mL of distilled water. On d 15, 5 birds/pen were then necropsied for intestinal lesion scores, histomorphology and cecal digesta pH, short chain fatty acids (SCFA), and microbial community using Illumina Miseq platform. Supplemental YN improved (P = 0.01) Feed conversion ratio (FCR) during the prechallenge phase (d 0 to 10). In the postchallenge period (d 11 to 15), Eimeria depressed (P < 0.05) Body weight gain (BWG) relative to non-challenged birds, whereas YN-fed birds had a higher (P = 0.05) BWG compared to that of non-YN-fed birds. There was an interaction between YN and Eimeria on jejunal villi height (VH) (P = 0.001) and expression of cationic amino acid transporter 1(CAT1) (P = 0.04). Specifically, in the absence of Eimeria, YN-fed birds had a shorter VH (892 vs. 1,020 MUm) relative to that of control but longer VH (533 vs. 447 MUm) in the presence of Eimeria. With respect to CAT1, YN-fed birds had a higher (1.65 vs. 0.78) expression when subjected to Eimeria than when not challenged. Independently, Eimeria decreased (P < 0.01) the jejunal expression of maltase, Na glucose transporter 1 and occludin genes, ceca digesta abundance of genus Clostridium cluster XlVa and Oscillibacter but increased (P < 0.01) jejunal proliferating cell nuclear antigen and interleukin 10. Interaction between YN and Eimeria was observed for ceca digesta pH (P = 0.04) and total SCFA (P = 0.01) such that YN increased SCFA in the absence of Eimeria but reduced SCFA and increased pH in the presence of Eimeria. In summary, Eimeria impaired performance and gut function and shifted gut microbiome; YN improved performance independently, attenuated Eimeria damage on indices of gut function, and modulated cecal microbiome. PMID- 30481336 TI - Commentary: Development of Machine Learning Algorithms for Prediction of 30-Day Mortality After Surgery for Spinal Metastasis. PMID- 30481337 TI - Apoptosis and genome instability in children with autoimmune diseases. AB - As apoptosis and genome instability in children with autoimmune diseases (AIDs) are insufficiently investigated, we aimed to analyse them in peripheral blood lymphocytes (PBLs) of children and adolescents with Hashimoto's thyroiditis (HT), Graves' disease (GD) and type 1 diabetes mellitus (T1DM), including possible factors that could affect their occurrence. The study population included 24 patients and 19 healthy controls. Apoptotic cells were detected using an Annexin V-FITC/7-AAD kit. Genome instability was measured as micronuclei (MNs) frequency using the cytokinesis-block MN assay. In addition, comet assay was performed for determination of genome instability as genome damage index (GDI) in new subpopulation of patients with T1DM. The percentage of apoptotic PBLs in patients with AID was significantly lower than in control subjects. There was a positive correlation between thyroid-stimulating homone (TSH) concentration and the proportion of cells in late stage apoptosis in patients with autoimmune thyroid diseases (AITDs). The MN frequency in patients was significantly higher than in controls. Individuals with HT or T1DM had a significantly higher MN frequency than those with GD. Similarly, the value of GDI in patients with T1DM was significantly higher than in controls. The level of apoptosis was positively correlated with MN frequency as well as with GDI in patients with AID. In conclusion, children with AITD (HT and GD) and T1DM have a significantly lower level of apoptosis in PBLs and significantly higher MN frequency as GDI than healthy subjects. Apoptosis and the level of genome instability in these patients with AID are positively correlated. PMID- 30481338 TI - Hetero-trimeric G protein signaling in plant immunity. AB - In animals, heterotrimeric guanine nucleotide-binding proteins (G proteins) transduce signals perceived by numerous G Protein Coupled Receptors (GPCRs). However, no canonical GPCRs with Guanine Nucleotide Exchange Factor (GEF) activity are presented in plant genomes. Accumulated evidence indicates that, instead of GPCRs, the Receptor-Like Kinases (RLKs) function upstream of G proteins in plants. Regulator of G Protein Signaling 1 (RGS1) functions to convert the GTP-bound Galpha to GDP-bound form through its GTPase-accelerating protein (GAP) activity. Because of the intrinsic differences in the biochemical properties between Arabidopsis and animal Galpha, the actions of animal and Arabidopsis RGS1 result in contrasting outcomes in G signaling activation/deactivation. Animal RGSs accelerate the deactivation of the activated G signaling, whereas Arabidopsis RGS1 prevents the activation of G signaling under resting state. Phosphorylation of Arabidopsis RGS1 triggered by ligand-RLK recognitions results in the endocytosis or degradation of RGS1, leading to the separation of RGS1 from Galpha and thus the de-repression of G signaling. Here, we summarize the involvement of the G proteins in plant immunity, with a special focus on the molecular mechanism of G signaling activation/de-activation regulated by RLKs and RGS1. We also raise the issues need to be addressed in the future. PMID- 30481339 TI - Managing employees with dementia: a systematic review. AB - Background: The experience of developing dementia while in employment has been explored from the point of view of the employee, but less is known about the perspectives, experiences and needs of employers. Aims: To review systematically literature about the management of employees who develop dementia whilst in employment. Methods: Databases searched included MEDLINE, EMBASE, PsycINFO, CINAHL, BNI, ABI Inform, ISI Web of Science, Open Grey and dementia journals database; 44 documents were identified for inclusion in the review: 22 journal papers, one PhD thesis and 21 articles, reports and webpages from the grey literature. As all documents were qualitative in nature a thematic synthesis of their content was undertaken. Results: Three main themes and ten sub-themes were identified. The main themes concerned early presentation and identification in the workplace; reasonable adjustments for people with working age dementia; and the provision of information to raise awareness and facilitate informed choice. The evidence suggested that there is a lack of awareness about working age dementia and that this may impact negatively on employees. Guidance for employers offered suggestions for good practice. Conclusions: Guidance for employers is increasingly available although it rarely refers to the evidence base. There is a need for future studies that explore the effectiveness of guidance and training initiatives for employers. Examples of good practice where employees with dementia have been well supported in the workplace and who have been able to leave the workforce with dignity, would be helpful. PMID- 30481340 TI - PERPETUAL FLOWERING2 coordinates the vernalization response and perennial flowering in Arabis alpina. AB - The floral repressor APETALA2 (AP2) in Arabidopsis regulates flowering through the age pathway. The AP2 orthologue in the alpine perennial Arabis alpina, PERPETUAL FLOWERING 2 (PEP2), was previously reported to regulate flowering through the vernalization pathway by enhancing the expression of another floral repressor PERPETUAL FLOWERING 1 (PEP1), the orthologue of Arabidopsis FLOWERING LOCUS C (FLC). However, PEP2 also regulates flowering independently of PEP1. To characterize the function of PEP2 we analyzed the transcriptomes of pep2 and pep1 mutants. The majority of differentially expressed genes were detected between pep2 and the wild type or between pep2 and pep1, highlighting the importance of the PEP2 role that is independent of PEP1. Here we demonstrate that PEP2 prevents the upregulation of the A. alpina floral meristem identity genes FRUITFUL (AaFUL), LEAFY (AaLFY) and APETALA1 (AaAP1) which ensure floral commitment during vernalization. Young pep2 seedlings respond to vernalization, suggesting that PEP2 regulates the age-dependent response to vernalization independently of PEP1. The major role of PEP2 through the PEP1-dependent pathway takes place after vernalization, when it facilitates PEP1 activation both in the main shoot apex and in the axillary branches. These multiple roles of PEP2 in vernalization response contribute to the A. alpina life-cycle. PMID- 30481341 TI - The origin and population history of the endangered golden snub-nosed monkey (Rhinopithecus roxellana). AB - The origin and population history of the endangered golden snub-nosed monkey (Rhinopitheucs roxellana) remain largely unavailable and/or controversial. We here integrate analyses of multiple genomic markers including mitochondrial (mt) genomes, Y chromosomes and autosomes of 54 golden monkey individuals from all three geographic populations (SG, QL and SNJ). Our results reveal contrasting population structures. Mt analyses suggest a division of golden monkeys into five lineages, one in SNJ and two in SG and two in QL. One of the SG lineages (a mixed SG/QL lineage) is basal to all other lineages. In contrast, autosomal analyses place SNJ as the most basal lineage and identify one QL and three SG lineages. Notably, Y analyses bears features similar to mt analyses in placing the SG/QL mixed lineage as the first-diverging lineage and dividing SG into two lineages, while resembles autosomal analyses in identifying one QL lineage. We further find bi-directional gene flow among all three populations at autosomal loci, while asymmetric gene flow is suggested at mt genomes and Y chromosomes. We propose that different population structures and gene flow scenarios are the result of sex-linked differences in the dispersal pattern of R. roxellana. Moreover, our demographic simulation analyses support an origin hypothesis suggesting that the ancestral R. roxellana population was once widespread and then divided into SNJ and non-SNJ (SG and QL) populations. This differs from previous mt-based "mono origin (SG is the source population)" and "multi-origin (SG is a fusion of QL and SNJ)" hypotheses. We provide a detailed and refined scenario for the origin and population history of this endangered primate species, which has a broader significance of Chinese biogeography. In addition, this study highlights the importance to investigate multiple genomic markers with different modes of inheritance to trace the complete evolutionary history of a species especially for those exhibiting differential or mixed patterns of sex dispersal. PMID- 30481342 TI - Endogenous oxytocin response to film scenes of attachment and loss is pronounced in schizophrenia. AB - Background: Oxytocin (OXT) is critically involved in the regulation of attachment and interpersonal function. In this study, emotional children's movies were used to stimulate OXT secretion in patients with schizophrenia and healthy controls. Furthermore, associations of OXT levels with measures of attachment style (Psychosis Attachment Measure), childhood adversity (Childhood Trauma Questionnaire) and symptom severity (Positive and Negative Syndrome Scale) were considered. Methods: In 35 patients with schizophrenia and 35 matched healthy controls, RIA with sample extraction was used to determine OXT plasma levels before and after viewing of movie scenes portraying emotional bonding and loss and compared to a non-emotional condition. Results: Statistical analysis indicated lower baseline OXT levels in female patients than in all other groups. OXT reactivity during emotional movies was significantly higher in patients when compared to healthy controls. OXT reactivity during the control movie related to PANSS "general psychopathology". No significant associations appeared between baseline or induced OXT levels and other PANSS subscales, attachment style or childhood adversity in patients. Conclusions: Our findings suggest differences of baseline OXT and a higher OXT reactivity towards strong emotional stimuli in patients with schizophrenia, suggesting a role of OXT as a gender- and context dependent modulator of socio-emotional function. PMID- 30481343 TI - Phylogenies and Diversification Rates: Variance Cannot Be Ignored. AB - A recent pair of articles published in the journal Evolution presented a test for assessing the validity of hierarchical macroevolutionary models. The premise of the test is to compare numerical point estimates of parameters from two levels of analysis; if the estimates differ, the hierarchical model is purportedly flawed. The articles in question (Meyer and Wiens 2017; Meyer et al. 2018) apply their proposed test to BAMM, a scientific software program that uses a Bayesian mixture model to estimate rates of evolution from phylogenetic trees. The authors use BAMM to estimate rates from large phylogenies (n > 60 tips) and they apply the method separately to subclades within those phylogenies (median size: n = 3 tips); they find that point estimates of rates differ between these levels and conclude that the method is flawed, but they do not test whether the observed differences are statistically meaningful. There is no consideration of sampling variation and its impact at any level of their analysis. Here, I show that numerical differences across groups that they report are fully explained by a failure to account for sampling variation in their point estimates. Variance in evolutionary rate estimates - from BAMM and all other methods - is an inverse function of clade size; this variance is extreme for clades with 5 or fewer tips (e.g., 70% of clades in the focal study). The articles in question rely on negative results that are easily explained by low statistical power to reject their preferred null hypothesis, and this low power is a trivial consequence of high variance in their point estimates. I describe additional mathematical and statistical mistakes that render the proposed testing framework invalid on first principles. Evolutionary rates are no different than any other population parameters we might wish to estimate, and biologists should use the training and tools already at their disposal to avoid erroneous results that follow from the neglect of variance. PMID- 30481344 TI - Identification and characterization of infectious bursal disease virus subviral particles by capillary zone electrophoresis: potential application for vaccine production and quality control. AB - The infectious bursal disease (IBD) causes immunosuppression in chicken of all ages and high mortality in young chicken, posing serious threat to poultry industry worldwide. One promising strategy for preventing this highly contagious disease is using recombinant subunit vaccine, employing VP2 subviral particles (SVP) as epitomic antigen. Analytical techniques of viral-like particles such as SDS-PAGE, western blot, or high-performance size-exclusion chromatography have been widely applied, but mostly unsatisfactory. In the present study, a simple, fast and cost-effective capillary zone electrophoresis (CZE) method with UV detection was developed to analyze purified IBDV-SVP (expressed by Escherichia coli system) using commercial monoclonal antibody (mAb) against VP2. To find satisfying CZE conditions, injection mode, separation voltage, and separation buffer were explored. Through the modified CZE, mAb and SVP could be well separated and shown distinct peaks in the electropherogram. Furthermore, to determine the stoichiometry, the area of the mAb peak versus SVP/mAb binding ratio was plotted and indicated that 2 or 3 receptor molecules were bound per SVP. The purity and integrity of SVP and the interactions between SVP and mAb could be analyzed by the developed simple CZE-UV method in less than half hour. This CZE-UV method proved to be a valuable and useful tool in detection, characterization, and quantification of IBDV-SVP and the mAb, offering potential applications of in-process quality control of vaccine production, surveillance of serum antibody produced against IBDV infection, or vaccine immunization. PMID- 30481346 TI - Corrigendum. PMID- 30481345 TI - Effect of IBDV infection on the interfollicular epithelium of chicken bursa of Fabricius. AB - In the chicken bursa of Fabricius (BF), the interfollicular epithelium (IFE) consists of cylindrical- and cuboidal-shaped cells. Among the cylindrical-shaped epithelial cells, mucus-producing and caveolin-1 (Cav-1)-expressing cells can be distinguished. Occasionally, the cuboidal-shaped cells also express Cav-1, which suggests that they are precursors of both mucus-producing and Cav-1-expressing cells. Very virulent infectious bursal disease virus (IBDV) impedes the differentiation of Cav-1-expressing cells and shifts the differentiation of cuboidal cells towards mucus-producing cells. In control birds exclusively, the IFE surface shows a mucous membrane, but after IBDV infection, the surfaces of both IFE and FAE are also covered by a mucous membrane. After IBDV infection, the cells of FAE also produce mucus, providing evidence for cell transformation. In late postinfection (pi; 28 d pi), the Cav-1 expression returned in the IFE cells, whereas the follicle (the primary lymphoid organ) underwent atrophy. The appearance of the renewed Cav-1-positive cells is similar to that of the normal basal cell, but they randomly locate in different levels of IFE, suggesting the loss of epithelial polarity. Between days 2 and 7 pi, the Cav-1 expression in the endothelial cells of the cortico-medullary capillary web is variable, which may explain the hemorrhage in several infected birds. The IBDV infection stops the Cav-1 expression and subsequently the cholesterol efflux into the bursal lumen. In the infected birds, the high cholesterol level may further worsen the clinical syndrome of IBDV. PMID- 30481347 TI - Hearing loss, mental well-being and healthcare use: results from the Health Survey for England (HSE). AB - Background: Hearing loss (HL) affects an estimated 17% of adults in Britain, 19% in Canada and 16% in the USA. Evidence points to the impact of HL on aspects of physical and mental health as well as autonomy, cognition, memory and social isolation. This suggests the relationship between HL and service use may arise indirectly as well as directly, an issue that warrants investigation. Methods: We used data from Health Survey for England (2014) on objectively and subjectively measured HL, mental and physical health as well as aspects of well-being related to autonomy, cognition, memory and social isolation within a series of bivariate probit models to examine the relationship between health and GP use in the past two weeks. Data for between ~3000 and 1700 individuals were examined. Results: A significant correlation in errors was found in each aspect of well-being demonstrating the appropriateness of the bivariate model. In three of the six regressions (concentration, memory and GHQ score) wearing a hearing aid (in some age groups) attenuated the impact of HL on outcome (relative to being younger or not wearing a hearing aid). Conclusions: While HL did not directly predict use of GP services, it consistently predicted aspects of cognition, autonomy, mobility and memory found to predict service use. PMID- 30481348 TI - Catechol-O-Methyltransferase Val158Met Polymorphism Is Associated with Anxiety, Depression, and Widespread Pressure Pain Sensitivity in Women with Chronic, but Not Episodic, Migraine. AB - Objectives: To analyze the association between the rs4680 catechol-O methyltransferase Val158Met polymorphism and to determine the association of this polymorphism with clinical, psychological, and pain sensitivity variables in women with episodic or chronic migraine. Methods: Fifty women with episodic migraine, 50 with chronic migraine, and 50 matched healthy women participated. After amplifying the Val158Met polymorphism by polymerase chain reaction, we assessed genotype frequencies and allele distributions. Participants were classified according to the Val158Met polymorphism genotype into Val/Val, Val/Met, or Met/Met. A headache diary was used for collecting migraine pain features. Disability was assessed with the Migraine Disability Assessment Scale, trait/state anxiety levels with the State-Trait Anxiety Inventory, and depression/anxiety with the Hospital Anxiety and Depression Scale. Pressure pain thresholds (PPTs) were bilaterally assessed over the temporalis, the upper trapezius, the second metacarpal, and the tibialis anterior. Results: The distribution of the rs4680 Val158Met genotype was not significantly different between women with and without migraine (P = 0.157). No differences in migraine features were found to be dependent on the Val158Met genotype. Women with the Met/Met genotype showed higher migraine-related disability than those with the Val/Val or Val/Met genotype in both migraine groups (P < 0.01). Women with chronic, but not episodic, migraine with the Met/Met genotype exhibited higher depressive and anxiety levels and lower PPTs than those with the Val/Val or Val/Met genotype. Conclusions: The Val158Met rs4680 polymorphism does not appear to be involved in predisposition to suffer from migraine; however, this genetic factor may be involved in the phenotypic expression of chronic migraine, as anxiety, depression, and widespread pressure pain sensitivity were greater in those women with chronic, but not episodic, migraine with the Met/Met genotype. PMID- 30481349 TI - AAPM 2019 Annual Meeting Preliminary Program: A Message from the AAPM President. PMID- 30481350 TI - Confidence of emotion expression recognition recruits brain regions outside the face perception network. AB - Metacognitive beliefs about emotions expressed by others are crucial to social life, yet very little studied. To what extent does our confidence in emotion expression recognition depend on perceptual or other non-perceptual information? We obtained behavioral and MRI measures while participants judged either the emotion in ambiguous faces or the size of two lines flanking these faces, and then rated their confidence on decision accuracy. Distinct behavioral and neural mechanisms were identified for confidence and perceptual decision in both tasks. Participants overestimated their emotion recognition accuracy, unlike visual size judgments. Whereas expression discrimination recruited several areas in the face processing network, confidence for emotion recognition uniquely engaged the bilateral retrosplenial/posterior cingulate complex and left parahippocampal gyrus. Further, structural white-matter connectivity of the former region predicted metacognitive sensitivity. These results highlight a key role for brain mechanisms integrating perception with contextual mnemonic information in the service of confidence during emotion recognition. PMID- 30481351 TI - Behavioral and Functional Connectivity Basis for Peer-Influenced Bystander Participation in Bullying. AB - Recent studies have shown that the reactions of bystanders who witness bullying significantly affect whether the bullying persists. However, the underlying behavioral and neural mechanisms that determine a peer-influenced bystander's participation in bullying remain largely unknown. Here, we designed a new "catch ball" task where four players choose to throw a sequence of normal or strong (aggressive) balls in turn and examined whether the players (n=43) participated in other players' bullying. We analyzed behaviors with a computational model that quantifies the tendencies of a participant's 1) baseline propensity for bullying, 2) reactive revenge, 3) conformity to bullying, and 4) capitulation to threat and estimated these effects on the choice of balls. We found only conformity had a positive effect on the throwing of strong balls. Furthermore, we identified a correlation between a participant's conformity and social anxiety. Our mediation analysis of resting-state fMRI revealed that there were significant relationships of each participant's functional connectivity between the amygdala and right temporoparietal junction (TPJ) and social anxiety to the participant's conformity to bullying. We also found that amygdala-TPJ connectivity partially mediated the relationship between social anxiety and conformity. These results highlighted the anxiety-based conformity and amygdala network on peer-influenced bystander participation in bullying. PMID- 30481352 TI - Estimating the impact of administration of dewormers on smallholder chickens in Odisha State, India. AB - Helminth infections, in particular infections with nematodes are highly prevalent and an impediment to the productivity of chickens in smallholder settings. Infections can be easily and cheaply treated using dewormers. We present an empirical framework for estimating the impact of administration of locally available dewormers on chicken weight in a smallholder setting in Odisha State of India.We recruited 1,040 chickens aged between 40 and 70 d from 168 households in 13 village groups in Odisha. Chickens were randomly assigned to treatment with a dewormer (fenbendazole), or non-treatment. Each chicken was tagged with 2 legbands and weighed, then followed up after 28 and 56 d and reweighed. To account for the local variations in exposure and for variations between flocks, the data were analyzed in a multilevel mixed model with flock within village as nested random effects.After 56 d, the modeled results showed that all chickens had gained a mean of 288.3 g but heavier chickens at the baseline gained more weight than lighter chickens. In addition to this, the treated chickens had gained an additional mean of 90.55 g relative to non-treated chickens (P < 0.001).In this setting, we have demonstrated that administration of dewormers has a clear beneficial impact on chicken weight, but it also indicates that other management practices can have a substantial impact on chicken weight. PMID- 30481353 TI - Factors Affecting Prognosis of Patients With Osteoblastoma of the Mobile Spine: A Long-Term Follow-up Study of 70 Patients in a Single Center. AB - BACKGROUND: Osteoblastoma (OBL) in the mobile spine is a benign tumor with aggressive potential. There is not much published information on OBL of the mobile spine as a result of rarity of the disease. There are controversies over the aggressive subtype and prognostic factors of the condition. OBJECTIVE: To explore the aggressive subtype and investigate prognostic factors of OBLs in the mobile spine. METHODS: A retrospective analysis of spinal OBL was performed by survival analysis. Patients in 2 cohorts were analyzed based on the Enneking grade and pathological evaluation. Local recurrence-free survival (RFS) was estimated using the Kaplan-Meier method to identify potential prognostic factors. Factors with P <= .05 were subjected to multivariate analysis by Cox regression analysis. P <= .05 were considered statistically significant. RESULTS: Included in this study were 70 patients with spinal OBL who were followed up by a mean of 67.1 mo (range 24-188). Local recurrence was detected in 9 cases after initial surgery, and death occurred in 2 cases. The result of statistical analysis suggested that Epithelioid OBL (EO) with Enneking stage 3 (St.3) and total spondylectomy were independent prognostic factors for RFS. CONCLUSION: St.3 or EO lesions seem to be more aggressive than St.2 or conventional osteoblastomas, but St.3 and EO should be considered simultaneously in predicting the aggressiveness of the lesion and the risk of recurrence. Total spondylectomy performed either by en bloc or piecemeal could significantly reduce recurrence of OBLs in the mobile spine. PMID- 30481354 TI - In Reply: Isolated Fourth Ventricle: To Shunt or Stent. PMID- 30481355 TI - Reappraisal of Incentives Ameliorates Choking Under Pressure and Is Correlated with Changes in the Neural Representations of Incentives. AB - It has been observed that the pressure of performing for high stakes can, paradoxically, lead to uncharacteristically poor performance. Here we investigate a novel approach to attenuating such 'choking under pressure' by instructing participants performing a demanding motor task that rewards successful performance with a monetary gain, to reappraise this incentive as a monetary loss for unsuccessful performance. We show that when participants applied this simple strategy, choking was significantly reduced. This strategy also influenced participants' neural and physiological activity. When participants reappraised the incentive as a potential monetary loss, the BOLD representation of the magnitude of the incentive in ventral striatum was attenuated. In addition, individual differences in the degree of attenuation of the neural response to incentive predicted the effectiveness of the reappraisal strategy in reducing choking. Furthermore, participants' skin conductance changed in proportion to the magnitude of the incentive being played for, and was exaggerated on high incentive trials on which participants failed. Reappraisal of the incentive abolished this exaggerated skin conductance response. This represents the first experimental association of sympathetic arousal with choking. Taken together, these results suggest that reappraisal of the incentive is indeed a promising intervention for attenuating choking under pressure. PMID- 30481356 TI - Increased functional coupling of the left amygdala and medial prefrontal cortex during the perception of communicative point-light stimuli. AB - Interpersonal predictive coding (IPPC) describes the behavioral phenomenon whereby seeing a communicative rather than an individual action helps to discern a masked second agent. As little is known, yet, about the neural correlates of IPPC, we conducted an fMRI study in a group of 27 healthy participants using point-light displays of moving agents embedded in distractors. We discovered that seeing communicative compared to individual actions was associated with higher activation of right superior frontal gyrus, whereas the reversed contrast elicited increased neural activation in an action observation network that was activated during all trials. Our findings, therefore, potentially indicate the formation of action predictions and a reduced demand for executive control in response to communicative actions. Further, in a regression analysis, we revealed that increased perceptual sensitivity was associated with a deactivation of the left amygdala during the perceptual task. A consecutive psychophysiological interaction analysis showed increased connectivity of the amygdala with medial prefrontal cortex in the context of communicative compared to individual actions. Thus, whereas increased amygdala signaling might interfere with task relevant processes, increased co-activation of the amygdala and the medial prefrontal cortex in a communicative context might represent the integration of mentalizing computations. PMID- 30481357 TI - Learning to see the threat: temporal dynamics of ERPs of motivated attention in fear conditioning. AB - Social threat detection is important in everyday life. Studies of cortical activity have shown that event-related potentials (ERPs) of motivated attention are modulated during fear conditioning. The time course of motivated attention in learning and extinction of fear is however still largely unknown. We aimed to study temporal dynamics of learning processes in classical fear conditioning to social cues (neutral faces) by selecting an experimental setup that produces large effects on well-studied ERP components (early posterior negativity, EPN; late positive potential, LPP; stimulus preceding negativity, SPN), and then exploring small consecutive groups of trials. EPN, LPP, and SPN markedly and quickly increased during the acquisition phase in response to the CS+ but not the CS-. These changes were visible even at high temporal resolution and vanished completely during extinction. Moreover, some evidence was found for component differences in extinction learning, with differences between CS+ and CS- extinguishing faster for late as compared to early ERP components. Results demonstrate that fear learning to social cues is a very fast and highly plastic process and conceptually different ERPs of motivated attention are sensitive to these changes at high temporal resolution, pointing to specific neurocognitive and affective processes of social fear learning. PMID- 30481358 TI - Reconstructing the Evolution of Giant Extinct Kangaroos: Comparing the Utility of DNA, Morphology, and Total Evidence. AB - Combined "total evidence" analysis of molecular and morphological data offers the opportunity to objectively merge fossils into the tree of life, and challenges the primacy of solely DNA based phylogenetic and dating inference, even among modern taxa. To investigate the relative utility of DNA, morphology, and total evidence for evolutionary inference, we sequenced the first near-complete mitochondrial genomes from extinct Australian megafauna: a 40-50 thousand year old giant short-faced kangaroo (Simosthenurus occidentalis) and giant wallaby (Protemnodon anak). We analysed the ancient DNA and fossil data alongside comparable data from extant species to infer phylogeny, divergence times, and ancestral body mass among macropods (kangaroos and wallabies). Our results confirm a close relationship between Protemnodon and the iconic kangaroo genus complex "Macropus", and unite the giant Simothenurus with the hare-sized Lagostrophus fasciatus (banded hare-wallaby), suggesting that the latter is the closest living link to the once diverse sthenurine kangaroo radiation. We find that large body size evolved multiple times among kangaroos, coincident with expansion of open woodland habitats beginning in the Late Miocene. In addition, our results suggest that morphological data mislead macropod phylogeny reconstruction and in turn can distort total evidence estimation of divergence dates. However, a novel result with potentially broad application is that the accuracy and precision of reconstructing ancestral body mass was improved by tracing body mass on morphological branch lengths. This is likely due to positive allometric correlation between morphological and body size variation - a relationship that may be masked or even misleadingly inverted with the temporal or molecular branch lengths that typically underpin ancestral body size reconstruction. Our study supports complementary roles for DNA and morphology in evolutionary inference, and opens a new window into the evolution of Australia's unique marsupial fauna. PMID- 30481359 TI - Prevalence of Nonopioid and Opioid Prescriptions Among Commercially Insured Patients with Chronic Pain. AB - Objective. : The increased use of opioids to treat chronic pain in the past 20 years has led to a drastic increase in opioid prescribing in the United States. The Centers for Disease Control and Prevention's (CDC's) Guideline for Prescribing Opioids for Chronic Pain recommends the use of nonopioid therapy as the preferred treatment for chronic pain. This study analyzes the prevalence of nonopioid prescribing among commercially insured patients with chronic pain. Data from the 2014 IBM (r) MarketScan (r) databases representing claims for commercially insured patients were used. International Classification of Diseases, Ninth Revision, codes were used to identify patients with chronic pain. Nonopioid prescriptions included nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics/antipyretics (e.g., acetaminophen), anticonvulsants, and antidepressant medications. The prevalence of nonopioid and opioid prescriptions was calculated by age, sex, insurance plan type, presence of a depressive or seizure disorder, and region. In 2014, among patients with chronic pain, 16% filled only an opioid, 17% filled only a nonopioid prescription, and 28% filled both a nonopioid and an opioid. NSAIDs and antidepressants were the most commonly prescribed nonopioids among patients with chronic pain. Having prescriptions for only nonopioids was more common among patients aged 50-64 years and among female patients. This study provides a baseline snapshot of nonopioid prescriptions before the release of the CDC Guideline and can be used to examine the impact of the CDC Guideline and other evidence-based guidelines on nonopioid use among commercially insured patients with chronic pain. PMID- 30481360 TI - Keel bone fractures affect egg laying performance but not egg quality in laying hens housed in a commercial aviary system. AB - The aim of this study was to investigate the effect of keel bone fracture (KBF) severity and healing activity on individual productivity of laying hens. Focal hens (75 Lohmann Selected Leghorn (LSL), 75 Lohmann Brown (LB)) were housed alongside non-focal hens in 10 identical pens containing a commercial aviary system (15 focal hens per pen). Eggs of focal hens were identified by orally administering a dye on 3 consecutive days, resulting in a hen-specific color pattern in the yolk. Eggs were collected at 7 time points (37 to 61 weeks of age; WOA) for 5 d to determine individual laying performance and to assess egg quality. Radiographs were performed to score KBF severity on a continuous scale. Healing activity was scored as inactive, healing, or fresh. Linear mixed effects models were used for statistical analyses.We found an association between KBF severity and reduced egg laying performance with increasing age (P = 0.005). At 37 WOA, egg laying performance was similar across KBF severities, whereas at 61 WOA, performance in hens with the highest observed KBF severity was 16.2% lower than in hens without fractures. Hens with fresh fractures had a lower performance than hens with healing and inactive fractures at 37 WOA but higher performance at 61 WOA (P = 0.02). Egg quality parameters were not affected by fractures but were associated with an age * hybrid interaction (egg mass: P = 0.039, shell breaking strength: P = 0.03, shell width: P = 0.001). In conclusion, hens could maintain high performance irrespective of fracture severity until shortly after peak of lay, but seemed to redirect available resources towards fracture healing if a fresh fracture was present. At the end of lay, the negative effect of KBF fracture severity on individual production amplified indicating that hens were no longer able to cope with the physiological challenge of a fracture. PMID- 30481361 TI - Tracking mood fluctuations with functional network patterns. AB - Subjective mood is a psychophysiological property that depends on complex interactions among the central and peripheral nervous systems. How network interactions in the brain drive temporal fluctuations in mood is unknown. Here we investigate how functional network configuration relates to mood profiles in a single individual over the course of 1 year. Using data from the MyConnectome Project, we construct a comprehensive mapping between resting state functional connectivity patterns and subjective mood scales using an associative multivariate technique (partial least squares). We report three principal findings. Functional connectivity patterns reliably tracked daily fluctuations in mood. Positive mood was marked by an integrated architecture, with prominent interactions between canonical resting state networks. One of the top-ranked nodes in mood-related network reconfiguration was the subgenual anterior cingulate cortex, an area commonly associated with mood regulation and dysregulation. Altogether, these results showcase the utility of highly sampled individual-focused datasets for affective neuroscience. PMID- 30481362 TI - Evidence-based practice is the gold standard and should be adhered to at all times-or should it? PMID- 30481363 TI - The soul of Rheumatology. PMID- 30481365 TI - Corrigendum. PMID- 30481364 TI - Editor's Acknowledgement. PMID- 30481366 TI - Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery. AB - BACKGROUND: This an update of the review first published in 2009.Major abdominal and pelvic surgery carries a high risk of venous thromboembolism (VTE). The efficacy of thromboprophylaxis with low molecular weight heparin (LMWH) administered during the in-hospital period is well-documented, but the optimal duration of prophylaxis after surgery remains controversial. Some studies suggest that patients undergoing major abdominopelvic surgery benefit from prolongation of the prophylaxis up to 28 days after surgery. OBJECTIVES: To evaluate the efficacy and safety of prolonged thromboprophylaxis with LMWH for at least 14 days after abdominal or pelvic surgery compared with thromboprophylaxis administered during the in-hospital period only in preventing late onset VTE. SEARCH METHODS: We performed electronic searches on 28 October 2017 in the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, LILACS and registered trials (Clinicaltrials.gov October 28, 2017 and World Health Organization International Clinical Trials Registry Platform (ICTRP) 28 October 2017). Abstract books from major congresses addressing thromboembolism were handsearched from 1976 to 28 October 2017, as were reference lists from relevant studies. SELECTION CRITERIA: We assessed randomized controlled clinical trials (RCTs) comparing prolonged thromboprophylaxis (>= fourteen days) with any LMWH agent with placebo, or other methods, or both to thromboprophylaxis during the admission period only. The population consisted of persons undergoing abdominal or pelvic surgery for both benign and malignant pathology. The outcome measures included VTE (deep venous thrombosis (DVT) or pulmonary embolism (PE)) as assessed by objective means (venography, ultrasonography, pulmonary ventilation/perfusion scintigraphy, spiral computed tomography (CT) scan or autopsy). We excluded studies exclusively reporting on clinical diagnosis of VTE without objective confirmation. DATA COLLECTION AND ANALYSIS: Review authors identified studies and extracted data. Outcomes were VTE (DVT or PE) assessed by objective means. Safety outcomes were defined as bleeding complications within three months after surgery. Sensitivity analyses were also performed with unpublished studies excluded, and with study participants limited to those undergoing solely open and not laparoscopic surgery. We used a fixed-effect model for analysis. MAIN RESULTS: We identified seven RCTs (1728 participants) evaluating prolonged thromboprophylaxis with LMWH compared with control or placebo. The searches resulted in 1632 studies, of which we excluded 1528. One hundred and four abstracts, eligible for inclusion, were assessed of which seven studies met the inclusion criteria.For the primary outcome, the incidence of overall VTE after major abdominal or pelvic surgery was 13.2% in the control group compared to 5.3% in the patients receiving out-of-hospital LMWH (Mantel Haentzel (M-H) odds ratio (OR) 0.38, 95% confidence interval (CI) 0.26 to 0.54; I2 = 28%; seven studies, n = 1728; moderate-quality evidence).For the secondary outcome of all DVT, seven studies, n = 1728, showed prolonged thromboprophylaxis with LMWH to be associated with a statistically significant reduction in the incidence of all DVT (M-H OR 0.39, 95% CI 0.27 to 0.55; I2 = 28%; moderate quality evidence).We found a similar reduction when analysis was limited to incidence in proximal DVT (M-H OR 0.22, 95% CI 0.10 to 0.47; I2 = 0%; moderate quality evidence).The incidence of symptomatic VTE was also reduced from 1.0% in the control group to 0.1% in patients receiving prolonged thromboprophylaxis (M-H OR 0.30, 95% CI 0.08 to 1.11; I2 = 0%; moderate-quality evidence).No difference in the incidence of bleeding between the control and LMWH group was found, 2.8% and 3.4%, respectively (HM-H OR 1.10, 95% CI 0.67 to 1.81; I2 = 0%; seven studies, n = 2239; moderate-quality evidence).Estimates of heterogeneity ranged between 0% and 28% depending on the analysis, suggesting low or unimportant heterogeneity. AUTHORS' CONCLUSIONS: Prolonged thromboprophylaxis with LMWH significantly reduces the risk of VTE compared to thromboprophylaxis during hospital admittance only, without increasing bleeding complications after major abdominal or pelvic surgery. This finding also holds true for DVT alone, and for both proximal and symptomatic DVT. The quality of the evidence is moderate and provides moderate support for routine use of prolonged thromboprophylaxis. Given the low heterogeneity between studies and the consistent and moderate evidence of a decrease in risk for VTE, our findings suggest that additional studies may help refine the degree of risk reduction but would be unlikely to significantly influence these findings. This updated review provides additional evidence and supports the previous results reported in the 2009 review. PMID- 30481367 TI - Biome: evolution of a crucial ecological and biogeographical concept. AB - Biome is and remains a key community ecological and biogeographical concept and as such profited from overall progress of community ecology which was punctuated by two major innovations: shifting focus from pure pattern description to understanding functionality, changing approach from observational to explanatory and, most importantly, from descriptive to predictive. The functional focus enabled development of mechanistic and function-focused predictive and retrodictive modelling; it also shaped the current understanding of the concept of biome as a dynamic biological entity having many faces, deep roots in evolutionary past, and undergoing changes. The evolution of the biome concept was punctuated by three synthetic steps: The First Synthesis formulated a solid body of theory explaining ecological and biogeographical meaning of zonality and collated our knowledge on drivers of vegetation patterns at large spatial scales. The Second Synthesis translated this knowledge into effective mechanistic modelling tools, developing further linking ecosystem functionality and biogeography. The Third Synthesis (still in progress) is seeking common grounds between large-scale ecological and biogeographic phenomena, using tools of macroecology and macroevolutionary research. This article is protected by copyright. All rights reserved. PMID- 30481368 TI - Melanoma of unknown primary. AB - Formally described in the 1960s, melanoma of unknown primary (MUP) is characterized by the finding of metastatic melanoma within the lymph nodes, subcutaneous tissues, and other distant sites without an evident primary lesion. The most likely hypothesis of its etiology is an immune-mediated regression of the primary after metastasis has occurred. In addition, patients with MUP appear to have equivalent or better outcomes compared with patients with known primaries of a similar stage. PMID- 30481369 TI - Tuning Photoinduced Electron Transfer Efficiency of Fluorogenic BODIPY-alpha Tocopherol Analogues. AB - Fluorogenic analogues of alpha-tocopherol developed by our group have been instrumental in monitoring reactive oxygen species (ROS) within lipid membranes. Prepared as two-segment trap-reporter (chromanol-BODIPY) probes, photoinduced electron transfer (PeT) was utilized to provide these probes with an off/on switch mechanism warranting the necessary sensitivity. Herein we rationalize within the context of Marcus theory of electron transfer how substituents on the BODIPY core and linker length joining the trap and reporter segments, tune PeT efficiency. DFT and electrochemical studies were used to estimate the thermodynamic driving force of PeT in our constructs. By tuning the redox potential over a 400 mV range, we observed over an order of magnitude increase in PeT efficiency. Increasing the linker length between the chromanol and BODIPY by 2.8 angstroms in turn decreased PeT efficiency 2.7-fold. Our results illustrate how substituent and linker choice enable "darkening" the off state of fluorogenic probes based on BODIPY fluorophores, by favoring PeT over radiative emission from the singlet excited state manifold. Ultimately, our work brings light to the sensitivity ceiling one may achieve in developing fluorogenic antioxidants analogues of alpha-tocopherol. The work provides general guidelines applicable to those developing fluorogenic probes based on PeT. This article is protected by copyright. All rights reserved. PMID- 30481370 TI - Identifying the barriers to gastric cancer care at safety-net hospitals: A novel comparison of a safety-net hospital to a neighboring quaternary referral academic center in the same healthcare system. AB - BACKGROUND: The three-delays model describes delays in seeking, reaching, and receiving care for vulnerable populations needing treatment. The dominant delay for patients with gastric adenocarcinoma (GAC) is unknown. We aimed to define patients with GAC who reached and received care at our regional safety-net hospital (Grady Memorial Hospital [GMH]) and our neighboring quaternary referral hospital (Emory University Hospital [EUH]). METHODS: Clinicopathologic data from National Cancer Database (NCDB) participating academic centers were compared with GMH from 2004 to 2014. Outcomes of patients undergoing surgery at GMH were compared to those at EUH. RESULTS: At presentation, compared to NCDB centers (n = 69 662), GMH patients (n = 154) were more often black (85.1 vs 17.2%; P < 0.001), uninsured (30.5 vs 4.7%; P < 0.001), have stage IV disease (43.5 vs 30.1%; P = 0.017), and received no treatment (40.3 vs 18.4%; P < 0.001). When only comparing patients who underwent curative-intent resection at GMH (n = 23) to EUH (n = 137), median overall survival was similar between both groups (GMH: median not reached; EUH: 59.8 mos; P = 0.785). CONCLUSION: Although vulnerable patients with GAC within a safety-net hospital present with later stages of the disease, those who received surgery have acceptable outcomes. Thus, efforts should be made to overcome barriers in seeking care. PMID- 30481371 TI - Assessment of hospital-level adjusted breast cancer sentinel lymph node positivity rates. AB - BACKGROUND/OBJECTIVES: Proficiency of performing sentinel lymph node biopsy (SLNB) for breast cancer varies among hospitals and may be reflected in the hospital's SLNB positivity rate. Our objectives were to examine whether hospital characteristics are associated with variation in SLNB positivity rates and whether hospitals with lower-than-expected SLNB positivity rates have worse patient survival. METHODS: Using the National Cancer Data Base, stage I to III breast cancer patients were identified (2004-2012). Hospital-level SLNB positivity rates were adjusted for tumor and patient factors. Hospitals were divided into terciles of SLNB positivity rates (lower-, higher-, as-expected). Hospital characteristics and survival were examined across terciles. RESULTS: Of 438 610 SLNB patients (from 1357 hospitals), 78 104 had one or more positive SLN (21.3%). Hospitals in the low and high terciles were more likely to be low volume (low: RRR, 4.40; 95% CI, 2.89-6.57; P < 0.001; and high: RRR, 1.79; 95% CI, 1.21 2.64; P < 0.001) compared to hospitals with as-expected (middle tercile) SLNB positivity rates. Stage I patients at low- and high-tercile hospitals had statistically worse survival. CONCLUSIONS: There is a wide variation in hospital SLNB positivity rates. Hospitals with lower- or higher-than-expected SLNB positivity rates were associated with survival differences. Hospital SLNB positivity rates may be a novel 'process measure' to report to hospitals for internal quality assessment. PMID- 30481372 TI - There is more than meets the eye: DNA cloning demonstrates high genetic heterogeneity in populations of the subaerial green alga Trentepohlia (Trentepohliales, Chlorophyta)1. AB - Mats of the green alga Trentepohlia, a genus widely distributed in the tropics as well as temperate regions, have always been perceived as homogeneous (i.e., formed by only one species). As such, their general nature and specific feature play a supportive role in the species delimitation. However, a presence of morphologically dissimilar thalli was observed under the light microscope and when cultivating a piece of a single mat. To address this, we performed DNA cloning of the rbcL gene on mat fragments of T. abietina, T. annulata, T. jolithus and T. umbrina sampled in Europe to reveal if they are composed of one or more species. We revealed that more Trentepohlia haplotypes may coexist in a single mat. In consideration of this, we conclude that the use of material isolated in unialgal culture will be almost mandatory for a taxonomic reassessment of this complicated genus. Another direct implication of this problem is that herbarium specimens consisting of field-collected material should not be used for direct sequencing. We further hypothesize the reasons why multiple haplotypes of Trentepohlia occur more frequently in the tuft-like mats. Possibly, fragments and/or cells of other microalgae, including other species of Trentepohlia, might be retained in such mats more easily than in the crustose trentepohlialean mats. This article is protected by copyright. All rights reserved. PMID- 30481373 TI - Laparoscopic synchronous resection of colorectal cancer and liver metastases: A systematic review. AB - While colorectal and hepatic resections are commonly performed through a laparoscopic approach, the safety and feasibility of total laparoscopic synchronous resections (LSR) of colorectal liver metastasis (CRLM) have not been established. In this systematic review, short- and long-term outcomes were comparable for patients undergoing LSR and open synchronous resection. LSR was safe and feasible for patients with synchronous CRLM and should be considered in well-selected patients. PMID- 30481374 TI - A 96-hour continuous wound infiltration with ropivacaine reduces analgesic consumption after liver resection: A randomized, double-blind, controlled trial. AB - BACKGROUND: Continuous wound infiltration (CWI) with local anesthetics to reduce morphine consumption in postoperative pain management after open liver resection in patients with cancer. METHODS: This single-center randomized double-blind study allocated patients requiring resection of liver metastases to receive a 3.75 mg/mL ropivacaine (ROP) infiltration, followed by a 2 mg/mL ROP CWI, or placebo (P) for 96 hours. Postoperative analgesia included acetaminophen and patient-controlled analgesia morphine pump. The primary endpoint was to investigate the reduction of total morphine consumption (mg/kg) over the first 96 postoperative hours. RESULTS: Eighty-five patients were recruited, and randomized (ROP: 42, P: 43) between 2009 and 2014. The median morphine consumption significantly decreased in the ROP arm in the first 96 postoperative hours (ROP: 1.0, P: 1.5 mg/kg; P = 0.026). Twenty-three (27%) patients had grade 3 adverse events (ROP: 14, P: 9) and four experienced grade 3 treatment-related adverse events (ROP: mental confusion [n = 1], hallucinations [n = 2], P: hematoma [n = 1]). Two (5%) patients showed a wound inflammation (ROP: 1, P: 1). Nine (11%) patients experienced at least one serious adverse event (ROP: 6, P: 3); none related to treatment. CONCLUSION: Preperitoneal CWI of 2 mg/mL ROP significantly reduces intravenous morphine consumption during the 96 postoperative hours resulting in an absolute reduction of 0.5 mg/kg. PMID- 30481375 TI - Updates in adjuvant systemic therapy for melanoma. AB - There has been a rapid increase in adjuvant therapies approved for treatment following surgical resection of stages III/IV melanoma. We review current indications for adjuvant therapy, which currently includes a heterogenous group of stages III and IV patients with melanoma. We describe several pivotal clinical trials of systemic immune therapies, targeted immune therapies, and adjuvant vaccine strategies. Finally, we discuss the evidence for selecting the most appropriate treatment regimen(s) for the individual patient. PMID- 30481376 TI - New lymph node staging for rectal neuroendocrine tumors. AB - BACKGROUND AND OBJECTIVES: Current guidelines of the American Joint Commission on Cancer (AJCC) for rectal neuroendocrine tumors (NETs) classify tumor nodal status as N0/N1. This staging does not take into consideration the number of positive lymph nodes. The goal of this study is to determine how the number of positive lymph nodes affects the prognosis for patients with rectal NETs. METHODS: The National Cancer Database was used to identify patients with rectal NETs who underwent rectal resection. Nearest-neighborhood grouping was used to classify patients by survival to create a new nodal staging system. RESULTS: There were 687 patients with rectal NETs. There were distinct 5-year survival estimates for patients with N0 [81.8% (95%CI:77.1%-85.6%)], N1 (1-4 positive lymph nodes) [57.8% (95% confidence interval (CI: 51.2%-63.9%)] and N2 (>=5 positive lymph nodes) [32.6% (95%CI:25.1%-40.3%)] patients, P < 0.0001. Distinct 5-year survival estimates using the new nodal staging system was apparent for patients in the external validation set. After adjusting for predictors of survival in multivariable analysis, the new nodal stage remained an independent predictor of overall survival. CONCLUSIONS: The number of positive locoregional lymph nodes is an independent prognostic factor in rectal NETs. The next AJCC edition should consider classifying patients with rectal NETs as N0, N1, and N2 to provide better estimates of survival for patients. PMID- 30481377 TI - Desmoplastic melanoma. AB - Desmoplastic melanoma (DM) is a rare melanoma variant that has unique biology and pathology compared with conventional melanoma (non-DM). Importantly, DM is classified into pure and mixed histologic subtypes, which have been correlated with outcomes. Management of DM broadly mirrors that of non-DM; however, there are unique considerations for DM that influence treatment approaches. This paper will provide a contemporary overview of this disease and will review the literature regarding the management of DM. PMID- 30481378 TI - Disinfect Porphyromonas gingivalis biofilm on titanium surface with combined application of chlorhexidine and antimicrobial photodynamic therapy. AB - Various antimicrobial modalities have been proposed to treat peri-implantitis but resulted in limited outcomes. The aim of this in vitro study was to evaluate the disinfection efficacy of combined application of chlorhexidine digluconate (CHX) and antimicrobial photodynamic therapy (aPDT) of titanium surfaces previously contaminated with a porphyromonas gingivalis biofilm. P. gingivalis biofilms were grown on 32 polished and 32 sandblasted large-grit acid-etched (SLA) titanium surfaces. Titanium disks were allocated into four groups as follows: (i) immersed in phosphate-buffered saline (PBS), (ii) immersed in 0.2% CHX, (iii) application of aPDT, (iv) immersed in 0.2% CHX and subsequent aPDT. Residual bacteria were determined by microbial culture analysis and by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) imaging. Combination protocol (CHX+ aPDT) was the most effective in eradicating P. gingivalis (P < 0.05) on both polished and SLA surfaces. There was no significant difference in the number of remaining P. gingivalis between polished titanium disks and the SLA ones in four groups (P > 0.05). Under the limitation of this study, combined technique of preceding application of CHX and subsequent aPDT was shown to be an efficient method in reducing P. gingivalis numbers in both polished and SLA titanium surfaces. This article is protected by copyright. All rights reserved. PMID- 30481379 TI - Clinico-pathological features and survival of patients with malignant exocrine pancreatic neoplasms: The AC Camargo Cancer Center experience. AB - BACKGROUND: Pancreatic cancer plays an important role in cancer-related mortality. Few studies have been performed in Brazil to characterize patients affected by this disease. We aimed to describe the clinico-pathological characteristics and the survival of patients with pancreatic cancer seen at AC Camargo Cancer Center (ACCCC). METHODS: We included patients >= 18-year old, with a histologically confirmed diagnosis of exocrine pancreatic cancer, that attended at least one visit at ACCCC from 2008 to 2016. RESULTS: The study included 739 patients. Median age at diagnosis was 64 years. Most patients were male. About 5% presented a family history of pancreatic cancer. A total of 40% had diabetes and 51.4% presented with ECOG performance status 1. Tumors most often arose in the pancreatic head and roughly half of the patients had metastatic disease at presentation. Median overall survival of patients with potentially resectable disease submitted to surgery at ACCCC was 35.4 months. Median overall survival times of patients with the unresectable and metastatic disease were 14.1 and 9.3 months, respectively. CONCLUSIONS: The features of our population match those of studies done in developed countries. We believe multicentric data from patients with pancreatic cancer in Brazil could enable more effective preventive and therapeutic approaches to the disease. PMID- 30481380 TI - Paint by Numbers. PMID- 30481381 TI - Hypomethylation of mismatch repair genes MLH1 and MSH2 is associated with chemotolerance of breast carcinoma: Clinical significance. AB - BACKGROUND AND OBJECTIVES: The aim of the study was to understand the importance of mismatch repair genes MLH1 and MSH2 in chemotolerance and prognosis of breast carcinoma (BC). METHODS: First, the alterations (deletion/methylation/expression) of MLH1 and MSH2 were analyzed in 45 neoadjuvant chemotherapy (NACT)-treated and 133 pretherapeutic BC samples. The chemotolerant BC cells were characterized by treating two BC cell lines MCF-7 and MDA MB 231 with two anthracycline antitumor antibiotics, doxorubicin and nogalamycin. RESULTS: The deletion frequencies were 32% to 38% in MLH1/MSH2 genes and promoter methylation frequencies were 49% to 62% in MLH1 and 41% to 51% in MSH2 in both NACT-treated and pretherapeutic samples. The overall alteration of MLH1 and MSH2 was 58% to 71% in the samples. Reduced messenger RNA (mRNA) and protein expression were found in both the genes and it showed concordance with the molecular alterations. NACT-treated patients showed better prognosis. The chemotherapeutic drug induced increased mRNA/protein expression of the genes in BC cell lines was due to their promoter hypomethylation, as analyzed by quantitative methylation assay. This phenomenon was also evident in NACT-treated BC samples. CONCLUSION: MLH1/MSH2 genes play a critical role in the development of BC. Hypomethylation of MLH1/MSH2 genes might be important in chemotolerance of the disease. PMID- 30481382 TI - Hospital at Home-Plus: A Platform of Facility-Based Care. AB - OBJECTIVES: To describe the evolution of a hospital at home (HaH) program to a HaH with a 30-day posthospitalization transition period (HaH-Plus) and results of a retrospective review of cases. DESIGN: After launching HaH-Plus, we used the same interdisciplinary clinical team to provide acute home-based care for a broader range of home-based acute-level services than originally conceived in the Hospital at Home model. These included a palliative care unit at home (PCUaH), an observation unit at home (OUaH), a post-acute care rehabilitation at home (RaH), and a program for the hospital averse - those patients needing to be in the hospital but who refuse. SETTING: Urban health system. PARTICIPANTS: Individuals 18 years or older residing in specified catchment area with Medicare fee-for service or accepted Medicare/Medicaid Advantage plans requiring facility-based care. INTERVENTION: Provision of facility-based acute-level care at home to 685 participants. MEASUREMENTS: Length of stay, readmission, and mortality. RESULTS: HaH-Plus cared for 685 individuals. The PCUaH had the oldest participants (mean age 87), and all groups were predominantly female and dually eligible for Medicare and Medicaid. Diagnoses and length of stay were similar in all groups except that those in RaH had a larger group of diagnoses, than those accepted in to HaH-Plus and those in OUaH had a shorter stay. Rate of readmission was highest for RaH (19%). Mortality during the active treatment episode was highest for PCUaH and hospital averse as compared to HaH-Plus, OUaH and RaH. CONCLUSION: Providing a broader range of facility-based care in the home has significant advantages for patients and increases the scalability of HaH. Developing a spectrum of services was possible by leveraging a robust, 24-hour HaH team. Community- and home-based care could become a greater part of the U.S. healthcare system if a platform of HaH services along with advances in technology and payment models were developed. PMID- 30481383 TI - The impact of failure to achieve symptom control after resection of functional neuroendocrine tumors: An 8-institution study from the US Neuroendocrine Tumor Study Group. AB - BACKGROUND: The goals of resection of functional neuroendocrine tumors (NETs) are two-fold: Oncological benefit and symptom control. The interaction between the two is not well understood. METHODS: All patients with functional NETs of the pancreas, duodenum, and ampulla who underwent curative-intent resection between 2000 and 2016 were identified. Using Cox regression analysis, factors associated with reduced recurrence-free survival (RFS) were identified. RESULTS: Two-hundred and thirty patients underwent curative-intent resection. Fifty-three percent were insulinomas, 35% gastrinomas, and 12% were other types. Twenty-one percent had a known genetic syndrome, 23% had lymph node (LN) positivity, 80% underwent an R0 resection, and 14% had no postoperative symptom improvement (SI). Factors associated with reduced RFS included noninsulinoma histology, the presence of a known genetic syndrome, LN positivity, R1 margin, and lack of SI. On multivariable analysis, only the failure to achieve SI following resection was associated with reduced RFS. Considering only those patients with an R0 resection, failure to achieve SI was associated with worse 3-year RFS compared with patients having SI (36% vs 80%; P = 0.006). CONCLUSIONS: Failure to achieve symptomatic improvement after resection of functional NETs is associated with worse RFS. These patients may benefit from short-interval surveillance imaging postoperatively to assess for earlier radiographical disease recurrence. PMID- 30481385 TI - Essential Steps to Ensure Publication in Headache (and Any Other Journal of Good Repute). PMID- 30481384 TI - Current management of regional lymph nodes in patients with melanoma. AB - The publication of recent randomized trials has prompted a significant shift in both our understanding and the management of patients with melanoma. Here, the current management of the regional lymph nodes in patients with melanoma is discussed. This review focuses on selection for sentinel lymph node biopsy, management of the positive sentinel node, management of the clinically positive node, and the controversy over the therapeutic value of early nodal intervention. PMID- 30481386 TI - Erratum. PMID- 30481387 TI - Transcriptome monitoring visualizes growth stage-dependent nutrient status dynamics in rice under field conditions. AB - Crop plants undergo morpho-physiological changes throughout the growth process in response to internal and external environment, and which eventually determine yield. However, the system-level adjustment of the morpho-physiological changes has remained largely unclear especially in field conditions. Here, we reveal the changes in nutrient status associated with tiller development and soil conditions based on the leaf transcriptome profile of rice throughout the entire growth. We performed gene co-expression network analysis and identified 3 gene sets as indicators for monitoring the internal nitrogen and phosphorus status. Expression profiling reveals that the phosphorus starvation response is expressed during the tillering stage and concurrently removed with the transition to nitrogen deficiency status. Coincident with the phosphorus status dynamics, the amount of phosphate in leaf is demonstrated to be low during the tillering stage and subsequently increase drastically. The phosphorus dynamics is genetically validated by analysing mutants with a defect in phosphorus homeostasis. Notably, we show that the nitrogen limitation directly suppresses the phosphorus starvation response. Finally, the phosphorus starvation response is demonstrated to be activated in soil with a high phosphate retention capacity without the visible phenotypes associated with phosphorus starvation. Our results uncover growth stage- and soil condition-dependent phosphorus demanding reaction, which would be expressed to promote phosphorus uptake required for developing tillers and directly adjusted by nitrogen status. Molecular framework for elucidating nutrient status dynamics under field conditions would provide insights in improving crop productivity. This article is protected by copyright. All rights reserved. PMID- 30481388 TI - Omalizumab discontinuation in children with severe allergic asthma: an observational real life study. PMID- 30481389 TI - Influence of solvent and a supplementary step with a finishing instrument on filling material removal from canals connected by an isthmus. AB - AIM: To evaluate the effectiveness of a solvent (eucalyptol) in improving filling material removal from canals connected by isthmuses, and the additional cleaning effect of a finishing instrument. METHODOLOGY: The mesial canals from 32 mandibular molars (Vertucci's type II morphology) were instrumented and filled with the single-cone technique using Reciproc R25 gutta-percha points (VDW, Munich, Germany) combined with Sealer 26 (Dentsply, Petropolis, RJ, Brazil). Each root was then subjected to retreatment using the Mtwo instrument system (VDW), with or without a solvent (n=16 per group). The volume of filling material in the canals was assessed by micro-computed tomographic (micro-CT) scans taken before and after retreatment. Canals with remnants of filling material received a supplementary procedure with the XP-endo Finisher R instrument (FKG Dentaire, La Chaux-de-Fonds, Switzerland), with or without eucalyptol, and another micro-CT scan was taken. All retreatment procedures were performed inside a cabinet under a controlled temperature (37 degrees C). Filling material removal was evaluated in the 5-mm apical canal system for the canal+isthmus space or the isthmus alone. Statistical analyses were performed to compare the removal of filling material with and without eucalyptol, and after a supplementary approach with XP-endo Finisher R. The level of significance was set at 5% for all statistical tests (P<0.05). RESULTS: The amount of filling material removed from the canal+isthmus with Mtwo instruments was 83.2% when no solvent was used and 83.8% using the solvent (P>0.05). When the isthmus area was evaluated separately, most specimens were associated with a reduction in the filling material, with no significant difference between the groups with or without using a solvent (P>0.05). The supplementary step with XP-endo Finisher R significantly improved removal of filling material from both canal and isthmus area (P<0.05), regardless of the use of a solvent (P>0.05). CONCLUSION: The use of eucalyptol did not improve filling material removal from Vertucci's type II molar mesial canals and isthmi. XP-endo Finisher R significantly enhanced removal of filling material from the canals and isthmi. PMID- 30481390 TI - Development of a Parents' Short Form Survey of Their Children's Oral Health. AB - BACKGROUND: Parents play an important role in their children's oral health behaviors, provide oral health access, initiate prevention, and coping strategies for health care. AIM: This paper develops a short form (SF) to assist parents to evaluate their children's oral health status using Patient Reported Outcome Measurement Information System (PROMIS) framework that conceptualized health as physical, mental, and social components. DESIGN: Surveys of parents were conducted at dental clinics in Los Angeles County, together with an onsite clinical exam by dentists to determine clinical outcomes, Children's Oral Health Status Index (COHSI) and referral recommendations (RRs). Graded Response Models in Item Response Theory was used to create the SF. A toolkit including SF, demographic information and algorithms were developed to predict the COHSI and RRs. RESULTS: The final SF questionnaire consists of 8 items. The square root means squared error for the prediction of COHSI is 7.6. The sensitivity and specificity of using SF to predict immediate treatment needs (binary RRs) are 85% and 31%. CONCLUSIONS: The parent SF is an additional component of the oral health evaluation toolkit that can be used for oral health screening, surveillance program, policy planning and research of school-aged children and adolescents from guardian perspectives. This article is protected by copyright. All rights reserved. PMID- 30481391 TI - Simultaneous detection of multiple hydroxylated polychlorinated biphenyls from biological samples using ultra-high performance liquid chromatography/isotope dilution tandem mass spectrometry. AB - In this paper, we established a method for the separation and detection of nine hydroxylated polychlorinated biphenyls in whole blood and urine samples using UPLC coupled with electrospray negative ionization tandem-mass spectrometry. Clean-up procedures involved a filtration step, and optimization involved a pretreatment step consisting of a simple liquid-liquid extraction, using hydrated silica-gel chromatography (5%). Nine hydroxylated polychlorinated biphenyls were separated on a UPLC HSS T3 column using a gradient elution program of 2 mmol ammonium formate aqueous solution (A), and methanol (B). Recovery ranged from 84.0%-105.4% for the nine different hydroxylated polychlorinated biphenyls in urine with three spiked levels of 0.1, 1, and 2 ng and from 73.5%-98.6% for the blood with spiked levels of 0.2, 1, and 2 ng. The relative standard deviations were less than 8.7% (n = 6), and the limits of detection in urine and whole blood for the nine hydroxylated polychlorinated biphenyls were in the range of 1.5-4.0 pg/g and 20-100 pg/g respectively. This analytical method may enable the simultaneous detection of various hydroxylated polychlorinated biphenyls from complex tissue matrices. This article is protected by copyright. All rights reserved. PMID- 30481392 TI - Reversible transformation between a [PdL2]2+ "figure-of-eight" complex and a [Pd2L2]4+ dimer: switching on and off self-recognition. AB - Structural changes to metallosupramolecular assemblies resulting in the release or uptake of guests are well established whereas transformations turning on and off specific self-recognition are far less developed. We report a novel ligand (2,6-bis(1-(3-pyridin-4-yl)phenyl-1H-1,2,3-triazol-4-yl)pyridine) possessing a tridentate central metal-binding site flanked by two pendant pyridyl arms. In a 2:1 ratio with PdII metal ions, a spiro-type [PdL2]2+ "figure-of-eight" complex forms with the central tridentate binding pocket unoccupied. Introduction of an additional one equivalent of PdII metal ion results in the conversion to a dimeric [Pd2L2]4+ molecule with the tridentate pocket occupied. There is site specific self-recognition between dimers in solution with strong NOE peaks between adjacent molecules. The self-recognition between dimers can be turned off in two ways: firstly, adding another equivalent of PdII metal ion brings about binding to the previously uncoordinated pyridyl arms which are key to the self recognition event, and; secondly, addition of sufficient ligand to return the stoichiometry to 2:1 regenerates the [PdL2]2+ complex. Hence the self-recognition event can be turned on or off through simple variation of L:PdII stoichiometry. PMID- 30481393 TI - Satisfaction with shortening the palatal extension of a mouthguard for water polo players: A randomized crossover study. AB - BACKGROUND/AIM: Approximately 50% of water polo players have suffered orofacial injuries. However, fewer than 8% of players wear a mouthguard. A more comfortable mouthguard design is therefore needed to increase compliance. The aim of this study was to assess the effect of reducing the palatal extension of a custom-made mouthguard on the degree of satisfaction with a mouthguard among water polo players. MATERIAL AND METHODS: Eighteen elite water polo players participated in this randomized crossover trial. Two custom-made mouthguards were fabricated for each participant using 4-mm-thick ethyl vinyl acetate foils, defined by the extension of the palatal margin from the cervical line: conventional (6 mm) and shortened (2 mm). The mouthguards were worn during all training sessions and matches, in a randomized sequence (one mouthguard type for the first and fourth weeks and the other for the second and third weeks). Mouthguards were evaluated on 10-point scales for discomfort, interference with oral functions, protection, and general satisfaction after each training session or match. RESULTS: Players evaluated the shortened mouthguard as having less interference with speech (Effect 1.30; P<0.001), breathing (Effect 0.98; P=0.004), swallowing (Effect 1.30; P<0.001), and athletic performance (Effect 0.61; P=0.03) compared with the conventional mouthguard. The perceived degree of protection was similar among participants when wearing each type of mouthguard. Overall, players were more satisfied with the shortened mouthguard (Effect 0.64; P=0.03). CONCLUSIONS: Reducing the palatal extension of a custom-made mouthguard from 6 to 2 mm improves the overall satisfaction of elite water polo players without affecting the perceived degree of protection. This article is protected by copyright. All rights reserved. PMID- 30481394 TI - Bone infarction of the hip after hand allotransplantation: A case report. AB - Vascularized composite allotransplantation represents as an emerging field in reconstructive surgery. However, some complications can be associated with the procedure. The authors describe a case of bone infarctions of the bilateral hip joints following the first hand allotransplantation in Taiwan. A 45-year-old man who experienced a traumatic amputation of the distal third of his forearm received a hand transplantation from a brain-dead donor. Immunosuppression included antithymocyte globulins, and bolus methylprednisolone (Solu-Medrol) was used for the induction. The maintenance therapy protocol included systemic tacrolimus, mycophenolate mofetil, and prednisone. The patient discontinued the systemic steroid 15 months after surgery. Two episodes of acute rejections were observed at 105 and 810 days after surgery. These signs disappeared after pulse therapy with Solu-Medrol, titration with tacrolimus, and topical immunosuppressive creams (tacrolimus and clobetasol). However, the patient felt pain in both hips after long periods of standing 30 months after the transplantation. A pelvic radiograph and magnetic resonance imaging revealed avascular necrosis (AVN) in both hip joints. Because of the progressive worsening of the pain, the patient underwent a decompression surgery on the left hip involving a fibula bone graft. The patient underwent a right hip hemi arthroplasty with a bipolar prosthesis 3 months later. The patient remained in good health without major complications. These findings indicate that systemic steroids and tacrolimus might be the major predisposing factors for the induction of AVN after hand allotransplantation. PMID- 30481395 TI - Synergistic Antifungal Activity of Isoquercitrin: Apoptosis and Membrane Permeabilization Related to Reactive Oxygen Species in Candida albicans. AB - Isoquercitrin (ISO), one of phytochemical isolated from aerial parts of Aster yomena, has been reported to have antifungal activity. However, the synergistic effect and the mechanism of ISO in combination with conventional antifungal agents are poorly understood. Therefore, synergistic antifungal effect between ISO and conventional antifungal agents was investigated. ISO at non-antifungal concentration interacts synergistically with amphotericin B (AMB) and fluconazole (FLC), but the combination with flucytosine (5-FC) showed no interaction. ISO disrupted an antioxidant system by inhibiting the activity of superoxide dismutase. This redox imbalance was shown to induce intracellular reactive oxygen species (ROS) accumulation and oxidative stress. ISO combined with FLC caused metacaspase activation and DNA condensation, markers of apoptosis, higher than the combination with ISO/AMB. In contrast, ISO with AMB synergistically stimulated membrane permeabilization compared to ISO/FLC. Scavenging ROS consequently reduced the synergy-induced apoptosis and membrane permeabilization, indicating combinations induced ROS were associated with the synergy effect of ISO. In conclusion, AMB and FLC enhanced the antifungal potency of ISO through oxidative stress when used in synergy. (c) 2018 IUBMB Life, 9999(9999):1-10, 2018. PMID- 30481396 TI - Harold Lewis Dibble (July 26, 1951-June 10, 2018). PMID- 30481397 TI - A minimal sequence for left-handed G-quadruplex formation. AB - Recently, we observed the first example of a left-handed G-quadruplex structure formed by natural DNA, named Z-G4. We analysed the Z-G4 structure and inspected its primary 28-nt sequence in order to identify motifs that convey the unique left-handed twist. Using CD, NMR spectroscopy and X-ray crystallography, we revealed a minimal sequence motif of 12 nt GTGGTGGTGGTG for the left-handed DNA G quadruplex formation, which is found to be highly abundant in the human genome. A systematic analysis of thymine loop mutations revealed a moderate sequence tolerance, which would further broaden the space of sequences prone to left handed G-quadruplex formation. PMID- 30481398 TI - UV-C priming of strawberry leaves against subsequent Mycosphaerella fragariae infection involves the action of ROS, plant hormones and terpenes. AB - UV-C radiation has been reported to induce defence responses to pathogens in growing crops and described as a new environmentally friendly method for disease control. However, whether the effect of the induced defence mechanisms will persist after the stress imposed by UV-C is alleviated, and how these mechanisms interact with pathogen elicitors upon infection has not yet been investigated. Thus, we inoculated strawberry plants with Mycosphaerella fragariae, the causal agent of leaf spot disease, after 5 weeks of repeated UV-C irradiation treatment (cumulative dose of 10.2 kJ m-2 ) and investigated the alteration of gene expression and biochemical phenotypes. The results revealed that UV-C treatment had a significant impact on gene expression in strawberry leaves and led to the overexpression of a set of genes involved in plant-pathogen interaction. UV-C treated leaves displayed a stronger response to infection after inoculation, with reduced symptoms and increases in accumulation of total phenolics and volatile terpenes, higher expression of pathogenesis-related proteins and the activity of several defence enzymes. This study presumptively describe, for the first time, the involvement of terpenes, ROS, as well as abscisic acid, salicylic acid, jasmonic acid and their transduction factors, in the network underpinning UV-C priming of growing crops for improved protection against pathogens. PMID- 30481399 TI - High salt diet impairs cerebral blood flow regulation via salt-induced angiotensin ii suppression. AB - OBJECTIVES: This study sought to determine whether salt-induced angiotensin II suppression contributes to impaired cerebral blood flow (CBF) autoregulation. METHODS: Cerebral autoregulation was evaluated with laser-Doppler flowmetry during graded reductions of blood pressure. Autoregulatory responses in rats fed high salt (HS; 4% NaCl) diet vs low salt (LS; 0.4% NaCl) diet were analyzed using linear regression analysis, model-free analysis, and a mechanistic theoretical model of blood flow through cerebral arterioles. RESULTS: Autoregulation was intact in LS-fed animals as mean arterial pressure (MAP) was reduced via graded hemorrhage to approximately 50 mmHg. Short term (3 days) and chronic (4 weeks) HS diet impaired CBF autoregulation, as evidenced by progressive reductions of laser Doppler flux with arterial pressure reduction. Chronic low dose angiotensin II infusion (5 mg/kg/min, i.v.) restored CBF autoregulation between the pre hemorrhage MAP and 50 mm Hg in rats fed short term HS diet. Mechanistic-based model analysis showed a reduced myogenic response and reduced baseline vascular smooth muscle tone with short-term HS diet, which was restored by angiotensin II infusion. CONCLUSIONS: Short term and chronic HS diet lead to impaired autoregulation in the cerebral circulation, with salt-induced ANG II suppression as a major factor in the initiation of impaired CBF regulation. This article is protected by copyright. All rights reserved. PMID- 30481400 TI - Ischemic preconditioning improved renal ischemia/reperfusion injury and hyperglycemia. AB - Renal ischemia/reperfusion (I/R) is an alternation of renal hemodynamics, which results in diverse postischemic responses and eventually acute kidney injury. Although renal ischemic preconditioning (IPC) is known to protect the kidney from I/R injury, the precise renoprotective mechanisms are not completely understood. The multiple renoprotective effects of IPC underscore the importance in understanding molecular mechanisms and the targets of action involved. This study aimed to identify the biochemical changes in renal I/R injury and investigate the renoprotective mechanisms of IPC. Herein, renal I/R was produced in adult male Sprague-Dawley rats through the bilateral ligation of renal pedicles for 45 min, followed by reperfusion for 24 h. For the IPC group, rats were subjected to three cycles of 2-min ischemia, followed by a 5-min reperfusion, 15 min prior to renal I/R. Our data confirmed the beneficial effects that IPC has on renal I/R injury. IPC-mediated renoprotection was associated with the resolution of oxidative stress, inflammation, apoptosis, and hyperglycemia. Among the numerous signaling molecules involved in the renoprotective mechanisms of IPC, an elevated protein expression of Nrf2, HO-1, LC3 II conversion, along with Atg12 and protein phosphorylation of AMPK, as well as a decreased protein phosphorylation of ERK, p38 MAPK, and Akt and NF-kappaB DNA binding activity were identified. Importantly, the post renal I/R overproduction of counter-regulatory hormones, impaired hepatic insulin action, and augmented hepatic gluconeogenesis were improved through IPC. As counter-regulatory hormones have been implicated in the induction of oxidative stress, inflammation, apoptosis, impaired insulin action, hyperglycemia, and tissue destruction, our findings suggest that counter regulatory hormones may well be valuable targets of IPC for combatting renal I/R injury. (c) 2018 IUBMB Life, 2018. PMID- 30481401 TI - Head trauma in sports - clinical characteristics, epidemiology and biomarkers. AB - Traumatic brain injury (TBI) is clinically divided into a spectrum of severities, with mild TBI being the least severe form and a frequent occurrence in contact sports, such as ice hockey, American football, rugby, horse riding and boxing. Mild TBI is caused by blunt non-penetrating head trauma that causes movement of the brain and stretching and tearing of axons, with diffuse axonal injury being a central pathogenic mechanism. Mild TBI is in principle synonymous with concussion; both have similar criteria in which the most important elements are acute alteration or loss of consciousness and/or post-traumatic amnesia following head trauma and no apparent brain changes on standard neuroimaging. Symptoms in mild TBI are highly variable and there are no validated imaging or fluid biomarkers to determine whether or not a patient with a normal computerized tomography scan of the brain has neuronal damage. Mild TBI typically resolves within a few weeks but 10-15% of concussion patients develop post-concussive syndrome. Repetitive mild TBI, which is frequent in contact sports, is a risk factor for a complicated recovery process. This overview paper discusses the relationships between repetitive head impacts in contact sports, mild TBI and chronic neurological symptoms. What are these conditions, how common are they, how are they linked and can they be objectified using imaging or fluid-based biomarkers? It gives an update on the current state of research on these questions with a specific focus on clinical characteristics, epidemiology and biomarkers. This article is protected by copyright. All rights reserved. PMID- 30481402 TI - Prevalence and characteristics of hepatitis E virus infection in kidney transplant recipients: a single-center experience in Japan. AB - BACKGROUND: Hepatitis E virus (HEV) infection can lead to chronic hepatitis in solid organ transplant recipients. To investigate whether HEV infection influences outcomes following kidney transplantation, we examined the prevalence of HEV infection and clinical characteristics of kidney transplant recipients in our hospital. METHODS: Our cross-sectional study included 184 kidney transplant recipients. Blood samples were obtained from all patients to detect anti-HEV immunoglobulin (Ig)A, IgM, and IgG by enzyme-linked immunosorbent assay and HEV RNA by reverse transcription-polymerase chain reaction. Clinical data were collected from medical charts for all patients. RESULTS: The prevalence of anti HEV IgG was 8/184 (4.3%). Anti-HEV IgA, anti-HEV IgM, and HEV RNA were not detected in any patients. Compared to their anti-HEV IgG-negative counterparts, anti-HEV IgG-positive patients were significantly older at the time of transplantation, and they were more likely to receive kidneys from deceased donors. No significant differences in other characteristics such as the prevalence of primary cause of end-stage renal disease, blood transfusion, and immunosuppressive therapy use; liver and renal function; and the frequencies of hepatitis B and hepatitis C virus infection were observed according to the patients' anti-HEV IgG status. CONCLUSION: HEV infection had no significant influence on the outcomes of kidney transplantation at our institution. However, HEV infection should be recognized in kidney transplant recipients similarly as hepatitis B and hepatitis C virus infection in cases of liver dysfunction. This article is protected by copyright. All rights reserved. PMID- 30481403 TI - IL-17A-mediated ERK1/2/p65 Signaling Pathway is Associated with Cell Apoptosis after Non-alcoholic Steatohepatitis. AB - Interleukin (IL)-17A is pro-inflammatory cytokine which has been identified as a noninvasive marker of the pathogenesis of non-alcoholic steatohepatitis (NASH). However, the underlying role of IL-17A in NASH progression remains unclear. This study was designed to investigate the biological function and molecular mechanism of IL-17A in the induction of NASH. The results showed that IL-17A was highly expressed in high-fat diet (HFD)-induced NASH mouse model. Intravenous injection of IL-17A exacerbated steatohepatitis process via promoting hepatocyte apoptosis. Furthermore, IL-17A-induced apoptosis was mediated by ERK1/2/p65 signaling pathway. In conclusion, we demonstrated that IL-17A-mediated ERK1/2/p65 signaling pathway was a promising target for the treatment of NASH. (c) 2018 IUBMB Life, 1 8, 2018. PMID- 30481404 TI - Circulating cell-free microRNAs in cutaneous melanoma staging and recurrence or survival prognosis. AB - Cutaneous melanoma is a skin cancer with increasing incidence. Identification of novel clinical biomarkers able to detect the stage of disease and suggest prognosis could improve treatment and outcome for melanoma patients. Cell-free microRNAs (cf-miRNAs), are the circulating copies of short non-coding RNAs involved in gene expression regulation. They are released into the interstitial fluid, are detectable in blood and other body fluids and have interesting features of ideal biomarker candidates. They are stable outside the cell, tissue specific, vary along with cancer development and are sensitive to change in the disease course such as progression or therapeutic response. Moreover, they are accessible by non-invasive methods or venepuncture. Some articles have reported different cf-miRNAs with the potential of diagnostic tools for melanoma staging, recurrence and survival prediction. Although some concordance of results is already emerging, differences in analytical methods, normalization strategies and tumour staging still will require further research and standardization prior to clinical usage of cf-miRNA analysis. This article reviews this literature with the aim of contributing to a shared focusing on these new promising tools for melanoma treatment and care. This article is protected by copyright. All rights reserved. PMID- 30481405 TI - Direct evidence for ferrous ions oxidation and incorporation in absence of oxidants by Dps from Marinobacter hydrocarbonoclasticus. AB - Dps (DNA-binding protein from starved cells) proteins are hollow sphere shaped, dodecameric enzymes found in bacteria and archaeal species. They are able to oxidize ferrous iron in a controlled manner using hydrogen peroxide or molecular oxygen as co-substrate and most of them confer physical protection through DNA binding. Oxidized iron is stored, as a mineral core, in a central cavity. In this study, we provide direct evidence that, in addition to these activities, Dps proteins containing small mineral cores are also able to oxidize and mineralize toxic ferrous ions in anaerobic conditions and in the absence of any additional aqueous oxidant co-substrate. We found that Dps proteins containing cores of 24 irons per dodecamer can oxidize ca. 5 ferrous irons per dodecamer, with that number approximately doubling for protein particles containing in average 96 irons per protein. This additional activity carries importance as it can be a detoxification mechanism present during anaerobic, or oxygen limited, growth conditions. PMID- 30481406 TI - Neotropical frogs and mating songs: The evolution of advertisement calls in glassfrogs. AB - Anurans emit advertisement calls with the purpose of attracting mates and repelling conspecific competitors. The evolution of call traits is expected to be associated with the evolution of anatomical and behavioral traits due to the physics of call emission and transmission. Additionally, since vocalizing might imply a trade-off with investment in parental care, the evolution of calls is expected to trade-off with parental care. Here, we investigated the association between body size, calling site, parental care and call properties (call duration, number of notes, peak frequency, frequency bandwidth and call structure) of the advertisement calls of glassfrogs (Centrolenidae)-a family of Neotropical, leaf-dwelling anurans-using phylogenetic comparative methods. We also explored the tempo and mode of evolution of these traits and compared them with those of three morphological traits associated with body size, locomotion and feeding. We generated and compiled acoustic data for 72 glassfrog species (46% of total species richness), including representatives of all genera. We found that almost all acoustic traits have significant, but generally modest, phylogenetic signal. Peak frequency of calls is significantly associated with body-size, while call structure is significantly associated with calling site and paternal care. Thus, the evolution of body size and calling site could constrain call evolution. The estimated disparity of acoustic traits was larger than that of morphological traits and the peak in disparity of acoustic traits generally occurred later in the evolution of glassfrogs, indicating a historically recent outset of the acoustic divergence in this clade. This article is protected by copyright. All rights reserved. PMID- 30481407 TI - Meaning in Life and Self-Esteem Help Hospice Nurses Withstand Prolonged Exposure to Death. AB - AIM: The purpose of this study was to investigate relationships between the presence of and search for meaning in life and self-esteem, psychological distress, burnout, and affect among hospice nurses. BACKGROUND: The nature of hospice nursing may prompt existential concerns. METHOD: Hospice nurses (N = 90) completed an online survey. RESULTS: The presence of meaning in life was associated with lower psychological distress, burnout, and negative affect, and higher levels of positive affect, whereas the search for meaning in life was only associated with higher negative affect. Self-esteem mediated the relationship between the presence of meaning in life and psychological distress, burnout, and negative affect. CONCLUSION: The presence of meaning in life promotes self esteem, which then buffers against negative outcomes. IMPLICATION FOR NURSING MANAGEMENT: Although managers cannot directly instill meaning in life in hospice nurses, they may be able to help nurses find or maintain meaning by promoting policies that allow them to participate in meaningful personal, cultural, or religious activities. Additionally, managers of hospice nurses could connect them with resources (e.g., mentors, counselors, or chaplains) to cope with the existential demands of providing end-of-life care. This article is protected by copyright. All rights reserved. PMID- 30481409 TI - Predation drives recurrent convergence of an interspecies mutualism. AB - Mutualisms are important ecological interactions that underpin much of the world's biodiversity. Predation risk has been shown to regulate mutualism dynamics in species-specific case studies; however, we lack studies which investigate whether predation can also explain broader patterns of mutualism evolution. We report that fish-anemone mutualisms have evolved on at least 55 occasions across 16 fish families over the past 60 million years and that adult body size is associated with the ontogenetic stage of anemone mutualisms: larger bodied species partner with anemones as juveniles, while smaller-bodied species partner with anemones throughout their lives. Field and laboratory studies show that predators target smaller prey, that smaller fishes associate more with anemones, and that these relationships confer protection to small fishes. Our results indicate that predation is likely driving the recurrent convergent evolution of fish-anemone mutualisms and suggest that similar ecological processes may have selected convergence in interspecies interactions in other animal clades. PMID- 30481410 TI - States move to bring value-based pay to community health centers. AB - More states are establishing reimbursement models that pay federally qualified health centers for value-based services such as at-hone visits, transportation services and telehealth. PMID- 30481411 TI - Fate of Medicaid expansion rests with senators from drug-torn states. AB - Two senators who represent states at the epicenter of the nation's opioid addiction crisis find themselves at the turbulent center of the Republican drive to repeal and replace Obamacare. PMID- 30481412 TI - Push is on to lift Medicaid restrictions on substance abuse centers. AB - Allowing substance abuse centers to be reimbursed under Medicaid could open more beds to patients in need, experts say. PMID- 30481413 TI - Most physicians have given up on owning a practice for joining larger networks. PMID- 30481414 TI - 'If I were a children's hospital, I'd be screaming from the rooftops'. AB - Andy Slavitt knows a thing or two about saving a sinking ship. In October 2013, Slavitt, then an executive at UnitedHealth Group's Optum division, was asked by the Obama administration to help rescue the falteringHealthCare.gov. As principal deputy administrator and then acting administrator at the CMS, Slavitt was unusually direct. Since leaving the agency this year, he's even more outspoken and is one ofthe most prominent voices opposing the GOP's efforts to repeal and replace the Affordable Care Act. He's strongly advocatedforsavingMedicaid and ensuring that the individual market remains accessible. Slavitt, now a senior adviser to the Avia Innovator Network, recently spoke with Modern Healthcare reporter Mara Lee about the ongoing repeal-and-replace debate. The following is an edited transcript. PMID- 30481415 TI - Frequent employee training helps stave off ransomware. AB - With ransomware attacks on the rise, hospitals are turning to employee training to keep their data safe. PMID- 30481416 TI - Healthuare boards need more diversity, but pace of change is 'glacial'. AB - Hospital and healthcare boards are adding newcomers at a slow pace, though consumerism and reimbursement changes are demanding new skill sets for trustees. PMID- 30481417 TI - It's now or never to fix next year's exchange rates. AB - As the ad hoc committee of 13 Republican senators rethinks the increasingly unpopular American Health Care Act, Congress and the administration face a more pressing question. Will they stabilize the individual insurance market for 2018? PMID- 30481418 TI - Integrated 'academic health system' offers new lessons for improving care delivery. AB - Academic medicine generates the knowledge every physician uses today when practicing contemporary, evidence-based medicine. To meet current challenges in healthcare, however, academic medicine must broaden its focus to include the science of how we improve the delivery of care. PMID- 30481419 TI - When the therapist is a piece of software. PMID- 30481421 TI - Largest professional societies and healthcare associations Ranked by 2015 revenue, based on Modern Healthcare's review of IRS Form 990s. PMID- 30481420 TI - 'We need to have as many Americans covered as possible'. AB - Unable to influence debate in the House of Representatives on the American Health Care Act, lobbyists and trade group executives are hoping for a more receptive ear in the Senate. "It really is a new day," said Chip Kahn, CEO of the Federation of American Hospitals, alluding to the fact that key Senate leaders have said they are writing their own bill. Among the federation's top priorities, Kahn said, is addressing Medicare cuts enacted in the Affordable Care Act, especially if a new law results in dramatic increases in the uninsured. Kahn recently spoke with Modern Healthcare Managing Editor Matthew Weinstock about the health reform debate, as well as Kahn's call to streamline quality measures. The following is an edited transcript. PMID- 30481423 TI - Valeant CEO is the healthcare industry's highest-paid executive ...if he meets his numbers. PMID- 30481422 TI - Insurers unhappy with White House's ACA marketplace concessions. AB - As the deadline for setting next year's premium rates looms, insurers are losing patience and hope the Trump administration will do enough to stabilize the individual insurance marketplace. PMID- 30481424 TI - Weighing CON laws against push for greater price transparency. AB - Controversial certificate-of-need laws could be replaced with regulations that offer transparency around prices and outcomes to encourage competition in markets, some economists say. PMID- 30481425 TI - Quality suffers, costs rise as hospital systems consolidate. PMID- 30481426 TI - In Medicare, states are far from equal. PMID- 30481427 TI - Low rates could drive insurers from Medicaid managed-care plans. PMID- 30481428 TI - Trump budget cuts threaten response to Zika and other disease outbreaks. AB - Extreme weather events coupled with milder winters as global temperatures rise have created environments that are breeding ground for diseases, including mosquito-borne infections. PMID- 30481430 TI - Tapping federal safety data to reduce hospital infection rates. AB - New CDC initiative enables facilities to pinpoint hot spots and develop solutions. PMID- 30481429 TI - Insurers moving slowly to improve addiction treatment but ACA repeal efforts could roll back progress. AB - Health insures make patients and their families jump through too many hoops to get coverage for needed inpatient and outpatient addiction care, including medication-assisted treatment. PMID- 30481431 TI - Curing the sickness at the heart of healthcare. AB - Who's responsible for making the U.S. healthcare system the most expensive in the world? If you are a top hospital or insurance executive, a well-paid physician or a drug company official or stockholder, the answer lies in the mirror. PMID- 30481433 TI - Making wellness programs personal. PMID- 30481432 TI - Using a systems approach in healthcare could eliminate much of what ails the industry. AB - I cannot recall a time during my 35 years in healthcare when changes in reimbursement models, government regulations, quality measures an cost controls were not being debated, planned or implemented. PMID- 30481434 TI - 'Climate change is the greatest public health threat we have'. AB - The Obama administration's public health efforts focused on acknowledging that social factors such as poverty and food insecurity affect the health outcomes of communities. The election of Donald Trump worries public health experts such as Dr. Georges Benjamin, executive director of the American Public Health Association, who sat down with Modern Healthcare reporter Steven Ross Johnson to discuss what's next for public health under a Trump administration and where he sees opportunities for collaboration in a potential post-ACA world. The following is an edited transcript. PMID- 30481436 TI - Silence from healthcare CEOs on AHCA politics is deafening. AB - Healthcare CEOs are hiding behind industry lobbying groups instead of publicly using their power to push for changes in the Republicans' healthcare reform bill. PMID- 30481435 TI - Providers' AHCA worries rise after latest CBO analysis. AB - The Congressional Budget Office estimated that 23 million people would lose health coverage by 2026 under the American Health Care Act. PMID- 30481437 TI - Patient preferences tug hospital spending toward outpatient facilities. AB - Hospital systems have begun in earnest to shift more of their capital spending to outpatient facilities to provide more cost-effective and convenient settings for consumers. PMID- 30481438 TI - Addressing behavioral health to improve all health. AB - More than a quarter of adults in the U.S. experience some type of behavioral health disorder in a given year, according to the Centers for Disease Control and Prevention. PMID- 30481439 TI - Minnesota deploys telehealth to expand mental health access to rural areas. PMID- 30481440 TI - Houston Police Department a leader in helping officers deal with mental health encounters. PMID- 30481441 TI - Everyone agrees mental health reform is essential, but will last year's promises be fulfilled? AB - Most of the systematic change has to be done in each community, with the federal government providing the financing. There's not a silver bullet. PMID- 30481443 TI - Mission Health finds solutions for better serving psych patients in the ED. AB - Mission Hospital has a special holding area for psych patients in its emergency department. PMID- 30481442 TI - Missouri tests new federal community mental health model. PMID- 30481444 TI - AHCA is an extremist attack on public health. AB - Anyone who knows anything about healthcare didn't need a Congressional Budget Officer scorecard to understand the disastrous consequences of the American Health Care Act. PMID- 30481445 TI - A 'learning system' in behavioral health can help in sharing best practices, innovations. AB - While the U.S. healthcare system's embrace of different health information technologies is still a work in progress, new models of capturing and sharing health data have already begun to transform the way healthcare providers practice medicine in this country. PMID- 30481447 TI - 'Too much money is going into correctional costs for people with untreated mental illness'. AB - For nearly 20 years, Miami-Dade Circuit Judge Steven Leifman has coordinated the work of state and local agencies in diverting mentally ill people from the jail system and getting them into comprehensive residential and outpatient recovery services. He was a top contender for the new HHS assistant secretary position in charge of mental health and substance abuse policy. In an interview with Modern Healthcare senior reporter Harris Meyer, Leifman described the structural reforms he believes are needed in mental healthcare and what the federal government must do to achieve those improvements. The following is an edited transcript. PMID- 30481446 TI - Making appointments a click away. PMID- 30481448 TI - Largest behavioral health providers: Ranked by 2015 net patient revenue, based on CMS cost report data. PMID- 30481449 TI - Surface Acoustic Wave Nebulization with Atmospheric-Pressure Chemical Ionization for Enhanced Ion Signal. AB - Many ambient desorption/ionization mass spectrometry (ADI-MS) techniques rely critically on thermal desorption. Mean-while, the analyte classes which are successfully studied by any particular ADI-MS are strongly dependent on the type of ionization source. Generally, spray-based ionization sources favor polar analytes, whereas plasma-based sources can be used for more hydrophobic analytes and more suitable for molecules with small molar masses. In the present work, classic atmos-pheric-pressure chemical ionization (APCI), is used. To provide improved desorption performance for APCI, a surface acous-tic wave nebulization (SAWN) device was implemented to convert liquid analytes into fine airborne particles. Compared to conventional SAWN that is used solely as an ionization source for liquid samples, the coupling of SAWN and APCI signif-icantly improves ion signal by up to four-orders of magnitude, reaching comparable ion abundances to electrospray ioniza-tion (ESI). Additionally, this coupling also extends the applicable mass range of an APCI source, conventionally known for the ionization of small molecules <500 Da. Herein, we discuss cursory evidence of this applicability to a variety of analytes including both polar and non-polar small molecules, and novel peptides that mimic biomolecules upwards of 1000 Da. Ob served species are similar to ESI-derived ions including doubly charged analyte ions despite presumably different charging mechanisms. SAWN-APCI coupling may thus involve more nuanced ionization pathways in comparison to other ADI ap proaches. PMID- 30481450 TI - Quantitative determination of protein-ligand affinity by size exclusion chromatography directly coupled to high-resolution native mass spectrometry. AB - High throughput protein-ligand interaction screening assays employing mass spectrometric detection are widely used in early stage drug discovery. Mass spectrometry-based screening approaches employ a target protein added to a pool of small mole-cule compounds, and binding is assessed by measuring ligands denatured from the complexes. Direct analysis of protein-ligand interaction using native mass spectrometry has been demonstrated, but is not widely used due to the detection limit on protein size, the requirement of volatile buffers, and the necessity for specialized instrumentation to preserve weak interac-tions under native conditions. Here we present a robust, quantitative and automated online size-exclusion chromatography-native mass spectrometry (SEC-nMS) platform for measuring affinities of non-covalent protein-small molecule interactions on an Orbitrap mass spectrometer. Indoleamine 2,3-dioxygenase 1, a catabolic enzyme, and inhibitory ligands, were em-ployed as a demonstration of the method. Efficient separation and elution enabled preservation of protein-ligand complexes and increased throughput. The high sensitivity and intra charge state resolution at high m/z offered by the Exactive Plus EMR Orbitrap allowed for protein ligand affinity quantitation, and resolved individual compounds close in mass. Vc50 val ues determined via collision-induced dissociation experiments enabled the evaluation of complex stability in the gas phase and were found to be independent of the extent of complex formation. For the first time, Vc50 determinations were achieved on an inline SEC-nMS platform. Systematic comparison of our method with optimized chip-based nanoelectrospray infusion served as a reference for ligand screening and affinity quantitation, and further revealed the advantages of our online SEC-nMS platform. PMID- 30481451 TI - Mechanism investigation of advanced metal-ion-mediated amine regeneration: a novel pathway to reducing CO2 reaction enthalpy in amine-based CO2 capture. AB - The high energy consumption of CO2 and absorbent regeneration is one of the most critical challenges facing commercial application of amine-based post-combustion CO2 capture. Here, we report a novel approach of metal-ion-mediated amine regeneration (MMAR) to advance the process of amine regeneration. MMAR uses the dual ability of amine to reversibly react with CO2 and reversibly complex with metal ions to reduce the enthalpy of the CO2 reaction, thus decrease the overall heat requirement for amine regeneration. To elucidate the mechanistic effects behind MMAR's ability to reduce CO2 reaction enthalpy, we developed a comprehensive chemical model describing the chemistry of Me(II) monoethanolamine(MEA)-CO2-H2O system. The model was then validated using experimentally determined CO2 partial pressures via vapour-liquid equilibrium (VLE) measurements. We used the validated chemical model to gain insight into VLE behaviour and solution chemistry, and to identify the specific changes in CO2 reaction enthalpy with and without metal ions. Two metals and five amines were evaluated in detail, which revealed that metal-ions with high complexation enthalpy and amines with large carbamate stability constant are preferred in MMAR, owing to their large reduction in reaction enthalpy and regeneration duty. We anticipate that MMAR could provide an alternative pathway to reducing the energy consumption of absorbent regeneration, ultimately making amine-based processes more technically and economically viable. PMID- 30481452 TI - Designing Long-Range Charge Delocalization from First Principles. AB - Efficient electronic communication over long distances is a desirable property of molecular wires. Charge delocalization in mixed-valence (MV) compounds where two redox centers are linked by a molecular bridge is a particularly well-controlled instance of such electronic communication, thus lending itself to comparisons between theory and experiment. We study how to achieve and control long-range charge delocalization in cationic organic MV systems by means of Kohn-Sham density functional theory (DFT), and show that a captodative substitution approach recently suggested for molecular conductance (T. Stuyver et al., J. Phys. Chem. C 122, 3194 (2018)) greatly enhances charge delocalization in para phenylene-based wires. To ensure the adequacy of our DFT methods, we validate different protocols for organic MV systems of different lengths. The BLYP35 hybrid functional combined with a polarizable continuum model, established by Renz and Kaupp, is indeed capable of correctly describing experimentally observed length-dependent charge delocalization, in contrast to the long-range corrected functionals omega-B97X-D and omega-PBE. We also discuss the implications of these results for a first-principles description of the transition between coherent tunneling and incoherent hopping regimes in molecular conductance. PMID- 30481453 TI - SchNetPack: A Deep Learning Toolbox For Atomistic Systems. AB - SchNetPack is a toolbox for the development and application of deep neural networks to the prediction of potential energy surfaces and other quantum chemical properties of molecules and materials. It contains basic building blocks of atomistic neural networks, manages their training and provides simple access to common benchmark datasets. This allows for an easy implementation and evaluation of new models. For now, SchNetPack includes implementations of (weighted) atom-centered symmetry functions and the deep tensor neural network SchNet as well as ready-to-use scripts that allow to train these models on molecule and material datasets. Based upon the PyTorch deep learning framework, SchNetPack allows to efficiently apply the neural networks to large datasets with millions of reference calculations as well as parallelize the model across multiple GPUs. Finally, SchNetPack provides an interface to the Atomic Simulation Environment in order to make trained models easily accessible to researchers that are not yet familiar with neural networks. PMID- 30481454 TI - Plasmonic Nanosensors Reveal a Height Dependence of MinDE Protein Oscillations on Membrane Features. AB - Single-particle plasmon spectroscopy has become a standard technique to detect and quantify the presence of unlabeled macromolecules. Here, we extend this method to determine their exact distance from the plasmon sensors with subnanometer resolution by systematically varying the sensing range into the surrounding by adjusting the size of the plasmonic nanoparticles. We improved cur rent single-particle plasmon spectroscopy to record the particle spectra of thousands of nanoparticles of different sizes simultaneously within two seconds - continuously for hours. We apply this technique to study the interaction dynamics of bacterial Min proteins with supported lipid membranes of different composition. Our experiments reveal a surprisingly flexible operating mode of the Min protein wave: In the presence of cardiolipin (CL) and membrane curvature induced by nanoparticles, the wave occurs on top of a stationary MinD patch. Our results reveal the need to consider membrane composition and local curvature as important parameters to quantitatively understand the Min protein system and could be extrapolated to other macromolecular systems. Our label-free method is generally well suited to reveal distances of interacting biological macromolecules and easily implementable. PMID- 30481455 TI - Micron-Sized Nanoporous Antimony with Tunable Porosity for High-Performance Potassium-Ion Batteries. AB - Potassium-ion batteries (KIBs) are considered favorable candidates for post lithium-ion batteries, a quality attributed to their low cost, abundance as a resource, and high working potential (-2.93 V for K+/K). Owning to its relatively low potassiation potential and high theoretical capacity, antimony (Sb) is one of the most favorable anodes for KIBs. However, the large volume changes during K-Sb alloying and dealloying causes fast capacity degradation. In this report, nanoporous Sb (NP-Sb) is fabricated by an environmentally friendly vacuum distillation method. The NP-Sb is formed via evaporating low-boiling-point zinc (Zn). The byproduct Zn can be recycled. It is further found that the morphology and porosity can be controlled by adjusting Zn-Sb composition and distillation temperature. The nanoporous structure can accommodate volume expansion and accelerate ion transport. The NP-Sb anode delivers an improved electrochemical performance. These results suggest that the vacuum-distillation method may provide a direction for the green, large-scale, and tunable fabrication of nanoporous materials. PMID- 30481456 TI - Recent Advances in Design of Fluorescence-based Assays for High-throughput Screening. AB - Significant improvements in disease management have been achieved in the past few decades. Using cancer as an example, survival rates have increased dramatically in economically developed countries, according to the World Cancer Report published by WHO in 2014.1 One of the highlights is the average 5-year survival rate of children diagnosed before the age of 15 years in Britain increased from less than 30% in 1966-70 to almost 80% in 1996-2000. The improvement can be attributed to the establishment of early screening and awareness programs, identification of a large number of genetic or non-genetic risk factors or markers, and availability of diverse therapeutic strategies including surgery and treatments using radioactive reagents, small molecules, or biological drugs. Still, cancer remains one of the major causes of deaths worldwide, affecting millions of people. Survival rates in developing countries are poor, and the global and regional burden of cancer in terms of both incidence and mortality keep increasing along with the growing population and aging society. Further improvement heavily relies on early diagnosis, wide access to treatment options, and discovery of more effective biomarkers as well as anticancer drugs with high efficacy. Such demands are also applied to diagnosis and cure for all other diseases, calling for rapid advancements in high-throughput screening (HTS) technologies that can efficiently test a large number of targets and samples, monitor diverse enzymatic processes in situ, and effectively identify biologically active substances.2. PMID- 30481457 TI - Land Use Influences Antibiotic Resistance in the Microbiome of Soil Collembolans Orchesellides sinensis. AB - Numerous studies have investigated the composition and diversity of antibiotic resistance genes (ARGs) in multiple environments but the pattern of ARGs in field collected soil fauna remains poorly understood. In the present study soil collembolans were collected from six sites with three different land use types (green belt, park land and arable land) and 285 ARGs and 10 mobile genetic elements (MGEs) in the microbiome of these 'wild' collembolans were quantified by high-throughput quantitative PCR. A total of 76 unique ARGs and 5 MGEs were detected. There were significant differences between collection sites in the antibiotic resistome in the collembolans. Land use significantly altered the distribution patterns of collembolan ARGs. Thirty shared ARGs and three shared MGEs were identified. The co-occurrences of shared resistomes were largely random, and more positive relationships were found in the co-association network. Partial redundancy analysis confirms that the changes in bacterial communities explained 29.62 % of the variation in ARGs. These findings suggest that resistance genes are pervasive in the microbiome associated with the field collembolan and the activity of the collembolans may contribute to the spread and dissemination of resistance genes in the environment, an aspect of ARGs that has until now been largely overlooked. PMID- 30481458 TI - N-doped Mesoporous Carbon Sheets/Hollow Carbon Spheres Composite for Supercapacitors. AB - The composite carbon materials with multiple morphologies (such as spheres/sheets and spheres/tubes, and so on) that combine the merits of both structures have a wide range of applications in electrochemistry, catalysis, energy storage and so on. Therefore, the development of an efficient and simple method for preparing carbonaceous composite materials is one of the research hotspots. In this work, we report a dissolution-reassembly strategy combining with hard-template to prepare the composite carbon materials of N-doped mesoporous carbon sheets/hollow carbon spheres (N-MCS/HCS). Basing on the inhomogeneity of 3 aminophenol/formaldehyde (3-AF) polymerization spheres, the hollow 3-AF spheres were obtained after the dissolution of internal 3-AF oligomer. The dispersed 3-AF oligomer reassembled with silicate oligomers on the hard template of Mg(OH)2 sheets and hollow 3-AF spheres linked by CTAB through electrostatic force. The obtained N-MCS/HCS possessed both sheet and sphere structure, showing high specific surface area and uniform mesoporous distribution. As electrode material, N-MCS/HCS exhibited a good specific capacity (270 F g-1 at the current density of 1 A g-1) and outstanding cycling life stability (96.3% after 5000 cycles) at the current density of 5 A g-1, and could be used as new electrode material. PMID- 30481459 TI - Non-Lytic Recombinant Phage Tail Fiber Protein for Specific Recognition of Pseudomonas aeruginosa. AB - Rapid and accurate bacterial detection is crucial to early diagnosis for treating various infectious diseases. A recombinant tail fiber protein (P069) of Pseudomonas aeruginosa (P. aeruginosa) phage was expressed in Escherichia coli. After renaturation at low temperature, the inclusion body of P069 was successfully transformed to an aqueous soluble protein that retained the capacity for recognizing P. aeruginosa. The recombinant P069 did not show lytic activity to P. aeruginosa, which facilitated capture and manipulation of bacterial whole cells with high flexibility for downstream identification and detection. Bioluminescent and fluorescent methods using this biorecognition element allowed P. aeruginosa detection with the detection limits of 6.7 * 102 CFU mL-1 and 1.7 * 102 CFU mL-1, respectively. Moreover, the specificity investigations showed that P069 was a species-specific protein. Therefore, it avoided the potential false negative results originating from the excessive high specificity of phage toward a given strain. It has been successfully applied to detect P. aeruginosa in spiked samples with acceptable recovery values ranging from 88% to 98%. The above results demonstrate that P069 is an ideal biorecognition element for the detection of P. aeruginosa in complicated sample matrixes. PMID- 30481460 TI - Rationalizing Perovskites Data for Machine Learning and Materials Design. AB - Machine learning has been recently used for novel perovskite designs, owing to the availability of large amount of perovskite formability data. Trustworthy results should be based on the valid and reliable data that can reveal the nature of materials as much as possible. In this study, a procedure has been developed to identify the formability of perovskites for all the compounds with the stoichiometry of ABX3 and (A'A'')(B'B'')X6, that exist in experiments and are stored in the database of Materials Projects. Our results have enriched data of perovskite formability in a large extent and corrected the possible errors of previous data in ABO3 compounds. Furthermore, machine learning with multiple models approach have identified the A2B'B''O6 compounds that have suspicious formability results in current experimental data. Therefore, further experimental validation experiments are called for. This work paves a way for cleaning perovskite formability data for reliable machine learning work in future. PMID- 30481461 TI - Dynamical and environmental effects on the optical properties of an heteroleptic Ru(II)-polypyridine complex: a multilevel approach combining accurate ground and excited state QM-derived force fields, MD and TD-DFT. AB - An integrated multilevel approach is here built by combining classical Molecular Dy- namic (MD) simulations, Time-Dependent Density Functional Theory (TD-DFT) calculations and solvation dynamics linear response (LR) analysis, and successively employed to investigate the optical properties and solvation structure of a prototypical heteroleptic Ru(II)-polypyridyl complex, widely employed in dye sensitized solar cells. The MD simulations are performed with an accurately parameterized intramolecular force field (FF), specifically derived from the quantum chemical (DFT) description of the molecule, both for its singlet and triplet ground states. Solvent effects, in ethanol (EtOH) and dimethyl sulfoxide (DMSO), are taken into account at different level of approximation, going from a totally implicit description (polarizable continuum) to an hybrid explicit/implicit scheme. Our results show that the developed FFs were able to accurately describe and preserve the octahedral coordination of the Ru(II) center along the MD trajectories, yielding an accurate picture of the solute dynamics. Noticeably, the dynamical effects and the inclusion of an explicit micro solvation shell were found to be crucial to get a good agreement with the experimental absorption spectrum in EtOH, in both shape and positions of the main bands. The significant experimental blue-shift of the two low-energy bands in DMSO, that is not reproduced by the simulated thermal-averaged spectra, is, instead, attributed to de-protonation phenomena of the carboxylic groups induced by the strong nucleophilic character of the solvent. Finally, analysis of the solvent response shows that the structural changes in the first solvation shell, following the metal-ligand to ligand charge transfer excitation, cause, in the protic medium (EtOH) the breakdown of the linear response approximation, which, on the contrary, holds for DMSO. PMID- 30481462 TI - Revealing the Spectrum of Unknown Layered Materials with Super-Human Predictive Abilities. AB - We discover the chemical composition of over 1000 materials that are likely to exhibit layered and two-dimensional phases but have yet to be synthesized. This includes two materials our calculations indicate can exist in distinct structures with different band gaps, expanding the short list of two-dimensional phase change materials. While databases of over 1000 layered materials have been reported, we provide the first full database of materials that are likely layered but yet to be synthesized, providing a roadmap for the synthesis community. We accomplish this by combining physics with machine learning on experimentally obtained data and verify a subset of candidates using density functional theory. We find our model performs five times better than practitioners in the field at identifying layered materials and is comparable or better than professional solid state chemists. Finally, we find that semi-supervised learning can offer benefits for materials design where labels for some of the materials are unknown. PMID- 30481464 TI - Electron transport in low dimensional solids: a surface chemistry perspective. AB - Electron transport is a fundamental process that controls the intrinsic chemical and physical properties of solid materials. The surface phase becomes dominant when downsized dimensionality into cluster scale in nanomaterials, and surface chemistry plays more and more important roles in regulating electron transport. During past decades, varieties of chemical approaches have been developed to modify the surface of low dimensional solids, substantially providing versatile perspectives on engineering electron transport. In this perspective, we focus on recent researches concerning surface chemical modification strategies, such as surface molecular adsorption, atomic incorporation, defect engineering and spin scattering to engineer electron transport of typical one- / two- dimensional systems. Under the framework of Drude's transport model, we highlight the core role of micro degrees of freedom, i. e. charge, lattice, and spin, in molecular level understanding and optimizing the regulation effect of surface chemistry. Finally, based on the discussion and current achievements of surface chemistry effect on electron transport of low dimensional solids, some personal perspectives on the future development are also presented. PMID- 30481463 TI - Alkaline Phosphatase-Triggered Self-Assembly of Near-Infrared Nanoparticles for the Enhanced Photoacoustic Imaging of Tumors. AB - Photoacoustic (PA) imaging is advantageous for the diagnosis of superficial cancer with high spatial resolution. However, to the best of our knowledge, using an alkaline phosphatase (ALP)-activatable probe for the enhanced PA imaging of tumors has not been reported. In this work, we rationally designed a NIR probe IR775-Phe-Phe-Tyr(H2PO3)-OH (1P) for PA imaging ALP activity in vitro and in tumor. Under the catalysis of ALP, 1P was efficiently converted to IR775-Phe-Phe Tyr-OH (1), which self-assembled into the nanoparticles 1-NPs. The formation of 1 NPs induced a 6.4-fold enhancement of the 795 nm PA signal of 1P. In vivo tumor PA imaging results indicated that, compared to that in the ALP inhibitor-treated control group, PA contrast in the experimental group enhanced 2.3 folds at 4 h after 1P injection. By replacing the Phe-Phe-Tyr(H2PO3)-OH motif in 1P with other enzyme-cleavable ones, we hope that more PA probes could be developed for the precise diagnoses of their corresponding cancers in the near future. PMID- 30481465 TI - Preferential Equilibrium Partitioning of Positively Charged Tryptophan into Phosphatidylcholine Bilayer Membranes. AB - The interactions between small molecules and lipid bilayers play a critical role in the function of cellular membranes. Understanding how a small molecule interacts with the lipid bilayer differently based on its charge reveals primordial mechanisms of transport across membranes and assists in the design of drug molecules that can penetrate cells. We have previously reported that tryptophan permeated through the phosphatidylcholine lipid bilayer membrane at a faster rate when it was positively charged (Trp+) than when negatively charged (Trp-), which corresponded to a lower potential of mean force (PMF) barrier determined through simulations and a slower permeation rate for Trp+ within the bilayer than Trp-. In this report, we demonstrate that Trp+ partitions into the lipid bilayer membrane to a greater degree than Trp- by interacting with the ester linkage of a phosphatidylcholine lipid, where it is stabilized by the electron withdrawing glycerol functional group. These results are in agreement with tryptophan's known role as an anchor for transmembrane proteins, though the tendency for a binding of a positively charge tryptophan is surprising. We discuss the implications of our results on the mechanisms of unassisted permeation and penetration of small molecules within and across lipid bilayer membranes based on molecular charge, shape, and molecular interactions within the bilayer structure. PMID- 30481466 TI - Simulating X-ray emission spectroscopy with algebraic diagrammatic construction schemes for the polarization propagator. AB - The calculation of X-ray emission spectra has been addressed with the algebraic diagrammatic construct (ADC) scheme, using a core-ionized wave function as the reference state. With this, the valence-to-core transitions are found as the first eigenstates with negative eigenvalues. The performance of the ADC hierarchical methods ADC(2), ADC(2)-x, and ADC(3/2) has been investigated on 17 transition of second-row elements (C, N, O, F, and Ne), and 5 transitions of third-row elements (S and Cl). We report ADC(2) results within 0.28$?pm$0.35 eV of experimental values with an appropriate choice of basis set and when accounting for relativistic effects, with a slight tendency towards underestimating emission energies. By comparison, ADC(2)-x yields a similar spread in relative energies, but a consistent overestimation of approximately 1.5 eV. Going to ADC(3/2), we now observe an underestimation of emission energies and a larger error spread. By comparison, calculations of X-ray absorption spectra have been reported to favour the ADC(2)-x method, with ADC(2) showing the largest error when comparing to experimental values. The difference in ADC performance trends between these core spectroscopies are attributed to the different electron rearrangement effects in X-ray absorption and emission processes. PMID- 30481467 TI - Novel In Vitro Method Reveals Drugs that Inhibit Solute Transporter Alpha/Beta (OSTalpha/beta). AB - Drug interactions with the organic solute transporter alpha/beta (OSTalpha/beta) are understudied even though OSTalpha/beta is an important transporter that is expressed in multiple human tissues including the intestine, kidneys and liver. In this study, an in vitro method to identify novel OSTalpha/beta inhibitors was first developed using OSTalpha/beta-overexpressing Flp-In 293 cells. Incubation conditions were optimized using previously reported OSTalpha/beta inhibitors. A method including a 10-min preincubation step with the test compound was used to screen for OSTalpha/beta inhibition by 77 structurally diverse compounds and fixed-dose combinations. Seven compounds and one fixed-dose combination (100 uM final concentration) inhibited OSTalpha/beta-mediated DHEAS uptake by >25%. Concentration-dependent OSTalpha/beta inhibition was evaluated for all putative inhibitors (atorvastatin, ethinylestradiol, fidaxomicin, glycochenodeoxycholate, norgestimate, troglitazone and troglitazone sulfate). Ethinylestradiol, fidaxomicin and troglitazone sulfate yielded a clear concentration-inhibition response with IC50 values <200 uM. Among all tested compounds, there was no clear association between physicochemical properties, the severity of hepatotoxicity, and the degree of OSTalpha/beta inhibition. This study utilized a novel in vitro method to identify OSTalpha/beta inhibitors, and for the first time, provided IC50 values for OSTalpha/beta inhibition. These data provide evidence that several drugs, some of which are associated with cholestatic drug-induced liver injury, may impair the function of the OSTalpha/beta transporter. PMID- 30481468 TI - Difluorophosphorane - Flattened Phosphorene through Difluorination. AB - We computationally showed that by difluorination of phosphorene we can make a new material difluorphosphorane (DFP) with perfectly planar honeycomb structure out of phosphorus atoms with fluorine atoms attached to every phosphorus atom from above and below. The structure is dynamically stable. It is a semiconductor with the direct band gap of 4.51 eV and 3.88 eV for the indirect band gap. We hope that with the passivation this new DFP material if made could find many applications in nanoelectronics. PMID- 30481469 TI - Generalized gradient approximation exchange energy functional with near-best semilocal performance. AB - We develop and validate a non-empirical generalized gradient approximation (GGA) exchange (X) density functional which performs as well as the SCAN meta-GGA on standard thermochemistry tests. Additionally, the new functional ("NCAP") yields Kohn-Sham eigenvalues that are useful approximations of the density functional theory (DFT) ionization potential theorem values by inclusion of a systematic derivative discontinuity shift of the X potential. NCAP also enables time dependent DFT (TD-DFT) calculations of good quality polarizabilities, hyper polarizabilities, and one-fermion excited states without modification (calculated or ad hoc) of the long-range behavior of the exchange potential or other patches. NCAP is constructed by reconsidering the imposition of the asymptotic correctness of the X potential (-1/r) as a constraint. Inclusion of derivative discontinuity and approximate integer self-interaction correction treatments along with first principles determination of the effective second-order gradient expansion coefficient yields a major advance over our earlier correct asymptotic potential functional ["CAP"; J. Chem. Phys. 142, 054105 (2015)]. The new functional reduces a spurious bump in the CAP atomic exchange potential and moves it to distances irrelevantly far from the nucleus (outside the tail of essentially all practical basis functions). It therefore has nearly correct atomic exchange-potential behavior out to rather large finite distances r from the nucleus but eventually goes as -c/r with an estimated value for the constant c of around 0.3,so as to achieve other important properties of exact DFT exchange within the restrictions of the GGA form. We illustrate the results with the Ne atom optimized effective potentials and with standard molecular benchmark test data sets for thermochemical, structural and response properties. PMID- 30481470 TI - Inhibition of serine palmitoyltransferase by a small organic molecule promotes neuronal survival after astrocyte amyloid beta 1-42 injury. AB - Alzheimer's disease (AD) is a slow-progressing disease of the brain characterized by symptoms such as impairment of memory and other cognitive functions. AD is associated with an inflammatory process that involves astrocytes and microglial cells, among other components. Astrocytes are the most abundant type of glial cells in the central nervous system (CNS). They are involved in inducing neuroinflammation. The present study uses astrocyte-neuron co-cultures to investigate how ARN14494, a serine palmitoyltransferase (SPT) inhibitor, affects the CNS in terms of anti-inflammation and neuroprotection. SPT is the first rate limiting enzyme in the de novo ceramide synthesis pathway. Consistent evidence suggests that ceramide is increased in AD brain patients. After beta-amyloid 1-42 injury in an in vitro model of AD, ARN14494 inhibits SPT activity and the synthesis of long-chain ceramides and dihydroceramides that are involved in AD progression. In mouse primary cortical astrocytes, ARN14494 prevents the synthesis of pro-inflammatory cytokines TNFalpha and IL1beta, growth factor TGFbeta1, and oxidative stress-related enzymes iNOS and COX2. ARN14494 also exerts neuroprotective properties in primary cortical neurons. ARN14494 decreases neuronal death and caspase-3 activation in neurons, when the neuroinflammation is attenuated in astrocytes. These findings suggest that ARN14494 protects neurons from beta-amyloid 1-42-induced neurotoxicity through a variety of mechanisms, including anti-oxidation, anti-apoptosis, and anti-inflammation. SPT inhibition could therefore be a safe therapeutic strategy for ameliorating the pathology of Alzheimer's disease. PMID- 30481471 TI - Unexpected favorable role of Ca2+ in phosphate removal by using nanosized ferric oxides confined in porous polystyrene beads. AB - Polystyrene-based nano-ferric oxide composite is a representative nanomaterial successfully applied in scale-up water decontamination for arsenic and phosphorous. However, little is available on the effect of solution chemistry (for instance, the coexisting Ca2+) on long-term performance of the nanocomposite. In this study, we carried out 20 cyclic runs of phosphate adsorption-desorption on a polymer-supported ferric nanocomposite HFO@201. Unexpectedly, an enhanced phosphate removal was observed in the presence of Ca2+, which is quite different from its adverse effect on phosphate capture by granular ferric oxide. Further mechanistic studies revealed that enhanced phosphate removal was mainly realized via the Ca-P co-precipitation inside the networking pores of HFO@201 as well as the possible formation of the multiple Fe-P-Ca-P complex. The complex formation led to a distinct increase in P adsorption, and the co-precipitation, driven by the accumulated OH- in confined pores during phosphate adsorption and alkaline regeneration, favored P removal via the formation of amorphous calcium phosphate (ACP) and hydroxyapatite inside. TEM-EDS spectra indicated that co-precipitation did not occur on the surface of loaded nano-HFO, greatly mitigating its adverse effect on P adsorption on the surface of nano-HFO. Fixed-bed column study showed that the presence of Ca2+ increased the effective treatable volume of HFO@201 towards P-containing influents by ~70%. This study is believed to shed new insights into the effect of solution chemistry on similar nanocomposites for advanced water treatment. PMID- 30481472 TI - Performance of PROMIS Global-10 Compared With Legacy Instruments for Rotator Cuff Disease. AB - BACKGROUND:: The Patient-Reported Outcomes Measurement Information System (PROMIS) Global-10 was recently developed to assess physical and mental health and provide an estimated EuroQol-5 Dimension (EQ-5D) score. This instrument needs to be validated for specific patient cohorts such as those with rotator cuff pathology. HYPOTHESIS:: There is moderate to high correlation between the PROMIS Global-10 and legacy patient-reported outcome measures; PROMIS Global-10 will not show ceiling effects; and estimated EQ-5D scores will show good correlation and low variance with actual EQ-5D scores. STUDY DESIGN:: Cohort study (diagnosis); Level of evidence, 2. METHODS:: A total of 323 patients with rotator cuff disease were prospectively enrolled before treatment. Each patient completed the PROMIS Global-10, EQ-5D, American Shoulder and Elbow Surgeons (ASES) shoulder assessment form, and Single Assessment Numeric Evaluation (SANE), and those with known rotator cuff tears completed the Western Ontario Rotator Cuff Index (WORC). Spearman correlations were calculated. Bland-Altman agreement tests were conducted between estimated EQ-5D scores from the PROMIS and actual EQ-5D scores. Ceiling and floor effects were assessed, defined as >=15% respondents with highest or lowest possible score. RESULTS:: Correlation between the PROMIS Global 10 and EQ-5D was excellent (0.70, P < .0001). Correlation of the PROMIS physical scores was excellent-good with the ASES (0.62, P < .0001), good with the WORC (0.47, P < .0001), and good with the SANE (0.41, P < .0005). Correlation between the PROMIS mental scores was poor with the ASES (0.34, P < .0001), the WORC (0.32, P = .0016), and the SANE (0.24, P < .0001). No floor or ceiling effects were found. Agreement analysis showed substantial variance in individual scores, despite the overall similarity in mean scores between the estimated and actual EQ 5D scores, indicating poor agreement. Bland-Altman 95% limits of agreement for estimated EQ-5D scores ranged from 34% below to 31% above actual EQ-5D scores. CONCLUSION:: Physical function scores of the PROMIS Global-10 show high correlation with legacy patient-reported outcome instruments, suggesting that it is a reliable tool for outcome assessment in a population with rotator cuff pathology. The large variability in 95% limit of agreement suggested that the estimated EQ-5D scores from the PROMIS Global-10 cannot replace traditional EQ-5D scores. PMID- 30481473 TI - Regional and Facility Differences in Interventions for Mastitis by Australian Physiotherapists. AB - BACKGROUND:: Little information has been documented regarding interventions for mastitis by Australian physiotherapists. It is currently not known if physiotherapy interventions vary across Australian regions and types of healthcare facilities. RESEARCH AIMS:: (1) To identify the interventions used by Australian physiotherapists treating mothers with mastitis and (2) to determine the variability in interventions used across regions and facilities. METHODS:: A retrospective observational design was used. A sample of case records of mothers with mastitis was identified (N=192). These case records documented physiotherapy interventions for mastitis in hospitals and private physiotherapy practices in Western Australia ( n=77; 40.1%), Victoria ( n=76; 39.6%), and New South Wales ( n=39; 20.3%). An electronic data collection tool was designed to examine intervention variables. RESULTS:: The physiotherapy interventions received by mothers included therapeutic ultrasound (n=175; 91.1%), education and advice (n=160; 83.3%), and massage (n=103; 53.6%). Therapeutic ultrasound parameters varied across regions and types of healthcare facilities. Mean documented therapeutic ultrasound intensity was approximately twice as high in New South Wales and Victoria than in Western Australia. CONCLUSIONS:: Regional and facility differences exist in physiotherapy interventions for mastitis in Australia. Healthcare professionals who refer to physiotherapists for mastitis should be aware that interventions received may differ across regions and facility types. PMID- 30481474 TI - Impact of Septal Deviation on Recurrent Chronic Rhinosinusitis after Primary Surgery: A Matched Case-Control Study. AB - OBJECTIVE: To evaluate the impact of untreated deviated nasal septum (DNS) on recalcitrant chronic rhinosinusitis (CRS) among patients undergoing revision endoscopic sinus surgery (ESS). STUDY DESIGN: Case-control study. SETTING: Tertiary academic center. SUBJECTS AND METHODS: We performed a retrospective review of 489 patients undergoing revision ESS for CRS at a tertiary academic center. Patients undergoing septoplasty were matched to nonseptoplasty controls based on age and sex. Preoperative Lund-Mackay score (LMS) was compared between cohorts. Linear regression was used to identify predictors of LMS and ostiomeatal complex (OMC) obstruction. RESULTS: Thirty-six matched pairs (72 patients) were selected for analysis: 36 undergoing septoplasty and revision ESS and 36 undergoing revision ESS alone. Compared with nonseptoplasty controls, the septoplasty group had a significantly higher average LMS (17.8 vs 14.6, P = .02) and a greater rate of OMC obstruction (89% vs 61%, P < .01). The septoplasty group also had significantly higher opacification scores in the maxillary (1.5 vs 1.2, P = .03) and posterior ethmoid (1.8 vs 1.4, P = .02) sinuses. On multivariable analysis, DNS was an independent predictor of LMS ( P = .02) and OMC obstruction ( P < .01). CONCLUSION: Untreated DNS is associated with radiographic markers of CRS severity among patients undergoing revision ESS and may contribute to the multifactorial pathogenesis of persistent CRS. PMID- 30481476 TI - IBFAN News Brief: Breastfeeding is a Human Right: Maternity Protection. PMID- 30481475 TI - Is Patient Satisfaction Associated With Clinical Outcomes After Osteochondral Allograft Transplantation in the Knee? AB - BACKGROUND:: The association between patient satisfaction and patient-reported outcomes after cartilage repair is not well understood. PURPOSE:: To investigate the association of patient satisfaction with pain, function, activity level, and quality of life after fresh osteochondral allograft (OCA) transplantation in the knee. STUDY DESIGN:: Case-control study; Level of evidence, 3. METHODS:: This study comprised 371 patients (396 knees) who underwent primary OCA transplantation for osteochondral lesions in the knee between 1997 and 2015. Mean +/- SD patient age was 31.8 +/- 11.6 years, and 62% were male. The majority of grafts (62%) were located on the femoral condyle; the mean number of grafts per knee was 1.5 +/- 0.8; and the median graft area was 6.9 cm2 (range, 1.8-50 cm2). Pain, function, activity level, and quality of life were evaluated pre- and postoperatively via International Knee Documentation Committee scores and Knee injury and Osteoarthritis Outcome Scores. Patient satisfaction with the results of the OCA transplantation was assessed postoperatively. All follow-up evaluations occurring at postoperative 1 year or later were included in the analysis. RESULTS:: The mean follow-up time was 5.5 years. Overall, the satisfaction rate was 88.1%, and this rate was constant over time. Satisfaction rates varied by diagnosis, age, sex, and anatomic location of the allograft. Postoperative International Knee Documentation Committee pain, function, and total scores differed between patients who were satisfied and not satisfied (all P < .001). All Knee injury and Osteoarthritis Outcome Score subscale results differed between those who were satisfied and not satisfied (all P < .001). Having a diagnosis of osteochondritis dissecans was the only variable that predicted which patients would be satisfied with the results of the allograft, after controlling for age, sex, anatomic location of the graft, and number of grafts. CONCLUSION:: A consistently high and durable patient satisfaction rate after OCA transplantation was found. Satisfied patients reported lower pain and higher function, activity levels, and quality of life as compared with patients who were not satisfied. Patients with osteochondritis dissecans had a particularly high level of satisfaction with the OCA procedure. PMID- 30481477 TI - WIC Data: We Want More! A Commentary on Berkowitz's Another Look at WIC's Breastfeeding Data. PMID- 30481478 TI - Human Milk Expression After Domperidone Treatment in Postpartum Women: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND:: Insufficient milk production is among the most cited reasons by mothers for discontinuing breastfeeding. Medications that can increase milk production, such as domperidone, an off-label galactagogue, are often prescribed. Domperidone is controversial as it is not approved for any purpose in the United States and is approved only for gastrokinetic purposes in Canada and other countries. RESEARCH AIM:: The aim was to update the existing literature on the efficacy of domperidone as a galactagogue compared to placebo when given to mothers with insufficient human milk production. The primary outcome is the change in expressed human milk volume per day from baseline. METHODS:: The authors independently searched the literature from inception to May 2018. The search included any randomized controlled trials examining the efficacy of domperidone increasing mothers' expressed human milk, measured via a human milk pump. Both authors independently assessed quality and risk of bias and extracted relevant data. Meta-analysis on expressed human milk volume per day was performed. RESULTS:: Seven studies met the inclusion criteria for review; two were excluded from the meta-analysis due to quality grading and insufficient reporting of the outcome of interest. Five studies ( N = 239) were combined in the meta-analysis. The effect size showed an increase in the mean difference of expressed human milk volume in mothers given domperidone, 93.97 mL per day (95% CI [71.12, 116.83 mL]; random effect, T2 0.00, I2 0%). CONCLUSION:: This meta analysis reports a significant improvement in expressed human milk volume per day with the use of domperidone in mothers experiencing insufficient human milk production. PMID- 30481479 TI - The Microbiology of Complicated Acute Sinusitis among Pediatric Patients: A Case Series. AB - OBJECTIVE: The microbiology of pediatric complicated acute rhinosinusitis (ARS) has evolved, and our current understanding of pathogenic organisms is limited. The objectives of this study are to describe the incidence of pathogens causing complicated ARS requiring surgical intervention at our institution over a 10-year period as well as their associated treatment outcomes. STUDY DESIGN: Retrospective cohort study. SETTING: A single tertiary care children's hospital. SUBJECTS AND METHODS: Data were reviewed from all patients who underwent surgery for complicated ARS and had positive culture data from 2006 to 2016. Associations among pathogens, complications, and outcomes were analyzed with Pearson chi2 and Wilcoxon rank-sum tests. RESULTS: Eighty-nine patients met criteria. Complications included orbital infections (78%), intracranial infections (48%), Pott's puffy tumor (13%), and cavernous sinus thrombosis (9.0%). Bacterial isolates were majority polymicrobial (55%) and included Streptococcus species (58%), Staphylococcus species (49%; including methicillin-resistant S aureus [MRSA], 11%), and anaerobic bacteria (35%). S pneumoniae (9.0%), Haemophilus species (4.5%), and Moraxella catarrhalis (1.1%) were relatively uncommon. Bacterial isolates were similar among patients with all types of complications. CONCLUSION: Among a large cohort of pediatric patients with complicated ARS, most bacterial isolates were polymicrobial, with Streptococcus and Staphylococcus species contributing to the majority of cases. S aureus species, including MRSA and anaerobic pathogens, were common. The pattern of bacterial isolates was similar among patients with all types of complications of ARS. We suggest treatment for complicated ARS with broad-spectrum antibiotics with coverage for Streptococcus species, Staphylococcus species including MRSA, and anaerobic bacteria. PMID- 30481480 TI - Professional Athletes Are Not at a Higher Risk of Infections After Anterior Cruciate Ligament Reconstruction: Incidence of Septic Arthritis, Additional Costs, and Clinical Outcomes From the French Prospective Anterior Cruciate Ligament Study (FAST) Cohort. AB - BACKGROUND:: The rate of septic arthritis in the knee after anterior cruciate ligament (ACL) reconstruction varies in the literature but is generally less than 1%. It has been reported to be higher in professional athletes (5.7%). PURPOSE:: The primary goal was to evaluate the rate of septic arthritis after ACL reconstruction in professional athletes compared with other patients. The secondary goals were to analyze the risk factors; increased cost of infections; return to sport, satisfaction, and functional results at 1-year follow-up; and resolution rate of infections at final follow-up. STUDY DESIGN:: Case-control study; Level of evidence, 3. METHODS:: This retrospective analysis of prospective data included a continuous series of patients who underwent isolated ACL reconstruction between 2012 and 2016. The main outcome criterion was the development of intra-articular infections in the operated knee. An infection was suggested clinically (knee pain with fever and/or chills) and confirmed bacteriologically in deep tissue samples obtained during revision surgery. All infected patients underwent an emergency reoperation with lavage and debridement along with dual antibiotic therapy first by an intravenous route and then orally for 6 weeks. RESULTS:: A total of 1809 of 1859 patients included in the cohort during this period fulfilled inclusion criteria; there were 1632 (90.2%) who underwent primary reconstruction and 177 (9.8%) who underwent revision. The series included 1249 (69%) men and 560 (31%) women, with a mean age of 29.1 +/- 9.8 years. Ninety-eight percent of the patients participated in a sport, including 90 (5.0%) at a professional level and 712 (39.4%) competitively. Septic arthritis of the knee developed after a mean 15.7 +/- 5.5 days in 7 (0.38%) patients: 5 of 1632 (0.31%) who underwent primary reconstruction and 2 of 177 (1.13%) who underwent revision. Septic arthritis did not develop in any professional or competitive athletes; all affected patients were recreational athletes ( P = .02). The risk factors identified for the development of septic arthritis on multivariate analysis were prior knee surgery (odds ratio [OR], 15; P = .002) and hemarthrosis during the immediate postoperative period (OR, 127.2; P = .002). There were no recurrent infections after a mean follow-up of 2.8 +/- 1.2 years. CONCLUSION:: None of the professional athletes in this cohort had septic arthritis after ACL reconstruction. There are no particular precautions to be taken in this population. The risk factors identified for the development of septic arthritis on multivariate analysis were prior knee surgery and hemarthrosis during the immediate postoperative period. Similar to all studies published on the subject, there were very few infected patients, which limits the identification of risk factors. REGISTRATION:: NCT02511158 (ClinicalTrials.gov identifier). PMID- 30481481 TI - Designing Longitudinal Clinical Studies Involving Lactating Women. AB - In designing longitudinal lactation research studies, certain factors must be taken into account that are necessary for the generation of meaningful data. Perhaps more like longitudinal childhood research studies in terms of ongoing changes that occur during childhood that challenge study design, longitudinal lactation research studies encompass a period of tremendous change in both the mother and her breastfeeding infant that affect study design, implementation, and analysis. Given this changing dynamic, studies should be designed to accommodate a whole host of factors, such as changes in maternal and infant health; coexisting conditions during the lactation period; the stage of lactation; diurnal variations; the frequency and exclusivity of breastfeeding; maternal diet and any complementary/supplementary foods given to the infant; geography; socioeconomic factors; body mass index; physical activity; and any changes in milk composition that occur across longer periods of lactation. The study of human milk composition itself has lacked rigor and any standardization of methods, and has only recently been revisited with more sophisticated laboratory techniques that have allowed a more meaningful understanding of milk structure and biology, with a greater global approach. In this Research Column, we review some of the issues and challenges in conducting longitudinal lactation research, and provide several references that will aid in the development of meaningful study designs and the interpretation of data. PMID- 30481482 TI - Advancing Retail Food Policy Debates: Estimating the Risk of Contaminated Servings of Food Attributed to Employee Food Handling Practices in Retail Food Establishments. AB - Food employee contamination of ready-to-eat foods through improper food handling practices is an important contributing factor for foodborne illness in retail and food service establishments. Decreasing the incidence of improper food handling practices is a frequent topic of retail food policy deliberations that often involves estimating the degree to which a proposed policy might affect a specific food handling practice. However, the potential reduction in contaminated servings of food, and therefore foodborne illnesses avoided, associated with a given proposed policy change, is all too often uncertain. This article discusses the components, assumptions, and applications of the food handling practices model, a quantitative model that estimates the impact of food handling practices on servings of food moving along three consecutive stages: the contamination stage, the pathogen control stage, and the foodborne illness stage. To our knowledge, this article is the first time the model has been presented in an academic platform, and we also explore unique and interesting aspects of the model not addressed in publicly available documents. Risk-based estimates for contaminated servings of food attributed to changes in one or multiple food handling practices are derived that provide an important link between increased compliance with proper food handling practices and public health. Model estimates show that decreases in the incidence of inappropriate food handling practices lead to varying levels of contaminated food servings avoided, depending on the food handling practice. The ability to derive such estimates provides stakeholders and the general public with a means of understanding the relative impact of proposals to reduce improper food handling and to help inform regulatory food safety policy discussions and decision making. PMID- 30481483 TI - Survival of Escherichia coli O157:H7 and Salmonella on Bruised and Unbruised Tomatoes from Three Ripeness Stages at Two Temperatures. AB - Tomatoes are one of the major fresh produce commodities consumed in the United States. Harvesting tomato fruit at a later stage of development can enhance consumer acceptance but can also increase damage due to bruising. Bruising can affect the quality of whole tomatoes by causing an unacceptable appearance and accelerating decay. Bruising may also facilitate bacterial attachment to the fruit surface and support growth of pathogens. This study evaluated the survival and/or proliferation of Escherichia coli O157:H7 and Salmonella on the surface of artificially bruised and unbruised tomatoes at three ripeness stages (breaker, pink, and red) and two storage temperatures (10 and 20 degrees C). A total of 1,440 tomatoes, 720 for each organism, were analyzed. Both E. coli O157:H7 and Salmonella counts declined significantly ( P < 0.05) on the bruised and unbruised tomatoes over the 7-day storage period, by approximately 2.5 and 2.0 log, respectively. E. coli O157:H7 was not detected on pink tomatoes on day 7, whereas Salmonella persisted on the tomato surfaces throughout the 7-day study at all ripeness stages. Bruising had no significant effect ( P > 0.05) on the survival of E. coli O157:H7 (CFU per tomato) compared with the unbruised tomatoes, in most cases. Tomatoes from the red ripeness stage showed a significant effect ( P < 0.05) of bruising on Salmonella survival at both 10 and 20 degrees C. Similar to the colony count results, the frequency (presence or absence) of inoculated tomatoes with detectable levels of inoculated bacteria decreased significantly ( P < 0.05) over time. At the lower temperature, E. coli O157:H7 was recovered from significantly higher ( P < 0.05) numbers of breaker and pink tomatoes, whereas there was no effect of temperature on the overall survival of E. coli O157:H7 on red tomatoes. Results from this study are essential for understanding the effects of bruising on produce safety and for producers and packers to develop mitigation strategies to control pathogenic and spoilage organisms. PMID- 30481484 TI - Effects of Bacteriophage P100 at Different Concentrations on the Structural Parameters of Listeria monocytogenes Biofilms. AB - Because listeriosis is one of the deadliest foodborne diseases, controlling and eradicating Listeria monocytogenes biofilms is a serious challenge for food safety. Biofilms (24 h old) formed on polystyrene by a L. monocytogenes strain of food origin were exposed for a further 24 h to 12 different concentrations (from 100 to 1011 PFU/mL) of the bacteriophage P100 (Listex P100). The structural parameters of biofilms were studied by using confocal laser scanning microscopy and digital image analysis. The biovolume in the observation field (14,121 MUm2) of control (untreated) biofilms was 237,333.1 +/- 2,692.6 MUm3. The biomass of treated biofilms ranged from 164.7 +/- 89.0 MUm3 (biofilms exposed to 1010 PFU/mL) to 231,170.5 +/- 15,142.0 MUm3 (100 PFU/mL). The lowest biomass was achieved after treatment with 108 PFU/mL, with no further decrease in biovolume when higher phage concentrations were used. A strong ( P < 0.001) correlation was found between phage concentration (log units) and biovolume (-0.965), surface coverage (-0.939), roughness (0.976), maximum thickness (-0.853), and average thickness (-0.965). Findings from this research suggest that bacteriophage P100 at concentrations equal to or greater than 8 log PFU/mL successfully removes L. monocytogenes biofilms from polystyrene surfaces. PMID- 30481485 TI - Erratum. PMID- 30481486 TI - IL-13 signaling through IL-13 receptor alpha2 mediates airway epithelial wound repair. AB - Asthma is an airway inflammatory disease characterized by epithelial barrier dysfunction and airway remodeling. Interleukin-13 (IL-13) is a pleiotropic cytokine shown to contribute to features of airway remodeling. We have previously demonstrated that IL-13 is an important mediator of normal airway epithelial repair and health. The role of IL-13 signaling via its receptor subunits (IL 13Ralpha1/IL-4Ralpha and IL-13Ralpha2) in airway epithelial repair and restoration of intact barrier function is not well understood and was investigated in this study using in vitro models. The blocking of IL-13 signaling via IL-13Ralpha2 significantly reduced airway epithelial repair by 24 h post mechanical wounding in 1HAEo- cells. Expression and release of repair-mediating growth factor, heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), and subsequent activation of EGF receptor (EGFR) were also significantly reduced in response to wounding when IL-13Ralpha2 was blocked. Our data support that IL-13 signals via IL-13Ralpha2 to mediate normal airway epithelial repair via HB-EGF-dependent activation of EGFR. In human donor lung tissues, we observed that airway epithelium of asthmatics expressed significantly decreased levels of IL-13Ralpha2 and increased levels of IL-13Ralpha1 compared with nonasthmatics. Dysregulated expression of IL-13 receptor subunits in the airways of asthmatics may thus contribute to the epithelial barrier dysfunction observed in asthma.-Yang, S. J., Allahverdian, S., Saunders, A. D. R., Liu, E., Dorscheid, D. R. IL-13 signaling through IL-13 receptor alpha2 mediates airway epithelial wound repair. PMID- 30481487 TI - Therapeutic effect of pirfenidone in the sugen/hypoxia rat model of severe pulmonary hypertension. AB - Heightened pulmonary artery smooth muscle cell (PA-SMC) proliferation and migration and dynamic remodeling of the extracellular matrix are hallmark pathogenic features of pulmonary arterial hypertension (PAH). Pirfenidone (PFD) is an orally bioavailable pyridone derivative with antifibrotic, antiinflammatory, and antioxidative properties currently used in the treatment of idiopathic pulmonary fibrosis. We therefore evaluated the efficacy of curative treatments with PFD in the sugen/hypoxia (SuHx) rat model of severe pulmonary hypertension. Treatment with PFD (30 mg/kg per day by mouth 3 times a day for 3 wk) started 5 wk after sugen injection partially reversed established pulmonary hypertension, reducing total pulmonary vascular resistance and remodeling. Consistent with these observations, we found that continued PFD treatment decreases PA-SMC proliferation and levels of extracellular matrix deposition in lungs and right ventricles in SuHx rats. Importantly, PFD attenuated the proproliferative and promigratory potentials of cultured PA-SMCs from patients with idiopathic PAH and their capacity to produce extracellular matrix components. Finally, we found that PFD dose dependently enhanced forkhead box O1 protein levels and its nuclear translocation in cultured idiopathic PAH PA-SMCs and in PFD-treated SuHx rats. PFD appears to be a potential therapy for PAH worthy of investigation and evaluation for clinical use in conjunction with current PAH treatments.-Poble, P.-B., Phan, C., Quatremare, T., Bordenave, J., Thuillet, R., Cumont, A., Huertas, A., Tu, L., Dorfmuller, P., Humbert, M., Ghigna, M.-R., Savale, L., Guignabert, C. Therapeutic effect of pirfenidone in the sugen/hypoxia rat model of severe pulmonary hypertension. PMID- 30481489 TI - Myoglianin triggers the pre-metamorphosis stage in hemimetabolan insects. AB - Insect metamorphosis is triggered by a decrease in juvenile hormone (JH) in the final juvenile instar. What induces this decrease is therefore a relevant question. Working with the cockroach Blattella germanica, we found that myoglianin (Myo), a ligand in the TGF-beta signaling pathway, is highly expressed in the corpora allata (CA, the JH-producing glands) and the prothoracic gland [(PG), which produce ecdysone] during the penultimate (fifth) nymphal instar (N5). In the CA, high Myo levels during N5 repress the expression of juvenile hormone acid methyl transferase, a JH biosynthesis gene. In the PG, decreasing JH levels trigger gland degeneration, regulated by the factors Kruppel homolog 1, FTZ-F1, E93, and inhibitor of apoptosis-1. Also in the PG, a peak of myo expression in N5 indirectly stimulates the expression of ecdysone biosynthesis genes, such as neverland, enhancing the production of the metamorphic ecdysone pulse in N6. The Myo expression peak in N5 also represses cell proliferation, which can enhance ecdysone production. The data indicate that Myo triggers the pre-metamorphic nymphal instar in B. germanica and possibly in other hemimetabolan insects.-Kamsoi, O., Belles, X. Myoglianin triggers the pre metamorphosis stage in hemimetabolan insects. PMID- 30481488 TI - Autotaxin determines colitis severity in mice and is secreted by B cells in the colon. AB - Autotaxin (ATX or ENPP2) is a secreted lysophospholipase D that produces lysophosphatidic acid (LPA), a pleiotropic lipid mediator acting on specific GPCRs. ATX and LPA have been implicated in key (patho)physiologic processes, including embryonic development, lymphocyte homing, inflammation, and cancer progression. Using LPA receptor knockout mice, we previously uncovered a role for LPA signaling in promoting colitis and colorectal cancer. Here, we examined the role of ATX in experimental colitis through inducible deletion of Enpp2 in adult mice. ATX expression was increased upon induction of colitis, whereas ATX deletion reduced the severity of inflammation in both acute and chronic colitis, accompanied by transient weight loss. ATX expression in lymphocytes was strongly reduced in Rag1-/- and MUMT mice, suggesting B cells as a major ATX-producing source, which was validated by immunofluorescence and biochemical analyses. ATX secretion by B cells from control, but not Enpp2 knockout, mice led to ERK activation in colorectal cancer cells and promoted T cell migration. We conclude that ATX deletion suppresses experimental colitis and that B cells are a major source of ATX in the colon. Our study suggests that pharmacological inhibition of ATX could be a therapeutic strategy in colitis.-Lin, S., Haque, A., Raeman, R., Guo, L., He, P., Denning, T. L., El-Rayes, B., Moolenaar, W. H., Yun, C. C. Autotaxin determines colitis severity in mice and is secreted by B cells in the colon. PMID- 30481490 TI - Intracellular metalloprotease activity controls intraneuronal Abeta aggregation and limits secretion of Abeta via exosomes. AB - Accumulating evidence suggests that the abnormal aggregation of amyloid-beta (Alphabeta) peptide in Alzheimer's disease (AD) begins intraneuronally, within vesicles of the endosomal-lysosomal pathway where Abeta is both generated and degraded. Metalloproteases, including endothelin-converting enzyme (ECE)-1 and 2, reside within these vesicles and normally limit the accumulation of intraneuronally produced Abeta. In this study, we determined whether disruption of Abeta catabolism could trigger Abeta aggregation within neurons and increase the amount of Abeta associated with exosomes, small extracellular vesicles derived from endosomal multivesicular bodies. Using cultured cell lines, primary neurons, and organotypic brain slices from an AD mouse model, we found that pharmacological inhibition of the ECE family of metalloproteases increased intracellular and extracellular Abeta levels and promoted the intracellular formation of Abeta oligomers, a process that did not require internalization of secreted Abeta. In vivo, the accumulation of intraneuronal Abeta aggregates was accompanied by increased levels of both extracellular and exosome-associated Abeta, including oligomeric species. Neuronal exosomes were found to contain both ECE-1 and -2 activities, suggesting that multivesicular bodies are intracellular sites of Abeta degradation by these enzymes. ECE dysfunction could lead to the accumulation of intraneuronal Abeta aggregates and their subsequent release into the extracellular space via exosomes.-Pacheco-Quinto, J., Clausen, D., Perez Gonzalez, R., Peng, H., Meszaros, A., Eckman, C. B., Levy, E., Eckman, E. A. Intracellular metalloprotease activity controls intraneuronal Abeta aggregation and limits secretion of Abeta via exosomes. PMID- 30481491 TI - A new inner-city specialist programme reduces readmission rates in frequently admitted patients with bipolar disorder. AB - Aims and methodThe OPTIMA mood disorders service is a newly established specialist programme for people with bipolar disorder requiring frequent admissions. This audit compared data on hospital admissions and home treatment team (HTT) spells in patients before entry to and after discharge from the core programme. We included patients admitted between April 2015 and March 2017 who were subsequently discharged. Basic demographic data and numbers of admissions and HTT spells three years before and after discharge were collected and analysed. RESULTS: Thirty patients who completed the programme were included in the analyses. The median monthly rate of hospital admissions after OPTIMA was significantly reduced compared with the rate prior to the programme. HTT utilisation was numerically reduced, but this difference was not statistically significant.Clinical implicationsThese results highlight the effectiveness and importance of individually tailored, specialist care for patients with bipolar disorder following discharge from hospital.Declaration of interestNone. PMID- 30481492 TI - Research Letter: Evaluation of Proposed Criteria for Research Reporting of Amniotic Fluid Embolism. PMID- 30481493 TI - Positive pressure ventilation compresses pulmonary acinar microvessels but not their supply vessels. AB - Pulmonary alveolar septal capillaries receive their perfusion from a web of larger surrounding acinar vessels. Using 4 MUm diam. Latex particles, we showed that positive pressure ventilation narrowed the acinar vessels as evidenced by venous 4 MUm particle concentrations and perfusate flows <50% of particle concentrations in negative pressure ventilated lungs. We aimed to understand the effects of positive and negative pressure ventilation on flows of larger particles through the lung. Isolated, ventilated rat lungs (air, transpulmonary pressures of 15/5 cm H2O, 25 breaths/min) were perfused with a hetastarch solution at Ppulm art/PLA pressures of 10/0 cm H2O. Red latex 7 MUm (2.5 mg, 4.8 * 106) or 15 MUm (2.5 mg, 5.5 * 105) particles were infused into each lung during positive or negative pressure ventilation. An equal number of green particles was infused 20 min later. Flows through lungs infused with 7 MUm and 15 MUm particles were not different from flows through lungs infused with 4 MUm particles (p = 0.811). Venous particle concentrations of 7 MUm particles relative to infused particles were lower in positive pressure lungs (0.03 +/- 0.03%) compared to negative pressure lungs (0.17 +/- 0.12%) (p = 0.041). Venous particle concentrations of 15 MUm particles were not different between positive (2.3 +/- 1.9%) and negative (3.3 +/- 1.8%) pressure ventilation (p = 0.406). Together with our previous study, we conclude that 4 MUm and 7 MUm particles both enter acinar vessels but that the 7 MUm particles are too large to flow through those vessels. In contrast, we conclude that 15 MUm particles bypass the acinar vessels, flowing instead through larger intrapulmonary vessels to enter the venous outflow. These findings suggest that intrapulmonary vessels are organized as a web that allows bypass of the acinar vessels by large particles and, that these bypass vessels are not compressed by positive pressure ventilation. PMID- 30481494 TI - Natural and synthetic peptides in the cardiovascular diseases: An update on diagnostic and therapeutic potentials. AB - Several peptides play an important role in physiological and pathological conditions into the cardiovascular system. In addition to well-known vasoactive agents such as angiotensin II, endothelin, serotonin or natriuretic peptides, the vasoconstrictor Urotensin-II (Uro-II) and the vasodilators Urocortins (UCNs) and Adrenomedullin (AM) have been implicated in the control of vascular tone and blood pressure as well as in cardiovascular disease states including congestive heart failure, atherosclerosis, coronary artery disease, and pulmonary and systemic hypertension. Therefore these peptides, together with their receptors, become important therapeutic targets in cardiovascular diseases (CVDs). Circulating levels of these agents in the blood are markedly modified in patients with specific CVDs compared with those in healthy patients, becoming also potential biomarkers for these pathologies. This review will provide an overview of current knowledge about the physiological roles of Uro-II, UCN and AM in the cardiovascular system and their implications in cardiovascular diseases. It will further focus on the structural modifications carried out on original peptide sequences in the search of analogues with improved physiochemical properties as well as in the delivery methods. Finally, we have overviewed the possible application of these peptides and/or their precursors as biomarkers of CVDs. PMID- 30481495 TI - Online Care versus In-Person Care for Improving Quality of Life in Psoriasis: A Randomized Controlled Equivalency Trial. AB - This 12-month, pragmatic, randomized controlled equivalency trial evaluated whether an online, collaborative connected-health model results in equivalent improvements in quality of life as compared to in-person care for psoriasis. 296 adults with physician-diagnosed psoriasis from ambulatory clinics were randomized to either online or in-person care; all were analyzed for outcomes. In the online group, patients and primary care providers (PCPs) sought dermatologists' care directly and asynchronously online. The in-person group sought care face-to-face. Interventions did not allow blinding of participants; investigators were blinded during analysis. Across 12 months, for the online group, the mean decline in Skindex-16 from baseline across follow-up visits was 9.02 (+/-20.67) compared with 10.55 (+/-23.50) for the in-person group. The difference in Skindex-16 between the two groups was -0.83 (95%CI -5.18, 3.51) and was within the equivalence margin (+/-7.0). For the online group, the mean decline in Dermatology Life Quality Index (DLQI) was 1.64 (+/-4.34) compared with 1.18 (+/ 4.77) for the in-person group. The difference in DLQI between the two groups was 0.45 (95%CI -1.29, 0.38) and was within the equivalence margin (+/-2.5). In conclusion, the online model was as effective as in-person care in improving quality of life among psoriasis patients. This study was funded by the Patient Centered Outcomes Research Institute (PCORI) and registered on clinicaltrials.gov (NCT02358135). PMID- 30481496 TI - Donor-Site Morbidity After Osteocutaneous Free Fibula Transfer: Longitudinal Analysis of Gait Performance. AB - PURPOSE: The purpose was to evaluate donor-site clinical morbidity and changes in kinematic gait parameters after the harvest of a vascularized free fibula flap for facial reconstruction. MATERIALS AND METHODS: We enrolled 14 patients (aged 50 +/- 15 years) in a longitudinal study. Every patient underwent a double evaluation in which a presurgical assessment and 6-month postsurgical assessment were performed. Subjective donor-site evaluation was carried out through unstructured clinical questioning about pain, paresthesia, walking ability, and restrictions in activity. Further subjective evaluations were assessed through the Western Ontario and McMaster Universities Osteoarthritis Index and the Point Evaluation System for Lower Extremity Fibulectomy. A clinical evaluation of the donor site assessed muscular deficits, sensibility disturbance, and wound healing. Temporal and spatial kinematic parameters were measured through gait analysis during overground walking at a comfortable speed. RESULTS: Postsurgical clinical examinations detected 1 patient affected by a neurologic disorder and 3 patients with donor-site pain, whereas 10 patients (71%) declared no residual alterations in the operated leg. On average, the Western Ontario and McMaster Universities Osteoarthritis Index score was 367 of 2,400, and the Point Evaluation System for Lower Extremity Fibulectomy score was 19 of 24. Presurgical versus postsurgical gait analysis comparison showed no significant differences in gait parameters except for a 6% reduction in the double-support phase. Stance values were higher for the operated limb in both evaluations (+1.3% before surgery, +1.8% after surgery). No alterations were detected in the range of motion of the lower-limb joints. CONCLUSIONS: Considering the slight modification of the gait pattern, which is not usually perceived by patients, vascularized free fibula flap harvest was generally associated with successful functional and subjective outcomes of the donor site. PMID- 30481497 TI - Cannabidiol reduces airway inflammation and fibrosis in experimental allergic asthma. AB - Asthma is characterized by chronic lung inflammation and airway hyperresponsiveness. Asthma remains a major public health problem and, at present, there are no effective interventions capable of reversing airway remodelling. Cannabidiol (CBD) is known to exert immunomodulatory effects through the activation of cannabinoid-1 and -2 (CB1 and CB2) receptors located in the central nervous system and immune cells, respectively. However, as the role of CBD on airway remodelling and the mechanisms of CB1 and CB2 aren't fully elucidated, this study was designed to evaluate the effects of cannabidiol in this scenario. Allergic asthma was induced in Balb/c mice exposed to ovalbumin, and respiratory mechanics, collagen fibre content in airway and alveolar septa, cytokine levels, and CB1 and CB2 expression were determined. Moreover, expressions of CB1 and CB2 in induced sputum of asthmatic individuals and their correlation with airway inflammation and lung function were also evaluated. CBD treatment, regardless of dosage, decreased airway hyperresponsiveness, whereas static lung elastance only reduced with high dose. These outcomes were accompanied by decreases in collagen fibre content in both airway and alveolar septa and the expression of markers associated with inflammation in the bronchoalveolar lavage fluid and lung homogenate. There was a significant and inverse correlation between CB1 levels and lung function in asthmatic patients. CBD treatment decreased the inflammatory and remodelling processes in the model of allergic asthma. The mechanisms of action appear to be mediated by CB1/CB2 signalling, but these receptors may act differently on lung inflammation and remodelling. PMID- 30481498 TI - Disturbance of energetic homeostasis and oxidative damage provoked by trichlorfon as relevant toxicological mechanisms using silver catfish as experimental model. AB - Recent evidences have suggested the involvement of phosphoryl transfer, catalyzed by creatine kinase (CK), adenylate kinase (AK) and pyruvate kinase (PK), to metabolic alterations and impairment of bioenergetics homeostasis linked to adenosine triphosphate (ATP) production, and utilization during exposure to pesticides. It is recognized that sublethal concentrations of trichlorfon alter hepatic and branchial metabolism, but the pathways involved in this process remains unknown. Thus, the aim of this study was to evaluate whether phosphoryl transfer network can be a pathway involved in the hepatic and branchial metabolic alterations during exposure to sublethal concentrations of trichlorfon. Hepatic and branchial CK (cytosolic and mitochondrial isoforms) and PK activities were inhibited after 48 h of exposure to 11 and 22 mg/L trichlorfon compared to control group, while AK activity did not differ between groups. In addition, sodium-potassium pump (Na+, K+-ATPase) activity was lower after 48 h of exposure to 22 mg/L trichlorfon compared to control group. Thiobarbituric acid reactive substances (TBARS) were higher in liver samples after 24 h of exposure to 22 mg/L trichlorfon compared to control group, as well as after 48 h of exposure to 11 and 22 mg/L trichlorfon in liver and gills. Finally, hepatic and branchial non protein thiol (NPSH) levels were lower after 48 h of exposure to 11 and 22 mg/L trichlorfon. All evaluated parameters did not recover after 48 h in clean water. Based on these evidence, the impairment of phosphoryl transfer network can be considered a pathway involved in the hepatic and branchial metabolic alterations during exposure to sublethal concentrations of trichlorfon. Moreover, alterations on CK and PK activities provoke an impairment on Na+, K+-ATPase activity, which can be mediated by lipid oxidative damage and reduction of NPSH content. PMID- 30481499 TI - Neuroprotective role of hyperforin on aluminum maltolate-induced oxidative damage and apoptosis in PC12 cells and SH-SY5Y cells. AB - Many reports demonstrated that aluminum maltolate (Almal) has potential toxicity to human and animal. Our study has demonstrated that Almal can induce oxidative damage and apoptosis in PC12 cells and SH-SY5Y Cells, two in vitro models of neuronal cells. Hyperforin (HF) is a well-known antioxidant, anti-inflammatory, anti-amyloid and anti-depressant compound extracted from Hypericum perforatum extract. Here, we investigated the neuroprotective effect of HF against Almal induced neurotoxicity in cultured PC12 cells and SH-SY5Y cells, mainly caused by oxidative stress. In the present study, HF significantly inhibited the formation of reactive oxygen species (ROS), decreased the level of lipid peroxide and enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) compared with Almal group in PC12 cells and SH-SY5Y cells. Additionally, HF suppressed the reduction of the mitochondrial membrane potential (MMP), cytochrome c (Cyt-c) release, activation of caspase-3, and the down-regulation of Bcl-2 expression and up-regulation of Bax expression induced by Almal in PC12 cells and SH-SY5Y cells. In summary, HF protects PC12 cells and SH-SY5Y cells from damage induced by Almal through reducing oxidative stress and preventing of mitochondrial-mediated apoptosis. PMID- 30481500 TI - Effects of inter-day and intra-day variation on salivary metabolomic profiles. AB - BACKGROUND: Salivary secretion is an important parameter reflecting the health status of an individual and has been used clinically for the diagnosis of various oral diseases, such as xerostomia. Salivary metabolomic profiling is considered an emerging potential tool for the detection of various systemic diseases. To our knowledge, this is the first study to investigate the quantitative relationship between salivary secretion volume and salivary metabolomic profile. METHODS: To evaluate inter- and intra-day variations in salivary secretion, 234 saliva samples were collected three times per day for three days from 13 subjects and analyzed. Capillary electrophoresis-mass spectrometry was used for non-targeted quantification of water-soluble metabolites. RESULTS: No significant inter- or intra-day variations were observed in salivary secretion volume. No significant inter-day variations were observed in metabolomic patterns. In contrast, significant intra-day variations were observed in salivary metabolomic profiles. The difference was more obvious for stimulated saliva than for unstimulated saliva. These profile changes were independent of salivary secretion volume. CONCLUSIONS: Our results indicated that diurnal change had a greater effect on salivary metabolomic profiles than the other factors. Hence, sampling time should be tightly controlled to minimize unexpected bias in the clinical use of salivary metabolomics. PMID- 30481501 TI - Successful treatment of pleural empyema caused by an intrathoracic esophageal fistula after iatrogenic esophageal perforation with polyglycolic acid sheets. PMID- 30481502 TI - ScFv-conjugated superparamagnetic iron oxide nanoparticles for MRI-based diagnosis in transgenic mouse models of Parkinson's and Huntington's diseases. AB - It is widely accepted that amyloid oligomers are the most toxic species to initiate the pathologic processes of Parkinson's disease (PD) and Huntingdon's disease (HD). But there is no definitive diagnosis for PD and HD at their early stages. Here, we conjugated an amyloid oligomer-specific scFv antibody (W20) to PEGylated superparamagnetic iron oxide nanoparticles (SPIONs) and detected the properties of the SPIONs conjugated with W20. The results showed that W20-SPIONs, with the size of around 11.8 nm in diameter, were stable and nontoxic, and had enough relaxation capacity to be used as an MRI contrast agent. When applied to the transgenic mouse models of PD and HD, W20-SPIONs crossed the blood-brain barrier and specifically bound to the oligomer area to give MRI signal, distinguishing PD and HD from healthy controls. These results indicated that W20 SPIONs had potential in early-stage diagnosis for PD and HD and also opened up a new strategy for evaluating the efficacy of new drugs. PMID- 30481503 TI - The role of dopamine in mood disorders and the associated changes in circadian rhythms and sleep-wake cycle. AB - Dopamine is primarily produced in the substantia nigra (SN) and the ventral tegmentum area (VTA) in the brain. It plays a well-established role in the motor control, reward, mood regulation and addiction behaviour. Dopamine release has been shown to be regulated by the circadian clock and hence, plays a regulatory role in the sleep-wake cycle. Clinically, dopaminergic agents have been widely used to modulate alertness. The following review offers a demonstration of the heterogeneous dopamine system in the brain and the various studies investigating the circadian rhythmicity of the dopamine system and its regulation of sleep-wake behaviour. Additionally, it suggests a potential link between the circadian clock and the sleep-wake cycle in mood regulation through the dopaminergic system. PMID- 30481504 TI - Orexin as a modulator of fear-related behavior: Hypothalamic control of noradrenaline circuit. AB - Fear is an important physiological function for survival. It appears when animals or humans are confronted with an environmental threat. The amygdala has been shown to play a highly important role in emergence of fear. Hypothalamic orexin neurons are activated by fearful stimuli to evoke a 'defense reaction' with an increase in arousal level and sympathetic outflow to deal with the imminent danger. However, how this system contributes to the emergence of fear-related behavior is not well understood. Orexin neurons in the hypothalamus send excitatory innervations to noradrenergic neurons in the locus coeruleus (NALC) which express orexin receptor 1 (OX1R) and send projections to the lateral amygdala (LA). Inhibition of this di-synaptic orexin->NALC->LA pathway by pharmacological or opto/chemogenetic methods reduces cue-induced fear expression. Excitatory manipulation of this pathway induces freezing, a fear-related behavior that only occurs when the environment contains some elements suggestive of danger. Although, fear memory helps animals respond to a context or cue previously paired with an aversive stimulus, fear-related behavior is sometimes evoked even in a distinct context containing some similar elements, which is known as fear generalization. Our recent observation suggests that the orexin >NALC->LA pathway might contribute to this response. This review focuses on recent advances regarding the role of hypothalamic orexin neurons in behavioral fear expression. We also discuss the potential effectiveness of orexin receptor antagonists for treating excessive fear response or overgeneralization seen in anxiety disorder and post-traumatic stress disorder (PTSD). PMID- 30481505 TI - Nerve growth factor metabolic dysfunction contributes to sevoflurane-induced cholinergic degeneration and cognitive impairments. AB - General anesthesia with sevoflurane is associated with an increased incidence of postoperative cognitive dysfunction. Previous studies have shown that sevoflurane anesthesia can affect the integrity and function of basal forebrain cholinergic neurons (BFCNs) which are essential for learning and memory. However, the underlying mechanisms remain largely unknown. Here, we demonstrated that exposure to 2.5% sevoflurane induced significant loss of BFCNs and caused impairments of the spatial and the fear memory. Further, sevoflurane exposure significantly reduced the level of nerve growth factor (NGF), an important factor for the survival and phenotype maintenance of BFCNs, by disrupting its synthesis pathways in the brain. More importantly, NGF administration not only prevented the loss of BFCNs but also ameliorated the cognitive impairments in sevoflurane-treated mice. Our findings indicate that NGF metabolic dysfunction contributes to sevoflurane associated BFCNs degeneration and subsequent cognitive deficits. PMID- 30481506 TI - Polydatin attenuates spinal cord injury in rats by inhibiting oxidative stress and microglia apoptosis via Nrf2/HO-1 pathway. AB - AIMS: Spinal cord injury (SCI) is one of the most devastating central lesions, resulting in serious locomotor deficit. Polydatin is a glucoside of resveratrol with proven anti-cardiovascular, anti-inflammatory and anti-oxidative properties. The main purpose of this study was to investigate whether polydatin could alleviate SCI in rats and explore the underlying mechanisms. MATERIALS AND METHODS: SCI rats induced by a weight-drop device were treated with intraperitoneal injection of 20 or 40 mg/kg polydatin. Then the locomotor function of SCI rats was evaluated by the Basso, Beattie and Bresnahan locomotor rating scale, spinal cord edema was measured by the wet/dry weight method, oxidative stress markers were detected by commercial kits and cell apoptosis status was measured by TUNEL staining. In addition, reactive oxygen species (ROS) generation, lactate dehydrogenase (LDH) production and apoptosis status were detected in murine microglia BV2 cells treated with 100 ng/ml lipopolysaccharides (LPS) and 4.0 MUM polydatin. The expression of apoptosis-related proteins involved in nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway was measured by western blot. KEY FINDINGS: Our data showed that polydatin treatment improved locomotor performance of SCI rats, as well as reduced oxidative stress and inhibited apoptosis by enhancing Nrf2/HO-1 signaling. In addition, polydatin was found to up-regulate Nrf2 activity and the inhibitory effects of polydatin on oxidative stress and apoptosis in LPS stimulated BV2 microglia was neutralized by silencing Nrf2 using specific siRNA. SIGNIFICANCE: We demonstrate that polydatin may protect the spinal cord from SCI by suppression of oxidative stress and apoptosis via improving Nrf2/HO-1 signaling in microglia. PMID- 30481507 TI - Ameliorative effect of alendronate against intracerebroventricular streptozotocin induced alteration in neurobehavioral, neuroinflammation and biochemical parameters with emphasis on Abeta and BACE-1. AB - Alzheimer's disease (AD) is the most prevalent age related neurodegenerative disorder manifested by progressive cognitive decline and neuronal loss in the brain, yet precise etiopathology of majority of sporadic or late-onset AD cases is unknown. AD is associated with various pathological events such as Abeta deposition due to BACE-1 induced cleavage of APP, neuroinflammation, increased cholesterol synthesis, cholinergic deficit and oxidative stress. It was found that bone drug, alendronate (ALN) that cross blood brain barrier inhibits brain cholesterol synthesis and AChE enzyme activity. As cholesterol modifying agents have been supposed to alter AD like pathologies, the current study was designed to investigate the possible neuroprotective and therapeutic potential of ALN against ICV STZ induced experimental sporadic AD (SAD) in mice in a non cholesterol dependent manner, using donepezil (5 mg/kg) as a reference standard. The preliminary study was done by molecular modelling to identify the binding affinity of ALN with BACE-1 in silico. The prevention of cognitive impairment in mice induced by ICV STZ (3 mg/kg) infused on first and third day, by ALN (1.76 mg/kg p.o.) administered for 15 consecutive days was assessed through Spontaneous Alternation Behavior (SAB) and Morris water maze (MWM) test. Additionally, the protective effect of ALN was also observed by the reversal of altered levels of Abeta1-42, BACE-,1 neuroinflammatory cytokines, AChE activity and oxidative stress markers (except TBARS) in ICV-STZ infused mice. However, the findings of the present study imply the therapeutic potential of ALN against SAD-like complications. PMID- 30481508 TI - Clinical validation of coexisting driver mutations in colorectal cancers. AB - Mutational profiling is recommended for selecting targeted therapy and predicting prognosis of metastatic colorectal cancer (CRC). Detection of coexisting mutations within the same pathway, which are usually mutually exclusive, raises the concern for potential laboratory errors. In this retrospective study for quality assessment of a next generation sequencing assay, we examined BRAF, KRAS and NRAS genes within the mitogen-activated protein kinase (MAPK) pathway and the PIK3CA gene within the phosphatidylinositol 3-kinase (mTOR) pathway in 744 CRC specimens submitted to our clinical diagnostics laboratory. While coexistence of mutations between the MAPK and mTOR pathways was observed, it rarely occurred within the MAPK pathway. Retrospective quality assessments identified false detection of coexisting activating KRAS and NRAS mutations in one specimen, and confirmed two activating KRAS mutations in 2 specimens and coexisting activating KRAS and NRAS mutations in 2 specimens, but no coexisting activating RAS and BRAF mutations. There were 15 CRCs with a kinase impaired BRAF mutation, including 3 with a coexisting activating KRAS mutation, which may have therapeutic implications. Multiregional analysis based on different histological features demonstrated that coexisting KRAS and NRAS mutations may be present in the same or different tumor populations, and showed that invasion of adenomas by synchronous adenocarcinomas of different clonal origin may result in detection of coexisting mutations within the MAPK pathway. In this study, we proposed an operating procedure for clinical validation of unexpected coexisting mutations. Further studies are warranted to elucidate the biological significance and clinical implications of coexisting mutations within the MAPK pathway. PMID- 30481509 TI - Evolving concepts in prostatic neuroendocrine manifestations: from focal divergent differentiation to AMPHICRINE carcinoma. AB - Prostatic neuroendocrine manifestations encompass a heterogeneous spectrum of morphological entities. In the era of evidence-based and precision-led treatment, distinction of biologically relevant clinical manifestations expanded the evolving clinical role of pathologists. Recent observations on the occurrence of hormone-therapy induced aggressive prostatic cancers with neuroendocrine features have triggered the need to refine the spectrum and nomenclature of prostatic neuroendocrine manifestations. Although the morphological assessment still remains the basis of the diagnostic workup of prostatic neoplasms, the application of ancillary biomarkers is crucial in the accurate classification of such presentations. This review provides a diagnostic roadmap for the practicing pathologist by reviewing the characteristic morphological, immunohistochemical and molecular correlates of various faces of prostatic neuroendocrine manifestations. PMID- 30481510 TI - Cardiorespiratory Fitness and Physical Activity: Two Important but Distinct Clinical Measures with Different Degrees of Precision - A Commentary. PMID- 30481511 TI - TLX knockdown in the dorsal dentate gyrus of juvenile rats differentially affects adolescent and adult behaviour. AB - The orphan nuclear receptor TLX is predominantly expressed in the central nervous system and is an important factor regulating the maintenance and self-renewal of neural stem cells from embryonic development through adulthood. In adolescence and adulthood, TLX expression is restricted to the neurogenic niches of the brain: the dentate gyrus of the hippocampus and the subventricular zone. The adolescent period is critical for maturation of the hippocampus with heightened levels of neurogenesis observed in rodents. Therefore, we investigated whether lentiviral silencing of TLX expression (TLX knockdown) in the dorsal dentate gyrus in juvenile rats incurred differential impairments in behaviour during late adolescence and adulthood. Our results showed that knockdown of TLX in the dorsal dentate gyrus led to a decrease in cell proliferation in the dorsal but not ventral dentate gyrus. At a behavioural level we observed differential effects in adolescence and adulthood across a number of parameters. A hyperactive phenotype was present in adolescent but not adult TLX knockdown rats, and an increase in immobility during adolescence and in swimming frequency during adulthood was observed in the forced swim test. There was an increased defecation frequency in the open field during adulthood but not adolescence. There were no changes in cognitive performance on hippocampus-dependent tasks or in anxiety-related behaviours. In conclusion, silencing of TLX in the dorsal dentate gyrus led to impairments in hippocampal-independent behaviours which either did not persist or were reversed during adulthood. The current data highlight the temporal importance and function of the nuclear receptor TLX during development. PMID- 30481512 TI - Comparison between stereotactic radiotherapy and sublobar resection for non-small cell lung cancer (Commentary). PMID- 30481514 TI - The Impact of Donor and Recipient Age: Older Lung Transplant Recipients Do Not Require Younger Lungs (Commentary). PMID- 30481513 TI - Prevalence and Natural History of Barrett's Esophagus in Lung Transplant: A Single-Center Experience. AB - BACKGROUND: Barrett's esophagus (BE)-intestinal metaplasia in the esophagus-may progress to low-grade dysplasia (LGD), high-grade dysplasia (HGD), and ultimately, invasive esophageal adenocarcinoma (EAC). The course of BE in immunosuppressed lung transplant recipients is unknown. METHODS: We retrospectively reviewed the records of patients who underwent lung transplant at our center between 01/01/2010 and 10/31/2016. We analyzed pre-transplant esophagram, esophagogastroduodenoscopy, 24-hour pH monitoring, high-resolution manometry, and gastric emptying studies. RESULTS: Of the 466 patients who underwent transplantation during the study period, 54 (11.59%) had BE on pre transplant esophagogastroduodenoscopy. Of these, one patient had HGD pre transplant. Median patient age was 64 years (interquartile range [IQR], 58.25 68.75) ; 66.6% were men. Median follow-up duration was 29.48 months (IQR, 19.69 37.98). 16/54 patients (29.62%) underwent antireflux surgery posttransplant. Three patients developed LGD or EAC during posttransplant surveillance. One patient was diagnosed with HGD 24 months after retransplant. She underwent complete endoscopic ablation and was dysplasia-free for 5 months, but ultimately recurred and underwent esophagectomy for invasive cancer. Two patients were diagnosed with LGD 7 and 13 months after transplant and were successfully treated with radiofrequency ablation. The rate of progression to dysplasia or EAC was 2.3% per patient-year. CONCLUSIONS: BE seems to be more prevalent in lung transplant recipients than in the general population. Our findings suggest that patients with BE have higher risk of BE-to-EAC progression after lung transplant, and that HGD may progress rapidly in immunosuppressed patients. More intensive surveillance endoscopy may be required in patients with BE after lung transplant. PMID- 30481515 TI - Damus-Kaye-Stansel: Valuable option for retraining of Left ventricle in late arterial switch for Transposition of great arteries. AB - Management of Transposition of great vessels (d-TGA) with intact interventricular septum along with regression of left ventricular (LV) remains a challenge. Atrial switch always raises concern of fate of right ventricle as a systemic ventricle in long run. Two stage repair with pulmonary artery banding and modified Blalock Taussig shunt or single stage arterial switch with mechanicalsupporthas a higher mortality and morbidity. Here, we report a case of 3 year girl with d-TGA with IVS managed by Damus-Kaye-Stansel with right bidirectional. cavopulmonary anastomosis in first stage to train LV followed by definitive surgery (arterial switch) in second stage. PMID- 30481516 TI - Endovascular Versus Open Repair For Chronic Type B Dissection Treatment: A meta analysis. AB - BACKGROUND: The respective place of endovascular versus open surgery in thoracic dissecting aneurysm treatment remains debatable. This comprehensive review seeks to analyse the outcomes of endovascular repair (ER) compared to open surgery (OS) in chronic type B aortic dissection treatment. METHODS: Embase and Medline searches (2000 - 2017)were performed following Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Outcomes data extracted comprised firstly early mortality and major complications: stroke, spinal cord ischemia (SCI), dialysis, respiratory complications; secondly, late survival and reinterventions. Reintervention causes were divided into proximal, adjacent, distal. Comparative studies provided comparative meta-analyses. Non-comparative studies were analysed in pooled proportion meta-analyses for each group. RESULTS: 39 studies were identified: 10 OS, 25 ER, 4 comparative. Comparative studies meta analyses revealed lower early mortality for ER (OR: 4.13, 95% CI: 1.10 - 15.4), stroke (OR: 4.33, 95% CI: 1.02-18.35), SCI (OR: 3.3, 95% CI: 0.97 - 11.25) and respiratory complications (OR: 6.88, 95% CI:1.52- 31.02), but higher reintervention rate (OR: 0.34, 95% CI: 0.16 - 0.69). Mid-term survival was similar (OR: 1.19, 95% CI:0.42 - 3.32). Non-comparative studies analyses showed distal causes as the principal reintervention indication in both groups: OS 73%; ER 59%. Reintervention procedures were mainly surgical for OS (85%), mainly endovascular for ER (75%). Rupture rates were: OS 1.2% , ER 3%. CONCLUSIONS: This recent non -randomised data shows early ER benefit, unsustained at mid-term. Reintervention is higher after ER, necessitating improved technique. However, OS is exempt neither from reintervention nor rupture. Both techniques have their place, but patient selection is key. PMID- 30481517 TI - What are the criteria of success after neonatal arch reconstruction in the long term? PMID- 30481518 TI - Patient-specific multiscale modeling of the Assisted Bidirectional Glenn (Commentary). PMID- 30481519 TI - Severity of presentation, not sex, increases risk of surgery for infective endocarditis (Commentary). PMID- 30481520 TI - Blunt trauma-induced pericardial tamponade after video-assisted thoracoscopic surgery. AB - We report a case of blunt cardiac injury and pericardial tamponade following video-assisted thoracoscopic surgery (VATS) in a lung cancer patient with hypertension and cardiac hypertrophy. Anatomical findings included massive hemorrhage in the pericardium, cardiac hypertrophy, and a superficial contusion with a ruptured blood vessel on the epicardium at the lateral wall of the left ventricle. The patient died of pericardial tamponade due to blunt trauma from the tip of the thoracoscopic instrument. This case suggests that detailed assessment of the cardiovascular system, especially cardiac hypertrophy, careful preparation before surgery and careful monitoring of postoperative conditions are important. PMID- 30481521 TI - Outcomes of Surgical Ablation in Patients with Atrial Fibrillation Undergoing Cardiac Surgeries. AB - BACKGROUND: Surgical ablation procedure is commonly performed in patients with atrial fibrillation (AF) undergoing cardiac surgeries; however, the evidence regarding its impact on in-hospital cardiovascular outcomes is controversial. METHODS: We queried the Nationwide Inpatient Sample Database from 1998-to-2013 for patients with AF who underwent cardiac surgeries. We performed a propensity score matching including 27 various baseline characteristics to compare those who underwent surgical ablation versus not. RESULTS: A total of 47,964 hospitalizations were included in our final analysis. On propensity matching, 23,975 were in the surgical ablation group and 23,990 in the control group. The primary outcome of in-hospital mortality was lower in the surgical ablation group compared with the control group (3.6% vs. 4.2%, p<0.001). The surgical ablation group was associated with lower in-hospital cerebrovascular accident (CVA; 2.0% vs. 2.8%, p<0.001), cardiogenic shock (2.6% vs. 3.6%, p<0.001), use of intra aortic balloon pump (5.1% vs. 5.8%, p=0.001) and shorter length of hospital stay (12.3+/-10.1 vs. 12.5 +/- 10.3 days, p=0.008). There was no difference between the surgical ablation and control groups in the incidence of cardiac tamponade (0.4% vs. 0.3%, p=0.296). The surgical ablation group was associated with a higher rate of complete heart block (5.2% vs. 4.3%, p<0.001) and permanent pacemaker insertion (8.6% vs. 8.0%, p=0.01). CONCLUSIONS: In this large analysis of almost 50,000 subjects with AF undergoing cardiac surgery, surgical ablation appears to be safe in the short term. Future studies should focus on evaluating the long term effectiveness of this procedure. PMID- 30481522 TI - Sexual differentiation of microglia. AB - Sex plays a role in the incidence and outcome of neurological illnesses, also influencing the response to treatments. Despite sexual differentiation of the brain has been extensively investigated, the study of sex differences in microglia, the brain's resident immune cells, has been largely neglected until recently. To fulfill this gap, our laboratory developed several tools, including cellular and animal models, which bolstered in-depth studies on sexual differentiation of microglia and its impact on brain physiology, as well as on the onset and progression of neurological disorders. Here, we summarize the current status of knowledge on the sex-dependent function of microglia, and report recent evidence linking these cells to the sexual bias in the susceptibility to neurological brain diseases. PMID- 30481523 TI - Extended cleavage specificity of sheep mast cell protease-2: A classical chymase with preference to aromatic P1 substrate residues. AB - Serine proteases constitute the major protein content of mammalian mast cell granules and the selectivity for substrates by these proteases is of major importance for the role of mast cells in immunity. In order to address this subject, we present here the extended cleavage specificity of sheep mast cell protease-2 (MCP2), a chymotrypsin-type serine protease. Comparison of the extended specificity results to a panel of mammalian mast cell chymases show, in almost all aspects, the same cleavage characteristics. This includes preference for aromatic residues (Phe, Tyr, Trp) in the P1 position of substrates and a preference for aliphatic residues in most other substrate positions around the cleavage site. MCP2 also cleaved, albeit relatively low efficiency, after Leu in the P1 position. In contrast to the human, mouse, hamster and opossum chymases that show a relatively strong preference for negatively charged amino acids in the P2'position, the sheep MCP2, however, lacked that preference. Therefore, together with the rat chymase (rMCP1), sheep MCP2 can be grouped to a small subfamily of mammalian chymases that show fairly unspecific preference in the P2'position. In summary, the results here support the view of a strong evolutionary conservation of a potent chymotrypsin-type protease as a key feature of mammalian mast cells. PMID- 30481524 TI - A comparative global proteomic analysis of the hematopoietic lineages in the crustacean Pacifastacus leniusculus. AB - In crustaceans as in other arthropods, the circulating hemocytes are vital for protecting the animal against attacking microorganisms. As many hemocytes are destroyed early during an infection, new hemocytes must fast get in place to prevent disperse of a pathogenic microbe, In order to understand the hematopoietic process in more detail we here report a complete proteomic analysis from purified cell types from the APC of the hematopoietic tissue, via the remaining parts of the HPT to the mature semigranular and granular hemocytes. Several possible cell type specific proteins are detected and new putative biomarkers within the crayfish hematopoietic lineage that can be used to increase the understanding of how the differentiation process is regulated is described. PMID- 30481525 TI - A synthetic glycosaminoglycan mimetic blocks HSV-1 infection in human iris stromal cells. AB - Herpes simplex virus type-1 (HSV-1) is a significant pathogen that affects vision by targeting multiple regions in the human eye including iris. Using a focused library of synthetic non-saccharide glycosaminoglycan mimetics (NSGMs), we identified sulfated pentagalloylglucoside (SPGG) as a potent inhibitor of HSV-1 entry and cell-to-cell spread in the primary cultures of human iris stromal (HIS) cells isolated from eye donors. Using in vitro beta-galactosidase reporter assay and plaque reduction assay, SPGG was found to inhibit HSV-1 entry in a dosage dependent manner (IC50 ~6.0 MUM). Interestingly, a pronounced inhibition in HSV-1 entry and spread was observed in HIS cells, or a cell line expressing specific gD receptor, when virions were pre-treated with mimetics suggesting a possible interaction between SPGG and the HSV-1 glycoprotein. To examine the significance of gD-SPGG interaction, HIS cells were pretreated with SPGG, which showed a significant reduction in gD binding. Taken together, our results provide strong evidence of SPGG being a novel viral entry inhibitor against ocular HSV infection. PMID- 30481526 TI - Pharmacological classification of centrally acting drugs using EEG in freely moving rats: An old tool to identify new atypical dopamine uptake inhibitors. AB - Atypical dopamine uptake inhibitors (DUIs) bind to the dopamine transporter and inhibit the reuptake of dopamine but have lower abuse potential than psychostimulants. Several atypical DUIs can block abuse-related effects of cocaine and methamphetamine, thus making them potential medication candidates for psychostimulant use disorders. The aim of the current study is to establish an in vivo assay using EEG for the rapid identification of atypical DUIs with potential for medication development. The typical DUIs cocaine and methylphenidate dose dependently decreased the power of the alpha, beta, and gamma bands. The atypical DUI modafinil and its F-analog, JBG1-049, decreased the power of beta, but in contrast to cocaine, none of the other frequency bands, while JHW007 did not significantly alter the EEG spectrum. The mu-opioid receptor agonists heroin and morphine dose-dependently decreased the power of gamma and increased power of the other bands. The effect of morphine on EEG power bands was antagonized by naltrexone. The NMDA receptor antagonist ketamine increased the power of all frequency bands. Therefore, typical and atypical DUIs and drugs of other classes differentially affected EEG spectra, showing distinctive features in the magnitude and direction of their effects on EEG. Comparative analysis of the effects of test drugs on EEG indicates a potential atypical profile of JBG1-049 with similar potency and effectiveness to its parent compound modafinil. These data suggest that EEG can be used to rapidly screen compounds for potential activity at specific pharmacological targets and provide valuable information for guiding the early stages of drug development. PMID- 30481527 TI - Continuous flash suppression operates in local spatial zones: Effects of mask size and contrast. AB - Continuous flash suppression (CFS) is a technique in which presenting one eye with a dynamic Mondrian sequence prevents a low-contrast target in the other eye from being perceived for many seconds. Frequently used to study unconscious visual processing, CFS bears many similarities with binocular rivalry (BR), another popular dichoptic stimulation technique. It is therefore puzzling that the effect of mask size and contrast seem to differ between CFS and BR. To resolve this discrepancy, we conducted a systematic investigation on the effects of mask size and contrast in CFS. Also, building on findings from BR, we asked if the collinearity of the contours in the Mondrian masker play a role in CFS suppression. Our results showed a robust effect of mask contrast on suppression durations, and an effect of mask size that depended on collinearity. Specifically, higher mask contrasts produced longer suppression regardless of collinearity and mask size. Mask size, on the other hand, had little effect on suppression when collinearity was low and it weakened suppression when collinearity is high. These observations parallel prior findings in BR, further substantiating the close link between the two paradigms and demonstrating the usefulness of a shared explanatory framework describing both phenomena. PMID- 30481528 TI - COUP-TFII revisited: Its role in metabolic gene regulation. AB - Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP-TFII) is an orphan member of the nuclear receptor family of transcriptional regulators. Although hormonal activation of COUP-TFII has not yet been identified, rodent genetic models have uncovered vital and diverse roles for COUP-TFII in biological processes. These include control of cardiac function and angiogenesis, reproduction, neuronal development, cell fate and organogenesis. Recently, an emerging body of evidence has demonstrated COUP-TFII involvement in various metabolic systems such as adipogenesis, lipid metabolism, hepatic gluconeogenesis, insulin secretion, and regulation of blood pressure. The potential relevance of these observations to human pathology has been corroborated by the identification of single nucleotide polymorphism in the human COUP-TFII promoter controlling insulin sensitivity. Of particular interest to metabolism is the ability of COUP-TFII to interact with the Glucocorticoid Receptor (GR). This interaction is known to control gluconeogenesis, principally through direct binding of COUP-TFII/GR complexes to the promoters of gluconeogenic enzyme genes. However, it is likely that this interaction is critical to other metabolic processes, since GR, like COUP-TFII, is an essential regulator of adipogenesis, insulin sensitivity, and blood pressure. This review will highlight these unique roles of COUP-TFII in metabolic gene regulation. PMID- 30481529 TI - Addressing sequelae of developmental regression associated with developmental disabilities: A systematic review of behavioral and educational intervention studies. AB - Developmental regression is characteristic of Rett syndrome and it also occurs in a number of other developmental disabilities. To assist clinicians in identifying promising therapeutic approaches, we identified 38 studies that sought to improve adaptive behavior functioning in cases where developmental regression had either already occurred or was likely to occur. Studies were summarized in terms of (a) participants, (b) intervention, (c) dependent variables, (d) outcomes, (e) study design, and (f) certainty of evidence. The available literature included 136 participants from preschoolers to adults. Most participants (n = 132) had Rett syndrome. Interventions targeted a range of dependent variables (e.g., challenging behavior, communication, motor, and play skills). Multi-component interventions derived from behavior analytic principles were the norm, suggesting the need for clinical expertise in the application of such principles. However, only 12 studies (with 44 participants) were rated as providing conclusive evidence of a positive intervention effect. Future research on the mechanisms underlying developmental regression might lead to new and more effective interventions. PMID- 30481530 TI - Neuroplastic and cognitive impairment in substance use disorders: a therapeutic potential of cognitive stimulation. AB - Drug addiction is a chronic and relapsing disorder in which repeated drug exposure compromises brain neuroplasticity. Brain areas normally involved in learning and goal-directed behaviors become corrupted, which may lead to cognitive deficits that coexist with other addiction symptoms and predict a worse treatment outcome. New learning experiences that are not motivated by drugs may improve both cognitive deficits and drug-induced symptoms by promoting adaptive neuroplastic changes that could alleviate or reverse those involved in addiction. The present review will focus on whether potentiating healthy cognitive function, either by formal cognitive training or non-drug related environmental experiences, could exert beneficial effects in the therapeutics of addiction. Although additional studies are needed, the available clinical and preclinical evidence suggests that cognitive stimulation may provide a valuable adjuvant intervention in drug addiction. PMID- 30481531 TI - What is the key mediator of the neurovascular coupling response? AB - The mechanisms of neurovascular coupling contribute to ensuring brain energy supply is sufficient to meet demand. Despite significant research interest, the mechanisms underlying increases in regional blood flow that follow heightened neuronal activity are not completely understood. This article presents a systematic review and analysis of published data reporting the effects of pharmacological or genetic blockade of all hypothesised signalling pathways of neurovascular coupling. Our primary outcome measure was the percent reduction of the neurovascular response assessed using in vivo animal models. Selection criteria were met by 56 primary sources reporting the effects of 79 treatments. Experimental conditions were grouped into categories targeting mechanisms mediated by nitric oxide (NO), prostanoids, purines, potassium, amongst others. Blockade of neuronal NO synthase was found to have the largest effect of inhibiting any individual target, reducing the neurovascular response by 64% (average of 11 studies). Inhibition of multiple targets in combination with nNOS blockade had no further effect. This analysis points to the existence of an unknown signalling mechanism accounting for approximately one third of the neurovascular response. PMID- 30481532 TI - Viscoelastic and textural properties of canary seed starch gels in comparison with wheat starch gel. AB - In this study, viscoelastic properties and textural profile analysis of starches from two canary seed varieties (CDC Maria and C05041) were compared with wheat starch. Based on amplitude sweep, the limiting strain values were 5.7%, 5.4% and 16.3% for CDC Maria, C05041, and wheat starch gels, respectively. The yield stress values at the linear viscoelastic limit (tauy) and flow point (tauf) of wheat starch (25.4 & 35.5 Pa, respectively) were higher than CDC Maria (14.3 and 24.2 Pa, respectively) and C05041 (6.5 and 9.1 Pa, respectively) starches. On the other hand, canary seed starches showed higher modulus at flow point (Gf, 51.2 108.4 Pa) than wheat starch (41.2 Pa). In frequency sweep, canary seed starch gels showed lower frequency dependency (n' = 0.033-0.009) in comparison with wheat starch gel (n' = 0.063), categorizing the samples between weak and strong gels. On the basis of creep parameters of Burger model, CSSs illustrated more elastic behavior than wheat starch. The results of dynamic temperature sweep showed that canary seed starches exhibited higher peak, final, breakdown and setback viscosities in compare to wheat starch. Textural profile analysis provided the values of hardness (32-101 g), adhesiveness (0.03-0.17 mJ), cohesiveness (0.60-0.97) and gumminess (24.7-83.3 g) for the gels (15% w/w). PMID- 30481533 TI - Comparison on characterization and antioxidant activity of polysaccharides from Ganoderma lucidum by ultrasound and conventional extraction. AB - The polysaccharides of Ganoderma lucidum (GLP) extracted by the methods of ultrasound assisted extraction (UAE) and hot water extraction (HWE) were characterized and the antioxidant activities of GLPUAE and GLPHWE were compared. High performance gel permeation chromatography (HPGPC) showed that the average molecular weight of GLPUAE and GLPHWE were 465.65 kDa and 703.45 kDa, respectively. GLPUAE was composed of mannose, rhamnose, glucose, galactose and arabinose in the molar ratio of 2.58:1.25:11.17:2.5:1, while GLPHWE was composed of the same monosaccharide in the ratio of 3.11:1.11:19.44:2.33:1. GLPHWE showed a relatively higher antioxidant activity than GLPUAE by testing the reducing power, the scavenging ability on 1.1-diphenyl-2-picryl-hydrazyl (DPPH), hydroxyl radical and cellular protective effect on yeast cells from ultraviolet radiation (UV) damage. GLPUAE and GLPHWE were purified by chromatographic column of DEAE-52 cellulose. GLPUAE, GLPHWE and the purified components could be novel antioxidants for functional food. PMID- 30481534 TI - Selective removal of cationic dyes using response surface methodology optimized gum acacia-sodium alginate blended superadsorbent. AB - Gum acacia and sodium alginate were blended to synthesize highly efficient superadsorbent formed by grafting of poly(acrylic acid) (AA) used as monomer onto the hybrid of gum acacia and sodium alginate and the polymeric chains were crosslinked through N,N'-methylene bisacrylamide (MBA). The overall reaction followed free radical polymerization with ammonium persulphate (APS) used as initiator. Response surface methodology integrated with central composite design (RSM-CCD) could synthesize semi-Interpenetrating network (semi-IPN) having maximum swelling capacity of 1749.2% at MBA, APS and AA concentrations of 0.89 * 10-2 mol L-1, 3.29 * 10-2 mol L-1 and 1.46 mol L-1, respectively using 15 mL water at 70 degrees C for 2.5 h. The synthesized sample was found to be selective for removal of cationic dyes upto 97.49%, 95.39% and 94.56% for auramine-O (AO), malachite green (MG) and crystal violet (CV), respectively. Adsorption capacities at equilibrium were calculated experimentally as 2.01 mg g 1, 3.06 mg g-1 and 7.55 mg g-1 for AO, MG and CV, respectively. These dyes could be desorbed with 0.1 N HCl for the recyclization of semi-IPN. Adsorption mechanism involved monolayer formation with three step process of adsorption and followed first order kinetics. Exothermic nature of adsorption was revealed by thermodynamic studies. PMID- 30481536 TI - Towards establishing a higher acceptance rate for PEPTIDES - The peer review process and criteria for acceptance or rejection. PMID- 30481535 TI - Effect of cellulose nanocrystals on the performance of drug loaded in situ gelling thermo-responsive ophthalmic formulations. AB - Triblock poloxamer copolymer (PM) has been extensively utilized to deliver various ophthalmic pharmaceutical compounds. The aim of efficient ophthalmic drug delivery strategy is to attain the longer precorneal resident time and good bioavailability of drugs. In this pursuit, the influence of cellulose nanocrystals (CNC) on the in situ gelation behavior of PM and in vitro release of pilocarpine hydrochloride from the nanocomposites formulations was studied. The critical concentration of gelation of PM being 18% (wt/v) was dropped to 16.6% (wt/v) by the addition of a very low percentage of CNC. The reinforcing nature of CNC via H-bonding in the in situ nanocomposite gel also led to an increase in gel strength along with the sustained release of loaded drugs when compared with the pure PM gel. All formulations revealed that the drug release mechanism is controlled by the Fickian diffusion. Thus, the CNC has a significant effect on the gelation behavior, gel strength, and drug release kinetics of PM-CNC formulations. PMID- 30481538 TI - Shared expression of mucin12 in Ascaris lumbricoides and the human small intestine. AB - This study focuses on the host-parasite relationship of human Ascaris lumbricoides, which is a parasite of the small intestine and is also one of the commonest parasites worldwide. As part of this investigation, we examined the host-parasite relationship assuming that there is a common antigenicity, shared protein between A. lumbricoides and human small intestinal mucosa, using molecular techniques. We obtained three DNA clones from human colon cDNA library by screening for anti-A. lumbricoides polyclonal antibodies. The transmembrane mucin12 gene was identified after sequencing analysis of these clones. Specific signals of immunostaining with polyclonal anti-mucin12 antibodies were observed in the mucous secretory organs, epidermis, and intestinal canal of A. lumbricoides. These signals disappeared when immunohistochemistry was performed using pre-absorbed polyclonal antibodies with a specific peptide. These results suggest that mucin12 is localized in the mucous secretory organs in the epidermis of A. lumbricoides. Furthermore, we examined the site of mucin12 localization in the host; specific mucin12 signals were observed on the mucosal epithelia present around intestinal crypts and villi of the small intestine. Therefore, we suggest that mucin12 is a protein that shows common antigenicity in both A. lumbricoides and its host. It is presumed that adult A. lumbricoides live in their preferred environment, which is the small intestine, by secreting mucin12 to avoid being attacked by the host immune system. PMID- 30481537 TI - Active-site directed peptide l-Phe-d-His-l-Leu inhibits angiotensin converting enzyme activity and dexamethasone-induced hypertension in rats. AB - Hypertension is the fundamental cause of cardiovascular and cerebrovascular disorders. Several natural and synthetic peptides are being used as antihypertensive agents, which target angiotensin converting enzyme (ACE), the master regulator of angiotensin (Ang) II production. In this study, we have evaluated ACE-inhibitory potential of the tripeptide l-Phenylalanyl-d-Histidyl-l Leucine (l-Phe-d-His-l-Leu) in vitro and its antihypertensive effect in rat model of dexamethasone-induced hypertension. l-Phe-d-His-l-Leu was custom-designed by changing the configuration of penultimate amino acid residue (histidine) from C terminal of Ang I, the site at which ACE acts upon and generates Ang II. l-Phe-d His-l-Leu effectively inhibited ACE activity in a dose-dependent and competitive manner with an IC50 of 53.32 +/- 0.13 nmol/L. Both fluorescence spectra and circular dichroism data revealed the direct interaction between l-Phe-d-His-l-Leu and ACE. In addition, molecular docking studies revealed the strong interaction of l-Phe-d-His-l-Leu with the critical active site amino acid residues of ACE. Further, the administration of l-Phe-d-His-l-Leu resulted in decrease in blood pressure (142 +/- 3 mmHg) compared to dexamethasone alone group (167 +/- 2 mmHg). Besides, l-Phe-d-His-l-Leu decreased the levels of circulating Ang II, and reduced fibrosis in heart and kidney, as evidenced by decreases in collagen deposition. Thus, the strategy of incorporation of d-amino acids in ACE inhibitory peptides could be valuable in the development of antihypertensive drugs. PMID- 30481539 TI - Thermodynamics and site stoichiometry of DNA binding by a large antiviral hairpin polyamide. AB - PA1 (dIm-PyPybetaPyPyPy-gamma-PyPybetaPyPyPyPybeta-Ta) is a large (14-ring) hairpin polyamide that was designed to recognize the DNA sequence 5'-W2GW7-3', where W is either A or T. As is common among the smaller 6-8-ring hairpin polyamides (PAs), it binds its target recognition sequence with low nM affinity. However, in addition to its large size, it is distinct from these more extensively characterized PAs in its high tolerance for mismatches and antiviral properties. In ongoing attempts to understand the basis for these distinctions, we conducted thermodynamics studies of PA1-DNA interactions. The temperature dependence of binding affinity was measured using TAMRA-labeled hairpin DNAs containing a single target sequence. PA1 binding to either an ATAT/TATA or an AAAA/TTTT pattern is consistently entropically driven. This is in contrast to the A/T pattern-dependent driving forces for DNA binding by netropsin, distamycin, and smaller hairpin polyamides. Analysis of the salt dependence of PA1-DNA binding reveals that within experimental error, there is no dependence on ionic strength, indicating that the polyelectrolyte effect does not contribute to PA1 DNA binding energetics. This is similar to that observed for smaller PAs. PA1-DNA recognition sequence binding stoichiometries were determined at both nM (fluorescence) and MUM (circular dichroism) concentrations. With all sequences and under both conditions, multiple PA1 molecules bind the small DNA hairpin that contains only a single recognition sequence. Implications for these observations are discussed. PMID- 30481540 TI - Thermodynamic signature of indoloquinolines interacting with G-quadruplexes: Impact of ligand side chain. AB - Binding of indoloquinolines with different aliphatic side chains to a parallel G quadruplex derived from the MYC promoter sequence was characterized by optical and calorimetric measurements. ITC experiments performed at different temperatures enabled the determination of molar heat capacity changes upon quadruplex binding and a partitioning of the total binding free enthalpy into contributing terms with hydrophobic effects being major driving forces for all derivatives. Whereas affinities increase for indoloquinolines equipped with a long and positively charged side arm, the highest contribution of specific intermolecular interactions anticipated to impart enhanced specificity is found for a ligand with an uncharged ether aliphatic tail. Obtained thermodynamic signatures may considerably aid in the rational selection of ligand side chains for G-quadruplex binders with enhanced affinity or selectivity. PMID- 30481541 TI - Long Noncoding RNA NPCCAT1 promotes nasopharyngeal carcinoma progression via upregulating YY1. AB - Long noncoding RNAs (lncRNAs) are frequently implicated in various cancers. However, the significances of lncRNAs in nasopharyngeal carcinoma (NPC) are largely unclear. In this study, we identified a novel lncRNA nasopharyngeal carcinoma copy number amplified transcript-1 (NPCCAT1), whose expression is increased in NPC tissues compared with nasopharyngeal normal tissues. Furthermore, we found the genomic copy number of NPCCAT1 is amplified in NPC, which contributes to the upregulation of NPCCAT1 in NPC. Functional experiments demonstrated that overexpression of NPCCAT1 promotes NPC cell growth and migration in vitro and NPC tumor growth in vivo. Knockdown of NPCCAT1 suppresses NPC cell grow and migration. Mechanistically, we found that NPCCAT1 directly binds YY1 mRNA 5'UTR, promotes YY1 mRNA translation, and upregulates YY1 protein level. Gain-of-function and loss-of-function assays revealed that YY1 promoted NPC cell proliferation and migration. Moreover, rescue assays showed that depletion of YY1 attenuated the roles of NPCCAT1 overexpression in promoting NPC cell growth and migration in vitro and NPC tumor growth in vivo. Overall, our study identified NPCCAT1 as an oncogenic lncRNA which promotes NPC progression via upregulating YY1, and suggested that lncRNA NPCCAT1 may be a promising therapeutic target for NPC. PMID- 30481542 TI - Accuracy of food preference predictions in couples. AB - The goal of this study was to identify and empirically test variables that indicate how well partners in relationships know each other's food preferences. Participants (n = 2854) lived in the same household and were part of a large, nationally representative panel study in Germany. Each partner independently predicted the other's preferences for several common food items. Results show that predictive accuracy was higher for likes and for extreme and stereotypical preferences as compared to dislikes and for moderate and idiosyncratic preferences. Accuracy was also higher for couples with a high similarity in preferences and with longer relationship duration but was independent of participants' age after controlling for relationship duration. The data also show that relationship duration was accompanied by higher similarity in couples' food preferences. There was a small positive correlation between partner knowledge and both partner similarity and satisfaction with family life, but no correlation between partner knowledge and general life satisfaction. The results reconcile both valence and base-rate accounts of preference prediction accuracy. PMID- 30481543 TI - Modeling myeloid malignancies with patient-derived iPSCs. AB - Modeling human diseases with patient-derived induced pluripotent stem cells (iPSCs) offers unique research opportunities and is particularly attractive for hematology research. Whereas monogenic inherited blood diseases featured prominently among the first proof-of-principle studies of iPSC modeling, malignant hematologic disorders have been off to a slower start due to challenges in the derivation of iPSCs from cancer cells and the need to establish robust differentiation protocols and standardize phenotypic assays of iPSC-derived hematopoiesis. Recent studies of iPSC modeling of myeloid malignancies exploited the clonal heterogeneity of patient samples to derive genetically matched normal controls and recapitulate the clonal evolution of the disease. Comparisons of the malignant phenotypes and molecular signatures of primary leukemic cells, derived iPSCs and their hematopoietic progeny stress the importance of the cell-of-origin in oncogenesis and enable investigation of the interplay between cell identity and the cancer genome. Larger collections of genetically diverse iPSC lines and more readily scalable hematopoietic differentiation protocols, ideally mimicking adult bone marrow-derived hematopoiesis, would further empower applications of iPSC modeling in myeloid malignancy in the future. Nevertheless, with recent progress in this field, the stage is set for the wider adoption of this model system by the hematology community. PMID- 30481544 TI - From biotechnology principles to functional and low-cost metallic bionanocatalysts. AB - Chemical, physical and mechanical methods of nanomaterial preparation are still regarded as mainstream methods, and the scientific community continues to search for new ways of nanomaterial preparation. The major objective of this review is to highlight the advantages of using green chemistry and bionanotechnology in the preparation of functional low-cost catalysts. Bionanotechnology employs biological principles and processes connected with bio-phase participation in both design and development of nano-structures and nano-materials, and the biosynthesis of metallic nanoparticles is becoming even more popular due to; (i) economic and ecologic effectiveness, (ii) simple one-step nanoparticle formation, stabilisation and biomass support and (iii) the possibility of bio-waste valorisation. Although it is quite difficult to determine the precise mechanisms in particular biosynthesis and research is performed with some risk in all trial and error experiments, there is also the incentive of understanding the exact mechanisms involved. This enables further optimisation of bionanoparticle preparation and increases their application potential. Moreover, it is very important in bionanotechnological procedures to ensure repeatability of the methods related to the recognised reaction mechanisms. This review, therefore, summarises the current state of nanoparticle biosynthesis. It then demonstrates the application of biosynthesised metallic nanoparticles in heterogeneous catalysis by identifying the many examples where bionanocatalysts have been successfully applied in model reactions. These describe the degradation of organic dyes, the reduction of aromatic nitro compounds, dehalogenation of chlorinated aromatic compounds, reduction of Cr(VI) and the synthesis of important commercial chemicals. To ensure sustainability, it is important to focus on nanomaterials that are capable of maintaining the important green chemistry principles directly from design inception to ultimate application. PMID- 30481545 TI - Engineering diverse eubacteria promoters for robust Gene expression in Streptomyces lividans. AB - Due to the lack of powerful gene regulation elements, the engineering development of Streptomyces is often limited. Here, we disclosed that the heterologous sigma70 -dependent promoters, which have been reported as inefficient tools for gene expression in Streptomyces, could be efficiently recognized by Streptomyces housekeeping factor sigmahrdB. Therefore, an effective strategy was developed to engineer these promoters for robust gene expression in Streptomyces by fusing them with optimized 5'-untranslation regions (5'-UTRs). As a proof of concept, the widely used Ptac in E. coli was engineered by fusing its core promoter region with the 5'-UTRR15 from a relatively powerful Streptomyces promoter PkasO*R15 and resulted in Ptac*, the activity of which was 8.1-fold that of Ptac and 1.7-fold that of PkasO*R15 in S. lividans TK24. Next, the 5'-UTRR15 was optimized by randomizing the ribosome binding site (RBS). Based on the base biases of those RBSs with higher activity, eight artificial RBSs were rationally designed, and the optimal resulting promoter Ptac*RBS3 showed about 2.1, 3.6, and 17.6 times the activity of Ptac*, PkasO*R15, and Ptac, respectively, demonstrating that the heterologous Ptac was converted into a type of robust Streptomyces promoters. This study thus greatly expands promoter diversity for the engineering of Streptomyces. PMID- 30481546 TI - Mathematical model for plant-insect interaction with dynamic response to PAD4 BIK1 interaction and effect of BIK1 inhibition. AB - Plant-insect interaction system is a widely studied model of the ecosystem. Numerical understanding of this counter system has developed from initial analogy based approach with a predator-prey model to its recent mathematical interpretation including plant immunity concept. In current work, we propose an extension to this model, including molecular interactions behind the plant defense system and its effect on ecological behaviour. Inspired from biomolecular interaction given by Louis and Shah in 2014, we propose here a mathematical model to depict molecular dependence and control of plant insect interaction system. Insect infestation mediated Botrytis Induced Kinase-1 (BIK1) induction resulted in inhibition of Phyto Alexin Deficient-4 (PAD4) protein. Lowered PAD4 triggers the plant defense mechanism, leading to degraded plant immune potential and thereby reducing the plant quality. We mathematically adapt these interactions to show their influence on plant-insect interaction system and hypothesize the significance of BIK1 inhibition leading to the improved plant quality. We implemented the plethora of computational modeling and all atom MD simulations to explain the Plant-Insect-PAD4-BIK1 interaction network and identify potential molecular mechanisms of plant improvement by BIK1 inhibition. PMID- 30481547 TI - Naturally occurring autoantibodies against alpha-synuclein rescues memory and motor deficits and attenuates alpha-synuclein pathology in mouse model of Parkinson's disease. AB - It has been suggested that aggregation of alpha-synuclein (alpha-syn) into oligomers leads to neurodegeneration in Parkinson's disease (PD), but intravenous immunoglobulin (IVIG) which contains antibodies against alpha-syn monomers and oligomers fails to treat PD mouse model. The reason may be because IVIG contains much low level of antibodies against alpha-syn, and of which only a small part can penetrate the blood-brain barrier, resulting in an extremely low level of effective antibodies in the brain, and limiting the beneficial effect of IVIG on PD mice. Here, we first isolated naturally occurring autoantibodies against alpha syn (NAbs-alpha-syn) from IVIG. Our further investigation results showed that NAbs-alpha-syn inhibited alpha-syn aggregation and attenuated alpha-syn-induced cytotoxicity in vitro. Compared with vehicles, NAbs-alpha-syn significantly attenuated the memory and motor deficits by reducing the levels of soluble alpha syn, total human alpha-syn and alpha-syn oligomers, decreasing the intracellular p-alpha-synser129 deposits and axonal pathology, inhibiting the microgliosis and astrogliosis, as well as the production of proinflammatory cytokines, increasing the levels of PSD95, synaptophysin and TH in the brain of A53T transgenic mice. These findings suggest that NAbs-alpha-syn overcomes the deficiency of IVIG and exhibits a promising therapeutic potential for the treatment of PD. PMID- 30481548 TI - Galectin-3 is involved in HIV-1 expression through NF-kappaB activation and associated with Tat in latently infected cells. AB - Galectin-3 (Gal-3) is involved in many biological processes and pathogenesis of diseases in part through nuclear factor (NF)-kappaB activation. We demonstrated that Gal-3 expression was significantly induced by tumor necrosis factor (TNF) alpha or phorbol 12-myristate 13-acetate in OM-10.1 and ACH-2 cells, which are considered as a model of HIV-1 latently infected cells. The expression of Gal-3 was also associated with their viral production. However, the induction of Gal-3 by TNF-alpha was not observed in their uninfected parental cells. Knockdown of Gal-3 resulted in the suppression of NF-kappaB activation and HIV-1 replication in the latently infected cells. The expression level of Gal-3 was highly correlated with that of HIV-1 Tat in the latently infected cells stimulated with TNF-alpha. Furthermore, colocalization and possible interaction of Gal-3 and Tat were observed in the stimulated cells. These results suggent that Gal-3 expression is closely correlated with HIV-1 expression in latently infected cells through NF-kappaB activation and the interaction with Tat. PMID- 30481550 TI - Seniorization of Tasks in the Academic Medical Center: A Worrisome Trend. PMID- 30481549 TI - Telomere length and redox balance in master endurance runners: The role of nitric oxide. AB - Leukocyte telomere length (LTL), a biological marker of aging that is associated with age-related diseases, is longer in master endurance runners (ER) than age matched controls, but the underlying mechanisms are poorly investigated. The LTL, nitric oxide (NO), and redox balance of ER master runners were analyzed and compared to untrained middle-aged and young adults. We hypothesized that NO and redox balance at baseline would be related to longer LTL in ER athletes. Participants (n = 38) were long-term ER runners (n = 10; 51.6 +/- 5.2 yrs.; 28.4 +/- 9.4 yrs. of experience) and untrained age-matched (n = 17; 46.6 +/- 7.1 yrs) and young controls (n = 11; 21.8 +/- 4.0 yrs). Volunteers were assessed for anamnesis, anthropometrics, and blood sampling. Measurements of pro-and anti oxidant status and DNA extraction were performed using commercial kits. Relative LTL was determined with qPCR analyses (T/S). While the middle-aged controls had shorter LTL than the young group, no difference was observed between ER athletes and young participants. A large effect size between the LTL of ER athletes and middle-aged controls (d = 0.85) was also observed. The ER athletes and untrained young group had better redox balance according to antioxidant/pro-oxidant ratios compared to middle-aged untrained participants, which also had lower values for redox parameters (TEAC/TBARS, SOD/TBARS, and CAT/TBARS; all p < 0.05). Furthermore, the NO level of ER athletes (175.2 +/- 31.9 MUM) was higher (p < 0.05) than middle-aged controls (67.2 +/- 23.3 MUM) and young participants (129.2 +/- 17.3 MUM), with a significant correlation with LTL (r = 0.766; p = 0.02). In conclusion, ER runners have longer LTL than age-matched controls, which in turn may be related to better NO bioavailability and redox balance status. PMID- 30481551 TI - Bioengineering-inspired three-dimensional culture systems: Organoids to create tumor microenvironment. AB - In recent years, in vitro three-dimensional (3D) cell culture systems that better mimic in vivo physiology and tissue microenvironment have become important. It is used for the pre-clinical evaluation of the efficacy and safety profiles of new drug candidates developed especially for the treatment of various diseases including cancer. 3D cell culture techniques overcome the inadequacy of conventional two-dimensional (2D) cell culture models as they are much more informative than the 2D systems. And they can easily replace or reduce the number of in vivo studies which arise many ethical problems in the development of novel therapeutics. This review focuses on the organoid cultures which are 3D bioengineered cell culture systems that guide cell behavior and cell order to mimic in vivo tumor microenvironment. PMID- 30481552 TI - Association between Toll-like receptors (TLR) and NOD-like receptor (NLR) polymorphisms and lipid and glucose metabolism. AB - Recent evidences had shown activation of TLR (toll-like receptors) and NLR (nod like receptors) in response to imbalance in nutrients intake, such as lipid and glucose. The main aim of this study was to investigate possible associations between 11 SNPs in TLR2, TLR4, NLRC4, CARD8 and NEK7 genes and lipid and glucose metabolism. Sample was composed by healthy children and adolescents (n = 158) and adults (n = 115). DNA extraction was obtained by salting-out and sample genotyping by matrix-assisted laser desorption ionization time-of-flight mass spectrometry based system. LDL-cholesterol, HDL-cholesterol, triglycerides, total cholesterol, glucose and insulin were measured by standard automated methods. Means were compared by t-test or Mann-Whitney test. Univariate and multivariate logistic regression were used to verify association between polymorphisms and lipid and glucose markers. Seven polymorphisms in 5 genes were associated with lipid and glucose parameters. For lipid parameters, the following associations were found: higher LDL-C levels and C allele of rs1554973 (TLR4) and G allele of rs6671879 (NEK7); higher HDL-cholesterol levels and A allele of rs13105517 (TLR2); higher total cholesterol and TT genotype of rs3804099 (TLR2) and G allele of rs6671879 (NEK7); higher triglycerides levels and G allele of rs455060 (NLRC4). For glucose parameters associations were found between C allele of rs7258674 (CARD8) and higher glucose levels, and between C allele of rs212704 (NLRC4) and G allele of rs455060 (NLRC4) and insulin levels. These findings indicate a relationship between polymorphisms of TLRs and NLRs genes and markers of lipid and glucose metabolism. PMID- 30481553 TI - Hindbrain Dorsal Vagal Complex AMPK Controls Hypothalamic Gluco-regulatory Transmitter and Counter-Regulatory Hormone Responses to Hypoglycemia. AB - Pharmacologic activation of the hindbrain dorsal vagal complex energy sensor 5' adenosine monophosphate-activated protein kinase (AMPK) causes site-specific adjustments in hypothalamic AMPK activity. DVC A2 noradrenergic neurons are a likely source of metabolo-sensory cues to downstream network components as they express substrate fuel-sensitive AMPK. This study investigated the hypothesis that DVC AMPK controls hypothalamic sensor, metabolic effector transmitter, and counter-regulatory hormone responses to insulin-induced hypoglycemia. Male rats were injected into the caudal fourth ventricle with the AMPK inhibitor compound C or vehicle before hypoglycemia. Arcuate (ARH), ventromedial (VMN), and dorsomedial (DMN) nuclei and lateral hypothalamic area (LHA) were micropunch dissected for norepinephrine ELISA and Western blot analyses. Hypoglycemic stimulation of norepinephrine activity in each site was impeded by compound C. Hypoglycemia caused drug-revocable (ARH) or -refractory (VMN, DMN) reductions in AMPK, alongside hindbrain AMPK-dependent augmentation of phospho-AMPK expression in each location. Compound C prevented hypoglycemic augmentation of gluco stimulatory ARH neuropeptide Y, VMN neuronal nitric oxide synthase, and LHA orexin-A expression, while hypoglycemic suppression of the catabolic neuron protein markers ARH pro-opiomelanocortin and VMN glutamate decarboxylase65/67 was respectively averted or unaffected by drug treatment. DMN RFamide-related peptide 1 and -3 profiles were correspondingly amplified or suppressed hindbrain AMPK reliant mechanisms during hypoglycemia. Results show that DVC AMPK is required for hypoglycemic intensification of norepinephrine activity in characterized hypothalamic gluco-regulatory structures, and that this sensor regulates AMPK activation and metabolic effector transmission in those sites. PMID- 30481554 TI - Central action of rapamycin on early ischemic injury and related cardiac depression following experimental subarachnoid hemorrhage. AB - Early brain injury and related cardiac consequences play a key role in the devastating outcomes after subarachnoid hemorrhage (SAH). We reported that rapamycin exerts neuroprotection against cortical hypoxia early after SAH, but its mechanism is poorly understood. This in vivo study aimed to determine the potential role of the transcription factor STAT3 in the rapamycin-mediated neuroprotection in a mouse model of SAH. Forty C57BL/6 N mice were treated with an intracerebroventricular injection of rapamycin or vehicle (control) given after SAH induction by a filament perforation method, with or without STAT3 (Stattic) or ERK (PD98059) inhibitor pretreatment. Cerebral blood flow signals (%vascularity), brain tissue oxygen saturation (SbtO2), and cardiac output (CO) were analyzed using an ultrasound/photoacoustic imaging system. Clinically relevant neurocardiac depression was notable in severe SAH mice. Rapamycin improved %vascularity, SbtO2, and CO on day 1 after SAH onset. The beneficial effects of rapamycin on cerebral blood flow and oxygenation persisted until day 3, resulting in a significant reduction in post-SAH new cerebral infarctions and survival, as well as improved neurological functions, compared to the control group. All of the effects were attenuated by pretreatment with Stattic or PD98059. These data suggest that ERK and JAK/STAT3 pathways play an important role in the neurocardiac protection by rapamycin after SAH. We propose that rapamycin is a novel pharmacological strategy to target STAT3 activation, with a possible crosstalk through the ERK pathway, for the treatment of post-SAH early brain injury. PMID- 30481555 TI - Metabotropic functions of the NMDA receptor and an evolving rationale for exploring NR2A-selective positive allosteric modulators for the treatment of autism spectrum disorder. AB - NMDA receptors are widely distributed throughout the brain and major therapeutic challenges include targeting specific NMDA receptor subtypes while preserving spatial and temporal specificity during their activation. The NR2A-subunit containing NMDA receptor is implicated in regulating synchronous oscillatory output of cortical pyramidal neurons, which may be disturbed in clinical presentations of autism spectrum disorder (ASD). Because NR2A-selective positive allosteric modulators (PAMs) preserve spatial and temporal selectivity while activating this subpopulation of receptors, they represent a promising strategy to address neocortical circuit abnormalities in ASD. In addition to promoting Ca2+ entry and membrane depolarization, diverse metabotropic effects of NMDA receptor activation on signal transduction pathways occur within the cell, some of which depend on alignment of protein binding partners. For example, NMDA receptor agonist interventions attenuate impaired sociability in transgenic mice with 'loss-of-function' mutations of the Shank family of scaffolding proteins, which highlights the necessity of a carefully orchestrated alignment of protein binding partners in the excitatory synapse. The current Review considers metabotropic functions of the NMDA receptor that could play a role in sociability and the pathogenesis of ASD (e.g., mTOR signaling), in addition to its more familiar ionotropic functions, and provides a rationale for therapeutic exploration of NR2A-selective PAMs. PMID- 30481556 TI - Phosphinic acids: current status and potential for drug discovery. AB - Phosphinic acid derivatives exhibit diverse biological activities and a high degree of structural diversity, rendering them a versatile tool in the development of new medicinal agents. Pronounced recent progress, coupled with previous research findings, highlights the impact of this moiety in medicinal chemistry. Here, we highlight the most important breakthroughs made with phosphinates with a range of pharmacological activities against many diseases, including anti-inflammatory, anti-Alzheimer, antiparasitic, antihepatitis, antiproliferative, anti-influenza, anti-HIV, antimalarial, and antimicrobial agents. We also provide the current status of the corresponding prodrugs, drug delivery systems, and drug applications of phosphinic acids in the clinical stage. PMID- 30481557 TI - Evidence for antimicrobial and anticancer activity of pituitary adenylate cyclase activating polypeptide (PACAP) from North African catfish (Clarias gariepinus): Its potential use as novel therapeutic agent in fish and humans. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) is a regulatory neuropeptide that belongs to the secretin/glucagon superfamily, of which some members have shown antimicrobial activities. Contrasting to mammals, published studies on the action of PACAP in non-mammalian vertebrate immune system remain scarce. Some of our recent studies added this peptide to the growing list of mediators that allow cross-talk between the nervous, endocrine and immune systems in teleost fish. Regulation of PACAP and expression of its receptor genes has been demonstrated during an immune response mounted against acute bacterial infection in fish, though the direct effect of PACAP against fish pathogenic bacteria has never been addressed. Current work provides evidence of antimicrobial activity of Clarias gariepinus PACAP against a wide spectrum of Gram-negative and Gram-positive bacteria and fungi of interest for human medicine and aquaculture, in which computational prediction studies supported the putative PACAP therapeutic activity. Results also indicated that catfish PACAP not only exhibits inhibitory effects on pathogen growth, but also affects the proliferation of human non-small cell lung cancer cell line H460 in a dose dependent manner. The observed cytotoxic activity of catfish PACAP against human tumor cells and pathogenic microorganisms, but not healthy fish and mammalian erythrocytes support a potential physiological role of this neuropeptide in selective microbial and cancer cell killing. All together, our findings extend the mechanisms by which PACAP could contribute to immune responses, and open up new avenues for future therapeutic application of this bioactive neuropeptide. PMID- 30481558 TI - Two immunoassays for the detection of 2C-B and related hallucinogenic phenethylamines. AB - INTRODUCTION: The use of new psychoactive substances as drugs of abuse has dramatically increased over the last years. Hallucinogenic phenethylamines gained particular popularity as they have both stimulating and psychedelic effects. Although generally perceived as safe, these illicit drugs pose a serious health risk; they have been linked to cases of severe poisoning or even deaths. Therefore, simple, cost-effective and reliable methods are needed for rapid determination of abused hallucinogens. METHODS: For this purpose, two haptens derived from 2C-H were designed, synthesized and subsequently attached to a carrier protein. Polyclonal antibodies obtained from a rabbit immunized with one of the prepared immunogens were used for the development of two immunoassays. RESULTS: In this study, a lateral flow immunoassay (LFIA) and an enzyme linked immunosorbent assay (ELISA) for the detection of 2C-B and related hallucinogenic phenethylamines in urine were developed. The presented LFIA is primarily suitable for on-site monitoring as it is simple and can provide a visual evidence of 2C-B presence within a few minutes. Its reasonable sensitivity (LODLFIA = 15 +/- 7 ng mL-1) allows detection of the drug presence in urine after acute exposure. For greater accuracy, highly sensitive ELISA (LODELISA = 6 +/- 3 pg mL-1) is proposed for toxicological quantitative analyses of positive samples captured by the LFIA. DISCUSSION: The comparison of the ELISA with the well-established UHPLC-MS-MS method shows excellent agreement of results, which confirms good potential of the ELISA to be used for routine analyses of 2C-B and related hallucinogenic phenethylamines of both main sub-families. PMID- 30481559 TI - Development of a flow-through USP 4 apparatus drug release assay for the evaluation of amphotericin B liposome. AB - AmBisome(r) is a liposomal formulation of amphotericin B (Amp B), a complex parenteral antifungal product with no US FDA approved generic version available to date. For generic Amp B liposomal product development, examination of the drug release profile is important for product quality control and analytical comparability evaluation with the reference listed drug. Yet, there is no standardized in vitro drug release (IVR) assay currently available for Amp B liposomes. In this study, we describe the development of a USP-4 apparatus-based IVR assay capable of discriminating liposomal Amp B formulations based on the drug release profile. The goal of the IVR assay development was to identify release media compositions and assay temperatures capable of facilitating 70-100% of drug release from AmBisome(r) in 24 hours without Amp B precipitation or disruption of liposome structure. We found that an addition of 5% w/v of gamma cyclodextrin to the release media of 5% sucrose, 10 mM HEPES, and 0.01% NaN3 (pH = 7.4) prevented Amp B precipitation and facilitated drug release. Increased IVR assay temperature led to increased drug release rate, and 55 degrees C was selected as the highest temperature that induced drug release close to our target without causing product precipitation. The developed IVR assay was used to discriminate between drug release rates from AmBisome(r) and micellar Amp B products like Fungizone(r) and Fungcosome. The IVR assay was also capable of discriminating between Amp B liposomes with the same composition as AmBisome(r) but prepared by either extrusion or homogenization processes, both of which resulted in measurable liposomal particle size heterogeneity and Amp B concentration differences. Finally, the USP-4 IVR assay was used to compare Amp B release profiles between AmBisome(r) and two generic products approved in India, Amphonex(r) (Bharat Serums and Vaccines Ltd.) (f2 = 66.3) and Phosome(r) (Cipla Ltd.) (f2 = 55.4). Taken together, the developed USP-4 IVR assay can be a useful tool for drug release profile characterization in generic liposomal Amp B formulation development. PMID- 30481560 TI - Exercise as a therapeutic intervention for motor and non-motor symptoms in Parkinson's disease: Evidence from rodent models. AB - Parkinson's disease (PD) is characterised by degeneration of dopaminergic neurons of the nigrostriatal pathway, which leads to the cardinal motor symptoms of the disease - tremor, rigidity and postural instability. A number of non-motor symptoms are also associated with PD, including cognitive impairment, mood disturbances and dysfunction of gastrointestinal and autonomic systems. Current therapies provide symptomatic relief but do not halt the disease process, so there is an urgent need for preventative strategies. Lifestyle interventions such as aerobic exercise have shown potential to lower the risk of developing PD and to alleviate both motor and non-motor symptoms. However, there is a lack of large scale randomised clinical trials that have employed exercise in PD patients. This review will focus on the evidence from studies on rodent models of PD, for employing exercise as an intervention for both motor and non-motor symptoms. PMID- 30481561 TI - Parvovirus B19 in dilated cardiomyopathy: there is more than meets the eye. PMID- 30481562 TI - Signaling transduction regulated by 5-hydroxytryptamine 1A receptor and orexin receptor 2 heterodimers. AB - As G-protein-coupled receptors (GPCRs), 5-hydroxytryptamine 1A receptor (5-HT1AR) and orexin receptor 2 (OX2R) regulate the levels of the cellular downstream molecules. The heterodimers of different GPCRs play important roles in various of neurological diseases. Moreover, 5-HT1AR and OX2R are involved in the pathogenesis of neurological diseases such as depression with deficiency of hippocampus plasticity. However, the direct interaction of the two receptors remains elusive. In the present study, we firstly demonstrated the heterodimer formation of 5-HT1AR and OX2R. Exchange protein directly activated by cAMP (Epac) cAMP bioluminescence resonance energy transfer (BRET) biosensor analysis revealed that the expression levels of cellular cAMP significantly increased in HEK293T cells transfected with the two receptors compared with the 5-HT1AR group. Additionally, the cellular level of calcium was upregulated robustly in HEK293T cells co-transfected with 5-HT1AR and OX2R group after agonist treatment. Furthermore, western blotting data showed that 5-HT1AR and OX2R heterodimer decreased the levels of phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP-response element-binding protein (CREB). These results not only unraveled the formation of 5-HT1AR and OX2R heterodimer but also suggested that the heterodimer affected the downstream signaling pathway, which will provide new insights into the function of the two receptors in the brain. PMID- 30481563 TI - Non-platelet-derived CXCL4 differentially regulates cytotoxic and regulatory T cells through CXCR3 to suppress the immune response to colon cancer. AB - CXCL4 is mainly produced by activated platelets, and certain somatic cells and cancer cells also express CXCL4. However, the physiological function of non platelet-derived CXCL4 is unclear. Previously, we reported that CXCL4 produced by cancer cells accelerated tumor growth by suppressing the antitumor activities of cytotoxic T lymphocytes (CTLs). To elucidate the mechanism of CXCL4 in tumor immunity, we compared the CTLs and regulatory T cells (Tregs) from CXCL4-/-, CXCR3-/- and C57BL/6 mice overexpressing CXCL4 via intramuscular electroporation. CXCL4 accelerated tumor growth in CXCL4-/- and C57BL/6 mice but not in CXCR3-/- mice. Furthermore, CXCL4 decreased CTLs proliferation and IFN-gamma production and enhanced CTLs apoptosis and programmed death 1 (PD-1) expression. Conversely, CXCL4 promoted Tregs proliferation and TGF-beta production and downregulated PD-1 expression in Tregs. Notably, these effects of CXCL4 were both observed in the splenic and tumor-infiltrating CTLs and Tregs from wild-type but not CXCR3-/- mice. Thus, we revealed a negative immune regulatory function for non-platelet derived CXCL4 through CXCR3 that cancer cells could hijack to evade the host immune system, suggesting that the CXCL4/CXCR3 axis may serve as a novel target for colorectal cancer immunotherapy. PMID- 30481564 TI - Cyclin B1/CDK1-regulated mitochondrial bioenergetics in cell cycle progression and tumor resistance. AB - A mammalian cell houses two genomes located separately in the nucleus and mitochondria. During evolution, communications and adaptations between these two genomes occur extensively to achieve and sustain homeostasis for cellular functions and regeneration. Mitochondria provide the major cellular energy and contribute to gene regulation in the nucleus, whereas more than 98% of mitochondrial proteins are encoded by the nuclear genome. Such two-way signaling traffic presents an orchestrated dynamic between energy metabolism and consumption in cells. Recent reports have elucidated the way how mitochondrial bioenergetics synchronizes with the energy consumption for cell cycle progression mediated by cyclin B1/CDK1 as the communicator. This review is to recapitulate cyclin B1/CDK1 mediated mitochondrial activities in cell cycle progression and stress response as well as its potential link to reprogram energy metabolism in tumor adaptive resistance. Cyclin B1/CDK1-mediated mitochondrial bioenergetics is applied as an example to show how mitochondria could timely sense the cellular fuel demand and then coordinate ATP output. Such nucleus-mitochondria oscillation may play key roles in the flexible bioenergetics required for tumor cell survival and compromising the efficacy of anti-cancer therapy. Further deciphering the cyclin B1/CDK1-controlled mitochondrial metabolism may invent effect targets to treat resistant cancers. PMID- 30481565 TI - Metabolic targeting synergizes with MAPK inhibition and delays drug resistance in melanoma. AB - Tumors, including melanomas, frequently show an accelerated glucose metabolism. Mutations in the v-Raf murine sarcoma viral oncogene homolog B (BRAF), detected in about 50% of all melanomas, result in further enhancement of glycolysis. Therefore anti-metabolic substances might enhance the impact of RAF inhibitors. We have identified the two non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac and lumiracoxib being able to restrict energy metabolism in human melanoma cells by targeting lactate release and oxidative phosphorylation (OXPHOS). In combination with the RAF inhibitor vemurafenib strong synergism was observed: Diclofenac as well as lumiracoxib increased the anti-glycolytic impact of vemurafenib and prevented RAF-inhibitor induced metabolic reprogramming towards OXPHOS. Consequently, both NSAIDs sensitized melanoma cells to vemurafenib triggered proliferation arrest and enhanced the anti-tumor effect of RAF inhibitors from cytostatic to cytotoxic. Furthermore the addition of NSAIDs delayed the onset of RAF inhibitor resistance, most likely by counteracting the upregulation of MITF. Our data suggest that selected NSAIDs could be a promising combination partner for MAPK pathway inhibitors for the treatment of BRAFV600E mutated melanomas. PMID- 30481566 TI - Stroke Longitudinal Volumetric Measures Correlate with the Behavioral Score in Non-Human Primates. AB - Stroke is the second leading cause of death worldwide. Brain imaging data from experimental rodent stroke models suggest that size and location of the ischemic lesion relate to behavioral outcome. However, such a relationship between these two variables has not been established in Non-Human Primate (NHP) models. Thus, we aimed to evaluate whether size, location, and severity of stroke following controlled Middle Cerebral Artery Occlusion (MCAO) in NHP model correlated to neurological outcome. Forty cynomolgus macaques underwent MCAO, after four mortalities, thirty-six subjects were followed up during the longitudinal study. Structural T2 scans were obtained by magnetic resonance imaging (MRI) prior to, 48 h, and 30 days post-MCAO. Neurological function was assessed with the Nonhuman Primate Stroke Scale (NHPSS). T2 whole lesion volume was calculated per subject. At chronic stages, remaining brain volume was computed, and the affected hemisphere parceled into 50 regions of interest (ROIs). Whole and parceled volumetric measures were analyzed in relation to the NHPSS score. The longitudinal lesion volume evaluation showed a positive correlation with the NHPSS score, whereas the remaining brain volume negatively correlated with the NHPSS. Following ROI parcellation, NHPSS outcome correlated with frontal, temporal, occipital, and middle white matter, as well as the internal capsule, and the superior temporal and middle temporal gyri, and the caudate nucleus. These results represent an important step in stroke translational research by demonstrating close similarities between the NHP stroke model and the clinical characteristics following a human stroke and illustrating significant areas that could represent targets for novel neuroprotective strategies. PMID- 30481567 TI - Investigating the Role of SNARE Proteins in Trafficking of Postsynaptic Receptors using Conditional Knockouts. AB - Trafficking or delivery of neurotransmitter receptors on postsynaptic membranes is critical for basal neurotransmission and synaptic plasticity. Importantly, dysfunction of such postsynaptic receptor trafficking can lead to severe brain diseases such as Alzheimer's Disease, autism spectrum disorder, and intellectual disability, yet underlying mechanisms remain elusive. One attractive hypothesis is that postsynaptic SNARE proteins play key roles in the delivery of receptors by mediating membrane fusion at postsynaptic neurons. However, the identities of the critical SNARE proteins mediating the delivery remain controversial. The lack of consensus in previous studies is partly due to differences in preparations and methodologies. In this review, we propose to employ a pyramidal-neuron specific conditional knockout (cKO) model to study the roles of candidate SNARE proteins in postsynaptic receptor trafficking. We highlight our recent results which we obtained from such approaches to syntaxin-4 protein. These results provide clear evidence on the critical role of syntaxin-4 in trafficking of ionotropic glutamate receptors which are essential for basal neurotransmission, synaptic plasticity and spatial memory. PMID- 30481568 TI - Chronic intermittent ethanol exposure selectively increases synaptic excitability in the ventral domain of the rat hippocampus. AB - Many studies have implicated hippocampal dysregulation in the pathophysiology of alcohol use disorder (AUD). However, over the past twenty years, a growing body of evidence has revealed distinct functional roles of the dorsal (dHC) and ventral (vHC) hippocampal subregions, with the dHC being primarily involved in spatial learning and memory and the vHC regulating anxiety- and depressive-like behaviors. Notably, to our knowledge, no rodent studies have examined the effects of chronic ethanol exposure on synaptic transmission along the dorsal/ventral axis. To that end, we examined the effects of the chronic intermittent ethanol vapor exposure (CIE) model of AUD on dHC and vHC synaptic excitability. Adult male Long Evans rats were exposed to CIE or air for 10 days (12 hrs/day; targeting blood ethanol levels of 175-225 mg%) and recordings were made 24 hours into withdrawal. As expected, this protocol increased anxiety-like behaviors on the elevated plus-maze and successive alleys test. Extracellular recordings revealed marked CIE-associated increases in synaptic excitation in the CA1 region that were exclusively restricted to the ventral domain of the hippocampus. Western blot analysis of synaptoneurosomal fractions revealed that the expression of two proteins that regulate synaptic strength, GluA2 and SK2, were dysregulated in the vHC, but not the dHC, following CIE. Together, these findings suggest that the ventral CA1 region may be particularly sensitive to the maladaptive effects of chronic ethanol exposure and provide new insight into some of the neural substrates that may contribute to the negative affective state that develops during withdrawal. PMID- 30481569 TI - Hemisphere-dependent Changes in mRNA Expression of GABAA Receptor Subunits and BDNF after Intra-prefrontal Cortex Allopregnanolone Infusion in Rats. AB - Allopregnanolone is a neurosteroid implicated in mood disorders such as depression and anxiety. It acts as a GABAA receptor (GABAAR)-positive allosteric modulator and changes the expression of GABAAR subunits and of brain-derived neurotrophic factor (BDNF) in different brain regions. It has been demonstrated that such neurochemical changes may have an asymmetrical pattern regarding brain hemispheres. The aim of this study was to verify the behavioral and hemisphere dependent neurochemical effects of the bilateral intra-prefrontal cortex (intra PFC) infusion of allopregnanolone in rats. Rats were exposed to the forced swim test and to the grooming microstructure test, followed by the right and left hemisphere-specific quantification of mRNA expression by Real-Time PCR of delta and gamma2 GABAAR subunits and BDNF in the PFC and in the hippocampus. Though we did not observe any significant effects in the behavioral tests, intra-PFC allopregnanolone infusion bilaterally increased the mRNA expression of the delta subunit in the same area and of BDNF in the hippocampus. Both mRNA expressions of the gamma2 subunit and BDNF were higher in the right than in the left PFC of control animals, and the hemisphere differences were not seen after allopregnanolone infusion. Overall hippocampal BDNF expression was also higher in the right hemisphere, but this asymmetry was not normalized by allopregnanolone. No asymmetries or changes were observed in the hippocampal mRNA expression of GABAAR subunits. These results point to a hemisphere-dependent regulation of GABAAR subunits and BDNF that can be modulated by intra-PFC allopregnanolone infusion, even in the absence of associated behavioral effects. PMID- 30481570 TI - Clinopodium vulgare L. (wild basil) extract and its active constituents modulate cyclooxygenase-2 expression in neutrophils. AB - Clinopodium vulgare L. (wild basil) has a wide range of ethnopharmacological applications and accumulates a broad spectrum of phenolic compounds, recognized for their anti-inflammatory and anticancer properties. The triggered cyclooxygenase-2 (COX-2) expression is creating an immunosuppressive microenvironment in the inflamed tissue and considered to be the main cause of failure of even new anticancer-/immune-therapies. Nowadays, selective and novel plant-derived COX-2 inhibitors with safe profile are subject of profound research interest. This study aimed to analyze the metabolic profile of C. vulgare and search for phenolic molecules with potential biological properties. By application of 1H and 2D-NMR (Nuclear Magnetic Resonance) profiling, caffeic, chlorogenic acids and catechin were identified along with a bunch of primary and secondary metabolites. Further, the biological effect of C. vulgare extract (CVE) and its constituents on zymosan-induced COX-2 expression and apoptosis of murine neutrophils have been studied. The CVE, caffeic and chlorogenic acids inhibited zymosan-induced COX-2 expression in bone marrow neutrophils, in vitro and in vivo activated. The obtained data indicate that CVE may have a good potential to manipulate neutrophil functions, however, its action may depend on the cellular state, the inflammatory milieu and the relative content of caffeic and chlorogenic acid in the extract. PMID- 30481571 TI - RIFM fragrance ingredient safety assessment, hexanoic acid, 4-methyl-, CAS Registry Number 1561-11-1. PMID- 30481572 TI - RIFM fragrance ingredient safety assessment, delta-3-carene, CAS Registry Number 13466-78-9. PMID- 30481573 TI - FEMA GRAS assessment of natural flavor complexes: Citrus-derived flavoring ingredients. AB - In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavoring ingredients. This publication is the first in a series and summarizes the evaluation of 54 Citrus-derived NFCs using the procedure outlined in Smith et al. (2005) and updated in Cohen et al. (2018) to evaluate the safety of naturally-occurring mixtures for their intended use as flavoring ingredients. The procedure relies on a complete chemical characterization of each NFC intended for commerce and organization of each NFC's chemical constituents into well-defined congeneric groups. The safety of the NFC is evaluated using the well-established and conservative threshold of toxicological concern (TTC) concept in addition to data on absorption, metabolism and toxicology of members of the congeneric groups and the NFC under evaluation. As a result of the application of the procedure, 54 natural flavor complexes derived from botanicals of the Citrus genus were affirmed as generally recognized as safe (GRAS) under their conditions of intended use as flavoring ingredients based on an evaluation of each NFC and the constituents and congeneric groups therein. PMID- 30481574 TI - Eplingiella fruticosa leaf essential oil complexed with beta-cyclodextrin produces a superior neuroprotective and behavioral profile in a mice model of Parkinson's disease. AB - Evidence indicates that oxidative stress has an important role in the onset and progression of Parkinson's disease (PD). Antioxidant agents from natural products have shown neuroprotective effects in animal models of PD. Eplingiella fruticosa is an aromatic and medicinal plant of the Lamiaceae family that include culinary herbs. The essential oil (EPL) has anti-inflammatory and antioxidant activities. Cyclodextrins are used to enhances pharmacological profile of essential oil. We obtained the EPL from leaves and complexed with beta-cyclodextrin (EPL-betaCD). Phytochemical analysis showed as main constituents: beta-caryophyllene, bicyclogermacrene and 1,8-cineole. We evaluated the effects of EPL and EPL-betaCD (5 mg/kg, p.o. for 40 days) on male mice submitted to the progressive reserpine PD model. Behavioral evaluations, lipid peroxidation quantification and immunohistochemistry for tyrosine hydroxylase were conducted. EPL delayed the onset of catalepsy and decreased membrane lipid peroxides levels in the striatum. EPL-betaCD also delayed the onset of catalepsy, reduced the frequency of oral diskynesia, restored memory deficit, produced anxiolytic activity and protected against dopaminergic depletion in the striatum and SNpc. These findings showed that EPL has a potential neuroprotective effect in a progressive PD animal model. Further, EPL-betaCD enhanced this protective effects, suggesting a novel therapeutic approach to ameliorate the symptoms of PD. PMID- 30481575 TI - Vitamin D controls the capacity of human dendritic cells to induce functional regulatory T cells by regulation of glucose metabolism. AB - Tolerogenic dendritic cells (tolDCs) instruct regulatory T cells (Tregs) to dampen autoimmunity. Active vitamin D3 (1alpha,25-dihydroxyvitamin D3; 1alpha,25(OH)2D3) imprints human monocyte-derived DCs with tolerogenic properties by reprogramming their glucose metabolism. Here we identify the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) as a critical checkpoint and direct transcriptional target of 1alpha,25(OH)2D3 in determining the tolDC profile. Using tracer metabolomics, we show that PFKFB4 activity is essential for glucose metabolism, especially for glucose oxidation, which is elevated upon 1alpha,25(OH)2D3 exposure. Pharmacological inhibition of PFKFB4 reversed the 1alpha,25(OH)2D3-mediated shift in metabolism, DC profile and function, as determined by expression of inhibitory surface markers and secretion of regulatory cytokines and factors. Moreover, PFKFB4 inhibition in 1alpha,25(OH)2D3-treated DCs blocked their hallmark capacity to induce suppressive Tregs. This work demonstrates that alterations in the bioenergetic metabolism of immune cells are central to the immunomodulatory effects induced by 1alpha,25(OH)2D3. PMID- 30481576 TI - Self-reported Low-energy Fractures and Associated Risk Factors in People with Diabetes: a National Population-based Study. AB - AIMS: Clinical risk factors and bone mineral densitometry underestimate low energy fracture (LEF) risk in people with diabetes. We aim to estimate the prevalence of LEF in diabetics, compare with nondiabetics; and evaluate possible predictors of LEF in people with diabetes. METHODS: Cross-sectional, population based study in Portuguese subjects over 40 years-old. Estimates computed as weighted proportions/means, considering sample design. Multivariate logistic regression models to evaluate the association of diabetes and LEF; and predictors of LEF in diabetics. RESULTS: 7675 subjects were analysed, of which 1173 reported diabetes. Diabetics were older (mean age 66.0+/-11.49y), more frequently reported osteoporosis and falls in the previous 12 months (32.4%vs.22.9%). Prevalence of self-reported LEF was 16.2% (95%CI:13.68-19.13) among diabetics (vs.13.3%, 95%CI:12.14-14.57, in nondiabetics); OR for the association diabetes and LEF:1.26, 95%CI:1.01-1.58, p=0.045 (in women, adjusted OR:1.41, 95%CI:1.05-1.89, p=0.02). Thirty percent of diabetics reported at least one major LEF and 70% in other sites. In diabetics, LEF was independently associated with self-reported osteoporosis and falls in the previous 12 months. CONCLUSION: People with diabetes reported more falls and had higher prevalence of self-reported LEF. Self reported osteoporosis and falls were associated with LEF in diabetics. Our findings emphasize the need for fracture and falls preventive measures in diabetics. PMID- 30481577 TI - Hypoglycemia in type 1A diabetes can develop before insulin therapy: a retrospective cohort study. AB - AIMS: There are as yet no cohort studies of hypoglycemia in type 1 diabetes before starting insulin therapy. Our aim was to determine the frequency and clinical features of hypoglycemia in patients with type 1A diabetes prior to commencing insulin therapy. METHODS: Eighty-seven patients with type 1A diabetes were enrolled, and a retrospective chart review of the patients was conducted. RESULTS: Hypoglycemia before insulin therapy occurred in six of 87 patients (6.9%). The HbA1c levels at the diagnosis of type 1A diabetes in the hypoglycemia group were lower than in the non-hypoglycemia group (median: 7.3% (56 mmol/mol) vs. 11.9% (106 mmol/mol), p<0.0001). Similarly, the 24-hour urinary C-peptide (UCPR) levels of the former group were higher than those of the latter group (16.5 MUg/day/m2 vs. 7.0 MUg/day/m2, p=0.0075). Hypoglycemic episodes occurred mostly in the postprandial period and gradually disappeared with a decrease in insulin secretion. CONCLUSIONS: We demonstrated that some patients with type 1A diabetes experience hypoglycemic episodes before insulin therapy. Patients with early-stage type 1A diabetes with relatively low HbA1c or high UCPR have a risk of hypoglycemia. These findings may impact when and how insulin is introduced in the treatment of early-stage type 1A diabetes. PMID- 30481578 TI - Diabetic ketoacidosis further increases risk of Alzheimer's disease in patients with type 2 diabetes. AB - AIM: Diabetes mellitus (DM) is a known risk factor for dementia. It is unclear whether diabetic ketoacidosis (DKA) further increases the risk of dementia in patients with type 2 DM. METHODS: This retrospective nationwide population-based cohort study was conducted using Taiwan's National Health Insurance database. We extracted claims data for 4451 patients with type 2 diabetes and DKA and 8902 diabetic controls matched for age, gender, diabetes complication severity index, frequency of clinic visits and baseline comorbidities between 2000 and 2002. Patients with type 1 diabetes or prior hypoglycemia before index date were excluded. All patients were tracked until new dementia diagnosis, death, or end of 2011. RESULTS: Of the 4451 DKA patients, 211 (4.7%) and 305 (3.4%) of the 8902 diabetic controls were diagnosed as having dementia during the follow-up period. The incidence rate ratio (IRR) for dementia was 1.62 (95% CI 1.35-1.93; P < 0.0001) for patients with DKA versus diabetic patients without DKA. After adjusting for age, baseline comorbidities, geographic area, and income, patients with DKA were found to have 1.86 times the risk of developing dementia, compared to controls (95% CI 1.56-2.22, P < 0.0001). They were found to have a higher risk of Alzheimer's dementia (HR:1.86; 95% CI 1.52-2.28, P < 0.0001) but not non Alzheimer's dementia. CONCLUSION: Type 2 diabetes patients with DKA are at increased risk of Alzheimer's dementia but not non-Alzheimer dementia. PMID- 30481579 TI - Paeonia arietina and Paeonia kesrounansis bioactive constituents: NMR, LC-DAD-MS fingerprinting and in vitro assays. AB - Paeonia species have been valued for their ethnomedicinal uses in various countries and received much interest among the scientific community for their therapeutic properties, including anti-microbial, anti-inflammatory, anti-cancer, nephroprotective and hepatoprotective effects. The multiple phytotherapeutical applications of Paeonia species inspired us to establish the phytochemical fingerprint and to evaluate the biological properties of ethyl acetate, methanol, and aqueous extracts from the roots and aerial parts of two Paeonia species (P. arietina G. Anderson and P. kesrounansis Thiebaut). Phytoconstituents of P. arietina and P. kesrounansis extracts were analyzed using 1D and 2D NMR and LC DAD-ESI-MS. The total content of phenolics (TPC) and flavonoids (TFC) in the extracts was also evaluated. The antioxidant activity was profiled using DPPH, ABTS, CUPRAC, FRAP, phosphomolybdenum, and metal chelation assays. Enzyme inhibitory properties were evaluated against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase, alpha-amylase, and alpha-glucosidase. Phytochemical analysis of P. arietina and P. kesrounansis extracts showed the presence of galloyl esters of sugars, galloyl monoterpenes, and glycosylated flavonoids. The three solvent extracts presented different behavior in the bioassays. The highest antioxidant activity, tyrosinase and AChE inhibition were observed for the methanolic extract of the aerial parts of P. kesrounansis. In addition, the ethyl acetate extracts of the aerial parts of both plants were the most effective inhibitors of alpha-amylase. The highest BChE inhibition was observed for root methanolic extract of P. kesrounansis while the root ethyl acetate extract of P. arietina exerted the strongest inhibition of alpha glucosidase. Methanol extract of P. kesrounansis aerial parts presented the highest TPC, while TFC was greatest in the corresponding extract of P. arietina. Our findings can be considered as a starting point for future studies to further validate the effectiveness and safety profiles of these plants in folk medicine. PMID- 30481580 TI - Indel-informed bayesian analysis suggests cryptic divisions between Plasmodium knowlesi of humans and long-tailed macaques (Macaca fascicularis) in Malaysian Borneo. AB - Plasmodium knowlesi is a major causative agent of malaria in humans of Southeast Asia. Macaques are natural hosts for this parasite, which is considered to be zoonotic, but little is conclusively known about its patterns of transmission within and between these hosts. Here, we apply a novel phylogenetic approach to test for patterns of cryptic population genetic structure between P. knowlesi isolated from humans and long-tailed macaques from the state of Sarawak in Malaysian Borneo. Our approach differs from previous investigations through our exhaustive use of archival 18S Small Subunit rRNA (18S) gene sequences from Plasmodium and Hepatocystis species, our inclusion of insertion and deletion information during phylogenetic inference, and our application of Bayesian phylogenetic inference to this problem. We report distinct clades of P. knowlesi that predominantly contained sequences from either human or macaque hosts species for paralogous A-type and S-type 18S gene loci. We report significant partitioning of sequence distances between host species across both types of loci, and confirmed that sequences of the same locus type showed significantly biased assortment into different clades depending on their host species. Our results support the zoonotic potential of Plasmodium knowlesi, but also suggest that humans may be preferentially infected with certain strains of this parasite. Broadly, such patterns could arise through preferential zoonotic transmission of some parasite lineages or a disposition of parasites to transmit within, rather than between, human and macaque hosts. Available data are insufficient to address these hypotheses, although human-to-human transmission would provide a parsimonious explanation for the phylogenetic patterns that we observe. Regardless, P. knowlesi is often assumed to be a strict zoonosis. Our results suggest this may not be a safe assumption, and highlight the need for renewed and more vigorous explorations of transmission patterns in the fifth human malarial parasite. PMID- 30481581 TI - PM2.5 exposure exacerbates allergic rhinitis in mice by increasing DNA methylation in the IFN-gamma gene promoter in CD4+T cells via the ERK-DNMT pathway. AB - Allergic rhinitis (AR) is a common chronic inflammatory disease that has a significant impact on the quality of life of patients. Our previous study suggested that PM2.5 might affect pediatric AR through epigenetic regulation, but the underlying mechanisms remained unclear. In this study, an experimental murine AR model was created, and the nasal symptoms, pathological changes, the DNA methylation level of the IFN-gamma gene promoter and activation of the ERK-DNMT pathway were evaluated after treatment with PM2.5. Our results showed that PM2.5 exposure led to more severe symptoms of AR in mice. In addition, PM2.5 exposure significantly decreased the percentage of Th1 T cells in the AR group, and this change was correlated with increased DNA methylation of the IFN-gamma gene promoter in CD4 + T cells (r=-0.916, p = 0.029). In addition, PM2.5 exposure increased the activation of the ERK-DNMT pathway in CD4+ T cells, and inhibiting this effect rescued the polarization of the Th1/Th2 balance toward Th2, thereby decreasing the risk of AR. Our findings demonstrate that PM2.5 exposure could exacerbate AR by increasing the DNA methylation of the IFN-gamma gene promoter in CD4 + T cells via the ERK-DNMT pathway, and these effects were rescued when the ERK-DNMT pathway was inhibited. PMID- 30481582 TI - Dermal disposition of Tetrabromobisphenol A Bis(2,3-dibromopropyl) ether (TBBPA BDBPE) using rat and human skin. AB - Tetrabromobisphenol A Bis(2,3-dibromopropyl) ether (TBBPA-BDBPE) is a high production volume brominated flame retardant (BFR) used in consumer products, resulting in ubiquitous human exposure. Although the major route of exposure for this chemical is believed to be via ingestion, dermal contact is likely via contaminated dust. Independent trials of a single dose of 100 nmol/cm2 (~1 MUCi [14C]/cm2) of [14C]-radiolabeled TBBPA-BDBPE was applied to whole rat skin (in vivo) or split-thickness human and rat skin (ex vivo) to estimate in vivo human percutaneous uptake. [14C]-radioactivity was quantified to determine dermal absorption (dose retained in dosed skin) and penetrance (dose recovered in receptor fluid [ex vivo] or tissues/excreta [in vivo]) over 24 h. In vivo absorption and penetration for rat skin was 26% and 1%, with a maximum flux of 44 +/- 9 pmol/cm2/h. In ex vivo rat skin, absorption and penetration and absorption values were 23% and 0.3% (flux = 26 +/- 8 pmol/cm2/h). In ex vivo human skin, 53% was absorbed and penetration was 0.2% with a maximal flux of 16 +/- 12 pmol/cm2/h. Computed maximal flux for in vivo human skin was 21 +/- 9 pmol/cm2/h with expected total absorption of ~80% and a penetration of <1%. HPLC-radiometric analyses of samples showed that TBBPA-BDBPE was not metabolized in ex vivo or in vivo studies. These studies indicate that TBBPA-BDBPE is likely to be dermally bioavailable even after washing and dermal contact with this chemical should be considered an important route of exposure. PMID- 30481583 TI - Perinatal exposure to nonylphenol induces microglia-mediated nitric oxide and prostaglandin E2 production in offspring hippocampus. AB - Nonylphenol (NP) is a persistent organic pollutant (POP) that has potential for neurotoxicity. The central nervous system (CNS) of fetus and child is highly sensitive to POPs, with environmental NP exposure, in particular, receiving increasing attention. Microglia (MG) are vital resident immune cells in CNS that defend against exogenous chemicals. This makes them a potentially target of NP. We sought to explore the effects of maternal exposure to NP during pregnancy and lactation on MG in the offspring hippocampus, the production of nitric oxide (NO) and prostaglandin E2 (PGE2) by MG, and the associated underlying mechanisms. We found that maternal exposure to NP activated MG and increased the production of NO and PGE2 in the offspring hippocampus. Nuclear translocation of p65 was found to co-localize with hippocampal MG. Activation of TLR4/MyD88/NF-kappaB and Nrf2 signaling were observed in the offspring hippocampus. Interestingly, the inhibition of TLR4 signaling with CLI-095 partly inhibited NP-induced NO and PGE2 expression in BV2, a MG cell line. Together, our results suggested that maternal exposure to NP might increase the production of NO and PGE2 by over-activated MG in the offspring hippocampus. TLR4/MyD88/NF-kappaB and Nrf2 signaling pathways may be involved in the activation of MG and the increased production of NO and PGE2. PMID- 30481584 TI - Ambient fine particulate matter induce toxicity in lung epithelial-endothelial co culture models. AB - Epidemiological and toxicological studies have reported that ambient fine particulate matter (PM2.5) exposure are linked to adverse effects of cardiopulmonary system. An in vitro suitable model that assesses the interaction among various cell types should be developed to explain the toxic mechanisms occurred in cardiopulmonary system. The Transwell culture method was used to establish bi-culture consisting of A549 alveolar epithelial cells monoculture in apical chamber and EA.hy926 endothelial cells in the basolateral chamber, while tri-culture systems consisting of co-culture (A549 cells and THP-1 differentiated macrophages) in the apical chamber and also EA.hy926 endothelial cells in the basolateral chamber. Ambient PM2.5 collecting from Shanghai city in China was used for experiments. Our results showed that apical exposure of co-cultured cells to PM2.5 (20, 60, 180 MUg/ml) for 24 h elicited stronger inflammatory responses than apical exposure of monocultured A549. Endothelial function was assessed via detecting gene expression in EA.hy926 cells, exposure of co-cultured cells induced more vigorous ICAM-1 and caveolin-1 mRNA expression in the tri culture model than monocultured cells at the same dose of PM2.5 in the bi-culture model. Particles uptake were observed in both epithelial cells and endothelial cells according to TEM images. In conclusion, PM2.5 were able to pass through epithelial barrier and deposited in endothelium to further induce direct effect on endothelium function. The tri-culture system was more realistic and sensitive model to evaluate the impact of particles on the cardiopulmonary system than the bi-culture system. Therefore, the tri-culture system will contribute to explaining of the relationships between PM2.5 and cardiopulmonary diseases. PMID- 30481585 TI - Accidental ingestion of aspirin and non-steroidal anti-inflammatory drugs is common in patients with aspirin-exacerbated respiratory disease. PMID- 30481586 TI - Cancer stem cells: Road to therapeutic resistance and strategies to overcome resistance. AB - Unlike other normal cells, a subpopulation of cells often termed as "stem cells" are long-lived and generate cellular progeny throughout life. Cancer stem cells (CSCs) are rare immortal cells within a tumor that can both self-renew by dividing and giving rise to many cell types that constitute the tumor. CSCs also have been shown to be involved in fundamental processes of cell proliferation and metastatic dissemination. CSCs are generally resistant to chemotherapy and radiotherapy, a subset of remaining CSCs after therapy can survive and promote cancer relapse and resistance to therapies. Understanding the biological characteristics of CSCs, the pathways leading to their sustainability and proliferation, and the CSCs role in drug resistance is crucial for establishing novel tumor diagnostic and therapeutic strategies. In this review, we address the pathways that regulate CSCs, the role of CSCs in the resistance to therapy, and strategies to overcome therapeutic resistance. PMID- 30481587 TI - Analysis of post-translational modifications in Alzheimer's disease by mass spectrometry. AB - The roles of post-translational modifications (PTMs) in the onset and progression of disease have been extensively studied for decades. More specifically, various PTMs have been the focus of research in Alzheimer's disease (AD). The two most discussed hallmarks of the disease, senile plaques and tau tangles, are the result of PTMs of the amyloidbeta protein precursor (AbetaPP) and the microtubule stabilizing protein: tau. While these modifications have been characterized indirectly by biochemical-based methods, the primary shortcoming to this research can be linked to a lack of a thorough molecular-based means of qualitative and quantitative analysis of many of these modifications within transgenic animal, and human samples. In this review, we discuss the important proteins and their associated PTMs linked to AD and the ways in which mass spectrometry has and will be utilized to analyze them. We also comment on novel ways in which molecular based mass spectrometry methods should be employed going forward to resolve the interconnections of the PTMs involvement in various stages of AD pathology (preclinical, mild cognitive impairment, advanced-stage AD). PMID- 30481588 TI - The role of posttranslational modifications of alpha-synuclein and LRRK2 in Parkinson's disease: Potential contributions of environmental factors. AB - Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD), and the most prevalent movement disorder. PD is characterized by dopaminergic neurodegeneration in the substantia nigra, but its etiology has yet to be established. Among several genetic variants contributing to PD pathogenesis, alpha-synuclein and leucine-rich repeat kinase (LRRK2) are widely associated with neuropathological phenotypes in familial and sporadic PD. alpha-Synuclein and LRRK2 found in Lewy bodies, a pathogenic hallmark of PD, are often posttranslationally modified. As posttranslational modifications (PTMs) are key processes in regulating the stability, localization, and function of proteins, PTMs have emerged as important modulators of alpha-synuclein and LRRK2 pathology. Aberrant PTMs altering phosphorylation, ubiquitination, nitration and truncation of these proteins promote PD pathogenesis, while other PTMs such as sumoylation may be protective. Although the causes of many aberrant PTMs are unknown, environmental risk factors may contribute to their aberrancy. Environmental toxicants such as rotenone and paraquat have been shown to interact with these proteins and promote their abnormal PTMs. Notably, manganese (Mn) exposure leads to a PD-like neurological disorder referred to as manganism-and induces pathogenic PTMs of alpha-synuclein and LRRK2. In this review, we highlight the role of PTMs of alpha-synuclein and LRRK2 in PD pathogenesis and discuss the impact of environmental risk factors on their aberrancy. PMID- 30481589 TI - Genetic regulation of longevity and age-associated diseases through the methionine sulfoxide reductase system. AB - Methionine sulfoxide reductase enzymes are a protective system against biological oxidative stress in aerobic organisms. Modifications to this antioxidant system have been shown to impact the lifespan of several model system organisms. In humans, methionine oxidation of critical proteins and deficiencies in the methionine sulfoxide reductase system have been linked to age-related diseases, including cancer and neurodegenerative disease. Substrates for methionine sulfoxide reductases have been reviewed multiple times, and are still an active area of discovery. In contrast, less is known about the genetic regulation of methionine sulfoxide reductases. In this review, we discuss studies on the genetic regulation of the methionine sulfoxide reductase system with relevance to longevity and age-related diseases. A better understanding of genetic regulation for methionine sulfoxide reductases may lead to new therapeutic approaches for age-related diseases in the future. PMID- 30481590 TI - EWSR1, a multifunctional protein, regulates cellular function and aging via genetic and epigenetic pathways. AB - Ewing's sarcoma (EWS) is a bone cancer arising predominantly in young children. EWSR1 (Ewing Sarcoma breakpoint region 1/EWS RNA binding protein 1) gene is ubiquitously expressed in most cell types, indicating it has diverse roles in various cellular processes and organ development. Recently, several studies have shown that missense mutations of EWSR1 genes are known to be associated with central nervous system disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Otherwise, EWSR1 plays epigenetic roles in gene expression, RNA processing, and cellular signal transduction. Interestingly, EWSR1 controls micro RNA (miRNA) levels via Drosha, leading to autophagy dysfunction and impaired dermal development. Ewsr1 deficiency also leads to premature senescence of blood cells and gamete cells with a high rate of apoptosis due to the abnormal meiosis. Despite these roles of EWSR1 in various cellular functions, the exact mechanisms are not yet understood. In this context, the current review overviews a large body of evidence and discusses on what EWSR1 genetic mutations are associated with brain diseases and on how EWSR1 modulates cellular function via the epigenetic pathway. This will provide a better understanding of bona fide roles of EWSR1 in aging and its association with brain disorders. PMID- 30481591 TI - How the brain makes sense beyond the processing of single words - An MEG study. AB - Human language processing involves combinatorial operations that make human communication stand out in the animal kingdom. These operations rely on a dynamic interplay between the inferior frontal and the posterior temporal cortices. Using source reconstructed magnetoencephalography, we tracked language processing in the brain, in order to investigate how individual words are interpreted when part of sentence context. The large sample size in this study (n = 68) allowed us to assess how event-related activity is associated across distinct cortical areas, by means of inter-areal co-modulation within an individual. We showed that, within 500 ms of seeing a word, the word's lexical information has been retrieved and unified with the sentence context. This does not happen in a strictly feed forward manner, but by means of co-modulation between the left posterior temporal cortex (LPTC) and left inferior frontal cortex (LIFC), for each individual word. The co-modulation of LIFC and LPTC occurs around 400 ms after the onset of each word, across the progression of a sentence. Moreover, these core language areas are supported early on by the attentional network. The results provide a detailed description of the temporal orchestration related to single word processing in the context of ongoing language. PMID- 30481592 TI - Detrended connectometry analysis to assess white matter correlates of performance in childhood. AB - The white matter of the brain develops in a robust, regionally-variant, nonlinear manner during childhood. To relate white matter connectivity to performance, these regional nonlinear effects of age must be accounted for. Here, we identify white matter correlates of gross intellectual functioning using cutting-edge diffusion analyses inside a data-driven two-step regression framework. A total of 98 participants, ages 3-18 years, were included in the analyses. First, white matter connectivity was modeled as a function of age for each fiber direction at each voxel, extracted from the spin distribution function, using a 6th-order B spline. The smoothing parameter for each direction was chosen by minimizing generalized cross-validation (GCV), which prevents overfitting while remaining sensitive to potentially nonlinear effects of age. In the second step, the resulting Gaussian residuals were modeled as a function of either full-scale IQ (FSIQ), or of verbal IQ (VIQ) and performance IQ (PIQ), using a linear regression framework (connectometry). Graph theoretical analyses were also performed to assess how each predictor relates to global topological changes, including average clustering coefficient, characteristic path length, global efficiency, average local efficiency, and small worldness. Analyses revealed widespread positive associations between white matter connectivity and FSIQ, including regions of the corpus callosum, fornix, and corticothalamic tracts (FDRq < .05). A separate regression model revealed a selective positive relationship between VIQ and white matter connectivity in predominately frontal tracts (e.g., anterior corticothalamic radiations, fornix, anterior corpus callosum, frontopontine tracts); in contrast, PIQ predicted white matter connectivity in the posterior brain (e.g. parietopontine tracts, posterior corticothalamic radiations, posterior corticostriatal projections), (FDRq < .05). No negative correlations were observed. Graph analyses revealed FSIQ, VIQ while controlling for PIQ, and PIQ while controlling for VIQ increase clustering coefficient, global efficiency, local efficiency, and small worldness, and decrease characteristic path length of the network. Results indicate regional white matter changes related to cognitive skills in childhood, independent of age. PMID- 30481593 TI - Can we study 3D grid codes non-invasively in the human brain? Methodological considerations and fMRI findings. AB - Recent human functional magnetic resonance imaging (fMRI) and animal electrophysiology studies suggest that grid cells in entorhinal cortex are an efficient neural mechanism for encoding knowledge about the world, not only for spatial location but also for more abstract cognitive information. The world, be it physical or abstract, is often high-dimensional, but grid cells have been mainly studied on a simple two-dimensional (2D) plane. Recent theoretical studies have proposed how grid cells encode three-dimensional (3D) physical space, but it is unknown whether grid codes can be examined non-invasively in humans. Here, we investigated whether it was feasible to test different 3D grid models using fMRI based on the direction-modulated property of grid signals. In doing so, we developed interactive software to help researchers visualize 3D grid fields and predict grid activity in 3D as a function of movement directions. We found that a direction-modulated grid analysis was sensitive to one type of 3D grid model - a face-centred cubic (FCC) lattice model. As a proof of concept, we searched for 3D grid-like signals in human entorhinal cortex using a novel 3D virtual reality paradigm and a new fMRI analysis method. We found that signals in the left entorhinal cortex were explained by the FCC model. This is preliminary evidence for 3D grid codes in the human brain, notwithstanding the inherent methodological limitations of fMRI. We believe that our findings and software serve as a useful initial stepping-stone for studying grid cells in realistic 3D worlds and also, potentially, for interrogating abstract high-dimensional cognitive processes. PMID- 30481595 TI - Fluoroquinolone prophylaxis is highly effective for the prevention of central line-associated bloodstream infections in autologous stem cell transplant patients. AB - OBJECTIVES: Patients undergoing stem cell transplant (SCT) for the treatment of hematologic malignancy are at increased risk for central line-associated bloodstream infections (CLABSIs). The use of prophylactic antibiotics to prevent CLABSIs in the setting of autologous SCT is of unclear benefit. We aimed to evaluate the impact of levofloxacin prophylaxis on reducing CLABSIs in this high risk population. METHODS: Patients undergoing autologous SCT at a tertiary-care hospital received levofloxacin prophylaxis from January 13, 2016 to January 12, 2017. Levofloxacin was administered from autologous SCT (day 0) until day 13, absolute neutrophil count > 500/mm3, or neutropenic fever, whichever occurred first. Clinical outcomes were compared to a baseline group who underwent autologous SCT but did not receive antibacterial prophylaxis during the previous year. The primary endpoint was incidence of CLABSIs assessed using Cox proportional hazards regression. RESULTS: A total of 324 patients underwent autologous SCT during the entire study period, with 150 receiving levofloxacin prophylaxis during the intervention period. The rate of CLABSIs was reduced from 18.4% during the baseline period to 6.0% during the intervention period. On multivariable analysis, levofloxacin prophylaxis significantly reduced CLABSI incidence (hazard ratio (HR) 0.33; 95% confidence interval (CI) 0.16-0.69; P=0.003). There was also a reduction in the risk of neutropenic fever (odds ratio (OR) 0.23; 95% CI 0.14-0.39; P<0.001) and a trend toward a reduction in intensive care unit transfer for sepsis (OR 0.33; 95% CI 0.09-1.24; P=0.10) in patients receiving levofloxacin prophylaxis. Notably, there was no increase in Clostridium difficile infection in the levofloxacin group (OR 0.66, 95% CI 0.29-1.49, P=0.32). CONCLUSIONS: Levofloxacin prophylaxis was effective in reducing CLABSIs and neutropenic fever in patients undergoing autologous SCT. Further studies are needed to identify specific patient groups who will benefit most from antibiotic prophylaxis. PMID- 30481594 TI - Ocular graft-versus-host disease after hematopoietic cell transplantation: expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT. AB - Ocular graft-versus-host disease (GVHD) occurs in more than half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity which affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD, regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed in this review. Ocular GVHD has at least three biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have found several novel pathogenic mechanisms including renin angiotensin system and endoplasmic reticulum stress signaling that can be targeted by therapeutic agents. Many studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. Efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important for all health professionals taking care of HCT recipients to have adequate knowledge of ocular GVHD for optimal care. PMID- 30481596 TI - Effects of low-dose glucocorticoid prophylaxis on chronic GVHD and GVHD-free, relapse-free survival after haploidentical transplantation: long-term follow-up of a controlled, randomized open-label trial. AB - This long-term follow-up study evaluated the effects of corticosteroid prophylaxis on GVHD-free, relapse-free survival (GRFS) based on a controlled open label randomized trial in which 228 allotransplant recipients were categorized as low-risk (N = 83, group A) or high-risk; patients at high-risk were randomly assigned to receive (N = 72, group B) or not receive (N = 73, group C) low-dose methylprednisolone prophylaxis. The cumulative incidences of chronic GVHD, relapse, NRM, LFS, OS, and GRFS were 60%, 19%, 16%, 68%, 73%, and 46%, respectively, in the total cases. Compared with the patients in group C, the cases in group B experienced a lower cumulative incidence of moderate to severe chronic GVHD (42% vs. 20%; P=0.010), herpes zoster infection (28% vs. 12%; P=0.010), pulmonary infections (42% vs. 21%; P=0.040), and osteonecrosis of the femoral head (ONFH, 16% vs. 6%; P=0.045) as well as better GRFS (59% vs. 33%; P=0.017). Factors associated with GRFS included total dose of corticosteroid used in the first 100 days after transplantation (HR, 1.547; P = 0.015) and platelet recovery (HR, 1.456; P = 0.037). Our results suggest that low-dose glucocorticoid prophylaxis reduces GVHD and thus reduces the total dose of steroids, which might contribute to lower incidence of infections and ONFH, as well as a superior GRFS, indicating that higher steroid doses are harmful- reducing the total dose is of course beneficial. (ClinicalTrials.gov number, NCT01607580). PMID- 30481597 TI - Peripheral Immunotype Correlates with Minimal Residual Disease Status and is Modulated by Immunomodulatory Drugs (IMiDs) in Multiple Myeloma. AB - There are data to indicate reversal of immune dysfunction with active treatment, however, the precise contribution of specific immune effector and immune suppressor components to achievement of minimal residual disease (MRD) state and IMiD-mediated immunomodulatory effects in multiple myeloma (MM) patients remains poorly understood. In this prospective proof-of-principle study we sought to determine the dynamic alterations in NK, NKT and T cell, including maturation and activating/inhibitory repertoire associated with MRDpos versus MRDneg status post autologous stem cell transplantation (ASCT) and during lenalidomide based maintenance therapy. Of the 46 MM patients enrolled, 36 had bone marrow MRD assessment 60+ days post-ASCT, 30 had longitudinal blood immunotyping during maintenance (pre-therapy, after cycles 1,3, and 6), and 20 had both MRD assessment and longitudinal immunotyping. Multicolor flow cytometry was used for MRD and immunotyping. While the absolute number of NK cells was significantly lower in patients with MRDpos response, phenotypically NK cell in these patients displayed higher expression of activating receptors KIRDS4 and decreased expression of inhibitory molecules NKG2A compared with the MRDneg group. Furthermore, we observed significantly lower frequencies of T cells displaying KIR3DL1 in MRDpos vs. MRDneg patients. Longitudinal immunotyping during lenalidomide maintenance showed loss of mature NK effector function, augmentation of NK-T effector function and acquisition of PD-1 independent anergic state. Our findings also suggest skewing of T cells toward an exhausted state during maintenance phase in MRDpos patients. Put together, these observations provide a distinctive signature for MRDneg and MRDpos groups. These data support exploration of immune profiling in prospective clinical trials according to MRD defined responses to identify patients that may benefit from maintenance intensification/modification, or maintenance withdrawal. PMID- 30481598 TI - A 4 or 5 Deauville score assessed by (18)F-FDG-PET CT early post-allotransplant is highly predictive of relapse in lymphoma patients. AB - The impact of early Fluorine-18 Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET-CT) status on survival after allogeneic transplantation for lymphoma is poorly reported.This retrospective study included all adult Hodgkin (HL) or non-Hodgkin (NHL) lymphoma patients (>18 years old) who benefited from FDG PET-CT before (within 1 month) and/or early (+3 months and within +6-9 months) after Allo-SCT in our institution between 2005 and 2015 and who were still without documented progression nor relapse at the time of the FDG PET-CT. All FDG PET-CT were reviewed by a nuclear medicine expert in hematology and restaged according to the Deauville Scale. FDG-PET CT was considered positive when the uptake was higher than liver background (Deauville score 4 or greater). The primary objective was to study the impact of pre-and post-transplant FDG PET CT on lymphoma-free survival (LFS) and overall survival (OS).Inclusion criteria were fulfilled for 103 patients (69 males, median age: 51.6 years old, range: 22 67). Diagnoses were high-grade NHL (N=47), low-grade NHL (N=6), T-cell lymphoma (N=34) and HL (N=16). More than half of the patients were in complete remission at the time of transplant (n=56). A reduced-intensity conditioning regimen was applied in most cases (n=90). With a median follow-up of 49.5 months (range: 6 140.5) for alive patients, median 3-year OS and LFS were respectively 81% (71-87) and 65% (54-74) for the whole cohort. In multivariate analysis, positive FDG PET CT at 3 months was the strongest independent factor significantly associated with poorer LFS (HR 9.22, 95%CI: 1.88-645.2, p=0.006). FDG PET-CT positivity at 3 months appears to be highly predictive of LFS in patients after allogeneic transplantation and may help to guide strategies to prevent relapse. These results have to be validated prospectively. PMID- 30481599 TI - Reduction in Mortality after Umbilical Cord Blood Transplantation in Children over a 20-Year Period (1995-2014). AB - BACKGROUND: Infections and graft-versus-host disease have historically resulted in high mortality among children undergoing umbilical cord blood transplantation (UCBT). However, recent advances in clinical practice have likely improved outcomes of these patients. METHODS: We conducted a retrospective cohort study of children (<18 years of age) undergoing UCBT at Duke University between January 1, 1995 and December 31, 2014. We compared two-year all-cause and cause-specific mortality during three time periods based on year of transplantation (1995-2001, 2002-2007, 2008-2014). We used multivariable Cox regression to identify demographic and UCBT characteristics that were associated with all-cause mortality, transplantation-related mortality, and death from invasive aspergillosis after adjustment for time period. RESULTS: During the 20-year study period, 824 children underwent UCBT. Two-year all-cause mortality declined from 48% in 1995-2001 to 30% in 2008-2014 (P=0.0002). White patient race and non malignant UCBT indications were associated with lower mortality. Black children tended to have a higher risk of death for which graft-versus-host disease (18% vs 11%; P=0.06) or graft failure (9% vs 3%; P=0.01) were contributory than white children. Comparing 2008-2014 to 1995-2001, more than half (59%) of the reduced mortality was attributable to a reduction in infectious mortality, with 45% specifically related to reduced mortality from invasive aspergillosis. Antifungal prophylaxis with voriconazole was associated with lower mortality from invasive aspergillosis than low-dose amphotericin B lipid complex [hazard ratio (HR): 0.09; 95% confidence interval (CI): 0.01-0.76]. With the decline in mortality from invasive aspergillosis, adenovirus and cytomegalovirus have become the most frequent infectious causes of death in children after UCBT. CONCLUSIONS: Advances in clinical practice over the past 20 years improved survival of children after UCBT. Reduced mortality from infections, particularly invasive aspergillosis, accounted for the largest improvement in survival and was associated with use of voriconazole for antifungal prophylaxis. PMID- 30481600 TI - Apixaban and rivaroxaban in patients with cerebral venous thrombosis. PMID- 30481601 TI - Degradation of dimethyl phthalate using a liquid phase plasma process with TiO2 photocatalysts. AB - The liquid phase plasma (LPP) method with a TiO2 photocatalyst and hydrogen peroxide was used to decompose dimethyl phthalate (DMP). As the applied voltage, pulse width, and frequency were increased, the rate of decomposition was increased and the decomposition rate was 63% for 180 min under plasma optimum conditions. The addition of TiO2 photocatalyst and hydrogen peroxide increased the DMP decomposition reaction rate, but an excess cause a decrease in decomposition rate due to a decrease in conductivity, blocking of ultraviolet light, and scavenger effect. When the TiO2 photocatalyst and hydrogen peroxide were used together, the decomposition reaction rate of DMP was greatly improved by using LPP single process alone. Also, when all the processes were used at the same time, the decomposition reaction rate was improved to about 2.8 times. DMP undergoes bond cleavage and ultimately decomposes into CO2 and H2O via dimethyl 4 hydroxyphthalate and methyl salicylates due to hydroxyl radicals and various active species generated by the LPP reaction. PMID- 30481602 TI - Total, methyl and inorganic mercury concentrations in blood and environmental exposure sources in newcomer women in Toronto, Canada. AB - Measurements of total blood Hg (tHg), often used as a proxy for methyl Hg (MeHg) concentrations, are most commonly the focus of population-based studies. Data on Hg species in biomarkers can allow for a more nuanced characterization of environmental exposure sources and risk but their availability is limited, especially for newcomer populations. The purpose of the Metals in Newcomer Women (MNW) study was to address existing data gaps on metal concentrations and exposure sources in newcomer women (19-45 years) and to examine tHg, MeHg and inorganic Hg (iHg) in the blood of East and South Asian women recently arrived to Toronto. Study participants were recruited in 2015 (n = 211). Total Hg concentrations were determined using both ICP-Q-MS and isotope dilution (ID)-SPME GC-ICP-MS. A sample subset (n = 76) was chosen for the analysis of blood MeHg and iHg concentrations (also using ID-SPME-GC-ICP-MS). Hierarchical regression models were used to assess associations between blood tHg concentrations and environmental exposure factors for MNW participants. For the sample subset, a log linear model was used to examine associations between blood iHg and MeHg concentrations and fish consumption patterns. The geometric mean (GM) blood tHg concentration was 1.05 ug/L (95% CI: 0.88-1.25), which was elevated compared to Canadian-born women (GM: 0.57 ug/L; 95% CI: 0.49-0.66), in a specialized data analysis of the Canadian Health Measures Survey (CHMS). GM concentrations for iHg and MeHg were 0.21 ug/L (95% CI: 0.16-0.28) and 2.66 ug/L (95% CI: 2.00-3.55), respectively. Significant distal determinants associated with blood tHg concentrations were: level of educational attainment, having lived in a coastal/fishing community prior to arrival, and global region of origin. Use of iron supplements and consumption of higher mercury fish species were also associated with tHg concentrations in the fully adjusted model. The study results demonstrate that blood Hg concentrations in newcomer women are slightly elevated, with some individuals in exceedance of recommended concentrations for women of reproductive age. The consumption of fish species low in Hg is recommended for newcomer women, especially those who consume fish frequently. PMID- 30481603 TI - Granular hydrogels: emergent properties of jammed hydrogel microparticles and their applications in tissue repair and regeneration. AB - Granular hydrogels are emerging as a versatile and effective platform for tissue engineered constructs in regenerative medicine. The hydrogel microparticles (HMPs) that compose these materials exhibit particle jamming above a minimum packing fraction, which results in a bulk, yet dynamic, granular hydrogel scaffold. These injectable, microporous scaffolds possess self-assembling, shear thinning, and self-healing properties. Recently, they have been utilized as cell cultures platforms and extracellular matrix mimics with remarkable success in promoting cellular infiltration and subsequent tissue remodeling in vivo. Furthermore, the modular nature of granular hydrogels accommodates heterogeneous HMP assembly, where varying HMPs have been fabricated to target distinct biological processes or deliver unique cargo. Such multifunctional materials offer enormous potential for capturing the structural and biofunctional complexity observed in native human tissue. PMID- 30481604 TI - Meta-analysis of the effect of a pulmonary rehabilitation program on respiratory muscle strength in patients with chronic obstructive pulmonary disease. AB - PURPOSE: Pulmonary rehabilitation (PR) programs are important in the treatment of patients with chronic obstructive pulmonary disease (COPD) but vary widely in type, duration, and efficacy. This meta-analysis investigated the effect of PR programs on respiratory muscle strength in patients with COPD. METHODS: PubMed, Embase, and CINAHL were searched. The primary outcome variables were maximal expiratory pressure (MEP) and maximal inspiratory pressure (MIP). The secondary outcome variables were the modified Borg score after the 6-min walking test, percent predicted forced expiratory volume in 1 second (FEV1%pred), and percent FEV1/forced volume capacity (FVC). Comprehensive Meta-Analysis version 3.0 was used to analyze the data. The effect size was calculated using the standardized mean difference (SMD) and 95% confidence interval (CI). RESULTS: Twenty randomized controlled trials (with 992 subjects) were included in the analysis. The PR programs had a significant effect on the MEP (SMD 0.87, 95% CI 0.42-1.32, p < .001), MIP (SMD 0.53, 95% CI 0.13-0.93, p = .009), and modified Borg score (SMD -0.37, 95% CI -0.52, -0.22, p < .001) in patients with COPD. There was no effect on FEV1%pred (SMD 0.09, 95% CI -0.12, 0.30, p = .406) or FEV1/FVC% (SMD 0.04, 95% CI -0.17, 0.26, p = .702). CONCLUSIONS: PR programs improve respiratory muscle strength in patients with COPD. Strategies for selecting a suitable PR program need to be developed, and future studies should evaluate the long-term effects of such programs on pulmonary function. PMID- 30481605 TI - 14N overtone NMR under MAS: Signal enhancement using cross-polarization methods. AB - Polarization transfer methods are widely adopted for the purpose of correlating different nuclear species as well as to achieve signal enhancement. Polarization transfer from 1H to the 14N overtone transition (Deltam = 2) can be achieved using cross polarization methods under magic-angle spinning conditions, where spin locks of the order of several milliseconds can be obtained on common bio solids (alpha-glycine and N-acetylvaline). Signal enhancement factors up to 4.4 per scan, can be achieved under favorable conditions, despite MHz-sized quadrupolar interaction. Moreover, we present a detailed theoretical treatment and accurate numerical simulations which are in excellent agreement the unusual experimental matching conditions observed for cross-polarization to 14N overtone. PMID- 30481606 TI - Expression of gelatinases (MMP-2 and MMP-9) and tissue inhibitors of metalloproteinases (TIMP-2 and TIMP-3) in the chicken ovary in relation to follicle development and atresia. AB - Matrix metalloproteinases (MMPs) are a family of peptidases that possess the ability to break down extracellular matrix macromolecules associated with tissue turnover in various physiological and pathological conditions. Their activity is largely regulated by specific tissue inhibitors of MMPs (TIMPs). Information concerning the role of MMPs in the chicken ovary is very limited. The aim of the present study was to determine the expression and localization of selected members of the MMP system in different compartments of the laying hen ovary and to investigate whether their expression changes at different stages of the ovulatory cycle. MMP-2 and -9 activity was also examined. Expression of MMP-2, -9 and tissue inhibitors of MMPs (TIMP-2 and -3) in the ovarian follicles was examined 22 h and 3 h before F1 ovulation. Real-time polymerase chain reaction and western blot revealed differential mRNA and protein expression of MMP-2, MMP 9, TIMP-2, and TIMP-3 in the ovarian follicles: white, yellowish, small yellow, the largest preovulatory (F3-F1), and white atretic. Within the ovary, the relative expression of MMP and TIMP mRNA depended on follicle development, the layer of follicular wall, and ovulation stage. The relatively higher expression of MMP-2 and MMP-9 mRNA in the ovarian follicles 3 h compared to 22 h before ovulation was found. As follicle development progressed toward ovulation, elevated MMP-2 and -9 activity was noted. Atresia of white follicles was accompanied by an increase in gelatinase activities. Immunohistochemistry demonstrated tissue- and follicle-dependent immunoreactivity of the examined MMPs and TIMPs. In summary, the results show tissue- and stage of the ovulatory cycle dependent differences in MMP and TIMP expression, as well as MMP-2 and -9 activity. Findings that suggest these molecules might significantly participate in the complex remodeling of extracellular matrix required for follicle development, ovulation, and atresia in the chicken ovary. PMID- 30481607 TI - Three-dimensional (3D) Printed Scaffold and Material Selection for Bone Repair. AB - Critical-sized bone defect remains a substantial challenge in clinical settings and requires bone grafts or bone substitute materials. However, existing biomaterials often do not meet the clinical requirements of structural support, osteoinductive property, and controllable biodegradability. To treat large-scale bone defects, the development of three-dimensional (3D) porous scaffolds has received considerable focus within bone engineering. A variety of biomaterials and manufacturing methods including 3D printing have emerged to fabricate patient specific bioactive scaffolds that possess controlled micro-architectures for bridging bone defects in complex configurations. During the last decade, with the development of the 3D printing industry, a large number of tissue-engineered scaffolds have been created for preclinical or clinical applications using novel materials and innovated technologies. Thus, this review provides a brief overview of current advances in existing biomaterials and tissue engineering scaffolds prepared by 3D printing technologies, with an emphasis on the material selection, scaffold designoptimization, and their preclinical or clinical applications in the repair of critical-sized bone defects. Furthermore, it will elaborate the current limitations and potential future prospects of 3D printing technology. Statement of Significance 3D printing has emerged as a critical fabrication process for bone engineering due to its ability to control bulk geometry and internal structure of tissue scaffolds. The advancement of bioprinting methods and compatible ink materials for bone engineering have been a major focus to develop optimal 3D scaffolds for bone defect repair. Achieving a successful balance between the properties of a scaffold favorable to cellular function, cellular viability, and mechanical integrity under load-bearing conditions is critical. Hybridization of naturalandsyntheticpolymer-basedmaterials is a promising approach to create novel tissue engineered scaffolds that combines the advantages of both materials and meets various requirements, including biological activity, mechanical strength, easy fabrication and controllable degradation. 3D printing is linked to the future of bone grafts to create on-demand patient specific grafts. PMID- 30481608 TI - Cell Armor for Protection Against Environmental Stress: Advances, Challenges and Applications in Micro- and Nanoencapsulation of Mammalian Cells. AB - Unlike unicellular organisms and plant cells surrounded with a cell wall, naked plasma membranes of mammalian cells make them more susceptible to environmental stresses encountered during in vitro biofabrication and in vivo cell therapy applications. Recent advances in micro- and nanoencapsulation of single mammalian cells provide an effective strategy to isolate cells from their surroundings and protect them against harsh environmental conditions. Microemulsification and droplet-based microfluidics have enabled researchers to encapsulate single cells within a variety of microscale hydrogel materials with a range of biochemical and mechanical properties and functionalities including enhanced cell-matrix interactions or on-demand degradation. In addition to microcapsules, nanocoatings of various organic and inorganic substances on mammalian cells have allowed for the formation of protective shells. A wide range of synthetic and natural polymers, minerals and supramolecular metal-organic complexes have been deposited as nanolayers on the cells via electrostatic interactions, receptor-ligand binding, non-specific interactions, and in situ polymerization/crosslinking. Here, current strategies in encapsulation of single mammalian cells along with challenges and advances are reviewed. Protection of encapsulated stem cells, fibroblasts, red and white blood cells and cancer cells against harsh in vitro and in vivo conditions including anoikis, UV radiation, physical forces, proteolytic enzymes and immune clearance are discussed. STATEMENT OF SIGNIFICANCE: The mechanical fragility of the plasma membrane and susceptibility to extracellular biochemical factors due to the lack of a physical barrier like a tough cell wall or exoskeleton make mammalian cells extra sensitive to harsh environmental conditions. This sensitively, in turn, limits the ex vivo storage, handling and manipulation of mammalian cells, as well as their in vivo applications. Environmental stresses such as exposure to UV, reactive chemicals and mechanical stress during biofabrication processes like 3D bioprinting can often compromise cell viability and function. Micro- and nanoencapsulation of single mammalian cells in protective shells have emerged as promising approaches to isolate cells from their surroundings and enhance resistance against perturbations in conditions during regenerative medicine and tissue engineering applications. In this review, the current state of art of single cell encapsulation strategies and the challenges associated with these technologies are discussed in detail. This is followed by the review of the protection provided by cell armor against a range of harsh in vitro and in vivo conditions. PMID- 30481609 TI - PARP family enzymes: regulation and catalysis of the poly(ADP-ribose) posttranslational modification. AB - Poly(ADP-ribose) is a posttranslational modification and signaling molecule that regulates many aspects of human cell biology, and it is synthesized by enzymes known as poly(ADP-ribose) polymerases, or PARPs. A diverse collection of domain structures dictates the different cellular roles of PARP enzymes and regulates the production of poly(ADP-ribose). Here we primarily review recent structural insights into the regulation and catalysis of two family members: PARP-1 and Tankyrase. PARP-1 has multiple roles in the cellular response to DNA damage and the regulation of gene transcription, and Tankyrase regulates a diverse set of target proteins involved in cellular processes such as mitosis, genome integrity, and cell signaling. Both enzymes offer interesting modes of regulating the production and the target site selectivity of the poly(ADP-ribose) modification. PMID- 30481610 TI - Hydrogen sulfide alleviates oxidative damage under excess nitrate stress through MAPK/NO signaling in cucumber. AB - Hydrogen sulfide (H2S) is emerging as a potential messenger molecule involved in modulation of physiological processes in plants. Mitogen-activated protein kinase (MAPK) and nitric oxide (NO) are essential for abiotic stress signaling. This work investigated the effects of H2S and the crosstalk between H2S, MAPK and NO in cucumber roots under nitrate stress. The inhibitory effect of 140 mM nitrate on the growth of shoot and root was substantially alleviated by treatment with H2S donor sodium hydrosulfide (NaHS), especially 100 MUM NaHS. Treatment with 100 MUM NaHS reduced malondialdehyde (MDA) and H2O2 contents, ROS accumulation and increased the activities of superoxide dismutase (SOD), catalase (CAT), peroxidase (POD) and ascorbate peroxidase (APX). CsNMAPK transcript level was up regulated by NaHS treatment, while significantly decreased by propargylglycine (PAG, specific inhibitor of H2S biosynthesis) and hypotaurine (HT, H2S scavenger) in cucumber roots under nitrate stress. NO accumulation was increased by NaHS treatment under nitrate stress, but reduced by HT, PAG and PD98059, indicating that NO might function downstream of MAPK and H2S. MAPK inhibitor PD98059 and NO scavenger (cPTIO) reversed the alleviating effect of H2S by increasing MDA and H2O2 contents, and decreasing antioxidant enzyme activities of SOD, CAT, POD, APX, and the endogenous H2S contents and LCD activities under nitrate stress. In conclusion, H2S played a protective role in cucumber seedlings under nitrate stress and MAPK/NO signaling were involved in the process by regulating antioxidant enzyme activities. PMID- 30481611 TI - A practical risk scale for predicting morbidity and mortality in the emergency general surgical setting: A prospective multi-center study. AB - BACKGROUND: Low albumin is a prognostic factor associated with poor surgical outcomes. We aimed to examine the predicative ability of easily obtainable point of-care variables in combination, to derive a practical risk scale for predicting older adults at risk of poor outcomes on admission to the emergency general surgical setting. METHODS: This is an international multi-center prospective cohort study conducted as part of the Older Persons Surgical Outcomes Collaboration (www.OPSOC.eu). The effect of having hypoalbuminemia (defined as albumin <=3.5 g/dL) on selected outcomes was examined using fully adjusted multivariable models. In a subgroup of patients with hypoalbuminemia, we observed four risk characteristics (Male, Anemia, Low albumin, Eighty-five and over [MALE]). Subsequently, the impact of incremental increase in MALE score (each characteristic scoring 1 point (maximum score 4) on measured outcomes was assessed. RESULTS: The cohort consisted of 1406 older patients with median (IQR) age of 76 (70-83) years. In fully adjusted models, hypoalbuminemia was significantly associated with undergoing emergency surgery (1.32 (95%CI 1.03 1.70); p = 0.03), 30-day mortality (4.23 (2.22-8.08); p < 0.001), 90-day mortality (3.36 (2.14-5.28); p < 0.001) (primary outcome), and increased hospital length of stay, irrespective of whether a patient received emergency surgical intervention. Every point increase in MALE score was associated with higher odds of mortality, with a MALE score of 4 being associated with 30-day mortality (adjusted OR(95% CI) = 33.38 (3.86-288.7); p = 0.001) and 90-day mortality (11.37 (3.85-33.59); p < 0.001) compared to the reference category of those with MALE score 0. CONCLUSIONS: The easy to use and practical MALE risk score calculated at point of care identifies older adults at a greater risk of poor outcomes, thereby allowing clinicians to prioritize patients who may benefit from early comprehensive geriatric assessment in the emergency general surgical setting. PMID- 30481612 TI - Critical steps for initiating an animal uterine transplantation model in sheep: Experience from a case series. AB - BACKGROUND: Recent reports have demonstrated uterus transplantation as a relevant solution to treat absolute uterine infertility. Training on animal models is a prerequisite to set up a uterine transplantation program in humans. Sheep have been used as an optimal model for training and research as they display similar vessels size to human. While the ovine model might seem easy there are many difficulties in performing this complex surgery. In this study we describe through our experience the critical initial steps toward building a learning curve toward an optimal ovine uterine transplantation model. MATERIALS: We performed nine orthotopic uterine autotransplantations using end-to-side anastomoses to the external iliac vessels in sheep. We recorded the duration of all surgical steps and pointed out specific difficulties and solution found. RESULTS: We were able to perform optimal uterine dissection after the first 5 cases and optimal bilateral arterial and venous anastomoses, after 7 and 9 cases respectively. The main factors associated to success rate were optimal exposure, appropriate equipment, careful vessel preparation and modification of the anastomosis technique. CONCLUSION: As uterine transplantation research programs are expanding, setting up an ovine model to train and perform research is critical. Such model is complex and requires optimized multidisciplinary approach to build an efficient learning curve. PMID- 30481613 TI - Come, sweet death: targeting glycosomal protein import for antitrypanosomal drug development. AB - Glycosomes evolved as specialized system for glycolysis in trypanosomatids. These organelle rely on protein import to maintain function. A machinery of peroxin (PEX) proteins is responsible for recognition and transport of glycosomal proteins to the organelle. Disruption of PEX-based import system was expected to be a strategy against trypanosomatids. Recently, a proof of this hypothesis has been presented. Here, we review current information about trypanosomatids' glycosomal transport components as targets for new trypanocidal therapies. PMID- 30481614 TI - Sulfatides ameliorate experimental autoimmune neuritis by suppressing Th1/Th17 cells. AB - Sulfatides have immunomodulatory functions, and play protective roles in multiple autoimmune diseases. In the present study, we showed that sulfatides ameliorated experimental autoimmune neuritis in Lewis rats induced with bovine peripheral myelin, which was associated with decreased proportions of Th1 and Th17 cells. Furthermore, compared control group, cells from sulfatide-treated rats exhibited lower potential in proliferation and IL-17 secretion in the presence of BPM or ConA in vitro. Moreover, sulfatides also reduced the proportions of NK and NKT cells. In summary, our study indicated that sulfatides might become a new therapeutic agent in Guillain-Barre syndrome in the future. PMID- 30481615 TI - Neuronal transcriptomic responses to Japanese encephalitis virus infection with a special focus on chemokine CXCL11 and pattern recognition receptors RIG-1 and MDA5. AB - Japanese encephalitis virus (JEV) causes central nervous system neuronal injury and inflammation. A clear understanding of neuronal responses to JEV infection remains elusive. Using the Affymetrix array to investigate the transcriptome of infected SK-N-MC cells, 1316 and 2737 dysregulated genes (>= 2/-2 fold change, P < 0.05) were found at 48 hours post-infection (hpi) and 60 hpi, respectively. The genes were mainly involved in anti-microbial responses, cell signalling, cellular function and maintenance, and cell death and survival. Among the most highly upregulated genes (>= 10 folds, P < 0.05) were chemokines CCL5, CXCL11, IL8 and CXCL10. The upregulation and expression of CXCL11 were confirmed by qRT-PCR and immunofluorescence. Pathogen recognition receptors retinoic acid-inducible gene-1 (RIG-1) and melanoma differentiation-associated protein 5 (MDA5) were also upregulated. Our results strongly suggest that neuronal cells play a significant role in immunity against JEV. CXCL11, RIG-1 and MDA5 and other cytokines may be important in neuropathogenesis. PMID- 30481616 TI - Effect of superchilled storage on shelf life and quality characteristics of M. longissimus lumborum from Chinese Yellow cattle. AB - The effect of superchilled storage (SC, -4 degrees C) on shelf life and quality characteristics of M. longissimus lumborum from Chinese Yellow cattle compared with traditional chilling (TC, 2 degrees C) and frozen storage (-18 degrees C) was studied. The shelf life of beef steaks held at -4 degrees C extended to 12 weeks based on the total volatile basic nitrogen (TVB-N) value, which was 2.4 times longer than steaks stored at 2 degrees C. As the storage time increased, SC samples showed a lower increase of the total aerobic count (TAC), pH and thiobarbituric acid reactive substances (TBARS) values compared to TC samples. Further, L* and a* values of SC samples changed more slowly than that of TC samples. Beef steaks held frozen had a longer shelf life than SC steaks, however, the shear force of frozen steaks remained above 55 N throughout the storage time indicative of toughness. Consequently, SC offers an effective approach for maintaining better shelf life and quality of beef steaks. PMID- 30481617 TI - Alterations of the gut microbiome and plasma proteome in Chinese patients with adolescent idiopathic scoliosis. AB - The etiology of adolescent idiopathic scoliosis (AIS), the most common rotational deformity of the spine, is still unclear. Emerging evidence suggests that gut microbiota dysbiosis influences musculoskeletal diseases such as arthritis and osteoporosis. However, the alterations of the fecal microbiome in AIS remain unknown. Thus, the current study was conducted to explore the gut microbiota compositions of Chinese AIS patients. Microbiota communities in the feces of 51 AIS patients and 34 age- and sex-matched healthy individuals were investigated using 16S rRNA sequencing. Meanwhile, the changes in the plasma proteome were detected using tandem mass tag (TMT) labeling coupled with liquid chromatography mass spectrometry (LC-MS). The relationship between gut microbiota and AIS clinical characteristics as well as the correlation between gut microbiota and the changes in plasma proteins were analyzed. The structure of the gut microbiota differed between the AIS and healthy groups, however, the richness was similar. The genera Prevotella, Gelria, and Desulfovibrio were enriched in the feces of AIS patients. In contrast, the abundance of Parasutterella, Tyzzerella, and Phascolarctobacterium was decreased in the AIS group. More remarkably, a positive correlation between the abundance of the fecal genera Prevotella and the Cobb angles of the AIS patients was observed. Moreover, the major differential plasma proteins related to AIS were Fibronectin 1 (FN1), voltage-dependent anion channel 1 (VDAC1), Ras homolog family member A (RHOA), and AHNAK nucleoprotein (AHNAK). Additionally, the positive correlations between fecal Prevotella and the expression of host plasma FN1 as well as the negative relationships between fecal Prevotella and the expression of host VDAC1 and AHNAK were confirmed. Elucidating these differences in the gut microbiota will provide a foundation to improve our understanding of the pathogenesis of AIS and to support potential therapeutic options based on modifying the gut microbiota. PMID- 30481618 TI - Comparison of Short-term Stimulation of the Globus Pallidus Interna and Subthalamic Nucleus for Treatment of Primary Dystonia. AB - OBJECTIVE: To compare the efficacy and side effects of bilateral globus pallidus internus (GPi) and subthalamic nucleus (STN) deep brain stimulation (DBS) in the same patient with primary dystonia. METHODS: Primary dystonia patients from the Department of Functional Neurosurgery in Beijing Tiantan Hospital were recruited for the study. Four electrodes were bilaterally implanted in the GPi and STN. A trial stimulation was applied to determine the preliminary therapeutic effects. Five evaluations were conducted: pre-operative, post-operative (before stimulation), after sham stimulation, and after 24 h stimulation of GPi and STN using optimal parameters, judged by the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). RESULTS: The BFMDRS movement score decreased after both short-term GPi stimulation (from 15.3 +/- 6.9 to 7.6 +/- 4.2, P < 0.05) and short-term STN stimulation (decreased to 8.6 +/- 5.0, P < 0.05). There were significant reductions in facial (eyes and mouth) movement scores after short-term GPi and STN DBS compared with baseline (P < 0.05), but not in cervical symptoms (P > 0.05). The cervical symptoms of tonic dystonia had an improvement after long term of DBS treatment (P < 0.05). There were more adverse events with STN-DBS, although most side effects could be ameliorated by adjusting the stimulation parameters. CONCLUSIONS: Both short-term GPi and STN stimulation improved the motor symptom of dystonia but no significant difference between GPi-DBS and STN DBS. There were more side effects associated with STN stimulation. PMID- 30481619 TI - Indocyanine-green videoangiography in the surgical treatment of spinal dural arterovenous fistula: a useful application. AB - BACKGROUND: Indocyanine-green videoangiography (ICG-V) is used with increasing frequency in neurovascular surgery. ICG-V use in spinal dural arteriovenous fistulas (DAVFs) allows visualization of the hemodynamics of the fistula and to confirm its exclusion after ligation of the feeder. Here, we illustrate how ICG-V is useful for centering the surgical exposure during mini-invasive approaches to spinal DAVFs. CASE DESCRIPTION: An overweight 66-year-old woman with progressive paraparesis and sphincter disturbances underwent treatment for a spinal DAVF fed by the left T6 radicular artery. After intraoperative fluoroscopy, T6 hemilaminectomy was performed. Due to to slight misplacement of the bone opening, the feeder was not visible at the dural opening. We placed a temporary clip on a perimedullary arterialized vein and performed ICG-V while removing the clip. Reviewing the video clip and analyzing the direction of ICG flow inside the perimedullary venous plexus allowed us to locate the fistula with respect to the bone window and to extend the laminectomy in the correct direction. CONCLUSIONS: IGC-V can be helpful in mini-invasive approaches to spinal DAVF to recalibrate the bone opening after misplacement of the initial hemilaminectomy. PMID- 30481620 TI - Minimally invasive management of spontaneous supratentorial intracerebral lobar hemorrhages by a "home made" endoscopic strategy. The evangelic doctrine of "venite ad me" allied to the legacy of King Leonida. AB - BACKGROUND: While the incidence of intracerebral haemorrhage (ICH) appear to be increasing over the year, its prognosis still remains dismal . Although no consensus about the management of ICH has be found, minimal invasive surgery should limit - when not avoid - the intra operative parenchymal damage. At this regard, we present a novel modified "home made" approach, aimed to shorten the operative time and minimize the corticectomy and brain manipulation, with our clinical series. METHODS: From 2008 to 2017, 53 patients (32 male and 21 female, mean age 63,8 years old) were admitted to our Department of Neurosurgery and treated for a surgical lobar ICH. A modified suction tube coupled with the endoscope light source was used. The clot evacuation was performed under the loupe magnification without either the use of the microscope or the endoscope, whose light source was only used to lighten the working cavity. RESULTS: The mean hematoma volume was 69.2 ml preoperatively (range 40-100) and 12.1 ml (range 0 20) postoperatively, with a mean clot evacuation of 84.3% (range 60-100%). The mean post operative GCS was 11.6, with an improvement of 14% from the admission score (mean 9.2). CONCLUSIONS: Our clinical series not only upholds the effectiveness of endoscopic clot evacuation in surgical ICH but also provides an efficient technique to be used in urgency and in less-developed backgrounds due to its reduced demand of resources and its shorter learning curve, with a good outcome such as the classical endoscopic approach. PMID- 30481621 TI - The biomechanical stability before and after graft fusion with unilateral and bilateral pedicle screw fixation: a finite element study. AB - BACKGROUND: Minimally invasive transformational lumbar interbody fusion (MI-TLIF) with unilateral pedicle screw (UPS) fixation was controversial. The aim of this study was to compare the stability between UPS and bilateral pedicle screw (BPS) fixation before and after graft fusion. METHODS: A L3-L5 finite element model was modified to simulate L4/5 MI-TLIF. Five different status of posterior instrumentation were simulated: UPS fixation or BPS fixation before and after graft fusion, and remove posterior instrumentation after graft fusion. Range of motion and Von Mises stress were evaluated for intact and instrumentation models in all loading planes. RESULTS: Range of motion of the L4/5 segment with UPS fixation was 2.1, 1.3 and 1.7 times than those with BPS fixation before fusion in flexion-extension, lateral bending and axial rotation respectively, while it was 1.3, 1.1 and 1.4 times after fusion. The peak Von Mises stresses on posterior instrumentations with UPS fixation was ranged from 1.0 to 1.7 times than those in BPS fixation before fusion, while it was ranged from 1.0 to 1.4 times after fusion. The peak Von Mises stresses on intervertebral graft with UPS fixation was ranged from 1.9 to 3.5 times than those with BPS fixation before fusion, while it was ranged from 0.9 to 1.2 times after fusion. CLNCLUSIONS: Fusion of graft improved the fixation effect of posterior instrumentation system. Unilateral pedicle screw fixation could provide similar biomechanical stability to bilateral pedicle screw fixation in one-level MI-TLIF after fusion. PMID- 30481622 TI - Stereotactic Placement of Intratumoral Catheters for Continuous Infusion Delivery of HSV-1 G207 in Pediatric Malignant Supratentorial Brain Tumors. AB - OBJECTIVE: G207, an engineered HSV-1, is a promising therapeutic option for CNS tumors. The first-ever pediatric Phase 1 trial of continuous-infusion delivery of G207 via intratumoral catheters for recurrent/progressive malignant brain tumors is ongoing. Herein, we describe surgical techniques for the accurate placement of catheters in multiple supratentorial locations and perioperative complications associated with such procedures. METHODS: A prospective study of G207 in children with recurrent malignant supratentorial tumors is ongoing. Preoperative stereotactic protocol MRI was performed and catheter trajectories planned using STEALTH software. Children underwent placement of 3-4 silastic catheters using a small incision burr hole and the Vertek system. Patients had a pre-infusion CT scan to confirm correct placement of catheters. RESULTS: Six children underwent implantation of 3-4 catheters. Locations of catheter placement included frontal, temporal, parietal, and occipital lobes, and the insula and thalamus. There were no clinically significant perioperative complications. Post-operative CT scan fused with preoperative MRI demonstrated accurate placement of 21 of 22 catheters, with one mal-placed catheter pulled back to an optimal location at the bedside. One patient had hemorrhage along the catheter tract that was clinically asymptomatic. Another patient had CSF leak from a biopsy incision 9 days after surgery that was oversewn without complication. CONCLUSION: The placement of multiple intratumoral catheters in pediatric patients with supratentorial tumors via frameless stereotactic techniques is feasible and safe. Intratumoral catheters provided a potentially effective route for the delivery of G207 and may be employed in other trials utilizing oncolytic virotherapy for brain tumors. PMID- 30481623 TI - ARE-related seizures after radiosurgery for cerebral AVMs. PMID- 30481624 TI - Surgical protocol for infections, nonhealing wound prophylaxis, and analgesia: development and implementation for posterior spinal fusions. AB - OBJECTIVE: To analyze the effects of a surgical protocol for infections, nonhealing wound prophylaxis, and analgesia among patients who underwent posterior spinal fusion at a single tertiary care neurosurgical center. METHODS: This prospective study was conducted in the neurosurgery department of a tertiary care neurosurgical center and compared a control group of patients who had posterior spinal fusion within 3 months before implementation of a surgical protocol with a study group of patients enrolled within 1 year after protocol implementation. The protocol included a surgical safety checklist, control of modifiable risks associated with surgical site infection, administration of intrawound vancomycin and local analgesia, and standard closure. Postoperative pain, demand for analgesics, and postoperative surgical site infections were assessed among patients before and after the introduction of the protocol. RESULTS: The control group (n = 35; 30 women; median age [interquartile range], 40 [31-54] years) experienced a higher-than-predicted rate of minor surgical infections and nonhealing wounds (12 patients; 34%). In the study group (n = 113; 74 women; median age [interquartile range], 45 [37-54] years), 11 patients (10%) had minor surgical infections and nonhealing wounds. Introduction of the protocol was associated with a 24% absolute risk reduction for minor surgical site infection and a significant decrease in pain on postoperative days 1 and 2 (P < 0.01 for both). Interpersonal communication improved among specialists involved in patient management. CONCLUSIONS: The protocol was effective in reducing postoperative pain and the rate of surgical site infection among patients with posterior spinal surgeries. PMID- 30481625 TI - miRNA-128b promotes cerebral infarction by regulating the expressions of Bcl-2 and Caspase 3. AB - OBJECTIVES: To investigate the effect of miRNA-128b on apoptosis and the Bcl-2 and Caspase 3 expression in rat middle cerebral artery occlusion (MCAO) model. METHODS: The MCAO model was established by thread embolism method. miRNA-128b agomir and antagomir were injected into ventricle of MCAO rats by stereotaxic intracerebral injection respectively. Then Rats were divided into Sham group, Model group, miR-128b agomir group and miR-128b antagomir group. Zea Longa was used to score the modeling rats. Area of cerebral infarction was assessed by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Apoptosis was detected by TUNEL assay. The miRNA-128b relative expression was detected by RT-PCR. The expressions of Bcl-2 and Caspase 3 were detected by Immunohistochemistry and Western blotting. RESULTS: MCAO model was constructed successfully. The expressions of miRNA-128b in MCAO groups were higher than that of Sham group (P < 0.05). Compared to model group, the cerebral infarction area in miR-128b agomir group was significantly bigger, and that of miRNA-128b antagomir group was smaller (P < 0.05). The number of apoptotic cell in miRNA-128b agomir group was more, and that of miR-128b antagomir group was less (P < 0.05 versus model group). The Bcl-2 expression reduced and Caspase 3 expression increased in MCAO groups (P < 0.05 versus sham group). Compared with model group, the Bcl-2 expression decreased and Caspase 3 expression increased in the miRNA-128b agomir group, and those in miRNA-128b antagomir group was opposite. CONCLUSION: miRNA 128b promoted cerebral infarction in MCAO rats by regulating Bcl-2 and Caspase 3 expression. PMID- 30481626 TI - Efficacy of oblique lateral interbody fusion in the treatment of degenerative lumbar disease. AB - OBJECTIVE: This study aimed to analyze the efficacy of OLIF (Oblique lumbar interbody fusion) in the treatment of degenerative lumbar disease. METHODS: Twenty-two patients with degenerative lumbar disease who underwent OLIF between October 2016 and January 2017 were included. Radiography, computed tomography (CT), and magnetic resonance imaging (MRI) were performed pre- and postoperatively. The cross-sectional area (CSA) of the dural sac, disc height (DH), cross-sectional height of the intervertebral foramina (CSH), and intervertebral foramina CSA (CSAF) were measured. Scores from the Visual Analogue Scale (VAS), Oswestry Disability Index (ODI), and Medical Outcome Study 36-Item Short-Form Health Survey (SF-36), obtained preoperatively, 1 week and 3 months postoperatively, and at the final follow-up, were compared. RESULTS: Forty-five segments were fused in 22 patients using OLIF. Postoperatively, CSA increased from 0.79+/-0.32 cm2 to 1.40+/-0.37 cm2, DH increased from 0.67+/-0.24 cm to 1.15+/-0.31 cm, CSH increased from 1.51+/-0.25 cm to 2.01+/-0.31 cm, and CSAF increased from 1.11+/-0.28 cm2 to 1.86+/-0.38 cm2 (P <0.01). The VAS, ODI, and SF 36 scores of all patients significantly improved postoperatively (P<0.05). There were no complications involving injuries to spinal nerves, great vessels, abdominal viscera, or ureters. Only one patient experienced injury to the psoas major. CONCLUSIONS: OLIF is a safe and effective minimally invasive procedure for the treatment of degenerative lumbar disease. PMID- 30481627 TI - Multiphasic side-switching seizures are easily misdiagnosed as unilateral seizures during a single EEG monitoring session-a specific subtype of bitemporal epilepsy. AB - BACKGROUND: Bitemporal epilepsy (BTLE) is a specific anatomo-electro-clinical phenotype in the spectrum of temporal lobe epilepsy. The diagnosis of BTLE and the evaluation of the degree of seizure lateralization in BTLE patients are greatly influenced by the duration of EEG recording and the number of recorded habitual seizures. CASE DESCRIPTION: A 25-year-old female patient had a 5-year history of seizures. Her habitual seizures were described as sudden behavioral arrest, staring, unresponsiveness and oral automatisms, with auras of fear and palpitation. Intermittent scalp EEG and intracranial EEG monitoring over three years showed multiphasic side-switching seizures. The seizures were limited to one temporal lobe within one phase and switched sides between phases. Despite antiepileptic drugs and vagus nerve stimulation, her seizures remained uncontrolled. The patient finally underwent unilateral anteromedial temporal lobectomy, mainly based on >60% of seizures recorded originating from the left side. The patient has been seizure-free for more than one year at last follow-up. CONCLUSIONS: This case presented one specific subtype of BTLE that is prone to be misdiagnosed as unilateral temporal lobe epilepsy if the patient is recorded for a relatively short term, e.g., over a common EEG monitoring duration of 1-2 weeks. PMID- 30481628 TI - Middle Meningeal Artery Embolization for Chronic Subdural Hematoma: Meta-Analysis and Systematic Review. AB - BACKGROUND: Chronic subdural hematoma (CSDH) is one of the most common diseases in neurosurgery. Though conventional surgical methods like burr-hole irrigation have been the mainstay of treatment, middle meningeal artery (MMA) embolization has recently emerged as a promising adjunctive or alternative treatment. We present the first meta-analysis and systematic review on this topic. METHODS: A literature search using the keywords "chronic subdural hematoma", "chronic subdural hemorrhage", "refractory subdural hematoma", "refractory subdural hemorrhage", or "middle meningeal artery embolization" was conducted through October 2018. Outcome variables of hematoma recurrence, surgical complications, and Modified Rankin Scale (mRS) were analyzed and compared between MMA embolization and conventional surgery cohorts. RESULTS: Three dual-armed studies that compared embolization and conventional surgery groups and six single-armed case series were identified and analyzed. Hematoma recurrence rate was significantly lower in the embolization group compared to the conventional treatment group (2.1% vs 27.7%, OR .087, 95% CI .026-.292, p<.001, I2=0%), whereas surgical complication rates were similar between the two (2.1% vs 4.4%, OR 0.563, 95% CI 0.107-2.96, p=.497, I2 =27.5%). Number of patients with mRS>2 in the embolization (12.5%) versus conventional treatment (9.1%) groups showed no statistical difference (p=.689). A composite hematoma recurrence rate of 3.6% was found after summing the six case series. Composite recurrence and complication rates in the embolization cohorts of the dual-armed studies as well as the case series were also lower than literature values for conventional surgical treatments. CONCLUSIONS: MMA embolization is a promising treatment for CSDH, and future randomized clinical trials are needed. PMID- 30481629 TI - Medial Branch Block versus Vertebroplasty for One-Level Osteoporotic Vertebral Compression Fracture: 2-Year Retrospective Study. PMID- 30481630 TI - Clinical evaluation of shot within shot optimization for Gamma Knife radiosurgery planning and delivery. PMID- 30481631 TI - Improvement of Hypothalamic Hamartoma-related Psychiatric Disorder After Stereotactic Laser Ablation: Case Report and Review of the Literature. AB - BACKGROUND: Hypothalamic hamartomas (HHs) are non-neoplastic congenital malformations associated with refractory epilepsy and behavioral disorders. Improvement in behavioral functioning following resection of HHs has been reported. Stereotactic laser ablation (SLA), a minimally invasive technique, has been used for the treatment of HH-related epilepsy. We report the case of child with a HH, gelastic seizures, and severe psychiatric dysfunction who was successfully treated via SLA therapy. CASE DESCRIPTION: The patient was an 11 year-old female with history of central hypothyroidism, precocious puberty, and localization-related epilepsy thought to be secondary to a HH. She had a significant psychiatric history including Attention-Deficit/Hyperactivity Disorder (ADHD), depressed mood, impulsivity, threatening behavior, and suicidal ideation requiring management with dexmethylphenidate, bupropion, and aripiprazole. Seizure onset occurred at age 7 and her semiology included nighttime hypermotor seizures and uncontrollable laughing spells thought to be gelastic seizures. Her hypermotor seizures were successfully managed with oxcabazepine monotherapy but she continued to have several weekly laughing spells and self-harming behavior. Her HH was successfully treated via SLA. Post operatively, she remained neurologically intact and was discharged the next day. At her 6-month follow-up, she had a markedly improved affect and general mood. At 3 years post-procedure, she remains seizure-free and has been weaned off her antiepileptic and antipsychotic medications. CONCLUSIONS: Severe behavioral dysfunction in the setting of a HH may constitute an indication for surgical intervention. The outcome of this case suggests there may be a role for SLA in the management of HH-related psychiatric dysfunction, even in patients with good seizure control. PMID- 30481632 TI - Technical Note: 3D Patient Specific Guides for Intraoperative Navigation for Cortical Screw Trajectory pedicle fixation. PMID- 30481633 TI - Omnidirectional malleable ring retractor: A new approach to retraction during carotid endarterectomy. AB - OBJECTIVE: To resolve problems with retraction instruments in order to obtain shallow and flat operative field in procedures such as carotid endarterectomy (CEA), we developed a new malleable tin-alloy omnidirectional retraction supporting (ORS) ring. METHODS: The new ORS ring has an ellipse-shaped (major axis: 275 mm; minor axis: 192 mm) bar frame (4 mm*6 mm). The bar has 22 equidistant outward protrusions (length,12 mm; diameter, 2.5 mm). The frame is made of tin alloy with approximately 1.0% silver, which provides sufficient malleability to fit different cervical surgical approaches. Rubber bands ending with hooks are attached around the protrusions. The new ORS ring can be placed closer to the skin surface, and skin incision edges are horizontally retracted by the hooks attached in the desired direction. The hooks are repositioned in a stepwise fashion at deeper layers of the surgical wound following dissection for carotid artery exposure. RESULTS: The tin-alloy ORS ring was used in 30 CEAs. As this ring could be closely positioned is all cases, the real depth of the operative fields (with all instruments in place) was reduced by the omnidirectional horizontal retraction without interference with surgical manipulations. Working on the distal internal carotid artery, such as putting a tacking suture and arteriotomy closure, could be easily performed. CONCLUSIONS: The newly developed malleable tin-alloy ORS ring can be a valuable instrument for the easy performance of surgery for cervical carotid lesions. Considering its advantages, it is better than conventional retractors and existing stainless steel ORS ring. PMID- 30481634 TI - Disparity in Leadership in Neurosurgical Societies: A Global Breakdown. AB - OBJECTIVE: Numerous studies have studied gender disparity in academic and organizational settings and have tried to extract its causes using H-index as the prime metric. The primary objective of our study was to assess gender disparity in leadership positions in Neurosurgical societies worldwide. A second objective was to evaluate scholarly output among Neurosurgeons in Neurosurgical societies worldwide utilizing H-index as a predominant metric. METHODS: World Federation of Neurosurgeons database was used to get details on the Neurosurgical societies present all around the world. Online data present for leadership positions were extracted from each of the respective societies. Neurosurgeons holding leadership positions were arranged according to their academic and hierarchical ranks. Scopus database was used to calculate H-index along with other bibliometrics variables. RESULTS: H-index was statistically significant between both genders with male Neurosurgeons having significantly higher H-index than female Neurosurgeons. A positive correlation was also found between H-index and academic ranks of Neurosurgeons. However, no statistical significance was found between H index and executive committee positions. Female Neurosurgeons held 29% executive committee positions globally. CONCLUSION: A paucity of female Neurosurgeons was seen in leadership positions in Neurosurgical societies worldwide. Significant disparity present in research productivity between genders is a highlighted predicament discussed in this study taking into account variables such as H-index and among others. The rise of female Neurosurgeons to Neurosurgical organizational echelons can be achieved by enhancing institutionalized support, setting up networking platforms and identifying mentorship opportunities for prospective leaders. PMID- 30481635 TI - Neurological Functional Surgery in Mexico: From Pre-Columbian Cranial Surgery to Functional Neurosurgery in the 21st Century. AB - From the predominance of the pre-Columbian cultures to date, there has been in Mexico an interest in brain structure and function, both in normal and pathological conditions. This interest has given rise to both medical and surgical attempts to treat some neurological conditions. Eighty years ago, due to the influence of American and European neurosurgeons, modern Mexican neurosurgery emerged and since then, it has progressively grown and diversified in several high-specialties. Nowadays, Functional Neurosurgery in Mexico constitutes, like in other countries, a recognized surgical subspecialty that provides valuable information to treat brain dysfunctions like movement disorders, pain, epilepsy and others conditions. In this paper, the authors briefly describe the main historical aspects of the emergence and development of Functional Neurosurgery in Mexico. PMID- 30481636 TI - Cavernous Sinus Hemangioma: Surgical Aspects. PMID- 30481637 TI - The relationships among monocyte subsets, miRNAs and inflammatory cytokines in patients with acute myocardial infarction. AB - BACKGROUND: Acute myocardial infarction (AMI) causes irreversible myocardial damage and release of inflammatory mediators, including cytokines, chemokines and miRNAs. We aimed to investigate changes in the levels of cytokines (IL-6, TNF alpha and IL-10), miRNAs profiles (miR-146 and miR-155) and distribution of different monocyte subsets (CD14++CD16-, CD14++CD16+, CD14+CD16++) in the acute and post-healing phases of AMI. METHODS: In eighteen consecutive AMI patients (mean age 56.78 +/- 12.4 years, mean left ventricle ejection fraction - LVEF: 41.9 +/- 9.8%), treated invasively, monocyte subsets frequencies were evaluated (flow cytometry), cytokine concentrations were analyzed (ELISA) as well as plasma miRNAs were isolated twice - on admission and after 19.2 +/- 5.9 weeks of follow up. Measurements were also performed among healthy volunteers. RESULTS: AMI patients presented significantly decreased frequencies of classical cells in comparison to healthy controls (median 71.22% [IQR: 64.4-79.04] vs. 84.35% [IQR: 81.2-86.7], p = 0.001) and higher percent of both intermediate and non-classical cells, yet without statistical significance (median 6.54% [IQR: 5.14-16.64] vs. 5.87% [IQR: 4.48-8.6], p = 0.37 and median 5.99% [IQR: 3.39-11.5] vs. 5.26% [IQR: 3.62-6.2], p = 0.42, respectively). In AMI patients both, analyzed plasma miRNA concentrations were higher than in healthy subjects (miR-146: median 5.48 [IQR: 2.4-11.27] vs. 1.84 [IQR: 0.87-2.53], p = 0.003; miR-155: median 25.35 [IQR: 8.17 43.15] vs. 8.4 [IQR: 0.08-16.9], p = 0.027, respectively), and returned back to the values found in the control group in follow-up. miR-155/miR-146 ratio correlated with the frequencies of classical monocytes (r=0.6, p = 0.01) and miR 155 correlated positively with the concentration of inflammatory cytokines - IL-6 and TNF-alpha. CONCLUSIONS: These results may suggest cooperation of both pro inflammatory and anti-inflammatory signals in AMI in order to promote appropriate healing of the infarcted myocardium. PMID- 30481638 TI - Regulation of phagosome functions by post-translational modifications: a new paradigm. AB - Phagosomes are highly dynamic organelles formed by the uptake of particles through phagocytic innate immune cells such as macrophages. Their key roles in microbe elimination and antigen presentation make them essential for innate and adaptive immunity. However, phagosomes are also important for tissue homeostasis as even in healthy individuals billions of dead cells are phagocytosed each day. In this short review, we highlight how the use of latex beads as inert baits for phagocytosis and subsequent analysis by proteomics has changed our understanding of the phagosome. We further discuss recent data on post-translational modifications such as phosphorylation and ubiquitylation that regulate phagosome functions and demonstrate that the phagosome is not only a 'degradative organelle' but also serves as a subcellular signalling platform. PMID- 30481639 TI - Large-scale profiling of carotenoids by using non aqueous reversed phase liquid chromatography - photodiode array detection - triple quadrupole linear ion trap mass spectrometry: Application to some varieties of sweet pepper (Capsicum annuum L.). AB - Analysis of carotenoids is very complex and demanding in terms of both separation and detection. In this article, an analytical strategy relying on high performance liquid chromatography-photodiode array detection-tandem mass spectrometry (HPLC-PAD-MS/MS) is presented for the large-scale screening of these phytochemicals. Separation was realized by means of Non-Aqueous Reversed Phase (NARP) chromatography on a triacontyl stationary phase kept at subambient temperature, using a mobile phase compatible with atmospheric pressure chemical ionization (APCI). The standards of 14 analytes were used to optimize the method and to predict the chromatographic behaviour of untargeted carotenoids. MS and MS/MS data, obtained during Information Dependent Acquisition (IDA) experiments, were utilized to set up a sensitive HPLC- selected reaction monitoring (SRM) method. Relative abundance between SRM ion currents (ion ratio) allowed the MS distinction of structural isomers (for example, bicyclic, monocyclic and acyclic isomers), while the identification of geometrical isomers was based on Qratio and fine structure, as calculated from UV-vis spectra. The comparison of LC-PAD- SRM chromatograms, acquired after applying two different extraction procedures (matrix solid-phase dispersion and overnight cold saponification), allowed verifying that sweet peppers are a good source of xanthophylls, prevalently occurring as esterified forms. The overall strategy could identify more than 40 carotenoids in some sweet pepper varieties (Jolly, horn and sweet chili pepper) available on the Italian and European food market. PMID- 30481640 TI - Preparation from Lepidium meyenii Walpers using high-speed countercurrent chromatography and thermal stability of macamides in air at various temperatures. AB - Originally cultivated in the Peruvian Andes, Maca (Lepidium meyenii) is now widely consumed as functional food which is known for its functional characteristic like relieving fatigue and enhancing stamina. Macamides are the unique fatty acids with long-chain and N-benzylamides among the various constituents extracted from Maca. N-benzyl-(9Z, 12Z, 15Z)-octadecatrienamide, N benzyl-(9Z, 12Z)-octadecadienamide, N-benzylhexadecanamide and N-benzyl-9Z octadecenamide were isolated from crude Maca extracts in two steps by using a combination of high-speed countercurrent chromatography (HSCCC) and semi preparative HPLC. The four macamides were identified by NMR, UV, HRMS and IR spectra. The thermal stability and autoxidative kinetics for N-benzyl-(9Z, 12Z, 15Z)-octadecatrienamide and N-benzyl-(9Z, 12Z)-octadecadienamide in the air were also studied at various temperatures and the apparent activation energies were 28.4 kJ/mol and 29.9 kJ/mol, respectively. The purity of the isolated macamides was up to 98% and the amount was enough for application as a reference substance. PMID- 30481641 TI - Assessment of red mud as sorptive landfill liner for the retention of arsenic (V). AB - The sorption of AsV on red mud (bauxite residue), produced in the ALCOA-San Cibrao factory (Spain), was assessed in view of its potential use as sorptive liner of landfills for the attenuation of As-rich leachates. The operating parameters evaluated, using batch-type procedures, comprised the effects of time, solution pH, AsV concentration (sorption isotherm) and presence of phosphate on the AsV sorption. The results showed that the red mud efficiently sorbed AsV. The sorption was fast, with a major fraction of initial AsV being removed in a few minutes or hours of contact, depending on AsV concentration. The kinetic process was well described by the pseudo-second order equation, which points to chemisorption is involved, whereas surface (film) diffusion chiefly governs the rate of AsV sorption for the red mud system. Sorption of AsV was strongly pH dependent. Maximum removal (>98%) was observed at slightly acidic pH (pHmax = 5.5 6), while AsV sorption considerably decreased at both highly acidic and alkaline pH. The percentages of sorbed AsV decreased with the increasing solution AsV concentration, and the AsV sorption capacity (up to 43.5 mmol/kg) of the red mud was higher (~4 -fold) at pH ~6 than at pH ~9.2 (natural pH of the red mud). The presence of P at equimolar or 1:10 As/P molar ratios reduced AsV sorption by ~20% and 30%, respectively. Simulations of AsV migration taking into account the effects of dispersion and diffusion through an hypothetical red mud liner, using the sorption parameters and the geotechnical-hydraulic conductivity characteristics of the RM, predicted a deeper migration of AsV in the liner at pH~9.2 than at pH~6 and a minimum thickness of ~90 cm and ~20 cm, respectively, for a RM liner to decrease the solution AsV concentration from highly toxic 1 mM to a safe <0.133 MUM (<10 MUg/L) level, after a 35-years period. PMID- 30481642 TI - Leaching potential of stabilized fly ash from the incineration of municipal solid waste with a new polymer. AB - The presence of toxic metals in municipal solid waste incineration fly ash is of great concern due to their leaching potential in landfills. To prevent groundwater or soil contamination caused by metal leaching from fly ash, recently the Chinese government began to require that the leachate concentrations of toxic metals not only satisfied the GB 16889-2008 criteria prior to landfilling but also introduced a series of measures to monitor the groundwater quality in the landfill site and its adjacent areas (GB/T 18772-2017). The stringent hazardous waste measures for pollution control on landfill sites of municipal solid waste demand the development of more efficient chemical stabilizers. To this end, a novel type of chemical stabilizer, a dithiocarboxylate functionalized polymer (TEM_CSSNa) was fabricated. Its efficiency for stabilizing toxic metals was evaluated at different dosages over a range of pH values. To compare with traditional stabilizers, sodium sulfide (Na2S) and thiourea (Tu) were also studied. The results showed that TEM_CSSNa-stabilized fly ash could satisfy the criteria at a dosage of only 3%, while those for Na2S and Tu were around 10%. In addition, this new polymer retained its stabilizing efficiency over a broad pH range. After TEM_CSSNa stabilization treatment, approximately 40-65% of the metals existed in the residual fraction, whereas only 35-55% were converted to the residual fraction using Na2S and Tu stabilization. The formation of a geochemically stable phase reduced the mobility of toxic metals and therefore diminished their leaching potential in landfills. PMID- 30481643 TI - Disparities of population exposed to flood hazards in the United States. AB - This study integrates publicly available datasets to provide a county-based assessment of socio-economic disparities of population exposure to flood hazards in the United States. Statistical analyses were applied to reveal the national trends and local deviations from the trends. Results show that approximately 21.8 million (6.87% of) U.S. population are exposed to 100-year-flood in 2015, and most of the exposure is near water bodies (e.g. ocean and rivers). Additionally, communities near water bodies are more responsive to potential flood hazards by avoiding residence in flood zones than inland communities. At the national scale, economically disadvantaged population are more likely to reside in flood zones than outside. At the local scale, economically disadvantaged population tend to reside in flood zones in inland areas, while coastal flood zones are more occupied by wealthier and elderly people. These findings point to an alarming situation of inland communities where people are generally less responsive to flood hazards and people in flood zones are in a lower economic condition. Using "hot spot" analysis, local clusters of disadvantaged population groups with high flood exposure were identified. Overall, this study provides important baseline information for policymaking at different levels of administration and pinpoints local areas where diversified and ad hoc strategies are needed to mitigate flood risk in communities with diverse socio-economic conditions. This study provides empirical evidence of socio-economic disparities and environmental injustice associated with flood exposure in the U.S. and offers valuable insights to the underlying factors. PMID- 30481644 TI - Immobilized Baliospermum montanum hydroxynitrile lyase catalyzed synthesis of chiral cyanohydrins. AB - Hydroxynitrile lyase (HNL) catalyzed enantioselective CC bond formation is an efficient approach to synthesize chiral cyanohydrins which are important building blocks in the synthesis of a number of fine chemicals, agrochemicals and pharmaceuticals. Immobilization of HNL is known to provide robustness, reusability and in some cases also enhances activity and selectivity. We optimized the preparation of immobilization of Baliospermium montanum HNL (BmHNL) by cross linking enzyme aggregate (CLEA) method and characterized it by SEM. Optimization of biocatalytic parameters was performed to obtain highest % conversion and ee of (S)-mandelonitrile from benzaldehyde using CLEA-BmHNL. The optimized reaction parameters were: 20 min of reaction time, 7 U of CLEA-BmHNL, 1.2 mM substrate, and 300 mM citrate buffer pH 4.2, that synthesized (S) mandelonitrile in ~99% ee and ~60% conversion. Addition of organic solvent in CLEA-BmHNL biocatalysis did not improve in % ee or conversion of product unlike other CLEA-HNLs. CLEA-BmHNL could be successfully reused for eight consecutive cycles without loss of conversion or product formation and five cycles with a little loss in enantioselectivity. Eleven different chiral cyanohydrins were synthesized under optimal biocatalytic conditions in up to 99% ee and 59% conversion, however the % conversion and ee varied for different products. CLEA BmHNL has improved the enantioselectivity of (S)-mandelonitrile synthesis compared to the use of purified BmHNL. Nine aldehydes not tested earlier with BmHNL were converted into their corresponding (S)-cyanohydrins for the first time using CLEA-BmHNL. Among the eleven (S)-cyanohydrins syntheses reported here, eight of them have not been synthesized by any CLEA-HNL. Overall, this study showed preparation, characterization of a stable, robust and recyclable biocatalyst i.e. CLEA-BmHNL and its biocatalytic application in the synthesis of different (S)-aromatic cyanohydrins. PMID- 30481645 TI - Synthesis and biological evaluation of new pyrazolone Schiff bases as monoamine oxidase and cholinesterase inhibitors. AB - In the current work, Schiff base derivatives of antipyrine were synthesized. The chemical characterization of the compounds was confirmed using IR, 1H NMR, 13C NMR and mass spectroscopies. The inhibitory potency of synthesized compounds was investigated towards acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidases A and B (MAO-A and MAO-B) enzymes. Some of the compounds displayed significant inhibitory activity against AChE and MAO-B enzymes, respectively. According to AChE enzyme inhibition assay, compounds 3e and 3g were found as the most potent derivatives with IC50 values of 0.285 uM and 0.057 uM, respectively. Also, compounds 3a (IC50 = 0.114 uM), 3h (IC50 = 0.049 uM), and 3i (IC50 = 0.054 uM) were the most active derivatives against MAO-B enzyme activity. So as to understand inhibition type, enzyme kinetics studies were carried out. Furthermore, molecular docking studies were performed to define and evaluate the interaction mechanism between compounds 3g and 3h and related enzymes. ADME (Absorption, Distribution, Metabolism, and Excretion) and BBB (Blood, Brain, Barier) permeability predictions were applied to estimate pharmacokinetic profiles of synthesized compounds. PMID- 30481646 TI - Design, synthesis and cytotoxicity of chimeric erlotinib-alkylphospholipid hybrids. AB - Two series of erlotinib-alkylphospholipid hybrids were prepared and evaluated for their antiproliferative activities against a panel of four cell lines representing lung, breast, liver and skin cancers using erlotinib and miltefosine as reference standards. Amide analogs elicited more enhanced cytotoxic activity than analogous esters. Amide derivatives 8d and 8e exhibited promising broad spectrum antiproliferative activity and higher efficacy than reference erlotinib and miltefosine. Their cellular GI50 values was in the ranges of 24.7-46.9 MUM and 26.8-43.1 MUM for 8e and 8d respectively. Assay results of the inhibitory activity of the prepared compounds on EGFR kinase reaction and Akt phosphorylation in conjugation with statistical correlation analysis indicated that other mechanisms might contribute to their elicited cytotoxicities. In addition, statistical correlation analysis revealed that mechanisms of elicited cytotoxicities for amide series might be different from ester series. In addition, correlation analysis indicated variations in the mechanisms according to the types of cell line. PMID- 30481647 TI - Switching of Trp-214 intrinsic rotamer population in human serum albumin: An insight into the aftermath of embracing therapeutic bioorganic luminophore azapodophyllotoxin into sudlow site I. AB - Human serum albumin is perceived to be the most abundant protein in human blood plasma and functions as a major carrier of different enzymes and drugs inside human body. The present article puts in an effort to demonstrate the attitude adopted by human serum albumin towards a potential therapeutic luminophore 4-(2 Hydroxyethyl)-10-phenyl-3,4,6,7,8,10-hexahydro-1H-cyclopenta[g]furo[3,4 b]quinoline-1-one (HPFQ). HPFQ is a prodigy from azapodophyllotoxin class of compounds, which have been synthesized from the perspective of improved bioactivity than its prologue podophyllotoxins. While, HPFQ has proved to be highly bioactive against most cancer cell lines with best GI50 values of <0.1 uM for a major number of cell lines; it also showed terrific fluorescent properties throughout the polarity scale, worthy of a promising imaging agent. The binding mechanism of HPFQ with HSA has been established by combining in vitro spectroscopic techniques, in silico molecular docking and induced fit docking (IFD). The competitive site-binding studies demonstrated that the otherwise anion receptor sudlow site I of HSA nurtures neutral HPFQ with prudent affinity (Binding constant, Kb = 0.74 * 105 M-1). The time-resolve fluorescence studies reveal an appreciable reduction in HSA average radiative lifetime against an increase in HPFQ concentration and provided evidence for Forster's resonance energy transfer (FRET) being responsible for the dominant quenching mechanism, escorted by minor structural deformations in the backbone of protein structure. HPFQ institutes itself near Trp-214 within protein matrix, and subsequently the "hydrophobic amino acids" dominated cybotactic environment of Trp-214 experiences a reduction in the micropolarity. The allosteric modulation triggered by the stronger association of HPFQ with HSA leads towards minor deformation in secondary structure of protein. Sudlow site I of HSA proficiently embraces a favourable conformation like malleable dough to furnish space for arriving bioactive HPFQ molecule. HPFQ is also believed to administer the conformational regulation in HSA domain by affecting inter-conversion of HSA rotamers, which may prove to be an enlightening area to decode the preferable interaction between them. The juxtaposed spectroscopic research described herein is expected to embolden design of azapodophyllotoxin based anti-proliferative clinical agents for efficient in vivo bio-distribution employing HSA-centred drug delivery and administration systems. PMID- 30481648 TI - 1,4-Dihydroquinazolin-3(2H)-yl benzamide derivatives as anti-inflammatory and analgesic agents with an improved gastric profile: Design, synthesis, COX-1/2 inhibitory activity and molecular docking study. AB - The design and synthesis of a new series of 1,4-dihydroquinazolin-3(2H)-yl benzamide derivatives (4a-o) as anti-inflammatory and analgesic agents and COX 1/2 inhibitors are reported. The target compounds (4a-o) were synthesized using a two-step scheme, and their chemical structures were confirmed with 1H NMR, 13C NMR, and mass spectra and elemental analysis. Compounds 4b, 4d, 4h, 4l, 4n and 4o showed the best in vitro COX-2 inhibitory activity (IC50 0.04-0.07 MUM), which was nearly the same as that of the reference drug celecoxib (IC50 0.049 MUM), but had a lower selectivity index, as dictated in our target design. In the in vivo anti-inflammatory inhibition assay, compounds 4b, 4c, 4e, 4f, 4m and 4o showed better oedema inhibition percentages, ranging from 38.1% to 54.1%, than did diclofenac sodium (37.8%). An in vivo analgesic assay revealed that compounds 4b and 4n had a potential analgesic effect 4- to 21-fold more potent than that of indomethacin and diclofenac sodium. All the tested compounds showed an improved ulcerogenic index when compared to indomethacin. In the synthesized series, compound 4b showed the best biological activity in all the experiments. The docking study results agreed with the in vitro COX inhibition assay results. Moreover, the predicted in silico studies of all the compounds support their potential as drug candidates. PMID- 30481649 TI - Detecting abnormal electroencephalograms using deep convolutional networks. AB - OBJECTIVES: Electroencephalography (EEG) is a central part of the medical evaluation for patients with neurological disorders. Training an algorithm to label the EEG normal vs abnormal seems challenging, because of EEG heterogeneity and dependence of contextual factors, including age and sleep stage. Our objectives were to validate prior work on an independent data set suggesting that deep learning methods can discriminate between normal vs abnormal EEGs, to understand whether age and sleep stage information can improve discrimination, and to understand what factors lead to errors. METHODS: We train a deep convolutional neural network on a heterogeneous set of 8522 routine EEGs from the Massachusetts General Hospital. We explore several strategies for optimizing model performance, including accounting for age and sleep stage. RESULTS: The area under the receiver operating characteristic curve (AUC) on an independent test set (n = 851) is 0.917 marginally improved by including age (AUC = 0.924), and both age and sleep stages (AUC = 0.925), though not statistically significant. CONCLUSIONS: The model architecture generalizes well to an independent dataset. Adding age and sleep stage to the model does not significantly improve performance. SIGNIFICANCE: Insights learned from misclassified examples, and minimal improvement by adding sleep stage and age suggest fruitful directions for further research. PMID- 30481650 TI - Electrophysiological evidence for changes in attentional orienting and selection in functional somatic symptoms. AB - OBJECTIVE: We investigated changes in attention mechanisms in people who report a high number of somatic symptoms which cannot be associated with a physical cause. METHOD: Based on scores on the Somatoform Disorder Questionnaire (SDQ-20; Nijenhuis et al., 1996) we compared two non-clinical groups, one with high symptoms on the SDQ-20 and a control group with low or no symptoms. We recorded EEG whilst participants performed an exogenous tactile attention task where they had to discriminate between tactile targets following a tactile cue to the same or opposite hand. RESULTS: The neural marker of attentional orienting to the body, the Late Somatosensory Negativity (LSN), was diminished in the high symptoms group and attentional modulation of touch processing was prolonged at mid and enhanced at later latency stages in this group. CONCLUSION: These results confirm that attentional processes are altered in people with somatic symptoms, even in a non-clinical group. Furthermore, the observed pattern fits explanations of changes in prior beliefs or expectations leading to diminished amplitudes of the marker of attentional orienting to the body (i.e. the LSN) and enhanced attentional gain of touch processing. SIGNIFICANCE: This study shows that high somatic symptoms are associated with neurocognitive attention changes. PMID- 30481651 TI - Widening the phenotypical spectrum of EGR2-related CMT: Unusual phenotype for R409W mutation. PMID- 30481652 TI - Effects of chlorination on the fluorescence of seawater: Pronounced changes of emission intensity and their relationships with the formation of disinfection byproducts. AB - Chlorination of coastal (CS) and deep ocean (DO) seawater was accompanied by a prominent decrease (of up to 70%) of the intensity of its emission which was measured using a 315 nm excitation wavelength. Deconvolution of the emission spectra of CS and DO seawater showed that these spectra comprised three Gauss shaped bands. The intensities of two of these bands decreased rapidly as the halogenation proceeded. For both DO and CS seawater, two stages of changes of their fluorescence were observed. The first stage in which the relative changes of the fluorescence intensity (DeltaF/F) were between zero to 0.30 and 0.40 was not accompanied by the release of individual disinfection byproduct (DBP) species. For DeltaF/F values above the corresponding thresholds, the relative changes of fluorescence intensity were well correlated with the concentrations of individual DBP species such as trihalomethanes and haloacetonitriles. R2 values for CHBr3, CHBr2Cl and CHBrCl2 formed in DO seawater were 0.83, 0.80 and 0.68, respectively while for CS seawater, the corresponding R2 values were 0.91, 0.93 and 0.92. The presented data demonstrate that the intrinsic chemistry of DBP formation and dissolved organic matter (DOM) halogenation in seawater can be well quantified based on the examination of changes of its fluorescence. This approach can also be employed for practical monitoring of changes of properties of marine DOM and generation of DBPs in desalination, marine aquaculture and other processes. PMID- 30481653 TI - Amphiphilic bromelain-synthesized oligo-phenylalanine grafted with methoxypolyethylene glycol possessing stabilizing thermo-responsive emulsion properties. AB - A thermo-responsive amphiphile was developed from oligo-phenylalanine [oligo(Phe)]. The hydrophobic moiety of the amphiphile, oligo(Phe) was synthesized via reverse hydrolysis catalyzed by bromelain in dimethyl sulfoxide and dioxane solutions. The production of oligo(Phe) increased by 80.7% by screening suitable reaction conditions. The average degree of polymerization of oligo(Phe) was determined to be four by 1H NMR. By grafting with aldehyde-ended methoxypolyethylene glycol (mPEG), oligo(Phe) was converted to amphiphilic oligo(Phe)-mPEG. The surface tension of oligo(Phe)-mPEG solution increased with decreasing chain length of the mPEG moiety. Cytotoxicity studies showed oligo(Phe)-mPEGs are biocompatible. On varying temperature, a reversible phase transition of oligo(Phe)-mPEG solutions could be observed. N-octane-in-water emulsions and 0.5% beta-carotene containing squalene-in-water emulsions stabilized by oligo(Phe)-mPEGs occurred at 25 degrees C but de-emulsification took place at >40 degrees C. Emulsification could be restored once the separated mixture cooled and re-homogenized. The emulsification/de-emulsification cycling could be repeated many times. The time required for de-emulsification decreased with elevated temperature but increased with a reduced concentration of oligo(Phe)-mPEGs and a reduction in the chain length of the mPEG moiety. PMID- 30481655 TI - Mindfulness and the contemplative life: pathways to connection, insight, and purpose. AB - Despite the growing popular and scientific interest in mindfulness and other forms of meditation, there are important gaps in our understanding of the full range of contemplative practices and the manner in which specific forms of meditation may contribute to well-being. In this article, we discuss the relationship between mindfulness and other forms of meditation, such as those related to prosocial qualities, cognitive insight, and meaning and purpose. We propose that mindfulness plays an important role as a foundation for other contemplative practices. We also discuss the importance of worldview as a variable in mindfulness practice and raise questions that may guide future research in this area. PMID- 30481654 TI - A comparison of long-term outcomes of nanohydroxyapatite/polyamide-66 cage and titanium mesh cage in anterior cervical corpectomy and fusion: A clinical follow up study of least 8 years. AB - OBJECTIVES: The nanohydroxyapatite/polyamide-66 (n-HA/PA66) cage is a novel biomimetic nonmetal cage device that is now used in some medical centers, while the titanium mesh cage (TMC) is a typical metal cage device that has been widely used for decades. This study was performed to compare the long-term outcomes of these two different cages in patients undergoing anterior cervical corpectomy. PATIENTS AND METHODS: This retrospective study involved 107 patients who underwent single-level anterior corpectomy using either a TMC (n = 52) or an n HA/PA66 cage (n = 55) for treatment of cervical degenerative disease with a minimum follow-up of 8 years. Their radiographic data (cage subsidence, fusion status, segmental sagittal alignment, and cervical spine degeneration) and clinical data [visual analog scale (VAS) and Japanese Orthopedic Association (JOA) scores] were evaluated preoperatively, postoperatively, and at the final follow-up. RESULTS: The mean duration of follow-up was 103.6 +/- 6.3 months in the n-HA/PA66 group and 102.4 +/- 4.6 months in the TMC group. The n-HA/PA66 group and the TMC group had similar final fusion rates (97% vs. 94%, respectively). The final n-HA/PA66 cage subsidence was 2.4 +/- 1.0 mm with 18.2% subsidence of >3 mm, which was significantly lower than the respective 3.0 +/- 0.7 mm and 40.4% for the TMC (p < 0.01). The n-HA/PA66 group also had better JOA scores than the TMC group (p < 0.01). No significant difference in the segmental sagittal alignment, cervical lordosis, or VAS score was observed between the two groups (p = 0.18, 0.42, and 0.17, respectively). CONCLUSIONS: The n-HA/PA66 cage is associated with excellent radiographic fusion, lower subsidence and better clinical outcomes than the TMC within 8 years after single-level anterior cervical corpectomy. With the addtional benefit of radiolucency, the n-HA/PA66 cage could be superior to the TMC in anterior cervical construction. PMID- 30481656 TI - Targeting optimal time for hyperbaric oxygen therapy following carbon monoxide poisoning for prevention of delayed neuropsychiatric sequelae: A retrospective study. AB - OBJECTIVES: Delayed neuropsychiatric sequelae (DNS) are serious complications of carbon monoxide poisoning; neuropsychiatric disorders can occur within a few days of recovery from acute poisoning. Hyperbaric oxygen therapy (HBOT) has been the main treatment of carbon monoxide (CO) poisoning and was recommended as the treatment choice for CO poisoning by the American Undersea and Hyperbaric Medical Society and the Tenth European Consensus Conference on Hyperbaric Medicine of the European Underwater and Baromedical Society. However, the optimal timing for commencing HBOT in patients with CO poisoning remains unknown. We therefore conducted a retrospective study in an attempt to target the optimal time of HBOT for DNS prevention. METHODS: A retrospective review of patient files/medical records was conducted on all patients with CO poisoning admitted to the Emergency Department of Linkou Chang-Gung Memorial Hospital, Taiwan between January 1, 2009 and December 31, 2015. A total of 279 patients who received HBOT were eligible for further DNS detection. DNS was defined as the presence of one of the following neurological, cognitive, or psychological sequelae that were documented in the medical record during hospital stay or outpatient clinic follow-up for at least 6 months. A multivariable logistic regression analysis was employed to identify potential determinants of DNS after receiving HBOT for CO poisoning. A receiver operating characteristic (ROC) curve was used to analyse the influence of duration from CO exposure to HBOT on DNS development. RESULTS: A Glasgow coma score of <9 (odds ratio [OR], 3.20; 95% confidence interval [CI], 1.19-8.60) and a longer duration from CO exposure to HBOT (OR, 1.06; 95% CI, 1.03-1.09) were associated with a higher risk of DNS. By contrast, the presence of multiple victims from the same incident was associated with a lower risk of DNS. The ROC curve for the duration between CO exposure and HBOT in predicting DNS development demonstrated an area under the curve of 0.638 (95% CI, 0.575-0.698). The optimal cut-off point according to the Youden index was 22.5 h, with a sensitivity of 41.7% and a specificity of 85.9%. We also stratified the duration from CO exposure to HBOT into 5 intervals (< 6 h, 6-11 h, 12-23 h, 24-47 h and >= 48 h) and revealed a trend of increasing DNS risk with time. CONCLUSIONS: We identified several potential predictors of DNS in patients with CO poisoning who received HBOT. Multivariable logistic regressions further revealed that longer duration from CO exposure to HBOT, loss of consciousness, and the presence of multiple victims were independent predictors of DNS development. HBOT should be performed as early as possible and preferably within 22.5 h after CO poisoning. PMID- 30481657 TI - Mechanical thrombectomy outcomes in large vessel stroke with high international normalized ratio. AB - OBJECTIVE: Evaluating the safety and efficacy of mechanical thrombectomy (MT) in acute stroke patients due to emergent large vessel occlusion (ELVO) with high international-normalized-ratio (INR). METHODS: Consecutive ELVO patients treated with MT were evaluated from two centers. Outcome measures included symptomatic intracranial-hemorrhage(sICH), three-month mortality, successful reperfusion(SR), and 3-month functional-independence(FI; mRS-scores of 0-2). Additionally, a meta analysis of available cohort studies was performed to evaluate safety and efficacy of MT in ELVO patients with high INR. RESULTS: A total of 315 ELVO patients were evaluated. Of those 10 patients had INR >1.7 [mean age 63.5 +/- 15, median NIHSS-score: 17 points (IQR 14-22)],and remaining 305 ELVO patients had INR <= 1.7 ([mean age 62 +/- 14.4, median NIHSS-score: 17 points (IQR 12-21)]. Patients with high INR did not differ in terms of sICH (10.0% vs. 6.9%; p = .706), 3-month mortality (20.0% vs. 24.2%; p = .762), SR (88.9% vs. 69.4%; p = .209) and 3-month FI (50% vs. 49.3%; p = .762) compared to the rest. Meta analysis of available studies (n = 5) showed that high INR was not related to sICH (OR: 0.94, 95%CI: 0.42-2.07; p = .88), 3-month mortality (OR: 1.07, 95%CI: CI 0.72-1.60; p = .73) and 3-month FI (OR: 0.69, 95%CI: 0.34-1.40; p = .30). CONCLUSIONS: MT can be performed safely and effectively in ELVO patients with high INR. PMID- 30481658 TI - Innovative nanofiber technology to improve carbon dioxide biofixation in microalgae cultivation. AB - The aim of this study was to develop nanofibers containing nanoparticles with potential for the biological fixation of CO2 together with the microalgae Chlorella fusca LEB 111. An electrospinning technique was used for the production of polymeric nanofibers with different concentrations of iron oxide nanoparticles: 0, 2, 4, 6, 8, and 10% (w v-1). Nanofibers with a nanoparticle concentration of 4% (w v-1) were selected for use in the microalgal cultivation due to their smaller diameter (434 nm), high specific surface area (13.8 m2 g-1) and higher CO2 adsorption capacity (164.2 mg g-1). The microalgae C. fusca LEB 111 presented a higher CO2 biofixation rate of 216.2 mg L-1 d-1 when cultivated with these nanofibers. The results demonstrated the potential of electrospun nanofibers as physical adsorbents of CO2 since they can increase the contact time between the gas and the microorganism and consequently increase the CO2 biofixation by the microalgae. PMID- 30481659 TI - Recovery of proteins from biomass grown in pig manure microalgae-based treatment plants by alkaline hydrolysis and acidic precipitation. AB - The influence of three variables on key parameters of the protein extraction process (an alkaline hydrolysis followed by an acidic precipitation) for biomass from innovative photo-bioreactors for pig manure treatment was evaluated. Alkaline hydrolysis provided high solubilisation values (up to 66.5% of the biomass), augmenting with increasing values of the three studied variables (NaOH concentration, temperature and time). Nevertheless, moderate total (13.2%) and protein extraction yields (16.9%) were obtained, which was attributable to protein denaturation or to the low effectivity of the precipitation method. Extracts rich in proteins (53.5%-77.9%) with suitable amino acid profiles were obtained, but significant amounts of the initial lipids (up to 44.6%) were co extracted probably due to fatty acids saponification. These results establish the first step for future studies in enhancing cell wall disruption and protein recovery by coupling alkaline hydrolysis with other mechanical pre-treatments, while considering alternative separation and purification methods. PMID- 30481660 TI - The algal trophic mode affects the interaction and oil production of a synergistic microalga-yeast consortium. AB - The use of non-food feedstocks to produce renewable microbial resources can limit our dependence on fossil fuels and lower CO2 emissions. Since microalgae display a virtuous CO2 and O2 exchange with heterotrophs, the microalga Chlamydomonas reinhardtii was combined with the oleaginous yeast Lipomyces starkeyi, known for their production of oil, base material for biodiesel. The coupled growth was shown to be synergistic for biomass and lipid production. The species were truly symbiotic since synergistic growth occurred even when the alga cannot use the organic carbon in the feedstock and in absence of air, thus depending entirely on CO2-O2 exchange. Since addition of acetate as the algal carbon source lowered the performance of the consortium, the microbial system design should take into account algal mixotrophy. The mixed biomass was found be suitable for biodiesel production, and whereas lipid production increased in the consortium, yields should be improved in future studies. PMID- 30481661 TI - Synergistic antimicrobial activities of essential oil vapours against Penicillium corylophilum on a laboratory medium and beef jerky. AB - This study was done to determine the antifungal activities of essential oil (EO) vapours of 97 plants against Penicillium corylophilum and to test combinations of EO vapours for synergistic antifungal effects. Among 97 commercially available EOs extracted from plant parts, garlic, cinnamon bark, may chang (mountain pepper), citronella, thyme thymol, oregano, spearmint, and thyme linalool EO vapours exhibited relatively strong antifungal activities. The minimal inhibitory concentrations of these EO vapours were 0.0390-0.6250 MUL/mL. A combination of cinnamon bark, citronella, and may chang EO vapours, as well as a combination of cinnamon bark and citronella EO vapours, showed synergistic inhibitory activities to P. corylophilum on a laboratory medium. A combination of cinnamon bark, citronella, and may chang EO vapours had synergistic activity in inhibiting growth of P. corylophilium on beef jerky. Observations reported here provide basic information valuable when developing strategies to inhibit the growth of P. corylophilum and possibly other moderately xerophilic molds on intermediate moisture foods. PMID- 30481662 TI - Intranuclear coccidiosis in tortoises - discovery of its causative agent and transmission. AB - Intranuclear coccidiosis of testudines (known as TINC) is an emerging disease in chelonians. Although endogenous stages were repeatedly detected in various tissues, attempts to find the oocysts in faeces failed, leaving the question of the transmission and classification of the causative agent of TINC unresolved. We recorded small spherical oocysts (~6-7 MUm in diameter) of an eimeriid coccidium in faeces of a leopard tortoise (Stigmochelys pardalis). Sporulated oocysts were used for the experimental oral inoculation of juvenile coccidia-free tortoises representing 5 species (S. pardalis, Testudo graeca, T. hermanni, T. horsfieldii, and Geochelone sulcata). The oocysts' association with TINC was confirmed based on clinical signs, histopathological findings of intranuclear endogenous stages of the coccidium in many organs (including intestine), and by the partial 18S rDNA sequence analysis of the DNA isolated from organs of the experimentally infected animals and from a single naturally infected as well as from all experimentally infected tortoises. Breeding colonies of chelonians should be screened for this pathogen in order to prevent its further spread and unwanted introduction into endangered free-ranging chelonian populations. PMID- 30481663 TI - Floral scent in Iris planifolia (Iridaceae) suggests food reward. AB - Iris species can adopt different pollination strategies to attract their pollinators, generalized shelter-mimicking, specialized deceptive sexual mimicking or food-rewarding. As attractive stimuli, Iris flowers may use their colours, large-size, symmetry, and volatile organic compounds (VOCs). However, relatively few studies investigated Iris floral olfactory cues in the context of plant-visitor/pollinator interactions. In the present study we combined the identification of the floral volatiles of the nectariferous I. planifolia with insects visiting its flowers to gather data on its biology. Floral volatiles were collected in the natural environment by dynamic headspace and analysed by gas chromatography-mass spectrometry (GC-MS). Insect visitors/pollinators were also recorded. The volatile bouquet was aromatic-dominated with 1,4 dimethoxybenzene as major compound. Among the insects visiting its flowers, bumble and honey bees were the most abundant followed by hover flies. Overall, our results suggest that I. planifolia advertises its food reward by an aromatic dominated volatile composition. PMID- 30481664 TI - A syn-ent-labdadiene derivative with a rare spiro-beta-lactone function from the male cones of Wollemia nobilis. AB - An undescribed labdane-like diterpene with a rare spiro-beta-lactone function was identified from the ethanol extract of the male cones of the coniferous tree Wollemia nobilis. This spirolabdadienolide (IUPAC name: syn-ent-8(17),13 labdadien-19,18-olid-15-oic acid methyl ester; trivial name: wollemolide), was isolated by means of traditional and high performance chromatography techniques and structurally elucidated through NMR and MS. In addition, six further known metabolites were evidenced in the extract. Wollemolide, which may be considered an additional chemotaxonomic marker, and 4'-O-methyl-scutellarein, a simple flavonoid, had not been isolated in our previous phytochemical study on the same plant organ. This demonstrates how the molecular pattern of a plant species is in continuous movement and changes with the passing of time according to the climate of the year. PMID- 30481665 TI - Palmitic acid ester of tetrahydrocannabinol (THC) and palmitic acid diester of 11 hydroxy-THC - Unsuccessful search for additional THC metabolites in human body fluids and tissues. AB - Fatty acid conjugates of hydroxy-metabolites of tetrahydrocannabinol (THC) or cannabinol have already been reported as metabolites in rats. In the herein presented investigation, palmitic acid esters of THC and its primary metabolite 11-hydroxy-delta9-tetrahydrocannabinol (11-OH-THC) were synthesized using esterification with palmitic acid chloride. Structural elucidation of the products was conducted using nuclear magnetic resonance spectroscopy (NMR) and liquid chromatography coupled to quadrupole time of flight mass spectrometry (LC QToF-MS). For the confirmation of a previous cannabis use, body fluids (femoral blood, heart blood, urine, bile) of 27 death cases (all with known cannabis use), including adipose tissue homogenates of six of these cases as well as eleven plasma samples (probably all with regular cannabis use, confirmed by a high 11 nor-9-carboxy-delta9-tetrahydrocannabinol (THC-COOH) concentration (except one sample, >200ng/mL), were tested for THC and its main metabolites 11-OH-THC and THC-COOH using gas chromatography coupled to mass spectrometry (GC-MS). These samples as well as further tissue homogenates of autopsy cases (liver, kidney, brain) were additionally tested for the presence of THC palmitic acid ester or 11 OH-THC palmitic acid diester by means of a liquid chromatographic triple quadrupole mass spectrometric (LC-QQQ-MS) method, in order to evaluate a possible presence of these conjugates in humans. In none of the analyzed samples (in total 196 specimens; plasma (N=11), femoral blood (N=23), heart blood (N=25), urine (N=23), bile (N=27), liver (N=27), kidney (N=27), brain (N=27), adipose tissue (N=6)), palmitic acid esters of THC or 11-OH-THC could be proven. Even if the existence of these esters in human samples cannot be ruled out definitely, suitability as cannabis consumption markers does not seem likely based on our findings. PMID- 30481666 TI - The frontal aslant tract (FAT) and its role in speech, language and executive function. AB - In this review, we examine the structural connectivity of a recently-identified fiber pathway, the frontal aslant tract (FAT), and explore its function. We first review structural connectivity studies using tract-tracing methods in non-human primates, and diffusion-weighted imaging and electrostimulation in humans. These studies suggest a monosynaptic connection exists between the lateral inferior frontal gyrus and the pre-supplementary and supplementary motor areas of the medial superior frontal gyrus. This connection is termed the FAT. We then review research on the left FAT's putative role in supporting speech and language function, with particular focus on speech initiation, stuttering and verbal fluency. Next, we review research on the right FAT's putative role supporting executive function, namely inhibitory control and conflict monitoring for action. We summarize the extant body of empirical work by suggesting that the FAT plays a domain general role in the planning, timing, and coordination of sequential motor movements through the resolution of competition among potential motor plans. However, we also propose some domain specialization across the hemispheres. On the left hemisphere, the circuit is proposed to be specialized for speech actions. On the right hemisphere, the circuit is proposed to be specialized for general action control of the organism, especially in the visuo-spatial domain. We close the review with a discussion of the clinical significance of the FAT, and suggestions for further research on the pathway. PMID- 30481667 TI - Silver coordination complex amplified electrochemiluminescence sensor for sensitive detection of coenzyme A and histone acetyltransferase activity. AB - A kind of coenzyme A (CoA)-silver coordination complex (CoA-Ag) was in-situ developed and verified to accelerate the electron transferring and electrochemical catalysis of H2O2 decomposition to enhance the cathode ECL intensity of CdTe@CdS QDs. Afterward, a convenient label-free signal-on ECL approach was constructed for CoA detection with excellent specificity. In addition, the unique ECL enhancing phenomenon was also proposed to assay the enzymatic activity of histone acetyltransferases (HAT) and screen relevant inhibitors, exhibiting a promising potential in the practical application of biochemical research, disease diagnosis and drug discovery. PMID- 30481668 TI - An ultrasensitive electrochemical immunosensor for procalcitonin detection based on the gold nanoparticles-enhanced tyramide signal amplification strategy. AB - In this study, we established an ultrasensitive electrochemical immunosensor based on the gold nanoparticles-enhanced tyramide signal amplification (AuNPs TSA) for the detection of procalcitonin (PCT, for discriminating bacterial infections from nonbacterial infections). Firstly, a facilely prepared, well conducting reduced graphene oxide nanosheets/GNP (rGO-AuNPs) nanocomposite was synthesized and immobilized on the electrode surface to absorb more capture antibodies (Ab1). Next another nanocomposite, acting as a signal tool, was modified with detection antibody (Ab2) and horseradish peroxidase (HRP), and then backfilled by bovine serum albumin (BSA). Because a single AuNP is able to load multiple HRPs and BSAs, a number of tyramine labeled biotins (T-B) could be deposited on the proteins adhering to the surface of AuNPs. Moreover, the high affinity between streptavidin (SA) and biotins significantly increases the loading of streptavidin labeled horseradish peroxidase (SA-HRP). The amplification system which was based on the two nanocomposites mentioned above, effectively amplified the electric current signals. This immunosensor exhibits a wide dynamic detection range from 0.05 ng mL-1 to 100 ng mL-1 and with an ultralow detection limit of 0.1 pg mL-1. We have successfully utilized this immunosensor to quantify the concentration of PCT in human serum samples, and the results suggest its potential use in clinical application. PMID- 30481669 TI - Influenza virus and factors that are associated with ICU admission, pulmonary co infections and ICU mortality. AB - PURPOSE: While most influenza patients have a self-limited respiratory illness, 5 10% of hospitalized patients develop severe disease requiring ICU admission. The aim of this study was to identify influenza-specific factors associated with ICU admission and mortality. Furthermore, influenza-specific pulmonary bacterial, fungal and viral co-infections were investigated. METHODS: 199 influenza patients, admitted to two academic hospitals in the Netherlands between 01 and 10 2015 and 01-04-2016 were investigated of which 45/199 were admitted to the ICU. RESULTS: A history of Obstructive/Central Sleep Apnea Syndrome, myocardial infarction, dyspnea, influenza type A, BMI > 30, the development of renal failure and bacterial and fungal co-infections, were observed more frequently in patients who were admitted to the ICU, compared with patients at the normal ward. Co infections were evident in 55.6% of ICU-admitted patients, compared with 20.1% of patients at the normal ward, mainly caused by Staphylococcus aureus, Streptococcus pneumoniae, and Aspergillus fumigatus. Non-survivors suffered from diabetes mellitus and (pre-existent) renal failure more often. CONCLUSIONS: The current study indicates that a history of OSAS/CSAS, myocardial infarction and BMI > 30 might be related to ICU admission in influenza patients. Second, ICU patients develop more pulmonary co-infections. Last, (pre-existent) renal failure and diabetes mellitus are more often observed in non-survivors. PMID- 30481670 TI - How to facilitate the placement of a transesophageal probe in a ventilated patient? AB - PURPOSE: Transesophageal probe insertion in the ventilated patients often is difficult. Different complex techniques were suggested for easier placement of the transesophageal probe. In this work, we describe a simple technique of TEE probe insertion in ventilated patients. METHODS AND RESULTS: In the period 2015 2018, 66 transesophageal echocardiographic examinations in anesthetized ventilated patients were carried out in accordance with the standard algorithm developed by us. During the transesophageal examination, all the patients were in the left decubital position and with their head tilted forward. In all the patients, TEE was done smoothly, from the 1st attempt, without complications. CONCLUSION: In the anesthetized intubated and ventilated patients, the TEE probe can be easily inserted when the patient is in the left decubital position. We suggest this algorithm in all such patients, when appropriate. PMID- 30481671 TI - A data driven diagnosis tool for thyroid hormones. AB - Thyroid hormones play a significant role in human health. Understanding their dynamics is crucial to diagnoses and maintaining the well-being of the thyroid. In this work we propose a data driven algorithm to detect a fixed point and a limit cycle in real data for thyroid hormones. This algorithm finds the maximum frequency point (fixed point) and extracts a smooth ellipse (limit cycle) from the data. These features characterize various data sets and provide interesting insights to differentiate healthy from malfunctioning thyroid data. This scheme which is backed by a solid dynamical analysis determines the size, orientation and location of a detected limit cycle and provides information about the behavior of the thyroid in its various normal and abnormal conditions. This algorithm does not require tuning any ad-hoc parameters. This approach could lead to an effective way of implementing a personal treatment strategy, and a control system to improve the performance of the thyroid. PMID- 30481672 TI - Extracellular electron transfer of Enterobacter cloacae SgZ-5T via bi-mediators for the biorecovery of palladium as nanorods. AB - In nature, microbes use extracellular electron transfer (EET) to recover noble metals. Most attention has been paid to the biorecovery process occurring intracellularly and on the cell surface. In this work, we report that Pd nanorods could be biosynthesized by Enterobacter cloacae SgZ-5T in the extracellular space. This bacterium possesses both a direct EET pathway through membrane redox systems and an indirect EET pathway via the self-secreted electron carrier hydroquinone (HQ). When exposed to Pd(II), the bacteria adjusted their metabolic pathway and membrane-bound proteins to secrete riboflavin (RF). However, no HQ was detected in the supernatant in presence of Pd(II). No significant change was observed through metabolomic analysis regarding the abundance of HQ in presence of Pd(II) compared to Pd(II)-free supernatant. Similar results were also obtained through transcriptomic analysis of YqjG gene encoding glutathionyl-HQ reductase synthase. X-ray photoelectron spectroscopic evidence indicated that HQ may adsorb to the surface of Pd nanorods. Moreover, the gene encoding RF synthase (ribE) was up-regulated in the present of Pd(II), suggesting that this bioreduction process induced RF synthase, which had been shown in previous results. The UV-vis spectroscopy data demonstrated that the Pd(II) reduction rate was enhanced by 5%, 5.5% and 30% by the addition of 3.33 MUM HQ, 3.33 MUM RF and the both, respectively. All these results revealed that the bi-mediators secreted by bacteria were beneficial for biorecovery of Pd. This work is of significance for understanding metal biorecovery processes and natural biogeochemical processes. PMID- 30481673 TI - The roles of free ammonia (FA) in biological wastewater treatment processes: A review. AB - Free ammonia (FA) can pose inhibitory and/or biocidal effects on a variety of microorganisms involved in different biological wastewater treatment process, which is widely presented in wastewater treatment plants (WWTPs) due to the high levels of ammonium in the systems. This review article gives the up-to-date status on several essential roles of FA in biological wastewater treatment processes: the impacts of FA, mechanisms of FA roles, modeling of FA impacts, and implications of FA for wastewater treatment. Specifically, the impacts of FA on both wastewater and sludge treatment lines were firstly summarized, including nitrification, denitrification, anaerobic ammonium oxidation (Anammox), enhanced biological phosphorus removal and anaerobic processes. The involved mechanisms were then analyzed, which indicated FA inhibition can slow specific microbial activities or even reconfigure the microbial community structure, likely due to negative impacts of FA on intracellular pH, specific enzymes and extracellular polymeric substances (EPS), thus causing cell inactivation/lysis. Mathematical models describing the impact of FA on both wastewater and sludge treatment processes were also explored to facilitate process optimization. Finally, the key implications of FA were identified, that is FA can be leveraged to substantially enhance the biodegradability of secondary sludge, which would further improve biological nutrient removal and enhance renewable energy production. PMID- 30481674 TI - Urinary concentrations of phenols and phthalate metabolites reflect extracellular vesicle microRNA expression in follicular fluid. AB - BACKGROUND: Phenols and phthalates are potential endocrine disrupting chemicals (EDCs) that are associated with adverse health outcomes. These EDCs dysregulate a number of biomolecules and pathways, including microRNAs. MicroRNAs can be carried in transport systems called extracellular vesicles (EVs) that are present in most biofluids. EVs in the follicular fluid, which fills the ovarian follicle and influences oocyte developmental competency, carry microRNAs (EV-miRNAs) that have been associated with In Vitro Fertilization (IVF) outcomes. However, it remains unclear whether EDCs affect EV-miRNAs in follicular fluid. OBJECTIVES: This study sought to determine whether urinary concentrations of phenols and phthalates biomarkers are associated with EV-miRNAs expression in follicular fluid collected from women undergoing IVF treatment. METHODS: This cross sectional study included 130 women recruited between January 2014 and August 2016 in a tertiary university-affiliated hospital. Participants provided urine samples during ovarian stimulation and on the day of oocyte retrieval. We assessed urinary concentrations of five phenols, eight phthalate metabolites, and one phthalate alternative metabolite. EV-miRNAs were isolated from follicular fluid and their expression profiles were measured using the TaqMan Open Array(r) Human microRNA panel. We fitted multivariable linear regression models and principal component analysis to examine associations between individual and molar sums of exposure biomarkers and EV-miRNAs. RESULTS: Of 754 miRNAs tested, we detected 133 EV-miRNAs in the microRNA array which expressed in at least 50% of the follicular fluid samples. After adjusting for multiple testing, we identified eight EV miRNAs associated with individual phenols and phthalate metabolites, as well as molar SigmaDEHP that met a q < 0.10 false-discovery rate (FDR) threshold. Hsa-miR 125b, hsa-miR-106b, hsa-miR-374a, and hsa-miR15b was associated with mono(2 ethylhexyl) phthalate concentrations, hsa-let-7c with concentrations mono-2-ethyl 5-hydroxyhexyl phthalate (MEHHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP), mono 2-ethyl-5-carboxypentyl phthalate (MECPP), and the sum of metabolites of di(2 ethylhexyl) phthalate, hsa-miR-24 with mono-n-butyl phthalate concentrations, hsa miR-19a with cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH), and hsa-miR-375 with ethyl paraben concentrations. Using Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, gene targets and pathways of these EV-miRNAs were predicted in silico and 17 KEGG FDR-significant pathways related to follicular development and oocyte competence were identified. CONCLUSIONS: Our results show that urinary concentrations of select phenol and phthalate metabolites are correlated with altered EV-miRNAs expression in follicular fluid. These findings may provide insight regarding the molecular mechanisms underlying adverse effects of phenol and phthalate exposure on female fertility. PMID- 30481675 TI - The use of augmented toys to facilitate play in school-aged children with visual impairments. AB - BACKGROUND: Children with visual impairments (VIs) face challenges in social play activities, which limits their opportunities to practice social skills. AIMS: We investigated whether augmented toys were effective to facilitate play in 52 children with VIs who attended special schools for students with visual impairments and blindness. METHODS AND PROCEDURES: 52 children with VIs (mean age: 9.22 years, SD = 2.07) played three times with both an augmented and a non augmented toy. A Playmobil(r) knight's castle was augmented with Radio Frequency Identification (RFID) technology, such that each play figure produced audio feedback during play. The RFID-technology could be activated and deactivated. Social and cognitive aspects of play were coded from video and data were analyzed using multilevel logistics. OUTCOMES AND RESULTS: Children showed less disengagement and more parallel play, but less cooperative play when they used the augmented versus the non-augmented castle. This pattern persisted after repeated play sessions with both toys. CONCLUSIONS: The addition of sounds to physical toys increased shared attention between children with VIs during the exploration of play materials, yet it interfered with social interaction during peer play. PMID- 30481676 TI - Proteomic analysis of the response of porcine adrenal gland to heat stress. AB - Heat stress (HS) and its associated pathologies are major challenges facing the pig industry in southern China, and are responsible for large economic losses. However, the molecular mechanisms governing the abnormal secretion of HS responsive hormones, such as glucocorticoids, are not fully understood. The goal of this study was to investigate differentially expressed proteins (DEPs) in the adrenal glands of pigs, and to elucidate changes in the immune neuroendocrine system in pigs following HS. Through a functional proteomics approach, we identified 1202 peptides, corresponding to 415 proteins. Of these, we found 226 DEPs between heat-stressed and control porcine adrenal gland tissue; 99 of these were up-regulated and 127 were down-regulated in response to HS. These DEPs included proteins involved in substrate transport, cytoskeletal changes, and stress responses. Ingenuity Pathway Analysis was used to identify the subcellular characterization, functional pathway involvement, regulatory networks, and upstream regulators of the identified proteins. Functional network and pathway analyses may provide insights into the complexity and dynamics of HS-host interactions, and may accelerate our understanding of the mechanisms of HS. PMID- 30481677 TI - The role of menisci in knee contact mechanics and secondary kinematics during human walking. AB - BACKGROUND: Meniscectomy is likely to result in an increase of joint loading on articular cartilage and initiates cartilage damages. However, the induced alterations in knee contact mechanics and secondary kinematics after the meniscal removal are still unclear during a walking gait. In this study, the role of menisci on the knee contact mechanics and secondary kinematics were investigated during a walking simulation. METHODS: Two natural knee models with or without menisci were established using a musculoskeletal multibody dynamics framework. Walking simulation were performed to qualify the knee contact forces and secondary kinematics, and ligament forces in these models. FINDINGS: After the meniscal removal, the redistributed contact forces on the medial tibial cartilage increased by twofold, while the contact area remained almost the same. The subsequent increase of contact pressure suggested potential cartilage damages. In terms of the kinematic alterations, the tibia moved more posteriorly and internally with respect to the femur. And, the displacement in the medial-lateral direction reversed. In addition, the sharp force increase in the anterior cruciate ligament explained the reason why meniscal and anterior cruciate ligament injuries always happened concurrently. And, the anterior lateral ligament may act as the stabilizer in the tibial posterior displacement and varus rotation. INTERPRETATION: This study shows that menisci served as the joint load distribution, and also as the kinematics constraints in the posterior and medial lateral direction, which is beneficial to the rehabilitation plan-making of meniscal injuries. PMID- 30481678 TI - Application of N-TiO2 for visible-light photocatalytic degradation of Cylindrospermopsis raciborskii - More difficult than that for photodegradation of Microcystis aeruginosa ? AB - Nowadays Cylindrospermopsis raciborskii (C. raciborskii) and the metabolites produced, such as cylindrospermopsin (CYN), pose a serious threat to the ecosystem. Advanced oxidation technologies have been verified as constituting a very promising means to eliminate the risk from harmful algae. But so far little research has focused on the visible-light photocatalytic destruction of C. raciborskii cells and the degradation of their metabolites. In our study, N-doped TiO2 (N-TiO2) was used to degrade C. raciborskii and the degradation was compared with that of the Microcystis aeruginosa (M. aeruginosa). Results showed that although the photodegradation of C. raciborskii was more difficult than that of M. aeruginosa, the treatment with N-TiO2 was still satisfactory. After adding 200 mg/L N-TiO2, C. raciborskii cells (5 * 106 cells/mL) were completely destroyed within 20 h under visible light irradiation, and nearly 90% of the organic matter and CYN in the suspensions were also degraded, thereby markedly improving the water quality. The photocatalytic process starts with damage to the cell membrane resulting in the leakage of internal components. Subsequently, the leaked metabolites were oxidised by the reactive oxidizing species produced by N-TiO2. Thus, the application of N-TiO2 is a promising method for the treatment of C. raciborskii. PMID- 30481679 TI - Acceleration of perchloroethylene dechlorination by extracellular secretions from Microbacterium in a mixed culture containing Desulfitobacterium. AB - The study was conducted to demonstrate the influence of extracellular secretions from Microbacterium on the reductive dechlorination of tetrachloroethene (PCE). A series of mixed cultures were established from a paddy soil sample. In the mixed cultures amended with extracellular secretions from Microbacterium, PCE was rapidly and completely converted into cis-1,2-dichloroethene (cis-DCE) and trans 1,2-dichloroethene (trans-DCE) within 40 days. The unamended mixed cultures showed weak signs of dechlorination after a pronounced lag phase, and trichloroethene (TCE) was accumulated as a major end product. This result means that amendment with extracellular secretions from Microbacterium shortened the lag phase, increased the dechlorination velocity and promoted the production of less-chlorinated chloroethene. The results were corroborated by defined subculture experiments, which proved that microorganisms from unamended mixed cultures could also be stimulated by extracellular secretions from Microbacterium. Desulfitobacterium was identified as the main dechlorinating population in all mixed cultures by direct PCR. Additionally, the 16S rRNA gene copies of Desulfitobacterium increased by one or two orders of magnitude with PCE dechlorination, which provided corroborative evidence for the identification result. The volatile fatty acids were monitored, and most interestingly, a close association between propionate oxidation and dechlorination was found, which has rarely been mentioned before. It was assumed that the oxidation of propionate provided hydrogen for dechlorination, while dechlorination facilitated the shift of the reaction toward propionate oxidation by reducing the partial pressure of hydrogen. PMID- 30481681 TI - A randomized controlled trial of the judicious use of safety behaviors during exposure therapy. AB - Safety behaviors-actions performed to prevent, escape from, or reduce the severity of perceived threat-are typically eliminated during exposure therapy for clinical anxiety. Yet some experts have called for the strategic and "judicious use" of safety behaviors during exposure to improve treatment acceptability/tolerability without diminishing its efficacy. Empirical findings regarding this debate are mixed and existing work is subject to several methodological limitations. The current randomized controlled trial incorporated longitudinal design and multimethod assessment to compare the efficacy of traditional exposure with the elimination of safety behaviors (E/ESB) and exposure with judiciously used safety behaviors (E/JU). Adults with clinically significant spider fear (N = 60) were randomized to four twice-weekly sessions of E/ESB or E/JU. Self-report and behavioral measures were administered at pretreatment, posttreatment, and 1-month follow-up. Participants exhibited large effects on all measures from pretreatment to posttreatment, with no change from posttreatment to follow-up. There were no significant group differences in treatment outcome or treatment acceptability/tolerability. Exploratory analyses were used to compare behavioral and inhibitory learning processes between conditions. Clinical implications, study limitations, and future directions are discussed in terms of inhibitory learning theory. PMID- 30481680 TI - The relationship between weight stigma, weight bias internalization, and physical health in military personnel with or at high-risk of overweight/obesity. AB - Perceived weight stigma is associated with adverse health indices, such as elevated cortisol, lipid/glucose dysregulation, and poorer self-rated health. This relationship may be particularly relevant for military personnel, given the cultural emphasis on fitness and weight/shape. Therefore, we investigated the relationship between weight stigma and physical health in 117 active duty personnel (66.7% male; 56.4% non-Hispanic White; age: 30.8 +/- 7.4 years; BMI: 29.5 +/- 2.5 kg/m2). Participants reported weight stigma (general and military specific), weight bias internalization, and the presence (>=1; n = 55) or absence (n = 62) of medical conditions. Logistic regressions were conducted examining the ability of weight stigma (general or military-specific) and weight bias internalization to predict the presence or absence of medical conditions. General weight stigma was not significantly associated with the presence of a medical condition (p > .05). However, individuals with military-specific weight stigma scores twice that of their peers were over three times more likely (p = .04) to report a medical condition. Weight bias internalization was not significant in any model (ps > .20). Longitudinal studies should prospectively examine the relationship between weight stigma in the military setting and health among service members. PMID- 30481682 TI - Heat stress induced alternative splicing in catfish as determined by transcriptome analysis. AB - Heat tolerance is increasingly becoming an important trait for aquaculture species with a changing climate. Transcriptional studies on responses to heat stress have been conducted in catfish, one of the most important economic aquaculture species around the world. The molecular mechanisms underlying heat tolerance is still poorly understood, especially at the post-transcriptional level including regulation of alternative splicing. In this study, existing RNA Seq datasets were utilized to characterize the change of alternative splicing in catfish following heat treatment. Heat-tolerant and -intolerant catfish were differentiated by the time to lost equilibrium after heat stress. With heat stress, alternative splicing was generally increased. In heat-intolerant fish, the thermal stress induced 29.2% increases in alternative splicing events and 25.8% increases in alternatively spliced genes. A total of 282, 189, and 44 differential alternative splicing (DAS) events were identified in control intolerant, control-tolerant, and intolerant-tolerant comparisons, corresponding to 252, 171, and 42 genes, respectively. Gene ontology analyses showed that genes involved in the molecular function of RNA binding were significantly enriched in DAS gene sets after heat stress in both heat-intolerant and -tolerant catfish compared with the control group. Similar results were also observed in the DAS genes between heat-intolerant and -tolerant catfish, and the biological process of RNA splicing was also enriched in this comparison, indicating the involvement of RNA splicing-related genes underlying heat tolerance. This is the first comprehensive study of alternative splicing in response to heat stress in fish species, providing insights into the molecular mechanisms of responses to the abiotic stress. PMID- 30481683 TI - ERK inhibitor JSI287 alleviates imiquimod-induced mice skin lesions by ERK/IL-17 signaling pathway. AB - Many studies confirmed that the over-activation of RAF-MEK-ERK signaling pathway plays a central role in human cancers. To avoid drug resistance during cancer treatment, many researchers focused on the study of the downstream therapeutic target of RAF-MEK-ERK signaling pathway. Therefore, ERK1/2 became a hot anticancer target. It has been shown that ERK phosphorylation could activate Th17 cells and therefore induce inflammatory diseases. Due to these results, inhibition of ERK, as a potential drug target, could provide a solution for autoimmune diseases, especially T cell mediated diseases. In this study, a small synthetic molecule JSI287 was found with the function of alleviating IMQ-induced mice skin lesions through ERK/IL-17 signaling pathway during the screening of small molecule databases targeting ERK. The results showed that JS1287 small molecule alleviated epidermal thickness, epidermis congestion, edema and inflammatory cell infiltration, decreased release of inflammatory cytokines of IL 6, IL-12 and IL-17A, and further regulated the mRNA expression of ATF1 and protein expression of ERK1/2 in IMQ-induced skin lesions. Our study suggested that ERK inhibitor JSI287 could be a promising candidate for psoriasis treatment. PMID- 30481685 TI - Kafnets: Kernel-based non-parametric activation functions for neural networks. AB - Neural networks are generally built by interleaving (adaptable) linear layers with (fixed) nonlinear activation functions. To increase their flexibility, several authors have proposed methods for adapting the activation functions themselves, endowing them with varying degrees of flexibility. None of these approaches, however, have gained wide acceptance in practice, and research in this topic remains open. In this paper, we introduce a novel family of flexible activation functions that are based on an inexpensive kernel expansion at every neuron. Leveraging several properties of kernel-based models, we propose multiple variations for designing and initializing these kernel activation functions (KAFs), including a multidimensional scheme allowing to nonlinearly combine information from different paths in the network. The resulting KAFs can approximate any mapping defined over a subset of the real line, either convex or non-convex. Furthermore, they are smooth over their entire domain, linear in their parameters, and they can be regularized using any known scheme, including the use of l1 penalties to enforce sparseness. To the best of our knowledge, no other known model satisfies all these properties simultaneously. In addition, we provide an overview on alternative techniques for adapting the activation functions, which is currently lacking in the literature. A large set of experiments validates our proposal. PMID- 30481684 TI - Self-reported violations, errors and lapses for older drivers: Measuring the change in frequency of aberrant driving behaviours across five time-points. AB - The current study aimed to: 1. to confirm the 21-item, three-factor Driver Behaviour Questionnaire (DBQ) structure suggested by Koppel et al. (2018) within an independent sample of Canadian older drivers; 2. to examine whether the structure of the DBQ remained stable over a four-year period; 3. to conduct a latent growth analysis to determine whether older drivers' DBQ scores changed across time. Five hundred and sixty Canadian older drivers (males = 61.3%) from the Candrive/Ozcandrive longitudinal study completed the DBQ yearly for four years across five time-points that were approximately 12 months apart. In Year 1, the average age of the older drivers was 76.0 years (SD = 4.5 years; Range = 70 92 years). Findings from the study support the 21-item, three-factor DBQ structure suggested by Koppel and colleagues for an Australian sample of older drivers as being acceptable in an independent sample of Canadian older drivers. In addition, Canadian older drivers' responses to this version of the DBQ were stable across the five time-points. More specifically, there was very little change in older drivers' self-reported violations, and no significant change for self-reported errors or lapses. The findings from the current study add further support for this version of the DBQ as being a suitable tool for examining self reported aberrant driving behaviours in older drivers. Future research should investigate the relationship between older drivers' self-reported aberrant driving behaviours and their performance on functional measures, their responses to other driving-related abilities and practice scales and/or questionnaires, as well their usual (or naturalistic) driving practices and/or performance on on road driving tasks. PMID- 30481686 TI - Saliency model based on a neural population for integrating figure direction and organizing Border Ownership. AB - Attentional selection is a function of the brain that allocates computational resources momentarily to the most important part of a visual scene. Saliency map models have been used to predict the location of attentional selection and gaze. Border Ownership (BO) indicates the direction of the figure with respect to the border. I here propose a biologically plausible saliency model based on neural population for integrating the activities of intermediate-level visual areas with neurons selective to BO. A variety of BO organizations produces a population of model neurons that represent the grouping structure. In the model I propose, the interactions and the population responses of these model neurons underlie the determination of saliency and the accurate prediction of gaze location. I tested 100 patterns for BO organizations and found that the proposed saliency model not only reproduced the characteristics of perceptual organization but also captured object locations in natural images. Furthermore, the saliency model based on the population responses of the BO organization significantly improved the gaze prediction accuracy compared with previous saliency-based models. These results suggest a crucial role for a wide variety of BO organizations and neural population coding to determine saliency mediating attentional selection and to predict gaze location. PMID- 30481687 TI - Design and synthesis of rosiglitazone-ferulic acid-nitric oxide donor trihybrids for improving glucose tolerance. AB - Glucose intolerance is associated with metabolic syndrome and type 2 diabetes mellitus (T2DM) while some new therapeutic drugs, such as rosiglitazone (Rosi), for T2DM can cause severe cardiovascular side effects. Herein we report the synthesis of Rosi-ferulic acid (FA)-nitric oxide (NO) donor trihybrids to improve glucose tolerance and minimize the side effects. In comparison with Rosi, the most active compound 21 exhibited better effects on improving glucose tolerance, which was associated with its NO production, antioxidant and anti-inflammatory activities. Furthermore, 21 displayed relatively high stability in the simulated gastrointestinal environments and human liver microsomes, and released Rosi in plasma. More importantly, 21, unlike Rosi, had little stimulatory effect on the membrane translocation of aquaporin-2 (AQP2) in kidney collecting duct epithelial cells. These, together with a better safety profile, suggest that the trihybrids, like 21, may be promising candidates for intervention of glucose intolerance related metabolic syndrome and T2DM. PMID- 30481688 TI - Edge chipping resistance of ceramics bonded to a dentine analogue. AB - OBJECTIVE: To evaluate the edge chip resistance (ReA) of two CAD/CAM monolithic ceramics (GC- IPS e.max CAD and YZ- Zenostar Zr Translucent) bonded to a dentine analogue substrate (G10- NEMA G10). METHODS: Plate-shaped specimens were prepared from GC and YZ ceramics and were either bonded (B) to G10 or attached (NB) to a universal testing machine for edge chipping test. Samples from all groups (GC-B, GC-NB, YZ-B and YZ-NB) were indented (n = 25) at different edge distances (d = 0.1, 0.2, 0.3, 0.4, 0.5 and 0.6 mm) to produce chips. Force (F, in N) and d values were recorded and ReA (in N/mm) were calculated. Data were statistically analyzed using Pearson's correlation, Student t, ANOVA and Tukey tests (alpha = 0.05). RESULTS: A strong correlation (R >= 0.98) was found between F and d values for all groups. ReA values increased with increasing d, irrespective of ceramic type (GC and YZ) or fixation method (B and NB). Significant differences (p < 0.05) in mean ReA values were found between B and NB ceramics at lower d (0.1-0.3 mm) that did not persist (p > 0.05) at greater d (0.5 and 0.6 mm), meaning, bonding (B) to G10 protected both materials against chipping close to the edge. CONCLUSIONS: The larger the distance from the occlusal contact to the restoration edge, the greater the chance to avoid ceramic chipping in monolithic restorations. For d <= 0.3 mm, such F vs d relation is less critical for edge resistance of YZ and for resin bonded monolithic ceramics. PMID- 30481689 TI - In silico modeling and structural analysis of asparaginyl endopeptidase of schistosoma mansoni (Sm32): Immunological and drug target implications. AB - Asparaginyl endopeptidase (AE) of Schistosoma mansoni (Sm32), also known as legumain, is a cysteine protease indirectly involved in the digestion of hemoglobin of Schistosoma sp. in the gastrodermis, being a vaccine candidate against this trematode and a potential drug target. This study presents a model for the three-dimensional structure of Sm32 determined by means of homology modeling and a molecular dynamics simulation with explicit solvent refinement. The structure proved to be consistent with other AEs of known crystal structures described in their proenzyme form, revealing a catalytic domain that has a caspase-like overall structure and a C-terminal prodomain that adopts a death domain-like architecture. We identified amino acid mutations in the betaIV strand, differences in the active site and in the surface electrostatic potentials between Sm32 and its homologous proteins of mouse and human. Additionally, amino acid changes in the activation peptide (AP) of the S. mansoni protein were determined. Our results strongly suggest that Sm32 can be exploited as a potential target for drug design and for the development of biomarkers used in diagnosis and in novel vaccines for the control of parasitic infection, opening the perspective of medicinal chemistry developments. PMID- 30481690 TI - Transcranial direct current stimulation (tDCS) selectively modulates semantic information during reading. AB - The left angular gyrus has long been implicated in semantic processing. Here we tested whether or not transcranial direct current stimulation (tDCS) over the left angular gyrus modulated reading performance. Adult readers (N = 77) (1) read aloud words that varied in degree of imageability, a semantic word property known to activate the angular gyrus, and (2) completed an N-back task (control task). Individuals were randomly assigned to either the anodal, cathodal or sham stimulation conditions. We found that anodal (p = 0.001) and cathodal (p < 0.001) stimulation impacted how imageability facilitates reading times such that readers who showed the largest imageability effects pre-stimulation showed the greatest reduction in these effects post-stimulation. No effects of stimulation were found in the sham group (p > 0.05) or for the control task (i.e., N-back; p > 0.05). These findings indicate that reading pathways can be modulated via brain stimulation (tDCS) to shift individuals' sensitivity to word-level characteristics, namely imageability. PMID- 30481691 TI - Evaluating opioid overdose using the National Violent Death Reporting System, 2016. AB - BACKGROUND: Unintentional opioid overdose death rates have increased nearly 500% in Connecticut from 1999 to 2016, resulting in a major public health crisis. Two primary types of opioids have been implicated in these fatalities - illicit and pharmaceutical. The objective of this study is to describe the epidemiology of fatal unintentional opioid overdoses by type. METHODS: Using the National Violent Death Reporting System, rates of unintentional opioid-related overdose death in Connecticut were calculated. Demographic and contextual characteristics (e.g., substance misuse, mental health issues), and concomitant drug use (e.g., benzodiazepines, cocaine) were compared by opioid type. RESULTS: In 2016, 867 victims of fatal unintentional opioid overdose were identified in Connecticut. The majority of deaths involved illicit opioids (79.6%). Overall, victims were mostly male, white, non-Hispanic, and aged 25-54 years. Victim sex, age, and contextual characteristics differed significantly according to opioid type. For illicit opioid deaths, victims were predominantly male, aged 44 and under, and more often had a history of substance misuse. In contrast, among pharmaceutical opioid deaths, the split between males and females was significantly less pronounced, victims were mostly aged 45 and over, and mental health diagnoses, a physical health problem and concomitant drug use were more prevalent. CONCLUSIONS: Based on our findings, efforts to curb opioid-related overdose should be specific to opioid type. Interventions pertaining to pharmaceutical opioids should target females and older adults, whereas interventions for illicit opioid use should target younger audiences. PMID- 30481692 TI - A prospective study of nonmedical use of prescription opioids during adolescence and subsequent substance use disorder symptoms in early midlife. AB - BACKGROUND: This longitudinal study assesses characteristics associated with adolescents' nonmedical use of prescription opioids (NMUPO) including: frequency, co-ingestion, motives, specific opioid type; sequence of initiation of medical use of prescription opioids and NMUPO in relationship to subsequent substance use disorder (SUD) symptoms. METHODS: Twenty-one independent national cohorts of U.S. high school seniors (n = 8,373) were surveyed and followed 17 years from adolescence to age 35. RESULTS: The majority of adolescents who engaged in NMUPO reported occasional/frequent NMUPO, non-pain relief motives for NMUPO, simultaneous co-ingestion involving NMUPO and other drugs, opioid analgesics with high misuse potential, and multiple types of opioid analgesics. Adolescents who reported NMUPO for pain relief, NMUPO involving opioid analgesics with high misuse potential, or multiple prescription opioids had significantly greater odds of SUD symptoms at age 35, relative to those who had no history of NMUPO during adolescence. In addition, medical use of prescription opioids after initiating NMUPO (or NMUPO only) during adolescence was associated with significantly greater odds of subsequent SUD symptoms at age 35 relative to those who reported the medical use of prescription opioids only or had no medical use or NMUPO during adolescence. CONCLUSIONS: This is the first U.S. national prospective study to examine the relationships between adolescents' NMUPO characteristics and later SUD symptoms in early midlife. Several characteristics (frequency, co ingestion, motives, opioid type, and medical/NMUPO initiation history) were identified that could be used to screen and detect high-risk youth for indicated interventions to reduce prescription opioid misuse and SUDs. PMID- 30481693 TI - Preliminary evidence linking complex-PTSD to insomnia in a sample of Yazidi genocide survivors. AB - Complex post-traumatic stress disorder (CPTSD) is a psychiatric diagnosis that includes three additional symptom clusters beyond those necessary for post traumatic stress disorder (PTSD) diagnosis. CPTSD is typically associated with a prolonged trauma exposure in which a person's destiny is under the control of other people and escape is not an option. Insomnia prevalence in women suffering from CPTSD was compared to the prevalence of insomnia in those with no-PTSD and those with only PTSD. Yazidi women (N = 108, age = 24.41 +/- 5.71) former captives of the Islamic State terrorist group were queried about captivity variables, psychological distress, resilience, PTSD, CPTSD, and insomnia. CPTSD prevalence was high (>50%) and was highly correlated with insomnia (95% of those with CPTSD had insomnia). A dichotomous insomnia variable was regressed on age and marital-status (Step 1), captivity-duration and number of fellow captives (Step 2), resilience and psychological distress (Step 3), and group (no PTSD/PTSD/CPTSD) (Step 4). Insomnia was 18 times more likely in the CPTSD group than in the no-PTSD group. There were no differences in insomnia prevalence between the no-PTSD and PTSD groups. Insomnia levels among Yazidi women released from captivity support an understanding of CPTSD as a separate entity than PTSD. Potential factors linking CPTSD to insomnia, beyond those associated with PTSD are discussed. PMID- 30481694 TI - Neurocognition, psychiatric symptoms, and lifetime homelessness among veterans with a history of traumatic brain injury. AB - We retrospectively investigated archival clinical data, including correlates of lifetime homelessness, in 503 Veterans with a history of traumatic brain injuries (86.5% mild) who completed neuropsychological evaluations and passed performance validity tests. The 471 never-homeless and 32 ever-homeless Veterans were compared on demographic factors, TBI severity, psychiatric diagnosis, subjective symptoms, and neuropsychological functioning. Homelessness history was significantly associated with unemployment, lower disability income, more severe depressive, anxiety, posttraumatic stress disorder, and postconcussive symptoms, and lower performances on two of fifteen neurocognitive tests. In a multiple logistic regression model, current unemployment and substance use disorder remained significantly associated with lifetime homelessness. PMID- 30481695 TI - Validation of an interview-only version of the Dimensional Yale-Brown Obsessive Compulsive Scale (DY-BOCS) in treatment-seeking youth with obsessive-compulsive disorder. AB - There is a growing body of evidence suggesting that individuals with obsessive compulsive disorder (OCD) may be sub-typed along different symptom dimensions. These dimensions may help explain responsiveness to current treatments. The Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS) is a validated instrument involving a self-report screening tool followed by a structured interview in which the presence/absence and severity of OCD symptom dimensions are assessed and rated. The present study investigated the validity of a briefer, interview-only version of the DY-BOCS modified for use in routine care. Clinically-referred children and adolescents (N = 119) with OCD were administered the DY-BOCS along with other measures of OCD, anxiety, depression, and overall functioning and a subset (N = 100) were reassessed on average 14 months after initial assessment. This briefer, interview-only version of the DY-BOCS demonstrated high levels of internal consistency and correlated in the moderate to strong range with alternative measures of OCD severity and OCD symptom dimensions. Change scores on the DY-BOCS from baseline to follow-up were significantly correlated with change scores on the alternative measures of OCD and clinician-rated improvement, suggesting that this brief version of the DY BOCS is valid and sensitive to the effects of treatment for OCD delivered in routine clinical care. PMID- 30481696 TI - Cognitive fusion and affective isolation: Blurred self-concept and empathy deficits in schizotypy. AB - This is a cross-sectional nonclinical sample study to examine the different levels of the Ipsiety Disturbance Model (IDM) for schizophrenia spectrum disorders (introduced by Sass and Parnas, 2003). Three faces of schizotypy were studied: diminished self-presence, hyper-reflexivity, and distortion in experience of own self and another person's self-discrimination. A sample of college students (N = 1312) was provided a questionnaire packet that contained the Schizotypy Personality Questionnaire Brief-Revisited (SPQ-BR), the Self Concept Clarity Sale, the Tellegen Absorption Scale, and Interpersonal Reactivity Index measures. Results: higher absorption capabilities predict higher scores on both the SPQ-BR cognitive and SPQ-BR disorganization factors. High scores in cognitive empathy predicted a low score on both SPQ-BR cognitive and SPQ-BR interpersonal scores. In contrast, higher affective empathy predicted high scores on the SPQ-BR interpersonal factor. The deficiency in self-concept clarity predicted an elevated score on the SPQ-BR cognitive, interpersonal, and disorganization schizotypy symptoms. We argue that a lack of self-concept clarity manifested in both the hyperreflexivity level (measured by absorption) and the metallization level (measured by empathy). We argue that the IDM is a reliable way to interpret functioning with different levels of schizotypy. PMID- 30481697 TI - Kinematics and shock attenuation during a prolonged run on the athletic track as measured with inertial magnetic measurement units. AB - BACKGROUND: Tibial stress fractures are common running related injury and their etiology may include biomechanical factors like impact forces, shock attenuation, lower limb kinematics and how these factors are influenced by intense or prolonged running. Inertial-magnetic measurement units (IMUs) have recently emerged as an alternative to motion capture but their use to date was mostly limited to segmental and joint motion. RESEARCH QUESTION: The present study sought to examine the effects of a prolonged run on shock attenuation, peak tibial and sacral acceleration (PTA, PSA), and lower limb kinematics using IMUs. METHODS: Ten trained male runners (31 +/- 5 yr, 183 +/- 3 cm, 76 +/- 9 kg) performed a twenty-minute prolonged run on an athletic track at estimated lactate threshold speed. Eight IMUs, positioned over the feet, lower and uppers legs, sacrum and sternum, were used to calculate joint kinematics, impact parameters and shock attenuation in the time domain (1-(PSA/PTA)*100). RESULTS: PTA increased while PSA and shock attenuation did not change following the prolonged run. Hip and knee flexion at midstance decreased. Vertical lower leg angle at initial contact did not change. CONCLUSION: By using IMUs, it was shown that a prolonged run at estimated lactate threshold speed had significant effects on kinematics and tibial acceleration parameters. By modifying hip and knee joint kinematics during stance, the body was able to maintain sacral acceleration possibly by shifting from active shock attenuation to more passive mechanisms. SIGNIFICANCE: The present study shows that inertial sensors can be used in outdoor running to measure joint kinematics and kinetic parameters like PTA, PSA and shock attenuation simultaneously. The results of this study show new insights into how the body copes with impact during prolonged running. PMID- 30481698 TI - A molecular modelling study of the effects of pivalate ligand substitutions on the magnetic properties of chromium-wheels host complexes. AB - In our recent article, we had a successful experience in applying binuclear chromium (III) model ([Cr2F(tBuCO2)2(H2O)2(OH)4]-1) instead of real chromium wheel host complex ([Cr8F8(tBuCO2)16]) to calculate the effect of bridged-ligands substitution on the exchange coupling constants (J) values of the complexes. In this work our experienced procedure was used to evaluate the effect of pivalate (tBuCO2) ligands substitution on the J values of the complexes. For this, at first two new groups of complexes were designed based on the replacement of pivalate by X-tBuCO2 and X-iPrCO2 anionic ligands (where X represents F, Cl, Br and I halogens) and then their J values were calculated. Since the existence of two halogen atoms in the structures of complexes leads to form different conformers, at first step a conformational analysis was carried out to identify the stable conformers of each complex. In X-tBuCO2-containing complexes four stable conformers were recognized, while X-iPrCO2-containing complexes had three stable conformers. At next step the J values of each of these conformers were calculated for all complexes. It was found that depending on which conformer was formed, the effect of these substitutions in each complex could be different, leading to a decrease or increase in the antiferromagnetic property of the complex. In both types of complexes, the formation of the least stable conformer, Conf1, led to the strengthening of the antiferromagnetic property of the complex but the impacts of the substitutions in other conformers were diverse. These new designed complexes could be considered as novel synthetic targets with different magnetic properties. PMID- 30481699 TI - Effects of different regimens for pelvic floor muscle training in young continent women: Randomized controlled clinical trial. AB - BACKGROUND: Physical therapy is recommended as first-line treatment to urinary incontinence (UI), and pelvic floor muscles (PFM) training is one of the most used resources for this purpose, no ideal PFM training protocol has been established. OBJECTIVES: The purpose of the present study was to verify whether more daily sessions of PFM training lead to better PFM function. METHODS: Twenty five young continent women volunteered and were randomly assigned to 2 different groups; group 1, in which they performed one PFM training session daily, and group 2, in which they performed 3 daily PFM training sessions. All volunteers were evaluated regarding PFM function, based on the Modified Oxford Scale, maximum voluntary contraction, with a manometer, and PFM activation, with electromyography. Both groups trained during 8 consecutive weeks and were evaluated before and after treatment. All evaluations had the reproducibility tested by intraclass correlation coefficients. Statistical analyzes included data normality (Shapiro-Wilks), intragroup (Wilcoxon) and intergroup (Mann-Whitney U) comparisons. Effect sizes were calculated to all variables analyzed. Significance level was set al p < 0.05. RESULTS: Even though an increase in PFM strength, pressure and muscle activation was achieved by both groups (p < 0.05, effect sizes from 0.24 to 0.81), no differences between groups for any variables were detected (p > 0.05). CONCLUSIONS: The number of daily training sessions does not interfere in the improvement of PFM function in young women without PFM dysfunction. PMID- 30481700 TI - A tale of two cities: A comparison of urban and rural trauma in Medieval Denmark. AB - OBJECTIVE: This study explores the differences in frequency and type of trauma found in two Medieval cemeteries in Denmark, as well as the cultural and community implications of those differences. MATERIALS: We examined 235 skeletons from the cemetery at Tjaerby (rural) and 170 skeletons from the cemetery at Randers (urban) for trauma from the Medieval period in Denmark, 1050 to 1536 CE. METHODS: Trauma was assessed through macroscopic examination and odds ratio and relative risk assessments were run to assess the difference in trauma. RESULTS: There was no significant difference in the presence of trauma between the rural and urban cemeteries or between males and females. There were some significant differences in relative risk for trauma between the two cemeteries. CONCLUSIONS: The division and variation in trauma between the two cemeteries is most likely related to differences in economy and occupation. SIGNIFICANCE: There are relatively few studies that examine the difference in inherent risk of trauma between rural and urban Medieval communities, especially in Denmark. This research also adds to the growing body of literature in paleopathology that uses epidemiology to explore the parallels between patterns of trauma and community lifeways. LIMITATIONS: The cemeteries are approximately 5 km distance from each other so similarities in the sample could be a result of location. SUGGESTIONS FOR FURTHER RESEARCH: A wider sample of Medieval cemeteries in Denmark needs be added to this analysis to provide a more complete picture of trauma patterns during this time period. PMID- 30481701 TI - Miconazole loaded chitosan-based nanoparticles for local treatment of vulvovaginal candidiasis fungal infections. AB - OBJECTIVES: In this study, polymeric nanoparticles based on chitosan incorporating the antifungal miconazole nitrate were fabricated and testedin vivo using murine vulvovaginal candidiasis. METHODS: Nanoparticles prepared by the ionotropic gelation method presented 200 to 300 nm diameter and polydispersity indexes ranging from 0.2 to 0.4. The nanoparticles were prepared to incorporate 63.9 mg/mL of miconazole nitrate to be testedin vivo. Murine vulvovaginal candidiasis was standardized using estradiol valerate before the animals were challenged by Candida albicans. RESULTS: The treatment using chitosan nanoparticles within miconazole nitrate presented the same therapeutic efficacy as miconazole nitrate in a commercial cream formulation, however using the antifungal content about seven-fold lower. This increase in the miconazole nitrate's therapeutic efficacy is may be due to the down-regulation of interleukin 10 (IL-10) expression. CONCLUSIONS: Our data represent a proof of concept that can be exploited to achieve an alternative and promising therapy for the treatment of vulvovaginal candidiasis. PMID- 30481702 TI - Ultrasound triggered phase-change nanodroplets for doxorubicin prodrug delivery and ultrasound diagnosis: An in vitro study. AB - Ultrasound-triggered delivery system is among the various multifunctional and stimuli-responsive strategies that hold great potential as a robust solution to the challenges of localized drug delivery and gene therapy. In this work, we developed an ultrasound-triggered delivery system PFP/C9F17-PAsp(DET)/CAD/PGA-g mPEG nanodroplet, which combined ultrasound responsive phase-change contrast agent, acid-cleavable doxorubicin prodrug and cationic amphiphilic fluorinated polymer carrier, aiming to achieve both high imaging contrast and preferable ultrasound-triggered anti-cancer therapeutic effect. The optimized nanodroplets were characterized as monodispersed particles with a diameter of about 400 nm, slightly positive surface charge and high drug-loading efficiency. The functional augmenter PGA-g-mPEG provided the nanodroplets good sustainability, low cytotoxicity and good serum compatibility, as confirmed by stability and biocompatibility tests. In ultrasound imaging study, the nanodroplets produced significant contrast with ultrasound irradiation (3.5 MHz, MI = 0.08) at 37 C. Cell uptake and cytotoxicity studies in HepG2 and CT-26 cells showed the enhanced drug uptake and therapeutic effect with the combination of nanodroplets and ultrasound irradiation. These results suggest that the PFP/CAD-loaded phase change nano-emulsion can be utilized as an efficient theranostic agent for both ultrasound contrast imaging and drug delivery. PMID- 30481703 TI - Spontaneous formation of tumor spheroid on a hydrophilic filter paper for cancer stem cell enrichment. AB - Emerging evidence has demonstrated that cancer stem cells (CSCs) play critical roles in tumor invasion, metastasis and recurrence. The specific targeting capability on CSCs is of high importance for the development of effective anti tumor therapeutics. However, isolation, enrichment and cultivation of these special and rare groups of tumor cells for in vitro analyses is a nontrivial job and requires particular culture medium and environmental control. Herein, we established a low-cost and efficient method for CSC enrichment by culturing prostate cancer cells on a hydrophilic filter paper. We found that tumor spheroids could form spontaneously on a pristine filter paper solely with regular cell culture medium. The paper-grown cells had elevated expression of putative CSC markers, indicating increased stemness of the cancer cells. Moreover, increased resistance of the chemotherapeutic drug doxorubicin was observed on the formed CSC spheroids compared to regular culture. The properties of the filter paper were characterized to investigate the underlying mechanism behind the promoted tumor spheroid formation. The obtained results suggested that the excellent hydrophilicity of the cellulose fibers retarded the hydrophobic interaction-mediated cell anchoring on the cellulose fibers, while the limited space/niche between fibers promoted the aggregation of cells. In addition, biocompatible paper-based materials are able to realize convenient assembly of tissue-like structures for developing in vitro disease models or organs-on-paper applications. Therefore, hydrophilic filter papers could be a low-cost material for construction of various assay platforms for isolating and enriching CSCs, screening anti-tumor drugs, and constructing tumor models in vitro. PMID- 30481704 TI - High and long-term antibacterial activity against Escherichia coli via synergy between the antibiotic penicillin G and its carrier ZnAl layered double hydroxide. AB - Antibiotic-resistant bacterial infections are a global health problem. A commonly used antibiotic Penicillin G was incorporated into ZnAl-layered double hydroxides (PNG/LDH) with a varied amount of PNG. PNG/LDH nanocomposites were well characterized in structure and composition using elemental analysis, X-ray diffraction pattern, Fourier transform infrared spectroscopy and TEM images, revealing that PNG were mostly adsorbed on the LDH surfaces at a lower PNG loading but some were intercalated into LDH interlayers at a higher PNG loading. The typical release profile of PNG and Zn2+ from PNG/LDH was a quick release, followed by a sustainable slow release. The antibacterial tests against Escherichia coli demonstrated that PNG/LDH with a suitable composition synergistically improved bacterial inhibition compared with free PNG and pristine LDHs. In specific, PNG/LDH with much higher cost-effectiveness showed a potent antimicrobial activity and maintained the activity for up to 10 days, significantly elongating the antibacterial effect compared with just 1 day for free PNG in the same conditions. Our results suggest suitable composition of nanoparticle carriers and antibiotics could significantly enhance antibacterial activity of antibiotics for a long period via the synergistic effect between carrier and antibiotics, a potential approach to overcome the bacterial resistance to antibiotics. PMID- 30481705 TI - Leaching of indium from end-of-life LCD panels via catalysis by synergistic microbial communities. AB - Currently, a large amount of discarded liquid crystal displays (LCDs) are being produced, and the improper treatment of discarded LCDs causes serious environmental pollution problems. Indium is the most valuable metal in LCDs and is present in such devices at a concentration of over 0.025%. In this study, the bioleaching of indium from end-of-life LCD panels was comprehensively investigated through three methods: S-mediated pathway, Fe-mediated pathway and Mixed pathway of S- and Fe-mediated, which yielded maximum bioleaching efficiencies of approximately 100%, 0% and 78%, respectively. Microbial community analysis showed that the dominant functional bacteria under the S-mediated pathway were Acidithiobacillus. The Acidithiobacillus genus catalysed the leaching of indium, which was mainly achieved by indirect bioleaching. In addition, the microorganisms can secrete enzymes and extracellular polymeric substances, which also contributed to the leaching of indium. Therefore, this work provides an economical and efficient biological method for future research and practical applications in indium recovery from solid waste. PMID- 30481706 TI - Inactivation of airborne bacteria using different UV sources: Performance modeling, energy utilization, and endotoxin degradation. AB - Airborne bacteria-containing bioaerosols have attracted increased research attention on account of their adverse effects on human health. Ultraviolet germicidal irradiation (UVGI) is an effective method to inactivate airborne microorganisms. The present study models and compares the inactivation performance of three UV sources in the UVGI for aerosolized Escherichia coli. Inactivation efficiency of 0.5, 2.2 and 3.1 logarithmic order was obtained at an exposure UV dose of 370 J/m3 under UVA (365 nm), UVC (254 nm) and UVD (185 nm) sources, respectively. A Beer-Lambert law-based model was developed and validated to compare the inactivation performances of the UV sources, and modeling enabled prediction of inactivation efficiency and analysis of the sensitivity of several parameters. Low influent E. coli concentrations and high UV doses resulted in high energy consumption (EC). The change in airborne endotoxin concentration during UV inactivation was analyzed, and UVC and UVA irradiation showed no marked effect on endotoxin degradation. By contrast, both free and bound endotoxins could be removed by UVD treatment, which is attributed to the ozone generated by the UVD source. The results of this study can provide a better understanding of the air disinfection and airborne endotoxin removal processes. PMID- 30481707 TI - Adsorption of bisphenol A on dispersed carbon nanotubes: Role of different dispersing agents. AB - Although the adsorption of organic contaminants on carbon nanotubes (CNTs) and the dispersion of CNTs have been extensively investigated separately, the adsorption behavior of organic contaminants on dispersed CNTs, which may be a missing link to understanding their environmental behavior and risks, remain unclear yet rarely studied. In this study, the effect of the dispersing agent structure on the adsorption characteristics of BPA (a representative organic contaminant) on dispersed CNTs were investigated using tannic acid (TA), sodium dodecylbenzenesulfonate (SDBS), and gallic acid (GA) as model dispersing agents. Our results showed that at low dispersing agent concentrations, adsorption of TA could lead to higher CNT suspension than adsorption of SDBS and GA due to greater steric hindrance. However, the presence of TA reduced the adsorption of BPA due to strong competitive adsorption on dispersed CNTs. At high concentrations of TA, the suspension of CNTs was reduced by the "bridging effect," in which adjacent dispersed CNTs form hydrogen bonds and re-aggregate. However, the adsorption of BPA dramatically increased due to the enhanced partition of BPA into pseudomicelles of TA on dispersed CNTs, as indicated by the significantly increased index of heterogeneity at high TA concentration. Transmission electron microscopy images confirmed the formation of TA pseudomicelles. This study highlights the key role of the dispersing agent structure on CNT dispersion and adsorption of organic contaminants. The high mobility and transport of CNT adsorbed contaminants may lead to higher environmental risks compared with aggregated CNTs. PMID- 30481708 TI - Effects of 7 years experimental warming on soil bacterial and fungal community structure in the Northern Tibet alpine meadow at three elevations. AB - A warming experiment was established along an altitudinal gradient (low elevation: 4313 m, mid-elevation: 4513 m and high elevation: 4693 m) in alpine meadows of the Northern Tibet to investigate the effects of warming on soil bacterial and fungal community structure. Elevation had significant effects on vegetation community coverage (CC), soil temperature (Ts) and pH, but not soil fungal diversity. Soil bacterial diversity at the high elevation was significantly lower than that at the low and mid-elevations, whereas there was no significant difference of soil bacterial diversity between the low and mid elevations. After seven years of warming, soil fungal diversity was significantly increased at the mid-elevation but not the low and high elevations, and soil bacterial diversity was not significantly altered at the low, mid- and high elevations. Soil bacterial community structure was significantly altered at the low and mid-elevations but not the high elevation. Soil fungal community structure was significantly altered at all the three elevations. CC, Ts and pH significantly explained 20.55%, 5.30% and 12.61% of the variation of bacterial community structure, respectively. CC and Ts significantly explained 17.40% and 5.86% of the variation of fungal community structure, respectively. Therefore, responses of soil microbial community structure to warming may vary with elevation, which was mainly attributed to different vegetation coverage, soil temperature and/or pH conditions among the three elevations in this study alpine meadows. PMID- 30481709 TI - Allelopathic effects of harmful algal extracts and exudates on biofilms on leaves of Vallisneria natans. AB - This study investigated the allelopathic effects of Microcystis aeruginosa (M. aeruginosa) extracts and exudates on the physiological responses, photosynthetic activity, and microbial structure of biofilms on leaves of Vallisneria natans (V. natans). By measuring physiological and photosynthetic indices, the results showed that M. aeruginosa allelochemicals inhibited photosynthesis, oxidative stress and antioxidant system stress response in the biofilms of V. natans leaves. Multifractal analysis found that the surface topography of V. natans leaves was altered due to the allelochemicals found in M. aeruginosa. Microbial diversity on the leaves was analyzed using high-throughput sequencing, and the results showed that M. aeruginosa exudates had a stronger effects on the microbial community structure of biofilms compared to extracts. These findings highlight how cyanobacterial allelochemicals induce negative effects on submerged macrophytes. PMID- 30481710 TI - Microbial life beyond the grave: 16S rRNA gene-based metagenomic analysis of bacteria diversity and their functional profiles in cemetery environments. AB - Recent studies have identified cemeteries as potential environmental reservoirs of multi-drug resistant pathogenic bacteria that could contaminate groundwater sources posing public health threats. However, these findings were based on the identification of culturable bacteria and at times not below burial grounds. Investigation on the bacterial diversity and functional profiles of bacterial communities above and below burial grounds in human cemeteries are few. The current study used high-throughput sequencing techniques to determine the bacterial composition and their associated functional profiles in cemetery soil samples collected at the surface and below burial ground in two South African cemeteries (Maitland Cemetery in Cape Town and Fontein Street Cemetery in Middelburg) to evaluate the potential health threat to surrounding populations through contamination of groundwater. Significant differences were observed between sample depths with the clustering of the surface (0 m) and the 2 m samples into separate groups. Pseudomonas and Corynebacterium were the most abundant genera across all samples. Pseudomonas and Rhodococcus were the dominant genera in the 2 m samples while Prauserella and Staphylococcus were dominant in the surface samples. The 2 m samples showed a lower alpha diversity but recorded higher proportions of human diseases functional classes compared to the surface samples. Human disease functional profiles revealed involvement, in infectious (cholera), neurodegenerative (Alzheimer's disease) cardiovascular (hypertrophic cardiomyopathy) immune system (Systemic lupus erythematosus) metabolic (Type I & II diabetes) diseases and cancer. Antibiotic resistance and antibiotics synthesis signatures were also identified. Thus, cemeteries could be potential sources of microbial and antibiotic pollution in groundwater, especially in areas with shallow water tables such as Maitland. Selection of sites for use as cemeteries should, therefore, require a proper understanding of the hydrogeological characteristics of the selected site. However, further studies are required to trace the actual movement of these pollutants into groundwater resources. PMID- 30481711 TI - Salino-alkaline lime of anthropogenic origin a reservoir of diverse microbial communities. AB - This paper presents study on the microbiome of a unique extreme environment - saline and alkaline lime, a by-product of soda ash and table salt production in Janikowo, central Poland. High-throughput 16S rDNA amplicon sequencing was used to reveal the structure of bacterial and archaeal communities in the lime samples, taken from repository ponds differing in salinity (2.3-25.5% NaCl). Surprisingly abundant and diverse bacterial communities were discovered in this extreme environment. The most important geochemical drivers of the observed microbial diversity were salinity, calcium ions, nutrients, and water content. The bacterial and archaeal communities in saline, alkaline lime were similar to those found in natural haloalkaline environments. Although the archaeal contribution to the whole microbial community was lower than 4%, the four archaeal genera Natronomonas, Halorubrum, Halobellus, and Halapricum constituted the core microbiome of saline, alkaline lime - a set of OTUs (> 0.1% of total archaeal relative abundance) present in all samples under study. The high proportion of novel, unclassified archaeal and bacterial sequences (not identified at 97% similarity level) in the 16S rRNA gene libraries indicated that potentially new genera, especially within the class of Thermoplasmata inhabit this unique environment. PMID- 30481712 TI - Tracking the historical sewage input in South American subtropical estuarine systems based on faecal sterols and bulk organic matter stable isotopes (delta13C and delta15N). AB - Faecal sterols and stable isotopes (delta13C and delta15N) from bulk organic matter (OM) were analysed in three sedimentary cores collected in two subtropical bays located in the South Atlantic to evaluate historical trends in the sewage input and to track possible changes in the bulk isotopic composition of OM in recent decades. The values of delta13C and delta15N ranged from -27.4 to 25.00/00 and from 0.5 to 3.90/00, respectively, without a clear trend in the variation over the whole period covered by sediment cores and with no conclusive interpretation of a specific range value typically related to the sewage input for these areas. The maximum coprostanol concentration was 0.19 MUg g-1 in the upper 4 cm of one core, which was not considered contaminated by evaluation of the sterols diagnostic ratios. Even at low levels, the coprostanol concentrations followed variations in urban and economical regional development. Baseline values for faecal sterols (in average between 0.03 and 0.05 MUg g-1), which may represent a previous non-impacted environment scenarios, were calculated for use in comparative perspectives for future evaluations of the sewage input and contamination. PMID- 30481713 TI - Effects of elevated carbon dioxide on environmental microbes and its mechanisms: A review. AB - Before the industrial revolution, the atmospheric CO2 concentration was 180-330 ppm; however, fossil-fuel combustion and forest destruction have led to increased atmospheric CO2 concentration. CO2 capture and storage is regarded as a promising strategy to prevent global warming and ocean acidification and to alleviate elevated atmospheric CO2 concentration, but the leakage of CO2 from storage system can lead to rapid acidification of the surrounding circumstance, which might cause negative influence on environmental microbes. The effects of elevated CO2 on microbes have been reported extensively, but the review regarding CO2 affecting different environmental microorganisms has never been done previously. Also, the mechanisms of CO2 affecting environmental microorganisms are usually contributed to the change of pH values, while the direct influences of CO2 on microorganisms were often neglected. This paper aimed to provide a systematic review of elevated CO2 affecting environmental microbes and its mechanisms. Firstly, the influences of elevated CO2 and potential leakage of CO2 from storage sites on community structures and diversity of different surrounding environmental microbes were assessed and compared. Secondly, the adverse impacts of CO2 on microbial growth, cell morphology and membranes, bacterial spores, and microbial metabolism were introduced. Then, based on biochemical principles and knowledge of microbiology and molecular biology, the fundamental mechanisms of the influences of carbon dioxide on environmental microbes were discussed from the aspects of enzyme activity, electron generation and transfer, and key gene and protein expressions. Finally, key questions relevant to the environmental effect of CO2 that need to be answered in the future were addressed. PMID- 30481714 TI - Prenatal exposure to PM2.5 and Congenital Heart Diseases in Taiwan. AB - Gestational exposure to ambient air pollution has been associated with Congenital Heart Diseases (CHDs). However, only a few studies, with inconsistent results, have investigated the effects of PM2.5 exposure during early pregnancy. This study aims to evaluate the association between prenatal exposure to PM2.5 and CHDs occurrence. We selected 782 births reported to have CHDs between 2007 and 2014 from the Taiwanese Birth Registry and randomly selected 4692 controls without any birth defects using a population-based case-control design. Data of exposure to ambient air pollutants, mainly PM2.5, PM10, CO, SO2, NO2, and O3 during weeks 3-8 of pregnancy were retrieved from air quality monitoring stations and interpolated to every township using ordinary kriging. We applied unconditional logistic regression models adjusted for potential confounders to evaluate the associations. The results revealed a positive correlation between increased PM2.5 exposure (adjusted odds ratio [aOR] = 1.21, 95% confidence interval [CI] = 1.03-1.42, per interquartile range change = 13.4 MUg/m3) during early pregnancy and overall CHDs occurrence. Furthermore, we found that atrial septal defect (aOR = 1.43, 95% CI = 1.01-2.02), endocardial cushion defect (aOR = 2.37, 95% CI = 1.01-5.58), and pulmonary artery and valve stenosis (aOR = 1.71, 95% CI = 1.06-2.78) were significantly associated with PM2.5 exposures. No similar effects were observed for the other air pollutants. This study has demonstrated some positive associations between increased PM2.5 exposure during the critical period of cardiac embryogenesis and certain CHDs occurrence. PMID- 30481715 TI - Carbon isotopic signature of interstitial soil gases reveals the potential role of ecosystems in mitigating geogenic greenhouse gas emissions: Case studies from hydrothermal systems in Italy. AB - Volcanic and hydrothermal areas largely contribute to the natural emission of greenhouse gases to the atmosphere, although large uncertainties in estimating their global output still remain. Nevertheless, CO2 and CH4 discharged from hydrothermal fluid reservoirs may support active soil microbial communities. Such secondary processes can control and reduce the flux of these gases to the atmosphere. In order to evaluate the effects deriving from the presence of microbial activity, chemical and carbon (in CO2 and CH4) isotopic composition of interstitial soil gases, as well as diffuse CO2 fluxes, of three hydrothermal systems from Italy were investigated, i.e. (i) Solfatara crater (Campi Flegrei), (ii) Monterotondo Marittimo (Larderello geothermal field) and (iii) Baia di Levante in Vulcano Island (Aeolian Archipelago), where soil CO2 fluxes up to 2400, 1920 and 346 g m-2 day-1 were measured, respectively. Despite the large supply of hydrothermal fluids, 13CO2 enrichments were observed in interstitial soil gases with respect to the fumarolic gas discharges, pointing to the occurrence of autotrophic CO2 fixation processes during the migration of deep sourced fluids towards the soil-air interface. On the other hand, (i) the delta13C-CH4 values (up to ~480/00 vs. V-PDB higher than those measured at the fumarolic emissions) of the interstitial soil gases and (ii) the comparison of the CO2/CH4 ratios between soil gases and fumarolic emissions suggested that the deep-sourced CH4 was partly consumed by methanotrophic activity, as supported by isotope fractionation modeling. These findings confirmed the key role that methanotrophs play in mitigating the release of geogenic greenhouse gases from volcanic and hydrothermal environments. PMID- 30481716 TI - Root microbiome response to treated wastewater irrigation. AB - With increasing fresh water (FW) scarcity, the use of treated wastewater (TWW) for crop irrigation is expanding globally. Besides clear benefits, some undesired long-term effects of irrigation with this low quality water on plant performance have been reported. As the rhizosphere microbiome can mediate plant-soil interactions, an examination of the response of these organisms to TWW is necessary to understand the full effects of water quality. In the current study, the effects of irrigation water quality on the microbial community structure of soil and roots as well as edaphic properties and plant performance were evaluated. We compared soil and roots microbiomes of two different plant species (tomato and lettuce), each grown in two distinct soils, and irrigated with either FW or TWW. Irrigation with TWW significantly increase soil pH, EC, K, Na and DOC, and decrease plant fruit and shoot weight, relatively to samples irrigated with FW. We calculated the effect size of plant species, soil type, and irrigation water quality on microbial community structure in soil and root. In the roots, plant species and irrigation water were the dominant factors in shaping both total (DNA based) and active (RNA based) microbial communities, with both factors contributing similarly to the observed microbial population. Soil type and irrigation water were the dominant factors shaping the total microbial community in the soil and were of similar magnitude. Irrigation water quality is demonstrated to be a major force in shaping root-associated microbiome, leading to altered microbial community structure in the critical juncture between plant and soil. PMID- 30481717 TI - Characterization and comparison of oxidative potential of real-world biodiesel and petroleum diesel particulate matter emitted from a nonroad heavy duty diesel engine. AB - Little is known regarding the oxidative potential of biodiesel particulate matter (PM) relative to diesel PM emitted from heavy duty diesel (HDD) nonroad engines generated in real-world occupational settings. The composition of biodiesel and diesel PM can include transition metals, polar, and nonpolar organic species which can increase oxidative potential via production of reactive oxygen species (ROS). Elevated ROS can lead to oxidative stress and induce antioxidant defense, inflammation, and toxicity. This study characterized the chemical composition of PM (water soluble organic carbon and elemental metals) collected in a real-world occupational setting. ROS production in a human epithelial cell line (BEAS-2B) treated with biodiesel and diesel PM extracts was compared to oxidative potential measured by an acellular dithiothreitol (DTT) assay. The oxidative potential (DTT consumption rate) of diesel PM was 21% greater than biodiesel PM at the highest treatment concentration (60 MUg/mL), yet the ROS generated in vitro were similar between fuel types. Average concentrations of Cu, Cr and Zn were higher in diesel PM compared to biodiesel PM. Additionally, there was a significant correlation between DTT consumption and Cu in diesel PM (r = 0.98), but not B20 PM. There was a strong correlation between WSOC content in diesel PM and ROS generated in vitro (r = 0.83), but no correlation between WSOC content in biodiesel PM and ROS. Taken together, the results indicate the influence of fuel type on the chemical composition and oxidative potential of PM generated by a nonroad HDD engine operated at a recycling center. While acknowledging the potential influence of other species of interest not measured (i.e., quinones), real-world petroleum diesel PM emissions had higher oxidative potential compared to biodiesel PM suggesting that biodiesel use may reduce risk to human health. PMID- 30481718 TI - Improved methane elimination by methane-oxidizing bacteria immobilized on modified oil shale semicoke. AB - Methane is a greenhouse gas with significant global warming potential. The methane-oxidizing bacteria (MOB) immobilized on biocarrier could perform effectively and environmentally in methane elimination. To further improve the efficiencies of MOB immobilization and methane elimination, the surface biocompatibility of biocarrier needs to be improved. In this work, the oil shale semicoke (SC) was chemically modified by sodium p-styrenesulfonate hydrate (SS) and 2-(methacryloyloxy)ethyltrimethylammonium chloride (DMC) to promote surface hydrophilicity and positive charge, respectively. Results revealed that, under methane concentrations of ~10% (v/v) and ~0.5% (v/v), the MOB immobilized on semicoke modified with 1.0 mol L-1 of SS permitted improved methane elimination capacities (ECs), which were 15.02% and 11.11% higher than that on SC, respectively. Additionally, under methane concentrations of ~10% (v/v) and ~0.5% (v/v), the MOB immobilized on semicoke modified with 0.4 mol L-1 of DMC held superior ECs, which were 17.88% and 11.29% higher than that on SC, respectively. The qPCR analysis indicated that the MOB abundance on modified semicoke were higher than that on SC. In consequence, the surface biocompatibility of semicoke could be promoted by SS and DMC modifications, which potentially provided methods for other biocarriers to improve surface biocompatibility. PMID- 30481719 TI - A review of selected microcontaminants and microorganisms in land runoff and tile drainage in treated sludge-amended soils. AB - The objective of this study is to provide a snapshot of the quality of surface runoff and tile drainage in sludge-amended soil in terms of 57 microcontaminants, including pharmaceuticals, hormones and fragrances, and 5 different species of bacteria. It also discusses the main factors affecting their occurrence (soil characteristics, applied sludge load and rate, sludge application method, rain intensity and frequency). It is based on 38 investigations carried out by different research groups in Canada, Australia, the USA and Ireland. The most frequently investigated compounds were hormones, the antiseptics triclosan and triclocarban, the analgesics and anti-inflammatories acetaminophen, ibuprofen and naproxen, the antibiotic sulfamethoxazole, the lipid regulator gemfibrozil and the psychiatric drug carbamazepine. Of all the bacteria, E. coli was the most monitored species. It was found that concentrations of the studied pollutants in surface runoff and tile drainage may vary, depending on many factors. They are generally lower than those observed in the secondary municipal effluent and in surface water, but their contribution to the deterioration of surface water quality might be relevant, mainly in wide rural areas. In this context, the reported data or their ranges represent an attempt to provide reference thresholds and bands of observed concentrations for a rough estimation of the contribution made by the release of the selected pollutants into surface water bodies via surface runoff and tile drainage. PMID- 30481720 TI - A pilot study on the allergen-specific IgE to molecular components on polysensitized mite allergic asthmatic patients in Guangzhou, China. AB - OBJECTIVE: Using multiplex microarray-based component resolved diagnosis (CRD) to investigate the allergen sensitization profile of allergic asthma patients in southern China. METHOD: Serum samples from 57 polysensitized mite allergic asthmatic patients in a tertiary referral centre of southern China were tested with multiplex CRD (ISAC) for specific immunoglobulin E (sIgE) against 112 single allergen and components. Result was then compared with those from singleplex ImmunoCAP. RESULTS: With ISAC, the highest sensitization was seen for nDer f 1 (71.9%), rDer f 2 (73.7%), nDer p 1 (70.2%) and rDer p 2 (66.7%), whereas rDer p 10 and other storage mites' components only showed 10% positivity. rFel d 1 and rCan f 1 were found positive in 29.8% and 14.0% samples respectively. Other epithelia components had less than 7.0% positive rate. Sensitization to pollen components was dominated by nCyn d 1 (17.5%) and nPhl p 4 (12.3%), Carbohydrate cross-reactive determinants (CCD) was positive in 4 patients who were also positive to nPhl p 4, nCyn d 1 and rPla a 2, and all of them have combined asthma and rhinitis. The sensitivity to mold (rAsp f 3), cockroach (nBla g 7) and Anisakis simplex component (rAni s 3) were all the same at 8.8%. 93.0% patients were sensitive to more than one component, with more than half of them (57.9%) positive to five or more components. Patients with combined asthma and rhinitis (AA + AR) were sensitive to more components than those with asthma only (AA). Positive rate to nPhl p 4 was significantly higher in patients with AA + AR than with AA only (chi2 = 4.31, P = 0.038). Compared with ImmunoCAP, ISAC showed a similar high detection rate for D. pteronyssinus and D. farinae, but only 10.0% of B. tropicalis sensitive patients were positive to rBlo t 5. Optimal scale analysis on correlation of allergens components showed rDer p 10 was associated to food allergy. CONCLUSION: Being the first multiplex microarray based CRD study on southern Chinese, ISAC showed house dust mites components were the major allergen components led to sensitization in asthmatic patients. Patients with combined AA + AR were sensitive to more components than those with AA only. Other components with higher positive rate include pollen components nCyn d 1, nPhl P 4 and animal dander components rFel d 1 and rCan f 1. For B. tropicalis, the rBlo t 5 in ISAC may not represent the major Blomia component in southern Chinese patients. PMID- 30481721 TI - Accelerated muscle contractility and decreased muscle steadiness following sauna recovery do not induce greater neuromuscular fatigability during sustained submaximal contractions. AB - Acute whole-body hyperthermia (WBH) increases blood markers concentration of stress, impairs motor drive to exercising muscles, and decreases resistance to neuromuscular fatigability. The functional natural residual consequences of WBH on neuromuscular functions remain unclear. We aimed to investigate the effects of residual WBH on voluntary and electrically induced ankle plantar flexor contractility properties, motor drive transmission (reflexes), muscle torque steadiness, resistance to neuromuscular fatigability, and markers of stress as the body temperature recovers naturally to normothermia. WBH was induced by Finnish sauna bathing in 16 apparently healthy young (24 +/- 4 years) adult men. Motor performance was monitored before and 2 h after the sauna, and immediately after submaximal exercise (120 s at 50% of maximal voluntary contraction). Markers of stress were monitored before and 2 h after the sauna. Finnish sauna exposure induced moderate to severe WBH (rectal temperature, 38.5-39.6 degrees C). At 2 h after the sauna, rectal temperature had recovered to the preheating level (preheating 37.11 +/- 0.33 degrees C versus postheating 37.00 +/- 0.29 degrees C, p > .05). Post-sauna recovery was accompanied by slowed salivary free cortisol diurnal kinetics, whereas noradrenaline, dopamine, and serotonin did not persist into the 2 h recovery after the sauna. Although recovery to normothermia after a sauna led to a greater acceleration of muscle contractility properties and decreased muscle steadiness, sustained isometric submaximal contraction did not provoke greater neuromuscular fatigability. PMID- 30481722 TI - Gradual increase of perturbation load induces a longer retention of locomotor adaptation in children with cerebral palsy. AB - The goal of this study is to determine whether the size and the variability of error have an impact on the retention of locomotor adaptation in children with cerebral palsy (CP). Eleven children with CP, aged 7-16 years old, were recruited to participate in this study. Three types of force perturbations (i.e., abrupt, gradual and noisy loads) were applied to the right leg above the ankle starting from late stance to mid-swing in three test sessions while the subject walked on a treadmill. Spatial-temporal gait parameters were recorded using a custom designed 3D position sensor during treadmill walking. We observed that children with CP adapted to the resistance force perturbation and showed an aftereffect consisting of increased step length after load release. Further, we observed a longer retention of the aftereffect for the condition with a gradual load than that with an abrupt load. Results from this study suggested that the size of error might have an impact on the retention of motor adaptation in children with CP with a longer retention of motor adaptation for the condition with a small size of error than that with a large error. In addition, enhanced variability of error seems facilitate motor learning during treadmill training. Results from this study may be used for the development of force perturbation based training paradigms for improving walking function in children with CP. PMID- 30481723 TI - Epidemiology of meningiomas. A nationwide study of surgically treated tumours on French medico-administrative data. AB - BACKGROUND: To describe the epidemiology of surgically treated meningiomas and compare the results with previously published studies. METHODS: We processed the French medico-administrative national hospital discharge summary database, Programme de Medicalisation des Systemes d'Information (PMSI) using an algorithm combining the type of surgical procedure and codes from the International Classification of Diseases to retrieve appropriate cases of meningiomas operated between 2008 and 2016. RESULTS: This nationwide study found 25,737 cases of operated meningiomas. Global incidence of operated meningiomas equals 4.51, 95%CI[4.46-4.57] for 100 000 person-years and increased over the last 9 years. Benign neoplasms account for 91.3%, neoplasms of uncertain or unknown behaviour for 6.2% and malignant for 2.5%. There is a decrement of female over male ratios as the malignancy potential progresses. Incidence of operated meningiomas was 3 times more frequent in women than men. Mean age at surgery was 57.6 years for women and 59.5 for men. The incidence of meningioma surgery increases with age and is maximal for the 60-64 years category. Only 0.4% of operated patients were under 18 years. Meningioma surgeries of the cranial convexity and the middle skull base are the most common. CONCLUSION: The PMSI database is a reliable and effective source for studying the epidemiology of surgically treated meningiomas, including the precise location of the tumour. Our findings comfort previous studies and are comparatively correlated. This may assert the usefulness of such a database to investigate the patients' outcome after meningioma surgery. PMID- 30481724 TI - What has Iran achieved in under-five mortality in terms of equity and efficiency in the past decades? AB - OBJECTIVE: Iran has made remarkable progress in reducing child mortality over the past few decades. However, this promising profile is mainly average driven, and inequalities are not counted in judgments about the progress. In the present study, we used an achievement index approach to combine average and inequalities to provide a better picture of Iran's achievement in under-five mortality over the last two decades. STUDY DESIGN: The study had a cross-sectional design. METHODS: Data gathered in the two recent national demographic health surveys (DHSs) in 2000 and 2010 were used to conduct the analyses. Accordingly, 45,646 live births covered by DHS 2000 and 10,604 live births covered by DHS 2010 were investigated. An achievement index was constructed by incorporating some extensions to the concentration index, namely by incorporation of the average into the index. RESULTS: The standard concentration index showed that under-five mortality was unequally distributed, hurting the poor, across all provinces and Iran overall in 2000 (concentration index = -0.1311 [standard error {SE} = 0.0139]) and 2010 (-0.1367 [SE = 0.0381]). The achievement index revealed that Iran has had achievements in under-five mortality (relative change in the mean has decreased from 29.5% to 25.8%), but the achievement was mostly due to reductions in the average mortality and not in its unequal distribution. The same result applied to a considerable number of provinces, and only a few have made achievements in both inequality and average. CONCLUSIONS: Considering the lack of progress in the reduction of inequalities in under-five mortality over the past decades, equity-oriented policies should be of prime importance for Iran's healthcare system. PMID- 30481725 TI - Androstadienone, a putative chemosignal of dominance, increases gaze avoidance among men with high social anxiety. AB - Socially anxious individuals show increased sensitivity toward social threat signals, including cues of dominance. This sensitivity may account for the hypervigilance and gaze avoidance commonly reported in individuals with social anxiety. This study examines visual scanning behavior in response to androstadienone (androsta-4,16,-dien-3-one), a putative chemosignal of dominance. We tested whether exposure to androstadienone would increase hypervigilance and gaze avoidance among individuals with high social anxiety. In a double-blind, placebo-controlled, within-subject design, 26 participants with high social anxiety and 26 with low social anxiety were exposed to androstadienone and a control solution on two separate days. On each day, an eye-tracker recorded their spontaneous scanning behavior while they viewed facial images of men depicting dominant and neutral poses. The results indicate that among participants with high social anxiety, androstadienone increased gaze avoidance by reducing the percentage of fixations made to the eye-region and the total amount of time spent gazing at the eye-region of the faces. Participants with low social anxiety did not show this effect. These findings indicate that androstadienone serves as a threatening chemosignal of dominance, further supporting the link between hypersensitivity toward social threat cues and the perpetuation of social anxiety. PMID- 30481726 TI - What and how ... but where does the why fit in? The disconnection between practice and research evidence from the perspective of UK nurses involved in a qualitative study. AB - An emphasis has been placed on evidence during nurse training and practice over recent decades. A qualitative study was undertaken to explore the meaning of and involvement in evidence-based practice for recently qualified general nurses. A purposive sample of 11 general nurses was recruited. Semi-structured interviews were conducted between March-June 2017. All were audio-recorded and transcribed verbatim. Thematic analysis was applied to transcripts. An overarching theme of disconnection between research and evidence and the participants' perceptions of contemporary nursing practice was underpinned by three themes: 1) We should be using it ... but we're not; 2) Leaving research behind at graduation; 3) Research is other people's business. Participants had been exposed to evidence-based practice during their training, but once qualified they appeared to move into a culture where this was not seen as a priority. Nurses on wards were unaware of research taking place locally and had limited contact with research staff in their organisation. Approaches to overcoming the disconnection between research/evidence and practice could include how it is introduced during training, and changes in nursing culture and leadership. This could include placements for student nurses within research teams. PMID- 30481727 TI - Natural anti-obesity agents and their therapeutic role in management of obesity: A future trend perspective. AB - In the present scenario, obesity is a challenging health problem and its prevalence along with comorbidities are on the rise around the world. According to world health organization and organisation for economic co-operation and development epidemiology reports, overweight and obesity are the fifth foremost causes of deaths globally. The increasing rate of obesity is becoming a mammoth problem which enormously affects an individual's quality of life. The conventional therapy of obesity mainly involves synthetic moieties and surgical procedures, which has many harmful side effects and chances of recurrence with severity. Hence, the Present review is a metanalysis of all the available data on the use of the plants with their biological source, active phytochemical constituents and a probable mechanism of action as natural anti-obesity agents. The metanalysis of data during the period of 2000-2018 was performed with the help of scientific data search engine National Center for Biotechnology Information (NCBI/PubMed). This data reveals the need and scope of further research in the development of new natural phytoconstituents for the management of obesity. PMID- 30481729 TI - Ag modified ZnS for photocatalytic water pollutants degradation: Influence of metal loading and preparation method. AB - In this paper, the photocatalytic degradation of organic pollutants was investigated using Ag/ZnS nanoparticles at different noble metal loadings. The photocatalysts were prepared at room temperature by two different methods: photodeposition and chemical reduction. The obtained samples were characterized by Specific surface area measurement, X-ray photoelectron spectroscopy, X-ray Powder diffraction, ultraviolet-visible diffuse reflectance and Raman spectroscopy. The X-ray photoelectron spectroscopy spectra showed that Ag is present on ZnS surface as intermediate state between nanostructured Ag0 and Ag2O. Moreover, the addition of silver caused a significant change of the absorption spectrum of bare ZnS, resulting in higher absorbance in the visible region, due to the Ag surface plasmon band. Methylene blue (MB) was used to evaluate the photocatalytic activity of the prepared samples. The best photocatalytic activity was observed using the sample at 0.1 wt% Ag loading prepared by chemical reduction method. In particular, the almost complete MB degradation was achieved using UV-LEDs as light sources and 6 g L-1 of catalyst dosage. Finally, the optimized photocatalyst was also effective in the degradation of phenol in aqueous solution under UV irradiation. PMID- 30481730 TI - Folding of cytosine-based nucleolipid monolayer by guanine recognition at the air water interface. AB - Monolayers of a cytosine-based nucleolipid (1,2-dipalmitoyl-sn-glycero-3 (cytidine diphosphate) (ammonium salt), CDP-DG) at basic subphase have been prepared at the air-water interface both in absence and presence of guanine. The formation of the complementary base pairing is demonstrated by combining surface experimental techniques, i.e., surface pressure (pi)-area (A), Brewster angle microscopy (BAM), infrared spectroscopy (PM-IRRAS) and computer simulations. A folding of the cytosine-based nucleolipid molecules forming monolayer at the air water interface occurs during the guanine recognition as absorbate host and is kept during several compression-expansion processes under set experimental conditions. The specificity between nitrogenous bases has been also registered. Finally, mixed monolayers of CDP-DG and a phospholipid (1,2-dimyristoyl-sn glycero-3-phosphate (sodium salt), DMPA) has been studied and a molecular segregation of the DMPA molecules has been inferred by the additivity rule. PMID- 30481731 TI - Left atrial appendage segmentation from 3D CCTA images for occluder placement procedure. AB - BACKGROUND: Percutaneous left atrial appendage (LAA) closure (placement of an occluder to close the appendage) is a novel procedure for stroke prevention in patients suffering from atrial fibrillation. The closure procedure planning requires accurate LAA measurements which can be obtained from computed tomography (CT) images. METHOD: We propose a novel semi-automatic LAA segmentation method from 3D coronary CT angiography (CCTA) images. The method segments the LAA, proposes the location for the occluder placement (a delineation plane between the left atrium and LAA) and calculates measurements needed for closure procedure planning. The method requires only two inputs from the user: a threshold value and a single seed point inside the LAA. Proposed location of the delineation plane can be intuitively corrected if necessary. Measurements are calculated from the segmented LAA according to the final delineation plane. RESULTS: Performance of the proposed method is validated on 17 CCTA images, manually segmented by two medical doctors. We achieve the average dice coefficient overlap of 92.52% and 91.63% against the ground truth segmentations. The average dice coefficient overlap between the two ground truth segmentations is 92.66%. Our proposed LAA orifice localization is evaluated against the desired location of the LAA orifice determined by the expert. The average distance between our proposed location and the desired location is 2.51 mm. CONCLUSION: Segmentation results show high correspondence to the ground truth segmentations. The occluder placement method shows high accuracy which indicates potential in clinical procedure planning. PMID- 30481728 TI - Stable integration of the Mrx1-roGFP2 biosensor to monitor dynamic changes of the mycothiol redox potential in Corynebacterium glutamicum. AB - Mycothiol (MSH) functions as major low molecular weight (LMW) thiol in the industrially important Corynebacterium glutamicum. In this study, we genomically integrated an Mrx1-roGFP2 biosensor in C. glutamicum to measure dynamic changes of the MSH redox potential (EMSH) during the growth and under oxidative stress. C. glutamicum maintains a highly reducing intrabacterial EMSH throughout the growth curve with basal EMSH levels of ~- 296 mV. Consistent with its H2O2 resistant phenotype, C. glutamicum responds only weakly to 40 mM H2O2, but is rapidly oxidized by low doses of NaOCl. We further monitored basal EMSH changes and the H2O2 response in various mutants which are compromised in redox-signaling of ROS (OxyR, SigH) and in the antioxidant defense (MSH, Mtr, KatA, Mpx, Tpx). While the probe was constitutively oxidized in the mshC and mtr mutants, a smaller oxidative shift in basal EMSH was observed in the sigH mutant. The catalase KatA was confirmed as major H2O2 detoxification enzyme required for fast biosensor re-equilibration upon return to non-stress conditions. In contrast, the peroxiredoxins Mpx and Tpx had only little impact on EMSH and H2O2 detoxification. Further live imaging experiments using confocal laser scanning microscopy revealed the stable biosensor expression and fluorescence at the single cell level. In conclusion, the stably expressed Mrx1-roGFP2 biosensor was successfully applied to monitor dynamic EMSH changes in C. glutamicum during the growth, under oxidative stress and in different mutants revealing the impact of Mtr and SigH for the basal level EMSH and the role of OxyR and KatA for efficient H2O2 detoxification under oxidative stress. PMID- 30481732 TI - The potential application of an autochthonous fungus from the northwest of Argentina for treatment of sugarcane vinasse. AB - Vinasse is a waste material from distillery industries, which causes major environmental problems around the world. Argentina alone produces about 4 billion liters of vinasse annually; consequently, diverse biological eco-friendly treatments are evaluated for their ability to reduce the detrimental effects. The present study reports on the degradation of a 50% (v/v) local vinasse sample by an autochthonous fungus identified as Aspergillus sp. V1. The Bioprocess was conducted for 15 d at 30 degrees C after inoculation of spores at an end concentration of 1 * 106 CFU/mL. Effluent neutralization was detected after 6 d of treatment, with maximum COD and BOD removal after 12 d (49% and 59%, respectively). Effects of vinasse before and after treatment were predicted using Caco-2 cells and Triticum aestivum L. (wheat) seeds as toxicological indicators. Only 13% viability was observed for Caco-2 cells exposed to untreated vinasse, but this percentage increased more than 3-fold for cells exposed to the treated effluent. While vinasse without treatment completely inhibited germination of seeds, exposure to treated effluent demonstrated a germination percentage of 60%. The present study highlights the use of a dual-purpose biotechnological process that aimed at reducing the detrimental effects of vinasse, enhancing its quality for agricultural practices. PMID- 30481733 TI - Passive in situ biobarrier for treatment of comingled nitramine explosives and perchlorate in groundwater on an active range. AB - Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), octahydro-1,3,5,7-tetranitro 1,3,5,7-tetrazocine (HMX), and perchlorate (ClO4-) are common, and often co mingled, contaminants at military ranges worldwide. This project investigated the feasibility of using a passive emulsified oil biobarrier plus a slow release pH buffering reagent to remediate RDX, HMX, and ClO4- in a low pH aquifer at an active range. A 33 m biobarrier was emplaced perpendicular to the contaminant plumes, and dissolved explosives, perchlorate, and other relevant parameters were monitored. The pH increased and the DO and ORP decreased after emulsified oil injection, leading to >90% reductions in perchlorate, RDX, and HMX compared to upgradient groundwater. Some nitroso breakdown products were observed immediately downstream of the barrier, but generally decreased to below detection limits farther downgradient. First-order rate constants of approximately 0.1/d were obtained for all three contaminants. Dissolved metals (including As) also increased in the wells immediately adjacent to the barrier, but attenuated as the plume re-aerated in downgradient areas. Biobarrier installation and sampling were performed during scheduled range downtime and had no impacts to ongoing range activities. The field trial suggests that an emulsified oil biobarrier with pH buffering can be a viable alternative to remove explosives and perchlorate from shallow groundwater on active ranges. PMID- 30481734 TI - Selective adsorption of uranyl and potentially toxic metal ions at the core-shell MFe2O4-TiO2 (M=Mn, Fe, Zn, Co, or Ni) nanoparticles. AB - Potentially toxic metal ions (Xn+: Rb+, Sr2+, Cr3+, Mn2+, Ni2+, Zn2+, Cd2+) usually coexist with uranyl (UO2+), which will have a great influence on the selective adsorption process. Here, the core-shell MFe2O4-TiO2 (M = Mn, Fe, Zn, Co, or Ni) nanoparticles were synthesized and assessed as new selective adsorbents. The results reveal that TiO2(101) preferentially grows along the MFe2O4(311)/(111) orientation. The M2+ ions as the mediators transfer the holes from MFe2O4 to TiO2, at the conduction bands. On the TiO2(101) surfaces and TiO2(101)-TiO2(101) gaps, the paired active electrons mainly complex with water molecules as hydroxyl radicals to capture Xn+ ions, forming an ion layer to block UO22+ from being adsorbed. Simultaneously, it should be noted that an interesting adsorption pathway was UO22+ being horizontally and irreversibly adsorbed in the MFe2O4(311)/(111)-TiO2(101) interface, and therein, the stable adsorption capacity was found to be 66.78 mg g-1 in the MnFe2O4(311)/(111)-TiO2(101) interface. Finally, a mechanism of hybrid orbitals between MnFe2O4-TiO2 and UO2+ Xn+ was proposed. PMID- 30481735 TI - Removal of phenol and chlorine from wastewater using steam activated biomass soot and tire carbon black. AB - This study aims to demonstrate a novel method for removing toxic chemicals using soot produced from wood and herbaceous biomass pyrolyzed in a drop tube reactor and tire pyrolytic carbon black. The influence of ash content, nanostructure, particle size, and porosity on the filter efficiency of steam activated carbon materials was studied. It has been shown for the first time that steam activated soot and carbon black can remove phenol and chloride with filter efficiencies as high as 95%. The correlation of filter efficiency to material properties showed that the presence of alkali and steam activation time were the key parameters affecting filter efficiencies. This study shows that steam activated biomass soot and tire carbon black are promising alternatives for the cleaning of wastewater. PMID- 30481736 TI - Arthroscopic minimum saucerization and inferior-leaf meniscectomy for a horizontal tear of a complete discoid lateral meniscus: Report of two cases. AB - INTRODUCTION: Treatment of a horizontal tear of a complete discoid lateral meniscus (DLM) is still controversial. Preserving peripheral rim as a normal shape of the meniscus with single-leaf resection is a conventional treatment, however meniscal function could not be fully restored. PRESENTATION OF CASE: A 28 year old woman and a 34-year old woman experienced knee pain and had restricted knee extension. MRI showed horizontal tears of complete DLM in both patients. Arthroscopic minimum saucerization preserving more than 10 mm peripheral rim and inferior-leaf meniscectomy was performed. Two years after the surgery, the patient had no pain and no restriction of ROM. MRI showed the remaining superior leaf maintained about half its width and no progression of coronal/sagittal extrusion. DISCUSSION AND CONCLUSION: As resecting more meniscal tissue has been considered to be a cause of degeneration or extrusion of the meniscus, arthroscopic minimum saucerization, preserving more meniscal tissue than standard saucerization, and inferior-leaf meniscectomy can be an alternative treatment option of horizontal tears of complete DLM with satisfying clinical and radiological results. PMID- 30481737 TI - Appendiceal neurofibroma with low-grade appendiceal mucinous neoplasm in neurofibromatosis type 1 patient: A case report. AB - INTRODUCTION: Neurofibromas are a characteristic of the autosomal dominant disorder Neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease. Appendiceal neurofibromas are extremely rare, and low-grade appendiceal mucinous neoplasms (LAMNs) have not previously been reported in NF1. PRESENTATION OF CASE: A 62-year-old man with NF1 was scheduled for elective surgical treatment of an asymptomatic, enlarged and diffusely thickened appendix that remained after curative antimicrobial treatment of acute appendicitis. Laboratory analysis revealed all normal. Colonoscopy showed thickened appendiceal mucosa projecting into the cecum. A sample of the mucosa was found to be pathologically benign. The patient was preoperatively diagnosed with treated acute appendicitis with chronic appendiceal inflammation versus appendiceal neoplasms. Laparoscopic cecectomy was performed. Multiple neurofibromas were observed in the muscle layer, submucosa, and mucosa of the appendix on histopathological examination. Immunohistochemical examination showed positive staining for S-100. Pathologically, the patient was diagnosed with appendiceal neurofibroma consistent with NF1 with LAMNs. His postoperative course was unremarkable. He was discharged on post-operative day 3 and remained in good health 7 month after surgery. CONCLUSIONS: Appendiceal neurofibromas are often preoperatively diagnosed as appendicitis. Appendiceal neurofibromas should be considered in patients with NF1 who are suspected of having appendicitis. PMID- 30481738 TI - Mesh trimming and suture reconstruction for wound dehiscence after huge abdominal intercostal hernia repair: A case report. AB - INTRODUCTION: Abdominal intercostal hernia repair for huge incisional hernia after thoracoabdominal surgery involves a complex anatomical structure. Hence, it is difficult to apply the laparoscopic approach to large hernias in the lateral upper abdomen. Further the optimal approach to mesh exposure without infection after incisional hernia repair is still controversial. Herein, we describe our experience of repairing a huge abdominal intercostal hernia by mesh trimming and suture reconstruction for wound dehiscence. PRESENTATION OF CASE: A 73-year-old man presented with an incisional hernia in the left flank from just below the eight intercostal space to the transverse umbilical region 6 months after thoracoabdominal aortic aneurysm surgery. Computed tomography revealed an incisional hernia orifice of 17 * 13 cm located on the left flank around the ninth rib. We chose the open approach as treatment because the hernia orifice was large, and we created a mesh placement space in the extraperitoneal cavity and placed expanded polytetrafluoroethylene mesh there with 1-0 nonabsorbable monofilament suture. At postoperative day 26, we observed mesh exposure due to wound dehiscence. Mesh trimming and suture reconstruction for wound dehiscence was performed because there were no signs of wound infection. The postoperative course was uneventful including infection and dehiscence. The patient has been well without recurrence for 14 months since last operation. CONCLUSIONS: Optimal treatment for repair of a large abdominal intercostal hernia with thoracoabdominal location is necessary. Moreover, partial mesh removal may be one of the treatment options for mesh exposure if conditions are met. PMID- 30481739 TI - Using electromagnetic navigation for intraoperative rib fracture localization during rib plating: A case report. AB - INTRODUCTION: The precise localization of fractured ribs represents one of the primary challenges of surgical rib fixation. Computed tomography (CT) provides the facture's general location, but it is difficult to use the imaging alone to properly place a surgical incision. We used electromagnetic navigation to identify the exact location of the fracture on the patient's skin. PRESENTATION OF CASE: A 64-year-old man fell and suffered multiple left-sided nonunion rib fractures (4th to 9th). He was initially treated with a chest tube and analgesia, but he developed chronic pain from the injury. On the CT scan of the chest, the rib fractures were displaced and on exam, the ribs were mobile with reproducible pain and clicks on palpation. We used electromagnetic navigation to determine the fracture's exact location on the skin during the operation, which aided in the location of the incision. The patient had open reduction and internal fixation of the broken ribs using rib plates. The patient had relief from his chronic pain after the surgery. DISCUSSION: The localization of the rib fracture on a patient's skin can be performed using a physical exam, landmarks from the CT scan, or video-assisted thoracic surgery (VATS) procedure. Each of the techniques sacrifices either time or accuracy during the operation. The electromagnetic navigation can provide precise localization of the fracture without sacrificing too much time during the operation. CONCLUSION: The use of electromagnetic navigation to identify the fracture on a patient's skin provides quick and accurate intraoperative localization for surgical rib fixation. PMID- 30481740 TI - Management of malignancy-associated bowel obstruction by cervical esophagostomy and total parenteral nutrition, case series of 2 patients. AB - BACKGROUND: Patients with gastrointestinal or gynecologic malignancy may show disease progression within the abdomen and pelvis causing bowel obstruction in the absence of clinical evidence of disease outside of the peritoneal space. Bowel obstruction eventually results and has a profound effect on quality of life eventually leading to the demise of these patients. METHODS: In order to improve the quality of life and combat the requirement for a nasogastric tube, a combination of total parenteral nutrition (TPN) to allow adequate caloric intake plus cervical esophagostomy to drain intestinal secretions was utilized as a palliative treatment long-term for patients with malignancy-associated bowel obstruction. RESULTS: In 2 patients with appendiceal malignancy no cancer spread outside of the peritoneal space occurred. Unfortunately, total obstruction of the bowel caused unremitting nausea, vomiting, and pain accompanied by an inability to take adequate nutrition by mouth. In these 2 patients TPN long-term was initiated and a cervical esophagostomy tube placed percutaneously. Relief of malnutrition and the symptoms of nausea and vomiting were well treated using this combined approach. Pain management continued as an ongoing problem. CONCLUSIONS: Long-term management of malignancy-associated bowel obstruction is possible with improvement in quality of life using a combination of TPN and a cervical esophagostomy tube. In these two cases the cervical esophagostomy tube was placed with limited adverse events, and adequate drainage of intestinal secretions long term. PMID- 30481741 TI - Generation of human iPSCs from human prostate cancer-associated fibroblasts IBPi002-A. AB - A human induced pluripotent stem cell line was generated from cancer-associated fibroblasts of a 68-years old patient with diagnosed prostate adenocarcinoma (PCa). The fibroblast cell line was reprogrammed with Epi5TM Episomal iPSC Reprogramming Kit. Pluripotency of the derived transgene-free iPS cell line was confirmed both in vitro by detecting expression of factors of pluripotency on a single-cell level, and also in vivo using teratoma formation assay. This new iPS cell line may be used for differentiation into different prostate-specific cell types in differentiation studies. PMID- 30481742 TI - Early Second-Trimester Peptidomic Identification of Serum Peptides for Potential Prediction of Gestational Diabetes Mellitus. AB - BACKGROUND/AIMS: Early screening and diagnosis is important for minimizing gestational adverse outcomes. Routine screening of gestational diabetes mellitus (GDM) at 24-28 weeks with 75 g oral glucose challenge test (OGCT) leaves limited time for intervention and prevention. This study aims to analyze maternal serum peptides in the early second-trimester for prediction of gestational diabetes mellitus (GDM). METHODS: Serum samples were collected from 16-18-week pregnant women that visited Nanjing Maternity and Child Health Care Hospital from April to August 2015. According to gestational outcome with or without GDM in late pregnancy, 200 of serum samples from GDM mothers and controls were randomly divided into two subgroups. Peptidomic identification of serum peptides was performed by combining ultrafiltration and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to investigate the differentially-expressed peptides between two groups. RESULTS: A total of 297 identified peptides, originating from 228 proteins, were significantly differentially expressed in the GDM group compared with control. These precursor proteins may play critical roles in cell death of cortical neurons, elongation of cellular protrusions, and stabilization of microtubules. Major networks identified included those involving lipid metabolism, molecular transport and small molecule biochemistry. CONCLUSION: We provide for the first time a validated peptidome profile of early second trimester serum in normal and GDM mothers, and we investigated the potential serum biomarkers for GDM. We concluded that 297 peptides could serve as potential biomarkers for GDM. PMID- 30481743 TI - PharmaForum. PMID- 30481744 TI - Establishment of a Nomogram by Integrating Molecular Markers and Tumor-Node Metastasis Staging System for Predicting the Prognosis of Hepatocellular Carcinoma. AB - AIMS: This study aimed to develop a valuable nomogram by integrating molecular markers and tumor-node-metastasis (TNM) staging system for predicting the long term outcome of patients with hepatocellular carcinoma (HCC). METHODS: The gene expression profiles of HCC patients undergoing liver resection were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. One hundred and ninety-nine patients from TCGA and 94 patients from GEO were selected to be part of the training cohort and validation cohort respectively. Univariate and multivariate cox analyses were performed to identify genes with independent prognostic values for overall survival (OS) of HCC patients in training cohort. Risk score was calculated based on the coefficients and Z-score of 3 genes for each patient. The nomogram was developed based on the risk score and TNM staging system. Discrimination and predictive accuracy of the nomogram were measured by using the concordance index (C-index) and calibration curve. The efficacy of the nomogram was tested in the external validation cohort. RESULTS: Univariate and multivariate cox analyses revealed that EXT2 (p = 0.035, hazard ratio 13.412), ETV5 (p = 0.010, hazard ratio 4.325), and CHODL (p < 0.001, hazard ratio 6.286) were independent prognostic factors and chosen for further nomogram establishment. The C-index of the nomogram for predicting the OS in the training cohort was superior to that of the TNM staging system (0.77 vs. 0.64, p < 0.01). The calibration curve of predicted 1-, 3-, and 5-year OS showed satisfactory accuracy. The external validation cohort showed good performance of comprehensive nomogram as well. CONCLUSION: The novel nomogram by integrating the molecular markers and TNM staging system has better performance in predicting long-term prognosis in HCC patients than the TNM staging system alone. PMID- 30481745 TI - Pro-Angiogenic Activity of Monocytic-Type Myeloid-Derived Suppressor Cells from Balb/C Mice Infected with Echinococcus Granulosus and the Regulatory Role of miRNAs. AB - BACKGROUND/AIMS: This study aims to predict the pro-angiogenic functions of monocytic-type myeloid-derived suppressor cells (M-MDSCs) derived from mice infected with Echinococcus granulosus. METHODS: M-MDSCs were collected from Balb/c mice infected with E. granulosus and normal mice (control) and cultured in vitro. Human umbilical vein endothelial cells (HUVECs) were stimulated with the cell supernatant, and angiogenesis was investigated and analysed by the Angiogenesis module of the software NIH Image J. RNA was extracted from fresh isolated M-MDSCs and analysed with miRNA microarray; differentially expressed miRNAs and their potential functions were analysed through several bioinformatics tools. Finally, quantitative PCR was used to confirm the results of microarray analysis. RESULTS: M-MDSCs from mice infected with E. granulosus could promote the formation of tubes from HUVECs in vitro. Moreover, vascular endothelial growth factor (VEGF) showed significantly high expression, whereas soluble fms like tyrosine kinase-1 (sFlt-1) showed low expression at the transcriptional level in M-MDSCs from mice infected with E. granulosus. Microarray analysis of miRNAs showed that 28 miRNAs were differentially expressed in M-MDSCs from the two experimental mice groups, and 272 target genes were predicted using the microRNA databases TargetScan, PITA and microRNAorg. These target genes were mainly involved in the biological processes of intracellular protein transport, protein targeting to the lysosome and protein transport, and mainly located in the cytoplasm, neuronal cell body and membrane. Moreover, they were mainly involved in the molecular functions of protein binding, metal ion binding and SH3 domain binding. Further, the differentially expressed miRNAs were mainly enriched in the endocytosis, Wnt and axon guidance pathways, as well as the MAPK, focal adhesion, PI3K-Akt, cAMP, mTOR and TGF-beta signalling pathways, which are linked to immunoregulation and angiogenesis based on the results of bioinformatics analysis with DIANA-miRPath 3.0. In addition, the expression of eight miRNAs was randomly verified by quantitative PCR independently in three mice infected with E. granulosus and three normal mice. CONCLUSION: M-MDSCs have a potential angiogenic role during E. granulosus infection, and miRNAs may play a role in the immune response and angiogenesis functions of M-MDSCs through regulation of the identified signalling pathways. PMID- 30481747 TI - Meetings and Conferences. PMID- 30481746 TI - Tracheal Diameter and Respiratory Outcome in Infants with Congenital Diaphragmatic Hernia Treated by Fetal Endoscopic Tracheal Occlusion. AB - AIM: To evaluate tracheal diameters and their clinical impact in patients with congenital diaphragmatic hernia (CDH) after fetal endoscopic tracheal occlusion (FETO). METHODS: Patients born with CDH between January 2012 and August 2016 were divided into two groups: noFETO and FETO. Tracheal diameters at three levels (T1, carina, and maximum tracheal dilation) on chest X-ray at 1, 3, 6, 12, 24, and 36 months of follow-up, requirements of invasive and noninvasive respiratory support, the incidence of respiratory infections, and results of pulmonary function tests (PFT) were compared. RESULTS: A total of 71 patients with CDH were born in the study period, and there were 34/41 survivors in the no-FETO group (82.9%) and 13/30 in the FETO group (43.3%). The maximum tracheal diameter was significantly greater in the FETO group at all ages. No differences were observed in the diameters at T1 and the carina, in the requirements of invasive and noninvasive respiratory support, and in the incidence respiratory infections. At the PFT (6-12 months), the FETO group presented higher respiratory rates (46.1 +/ 6.2 vs. 36.5 +/- 10.6, p = 0.02). No differences in PFT results were found between the groups after the 1st year of life. CONCLUSIONS: The FETO procedure leads to persistent tracheomegaly. However, the tracheomegaly does not seem to have a significant clinical impact. PMID- 30481748 TI - LncRNA MALAT1 Promotes Cancer Metastasis in Osteosarcoma via Activation of the PI3K-Akt Signaling Pathway. AB - BACKGROUND/AIMS: LncRNAs have been reported to be vital regulators of the progression of osteosarcoma, although the underlying mechanisms are not completely understood. METHODS: The levels of MALAT1 and miR-129-5p expression were measured using qRT-PCR. Cell growth was determined using the CCK-8 and colony formation assays. Cell migration and invasion were detected using the wound healing and Transwell invasion assays, respectively. Tumor growth was determined with a xenograft model. RESULTS: MALAT1 was significantly up-regulated in osteosarcoma tissues compared with adjacent non-tumor soft tissues. Overexpression of MALAT1 promoted osteosarcoma cell proliferation, migration, and invasion in vitro and enhanced tumor growth in a tumor xenograft mouse model. MALAT1 promoted osteosarcoma progression by modulating stem cell-like properties. Moreover, rescue experiment and luciferase reporter assay results indicated that MALAT1 modulates RET expression by sponging miR-129-5p in osteosarcomas. Furthermore, MALAT1 augmented the expression of downstream proteins of the RET Akt pathway. MALAT1 was consistently significantly increased in osteosarcoma tissues and MALAT1 expression was positively correlated with tumor size and metastasis. High expression of MALAT1 was significantly associated with poor outcomes in patients with osteosarcomas. MALAT1 expression was positively related to RET and negatively related to miR-129-5p in osteosarcoma samples and xenograft tumors. MALAT1 functioned as an oncogenic lncRNA in osteosarcomas and was as an independent prognostic indicator. CONCLUSION: Our data revealed for the first time that MALAT1 increases stem cell-like properties by up-regulating RET via sponging miR-129-5p, and thus activates the PI3K-Akt signaling pathway and provides potential therapeutic targets for osteosarcoma treatment. PMID- 30481749 TI - Relationship between Aortic Arch Calcification, Detected by Chest X-Ray, and Renal Resistive Index in Patients with Hypertension

. AB - OBJECTIVE: Aortic arch calcification is a surrogate marker for arterial stiffness and hypertension-related vascular damage. Renal Resistive Index, a renal Doppler ultrasound parameter, is used to assess renal hemodynamics. In this study, the authors aimed to evaluate the relationship between Renal Resistive Index and aortic arch calcification in patients with hypertension. MATERIALS AND METHODS: Patients with hypertension underwent a chest x-ray and renal Doppler ultrasound. They were divided into two groups according to the Renal Resistive Index (Group I: Renal Resistive Index >= 0.70, Group II: Renal Resistive Index < 0.70). Two examiners, blinded to the findings of Renal Resistive Index, reviewed the aortic arch calcification in these patients. Kappa value was detected to be 0.781 and p value < 0.001 was considered significant. RESULTS: The study included 289 hypertensive patients (mean age 63.87 +/- 11.38). In 53.6% (n = 155) of the study subjects, Renal Resistive Index was observed to be 0.70 and above. Patients with Renal Resistive Index >= 70 were older, possessed a more prevalent aortic arch calcification as well as left ventricular hypertrophy. A multiple linear regression analysis was carried out to test if presence of aortic arch calcification significantly predicted Renal Resistive Index. The results of the regression indicated that presence of AAC significantly predicted Renal Resistive Index (beta=0.053, p < 0.001). CONCLUSIONS: A strong, independent relationship was found between aortic arch calcification as seen on chest x-ray and Renal Resistive Index, in patients with hypertension. PMID- 30481750 TI - iTRAQ-Based Differential Proteomic Analysis Reveals the Pathways Associated with Tigecycline Resistance in Acinetobacter baumannii. AB - BACKGROUND/AIMS: Acinetobacter baumannii is an aerobic and Gram-negative bacterial pathogen with high morbidity and mortality. It remains a serious public health problem arising from its multidrug-resistant and extensive antibiotic resistance spectrum. METHODS: In the present study, iTRAQ coupled with 2D LC MS/MS was used to evaluate the proteome in standard Acinetobacter baumannii standard strains and tigecycline-resistant strains. RESULTS: A total of 3639 proteins were identified and 961 proteins were identified to be differentially expressed in tigecycline-resistant Acinetobacter baumannii strains compared to the standard strains. 506 (52.6%) proteins were up-regulated and 455 (47.4%) proteins were down-regulated. Based on the GO enrichment analysis and KEGG pathway analysis, we concluded that most differentially expressed proteins were associated with stress responses, cellular component organization, proteins synthesis, degradation and function. Moreover, beta-lactam resistance, the longevity regulating pathway and other related pathways were also involved in the regulation of tigecycline-resistant Acinetobacter baumannii. The differential expression of key proteins were evaluated by transcript analysis using quantitative RT-PCR. CONCLUSION: These results may provide new insights into the mechanisms of drug resistance in Acinetobacter baumannii. PMID- 30481751 TI - Long Non-Coding RNA Urothelial Carcinoma Associated 1 Promotes Proliferation, Migration and Invasion of Osteosarcoma Cells by Regulating microRNA-182. AB - BACKGROUND/AIMS: Previous studies demonstrated the oncogenic roles of lncRNA UCA1 in osteosarcoma. This study aimed to explore the internal molecular mechanism of UCA1 on promoting osteosarcoma cell proliferation, migration and invasion. METHODS: qRT-PCR was conducted to measure the expression levels of UCA1, miR-182 and TIMP2. Cell transfection was used to change the expression levels of UCA1, miR-182 and TIMP2. Cell viability, migration, invasion and apoptosis were measured using CCK-8 assay, two-chamber migration (invasion) assay and Guava Nexin assay, respectively. The associations between UCA1, miR-182 and iASPP were analyzed by dual luciferase activity assay. The protein expression levels of key factors involved in cell apoptosis, PI3K/AKT/GSK3beta pathway and NF-kappaB pathway, as well as p53, Rb, RECQ family and iASPP were evaluated by western blotting. RESULTS: UCA1 was highly expressed in osteosarcoma MG63 and OS-732 cells. Knockdown of UCA1 inhibited OS-732 cell viability, migration and invasion, but promoted cell apoptosis. miR-182 was up-regulated in OS-732 cells after UCA1 knockdown and participated in the effects of UCA1 on OS-732 cells. TIMP2 was downstream factor of miR-182 and involved in the regulatory roles of miR-182 on OS-732 cell viability, migration, invasion, apoptosis, as well as PI3K/AKT/GSK3beta and NF-kappaB pathways. UCA1 knockdown up-regulated p53, Rb and RECQL5 levels in OS-732 cells, while down-regulated the expression of iASPP. TGF beta or TNF-alpha treatment could enhance the expression of UCA1 in OS-732 cells. CONCLUSION: Our research verified that UCA1 exerted oncogenic roles in osteosarcoma cells by regulating miR-182 and TIMP2, as well as PI3K/AKT/GSK3beta and NF-kappaB pathways. PMID- 30481752 TI - Towards the Quantification of Peggy Babcock: Speech Errors and Their Position within the Word. AB - Sequences of similar (i.e., partially identical) words can be hard to say, as indicated by error frequencies, longer reaction and execution times. This study investigates the role of the location of this partial identity and the accompanying differences, i.e. whether errors are more frequent with mismatches in word onsets (top cop), codas (top tock) or both (pop tot). Number of syllables (tippy ticky) and empty positions (top ta) were also varied. Since the gradient nature of errors can be difficult to determine acoustically, articulatory data were investigated. Articulator movements were recorded using electromagnetic articulography, for up to 9 speakers of American English repeatedly producing 2 word sequences to an accelerating metronome. Most word pairs showed more intrusions and greater variability in coda than in onset position, in contrast to the predominance of onset position errors in corpora from perceptual observation. PMID- 30481753 TI - Maturity Onset Diabetes of the Young due to Glucokinase, HNF1-A, HNF1-B, and HNF4 A Mutations in a Cohort of Turkish Children Diagnosed as Type 1 Diabetes Mellitus. AB - BACKGROUND/AIMS: Maturity onset diabetes of the young (MODY) is a rare condition often misdiagnosed as type 1 diabetes (T1D). The purposes of this study were: to identify any patients followed in a large Turkish cohort as T1D, with an atypical natural history, who may in fact have MODY, and to define the criteria which would indicate patients with likely MODY as early as possible after presentation to allow prompt genetic testing. METHODS: Urinary C-peptide/creatinine ratio (UCPCR) was studied in 152 patients having a diagnosis of T1D for at least 3 years. Those with a UCPCR >=0.2 nmol/mmol were selected for genetic analysis of the Glucokinase (GCK), Hepatocyte nuclear factor 1a (HNF1A), Hepatocyte nuclear factor 4a (HNF4A), and Hepatocyte nuclear factor 1b (HNF1B) genes. This UCPCR cut off was used because of the reported high sensitivity and specificity. Cases were also evaluated using a MODY probability calculator. RESULTS: Twenty-three patients from 152 participants (15.1%) had a UCPCR indicating persistent insulin reserve. The mean age +/- SD of the patients was 13.6 +/- 3.6 years (range 8.30 21.6). Of these 23, two (8.7%) were found to have a mutation, one with HNF4A and one with HNF1B mutation. No mutations were detected in the GCK or HNF1A genes. CONCLUSION: In Turkish children with a diagnosis of T1D but who have persistent insulin reserve 3 years after diagnosis, up to 9% may have a genetic mutation indicating a diagnosis of MODY. PMID- 30481754 TI - The Depistage Cognitif de Quebec: A New Clinician's Tool for Early Recognition of Atypical Dementia. AB - INTRODUCTION: Early recognition of atypical dementia remains challenging partly because of lack of cognitive screening instruments precisely tailored for this purpose. METHODS: We assessed the validity and reliability of the Depistage Cognitif de Quebec (DCQ; www.dcqtest.org), a newly developed cognitive screening test, to detect atypical dementia using a multicenter cohort of 628 participants. Sensitivity and specificity were compared to the Montreal Cognitive Assessment (MoCA). A predictive diagnostic algorithm for atypical dementia was determined using classification tree analysis. RESULTS: The DCQ showed excellent psychometric properties. It was significantly more accurate than the MoCA to detect atypical dementia. All correlations between DCQ indexes and standard neuropsychological measures were significant. A statistical model distinguished typical from atypical dementia with a predictive power of 79%. DISCUSSION: The DCQ is a better tool to detect atypical dementia than standard cognitive screening tests. Expanding the clinician's tool kit with the DCQ could reduce missed/delayed identification of atypical dementia and accelerate therapeutic intervention. PMID- 30481756 TI - Management of dopamine agonist-resistant prolactinoma. AB -
Dopamine agonists are usually very effective in the treatment of prolactinomas. Nonetheless, a subset of individuals does not respond satisfactorily to these agents and this resistance is characterized by failure to achieve normoprolactinaemia and a 30% or more reduction in maximal tumor diameter (in the case of macroprolactinoma) under maximally tolerated doses. Its overall prevalence is 20-30% for bromocriptine (BRC) and around 10% for cabergoline (CAB). The two main predictive factors are male gender and tumor invasiveness. The management of drug-resistant prolactinomas includes several options. Any BRC resistant patient should be switched to CAB which will normalize prolactin in 80% of them. As long as adverse effects do not develop, dose escalation of CAB is reasonable, with the expectation that subsequent dose reduction will be possible. Echocardiographic monitoring is advised in such patients because of the potential association with cardiac valvular fibrosis. Also, maintaining maximal CAB doses at 3.5 mg/week may lead to progressive hormonal control in a significant proportion of patients. Complete resistance to CAB is infrequent. In a study of 122 patients with a macroprolactinoma, only 7 (6%) could not achieve control despite maximal CAB doses for more than 12 months. A large resistant prolactinoma is also an indication for transsphenoidal neurosurgery, aiming at a debulking which may improve postoperative medical control. For patients who harbor aggressive prolactinomas, radiotherapy may be considered. However, normal prolactinemia will eventually occur in only one third of patients after many years. Finally, temozolomide may be a therapeutic option in malignant/aggressive prolactinomas.
. PMID- 30481755 TI - Prognostic Value of the Glasgow Prognostic Score or Modified Glasgow Prognostic Score for Patients with Colorectal Cancer Receiving Various Treatments: a Systematic Review and Meta-Analysis. AB - BACKGROUND/AIMS: Increasing evidence indicates that the systemic inflammatory response plays a vital role in carcinogenesis. The Glasgow Prognostic Score or modified Glasgow Prognostic Score (GPS/mGPS) is a novel inflammatory indicator which consists of CRP and albumin. Here, we performed a meta-analysis to evaluate the prognostic value of the GPS/ mGPS in patients with colorectal cancer (CRC) and to assess its consistency in different CRC therapies. METHODS: The electronic databases PubMed, Embase, Scopus, Web of Science, and Cochrane Library were searched from inception through December 2017 for the association between the GPS/mGPS and clinical outcomes. Study characteristics and prognostic data were extracted from each relevant study. Overall survival (OS) and cancer-specific survival (CSS) were considered the primary outcomes, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. The quality of each study was pooled using the random-effects Mantel-Haenszel model. Finally, subgroup analyses were performed to detect the heterogeneity of different CRC treatments. RESULTS: Thirty-four studies, with a combined total of 8834 patients, were eligible for this meta-analysis. Data on OS and CSS were available in 23 and 22 studies, respectively. By comparing the prognostic values of different levels of the GPS in CRC patients, the summary HRs for OS and CSS were 2.18 (95% CI 1.83-2.60) and 1.82 (95% CI 1.57-2.11), respectively. According to the different tumor stages, the subgroup analyses were stratified by different treatments, including curative or palliative therapy. The results robustly confirmed the prognostic role of the GPS/mGPS. CONCLUSION: Our results suggest that the GPS/mGPS is a novel and effective prognostic indicator for the OS and CSS of patients with CRC. PMID- 30481757 TI - Marital Transitions and Depressive Symptoms among Older Adults: Examining Educational Differences. AB - BACKGROUND: Later decades of the life course have undergone rapid transformations due to demographic changes in ageing societies, such as more frequent occurrences of later-life marital transitions. Adaption to these transitions, even when welcomed, brings novel chances and challenges in negotiating new social roles in old age, which could reinforce preexisting disparities in the acquisition and mastery of resources, social ties, and coping strategies. OBJECTIVES: Because the ability to weather later-life marital transitions may depend on the long arm of education acquired earlier in the life course, the present study aims to identify and track trends in the prevalence of marriage, divorce/separation, and widowhood among sociodemographic subgroups; link the occurrence of those transitions with mental health; and test the influence of educational attainment on these associations. METHODS: We employ an intraindividual, within-person approach to quantify the occurrence of marital transitions and their impact using data from the Health and Retirement Study (n = 22,013; 1992-2010). Measures of transition occurrence, depressive symptoms, and educational attainment were available across up to 10 biennial assessments. RESULTS: Individuals with less than a high school diploma displayed the highest likelihood of losing their significant other through divorce/separation or death. Marital loss was associated with increasing, and marital gain with decreasing, depressive symptoms. Compared to those with less than a high school diploma, individuals with a high school or general equivalency diploma exhibited larger increases in depressive symptoms associated with widowhood, even though their average levels of depressive symptoms were lower in the absence of this transition. CONCLUSIONS: Our findings revealed a predictable educational gradient for the occurrence of marital transitions and later-life mental health. Yet higher, formalized education did not protect the participants from increased depression in the presence of a loss-related transition, which could suggest that the strains of spousal loss may to some degree function as a leveler of the preexisting social inequalities of stratified life courses. We conclude that the benefits conferred by education are not necessarily ubiquitous, and its impact on the adaptation to spousal loss may be more complex and nuanced depending on the range of prior experiences and available coping strategies. PMID- 30481758 TI - Endovascular Treatment of a Dural Arteriovenous Fistula after Cerebral Sinovenous Thrombosis in a Child. AB - BACKGROUND: Dural arteriovenous fistula (DAVF) is rare in children. Development theories postulate a response to cerebral sinovenous thrombosis (CSVT) or to venous hypertension. The symptoms are highly nonspecific and depend on lesion location. Standard treatment of thrombosis is based on antithrombotic therapy, while the main therapy for DAVF is embolization. CASE REPORT: An 8-year-old boy presented with headache was diagnosed with CSVT and treated with anticoagulant. He developed tinnitus, mental confusion, and lowering of consciousness. Magnetic resonance imaging showed a DAVF draining through a single stenotic venous sinus. Successful endovascular treatment was performed with arterial embolization of multiple feeders and stent and balloon sinus angioplasty. CONCLUSION: Risk factors associated with sinus thrombosis must be always investigated; endovascular treatment is safe and reasonable in a clinical deterioration scenario. PMID- 30481759 TI - Comments on the Article 'Beliefs, Endorsement and Application of Homeopathy Disclosed: A Survey among Ambulatory Care Physicians' by Markun et al. PMID- 30481760 TI - A Randomized Controlled Trial of Immediate versus Delayed Umbilical Cord Clamping in Multiple-Birth Infants Born Preterm. AB - BACKGROUND: Delayed cord clamping (DCC) improves placental transfusion and increases blood volume in preterm infants when compared with immediate cord clamping (ICC). However, evidence to support DCC in multiple-birth preterm infants is still lacking. OBJECTIVE: To compare the outcomes of ICC versus DCC in preterm infants of multiple births. STUDY DESIGN: Women with a multiple pregnancy, including twins and triplets with a gestational age of 28-36 weeks, were randomized to receive ICC (23 women and 50 infants) or DCC for 30-60 s (24 and 51 infants). The infants' hematocrit on admission, superior vena cava (SVC) flow measured within 24 h, and hematocrit at 8 weeks of age were compared. The use of uterotonic agents during delivery was not controlled in this study. RESULT: All infants were delivered by cesarean section (CS) except for 2 sets of twins, 1 in each group. Maternal and infant baseline characteristics in both groups were comparable. There were no significant differences between the groups in admission hematocrit, SVC flow measured within 24 h, hematocrit at 8 weeks of age, or any other neonatal outcomes. The incidence of maternal postpartum hemorrhage (PPH) was higher in the DCC group (4.3% in ICC vs. 25% in DCC, p = 0.04). CONCLUSION: DCC for 30-60 s did not improve placental transfusion or increase systemic blood flow in multiple-birth infants born preterm, mostly by CS, when compared with ICC. The finding of a higher PPH rate in the DCC group raises concerns about the maternal safety of this procedure in this patient population. PMID- 30481761 TI - Thymosin-beta4 Mediates Hepatic Stellate Cell Activation by Interfering with CircRNA-0067835/miR-155/FoxO3 Signaling Pathway. AB - BACKGROUND/AIMS: Hepatic stellate cells (HSCs) are the primary cell type responsible for liver fibrosis. Our study proved that thymosin beta 4 (Tbeta4) has anti-fibrogenic effects in HSCs through PI3K/AKT pathway. However, the underlying mechanisms are not fully elucidated. Circular RNAs (circRNAs) play important roles in fine-tuning gene expression and are often deregulated in cancers. However, the expression profile and clinical significance of in liver fibrosis is still unknown. Therefore, we hypothesize that Tbeta4 influences circRNAs in liver fibrosis. METHODS: Circular RNA microarray was conducted to identify Tbeta4-related circRNAs. Pathway analysis and miRNA response elements analysis was conducted to predict the potential roles of differentially expressed circRNAs in liver fibrosis. CCK8 assays and flow cytometric assays were conducted to clarify the role of circRNA in liver fibrosis. Bioinformatics analysis and in vitro experiments were conducted to clarify the mechanism of circRNA-mediated gene regulation in liver fibrosis. RESULTS: A total of 644 differentially expressed circRNAs were identified between the Tbeta4-depleted LX-2 cells and the control LX2 cells. The expression of circRNA-0067835 was significantly increased in the Tbeta4-depleted LX-2 cells compared with control. Knockdown of circRNA 0067835 observably decreased LX-2 cell proliferation by causing G1 arrest and promoting apoptosis. Bioinformatics online programs predicted that circRNA 0067835 acted as miR-155 sponge to regulate FOXO3a expression, which was validated using luciferase reporter assay. CONCLUSION: Our experiments showed that circRNA-0067835 regulated liver fibrosis progression by acting as a sponge of miR-155 to promote FOXO3a expression, indicating that circRNA-0067835 may serve as a potential therapeutic target for patients with liver fibrosis. PMID- 30481763 TI - The Present Status and Future of Barrett's Esophageal Adenocarcinoma in Japan. AB - BACKGROUND: The incidence of esophageal adenocarcinoma in Europe and the United States rapidly increased from the latter half of the 1970s and exceeded that of esophageal squamous cell carcinoma in the latter half of the 1990s, currently accounting for approximately 60% of all esophageal carcinomas. Recently, its incidence has also increased in Japan, raising concerns that it will follow a course similar to that in Europe and the United States. SUMMARY: The incidence of esophageal adenocarcinoma in Japan was about 2% until the 1990s, but in recent years, it has risen to 6.5-7.1%. Causes include the increase in the incidence of obesity due to changes in eating habits with resultant increases in the incidence of hiatal hernia and reflux esophagitis, a decrease in the rate of Helicobacter pylori infection, and the increased interest of physicians in the gastroesophageal junction. The number of gastroesophageal reflux disease patients in Japan rapidly increased from the 1990s, which accordingly increased the number of Barrett's esophageal adenocarcinoma patients from the latter half of the 1990s. Tabulation and analysis of 1,794 reported cases of Barrett's esophageal adenocarcinoma in Japan showed that superficial cancers accounted for 77.6%, and that the concomitant rates of hiatal hernia and reflux esophagitis were high at 87 and 70% respectively. Key Message: The future trend in the incidence of Barrett's esophageal adenocarcinoma in Japan will depend on the increase in the incidence of reflux esophagitis, which is essential for the development of Barrett's esophagus and Barrett's esophageal carcinoma. The obesity rate is lower in Japan than that in Europe and the United States, and the incidence and severity of reflux esophagitis are low. We expect that the incidence of Barrett's esophageal adenocarcinoma in Japan will not rise as high as in Europe and the United States, and will remain below 10%. PMID- 30481762 TI - On the Enigma of the Human Neurenteric Canal. AB - Existence and biomedical relevance of the neurenteric canal, a transient midline structure during early neurulation in the human embryo, have been controversially discussed for more than a century by embryologists and clinicians alike. In this study, the authors address the long-standing enigma by high-resolution histology and three-dimensional reconstruction using new and historic histological sections of 5 human 17- to 21-day-old embryos and of 2 marmoset monkey embryos of the species Callithrix jacchus at corresponding stages. The neurenteric canal presents itself as the classical vertical connection between the amniotic cavity and the yolk sac cavity and is lined (a) craniolaterally by a horseshoe-shaped "hinge of involuting notochordal cells" within Hensen's node and (b) caudally by the receding primitive streak epiblast dorsally and by notochordal plate epithelium ventrally, the latter of which covered the (longitudinal) notochordal canal on its ventral side at the preceding stage. Furthermore, asymmetric parachordal nodal expression in Callithrix and morphological asymmetries within the nodes of the other specimens suggest an early non-cilium-dependent left-right symmetry breaking mode previously postulated for other mammals. We conclude that structure and position of the mammalian neurenteric canal support the notion of its homology with the reptilian blastopore as a whole and with a dorsal segment of the blastopore in amphibia. These new features of the neurenteric canal may further clarify the aetiology of foetal malformations such as junctional neurulation defects, neuroendodermal cysts, and the split notochord syndrome. PMID- 30481765 TI - Patterns of recurrence after resection for pancreatic neuroendocrine tumors: who, when, and where? AB -
Background/Aims Pancreatic Neuroendocrine Tumors (pan-NENs) represent an increasingly common indication for pancreatic resection, but there are few data regarding possible recurrence after surgery. Aim of the study is describing the frequency, timing, and patterns of recurrence after resection for pan-NENs with consequent implications for postoperative follow-up. Methods Retrospective analysis of pan-NEN resected between 1990 and 2015 at The Pancreas Institute, University of Verona Hospital Trust. Predictors of recurrence were assessed. Survival analysis was conducted using Kaplan-Maier and conditional survival (CS) methods. Results The cohort consisted of 487 patients with a median follow-up of 71 months. Recurrence developed in 12.3%: 54 (11.1%) liver metastases, 11 (2.3%) local recurrence, 10 (2.1%) nodal recurrence, and 8 (1.6%) metastases in other organs. Thirty-one (6.4%) died due to disease recurrence. Size >21 mm, G3 grade, nodal metastasis, and vascular infiltration were independent predictors of overall recurrence. Recurrence occurred either during the first year of follow-up (n= 9), or after ten years (n= 4). CS analysis revealed that non-functioning G1 pan-NEN <=20mm without nodal metastasis or vascular invasion, had a negligible risk of developing recurrence. In the present series, after 5 years of follow-up without developing recurrence, tumor recurrence occurred only in the form of liver metastases. Conclusions Recurrence of pan-NENs is rare and is predicted by tumor size, nodal metastasis, grading, and vascular invasion. Patients with G1 pan-NEN without nodal metastasis and vascular invasion may be considered cured by surgery. After 5 years without recurrence, follow-up should focus on excluding the development of liver metastases.
. PMID- 30481764 TI - Prediction of Complications in Radical Prostatectomy Prostate Cancer Patients: Simulated Annealing versus Co-Morbidity Indexes. AB - BACKGROUND: The Deyo/Charlson co-morbidity index (CCI) and Klabunde co-morbidity index (KCI) co-morbidity indexes represent outdated indexes when the endpoint of complications after radical prostatectomy (RP) is considered. A novel group of co morbidities derived from International Classification of Diseases-9 diagnostic codes in a contemporary RP database could provide better accuracy. Research Design, Subjects and Measures: We relied on 20,484 patients with clinically localized non-metastatic prostate cancer treated with RP between 2000 and 2009 in the Surveillance, Epidemiology, and End Results-Medicare linked database. We examined 2 endpoints, namely, 90-day medical complication rate and 90-day surgical complication rate after RP. Simulated annealing (SA) was used to develop a novel co-morbidity index. Finally, the newly identified groups of co-morbid conditions were compared with the CCI and Klabunde indexes. RESULTS: Our SA identified 10 and 7 individual co-morbid conditions able to predict 90-day medical and surgical complications respectively. This novel model showed improved predictive accuracy over CCI and KCI for the 2 endpoints considered (respectively: 59.4 vs. 58.1 and 58.0% for medical complications, 58.0 vs. 56.8 and 56.7% for surgical complications). CONCLUSIONS: The newly defined groupings of co-morbid conditions resulted in better ability to predict the 2 endpoints of interest compared to CCI and KCI. However, the gain was marginal. This implies that better tools should be defined to more accurately predict these outcomes. PMID- 30481767 TI - PharmaForum Teva. PMID- 30481766 TI - Long Non-Coding RNA XLOC_006753 Promotes the Development of Multidrug Resistance in Gastric Cancer Cells Through the PI3K/AKT/mTOR Signaling Pathway. AB - BACKGROUND/AIMS: The development of multidrug resistance (MDR), which results in disease recurrence and metastasis, is a crucial obstacle to successful chemotherapy for patients with gastric cancer (GC). Long non-coding RNAs (lncRNAs) have been found to play various roles in cancer. This study aimed to investigate the effect of XLOC_006753 on the development of MDR in GC cells. METHODS: The expression levels of XLOC_006753 in GC patients and MDR GC cell lines (SGC-7901/5-FU and SGC-7901/DDP cell line) were assessed by qRT-PCR. Statistical analyses were conducted to determine the relationship between XLOC_006753 expression and clinical features and to assess the prognostic value of XLOC_006753 for overall survival and progression-free survival. Then, a CCK-8 assay was used to detect cell proliferation ability and chemosensitivity. Flow cytometry was used to detect cell cycle and cell apoptosis. A wound-healing assay and transwell assay were used to detect cell migration. The expression of markers for MDR, G1/S transition, epithelial-mesenchymal transition (EMT) and PI3K/ AKT/mTOR signaling pathway were examined by western blot. RESULTS: XLOC_006753 was highly expressed in GC patients and MDR GC cell lines (SGC-7901/5-FU and SGC 7901/DDP cell lines), and its high expression was positively associated with metastasis, TNM stage, tumor size, and poor survival in GC patients. Moreover, XLOC_006753 was an independent prognostic biomarker of overall survival and progression-free survival for gastric cancer patients. Knocking down XLOC_006753 in the two MDR GC cell lines significantly inhibited cell proliferation, cell viability, cell cycle G1/S transition, and migration. XLOC_006753 knockdown also promoted apoptosis. Furthermore, western blots showed that XLOC_006753 knockdown decreased some markers of MDR, G1/S transition, and EMT expression, while increasing caspase9 expression and inhibiting the PI3K/AKT/mTOR signaling pathway in SGC-7901/5-FU and SGC-7901/DDP cells. CONCLUSION: High expression of XLOC_006753 promoted the development of MDR, which was activated by the PI3K/AKT/mTOR pathway in GC cells. PMID- 30481768 TI - EFHB is a Novel Cytosolic Ca2+ Sensor That Modulates STIM1-SARAF Interaction. AB - BACKGROUND/AIMS: STIM1 and Orai1 are the key components of store-operated Ca2+ entry (SOCE). Among the proteins involved in the regulation of SOCE, SARAF prevents spontaneous activation of SOCE and modulates STIM1 function. METHODS: Cytosolic Ca2+ mobilization was estimated in fura-2-loaded cells using an epifluorescence inverted microscope. STIM1 interaction with Orai1, EFHB (EF-hand domain family member B, also known as CFAP21) and SARAF was detected by immunoprecipitation followed by Western blotting using specific antibodies. The involvement of EFHB in the translocation of NFAT to the nucleus was detected by confocal microscopy. RESULTS: Here, we report the identification of EFHB as a new SOCE regulator. EFHB interacts with STIM1 upon store depletion and dissociates through a Ca2+-dependent mechanism. RNAi-mediated silencing as well as overexpression studies revealed that EFHB plays a relevant role in the interaction of STIM1 and Orai1 upon store depletion, the activation of SOCE and NFAT translocation from the cytosol to the nucleus. Silencing EFHB expression abolished the dissociation of SARAF from STIM1, which indicates that EFHB might play an important role in the dynamic interaction between both proteins, which is relevant for the activation of Orai1 channels upon Ca2+ store depletion and their subsequent modulation via slow Ca2+-dependent inactivation. CONCLUSION: Our results indicate that EFHB is a new SOCE regulator that modulates STIM1-SARAF interaction. PMID- 30481769 TI - Platelet-Neutrophil Interactions Are Lower in Cord Blood of Premature Newborns. AB - OBJECTIVE: To quantify platelet-neutrophil interaction by flow cytometry, in newborn cord blood, as a function of gestational age. RATIONALE: Little is known about platelet function markers in the newborn, and developmental variations in these markers are not well described. METHODS: Cord blood samples were obtained from 64 newborns between 23 and 40 weeks' gestation. The neonates were grouped into three categories: preterm (< 34 weeks' gestation, n = 21), late preterm (34 to < 37 weeks' gestation, n = 22), and term (>=37 weeks' gestation, n = 21). We monitored the expression of P-selectin and the formation of platelet-neutrophil aggregates (PNAs) by flow cytometry while using adenosine 5'-diphosphate (ADP) or thrombin receptor-activating peptide (TRAP) as agonists. RESULTS: PNAs were significantly lower in preterm compared to term neonates after TRAP or ADP stimulations (11.5 +/- 5.2% vs. 19.9 +/- 9.1%, p < 0.001, or 24.0 +/- 10.1% vs. 39.1 +/- 18.2%, p = 0.008, respectively). The expression of P-selectin also tended to be lower in preterm neonates, with significant positive correlations between P-selectin expression and PNA formation. CONCLUSIONS: The potential formation of PNAs correlates with gestational age. This suggests that the development of functional competencies of platelets and neutrophils continues throughout gestation, progressively enabling interactions between them. PMID- 30481770 TI - Comparative Study of Robot-Assisted versus Conventional Frame-Based Deep Brain Stimulation Stereotactic Neurosurgery. AB - BACKGROUND/AIMS: Technological advancements had a serious impact on the evolution of robotic systems in stereotactic neurosurgery over the last three decades and may turn robot-assisted stereotactic neurosurgery into a sophisticated alternative to purely mechanical guiding devices. OBJECTIVES: To compare robot assisted and conventional frame-based deep brain stimulation (DBS) surgery with regard to accuracy, precision, reliability, duration of surgery, intraoperative imaging quality, safety and maintenance using a standardized setup. METHODS: Retrospective evaluation of 80 consecutive patients was performed who underwent DBS surgery using either a frame-based mechanical stereotactic guiding device (n = 40) or a stereotactic robot (ROSA Brain, MedTech, Montpellier, France) (n = 40). RESULTS: The mean accuracy of robot-assisted and conventional lead implantation was 0.76 mm (SD: 0.37 mm, range: 0.17-1.52 mm) and 1.11 mm (SD: 0.59 mm, range: 0.10-2.90 mm), respectively. We observed a statistically significant difference in accuracy (p < 0.001) when comparing lateral deviations between both modalities. Furthermore, a statistical significance was observed when investigating the proportion of values exceeding 2.00 mm between both groups (p = 0.013). In 8.75% (n = 7) of conventionally implanted leads, lateral deviations were greater than 2.0 mm. With a maximum value of 1.52 mm, this threshold was never reached during robot-guided DBS. The mean duration of DBS surgery could be reduced significantly (p < 0.001) when comparing robot-guided DBS (mean: 325.1 +/ 81.6 min) to conventional lead implantation (mean: 394.8 +/- 66.6 min). CONCLUSIONS: Robot-assisted DBS was shown to be superior to conventional lead implantation with respect to accuracy, precision and operation time. Improved quality control, continuous intraoperative monitoring and less manual adjustment likely contribute to the robotic system's reliability allowing high accuracy during lead implantation despite limited experience. Hence, robot-assisted lead implantation can be considered an appropriate and reliable alternative to purely mechanical devices. PMID- 30481771 TI - Risk Factors for Ureteral Damage in Ureteroscopic stone Treatment: Results of the German Prospective Multicentre Benchmarks of Ureterorenoscopic Stone Treatment Results in Terms of Complications, Quality of Life, and Stone-Free Rates Project. AB - BACKGROUND: The Post-Ureteroscopic Lesion Scale (PULS) is a validated, standardised scale that classifies iatrogenic ureteral lesions during ureteroscopy (URS). OBJECTIVE: To determine risk factors for the various PULS grades caused by URS. METHOD: We prospectively investigated the independent influence of various risk factors in correlation with PULS-Grade 1+ and 2+ on 307 patients with ureterorenoscopic stone treatment from 14 German urologic departments. RESULTS: The following are the outcomes of the study: 117 (38.4%) and 188 (61.6%) of the calculi (median stone size 6 mm) were found in the kidney or ureter; 70% and 82.4% underwent preoperative or postoperative ureteral stenting; 44.3 and 7.2% received laser or ballistic lithotripsy; 60% of the patients presented with PULS grade 1+ and 8% with PULS grade of 2+. Only intracorporal lithotripsy revealed a significant independent risk factor for PULS grade 1+ or 2+. Both laser and ballistic therapies raised the probability of PULS grade 1+ by the factors 3.6 (p < 0.001) and 3.9 (p = 0.021), respectively. The ORs in conjunction with PULS grade 2+ were 3.1 (p = 0.038) and 5.8 (p = 0.014) respectively. Neither endpoint exhibited a significant difference regarding the lithotripsic procedure (laser vs. ballistic). CONCLUSION: Intracorporal lithotripsy is associated with a significant increase in damage to the ureter; further research is needed to determine its long-term effects. PMID- 30481773 TI - Editorial Board / Contents / Imprint. PMID- 30481772 TI - DiODe: Directional Orientation Detection of Segmented Deep Brain Stimulation Leads: A Sequential Algorithm Based on CT Imaging. AB - BACKGROUND: Directional deep brain stimulation (DBS) allows steering the stimulation in an axial direction which offers greater flexibility in programming. However, accurate anatomical visualization of the lead orientation is required for interpreting the observed stimulation effects and to guide programming. OBJECTIVES: In this study we aimed to develop and test an accurate and robust algorithm for determining the orientation of segmented electrodes based on standard postoperative CT imaging used in DBS. METHODS: Orientation angles of directional leads (CartesiaTM; Boston Scientific, Marlborough, MA, USA) were determined using CT imaging. Therefore, a sequential algorithm was developed that quantitatively compares the similarity of the observed CT artifacts with calculated artifact patterns based on the lead's orientation marker and a geometric model of the segmented electrodes. Measurements of seven ground truth phantoms and three leads with 60 different configurations of lead implantation and orientation angles were analyzed for validation. RESULTS: The accuracy of the determined electrode orientation angles was -0.6 +/- 1.5 degrees (range: -5.4 to 4.2 degrees ). This accuracy proved to be sufficiently high to resolve even subtle differences between individual leads. CONCLUSIONS: The presented algorithm is user independent and provides highly accurate results for the orientation of the segmented electrodes for all angular constellations that typically occur in clinical cases. PMID- 30481774 TI - Symptoms and Vocal Risk Factors in Individuals with High and Low Anxiety. AB - AIMS: To assess the frequency of vocal symptoms and risk factors in individuals with high and low anxiety and to investigate the relationships among vocal symptoms, risk factors, and anxiety levels. PATIENTS AND METHODS: A total of 201 patients of both sexes with a mean age of 42.88 years (SD = 15.78) served as participants. The patients were divided into two groups according to the level of trait anxiety: a low-anxiety group (n = 108) and a high-anxiety group (HAG, n = 93). Data were collected using three self-assessment instruments: the Vocal Screening Protocol, the Voice Symptom Scale (VoiSS), and the State-Trait Anxiety Inventory (STAI). RESULTS: The HAG presented higher scores in all VoiSS domains. There were positive correlations between the total and emotional scores on the VoiSS and the STAI Trait subscale. There were significant associations between 13 vocal risk factors and anxiety levels. CONCLUSION: Individuals with high anxiety present a higher frequency of vocal symptoms related to either vocal limitation, physical aspects, or the emotional impact of dysphonia. The higher the trait anxiety, the greater the total and emotional scores on the VoiSS. Anxiety levels are associated with certain vocal risk factors. PMID- 30481775 TI - Targeting Voltage-Dependent Calcium Channels with Pregabalin Exerts a Direct Neuroprotective Effect in an Animal Model of Multiple Sclerosis. AB - BACKGROUND/AIMS: Multiple sclerosis (MS) is a prototypical autoimmune central nervous system (CNS) disease. Particularly progressive forms of MS (PMS) show significant neuroaxonal damage as consequence of demyelination and neuronal hyperexcitation. Immuno-modulatory treatment strategies are beneficial in relapsing MS (RMS), but mostly fail in PMS. Pregabalin (Lyrica(r)) is prescribed to MS patients to treat neuropathic pain. Mechanistically, it targets voltage dependent Ca2+ channels and reduces harmful neuronal hyperexcitation in mouse epilepsy models. Studies suggest that GABA analogues like pregabalin exert neuroprotective effects in animal models of ischemia and trauma. METHODS: We tested the impact of pregabalin in a mouse model of MS (experimental autoimmune encephalomyelitis, EAE) and performed histological and immunological evaluations as well as intravital two-photon-microscopy of brainstem EAE lesions. RESULTS: Both prophylactic and therapeutic treatments ameliorated the clinical symptoms of EAE and reduced immune cell infiltration into the CNS. On neuronal level, pregabalin reduced long-term potentiation in hippocampal brain slices indicating an impact on mechanisms of learning and memory. In contrast, T cells, microglia and brain endothelial cells were unaffected by pregabalin. However, we found a direct impact of pregabalin on neurons during CNS inflammation as it reversed the pathological elevation of neuronal intracellular Ca2+ levels in EAE lesions. CONCLUSION: The presented data suggest that pregabalin primarily acts on neuronal Ca2+ channel trafficking thereby reducing Ca2+-mediated cytotoxicity and neuronal damage in an animal model of MS. Future clinical trials need to assess the benefit for neuronal survival by expanding the indication for pregabalin administration to MS patients in further disease phases. PMID- 30481776 TI - A Heterozygous Missense hERG Mutation Associated with Early Repolarization Syndrome. AB - BACKGROUND/AIMS: Early repolarization syndrome (ERS) has been recently recognized as early repolarization pattern with idiopathic ventricular fibrillation. However, the genetic background of ERS has not been fully understood. METHODS: A Chinese family with sudden cardiac death associated with ERS was investigated. Direct sequencing of ERS susceptibility genes was performed on the proband and family members. Whole-cell patch-clamp methods were used to characterize the mutant channel expressed in HEK 293 cells. RESULTS: One missense mutation (p. K801T) was found in the hERG (KCNH2 gene) by the direct sequencing of candidate genes. Whole cell voltage clamp studies of the K801T mutation in HEK 293 cells demonstrated a 1.5-fold increase in maximum steady state current (37.2+/-7.3 vs 20.3+/-4.4 pA/pF) that occurred at a 20 mV more positive potential compared to the wild type channels. The voltage dependence of inactivation was significantly shifted in the positive voltage direction (WT -59.5+/-1.4 vs K801T -44.3+/-1.2 mV). Kinetic analysis revealed slower inactivation rates of K801T, but faster rates of activation and deactivation. The hERG channel blockers tested inhibited K801T-hERG channel in concentration response, and the potencies of these drugs can be rank-ordered as follows: quinidine> disopyramide> sotalol> flecainide. CONCLUSION: Our study indicated that the K801T mutation caused the gain of function of hERG channels that may account for the clinical phenotype of ERS. Quinidine and disopyramide could improve the function of K801T-hERG mutant channel, and may be therapeutic options for patients with the K801T hERG mutation. PMID- 30481777 TI - Skeletal Morbidity in Children and Adolescents during and following Cancer Therapy. AB - Skeletal abnormalities are common in children and adolescents diagnosed and treated for a malignancy. The spectrum ranges from mild pain to debilitating osteonecrosis and fractures. In this review, we summarize the impact of cancer therapy on the developing skeleton, provide an update on therapeutic strategies for prevention and treatment, and discuss the most recent advances in musculoskeletal research. Early recognition of skeletal abnormalities and strategies to optimize bone health are essential to prevent long-term skeletal sequelae and diminished quality of life in childhood cancer survivors. PMID- 30481778 TI - Contents Vol. 41, 2018. PMID- 30481779 TI - Galangin Alleviates Liver Ischemia-Reperfusion Injury in a Rat Model by Mediating the PI3K/AKT Pathway. AB - BACKGROUND/AIMS: Liver ischemia-reperfusion (I/R) injury is a pathological process that often occurs during liver and trauma surgery. There are numerous causes of liver I/R injury, but the mechanism is unknown. Galangin (GA) is a flavonoid, a polyphenolic compound widely distributed in medicinal herbs that has anti-inflammatory, antioxidant, and antitumor activity. This study evaluated the protective effect of GA on hepatic I/R injury. METHODS: An I/R model was created in male Wistar rats by clamping the hepatoportal vein, hepatic artery and hepatic duct for 30 min followed by reperfusion for 2 h. A hypoxia/restoration (H/R) model was established in buffalo rat liver (BRL) cells by hypoxia for 4 h followed by normoxic conditions for 10 h. The extent of liver injury was assayed by serum ALT/AST, hepatic histology, and MPO activity. Oxidative stress was assayed by serum superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and malondialdehyde (MDA). Expression of apoptosis-related proteins in BRL cells was assayed in western blots. Expression of AKT and p-AKT proteins in vivo and vitro were assayed in western blots. RESULTS: GA significantly decreased ALT/AST expression, reversed changes in oxidative stress markers induced by I/R, and mediated caspase-3 activity expression of apoptosis-related proteins in vivo and in vitro. Methylthiazol tetrazolium (MTT) assay, flow cytometry, and Hoechst 33258 staining confirmed that GA inhibited apoptosis of BRL cells. GA also increased the expression of phosphorylated AKT after H/R. CONCLUSION: GA reduced liver I/R injury both in vivo and vitro and inhibited BRL cell apoptosis. PI3K/AKT signaling have been involved. GA may protect against liver I/R and be a potential therapeutic candidate. PMID- 30481780 TI - miR-650 Promotes the Metastasis and Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma by Directly Inhibiting LATS2 Expression. AB - BACKGROUND/AIMS: Previous studies have confirmed that microRNAs are involved in the metastasis and epithelial-mesenchymal transition (EMT) of malignancies. In this study, we examined whether miR-650 promotes the migration, invasion, and EMT of hepatocellular carcinoma (HCC) cells by targeting the large tumor suppressor kinase 2 gene (LATS2). METHODS: qRT-PCR was used to detect expression of miR-650 in HCC tissues and paired normal tissues. MTT and Transwell assay were used to observe the effect of miR-650 on proliferation, migration and invasion of HCC cells. Western blot assay and Immunohistochemistry were performed to demonstrate association between miR-650 expression level and epithelial-mesenchymal transition (EMT) related protein. Mechanistically, Reporter luciferase assay was performed to reveal whether large tumor suppressor kinase 2 (LATS2) was a direct target of miR-650 in HCC cells. RESULTS: We observed that miR-650 levels were largely up-regulated in HCC tissues, and that the increased expression was closely associated with the adverse clinical features of HCC patients. Additionally, the expression of LATS2, which was identified as a direct target of miR-650, can counteract the effects of miR-650 in HCC. Furthermore, we demonstrated that high miR-650 expression levels and low LATS2 expression levels in tumors may indicate a poor prognosis for HCC patients. CONCLUSION: In conclusion, the miR-650/LATS2 pathway may serve as a novel prognostic biomarker and an attractive therapeutic target for HCC patients. PMID- 30481781 TI - Protective Effects of Morus Root Extract (MRE) Against Lipopolysaccharide Activated RAW264.7 Cells and CCl4-Induced Mouse Hepatic Damage. AB - BACKGROUND/AIMS: Inflammation is one of the main contributors to chronic diseases such as cancer. It is of great value to identify the potential activity of various medicinal plants for regulating or blocking uncontrolled chronic inflammation. We investigated whether the root extract of Morus australis possesses antiinflammatory and antioxidative stress potential and hepatic protective activity. METHODS: The microwave-assisted extractionwere was used to prepare the ethanol extract from the dried root of Morus australis (MRE), including polyphenolic and flavonoid contents. Lipopolysaccharide (LPS) stimulated RAW264.7 cells was examined the anti-inflammatory and anti-oxidative potential of MRE. CCl4-induced mouse hepatic damage were performed to detect the hepatic protective potential in vivo. Immunohistochemistry (IHC) and western blot assays were used to detect target proteins. RESULTS: MRE contained approximately 23% phenolic compounds and 3% flavonoids. The major flavonoid component of MRE was morusin. MRE and morusin inhibited lipopolysaccharide-induced production of nitrite and prostaglandin E2 in RAW264.7 cells. MRE and morusin also suppressed the formation of intracellular reactive oxygen species and the expression of iNOS and COX-2. In an in vivo study, a thiobarbituric acid reactive substances assay showed that MRE inhibited CCl4-induced oxidative stress and expression of nitrotyrosine. MRE also decreased CCl4-induced hepatic iNOS and COX-2 expression, as well as CCl4-induced hepatic inflammation and necrosis in mice. CONCLUSION: MRE exhibited antiinflammatory and hepatic protective activity. PMID- 30481782 TI - Ginsenoside 20(S)-Rg3 Prevents PKM2-Targeting miR-324-5p from H19 Sponging to Antagonize the Warburg Effect in Ovarian Cancer Cells. AB - BACKGROUND/AIMS: The Warburg effect is one of the main metabolic features for cancers, with long non-coding RNA (lncRNA) being involved as a class of crucial regulators. Our previous studies have shown that ginsenoside 20(S)-Rg3, an active saponin monomer extracted from red ginseng, inhibits the Warburg effect in ovarian cancer cells. However, the detailed lncRNA regulatory network modulated by 20(S)-Rg3 to prevent the Warburg effect in ovarian cancer cells has not been explored. METHODS: High-throughput sequencing was used to screen out the differentially expressed lncRNAs between 20(S)-Rg3-treated and non-treated SKOV3 cells. The levels of lncRNA H19 and miR-324-5p were manipulated in SKOV3 and A2780, and the glucose consumption, lactate production and PKM2 protein level were detected. Dual-luciferase reporter assay and RIP were utilized to verify the direct binding of H19 to miR-324-5p and miR-324-5p to PKM2. Cell proliferation was examined by CCK8 and colony formation assay. Nude mice subcutaneous xenograft tumor models were established to evaluate the impact of miR-324-5p on tumor growth in vivo. RESULTS: 20(S)-Rg3 downregulated 67 lncRNAs, and H19 was one of the most decreased lncRNAs. Suppression of H19 by siRNA transfection reduced glucose consumption, lactate production and PKM2 expression in ovarian cancer cells, while H19 overexpression in 20(S)-Rg3-treated ovarian cancer cells enhanced glucose consumption, lactate production and PKM2 expression. Dual luciferase reporter assay and RIP results showed that H19 directly bound to miR 324-5p. Dual-luciferase reporter assay showed that miR-324-5p directly targeted PKM2, and miR-324-5p negatively regulated glucose consumption and lactate production in ovarian cancer cells. miR-324-5p overexpression inhibited cell proliferation in vitro and in vivo. CONCLUSION: Our study revealed that 20(S)-Rg3 blocked the competitive inhibition of H19 on miR-324-5p, which enhanced the suppression of miR-324-5p on PKM2 and therefore inhibited the Warburg effect and repressed tumorigenesis. In a word, 20(S)-Rg3 inhibited the Warburg effect in ovarian cancer cells via H19/miR-324-5p/PKM2 pathway. PMID- 30481785 TI - ZEB1 Promotes Chemoresistance to Cisplatin in Ovarian Cancer Cells by Suppressing SLC3A2. AB - Ovarian cancer is one of the deadliest gynecological malignancies in women. Chemoresistance has been a major obstacle for ovarian cancer treatment. Zinc finger E-box-binding homeobox 1 (ZEB1) is an important regulator of tumor development in various types of cancer. Abnormal expression of SLC3A2 (CD98hc), a type 2 transmembrane cell surface molecule, has been described in several cancers. This study was designed to investigate the role of ZEB1 and SLC3A2 in the chemoresistance to cisplatin in ovarian cancer cells. We found that ZEB1 was increased in cisplatin-resistant SKOV3/DPP cells. Downregulation of ZEB1 significantly decreased cell viability in response to cisplatin, increased cis platin-induced apoptosis, and decreased migration and invasion in the presence of cisplatin. In addition, downregulation of ZEB1 decreased the volume and weight of implanted tumors. SLC3A2 was decreased in cisplatin-resistant SKOV3/DPP cells. Upregulation of SLC3A2 significantly decreased cell viability in response to cisplatin, increased cisplatin-induced apoptosis, and decreased migration and invasion in the presence of cisplatin. Moreover, upregulation of SLC3A2 decreased the volume and weight of implanted tumors. Downregulation of ZEB1 resulted in a significant increase of SLC3A2 expression. Moreover, downregulation of SLC3A2 significantly inhibited ZEB1 knockdown-mediated inhibition of cisplatin resistance. ZEB1-mediated regulation of SLC3A2 was involved in the chemoresistance to cisplatin in ovarian cancer cells. Overall, we provide new insights into the mechanism of chemoresistance to cisplatin in ovarian cancer cells. ZEB1/SLC3A2 may be promising therapeutic targets for enhancement of the sensitivity of ovarian cancer cells to cisplatin-mediated chemotherapy. PMID- 30481786 TI - Multisegmental Lumbar Corporectomy and Transcorporal Fixation for Correction of Extreme Thoracolumbar Kyphosis in Myelomeningocele with Chronic Decubitus. AB - We introduce a novel technique for the treatment of severe kyphosis in myelomeningocele. A 5-year-old paraplegic boy with myelomeningocele presented with severe thoracolumbar kyphosis and a chronic ulcus at the site of the gibbus. The myelomeningocele had been treated during his first week of life, and an accompanying Chiari type II malformation had been treated by ventriculoperitoneal shunting. He subsequently developed a rapidly progressive thoracolumbar kyphosis with an angle of 180 degrees between T10 and L5. He also suffered from a chronic superinfected skin ulcus at the site of the gibbus. Since the skin ulcus required plastic surgery reconstruction, we deemed classical posterior fixation after kyphectomy unfeasible. The subsequent operative steps of our novel surgical approach were performed in a single-stage surgery. First, a three-level lumbar corporectomy from L1 to L3 was performed. Subsequently, the body of the removed L2 vertebra was isolated and configured as an autologous graft to bridge the gap between the thoracic and the caudal lumbar spine. The graft was fixed via a transcorporal interbody fusion technique with titanium screws, and chopped autologous bone was added for fusion. The skin was closed using rotation flaps. At the 3-year follow-up, the patient and his family reported marked improvement of quality of life, imaging showed solid fusion and the wound was unremarkable. Our novel technique with transcorporal fixation provides new perspectives in the treatment of severe kyphosis and skin ulceration in myelomeningocele. PMID- 30481787 TI - Long Noncoding RNA FER1L4 Suppresses Tumorigenesis by Regulating the Expression of PTEN Targeting miR-18a-5p in Osteosarcoma. AB - BACKGROUND/AIMS: Novel long non-coding RNA Fer-1-like protein 4 (FER1L4) has been reported to play crucial regulatory roles in tumor progression. However, its clinical significance and biological role in osteosarcoma (OS) is completely unknown. The aim of the present study was to investigate the role of FER1L4 in OS progression and the underlying mechanism. METHODS: We analyzed the expression levels of FER1L4 in tissues of OS patients and cell lines via quantitative RT-PCR (qRT-PCR). The effect of FER1L4 on cell proliferation, colony formation, migration and invasion was analyzed by cell counting kit-8 (CCK-8), colony formation, wound healing and transwell invasion assay, respectively. Novel targets of FER1L4 were selected through a bioinformatics soft and confirmed using a dual-luciferase reporter system and qRT-PCR. To detect the role of FER1L4 in vivo tumorigenesis, tumor xenografts were created. RESULTS: We found that the expression of FER1L4 was significantly downregulated in OS tissues and cell lines; moreover, low expression of FER1L4 was associated with advanced tumor-nude metastasis (TNM) stage, lymph node metastases, and poor overall survival. Functional assays showed that upregulation of FER1L4 significantly inhibited OS cell proliferation, colony formation, migration, and invasion in vitro, as well as suppressed tumor growth in vivo. Assays performed to determine the underlying mechanism, indicated that FER1L4 interacted directly with miR-18a-5p. Subsequently, we found that FER1L4 significantly increased PTEN expression, a known target of miR-18a-5p, in OS cells. Furthermore, PTEN was found to be down regulated, and positively correlated with FER1L4 in OS tissues. CONCLUSION: These findings suggest that FER1L4, acting as a competing endogenous RNA (ceRNA) of miR 18a-5p, exerts its anti-cancer role by modulating the expression of PTEN. Thus, FER1L4 may be a novel target for the prevention and treatment of OS. PMID- 30481788 TI - Long-Term Outcomes of Bilateral Pallidal Deep Brain Stimulation for X-Linked Dystonia and Parkinsonism. AB - BACKGROUND: X-linked dystonia parkinsonism (XDP) causes adult-onset progressive dystonia and parkinsonism, which may not respond to pharmacotherapy. OBJECTIVE: Previous case reports have reported beneficial effects from bilateral pallidal (GPi) deep brain stimulation (DBS). Here, we report the long-term clinical outcomes of 3 patients treated at our center. METHODS: All patients presented with medication refractory dystonia and parkinsonism. They were followed prospectively. Clinical evaluations included the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the Unified Parkinson's Disease Rating Scale (UPDRS). Adverse events were recorded. RESULTS: The average length of follow-up was 45.7 months. No serious adverse events occurred. All patients experienced an immediate and sustained improvement in dystonia. Mean percentage improvement in motor subscores of BFMDRS was 63.5% at the last follow-up visit. Parkinsonism was less responsive to neuromodulation, with a mean improvement in UPDRS-III of 39.5%. Standard pallidal stimulation parameters were used. Freezing of gait developed after DBS therapy in 2 patients, stimulation-induced in one and due to disease progression in the other. CONCLUSION: Bilateral pallidal DBS resulted in significant and sustained improvement in dystonia and moderate improvement in parkinsonism. Pallidal DBS represents an important treatment option for XPD for the management of motor symptoms. PMID- 30481789 TI - Antioxidant and Anti-Inflammatory Strategies Based on the Potentiation of Glutathione Peroxidase Activity Prevent Endothelial Dysfunction in Chronic Kidney Disease. AB - BACKGROUND/AIMS: Accelerated atherosclerosis in chronic kidney disease (CKD) is preceded by endothelial dysfunction (ED), which exhibits a proinflammatory and prothrombotic phenotype and enhanced oxidative stress. In this study, the effect of several compounds with anti-inflammatory and/or antioxidant properties on uremia-induced endothelial dysfunction has been evaluated in an in vitro model. METHODS: Endothelial cells (ECs) were exposed to sera from uremic patients in the absence and presence of the flavonoids apigenin, genistein and quercetin, the antioxidant enzyme mimetics (AEM) ebselen (glutathione peroxidase mimetic), EUK 134 and EUK-118 (both superoxide dismutase mimetics), and the pharmacological drug N-acetylcysteine (NAC). We explored changes in the expression of adhesion receptors on the cell surface, by immunofluorescence, the production of radical oxygen species (ROS), by fluorescence detection, and the activation of signaling proteins related to inflammation, by both a phosphospecific antibody cell-based ELISA and immunoblotting techniques. RESULTS: Uremic media induced a significantly increased expression of ICAM-1, overproduction of radical oxygen species (ROS) and activation of p38 mitogen activated protein kinase (p38MAPK) and Nuclear Factor kB (NFkB) in ECs. Quercetin, the AEM and NAC showed a significant inhibitory effect on both ICAM-1 expression and ROS generation (p<0.05). All the compounds reduced p38MAPK activation, but only the AEM, especially ebselen, and NAC, both potentiating the glutathione peroxidase pathway, also inhibited NFkB activation. These two compounds were capable of increasing endothelial glutathione levels, especially in response to uremia. CONCLUSION: Our results indicate that the potentiation of the antioxidant pathways can be an effective strategy to improve endothelial dysfunction in uremia and a potential target to reduce the cardiovascular risk in this population. PMID- 30481790 TI - Ophthalmic Insert versus Eye Drops for Mydriasis in Neonates: A Randomized Clinical Trial. AB - BACKGROUND: Eye drop treatment routinely used to obtain mydriasis prior to fundoscopy in neonates requires repeated instillations of mydriatic agents that can lead to systemic side effects. OBJECTIVES: The aim of this study was to compare the mydriatic efficacy and tolerance of administration of phenylephrine and tropicamide via the ophthalmic insert Mydriasert(r) versus standard eye drop treatment in neonates. METHODS: In this prospective, single-blinded, noninferiority study, 80 hospitalized neonates (age < 18 months) requiring bilateral fundus examination were randomized to receive eye drops (repeated instillations of 2.5% phenylephrine and 0.5% tropicamide) or the insert. The primary outcome was mydriasis suitable for fundoscopy 75 min after mydriatic agent introduction (T75). RESULTS: Mydriasis was successfully achieved in both eyes at T75 in 97.5% (n = 39/40) of the insert group patients versus 90% (n = 36/40) receiving eye drops (between-group difference 7.5%, demonstrating noninferiority). Mydriasis remained stable in 60.0% of patients (n = 24/40) in the insert group versus 15% (n = 6/40) in the eye drop group (p < 0.0001). The insert group required fewer nursing interventions than the eye drop group (p = 0.0001). Mean blood pressure were significantly higher in the insert versus the eye drop group (p < 0.0001 and p = 0.0003, respectively); mean heart rate was not significantly different between the groups (p = 0.37). In the insert group, 2 patients reported an adverse event (bradycardia, n = 1, and gastroesophageal reflux, n = 1; both appeared to be related to neonate pathology). CONCLUSIONS: The degree of mydriasis achieved with Mydriasert(r) was noninferior to that obtained with eye drops. The insert appears to be safe to use in neonates without a history of increased vagal tone or gastrointestinal reflux. PMID- 30481791 TI - The Ratio Serum Creatinine/Serum Cystatin C (a Surrogate Marker of Muscle Mass) as a Predictor of Hospitalization in Chronic Obstructive Pulmonary Disease Outpatients. AB - BACKGROUND: In chronic obstructive pulmonary disease (COPD), low muscle mass has been associated with several clinical outcomes such as low exercise capacity, hospital admission, and mortality. The Sarcopenia Index (SI) is a novel way to estimate muscle mass based on the ratio of serum creatinine (produced exclusively by muscle)/cystatin C (produced by all nucleated body cells). OBJECTIVES: This study aims to assess the SI in stable COPD outpatients, as compared with a healthy control group, to quantify its relationship with several important clinical features in COPD, and to study its potential usefulness to predict COPD exacerbations and hospital admissions. METHODS: The SI was calculated in 18 healthy control subjects and 65 stable COPD outpatients were included in the study. Patients were prospectively followed for 1 year after being enrolled in the study. RESULTS: COPD patients had a lower SI than controls, that is lower muscle mass. Furthermore, patients with a modified Medical Research Council dyspnea score >=2, patients with a COPD Assessment Test score >=10, and patients with a high risk of exacerbation had lower levels of SI compared with patients without these characteristics. SI correlated with FEV1 (r = 0.491, p < 0.001), the 6-min walking test (r = 0.560, p = 0.001), and the Fat-Free Mass Index (r = 0.431, p = 0.017). Univariate and multivariate Cox proportional risk analysis showed that a low SI is an independent predictor of hospital admission in COPD outpatients followed for 1 year (HR 5.16, p = 0.025). CONCLUSIONS: The ratio serum creatinine/serum cystatin C correlates with several COPD characteristics, and it can be used to predict COPD hospitalization. PMID- 30481792 TI - PharmaNews. PMID- 30481794 TI - PharmaForum BMS. PMID- 30481793 TI - Metformin Inhibited Growth, Invasion and Metastasis of Esophageal Squamous Cell Carcinoma in Vitro and in Vivo. AB - BACKGROUND/AIMS: This study aimed at investigating the effects of metformin on the growth and metastasis of esophageal squamous cell carcinoma (ESCC) in vitro and in vivo. METHODS: Two human ESCC cell lines EC9706 and Eca109 were selected and challenged with metformin in this study. Western blot assay was performed to detect th level of Bcl-2, Bax and Caspase-3. Scratch wound assay, transwell assay and Millicell invasion assay were used to assay the invasion and migration of EC9706 and Eca109 cells. Nude mice tumor models were used to assay the growth and lung metastasis of ESCC cells after metformin treatment. The plasma glucose level was also assayed. RESULTS: We found that metformin significantly inhibited proliferation and induced apoptosis of both ESCC cell lines in a dose- and time dependent manner, and the expression of Bcl-2 was down-regulated and Bax and Caspase-3 were up-regulated. Metformin significantly inhibited the invasion and migration of EC9706 and Eca109 cells (p < 0.05). mRNA and protein levels of MMP-2 and MMP-9 decreased significantly upon treatment with metformin of 10mM for 12, 24 and 48h in a time-dependent manner (p < 0.05). In line with in vitro results, in vivo experiments demonstrated that metformin inhibited tumorigenicity, inhibited lung metastasis and down-regulated the expression of MMP-2 and MMP-9. Moreover, we showed that metformin treatment did not cause significant alteration in liver and renal functions and plasma glucose level. CONCLUSION: Our study for the first time demonstrated the anti-invasive and anti-metastatic effects of metformin on human ESCC cells both in vitro and in vivo, which might be associated with the down-regulation of MMP-2 and MMP-9. As a whole, our results indicate the potential of metformin to be developed as a chemotherapeutic agent for patients with ESCC and might stimulate future studies on this area. PMID- 30481795 TI - Lysyl Hydroxylase Inhibition by Minoxidil Blocks Collagen Deposition and Prevents Pulmonary Fibrosis via TGF-beta1/Smad3 Signaling Pathway. AB - BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a deadly disease characterized by excessive collagen in the extracellular matrix (ECM) of the lungs. Collagen is the primary protein component of the ECM. However, the exact mechanisms underlying the formation and deposition of collagen in the ECM under normal and pathological conditions remain unclear. Previous studies showed that lysyl hydroxylase (LH) plays a crucial role in the formation of collagen. Minoxidil is an FDA-approved anti-hypertensive agent that inhibits LH that reduces fibrosis. In this study, we investigated the functional roles of LHs (LH1, LH2, and LH3) in pulmonary fibrosis and the anti-fibrotic effects of minoxidil. MATERIAL AND METHODS Patient serum samples were examined for their expression of procollagen lysine, 2-oxoglutarate 5-dioxygenases (PLOD) 1-3, the genes encoding LH 1-3. Mice with bleomycin (BLM 2.5 mg/kg)-induced pulmonary fibrosis were administered a minoxidil solution (30 mg/kg) by oral gavage. RESULTS The PLOD mRNA levels were significantly higher in the IPF patients than in the healthy control subjects. Minoxidil suppressed the BLM-induced pulmonary fibrosis in vivo. These effects were associated with blocking TGF-beta1/Smad3 signal transduction and attenuating the expression and activity of LHs, resulting in decreased collagen formation, thus reducing the pulmonary fibrosis. The anti-fibrotic effects of minoxidil may be mediated through competitive inhibition of LHs activity, resulting in decreased pyridine cross-link formation and collagen production and deposition. CONCLUSIONS The results of this study suggest that LH represents a target to prevent or treat pulmonary fibrosis, and minoxidil may provide an effective agent to inhibit LHs. PMID- 30481796 TI - School-Aged Children's Phonological Accuracy in Multisyllabic Words on a Whole Word Metric. AB - Purpose: The purpose of this study is to examine differences in phonological accuracy in multisyllabic words (MSWs) on a whole-word metric, longitudinally and cross-sectionally, for elementary school-aged children with typical development (TD) and with history of protracted phonological development (PPD). Method: Three mismatch subtotals, Lexical influence, Word Structure, and segmental Features (forming a Whole Word total), were evaluated in 3 multivariate analyses: (a) a longitudinal comparison (n = 22), at age 5 and 8 years; (b) a cross-sectional comparison of 8- to 10-year-olds (n = 12 per group) with TD and with history of PPD; and (c) a comparison of the group with history of PPD (n = 12) with a larger 5-year-old group (n = 62). Results: Significant effect sizes (etap2) found for mismatch totals were as follows: (a) moderate (Lexical, Structure) and large (Features) between ages 5 and 8 to 10 years, mismatch frequency decreasing developmentally, and (b) large between 8- to 10-year-olds with TD and with history of PPD (Structure, Features; minimal lexical influences), in favor of participants with TD. Mismatch frequencies were equivalent for 8- to 10-year-olds with history of PPD and 5-year-olds with TD. Classification accuracy in original subgroupings was 100% and 91% for 8- to 10-year-olds with TD and with history of PPD, respectively, and 86% for 5-year-olds with TD. Conclusion: Phonological accuracy in MSW production was differentiated for elementary school-aged children with TD and PPD, using a whole-word metric. To assist with the identification of children with ongoing PPD, the metric has the ability to detect weaknesses and track progress in global MSW phonological production. PMID- 30481798 TI - Dry Eye Research Update in Japan in Celebration of the 25th Anniversary of the Dry Eye Society and the 10th Anniversary of Hakone Dry Eye Club. PMID- 30481797 TI - Identification of Affective State Change in Adults With Aphasia Using Speech Acoustics. AB - Purpose: The current study aimed to identify objective acoustic measures related to affective state change in the speech of adults with post-stroke aphasia. Method: The speech of 20 post-stroke adults with aphasia was recorded during picture description and administration of the Western Aphasia Battery-Revised (Kertesz, 2006). In addition, participants completed the Self-Assessment Manikin (Bradley & Lang, 1994) and the Stress Scale (Tobii Dynavox, 1981-2016) before and after the language tasks. Speech from each participant was used to detect a change in affective state test scores between the beginning and ending speech. Results: Machine learning revealed moderate success in classifying depression, minimal success in predicting depression and stress numeric scores, and minimal success in classifying changes in affective state class between the beginning and ending speech. Conclusions: The results suggest the existence of objectively measurable aspects of speech that may be used to identify changes in acute affect from adults with aphasia. This work is exploratory and hypothesis-generating; more work will be needed to make conclusive claims. Further work in this area could lead to automated tools to assist clinicians with their diagnoses of stress, depression, and other forms of affect in adults with aphasia. PMID- 30481799 TI - What We Know About the Epidemiology of Dry Eye Disease in Japan. AB - The aim of this paper is to propose a systematic review on the prevalence of dry eye disease (DED) and its economic burden in Japan and other countries. A systematic review was performed of data gathered from a PubMed search between 2002 to 2017, using the following key words: "dry eye," "prevalence," "epidemiology," and "risk factors." There have been several cross-sectional studies evaluating the epidemiological aspect of DED in Japan: two population based studies, two cross-sectional studies on visual display terminal (VDT) users, and one study focusing on high school students. One study calculated the direct cost of DED, and two calculated the indirect cost using a work productivity assessment to evaluate the economic burden. The prevalence of DED in the Japanese population was relatively high in all studies compared to reports from other countries. In Japan, the annual health plan cost per patient was estimated to be $323 (US). Work productivity loss per patient associated with definite DED was estimated to be between $741 and $6160. To conclude, it was found that DED is prevalent across generations in the Japanese population, and costs related to the disease lead to considerable economic burden. PMID- 30481800 TI - Definition and Diagnostic Criteria of Dry Eye Disease: Historical Overview and Future Directions. AB - The definition and diagnostic criteria of dry eye disease (DED) proposed by the Japan Dry Eye Society and other countries are reviewed. The first definition and criteria of DED in Japan were proposed in 1995. In that report, DED was considered a disease of tears, which subsequently damaged ocular epithelia. The presence of subjective symptoms was not included in the criteria. In 2006, a new definition proposed that interactions between the tear film and ocular surface epithelia play important roles in DED. The presence of subjective symptoms, including visual disturbances, changes in tears, and epithelial damage were proposed to be major components of DED, and eyes positive for all three components were diagnosed as "definitive dry eye." A third version was proposed in 2016, which emphasized unstable tear films as a core finding in DED. Following this guideline, eyes with an abnormally low tear film breakup time and the presence of subjective symptoms are considered to have DED. The current definition and criteria are different from those proposed in other countries. For example, the recently published DED definition by the Dry Eye WorkShop II (DEWS II) of the Tear Film and Ocular Surface Society (TFOS) focuses more on the underlying pathogenesis of DED, including inflammation, hyperosmolarity of tears, and neurosensory abnormalities, as well as unstable tear films. PMID- 30481801 TI - Tear Film-Oriented Diagnosis and Tear Film-Oriented Therapy for Dry Eye Based on Tear Film Dynamics. AB - In December 2010 and January 2012, 3% diquafosol sodium ophthalmic solution and 2% rebamipide ophthalmic suspension, respectively, appeared first in Japan as prescription drugs for the treatment of dry eye (DE). Since then, not only the diagnosis and treatment but also the understanding of the pathophysiology of DE have greatly advanced, and a new concept of layer-by-layer diagnosis and treatment for DE, respectively termed "tear-film-oriented diagnosis" (TFOD) and "tear-film-oriented therapy" (TFOT) was born. This new concept is currently in the process of expanding from Japan to other Asian countries. TFOD is the method used for the differential diagnosis of DE, which includes aqueous-deficiency DE (ADDE), decreased wettability DE (DWDE), and increased evaporation DE (IEDE), through the dynamics of tear film (TF) and breakup patterns (BUPs) after the eye is opened. BUPs and/or each diagnosed DE subtype are/is able to distinguish the insufficient components of the ocular surface that are responsible for each BUP in a layer-by-layer fashion. Aqueous fluid, membrane-associated mucins (especially MUC16), and the lipid layer and/or secretory mucins must be insufficient in ADDE, DWDE, and IEDE, respectively, and this allows for a layer by-layer treatment to be proposed for each BUP via the supplementation of the insufficient components, using the topical therapy currently available. In Japan, TF breakup is regarded as a visible core mechanism for DE, and an abnormal breakup time (i.e., <=5 seconds) and symptoms are currently used for the diagnosis of DE. Therefore, TFOD and TFOT could be an ideal and practical pathway for clinicians to manage DE. PMID- 30481802 TI - Assessment of Dry Eye Symptoms: Current Trends and Issues of Dry Eye Questionnaires in Japan. AB - Dry eye disease (DED) is one of the most common disease in the ophthalmic clinic, and the reasons DED patients visit ophthalmic clinics are symptoms such as stinging, burning, or scratchy sensations. The symptoms and visual disturbances of DED have a negative impact on the daily routines and social lives of the patients (i.e., their quality of life [QOL]). The presence of symptoms was required in the definition of DED by the National Eye Institute/Industry Workshop in 1995; therefore, disease-specific questionnaires were essential for monitoring and managing patients with DED. Thereafter, many questionnaires have been developed to evaluate the specific symptoms of dry eyes. Although many questionnaires are available to assess the dry eye symptoms, it is essential that they provide valid answers and are easy to use to assess the effects of DED on the QOL. The Asia Dry Eye Society and Japan Dry Eye Society have proposed a new definition of DED that is a combination of symptoms and an unstable tear film, and information on these two factors is sufficient to make a definitive diagnosis of DED. Therefore, the assessments of the symptoms are fundamental in the diagnosis of DED. PMID- 30481803 TI - Functional Visual Acuity. AB - Dry eye (DE) causes irregularity of the ocular surface and reduces the quality of vision. An intact, regular tear film is essential for high-quality retinal images; however, visual tasks requiring sustained gazing can disrupt the tear film, eventually degrading visual function. A functional visual acuity (FVA) measurement system has been uniquely developed in Japan to evaluate visual function related to tear stability in patients with DE. FVA has been shown to correlate with optical quality. The system measures the change in visual acuity (VA) over time automatically in aqueous-deficient DE and short tear breakup tear film DE characterized by decreased tear stability and minimal epithelial damage. It is also useful to detect minimal visual deterioration correlated with minimal ocular surface abnormality and vision-related quality of life otherwise undetectable by conventional VA testing, to assess and quantify vision-related symptomatology, and to determine the efficacy of treatments for DE disease. Recently, its use has been expanded, such as for the analysis of visual function accompanying refractive surgery, contact lens, cataract and cataract-related disease, retinal disease, glaucoma, amblyopia, presbyopia, and vehicle driving. Its use has revealed that FVA reflects not only visual function related to tear dynamics, but also visual function related to quick recognition of the target. This simple, noninvasive, and sensitive FVA measurement system may be expected to be used worldwide. PMID- 30481804 TI - Irregular Astigmatism and Higher-Order Aberrations in Eyes With Dry Eye Disease. AB - Visual disturbances were included in the definition of dry eye disease in the 2007 Dry Eye Workshop report. As a result, quality of vision (QoV) in dry eye patients has received increased attention. Corneal topography and wavefront sensors have been used to objectively and quantitatively evaluate optical quality, with data showing increases in irregular astigmatism and higher-order aberrations (HOAs) in dry eye patients. Furthermore, ocular optical characteristics are influenced by the tear film, which constantly fluctuates over time. Therefore, dynamic quantitative assessments of optical quality with continuous measurements are essential to understanding QoV in dry eye patients. This review summarizes what is known and what advances have been made in evaluating and understanding QoV in dry eye patients. In particular, corneal topographic and wavefront analyses, conducted both overseas and in Japan, are described. PMID- 30481805 TI - Application of In Vivo Confocal Microscopy in Dry Eye Disease. AB - Confocal microscopy is a new, emerging, noninvasive technology that can aid in the in vivo assessment of structural changes in several ocular surface diseases at the cellular level. In the dry eye field, in vivo confocal microscopy has been applied to the examination of the cornea, bulbar and palpebral conjunctiva, Meibomian gland, and lacrimal gland. The device can assess the morphology, including superficial/wing/basal epithelial cell density, stromal keratocyte density, endothelial cell density, nerve fiber density, the number of beadings, nerve tortuosity, nerve reflectivity, and inflammatory cell density in the cornea. Furthermore, the device can not only assess epithelial cell density and area, goblet cell, microcyst, and inflammatory cell density but also the cellular architecture, including nucleocytoplasmic ratio in conjunctiva. The device also can disclose acinar unit density, acinar unit longest diameter, acinar unit shortest diameter, and inflammatory cell density in the Meibomian gland and lacrimal gland by other potential applications. Relevant research in Europe and the United States focused on the morphologic changes in the cornea in the dry eye field, while Japanese research focused on the conjunctival, Meibomian gland, and lacrimal gland alterations. The application of in vivo confocal microscopy in dry eye disease will be a powerful method to evaluate the morphologic change of the ocular surface around the world in the future. PMID- 30481806 TI - Meibography: A Japanese Perspective. AB - Meibography allows observation of meibomian glands in an objective and repeatable manner. Original meibography systems were invasive and not readily adopted by ophthalmology clinics. The development of noncontact infrared meibography allowed the rapid and noninvasive observation of meibomian glands, and such systems have now been widely adopted for standard examinations in dry eye clinics. Noncontact meibography has also spurred research into meibomian glands and has been applied to evaluation of their structure and status in various ocular surface diseases. Although the images obtained by meibography are objective and repeatable, the interpretation of these images is subjective, with the relationship between image features and actual gland structure and composition remaining unclear. Additional clinical and basic research with regard to the interpretation of meibography images is thus necessary. Future improvements to meibography will likely provide new insights into the pathophysiology of meibomian gland diseases as well as enhance its contribution to the diagnosis and evaluation of treatments for such diseases. PMID- 30481807 TI - Relationship Between Eyelid Pressure and Ocular Surface Disorders in Patients With Healthy and Dry Eyes. AB - Purpose: To determine whether an eyelid pressure measurement device, called a blepharo-tensiometer, can detect changes in the eyelid pressure in different types of ocular surface disorders. Methods: First, the repeatability of the blepharo-tensiometer was determined by measuring the eyelid pressures on 3 separate days from healthy volunteers and calculating the intraclass correlation coefficients (ICCs). Second, to determine the ability of the blepharo-tensiometer to detect changes in the eyelid pressures in different types of ocular surface disorders, we compared the eyelid pressure of healthy eyes with dry eyes. Third, the correlations between the eyelid pressure and the location and magnitude of fluorescein staining of the ocular surface were analyzed. Fourth, the eyelid pressure in eyes with lid-wiper epitheliopathy (LWE) was measured. Results: The ICCs ranged from 0.675 to 0.911 for the upper eyelid and 0.663 to 0.925 for the lower eyelid. The pressures of the upper and lower eyelids were significantly higher in dry eyes than in healthy eyes. The inferior ocular surface staining scores were strongly correlated with the lower eyelid pressure by multivariate analysis. The lower eyelid pressure was significantly correlated with the grade of the lower LWE. Conclusions: The blepahro-tensiometer can obtain repeatable measurements of the eyelid pressure and can be used to evaluate the pressure of the eyelids on the ocular surface in healthy and diseased eyes. The significant correlations between the eyelid pressure and the ocular surface staining suggests that the pressure on the ocular surface probably contributes to ocular surface disorders. PMID- 30481808 TI - Short Tear Film Breakup Time-Type Dry Eye. AB - Measurement of tear film breakup time (TBUT) has become a standard diagnostic procedure in the dry eye clinic. Short TBUT-type dry eye is characterized by TBUT of less than 5 seconds and dry eye symptoms such as ocular fatigue or dryness; the importance of this type has recently been gaining prominence. Patients with this condition show no reduction in tear production and no staining of the ocular surface. The severity of symptoms is almost the same as in dry eye in which the ocular surface is stained with rose bengal or fluorescein. In addition to discomfort, patients suffer from decreased vision due to the unstable tear film, which can be attributed to the relative abnormality of the lipid layer, aqueous layer, and/or mucin layer. The diagnosis should be performed carefully on the basis of the patient's symptoms and the TBUT test, because the ocular surface appears normal and remains unstained. PMID- 30481809 TI - Sjogren's Syndrome, Non-Sjogren's Syndrome, and Graft-Versus-Host Disease Related Dry Eye. AB - I have reviewed available literature on dry eye related to Sjogren's syndrome (SS), non-Sjogren's syndrome (non-SS), and graft-versus-host disease (GVHD) to examine aqueous tear deficient dry eye as a subtype of dry eye. This section will focus on clinical studies regarding those subtypes of dry eye. I searched the PubMed database from 1990-2017 for discussion of clinical features, diagnostic criteria, and risk factors of SS, non-SS, and GVHD-related dry eye. In addition, therapeutic options for each subtype of dry eye are described. Although the clinical presentations of SS and chronic graft-versus-host disease (cGVHD) are similar, ocular surface fibrotic changes are characteristic of ocular GVHD but not SS- or non-SS-related dry eye. Recently, diagnostic criteria for each disease have been proposed and include the American College of Rheumatology/European League Against Rheumatism (ACR-EULAR) for SS and the International Chronic Ocular GVHD consensus criteria. Although there has been gradual progress, there are currently no specific therapies and few approved treatment options for these intractable diseases, including SS and GVHD. As judged by the findings, these subtypes of dry eye are different clinical entities from simple dry eye. Therefore, novel therapies, specific to these subtypes of dry eye, may be required in the future. PMID- 30481810 TI - Severe Dry Eye With Combined Mechanisms is Involved in the Ocular Sequelae of SJS/TEN at the Chronic Stage. AB - Stevens-Johnson syndrome (SJS), and its more severe variant, toxic epidermal necrolysis (TEN), are life-threatening diseases of the skin and mucous membranes. After the acute-stage damage subsides, serious visual impairment and severe dry eye remains as ocular sequelae. At the acute stage, ocular complications occur in 77% of SJS/TEN patients. In cases with pseudomembranous formation and/or epithelial defects, the risk of ocular sequelae increases. Among 13 slit-lamp microscopy images that we obtained of SJS/TEN patients at the chronic stage, the loss of corneal epithelial stem cells and severe meibomian gland involvement were found to be the most common disorders. Severe dry eye in SJS includes three important mechanisms: (1) aqueous tear deficiency, (2) decreased wettability of corneal surface, and (3) increased evaporation. Dry eye severity in SJS patients is often underestimated when the meniscus is first observed, as the punctum is closed due to scarring or surgery. In SJS patients with severe dry eye, the dryness results in immense eye pain, and unstable tear film related to dry eye result in a change/loss of vision. For the treatment of dry eye in SJS, it is important to suppress chronic inflammation on the ocular surface, and 2% rebamipide ophthalmic solution reportedly helps to obtain ocular surface stabilization. Scleral contact lenses, as well as the newly developed limbal rigid contact lenses, improve the patients' visual acuity and reduce symptoms related to severe dry eye. Further studies and new therapeutic methods are needed to more effectively treat dry eye in patients afflicted with SJS/TEN. PMID- 30481811 TI - Meibomian Gland Dysfunction: Recent Progress Worldwide and in Japan. AB - In this review, the importance of Japanese research on meibomian gland dysfunction (MGD) is discussed from the perspective of global academic and clinical research on this topic. Many Japanese physicians and researchers have contributed to recent worldwide progress in various fields of MGD research, including pathophysiology, epidemiology, diagnosis, and therapy. In Japan, recent studies in the field of pathophysiology have provided direct evidence for the hypothesis that lipid composition and reactive oxygen species play a crucial role in the development and worsening of MGD. In the field of diagnosis, slit-lamp examination, in vivo confocal microscopy, and meibography have been widely used in studies from Japan. On the basis of the results of these studies, the MGD working group in Japan has proposed new diagnostic criteria for obstructive MGD. According to these criteria, obstructive MGD is considered present when ocular symptoms, anatomic abnormalities, and meibomian gland obstruction are present. In the field of therapy, devices and drugs newly developed in Japan have been shown to enhance the efficacy of lid hygiene and warm compression. Moreover, diquafosol and vitamin D3 have been shown to be effective for MGD. In conclusion, standardization of the diagnosis and treatment of MGD is necessary to enable all patients with MGD to receive appropriate treatment, and specific diagnostic criteria with cutoff values for each parameter are necessary to standardize the diagnosis of MGD. PMID- 30481812 TI - Inflamed Obstructive Meibomian Gland Dysfunction Causes Ocular Surface Inflammation. AB - Meibomian gland dysfunction (MGD) is one of the primary causes of evaporative dry eye. Stagnation of meibum induces an unstable tear film, thus resulting in shortened tear film breakup time and superficial punctate keratopathy (SPK) in the lower cornea and punctate staining of lower bulbar conjunctiva. MGD is sometimes accompanied with inflammation (termed "meibomitis") via the proliferation of bacteria in the meibomian gland and eyelash area. Meibomitis is strongly related to ocular surface inflammation such as corneal cellular infiltrates and neovascularization, SPK, and conjunctivitis. It is difficult to differentiate SPK caused by dry eye from that caused by meibomitis. When clinicians are unaware of the existence of meibomitis, and only aware of SPK on the cornea, they often try to treat SPK as it is caused by dry eye using dry eye specific eyedrops or even using punctual plugs when conservative therapy is ineffective. However, even when intensive dry eye therapy is applied, it may be unsuccessful until SPK caused by meibomitis is recognized and treated with systemic antimicrobial agents. Hence, the tear secreting glands, including the meibomian glands, and the ocular surface should be clinically considered as one unit (i.e., the meibomian gland and ocular surface [MOS]) when considering the pathophysiology and treatment of ocular surface inflammatory diseases (i.e., corneal epithelial damage). Following this clinical pathway, a treatment focusing on meibomian gland inflammation may be a more reasonable approach for meibomitis related or associated keratoconjunctivitis to more effectively treat this ocular surface disease. PMID- 30481813 TI - Contact Lens-Associated Dry Eye Disease: Recent Advances Worldwide and in Japan. AB - Contact lens wearers complain of various types of contact lens discomfort (CLD), which may result in the discontinuation of contact lenses. CLD is often associated with dry eye disease. A contact lens divides the tear film into two layers: the pre- and post-lens tear film. This change leads to instability of the pre-lens tear film, thinning of pre- and post-lens tear film thickness, and increased friction between the contact lens and the ocular surface. The Japanese Dry Eye Society recommends the diagnosis of tear film abnormality first (tear film-oriented diagnosis [TFOD]) and the treatment of dry eye disease based on TFOD (tear film-oriented therapy [TFOT]). These concepts can be applied for contact lens-associated dry eye disease (CLADE). Noninvasive tear film breakup time, tear volume evaluation, vital staining, and assessment of Meibomian glands are performed to evaluate the tear film. On vital staining analysis of CLADE, lid wiper epitheliopathy and conjunctival edge staining are major findings. In TFOT of CLADE, secretagogues of water or mucins, such as diquafosol and rebamipide, have been first used in Japan. Material, design, wettability, and friction coefficient of the contact lens could affect CLADE. Changes of contact lens may be an option in TFOD. However, the effects of contact lens properties on the tear film and ocular surface are still unclear. Further controlled studies are needed in the future. PMID- 30481814 TI - Dry Eye After LASIK. AB - Post-LASIK dry eye is the most common postoperative dry eye after ophthalmic surgeries. The clinical signs of post-LASIK dry eye include positive vital staining of the ocular surface, decreased tear breakup time and Schirmer test values, reduced corneal sensitivity, and decreased functional visual acuity. The symptoms and signs usually last for about 1 month after LASIK. A small number of patients continue to experience symptoms more than 1 year postoperatively. It has been suggested that the loss of corneal innervation caused by flap-making is the major cause, affecting the corneal-lacrimal gland, corneal-blinking, and blinking meibomian gland reflexes, resulting in decreased aqueous and lipid tear secretion and mucin expression. A new type of corneal refractive surgery, SMILE, which has less impact on corneal nerves, induces less postoperative dry eye, supporting the association between corneal denervation and postoperative dry eye. As LASIK enhancement by flap-lifting induces fewer dry eye symptoms and signs than initial surgery, factors other than neurotrophic effects may be involved in the mechanisms of post-LASIK dry eye. Post-LASIK ocular surface pain is a type of postoperative chronic pain and discomfort, and is thought to be a different clinical entity from dry eye, possibly induced by abnormal reinnervation or neural sensitization of peripheral nerves and the central nervous system after LASIK. Treatments include tear supplements, anti-inflammatory agents, meibomian gland dysfunction management, ointment and eye patches, punctal plugs, and autologous serum eye drops. For patients with preoperative dry eye, careful patient selection, and preoperative ocular surface management are mandatory. PMID- 30481815 TI - Medical Treatment for Dry Eye in Japan. AB - The etiology of dry eye has not been clarified. In the United States, the inflammation theory is supported as the main cause of dry eye, whereas the Asia Dry Eye Society has identified tear instability as the main cause. Based on this tear instability concept, the P2Y2 antagonist Diquas and the mucin secretagogue Mucosta were developed and launched in Japan over the last 5 years, and they have been widely prescribed to patients with dry eye. Moreover, Diquas has also been launched in other Asian countries, such as Korea, Thailand, and Vietnam. This report summarizes the efficacy and characteristics of these two eye drops to improve our understanding of dry eye. PMID- 30481816 TI - Autologous Serum and Serum Components. AB - Dry eye syndrome is a multifactorial condition on the tear and ocular surface. Autologous serum eye drop is an effective method for treating dry eye. Autologous serum eye drops are now widely used by specialists since a first report in 1975. The results of a systematic study showed that the efficacy of autologous serum eye drops remains ambiguous because its preparation methods and clinical application have not been standardized. To elucidate the efficacy of autologous serum eye drops, well-designed, large-scale, high-quality randomized controlled trials need to be conducted with standardized treatment and use. Since serum components are partially similar to tear components, autologous serum eye drops improve dry eye by supplying tear components such as growth factors, proteins, and vitamins. Adding to the evidence based on the treatment of dry eye, we have found a new treatment candidate from serum: selenoprotein P (SeP). The efficacy of SeP as a treatment for dry eye was revealed by applying SeP eye drops to a dry eye rat model. Compared with phosphate-buffered saline treatment, SeP eye drops significantly reduced the fluorescein score of the cornea and suppressed the oxidative stress in the cornea, which is related to onset of dry eye, leading to improved corneal disorder. We have developed a new dry eye model caused by oxidative stress that will be used to screen candidate molecules for antioxidative activity. PMID- 30481817 TI - Approach to Dry Eye in Video Display Terminal Workers (Basic Science). AB - The use of video display terminals (VDT) and staring at screens of technologic devices, including desktops, laptops, tablets, and smartphones have become ubiquitous in a wide range of age groups because of the rapid advance of network culture-mediated communications. The incidence of dry eye is particularly high in workers that work with VDT. To facilitate an understanding of the mechanisms of VDT-associated dry eye, as well as to develop novel treatment approaches, a VDT worker dry eye model was created. The procedure involved placing rats on a swing in combination with exposure to an evaporative environment. This animal model reveals that the blink frequency was reduced to one-third of the nonswing riding levels, which is similar to the results that have been reported by VDT users. Pathologic analysis of the lacrimal gland in this dry eye model showed that the decrease in tear secretion was accompanied by a decrease in the acinar cell number, and an enlargement of acinar cells was accompanied by filling with an increased volume of secretory vesicles and a loss of intracellular cell structure, suggesting the involvement of lacrimal hypofunction. An interventional study using this dry eye model showed that oral supplementation of some natural ingredients is a possible therapy for relieving symptoms of VDT-associated dry eye. Further investigations for the establishment of VDT use-associated dry eye models that may be used to evaluate ocular discomfort that mimic the condition in humans are needed to understand and modify this type of dry eye. PMID- 30481818 TI - Systemic Health and Dry Eye. AB - Dry eye disease (DED) is a local ocular surface disease caused by a multitude of factors and involves multiple interacting mechanisms. The prevalence of DED is rapidly increasing in the modern aged society, and it is considered a major ocular condition with a high prevalence among the elderly, who frequently have multiple comorbidities. Systemic medical conditions can have a negative impact on ocular health. In addition, a variety of systemic drugs can also induce DED via multiple mechanisms. The adequate management of general systemic diseases may control DED progression. Furthermore, according to the antiaging theory, an appropriate lifestyle intervention is preventive for both DED and general systemic disease. In this article, we focus on systemic health and DED to provide a broad overview of the association between systemic health, particularly in relation to aging, and DED. Ophthalmologists should carefully interview patients with DED regarding systemic comorbidities to deliver optimal treatment. A systemic approach, including the use of supplements and lifestyle intervention, should be used in addition to conventional local treatment. PMID- 30481819 TI - Sleep Disorders are a Prevalent and Serious Comorbidity in Dry Eye. AB - Purpose: Sleep is an essential life habit and closely associated with lifespan, diabetes, hypertension, and mental health. Sleep disorders are a prominent, but overlooked problem in patients with dry eye disease (DED), characterized by a poor sleep index, short sleep duration, long sleep latency, and poor subjective sleep. DED and sleep disorders are more prevalent in women than men. Moreover, sleep quality in DED is worse than in other eye diseases, including glaucoma, retinal diseases, cataract, and allergic and chronic conjunctivitis. Methods: We reviewed the literature for studies investigating sleep and health, eyes and sleep, and DED and sleep, in terms of systemic and eye health, especially in women. Results: Two studies reported that approximately half of patients with DED suffer from poor sleep. The severity of mood disorders, including anxiety and depression, is correlated strongly with sleep disorders in DED, and the symptoms and signs of DED, especially pain, also are correlated with sleep quality. Sleep disorders are documented in primary Sjogren's syndrome and an association with sleep apnea and depression is suggested. Primary Sjogren's syndrome includes arthritis and other rheumatic disease causing pain and fatigue; however, how sicca contributes to sleep disorders is not known. Conclusions: Possible explanations for sleep disorders in DED may be depression, pain, and eye exposure at night. Reciprocal effects may be expected and consultation-liaison psychiatry is recommended for the management of sleep disorders in DED. Topical medication and lid heating also may be advantageous for sleep quality in DED. PMID- 30481820 TI - Secreted Mucins on the Ocular Surface. AB - Mucins, which play important roles on the ocular surface in wettability, lubrication, and barrier function, are classified into two categories: secreted mucins and membrane-associated mucins. The most important secreted mucin on the ocular surface is MUC5AC, which is secreted by the conjunctival goblet cells. In the human conjunctiva, goblet cells are present in higher concentrations in the fornix, inferior nasal bulbar, and the lid wiper on the lid margin. The number of conjunctival goblet cells and MUC5AC expression/secretion are decreased in a patient with dry eye. In Japan, drugs that stimulate mucin secretion or increase the number of conjunctival goblet cells are commercially available. A P2Y2 receptor, diquafosol, stimulates tear fluid secretion from conjunctival epithelial cells and promotes mucin secretion from conjunctival goblet cells. Rebamipide was marketed originally as an oral therapeutic drug to treat gastritis in Japan. Topical rebamipide increases numbers of goblet cells in the bulbar conjunctiva and the lid wiper area of palpebral conjunctiva. Many researchers have reported decreases in the ocular surface mucin expression including MUC5AC secreted by goblet cells in patients with dry eye. However, it is unknown whether changes in mucin expression on the ocular surface cause or result from dry eye. Further study is needed to determine the true mechanism of dry eye disease. PMID- 30481821 TI - The Ocular Surface Glycocalyx and its Alteration in Dry Eye Disease: A Review. AB - Many studies have revealed that transmembrane mucins, large glycoproteins with heavily glycosylated glycans, are essential for maintaining ocular surface epithelium lubrication and wettability. Recent reports indicate that transmembrane mucins and galectin-3, a chimera type of galectin that binds beta galactoside in the glycan, play a crucial role in maintaining the epithelial glycocalyx barrier. This review summarizes current evidence regarding the role of galectin-3, the role of the three major transmembrane mucins (i.e., MUC1, MUC4, and MUC16), in the maintenance of ocular surface wettability and transcellular barrier. Pathological mechanisms of glycocalyx barrier disruption and epithelial surface wettability decreases in dry eye disease are also summarized. Lastly, new ophthalmic drugs that target transmembrane mucin are described. PMID- 30481822 TI - Potential Role of Oxidative Stress in Ocular Surface Inflammation and Dry Eye Disease. AB - Reactive oxygen species (ROS) are produced as a by-product during the mitochondrial respiration of the oxygen and potentially able to damage the tissues. Oxidative stress occurs as a result of the disruption of the balance between the anti-oxidant system and the pro-oxidant system found in cells. It has been accepted that overexpression of ROS can be induced in the ocular surface as a result of many acute and chronic diseases and even in normal aging. Recent studies demonstrated that oxidative stress damages the ocular surface and plays an important role in the mechanism of dry eye disease. There is a need to investigate the therapeutic modalities employing topical/systemic use of antioxidants in dry eye disease. This review will summarize the recent studies showing the important relationship between oxidative stress and dry eye disease. PMID- 30481823 TI - Regeneration of Lacrimal Gland Function to Maintain the Health of the Ocular Surface. AB - Dry eye is a multifactorial disease that is one of the most common diseases worldwide. A major cause of dry eye is the deficiency of aqueous tears, which are mainly secreted from the lacrimal gland. The lacrimal gland plays an important role in maintaining the health of the ocular surface and protecting it from environmental exposure. Dry eye can lead to ocular irritation and discomfort, as well as severe ocular surface diseases (e.g., ocular infections, corneal ulcerations, and ocular surface keratinization). These severe diseases can be induced by an atrophied or injured lacrimal gland; current therapies cannot completely restore the function of lacrimal gland. To develop more definitive therapies, it is important to understand lacrimal gland biology at the molecular level, as well as inflammatory processes affecting the function of the gland. During severe inflammation, the tissue structure of the lacrimal gland is destroyed; it is replaced by scar formation during wound healing, which leads to lacrimal gland dysfunction. Using an animal model of lacrimal gland dysfunction, many investigators have studied molecular mechanisms of inflammation in the lacrimal gland. To restore lacrimal gland function, the lacrimal acini must be restored in their niche. Notably, organ transplantation therapies have been reported to restore lacrimal gland function, directly or indirectly, in animal models. In this review, we describe the current understanding of the lacrimal gland as the therapeutic target for dry eye diseases, as well as recent advances in the field of lacrimal gland cell-based therapy to treat severe dry eye diseases. PMID- 30481824 TI - Advances in Functional Restoration of the Lacrimal Glands. AB - The lacrimal glands produce tears to support a healthy homeostatic environment on the ocular surface. The lacrimal gland dysfunction characteristic of dry eye disease causes ocular discomfort and visual disturbances and in severe cases can result in a loss of vision. The demand for adequate restoration of lacrimal gland function has been intensified due to advances in stem cell biology, developmental biology, and bioengineering technologies. In addition to conventional therapies, including artificial tears, tear alternatives (such as autologous serum eye drops) and salivary gland transplantation, a regenerative medicine approach has been identified as a novel strategy to restore the function of the lacrimal gland. Recent studies have demonstrated the potential of progenitor cell injection therapy to repair the tissue of the lacrimal glands. A current three dimensional (3D) tissue engineering technique has been shown to regenerate a secretory gland structure by reproducing reciprocal epithelial-mesenchymal interactions during ontogenesis in vitro and in vivo. A novel direct reprogramming method has suggested a possibility to induce markers in the lacrimal gland developmental process from human pluripotent stem cells. The development of this method is supported by advances in our understanding of gene expression and regulatory networks involved in the development and differentiation of the lacrimal glands. Engineering science has proposed a medical device to stimulate tearing and a bio-hybrid scaffold to reconstruct the 3D lacrimal gland structure. In this review, we will summarize recent bioengineering advances in lacrimal gland regeneration toward the functional restoration of the lacrimal glands as a future dry eye therapy. PMID- 30481825 TI - Results of Detailed Investigations Into Stevens-Johnson Syndrome With Severe Ocular Complications. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute inflammatory vesiculobullous reactions of the mucosa of the ocular surface, oral cavity, and genitals, and of the skin. Severe ocular complications (SOC) are present in about half of SJS/TEN patients diagnosed by dermatologists. We review our group's findings on the genetic predisposition for and the etiology of SJS/TEN with SOC. We suspected that abnormal innate mucosal immunity, resulting in an anomalous response to commensal bacteria that usually do not elicit such a response, contributes to the ocular surface inflammation seen in SJS/TEN with SOC. We found that cold medicines, including multi-ingredient cold medications and nonsteroidal anti-inflammatory drugs, were the main causative drugs especially in patients with SJS/TEN with SOC. Cold medicine-related SJS/TEN (CM SJS/TEN) with SOC was strongly associated with HLA-A*02:06 in the Japanese populations, and significantly associated with HLA-B*44:03 in the Japanese and in Indian and Brazilian populations. Single nucleotide polymorphism association analysis showed that the Toll-like receptor 3 (TLR3), prostaglandin-E receptor 3 (PTGER3), and IKZF1 gene were significantly associated with CM-SJS/TEN with SOC and that they could regulate mucocutaneous inflammation including that of the ocular surface. As we found several HLA-SNP sets with a high odds ratio, we postulated that they may help to predict the possible development of SJS/TEN with SOC. From our findings we suggest that besides microbial infection and cold medicines, a combination of multiple gene polymorphisms and their interactions contribute strongly to the onset of CM-SJS/TEN with SOC. PMID- 30481826 TI - Inflammatory Response in Dry Eye. AB - Purpose: Dry eye is a major ocular pathology worldwide. Although dry eye is a multifactorial disease, recent studies have shown that chronic immunologic processes have a pivotal role in its pathogenesis, characterized by the infiltration of immune cells in the lacrimal glands, elevated levels of tear inflammatory cytokines, and increased density of immune cells in the cornea and conjunctiva. This review describes the recent advances in understanding the relationship between dry eye and inflammation. Methods: This narrative review is based on searches of recent international literature using terms related to the immune response in dry eye, and includes clinical trials, animal experiments, and expert reviews. Results: Although dry eye presents clinically as tear film instability associated with corneal/conjunctival epithelial disorders, Meibomian gland dysfunction, and decreased visual function, recent laboratory and clinical studies have indicated inflammation in the lacrimal glands, Meibomian glands, conjunctiva, cornea, and aqueous tears. Furthermore, inflammation at these locations leads to conjunctival goblet cell apoptosis, corneal epithelial barrier disruption, and corneal nerve damage. These inflammatory outcomes can be exacerbated by intrinsic and extrinsic factors, such as aging, sex steroid hormone, autoimmune diseases, contact lens use, visual display terminals, and dry environment. Conclusions: Recent advances in dry eye research have revealed the inflammatory process and its pathogenesis, which has been proposed as an "inflammatory vicious cycle" of dry eye. Comprehensive assessment of dry eye based on inflammation will improve the selection of treatments and help break the inflammatory cycle in clinical settings. PMID- 30481827 TI - Data-Driven Classification of Dysarthria Profiles in Children With Cerebral Palsy. AB - Purpose: The objectives of this study were to examine different speech profiles among children with dysarthria secondary to cerebral palsy (CP) and to characterize the effect of different speech profiles on intelligibility. Method: Twenty 5-year-old children with dysarthria secondary to CP and 20 typically developing children were included in this study. Six acoustic and perceptual speech measures were selected to quantify a range of segmental and suprasegmental speech characteristics and were measured from children's sentence productions. Hierarchical cluster analysis was used to identify naturally occurring subgroups of children who had similar profiles of speech features. Results: Results revealed 4 naturally occurring speech clusters among children: 1 cluster of children with typical development and 3 clusters of children with dysarthria secondary to CP. Two of the 3 dysarthria clusters had statistically equivalent intelligibility levels but significantly differed in articulation rate and degree of hypernasality. Conclusion: This study provides initial evidence that different speech profiles exist among 5-year-old children with dysarthria secondary to CP, even among children with similar intelligibility levels, suggesting the potential for developing a pediatric dysarthria classification system that could be used to stratify children with dysarthria into meaningful subgroups for studying speech motor development and efficacy of interventions. PMID- 30481828 TI - Role of Cross-training in Orthopaedic Injuries and Healthcare Burden in Masters Swimmers. AB - We determined whether the incidence of injuries would increase with advancing age and whether the participation in cross-training would be related to a decreased rate of injuries and healthcare costs in Masters swimmers. A total of 499 swimmers (55+/-14 years of age) belonging to US Masters Swimming completed a comprehensive questionnaire that included questions regarding their medical history as well as their training history. In average, swimmers had been training for 13+/-12 years, and 35, 40, and 47% participated in running, cycling, and dryland resistance training, respectively. According to the logistic regression, prevalence of injuries increased significantly but modestly with advancing age (p<0.05). Linear regression analysis showed that for every 1 month increase in the length of injury, healthcare costs increased by 7.4% (p<0.05). Linear regression and logistic regression analyses determined that overall volume of swimming training was not related to age or incidence of injuries, respectively. Multinomial logistic regression analyses using age and sex as predictors demonstrated that the odds of reporting a swim-related injury were significantly lower for individuals who participated in any number of cross-training activities compared with those who do not cross-train (p<0.05). Regular participation in any cross-training modality was inversely related to age (p<0.05). We concluded that the diversification of the overall training program by incorporating cross training may be an important strategy to reduce sport-specific injuries among Masters athletes. PMID- 30481829 TI - Seasonal Difference in Bone Characteristics and Body Composition of Elite Speed Skaters. AB - We investigated the changes in bone characteristics and body composition of elite speed skaters across two competitive seasons. Twelve elite speed skaters (age 23+/-4 years; height 1.73+/-0.09 m; body mass 68.5+/-8.8 kg; mean+/-1 SD) were assessed by DXA and pQCT for Bone Mineral Density (BMD), Bone Mineral Content (BMC), area, bone strength, cortical thickness and density at four points over the course of four competitive seasons. Body composition data was also collected. A main effect of time was shown for whole body BMC, right leg BMC, and trabecular area (P<0.05). Whole body BMC was higher during pre-season and end of season in comparison to mid-season (1.0%, P=0.007; 0.8%, P=0.017), right leg BMC was higher at the pre-season scan in comparison to the post pre-season scan (1.8%,P=0.020) and trabecular area was higher during the mid-season and end of season when compared to the pre-season (1.4%, P=0.012; 1.0%, P=0.003). Seasonal changes in bone characteristics and body composition are shown in elite speed skaters over a competitive season. The changes are thought to be a result of fluctuations in training load. These data may have implications for training design and injury risk management in elite sport. PMID- 30481830 TI - 8-Week Basic Military Training Improves Adiponectin Multimer Ratio in Healthy Young Males. AB - To investigate the effect of exercise on adiponectin in young healthy human males, we examined serum total adiponectin and high-molecular-weight (HMW) adiponectin in newly recruited male soldiers who participated in an 8-week basic military training (BMT). A total of 95 males (mean age, 18.79+/-1.50 years) were sampled from among 1,100 new male army recruits in China. Participants were separated into 3 groups according to their body mass index (BMI): overweight group (BMI: 24.9 kg/m2 to<30 kg/m2; n=26); normal-weight group (BMI: 18.5 kg/m2 to<24.9 kg/m2; n=40); and underweight group (BMI:<18.5 kg/m2; n=29). Anthropometric measurements, fasting serum total adiponectin, HMW adiponectin, and lipid profiles were recorded at baseline and at the end of the 8-week BMT. After the 8-week BMT, the HMW/total adiponectin ratio (HMW/total ratio) and HDL cholesterol improved significantly (p<0.001 and p<0.001, respectively). HMW/total ratio showed significant correlations with HDL cholesterol. Our study suggests that an 8-week BMT can improve the HMW/total ratio in healthy young males regardless of their BMI and anthropometry. Both HMW/total ratio and HDL cholesterol can serve as potential biomarkers for assessing the efficacy of exercise and may have metabolic benefits for preventing obesity and obesity related disease. PMID- 30481831 TI - Body Composition and Strength Parameters in Elite Judo Athletes 5 Years after Anterior Cruciate Ligament Reconstruction. AB - The purpose of this study was to investigate if there are still deficits in muscle mass or strength capabilities in elite judo athletes with a history of anterior cruciate ligament reconstruction (ACLR) after their return to the sport. Therefore, bioimpedance analysis, 3D-laser thigh circumference measurement and isokinetic dynamometry in a closed kinetic chain were used. The side-to-side differences were investigated in a group of judo athletes 5 years after ACLR (n=17) and compared with a group of healthy judo athletes (n=27). Neither thigh circumferences, nor muscle masses of the lower extremities differed in formerly injured judo athletes compared to healthy judo athletes. In contrast, isokinetic strength testing showed a significantly larger side-to-side difference of peak muscle force in formerly injured judo athletes (p=0.021). They provided significantly lower peak forces with the formerly injured leg than with the non injured leg (p<0.001). The authors conclude that strength capabilities, but not body composition, remains altered in recovered judo athletes in mean 5 years after ACLR and definitely after their return to sports. This indicates that the focus of rehabilitation protocols and return to sports assessments should focus more on maximum strength capabilities. PMID- 30481832 TI - [Correction: Pregnancy Rhinitis - an Update]. PMID- 30481833 TI - Retrospective Analysis of Whole-Body Magnetic Resonance Imaging of Bone Manifestations in Long-Term Treated Patients with Gaucher Disease Type 1. AB - PURPOSE: We retrospectively assessed bone and visceral manifestations in patients with Gaucher disease type 1 (GD1) with whole-body magnetic resonance imaging (WB MRI) to determine the effects of different timing in initiating long-term enzyme replacement therapy. MATERIALS AND METHODS: In 17 patients with GD1, we performed 2 WB-MRI examinations at a median interval of 13 months. Patients had received enzyme replacement therapy with alglucerase/imiglucerase for a median of 13 years prior to the first examination. MRI results were retrospectively stratified based on treatment initiation into 2 groups: "early" (age <=12 years, median 5 years) and "late" (during adulthood, median 32 years). We evaluated occurrence of irreversible avascular necroses (AVN) and applied several semi-quantitative scores, including the Bone-Marrow-Burden (BMB) score, the Dusseldorf-Gaucher score (DGS), the Vertebra-Disc-Ratio (VDR), and the Gaucher disease type 1 Severity Scoring System (GD-DS3). RESULTS: MRI assessments showed no AVN in the "early" group. AVN were observed in 2 patients of the "late" group; one also had a splenic Gaucheroma. The follow-up examinations showed slight improvements in the BMB-score, DGS, and VDR, with similar tendencies in both treatment groups. The GD-DS3 score only improved in "late" group. CONCLUSION: This retrospective study supported the ongoing clinical value of enzyme replacement therapy with alglucerase/imiglucerase, as WB-MRI-based scores stayed constant or slightly improved even after long-term treatment. Secondary complications were only observed in the late treatment group. Our results suggest that "early initiation" of enzyme replacement therapy may protect the bone. PMID- 30481834 TI - [Avulsion Fractures of the Ischial Tuberosity and Resulting Ischiofemoral Impingement - a Case Report with Literature Review]. AB - INTRODUCTION: Apophyseal avulsion fractures of the ischial tuberosity are rare injuries and therefore often not diagnosed in a timely manner. Healing may then result in massive hypertrophic ischial tuberosity. This can cause ischiofemoral impingement symptoms. Due to the low incidence and scarce literature, the optimal treatment and surgery is unclear. MATERIALS AND METHODS: A literature search was carried out using the online medical database "PubMed". The findings of the literature were then applied to a clinical case of delayed diagnosis of the apophyseal avulsion fracture of the ischial tuberosity. RESULTS: There is no gold standard in the literature for the treatment of avulsion fractures on the ischial tuberosity. Nearly 90% are treated conservatively and a fragment dislocation of more than 2 cm is often the indication for surgical care. However, the surgical procedures described are very diverse. An ischiofemoral impingement symptom may result from excessive ossification of the ischial tuberosity, bringing the ischiofemoral distance to the critical limit of 2 cm. CONCLUSIONS: The timely correct diagnosis and initiation of a therapy is crucial for the later outcome of the patient. Ischiofemoral impingement symptoms may be the indication of bony displacement of the ischial tuberosity as a result of injury. Therapy is then surgical with partial resection of the ischial tuberosity and plate osteosynthesis. PMID- 30481835 TI - [Characterisation of Victims Of Violence in the A & E Department and Analysis of the Acceptance of a Medico-Legal Expertise Centre After its Implementation vs. Multi-Year Consolidation]. AB - BACKGROUND: People who have become victims of domestic or public violence often suffer long-term physical, psychological and social impairment. Due to physical injury, the first contact with the health care system is frequently an A & E Department. Thus, physicians and especially surgeons play a key role in detecting victims of domestic or public violence. The specific needs of victims are adequate medical treatment of injuries, forensic documentation, as well as interdisciplinary medical support to prevent further morbidity and violence. To take this into account, so-called expertise centres for victims of violence have been established at several locations in Germany in recent years. In this study: I. We tried to define the characteristics of victims of domestic and public violence to ensure better identification by physicians/surgeons. II. We elucidate the acceptance and effectiveness of such an expertise centre one year after its implementation and for a period of three years (2007 - 2009) and for a follow-up period of three years (2014 - 2016) after establishment. MATERIAL AND METHODS: Patients were prospectively classified as victims of violence by the attending physician at the A & E Department and further treatment was initiated by the expertise centre for victims of violence. Medical reports from the A & E Department were analysed anonymously and compared with the number of patients of the expertise centre for victims of violence who had been referred from A & E Department. RESULTS: Orthopaedic and trauma surgery is the main referring discipline for the expertise centre for victims of violence. 0.9% of patients (2007 - 2009) and in the follow-up period (2014 - 2016) even 1.6% of patients were identified as victims of violence. However, the acceptance of such a centre fell from 22.2% (2007 - 2009) to 17.2% (2014 - 2016). CONCLUSION: Physicians and especially trauma surgeons are responsible for identifying victims of domestic or public violence and ensuring further treatment. Accordingly, it is crucial that the expertise centre should characterise the victims of violence and be aware of their different needs, if the expertise centre is to be accepted. The results of this study indicate that interdisciplinary training and close cooperation between traumatology and legal medicine are the main prerequisites for continuous improvement in the treatment of victims of violence. PMID- 30481836 TI - [An Opinion Survey of Orthopaedic and Traumatology Surgeons Working in Outpatient Care (Society, Laws and Patients)]. AB - BACKGROUND: The German health care system is well accepted, but efficiency, costs and patient satisfaction are sometimes criticised. Opinions and models prevail, and empirical data are rarely presented, although quantitative data are a precondition to assess the acceptance of the health care system. METHOD: To determine the appraisal of the patient-doctor relationship, economic situation and cooperation with clinical institutions, a 37 item was developed where participants indicated their agreement with a statement on a four point Likert scale. This questionnaire was answered by 525 German orthopaedic and/or traumatology surgeons, representing 7.7% of all German specialists working in outpatient care. RESULTS: 75% of all respondents felt challenged by demanding patients and a need for justification; what was less pronounced was the feeling of being exploited as physicians. Restrictions in medical treatment from budgeting expenses were seen by 74%. More than 90% considered that it was impossible to finance their medical practice expenses by conservative medical treatment only. The respondents felt similarly critical about the current cooperation with hospitals - only 19% were not interested in closer cooperation and 96% advocated higher fees for this cooperation. 74% confirmed that hospitals are taking over outpatient tasks, whereas only 35% agreed that more clinical patient care can be provided by outpatient providers, especially due to legal restrictions. DISCUSSION: Practitioning orthopaedic and traumatology surgeons feel exploited by uninformed patients, misallocation of reimbursement funds and legal restrictions, as well as unilateral substitution of outpatient care by hospitals. They do not consider that the current structures are sustainable for long term patient care. PMID- 30481837 TI - [Clubfoot Therapy in Accordance with Ponseti - Current Standard]. AB - This manuscript evaluates the recent standard concept for clubfoot treatment. With regard to the history of clubfoot therapy and the return to conservative methods, the focus is laid on Ponseti's treatment concept. Due to its development according to the precise analysis of the pathoanatomy, the practical principle is simple and easy to learn and consists basically of two redression maneuvers, percutaneous achillotenotomy, and boots and bar abduction treatment. Therefore, about 60 years after its implementation in Iowa it can be said to be the worldwide golden standard. It is known that Ponseti treated feet are better with regard to function and pain when compared to surgically treated clubfeet. The best results can be achieved when one sticks exactly to the method. Hence, plaster of Paris above the knee casts yield better results than fibreglass materials or short-leg casts. The brace should be worn 23 hours a day for 3 months and during sleep until the fourth birthday of the child. For reasons including the structured concept of treating relapses, the method is applicable in high and low income countries. Before transferring the tibialis anterior tendon, it is mandatory to correct the relapse of the heel varus. The Ponseti method can also correct clubfeet of non-idiopathic origin. Although a higher rate of relapses must be expected in these cases, initial Ponseti treatment lowers the extent of the necessary surgery. Emphasis is put on the importance of counselling prenatally as well as during the boots and bar period. To yield the best results, it is necessary to train and counsel physicians as well as parents. There is no need to fear significant delay in reaching motor milestones when clubfeet are treated conservatively. Other conservative methods - such as the French physiotherapy method - are able to correct the deformity, but usually do not consist of a concept as structured as the Ponseti method. They are also often more time consuming for the families when compared to Ponseti's technique and are not available ubiquitously. While the diagnosis of the clubfoot deformity is still a clinical one and scores are the main tools for grading the severity today followed by X-rays and to some extent sonography, in experimental settings MRI may be helpful in finding abnormalities in muscles, blood vessels, and cartilage structures. The study of genetic associations of pathway abnormalities and single nucleotide polymorphisms with regard to the development of clubfeet enhances our knowledge concerning the origin of the deformity during limb development. In the future, this may enable us to provide not only a better prognosis for the outcome but also a more individualised therapy for each child born with a clubfoot. PMID- 30481839 TI - Two sides of the same coin [Editorial]. PMID- 30481838 TI - [Spinal Injections, Epidural Neurolysis and Denervation for Specific Low Back Pain and Sciatica]. AB - BACKGROUND: Many members of the adult population suffer acute low back pain at some stage in life. A specific cause is found in only a rather small number of these patients. Some of the patients develop chronic low back pain and this is a major source of disability. On the other hand, there has been a great increase in Germany in the number of spinal operations due to degenerative spine disease and, in turn, unnecessary surgery on the spine is under debate. METHODS: This is a narrative review of different minimally invasive spine procedures in the treatment of specific low back pain. The effectiveness of spinal injections, radiofrequency of the facet joints as well as epidural adhesiolysis/neurolysis are described. An analysis of the literature was performed via PubMed, Medline and the Cochrane Database. RESULTS: Facet-, epidural and intradiscal steroid injections for specific pain generators in the degenerative spine show different short- and long-term results; they are able to improve low back pain in specific patients with chronic low back pain and may be able to prevent some of these patients from having to undergo open surgery. Furthermore, there are promising results from interventions such as epidural neurolysis for sciatica and radiofrequency of the medial branch of the dorsal root for the treatment of axial facet-related back pain. Facet and intradiscal steroid injections give only short term effects in axial low back pain and should therefore only be considered reluctantly, whereas the different forms of epidural steroid injections in patients with sciatica due to radicular compression offer a well proven adjuvant treatment option within a conservative therapeutic regimen. The overview of the literature with the use of different steroids has shown that use of non particulate steroids show better results with respect to the safety and avoidance of major complications, especially when used at the cervical spine. However, in Germany the use of these steroids is still off label and patients have to give informed consent prior to injection. In summary, careful use of spinal injections and interventions within a conservative physiotherapeutic regimen seem to improve chronic back pain and, in turn, to be able to prevent some patients from having to undergo spine surgery. PMID- 30481840 TI - Iatrogenic external auditory canal cholesteatoma with mastoid erosion. PMID- 30481841 TI - Eagle syndrome: Transient ischemic attack and subsequent carotid dissection. PMID- 30481842 TI - Primary cutaneous histoplasmosis. PMID- 30481843 TI - Huge primary leiomyosarcoma of the thyroid gland. PMID- 30481844 TI - Clinical outcome of revision cartilage tympanoplasty. AB - We retrospectively reviewed 32 ears from 30 adult patients with chronic otitis media who underwent revision tympanoplasty using cartilage graft (performed by a single surgeon) from January 10, 2011, to May 10, 2016. All procedures were performed using an endaural incision for both temporalis fascia graft and tragal cartilage graft harvesting. The overall surgical success rate was 93.3%. The average preoperative hearing level was 43.1 +/- 17.3 dBHL, and the average postoperative hearing level was 39.2 +/- 18.2 dBHL, representing a significant improvement. The average air-bone gap was 19.4 +/-7.6 dB preoperatively and 16.9 +/- 9.9 dB postoperatively. Also of note, the improvement in air-bone gap reached the level of significance at 500 Hz (p = 0.023). We conclude that using cartilage graft in revision tympanoplasty is a safe and reliable technique with good surgical outcomes. Using one single endaural incision for both fascia and cartilage harvesting is simple while achieving aesthetic wound healing. PMID- 30481845 TI - Persistent local demucosalization after endoscopic sinus surgery: A report of 3 cases. AB - Mucosal preservation is paramount to achieving successful outcomes after endoscopic sinus surgery (ESS). Despite best surgical practices and implementation of evidenced-based postoperative care, patients in rare cases might exhibit persistent demucosalization that is recalcitrant to conservative therapies. We retrospectively reviewed the records of 3 patients-a 63-year-old woman, a 67-year-old woman, and a 43-year-old man-who experienced clinically significant local demucosalization after uncomplicated ESS despite routine surgical and postoperative management. We collected data on the characteristics of presentation, wound management strategies, and postoperative care practices. Two patients achieved remucosalization with mechanical debridement, gelatin sponge placement, and intensive moisturization therapy. Our experience suggests that surgical debridement of these chronic, persistent demucosalized wounds may be an effective management strategy for patients who develop this unusual and rare postoperative complication. Biopsy and culture of the persistently demucosalized wound bed may be useful in recognizing the presence of worrisome disease processes and identifying any tenacious infectious agents so that more appropriate therapy can be initiated if necessary. PMID- 30481846 TI - Desmoid tumors of the head and neck: Two decades in a single tertiary care unit and review of the literature. AB - Desmoid tumors (DTs) of the head and neck have typically been classified as extra abdominal, although the anatomic challenges of the head and neck warrant consideration of these DTs as a special entity. We present a review of DTs and describe our series of five patients with DTs of the head and neck treated within 2 decades. Altogether, 53 patients with DTs treated surgically at a tertiary care center over a 20-year period were retrospectively reviewed. Outcomes of the treatment of DTs of the head and neck (n = 5) were analyzed as a case series. DTs are rare, histologically benign, but locally aggressive tumors. In our series of 5 patients with head and neck DTs, no patient experienced a recurrence during a median follow-up of 47.5 months (range 13 to 150), although all had positive histologic margins. The functional integrity of vital structures over meticulous radicality of the tumor resection must be considered, especially in the head and neck. PMID- 30481847 TI - Invasive fungal rhinosinusitis: An Indian perspective. AB - Invasive fungal rhinosinusitis (IFRS) is a fatal disease of the nose and paranasal sinuses that typically affects immunocompromised patients. Data on this disorder, which is rare and difficult to diagnose, are lacking in the literature. We collected comprehensive data from 9 patients (7 males, 2 females) with a mean age of 34 years (range: 6 to 58) with IFRS who were treated at our center and examined the factors associated with successful treatment. The parameters examined were patient demographics, disease characteristics, clinical course including surgical and medical therapy, treatment, fungal species involved, and long-term survival at follow-up. The mean duration of symptoms was 33 days. The most common presenting symptoms were loss of vision (67%), headache (55%), and nasal discharge (33%). The middle meatus, middle turbinate, and sphenoethmoidal recess were the most commonly involved sites. Imaging criteria were not definitive in diagnosing IFRS. Early aggressive endoscopic debridement of involved structures was done in all patients with supplementary medical treatment with antifungal agents, which led to complete recovery in most patients. In the remaining patients, subsequent debridement was needed along with more aggressive medical treatment with more than one antifungal agent concurrently. Mortality was 0% after follow-up of 1 year. IFRS is rare, difficult to diagnose, and can present with inconsistent symptoms. Aggressive surgical treatment along with medical treatment should be considered in these patients for complete recovery. PMID- 30481848 TI - Anxiety and depression in patients with sudden one-sided hearing loss. AB - Sudden sensorineural hearing loss is a hearing loss of >30 dB in at least three consecutive frequencies that occurs in 3 days. The aim of this study was to investigate anxiety and depression caused by sudden, idiopathic, one-sided hearing loss. The levels of anxiety and depression in patients with this type of hearing loss were determined using the Beck Anxiety Scale (BAS) and the Beck Depression Inventory (BDI) at the time of the patient's first visit. In total, 56 patients (32 men and 24 women) with a mean age of 32.8 +/- 9.9 years (range: 20 to 58 years) were selected as the patient group and 45 individuals without symptoms of anxiety and depression were selected as the control group. The mean pretreatment air-conduction threshold and bone-conduction threshold were 61.1 +/- 26.1 and 49.4 +/- 13.8, respectively. In the patient group, the pretreatment mean anxiety, depression, and hopelessness scores were 19.5 +/- 10.7, 11.6 +/- 8.4, and 6.2 +/- 4.7, respectively. The control group's mean anxiety, depression, and hopelessness scores were 4.1 +/- 3.0, 3.8 +/- 2.1, and 1.8 +/- 1.0, respectively. For all the tests, the difference between the patient group and the control group was statistically significant (p < 0.001 for all). Hearing levels were not correlated with scores on the BAS, BDI, and Beck Hopelessness Scale (p = 0.1, p = 0.6, and p = 0.4, respectively). In conclusion, the results of this study show that sudden hearing loss can cause anxiety and depression. Questioning patients with sudden hearing loss about symptoms associated with anxiety and depression might be useful, and a psychiatric consultation should be requested if necessary. PMID- 30481849 TI - Serum levels of oxidative stress indicators and antioxidant enzymes in Bell palsy. AB - We conducted a prospective study to comparatively evaluate serum levels of malondialdehyde, an oxidative stress indicator, and the antioxidant enzymes glutathione, catalase, and superoxide dismutase in patients with Bell palsy. Our study population was made up of 30 patients with Bell palsy-15 men and 15 women, aged 25 to 68 years (mean: 50.4)-who were seen in the Department of Otorhinolaryngology at a tertiary care medical center. For comparison purposes, we recruited 26 healthy age- and sex-matched controls-16 men and 10 women, aged 40 to 67 years (mean: 54.3). Serum samples were obtained from all participants before the initiation of steroid treatment to the Bell palsy patients. A correlation was sought between demographic data and serum levels of malondialdehyde, glutathione, catalase, and superoxide dismutase. We found that the serum level of malondialdehyde was significantly higher in the Bell palsy group and that the levels of glutathione, catalase, and superoxide dismutase were all significantly lower (p < 0.001 for all comparisons). Correlation analysis revealed that only superoxide dismutase levels were positively correlated with age (r = 0.347, p = 0.009). We suggest that oxidative stress and antioxidant mechanisms may be involved in the pathogenesis of Bell palsy. In this context, serum levels of malondialdehyde, glutathione, catalase, and superoxide dismutase may serve as biomarkers in the diagnosis and follow-up of Bell palsy. Confirmation of the validity, reliability, and reproducibility of these findings necessitates further prospective, randomized clinical trials in larger populations. PMID- 30481850 TI - Paraneoplastic syndrome or metastatic sinonasal neuroendocrine carcinoma? Clinical conundrum. AB - We report a case of a middle-aged woman with a diffuse, nonenhancing, progressively atrophic T2-hyperintense lesion involving the left frontotemporal lobes and insula found to be synchronous high-grade sinonasal neuroendocrine carcinoma (SNEC) after initial endonasal resection. In 2014, a 47-year old woman underwent resection of a left-sided high-grade ethmoidal neuroendocrine carcinoma after presentation with weight gain and increased levels of serum and urine cortisol. Concurrent with the initial presentation, she was noted to have a nonenhancing, hyperintense signal change on T2-weighted images on the left frontotemporal lobes and insula thought to be paraneoplastic. Moreover, low titer antibodies to voltage-gated potassium channels were present, raising concern for limbic encephalitis. However, the patient was asymptomatic. A little more than a year after initial presentation, she noted excessive fatigue, daytime somnolence, and cognitive decline. Imaging revealed a gradually progressive, nonenhancing, T2 hyperintense signal abnormality with progressive atrophy in the left anteroinferior frontal lobe, anteromedial temporal lobe, insula bilateral cingulate gyri, and bilateral thalami. Given the progressive nature of the abnormality, stereotactic biopsy was performed, which confirmed the lesion to be metastatic, infiltrative SNEC. In summary, this is a rare case of a synchronous presentation of a high-grade SNEC with an unusual appearance that diffusely infiltrated the brain, likely directly involving the left olfactory nerve and spreading along olfactory projections. This case draws physicians' attention to the possibility that although paraneoplastic syndromes are most likely benign, dissemination of the primary cancer is a diagnostic possibility. PMID- 30481851 TI - Risk of developing sudden sensorineural hearing loss in patients with hepatitis B virus infection: A population-based study. AB - Sudden sensorineural hearing loss (SSNHL) has significant impact on quality of life. It may result from viral infection, but the relationship between hepatitis B virus (HBV) infection and SSNHL remains uncertain. To investigate the risk of developing SSNHL in patients with HBV, we conducted a nationwide, population based, retrospective cohort study from the Taiwan National Health Insurance Research Database. A total of 33,234 patients diagnosed with HBV infection and 132,936 control subjects without viral hepatitis were selected from claims made from 2000 to 2008. Each patient was followed for at least 5 years to identify new onset SSNHL. Among the 166,170 patients, 279 patients (303,793 person-years) from the HBV cohort and 845 patients (1,225,622 person-years) from the control cohort were diagnosed with SSNHL. The incidence of SSNHL was 1.33-fold higher in the HBV group than in the control group (0.92 vs. 0.69 per 10,000 person-years), with an adjusted hazard ratio (HR) of 1.315 (95% confidence interval [CI] = 1.148 to 1.506) calculated using a Cox proportional hazard regression model. We also observed that HBV patients in the 50 to 64 years of age subgroup showed the highest incidence of SSNHL and the highest adjusted hazard ratio (HR = 2.367; 95% CI = 1.958 to 2.861). Patients with HBV infection had a higher risk of acquiring SSNHL than patients without viral hepatitis. For the early detection and timely treatment of SSNHL, clinicians should be aware of the increased risk of SSNHL in HBV patients and arrange auditory examinations for those complaining about acute hearing change. PMID- 30481852 TI - Primary parapharyngeal leiomyosarcoma: A case report. AB - Leiomyosarcoma is a rare malignant soft-tissue tumor whose cells resemble smooth muscle tissue. It has been reported to arise in different areas of the head and neck region. Primary leiomyosarcoma of the parapharyngeal space, however, is extremely rare, as only 4 cases have been previously reported to date. We describe the somewhat urgent case of a primary leiomyosarcoma of the right parapharyngeal space in a 30-year-old man. We also review the diagnostic and therapeutic challenges that clinicians face in managing this rare tumor. PMID- 30481853 TI - A rare case of coexisting lacrimal sac adenocarcinoma and transitional cell carcinoma. AB - Lacrimal sac tumors are rare and difficult to diagnose. We present a case of coexisting lacrimal sac adenocarcinoma and transitional cell carcinoma in a 73 year-old woman who presented with swelling of the inner canthus. Biopsy identified the growth as an adenocarcinoma. After dissection of the lacrimal carcinoma via a lateral rhinotomy, histopathologic examination confirmed the adenocarcinoma and identified a coexisting transitional cell carcinoma. A recurrence developed, but only of the adenocarcinoma component. For the recurrence, the patient was treated with wide resection, including the orbital contents, and subsequent irradiation. At 49 months postoperatively, the patient remained alive but with a lung metastasis. Wide resection was the key to treatment. PMID- 30481854 TI - Long-term use of Le Fort I osteotomy for the management of nasopharyngeal rhinosporidiosis: A case series. AB - Rhinosporidiosis is a rare, chronic, granulomatous infection of the mucous membranes that mainly involves the nose and nasopharynx; it occasionally involves the pharynx, conjunctiva, larynx, trachea and, rarely, the skin. The characteristic clinical features of this disease include the formation of painless polyps in the nasal mucosa or the nasopharynx that bleed easily on touch. At our center, excision of the lesion with a Le Fort I osteotomy is carried out in patients (1) in whom two or more previous attempts at excision of biopsy-proven rhinosporidiosis arising from the nasal mucosa was carried out or (2) in whom the rhinosporidiosis arises from the nasophayrngeal mucosa and/or extranasal sites. In this article we retrospectively present 7 cases in which, according to our inclusion criteria, complete excision of the lesion was carried out with a Le Fort I osteotomy. Excellent visualization of the entire maxillary and ethmoidal air cells after the down-fracture of the maxilla helped in the total removal of the lesions. Most of these lesions had multiple points of origin through the nasal, maxillary, and ethmoidal mucosa; the excellent visualization enabled direct cauterization of all these points of origin. The mean follow-up period was 7.96 years, and all patients were disease-free by the time the study was prepared. This article presents details of the treatment protocol and technique followed at our center for the treatment of nasopharyngeal rhinosporidiosis and the details of long-term follow-up. Through this study we hope to prove the efficacy of Le Fort I osteotomy in the definitive management of nasopharyngeal rhinosporidiosis. PMID- 30481855 TI - The effect of zoledronic acid on middle ear osteoporosis: An animal study. AB - Hearing function in older patients may be related to bone structure. We conducted an experiment to evaluate the effect of zoledronic acid on osteoporotic middle ear ossicles in an animal model. Our subjects were 19 female New Zealand white rabbits (38 ears) weighing 2 to 4 kg. We divided the rabbits into three groups: one group consisted of 6 rabbits with osteoporotic ears that were treated with zoledronic acid; the second group was made up of 8 rabbits with osteoporotic ears that were not treated; a control group included 5 rabbits with normal ears that were untreated. After an oophorectomy, the 6 study rabbits were administered 0.1 ml/kg of zoledronic acid intravenously. All rabbits were sacrificed 16 weeks later, and the middle ear ossicles were removed for investigation under light microscopy. Although osteoporosis enhanced the osteoclastic bone resorption of the ossicles, zoledronic acid enhanced osteoblastic activity on osteoporotic middle ear ossicles. The incidence of osteoporosis was 93.8% in the untreated osteoporosis group and 33.3% in zoledronic acid group-a statistically significant difference (OR: 0.24; 95% CI: 0.09 to 0.58; p < 0.001). Osteoporosis appears to increase the resorption of the middle ear ossicles, a process that can be avoided with zoledronic acid administration. Prevention of the effects of osteoporosis in humans may help decrease the irreversible changes in the middle ear ossicles. PMID- 30481856 TI - Oropharyngeal histoplasmosis in an HIV-negative patient. PMID- 30481857 TI - Endoscopic view of a posterior nasal and nasopharyngeal vascular plexus. PMID- 30481858 TI - [Establish a predictive modeling under antiviral therapy for hepatitis B e antigen seroconversion in chronic hepatitis B]. AB - Objective: To explore the predictive factors by demonstrating a predictive modeling under antiviral therapy for hepatitis B e antigen seroconversion in HBeAg-positive chronic hepatitis B patients. Methods: 198 cases with HBeAg positive chronic hepatitis B were enrolled. Fatty liver, family history of hepatitis B, age, sex, drinking history, HBsAg, HBeAg, HBV-DNA levels, total bilirubin (TBil), CD4/CD8, albumin (ALB), alanine amino transferase (ALT) levels were used as a predictor variables of HBeAg seroconversion. Serological seroconversion of HBeAg was observed at 144 weeks of antiviral therapy. Predictive factors of HBeAg seroconversion was analyzed by logistic regression analysis, and the receiver operating characteristic curve was plotted. Results: HBeAg seroconversion rate was 36.87%. Univariate analysis demonstrated that fatty liver (chi(2) = 35.377; P < 0.001), family history of hepatitis B (chi(2) = 15.687; P < 0.001), the levels of HBeAg (t = 5.034; P < 0.001), HBsAg (t = 3.454; P < 0.001) and HBV-DNA levels (Z = 4.651; P < 0.001) were predictor variables of HBeAg seroconversion. Multivariate analysis showed that family history of hepatitis B, fatty liver, HBV-DNA levels and HBeAg were independent predictors of HBeAg seroconversion. The established logistic regression model for HBeAg through regression analysis was logit P = 9.623-1.228 * family history of hepatitis B - 1.726 * fatty liver - 0.764 * HBV-DNA levels - 0.146 * HBeAg and area under curve was 0.875. When the cut-off value was -0.9350, the sensitivity and specificity were 92.70%, 75.50%, 83.22%, respectively. Conclusion: Family history of hepatitis B, fatty liver, HBV-DNA levels and HBeAg may be independent predictors of HBeAg seroconversion at 144 weeks of antiviral therapy in HBeAg-positive chronic hepatitis B patients. PMID- 30481859 TI - [Clinical observation of continuous and intermittent application of lamivudine or entecavir resistance mutations in patients with chronic hepatitis B]. AB - Objective: To observe continuous and intermittent application of lamivudine or entecavir resistance mutations in patients with chronic hepatitis B. Methods: Data of patients with active stage of chronic hepatitis B over the past 6 years were collected and analyzed retrospectively. The incidence of drug resistance mutation and related factors between patients taking LAM or ETV continuously and intermittently were compared with those taking LAM or ETV. Data comparison was performed using chi(2) test. Results: Patients with HBV DNA>=10(5) copies / ml at the time of initial treatment had higher resistance mutation rates than those with HBV DNA < 10(5) copies / ml at either continuous or intermittent treatment, and patients with intermittent treatment had higher resistance mutation rates than those with continuous treatment. Simultaneously, the incidence of drug resistance mutation in LAM and ETV in the first, second and third years were significantly higher in intermittent treatment than that of continuous treatment (P < 0.05). There was a positive correlation between the frequency of drug withdrawal and the rate of drug resistance mutation. There were no individual difference and drug difference between LAM and ETV. Conclusion: In the treatment of chronic hepatitis B with oral nucleoside analogues, drug resistance may occur in either continuous or intermittent treatment. When comparing continuous with intermittent treatment, it suggests that intermittent is more likely to cause viral resistance mutation. PMID- 30481860 TI - [Study on diagnostic value of extracellular volume imaging by magnetic resonance imaging for liver fibrosis of hepatitis B]. AB - Objective: To investigate the diagnostic value of extracellular volume (ECV) imaging by magnetic resonance imaging for liver fibrosis of hepatitis B. Methods: A retrospective analysis was recruited in patients with chronic hepatitis B, who underwent liver surgery from April to October 2017 for pathological evaluation of liver tissues, and all patients underwent Gd-EOB-DTPA-enhanced T1 mapping to calculate the liver ECV score. The correlation between ECV and staging of hepatic fibrosis and inflammatory activity were compared to clarify the diagnostic value of staging of fibrosis. Results: 66 patients were enrolled in this study. Concerning the staging of liver fibrosis, there were 13, 4, 13, 10, and 26 cases with F0, F1, F2, F3 and F4 stages, respectively. ECV values had high interobserver consistency (correlation coefficient 0.860). The ECV difference between different stages of liver fibrosis was statistically significant (F = 15.02, P < 0.001). There was a significant positive correlation between ECV and fibrosis stage (r = 0.622, P < 0.001), and weak correlation with inflammatory activity (r = 0.332, P = 0.007). Fibrosis staging was an independent factor influencing ECV (P < 0.001). The area under the receiver operator characteristic curve for the diagnosis of liver fibrosis staging F>=1, F>=3 and F4 were 0.760, 0.846 and 0.873, respectively. The diagnostic sensitivity and specificity were 64.15%, 92.31%, 77.78%, 80.00% and 88.46, 72.50%, respectively. Conclusion: MRI ECV imaging has great value for staging hepatic fibrosis of hepatitis B, and it can provide an effective method for diagnosis, staging, and evaluating the curative effect of fibrosis. PMID- 30481861 TI - [Hemin regulates the expression of nuclear factor kappa B of heme oxygenase -1 in hepatic fibrosis]. AB - Objective: To observe the therapeutic effects and related mechanism of hemin on the progression of hepatic fibrosis in rats. Methods: Sixty male Wistar rats were randomly divided into normal control group, 4-week model group, 6-week model group, hemin inhibitor zinc protoporphyrin-IX (ZnPP-IX) intervention group and hemin intervention group. Hemin intervention group in complex liver fibrosis model was intraperitonealy administered ZnPP-IX or hemin every other day for 2 weeks from the fourth week. The mRNA expression of HO-1, alpha-smooth muscle actin (alpha-SMA) and nuclear factor-kappaB (NF-kappaB) in the liver tissue was detected by real-time polymerase chain reaction. Immunohistochemistry was used to detect HO-1 and localization of alpha-SMA expression. Serum hyaluronic acid, propeptide of type III collagen and hepatic transforming growth factor beta (TGFbeta), and interleukin 6 (IL-6) expressions were detected by enzyme-linked immunosorbent assay. The content of hydroxyproline in hepatic tissues was measured by alkaline hydrolysis method. One-way ANOVA was used to compare the mean of each group. The difference between the two groups was compared by independent samples t- test. P-values < 0.05 was considered statistically significant. Results: Compared with model groups and ZnPP-IX intervention group, Hemin's intervention significantly increased the expression of HO-1 mRNA (P < 0.01) and protein distribution in liver tissues, while the expression of alpha SMA mRNA was significantly decreased (P < 0.05) in portal space and areas around the fibrotic septum, and hepatic sinus. Hyp content and serum hyaluronic acid and propeptide of type III collagen decreased significantly (P < 0.05). Meanwhile, NF kappaB p65 mRNA expression and the downstream production of TGFbeta and IL-6 in Hemin intervention group were also inhibited (P < 0.05). Conclusion: Hemin can significantly inhibit the progression of hepatic fibrosis in rats by up regulating HO-1 expression, and the inhibiting activity of NF-kappaB p65 leads to downstream of the inflammatory factors. PMID- 30481862 TI - [Study of antioxidant effect of cannabinoid receptor type 2 agonist on rat hepatic stellate cell line]. AB - Objective: To investigate the action and antioxidant effects of CB2 agonist AM 1241 on rat hepatic stellate cell line (HSC-T6). Methods: HSC-T6 was randomly divided into four groups: control group, oxidative stress group, AM-1241 intervention group and AM-1241+AM-630 antagonist group. Survival rate of HSC-T6 was detected by thiazolyl blue assay under 24 h interventions with 0, 20, 50, 80 MUmol/L AM-1241 and 0, 10, 20, 30, 40 MUmol/L AM-630, respectively. Besides control group, the remaining groups were well cultured in low-glucose DMEM containing 100 mU/L glucose oxidase (GO) for 12 h to prepare the oxidative stress model. Then, AM-1241 intervention group was treated with 50 MUmol/L low-glucose DMEM medium. After incubation for 12 h, the AM-1241+AM-630 antagonist group was treated with CB2 antagonist AM-630 (20 MUmol/L) for 2 h, and cultured with 50 MUmol/L AM-1241 in complete low-glucose medium for 12 h. The optimal drug concentration was selected according to the cell viability considered by the experiment results. Type III collagen (C III) content in the HSC-T6 supernatant was detected by enzyme-linked immunosorbent assay. Glutathione (GSH) content in HSC-T6 was detected by spectrophotometry. CB2 and heme oxygenase-1(HO-1) in each group of HSC-T6 were detected by western blotting. Results: HSC-T6 proliferation was inhibited in each group of AM-1241 in a concentration-dependent manner (P < 0.05). The inhibition was highest at 80MUmol/L, and the cell survival rate was (41.61% +/- 3.13%) (P < 0.05). AM-630 concentration group had no significant inhibitory effect on the proliferation of HSC-T6 (P > 0.05). HSC-T6 expressed CB2 receptor in each group. The expression level of CB2 in the AM-1241 intervention group was higher compare with control group (P < 0.05).The expression of Col III were significantly higher in oxidative stress group (P < 0.05) than in control group, and the expression of Col III of AM-1241 intervention group was significantly lower than that in oxidative stress group (P < 0.05). Col III level in AM-1241+AM-630 antagonistic group was significantly higher than that in AM 1241 intervention group (P < 0.05). There was no significant difference between AM-1241+AM-630 antagonistic group and oxidative stress group (P > 0.05). The content of GSH and HO-1 in oxidative stress group was higher (P < 0.05) than control group. The content of GSH and HO-1 in the AM-1241 intervention group was higher compared with oxidative stress group, while content of AM-1241 + AM-630 antagonist group was lower compared to AM-1241 intervention group (P < 0.05), and the differences were not statistically significant for oxidative stress group. Conclusion: CB2 agonist AM-1241 can inhibit the proliferation and activation of HSC-T6 and its mechanism may activate the nuclear translocation of Nrf2 binding to HSC-T6, initiating the up-regulation of antioxidant enzymes HO-1 and GSH protein expression, and thus increase the antioxidant effect of HSC-T6. PMID- 30481863 TI - [Clinical significance of epidermal growth factor receptor and thymidylate synthase expression in primary liver cancer]. AB - Objective: To investigate epidermal growth factor receptor (EGFR) and thymidylate synthase (TS) expression in primary liver cancer, and analyze its clinicopathological features and prognostic significance. Methods: Immunohistochemistry was performed using EnVision method to detect EGFR and TS expression in 41 cases of liver cancer. Correlation coefficient between EGFR and TS was calculated by Spearman method. Fisher's exact probability method or chi(2) test was used to analyze the clinicopathological features of EGFR and TS. Kaplan Meier method was used to calculate the survival rate of patients in conjunction with the log-rank test.COX proportional hazard regression model was used to analyze the prognostic factors of patients. ROC curve was used to analyze the predictive accuracy of EGFR and TS for prognosis. Results: The positive rates of EGFR and TS in liver cancer tissues were 34.15% and 39.02%, respectively. There was a positive correlation between EGFR and TS expressions, and the difference was statistically significant (P < 0.05). EGFR was associated with tumor size and tissue differentiation (P < 0.05) in HCC patients, whereas TS was associated with tissue differentiation (P < 0.05). There was no significant difference in prognostic effect of EGFR on survival rate (P > 0.05). TS prognostic effect on survival rate was statistically significant (P < 0.05). HR of EGFR was 0.210 with 95% CI, 0.052-0.852, P = 0.029; indicating that the risk of death in patients with negative EGFR was 0.210 times higher than that in patients with positive EGFR. HR of TS was 2.496, with 95% CI, 1.325-4.701, P = 0.005, indicating that the risk of death increased by 2.496 times with the same level of EGFR. The area under the EGFR curve was 0.553 and its approximate reference confidence interval was 95% (0.355, 0.751), indicating that EGFR was a risk factor for death and the area under the TS curve was 0.695, and its approximate reference confidence interval was 95% (0.513, 0.878), indicating that TS was a risk factor for death. Conclusion: EGFR and TS were equally expressed in primary liver cancer, and EGFR and TS expressions were positively correlated. EGFR and TS had an effect on the degree of tissue differentiation in patients with liver cancer. EGFR and TS were risk factors for prognosis, and TS may assist EGFR. PMID- 30481864 TI - [Prognostic significance of albumin/globulin ratio on postoperative survival of patients with hepatocellular carcinoma]. AB - Objective: To investigate the prognostic value of albumin/globulin ratio on postoperative survival outcomes in patients with hepatocellular carcinoma. Methods: Data of 630 patients with HCC, who underwent surgical resection from February 2009 to July 2013, were retrospectively analyzed. Patients were divided into low-value group (A/G < 1.5, defined as L group) and high-value group (A/G>=1.5, defined as H group), and their distribution characteristics were observed with the normal A/G threshold value. Independent risk factors' affecting survival and prognosis was analyzed with univariate and multivariate Cox's regression model. Survival trend of all patients with low-value and high-value groups in A, B and C of Barcelona stage (BCLC stage) were analyzed using the Kaplan-Meier method. Results: Multivariate analysis showed that preoperative A/G ratio (P = 0.007), alpha-fetoprotein (P < 0.001), gamma-glutamyltransferase (P = 0.006), RBC (P = 0.014), international normalized ratio (P = 0.009), preoperative BCLC staging (P < 0.001) and number of tumors (P = 0.003), and intraoperative blood transfusion (P < 0.001) were independent prognostic factors affecting long term survival in HCC patients. The median overall survival time in-group L was 15 months, significantly lower than that in group H of 42 months (P < 0.001). Stratified analysis showed that the short-term survival advantage of patients with high A / G value was limited to those with Barcelona stage A (P < 0.001), and disappeared in patients with Barcelona stage B and C (P > 0.05). The long term survival advantage existed in patients with Barcelona stage A (P < 0.001), B (P < 0.05), and disappeared in C (P > 0.05). Conclusion: Preoperative albumin/globulin ratio can predict postoperative prognosis and survival, and direct towards the treatment for early stage of HCC and thus representing as an indicator of high clinical value. PMID- 30481865 TI - [Artificial liver support system for acute-on-chronic liver failure combined with successful liver transplantation in stage III - IV hepatic encephalopathy: an analysis of 14 cases]. AB - Objective: To evaluate the effect of plasma exchange combined with high-dose continuous venovenous hemodiafiltration method (CVVHDF) in the treatment of patients with acute-on-chronic liver failure with stage III-IV hepatic encephalopathy and the feasibility of pre-operative preparation for liver transplantation. Methods: Clinical data of 14 cases of medical intensive care unit of our hospital with acute-on- chronic liver failure accompanied with stage III-IV hepatic encephalopathy that underwent plasma exchange combined with high dose CVVHDF from March 2015 to September 2017 were retrospectively summarized. The indexes of liver and kidney function, blood coagulation function, arterial blood PH, lactic acid and blood ammonia were monitored before and after treatment. Heart rate, blood pressure, APACHE II score, and consciousness recovery time were observed. Student's t- test was used to compare the mean values between the two groups. Results: Serum total bilirubin (t = 9.43, P < 0.01), serum creatinine (t = 3.40, P < 0.01), serum ammonia (t = 10.64, P < 0.01), prothrombin activity (t = 9.19, P < 0.01), serum lactate (t = 9.25, P < 0.01), heart rate (t = 4.47, P < 0.01), and mean arterial pressure (t = 4.41, P < 0.05) were significantly improved in 14 patients before and after treatment. In addition, respiratory rate (t = 6.01, P < 0.01) and APACHE II score (t = 7.19, P < 0.01) were significantly improved (P < 0.05). Eight patients with stage III hepatic encephalopathy were treated with intermittent plasma exchange combined with CVVHDF for 3 to 14 days, and six patients with stage IV were transformed to stage III to II. Liver transplantation was successfully performed on 14 patients with shortest time duration of 3days, and longest time duration of 1 month. Conclusion: Plasma exchange combined with CVVHDF can significantly improve liver and kidney functions, reduce blood ammonia level and improve mental health in patients with hepatic failure accompanied with stage III-IV hepatic coma. In addition, it also effectively increases the average arterial pressure, maintain stability of vital signs, maintain fluids, electrolytes and acid-base balance, create a stable internal environment for liver transplantation before operation, and extend time for liver transplantation. PMID- 30481866 TI - [Transforming growth factor beta regulates hepatic progenitor cells migration via PI3K/AKT/mTOR/p70S6K pathway]. AB - Objective: To investigate the effect and mechanism of transforming growth factor beta (TGFbeta) on the migration ability of hepatic progenitor cells in vitro. Methods: Primary hepatic progenitor cells of male wild-type C57BL/6J mice were isolated by two-step perfusion method and stimulated with different concentrations of TGFbeta .The morphological changes were observed under phase contrast microscopy. The effects of TGFbeta on migration ability of hepatic progenitor cells were evaluated by scratch test and transwell method. Expression profiling and signaling phospho antibody array detected the signaling pathways involved in the regulation of TGFbeta on hepatic progenitor cells. Protein level of PI3K/AKT/mTOR/p70S6K signaling pathway and the localization of each signaling molecules in hepatic progenitor cells were detected. Data comparison between the two groups was performed by independent sample t-test. One-way ANOVA was used for data comparison between multiple groups. Results: TGFbeta made the liver progenitor cells from oval to long spindle type. Scratch test showed that the scratch healing rates of 24 h control group, and 2 ng/ml and 10 ng/ml TGF-beta groups were 36.48% +/- 4.37%, 57.35% +/- 4.60%, and 73.14% +/- 5.02% (F = 65.87, P < 0.01), respectively. Transwell test showed that the number of migrating cells in 24 h control group, 2 ng/ml and 10 ng/ml TGF-beta groups were 127 +/- 16, 230 +/- 18, and 385 +/-36 (F = 94.99, P < 0.01), respectively. The results of expression profiling showed that TGFbeta regulates gene expression in hepatic progenitor cells, and differentially expressed genes participate in the PI3K-AKT signaling pathway. Signaling phospho antibody array and western blot showed that TGFbeta regulated PI3K/AKT/mTOR/p70S6K signaling pathway in hepatic progenitor cells. Concurrently, immunofluorescence assay showed phosphorylation (p) 70s6k, p AKT1 and PI3K and F-actin co-localizations. Conclusion: TGFbeta can promote hepatic progenitor cell migration through PI3K/AKT/mTOR/p70S6K pathway, and p70S6K, pAKT1 and PI3K signaling molecules are involved in the regulation of morphology and migration of liver progenitor cells. PMID- 30481867 TI - [Clinical features of drug-induced liver injury rechallenge with polygonum multiflorum]. PMID- 30481868 TI - [Analysis of curative and prognostic effects of combined therapy of transarterial chemoembolization and sorafenib in hepatocellular carcinoma]. PMID- 30481869 TI - [Effects of PDSS2 on gene expression profiling of hepatocellular carcinoma HepG2 cells]. PMID- 30481870 TI - [A special case of hyperthyroidism with liver injury in Graves' disease]. PMID- 30481871 TI - [Successful treatment of two cases of decompensated liver cirrhosis underlying with pulmonary aspergillosis infection]. PMID- 30481872 TI - [A case of Langerhans cell histiocytosis of the liver in adults with abdominal pain as the initial manifestation]. PMID- 30481873 TI - [A case of drug-induced liver injury combined with drug-induced immune thrombocytopenia]. PMID- 30481874 TI - [Research progress of ischemic hepatitis]. AB - Ischemic hepatitis, also known as hypoxic hepatitis or shock liver, refers to liver cell damage without any known cause of acute hepatitis, and is characterized by transient elevation of transaminase levels (20 times higher than normal value).The incidence of the disease is about 2.5% to 10%, and the hospital mortality rate is greater than 50%. Current research suggests that there are many risk factors for the disease, including systemic hypotension, low cardiac output, sepsis and respiratory distress, but eventually it will manifest as hepatocyte dysfunction. Unfortunately, the mortality rate related with hypotension is high, and the key to treatment is to correct hemodynamic disorders. This article reviews the research progress in the etiology, mechanism and clinical manifestations of ischemic hepatitis. PMID- 30481875 TI - [Advances in combination therapy of ombitasvir and dasabuvir for chronic hepatitis C virus genotype 1 infection]. AB - Since 2014, the United States and Europe has approved all oral, interferon free- regimens that combine with direct-acting antiviral agents. Hence, the sustained virological response rate of patients with chronic HCV genotype 1 infection has improved over 90%, and the treatment modalities has introduced a new era. These drugs, ombitasvir and dasabuvir, received customary authorization of Food and Drug Administration in 2015 and are the first combined direct-acting antiviral agents for treating HCV genotype 1 infection. It has superior application prospects in China because of its high-sustained virological response rate and safety profile. This article reviews the pharmacokinetics, drug interactions, efficacy and safety of this therapeutic regimen. PMID- 30481876 TI - [Advances in research on cell fate determinant Numb regulating liver cancer]. AB - Liver cancer is one of the most common malignant tumors in China, ranking fifth in malignant tumors and the third in tumor-related deaths. As a membrane-related protein, the asymmetric distribution of cell fate determinant Numb plays a key role in cell differentiation. Research reports that Numb may be closely associated to the occurrence and development of tumors. Recently, scholars have gradually valued its important role in liver cancer. This article briefly reviews the structure of Numb molecule, relationship between Numb and tumorigenesis, the molecular mechanism of Numb-regulated tumors, and the role of Numb in the development of liver cancer. PMID- 30481877 TI - [Genes and molecular mechanisms affecting the correlation between liver cancer and diabetes mellitus]. AB - Hepatocellular carcinoma (HCC) is a common and high incidence disease in China. It is presently thought that diabetes is one of the independent risk factor for HCC. Diabetes and liver cancer are closely related, but the relationship and mechanism of diabetes and liver cancer are quite complex and controversial. Insulin resistance, glucose metabolism and lipid metabolism disorders, and abnormal release of inflammatory mediators are the common bases of these two diseases. The molecular mechanisms of glycogen synthase kinase-3, toll like receptor 4, CCL5, CXCL14 and NCOA5, TCF7L2 genes affecting the correlation between liver cancer and diabetes mellitus are discussed and explained to provide the basis for the study and treatment of disease. PMID- 30481878 TI - [Guidelines for the diagnosis and management of hepatic encephalopathy in cirrhosis]. AB - Current guideline developed by the Chinese Society of Hepatology on the management of hepatic encephalopathy in cirrhosis is grounded on the published evidences and panelists' consensus. This guideline presents recommendations for diagnosis and management of covert and overt hepatic encephalopathy, and underline the importance of screening minimal hepatic encephalopathy in patients with end-stage liver diseases. In addition, it also stresses that early identification and timely treatments are the means to know the prognosis. The principles of treatment are primary and secondary prevention, prompt removal of the cause, and recovery of acute neuropsychiatric abnormalities to baseline status. PMID- 30481879 TI - [Study on characteristics and prognosis of organ failure in patients with hepatitis B virus-associated acute-on-chronic liver failure]. AB - Objective: To evaluate the incidence, and the characteristics of organ failure in relationship to prognosis in hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) patients using chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score for judgments of clinical treatment and prognosis. Methods: Clinical data of 316 patients who were diagnosed as HBV-ACLF during hospitalization from February 2015 to February 2016 were retrospectively analyzed. Intrahepatic and extrahepatic organ failures were assessed according to CLIF-SOFA score, and the relationship between clinical characteristics and prognosis was analyzed. Continuity variables were analyzed by analysis of variance, or Kruskal-Wallis H test. Comparison of the categorical data were done using chi (2) or Fisher's exact test, and the predictive efficacy of various prognostic scores was compared using the area under the receiver operating characteristic curve (AUROC) and Z-test. Results: Of 316 cases (87.3% men) of HBV ACLF, the mean age was (45 +/- 11) years old. 78.8% of patients with underlying liver disease had hepatitis B virus induced cirrhosis. Mortality rates in patients without liver transplantation at 28 days, 90 days and 180 days were 20.5% (63/307), 36.7% (110/300) and 39.2% (116/296), respectively. According to the CLIF-SOFA score, 89.9% (284 patients) had organ failure at baseline, of which 97.5% had liver failure (Total bilirubin >= 12 mg/dl) and only 2.5% had coagulation, kidney, circulation or respiratory failure without liver failure. Besides liver failure, the incidence of extrahepatic organ failure was coagulation (23.1%), kidney (5.7%), brain (3.8%), circulation (1.3%) and respiratory failure (0.3%). With increasing number of organ failure, the mortality rate of two and three or more organ failures were 69.6% and 69.2%, respectively, which was significantly higher than that of single organ failure and non-organ failure patients (27% and 6.9%, respectively; P < 0.001). Liver failure with coagulation failure (International normalized ratio>=2.5 or platelet count<=20*10(9)/L) had worst prognosis with a mortality rate of up to 75% at 90 days. Conclusion: According to the CLIF-SOFA score, the main organ failure in patients with HBV-ACLF in China is liver failure. The mortality rate in patients with two or more organ failures is as high as 70% within 3 months. Therefore, timely manner liver transplantation should be considered. PMID- 30481880 TI - [Plasma exchange combined with double plasma absorption therapy improve the prognosis of acute-on-chronic liver failure]. AB - Objective: To compare the efficacy and safety of plasma exchange (PE) combined with double plasma absorption and simple PE in the treatment of acute-on-chronic liver failure. Methods: We retrospectively analyzed 251 cases of acute-on-chronic liver failure treated with artificial liver treatment since January 2015. Changes in clinical manifestations, laboratory tests, and complications of the patients before and after different modes of treatment were compared and short-term efficacy was tracked. In accordance with different data, t-test, Pearson's chi squared test and Fisher's exact test were used for statistical analysis. Results: The effectiveness of low-volume PE combined with double plasma molecular adsorption system (DPMAS) and equal amount of PE combined with DPMAS was significantly better than simple PE (83.7%, 84.05% and 82.15 vs 55.6%, P < 0.05) in early stage of liver failure. In late-stage of liver failure, there was no significant difference in the treatment efficiency of each group (P > 0.05). Bilirubin and bile acid levels were significantly decreased in combined treatment groups than that to simple PE group (P < 0.05). PTA and albumin improvement rate of DPMAS PE groups were significantly lower than that of simple PE group (P < 0.05). There was no statistical difference in adverse reactions between each group. Conclusion: PE combined with DPMAS improves the treatment efficiency of early hepatic failure and decrease dosage of plasma when compared with simple PE. A beforehand DPMAS treatment after PE treatment can improve the adverse effects of DPMAS on blood coagulation function and albumin levels. PMID- 30481881 TI - [Effects of bone marrow mesenchymal stem cell transplantation on the expression of stromal cell-derived factor-1alpha and vascular endothelial growth factor in rats with acute hepatic failure]. AB - Objective: To investigate the curative effect of bone marrow mesenchymal stem cells (BMSCs) transplantation on the expression of stromal cell-derived growth factor (SDF-1 alpha) and vascular endothelial growth factor (VEGF) in rats with acute hepatic failure, and to compare the effects of two transplantation pathways. Methods: Eighty-four rats with acute liver failure (ALF) induced by D galactosamine combined with lipopolysaccharide were randomly divided into control group, tail vein and portal vein transplantation group. The latter two groups were injected allogenic BMSCs into the tail vein and portal vein. Blood samples and liver tissue samples were collected at 24, 72, 120, and 168h after transplantation to detect serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The improvement of liver function before and after BMSCs transplantation was compared. The expression of VEGF and SDF-1a in liver tissue was detected by immunofluorescence and Western blot. Data measurement between two groups was performed by analysis of variance and the correlation analysis was performed by Spearman's rank correlation coefficient. Results: Serum ALT and AST levels in the tail vein and portal vein transplantation group peaked at 24 h after transplantation, which were (134.60 +/- 58.08 IU/L), (179.20 +/- 86.68 IU/L), and (131.00 +/- 54.47 IU/L), (173.50 +/- 93.10 IU/L). In addition, 168h after transplantation it decreased to (46.10 +/- 8.40 IU/L), (95.67 +/- 13.80 IU/L) and (19.30 +/- 1.30 IU/L), (54.30 +/- 6.00 IU/L). After 120 and 168 hours of BMSCs transplantation, the levels of serum ALT and AST in tail vein and portal vein transplantation group were significantly higher than control group (F >= 12.51, P < 0.01). The results of western blot and immunofluorescence showed that the expression levels of SDF-1alpha and VEGF protein in the two BMSCs transplantation groups increased with the improvement of liver function, and the difference was statistically significant at 120 and 168 hours after transplantation (F >= 9.069, P < 0.05). There was no significant difference in the expression of SDF-1a and VEGF between the tail vein and portal vein transplantation groups (P > 0.05). Correlation analysis showed that the expression levels of SDF-1alpha and VEGF in liver tissues were positively correlated (r = 0.923, P < 0.05). Conclusion: BMSCs transplantation can promote the secretion of VEGF for recovery of liver function to reduce the degree of inflammation and necrosis in rats with ALF. PMID- 30481882 TI - [HBsAg loss with Pegylated-interferon alfa-2a in hepatitis B patients with partial response to nucleos(t)-ide analog: new switch study]. AB - Objective: Hepatitis B surface antigen (HBsAg) loss is seldom achieved with nucleos(t)ide analog (NA) therapy in chronic hepatitis B patients but may be enhanced by switching to finite pegylated-interferon (Peg-IFN) alfa-2a. We assessed HBsAg loss with 48- and 96-week Peg-IFN alfa-2a in chronic hepatitis B patients with partial response to a previous NA. Methods: Hepatitis B e antigen (HBeAg)-positive patients who achieved HBeAg loss and hepatitis B virus DNA < 200 IU/mL with previous adefovir, lamivudine or entecavir treatment were randomized 1:1 to receive Peg-IFN alfa-2a for 48 (n = 153) or 96 weeks (n = 150). The primary endpoint of this study was HBsAg loss at end of treatment. The ClinicalTrials.gov identifier is NCT01464281. Results: At the end of 48 and 96 weeks' treatment, 14.4% (22/153) and 20.7% (31/150) of patients, respectively, who switched from NA to Peg-IFN alfa-2a cleared HBsAg. Rates were similar irrespective of prior NA or baseline HBeAg seroconversion. Among those who cleared HBsAg by the end of 48 and 96 weeks' treatment, 77.8% (14/18) and 71.4% (20/28), respectively, sustained HBsAg loss for a further 48 weeks. Baseline HBsAg < 1 500 IU/mL and week 24 HBsAg < 200 IU/mL were associated with the highest rates of HBsAg loss at the end of both 48- and 96-week treatment (51.4% and 58.7%, respectively). Importantly, extending treatment from 48 to 96 weeks enabled 48.3% (14/29) more patients to achieve HBsAg loss. Conclusion: Patients on long-term NA who are unlikely to meet therapeutic goals can achieve high rates of HBsAg loss by switching to Peg-IFN alfa-2a. HBsAg loss rates may be improved for some patients by extending treatment from 48 to 96 weeks, although the differences in our study cohort were not statistically significant. Baseline and on-treatment HBsAg may predict HBsAg loss with Peg-IFN alfa-2a. PMID- 30481883 TI - [Predictive value of serum glycosylated hemoglobin for the onset of nonalcoholic fatty liver disease]. AB - Objective: To discuss the affect of glycosylated hemoglobin (HbA1c) level for the onset of nonalcoholic fatty liver disease (NAFLD) in cohort population. Methods: An epidemiological survey of the relationship between HbA1c and NAFLD conducted in 2012 was based at cohort baseline, and three follow-up sessions conducted in 2013, 2014 and 2015. In total 2 811 subjects were included in the study after exclusion of NAFLD patients at baseline and those who lost their lives due to relocation, and death. The Cox proportional hazard model was used to analyze the relationship between glycosylated hemoglobin and other risk factors of NAFLD. Continuous variables were compared using the t-test or the Mann-Whitney test. chi (2)-test was used for the measurement of categorical data. Results: A total of 2 811 subjects with mean age of 59 (58.2+/-9.8) years old, including 1 664 males and 1 147 females. Age, waist circumference, body mass index, systolic blood pressure, gamma-glutamyltransferase and fasting blood glucose level of HbA1c abnormal group were higher than normal group. The incidence of NAFLD in the abnormal HbA1c level group (25.4%) was higher than normal group (14.9 %), and diastolic blood pressure, high-density lipoprotein cholesterol was lower than normal group and the differences were statistically significant. During the three follow-up intervals, there were 440 new cases of NAFLD, consisting 285 males and 155 females with cumulative incidence of 15.7% (440/2 811). Multivariate Cox regression analysis showed that patients with elevated HbA1c had a higher risk of developing NAFLD (HR 1.796; 95% CI 1.335~2.418; P < 0.01), and the increased HbA1c level after adjustment for gender, age, and metabolic syndrome-related factors remained an independent risk factors for NAFLD (HR 1.580; 95.0% CI 1.161 2.152; P < 0.01). Conclusion: An elevated HbA1c levels have a positive predictive value for the onset of NAFLD. PMID- 30481884 TI - [Transfection of angiotensin-converting-enzyme 2 gene inhibits hepatic fibrosis in rats with nonalcoholic fatty liver disease]. PMID- 30481886 TI - [Expression of cyclin Y in hepatocellular carcinoma cells and its correlation with clinical characteristics of hepatocellular carcinoma patients]. PMID- 30481885 TI - [Combined effect of curcumin and anti-adhesive membrane to block multi- channel blood supply in the treatment of hepatic VX2 carcinoma in rabbit and neovascularization in residual cancer tissues]. PMID- 30481887 TI - [B-cell acute lymphoblastic leukemia complicated by hepatic failure: a case report]. PMID- 30481888 TI - [A case of liver cirrhosis with central pontine myelinolysis]. PMID- 30481889 TI - [A case report of liver actinomycosis]. PMID- 30481890 TI - [Highlights and minutes from the Eighth Chinese National Symposium for nonalcoholic fatty liver disease and alcoholic fatty liver disease]. PMID- 30481891 TI - [Interactions between transforming growth factor beta and signal transducer and activator of transcription 3 in the development of liver fibrosis]. AB - Liver fibrosis is a common pathological response in chronic liver injury. In the pathological process of hepatic injury, signaling pathways associated with hepatic fibrosis, which mediates the repair, proliferation and fibrosis of the liver secrete different cytokines. In these pathways, transforming growth factor beta (TGFbeta) and signal transducer and activator of transcription 3 (STAT3) play key roles in the proliferation and activation of hepatic stellate cells (HSCs) and promote epithelial mesenchymal transition. In addition, it is also involved in the process of proliferation and transformation of collagen and extracellular matrix molecules into myofibroblasts. TGFbeta and STAT3 molecular related signaling pathways mediate the loss of epithelial phenotype and gene expression in mature epithelial cells, transforming them into mesenchymal cells, and producing anti-apoptosis to hepatocytes and promoting the proliferation of HSCs. However, the mechanisms by which STAT3 and TGFbeta molecules are involved in the development and progression of liver fibrosis are not sound distinct. In this review, we attempt to know the mechanisms and interactions of TGFbeta and STAT3 molecules that mediate potential liver fibrosis, and promote their role in promoting HSCs production and epithelial mesenchymal transition. PMID- 30481893 TI - [Difficult point in monitoring and treatment of respiratory pump failure]. PMID- 30481892 TI - [Research progress on non-coding RNAs in the molecular pathogenesis of hepatocellular carcinoma]. AB - Primary liver cancer arises from chronic liver disease, and cirrhotic liver gradually develops into dysplastic nodules that eventually form malignant tumors. In recent years, molecular biotechnology development has deepened people's understanding on the pathogenesis of liver cancer. Epigenetic modifications play a significant role in DNA methylation, non-coding RNAs, chromatin remodeling, and histone modification. This review focuses on the progress of currently implicated non-coding RNAs in the molecular pathogenesis of hepatocellular carcinoma, and its potential application in improving the diagnosis and treatment. PMID- 30481894 TI - [Safety and efficacy of second generation drug eluting stents in diabetic and non diabetic patients]. AB - Objective: To investigate the long-term prognosis of Second generation drug eluting stents(G2-DES) in diabetic mellitus(DM) and non-DM patients. Methods: Patients with coronary heart disease(CHD) in Fuwai Hospital from January 2013 to December 2013 who had exclusively G2-DES implantation, were consecutively included the follow-up period was 2 years. Results: A total of 6 094 patients with CHD were implanted with G2-DES, of which 1 862 patients with DM, and 4 232 patients without DM.The proportion of DM patients receiving G2-DES implantation with the following characteristics: advanced age, female, hypertension, hyperlipidemia, history of previous stroke, history of peripheral artery disease, previous history of PCI, and with triple vessel, high preoperative Syntax score, high number of target lesions, B2 or C type lesions, severe calcification lesions, and chronic occlusive disease were significantly higher than those of non-DM patients(P<0.05). The incidence of major adverse cardiac and cerebral vascular events(MACCE), target vascular revascularization(TVR) and target lesion revascularization(TLR) were higher in DM patients than in non-DM patients during 2 year's follow-up(P<0.05). The univariate COX regression analysis showed that diabetes was risk factor for MACCE in patients with CHD implanting G2 DES(HR=1.241, 95%CI: 1.053-1.463, P=0.010). However, multivariable COX analysis showed that DM was not an independent risk factor for MACCE in CHD patients with G2-DES(HR=1.125, 95%CI: 0.952-1.330, P=0.167). While age, female, preoperative Syntex score, triple vessel, B2 or C lesion were independent risk factors for poor clinical prognosis in CHD patients with G2-DES. Conclusions: (1) CHD patients with DM often accompany more clinical risk factors and complicated coronary lesions; (2) the incidence of MACCE, TVR and TLR in DM patients is significantly higher than non-DM patients with G2-DES during the 2 year's follow up; (3) after multivariate adjustment, DM is not an independent risk factor for poor clinical prognosis in CHD patients with G2-DES, while traditional risk factors and complex coronary lesions are independent risk factors for poor clinical prognosis. PMID- 30481895 TI - [Reliability and repeatability analysis of simplified skeletal maturity scoring and thumb ossification composite index in the assessment of skeletal maturity inadolescent idiopathic scoliosis]. AB - Objective: To compare the reliability and repeatability of simplified skeletal maturity scoring (SSMS) and thumb ossification composite index (TOCI) in the assessment of skeletal maturity in adolescent idiopathic scoliosis(AIS) and their clinical utilization. Methods: A review was conducted on 500 AIS patients treated between October 2006 and August 2013 in Nanjing Drum Tower Hospital and one follow-up of each patient was randomly selected for this study.Based on SSMS and TOCI, the radiographs of the left palm were assessed by three observers independently with an interval of 2 weeks.The inter-observer reliability and intra-observer repeatability of two methods were analyzed by using Kappa value. Results: A total of 3 000 measurements were performed by the 3 surgeons for each method.For SSMS, 50 cases were described as stage 1 258 cases as stage 2 962 cases as stage 3 340 cases as stage 4 315 cases as stage 5 304 cases as stage 6 589 cases as stage 7 and 182 cases as stage 8.The inter-observer and intra observer agreements was 76.8%-82.0% (Kappa value 0.716-0.778) and 75.8%-82.4% (Kappa value 0.705-0.782), respectively.For TOCI, 27 cases were described as stage 1 183 cases as stage 2 167 cases as stage 3 171 cases as stage 4 745 cases as stage 5 536 cases as stage 6 410 cases as stage 7 and 761 cases as stage 8.The inter-observer and intra-observer agreements was 91.6%-92.4% (Kappa value 0.897 0.907) and 90.4%-92.0%(Kappa value 0.882-0.902), respectively. Conclusions: The two methods of SSMS and TOCI have substantial inter-observer reliability and intra-observer reproducibility for the assessment of skeletal maturity in AIS.TOCI has relatively higher reliability and repeatability when compared with SSMS. PMID- 30481896 TI - [Assessment of biomechanical properties of paraspinal muscles in adolescent idiopathic scoliosis]. AB - Objective: To assess the bio-mechanical properties of paraspinal muscles in adolescent idiopathic scoliosis (AIS). Methods: The MyotonPro(r) device and shear wave elasticity imaging(SWEI) technique were applied to detect the paraspinal muscle tone (F), stiffness (S), relaxation time (R), Deborah number (C) and elasticity (D) of paravertebral muscles on the concave side and convex side of scoliosis curvature at several points: apex of the curve (a), upper (b) and lower (c) limits of the curve in 23 cases of AIS treated from October to December 2017 in Beijing Chaoyang Hospital.Cobb angle of the main curve was measured on the standing anteroposterior whole spine radiograph.Pearson correlation analysis was applied to detect the relation between the bio-mechanical properties and Cobb angle of the main curve. Results: A total of 23 AIS patients [3 males and 20 females, mean age was (15+/-4) years] were assessed in this study.The mean Cobb angle was (66+/-33) degrees.The MyotonPro(r) data showed that the muscle tone on the concave side were all significantly greater than those on the convex side [a: (18.9+/-2.2) Hz vs (17.4+/-1.6) Hz, t=4.435, P<0.05; b: (18.2+/-2.0) Hz vs (16.7+/-1.7) Hz, t=4.183, P<0.05; c: (18.0+/-2.3) Hz vs (16.8+/-1.7) Hz, t=4.520, P<0.05]. The muscle stiffness on the concave side were all significantly greater than those on the convex side at the three points (t=1.974, 2.048, 1.749, all P<0.05). The relaxation time were all longer on the convex side (t=-3.422, 2.713, -2.380, all P<0.05). The Deborah number were greater on the convex side at a and b points (t=-2.939, -2.466, both P<0.05). No significant difference in elasticity was found between the muscles of the two sides.The SWEI results also indicated that the elasticity of the paraspinal muscles of the two sides were similar.The Pearson correlation analysis showed that stiffness on the concave side was moderate positively correlated with Cobb angle of the main curve (r=0.582, P<0.05). Deborah number on the two sides and relaxation time on the concave were moderate negatively correlated with Cobb angle of the main curve (r= 0.632, -0.432, -0.611, all P<0.05). Conclusions: The bio-mechanical properties of paraspinal muscles in AIS are different significantly between the concave and convex side and affected by the severity of scoliosis. PMID- 30481897 TI - [Mode of median nerve irritation under different wrist forcing postures observed by ultrasonography and foot pressure measurement system]. AB - Objective: To analyze the influence of simulation mouse use motion under different wrist forcing postures on median nerve, tendons and ligaments in the carpal tunnel. Methods: From June to November in 2017, a total of 49 healthy volunteers [aged from 18 to 27 years, 24 males (48 cases of hands) and 25 females (50 cases of hands)] were selected in the Institute of Digitized Medicine and First Affiliated Hospital of Wenzhou Medical University.Three hand postures of the volunteers were simultaneously and continuously measured by using LOGIQ E9 ultrasonic diagnostic apparatus and Zebris foot pressure distribution measurement system.Seventeen parameters of nerves, tendons and ligaments in carpal tunnel were observed under natural (0 N), and two forced (25 and 50 N) states.Double factor variance analysis was performed with generalized estimating equation (GEE). Results: With increasing pressure (0, 25 and 50 N) of hand postures, the distance between median nerve and transverse carpal ligament were all less than 0.2 cm.The differences in both the distance between median nerve and flexor pollicis longus under the hand pressure changes or under the hand posture changes and the top angle of a triangle composed of median nerve, flexor pollicis longus and flexor digitorum superficialis group under the hand pressure changes or under the hand posture changes were all significant under the GEE analysis (all P<0.01). There were no significant changes in all other structural parameters in the carpal tunnel with the increasing of hand pressure (all P>0.05). Conclusions: The influence of the transverse carpal ligament to the median nerve belongs to the mechanism of pressure-induced irritation damage.The influence of flexor pollicis longus to median nerve belongs to the mechanism of tension-induced irritation damage.The influence of flexor digitorum superficialis to median nerve belongs to the mechanism of mixed shear irritation damage. PMID- 30481898 TI - [Correlation analysis between the progression of HIV infection and HLA polymorphism]. AB - Objective: To analyze the polymorphisms of human leukocyte differentiation antigens I and II (HLA-A, B, DRB1) alleles and explore the association between HIV infection and HLA loci, for discovering the distribution of HLA loci in HIV infected with different disease progression in different parts of Henan Province. Methods: A total of 48 cases of slow progressers and 80 typical progressers in Weishi County, Shangcai County, Xihua County and Xuchang City of Henan Province were studied, and compared with 380 healthy blood donors.For analyzing HLA-A, B, DRB1 alleles and comparing difference among the study subjects, the method of polymerase chain reaction-sequence special oligonucleotide (PCR-SSO) was used. Results: The association of HLA alleles and HIV infection showed that HLA B*40?02, HLA-DRB1*04?05 was significantly more common in healthy people, while HLA-B*15?18, B*44?02, B*67?01 and HLA-DRB1*14?01 were present in HIV/AIDS.HLA A*02?06, HLA-B*13?02, B*40?06 in slow progressers were higher than typical progressers from the grouped study, and HLA-B*46?01 only appeared in the typical progressers. Conclusion: HLA-B*15?18, B*44?02, B*67?01, and HLA-DRB1*14?01 may be associated with HIV susceptibility.HLA-A*02?06, HLA-B*13?02, and B*40?06 may be associated with delayed disease progression in HIV-infected people, while HLA B*46?01 may be associated with accelerated disease progression. PMID- 30481899 TI - [Effects of tenofovir and telbivudine on HBV RNA in pregnant women with different genotypes of HBeAg-positive hepatitis B in Guizhou Province]. AB - Objective: To investigate whether HBV genotype influences HBV DNA and RNA responses to tenofovir(TDF) and telbivudine(LDT) in pregnant women with HBeAg positive in Guizhou. Methods: This was a retrospective analysis of 75 pregnant women hepatitis B with HBsAg and HBeAg double-positive(19-38 years old, median age 26 years old), who were enrolled in the Department of Infectious Diseases and Obstetrics Clinic of the Affiliated Hospital of Guizhou Medical University from May 2016 to July 2017.Blood samples were collected at 12-24, 28-32 and 36-40 weeks of pregnancy for analyses of genotype, including hepatitis B surface antigen(HBsAg), hepatitis B e antigen (HBeAg), HBV DNA, HBV RNA and liver function, alanine transaminase(ALT), aspartate transaminase(AST), total bilirubin(TBiL), total bile acids(TBA), cholinesterase(CHE), alkaline phosphatase (ALP). Continuous variable was adopted by means of mean+/-standard deviation, and categorical variables were used for statistical analysis. Results: The HBV genotype was B in 64.0%(48/75)and C in 36.0%(27/75). The TDF and LDT groups showed no differences in demographic and clinical characteristics, including liver function tests, HBsAg, HBeAg, log(10)HBV DNA and log(10)HBV RNA.TDF groups, pre-treatment: HBV DNA (4.8+/-2.0), HBV RNA (6.4+/-1.1); at 4 weeks of treatment: HBV DNA (4.0+/-0.8), HBV RNA (6.0+/-0.9); at the end of treatment: HBV DNA (3.1+/ 0.7), HBV RNA (5.5+/-0.8). LDT groups, pre-treatment HBV DNA (5.1+/-2.0), HBV RNA(6.5+/-0.9); at 4 weeks of treatment: HBV DNA (4.4+/-1.2), HBV RNA(6.5+/-0.8); at the end of treatment: HBV DNA(3.5+/-1.2), HBV RNA (6.1+/-0.7). Compared with pre-treatment (12-24 weeks), the TDF and LDT group showed significant reductions in log(10)(HBV DNA) and log(10)(HBV RNA) at 36-40 weeks ( P<0.05). Under the influence of excluding other variables, the genotype had a certain influence on the HBV RNA load.That was, HBV RNA in patients with the C genome decreased by 0.54 units(log(10)) at the end of the treatment compared to patients with the B genome, and the P value was less than 0.05. Conclusion: B and C genotypes are predominant in pregnant women with hepatitis B in Guizhou Province. B-type viruses are more easily controlled when different genotypes are treated with nucleotide analogues. PMID- 30481900 TI - [Relationships between the levels of serum 25-hydroxyvitamin D and interleukin-6 in patients with Takayasu's arteritis]. AB - Objective: The main purpose of this paper is to evaluate the level of serum 25 hydroxyvitamin D (25-OH-D) and clinical significance in patients with Takayasu's Arteritis (TA). Methods: A total of 62 untreated TA patients (TA group) and 60 healthy people (control group) were enrolled. The level of serum 25-OH-D were measured and compared between groups. The correlations of 25-OH-D level with related indicators were analyzed. Results: Lower concentrations of serum 25-OH-D were detected in TA patients compared with healthy subjects[(11.8+/-4.7) MUg/L versus (23.2+/-8.3) MUg/L](P<0.001). In active stage group, the 25-(OH)-D level of TA were significantly lower than that in remission stage group[(10.5+/-4.3) MUg/L vs (13.3+/-4.9) MUg/L](P=0.021). In all patients with TA, serum 25-OH-D correlated negatively with interleukin (IL)-6 (r=-0.296, P=0.023). There was no correlation between serum 25-OH-D level and C-reactive protein , erythrocyte sedimentation rate , National Institutes of Health Score, Indian Takayasu Clinical Activity Score 2010, and anti-tumor necrosis factor (TNF)-alpha antibody. Conclusion: A high prevalence of vitamin D deficiency was observed in patients with TA. The serum 25-OH-D level were negatively correlated with IL-6. PMID- 30481901 TI - [Dynamic features of tumefactive demyelinating lesions in different clinical stages by contrast-enhanced magnetic resonance imaging]. AB - Objective: To explore the dynamic features of tumefactive demyelinating lesions (TDLs) in different clinical stages by contrast-enhanced magnetic resonance imaging (MRI). Methods: Thirty-five patients with TDLs proven by pathological studies were prospectively recruited from January 2015 to January 2017.Brain contrast-enhanced MRI of the patients in different clinical stages including acute phase, subacute phase and chronic phase were completed after enrollment.The characteristics of contrast-enhanced MRI in different clinical stages were compared and the evolutional characteristics were summarized. Results: (1) Acute phase (35/35): the patterns of enhancement were patchy (74.3%, n=26), nodule (34.3%, n=12), closed ring (14.3%, n=5) and open ring (11.4%, n=4). (2) Subacute phase (32/35): the patterns of enhancement were open ring (40.6%, n=13), closed ring (31.3%, n=10), patchy (25.0%, n=8) and irregular edge of enhancement (21.9%, n=7). (3) Chronic phase (15/35): the patterns of enhancement were pale patchy (10/15), open ring (5/15) and closed ring (2/15). (4) The proportions of enhancement patterns including patchy, nodule, edge enhancement and pale patchy were significantly different among different clinical stages: 1 The patchy and nodule were the more common enhancement patterns in acute phase. 2 The edge enhancement was found mostly in subacute phase. 3 The pale patchy was found mostly in chronic phase. Conclusions: The manifestation of the lesions on contrast-enhanced MRI may have some characteristics of dynamic evolution according to different clinical stages.The dynamic observation may be helpful for the diagnosis and differential diagnosis of TDLs. PMID- 30481902 TI - [Neuronavigation-assisted percutaneous radiofrequency thermocoagulation of trigeminal gasserian ganglion for refractory craniofacial pain]. AB - Objective: Percutaneous radiofrequency thermocoagulation (RFT) of the Gasserian ganglion is an effective treatment for refractory trigeminal craniofacial pain.In the present study, we assessed the feasibility of accessing the Gasserian ganglion through the foramen ovale with neuronavigation guidance in the patients of trigeminal craniofacial pain. Method: We retrospectively analyzed forty-four patients with type I trigeminal neuralgia who had undergone percutaneous RFT treatment in our hospital from June 2014 to December 2016.The patients were divided into fluoroscopy group and navigation group according to the intraoperative guiding manners for foramen ovale cannulation.We compared groups in terms of the duration of the whole RFT procedure and times of intraoperative fluoroscopy.We also analyzed the immediate and late outcome accessing by Barrow Neurological Institute (BNI) pain scale, as well as the complication rates in groups. Result: There were 32 patients in the fluoroscopy group and 12 in the navigation group.The duration of the surgical procedure in navigation group was less than that in fluoroscopy group (46+/-12 min versus 67+/-16 min, P=0.00), and times of intraoperative fluoroscopy was reduced (6.3+/-2.2 versus 1.3+/-1.6, P=0.00). The learning curve of navigation-aid RFT was not steep in the present study overall.There was no significant difference between groups regarding pain reduction at the immediate (P=0.07) or late follow-up (P=0.400) time points.However, the rate of pain reduction to BNI-I grade was greater in navigation group (P=0.026). No significant difference in the complication rate between both groups, and no serious complications were observed in the both groups. Conclusion: Neuronavigation may be encouraged in trigeminal Gasserian ganglion RFT with better operating efficiency and less radiation exposure.The immediate and late therapeutic effects for craniofacial pain control were positive, whereas further studies are necessary. PMID- 30481903 TI - [Cyto-inactivation instantly induced by microwave ablation on thyroid nodules]. AB - Objective: To explore the effect of microwave ablation on thyroid nodules cell activity by the reaction of key enzyme of cell activation. Methods: From November 2017 to February 2018, 104 patients with 120 thyroid nodules underwent ultrasound guided microwave ablation at Super-minimally Invasive Medicals, Shanghai International Medical Center, aged 14-55 years, 42 males and 62 females.Twice core needle biopsy were performed before and after thermal ablation.The specimen were using hematoxylin and eosin (HE) staining and enzyme histochemical staining with include succinate dehydrogenase (SDH) and nicotinamide adeninedinucleotide phosphate diaphorase (NADPH-d), respectively, and observe under microscope. Results: Enzyme histochemical staining showed that the positive rate of SDH and NADPH-d in the marginal region and transitional region were 100% before ablation, and were 0% immediately after ablation.The positive rate of SDH and NADPH-d histochemical staining in the same area before and immediately after ablation was statistically significant (P<0.05). Shortly after microwave ablation, the tissue structure and cell morphology showed no obvious alteration in HE stained sections, but in sections with enzyme histochemical staining, the activity of SDH and NADPH-d in ablated tissue disappeared.The accuracy rate of pathologic diagnosis was 100% after ablation. Conclusions: SDH and NADPH-d enzyme activity may be better in evaluating the short-term efficacy of microwave ablation of thyroid nodules than HE staining. PMID- 30481904 TI - [Assessing right ventricular function in patients with pulmonary artery hypertension based on noninvasive measurements: correlation between cardiac MRI, ultrasonic cardiogram, multidetector CT and right heart catheterization]. AB - Objective: To compare the value of cardiac MRI (CMRI), ultrasonic cardiogram (UCG), multidetector CT (MDCT) in assessing right ventricular function (RV) in patients with PAH. Methods: A total of 31 consecutive patients with PAH (17 males and 14 females, 55+/-12 years) in Beijing Chao-Yang Hospital from August 2012 to February 2014 were prospectively enrolled. All patients underwent CMRI to get parameters including right ventricular end-systolic volume (ESV), end-diastolic dimension (EDV), stroke volume (SV), ejection fraction (EF), ventricular mass index (VMI). UCG parameters included Tei index, RV fractional area change (FAC), ESV, EDV. MDCT parameters included right /left ventricular internal diameter (RVd/LVd), right /left ventricular diastole maximum area (RVa/LVa), Cobb angle.These parameters obtained by MRI, UCG and MDCT were correlated with those of RHC respectively by Spearman or Pearson correlation analysis. Results: Six minutes walk distance had moderate negative correlation with CMRI-EF (40+/-9), VMI 44-115(71+/-20) g/m(2,) Cobb angle(67 degrees +/-12 degrees ); RHC-SV had moderate negative correlation with CMRI-SV(57+/-21) ml, EF, VMI, UCG-EF(41+/-14), Tei(0.82+/-0.29), FAC(30+/-9), RVd(45+/-7) mm, RVa(2 484+/-596) mm(2), Cobb angle ; Right cardiac work index had moderate negative correlation with CMRI-EF, RVd and Cobb angle. Conclusions: MRI-EF is the best parameter to reflect RV function. CMRI is the optimal method to assess RV function, and then is the MDCT and the last is UCG. PMID- 30481905 TI - [Application of chromosomal analysis for 29 cases of fetuses with nasal bone absence or hypoplasia]. AB - Objectives: To explore the chromosomal analysis for fetuses with nasal bone absence or hypoplasia. Methods: This was a retrospective study on 29 pregnancies nasal bone absence or hypoplasia which underwent prenatal diagnosis, including chorionic villi (CV), amniotic fluid or cordocentesis.The indication of the procedures and results were evaluated. Result: Fifteen (51.7%, 15/29) of chromosome abnormities were diagnosed with indication of fetal nasal bone absence or hypoplasia, including eight with trisomy 21, two with trisomy 13, two with X chromosome aneuploidy and three with pathogenic copy number variations (CNVs) respectively.The incidence of chromosomal abnormalities in fetus with nasal bone hypoplasia (2/5, 40%) was lower than that in fetus with nasal bone absence (13/29, 54.2%). The incidence of chromosomal abnormalities in fetus with non syndromic nasal bone absence or hypoplasia (4/13) was lower than that in fetus with syndromic nasal bone absence or hypoplasia (11/16). Conclusion: The incidence of chromosomal abnormalities in fetus with nasal bone absence or hypoplasia was higher and prenatal diagnosis was recommended for all types of the disease.For the fetus with nasal bone absence or hypoplasia, it is recommended to give priority to CNVs for prenatal diagnosis. PMID- 30481906 TI - [Rosuvastatin protects acute myocardial infarction rats through autophagy regulation via AMPK signaling]. AB - Objective: To investigate the effects of rosuvastatin (RSV)on autophagy and apoptosis of myocardial cells in rats with acute myocardial infarction. Methods: SD rats were divided into control (Sham group), acute myocardial infarction model rats (AMI group), AMI rats treated by RSV with the dose of 5 mg.kg(-1).d(-1) (RSV group), AMI rats treated by RSV and AMPK inhibitor Compound C at the same time (RSV+ CC group)(n=8) based on simple random sampling methods.Rat myocardial cell line H9c2 was divided into control group, Hypoxia group, Hypoxia+ RSV group, Hypoxia+ RSV+ Compound C group, Hypoxia+ AICAR (AMPK activator)group.After 6 weeks, the rats were examined by hemodynamics, and pathological observation of myocardial tissue by HE staining was also carried out.RT-PCR/Western blot were used to detect the expression of Beclin1, p62, BAX and Bcl-2 mRNA or protein of different groups in vivo and in vitro.Western blot was used to detect the expression of mTOR and AMPK protein and phosphorylation in cardiac tissue of each group. Results: In this study, the rat model of acute myocardial infarction was successfully prepared.Compared with the AMI group, the myocardium inflammation in the RSV group was alleviated, the LVMI decreased significantly, LVSP increased significantly, LVEDP decreased significantly, HR decreased significantly, the absolute value of dP/dTmax and -dP/dTmax increased significantly.The levels of Beclin1 and Bcl-2 mRNA were significantly up-regulated from 0.43 to 2.01 and 0.30 to 0.72, the expression of p62 and BAX mRNA decreased in half, the phosphorylation level of AMPK was significantly up-regulated, and the level of mTOR phosphorylation significantly reduced(P<0.05). These changes were antagonized by AMPK inhibitors in RSV+ CC group.In vitro experiments showed that, after RSV intervening, the levels of Beclin1 and Bcl-2 mRNA and protein in the myocardial cells of Hypoxia group significantly increased in triple, while the expressions of p62 and BAX mRNA and protein significantly decreased above a half.The above changes were consistent with those of the AMPK activator group and were antagonized by Compound C. Conclusion: RSV can effectively promote autophagy and decrease apoptosis in rat heart after myocardial infarction through AMPK/mTOR pathway. PMID- 30481907 TI - [Review of development of Department of Burn Surgery in the First Hospital of Naval Medical University over the past 60 years]. AB - This paper briefly described the establishment and development of Department of Burn Surgery in the First Affiliated Hospital of Naval Military Medical University (the former Changhai Hospital of the Second Military Medical University) over the past 60 years. After several generations of hard work and innovative development, our department has accumulated a wealth of experience and outstanding treatment effects in the treatment of severe burn and trauma patients. We have made great achievements in clinical practice, scientific development, and talent cultivation, as well as making important contribution to the development of burn and trauma medicine in Shanghai and even in China. PMID- 30481908 TI - [Inheriting, innovating, and developing: a celebration of the 60th anniversary of Chinese modern burn discipline]. AB - In 1958, with the national steelmaking, the number of burn victims greatly increased. With general surgery, trauma, and plastic surgeons as the core, a burn rescue group formed through multi-disciplinary cooperation, which gradually developed into an independent discipline. With great love and responsibility, the vast number of medical and nursing staff of burn discipline learned and discussed in practice, who were constantly improving and daring to break through and innovate. At that time, Qiu Caikang, the steel-making worker, with 89% total body surface area (TBSA) of total burn area and 23% TBSA of full-thickness burn, was rescued in Shanghai Guangci Hospital (now known as Ruijin Hospital, Shanghai Jiao Tong University School of Medicine), which was the first to succeed, rewriting the world record, followed by successful reports from hospitals in Chongqing, Xi'an, Beijing, and other places. The modern Chinese burn discipline has gone through 60 years since its inception in 1958. Several generations have carried out experimental research in combination with clinical practice, established the Society of Burn Surgery of the Chinese Medical Association and academic journals, created a treatment program for severe burns in China with treatment level in the world's leading position, enriching the world's treasure trove of burn medicine! PMID- 30481909 TI - [Sixty years of classics and sixty years of fulfilling mission]. AB - The Department of Burns of Beijing Jishuitan Hospital has gone through 60 years of glorious course as well as Chinese burn surgery. Over the past 60 years, our department developed from scratch, from weak to strong, with continuous innovation. Under the efforts of several generations, remarkable achievements have been made one after another. This article mainly introduces the contribution of our department to burn medicine from five aspects as follows: critical burn treatment, wound repair, electric burn treatment, flap transplantation, and emergency rescue. PMID- 30481910 TI - [Keep initiative mind to save burn crisis and strive hard to reach the summit of the burn discipline]. AB - The Department of Burns and Plastic Surgery in Guangzhou Red Cross Hospital of Medical College of Ji'nan University grew up along with the development of burn discipline in China. In the past 60 years, it has developed into a burn specialty with three wards, 100 beds, and nearly 100 medical staff from several beds and surgeons. It is characterized by the treatment of severe burns and is a medical burn center integrating medical treatment, teaching and scientific research. In recent ten years or more, the subject development has closely followed the changes of burn discipline and society and has carried out the construction of sub-specialties. It has formed obvious speciality features in the network construction for severe burn rescue, the construction and management of burn intensive care unit and the comprehensive prevention and treatment of multiple organ dysfunction syndrome for severe burn patients and has enjoyed a good reputation in our speciality. We will continue to maintain the professional spirit of burn medicine workers for emergency and disaster relief for burned patients, keep initiative mind, strive hard to continuously improve the professional and technical level, and strive to establish a regional burn treatment center to make more contributions to the development of burn discipline. PMID- 30481911 TI - [Review of development of Department of Burns and Plastic Surgery in the Affiliated Hospital of Zunyi Medical College]. AB - In the 60th anniversary of Chinese burn medicine, I am honored to review the development of Department of Burns and Plastic Surgery in the Affiliated Hospital of Zunyi Medical College. The Affiliated Hospital of Dalian Medical college was relocated to Zunyi in 1969 to support the development of southwestern China and renamed Affiliated Hospital of Zunyi Medical College. Only a few medical workers stayed in Zunyi when the State Council decided to reestablish Dalian Medical University in 1978. In the last 30 years, our department made great progress in the field of burns treatment with Chinese and Western medicine and complex wounds repair with flap, especially with perforator flap. We also took the lead to achieve the integrated treatment model, including peripheral vascular intervention, autogenous adipose cells/adipose-derived stem cells transplantation, platelet-rich plasma/platelet-rich fibrin, flap grafting, vacuum sealing drainage, Ilizarov technology, and functional active dressing for the treatment of chronic and ischemic wounds. Our department has become one of the national key clinical subject with certain influence from low ebb. PMID- 30481912 TI - [Retrospect on 60 years' history and prospect of Department of Burns and Plastic Surgery of Provincial Hospital Affiliated to Shandong University]. AB - The Department of Burns and Plastic Surgery of Provincial Hospital Affiliated to Shandong University is the leading team in Shandong province. It is integrated with clinical treatment, scientific research, teaching, personnel training, and medical service for social crisis, which undertakes the tasks of giving lessons and offering chances for noviciate and internship of burns and plastic surgery in College of Medicine of Shandong University. It is not only the training unit affiliated to College of Medicine of Shandong University for master students and doctoral students major in burns and plastic surgery, but also the national training base for specialists of burns and plastic surgery. It is the national key clinical subject of burn surgery. Over the past 60 years, with the concerted efforts of several generations, it has made significant contributions to the development and innovation of burns and plastic surgery in Shandong province and the whole China. PMID- 30481913 TI - [Chinese burn referral criteria (2018 version)]. AB - There is no national referral criteria for burns in China till now, which brings inconvenience and confusion. Based on the oversea experiences and the actual situation in China, many famous experts in burns discussed and developed this Chinese burn referral criteria (2018 version). We hope these referral criteria will be helpful in clinical practice of burns and can be improved continuously through application. PMID- 30481914 TI - [National experts consensus on application of silver-containing dressings in wound therapy (2018 version)]. AB - New silver-containing dressings developed in recent years have brought new and powerful means for the prevention and treatment of wound infection, which promote development and progress of wound therapy. There are many kinds of silver containing dressings, however, misunderstanding and even misapplication exist in how to choose and use these dressings. Based on literature evidence, we propose this national expert consensus on clinical application of silver-containing dressings, particularly in terms of kinds and mechanisms, indications, contraindications, rational selections in different wounds, and cautions in the clinical application of silver-containing dressings. This consensus would be helpful for medical and nursing personnel to use silver-containing dressings in wound repair field in clinic correctly and professionally. PMID- 30481915 TI - [National experts consensus on clinical application of collagen-based wound biomaterials (2018 version)]. AB - Collagen, as the main structural protein in human body, plays an important role in the wound healing process. Due to their inherent hemostatic characteristics, good biocompatibility, low immunogenicity, as well as controllable biodegradability, collagen-based materials have attracted much attention. In this article, we mainly introduce the characteristics of collagen-based wound biomaterials and the application mechanism as scaffold and wound dressing. And the standard and unified experts' consensus formed on the clinical indications, recommended applications, contraindications, and matters needing attention. The consensus wound help clinicians and patients to recognize collagen-based wound biomaterials correctly and use them rationally. PMID- 30481916 TI - [National experts consensus on clinical diagnosis and treatment of inhalation injury (2018 version)]. AB - Inhalation injury is caused by inhalation of heat, toxic or irritating gases which lead to respiratory and pulmonary parenchyma damage. At present, the clinical understanding about it is still limited and lack of effective diagnosis and treatment standard. Based on the experience of diagnosis and treatment of domestic inhalation injury, combined with reports of international researches, criteria (expert consensus) for inhalation injury were systematically discussed from pathological and pathophysiological changes, clinical diagnosis and evaluation, and clinical treatment, which provides reference for clinical diagnosis and treatment of patients inflicted with inhalation injury. PMID- 30481917 TI - [National experts consensus on application of pulse contour cardiac output monitoring technique in severe burn treatment (2018 version)]. AB - As a newly developed technique for hemodynamic monitoring, pulse contour cardiac output (PiCCO) monitoring takes great advantages in guiding shock resuscitation and fluid administration. PiCCO has been used more and more in burn patients in recent years, however there is no clinic consensus on how to apply PiCCO monitoring, understand the significance of PiCCO monitored parameters, and guide the treatment using PiCCO monitored parameters in patients with severe burns. Based on the current literature and the experts' clinical experience, national experts consensus on application of pulse contour cardiac output monitoring technique in severe burn treatment (2018 version) is now issued by the Burn and Trauma Branch of Chinese Geriatrics Society, aiming to provide practical guidance for its usage in clinic. PMID- 30481918 TI - [National experts consensus on tracheotomy and intubation for burn patients (2018 version)]. AB - Airway edema, stenosis, obstruction and even asphyxia are easy to occur in patients with extensive burn, deep burn of head, face, and neck area, inhalation injuries, etc., which threaten life. Timely tracheotomy and intubation is an important treatment measure, but lack of knowledge and improper handling in some hospitals resulted in airway obstruction. The technique of percutaneous tracheotomy and intubation provides convenience for emergency treatment of critical burns and mass burn. The Burn and Trauma Branch of Chinese Geriatrics Society organized some experts in China to discuss the indications, timing, methods, extubation, and precautions of tracheotomy and intubation for burn patients. The national experts consensus on tracheotomy and intubation for burn patients (2018 version) was written to provide a reference standard for clinical treatment. PMID- 30481919 TI - [Precision evaluation of immune status and its significance in sepsis after burns or trauma]. AB - Sepsis induced by major burns, trauma, and hemorrhage, remains a major cause of death of patients in intensive care units, and it may result in both the widespread activation and dysfunction of the innate as well as adaptive responses in host immune system. A large amount of information concerning subsets of innate and adaptive immune cells in sepsis has implicated that these cells, including neutrophils, macrophages, dendritic cells, T lymphocytes, regulatory T lymphocytes, and natural killer cells, have profound effects on immunoreactivity during acute insults or sepsis through modulating multiple receptor expressions or cytokine secretion, in turn contributing to the development and outcome of sepsis. It is of great significance that precision monitoring of immune function and the related indicators might help to assess the risk of secondary infection, the prognosis of septic patients, and guide the treatment of septic complications. PMID- 30481920 TI - [Further understanding of infection of carbapenems-resistant Klebsiella pneumoniae among burn patients and the related strategies for antimicrobial treatment]. AB - The prevalence of carbapenems-resistant Klebsiella pneumoniae (CRKP ) in burn wards has become one of the most troublesome issues in current management of bacterial infections. It is necessary for us to reconsider the epidemiology, risk factors and clinical characteristics of CRKP infection as well as therapeutic options. Formulating the principles of antimicrobial therapy of CRKP infection and combined antibiotics therapy and implementing appropriate dosage regimens designed by pharmacokinetic and pharmacodynamic profiles will be of importance. Common antimicrobial agents for the treatment of CRKP infection include polymyxins, tigecycline, fosfomycin, and carbapenems. Infection control measures such as contact isolation, active screening, and environmental surface disinfection must be integrated with antimicrobial stewardship to effectively curb and prevent the spread of CRKP. PMID- 30481921 TI - [Preliminary study on resistance mechanism and virulence features in carbapenems resistant Klebsiella pneumoniae from burn patients]. AB - Objective: To investigate resistance mechanism and virulence features of carbapenems-resistant Klebsiella pneumoniae (CRKP) and to provide theoretical foundation for the prevention and control of nosocomial infections in burn wards as well as clinical therapy of CRKP. Methods: Strains of Klebsiella pneumoniae isolated from clinical samples of burn patients hospitalized in our unit from February to December 2016 were collected. The diameters of inhibition zone of imipemen or meropenem susceptibility disk of the above strains were<=22 mm. Kirby Bauer disk diffusion method and automated instrument were applied to test drug resistance of the strains to 17 antibiotics of cephalosporins, aminoglycosides, sulfonamides, quinolones, and carbapenems. Pulsed-field gel electrophoresis (PFGE) was used to analyze homology of the strains. Crystal violet staining was applied to assess ability of biofilm formation of the strains. The hypermucoviscosity (HM) phenotype of the strains was determined by string test. Polymerase chain reaction was used to detect common carbapenemase genes of bla(KPC), bla(IMP), bla(OXA-48), and bla(NDM), capsular serotype genes of K1, K2, and K57, and virulence-associated gene of rmpA. Results: (1) A total of 29 CRKP strains were isolated. The 29 CRKP strains were with high drug resistance rate to carbapenems antibiotics of imipenen, meropenem, and ertapenem, and cephalosporins, aminoglycosides, and quinolones antibiotics, while the strains were with low drug resistance rate to sulfonamides antibiotics and tegafycline. (2) The 29 CRKP strains had 4 types of A, B, C, and D according to PFGE, with 11 strains of type A, 10 strains of type B, 6 strains of type C, and 2 strains of type D. (3) Among the 29 CRKP strains, 25 strains were positive in biofilm formation, with positive rate of 86.2%. (4) None of the 29 CRKP strains was positive in the string test with HM phenotype. (5) All the 29 CRKP strains carried carbapenemase genes. Among the 29 CRKP strains, 11 strains carried both bla(NDM-1) and bla(OXA-48) genes, 1 strain carried both bla(NDM-1) and bla(KPC-2) genes, 12 strains only carried bla(KPC-2) gene, and 5 strains only carried bla(NDM-1) gene. The 79.3% (23/29) strains were completely resistant to 3 kinds of carbapenems antibiotics. (6) Among the 29 CRKP strains, 3 strains carried K2 gene, 2 of which were completely resistant to 3 kinds of carbapenems antibiotics, 1 strain carried rmpA gene, and no strain carried K1 or K57 gene. Conclusions: The detection rate of CRKP isolated from burn patients hospitalized in our unit is high. The strains are mostly extensively drug-resistant bacteria, and the mechanism of drug resistance of which is complicated. There may have clonal spread of CRKP. And appropriate measures should be taken timely and effectively to prevent nosocomial spread of CRKP. PMID- 30481922 TI - [Analysis of distribution and drug resistance of pathogens from the wounds of 1 310 thermal burn patients]. AB - Objective: To analyze the distribution and drug resistance of pathogens from the wounds of thermal burn patients, so as to provide reliable basis for the rational use of antibiotics and the effective control over nosocomial infection. Methods: Wound samples of 1 310 thermal burn patients admitted into our burn wards from January 2012 to December 2017 were collected and retrospectively analyzed. API bacteria identification panels and automatical bacteria identification equipment were used to identify pathogens. E test was conducted to detect drug resistance of pathogens to vancomycin, tigecycline, and oxacillin. Kirby-Bauer paper disk diffusion method was used to detect drug resistance of pathogens to 31 antibiotics including penicillin G, gentamicin and rifampicin, etc., and drug resistance of fungi to 5 antifungal agents (voriconazole, amphotericin B, fluconazole, itraconazole, and ketoconazole). The WHONET 5.6 software was used to analyze the constituent ratios of Gram-negative bacteria, Gram-positive bacteria, and fungi in each year; the distribution of fungi; the distribution of top 10 bacteria with the highest constituent ratios in each year; the constituent ratios of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA); the drug resistance of top 3 bacteria with the highest constituent ratios to commonly used antibiotics in each year; and the drug resistance of Candida to commonly used antifungal agents. Results: (1) Totally 2 183 strains of pathogens were isolated for the first time, including Gram-negative bacteria 1 194 (54.70%) strains, Gram-positive bacteria 879 (40.27%) strains, and fungi 110 (5.04%) strains. From 2012 to 2016, the constituent ratio of Gram-negative bacteria showed a decreasing trend, while that of Gram-positive bacteria showed an increasing trend year by year; and the constituent ratio of fungi was with a significantly increasing trend from 2016 to 2017. (2) Among all the fungi, the constituent ratio of Candida parapsilosis ranked the first, Aflatoxin ranked the second, Candida albicans and Candida tropicalis both ranked the third. (3) From 2012 to 2017, top 10 bacteria with the highest constituent ratios, from high to low, were Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacter cloacae, Escherichia coli, Staphylococcus haemolyticus, Klebsiella pneumoniae, Enterococcus faecalis, Aeromonas hydrophila, and Stenotrophomonas maltophilia respectively. The constituent ratio of Staphylococcus aureus ranked the first in each year. The constituent ratio of Pseudomonas aeruginosa was fluctuating but showed a rising trend comprehensively. The constituent ratio of Acinetobacter baumannii went up after decreasing. (4) Among all the Staphylococcus aureus, constituent ratio of MRSA was above 65.00%, while that of MSSA was below 31.00% in each year. (5) From 2012 to 2017, Staphylococcus aureus resistant to vancomycin, linezolid, or teicoplanin was not detected; the drug-resistant rates of MRSA to penicillin G, oxacillin, gentamicin, rifampicin, tetracycline, ciprofloxacin, ofloxacin, and levofloxacin were above or equal to 80.0% in each year; the drug-resistant rates of Staphylococcus aureus to clindamycin and erythrocin showed an obviously increasing trend, the drug-resistant rates of Staphylococcus aureus to moxifloxacin and queenoputin/daputin in 2017 were higher than those in 2016, while the drug-resistant rates of Staphylococcus aureus to the other 14 antibiotics showed no significant change in trend. From 2012 to 2017, Acinetobacter baumannii was sensitive to polymyxin B and tigecycline; the drug-resistant rate of Acinetobacter baumannii to ceftriaxone was relatively high; the drug-resistant rates of Acinetobacter baumannii to levofloxacin, minocycline, and tetracycline were decreasing while those to the other 14 antibiotics went up after decreasing. From 2012 to 2017, Pseudomonas aeruginosa wasn't resistant to polymyxin B, and its drug-resistant rates to the other 14 antibiotics showed decreasing trends. (6) The drug-resistant rates of Candida albicans to voriconazole, amphotericin B, fluconazole, itraconazole, and ketoconazole were all zero. The drug-resistant rates of non-Candida albicans to voriconazole, fluconazole, itraconazole, and ketoconazole were higher than those of Candida albicans. Conclusions: Among the pathogens from the wounds of thermal burn patients, Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii had the top 3 constituent ratios; the constituent ratio of non-Candida albicans was obviously higher than that of Candida albicans. The high drug resistance rates of Staphylococcus aureus and Acinetobacter baumanni require more attention from clinicians and the local hospital's infection control department. PMID- 30481923 TI - [Effects of endotoxin/lipopolysaccharide on early apoptosis of human neutrophil through PIM3]. AB - Objective: To explore the effects of endotoxin/lipopolysaccharide (LPS) on early apoptosis of human neutrophil through PIM3. Methods: Venous blood samples were collected from a healthy adult volunteer to isolate neutrophils. The neutrophils were divided into control group, LPS group, and LPS+ PIM447 group according to the random number table. No treatment was given to the cells in control group. The cells in LPS group underwent LPS stimulation (1 MUL, 1 MUg/mL). The cells in LPS+ PIM447 group underwent PIM447 (1 MUL, final amount-of-substance concentration of 5 MUmol/L) intervention 30 min before having the same LPS stimulation as that in LPS group. After conventional culture for 1 h, the early cell apoptosis rate was determined with flow cytometer; the generation level of reactive oxygen species (ROS) was assessed with dihydrogenrhodamine 123 fluorescent probe staining method; and the level of PIM3 was detected by Western blotting. After conventional culture for 2 h, the cell chemotaxis distance was measured by agarose chemotaxis cell model. The sample numbers of each group in the 4 experiments were all 5. Data were processed with one-way analysis of variance and Student-Newman-Keuls test. Results: (1) The early apoptosis rate of cells in LPS group [(0.891+/-0.012)%] was close to that in control group [(1.351+/-0.183)%, P>0.05)]. The early apoptosis rate of cells in LPS+ PIM447 group [(82.057+/-0.121)%] was higher than that in LPS group (P<0.01). (2) The cell chemotaxis distance of cells in LPS group [(984+/-5) MUm] was significantly shorter than that in control group [(2 241+/-7) MUm, P<0.01]. The cell chemotaxis distance of cells in LPS+ PIM447 group [(1 785+/-11) MUm]was significantly longer than that in LPS group (P<0.05). (3) The generation level of ROS in cells of LPS group was significantly higher than that in control group (P<0.05). The generation level of ROS in cells of LPS+ PIM447 group was significantly lower than that in LPS group (P<0.05). (4) The expression level of PIM3 in cells of LPS group (1.297+/-0.015) was significantly higher than that in control group (0.789+/-0.021, P<0.05). The expression level of PIM3 in cells of LPS+ PIM447 group (0.731+/-0.011) was significantly lower than that in LPS group (P<0.05). Conclusions: LPS stimulation can reduce the early apoptosis of human neutrophils. Pre-intervention with PIM447 can significantly increase the early apoptosis of neutrophils after LPS stimulation, recover the chemotaxis, and inhibit the production of ROS. The mechanism may be related to LPS promoting the expression of PIM3. PMID- 30481924 TI - [Influence of vagus nerve on multiple organ function and immune reaction of T lymphocytes in septic rats]. AB - Objective: To explore influence of vagus nerve on multiple organ function and immune reaction of T lymphocytes in septic rats. Methods: Forty Sprague-Dawley rats were divided into sham injury group, sepsis group, vagus nerve stimulation (VNS) group, and vagotomy (VGX) group, according to the random number table, with 10 rats in each group. Rats in sepsis group, VNS group, and VGX group were inflicted with sepsis by cecal ligation and puncture (CLP). Rats in VNS group were given electrical stimulation on left cervical vagus nerve for 15 min right after CLP. Rats in VGX group underwent vagotomy of left cervical vagus nerve at 30 min before CLP. At 24 h after CLP, serum of rats was collected to detect levels of alanine transaminase (ALT), aspartate aminotransferase (AST), glycocholic acid (CG), creatine kinase (CK), myocardial creatine kinase (CK-MB), blood urea nitrogen (BUN), and serum creatinine by fully automatic biochemistry analyzer. The left lung of rats was collected to determine wet or dry mass, and wet to dry (W/D) ratio was calculated. The right lung of rats was collected to measure the activity of pulmonary myeloperoxidase (MPO) by enzyme linked immunosorbent assay (ELISA). Spleen of rats was collected to determine the proliferative activity of CD4(+) T lymphocytes by cell counting kit 8, and real time fluorescence quantitative polymerase chain reaction and ELISA were used to quantify mRNA expressions and levels of interleukin 2 (IL-2), interferon-gamma, and IL-4, respectively. Data were processed with one-way analysis of variance and Tukey's honest significant difference test. Results: (1) The levels of serum ALT, AST, CG, CK, CK-MB, BUN, and creatinine, pulmonary W/D ratio, as well as MPO activity of rats in sepsis group were significantly higher than those in sham injury group and VNS group (P<0.01) and were significantly lower than those in VGX group (P<0.01). (2) The proliferative activity of CD4(+) T lymphocytes of rats in sepsis group was 0.93+/-0.03, which was significantly lower than 1.54+/ 0.07 of rats in sham injury group (P<0.01). The proliferative activity of CD4(+) T lymphocytes of rats in VNS group was 1.15+/-0.15, which was significantly higher than that of rats in sepsis group (P<0.01). The proliferative activity of CD4(+) T lymphocytes of rats in VGX group was 0.75+/-0.06, which was obviously lower than that of rats in sepsis group (P<0.01). (3) In comparison with those of rats in sham injury group, the levels of IL-2 and interferon-gamma in CD4(+) T lymphocytes of rats in sepsis group were markedly decreased (P<0.01), while the level of IL-4 was significantly increased (P<0.01). In comparison with those of rats in sepsis group, the levels of IL-2 and interferon-gamma in CD4(+) T lymphocytes of rats in VNS group were obviously increased (P<0.01), while the level of IL-4 was markedly decreased (P<0.01). As compared with those of rats in sepsis group, the levels of IL-2 and interferon-gamma in CD4(+) T lymphocytes of rats in VGX group were markedly decreased (P<0.01), while the level of IL-4 was significantly increased (P<0.01). (4) As compared with those of rats in sham injury group, expressions of IL-2 and interferon-gamma mRNA in CD4(+) T lymphocytes of rats in sepsis group were markedly decreased (P<0.01), while expression of IL-4 mRNA was significantly increased (P<0.01). Expressions of IL-2 and interferon-gamma mRNA in CD4(+) T lymphocytes of rats in VNS group were obviously increased when compared with those of rats in sepsis group (P<0.01), while expression of IL-4 mRNA was markedly decreased (P<0.01). In comparison with those of rats in sepsis group, expressions of IL-2 and interferon-gamma mRNA in CD4(+) T lymphocytes of rats in VGX group were markedly decreased (P<0.01), while expression of IL-4 mRNA was significantly increased (P<0.01). Conclusions: Electrical stimulation of vagus nerve can significantly improve multiple organ dysfunction and reverse immunosuppression of T lymphocytes in septic rats, while vagotomy of vagus nerve may enhance the susceptibility of rats to sepsis. PMID- 30481925 TI - [Influence of nicotinic acid adenine dinucleotide phosphate on autophagy in hypoxic cardiomyocytes of rats and its mechanism]. AB - Objective: To investigate influence of nicotinic acid adenine dinucleotide phosphate (NAADP) on autophagy in hypoxic cardiomyocytes of rats and its mechanism. Methods: Five neonatal Sprague-Dawley rats were collected and sacrificed to harvest the hearts, and primary cardiomyocytes were separated for the following experiments. (1) Primary cardiomyocytes were collected and divided into normoxia group, hypoxia 9 h group, and hypoxia 9 h+ NAADP group according to random number table, with 5 wells in each group. Cells in normoxia group were cultured routinely in the constant temperature incubator at 37 C for 9 hours. Cells in hypoxia 9 h group and hypoxia 9 h+ NAADP group were cultured in hypoxic incubator with volume fraction 94% nitrogen, 5% carbon dioxide, and 1% oxygen for 9 hours. Before hypoxia, cells in hypoxia 9 h+ NAADP group were dealt with final amount-of-substance concentration 10 MUmol/L NAADP. Cell counting kit 8 was used to measure cell viability. (2) Primary cardiomyocytes were collected and divided into normoxia group, hypoxia 9 h group, hypoxia 9 h+ NAADP group, hypoxia 9 h+ tran-Ned-19 group, and hypoxia 9 h+ trans-Ned-19+ NAADP group according to the random number table, with 2 wells in each group. Cells in normoxia group were cultured routinely in the constant temperature incubator at 37 C for 9 hours. And cells in the other 4 groups were cultured in hypoxic incubator as that in experiment (1) Before hypoxia, cells in hypoxia 9 h+ NAADP group were dealt with amount-of-substance concentration 10 MUmol/L NAADP, cells in hypoxia 9 h+ tran Ned-19 group were dealt with amount-of-substance concentration 1 MUmol/L trans Ned-19, and cells in hypoxia 9 h+ trans-Ned-19 + NAADP group were dealt with amount-of-substance concentration 10 MUmol/L NAADP and 1 MUmol/L trans-Ned-19. Protein expressions of microtubule associated protein 1 light chain 3-II and P62 were detected by Western blotting. (3) Primary cardiomyocytes were collected and grouped as those in experiment (1). The lysosomal acidity was determined by immunofluorescence method. Data were processed with one-way analysis of variance and least-significant difference test. Results: (1) The cell viability in normoxia group was 1.114+/-0.024, which was significantly higher than 0.685+/ 0.079 of cells in hypoxia 9 h group (P<0.01). The cell viability of hypoxia 9 h+ NAADP group was 0.886+/-0.061, which was obviously higher than that of cells in hypoxia 9 h group (P<0.05). (2) Expressions of microtubule-associated protein 1 light chain 3-II and P62 of cells in hypoxia 9 h group were significantly higher than those of cells in normoxia group (P<0.01). Compared with those in hypoxia 9 h group, expression of P62 in hypoxia 9 h+ NAADP group was significantly decreased (P<0.01), while expression of microtubule-associated protein 1 light chain 3-II did not change significantly (P>0.05). There were no significantly statistical difference in expressions of microtubule-associated protein 1 light chain 3-II and P62 between hypoxia 9 h group and hypoxia 9 h+ trans-Ned-19 group (P>0.05). Compared with those of cells in hypoxia 9 h+ NAADP group, expression of P62 of cells in hypoxia 9 h+ trans-Ned-19+ NAADP group was obviously increased (P<0.01), while expression of microtubule-associated protein 1 light chain 3-II did not change significantly (P>0.05). (3) The intensity of green fluorescence of cells in normoxia group was strong and co-localized well with red fluorescence, and internal environment of lysosome was with stronger acidity. The intensity of green fluorescence in cells of hypoxia 9 h group was significantly lower than that of cells in normoxia group, and acidity of internal environment of lysosome was weakened. The intensity of green fluorescence and acidity of internal environment of lysosome in hypoxia 9 h+ NAADP were significantly stronger than those of cells in hypoxia 9 h group, but significantly lower than those of cells in normoxia group. Conclusions: NAADP can improve myocardial cell viability through acidifying internal environment of lysosome of cardiomyocyte after hypoxia, promoting degradation of autophagosomes, reducing autophagic lysosomal accumulation, and repairing damaged autophagic flow. PMID- 30481926 TI - [Application of self-made stretch pants in patients with burn in special sites]. AB - The change and fixation of dressing are difficult in patients with burn in special sites of perineum, buttocks, and bilateral thighs. Therefore, we designed and made stretch pants by ourselves for dressing fixation after dressing change in patients with burns in abdomen, buttocks, and bilateral thighs. The stretch pants are made by cutting and splicing elastic fabric according to perimeters of abdomen and legs. The stretch pants are used after wound dressing change, which can fix the dressing stably, accelerate wound healing, and reduce the medical workers' labor intensity of dressing change and economic burden of patients. And patients can walk out of bed early. It's especially suitable for dressing fixation of infants and other patients who are unwilling to cooperate. Besides, it's easy to make with low cost and suitable for clinical promotion. PMID- 30481927 TI - [Advances in the research of the relationship between wound temperature and wound healing]. AB - There are many factors that may affect the microenvironment of acute and chronic wounds. This article reviews the relationship between temperature factor in the external microenvironment of wound surface and wound healing. The temperature changes in different types and stages of wounds are closely related to the wound healing status. Therefore, wound temperature monitoring provides timely, reliable, and non-invasive method in the evaluation of wound status. As low temperature affects the physiological state of wound, relieving the low temperature state and maintaining normal temperature of the microenvironment of wound can promote wound healing. Further research is needed on the wound repair related effector cell proliferation and the mechanism of regulatory function to determine the optimal constant temperature and heat treatment duration needed for wound healing. PMID- 30481928 TI - [Radiomics: the process and applications in tumor research]. AB - Radiomics enables extraction of innumerable quantitative features from medical images with high-throughput computing for diagnosis and prediction. The practice of radiomics involves image acquisition, identifying and segmenting the volumes of interest, extracting and analyzing of quantitative features, and classification or prediction model development. Compared with traditional visual interpretation of medical images, the deep mining of medical images by computer technology from radiomics makes feature uptake more efficient, relatively objective and rich in feature types. Whereas, radiomic analysis requires high image quality and consistent scan parameters. The features extracted are confined to the segmented area. Radiomics is promising in tumor screening, early diagnosis, accurate grading and staging, treatment and prognosis, molecular characteristics and so on. Combined with traditional visual interpretation of medical images, radiomics is helpful in tumor diagnosis and prediction. PMID- 30481929 TI - [The incidence and mortality of lung cancer in China, 2014]. AB - Objective: To estimate lung cancer incidence and mortality in China using population-based cancer registry data in 2014 collected by National Central Cancer Registry of China (NCCRC). Methods: 449 cancer registries submitted cancer registry data in 2014. All datasets were evaluated and 339 registries' data which met the quality control criteria of NCCRC were analyzed. Numbers of new lung cancer cases and deaths were estimated using calculated incidence and mortality rates and corresponding national population stratified by areas, sexes and age groups. The standard population of Chinese census in 2000 and world Segi' s population were applied to calculate age-standardized incidence and mortality rates in China and worldwide, respectively. Results: A total of 781, 500 new lung cancer cases were diagnosed in 2014. The crude incidence rate was 57.13 per 100 000 and the age-standardized incidence rates by Chinese standard population (ASIRC) and by world standard population (ASIRW) were 36.71 per 100 000 and 36.63 per 100 000, respectively. The cumulative incidence rate (0-74 years old) was 4.50%. Lung cancer was the most common cancer in male (ASIRW: 50.04 per 100 000) and the second most common cancer in female (ASIRW: 23.63 per 100 000). The incidence rates were slightly similar in urban areas and in rural areas (ASIRW: 36.64 per 100 000 vs 36.56 per 100 000). A total of 626 400 lung cancer deaths were reported. The crude mortality rate was 45.80 per 100 000 and the age standardized mortality rates by Chinese standard population (ASMRC) and by world standard population (ASMRW) were 28.49 per 100 000 and 28.31 per 100 000, respectively. The cumulative mortality rate (0-74 years old) was 3.32%. Lung cancer was the most common cause of cancer deaths both in male (ASMRW: 40.21 per 100 000) and female (ASMRW: 16.88 per 100 000). The mortality rate was slightly higher in rural areas than in urban areas (ASMRW: 28.63 per 100 000 vs 28.04 per 100 000). Both lung cancer incidence and mortality rates increased with age, and the peak age was 80-84 years group. Conclusions: The disease burden of lung cancer is heavy in China. Efficient national health policies and prevention and control strategies against lung cancer should be promoted. PMID- 30481930 TI - [The anti-cancer effect of ZR30 protein via targeting extracellular signal proteins of different cell subpopulations of glioma]. AB - Objective: To investigate the roles and anti-cancer mechanism of artificially synthesized EGF-containing fibulin-like extracellular matrix protein (EFEMP1) derived tumor suppressor ZR30 protein in glioma (GBM). Methods: ZR30 protein were in vitro expressed using a wheat germ cell-free system. GBM cell lines (U251, U251NS, and U87) were cultured for 2-3 days in the presence or absence of ZR30 treatment. MMP-2 level was detected by gelatin zymography assay, moreover, the expression of EGFR, Notch-1 and p-Akt/Akt levels were determined by western blot. Additionally, MTT assay was used to measure ZR30's effect on the cell proliferation of U251 and U251NS cells. Furthermore, pre-mixed U251-GFP and U251NS-RFP cells (1?9) were injected into the brain of nude mice, and then ZR30 or PBS was injected into the intra-tumor after 10 and 21 days, respectively. Then DNA was extracted from the right brain of nude mice in each group. Comparative quantitative polymerase chain reaction (CQ-PCR) was used to examine the copy numbers of human gene hSPAG16, mouse gene mSpag16, GFP and RFP. The survival status of each group of nude mice was also observed. Results: The levels of activated MMP-2 in U87 and U251 cells were lower after 10, 50 and 100 ng/ml ZR30 treatment for 2-3 days. Western blot analysis showed that ZR30 treatment reduced the expression of EGFR, Notch-1 and p-Akt/Akt in U251 cells, and inhibited Notch 1 and p-Akt/Akt expression in U251NS cells, and then decreased the response of U251 cells to EGF stimulation. Moreover, ZR30 inhibited the cell proliferation of U251 and U251NS two days after exposure. The in vivo orthotopic GBM xenografts were successfully constructed. CQ-PCR results indicated that the hSPAG16/mSpag16 ratios of mice in PBS group and ZR30 treatment groups at 180, 700, and 1 800 ng dosages were 3.67+/-2.82, 1.18+/-0.97, 1.75+/-1.55 and 1.38+/-1.17, respectively, and ZR30 treatment groups showed significantly lower ratios than the PBS group (P<0.05 for all). Correspondingly, the ratios of GFP/RFP in each group were 1.97+/-0.80, 1.97+/-0.85, 1.48+/-0.71 and 1.73+/-0.77, respectively, showing no statistical significance (P>0.05 for all). When treatment was performed 10 d after cell implantation, and the median survival time of mice in PBS group and ZR30 group was 40.5 days and 59.0 days, respectively. When treatment was performed 21 d after cell implantation, the median survival time of mice in PBS group and ZR30 group was extended to 57.0 days and 74.5 days, respectively. The median survival time of ZR30 treatment groups significantly prolonged (P<0.05 for all). Conclusions: ZR30 inhibits in vitro cell growth, invasion, angiogenesis and stemness maintenance in glioma via suppressing activated MMP-2, EGFR, p-Akt/Akt and Notch-1 proteins. In vivo, ZR30 markedly increased survival of mice harboring glioma xenografts, even for only one intra-tumoral injection at the time of early tumor formation. Overall, the in vivo and in vitro experiments supported the therapeutic potential of ZR30 for GBM. PMID- 30481931 TI - [YAP regulates the proliferation and modifies the sensitivity to sorafenib in hepatocellular carcinoma cells]. AB - Objective: To detect the expression level of YES-associated protein 1 (YAP) in hepatocellular carcinoma (HCC) cell lines and investigate its effects on the proliferation activity and the sensitivity to sorafenib in HCC cells. Methods: Western blot was used to detect the protein expression levels of YAP in SMMC 7721, SK-Hep-1, HepG-2, Huh7 and the normal liver cell line L-O2. YAP specific small interfering RNA (si-YAP) or YAP expression plasmid were transfected in SK Hep-1 or Huh7 cells, respectively. Cell counting kit-8 (CCK-8) test was used to detect the cell proliferation activity and the cell cycle test was conducted by flow cytometry. SK-Hep-1 and SK-Hep-1 si-YAP cells were subcutaneously injected into the nude mice which were sequentially treated by intragastric administration of sorafenib, and the tumor growth in vivo were observed and compared. Results: The expression of YAP was upregulated in HCC cell lines. Deletion of YAP expression significantly decreased the survival rate of SK-Hep-1 cells [(78.5+/ 0.3)% vs (92.3+/-0.2)%, P=0.025]. Knockdown of YAP significantly increased the percentage of G(0)/G(1)-phase cells [ (65.4+/-3.3) % vs (55.7+/-3.4) %, P=0.039]. On the contrary, upregulation of the YAP expression in Huh7 cells significantly increased the cell survival rate [(81.2+/-1.3)% vs (62.5+/-1.1)%, P=0.013] and reduced the percentage of G(0)/G(1)-phase cells [(38.2+/-3.8)% vs (48.8+/-2.9)%, P=0.019]. The survival rate of SK-Hep-1 cells treated by si-YAP combined with sorafenib was (31.13+/-1.79)%, significantly lower than (48.87+/-0.58) % of SK Hep-1 cells treated by sorafenib alone (P=0.001), while overexpression of YAP attenuated the inhibitory effect of sorafenib on the survival of Huh7 cells [(69.98+/-2.94) % vs (53.53+/-1.93)%, P=0.001]. The tumor weights of SK-Hep-1 group, sorafenib alone group, SK-Hep-1 si-YAP group and SK-Hep-1 si-YAP combined with sorafenib group were (0.96+/-0.08) g, (0.62+/-0.08) g, (0.70+/-0.06) g and (0.27+/-0.02) g, respectively. The tumor weights of sorafenib alone group and SK Hep-1 si-YAP group were significantly lower than that of SK-Hep-1 group (P=0.012 and P=0.031, respectively). The tumor weight of SK-Hep-1 si-YAP combined with sorafenib group was significantly lower than that of SK-Hep-1 si-YAP group (P=0.001). Conclusions: The expression of YAP is upregulated in HCC cell lines, which regulates the proliferation, cell cycle, and sensitivity to sorafenib of HCC cells. YAP is a potential molecular target for HCC treatment. PMID- 30481932 TI - [Comparison of parameters for diffusion-weighted intravoxel incoherent motion imaging in lung cancer patients with different histopathological subtypes]. AB - Objective: To explore the intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) model in lung cancer patients with different histopathological subtypes. Methods: A total of 105 patients were recruited, including 68 cases of adenocarcinoma, 22 cases of squamous carcinoma and 15 cases of small cell carcinoma. All patients underwent magnetic resonance examination consisting of axial IVIM-DWI sequence on a 3.0 T whole body scanner, then the standard ADC (sADC), diffusion coefficient (D), pseudo-diffusion coefficient(D(*)), perfusion fraction (f), distributed diffusion coefficient (DDC) and water diffusion heterogeneity index (alpha) were calculated for each lesion within the IVIM-DWI model. Results: Mean sADC values were (1.45+/-0.26) *10(-3)mm(2)/s, (1.36+/-0.48) *10(-3)mm(2)/s and (1.35+/-0.40) *10(-3)mm(2)/s for adenocarcinoma, squamous carcinoma and small cell carcinoma, respectively. Mean f values were (59.75+/ 16.37) %, (47.41+/-18.69) % and (48.96+/-19.88) % for adenocarcinoma, squamous carcinoma and small cell carcinoma, respectively. Mean alpha values were 0.72+/ 0.13 for adenocarcinoma, 0.62+/-0.12 for squamous carcinoma, and 0.63+/-0.11 for small cell carcinoma, respectively. Statistical analyses indicated that the sADC, f and alpha values among different histopathological subtypes were significantly different (P<0.05), while there was no significant difference in D, D(*) and DDC values (P>0.05). Furthermore, the comparison showed that the sADC, f and alpha values of patients with adenocarcinoma were significantly higher than those with squamous carcinoma or small cell carcinoma (P<0.05), whereas there was no significant difference between squamous carcinoma group and small cell carcinoma group (P>0.05). Conclusions: The sADC, f and alpha values derived from the IVIM DWI model can be used for comprehensive non-invasive evaluation of diffusion, perfusion and heterogeneity of microenvironment in lung cancer patients. And the IVIM-DWI model may be a promising tool for predicting histopathological subtypes of lung cancer. PMID- 30481933 TI - [Contrastive analysis of ultrasonographic features of synchronous and heterochronic liver metastasis in patients with stromal tumor]. AB - Objective: To investigate the ultrasonographic features of synchronous and heterochronic liver metastasis in patients with stromal tumors, and to elucidate the value of ultrasonic examination in follow-up surgery. Methods: A total of 1 516 patients with pathologically confirmed gastrointestinal stromal tumors (GISTs) and extra-gastrointestinal stromal tumors (EGISTs) were enrolled. The ultrasonographic features of primary lesions and liver metastases in a total of 46 cases with 95 liver metastases were analyzed. Results: 24 out of 46 cases had primary lesion in the small intestine, 14 in the stomach, 4 in the abdominal cavity, 1 in the colon, 2 in the esophagus, and 1 in the mesentery. The expression of CD117, Dog-1 and CD34were detected by immunohistochemical staining. The positive rate of CD117 was 100%, the Dog-1 was 95.7% and the CD34 was 69.6%. There were statistically significant differences in the maximum diameter, boundary and blood flow of primary tumors in 28 patients with synchronous liver metastasis and 18 patients with heterochronic liver metastasis (P=0.001, 0.022 and 0.036, respectively). Of the 95 liver metastases, 86 (90.5%) were located in the right lobe of the liver, 79 (83.2%) had clear boundaries, 75 (78.9%) were hypoechoic or isoechoic, 55 (57.9%) showed colored patterns, and 68 (71.6%) had no halo.11 liver metastases were cystic masses, 59 were solid masses, and 25 were mixed masses. There was a statistically significant difference in blood flow between 65 synchronous hepatic metastases and 30 heterochronic liver metastases (P=0.017). Conclusions: There were differences of the primary tumor ultrasonographic features between the synchronous metastasis group and heterochronic metastasis group. The ultrasonographic features of primary tumors and liver metastases have important clinical significance for the diagnosis, follow-up and treatment of malignant mesenchymal tumors. PMID- 30481934 TI - [Impact of interval between noeadjuvant chemoradiotherapy and surgery on short and long-term outcomes of patients with rectal cancer]. AB - Objective: To explore the best surgical timing after neoadjuvant chemoradiation for advanced rectal cancer patients. Methods: According to the time interval between neoadjuvant chemoradiation and surgery, 117 patients with advanced rectal cancer were divided into short interval group (<=7 weeks, n=54) and long interval group (>7 weeks, n=64). The endpoints included postoperative pathology, short term efficacy, tumor recurrence and patient survival between the two groups. Results: There were 8 cases PCR in short interval group and 20 cases in long interval group(P=0.415). There were 23 cases of T downgrade in short interval group and 40 cases in the long interval group, which has significant difference (P=0.039). There were 21 cases of N downgrade in short interval group and 38 cases in long interval group, which has significant different (P=0.033). The short-term group was effective in 28 cases, stable in 20 cases, and progressed in 5 cases. In short term efficacy comparison, the cases of complete response, stable disease and progressive disease in short interval group was 28 cases, 20 and 5, long interval group was 47 cases, 14 cases and 3 cases, which has no significant difference(P=0.068). The 3-year local recurrence rate of short interval group and long interval group was 17.0% and 4.7%, respectively, and the difference was statistically significant(P=0.029). The incidence of recurrence in 3 years of short interval group and long interval group was 64.2% and 79.7%, respectively, and the difference was not significant (P=0.061). The highest PCR rate was reached in the 10th and 11th week after neoadjuvant chemoradiotherapy. Of the 12 and 8 patients who underwent surgery, 3 (25.0%) and 2 (25.0%) achieved PCR, respectively. Conclusion: PCR and local recurrence rate might be improved by time interval between neoadjuvant chemoradiation and surgery was more than 7 weeks. PMID- 30481935 TI - [Comprehensive analysis of unplanned reoperations in colorectal cancer surgery]. AB - Objective: To investigate the causes and impacts of unplanned reoperations (UO) in patients underwent colorectal cancer surgery, and its effect on the length of hospital stays and hospitalization fees of these patients. Methods: we retrospectively analyzed the data of colorectal tumor patients underwent resection and UO from January 2014 to November 2017 in Cancer Hospital, Chinese Academy of Medical Sciences (CAMS). Student t tests, ANOVA analysis and chi square test were used to compare the paired data and data of multiple groups, respectively. Results: There were 5 923 cases who underwent colorectal cancer surgery from 2014 to 2017. Among them, 75 cases further accepted UO, the incidence rate of UO was 1.27%. Among the 75 patients of UO, 60 were male and 15 were female, 21 patients underwent colonic operation and 54 patients underwent rectal operation. The average length of hospital stays were 25.8 days and the average hospitalization fees were 110 647.04 yuan. The gender construction, surgical site, average length of hospital stays and hospitalization fees of UO were significantly different from those of operative colorectal tumor patients during this period (all P<0.01). There were 40 patients underwent anastomotic fistula, 11 patients underwent stoma complications and 10 patients underwent bowel obstruction, respectively, which accounts for the three most common causes of UO after colorectal cancer surgery, and the total incidence was 81.3%. The interval of reoperation and the first operation significantly impacted the average length of hospital stays of UO patients (P=0.003), while marginally affected the hospitalization fees (P=0.847). Conclusions: UO are more possible to occur to the male patients who undergo rectal operation. The length of hospital stays and hospitalization fees of UO are significantly increased when compare to those of operative colorectal cancer patients. The time of reoperation significantly impacts the length of hospital stays but has little effect on the hospitalization fees of UO patients. PMID- 30481936 TI - [High-throughput texture analysis in the distinction of single metastatic brain tumors from high-grade gliomas]. AB - Objective: To explore the feasibility of high-throughput texture analysis in the distinction of single brain metastases (SBM) from high-grade gliomas (HGG) and validate the established model. Methods: A total of 86 patients who were histologically diagnosed with SBM or HGG were retrospectively collected, including 43 patients with SBM and 43 with HGG. All of patients were performed preoperative conventional head magnetic resonance imaging (MRI) scans. A total of 236 fluid-attenuated inversion recovery (FLALR) images containing the information of tumors were selected from the MRI images and each image was considered as an object. The training set had 200 images, including 106 from SBM group and 94 from HGG group, whereas the validation set had 36 images, including 19 from SBM group and 17 from HGG. After images preprocessing, images segmentation, features extraction, and features selection, a radiomic diagnostic model was finally established using the training set. The diagnostic performance of the diagnostic model was evaluated using a receiver operating characteristic (ROC) curve. Hierarchical clustering analysis was used to evaluate the quality of the extracted feature data and the classification effect of the model. The model was further validated using the independent validation set. Results: A total of 629 features were extracted and quantified from each sample, and 41 features were selected to establish feature subsets and the diagnostic model. The classification decision function of the model is f(x)=sign? and the kernel function of the model is K(x, x(i))=exp?. In the training set, the diagnostic accuracy, sensitivity, specificity, positive predictive value and negative predictive value were 0.845, 0.849, 0.840, 0.857 and 0.832, respectively. The area under the ROC curve reached to 0.939. Similar results were obtained in the validation set. Conclusion: The high-throughput texture analysis shows high accuracy in differentiating SBM from HGG. PMID- 30481937 TI - [Comparative analysis of computed tomography texture features between pulmonary inflammatory nodules and lung cancer]. AB - Objective: To investigate the value of computed tomography (CT) texture analysis in differential diagnosis of inflammatory and malignant pulmonary nodules. Methods: The image data of 54 patients with lung cancer and 36 patients with pulmonary inflammatory nodules were retrospectively collected in our hospital. All the patients received chest CT scan. CT texture analysis of entropy, correlation degree and contrast ratio were performed by the MaZda software. The receiver operating characteristic curve (ROC) was established and the area under the curve (AUC) was calculated to evaluate the value of CT texture analysis in differential diagnosis of inflammatory and malignant pulmonary nodules. Results: In the lung cancer group, the value of entropy, correlation degree and contrast ratio were 1.58+/-0.07, 0.02+/-0.17 and 8.79+/-2.59, respectively. In the inflammatory nodules group, the value of entropy, correlation degree and contrast ratio were 1.51+/-0.04, 0.22+/-0.16 and 12.53+/-2.24, respectively. The differences were all statistically significant (P values were 0.008, 0.027, and 0.006, respectively) between two groups. There was not statistically significant difference (P>0.05) in the CT values between the lung cancer group and the inflammatory nodule group based on the non-contrast enhanced CT scan. Meanwhile, there was no statistically significant difference (P>0.05) in the value of entropy, correlation degree or contrast ratio between two groups based on arterial phase or venous phase of contrast enhanced CT. The ROC analysis showed that the AUC in differentiating the lung cancer and inflammatory nodules was 0.821, 0.778 and 0.875, respectively. The AUC of combination of three phases was 0.931, which was higher than the AUC of entropy, correlation degree and contrast ratio respectively (P<0.01). The sensitivity was 88.9%, and the specificity was 87.5%. Conclusion: CT texture analysis is a high-potential image analysis method, which can provide more information for the differential diagnosis of benign and malignant pulmonary nodules. PMID- 30481938 TI - [Study on the significance of intravoxel incoherent motion quantitative index combined with time-signal intensity curve in the early diagnosis of residual lesions in non-small cell lung cancer after argon-helium cryosurgery]. AB - Objective: To study the application of intravoxel incoherent motion (IVIM) quantitative index combined with time-signal intensity curve (TIC) of dynamic contrast enhanced 3.0T magnetic resonance in the early precise diagnosis of residual lesions in non-small cell lung cancer (NSCLC) after argon-helium cryosurgery. Methods: One hundred NSCLC patients who underwent argon-helium cryosurgery were collected and divided into the residual group (21 cases) and non residual group (79 cases) according to the result of needle biopsy and follow-up. The apparent diffusion coefficient (ADC), slow apparent diffusion coefficient (sADC), fast apparent diffusion coefficient (fADC), fraction of fast apparent diffusion coefficient (ffADC) and TIC type of IVIM quantitative index between the two groups were compared at 7 days and 1 month after argon-helium cryosurgery, respectively. The diagnosis performance of each quantitative index was analyzed by receiver operating characteristic (ROC) curve and the best cut-off value was computed. The specificity and sensitivity of TIC types were calculated as diagnostic criteria. The diagnosis performance of IVIM quantitative index combined with TIC type was evaluated and compared with the conventional MRI and DWI. Results: The differences of ADC, sADC and ffADC at 7 days and 1 month after argon-helium cryosurgery between the residual group and non-residual group were statistically significant (all P<0.05), in which the diagnosis performance of sADC and ffADC were better. The AUC of sADC and ffADC at 7 days after argon helium cryosurgery were 0.861 and 0.895, the sensitivity were 81.0% and 90.5%, and the specificity were 77.2% and 73.4%, respectively. The AUC of sADC and ffADC at 1 month after argon-helium cryosurgery were 0.836 and 0.883, the sensitivity were 100.0% and 76.2%, and the specificity were 58.2% and 89.9%, respectively. The diagnosis performance of TIC type II&III was best. The sensitivity and specificity were 80.9% and 58.2% at 7 days after treatment, 85.7% and 62.0% at 1 month after treatment, respectively. At 7 days after treatment, the sensitivity and specificity of IVIM combined with TIC were 97.5% and 85.7%, while at 1 month after treatment, the sensitivity and specificity of IVIM combined with TIC were 97.5% and 90.5%, respectively. The diagnosis performance of IVIM quantitative index combined with TIC type was better than conventional MRI and DWI. Conclusion: The combination of IVIM quantitative index and TIC type can be used in the early diagnosis of residual lesions after argon-helium cryosurgery for NSCLC, whose effect is better than conventional MRI and DWI. PMID- 30481939 TI - [Value of double contrast-enhanced ultrasound QontraXt three-dimensional pseudocolor quantitative analysis to therapeutic effect evaluation of preoperative neoadjuvant chemotherapy in advanced gastric cancer patients]. AB - Objective: To investigate the value of tumor perfusion parameter measured by using double contrast-enhanced ultrasound (DCEUS) QontraXt three-dimensional pseudocolor quantitative analysis to the therapeutic effect evaluation of preoperative neoadjuvant chemotherapy (NAC) in advanced gastric cancer (AGC) patients. Methods: Eighty-nine AGC patients underwent 3 cycles of preoperative NAC (XELOX) followed by complete resection of lesion. The DCEUS QontraXt three dimensional pseudocolor was performed one or two weeks before the NAC and operation were applied, respectively. The peak enhancement (PE), time to peak (TP), sharpness of the bolus (beta) and area under the enhancement curve (AUC) of primary gastric tumor were measured by QontraXt three-dimensional pseudocolor quantitative analysis. These DCEUS parameters between respond and non-respond groups before and after NAC therapy were compared. The prediction accuracy of DCEUS to the therapeutic effect evaluation of preoperative NAC was determined by the receive operating characteristic (ROC) curves. Results: Among 89 AGC patients, 52 patients responded to NAC therapy, while 37 patients resisted to NAC therapy. Twelve cases in respond group and 26 cases in non-respond group were mucinous carcinoma. Forty cases in respond group and 11 cases in non-respond group were non-mucinous carcinoma (P<0.05). In responder group, the PE and TP before NAC were (53.7+/-9.3)% and (14 521+/-2 667) ms, and (32.2+/-5.5)% and (17 235+/-1 898) ms after NAC. The ratio of changes of PE (DeltaPE) and TP (DeltaTP) were 0.43+/-0.17 and 0.36+/-0.14, respectively. In non-respond group, the PE and TP before NAC were (54.4+/-7.2)% and (13 869+/-3 247) ms, and (45.3+/-6.1)% and (15 127+/-1 423) ms after NAC therapy. The ratio of DeltaPE and DeltaTP were 0.24+/-0.20 and 0.22+/-0.12. The PE and TP after NAC, the ratio of DeltaPE and DeltaTP were significant different among these two groups (all of P<0.05). The ROC curves showed that the ratio of DeltaPE in assessing the respond of gastric cancer patients to NAC was superior compared to other parameters (AUC=0.784, P=0.004). The optimal cut-off value of the ratio of DeltaPE was 24% and its sensitivity and specificity to the therapeutic effect evaluation of NAC in gastric cancer were 82.7% and 64.9%. Conclusion: DCEUS QontraXt three-dimensional pseudocolor quantitative analysis might be a novel, noninvasive and reliable method to evaluate the therapeutic effect of preoperative NAC in AGC patients. PMID- 30481943 TI - [Leptomeningeal metastasis of myxofibrosarcoma: a case report]. PMID- 30481945 TI - Simulation-based ultrasound-guided regional anesthesia curriculum for anesthesiology residents. AB - Proficiency in ultrasound-guided regional anesthesia (UGRA) requires the practitioner to acquire cognitive and technical skills. For anesthesiology residents, an assortment of challenges has been identified to learning UGRA skills. Currently, a validated UGRA curriculum for residents does not exist and the level of UGRA proficiency achieved during residency training can vary considerably. Simulated practice has been shown to enhance proficiency in UGRA, and a competency-based education with simulation training has been endorsed for anesthesiology residents. The objective of this review is to outline simulation based training that can be implemented into a UGRA curriculum and explore educational tools like gamification to facilitate competency in regional anesthesiology. PMID- 30481946 TI - Combined supraclavicular-superficial cervical plexus block for clavicle surgery. AB - 35% of the shoulder girdle fractures include clavicle fractures. Surgical fixation is preferred especially for young patients for optimal functional outcomes while unresolved fractures are usually treated conservatively. A 38-year old male patient was admitted to the emergency service after falling resulting a left clavicle fracture. During the preoperative evaluation, the patient requested to be awake during the surgery. Combined supraclavicular-superficial cervical plexus block was performed under ultrasound guidance and no complications and pain was seen. This approach may be successful to avoid the possible complications related with interscalene brachial plexus block and more studies are needed in the near future. PMID- 30481944 TI - [Eight primary malignant tumors in a female patient]. PMID- 30481942 TI - [Applying decision trees to establish risk rating model of breast cancer incidence based on non-genetic factors among Southwest China females]. AB - Objective: To estimate incident probability and establish risk rating model of breast cancer incidence under different combinations of non-genetic factors among Southwest China females, applying the decision trees. Methods: From 2014 to 2015, a total of 783 cases, which were pathologically diagnosed as primary breast cancer, were sequentially collected from West China Hospital of Sichuan University, Sichuan Cancer Hospital and Sichuan Province People's Hospital. 3, 879(excluding 36 samples with missing data) controls were randomly selected and matched by area of residence and age. Classification and regression tree (CART) algorithm was applied to construct breast cancer risk rating model according to non-genetic factors. 5 test sets were randomly selected for model validation. Results: BI-RADS classes, menopausal status, age, history of benign breast disease, menarche age, age of first delivery and number of live births were identified as risk factors and included in the risk rating model of breast cancer incidence. Among these factors, BI-RADS classes, menopausal status and age were the most important. The risk rating model developed were vitrificated by 5 test sets, and the average sensitivity, positive predictive value, accuracy were 95.60%, 92.26%, 97.93%, respectively. Conclusions: Breast cancer risk rating model constructed by decision trees was valid and reliable. The model could be used as the basic tool of breast cancer risk assessment among Southwest China females. PMID- 30481941 TI - [Treatment of giant cell tumor of distal radius with vascular anastomosis with proximal graft of vascular]. AB - Objective: To evaluate the curative effect of proximal fibula graft of vascular anastomosis for giant cell tumor(GCT) of distal radius of bone. Methods: 38 patients with distal radius GCT were treated with proximal articular graft of anastomotic vessels. We evaluated the wrist joint function before and after surgery using wrist activity, visual analogue scale(VAS)pain score, grip recovery rate and Cooney scoring system. Results: All patients' wounds healed in stage I, and recovered smoothly during the perioperative period. No obvious wrist deformity was observed during the follow-up period. Bony union was achieved at the tibial and humerus osteotomy ends. The average healing time was 11 weeks. At third month postoperatively, the patient's wrist motion ranged from dorsiflexion to palmar flexion (69.15+/-15.24) degrees , ulnar/spasm deviation was (22.74+/ 10.55) degrees , grip strength was (88.69+/-12.75)%, wrist VAS pain The score was (2.45+/-1.11) points and the Cooney score was (89.58+/-11.25) points, which was significantly better than preoperation (all P<0.05). No recurrence or metastasis occurred during follow-up in all patients. Conclusions: Distal humerus GCT treated with distal radius with vascular anastomosis with proximal graft of vascular has little effect on the activity of the lower extremities. However, its reconstruction of the wrist joint function might achieve better results. PMID- 30481940 TI - [The clinicopathological features and curative effect of the bronchoscopic interventional therapy combined with radiotherapy for the treatment of locally recurrent lung adenoid cystic carcinoma]. AB - Objective: To explore the clinical value of endoscopic interventional therapy for locally recurrent primary lung adenoid cystic carcinoma (ACC). Methods: The clinical data of 42 patients with locally recurrent ACC were retrospectively analyzed, and the differences of tracheal and bronchial diameter, airway scoring grade and airway obstruction degree before and after treatment were compared among three treatment methods: bronchoscopic interventional therapy + palliative radiotherapy, interventional therapy alone, and non-interventional therapy. Log rank test and Cox proportional risk model multi-factor analysis were used to determine the prognostic factors of ACC patients with local recurrence, and the long-term effect of bronchoscopic interventional therapy on ACC with local recurrence was determined. Results: The median overall survival of 42 patients was 59 months and 5-year survival rate was 54.2%.Univariate analysis showed that vascularized cancer, pleural invasion, pulmonary atelectasis, incisal margin, microscopic classification, tumor diameter, initial TNM stage, ki-67 index, and treatment after local recurrence were associated with long-term survival of ACC patients with local recurrence (all P<0.05). Cox multivariate regression analysis showed that margin status (RR=0.272, P=0.011), tumor diameter (RR=2.586, P=0.005), initial TNM staging (RR=0.369, P=0.035), ki-67 index (RR=3.569, P<0.001), and treatment methods after local recurrence (RR=0.126, P<0.001) were independent factors influencing the prognosis of ACC patients with local recurrence. After three months of treatment, the tracheal bronchus diameters, rating of shortness of breath, and degree of airway obstruction were all improved significantly (all P<0.05), both in the interventional therapy + palliative radiotherapy group [(14.5+/-2.8 mm, 0.86+/-0.45, (14.50+/-10.67)%, respectively], and the interventional therapy alone group [(13.7+/-2.3) mm, 0.97+/-0.25, (15.38+/-12.02)%, respectively]. Meanwhile, the difference before and after non interventional therapy was not statistically significant (all P>0.05). 5-year overall survival rates were 55.8%, 46.6% and 42.6% for patients undergoing interventional therapy+ palliative radiotherapy, interventional therapy alone, and non-interventional therapy after recurrence, with statistically significant differences (P=0.015). Patients underwent bronchial endoscopic interventional therapy and palliative radiotherapy had the best efficacy of treatment. Conclusion: Endoscopic interventional therapy plus palliative radiotherapy is an effective local palliative treatment for locally recurrent ACC patients, which can rapidly relieve airway stenosis, improve the quality of life of patients and prolong the survival time of patients. PMID- 30481947 TI - Erector spinae plane block combined with a novel technique for selective brachial plexus block in breast cancer surgery. AB - Breast innervation consists of intercostal nerves and brachial plexus. Here we propose a technique to execute breast surgery without general anesthesia using erector spinae plane (ESP) block and selective block of four nerves arising from brachial plexus and innervating breast and axilla (from now on SBP block. A 77 year-old male presented for breast cancer with indication to radical mastectomy and axillary clearance. He had a history of myocardial infarction resulting in postinfarction dilated cardiomyopathy with a severe reduction in ejection fraction. We planned a regional anesthesia technique consisting of an ESP block and a SBP block. No opioids were needed and patient remained comfortable throughout surgery, no additional analgesic administration was required by the patient both during surgery as well as for the following postoperatively days until discharge. In conclusion, SBP is a novel block thought to provide anesthesia to brachial plexus components involved in innervation of the breast region. PMID- 30481948 TI - Anaphylactic shock after sugammadex administration, induced by formation of a sugammadex-rocuronium complex. AB - A 42-year-old man developed anaphylactic shock in the postanesthesia care unit. Initially, sugammadex, a reversal agent for a non-depolarizing neuromuscular blocking agent, was suspected as the causative agent, but an intradermal skin test revealed negative results. A further skin test was performed with sugammadex rocuronium complex, which yielded positive results. Thus, we concluded that the sugammadex-rocuronium complex had led to anaphylactic shock. PMID- 30481951 TI - Comet tail artifact on ultrasonography: is it a reliable finding of benign gallbladder diseases? AB - Purpose: The aim of this study was to evaluate whether the comet tail artifact on ultrasonography can be used to reliably diagnose benign gallbladder diseases. Methods: This retrospective study reviewed the clinical findings, imaging findings, preoperative ultrasonographic diagnoses, and pathological diagnoses of 150 patients with comet tail artifacts who underwent laparoscopic cholecystectomy with pathologic confirmation. The extent of the involved lesion was classified as localized or diffuse, depending on the degree of involvement and the anatomical section of the gallbladder that was involved. This study evaluated the differences in clinical and imaging findings among pathologic diagnoses. Results: All gallbladder lesions exhibiting the comet tail artifact on ultrasound examination were confirmed as benign gallbladder diseases after cholecystectomy, including 71 cases of adenomyomatosis (47.3%), 74 cases of chronic cholecystitis (49.3%), two cases of xanthogranulomatous cholecystitis (1.3%), and three cases of cholesterolosis (2.0%); there were two cases of coexistent chronic cholecystitis and low-grade dysplasia. There were no statistically significant differences in any of the clinical and ultrasonographic findings, with the exception of gallstones (P=0.007), among the four diseases. There were no significant differences in the average length, thickness, or number of comet tail artifacts among the four diagnoses. No malignancies were detected in any of the 150 thickened gallbladder lesions. Conclusion: The ultrasonographic finding of the comet tail artifact in patients with thickened gallbladder lesions is associated with the presence of benign gallbladder diseases, and can be considered a reliable sign of benign gallbladder disease. PMID- 30481949 TI - The relationship of heart rate between natural sleep and dexmedetomidine sedation. AB - Background: Sedation by dexmedetomidine is similar to natural sleep and often causes bradycardia. We attempted to determine the relationship of heart rate changes between natural sleep and dexmedetomidine sedation. Methods: The present study included 30 who were scheduled to undergo elective surgery under spinal anesthesia. To assess heart rate (HR) and sedation, pulse oximeter and bispectral index (BIS) monitor were attached to the patient in the ward and the operating room. After measuring the HR and BIS before sleep, the BIS decreased to less than 70 and the HR and BIS were measured at 5 min intervals. HR and BIS were measured before spinal anesthesia, and HR and BIS were measured at 5 min interval after dexmedetomidine injection. Results: At natural sleep, heart rate changes ranged from 2 to 19 beats/min (13.4 +/- 4.4 beats/min), while in dexmedetomidine sedation from 9 to 40 beats/min (25.4 +/- 8.5 beats/min). Decrease in heart rate was significantly correlated between natural sleep and dexmedetomidine sedation (R2=0.41, P < 0.001). The lowest heart rate was 59 beats/min at 66 minutes in natural sleep and 55 beats/min at 13 min in dexmedetomidine sedation. There was a difference in the time of the lowest heart rate (P < 0.001) but there was no difference in the rate (P = 0.09). Conclusions: There was a correlation between the change in heart rate during natural sleep and dexmedetomidine sedation. The bradycardia that occurs when using dexmedetomidine may be one of the normal changes, and this may be observed rather than corrected. PMID- 30481954 TI - Hybrid Fractional Laser: A Multi-Center Trial on the Safety and Efficacy for Photorejuvenation AB - BACKGROUND: Laser skin resurfacing has continued to evolve over the past two decades. One of the most recent advances included a hybrid fractional laser resurfacing system that can sequentially utilize two wavelengths in its delivery, non-ablative coagulation with 1470 nm, and ablative vaporization with 2940 nm. The 1470 nm laser wavelength is absorbed by water, which is ideal for creating controlled zones of coagulation to chosen depths into the dermis up to 700 micrometers. The 2940 nm laser wavelength has a large water absorption coefficient, which results in precise ablation as desired in the epidermis up to 110 micrometers. This combination allows for fractionated non-ablative and ablative skin resurfacing simultaneously resulting in a cosmetic improvement in pigmentation, tone, texture of skin as well as other effects of photoaging.METHODS: Open-label prospective, multi-center study in which 34 female subjects were enrolled with Fitzpatrick skin types I-IV, mean age of 52 +/- 14 years. Each subject underwent two treatments, spaced 4-6 weeks apart. Follow up visits at 1 week, 2 weeks, and 1, 2, and 3 months after the first treatment. Photographs, numeric pain scores during treatment, and subject satisfaction survey questionnaires were evaluated. Photographs were analyzed by six blinded evaluators. The primary endpoint was to evaluate safety and efficacy of hybrid laser treatments for photodamage and dyschromia. The secondary endpoints included evaluating the tolerability of the treatment using the Wong Baker Face scale and patient satisfaction survey results.RESULTS: Of the 29 subjects completing the study, 80% showed significant skin improvement on photographic analysis. Average numeric pain score was a 4 on a 0-10 scale. Survey results showed 100% satisfaction with treatment and achieved results. Two patients experienced post inflammatory hyperpigmentation that resolved within 90 days. No other adverse events were reported.CONCLUSION: The non-ablative and ablative hybrid fractional laser can be used to safely and efficaciously treat photodamaged skin with high patient satisfaction and minimal adverse events.J Drugs Dermatol. 2018;17(11):1164-1168. PMID- 30481952 TI - Lasers and Energy-Based Devices for Women's Genitourinary Health: Scientific and Clinical Evidence and FDA Clearance PMID- 30481955 TI - Clinical Evaluation of Safety and Efficacy of Fractional Radiofrequency Facial Treatment of Skin Type VI Patients AB - INTRODUCTION: It has been well established that patients with darker skin types (Fitzpatrick skin types IV-VI) have an increased incidence of thermal induced side effects from laser and radio frequency (RF) treatments. Complications include a higher risk of post-inflammatory hyperpigmentation, hypopigmentation, and scarring, leading to unsatisfactory clinical outcomes. Fractional technologies improve the safety when treating patients with skin of color by treating only fractions of the skin while leaving a healing reservoir of untreated skin that improves the healing process. Fractional RF tips with coated pins may offer a more advantageous safety profile, particularly in the skin-of color population (Fitzpatrick skin types IV-VI) by increasing the protection of the epidermal layer by minimizing epidermal heating The current study was intended to evaluate the safety and efficacy of fractional RF technology for the treatment of patients with Fitzpatrick skin type VI.METHODS: 35 subjects with skin type VI received 3 sessions of facial treatments, 4 weeks apart using a fractional RF device with 24 pin coated tip. The treatment's safety and efficacy were evaluated at 2 follow-up visits, 6 and 12 weeks after the last treatment.RESULTS: Skin characteristics evaluations, including Fitzpatrick Wrinkles Classification, acne scars, and overall facial appearance demonstrated improvement in follow-up visits comparing to baseline. No significant unexpected adverse events were detected.CONCLUSION: The current study proves the safety and efficacy of the fractional RF treatment modality with coated pins tips for skin rejuvenation treatments resulting in improved wrinkles, acne scars, and overall skin appearance, in patients with skin type VI.J Drugs Dermatol. 2018;17(11):1169 1172. PMID- 30481953 TI - The Safety of Laser Skin Resurfacing With the Microablative Carbon Dioxide Laser and Review of the Literature AB - OBJECTIVE: The aim of this study was to evaluate the incidence of adverse effects following laser skin resurfacing with the microablative carbon dioxide (CO2) laser system (SmartXide DOT; DEKA, Calenzano, Italy).METHODS: A retrospective chart review was performed. Data was collected for DOT laser procedures performed at three clinical centers from 2008-2014.Results: Of the 1,081 DOT laser procedures, there were 13 complications (1.3% of all cases), which included eleven cases of prolonged erythema and two cases of post-inflammatory hyperpigmentation. Of note, there were no cases of scarring.LIMITATIONS: This was a retrospective chart review. Data was collected from laser case logs. However, all patients with complications were evaluated clinically by a physician.CONCLUSION: Microablative fractional resurfacing with the DOT laser enables treatment of a diversity of skin conditions with short post-procedure recovery time and an extremely low incidence of adverse side effects.J Drugs Dermatol. 2018;17(11):1157-1162. PMID- 30481956 TI - 7,8-Dihydroxyflavone Protects High Glucose-Damaged Neuronal Cells against Oxidative Stress. AB - Oxidative stress is considered a major contributor in the pathogenesis of diabetic neuropathy and in diabetes complications, such as nephropathy and cardiovascular diseases. Diabetic neuropathy, which is the most frequent complications of diabetes, affect sensory, motor, and autonomic nerves. This study aimed to investigate whether 7,8-dihydroxyflavone (7,8-DHF) protects SH SY5Y neuronal cells against high glucose-induced toxicity. In the current study, we found that diabetic patients exhibited higher lipid peroxidation caused by oxidative stress than healthy subjects. 7,8-DHF exhibits superoxide anion and hydroxyl radical scavenging activities. High glucose-induced toxicity severely damaged SH-SY5Y neuronal cells, causing mitochondrial depolarization; however, 7,8-DHF recovered mitochondrial polarization. Furthermore, 7,8-DHF effectively modulated the expression of pro-apoptotic protein (Bax) and anti-apoptotic protein (Bcl-2) under high glucose, thus inhibiting the activation of caspase signaling pathways. These results indicate that 7,8-DHF has antioxidant effects and protects cells from apoptotic cell death induced by high glucose. Thus, 7,8 DHF may be developed into a promising candidate for the treatment of diabetic neuropathy. PMID- 30481957 TI - Possible Effects of Radiofrequency Electromagnetic Field Exposure on Central Nerve System. AB - Technological advances of mankind, through the development of electrical and communication technologies, have resulted in the exposure to artificial electromagnetic fields (EMF). Technological growth is expected to continue; as such, the amount of EMF exposure will continue to increase steadily. In particular, the use-time of smart phones, that have become a necessity for modern people, is steadily increasing. Social concerns and interest in the impact on the cranial nervous system are increased when considering the area where the mobile phone is used. However, before discussing possible effects of radiofrequency electromagnetic field (RF-EMF) on the human body, several factors must be investigated about the influence of EMFs at the level of research using in vitro or animal models. Scientific studies on the mechanism of biological effects are also required. It has been found that RF-EMF can induce changes in central nervous system nerve cells, including neuronal cell apoptosis, changes in the function of the nerve myelin and ion channels; furthermore, RF-EMF act as a stress source in living creatures. The possible biological effects of RF-EMF exposure have not yet been proven, and there are insufficient data on biological hazards to provide a clear answer to possible health risks. Therefore, it is necessary to study the biological response to RF-EMF in consideration of the comprehensive exposure with regard to the use of various devices by individuals. In this review, we summarize the possible biological effects of RF-EMF exposure. PMID- 30481950 TI - Cerebrovascular reactivity to hypercapnia during sevoflurane or desflurane anesthesia in rats. AB - Background: Hypercapnia dilates cerebral vessels and increases cerebral blood flow, resulting in increases in intracranial pressure. Sevoflurane is reported to preserve cerebrovascular carbon dioxide reactivity. However, the contribution of inhaled anesthetics to vasodilatory responses to hypercapnia have not been clarified. Moreover, the cerebrovascular response to desflurane under hypercapnia has not been reported. We examined the effects of sevoflurane and desflurane on vasodilatory responses to hypercapnia in rats. Methods: A closed cranial window preparation are used to measure the changes in pial vessel diameters. To evaluate the cerebrovascular response to hypercapnia and/or inhaled anesthetics, the pial vessel diameters were measured in the following states: under without inhaled anesthetics at normocapnia (control values) and hypercapnia, under inhaled end tidal 0.5 minimal alveolar concentration (MAC) or 1.0 MAC of either sevoflurane or desflurane at normocapnia, and under 1.0 MAC of sevoflurane or desflurane at hypercapnia. Results: Under normocapnia, 1.0 MAC, but not 0.5 MAC, of sevoflurane or desflurane dilated pial arterioles and venules. In addition, under both 1.0 MAC of sevoflurane and 1.0 MAC of desflurane, hypercapnia significantly dilated pial arteriolar and venular diameters compared to their diameters without inhaled anesthetics. The amounts of vasodilation were similar for desflurane and sevoflurane under both normocapnia and hypercapnia. Conclusions: Desflurane induces cerebrovascular responses similar to those of sevoflurane. Desflurane can be used as safely as sevoflurane in neurosurgical anesthesia. PMID- 30481958 TI - Regulation of Neural Stem Cell Fate by Natural Products. AB - Neural stem cells (NSCs) can proliferate and differentiate into multiple cell types that constitute the nervous system. NSCs can be derived from developing fetuses, embryonic stem cells, or induced pluripotent stem cells. NSCs provide a good platform to screen drugs for neurodegenerative diseases and also have potential applications in regenerative medicine. Natural products have long been used as compounds to develop new drugs. In this review, natural products that control NSC fate and induce their differentiation into neurons or glia are discussed. These phytochemicals enable promising advances to be made in the treatment of neurodegenerative diseases. PMID- 30481960 TI - Biomimetic Elastomeric Polypeptide-Based Nanofibrous Matrix for Overcoming Multidrug-Resistant Bacteria and Enhancing Full-Thickness Wound Healing/Skin Regeneration. AB - Overcoming the multidrug-resistant (MDR) bacterial infection is a challenge and urgently needed in wound healing. Few wound dressings possess the capacity to treat MDR bacterial infections and enhance wound healing. Herein, we develop an elastomeric, photoluminescent, and antibacterial hybrid polypeptide-based nanofibrous matrix as a multifunctional platform to inhibit the MDR bacteria and enhance wound healing. The hybrid nanofibrous matrix was composed of poly(citrate)-epsilon-poly lysine (PCE) and poly caprolactone (PCL). The PCL-PCE hybrid nanofibrous matrix showed a biomimetic elastomeric behavior, robust antibacterial activity including killing MDR bacteria capacity, and excellent biocompatibility. PCL-PCE nanofibrous system can efficiently prevent the MDR bacteria-derived wound infection and significantly enhance the complete skin thickness wound healing and skin regeneration in a mouse model. PCL-PCE hybrid nanofibrous matrix might become a competitive multifunctional dressing for bacteria-infected wound healing and skin regeneration. PMID- 30481961 TI - Conversion of a Patterned Organic Resist into a High Performance Inorganic Hard Mask for High Resolution Pattern Transfer. AB - Polyphthalaldehyde is a self-developing resist material for electron beam and thermal scanning probe lithography (t-SPL). Removing the resist in situ (during the lithography process itself) simplifies processing and enables direct pattern inspection, however, at the price of a low etch resistance of the resist. To convert the material into a etch resistant hard mask, we study the selective cyclic infiltration of trimethyl-aluminum (TMA)/water into polyphthalaldehyde. It is found that TMA diffuses homogeneously through the resist, leading to material expansion and formation of aluminum oxide concurrent to the exposure to water and the degradation of the polyphthalaldehyde polymer. The plasma etch resistance of the infiltrated resist is significantly improved, as well as its stability. Using a silicon substrate coated with 13 nm silicon nitride and 7 nm cross-linked polystyrene, high resolution polyphthalaldehyde patterning is performed using t SPL. After TMA/H2O infiltration, it is demonstrated that pattern transfer into silicon can be achieved with good fidelity for structures as small as 10 nm, enabling >10* amplification and low surface roughness. The presented results demonstrate a simplified use of polyphthalaldehyde resist, targeting feature scales at nanometer range, and suggest that trimethyl-aluminum infiltration can be applied to other resist-based lithography techniques. PMID- 30481962 TI - Reply to "Overtone Vibrational Transition-Induced Lanthanide Excited-State Quenching in Yb3+/Er3+-Doped Upconversion Nanocrystals". PMID- 30481963 TI - Correction to Tissue-Factor Targeted Peptide Amphiphile Nanofibers as an Injectable Therapy To Control Hemorrhage. PMID- 30481964 TI - In Nano, Volume 12, Issue 11. PMID- 30481959 TI - Breast Cancer Chemo-immunotherapy through Liposomal Delivery of an Immunogenic Cell Death Stimulus Plus Interference in the IDO-1 Pathway. AB - Immunotherapy provides the best approach to reduce the high mortality of metastatic breast cancer (BC). We demonstrate a chemo-immunotherapy approach, which utilizes a liposomal carrier to simultaneously trigger immunogenic cell death (ICD) as well as interfere in the regionally overexpressed immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO-1) at the BC tumor site. The liposome was constructed by self-assembly of a phospholipid-conjugated prodrug, indoximod (IND), which inhibits the IDO-1 pathway, followed by the remote loading of the ICD-inducing chemo drug, doxorubicin (DOX). Intravenous injection of the encapsulated two-drug combination dramatically improved the pharmacokinetics and tumor drug concentrations of DOX and IND in an orthotopic 4T1 tumor model in syngeneic mice. Delivery of a threshold ICD stimulus resulted in the uptake of dying BC cells by dendritic cells, tumor antigen presentation and the activation/recruitment of naive T-cells. The subsequent activation of perforin- and IFN-gamma releasing cytotoxic T-cells induced robust tumor cell killing at the primary as well as metastatic tumor sites. Immune phenotyping of the tumor tissues confirmed the recruitment of CD8+ cytotoxic T lymphocytes (CTLs), disappearance of Tregs, and an increase in CD8+/FOXP3+ T-cell ratios. Not only does the DOX/IND-Liposome provide a synergistic antitumor response that is superior to a DOX-only liposome, but it also demonstrated that the carrier could be effectively combined with PD-1 blocking antibodies to eradicate lung metastases. All considered, an innovative nano-enabled approach has been established to allow deliberate use of ICD to switch an immune deplete to an immune replete BC microenvironment, allowing further boosting of the response by coadministered IDO inhibitors or immune checkpoint blocking antibodies. PMID- 30481965 TI - Comment on "Superior Photodetectors Based on All-Inorganic Perovskite CsPbI3 Nanorods with Ultrafast Response and High Stability". PMID- 30481966 TI - Overtone Vibrational Transition-Induced Lanthanide Excited-State Quenching in Yb3+/Er3+-Doped Upconversion Nanocrystals. PMID- 30481967 TI - Neuron-Inspired Design of High-Performance Electrode Materials for Sodium-Ion Batteries. AB - Sodium-ion batteries (SIBs) are generally considered as promising cheap alternatives of lithium-ion batteries for stationary renewable energy storage and have received increasing attention in recent years. The exploration of anode materials with efficient electron transportation is essential for improving the performance of SIBs. Inspired by the signal transfer mode of a neuron, we designed a composite by stringing MoS2 nanoflower (soma) with multiwall carbon nanotubes (MWCNTs) (axons). High-resolution TEM observation reveals a lattice matching growth mechanism of MoS2 nanosheets on the interface of MWCNTs and the lattice expansion of the (002) plane of MoS2. The lattice matching among the MoS2 nanosheet and MWCNT could facilitate electron transfer and structure maintenance upon cycling. The expanded distance of the (002) plane of MoS2 would also promote the sodium-ion intercalation/deintercalation kinetics of the composite. Benefiting from the structural features, when used as an anode material for SIBs, the composite exhibits excellent electrochemical performance, including high specific capacity, excellent cycle stability, and superior rate capabilities. A stable capacity of 527.7 mAh g-1 can be achieved after 110 cycles at a current density of 100 mA g-1. The neuron-inspired design proposed is a promising and efficient strategy for the development of electrode materials for SIBs with high mass transport kinetics and structural stability. PMID- 30481968 TI - Nanoparticles for Immune Stimulation Against Infection, Cancer, and Autoimmunity. AB - Vaccination using nanocarrier-based delivery systems has recently emerged as a promising approach for meeting the continued challenge posed by infectious diseases and cancer. A diverse portfolio of nanocarriers of various sizes, compositions, and physical parameters have now been developed, and this diversity provides an opportunity for the rational design of vaccines that can mediate targeted delivery of various antigens and adjuvants or immune regulatory agents in ways unachievable with classical vaccination approaches. This flexibility allows control over the characteristics of vaccine-elicited immune responses such that they can be tailored to be effective in circumstances where classical vaccines have failed. Furthermore, the utility of nanocarrier-based immune modulation extends to the treatment of autoimmune disease where precisely targeted inhibition of immune responses is desirable. Clearly, the selection of appropriate nanocarriers, antigens, adjuvants, and other components underpins the efficacy of these nanoimmune interventions. Herein, we provide an overview of currently available nanocarriers of various types and their physical and pharmacological properties with the goal of providing a resource for researchers exploring nanomaterial-based approaches for immune modulation and identify some information gaps and unexplored questions to help guide future investigation. PMID- 30481969 TI - Reply to "Comment on 'Superior Photodetectors Based on All-Inorganic Perovskite CsPbI3 Nanorods with Ultrafast Response and High Stability'". PMID- 30481971 TI - The 15th Anniversary of the U.S. National Nanotechnology Initiative. PMID- 30481970 TI - Stabilizing and Activating Metastable Nickel Nanocrystals for Highly Efficient Hydrogen Evolution Electrocatalysis. AB - Exploring high-performance and cost-efficient electrocatalysts with unusual metastable phase offers opportunities for improving the electrochemical hydrogen generation, while it remains a great challenge to achieve them with desirable activity and stability. Herein, we report that the doping engineering in a metastable, hexagonal-close-packed nickel (hcp Ni) electrocatalyst is a largely unrevealed yet important factor in achieving an extremely active and stable electrocatalyst toward alkaline hydrogen evolution reaction (HER). Theoretical predications and experimental results suggest that, while the stability of metastable hcp Ni electrocatalyst can be largely improved via the manganese (Mn) doping due to the lower formation energy and lattice stabilization, the MnO/hcp Ni surface promotes the HER via intrinsic favorable H2O adsorption and fast water dissociation kinetics. Consequently, the Mn-doped hcp Ni electrocatalyst shows a small overpotential of 80 mV at 10 mA/cm2 and a low Tafel slope of 68 mV/dec. The result is even approaching that of the commercial Pt/C, being one of the best reported non-noble metal HER electrocatalysts in alkaline media. Under long-term chronopotentiometry measurement, such electrocatalyst can endure at least 10 h with negligible activity decay and structure change. The present work demonstrates the dimension in boosting the electrocatalysis by doping engineering of metastable electrocatalysts. PMID- 30481972 TI - Homogeneous Quenching Immunoassay for Fumonisin B1 Based on Gold Nanoparticles and an Epitope-Mimicking Yellow Fluorescent Protein. AB - Homogeneous immunoassays represent an attractive alternative to traditional heterogeneous assays due to their simplicity, sensitivity, and speed. On the basis of a previously identified epitope-mimicking peptide, or mimotope, we developed a homogeneous fluorescence quenching immunoassay based on gold nanoparticles (AuNPs) and a recombinant epitope-mimicking fusion protein for the detection of mycotoxin fumonisin B1 (FB1). The fumonisin mimotope was cloned as a fusion protein with a yellow fluorescent protein that could be used directly as the tracer for FB1 detection without the need of labeling or a secondary antibody. Furthermore, owing to the fluorescence quenching ability of AuNPs, a homogeneous immunoassay could be performed in a single step without washing steps to separate the unbound tracer. The homogeneous quenching assay showed negligible matrix effects in 5% wheat extract and high sensitivity for FB1 detection, with a dynamic range from 7.3 to 22.6 ng mL-1, a detection limit of 1.1 ng mL-1, and IC50 value of 12.9 ng mL-1, which was significantly lower than the IC50 value of the previously reported assay using the synthetic counterpart of the same mimotope in a microarray format. The homogeneous assay was demonstrated to be specific for fumonisins B1 and B2, as no significant cross-reactivity with other mycotoxins was observed, and acceptable recoveries (86% for FB1 2000 MUg kg-1 and 103% for FB1 4000 MUg kg-1), with relative standard deviation less than 6.5%, were reported from spiked wheat samples, proving that the method could provide a valuable tool for simple analysis of mycotoxin-contaminated food samples. PMID- 30481973 TI - Understanding and Improving the Burden and Unmet Needs of Informal Caregivers of Homebound Patients Enrolled in a Home-Based Primary Care Program. AB - The growing homebound population is heavily reliant on informal caregivers, who are increasingly burdened by their roles. This study describes informal caregivers of the homebound who remain caregivers at a 9-month follow-up and examines the impact of a home-based primary care (HBPC) program on caregiver burden and unmet needs using a prospective design with a pre-post intervention assessment. Informal caregivers of the urban homebound are similar to caregivers of other populations and have a broad range of unmet needs. The intervention described is the regular provision of multidisciplinary HBPC. Hundred fourteen caregivers of newly admitted patients complete a baseline interview. For the 56 caregivers who complete a 9-month follow-up interview, participation in HBPC is associated with a statistically significant decrease in overall caregiver burden. At 9 months, caregivers demonstrate an overall decrease in unmet needs, with a statistically significant decrease across two measured domains. These results suggest that the regular provision of multidisciplinary care in the home can mitigate the deleterious impact of informal caregiving. PMID- 30481974 TI - Early Adjacent Vertebral Fractures after Balloon Kyphoplasty for Osteoporotic Vertebral Compression Fractures. AB - Study Design: Retrospective cohort study. Purpose: To evaluate the incidence and risk factors for early adjacent vertebral fractures following balloon kyphoplasty (KP). Overview of Literature: KP is a safe and effective treatment for pain alleviation in patients with osteoporotic vertebral compression fractures (OVCF). However, some studies have reported that the risk of newly developed fractures increases at the adjacent vertebra after KP. Methods: Total 123 consecutive patients with painful OVCF who underwent KP were enrolled from January 2009 to June 2016. Early adjacent vertebral fractures were defined as new fractures that had developed within 3 months after surgery. Sex, age, body mass index (BMI), bone mineral density (BMD), vertebral height, kyphotic angle, Visual Analog Scale score, cement amount, and leakage were evaluated as risk factors for adjacent vertebral fractures. Only cement leakage into the disc space was included in this study. Results: Early adjacent vertebral fractures were identified in 20 (16.2%) of the 123 patients. The mean time to diagnosis of fractures was 1.7+/-0.7 months after KP. The average patient age was 78.0+/-0.7 years, average BMI was 23.06+/ 3.83 kg/m2 , and mean BMD was -3.61+/-1.22 g/m2 . Cement leakage was present in 16 patients, and fractures developed in 11 (68.7%). In contrast, fractures developed in nine patients (8.2%) without cement leakage. There were no significant differences in terms of age, BMI, BMD, kyphotic angle, or vertebral body height ratio between the fracture and control groups. Conclusions: Cement leakage into the disc increased the risk of early adjacent vertebral fractures after balloon KP. PMID- 30481975 TI - Million Visual Analogue Scale Questionnaire: Validation of the Persian Version. AB - Study Design: Descriptive cross-sectional study. Purpose: To validate the Persian version of the Million Visual Analogue Scale Questionnaire (MVAS), a self administered low back pain (LBP) questionnaire. Overview of Literature: The majority of LBP questionnaires translated into Persian evaluate the impact of LBP on daily living. The MVAS is one of the most commonly used self-administered LBP questionnaires, and was developed to assess a different direction and effect of activities of daily living on LBP intensity. Methods: The questionnaire was translated into Persian with the forward-backward method and was administered to 150 patients randomly sampled from an occupational medicine clinic in Tehran in 2017. Results: Cronbach's alpha for all subscales ranged between 0.670 and 0.799. Confirmatory factor analysis showed adequate construct validity of the Persian version of the MVAS, with root mean square error of approximation 0.046, goodness of fit index 0.902, and comparative fit index 0.969. Other indexes were satisfactory. Conclusions: The Persian MVAS is a valid and reliable instrument that can assess the effect of various daily activities on the intensity of LBP. PMID- 30481976 TI - Early Fusion Status after Posterior Lumbar Interbody Fusion with Cortical Bone Trajectory Screw Fixation: A Comparison of Titanium-Coated Polyetheretherketone Cages and Carbon Polyetheretherketone Cages. AB - Study Design: Retrospective cohort study. Purpose: We recently reported that when compared to posterior lumbar interbody fusion (PLIF) using traditional pedicle screw fixation, PLIF with cortical bone trajectory screw fixation (CBT-PLIF) provided favorable clinical outcomes and reduced the incidence of symptomatic adjacent segment pathology, but resulted in relatively lower fusion rates. Since titanium-coated polyetheretherketone (PEEK) cages (TP) could improve and accelerate fusion status after CBT-PLIF, early fusion status was compared between CBT-PLIF using TP and carbon PEEK cages (CP). Overview of Literature: A systematic review demonstrated that clinical studies at this early stage show similar fusion rates for TP compared to PEEK cages. Methods: We studied 36 consecutive patients undergoing CBT-PLIF with TP (TP group) and 92 undergoing CBT PLIF with CP (CP group). On multiplanar reconstruction computed tomography (MPR CT) at 6 months postoperatively, vertebral endplate cysts (cyst signs) were evaluated and classified as diffuse or local cysts. Early fusion status was assessed by dynamic plain radiographs and MPR-CT at 1 year postoperatively. Results: The incidences of cyst signs, diffuse cysts, and early fusion rate in the TP and CP groups were 38.9% and 66.3% (p<0.01), 16.7% and 32.6% (p=0.07), and 83.3% and 79.3% (p>0.05), respectively. Combining the two groups, 22 of 36 patients with diffuse cysts had nonunion at 1-year follow-up, compared to only three of 92 patients with local cysts or without cyst signs (p<0.01). Conclusions: Despite having fewer patients with endplate cysts at 6 months (a known risk factor for nonunion), the TP group had the same fusion rate as the CP group at 1-year follow-up. Thus, TP did not accelerate the fusion process after CBT-PLIF. PMID- 30481977 TI - Palliative Posterior Instrumentation versus Corpectomy with Cage Reconstruction Treatment for Thoracolumbar Pathological Fracture. AB - Study Design: Single-center, retrospective cohort study. Purpose: We aimed to evaluate and compare the clinical outcomes in patients who underwent palliative posterior instrumentation (PPI) versus those who underwent corpectomy with cage reconstruction (CCR) for thoracolumbar pathological fracture. Overview of Literature: The requirement for anterior support after corpectomy has been emphasized in the treatment of pathological fractures of the vertebrae. However, for patients with a relatively short life expectancy, anterior reconstruction may not be required and posterior instrumentation alone may provide adequate stabilization. Methods: A total of 43 patients with metastases of the thoracolumbar spine underwent surgery in the department of orthopaedic and traumatology of Istanbul University Faculty of Medicine from 2003 to 2016. Surgical outcomes were assessed on the basis of survival status, pre- and postoperative pain, complication rate, and operation time. Results: PPI was performed for 22 patients and CCR was performed for 21 patients. In the PPI group, the follow-up period of the five surviving patients was 32 months. The remaining 17 patients died with a mean survival duration of 12.3 months postoperatively. In the CCR group, the five surviving patients were followed up for an average of 14.1 months. The remaining 16 patients died with a mean survival duration of 18.7 months postoperatively. No statistically significant difference (p=0.812) was noted in the survival duration. The Visual Analog Scale scores of the patients were significantly reduced after both procedures, with no significant difference noted on the basis of the type of surgical intervention (p>0.05). The complication rate in the CCR group (33.3%) was higher compared with that in the PPI group (22.7%); however, this difference was not noted to be statistically significant (p=0.379). The average operation time in the PPI group (149 minutes) was significantly shorter (p=0.04) than that in the CCR group (192 minutes). Conclusions: The PPI technique can decompress the tumor for functional improvement and can stabilize the spinal structure to provide pain relief. PMID- 30481979 TI - Use of Cement-Augmented Percutaneous Pedicular Screws in the Management of Multifocal Tumoral Spinal Fractures. AB - Study Design: Retrospective case series observational study. Purpose: Cancer patients are often aged and are further weakened by their illness and treatments. Our goal was to evaluate the efficiency and safety of using minimally invasive techniques to operate on spinal fractures in these patients. Overview of Literature: Vertebroplasty is now considered to be a safe technique that allows a significant reduction of the pain induced by a spinal tumoral fracture. However, few papers describe the kyphosis reduction that can be achieved by combining percutaneous fixation and anterior vertebral reconstruction. Methods: We studied 35 patients seen between December 2013 and October 2016 who had at least one pathological spinal fracture and multiple vertebral metastases. The population's mean age was 67 years, and no patients included had preoperative neurological deficits. The patients underwent a minimally invasive surgery consisting of a percutaneous pedicular fixation with cement-enhanced screws and anterior reconstruction comprising kyphoplasty when possible or corpectomy in cases of excessive damage to the vertebral body. Back pain, traumatic local and regional kyphosis, and Beck's Index were collected pre- and postoperatively, and at 3-, 6 , and 12-month follow-ups. Results: Mean follow-up time was 13.4 months. Significant reductions in back pain (p<0.001) and local (p<0.001) and regional kyphosis (p=0.006) were found at the 6-month follow-up (alpha risk level <0.05). Beck's Index was also significantly increased, indicating good restoration of the anterior vertebral height. By the final follow-up, no screws had fallen/pulled out. There were no infectious or neurological complications. Conclusions: Percutaneous cement-enhanced fixation for pathological fractures has proven a safe and efficient technique in our experience, enabling weak patients to rapidly become ambulatory again without complications. Further follow-up of the patients is necessary to assess the long-term effects of this technique and the continued quality of life of our patients. PMID- 30481978 TI - En Bloc Spondylectomy for Spinal Metastases: Detailed Oncological Outcomes at a Minimum of 2 Years after Surgery. AB - Study Design: Retrospective case series. Purpose: To investigate the oncological outcomes, including distant relapse, after en bloc spondylectomy (EBS) for spinal metastases in patients with a minimum of 2-year follow-up. Overview of Literature: Although EBS has been reported to be locally curative and extend survival in select patients with spinal metastases, detailed reports regarding the control of distant relapse after EBS are lacking. Methods: We conducted a retrospective review of 18 consecutive patients (median age at EBS, 62 years; range, 40-77 years) who underwent EBS for spinal metastases between 1991 and 2015. The primary cancer sites included the kidney (n=7), thyroid (n=4), liver (n=3), and other locations (n=4). Survival rates were estimated using the Kaplan Meier method, and groups were compared using the log-rank method. Results: The median operative time and intraoperative blood loss were 767.5 minutes and 2,375 g, respectively. Twelve patients (66.7%) experienced perioperative complications. Five patients (27.8%) experienced local recurrence of the tumor at a median of 12.5 months after EBS, four of which had a positive resection margin status. Thirteen patients (72.2%) experienced distant relapse at a median of 21 months after EBS. The estimated median survival period after distant relapse was 20 months (95% confidence interval, 0.71-39.29 months). No association was found between resection margin status and distant relapse. Overall, the 2-year, 5-year, and 10-year survival rates after EBS were 72.2%, 48.8%, and 27.1%, respectively. Importantly, the era in which EBS was performed did not impact the oncological outcomes. Conclusions: Our results suggest that EBS by itself, even if margin free, cannot prevent further dissemination, which occurred in >70% of patients at a median of 21 months after EBS. These results should be considered and conveyed to patients for clinical decision-making. PMID- 30481980 TI - Effect of Teriparatide on Subsequent Vertebral Fractures after Instrumented Fusion Surgery for Osteoporotic Vertebral Fractures with Neurological Deficits. AB - Study Design: Retrospective case review. Purpose: To assess the incidence and effect of teriparatide (TP) on subsequent vertebral fractures following a long instrumented fusion surgery for osteoporotic vertebral fractures (OVFs). Overview of Literature: TP treatment may be a useful strategy for patients with OVFs treated with a long-instrumented surgery. Methods: Overall, 47 patients who underwent long-instrumented fusion surgery (>=3 levels) for OVFs with neurological deficits between 2010 and 2013 were enrolled. The mean age of the subjects was 76 years; the study population comprised 20 males and 27 females. The mean follow-up duration was 23 months. The average of fused vertebrae was 4.9. TP was used for 19 patients who comprised the TP group. The incidence of subsequent VFs was estimated with Kaplan-Meier analyses and compared between the TP and non-TP groups using the log-rank test. Risk factors were evaluated using a Cox proportional hazards model. Results: A total of 38% (18/47 cases) of the subjects were identified with subsequent VFs. There were no significant differences in the age, sex, fused levels, presence of prevalent fractures, and correction loss of the two groups. The occurrence of subsequent VFs was lower in the TP group than in the non-TP group (16% vs. 54%, p=0.014). The log-rank test revealed that the TP treatment significantly reduced the risk of subsequent VFs (p=0.048). A Cox proportional hazards model revealed that preoperative TP treatment is only a protective factor of subsequent VFs after instrumented fusion surgery for OVFs (hazard ratio, 0.281; p=0.047). Conclusions: In this retrospective study, pre- and postoperative TP treatment significantly reduced the incidence of subsequent VFs after instrumented fusion surgery for OVFs. A prospective randomized study is warranted to determine the efficacy of TP treatments. PMID- 30481981 TI - Novel application of Influenza A virus inoculated chorioallantoic membrane to characterize a nucleoprotein specific monoclonal antibody for immunohistochemistry assay. AB - Monoclonal antibody (MAb) is widely applied in disease diagnosis. Here we report a MAb, 1 WF-4, against Influenza A virus nucleoprotein (NP), its broad response with Influenza A virus, and its application in immunohistochemistry (IHC) assay. WF-4 was screened by immunofluorescence assay (IFA). The results showed that its reactivity with baculovirus expressed full-length recombinant NP (rNP) in western blot (WB) and applicability in IHC. Fifteen Influenza A virus reference subtypes, H1 to H15, infected chicken embryonated chorioallantoic membranes (CAM) fixed by formalin, were all detectable in WF-4 based IHC. Also, the reactivity of the IHC test with NP from experimentally inoculated H6N1 and from all recent outbreak of H5 subtype avian Influenza A virus (AIV) field cases in Taiwan showed positive results. Our data indicate that CAM, the by-product of Influenza A virus preparation, is helpful for Influenza A virus specific MAb characterization, and that MAb WF-4 recognizes conserved and linear epitopes of Influenza A virus NP. Therefore, WF-4 is capable of detecting NP antigen in IHC and may be suitable for developing various tests for diagnosis of Influenza A virus, and especially AIV infection. PMID- 30481982 TI - Expression of polo-like kinase 1 in pre-implantation-stage murine somatic cell nuclear transfer embryos. AB - Somatic cell nuclear transfer (SCNT) has various abilities of application in research, as well as the medical field and industry. However, the efficiency of SCNT is very low because the accurate mechanism of SCNT murine embryo development is still unknown. In previous studies, Polo-like kinase 1 (Plk1) has been found to be a crucial element in cell division including centrosome maturation, cytokinesis and spindle formation, and, in general, the developmental rate of SCNT murine embryos is lower than in vivo counterpart. In the first series of the experiments, BI2536, a Plk1 inhibitor, was treated to in vivo-fertilized embryos and the embryos failed to develop over the 2-cell stage. This re-confirms that Plk1 is crucial for the first mitotic division of murine embryos as previously reported by others. Next, we checked the Plk1's localization and intensity by immunofluorescence. The SCNT murine embryos, which were not developed, have two types of different Plk1 expressions in comparison with normal developed embryos. One is a, low expression pattern of Plk1 and the other is ectopic expression of Plk1. Therefore, this result shows that Plk1 also plays critical role in SCNT murine embryos. In conclusion, this study demonstrated that the SCNT murine embryos which failed to develop over 2-cell stage show abnormal expression patterns of Plk1, and this may one of the main causes of developmental failure of early SCNT murine embryos. PMID- 30481983 TI - The development of oligonucleotide microarray for simultaneous detection of two canine MDR1 genotypes and the association with chemotherapy side effects. AB - Canine MDR1 gene mutations produce the translated P-glycoprotein, an active drug efflux transporter, dysfunction or over-expression. The 4-base deletion of MDR1 gene at nucleotide position 230 (nt230[del4]) in exon 4 makes P-glycoprotein lose function, leading to drug accumulation and toxicity. The G-allele of the c.-6 180T>G variation in intron 1 of MDR1 gene (SNP 180) causes P-glycoprotein over expression, making epileptic dogs resistant to phenobarbital treatment. Both of these mutations were reported to concentrate in collies. This study develops a more efficient method to detect these two mutations simultaneously, and clarifies the genotype association with the side effects of chemotherapy. The genotype distribution in Taiwan was also investigated. Oligonucleotide microarray was successfully developed for the detection of both genotypes and applied to clinical samples. No 4-base deletion mutant allele was found in dogs in Taiwan. However, the G allele variation of SNP 180 was spread across all species of dogs, not only in collies. The chemotherapy adverse effect percentages of SNP 180 T/T, T/G and G/G genotypes were 16.6%, 6.3% and 0%, respectively. This study presented an efficient way for MDR1 gene mutation detection, clarifying the genotype distribution and the association with chemotherapy. PMID- 30481984 TI - Prevalence of O-serogroups, virulence genes and F18 antigenic variants in Escherichia coli isolated from weaned piglets with diarrhea in Korea during 2008 2016. AB - To diagnose the colibacillosis, the detection of O-serogroups and virulence genes has been recommended worldwide. The prevalence of the viruence factors can fluctuate over time. The objectives of this the present study were to determine the prevalence of O-serogroups, virulence genes, and F18 subtypes among pathogenic Escherichia (E.) coli isolated from weaned piglets with diarrhea in Korea. Between 2008 and 2016, 362 E. coli were isolated from weaned piglets with diarrhea. Hemolysis was determined in blood agar, and O-serogroups were identified using the slide agglutination technique. The genes for the toxins and fimbria were amplified by PCR. Real-time PCR was conducted to discriminate between F18 subtypes. Although the most prevalent serogroup was O149 (11.3%) for last 9 years, O139 (19.1%) became the most prevalent in recent years (2015-2016). The most predominant pathotype was enterotoxigenic E. coli (61.4%). The frequencies of shiga-like toxin-producing E. coli (23.4%), O139 (19.1%), Stx2e (35.1%), and F18ab (48.7%) increased over the most recent years. Although enterotoxigenic E. coli was the most predominant pathotype, the frequencies of O139, Stx2e, STEC, and F18ab increased over the most recent years. These results demonstrate that there were temporal changes of predominant O-serogroups and virulence genes over the last decade in Korea. These findings can be a feasible data for epidemiology and control measures for enteric colibacillosis in Korean piggeries. PMID- 30481985 TI - High-content analysis of in vitro hepatocyte injury induced by various hepatotoxicants. AB - In vitro prediction of hepatotoxicity can enhance the performance of non-clinical animal testing for identifying the hazards of chemicals. Here, we assessed high content analysis (HCA) using multi-parameter cell-based assays as an in vitro hepatotoxicity testing model using various hepatotoxicants and human hepatocytes such as HepG2 cells and human primary hepatocytes (hPHs). Both types of hepatocyte were exposed to multiple doses of ten hepatotoxicants associated with liver injury whose mechanisms of action are known. HCA data were obtained using fluorescence probes for nuclear size (Hoechst), mitochondrial membrane potential (TMRM), cytosolic free calcium (Fluo-4AM), and lipid peroxidation (BODIPY). Cellular alterations were observed in response to all hepatotoxicants tested. The most sensitive parameter is alteration of TMRM, with high sensitivity at low dose, then BODIPY, followed by Fluo-4AM. HCA data from HepG2 cells and hPHs were generally concordant, although some inconsistencies were noted. Both types of hepatocyte showed mild or severe mitochondrial impairment and lipid peroxidation in response to several hepatotoxicants. These findings demonstrate that the application of HCA to in vitro hepatotoxicity testing enables more efficient hazard identification, and further suggests that certain parameters could serve as sensitive endpoints for predicting the hepatotoxic potential of chemical compounds. PMID- 30481986 TI - Corneoconjunctival manifestations of lymphoma in three dogs. AB - An 8-year-old Shih Tzu, a 5-year-old Maltese, and a 10-year-old Maltese presented with conjunctival hyperemia and peripheral corneal edema. Severe conjunctival thickening with varying degrees of corneal extension were observed. Cytological examination showed many large lymphocytes with malignant changes in the conjunctiva and were consistent with findings in fine-needle aspiration samples taken from the regional lymph nodes. They were diagnosed as having stage V multicentric lymphoma. When conjunctival thickening is observed in canine patients with multicentric lymphoma, conjunctival metastasis with infiltration of neoplastic lymphoid cells should be included in the differential diagnosis. PMID- 30481987 TI - Molecular epidemiology of sequence type 33 of Shiga toxin-producing Escherichia coli O91:H14 isolates from human patients and retail meats in Korea. AB - Sequence type (ST) 33 of STEC O91:H14 has been proposed as a potential domestic clone of Shiga toxin-producing Escherichia coli (STEC) in Korea because of its high prevalence among human patients with mild diarrhea or asymptomatic carriers. Here, the clonal diversity of 17 STEC O91:H14 isolates of ST33 during 2003-2014 was analyzed by pulsed-field gel electrophoresis, including 14 isolates from human patients and 3 from retail meats. Their virulence characteristics, acid resistance, and antimicrobial susceptibility were also determined. Our results showed that all the isolates were clustered mainly into three different pulsotypes and likely low pathogenic with no antimicrobial resistance. PMID- 30481989 TI - Correlation of spontaneous adipocyte generation with osteogenic differentiation of porcine skin-derived stem cells. AB - The objective of this study was to examine effects of spontaneous adipocyte generation on osteogenic differentiation of porcine skin-derived stem cells (pSSCs). Correlation between osteogenic differentiation and adipocyte differentiation induced by osteocyte induction culture was determined using different cell lines. Osteogenic differentiation efficiency of pSSCs was then analyzed by controlling the expression of adipocyte-specific transcription factors during osteogenic induction culture. Among four cell lines, pSSCs-II had the lowest level of lipid droplet but the highest calcium content (P < 0.05). It also expressed significantly low levels of peroxisome proliferator-activated receptor gamma 2 (PPARgamma2) and adipocyte Protein 2 (aP2) mRNAs but very high levels of runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP) mRNAs as osteogenic makers (P < 0.05). Oil red O extraction was increased by 0.1 uM troglitazone (TGZ) but decreased by 50 uM Bisphenol A diglycidyl ether (BADGE) (P<0.05). Calcium content was drastically increased after BADGE treatment compared to that in osteogenic induction control and TGZ-treated pSSCs (P < 0.05). Relative expression levels of PPARgamma2 and aP2 mRNAs were increased by TGZ but decreased by BADGE. Expression levels of Rucx2 and ALP mRNAs as osteoblast-specific marker genes were significantly increased by BADGE treatment (P < 0.05). The expression level of BCL2L1 was significantly higher in BADGE treated pSSCs than that in TGZ-treated ones (P < 0.05). These results demonstrate that spontaneous adipocyte generation does not adversely affect osteogenic differentiation. However, reducing spontaneous adipocyte generation by inhibiting PPARgamma2 mRNA expression can enhance in vitro osteogenic differentiation of pSSCs. PMID- 30481988 TI - Iodixanol supplementation during sperm cryopreservation improves protamine level and reduces reactive oxygen species of canine sperm. AB - The objectives of this study were to analyze the protective effects of OptiprepTM (iodixanol) on dog spermatozoa during cryopreservation. The optimal concentration of OptiprepTM, 2.5%, was determined using fresh spermatozoa, and applied for the following experiment. The 2.5% OptiprepTM group showed significantly increased sperm motility than the control (P < 0.05). Lower mitochondrial ROS modulator (ROMO1) and pro-apoptotic gene (BAX), together with higher expression of protamine-2 (PRM2), protamine-3 (PRM3), anti-apoptotic gene (BCL2) and sperm acrosome associated-3 (SPACA3), were expressed in the iodixanol treated group. In addition, decreased protamine deficiency and cryocapacitation was observed in the treatment group. Our findings show that supplementation of 2.5% OptiprepTM is ideal for reducing production of ROS and preventing detrimental effects during cryopreservation process of canine sperm, manifested as increased motility and reduced cryocapacitation in the frozen-thawed spermatozoa. PMID- 30481990 TI - Genetic identification of astroviruses in wild boars. AB - Astroviruses were widely detected in pigs but their detection in wild boars is rather sporadic. In this study astroviruses were detected in organ homogenates of wild boars by a nested RT-PCR and the typing was carried out by phylogenetic analysis. Overall, 30/200 (15%) homogenates were positive for astroviruses. Genetic typing revealed that of 13 amplicons analysed, 8 were typed as porcine astrovirus lineage 2 (PAstV-2), and 2 as lineage 4 (PAstV-4). Two identical sequences were grouped with chicken astrovirus, and 1 sequence belonged to bat astrovirus. The first identification of chicken and bat astroviruses in wild boars indicates interspecies transmission. PMID- 30481991 TI - The Mixed-Features Specifier of Major Depressive Disorder in DSM-5: Is It Practical? PMID- 30481992 TI - Screening Tool for Anxiety Disorders: Development and Validation of the Korean Anxiety Screening Assessment. AB - OBJECTIVE: This study evaluated the psychometric properties of the Korean Anxiety Screening Assessment (K-ANX) developed for screening anxiety disorders. METHODS: Data from 613 participants were analyzed. The K-ANX was evaluated for reliability using Cronbach's alpha, item-total correlation, and test information curve, and for validity using focus group interviews, factor analysis, correlational analysis, and item characteristics based on item response theory (IRT). The diagnostic sensitivity and specificity of the K-ANX were compared with those of the Beck Anxiety Inventory (BAI) and Generalized Anxiety Disorder 7-item scale (GAD-7). RESULTS: The K-ANX showed excellent internal consistency (alpha=0.97) and item-total coefficients (0.92-0.97), and a one-factor structure was suggested. All items were highly correlated with the total scores of the BAI, GAD 7, and Penn State Worry Questionnaire. IRT analysis indicated the K-ANX was most informative as a screening tool for anxiety disorders at the range between 0.8 and 1.6 (i.e., top 21.2 to 5.5 percentiles). Higher sensitivity (0.795) and specificity (0.937) for identifying anxiety disorders were observed in the K-ANX compared to the BAI and GAD-7. CONCLUSION: The K-ANX is a reliable and valid measure to screen anxiety disorders in a Korean sample, with greater sensitivity and specificity than current measures of anxiety symptoms. PMID- 30481993 TI - Association between Thioridazine Use and Cancer Risk in Adult Patients with Schizophrenia-A Population-Based Study. AB - OBJECTIVE: Several cell line studies have demonstrated thioridazine's anticancer, multidrug resistance-reversing and apoptosis-inducing properties in various tumors. We conducted this nationwide population-based study to investigate the association between thioridazine use and cancer risk among adult patients with schizophrenia. METHODS: Based on the Psychiatric Inpatient Medical Claim of the National Health Insurance Research Database of Taiwan, a total of 185,689 insured psychiatric patients during 2000 to 2005 were identified. After excluding patients with prior history of schizophrenia, only 42,273 newly diagnosed patients were included. Among them, 1,631 patients ever receiving thioridazine for more than 30 days within 6 months were selected and paired with 6,256 randomly selected non-thioridazine controls. These patients were traced till 2012/12/31 to see if they have any malignancy. RESULTS: The incidence rates of hypertension and cerebrovascular disease were higher among cases than among matched controls. The incidence of hyperlipidemia, coronary artery disease and chronic pulmonary disease did not differ between the two groups. By using Cox proportional hazard model for cancer incidence, the crude hazard ratio was significantly higher in age, hypertension, hyperlipidemia, cerebrovascular disease, coronary artery disease and chronic pulmornary disease. However, after adjusting for other covariates, only age and hypertension remained significant. Thioridazine use in adult patients with schizophrenia had no significant association with cancer. CONCLUSION: Despite our finding that thioridazine use had no prevention in cancer in adult patients with schizophrenia. Based on the biological activity, thioridazine is a potential anticancer drug and further investigation in human with cancer is warranted. PMID- 30481994 TI - Increased Frontal Gamma and Posterior Delta Powers as Potential Neurophysiological Correlates Differentiating Posttraumatic Stress Disorder from Anxiety Disorders. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) is distinct from anxiety disorders in its etiology and clinical symptomatology, and was reclassified into trauma- and stressor-related disorders in DSM-5. This study aimed to find neurophysiological correlates differentiating PTSD from anxiety disorders using resting-state quantitative electroencephalography (qEEG). METHODS: Thirty-six patients with either PTSD or acute stress disorder and 79 patients with anxiety disorder were included in the analysis. qEEG data of absolute and relative powers and patients' medication status on the day of qEEG examination were obtained. Electrodes were grouped into frontal, central, and posterior regions to analyze for regional differences. General linear models were utilized to test for group differences in absolute and relative powers while controlling for medications. RESULTS: PTSD patients differed from those with anxiety disorders in overall absolute powers [F(5,327)=2.601, p=0.025]. Specifically, overall absolute delta powers [F(1,331)=4.363, p=0.037], and overall relative gamma powers [F(1,331)=3.965, p=0.047] were increased in PTSD group compared to anxiety disorder group. Post hoc analysis regarding brain regions showed that the increase in absolute delta powers were localized to the posterior region [F(1,107)=4.001, p=0.048]. Additionally, frontal absolute gamma powers [F(1,107)=4.138, p=0.044] were increased in PTSD group compared to anxiety disorder group. CONCLUSION: Our study suggests increased overall absolute delta powers and relative gamma powers as potential markers that could differentiate PTSD from anxiety disorders. Moreover, increased frontal absolute gamma and posterior delta powers might pose as novel markers of PTSD, which may reflect its distinct symptomatology. PMID- 30481996 TI - Discrimination and calibration properties of the hypotension probability indicator during cardiac and vascular surgery. AB - BACKGROUND: Hypotension during surgery is linked to postoperative complications. Recently, a new hemodynamic algorithm intended to predict hypotensive events (hypotension probability indicator, HPI) has been developed. The aim of the present study is to test the discrimination and calibration properties of the HPI. METHODS: The intraoperative files of 23 patients undergoing cardiac and major vascular surgery receiving the HPI-based hemodynamic monitoring were retrospectively investigated for prediction of hypotensive events (mean arterial pressure < 65 mmHg). The HPI was available at 20 seconds intervals; the values of HPI 5 to 7 minutes before an hypotensive event (HPI5-7) were tested for discrimination and calibration. RESULTS: The HPI5-7 has a fair level of discrimination (area under the curve 0.768) and a poor calibration, due to overestimation of the hypotensive risk. At the observed prevalence, a cut-off value of 85% carries a sensitivity of 62.4% and a specificity of 77.7%, a negative predictive value (NPV) of 97.8% and a positive predictive value (PPV) of 12.6%; a value of 98% has a PPV of 64% and an NPV of 95.3%. CONCLUSIONS: The HPI5 7 may offer some useful insights. Values <= 85% carry a clinically acceptable NPV for hypotensive events at the observed prevalence and may represent a "safe zone" during surgery. Values > 85% do not carry enough PPV to trigger hemodynamic interventions, but represent a warning signal. Values > 98% are highly suggesting a hypotensive event after 5-7 minutes. Further studies exploring the predictive ability of the HPI at different times are needed. PMID- 30481995 TI - A contact investigation after exposure to a child with disseminated tuberculosis mimicking inflammatory bowel disease. AB - PURPOSE: Tuberculosis (TB) is one of the most important diseases that cause significant mortality and morbidity in young children. Data on TB transmission from an infected child are limited. Herein, we report a case of disseminated TB in a child and conducted a contact investigation among exposed individuals. METHODS: A 4-year-old child without Bacille Calmette-Guerin vaccination was diagnosed as having culture-proven disseminated TB. The child initially presented with symptoms of inflammatory bowel disease, and nosocomial and kindergarten exposures were reported. The exposed individuals to the index case were divided into 3 groups, namely household, nosocomial, or kindergarten contacts. Evaluation was performed following the Korean guidelines for TB. Kindergarten contacts were further divided into close or casual contacts. Chest radiography and tuberculin skin test or interferon-gamma-releasing assay were performed for the contacts. RESULTS: We examined 327 individuals (3 household, 10 nosocomial, and 314 kindergarten contacts), of whom 18 (5.5%), the brother of the index patient, and 17 kindergarten children were diagnosed as having latent TB infection (LTBI). LTBI diagnosis was more frequent in the children who had close kindergarten contact with the index case (17.1% vs. 4.4%, P=0.007). None of the cases had active TB. CONCLUSION: This is the first reported case of TB transmission among young children from a pediatric patient with disseminated TB in Korea. TB should be emphasized as a possible cause of chronic diarrhea and failure to thrive in children. A national TB control policy has been actively applied to identify Korean children with LTBI. PMID- 30481997 TI - Levels of circulating microparticles in septic shock and sepsis-related complications: a case-control study. AB - BACKGROUND: Microparticles (MP) have been largely studied as potential biomarkers in septic shock (SS) though their biological and clinical relevance is still unclear. This casecontrol study describes the trend of various MP subtypes during SS to evaluate their possible association with severity of illness and sepsisrelated complications (disseminated intravascular coagulation [DIC] and acute kidney injury [AKI]). METHODS: Forty patients admitted to the Intensive Care Unit with SS and forty matched healthy volunteers were recruited. AnnexinV+, Eselectin+, thrombomodulin (TM+), leukocytederived (CD45+,CD36+) and plateletderived MP (PMPexpressed as PMP/plts ratio) were measured by flowcytometry at baseline, on day 1, 3 and 7 after diagnosis. Severity of illness was assessed by SOFAscore, duration of vasoactive support and mechanical ventilation. Sepsisrelated complications were considered. RESULTS: Overall, septic patients showed higher levels of all MP considered compared to controls. TM+MP were significantly lower in more severe sepsis, while CD36+MP and PMP/plts ratio were significantly increased in patients requiring longer vasoactive support and mechanical ventilation. As for sepsisrelated complications, a higher PMP/plts ratio in patients who developed DIC and increased Eselectin+MP in subjects who developed AKI were observed. PMP/plts ratio at baseline was significantly associated with longer vasoactive support (OR 1.59 [1.052.42]), longer mechanical ventilation (OR 1.6 [1.062.42]) and DIC occurrence (OR 1.45 [1.081.96]). CONCLUSIONS: A global response through extravesiculation of endothelial cells, leukocytes and platelets during the early stages of SS was confirmed. The cellular activation was detected until day 3 after diagnosis. PMP/plts ratio at diagnosis may be useful to evaluate SS severity and DIC occurrence. PMID- 30481998 TI - Out-of-hospital cardiac arrest at place of residence is associated with worse outcomes in patients admitted to intensive care: a post-hoc analysis of the Targeted Temperature Management trial. AB - BACKGROUND: The majority of out-of-hospital cardiac arrests (OHCAs) occur at place residence, which is associated with worse outcomes in unselected prehospital populations. Our aim was to investigate whether location of arrest was associated with outcome in a selected group of initial survivors admitted to intensive care. METHODS: This is a post-hoc analysis of the Targeted Temperature Management after cardiac arrest trial (TTM trial), a multicenter controlled trial, randomizing 950 OHCA patients to an intervention of 33 degrees C or 36 degrees C. The location of cardiac arrest was defined as place of residence vs. public place or other. The outcome measures were mortality and neurological outcome, as defined by the Cerebral Performance Category scale, at 180 days. RESULTS: Approximately half of 938 included patients arrested at place of residence (53%). Location groups did not differ with respect to age (p=0.11) or witnessed arrests (p=0.48) but bystander CPR was less common (p=0.02) at place of residence. OHCA at place of residence was associated with higher 180-day mortality, 55% vs. 38% (p<0.001) and worse neurological outcome, 61% vs. 43% (p<0.001) compared with a public place or other. After adjusting for known confounders, OHCA at place of residence remained an independent predictor of mortality (p=0.007). CONCLUSIONS: Half of all initial survivors after OHCA admitted to intensive care had an at place of residence which was independently associated with poor outcomes. Actions improve outcomes after OHCA at place of residence should be addressed in future trials. PMID- 30481999 TI - Hemadsorption during cardiopulmonary bypass reduces interleukin 8 and tumor necrosis factor alpha serum levels in cardiac surgery: a randomized controlled trial. AB - BACKGROUND: Surgical trauma and cardiopulmonary bypass (CPB) are associated with the liberation of pro inflammatory cytokines. With hemadsorption (Cytosorb(r)) during CPB, pro-inflammatory cytokines may be reduced and the inflammatory response may be decreased. METHODS: In this prospective, randomized single centre study, serum cytokine levels of interleukin 8 (Il-8), interleukin 6 (Il-6) and tumor-necrosis-factor alpha (TNFalpha) were assessed in elective on-pump cardiac surgery patients with hemadsorption on CPB (study-group (SG), n=20) and without (control-group (CG), n=20). Cytokine levels were assessed prior to CPB, at the end of CPB, and 6 hours (h) and 24h after the end of CPB, together with a hemodynamic assessment. Cardiac-index (CI) was assessed with transcardiopulmonary thermodilution. RESULTS: For Il-8, significantly lower serum levels were observed in the SG compared to the CG at the end of CPB (p=0.008). In the SG, TNFalpha levels were also below those in the CG at both the end of and 6h after CPB (p=0.034). After 24 hours, TNFalpha levels were at baseline in both groups. No significant differences were found for Il-6. The CI was significantly higher in the SG at the end of CPB (p=0.025). However, there was no difference between both groups 6h after CPB. CONCLUSIONS: This prospective study shows a significant reduction in pro-inflammatory cytokine levels of Il-8 and TNFalpha with hemadsorption in on-pump cardiac surgery whilst also demonstrating safety in its applications. However, the differences in cytokine levels and CI between patients treated with hemadsorption and those without were minor and of short duration. PMID- 30482000 TI - Size and shape of the inferior vena cava before and after a fluid challenge: a pilot study. AB - BACKGROUND: Recent meta-analyses failed to support the reliability of ultrasound assessment of the inferior vena cava (IVC) to predict fluid responsiveness. However, the techniques utilized were heterogeneous. We hypothesized that the variability of the elliptic section and caliber of the IVC along its course may influence ultrasound evaluation. Therefore, we investigated IVC size and shape at four levels, before and after a fluid challenge. METHODS: Twenty mechanically ventilated adult patients who received a fluid challenge after cardiac surgery were enrolled. They were regarded as responders if the cardiac index increased more than 15%. Before and after the fluid challenge, IVC anteroposterior (AP) and lateral (LA) diameters, the flat ratio, and the distensibility index were assessed by ultrasound just above the iliac veins, at the confluence of the renal veins, before the confluence of the hepatic veins (where blood flow velocity was also measured), and after it. RESULTS: At all levels, IVC section was elliptical, so that IVC diameters varied between a minimum and a maximum according to the measurement angle. Such interval increased in correspondence of the renal veins, where IVC section was more eccentric. The distensibility index was higher when assessed on AP diameters. After the fluid challenge, non responders showed a diffuse increase of AP diameters, whereas responders showed an increase of blood velocity before the confluence of the hepatic veins. CONCLUSIONS: The elliptic section should be considered when assessing IVC size. AP diameters are shorter and more affected by the respiratory cycle. After a fluid challenge, an increase of blood velocity associated with unchanged AP diameters may suggest fluid responsiveness. PMID- 30482001 TI - A systematic review of the diagnostic accuracy of epidural wave form analysis to identify the epidural space in surgical and labour patients. AB - INTRODUCTION: Epidural failure due to misidentification of the epidural space is not uncommon. Epidural wave form analysis has been suggested to identify the epidural space. EVIDENCE ACQUISITION: A systematic literature search (Medline, Epub, Embase.com (Embase plus Medline), Cochrane Central, Web of Science, and Google Scholar) was performed to identify studies comparing epidural wave form analysis (index test) to epidural analgesia (reference test). EVIDENCE SYNTHESIS: 8 studies (3901 patients) were retrieved that provided data on diagnostic accuracy. These studies had a low risk of bias and of applicability concerns, as assessed by the quality assessment of diagnostic accuracy studies (QUADAS-2) tool. One study did not observe an epidural wave form in parturients, a finding that was not corroborated in another study. Because the reference test was different across the studies we decided not aggregate the data. The sensitivity values of the individual studies varied between 0.81 and 1.00, for the specificity values between 0.42 and 1.00 were found. CONCLUSIONS: Our study suggests that epidural wave form analysis is a reliable method for identification of the epidural space that could become a useful adjunct especially in anticipated difficult catheter placements or in teaching situations. Further research is warranted to define the role of epidural wave form analysis in pregnant women. PMID- 30482002 TI - The Weaning Index combining EtCO2 and respiratory rate early identifies Spontaneous Breathing trial failure. A pilot study. AB - BACKGROUND: We aimed to evaluate the predictive value of the end-tidal CO2 (EtCO2) alone or combined with ventilation related parameters on spontaneous breathing trial (SBT) outcome on mechanically ventilated patients. METHODS: Prospective observational study in a medical ICU. Mechanically ventilated adult patients who met predefined criteria for weaning were included. Patients underwent a T-piece SBT for 30 minutes and the usual hemodynamic and respiratory clinical parameters including EtCO2 were recorded every 5 minutes. RESULTS: 280 patients were studied (age: 64+/-17 years, SAPS II: 44 [34-56]) during a first SBT and 76 patients during a second SBT. The Weaning Index, defined as the product of the respiratory rate and EtCO2, was a strong early predictive factor of SBT outcome; at 10 minutes, the area under the curve (AUC) was 86% ([80-90], P<0.0001) during the first SBT and 88% ([80-96], P<0.0001) during the second SBT. After 10 minutes of SBT, a Weaning Index >1100 identified patients that will not successfully complete the SBT at 30 minutes with a specificity of 98%. CONCLUSIONS: In unselected mechanically ventilated patients, the Weaning Index is helpful to early identify patients who will fail the SBT during a first and a second trial. PMID- 30482003 TI - Color your epidural: color flow doppler to confirm labor epidural needle position. AB - BACKGROUND: Labor epidural analgesia success depends on precise needle position placement within the epidural space, with reported failure rates to be as high as 32%. In this study, we describe a novel technique employing color Doppler to aid in the confirmation of the correct position of the epidural needle tip. METHODS: Retrospective evaluation of 35 patients who received labor combined spinal- epidural (CSE) with confirmation of epidural needle position with color flow Doppler (CFD) ultrasonography. Demographic data, intervertebral level of insertion and dermatome sensory level were extracted. Video and image evaluation of CFD patterns were used to confirm epidural needle tip and catheter position. CFD was used to visualize intrathecal injection of local anesthetic in two patients. RESULTS: Three different color flow patterns were visualized after the loss of resistance technique: visualization of a red and blue mosaic adjacent to the posterior complex, a mosaic pattern enveloping the trajectory of the epidural needle, and a linear deeper mosaic color pattern during spinal injection in relation to the posterior complex. Identification of epidural needle tip and epidural catheter tip occurred in 77% and 37.1% of patients, respectively. CONCLUSIONS: CFD is a novel and useful technique to confirm the precise position of the epidural needle tip in the context of labor analgesia. Identification of the epidural catheter with CFD is difficult despite an adequate CSE technique. PMID- 30482004 TI - Ultrasound guided erector spinae plane block for breast reconstruction surgery with latissimus dorsi muscle flap. PMID- 30482005 TI - Dynamic of lipid droplets and gene expression in response to beta-aminoisobutyric acid treatment on 3T3-L1 cells. AB - Research on adipobiology has recognized the browning process of white adipocytes as a potential therapeutic strategy for the treatment of obesity and related morbidities. Physical exercise stimulates the secretion of myokines, such as b aminoisobutyric acid (BAIBA), which in turn promotes adaptive thermogenesis. White adipocyte conversion to brown cells involves dynamic changes in lipid droplet (LD) dimension and in the transcription of brown-specific marker genes. This study analyzes the effect of different doses of BAIBA and at different days of development on 3T3-L1 cells by evaluating morphological changes in LDs and the expression of browning gene markers. Results suggested that the highest concentration of BAIBA after 4 days of differentiation produced the most significant effects. The number of LDs per cell increased in comparison to control cells, whereas the surface area significantly decreased. Brown adipocyte markers were up-regulated, but the effect of treatment was lost at 10 days of differentiation. The thermogenic program induced by BAIBA may reflect a rapid adaptation of adipose tissue to physical exercise. This connection stresses the beneficial impact of physical exercise on metabolic health. The thermogenic program induced by BAIBA may reflect a rapid adaptation of adipose tissue to physical exercise. This connection stresses the beneficial impact of physical exercise on metabolic health. PMID- 30482006 TI - Novel transcatheter therapies for treating tricuspid regurgitation. AB - Until recently, tricuspid valve (TV) disease has been relatively neglected for a long time, but recently tricuspid regurgitation (TR) has attracted attention. Although the prognosis of patients with these disorders is poor, the high mortality and morbidity associated with TV surgery have resulted in many patients not receiving surgical therapy. Current guidelines recommend that TV surgery should be considered in patients with severe TR who are symptomatic or have progressive right ventricle (RV) dilatation or dysfunction. In the absence of severe RV or left ventricle (LV) dysfunction, surgery should be considered in cases of severe pulmonary vascular disease or hypertension; however, it is difficult to assess RV dysfunction. Symptoms of right heart failure are more nonspecific and difficult to diagnose than those of left heart failure. Furthermore, the severity of TR is easily influenced by the use of diuretics. These factors lead to difficulties in patient selection and in determination of optimal timing for surgery. Transcatheter therapies for TR have begun to emerge as an alternative for patients with severe symptomatic TR who are at high-risk for standard surgery. Although initial results from a recent international multicenter registry have demonstrated that transcatheter TV therapy is feasible and safe, its clinical experience is still under development. In the present review, we describe the currently available techniques of transcatheter TV intervention and preliminary clinical results. PMID- 30482007 TI - Monitoring of treament adherence with easypodTM in 6 Italian centres: a real world experience. AB - BACKGROUND: A poor adherence to r-hGH therapy is associated to a low growth rate in patients with growth deficiency. For this reason, the choice of an objective method, such as an electronic device, for monitoring treatment adherence is very important. This retrospective study evaluated the r-hGH treatment adherence of patients with growth deficiency, monitored through the easypodTM device. METHODS: Data from 90 patients (52 males; mean age at the end of the study: 11.9 years) enrolled in 6 Italian centres, was collected from the beginning of the r-hGH therapy until the end of the study through the easypodTM device. The primary objective - treatment adherence- was the rate (%) between the number of effective days of treatment and the number of planned days. Secondary objectives were: relationship between heights measured at the beginning and at the end of the study, the change of the height SDS and the growth rate. RESULTS: EasypodTM data showed that the mean adherence was 70% (SD 13%). The mean age-adjusted growth of the patients was 28.68 cm (SD +/- 13.8 cm) during the treatment period of 977 days, and the 6 months growth rate for the planned period was 3.78 cm (SD +/- 8.1). A positive correlation between the adherence rate and the change of the height SDS value was observed (p < 0.0006). CONCLUSIONS: EasypodTM seems to be a valid tool for quickly identifying non-adherence habits, allowing physicians to implement actions focused on reinforcing the importance of treatment both for patients and caregivers. PMID- 30482008 TI - Bone health among patients with primary aldosteronism: a systematic review and meta-analysis. AB - BACKGROUND: Recent studies showed a possible association between hyperaldosteronism and secondary hyperparathyroidism leading to reduced bone health, however results are conflicting. METHODS: We conducted a meta-analysis to evaluate the relationship between primary aldosteronism (PA) with bone biochemical markers and to assess bone mineral density in patients with primary aldosteronism. RESULTS: A total of 939 subjects were examined (37.5% with PA). Patients with PA had significantly higher serum parathyroid hormone, lower serum calcium, higher urine calcium excretion and higher serum alkaline phosphatase compared to patients without PA, with no significant difference in serum vitamin D between both groups. Bone mineral density of lumbar spine, femoral neck and total neck of femur were similar between two groups. With PA treatment, there was a significant increment in serum calcium and reduction in serum parathyroid hormone. CONCLUSIONS: PA is associated with hypercalciuria with subsequent secondary hyperparathyroidism. This potentially affects bone health. We recommend this to be part of complication screening among patients with PA. PMID- 30482009 TI - Heterogeneous clinical features of ketosis-prone type 2 diabetes mellitus patients: gender, age, loss of weight and HbA1c. AB - BACKGROUND: To observe the clinical features of type 2 diabetes mellitus (T2DM) patients with ketosis as the initial symptom, and investigate its differences from clinical features of non-ketotic T2DM patients. METHODS: A total of 385 T2DM patients treated in our hospital from 2014 to 2017 were selected and divided into ketosis-prone T2DM group and non-ketotic T2DM group. Ketosis-prone T2DM patients refer to DM patients with the urine ketone body++ or above or the blood ketone body >=1.0 mmol/L when treated. Fasting venous blood was collected from all patients in the early morning at 2 d after admission to detect the liver function, renal function, blood glucose, triglyceride, total cholesterol, glycosylated hemoglobin and fasting C-peptide, glutamic acid decarboxylase antibody (GAD-Ab) and islet cell antibody (ICA) were also detected, and the 24 h urine specimen was retained to detect the 24 h urine microalbumin excretion rate. RESULTS: The proportion of male in ketosis-prone T2DM group was significantly higher than that in non-ketotic T2DM group (P<0.01). Patients in ketosis-prone T2DM group was younger than those in non-ketotic T2DM group (P<0.05). The number of days from initial symptom to treatment in ketosis-prone T2DM group was smaller than that in non-ketotic T2DM group (P<0.05). The fasting C-peptide level in ketosis-prone T2DM group was significantly lower than that in non-ketotic T2DM group (P<0.05). The degree of weight loss and level of glycosylated hemoglobin in ketosis-prone T2DM group were significantly higher than those in non-ketotic T2DM group (P<0.05). CONCLUSIONS: Ketosis-prone T2DM patients are characterized by lower age at onset, higher proportion of male, shorter duration of disease, poorer islet function, higher blood glucose and more significant weight loss than non-ketotic T2DM patients. PMID- 30482010 TI - Sleep apnea and cardiovascular complications of the acromegaly. Response to the medical treatment. AB - Acromegaly is a rare disease characterized by high levels of growth hormone (GH) and insulin- like growth factor 1 (IGF-1). The excess of GH leads to the development of different manifestations in different organs, from subtle signs in the bones and soft tissues to the development of respiratory and cardiac insufficiency. In the cardiovascular system, the GH/IGF-1 axis exerts its influence on three major aspects: myocyte growth and structure, cardiac contractility and vascular function. In this article, we review the different cardiovascular and respiratory complications as well as the effects of the different treatments on these complications. Cardiovascular complications that occur in acromegaly are known as "acromegalic cardiomyopathy," and include ventricular hypertrophy, impaired diastolic and systolic function, valve diseases, coronary artery disease, and arrhythmias. Acromegaly is also associated with relevant complications of the respiratory system, mainly sleep apnea and respiratory insufficiency. Regarding treatment, there are different therapeutic strategies. Surgery is the first-choice treatment, but in general, half of patients will require adjuvant treatments, such as medical treatment (somatostatin analogues, dopamine agonists and GH receptor antagonists) or radiotherapy. The treatment can improve some complications of acromegaly, such as left ventricular hypertrophy, hypertension, or obstructive sleep apnea. On the other hand, when strict control of the disease is achieved, a reduction in mortality and cardiovascular morbidity is assured, reaching rates similar to those of the general population. PMID- 30482011 TI - Efficient synthesis of theaflavin-3-gallate by a tyrosinase-catalyzed reaction with (-)-epicatechin and (-)-epigallocatechin gallate in a 1-octanol/buffer biphasic system. AB - Theaflavins, the orange-red pigments contained in black tea, have attracted attention due to their health-promoting effects. However, their synthetic preparation, in which the enzymatic oxidation of catechol-type catechin is followed by the quinone-induced oxidative dimerization of selectively combined catechol- and pyrogallol-type catechins, provides only a low yield. In the present study, we found that a 1-octanol/buffer biphasic system improved the yield of theaflavin 3-gallate in a tyrosinase-catalyzed synthetic reaction with ( )-epicatechin and (-)-epigallocatechin gallate. When the enzymatic reaction proceeded in a buffer solution, oxidized (-)-epigallocatechin gallate was preferentially used for self-dimerization. However, self-dimerization was suppressed in the octanol phase, allowing oxidized (-)-epigallocatechin gallate to participate in coupling with (-)-epicatechin quinone leading to effective production of theaflavin 3-gallate. Furthermore, the preferential localization of theaflavin 3-gallate in the octanol phase prevented (-)-epicatechin quinone induced degradation. PMID- 30482012 TI - Colorimetric and NIR fluorescence probe with multiple binding sites for distinguishing detection of Cys/Hcy and GSH in vivo. AB - Although some progress has been made in distinguishing detection of biothiols, NIR biothiol fluorescent probes for simultaneous distinguishing detection of Cys, Hcy and GSH in vivo have not been reported. The design of these probes involves the introduction of NIR fluorophores and multiple binding sites, so the integrated design of probes remains a challenge. Although Cys, Hcy and GSH have the common functional group: a sulfydryl group and an amino group, due to their differences in spatial structure, they may react with multiple binding sites probes to produce different reaction products in different bonding mechanisms, resulting in the different colors and fluorescent signals changes of the system. Therefore, multiple binding sites fluorescent probes can realize their discrimi nation detection. For NIR fluorescent probe, it is easier to realize in vivo imaging to promote the research of biothiols in clinical diagnosis. In our work, not only multiple binding sites were constructed in the compound, but also NIR fluorophores were introduced. This enables the probe to not only efficiently distinguish detection of Cys/Hcy and GSH but also achieve fluorescence imaging in vivo. We believe this result is a milestone in the discrimination detection of biothiols. PMID- 30482013 TI - Dielectrophoresis: From molecular to micrometer scale analytes. AB - The complexity of biological analytes demands powerful analysis techniques in order to reveal cellular processes and pathways on the molecular level.1 Thus, ever refining analytical tools or combinations of various analysis techniques are required to reveal such complexities. Dielectrophoresis (DEP) refers to an analytical technique in which a polarizable particle experiences an attractive or repulsive force when placed in a non-uniform electric field. Realized in microenvironments, DEP phenomena have allowed innovative analytical applications due to the strong dependency on the size of the analyte in conjunction with its dielectric properties and are especially suitable for manipulating um-sized, cellular bioanalytes. However, the demonstration of DEP for smaller sub-cellular entities or non-biological, sub-um sized particles has been more difficult, as the required DEP forces impose design challenges.2 In addition, the structural complexity of sub-cellular bioanalytes, and the huge variety of microbes such as bacteria and viruses as well as innovative nanoparticles imposes the need of refined theoretical models as well as suitable DEP platforms for these analytes. Here, we specifically focus on recent DEP studies and applications for analyte dimensions below the size of a typical mammalian cells and include DEP studies related to microbes, sub-cellular entities such as organelles and exosomes but also to biomolecules such as nucleic acids and proteins. We also include non biological analytes that fall under this size range and review related DEP applications in the past 10 years. PMID- 30482014 TI - Highly Active Platinum Catalysts for Nitrile and Cyanohydrin Hydration: Catalyst Design and Ligand Screening via High-Throughput Techniques. AB - Nitrile hydration provides access to amides that are indispensable to researchers in chemical and pharmaceutical industries. Prohibiting the use of this venerable reaction, however, are 1) the dearth of biphasic catalysts that can effectively hydrate nitriles at ambient temperatures with high turnover numbers, and 2) the unsolved challenge of hydrating cyanohydrins. Herein, we report the design of new "donor-acceptor"-type platinum catalysts by precisely arranging electron-rich and electron-deficient ligands trans to one other, thereby enhancing both the nucleophilicity of the hydroxyl group and the electrophilicity of the nitrile group. Leveraging a high-throughput, automated workflow and evaluating a library of bidentate ligands, we have discovered that commercially available, inexpensive DPPF [1,1'-ferrocenendiyl-bis(diphenylphosphine)] provides superior reactivity. The corresponding "donor-acceptor"-type catalyst 2a is readily prepared from (DPPF)PtCl2, PMe2OH and AgOTf. The enhanced activity of 2a permits the hydration of a wide range of nitriles and cyanohydrins to proceed at 40 degrees C with excellent turnover numbers. Rational reevaluation of the ligand structure has led to the discovery of modified catalyst 2c, harboring the more electron-rich 1,1' bis[bis(5- methyl-2-furanyl) phosphino] ferrocene ligand, which demonstrates the highest activity towards hydration of nitriles and cyanohydrins at room temperature. Finally, the correlation between the electron-donating ability of the phosphine ligands with catalyst efficiencies of 2a, 2c, 2d and 2e in the hydration of nitrile 7 are examined, and the results support the "donor-acceptor" hypothesis. PMID- 30482015 TI - Chemical Degradation Pathways in Siloxane Polymers Following Phenyl Excitations. AB - We use ensembles of quantum-based molecular dynamics simulations to predict the chemical reactions that follow radiation-induced excitations of phenyl groups in a model copolymer of polydimethylsiloxane and polydiphenylsiloxane. Our simulations span a wide range of highly porous and condensed phase densities, and include both wet and dry conditions. We observe that in the absence of water, excited phenyl groups tend to abstract hydrogen from other methyl or phenyl side groups to produce benzene, with the under-hydrogenated group initiating subsequent intrachain cyclization reactions. These systems also yield minor products of diphenyl moieties formed by the complete abstraction of both phenyl groups from a single polydiphenylsiloxane subunit. In contrast, we find that the presence of water promotes the formation of free benzene and silanol side groups, reduces the likelyhood for intrachain cyclization reactions, and completely suppresses the formation of diphenyl species. In addition, we predict that water plays a critical role in chain scission reactions, which indicates a possible synergistic effect between environmental moisture and radiation that could promote alterations of a larger polymer network. These results could have impact in interpreting accelerated aging experiments, where polymer decomposition reactions and network rearrangements are thought to have a significant effect on the ensuing mechanical properties. PMID- 30482016 TI - Pyrolyzed Triazine-based Nanoporous Frameworks Enable Electrochemical CO2 Reduction in Water. AB - The first study of rational synthesis of triazine-based nanoporous frameworks as electrocatalysts for CO2 reduction reaction (CO2RR) was presented. The resulting optimized framework with rich pyridinic nitrogen-containing sites can selectively reduce CO2 to CO in water with a high Faradaic efficiency of ca. 82% under a moderate overpotential of 560 mV. The key of our success lies in the use of pyridine-based backbones as sacrificial groups inside the triazine framework for in situ generation of CO2RR-active pyridinic N-doped sites during the high temperature ZnCl2-promoted polymerization process. We anticipate that this study may facilitate new possibilities for the development of porous organic polymers for electrochemical conversion of CO2. PMID- 30482017 TI - Extraordinary dielectric properties at heterojunctions of amorphous ferroelectrics. AB - Materials having a high dielectric constant are needed for a variety of electrical applications from transistors to capacitors. Ferroelectric amorphous oxide (glass) alkali-ion electrolytes of composition A2.99Ba0.005ClO (A = Li, Na) are shown by two different types of measurement and different consistent analysis to have extraordinarily high dielectric constants varying from 109 at 25 degrees C to 1010 at 220 degrees C if the glass is properly conditioned. These anomalously high dielectric properties coexist with alkali-ion conductivities at 25 degrees C that are equivalent to those of the best organic-liquid electrolytes of a Li-ion cell, and cyclic voltammetry (CV) in a Au/glass electrolyte/Au cell is stable from -10 to +10 V. A model to interpret microscopically all the key features of the CV curves shows that the electric-double-layer capacitors (EDLCs) that form at the gold/electrolyte interfaces in the Au/glass electrolyte/Au heterojunction reverse polarization at an applied voltage V = + 2.1 V resulting in three almost equivalent discharging capacitances for a single physical capacitor from -10 to +10 V. PMID- 30482018 TI - Identification and Structure Elucidation of Janthitrems A and D from Penicillium janthinellum and Determination of the Tremorgenic and Anti-Insect Activity of Janthitrems A and B. AB - New compounds, 11,12-epoxyjanthitrem B, 1, and 11,12-epoxyjanthitrem C, 4, were isolated from Penicillium janthinellum, and given the trivial names janthitrem A and janthitrem D, respectively. The known compounds janthitrem B, 2, and janthitrem C, 3, were also isolated and NMR assignments made for all 4 compounds. This showed that the previously published NMR assignments for 3 needed considerable revision. 1 and 2 were used as model compounds for the more complex, and highly unstable, epoxyjanthitrems that have been isolated from perennial ryegrass infected with the AR37 endophyte and which contain an epoxide group analogous to that of 1. Both 1 and 2 induced tremors in mice and reduced weight gain and food consumption of porina ( Wiseana cervinata) larvae although 1 showed greater potency. This shows the importance of the epoxy group and suggests that epoxyjanthitrems are likely to be involved in the observed effects of the AR37 endophyte on livestock and insects. PMID- 30482019 TI - Influence of Drug-Polymer Interactions on Dissolution of Thermodynamically Highly Unstable Cocrystal. AB - Solubility advantage of thermodynamically highly unstable cocrystals, which undergo solution-mediated phase transformation (SMPT) in less than 1 minute, does not translate to enhanced dissolution. The present study was aimed to understand the impact of polymeric additives on dissolution of thermodynamically highly unstable cocrystal with specific emphasis on influence of drug-polymer interactions. Exemestane-maleic acid was selected as a model cocrystal with SMPT time of <30 sec and eutectic constant (Keu) of 75475. Hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS) and polyvinylpyrrolidone (PVP) were selected as polymers for dissolution study based on measurement of induction time using precipitation study. In presence of 0.2 %w/v of HPC, the cocrystal showed significantly higher drug release (~3 folds) as compared with the cocrystal in absence of pre-dissolved polymers. Differential dissolution profiles of the cocrystal were observed with each polymer and the order of increasing dissolution rate was found to be HPC ~ HPMCAS > PVP. The molecular basis of the differential dissolution performance was investigated using infrared spectroscopy, solution-state nuclear magnetic resonance spectroscopy and nuclear Overhauser effect spectroscopy (NOESY). The polymers with stronger interactions with drug in the cocrystal (HPMCAS and HPC) displayed higher dissolution rate as compared with that of no intermolecular interaction (PVP). The study also highlighted that despite no influence of the polymers on the cocrystal SMPT, dissolution enhancement was achieved. This was attributed to small-sized API crystals (1-3 microns) generated from the supersaturated-mediated crystallization and improved solvation due to drug-polymer interaction. These findings have implications on development of drug products using thermodynamically unstable cocrystals. PMID- 30482020 TI - [1]Benzothiophene-Fused Chiral Spiro Polycyclic Aromatic Compounds: Optical Resolution, Functionalization, and Optical Properties. AB - Spiro polycyclic aromatic compounds have been known as rigid chiral scaffolds. In order to extend their applications, an efficient preparation route to enantiopure derivatives is highly required. Here, we design 10,10'-spirobi[indeno[1,2 b][1]benzothiophene]-7,7'-diol to achieve efficient optical resolution. The compound was successfully synthesized and resolved by chiral HPLC on a semipreparative scale. The absolute configuration of its enantiopure isomer was determined through single crystal X-ray structure analysis of its derivative. The compound was also transformed into its derivatives with donor-acceptor (D-A) type systems. The obtained chiral D-A type molecules exhibited remarkable solvent dependence fluorescence and were found to be solvent-sensitive circularly polarized luminescent materials. These results clearly demonstrated the utility of 10,10'-spirobi[indeno[1,2-b][1]benzothiophene]-7,7'-diol as a versatile building block for chiral spiro polycyclic aromatic compounds. PMID- 30482021 TI - Calculation of Vibrational Relaxation Times Using a Kinetic Theory Approach. AB - In the present work, a method for computation of vibrational relaxation times based on a kinetic theory definition is utilized to calculate vibrational relaxation times of molecules present in air (N2, O2 and NO) in collisions with air species particles. An overview of available experiment VT relaxation time measurements, as well as quasi-classical trajectory (QCT) calculation results, and various empirical models, is given. Different inelastic cross-section models are used for the computation of the relaxation times, and their parameters are adjusted to fit the available experimental data and QCT results. It is shown that the proposed method of calculation can give a quantative and qualitative agreement with the available data in a wide range of temperatures; the obtained interaction parameters may be used not only for vibrational relaxation time calculation within a multi-temperature framework, but also for development of state-specific models for use in CFD and DSMC codes. PMID- 30482023 TI - Surface-grafted antimicrobial drugs: Possible misinterpretation of mechanism of action. AB - Antimicrobial surface coatings that act through a contact-killing mechanism (not diffusive release) could offer many advantages to the design of medical device coatings that prevent microbial colonization and infections. However, as the authors show here, to prevent arriving at an incorrect conclusion about their mechanism of action, it is essential to employ thorough washing protocols validated by surface analytical data. Antimicrobial surface coatings were fabricated by covalently attaching polyene antifungal drugs to surface coatings. Thorough washing (often considered to be sufficient to remove noncovalently attached molecules) was used after immobilization and produced samples that showed a strong antifungal effect, with a log 6 reduction in Candida albicans colony forming units. However, when an additional washing step using surfactants and warmed solutions was used, more firmly adsorbed compounds were eluted from the surface as evidenced by XPS and ToF-SIMS, resulting in reduction and complete elimination of in vitro antifungal activity. Thus, polyene molecules covalently attached to surfaces appear not to have a contact-killing effect, probably because they fail to reach their membrane target. Without additional stringent washing and surface analysis, the initial favorable antimicrobial testing results could have been misinterpreted as evidencing activity of covalently grafted polyenes, while in reality activity arose from desorbing physisorbed molecules. To avoid unintentional confirmation bias, they suggest that binding and washing protocols be analytically verified by qualitative/quantitative instrumental methods, rather than relying on false assumptions of the rigors of washing/soaking protocols. PMID- 30482024 TI - Influence of surface topography on bacterial adhesion: A review (Review). AB - Bacterial adhesion and biofilm formation are ubiquitous undesirable phenomena in the marine industry and the medical industry, usually causing economic losses and serious health problems. Numerous efforts have been made to reduce bacterial adhesion and subsequent biofilm formation, most of which are based on the release of toxic biocides from coatings or substrates. In recent years, surface topography has been found to substantially influence the interaction between bacteria and surfaces. This review summarizes previous work dedicated in searching for the relationship between bacterial adhesion and surface topography in the last eight years, as well as the proposed mechanisms by which surface topographic features interact with bacterial cells. Next, various natural and artificial surfaces with bactericidal surface topography along with their bactericidal mechanisms and efficiency are introduced. Finally, the technologies for constructing antibacterial surfaces are briefly summarized. PMID- 30482025 TI - Recent Advances in Drug Delivery System for Bioactive Glycosides from Traditional Chinese Medicine. AB - Traditional Chinese Medicine (TCM) has been used in China for thousands of years for the prevention and treatment of various diseases. The materials that exert a therapeutic effect are called the active ingredients. The bioactive glycosides are important active ingredients from TCM that can make significant contributions to treating diseases. Because of the possibilities of various clinical applications, the properties and administration of these bioactive glycosides deserve further investigation. Their promising treatment effects, however, are hindered by their poor solubility, poor stability and rapid elimination. Therefore, it is necessary that we improve the therapeutic efficacy of bioactive glycosides by overcoming these problems. Meanwhile, some practical design strategies and novel drug delivery vehicles based on drug delivery systems provide favorable support in clinical practice for these active ingredients. This review summarizes diverse pharmacological activities of bioactive glycosides and focuses on recent advances in delivery system for these active constitutes; in particular, some glycol glycosides can effectively cure intractable diseases through targeted drug delivery. This review elucidates some design strategies for drug delivery system that are mainly based on two methods (avoiding physical barriers by changing dosage forms and enhancing the ability to bind to receptors or proteins after administration) and indicate the current challenges during the combination of delivery vehicles and these glycosides in hopes of promoting the process of receiving ideal therapeutic efficacy of them in future studies. PMID- 30482026 TI - Alternations of interhemispheric functional connectivity in corneal ulcer patients using voxel-mirrored homotopic connectivity: a resting state fMRI study. AB - BACKGROUND: Corneal ulcer (CU) is the second ocular disease leading to blindness. Millions of people around the world suffer from CU. However, the relationship between CU and altered functional connectivity in the brain is still unknown. PURPOSE: The aim of the present study was to investigate the alterations of the brain interhemispheric functional connectivity (FC) in patients with CU using the voxel-mirrored homotopic connectivity (VMHC) method and their relationship with clinical manifestations. MATERIAL AND METHODS: The present study involved 24 patients with CU (12 men, 12 women) and 24 healthy controls (HCs) with their age, sex, and weight closely matched. Independent sample t-test, VMHC method, and Pearson's correlation analysis were applied. Receiver operating characteristic (ROC) curve analysis was used to estimate the effect in distinguishing CU patients from HCs. RESULTS: The CU patients showed decreased VMHC values in bilateral lingual/calcarine, precentral/postcentral gyrus, and medial frontal gyrus compared with HCs. There were positive correlations between Visual Analogue Score (VAS) and VMHC values of bilateral media frontal gyrus ( r = 0.654, p = 0.001), the best-corrected VA of the affected eye and VMHC values of the bilateral lingual/calcarine region ( r = 0.960, p < 0.001). ROC curve also showed high diagnostic values in those regions. CONCLUSION: Our study was the first to explore FC changes in CU patients' brains using VMHC methods. We demonstrated that ocular pain of CU patients had a close relationship with altered VMHC values. Decreased VMHC values in the brain of CU patients may be useful markers to reflect the condition of progress in patients with CU. PMID- 30482027 TI - Honoring Life After Death: Mapping the Spread of the Pause. AB - BACKGROUND:: Health care is a high-risk environment for clinicians and patients. The risk of burnout increases with increased patient acuity and workload demands. The Pause is a contemplative intervention that has been deployed to foster honor and self-care. OBJECTIVE:: We aimed to reveal how clinicians and educators use The Pause and how it changes systems of thinking or practice. METHODS:: Using a modified Delphi method, we interviewed 11 participants who had used The Pause or intend on using it. RESULTS:: The Pause is being used in 4 continents and many countries. It is most widely learned about by the bedside in practice settings. Participants believe it is malleable and has a powerful systemic effect in fostering a culture of support and honor. CONCLUSION:: The Pause should continue to be taught in clinical scenarios to foster a broader humanistic ethos in health care. PMID- 30482028 TI - Favorable outcome of mechanical support for iatrogenic aortic dissection. PMID- 30482029 TI - Complementary and Alternative Medicine in Chronic Rhinosinusitis: A Systematic Review and Qualitative Analysis. AB - BACKGROUND: Complementary and alternative medicine (CAM) is frequently used in the treatment of chronic rhinosinusitis (CRS) in developed countries. With a plethora of CAM therapies available, their effectiveness and safety are poorly understood in the context of CRS. OBJECTIVES: This article aims to critically appraise the evidence for CAM use in CRS through a systematic review of current literature that investigate the effects of CAM on symptoms and clinical status of adults with CRS. STUDY DESIGN: Systematic review and qualitative analysis. REVIEW METHODS: A comprehensive systematic review of the literature was conducted by the authors using 5 databases from inception to July 2017: CINAHL, Cochrane, Embase, PubMed, and SCOPUS. Inclusive medical subject headings and keywords consisted of, but were not limited to, sinusitis and complementary therapies, naturopathy, or traditional Chinese medicine. PRISMA guideline was followed. Using templates by Cochrane Public Health Group and Newcastle-Ottawa Scale, each author extracted data, assessed bias, and computed minimal clinically important difference. Any conflicts were resolved through discussion. RESULTS: In total, 7 of 7141 articles from 1995 to 2016 were included. Three randomized controlled trials and 4 observational studies were organized into 4 categories of CAM: naturopathy, Chinese medicine, homeopathy, and others. Limited evidence supported the use of Pimpinella anisum and crenotherapy for CRS. Data available on Chinese medicine, homeopathy, and liposomal therapy in CRS were inconclusive due to inherent flaws in the studies. CONCLUSION: Overall, there is very limited evidence to support the use of CAM in the treatment of CRS. No significant adverse effects have been found. Given its widespread use, more rigorous data from high-quality research are needed before it can be routinely recommended. PMID- 30482030 TI - Auxiliary partial orthotopic liver transplantation for acute liver failure. AB - INTRODUCTION: Auxiliary partial orthotopic liver transplantation (APOLT) in acute liver failure acts as a bridge to native liver regeneration with potential for immunosuppression free survival. While technical concerns limit its universal acceptance, the indications in acute liver failure also need to be examined for this procedure to ultimately succeed. CASE HISTORY: We present the case of an eight-month-old girl with cryptogenic acute liver failure who underwent APOLT. She developed postoperative liver dysfunction, most likely owing to the persistence of the diseased native liver, ultimately leading to an orthotopic retransplantation. She remains well on follow-up review. CONCLUSIONS: A tempered approach to selecting patients for APOLT (especially with regard to aetiology of acute liver failure) makes it a safe and effective alternative to orthotopic liver transplantation. PMID- 30482031 TI - A Typology of Social Networks and Its Relationship to Psychological Well-Being in Korean Adults. AB - The purposes of this study were to (a) develop an empirical typology of the social networks in Korean adults aged 18 years or older and (b) examine the relation of network types on depressive symptoms and satisfaction with life. Data for this study were drawn from the survey with 1,017 community-dwelling adults aged 18 years or older in South Korea representing three life stages: young adults, middle-aged adults, and older adults. Latent profile analysis was conducted based on eight social network-related variables: marital status, living arrangement, number of family confidants, number of friend confidants, frequency of contact with friends using phone or social media, frequency of participation in social groups, frequency of conversation with neighbors, and perceived closeness of family. The identified typologies were then regressed on depressive symptoms and satisfaction with life. A model with four network types was identified as being the most optimal, and the groups were labeled as: diverse family, diverse-friend, solo-restricted, and coresident-restricted. Regression analyses showed that in comparison with the coresident-restricted group referent, diverse-friend and solo-restricted groups exhibited elevated levels of depressive symptoms; diverse-family and diverse-friend type had higher levels of satisfaction with life. Implications of the study findings were discussed in line with current research and intervention efforts. PMID- 30482032 TI - Surgical management of a giant hepatic cyst with suspicious radiological features. AB - Cysts in the liver have a wide variety of aetiologies. Important features of malignancy based on various imaging techniques must be considered prior to any intervention. Perioperative decision making in complex or difficult cysts is key to appropriate patient management. A 66-year-old woman was referred to the outpatient department with a one-year history of intermittent, sharp, right upper quadrant pain, radiating to her back. Computed tomography and magnetic resonance imaging showed a large cyst in the right and left lobes of the liver with portal inflow closely related. Features such as wall thickening suspicious for cystadenocarcinoma were present. An open resection was planned but, based on perioperative findings, the cyst had features making it unsafe to perform excision. De-roofing, carefully controlled drainage and assessment of the internal aspect of the cyst were performed, which revealed an extremely close relationship to portal inflow. This case describes the decision-making process when faced with complex indeterminate pathology of the liver and proximity of critical structures. PMID- 30482033 TI - Stripped screwhead removal - a simple glove technique. PMID- 30482034 TI - Endoscopic and Radiologic Findings in Failed Dacryocystorhinostomy: Teaching Pearls for Success. AB - BACKGROUND: Although several studies have commented on causes of dacryocystorhinostomy (DCR) failure, detailed description of anatomical findings in such cases remains insufficient. OBJECTIVE: Our objective was primarily to analyze radiologic, endoscopic, and intraoperative findings in patients presenting with failed DCR and secondarily to assess the outcome of revision endoscopic DCR (endo-DCR) carried out at our institution. METHODS: Twenty-four failed DCRs presenting to our tertiary care center were retrospectively analyzed. Data collection included patients' history, diagnostic, and management data, as well as thorough analysis of sinonasal CT scans, along with endoscopic and intraoperative findings. Outcome was also assessed in 21 cases with revision endo DCR performed. RESULTS: The anterior part of uncinate process was not previously removed in 15 sides (62.5%), with unopened agger nasi in 13 sides (54.2%). The lacrimal bone was detected covering the posterior sac despite removal of the anterior ascending process of maxilla in 9 sides (37.5%). Rhinostoma was anterior to lacrimal sac in 2 sides (8.3%) and was below the sac in 7 sides (29.2%). Fibrous membrane covered the rhinostoma despite removal of all sac-overlying bones in 6 sides (25%). Other findings included intranasal adhesions, septal deviation, lateralized middle turbinate, granulation tissue, foreign body reaction, and chronic sinusitis. Nineteen of the 21 revision endo-DCRs were successful (90.5%). CONCLUSION: This study provides a precise anatomical description of findings in cases of failed DCR. Such information is paramount in helping surgeons enhance their learning curve, refine the surgical technique, and improve patients' outcome. PMID- 30482035 TI - Laparoscopic hemi-splenectomy: a valid option in selected cases such as epidermoid cyst. AB - Splenic cysts are a rare pathology, which can be classified as true (25%) or pseudocysts (75%). Total splenectomy has been the treatment of choice, particularly in recent times with the advent of the laparoscopic approach. However, as the spleen is an organ with multiple immunological functions, the laparoscopic partial splenectomy is an alternative, which is technically difficult but effective. We present a case of a 26-year-old woman with incidental evidence of a splenic cyst in an abdominal ultrasound scan. We performed a laparoscopic partial splenectomy to preserve the function of the spleen because of the patient's youth. Laparoscopic partial splenectomy allows the effective removal of lesions and preservation of splenic function. Although more research is needed to clarify the most effective approach, this case is further evidence that this surgical approach may be beneficial for selected patients. PMID- 30482036 TI - Prevalence and Risk Factors of Chronic Rhinosinusitis in the Elderly Population of Korea. AB - BACKGROUND: Although a significant number of the clinical features and pathophysiologic mechanisms of chronic rhinosinusitis (CRS) have been described, only a few studies have been published on characterization of CRS in the field of aging. OBJECTIVE: We investigated the prevalence and risk factors of CRS in elderly (>=65 years old) Koreans using large-scale nationwide epidemiological data and compared the risk factors of elderly with those of younger adult participants (19-64 years old). METHODS: Data from 25 529 participants who completed the 2008-2012 Korean National Health and Nutrition Examination Survey were analyzed. Diagnosis of CRS was done according to the EP3OS 2012 guideline for epidemiologic study. Risk factors of CRS were compared in the aspects of sociodemographics, general health behaviors, clinical characteristics, and comorbidities of participants. RESULTS: The prevalence of CRS was significantly higher in 5590 elderly than in 19 939 younger adults (6.55% vs 5.69%; P = .016. Some variables of socioeconomic status and mental health in the adult group were associated with increased risk of CRS but did not show association in the elderly group. We observed a significant association between CRS prevalence and comorbid allergic rhinitis, asthma, and atopic dermatitis in both groups ( P < .05). However, in the elderly group, the associations were significantly weaker with regard to allergic rhinitis ( P-interaction = .03) and asthma ( P-interaction = .002). CONCLUSION: These results suggest that elderly populations have distinct pathophysiology and clinical presentations from adult CRS, and management for elderly patients with CRS may require different or additional therapeutic approaches. PMID- 30482037 TI - Toxicity and survival of anal cancer patients treated with intensity-modulated radiation therapy. AB - INTRODUCTION: The definitive treatment of anal cancer with chemoradiotherapy spares abdominoperineal resection for salvage treatment but carries a high burden of toxicity. Intensity-modulated radiation therapy has been implemented to reduce toxicity, reduce treatment breaks and improve survival. However, large and long term studies are lacking. We aimed to investigate the toxicities and long-term survival of anal cancer patients treated with intensity-modulated radiation therapy at James Cook University Hospital, Middlesbrough. MATERIALS AND METHODS: We conducted a retrospective analysis of all patients with squamous cell anal cancer treated at James Cook University Hospital between July 2010 and April 2017. All patients were uniformly treated with intensity-modulated radiation therapy-based chemoradiation with curative intent. A subset of these patients was followed-up prospectively by an oncologist for acute and late toxicity. We calculated Kaplan-Meier estimates of survival statistics and compared our results with those of previous trials which used conventional radiotherapy. RESULTS: We studied 132 patients, including a toxicity subset of 64, for a median follow-up time of 43 months (range 3-84 months). Eleven patients (8.3%) underwent salvage abdominoperineal resection. Grade 3+ acute non-haematological, gastrointestinal, genitourinary and dermatological toxicity were found in 56.2%, 12.3%, 0% and 50.7% of the toxicity subset (n = 64). Median treatment duration was 37 days. Overall and colostomy-free survival at five years were 68.3% and 85.3%, respectively. Tumour size (P = 0.006) and age (P = 0.002) predicted shorter overall survival. CONCLUSIONS: Intensity-modulated radiation therapy probably reduces acute gastrointestinal and genitourinary toxicity compared with conventional radiotherapy, while resulting in similar overall and colostomy-free survival. We suggest that further dose escalation may improve survival in patients with T3/T4 tumours. PMID- 30482038 TI - Abscess drainage without the mess. AB - A technique to reduce mess and odour in abscess drainage is presented. PMID- 30482040 TI - Functional optical coherence tomography of retinal photoreceptors. AB - IMPACT STATEMENT: Retinal photoreceptors are the primary target of age-related macular degeneration (AMD) which is the leading cause of severe vision loss and legal blindness. An objective method for functional assessment of photoreceptor physiology can benefit early detection and better treatment evaluation of AMD and other eye diseases that are known to cause photoreceptor dysfunctions. This article summarizes in vitro study of IOS mechanisms and in vivo demonstration of IOS imaging of intact animals. Further development of the functional IOS imaging may provide a revolutionary solution to achieve objective assessment of human photoreceptors. PMID- 30482041 TI - Cross-cultural comparative study of psychological distress between older Korean immigrants in the United States and older Koreans in South Korea. AB - OBJECTIVE: This study aims to answer questions about the similarities and differences in the prevalence and distribution of psychological distress across these populations. METHODS: Survey data from older Koreans between the ages 60 and 79 from the two countries (n = 480) was analyzed descriptively and in hierarchical multiple regressions. The stress coping framework was used as a conceptual model Results: This study found significantly different prevalence of psychological distress in both countries. About 13% of older Korean immigrants(US) experienced 'severe' psychological distress versus 21% of their counterparts ( Korea). Health status and overall financial status were significantly associated with the experience of psychological distress in both countries, while income was not significantly associated with psychological distress. Hierarchical multiple regression revealed significant associations between family relationships and help-seeking behavior among older Korean immigrants in the United States while there were significant associations between social support, social networks and psychological distress among older Koreans in South Korea. CONCLUSION: This is the first time that a comparative study has been used to understand psychological distress among older Koreans in both countries. The findings build on prior research on social support and social networks as stress coping buffers, adding a much-needed understanding of how stressors and different types of resources influence psychological distress outcomes. PMID- 30482042 TI - Water transport during bread baking: Impact of the baking temperature and the baking time. AB - The impact of the baking temperature on the moisture profile (in terms of water content), during bread baking was analyzed using a convection oven (three oven temperatures and different baking times). During baking, local water content and temperature were measured at different regions of the crust and crumb. There was found an increase in water content at the core. Water content reached a maximum level (at about 2.5%), with no effect of the baking temperature, and decreased slowly at advanced baking times. Regarding the crust, a theoretical model relating water flux to the driven force (temperature difference between the oven environment and the vaporization front) and the crust thermal resistance was validated with experimental values. Water losses were also reported. The water lost by bread contributes significantly to the energy consumption by this process and its reduction is of concern for conducting the process in a more sustainable manner. A better optimization of heat transfer between the surface (for coloration purposes) and the core (for inflation purposes) could help in this way, together with shorter baking duration and hence higher yield. PMID- 30482043 TI - The role of core needle biopsies in the management of neck lumps. AB - INTRODUCTION: King's College Hospital has proudly provided a one-stop neck lump clinic since 2012. These multidisciplinary clinics allow for rapid diagnoses due to in-clinic investigations. In April 2013, ultrasound-guided core needle biopsies were introduced as an alternative/adjunct to fine-needle aspiration cytology and open biopsies for obtaining histological diagnoses. The aim of the study was to assess the impact of core needle biopsies on the diagnosis of neck lumps compared with fine-needle aspiration cytology and open biopsies between April 2015 and May 2016. MATERIALS AND METHODS: Data were collected prospectively between April 2015 and May 2016 and analysed for numbers of fine-needle aspiration cytology, core needle biopsies and open biopsies performed and diagnoses made. RESULTS: A total of 190 patients were seen on the clinic; 51 had fine-needle aspiration cytology and 19 procedures gave a diagnosis. Of the remainder of these patients, 21 went on to have a core needle biopsy and 12 biopsies gave a diagnosis. An additional eight patients only had a core needle biopsy, of which five biopsies gave a diagnosis. Of the ten patients who had an open biopsy, four had a previous fine-needle aspiration cytology and core needle biopsy, three only a core needle biopsy, two had neither and one had fine-needle aspiration cytology. CONCLUSION: The introduction of core needle biopsies has reduced the number of open biopsies performed. With increasing acceptance of this minimally invasive technique, core needle biopsies appear to be forming the key diagnostic investigation in patients with neck lumps. PMID- 30482039 TI - alpha-Synuclein Trafficking in Parkinson's Disease: Insights From Fly and Mouse Models. AB - Protein aggregation and accumulation are common pathological hallmarks in neurodegenerative diseases. To efficiently clear and eliminate such aggregation becomes an important cellular strategy for cell survival. Lewy bodies inclusion and aggregation of alpha-Synuclein (alpha-Syn) during the pathogenesis of Parkinson's disease (PD) serve as a good example and are potentially linked to other pathological PD features such as progressive dopaminergic neuron cell death, behavioral defects, and nonmotor symptoms like anosmia, cognitive impairment, and depression. Years of research have revealed a variety of mechanisms underlying alpha-Syn aggregation, clearance, and spread. Particularly, vesicular routes associated with the trafficking of alpha-Syn, leading to its aggregation and accumulation, have been shown to play vital roles in PD pathogenesis. How alpha-Syn proteins propagate among cells in a prion-like manner, either from or to neurons and glia, via means of uptake or secretion, are questions under active investigation and have been of central interest in the field of PD study. This review covers components and pathways of possible vesicular routes involved in alpha-Syn trafficking. Events including but not limited to exocytosis and endocytosis will be discussed within the context of an overall cellular trafficking theme. Recent advances on alpha-Syn trafficking mechanisms and their significance in mediating PD pathogenesis will be thoroughly reviewed, ending with a discussion on the advantages and limitations of different animal PD models. PMID- 30482044 TI - EXPRESS: Elemental Analysis of Asphaltenes Using Simultaneous Laser-Induced Breakdown Spectroscopy (LIBS)-Laser Ablation Inductively Coupled Optical Emission Spectrometry (LA-ICP-OES). PMID- 30482045 TI - An unusual case of short-lasting unilateral neuralgiform headache attacks. AB - BACKGROUND: Short-lasting unilateral neuralgiform headaches include those with conjunctival injection and tearing and with cranial autonomic symptoms. Most frequently reported as idiopathic, there is a growing number of symptomatic cases described. CASE REPORT: A 57-year old man presented a 16-year history of right hemifacial short-lasting pain attacks accompanied by ipsilateral autonomic symptoms and simultaneous malar contractions. Brain MRI disclosed a right acoustic neuroma compressing the right facial nerve and a venous developmental anomaly perpendicular to the right facial nerve root entry zone, without lesions affecting the trigeminal nerve. He was started on lamotrigine, resulting in complete remission of pain attacks, autonomic signs and facial contractions. CONCLUSIONS: This patient presents a typical short-lasting unilateral neuralgiform headache with response to lamotrigine. The uniqueness of the case is the co-occurring malar contractions, evocative of facial nerve involvement. We speculate whether facial nerve compression renders this nerve more susceptible to triggering during a short-lasting unilateral neuralgiform headache attack. PMID- 30482046 TI - An Analysis of Protein Consumption in India Through Plant and Animal Sources. AB - BACKGROUND:: India became self-sufficient in food because of the Green Revolution in the 1960s. However, both the technological innovation and policy support have been biased toward cereals. It is expected that cereals are the major source of proteins in the diet. In recent years, the consumption of cereals is declining in spite of increasing output due to declining preference. Therefore, the country needs to increase production and consumption of pulses to meet the nutritional requirements of the population. OBJECTIVES:: This article discusses the trends in pulse and protein consumption over the years. Further, it focuses on the substitutability and complementarity between various sources of proteins. METHODS:: A Seemingly Unrelated Regression Estimation framework is used to study the price and income effect on proteins from different sources-cereals and pulses (plant sources), milk and milk products, animal sources such as eggs, fish, and meat, and other sources of protein. RESULTS:: It is found that the expenditure on proteins is large and significant. As income increases, consumption of proteins increases. Higher disposable incomes have led to higher demand of animal sources of proteins. There are significant food price effects in our analysis-negative for cereals and positive for eggs. As the price of pulses increases, consumption of animal sources of proteins increases. CONCLUSION:: It becomes important to contain volatility in pulse prices given that it is a major source of plant protein. States distributing pulses in the Public Distribution System show higher consumption of proteins than other states. PMID- 30482048 TI - Can cardiac rehabilitation improve LDL-cholesterol target attainment after acute coronary syndromes? PMID- 30482047 TI - Theory of mind, mental state talk and social relationships in aging: The case of friendship. AB - OBJECTIVES: Previous research has shown a decline in Theory of mind (ToM) associated with normal aging. However, very few studies have investigated older people's ToM using an ecological approach. The present study was designed to fill this gap and examine older people's frequency of mental state talk (MST) in describing their best friend, together with their performance on a traditional ToM task. In addition, the study examined the association between these two ToM indices and relationships with friends and family members. METHOD: Seventy-two healthy older adults (age range 60-79) participated in the study. We measured ToM ability with a classic measure, the Faux Pas task, and selected the Describe-a friend task to measure MST frequency; social relationships were investigated with the Lubben Social Network Scale. Correlation and regression analyses were performed. RESULTS: No significant association between MST and scores on the Faux Pas task emerged. In addition, MST (but not Faux Pas scores) significantly predicted friendships (but not family relationships) over and above general cognitive functioning. CONCLUSION: These findings show the crucial distinction between possessing an ability and using it in daily life and suggest the need to move toward more ecological measures of older adults' abilities. In addition, the present results indicate that the spontaneous use of ToM ability, not the ability per se, impacts on older adults' social relationships. PMID- 30482049 TI - Contribution of aerobic/resistance/inspiratory muscle training to cardiopulmonary recovery in a recipient of a ventricular assist device: Off-pump evaluation. PMID- 30482050 TI - Opportunistic screening models for high-risk men and women to detect diastolic dysfunction and heart failure with preserved ejection fraction in the community. AB - BACKGROUND: The prevalence of undetected left ventricular diastolic dysfunction is high, especially in the elderly with comorbidities. Left ventricular diastolic dysfunction is a prognostic indicator of heart failure, in particularly of heart failure with preserved ejection fraction and of future cardiovascular and all cause mortality. Therefore we aimed to develop sex-specific diagnostic models to enable the early identification of men and women at high-risk of left ventricular diastolic dysfunction with or without symptoms of heart failure who require more aggressive preventative strategies. DESIGN: Individual patient data from four primary care heart failure-screening studies were analysed (1371 participants, excluding patients classified as heart failure and left ventricular ejection fraction <50%). METHODS: Eleven candidate predictors were entered into logistic regression models to be associated with the presence of left ventricular diastolic dysfunction/heart failure with preserved ejection fraction in men and women separately. Internal-external cross-validation was performed to develop and validate the models. RESULTS: Increased age and beta-blocker therapy remained as predictors in both the models for men and women. The model for men additionally consisted of increased body mass index, moderate to severe shortness of breath, increased pulse pressure and history of ischaemic heart disease. The models performed moderately and similarly well in men (c-statistics range 0.60-0.75) and women (c-statistics range 0.51-0.76) and the performance improved significantly following the addition of N-terminal pro b-type natriuretic peptide (c-statistics range 0.61-0.80 in women and 0.68-0.80 in men). CONCLUSIONS: We provide an easy to-use screening tool for use in the community, which can improve the early detection of left ventricular diastolic dysfunction/heart failure with preserved ejection fraction in high-risk men and women and optimise tailoring of preventive interventions. PMID- 30482051 TI - Microarray analysis of long non-coding RNA and mRNA expression profiles in diabetic cardiomyopathy using human induced pluripotent stem cell-derived cardiomyocytes. AB - AIM:: This study aims to investigate the altered expression signature of long non coding RNAs, mRNAs and deregulated pathways related to diabetic cardiomyopathy disease pathogenesis. METHOD:: We utilize the previously established in vitro diabetic cardiomyopathy model of human induced pluripotent stem cell-derived human cardiomyocytes to perform long non-coding RNA and mRNA expression analysis on glucose (11 mM), endothelin-1 (10 nM) and cortisol (1 uM) stimulated human induced pluripotent stem cell-derived human cardiomyocytes to interrogate diabetic cardiomyopathy associated RNA expression profile. RESULT:: Out of 20,730 mRNAs and 40,173 long non-coding RNAs being screened, 2046 long non-coding RNAs and 1582 mRNAs were differentially regulated (fold change > 2, p < 0.05) between diabetic cardiomyopathy and control group, of which more than half were intergenic and antisense long non-coding RNAs. Most of the coding transcripts were associated with processes like inflammation, structural reorganization, metabolism, smooth muscle contraction, focal adhesion and repair contributing towards the development of diabetic cardiomyopathy. The subgroup analysis further revealed 411 long non-coding RNAs being co-expressed with neighbouring genes. However, our coding-non-coding co-expression analysis showed an overall 48,155 co expression network connections. In addition to that, the long non-coding RNAs with highest network connections were profoundly enriched for focal adhesion, cell-matrix adhesion and muscle contraction. CONCLUSION:: These results provide comprehensive data about the pathways and regulatory mechanisms associated with diabetic cardiomyopathy and indicate that long non-coding RNAs may play a crucial role in diabetic cardiomyopathy. PMID- 30482052 TI - Effectiveness of fascial closure technique following percutaneous endovascular aneurysm repair. AB - INTRODUCTION: Percutaneous access and closure is commonly performed for patients undergoing endovascular aneurysm repair (EVAR). It has proven to be a safe and successful method of closure associated with fewer complications when compared with the traditional open technique. Fascial closure is an alternative technique that can be used for closure reducing the risks associated with the open technique. The aim of this study was to assess the safety and durability of fascial closure for failed percutaneous closure device following EVAR. MATERIALS AND METHODS: Over a 12-month period, 49 patients who had undergone EVAR were identified via our EVAR register. Retrospective analysis of the clinical records was undertaken. We identified all the patients who had fascial closure of the groins following a failed percutaneous closure device. Patients had a computed tomography angiogram one month postoperatively, with duplex imaging and clinic follow-up three months later. RESULTS: Fascial closure was performed in 14 groins. It failed in three groins and these patients had traditional open repair. Fascial closure was successful in 11 groins (7 patients). Of these seven patients, one was female (6%). The mean age was 80 years (range 68-92 years). Two patients died and one was lost to follow-up. One pseudoaneurysms were seen on computed tomography angiogram, which was managed conservatively and had resolved on follow-up imaging. CONCLUSIONS: Fascial closure is a very good alternative to open repair after failure of the closure device. PMID- 30482053 TI - Reflections on emerging trends in clinical work with gender diverse children and adolescents. AB - Gender is a fast-evolving and topical field which is often the centre of attention in the media and in public policy debates. The current cultural and social climate provides possibilities for young people to express themselves. Gender diverse young people are not only developing new ways of describing gender, but they are also shaping what is required of clinical interventions. Emerging cultural, social and clinical trends, such as increases in referrals, shifts in sex ratio and diversification in gender identification, illustrate that gender diverse individuals are not a homogeneous group. How do evolving concepts of gender impact the clinical care of gender diverse young people presenting to specialist gender clinics today? PMID- 30482054 TI - Increased Corneal Ectasia Risk in Patients with Familial Mediterranean Fever. AB - PURPOSE: To evaluate the corneal tomographical parameters in patients with familial mediterranean fever and to compare data with those of healthy control subjects. MATERIALS AND METHODS: Forty eyes of 40 patients with familial mediterranean fever (familial mediterranean fever group) and 35 eyes of 35 healthy subjects (control group) were included to this prospective study. All participants underwent complete ophthalmological examination and tomographical analysis with Pentacam HR. Maximum keratometry, front and back astigmatism, thinnest pachymetry, maximum anterior and posterior elevation best-fit-sphere (BFS) at the 5.0 mm zone, front and back difference elevation, final D, average and maximum pachymetric progression index, maximum Ambrosio relational thickness parameters were noted. RESULTS: Groups were similar in terms of age and gender (p = 0.77 and p = 0.35). Maximum keratometry, thinnest pachymetry, front and back astigmatism, maximum anterior elevation BFS at the 5.0 mm values were similar between groups (p = 0.22, p = 0.52, p = 0.49, p = 0.29, and p = 0.31, respectively). Maximum posterior elevation BFS at the 5.0 mm and back difference elevation values were higher than control group in familial mediterranean fever group (p = 0.001 and p = 0.04). The mean values of final D, average and maximum pachymetric progression index were higher, and Ambrosio relational thickness was lower in familial mediterranean fever group compared to control group (p = 0.03, p = 0.002, p = 0.006, and p = 0.01, respectively). CONCLUSIONS: Familial mediterranean fever patients carry increased corneal ectasia risk compared to healthy subjects. The corneal tomographical characteristics and the association of keratoconus with familial mediterranean fever may be important in a detailed refractive surgery work-up. PMID- 30482055 TI - External Validity of the Multicomponent Group Treatment KiSS for School-Aged Children With Insomnia. AB - BACKGROUND: Insomnia is common in school-aged children and often associated with other mental disorders. Here, we investigated the effectiveness and acceptance of the KiSS program in an "all-comer" pediatric insomnia clinic. PARTICIPANTS/METHODS: Forty-five families (children: 5-10 years, 57.8% female) were randomly assigned to the multicomponent six-session KiSS treatment (CBT-I, hypnotherapy, and imaginations) or a wait-list control group. A sleep diary was recorded before intervention or waiting time, immediately after, as well as 3, 6, and 12 months postintervention (primary outcome: sleep efficiency, SE; sleep onset latency, SOL). RESULTS: Sleep improved significantly after the KiSS intervention. Three to 12 months after the intervention, only 1.75% of treated children still met the diagnostic criteria for insomnia. SE improved to 96%, and both SOL (reduced to 23 min) and total sleep time were normalized. All improvements were stable for at least one year after the intervention. KiSS was well accepted (0% dropout during intervention) and well tolerated. CONCLUSIONS: Treatment with the multimodal sleep training KiSS leads to positive changes in the sleep of children with insomnia, including a subset of children that presented with comorbid mental disorders. With only three sessions for parents and three sessions for children, the treatment can be readily implemented as a stand-alone treatment or be combined with other interventions. Dismantling studies and studies with an active control group are ongoing. PMID- 30482056 TI - Accessing Green Spaces Within a Healthcare Setting: A Mixed Studies Review of Barriers and Facilitators. AB - This review describes the facilitators and barriers impacting on passive access to green spaces within healthcare settings. A systematic mixed-studies review was undertaken to review the quantitative and qualitative evidence on access to green spaces within healthcare settings, as well as to review the methodological quality of the studies eligible for inclusion. A total of 24 articles met the inclusion criteria and were included in the review. The barriers to access were grouped into three themes: "awareness," "accessibility," and "comfort." The facilitators were grouped into 13 themes: "flora and foliage," "views," "water features," "sun, rain, fresh air, wind," "animal life," "diverse textures, heights, shapes," "lawn," "natural versus artificial material," "rest areas," "shade," "private areas," "play equipment," and "safety." These findings can be explained through multiple lenses, using existing theories on contact with nature and supportive garden design. In an era of elevated stress, patient admissions, and staff turnover in hospitals, and rising costs of providing healthcare services, the creation of settings conducive to health promotion, stress reduction, and faster recovery is relevant and timely. This article, which has collated over three decades of research evidence, is invaluable in addressing this issue. PMID- 30482057 TI - Advances with extended and controlled release formulations of antiepileptics in the elderly. AB - INTRODUCTION: As a matter of course, elderly people are more sensitive to both the pharmacological and toxicological effects of pharmacotherapy. A senior's treatment, therefore, requires more attention compared to younger adults. Extended release (ER) formulations of anti-epileptic drugs (AEDs) have been developed to improve safety, efficacy and long-term adherence. In senior patients, ER AEDs are used to treat epilepsy, psychiatric conditions, and neuropathic pain. However, very limited clinical evidence is available on the use of these ER AEDs in these populations. Areas covered: The authors of this paper have identified clinical studies of ER AED formulations used in elderly populations through literature searches looking, both, at their use in epileptic and non-epileptic indications. Additionally, immediate release (IR) and ER formulations of AEDs were compared whenever possible. Expert opinion: The broad use of ER AED formulations in elderly patients with swallowing problems is limited by the fact that ER AED tablets (or capsules) must not be cut, crushed or chewed. The only exception is the ER formulation of valproate or topiramate which can be mixed with soft food. Although, the ER formulations of AEDs seem better tolerated than the IR equivalents, a possibility of numerous interactions with drugs prescribed for other reasons must be carefully considered. PMID- 30482058 TI - Does Perceived Message Effectiveness Predict the Actual Effectiveness of Tobacco Education Messages? A Systematic Review and Meta-Analysis. AB - Target audience ratings of the likely impact of persuasive messages, known as perceived message effectiveness (PME), are commonly used in health communication campaigns. However, applications of PME rely on a critical assumption-that is, that PME is a valid indicator of the likely effectiveness of messages. To examine the evidence supporting this assumption, we conducted a systematic review and meta-analysis of longitudinal studies in the tobacco education campaigns literature. Six longitudinal studies examining the predictive validity of PME met inclusion criteria. Results indicated that PME ratings were significantly associated with the majority of outcomes studied. In fact, each of the six studies found PME to be associated with at least one outcome, and across the six studies, PME was associated with message recall, conversations about ads, beliefs about smoking and quitting smoking, quit intentions, and cessation behavior. Meta analyses demonstrated that PME predicted quit intentions (r = .256, p < .001) and cessation behavior (r = .201, p < .001), revealing effects that were small to medium in magnitude. Our results suggest that PME provides some predictive value as to the likely effectiveness of messages, although additional work using different validation designs, with other health behaviors, and among other populations is needed. PMID- 30482059 TI - Synthesis and biological evaluation of benzothiazin-4-ones: a possible new class of acetylcholinesterase inhibitors. AB - A series of nineteen benzothiazin-4-ones from N-(3-aminopropyl) piperidine, 4-(2 aminoethyl)morpholine or 1-(2-aminoethyl)piperidine, aliphatic or aromatic aldehyde and thiosalicylic acid, were synthesized in good yields by multicomponent one-pot reactions. The solvent was toluene and this efficient procedure afforded the desired heterocycles in 5 h. Identification and characterization were achieved by NMR and GC-MS techniques. In vitro AChE activities of all compounds were evaluated in cerebral cortex and hippocampus of rats and in general, the results in cortex were more promising than hippocampus. The benzothiazinone 5Bd showed the best AChE inhibition activity IC50 8.48 MUM (cortex) and IC50 39.80 MUM (hippocampus). The cytotoxicity of seven compounds in MCR-5 human fibroblast cell by SRB test in 24 h were evaluated and 5Bd suggest preliminary safety, showing no cytotoxicity at 100 uM. Finally, these important findings could be a starting point for the development of new AChE inhibitors agents and will provide the basis for new studies. PMID- 30482060 TI - Radiofrequency radiation at 2.856 GHz does not affect key cellular endpoints in neuron-like PC12 cells. AB - To investigate the potential cytotoxicity of radiofrequency (RF) radiation on central nervous system, rat pheochromocytoma (PC12) cells were exposed to 2.856 GHz RF radiation at a specific absorption rate (SAR) of 4 W/kg for 8 h a day for 2 days in 35 mm Petri dishes. During exposure, the real-time variation of the culture medium temperature was monitored in the first hour. Reactive oxygen species (ROS) production, intracellular Ca2+ concentration, and cell apoptosis rate were assessed immediately after exposure by flow cytometry. The results showed that the medium temperature raised about 0.93 degrees C, but no significant changes were observed in apoptosis, ROS levels or intracellular Ca2+ concentration after treatment. Although several studies suggested that RF radiation does indeed cause neurological effects, this study presented inconsistent results, indicating that 2.856 GHz RF radiation exposure at a SAR of 4 W/kg does not have a dramatic impact on PC12 cells, and suggests the need for further investigation on the key cellular endpoints of other nerve cells after exposure to RF radiation. PMID- 30482061 TI - An evaluation of pitavastatin for the treatment of hypercholesterolemia. AB - INTRODUCTION: Statins are the first line of therapy to reduce low-density lipoprotein cholesterol (LDL-C) in order to decrease cardiovascular events. Pitavastatin is the latest statin to be introduced to the market. Areas covered: In this article, the authors review the efficacy, safety, and tolerability of pitavastatin. The authors also review a recent cardiovascular outcome study. Expert opinion: Pitavastatin produces dose-dependent reductions in LDL-C at lower doses than other statins. The maximum approved dose of 4 mg reduces LDL-C by about 40-49% in different patient groups and is equivalent to atorvastatin 20 mg in this effect. Pitavastatin undergoes minimal metabolism so drug-drug interactions are less likely than with many other statins, but it can interact with some drugs that inhibit drug transporters. Compared with other statins, it has been associated with greater increases in high-density lipoprotein cholesterol and it was found to be less likely to cause new onset diabetes. In a recent study in Japanese patients with stable coronary artery disease, pitavastatin 4 mg was more effective than pitavastatin 1 mg in reducing cardiovascular events. Therefore, the highest dose may be preferred in high-risk patients. PMID- 30482063 TI - Emerging drugs for the treatment of Dravet syndrome. AB - INTRODUCTION: Dravet syndrome (DS) is an early-onset genetic developmental epileptic encephalopathy characterized by multiple seizure types which are refractory to antiseizure medication. There is an unmet need for effective and tolerable drugs to control different seizure types in DS types, with the aim of improving quality of life and preventing neurological impairment. Areas covered: Narrative review of efficacy and tolerability of fenfluramine, cannabidiol (CBD), verapamil and modulators of serotonin signaling pathways (lorcaserin or trazodone) in the treatment of DS. Expert Opinion/Commentary: A recent large randomized controlled-trial has shown that CBD is effective in the treatment of DS; preliminary data from the placebo-controlled trial on fenfluramine are also promising. Further studies are definitely required to evaluate the role of verapamil and modulators of serotonin signaling in DS. At present, drugs used to treat seizures in DS treat the symptoms of epilepsy rather than its cause(s). Future research should focus on elucidating the natural history of DS and whether appropriate treatment can have a beneficial impact on its disease course. A multidisciplinary, individualized approach to care of DS patients is required. PMID- 30482062 TI - Synthesis and biological assessment of KojoTacrines as new agents for Alzheimer's disease therapy. AB - In view of the multifactorial nature of Alzheimer's disease (AD), multitarget small molecules (MTSM) represent the most potent and attractive therapeutic strategy to design new drugs for Alzheimer's disease therapy. The new MTSM KojoTacrines (KTs) were designed and synthesized by juxtaposition of selected pharmacophoric motifs from kojic acid and tacrine. Among them, 11-amino-2 (hydroxymethyl)-12-(3-methoxyphenyl)-7,9,10,12-tetrahydropyrano [2',3':5,6] pyrano[2,3-b]quinolin-4(8H)-one (KT2d) was identified as less-hepatotoxic than tacrine, at higher concentration, a moderate, but selective human acetylcholinesterase inhibitor (IC50 = 4.52 +/- 0.24 uM), as well as an antioxidant agent (TE = 4.79) showing significant neuroprotection against Abeta1 40 at 3 uM and 10 uM concentrations. Consequently, KT2d is a potential new hit ligand for AD therapy for further biological exploration. PMID- 30482064 TI - Comparison of p63/p40 Expression With Myoepithelial Markers in Minor Salivary Gland Tumors. AB - The present study aimed to compare the expression of p63/p40 with smooth muscle actin (SMA) and vimentin (VIM) by myoepithelial cells in minor salivary gland tumors. Fifty-two formalin-fixed paraffin-embedded samples of minor salivary gland tumors derived from intercalated duct (pleomorphic adenoma [PA], adenoid cystic carcinoma [ACC], epithelial-myoepithelial carcinoma [EMC], polymorphous adenocarcinoma [PAC], and secretory carcinoma [SC]) and 3 samples of minor salivary gland tumors derived from excretory duct (mucoepidermoid carcinoma [MEC]) were evaluated by means of immunohistochemistry. The data were analyzed qualitatively. The results indicated that p63 and p40 expression were detected in myoepithelial cells present in PA, ACC, and EMC. However, both proteins were also observed in squamous areas of PA and all cases of MEC. SMA were noticed in some myoepithelial cells of PA, ACC, and EMC. Expression of SMA was negative in the other salivary gland tumors evaluated. VIM was constantly expressed by myoepithelial cells in PA, ACC, and EMC. VIM was also observed in cells of PAC and SC, but not in squamous areas of PA and MEC. In conclusion, p63 expression is almost comparable with VIM in detecting myoepithelial cells, an immunolabeling pattern not followed by p40, and consequently, caution has to be taken during the interpretation of salivary gland tumor exhibiting an p63/p40 phenotype in order to avoid a misdiagnosis. PMID- 30482065 TI - Aidi Injection, a Traditional Chinese Medicine Injection, Could Be Used as an Adjuvant Drug to Improve Quality of Life of Cancer Patients Receiving Chemotherapy: A Propensity Score Matching Analysis. AB - BACKGROUND: Clinical research has paid increasing attention to quality of life (QoL) in recent years, but the assessment of QoL is difficult, hampered by the subjectivity, complexity, and adherence of patients and physicians. According to previous studies, QoL in cancer patients is related to performance status (PS) and influenced by chemotherapy-related toxicity. Aidi injection, a traditional Chinese medicine injection, is used as an adjuvant drug to enhance effectiveness of chemotherapy. The study aims to investigate whether Aidi injection could improve QoL by improving PS and reducing toxicity caused by chemotherapy. METHODS: A retrospective cohort study was performed at the First Affiliated Hospital of Anhui Medicine University. Data of consecutive patients diagnosed with cancers between January 2014 and June 2017 were retrieved from the electronic medical record system. After a 1:1 propensity score match, patients were then divided into 2 groups based on the therapies used, that is, Aidi injection combined with chemotherapy and chemotherapy alone, and the PS, chemotherapy-related toxicity, and combined medication information were compared. The effect of different dosages of Aidi injection on patients was further explored. RESULTS: A total of 3200 patients were included in this study. Aidi injection combined with chemotherapy exhibited significantly benefit in PS ( P < .001, odds ratio [OR] 3.4, 95% confidence interval [CI] 2.4-4.8) compared with chemotherapy alone after adjusting for the factors that affect PS. The improvement rate of PS in the Aidi group was significantly higher than in the control group across the stratification of gender, age, tumor type, TNM stage, body mass index, nodal metastasis, prior chemotherapy, chemotherapy regimens, other Chinese tradition medicines, and chemotherapy cycle. Meanwhile, Aidi injection used synchronously with chemotherapeutic drugs could decrease the incident rate of damage to liver and kidney function, myelosuppression, and gastrointestinal reactions caused by chemotherapy. CONCLUSION: It was indicated that the integrative approach combining chemotherapy with Aidi injection, especially with the conventional dosage of Aidi injection, had significant benefit on QoL in cancer patients. PMID- 30482066 TI - Adipose tissue transplant in recurrent folliculitis decalvans. AB - Folliculitis decalvans is a rare clinical disorder classified as primary neutrophilic scarring alopecia with a slight preference for the male gender. Here, we report the use of autologous fat transplantation as a source of stem cell therapy for hair re-growth assisted by inflammatory action of the fat itself in a female patient. The patient underwent adipose transplantation in April and September 2017. After treatments, the patient had no new pustules and no longer had pain or burning sensation in the affected area. The hair has re-grown at the periphery area of alopecia appearing stronger and shinier. PMID- 30482067 TI - Fetal abdominal circumference in the second trimester and prediction of small for gestational age at birth. AB - BACKGROUND: Infants that are small for gestational age (SGA) at birth are at increased risk for morbidity and mortality. Unfortunately, the antenatal prediction of SGA is suboptimal. OBJECTIVES: We sought to: 1. examine the association between second trimester fetal abdominal circumference < 10% (2T AClag) with SGA and other gestational and neonatal adverse outcomes; 2. assess 2T AClag as a predictor of SGA. STUDY DESIGN: Retrospective study of 212 singleton gestations with 2T-AClag on routine ultrasound between 18-24 weeks. The study group was compared to 424 gestations without 2T-AClag for maternal characteristics as well as pregnancy and neonatal adverse outcomes. A multivariate logistic regression was used to determine the predictive value of 2T AClag for SGA, adjusting for maternal and pregnancy characteristics. The screening model accuracy was assessed through receiver operating characteristic (ROC) curves. Fetal growth restriction (FGR) was defined as an estimated fetal weight (EFW) less than the 10th percentile. RESULTS: Gestations with 2T-AClag had higher rates of SGA (35.7 versus 11.6%, p < 0.0001), FGR (17 versus 1.7%, p < 0.0001), pregnancy induced hypertension (31.1 versus 17%, p < 0.0001), preeclampsia (14.6 versus 7.8%, 0 = 0.01), abnormal umbilical artery Doppler (30 versus 5.1%, p < 0.0001), indicated preterm birth (5.7 versus 1.9%, p = 0.01), primary cesarean birth (29.6 versus 20.1%, p = 0.01) and NICU admission (12.9 versus 6.4%, p = 0.009). After adjusting for maternal and gestational risk factors, 2T-AClag remained an independent risk factor for SGA (OR 4.53, 95%CI 2.91-7.05, p < 0.0001) and FGR (OR 11.57, 95%CI 5.02-26.65, p < 0.0001). The inclusion of 2T-AClag in a regression model with traditional risk factors, significantly improved the model's predictability for SGA and FGR (area under ROC curve increased from 0.618 to 0.723 and 0.653-0.819, respectively, p < 0.0001). CONCLUSIONS: Second trimester abdominal circumference (AC) lag is associated with an increased risk of SGA, FGR and other adverse outcomes. The inclusion of 2T AClag in a screening model for prediction of SGA and FGR may improve the identification of this at-risk group and assist in customizing surveillance plans. PMID- 30482068 TI - Comparison of statistical analysis methods for object case best-worst scaling. AB - AIMS: Different methods have been used to analyse 'object case' best-worst scaling (BWS). This study aims to compare the most common statistical analysis methods for object case BWS (i.e. the count analysis, multinomial logit, mixed logit, latent class analysis and hierarchical Bayes estimation) and to analyse their potential advantages and limitations based on an applied example. METHODS: Data were analysed using the five analysis methods. Ranking results were compared among the methods, and methods that take respondent heterogeneity into account were presented specifically. A BWS object case survey with 22 factors was used as a case study, tested among 136 policy makers and HTA experts from the Netherlands, Germany, France, and the United Kingdom to assess the most important barriers to HTA usage. RESULTS: Overall, the five statistical methods yielded similar rankings, particularly in the extreme ends. Latent class analysis identified five clusters and the mixed logit model revealed significant preference heterogeneity for all, with the exception of three factors. LIMITATIONS: The variety of software used to analyse BWS data may affect the results. Moreover, this study focuses solely on the comparison of different analysis methods for the BWS object case. CONCLUSIONS: The most common statistical methods provide similar rankings of the factors. Therefore, for main preference elicitation, count analysis may be considered as a valid and simple first-choice approach. However, the latent class and mixed logit models reveal additional information: identifying latent segments and/or recognizing respondent heterogeneity. PMID- 30482069 TI - Proteomic approaches for cancer epigenetics research. AB - INTRODUCTION: Epigenetic dysregulation drives or supports numerous human cancers. The chromatin landscape in cancer cells is often marked by abnormal histone post translational modification (PTM) patterns and by aberrant assembly and recruitment of protein complexes to specific genomic loci. Mass spectrometry based proteomic analyses can support the discovery and characterization of both phenomena. Areas covered: We broadly divide this literature into two parts: 'modification-centric' analyses that link histone PTMs to cancer biology; and 'complex-centric' analyses that examine protein-protein interactions that occur de novo as a result of oncogenic mutations. We also discuss proteomic studies of oncohistones. We highlight relevant examples, discuss limitations, and speculate about forthcoming innovations regarding each application. Expert commentary: 'Modification-centric' analyses have been used to further understanding of cancer's histone code and to identify associated therapeutic vulnerabilities. 'Complex-centric' analyses have likewise revealed insights into mechanisms of oncogenesis and suggested potential therapeutic targets, particularly in MLL associated leukemia. Proteomic experiments have also supported some of the pioneering studies of oncohistone-mediated tumorigenesis. Additional applications of proteomics that may benefit cancer epigenetics research include middle-down and top-down histone PTM analysis, chromatin reader profiling, and genomic locus specific protein identification. In the coming years, proteomic approaches will remain powerful ways to interrogate the biology of cancer. PMID- 30482070 TI - Treatment goals in psoriasis from a patient perspective: a qualitative study. AB - BACKGROUND: Psoriasis is a chronic inflammatory skin disorder with marked impact on quality of life. In view of the well-recognized need to integrate the patient perspective in psoriasis care, treatment goals which originate entirely from the experiences of the patients are of utmost importance. OBJECTIVE: To explore treatment goals in patients with psoriasis that originate entirely from the patient perspective. METHODS: Data was generated using face-to-face in-depth interviews with 15 Dutch psoriasis patients, which were analysed using template analysis resulting in 2 first-level, 10 second-level and 14 third-level themes. RESULTS: A wide variety of treatment goals was reported. Almost all patients reported their 'ultimate' treatment goal would be achieving total skin clearance. Barriers in achieving treatment goals included the fact that psoriasis is a chronic disease with no cure available, lack of effectiveness of current treatment options and side effects of treatments of which the treatment effect does not compensate. CONCLUSION: There is a great variety and inter-individual difference in treatment goals. Therefore, we recommend to define individualized patient-defined treatment goals, as every patient with psoriasis requires a tailor made treatment program. PMID- 30482071 TI - Multiple Myeloma 1 Transcription Factor Is Superior to CD138 as a Marker of Plasma Cells in Endometrium. AB - Chronic endometritis is characterized by plasma cell (PC) infiltration of endometrial stroma. Identification of PCs can be challenging by routine hematoxylin and eosin (H&E) stain due to the low numbers of PCs or to their being obscured by other cells in the stroma. CD138 is widely used as an ancillary immunohistochemistry stain to identify PCs; however, it has a high background reaction. In this study, multiple myeloma 1 (MUM1) transcription factor is introduced as an alternative PC marker in endometrial tissues. In this study, 311 endometrial biopsies, submitted to rule out chronic endometritis, were selected. They were divided into Group I (n = 87) and Group II (n = 224). Both had MUM1 and H&E while Group I also had accompanying CD138 stains. In both groups combined, MUM1 detected plasma cells in 48% of the cases, while CD138 and H&E identified the cells in 23% and 15% of the biopsies, respectively. In addition to having a clean background, MUM1 is a more sensitive stain than CD138 for detection of PCs in endometrium. PMID- 30482072 TI - Getting on the Nerves: A Case of Perineural Invasion by Mammary Ductal Carcinoma In Situ. PMID- 30482073 TI - Adenoid Cystic Carcinoma With Sialolithiasis of the Left Submandibular Gland: A Case Report and Literature Review. AB - Adenoid cystic carcinoma is one of the most common salivary gland malignancies with poor long-term prognosis, but the coexistence of sialoliths is extraordinarily rare. In this article, we report a case of 30-year-old woman with a history of submandibular area swelling with intermittent pain increasing during mealtimes that had led her attending physician to diagnose a sialolith in the left submandibular gland on a radiograph 10 years before. However, the surgical specimen proved to be an adenoid cystic carcinoma accompanied with a sialolith. Histopathologically, the submandibular gland was displaced with a fibrous granulation tissue containing a small cribriform carcinoma invading the extracapsular region of the gland. We performed fluorescence in situ hybridization examination with an MYB-NFIB fusion probe of the lesion, with positive results. The patient underwent a supraomohyoid neck dissection as additional procedure because of the possibility of the extracapsular cancer nest remaining around the submandibular gland, but she remains well and disease free 11 years after the first operation. PMID- 30482074 TI - The biochemistry of early meiotic recombination intermediates. AB - Meiosis is the basis for sexual reproduction and is marked by the sequential reduction of chromosome number during successive cell cycles, resulting in four haploid gametes. A central component of the meiotic program is the formation and repair of programmed double strand breaks. Recombination-driven repair of these meiotic breaks differs from recombination during mitosis in that meiotic breaks are preferentially repaired using the homologous chromosomes in a process known as homolog bias. Homolog bias allows for physical interactions between homologous chromosomes that are required for proper chromosome segregation, and the formation of crossover products ensuring genetic diversity in progeny. An important aspect of meiosis in the differential regulation of the two eukaryotic RecA homologs, Rad51 and Dmc1. In this review we will discuss the relationship between biological programs designed to regulate recombinase function. PMID- 30482075 TI - Clinical predictors of inadequate response to conventional synthetic disease modifying antirheumatic drugs (csDMARDs) including methotrexate (MTX) in untreated rheumatoid arthritis patients -A single-center observational study. AB - OBJECTIVES: To investigate predictors of inadequate response to first conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) including methotrexate (MTX) in untreated rheumatoid arthritis (RA) patients in daily clinical practice. METHODS: Inadequate response to MTX or other csDMARDs was defined as being not low disease activity at 12 months in more than 3 of 4 composite measures, and discontinuation or start of biologic DMARDs. The association between baseline factors and csDMARDs-IR was assessed by univariate and multivariate logistic regression analyses. RESULTS: 411 and 146 patients were started on MTX and other csDMARDs, respectively; 218 patients were responsive to MTX, with a response rate of 47.0%. Tender joint count (TJC, >=6 in 28joints, odds ratio [OR] = 1.67, 95% confidence interval [CI] 1.06 - 2.64) and CRP (>=1.0mg/dL, OR =1.72, 95%CI 1.10 - 2.70) at baseline were identified as predictors on multivariate logistic regression analysis. TJC (OR =3.60, 95%CI 1.29 - 10.00) was the factor identified as a predictor of the development of other csDMARDs-IR. CONCLUSIONS: In this observational study, patients with untreated RA at risk of inadequate response to MTX included those with a higher TJC and higher CRP, while a higher TJC was the only independent predictor of an inadequate response to csDMARDs other than MTX. PMID- 30482077 TI - Emergency medical services provider perspectives on pediatric calls: A qualitative study. AB - OBJECTIVE: Previous research indicates that 9-1-1 response to incidents involving children is particularly distressing for emergency medical services (EMS) clinicians. This qualitative study was conducted to increase understanding about the difficulties of responding to pediatric calls and to obtain information about how organizations can better support EMS providers in managing potentially difficult calls. METHODS: Paramedics and emergency medical technicians from a single US ambulance service were invited to participate in focus groups about responding to 9-1-1 calls involving pediatric patients. A total of 17 providers from both rural and metro service regions participated in six focus groups held in community meeting spaces. A semi-structured focus group guide was used to explore (1) elements that make pediatric calls difficult, (2) pre-arrival preparation practices, (3) experiences with coping after difficult pediatric calls, and (4) perspectives about offered and desired resources or support. Focus groups were audio recorded and transcripts were analyzed using standard coding, memoing, and content analysis methods in qualitative analysis software (NVivo). RESULTS: Responses about elements that make pediatric calls difficult were organized into the following themes: (1) special social value of children, (2) clinical difficulties with pediatric patients, (3) added acuity to already challenging calls, (4) caregivers as secondary patient, and (5) identifying with patient or patient's family. Pre-arrival preparation methods included mental or verbal review of hypothetical scenarios and refocusing nerves or emotions back to the technical aspect of the job. Participants described using available resources that largely took the form of social support. Suggestions for additional resources included: increased opportunities for external feedback; more frequent pediatric clinical training; institutionalization of recovery time after difficult calls; and improved storage and labeling of pediatric equipment. CONCLUSIONS: This study provides qualitative data about the difficulties of responding to pediatric calls and resources needed to support clinicians. Findings from this study can be used to guide EMS leaders in designing and implementing institutional initiatives to enhance training and support for prehospital clinicians providing care to children. PMID- 30482076 TI - The association between neck and shoulder discomfort-Katakori-and high somatizing tendency. AB - OBJECTIVES: "Katakori", discomfort or dull pain around the neck and shoulder, is common in Japan. Somatizing tendency is important in the quality of daily living. This study aimed to examine the association between disability due to Katakori and high somatizing tendency. METHODS: This internet study included 35,754 Japanese adults who reported Katakori in the past four weeks. Katakori was classified into four grades: 1) no Katakori, 2) Katakori without difficulty in activities for daily living (ADL), 3) Katakori with ADL difficulty but without absence from social activities, and 4) Katakori with absence from social activities. Somatizing tendency was assessed using the Somatic Symptom Scale-8 (SSS-8). The association between a very high (SSS-8 >= 16) somatizing tendency and Katakori grade was examined using logistic regression adjusting for age, sex, body mass index, marital status, smoking, regular exercise, low back pain, depression, and the number of chronic conditions. RESULTS: Katakori grade was significantly associated with a very high somatizing tendency (Odds ratio (OR)= 5.36 [4.36-6.60] in grade 4 vs. 2, and OR= 2.57 [2.30-2.89] in grade 3 vs. 2). CONCLUSIONS: When treating severe Katakori with disability, somatizing tendency should be assessed to facilitate better management. PMID- 30482078 TI - Diffuse Large B-Cell Lymphoma With Clear Cell Morphology. PMID- 30482079 TI - Healthy Lifestyle During the Midlife Is Prospectively Associated With Less Subclinical Carotid Atherosclerosis: The Study of Women's Health Across the Nation. AB - Background Measures of subclinical atherosclerosis are predictors of future cardiovascular outcomes as well as of physical and cognitive functioning. The menopausal transition is associated with accelerated progression of atherosclerosis in women. The prospective association between a healthy lifestyle during the midlife and subclinical atherosclerosis is unclear. Methods and Results Self-reported data on smoking, diet, and physical activity from 1143 women in the Study of Women's Health Across the Nation were used to construct a 10-year average Healthy Lifestyle Score ( HLS ) during the midlife. Markers of subclinical atherosclerosis were measured 14 years after baseline and included common carotid artery intima-media thickness ( CCA - IMT ), adventitial diameter ( CCA - AD ), and carotid plaque. The associations of average HLS with CCA - IMT and CCA - AD were estimated using linear models; the association of average HLS with carotid plaque was estimated using cumulative logit models. Average HLS was associated with smaller CCA - IMT and CCA - AD in the fully adjusted models ( P=0.0031 and <0.001, respectively). Compared with participants in the lowest HLS level, those in the highest level had 0.024 mm smaller CCA - IMT (95% confidence interval: -0.048, 0.000), which equals 17% of the SD of CCA - IMT , and 0.16 mm smaller CCA - AD (95% confidence interval: -0.27, -0.04), which equals 24% of the SD of CCA - AD . Among the 3 components of the HLS , abstinence from smoking had the strongest association with subclinical atherosclerosis. Conclusions Healthy lifestyle during the menopausal transition is associated with less subclinical atherosclerosis, highlighting the growing recognition that the midlife is a critical window for cardiovascular prevention in women. PMID- 30482080 TI - Eyelash hair transplantation with strip composite eyebrow graft: an enhancing technique in tarsoconjunctival flap eyelid reconstruction procedure. AB - PURPOSE: To describe and evaluate the eyelash transplantation with strip composite eyebrow graft to improve eyelid anatomy in tarsoconjunctival flap eyelid reconstruction procedure. METHODS: Twenty two patients with eyelid tumors managed by local excision and reconstruction using tarsoconjunctival flap reconstruction procedure were included. Eyelash graft was performed during flap division by harvesting a graft from the eyebrow and creating a recipient pocket in the receptor eyelid. Patients had a 1-year follow up. Eyelash orientation and follicle survival rate were recorded. Demographic variables were analyzed with descriptive statistics. For eyelash follicles survival rate assessment, we evaluated the number of follicles found in the first postoperative day with the follicles found at the end of the study using the Wilcoxon signed rank test. P < 0.05 was considered statistically significant. RESULTS: All eyelash grafts showed a good follicle orientation and no cases of eyelashes misdirection toward the eyeball were reported. No statistical differences (p > 0.05) were found in Wilcoxon signed rank test when comparing the number of follicles present at the first postoperative day and the number of follicles present at the 12th postoperative month, meaning that the vast majority of follicles survived at the end of the study. Graft ischemia, necrosis or infection were not observed. CONCLUSIONS: Tarsoconjunctival flap is an outstanding option for eyelid reconstruction and eyelash transplantation with an eyebrow composite graft is an excellent procedure to enhance and recreate a normal eyelid. PMID- 30482081 TI - Devices to Reduce the Volume of Blood Taken for Laboratory Testing in ICU Patients: A Systematic Review. AB - BACKGROUND:: Intensive care unit (ICU) patients are at high risk of anemia, which is associated with adverse clinical outcomes and death. Blood sampling for diagnostic testing is a potentially modifiable contributor to anemia. METHODS:: We conducted a systematic review by searching MEDLINE and EMBASE from inception to October 5, 2017, for studies reporting the volume of blood taken for laboratory testing using blood sampling conservation devices compared to standard care or another intervention in adult ICU patients. RESULTS:: We identified 8 eligible studies (n = 1204 patients) that used 2 types of devices: arterial access devices (n = 5) and reduced-volume blood collection tubes (n = 3). All studies reported a reduction in the volume of blood taken for laboratory testing with devices compared to standard practice (range 19%-80%). The studies were judged to have serious risk of bias, and due to heterogeneity, pooling for meta analysis was not considered appropriate. CONCLUSIONS:: Devices used to reduce the volume of blood taken for laboratory testing in ICU patients appear to be effective, although study heterogeneity limited our ability to calculate pooled estimates of efficacy for each device. Further assessment of clinical outcomes may establish clinical benefit with minimal negative consequences for hospitals and laboratories to facilitate the use of small-volume tubes. PMID- 30482082 TI - Individual differences in apology acceptance and forgiveness: the influence of handedness. AB - The purpose of the current study was to determine if the relationship between interhemispheric interaction and cognitive flexibility extends to explanations of forgiveness and apology acceptance. A growing body of research indicates that consistency of handedness may be reflective of an individual's degree of interhemispheric interaction and access to processes of the right hemisphere. As such, individual differences in processing that require interhemispheric interaction, such as belief updating, are associated with consistency of handedness. Participants completed the Edinburgh Handedness Inventory (EHI) and read descriptions of interpersonal transgressions, then rated their willingness to forgive before and after an apology was offered. There was a main effect such that the presence of apology increased forgiveness. However, inconsistent handedness was associated with greater forgiveness prior to apology compared to consistent handedness. A second study was conducted to determine if the individual differences in forgiveness were mediated by different dimensions of empathy (personal distress, perspective taking, empathic concern and fantasy). Participants completed the Interpersonal Reactivity Index, the Forgiveness Scale and the EHI. Results revealed those with inconsistent handedness who scored lower on personal distress reported decreased negative thoughts about transgressors compared to those with consistent handedness. PMID- 30482083 TI - S-phase Cancer Associated lncRNAs. AB - Comment on: Ali MM, et al. Nature Communications 2018; 9:883. PMID- 30482084 TI - Development of a simvastatin loaded injectable porous scaffold in situ formed by phase inversion method for bone tissue regeneration. AB - INTRODUCTION:: The use of injectable scaffolds as a minimally invasive method is a good choice in tissue engineering applications. A critical parameter for the tissue engineering scaffolds is a suitable morphology with interconnected pores. We present the development of a simvastatin loaded scaffold that forms in situ and provides the porous structure with interconnected pores. METHODS:: The formulation of these scaffolds includes a polymeric solution of poly lactic-co glycolic acid (25 wt%) in N-methyl-2-pyrrolidone containing 6 wt% deionized water and porogen (mannitol, four times the weight of the polymer). We have grafted simvastatin to poly lactic-co-glycolic acid by the esterification reactions. Simvastatin or simvastatin-grafted poly lactic-co-glycolic acid in different levels was added to polymer solution and finally the solution was injected into phosphate buffered saline. The simvastatin-grafted poly lactic-co-glycolic acid was characterized by attenuated total reflection Fourier-transform infra-red and 1H-nuclear magnetic resonance spectroscopy. The morphology, porosity, and biocompatibility of the scaffolds were evaluated. The in vitro simvastatin release from the various formulations was studied. Osteogenic differentiation of the adipose-derived stem cells was investigated using alkaline phosphatase activity assay and cell mineralization was evaluated using Alizarin red staining. RESULTS:: The morphology results showed the resultant scaffold was porous with the interconnected pores. The scaffolds presented 91% porosity. Non-toxic doses of simvastatin in the scaffolds were determined by methyl-thiazolyl diphenyl tetrazolium bromide assay. The released simvastatin from the scaffolds continues over 80 days. Alkaline phosphatase activity and Alizarin red results indicated that cell osteogenic differentiation is promoted. CONCLUSION:: The results demonstrated that release of simvastatin from the injectable scaffolds can have positive effects on osteogenic differentiation of the adipose-derived stem cells. PMID- 30482085 TI - Struggling and Overcoming Daily Life Barriers Among Children With Congenital Heart Disease and Their Parents in the West Bank, Palestine. AB - Advances in early diagnosis, treatment, and postoperative care have resulted in increased survival rates among children with congenital heart disease (CHD). Research focus has shifted from survival to long-term follow-up, well-being, daily life experiences, and psychosocial consequences. This study explored the everyday experiences of children with CHD and of their parents living in the Palestinian West Bank. Interviews with nine children aged 8 to 18 years with CHD and nine parents were analyzed using content analysis. The overall theme that emerged was facing and managing challenges, consisting of four themes: sociocultural burden and finding comfort, physical and external limitations, self perception and concerns about not standing out, and limitations in access to health care due to the political situation. To provide optimum care for children with CHD and their parents, health care providers and policy makers must understand the negative consequences associated with sociocultural conditions and beliefs about chronic illness. PMID- 30482086 TI - Health-Care Workers' Perception of Patients' Suicide Intention and Factors Leading to It: A Qualitative Study. AB - This study explored health-care workers' perception of patients' suicide intention and their understanding of factors leading to particular interpretations. Semistructured face-to-face in-depth interviews were conducted with 32 health-care workers from a general hospital in Klang Valley, Malaysia. Interview data were transcribed verbatim and analyzed using the interpretative phenomenological analysis. The health-care workers were found to have four types of perceptions: to end life, not to end life, ambivalence about intention, and an evolving understanding of intention. Factors leading to their perceptions of patients' suicide intention were patient demographics, health status, severity of ideation/attempt, suicide method, history of treatment, moral character, communication of suicide intention, affective/cognitive status, availability of social support, and health-care workers' limited knowledge of patients' condition/situation. Insufficient knowledge and negative attitudes toward suicidal patients led to risk minimization and empathic failure, although most health-care workers used the correct parameters in determining suicide intention. PMID- 30482087 TI - Effect of three opioid-based analgesic protocols on the perioperative autonomic mediated cardiovascular response in sheep. AB - Few reports evaluate the clinical effects of opioids in sheep during experimental surgical procedures. Catecholamine-mediated haemodynamic changes resulting from surgical noxious stimulation are blunted by opioids. The aim of this study was to evaluate the efficacy of three opioid-based analgesic protocols in avoiding a 20% increase in heart rate (HR) and/or mean arterial blood pressure (MAP) during experimental intervertebral disk nucleotomy in sheep. Eighteen female Brogna sheep were anaesthetized with propofol and maintained with a fixed end-tidal isoflurane concentration of 1.5 +/- 0.1%. Sheep were assigned to one of three groups that intravenously received methadone 0.3 mg/kg (group M), fentanyl 2 ug/kg followed by 10 ug/kg/h (group F), or buprenorphine 10 ug/kg and 30 minutes later ketamine 1 mg/kg followed by 5 mg/kg/h (group BK). Intravenous fentanyl at 2 ug/kg would have been used for rescue analgesia in case HR and/or MAP had increased. During surgery, HR and MAP values did not increase over 20% in all groups. All animals maintained the percentage change between -4 and 7% for both variables; only one sheep in group BK had an increase in MAP superior to 20% after ketamine administration before surgical stimulation. In group M, HR decreased over time and in group BK, MAP tended to increase during surgery. All the opioid-based protocols tested were able to control the cardiovascular response to noxious stimulation in sheep undergoing spinal surgery, although ketamine may have represented a confounding factor. PMID- 30482088 TI - Reliability of behavioral tests in the middle cerebral artery occlusion model of rat. AB - Stroke is one of the leading causes of death and disability worldwide, and its incidence is increasing. To overcome impairment from stroke, translational research for developing new therapeutic technologies has been conducted and middle cerebral artery occlusion (MCAo) in rat is the representative model. Since recovery from neurological impairment in contralateral limbs caused by brain damage is the major goal of treatment, behavioral tests that assess the relevant function are used. To determine therapeutic effect, obtaining reliable results of behavioral assessment is a prerequisite. However, studies on the reliability of behavioral tests in the MCAo rat model and necessity of prior training have not yet been reported. In this study, the authors investigate relative and absolute inter-rater reliabilities of modified neurological severity score (mNSS), cylinder test, and grid-walking test before training and repeated training every week until the reliability of results reached a satisfactory level. The training included repeated learning of the scoring system and decreasing disagreements among the raters. For MCAo modeling, adult male Sprague-Dawley rats were subjected to 90 min of transient MCAo. Six raters conducted behavioral tests via observation of video-recording on sham-operated and MCAo model rats at 3 or 7 days after the intervention. An independent experimenter randomly numbered each video clip to blind the experiment. The results of reliabilities were unacceptable before training and improved to a satisfactory level after 6 weeks of training in all of the tests. In conclusion, mNSS, cylinder test, and grid walking test on the MCAo rat model are reliable evaluation methods after conducting appropriate training. PMID- 30482089 TI - A pilot study on the impact of a pottery workshop on the well-being of people with dementia. AB - OBJECTIVE: This study seeks to assess the impact of a pottery workshop as a creative arts programme and discover the extent to which people with dementia taking part in an artistic and creative activity engage with it, experience a feeling of well-being, and improve their mood state. In addition, the study will seek to answer the question of whether taking part in a programme of creative activities improves the self-esteem of people with dementia. METHOD: The research used an uncontrolled, repeated measures design. Thirty users of the National Reference Centre for Alzheimer's and Dementia care in Salamanca (Spain) in a moderate to advanced stage of dementia (Global Deterioration Scale 4, 5, or 6) were divided into five intervention groups that received ten 45-minute sessions in which they were helped by facilitators to make different ceramic pieces. The participants were assessed before and after the intervention with a self-esteem scale, and they rated their mood before and after the sessions on a graphic scale. During the art sessions, two observers recorded the presence of multiple indicators of well-being. RESULTS: The intervention was found to have a significant impact on mood and self-esteem that was independent of the participants' Global Deterioration Scale. Regarding the tool used to observe well being, the participants scored highly in the domains of sustained attention, pleasure, self-esteem, and normalcy, with low scores in negative affect and sadness. CONCLUSIONS: Pottery may be a highly suitable activity for people with dementia, as they may enjoy both the activity and the creative process, with it triggering a positive mood during the sessions, providing psychological well being and reinforcing their self-esteem. PMID- 30482090 TI - Facilitators and barriers to optimizing eating performance among cognitively impaired older adults: A qualitative study of nursing assistants' perspectives. AB - BACKGROUND AND OBJECTIVES: Cognitively impaired individuals are at increased risk for functional and behavioral difficulties at mealtimes, leading to compromised eating performance, low food and fluid intake, and negative functional and nutritional outcomes. Nursing assistants are the most critical front-line care staff and best positioned to manage the personal and environmental factors that influence resident eating performance. Identifying nursing assistants' perceptions of barriers and facilitators to engaging residents in eating will provide important experientially based foundation for developing and testing evidence-driven interventions to promote mealtime care. METHODS: A qualitative descriptive study was conducted in three sites: two nursing homes and one hospital gero-psychiatric inpatient unit. Six focus groups were conducted with a purposive sample of 23 nursing assistants who regularly provided mealtime care to residents with cognitive impairment. Interview questions addressed barriers and facilitators at resident, caregiver, environmental (facility), and policy levels in optimizing mealtime care. Audio recordings of focus groups were transcribed and analyzed using qualitative descriptive content analysis. Both barriers and facilitators were organized into a hierarchical taxonomy based on similarities and differences framed by the Social Ecological Model. RESULTS: The majority of barriers and facilitators were at the caregiver level. Caregiver-level barriers included lack of preparation and training, competing work demands, time pressure, and frustration. Caregiver-level facilitators included caregiver preparation and motivational, technical, informational, and instrumental assistance. Environmental-level barriers and facilitators related to the physical, social, and cultural environment and facility practices. Only barriers to optimizing mealtime care were identified at resident and policy levels. CONCLUSIONS: Nursing assistants identified multilevel barriers as well as a wide range of caregiver and environmental facilitators to optimizing dementia mealtime care. Findings can inform the development and implementation of multifaceted innovative mealtime assistance and staff training programs to promote resident eating performance while fostering person-centered individualized mealtime care practice. PMID- 30482091 TI - The perceived and observed needs of patients with dementia admitted to acute medical wards. AB - It is acknowledged that the needs of persons living with dementia admitted in acute hospitals are not always met. Previous studies have focused on the perceived needs of professional caregivers or family members whilst the voices of patients with dementia in acute hospitals have not been extensively reported. This may have contributed to the under-recognition of the needs of persons living with dementia. The aim of this study was to categorise the perceived and observed needs of persons with dementia admitted in acute medical wards and to explore whether these needs are being or have been met. Thirteen people with dementia in three medical wards, who could verbally communicate with the researcher, were purposively selected as research participants. Semi-structured interviews were conducted to elicit each participant's experiences of their hospital stay and whether their needs were perceived to have been/are being met. Moreover, routine care with the same participants was observed using Dementia Care Mapping. Maslow's Hierarchy of Needs was used as a framework to categorise care needs. Our findings demonstrate that basic needs such as toileting, feeding, drinking, continence and comfort were not always met. Moreover, the largest gap between met and unmet needs was found in patients who were either under constant observation or unable to communicate. Too much emphasis was perceived and observed to be given on what staff considered as safety needs at the expense of other needs. The patients' need for social contact and self-esteem such as dignity and respect were often ignored and this led to patients feeling devalued. Hospital staff have to be more aware of the holistic needs of patients with dementia in acute settings and the way care is delivered in order to make up for these unmet needs, thus facilitating person-centred care. PMID- 30482092 TI - Screening for cognitive dysfunction in systemic lupus erythematosus: the Montreal Cognitive Assessment Questionnaire and the Informant Questionnaire on Cognitive Decline in the Elderly. AB - BACKGROUND: Cognitive dysfunction (CD) is among the most common neuropsychiatric manifestations of systemic lupus erythematosus (SLE). Traditional neuropsychological testing and the Automated Neuropsychologic Assessment Metrics (ANAM) have been used to assess CD but neither is an ideal screening test. The Montreal Cognitive Assessment Questionnaire (MoCA) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) are brief and inexpensive tests. This study evaluated the MoCA and IQCODE as screening tools. METHODS: SLE patients fulfilling American College of Rheumatology (ACR) classification criteria were evaluated using the ANAM as the reference standard. The performance characteristics of the MoCA and IQCODE were assessed in comparison with normal controls (NCs) and rheumatoid arthritis (RA) patients. Four different definitions of CD were utilized. RESULTS: In total, 78 patients were evaluated. MoCA and ANAM scores were significantly correlated ( r = 0.51, p < 0.001). At the optimal cutoff, the sensitivity of the MoCA was >= 90% (depending on definition of CD) vs RA patients and >=83% vs NCs. ANAM and IQCODE scores did not correlate ( p = 0.8152). IQCODE sensitivities were low for both RA patients and NCs regardless of definition and cutoff used. CONCLUSION: The MoCA appears to be a promising and practical screening tool for identification of patients with SLE at risk for CD. PMID- 30482094 TI - Appointment of a new Deputy Executive Editor-in-Chief. PMID- 30482093 TI - Relationships among organ damage, social support, and depression in African American women with systemic lupus erythematosus. AB - OBJECTIVES: Systemic lupus erythematosus (SLE) disproportionately strikes African American women. Social support can potentially reduce disease impact. The purpose of this study is to understand the relationship between organ damage and depression in African American women and how social support influences this relationship. METHODS: We used a mixed methods design, analyzing self-reported data on lupus-related organ damage, depression, and social support in 437 African American women with SLE recruited in the Georgians Organized Against Lupus (GOAL) cohort. Moreover, we conducted interviews among 15 GOAL participants to gather patients' perspectives about the role of social support in people who live with lupus. RESULTS: We found a significant association between organ damage and depression ( r = 0.163, p = 0.001), as well as between depression and social support ( F = 17.574, p < 0.001). The quantitative analysis did not render social support as a significant moderator in the organ damage-depression relationship. Interviews, however, revealed that African American women with the most severe organ damage have the greatest need for support. CONCLUSIONS: Social support is a key resource for lupus patients with high disease burden. Overall, these findings highlight the importance of monitoring depressive symptoms in this population and developing interventions aimed to increase social support available to lupus patients. PMID- 30482096 TI - Are There Sufficient Number of Exercise Therapists in South Africa In Order To Equitably Manage the Noncommunicable Disease Epidemic? AB - The mortality of South African noncommunicable diseases (NCDs) is rising. One of its primary contributors is physical inactivity. Therefore, South African National Health Plan included exercise therapy as part of their strategy to inhibit the NCDs upsurge. This study aimed to determine whether the number of South African exercise therapists is sufficient to equitably manage this NCD epidemic. The 2013 and 2017 Health Professions Council of South Africa reports identified the number of physiotherapists, biokineticists, and their respective students-in-training. In 2012, 10,623,820 people were identified with NCDs; however, South African Department of Health only treated 6,058,186 patients (57.0%) ( p < .05). South African Health Review has estimated a 28.7% increase in the number of NCDs patients treated from 2012 (6,058,186) to 2025 (7,799,770) ( p < .05). The average yearly growth of practicing physiotherapists (3.4%) and the physiotherapy student-in-training (2.2%) is inequitable to manage this NCD epidemic. In 2012, the extrapolated physiotherapist-to-NCD patient ratio was 1:5667. The South African Department of Health should consider including biokineticists to aid in the management of the NCD epidemic. PMID- 30482098 TI - Spontaneous Arteriovenous Fistula of the Middle Deep Temporal Artery. PMID- 30482097 TI - SLC25A22 Promotes Proliferation and Metastasis of Osteosarcoma Cells via the PTEN Signaling Pathway. AB - Osteosarcoma is a highly malignant bone tumor. However, due to the high complexity of the occurrence and metastasis of osteosarcoma, the exact mechanism promoting its development and progression remains to be elucidated. This study highlights the causal link between solute carrier family 25 member 22 (SLC25A22) and the development, progression, and metastasis of osteosarcoma. SLC25A22 is upregulated in human osteosarcoma and predicts a poor prognosis. The upregulation of SLC25A22 in osteosarcoma tissues was significantly associated with cell proliferation, invasion, and metastasis. Studies of functional gain (overexpression) and loss (knockdown) showed that SLC25A22 significantly increases the ability of osteosarcoma cells to proliferate, as well as invade and metastasize in vitro. At the same time, the expression of SLC25A22 promoted the progression of the cellcycle of osteosarcoma cell lines and inhibited the apoptosis of osteosarcoma cells. Analysis using a mouse xenograft model showed that xenografts of SLC25A22 stable overexpressing osteosarcoma cells had a significant increase in tumor volume and weight compared to the control group. Lung metastasis models in mice showed that expression of SLC25A22 promoted lung metastasis of osteosarcoma in vivo. Furthermore, SLC25A22 inhibited phosphatase and tensin homolog expression and increased phosphorylation of protein kinase b (Akt) and Focal Adhesion Kinase (FAK) in the phosphatase and tensin homolog signaling pathway. In summary, SLC25A22 is highly expressed in osteosarcoma, promoting osteosarcoma cell proliferation and invasion by inhibiting the phosphatase and tensin homolog signaling pathway. PMID- 30482099 TI - Secondary syphilis presenting as erythema multiforme in a HIV-positive homosexual man: a case report and literature review. AB - Early syphilis can rarely cause erythema multiforme-type eruptions as well as triggering erythema multiforme (EM). EM-like lesions in secondary syphilis are characterized by clinical features of EM and laboratory tests consistent with secondary syphilis and the skin histology shows predominantly a plasma cell infiltrate with the presence of treponemes. When EM is triggered by early syphilis, the skin histology shows mixed inflammatory cells usually in the absence of treponemes in the skin lesion. There may also be mixed histology with the presence of treponemes in the absence of a plasma cell infiltrate and vice versa. We describe a case of secondary syphilis presenting as EM with bullae and histology showing EM features without a plasma cell infiltrate but positive for Treponema pallidum by immunohistochemical staining. The patient was also coinfected with cytomegalovirus, human immunodeficiency virus, and anal warts. The EM eruptions resolved with treatment for secondary syphilis with benzathine penicillin G. PMID- 30482100 TI - Assessing the perceived benefits of a new condom wrapper/integrated applicator: an exploratory study. AB - Errors and problems associated with male condom use are very prevalent and increase the likelihood of inconsistent and incomplete use, thereby compromising condom effectiveness. The aim of this study was to assess the perceived benefits of a new condom wrapper/integrated applicator designed to reduce barriers to condom use and lessen the likelihood of user errors and problems. After viewing videos depicting features of the wrapper/applicator, participants (N = 547; 62.9% male, M age = 29.2) completed online questionnaires. Most participants reported that the product would make condom application easier and quicker, make them more confident that condoms had been applied correctly and make sex more pleasurable and playful. The majority of participants who had recent experience of condom use errors/problems reported that the use of the product would likely prevent these issues from occurring. Reduced chance of condom damage, the design features of the wrapper and not having to touch the condom itself during application were perceived as particular benefits of the product. The findings suggest that the product might reduce the likelihood of a range of condom user errors and problems and enhance pleasure during condom-protected sex. Future larger-scale studies that involve participants physically testing the condom wrapper/applicator are warranted. PMID- 30482101 TI - Which Child Is Parents' Preferred Caregiver/Listener in China? AB - Adult children are an important source of care providers for parents in a rapidly aging Chinese society, but we know little of which particular child is preferred by parents in time of need. Using the China Longitudinal Aging Social Survey, we investigate the factors associated with parental preference of caregivers and listeners among all his or her children. With children nested within each parent, we fit the conditional (family) fixed-effect fractional logit model. The main results for both caregivers and listeners suggest a preference for the unmarried, the oldest or the youngest, and children who have provided them with support before. Coresident children are favored in rural but not urban China. We did not find preference for sons over daughters. Neither did we find any effect of prior transfers from parents to children. Our findings shed light on the changing norms of eldercare provision in a transitioning society. PMID- 30482103 TI - A systematic review of the use of adolescent mystery clients in assessing the adolescent friendliness of health services in high, middle, and low-income countries. AB - BACKGROUND: Mystery client methodology is a form of participatory research that provides a unique opportunity to monitor and evaluate the performance of health care providers or health facilities from the perspective of the service user. However, there are no systematic reviews that analyse the use of mystery clients in adolescent sexual and reproductive health (ASRH) research and monitoring and evaluation of programmes. OBJECTIVE: To assess the use of adolescent mystery clients in examining health care provider and facility performance in providing ASRH services in high, middle, and low-income countries. METHODS: We carried out a systematic review of published journal articles and reports from the grey literature on this topic from 2000 to 2017 (inclusive). Thirty research evaluations/studies were identified and included in the analysis. We identified common themes through thematic analysis. RESULTS: The findings reveal that researchers and evaluators used mystery client methodology to observe client provider relationships, and to reduce observation bias, in government or private health facilities, NGOs, and pharmacies. The mystery clients in the evaluations/studies were young people who played varying roles; in most cases, they were trained for these roles. Most reported good experiences and friendly providers; however, some reported lack of privacy and confidentiality, lack of sufficient written/verbal information, and unfavourable experiences such as sexual harassment and judgmental comments. Female mystery clients were more likely than males to report unfavourable experiences. Generally, the methodology was considered useful in monitoring and evaluating the attitudes of health service providers and ASRH service provision. CONCLUSIONS: The research evaluations/studies in this review highlight the usefulness of mystery clients as a method to gain insight, from an adolescent perspective, on the quality of ASRH services for research and monitoring and evaluation of programmes. PMID- 30482104 TI - An Experimental Study on Individual and Group Affect in Multi-Tasking Teams. AB - Research has shown that affect can influence human performance in various settings. This study aimed to explore the effects of individual and group affect on task perceptions and performance under different stress conditions (task demand and technology reliability) and team training methods in multi-tasking environments. Seventy-two participants participated in the experiment in two person teams. The participants' affect was measured using facial expression recognition technology. Affect aggregated mean and affect similarity were used as indicators of group affect. Self-reports of workload, teamwork satisfaction, trust in team, and trust in technology were collected. The results demonstrated that different stress conditions and training methods altered individual and group affect. Individual affect did not significantly correlate with the task perception measures, while group affect was related to performance in the team oriented task but not the individual-oriented tasks. These findings suggested that group affect may have an important role in both multi-tasking and team coordination. PMID- 30482102 TI - Why Is Tinnitus a Problem? A Qualitative Analysis of Problems Reported by Tinnitus Patients. AB - Tinnitus is a prevalent complaint, and people with bothersome tinnitus can report any number of associated problems. Yet, to date, only a few studies, with different populations and relatively modest sample sizes, have qualitatively evaluated what those problems are. Our primary objective was to determine domains of tinnitus problem according to a large clinical data set. This was a retrospective analysis of anonymized clinical data from patients who attended a U.K. Tinnitus Treatment Center between 1989 and 2014. Content analysis was used to code and collate the responses of 678 patients to the clinical interview question "Why is tinnitus a problem?" into categories of problems (domains). We identified 18 distinct domains of tinnitus-associated problems. Reduced quality of life, tinnitus-related fear, and constant awareness were notably common problems. Clinicians need to be mindful of the numerous problem domains that might affect their tinnitus patients. Current questionnaires, as well as being measures of severity, are useful clinical tools for identifying problem domains that need further discussion and possibly measurement with additional questionnaires. The domains identified in this work should inform clinical assessment and the development of future clinical tinnitus questionnaire. PMID- 30482105 TI - Pupil Responses of Adults With Traumatic Brain Injury During Processing of Speech in Noise. AB - Previous research has shown the effects of task demands on pupil responses in both normal hearing (NH) and hearing impaired (HI) adults. One consistent finding is that HI listeners have smaller pupil dilations at low levels of speech recognition performance (<=50%). This study aimed to examine the pupil dilation in adults with a normal pure-tone audiogram who experience serious difficulties when processing speech-in-noise. Hence, 20 adults, aged 26 to 62 years, with traumatic brain injury (TBI) or cerebrovascular accident (CVA) but with a normal audiogram participated. Their pupil size was recorded while they listened to sentences masked by fluctuating noise or interfering speech at 50% and 84% intelligibility. In each condition, participants rated their perceived performance, effort, and task persistence. In addition, participants performed the text reception threshold task-a visual sentence completion task-that measured language-related processing. Data were compared with those of age-matched NH and HI participants with no neurological problems obtained in earlier studies using the same setup and design. The TBI group had the same pure-tone audiogram and text reception threshold scores as the NH listeners, yet their speech reception thresholds were significantly worse. Although the pupil dilation responses on average did not differ between groups, self-rated effort scores were highest in the TBI group. Results of a correlation analyses showed that TBI participants with worse speech reception thresholds had a smaller pupil response. We speculate that increased distractibility or fatigue affected the ability of TBI participants to allocate effort during speech perception in noise. PMID- 30482106 TI - Servelle-Martorell syndrome. PMID- 30482107 TI - Simultaneous use of two rapid diagnostic tests for the diagnosis of Chagas disease. AB - The sensitivity of rapid diagnostic tests (RDT) for Chagas disease is not great enough for their single use. The aim of this paper was to evaluate the performance of two RDTs for Chagas disease, used simultaneously. Two different RDTs (A and B) were performed in 64 and 42 serum samples that were negative and positive, respectively, by conventional serological techniques. Validity and reliability of both tests were evaluated individually and simultaneously. Sensitivity was 90.5% and 97.6%, and specificity was 100% and 93.8%, for RDT A and B, respectively. The kappa statistic was 0.96. When both RDTs were used simultaneously, sensitivity was 97.4%, specificity was 100% and the discordance percentage 6.6%. The combined use of two RDTs with serum samples is an acceptable application in healthcare centres. PMID- 30482108 TI - Emotional Responses to Pleasant Sounds Are Related to Social Disconnectedness and Loneliness Independent of Hearing Loss. AB - The purpose of this study was to evaluate the relationship between emotional responses to sounds, hearing acuity, and isolation, specifically objective isolation (social disconnectedness) and subjective isolation (loneliness). It was predicted that ratings of valence in response to pleasant and unpleasant stimuli would influence the relationship between hearing loss and isolation. Participants included 83 adults, without depression, who were categorized into three groups (young with normal hearing, older with normal hearing, and adults with mild-to moderately severe hearing loss). Participants made ratings of valence in response to pleasant and unpleasant nonspeech sounds, presented at a moderate overall level in the laboratory. Participants also completed questionnaires related to social disconnectedness and loneliness. Data were analyzed using multiple regression with questionnaire scores as dependent variables. Independent variables were age, gender, degree of hearing loss, perceived hearing handicap, number of depressive symptoms, mean valence rating in response to unpleasant sounds, and mean valence rating in response to pleasant sounds. Emotional responses to pleasant sounds explained significant variability in scores of both social disconnectedness and loneliness. Depressive symptoms also explained variability in loneliness scores. Hearing loss was not significantly related to social disconnectedness or loneliness, although it was the only variable significantly related to ratings of valence in response to pleasant sounds. Emotional responses to pleasant sounds are related to disconnectedness and loneliness. Although not related to isolation in this study, hearing loss was related to emotional responses. Thus, emotional responses should be considered in future models of isolation and hearing loss. PMID- 30482109 TI - Effects of backpack and double pack loads on postural stability. AB - Measurement of postural stability is crucial for identifying predictors of performance, determining the efficacy of physical training and rehabilitation techniques, and evaluating and preventing injuries, particularly for heavy load carriage in hikers, mountain search and rescue personnel, and soldiers. This study investigated the effect of load distribution on postural stability in an upright stance using backpack and double pack loads under conflicting or impaired somatosensory, visual, and vestibular conditions. The sensory organisation tests were conducted on 20 young adults before and after a 10-min level walking exercise. Young adults' ability to use inputs from somatosensory and visual systems to maintain postural stability was significantly reduced following a 10 min walking exercise with a heavy backpack (30% of body weight), whereas no significant changes were observed for double pack carriage. Thus, the distribution of heavy loads to the front and back provides superior balance control compared with back-only loading. Practitioner Summary: This study investigated the effects of heavy (30% of body weight) load distribution on postural stability after a 10-min walking exercise. Backpack carriage significantly reduced postural stability, whereas there was no significant effect under double pack loads. Distribution of heavy loads on the front-and-back is desirable for superior balance control. PMID- 30482111 TI - Serum YKL-40 in patients with psoriasis vulgaris treated by narrow-band UVB phototherapy. AB - BACKGROUND: Psoriasis is a common chronic and immune-mediated inflammatory skin disease. OBJECTIVES: This study aimed to investigate the serum levels of Chitinase-3-like protein 1 (YKL-40) in patients with psoriasis vulgaris before and after narrow-band ultraviolet B (NB-UVB) phototherapy. METHODS: This study was designed as a cross-sectional case-control. This study included 30 patients with psoriasis vulgaris and 20 healthy individuals. Psoriasis Area and Severity Index (PASI) score were used to evaluate the patients with psoriasis vulgaris before and after treatment. All patients were treated 2 times per week for 3 months with NB-UVB phototherapy. Enzyme-linked immunosorbent assay (ELISA) was used to assess serum levels of YKL-40 of the healthy control subjects and psoriatic patients before and after treatment by NB-UVB phototherapy. RESULTS: The serum level of YKL-40 was significantly higher in patients with psoriasis vulgaris versus healthy control subjects (p value<.001). There were significant reductions in the serum levels of YKL-40 and PASI scores after 3 months of treatment with NB-UVB phototherapy in patients with psoriasis vulgaris (p value<.001). CONCLUSIONS: This study concluded that NB-UVB phototherapy for three months in patients with psoriasis vulgaris was an essential method for decreasing the serum levels of YKL-40 and PASI scores. PMID- 30482110 TI - Electrolytes disturbances after kidney transplantation. AB - OBJECTIVES: Water and electrolytes disturbances often occur in renal transplant recipients. The objective is to describe the pathophysiology and the treatment of the most prevalent abnormalities. METHODS: We screened PubMed for the following words in various combination: kidney transplantation and (disturbances or abnormalities) of (electrolytes or sodium or potassium or phosphate or calcium or acid-base). RESULTS: We found abnormalities in all major electrolytes, as a consequence of tubular dysfunction caused by both rejection episodes and toxic effects of calcineurin inhibitors (CNIs; cyclosporine or tacrolimus). The renal tubular acidosis found in kidney transplant recipients is characterized by a normal anion gap and normal or high serum chloride levels. The incidence of hyperkalemia is 5-40% of patients treated with CNIs. The majority of kidney transplant recipients develop hypomagnesemia within the first weeks and months. Both cyclosporine and tacrolimus do induce hypomagnesemia by several mechanisms. Severe magnesium depletion may include clinical manifestations such as confusion, muscle weakness, tremor, dysphagia, tetany and convulsions. The immediate posttransplant period (first 3 months) is often accompanied by a decline in serum phosphate. Phosphate substitution is needed when serum levels fall below 0.5 mmol/l, or in patients with clinical symptoms and serum levels between 0.5 and 1.0 mmol/l. Hypercalcemia is also a common disorder in the chronic posttransplant phase, and is most often due to persistent hyperparathyroidism. CONCLUSIONS: Patients with kidney transplants display electrolytes abnormalities more frequently than non-transplanted patients with the same levels of renal function. A good knowledge of their physiopathology and treatment is important in the care of those patients. PMID- 30482112 TI - Hippo pathway inhibition by blocking the YAP/TAZ-TEAD interface: a patent review. AB - INTRODUCTION: The Hippo pathway represents a new and intriguing opportunity for the treatment of cancer. Activation or overexpression of YAP or TAZ has been shown to lead to cell transformation and tumor development. To date, no small molecule compounds targeting this pathway have progressed to the clinic, illustrating both its potential and its infancy. Areas covered: The present review seeks to summarize published patent applications from assignee companies that have disclosed direct small molecule inhibitors of the YAP/TAZ -TEAD interaction. Expert opinion: The Hippo pathway, and specifically the YAP/TAZ-TEAD transcriptional complex, has been shown to be a promising target for the treatment of cancer. However, reports in the area of small molecules targeting the YAP/TAZ-TEAD transcriptional activation complex are few and far between, with only two published patent applications that disclose compounds with moderate levels of pathway inhibition. Interestingly, the YAP/TAZ-TEAD complex can be disrupted through two very different mechanisms, one of which is direct inhibition at either the Omega-loop or the alpha-helix of the YAP-TEAD binding interface. Both YAP protein segments have been shown to be important to TEAD binding. Alternatively, it has been reported that allosteric inhibition might be accomplished by binding the TEAD palmitoylation pocket, thus disrupting YAP binding and also native protein stabilization. The advantages and liabilities of disrupting the YAP/TAZ-TEAD complex through these two distinct mechanisms have yet to be fully elucidated, and it remains unclear which approach, if any, will generate the first clinical stage inhibitor of the Hippo pathway. PMID- 30482113 TI - Prediction Model of Academic Performance and Satisfaction With School According to Some Subjects of Compulsory Secondary Education. AB - The purpose of the study was to know which subjects in the curriculum best predict school satisfaction and boredom as well as the student's academic grade. The sample was of 680 adolescents of physical education (339 males, 341 females) with age between 12 and 18 years (M = 14.83; SD = 1.45). We used a questionnaire composed of the satisfaction scales with the subjects, intrinsic satisfaction in the school and related to academic grades. Descriptive analyses, correlations, and structural regression models were performed. The high levels of satisfaction and academic performance in physical education stand out. In the structural model, English is the subject that most predicts academic grades, while language predicts satisfaction at school and physical education boredom at it. PMID- 30482114 TI - ? PMID- 30482115 TI - [Usefulness of Electroanatomical Mapping in Rhythmology]. AB - Usefulness of Electroanatomical Mapping in Rhythmology Abstract. Atrial fibrillation is the most common arrhythmia and its prevalence is rising. Therapeutic options include drug treatment and interventional catheter ablation via pulmonary vein isolation (PVI). This procedure was associated with long fluoroscopy times which carried risks for patients and physicians. Electroanatomical mapping (EAM) is a tool to visualize anatomy, voltage and activation of the heart chambers. Current EAM systems used in clinical practice include CARTO(r), EnSite NavX(r) and Rhythmia(r). Magnetic fields and impendance approaches are used to create 3D shells of the chambers. The catheter can be used to either collect electrograms or to ablate the target tissue. When using EAM, fluoroscopy time is significantly decreased, and complications can be monitored. Images from CT, MRI or intracardiac echo can be used as a template for creating a map or merged with an existing map to enhance anatomic accuracy. PMID- 30482116 TI - [Preeclampsia: New Classifications]. AB - Preeclampsia: New Classifications Abstract. Preeclampsia is a multisystem disease leading to systemic impairment of the maternal endothelial function. A dysbalance of pro- and antiangiogenic factors appears to be significantly involved. The vascular disease leads to the manifestation of symptoms such as arterial hypertension and involvement of end organs such as kidney, liver and brain. The classical diagnostic criterion for arterial hypertension, 'proteinuria' has been downgraded and is no longer obligatory for diagnosis, if other criteria, as maternal organ dysfunction or intrauterine growth retardation, are present. In addition, white-coat hypertension has been included in the classification of hypertension in pregnancy. To classify preeclampsia as 'mild' is being discouraged in the clinical setting to account for the possibility of rapid worsening with significant danger for mother and foetus. PMID- 30482117 TI - [CME: Paraneoplastic Endocrine Syndromes]. AB - CME: Paraneoplastic Endocrine Syndromes Abstract. Paraneoplastic endocrine syndromes are caused by ectopic hormone production by malignant tumor cells. Knowledge of paraneoplastic endocrine syndromes may allow a timely diagnosis of the underlying cancer at a treatable stage and, on the other hand, appropriate treatment of the endocrine manifestations reduces morbidity and mortality of the affected patients. The most common endocrine syndromes are paraneoplastic hypercalcaemia, caused by the secretion of PTHrP, and hyponatremia, caused by the inadequate secretion of ADH. Although there may be clinical symptoms like fatigue, nausea/vomiting and renal insufficiency for hypercalcaemia and gait disturbances and mental alterations for hyponatremia, the diagnosis must be confirmed by laboratory testing and prompt the search for associated tumors. PMID- 30482118 TI - [CME-Laboratory 57: Preventive Health Check-Ups for Adults]. PMID- 30482119 TI - ? PMID- 30482121 TI - ? PMID- 30482122 TI - [CME Sonography 84/Answer: Scrotal Node Palpated]. PMID- 30482120 TI - [Diagnosis and Treatment of Familial Hypercholesterolemia]. AB - Diagnosis and Treatment of Familial Hypercholesterolemia Abstract. Familial hypercholesterolemia secondary to heterozygous mutations in the LDL receptor, Apolipoprotein B or PCSK9 gene is characterized by 2- to 3-fold elevated LDL cholesterol levels, premature atherosclerosis and extravascular cholesterol deposits (tendon xanthomata, corneal arcus). The same phenotype may occur if a person carries several LDL cholesterol rising polymorphisms (polygenic FH). Primary prevention with statins has been shown to dramatically reduce the cardiovascular burden in patients with the disease. However, it is estimated that less than 10 % of affected subjects in Switzerland have received the diagnosis, and undertreatment is frequent. Thus, clinical cardiovascular events are still the first manifestation of the disease in many cases. A correct diagnosis in index patients and cascade screening of families are mandatory to identify and treat patients before they suffer the sequelae of untreated severe hypercholesterolemia. In patients with clinical cardiovascular disease combination lipid lowering treatment with potent statins, ezetimibe and the newly available PCSK9 inhibitors will successfully lower LDL cholesterol to normal or even target levels. PMID- 30482123 TI - [CME Answers: 'Thoracic Sonography in Thoracic Trauma', Praxis No. 23]. PMID- 30482124 TI - ? PMID- 30482125 TI - [Evidence-Based Treatment of Insomnia]. AB - Evidence-Based Treatment of Insomnia Abstract. This review article presents current evidence on the diagnosis and efficacy of treatment methods for non organic insomnia. In diagnostics, it is particularly important to examine differential diagnoses individually and, if available, to treat them. Regarding the actual insomnia treatment, it should be emphasized that drug treatment provides proof of efficacy only in short-term treatments lasting less than four weeks. The most effective treatment for insomnia is disorder-specific cognitive behavioral psychotherapy (CBT-I). CBT-I should therefore be accessible to every patient with insomnia. PMID- 30482126 TI - [Daytime Sleepiness in Patients with Restless Legs Syndrome: A Risk Factor for Traffic Accidents?] AB - Daytime Sleepiness in Patients with Restless Legs Syndrome: A Risk Factor for Traffic Accidents? Abstract. Restless legs syndrome (RLS) is a symptom complex of predominantly leg-focused paraesthesias and the associated increased urge to move. Since evening exacerbations are typical, many patients suffer from sleep disorders, which can lead to increased daytime fatigue in the long term. The present retrospective data analysis investigated a potentially relevant relationship between RLS and an increased incidence of traffic accidents due to daytime sleepiness in Swiss road traffic. A direct correlation between RLS and the occurrence of traffic accidents could not be found. Nevertheless, the question of increased daytime sleepiness should not be absent from any (traffic) medical discussion. PMID- 30482127 TI - Implementing value assessment in oncology practice: A single-center experience. AB - Cancer treatment costs in the United States are rising. Evidence suggests that increased costs do not always correlate with improved outcomes. Several organizations have developed tools and frameworks to assess cancer treatment value; however, many centers have reported difficulty in implementing these tools and effectively incorporating value-based decision making into clinical practice. After evaluating existing frameworks, the Carbone Cancer Center at UW Health set out to create a value-based tool that could be used to inform the decisions of clinicians and patients. This tool was piloted in metastatic or advanced non small cell lung cancer, specifically in the second-line setting to assess the value of immune checkpoint inhibitors nivolumab, atezolizumab, and pembrolizumab. The results of the pilot suggest that atezolizumab is the best value of the three agents in this patient population. Challenges and opportunities for improvement that were identified during the pilot process have helped refine the tool for use in a variety of disease states within oncology. PMID- 30482128 TI - Do Out-of-Hospital Cardiac Arrest Patients Have Increased Chances of Survival When Transported to a Cardiac Resuscitation Center? AB - Background Patients suffering from an out-of-hospital cardiac arrest are often transported to the closest hospital. Although it has been suggested that these patients be transported to cardiac resuscitation centers, few jurisdictions have acted on this recommendation. To better evaluate the evidence on this subject, a systematic review and meta-analysis of the currently available literature evaluating the association between the destination hospital's capability (cardiac resuscitation center or not) and resuscitation outcomes for adult patients suffering from an out-of-hospital cardiac arrest was performed. Methods and Results PubMed, EMBASE , and the Cochrane Library databases were first searched using a specifically designed search strategy. Both original randomized controlled trials and observational studies were considered for inclusion. Cardiac resuscitation centers were defined as having on-site percutaneous coronary intervention and targeted temperature management capability at all times. The primary outcome measure was survival. Twelve nonrandomized observational studies were retained in this review. A total of 61 240 patients were included in the 10 studies that could be included in the meta-analysis regarding the survival outcome. Being transported to a cardiac resuscitation center was associated with an increase in survival (odds ratio=1.95 [95% confidence interval 1.47-2.59], P<0.001). Conclusions Adult patients suffering from an out-of-hospital cardiac arrest transported to cardiac resuscitation centers have better outcomes than their counterparts. When possible, it is reasonable to transport these patients directly to cardiac resuscitation centers (class II a, level of evidence B, nonrandomized). Clinical Trial Registration URL : www.crd.york.ac.uk/PROSPERO/ . Unique identifier: CRD 42018086608. PMID- 30482129 TI - Structure and properties of nano-hydroxyapatite/poly(butylene succinate) porous scaffold for bone tissue engineering prepared by using ethanol as porogen. AB - Biodegradable polymers, because their degradation products are small molecules that do not cause immune system rejection, have been increasingly used by researchers to explore the preparation of scaffold with excellent mechanical properties, biocompatibility and biodegradability. In this study, nano hydroxyapatite and polybutylene succinate were mixed by solution-blending to prepare a porous scaffold that could be used in the biomedical industry. Based on the viewpoint of bionics, porous scaffold with well pore structure and uniform dispersion of nano-hydroxyapatite particles was prepared using ethanol as a porogen. When ethanol was used as a porogen to prepare the porous scaffold, the effects of different mass ratios of nano-hydroxyapatite and polybutylene succinate on the porosity and pore structure of the porous scaffold were investigated under the same amount of ethanol. The mercury intrusion tests showed that the porosity of the 30 nano-hydroxyapatite/polybutylene succinate porous scaffold was 38.987%. The experiment results of in vitro mineralization and cell culture showed that the porous scaffolds have good osteogenic capacity and cell compatibility, including attachment and proliferation. All experiment results indicated that ethanol can be used as a porogen to prepare nano hydroxyapatite/polybutylene succinate porous scaffold, and it has great potential as a scaffold for bone tissue engineering. PMID- 30482130 TI - Patient factors associated with the initiation of telehealth services among heart failure patients at home. AB - Telehealth is an intervention that can assist patients with heart failure to manage their symptoms at home. However, it is reported that between 24-70% of eligible patients do not receive telehealth. This study aimed to explore factors associated with the initiation of telehealth among home care patients with heart failure using the Outcome and Assessment Information Set data (N = 2,832). The findings indicate patients who received high-risk drugs education by visiting nurses had an 80% increase in the odds of receiving telehealth, and patients who received no assistance from caregivers had a 46% decrease in odds compared to those who were assisted at least daily. PMID- 30482131 TI - What should we target after TARGET? PMID- 30482132 TI - Organ donation after circulatory death following voluntary assisted dying: practical and ethical considerations for Victoria. AB - On 19 June 2019, the Voluntary Assisted Dying Bill 2017 (Vic) will be enacted. Up to ten per cent of people deemed eligible for voluntary assisted dying will be medically suitable for organ donation. Donation after circulatory death after assisted dying is possible, although there are important challenges to address for donation to be successful in this context. This article explores the practical and ethical considerations that need to be reviewed in order to support organ donation after assisted dying. In particular, it discusses the ways in which organ donation will affect the place, timing and mechanism of death, and the ethics around consent for donation. The article explores potential ways to minimise warm ischaemic time, and finally discusses the potential for donation to influence the decision to consume the voluntary assisted dying substance. PMID- 30482133 TI - Prediction of tracheostomy in critically ill trauma patients: a systematic review. AB - BACKGROUND: Tracheostomy is relatively common in mechanically ventilated patients in the intensive care unit (ICU). The prediction of which patients will receive a tracheostomy is crucial to both clinical decision making and the design of targeted interventional trials of its timing. OBJECTIVES: We aimed to systematically review the literature to ascertain whether useful predictors of eventual tracheostomy can be identified, with a particular focus on trauma patients. DATA SOURCES AND REVIEW METHODS: We searched three electronic databases to identify all studies of any design evaluating potential predictors of tracheostomy in mechanically ventilated ICU patients. Bias was assessed using the Quality in Prognosis Studies tool. RESULTS: Of 140 potentially eligible studies, we identified 12 relevant observational studies recruiting a total of 119 945 mechanically ventilated patients, of whom 14 080 (11.7%) received a tracheostomy. Seven studies were performed in trauma populations and included 24 858 patients, of whom 6140 (24.7%) received a tracheostomy. Factors predictive of receiving a tracheostomy in the trauma population included patient factors (age and comorbidities), diagnostic factors (injury type and injury severity score), and intervention factors (craniotomy or laparotomy). Profound clinical and methodological heterogeneity prevented meaningful metaanalysis. Significantly, more predictors were present on the day of admission in trauma populations than in non-trauma patients with brain injury and in other populations (89.7% v 73.3% v 25.0%). CONCLUSION: There are a number of clinical factors associated with subsequent tracheostomy in mechanically ventilated patients, in particular trauma patients. Given the need to prevent patients from receiving an unnecessary tracheostomy, these findings indicate that better predictive models are needed before the conduct of interventional trials. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO registry no. CRD42018084987. PMID- 30482134 TI - Communication with Families Regarding Organ and Tissue Donation after Death in Intensive Care (COMFORT): a multicentre before-and-after study. AB - OBJECTIVE: To implement a best-practice intervention offering deceased organ donation, testing whether it increased family consent rates. DESIGN: A multicentre before-and-after study of a prospective cohort compared with pre intervention controls. SETTING: Nine Australian intensive care units. PARTICIPANTS: Families and health care professionals caring for donor-eligible patients without registered donation preferences or aged <= 16 years. INTERVENTION: A multicomponent intervention including offers of deceased organ donation from specially trained designated requesters using a structured conversation separate to end-of-life discussions. MAIN OUTCOME MEASURE: Proportion of families consenting to organ donation. RESULTS: Consent was obtained in 87/164 cases (53%) during the intervention period compared with 14/25 cases (56%) pre-intervention (P = 0.83). The odds ratio (OR) of obtaining consent during the intervention period relative to preintervention was 1.13 (95% CI, 0.48 2.63; P = 0.78). During the intervention period, designated requesters obtained consent in 55/98 cases (56%), compared with 32/66 cases (48%) in which the medical team managing patient care raised donation (P = 0.34). Factors independently associated with increased consent were: family-raised organ donation (OR, 4.34; 95% CI, 1.79-10.52; P = 0.001), presence of an independent designated requester (OR, 3.84; 95% CI, 1.35- 10.98; P = 0.012), and multiple donation conversations per case (OR, 3.35; 95% CI, 1.93-5.81; P < 0.001). Consent decreased when patients were of non-Christian religion (OR, 0.18; 95% CI, 0.04 0.91; P = 0.038) and end-of-life and donation meetings were separate (OR, 0.38; 95% CI, 0.16-0.89; P = 0.026). CONCLUSION: Implementation of a multicomponent intervention did not increase consent rates for organ donation, although some components of the intervention exerted significant effect. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12613000815763. ClinicalTrials.gov: NCT01922310. PMID- 30482135 TI - Haemodynamic effects of cold versus warm fluid bolus in healthy volunteers: a randomised crossover trial. AB - OBJECTIVE: To test the hypothesis that changes in cardiac index and mean arterial pressure (MAP) during and after a fluid bolus (FB) are altered by fluid temperature. DESIGN: Randomised, controlled, crossover trial. SETTING: Research laboratory at Swedish teaching hospital. PARTICIPANTS: Twenty-one healthy adult volunteers. INTERVENTIONS: Subjects were randomly allocated to 500 mL of Ringer's acetate at room temperature (22 degrees C; cold) or body temperature (38 degrees C; warm). MAIN OUTCOME MEASURES: For 2 hours after starting the FB, we measured cardiac index, MAP, systolic blood pressure, diastolic blood pressure and pulse rate (PR) continuously. We recorded temperature and O2 saturation every 5 minutes during infusion and every 15 minutes thereafter. In a second session, volunteers crossed over. RESULTS: During the first 15 minutes, mean cardiac index increased more with warm FB (0.09 L/min/m2 [95% CI, 0.06-0.11] v 0.03 L/min/m2 [95% CI, 0.01-0.06]; P < 0.001). This effect was mediated by a significant difference in mean PR (+0.80 beats/min [95% CI, 0.47-1.13] v -1.33 beats/ min [95% CI, -1.66 to -1.01]; P < 0.010). In contrast, MAP increased more with cold FB (4.02 mmHg [95% CI, 3.63-4.41] v 0.60 mmHg [95% CI, 0.26-0.95]; P < 0.001). Cardiac index and MAP returned to baseline after a median of 45.3 min (interquartile range [IQR], 10.7 60.7 min) and 27.7 min (IQR, 5.3-105.0 min), respectively, after cold FB, and by 15.8 min (IQR, 3.8-64.3 min) and 22.7 min (IQR, 3.3-105.0 min), respectively, after warm FB. CONCLUSION: Intravenous FB at body temperature leads to a greater increase in cardiac index compared with room temperature, while the reverse applies to MAP. These findings imply that in healthy volunteers, when a room temperature FB is given, the temperature of the fluid rather than its volume accounts for most of the MAP increase. TRIAL REGISTRATION: EudraCT no. 2016 002548-18 and Clinicaltrials.gov NCT03209271. PMID- 30482136 TI - Addressing the inadvertent sodium and chloride burden in critically ill patients: a prospective before-and-after study in a tertiary mixed intensive care unit population. AB - BACKGROUND: Inadvertent fluid loading - and resultant sodium and chloride - is common in critically ill patients. Sources such as fluid used as vehicles for drug infusions and boluses (fluid creep) and maintenance fluid are a common cause. We hypothesised that total sodium and chloride loading can be safely reduced in critically ill patients both by the use of 5% glucose as a diluent for infusions and boluses, when possible, and by its use as a maintenance fluid. METHODS: This was a prospective before-and-after study design in a single centre tertiary mixed intensive care unit (ICU). Comprehensive data about patient demographics, sources of fluid, feeds, intravenous drugs, fluid balance and electrolyte levels were collected for 4 weeks before and after the intervention (2016 and 2017). The amount of administered sodium was estimated from these sources. RESULTS: There were 146 patients (643 study days) and 133 patients (684 study days) examined in 2016 and 2017 respectively. The change of practice lead to an increase in the use of 5% glucose as the maintenance fluid and as a diluent, which resulted in a decrease in the total daily administered sodium from a median of 197 mmol (interquartile range [IQR], 155-328 mmol) to a median of 109 mmol (IQR, 77-288 mmol) (P = 0.0001). It also resulted in decrease in daily fluid balance, plasma chloride and ICU-acquired hypernatraemia. CONCLUSIONS: It is safely possible to decrease the total sodium and chloride loading to ICU patients by intervening on fluid creep and on maintenance fluid types. This intervention was accompanied by favourable changes in serum electrolyte and fluid balance. PMID- 30482137 TI - Intensive care implications of epidemic thunderstorm asthma. AB - OBJECTIVE: To investigate the environmental precipitants, treatment and outcome of critically ill patients affected by the largest and most lethal reported epidemic of thunderstorm asthma. DESIGN, SETTING AND PARTICIPANTS: Retrospective multicentre observational study. Meteorological, airborne particulate and pollen data, and a case series of 35 patients admitted to 15 intensive care units (ICUs) due to the thunderstorm asthma event of 21-22 November 2016, in Victoria, Australia, were analysed and compared with 1062 total ICU-admitted Australian patients with asthma in 2016. MAIN OUTCOME MEASURES: Characteristics and outcomes of total ICU versus patients with thunderstorm asthma, the association between airborne particulate counts and storm arrival, and ICU resource utilisation. RESULTS: All 35 patients had an asthma diagnosis; 13 (37%) had a cardiac or respiratory arrest, five (14%) died. Compared with total Australian ICU-admitted patients with asthma in 2016, patients with thunderstorm asthma had a higher mortality (15% v 1.3%, P < 0.001), were more likely to be male (63% v 34%, P < 0.001), to be mechanically ventilated, and had shorter ICU length of stay in survivors (median, 31.8 hours [interquartile range (IQR), 14.8-43.6 hours] v 40.7 hours [IQR, 22.3-75.1 hours]; P = 0.025). Patients with cardiac arrest were more likely to be born in Asian or subcontinental countries (5/10 [50%] v 4/25 [16%]; relative risk, 3.13; 95% CI, 1.05-9.31). A temporal link was demonstrated between airborne particulate counts and arrival of the storm. The event used 15% of the public ICU beds in the region. CONCLUSION: Arrival of a triggering storm is associated with an increase in respirable airborne particles. Affected critically ill patients are young, have a high mortality, a short duration of bronchospasm, and a prior diagnosis of asthma is common. PMID- 30482138 TI - The carbon footprint of treating patients with septic shock in the intensive care unit. AB - OBJECTIVE: To use life cycle assessment to determine the environmental footprint of the care of patients with septic shock in the intensive care unit (ICU). DESIGN, SETTING AND PARTICIPANTS: Prospective, observational life cycle assessment examining the use of energy for heating, ventilation and air conditioning; lighting; machines; and all consumables and waste associated with treating ten patients with septic shock in the ICU at BarnesJewish Hospital, St. Louis, MO, United States (US-ICU) and ten patients at Footscray Hospital, Melbourne, Vic, Australia (Aus-ICU). MAIN OUTCOME MEASURES: Environmental footprint, particularly greenhouse gas emissions. RESULTS: Energy use per patient averaged 272 kWh/day for the US-ICU and 143 kWh/day for the Aus-ICU. The average daily amount of single-use materials per patient was 3.4 kg (range, 1.0-6.3 kg) for the US-ICU and 3.4 kg (range, 1.2-8.7 kg) for the Aus-ICU. The average daily particularly greenhouse gas emissions arising from treating patients in the US ICU was 178 kg carbon dioxide equivalent (CO2-e) emissions (range, 165-228 kg CO2 e), while for the Aus-ICU the carbon footprint was 88 kg CO2-e (range, 77-107 kg CO2-e). Energy accounted for 155 kg CO2-e in the US-ICU (87%) and 67 kg CO2-e in the Aus-ICU (76%). The daily treatment of one patient with septic shock in the US ICU was equivalent to the total daily carbon footprint of 3.5 Americans' CO2-e emissions, and for the Aus-ICU, it was equivalent to the emissions of 1.5 Australians. CONCLUSION: The carbon footprints of the ICUs were dominated by the energy use for heating, ventilation and air conditioning; consumables were relatively less important, with limited effect of intensity of patient care. There is large opportunity for reducing the ICUs' carbon footprint by improving the energy efficiency of buildings and increasing the use of renewable energy sources. PMID- 30482139 TI - Risk factors for candidaemia and their cumulative effect over time in a cohort of critically ill, non-neutropenic patients. AB - OBJECTIVES: There is an increasing incidence of invasive candidal infections in critically ill patients worldwide, which has prompted development of various risk prediction rules, both clinical and microbiological. To date, however, there is a lack of research into how cumulative risk factors over time affect transition to candidaemia. The aim of this study was to investigate the association of risk factor accumulation over time with candidaemia in a cohort of critically ill, non neutropenic adult patients. DESIGN, SETTING AND PARTICIPANTS: A single centre, retrospective, matched case-control study in a tertiary referral intensive care unit (ICU). Data were retrieved and analysed from 108 patients (54 cases and 54 controls) admitted between 1 January 2008 and 1 August 2016. MAIN OUTCOME MEASURES: Primary outcome was the association between time-dependent risk factors and candidaemia. Secondary outcomes were ICU and inhospital mortality. RESULTS: Baseline demographic and clinical factors were similar across both groups. Time dependent univariate factors associated with candidaemia were days of mechanical ventilation, systemic antibiotic use, renal replacement therapy, central venous access, total parenteral nutrition (TPN), systemic inflammatory response syndrome, Candida site colonisation and number of surgeries. Factors persisting on multivariate analysis were days of TPN use (odds ratio [OR], 1.8; 95% CI, 1.02 3.22; P = 0.041) and total Candida site colonisation days (OR, 2.41; 95% CI, 1.30 4.46; P = 0.005). Mortality and length of stay (LOS) was greater in patients with candidaemia v control patients (ICU mortality, 15 [28%] v 10 [19%]; P = 0.254; hospital mortality, 26 [48%] v 16 [30%]; P = 0.048; ICU LOS median, 13 days [interquartile range (IQR), 5-29 days] v 2 days [IQR, 1-5 days]; P < 0.001; hospital LOS median, 36 days [IQR,19- 63 days] v 13 days [IQR, 6-28 days]; P < 0.001). CONCLUSION: This study demonstrates an association between TPN use, Candida colonisation and cumulative risk over time of developing candidaemia. PMID- 30482140 TI - In-hospital cardiac arrests: events worth monitoring? PMID- 30482141 TI - In-hospital cardiac arrests: events worth monitoring? PMID- 30482142 TI - Regulation of Tumor Suppressor Gene CDKN2A and Encoded p16-INK4a Protein by Covalent Modifications. AB - CDKN2A is one of the most studied tumor suppressor genes. It encodes the p16 INK4a protein that plays a critical role in the cell cycle progression, differentiation, senescence, and apoptosis. Mutations in CDKN2A or dysregulation of its functional activity are frequently associated with various types of human cancer. As a cyclin-dependent kinase inhibitor, p16-INK4a forms a complex with cyclin-dependent kinases 4/6 (CDK4/6) thereby competing with cyclin D. It is believed that the helix-turn-helix structures in the content of tandem ankyrin repeats in p16-INK4a are required for the protein interaction with CDK4. Until recently, the mechanisms considered to be involved in the regulation of p16-INK4a functions and cancer development have been mutations in DNA, homozygous or heterozygous gene loss, and methylation of CDKN2A promoter region. In this review, we discuss recent findings on the regulation of p16-INK4a by covalent modifications at both transcriptional and post-translational levels. PMID- 30482143 TI - Regulation of Protein Synthesis in Inactivated Skeletal Muscle: Signal Inputs, Protein Kinase Cascades, and Ribosome Biogenesis. AB - Disuse atrophy of skeletal muscles is characterized by a significant decrease in the mass and size of muscle fibers. Disuse atrophy develops as a result of prolonged reduction in the muscle functional activity caused by bed rest, limb immobilization, and real or simulated microgravity. Disuse atrophy is associated with the downregulation of protein biosynthesis and simultaneous activation of protein degradation. This review is focused on the key molecular mechanisms regulating the rate of protein synthesis in mammalian skeletal muscles during functional unloading. PMID- 30482144 TI - Molecular Factors of the Maintenance and Activation of the Juvenile Phenotype of Cellular Sources for Eye Tissue Regeneration. AB - Modern achievements in the understanding of tissue regeneration, identification of endogenous cell sources for regeneration, and development of approaches for induction and differentiation of pluripotent stem cells have open broad prospects for regenerative medicine. However, application of the obtained information in medicine is hindered by insufficient knowledge on the molecular factors and their combinations capable of regulating the age and fate of cellular sources for eye tissue reparation as well as on the regenerative responses of these cells. In the review, we present our own and literature data on cells serving as endogenous sources for eye tissue regeneration in lower and higher vertebrates and properties of gene expression that allow these cells to maintain their juvenile phenotype. Transcription factors and signal pathways providing cell juvenile status as well as cell reprogramming and entry into the S-phase are discussed. The role of systemic factors (blood and immune system factors, hormones, oxidative stress products, and cell rejuvenation factors) in these processes and their interaction with local factors of the cell environment are described. Molecular factors and conditions for induction of reprogramming and proliferation of cellular sources involved in regeneration in vitro are analyzed with special attention to the role of epigenetic factors (associated with cell senescence, in particular) in the source cells conversion during eye tissue regeneration. PMID- 30482145 TI - Pseudogenes as Functionally Significant Elements of the Genome. AB - Pseudogene is a gene copy that has lost its original function. For a long time, pseudogenes have been considered as "junk DNA" that inevitably arises as a result of ongoing evolutionary process. However, experimental data obtained during recent years indicate this understanding of the nature of pseudogenes is not entirely correct, and many pseudogenes perform important genetic functions. In the review, we have addressed classification of pseudogenes, methods of their detection in the genome, and the problem of their evolutionary conservatism and prevalence among species belonging to different taxonomic groups in the light of modern data. The mechanisms of gene expression regulation by pseudogenes and the role of pseudogenes in pathogenesis of various human diseases are discussed. PMID- 30482146 TI - Vitamin D in Nature: A Product of Synthesis and/or Degradation of Cell Membrane Components. AB - The review discusses the data on vitamin D accumulation in animals, plants, and other organisms. 7-Dehydrocholesterol (7-DHC) and ergosterol are considered to be the only true precursors of vitamin D, although even vitamin D2 (ergocalciferol) is not fully comparable to vitamin D3 (cholecalciferol) in regard to their functions. These precursors are converted by UV radiation into the corresponding D vitamins. There are a few published reports that this reaction can also occur in the dark or under blue light, which is unexpected and requires explanation. Another unexpected result is conversion of pro-vitamins D (7-DHC and ergosterol) into vitamin D3 and D2 via pre-vitamin D at low temperatures (<16 degrees C) in the lichen Cladonia rangiferina. An extensive survey of literature data leads to the conclusion that vitamin D is synthesized from (1) 7-DHC via lanosterol (D3) in land animals; (2) 7-DHC via cycloartenol (D3) in plants; (3) ergosterol via lanosterol (D2) in fungi; and (4) 7-DHC or ergosterol (D3 or D2) in algae. Vitamin D primarily accumulates in organisms, in which it acts as a pro-hormone, e.g., land animals. It can also be found as a degradation product in many other species, in which spontaneous conversion of some membrane sterols upon UV irradiation leads to the formation of vitamins D3 or D2, even if they are not necessarily needed by the organism. Such products accumulate due to the absence of metabolizing enzymes, e.g., in algae, fungi, or lichens. Other organisms (e.g., zooplankton and fish) receive vitamins D with food; in this case, vitamins D do not seem to carry out biological functions; they are not metabolized but stored in cells. A few exceptions were found: the rainbow trout and at least four plant species that accumulate active hormone calcitriol (but not vitamin D) in relatively high amounts. As a result, these plants are very toxic for grazing animals (cause enzootic calcinosis). In connection with the proposal of some scientists to produce large quantities of vitamin D with the help of plants, the accumulation of calcitriol in some plants is discussed. PMID- 30482147 TI - Exogenous 3-Deoxyglucosone-Induced Carbonyl and Oxidative Stress Causes beta Cells Dysfunction by Impairing Gut Permeability in Rats. AB - 3-Deoxyglucosone (3DG) is a highly reactive dicarbonyl species, and its accumulation evokes carbonyl and oxidative stress. Our recent data reveal the role of 3DG as an independent factor for the development of prediabetes and suggest that intestine could be its novel target tissue. The present study investigated whether exogenous 3DG increases intestinal permeability by triggering carbonyl and oxidative stress, thus contributing to beta-cell dysfunction. Rats were administered 3DG for two weeks by gastric gavage. Then levels of insulin, ROS, MDA, SOD, NLRP3, TNF-alpha and IL-1beta in blood plasma as well as the ROS level and content of TNF-alpha and IL-1beta in pancreas were assessed. Also, the expression of E-cadherin and ZO-1 as well as levels of 3DG, protein carbonylation, ROS, TNF-alpha and IL-1beta in colon were determined. The 3DG-treated rats showed an elevation in systemic oxidative stress (ROS, MDA and SOD) and in inflammation (TNF-alpha and IL-1beta), decreased plasma insulin level 15 min after the glucose load, and increased levels of TNF-alpha, IL-1beta and ROS in pancreatic tissue. In colon tissues of the 3DG-treated rats, decreased E cadherin expression and increased ROS production as well as an elevation of TNF alpha and IL-1beta levels were observed. Interestingly, elevation of colon protein carbonylation was observed in the 3DG-treated rats that displayed 3DG deposition in colon tissues. We revealed for the first time that 3DG deposition in colon triggers carbonyl and oxidative stress and, as a consequence, impairs gut permeability. The enhanced intestinal permeability caused by 3DG deposition in colon results in systemic and pancreatic oxidative stress and inflammatory process, contributing to the development of beta-cell dysfunction. PMID- 30482148 TI - Contribution of Eutrema salsugineum Cold Shock Domain Structure to the Interaction with RNA. AB - Plant cold shock domain proteins (CSDPs) are DNA/RNA-binding proteins. CSDPs contain the conserved cold shock domain (CSD) in the N-terminal part and a varying number of the CCHC-type zinc finger (ZnF) motifs alternating with glycine rich regions in the C-terminus. CSDPs exhibit RNA chaperone and RNA-melting activities due to their nonspecific interaction with RNA. At the same time, there are reasons to believe that CSDPs also interact with specific RNA targets. In the present study, we used three recombinant CSDPs from the saltwater cress plant (Eutrema salsugineum) - EsCSDP1, EsCSDP2, EsCSDP3 with 6, 2, and 7 ZnF motifs, respectively, and showed that their nonspecific interaction with RNA is determined by their C-terminal fragments. All three proteins exhibited high affinity to the single-stranded regions over four nucleotides long within RNA oligonucleotides. The presence of guanine in the single- or double-stranded regions was crucial for the interaction with CSDPs. Complementation test using E. coli BX04 cells lacking four cold shock protein genes (DeltacspA, DeltacspB, DeltacspE, DeltacspG) revealed that the specific binding of plant CSDPs with RNA is determined by CSD. PMID- 30482149 TI - Lymphocyte Phosphatase-Associated Phosphoprotein Is a Substrate of Protein Kinase CK2. AB - Lymphocyte phosphatase-associated phosphoprotein (LPAP) is a molecular partner of CD45 phosphatase that plays a key role in the regulation of antigen-specific activation of lymphocytes. The functions of LPAP still remain unknown. We believe that studying LPAP phosphorylation pathways could shed light on its functions. In this work, we studied the phosphorylation of LPAP ectopically expressed in non lymphoid cells in order to determine the effect of LPAP interaction partners on its phosphorylation. We found that phosphorylation at Ser153 and Ser163 in non hematopoietic HEK293 cells was conserved, while phosphorylation at Ser99 and Ser172 was almost absent. The pattern of LPAP phosphorylation in K562 erythroid and U937 myeloid cells expressing endogenous CD45 protein was similar to that observed in T and B lymphocytes. We demonstrated for the first time that LPAP is a substrate for protein kinase CK2 that phosphorylates it at Ser153, presumably ensuring LPAP resistance to degradation. PMID- 30482150 TI - Effect of Disulfide Bond Incorporation on the Structure and Activity of Endostatin Peptide. AB - The structure and function of a 27-a.a. fragment of the N-terminal sequence of human endostatin (ES-Zn) were compared to those of the mutant peptide (ES-SSZn) obtained by adding Cys-Pro-Ala to the endostatin N-terminus and substituting Asn16 for Cys ensuring formation of a disulfide bond. Structural comparison of ES Zn and ES-SSZn by far-UV circular dichroism (CD), intrinsic fluorescence, and molecular dynamics simulation methods revealed significant structural perturbations in ES-SSZn, such as elimination of the beta-sheet conformer, modification of the N-terminal loop structure, and reorganization of dynamic properties of the entire peptide backbone. ES-SSZn was approximately 2 and 3 times less efficient than ES-Zn and the full-length human endostatin, respectively, in the induction of caspase-3-dependent apoptosis in human umbilical vein endothelial cells (HUVECs) in vitro (p < 0.05). In contrast, treatment of metastatic 4T1 breast tumors in mice with ES-Zn and ES-SSZn (5 mg/kg body weight daily) for 14 days resulted in similar regression of tumor size, comparable downregulation of angiogenesis (CD31 and CD34) and cell proliferation (Ki67), and therefore, the same extent of apoptosis induction (TUNEL, p53, and Bcl-2) for both peptides (as compared to the untreated controls). Western blot analysis of HUVEC and 4T1 tumor lysates revealed the same levels of suppression of key signaling mediators Akt and ERK1/2 by ES-Zn and ES-SSZn. Contrary to the earlier studies, our results showed that the function of the 1-27 endostatin fragment is independent of its overall structure. Stabilization of the N-terminal loop structure by the disulfide bond incorporation causes relief from structural deviations. PMID- 30482151 TI - Comprehensive Analysis of Carbohydrate-Active Enzymes from the Filamentous Fungus Scytalidium candidum 3C. AB - Complete enzymatic degradation of plant polysaccharides is a result of combined action of various carbohydrate-active enzymes (CAZymes). In this paper, we demonstrate the potential of the filamentous fungus Scytalidium candidum 3C for processing of plant biomass. Structural annotation of the improved assembly of S. candidum 3C genome and functional annotation of CAZymes revealed putative gene sequences encoding such proteins. A total of 190 CAZyme-encoding genes were identified, including 104 glycoside hydrolases, 52 glycosyltransferases, 28 oxidative enzymes, and 6 carbohydrate esterases. In addition, 14 carbohydrate binding modules were found. Glycoside hydrolases secreted during the growth of S. candidum 3C in three media were analyzed with a variety of substrates. Mass spectrometry analysis of the fungal culture liquid revealed the presence of peptides identical to 36 glycoside hydrolases, three proteins without known enzymatic function belonging to the same group of families, and 11 oxidative enzymes. The activity of endo-hemicellulases was determined using specially synthesized substrates in which the glycosidic bond between monosaccharide residues was replaced by a thio-linkage. During analysis of the CAZyme profile of S. candidum 3C, four beta-xylanases from the GH10 family and two beta-glucanases from the GH7 and GH55 families were detected, partially purified, and identified. PMID- 30482152 TI - Aggregation of Influenza A Virus Nuclear Export Protein. AB - Influenza A virus nuclear export protein (NEP) plays an important role in the viral life cycle. Recombinant NEP proteins containing (His)6-tag at either N- or C-terminus were obtained by heterologous expression in Escherichia coli cells and their high propensity for aggregation was demonstrated. Dynamic light scattering technique was used to study the kinetics and properties of NEP aggregation in solutions under different conditions (pH, ionic strength, presence of low molecular-weight additives and organic solvents). Using atomic force microscopy, the predominance of spherical aggregates in all examined NEP preparations was shown, with some amyloid-like structures being observed in the case of NEP-C protein. A number of structure prediction programs were used to identify aggregation-prone regions in the NEP structure. All-atom molecular dynamics simulations indicate a high rate of NEP molecule aggregation and reveal the regions preferentially involved in the intermolecular contacts that are located at the edges of the rod-like protein molecule. Our results suggest that NEP aggregation is determined by different types of interactions and represents an intrinsic property of the protein that appears to be necessary for its functioning in vivo. PMID- 30482153 TI - Erratum to: "Structural Relationships Between Genetically Closely Related O Antigens of Escherichia coli and Shigella spp." [Biochemistry (Moscow), 81, 600 (2016)]. AB - This corrects the article DOI: 10.1134/S0006297916060067. PMID- 30482154 TI - Cysmotif Searcher Pipeline for Antimicrobial Peptide Identification in Plant Transcriptomes. AB - In this paper, we present the new Cysmotif searcher pipeline for identification of various antimicrobial peptides (AMPs), the most important components of innate immunity, in plant transcriptomes. Cysmotif searcher reveals and classifies short cysteine-rich amino acid sequences containing an open reading frame and a signal peptide cleavage site. Due to the combination of various search methods, Cysmotif searcher allows to obtain the most complete repertoire of AMPs for one or more transcriptomes in a short amount of time. The pipeline performance is estimated on the model plant Arabidopsis thaliana and nine other plants, including cultivated and wild species. The obtained results are compared to the existing annotation (A. thaliana) and results of conventional homology search (other plants). The comparison is carried out for known families of plant AMPs and newly discovered peptides that could not be assigned to existing families. The applicability of Cysmotif searcher in detecting new AMPs is discussed, and some practical recommendations on the pipeline usage for end users are given. The Cysmotif searcher pipeline is free for academic use and can be downloaded from Github (http://github.com/fallandar/cysmotifsearcher). PMID- 30482155 TI - A data science approach for the classification of low-grade and high-grade ovarian serous carcinomas. AB - BACKGROUND: Copy Number Alternations (CNAs) is defined as somatic gain or loss of DNA regions. The profiles of CNAs may provide a fingerprint specific to a tumor type or tumor grade. Low-coverage sequencing for reporting CNAs has recently gained interest since successfully translated into clinical applications. Ovarian serous carcinomas can be classified into two largely mutually exclusive grades, low grade and high grade, based on their histologic features. The grade classification based on the genomics may provide valuable clue on how to best manage these patients in clinic. Based on the study of ovarian serous carcinomas, we explore the methodology of combining CNAs reporting from low-coverage sequencing with machine learning techniques to stratify tumor biospecimens of different grades. RESULTS: We have developed a data-driven methodology for tumor classification using the profiles of CNAs reported by low-coverage sequencing. The proposed method called Bag-of-Segments is used to summarize fixed-length CNA features predictive of tumor grades. These features are further processed by machine learning techniques to obtain classification models. High accuracy is obtained for classifying ovarian serous carcinoma into high and low grades based on leave-one-out cross-validation experiments. The models that are weakly influenced by the sequence coverage and the purity of the sample can also be built, which would be of higher relevance for clinical applications. The patterns captured by Bag-of-Segments features correlate with current clinical knowledge: low grade ovarian tumors being related to aneuploidy events associated to mitotic errors while high grade ovarian tumors are induced by DNA repair gene malfunction. CONCLUSIONS: The proposed data-driven method obtains high accuracy with various parametrizations for the ovarian serous carcinoma study, indicating that it has good generalization potential towards other CNA classification problems. This method could be applied to the more difficult task of classifying ovarian serous carcinomas with ambiguous histology or in those with low grade tumor co-existing with high grade tumor. The closer genomic relationship of these tumor samples to low or high grade may provide important clinical value. PMID- 30482156 TI - Identification of proteins responding to pathogen-infection in the red alga Pyropia yezoensis using iTRAQ quantitative proteomics. AB - BACKGROUND: Pyropia yezoensis is an important marine crop which, due to its high protein content, is widely used as a seafood in China. Unfortunately, red rot disease, caused by Pythium porphyrae, seriously damages P. yezoensis farms every year in China, Japan, and Korea. Proteomic methods are often used to study the interactions between hosts and pathogens. Therefore, an iTRAQ-based proteomic analysis was used to identify pathogen-responsive proteins following the artificial infection of P. yezoensis with P. porphyrae spores. RESULTS: A total of 762 differentially expressed proteins were identified, of which 378 were up regulated and 384 were down-regulated following infection. A large amount of these proteins were involved in disease stress, carbohydrate metabolism, cell signaling, chaperone activity, photosynthesis, and energy metabolism, as annotated in the KEGG database. Overall, the data showed that P. yezoensis resists infection by inhibiting photosynthesis, and energy and carbohydrate metabolism pathways, as supported by changes in the expression levels of related proteins. The expression data are available via ProteomeXchange with the identifier PXD009363. CONCLUSIONS: The current data provide an overall summary of the red algae responses to pathogen infection. This study improves our understanding of infection resistance in P. yezoensis, and may help in increasing the breeding of P. porphyrae-infection tolerant macroalgae. PMID- 30482157 TI - Extracorporeal shockwave against inflammation mediated by GPR120 receptor in cyclophosphamide-induced rat cystitis model. AB - BACKGROUND: We tested the hypothesis that extracorporeal shockwave treatment (ESWT) can abolish inflammation and restore urothelial barrier integrity in acute interstitial cystitis by upregulating the fatty acid receptor GPR120. METHODS: A total of 30 female Sprague-Dawley rats were categorized into five groups: (1) sham-operated rats (SC); (2) rats treated with ESWT (SC + ESWT); (3) rats with bladder irritation using 150 mg/kg cyclophosphamide through intraperitoneal injection; (4) cyclophosphamide rats treated with ESWT (cyclophosphamide+ESWT); (5) cyclophosphamide rats treated with GPR120 agonist (cyclophosphamide+GW9508). RESULTS: On Day 3, urine and bladder specimens were collected for biochemical, histopathological, immunological, and immunoblotting analysis. Following stimulation with cyclophosphamide, the inhibition of the elevated levels of TAK1/NF-kappaB and phospho-TAK1/NF-kappaB by ESWT and GPR120 agonists in RT4 cells was associated with a suppression of NF-kappaB translocation from the cytosol to the nucleus. Accordingly, this anti-inflammatory effect was abolished by GPR120 antagonist and knockdown of GPR120. Histologically, bladder inflammation in cyclophosphamide-treated rats was suppressed by GW9508 or ESWT. Masson's trichrome and Sirius red staining revealed that cyclophosphamide treatment enhanced synthesis of extracellular matrix in rats that was reversed by GW9508 or ESWT. Upregulated pro-inflammatory mediators and cytokines in the cyclophosphamide-treated rats were also suppressed in the GW9508- or ESWT-treated rats. The significantly increased inflammatory cell infiltration as well as the impaired urothelial integrity of the bladder after cyclophosphamide treatment were reversed by treatment with GW9508 or ESWT. CONCLUSIONS: These findings suggest that GPR120, the sensing receptor for ESWT, may be useful in the treatment of interstitial cystitis by inhibiting inflammatory response in bladder cells. PMID- 30482158 TI - Adaptive genetic differentiation in Pterocarya stenoptera (Juglandaceae) driven by multiple environmental variables were revealed by landscape genomics. AB - BACKGROUND: The investigation of the genetic basis of local adaptation in non model species is an interesting focus of evolutionary biologists and molecular ecologists. Identifying these adaptive genetic variabilities on the genome responsible can provide insight into the genetic mechanism of local adaptation. RESULTS: We investigated the spatial distribution of genetic variation in 22 natural populations of Pterocarya stenoptera across its distribution area in China to provide insights into the complex interplay between multiple environmental variables and adaptive genetic differentiation. The Bayesian analysis of population structure showed that the 22 populations of P. stenoptera were subdivided into two groups. Redundancy analysis demonstrated that this genetic differentiation was caused by the divergent selection of environmental difference. A total of 44 outlier loci were mutually identified by Arlequin and BayeScan, 43 of which were environment-associated loci (EAL). The results of latent factor mixed model analysis showed that solar radiation in June (Sr6), minimum temperature of the coldest month (Bio6), temperature seasonality (Bio4), and water vapor pressure in January (Wvp1) were associated with the highest numbers of EAL. Sr6 was associated with the ecological habitat of "prefered light", and Bio6 and Wvp1 were associated with the ecological habitat of "warm and humid environment". CONCLUSIONS: Our results provided empirical evidence that environmental variables related to the ecological habitats of species play key roles in driving adaptive differentiation of species genome. PMID- 30482159 TI - Periodic reflections: a method of guided discussions for documenting implementation phenomena. AB - BACKGROUND: Ethnography has been proposed as a valuable method for understanding how implementation occurs within dynamic healthcare contexts, yet this method can be time-intensive and challenging to operationalize in pragmatic implementation. The current study describes an ethnographically-informed method of guided discussions developed for use by a multi-project national implementation program. METHODS: The EMPOWER QUERI is conducting three projects to implement innovative care models in VA women's health for high-priority health concerns - prediabetes, cardiovascular risk, and mental health - utilizing the Replicating Effective Programs (REP) implementation strategy enhanced with stakeholder engagement and complexity science. Drawing on tenets of ethnographic research, we developed a lightly-structured method of guided "periodic reflections" to aid in documenting implementation phenomena over time. Reflections are completed as 30-60 min telephone discussions with implementation team members at monthly or bi-monthly intervals, led by a member of the implementation core. Discussion notes are coded to reflect key domains of interest and emergent themes, and can be analyzed singly or in triangulation with other qualitative and quantitative assessments to inform evaluation and implementation activities. RESULTS: Thirty structured reflections were completed across the three projects during a 15-month period spanning pre-implementation, implementation, and sustainment activities. Reflections provide detailed, near-real-time information on projects' dynamic implementation context, including characteristics of implementation settings and changes in the local or national environment, adaptations to the intervention and implementation plan, and implementation team sensemaking and learning. Reflections also provide an opportunity for implementation teams to engage in recurring reflection and problem-solving. CONCLUSIONS: To implement new, complex interventions into dynamic organizations, we must better understand the implementation process as it unfolds in real time. Ethnography is well suited to this task, but few approaches exist to aid in integrating ethnographic insights into implementation research. Periodic reflections show potential as a straightforward and low-burden method for documenting events across the life cycle of an implementation effort. They offer an effective means for capturing information on context, unfolding process and sensemaking, unexpected events, and diverse viewpoints, illustrating their value for use as part of an ethnographically-minded implementation approach. TRIAL REGISTRATION: The two implementation research studies described in this article have been registered as required: Facilitating Cardiovascular Risk Screening and Risk Reduction in Women Veterans (NCT02991534); and Implementation of Tailored Collaborative Care for Women Veterans (NCT02950961). PMID- 30482160 TI - Microenvironment in neuroblastoma: isolation and characterization of tumor derived mesenchymal stromal cells. AB - BACKGROUND: It has been proposed that mesenchymal stromal cells (MSCs) promote tumor progression by interacting with tumor cells and other stroma cells in the complex network of the tumor microenvironment. We characterized MSCs isolated and expanded from tumor tissues of pediatric patients diagnosed with neuroblastomas (NB-MSCs) to define interactions with the tumor microenvironment. METHODS: Specimens were obtained from 7 pediatric patients diagnosed with neuroblastoma (NB). Morphology, immunophenotype, differentiation capacity, proliferative growth, expression of stemness and neural differentiation markers were evaluated. Moreover, the ability of cells to modulate the immune response, i.e. inhibition of phytohemagglutinin (PHA) activated peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cytotoxic function, was examined. Gene expression profiles, known to be related to tumor cell stemness, Wnt pathway activation, epithelial-mesenchymal transition (EMT) and tumor metastasis were also evaluated. Healthy donor bone marrow-derived MSCs (BM-MSC) were employed as controls. RESULTS: NB-MSCs presented the typical MSC morphology and phenotype. They showed a proliferative capacity superimposable to BM-MSCs. Stemness marker expression (Sox2, Nanog, Oct3/4) was comparable to BM-MSCs. NB-MSC in vitro osteogenic and chondrogenic differentiation was similar to BM-MSCs, but NB-MSCs lacked adipogenic differentiation capacity. NB-MSCs reached senescence phases at a median passage of P7 (range, P5-P13). NB-MSCs exhibited greater immunosuppressive capacity on activated T lymphocytes at a 1:2 (MSC: PBMC) ratio compared with BM MSCs (p = 0.018). NK cytotoxic activity was not influenced by co-culture, either with BM-MSCs or NB-MSCs. Flow-cytometry cell cycle analysis showed that NB-MSCs had an increased number of cells in the G0-G1 phase compared to BM-MSCs. Transcriptomic profiling results indicated that NB-MSCs were enriched with EMT genes compared to BM-MSCs. CONCLUSIONS: We characterized the biological features, the immunomodulatory capacity and the gene expression profile of NB-MSCs. The NB MSC gene expression profile and their functional properties suggest a potential role in promoting tumor escape, invasiveness and metastatic traits of NB cancer cells. A better understanding of the complex mechanisms underlying the interactions between NB cells and NB-derived MSCs should shed new light on potential novel therapeutic approaches. PMID- 30482161 TI - Serum levels of sclerostin as a potential biomarker in central arterial stiffness among hypertensive patients. AB - BACKGROUND: Sclerostin is known to be a canonical Wnt/beta-catenin signaling pathway inhibitor, while the Wnt/beta-catenin signaling pathway is proposed to be involved in the development of arterial stiffness. This study aims to investigate the relationship between serum sclerostin levels and carotid-femoral pulse wave velocity (cfPWV) among hypertensive patients. METHODS: Fasting blood samples were obtained from 105 hypertensive patients. Patients with cfPWV values of > 10 m/s were classified in the high arterial stiffness group, whereas those with cfPWV values of <=10 m/s were assigned to the low arterial stiffness group. Serum sclerostin and Dickkopf-1 (DKK1) levels were quantified using commercially available enzyme-linked immunosorbent assays. RESULTS: Thirty-six hypertensive patients (34.3%) who belonged to the high arterial stiffness group were generally older (p < 0.001), presented with lower estimated glomerular filtration rates (eGFR, p = 0.014), higher incidence of diabetes mellitus (p = 0.030), average systolic blood pressures (SBP, p = 0.013), pulse pressure (p = 0.026), serum creatinine levels (p = 0.013), intact parathyroid hormone levels (iPTH, p = 0.003), and sclerostin levels (p < 0.001) than their counterparts in the low arterial stiffness group. A multivariable logistic regression analysis identified sclerostin as an independent predictor of arterial stiffness in hypertensive patients (odds ratio, 1.042; 95% confidence interval (CI), 1.017-1.068; p = 0.001). Multivariable forward stepwise linear regression analysis also showed that serum sclerostin level (beta = 0.255, adjusted R2 change: 0.146, p = 0.003) was positively associated with cfPWV values in patients with hypertension. CONCLUSIONS: In this study, serum sclerostin level, but not DKK1, is found to be positively correlated with cfPWV values and is identified as an independent predictor of arterial stiffness in hypertensive patients after adjusting for significant confounders. PMID- 30482162 TI - Dual positive and negative control of Chlamydomonas PII signal transduction protein expression by nitrate/nitrite and NO via the components of nitric oxide cycle. AB - BACKGROUND: The PII proteins constitute a large superfamily, present in all domains of life. Until now, PII proteins research in Chloroplastida (green algae and land plants) has mainly focused on post-translation regulation of these signal transductors. Emerging evidence suggests that PII level is tightly controlled with regard to the nitrogen source and the physiological state of cells. RESULT: Here we identify that a balance of positive (nitrate and nitrite) and negative (nitric oxide) signals regulates Chlamydomonas GLB1. We found that PII expression is downregulated by ammonium through a nitric oxide (NO)-dependent mechanism. We show that nitrate reductase (NR) and its partner, truncated hemoglobin 1 (THB1), participate in a signaling pathway for dual control of GLB1 expression. Moreover, NO dependent guanilate cyclase appeared to be involved in the negative control of GLB1 transcription. CONCLUSION: This study has revealed the existence of the complex GLB1 control at transcription level, which is dependent on nitrogen source. Importantly, we found that GLB1 gene expression pattern is very similar to that observed for nitrate assimilation genes, suggesting interconnecting/coordinating PII-dependent and nitrate assimilation pathways. PMID- 30482163 TI - The short-term effects of a mass reach physical activity campaign: an evaluation using hierarchy of effects model and intention profiles. AB - BACKGROUND: Mass reach physical activity campaigns are designed to deliver physical-activity related messages to a large population across different media including print, television, radio, and websites. Few evaluations have examined the short-term effects of a mass reach campaign on participants who were engaged with the campaign. The current research examined the short-term effects of the ParticipACTION 150 Play List, a mass reach physical activity campaign, on participants who registered with the campaign website. METHODS: Participants (N = 7801) completed a registration questionnaire measuring demographic information, awareness and recall of physical activity and sport advertising, and self reported number of activities tried or planned to try from the 150 Play List. A follow-up survey was completed by 1298 participants from the original sample. Additional questions assessed experience with the 150 Play List and attitudes towards campaign advertisements. RESULTS: Approximately 14.5% of participants cited the ParticipACTION 150 Play List and 23.6% mentioned a 'getting active' message when recalling advertisements. Those who named the 150 Play List or getting active reported more activities tried and more activities planned than those who did not. They were also more likely to say they had tried a new activity and planned ongoing participation. It was also found that participants with a disability were more likely to have tried a new activity compared to those not in a minority group. Other correlates of trying new activities at follow-up were younger age, more positive reported experience with the 150 Play List, and more favourable attitudes towards campaign advertisements. Those who did not intend continued participation, or who were unsure at baseline and then decided against continued participation at follow-up, reported they were less sedentary or encouraging others to be active. CONCLUSIONS: This research addresses the gap in evidence regarding the efficacy of mass reach physical activity campaigns by informing whether a year-long campaign like the 150 Play List can be effective in influencing the behavior of those engaged with the campaign. The results reinforce the idea that 'top of mind' awareness should be measured. Investigating intention profiles can help inform campaign impacts and continuation intentions. PMID- 30482164 TI - Assessing the social climate of physical (in)activity in Canada. AB - BACKGROUND: Ecological models suggest that a strategy for increasing physical activity participation within a population is to reconstruct the "social climate". This can be accomplished through 1) changing norms and beliefs, 2) providing direct support for modifying environments, and 3) implementing policies to encourage physical activity. Nevertheless, surveillance efforts have paid limited attention to empirical assessment of social climate. This study responds to this gap by assessing the social climate of physical activity in Canada. METHODS: A representative sample of Canadian adults (n = 2519, male/female = 50.3%/49.7%, Mage = 49.1 +/- 16.3 years) completed an online survey asking them to assess social climate dimensions including social norms of physical (in)activity, perceptions of who causes physical inactivity and who is responsible for solving physical inactivity, and support for physical activity related policy. Descriptive statistics (frequencies) were calculated. Multinomial logistic regressions were constructed to identify whether demographic variables and physical activity participation associated with social climate dimensions. RESULTS: Physical inactivity was considered a serious public health concern by 55% of the respondents; similar to unhealthy diets (58%) and tobacco use (57%). Thirty-nine percent of the respondents reported that they often see other people exercising. Twenty-eight percent of the sample believed that society disapproves of physical inactivity. The majority of respondents (63%) viewed the cause of physical inactivity as both an individual responsibility and other factors beyond an individuals' control. Sixty-seven percent of respondents reported physical inactivity as being both a private matter and a public health matter. Strong support existed for environmental-, individual-, and economic-level policies but much less for legislative approaches. The social climate indicators were associated with respondents' level of physical activity participation and demographic variables in expected directions. CONCLUSION: This study is the first known attempt to assess social climate at a national level, addressing an important gap in knowledge related to advocating for, and implementing population level physical activity interventions. Future tracking will be needed to identify any temporal (in)stability of these constructs over time and to explore the relationship between physical activity participation and indicators of the national social climate of physical activity. PMID- 30482165 TI - Prevalence of breast and ovarian cancer subtypes in Hispanic populations from Puerto Rico. AB - BACKGROUND: Previous epidemiological studies aimed at describing characteristics of breast (BC) and ovarian cancer (OC) patients tend to examine Hispanic populations using a mix of individuals that come from ethnically different Hispanic backgrounds. Since most USA cancer statistics do not include cancer data from Puerto Rico (PR), there is a lack of historical and descriptive data analysis for Hispanic women in the island that suffer from these diseases. Therefore, the aim of our study is to provide a comprehensive clinicopathological characterization of BC and OC cases in PR. METHODS: Our study consisted of a longitudinal retrospective review of archived pathology reports at Southern Pathology Services (SPS), which mostly serves southwestern PR, from years 2000 2015. After filtering SPS records with pre-established criteria, tumor samples from 3451 BC and 170 OC cases were used for descriptive statistics and analysis using R program. RESULTS: In our cohort, the mean age of diagnosis for BC was 60.5 years and 60.3 years for OC. Available data for subtype characterization from BC cases, exhibited an expected subtype distribution that remained stable over time (Luminal A = 68.8%, Luminal B = 9.7%, HER-2 = 6.1% and Triple negative = 15.4%). Additionally, tumor grades distribution varied within different BC subtypes in which the majority of Luminal A tumors were G2 and most Triple negative tumors were G3. For OC cases, available subtype and tumor grade information identified serous histology in 64.71% of all cases and G3 as being the most prevalent tumor grade. Pathology reports revealed that 39.42% of all OC cases were described as late stage, while 50.5% as early stage (by pathological staging). CONCLUSION: Our data suggests that OC and BC subtypes distribution in Hispanic populations from PR are in-line with national averages. In a significant number of BC cases, subtype could not be determined due to study limitations, health insurance coverage, or other reasons described here and may constitute a health disparity. Altogether, and despite these gaps, this study represents one of the most complete reviews of BC and OC in PR and provides an opportunity to further study this population separate from other US Hispanic populations. PMID- 30482166 TI - Spatial overlaps in the distribution of HIV/AIDS and malaria in Zimbabwe. AB - BACKGROUND: In most developing economies particularly in Africa, more people are likely to die of HIV/AIDS and malaria compared to other diseases. HIV/AIDS tends to be superimposed on the long standing malaria burden particularly in sub Saharan Africa. The detection and understanding of spatial overlaps in disease occurrence is important for integrated and targeted disease control. Integrated disease control can enhance efficiency and cost-effectiveness through the development of drugs targeting multiple infections in the same geographic space. METHODS: Using Zimbabwe as a case study, this study tests the hypothesis that malaria clusters coincide with HIV/AIDS clusters in space. Case data for the two diseases were obtained from the Ministry of Health and Child Care in Zimbabwe at district level via the District Health Information System (DHIS). Kulldorff's spatial scan statistic was used to test for spatial overlaps in clusters of high cases of HIV/AIDS and malaria at district level. The spatial scan test was used to identify areas with higher cases of HIV/AIDS and malaria than would be expected under spatial randomness. RESULTS: Results of this study indicate that primary clusters of HIV/AIDS and malaria were not spatially coincident in Zimbabwe. While no spatial overlaps were detected between primary clusters of the two diseases, spatial overlaps were detected among statistically significant secondary clusters of HIV/AIDS and malaria. Spatial overlaps between HIV/AIDS and malaria occurred in five districts in the northern and eastern regions of Zimbabwe. In addition, findings of this study indicate that HIV/AIDS is more widespread in Zimbabwe compared to malaria. CONCLUSIONS: The results of this study may therefore be used as a basis for spatially-targeted control of HIV/AIDS and malaria particularly in high disease burden areas. This is important as previous interventions have targeted the two diseases separately. Thus, targeted control could assist in resource allocation through prioritising areas in greatest need hence maximising the impact of disease control. PMID- 30482167 TI - Differences in prostate tumor characteristics and survival among religious groups in Songkhla, Thailand. AB - BACKGROUND: The incidence and mortality from prostate cancer is expected to increase in the next decade in Thailand. Despite the perceived lower risk in this population vs. developed, western countries, it is becoming an important public health issue. Prostate cancer incidence varies between the most predominant religious groups in Thailand, Buddhists and Muslims. However limited data is available describing the prostate cancer survival in these two populations. Here we examine differences in prostate tumor characteristics and survival between Buddhists and Muslims in the province of Songkhla, Thailand. METHODS: 945 incident prostate cancer cases (1990-2014) from the population-based Songkhla Cancer Registry were used in this analysis. Age, grade, stage, and year at diagnosis were compared across religious groups, using Wilcoxon or Chi-square tests. Kaplan Meier methods were used to estimate the median survival time and 5 year survival probabilities. Cox proportional hazards models were used to estimate hazard ratios (HR) between religious groups and 95% confidence intervals (CI) for mortality in age-adjusted and fully-adjusted models. RESULTS: Prostate tumor characteristics, age, and year at diagnosis were similar across religious groups. The median survival time after diagnosis of prostate cancer was longer in Buddhists 3.8 years compared with Muslims 3.2 years (p = 0.08). The age-adjusted risk of death after prostate cancer diagnosis was higher in Muslims compared with Buddhists (HR: 1.31; 95%CI: 1.00, 1.72). After adjustment by stage and grade, results were slightly attenuated (HR: 1.27, 95%CI: 0.97, 1.67). CONCLUSION: Muslims have shorter survival after prostate cancer diagnosis than do Buddhists in Thailand. The reasons underlying this difference require additional investigation in order to design targeted interventions for both populations. PMID- 30482168 TI - Interventions maintaining eating Independence in nursing home residents: a multicentre qualitative study. AB - BACKGROUND: Despite 32 years of research and 13 reviews published in the field, no intervention can be considered a gold standard for maintaining eating performance among residents with dementia. The study aim was to highlight the interventions derived from tacit knowledge and offered daily in assisting eating by healthcare professionals (HCPs) in nursing homes (NHs). METHOD: A multicentre descriptive qualitative study was performed in 2017. Thirteen NHs admitting residents with moderate/severe functional dependence in eating mainly due to dementia, were approached. A purposeful sample of 54 HCPs involved on a daily basis in assisting residents during mealtime were interviewed in 13 focus groups. Data analysis was conducted via qualitative content analysis. RESULTS: The promotion and maintenance of eating performance for as long as possible is ensured by a set of interventions targeting three levels: (a) environmental, by 'Ritualising the mealtime experience by creating a controlled stimulated environment'; (b) social, by 'Structuring effective mealtime social interactions'; and (c) individual, by 'Individualising eating care' for each resident. CONCLUSIONS: In NHs, the eating decline is juxtaposed with complex interventions regulated on a daily basis and targeting the environment, the social interactions, and the residents' needs. Several interventions that emerged as effective, according to the experience of participants, have never been documented before; while others are in contrast to the evidence documented. This suggests the need for further studies in the field; as no conclusions regarding the best interventions have been established to date. PMID- 30482169 TI - Comparing barriers to breastfeeding success in the first month for non-overweight and overweight women. AB - BACKGROUND: Women who enter pregnancy overweight or obese tend to have poorer breastfeeding outcomes compared to non-overweight women. Women's experiences of specific breastfeeding-related problems and reasons for use of formula have not been systematically investigated according to pre-pregnancy BMI. The aim of this study was to compare self-reported breastfeeding problems in non-overweight and overweight women and identify the main reasons for use of infant formula during the first month postpartum. METHODS: The present study involved a cross-sectional secondary analysis of data collected as part of a hospital-based longitudinal study of women that commenced in pregnancy (~ 16 weeks). At ~ 4 months postpartum Australian women (N = 477) self-reported breastfeeding problems and reasons for use of infant formula during the first month postpartum. Pre-pregnancy BMI was calculated based on self-reported pre-pregnancy weight and measured height. Binary logistic regression analyses were used to compare pre-pregnancy weight status groups ("non-overweight" [BMI < 25 km/m2] and "overweight" [BMI >=25 km/m2]) on self-reported breastfeeding problems and reasons for use of infant formula. Analyses were adjusted for covariates that differed between groups (P < .1). RESULTS: Frequency of self-reported breastfeeding problems was similar across weight status groups. "Not enough milk" was the predominant reason for giving infant formula. Overweight women were more likely than non-overweight women to agree that infant formula was as good as breastmilk. CONCLUSIONS: Overall it does not appear that overweight women are more likely to experience a range of specific breastfeeding problems in the first months compared to non overweight women. However, the severity and duration of the problems needs to be examined. Breastfeeding interventions need to addresses concerns around milk supply as these are common and are likely to be of universal benefit however overweight women in particular may benefit from guidance regarding the benefits of breastfeeding for both themselves and their infants. PMID- 30482170 TI - Beyond dialysis decisions: a qualitative exploration of decision-making among culturally and linguistically diverse adults with chronic kidney disease on haemodialysis. AB - BACKGROUND: To date, limited research has been dedicated to exploring the experience of decision-making for chronic kidney disease (CKD) patients who have initiated dialysis and have to make decisions in the context of managing multiple illnesses. Evidence about the experience of decision-making for minority or disadvantaged groups living with CKD (e.g. culturally and linguistically diverse adults; those with lower health literacy or cognitive impairment) is also lacking. This study aimed to explore the experience of healthcare decision-making among culturally and linguistically diverse adults receiving in-centre haemodialysis for advanced CKD. METHODS: Semi-structured interviews with English or Arabic-speaking adults recruited from four large haemodialysis units in Greater Western Sydney, Australia using stratified, purposive sampling. Interviews were audio-recorded, transcribed verbatim, and analysed using the Framework method. RESULTS: Interviews were conducted with 35 participants from a range of cultural backgrounds (26 English-language; 9 Arabic-language). One quarter had limited health literacy as assessed by the Single Item Literacy Screener. Four major themes were identified from the data, highlighting that participants had limited awareness of decision-points throughout the CKD trajectory (other than the decision to initiate dialysis), expressed passivity regarding their involvement in healthcare decisions, and reported inconsistent information provision within and across dialysis units. There was diversity within cultural and linguistic groups in terms of preferences and beliefs regarding religiosity, decision-making and internalised prototypical cultural values. CONCLUSION: Without sustained effort, adults living with CKD may be uninformed about decision points throughout the CKD trajectory and/or unengaged in the process of making decisions. While culture may be an important component of people's lives, cultural assumptions may oversimplify the diverse individual differences that exist within cultural groups. PMID- 30482171 TI - Can clinical signs or symptoms combined with basic hematology data be used to predict the presence of bacterial infections in febrile children under - 5 years? AB - BACKGROUND: Infectious diseases in children living in resource-limited settings are often presumptively managed on the basis of clinical signs and symptoms. Malaria is an exception. However, the interpretation of clinical signs and symptoms in relation to bacterial infections is often challenging, which may lead to an over prescription of antibiotics when a malaria infection is excluded. The present study aims to determine the association between clinical signs and symptoms and basic hematology data, with laboratory confirmed bacterial infections. METHODS: A health survey was done by study nurses to collect clinical signs/symptoms in febrile (axillary temperature >= 37.5 degrees C) children under - 5 years of age. In addition, blood, stool and urine specimen were systematically collected from each child to perform bacterial culture and full blood cell counts. To determine the association between a bacterial infection with clinical signs/symptoms, and if possible supported by basic hematology data (hemoglobin and leucocyte rates), a univariate analysis was done. This was followed by a multivariate analysis only on those variables with a p-value p < 0.1 in the univariate analysis. Only a p-value of < 0.05 was considered as significant for multivariate analysis. RESULTS: In total, 1099 febrile children were included. Bacteria were isolated from clinical specimens (blood-, stool- and urine- culture) of 127 (11.6%) febrile children. Multivariate logistical regression analysis revealed that a general bacterial infection (irrespective of the site of infection) was significantly associated with the following clinical signs/symptoms: diarrhea (p = 0.003), edema (p = 0.010) and convulsion (p = 0.021). Bacterial bloodstream infection was significantly associated with fever> 39.5 degrees C (p = 0.002), diarrhea (p = 0.019) and edema (p = 0.017). There was no association found between bacterial infections and basic haematological findings. If diarrhea and edema were absent, a good negative predictive value (100%) of a bacterial bloodstream infection was found, but the positive predictive value was low (33.3%) and the confidence interval was very large (2.5 100; 7.5-70.1). CONCLUSION: Our study demonstrates that clinical signs and symptoms, combined with basic hematology data only, cannot predict bacterial infections in febrile children under - 5 years of age. The development of practical and easy deployable diagnostic tools to diagnose bacterial infections remains a priority. PMID- 30482172 TI - dbMPIKT: a database of kinetic and thermodynamic mutant protein interactions. AB - BACKGROUND: Protein-protein interactions (PPIs) play important roles in biological functions. Studies of the effects of mutants on protein interactions can provide further understanding of PPIs. Currently, many databases collect experimental mutants to assess protein interactions, but most of these databases are old and have not been updated for several years. RESULTS: To address this issue, we manually curated a kinetic and thermodynamic database of mutant protein interactions (dbMPIKT) that is freely accessible at our website. This database contains 5291 mutants in protein interactions collected from previous databases and the literature published within the last three years. Furthermore, some data analysis, such as mutation number, mutation type, protein pair source and network map construction, can be performed online. CONCLUSION: Our work can promote the study on PPIs, and novel information can be mined from the new database. Our database is available in http://DeepLearner.ahu.edu.cn/web/dbMPIKT/ for use by all, including both academics and non-academics. PMID- 30482173 TI - Correction to: cuRnet: an R package for graph traversing on GPU. AB - After publication of this supplement article [1], it was brought to our attention that reference 10 and reference 12 in the article are incorrect. PMID- 30482174 TI - Perceived parental support in childhood and adolescence and suicidal ideation in young adults: a cross-sectional analysis of the i-Share study. AB - BACKGROUND: Suicidal ideation and suicidal risk assessment are major concerns for health professionals. The perception of a low level of parental support is a risk factor for suicidal tendencies among adolescents, but little is known about its long-term impact on the vulnerability to suicidal behavior in young adults. We investigated whether the perceived level of parental support during childhood and adolescence was associated with current suicidal ideation in young adults. METHODS: We retrieved data collected in the i-Share study from February 1st, 2013 through January 30, 2017. This cross-sectional study included 10,015 French students, aged 18-24 years that completed an on-line self-reported questionnaire about suicidal ideation in the last 12 months and their perceived parental support in childhood and adolescence. We performed multinomial logistic regressions and sensitivity analyses to assess associations between the degree of perceived parental support and the frequency suicidal thoughts, after adjusting for the main known risk factors of suicidal ideation. We employed multiple imputations to account for missing data. RESULTS: The study sample included 7539 female (75.7%) and 2436 male (24.3%) students (mean [SD] age 20.0 [1.8] years). About one in five students reported occasional suicidal thoughts (n = 1775, 17.7%) and 368 students (3.7%) reported frequent suicidal thoughts. The adjusted multinomial logistic regression revealed a significant negative association between perceived parental support and suicidal thoughts. A lack of perceived parental support in childhood and adolescence was associated with > 4-fold elevated risk of occasional (adjusted OR, 4.55; 95% CI: 2.97-6.99) and nearly 9 fold elevated risk of frequent (adjusted OR, 8.58; 95% CI: 4.62-15.96) suicidal thoughts, compared to individuals that perceived extremely strong parental support. This association was strongest among students with no personal history of depression or suicide attempts. CONCLUSIONS: Students that perceived low levels of past parental support had a higher risk of suicidal ideation. Past perceived parental support appeared to be a potent marker of suicidal risk in young adults. This marker should be routinely collected in studies on suicidal risk in young adults, and it could be considered an additional screening tool. PMID- 30482176 TI - Multi-arm multi-stage trials can improve the efficiency of finding effective treatments for stroke: a case study. AB - BACKGROUND: Many recent Stroke trials fail to show a beneficial effect of the intervention late in the development. Currently a large number of new treatment options are being developed. Multi-arm multi-stage (MAMS) designs offer one potential strategy to avoid lengthy studies of treatments without beneficial effects while at the same time allowing evaluation of several novel treatments. In this paper we provide a review of what MAMS designs are and argue that they are of particular value for Stroke trials. We illustrate this benefit through a case study based on previous published trials of endovascular treatment for acute ischemic stroke. We show in this case study that MAMS trials provide additional power for the same sample size compared to alternative trial designs. This level of additional power depends on the recruitment length of the trial, with most efficiency gained when recruitment is relatively slow. We conclude with a discussion of additional considerations required when starting a MAMS trial. CONCLUSION: MAMS trial designs are potentially very useful for stroke trials due to their improved statistical power compared to the traditional approach. PMID- 30482175 TI - Tracking progress in suicide prevention in Indigenous communities: a challenge for public health surveillance in Canada. AB - Indigenous peoples in Canada experience disproportionate rates of suicide compared to non-Indigenous populations. Indigenous communities and organizations have designed local and regional approaches to prevention, and the federal government has developed a national suicide prevention framework. However, public health systems continue to face challenges in monitoring the population burden of suicide and suicidal behaviour. National health data systems lack Indigenous identifiers, do not capture data from some regions, and do not routinely engage Indigenous communities in data governance. These challenges hamper efforts to detect changes in population-level outcomes and assess the impact of suicide prevention activities. Consequently, this limits the ability to achieve public health prevention goals and reduce suicide rates and rate inequities.This paper provides a critical analysis of the challenges related to suicide surveillance in Canada and assesses the strengths and limitations of existing data infrastructure for monitoring outcomes in Indigenous communities. To better understand these challenges, we discuss the policy context for suicide surveillance and examine the survey and administrative data sources that are commonly used in public health surveillance. We then review recent data on the epidemiology of suicide and suicidal behaviour among Indigenous populations, and identify challenges related to national surveillance.To enhance capacity for suicide surveillance, we propose strategies to better track progress in Indigenous suicide prevention. Specifically, we recommend establishing an independent community and scientific governing council, integrating Indigenous identifiers into population health datasets, increasing geographic coverage, improving suicide data quality, comprehensiveness, and timeliness, and developing a platform for making suicide data accessible to all stakeholders. Overall, the strategies we propose can build on the strengths of the existing national suicide surveillance system by adopting a collaborative and inclusive governance model that recognizes the stake Indigenous communities have in suicide prevention. PMID- 30482177 TI - Characterization of bHLH/HLH genes that are involved in brassinosteroid (BR) signaling in fiber development of cotton (Gossypium hirsutum). AB - BACKGROUND: Basic helix-loop-helix/helix-loop-helix (bHLH/HLH) transcription factors play important roles in plant development. Many reports have suggested that bHLH/HLH proteins participate in brassinosteroid (BR) hormone signaling pathways to promote cell elongation. Cotton fibers are single-cells and derived from seed surface. To explore the roles of bHLH/HLH proteins in cotton fiber development progress by modulating BR signaling pathway, we performed a systematic analysis of the bHLH/HLH gene family in upland cotton (Gossypium hirsutum) genome. RESULTS: In this study, we identified 437 bHLH/HLH genes in upland cotton (G. hirsutum) genome. Phylogenetic analysis revealed that GhbHLH/HLH proteins were split into twenty six clades in the tree. These GhbHLH/HLH genes are distributed unevenly in different chromosomes of cotton genome. Segmental duplication is the predominant gene duplication event and the major contributor for amplification of GhbHLH/HLH gene family. The GhbHLH/HLHs within the same group have conserved exon/intron pattern and their encoding proteins show conserved motif composition. Based on transcriptome data, we identified 77 GhbHLH/HLH candidates that are expressed at relatively high levels in cotton fibers. As adding exogenous BR (brassinolide, BL) or brassinazole (Brz, a BR biosynthesis inhibitor), expressions of these GhbHLH/HLH genes were up regulated or down-regulated in cotton fibers. Furthermore, overexpression of GhbHLH282 (one of the BR-response genes) in Arabidopsis not only promoted the plant growth, but also changed plant response to BR signaling. CONCLUSION: Collectively, these data suggested that these GhbHLH/HLH genes may participate in BR signaling transduction during cotton fiber development. Thus, our results may provide a valuable reference data as the basis for further studying the roles of these bHLH/HLH genes in cotton fiber development. PMID- 30482179 TI - Pharmacological management of cachexia in adult cancer patients: a systematic review of clinical trials. AB - BACKGROUND: Cachexia is a multisystem syndrome characterized by weight loss, anorexia, loss of muscle mass, systemic inflammation, insulin resistance, and functional decline. Management of cachexia involves addressing multiple underlying biological mechanisms. Previous review on pharmacological management of cancer cachexia identified progestins and corticosteroids as effective agents for treatment of cachexia. However, to date no consensus exists on a single effective or standard treatment for management of cachexia. The aim of this systematic review is to determine the effectiveness of pharmacological treatments used to manage cachexia among adult cancer patients. METHODS: We performed literature searches of PubMed (NLM), Embase (Ovid), and Medline(Ovid) to identify clinical trials focused on pharmacological management of cancer cachexia among adult cancer patients from 2004 to 2018. Three reviewers screened a random selection of abstracts to measure for interrater reliability. After this step, each screener screened two-thirds of all abstracts and 177 studies were identified for full text review. The primary outcome was impact of pharmacological management on change in either weight or lean body mass in cancer patients. RESULTS: We identified 19 articles (representing 20 RCTs) that focused on pharmacological management of cancer cachexia. Agents showing promising results included Anamorelin and Enobosarm. Anamorelin at 50 or 100 mg per day for 12 weeks showed a consistent benefit across all studies and resulted in significant improvement in weight as compared to baseline among cancer patients. Enobosarm at 1 and 3 mg per day was also effective in improving lean body mass and QOL symptoms among advancer stage cancer patients. Finally, use of combination agents provide evidence for targeting multiple pathways underlying cachexia mechanism to achieve maximum benefit. No agents showed functional improvement in cancer patients. CONCLUSION: Anamorelin as a single agent shows promising results in improving cachexia related weight loss among cancer patients. Further research on combination therapies may be helpful to address critical gaps in cachexia management. PMID- 30482178 TI - Genomic traits of Klebsiella oxytoca DSM 29614, an uncommon metal-nanoparticle producer strain isolated from acid mine drainages. AB - BACKGROUND: Klebsiella oxytoca DSM 29614 - isolated from acid mine drainages - grows anaerobically using Fe(III)-citrate as sole carbon and energy source, unlike other enterobacteria and K. oxytoca clinical isolates. The DSM 29614 strain is multi metal resistant and produces metal nanoparticles that are embedded in its very peculiar capsular exopolysaccharide. These metal nanoparticles were effective as antimicrobial and anticancer compounds, chemical catalysts and nano-fertilizers. RESULTS: The DSM 29614 strain genome was sequenced and analysed by a combination of in silico procedures. Comparative genomics, performed between 85 K. oxytoca representatives and K. oxytoca DSM 29614, revealed that this bacterial group has an open pangenome, characterized by a very small core genome (1009 genes, about 2%), a high fraction of unique (43,808 genes, about 87%) and accessory genes (5559 genes, about 11%). Proteins belonging to COG categories "Carbohydrate transport and metabolism" (G), "Amino acid transport and metabolism" (E), "Coenzyme transport and metabolism" (H), "Inorganic ion transport and metabolism" (P), and "membrane biogenesis-related proteins" (M) are particularly abundant in the predicted proteome of DSM 29614 strain. The results of a protein functional enrichment analysis - based on a previous proteomic analysis - revealed metabolic optimization during Fe(III) citrate anaerobic utilization. In this growth condition, the observed high levels of Fe(II) may be due to different flavin metal reductases and siderophores as inferred form genome analysis. The presence of genes responsible for the synthesis of exopolysaccharide and for the tolerance to heavy metals was highlighted too. The inferred genomic insights were confirmed by a set of phenotypic tests showing specific metabolic capability in terms of i) Fe2+ and exopolysaccharide production and ii) phosphatase activity involved in precipitation of metal ion-phosphate salts. CONCLUSION: The K. oxytoca DSM 29614 unique capabilities of using Fe(III)-citrate as sole carbon and energy source in anaerobiosis and tolerating diverse metals coincides with the presence at the genomic level of specific genes that can support i) energy metabolism optimization, ii) cell protection by the biosynthesis of a peculiar exopolysaccharide armour entrapping metal ions and iii) general and metal specific detoxifying activities by different proteins and metabolites. PMID- 30482181 TI - My Migraine Voice survey: a global study of disease burden among individuals with migraine for whom preventive treatments have failed. AB - BACKGROUND: Migraine is associated with many debilitating symptoms that affect daily functioning. My Migraine Voice is a large global cross-sectional study aimed at understanding the full burden and impact of migraine directly from patients suffering from >=4 monthly migraine days (MMDs) with a history of prophylactic treatment failure. METHODS: This study was conducted worldwide (31 countries across North and South Americas, Europe, the Middle East and Northern Africa, and the Asia-Pacific region) using an online survey administered to adults with migraine who reported >=4 MMDs in the 3 months preceding survey administration, with pre-specified criteria of 90% having used preventive migraine treatment (80% with history of >=1 treatment failure). Prophylactic treatment failure was defined as a reported change in preventive medication by individuals with migraine for any reason, at least once. RESULTS: In total, 11,266 individuals participated in the survey. Seventy-four percent of the participants reported spending time in darkness/isolation due to migraine (average: 19 h/month). While 85% of all respondents reported negative aspects of living with migraine (feeling helpless, depressed, not understood), sleeping difficulties (83%), and fear of the next attack (55%), 57% shared >=1 positive aspect (learning to cope, becoming a stronger person). Forty-nine percent reported feeling limited in daily activities throughout all migraine phases. Migraine impact on professional, private, or social domains was reported by 87% of respondents (51% in all domains). In the previous 12 months, 38% of respondents had visited the emergency department (average: 3.3 visits), whereas 23% stayed in hospital overnight (average: 3.2 nights) due to migraine. CONCLUSIONS: The burden of migraine is substantial among this cohort of individuals with at least 4 migraine days per month and for whom at least 1 preventive migraine treatment had failed. Interestingly, respondents reported some positive aspects in their migraine journey; the greater resilience and strength brought on by coping with migraine suggests that if future treatments could address existing unmet needs, these individuals with migraine will be able to maximize their contribution to society. PMID- 30482182 TI - Genome of tiny predator with big appetite. AB - The capture and enslavement of eukaryotic algae by unicellular predators to acquire photosynthesis was a major driving force in early eukaryotic diversification. A genome presented in BMC Biology provides a glimpse of how such a tiny predator might have preyed on red algae and detained them to create new lineages of photosynthetic organisms. PMID- 30482180 TI - Hand hygiene in hospitals: an observational study in hospitals from two southern states of India. AB - BACKGROUND: Hand hygiene is a simple and low-cost measure to reduce healthcare associated infection yet it has always been a concern in low as well as high resource settings across the globe. Poor hand hygiene during intra-partum and newborn care may result in sepsis, which is a major cause of death among newborns and puts a financial burden on already strained health systems. METHODS: We conducted non-participatory observations in newborn care units and labour rooms from secondary and tertiary level, public and private hospitals, as part of a baseline evaluation of a quality improvement collaborative across two southern states of India. We assessed hand hygiene compliance during examinations and common procedures, using tools adapted from internationally recommended checklists and World Health Organization's concept of five moments of hand hygiene. We assessed differences in compliance by type (public/private), level (secondary/tertiary) and case load (low/intermediate/high). Analysis was adjusted for clustering and weighted as appropriate. RESULTS: We included 49 newborn care units (19 private, 30 public) and 35 labour rooms (5 private, 30 public) that granted permission. We observed 3661 contacts with newborns and their environment, 242 per-vaginal examinations and 235 deliveries. For the newborns, a greater proportion of contacts in private newborn units than public complied with all steps of hand hygiene (44% vs 12%, p < 0.001), and similarly in tertiary than secondary units (33% vs 12%, p < 0.001) but there was no evidence of a difference by case load of the facility (low load-28%; intermediate load-14%; high load- 24%, p = 0.246). The component with lowest compliance was glove usage where indicated (20%). For deliveries, hand hygiene compliance before delivery was universal in private facilities but seen in only about one-quarter of observations in public facilities (100% vs 27%, p = 0.012). Average overall compliance for hand-hygiene during per-vaginal examinations was 35% and we found no evidence of differences by type of facility. CONCLUSION: Observed compliance with hand hygiene was low overall, although better in private than public facilities in both newborn units and labour rooms. Glove usage was a particular problem in newborn care units. TRIAL REGISTRATION: Retrospectively registered with Clinical Trials Registry- India ( CTRI/2018/04/013014 ). PMID- 30482183 TI - Adapting the supervisory relationship measure for general medical practice. AB - BACKGROUND: The relationship between general practice (GP) supervisors and registrars is a critical component in effective training for the next generation of medical practitioners. Despite the importance of the relational aspect of clinical education, most evaluation has traditionally occurred from the perspective of the registrar only. As such, no validated tools exist to measure the quality of the supervisory relationship from the perspective of the supervisor. This paper presents an adaptation and validation of the clinical psychology supervisory relationship measure (Pearce et al, Br J Clin Psychol 52:249-68, 2013) for GP supervisors in an Australian context. METHOD: Following an Expert Group review and adaptation of the items, 338 GP supervisors completed the adapted tool. RESULTS: Using principal components analysis and Procrustes confirmatory rotation, an optimal three-component model of supervisory relationship was identified, reflecting measures of Safe base (alpha = .96), Supervisor investment (alpha = .85), and Registrar professionalism (alpha = .94). CONCLUSIONS: The general practice supervisory relationship measure (GP-SRM) demonstrated excellent model fit, high internal consistency, and was theoretically consistent with the original tool. Implications for clinical education and future research are presented. PMID- 30482184 TI - Spigelian hernia in the right upper abdominal wall: a case report. AB - BACKGROUND: Spigelian hernia (SH) is rare and constitutes less than 2% of all hernias. It is reported that more than 90% of SHs lie in the "Spigelian belt", but SH in the upper abdominal wall is extremely uncommon. Here, we report a case of SH in the right upper quadrant of abdomen. CASE PRESENTATION: A 38-year-old female was admitted to hospital with complaints of abdominal pain and right upper quadrant mass for 10 days. Contrast-enhanced computed tomography (CECT) of abdomen revealed the dilated small intestine between the swelling ventral muscles in the right upper abdominal wall which suggested a ventral hernia. The surgeons considered it was a spontaneous hernia because there was no history of surgery or trauma in the upper abdomen. About two hours later, the patient underwent emergency surgery. According to laparotomy, a diagnosis of SH with ileum herniation in the right upper abdominal wall was confirmed. The necrotic ileum segment was resected. Meanwhile the abdominal wall defect was repaired by suturing the internal oblique and transverse muscles to the rectus sheath. The patient had a favorable outcome for 1 year without recurrence. CONCLUSION: A mass and pain in the upper abdominal wall may suggest an atypical SH. SH occurring in the upper abdominal wall is a rare condition with possibility of dire outcome if not managed early. PMID- 30482185 TI - Measles vaccination coverage, determinants of delayed vaccination and reasons for non-vaccination among children aged 24-35 months in Zhejiang province, China. AB - BACKGROUND: This study was aimed to assess the coverage of two doses of measles vaccine and identify the determinants of the delayed vaccination. METHODS: A cluster survey among 1386 children aged 24-35 months was conducted. Characteristics on demographic and socio-economic and vaccination records was collected. The overall coverage was defined as the proportion of children receiving the first dose of measles vaccination and the second dose of measles vaccination by 24 months of age. The age-appropriate coverage was defined as the proportion of children receiving the measles vaccine doses within one month after its relevant due date. Timeliness was evaluated with the Kaplan-Meier analysis. Cox proportional hazard regression was adopted to identify determinants of the delayed vaccination. RESULTS: The overall coverage was 96.9% for the first dose of measles vaccine and 93.9% for the second dose of measles vaccine. The age appropriate coverage of the first and the second dose of measles vaccine was 76.6 and 68.2%, respectively. Household having more than one child, non-local children were associated with the delayed vaccination for the first and the second dose of measles vaccine. Children delivered at home, younger mothers, low maternal education background, mothers with a fixed job, and low household income were associated with the delayed vaccination for the second dose of measles vaccine. CONCLUSIONS: The coverage of measles vaccine had been improved for both the first and the second dose, while the timeliness still needed improvement. We suggested the policy-makers pay more attention to the reasons for non-vaccination and determinants of delayed vaccination when planning efforts to ensure the high age appropriate coverage of measles vaccination. PMID- 30482186 TI - The levonorgestrel intrauterine device in Australia: analysis of prescribing data 2008-2012. AB - BACKGROUND: Unplanned pregnancy is a significant problem in Australia. Local data pertaining to use of the levonorgestrel-releasing intra-uterine device (LNG-IUD), and associated factors are limited. The aim of this analysis was to calculate prescribing rates of the LNG-IUD in Australia, including trends in prescribing and associations with socio-demographic factors, in order to increase understanding regarding potential use. METHODS: We examined prescriptions for the LNG-IUD recorded in the national Pharmaceutical Benefits Scheme (PBS) from 2008 to 2012. Prescribing trends were examined according to patient age, remoteness of residential location, and proximity to relevant specialist health services. Associations between these factors and prescription rates were examined using poisson regression. Analyses were stratified by 5-year age-groups. RESULTS: Age adjusted prescription rates rose from 11.50 per 1000 women aged 15-49 (95% CI: 11.41-11.59) in 2008 to 15.95 (95% CI:15.85-16.01) in 2012. Prescription rates increased most among 15-19-year-olds but remain very low at 2.76 per 1000 women (95% CI: 2.52-3.01). Absolute increases in prescriptions were greatest among 40 44-year-olds, rising from 16.73 per 1000 women in 2008 (95% CI: 16.12-17.34) to 23.77 in 2012 (95% CI: 22.58-24.29). Rates increased significantly within all geographical locations (p < 0.01). Non-metropolitan location was significantly associated with increased prescribing rates, the association diminishing with increasing age groups. CONCLUSIONS: Prescription of LNG-IUD in Australia is very low, especially among young women and those in major cities. Service providers and young women may benefit from targeted education outlining use of the LNG-IUD, strengthened training and referral pathways. Disparities in prescription according to location require further investigation. PMID- 30482188 TI - Fake spawns and floating particles: a rebuttal of Karkarey et al. "Alternative reproductive tactics and inverse size-assortment in a high-density fish spawning aggregation". AB - Courtship and spawning behaviors of coral reef fishes are very complex, and sufficient sampling effort and proper methods are required to draw informed conclusions on their mating systems that are grounded in contemporary theories of mate choice and sexual selection. We reviewed the recent study by Karkarey et al. (BMC Ecol 17:10, 2017) on the spawning behavior of Squaretail coralgrouper (Plectropomus areolatus) from India and found no evidence to support their findings of alternative reproductive tactics, unique school-spawning involving a single male with multiple females, or inverse size-assortment. The study lacks scientific credibility due to a lack of rigor in the methodology used, misinterpretation of observed behaviors, misinterpretation of the literature, and insufficient data. Their approach led the authors to produce spurious results and profound, invalid conclusions that violate the most basic assumptions of mate choice and sexual selection theory as applied to mating systems in marine fishes. PMID- 30482187 TI - Prevalence and in-hospital outcomes of diabetes among patients with acute coronary syndrome in China: findings from the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome Project. AB - BACKGROUND: Guidelines have classified patients with acute coronary syndrome (ACS) and diabetes as a special population, with specific sections presented for the management of these patients considering their extremely high risk. However, in China up-to-date information is lacking regarding the burden of diabetes in patients with ACS and the potential impact of diabetes status on the in-hospital outcomes of these patients. This study aims to provide updated estimation for the burden of diabetes in patients with ACS in China and to evaluate whether diabetes is still associated with excess risks of early mortality and major adverse cardiovascular and cerebrovascular events (MACCE) for ACS patients. METHODS: The Improving Care for Cardiovascular Disease in China-ACS Project was a collaborative study of the American Heart Association and the Chinese Society of Cardiology. A total of 63,450 inpatients with a definitive diagnosis of ACS were included. Prevalence of diabetes was evaluated in the overall study population and subgroups. Multivariate logistic regression was performed to examine the association between diabetes and in-hospital outcomes, and a propensity-score matched analysis was further conducted. RESULTS: Among these ACS patients, 23,880 (37.6%) had diabetes/possible diabetes. Both STEMI and NSTE-ACS patients had a high prevalence of diabetes/possible diabetes (36.8% versus 39.0%). The prevalence of diabetes/possible diabetes was higher in women (45.0% versus 35.2%, p < 0.001). Even in patients younger than 45 years, 26.9% had diabetes/possible diabetes. While receiving comparable treatments for ACS, diabetes/possible diabetes was associated with a twofold higher risk of all-cause death (adjusted odds ratio 2.04 [95% confidence interval 1.78-2.33]) and a 1.5-fold higher risk of MACCE (adjusted odds ratio 1.54 [95% confidence interval 1.39-1.72]). CONCLUSIONS: Diabetes was highly prevalent in patients with ACS in China. Considerable excess risks for early mortality and major adverse cardiovascular events were found in these patients. Trial registration NCT02306616. Registered December 3, 2014. PMID- 30482189 TI - In vitro and in vivo accumulation of magnetic nanoporous silica nanoparticles on implant materials with different magnetic properties. AB - BACKGROUND: In orthopedic surgery, implant-associated infections are still a major problem. For the improvement of the selective therapy in the infection area, magnetic nanoparticles as drug carriers are promising when used in combination with magnetizable implants and an externally applied magnetic field. These implants principally increase the strength of the magnetic field resulting in an enhanced accumulation of the drug loaded particles in the target area and therewith a reduction of the needed amount and the risk of undesirable side effects. In the present study magnetic nanoporous silica core-shell nanoparticles, modified with fluorophores (fluorescein isothiocyanate/FITC or rhodamine B isothiocyanate/RITC) and poly(ethylene glycol) (PEG), were used in combination with metallic plates of different magnetic properties and with a magnetic field. In vitro and in vivo experiments were performed to investigate particle accumulation and retention and their biocompatibility. RESULTS: Spherical magnetic silica core-shell nanoparticles with reproducible superparamagnetic behavior and high porosity were synthesized. Based on in vitro proliferation and viability tests the modification with organic fluorophores and PEG led to highly biocompatible fluorescent particles, and good dispersibility. In a circular tube system martensitic steel 1.4112 showed superior accumulation and retention of the magnetic particles in comparison to ferritic steel 1.4521 and a Ti90Al6V4 control. In vivo tests in a mouse model where the nanoparticles were injected subcutaneously showed the good biocompatibility of the magnetic silica nanoparticles and their accumulation on the surface of a metallic plate, which had been implanted before, and in the surrounding tissue. CONCLUSION: With their superparamagnetic properties and their high porosity, multifunctional magnetic nanoporous silica nanoparticles are ideal candidates as drug carriers. In combination with their good biocompatibility in vitro, they have ideal properties for an implant directed magnetic drug targeting. Missing adverse clinical and histological effects proved the good biocompatibility in vivo. Accumulation and retention of the nanoparticles could be influenced by the magnetic properties of the implanted plates; a remanent martensitic steel plate significantly improved both values in vitro. Therefore, the use of magnetizable implant materials in combination with the magnetic nanoparticles has promising potential for the selective treatment of implant-associated infections. PMID- 30482190 TI - Necrotizing enterocolitis leads to disruption of tight junctions and increase in gut permeability in a mouse model. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a leading cause of death in preterm infants. Neonates weighing <1500 grams are at the highest risk for acquiring NEC, with a prevalence of nearly 7-10%, mortality up to 30%, and several long-term complications among survivors. Despite advancements in neonatal medicine, this disease remains a challenge to treat. The aim of this study is to investigate the effect of NEC on gut epithelial tight junctions and its barrier function using a NEC mouse model. METHODS: Three-day old C57BL/6 mouse pups were fed with Esbilac formula every 3 hours and then subjected to hypoxia twice daily followed by cold stress. Dam fed pups from the same litters served as controls. Pups were observed and sacrificed 96 hours after the treatments and intestines were removed for experiments. The successful induction of NEC was confirmed by histopathology. Changes in tight junction proteins in NEC intestines were studied by western blotting and immunofluorescent microscopy using specific protein markers. The gut leakage in NEC was visualized using biotin tracer molecules. RESULTS: Our study results demonstrate that we induced NEC in >50% of experimental pups, pups lost nearly 40% of weight and their intestines showed gross changes and microscopic changes associated with NEC. There were inflammatory changes with loss of tight junction barrier function and disruption of tight junction claudin proteins in the intestines of NEC mouse model. We have demonstrated for the first time that NEC intestines develop increased leakiness as visualized by biotin tracer leakage. CONCLUSIONS: NEC leads to breakdown of epithelial barrier due to changes in tight junction proteins with increased leakiness which may explain the transmigration of microbes and microbial products from the gut lumen into the blood stream leading to sepsis like signs clinically witnessed. PMID- 30482191 TI - Does glucagon have a positive inotropic effect in the human heart? AB - Glucagon is considered to exert cardiostimulant effects, most notably the enhancement of heart rate and contractility, due to the stimulation of glucagon receptors associated with Gs protein stimulation which causes adenylyl cyclase activation and the consequent increase in 3',5'-cyclic adenosine monophosphate production in the myocardium. These effects have been extensively demonstrated in experimental studies in different animal species. However, efforts to extrapolate the experimental data to patients with low cardiac output states, such as acute heart failure or cardiogenic shock, have been disappointing. The experimental and clinical data on the cardiac effects of glucagon are described here. PMID- 30482192 TI - A randomised controlled pilot and feasibility study of music therapy for improving the quality of life of hospice inpatients. AB - BACKGROUND: Evidence about the effectiveness of music therapy for improving the quality of life of palliative care patients is positive but weak in terms of risk of bias. METHODS: This study aimed to determine the feasibility of a randomised controlled trial to evaluate the effectiveness of music therapy for improving the quality of life of hospice inpatients, as measured by the McGill Quality of Life questionnaire. Objectives included recruitment of 52 participants over 12 months and provision of data to support the calculation of the required sample size for a definitive randomised trial, taking into account the retention rates of recruited participants; and evaluation of the viability of the intervention and the acceptability of the assessment tool. The design was a single-centre, researcher-blinded randomised pilot and feasibility study involving two parallel groups. Participants were recruited from one inpatient hospice unit in Northern Ireland. Eligibility criteria were an Eastern Cooperative Oncology Group performance status of two or lower and an Abbreviated Mental Test score of seven or more. Consenting patients were randomly allocated to the intervention or control group using a 1:1 allocation ratio. The intervention group received up to six individual music therapy sessions over 3 weeks in addition to usual care. The control group received usual care only. RESULTS: Fifty one participants were recruited over 12 months. Twenty five were allocated to the intervention group and 26 to the control group. Seventy one percent of participants were lost to follow up by week 3, the proposed primary endpoint. The primary endpoint was moved from week 3, when 71% were lost to follow up to week 1, when 33% were lost. The McGill Quality of Life questionnaire was generally acceptable to participants. In order to detect a small to moderate effect size of 0.3, a fully powered study would require the recruitment of 698 participants. CONCLUSIONS: A Phase III randomised controlled trial to evaluate the effectiveness of music therapy in improving the quality of life of hospice inpatients is feasible. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02791048 . Registered 6 June 2016. PMID- 30482193 TI - Self-compassion is associated with less stress and depression and greater attention and brain response to affective stimuli in women managers. AB - BACKGROUND: Women have been assuming more responsibilities and higher positions in major companies, which exposes them to high levels of stress. Higher perceived work stress is related to higher emotional reactivity. Difficulties with emotional regulation can lead to anxiety and mood disorders, which are more prevalent in women than men. Indeed, women leaders are more likely to experience emotional fatigue than men due to excessive empathy. Our aim was to evaluate the associations between self-compassion (SC) scores to depression symptoms, perceived stress and mindfulness, as well as with brain responses to high-arousal unpleasant and pleasant pictures from the International Affective Picture System (IAPS), as measured through functional Magnetic Resonance Imaging (fMRI) in women managers. METHODS: Forty-six participants were selected for the study. All participants filled the Self Compassion Scale (SCS), Beck Depression Inventory (BDI), Mindful Awareness Attention Scale (MAAS) and the Perceived Stress Scale (PSS). After that they were scanned during an fMRI affective response paradigm. Correlation analysis were performed among these variables. RESULTS: Our data suggest that women with higher SC scores respond to affective stimuli with higher activation of the precuneus (a brain region related to self-referential processing), lower levels of stress and depression and show greater attention in everyday activities. CONCLUSION: SC may be an important characteristic for women leaders because of its association with higher sensitivity to emotional stimuli and mindfulness. These skills may allow them to be more aware of others while being less susceptible for stress and depression symptoms. PMID- 30482195 TI - Factors perceived to influence implementation of task shifting in highly specialised healthcare: a theory-based qualitative approach. AB - BACKGROUND: New approaches to control healthcare expenditures and increase access to quality care are required by decision-makers in high-income countries. One strategy is to reallocate tasks from doctors to nurses. Evidence suggests that quality, effectiveness and efficiency of task shifting are context sensitive and affected by implementation. However, little is known about implementability of task shifting in specialised healthcare. We aimed to identify factors perceived to influence implementation of doctor-to-nurse task shifting in a hospital setting and improve understanding of task shifting implementability by using theory-based frameworks for analysing behaviour. Nurse-led bone marrow examination exemplified task shifting from the medical to the nursing domain. METHODS: Doctors and nurses (n = 17) in a haematology department at a Norwegian university hospital were asked about factors perceived to influence implementation of nurse-led bone marrow aspirations and biopsies. Methods included in-depth semi-structured interviews (n = 11) and focus-group discussion (n = 6). Data were analysed using the Capability, Opportunity, and Motivation behaviour model and the Theoretical Domains Framework. RESULTS: Ten factors perceived to influence implementation were identified. Three factors were related to capability, including (1) knowledge and acceptability of task shifting rationale; (2) dynamic role boundaries; and (3) technical skills to perform biopsies and aspirations. Five factors were related to motivation, including (4) beliefs about task shifting consequences, such as efficiency, quality and patient satisfaction; (5) beliefs about capabilities, such as technical, communicative and emotional skills; (6) job satisfaction and esteem; (7) organisational culture, such as team optimism; and (8) emotions, such as fear of informal nurse hierarchy and envy. The last two factors were related to opportunity, including (9) project planning and leadership, and voluntariness; and (10) patient preferences. CONCLUSION: Task shifting from doctors to nurses in specialised healthcare requires not only development of technical skills but also complex changes in organisation, clinical routines and role identity. Educational and organisational interventions to build a team-oriented culture could potentially increase the possibility of successful task shifting and stimulate nurses to take on untraditional responsibilities. Environmental restructuring to support doctors using their time in activities only doctors can perform may be needed to realise potential efficiency gains. PMID- 30482194 TI - Emotional release and physical symptom improvement: a qualitative analysis of self-reported outcomes and mechanisms in patients treated with neural therapy. AB - BACKGROUND: Neural Therapy (NT) is a common complementary treatment approach using injections with short-acting local anesthetics to treat pain and chronic diseases. However, little is known about the underlying mechanisms and the domains of treatment response. This study therefore analyzed patient experiences following NT injections with procaine. METHODS: Maximum variation sampling was used to collect data from semi-structured interviews conducted with 22 hospital inpatients aged 59.6 +/- 14.9 years (81.8% female). Each had multiple (9.4 +/- 6.9) diagnoses. They were undergoing two weeks of integrative treatment, which included individualized NT. The interview data were analyzed in MAXQDA using qualitative content analysis. RESULTS: With injection, patients first described local anesthetic effects including temporary blocking of pain and increased local warmth. Second, patients reported on vegetative reactions frequently leading to turmoil within the body like initial aggravation of existing symptoms or the appearance of new, concealed or phantom symptoms. This often required the need for rest to deal with the treatment stimulus. As a third step, many patients could gain physical and emotional release and relief in symptoms, mood and functioning. Emotional release was often accompanied by weeping and initially overwhelmed affected patients with dissociated memories. However, in cases where patients were able to experience those memories with a new distance, a fourth step of integration was achievable. It included reframing processes as well as a gain in pain perception and body-awareness. As a possible fifth step, patients experienced improved mood, increased pain acceptance and empowerment. Adverse events of NT included pain from the injections, vegetative complaints and emotional turmoil that lasted for minutes or hours, with a maximum of two days. CONCLUSIONS: Patients treated with procaine injections reported different psychophysiological outcomes contributing to the understanding of the mechanisms underlying NT. Further efficacy studies should separate specific NT from non specific/placebo effects. TRIAL REGISTRATION: DRKS00004567 . PMID- 30482196 TI - In vitro and in vivo delivery of a sustained release nanocarrier-based formulation of an MRTF/SRF inhibitor in conjunctival fibrosis. AB - BACKGROUND: Sustained drug delivery is a large unmet clinical need in glaucoma. Here, we incorporated a Myocardin-Related Transcription Factor/Serum Response Factor inhibitor, CCG-222740, into slow release large unilamellar vesicles derived from the liposomes DOTMA (1,2-di-O-octadecenyl-3-trimethylammonium propane) and DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), and tested their effects in vitro and in vivo. RESULTS: The vesicles were spherical particles of around 130 nm and were strongly cationic. A large amount of inhibitor could be incorporated into the vesicles. We showed that the nanocarrier CCG-222740 formulation gradually released the inhibitor over 14 days using high performance liquid chromatography. Nanocarrier CCG-222740 significantly decreased ACTA2 gene expression and was not cytotoxic in human conjunctival fibroblasts. In vivo, nanocarrier CCG-222740 doubled the bleb survival from 11.0 +/- 0.6 days to 22.0 +/- 1.3 days (p = 0.001), decreased conjunctival scarring and did not have any local or systemic adverse effects in a rabbit model of glaucoma filtration surgery. CONCLUSIONS: Our study demonstrates proof-of-concept that a nanocarrier based formulation efficiently achieves a sustained release of a Myocardin-Related Transcription Factor/Serum Response Factor inhibitor and prevents conjunctival fibrosis in an established rabbit model of glaucoma filtration surgery. PMID- 30482198 TI - Multiple infarcts and hemorrhages in the central nervous system of a dog with cerebral amyloid angiopathy: a case report. AB - BACKGROUND: beta-amyloid (Abeta) can accumulate in the brain of aged dogs, and within vessels walls, the disease is called cerebral amyloid angiopathy (CAA). In humans, Alzheimer's disease and CAA are strongly correlated with cerebrovascular disease. However, in dogs, this association has not been extensively studied yet. The present report highlights the pathological and clinical features of a concomitant cerebrovascular disease and amyloid precursor protein (APP) accumulation in the brain of a dog. CASE PRESENTATION: A female, 16-year-old, Standard Poodle with a one-year history of cognitive deficits presented with an acute onset of right-sided postural reaction deficit and circling, left-sided head tilt, positional nystagmus, and ataxia. Due to poor prognosis the dog was euthanized, and pathological examination of the brain revealed an acute lacunar infarction within the thalamus extending to rostral colliculus. Additional findings included subacute and chronic areas of ischemia throughout the brain and areas of hemorrhage within the medulla. Immunolabeling revealed APP deposition within intraparenchymal vessels of frontal, temporal and occipital cortex, hippocampus, diencephalon, mesencephalon and myelencephalon, besides meningeal vessels walls. Glial fibrillary acidic protein (GFAP) immunolabeling showed marked astrocytosis around the acute area of infarction and within chronic areas of ischemia. Histological examination of the brain along with immunohistochemistry results showed a concomitant APP, which is an Abeta precursor, accumulation within the neuroparenchyma and vessels (CAA) with histological evidences of a cerebrovascular disease in an aged dog. CONCLUSIONS: This report shows that APP accumulation in the brain can occur concomitantly to a severe cerebrovascular disease in a dog. Further studies are necessary to elucidate if cerebrovascular disease is associated with Abeta accumulation in the brain of dogs. PMID- 30482197 TI - Increased glycated albumin and decreased esRAGE levels in serum are related to negative coronary artery remodeling in patients with type 2 diabetes: an Intravascular ultrasound study. AB - BACKGROUND: Negative coronary artery remodeling is frequent in patients with diabetes, but its mechanism remains unclear. We here evaluated the association of serum levels of glycated albumin (GA) and endogenous secretory receptor for advanced glycation end products (esRAGE) with coronary artery remodeling in type 2 diabetic patients. METHODS: Serum levels of GA and esRAGE were measured and intravascular ultrasound was performed in 136 consecutive diabetic patients with 143 coronary intermediate lesions. The remodeling index (RI) was calculated as the ratio between external elastic membrane (EEM) area at the lesion site and EEM area at the reference segment. Negative remodeling (NR) was defined as an RI < 0.95 and intermediate or positive remodeling as an RI >= 0.95. RESULTS: Mean plaque burden at the lesion site was 70.96 +/- 9.98%, and RI was 0.96 +/- 0.18. Negative coronary arterial remodeling existed in 81 (56.6%) lesions. RI correlated closely with serum esRAGE level (r = 0.236, P = 0.005) and was inversely related to serum GA level (r = - 0.240, P = 0.004) and plasma low density lipoprotein cholesterol (LDL-C) (r = - 0.206, P = 0.014) and total cholesterol levels (r = - 0.183, P = 0.028). Generalized estimating equations logistic regression analysis identified esRAGE (OR 0.037; 95% CI 0.012-0.564, P = 0.021), GA (OR 1.093; 95% CI 1.013-1.179, P = 0.018) and LDL-C (OR 1.479; 95% CI 1.072-2.835, P = 0.023) as independent predictors for negative remodeling. CONCLUSIONS: In diabetic patients, negative coronary artery remodeling is associated with increased GA and decreased esRAGE levels in serum. PMID- 30482199 TI - Chi-miR-3031 regulates beta-casein via the PI3K/AKT-mTOR signaling pathway in goat mammary epithelial cells (GMECs). AB - BACKGROUND: MicroRNAs can regulate gene expression at the posttranscriptional level through translational repression or target degradation. Our previous investigations examined the differential expression levels of chi-miR-3031 in caprine mammary gland tissues in colostrum and common milk stages. RESULTS: The present study detected the role of chi-miR-3031 in the lactation mechanisms of GMECs. High-throughput sequencing was used to analyze transcriptomic landscapes of GMECs transfected with chi-miR-3031 mimics (MC) and a mimic negative control (NC). In the MC and NC groups, we acquired 39,793,503 and 36,531,517 uniquely mapped reads, respectively, accounting for 85.85 and 81.66% of total reads. In the MC group, 180 differentially expressed unigenes were downregulated, whereas 157 unigenes were upregulated. KEGG pathway analyses showed that the prolactin, TNF and ErbB signaling pathways, including TGFalpha, PIK3R3, IGF2, ELF5, IGFBP5 and LHbeta genes, played important roles in mammary development and milk secretion. Results from transcriptome sequencing, real-time PCR and western blotting showed that chi-miR-3031 suppressed the expression of IGFBP5 mRNA and protein. The expression levels of beta-casein significantly increased in the MC and siRNA-IGFBP5 groups. We observed that the down-regulation of IGFBP5 activated mTOR at the Ser2448 site in GMECs transfected with MC and siRNA-IGFBP5. Previous findings and our results showed that chi-miR-3031 activated the PI3K-AKT-mTOR pathway and increased beta-casein expression by down-regulating IGFBP5. CONCLUSIONS: These findings will afford valuable information for improving milk quality and contribute the development of potential methods for amending lactation performance. PMID- 30482200 TI - Role of TLR4-p38 MAPK-Hsp27 signal pathway in LPS-induced pulmonary epithelial hyperpermeability. AB - BACKGROUND: The breakdown of alveolar barrier dysfunction contributes to Lipopolysaccharide stimulated pulmonary edema and acute lung injury. Actin cytoskeleton has been implicated to be critical in regulation of epithelial barrier. Here, we performed in vivo and in vitro study to investigate role of TLR4-p38 MAPK-Hsp27 signal pathway in LPS-induced ALI. METHODS: For in vivo studies, 6-8-week-old C57 mice were used, Bronchoalveolar lavage Fluid /Blood fluorescent ratio, wet-to-dry lung weight ratio, as well as protein concentrations and neutrophil cell counts in BALF were detected as either directly or indirectly indicators of pulmonary alveolar barrier dysfunction. And hematoxylin and eosin staining was performed to estimate pulmonary injury. The in vitro explorations of transepithelial permeability were achieved through transepithelial electrical resistance measurement and testing of FITC-Dextran transepithelial flux in A549. In addition, cytoskeletal rearrangement was tested through F-actin immunostaining. And SB203580 was used to inhibit p38 MAPK activation, while siRNA was administered to genetically knockdown specific protein. RESULTS: We showed that LPS triggered activation of p38 MAPK, rearrangement of cytoskeleton which resulted in severe epithelial hyperpermeability and lung edema. A549 pretreated with TLR4 siRNA,p38 MAPK siRNA and its inhibitor SB203580 displayed a lower permeability and fewer stress fibers formation after LPS stimulation, accompanied with lower phosphorylation level of p38 MAPK and Hsp27, which verified the involvement of TLR4-p38 MAPK-Hsp27 in LPS evoked alveolar epithelial injury. Inhibition of p38 MAPK activity with SB203580 in vivo attenuated pulmonary edema formation and hyperpermeability in response to LPS. CONCLUSIONS: Our study demonstrated that LPS increased alveolar epithelial permeability both in vitro and in vivo and that TLR4- p38 MAPK- Hsp27 signal pathway dependent actin remolding was involved in this process. PMID- 30482202 TI - Follow-Up Support for Effective type 1 Diabetes self-management (The FUSED Model): A systematic review and meta-ethnography of the barriers, facilitators and recommendations for sustaining self-management skills after attending a structured education programme. AB - BACKGROUND: People with type 1 diabetes who attend structured education training in self-management using flexible intensive therapy achieve improved blood glucose control and experience fewer episodes of severe hypoglycaemia. However, many struggle to sustain these improvements over time. To inform the design of more effective follow-up support we undertook a review of qualitative studies which have identified factors that influence and inform participants' self management behaviours after attending structured education and their need for support to sustain improvements in glycaemic control. METHODS: We undertook a meta-ethnography of relevant qualitative studies, identified using systematic search methods. Studies were included which focused on participants' experiences of self-managing type 1 diabetes after attending structured education which incorporated training in flexible intensive insulin therapy. A line of argument approach was used to synthesise the findings. RESULTS: The search identified 18 papers from six studies. The studies included were judged to be of high methodological quality. The line of argument synthesis developed the Follow-Up Support for Effective type 1 Diabetes self-management (FUSED) model. This model outlines the challenges participants encounter in maintaining diabetes self management practices after attending structured education, and describes how participants try to address these barriers by adapting, simplifying or personalising the self-management approaches they have learned. To help participants maintain the skills taught during courses, the FUSED model presents ten recommendations abstracted from the included papers to provide a logic model for a programme of individualised and responsive follow-up support. CONCLUSIONS: This meta-ethnography highlights how providing skills training using structured education to people with type 1 diabetes does not necessarily result in participants adopting and sustaining recommended changes in behaviour. To help people sustain diabetes self-management skills after attending structured education, it is recommended that support be provided over the longer-term by appropriately trained healthcare professionals which is responsive to individuals' needs. Although developed to inform support for people with type 1 diabetes, the FUSED model provides a framework that could also be applied to support individuals with other long term conditions which require complex self management skills to be learned and sustained over time. TRIAL REGISTRATION: PROSPERO registration: CRD42017067961 . PMID- 30482201 TI - Nuclear genome sequence of the plastid-lacking cryptomonad Goniomonas avonlea provides insights into the evolution of secondary plastids. AB - BACKGROUND: The evolution of photosynthesis has been a major driver in eukaryotic diversification. Eukaryotes have acquired plastids (chloroplasts) either directly via the engulfment and integration of a photosynthetic cyanobacterium (primary endosymbiosis) or indirectly by engulfing a photosynthetic eukaryote (secondary or tertiary endosymbiosis). The timing and frequency of secondary endosymbiosis during eukaryotic evolution is currently unclear but may be resolved in part by studying cryptomonads, a group of single-celled eukaryotes comprised of both photosynthetic and non-photosynthetic species. While cryptomonads such as Guillardia theta harbor a red algal-derived plastid of secondary endosymbiotic origin, members of the sister group Goniomonadea lack plastids. Here, we present the genome of Goniomonas avonlea-the first for any goniomonad-to address whether Goniomonadea are ancestrally non-photosynthetic or whether they lost a plastid secondarily. RESULTS: We sequenced the nuclear and mitochondrial genomes of Goniomonas avonlea and carried out a comparative analysis of Go. avonlea, Gu. theta, and other cryptomonads. The Go. avonlea genome assembly is ~ 92 Mbp in size, with 33,470 predicted protein-coding genes. Interestingly, some metabolic pathways (e.g., fatty acid biosynthesis) predicted to occur in the plastid and periplastidal compartment of Gu. theta appear to operate in the cytoplasm of Go. avonlea, suggesting that metabolic redundancies were generated during the course of secondary plastid integration. Other cytosolic pathways found in Go. avonlea are not found in Gu. theta, suggesting secondary loss in Gu. theta and other plastid-bearing cryptomonads. Phylogenetic analyses revealed no evidence for algal endosymbiont-derived genes in the Go. avonlea genome. Phylogenomic analyses point to a specific relationship between Cryptista (to which cryptomonads belong) and Archaeplastida. CONCLUSION: We found no convincing genomic or phylogenomic evidence that Go. avonlea evolved from a secondary red algal plastid-bearing ancestor, consistent with goniomonads being ancestrally non-photosynthetic eukaryotes. The Go. avonlea genome sheds light on the physiology of heterotrophic cryptomonads and serves as an important reference point for studying the metabolic "rewiring" that took place during secondary plastid integration in the ancestor of modern-day Cryptophyceae. PMID- 30482203 TI - The growth of assisted reproductive treatment-conceived children from birth to 5 years: a national cohort study. AB - BACKGROUND: Birth weight and early child growth are important predictors of long term cardiometabolic disease risk, in line with the Developmental Origins of Health and Disease hypothesis. As human assisted reproductive technologies (ARTs) occur during the sensitive periconceptional window of development, it has recently become a matter of urgency to investigate risk in ART-conceived children. METHODS: We have conducted the first large-scale, national cohort study of early growth in ART children from birth to school age, linking the register of ART, held by the UK's Human Fertilisation and Embryology Authority, to Scottish maternity and child health databases. RESULTS: In this study of 5200 ART and 20,800 naturally conceived (NC) control children, linear regression analysis revealed the birthweight of babies born from fresh embryo transfer cycles is 93.7 g [95% CI (76.6, 110.6)g] less than NC controls, whereas babies born from frozen embryo transfer (FET) cycles are 57.5 g [95% CI (30.7, 86.5)g] heavier. Fresh ART babies grew faster from birth (by 7.2 g/week) but remained lighter (by 171 g), at 6-8 weeks, than NC babies and 133 g smaller than FET babies; FET and NC babies were similar. Length and occipital-frontal circumference followed the same pattern. By school entry (4-7 years), weight, length and BMI in boys and girls conceived by fresh ART and FET were similar to those in NC children. CONCLUSIONS: ART babies born from fresh embryo transfer grow more slowly in utero and in the first few weeks of life, but then show postnatal catch up growth by school age, compared to NC and FET babies. As low birth weight and postnatal catch-up are independent risk factors for cardiometabolic disease over the life-course, we suggest that further studies in this area are now warranted. PMID- 30482204 TI - Exploratory laparoscopy combined with pathological examination in the diagnosis of obscure gastrointestinal bleeding in a child: a case report. AB - BACKGROUND: The diagnosis of obscure gastrointestinal bleeding (OGIB) which is defined as bleeding of unknown origin of the small bowel by routine evaluation in childhood is a challenge. CASE PRESENTATION: Here we report a one-year-old Chinese girl who was suspected with idiopathic pulmonary haemosiderosis (IPH) and referred to our department for further diagnosis. Finally she was diagnosed with vascular malformations (VM) by exploratory laparoscopy combined with pathological examination. CONCLUSIONS: Children OGIB could be easily misdiagnosed in the beginning, and OGIB children with active ongoing bleeding may benefit from proceeding directly to exploratory laparoscopy, followed by pathological confirmation of the diagnosis. PMID- 30482206 TI - Residual bone fragments in tibiofibular joint and postoperative local recurrence: an analysis of 21 cases of proximal fibular giant cell tumour. AB - BACKGROUND: Currently, there are no known reports on the aetiology of local giant cell tumour (GCT) recurrence in the proximal fibula following en bloc resection. We analysed 21 cases of proximal fibular GCT, focusing on the presence of residual bone in the tibiofibular joint, its causes and its impact on postoperative recurrence. METHODS: We retrospectively analysed 21 cases with proximal fibular GCT occurring between 2000 and 2017. RESULTS: There were 14 males and 7 females. The average patient age was 25.0 years. Seventeen patients were diagnosed and treated at our facility, while 4 were referred after local recurrence. Six patients presented with residual bone fragments in the tibiofibular joint during their first month of follow-up. Patients with residual bone fragments had a higher local recurrence rate (83.3%) than those without (0%, p = 0.0003). Upon further analysis, patients with a preoperative Campanacci grade III tumour (p = 0.0055) and pathological fractures (p = 0.0109) were at a higher risk of exhibiting postoperative residual bone fragments. CONCLUSIONS: The presence of residual bone fragments in the tibiofibular joint was the main cause of postoperative local recurrence. The presence of residual bone fragments may be related to the preoperative Campanacci grade and pathological fractures. Therefore, close attention should be paid to postoperative follow-up examinations, and if recurrence is suspected, surgical resection should be planned. PMID- 30482205 TI - Breast cancer risk and serum levels of per- and poly-fluoroalkyl substances: a case-control study nested in the California Teachers Study. AB - BACKGROUND: Per- and poly- fluoroalkyl substances (PFASs) are a large family of synthetic chemicals, some of which are mammary toxicants and endocrine disruptors. Their potential as breast carcinogens is unclear. Our objective was to evaluate the risk of breast cancer associated with serum PFAS concentrations in a nested case-control study within the California Teachers Study. METHODS: Participants were 902 women with invasive breast cancer (cases) and 858 with no such diagnosis (controls) who provided 10 mL of blood and were interviewed during 2011-2015, an average of 35 months after case diagnosis. PFASs were measured using automated online SPE-HPLC-MS/MS methods. Statistical analyses were restricted to six PFASs with detection frequencies >= 95%: PFOA (Perfluorooctanoic acid), PFNA (Perfluorononanoic acid), PFUnDA (Perfluoroundecanoic acid), PFHxS (Perfluorohexane sulfonic acid), PFOS (Perfluorooctane sulfonic acid), and MeFOSAA (2-(N-Methyl-perfluorooctane sulfonamido) acetic acid. Unconditional logistic regression was used to calculate adjusted odds ratios (ORs), estimating the breast cancer risk associated with each PFAS. RESULTS: For all cases of invasive breast cancer, none of the adjusted ORs were statistically significant but marginally significant ORs < 1.0 were observed for PFUnDA and PFHxS (p-trend = 0.08). Adjusted ORs < 1.0 for PFUnDA and PFHxS were statistically significant (p <= 0.05) among the 107 cases with hormone negative tumors but not the 743 with hormone-positive tumors. CONCLUSION: Overall, these findings do not provide evidence that serum PFAS levels measured after diagnosis are related to breast cancer risk. The few inverse associations found may be due to chance or may be artifacts of study design. Future studies should incorporate information about genetic susceptibility, endogenous estrogen levels, and measurements of PFASs prior to diagnosis and treatment. PMID- 30482207 TI - SDH-deficient renal cell carcinoma - clinical, pathologic and genetic correlates: a case report. AB - BACKGROUND: Succinate dehydrogenase (SDH)- deficient renal cell carcinoma (RCC) is a newly identified rare subtype of RCC, having only gained acceptance from the World Health Organization in 2016. To the best of our knowledge, there are only 55 reported cases worldwide. Here, we report a new case of SDH-deficient RCC. CASE PRESENTATION: A 49-year-old male patient was incidentally found to have a large right renal mass. He had no personal or family history of paragangliomas (PGL), pheochromocytomas (PC), or gastrointestinal stromal tumors (GIST). The neoplasm was unilateral and unifocal. He underwent an open partial nephrectomy. Detailed pathological analysis was conducted to confirm the diagnosis. Genetic testing revealed a pathogenic mutation in the SDHB gene. He has been followed for 24 months now and has remained well without any evidence of local or distant recurrence. In this report we describe our experience with this diagnosis and review the relevant clinical, pathological, and genetic features. CONCLUSIONS: Without the identification of SDHB deficiency, this patient's personal and familial predisposition to PC, PGL, GIST and metachronous RCCs may have gone undetected despite his RCC diagnosis. When faced with an eosinophilic RCC, pathologists should routinely search for vacuoles or flocculent cytoplasmic inclusions. When these are present, or in cases of difficult eosinophilic renal tumors, staining for SDHB is recommended. For tumours without adverse pathologic features (i.e. high nuclear grade, coagulative necrosis, or sarcomatoid differentiation) excision alone may be a reasonable option, with the addition of regular surveillance for PC and PGLs in those found to harbor germline SDH mutations. PMID- 30482208 TI - Personal Genome Project UK (PGP-UK): a research and citizen science hybrid project in support of personalized medicine. AB - BACKGROUND: Molecular analyses such as whole-genome sequencing have become routine and are expected to be transformational for future healthcare and lifestyle decisions. Population-wide implementation of such analyses is, however, not without challenges, and multiple studies are ongoing to identify what these are and explore how they can be addressed. METHODS: Defined as a research project, the Personal Genome Project UK (PGP-UK) is part of the global PGP network and focuses on open data sharing and citizen science to advance and accelerate personalized genomics and medicine. RESULTS: Here we report our findings on using an open consent recruitment protocol, active participant involvement, open access release of personal genome, methylome and transcriptome data and associated analyses, including 47 new variants predicted to affect gene function and innovative reports based on the analysis of genetic and epigenetic variants. For this pilot study, we recruited 10 participants willing to actively engage as citizen scientists with the project. In addition, we introduce Genome Donation as a novel mechanism for openly sharing previously restricted data and discuss the first three donations received. Lastly, we present GenoME, a free, open-source educational app suitable for the lay public to allow exploration of personal genomes. CONCLUSIONS: Our findings demonstrate that citizen science based approaches like PGP-UK have an important role to play in the public awareness, acceptance and implementation of genomics and personalized medicine. PMID- 30482209 TI - Identification of gene expression profiles in myocardial infarction: a systematic review and meta-analysis. AB - BACKGROUND: Myocardial infarction (MI) is a multifactorial disease with complex pathogenesis, mainly the result of the interplay of genetic and environmental risk factors. The regulation of thrombosis, inflammation and cholesterol and lipid metabolism are the main factors that have been proposed thus far to be involved in the pathogenesis of MI. Traditional risk-estimation tools depend largely on conventional risk factors but there is a need for identification of novel biochemical and genetic markers. The aim of the study is to identify differentially expressed genes that are consistently associated with the incidence myocardial infarction (MI), which could be potentially incorporated into the traditional cardiovascular diseases risk factors models. METHODS: The biomedical literature and gene expression databases, PubMed and GEO, respectively, were searched following the PRISMA guidelines. The key inclusion criteria were gene expression data derived from case-control studies on MI patients from blood samples. Gene expression datasets regarding the effect of medicinal drugs on MI were excluded. The t-test was applied to gene expression data from case-control studies in MI patients. RESULTS: A total of 162 articles and 174 gene expression datasets were retrieved. Of those a total of 4 gene expression datasets met the inclusion criteria, which contained data on 31,180 loci in 93 MI patients and 89 healthy individuals. Collectively, 626 differentially expressed genes were detected in MI patients as compared to non affected individuals at an FDR q-value = 0.01. Of those, 88 genes/gene products were interconnected in an interaction network. Totally, 15 genes were identified as hubs of the network. CONCLUSIONS: Functional enrichment analyses revealed that the DEGs and that they are mainly involved in inflammatory/wound healing, RNA processing/transport mechanisms and a yet not fully characterized pathway implicated in RNA transport and nuclear pore proteins. The overlap between the DEGs identified in this study and the genes identified through genetic association studies is minimal. These data could be useful in future studies on the molecular mechanisms of MI as well as diagnostic and prognostic markers. PMID- 30482210 TI - Comparison of non-invasive to invasive oxygenation ratios for diagnosing acute respiratory distress syndrome following coronary artery bypass graft surgery: a prospective derivation-validation cohort study. AB - OBJECTIVE: To determine if non-invasive oxygenation indices, namely peripheral capillary oxygen saturation (SpO2)/fraction of inspired oxygen (FiO2) and partial pressure of alveolar oxygen (PAO2)/FiO2 may be used as effective surrogates for the partial pressure of arterial oxygen (PaO2)/FiO2. Also, to determine the SpO2/FiO2 and PAO2/FiO2 values that correspond to PaO2/FiO2 thresholds for identifying acute respiratory distress syndrome (ARDS) in patients following coronary artery bypass graft (CABG) surgery. METHODS: A prospective derivation validation cohort study in the Open-Heart ICU of an academic teaching hospital. Recorded variables included patient demographics, ventilator settings, chest radiograph results, and SPO2, PaO2, PAO2, SaO2, and FiO2. Linear regression modeling was used to quantify the relationship between indices. Receiver operating characteristic (ROC) curves were used to determine the sensitivity and specificity of the threshold values. RESULTS: One-hundred seventy-five patients were enrolled in the derivation cohort, and 358 in the validation cohort. The SPO2/FiO2 and PAO2/FiO2 ratios could be predicted well from PaO2/FiO2, described by the linear regression models SPO2/FiO2 = 71.149 + 0.8PF and PAO2/FiO2 = 38.098 + 2.312PF, respectively. According to the linear regression equation, a PaO2/FiO2 ratio of 300 equaled an SPO2/FiO2 ratio of 311 (R2 0.857, F 1035.742, < 0.0001) and a PAO2/FiO2 ratio of 732 (R2 0.576, F 234.887, < 0.0001). The SPO2/FiO2 threshold of 311 had 90% sensitivity, 80% specificity, LR+ 4.50, LR- 0.13, PPV 98, and NPV 42.1 for the diagnosis of mild ARDS. The PAO2/FiO2 threshold of 732 had 86% sensitivity, 90% specificity, LR+ 8.45, LR- 0.16, PPV 98.9, and NPV 36 for the diagnosis of mild ARDS. SPO2/FiO2 had excellent discrimination ability for mild ARDS (AUC +/- SE = 0.92 +/- 0.017; 95% CI 0.889 to 0.947) as did PAO2/FiO2 (AUC +/- SE = 0.915 +/- 0.018; 95% CI 0.881 to0.942). CONCLUSIONS: PaO2 and SaO2 correlated in the diagnosis of ARDS, with a PaO2/FiO2 of 300 correlating to an SPO2/ FiO2 of 311 (Sensitivity 90%, Specificity 80%). The SPO2/ FiO2 ratio may allow for early real-time rapid identification of ARDS, while decreasing the cost, phlebotomy, blood loss, pain, skin breaks, and vascular punctures associated with serial arterial blood gas measurements. PMID- 30482211 TI - Examining changes in school vending machine beverage availability and sugar sweetened beverage intake among Canadian adolescents participating in the COMPASS study: a longitudinal assessment of provincial school nutrition policy compliance and effectiveness. AB - BACKGROUND: School nutrition policies can encourage restrictions in sugar sweetened beverage (SSB) availability in school food outlets in order to discourage students' SSB intake. The main objective was to examine how beverage availability in school vending machines changes over three school years across schools in distinct school nutrition policy contexts. Secondary objectives were to examine how students' weekday SSB intake varies with time and identify longitudinal associations between beverage availability and SSB intake. METHODS: This longitudinal study used data from the COMPASS study (2013/14-2015/16), representing 7679 students from 78 Canadian secondary schools and three provincial school nutrition policy contexts (Alberta - voluntary guidelines, Ontario public - mandatory guidelines, and Ontario private schools - no guidelines). We assessed availability of 10 beverage categories in schools' vending machines via the COMPASS School Environment Application and participants' intake of three SSB varieties (soft drinks, sweetened coffees/teas, and energy drinks) via a questionnaire. Hierarchical regression models were used to examine whether: i) progression of time and policy group were associated with beverage availability; and, ii) beverage availability was associated with students' SSB intake. RESULTS: Ontario public schools were significantly less likely than the other policy groups to serve SSBs in their vending machines, with the exception of flavoured milks. Vending machine beverage availability was consistent over time. Participants' overall SSB intake remained relatively stable; reductions in soft drink intake were partially offset by increased sweetened coffee/tea consumption. Relative to Ontario public schools, attending school in Alberta was associated with more frequent energy drink intake and overall SSB intake whereas attending an Ontario private school was associated with less frequent soft drink intake, with no differences in overall SSB intake. Few beverage availability variables were significantly associated with participants' SSB intake. CONCLUSIONS: Mandatory provincial school nutrition policies were predictive of more limited SSB availability in school vending machines. SSB intake was significantly lower in Ontario public and private schools, although we did not detect a direct association between SSB consumption and availability. The findings provide support for mandatory school nutrition policies, as well as the need for comprehensive school- and broader population-level efforts to reduce SSB intake. PMID- 30482212 TI - A comparison of treatment outcome between fiducial-based and bone-based image guided radiotherapy in prostate cancer patients. AB - BACKGROUND AND PURPOSE: To compare the clinical outcome in prostate cancer patients treated with radiotherapy using two forms of image guidance: bone-based (BB) or fiducial-based (FB). MATERIAL AND METHODS: This retrospective study consisted of 180 patients treated with kV-kV image-guided radiotherapy (IGRT) between the years 2008 and 2011. A total of 89 patients were aligned to pelvic bone (Group BB) and 91 patients to the fiducial implanted into prostate for image guidance (Group FB). Patients were treated to a total dose of 76 Gy in 38 fractions. The Cox Regression Model was used to evaluate the influence of clinical and treatment-related parameters on overall survival, biochemical progression and progression-free survival. Acute and late toxicity were evaluated based on the RTOG/EORTC criteria. Sexual function was assessed with QLQ PR-25 (EORTC QLQ forms). An assessment of the differences in patient daily set-up from the time of simulation was performed. RESULTS: The incidence of acute G2/G3 genitourinary (GU) and gastrointestinal (GI) toxicity was similar between groups. In the BB group, 34 patients had G2 and 5 had G3 GU acute toxicity - compared to 40 patients with G2 and 2 with G3 in the FB group. G2 and G3 GI acute toxicity was observed respectively in 24 patients and in 1 patient in the BB group compared to 18 patients with G2 and 1 patient with G3 toxicity in the FB group. The five-year incidence of late >=G2 GU toxicity was 12% in both groups (p = 0.98) and >= G2 GI toxicity 19% (BB) vs 15% (FB, p = 0.55), respectively. The five-year progression-free survival rate was 87% in BB and 81% in the FB Group (p = 0.15). The 5-year Overall Survival rate (OS) was 80% (BB) vs 91% % (FB, p = 0.20), but the difference was most pronounced in the intermediate-risk group: 5 year OS of 93% (FB) and 75% (BB), respectively (p = 0.06). No significant changes were observed in sexual or erectile functioning as compared to that specified at the beginning of radiotherapy and between the FB and BB Groups. CONCLUSION: When comparing bone-based to fiducial-based techniques, no differences in clinical outcomes or late toxicity were seen in this population. However, intermediate risk prostate cancer patients are those who might benefit most from implementation of fiducial-based IGRT. PMID- 30482214 TI - The role of the hotel industry in the response to emerging epidemics: a case study of SARS in 2003 and H1N1 swine flu in 2009 in Hong Kong. AB - BACKGROUND: The global travel and tourism industry has been rapidly expanding in the past decades. The traditional focus on border screening, and by airline and cruise industries may be inadequate due to the incubation period of an infectious disease. This case study highlights the potential role of the hotel industry in epidemic preparedness and response. METHODS: This case study focuses on the epidemic outbreaks of SARS in 2003 and H1N1 swine flu in 2009 in Hong Kong, and the subsequent guidelines published by the health authority in relation to the hotel industry in Hong Kong which provide the backbone for discussion. RESULTS: The Metropole Hotel hastened the international spread of the 2003 SARS outbreak by the index case infecting visitors from Singapore, Vietnam, Canada as well as local people via close contact with the index case and the environmental contamination. The one-week quarantine of more than 300 guests and staff at the Metropark Hotel during the 2009 H1N1 swine flu exposed gaps in the partnership with the hotel industry. The subsequent guidelines for the hotel industry from the Centre of Health Protection focused largely on the maintenance of hygiene within the hotel premises. CONCLUSION: Positive collaborations may bring about effective preparedness across the health and the tourism sectors for future epidemics. Regular hygiene surveillance at hotel facilities, and developing coordination mechanism for impending epidemics on the use of screening, swift reporting and isolation of infected persons may help mitigate the impact of future events. Preparedness and contingency plans for infectious disease control for the hotel industry requires continuous engagement and dialogue. PMID- 30482213 TI - MBL2 gene polymorphisms in HHV-8 infection in people living with HIV/AIDS. AB - BACKGROUND: Host genetic factors such as MBL2 gene polymorphisms cause defects in the polymerization of MBL protein and result in a functional deficiency and/or in low serum levels that can influence susceptibility to various viral infections. The aim of this study was to estimate the frequency of alleles, genotypes and haplotypes related to -550, -221 and exon 1 polymorphisms of the MBL2 gene and investigate their association with HHV-8 in people living with HIV/AIDS (PLWHA), as well as the impacts on CD4 cell count and HIV viral load in HIV/HHV-8 coinfected and HIV monoinfected patients. RESULTS: A cross sectional study in PLWHA, with and without HHV-8 infection, exploring associations between different factors, was performed in the outpatient infectious and parasitic diseases clinic at a referral hospital. Genomic DNA extractions from leukocytes were performed using a commercial Wizard(r) Genomic DNA Purification kit (Promega, Madison, WI). The promoter region (-550 and -221) was genotyped with the TaqMan system (Applied TaqMan Biosystems(r) genotyping Assays), and the structural region (exon1) was genotyped with Express Sybr Greener Supermix kit (Invitrogen, USA). In total, 124 HIV/HHV-8 coinfected and 213 HIV monoinfected patients were analysed. Median TCD4 counts were significantly lower in HIV/HHV-8 coinfected patients, whereas the mean of the first and last viral load of HIV did not present significant difference. There was no difference in frequency between the LL, YY and AA genotypes between the HIV/HHV-8 coinfected or HIV monoinfected patients. However, in a multivariate analysis, coinfected patients with the intermediate expression haplotype of the MBL2 gene had an odds ratio of 3.1-fold (CI = 1.2-7.6) of their last CD4 cell count being below 350 cells/mm3. Among the coinfected individuals, four developed KS and presented the intermediate expression MBL haplotype, with three being HYA/LXA and one being LYA/LYO. CONCLUSIONS: Host genetic factors, such as -550, -221 and exon 1 polymorphisms, can be related to the may modify coinfections and/or to the development clinical manifestations caused by HHV-8, especially in HIV/HHV-8 coinfected patients who present the intermediate expression haplotypes of MBL. PMID- 30482216 TI - Mutational and phenotypic spectrum of OTOF-related auditory neuropathy in Koreans: eliciting reciprocal interaction between bench and clinics. AB - BACKGROUND: While auditory neuropathy spectrum disorder (ANSD) is a heterogeneous disorder and its management quite varies depending upon the etiology, even including self-resolution, OTOF is an important molecular etiology of prelingual ANSD and has emerged as an attractive target for implementation of precision medicine in terms of timing and prognosis prediction of auditory rehabilitation. However, to date, the literature is lacking in the genotype-phenotype relationship of this gene as well as efficient molecular testing strategy in the clinic in many populations and to make things more complicated in Koreans, the most prevalent variant p.Arg1939Gln among Korean ANSD children frequently evaded detection by next generation sequencing (NGS), resulting in delayed genetic diagnosis and late cochlear implantation (CI). The aims of this study are to document the mutational and phenotypic spectrum of OTOF-related ANSD (DFNB9) in the Korean population, further establishing genotype-phenotype correlation and proposing a set of the most commonly found OTOF variants to be screened first. METHODS: Genetic diagnosis through the NGS-based sequencing was made on patients with ANSD in two tertiary hospitals. Genotype and phenotypes of eleven DFNB9 patients were reviewed. For data analysis, Mann-Whitney test and Fisher's exact test were applied. RESULTS: This study disclosed four prevalent variants in Koreans: p.Arg1939Gln with an allele frequency of 40.9%, p.Glu841Lys (13.6%), p.Leu1011Pro and p.Arg1856Trp (9.1%). Three novel variants (c.4227 + 5G > C, p.Gly1845Glu, and p.Pro1931Thr) were identified. Interestingly, a significant association of p.Arg1939Gln with worse ASSR thresholds was observed despite consistently no ABR response. Ten of 11 DFNB9 patients received CI for auditory rehabilitation, showing favorable outcomes with more rapid improvement on early CI group (age at CI <= 18 mo.) than late-CI group. CONCLUSIONS: This study included the largest Korean DFNB9 cohort to date and proposed a set of the most frequent four OTOF variants, allowing the potential prioritization of exons during Sanger sequencing. Further, a significant association of p.Arg1939Gln homozygotes with poor residual hearing was observed. We may have to suspect p.Arg1939Gln homozygosity in cases of poor auditory thresholds in ANSD children with putative negative OTOF variants solely screened by NGS. Reciprocal feedback between bench and clinics regarding DFNB9 would complement each other. PMID- 30482217 TI - Low inter-observer agreement among experienced shoulder surgeons assessing overstuffing of glenohumeral resurfacing hemiarthroplasty based on plain radiographs. AB - BACKGROUND: In a clinical setting, a visual evaluation of post-implant radiographs is often used to assess the restoration of glenohumeral joint anatomy after resurfacing hemiarthroplasty and is a part of the decision-making process, in combination with other parameters, when evaluating patients with inferior clinical results. However, the reliability of this method of visual evaluation has not been reported. The aim of this study was to investigate the inter- and intra-observer agreement among experienced shoulder surgeons assessing overstuffing, implant positioning, and size following resurfacing hemiarthroplasty using plain standardized radiographs. METHODS: Six experienced shoulder surgeons independently classified implant inclination, size of the implant and if the joint seemed overstuffed, in 219 cases of post-implant radiographs. All cases were classified twice 3 weeks apart. Only radiographs with an anterior-posterior projection with a freely visible joint space were used. Non weighted Cohen's kappa values were calculated for each coder pair and the mean used as an estimate of the overall inter-observer agreement. RESULTS: The overall inter-observer agreement for implant size (kappa, 0.48 and 0.41) and inclination angle was moderate in both rounds (kappa, 0.46 and 0.44), but only a fair agreement was found concerning the evaluation for stuffing of the joint (kappa, 0.24 and 0.28). Intra-observer agreement for implant size and stuffing ranged from fair to substantial while the agreement for inclination was moderate to substantial. CONCLUSIONS: Our results indicate that a visual evaluation of plain radiographs may be inadequate to evaluate overstuffing, implant positioning, and size following resurfacing hemiarthroplasty using plain standardized radiographs. Future studies may contribute to elucidate whether reliability increases if consensus on clear definitions and standardized methods of evaluation is made. PMID- 30482215 TI - An age-based analysis of nonmedical prescription opioid use among people who use illegal drugs in Vancouver, Canada. AB - BACKGROUND: Nonmedical prescription opioid use (NMPOU) is a serious public health problem in North America. At a population-level, previous research has identified differences in the prevalence and correlates of NMPOU among younger versus older age groups; however, less is known about age-related differences in NMPOU among people who use illegal drugs. METHODS: Data were collected between 2013 and 2015 from two linked prospective cohort studies in Vancouver, Canada: the At-Risk Youth Study (ARYS) and the Vancouver Injection Drug Users Study (VIDUS). Factors independently associated with NMPOU among younger (ARYS) and older (VIDUS) participants were examined separately using bivariate and multivariate generalized estimating equations. RESULTS: A total of 1162 participants were included. Among 405 eligible younger participants (Median age = 25; Inter Quartile Range [IQR]: 22-28), 40% (n = 160) reported engaging in NMPOU at baseline; among 757 older participants (Median age = 48, IQR: 40-55), 35% (n = 262) reported engaging in NMPOU at baseline. In separate multivariate analyses of younger and older participants, NMPOU was positively and independently associated with heroin use (younger: Adjusted Odds Ratio [AOR] = 3.12, 95% Confidence Interval [CI]: 2.08-4.68; older: AOR = 2.79, 95% CI: 2.08-3.74), drug dealing (younger: AOR = 2.22, 95% CI: 1.58-3.13; older: AOR = 1.87, 95% CI: 1.40-2.49), and difficulty accessing services (younger: AOR = 1.47, 95% CI: 1.04-2.09; older: AOR = 1.74, 95% CI: 1.32-2.29). Among the youth cohort only, NMPOU was associated with younger age (AOR = 1.12, 95% CI: 1.05-1.19), crack use (AOR = 1.56, 95% CI: 1.06-2.30), and binge drug use (AOR = 1.41, 95% CI: 1.00-1.97); older participants who engaged in NMPOU were more likely to report crystal methamphetamine use (AOR = 1.97, 95% CI: 1.46-2.66), non-fatal overdose (AOR = 1.76, 95% CI: 1.20-2.60) and sex work (AOR = 1.49, 95% CI: 1.00-2.22). DISCUSSION: The prevalence of NMPOU is similar among younger and older people who use drugs, and independently associated with markers of vulnerability among both age groups. Adults who engage in NMPOU are at risk for non-fatal overdose, which highlights the need for youth and adult-specific strategies to address NMPOU that include better access to health and social services, as well as a range of addiction treatment options for opioid use. Findings also underscore the importance of improving pain treatment strategies tailored for PWUD. PMID- 30482219 TI - Characterization of a PCV2d-2 isolate by experimental infection of pigs. AB - Porcine circovirus type 2 (PCV2), a highly prevalent, economically important swine pathogen is classified into different genotypes (PCV2a-f) based on phylogenetic analysis. Since the introduction of extensive vaccination programs, at least two major shifts have been observed in the prevalence of PCV2 genotypes. The first genotype shift from 2a towards 2b occurred around 2003, while in recent years, we are witnessing the second change in genotype prevalence from the predominant 2b towards 2d.In this study, a PCV2d-2 isolate was characterized as a potential challenge virus for the evaluation of PCV2 vaccine efficacy. Ten-week old pigs carrying low to moderate levels of maternally derived antibodies to PCV2 were infected with the isolate by the nasal route. Over the next 4 weeks post infection, the pigs were monitored for the presence of viremia, fecal virus excretion, and humoral immune responses. At the end of the post-infection observation period, samples were taken from the mediastinal and mesenteric lymph nodes of the animals and tested for viral load. The gradual depletion of maternally derived antibodies in the sera of piglets was demonstrated by ELISA and virus neutralization tests. Following experimental infection by PCV2d-2, specific IgM antibodies were first detected at 14 days post challenge (dpch), while IgG class antibodies were first detected at 21 dpch. Both viremia and virus shedding could be detected at 7 dpch, in 36 and 50% of the pigs, respectively. The proportion of shedders reached 100% by 14 dpch and remained at this level, while viremia was demonstrated in 86, 100, and 100% of the pigs at 14, 21, and 28 dpch, respectively. Both the mediastinal and mesenteric lymph nodes contained high levels of virus (7.6 and 8.5 log10 copies/mg tissue, respectively). PMID- 30482218 TI - Comparison of the NHANES dietary screener questionnaire to the Automated Self Administered 24-Hour Recall for Children in the Healthy Communities Study. AB - BACKGROUND: A dietary screener questionnaire (DSQ) was used to assess dietary outcomes among children in the Healthy Communities Study (HCS), a study of the relationships between programs and policies to prevent child obesity and child diet, physical activity and weight outcomes. METHODS: To compare dietary intake estimates derived from the DSQ against those from the Automated Self-Administered 24-Hour Recalls for Children (ASA24-Kids) among children, a measurement error model, using structural equation modelling, was utilized to estimate slopes, deattenuated correlation coefficients, and attenuation factors by age and sex, ethnicity, and BMI status. PARTICIPANTS/SETTING: A randomly selected sub-sample of HCS participants aged 4-15 years in 130 communities throughout the U.S. who completed the DSQ and up to two ASA24-Kids recalls (n = 656;13% of HCS participants). RESULTS: For most nutrient/foods examined, the DSQ yielded larger mean intake estimates than the ASA24-Kids, and agreement between the two measures varied by food/nutrient, age and sex, ethnicity, and BMI category. Deattenuated correlation coefficients of 0.4 or greater were observed for added sugars from SSBs (0.54), fruits and vegetables (0.40), and dairy foods (0.50). Lower deattenuated correlation coefficients were seen for total added sugars (0.37), whole grains (0.34), and fiber (0.34). Attenuation factors were most severe for total added sugars intake among overweight children, and for several other dietary outcomes among children aged 9-11 years. CONCLUSIONS: The DSQ was found to be a tool with acceptable agreement with the ASA24-Kids for measuring multiple dietary outcomes of interest in the HCS, although there may be potential due to measurement error to underestimate results (bias towards the null). In future studies, measurement error modelling and regression calibration may be possible solutions to correct for bias due to measurement error in most food/nutrient intake estimates from the DSQ when used among children. PMID- 30482220 TI - Interactive online application for the prediction, ranking and prioritisation of drug targets in Schistosoma haematobium. AB - BACKGROUND: Human schistosomiasis is a neglected tropical disease caused by parasitic worms of the genus Schistosoma that still affects some 200 million people. The mainstay of schistosomiasis control is a single drug, praziquantel. The reliance on this drug carries a risk of resistance emerging to this anthelmintic, such that research towards alternative anti-schistosomal drugs is warranted. In this context, a number of studies have employed computational approaches to prioritise proteins for investigation as drug targets, based on extensive genomic, transcriptomic and small-molecule data now available. METHODS: Here, we established a customisable, online application for the prioritisation of drug targets and applied it, for the first time, to the entire inferred proteome of S. haematobium. This application enables selection of weighted and ranked proteins representing potential drug targets, and integrates transcriptional data, orthology and gene essentiality information as well as drug-drug target associations and chemical properties of predicted ligands. RESULTS: Using this application, we defined 25 potential drug targets in S. haematobium that associated with approved drugs, and 3402 targets that (although they could not be linked to any compounds) are conserved among a range of socioeconomically important flatworm species and might represent targets for new trematocides. CONCLUSIONS: The online application developed here represents an interactive, customisable, expandable and reproducible drug target ranking and prioritisation approach that should be useful for the prediction of drug targets in schistosomes and other species of parasitic worms in the future. We have demonstrated the utility of this online application by predicting potential drug targets in S. haematobium that can now be evaluated using functional genomics tools and/or small molecules, to establish whether they are indeed essential for parasite survival, and to assist in the discovery of novel anti-schistosomal compounds. PMID- 30482221 TI - Universal CARs, universal T cells, and universal CAR T cells. AB - Currently, the two approved T cell products with chimeric antigen receptors (CAR) are from autologous T cells. These CAR T cells approved for clinical use must be generated on a custom-made basis. This case-by-case autologous T cell production platform remains a significant limiting factor for large-scale clinical application due to the costly and lengthy production process. There is also an inherent risk of production failure. The individualized, custom-made autologous CAR T cell production process also posts constriction on the wide application on diverse tumor types. Therefore, universal allogeneic T cells are needed for the preparation of universal CAR T cells that can serve as the "off-the-shelf" ready to-use therapeutic agents for large-scale clinical applications. Genome-editing technologies including ZFN (zinc finger nuclease), TALEN (transcription activator like effector nuclease), and CRISPR-Cas9 are being used to generate the universal third-party T cells. In addition, split, universal, and programmable (SUPRA) CARs are being developed to enhance the flexibility and controllability of CAR T cells. The engineered universal T cells and universal CARs are paving the road for a totally new generation of CAR T cells capable of targeting multiple antigens and/ or being delivered to multiple recipients without re-editing of T cells. This may escalate to a new wave of revolution in cancer immunotherapy. This review summarized the latest advances on designs and development of universal CARs, universal T cells, and clinical application of universal CAR T cells. PMID- 30482224 TI - Transparent peer review trial: the results. AB - We describe the results of our year-long trial of transparent peer review and announce the adoption of transparent review as permanent policy. PMID- 30482223 TI - Assessing Ghana's eHealth workforce: implications for planning and training. AB - BACKGROUND: eHealth-the proficient application of information and communication technology to support healthcare delivery-has been touted as one of the best solutions to address quality and accessibility challenges in healthcare. Although eHealth could be of more value to health systems in low- and middle-income countries (LMICs) where resources are limited, identification of a competent workforce which can develop and maintain eHealth systems is a key barrier to adoption. Very little is known about the actual or optimal states of the eHealth workforce needs of LMICs. The objective of this study was to develop a framework to characterize and assess the eHealth workforce of hospitals in LMICs. METHODS: To characterize and assess the sufficiency of the workforce, we designed this study in twofold. First, we developed a general framework to categorize the eHealth workforce at any LMIC setting. Second, we combined qualitative data, using semi-structured interviews and the Workload Indicator of Staffing Needs (WISN) to assess the sufficiency of the eHealth workforce in selected hospitals in a LMIC setting like Ghana. RESULTS: We surveyed 76 (60%) of the eHealth staff from three hospitals in Ghana-La General Hospital, University of Ghana Hospital, and Greater Accra Regional Hospital. We identified two main eHealth cadres, technical support/information technology (IT) and health information management (HIM). While the HIM cadre presented diversity in expertise, the IT group was dominated by training in Science (42%) and Engineering (55%), and the majority (87%) had at least a bachelor's degree. Health information clerk (32%), health information officer (25%), help desk specialist (20%), and network administrator (11%) were the most dominant roles. Based on the WISN assessment, the eHealth workforce at all the surveyed sites was insufficient. La General and University of Ghana were operating at 10% of required IT staff capacity, while Ridge was short by 42%. CONCLUSIONS: We have developed a framework to characterize and assess the eHealth workforce in LMICs. Applying it to a case study in Ghana has given us a better understanding of potential eHealth staffing needs in LMICs, while providing the quantitative basis for building the requisite human capital to drive eHealth initiatives. Educators can also use our results to explore competency gaps and refine curricula for burgeoning training programs. The findings of this study can serve as a springboard for other LMICs to assess the effects of a well-trained eHealth workforce on the return on eHealth investments. PMID- 30482222 TI - Linking single-cell measurements of mass, growth rate, and gene expression. AB - Mass and growth rate are highly integrative measures of cell physiology not discernable via genomic measurements. Here, we introduce a microfluidic platform enabling direct measurement of single-cell mass and growth rate upstream of highly multiplexed single-cell profiling such as single-cell RNA sequencing. We resolve transcriptional signatures associated with single-cell mass and growth rate in L1210 and FL5.12 cell lines and activated CD8+ T cells. Further, we demonstrate a framework using these linked measurements to characterize biophysical heterogeneity in a patient-derived glioblastoma cell line with and without drug treatment. Our results highlight the value of coupled phenotypic metrics in guiding single-cell genomics. PMID- 30482225 TI - Correction to: PAKs supplement improves immune status and body composition but not muscle strength in resistance trained individuals. AB - The original article [1] contains an error whereby the author, Frederico G Romero's name is displayed incorrectly; the correct spelling is instead displayed in this Correction article. PMID- 30482226 TI - Increasing intratumor C/EBP-beta LIP and nitric oxide levels overcome resistance to doxorubicin in triple negative breast cancer. AB - BACKGROUND: Triple negative breast cancer (TNBC) easily develops resistance to the first-line drug doxorubicin, because of the high levels of the drug efflux transporter P-glycoprotein (Pgp) and the activation of pro-survival pathways dependent on endoplasmic reticulum (ER). Interfering with these mechanisms may overcome the resistance to doxorubicin, a still unmet need in TNBC. METHODS: We analyzed a panel of human and murine breast cancer cells for their resistance to doxorubicin, Pgp expression, lysosome and proteasome activity, nitrite production, ER-dependent cell death and immunogenic cell death parameters. We evaluated the efficacy of genetic (C/EBP-beta LIP induction) and pharmacological strategies (lysosome and proteasome inhibitors), in restoring the ER-dependent and immunogenic-dependent cell death induced by doxorubicin, in vitro and in syngeneic mice bearing chemoresistant TNBC. The results were analyzed by one-way analysis of variance test. RESULTS: We found that TNBC cells characterized by high levels of Pgp and resistance to doxorubicin, had low induction of the ER dependent pro-apoptotic factor C/EBP-beta LIP upon doxorubicin treatment and high activities of lysosome and proteasome that constitutively destroyed LIP. The combination of chloroquine and bortezomib restored doxorubicin sensitivity by activating multiple and interconnected mechanisms. First, chloroquine and bortezomib prevented C/EBP-beta LIP degradation and activated LIP-dependent CHOP/TRB3/caspase 3 axis in response to doxorubicin. Second, C/EBP-beta LIP down regulated Pgp and up-regulated calreticulin that triggered the dendritic cell (DC)-mediated phagocytosis of tumor cell, followed by the activation of anti tumor CD8+T-lymphocytes upon doxorubicin treatment. Third, chloroquine and bortezomib increased the endogenous production of nitric oxide that further induced C/EBP-beta LIP and inhibited Pgp activity, enhancing doxorubicin's cytotoxicity. In orthotopic models of resistant TNBC, intratumor C/EBP-beta LIP induction - achieved by a specific expression vector or by chloroquine and bortezomib - effectively reduced tumor growth and Pgp expression, increased intra tumor apoptosis and anti-tumor immune-infiltrate, rescuing the efficacy of doxorubicin. CONCLUSIONS: We suggest that preventing C/EBP-beta LIP degradation by lysosome and proteasome inhibitors triggers multiple virtuous circuitries that restore ER-dependent apoptosis, down-regulate Pgp and re-activate the DC/CD8+T lymphocytes response against TNBC. Lysosome and proteasome inhibitors associated with doxorubicin may overcome the resistance to the drug in TNBC. PMID- 30482227 TI - Inhibition of TPL2 by interferon-alpha suppresses bladder cancer through activation of PDE4D. AB - BACKGROUND: Drugs that inhibit the MEK/ERK pathway have therapeutic benefit in bladder cancer treatment but responses vary with patients, for reasons that are still not very clear. Interferon-alpha (IFN-alpha) is also used as a therapeutic agent for bladder cancer treatment but the response rate is low. It was found that IFN-alpha could enhance the cytotoxic effect of MEK inhibition. However, the potential mechanisms of that are still unclear. Understanding of the cross-talk between the IFN-alpha and MEK/ERK pathway will help enhance the efficacy of IFN alpha or MEK inhibitors on bladder cancer. METHODS: Immunoprecipitation and pull down assay were used to reveal the formation of signaling complex. The protein expressions were detected by western blot and immunohistochemistry. The cAMP level, Phosphodiesterase 4D (PDE4D) activity and Prostaglandin E2 (PGE2) concentration in cells, serum and tissues were detected by enzyme-linked immunosorbent assay. The role of PDE4D in bladder tumorigenesis in vivo was examined by the xenograft model. Tissue microarray chips were used to investigate the prognostic roles of PDE4D and tumor progression locus 2 (TPL2) in bladder cancer patients. RESULTS: IFN-alpha down-regulated the cyclooxygenase-2 (COX-2) expression in bladder cancer cells through the inhibition of TPL2/NF-kappaB pathway; IFN-alpha also inhibited COX-2 expression by suppressing cAMP signaling through TPL2-ERK mediated PDE4D activity. Reduction of the intracellular cAMP level by PDE4D potentiated the antitumor effect of IFN-alpha against bladder cancer in vitro and in vivo. Further analysis of clinical samples indicated that low PDE4D expression and high level of TPL2 phosphorylation were correlated to the development and poor prognosis in bladder cancer patients. CONCLUSIONS: Our data reveal that IFN-alpha can exert its antitumor effect through a non-canonical JAK-STAT pathway in the bladder cancer cells with low activity of IFN pathway, and the TPL2 inhibition is another function of IFN-alpha in the context of bladder cancer therapy. The antitumor effects of IFN-alpha and MEK inhibition also depend on the PDE4D-mediated cAMP level in bladder cancer cells. Suppression of the TPL2 phosphorylation and intracellular cAMP level may be possible therapeutic strategies for enhancing the effectiveness of IFN-alpha and MEK inhibitors in bladder cancer treatment. PMID- 30482228 TI - Spliceosomal introns in Trichomonas vaginalis revisited. AB - BACKGROUND: The human protozoan parasite Trichomonas vaginalis is an organism of interest for understanding eukaryotic evolution. Despite having an unusually large genome and a rich gene repertoire among protists, spliceosomal introns in T. vaginalis appear rare: only 62 putative introns have been annotated in this genome, and little or no experimental evidence exists to back up these predictions. RESULTS: This study revisited the 62 annotated introns of T. vaginalis derived from the genome sequencing plus previous publications. After experimental validation and a new genome-wide search, we confirmed the presence of introns in 32 genes and 18 others were concluded to be intronless. Sequence analyses classified the validated introns into two types, based on distinctive features such as length and conservation of splice site motifs. CONCLUSIONS: Our study provides an updated list of intron-containing genes in the genome of T. vaginalis. Our findings suggests the existence of two intron 'families' spread among T. vaginalis protein-coding genes. Additional studies are needed to understand the functional separation of these two classes of introns and to assess the existence of further introns in the T. vaginalis genome. PMID- 30482229 TI - Descriptive epidemiology of changes in objectively measured sedentary behaviour and physical activity: six-year follow-up of the EPIC-Norfolk cohort. AB - BACKGROUND: Sedentary time increases and total physical activity decreases with age. The magnitude and correlates of changes in sedentary time, light-intensity physical activity (LPA), moderate-to-vigorous intensity physical activity (MVPA), and overall physical activity remain unclear. We quantified these changes and identified their individual and sociodemographic correlates. METHODS: We used data from 1259 adults (67.8 +/- 6.9 years; 41.9% women) who participated in the EPIC-Norfolk Study. Activity was assessed at baseline (2004-2011) and follow-up (2012-2016) for 7 days using accelerometers. Potential correlates of change were specified a priori. We used unadjusted and adjusted sex-stratified linear regressions to identify correlates of change. RESULTS: Only 3.7% of adults met the current MVPA recommendations. Sedentary time increased by 3.0 min/day/year (SD = 12.3). LPA, MVPA, and overall PA decreased by 1.7 min/day/year (SD = 5.4), 3.0 min/day/year (SD = 6.0), and 8.8 cpm/year (SD = 18.8), respectively. Correlates of greater rates of increase in sedentary time included older age and higher BMI in men, and older age, higher BMI, smoking, and urban dwelling in women. Correlates of greater rates of decrease in physical activity included older age, higher BMI, living alone, depression, car use, and/or fair/poor self rated health in men, and older age, higher BMI, depression, smoking, and/or urban dwelling in women (e.g. depressed women had a 1.0 min/day/year greater rate of decline in MVPA than non-depressed women, 95% CI -1.8, - 0.2). CONCLUSIONS: Most (> 95%) adults are insufficiently active. Sedentary time increases and LPA, MVPA and overall physical activity decreases over time, with more pronounced rates of change observed in specific sub-groups (e.g. among older and depressed adults). To promote active living, the correlates of these changes should be considered in future interventions. PMID- 30482230 TI - Mechanical simulation study of postoperative displacement of trochanteric fractures using the finite element method. AB - BACKGROUND: Femoral trochanteric fractures are common among older adults. In the reduction of trochanteric fractures, acquiring the support of the anterior cortex at the fracture site on lateral view immediately after surgery is important. However, even if the cortical support is acquired, postoperative displacement due to the loss of this support often occurs. This study aimed to investigate local stress distribution in several trochanteric fracture models and to evaluate risk factors for postoperative displacement using the finite element (FE) method. METHODS: Displaced two-fragment fracture models with an angulation deformity at the fracture site and a non-displaced two-fragment fracture model were constructed. The models with an angulation deformity were of two types, one with the proximal fragment directed backward (type A) and the other with the proximal fragment rotated forward from the femoral neck axis (type B). Thereafter, FE models of the femur and a sliding hip screw mounted on a 135 degrees three-hole side-plate were constructed. A 2010-N load was applied to the femoral head, and a 1086-N load was applied to the greater trochanter. Under this condition, the maximum value of the von Mises stress distribution and the amount of displacement of the femoral head vertex in the distal direction were investigated. RESULTS: A larger maximum stress value at the medial femoral neck cortex and a higher amount of displacement in the distal direction were particularly recognized in type A models. These results indicate that microstructural damage was larger in type A models and that type A fracture alignment may be particularly related to fracture collapse and subsequent postoperative displacement. CONCLUSION: Even if support of the anterior cortex at the fracture site on lateral view is acquired immediately after surgery, caution is necessary for cases in which the proximal fragment is directed backward in the postoperative displacement from the viewpoint of the biomechanics of the FE method. PMID- 30482231 TI - Metal artifact reduction on cervical CT images by deep residual learning. AB - BACKGROUND: Cervical cancer is the fifth most common cancer among women, which is the third leading cause of cancer death in women worldwide. Brachytherapy is the most effective treatment for cervical cancer. For brachytherapy, computed tomography (CT) imaging is necessary since it conveys tissue density information which can be used for dose planning. However, the metal artifacts caused by brachytherapy applicators remain a challenge for the automatic processing of image data for image-guided procedures or accurate dose calculations. Therefore, developing an effective metal artifact reduction (MAR) algorithm in cervical CT images is of high demand. METHODS: A novel residual learning method based on convolutional neural network (RL-ARCNN) is proposed to reduce metal artifacts in cervical CT images. For MAR, a dataset is generated by simulating various metal artifacts in the first step, which will be applied to train the CNN. This dataset includes artifact-insert, artifact-free, and artifact-residual images. Numerous image patches are extracted from the dataset for training on deep residual learning artifact reduction based on CNN (RL-ARCNN). Afterwards, the trained model can be used for MAR on cervical CT images. RESULTS: The proposed method provides a good MAR result with a PSNR of 38.09 on the test set of simulated artifact images. The PSNR of residual learning (38.09) is higher than that of ordinary learning (37.79) which shows that CNN-based residual images achieve favorable artifact reduction. Moreover, for a 512 * 512 image, the average removal artifact time is less than 1 s. CONCLUSIONS: The RL-ARCNN indicates that residual learning of CNN remarkably reduces metal artifacts and improves critical structure visualization and confidence of radiation oncologists in target delineation. Metal artifacts are eliminated efficiently free of sinogram data and complicated post-processing procedure. PMID- 30482232 TI - Abnormally elevated USP37 expression in breast cancer stem cells regulates stemness, epithelial-mesenchymal transition and cisplatin sensitivity. AB - BACKGROUND: Recent studies have indicated that deubiquitinating enzymes (DUBs) are related to the stem-cell pathway network and chemo-resistance in cancer. Ubiquitin-specific peptidase 37 (USP37), a novel DUB, was identified to be a potential factor associated with tumor progression. However, the biological functions of USP37 in breast cancer remain unclear. METHODS: The distribution of USP37 expression in breast cancer and the correlation between USP37 expression and the overall survival rate were detected by The Cancer Genome Atlas (TCGA) database. Gene set enrichment analysis (GSEA) was utilized to evaluate potential mechanism of USP37 in breast cancer. The USP37 expression in breast cancer tissues and breast cancer cell lines were detected by immunohistochemistry and western blotting. Sorting of breast cancer stem cells (BCSCs) were by using MACS assay. In vitro and in vivo assays were performed to examine the biological functions of USP37 in breast cancer cells. MG132, CHX chase, immunofluorescence staining and co-immunoprecipitation assays were used to test the interaction between USP37 and Gli-1. RESULTS: Bioinformatics analysis demonstrated that USP37 gene was elevated in breast cancer tissues and its overexpression was strongly correlated with the increased mortality rate. GSEA analysis showed that USP37 expression was positively associated with cell growth and metastasis while negatively related to cell apoptosis in the TCGA breast cancer samples. USP37 expression was elevated in breast cancer tissues and breast cancer cell lines. Moreover, we also detected that USP37 was overexpressed in BCSCs. USP37 regulated the ability of cell invasion, epithelial-mesenchymal transition (EMT), stemness and cisplatin sensitivity in breast cancer cell lines. Additionally, USP37 knockdown inhibited tumorigenicity and increased anticancer effect of cisplatin in vivo. Knockdown of USP37 significantly decreased hedgehog (Hh) pathway components Smo and Gli-1. Gli-1 was stabilized by USP37 and they interacted with each other. Further studies indicated that USP37 knockdown could inhibit the stemness, cell invasion and EMT in breast cancer via downregulation of Hh pathway. CONCLUSIONS: These findings reveal that USP37 is highly expressed in BCSCs and is correlated with poor prognosis in breast cancer patients. USP37 can regulate the stemness, cell invasion and EMT via Hh pathway, and decreased USP37 confers sensitivity to cisplatin in breast cancer cells. USP37 is required for the regulation of breast cancer progression, as well as a critical target for clinical treatment of breast cancer. PMID- 30482234 TI - Transcriptome analysis of Shank3-overexpressing mice reveals unique molecular changes in the hypothalamus. AB - Various mutations in the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene are associated with neurodevelopmental and neuropsychiatric disorders. Thus far, synaptic abnormalities in multiple brain regions, including the hippocampus, prefrontal cortex, striatum, and ventral tegmental area, have been investigated in several lines of Shank3 mutant mice. However, although some reports have shown loss and gain of body weight in Shank3 knock-out and overexpressing transgenic (TG) mice, respectively, the potential functions of Shank3 in the hypothalamus, a brain region critically involved in energy intake and expenditure, are unknown. Hence, we first characterized endogenous Shank3 mRNA and protein expression in the hypothalamus of adult wild-type mice. Thereafter, we performed transcriptome analysis (RNA-sequencing) in the hypothalamus of adult Shank3 TG mice which mildly overexpress Shank3 proteins. By comparing the 174 differentially expressed genes in the hypothalamus with those previously reported in the striatum and medial prefrontal cortex (mPFC) of Shank3 TG mice, we found that 159 were hypothalamus-specific while only 15 were also observed in either the striatum or mPFC. Furthermore, gene set enrichment analysis of the RNA-sequencing analysis revealed that ribosome-related genes were enriched especially in the up-regulated genes of Shank3 TG hypothalamus, which is in contrast to the results of the Shank3 TG striatum and mPFC analyses, where ribosome-related genes were enriched in the down-regulated genes. Beyond revealing endogenous Shank3 mRNA and protein expression in the hypothalamus, our results suggest unique molecular changes in the hypothalamus of Shank3 TG mice compared with those in the striatum and mPFC. PMID- 30482233 TI - Enhanced tendon-bone healing with acidic fibroblast growth factor delivered in collagen in a rabbit anterior cruciate ligament reconstruction model. AB - BACKGROUND: The objective of the present study was to investigate the effectiveness of acidic fibroblast growth factor delivered in collagen (aFGF/collagen) for promoting tendon-bone interface healing after anterior cruciate ligament (ACL) reconstruction in rabbits. METHODS: ACL reconstructions were performed in the right hind limbs of New Zealand rabbits. Each left long digital extensor tendon was harvested as an autograft, and collagen incorporating different concentrations of aFGF or same amount of collagen alone was applied at the tendon-bone interface after ACL reconstruction. The control group underwent ACL reconstruction only. There were high and low aFGF/collagen groups, collagen alone group, and control group (n = 21 rabbits per group). Histological and biomechanical analyses were performed at 4, 8, and 12 weeks postoperatively to evaluate the effect of aFGF/collagen on tendon-bone interface healing. RESULTS: Results of biomechanical tests showed that at both 8 and 12 weeks postoperatively, the elastic modulus and stiffness in both the high and low aFGF/collagen treatment groups were significantly higher than those in the control group and collagen alone group, with that in the high aFGF/collagen concentration group being the highest. Histological analysis showed that at 8 weeks, tightly organized Sharpey-like fibers were observed in both aFGF/collagen groups with new bone growth into the tendon in the high concentration group. At 12 weeks postoperatively, a fibrocartilage transition zone was observed in the bone tunnels in both aFGF/collagen groups, especially in the high aFGF/collagen group. CONCLUSION: Application of the aFGF/collagen composite could enhance early healing at the tendon-bone interface after ACL reconstruction, especially with the use of a high aFGF/collagen concentration. PMID- 30482235 TI - The ins and outs of telomere crisis in cancer. AB - Telomere crisis is linked with many of the genomic alterations found in cancer genomes. A new understanding of how these alterations arise points towards an active role for innate immune sensors during crisis and to new opportunities for the treatment and diagnosis of cancer. PMID- 30482236 TI - Long noncoding RNA LINC00511 contributes to breast cancer tumourigenesis and stemness by inducing the miR-185-3p/E2F1/Nanog axis. AB - BACKGROUND: Emerging evidence have illustrated the vital role of long noncoding RNAs (lncRNAs) long intergenic non-protein coding RNA 00511 (LINC00511) on the human cancer progression and tumorigenesis. However, the role of LINC00511 in breast cancer tumourigenesis is still unknown. This research puts emphasis on the function of LINC00511 on the breast cancer tumourigenesis and stemness, and investigates the in-depth mechanism. METHODS: The lncRNA and RNA expression were measured using RT-PCR. Protein levels were measured using western blotting analysis. CCK-8, colony formation assays and transwell assay were performed to evaluate the cell proliferation ability and invasion. Sphere-formation assay was also performed for the stemness. Bioinformatic analysis, chromatin immunoprecipitation (ChIP) and luciferase reporter assays were carried to confirm the molecular binding. RESULTS: LINC00511 was measured to be highly expressed in the breast cancer specimens and the high-expression was correlated with the poor prognosis. Functionally, the gain and loss-of-functional experiments revealed that LINC00511 promoted the proliferation, sphere-formation ability, stem factors (Oct4, Nanog, SOX2) expression and tumor growth in breast cancer cells. Mechanically, LINC00511 functioned as competing endogenous RNA (ceRNA) for miR 185-3p to positively recover E2F1 protein. Furthermore, transcription factor E2F1 bind with the promoter region of Nanog gene to promote it transcription. CONCLUSION: In conclusion, our data concludes that LINC00511/miR-185 3p/E2F1/Nanog axis facilitates the breast cancer stemness and tumorigenesis, providing a vital insight for them. PMID- 30482237 TI - Epicutaneous immunotherapy in rhino-conjunctivitis and food allergies: a review of the literature. AB - BACKGROUND: Epicutaneous immunotherapy (EPIT) is a new way of allergen administration that has a high rate of adherence and safety. The aim of this manuscript is to review clinical trials on EPIT for respiratory and food allergies published in the last 10 years, taking into account how different variables (i.e., dose, patch application duration, skin preparation, and efficacy and safety evaluation) have influenced study results. MAIN BODY: From a review of the literature, we identified eight placebo-controlled, double-blind trials conducted on children and adults, including four studies on grass pollen rhino conjunctivitis, one on cow's milk allergy and three on peanut allergy. Different methods for skin pre-treatment, such as skin abrasion and tape stripping or stratum corneous hydration by an occlusive system, different endpoints and cumulative allergen doses, and different durations of patch application and tape stripping, were used in the rhino-conjunctivitis studies. A visual analogue system was used for the efficacy evaluation. Several local skin reactions (eczema) and some systemic adverse reactions were reported at higher rates in the active group compared to placebo in one study, but this was not shown by other authors. Local eczema reactions were correlated to the times for applying the tape stripping, while systemic side effects were correlated to the deepness of scraping. In the food allergy trials, differences in the food challenge thresholds, endpoints and allergen sites of the cutaneous patch application influenced the study results. A slight dose-dependent efficacy was found in the peanut allergy studies, which was confirmed by a more significant increase in the following progressive open study. Few adverse events and high adherence in all of the food allergen trials were reported. CONCLUSIONS: Overall, the EPIT study results, even if they were affected by great heterogeneity among the methodologies applied, have shown not only the high safety and adherence with this kind of immunotherapy but also suggested the possibility for obtaining definitive evidence of the efficacy of EPIT, especially for food allergies. PMID- 30482238 TI - An analysis of reporting quality of prospective studies examining community antibiotic use and resistance. AB - BACKGROUND: Antibiotic resistance is a global problem, but the relationship between antibiotic use and resistance development and decay is not well understood. This knowledge is best provided by prospective studies, but to be useful they must be both conducted and reported well. Little is known about the reporting quality of these studies. This study aimed to assess the quality of reporting in prospective studies that investigated antibiotic resistance following antibiotic exposure in community-based individuals. METHODS: The quality of reporting of prospective studies (17 randomised trials, eight cohort studies) identified in a systematic review of the relationship between antibiotic use and resistance were assessed independently by two researchers using checklists (one for trials, one for cohort studies) developed from existing reporting guidelines for these designs and this field. RESULTS: The mean percentage (SD, minimum-maximum) of mandatory items that were adequately described by the included studies was 59% for trials (14%, 36-84%) and 52% for cohort studies (17%, 13-70%). Most studies adequately described the study background and rationale, the type, combination, and duration of the antibiotic intervention, and the sampling procedures followed to isolate resistant bacteria. Most studies did not report the incident numbers of resistant and susceptible isolates analysed at each time point. Blinding and sample size calculation was inadequately reported in almost half of the trials and all cohort studies. CONCLUSIONS: The quality of reporting in prospective studies investigating the association between antibiotic exposure in the community and isolation of resistance isolates is variable. Some details were missing in more than half of the studies, which precludes a complete risk of bias assessment and accurate interpretation and synthesis of results. PMID- 30482241 TI - Gain of UBE2D1 facilitates hepatocellular carcinoma progression and is associated with DNA damage caused by continuous IL-6. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of liver cancer with increasing incidence and poor prognosis. Ubiquitination regulators are reported to play crucial roles in HCC carcinogenesis. UBE2D1, one of family member of E2 ubiquitin conjugating enzyme, mediates the ubiquitination and degradation of tumor suppressor protein p53. However, the expression and functional roles of UBE2D1 in HCC was unknown. METHODS: Immunohistochemistry (IHC), western blotting, and real-time PCR were used to detect the protein, transcription and genomic levels of UBE2D1 in HCC tissues with paired nontumor tissues, precancerous lesions and hepatitis liver tissues. Four HCC cell lines and two immortalized hepatic cell lines were used to evaluate the functional roles and underlying mechanisms of UBE2D1 in HCC initiation and progression in vitro and in vivo. The contributors to UBE2D1 genomic amplification were first evaluated by performing a correlation analysis between UBE2D1 genomic levels with clinical data of HCC patients, and then evaluated in HCC and hepatic cell lines. RESULTS: Expression of UBE2D1 was significantly increased in HCC tissues and precancerous lesions and was associated with reduced survival of HCC patients. Upregulation of UBE2D1 promoted HCC growth in vitro and in vivo by decreasing the p53 in ubiquitination-dependent pathway. High expression of UBE2D1 was attributed to the recurrent genomic copy number gain, which was associated with high serum IL-6 level of HCC patients. Further experiments showed that continuous IL-6 activated the DNA damage response and genomic instability by repressing DNA damage checkpoint protein RAD51B. Moreover, continuous IL-6 could significantly facilitate the HCC growth especially with the genomic gain of UBE2D1. CONCLUSIONS: Our findings showed that UBE2D1 played a crucial role in HCC progression, and suggested a novel pattern of continuous IL-6 to promote cancers by inducing the genomic alterations of specific oncogenes. PMID- 30482239 TI - Spatial-temporal heterogeneity in malaria receptivity is best estimated by vector biting rates in areas nearing elimination. AB - BACKGROUND: Decisions on when vector control can be withdrawn after malaria is eliminated depend on the receptivity or potential of an area to support vector populations. To guide malaria control and elimination programmes, the potential of biting rates, sporozoite rates, entomological inoculation rates and parity rates to estimate malaria receptivity and transmission were compared within and among geographically localised villages of active transmission in the Western Province of the Solomon Islands. RESULTS: Malaria transmission and transmission potential was heterogeneous in both time and space both among and within villages as defined by anopheline species composition and biting densities. Biting rates during the peak biting period (from 18:00 to 00:00 h) of the primary vector, Anopheles farauti, ranged from less than 0.3 bites per person per half night in low receptivity villages to 26 bites per person in highly receptive villages. Within villages, sites with high anopheline biting rates were significantly clustered. Sporozoite rates provided evidence for continued transmission of Plasmodium falciparum, P. vivax and P. ovale by An. farauti and for incriminating An. hinesorum, as a minor vector, but were unreliable as indicators of transmission intensity. CONCLUSIONS: In the low transmission area studied, sporozoite, entomological inoculation and parity rates could not be measured with the precision required to provide guidance to malaria programmes. Receptivity and potential transmission risk may be most reliably estimated by the vector biting rate. These results support the meaningful design of operational research programmes to ensure that resources are focused on providing information that can be utilised by malaria control programmes to best understand both transmission, transmission risk and receptivity across different areas. PMID- 30482242 TI - A family with PTEN mutations with malignancy and an unusually high number of offspring with autism spectrum disorder: a case report. AB - BACKGROUND: Cowden's syndrome (OMIM:158350), a rare genetic disorder (incidence ~ 1:250,000), is caused by mutations of the tumor suppressor gene PTEN. In this report, we describe clinical manifestations of a 56-year-old patient diagnosed with Cowden's syndrome and his family with PTEN mutations. The family has an unusually high number of offspring with autism spectrum disorder. CASE PRESENTATION: Except for his 80-year-old Caucasian father, all of our index case's living Caucasian kindred (three children, brother, and nephew) had PTEN mutations and macrocephaly. Prior to genetic testing, his mother and sister died of breast cancer at 42 and 38 years old, respectively. After PTEN mutation was identified, our patient underwent complete thyroidectomy (histology showing micropapillary carcinoma) and right nephrectomy for renal cell carcinoma. All of his three children (13-year-old son, 11- and 8-year-old daughters) have been diagnosed with autism spectrum disorder. His son and brother underwent total thyroidectomy. His nephew had thyroid nodules. Management of Cowden's syndrome requires clinical examinations and investigations every 6 to 12 months from 18 years old or 5 years before the family's earliest age of cancer diagnosis and should focus on all clinical manifestations associated with PTEN mutations to identify early abnormal changes in skin, breasts, thyroid, endometrium, gut, and kidneys. Input from specialists across different disciplines is necessary. CONCLUSIONS: We describe a man and his family with PTEN mutations who have increased risk of cancers and an unusually high number of offspring with autism spectrum disorder. Early recognition and close surveillance are vital in order to provide treatment and early screening for asymptomatic at-risk relatives. PMID- 30482240 TI - The chicken gut metagenome and the modulatory effects of plant-derived benzylisoquinoline alkaloids. AB - BACKGROUND: Sub-therapeutic antibiotics are widely used as growth promoters in the poultry industry; however, the resulting antibiotic resistance threatens public health. A plant-derived growth promoter, Macleaya cordata extract (MCE), with effective ingredients of benzylisoquinoline alkaloids, is a potential alternative to antibiotic growth promoters. Altered intestinal microbiota play important roles in growth promotion, but the underlying mechanism remains unknown. RESULTS: We generated 1.64 terabases of metagenomic data from 495 chicken intestinal digesta samples and constructed a comprehensive chicken gut microbial gene catalog (9.04 million genes), which is also the first gene catalog of an animal's gut microbiome that covers all intestinal compartments. Then, we identified the distinctive characteristics and temporal changes in the foregut and hindgut microbiota. Next, we assessed the impact of MCE on chickens and gut microbiota. Chickens fed with MCE had improved growth performance, and major microbial changes were confined to the foregut, with the predominant role of Lactobacillus being enhanced, and the amino acids, vitamins, and secondary bile acids biosynthesis pathways being upregulated, but lacked the accumulation of antibiotic-resistance genes. In comparison, treatment with chlortetracycline similarly enriched some biosynthesis pathways of nutrients in the foregut microbiota, but elicited an increase in antibiotic-producing bacteria and antibiotic-resistance genes. CONCLUSION: The reference gene catalog of the chicken gut microbiome is an important supplement to animal gut metagenomes. Metagenomic analysis provides insights into the growth-promoting mechanism of MCE, and underscored the importance of utilizing safe and effective growth promoters. PMID- 30482243 TI - Atypical response with bone pseudoprogression in a patient receiving nivolumab for advanced cutaneous squamous cell carcinoma. AB - Currently, there is no established standard of care for patients with metastatic CSCC. Based on the mechanisms of CSCC carcinogenesis has been postulated that these tumors may be amenable to PD-1/PD-L1 blockade.This case illustrates a patient with CSCC with nodal involvement and pulmonary metastases, refractory to two lines of platinum-based regimens and salvage surgery, for whom treatment with nivolumab was recommended. His clinical course was marked by an atypical pattern of response, with initial reduction of soft tissue/visceral lesions, yet development of new bone findings, followed by overall improvement in subsequent scans and sustained disease control upon treatment continuation.The case of patient with metastatic CSCC, refractory, received immunotherapy and evolved with atypical pattern of response. PMID- 30482245 TI - Correction to: Dynamic linear models guide design and analysis of microbiota studies within artificial human guts. AB - AbstractFollowing publication of the original article [1], the authors noticed an error in the presentation of equations in the PDF version. PMID- 30482244 TI - Determinants of late initiation for antenatal care follow up: the case of northern Ethiopian pregnant women. AB - OBJECTIVE: Early antenatal care follow-up is the main strategy of preventing pregnancy related adverse outcomes; in which World Health Organization recommends first antenatal care visit should be offered within the first trimester. However, Low utilization and late booking is the predominant problem in most developing countries including Ethiopia. This study aimed to determine the prevalence of late initiation for antenatal care follow-up and associated factors among pregnant women. Institutional based cross-sectional study was conducted among 423 pregnant mothers using systematic sampling technique. Multivariable logistic regression analysis was performed at the level of significance of p-value <= 0.05. RESULTS: The findings showed 59.4% of pregnant women started their first visit after first trimester. Having age >= 25 years (AOR = 1.62, CI 1.1, 2.49), recognition of pregnancy by missed period (AOR = 2.54 CI 1.63, 3.96), pregnant mother who were not advised to start antenatal-care (AOR = 3.36, CI 1.74, 6.5) and primary educational level (AOR = 2.22, CI 1.16, 4.25) were found to be significantly associated with late initiation for antenatal care. The prevalence of late antenatal care follow-up is high. Multidisciplinary approaches to keep empowering women through education are recommended for early initiation of antenatal care. PMID- 30482246 TI - A role for the unfolded protein response stress sensor ERN1 in regulating the response to MEK inhibitors in KRAS mutant colon cancers. AB - BACKGROUND: Mutations in KRAS are frequent in human cancer, yet effective targeted therapeutics for these cancers are still lacking. Attempts to drug the MEK kinases downstream of KRAS have had limited success in clinical trials. Understanding the specific genomic vulnerabilities of KRAS-driven cancers may uncover novel patient-tailored treatment options. METHODS: We first searched for synthetic lethal (SL) genetic interactions with mutant RAS in yeast with the ultimate aim to identify novel cancer-specific targets for therapy. Our method used selective ploidy ablation, which enables replication of cancer-specific gene expression changes in the yeast gene disruption library. Second, we used a genome wide CRISPR/Cas9-based genetic screen in KRAS mutant human colon cancer cells to understand the mechanistic connection between the synthetic lethal interaction discovered in yeast and downstream RAS signaling in human cells. RESULTS: We identify loss of the endoplasmic reticulum (ER) stress sensor IRE1 as synthetic lethal with activated RAS mutants in yeast. In KRAS mutant colorectal cancer cell lines, genetic ablation of the human ortholog of IRE1, ERN1, does not affect growth but sensitizes to MEK inhibition. However, an ERN1 kinase inhibitor failed to show synergy with MEK inhibition, suggesting that a non-kinase function of ERN1 confers MEK inhibitor resistance. To investigate how ERN1 modulates MEK inhibitor responses, we performed genetic screens in ERN1 knockout KRAS mutant colon cancer cells to identify genes whose inactivation confers resistance to MEK inhibition. This genetic screen identified multiple negative regulators of JUN N terminal kinase (JNK) /JUN signaling. Consistently, compounds targeting JNK/MAPK8 or TAK1/MAP3K7, which relay signals from ERN1 to JUN, display synergy with MEK inhibition. CONCLUSIONS: We identify the ERN1-JNK-JUN pathway as a novel regulator of MEK inhibitor response in KRAS mutant colon cancer. The notion that multiple signaling pathways can activate JUN may explain why KRAS mutant tumor cells are traditionally seen as highly refractory to MEK inhibitor therapy. Our findings emphasize the need for the development of new therapeutics targeting JUN activating kinases, TAK1 and JNK, to sensitize KRAS mutant cancer cells to MEK inhibitors. PMID- 30482247 TI - Merkel cell polyomavirus-specific immune responses in patients with Merkel cell carcinoma receiving anti-PD-1 therapy. AB - BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer that frequently responds to anti-PD-1 therapy. MCC is associated with sun exposure and, in 80% of cases, Merkel cell polyomavirus (MCPyV). MCPyV-specific T and B cell responses provide a unique opportunity to study cancer-specific immunity throughout PD-1 blockade therapy. METHODS: Immune responses were assessed in patients (n = 26) with advanced MCC receiving pembrolizumab. Peripheral blood mononuclear cells (PBMC) were collected at baseline and throughout treatment. MCPyV-oncoprotein antibodies were quantified and T cells were assessed for MCPyV specificity via tetramer staining and/or cytokine secretion. Pre-treatment tumor biopsies were analyzed for T cell receptor clonality. RESULTS: MCPyV oncoprotein antibodies were detectable in 15 of 17 (88%) of virus-positive MCC (VP-MCC) patients. Antibodies decreased in 10 of 11 (91%) patients with responding tumors. Virus-specific T cells decreased over time in patients who had a complete response, and increased in patients who had persistent disease. Tumors that were MCPyV(+) had a strikingly more clonal (less diverse) intratumoral TCR repertoire than virus-negative tumors (p = 0.0001). CONCLUSIONS: Cancer-specific T and B cell responses generally track with disease burden during PD-1 blockade, in proportion to presence of antigen. Intratumoral TCR clonality was significantly greater in VP-MCC than VN-MCC tumors, suggesting expansion of a limited number of dominant clones in response to fewer immunogenic MCPyV antigens. In contrast, VN MCC tumors had lower clonality, suggesting a diverse T cell response to numerous neoantigens. These findings reveal differences in tumor-specific immunity for VP MCC and VN-MCC, both of which often respond to anti-PD-1 therapy. PMID- 30482249 TI - Development of a Core Outcome Set for Studies on Obesity in Pregnant Patients (COSSOPP): a study protocol. AB - BACKGROUND: Maternal obesity is a risk factor for adverse maternal, fetal, and neonatal events. Numerous clinical trials are currently exploring the effectiveness of antenatal and peripartum interventions in improving pregnancy outcomes that can in future inform clinical practice. However, the heterogeneity in outcome reporting limits our ability to compare outcomes across studies, and there is a lack of stakeholder representation in outcome choice. A pragmatic solution to this problem is the development of a core outcome set (COS) that defines the minimum criteria for outcome reporting in clinical trials undertaken in this population, arrived at by the involvement of relevant stakeholders. METHODS: The development of a COS for studies on obesity in pregnant patients (COSSOPP) will comprise five steps. First, a systematic review of published literature will identify the long list of outcomes, their definitions and measurements if applicable, and outcome reporting quality. This will be followed by a meta-synthesis of qualitative studies with patients, and qualitative interviews in Toronto with patients, clinicians, researchers, hospital administrators, and policy-makers, to identify novel outcomes that were not obtained through systematic review. Third, the long list of outcomes will be narrowed down through online Delphi surveys involving an international group of patients and relevant stakeholders. This will be followed by a face-to-face consensus meeting with representatives of all stakeholder groups to arrive at a consensus on the final COS. Finally, in order to determine how the identified core outcomes should be measured, we will conduct another literature review and Delphi process. DISCUSSION: COSSOPP will engage patients, clinicians, researchers, and other relevant stakeholders in determining the core set of outcomes that should be reported and measured in order to harmonize outcome reporting in studies evaluating the effectiveness of antepartum and peripartum interventions in obese pregnant women. This protocol provides a detailed overview of the steps involved in the development of a COS, to guide researchers in developing COS within their areas of specialization. COMET CORE OUTCOME SET REGISTRATION: http://www.comet-initiative.org/studies/details/939 . PMID- 30482250 TI - A neo-institutional analysis of the hidden interaction between the Israeli Supreme Court and the Ministry of Finance: the right to healthcare services. AB - BACKGROUND: Under structural conditions of non-governability, most players in the policy arena in Israel turn to two main channels that have proven effective in promoting the policies they seek: the submission of petitions to the High Court of Justice and making legislative amendments through the Economic Arrangements Law initiated by the Ministry of Finance. Nevertheless, an analysis of the principal trends emerging from the High Court of Justice rulings and legislative amendments through the Economic Arrangements Law indicates that these channels are open to influence, primarily by forces that are essentially neo-liberal. Little is known about the effects of these trends on the right to healthcare services, which in Israel has not been legislated as an independent constitutional law in Basic Laws. METHODS: We use four major legal cases decided by the Supreme Court of Israel in the past 10 years where the Court reviewed new legislative initiatives proposed by the Economic Arrangements Law in the area of healthcare. We utilize an institutional approach in our analysis. RESULTS: A neo institutional analysis of the legal cases demonstrates that petitions against the Economic Arrangements Law in the area of healthcare services have been denied, even though the Court uses strong rhetoric against that law and the government more generally in addressing issues that concern access to healthcare services and reforms in the healthcare system. This move strengthens the trend toward a neo-liberal public policy and significantly weakens the legal protection of the right to healthcare services. CONCLUSION: In deciding petitions against the Economic Arrangements Law in the area of healthcare, the Supreme Court allows the Ministry of Finance to be a dominant player in the formation of public policy. In doing so, it may be promoting a goal of strengthening its position as a political institution that aspires to increase the public's trust in the judiciary and especially in the Supreme Court itself, in addition to exercising judicial restraint and allowing more leeway to the executive and legislative branches more generally. PMID- 30482248 TI - Soluble immune checkpoints in cancer: production, function and biological significance. AB - Immune checkpoints play important roles in immune regulation, and blocking immune checkpoints on the cell membrane is a promising strategy in the treatment of cancer. Based on this, monoclonal antibodies are having much rapid development, such as those against CTLA-4 (cytotoxic T lymphocyte antigen 4) and PD-1 (programmed cell death protein 1).But the cost of preparation of monoclonal antibodies is too high and the therapeutic effect is still under restrictions. Recently, a series of soluble immune checkpoints have been found such as sCTLA-4 (soluble CTLA-4) and sPD-1 (soluble PD-1). They are functional parts of membrane immune checkpoints produced in different ways and can be secreted by immune cells. Moreover, these soluble checkpoints can diffuse in the serum. Much evidence has demonstrated that these soluble checkpoints are involved in positive or negative immune regulation and that changes in their plasma levels affect the development, prognosis and treatment of cancer. Since they are endogenous molecules, they will not induce immunological rejection in human beings, which might make up for the deficiencies of monoclonal antibodies and enhance the utility value of these molecules. Therefore, there is an increasing need for investigating novel soluble checkpoints and their functions, and it is promising to develop relevant therapies in the future. In this review, we describe the production mechanisms and functions of various soluble immune checkpoint receptors and ligands and discuss their biological significance in regard to biomarkers, potential candidate drugs, therapeutic targets, and other topics. PMID- 30482251 TI - Outcomes following calcium channel blocker exposures reported to a poison information center. AB - BACKGROUND: Calcium channel blockers (CCBs) are widely used drugs that have a narrow therapeutic index. Even minor overdoses must be treated in-hospital due to the risk of severe hypotension and bradycardia. We aimed to describe trends in CCB use and overdoses in Denmark. METHODS: Data on enquiries concerning CCBs reported to the Danish Poisons Information Center (DPIC) from January 2009 to January 2015 was coupled with data on hospitalization and mortality obtained from Danish National Registers. We obtained data on the general use of CCBs in Denmark and retrieved medical charts on fatal cases. RESULTS: From a total of 126,987 enquiries to the DPIC in 2009-2014 we identified 339 CCB unique exposures (30/00 of all). Children < 5 years accounted for 20% all exposures and these were classified as 'intake during playing' (61%) and 'medication errors' (39%). Among adults 'suicidal poisonings' (58%), and 'medication errors' (34%) were most frequent. A majority (81%) of exposures led to hospital admission. Seven patients (2%) died from the CCB exposure and all were adults with 'suicidal poisoning'. Amlodipine accounted for 95% of all CCB prescriptions, was involved in 71% of enquiries and in 29% of fatalities. Verapamil accounted for 3% of prescriptions, was involved in 13% of enquiries and 57% of fatalities. CONCLUSION: Four fifths of enquiries to the DPIC result in hospitalization and one fifth concern small children. Mortality were infrequent and occurred only in adults with suicidal exposures and with and an overrepresentation of verapamil exposures. PMID- 30482252 TI - High spatial resolution identification of hematoma in inhomogeneous head phantom using broadband fNIR system. AB - This paper presents a novel method for early detection of hematomas using highly sensitive optical fNIR imaging methods based on broadband photon migration. The NIR experimental measurements of inhomogeneous multi-layer phantoms representing human head are compared to 3D numerical modeling over broadband frequencies of 30 1000 MHz. A finite element method (FEM) simulation of the head phantom are compared to measurements of insertion loss and phase using custom-designed broadband free space optical transmitter (Tx) and receiver (Rx) modules that are developed for photon migration at wavelengths of 670 nm, 795 nm, 850 nm, though results of 670 nm are discussed here. Standard error is used to compute error between 3D FEM modeling and experimental measurements by fitting experimental data to the [Formula: see text]. Error results are shown at narrowband and broadband frequency modulation in order to have confidence in 3D numerical modeling. A novel method is established here to identify presence of hematoma based on first and second derivatives of changes in insertion loss and phase (?IL and ?IP), where frequency modulated photons sensitive to different sizes of hematoma is identified for wavelength of 670 nm. The high accuracy of this comparison provides confidence in optical bio-imaging and its eventual application to TBI detection. PMID- 30482253 TI - Sex differences in distribution of cannabinoid receptors (CB1 and CB2), S100A6 and CacyBP/SIP in human ageing hearts. AB - BACKGROUND: Women live about 4 years longer due to lower prevalence of cardiovascular complication with ageing. However, the mechanisms involved in the preservation of heart functionality in women have not been fully elucidated. The endocannabinoid system fulfils a significant role in the regulation of cardiovascular system functioning. Cannabinoids, acting through specific receptors (CB1 and CB2), influence on blood pressure, heart rate and myocardial contractility. The function of cardiac muscle cells is strictly dependent on calcium ions. Calcium homeostasis in cardiomyocytes is subjected to complex regulation via calcium-binding proteins. Among them, increasing attention has been paid to the recently discovered S100A6 and CacyBP/SIP. In order to better understand sex differences in the regulation of cardiomyocyte function during ageing, we undertook the present research aimed at immunohistochemical identification and comparative evaluation of cannabinoid receptors, S100A6 and CacyBP/SIP, in the myocardium of ageing men and women. METHODS: The study was conducted on the hearts of 12 men and 10 women (organ donors) without a history of cardiovascular disease. The subjects were divided into two age groups: subjects older than 50 years and subjects under 50 years old. Paraffin heart sections were processed by immunohistochemistry for detection of cannabinoids receptors, S100A6 and CacyBP/SIP. In the heart samples from each study, participant's expression of genes coding for CB1, CB2, S100A6 and CacyBP/SIP using real-time PCR method was measured. RESULTS: CB1 and CB2 immunoreactivity in the cytoplasm of cardiomyocytes in the heart of subjects over 50 was weaker than in younger individuals. In the heart of younger men, CB1-immunoreactivity was weaker and CB2-immunoreaction was stronger compared to women. In the hearts of older men, the CB1-immunostaining was more intense and CB2-immunoreactivity was weaker than in women. Immunodetection of CB1 shoved the presence of receptor in the intercalated discs, but only in the hearts of individuals over the 50 years old. In the hearts of older individuals, stronger immunolabelling was observed for S100A6 and CacyBP/SIP. Male hearts had greater S100A6-immunoreactivity (both age groups) but less CacyBP/SIP immunostaining (individuals over 50 years) compared to the age-matched women. The expression of genes coding CB1, CB2, S100A6 and CacyBP/SIP in the human heart was sex and age-dependent. Observed changes between men and women as well as between subject under and over 50 years were consistent with immunohistochemically stated changes in peptide content. CONCLUSION: Together, the data presented here indicate a close interaction between ageing and sex on the distribution and levels of cannabinoid receptors (CB1, CB2), S100A6 and CacyBP/SIP in the human heart. PMID- 30482254 TI - Ursodeoxycholic acid versus placebo in the treatment of women with intrahepatic cholestasis of pregnancy (ICP) to improve perinatal outcomes: protocol for a randomised controlled trial (PITCHES). AB - BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder specific to pregnancy and presents with maternal pruritus, raised concentrations of serum bile acids and abnormal liver function tests. ICP is associated with increased rates of spontaneous and iatrogenic preterm labour, fetal hypoxia, meconium-stained amniotic fluid and intrauterine death. Some clinicians treat ICP with ursodeoxycholic acid (UDCA) to improve maternal pruritus and biochemical abnormalities. However, there are currently no data to support the use of UDCA to improve pregnancy outcome as none of the trials performed to date have been powered to address this question. METHODS: The PITCHES trial is a triple-masked, placebo-controlled randomised trial, to evaluate UDCA versus placebo in women with ICP between 20 + 0 to 40 + 6 weeks' gestation. The primary objective of the trial is to determine if UDCA treatment of women with ICP between 20 + 0 and 40 + 6 weeks' gestation reduces the primary perinatal outcome: a composite of perinatal death (as defined by in utero fetal death after randomisation or known neonatal death up to 7 days) or preterm delivery (less than 37 weeks' gestation) or neonatal unit admission for at least 4 h (from infant delivery until hospital discharge). The secondary objectives of the trial are (1) to investigate the effect of UDCA on other short-term outcomes for both mother and infant and (2) to assess the impact of UDCA on health care resource use, in terms of the total number of nights for mother and infant, together with level of care. DISCUSSION: Current practice in the UK at the time of trial commencement for the treatment of ICP is inconsistent, with some units routinely prescribing UDCA, others prescribing very little and the remainder offering it variably. Our previous pilot trial of UDCA in women with ICP demonstrated that the trial would be feasible, and the research question remains active and unanswered. Results are highly likely to influence clinical practice, through direct management and impact on national and international guidelines. TRIAL REGISTRATION: ISRCTN registry, ID: ISRCTN91918806 . Prospectively registered on 27 August 2015. PMID- 30482255 TI - Effects of Sahaj Samadhi meditation on heart rate variability and depressive symptoms in patients with late-life depression. AB - BACKGROUND: Late-life depression (LLD) is a disabling disorder and antidepressants are ineffective in as many as 60% of cases. Converging evidence shows a strong correlation between LLD and subsequent risk of cardiovascular disease. There is a need for new, well-tolerated, non-pharmacological augmentation interventions that can treat depressive symptoms as well as improve heart rate variability (HRV), an important prognostic marker for development of subsequent cardiovascular disease. Meditation-based techniques are of interest based on positive findings in other samples.AimsWe aimed to assess the efficacy of Sahaj Samadhi meditation (SSM), an underevaluated, standardised and manualised meditation intervention, on HRV and depressive symptoms. METHOD: Eighty-three men and women aged 60-85 years, with mild to moderate depression and receiving treatment as usual (TAU) were randomised to either the SSM or TAU arm. Those allocated to SSM attended 4 consecutive days of group meditation training, using personalised mantras followed by 11 weekly reinforcement sessions. HRV and Hamilton Rating Scale for Depression (HRSD; 17-item) score were measured at baseline and 12 weeks. RESULTS: All time and frequency domain measures of HRV did not significantly change in either arm. However, there was significant improvement in the SSM arm, compared with TAU, on the HRSD (difference in mean, 2.66; 95% CI 0.26-5.05; P = 0.03). CONCLUSIONS: Compared with TAU, SSM is associated with improvements in depressive symptoms but does not significantly improve HRV in patients with LLD. These results need to be replicated in subsequent studies incorporating a group-based, active control arm.Declaration of interestR.I.N. is the Director of Research and Health Promotion for the Art of Living Foundation, Canada and supervised the staff providing Sahaj Samadhi meditation. S.R. has received research funding from Satellite Healthcare for a mindfulness meditation trial in patients on haemodialysis. The remaining authors report no financial or other relationship relevant to the subject of this article. PMID- 30482257 TI - Longitudinal Standards for Mid-life Cognitive Performance: Identifying Abnormal Within-Person Changes in the Wisconsin Registry for Alzheimer's Prevention. AB - OBJECTIVES: A major challenge in cognitive aging is differentiating preclinical disease-related cognitive decline from changes associated with normal aging. Neuropsychological test authors typically publish single time-point norms, referred to here as unconditional reference values. However, detecting significant change requires longitudinal, or conditional reference values, created by modeling cognition as a function of prior performance. Our objectives were to create, depict, and examine preliminary validity of unconditional and conditional reference values for ages 40-75 years on neuropsychological tests. METHOD: We used quantile regression to create growth-curve-like models of performance on tests of memory and executive function using participants from the Wisconsin Registry for Alzheimer's Prevention. Unconditional and conditional models accounted for age, sex, education, and verbal ability/literacy; conditional models also included past performance on and number of prior exposures to the test. Models were then used to estimate individuals' unconditional and conditional percentile ranks for each test. We examined how low performance on each test (operationalized as <7th percentile) related to consensus-conference-determined cognitive statuses and subjective impairment. RESULTS: Participants with low performance were more likely to receive an abnormal cognitive diagnosis at the current visit (but not later visits). Low performance was also linked to subjective and informant reports of worsening memory function. CONCLUSIONS: The percentile-based methods and single-test results described here show potential for detecting troublesome within-person cognitive change. Development of reference values for additional cognitive measures, investigation of alternative thresholds for abnormality (including multi-test criteria), and validation in samples with more clinical endpoints are needed. (JINS, 2018, 00, 1-14). PMID- 30482256 TI - The effect of maternal iron deficiency on zinc and copper levels and on genes of zinc and copper metabolism during pregnancy in the rat. AB - Fe deficiency is relatively common in pregnancy and has both short- and long-term consequences. However, little is known about the effect on the metabolism of other micronutrients. A total of fifty-four female rats were fed control (50 mg Fe/kg) or Fe-deficient diets (7.5 mg/kg) before and during pregnancy. Maternal liver, placenta and fetal liver were collected at day 21 of pregnancy for Cu and Zn analysis and to measure expression of the major genes of Cu and Zn metabolism. Cu levels increased in the maternal liver (P=0.002) and placenta (P=0.018) of Fe deficient rats. Zn increased (P<0.0001) and Cu decreased (P=0.006) in the fetal liver. Hepatic expression of the Cu chaperones antioxidant 1 Cu chaperone (P=0.042) and cytochrome c oxidase Cu chaperone (COX17, P=0.020) decreased in the Fe-deficient dams, while the expression of the genes of Zn metabolism was unaltered. In the placenta, Fe deficiency reduced the expression of the chaperone for superoxide dismutase 1, Cu chaperone for superoxide dismutase (P=0.030), ceruloplasmin (P=0.042) and Zn transport genes, ZRT/IRT-like protein 4 (ZIP4, P=0.047) and Zn transporter 1 (ZnT1, P=0.012). In fetal liver, Fe deficiency increased COX17 (P=0.020), ZRT/IRT-like protein 14 (P=0.036) and ZnT1 (P=0.0003) and decreased ZIP4 (P=0.004). The results demonstrate that Fe deficiency during pregnancy has opposite effects on Cu and Zn levels in the fetal liver. This may, in turn, alter metabolism of these nutrients, with consequences for development in the fetus and the neonate. PMID- 30482258 TI - Success in a Fontan pregnancy: how important is ventricular function? AB - The Fontan operation is a palliative surgical procedure for patients whose hearts cannot support a biventricular circulation. The haemodynamic changes that occur in pregnancy are particularly challenging for Fontan patients and the outcomes are variable. We present a case where fetal outcome was particularly poor despite a lack of high risk features pre-pregnancy. PMID- 30482259 TI - Epidemiology & Infection goes open access. PMID- 30482260 TI - Authors' correction for Euro Surveill. 2018;23(46). PMID- 30482262 TI - Erratum for Euro Surveill. 2018;23(46). PMID- 30482261 TI - Polio eradication: next steps and future challenges. PMID- 30482263 TI - Acute flaccid paralysis (AFP) surveillance: challenges and opportunities from 18 years' experience, Spain, 1998 to 2015. AB - Acute flaccid paralysis (AFP) surveillance is key for global polio eradication. It allows detecting poliovirus (PV) reintroductions from endemic countries. This study describes AFP surveillance in Spain from 1998 to 2015. During this time, 678 AFP cases were reported to the Spanish National Surveillance Network. The mean notification rate was 0.58 AFP cases/100,000 population under 15 years old (range: 0.45/100,000-0.78/100,000). Two periods (P) are described: P1 (1998-2006) with the AFP notification rate ranging from 0.66/100,000 to 0.78/100,000, peaking in 2001 (0.84/100,000); and P2 (2007-2015) when the AFP rate ranged from 0.43/100,000 to 0.57/100,000, with the lowest rate in 2009 (0.31/100,000). No poliomyelitis cases were caused by wild PV infections, although two Sabin-like PVs and one imported vaccine-derived PV-2 were detected. Overall, 23 (3.4%) cases met the hot case definition. Most cases were clinically diagnosed with Guillain Barre syndrome (76.9%; 504/655). The adequate stool collection rate ranged from 33.3% (7/21) to 72.5% (29/40). The annual proportion of AFP cases with non-polio enterovirus findings varied widely across the study period. AFP surveillance with laboratory testing for non-polio enteroviruses must be maintained and enhanced both to monitor polio eradication and to establish sensitive surveillance for prompt detection of other enteroviruses causing serious symptoms. PMID- 30482264 TI - Impact of pneumococcal conjugate vaccines introduction on antibiotic resistance of Streptococcus pneumoniae meningitis in children aged 5 years or younger, Israel, 2004 to 2016. PMID- 30482265 TI - A comparison of two biological markers of recent hepatitis C virus (HCV) infection: implications for the monitoring of interventions and strategies to reduce HCV transmission among people who inject drugs. AB - BackgroundMonitoring hepatitis C virus (HCV) incidence is important for assessing intervention impact. Longitudinal studies of people who inject drugs (PWID), using repeated biological tests, are costly; alternatively, incidence can be estimated using biological markers of recent infection in cross-sectional studies.AimWe aimed to compare incidence estimates obtained from two different biological markers of recent infection in a cross-sectional study to inform monitoring approaches for HCV elimination strategies.MethodSamples from an unlinked anonymous bio-behavioural survey of PWID were tested for two recent infection markers: HCV RNA with anti-HCV negative ('RNA') and low-avidity anti HCV with HCV RNA present ('avidity'). These two markers were used separately and in combination to estimate HCV incidence.ResultsBetween 2011 and 2013, 2,816 anti HIV-negative PWID (25% female) who had injected during the preceding year were either HCV-negative or had one of the two markers of recent infection: 57 (2.0%) had the RNA marker and 90 (3.2%) the avidity marker. The two markers had similar distributions of risk and demographic factors. Pooled estimated incidence was 12.3 per 100 person-years (pyrs) (95% credible interval: 8.8-17.0) and not significantly different to avidity-only (p = 0.865) and RNA-only (p = 0.691) estimates. However, the RNA marker is limited by its short duration before anti HCV seroconversion and the avidity marker by uncertainty around its duration.ConclusionBoth markers have utility in monitoring HCV incidence among PWID. When HCV transmission is high, one marker may provide an accurate estimate of incidence; when it is low or decreasing, a combination may be required. PMID- 30482266 TI - Arbovirus surveillance: first dengue virus detection in local Aedes albopictus mosquitoes in Europe, Catalonia, Spain, 2015. AB - Dengue has emerged as the most important viral mosquito-borne disease globally. The current risk of dengue outbreaks in Europe appeared with the introduction of the vector Aedes albopictus mosquito in Mediterranean countries. Considering the increasing frequency of dengue epidemics worldwide and the movement of viraemic hosts, it is expected that new autochthonous cases will occur in the future in Europe. Arbovirus surveillance started in Catalonia in 2015 to monitor imported cases and detect possible local arboviral transmission. During 2015, 131 patients with a recent travel history to endemic countries were tested for dengue virus (DENV) and 65 dengue cases were detected. Twenty-eight patients with a febrile illness were viraemic, as demonstrated by a positive real-time RT-PCR test for DENV in serum samples. Entomological investigations around the viraemic cases led to the detection of DENV in a pool of local Ae. albopictus captured in the residency of one case. The sequence of the DENV envelope gene detected in the mosquito pool was identical to that detected in the patient. Our results show how entomological surveillance conducted around viraemic travellers can be effective for early detection of DENV in mosquitoes and thus might help to prevent possible autochthonous transmission. PMID- 30482267 TI - Multidrug-resistant Neisseria gonorrhoeae isolate, belonging to the internationally spreading Japanese FC428 clone, with ceftriaxone resistance and intermediate resistance to azithromycin, Ireland, August 2018. AB - We describe a multidrug-resistant Neisseria gonorrhoeae urethritis case with ceftriaxone resistance and azithromycin intermediate resistance in a heterosexual man in Ireland, August 2018. Whole-genome sequencing showed that the isolate IR72 belongs to the internationally spreading multidrug-resistant ceftriaxone resistant FC428 clade, initially described in Japan in 2015. IR72 was assigned MSLT ST1903, NG-MAST ST17842 and NG-STAR type 1133, including the ceftriaxone resistance-mediating penA-60.001. Global awareness of spreading ceftriaxone resistant gonococcal strains that threaten recommended dual therapies is essential. PMID- 30482268 TI - Marsupial genomics meet marsupial reproduction. AB - We came from very different backgrounds, with different skills and interests. Marilyn Renfree was recognised as 'a giant of marsupial embryology'; I had spent my working life studying genes and chromosomes. We teamed up out of mutual respect (awe on my side) to form, with Des Cooper, the ARC Centre of Excellence in Kangaroo Genomics. This is the story of how our collaboration came to be, and what it has produced for our knowledge of some of the world's most remarkable animals. PMID- 30482269 TI - Haemoglobin expression in invivo murine preimplantation embryos suggests a role in oxygen-regulated gene expression. AB - Haemoglobin expression is not restricted to erythroid cells. We investigated the gene expression of the haemoglobin subunits haemoglobin, alpha adult chain 1 (Hba a1) and haemoglobin, beta (Hbb), 2,3-bisphosphoglycerate mutase (Bpgm) and the oxygen-regulated genes BCL2/adenovirus E1B interacting protein 3 (Bnip3), solute carrier family 2 (facilitated glucose transporter), member 1 (Slc2a1) and N-myc downstream regulated gene 1 (Ndrg1) in the murine preimplantation embryo, comparing in vivo to in vitro gene expression. Relatively high levels of Hba-a1 and Hbb were expressed in vivo from the 2-cell to blastocyst stage; in contrast, little or no expression occurred in vitro. We hypothesised that the presence of haemoglobin in vivo creates a low oxygen environment to induce oxygen-regulated gene expression, supported by high expression of Slc2a1 and Ndrg1 in in vivo relative to in vitro embryos. In addition, analysis of an in vitro-derived human embryo gene expression public dataset revealed low expression of haemoglobin subunit alpha (HBA) and HBB, and high expression of BPGM. To explore whether there was a developmental stage-specific effect of haemoglobin, we added exogenous haemoglobin either up to the 4-cell stage or throughout development to the blastocyst stage, but observed no difference in blastocyst rate or the inner cell mass to trophectoderm cell ratio. We conclude that haemoglobin in the in vivo preimplantation embryo raises an interesting premise of potential mechanisms for oxygen regulation, which may influence oxygen-regulated gene expression. PMID- 30482270 TI - [Predatory journals: An evil of this time?] PMID- 30482271 TI - Highlights of genetics research over the past four decades in China. PMID- 30482272 TI - An overview of rice genetics research in China. PMID- 30482273 TI - Endoplasmic Reticulum Stress in the Dorsal Root Ganglion Contributes to the Development of Pain Hypersensitivity after Nerve Injury. AB - Little is known about the functional relationship between endoplasmic reticulum (ER) stress and development of pain hypersensitivity after nerve injury. The aim of this study was to investigate the role of ER stress in the development of pain hypersensitivity in the dorsal root ganglion (DRG) after spinal nerve ligation (SNL). SNL was performed in male Sprague-Dawley rats. Real-time PCR and immunohistochemistry were performed to investigate ER stress markers including glucose-regulated protein (GRP) 78, C/EBP homologous protein (CHOP), and spliced form of the X-box binding protein 1 (sXBP1) in L4 and L5 DRG. Behavioral assessment with von Frey filaments, radiant heat, and acetone stimulation was performed to investigate pain hypersensitivity. The ER stress inhibitor salubrinal was administered prior to and 1, 3, and 5 days after SNL treatment. Separately, the ER stress inducer tunicamycin was applied to L5 DRG. GRP78, CHOP, and sXBP1 mRNA and protein expression in L5 DRG was increased 1 and 3 days after SNL but returned to baseline 7 days after SNL. In L4 DRG, ER stress markers showed no remarkable change. Immunohistochemistry demonstrated that GRP78 expression was detected in the majority of DRG neurons and in satellite glial cells. Treatment with salubrinal inhibited CHOP expression in L5 DRG and alleviated pain hypersensitivity for 5 days after SNL. Tunicamycin induced ER stress in the DRG and pain hypersensitivity 2 h after treatment. These results demonstrated that ER stress is induced in the injured DRG and contributes to the development of pain hypersensitivity after nerve injury. PMID- 30482274 TI - Estrogen Alters the Synaptic Distribution of Phospho-GluN2B in the Dorsolateral Prefrontal Cortex While Promoting Working Memory in Aged Rhesus Monkeys. AB - Age- and menopause-related deficits in working memory can be partially restored with estradiol replacement in women and female nonhuman primates. Working memory is a cognitive function reliant on persistent firing of dorsolateral prefrontal cortex (dlPFC) neurons that requires the activation of GluN2B-containing glutamate NMDA receptors. We tested the hypothesis that the distribution of phospho-Tyr1472-GluN2B (pGluN2B), a predominant form of GluN2B seen at the synapse, is sensitive to aging or estradiol treatment and coupled to working memory performance. First, ovariectomized young and aged rhesus monkeys (Macaca mulatta) received long-term cyclic vehicle (V) or estradiol (E) treatment and were tested on the delayed response (DR) test of working memory. Then, serial section electron microscopic immunocytochemistry was performed to quantitatively assess the subcellular distribution of pGluN2B. While the densities of pGluN2B immunogold particles in dlPFC dendritic spines were not different across age or treatment groups, the percentage of gold particles located within the synaptic compartment was significantly lower in aged-E monkeys compared to young-E and aged-V monkeys. On the other hand, the percentage of pGluN2B gold particles in the spine cytoplasm was decreased with E treatment in young, but increased with E in aged monkeys. In aged monkeys, DR average accuracy inversely correlated with the percentage of synaptic pGluN2B, while it positively correlated with the percentage of cytoplasmic pGluN2B. Together, E replacement may promote cognitive health in aged monkeys, in part, by decreasing the relative representation of synaptic pGluN2B and potentially protecting the dlPFC from calcium toxicity. PMID- 30482275 TI - Impact of light quality and space weather in Alexandrium catenella (Dinophyceae) cultures. AB - The chain-forming dinoflagellate Alexandrium catenella was grown with LED or fluorescent light. With LED light, the pool of mycosporine-like amino acids (MAAs) with strong antioxidant properties, such as mycosporine-glycine and palythene, was reduced in comparison to fluorescent light. The conjugated MAAs M 320 and M-335/360 presented similar stability to light and oxidation than their respective more sensitive moiety: mycosporine-glycine and palythene, respectively. A. catenella was exposed to extracellular hydrogen peroxide under LED or fluorescent light. It triggered an increase in chain formation at a final concentration of 98 and 196 uM, typical of an inverted U-shaped hormetic response, and reduced cell survival above 294 uM. LED light, minimizing UV-stress photoprotection, was chosen to render cells more susceptible to space weather. Cultures were exposed to 490 uM H2O2 multiple times between November 2017 and February 2018, close to the minimum of solar cycle 24. Cell survival was dependent on temperature, geomagnetic activity, solar X-rays and neutron flux. Geomagnetic activity originated an inverted U-shaped survival curve and X-ray flux a J-shaped survival curve, this second type of hormetic response being more rarely found. The percentage of cells in chains increased moderately with temperature, and more significantly with solar X-ray flux. Chain formation reduced along culture growth, but these observations were dependent on the occurring X-ray flux. PMID- 30482276 TI - Tardigrade indexing approach on exoplanets. AB - Finding life on other worlds is a fascinating area of astrobiology and planetary sciences. Presently, over 3800 exoplanets, representing a very wide range of physical and chemical environments, are known. Scientists are not only looking for traces of life outside Earth, but they are also trying to find out which of Earth's known organisms (ex: tardigrades (water bears)) would be able to survive on other planets. In our study, we have established a metric tool for distinguishing the potential survivability of active and cryptobiotic tardigrades on rocky-water and water-gas planets in our solar system and exoplanets, taking into consideration the geometrical means of six physical parameters such as radius, density, escape velocity, revolution period, surface temperature, and surface pressure of the considered planets. More than 3800 exoplanets are available as the main sample from Planetary Habitable Laboratory - Exoplanet Catalog (PHL-EC), from which we have chosen 57 exoplanets in our study including Earth and Mars, with water composition as reference. The Active Tardigrade Index (ATI) and Cryptobiotic Tardigrade Index (CTI) are two metric indices with minimum value 0 (= tardigrades cannot survive) and maximum 1 (= tardigrades will survive in their respective state). Values between 0 and 1 indicate a percentage chance of the active or cryptobiotic tardigrades surviving on a given exoplanet. Among known planets some of the exoplanets are tabulated as ATI and CTI indices for sample representation like: Kepler-100d, Kepler-48d, Kepler-289b, TRAPPIST-1 f and Kepler-106e. The results with Mars as the threshold indicates that Mars could be the only rock-water composition planet that could be more suitable for tardigrades than other considered exoplanets. PMID- 30482277 TI - Dependence of the human leukemia risk on the dose and dose rate of continuous irradiation: Modeling study. AB - A biologically motivated dynamical model of the radiogenic leukemia risk assessment (Smirnova, 2015, 2017; Smirnova and Cucinotta, 2018) is applied to the study of the effects of dose rate N and dose D on the excess relative risk ERR for non-CLL leukemia among continuously irradiated humans. In the study, the dose rate N of continuous irradiation is varied from 3*10-6 to 0.576 Sv/day and the dose D is varied from zero to 2.2 Sv. In the considered range of doses D, the developed model reproduces the linear dependence of ERR on D for the low dose rates N. For higher N, the dependence of ERR on D remains linear for low doses D and becomes nonlinear for higher D, that agrees with empirical observations. In turn, for the considered values of D, the developed model reproduces the practical independence of the ratio ERR/D on N at low N, the inverse dependence of the ratio ERR/D on N at higher N, and the direct dependence of the ratio ERR/D on N at more high N, that also conforms to empirical observations. Additionally, the modeling values of ERR obtained for the scenarios of continuous irradiation corresponding to those for the nuclear industry workers, Chernobyl cleanup workers, and patients treated with radiotherapy, practically, coincide with the respective empirical data. All these modeling findings, along with those obtained in our previous works, demonstrate the predictive power of the developed model and its capability of estimating, on quantitative level, the excess relative risk for non-CLL leukemia among humans exposed to continuous irradiation in wide ranges of doses and dose rates. PMID- 30482278 TI - Irradiation effects of MeV protons on dry and hydrated Brassica rapa seeds. AB - Although space radiation is a known risk for space travel and eventual colonization of Moon or Mars, relatively few data exist on radiation effects on potential crop plants. We studied Brassica rapa to assess the tolerance of seeds and seedlings to radiation by exposing dry and hydrated B. rapa seeds to 1, 2 and 3 MeV proton ions of various fluences and examined the effect on germination and root growth. Modeling penetration depth with SRIM code indicated that the applied energy was insufficient to penetrate the seeds; therefore, all energy was deposited into the tissue. Subsequent germination varied based on the incident ion energy and fluence (dose). Dry and hydrated seeds germinate after ion fluence (1013 ions cm-2) irradiation, but the germination percentage decreased with increasing fluence for ions that could penetrate the seed coat (> 1 MeV). Despite their greater volume and mass, hydrated seeds were more sensitive to irradiation than dry seeds. Damage of the seed coat after irradiation led to faster germination and initial seedling growth. Our results suggest that the seed coat represents a valuable natural radiation protection and that low energy protons, the prevailing solar radiation, are suitable for studying radiation effects in seeds and plants. PMID- 30482279 TI - Proton radiation-induced cancer progression. AB - There are considerable health risks related to ionizing and proton radiation exposure. While there is a long history of health risks associated with ionizing (photon) radiation exposure, there is a limited understanding of the long-term health risks associated with proton radiation exposure. Since proton radiation is becoming more common in cancer therapy, the long-term biological effects of proton radiation remain less well characterized in terms of radiotherapy and well as for astronauts during deep space explorations. In this study, we compared the long-term side effects of proton radiation to equivalent doses of X-rays in the initiation and progression of premalignant lesions in a lung cancer susceptible mouse model (K-rasLA1). We show proton irradiation causes more complex DNA damage that is not completely repaired resulting in increased oxidative stress in the lungs both acutely and persistently. We further observed K-rasLA1 mice irradiated with protons had an increased number and size of initiated and premalignant lesions and adenomas that were often infiltrated with inflammatory cells. Proton irradiated mice had a lower median survival and increased carcinoma incidence as compared to unirradiated controls and X-rays exposed mice. Our conclusion is that exposure to proton irradiation enhances the progression of premalignant lesions to invasive carcinomas through persistent DNA damage, chronic oxidative stress, and immunosuppression. PMID- 30482281 TI - Comments on "Irradiation effects of MeV protons on dry and hydrated Brassica rapa seeds". PMID- 30482280 TI - Reduction of geomagnetic field (GMF) to near null magnetic field (NNMF) affects Arabidopsis thaliana root mineral nutrition. AB - The Earth magnetic field (or geomagnetic field, GMF) is a natural component of our planet and variations of the GMF are perceived by plants with a still uncharacterized magnetoreceptor. The purpose of this work was to assess the effect of near null magnetic field (NNMF, ~40 nT) on Arabidopsis thaliana Col0 root ion modulation. A time-course (from 10 min to 96 h) exposure of Arabidopsis to NNMF was compared to GMF and the content of some cations (NH4+, K+, Ca2+ and Mg2+) and anions (Cl-, SO4=, NO3- and PO4=) was evaluated by capillary electrophoresis. The expression of several cation and anion channel- and transporter-related genes was assessed by gene microarray. A few minutes after exposure to NNMF, Arabidopsis roots responded with a significant change in the content and gene expression of all nutrient ions under study, indicating the presence of a plant magnetoreceptor that responds immediately to MF variations by modulating channels, transporters and genes involved in mineral nutrition. The response of Arabidopsis to reduced MF was a general reduction of plant ion uptake and transport. Our data suggest the importance to understand the nature and function of the plant magnetoreceptor for future space programs involving plant growth in environments with a reduced MF. PMID- 30482282 TI - Response to commentary on "Irradiation effects of MeV protons on dry and hydrated Brassica rapa seeds" by Bevelacqua et al. PMID- 30482283 TI - A strategic approach for investigating light recipes for 'Outredgeous' red romaine lettuce using white and monochromatic LEDs. AB - To optimize crop production/quality in space, we studied various "light recipes" that could be used in the Advanced Plant Habitat currently aboard the International Space Station (ISS). Lettuce (Lactuca sativa cv. 'Outredgeous') plants were grown for 28 days under seven treatments of white (W) LEDs (control), red (635 nm) and blue (460 nm) (RB) LEDs, W + blue (B) LEDs, W + green (520 nm) (G) LEDs, W + red (R) LEDs, W + far red (745 nm) (FR) LEDs, and RGB + FR LEDs with ratios similar to natural sunlight. Total PAR was maintained near 180 umol m 2 s-1 with an 18 h photoperiod. Lettuce grown under RGB + FR produced the greatest leaf expansion and overall shoot biomass, while leaves from WB and RB showed the highest levels of pigmentation, secondary metabolites, and elemental nutrients. All other supplemental treatments had varying impacts on morphology that were dependent on crop age. The WG treatment increased fresh mass early in the cycle, while WR increased biomass later in the cycle. The plants grown under WFR exhibited elongation of petioles, lower nutrient content, and similar shoot biomass to the W control. The findings suggest that supplementing a broad spectrum, white light background with discrete wavelengths can be used to manipulate total yield, morphology, and levels of phytonutrients in lettuce at various times during the crop cycle. PMID- 30482284 TI - A small closed ecosystem with an estimated portion of human metabolism. AB - The study describes a small closed ecosystem used to test technologies to be further employed in full-scale manned closed ecosystems. The experimental ecosystem is designed to use a certain portion of human metabolism, which is included in the gas, water, and organic waste loops of the system. In this experimental ecosystem, gas and water loops are fully closed, and the model enables processing of human waste and plant inedible biomass. A physicochemical method is used to remove pollutants from the air in the system. A human takes part in the gas exchange of the system through its respiration loop. This experimental ecosystem can be used for testing and improving new technologies to be further used in the future space stations. PMID- 30482285 TI - Dose calculations in a cell monolayer for high-throughput irradiation with proton beams generated by PW lasers for space applications. AB - One of the specific properties of laser-driven radiation is a broadband energy spectrum, which is also a feature of the space radiation fields. This property can be used in materials science studies or radiobiology experiments to simulate the energy spectrum of space radiation exposures in a ground-based laboratory. However, the differences in effects between the higher dose rates of laser generated radiation and the lower dose rates of space radiation have to be investigated in separate, prior studies. A design for a high-throughput irradiation experiment and the associated Monte Carlo dose calculations for a broadband energy proton beam depositing energy in a cell monolayer is presented. Dose control and dose uniformity in the cell monolayer was achieved in the simulations using a variable thickness Ni attenuator. A set of target doses from 0.2 Gy to 4 Gy was obtained and dose uniformity was optimized to less than 4% variability. This work opens the possibility of single or multiple exposures, controllable, high-throughput irradiation experiments on biological samples or materials, using broadband energy particle beams generated by lasers, with relevance for space applications. PMID- 30482286 TI - Comprehensive MS/MS profiling by UHPLC-ESI-QTOF-MS/MS using SWATH data independent acquisition for the study of platelet lipidomes in coronary artery disease. AB - A non-targeted lipidomics workflow based on C8 core-shell particle ultra high performance liquid chromatography (UHPLC) hyphenated to ESI-QTOF-MS in data independent acquisition (DIA) mode with sequential window acquisition of all theoretical fragment ion spectra (SWATH) was developed and applied to differential platelet lipidomics profiling of cardiovascular disease patients (stable angina pectoris (n = 10), ST-elevated myocardial infarction (n = 13)) against healthy controls (n = 10). DIA with SWATH generates comprehensive MS and MS/MS data throughout the entire chromatograms and all study samples. Hence, chromatograms can be extracted based on precursors or fragments which provided some benefits in terms of assay specificity in some cases. SWATH acquisition offers flexible experimental design with variable Q1 isolation windows. Liquid chromatography as well as SWATH settings were optimized to cover the lipidome of human platelets. The flexibility of the SWATH experiment design was utilized to implement target SWATH windows with narrow 5 Da Q1 precursor ion selection width (multiple reaction monitoring (MRM)-like SWATH windows) for the detection of low abundant oxidized phospholipids. Data processing was performed with MS-DIAL, and its feasibilities and caveats are discussed by illustrative examples. Thereby, identification of lipids is still a bottleneck in non-targeted lipidomics workflow. MS-DIAL, however, offers automatic identification via spectral matching using an in silico library. In total 1971 molecular features were detected cross the samples of which 611 were identified (total score >70%). The quality of the acquired data was validated with embedded quality control samples (n = 11). 80.3% of all features detected in the QC samples showed a coefficient of variation of below 30%. Multivariate statistics were used to visualize differences in the lipidome of distinct sample groups at a false discovery rate of 5%. PMID- 30482287 TI - Concentration cell-based potentiometric analysis for point-of-care testing with minimum background. AB - One of the most critical problems of point-of-care testing is how to reduce the interference of background, especially under resource-limited conditions when sample pretreatment is not available. In this work we report a potentiometric method for point-of-care testing with minimum background. The method is based on the principles of a concentration cell which is a type of galvanic cells. It is an electrochemical cell having two carbon electrodes. The potential of each electrode is determined by ratio of a redox couple (i.e. Fe(CN)64-/3-) on the electrode surface. On one electrode, the adsorbed enzyme catalyzes the oxidation of analyte by Fe(CN)63- which produces Fe(CN)64-. The shift of the potential was because of the analyte as well as the background. In the other channel, no enzyme was present so that the shift of the potential, if any, is owing to the background. By measuring the potential difference between the two electrodes (i.e. voltage of the concentration cell), analyte can be quantitatively determined with most of the background eliminated. As the proof-of-concept analyte, blood glucose is quantitatively detected using a voltammeter with acceptable selectivity and accuracy. Noble metal electrodes that are indispensable for conventional electrochemical sensing are not required. All these features simplify the fabrication procedure and reduce the cost for the detection. Therefore, we believe it is promising for electrochemical point-of care testing. PMID- 30482288 TI - A highly sensitive electrochemical sensor for Cd(II) based on protic salt derived nitrogen and sulfur co-doped porous carbon. AB - Lately, an "all-in-one" strategy via direct pyrolysis of protic salt has attracted great attention in the preparation of hetero-doped porous carbons due to its distinctive simplicity. However, protic salt derived carbons usually process large grain sizes thus hamper their applications. Herein, a protic salt derived N, S co-doped porous carbon (N, S-PC) with improved porosity was synthesized by nanocasting and carbonization of protic salt. In the nanocasting silica sphere was used as auxiliary template and an easily obtained protic salt ([pPDA][nHSO4]) was served as C, N and S sources. The obtained N, S-PC contains rich N, S contents and hierarchical textural porosity, thus favors the electrochemical detection of toxic cadmium ions. The N, S-PC based sensor shows excellent sensitivity and selectivity for Cd(II) versus other metals, with a low detection limit of 0.1 MUg L-1 (S/N = 3) over a wide concentration range of 4-80 MUg L-1. Applications of the N, S-PC based sensor for Cd(II) assay in tap water samples achieved results with good recoveries, indicating that the N, S-PC based electrode is promising in real sample analysis. PMID- 30482289 TI - Electrochemical detection of plant virus using gold nanoparticle-modified electrodes. AB - Tristeza is one of the destructive diseases of citrus causing by citrus tristeza virus (CTV). Historically, CTV has been associated with serious outbreaks of quick decline of citrus, therefore CTV monitoring is important aspect for avoiding such re-emerging epidemics, which would threat citrus production through the world. In this context, we have designed for the first time a label-free impedimetric biosensor for the detection of nucleic acid of CTV. The sensing platform based on a screen-printed carbon electrode (SPCE) was modified by electrodeposited gold nanoparticles (AuNPs), which allowed to efficiently immobilizing thiolated ssDNA probes as well to enhance the electrode conductivity. The growth of AuNPs was optimized and characterized using scanning electron microscopy (SEM), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). We investigated the behavior of thiolated ssDNA probe layer and its hybridization with target DNA onto AuNP surfaces by EIS measurements in Fe(CN6)4-/Fe(CN6)3- red-ox system. The main sensor design aspects such as AuNPs size, probe DNA concentration and immobilization time together with DNA hybridization time were optimized so as to achieve the best performance. Impedance values of DNA hybridization increased with Citrus tristeza-related synthetic DNA concentration, showing a logarithmic relation in the range of 0.1 10 MUM. The results also indicate that the biosensor was able to selectively detect CTV nucleic acids in the presence of other non-specific DNAs. Moreover, we have demonstrated the good performance of the system in a real plant sample matrix. In addition, the sensor reproducibility enhanced after the hybridization onto MCH/poly (AT) thiolated DNA probes which was confirmed by intra- and inter day variability assays. PMID- 30482290 TI - A high thermally stable oligomer-based supramolecular solvent for universal headspace Gas Chromatography: Proof-of-principle determination of residual solvents in drugs. AB - Supramolecular solvent (SUPRAS) extraction is gaining attraction as a sample treatment technique because of its great performance in terms of effectiveness, versatility, sample clean-up, quickness, cost and sustainability. However, the nature of SUPRASs, being formed by amphiphile molecules, results in poor compatibility with Gas Chromatography (GC). Here, we show the hitherto unexplored development of a SUPRAS with high thermal stability (HTS) suitable for subsequent direct analysis by Headspace (HS)-GC. This novel HTS-SUPRAS, based on poly undecylenic acid -an oligomeric surfactant-, tetraglyme -a polar aprotic solvent with excellent chemical and thermal stability- and water, was fully characterized in terms of composition and physical properties such as thermal stability. Subsequently, the HTS-SUPRAS developed was further successfully applied, as a proof-of-principle, to the extraction and determination of residual solvents in pharmaceutical drugs, including several solvents (class 2C) whose analysis by HS GC has been shown to be highly complex. Analytical performance was demonstrated as mandated by the International Council for Harmonisation of technical requirements for pharmaceuticals for human use (ICH). Furthermore, excellent recoveries (70-120%) and high precisions (<20%, expressed as relative standard deviations) were obtained for the analysis of several different drug formulations spiked with the analyzed 37 residual solvents at their respective maximum residue levels. PMID- 30482291 TI - Detection of the tuberculosis biomarker mannose-capped lipoarabinomannan in human serum: Impact of sample pretreatment with perchloric acid. AB - The development of an accurate and rapid diagnostic test for tuberculosis (TB) to use at point of need is vital to efforts aimed at reducing the global burden from this disease. This paper builds on our previous studies of mannose-capped lipoarabinomannan (ManLAM) as a serum biomarker for active TB infection by means of a heterogeneous immunoassay. That work found that complexation with components in serum (e.g., proteins) sterically hindered the capture and/or labeling of ManLAM in an immunoassay at levels <10 ng mL-1, compromising the clinical utility of this biomarker for detection of active TB infection. We also showed that the acidification of ManLAM-containing serum samples with perchloric acid improved the detectability of ManLAM by 250* by complex disruption when compared to measurements of untreated serum. The present study examined what effects the PCA treatment of serum samples may have on the recovery and structural integrity of ManLAM, owing to its potential susceptibility to acid hydrolysis. Recovery was assessed with an enzyme-linked immunosorbent assay (ELISA). The possible impact of acid hydrolysis on the ManLAM structure was investigated by gas chromatography mass spectrometry and carbohydrate chemical degradation methods. The ELISA study indicated that while the signal strength for ManLAM in the serum spike-in experiments was significantly stronger after PCA pretreatment when compared to untreated human serum, it was only ~20% of the ManLAM measured in physiological buffer. This loss in detectability was shown by structural analysis to arise mainly from the acid-induced degradation of the arabinan domains of ManLAM that are targeted by antibodies used for antigen capture and/or tagging. The implications of these findings in terms of the detection of this important biomarker for TB are also discussed. PMID- 30482292 TI - Chemiluminescence quenching microarrays for high throughput screening of antioxidants and its application in evaluating herbal extracts and pure compounds. AB - In this paper, a novel high throughput screening method for antioxidants was described. The screening process was completed on a 5 cm * 5 cm silica gel 60 plate. Luminol was used as the fluorogenic substrate while hydrogen peroxide employed to excite the chemiluminescence. A dark spot was observed due to quenching effect of antioxidant. A linear model of the integral area of the spot as a function of analyte amount was fit by using vitamin C as positive control. Excellent linearity (R2 = 0.9978) was obtained in the range of 2.31-23.1 MUg. The variation coefficients of intra- and inter-chip precisions were below 5% (n = 10) and 10% (n = 6) respectively. The new method was validated by comparing the analysis result of six flavonoids with that from a sequential injection method. The Pearson correlation coefficient was up to 0.98. A set of traditionally used herbal medicines was screened, and Rhei Radix et Rhizoma showed the strongest signal. The major bioactive ingredients were further assigned by flow injection and MS analyses. These results reveal the prospects of the proposed method to supply a promising tool in vitro for high throughput screening and activity evaluation of antioxidants in a fast, low-cost and reliable manner. PMID- 30482293 TI - A multi-gene panel beyond BRCA1/BRCA2 to identify new breast cancer-predisposing mutations by a picodroplet PCR followed by a next-generation sequencing strategy: a pilot study. AB - By analyzing multiple gene panels, next-generation sequencing is more effective than conventional procedures in identifying disease-related mutations that are useful for clinical decision-making. Here, we aimed to test the efficacy of an 84 genes customized-panel in BRCA1 and BRCA2 mutation-negative patients. Twenty-four patients were enrolled in this study. DNA libraries were prepared using a picodroplet PCR-based approach and sequenced with the MiSeq System. Highly putative pathogenic mutations were identified in genes other than the commonly tested BRCA1/2: 2 pathogenic mutations one in TP53 and one in MUTYH; 2 missense variants in MSH6 and ATM, respectively; 2 frameshift variants in KLLN, and ATAD2, respectively; an intronic variant in ANPEP, and 3 not functionally known variants (a frameshift variant in ATM a nonsense variant in ATM and a missense variant in NFE2L2). Our results show that this molecular screening will increase diagnostic sensitivity leading to a better risk assessment in breast cancer patients and their families. This strategy could also reveal genes that have a higher penetrance for breast and ovarian cancers by matching gene mutation with familial and clinical data, thereby increasing information about hereditary breast and ovarian cancer genetics and improving cancer prevention measures or therapeutic approaches. PMID- 30482294 TI - Functionalized phosphorescent nanoparticles in (bio)chemical sensing and imaging A review. AB - Inorganic nanoparticles are a fascinating class of materials which promise great potential in numerous fields, including optical (bio)sensing. Many different kinds of such nanoparticles have been widely used for fluorescent sensing and imaging due to the different merits of fluorescent nanoparticles compared to molecular fluorophores. Progress made in the rational design of nanomaterials also allowed the synthesis of hybrid phosphorescent nanoparticles, that finds growing applications in sensing due to the combination of the interesting size- and shape-dependent properties of nanomaterials with a phosphorescence-type emission. In this review, we intend to highlight some of progress made in this active research area and update the database of various phosphorescent nanoparticles-based sensors on the basis of different sensing targets of interest in environmental, industrial and biomedical areas. Following an introduction and a discussion of merits of the synergy between nanomaterials and phosphorescence detection as compared to molecular luminophores the article assesses the kinds and specific features of nanomaterials often used in phosphorescence sensing. Specific examples on the use of phosphorescence nanoparticles in chemical sensing and bioimaging are given next. A final section intends to provide an overview of the prospects of such type of nanomaterials in the design of future devices for analytical chemistry. PMID- 30482295 TI - Detection of antibiotic residues in pork using paper-based microfluidic device coupled with filtration and concentration. AB - This work demonstrates a sensitive and rapid method for the detection of antibiotic residues in food samples by employing the filtration behaviour of paper combined with aggregation and precipitation of chemical reagents. Using this concept, we successfully determined the presence of oxytetracycline and norfloxacin residues in pork using metal complexation on microfluidic paper-based analytical devices (MUPADs). The base substrate (top layer of the device) was fabricated by printing letter channels of the words "oxytetracycline" and "norfloxacin" before functionalization with copper (II) sulfate pentahydrate in 0.5 M sodium hydroxide and iron (III) nitrate nanohydrate in 5 mM ammonia solution for the detection of oxytetracycline and norfloxacin separately. A transition metal hydroxide formed upon reaction that created solid precipitates on paper and allowed antibiotic residues to bind to the metal ions via coordination chemistry. The metal ion-antibiotic complex could form on the filter paper and generated a visible color change with the detection limit of 1 ppm for both oxytetracycline and norfloxacin in pork. This procedure of filtration and concentration in combination with a simple text-reporting approach allows the end users to achieve a low limit of detection as well as easy result interpretation in food safety monitoring. PMID- 30482296 TI - Aggregation-induced emission enhancement of gold nanoclusters triggered by silicon nanoparticles for ratiometric detection of protamine and trypsin. AB - Metal nanoclusters protected by glutathione (GSH) have attracted a wide attention due to the unique aggregation-induced emission (AIE) feature. However, the "trigger" effects of ethanol, temperature, pH values, and metal ions may restrict the application of these particles. In this work, the amino modified silicon nanoparticles (SiNPs) and GSH-capped gold nanoclusters (GSH-AuNCs) can self assemble into well-defined spherical particles due to the electrostatic interaction. As a result, the unique aggregation-induced emission enhancement (AIEE) of GSH-AuNCs arises at 570 nm, and the SiNPs keep their own blue fluorescence at 450 nm, so a novel nanohybrid probe (SiNPs@GSH-AuNCs) with dual emission property has been constructed. When protamine is added to SiNPs@GSH AuNCs, the cationic protamine can compete with SiNPs and absorb onto the surface of GSH-AuNCs, which inhibits the self-assembly and leads to the fluorescence quenching of GSH-AuNCs; while trypsin can catalyze the hydrolysis of protamine, the self-assembly starts again, producing the AIEE recovery. In the whole process, the SiNPs act as an internal standard and their emission stays constant. By means of the fluorescence intensity ratios I570/I450, the linear range of protamine is from 0.15 to 3.00 MUg mL-1 with the limit of detection (LOD) of 0.07 MUg mL-1, and trypsin shows a linear response in the range from 10 to 100 ng mL-1 with LOD of 4.50 ng mL-1. Furthermore, this strategy exhibits good sensitivity and selectivity, and has been further validated by applying it for the determination of protamine and trypsin in serum samples. PMID- 30482297 TI - Highly sensitive fluorescent bioassay of 2,3,7,8-tetrachloro-dibenzo-p-dioxin based on abnormal expression of cytochrome P450 1A2 in human cells. AB - Current in vitro bioassays of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, a major threat carcinogen) are relied on murine cells and fluorescent probe 7 ethoxyresorufin (7-ER), in which TCDD mostly causes abnormal expression of cytochrome P450 1A1 (CYP1A1). However, for human cells, TCDD mainly leads to a distinct abnormal expression of cytochrome P450 1A2 (CYP1A2). The poor response of 7-ER to CYP1A2 limits the traditional bioassay for human cells. Herein, we report a fluorescent probe N-(3-hydroxybutyl)-4-methoxy-1,8-naphthalimide (HBMN) for in vitro bioassay of TCDD with human cells. HBMN had ca. 60 times higher affinity to CYP1A2 than 7-ER. As such, the sensing sensitivity increased by 10 times, and different expression of CYP1A2 by TCDD induction in different human cells was found. Besides, HBMN was also feasible in rapid screening of TCDD concentration by naked eye. It would open a new way to highly sensitive detect TCDD and understand the pathogenesis of TCDD in different human organs. PMID- 30482298 TI - A rhodamine B-based probe for the detection of HOCl in lysosomes. AB - A rhodamine B-based derivative (RL1) was developed as a specific fluorescent probe for HOCl. Meanwhile, morpholine moiety was introduced into the probe. It was found that the probe could display highly selective, sensitive and naked-eye detection upon the addition of HOCl. And the detection limit (LOD) was calculated to be as low as 2.8 nM. Furthermore, cellular confocal microscopic studies revealed that the introduction of morpholine moiety realized the lysosome targeting capability. Moreover, RL1 was successfully applied for the imaging of endogenous HOCl with low cytotoxicity. Therefore, all the desirable features made probe RL1 particularly suitable for HOCl detection in aqueous buffer solution samples as well as the bio-imaging applications. PMID- 30482299 TI - Combination of field amplified sample injection and hydrophobic interaction electrokinetic chromatography (FASI-HIEKC) as a signal amplification method for the determination of selected macrocyclic antibiotics. AB - In this study, a field amplified sample injection (FASI) and hydrophobic interaction electrokinetic chromatography (HIEKC) method has been developed for the separation of five macrolide antibiotics: spiramycin, ivermectin, tylosin, josamycin, rapamycin, and one ansamycin drug - rifamycin. By the manipulation of both the sample and separation buffer compositions, their pH values and molarity, a systematic approach has been achieved to maximize analyte differential electrophoretic mobility and signal amplification. The impact of the sample solution composition and the injection mode on the signal amplification effect of the six tested antibiotics was also investigated. Moreover, the influence of the injection of the sample and the water plug on the quantity, symmetry and height of the analyte signal was demonstrated. All the analytes were completely resolved in less than 8 min in an uncoated fused-silica capillary of 75 MUm internal diameter (I.D.) x 50 cm length. The electrophoretic separations were performed in a 60% (v/v) acetonitrile and 20 mM phosphate electrolyte system (pH 7.1) with an applied voltage of 25 kV. The established method was validated and confirmed to be applicable for the determination of the active ingredients in a quality control analysis. PMID- 30482300 TI - Sol-gel preparation of titanium (IV)-immobilized hierarchically porous organosilica hybrid monoliths. AB - Hierarchically porous monoliths as a key feature of biological materials have been applied in enrichment and separation. In this work, a metal immobilized hierarchically porous organosilica hybrid monolith was synthesized by hydrolysis and condensation of tetraethoxysilane (TEOS) and diethoxyphosphorylethyl triethoxysilane (DPTS) under alkaline environment. Phosphonate ester groups were firstly introduced by the employment of DPTS as functional monomer, and then acidified to phosphonic acids. The surface area of optimal monolith could reach to 1170 m2/g, which simultaneously contained micropores and mesopores (4 nm) obtained from nitrogen sorption measurement. Meanwhile, mercury intrusion porosimetry (MIP) further demonstrated that macropores (1-3 MUm) existed in monoliths. Followed by chelating with titanium ion (Ti4+), the hierarchically porous organosilica hybrid monoliths could be applied as IMAC materials. This synthesized process was easy-operating and time-saving, and avoided the tedious and complex process of traditional Ti4+-IMAC materials. Furthermore, the Ti4+ IMAC monoliths exhibited high adsorption capacity for pyridoxal 5'-phosphate (82.6 mg/g). The 3282 unique phosphopeptides could be identified from 100 MUg of HeLa digests after enrichment with the monolith, exhibiting excellent enrichment performance of low-abundance phosphopeptides. PMID- 30482301 TI - Retracted: Rapid and effective sample cleanup based on graphene oxide encapsulated core-shell magnetic microspheres for determination of fifteen trace environmental phenols in seafood by liquid chromatography-tandem mass spectrometry. AB - This article has been retracted at the request of the Editor after the corresponding author pointed the Editor to comments from an anonymous reader. The article reports electron micrographs of different preparations while showing identical images as used in previous publications by the same authors. The particles in Fig. 4C (SEM image of Fe3O4@SiO2) are identical to each other and the corresponding author confirmed that these have been copy-pasted. In addition, these particles have previously been communicated as different substances in Fig. 1B from Pan et al., J. Mater. Chem. A, 2015,3, 23042-23052 (DOI: 10.1039/C5TA05840F) and Fig. 3F from Pan et al., Anal. Methods, 2017,9, 5281-5292 (DOI: 10.1039/C7AY01444A). Furthermore, the curves in Fig. 7, especially the baseline, shows a remarkable similarity to Fig. 8 from Pan et al., J. Mater. Chem. A, 2015,3, 23042-23052 (DOI: 10.1039/C5TA05840F) and Fig. 5F from Pan et al., J. Mater. Chem. A, 2014,2, 15345-15356 (DOI: 10.1039/c4ta02600d). The manipulation of images and data in this way is a serious offense to the integrity of the scientific community and casts doubts on all the data, and accordingly also the conclusions based on that data, in this publication. As such this article represents a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process. This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our business/policies/article-withdrawal). PMID- 30482302 TI - Tutorial: Volumetric absorptive microsampling (VAMS). AB - Volumetric absorptive microsampling (VAMS) is a recent microsampling technique used to obtain dried specimens of blood and other biological matrices for application to a plethora of bioanalytical purposes. As such, it can be likened to dried blood spot (DBS) technique that has been in wide use for the last 40 years. However, VAMS promises to bring some significant advantages over DBS, related to sampling volume accuracy, haematocrit (HCT) dependence, pre-treatment and automation. Although some aspects still need to be investigated in depth, VAMS is increasingly recognised as a viable alternative to DBS and other dried microsampling techniques. In this tutorial, different aspects of VAMS approach are described and discussed, presenting the procedures adopted and the results obtained by those authors who have developed this kind of analytical workflow in the last few years. Hopefully, this will help other scientists to find new solutions to old and recent problems related to microsampling and to produce new, sound and interesting science in this field. PMID- 30482303 TI - Monolith columns for liquid chromatographic separations of intact proteins: A review of recent advances and applications. AB - In this article we survey 256 references (with an emphasis on the papers published in the past decade) on monolithic columns for intact protein separation. Protein enrichment and purification are included in the broadly defined separation. After a brief introduction, we describe the types of monolithic columns and modes of chromatographic separations employed for protein separations. While the majority of the work is still in the research and development phase, papers have been published toward utilizing monolithic columns for practical applications. We survey these papers as well in this review. Characteristics of selected methods along with their pros and cons will also be discussed. PMID- 30482304 TI - New antiradical capacity assay with the use potentiometric method. AB - For the first time, the dependence of a redox potential change during a reaction of peroxyl radical generation and their interaction with antioxidants was studied. A regular change of a potential is due to oxidation of an antioxidant by initiating peroxyl radicals accompanied by an electron transfer. An original direct method for determining induction periods, inhibition coefficients and an antiradical capacity using the potentiometric method is proposed. Using the proposed approach the induction periods and the inhibition coefficients of various OH, NH, SH containing antioxidants were determined. The antiradical capacity of a herbal extract was studied. A high degree of correlation with a DPPH assay was obtained. RSD results obtained using the proposed approach do not exceed 7%. PMID- 30482305 TI - Acid-base properties of phosphoric and acetic acid in aprotic organic solvents - A complete thermodynamic characterisation. AB - Knowledge regarding the acid-base behaviour in non-aqueous media has remained relatively scarce in spite of its importance for many aspects of chemistry. The research presented in this work fills some of particularly important gaps in the corresponding thermodynamic data. We report on a detailed study of acid-base properties of dihydrogen phosphate and acetate in aprotic organic solvents (acetonitrile, dimethyl sulfoxide, and dimethylformamide). It was found that several processes, i.e. protonation, homoassociation, and dimerisation play important roles in defining the basicity of these widely important anions. In the case of dihydrogen phosphate, formation of higher homoassociates (two anions, one acid molecule and vice versa) was detected, whereas acetate formed only simple homoassociates of 1:1 stoichiometry. The dimerisation of dihydrogen phosphate and acetic acid were confirmed to be important processes as well. The thermodynamics of the above mentioned reactions was characterised in detail by means of various experimental methods: ITC, spectrophotometry, NMR-spectroscopy, and conductometry. Reliable equilibrium constants and other thermodynamic reaction functions were determined. The obtained results were discussed in terms of hydrogen bonding potential of the anions and their conjugated acids, as well as solvent properties, i.e. their ability to solvate the species involved in the studied processes. PMID- 30482306 TI - Platinum-loaded mesoporous nickel phosphonate and its electrochemical application for sarcosine detection. AB - In 2009, Sreekumar found that sarcosine, as an effective biomarker, can be used to identify prostate cancer. However, it is difficult to detect sarcosine in urine or plasma because of its low concentration. In this work, we describe a simple strategy for the preparation of sarcosine biosensor based on platinum loaded mesoporous nickel phosphonate (Pt/MNP) and subsequently apply it to detect sarcosine. Mesoporous structure could increase the active sites on the MNP surface, which makes the Pt/MNP have excellent electrochemical performance for detecting hydrogen peroxide, one of the enzymatic products, and the sarcosine biosensor exhibited a superior electrochemical performance. The linear range of sarcosine biosensor is from 5 to 40 MUM and the sensitivity is 123.51 MUA mM-1 cm 2. The limit of detection is estimated to be 0.24 MUM (S/N = 3). Additionally, the sarcosine biosensor based on Pt/MNP also shows an excellent performance in the anti-interference test and the real serum sample. This work manifests the potential application of Pt/MNP as a novel biosensor material for sarcosine detection, which could be extended to other oxidase-based detection systems. PMID- 30482307 TI - WO3 decorated graphene nanocomposite based electrochemical sensor: A prospect for the detection of anti-anginal drug. AB - Ranolazine (RZ) is an anti-anginal drug with a distinct mechanism of action and widely employed in patients with chronic angina. Its measurement is essential in clinical environment to ensure adequate drug level and understand the redox mechanism which gives an idea of in-vivo fate of the drug. In view of this, an exemplary voltammetric approach is proposed here for determination of RZ utilizing glassy carbon electrode (GCE) fabricated with WO3 decorated graphene nanocomposite. The structural and morphological characterizations of modifier were made by employing XRD, FESEM, EDAX, HRTEM, XPS, Raman and FT-IR spectroscopy which revealed successful formation of the nanocomposite. As a result of high electrical conductivity and large effective surface area of WO3 nanoparticles and graphene nanosheets, the developed sensor WO3/Graphene/GCE displayed effectual and unrelenting electron interceding behavior exhibiting higher peak currents at lower potentials for RZ oxidation. Using square wave voltammetry, the drug showcased well-defined voltammetric response in Britton-Robinson buffer at pH 4.5 in concentration range from 0.2-1.4 MUM and 1.4-14 MUM with the low detection limit of 0.13 MUM. The developed protocol was then implemented successfully to quantify RZ in commercially accessible pharmaceutical tablets with satisfactory recovery (99.8%-100.2%). The experimental results illustrated the applicability of the fabricated sensor for drug quality control and clinical analysis along with pharmacokinetic studies. PMID- 30482308 TI - Voluntary steps and gait initiation. AB - This chapter explores mechanisms that control goal-directed steps for the purpose of reorienting the body or initiating gait. A key issue concerns the control of balance. We argue that standing balance is relinquished while the stepping foot is in the air thus allowing the body to fall under gravity. The falling body's trajectory is largely controlled by motor activity that occurs before the stepping foot leaves the ground (the throw), and is finely tuned to where and when the foot is planned to land (the catch). This close coupling between the throw and catch is paramount for achieving the stepping goal while simultaneously ensuring balance is regained at the end of the step. Nonetheless, there is some scope for making midstep adjustments by modifying the body's trajectory and/or the stepping leg's movement. The magnitude of midstep adjustment is severely limited by mechanical and balance constraints, but can occur at remarkably short latency in response to new visual information, possibly controlled by subcortical neural networks. We conclude that taking a step is a highly predictive and coordinated action that is vulnerable to errors leading to falls, particularly in the face of neural and muscular degeneration associated with aging or neurologic disease. PMID- 30482310 TI - Gait adaptability. AB - Our activities of daily living inherently involve interacting with the physical environment. This interaction involves both reactive (feedback) and proactive (feedforward) gait adaptations. Reactive adaptations involve responses to mechanical perturbations and occur, for instance, when we stumble over a doorstep or slip on an icy spot on the pavement. Examples of proactive adaptations in response to visual stimuli include stepping over an obstacle, targeting precise foot placements when walking on rough terrain, stepping up to the pavement, or making a turn for going around a corner. These adaptations have to be implemented in our steady-state gait pattern, thus posing a challenge to center-of-mass control and maintenance of forward progression. Yet, despite the apparent complexity of adaptive bipedal walking, we commonly do this with remarkable ease. This chapter will provide a comprehensive overview of the behavioral strategies and control mechanisms that we apply for executing these common, yet complex, gait adaptations. In addition, how we use visual information for guiding proactive gait adaptations and path selection will be discussed. Finally, cognitive involvement during gait adaptations will also be addressed. PMID- 30482309 TI - Gait. AB - Gait is one of the keys to functional independence. For a long-time, walking was considered an automatic process involving minimal higher-level cognitive input. Indeed, walking does not take place without muscles that move the limbs and the "lower-level" control that regulates the timely activation of the muscles. However, a growing body of literature suggests that walking can be viewed as a cognitive process that requires "higher-level" cognitive control, especially during challenging walking conditions that require executive function and attention. Two main locomotor pathways have been identified involving multiple brain areas for the control of posture and gait: the dorsal pathway of cognitive locomotor control and the ventral pathway for emotional locomotor control. These pathways may be distinctly affected in different pathologies that have important implications for rehabilitation and therapy. The clinical assessment of gait should be a focused, simple, and cost-effective process that provides both quantifiable and qualitative information on performance. In the last two decades, gait analysis has gradually shifted from analysis of a few steps in a restricted space to long-term monitoring of gait using body fixed sensors, capturing real life and routine behavior in the home and community environment. The chapter also describes this evolution and its implications. PMID- 30482311 TI - Ecology of falls. AB - In this chapter, we consider how falls result from interactions between humans and their environment, and the implications of these interactions on the prevention of falls and fall-related injuries. We take a lifespan approach, and examine the human behaviors that create risk for falls and injuries in various environments, and the social and biologic factors that shape those behaviors. While not always stated explicitly, we draw on our experience in collecting and analyzing video footage of hundreds of falls. We consider that most falls do not result in significant injury, and issues of self-autonomy for pursuing a lifestyle that may create risk for falls. To help guide falls management, we propose a mechanism for classifying falls as "acceptable" versus "unacceptable." We also provide an ecology of falls checklist to guide stakeholders in identifying ecologic aspects of falls that may be useful targets for intervention. PMID- 30482312 TI - Aging. AB - This chapter reviews studies that have examined age-related anatomic and functional changes in sensory, neuromuscular, and cognitive systems that impair the control of balance and gait. Specifically, we examine age-related changes in peripheral systems: lower-limb sensation, visual functions such as contrast sensitivity and depth perception, vestibular sense, strength, and power in the lower-limb muscle groups, as well as central factors including processing speed and executive functioning. Significant impairments in any one of the above systems can predispose older people to falls, with the risk of falling increasing substantially with the number of impairments present. There is increasing evidence that interventions aimed at addressing specific sensory and neuromuscular impairments can improve balance control and reduce fall risk. In particular, task-specific exercise can improve muscle strength, balance, gait and mobility and prevent falls in older people. PMID- 30482313 TI - Parkinson disease. AB - Parkinson disease (PD) is a complex, multisystem disorder with both neurologic and systemic nonmotor manifestations. It is neurodegenerative in nature in which disordered balance, gait, and falls are universal problems that can be present at initial diagnosis, and which progress over time. Freezing of gait is a particularly debilitating feature of PD that becomes more prevalent over time with disease progression, being present in approximately 7% after 2 years of disease and 28% after 5 years. Approximately 60% of people with PD fall each year, with around 70% of fallers falling recurrently, and some recurrent fallers falling multiple times per week. Many risk factors for falls in people with PD have been identified; these include a history of falls, freezing of gait, and abnormalities in measures of balance, leg muscle strength, mobility, cognition, and fear of falling. Therapies for improving physical function and mobility include levodopa, cholinesterase inhibitors, methylphenidate, deep-brain stimulation, cuing for freezing of gait, and exercise. This chapter reviews the clinical, pathologic, and physiologic correlates of gait disturbance and falls in PD, as well as the evidence for medical and nonmedical interventions. PMID- 30482314 TI - Falls in frontotemporal dementia and related syndromes. AB - Frontotemporal dementia (FTD) and related diseases are important causes of younger-onset dementia. Falls may be a source of morbidity and mortality in FTD, but remain underreported, and very few high-quality studies have been performed. In this chapter, we briefly review the clinical features of FTD and related syndromes such as motor neuron disease (MND) and atypical parkinsonian syndromes, such as progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). Falls are frequently encountered in patients who present with FTD syndromes. Although cognitive impairment is associated with falls generally, motor symptoms and signs, as seen in FTD cases that overlap with atypical parkinsonian disorders such as PSP or CBS, or MND, appear to pose the greatest risk. At present, very few systematic studies have been performed to determine the precise frequency, timing, diagnostic implications, and complications of falls in FTD. Further studies are required to understand the scope of this problem, and to develop effective treatments and management strategies. PMID- 30482315 TI - Stroke. AB - Stroke, or cerebrovascular accident, involves injury to the central nervous system as a result of a vascular cause, and is a leading cause of disability worldwide. People with stroke often experience sensory, cognitive, and motor sequelae that can lead to difficulty walking, controlling balance in standing and voluntary tasks, and reacting to prevent a fall following an unexpected postural perturbation. This chapter discusses the interrelationships between stroke related impairments, problems with control of balance and gait, fall risk, fear of falling, and participation in daily physical activity. Rehabilitation can improve balance and walking function, and consequently independence and quality of life, for those with stroke. This chapter also describes effective interventions for improving balance and walking function poststroke, and identifies some areas for further research in poststroke rehabilitation. PMID- 30482316 TI - Dystonia. AB - This chapter presents a review of the literature for falls and abnormalities of balance and gait in isolated dystonia syndromes. Balance appears to be relatively preserved in primary and focal dystonias, except when postural abnormalities significantly displace the center of gravity of the body. Gait can be affected by abnormal dystonic movements and limb deformities, and is commonly abnormal in generalized dystonia. Impairment of gait can also be seen in patients with cervical dystonia when it results in abnormal posturing, and severe cases of blepharospasm leading to functional blindness. Gait abnormalities have also been described in dystonia associated with dopa-responsive dystonia (DRD) and Wilson disease. The data on dystonia and falls are scarce but it has been described as one of the main symptoms of DRD. Local field potential recordings point to abnormal synchronization activity in the pallidum as the main pathophysiologic finding. Cerebellar dysfunction has been reported in patients with primary dystonia and some forms of focal dystonia. While contradictory data have been published on the association between vestibular dysfunction and cervical dystonia, abnormal neck proprioception appears to be present in the latter. Treatment of the dystonia can improve balance and gait, as well as reduce the frequency of falls. PMID- 30482317 TI - Balance, gait, and falls in multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) and the most widespread nontraumatic cause of disability in young adults around the world. MS occurs in people of all ages, races, and ethnicities. MS is characterized by clinical symptoms resulting from lesions in the brain, spinal cord, or optic nerves that can affect balance, gait, and fall risk. Lesions accumulate over time and occur in different areas of the CNS causing symptoms that include weakness, spasticity, and fatigue, as well as changes in sensation, coordination, vision, cognition, and bladder function. Thus, it is not surprising that imbalance, gait dysfunction, and falls are common in people with MS. The overwhelming majority have abnormalities of postural control and gait even early in the disease course. In all, 50-80% have balance and gait dysfunction and over 50% fall at least once each year. Balance dysfunction in MS is conceptualized as three interrelated problems: decreased ability to maintain position, limited and slowed movement towards limits of stability, and delayed responses to postural displacements and perturbations. In addition, functional balance performance may be affected by impaired dual-task integration. Walking changes in MS include reduced gait speed, impaired walking balance, and reduced walking-related physical activity. Falls in people with MS are associated with injuries, reduced participation, and increased fear of falling. A wide and growing range of rehabilitation and medical interventions are available to address the changes in balance, gait, and fall risk associated with MS. PMID- 30482319 TI - Cerebellar ataxia. AB - The cerebellum plays an integral role in the control of limb and ocular movements, balance, and walking. Cerebellar disorders may be classified as sporadic or hereditary with clinical presentation varying with the extent and site of cerebellar damage and extracerebellar signs. Deficits in balance and walking reflect the cerebellum's proposed role in coordination, sensory integration, coordinate transformation, motor learning, and adaptation. Cerebellar dysfunction results in increased postural sway, hypermetric postural responses to perturbations and optokinetic stimuli, and postural responses that are poorly coordinated with volitional movement. Gait variability is characteristic and may arise from a combination of balance impairments, interlimb incoordination, and incoordination between postural activity and leg movement. Intrinsic problems with balance lead to a high prevalence of injurious falls. Evidence for pharmacologic management is limited, although aminopyridines reduce attacks in episodic ataxias and may have a role in improving gait ataxia in other conditions. Intensive exercises targeting balance and coordination lead to improvements in balance and walking but require ongoing training to maintain/maximize any effects. Noninvasive brain stimulation of the cerebellum may become a useful adjunct to therapy in the future. Walking aids, orthoses, specialized footwear and seating may be required for more severe cases of cerebellar ataxia. PMID- 30482318 TI - Gait, balance, and falls in Huntington disease. AB - Huntington disease (HD) is an autosomal-dominant, progressive, neurodegenerative disorder, characterized by involuntary movements and other motor impairments, cognitive/behavioral symptoms, and psychiatric disorders. Gait and balance impairments and falls greatly impact on the quality of life among people with HD, and being fall-prone is one of the strongest predictors of nursing-home placement. Gait impairment in HD is characterized by bradykinesia, reduced velocity, and increased variability in spatiotemporal features. Detrimental changes in symmetry, step length, stride time, balance measures, gait adaptability (external cues, dual tasking), and hypo/hyperkinesia have also been observed. Balance impairment is characterized by impairments of anticipatory balance without a change in base of support, anticipatory balance with a change in base of support, and reactive balance. In addition to gait and balance impairment, people with HD have a range of intrinsic and extrinsic factors that increase fall risk, including reduced cognitive reserve for dual tasking. Currently there is some evidence to suggest exercise interventions can address some HD-specific gait and balance deficits. However, no intervention studies to date have specifically targeted falls. Large, well-designed, randomized controlled trials are needed to guide future fall prevention interventions in people with HD. PMID- 30482320 TI - Sensory integration for human balance control. AB - The upright stance position is inherently unstable since the smallest deviation from a perfect upright orientation produces forces due to gravity that accelerate the body toward the ground. Stability is achieved by generating appropriate joint torques that correct for deviations from a desired orientation with orientation changes detected by sensory systems (primarily somatosensory/proprioceptive, visual, and vestibular systems). Functionally, balance control can be viewed as a closed-loop feedback control system with the integration of different sources of sensory orientation information being one component of the overall system, but with the system's feedback nature placing constraints on the sensory integration process. Analysis of body sway evoked by balance perturbations allows for the measurement of "sensory weights" that represent the relative contributions of different sensory systems to an internal estimate of orientation that, in turn, is used to generate corrective actions. Experiments reveal that sensory weights are not fixed quantities, but vary as a function of environmental and experimental conditions as well as neurologic disorders that affect the quality of sensory information available from different sensory systems. Because environmental conditions can change rapidly, sensory reweighting must also occur rapidly enough to prevent instability due to an under- or overproduction of corrective action. PMID- 30482321 TI - Tremor. AB - Tremor is a phenomenon observed in a broad spectrum of diseases with different pathophysiologies. While patients with tremor may not complain in the clinic of symptoms of imbalance, gait difficulties, or falls, laboratory research studies using quantitative analysis of gait and posture and neurophysiologic techniques have demonstrated impaired gait and balance across a variety of tremor etiologies. These findings have been supported by careful epidemiologic studies assessing symptoms of imbalance. Imaging and neurophysiologic studies have identified cerebellar networks as important mediators of tremor, and therefore a likely common site of dysfunction to explain the phenomenologic overlap between impaired postural and gait control with tremor. Further understanding of these mechanisms and networks is of crucial importance in the development of new treatments, particularly surgical or minimally invasive lesional therapies. PMID- 30482322 TI - Sensorimotor anatomy of gait, balance, and falls. AB - The review demonstrates that control of posture and locomotion is provided by systems across the caudal-to-rostral extent of the neuraxis. A common feature of the neuroanatomic organization of the postural and locomotor control systems is the presence of key nodes for convergent input of multisensory feedback in conjunction with efferent copies of the motor command. These nodes include the vestibular and reticular nuclei and interneurons in the intermediate zone of the spinal cord (Rexed's laminae VI-VIII). This organization provides both spatial and temporal coordination of the various goals of the system and ensures that the large repertoire of voluntary movements is appropriately coupled to either anticipatory or reactive postural adjustments that ensure stability and provide the framework to support the intended action. Redundancies in the system allow adaptation and compensation when sensory modalities are impaired. These alterations in behavior are learned through reward- and error-based learning processes implemented through basal ganglia and cerebellar pathways respectively. However, neurodegenerative processes or lesions of these systems can greatly compromise the capacity to sufficiently adapt and sometimes leads to maladaptive changes that impair movement control. When these impairments occur, the risk of falls can be significantly increased and interventions are required to reduce morbidity. PMID- 30482323 TI - Dementia. AB - Dementia is a syndrome seen most commonly in older people and characterized by a decline in cognitive performance which impacts on the person's ability to function. There are approximately 47 million people worldwide with dementia and there are 10 million new cases every year. It is a major cause of disability and dependence and impacts on the physical, psychologic, and social well-being of families and carers. Alzheimer's disease is the most common form of dementia. Gait and balance impairments are common in people with dementia and contribute to the significantly elevated risk of falls. Older people with dementia are at increased risk of injury, institutionalization, hospitalization, morbidity, and death after a fall. There is preliminary evidence, predominantly from relatively small studies, that falls and disability can be prevented in this population. However, more good-quality research is needed, both to provide some certainty around the existing evidence base as well as to explore alternate approaches to prevention, including combined cognitive-motor training and cognitive pharmacotherapy. PMID- 30482324 TI - Cerebral palsy. AB - Cerebral palsy (CP) is a lifespan motor disorder arising from damage to the developing brain before or shortly after birth. People with CP may experience problems with muscle coordination and difficulties with the organization and processing of sensory information. Functional mobility is impaired and commonly influenced by spasticity and musculoskeletal system problems such as contractures or bony torsion. Around 60% of individuals with CP are able to walk independently or with aids when entering adulthood. However, many adults with CP experience increasing balance and mobility dysfunction associated with premature aging. Falls and reduced falls efficacy are commonly experienced, with associated physical and psychosocial consequences. There is evidence that ambulant adults with CP may be able to enhance their functional balance and mobility as a result of an individualized exercise program of sufficient duration and intensity. However, whether such programs result in a reduction in falls is unknown. Given the high number of falls with injury experienced by this population, attention to fall risk factors and provision of basic fall prevention strategies are warranted. PMID- 30482325 TI - Poliomyelitis. AB - Poliomyelitis, often termed "polio," is an acute infectious disease caused by an enterovirus which damages the anterior horn cells of the spinal cord and brainstem. Progress to lower motor neurone cell death leads to disruption of motor units and subsequent muscle weakness or complete paralysis. Although the virus is mostly eradicated from the Western world, postpolio decline is prevalent among people aged 60 years and over. It is characterized primarily by fatigability and muscle weakness, but pain is also common. Reductions in lower limb muscle strength, voluntary drive, and endurance are likely to contribute to the impaired balance control, slow gait, and dysfunctional lower-limb kinematics reported in polio survivors. Given these significant risk factors, polio survivors fall up to four times more often than their age-matched healthy peers. Interventions to improve function, reduce disability, and prevent falls in polio survivors are therefore clinically relevant but studies are lacking, limiting the evidence base. Balance training, cognitive behavioral therapy, and orthoses prescription might be recommended. Muscle-strengthening programs should be carefully designed and delivered due to their potential detrimental effects related to excessive use and potential dysfunction of motor neurones and their axons. PMID- 30482326 TI - Motor neurone disease. AB - Motor neurone disease (MND) patients exhibit poor gait, balance, and postural control, all of which significantly increases their risk of falling. Falls are frequent in the MND population, and are associated with an increased burden of disease. The complex interplay of both motor and extramotor manifestations in this disease contributes to the heterogeneous and multifactorial causes of such dysfunction. This review highlights the pathophysiologic influence of motor degeneration in gait disturbance, but also the additional influence on postural instability from other inputs such as cognitive impairment, autonomic dysregulation, cerebellar dysfunction, sensory impairment, and extrapyramidal involvement. In various combinations, these impairments are responsible for reduced gait speed and alteration in gait cycle, as well as structurally more variable and disorganized gait patterns. Based on these features, this chapter will also provide disease-specific interventions to assess, manage, and prevent falls in the MND cohort. PMID- 30482327 TI - Brainstem lesions and gait. AB - The brainstem contains virtually all of the important structures involved in experimental models of locomotion, encompassing control of upright posture, balance, and stepping. The physiologic basis for these functions is intricately related. Studies of the effects of lesions and disease on these functions in humans are limited to clinical observation and hampered by the anatomic complexity of closely spaced structures and lack of selectivity of lesions. Accordingly, any description of the clinical effects of brainstem lesions on gait and posture is imprecise because weakness and ataxia either predominate over or obscure any selective disturbance of the control of locomotion that may be correlated with the findings in experimental models. New and more sophisticated methods of brain imaging along with physiologic studies of balance and stepping may provide advances in human gait disorders, especially in relation to the brainstem control of locomotion. PMID- 30482328 TI - Balance, gait, and falls in spinal cord injury. AB - This chapter covers balance, gait, and falls in individuals with spinal cord injury (SCI) from a clinical perspective. First, the consequences of an SCI on functioning are explained, including etiology, clinical presentation, classification, and epidemiologic data. Then, the specific aspects of balance disorders, gait disorders, and falls are discussed with respect to motor complete (cSCI) and incomplete (iSCI) SCI. Typically, these activities are affected by impaired afferent and efferent nerves, but not by central nervous processing. Performance of daily life activities in cSCI depends on the ability to control the interaction between the center of mass and the base of support or limits of stability. In iSCI, impaired proprioception and muscle strength are important factors for completing balancing tasks and for walking. Falls are common in patients with SCI. Subsequent sections describe therapy approaches aimed at modifying balance, gait, and the risk for falls by means of therapeutic exercises, assistive devices like robots or functional electric stimulation, and environmental adaptations. The last part covers recent developments and future directions. These encompass interventions for maximizing residual neural function and regeneration of axons, as well as technical solutions like epidural or intraspinal electric stimulation, powered exoskeletons, and brain computer interfaces. PMID- 30482329 TI - Disorders of the inner-ear balance organs and their pathways. AB - Disorders of the inner-ear balance organs can be grouped by their manner of presentation into acute, episodic, or chronic vestibular syndromes. A sudden unilateral vestibular injury produces severe vertigo, nausea, and imbalance lasting days, known as the acute vestibular syndrome (AVS). A bedside head impulse and oculomotor examination helps separate vestibular neuritis, the more common and innocuous cause of AVS, from stroke. Benign positional vertigo, a common cause of episodic positional vertigo, occurs when otoconia overlying the otolith membrane falls into the semicircular canals, producing brief spells of spinning vertigo triggered by head movement. Benign positional vertigo is diagnosed by a positional test, which triggers paroxysmal positional nystagmus in the plane of the affected semicircular canal. Episodic spontaneous vertigo caused by vestibular migraine and Meniere's disease can sometimes prove hard to separate. Typically, Meniere's disease is associated with spinning vertigo lasting hours, aural fullness, tinnitus, and fluctuating hearing loss while VM can produce spinning, rocking, or tilting sensations and light-headedness lasting minutes to days, sometimes but not always associated with migraine headaches or photophobia. Injury to both vestibular end-organs results in ataxia and oscillopsia rather than vertigo. Head impulse testing, dynamic visual acuity, and matted Romberg tests are abnormal while conventional neurologic assessments are normal. A defect in the bony roof overlying the superior semicircular canal produces vertigo and oscillopsia provoked by loud sound and pressure (when coughing or sneezing). Three-dimensional temporal bone computed tomography scan and vestibular evoked myogenic potential testing help confirm the diagnosis of superior canal dehiscence. Collectively, these clinical syndromes account for a large proportion of dizzy and unbalanced patients. PMID- 30482330 TI - Peripheral nerve disease. AB - Polyneuropathies are common neurologic disorders affecting the peripheral nerves. There are a number of causes of damage to these structures, such as genetic and metabolic factors, autoimmune disorders, infection, drug or environmental toxicity, and malignancy. Motor and sensory impairments are commonly encountered in these conditions, leading to altered balance and gait with increased risk of falling. Diabetic neuropathy is the most common cause of peripheral nerve disease and extensive investigation of balance and walking function revealed greater postural instability and delayed activation of distal muscles during walking. Although classically thought to be due to sensory impairment, it is now recognized that a motor contribution to balance and gait impairment cannot be ruled out in diabetic neuropathy. Inflammatory and inherited neuropathies have had less investigation. Variations in static and dynamic balance and depend on the sensory afferents affected and the degree of motor impairment. Motor impairment is a major contributor to alterations in gait pattern. Exercise is an effective rehabilitation approach that can improve muscle strength and postural responses. The gains can carry over into improved functional balance and walking. Orthotic interventions are also promising in supporting joints where there is significant muscle weakness, but newer devices are being developed that provide sensory feedback, e.g., vibration, which may be effective where sensory impairment is a key contributor to postural instability. PMID- 30482331 TI - Functional (psychogenic) gait disorder: diagnosis and management. AB - Functional (psychogenic) gait disorders are a common presentation of functional neurological disorder - one of the commonest diagnoses made in neurology practice. People with functional neurological disorder are as disabled and experience as poor a quality of life as patients with multiple sclerosis and Parkinson's disease. People with functional neurological disorder, including gait disorder, are often perceived as being challenging to diagnose and manage, and as a result attitudes of health professionals towards them are often negative. However, a rapid positive diagnosis of functional gait disorder can often be made, and with a specific approach to diagnostic explanation and treatment, many patients experience improvement in symptoms and disability, with such improvements sustained in the long term. Here I review current evidence regarding the diagnosis, pathophysiology and management of functional gait disturbance with an emphasis on how to make a positive diagnosis and how to select the most appropriate treatment approach. Rehabilitative treatments, with an emphasis on specific physiotherapy interventions, have increasing evidence for benefit, particularly if carried out following a comprehensive explanation of the diagnosis. PMID- 30482332 TI - Gravity estimation and verticality perception. AB - Gravity is a defining force that governs the evolution of mechanical forms, shapes and anchors our perception of the environment, and imposes fundamental constraints on our interactions with the world. Within the animal kingdom, humans are relatively unique in having evolved a vertical, bipedal posture. Although a vertical posture confers numerous benefits, it also renders us less stable than quadrupeds, increasing susceptibility to falls. The ability to accurately and precisely estimate our orientation relative to gravity is therefore of utmost importance. Here we review sensory information and computational processes underlying gravity estimation and verticality perception. Central to gravity estimation and verticality perception is multisensory cue combination, which serves to improve the precision of perception and resolve ambiguities in sensory representations by combining information from across the visual, vestibular, and somatosensory systems. We additionally review experimental paradigms for evaluating verticality perception, and discuss how particular disorders affect the perception of upright. Together, the work reviewed here highlights the critical role of multisensory cue combination in gravity estimation, verticality perception, and creating stable gravity-centered representations of our environment. PMID- 30482333 TI - Sensorimotor control of standing balance. AB - For most individuals, balancing upright is a simple task that requires little effort. The inherent difficulties associated with standing balance are not revealed until a pathology or injury impairs its control. Fundamentally, standing upright requires us to balance our unstable whole-body load within a small base of support. Small movements of the upright body are detected by various sensory receptors, all encoding these movements through their own coordinate system with specific dynamics. The balance controller filters, processes, and integrates sensory cues of body motion to produce an error signal between predicted and actual sensory consequences of balance-related movements. Compensatory motor commands are generated in response to this error to maintain upright standing. In the present review, we first briefly describe the biomechanics and sensor dynamics of standing balance. We further review sensorimotor and perceptual approaches revealing operational principles of the balance system, along with computational approaches that explore control processes underlying upright stance. Finally, we present robotic tools that virtualize the sensory consequences, biomechanics, and/or environmental factors inherent to the standing balance task. Throughout, we emphasize works that combine sensorimotor, computational, and/or robotics approaches to highlight the task dependency, multisensory cue combinations, cortical-subcortical contributions, and internal representations underpinning balance control. PMID- 30482334 TI - Balance perturbations. AB - Impairments of balance and gait leading to loss of mobility, falls, and disability are common occurrences in many neurologic conditions and with older age. Much of our current understanding about posture and balance control and its impairments has come from investigations of how healthy individuals and those with neurologic disorders respond to situations that perturb standing balance during instructed voluntary tasks or in reaction to externally imposed challenges to stability. Knowledge obtained from these investigations has come from documenting the physical and physiologic characteristics of the perturbations together with the body's electrophysiologic, structural, kinetic, kinematic, and behavioral responses. From these findings, basic mechanisms, diagnostic and pathologic criteria, and targets for clinical care have been identified while continued gaps in understanding have been exposed. In this chapter, we synthesize and discuss current concepts and understanding concerning the sensorimotor control of posture and balance while standing. We draw insights gained from perturbation studies investigating these functions in healthy adults, and those with neurologic pathologies. PMID- 30482337 TI - Office-based concussion evaluation, diagnosis, and management: pediatric. AB - More children and adolescents are participating in competitive sports than ever before, causing an overall increase in sport-related injuries. Concussion is a common injury in the pediatric population and its prevalence has increased with increased visibility and awareness. This chapter will discuss the clinical presentation, evaluation, and management of concussions sustained by pediatric athletes, while addressing the distinctive factors that pertain to this population. Management of concussion should be tailored to patients' symptoms and should focus on an early and gradual return to both cognitive and noncontact low risk physical activity. A multidisciplinary approach is often helpful in addressing more specific symptoms, which fall into the somatic, cognitive, vestibular, emotional, and sleep domains. A prolonged recovery is defined by symptoms lasting more than 4 weeks. Individualized return-to-play decisions should focus on the safety of the young athlete. PMID- 30482338 TI - Sports neurology as a multidisciplinary field. AB - A multidisciplinary approach within sports neurology fills a critical role in the management of athletes with neurologic injury. This model promotes streamlined access to sports medicine providers who can offer high-quality multispecialty care in a collaborative manner, to provide optimal outcomes for athletes. This chapter highlights the rise of the multidisciplinary care approach in nonathletic healthcare settings and introduces the concept of the interdisciplinary sports medicine care model. Next, we review the roles of medical providers who are integral in effective management of sport-related concussion, followed by a discussion of the athletic healthcare teams that treat other sport-related neurologic injuries and athletes with pre-existing neurologic conditions. Finally, we note important educational, legal, and independent medical care issues in athletic healthcare settings, and summarize the applicability of multidisciplinary and interdisciplinary care models to the subspecialty of sports neurology. PMID- 30482339 TI - The relationship of migraine and other headache disorders to concussion. AB - Concussion and migraine share many similar pathophysiologic mechanisms, including cortical spreading depression and failure in brain ion homeostasis. Migraine may predispose to concussion, and migraine and posttraumatic headache are common following concussion. This overlap may interfere with proper diagnosis following sport injury, thereby delaying either appropriate treatment or return-to-play. Posttraumatic headache is the most common symptom following concussion, and although symptoms are indistinguishable from migraine, persistent posttraumatic headache may be a unique entity that is more refractory to traditional headache management. There are few studies investigating the diagnosis and treatment of posttraumatic headache. This chapter provides a broad overview of migraine and other headache disorders in sport, with a specific focus on emerging treatment paradigms for posttraumatic headache. PMID- 30482340 TI - Sleep disorders and concussion. AB - Sleep disorders are a common sequel of sports-related concussion. Sleep-wake dysfunction can vary among patients, independent of cause or severity of concussive injury. The pathogenesis of postconcussive sleep disorder is unclear, but may be related to impaired signaling in neurons involved in normal sleep-wake control and circadian rhythm maintenance. Standardized methods of assessment for sleep disorders following concussion are important for diagnosis and management. Appropriate management is key because sleep dysfunction can have deleterious effects on concussion recovery. Management is patient-specific, based on sleep pathology and comorbid postconcussive symptomatology. PMID- 30482341 TI - Vestibular dysfunction and concussion. AB - The assessment and treatment of sport-related concussion (SRC) often requires a multifaceted approach. Vestibular dysfunction represents an important profile of symptoms and pathology following SRC, with high prevalence and association with prolonged recovery. Signs and symptoms of vestibular dysfunction may include dizziness, vertigo, disequilibrium, nausea, and visual impairment. Identifying the central and peripheral vestibular mechanisms responsible for pathology can aid in management of SRC. The most common vestibular disturbances after SRC include benign paroxysmal positional vertigo, vestibulo-ocular reflex impairment, visual motion sensitivity, and balance impairment. A variety of evidence-based screening and assessment tools can help to identify the various types of vestibular pathology in SRC. When vestibular dysfunction is identified, there is emerging support for applying targeted vestibular rehabilitation to manage this condition. PMID- 30482342 TI - Neuro-ophthalmologic disorders following concussion. AB - Visual symptoms, such as photophobia and blurred vision, are common in patients with concussion. Such symptoms may be accompanied by abnormalities of specific eye movements, such as saccades and convergence, or accommodation deficits. The high frequency of visual involvement in concussion is not surprising, since more than half of the brain's pathways are dedicated to vision and eye movement control. These areas include many that are most vulnerable to head trauma, including the frontal and temporal lobes. Vision and eye movement testing is important at the bedside and on the sidelines of athletic events, where brief performance measures that require eye movements, such as rapid number naming, are reliable and sensitive measures for concussion detection. Tests of vision and eye movements are also being explored clinically to identify and monitor patients with symptoms of both sport- and nonsport-related concussion. Evaluation of vision and eye movements can assist in making important decisions after concussion, including the prognosis for symptom recovery, and to direct further visual rehabilitation as necessary. PMID- 30482343 TI - Neuropsychiatry of sport-related concussion. AB - Changes in mood, emotions, and behavior are common components of the acute clinical picture of sport-related concussion (SRC). Common concussion symptom inventories such as the Sport Concussion Assessment Tool-5 (SCAT5) contain a large number of questions that assess these neuropsychiatric domains. In fact, of 22 items assessed by the SCAT5, arguably only five of the items do not overlap with symptoms assessed by standard measures of anxiety and depression, suggesting that concussion is best viewed as a neuropsychiatric syndrome. Furthermore, it is important to understand the complex relationship between preinjury psychologic health, acute injury symptom profile, and the role that changes in mood, emotions, and behavior play in the recovery trajectory after concussion. Some research suggests that there may also be long-term neuropsychiatric effects of concussion, repetitive concussion, and repetitive head impacts. This chapter provides a review of the neuropsychiatric sequelae of acute SRC, the current evidence for long-term neuropsychiatric effects of repetitive concussion, and the impact of neuropsychiatric symptoms on recovery trajectory. Clinical principles relevant to management are described. PMID- 30482344 TI - Postconcussion syndrome. AB - Postconcussion syndrome (PCS) is a heterogeneous condition comprised of a set of signs and symptoms in somatic, cognitive, and emotional domains. PCS is a controversial concept because of differing consensus criteria, variability in presentation, and lack of specificity to concussion. Whereas symptoms of concussion resolve in most individuals over days to weeks, a minority of individuals experience symptoms persisting months to years. The clinical consequences of concussion may be best conceptualized as two multidimensional disorders: (1) a constellation of acute symptoms termed early-phase posttraumatic disorder (commonly headache, dizziness, imbalance, fatigue, sleep disruption, impaired cognition, photo- and phonophobia); and (2) late-phase posttraumatic disorder, consisting of somatic, emotional, and cognitive symptoms. This phase is highly influenced by various psychosocial factors and is much less specific to the brain injury itself. Risk factors for development of a late-phase disorder include a high early symptom burden (e.g., headache, fatigue), a history of multiple concussions, psychiatric conditions (anxiety, depression), longer duration of unconsciousness or amnesia, and younger age. Successful treatment requires thoughtful differential diagnosis, including consideration of comorbid and premorbid conditions and other possible contributing factors. Treatment should include a hierarchic, sequential approach to management of treatable symptoms that impact functioning, such as depression, anxiety, insomnia, headache, musculoskeletal pain, and vertigo. A guided prescription of aerobic exercise is beneficial for early- and late-phase disorders after concussion. PMID- 30482345 TI - The role of neuropsychologists in concussion evaluation and management. AB - Sport-related concussions are complex injuries of the brain. Since concussions can only be diagnosed clinically and manifest in different ways among athletes, diagnosis and management often require a multidisciplinary team approach. Sports neuropsychologists contribute to the team through their ability to assess cognitive, behavioral, and social-emotional domains that may or may not be a direct effect of the injury. This chapter describes the new field of sports neuropsychology and articulates how neuropsychologists can contribute to assessment and management. The strengths and weaknesses of neuropsychological assessment are reviewed, including traditional paper-and-pencil testing and computer-administered tests, both as baseline and postinjury evaluations. Neuropsychologists can provide biopsychosocial evaluation and treatment services to athletes, including postinjury education and emotional reassurance, guiding symptom management and emotional support, and assisting with return-to-play and return-to-school processes. They also provide important insight for decisions regarding retirement, including articulating the relevant factors and supporting athletes in their decision process. Given the varying and behavioral responses that can accompany concussion, neuropsychologists can provide unique support to athletes to help them cope with their injury and its effects. PMID- 30482346 TI - Return to play following sports-related concussion. AB - Returning a concussed athlete to practice and competition is an ever-evolving concept that has received considerable scientific and public attention during the past 20 years. Whereas there is now more international consensus regarding return to play, the decision to do so is clinically based with scant objective measures to guide decision making. To encapsulate the return-to-play process, this chapter will give a historic overview of the graded progression process, outline how rest can be both beneficial and detrimental in recovery, and how exercise is emerging as a management tool. PMID- 30482347 TI - Return to learn. AB - Students who have sustained a concussion often have symptoms that affect their full participation in academics. Physical symptoms, such as headaches and dizziness, and cognitive symptoms, such as difficulty concentrating or remembering, may affect students as they try to get through their normal academic workload. The concept of returning a student to normal learning following a concussion is gaining attention, as previously the emphasis has been on the process of returning a student back to full physical activity. Appropriate guidance is needed to assist the student with the transition back into the school environment. PMID- 30482348 TI - Neuroimaging of brain trauma in sports. AB - Computed tomography (CT) and magnetic resonance imaging (MRI) have revolutionized the assessment of traumatic brain injury (TBI) by permitting rapid detection and localization of acute intracranial injuries. In concussion, the most common presentation of sports-related head trauma, CT and MRI are unrevealing. This normal appearance of the brain on standard neuroimaging, however, belies the structural and functional pathology that underpins concussion-related symptoms and dysfunction. Advances in neuroimaging have expanded our ability to gain insight into this microstructural and functional brain pathology. This chapter will present both conventional and more advanced imaging approaches (e.g., diffusion tensor imaging, magnetization transfer imaging, magnetic resonance spectroscopy, functional MRI, arterial spin labeling, magnetoencephalography) to the assessment of TBI in sports and discuss some of the current and potential future roles of brain imaging in the assessment of injured athletes. PMID- 30482349 TI - Mild traumatic brain injury and concussion: terminology and classification. AB - Traumatic brain injury (TBI) is a major cause of morbidity and mortality throughout the world. Mild TBI, which is typically defined by Glasgow Coma Scale score >=13, accounts for the vast majority of all TBIs, particularly in the setting of sports-related injuries. The terms concussion and TBI are often used interchangeably, both in the medical literature and in clinical care of this patient population. However, the lack of clearly defined definitions of these terms often leads to confusion, and this confusion may lead to delayed diagnosis and inconsistent management of affected patients. Here, we review the current terminology and classification of mild TBI and concussion. We will also discuss recent efforts to stratify these injuries into clinically relevant subtypes or profiles that are both diagnostic- and treatment-targeted. PMID- 30482350 TI - Blood and cerebrospinal fluid biomarkers. AB - Sports-related traumatic brain injuries (TBIs) range in severity from severe to subconcussive. Although technologies exist for clinical diagnosis of more severe injuries, methods for diagnosis of milder forms of brain injury are limited. Developing objective measures to indicate pathogenic processes after a suspected mild TBI is challenging for multiple reasons. The field of biomarker discovery for diagnosing TBI continues to expand, with newly identified candidate biomarkers being reported regularly. Brain-specific biomarkers include proteins derived from neurons and glia, and are often measured to assess neural injury and repair, and to predict outcomes. Ideally, changes in biomarker levels should indicate pathologic events and answer critical questions for accurate diagnosis and prognosis. For example, does the presence or a change in the biomarker level suggest greater vulnerability for sustaining a second concussion or show that the window of increased vulnerability has passed? Likewise, do changes in biomarker levels predict postconcussion syndrome or recovery/repair? Although there are numerous promising candidates for fluid biomarkers that may diagnose mild TBI or concussion, none has reached the clinic to date. In this chapter, we will define biomarkers, discuss the importance of understanding their normal and pathologic functions, and outline some considerations for interpreting detection assay results in TBI. We will then review five proposed blood and cerebrospinal fluid biomarkers (tau, neurofilament, ubiquitin carboxyl-terminal hydrolase L1, S100beta, and glial fibrillary acidic protein) used currently to address TBI. Lastly, we will discuss a future trajectory for developing new, clinically useful fluid biomarkers. PMID- 30482352 TI - Subconcussive trauma. AB - Even impacts that do not immediately elicit symptoms of a concussion can induce changes in neural integrity. Because these so-called "subconcussive" head acceleration events, or head impact exposures, do not elicit identifiable symptoms, athletes continue to participate with unclear consequences. Neuroimaging studies reveal that neurologic changes, including inflammation, are associated with repetitive head impact exposures. Given that brain changes have been observed in athletes following repetitive head impact exposure, it is important to understand better and mitigate against this phenomenon. It is important to transition from the metric of concussion alone to one that includes repetitive head impact exposure, including the development of models that address why brain integrity may be compromised, who is at risk, and how to mitigate the risk of such exposure. Future work can include a health-monitoring framework to effect change and promote athlete safety. PMID- 30482351 TI - Measuring head impacts: accelerometers and other sensors. AB - Understanding the biomechanics of head injuries is essential for the development of preventive strategies and protective equipment design. However, there are many challenges associated with determining the forces that cause injury. Acceleration of the skull is often measured because it is relatively easy to quantify and relates to severity of impact, but it is difficult to relate those measurements to the type and extent of injury that occurs. Experimental work in the laboratory has used either human cadavers or volunteers. Cadavers can be instrumented with high-grade sensors that are tightly coupled to the skull for accurate measurements, but they cannot exhibit a functional response to determine a threshold for brain injury. Volunteers can also be instrumented with high-grade sensors in controlled laboratory experiments, but any head accelerations they experience must be well below an injurious level. Athletes participating in contact sports present a unique opportunity to collect biomechanical data from populations that have increased exposure to head impacts and a higher risk of head injury than the general population. Recent advances in sensor technology have allowed for more accurate measurements from instrumented athletes during play, but it is challenging to tightly couple the instrumentation to the skull to provide meaningful measurements. Because of the challenges associated with on field measurements, it is important to consider the type of sensor used and its accuracy in the field when evaluating head impact data from athletes. PMID- 30482353 TI - Catastrophic neurologic injuries in sport. AB - Tens of millions of children and adults participate in organized sport in the United States each year. Although uncommon, fatal and severe nonfatal brain and spine injuries can occur during these activities. These "catastrophic" injuries have been noted in contact sports such as football, rugby, and ice hockey, as well as in noncontact sports including baseball, cheerleading, swimming and diving, equestrian, gymnastics, pole vault, rodeo, snow skiing, snowboarding, and wrestling. They happen at all levels of play, from youth to professional. Among all sports, football has the highest number of fatal brain and cervical spine injuries. While these injuries are more frequent in high school football, the rate is higher amongst college football athletes. Patterns exist in the types of brain and spine injuries most often occurring as a result of traumatic impacts in sport, but incidence and mechanisms of injury vary dramatically between sports. Understanding these patterns is essential to informing prevention efforts; football, pole vault, and cheer are all examples of sports benefiting from successful catastrophic injury prevention efforts. Participating in sport provides many benefits to physical and mental health. Despite these benefits, rare devastating injuries can be traumatic for the athletes, their families, and communities and can raise safety concerns that may reduce participation in sport. Understanding and preventing these types of injuries are critical to fostering participation in sport and ensuring both children and adults reap the physical, social, and mental benefits of sport. PMID- 30482354 TI - The evolving landscape of policies, rules, and law in sport-related concussion. AB - Beginning in 2009 with the passage of the Zackery Lystedt law in the state of Washington, all 50 states have passed concussion laws that implement a mandatory framework of care for high school and youth athletes. The structure of these laws generally shares the three primary components of the Lystedt law: (1) preseason concussion education; (2) mandatory removal from play with suspected concussion; and (3) clearance from a healthcare professional prior to return to play. These same three policy components are also found at the collegiate and professional levels of sport, either through established policy or labor contracts. This chapter explores concussion-specific legal and policy developments that currently inform concussion management practices across multiple levels of the US athletic system. PMID- 30482355 TI - The modern landscape of sport-related concussion research: key achievements and future directions. AB - The study of contact and collision sport athletes at risk for concussion began approximately three decades ago. Since then, sport-related concussion (SRC) research across several medical specialties has helped to develop consensus guidelines for clinical management through interdisciplinary efforts. The modern landscape of SRC research includes large-scale investigations to define the natural history of concussion and identify factors that should guide prevention, diagnosis, and treatment specific to the individual patient. We now know that the clinical and physiologic effects of concussion are related but independent constructs deserving further scientific exploration. This has sparked research that incorporates advanced neuroimaging, fluid biomarkers, biomechanics, and genomics, in addition to standard clinical outcomes. Additionally, translational research has informed our understanding of optimal rehabilitation strategies and led to a shift from the "complete rest" approach to earlier, active management interventions after concussion. Collectively, these advancements are likely to substantially improve patient outcomes after SRC and, ultimately, may prove beneficial for identifying and appropriately managing those at risk for longer term difficulties associated with repetitive head impact exposure. The broader public health implications of improving sports safety and encouraging developmentally appropriate participation among youth and adolescents are a particularly important byproduct of continued research into SRC. PMID- 30482356 TI - Chronic traumatic encephalopathy: clinical presentation and in vivo diagnosis. AB - Exposure to repetitive head impacts from contact sport participation (e.g., American football, boxing, soccer) is associated with the neurodegenerative disorder known as chronic traumatic encephalopathy (CTE). The neuropathology of CTE is becoming well defined, and diagnostic criteria have been developed and are being refined. The critical next step in this emerging field is the diagnosis of CTE during life. The objective of this chapter is to describe what is currently known about the clinical presentation and in vivo diagnosis of CTE. This chapter reviews studies in which clinical manifestation of CTE was examined through retrospective telephone interviews with informants of individuals whose brains were donated and were diagnosed with CTE through neuropathologic examination. In vivo research examining the long-term neurobehavioral consequences of repetitive head impacts is also reviewed, followed by a comparison of the existing provisional clinical diagnostic criteria for CTE, as well as preliminary research on possible fluid and neuroimaging biomarkers. An illustrative case study of CTE is presented, and the chapter concludes with a discussion of gaps in knowledge and future directions. PMID- 30482357 TI - The neuropathology of chronic traumatic encephalopathy. AB - Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head trauma, including concussion and subconcussion. CTE was first recognized in boxers nearly a century ago as "dementia pugilistica" or "punch drunk," but has been recently identified in contact sports athletes (including American football, ice hockey, soccer, baseball, rugby, boxing, and wrestling) and military veterans exposed to blast. Similar to many other neurodegenerative diseases, CTE is diagnosed conclusively only by neuropathologic examination of brain tissue. CTE is characterized by the buildup of hyperphosphorylated tau as neurofibrillary tangles, abnormal neurites, and inclusions in astrocytes around small blood vessels with a tendency to occur in clusters at the sulcal depths of the cortex. Using the McKee criteria, a consensus panel of expert neuropathologists confirmed CTE as a unique neurodegenerative disease with a pathognomonic CTE lesion that has only been found in individuals exposed to brain trauma. Recently, 177 instances of CTE were reported in a convenience sample of 202 former American football players, including 110 of 111 former National Football League players (99%), 48 of 53 former college football players (91%), and 3 of 14 former high school players (21%), by far the largest case series ever reported. Significant increases in active microglia and inflammation also occur after repetitive head impact injury and in CTE. A preliminary study showed that inflammatory cytokines were elevated in the brain tissue and cerebrospinal fluid of individuals with pathologically confirmed CTE compared to controls and individuals with Alzheimer disease, which may some day be useful in diagnosis of CTE during life. Although many fundamental questions remain to be answered regarding CTE, postmortem analysis of tissue from brain donors and tissue-based research have accelerated and expanded our current understanding of CTE and its pathogenesis. Guided by the neuropathologic findings, current research efforts are underway to develop biomarkers to diagnose CTE and effective ways to treat the disorder during life. PMID- 30482358 TI - Sports and the human brain: an evolutionary perspective. AB - An evolutionary perspective helps explain a conundrum faced by sports neurologists: why is the human brain dependent on physical activity to function optimally, yet simultaneously susceptible to harm from particular types of athletics? For millions of years, human bodies and brains co-evolved to meet the physical and cognitive demands of the uniquely human subsistence strategy of hunting and gathering. Natural selection favored bodies with adaptations for endurance-based physical activity patterns, whereas brains were selected to be big and powerful to navigate the complex cultural and ecologic landscapes of hunter-gatherers. Human brains require physical activity to function optimally because their physiology evolved among individuals who were rarely able to avoid regular physical activity. Moreover, because energy from food was limited, human brains, like most energetically costly physiologic systems, evolved to require stimuli from physical activity to adjust capacity to demand. Consequently, human brains are poorly adapted to excessive physical inactivity. In addition, while brain enlargement during human evolution was vital to successful hunting and gathering, it came at the cost of a decreased ability to withstand brain accelerations and decelerations, which commonly occur during contact/collision sports. PMID- 30482359 TI - Chronic traumatic encephalopathy: neuroimaging biomarkers. AB - Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with repetitive head impact exposure, such as that resulting from sports-related concussive and subconcussive brain trauma. Currently, the only way to diagnose CTE is by using neuropathologic markers obtained postmortem. To diagnose CTE earlier, so that possible treatment interventions may be employed, there is a need to develop noninvasive in vivo biomarkers of CTE. Neuroimaging provides promising biomarkers for the diagnosis of CTE and may also help elucidate pathophysiologic changes that occur with chronic sports-related brain injury. To describe the use of neuroimaging as presumed biomarkers of CTE, this chapter focuses on only those studies that report the chronic stages of sports-related brain injury, as opposed to previous chapters that described neuroimaging in the context of acute and subacute injury. Studies using positron emission tomography and magnetic resonance imaging and spectroscopy will be discussed for contact/collision sports such as American football, boxing, mixed martial arts, rugby, and soccer, in which repetitive head impacts are common. PMID- 30482360 TI - Chronic traumatic encephalopathy: fluid biomarkers. AB - Chronic traumatic encephalopathy (CTE) is a neuropathologic condition that has been described in individuals who have been exposed to repetitive head impacts, including concussions and subconcussive trauma. CTE cannot currently be diagnosed during life. Clinical symptoms of CTE (including changes in mood, behavior, and cognition) are nonspecific and may develop after a latency phase following the injuries. Differential diagnosis based solely on clinical features is, therefore, difficult. For example, some younger patients who do not experience the latency phase (i.e., symptoms of CTE may begin while still being exposed to the repetitive head impacts) may be clinically diagnosed with postconcussive syndrome, a vaguely defined condition that is described in a minority of concussed patients. Some older patients whose initial features of CTE include memory and executive dysfunction and progress to impaired activities of daily living may be clinically diagnosed with Alzheimer disease or another dementia. Although concussions are common in athletes and nonathletes, contact/collision sport athletes, such as boxers, American football players, and ice hockey players, are at greater risk of exposure to both concussion and repetitive subconcussive head impacts. Biomarkers for CTE pathophysiology would be of great value to study and improve our understanding of when and how the disease process starts and develops, as well as how it can be prevented or treated. Here, we review the literature regarding fluid biomarkers for repetitive subconcussive impacts, concussion, postconcussive syndrome, and CTE. We also discuss technical issues and potential pathways forward regarding how to move the most promising biomarker candidates into clinical laboratory practice. PMID- 30482361 TI - Biomechanics and common mechanisms of injury of the cervical spine. AB - The cervical spine functions to position the head while maintaining stability and protecting the spinal cord. The anatomy of the cervical spine dictates the amount of physiologic motion at each level. Knowledge of the normal biomechanical anatomy of the cervical spine is imperative to the understanding of the biomechanics of injury to the cervical spine. There are a variety of reproducible injury patterns based on the direction and magnitude of force applied to the cervical spine. Knowledge of these forces can allow an understanding of the mechanical and neurologic stability of the cervical spine and can also help guide treatment options. It is also important to understand the mechanism of injury and injured cervical structures based on radiographic findings, as often patients will present with neurologic examinations that also reflect noncervical spine related injuries. The goal of this chapter is to present a review of the normal biomechanics of the cervical spine, in addition to presenting different injury patterns of the cervical spine from the minor to life-threatening, with the goal of maximizing postinjury function by ensuring proper treatment protocols are followed. PMID- 30482362 TI - Cervical spine trauma evaluation. AB - Cervical spine trauma is a relatively rare but catastrophic event in sports. These critical situations depend on sports medicine personnel understanding every aspect of sideline care to ensure a safe and successful evaluation. This involves thorough preparation, vigilant observation of the sporting event to detect the possible mechanism of injury, and initiation of the appropriate action plan when a potentially catastrophic injury is suspected. Sideline management of cervical spine trauma requires the appropriate primary survey, with spine stabilization if necessary, secondary survey for concomitant injury, and, potentially, initiation of full spine stabilization with a spine board. In this chapter, our primary focus is discussion of the sideline evaluation of cervical spine trauma, and sideline practices designed to stabilize the athlete and minimize risk for further injury. PMID- 30482363 TI - Acute management of cervical spine trauma. AB - Traumatic cervical spine injuries represent a significant cause of morbidity and mortality in sports. Appropriate management of such injuries is critical to minimizing harm and facilitating optimal long-term recovery and outcome. Management strategies begin with emergency preparedness amongst sideline providers and extends to paramedic services and medical teams in the acute care setting. This chapter outlines the principles of treatment across the care continuum, with a primary focus on hospital-based care. Diagnostic imaging and equipment considerations are reviewed, with discussion of corticosteroid administration, therapeutic hypothermia, and traction of the cervical spine. Approaches to cervical spine stabilization and return to play are also detailed, with an emphasis on patient-centered care and individualized treatment approaches to the athlete. PMID- 30482364 TI - Cervical spine trauma: prevention strategies. AB - Participation in any sport activity carries risk of cervical spine trauma, but certain activities have a higher risk than others, and hence, demand concerted efforts in developing prevention strategies. Prevention often includes efforts surrounding education of stakeholders, creating or modifying rules, and specific policies adopted for decreasing such risk. Stakeholders include sport clinicians, participants, coaches, parents, league administrators, officials, and the public. Thus, both athlete-specific and setting-specific factors must be considered and controlled to the extent possible for a multipronged approach for decreasing cervical spine injury risk. The effectiveness of certain strategies put into place in collision sports, such as American football, rugby, and ice hockey, is reviewed to illustrate this approach. Some research evidence exists that either has informed a strategy, or validated its effectiveness after the fact. More research of a higher level needs to be conducted in all sports to continue to contain the risk of cervical spine trauma to the fullest extent possible. PMID- 30482365 TI - Classification in para sport for athletes following cervical spine trauma. AB - Classification of athletes for para sport is a complex process, and provides the necessary structure for competition. Classification systems aim to ensure that para athletes achieve sporting excellence. By minimizing the effect of the impairment on sports performance, classification systems ensure para sport is not dominated by those athletes with the least impairment, but rather athletic excellence is the key determinant of success. For athletes with cervical spinal cord injuries, assessment of manual muscle power is most commonly used as the starting point for athlete evaluation. However, each individual para sport describes how the results of this evaluation contribute to the allocation of a sports class, based on evidence developed for each sport, or sporting activity. Classification systems will continue to develop and evolve, driven by evidence based approaches which are promoted by the International Paralympic Committee Classification Code. PMID- 30482366 TI - Peripheral nerve injury in sport: an overview. AB - Peripheral nerve injury in sport results from acute trauma or repetitive overuse. Repetitive overuse injuries must be assessed with the broad context of tissue overload, kinetic chain continuum, periodization, recovery, equipment, and sport specific biomechanics. Simply diagnosing the anatomic location and extent of nerve injury is inadequate. Management must consider all contributors to nerve injury. This chapter provides an overview of emerging information for assessing and managing peripheral nerve injury in sport. PMID- 30482367 TI - Neuromuscular adaptations in shoulder function and dysfunction. AB - Neuromuscular activity, organized in coordinated patterns, forms the basis of task-specific function in sports and exercise. The content and extent of these patterns may be variable, but include elements of activation/inhibition, co activation, concentric/eccentric activation, proximal-to-distal activation, plyometric activation, and preactivation stiffness. They may be based on inherent neuromuscular architecture, but are commonly affected by positive or negative adaptations to imposed functional demands. Positive neuromuscular adaptations improve the efficiency of performing the task, which can result in less energy expenditure, maximum force delivered to the task, and protection of involved joints from excessive loads/motions, and improve the effectiveness of task performance. They frequently result from specific training in task mechanics and optimal conditioning of the neuromuscular structures involved in the task. Negative neuromuscular maladaptations can affect the efficiency of performing the task, increase energy expenditure and loads, decrease the effectiveness of task performance, and can be associated with clinical presentation of injury symptoms. They can result from overload, injury, and/or limited recovery. This chapter will focus specifically on shoulder joint function to provide examples of positive adaptations and negative maladaptations. It will then provide guidelines for clinical evaluation, treatment of clinical injury, and training/conditioning, based on understanding the neuromuscular activation. PMID- 30482368 TI - Concussive and subconcussive brain trauma: the complexity of impact biomechanics and injury risk in contact sport. AB - Head impacts that transfer mechanical energy to the skull and create brain injuries have unique dynamic responses and brain tissue trauma characteristics. The magnitude of the impact energy and how it is transmitted creates three dimensional linear and rotational accelerations of the head, resulting in unique strains on brain tissue. Biomechanical investigations of head injuries in contact sports have historically focused on attenuating energy transfer to the skull and brain. Typically, severe life-threatening events are caused by high-energy impact events that result in anatomic damage. Protective equipment attenuates energy transmission to neural tissues to decrease the risk of structural damage. In addition to reducing risk of skull fracture, helmets work by increasing impact compliance, to decrease the magnitude of the head's dynamic response and increase the duration of the event. This strategy helps prevent severe traumatic brain injuries and shifts the risk to concussion and repetitive head impact exposure. Metabolic, cellular, and physiologic responses characterize cumulative brain trauma that may manifest years later. Relying on the presence of symptoms to establish injury is subjective and limited in capturing the risks associated with neural tissue trauma. To more effectively capture brain injury risks in contact sports, we present the concept of brain trauma profiling, involving impact magnitude, frequency, interval, and duration of exposure. Brain trauma profiling captures and describes the cumulative and acute trauma-associated injury risks unique to each sport, level of play, and player position. PMID- 30482369 TI - Common peripheral nerve injuries in sport: diagnosis and management. AB - Peripheral nerve injuries are unusual in sport but impact an athlete's safe return to play. Nerve injuries result from either acute trauma (most commonly in contact/collision sports) or from repetitive microtrauma and overuse. Diagnosis of overuse nerve injuries includes nerve localization and surrounding soft-tissue anatomy, and must account for possible causes of repetitive microtrauma, including biomechanics, equipment, training schedule, and recovery. Prognosis is related to the type of nerve injury. Management should not simply be rest and gradual return to sport but should address biomechanical and training predispositions to injury. Understanding the type of injury and the tissues involved will guide appropriate rehabilitation decisions. Recognizing acute care considerations and implementing appropriate strategies can help minimize secondary trauma to an area following acute injury. PMID- 30482370 TI - Sport-related injury and pain classification. AB - Pain is common in athletes, and pain management in sport has traditionally been equated with injury management. Although both pain and injury interfere with sport performance, they are not synonymous. Acute musculoskeletal injury commonly manifests as nociceptive pain, inflammatory pain, or both. Pain that persists beyond expected injury recovery must account for all potential contributors to pain, including ongoing biomechanical abnormalities, underlying pathophysiology, and psychosocial issues. Pain chronification involves multiple pathophysiologic and neurobehavioral processes that lead from acute injury-related pain to subacute and chronic pain, and must be distinguished from an ongoing biomechanical overuse pattern. The foundation of pain management in athletes is proper pain classification, which involves assessing for any combination of nociceptive/inflammatory pain, neuropathic pain, central sensitization, and autonomic/motor/affective manifestations of pain. Understanding this foundation is critical because there are scant evidence-based guidelines for the management of pain in sport. This chapter will explore the relationship of sport-related injury and pain, and will provide a management framework that is consistent with International Olympic Committee consensus. PMID- 30482371 TI - Pain management in sport: therapeutic injections. AB - Corticosteroid, hyaluronic acid, and platelet-rich plasma injections are commonly utilized when managing pain and injury in the athlete. Although there is ample scientific literature on these injection types, there is a paucity of evidence guiding the use of any of these modalities in a younger, athletic population. Injection strategies should be used as just one aspect of a detailed and athlete specific return to sport and rehabilitation plan. More high-quality research is needed to determine the most appropriate and optimum injection use in the management of painful musculoskeletal conditions, including patient factors and injection formulations. PMID- 30482372 TI - Athletes with neurologic disease. AB - Neurologic disease does not discriminate, even among athletes. Common neurologic diseases among athletes include multiple sclerosis, seizures, headaches, and sleep disorders. Although concrete guidelines for sport participation among athletes with neurologic diseases do not exist, evidence-based and consensus statements can aid healthcare providers in determining whether and to what extent such athletes should participate in sports. Moreover, sport participation is important, since multiple studies indicate that exercise improves disease specific symptoms, manifestations, and overall quality of life. Although some risk is involved for athletes with neurologic disease, risk is mitigated with proper supervision and neurologic oversight, disease-specific accommodations, and counseling of the athletic staff and the athletes. Neurologic oversight entails an initial comprehensive neurologic assessment by a neurologist followed by regular follow-up. Preparation for environmental conditions encountered by athletes with neurologic disease will further improve safety during their participation in sport. With sound recommendations, neurologic oversight, and proper supervision, most athletes with neurologic disease can participate in athletics. The health benefits that they will gain from participation in athletics outweigh the risks. PMID- 30482373 TI - Neurologic benefits of sports and exercise. AB - Traumatic brain injury (TBI) is associated with several pathophysiologic changes, including: neurostructural alterations; molecular changes with shifts in circulating neurotrophins; impaired neural metabolism; changes in cerebrovascular autoregulation, vasoreactivity, and neurovascular coupling; and alterations in functional brain connectivity. In animal models of TBI, aerobic exercise reduces neuronal injury, promotes neuronal survival, and enhances the production of neuroprotective trophic factors. However, the timing of exercise initiation is an important consideration as early exercise in the acute postinjury period may impede recovery mechanisms, although evidence for this in humans is lacking. Though human clinical studies are limited, aerobic exercise post-TBI engages cerebrovascular mechanisms and may impart neurophysiologic benefits to mitigate post-TBI pathophysiologic changes. Additionally, subsymptom threshold exercise in humans has been demonstrated to be safe, feasible, and effective in decreasing symptom burden in individuals with mild TBI, and to counteract the detrimental effects of prolonged inactivity, subsequent physical deconditioning, and its negative emotional sequelae. This chapter will explore the potential role of aerobic exercise in neurorecovery after TBI. PMID- 30482374 TI - Future directions. PMID- 30482375 TI - Concussion: pathophysiology and clinical translation. AB - The majority of the 3.8 million estimated annual traumatic brain injuries (TBI) in the United States are mild TBIs, or concussions, and they occur primarily in adolescents and young adults. A concussion is a brain injury associated with rapid brain movement and characteristic clinical symptoms, with no associated objective biomarkers or overt pathologic brain changes, thereby making it difficult to diagnose by neuroimaging or other objective diagnostic tests. Most concussion symptoms are transient and resolve within 1-2 weeks. Concussions share similar acute pathophysiologic perturbations to more severe TBI: there is a rapid release of neurotransmitters, which causes ionic disequilibrium across neuronal membranes. Re-establishing ionic homeostasis consumes energy and leads to dynamic changes in cerebral glucose uptake. The magnitude and duration of these changes are related to injury severity, with milder injuries showing faster normalization. Cerebral sex differences add further variation to concussion manifestation. Relative to the male brain, the female brain has higher overall cerebral blood flow, and demonstrates regional differences in glucose metabolism, inflammatory responses, and connectivity. Understanding the pathophysiology and clinical translation of concussion can move research towards management paradigms that will minimize the risk for prolonged recovery and repeat injury. PMID- 30482377 TI - Sideline assessment of concussion. AB - The recognition and sideline evaluation of possible sport-related concussion are difficult tasks for a physician and other clinicians. Sideline assessment tools have continued to evolve over the years, but objective biomarkers of concussion do not currently exist. Sideline video review programs may aid in the recognition of possible concussion as additional information for the sideline athletic medicine staff. Additional investigational assessments include visual oculomotor processing, reaction time, and rapid eye movements and attention. As the presentation of concussion is variable and symptoms may evolve over time, it is important that athletes with possible concussion are followed with serial assessments. If the diagnosis is unclear, it is advised to err on the side of caution and not allow the athlete to return to competition on the day of the injury. This chapter will review the current issues regarding the sideline assessment of concussion. PMID- 30482376 TI - Epidemiology of sports concussion in the United States. AB - Sports and recreation-related (SRR) activities are common in the United States. Beyond the benefits to health, SRR activities can create new friendships, give people a sense of belonging, foster teamwork and other leadership skills, and develop sportsmanship and a respect for rules that govern play. Public awareness about the risk of concussion has grown as the long-term consequences of traumatic brain injury (TBI) have become better known, and likely explains the increasing concussion incidence rates. Currently, surveillance systems capture SRR concussions among high school and college athletes participating in sanctioned sports. National estimates of SRR TBI presenting to an emergency department also exist. Persons under the age of 19 sustain a majority of SRR concussions. Concussion risk is greatest for boys in contact/collision sports like football, ice hockey, and lacrosse, and is more likely to occur in competition versus practice settings. Girls have elevated concussion rates in gender-comparable sports. Despite better data, concussions are still underreported, undermanaged, and often not properly identified. This is especially true for concussions occurring outside organized sports, in nonsport recreational activities, and for concussions either not seen or evaluated in nonemergency department settings. A new surveillance system proposed by the Centers for Disease Control and Prevention aims to fill the gap. PMID- 30482378 TI - Emergency department evaluation of the concussed athlete. AB - The concussion evaluation commonly takes place in the emergency department (ED), but most clinicians have not received formal training in concussion diagnosis and management. Proper diagnosis and management of concussion in the ED diminish postconcussion complications and improve the likelihood of successful concussion recovery. The ED assessment begins with early recognition of the signs and symptoms of concussion, a directed history, appropriate documentation, and identification of conditions ("red flags") that need immediate intervention such as traumatic intracranial hemorrhage, followed by a systematic assessment for risk factors that can predict prolonged recovery, and a concussion-focused physical exam. The four key components to this exam are determining the level of alertness, assessing memory and attention, assessing vestibular function, and determining the adequacy of ocular near response. After assessment, ED management focuses on treating acute symptoms, setting expectations for recovery, educating patients regarding prevention of subsequent concussion, determining suitability for discharge, and providing meaningful written discharge instructions. PMID- 30482379 TI - Office-based concussion evaluation, diagnosis, and management: adult. AB - Concussion is a major public health concern, with an estimated 1.6-3.8 million sport-related concussions occurring annually in the United States. Although the majority of injured athletes recover within 7-21 days, 20-30% of athletes experience protracted recovery spanning more than a month, suggesting as many as 320,000-760,000 athletes may experience prolonged symptoms. This highlights the need for efficacious clinical interventions to facilitate recovery. While concussion was historically conceptualized as a homogeneous injury, a more nuanced understanding has recently emerged and led to a refined approach of categorizing concussions into clinical trajectories or symptom profiles. These categorizations correspond with targeted rehabilitation strategies focused on specific symptom clusters and deficits. Multidisciplinary teams, with collaborating neuropsychologists, neurologists, neurosurgeons, sports medicine physicians, athletic trainers, and physical therapists, are valuable to concussion management due to the heterogeneous nature of the injury. This chapter will provide an overview of a multimodal, clinical profile-based approach to assessment and targeted treatment of athletes with sport-related concussion. We describe a profile-based model for conceptualizing the injury, review relevant modifying factors, discuss components of a comprehensive assessment, and examine targeted treatment approaches. PMID- 30482382 TI - Geographic and socioeconomic predictors of perforated appendicitis: A national Canadian cohort study. AB - BACKGROUND/PURPOSE: Appendiceal perforation significantly impacts the outcomes of pediatric appendicitis. While socioeconomic status affects perforation risk in the United States, these effects should dissipate in a universal healthcare system. The specific spatial patterns associated with perforation have also never been delineated. This study examined the effect of geography and SES on appendiceal perforation in Canada's universal healthcare system. METHODS: Using administrative databases, Canadian children with appendicitis from 2008 to 2015 were identified. Perforation rates were examined based on rurality, distance from treating hospital, and SES. A spatial analysis identified neighborhoods with high perforation rates. Predictors of high perforation clusters were determined using logistic regression. RESULTS: Over the study period, 43,055 children with appendicitis were identified. The overall perforation rate was 31.5%. Rural neighborhoods and those >125 km from the treating hospital were more likely to be within a high perforation cluster (OR 2.39, 95%CI 1.31-4. 02, p = 0.001; and OR 2.55, 95%CI 1.35-4.47, p = 0.001, respectively). Children in high perforation clusters were more likely to suffer complications. SES was not associated with perforation rates. CONCLUSIONS: In this population-based study, appendiceal perforation was not a function of SES, but a spatial phenomenon. These findings highlight disparities in access to surgical care in Canada. LEVEL OF EVIDENCE: Prognosis study, level II. PMID- 30482383 TI - Erosive and crusty plaque located in the ear of a patient with a childhood burn history. PMID- 30482384 TI - Comments on "Optimising treatment of hyperlipidaemia: Quantitative evaluation of UK, USA and European guidelines taking account of both LDL cholesterol levels and cardiovascular disease risk". PMID- 30482385 TI - Clinical and Ultrasound Image of a Cutaneous Fibrolipomatous Hamartoma. PMID- 30482386 TI - Implementation and Operation of an Integrated Quality Management System in Accordance With ISO 9001:2015 in a Dermatology Department. AB - Quality management systems (QMS) are tools that serve to structure, control and improve the usual activities that take place in an organization or service. The ISO 9001:2015 is an internationally recognized standard, which provides the necessary resources to help an organization to improve its performance, based on the principle of plan-do-control-act, in order to obtain continuous improvement. In the field of health, it is an essential tool for the management of the services offered to patients. The ISO quality certification allows to demonstrate compliance, according to established quality standards. The process of implementing a QMS follows several phases that culminate with the completion of an external audit, which once passed, allows obtaining the quality certification ISO 9001:2015. This article describes the steps to follow to obtain this certification in a Dermatology Service. PMID- 30482387 TI - The cyclicality of government health expenditure and its effects on population health. AB - Scholars have raised concerns that cutbacks on government health expenditure (GHE) during recessions may jeopardise population health. The present research investigates the extent to which population health outcomes are affected by responses of GHE to business cycles, i.e., cyclicality of GHE. We estimate GHE cyclicality by regressing detrended GHE on detrended gross domestic product (GDP). Our analysis of data for 1995 through 2014 from 135 developing countries shows that mean cyclicality is 0.61, or that a one percent deviation from the GDP trend is positively correlated with a 0.61 percent deviation from the GHE trend. Further, countries in which GHE is less procyclical appear to have shorter life expectancies and higher adult mortality rates. These results suggest that reducing procyclicality of GHE by protecting GHE in bad times may generate substantial health gains. Importantly, our results show that increasing the weight of social security funds in health budgets, and improving institutional quality, can be critical to breaking the procyclical pattern of GHE. PMID- 30482388 TI - A mixed methods study of challenges in the implementation and use of the surgical safety checklist. AB - BACKGROUND: The surgical safety checklist is an evidence-based global initiative designed to reduce perioperative morbidity and mortality. However, the expounded benefits of the surgical safety checklist have not been realized in naturalistic settings. This may be related to the quality of surgical safety checklists being performed in operating rooms. METHODS: In this explanatory, sequential, mixed methods study, 2 trained observers used a standardized tool to record the compliance and quality of the surgical safety checklist completed during 51 surgeries performed at a pediatric academic hospital. We compared compliance with each phase of the surgical safety checklist, the number of checklist items completed, and professionals initiating the surgical safety checklist across surgical specialties and case urgency levels. Interviews with nurses, anesthesiologists, and surgeons (n = 18) were subsequently conducted to explore and contextualize the findings. RESULTS: Hospital-recorded surgical safety checklist compliance (94%, 100%, and 100% on briefing, time out, and debriefing) was higher than the proportion of checklist items completed in matched cases (26%, 59%, and 42%, respectively). Thematic analysis of the interview data suggests this may result from limited staff "buy in," arising from the "top-down" mandated nature of the surgical safety checklist, the perceived lack of benefit in surgical safety checklist completion, and redundancies with other operating room processes. This has led to the surgical safety checklist becoming "an exercise in box ticking" (ie, compliance is recorded without ensuring quality), thereby obfuscating potential safety benefits. CONCLUSION: These results highlight that compliance data are insufficient for monitoring surgical safety checklist quality. Our study suggests that surgical safety checklist quality may be enhanced through better calibration of the surgical safety checklist with existing procedures and staff expectations through a bottom-up implementation strategy. PMID- 30482389 TI - Label-free based comparative proteomic analysis of whey proteins between different milk yields of Dezhou donkey. AB - Donkey milk, similar to human milk in compositions, has been suggested as the best potential hypoallergenic replacement diet for babies suffering from cow milk protein allergens and a promising nutraceutical for aged people. In this study, label-free mass spectrometry analysis was conducted to quantitatively identify the whey proteins differentially expressed in high-milk-yield samples compared with low-milk-yield samples. A total of 216 whey proteins were identified, and 19 of them showed significant differences in high-milk-yield samples. Of these proteins, 16 were upregulated and 3 were downregulated. Differentially expressed proteins (DEPs) were subjected to intensive bioinformatic analysis. Results revealed that the majority of DEPs participated in protein processing in endoplasmic reticulum, estrogen signaling pathway, progesterone-mediated oocyte maturation, and PI3K-Akt signaling pathway. Functional protein analysis suggested that proteins functioned in binding, catalytic activity, molecular function regulation, structural molecule activity, and transporter activity. Our study was the first to analyze the whey protein profile of different samples of donkey milk and to identify candidate proteins that could be used to explore the molecular mechanism related to the yield traits of Dezhou donkey milk. This study provided the biomarkers for the selection of high-milk-yielding donkey and obtained valuable information for future studies. PMID- 30482390 TI - Stabilization of P/CAF, as a ubiquitin ligase toward MDM2, suppresses mitotic cell death through p53-p21 activation in HCT116 cells with SIRT2 suppression. AB - We previously reported that the suppression of SIRT2, an NAD + -dependent protein deacetylases, induces p53 accumulation via degradation of p300 and the subsequent MDM2 degradation, eventually leading to apoptosis in HeLa cells. The present study identified a novel pathway of p53 accumulation by SIRT2 suppression in HCT116(p53+/+) cells in which SIRT2 suppression led to escape from mitotic cell death caused by spindle assembly checkpoint activation induced by microtubule inhibitors such as nocodazole but not apoptosis or G1 or G2 arrest. We found that SIRT2 interacts with P/CAF, a histone acetyltransferase, which also acts as a ubiquitin ligase against MDM2. SIRT2 suppression led to an increase of P/CAF acetylation and its stabilization followed by a decrease in MDM2 and activation of the p53-p21 pathway. Depression of mitotic cell death in HCT116(p53+/+) cells with SIRT2 suppression was released by suppression of P/CAF or p21. Thus, the P/CAF-MDM2-p53-p21 axis enables the escape from mitotic cell death and confers resistance to nocodazole in HCT116(p53+/+) cells with SIRT2 suppression. As SIRT2 has attracted attention as a potential target for cancer therapeutics for p53 regulation, the present study provides a molecular basis for the efficacy of SIRT2 for future cancer therapy based on p53 regulation. These findings also suggest an undesirable function of the SIRT2 suppression associated with activation of the p53-p21 pathway in the suppression of mitotic cell death caused by spindle assembly checkpoint activation. PMID- 30482391 TI - Influence of glass-ceramic coating on composite zirconia bonding and its characterization. AB - OBJECTIVE: The aims of this study were to compare micro-tensile bond strength and characterize the bond of ceramic-coated versus air-abraded and chemically treated zirconia specimens. METHODS: Eight zirconia blocks were fabricated and assigned to two groups as follows: AA-alumina air-abrasion; and CC-DCMhotbond coating followed by alumina air-abrasion and hydrofluoric acid etching. For each group, two identically pre-treated zirconia blocks were applied G-Multi Primer, cemented together with G-Cem Linkforce cement and cut into 30 stick-shaped specimens (1*1*9mm3). A total of 120 specimens were stored in distilled water for 24h and then assigned to three groups: (i) short-term test, (ii) thermocycling for 5000, and (iii) thermocycling for 10,000 cycles. The specimens were tested in tensile mode. The bond strength results were analyzed using two-way ANOVA, followed by one-way ANOVA and Dunnett T3 (alpha=0.05). Failure mode and surfaces were analyzed with optical microscopy and SEM. The EDS, FTIR, XRD, and FIB-SEM were used for chemical, crystalline phase analyses. RESULTS: The AA groups recorded higher mean bond strength than the CC groups in all aging conditions. Thermocycling did not affect the bond strength of the AA groups, whereas the bond strength of the CC groups decreased significantly after aging. The MDP monomer and silane in G-Multi Primer chemically reacted with mechanically pre-treated AA and CC surfaces via the absorption of P-O and Si-O groups. SIGNIFICANCE: The bond strength of a conventional protocol involving alumina air-abrasion was greater than ceramic coating technique. PMID- 30482392 TI - Apremilast for moderate hidradenitis suppurativa: Results of a randomized controlled trial. AB - BACKGROUND: Effective anti-inflammatory treatments for hidradenitis suppurativa (HS) are limited. OBJECTIVE: To evaluate the efficacy and short-term safety of apremilast in patients with moderate HS. METHODS: A total of 20 patients with moderate HS were randomized in a 3:1 ratio to receive blinded treatment with apremilast, 30 mg twice daily, or placebo for 16 weeks. The primary outcome was the Hidradenitis Suppurativa Clinical Response at week 16. Linear mixed effects modeling (analysis of covariance) was used to assess secondary clinical outcomes between treatment groups. RESULTS: The HS clinical response was met in 8 of 15 patients in the apremilast group (53.3%) and none of 5 patients in the placebo group (0%) (P = .055) at week 16. Moreover, the apremilast-treated patients showed a significantly lower abscess and nodule count (mean difference, -2.6; 95% confidence interval, -6.0 to -0.9; P = .011), NRS for pain (mean difference, 2.7; 95% -4.5 to -0.9; P = .009), and itch (mean difference, -2.8; 95% confidence interval, -5.0 to -0.6; P = .015) over 16 weeks compared with the placebo-treated patients. There was no significant difference in the Dermatology Life Quality Index over time between the 2 treatment groups (mean difference, -3.4; 95% confidence interval, -9.0 to 2.3; P = .230). The most frequently reported adverse events in the apremilast-treated patients were mild-to-moderate headache and gastrointestinal symptoms, which did not result in dropouts. LIMITATIONS: Small number of patients, relatively short study duration. CONCLUSION: Apremilast, at a dose of 30 mg twice daily, demonstrated clinically meaningful efficacy and was generally well tolerated in patients with moderate HS. PMID- 30482393 TI - Laparoscopic transduodenal ampullectomy for ampullary tumor. PMID- 30482394 TI - Influenza vaccination in health-care workers: Auctoritas and potestas. PMID- 30482395 TI - Treatment of migraine in the year 2020. PMID- 30482396 TI - Unstained cell imaging: Morphological insights from coupled fixation and darkfield microscopy. AB - Cell staining techniques are well established in cell biology and associated with a broad range of dedicated dyes; however, they are accompanied by non-negligible costs, preparation time and unavoidable alterations of the sample with foreign molecules. In this context, we point out and propose the use of darkfield microscopy (DM) combined with different fixation protocols (to be used anyway) to enhance the different cell structures and districts as a timesaving and inexpensive support to the techniques that need staining or immuno-staining protocols and products. In a first step, we have analysed the effect of different fixation protocols on DM images for various human cellular lines. The presented imaging study shows that cell morphology actually changes with the fixation protocols that enhance, through contrast and luminosity variations, different shapes and patterns and thus structures of the cells. The different chemical action of various fixations, in fact, modifies the local scattering coefficient, thus affecting in a different way the morphology shown by DM images. As a second step we have compared the observed DM morphologies to those of selective fluorescent staining being therefore able to associate them to specific cell districts (e.g. nucleus, membrane or cytoskeleton). The obtained results indicate that this common microscopy technique can give images with particular cellular structures or districts enhanced more than others depending on the choice of fixation protocol. Therefore Darkfield Microscopy can be considered as a simpler, cheaper and faster method to provide morphological indications, respect to staining techniques, even at low and medium magnifications. PMID- 30482397 TI - Oyster disease in a changing environment: Decrypting the link between pathogen, microbiome and environment. AB - Shifting environmental conditions are known to be important triggers of oyster diseases. The mechanism(s) behind these synergistic effects (interplay between host, environment and pathogen/s) are often not clear, although there is evidence that shifts in environmental conditions can affect oyster immunity, and pathogen growth and virulence. However, the impact of shifting environmental parameters on the oyster microbiome and how this affects oyster health and susceptibility to infectious pathogens remains understudied. In this review, we summarise the major diseases afflicting oysters with a focus on the role of environmental factors that can catalyse or amplify disease outbreaks. We also consider the potential role of the oyster microbiome in buffering or augmenting oyster disease outbreaks and suggest that a deeper understanding of the oyster microbiome, its links to the environment and its effect on oyster health and disease susceptibility, is required to develop new frameworks for the prevention and management of oyster diseases. PMID- 30482398 TI - Response to the requests received concerning the paper "Investigation of potential risk factors associated with Salmonella presence in commercial laying hen farms in Nigeria". PMID- 30482399 TI - Clinical presentation, risk factors and outcome of central nervous system metastasis vs stroke in cancer patients. AB - BACKGROUND AND PURPOSE: Cancer and stroke are the second and third causes of death worldwide; brain metastases (BM) occur in one third of patients with cancer, any neurologic deficit in these population always prompts the clinician to discard metastases for their presence carries a bad outcome. Both might share clinical presentation and differences in their outcome are not entirely known. The aim was to compare risk factors, clinical presentation, and outcome of cancer patients with BM vs stroke. METHODS: A descriptive study with prospectively acquired data from a cancer referral center included patients seen at the neuro oncologic unit from March 2011 to February 2018 with confirmed cancer who had BM or stroke. RESULTS: Six hundred and thirteen BM patients were compared with 268 with stroke and cancer. Demographic factors, cancer type, risk factors, clinical presentation, and outcome are presented. Median overall survival in months for those with any stroke was 15 (95%confidence interval [CI] 8.6-21.4)-5 (95%CI 0.12.4) for hemorrhagic stroke and 22 (95%CI 13.4-30.6) in the ischemic group-and for those with BM 12 (95%CI 10.4-13.6). Hemorrhagic stroke commonly found in stroke patients as well as focal motor weakness, aphasia, and altered mental status. BM was more common in breast and lung cancer with headache, visual complaint, and/or vertigo. CONCLUSION: Survival in cancer patients with BM is not that different than those with stroke, but clinical presentation and risk factors were found different. PMID- 30482400 TI - Acute Epstein-Barr virus hepatitis superimposed on drug induced liver injury causing severe hepatic dysfunction. PMID- 30482401 TI - Blastic plasmacytoid dendritic cell neoplasm with immunoblastoid morphology and MYC rearrangement and overexpression. PMID- 30482402 TI - Abnormal level of consciousness predicts outcomes of patients with anti-NMDA encephalitis. AB - Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is an acute form of encephalitis with an autoimmune etiology. We aimed to study clinical characteristics and treatment outcomes and assess the predictive factors associated with patient outcome. In this retrospective study, patients who presented with cardinal symptoms of anti-NMDA encephalitis and positive anti-NMDA receptor antibody results in their cerebrospinal fluid were included in the study. Thirty-one patients were identified. The median age of onset was 19 years (IQR 15.0-31.0). Females were predominant (61.8%). The main clinical symptoms were neuropsychiatric symptoms (87.1%) followed by abnormal movement (71%), seizures (51.1%), and autonomic instability (41.9%). Eleven patients (35.5%) exhibited decreased levels of consciousness. Abnormal MRI results were found in only 35.5% of the patients. CSF abnormalities usually involved mild pleocytosis. Only 67.7% of serum samples were positive against the anti-NMDAR antibody, whereas 100% of CSF samples were positive. Tumor-related information was only available for 20 patients. Only one case involved an ovarian teratoma. All patients received first-line therapy (intravenous pulse methylprednisolone and plasmapheresis). Three patients were treated with second-line therapy (IV cyclophosphamide). Twenty patients (64.5%) had favorable outcomes in our cohort (mRS 0-2) after a 1-year follow-up. An abnormal level of consciousness was a factor associated with a nonfavorable outcome (OR 15.65, 95% CI 2.30-106.29, p value <0.01). PMID- 30482403 TI - Plasma and CSF miRNA dysregulations in subarachnoid hemorrhage reveal clinical courses and underlying pathways. AB - BACKGROUND: Subarachnoid hemorrhage (SAH) is fatal and detrimental to quality of life. Clinically, options for monitoring are often limited, potentially missing subtle neurological changes especially in low-grade patients. This article reviewed miRNA dysregulation in SAH and analyzed their functional and clinical relevance. METHODS: With adherence to PRISMA guideline, PubMed, EMBASE, GEO and ArrayExpress were searched comprehensively for relevant clinical and animal models. Datasets were analyzed and enriched by experimentally validated targets and multiple databases using R v3.4.2, Ingenuity Pathway Analysis, and miRPath v3.0. RESULTS: Among 1926 search results, 18 studies were screened for full-text assessment. The 8 included studies revealed a marked miRNA dysregulation after SAH. 2 datasets were retrieved. In both serum and CSF, different miRNA profiles were associated with Early Brain Injury, Delayed Cerebral Infarction, vasospasm and prognosis. In CSF, a dramatic restructure of inter-miRNA correlation matrix was observed. Enrichment analysis revealed strong association (1) BBB instability, with adherens, extra-cellular matrix, actin cytoskeleton, integrin, TGF-beta, Wnt/beta-catenin etc; (2) autophagy, with MTORC1, HIF-1, ULK2, and FoxO etc; (3) apoptosis, with PI3K-Akt, p53, and AMPK. We analyzed common miRNAs across SAH and cerebral ischemia. They were related to neuronal differentiation, oxidation stress, apoptosis, angiogenesis, Alzheimer's disease, NMDA-induced calcium influx, excitotoxicity and NO production. CONCLUSIONS: Clinical progression of SAH is associated with different miRNA fingerprints. They carry neuro-pathological relevance and can be a potential biomarker which compliments SAH management. PMID- 30482404 TI - Vascular malformation of the sphenoid and temporal bone: A diagnostic dilemma. AB - We present a rare case of a vascular anomaly of the sphenoid and temporal bones causing an expandable mass of the temporal region with dependent patient positioning and characteristic osseous changes on imaging. Initial diagnosis considerations included multiple myeloma (MM), fibrous dysplasia (FD), Paget's disease, lymphoma, meningoencephalocele (MEC), and vascular malformation (VaM). VaMs of the head and neck are rare and typically arise in the mandible and maxilla. However, this case demonstrates a unique finding of a VaM of the sphenoid and temporal bones with important radiological features to distinguish the diagnosis of vascular anomaly from other etiologies. PMID- 30482405 TI - Application of indocyanine green in the parathyroid detection and protection: Report of 3 cases. AB - BACKGROUND: It was thought that identifying the parathyroid gland during surgery was difficult for surgeons. It may be critical to locate the parathyroid for surgeons during thyroidectomy or parathyroidectomy due to the significant function of the parathyroid in calcium balance. According to recent reports, intrinsic fluorescence of the parathyroid has been found. There is some evidence to suggest that new equipment can detect the intrinsic fluorescence via imaging technology. In this case reports, a newly-invented intraoperative fluorescence imaging system and indocyanine green dye were applied to detect the parathyroid gland and evaluate the vascularization of parathyroid. CASE PRESENTATION: From July 1st to August 8st, 2018, 3 patients underwent total thyroidectomy in Zhuhai People's Hospital. The 3 subjects were recruited into our research. Indocyanine green angiography was performed on all the three participants. By ICG angiography, parathyroid glands were identified and protected. In the 3 patients, postoperative PTH levels were in the normal range. No one of them developed transient hypoparathyroidism. CONCLUSIONS: This study has identified that the fluorescence imaging system applied with indocyanine green is a safe, easy and effective method to protect the parathyroid and predict postoperative parathyroidism. PMID- 30482406 TI - The use of ECMO in ICU. Recommendations of the Spanish Society of Critical Care Medicine and Coronary Units. AB - The use of extracorporeal membrane oxygenation systems has increased significantly in recent years; given this reality, the Spanish Society of Critical Intensive Care Medicine and Coronary Units (SEMICYUC) has decided to draw up a series of recommendations that serve as a framework for the use of this technique in intensive care units. The three most frequent areas of extracorporeal membrane oxygenation systems use in our setting are: as a cardiocirculatory support, as a respiratory support and for the maintenance of the abdominal organs in donors. The SEMICYUC appointed a series of experts belonging to the three working groups involved (Cardiological Intensive Care and CPR, Acute Respiratory Failure and Transplant work group) that, after reviewing the existing literature until March 2018, developed a series of recommendations. These recommendations were posted on the SEMICYUC website to receive suggestions from the intensivists and finally approved by the Scientific Committee of the Society. The recommendations, based on current knowledge, are about which patients may be candidates for the technique, when to start it and the necessary infrastructure conditions of the hospital centers or, the conditions for transfer to centers with experience. Although from a physiopathological point of view, there are clear arguments for the use of extracorporeal membrane oxygenation systems, the current scientific evidence is weak, so studies are needed that define more precisely which patients benefit most from the technique and when they should start. PMID- 30482407 TI - [Impact of the Dependency Act on regional spending on social services]. AB - OBJECTIVE: In this paper we address whether the System for Personal Autonomy and Care of Dependent Persons contributes to increasing the volume of resources of the public social services system (displacement effect) or, on the contrary, whether this development has taken place at the expense of other social services (substitution effect). METHOD: Panel data analysis is used to explain how per capita expenditure on social services evolves in the Spanish Regions under the common regime in the period 2002-2016. RESULTS: The implementation of the Dependency Act is associated with a 14% increase in the level of per capita expenditure on social services. This effect raises 25% when the variable explained is expenditure on current transfers of a social nature. On the other hand, law changes introduced in 2012 and 2013 were associated with a reduction in per capita expenditure on current transfers of around 10%. CONCLUSIONS: This evidence would refute the hypothesis that the System for Personal Autonomy and Care of Dependent Persons had merely a "substitution" effect on autonomous spending on social services. PMID- 30482408 TI - [Heroine, but no Superwoman. Evaluation of a peer-training activity for women with breast cancer]. AB - OBJECTIVE: To evaluate a peer-training intervention for women with breast cancer, from a gender perspective: to discover the results of the intervention and examine in-depth the personal experiences of patients and health professionals participating in the training activity. METHOD: Mixed method multicentre design completed in 2017 in Andalusia (Spain), with a pre and post evaluation questionnaire with 102 patients, measuring life style, limitations, use of health services, communication with professionals and self-management; and content analysis of semi-structured interviews and focus groups with 21 patient-trainers and 5 health professionals, looking at experiences, needs and suggestions for improvement. RESULTS: The patients described a good general health status, with improvements of: diet quality (7 in pre-test to 7.7 in post-test), limitations for daily life (from 1.93 to 1.64 points), self-efficacy (from 6.46 to 7.42 points). Age, civil status and level of education generated statistically significant differences, with more improvement in more vulnerable social profiles. Participants revealed the benefits of the peer-training at a personal, relational, psycho-emotional and socio-cultural level and expressed how the training changed their experiences around identity-construction and gender roles. The improvement dimensions related to organization, evaluation and continuity. CONCLUSIONS: The peer-training intervention is a positive experience for women's physical, relational and emotional health and, from a gender perspective, it represents an opportunity, at both individual and group level, to negotiate and deconstruct gender roles when living with breast cancer. PMID- 30482409 TI - Measuring outcomes following tibial fracture. AB - AIM: The aim of this study was to determine how outcome is measured following adult tibial fracture in the modern era of functional outcome measurement and patient reported outcomes. METHODS: A systematic review of publications since 2009 was performed, looking specifically at acute, adult tibial shaft fractures. Ovid Medline, Embase, PubMed and PsycINFO databases were searched for relevant titles which were then screened by two authors with adjudication where necessary by a third. Relevant articles were reviewed in full and data was extracted concerning the study participants, study design and any measures that were used to quantify the results following fracture. The results were collated and patient reported outcome measures were assessed using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) standards. RESULTS: A total of 943 titles and articles were reviewed, with 117 included for full analysis. A wide range of clinical and radiological "outcomes" were described, along with named clinician- and patient-reported outcome measures. There was considerable heterogeneity and lack of detail in the description of the simplest outcomes, such as union, infection or reoperation. Reported clinician and patient reported outcome measures are variably used. None of the identified patient reported outcome measures have been validated for use following tibial fracture. CONCLUSION: We recommend definition of a core outcome set for use following tibial fracture. This will standardise outcome reporting following these injuries. Furthermore, there is need for a validated patient reported outcome measure to better assess patient important outcomes in this patient group. PMID- 30482410 TI - Inter- and intraobserver reliability and critical analysis of the FFP classification of osteoporotic pelvic ring injuries. AB - INTRODUCTION: The classification and management of osteoporotic pelvic ring injuries (OPRI) remain challenging. The fragility fractures of the pelvis (FFP) classification system proposed by Rommens and Hofmann constitutes the first comprehensive classification system of OPRI and may contribute to a more thorough assessment and grading of these injuries. The reliability of the FFP classification system, however, has not been evaluated yet. The purpose of this study therefore was to determine the inter- and intraobserver reliability of the FFP classification system and to critically analyse its strengths and weaknesses. MATERIALS AND METHODS: One-hundred pelvic CT scans obtained from a consecutive series of patients aged 70 years and older who sustained a low-energy pelvic ring injury were included in this study. Three orthopaedic traumatologists of varying levels of experience (one experienced pelvic surgeon, one consultant, one resident) and one musculoskeletal radiologist independently classified each OPRI according to the FFP classification in two different sessions. Intra- and interobserver reliability were determined using percentage agreement and Cohen's Kappa coefficients. RESULTS: The observed relative distribution of FFP fracture types was comparable to that reported in the original study by Rommens and Hofmann. Overall interobserver reliability for all 100 cases was moderate with Kappa values from 0.42 to 0.59 (mean percentage agreement: 61% (54%-68%)), while intraobserver reliability was substantial with Kappa values from 0.68 to 0.72 (mean percentage agreement: 77% (76%-78%)). Subgroup analysis revealed lowest reliability for the classification of Type IIc, IIIc and IVb injuries (32 cases). Within this subgroup of combined anterior and posterior OPRI involving a complete nondisplaced or displaced (uni- or bilateral) sacral fracture, Kappa values for interobserver reliability ranged from 0.10 to 0.52, while those for intraobserver reliability ranged from 0.29 to 0.66. CONCLUSION: Overall interobserver reliability of the FFP classification system was moderate, while intraobserver reliability was substantial. Despite the acceptable overall reliability, classification of FFP subtypes involving a complete nondisplaced or displaced sacral fracture showed relatively poor reliability. The latter limits the usefulness of the FFP classification for both clinical and research purposes and needs to be addressed in future studies. PMID- 30482412 TI - Exploring the roles of motivation and cognition in label-usage using a combined eye-tracking and retrospective think aloud approach. AB - This study investigates the factors affecting consumers' motivation to engage with food product labelling in the new product context. Using yogurt as a case food, due to its positive association with health, enjoyment and convenience, this study uses eye-tracking experiments, a retrospective think-aloud protocol and semi-structured interviews, to bring to light the conscious and subconscious mechanisms associated with label usage, in order to explore the cognitive processes underlying usage of labels for new product offerings and situate these within the participant's personal context. Key information usage and decision making strategies and the factors which give rise to these are identified. Findings suggest that consumer involvement is being shaped by the perceived importance of negative consequences (i.e. risk importance) and is further reflected in the label usage strategies identified, which align to the negotiability and specificity of health-related goals. Integration of eye tracking, retrospective think-aloud and interview data reveal that although labelling cues promoted non-volitional attention through design features, in the absence of 'personal motivational relevance', information attended to was discounted from the evaluation process, confirming the importance of needs-based information provision. PMID- 30482411 TI - Outcomes and predictors of mortality following periprosthethic proximal femoral fractures. AB - BACKGROUND: Periprosthetic fractures are a well-documented, serious complication of joint arthroplasty, occurring in up to 11% of hip replacements. We examined periprosthetic femoral fractures over an 8 year period to determine the demographics, fracture pattern and management options and associated outcomes. Furthermore, we sought to determine which comorbidities resulted in increased risk of 12 month mortality after periprosthetic fractures about hip replacements Methods: A retrospective review of a prospective fracture database was conducted for the years 2007-2015. The Fracture Outcomes Research Database (FORD) was interrogated for patients aged >60 years, admitted with periprosthetic hip fracture. Radiographic and Electronic Clinical Record review was performed to classify fractures, record treatments, comorbidies and 12 month mortality. A multivariate analysis was performed to determine comorbidities that significantly increased the risk of 12 month mortality. RESULTS: A total of 189 patients were identified. The majority were Vancouver B1 fractures (61.9%); the operations were primarily cable plating (75.1%), with a smaller number of revision arthroplasties (21.2%) and only three proximal femoral replacement (1.6%). Four patients (2.1%) died before surgery. Only 27.3% returned to their usual residence post-discharge. Overall 30-day mortality was 2.1%, and one-year mortality was 11.6%. Patients who died tended to be older. In the multivariate analysis, ASA grade III/IV and active neoplasia were significant contributors to 12 month mortality. CONCLUSION(S): Our 12 month mortality (11.6%) is at the lower end of existing reported literature, and serves as a benchmark for UK practice. In the multivariate analysis, only ASA grade III/IV and an active neoplastic process were significantly associated with increased risk of mortality. Whilst large, multicenter trials, utilizing standardized treatment techniques are required to fully assess risk factors for 12-month mortality, it appears that those at significant risk are elderly, frail individuals with an active malignancy. PMID- 30482413 TI - Biopiracy and the right to self-determination of indigenous peoples. AB - BACKGROUND: Since over thirty years, I work on the unclear legal situation of in which indigenous peoples find themselves today in the beginning mainly in the USA and later also in Canada, Australia and New Zealand. The status of indigenous people and native nations is characterized as a mixture of national and international law. Hypothesis/Purpose: To clarify the status of indigenous people it is necessary to analyze and interpret carefully hundreds of old treaties, international declarations and covenants, national statutes and jurisprudence, especially the old leading decisions of the US-Supreme Court. Such an analysis and interpretation should prove that indigenous people have the defensive right of self determination. RESULTS: The study outlines the old decisions of the US Supreme Court with its inherent contradictions which highly influenced the status of indigenous people in all other countries until now. It clarifies the important new developments in international law especially the non binding Declaration on the Rights of Indigenous Peoples and its effects on the interpretation of international and national law in regard to biopiracy. For this purpose it is necessary to use the methods of judgmental comparative law, historical and teleological interpretation. CONCLUSION: By expressly stating that indigenous peoples have a right to self-determination, the Declaration on the Rights of Indigenous Peoples of 2007 complements the protection stipulated in the Charter and the Covenants of 1966. Although the declaration itself is not legally binding as it is a resolution of the UN General Assembly, it can serve as a blueprint to show the rights that indigenous peoples can derive from international law as well as rights which should ideally be granted to them by the states even though they are not yet binding customary or treaty law. Self-determination means exactly that, it is up to the bearers of the right to decide how they want to utilize this right and then work together with the state in which they live in defining a joint framework. PMID- 30482414 TI - Point-of-care endoscopic optical coherence tomography detects changes in mucosal thickness in ARDS due to smoke inhalation and burns. AB - BACKGROUND: The prevalence of acute respiratory distress syndrome (ARDS) in mechanically ventilated burn patients is 33%, with mortality varying from 11-46% depending on ARDS severity. Despite the new Berlin definition for ARDS, prompt bedside diagnosis is lacking. We developed and tested a bedside technique of fiberoptic-bronchoscopy-based optical coherence tomography (OCT) measurement of airway mucosal thickness (MT) for diagnosis of ARDS following smoke inhalation injury (SII) and burns. METHODS: 16 female Yorkshire pigs received SII and 40% thermal burns. OCT MT and PaO2-to-FiO2 ratio (PFR) measurements were taken at baseline, after injury, and at 24, 48, and 72h after injury. RESULTS: Injury led to thickening of MT which was sustained in animals that developed ARDS. Significant correlations were found between MT, PFR, peak inspiratory pressure (PIP), and total infused fluid volume. CONCLUSIONS: OCT is a useful tool to quantify MT changes in the airway following SII and burns. OCT may be effective as a diagnostic tool in the early stages of SII-induced ARDS and should be tested in humans. PMID- 30482415 TI - Tobacco Smoking Independently Predicts Lower Patient-Reported Outcomes: New Insights on a Forgotten Epidemic. AB - BACKGROUND: Although smoking is a well-accepted risk factor for surgical complications, the effect of smoking on patient-reported outcomes (PROs) has not been previously investigated. Prompted by an increasingly value-conscious healthcare environment, the purpose of this study is to investigate the association between smoking and PROs in total joint arthroplasty (TJA). METHODS: A retrospective review of 713 primary total hip and knee replacements was performed. Two cohorts were compared: (1) current smokers and (2) previous/never smokers at the time of TJA. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Short Form-12 Physical Composite Summary (SF 12 PCS) and Short Form-12 Mental Composite Summary were assessed preoperatively and again at 6 and 12 months postoperatively. The primary outcomes were the net changes and absolute outcome scores at final follow-up. Postoperative patient satisfaction was also assessed as a secondary outcome. Linear mixed-effects regression analysis was performed. RESULTS: There were significant demographic and preoperative health disparities as measured by PROs among smokers. After adjusting for baseline differences, smokers achieved significantly lower improvements in WOMAC (P = .002) and SF-12 PCS (P = .03) compared to nonsmokers. For each unit increase in packs per day smoked, the WOMAC scores increased (worsened) by 7.7 points (P = .003) and SF-12 PCS decreased by 4.8 points (P = .001). At final follow up, nonsmokers had significantly better absolute scores for all outcomes (except for mental health) and were more likely to be satisfied with surgery (89% vs 82%, P = .052). CONCLUSION: Tobacco smoking is an independent predictor for lower PROs after TJA and this relationship is dose dependent. The negative impact of smoking does not appear to be related to impaired psychological health. As we transition to value-based care delivery models, this study provides further evidence that smoking cessation should be strongly recommended as a modifiable risk factor before embarking on elective TJA. Studies are still needed to define the optimal window for smoking cessation. PMID- 30482416 TI - Intussusception as the main manifestation of Schonlein-Henoch purpura in an adult patient. PMID- 30482417 TI - Malformations, choristomas, and hamartomas of the gastrointestinal tract and pancreas. AB - Congenital and hamartomatous lesions of the gastrointestinal tract cause diagnostic challenges for surgical pathologists. Many of these are merely histologic curiosities, whereas others have substantial clinical implications because they herald cancer syndromes or associated anomalies. Although a comprehensive discussion of all developmental abnormalities that can occur in the gastrointestinal tract is beyond the scope of a single manuscript, some entities are more likely to be encountered by surgical pathologists, have important clinical consequences, or pose diagnostic difficulties. The purpose of this review is to discuss the more common malformations and choristomas, as well as hamartomatous lesions that may be clinically important due to their risk for cancer development, frequent associations with heritable cancer syndromes and other anomalies, or potential to simulate other entities. PMID- 30482418 TI - Hamartoma, choristomas and malformation of the spleen and lymph node. PMID- 30482419 TI - Hypothesis: Presymptomatic treatment of Sturge-Weber Syndrome With Aspirin and Antiepileptic Drugs May Delay Seizure Onset. PMID- 30482420 TI - Single- Versus Double-Unit Umbilical Cord Blood Transplantation for Hematologic Diseases: A Systematic Review. AB - Controversial results exist regarding the clinical benefits of single- vs double unit umbilical cord blood transplantation (UCBT) in patients with hematologic diseases. A systematic review was conducted to evaluate this issue. The PubMed, Embase, and Cochrane Library databases were searched up to May 2018. A total of 25 studies including 6571 recipients were identified. Although double-unit UCB contained higher doses of total nucleated cells and CD34+ cells, it offered no advantages over single-unit UCB in terms of hematologic recovery, including the rate and speed of neutrophil and platelet engraftment. Double-unit UCBT was associated with higher incidences of grades II-IV acute and extensive chronic graft-vs-host disease, accompanied by a lower relapse incidence, which may be attributed to a graft-vs-graft effect induced by double-unit UCB. However, transplant-related mortality, disease-free survival, and overall survival were comparable between single- and double-unit UCBT. Although double-unit UCBT confers no clinical advantages over single-unit UCBT, certain patients, such as those at high risk of relapse, might benefit from double-unit UCBT, a possibility that needs to be clarified in future randomized trials. PMID- 30482421 TI - Prostaglandin E2 promotes Pam3CSK4-induced inflammation in endometrial epithelial cells of cattle. AB - Bacterial contamination often impairs uterine function in cattle leading to uterine diseases such as endometritis. Inflammatory responses to bacterial infections in the uterus of cattle are generated through pattern recognition receptors, including Toll-like receptor 2 (TLR2), which is responsible for Pam3CSK4 recognition. This cellular response induces inflammatory responses through stimulation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-kappaB signaling activation, stimulating the expression of inflammatory mediators. Prostaglandin (PG) E2 has important actions in bacterial endometritis, although details through which these mechanisms regulate Pam3CSK4 induced inflammatory responses in cattle endometrial epithelial cells (bEECs) remain unclear. In the present study there was examination of the actions of exogenous PGE2 in Pam3CSK4-induced inflammatory responses. The bEECs pre-treated with exogenous PGE2 prior to Pam3CSK4 treatment had an augmented Pam3CSK4 stimulated phosphorylation of protein kinase A (PKA), extracellular signal regulated kinase (ERK), and IkappaB-alpha; stimulation of TLR2, cyclooxygenase-2, and interleukin-6 functions; and suppression of the activation of PGE2 receptor 4. Thus, Pam3CSK4-induced inflammatory responses through TLR2 signaling in bEECs were enhanced by exogenous PGE2 pre-treatment. PMID- 30482422 TI - Superdiluted atropine at 0.01% reduces progression of myopia in children and adolescents. A 5-year study of safety and effectiveness. PMID- 30482423 TI - Evaluation of the angle of the anterior chamber using ultrasound biomicroscopy, gonioscopy and a Van Herick examination. AB - OBJECTIVE: To compare the measurement of the angle of the anterior chamber using ultrasound biomicroscopy (UBM), gonioscopy and the Van Herick examination. METHODS: An observational comparative study was carried out between 3different methods for the estimation of the iridocorneal angle. A total of 30 subjects with open and closed angles were evaluated using UBM, gonioscopy and Van Herick. In the UBM and gonioscopy assessment all the quadrants were included in the analysis, and in the Van Herick examination the nasal and temporal quadrant were also analysed. All the examinations included the assessment of both eyes under photo-optical and scotopic illumination conditions. These findings were compared with the kappa concordance test. RESULTS: There was no statistically significant difference between the 3methods in the evaluation of the state of the iridocorneal angle. The consistency between UBM and gonioscopy was better (kappa 0.93) in relation to the estimation of the angle with Van Herick (kappa 0.83). CONCLUSIONS: The UBM, gonioscopy and Van Herick examinations have comparable results, although gonioscopy in the first instance would be indicated as a routine test for identification of angular closure. PMID- 30482424 TI - Correct determination of glycemia in the diagnosis and management of diabetes: Recommendations for the optimization of the pre-analytical phase. PMID- 30482425 TI - Letter to the editor regarding an update of the "Evaluation of relative criteria for single-incision laparoscopic cholecystectomy". PMID- 30482426 TI - Modified complex open cholecystectomy reduces the risk of bile duct injury: A surgeon's experience. PMID- 30482427 TI - Synergistic effects of melatonin and distinct spectral lights for enhanced production of anti-cancerous compounds in callus cultures of Fagonia indica. AB - Fagonia indica is one of the commercially vital medicinal plant species. It is well-known for biosynthesis of anticancer phenolics and flavonoids metabolites. The plant has been exploited for in vitro studies and production of vital phytochemicals, however, the synergistic effects of melatonin and lights remains to be investigated. In current study, we have evaluated the synergistic effects of melatonin and different light emitting diodes (LEDs) in callus cultures of F. indica. Both, light and melatonin play vital role in physiological and biochemical processes of plant cell. The highest Fresh weight (FW: 320 g/L) and Dry weight (DW: 20 g/L) was recorded in cultures under white LEDs. Optimum total phenolics content (11.3 MUg GAE/mg), total flavonoids content (4.02 MUg QAE/mg) and Free radical scavenging activity (97%) was found in cultures grown under white LED and melatonin. Furthermore, cultures maintained under white light were also found with highest levels of phenolic and flavonoids production (total phenolic production; 226.9 MUg GAE/mg, Total flavonoid production; 81 MUg QAE/mg) than other LED-grown cultures. However, the antioxidant enzymes; Superoxide dismutase (SOD: 0.53 nM/min/mg FW) and Peroxidase (POD:1.18 nM/min/mg FW) were found optimum in cultures grown under blue LED. The HPLC data showed that enhanced total production of metabolites was recorded in cultures under white LED (6.765 MUg/mg DW) than other lights and control. The findings of this study comprehend the role of melatonin and influence of light quality on biomass accumulation and production of phytochemicals in callus cultures of F. indica. PMID- 30482428 TI - Higher concentration of selenium in placental tissues is associated with reduced risk for orofacial clefts. AB - BACKGROUND & AIMS: Growing evidence suggests that essential trace element imbalance during pregnancy may contribute to fetal malformations, but the role of essential trace elements in the occurrence of orofacial clefts (OFCs) is unknown. We aimed to examine the association between concentrations of zinc (Zn), manganese (Mn), selenium (Se), cobalt (Co), molybdenum (Mo), and nickel (Ni) in placental tissues and the risk for OFCs in offspring in a rural population in northern China with a high prevalence of OFCs. METHODS: The case-control study subjects were 103 OFC infants and 206 non-malformed infants. The concentrations of selected trace elements in placental tissues were determined using inductively coupled plasma-mass spectrometry. Sociodemographic information was collected from the mothers through face-to-face interviews using a structured questionnaire. The risk for OFCs in association with higher concentrations of the trace elements was estimated using the odds ratio (OR) with its 95% confidence interval (95% CI). RESULTS: The placental median concentrations of Se and Ni were significantly lower, but those of Mo were significantly higher in OFC cases than in controls (all P < 0.05). A Se concentration above the median of all subjects was associated with a 58% reduced risk for OFCs (adjusted OR 0.42, 95% CI 0.23, 0.77) after adjusting for potential confounding factors. The risk for OFCs decreased with increases in placental Se concentrations, with adjusted ORs of 0.45 (95% CI 0.22, 0.92) for the second tertile and 0.22 (95% CI 0.10, 0.49) for the top tertile of Se concentration, with the lowest tertile concentration as the referent (Ptrend < 0.001). No association was observed between placental Zn, Mn, Co, Mo, or Ni concentration and risk for OFC. CONCLUSIONS: The concentration of Se in placental tissues was dose-dependently associated with decreased risk for OFCs in offspring. This finding suggests that maternal Se intake during pregnancy may protect against OFCs in offspring. PMID- 30482429 TI - Evaluating the reliability of specific and global methods to assess the phenolic content of virgin olive oil: Do they drive to equivalent results? AB - Despite the huge number of different published methodologies, there is an open debate regarding which one is the most convenient analytical strategy for the determination of phenolic compounds from virgin olive oils. Diverse technical issues together with the disparity of criteria regarding results expression cause a lot of confusion. Herewith, a systematic comparison between specific (a powerful and LC-MS method) and global methodologies (the Folin-Ciocalteau (FC) colorimetric assay, the International Olive Council (IOC) method and hydrolysis plus HPLC-DAD) has been carried out. Thus, these strategies have been applied to the analysis of 50 extra virgin olive oils (covering all the possible quantitative ranges of these substances). This is the first time in which the individual LC-MS quantification of so many phenolic substances is included in this kind of comprehensive comparison. The outcomes of all the strategies have been thoroughly confronted and their equivalence (or divergence) has been carefully evaluated, establishing possible correspondence factors. The LC-MS individual determination with the pure standard of every analyte represented the ideal situation; when only the commercially available standards were used, a drastic change was observed in the absolute concentrations of oleuropein derivatives (in terms of hydroxytyrosol). Total phenolic content (summing individual levels) proved to be higher (1.9-3.0 times when data was expressed in mg/kg) than the values given by the three non-specific methods (with R2 from 0.84 to 0.90). In any case, the IOC method, the FC assay and the hydrolysis approach could be considered as feasible strategies when a global value is pursued. Good correlations between their results were found (R2 > 0.89), with the following equivalence factors: FC(mg caffeic acid/kg) ~ 0.60 IOC(mg TY/kg); IOC(mg TY/kg) ~ 1.27 Sum acid hydrolysis(mg TY+HTY/kg); FC(mg HTY/kg) ~ 1.04 Sum acid hydrolysis(mg TY+HTY/kg). PMID- 30482430 TI - Determination of potential childhood asthma biomarkers using a powerful methodology based on microextraction by packed sorbent combined with ultra-high pressure liquid chromatography. Eicosanoids as case study. AB - Leukotrienes and prostaglandins are arachidonic acid bioactive derived eicosanoids and key mediators of bronchial inflammation and response modulation in the airways contributing to the pathophysiology of asthma. An easy-to-use ultra-high pressure liquid chromatography (UHPLC)-based strategy was developed to characterize biomarkers of lipid peroxidation: leukotrienes E (LTE4) and B4 (LTB4) and 11beta-prostaglandin F2alpha (11betaPGF2alpha), present in urine of asthmatic patients (N = 27) and healthy individuals (N = 17). A semi-automatic eVol(r)-microextraction by packed sorbent (MEPS) was used to isolate the target analytes. Several experimental parameters with influence on the extraction efficiency and on the chromatographic resolution, were evaluated and optimized. The method was fully validated under optimal extraction (R-AX sorbent, 3 conditioning-equilibration cycles with 250 MUL of ACN-water at 0.1% FA, 10 extract-discard cycles of 250 MUL of sample at a pH of 5.1, elution with 2 times 50 MUL of MeOH and concentration of the eluate until half of its volume) and chromatographic conditions (14-min analysis at a flow rate of 300 MUL min-1 in an UHPLC-PDA equipped with a BEH C18 column), according to IUPAC guidelines. The findings indicated good recoveries (>95%) in addition to excellent extraction efficiency (>95%) at three concentration levels (low mid and high) with precision (RSDs) less than 11%. The lack-of-fit test, goodness-of-fit test and Mandel's fitting test, revealed good linearity within the concentration range. Good selectivity and sensitivity were achieved with a limits of detection ranging from 0.04 MUg L-1 for LTB4 to 1.12 MUg L-1 for 11betaPGF2alpha, and limits of quantification from 0.10 MUg L-1 for the LTB4 to 2.11 MUg L-1 for 11betaPGF2alpha. The successful application of the fully validated method shows that, on average, the asthmatic patients had significantly higher concentrations of 11betaPGF2alpha (112.96 MUg L-1vs 62.56 MUg L-1 in normal controls), LTE4 (1.27 MUg L-1vs 0.89 MUg L-1 in normal controls), and LTB4 (1.39 MUg L-1vs 0.76 MUg L-1 in normal controls). The results suggest the potential of the target eicosanoids on asthma diagnosis, however, a larger and more extensive study will be necessary to confirm the data obtained and to guarantee a greater robustness to the approach. PMID- 30482431 TI - Identification and quantification of oxo-bile acids in human faeces with liquid chromatography-mass spectrometry: A potent tool for human gut acidic sterolbiome studies. AB - Bile acids (BAs) are endogenous steroids involved in the transport of lipids in bile, acting also as molecular signaling hormones. Primary BAs synthesized in the liver undergo several metabolic pathways in the intestine by gut microbiota to produce secondary BAs. Together with secondary BAs, other metabolites have been recovered from human faeces, including many oxo-BA analogues produced in the colon through oxidation of BA hydroxy groups. However, the complete oxo-BA characterization in biospecimens (particularly intestinal content and faeces) has not been reported yet, hampering the assessment of their potential physiological role. Herein, we have developed and validated a new RP-HPLC-ESI-MS/MS method in negative ionization mode for the simultaneous analysis of 21 oxo-BAs and their 7 metabolic BAs precursors in human faeces. The elution was performed in gradient mode and 28 compounds, including primary, secondary BAs, and their oxo derivatives, were separated within 50 min at 40 degrees C column temperature. The method is accurate (bias% <13%), precise (CV% <10%), with limits of quantification (LOQ <30 ng/mLextract samples), similar for all the studied compounds. The matrix effect does not significantly affect the analysis accuracy, allowing the use of standard solutions for the quantifications, without matrix matched protocols. Thanks to the high detectability and the relatively high concentration of oxo-BAs (about MUg/gwet faeces), the method does not require a pre-analytical clean-up step. This method was used to identify and quantify oxo BAs in human faecal samples from healthy subjects, serving as a proof of concept for application in patients with hepatobiliary disease and bacteria overgrowth. PMID- 30482432 TI - Accurate determination of melting Point of industrial grade alkyl ketene dimer wax by a simple and automated headspace gas chromatographic technique. AB - This study demonstrated a novel method for determining the melting point (MP) of industrial grade alkyl ketene dimer (AKD) wax by an automated headspace gas chromatographic (HS-GC) technique, in which methanol was used as the tracer. It was based on measuring the GC signal of methanol released from an aqueous solution during the temperature increasing. When the temperature of AKD MP reached, the AKD granules floated on the surface aqueous solution was liquidized and completely isolated the methanol transfer from the solution to the headspace. Thus, a transition point, corresponding to the MP of AKD wax, was observed when plotting the GC signal of methanol vs. the temperature. The results showed that the method has a good measurement precision (RSD < 0.68%) and accuracy (the relative differences were < 7.16%, compared to a reference method). The present method is simple, accurate and particularly suitable to be used in the batch sample testing. This new measurement concept can be also adopted to many related applications. PMID- 30482433 TI - Regarding "Diabetes-Related Factors and Abdominal Aortic Aneurysm Events: The Atherosclerotic Risk in Communities Study". PMID- 30482434 TI - Assessing trends in urinary diversion after radical cystectomy for bladder cancer in the United States. AB - OBJECTIVES: We assessed recent trends in both urinary diversion after radical cystectomy for bladder cancer in the United States and patient- and hospital related characteristics. We also identified variables associated with undergoing continent diversion. MATERIALS AND METHODS: We queried the National Cancer Database and identified 27,170 patients who underwent radical cystectomy with urinary diversion from 2004 to 2013. Patient demographics, socioeconomic variables, and hospital-related factors were compared between incontinent and continent diversion and trended over time. Multivariable logistic regression was used to identify variables associated with undergoing continent diversion. RESULTS: Overall, 23,224 (85.5%) and 3,946 (14.5%) patients underwent incontinent and continent diversion, respectively. Continent diversion declined from 17.2% in 2004 to 2006 to 12.1% in 2010 to 2013 (P < 0.01). When analyzing high-volume facilities, those performing >=75% minimally invasive radical cystectomy had fewer continent diversions (10.2%) compared to centers with higher rate of open approach (19.7%), P < 0.01. Higher income, facility located in the West, academic programs, high-volume facilities, and patients traveling >60 miles for care were significantly associated with undergoing continent diversion. Rate of continent diversion has declined in most patient- and hospital-related subgroups. Compared to 2004 to 2006, patients in 2010 to 2013 were more likely to be older, have more comorbidities, and be operated on at a high-volume academic facility. CONCLUSION: The rate of continent diversion has declined to 12.1% in the United States. Hospital volume and type, patient income, distance traveled for care, and geography are significantly associated with undergoing continent diversion. Even among high-volume and academic centers, the rate of continent diversion is declining. PMID- 30482435 TI - Positron emission tomography costs less to patients than conventional screening for malignancy in dermatomyositis. AB - BACKGROUND: Dermatomyositis (DM) is associated with malignancy and interstitial lung disease. Many malignancies associated with DM occur in organs not routinely screened by national guidelines; thus, best screening practices are still debated. Positron emission tomography (PET) has been suggested as a single study alternative to more complex screening panels and may also be valuable in detecting interstitial lung disease progression. Criticisms of PET screening exams have focused on cost and radiation exposure. OBJECTIVE: To compare the cost of PET and its variants to conventional malignancy screening panels, and to review concerns regarding radiation exposure in PET. METHODS: Four variants of PET and PET-CT were included in the study. The conventional screening panel was defined as CT of the abdomen and pelvis without contrast, CT of the thorax without contrast, CEA, CA 19.9, PSA (men), mammography (women), transvaginal ultrasound (women), cytopathology (women), and CA 125 (women). The MarketScan(r) Commercial Claims and Encounters database, a collection of private insurance claims data from 53 million Americans, was queried for every instance of each test from 2005 to 2014 and the mean inflation-adjusted cost of each was recorded. The mean total cost to insurance companies and the mean out-of-pocket costs to patients for PET variants were compared to the costs for conventional panels. Additionally, the cost of pulmonary function tests (PFT) from the same period was evaluated. RESULTS: From 2005-2014, the mean inflation-adjusted costs of PET have trended downward, but the mean cost of PET-CT have trended upward. The mean total cost to insurance companies for PET-CT whole body was $730.70 and $537.62 greater than the cost of conventional panels for men and women, respectively. The out-of pocket patient costs for PET-CT whole body was $109.82 and $111.33 less than the cost of conventional panels for men and women, respectively. The mean total cost of PFT was $205.02. CONCLUSIONS: The cost of PET-CT whole body was greater than conventional panels for insurance companies, but patient out-of-pocket costs were lower. PET-CT may also have added value in detecting and monitoring interstitial lung disease progression in DM patients. More data are needed on the efficacy of PET-CT in detecting malignancy in DM patients; however, the cost difference is less than expected, suggesting the single scan could be a reasonable alternative to the conventional screening panel in some patients. PMID- 30482436 TI - Lipid-modulate activity of Cichorium glandulosum Boiss.et Huet polysaccharide in nonalcoholic fatty liver disease larval zebrafish model. AB - Nonalcoholic fatty liver disease (NAFLD)1 is the most common chronic liver disease worldwide. Cichorium glandulosum Boiss.et Huet (CG) is a common traditional Uighur medicine, and it has been widely used as active therapy on various hepatic diseases. Recently, lipid-lowering effect has been revealed on CG. Polysaccharides are principal component of CG which could be the possible lipid-lowering compound in CG. In this study, extraction and purification of CG polysaccharides (CGP) was performed, and the lipid regulation effect of CGP was investigated on NAFLD zebrafish model. The results showed that CGP significantly decreased the levels of TC, TG, and decreased the mRNA expression of srebf-1, and fas, increased the expression of pparab. The findings suggest that the lipid lowering effects of CGP mainly depend on facilitation of lipolysis (mainly beta oxidation) or inhibition of lipogenesis. Furthermore, CGP could prevent and causes the regression of steatosis in NAFLD via its lipid metabolism regulation effect. PMID- 30482437 TI - Ultrasonic nano-emulsification - A review. AB - The emulsions with nano-sized dispersed phase is called nanoemulsions having a wide variety of applications ranging from food, dairy, pharmaceutics to paint and oil industries. As one of the high energy consumer methods, ultrasonic emulsification (UE) are being utilized in many processes providing unique benefits and advantages. In the present review, ultrasonic nano-emulsification is critically reviewed and assessed by focusing on the main parameters such pre emulsion processes, multi-frequency or multi-step irradiations and also surfactant-free parameters. Furthermore, categorizing aposematic data of experimental researches such as frequency, irradiation power and time, oil phase and surfactant concentration and also droplet size and stability duration are analyzed and conceded in tables being beneficial to indicate uncovered fields. It is believed that the UE with optimized parameters and stimulated conditions is a developing method with various advantages. PMID- 30482438 TI - High-sensitivity detection of nitroaromatic compounds (NACs) by the pillared layer metal-organic framework synthesized via ultrasonic method. AB - Nanorods of zinc(II) based metal-organic framework (MOF) were prepared via ultrasonic method without any surfactants at room temperature and atmospheric pressure. Control of particle size and morphology was enhanced in this synthesis method. Nanorods of pillared-layer metal organic framework, [Zn2(ubl)2(bipy)].DMF (TMU-18), where ubl (urea-based ligand) is 4,4'-carbonylbis(azanediyl)dibenzoic acid, 4,4'-Bipyridine (bipy) DMF = N,N-dimethyl formamide), was synthesized under ultrasound irradiation in different concentrations of initial precursor. The nano structure and morphology of the synthesized MOF were characterized by Field Emission Scanning Electron Microscopy (FE-SEM), powder X-ray diffraction, elemental analysis and FT-IR spectroscopy. Moreover, Fluorescence emissions of nanorods have been studied. Luminescent MOFs (LMOFs) have shown great potential as sensor for various nitro explosives by modulating the luminescence behavior in presence of nitro explosives. Urea-functionalized MOF shows high selectivity for sensing of the nitro explosive 2,4,6-trinitrophenol (TNP) even in the presence of other nitroaromatic compounds in methanol solution. Fluorescence intensity decreased with increasing contents of nitroaromatics in organic solution due to fluorescence quenching effect. The ultrasound method has some advantages such as short duration time of reaction, no need to high temperatures and pressures for synthesis nano-materials and low costs in comparison to other methods. Considering these advantages we used ultrasonic method to produce these nanorods which show high sensitivity in detecting nitroaromatics. PMID- 30482439 TI - Long term results of the revisited Meary closing wedge tarsectomy for the treatment of the fixed cavo-varus foot in adolescent with Charcot-Marie-Tooth disease. AB - BACKGROUND: Various techniques have been proposed for the treatment of cavovarus feet (CVF). The aim of this study was to report outcomes of the revisited Meary's dorsal closing wedge tarsectomy for fixed CVF secondary to Charcot-Marie-Tooth (CMT) disease. METHODS: All CVF operated on between 1977 and 2011 were included. The tarsectomy design was modified from its original description and systemically combined with a plantar fascia release, a Dwyer osteotomy and a proximal extension osteotomy of the 1st metatarsal bone if required. Outcomes were assessed by 2 functional scores and radiographically. RESULTS: Among the 26 feet (20 patients), the Wicart and Seringe score was very good or good, fair and poor in respectively 58%, 23% and 19% of the feet. Hindfoot and midfoot AOFASs were of 95.5 and 75 respectively. All radiographic measures were significantly improved. CONCLUSIONS: This complete revisited procedure is an efficient and safe surgical technique for the treatment of the CMT disease CVF. LEVEL OF EVIDENCE: Level IV. PMID- 30482440 TI - Adding deltoid ligament repair in ankle fracture treatment: Is it necessary? A systematic review. AB - BACKGROUND: Deltoid ligament injuries are typically caused by supination-external rotation or pronation injury. Numerous ligament reconstruction techniques have been proposed; however, clear indications for operative repair have not yet been well established in the literature. METHODS: We reviewed primary research articles comparing ORIF treatment for ankle fracture with versus without deltoid ligament repair. RESULTS: Five studies were identified with a total of 281 patients. 137 patients underwent ORIF with deltoid repair, while 144 patients underwent ORIF without deltoid ligament repair. Clinical, radiographic, and functional outcomes, as well as complications were considered. The average follow up was 31 months (range, 5-120). CONCLUSIONS: Current literature does not provide clear indication for repair of the deltoid ligament at the time of ankle fracture repair. There may be some advantages of adding deltoid ligament repair for patients with high fibular fractures or in patients with concomitant syndesmotic fixation. LEVEL OF CLINICAL EVIDENCE: III. PMID- 30482441 TI - Finite element analysis of knee and ankle joint during gait based on motion analysis. AB - Contact pressures in the articular cartilage during gait affect injuries and the degenerative arthritis of knee and ankle joints. However, only contact forces at the knee and ankle joints during gait can be estimated by using a rigid body dynamic model. The contact pressure distribution can be obtained quantitatively for a static posture by using finite element (FE) analysis in most cases. The purpose of this study is to develop a new method to obtain the contact pressure distribution at the knee and ankle joints during gait by integrating FE analysis with rigid body dynamic analysis. In this method, a reference FE model of the lower extremity is constructed first and is then transformed to each stance phase of the gait obtained from dynamic analysis by using homogeneous transformation. The muscle forces and ground reaction force (GRF) during gait obtained from the dynamic analysis were used as loading conditions for FE analysis. Finally, the contact pressure distribution at the tibia plateau cartilage and talus cartilage were estimated at the 1st peak, mid-stance, and the 2nd peak at the same time. The present method can provide the contact pressure distribution at the knee and ankle joints over the entire gait. PMID- 30482442 TI - Coronary atherosclerosis in apparently healthy master athletes discovered during pre-PARTECIPATION screening. Role of coronary CT angiography (CCTA). AB - BACKGROUND: Pre-participation screening (PPS) of athletes aged over 35 years (master athletes, MA) is a major concern in Sports Cardiology. In this population, sports-related sudden cardiac death is rare but usually due to coronary atherosclerosis (CA). Coronary CT Angiography (CCTA) has changed the approach to diagnosis/management of CA, but its role in this context still needs to be assessed. METHODS AND RESULTS: We retrospectively examined 167 MA who underwent CCTA in our hospital since 2006, analyzing symptoms, stress-test ECG, cardiovascular risk profiles (SCORE) and CCTA findings. Among the whole enrolled population, 153 (91.6%) MA underwent CCTA for equivocal/positive stress-test ECG with/without symptoms, 13 (7.8%) just for clinical symptoms, 1 (0.6%) for the family history. The CCTA showed the presence of CA in 69 MA (41.3%), congenital coronary anomalies (anomalous origin or deep myocardial bridge) in 8 (4.8%), both in 7 (4.2%). A negative CCTA was observed in 83 MA (49.7%). The risk-SCORE (age, hypertension, hypercholesterolemia, smoking) was a good indicator for the presence of moderate/severe CA on CCTA. However, mild/moderate CA was present in 17.8% of MA clinically stratified at a low risk-SCORE. CONCLUSION: While coronary angiography is more indicated in athletes with positive stress-test ECG and high clinical risk, the CCTA may be useful in the evaluation of MA with an abnormal stress test ECG and/or clinical symptoms engaged in competitive sports with a high cardiovascular involvement. Age, gender, presence of symptoms and clinical risk-SCORE assessment may help sports physicians and cardiologists to decide whether to request a CCTA or not. PMID- 30482443 TI - Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis. AB - BACKGROUND: Aortic valve stenosis (AVS) and coronary artery disease (CAD) have a significant genetic contribution and commonly co-exist. To compare and contrast genetic determinants of the two diseases, we investigated associations of the LPA and 9p21 loci, i.e. the two strongest CAD risk loci, with risk of AVS. METHODS: We genotyped the CAD-associated variants at the LPA (rs10455872) and 9p21 loci (rs1333049) in the GeneCAST (Genetics of Calcific Aortic STenosis) Consortium and conducted a meta-analysis for their association with AVS. Cases and controls were stratified by CAD status. External validation of findings was undertaken in five cohorts including 7880 cases and 851,152 controls. RESULTS: In the meta-analysis including 4651 cases and 8231 controls the CAD-associated allele at the LPA locus was associated with increased risk of AVS (OR 1.37; 95%CI 1.24-1.52, p = 6.9 * 10 10) with a larger effect size in those without CAD (OR 1.53; 95%CI 1.31-1.79) compared to those with CAD (OR 1.27; 95%CI 1.12-1.45). The CAD-associated allele at 9p21 was associated with a trend towards lower risk of AVS (OR 0.93; 95%CI 0.88-0.99, p = 0.014). External validation confirmed the association of the LPA risk allele with risk of AVS (OR 1.37; 95%CI 1.27-1.47), again with a higher effect size in those without CAD. The small protective effect of the 9p21 CAD risk allele could not be replicated (OR 0.98; 95%CI 0.95-1.02). CONCLUSIONS: Our study confirms the association of the LPA locus with risk of AVS, with a higher effect in those without concomitant CAD. Overall, 9p21 was not associated with AVS. PMID- 30482444 TI - Mortality in status 2 patients listed for heart transplantation in the United States: Will understanding cause of death help justify implantation of left ventricular assist devices into less sick patients? AB - OBJECTIVE: It remains unclear whether left ventricular assist device (LVAD) implantation in non-inotrope dependent patients is of clinical benefit. This study sought to evaluate cause of death in patients listed for heart transplant (HT) to determine the relative risks and benefits of implanting LVAD into patients who are less sick than those included in the original clinical trials. METHODS: We examined death as the primary outcome in 23,098 patients listed for HT from 2006 to 2014 using proportional subdistribution hazards modeling. Cause of death was examined as a secondary outcome using chi2 tests. RESULTS: 1859 (8.1%) patients were removed from the wait list for death, including 229 (2.7%) status 1A, 349 (4.6%) status 1B, 246 (13.2%) status 2, and 1035 (26.0%) status 7 patients (P < 0.0001). Status 2 patients who received LVAD while listed had a higher risk of death compared to those who did not (adjusted HR 1.68; 95% CI 1.09 2.59; P = 0.02), while there was no increased risk of death in status 1A (HR 1.02; 95% CI 0.68-1.51; P = 0.9) and status 1B (HR 0.89; 95% CI 0.65-1.23; P = 0.5) who received LVAD. Status 2 patients who received LVAD were more likely to die cerebrovascular causes (0.6% vs. 0.1%, P = 0.009) and organ failure (70.6% vs. 29.4%, P = 0.003). CONCLUSIONS: LVAD implantation in status 2 patients listed for HT is associated with a higher risk of death. More research is needed to determine the impact LVAD implantation will have on mortality in patients with ambulatory, non-inotrope dependent HF. PMID- 30482445 TI - Pressure-derived estimations of coronary flow reserve are inferior to flow derived coronary flow reserve as diagnostic and risk stratification tools. AB - BACKGROUND: Pressure-derived coronary flow reserve (CFRpres) and pressure-bounded CFR (CFRpb) enable simple estimation of CFR from routine pressure measurements, but have been inadequately validated. We sought to compare CFRpres and CFRpb against flow-derived CFR (CFRflow) in terms of diagnostic accuracy, as well as regarding their comparative prognostic relevance. METHODS: We evaluated 453 intermediate coronary lesions with intracoronary pressure and flow measurements. CFR was defined as hyperemic flow/baseline flow. The lower bound (CFRpres) and upper bound of CFRpb were defined as ?[(DeltaPhyperemia) / (DeltaPrest)] and [(DeltaPhyperemia) / (DeltaPrest)], respectively. Long-term follow-up (median: 11.8-years) was performed in 153 lesions deferred from treatment to document the occurrence of major adverse cardiac events (MACE) defined as a composite of cardiac death, myocardial infarction and target vessel revascularization. CFR < 2.0 was considered abnormal. RESULTS: CFRpb was normal or abnormal in 56.7% of stenoses, and indeterminate in 43.3% of stenoses. There was a poor diagnostic agreement between CFRpres and CFRpb with CFRflow (overall agreement: 45.5% and 71.6% of vessels, respectively). There was equivalent risk for long-term MACE for lesions with abnormal versus normal CFRpres (Breslow p = 0.562), whereas vessels with abnormal CFRflow were significantly associated with increased long-term MACE (Breslow p < 0.001). For vessels where CFRpb was abnormal or normal, there was equivalent risk for long-term MACE for vessels with abnormal versus normal CFRpb (Breslow p = 0.194), whereas vessels with abnormal CFRflow were associated with increased MACE rates over time (Breslow p < 0.001). CONCLUSIONS: Pressure-derived estimations of CFR poorly agree with flow-derived measurements of CFR, which may explain the inferior association with long-term MACE as compared to flow-derived CFR. PMID- 30482446 TI - Cortex Is Cortex: Ubiquitous Principles Drive Face-Domain Development. PMID- 30482447 TI - Editorial overview. PMID- 30482448 TI - Shoulder extension strength: a potential risk factor for shoulder pain in young swimmers? AB - OBJECTIVES: To determine the relationship and predictive value of isometric shoulder strength in the development of shoulder pain in young swimmers. DESIGN: Prospective, cohort study. METHODS: Shoulder flexion, extension, external and internal rotation strength tests were performed in elevation on 85 swimmers (14 20 years; 48 females) without current shoulder pain using a hand-held dynamometer. Following testing, swimmers were emailed questionnaires to determine if significant shoulder pain developed within 24 months subsequent to testing. The differences between shoulders that did and did not develop pain and the predictive ability of shoulder strength and strength ratios were investigated using Mann Whitney U tests and receiver operating characteristic curves. RESULTS: Thirty-seven swimmers (47%) returned questionnaires and 18 reported shoulder pain. A comparison of individual shoulders (27 with pain reported and 47 without) determined that shoulder extension strength was lower and flexion:extension strength ratio was higher for male swimmers (n=36 shoulders) who reported shoulder pain compared to those who did not (p=0.04). The predictive value of extension strength was fair (0.72; p=0.03) for males with a cut-off value for extension strength calculated at 13.5% body mass. There were no differences between the two groups in shoulder rotation strength, age, training hours or previous pain history. CONCLUSIONS: Shoulder extension strength, a functional test for swimmers, was associated with and predictive of the development of shoulder pain in male swimmers. Low shoulder extension strength may be a risk factor for the development of shoulder pain in swimmers, proposing a direction for injury prevention and future investigation. PMID- 30482449 TI - Early life factors are associated with trajectories of consistent organized sport participation over childhood and adolescence: Longitudinal analysis from the Raine Study. AB - OBJECTIVES: The purpose of this study was to identify early life factors that were associated with childhood and adolescent organized sport participation trajectories. DESIGN: Participants were in the Raine Study, a pregnancy cohort in Western Australia recruited from 1989 to 1991. METHODS: Three organized sport trajectories over ages 5-17years were previously identified for girls (n=824: consistent participators, dropouts, and non-participators in sport) and boys (n=855: consistent participators, dropouts, joiners - those who joined sport in adolescence). Physical, psychological and social factors were measured from birth to age 5. RESULTS: For girls and boys, children who were breastfed, were taller, did not have behavior problems, and attended childcare were more likely to consistently participate. Girls who had a previous injury (Relative risk ratio 1.55: 95% confidence interval 1.05, 2.29 vs never been injured) or who had parents who had worries about their child's health (1.56: 1.00, 2.42 vs no worries) were more likely to be in the dropout trajectory. Boys born preterm (2.00, 2.06, 3.76 vs full-term), did not have a previous injury (0.72, 0.53, 0.97 those with injury vs never been injured), had more difficult temperament (1.63, 1.02, 2.60 vs easy temperament), and higher family dysfunction (1.49, 1.06, 2.08) were more likely to be in the dropout trajectory. CONCLUSIONS: Early life factors were associated with membership in sport trajectories. Physical, psychological, and social factors may serve as early warning signs for parents and practitioners that children may be at higher risk of dropping out of sports. PMID- 30482450 TI - Relationship of quality of life, psychopathologic symptoms and ways of coping in Greek nursing staff. AB - OBJECTIVE: Our aim was to investigate the relationship of quality of life, psychopathological symptoms and ways of coping of nursing staff in two General Hospitals in Greece. METHOD: This was a cross-sectional study of 302 nurses in two General Hospitals in Greece between October and November of 2015. Data collection was performed using three questionnaires; the World Health Organisation Quality Of Life BREF; the Falk Self-Reporting Questionnaire for the detection of possible psychiatric comorbidity and the Ways of Coping Scale for Stressful Situations. RESULTS: From a sample of 302 nurses, the poorer the mental and physical health of the nursing staff, the more their quality of life was impaired in all dimensions (physical, psychological, social and environmental) (p<.001, p=.047, p=.001). Also, while the scores in coping strategies "Positive Approach-Positive reappraisal", "Positive Approach-problem solving" and "Positive Approach (overall)" rose, the score in the General Scale dropped, in other words, the employees' general health improved. CONCLUSION: Coping strategies such as Positive Approach, improved the nurses' general health. In contrast, their mental health deteriorated when they adopted the Wishful thinking/Daydream and/or the Escape/Avoidance strategies. Finally, as their general health worsened, their quality of life was impaired in all dimensions, whereas poor mental health of nurses was associated with lower quality of life in the physical and psychological dimensions. PMID- 30482451 TI - [Occult foreign body: A rare cause of recurrent vulvovaginitis]. PMID- 30482452 TI - [Evaluation of double aortic arch by ultrasound and computed tomography]. PMID- 30482454 TI - IL-6 blockade for myocardial infarction. PMID- 30482453 TI - Non-cardiac comorbidities in heart failure with reduced, mid-range and preserved ejection fraction. AB - BACKGROUND: Comorbidities play a major role in heart failure. Whether prevalence and prognostic importance of comorbidities differ between heart failure with preserved ejection fraction (HFpEF), mid-range (HFmrEF) or reduced ejection fraction (HFrEF) is unknown. METHODS: Patients from index (n = 2516) and validation cohort (n = 1738) of The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) were pooled. Eight non-cardiac comorbidities were assessed; diabetes mellitus, thyroid dysfunction, obesity, anaemia, chronic kidney disease (CKD, estimated glomerular filtration rate < 60 mL/min/1.73 m2), COPD, stroke and peripheral arterial disease. Patients were classified based on ejection fraction. The association of each comorbidity with quality of life (QoL), all-cause mortality and hospitalisation was evaluated. RESULTS: Patients with complete comorbidity data were included (n = 3499). Most prevalent comorbidity was CKD (50%). All comorbidities showed the highest prevalence in HFpEF, except for stroke. Prevalences of HFmrEF were in between the other entities. COPD was the comorbidity associated with the greatest reduction in QoL. In HFrEF, almost all were associated with a significant reduction in QoL, while in HFpEF only CKD and obesity were associated with a reduction. Most comorbidities in HFrEF were associated with an increased mortality risk, while in HFpEF only CKD, anaemia and COPD were associated with higher mortality risks. CONCLUSIONS: The highest prevalence of comorbidities was seen in patients with HFpEF. Overall, comorbidities were associated with a lower QoL, but this was more pronounced in patients with HFrEF. Most comorbidities were associated with higher mortality risks, although the associations with diabetes were only present in patients with HFrEF. PMID- 30482455 TI - Extracellular signal-regulated kinase (ERK) in left ventricular pathological hypertrophy: not a new kid on the block anymore. PMID- 30482456 TI - Disparities in hypertension and cardiovascular disease in African Americans: Is the answer in the gut microbiota? PMID- 30482458 TI - Bee venom acupuncture in addition to anti-Parkinsonian medications may improve activities of daily living and motor symptoms more than medication alone in idiopathic Parkinson's disease. PMID- 30482457 TI - Systematic review of medication synchronization in community pharmacy practice. AB - BACKGROUND: Medication non-adherence costs more than 100 billion dollars in avoidable hospitalizations yearly. As a result, community pharmacies have implemented medication synchronization programs to improve adherence. One function of most medication synchronization programs is the alignment of all of a patient's medications to refill on a single date. While aligning refills is a standard aspect of most programs, other features vary making it difficult to identify which program components lead to improved adherence. OBJECTIVE: To review available literature and identify core components of medication synchronization and associated implementation techniques in community pharmacy. METHODS: A systematic review was performed by searching electronic databases for studies, reviews, and other sources for grey literature discussing medication synchronization in community pharmacy settings. Studies were eligible for inclusion if they documented the operation of medication synchronization program in a community pharmacy. A framework analysis identified common themes present in the literature. RESULTS: Twenty-six studies met criteria for final inclusion in this review. The majority of studies were retrospective cohorts, commentaries, and implementation guides. A wide variety of core components were included as part of medication synchronization program descriptions in the available literature. Several core components were identified as consistent throughout most of the published literature. These components were the identification and enrollment of patients, inclusion of a medication review and patient assessment, the alignment of refills, a formal process for preparation of medications, and the delivery of medications and other services. CONCLUSIONS: This review identified several common themes of medication synchronization in the literature, which could help standardize medication synchronization within community pharmacy and facilitate future research. Themes found in this review provide the foundation upon which a consensus definition of medication synchronization can be built. PMID- 30482459 TI - [The lack of adherence to a structured multicomponent program of physical exercise by the frail elderly]. PMID- 30482460 TI - [Effect on fear of falling and functionality of three intervention programs. A randomised clinical trial]. AB - INTRODUCTION: The fear of falling has a high prevalence in the community, and intervention programs for this condition are scarce, making it is necessary to strengthen this type of therapy in order to prevent adverse consequences in the elderly population. OBJECTIVE: To establish the effectiveness of three intervention programs in reducing the fear of falling and increasing functionality in elderly people in the city of Manizales. PARTICIPANTS AND METHODS: A randomised trial was conducted on ambulatory elderly patients with fear of falling and functional limitation of the city of Manizales. A total of 125 individuals were randomised to one of three interventions: Tai Chi (TCh), cognitive behavioural therapy (CBT), and postural control (CP) exercises. The primary outcomes were: fear of falling (evaluated by the Falls Efficacy Scale [FES-I]), and functionality using the Short Physical Performance Battery (SPPB). The data was collected before initiating the interventions and after the 8 weeks intervention. RESULTS: An intention-to-treat analysis was conducted on 119 elderly patients. The three interventions reduced the fear of falling and increased physical performance, with no significant differences observed between them (P=.13). As regards gait speed, differences were only found between the pre- and post-intervention with CP (P<.001). CONCLUSIONS: The results suggest that the TCh, CBT and CP interventions helped the elderly to reduce their fear of falling. Only CP demonstrated an improvement in the speed of walking at the end of the eight weeks of intervention (identifier NCT03211429). PMID- 30482461 TI - [Effectiveness of a mindfulness-based stress reduction program for family caregivers of people with dementia. Systematic review of randomised clinical trials]. AB - Family caregivers of people with dementia usually have high levels of anxiety, depression, and overload symptoms, and are reasons for being considered a clinically vulnerable population. The objective of the present review is to examine the effectiveness of the mindfulness-based stress reduction program (MBSR) applied to this population. A search was made in the electronic databases for randomised trials with pre-post measurement in the last 15 years. The methodological quality was obtained using the Jadad scale. Finally, 5 articles were included, obtaining a sample of 309 participants. The score on the Jadad scale was 3.4 out of 5. In general, the MBSR program reduces anxiety and depression symptoms, as well as overload levels in the post-measurement. However, some studies showed a significant reduction in the psychological effects of the program during follow-up. More empirical studies are needed that can establish a more homogeneous protocol that reduces the ambiguity of some results. PMID- 30482462 TI - [Premorbid personality as a risk factor in the appearance of psychological and behavioural symptoms of dementia: Systematic review]. AB - The aetiology of behavioural and psychological symptoms of dementia (BPSD) is defined by a diversity of factors, and recent studies suggest that premorbid personality could be a risk factor for BPSD. This study aimed to review studies on the relationship between premorbid personality and BPSD. Studies were identified using PsycInfo, MedLine, and PubMed. The searches combined terms for premorbid personality, dementia and BPSD. Ten studies have been included in this review. Eight out of ten studies show a relationship between premorbid personality and BPSD. Neuroticism is associated with behavioural disturbances and anxiety. Extraversion is associated with wandering. Low agreeableness is associated with affective disturbance and aggression-related behaviours and high agreeableness is associated with wandering. The studies found no congruent results for openness and conscientiousness. In conclusion, premorbid personality may increase the risk of developing BPSD during the course of the disease. Even so, the relationship between personality and BPSD is complex due to multifactorial aetiology. PMID- 30482463 TI - KIR2DL4-HLAG interaction at human NK cell-oligodendrocyte interfaces regulates IFN-gamma-mediated effects. AB - Interactions between germline-encoded natural killer (NK) cell receptors and their respective ligands on tumorigenic or virus-infected cells determine NK cell cytotoxic activity and/or cytokine secretion. NK cell cytokine responses can be augmented in and can potentially contribute to multiple sclerosis (MS), an inflammatory disease of the central nervous system focused upon the oligodendrocytes (OLs). To investigate mechanisms by which NK cells may contribute to MS pathogenesis, we developed an in vitro human model of OL-NK cell interaction. We found that activated, but not resting human NK cells form conjugates with, and mediate cytotoxicity against, human oligodendrocytes. NK cells, when in conjugate with OLs, rapidly synthesize and polarize IFN-gamma toward the OLs. IFN-gamma is capable of reducing myelin oligodendrocyte and myelin associated glycoproteins (MOG and MAG) content. This activity is independent of MHC class-I mediated inhibition via KIR2DL1, but dependent upon the interaction between NK cell-expressed KIR2DL4 and its oligodendrocyte expressed ligand, HLA-G. NK cells from patients with MS express higher levels of IFN-gamma following conjugation to OLs, more actively promote in vitro reduction of MOG and MAG and have higher frequencies of the KIR2DL4 positive population. These data collectively suggest a mechanism by which NK cells can promote pathogenic effects upon OLs. PMID- 30482464 TI - Polymorphisms of sperm protamine genes and CMA3 staining in infertile men with varicocele. AB - OBJECTIVES: The aim of this study was to evaluate polymorphisms of sperm protamine genes and their effects on the result of CMA3 staining in varicocele men. MATERIAL AND METHODS: In a case control study, 128 patients with male infertility due to varicocele and 128 controls were recruited. Polymorphisms of PRM1 and PRM2 genes in extracted DNA samples were assessed by PCR-SSCP and sequencing. Protamine deficiency was also indirectly estimated by CMA3 staining. RESULT: Nine different variants including six variants in PRM1 gene and three variants in PRM2 gene were found among varicocele patients. The results showed that sperm count, motility and morphology were significantly different between control group without gene variations and varicocele group who had several variations in their protamine genes (P<0.05). CONCLUSION: Therefore, PRM1 and PRM2 variations in varicocele patients are associated with the production of spermatozoa with more protamine deficiency and this is one of the possible causes of infertility due to varicocele. PMID- 30482465 TI - Does mean platelet volume (MPV) have a role in evaluation of erectile dysfunction and its severity? AB - PURPOSE: The mean platelet volume (MPV) has important role in the pathophysiology of vascular diseases as a marker of the platelet activity. To investigate the association between mean platelet volume and erectile dysfunction (ED) and to search whether this marker can be used for diagnosis of ED. MATERIALS AND METHODS: Of the 312 patients with ED of various degrees, 122 patients without ED (IIEF-5>21) were included in this prospective study. Severity of ED was determined according to IIEF-5 questionnaire. MPV, fasting serum glucose, cholesterol, low density lipoprotein (LDL) and serum testosterone levels are also recorded. The mean platelet volume was calculated by the Coulter counter technique and sexual function was determined by International Index of Erectile Function erectile function domain (IIEF-5). RESULTS: The mean age of patients was 58.4 years. The mean MPV value of patients with ED was significantly higher compared to the non-ED patients (8.91 vs. 8.22, p=0.0001). The severity of ED was shown to have a positive strong correlation with MPV values (r=0.719, p=0.001). Mean serum triglyceride, glucose, total cholesterol and LDL cholesterol levels were noted higher in patients with ED. MPV values were found to be significantly higher in patients with ED. CONCLUSION: MPV level shows significant correlation with severity of ED. This cheap laboratory test can have potential to be a marker of ED. Further prospective larger studies with vascular wall thickness measurements should be conducted. PMID- 30482467 TI - Lipomatous hypertrophy of interatrial septum causing hot spot on 18FDG PET/CT. PMID- 30482466 TI - Transtibial pullout repair of medial meniscus posterior root tear restores physiological rotation of the tibia in the knee-flexed position. AB - BACKGROUND: Medial meniscus posterior root tear (MMPRT) results in joint overloading and degenerative changes in the knee. Favorable clinical outcomes have been reported after transtibial pullout repair of MMPRT. To date, however, in vivo tibial rotational changes before and after root repair remain poorly understood. The purpose of this study was to investigate postoperative changes in tibial rotation following MMPRT pullout repair. HYPOTHESIS: Pathological external rotation of the tibia in the knee-flexed position is caused by MMPRT and is reduced after transtibial pullout repair. PATIENTS AND METHODS: Fifteen patients who underwent MMPRT pullout repair and 7 healthy volunteers were included. Magnetic resonance imaging examinations were performed in the 10 degrees and 90 degrees knee-flexed positions. The angles between the surgical epicondylar axis and a line between the medial border of the patellar tendon and the apex of the medial tibial spine were measured. Baseline was defined as a line lying at a right angle to the other, and a value was positive and negative when the tibia rotated internally and externally, respectively. RESULTS: In the volunteer's normal knees, tibial internal rotation was +1.00 degrees +/-3.27 degrees at 10 degrees flexion and +4.14 degrees +/-3.46 degrees at 90 degrees flexion. In the MMPRT preoperative knees, tibial internal rotation was +1.07 degrees +/-3.01 degrees at 10 degrees flexion and +1.27 degrees +/-2.96 degrees at 90 degrees flexion. In the postoperative knees, tibial internal rotation was +1.60 degrees +/-2.85 degrees at 10 degrees flexion and +4.33 degrees +/-2.89 degrees at 90 degrees flexion. DISCUSSION: This study demonstrates discontinuity of the MM posterior root may induce a pathological external rotation of the tibia during knee flexion and that MMPRT pullout repair reduces the pathological external rotation of the tibia in the knee-flexed position. LEVEL OF EVIDENCE: III, comparative retrospective study. PMID- 30482468 TI - Motivational interviewing training for physiotherapy and occupational therapy students: Effect on confidence, knowledge and skills. AB - OBJECTIVE: To examine the effectiveness of a three-day training programme on knowledge, confidence and fidelity to Motivational Interviewing (MI) delivery in an undergraduate occupational therapy and physiotherapy cohort (n = 25). METHODS: Training outcomes were assessed pre-training, post-training and following a subsequent clinical placement. The Motivational Interviewing Knowledge and Attitudes Test (MIKAT) and an 8-item survey assessed knowledge, attitudes and confidence respectively. MI fidelity was evaluated by a simulated patient interview rated with the Motivational Interviewing Treatment Integrity scale (MITI). Analysis was by one-way repeated measures ANOVA. RESULTS: Self-report measurements indicated increased confidence but no effect on knowledge or attitude. MITI analysis showed superior performance in all four global criteria and an increased frequency of MI adherent behaviours post-training. Positive changes were maintained following clinical placement. MITI summary scores indicated an improvement in question to reflection ratio in line with beginner competency. CONCLUSION(S): Participation in a three-day MI training programme significantly improved student confidence and MI skilfulness. PRACTICE IMPLICATIONS: Where feasible, MI training should be embedded within the curriculum. Further research is needed elucidate the best practices to incorporate teaching this skill set within the curriculum in order to best prepare students to counsel clients in behaviour change in their applied settings. PMID- 30482469 TI - Exome sequencing disclosures in pediatric cancer care: Patterns of communication among oncologists, genetic counselors, and parents. AB - OBJECTIVE: To examine communication patterns and behaviors during disclosure of exome sequencing (ES) results to parents of pediatric cancer patients, and describe common themes in parental communication. METHODS: Using mixed methods, we analyzed transcripts of sessions where parents of pediatric cancer patients received ES results from an oncologist and genetic counselor. Seventy-six transcripts were analyzed for frequency of clinician information-giving, partnering-supportive talk, and active parent participation. A subset of 40 transcripts were analyzed using thematic content analysis. RESULTS: Disclosures consisted mostly of clinician talk (84% of total talk), which was focused on providing information (62% of clinicians' utterances) with occasional partnering supportive talk (7% of clinicians' utterances). Most parents assumed a passive, listening role (16% of total talk). Themes in parental communication included expressing relief and the significance of an answer, concern about sharing results and responsibility for inheritance, and seeking clarification of health implications of results. CONCLUSION: Our finding of low levels of active parent participation during ES disclosures highlights the need to improve patient/parent engagement and understanding in a genetic setting. PRACTICE IMPLICATIONS: Clinician communication strategies that could encourage parent participation and understanding include checking for parent understanding, partnership-building, and tailoring ES discussions to address parent concerns and preferences. PMID- 30482470 TI - Severe compression of the left circumflex coronary artery by a large sinus of Valsalva aneurysm. PMID- 30482471 TI - A risk score for carotid plaque as an assessment risk of cardiovascular risk among patients with hypertension. AB - This study aimed to describe the status of carotid plaques and develop a simple scoring system to predict the risk of carotid lesions in patients with hypertension. Basic testing for carotid plaques was carried out and used for risk score development (the training dataset, n = 2665) and validation (the test dataset, n = 1333). Independent predictors of carotid plaques from the multivariate model were assigned integer weights based on their coefficients and incorporated into a risk score. The discriminant ability of the score was tested by receiver operating characteristic analysis using the test dataset. A total of 1346 of 2665 patients were examined for carotid plaques, which were more frequent in men than in women, and increased with age. The final model included eight significant variables, and these variables were then used to develop a risk score for the prediction of carotid plaques. Receiver operating characteristic analysis demonstrated good discriminant power with a C-statistic of 0.732 (95% confidence interval: 0.713-0.751) and good calibration across quantiles of observed predicted risk (74.6%). We developed a simple risk score for the prediction of carotid plaques based on eight variables. The prediction model showed good discriminant power and calibration. PMID- 30482472 TI - Internet survey on the provision of complementary and alternative medicine in Japanese private clinics: a cross-sectional study. AB - OBJECTIVE: Although the use of complementary and alternative medicine (CAM) by the general population has been surveyed previously, the provision of CAM by Japanese physicians in private clinics has not been studied. Universal health insurance system was established in Japan in 1961, and most CAMs are not on the drug tariff. We aimed to clarify the current status of CAM provided by physicians at private clinics in Japan. METHODS: We conducted an internet survey on 400 directors/physicians of private clinics nationwide on the provision of CAM from February 6 to February 10, 2017. Survey items included attributes of subjects, presence/absence of sections or facilities for provision of CAM, proportions of health insurance coverage for medical practices, and source of information. Private clinic was defined as a clinic run by one physician, with less than 20 beds. RESULTS: Commonly provided CAMs were Kampo (traditional Japanese herbal) medicines (34.8%) and supplements/health foods (19.3%). CAMs on the drug tariff were provided in 46.5% of cases at the clinics, but only 16.5% of cases were provided CAMs which were not on the drug tariff, at different neighboring facilities. Among different specialties, Kampo medicines were prescribed at obstetrics/gynecology (54.0%), orthopedics (44.4%), and dermatology (43.0%). Clinics not providing any CAM accounted for 53.5%. With regard to health insurance coverage, 96.8% of the clinics provided only or mainly health services on the universal national health insurance tariff (29.8% and 67.0%, respectively). CONCLUSION: Kampo medicines represent the most commonly used CAM in private clinics in Japan, and universal national health insurance coverage is considered to be the reason for the high rate of their use. PMID- 30482473 TI - Effectiveness of hand self-shiatsu to improve sleep following sport-related concussion in young athletes: a proof-of-concept study. AB - OBJECTIVE: The prevalence of sport-related concussion (SRC) is high and results in a number of serious health consequences. One area that has received minimal research is the relationship between SRC and sleep. The literature shows that sleep deficiency is a frequent negative consequence of SRC. At the same time, sleep deficiency delays recovery from SRC and contributes added risk of symptom recurrence. A 2014 study of chronic pain patients who learned to apply the complementary and alternative medicine intervention hand self-shiatsu (HSS) had promising, sleep-promoting results that warrant further investigation with other populations. This proof-of-concept study explored the feasibility of HSS as an intervention to promote sleep onset and continuity for young adults with SRC. METHODS: This study employed a prospective case-series design, where participants act as their own controls. Baseline and follow-up data included standardized self reported assessment tools and sleep actigraphy. RESULTS: Seven athletes, aged between 18 and 25 years, participated in the study. Although statistically significant improvement in actigraphy sleep scores between baseline and follow-up was not achieved, metrics for sleep quality and daytime fatigue showed significant improvement. CONCLUSION: These findings support the hypothesis that HSS has the potential to improve sleep and reduce daytime fatigue in young postconcussion athletes. This pilot study provides guidance to refine research protocols and lays a foundation for further, large-sample, controlled studies. PMID- 30482474 TI - On hepatocellular carcinoma in South America and early-age onset of the disease. AB - Hepatocellular carcinoma (HCC) is one of the most predominant tumor types worldwide, being particularly prevalent in sub-Saharan Africa and East Asia. However, HCC is inexplicably underreported in South America, despite unsettling clinical epidemiological trends of the disease on this continent. Here, we review the current knowledge on HCC presentation in Peru. We emphasize the well documented occurrence of an early-age nosological form of the disease in Andean descent populations. We further discuss the reasons for such HCC clinical presentation, as well as the implications for liver cancer screening, management, and prevention. PMID- 30482475 TI - Anesthetic Management for Medialization Laryngoplasty Performed Under Concurrent Dexmedetomidine, Remifentanil, and Propofol Infusions. AB - INTRODUCTION: Type I thyroplasty, or medialization larygoplasty (ML), is a procedure which improves the voice by medializing a vocal fold with a permanent implant. Anesthetic management of these cases is challenging because patients can require periods of deep sedation followed by fully awake moments for phonation to assess the implant size. We present our experience of ML with or without arytenoid adduction (AA) using a multimodal anesthetic regimen consisting of concurrent infusions of dexmedetomidine, remifentanil, and propofol. METHODS: This is a retrospective case series of patients anesthetized using this protocol from June 1, 2015 through June 30, 2017. RESULTS: Seventy-five consecutive ML with or without AA patients anesthetized with dexmedetomidine and remifentanil infusions were identified, of which 74 (98.7%) also received concurrent propofol infusions. Mean duration of sedation was 190.9 +/- 36.9 minutes and surgery was 139 +/- 35.3 minutes. Transient hypopnea treated with supplemental oxygen complicated 18 (24%) cases and bradycardia requiring pharmacologic treatment complicated 3 (4%) cases. There were no other adverse anesthetic complications. One patient required surgical re-exploration due to postsurgical bleeding after the initial hospital discharge. CONCLUSION: In this cohort, a combination of remifentanil, dexmedetomidine and propofol infusions was well tolerated without serious adverse perioperative events. PMID- 30482477 TI - Gastric anisakiasis after eating raw salmon. PMID- 30482478 TI - Surgeons see anatomical structures faster and more accurately compared to novices: Development of a pattern recognition skill assessment platform. AB - BACKGROUND: This study aimed to identify differences in pattern recognition skill among individuals with varying surgical experience. METHODS: Participants reviewed laparoscopic cholecystectomy videos of various difficulty, and paused them when the cystic duct or artery was identified to outline each structure on the monitor. Time taken to identify each structure, accuracy and work load, which was assessed using the NASA-Task Load Index (TLX), were compared among the three groups. RESULTS: Ten students, ten residents and eight attendings participated in the study. Attendings identified the cystic duct and artery significantly faster and more accurately than students, and identified the cystic artery faster than residents. The NASA-TLX score of attendings was significantly lower than that of students and residents. CONCLUSIONS: Attendings identified anatomical structures faster, more accurately, and with less effort than students or residents. This platform may be valuable for the assessment and teaching of pattern recognition skill to novice surgeons. SHORT SUMMARY: Accurate anatomical recognition is paramount to proceeding safely in surgery. The assessment platform used in this study differentiated recognition skill among individuals with varing surgical experience. PMID- 30482476 TI - Metformin intervention prevents cardiac dysfunction in a murine model of adult congenital heart disease. AB - OBJECTIVE: Congenital heart disease (CHD) is the most frequent birth defect worldwide. The number of adult patients with CHD, now referred to as ACHD, is increasing with improved surgical and treatment interventions. However the mechanisms whereby ACHD predisposes patients to heart dysfunction are still unclear. ACHD is strongly associated with metabolic syndrome, but how ACHD interacts with poor modern lifestyle choices and other comorbidities, such as hypertension, obesity, and diabetes, is mostly unknown. METHODS: We used a newly characterized mouse genetic model of ACHD to investigate the consequences and the mechanisms associated with combined obesity and ACHD predisposition. Metformin intervention was used to further evaluate potential therapeutic amelioration of cardiac dysfunction in this model. RESULTS: ACHD mice placed under metabolic stress (high fat diet) displayed decreased left ventricular ejection fraction. Comprehensive physiological, biochemical, and molecular analysis showed that ACHD hearts exhibited early changes in energy metabolism with increased glucose dependence as main cardiac energy source. These changes preceded cardiac dysfunction mediated by exposure to high fat diet and were associated with increased disease severity. Restoration of metabolic balance by metformin administration prevented the development of heart dysfunction in ACHD predisposed mice. CONCLUSIONS: This study reveals that early metabolic impairment reinforces heart dysfunction in ACHD predisposed individuals and diet or pharmacological interventions can be used to modulate heart function and attenuate heart failure. Our study suggests that interactions between genetic and metabolic disturbances ultimately lead to the clinical presentation of heart failure in patients with ACHD. Early manipulation of energy metabolism may be an important avenue for intervention in ACHD patients to prevent or delay onset of heart failure and secondary comorbidities. These interactions raise the prospect for a translational reassessment of ACHD presentation in the clinic. PMID- 30482479 TI - A novel overlapping NLS/NES region within the PH domain of Rho Guanine Nucleotide Exchange Factor (RGNEF) regulates its nuclear-cytoplasmic localization. AB - Rho Guanine Nucleotide Exchange Factor (RGNEF) is a 190 kDa protein implicated in both amyotrophic lateral sclerosis (ALS) and cancer. Under normal physiological conditions, RGNEF is predominantly cytoplasmic with moderate levels of nuclear localization. We have identified a 23-amino acid region containing a bipartite nuclear localization signal (NLS) within the Pleckstrin Homology (PH) domain of RGNEF, which when deleted or mutated abolishes the nuclear localization of this protein. Fusion proteins containing only the PH domain demonstrated that this region by itself is able to translocate a 160 kDa protein to the nucleus. Interestingly, we also detected a nuclear export signal (NES) within the linker region of this bipartite NLS which is able to export from the nucleus a fusion protein containing two NLSs. Experiments using Leptomycin-B -an inhibitor of nuclear export- confirmed that this region promotes nuclear export in an exportin 1 dependent manner. This study is the first report demonstrating either of these signals embedded within a PH domain. Notably, this is also the first description of a functional overlapped NLS/NES signal. PMID- 30482481 TI - SNPs in 3'-UTR region of MBL2 increases susceptibility to recurrent vulvovaginal infections by altering sMBL levels. AB - Recurrent vulvovaginal infections (RVVI), owing to their adverse health consequences, have become a serious dilemma worldwide. Low serum levels of Mannose-Binding Lectin (sMBL), a main component of innate immunity, was found to be associated with RVVI risk, though complete genetic bases are still elusive. To reveal unrecognised regulatory variants, 3'-UTR region of MBL2 with six putative functional SNPs i.e. rs10824792, rs2120132, rs2120131, rs2165813, rs2099903 and rs2099902 was sequenced and genotyped in the present study for 109 RVVI cases and age matched healthy controls. sMBL levels were measured by enzyme-linked immunosorbent assay. The homozygous CC genotype of rs10824792 polymorphism was found to be conferring risk (OR = 2.94) of developing RVVI. Significantly high frequency of corresponding CC genotype was found in Vulvovaginal Candidiasis (VVC) and Mixed Infections (MI) relative to controls. Significantly insufficient sMBL levels were observed in RVVI and its types (Bacterial Vaginosis, VVC and MI) than controls. sMBL levels varied for rs10824792 SNP as expected from the genetic analyses. Six marker haplotype analyses have shown CTTGCT, the haplotype containing only risk allele of rs10824792, conferred risk of RVVI and its types by lowering sMBL levels. In conclusion, a 3'-UTR SNP i.e. rs10824792 was identified as novel associated genetic marker for contributing low sMBL levels and RVVI risk. Our findings contribute to the novel future research directions for the development of emerging MBL substitution as effectual therapy for RVVI. PMID- 30482482 TI - Are implanted electronic devices hackable? AB - Medical devices have become increasingly connected in recent years. While this added interconnectivity has provided capabilities for wireless communication and remote monitoring, it has also introduced possible risks for cybersecurity vulnerabilities. Lately, there has been an increased awareness of the potential for cybersecurity breaches in implanted cardiac devices (pacemakers and defibrillators) among patients, healthcare providers, and the media. In this article, we review the current perspective on cybersecurity in implanted medical devices, including a recent high-profile case example of a cybersecurity threat. We outline the actions taken by all the involved stakeholders in response to the disclosure of potential vulnerabilities in medical devices and summarize the positions of major societies in response to these events. PMID- 30482480 TI - [Cost-effectiveness analysis of aripiprazole once-monthly versus paliperidone palmitate once-monthly in the treatment of schizophrenia in France]. AB - OBJECTIVE: The aim of the study was to estimate the cost-effectiveness ratio of aripiprazole once-monthly compared to once-monthly injectable paliperidone palmitate in the treatment of schizophrenia in France on the basis of results and data from the QUALIFY study. METHODS: Consumed resources data measured with a dedicated questionnaire and results on the quality of life scales from the QUALIFY study were combined with French standard unit costs of each collected consumed resources during QUALIFY to estimate the cost-effectiveness ratios of the two products. Multivariate sensitivity analyses were performed to test the combined impact of the different assumptions. RESULTS: Findings of the study showed greater efficacy on the quality of life (QLS) and psychiatric evaluation scales (CGI-S and CGI-I) observed in QUALIFY of aripiprazole compared with paliperidone palmitate. Findings also suggest a trend (P=0.0733) in the reduction of total costs linked to a statistical decrease (P<0,0001) in drug costs in the aripiprazole group. These findings are reinforced by the probabilistic sensitivity analyses. CONCLUSION: Aripiprazole appeared to be more cost-effective than paliperidone palmitate in the French context. Limits of this study are mainly related with the duration of the clinical trial and to assumptions on the transposability of measured consumed resources in the international clinical trial to the French healthcare system. PMID- 30482483 TI - A contemporary look at pericardiocentesis. AB - Percutaneous drainage is the default strategy for evacuating a pericardial effusion. A pericardiocentesis can be necessary or required in a wide variety of clinical settings ranging from urgent tamponade to relieve in iatrogenic hemorrhagic effusions in the electrophysiology or catheterization room, to planned diagnostic procedures in patients with suspected or known malignancy or infections. With the help of several procedural improvements over the past decades, echocardiography and fluoroscopy-guided percutaneous pericardiocentesis has become the standard intervention for evacuating pericardial effusions, as well as an essential tool in the diagnostic work-up of an unexplained pericardial effusion. When performed by skilled physicians assisted by appropriate imaging it is a very safe procedure, and provided that an indwelling catheter is placed, it is also very effective with an acceptably low risk of recurrences. In this review, the indications and standard techniques for pericardiocentesis are discussed, as well as their consequences for patients with iatrogenic and malignant effusions. PMID- 30482484 TI - Parity As a Protective Biomarker Against Silent Brain Infarction in Community Dwelling Older Adults: The Sefuri Study. AB - BACKGROUND: Although several studies have reported an association between parity and increased risk of stroke, this relationship remains controversial. AIMS: The present study aimed to determine whether parity is associated with silent brain infarction (SBI), independent of other confounders. METHODS: We analyzed the brain magnetic resonance imaging findings in 576 of community-dwelling older adults with a mean age of 72.1 years. All female participants were asked to provide information regarding the total number of live births, their age at the last parity, and their age at menopause. RESULTS: The prevalence of SBI and the number of infarcts per participant were higher in men than in women. Although all women who had given birth (0, 1-2, 3-4, or 5+ times) exhibited lower age-adjusted odds ratios (ORs) for SBI than men, a significant difference was observed between women with ?5 births and men after adjustment for common vascular risk factors (OR: .348, 95% confidence interval [95% CI]: .123-.986). Among women who had given birth, the relationship between fertility and SBI was attenuated, but was enhanced after adjustment for age at the last parity (OR: .300, 95% CI: .102 .886). CONCLUSIONS: Our findings indicate that fertile women may be protected against SBI or cerebral small vessel disease via the biological effects associated with reproductive activity, and that high fertility may be a marker of protection against SBI. However, late childbearing may blunt protective effects of fertility against SBI. PMID- 30482485 TI - Intravenous Transplants of Human Adipose-Derived Stem Cell Protect the Rat Brain From Ischemia-Induced Damage. AB - BACKGROUND: Survival following cardiac arrest (CA) and subsequent cardiopulmonary resuscitation (CPR), to a great extent, depends on brain damage. Adipose-derived stem cells (ADSCs), as a source of paracrine growth factors and the capacity of neural differentiation may reduce this brain damage. OBJECTIVE: The purpose of this study is to evaluate the protection of ADSCs to brain damage following CPR. METHODS: Rats were divided into 3 groups, sham, CA, and ADSCs group. Rats in sham group went through sham surgery. Rats in CA group went through CA, CPR, and injection PBS (phosphate buffer saline). Rats in ADSCs group went through CA, CPR, and intravenous injection of ADSCs. Rats in sham group were sacrificed immediately after operation. At 24, 72, and 168 hours after return of spontaneous circulation operation, rats in CA and ADSCs group were randomly selected and sacrificed. Brain damage was evaluated by using Neurological Deficit Scale (NDS) score, hippocampal pathology, serum level of S100beta, and apoptosis ratio of hippocampal neurons. Protein of brain derived neurotrophic factor (BDNF) and IL-6 (interleukin-6) in the hippocampus were detected. RESULTS: Compared with sham group, CA and ADSCs group showed a decrease in NDS score, an increased apoptosis ratio of hippocampal nerve cells, increased serum level of S100-beta, and a significant increase in neuroprotective IL-6 and BDNF. In comparison to CA group, ADSCs group had a mild degree of brain damage and higher expression of IL-6 and BDNF. CONCLUSIONS: In the acute stage of cerebral injury following CA, ADSCs might improve the prognosis of brain damage by stimulating the expression of neuroprotective IL-6 and BDNF. PMID- 30482486 TI - Temporal Profile of CT and T2*-Weighted Gradient-Echo MRI in a Patient with Unilateral Thalamostriate Vein Thrombosis. AB - Deep cerebral venous system thrombosis (DCVST) is an uncommon variety of thrombosis that accounts for 11% of cases of cerebral venous thrombosis. Thalamostriate vein (TSV) thrombosis is further rare among patients with DCVST. Although patients with cerebral venous thrombosis commonly have characteristic neurological deficits including headache, deterioration of consciousness, and seizures, patients with DCVST do not necessarily show such symptoms. Therefore, diagnose of DCVST is sometimes difficult. Here we report a case of TSV thrombosis with a unilateral basal ganglion lesion presenting with right-sided hemiparesis. A 61-year-old Japanese female was referred to our hospital. On neurological examination, she had no headache but presented with right facial paresis with dysarthria. Her right hemiparesis was present in the upper and lower extremities. We repeatedly performed brain computed tomography (CT) and T2*-weighted conventional gradient-echo (GRE) magnetic resonance imaging, and conclusively diagnosed as left TSV thrombosis. We firstly report a case of unilateral DCVST associated with TSV thrombosis in which a temporal profile of CT and T2*-weighted GRE images was obtained. Although DCVST is a rare clinical entity, physicians should be aware that repeated radiological observations can be useful for the diagnosis and early medical treatment for DCVST. PMID- 30482487 TI - Relationship between the Angle of the Posterior Inferior Cerebellar Artery and Cardioembolic Stroke. AB - BACKGROUND: In patients with unilateral posterior inferior cerebellar artery (PICA) territory infarction, the absence of relevant vessel stenosis may make it difficult to determine the etiology of the infarction. The incidence of cardioembolic (CE) infarction and the factors associated with infarction in such patients remains largely unknown. We hypothesized that the PICA angle would affect the flow direction of embolic sources. Thus, we analyzed the association between high-risk CE sources and the PICA angle. METHODS: Patients with an isolated unilateral PICA territory infarction without relevant vessel stenosis who were admitted between 2014 and 2017 were included from the Korea University Stroke Registry, which includes data from 3 university hospitals. We classified patients according to the presence of CE sources. For each case, we measured the angle between the vertebral artery (VA) and the proximal PICA. RESULTS: In all, 71 patients met the final study entry criteria. Multivariable analysis showed that the PICA angle was independently associated with the risk of a CE source. The optimal cut-off value using Youden's index was 89 degrees . We classified the PICA shape based on the optimal cut-off value. A CE source was identified in 83.3% of cases in which the PICA angle exceeded 89 degrees . CONCLUSIONS: The angle between the PICA and VA was an independent predictor of unilateral PICA stroke with high-risk CE sources without relevant artery stenosis, suggesting that an angle greater than 89 degrees could be a new image marker for determining the stroke subtype. PMID- 30482488 TI - Modeling the Impact of Transcendental Meditation on Stroke Incidence and Mortality. AB - OBJECTIVES: Meditation has shown promise in clinical trials in reducing systolic blood pressure, one of the main risk factors for stroke. We aim to estimate the potential benefits of popularizing meditation on stroke incidence and mortality in the United States (U.S.). METHODS: We developed a dynamic population-based microsimulation model to simulate the disease progression of each individual and compute disease burden. We calibrated the microsimulation model for stroke incidence and further validated it by comparing the stroke-related mortality for each age group generated by the model with that observed in the U.S. We used the population simulation model to estimate the effects of meditation intervention on the number of stroke cases and deaths over a course of 15 years. RESULTS: Our results show that we could avert nearly 200,000 stroke cases and 50,000 stroke related deaths over the course of 15 years. Our sensitivity analysis reveals that most of the benefits come from applying the intervention for individuals older than 60 years. In addition, meditation acceptance and adherence rate play a critical role in its effectiveness. CONCLUSIONS: The practice of meditation, if properly utilized along with the regular antihypertensive medication, could substantially alleviate the burden of stroke in the U.S. In order to design an effective meditation program, policymakers may prioritize funding to the programs that aim to encourage older individuals to practice meditation. PMID- 30482489 TI - Restoring self-tolerance in autoimmune diseases by enhancing regulatory T-cells. AB - Self-tolerance, the state of unresponsiveness to self-tissues/antigens, is maintained through central and peripheral tolerance mechanisms, and a breach of these mechanisms leads to autoimmune diseases. Foxp3 + T-regulatory cells (Tregs) play an essential role in suppressing autoimmune response directed against self antigens and thereby regulate self-tolerance. Natural Tregs are differentiated in the thymus on the basis of their higher TCR-affinity to self-antigens and migrate to the periphery where they maintain peripheral tolerance. In addition, extra thymic differentiation of induced Tregs can occur in the periphery which can control abrupt immune responses under inflammatory conditions. A defect in Treg cell numbers and/or function is found to be associated with the development of autoimmune disease in several experimental models and human autoimmune diseases. Moreover, augmentation of Tregs has been shown to be beneficial in treating autoimmunity in preclinical models, and Treg based cellular therapy has shown initial promise in clinical trials. However, emerging studies have identified an unstable subpopulation of Tregs which expresses pro-inflammatory cytokines under both homeostatic and autoimmune conditions, as well as in ex vivo cultures. In addition, clinical translation of Treg cellular therapy is impeded by limitations such as lack of easier methods for selective expansion of Tregs and higher cost associated with GMP-facilities required for cell sorting, ex vivo expansion and infusion of ex vivo expanded Tregs. Here, we discuss the recent advances in molecular mechanisms regulating Treg differentiation, Foxp3 expression and lineage stability, the role of Tregs in the prevention of various autoimmune diseases, and critically review their clinical utility for treating human autoimmune diseases. PMID- 30482490 TI - [Sexual disorders in the renal patient]. AB - Quality of Life Related to Health is currently considered one of the primary therapeutic objectives in renal failure patients who need substitution treatment as life prolonging therapy. Sexual health is a basic right that positively affects the quality of life. Although a significant percentage of chronic patients have some type of sexual dysfunction, this is not openly discussed, making it important for doctors to address these issues in the clinic. A review is presented on the pathophysiology of sexual dysfunctions in both male and female chronic renal patients. The effects of dialysis and transplantation on sexual function will be addressed, as well as presenting the main sexual dysfunctions and their treatment. PMID- 30482491 TI - Effectiveness of a Voice Smoke Alarm Using the Child's Name for Sleeping Children: A Randomized Trial. AB - OBJECTIVES: To test maternal voice alarm effectiveness under residential conditions and determine whether personalizing the maternal voice alarm message with the child's first name improves effectiveness. STUDY DESIGN: Using a randomized, nonblinded, repeated measures design, we compared 3 maternal voice smoke alarms with respect to their ability to awaken 176 children 5-12 years old from stage 4 slow-wave sleep and prompt their performance of an escape procedure. A conventional residential high-frequency tone smoke alarm was used as a comparative reference. Children's sleep stage was monitored in a residence-like research setting. RESULTS: Maternal voice alarms awakened 86%-91% of children and prompted 84%-86% to escape compared with 53% awakened and 51% escaped for the tone alarm. A sleeping child was 2.9-3.4 times more likely to be awakened by each of the 3 voice alarms than the tone alarm. The median time to awaken was 156 seconds for the tone alarm and 2 seconds for each voice alarm. The proportions of children who awakened and escaped differed significantly between the tone alarm and each voice alarm, but no significant differences were found between each pair of the voice alarms, regardless of whether the child's first name was included in the alarm message. CONCLUSIONS: The maternal voice alarms significantly outperformed the tone alarm under residential conditions. Personalizing the alarm message with the child's first name did not increase alarm effectiveness. These findings have important implications for development of an effective and practical smoke alarm for children. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01169155. PMID- 30482492 TI - Low proliferative potential of adipose-derived stromal cells associates with hypertrophy and inflammation in subcutaneous and omental adipose tissue of patients with type 2 diabetes mellitus. AB - BACKGROUND: Obesity and type 2 diabetes mellitus (T2DM) are among the most important morbidity factors. In this study we tested the hypothesis that low proliferative potential of adipose derived stromal cells (ADSC) associates with reduced formation of new fat depots, excess accumulation of fat in the functional adipocytes and their hypertrophy, resulting in fat inflammation and insulin resistance. METHODS: We screened two groups of obese patients with or without T2DM, matched for BMI, age, and duration of obesity to test the hypothesis that hypertrophy and decreased renewal of adipocytes may underlie transition from obesity to T2DM. All patients were matched for carbohydrate metabolism (fasting blood glucose level, glycated hemoglobin, HOMA-IR index and M-index). The subcutaneous and omental fat tissue biopsies were obtained during bariatric surgery from obese individuals with or without T2DM. The morphology and immunophenotype of subcutaneous and omental fat was assessed in frozen tissue sections. ADSC were isolated from both types of fat tissue biopsies and screened for morphology, proliferative potential and inflammatory status. RESULTS: The non diabetic patients had normal carbohydrate metabolism and moderate insulin resistance measured by HOMA-IR and hyperinsulinemic clamp (M-index), while T2DM patients were extremely insulin resistant by both indexes. The average size of diabetic adipocytes was higher than that of non-diabetic in both subcutaneous and omental fat tissues, indicating adipocyte hypertrophy in T2DM. Both these tissues contained higher level of macrophage infiltration and increased M1-like to M2 like ratio of macrophage subpopulations, suggesting increased fat inflammation in T2DM. This was confirmed by increased activatory phosphorylation of stress induced JNK1/2 in diabetic ADSC. CONCLUSION: These results suggest that blunted proliferation and increased hypertrophy of diabetic ADSC may lead to reduced insulin sensitivity via increased inflammation mediated by M1 macrophages and JNK1/2 pathway. PMID- 30482493 TI - Clinical features and long-term outcomes of diabetic kidney disease - A prospective cohort study from China. AB - BACKGROUND: Information regarding the clinical phenotypes of diabetic kidney disease (DKD) might guide better practice for clinicians. We aim to compare the clinical features and long-term outcomes of proteinuric and non-proteinuric phenotypes of DKD, based on a prospective cohort of Chinese population. METHODS: Altogether 8811 Chinese participants with diabetes were included. Kidney function decline was defined as estimated glomerular filtration rate <60 mL/min.1.73 m-2. The presence of proteinuria by urine dipstick test was further divided into micro proteinuria (trace or 1+) and overt-proteinuria (>=2+). Participants were then stratified into 5 groups: no DKD, isolated kidney function decline, isolated micro-proteinuria, isolated overt-proteinuria, and proteinuria combined with kidney function decline. Outcomes include the first occurrence of composite cardiovascular events, end-stage renal disease (ESRD), and all-cause mortality. MAIN FINDINGS: After a median follow-up of 6.9 years, there were 646 composite cardiovascular events, 31 ESRD events, and 718 deaths. Isolated kidney function decline was only associated with the higher risk of ESRD (HRs 31.33 (95% CI 3.65 269.27)). Participants of overt-proteinuria and proteinuria combined with kidney function decline phenotypes were associated with increased risk of all predefined adverse outcomes. CONCLUSIONS: Proteinuric and non-proteinuric DKD phenotypes might follow different pathophysiological pathways, and result in heterogeneous clinical features and prognosis. PMID- 30482494 TI - Clinically significant ventricular arrhythmias and progression of depression and anxiety following an acute coronary syndrome. AB - BACKGROUND: Depression and anxiety are common and associated with worse clinical outcomes in patients who experience an acute coronary syndrome (ACS). We investigated the association between major ventricular arrhythmias (VAs) with the progression of depression and anxiety among hospital survivors of an ACS. METHODS: Patients were interviewed in hospital and by telephone up to 12 months after hospital discharge. The primary outcome was the presence of moderate/severe symptoms of depression and anxiety defined as a Patient Health Questionnaire (PHQ)-9 score >= 10 and a Generalized Anxiety Disorder (GAD)-7 score >= 10 at baseline and 1 month and PHQ-2 >= 3 and GAD-2 >= 3 at 3, 6, and 12 months. We used marginal models to examine the association between major VAs and the symptoms of depression or anxiety over time. RESULTS: The average age of the study population (n = 2074) was 61.1 years, 33.5% were women, and 78.3% were white. VAs developed in 105 patients (5.1%). Symptoms of depression and anxiety were present in 22.2% and 23.5% of patients at baseline, respectively, and declined to 14.1% and 12.6%, respectively, at 1-month post-discharge. VAs were not significantly associated with the progression of symptoms of depression (adjusted relative risk [aRR] = 1.29, 95% confidence interval [CI] = 0.94-1.77) and anxiety (aRR = 1.22, 95% CI = 0.86-1.72), or with change in average scores of PHQ-2 and GAD-2 over time, both before and after risk adjustment. CONCLUSION: The prevalence of symptoms of depression and anxiety was high after an ACS but declined thereafter and may not be associated with the occurrence of major in hospital VAs. PMID- 30482495 TI - Analysis of the Increase in Bone Mineral Density After Surgical Treatment of Primary Hyperparathyroidism. AB - AIM: To analyze the effect of the surgery in bone mineral density (BMD) and to study the value of preoperative clinical and analytical factors as predictors of bone increase. MATERIAL AND METHODS: Prospective observational study. Postmenopausal women who were operated for primary hyperparathyroidism were included. A bone densitometry of the lumbar spine and femoral neck and analytical determinations (parathyroid hormone [PTH], alkaline phosphatase, albumin, phosphate, creatinine, 25-hydroxy-vitamin D3, creatinine clearance, and calciuria) were performed previous to the intervention and after 12 months from surgery. RESULTS: Two hundred and twenty-eight patients were operated on for primary hyperparathyroidism were considered for study, 108 postmenopausal women entered in the final analysis. The mean age was 63 +/- 7 yr. After the intervention, a significant increase in BMD was observed in the two locations analyzed, although this increase was significant greater at the level of the lumbar spine. In the lumbar spine, 68 patients (63%) recorded a significant postoperative increase in bone density. Median postoperative BMD was 0.860 g/cm2 (interquartile range: 0.93). The observed average percentage of density increase was 6.63 +/- 17.9. In femoral neck, 61 patients (56.6%) registered a significant increase in bone density. Median postoperative BMD value was 0.741 g/cm2 (interquartile range: 0.76). The average percentage of density increase was 3.19 +/- 17.9. In the lumbar spine, patients with osteoporosis before surgery increased postoperative BMD more frequently than those with osteopenia or normal density. Patients who increased BMD preoperatively presented lower bone density levels both in the lumbar spine (median: 0.775, interquartile range: 0.882) and in the hip (median: 0.655, interquartile range: 0.562) than patients in whom it was not observed postoperative increase. PTH preoperative serum was lower among patients who increased bone density in the femur (median: 141 pg/ml, interquartile range: 291) than among those who did not (median: 152 pg/ml, interquartile range: 342) (p = 0.01). In the multivariate analysis, the increase in BMD in the lumbar spine was related to preoperative BMD (odds ratio [OR] 0.084, 95% confidence interval [CI]: 0.007-0.961); in femoral neck it was related to preoperative BMD (OR 0.001; 95% CI: 0.0-0.028) and to the preoperative PTH serum concentration (OR 0.99; 95% CI: 0.98-0.99). CONCLUSIONS: After surgery, a significant increase in BMD was observed in the lumbar spine and femoral neck. In the multivariate analysis, preoperative bone density was the factor that showed the highest predictive value of the increase in BMD after surgery. PMID- 30482496 TI - Bone Density at the Entry Point Correlates With the Trabecular Bone of the Thoracolumbar Vertebral Bodies - Quantitative Computed Tomography Study. AB - PURPOSE: To evaluate the relationship between cortical Bone Mineral Density (BMD) at pedicle entry points with trabecular BMD of the vertebral body in a spinal fracture. METHODS: Quantitative computed tomography of the thoracolumbar spine was analyzed using dedicated software - QCT Pro (Mindways, Austin, TX). RESULTS: Forty-six patients were evaluated. Among them 36 females were diagnosed with osteoporosis; the remaining 10 randomly selected from the database both males and females served as a control group. Overall measurements for 138 vertebrae were assessed. Cortical BMD of entry points for transpedicular screws was higher than trabecular vertebral BMD in osteoporotic (p < 0.001) and non-osteoporotic patients (p = 0.003). The difference was 3.6 times higher in low BMD cases (osteoporosis), compared to 2.3 times in normal subjects. Spearman's rank correlation coefficient showed the strongest correlation between patient's age and trabecular bone mineral density of L1 vertebral body (r = -0.94, p < 0.05), while cortical entry points were less correlated (r = -0.8, p < 0.05 and r = 0.65, p < 0.05 for left and right entry points, respectively). The strength of the correlations between BMD and age decreased gradually from L1 to L4, from r = 0.94 to r = -0.58 for the trabecular vertebral body; from r = -0.8 to r = -0.37 for entry points. Significant correlations were not found for BMD and the height or weight of the patients. CONCLUSIONS: Cortical BMD at pedicle entry points decreases with osteoporosis. The relative contribution of cortical vs trabecular BMD increases with osteoporosis. Vertebral trabecular BMD is highly correlated with the cortical BMD of the entry points and allows predicting the bone support in fracture cases. PMID- 30482497 TI - The biomechanical properties of the urethra in boys with hypospadias: a preliminary study. AB - PURPOSE: The ventral aspect of the penis in boys with hypospadias is composed of dysplastic tissue of the skin and the urethra. The aim of this study was to assess the pre-operative size and biomechanical properties of urethrae in boys with and without hypospadias using a more objective catheter-based system. MATERIALS & METHODS: In this non-blinded clinical observation study, the study population consisted of 19 boys with hypospadias-the case group (median age 13.9 months [range: 12.2-21.3])-and seven boys without hypospadias-the control group (median age 8.5 months [range: 3.8-18.1]). Modified measurements of impedance were used to assess the size, compliance and viscoelasticity of the urethrae under stepwise increased pressures (between 0, 40 and 60 cmH2O) using a customised Endolumenal Functional Lumen Imaging probe (EndoFLIP(r)). RESULTS: The sizes of the urethrae in boys with hypospadias are variable but tend towards being narrower and less compliant than those of the control subjects i.e. median diameter for meatus urethra was 3.2 mm (range: 2.98-3.92) in the hypospadias group compared with 3.64 (range: 3.22-4.44) in the control group at 40 cmH2O, and the median change in diameter at meatus urethra was 0.08 mm (range: -0.02 to 0.52) in the hypospadias group compared with 0.23 mm (range: -0.02 to 0.34) when the pressure was increased from 40 to 60 cmH2O. This biomechanical analysis found that there was no significant viscoelasticity of the urethral meatus in both the groups, whereas the remainder of the urethral structure generally had viscoelastic properties in the control group, seen as a creep on the time/diameter curves (Figure). In the group of boys with hypospadias, evaluations of the urethrae revealed varying viscoelastic abilities, ranging from abilities that were comparable with those of the control subjects to no sign of viscoelasticity at all. CONCLUSIONS: This study is the first to measure the biomechanical properties of the urethra in children, which might help to provide an understanding as to the structural and functional changes associated with hypospadias. The urethrae in the subjects with hypospadias were variable in diameter but tended to be narrower overall, especially in the distal portion of the urethra. Furthermore, the urethrae in boys with hypospadias were frequently less viscoelastic than those of controls. CLINICAL RELEVANCE: The EndoFLIP(r) system may be a future way of objectively estimating the severity of a urethral obstruction and could potentially be included in the postoperative assessment of patients with signs of hampered voiding. PMID- 30482498 TI - Surgical management of genitourinary lichen sclerosus et atrophicus in boys in England: A 10-year review of practices and outcomes. AB - INTRODUCTION: Circumcision has long been the mainstay of management for genitourinary lichen sclerosus et atrophicus (LS); however, there has been growing interest in surgical techniques that preserve the foreskin. OBJECTIVE: The aim of this study was to assess population-based surgical management of LS in England and determine surgical outcomes. STUDY DESIGN: Cases of LS treated in English NHS trusts (2002-2011) were extracted from the Hospital Episode Statistics (HES) Database. Cases were identified by both an ICD-10 code for LS and either an OPCS4.6 code for circumcision or preputioplasty (with/without injection of steroid). Subsequent admissions were analysed for related complications/procedures. Data are presented as median (interquartile range) unless otherwise stated. RESULTS: 7893 patients had surgery for LS, of whom 7567 (95.8%) underwent circumcision (Table). Primary preputioplasty was performed in 326 (4.1%) in 44/130 centres; of these 151/326 had concomitant injection of steroid. Age at surgical intervention was 9 (6-11) years. There were no postoperative bleeds following preputioplasty. Of those treated with preputioplasty, 74 (22%) had subsequent circumcision at a median of 677 (277 1203) days post operation. Concomitant steroid injection reduced the risk of subsequent circumcision (21/151 (14%) vs. 53/175 (30%), p < 0.001). More children underwent a second operative procedure following preputioplasty than those having had a primary circumcision (27.9% vs. 7.9%, p < 0.001). CONCLUSION: Although circumcision is the predominant treatment for LS, these data suggest that preputioplasty is a valid option in management, albeit with a higher re intervention rate. Selection bias may play a role and a randomized controlled trial is needed. Preputioplasty combined with steroid injection appears to reduce the chance of completion circumcision. PMID- 30482499 TI - A meta-analysis of the incidence and fate of contralateral vesicoureteral reflux in unilateral multicystic dysplastic kidney. AB - INTRODUCTION: Multicystic dysplastic kidney (MCDK) is the most common type of renal cystic disease. It is associated with urinary tract abnormalities in the contralateral kidney in up to 30% of cases, most commonly vesicoureteral reflux (VUR). OBJECTIVES: The objective of this study were to describe the incidence and selected issues in management and evolution for each VUR grade in the contralateral kidney of patients with unilateral MCDK to strengthen the scientific basis regarding the need for voiding cystourethrography (VCUG) screening. METHODS: A comprehensive search of standard and gray literature was performed. Full-text screening, data abstraction, and quality appraisal were conducted in duplicates. Included studies reported a primary diagnosis of unilateral MCDK with contralateral VUR determined by VCUG. Articles had to include a distribution of VUR grade to meet the eligibility criteria. RESULTS: From 698 retrieved articles, 37 studies enrolling 2057 patients were analyzed. A proportion of 80% were males; 50% had left unilateral MCDK; and 87% were diagnosed prenatally. A total of 1800 patients had VCUG, of whom 303 had VUR (weighted proportion: 17%; 95% confidence interval [CI]: 14-20%). Weighted proportions of VUR were 9%, 7%, and 17% for grades I-II, III-V, and I-V, respectively. A proportion of 99% (95% CI: 97-100%) of patients were on continuous antibiotic prophylaxis (CAP) and 18% (95% CI: 8-37%) had urinary tract infections (UTIs), with a higher rate of UTIs (23% vs 10%) in patients with dilating (grades III-V) VUR, over a mean follow-up of 40 months. In patients with dilating VUR, reflux resolved or downgraded to grade I in 52% (95% CI: 37-67%) of patients, and 32% (95% CI: 19-49%) had surgical correction of VUR. CONCLUSIONS: Among patients with unilateral MCDK, 17% have VUR in the contralateral kidney, 41% of which is dilating VUR. Of the cases with dilating VUR, half will resolve or downgrade to grade I during follow-up; 23% will develop a UTI despite CAP; and one-third will undergo ureteral re-implantation. While many physicians may thus choose to forego routine VCUG screening of the single functional kidney, shared decision-making with the patient's caregivers is currently recommended, where the risks and benefits of the different approaches can be discussed. The data from this analysis can help inform the discussions. PMID- 30482500 TI - Kinetic modeling and sensitivity analysis for higher ethanol production in self cloning xylose-using Saccharomyces cerevisiae. AB - We constructed a xylose-utilizing Saccharomyces cerevisiae strain using endogenous xylose-assimilating genes (strain K7-XYL). Such self-cloning yeast is expected to make a great contribution to cost reduction of ethanol production processes. However, it is difficult to modify self-cloning yeast for optimal performance because the available gene source is limited. To improve the ethanol productivity of our self-cloning yeast, a kinetic model of ethanol production was constructed and sensitivity analysis was performed. Alcohol dehydrogenase (ADH1) was identified as a metabolic bottleneck reaction in the ethanol production pathway. An ADH1 overexpression strain (K7-XYL-ADH1) was constructed and evaluated in YP (yeast extract 10 g/L, peptone 20 g/L) medium containing 50 g/L xylose as the sole carbon source. Strain K7-XYL-ADH1 showed higher ethanol productivity (13.8 g/L) than strain K7-XYL (12.5 g/L). Then, K7-XYL-ADH1 was evaluated in YP medium containing 80 g/L glucose and 50 g/L xylose; however, the ethanol productivity did not change relative to that of K7-XYL (K7-XYL 46.3 g/L, K7-XYL-ADH1 45.9 g/L). We presumed that due to the presence of glucose, the internal redox balance of the cells had changed. On culturing in an aerated 5-L jar fermentor to change the internal redox balance of cells, strain K7-XYL-ADH1 showed higher ethanol productivity than K7-XYL (K7-XYL 45.0 g/L, K7-XYL-ADH1 49.4 g/L). Our results confirmed that ADH1 was a metabolic bottleneck in the ethanol production pathway. By eliminating the bottleneck, self-cloning yeast showed almost the same ethanol productivity as genetically modified yeast. PMID- 30482501 TI - Dysregulation of Kruppel-like factor 12 in the development of endometrial cancer. AB - OBJECTIVE: Endometrial cancer (EC) remains a malignancy with poor survival outcome. To investigate the role of Kruppel-like factor 12 (KLF12), a transcription factor, in the progression of human EC. METHODS: Immunohistochemistry, real time-PCR and western blot analysis of KLF12 expression in EC patients' tissues. Bioinformatics analysis revealed the clinical importance of KLF12 expression and survival ratio. Overexpression of KLF12 was generated using the ViraPower Adenoviral Expression System in EC cell lines. Cell viability assay, cell apoptosis assay and cell migration assay were used to determine cell proliferation, cell apoptosis and cell migration, respectively. Western blot analysis was carried out to determine the protein levels in cell lines and animal tissues. RESULTS: The expression of KLF12 was observed to be much higher in human EC tissues compared with normal endometrium. Moreover, KLF12 expression was correlated positively with disease recurrence and was also associated with decreased survival probability. The overexpression of KLF12 in EC cell lines resulted in increased cell proliferation, decreased cell apoptosis and enhanced cell migration. Furthermore, overexpression of KLF12 also increased tumor size in vivo. Moreover, up-regulation of KLF12 dramatically increased the expression levels of MMP2, MMP9, pAKT S473 and CCND1. Our research reveals that overexpressed KLF12 contributes the growth of EC tumor by activating AKT signaling and increasing CCND1expression level. CONCLUSIONS: To our knowledge, this is the first study to explore the significance of KLF12 in the development of EC, and KLF12 is expected to provide a novel potential therapeutic target for EC treatment. PMID- 30482502 TI - Neuroimaging in dementia. Clinical-radiological correlation. AB - Dementia is a syndrome characterised by chronic, multi-domain, acquired cognitive impairment that causes significant functional limitations. MRI is the standard imaging study for these cases, since it enables detection of the atrophy patterns of the various neurodegenerative diseases (Alzheimer's disease, frontotemporal degeneration, Lewy body dementia), the vascular lesions associated with vascular dementia, and various potentially reversible diseases (for example, tumours, hydrocephaly) or diseases that require special management measures (for example, prion diseases). In certain cases other imaging methods can be used, such as CT, functional MRI, HMPAO SPECT or dopaminergic markers and FDG PET, amyloid markers or dopaminergic markers. The indications for these methods have not yet been clearly established, and therefore should be used in multidisciplinary dementia units. PMID- 30482503 TI - The Role of Microbiota in Cardiovascular Risk: Focus on Trimethylamine Oxide. AB - The extensive collection of bacteria cohabiting within the host collaborates with human functions and metabolisms in both health and disease. The fine equilibrium of commensals is tightly controlled and an imbalance ("dysbiosis") in the gut microbiota can play different roles in human disease. The development of new genome sequencing techniques has allowed a better understanding of the role of human gut microbiota. This led to the identification of numerous metabolites produced in the gut, which have been suggested to play a role in human disease. Among these, trimethylamine oxide (TMAO) appears to be of particular importance as a risk factor and potentially as a causative agent of various pathologies, most remarkably cardiovascular and disease and other associated conditions. Mechanistic links are yet to be established, however, increased levels of TMAO have been shown to augment the risk of developing renal failure, metabolic syndrome, diabetes mellitus, heart failure, hypertension, atherosclerosis, and dyslipidemia ultimately leading to increased risk of serious cardiovascular events. This article reviews the potential impact of TMAO in human cardiovascular disease. PMID- 30482504 TI - Mimosine accumulation in Leucaena leucocephala in response to stress signaling molecules and acute UV exposure. AB - Mimosine is a non-protein amino acid of Fabaceae, such as Leucaena spp. and Mimosa spp. Several relevant biological activities have been described for this molecule, including cell cycle blocker, anticancer, antifungal, antimicrobial, herbivore deterrent and allelopathic activities, raising increased economic interest in its production. In addition, information on mimosine dynamics in planta remains limited. In order to address this topic and propose strategies to increase mimosine production aiming at economic uses, the effects of several stress-related elicitors of secondary metabolism and UV acute exposure were examined on mimosine accumulation in growth room-cultivated seedlings of Leucaena leucocephala spp. glabrata. Mimosine concentration was not significantly affected by 10 ppm salicylic acid (SA) treatment, but increased in roots and shoots of seedlings treated with 84 ppm jasmonic acid (JA) and 10 ppm Ethephon (an ethylene releasing compound), and in shoots treated with UV-C radiation. Quantification of mimosine amidohydrolase (mimosinase) gene expression showed that ethephon yielded variable effect over time, whereas JA and UV-C did not show significant impact. Considering the strong induction of mimosine accumulation by acute UV-C exposure, additional in situ ROS localization, as well as in vitro antioxidant assays were performed, suggesting that, akin to several secondary metabolites, mimosine may be involved in general oxidative stress modulation, acting as a hydrogen peroxide and superoxide anion quencher. PMID- 30482505 TI - Simultaneous integrated boost by Intensity Modulated Radiotherapy (SIB-IMRT) in patients undergoing breast conserving surgery - A clinical and dosimetric perspective. AB - AIM: To study feasibility of simultaneous integrated boost by intensity modulated radiotherapy (SIB-IMRT) in patients undergoing breast conserving surgery and its impact on cosmesis and dosimetry. PATIENTS AND METHODS: Between January 2014 and June 2017, all breast cancer patients fulfilling inclusion and exclusion criteria were enrolled in a prospective study conducted at a tertiary cancer centre in North India. All patients received adjuvant radiotherapy by simultaneous integrated boost technique following breast conserving surgery. Clinical information including patient and pathological characteristics, observed acute and chronic toxicities along with cosmesis using Harvard score were recorded and analysed. Univariate analysis and multivariate logistic regression analysis were performed for those variables which were found to be significant (p < 0.050) to study the influence of clinicopathological and dosimetric factors on toxicity and cosmetic outcome. RESULTS: Maximum acute skin toxicity during treatment was Grade 0-1 in 68.2% and Grade 2-3 in 31.8% of cases, respectively. Fibrosis was the commonest late toxicity with >=Grade II fibrosis being noted in 16.3% of cases. Assessment of global cosmesis at 12 months follow-up showed good/excellent cosmesis in 88.4% of cases. Mean age, tumor size and homogeneity index (HI) were the significant factors associated with fair or poor cosmetic outcome and >=Grade 2 fibrosis on multivariate analysis. Telengectasia and breast edema were more frequent in patients with larger tumor size/GTV volume. There were 5 recurrences including 1 ipsilateral local breast tumor recurrence. CONCLUSION: SIB-IMRT is a dosimetrically feasible option in patients undergoing breast conserving surgery and provides good/excellent cosmetic outcome. PMID- 30482506 TI - Laryngeal synovial sarcoma: Report of 2 cases. AB - Synovial sarcoma is a malignant mesenchymal tumor. It most commonly occurs in the lower extremities of young adults. The head and neck are rare sites, accounting for less than 10%. The larynx is an extremely rare site. We report two cases of 27 and 18 year-old men who developed a synovial sarcoma of the larynx. They presented with hoarseness of voice and hemoptysis. Endoscopy detected a mass in the supraglottic region. The biopsy concluded a synovial sarcoma. Immunohistochemistry conveyed diagnostic certainty. They had been treated with total laryngectomy and post-operative radiotherapy. The 2 patients are seen for regular follow-ups in our department and they remained recurrence-free for 10 years and 24 months, respectively. Synovial sarcoma is a very rare tumor of the larynx. A multidisciplinary therapeutic approach is essential for the management of this malignancy. Long-term follow-up is required to monitor for recurrence and improve disease-free survival. PMID- 30482507 TI - Leptin in sperm analysis can be a new indicator. AB - Purpose Radiotherapy, chemotherapy, various tumors and invasive surgery can result in ejaculatory dysfunction and testicular insufficiency. Sperm cryopreservation is the only method which can provide a baby for couples. Cryopreservation freezes tissues and cells, allowing them to be stored for future use by stopping all biological activities. Cryopreservation can cause some harmful changes in the structure and function of the sperm. Leptin molecule plays many roles in most biological processes including the satiety and cell renewal, proliferation, angiogenesis, modulation of energy expenditure and regulation of the neuroendocrine system. Leptin was also reported to be associated with spermatogenesis in several studies. Methods This study aims to use leptin molecule as a parameter for sperm motility and DNA fragmentation before and after the cryopreservation. In this study, semen samples were taken from 30 normospermic male volunteers. Each semen sample was examined for the same parameters before and after the cryopreservation. Samples were analyzed before and after cryopreservation in terms of sperm motility by morphological sperm analysis with spermac stain dye, DNA fragmentation by TUNEL assay, ultrastructural analysis with transmission electron microscopy (TEM), seminal leptin levels by ELISA method and reactive oxygen species (ROS) levels by colorimetric method. Results Decreased sperm motility, distribution of sperm morphology and increased DNA fragmentation were determined after cryopreservation. Similarly, seminal ROS and leptin levels were also increased significantly. There was a negative correlation between seminal leptin and sperm motility. Additionally, there was a positive correlation between seminal leptin and DNA fragmentation. Conclusion According to these results, leptin molecule can be used as a marker for sperm motility and DNA fragmentation before and after cryopreservation. We think that the results of this study can contribute to further studies in the clinical aspect. PMID- 30482508 TI - The Macaroni Sign: The Pathognomonic Ultrasonography Sign of Takayasu Arteritis. PMID- 30482509 TI - Prognostic Factors for Sustained Remission in a "Real Life" Cohort of Rheumatoid Arthritis Patients. AB - INTRODUCTION: Rheumatoid arthritis (RA) is the most frequent chronic polyarthritis. The current goal of RA treatment is to achieve clinical remission. OBJECTIVE: The goal of this study was to determine the prevalence of remission in a cohort of patients from clinical practice, and to identify potentially modifiable factors associated with remission. METHODS: A retrospective study was performed on a cohort of RA patients seen at the first consultation at the HUGC Rheumatology Service Dr. Negrin (HUGCDN) between first of January 2000 and thirtieth of April 2014. Sustained remission was defined as DAS28 less than 2.6 in the last two available visits in the medical history. RESULTS: A total of 463 patients were consecutively included, most (75%) women, with a mean age at the onset of RA of 50 years and a mean duration of the disease at follow-up of 8 years. 46% of the patients achieved sustained remission. Multiple logistic regression analyses found male sex (P=.031, OR 1.7, 95% CI 1.05-2.82), diagnosis in the first year of symptoms (P=.023, OR 1.7, 95% CI 1.07-2.69) and the initial DAS28 (P=.035) to be independent predictors for sustained remission. CONCLUSIONS: The 46% of the patients with RA followed in the HUGC Dr. Negrin are in persistent remission, being the early diagnosis a modifiable factor predictor of remission. Thus, an objective of the Rheumatology Service should be to improve the diagnostic delay of RA in the health area. PMID- 30482510 TI - Adjunctive effect of orthokeratology and low dose atropine on axial elongation in fast-progressing myopic children-A preliminary retrospective study. AB - PURPOSE: To investigate the adjunctive effect of orthokeratology (ortho-k) and low-dose atropine eye drops on axial length elongation in fast-progressing myopic children. METHODS: Axial elongation in 60 eyes of 60 subjects who completed two years of ortho-k treatment was retrospectively reviewed. They were aged between 5.6-11.6 (mean, 8.3 +/- 1.5) years old when they started ortho-k treatment. During their first year of ortho-k treatment (Phase One), they all demonstrated a faster than 0.25 mm/yr axial elongation rate. They were then treated with nightly 0.01% atropine in addition to ortho-k treatment for another year (Phase Two). Annual axial elongation rates before and after atropine treatment were compared. RESULTS: Baseline spherical equivalent refractive error was -2.65 +/- 1.08 DS and axial length was 24.34 +/- 0.92 mm for the study cohort. The mean axial elongation rate was 0.46 +/- 0.16 mm/yr during Phase One, being significantly faster in younger children (t = -4.920, P < 0.001). When atropine was added, annual axial elongation rate significantly decreased to 0.14 +/- 0.14 mm/yr (t = 11.988, P < 0.001), and those who were fast progressors in Phase One had a greater reduction in the rate of axial elongation during Phase Two (t = -8.052, P < 0.001). CONCLUSIONS: Axial elongation rate is faster in younger children undergoing ortho-k treatment. For fast myopia progressors, low dose atropine may significantly slow axial elongation in addition to ortho-k's treatment effect. Those who have faster axial elongation after ortho-k treatment will benefit more from the addition of low dose atropine, regardless of their refractive error and age. PMID- 30482511 TI - The effect of pregnancy on tear osmolarity. AB - OBJECTIVE: To examine the effect of pregnancy on the lacrimal system through tear osmolarity measurement and the Schirmer test. MATERIAL AND METHOD: The study consisted of two groups of 30 women between 20 and 40 years old; the women in the study group were in their first trimester of pregnancy, and the women in the control group were not pregnant and did not have any diseases other than refractive error. Tear osmolarity measurement with the TearLab osmolarity system and tear function test Schirmer 1 were carried out on one, randomly chosen eye of each participant. The pregnant women's measurements were repeated on the same eye in their last trimester. RESULTS: The study group's first trimester tear osmolarity measurement was 304.9 +/- 8.0 mOsm/L, while their last trimester tear osmolarity measurement was 300.2 +/- 7.1mOsm/L and the control group's was 306.3 +/- 6.2 mOsm/L. There was a statistical difference between the study group's first and last trimester results and between the study group's last trimester and the control group's results (p < 0.05). The Schirmer test results were 18.1 +/- 6.3 mm for the study group's first trimester, 16.6 +/- 6.9 mm for the last trimester and 21.3 +/- 9.0 mm for the control group. There was a statistically significant difference between the study group's last trimester results and the control group's Schirmer test results (p < 0.05). CONCLUSION: Both the tear osmolarity values and Schirmer values were found to decrease significantly towards the end of pregnancy. These results suggest that decrease in both test results may play a protective role in the ocular surface during pregnancy. PMID- 30482512 TI - Antenatal education for pregnant women attending maternal and child health clinics in Brunei Darussalam. AB - BACKGROUND: Antenatal education is an essential component of antenatal care that prepares and facilitates the acquisition of women's skills and confidence required for positive experiences throughout pregnancy, birth and the postnatal period. AIM: To evaluate pregnant women's experiences of education during the antenatal period in Brunei Darussalam. METHODS: A descriptive cross-sectional study was conducted using a pre-designed instrument to examine the provision of antenatal education among 110 pregnant women attending two major Maternal and Child Health Clinics in Brunei Darussalam. The quantitative data was analysed descriptively whereby the scores of each scale was calculated and reported accordingly. FINDINGS: A majority of participants possess good health knowledge and live a healthy lifestyle. They have a positive perception about baby and postnatal care. However, participants only possess average knowledge about practical health techniques. DISCUSSION: Overall, the majority of women were satisfied with the antenatal education provided in the Maternal and Child Health Clinics in Brunei Darussalam. Good rapport and interactive learning were the two most quoted important characteristics in antenatal education classes. Breastfeeding, which required both practical knowledge and the acquisition of skills was found to be the most interesting antenatal education topic. Antenatal education provided through verbal information was identified as the least interesting to the women. CONCLUSION: This first study, which aimed to evaluate antenatal education in Brunei Darussalam could provide baseline data and guide strategies to engage pregnant women and relevant agencies in antenatal education. Future studies involving a more in-depth exploration of the women's experiences are recommended. PMID- 30482513 TI - Characterization of the bacterial microbiota in wild-caught Ixodes ventalloi. AB - Exploring the microbial diversity of ticks is crucial to understand geographical dispersion and pathogen transmission. Tick microbes participate in many biological processes implicated in the acquisition, maintenance, and transmission of pathogens, and actively promote host phenotypic changes, and adaptation to new environments. The microbial community of Ixodes ventalloi still remains unexplored. In this study, the bacterial microbiota of wild-caught I. ventalloi was characterized using shotgun-metagenomic sequencing in samples from unfed adults collected during December 2013-January 2014 in two locations from Sicily, Italy. The microbiota identified in I. ventalloi was mainly composed of symbiotic, commensal, and environmental bacteria. Interestingly, we identified the genera Anaplasma and Borrelia as members of the microbiota of I. ventalloi. These results advance our information on I. ventalloi microbiota composition, with potential implications in tick-host adaptation, geographic expansion, and vector competence. PMID- 30482515 TI - Review of catastrophic hand diagnosis over 15 years in a tertiary hospital: do we make proper use of the term? AB - OBJECTIVE: To describe the characteristics of patients diagnosed with 'catastrophic hand' by the plastic surgery department in a tertiary hospital in the period between 2000-2015, analyse the evolution of the use of the term 'catastrophic hand' and conduct a review of the literature with a view to proposing the optimal definition for said expression. MATERIAL AND METHOD: We conducted a descriptive and retrospective study of patients diagnosed with 'catastrophic hand' who required hospital care by the plastic surgery department of a tertiary hospital in the period between 2000-2015. We conducted a literature review on the use of the term 'catastrophic hand' and we applied the classifications proposed in the publications consulted to our results. RESULTS: The number of 'catastrophic hand' diagnoses was 133. We observed a downward trend in the use of the term over the years. Applying classifications based on the impossibility of recovery of an acceptable hand (presence of three long fingers and thumb) by reconstructive procedures, only 9 out of 133 patients could be considered to have 'catastrophic hands', constituting 6.7% of the total cases. DISCUSSION: The term 'catastrophic hand' has different meanings, and this generates ambiguity. The use of a classification based on the possibility of obtaining an acceptable hand diminishes its use and improves the approach for such injuries. CONCLUSION: We advocate limiting the use of 'catastrophic hand' to cases that meet criteria of 'mutilated hand' and 'metacarpal hand' to avoid indiscriminate use of the term and optimise therapeutic management. PMID- 30482514 TI - Discoid meniscus in children and adolescents: Correlation between morphology and meniscal tears. AB - BACKGROUND: Some authors have suggested that the diminished vascular blood supply, peripheral stability and thickness of the discoid meniscus (DM) would make it more prone to tears. The aims of this study are two-fold: 1) To analyse morphological characteristics by magnetic resonance (MRI), and 2) To correlate the size of the meniscus with the presence of meniscal tears. METHODS: The MRI of patients <=18 years-old over a period of 5 years were reviewed, and patients with DM were identified. We analysed demographic data, location (medial or lateral), morphology (Watanabe), meniscal tears (Crues classification), pattern, displacement, and other associated findings. Meniscal height and thickness per width (TxW) were also calculated. The correlation between variables: morphology, height and TxW with the presence of meniscal tears were statistically analysed. RESULTS: Six hundred and eighty-five MRI (675 patients) were analysed. Forty three knees (38 patients, 20 males) were found to have a DM (6.3%). The average age was 12.2+/-3.8 years (range: 4-18 years). Sixty-three percent had some type of meniscal injury. Patients with complete MD had a higher incidence of injuries (77.3 vs. 47.6%; P=.001). Longitudinal (bucket handle) and complex tears (n ??=11) only occurred in patients with complete DM. DM with tears presented a nonsignificant tendency to have higher meniscal height and higher TxW (6.29+/ 1.26 vs 5.75+/-.66mm; P=.20 and 107.5+/-36.02 vs. 91.54+/-16.5mm2; P=.162). CONCLUSION: The results of this series support the theory that a larger meniscal size would be one of the main predisposing factors for the DM to be injured. STUDY DESIGN: Cross-sectional study (Level of evidence: III). PMID- 30482516 TI - Does the Severe Sepsis and Septic Shock Early Management Bundle (SEP-1) Improve Survival in Septic Adults? PMID- 30482517 TI - Simultaneous hepatic and portal vein ligation induces rapid liver hypertrophy: A study in pigs. AB - BACKGROUND: Liver hypertrophy induced by partial portal vein occlusion (PVL) is accelerated by adding simultaneous parenchymal transection ("ALPPS procedure"). This preclinical experimental study in pigs tests the hypothesis that simultaneous ligation of portal and hepatic veins of the liver also accelerates regeneration by abrogation of porto-portal collaterals without need for operative transection. METHODS: A pig model of portal vein occlusion was compared with the novel model of simultaneous portal and hepatic vein occlusion, where major hepatic veins draining the portal vein-deprived lobe were identified with intraoperative ultrasonography and ligated using pledgeted transparenchymal sutures. Kinetic growth was compared, and the portal vein system was then studied after 7 days using epoxy casts of the portal circulation. Portal vein flow and portal pressure were measured, and Ki-67 staining was used to evaluate the proliferative response. RESULTS: Pigs were randomly assigned to portal vein occlusion (n = 8) or simultaneous portal and hepatic vein occlusion (n = 6). Simultaneous portal and hepatic vein occlusion was well tolerated and led to mild cytolysis, with no necrosis in the outflow vein-deprived liver sectors. The portal vein-supplied sector increased by 90 +/- 22% (mean +/- standard deviation) after simultaneous portal and hepatic vein occlusion compared with 29 +/- 18% after PVL (P < .001). Collaterals to the deportalized liver developed after 7 days in both procedures but were markedly reduced in simultaneous portal and hepatic vein occlusion. Ki-67 staining at 7 days was comparable. CONCLUSION: This study in pigs found that simultaneous portal and hepatic vein occlusion led to rapid hypertrophy without necrosis of the deportalized liver. The findings suggest that the use of simultaneous portal and hepatic vein occlusion accelerates liver hypertrophy for extended liver resections and should be evaluated further. PMID- 30482518 TI - The impact of R1 resection for colorectal liver metastases on local recurrence and overall survival in the era of modern chemotherapy: An analysis of 1,428 resection areas. AB - BACKGROUND: It is still unclear whether a positive surgical margin after resection of colorectal liver metastases remains a poor prognostic factor in the era of modern perioperative chemotherapy. The aim of this study was to evaluate whether preoperative chemotherapy has an impact on reducing local recurrence after R1 resection, and the impact of local recurrence on overall survival. METHODS: Between 2000 and 2014, a total of 421 patients underwent resection for colorectal liver metastases at our unit after preoperative chemotherapy. The overall number of analyzed resection areas was 1,428. RESULTS: The local recurrence rate was 12.8%, significantly higher after R1 resection than after R0 (24.5% vs 8.7%; P < .001). These results were also confirmed in patients with response to preoperative chemotherapy (23.1% after R1 vs 11.2% after R0; P < .001). At multivariate analysis, R1 resection was the only independent risk factor for local recurrence (P < .001). At the analysis of the 1,428 resection areas, local recurrence significantly decreased according to the increase of the surgical margin width (from 19.1% in 0 mm margin to 2.4% in >=10 mm). At multivariable logistic regression analysis for overall survival, the presence of local recurrence showed a significant negative impact on 5-year overall survival (P < .001). CONCLUSION: Surgical margin recurrence after modern preoperative chemotherapy for colorectal liver metastases was still significantly higher after R1 resection than it was after R0 resection. Local recurrence showed a negative prognostic impact on overall survival. R0 resection should be recommended whenever technically achievable, as well as in patients treated by modern preoperative chemotherapy. PMID- 30482519 TI - Operation duration and adrenal gland size, but not BMI, are correlated with complication rate for posterior retroperitoneoscopic adrenalectomy for benign diseases. AB - BACKGROUND: We sought to determine whether obesity is correlated with complications after posterior retroperitoneoscopic adrenalectomy for benign diseases and to develop surrogate markers of abdominal fat in preoperative computed tomography. METHODS: We conducted a retrospective chart review of all patients who had undergone posterior retroperitoneoscopic adrenalectomy and preoperative computed tomography between January 1, 2008 and December 31, 2015. The cross-sectional components of fat assessed by computed tomography included total fat area, subcutaneous fat area, retroperitoneal fat area, and peritoneal fat area. The patients were grouped into 2 categories according to the absence or presence of a postoperative complication (the no-complications group and the complications group, respectively). RESULTS: Of 116 study patients, 20 patients (17%) had a postoperative complication. Operations of greater duration and smaller adrenal gland size were significantly correlated with complications both in univariate and multivariate analyses. Body mass index, total fat area, subcutaneous fat area, retroperitoneal fat area, peritoneal fat area, and distance of skin to muscle (in axial and sagittal images) correlated with complications in univariate analysis but not in multivariate analysis. In the no complications group, the removed adrenal gland was larger than that removed in the complications group (6 vs 4 cm, respectively, P = .001), whereas the complications group had a greater operative duration (139 vs 104 min, respectively, P = .001) and a greater duration of hospital stay (3 days vs 1 day, respectively, P = .001). CONCLUSION: In this study, operations of greater duration and smaller adrenal gland size were better predictors of complications after posterior retroperitoneoscopic adrenalectomy for benign disease than measures of obesity, including body mass index. PMID- 30482520 TI - Surgeons and Surgical Trainees Underestimate the Total Charges and Reimbursements Associated With Commonly Performed General Surgery Procedures?. AB - INTRODUCTION: Surgical care contributes significantly to the fiscal challenges facing the US health care system. Multiple studies have demonstrated surgeons' lack of awareness of the costs associated with individual portions of surgical care, namely operating room supplies. We sought to assess surgeon and trainee awareness of the comprehensive charges and reimbursements associated with procedures they perform. METHODS: We administered a voluntary anonymous survey to attending surgeons, general surgery residents, and fourth-year medical students who applied to general surgery residencies. We compared charge and reimbursement estimates for laparoscopic cholecystectomy and open inguinal hernia repair to the actual values. Additionally, we assessed the importance placed on the financial aspects of surgical care. RESULTS: We had an overall response rate of 94% (n = 45). A majority of attendings, residents, and medical students underestimated charges and reimbursements for open inguinal hernia repair and laparoscopic cholecystectomy. There was no significant difference in the accuracy of charge or reimbursement estimates between attendings, residents, and students for herniorrhaphy or cholecystectomy (Charge: hernia p = 0.08, cholecystectomy p = 0.30; Reimbursement: hernia p = 0.47, cholecystectomy p = 0.89). Years of training as an attending or resident did not predict accuracy of charge or reimbursement estimates for hernia repair or cholecystectomy (p > 0.3 for all regressions). The median (interquartile range) charge estimate for inguinal hernia repair was -$5914 (-$7914 to -$2914) from the actual charge, 45.8% of the true value, and the median reimbursement estimate was -$4519 (-$5369 to -$1218) from actual reimbursement, 27.3% of the true value. The median charge estimate for cholecystectomy was -$5734 (-$8733 to +$1266) from the actual charge, 58.3% of the true value, and the median reimbursement estimate was -$4847 (-$6847 to +$153) from actual reimbursement, 38.2% of the true value. CONCLUSIONS: Surgeons and their trainees underestimate the charges and reimbursements associated with commonly performed procedures. PMID- 30482521 TI - Subjective benign paroxysmal positional vertigo in patients with osteoporosis or migraine. AB - INTRODUCTION: Subjective benign paroxysmal positional vertigo is a form of benign paroxysmal positional vertigo in which during the diagnostic positional maneuvers patients only present vertigo symptoms with no nystagmus. OBJECTIVE: To study the characteristics of subjects with subjective benign paroxysmal positional vertigo. METHODS: Prospective multicenter case-control study. All patients presenting with vertigo in the Dix-Hallpike test that presented to the participating hospitals were included. The patients were separated into two groups depending on whether nystagmus was present or not. An Epley Maneuver of the affected side was performed. In the follow-up visit, patients were checked to see if nystagmus and vertigo was present. Both groups of patients were compared to assess the success rate of the Epley maneuver and also to compare the presence of 19 variables. RESULTS: 259 patients were recruited, of which 64 belonged to the subjective group. Nystagmus was eliminated in 67.2% of the patients with benign paroxysmal positional vertigo. 89.1% of the patients with subjective benign paroxysmal positional vertigo remained unaffected by nystagmus, thus showing a significant difference (p=0.001). Osteoporosis and migraine were the variables which reached the closest to the significance level. In those patients who were taking vestibular suppressors, the percentage of subjective benign paroxysmal positional vertigo was not significant higher. CONCLUSIONS: Subjective benign paroxysmal positional vertigo must be treated using the Epley maneuver. More studies are needed to establish a relationship between osteoporosis, migraine and sBPPV. The use of vestibular suppressants does not affect the detection of nystagmus. PMID- 30482522 TI - Corticotropin secreting pancreatic neuroendocrine tumour, a therapeutic management challenge. A presentation of 2 cases. PMID- 30482523 TI - [How I do... easily a vaginal hysterectomy? (Lyons school of vaginal surgery)]. PMID- 30482524 TI - A systematic review and meta-analysis of stereotactic body radiation therapy versus surgery for patients with non-small cell lung cancer. AB - OBJECTIVE: Stereotactic body radiation therapy is the preferred treatment modality for patients with inoperable early-stage non-small cell lung cancer. However, comparative outcomes between stereotactic body radiation therapy and surgery for high-risk patients remain controversial. The primary aim of the present meta-analysis was to assess overall survival in matched and unmatched patient cohorts undergoing stereotactic body radiation therapy or surgery. Secondary end points included cancer-specific survival, disease-free survival, disease recurrence, and perioperative outcomes. METHODS: A systematic review of relevant studies was performed through online databases using predefined criteria. The most updated studies were selected for meta-analysis according to unmatched and matched patient cohorts. RESULTS: Thirty-two studies were identified in the systematic review, and 23 were selected for quantitative analysis. Surgery was associated with superior overall survival in both unmatched (odds ratio, 2.49; 95% confidence interval, 2.10-2.94; P < .00001) and matched (odds ratio, 1.71; 95% confidence interval, 1.52-1.93; P < .00001) cohorts. Subgroup analysis demonstrated superior overall survival for lobectomy and sublobar resection compared with stereotactic body radiation therapy. In unmatched and matched cohorts, cancer-specific survival, disease-free survival, and freedom from locoregional recurrence were superior after surgery. However, stereotactic body radiation therapy was associated with fewer perioperative deaths. CONCLUSIONS: The current evidence suggests surgery is superior to stereotactic body radiation therapy in terms of mid- and long-term clinical outcomes; stereotactic body radiation therapy is associated with lower perioperative mortality. However, the improved outcomes after surgery may be due at least in part to an imbalance of baseline characteristics. Future studies should aim to provide histopathologic confirmation of malignancy and compare stereotactic body radiation therapy with minimally invasive anatomical resections. PMID- 30482525 TI - Noninvasive mapping before surgical ablation for persistent, long-standing atrial fibrillation. AB - OBJECTIVE: The study objective was to study the electrophysiologic mechanism of atrial fibrillation using a noninvasive, beat-by-beat, 3-dimensional mapping technique in patients with persistent and long-standing persistent atrial fibrillation undergoing concomitant surgical ablation. METHODS: In this pilot trial, 10 patients (6 male; mean age, 70 +/- 10 years) with persistent atrial fibrillation were mapped preoperatively with a noninvasive surface system (ECVUE, CardioInsight, Medtronic Inc, Minneapolis, Minn). Eight patients were candidates for mitral valve surgery, 1 patient was a candidate for aortic valve and ascending aortic replacement, and 1 patient was a candidate for coronary bypass surgery. In 5 patients, tricuspid valve repair was also performed. The Cox-Maze III/IV was performed using combined cryoablation and bipolar radiofrequency, and the left appendage was removed in all cases. The median preprocedural duration of atrial fibrillation was 30 months, and the diameter of the left atrium was 63 mm. Atrial regions were divided according to the Bordeaux classification. RESULTS: Preoperative mapping was successful in all patients with clear identification of the potential mechanism of atrial fibrillation. Biatrial pathology was recognized in all subjects. Rotor and macro re-entry activity were present in all patients, whereas focal activity was demonstrated in only 6 patients. Rotor activity in the right atrium was documented in all patients. CONCLUSIONS: This is the first report on the preoperative use of the ECUVE in surgical candidates for concomitant surgical procedures. The fact that a biatrial mechanism for atrial fibrillation was detected in all patients emphasizes the importance of a Cox-Maze III/IV procedure to treat patients with valvular heart disease and nonparoxysmal atrial fibrillation. Preoperative mapping has the potential to significantly improve our understanding of the pathophysiology in atrial fibrillation and better guide the surgical ablation procedure of choice in a single patient. PMID- 30482526 TI - Late outcomes of off-pump versus on-pump coronary bypass in patients with diabetes: A nationwide study from Taiwan. AB - OBJECTIVES: Although the benefits and risks of on- and off-pump coronary artery bypass have been compared in several clinical trials, large-scale studies regarding long-term outcomes in patients with diabetes are lacking. We compared long-term outcomes after on- and off-pump coronary artery bypass in patients with diabetes. METHODS: We evaluated outcomes in 16,215 patients with diabetes who underwent isolated coronary artery bypass from 2000 to 2011. Clinical data validity was regulated by the single-payer, universal, and nationwide reimbursement systems. Long-term outcomes were compared using propensity score matched analyses. RESULTS: Off-pump surgery was associated with a greater incidence of repeat revascularization (P = .0036) in the long term. Propensity score matching identified 3796 patients in each group. There were no significant differences between on- and off-pump surgery regarding the long-term risks of mortality (hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.87-1.02, P = .1667), stroke (HR, 0.97; 95% CI, 0.87-1.09, P = .6074), and myocardial infarction (HR, 1.05; 95% CI, 0.91-1.20, P = .5207). Off-pump surgery offered a survival benefit within 30 days (HR on vs off, 1.52, 95% CI, 1.24-1.85, P < .0001). In patients with diabetes and end-stage renal disease, on-pump surgery provided a significant long-term survival benefit (HR on vs off, 0.68, 95% CI, 0.51-0.91). CONCLUSIONS: In patients with diabetes undergoing isolated coronary artery bypass, off-pump surgery provided a 30-day benefit in mortality, but both groups had similar long-term survival. In off-pump surgery, repeat revascularization was a concern in the long term. In patients with diabetes and end-stage renal disease, on-pump surgery has long-term survival benefits. PMID- 30482527 TI - Risk factors for paravalvular leak after transcatheter aortic valve replacement. AB - OBJECTIVE: To assess risk factors for paravalvular leak (PVL) after transcatheter aortic valve implantation in a large single-center cohort, including measurement of aortic valve calcification using a reproducible method. METHODS: We retrospectively analyzed preoperative contrast-enhanced multidetector computed tomography scans of patients who underwent transcatheter aortic valve implantation in our center between 2009 and 2016. Calcium volume was calculated for each aortic cusp in the aortic valve, left ventricular outflow tract, and device landing zone. RESULTS: Overall, 539 patients were included in the study who had experience with 4 prothesis types (SapienXT [Edwards Lifesciences, Irvine, Calif] [n = 192], Sapien3 [Edwards Lifesciences] [n = 206], CoreValve EvolutR [Medtronic, Minneapolis, Minn] [n = 44], and Acurate [Symetis, Ecublens, Switzerland] [n = 97]). Median calcium volume in the device landing zone was 757 mm3, with no significant differences among the 4 prosthesis groups. None of the patients had severe PVL. The overall incidence of mild-to-moderate PVL was 15.8% (95% confidence interval [CI], 12.8%-19.1%). On multivariate logistic regression, device landing zone calcification (P = .00006; odds ratio for an increase of 100 mm3, 1.08; 95% CI, 1.04-1.13) and use of the CoreValve (P = .0028; odds ratio, 4.1; 95% CI, 1.6-10 with SapienXT as reference) prosthesis were found to be associated with mild or greater PVL. In contrast, degree of oversizing (P = .002; odds ratio, 0.97; 95% CI, 0.95-0.99), and use of Sapien3 (P = .00005; odds ratio, 0.23; 95% CI, 0.11-0.47 with SapienXT as reference) were associated with a lower incidence of mild or greater PVL. CONCLUSIONS: Aortic calcification volume in the device landing zone is associated with residual PVL after transcatheter aortic valve implantation. When taking calcification into account, the balloon expandable prosthesis Sapien3 seems to be associated with a lower incidence of PVL. PMID- 30482528 TI - The dark side of fluoroquinolones. PMID- 30482530 TI - Artificial mitral chordae: When length matters. PMID- 30482529 TI - Right ventricular load adaptability metrics in patients undergoing left ventricular assist device implantation. AB - OBJECTIVE: Several right load adaptability metrics have been proposed as predictors of right heart failure (RHF) following left ventricular assist device implantation. This study sought to validate and compare the prognostic value of these indices. METHODS: This retrospective study included 194 patients undergoing continuous-flow left ventricular assist device implantation. The primary end point was unplanned right atrial assist device (RVAD) need within 30 days after left ventricular assist device implantation; the secondary end points included clinical RHF syndrome without RVAD need and the composite of RHF or RVAD need. Load adaptability indices or interventricular ratios were divided into surrogates of ventriculoarterial coupling (RV area change:end-systolic area), indices reflecting adaptation proportionality (Dandel's index = tricuspid regurgitation velocity-time integral normalized for average RV radius in diastole or systole), and simple ratios (eg, pulse pressure:right atrial pressure or right arterial pressure:pulmonary arterial wedge pressure). RESULTS: Mean age was 55 +/- 13 years with 77% of men. RHF occurred in 75 patients with 30 patients requiring RVAD implantation. Among right heart metrics, right arterial pressure (normalized odd ratio, 1.62; 95% confidence interval, 1.15-2.38), right arterial pressure:pulmonary arterial wedge pressure (normalized odds ratio, 1.59; 95% confidence interval, 1.08-2.32) and pulse pressure:right arterial pressure < 2.0 (normalized odds ratio, 2.56; 95% confidence interval, 1.16-5.56) were associated with RVAD need (all P values < .02). These 3 metrics significantly added incremental prognostic value to the Interagency Registry for Mechanically Assisted Circulatory Support classification score in a similar range, whereas only RAP was incremental to the Michigan score. Correlates of RHF not requiring RVAD included RV end-systolic area index and the Dandel indices, which provided similar incremental value to the Interagency Registry for Mechanically Assisted Circulatory Support, Michigan, and European Registry for Patients with Mechanical Circulatory Support scores. CONCLUSIONS: Although associated with outcome, right load adaptability indices do not appear to provide strong incremental value when compared with simple metrics. PMID- 30482531 TI - Results of staged repair of aortic disease in patients with Marfan syndrome: Can we dramatically reduce the number of staged repairs? PMID- 30482532 TI - Mitral valve repair versus replacement for patients with preserved left ventricular function without heart failure symptoms. AB - OBJECTIVE: The purposes of this study are to compare outcomes of mitral valve repair (MV-repair) and mitral valve replacement for patients with severe mitral regurgitation with preserved ventricular function and no congestive heart failure (CHF) symptoms and to examine variations in surgeon choice of procedure and outcomes by surgeon volume. METHODS: In total, 2259 consecutive patients in 42 New York State hospitals with the characteristics mentioned previously who underwent mitral valve repair (1801, 79.7%) or replacement between January 1, 2008, and December 31, 2014, were identified from a mandatory statewide clinical registry. Propensity-matching was used to compare mortality and competing risk analyses were used to compare nonfatal outcomes. Median follow-up was 4.0 years. The use of mitral repair and risk-adjusted mortality for surgery were also examined as a function of individual surgeon mitral case volume. RESULTS: Propensity-matched patients who underwent MV-repair experienced a significantly lower mortality rate at 4 years (3.5% vs 12.1%, P < .001). Greater-volume surgeons were more likely to perform MV-repairs (92% vs 84%, 74%, and 69% in lower volume quartiles, respectively). No significant differences in mortality were observed among volume quartiles. CONCLUSIONS: Patients with chronic severe primary mitral valve regurgitation with preserved ventricular function and no CHF symptoms who underwent MV-repair experienced lower mortality and no different reoperation, CHF, or stroke readmission rates than patients who underwent replacement. Greater-volume surgeons were more likely than their lower volume counterparts to choose mitral repair. Repair should be considered as the surgical option for these patients whenever possible. PMID- 30482533 TI - The effect of single-ossicle ear flexibility and eardrum cone orientation on quasi-static behavior of the chicken middle ear. AB - In the single-ossicle ear of chickens, the quasi-static displacement of the umbo shows great asymmetry; umbo displacements are much larger for negative than for positive pressure in the middle ear, which is opposite to the typical asymmetry observed in mammal ears. To better understand this behavior, a finite-element model was created of the static response of the chicken middle ear. The role of flexibility of the extracolumella in the model was investigated, and the potential effect of the outward orientation of the tympanic-membrane cone was studied by building two adapted models with a flat membrane and an inverted conical membrane. It is found that the extracolumella must be made of flexible material to explain the large inward displacements of the umbo, and that displacements of the footplate are much smaller due to bending of the flexible extracolumella. However, increasing extracolumellar stiffness mostly reduces umbo displacement rather than increasing footplate displacement. The results suggest that the inverted orientation of the membrane cone is responsible for the change in asymmetry of the umbo displacement curve. The asymmetry of the footplate displacement curve in the normal model is smaller, but increases towards positive middle-ear pressure in the case of a flat or inverted membrane geometry. PMID- 30482534 TI - Biomechanical behavior of mandibles reconstructed with fibular grafts at different vertical positions using finite element method. AB - BACKGROUND: For large mandibular defects, surgical reconstruction using microvascular fibular grafts has advantages over other alternatives in terms of blood supply and good quality of grafted bone. However, the fibular segment is usually lower in height than that of the original mandible, meaning that the vertical positioning of the fibular graft is variable, with different biomechanical consequences on the reconstructed mandible. OBJECTIVES: To use finite element method (FEM) to evaluate stress distribution and displacement of a reconstructed mandible versus an intact mandible under occlusal loads. METHODS: A three-dimensional intact edentulous mandibular bone (Model I) and a reconstructed mandible bone with fibular graft were created from CBCT images. Calculation models were generated with fibular bone graft extracted from the reconstructed mandible of identical length placed into a mimicked defect area on the right-hand side of the mandible at three different vertical positions: superior (Model II), intermediate (Model III), and inferior (Model IV). Forces were applied at lower left first molar region and lower left central incisor area. Von Mises stresses and mandibular displacement were calculated as outcome measurements during loadings. RESULTS: Maximum stress and strain within the reconstructed mandible were identified at the posterior border of the graft and the contralateral condyle. Maximum displacement occurred near the interface of fibular graft and anterior segment of the mandible. Stress distribution in the graft under functional loads is much higher than that in the residual mandibular segments from Models II to IV. The combined average maximum stress from anterior and posterior loads is 10.66 times higher in the mandible with inferiorly positioned graft (Model IV), 8.72 times for superior graft (Model II), and 3.68 times for intermediate graft (Model III) than that in the control group (Model I). The worst displacement result during functional loadings was in the group with fibular graft located at the inferior border of the mandible. CONCLUSIONS: The position of fibular graft placed in the surgical resection site has significant effects on the mechanical behavior of the reconstructed mandible. The fibular graft aligned with the inferior border of the mandible, the most common site designated location by clinicians, has the worst effects on the stress distribution and displacement to the mandibular under functional loads. The fibular graft placed at the intermediate location has the best biomechanics and provides favorable condition for subsequent prosthetic reconstruction. PMID- 30482535 TI - Lower eyelid excursion: A functional and cosmetically relevant parameter in the treatment of lower eyelid retraction. AB - The purpose of this study was to assess and quantify lower lid excursion following repair of lower lid retraction. In this retrospective cohort study, a case review of patients who had undergone ear cartilage grafting for lower lid retraction was undertaken. Surgical correction involved the placement of autologous cartilage between the tarsal plate and lower lid retractors. Measurements taken preoperatively and postoperatively were the marginal reflex 2 (MRD2) and the lower scleral show (LSS). The lower lid excursion on downgaze (LLE) was measured only postoperatively with a comparison made between operated eyes and control eyes. Thirteen eyelids of 10 patients were included in the study. Preoperatively, MRD-2 ranged from 4 to 8 mm (6.5 +/- 1.5 mm) - mean +/- SD. Postoperatively, MRD-2 ranged from 4 to 6 mm (5.1 +/- 0.7 mm). The difference in mean MRD2 was statistically significant (p < 0.05). Preoperatively, LSS ranged from 0 to 5 mm (2.5 +/- 1.6 mm). Postoperatively, LSS ranged from 0-1 mm (0.1 +/- 0.3 mm). The difference in mean LSS was statistically significant (p < 0.01). Postoperatively, all lower eyelids achieved movement on downgaze. On the operated eyes, the eyelid excursion ranged from 2 to 5 mm (3.1 +/- 1.0 mm) on downgaze. On the nonoperated (control) eyes (where the operations were not performed bilaterally), the eyelid excursion ranged from 1 to 4 mm (2.8 +/- 1.2 mm). There was no statistically significant difference in the lid excursion of operated and nonoperated eyes (p > 0.05). It is possible to correct lower lid retraction in both primary and secondary positions of gaze if an appropriate surgical technique is employed. PMID- 30482536 TI - A retrospective comparison of 3MTM MicroporeTM with other common dressings in cosmetic breast surgery. AB - BACKGROUND: Surgical site infection has considerable cost implications for healthcare providers. Evidence suggests that the use of MicroporeTM tape as a dressing for surgical incisions may be associated with reduced/comparable rates of infection in surgical wounds. 3MTM MicroporeTM tape is significantly cheaper than conventional wound dressings. The purpose of this study was to compare differences in the rate of wound healing problems including superficial incisional surgical site infection (SSI) and wound healing problems following cosmetic breast procedures between MicroporeTM tape and other common wound dressings. METHODS: A clinical database was utilised to identify all patients undergoing elective breast surgery at a UK private cosmetic surgery group between May and November 2017. The patients were divided into 2 groups: those whose wounds were dressed with 3MTM MicroporeTM tape post-operatively and those dressed with other common wound dressings. Data was analysed to assess the prevalence of post-operative wound healing problems (superficial incisional surgical site infection and delayed wound healing) in each group. RESULTS: 1216 patients were identified in our database, 659 patients receiving MicroporeTM and 557 patients receiving conventional wound dressings. The overall prevalence of wound healing problems in the MicroporeTM tape and conventional wound dressing group were 12% and 10% respectively, with no statistical difference (p = 0.3913). There was no statistical significance between the use of antibiotics and prevalence of wound healing problems in either group. CONCLUSION: The results of our study suggest that there is no difference between the use of MicroporeTM tape and other conventional wound dressings in the prevalence of post-operative wound healing problems in cosmetic breast surgery. Our findings support the routine use of MicroporeTM tape in post-operative dressing for clean, non-contaminated, directly closed, elective surgical wounds. We suggest a larger scale, prospective, randomized study should be conducted to confirm these initial findings. PMID- 30482537 TI - Model to estimate abdominal wall thickness in children undergoing placement or replacement of gastrostomy devices. AB - OBJECTIVES: Abdominal wall thickness (AWT) is a key measurement when placing or replacing low profile gastrostomy devices. This measurement varies, depending on nutritional status and body habitus. We developed a mathematical model to estimate AWT using a compendium of body measurements. METHODS: Ultrasonography was used to measure AWT at the initial gastrostomy site in subjects aged 22 days to 24 years old. Other body measurements (height, weight, waist circumference and distance from xiphisternum to pubis) were also obtained. Multiple linear regression was used to develop two separate models using age of 2 years to separate the groups. For analysis, AWT is log transformed. RESULTS: Data from 97 subjects were used for analysis. The final model for those <=24 months old is the following: ln(Estimated AWT) = -1.255 + 0.082*(1 if age 3-24 months, 0 if <3 months) + 0.022*(waist circumference in cm). The final model for those >24 months old is the following: ln(Estimated AWT) = -1.335 + 0.271*(1 if age >84 months, 0 if 24-84 months) + 0.082*(BMI) CONCLUSION: This model to estimate AWT is useful for determining the length of a gastrostomy device at initial placement and with subsequent changes. More data are needed to refine and further validate the model. LEVEL OF EVIDENCE: Level IV, study of prognostic test. PMID- 30482538 TI - Twenty years of pediatric gunshot wounds in our community: Have we made a difference? AB - BACKGROUND/PURPOSE: Pediatric gunshot wounds (GSWs) carry significant incidence, mortality, and cost. We evaluated 20 years of GSW demographics at this level 1 trauma center and constructed a risk map triangulating areas of high incidence with risk factors. METHODS: Children 0-18 years suffering a GSW between 1996 and 2016 were identified via our trauma registry. Hospital charges, demographic, socioeconomic, and institutional variables were retrospectively reviewed. Multivariable logistic regression identified predictors of mortality. Geographic information system (GIS) mapping of incident location and residence identified areas of higher incidence. RESULTS: The cohort (n = 898) was 86.4% male. Mean age was 15.6 +/- 3.4 years. Median Injury Severity Score (ISS) was 9 (1-75). Procedural and/or operative intervention occurred in 52.9%. Intent included assault (81.5%) and unintentional injury (12.8%). Hospital charges showed significant annual increase. Annual incidence varied without trend (p = 0.89). Mapping revealed significant clustering of GSWs in known lower socioeconomic areas. Yearly and total GSWs were highest in one particular zip code. ISS was a significant predictor of mortality (n = 18) (OR 1.19, 95% CI 1.15-1.22, p < 0.001). CONCLUSIONS: Our impoverished neighborhoods have higher pediatric GSW incidence, unchanged over 20 years. Alternative community-based prevention efforts should involve neighborhood capacity building and economic strengthening. TYPE OF STUDY: Retrospective study. LEVEL OF EVIDENCE: Level IV. PMID- 30482539 TI - Congenital diaphragmatic hernia repair in patients on extracorporeal membrane oxygenation: How early can we repair? AB - BACKGROUND: The benefits to early repair (<72 h postcannulation) of infants with congenital diaphragmatic hernia (CDH) on extracorporeal membrane oxygenation (ECMO) are increasingly recognized. Yet it is not known if even earlier repair (<24 h) results in comparable or improved patient outcomes. The goal of this study was to compare "super-early" (<24 h) to early repair (24-72 h) of CDH patients on ECMO. METHODS: A retrospective review of infants with CDH placed on ECMO (2004-2017; n = 72) was performed. Data collected on the patients repaired while on ECMO within 72 h of cannulation (n = 33) included pre- and postnatal disease severity stratification variables and postnatal outcomes. Comparison groups were those patients repaired within 24 h of cannulation (n = 14) and those repaired between 24 and 72 h postcannulation (n = 19). RESULTS: Patients undergoing "super-early" (<24 h) repair had an average survival of 71.4% compared to the average survival of 59.7% in the early repair group. Pre- and postnatal variables predicting disease severity were not significantly different between the groups. Mean hospital stays, ventilator days, and cannulation days were statistically similar between the groups. CONCLUSIONS: Repair of patients with CDH patients on ECMO at less than 24 h postcannulation achieves outcomes that are comparable to those of repair between 24 and 72 h. While the present data suggest that there is not a "too early" time point for CDH repair on ECMO, larger multicenter studies are needed to validate our findings and determine the overall benefits. TYPE OF STUDY: Retrospective comparative study. LEVEL OF EVIDENCE: Level III. PMID- 30482540 TI - Fertility in males after childhood, adolescent, and adult inguinal operations. AB - BACKGROUND/PURPOSE: Inguinal hernia repair and orchidopexy are among the most common operations in boys. The impact on future fertility has not been conclusively defined. This study evaluates sperm quality after previous inguinal surgery. METHODS: Spermiograms of men with a desire to conceive children were analyzed. History of previous inguinal surgery (hernia repair, orchidopexy, varicocele ligation) was correlated with sperm quality. Other influential factors (age, BMI, chronic medication, tobacco use) were also tested. RESULTS: A total of 333 patients were included. Overall, 12.6% of the subjects had undergone previous inguinal surgery. Of these, 17 (43%) were inguinal hernia repairs, 8 (20%) orchidopexies, and 6 (15%) varicocele ligations, while 9 (22%) could not give an exact history. Abnormal spermiograms were found in 60% (n = 24) of those with previous inguinal surgery versus 48% in controls (p = 0.16). On multivariate analysis, pathologic spermiogram parameters were associated with previous inguinal surgery, orchidopexy, use of chronic medication, and smoking, but NOT with inguinal hernia or varicocele repair alone. CONCLUSIONS: Previous inguinal hernia or varicocele repair does not seem to impact negatively on quality of sperm later in life. Orchidopexy, smoking, and use of chronic medication, however, were all associated with pathologic sperm quality parameters. TYPE OF STUDY: Prospective comparative study. LEVEL OF EVIDENCE: Level II. PMID- 30482541 TI - Closing gastroschisis: The good, the bad, and the not-so ugly. AB - PURPOSE: The diagnosis of "closing" or "closed gastroschisis" is made when bowel is incarcerated within a closed or nearly closed ring of fascia, usually with associated bowel atresia. It has been described as having a high morbidity and mortality. METHODS: A retrospective review of closing gastroschisis cases (n = 53) at six children's hospitals between 2000 and 2016 was completed after IRB approval. RESULTS: A new classification system for this disease was developed to represent the spectrum of the disease: Type A (15%): ischemic bowel that is constricted at the ring but without atresia; Type B (51%): intestinal atresia with a mass of ischemic, but viable, external bowel (owing to constriction at the ring); Type C (26%): closing ring with nonviable external bowel +/- atresia; and Type D (8%): completely closed defect with either a nubbin of exposed tissue or no external bowel. Overall, 87% of infants survived, and long-term data are provided for each type. CONCLUSIONS: This new classification system better captures the spectrum of disease and describes the expected long-term results for counseling. Unless the external bowel in a closing gastroschisis is clearly necrotic, it should be reduced and evaluated later. Survival was found to be much better than previously reported. TYPE OF STUDY: Retrospective case series with no comparison group. LEVEL OF EVIDENCE: Level IV. PMID- 30482542 TI - Ileal-pouch anal anastomosis in pediatric NSQIP: Does a laparoscopic approach reduce complications and length of stay? AB - PURPOSE: The purpose of this study was to determine if a laparoscopic approach reduces complications and length of stay (LOS) after total proctocolectomy with ileal pouch-anal anastomosis (TPC-IPAA) in pediatric patients using a multicenter prospective database. METHODS: The American College of Surgeons National Surgical Quality Improvement Project Pediatric database from 2012 to 2015 was used to identify patients with a diagnosis of chronic ulcerative colitis (CUC) or familial adenomatous polyposis (FAP) undergoing TPC-IPAA. Major complications, minor complications, and prolonged LOS were compared based on laparoscopic versus open approach. RESULTS: 195 (108 female) patients underwent TPC-IPAA at a median age of 14 years (IQR: 11-16) for CUC (N = 99) or FAP (N = 96). Two-thirds of cases were laparoscopic. A laparoscopic approach was not associated with major complications, but lower odds of minor complications were observed. A reduced LOS was seen in laparoscopic versus open surgery (median LOS 6 vs 8 days, p < 0.01). Open IPAA was independently associated with prolonged LOS (>9 days) in the FAP cohort (OR 4.0, 95% CI 1.1-14.0). CONCLUSION: A laparoscopic approach was not associated with increased major complications but was associated with lower odds of minor complications and shorter LOS. The laparoscopic approach should continue to be preferred for pouch procedures in pediatric patients. TYPE OF STUDY: Treatment; retrospective study. LEVEL OF EVIDENCE: Level III. PMID- 30482543 TI - Microinvasive breast carcinoma: An analysis from ten Senonetwork Italia breast centres. AB - BACKGROUND AND OBJECTIVES: We studied a large series of ductal carcinoma in situ with microinvasion (MIDC) an infrequent disease whose diagnosis and management are not well defined. METHODS: 17,431 cases of breast carcinoma were treated between 2011 and 2016 by ten Italian Breast Units. Our analysis included diagnostic and clinic-pathological characteristics, surgical management, and the use of adjuvant therapies. RESULTS: 15,091 cases (86.6%) were infiltrating carcinomas (IC), 2107 (12.1%) ductal carcinoma in situ (DCIS), and 233 (1.3%) MIDC. Age at diagnosis did not differ between DCIS and MIDC. MIDC were usually larger and expressed more frequently biologically aggressive features (higher Ki67 values, hormone receptor negativity and HER2/neu over-expression) (p < 0.01). Axillary lymph nodes were involved in 25 MIDC cases (12%), but >3 lymph nodes were involved in two cases only (1%). At multivariable analysis, only lymphovascular invasion (LVI) was associated with lymph node status (p < 0.01). Hormone therapy was prescribed in 388/1462 DCIS cases (26.5%), in 84/200 MIDC cases (42%), and in 11,086/14,188 IC cases (84.7%) (p < 0.01). Chemotherapy was administered in 28/190 MIDC cases (14.7%), and in 4080/11,548 IC cases (35.3%) (p < 0.001). CONCLUSIONS: This is one of the largest studies of MIDC reported in the literature. Approximately 10% of DCIS harbor one or more foci of MIDC, and the latter often expresses aggressive biological features. LVI is a predictor of axillary node involvement, but this is infrequent and usually limited. Conservative surgery is performed less often than in DCIS, and adjuvant chemotherapy is less frequently utilized compared to IC. PMID- 30482544 TI - Degenerated Aortic Self-expanding Prosthesis: Percutaneous Valve-in-valve Implantation. PMID- 30482545 TI - Association Between Maximal Oxygen Consumption and Physical Activity and Sedentary Lifestyle in Metabolic Syndrome. Usefulness of Questionnaires. AB - INTRODUCTION AND OBJECTIVES: To analyze whether variations in physical activity (PA) and sedentary behaviors are accompanied by differences in maximal oxygen consumption (VO2max). METHODS: We conducted a prospective cross-sectional study of 243 participants (82 women), aged 65.0+/-4.9 years old, with metabolic syndrome and overweight/obesity who performed a maximal exercise test with expired gas analysis. PA was evaluated using subjective methods, the REGICOR and RAPA 1 self-reported questionnaires, and objective methods, the chair test and accelerometry. Sedentariness was analyzed with the Nurses' Health Study questionnaire and accelerometry. RESULTS: VO2max was higher in participants who reported they adhered to the recommendations of the PA guidelines in the REGICOR questionnaire (21.3+/-4.6 vs 18.0+/-4.4 mL/kg/min; P <.001) and was 18% higher in those who reported more PA in the RAPA 1 questionnaire than the less active group (P <.001). The chair test (> 15 vs <= 15 repetitions) also showed significant differences in VO2max (21.2+/-4.8 vs 18.7+/-4.5 ml/kg/min; P <.001). Correlations between PA variables and VO2max were significant but low (r: 0.2 to 0.4). Sedentary activities showed less relationship with VO2max. CONCLUSIONS: Participants with metabolic syndrome and overweight/obesity who reported adhering to PA recommendations achieved higher VO2max. The self-reported questionnaires and the chair test identified significant variations in VO2max. Sedentary activities do not appear to modify VO2max. PMID- 30482546 TI - Antileishmanial activity and cytotoxicity of ent-beyerene diterpenoids. AB - We describe the in vitro activity of two natural isomeric ent-beyerene diterpenes, several derivatives and synthetic intermediates. Beyerenols 1 and 2 showed EC50 of 4.6 +/- 9.4 and 5.3 +/- 9.4 MUg/mL against amastigotes of L. (V) brazilensis, with SI of 5.1 and 7.7, respectively. Beyerenol 1 was synthesized from stevioside. In vivo experiments with bereyenols showed cure in 50% of hamsters infected with L. (V) brazilensis topically applied as Cream I (beyerenol 1, 0.81%, w/w) and Cream III (beyerenol 2, 1.96%, w/w). These results suggest that beyerenols are potential candidates for cutaneous leishmaniasis chemotherapy by topical application. In vitro assays of amastigotes of L. (V) brazilensis showed EC50 of 1.1 +/- 0.1 and 1.3 +/- 0.04 MUg/mL, with SI of 3.1 and 3.5 for hydrazone intermediates 10 and 11, respectively. PMID- 30482548 TI - Design, synthesis and QSAR study of 2'-hydroxy-4'-alkoxy chalcone derivatives that exert cytotoxic activity by the mitochondrial apoptotic pathway. AB - Eleven 4'-alkoxy chalcones were synthesized and biologically evaluated for their antiproliferative activity against four human tumor cell lines (PC-3, MCF-7, HF 6, and CaSki). Compounds 3a-3d and 3f were selective against PC-3, with IC50 values ranging from 8.08 to 13.75 MUM. In addition, chalcones 3a-3c did not affect the normal fibroblasts BJ cells. The most active and selective compounds were further evaluated for their effect on the progression of cell cycle in PC-3 cells, and chalcones 3a and 3c induced a G2/M phase arrest. Furthermore, it was found that these three chalcones induced the mitochondrial apoptotic pathway by regulating Bax and Bcl-2 transcripts and by increasing caspase 3/7 activation. Otherwise, the QSAR model indicates that the double bond of the alpha,beta unsaturated carbonyl, as well as the planar structure geometry, are important to the biological activity of the synthetized chalcones. Based on these studies, it was concluded that withdrawing substituents in ring A, decrease the antiproliferative activity. This is related to the possible mechanism of action of these compounds, where a Michael addition needs to take place in order to be a potent anticancer agent. PMID- 30482547 TI - Synthesis and biological evaluation of arylpiperazine derivatives as potential anti-prostate cancer agents. AB - A novel scaffold of arylpiperazine derivatives was discovered as potent androgen receptor (AR) antagonist through rational drug designation based on our pre-work, leading to the discovery of a series of new antiproliferative compounds. Compounds 10, 16, 27, 29 and 31 exhibited relatively strong antagonistic potency against AR and exhibited potent AR binding affinities, while compounds 5, 6, 10, 14, 16, 19, 21, 27 and 31 exhibited strong cytotoxic activities against LNCaP cells (AR-rich) as well as also displayed the higher activities than finasteride toward PC-3 (AR-deficient) and DU145 (AR-deficient). Docking study suggested that the most potent antagonist 16 mainly bind to AR ligand binding pocket (LBP) site through hydrogen bonding interactions. The structure-activity relationship (SAR) of these designed arylpiperazine derivatives was rationally explored and discussed. These results indicated that the novel scaffold compounds demonstrated a step towards the development of novel and improved AR antagonists, and promising candidates for future development were identified. PMID- 30482549 TI - A novel mutation in the GATAD2B gene associated with severe intellectual disability. AB - BACKGROUND: The human GATA zinc finger domain containing 2B (GATAD2B) encodes a subunit of the MeCP1-Mi-2/nucleosome remodeling and deacetylase complex, which is involved in chromatin modification and transcription. Recently, patients with severe intellectual disabilities and characteristic features associated with GATAD2B mutations have been identified. CASE REPORT: The patient was a 4-year-old male with dysmorphic features, including frontal bossing, hypertelorism, epicanthal folds, down-slanting palpebral fissures, a flat nasal bridge, a high arched palate, and micrognathia. He spoke no meaningful words and exhibited severe intellectual disability. Hypermetropic astigmatism and mild spasticity of the lower extremities were noted. Whole-exome sequencing revealed a de novo missense mutation in GATAD2B (NM_020699:exon4:c.502C>T; p.(Glu168*)). CONCLUSION: We report a novel GATAD2B mutation in a boy exhibiting bilateral leg spasticity and white matter abnormalities on brain magnetic resonance imaging. PMID- 30482550 TI - Optimal interval type-2 fuzzy fractional order super twisting algorithm: A second order sliding mode controller for fully-actuated and under-actuated nonlinear systems. AB - In this paper, a novel interval type-2 fuzzy fractional order super twisting algorithm (IT2FFOSTA) which is essentially a second order sliding mode controller is presented. The proposed IT2FFOSTA enhances fractional order super twisting algorithm (FOSTA) by taking advantage of an interval type-2 fuzzy fractional order sliding surface (IT2FFOSS) for some classes of fully-actuated and under actuated nonlinear systems in presence of uncertainty. The FOSTA significantly reduces the amount of chattering and the IT2FFOSS results in decreasing the tracking error, control effort, and chattering level. In order to control under actuated systems, a hierarchical sliding surface is employed. The multi-tracker optimization algorithm is utilized to adjust the controller's parameters; this leads to an optimal performance for the IT2FFOSTA. To examine the performance of the IT2FFOSTA, some simulation and experimental tests on three examples of different classes of fully-actuated and under-actuated systems, including ball and plate, inverted pendulum, and ball and beam systems are carried out. The simulation and experimental results demonstrate the superiority of the IT2FFOSTA in reducing the amount of chattering, tracking error, and control effort compared to those of the other control methods. PMID- 30482551 TI - Distributed output-feedback consensus control of multi-agent systems with dynamically changing directed interaction topologies. AB - This paper considers the distributed output-feedback consensus control problem for a multi-agent system with higher order linear dynamics and subject to external disturbance, under dynamically changing directed topologies and weighting factors. An extended state observer (ESO) is first designed to estimate not only the unmeasurable agent states but also the external disturbance. Based on the output of the ESO, a novel distributed control protocol is proposed. We show that, with the application of the proposed control protocol, the consensus can be achieved asymptotically by the group of agents if the union of the directed interaction graphs contains a spanning tree frequently enough. A numerical example is given to verify the effectiveness of the theoretical results. PMID- 30482552 TI - [Combination of clonidine-bupivacaine in caudal epidural anesthesia for hypospadias surgery in children: prospective, randomized, blind study]. AB - BACKGROUND AND OBJECTIVES: The combination of clonidine with local anesthetic administered for epidural anesthesia via caudal route seems to improve the quality of postoperative analgesia, but with conflicting results. This study compared the postoperative analgesia of three different doses of clonidine combined with bupivacaine in caudal epidural anesthesia in children undergoing hypospadias repair. METHODS: Eighty children aged 1 to 10 years, candidates for surgical repair of hypospadias, were randomly divided into four groups of 20 patients to receive general anesthesia combined with caudal epidural anesthesia with bupivacaine 0.165% alone or in combination with 1, 2 or 3MUg.kg-1 of clonidine. The primary outcome was morphine consumption in the first 24hours postoperatively. Mean arterial pressure, heart rate, end-tidal concentration of sevoflurane, time to awakening, pain severity (FLACC scale), level of sedation (RAMSAY), duration of analgesia, and occurrence of adverse effects were also compared. RESULTS: Intraoperatively, there was no difference between groups regarding mean arterial pressure, heart rate, end-tidal concentration of sevoflurane, and time to awakening. Postoperative morphine consumption and pain severity were similar between groups, but the group receiving clonidine (3MUg.kg 1) had lower heart rate and higher sedation level than the group receiving bupivacaine alone. CONCLUSIONS: The combination of clonidine at doses of 1, 2 or 3MUg.kg-1 with bupivacaine 0.16% via caudal epidural route did not alter the consumption of morphine in the early postoperative period of children undergoing hypospadias repair. PMID- 30482553 TI - Treatment and prognosis of fetal lymphangioma. AB - OBJECTIVE: To investigate the treatment and prognosis of fetal lymphangioma and factors that inform treatment selection. STUDY DESIGN: Retrospective analysis of 79 patients with fetal lymphangioma treated at our hospital. Treatment methods included medical termination (death in-utero), expectant treatment, surgery, and interventional sclerotherapy (including ex utero intrapartum treatment, EXIT). Methods of treatment were selected according to the location and size of the lymphangioma. RESULTS: Among the 133,322 fetuses, in 130,202 pregnant women, examined at our hospital, a lymphangioma was identified in 79. The lymphangioma was confirmed by ultrasound, magnetic resonance imaging and post-natal computed tomography, as appropriate, and pathological results obtained postoperatively or on autopsy. Septation of the mass was identified in 66 of the 79 cases (83.54%). With regard to location, the lymphangioma was located in the neck in 50 fetuses (63.29%). Interventional sclerotherapy, using bleomycin, was performed in 22 neonates, of which 3 underwent ex utero intrapartum treatment (EXIT), due to evidence of airway or esophageal obstruction, 16 underwent expectant management and 7 surgical treatment. Medical termination of the pregnancy was performed in 32 cases, and 2 fetuses died in-utero. Of the 16 cases of expectant treatment, the lesions retrogressed during the intra-uterine period in 7 cases, before the post-natal age of 6 months in 4 neonates, and before the age of 2 years in 3 neonates, with no change in the size of the lymphangioma identified in 2 cases. Of the 7 neonates who were treated surgically, relapse occurred in 1 case, which required re-operation. CONCLUSIONS: Several treatment options for lymphangioma are available, with treatment selection being based on the location and size of the lymphangioma. PMID- 30482554 TI - Erratum to "Vaginal cervico-isthmic cerclage versus McDonald cerclage in women with a previous failure of prophylactic cerclage: A retrospective study" [Eur. J. Obst. Gynecol. Reprod. Biol. 216 (September 2017) 27-32]. PMID- 30482555 TI - Reducing the use of physical restraints, a pending and emerging matter at the ICU. PMID- 30482557 TI - Daily skin antisepsis and hygiene in the critically ill patient. AB - Hygiene and skin care of patients admitted to the Intensive Care Unit (ICU) are part of basic care. For some years there has been evidence of skin colonization by multiresistant gramnegative and grampositive pathogens. The increase in nosocomial infections due to multiresistant microorganisms has led to evaluation of the role of the use of antiseptics, mainly chlorhexidine, as a strategy for reducing the number of such infections. This article reviews the current situation of this strategy, as well as the positioning of the authors in relation to the spreading of its use in ICUs. PMID- 30482558 TI - The thumbs angle used in the novel infant chest compression technique (new two thumb technique, nTTT) can influence the quality parameters of resuscitation. PMID- 30482556 TI - The Pan American and Iberian Federation of Critical Medicine and Intensive Therapy develops its Strategic Plan. AB - The Pan-American and Iberian Federation of Critical Medicine and Intensive Therapy, A.C. (FEPIMCTI), has prepared its Strategic Plan for the next 5 years. In this Plan, it defines its course towards the future, establishes its long-term objectives and works to achieve success. Its strategic objectives are framed in consolidating the legal, fiscal and administrative structure, the updating of its statutes, the implementation of a process management system encompassed in a quality culture, the implementation of committees of experts, achieving academic excellence by developing training programs and giving visibility to the Federation. Their main values refer to equity, professionalism, respect and social solidarity. The implementation of the Strategic Plan in a collaborative manner must serve as a driving force for change to position FEPIMCTI as a relevant Scientific Society in the Critical Medicine of its member countries. PMID- 30482559 TI - Severity scores should incorporate limitations on life support for predicting mortality. PMID- 30482561 TI - A systematic review and meta-analysis of the Kwak TIRADS for the diagnostic assessment of indeterminate thyroid nodules. AB - AIM: To explore the diagnostic usefulness of the Thyroid Imaging Reporting and Data System (TIRADS) classification proposed by Kwak in indeterminate nodules using a systematic literature review. MATERIAL AND METHODS: The PubMed, Cochrane database, ScienceDirect, and EMBASE databases were searched for relevant articles. A meta-analysis was performed to calculate pooled sensitivity, specificity, negative and positive likelihood ratios (LR- and LR+), diagnostic odds ratio (DOR), and area under the curve (AUC) from summarised receiver operating characteristic (SROC) curves. RESULTS: Six publications describing 1,096 nodules were analysed. Overall pooled sensitivity, specificity, LR+, LR-, DOR, and AUC for SROC were 0.913, 0.347, 1.396, 0.341, 5.832, and 0.7180, respectively. CONCLUSIONS: Kwak TIRADS classification with 3/4a cut-off for indeterminate lesions has high sensitivity but low specificity to exclude benign lesions. A higher Kwak TIRADS cut-off could help exclude larger numbers of benign lesions and lower the rate of unnecessary surgeries. PMID- 30482560 TI - Evaluation of FDG PET combined with cardiac MRI for the diagnosis and therapeutic monitoring of cardiac sarcoidosis. AB - AIM: To compare combined 2-[18F]-fluoro-2-deoxy-d-glucose (FDG)-positron-emission tomography (PET) and cardiac magnetic resonance imaging (CMR) for the diagnosis and therapy monitoring of cardiac sarcoidosis (CS). MATERIALS AND METHODS: Eighty patients with sarcoidosis and a suspicion of CS who underwent PET and CMR were included retrospectively. PET was undertaken after a low-carbohydrate-high-fat diet in all patients using a combined 16-section PET/computed tomography (CT) camera. PET was considered positive (PET+) in cases of focal or multifocal FDG uptake. CMR was considered positive (CMR+) in cases of subepicardial late gadolinium enhancement (LGE). A subgroup of 50 patients (50/80) was monitored during therapy and classified as responders or non-responders. RESULTS: Eighty two percent of patients with PET+ (9/11) also had CMR+ imaging, with good spatial agreement (kappa=0,79; 95% confidence interval [CI]: 0.65-0.94). Twenty-seven percent (22/80) had residual physiological FDG uptake, with a standardised uptake value (SUV) not significantly different compared to the SUV from pathological uptake (6.4 versus 6 respectively, p=0,92). The clinical response was more frequent in patients with baseline PET+ compared to baseline PET- (80% versus 45%, p=0.07). PET findings improved in all cases under treatment (7/7), whereas LGE improved in only 33% of patients (3/9). CONCLUSION: Due to high risk of false positive or undetermined findings, PET might be performed as a second-line study in cases of LGE, to assess inflammatory load. In addition, PET seems suitable to predict and assess response under therapy. PMID- 30482563 TI - Lipid paradox in patients with acute myocardial infarction: Potential impact of malnutrition. AB - BACKGROUND & AIMS: Aggressive lipid reduction is recommended for patients with AMI, but reverse epidemiology, the lipid paradox, has been reported in several clinical studies. The cause of lipid paradox remains uncertain, and nutrition is one possible explanation. In this single-center retrospective study, we investigated the relationships between baseline LDL concentrations and clinical outcomes in patients with AMI, stratified by different nutritional status. METHODS: Totally 409 patients were enrolled for analysis. The Nutritional Risk Index (NRI) was used to estimate the risk of malnutrition. Subjects were grouped into tertiles according to their NRIs. Clinical outcomes were compared among patients with varying NRIs and LDL levels. RESULTS: Patients in the lowest NRI tertile had increased incidences of in-hospital mortality, cardiogenic shock, decompensated heart failure, renal failure, and sepsis. This tertile was also associated with increased long-term mortality during the follow-up period of 832 +/- 744 days. Mortality was increased among patients with baseline LDL concentrations <=70 mg/dL in the lowest NRI tertile (log rank test, p = 0.0257), but not in the high or median tertiles. Moreover, baseline LDL level <=70 mg/dL was an independent risk factor of all-cause mortality (adjusted hazard ratio = 1.73; 95% confidence interval, 1.01-2.94; p = 0.045) in the lowest NRI tertile. CONCLUSIONS: Lipid paradox was observed in the high-risk of malnutrition population among patients with AMI. Aggressive lipid-lowering therapy is still recommended for patients with AMI and fair nutritional status. However, when treating patients at high risk of malnutrition, the improvement of nutritional status may be more beneficial than strict LDL control. PMID- 30482562 TI - Impact of sarcopenic obesity on outcomes in patients undergoing living donor liver transplantation. AB - BACKGROUND & AIM: Sarcopenia is known to be a poor prognostic factor after liver transplantation (LT). However, the significance of obesity in combination with sarcopenia (sarcopenic obesity) remains unclear. This study examined the impact of sarcopenic obesity on outcomes after living donor LT (LDLT). METHODS: We retrospectively analyzed 277 adult patients who underwent LDLT at our center between January 2008 and June 2016. Body composition parameters including skeletal muscle mass index (SMI), intramuscular adipose tissue content (IMAC), visceral fat area (VFA), and visceral-to-subcutaneous adipose tissue area ratio (VSR) were evaluated by preoperative plain computed tomography imaging at the level of the third lumbar vertebra. This study defined sarcopenic obesity as a low SMI (male <40.31 cm2/m2; female <30.88 cm2/m2) with VFA >=100 cm2 or body mass index (BMI) >=25 kg/m2. We examined outcomes among four groups: nonsarcopenic/nonobesity (NN), nonsarcopenic/obesity (NO), sarcopenic/nonobesity (SN), and sarcopenic/obesity (SO) groups. RESULTS: On the basis of VFA, 1/5-year overall survival (OS) rates in patients of SN (n = 46, 59%/46%, P < 0.001) and SO (n = 9, 56%/56%, P = 0.338) groups were lower than those in patients of the NN group (86%/80%). On the other hand, on the basis of BMI, 1/5-year OS rates in patients of SN (n = 49, 59%/52%, P < 0.001) and SO (n = 6, 50%/17%, P = 0.002) groups were significantly lower than those in patients of the NN group (87%/81%). Multivariate analysis identified ABO incompatibility (P = 0.030), low SMI (P = 0.002), high IMAC (P = 0.002), and high VSR (P < 0.001) as independent risk factors for death after LT. CONCLUSION: Patients with sarcopenic obesity showed worse survival after LDLT compared with nonsarcopenic/nonobesity patients. PMID- 30482564 TI - Pterostilbene raises low density lipoprotein cholesterol in people. PMID- 30482565 TI - Reply-Letter to the Editor - Metabolic healthy overweight/obese individuals: Not just a restricted group. PMID- 30482566 TI - Electrophysiology in diagnosis and management of neuropathic pain. AB - Electrophysiological techniques demonstrate abnormalities in somatosensory transmission, hence providing objective evidence of 'somatosensory lesion or disease' which is crucial to the diagnosis of neuropathic pain (NP). Since most instances of NP result from damage to thermo-nociceptive pathways (thin fibres and spino-thalamo-cortical systems), specific activation of these is critical to ensure diagnostic accuracy. This is currently achieved using laser pulses or contact heat stimuli, and in a near future probably also with contact cold and intra-epidermal low-intensity currents. Standard electrical stimuli, although of lesser diagnostic yield, are useful when large and small fibres are affected together. Nociceptive evoked potentials to laser (LEPs) and contact heat (CHEPs) have shown adequate sensitivity and specificity to be of clinical use in the differential diagnosis of NP, in conditions involving Adelta of C-fibres and spino-thalamo-cortical pathways. LEPs have also a role in the detection of patients at risk of developing central post-stroke pain after brainstem, thalamic or cortical injury. Cognitive cortical responses and autonomic reactions (sympathetic skin responses) reflect pain-related arousal and can document objectively positive symptoms such as allodynia and hyperalgesia. They are of help in the differential diagnosis of somatisation disorders, by discriminating conscious simulation (malingering) from conversive sensory loss. The electrophysiological approach to patients suspected, or at risk, of NP is a cost effective procedure that should never be absent in the diagnostic armamentarium of pain clinics. PMID- 30482568 TI - Predicting critical drug concentrations and torsadogenic risk using a multiscale exposure-response simulator. AB - Torsades de pointes is a serious side effect of many drugs that can trigger sudden cardiac death, even in patients with structurally normal hearts. Torsadogenic risk has traditionally been correlated with the blockage of a specific potassium channel and a prolonged recovery period in the electrocardiogram. However, the precise mechanisms by which single channel block translates into heart rhythm disorders remain incompletely understood. Here we establish a multiscale exposure-response simulator that converts block concentration characteristics from single cell recordings into three-dimensional excitation profiles and electrocardiograms to rapidly assess torsadogenic risk. For the drug dofetilide, we characterize the QT interval and heart rate at different drug concentrations and identify the critical concentration at the onset of torsades de pointes: For dofetilide concentrations of 2x, 3x, and 4x, as multiples of the free plasma concentration Cmax = 2.1 nM, the QT interval increased by +62.0%, +71.2%, and +82.3% compared to baseline, and the heart rate changed by -21.7%, -23.3%, and +88.3%. The last number indicates that, at the critical concentration of 4x, the heart spontaneously developed an episode of a torsades-like arrhythmia. Strikingly, this critical drug concentration is higher than the concentration estimated from early afterdepolarizations in single cells and lower than in one-dimensional cable models. Our results highlight the importance of whole heart modeling and explain, at least in part, why current regulatory paradigms often fail to accurately quantify the pro-arrhythmic potential of a drug. Our exposure-response simulator could provide a more mechanistic assessment of pro-arrhythmic risk and help establish science-based guidelines to reduce rhythm disorders, design safer drugs, and accelerate drug development. PMID- 30482567 TI - Understanding longer-term disability outcomes for Maori and non-Maori after hospitalisation for injury: results from a longitudinal cohort study. AB - OBJECTIVES: The objectives are to (1) describe disability outcomes at 24 months after injury and (2) identify factors contributing to disability outcomes at 24 months after injury, for Maori and non-Maori who have been hospitalised for injury. STUDY DESIGN: This is a prospective cohort study. METHODS: Prospective Outcomes of Injury Study participants were injured New Zealanders aged 18-64 years and recruited from New Zealand's no-fault injury insurer, the Accident Compensation Corporation's entitlement claims register. Data about a number of pre-injury, injury-related and early post-injury characteristics were collected from interviews held at 3 and 24 months after injury. Disability was measured using the World Health Organization Disability Assessment Schedule (WHODAS). Modified Poisson regression modelling was used to estimate relative risks (RRs) of disability for Maori and non-Maori who were hospitalised for injury. RESULTS: Analyses were restricted to 375 Maori and 1824 non-Maori participants for whom complete data were available. Of these, 105 (28%) Maori and 446 (24%) non-Maori were hospitalised for their injury. Of these hospitalised groups, 26% of Maori and 10% of non-Maori were experiencing disability (WHODAS >=10) at 24 months after injury. Maori who were hospitalised for injury and who were not working for pay before their injury (RR = 2.7; 95% confidence interval [CI] 1.4-4.9), who were experiencing disability before their injury (RR = 3.1; 95% CI 1.6-5.8) or who reported trouble accessing healthcare services for their injury (RR = 2.6; 95% CI 1.3-5.2) were independently at increased risk of disability 24 months after injury. Non-Maori who were hospitalised for injury and who had inadequate household income before injury (RR = 2.4; 95% CI 1.4-4.1), less than the secondary school qualifications (RR = 2.0; 95% CI 1.1-3.8), were not working for pay before injury (RR = 2.8; 95% CI 1.5-5.1), were experiencing disability before their injury (RR = 3.0; 95% CI 1.7-5.2), had >=2 chronic conditions (RR = 3.5; 95% CI 2.0-6.4) or had body mass index >=30 kg/m2/undisclosed (RR = 2.4; 95% CI 1.3-4.4) were at increased risk of disability 24 months after injury. CONCLUSIONS: Variables predicting disability 24 months after injury for Maori, also predict disability 24 months after injury for non-Maori, with one notable exception-trouble accessing healthcare services. Our findings show that having access to healthcare services for injury plays an important role after injury and must be focussed on to ensure that the burden of poor injury-related outcomes and injury-related inequities are reduced and ultimately eliminated. PMID- 30482569 TI - Combination of left atrial appendage closure and catheter ablation in a single procedure for patients with atrial fibrillation: Multicenter experience. AB - BACKGROUND/PURPOSE: Experience in procedures combining left atrial appendage (LAA) closure (LAAC) and catheter ablation (CA) was scarce in Chinese nonvalvular atrial fibrillation (AF) patients with high risks for stroke and bleeding. We aimed to investigate the efficacy and safety of the combination therapy with LAAC and AF CA in a single procedure based on the multicenter data and medium-term follow-up results. METHODS: A total of 122 AF patients with a mean CHA2DS2-VASc score of 4.3 +/- 1.4 and HAS-BLED score of 3.3 +/- 1.0 were enrolled. The Watchman (n = 83) devices were implanted either before or after AF ablations in the same procedure, while the Amplatzer Cardiac Plug (ACP, n = 39) devices were implanted immediately after CA. AF recurrence and transesophageal echocardiography results were evaluated. RESULTS: All devices were successfully implanted and acute complete LAA occlusions were achieved in 115 (94.3%) of patients. Neither acute nor chronic peri-device leaks greater than 5 mm were detected. Oral anticoagulation was held in all patients but two with asymptomatic device-related thrombi, which were resolved after prolonged anticoagulation. AF free success rate without antiarrhythmic drugs was 76.2% after a mean follow-up of 11.5 +/- 6.8 months. No serious complications were observed during the follow up. CONCLUSION: The combination therapy with LAAC and AF ablation in a single procedure was efficacious and safe in the Chinese symptomatic AF population with high risk for stroke and bleeding. PMID- 30482570 TI - Survival outcomes of liver transplantation versus liver resection among patients with hepatocellular carcinoma: A SEER-based longitudinal study. AB - BACKGROUND/PURPOSE: This study aimed to compare the survival benefit in hepatocellular carcinoma (HCC) patients following liver transplantation or surgical resection utilizing Surveillance, Epidemiology, and End Results Program (SEER) database (2004-2013). METHODS: Overall and cancer-specific mortality were evaluated in HCC patients who were treated by liver resection or transplantation. Patients newly-diagnosed with primary HCC were included. RESULTS: Kaplan-Meier survival curves found that patients with liver transplantation had lower risk of overall mortality and cancer-free mortality than patients who received liver resection (P < 0.001). Multivariate analysis found the risk of overall and cancer specific mortality were lower with liver transplantation than with resection (aHR = 0.51 for overall mortality and aHR = 0.37 for cancer specific mortality), and that the risk of overall mortality decreased for patients with liver transplantation relative to surgical resection as disease severity increased (T1: aHR = 0.53; T2: aHR = 0.47; T3 and T4: aHR = 0.33). CONCLUSION: The findings indicated that transplantation has survival advantages compared with resection in treating patients with HCC, particularly in later stage disease. PMID- 30482571 TI - Skin, Body Dysmorphic Disorder, and Other Syndromes. PMID- 30482572 TI - Spontaneous Regression of Medium-Sized Congenital Melanocytic Nevi: Report of 3 New Cases. PMID- 30482573 TI - Osteonevus of Nanta: A Rare Skin Condition. PMID- 30482574 TI - Fast-Growing Occipital Tumor. PMID- 30482575 TI - Frontal Fibrosing Alopecia and Discoid Lupus Erythematosus: More Than a Coincidence. PMID- 30482576 TI - Papular Eruption on Sun-Exposed Skin. PMID- 30482577 TI - Risk Factors for Recurrent Acute Kidney Injury in a Large Population-Based Cohort. AB - RATIONALE & OBJECTIVE: Acute kidney injury (AKI) has numerous sequelae. Repeated episodes of AKI may be an important determinant of adverse outcomes, including chronic kidney disease and death. In a population-based cohort study, we sought to determine the incidence of and predictors for recurrent AKI. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 38,659 hospitalized members of Kaiser Permanente Northern California who experienced an episode of AKI from 2006 to 2013. PREDICTORS: Demographic, clinical, and laboratory data, including baseline kidney function, proteinuria, hemoglobin level, comorbid conditions, and severity of AKI. OUTCOMES: Incidence and predictors of recurrent AKI. ANALYTICAL APPROACH: Multivariable Cox proportional hazard regression. RESULTS: 11,048 (28.6%) experienced a second hospitalization complicated by AKI during follow-up (11.2 episodes/100 person-years), with the second episode of AKI occurring a median of 0.6 (interquartile range, 0.2-1.9) years after the first hospitalization. In multivariable analyses, older age, black race, and Hispanic ethnicity were associated with recurrent AKI, along with lower estimated glomerular filtration rate, proteinuria, and anemia. Concomitant conditions, including heart failure, acute coronary syndrome, diabetes, and chronic liver disease, were also multivariable predictors of recurrent AKI. Those who had higher acuity of illness during the initial hospitalization were more likely to have recurrent AKI, but greater AKI severity of the index episode was not independently associated with increased risk for recurrent AKI. In multivariable analysis of matched patients, recurrent AKI was associated with an increased rate of death (HR, 1.66; 95% CI, 1.57-1.77). LIMITATIONS: Analyses were based on clinically available data, rather than protocol-driven timed measurements of kidney function. CONCLUSIONS: Recurrent AKI is a common occurrence after a hospitalization complicated by AKI. Based on routinely available patient characteristics, our findings could facilitate identification of the subgroup of patients with AKI who may benefit from more intensive follow-up to potentially avoid recurrent AKI episodes. PMID- 30482578 TI - Identification and Prioritization of Quality Indicators for Conservative Kidney Management. AB - RATIONALE & OBJECTIVE: Conservative kidney management is holistic patient centered care for patients with kidney failure that focuses on delaying the progression of kidney disease and symptom management, without the provision of renal replacement therapy. Currently there is no consensus as to what constitutes high-quality conservative kidney management. We aimed to develop a set of quality indicators for the conservative management of kidney failure. STUDY DESIGN: Nominal group technique and Delphi survey process. SETTING & PARTICIPANTS: 16 patients and caregivers from Calgary, Canada, participated in 2 nominal group meetings. 91 multidisciplinary health care professionals from 10 countries took part in a Delphi process. ANALYTICAL APPROACH: Nominal group technique study of patients and caregivers was used to identify and prioritize a list of quality indicators. A 4-round Delphi process with health care professionals was used to rate the quality indicators until consensus was reached (defined as a mean rating on the Likert scale >=7.0 and percent agreement >75%). Quality indicators that met criteria for consensus inclusion in the Delphi survey were ranked, and comparisons were made with nominal group priorities. RESULTS: 99 quality indicators met consensus criteria for inclusion. The most highly rated quality indicator in the Delphi process was the "percentage of patients that die in the place they desire." There was significant discordance between priorities of the nominal groups with that of the Delphi survey, with only 1 quality indicator being shared on each groups' top 10 list of quality indicators. LIMITATIONS: Participants were largely from high-income English-speaking countries, and most already had structured conservative kidney management programs in place, all potentially limiting generalizability. CONCLUSIONS: Quality of conservative kidney management care is important to patients, caregivers, and health care professionals. However, discordant quality indicator priorities between groups suggested that care providers delivering conservative kidney management may not prioritize what is most important to those receiving this care. Conservative kidney management programs and health care providers can improve the applicability of this consensus-based quality indicator list to their program by further developing and evaluating it for use in their program. PMID- 30482579 TI - Three Hours, Three Days a Week. PMID- 30482580 TI - Dialysis in Older Adults: Is Later Start the Preferred Approach? PMID- 30482581 TI - Hypokalemia Associated With a Claudin 10 Mutation: A Case Report. AB - Hypokalemia of renal origin can arise from genetic abnormalities in a variety of transporters or channel proteins that mediate tubular handling of potassium. Recently, mutations in claudin 10 have been documented in patients with hypokalemia in association with a range of other electrolyte abnormalities and skin and sweat gland manifestations. We report a 12-year-old Hispanic boy who presented with anhydrosis, aptyalism, alacrima, hypokalemia, and hypocalciuria, in whom we detected a homozygous mutation in the claudin 10 gene. During the 4 year follow-up period, he developed hypermagnesemia and a decline in estimated glomerular filtration rate to 59mL/min/1.73m2. His unaffected parents and siblings were heterozygous for the mutation. We summarize the clinical phenotype encountered in patients with claudin 10 mutations. It is characterized by significant heterogeneity in electrolyte and extrarenal abnormalities and is associated with a risk for progressive loss of kidney function in up to 33% of cases. Awareness of this association between claudin 10 mutations and electrolyte abnormalities, namely hypokalemia and hypermagnesemia, sheds new light on the physiology of potassium and magnesium handling along the nephron and increases the likelihood of identifying the underlying tubular mechanism in patients with newly diagnosed hypokalemia with or without concomitant hypermagnesemia. PMID- 30482582 TI - Persistent disease and recurrence in medullary thyroid carcinoma: A case series. PMID- 30482583 TI - Exhaled-breath Testing for Prostate Cancer Based on Volatile Organic Compound Profiling Using an Electronic Nose Device (AeonoseTM): A Preliminary Report. AB - BACKGROUND: Prostate biopsy, an invasive examination, is the gold standard for diagnosing prostate cancer (PCa). There is a need for a novel noninvasive diagnostic tool that achieves a significantly high pretest probability for PCa, reducing unnecessary biopsy numbers. Recent studies have shown that volatile organic compounds (VOCs) in exhaled breath can be used to detect different types of cancers via training of an artificial neural network (ANN). OBJECTIVE: To determine whether exhaled-breath analysis using a handheld electronic nose device can be used to discriminate between VOC patterns between PCa patients and healthy individuals. DESIGN, SETTING, AND PARTICIPANTS: This prospective pilot study was conducted in the outpatient urology clinic of the Maastricht University Medical Center, the Netherlands. Patients with histologically proven PCa were already included before initial biopsy or during follow-up, with no prior treatment for their PCa. Urological patients with negative biopsies in the past year or patients with prostate enlargement (PE) with low or stable serum prostate specific antigen were used as controls. Exhaled breath was probed from 85 patients: 32 with PCa and 53 controls (30 having negative biopsies and 23 PE). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patient characteristics were statistically analyzed using independent sample t test and Pearson's chi-square test. Data analysis was performed by Aethena software after data compression using the TUCKER3 algorithm. ANN models were trained and evaluated using the leave-10%-out cross-validation method. RESULTS AND LIMITATIONS: Our trained ANN showed an accuracy of 0.75, with an area under the curve of 0.79 with sensitivity and specificity of 0.84 (95% confidence interval [CI] 0.66-0.94) and 0.70 (95% CI 0.55-0.81) respectively, comparing PCa with control individuals. The negative predictive value was found to be 0.88. The main limitation is the relatively small sample size. CONCLUSIONS: Our findings imply that the Aeonose allows us to discriminate between patients with untreated, histologically proven primary PCa and control patients based on exhaled-breath analysis. PATIENT SUMMARY: We explored the possibility of exhaled-breath analysis using an electronic nose, to be used as a noninvasive tool in clinical practice, as a pretest for diagnosing prostate cancer. We found that the electronic nose was able to discriminate between prostate cancer patients and control individuals. PMID- 30482584 TI - Are There Still Patients with Metastatic Hormone-sensitive Prostate Cancer Who Should Be Treated with Androgen Deprivation Monotherapy? AB - Combinations of conventional androgen deprivation therapy (ADT) with docetaxel or abiraterone have shown encouraging results in several phase 3 randomized trials and were consequently implemented in current clinical guidelines. However, to date it is still not clear which patients benefit the most from combination therapy and whether there are still patients who are candidates for ADT monotherapy. Here we highlight evidence that indications for conventional ADT have been significantly reduced over the past years and should only be offered to highly selected patients. Since current knowledge is still based on subgroup analyses using mostly arbitrary post hoc cutoff values, general recommendations have to be given with caution. PMID- 30482585 TI - Sexual Function and Quality of Life in a National Cohort of Survivors of Bilateral Testicular Cancer. AB - BACKGROUND: Sexual function and quality of life remain unexplored among long-term survivors of bilateral testicular cancer (TC). OBJECTIVE: To investigate sexual function, fatigue, anxiety, and depression among long-term survivors of bilateral TC (unilateral TC with contralateral germ cell neoplasia in situ [TC+GCNIS] or bilateral TC [BTC]). DESIGN, SETTING, AND PARTICIPANTS: This was a cross sectional study of 2479 long-term TC survivors, of whom 126 were treated with contralateral radiotherapy for GCNIS, 93 were treated with bilateral orchiectomy for BTC, and 2260 had unilateral TC (reference group). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes were assessed using validated questionnaires at a median time since diagnosis of 17 yr (interquartile range 12-23). Results for survivors of TC+GCNIS and of BTC were compared with those for the reference group. Adjustment was made for age and treatment for disseminated disease. RESULTS AND LIMITATIONS: The age-adjusted risk of anxiety was significantly higher among BTC survivors (odds ratio 1.7, 95% confidence interval [CI] 1.1-2.8; p=0.002) than in the reference group. Apart from a higher risk of reduced motivation among survivors of TC+GCNIS (beta=0.067, 95% CI 0.0013-0.13; p=0.046) there were no significant differences between the groups. Limitations include the low number of cases with symptoms of depression. CONCLUSIONS: Survivors of BTC had a higher risk of anxiety but did not experience impairment of other aspects of quality of life when compared to survivors of unilateral TC. These results are of importance for evidence-based information on late effects for bilateral TC patients. PATIENT SUMMARY: We evaluated quality of life and sexual function among long-term survivors of bilateral testicular cancer. Reassuringly, we did not find impaired quality of life apart from a higher risk of anxiety when comparing survivors of bilateral testicular cancer with survivors of unilateral testicular cancer. PMID- 30482586 TI - Nano-metal oxides induce antimicrobial resistance via radical-mediated mutagenesis. AB - The widespread use of nanoparticles has triggered increasing concern and interest due to the adverse effects on global public health and environmental safety. Whether the presence of nano-metal oxides (NMOs) could facilitate the formation of new antimicrobial resistance genes (ARGs) via de novo mutation is largely unknown. Here, we proved that two widely used NMOs could significantly improve the mutation frequencies of CIP- and CHL-resistant E. coli isolates; however, the corresponding metal ions have weaker effects. Distinct concentration-dependent increases of 1.0-14.2 and 1.1-456.3 folds were observed in the resistance mutations after treatment with 0.16-100 mg/L nano-Al2O3 and 0.16-500 mg/L nano ZnO, respectively, compared with those in the control. The resistant mutants showed resistance to multiple antibiotics and hereditary stability after sub culturing for 5 days. We also explored the mechanism underlying the induction of antimicrobial resistance by NMOs. Whole-genome sequencing analysis showed that the mutated genes correlated with mono- and multidrug resistance, as well as undetected resistance to antibiotics. Furthermore, NMOs significantly promoted intracellular reactive oxygen species (ROS), which would lead to oxidative DNA damage and an error-prone SOS response, and consequently, mutation rates were enhanced. Our findings indicate that NMOs could accelerate the mutagenesis of multiple-antibiotic resistance and expanded the understanding of the mechanisms in nanoparticle-induced resistance, which may be significant for guiding the production and application of nanoparticles. PMID- 30482587 TI - CT-lung volume estimates in trauma patients undergoing stabilizing surgery for flail chest. AB - AIM: To estimate and compare lung volumes from pre- and post-operative computed tomography (CT) images and correlate findings with post-operative lung function tests in trauma patients with flail chest undergoing stabilizing surgery. PATIENTS AND METHODS: Pre- and post-operative CT images of the thorax were used to estimate lung volumes in 37 patients who had undergone rib plate fixation at least 6 months before inclusion for flail chest due to blunt thoracic trauma. Computed tomography lung volumes were estimated from airway distal to each lung hilum by outlining air-filled lung tissue either manually in images of 5 mm slice thickness or automatically in images of 0.6 mm slice thickness. Demographics, pain, range of motion in the thorax, breathing movements and Forced Vital Capacity (FVC) were assessed. Total Lung Capacity (TLC) measurements were also made in a subgroup of patients (n = 17) who had not been intubated at time of the initial CT. Post-operative CT lung volumes were correlated to FVC and TLC. RESULTS: Patients with a median age of 62 (19-90) years, a median Injury Severity Score (ISS) of 20 (9-54), and a median New Injury Severity Score (NISS) of 27 (17 66) were enrolled in the study. Median follow-up time was 3.9 (0.5-5.6) years. Two patients complained of pain at rest and when breathing. Pre-operative CT lung volumes were significantly different (p < 0.0001) from post-operative CT lung volumes, 3.51 l (1.50-6.05) vs. 5.59 l (2.18-7.78), respectively. At follow-up, median FVC was 3.76 l (1.48-5.84) and median TLC was 6.93 l (4.21-8.42). Post operative CT lung volumes correlated highly with both FVC [rs = 0.75 (95% CI 0.57 0.87, p < 0.0001)] and TLC [rs = 0.90 (95% CI 0.73-0.96, p < 0.0001)]. The operated thoracic side showed decreased breathing movements. Range of motion in the lower thorax showed a low correlation with FVC [rs = 0.48 (95% CI 0.19-0.70, p = 0.002)] and a high correlation with TLC [rs = 0.80 (95% CI 0.51-0.92, p < 0.0001)]. CONCLUSIONS: Post-operative CT-lung volume estimates improve compared to pre-operative values in trauma patients undergoing stabilizing surgery for flail chest, and can be used as a marker for lung function when deciding which patient with chest wall injuries can benefit from surgery. PMID- 30482588 TI - The expedited discharge of patients with multiple traumatic rib fractures is cost effective. AB - INTRODUCTION: Rib fractures are a cause of significant morbidity and mortality in trauma patients. It is well documented that optimizing pain control, mobilization, and respiratory care decreases complications. However, the impact of these interventions on hospital costs and length of stay is not well defined. We hypothesized patients with multiple rib fractures can be discharged within three hospital days resulting in decreased hospital costs. METHODS: A retrospective review of adult patients (>=18yrs) admitted to our Level 1 trauma center (2011-2013) with >=2 rib fractures was performed. Patients were excluded if they were intubated, admitted to the ICU, required chest tube placement, or sustained significant multi-system trauma. (n = 202) Demographics, clinical characteristics, hospital costs, and outcome data were analyzed. Patients discharged within three hospital days of admission were considered to have achieved expedited discharge (ED). Univariate and multivariate analyses determined predictors of failure to achieve ED. A p value of <0.05 was considered significant. RESULTS: Study patients (n = 202) were 60 (SD = 19) years of age with an injury severity score (ISS) of 10 (SD = 5), and 4 (SD = 2) rib fractures. Of 202 patients, 127 (63%) achieved ED while 75 (37%) did not. No differences in chest AIS, ISS, smoking status or history of pulmonary disease were identified between the two groups (all p > 0.05). Average LOS (2 (SD = 1) vs. 7 (SD = 4) days; p < 0.001) and hospital costs ($2865 (SD = 1200) vs. $6085 (SD = 3033)); p < 0.001). were lower in the ED group A lower percentage of ED patients required placement in rehabilitation facilities (6% vs. 48%; p < 0.001). There were no readmissions within 30 days in either group. After controlling for potential confounding variables, multiple variable logistic regression analysis revealed that advancing age (OR 1.05 per year, 1.02-1.07) independently predicted failure to achieve ED. CONCLUSION: The majority of patients admitted to the hospital with multiple rib fractures can be discharged within three days. This expedited discharge results in significant cost savings to the hospital. Early identification of patients who cannot meet the goal of expedited discharge can facilitate improvement in management strategies. PMID- 30482589 TI - Alterations in energy consumption and plantar pressure distribution during walking in young adults with patellofemoral pain syndrome. AB - OBJECTIVE: The aim of this study was to determine the alterations of walking energy expenditure and plantar pressure distribution in young adults with patellofemoral pain syndrome (PFPS). METHODS: Thirty five individuals (mean age: 21.31 +/- 1.76) with PFPS constituted the patient group and forty healthy participants (mean age: 21.40 +/- 2.11) the control group. Preferred walking speeds (PWS) were determined on the over ground. Individuals walked on a treadmill for 7 min at their PWS and 30% above PWS and oxygen consumption was recorded via a metabolic analyzer. Net oxygen consumption was calculated for each walking trial. Borg scale was applied to assess perceived exertion during walking trial. Plantar pressure distributions were measured by a pedobarography device. Plantar area was subdivided into six zones to evaluate the dynamic plantar pressure data. RESULTS: The mean PWS of PFPS and control groups were 4.69 +/- 0.51 and 4.52 +/- 0.60 km/h, respectively (p > .09). No significant difference was observed in energy expenditure during walking at PWS between 2 groups while oxygen consumption during 30% above PWS was higher in patient group (18.72 +/- 3.75 and 16.64 +/- 3.27) (p = .007). Net oxygen consumption was also found to be higher in PFPS group (15.12 +/- 3.62 and 13.04 +/- 3.24) (p = .005). The mean Borg scores were significantly higher in PFPS group at each walking trials (p < .001). No statistically significant difference was found between weight distribution (%) of symptomatic and nonsymptomatic extremity (50.45 +/- 3.92% and 49.56 +/- 3.93%, respectively) (p = .509). Dynamic pedobarography parameters were not different between 2 groups, and also between symptomatic and nonsymptomatic extremities (p > .05). CONCLUSION: Although, rate of perceived exertion and energy expenditure during walking at 30% above PWS are affected negatively in young adults with PFPS, we may speculate that energy consumption and plantar pressure distribution can be compensated by a physiologic adaptation mechanism during walking at PWS. LEVEL OF EVIDENCE: Level III, Therapeutic Study. PMID- 30482590 TI - CRISPR/Cas9 gene-editing: Research technologies, clinical applications and ethical considerations. AB - Gene therapy carries the potential to treat more than 10,000 human monogenic diseases and benefit an even greater number of complex polygenic conditions. The repurposing of CRISPR/Cas9, an ancient bacterial immune defense system, into a gene-editing technology has armed researchers with a revolutionary tool for gene therapy. However, as the breadth of research and clinical applications of this technology continues to expand, outstanding technical challenges and ethical considerations will need to be addressed before clinical applications become commonplace. Here, we review CRISPR/Cas9 technology and discuss its benefits and limitations in research and the clinical context, as well as ethical considerations surrounding the use of CRISPR gene editing. PMID- 30482591 TI - Public health applications of CRISPR: How children's health can benefit. AB - Children under the age of five years old face significant mortality risks around the world. Public health innovations, particularly gene-editing technologies such as clustered regularly interspaced short palindromic repeats (CRISPR) could help to reduce the risk of death in children under the age of five years old. For example, CRISPR-based strategies could reduce infectious disease morbidity by gene editing mosquitoes to prevent transmission of malaria. CRISPR gene editing technology could also help to screen for influenza virus and prevent it from replicating; influenza is a particularly difficult to treat and severe virus causing many deaths in children. The lack of liver, kidney, and heart donations for children on the organ donation waiting list could also benefit from CRISPR. Gene editing of pigs to reduce rejection rates and associated risks of porcine endogenous retroviruses could allow for the utilization of pig organs for transplant. Here we review proposed applications of gene-editing technology in public health and discuss its potential to reduce child mortality and morbidity globally. PMID- 30482592 TI - In search of: Suggesting a course of action for the scientific community to research potential impacts of heritable gene editing on the maternal carrier. AB - Prospective parents with a high risk of transmission of a disease-causing mutation may want to have an unaffected genetically related child. With advances in scientific technologies, including CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats), they may be able to do so through heritable gene editing of the human germline at the pre-implantation stage. CRISPR technology in the reproduction and fertility context could potentially correct mutations in the germline, allow for the production of embryos that are free from a mutation and terminate the transmission of a disease-causing mutation from parent to child. As reproductive technologies evolve, a gap in the available literature exists that fails to address the potential impacts of edited fetal DNA on the maternal carrier. Both critical technical issues related to employing CRISPR, and germline editing based technologies in human reproduction and long-term impacts need to be studied and clarified to ensure positive application and outcomes for both offspring and mother. PMID- 30482593 TI - Spread Through Air Spaces (STAS): A New Pathologic Morphology in Lung Cancer. AB - In 2015, the World Health Organization classification of lung cancer proposed the concept of spread through air spaces (STAS) as a new pattern of invasion in lung adenocarcinoma. The definition of STAS included one or more pathologic micropapillary clusters, solid nests or single cells beyond the edge of the tumor into air spaces in the surrounding lung parenchyma, and separation from the main tumor other than tumor islands. The roles of STAS has been investigated in many studies. The results indicated that STAS is associated with key clinical variables and the prognosis of patients both in lung adenocarcinoma, lung squamous cell carcinoma, small-cell lung cancer, and lung pleomorphic carcinoma. This mini review will be focused on the developments and perspectives of STAS in lung cancer. PMID- 30482594 TI - Gender Differences in the Rate of 30-Day Readmissions After Percutaneous Coronary Intervention for Acute Coronary Syndrome. AB - BACKGROUND: It has been reported that women have higher 30-day readmission rates than men after acute coronary syndrome (ACS). However, readmission after percutaneous coronary intervention (PCI) for ACS is a distinct subset of patients in whom gender differences have not been adequately studied. METHODS: Hawaii statewide hospitalization data from 2010 to 2015 were assessed to compare gender differences in 30-day readmission rates among patients hospitalized with ACS who underwent PCI during the index hospitalization. Readmission diagnoses were categorized using an aggregated version of the Centers for Medicare and Medicaid Services Condition Categories. Multivariable logistic regression was applied to evaluate the effect of gender on the 30-day readmission rate. RESULTS: A total of 5,354 patients (29.4% women) who were hospitalized with a diagnosis of ACS and underwent PCI were studied. Overall, women were older with more identified as Native Hawaiian, and had a higher prevalence of cardiovascular risk factors compared with men. The 30-day readmission rate was 13.9% in women and 9.6% in men (p < .0001). In the multivariable model, female gender (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.09-1.60), Medicaid (OR, 1.48; 95% CI, 1.07-2.06), Medicare (1.72; 95% CI, 1.35-2.19), heart failure (1.88; 95% CI, 1.53-2.33), atrial fibrillation (OR, 1.54; 95% CI-1.21-1.95), substance use (OR, 1.88; 95% CI, 1.27-2.77), history of gastrointestinal bleeding (OR, 2.43; 95% CI, 1.29 4.58), and chronic kidney disease (OR, 1.78; 95% CI, 1.42-2.22) were independent predictors of 30-day readmissions. Readmission rates were highest during days 1 through 6 (peak, day 3) after discharge. The top three cardiac causes of readmissions were heart failure, recurrent angina, and recurrent ACS. CONCLUSIONS: Female gender is an independent predictor of 30-day readmission after ACS that requires PCI. Our finding suggests women are at a higher risk of post-ACS cardiac events such as heart failure and recurrent ACS, and further gender specific intervention is needed to reduce 30-day readmission rate in women after ACS. PMID- 30482595 TI - Bio-electrodegradation of 2,4,6-Trichlorophenol by mixed microbial culture in dual chambered microbial fuel cells. AB - 2,4,6-Trichlorophenol (TCP) was bioelectrochemically treated in anodic and cathodic compartments of two identical dual chambered microbial fuel cells MFC-A and MFC-B under anaerobic and aerobic conditions, respectively, and energy was recovered in the form of electricity. It was observed that MFC-B with bio cathodic treatment of TCP outcompeted the MFC-A with bio-anodic treatment. The maximum power density for MFC-A with bio-anode was found to be 446.76 mW/m2 while for MFC-B with bio-cathode it was 1059.58 mW/m2. The MFC-B consistently showed higher coulombic efficiency, power density and chemical oxygen demand removal efficiency indicating the better performance of the MFC-B as compared to the MFC A. Scanning electron micrograph also confirmed better accumulation of microbes on the anode of MFC-B and hence its better performance in terms of energy recovery. Some major genera present in the microbial community were quantified using quantitative real-time polymerase chain reaction technique. It also confirmed the dominance of electroactive species in the bio-anodic sludge of MFC-B over the bio anodic sludge of MFC-A. Cyclic voltammogram also asserted better electrochemical activity of the bio-cathode in the treatment of chlorinated phenol toxicants in MFC-B system. The study shows that MFC can be a viable option in treatment of recalcitrant chemical compounds like TCP with the generation of energy in the form of electrical power. PMID- 30482596 TI - Metabolome analysis revealed the knockout of glyoxylate shunt as an effective strategy for improvement of 1-butanol production in transgenic Escherichia coli. AB - High 1-butanol titer has been achieved in a transgenic Escherichia coli strain JCL299FT with a heterologous 1-butanol pathway by deleting competing pathways, balancing of cofactor and resolving free CoA imbalance. However, further improvement of 1-butanol production is still possible in the highest producing strain JCL299FT as indicated by the accumulation of acetate, a major undesired by product during bio-production by microorganisms that competes with 1-butanol production for the available acetyl-CoA and inhibits protein synthesis resulting in poor growth. In this study, liquid chromatography/tandem mass spectrometry (LC/MS/MS)-based metabolome analysis was performed to identify new rate limiting steps in the 1-butanol production pathway of E. coli strain JCL299FT. The results of metabolome analysis showed increased amounts of glyoxylate in JCL299FT compared to the previous highest-producing strain JCL299F. Knocking out aceA successfully decreased the amount of glyoxylate and reduced acetate accumulation, resulting in the increased levels of TCA cycle and 1-butanol pathway metabolites. These observations indicated that there was a redirection of flux from acetate to TCA cycle and 1-butanol producing pathway, which led to better growth of the 1 butanol producing strain. Consequently, 1-butanol production titer was improved by 39% and the production yield was improved by 12% in M9 medium supplemented with yeast extract. This study is the first report of using the knockout of aceA, the first gene in the glyoxylate shunt that encodes isocitrate lyase, as an effective strategy to reduce acetate overflow in 1-butanol producing E. coli. PMID- 30482597 TI - Melanoma Early Detection: Big Data, Bigger Picture. AB - Innovative technologies, including novel communication and imaging tools, are affecting dermatology in profound ways. A burning question for the field is whether we will retrospectively react to innovations or proactively leverage them to benefit precision medicine. Early detection of melanoma is a dermatologic area particularly poised to benefit from such innovation. This session of the Montagna Symposium on Biology of Skin focused on provocative, potentially disruptive advances, including crowdsourcing of patient advocacy efforts, rigorous experimental design of public education campaigns, research with mobile phone applications, advanced skin imaging technologies, and the emergence of artificial intelligence as a diagnostic supplement. PMID- 30482598 TI - Daily-life stress differentially impacts ventral striatal dopaminergic modulation of reward processing in first-degree relatives of individuals with psychosis. AB - Emerging evidence shows that stress can impair the ability to learn from and pursue rewards, which in turn has been linked to motivational impairments characteristic of the psychotic disorder. Ventral striatal dopaminergic neurotransmission has been found to modulate reward processing, and appears to be disrupted by exposure to stress. We investigated the hypothesis that stress experienced in the everyday life has a blunting effect on reward-induced dopamine release in the ventral striatum of 16 individuals at a familial risk for psychosis compared to 16 matched control subjects. Six days of ecological momentary assessments quantified the amount of daily-life stress prior to [18F]fallypride PET imaging while performing a probabilistic reinforcement learning task. Relative to the controls, individuals at a familial risk for psychosis who encountered more daily-life stress showed significantly diminished extent of reward-induced dopamine release in the right ventral striatum, as well as poorer performance on the reward task. These findings provide the first neuromolecular evidence for stress-related deregulation of reward processing in familial predisposition to psychosis. The implication of daily-life stress in compromised modulation of reward function may facilitate the design of targeted neuropharmacological and ecological interventions. PMID- 30482599 TI - Successful oral desensitization in children with cow's milk anaphylaxis: Clinical and laboratory evaluation up to nine-years follow-up. AB - INTRODUCTION: Cow's milk protein allergy (CMPA) is the most common food allergy in children worldwide. Some children have severe and persistent CMPA, with near fatal reactions after exposure to trace amounts of cow's milk-proteins (CMP). Strict avoidance diet is difficult, negatively affects quality of life and represents a conservative approach. Therefore, different therapeutic strategies are necessary. OBJECTIVE: We aimed to assess long-term efficacy and safety of oral immunotherapy (OIT) in children with severe and long-lasting IgE-mediated CMPA. MATERIALS AND METHODS: The authors present four case reports of patients with CMPA who underwent CMP-OIT, that have been under long-term follow-up up to nine years. We provide information about the clinical and laboratory evaluation. Skin prick tests (SPT), specific IgE and IgG4 were performed before, during, and after OIT. Immune profile after OIT was assessed by flow cytometry (lymphocyte subsets, regulatory T and B cells). RESULTS: The success rate was 100%, and all patients currently have a free diet with minimal diary ingestion of 200mL CMP or equivalent. Specific IgE levels and SPT to CMP have progressively decreased, and specific IgG4 levels have increased. CD4+CD25+CD127-/dim regulatory T cells were increased after OIT. CONCLUSIONS: OIT ensured a clinical tolerance state after up to nine years, confirmed by both clinical and immune profile, allowing a diet without restrictions, with high satisfaction from patients and caregivers. We emphasize that OIT should be performed only by allergy experts in the hospital setting, and that only motivated families should be enrolled, since it is essential to ensure CMP daily intake at home. PMID- 30482600 TI - Rural and urban differences in orthognathic surgical patients in the north east of Scotland. AB - We have previously identified differences in the presentation and treatment of cancer between patients who live in rural compared with urban areas, but have not yet seen differences in those treated by orthognathic surgery. We hypothesised that patients from areas further away from the hospital face higher costs to attend and may not present with minor problems as often as those who live nearby. We therefore retrospectively reviewed all those (n=216) who had presented for orthognathic surgery over a six-year period (May 2011 to May 2017). The severity of malocclusion and facial asymmetry was established by combining measurements of intraoperative movements. Rurality was measured as the distance from home to the hospital at the time of operation. Those with smaller intraoperative movements (less than 7mm combined movement) lived significantly closer to the hospital as the crow flies (mean difference 15.13 miles, 95% CI 0.20 to 30.48, p=0.05) and could travel there more quickly (mean difference 65minutes 95% CI 9.8 to 121.7, p=0.02) than those with larger movements. Our results suggest that patients with small malocclusions and slight facial asymmetry who live further away from the hospital, may be less likely to present for operation than those who live closer. We explain why socioeconomic class is unlikely to confound our results, and suggest potential ways to minimise the effect observed. PMID- 30482601 TI - Re: Knowledge of final-year medical students about oral and maxillofacial surgery: a two-centre study. PMID- 30482602 TI - Stabilization exercises combined with neuromuscular electrical stimulation for patients with chronic low back pain: a randomized controlled trial. AB - BACKGROUND: One proposed mechanism of chronic low back pain might be paraspinal muscle impairment. Commonly, this impairment is treated with stabilization exercises. However, the effect size of stabilization exercises has been previously reported to be small. DESIGN: Randomized controlled trial. OBJECTIVE: To investigate the clinical benefit of using neuromuscular electrical stimulation as a supplement to stabilization exercises in patients with chronic low back pain. METHODS: Thirty participants with chronic low back pain were randomized into a stabilization exercise only group (n=15) or a stabilization exercise plus neuromuscular electrical stimulation group (n=15). The stabilization exercises included abdominal, side support, and quadruped exercises. The neuromuscular electrical stimulation was applied to the lumbar paraspinal muscles for 20min each session. Both groups received their respective interventions twice a week for 6 weeks. Participant eligibility for inclusion was age between 18 and 60 years, body mass index <=34, chronic low back pain >=3 months, Numeric Pain Rating Scale >=3, Modified Oswestry Disability Questionnaire score >=20 and ability to understand English. Outcome measurements were self-reported neuromuscular electrical stimulation tolerability scale, Modified Oswestry Disability Questionnaire, Numeric Pain Rating Scale, Fear-Avoidance Beliefs Questionnaire and paraspinal muscle strength. RESULTS: The neuromuscular electrical stimulation was reported to be tolerable. There were no significant between-group differences on any of the outcome measures (p>0.05). CONCLUSIONS: The application of neuromuscular electrical stimulation on the paraspinal muscles was reported to be tolerable. Supplementing stabilization exercises with neuromuscular electrical stimulation did not offer any additional clinical benefit for the chronic low back pain patients. PMID- 30482603 TI - Erratum. PMID- 30482604 TI - Clinical outcomes and significant factors in the survival rate after decompression surgery for patients who were non-ambulatory due to spinal metastases. AB - BACKGROUND: The development of effective chemotherapy regimens and molecular targeting agents are improving the overall survival rates in patients with cancer. However, patients who are non-ambulatory due to metastatic epidural spinal cord compression (MESCC) may be assessed as unable to tolerate chemotherapy secondary to poor performance status. This means that the ambulatory status of patients with cancer might be significant for survival time. METHODS: We investigated the functional outcomes and factors influencing overall survival in 31 patients who were non-ambulatory due to MESCC and underwent decompression surgery. The functional outcome was determined by the Frankel grading system. RESULT: Twenty-one patients (68%) improved by at least 1 Frankel grade; 17 patients (55%) became ambulatory postoperatively. Most of postoperatively ambulatory patients could undergo postoperative chemotherapy (14/17, 82%). On the other hand, only a few postoperatively non-ambulatory patients could undergo postoperative chemotherapy (2/15, 13%). We observed a complication rate of 35.5% with specific complications including wound infection, pneumonia, and deep vein thrombosis/pulmonary embolus. The median survival duration was 7.0 months. Factors that significantly affected the overall survival in univariate analyses were revised Tokuhashi score (RTS) >= 4, postoperative chemotherapy, ambulatory status, and complications (RTS >= 4, P < 0.05; postoperative chemotherapy, P < 0.001; ambulatory status, P < 0.001; complications, P < 0.01). CONCLUSIONS: Decompression surgery for patients who are non-ambulatory due to MESCC directly contributes to functional outcomes and may indirectly contribute to overall survival. If non-ambulatory patients who are assessed as unable to tolerate chemotherapy due to poor performance status regain the ability to walk by decompression surgery, they will have a chance to receive postoperative chemotherapy, thereby increasing their chances of prolonging survival. However, postoperative complications may shorten their survival; therefore, we should carefully consider the surgical indications. RTS is useful for judging the surgical indication. PMID- 30482605 TI - Genome-Wide Evolutionary Analysis of Natural History and Adaptation in the World's Tigers. AB - No other species attracts more international resources, public attention, and protracted controversies over its intraspecific taxonomy than the tiger (Panthera tigris) [1, 2]. Today, fewer than 4,000 free-ranging tigers survive, covering only 7% of their historical range, and debates persist over whether they comprise six, five, or two subspecies [3-6]. The lack of consensus over the number of tiger subspecies has partially hindered the global effort to recover the species from the brink of extinction, as both captive breeding and landscape intervention of wild populations increasingly require an explicit delineation of the conservation management units [7]. The recent coalescence to a late Pleistocene bottleneck (circa 110 kya) [5, 8, 9] poses challenges for detecting tiger subspecific morphological traits, suggesting that elucidating intraspecific evolution in the tiger requires analyses at the genomic scale. Here, we present whole-genome sequencing analyses from 32 voucher specimens that resolve six statistically robust monophyletic clades corresponding to extant subspecies, including the recently recognized Malayan tiger (P. tigris jacksoni). The intersubspecies gene flow is very low, corroborating the recognized phylogeographic units. We identified multiple genomic regions that are candidates for identifying the adaptive divergence of subspecies. The body-size-related gene ADH7 appears to have been strongly selected in the Sumatran tiger, perhaps in association with adaptation to the tropical Sunda Islands. The identified genomic signatures provide a solid basis for recognizing appropriate conservation management units in the tiger and can benefit global conservation strategic planning for this charismatic megafauna icon. PMID- 30482606 TI - Toward a Model of Interpersonal Trust Drawn from Neuroscience, Psychology, and Economics. AB - Trust pervades nearly every social aspect of our daily lives, and its disruption is a significant factor in mental illness. Research in the field of neuroeconomics has gained a deeper understanding of the neuropsychoeconomic (NPE) underpinnings of trust by combining complementary methodologies from neuroscience, psychology, and economics. However, a coherent model of trust that integrates separate findings under a conceptual framework is still lacking. Here, we sketch out an integrative NPE model that explains how the interactions of psychoeconomic components engage domain-general large-scale brain networks in shaping trust behavior over time. We also point out caveats of current research approaches and outline open questions that can help guide future transdisciplinary investigations for a better understanding of the neuropsychology of trust. PMID- 30482607 TI - Reducing the global burden of depression: a Lancet-World Psychiatric Association Commission. PMID- 30482608 TI - Cost-effective implementation of a custom MALDI-TOF library for the identification of South Australian Nocardia isolates. AB - Mass spectrometry plays a significant role in the routine identification of micro organisms and provides the ability to incorporate newly found pathogens into the database in a cost-effective fashion. This work aims to highlight the role of mass spectrometry through improved identification of Nocardia species in a diagnostic clinical microbiology laboratory. Prior to this study we constructed a custom in-house matrix-assisted laser desorption ionisation-time of flight (MALDI TOF) library for Nocardia isolates consisting of isolates identified to the species level. Subsequently over a period of 5 years, we isolated a further 153 Nocardia clinical isolates, of which 91.5% (140/153) were identified correctly with the custom MALDI-TOF library and 8.5% (13/153) needed further molecular sequencing for final identification. We estimate our cost savings to be approximately 9,800 AUD overall with this implementation over the study period. Continued expansion and maintenance of this custom library will eventually result in little or no 16S ribosomal DNA sequencing needed for specific identification of Nocardia isolates. PMID- 30482609 TI - Mentalization in CALM psychotherapy sessions: Helping patients engage with alternative perspectives at the end of life. AB - OBJECTIVE: To identify how therapists invite patients with advanced cancer to engage with alternative perspectives about their illness trajectory and their end of life. METHODS: Sequences of talk in which a therapist introduced a patient to alternative perspectives, were transcribed and analysed using the method of conversation analysis. RESULTS: The analysis identifies one subtle way a patient is invited to consider an alternative perspective relating to their disease progression. Meaning expansion enquiries invite the patient to expand on the meaning of an utterance and in doing so, implicitly problematize the singularity of the patient's assumptions, without directly challenging them. The questions work as preliminary moves, providing the patient with the opportunity to expand on their assumptions. This enables the therapist to subsequently present an alternative perspective in a way that incorporates the patient's expanded perspective. CONCLUSION: The analysis reveals a skilful way in which therapists can cautiously and collaboratively introduce a patient to alternative perspectives concerning end-of-life, without invalidating the patient's perspective in this particularly delicate context. PRACTICE IMPLICATIONS: Whilst mentalization is considered an important therapeutic process, the present study reveals precisely how this phenomenon can be enacted in therapy and within the particularly challenging context of end-of-life. PMID- 30482610 TI - Synthesis of core-shell structured ZnO@m-SiO2 with excellent reinforcing effect and antimicrobial activity for dental resin composites. AB - OBJECTIVE: The aim of this study is to explore the reinforcing effect and the antimicrobial activity of the core-mesoporous shell structured ZnO@m-SiO2, which possesses the micromechanical resin matrix/filler interlocking in dental composites, and to investigate the effect of filler compositions on their physical-mechanical properties. METHODS: ZnO@m-SiO2 was synthesized by a simple self-assembly method and then characterized by electron microscopy, X-ray diffraction (XRD) and N2 adsorption/desorption measurements. Mechanical properties of dental composites reinforced with ZnO@m-SiO2 and nonporous SiO2 particles were measured with a universal mechanical testing machine. Fracture morphologies of these composites were observed by field-emission scanning electron microscopy (FE-SEM), and their antimicrobial activities were evaluated according to the ASTM E 2180-07 (2012) method. Resin composites containing unimodal silanized SiO2 were served as the control group. RESULTS: The impregnation of lower loading of ZnO@m-SiO2 (<=7wt%) into dental composites including silanized SiO2 substantially increased their mechanical properties. Among all composites, the optimal composite Z7S63 (ZnO@m-SiO2: silanized SiO2=7:63, wt/wt, total filler loading 70wt%) demonstrated the best flexural strength, flexural modulus and compression strength, which were increased by 121.2, 67.1 and 32.5%, respectively, in comparison with the control composite Z0S70. In addition, this optimal composite also exhibited superior antimicrobial activity (>99.9%) and acceptable degree of conversion, polymerization shrinkage and curing depth. SIGNIFICANCE: The incorporation of ZnO@m-SiO2 and silanized SiO2 as bimodal fillers led to the design and formulation of dental composites with excellent comprehensive performance, especially the improved mechanical properties and the superior antimicrobial activity. PMID- 30482611 TI - Remineralisation of enamel with silver diamine fluoride and sodium fluoride. AB - OBJECTIVE: To evaluate the remineralising effect of the adjunctive application of 38% silver diamine fluoride (SDF) solution and 5% sodium fluoride (NaF) varnish on artificial enamel caries lesions. METHODS: Forty-eight demineralised enamel specimens were allocated into four groups. Group 1 received 38% SDF and 5% NaF; Group 2 received 38% SDF; Group 3 received 5% NaF; and Group 4 received deionized water. After pH cycling, the surface morphology and fluoride content of the specimens were studied via scanning electron microscopy (SEM)/energy dispersive spectroscopy (EDS). The lesion depth and crystal characteristics were assessed using micro-computed tomography and X-ray diffraction (XRD) respectively. The crystallization reaction was performed by incubating hydroxyapatite powder with NaF or SDF for 48h. The precipitates were studied via transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS). RESULTS: SEM demonstrated the destruction of the enamel surface in Group 4. EDS revealed that the mean fluoride weight percentage of Groups 1-4 were 1.28+/-0.15, 1.33+/-0.19, 1.03+/-0.09 and 0.87+/-0.04 respectively. The mean lesion depths of Groups 1-4 were 129+/-14MUm, 131+/-16MUm, 153+/-10MUm and 181+/-21MUm respectively. The addition of NaF to SDF did not reduce the lesion depths (p=0.779). XRD revealed that silver chloride formed as a main product in Groups 1 and 2. Meanwhile, TEM analysis indicated that silver nanoparticles were incorporated into hydroxyapatite crystal in SDF-treated hydroxyapatite. XPS spectra suggested that the chemical state of the silver was metallic. SIGNIFICANCE: The adjunctive application of SDF and NaF varnish had a similar remineralising effect to that of SDF on enamel caries. PMID- 30482612 TI - Managing hemodynamic instability - If you want to know cardiac output, you need to measure it! PMID- 30482613 TI - Rapid response team review of hemodynamically unstable ward patients: The accuracy of cardiac index assessment. AB - PURPOSE: Intensive care doctors commonly attend rapid response team (RRT) reviews of hospital-ward patients with hemodynamic instability and estimate the patient's likely cardiac index (CI). We aimed to non-invasively measure the CI of such patients and assess the level of agreement between such measurements and clinically estimated CI categories (low <2L/min/m2, normal 2-2.99L/min/m2 or high >=3L/min/m2). MATERIALS AND METHODS: A prospective, observational study of non invasive measurement and clinical estimation of CI categories in 50 adult hospital-ward patients who activated the RRT for 'hemodynamic instability' (tachycardia > 100BPM or hypotension < 90mmHg or both). RESULTS: The CI was measured in 47/50(94%) patients and the mean CI was 3.5(95% CI 3.2-3.7) L/min/m2. Overall, 30(64%) patients had a high CI, 13(28%) and 4(9%) had a normal and a low CI, respectively. The level of agreement between measured and clinically estimated CI categories was low(19.2%). Sensitivity and positive predictive values of clinical estimation were low(0% and 3.3% for high CI, and 0% and 50% for low CI, respectively). CONCLUSIONS: Non-invasive CI measurement was possible in almost all hospital-ward patients triggering RRT review for hemodynamic instability. In such patients, the CI was high, and intensive care clinicians were unable to identify a low or a high CI state. PMID- 30482614 TI - Ephrin-A2 affects wound healing and scarring in a murine model of excisional injury. AB - Ephrin ligand/Eph receptor signaling is important in both tissue development and homeostasis. There is increasing evidence that Ephrin/Eph signaling is important in the skin, involved in hair follicle cycling, epidermal differentiation, cutaneous innervation and skin cancer. However, there is currently limited information on the role of Ephrin/Eph signaling in cutaneous wound healing. Here we report the effects of the Ephrin-A2 and A5 ligands on wound healing. Using Ephrin-A2-/-, Ephrin-A5-/- and Ephrin-A2A5-/- transgenic mice, in vitro wound healing assays were conducted using isolated keratinocytes and fibroblasts. Ephrin-A2-/-, Ephrin-A2A5-/- and wild type mice with excisional wounds were used to analyze the impact of these ligands on wound closure, scar outcome, collagen orientation and re-innervation in vivo. The absence of the Ephrin-A2 and A5 ligands did not have any effect on dermal fibroblast proliferation or on fibroblast or keratinocyte migration. The loss of Ephrin-A2 and A5 ligands did not impact on the rate of wound closure or re-innervation after injury. However, changes in the gross morphology of the healed scar and in collagen histology of the scar dermis were observed in transgenic mice. Therefore Ephrin-A2 and A5 ligands may play an important role in final scar appearance associated with collagen deposition and structure. PMID- 30482615 TI - Sodium butyrate inhibits the production of HMGB1 and attenuates severe burn plus delayed resuscitation-induced intestine injury via the p38 signaling pathway. AB - BACKGROUND: Inflammatory response triggered by high mobility group box-1 (HMGB1) protein and oxidative stress play critical roles in the intestinal injury after severe burn. Sodium butyrate, a histone deacetylase inhibitor, has potential anti inflammatory properties, inhibiting the expression of inflammatory mediators such as HMGB1 in diverse diseases. This study was designed to investigate the effects of sodium butyrate on severe burn plus delayed resuscitation-induced intestine injury, intestinal expressions of HMGB1 and intracellular adhesion molecule-1 (ICAM-1), oxidative stress, and signal transduction pathway changes in rats. MATERIALS AND METHODS: Fifty-six Sprague-Dawley rats were divided into 3 groups randomly: (1) sham group, animals underwent sham burn; (2) burn group, rats subjected to full-thickness burns of 30% total body surface area (TBSA) and received 2ml/kg/TBSA lactated Ringer solution for resuscitation at 6, 12, and 36h after burn injury; (3) burn plus sodium butyrate (burn+SB) group, animals received burn injury and lactated Ringer solution with sodium butyrate inside for resuscitation in the same manner. Diamine oxidase (DAO) concentration in plasma was measured by enzyme-linked immunosorbent assay. Intestinal fatty acid binding protein (I-FABP) and ICAM-1 expressions in the intestine were analyzed by immunohistochemical method. HMGB1 and p38 mitogen-activated protein kinase (MAPK) expressions in the intestine tissues were examined by Western blot. The intestinal concentration of malondialdehyde (MDA) was also determined. RESULTS: Intestinal HMGB1 expression was significantly increased in burn group compared with sham group. Sodium butyrate administration significantly inhibited the HMGB1 expression in the intestine, decreased the DAO concentration in plasma, reduced the intestinal I-FABP expression, and improved the intestinal histologic changes induced by burn injury plus delayed resuscitation. Sodium butyrate treatment also markedly reduced the increase of intestinal ICAM-1 expression and MDA content, and inhibited p38 MAPK activity in the intestine of severely burned rats with delayed resuscitation. CONCLUSIONS: Sodium butyrate inhibits HMGB1 expression which could be attributed to p38 MAPK signal transduction pathway and decreases intestinal inflammatory responses and oxidative stress, thus attenuates burn plus delayed resuscitation-induced intestine injury. PMID- 30482616 TI - Comparative evaluation of three methods of skin graft fixation for split thickness skin graft after release of post burn contracture of the neck. AB - OBJECTIVES: Split thickness skin graft is an essential component of release of post burn contracture of neck. There are many methods of fixation of skin grafts; however, there is lack of objective comparison between different techniques. This study has been designed to compare three commonly used techniques of split thickness skin graft fixation methods. Surgical time, advantages, cost factor and post-operative outcome have been compared amongst three techniques. METHODS: A randomized interventional comparative study was conducted to compare three methods of skin graft fixation in patients of 10-50 years age group, with contracture of more than 3 month duration having more than 100cm2 skin defects after contracture release. Resurfacing of the defects after contracture release was carried out in all the groups using autologous split skin grafts. Patients were included in three groups; Group 1: tie over method, Group 2: skin stapler fixation and Group 3: Cyanoacrylate glue fixation. RESULTS: Mean duration of fixation procedure was 34min in tie over group, in skin stapler group 7min and in cyanoacrylate group 12min. Mean cost of fixation material was 10.23 USD in tie over group, 11.23 USD in stapler group and 40.06 USD in cyanoacrylate group. Mean score of pain/discomfort (visual analog score) on dressing removal in tie-over group was 3, for skin stapler group was 2.9 and that for cyanoacrylate glue group was 1.8. mean graft take was found to be 90.1% in tie-over group, 94.1% in skin stapler group & 93.8% in cyanoacrylate glue group. On logistic regression analysis, keeping all the variables constant in the groups the complications as the outcome variable, three groups are comparable. The need for regrafting remains inconclusive. CONCLUSIONS: Skin stapler method for skin graft fixation was least time consuming, affordable and highly reliable when graft take success was considered. Cyanoacrylate glue fixation method was least painful and reliable in terms of graft take success though costlier than other two. PMID- 30482617 TI - Epidemiological analysis of the 2015-2017 African swine fever outbreaks in Estonia. AB - African swine fever (ASF) was first detected in the Estonian wild boar population in September 2014, while the first domestic pig farm was affected in July 2015. In the present study, we aimed to analyse, retrospectively, the epidemiology of the disease in all 26 outbreaks in domestic pig herds that occurred in Estonia during the period 2015-2017. Formal interviews were conducted to estimate the high-risk period for every farm, and to identify the possible origin of the ASF virus and the mode of virus introduction. Furthermore, the clinical manifestation of the disease as well as the course of the disease within the farm were investigated. Survival analysis was used to calculate herd incidence and to estimate outbreak risk. A hierarchical Bayesian space-time model was used to analyse the associations between outbreaks and ASF occurrence in wild boar. The spatial and temporal distribution of outbreaks was analysed to characterise the ASF epidemic in the Estonian domestic pig population from 2015 to 2017. The estimated high-risk period varied from seven to 20 days with a median of 11 days. On most of the affected farms, the first clinical signs were mild and not specific to ASF despite the high virulence of the circulating virus. Morbidity and mortality were often limited to a single pen or unit of the farm. The highest mortality (29.7%) was seen on backyard farms with 1-10 pigs and the lowest (0.7%) on large commercial farms (>1000 pigs). The spread of the virus within affected farms has been slow and the contagiousness of the virus has been relatively low. Farms of all sizes and types have been at risk, including large commercial farms operating at a high biosecurity level. In none of the affected farms could the specific route of introduction be verified. However, the findings suggested that virus introduction occurred via indirect transmission routes due to insufficient biosecurity. The total herd incidence of outbreaks was similar across all three years, being 2.4% in 2015 and 2016, and 2.0% in 2017. All outbreaks occurred from June to September, during the warmest period of the year. The results suggest that the increase in ASF cases in local wild boar populations is the main risk factor leading to the infection of farms; 88% of outbreaks occurred in areas where ASF virus was detected in wild boar prior to the outbreak, within a radius of 15 km from the outbreak farm. PMID- 30482618 TI - Posing the APC/C E3 Ubiquitin Ligase to Orchestrate Cell Division. AB - The anaphase promoting complex/cyclosome (APC/C) E3 ligase controls mitosis and nonmitotic pathways through interactions with proteins that coordinate ubiquitylation. Since the discovery that the catalytic subunits of APC/C are conformationally dynamic cullin and RING proteins, many unexpected and intricate regulatory mechanisms have emerged. Here, we review structural knowledge of this regulation, focusing on: (i) coactivators, E2 ubiquitin (Ub)-conjugating enzymes, and inhibitors engage or influence multiple sites on APC/C including the cullin RING catalytic core; and (ii) the outcomes of these interactions rely on mobility of coactivators and cullin-RING domains, which permits distinct conformations specifying different functions. Thus, APC/C is not simply an interaction hub, but is instead a dynamic, multifunctional molecular machine whose structure is remodeled by binding partners to achieve temporal ubiquitylation regulating cell division. PMID- 30482619 TI - Sleep apnea screening is uncommon after stroke. AB - OBJECTIVE/BACKGROUND: To assess (1) pre and post-stroke screening for sleep apnea (SA) within a population-based study without an academic medical center, and (2) ethnic differences in post-stroke sleep apnea screening among Mexican Americans (MAs) and non-Hispanic whites (NHWs). PATIENTS/METHODS: MAs and NHWs with stroke in the Brain Attack Surveillance in Corpus Christi project (2011-2015) were interviewed shortly after stroke about the pre-stroke period, and again at approximately 90 days after stroke in reference to the post-stroke period. Questions included whether any clinical provider directly asked about snoring or daytime sleepiness or had offered polysomnography. Logistic regression tested the association between these outcomes and ethnicity both unadjusted and adjusted for potential confounders. RESULTS: Among 981 participants, 63% were MA. MAs in comparison to NHWs were younger, had a higher prevalence of hypertension, diabetes, and never smoking, a higher body mass index, and a lower prevalence of atrial fibrillation. Only 17% reported having been offered SA diagnostic testing pre-stroke, without a difference by ethnicity. In the post-stroke period, only 50 (5%) participants reported being directly queried about snoring; 86 (9%) reported being directly queried about sleepiness; and 55 (6%) reported having been offered polysomnography. No ethnic differences were found for these three outcomes, in unadjusted or adjusted analyses. CONCLUSIONS: Screening for classic symptoms of SA, and formal testing for SA, are rare within the first 90 days after stroke, for both MAs and NHWs. Provider education is needed to raise awareness that SA affects most patients after stroke and is associated with poor outcomes. PMID- 30482620 TI - Discovery of N-(piperidin-3-yl)-N-(pyridin-2-yl)piperidine/piperazine-1 carboxamides as small molecule inhibitors of PCSK9. AB - A series of N-(piperidin-3-yl)-N-(pyridin-2-yl)piperidine/piperazine-1 carboxamides were identified as small molecule PCSK9 mRNA translation inhibitors. Analogues from this new chemical series, such as 4d and 4g, exhibited improved PCSK9 potency, ADME properties, and in vitro safety profiles when compared to earlier lead structures. PMID- 30482621 TI - Discovery of 2-(1H-imidazo-2-yl)piperazines as a new class of potent and non cytotoxic inhibitors of Trypanosoma brucei growth in vitro. AB - The identification of a new series of growth inhibitors of Trypanosoma brucei rhodesiense, causative agent of Human African Trypanosomiasis (HAT), is described. A selection of compounds from our in-house compound collection was screened in vitro against the parasite leading to the identification of compounds with nanomolar inhibition of T. brucei growth. Preliminary SAR on the hit compound led to the identification of compound 34 that shows low nanomolar parasite growth inhibition (T. brucei EC50 5 nM), is not cytotoxic (HeLa CC50 > 25,000 nM) and is selective over other parasites, such as Trypanosoma cruzi and Plasmodium falciparum (T. cruzi EC50 8120 nM, P. falciparum EC50 3624 nM). PMID- 30482622 TI - Radical dose escalation by high-dose-rate brachytherapy for localized prostate cancer-Significance of prostate-specific antigen nadir level within 18 months as correlation for long-term biochemical control. AB - PURPOSE: High-dose-rate brachytherapy (HDR-BT) for dose escalation in localized prostate cancer has been established as one standard treatment option. However, long-term results at followup (FU) >=5 years are usually needed to ensure robustness of reported outcomes. Potential benefit of salvage therapy is, nevertheless, higher when relapse is diagnosed early. This study aimed to solve this dilemma by evaluating the prostate-specific antigen (PSA) nadir for early prediction of long-term biochemical control. METHODS AND MATERIALS: Combined pelvis-external beam radiation/HDR-BT boost to EQD2 >100 Gy (alpha/beta = 3) was performed in 459 consecutively treated patients. These patients with an FU >= 24 months were analyzed and stratified in PSA nadir (nPSA)-groups by PSA nadir within 18 months after radiotherapy (nPSA18). Kaplan-Meier/log-rank tests and Cox regression models were used to compare the study endpoints. RESULTS: The mean FU was 77 months. A PSA nadir within 18 months (nPSA18) <0.5 ng/mL was achieved in 222 patients with median time to reach nPSA18 of 7 months. The 5-year American Society of Therapeutic Radiology and Oncology (ASTRO) biochemical control (prostate-specific antigen disease-free survival) for the nPSA18 group <0.5 ng/mL was 89% and for the group >= 0.5 ng/mL, it was 78.6% (p = 0.011). nPSA18 was an independent predictor of cancer-specific survival, distant metastasis-free survival, and biochemical control (ASTRO) (p = 0.026, p = 0.020, and p = 0.01, respectively). CONCLUSIONS: The present results suggest that the PSA nadir level within 18 months after radiotherapy may serve as an early parameter for long-term biochemical control according to ASTRO definitions following radical dose escalation by HDR-BT for prostate cancer. Excellent outcomes were associated with nPSA18 < 0.5 ng/mL. PMID- 30482623 TI - Comparison of two iodine-125 brachytherapy implant techniques for the treatment of lung tumor: Preplanning and intraoperative planning. AB - PURPOSE: To compare preplanning and intraoperative planning methods of lung tumor brachytherapy based on postimplant CT images and dosimetric outcomes. METHODS AND MATERIALS: Detailed postimplant evaluations of iodine-125 seed implants were performed in 15 patients using a preplanning technique and in 15 patients treated with an intraoperative planning technique. The implant details, dosimetric parameters, and implant quality indices were compared. Furthermore, the dose to the lung and the incidence of complications were compared. RESULTS: The planning target volume was similar in both groups (p = 0.496). The median V100%, V150%, and V200% values (the percent of the planning target volume receiving 100%, 150%, and 200% of the prescription dose) for the intraoperative planning technique were 95.65%, 76.47%, and 59.80%, respectively. The median V100%, V150%, and V200% values for the preplanning methodology were 88.86%, 69.23%, and 28.30%, respectively (p < 0.01). The median values of the coverage index, c1, conformity index, and plan quality index were higher in the intraoperative planning group than in the preplanning group (p < 0.05). The overdose volume index and dose nonhomogeneity ratio were higher in the intraoperative group (p < 0.05), and the dose homogeneity index was lower in the intraoperative group (p < 0.05) than in the preplanning group. No significant differences were observed in the reference dose (VREF), external index, or lung doses between the two groups. The incidences of pneumothorax and hemoptysis were minimal in both groups. CONCLUSION: These data showed that the intraoperative planning method was superior to the preplanning method for the treatment of lung tumors. PMID- 30482624 TI - Emergency room visits and admission rates of children with neuromuscular disorders: A 10-year experience in a medical center in Taiwan. AB - BACKGROUND: No previous studies have explored emergency medical care for children with chronic neuromuscular disorders (NMDs). We aimed to determine the major reasons for the emergency room (ER) readmission of pediatric patients with NMDs and suggest changes to the care plan to decrease readmissions. METHODS: Children with chronic NMDs (aged <18 years) who visited a medical center-based ER between January 2005 and January 2015 were included. The following data were extracted from the patient's ER records: presentations; demographic data, including sex and age; NMD diagnosis; triage classification; emergency examination; initial management and outcomes. The outcomes were death inside or outside the ER, admission to the ward or pediatric intensive care unit (PICU), uneventful discharge, and repeated ER visits. RESULTS: In 10 years, 44 children with heterogeneous NMDs (boys/girls: 30/14, mean age: 9.9 years) visited the ER for a total of 204 times. Repeated ER visits and readmissions occurred in 56.8% and 55.6% of the patients, respectively. Most NMD children belonged to triage class 3 (35.3%), with underlying congenital hereditary muscular dystrophy (44.1%). The major symptoms were usually multiple and concurrent, and primarily respiratory (62.3%) or gastrointestinal (28.9%). The most common causes of hospitalization were pneumonia (48.5%) or acute gastritis (20.4%), and approximately half of the ER visits required further hospitalization, of which 28.2% involved PICU admission. Twenty of the 36 children admitted to the ER required readmission. The most commonly prescribed examinations were complete blood count (38%) and C reactive protein (38%), and the most common therapy was intravenous fluid administration (34%). Although respiratory compromise caused most ER visits and admissions, pulmonary assessments, including chest films (28%), pulse oximetry (15%), and blood gas analysis (11%), were performed in a relatively small proportion. CONCLUSION: The ER staff must recognize patients' unmet needs for respiratory and gastrointestinal care related to underlying NMDs. PMID- 30482625 TI - Should we believe emergency department patients self-reported tetanus vaccine status? PMID- 30482626 TI - Dose Optimization of Perfusion-derived Response Assessment in Hepatocellular Carcinoma Treated with Transarterial Chemoembolization: Comparison of Volume Perfusion CT and Iodine Concentration. AB - RATIONALE AND OBJECTIVES: We assessed the value of iodine concentration (IC) as a perfusion-derived response marker for hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) in comparison with volume perfusion computed tomography (VPCT) parameters. MATERIALS AND METHODS: Forty-one HCC lesions in 32 patients examined before and after TACE were analyzed retrospectively. VPCT-parameters were calculated and lesion iodine-maps were computed using subtraction of the baseline and the scan 7 seconds after aortic peak enhancement from the corresponding 80 kVp-VPCT data set. Modified RECIST was used as standard response criteria. Comparisons were performed using Student's t test for normal distributed data and Mann-Whitney U test for non-normal distributed data. Additionally, correlation analysis, receiver operating characteristics (ROC) and interreader agreement were assessed. RESULTS: In responding lesions, mean pre-TACE IC and blood flow (BF) were 131.2 mg/100 mL and 96.7 mL/100 mL/min, decreasing to IC 25.6 mg/100 mL (P < 0.001) and BF 28.5 mL/100 mL/min (P < 0.001) post-TACE. In nonresponding lesions, the values remained almost unchanged: pre-TACE: mean BF 79.3 mL/100 mL/min and mean IC 90.4 mg/100 mL; post-TACE: mean BF 71.3 mL/100 mL/min (n.s.) and mean IC 105.4 mg/100 mL (n.s.). Differences in IC-values revealed a high sensitivity/specificity of 96.7%/81.8%. IC and VPCT-parameters showed strong, positive correlations. Mean volume CT dose index for VPCT was 63.4 mGy and 4.9 mGy for iodine maps. CONCLUSION: Thus, IC is a meaningful perfusion marker for local therapy response monitoring in HCC that can be acquired with low radiation dose. This information is important for further therapy response applications using dual and single energy CT. PMID- 30482627 TI - Image Quality Performance of Virtual Single-Source CT Using Dual-Source Computed Tomography. AB - RATIONALE AND OBJECTIVES: The aim of this study is to analyze the image quality provided by a dual-source (DS) data set and a single-source (SS) data set at the same radiation exposure, in order to evaluate a dose splitting method for dual source scanning protocols. MATERIALS AND METHODS: A 192-slice dual-source third generation CT (Somatom Force; Siemens Healthcare, Forchheim, Germany) was used to image a Catphan phantom (Catphan503; The Phantom Laboratory, Salem, New York) utilizing different X-ray tube voltages from 70 to 120 kVp with an organ-based tube-current modulation technique (X-CARE; Siemens Healthcare, Forchheim, Germany). In order to keep the radiation dose (given by volume computed tomography dose index) in a clinically relevant range, different X-ray tube time current products ranging from 80 to 300 mAs were selected. The data sets by each X-ray tube voltage were collected using a single-source as well as a dual-source mode. The measurements in the dual-source mode were performed with five different tube currents of the X-ray tube A and B. Thereby, the tube current ratios were 50%|50% (DS 0.5), 60%|40% (DS 0.6), 70%|30% (DS 0.7), 80%|20% (DS 0.8), and 90%|10% (DS 0.9). The images were reconstructed by the use of a filter-back projection (Br40) and an advanced mode led iterative reconstruction algorithms (advanced modeled iterative reconstruction algorithms [ADMIRE]; Siemens Healthcare, Forchheim, Germany) with a strength range of 1-5. The image quality was evaluated in terms of noise, contrast-to-noise ratio (CNR), low-contrast detectability expressed as the structural similarity index (SSIM) and spatial resolution quantified by the full width at half maximum of the line-spread function. RESULTS: Image noise decreased by the use of the dual-source mode, which led to improvement of their CNR compared to the single-source mode. SSIM showed an almost constant behavior by both modes. The spatial resolution indicated a lower trend by the dual-source mode in comparison to the single source mode. However, the loss of the spatial resolution performance was lower than 5% for the dual-source modes. CONCLUSION: The presented phantom study demonstrated that SSIM and spatial resolution performance obtained by dual-source CT protocols showed a negligible variation to those by the single-source CT. However, the noise and CNR displayed an improvement for the dual-source CT. Therefore, the use of the dual-source CT enables to split the radiation dose between X-ray tubes and to compare the data sets with different radiation dose levels without loss in the image quality. PMID- 30482629 TI - Predicting acquired cardiovascular disease in adults with congenital heart disease is risky business. PMID- 30482628 TI - Consumption of individual saturated fatty acids and the risk of myocardial infarction in a UK and a Danish cohort. AB - BACKGROUND: The effect of individual saturated fatty acids (SFAs) on serum cholesterol levels depends on their carbon-chain length. Whether the association with myocardial infarction (MI) also differs across individual SFAs is unclear. We examined the association between consumption of individual SFAs, differing in chain lengths ranging from 4 through 18 carbons, and risk of MI. METHODS: We used data from 22,050 and 53,375 participants from EPIC-Norfolk (UK) and EPIC-Denmark, respectively. Baseline SFA intakes were assessed through validated, country specific food frequency questionnaires. Cox regression analysis was used to estimate associations between intakes of individual SFAs and MI risk, for each cohort separately. RESULTS: During median follow-up times of 18.8 years in EPIC Norfolk and 13.6 years in Denmark, respectively, 1204 and 2260 MI events occurred. Mean (+/-SD) total SFA intake was 13.3 (+/-3.5) en% in EPIC-Norfolk, and 12.5 (+/-2.6) en% in EPIC-Denmark. After multivariable adjustment, intakes of C12:0 (lauric acid) and C14:0 (myristic acid) inversely associated with MI risk in EPIC-Denmark (HR upper versus lowest quintile: 0.80 (95%CI: 0.66, 0.96) for both SFAs). Intakes in the third and fourth quintiles of C4:0-C10:0 also associated with lower MI risk in EPIC-Denmark. Moreover, substitution of C16:0 (palmitic acid) and C18:0 (stearic acid) with plant proteins resulted in a reduction of MI risk in EPIC-Denmark (HR per 1 energy%: 0.86 (95%CI: 0.78, 0.95) and 0.87 (95%CI: 0.79, 0.96) respectively). No such associations were found in EPIC-Norfolk. CONCLUSION: The results from the present study suggest that the association between SFA and MI risk depends on the carbon chain-length of the SFA. PMID- 30482631 TI - An efficacy study of a metacognitive group intervention for people with schizophrenia. AB - Poor cognitive outcomes among people with schizophrenia are associated with poor function in daily life. Cognitive interventions aimed at improving function lead to better cognitive outcomes, but the question of generalization to real-world functioning remains relevant. The ability to generalize or to apply learned skills in the clinic to everyday functioning must include metacognitive components which are the underlying mechanisms of function. To address such generalization, we developed a metacognitive group intervention based on Toglia's (2005) dynamic interactional model, which aims to promote daily activities and participation by focusing on metacognitive components. We assessed 84 participants with schizophrenia (41 in the control group and 43 in the intervention group) before and after completing the intervention and at a 12-week follow-up. Assessments addressed executive function, performance, and participation. The intervention group's performance, participation, and everyday functions significantly increased post-intervention and at follow-up, compared with the control group. Results provide important information about the potential for change in real-world functioning and a basis for the rationale of employing metacognitive interventions in this population. PMID- 30482630 TI - Clinical profile and outcome of cardiac involvement in MELAS syndrome. AB - BACKGROUND: Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like (MELAS) syndrome is a rare condition with heterogeneous clinical presentation. Cardiac involvement commonly develops during adulthood, comprising both structural and conduction/arrhythmic abnormalities; early paediatric onset has rarely been reported. We describe the clinical profile, outcome and clinical implication of MELAS-associated cardiomyopathy at a tertiary referral centre. METHODS: From 2000 to 2016 we enrolled 21 patients affected by genetically-proven MELAS. Patients were followed-up at least annually over a mean of 8.5 years. RESULTS: All patients carried the MT-TL1 3243A>G mutation. Cardiac involvement was documented in 8 (38%) patients (three <18 years; five >=18 years), including 6 (75%) with hypertrophic cardiomyopathy, 1 (12.5%) with dilated cardiomyopathy, and 1 (12.5%) with persistent pulmonary hypertension. During follow-up, 3 patients died, all with cardiac onset <18 years. The cause of death, however, was non-cardiac (infections, respiratory failure, stroke). Neither events nor cardiac progression were recorded among patients with onset >=18 years. Adult cardiologists were responsible for 5/8 of referrals, even in patients with long standing extra-cardiac involvement. CONCLUSIONS: Cardiac involvement was found in over 1/3 of patients with MELAS syndrome, and exhibited a bimodal age-related distribution with distinct final outcomes. Paediatric-onset cardiomyopathy represented a hallmark of systemic disease severity, without being the main determinant of outcome. Conversely, adult-onset cardiomyopathy appeared to represent a mild and non-progressive mid-term manifestation. Adult cardiologists played an important role in the diagnostic process, triggering suspicion of MELAS in most of patients diagnosis >18 years. PMID- 30482632 TI - Commentary to 'One-stage combined delayed bladder closure with Kelly radical soft tissue mobilization in bladder exstrophy: preliminary results'. PMID- 30482633 TI - Age-related differences in patient-reported outcomes in patients with advanced lung cancer receiving anti-PD-1/PD-L1 therapy. AB - BACKGROUND: Older adults with lung cancer often have comorbidities that may increase risk of symptomatic adverse events (AEs) and physical function decline. The objective of this study was to examine age-related differences in patient reported symptoms and functional domains in patients with advanced lung cancer receiving immunotherapy drugs. METHODS: Three randomized controlled trials of anti-programmed death receptor-1/programmed death-ligand 1 therapy in patients with advanced non-small cell lung cancer that included patient-reported outcomes (PROs) were identified. Baseline PRO data were pooled for treatment arms from 2 trials that included the same PRO tools. Age-related differences in baseline mean scores for each of the health-related quality of life functional and symptom scales were assessed for patients >=70 years and <70 years. Mean change from Baseline at 3 months was also calculated and plotted for each age group. The adequacy of PRO assessments was assessed by comparing clinician-reported AE data in the 3 trials to the item content of the PRO tools included. RESULTS: Across the 3 trials, 75 of patients were under 70 and 26% patients were 70 and older. Comparing baseline scores in the 2 trials with the same PRO tool, older adults reported small differences including lower physical functioning, less pain, insomnia and financial difficulties, and higher social functioning than younger patients at baseline. No large differences in the distributions of mean change from baseline in function or symptom were identified. Several common clinician reported symptomatic AEs were not assessed by the PRO strategy employed in the 3 trials. Three clinician-reported symptomatic AEs (rash, fever, and pruritus) that were commonly reported in the safety data (9%-19%) were not assessed using the PRO tools employed. CONCLUSION: While several small differences were seen, there did not appear to be large differences at baseline or in the distributions of change from baseline in PRO functional domains between younger and older patients with lung cancer undergoing anti-programmed death receptor -1/programmed death ligand 1 therapy. Relevant symptomatic side effects were not assessed by PRO measures in these trials, and this is a limitation of current PRO assessment strategies. PMID- 30482634 TI - Management of hepatitis C positive patients undergoing active treatment for malignancies: A position paper from the Associazione Italiana di Oncologia Medica (AIOM) and the Societa Italiana di Malattie Infettive e Tropicali (SIMIT). AB - PURPOSE: To develop, on behalf of Associazione Italiana di Oncologia Medica and Societa Italiana di Malattie Infettive e Tropicali, evidence-based and practical recommendations for the management of cancer patients who are Hepatitis C virus (HCV)-positive and are undergoing antitumor treatment. METHODS: Recommendations were generated by panel of experts selected by the boards of the Societies Associazione Italiana di Oncologia Medica and Societa Italiana di Malattie Infettive e Tropicali (4 oncologists and 6 infectious disease and hepatology specialist). The level of evidence and grade or recommendation was assessed according to the Grading of Recommendations Assessment, Development and Evaluation for practice guidelines [5]: A (high), B (moderate), and C (low), together with 2 recommendation levels: 1 (strong), and 2 (weak). Experts provided additional information, which helped greatly in clarifying some issues in the absence of clear-cut information from the literature. The final draft was then submitted to the evaluation of experts and the text modified according to their suggestion and comments. RESULTS: HCV screening rates are low in patients with malignancies. The risk of reactivation or exacerbation of hepatitis C is higher in patients receiving immunosuppressive agents. It may be difficult to discriminate naturally occurring cancer-related complications from true reactivation or exacerbation of hepatitis C and hepatotoxicity due to cancer treatment. No conclusive data are available concerning the appropriate monitoring of liver function and when an antiviral regimen should be proposed. CONCLUSIONS: Patients at risk of any flare of HCV-related liver disease during active therapy for cancer should be managed with a multidisciplinary approach where all relevant diagnostic techniques and therapeutic resources are available. Prospective studies are needed to identify optimal strategies for the management of HCV infected cancer patients. PMID- 30482636 TI - Assessment of the clinical relevance of pharmacists' interventions performed during medication review in a rheumatology ward. AB - BACKGROUND: Pharmacists contribute to reduce the number of medication errors during medication review. Nevertheless, few French studies report the potential clinical impact of pharmacists' interventions performed after detecting drug related problems. The objective was to evaluate the clinical relevance of pharmacists' interventions in a rheumatology ward from medical and pharmaceutical perspectives. METHOD: The analysis was conducted on pharmacists' interventions performed between January 1 and December 31, 2015 in a French teaching hospital. Similar pharmacists' interventions were grouped in one item and they were analysed according to 11 drug categories. The clinical significance of pharmacists' interventions was considered independently by a pharmacist and a rheumatologist using a validated French scale that categorises drug-related problems from minor to catastrophic. The agreement between the two professionals was analysed using the weighted kappa coefficient. RESULTS: Of 1313 prescriptions reviewed, 461 pharmacists' interventions (171 items) were formulated for drug related problems with an acceptance rate of 67.2%. Of the 418 interventions selected for clinical significance analysis, 235 interventions (56.2%) for the physician and 400 interventions (95.7%) for the pharmacist were at least significant. The two professionals evaluated equally the clinical relevance of 90 items (50.6%). The categories with the most similarities were the analgesics/anti inflammatory drugs (78.1%), the antidiabetics (75.0%) and the anticoagulants (71.4%). The agreement was estimated by a weighted kappa coefficient of 0.29. CONCLUSION: This work highlights the positive clinical relevance of pharmacists' interventions in rheumatology and the importance of medico-pharmaceutical collaboration to prevent medication errors. PMID- 30482637 TI - The Prognostic Value of Coronary Flow Velocity Reserve in Two Coronary Arteries During Vasodilator Stress Echocardiography. AB - BACKGROUND: Vasodilator stress echocardiography (SE) allows combined evaluation of regional wall motion and Doppler coronary flow velocity reserve (CFVR) of both the left anterior descending coronary artery (LAD) and the right coronary artery (RCA). The aim of this study was to prospectively assess the prognostic correlates of LAD and RCA CFVR on SE. METHODS: A total of 1,365 patients with known or suspected coronary artery disease underwent dipyridamole SE with combined evaluation of CFVR in both the LAD and the RCA. RESULTS: Ischemia was present on SE in 263 patients (19%). CFVR was abnormal (<=2.0) in 545 patients (40%): 172 in the LAD only, 149 in the RCA only, and 224 in both the LAD and the RCA. During a median follow-up period of 20 months, 44 deaths and 98 myocardial infarctions occurred. In the overall population, LAD CFVR <= 2.0 (hazard ratio [HR], 3.93) and inducible ischemia (HR, 2.74) were multivariate prognostic predictors. In the subset with ischemia on SE, CFVR did not add to peak wall motion score index (HR, 2.23). In patients without ischemia on SE, age (HR, 1.04), anti-ischemic therapy at the time of testing (HR, 1.6) and LAD CFVR <= 2.0 (HR, 10.8) were independent prognostic indicators. In patients without ischemia on SE and LAD CFVR >2.0, the 4-year event rate was 4% in those with RCA CFVR > 2.0 and 18% in those with RCA CFVR <= 2.0 (P < .0001). CONCLUSIONS: Ischemia on SE with high peak wall motion score index identifies a high-risk subset regardless of the underlying CFVR response. Absence of ischemia on SE is associated with intermediate risk, and LAD CFVR is essential to identify a truly low-risk subset. RCA CFVR is less useful than LAD CFVR but may have a role for further risk stratification in patients without ischemia and normal LAD CFVR. PMID- 30482635 TI - Prevalence, predictors and clinical implications of prolonged corrected QT in elderly patients with dementia and suspected syncope. AB - BACKGROUND: Long QT and use of QT-prolonging drugs are common among older patients receiving polytherapies, but real-world evidence on their impact in clinical practice is controversial. We investigated prevalence, variables associated and clinical implications of prolonged corrected QT (QTc) among patients from the Syncope and Dementia study. METHODS: Observational, prospective, multicenter study. Patients>=65 years with dementia and fall suspected for syncope in the previous three months were enrolled. Several clinical variables and the complete list of medications were recorded for each patient. A 12-lead ECG was obtained and corrected QT was calculated by the Bazett's formula. One-year followup for death and recurrent syncope was performed. RESULTS: Prolonged QTc was observed in 25% of the 432 enrolled patients (mean age 83.3), and was significantly associated with male gender (OR 2.09; 95% CI 1.34-3.26) and diuretics use (OR 1.85; 95% CI 1.18-2.90). At one year 23.3% of patients died and 30.4% reported at least one recurrent event. Variables associated with one-year mortality were: age, male gender, atrial fibrillation (AF), use of calcium channel blockers and prolonged QTc (OR 1.80; 95% CI 1.01-3.20). Among patients with prolonged QTc a significant interaction for mortality was found with AF. Recurrent events were associated with the use of antiplatelets, cholinesterase. inhibitors and antipsychotics, but not with prolonged QTc. CONCLUSIONS: We documented a high prevalence of prolonged QTc, that was associated with male gender and diuretics but not with psychoactive medications. Patients with prolonged QTc had higher one-year mortality, that was four-fold increased in those with concomitant AF. PMID- 30482638 TI - Diversity of resistance mechanisms in carbapenem-resistant Enterobacteriaceae at a health care system in Northern California, from 2013 to 2016. AB - The mechanism of resistance in carbapenem-resistant Enterobacteriaceae (CRE) has therapeutic implications. We comprehensively characterized emerging mechanisms of resistance in CRE between 2013 and 2016 at a health system in Northern California. A total of 38.7% (24/62) of CRE isolates were carbapenemase gene positive, comprising 25.0% (6/24) blaOXA-48 like, 20.8% (5/24) blaKPC, 20.8% (5/24) blaNDM, 20.8% (5/24) blaSME, 8.3% (2/24) blaIMP, and 4.2% (1/24) blaVIM. Between carbapenemases and porin loss, the resistance mechanism was identified in 95.2% (59/62) of CRE isolates. Isolates expressing blaKPC were 100% susceptible to ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam; blaOXA 48 like-positive isolates were 100% susceptible to ceftazidime-avibactam; and metallo beta-lactamase-positive isolates were nearly all nonsusceptible to above antibiotics. Carbapenemase gene-negative CRE were 100% (38/38), 92.1% (35/38), 89.5% (34/38), and 31.6% (12/38) susceptible to ceftazidime-avibactam, meropenem vaborbactam, imipenem-relebactam, and ceftolozane-tazobactam, respectively. None of the CRE strains were identical by whole genome sequencing. At this health system, CRE were mediated by diverse mechanisms with predictable susceptibility to newer beta-lactamase inhibitors. PMID- 30482639 TI - High temperature/pressure MAS-NMR for the study of dynamic processes in mixed phase systems. AB - A new MAS-NMR rotor (the WHiMS rotor) has been developed which can reach pressures of 400 bar at 20 degrees C or 225 bar at 250 degrees C. These rotors are ideal for mixed phase systems such as a reaction using a solid catalyst with a liquid/supercritical solvent topped with high pressure gas in the head space. After solid and liquid portions of the sample are loaded, the rotor is capped with an o-ring equipped polymer bushing that snaps into a mating groove in the rotor. The bushings incorporate a check valve into the sealing mechanism which allows for pressurization without mechanical manipulation - they will allow gas to flow in but not out. This WHiMS rotor design has enabled experiments on a wide variety of biotic and abiotic mixed-phase systems. Geochemical systems have also been studied, for example, adsorption and confinement studies of supercritical methane/CO2 in clays and other minerals which display pressure dependent 13C chemical shifts. Example data from other mixed-phase chemical and microbial systems are reported. These include monitoring metabolite conversion of extremophilic bacteria found in subsurface systems at elevated pressures and real time operando reactions in catalysis systems - with liquid-quality resolution for 1H and 13C NMR spectra. PMID- 30482640 TI - A 15 to 17-year follow-up of the Kinemax total knee replacement. AB - BACKGROUND: There is a paucity of long-term data concerning the pre- and postoperative patient reported function of total knee replacement. The aim of this study was to determine the mortality, implant survivorship, patient reported function and satisfaction in a cohort of 114 patients, from a single centre, who received a Kinemax total knee replacement more than 15 years ago. METHODS: Patients completed a questionnaire incorporating validated disease- and joint specific scores, patient satisfaction and overall health preoperatively, at three months, one year, two years and a minimum of 15 years following surgery. NHS National Strategic Tracing Service, hospital and primary care records were used to establish mortality and for implant survivorship in deceased patients. RESULTS: Forty five patients were alive at final follow-up. The survivorship of the cohort with revision of the TKR as the endpoint was 84%. Four cases were revised for wear, three for loosening and one for peri-prosthetic fracture. There was a significant improvement in WOMAC Pain, Function and Stiffness Scores, Oxford Knee Score and Self-Administered Patient Satisfaction Scale between pre operative and all post-operative time points, although patient satisfaction had decreased significantly by the time of final follow-up. CONCLUSION: In this cohort, the Kinemax TKR showed survivorship of 84% at 16.3 years with functional scores demonstrating a high level of patient satisfaction at all follow-up time points. LEVEL OF EVIDENCE: 2 - Prospective Cohort Study. PMID- 30482641 TI - Landing biomechanics in anterior cruciate ligament reconstructed females who pass or fail a functional test battery. AB - BACKGROUND: A functional test battery (FTB) has been proposed to determine return to full activity following anterior cruciate ligament reconstruction (ACLR). However, there is little biomechanical evidence of FTB usefulness. The purpose of this study was to compare knee joint landing and cutting biomechanics between ACLR patients who passed (ACLR-Pass), failed (ACLR-Fail), and healthy females (Healthy) before and after exercise. METHODS: Thirty females were included: 10 ACLR-Pass, eight ACLR-Fail and 12 Healthy. Participants performed a FTB consisting of The 2000 International Knee Documentation Committee Subjective Knee Evaluation Form, the Knee Outcome Survey Activities of Daily Living Scale, and quadricep strength and single-leg hop tests. Double-leg jump landing (DLJL) and single-leg jump cutting (SLJC) biomechanics were assessed before and after exercise. RESULTS: Significant main effects of exercise were found during DLJL: lesser knee flexion angle at initial contact after exercise (before exercise: 15.8 +/- 5.0, after exercise: 14.2 +/- 5.4, P = 0.01, etap 2 = 0.25); and during SLJC: smaller peak knee extension moment (before exercise: -0.33 +/- 0.1, after exercise: -0.31 +/- 0.1, P = 0.02, etap 2 = 0.18). While there was a significant group by time interaction effect with lesser peak knee flexion angle after exercise, this interaction effect was likely driven by a reduction in peak knee flexion in only the Healthy group. CONCLUSIONS: Healthy females exhibited a reduction in peak knee flexion during SLJC after exercise. However, there were no differences in ACLR knee biomechanics during DLJL and SLJC performed before and after exercise. PMID- 30482642 TI - What's in a name? A call for consistency in the classification of tenosynovial giant cell tumour. PMID- 30482643 TI - Persistent negative symptoms in individuals at Ultra High Risk for psychosis. AB - Persistent negative symptoms (PNS) defined as negative symptoms that persist for at least six months in the absence of high levels of positive, depressive and extrapyramidal symptoms, are evident early in the course of schizophrenia from the first episode of psychosis. However, their presence even earlier in the illness, in those at Ultra High Risk of psychosis, has not been investigated. In this study, we examined the prevalence, baseline correlates and outcome of PNS in 363 Ultra High Risk individuals. Assessments were conducted at baseline and 2-14 years later (mean follow up time 7.4 years). Baseline assessments included demographic, clinical and neurocognitive measures, which were repeated at follow up. The prevalence of PNS in the UHR group was 6.1%. Poor premorbid social adjustment, deficits in verbal fluency and childhood maltreatment, specifically emotional neglect, were evident at baseline in the PNS group compared to the group without PNS. PNS were associated with poor psychosocial functioning and deficits in processing speed at follow up. Our findings suggest that PNS can be detected early, allowing for the identification of a subset of Ultra High Risk patients who are likely to have poor outcome. These individuals could be the target for specific intervention. Further research is needed into the pathophysiology of these PNS to develop specific interventions. PMID- 30482645 TI - Clinical correlates of subsyndromal depression in African American individuals with psychosis: The relationship with positive symptoms and comorbid substance dependence. AB - Patients with psychosis exhibit subsyndromal depressive symptoms during the course of illness and yet the clinical correlates of these symptoms remain under investigated. We aimed to investigate the clinical correlates of subsyndromal depression in psychosis including the extent to which they mediate commonly observed comorbid substance dependence. We developed a model of depression in a non-clinical sample recruited via Amazon's Mechanical Turk (N = 266), and confirmed that model in a locally recruited African-American clinical sample comprising psychotic and non-psychotic individuals (N = 256). Using scores from this model we tested: the strength of relationships between depressive symptomatology and positive, negative and disorganized symptoms in a range of psychotic disorders; whether depressive symptoms were higher in individuals with affective psychoses versus schizophrenia; and if depressive symptomatology mediated the relationship between psychosis and substance dependence. Subsyndromal depressive symptomatology was significantly higher in individuals with psychosis than without psychosis, but did not significantly differ between affective and non-affective psychotic groups. Depressive symptomatology was significantly related to positive (but not negative or disorganized) psychotic symptoms, and mediated the relationship between psychosis and substance dependence. The present study underlines the importance of assessing subsyndromal depression in patients with psychosis, and generates a number of testable predictions for future work. In particular, the examination of the relationships between comorbid psychopathology, namely depression and substance abuse, may improve insight into the neurobiology of psychosis. PMID- 30482644 TI - Body mass index trajectories in childhood and adolescence - Risk for non affective psychosis. AB - BACKGROUND: Underweight in early adulthood increases risk for schizophrenia, but the effect of early childhood underweight on psychosis risk is not well known. METHODS: We studied whether underweight or overweight in childhood and adolescence increases risk for non-affective psychosis or other psychiatric disorders in a population-based cohort study 'Cardiovascular Risk in Young Finns'. Body mass index (BMI) trajectories were recorded in the years 1980, 1983 and 1986 (in 3-18 years of age), before the first hospitalization due to a psychiatric disorder. BMI was categorized as underweight, normal weight or overweight, using the BMI classification for children and adolescents. We formed DSM-IV based diagnostic groups of non-affective psychosis (n = 69, including a schizophrenia subgroup, n = 41) and affective disorders (i.e. mood and anxiety disorders, n = 112) based on the Care Register for Health Care. Groups were compared with subjects with no psychiatric diagnoses (n = 3310). Sex, age, low birthweight and mother's mental disorders were included in the analyses. RESULTS: Underweight, but not overweight, independently predicted later development of non affective psychosis. The risk of psychosis was over two-fold (relative risk (RR) [95% CI] 2.31 [1.2-4.4]) and of schizophrenia nearly 2.5-fold (RR 2.44 [1.03 5.8]) after underweight in childhood/adolescence. Underweight or overweight in childhood and adolescence was not associated with mood or anxiety disorders. CONCLUSIONS: These results support the hypothesis of non-affective psychosis as a neurodevelopmental disorder with somatic manifestations throughout childhood and adolescence. PMID- 30482646 TI - Trends in smoking prevalence and implication for chronic diseases in China: serial national cross-sectional surveys from 2003 to 2013. AB - BACKGROUND: China is the world's largest consumer of tobacco and has a large smoking-related chronic disease burden. In this nationwide study, we aimed to evaluate smoking prevalence and its implication on chronic diseases in the Chinese population. METHODS: We collected data from serial cross-sectional National Health Service Surveys done in China in 2003, 2008, and 2013. These surveys cover all 31 provinces, autonomous regions, and municipalities in mainland China, and use multistage stratified cluster sampling. We divided mainland China into east, central, and west regions and then sampled counties from each region stratified by urban and rural areas. All respondents aged 15 years or older in the selected households were eligible. We analysed the variation in smoking prevalence from 2003 to 2013, further identified risk factors for smoking, and assessed the association between smoking and chronic diseases by using multiple logistic regression. FINDINGS: The number of individuals interviewed and involved in the study was 153 450 in 2003, 145 223 in 2008, and 229 676 in 2013. The standardised smoking prevalence in China was consistently high, with a proportion of current smokers of 26.0% (95% CI 25.8 26.2) in 2003, 24.9% (24.8-25.1) in 2008, and 25.2% (25.1-25.4) in 2013 (p value for trend 0.5062). For men, prevalence was 48.4% (48.1-48.7) in 2003, 47.0% (46.6 47.4) in 2008, and 47.2% (46.9-47.5) in 2013. For women, prevalence was 3.1% (3.0 3.2) in 2003, 2.3% (2.2-2.5) in 2008, and 2.7% (2.6-2.8) in 2013. Smoking prevalence varied in different regions, and we identified four major patterns. While a consistently high proportion of Chinese men smoked, the standardised smoking prevalence in women younger than 40 years increased from 1.0% in 2003 to 1.6% in 2013. Moreover, the smoking prevalence among adolescent smokers aged 15 24 years increased from 8.3% in 2003 to 12.5% in 2013. Alcohol consumption was closely linked to smoking in adolescents (odds ratio 7.5, 95% CI 6.9-8.1). Risk factors for adolescent smoking were having older family members who smoke (1.9, 1.8-1.9) and low level education (1.3, 1.2-1.4). Increased risks of chronic diseases were related to smoking (1.1, 1.0-1.1), with higher risks related to early smoking initiation (1.1, 1.0-1.1) and long-term smoking (1.2, 1.2-1.3). INTERPRETATION: The implementation of tobacco control policies in China since the signing of the WHO Framework Convention on Tobacco Control in 2003 has not been effective in reducing smoking prevalence. Smoking prevalence among adolescents of both genders has increased substantially and there has been a steady increase among young women. More practical and effective policies targeting adolescents and women are urgently needed. Action is needed to prevent the large and growing smoking-related chronic disease burden further increasing as China's population ages. FUNDING: National Health Commission of the People's Republic of China. PMID- 30482647 TI - Analysis of the quality of patient therapeutic education and information in a high complexity reference hospital. AB - BACKGROUND AND OBJECTIVES: The application and monitoring of quality criteria in information and therapeutic patient education can identify areas to improve care. The objectives of this study were: (1) To analyze the characteristics of patient information materials, educational activities, and self-management programs, and (2) to determine health care provider (HCP) proposals on therapeutic patient education. MATERIALS AND METHODS: Using a cross-sectional study, an online questionnaire was sent to hospital departments in a high complexity reference hospital from September to December 2013 to record: (a) information materials, (b) patient educational activities, and self-management program characteristics, (c) HCP proposals. The materials were analyzed using Health Promoting Hospitals (HPH) recommendations. RESULTS: (1) An analysis was performed on 258 materials (leaflets [54%]) for chronic patients (86%), acute patients (7%), and the general population (7%). More than half (55%) lacked the authors, and 43% the year issued, and 69% followed HPH recommendations. (2) An evaluation was made of 70 educational activities and 37 self-management programs addressed to patients/relatives with diabetes/obesity, musculoskeletal disorders, COPD/asthma, pelvic-floor disorders, transplantation, bowel-inflammation/liver disease, hypertension, cancer, heart failure, acquired immune deficiency syndrome, chronic renal insufficiency, splenectomy, anticoagulation and older-patient dependence. The structure, process and outcome evaluation varied. (3) HCP proposals included: standardization of materials criteria, web accessibility, list of accredited websites, cross-sectional use, and HCP training in self-management education. CONCLUSIONS: The online questionnaire showed the weaknesses and strengths of patient information and education, and can be used to monitor their quantity and quality. These results help in the definition of a useful model to improve patient information and education policies. PMID- 30482648 TI - [Drugs that require a visa, principle of equity and quality of care]. PMID- 30482649 TI - [Factors that determine the intention to use telemedicine in a healthcare organisation]. AB - INTRODUCTION: There are numerous factors and barriers that hinder the use of telemedicine, among which some aspects of the organisation stand out. Thus, it would be interesting to determine its intention to use it in a health institution. The objective of this paper was to identify the factors that influence the intent to use telemedicine by the group of professionals of the Andalusian Health Service and the type of professionals based on the use and expectations of (information and communications technology (ICT). METHODS: A specific questionnaire was designed based on an extended Model of Technological Acceptance that was distributed to a sample of 2,847 professionals of all the categories of this institution. A univariate analysis, exploratory factor analysis and logistic regression were carried out to determine those explanatory variables that are related to the use of telemedicine. RESULTS: A total of 424 responses were obtained. The study determined that the institution's support, perceived usefulness and ease of use (P<.05) were factors that influence the use of telemedicine. The support of the workers and the technological profile of the professionals (P<.05) were significant. CONCLUSIONS: Due to there being a high number of factors in health services, it is possible to find differences between the explanatory models in each specific organisation. For this reason, studies need to be carried out before the implantation and use of telemedicine systems in order to identify which of the possible variables influence favourable adoption as a prerequisite for the generalised use of telemedicine. PMID- 30482650 TI - A Comparison of Structured Education Programs for Pediatric Patients With Type 1 Diabetes: Multiple Daily Injection Therapy Delivered by Group Workshop vs. Self Study Course. PMID- 30482651 TI - Apical U-shape splitting technique for undercut areas of the anterior alveolar ridge: a prospective non-randomized controlled study. AB - The aim of this study was to investigate a novel apical U-shape splitting technique for horizontal bone augmentation in undercut areas and to compare its efficacy with that of guided bone regeneration (GBR). This was a prospective non randomized controlled clinical trial. A total of 36 patients, who presented with a labial undercut that was not able to house a normally inclined implant, underwent the new technique or GBR. Radiographic and clinical data were obtained preoperatively, immediately after surgery, and 12 months after surgery. Pairwise comparisons of changes in ridge width gain, marginal bone loss, and pink aesthetic score were performed; correlations with pristine ridge morphology were investigated. The results showed similar marginal bone loss in the two groups. The overall ridge width gains in the new technique group (2.56+/-1.92mm) and GBR group (0.73+/-1.21mm) differed significantly (P<0.05). The pink aesthetic score was higher for the new technique group (11.75+/-1.22) than for the GBR group (9.25+/-1.86) (P<0.01). The morphology of the concavity had different impacts on regeneration in the two groups. The apical U-shape splitting technique, as a safe and effective alternative to GBR, provided a significant increase in bone volume gain where labial fenestration was inevitable during implant placement. PMID- 30482652 TI - 'Corseting' and 'strangling'-two techniques sharing similar concepts to treat large venous malformations in the head and neck region. PMID- 30482653 TI - Considerations on the 'corseting' or 'strangling' technique to treat large venous malformations. PMID- 30482654 TI - New onset refractory status epilepticus (NORSE). AB - PURPOSE: To summarize the clinical features, suggested work-up, treatment and prognosis of new-onset refractory status epilepticus (NORSE), a condition recently defined as the occurrence of refractory status epilepticus (RSE) in a patient without active epilepsy, and without a clear acute or active structural, toxic or metabolic cause; and of the related syndrome of febrile infection related epilepsy syndrome (FIRES), also recently defined as a subgroup of NORSE preceded by a febrile illness between 2 weeks and 24 h prior to the onset of RSE. METHOD: Narrative review of the medical literature about NORSE and FIRES. RESULTS: NORSE and FIRES mainly affect school-age children and young adults. A prodromal phase with flu-like symptoms precedes the SE onset in two third of NORSE cases, and by definition in all FIRES. Status epilepticus usually starts with repeated focal seizures with secondary bilateralization. Most cases evolve to super RSE (SRSE) and have unfavorable outcome, with short-term mortality of 12 27%, long-term disability and epilepsy. No specific imaging or laboratory abnormalities have been identified so far that allows an early diagnosis and half of adult cases remain of unknown etiology. A standardized diagnostic algorithm is provided and. Autoimmune encephalitis is the most frequent identified cause. In the absence of specific diagnosis, immunotherapy could be tried in addition to antiepileptic treatment. CONCLUSIONS: This review presents the rare but devastating syndrome of NORSE, including the subcategory of FIRES. Early recognition with complete work-up is primordial to identify the underlying cause and promptly start appropriate treatment. PMID- 30482655 TI - Ripple Effect Mapping Outcomes of a Childhood Obesity Prevention Program From Youth and Adult Dyads Using a Qualitative Approach: iCook 4-H. AB - OBJECTIVE: To describe the impact of the iCook 4-H intervention study based on data gathered through ripple effect mapping focus groups through an explorative approach. DESIGN: Youth-adult dyads responded about ways in which iCook had affected the individual, family, and community. Three questions were asked: (1) What were people doing differently as a result of iCook? (2) Who benefited from iCook and how? (3) Were there changes in the way community groups and institutions did things as a result of iCook? SETTING: Ripple effect mapping sessions took place across 5 states (Maine, Nebraska, South Dakota, Tennessee, and West Virginia). PARTICIPANTS: Seventy dyad participants (n = 35 youth, n = 35 adults) from the iCook 4-H intervention. MAIN OUTCOME MEASURE: Three core themes of iCook 4-H were assessed: cooking, eating, and playing together. ANALYSIS: Direct content analysis and word frequencies were used. RESULTS: Seven categories emerged: improved health, increased community involvement, increased knowledge, increased communication, changed motivation, financial mindfulness, and increased appreciation for family. An overarching theme that was determined was that learning new skills together through trying new things (cooking, eating, and playing) leads to positive individual family and community change. CONCLUSIONS AND IMPLICATIONS: Ripple effect mapping was effective in determining the perceived impact of iCook 4-H on oneself, family, and community. PMID- 30482656 TI - Use of a Novel Measure of Nontechnical Skills in Surgical Trainees: Is There an Association With Technical Skills Performance? AB - OBJECTIVE: To investigate whether scores on a psychological measure of concentration and interpersonal characteristics, The Attentional and Interpersonal Style Inventory (TAIS), are associated with performance of surgical skills. DESIGN: Postgraduate surgical trainees completed an operative surgical skills assessment in the simulation laboratory and the psychological measure (TAIS). The surgical skills assessment consisted of 6 tasks (3 per trainee): laceration suturing; lipoma excision; incision and closure of a laparotomy wound; bowel anastomosis; saphenofemoral junction ligation and basic laparoscopic skills. The association between operative surgical skill performance and TAIS factors was investigated. SETTING: The TAIS assessments and surgical skills assessments were conducted at the National Surgical Training Centre at the Royal College of Surgeons in Ireland (RCSI). PARTICIPANTS: One hundred and two surgical trainees in years one and two (PGY 2-3 equivalent) participated in the study. RESULTS: Performance on 2 of the 6 tasks assessed (bowel anastomosis and lipoma excision) were positively associated with multiple TAIS factors (energy, confidence, competitiveness, extroversion, self-criticism and performing under pressure). Another factor, focus over time, was significantly associated with scores on the lipoma excision task. CONCLUSIONS: Trainees with high levels of energy, confidence, competitiveness, extroversion, and focus over time and low levels of self-criticism demonstrated better performance on specific technical skills tasks. PMID- 30482657 TI - Genetic diversity of glacier-inhabiting Cryobacterium bacteria in China and description of Cryobacterium zongtaii sp. nov. and Arthrobacter glacialis sp. nov. AB - Cryobacterium and Arthrobacter are members of Actinobacteria, and are often found in cold environments. In this study, 48 Cryobacterium strains, including 9 type strains and 39 new isolates collected from glaciers in China were subjected to multilocus sequence analysis (MLSA). Phylogenetic analysis revealed that Cryobacterium comprised four cold-adapted clusters. Also, 19 potential novel Cryobacterium species were found using 0.065 as the cut-off point of genetic distance between the concatenated gene sequences. Additionally, three Cryobacterium strains (TMN-42T, TMN-39-1 and TMB1-8) and two Arthrobacter strains (HLT2-12-2T, TMN-18) isolated from glaciers were subjected to taxonomic analysis. Based on 16S rRNA gene sequences, MLSA data and average nucleotide identity (ANI) values, they represented a novel Cryobacterium species and a novel Arthrobacter species. Specifically, strain TMN-42T was most closely related to the type strains of Cryobacterium arcticum and Cryobacterium psychrotolerans with 83.79% and 77.78% ANI values, respectively. The ANI values between strain HLT2-12-2T and its closely relatives Arthrobacter psychrochitiniphilus GP3T and Arthrobacter alpinus S6-3T were 76.66% and 77.94%, respectively. Therefore, we propose two novel species, Cryobacterium zongtaii sp. nov. (TMN-42T=CGMCC 1.9695T=NBRC 111591T) and Arthrobacter glacialis sp. nov. (HLT2-12-2T=CGMCC 1.10025T=NBRC 113092T). PMID- 30482658 TI - Boys, Bulk, and Body Ideals: Sex Differences in Weight-Gain Attempts Among Adolescents in the United States. AB - OBJECTIVE: To determine the prevalence of weight-gain attempts in adolescent boys in the United States. METHODS: Participants were 15,624 high school students from the nationally representative 2015 Youth Risk Behavior Survey. RESULTS: Overall, 29.6% of adolescent boys reported attempts to gain weight, including 39.6% of boys who were normal weight, 12.8% who were overweight, and 10.6% who were obese by body mass index (BMI). In contrast, only 6.5% of adolescent girls reported attempts to gain weight. Although only 3.3% of adolescent males are underweight by BMI, 19.3% perceive themselves to be underweight. Further, over half of adolescent males who are overweight by BMI perceive themselves to be about the right weight. Black/African-American (odds ratio [OR] 1.89; 95% confidence interval [CI] 1.50-2.38) and multiracial (OR 1.62; 95% CI 1.16-2.26) adolescent males had greater odds of weight-gain attempts than white adolescent males. Adolescent males identifying as bisexual had lower odds (OR .47; 95% CI .25-.88) of weight-gain attempts than adolescent males identifying as heterosexual. CONCLUSIONS: Weight-gain attempts are common among adolescent boys including those who are considered normal weight, overweight, or obese by BMI; African American or multiracial; and those self-identifying as heterosexual. Consideration of the unique nature of male body image, particularly adolescent boys' perceptions of their own weight and weight-gain attempts, should be incorporated into primary care screening for adolescent boys. PMID- 30482659 TI - Disclosure and Clinical Outcomes Among Young Adolescents Living With HIV in Kenya. AB - PURPOSE: Informing adolescents of their own HIV infection is critical as the number of adolescents living with HIV increases. We assessed the association between HIV disclosure and retention in care and mortality among adolescents aged 10-14 years in Kenya's national program. METHODS: We abstracted routinely collected patient-level data for adolescents enrolled into HIV care in 50 health facilities from November 1, 2004, through March 31, 2010. We defined disclosure as any documentation that the adolescent had been fully or partially made aware of his or her HIV status. We compared weighted proportions for categorical variables using chi2 and weighted logistic regression to identify predictors of HIV disclosure; we estimated the probability of LTFU using Kaplan-Meier methods and dying using Cox regression-based test for equality of survival curves. RESULTS: Of the 710 adolescents aged 10-14 years analyzed; 51.3% had severe immunosuppression, 60.3% were in WHO stage 3 or 4, and 36.6% were aware of their HIV status. Adolescents with HIV-infected parents, histories of opportunistic infections (OIs), and enrolled in support groups were more likely to be disclosed to. At 36 months, disclosure was associated with lower mortality [1.5% (95% CI .6%-4.1%) versus 5.4% (95% CI 3.6.6%-8.0%, p < .001)] and lower LTFU [6.2% (95% CI 3.0%-12.6%) versus 33.9% (95% CI 27.3%-41.1%) p < .001]. CONCLUSIONS: Only one third of HIV-infected Kenyan adolescents in treatment programs had been told they were infected, and knowing their HIV status was associated with reduced LTFU and mortality. The disclosure process should be systematically encouraged and organized for HIV-infected adolescents. PMID- 30482660 TI - Is sperm DNA fragmentation a useful test that identifies a treatable cause of male infertility? AB - The present-day laboratory methods of sperm analysis are a poor predictor of reproductive outcome, and for many years it has been clear that newer and better tests are required. Although many such tests have been proposed, only those which determine sperm DNA quality are still being considered. Of these, several tests of sperm DNA fragmentation are available, although there is presently no consensus about the most appropriate test, the best test specimen (fresh or washed sperm) or what level of fragmentation is of clinical concern. Moreover, although several strategies have been proposed to reduce DNA fragmentation, there is no universal approach and few randomised trials have tested these in a clinical context. As such, most professional bodies do not presently support the use of sperm DNA fragmentation tests, and it is clear that large randomised trials are still required to further evaluate their clinical effectiveness. PMID- 30482661 TI - Comparative Effectiveness of Bladder-preserving Tri-modality Therapy Versus Radical Cystectomy for Muscle-invasive Bladder Cancer. AB - INTRODUCTION: There are limited randomized data comparing radical cystectomy (RC) with bladder-sparing tri-modality therapy (TMT) in the treatment of muscle invasive bladder cancer (MIBC). Both strategies are thought to have similar survival outcomes with different morbidity profiles. We compare the effectiveness of TMT and RC using decision-analytic modeling and the endpoint of quality adjusted life years (QALYs). PATIENTS AND METHODS: Using a Markov model, we simulated the lifetime outcomes after TMT versus RC +/- neoadjuvant chemotherapy for 67-year-old patients with clinical stage T2-T4aN0M0 MIBC. Model probabilities and utilities were extracted from the literature. The incremental effectiveness was reported in QALYs and sensitivity analyses were performed. RESULTS: For all patients with MIBC, although the model showed identical survival, TMT was the most effective strategy with an incremental gain of 0.59 QALYs over RC (7.83 vs. 7.24 QALYs, respectively). When limiting the model to favorable, contemporary cohorts in both the TMT and RC strategies, TMT remained more effective with an incremental gain of 1.61 QALYs (9.37 vs. 7.76 QALYs, respectively). One-way sensitivity analyses demonstrated the model was sensitive to the quality of life parameters (ie, the utilities) for RC and TMT. When testing the 95% confidence interval of the RC utility parameter the model demonstrated an incremental gain with TMT from -0.54 to 4.23 QALYs. Probabilistic sensitivity analysis demonstrated that TMT was more effective than RC for 63% of model iterations. CONCLUSIONS: This modeling study found that treatment of MIBC with organ-sparing TMT in appropriately-selected patients may result in a gain of QALYs relative to RC. PMID- 30482662 TI - Impact of Hospitalist-Led Interdisciplinary Antimicrobial Stewardship Interventions at an Academic Medical Center. AB - BACKGROUND: Approximately 20%-50% of antimicrobial use in hospitals is inappropriate. Limited data exist on the effect of frontline provider engagement on antimicrobial stewardship outcomes. METHODS: A three-arm pre-post quality improvement study was conducted on three adult internal medicine teaching services at an urban academic hospital. Data from September through December 2016 were compared to historic data from corresponding months in 2015. Intervention arms were (1) Educational bundle (Ed-only); (2) Educational bundle plus antimicrobial stewardship rounds twice weekly with an infectious disease-trained clinical pharmacist (Ed+IDPharmDx2); and (3) Educational bundle plus internal medicine-trained clinical pharmacist embedded into daily attending rounds (Ed+IMPharmDx5). RESULTS: Total antibiotic use decreased by 16.8% (p < 0.001), 6.8% (p = 0.08), and 33.0% (p < 0.001) on Ed-only, Ed+IDPharmDx2, and Ed+IMPharmDx5 teams, respectively. Broad-spectrum antibiotic use decreased by 26.2% (p < 0.001), 7.8% (p = 0.09), and 32.4% (p < 0.001) on the Ed-only, Ed+IDPharmDx2, and Ed+IMPharmDx5 teams, respectively. Duration of inpatient antibiotic therapy decreased from 4 to 3 days on the Ed+IMPharmDx5 team (p = 0.01). Length of stay for patients who received any antibiotic decreased from 9 to 7 days on the Ed-only team (p < 0.001) and from 9 to 6 days on the Ed+IMPharmDx5 team (p < 0.001). There was no significant change in 30-day readmission to the same facility, transfer to ICU, or in-hospital mortality for any team. CONCLUSION: Multidisciplinary, frontline provider-driven approaches to antimicrobial stewardship may contribute to reduced antibiotic use and length of hospital stay. PMID- 30482663 TI - Outcomes of Primary Total Knee Arthroplasty in Patients With Ehlers-Danlos Syndromes. AB - BACKGROUND: Ehlers-Danlos syndromes (EDS) are connective tissue disorders that cause defects in collagen synthesis or processing, resulting in joint hypermobility. Following total knee arthroplasty (TKA), concern exists that hypermobility will affect the outcome as prosthesis relies on soft tissues for stability. The purpose of this study is to investigate the outcome of TKA in the setting of EDS compared to patients undergoing TKA for osteoarthritis (OA). METHODS: We identified 16 patients (20 knees) with EDS who underwent a TKA between 2001 and 2016. Patients were matched 1:2 (n = 40) on age, gender, body mass index, and surgical date to patients undergoing TKA for OA. RESULTS: We found no difference in age, body mass index, or follow-up between the cohorts (P > .05). EDS patients had significantly more surgical interventions prior to TKA (P = .03) and were more likely to require constrained components (x2 = 0.002). Following TKA, 4 patients in the EDS group and 9 patients in the matched cohort underwent a reoperation for any reason including 1 revision in the EDS cohort and 3 in the OA cohort. We found no significant difference in reoperation or revision rates between the cohorts (P > .05). There was no difference in Knee Society Scores between groups at last follow-up (P = .63) or radiographic evidence of loosening. CONCLUSION: Although patients with EDS were more likely to require a constrained component, they are not at increased risk of revision or reoperation following TKA in the intermediate term. PMID- 30482664 TI - Treatment of Prosthetic Joint Infection: Established Patient Relationships May Impact Medical Decision-Making. AB - BACKGROUND: Choosing the intervention for prosthetic joint infections, whether debridement, antibiotics, and implant retention (DAIR), or explant and antibiotic spacer placement, is multifactorial. One characteristic that may influence this decision is a previously established relationship with the patient. We hypothesized that patients receiving their arthroplasty at an outside institution and presenting with infection would be more likely to undergo removal of their implant without an attempt at DAIR compared to patients who underwent primary arthroplasty at the investigating institution. METHODS: The institutional database was queried for primary total hip and knee arthroplasty infections. Manual review of medical records was performed, excluding patients who did not meet the Musculoskeletal Infection Society definition of infection. Patient demographics, medical comorbidities, presenting infection characteristics, and surgical intervention were collected. Multivariable analysis was performed to determine the independent predictors of treatment. RESULTS: A total of 270 patients were included for analysis. McPherson score (P < .001) and duration of symptoms (P < .001) were associated with subsequent treatment. Additionally, when controlling for age, gender, symptom duration category, procedure, McPherson score, and American Society of Anesthesiologists category, patients with index procedures at outside hospitals were more likely to undergo implant removal (odds ratio, 36.30; 95% confidence interval, 8.16-161.51; P < .001). CONCLUSION: Patients receiving their primary arthroplasty at an outside hospital and presenting with infection are more likely to undergo removal of hardware as their initial treatment. To avoid treatment bias, institutional protocols should be implemented to guide the shared decision-making process. PMID- 30482665 TI - Cost-Effectiveness of Preoperative Smoking Cessation Interventions in Total Joint Arthroplasty. AB - BACKGROUND: Smoking is associated with adverse outcomes after total joint arthroplasty (TJA), including periprosthetic joint infection (PJI). Although preoperative smoking cessation interventions may help reduce the risk PJI, the short-term cost-effectiveness of these programs remains unclear. METHODS: Decision analysis was used to evaluate the cost-effectiveness of a preoperative smoking cessation intervention over a 90-day TJA episode of care. Costs and probabilities were derived from literature review and published Medicare data. Thresholds for cost and efficacy of the intervention were determined using sensitivity analysis. RESULTS: In our model, the average 90-day cost was $32 less for patients enrolled in a mandatory smoking cessation intervention ($23,457) compared with patients who were not ($23,489). In sensitivity analyses, the smoking cessation intervention was cost-saving vs no intervention when the short term cost of PJI was greater than $95,410, the rate of PJI was reduced by at least 25% for former vs current smokers, the cost of the intervention was less than $219, or the success rate of the intervention was greater than 56%. CONCLUSION: Smoking cessation interventions prior to TJA can increase the value of care and are an important public health initiative. Routine referral to smoking cessation interventions should be considered for smokers indicated for TJA. LEVEL OF EVIDENCE: Level II, economic and decision analyses. PMID- 30482666 TI - Association between venous thromboembolism events and fibrates: A comparative study. AB - AIM: Previous studies highlighted a significant association between fibrates and venous thromboembolism (VTE) events in dyslipidemia diabetic patients. Studies in non-diabetic patients are divergent. The present study investigated the association between VTE events and fibrates in diabetic and non-diabetic patients. METHODS: Two approaches were used: (1) a disproportionality analysis using the World health organization pharmacovigilance database VigiBase(r) was used to evaluate the reporting odds-ratio (ROR) of fibrates for VTE events. Clinical and demographic characterizations of patients with fibrates-related VTE reports are described; (2) a case control-study was performed using the Caen university hospital medical information database between January 2008 and December 2012. Cases were dyslipidemia patients who were hospitalized for VTE without an evident provoking factor. Up to four controls per case were selected in dyslipidemia patients hospitalized for a non-VTE event. Controls were matched to cases by age, gender, date of hospitalization, diabetes, chronic kidney disease and hospitalization department. A multivariate conditional logistic regression was performed. RESULTS: Disproportionality analysis: a total of 946 notifications were identified in VigiBase(r) (32.9% of diabetic patients). Fibrates were significantly associated with an increased report of VTE (ROR 1.14, CI 1.07-1.22). Case-control study: a total of 163 cases (21.5% of diabetic patients) and 514 matched controls were recruited. Fibrates were significantly associated with a higher risk of VTE events that required hospitalization in multivariate analysis (odds-ratio (OR) 3.67, CI 1.82-7.37, P=0.0003). The association was only significant for fenofibrate in both approaches. CONCLUSION: Fenofibrate was associated with a higher incidence of VTE events in diabetic and non-diabetic patients. PMID- 30482667 TI - The Drosophila Blood-Brain Barrier Adapts to Cell Growth by Unfolding of Pre existing Septate Junctions. AB - The blood-brain barrier is crucial for nervous system function. It is established early during development and stays intact during growth of the brain. In invertebrates, septate junctions are the occluding junctions of this barrier. Here, we used Drosophila to address how septate junctions grow during larval stages when brain size increases dramatically. We show that septate junctions are preassembled as long, highly folded strands during embryonic stages, connecting cell vertices. During subsequent cell growth, these corrugated strands are stretched out and stay intact during larval life with very little protein turnover. The G-protein coupled receptor Moody orchestrates the continuous organization of junctional strands in a process requiring F-actin. Consequently, in moody mutants, septate junction strands cannot properly stretch out during cell growth. To compensate for the loss of blood-brain barrier function, moody mutants form interdigitating cell-cell protrusions, resembling the evolutionary ancient barrier type found in primitive vertebrates or invertebrates such as cuttlefish. PMID- 30482668 TI - Effects of exercise training on endothelial function in individuals with hypertension: a systematic review with meta-analysis. AB - A slight increase (1%) in endothelial function is associated with reduction of cardiovascular risks by 13% in individuals with cardiovascular disease risk, including those with hypertension. Thus, we conducted a systematic review and meta-analysis to assess the efficacy of exercise training on endothelial function in individuals with hypertension.We included randomized clinical trials (RCTs) with adult participants diagnosed with hypertension undergoing exercise training (>=4 weeks), and the primary outcome was endothelial function, measured by flow mediated dilatation (FMD). Five studies comprising a total of 362 participants (252 exercise and 110 controls; 59.3 years old, ranged from 52.0 to 67.2 years) were included in the meta-analysis. The pooled mean estimate indicated increased FMD after exercise training of 1.45 (P = .001), and 95% confidence interval -0.11 to 3.00 compared with control comparators. The studies were characterized by significant heterogeneity (chi2 = 23.34, P < .001, I2 = 70%). The present results are consistent with the notion that aerobic exercise training elicits favorable adaptations in endothelial function in individuals with hypertension. However, more studies are needed to make more definitive conclusions. PMID- 30482669 TI - Active Surveillance for Low-risk Prostate Cancer: Will it Become Obsolete? PMID- 30482670 TI - Prevalence of and Risk Factors for Urinary Incontinence in Home Hospice Patients. AB - Urinary incontinence (UI) is a debilitating and embarrassing condition that is prevalent among aging males and females. Little is known about UI in the home hospice setting. We sought to determine UI prevalence and risk factors in a cohort of 15432 home hospice patients over 4yr. Most of the study patients were female (59%) and aged >=75yr. This was a retrospective observational study and no patients were excluded. The median length of service was 19 d. Approximately one third of patients were diagnosed with UI during their hospice stay. Female sex and age were associated with a greater risk of UI. Diagnoses that increased the risk of UI included dementia and stroke. The risk of UI diagnosis was lower among those without a health care proxy, as well among those with higher Palliative Performance Scale scores. UI affects a substantial number of patients in home hospice and there are no guidelines for its diagnosis or mitigation. There is a pressing need to further understand the impact of UI on home hospice patients. PATIENT SUMMARY: We investigated the prevalence of urinary incontinence (UI) among home hospice patients. Approximately one-third of patients were diagnosed with UI during their hospice care. Female sex, age, dementia, and stroke were associated with a greater risk of UI. Guidelines are required for UI diagnosis and mitigation in home hospice care. PMID- 30482671 TI - Patient Decision-making: Where Are We Going? PMID- 30482672 TI - An Imprecise Path to Precision Medicine. PMID- 30482673 TI - Localized pulmonary venous calcification in a patient with prior history of radiofrequency ablation. PMID- 30482674 TI - Temperature increases by kilohertz frequency spinal cord stimulation. AB - INTRODUCTION: Kilohertz frequency spinal cord stimulation (kHz-SCS) deposits significantly more power in tissue compared to SCS at conventional frequencies, reflecting increased duty cycle (pulse compression). We hypothesize kHz-SCS increases local tissue temperature by joule heat, which may influence the clinical outcomes. METHODS: To establish the role of tissue heating in KHZ-SCS, a decisive first step is to characterize the range of temperature changes expected during conventional and KHZ-SCS protocols. Fiber optic probes quantified temperature increases around an experimental SCS lead in a bath phantom. These data were used to verify a SCS lead heat-transfer model based on joule heat. Temperature increases were then predicted in a seven-compartment (soft tissue, vertebral bone, fat, intervertebral disc, meninges, spinal cord with nerve roots) geometric human spinal cord model under varied parameterization. RESULTS: The experimentally constrained bio-heat model shows SCS waveform power (waveform RMS) determines tissue heating at the spinal cord and surrounding tissues. For example, we predict temperature increased at dorsal spinal cord of 0.18-1.72 degrees C during 3.5 mA peak 10 KHz stimulation with a 40-10-40 MUs biphasic pulse pattern, 0.09-0.22 degrees C during 3.5 mA 1 KHz 100-100-100 MUs stimulation, and less than 0.05 degrees C during 3.5 mA 50 Hz 200-100-200 MUs stimulation. Notably, peak heating of the spinal cord and other tissues increases superlinearly with stimulation power and so are especially sensitive to incremental changes in SCS pulse amplitude or frequency (with associated pulse compression). Further supporting distinct SCS intervention strategies based on heating; the spatial profile of temperature changes is more uniform compared to electric fields, which suggests less sensitivity to lead position. CONCLUSIONS: Tissue heating may impact short and long-term outcomes of KHZ-SCS, and even as an adjunct mechanism, suggests distinct strategies for lead position and programming optimization. PMID- 30482675 TI - Moving the needle-what does RSAP look for and what does it aim to do? PMID- 30482676 TI - Three-component herbal tea alleviates prolonged fatigue and improves sleep quality: A randomized controlled pilot study. AB - INTRODUCTION: Prolonged fatigue is common among adults, yet only a small percentage of affected individuals seek medical attention. Following findings that complementary and alternative medicine can be effective strategies for improving fatigue, we evaluated the effect of an herbal tea regimen on prolonged fatigue. METHODS: In this pilot randomized controlled trial, participants with prolonged fatigue were randomly allocated to either a tea (n = 20) or control (n = 20) group. The tea group consumed herbal tea consisting of Astragali Radix, Angelicae gigantis Radix, and Zizyphi Fructus twice daily for 4 weeks, whereas the control group received no intervention. Outcomes were assessed at baseline and 4 and 8 weeks. The primary outcome was fatigue severity, measured using the Chalder Fatigue Scale. Secondary outcomes included sleep quality, depression symptoms, and quality of life. RESULTS: Among the 40 individuals screened, 35 completed the study. Fatigue severity was significantly lower in the tea group than the control group at 4 weeks, and within the tea group, fatigue severity and sleep quality improved at the 4- and 8-week follow-ups vs. baseline in the tea group. Depression also significantly improved in the tea group at 8 weeks. There were no changes within the control group on any measure. CONCLUSION: The findings suggest that our herbal tea formulation reduces fatigue severity and improves sleep quality in adults with prolonged fatigue. PMID- 30482678 TI - Fragment-Based Drug Discovery: Advancing Fragments in the Absence of Crystal Structures. AB - Fragment-based drug discovery typically requires an interplay between screening methods, structural methods, and medicinal chemistry. X-ray crystallography is generally the method of choice to obtain three-dimensional structures of the bound ligand/protein complex, but this can sometimes be difficult, particularly for early, low-affinity fragment hits. In this Perspective, we discuss strategies to advance and evolve fragments in the absence of crystal structures of protein fragment complexes, although the structure of the unliganded protein may be available. The strategies can involve other structural techniques, such as NMR spectroscopy, molecular modeling, or a variety of chemical approaches. Often, these strategies are aimed at guiding evolution of initial fragment hits to a stage where crystal structures can be obtained for further structure-based optimization. PMID- 30482679 TI - Bile Acid 7alpha-Dehydroxylating Gut Bacteria Secrete Antibiotics that Inhibit Clostridium difficile: Role of Secondary Bile Acids. AB - Clostridium scindens biotransforms primary bile acids into secondary bile acids, and is correlated with inhibition of Clostridium difficile growth in vivo. The aim of the current study was to determine how C. scindens regulates C. difficile growth in vitro and if these interactions might relate to the regulation of gut microbiome structure in vivo. The bile acid 7alpha-dehydroxylating gut bacteria, C. scindens and C. sordellii, were found to secrete the tryptophan-derived antibiotics, 1-acetyl-beta-carboline and turbomycin A, respectively. Both antibiotics inhibited growth of C. difficile and other gut bacteria. The secondary bile acids, deoxycholic acid and lithocholic acid, but not cholic acid, enhanced the inhibitory activity of these antibiotics. These antibiotics appear to inhibit cell division of C. difficile. The results help explain how endogenously synthesized antibiotics and secondary bile acids may regulate C. difficile growth and the structure of the gut microbiome in health and disease. PMID- 30482677 TI - Health disparities across the counties of Kenya and implications for policy makers, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. AB - BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 provided comprehensive estimates of health loss globally. Decision makers in Kenya can use GBD subnational data to target health interventions and address county-level variation in the burden of disease. METHODS: We used GBD 2016 estimates of life expectancy at birth, healthy life expectancy, all-cause and cause-specific mortality, years of life lost, years lived with disability, disability-adjusted life-years, and risk factors to analyse health by age and sex at the national and county levels in Kenya from 1990 to 2016. FINDINGS: The national all-cause mortality rate decreased from 850.3 (95% uncertainty interval [UI] 829.8-871.1) deaths per 100 000 in 1990 to 579.0 (562.1-596.0) deaths per 100 000 in 2016. Under-5 mortality declined from 95.4 (95% UI 90.1-101.3) deaths per 1000 livebirths in 1990 to 43.4 (36.9-51.2) deaths per 1000 livebirths in 2016, and maternal mortality fell from 315.7 (242.9-399.4) deaths per 100 000 in 1990 to 257.6 (195.1-335.3) deaths per 100 000 in 2016, with steeper declines after 2006 and heterogeneously across counties. Life expectancy at birth increased by 5.4 (95% UI 3.7-7.2) years, with higher gains in females than males in all but ten counties. Unsafe water, sanitation, and handwashing, unsafe sex, and malnutrition were the leading national risk factors in 2016. INTERPRETATION: Health outcomes have improved in Kenya since 2006. The burden of communicable diseases decreased but continues to predominate the total disease burden in 2016, whereas the non-communicable disease burden increased. Health gains varied strikingly across counties, indicating targeted approaches for health policy are necessary. FUNDING: Bill & Melinda Gates Foundation. PMID- 30482680 TI - Small-Molecule Allosteric Triggers of Clostridium difficile Toxin B Auto proteolysis as a Therapeutic Strategy. AB - Clostridium difficile causes increasing numbers of life-threatening intestinal infections. Symptoms associated with C. difficile infection (CDI) are mediated by secreted protein toxins, whose virulence is modulated by intracellular auto proteolysis following allosteric activation of their protease domains by inositol hexakisphosphate (IP6). Here, we explore the possibility of inactivating the C. difficile toxin B (TcdB) by triggering its auto-proteolysis in the gut lumen prior to cell uptake using gain-of-function small molecules. We anticipated that high calcium concentrations typically found in the gut would strongly chelate IP6, precluding it from pre-emptively inducing toxin auto-proteolysis if administered exogenously. We therefore designed IP6 analogs with reduced susceptibility to complexation by calcium, which maintained allosteric activity at physiological calcium concentrations. We found that oral administration of IP6 analogs attenuated inflammation and promoted survival in mouse models of CDI. Our data provide impetus to further develop small-molecule allosteric triggers of toxin auto-proteolysis as a therapeutic strategy. PMID- 30482681 TI - Gait in children with infantile/atypical autism: Age-dependent decrease in gait variability and associations with motor skills. AB - Gait and its associations with prewalking motor milestones, motor skills, and age were investigated in 32 children with infantile/atypical autism and 36 typically developing controls. Gait was assessed using GAITRite recordings of spatiotemporal and variability gait parameters. Parents reported their child's prewalking motor milestones. Motor skills were assessed using the Movement Assessment Battery for Children. Children with infantile/atypical autism showed higher gait variability than controls, indicating a less regular walking pattern. In children with infantile/atypical autism gait variability was negatively associated with motor skills, but there was no such association with prewalking motor milestones. The higher gait variability in children with infantile/atypical autism showed an age-dependent decrease, suggesting that their gait regularity converges toward that of typically developing children. PMID- 30482682 TI - Pre-transplant factors associated with mortality after lung transplantation in cystic fibrosis: A systematic review and meta-analysis. AB - BACKGROUND: Mortality risk stratification is essential in lung transplantation (LTx) to allow listing, prioritization and mitigating strategies. In cystic fibrosis (CF) patients, predictors of post-LTx mortality are not established. METHODS: For this systematic review and meta-analysis, seven databases were searched until January 3, 2018 to identify predictors of post-LTx mortality in CF. We excluded studies of multi-organ transplantation, re-transplantation and graft survival. For multiple studies assessing the same population during overlapping time-periods, the largest one was analyzed. Risk of bias was assessed with the Newcastle-Ottawa scale (NOS). Pooled hazard ratios were calculated using random-effects models. RESULTS: Fifty-four studies were included in the systematic review and 11 studies in the meta-analyses (low-to-moderate bias risk, NOS score >= 5). Among 10 factors assessed in the meta-analysis, B. cepacia complex (BCC) (N = 1451, unadjusted HR = 2.35, 95%CI:1.80-3.06; I2 = 20.4% and adjusted HR = 2.49, 95%CI:1.74-3.57; I2 = 46.2%) and ascending chronological year of LTx (N = 4207, unadjusted HR = 0.98, 95%CI:0.97-0.98, I2 = 4.8%) were predictors of post-LTx mortality. Male gender (N = 2903, adjusted HR = 1.12, 95%CI:1.0-1.26, I2 = 0%) and age in adults (N = 3677, unadjusted HR = 0.99, 95%CI:0.97-1.00; I2 = 64.1% and N = 2605, adjusted HR = 0.98, 95%CI:0.97-0.99; I2 = 34.3%) had borderline significant associations with post-LTx mortality. P. aeruginosa colonization, forced expiratory volume in one second (FEV1), pulmonary hypertension, body mass index (BMI), pancreatic insufficiency and CF-related diabetes (CFRD) were not predictors of mortality. CONCLUSIONS: BCC was associated with a higher post-LTx mortality whereas FEV1, pulmonary hypertension, BMI, CFRD and female gender were not associated with post-LTx mortality. These findings indicate that CF-specific risk estimates of post-LTx mortality should be considered. PMID- 30482683 TI - Epidemiology of Sudden Cardiac Death: Global and Regional Perspectives. AB - Despite advancements in prevention and treatment, sudden cardiac death (SCD) remains a leading cause of mortality and is responsible for approximately half of all deaths from cardiovascular disease. Outcomes continue to remain poor following a sudden cardiac arrest, with most individuals not surviving. Although coronary heart disease remains the dominant underlying condition, our understanding of SCD is improving through greater knowledge of clinical risk factors, cardiomyopathies, and primary arrhythmic disorders. However, despite a growing wealth of information from studies in North America, Europe, and Japan, data from other global regions (and particularly from low-and middle-income countries) remains scarce. PMID- 30482684 TI - Sudden Death Risk-Stratification in 2018-2019: The Old and the New. AB - Sudden Cardiac Death (SCD) is a major public health issue, accounting for half of all cardiovascular deaths world-wide. The implantable cardioverter-defibrillator (ICD) has been solidified as the cornerstone therapy in primary prevention of SCD in ischaemic and non-ischaemic cardiomyopathy. However, what has become increasingly clear is that the left ventricular ejection fraction (LVEF) is an inadequate tool to select patients for a prophylactic ICD, despite its widespread use for this purpose. Use of LVEF alone has poor specificity for arrhythmic versus non-arrhythmic death. In addition, the vast majority of sudden deaths occur in patients with more preserved cardiac function. Alternate predictors of sudden death include electrophysiology study, non-invasive markers of electrical instability, myocardial fibrosis, genetic and bio-markers. The challenge for the future is finding a risk stratification test, or combination of tests, that adequately select patients at high risk of SCD with low competing risk of non sudden death. PMID- 30482685 TI - Inappropriate Shock Due to Myopotentials Oversensing in a Patient With Subcutaneous Implantable Cardioverter-Defibrillator. PMID- 30482686 TI - Catheter Ablation of Post-Infarct VT: Mechanisms, Strategies and Outcomes. AB - Ventricular arrhythmias are one of the leading causes of death in patients with a prior myocardial infarction. Implantable cardioverter-defibrillators (ICDs) are very effective in the prevention of sudden cardiac death but the risk of recurrence remains an issue since defibrillation does not alter the underlying substrate. Recurrent ICD shocks are distressing and are associated with an increase in mortality. Catheter ablation is an effective treatment for recurrent ventricular tachycardia in these patients, particularly when antiarrhythmic therapy produces side effects or is ineffective. This paper reviews the underlying mechanisms of VT in patients with a prior myocardial infarction, indications, strategies and the outcomes of catheter ablation. PMID- 30482687 TI - Arrhythmic Genotypes in Familial Dilated Cardiomyopathy: Implications for Genetic Testing and Clinical Management. AB - Cardiac arrhythmias are frequently seen in patients with dilated cardiomyopathy (DCM) and can precipitate heart failure and death. In patients with non-ischaemic DCM, evidence for the benefit of an implantable cardioverter-defibrillator (ICD) for primary prevention of sudden cardiac death has recently been questioned. Algorithms devised to identify high-risk individuals who might benefit most from ICD implantation have focussed on clinical criteria with little attention paid to the underlying aetiology of DCM. Malignant ventricular arrhythmias often occur as a nonspecific consequence of DCM but can also be a primary manifestation of disease in heritable forms of DCM and may precede DCM onset. We undertook a literature search and identified 11 genes that have been associated with DCM and ventricular arrhythmias in multiple kindreds. Many of these genes fall into a diagnostic grey zone between left-dominant arrhythmogenic right ventricular cardiomyopathy and arrhythmic DCM. Genes associated predominantly with arrhythmic DCM included LMNA and SCN5A, as well as the more recently-reported DCM disease genes, RBM20, FLNC, and TTN. Recognition of arrhythmic DCM genotypes is important, as this may impact on clinical management. In particular, prophylactic ICD implantation and early referral for heart transplantation may be indicated in genotype-positive individuals. Collectively, these findings argue in favour of including genetic testing in standard-of-care management of familial DCM. Further studies in genotyped patient cohorts are required to establish the long-term health and economic benefits of this strategy. PMID- 30482688 TI - Dissecting the Synapse- and Frequency-Dependent Network Mechanisms of In Vivo Hippocampal Sharp Wave-Ripples. AB - Hippocampal ripple oscillations likely support reactivation of memory traces that manifest themselves as temporally organized spiking of sparse neuronal ensembles. However, the network mechanisms concurring to achieve this function are largely unknown. We designed a multi-compartmental model of the CA3-CA1 subfields to generate biophysically realistic ripple dynamics from the cellular level to local field potentials. Simulations broadly parallel in vivo observations and support that ripples emerge from CA1 pyramidal spiking paced by recurrent inhibition. In addition to ripple oscillations, key coordination mechanisms involve concomitant aspects of network activity. Recurrent synaptic interactions in CA1 exhibit slow gamma band coherence with CA3 input, thus offering a way to coordinate CA1 activities with CA3 inducers. Moreover, CA1 feedback inhibition controls the content of spontaneous replay during CA1 ripples, forming new mnemonic representations through plasticity. These insights are consistent with slow-gamma interactions and interneuronal circuit plasticity observed in vivo, suggesting a multifaceted ripple-related replay phenomenon. PMID- 30482689 TI - Astrocytes Integrate Behavioral State and Vascular Signals during Functional Hyperemia. AB - Dynamic changes in astrocyte free Ca2+ regulate synaptic signaling and local blood flow. Although astrocytes are poised to integrate signals from synapses and the vasculature to perform their functional roles, it remains unclear what dictates astrocyte responses during neurovascular coupling under realistic conditions. We examined peri-arteriole and peri-capillary astrocytes in the barrel cortex of active mice in response to sensory stimulation or volitional behaviors. We observed an AMPA and NMDA receptor-dependent elevation in astrocyte endfoot Ca2+ that followed functional hyperemia onset. This delayed astrocyte Ca2+ signal was dependent on the animal's action at the time of measurement as well as a neurovascular pathway that linked to endothelial-derived nitric oxide. A similar elevation in endfoot Ca2+ was evoked using vascular chemogenetics or optogenetics, and opto-stimulated dilation recruited the same nitric oxide pathway as functional hyperemia. These data show that behavioral state and microvasculature influence astrocyte Ca2+ in active mice. VIDEO ABSTRACT. PMID- 30482690 TI - A Self-Regulating Gap Junction Network of Amacrine Cells Controls Nitric Oxide Release in the Retina. AB - Neuromodulators regulate circuits throughout the nervous system, and revealing the cell types and stimulus conditions controlling their release is vital to understanding their function. The effects of the neuromodulator nitric oxide (NO) have been studied in many circuits, including in the vertebrate retina, where it regulates synaptic release, gap junction coupling, and blood vessel dilation, but little is known about the cells that release NO. We show that a single type of amacrine cell (AC) controls NO release in the inner retina, and we report its light responses, electrical properties, and calcium dynamics. We discover that this AC forms a dense gap junction network and that the strength of electrical coupling in the network is regulated by light through NO. A model of the network offers insights into the biophysical specializations leading to auto-regulation of NO release within the network. PMID- 30482692 TI - Large-Scale Cortical Networks for Hierarchical Prediction and Prediction Error in the Primate Brain. AB - According to predictive-coding theory, cortical areas continuously generate and update predictions of sensory inputs at different hierarchical levels and emit prediction errors when the predicted and actual inputs differ. However, predictions and prediction errors are simultaneous and interdependent processes, making it difficult to disentangle their constituent neural network organization. Here, we test the theory by using high-density electrocorticography (ECoG) in monkeys during an auditory "local-global" paradigm in which the temporal regularities of the stimuli were controlled at two hierarchical levels. We decomposed the broadband data and identified lower- and higher-level prediction error signals in early auditory cortex and anterior temporal cortex, respectively, and a prediction-update signal sent from prefrontal cortex back to temporal cortex. The prediction-error and prediction-update signals were transmitted via gamma (>40 Hz) and alpha/beta (<30 Hz) oscillations, respectively. Our findings provide strong support for hierarchical predictive coding and outline how it is dynamically implemented using distinct cortical areas and frequencies. PMID- 30482693 TI - Alcohol Activates Scabrous-Notch to Influence Associated Memories. AB - Drugs of abuse, like alcohol, modulate gene expression in reward circuits and consequently alter behavior. However, the in vivo cellular mechanisms through which alcohol induces lasting transcriptional changes are unclear. We show that Drosophila Notch/Su(H) signaling and the secreted fibrinogen-related protein Scabrous in mushroom body (MB) memory circuitry are important for the enduring preference of cues associated with alcohol's rewarding properties. Alcohol exposure affects Notch responsivity in the adult MB and alters Su(H) targeting at the dopamine-2-like receptor (Dop2R). Alcohol cue training also caused lasting changes to the MB nuclear transcriptome, including changes in the alternative splicing of Dop2R and newly implicated transcripts like Stat92E. Together, our data suggest that alcohol-induced activation of the highly conserved Notch pathway and accompanying transcriptional responses in memory circuitry contribute to addiction. Ultimately, this provides mechanistic insight into the etiology and pathophysiology of alcohol use disorder. PMID- 30482691 TI - A Population of Navigator Neurons Is Essential for Olfactory Map Formation during the Critical Period. AB - In the developing brain, heightened plasticity during the critical period enables the proper formation of neural circuits. Here, we identify the "navigator" neurons, a group of perinatally born olfactory sensory neurons, as playing an essential role in establishing the olfactory map during the critical period. The navigator axons project circuitously in the olfactory bulb and traverse multiple glomeruli before terminating in perspective glomeruli. These neurons undergo a phase of exuberant axon growth and exhibit a shortened lifespan. Single-cell transcriptome analyses reveal distinct molecular signatures for the navigators. Extending their lifespan prolongs the period of exuberant growth and perturbs axon convergence. Conversely, a genetic ablation experiment indicates that, despite postnatal neurogenesis, only the navigators are endowed with the ability to establish a convergent map. The presence and the proper removal of the navigator neurons are both required to establish tight axon convergence into the glomeruli. PMID- 30482695 TI - A case report of an intramedullary cervical teratoma in an adult patient with cervical spondylotic radiculopathy. AB - Spinal cord teratomas are rare. There are few reports of teratomas affecting the cervical spine and their association with spondylotic radiculopathy has not been described. A 59-year-old woman with history of fecal incontinence attended with cervical radicular pain radiating to upper limbs. Physical examination showed distal muscle hypotrophy and abolishment of bicipital, tricipital, and brachioradialis reflexes of the right arm, preserving proximal strength. Also, hiporreflexia and loss of proprioception in the right lower limb was observed. Magnetic resonance imaging showed an intramedullary mass at C7-T1, accompanied by intervertebral disk protrusions and dural sac compressions at the same level. One stage posterior-anterior operative approach for tumor resection, decompression of the radiculopathy and replacement of intervertebral discs was performed. The histopathological diagnosis was for a mature teratoma. We described the first case of an intramedullary cervical teratoma associated with radiculopathy in an adult, providing evidence of rare long-lasting teratomas affecting the cervical spine. PMID- 30482694 TI - Imaging Cortical Dynamics in GCaMP Transgenic Rats with a Head-Mounted Widefield Macroscope. AB - Widefield imaging of calcium dynamics is an emerging method for mapping regional neural activity but is currently limited to restrained animals. Here we describe cScope, a head-mounted widefield macroscope developed to image large-scale cortical dynamics in rats during natural behavior. cScope provides a 7.8 * 4 mm field of view and dual illumination paths for both fluorescence and hemodynamic correction and can be fabricated at low cost using readily attainable components. We also report the development of Thy-1 transgenic rat strains with widespread neuronal expression of the calcium indicator GCaMP6f. We combined these two technologies to image large-scale calcium dynamics in the dorsal neocortex during a visual evidence accumulation task. Quantitative analysis of task-related dynamics revealed multiple regions having neural signals that encode behavioral choice and sensory evidence. Our results provide a new transgenic resource for calcium imaging in rats and extend the domain of head-mounted microscopes to larger-scale cortical dynamics. VIDEO ABSTRACT. PMID- 30482696 TI - Disconnection: Exploring transfer from midwifery-led to consultant-led care a phenomenological study of women's views. AB - BACKGROUND: Understanding women's feelings during the transfer process can illuminate women's perspectives thus minimising the risk for postnatal psychological and emotional morbidity, and inform midwifery practice. AIM: To explore the meaning women ascribe to their feelings when transferred from an environment emphasising a social model of pregnancy and birth in a Midwifery Led Unit, to a contrasting, more 'medicalised' setting of a Consultant Led Unit. METHODS: The study adopted an idiographic focus, by conducting semi-structured interviews with new mothers. A purposive sample of eleven women was recruited via participating midwifery led units and their 'Facebook' page. An interpretative phenomenological approach was selected to explore mothers' individual perceptions of experiences. FINDINGS: Participants described feeling a strong sense of community in the midwifery led unit, where they enjoyed a sense of belonging, safety, and support. The overarching theme of 'disconnection' signified feelings of muted agency when transferred to a different environment. Women used adaptive processes to reconcile themselves to a medicalised ideology. The impact of the transfer also resulted in a sense of alienation and 'not belonging'. CONCLUSION: Adjustment to a different model of care meant women needed to rapidly amend their notions of normality and agency, at the same time as entering motherhood. Raising awareness about the possible psychological adjustments women have to make during at this time could provide reassurance to other women. It also highlights the need for support during and after transfer. Strengthening continuity of care could help facilitate the adjustment process. PMID- 30482697 TI - Fatal sepsis caused by mecA-positive oxacillin-susceptible Staphylococcus aureus: First report in a tertiary hospital of southern Brazil. AB - mecA-positive oxacillin phenotypically susceptible Staphylococcus aureus (OS MRSA) is increasingly reported worldwide. This bacterium poses a therapeutic threat, as it can be misidentified as an oxacillin-susceptible organism by phenotypic methods that are routinely used in the majority of clinical microbiology laboratories. Herein, we report the first case of fatal sepsis in a 43-year-old female patient caused by an OS-MRSA SCCmec type IVa/ST1/CC1 in a tertiary hospital in southern Brazil, which highlights the difficulties involved in diagnosing this bacterium. Blood cultures and phenotypic susceptibility tests on admission yielded a penicillin-resistant S. aureus. Although vancomycin therapy was initiated, this antibacterial was replaced by oxacillin, based on the susceptibility result. However, the clinical conditions of the patient deteriorated rapidly evolving to fatal septic shock. Clinical microbiology laboratories should consider the use of additional tests to accurately distinguish between various antimicrobial phenotypes of S. aureus. PMID- 30482698 TI - Changing epidemiology of non-albicans candidemia in Korea. AB - An epidemiologic surveillance of non-albicans candidemia for a 6-year period was conducted in Korea. Compared to the published epidemiologic data for the previous 6 years, an increase of C. glabrata (from 21.3% to 28.5%) and a decrease of C. parapsilosis (from 36.5% to 24.7%) were noticed. During the study period, C. tropicalis (36.4%) was most frequently isolated non-albicans Candida, followed by C. glabrata (28.5%), C. parapsilosis (24.7%), and C. krusei (2.6%). Replacement of primary amphotericin B treatment with echinocandins (P < 0.001) eliminated amphotericin B resistance (from 7.8% in 2011 to 0% in 2014). PMID- 30482699 TI - Isolation of multidrug-resistant Haemophilus influenzae harbouring multiple exogenous genes from a patient diagnosed with acute sinusitis. AB - In paediatric patients, beta-lactams and macrolides are widely used to treat acute otitis media and sinusitis, which are often caused by either Streptococcus pneumoniae or Haemophilus influenzae. However, resistant isolates have emerged and are becoming more prevalent. H. influenzae generally acquires antimicrobial resistance by mutation or by expression of beta-lactamase. In this study, we isolated H. influenzae from a paediatric patient diagnosed with acute sinusitis. This strain harboured multiple exogenous resistance genes: blaTEM-1, mef(A) and tet(M). DNA sequencing suggested that both mef(A) and tet(M) had been transferred from S. pneumoniae or another Streptococcus. This typical outpatient had not been exposed to excessive levels of antibiotics and had no underlying diseases, strongly suggesting that this type of resistant isolate could become more prevalent. PMID- 30482700 TI - Pelvic cellulitis caused by Raoultella planticola in a neutropenic patient. AB - Raoultella planticola is a gram-negative, encapsulated, aerobic bacterium within the Enterobacteriaceae family. It has been primarily described as pathogen in cases with pneumonia and gastrointestinal infections. Here we describe a case of severe pelvic cellulitis in a patient with neutropenia following induction therapy for myeloid sarcoma. The patient experienced a septic shock and was treated successfully with antibiotic therapy. A literature review is provided to put this case in context with previous reports on R. planticola. This report highlights that awareness for uncommon pathogens is crucial in the clinical management of infections in neutropenic patients. PMID- 30482701 TI - Randomized Controlled Trial of Heparin Versus Bivalirudin Anticoagulation in Acyanotic Children Undergoing Open Heart Surgery. AB - OBJECTIVE: To determine the safety and efficacy of bivalirudin as an anticoagulant for pediatric open heart surgery (OHS) and to determine its appropriate dosage for this purpose. DESIGN: Prospective, randomized controlled trial. SETTING: Tertiary care hospital. PARTICIPANTS: Fifty acyanotic children aged 1-12 years undergoing OHS. INTERVENTIONS: The children were randomized to receive either 4 mg/kg of heparin (n = 25, group H) or 1 mg/kg of bivalirudin bolus followed by 2.5 mg/kg/h infusion (n = 25, group B) as the anticoagulant. The doses were adjusted to maintain activated clotting time (ACT) above 480 seconds. At the conclusion of surgery, protamine (1.3 mg/100 U of heparin) was administered to children in group H. MEASUREMENTS AND MAIN RESULTS: The children were comparable in both groups with regard to demographic characteristics. The mean age and weight were 51.5 months and 13.4 kg in group H, and 59.3 months and 13.4 kg in group B. The dose of anticoagulant required was 4.0 +/- 0.2 mg/kg in group H and 1.7 +/- 0.2 mg/kg followed by 3.0 +/- 0.7 mg/kg/h infusion in group B (p < 0.001). One child in group H required an additional dose compared to 13 (54.2%) children in group B. Intraoperatively, the ACT achieved was higher in group H compared to group B (p < 0.05). The ACT returned to baseline value after protamine administration in group H, but it remained elevated for 2 hours after termination of cardiopulmonary bypass (CPB) in group B (p < 0.01). The ACT was higher in group B compared to group H for 6 hours after termination of CPB (p < 0.05). Heparin prolonged the onset of clotting, decreased the rate and strength of thrombus formation, and inhibited platelet function to a greater extent than bivalirudin on viscoelastic coagulation testing. The total duration of surgery was prolonged in group B. The postoperative chest tube drainage was similar in group B (4.9 mL/kg) as in group H (5.9 mL/kg) in spite of higher ACT. The transfusion requirements were similar. No adverse event occurred in any patient. CONCLUSION: Bivalirudin is a safe and effective anticoagulant for pediatric OHS. Though it is not suitable as a routine anticoagulant for this purpose, it may be used as a heparin alternative in instances when heparin cannot be used. The dose required to maintain ACT for more than 480 seconds was 1.7 +/- 0.2 mg/kg followed by 3.0 +/- 0.7 mg/kg/h infusion. The ACT remained elevated for 2 hours after stopping the infusion. Bivalirudin did not increase postoperative bleeding and transfusion requirement. PMID- 30482702 TI - Echocardiographic Assessment of Biventricular Function in 249 Patients During the Peri-Extracorporeal Membrane Oxygenation Period. AB - OBJECTIVES: At a quaternary care center that regularly performs and cares for patients undergoing extracorporeal membrane oxygenation (ECMO), a database of all adult patients since 2009 was assembled with echocardiographic parameters of left (LV) and right (RV) ventricular function. From the database, 175 venoarterial (VA) and 74 venovenous (VV) ECMO patients were analyzed to compare the decannulation echocardiographic assessments of biventricular function before, during, and after ECMO in survivors and nonsurvivors. DESIGN: Retrospective chart review-based study. SETTING: A single quaternary care center. PARTICIPANTS: All adult patients who received ECMO from 2009 to 2017 with both survival data and echographic studies were included in this retrospective study. INTERVENTIONS: When indicated, transthoracic and transesophageal echocardiograms were performed for ECMO patients. The results of these echocardiograms were reviewed retrospectively, and differences between survivors and nonsurvivors were examined. MEASUREMENTS AND MAIN RESULTS: A retrospective chart review of before, during cannulation, and after decannulation echocardiographic assessments of biventricular function was performed. On average, VA ECMO survivors had better post-decannulation LV function than did nonsurvivors by a full clinical grade mild impairment versus moderate impairment (p < 0.001). RV function comparison was similar-mild impairment in survivors versus moderate impairment in nonsurvivors (p = 0.007). LV and RV function before and during ECMO in survivors was not different from that of nonsurvivors. The change in biventricular function from before to after cannulation and during cannulation to post-cannulation was approximately a full clinical grade better in survivors than nonsurvivors (p < 0.01 in all cases). In VV ECMO patients, post-decannulation RV function was significantly worse in nonsurvivors (moderate dysfunction vs borderline normal function) (p = 0.013). CONCLUSIONS: Retrospective chart review of 249 patients suggests that echocardiographic assessment of biventricular function before ECMO cannulation is not prognostic in VA or VV ECMO patients. Post-decannulation assessment of biventricular function may aid in triaging more "at risk" patients because nonsurvivors have significantly worse biventricular function after decannulation. The failure to improve biventricular function from the before to after ECMO phases and the during to after ECMO phases is concerning for a poor prognosis. PMID- 30482703 TI - Review of the 2017 European Society of Cardiology's Guidelines for the Management of Acute Myocardial Infarction in Patients Presenting with ST-Segment Elevation and Focused Update on Dual Antiplatelet Therapy in Coronary Artery Disease Developed in Collaboration with the European Association for Cardio-Thoracic Surgery. PMID- 30482704 TI - [Primary intestinal lymphangiectasia: Could propranolol be an effective alternative treatment?] PMID- 30482705 TI - [How do we treat Kaposiform Haemangioendothelioma?] PMID- 30482706 TI - Lateral pharyngotomy. AB - Based on a review of the medical literature, the authors document the key technical points, variants, technical errors to avoid and main functional results of lateral pharyngotomy for resection of cancers originating from the lateral oro and/or hypopharynx. PMID- 30482707 TI - Assessment of swallowing function after circumferential pharyngolaryngectomy. A multicenter study by the GETTEC group. AB - OBJECTIVE: Circumferential pharyngolaryngectomy is performed for advanced pharyngeal tumor or in a context of postradiation recurrence. Several free or pedicle flaps have been described for pharyngeal defect reconstruction, with choice at the surgeon's discretion. The aim of this study was to evaluate long term swallowing function according to the type of flap used for reconstruction. MATERIAL AND METHOD: A multicenter retrospective study was conducted from January to September 2016 within the French GETTEC head and neck tumor study group. All patients in remission after circumferential pharyngolaryngectomy were included and filled out the Deglutition Handicap Index (DHI) questionnaire and underwent swallowing function fiberoptic endoscopy assessment. 46 patients (39 men, 7 women) were included. Reconstruction used a tubularized forearm free flap (FFF group) in 19 cases, pectoralis major myocutaneous flap (PMMF group) in 15 cases and free jejunum flap (FJF group) in 12 cases. RESULTS: Mean DHI was 24: 20 in the FFF group, 23 in the FJF group and 25 in the PMMF group, without significant differences. 27 patients had normal swallowing, 9 mixed diet, 8 liquid diet and 3 were fed by gastrostomy. On endoscopy, free flaps (FJF and FFF) were associated with significantly greater rates of normal swallowing of saliva and yogurt than in the PMMF group (P=0.04). CONCLUSION: Type of flap reconstruction after circumferential pharyngolaryngectomy had no significant impact on postoperative swallowing function assessed on the self-administered DHI questionnaire. PMID- 30482708 TI - Serodiagnosis and early detection of Strongyloides stercoralis infection. AB - Strongyloidiasis is a major neglected tropical disease with the potential of causing lifelong infection and mortality. One of the ways for effective control of this disease is developing improved diagnostics, particularly using serological approaches. A serological test can achieve high diagnostic sensitivity and specificity, has the potential for point-of-care translation, and can be used as a screening tool for early detection. More research is needed to find clinically important antibody biomarkers for early disease detection, mapping, and epidemiological surveillance. This article summarizes human strongyloidiasis and the available diagnostic tools for the disease, focusing on describing the current antibody assays for strongyloidiasis. Finally, prospects of developing a more effective serodiagnostic tool for strongyloidiasis are discussed. PMID- 30482709 TI - Vaporization Detection Imaging: A Technique for Imaging Low-Boiling-Point Phase Change Contrast Agents with a High Depth of Penetration and Contrast-to-Tissue Ratio. AB - Phase-change contrast agents (PCCAs) possess advantages over microbubble contrast agents, such as the ability to extravasate and circulate longer in the vasculature that could enhance the diagnostic capabilities of contrast-enhanced ultrasound. PCCAs typically have a liquid perfluorocarbon (PFC) core that can be vaporized into echogenic microbubbles. Vaporization of submicron agents filled with liquid PFCs at body temperature usually requires therapeutic pressures higher than typically used for diagnostic imaging, but low-boiling-point PCCAs using decafluorobutane or octafluoropropane can be vaporized using pressures in the diagnostic imaging regime. Low-boiling-point PCCAs produce a unique acoustic signature that can be separated from tissue and bubble signals to make images with high contrast-to-tissue ratios. In this work, we explore the effect of pulse length and concentration on the vaporization signal of PCCAs and a new technique to capture and use the signals to make high contrast-to-tissue ratio images in vivo. The results indicate that using a short pulse may be ideal for imaging because it does not interact with created bubbles but still produces strong signals for making images. Furthermore, it was found that capturing PCCA vaporization signals produced higher contrast-to-tissue ratio values and better depth of penetration than imaging the bubbles generated by droplet activation using conventional contrast imaging techniques. The resolution of the vaporization signal images is poor because of the low frequency of the signals, but their high sensitivity may be used for applications such as molecular imaging, where the detection of small numbers of contrast agents is important. PMID- 30482710 TI - Effect of Age on Substantia Nigra Hyper-echogenicity in Parkinson's Disease Patients and Healthy Controls. AB - Substantia nigra (SN) hyper-echogenicity (SN+) describes an enlargement (>90th percentile) of the area of echogenicity at the anatomic site of the SN in the midbrain detected by transcranial sonography. This ultrasound sign has proven to be a valuable marker supporting the clinical diagnosis of Parkinson's disease (PD). Although there is considerable variation in the extent of echogenic signals at the anatomic site of the SN among PD patients, previous work suggests that SN+ is a stable marker throughout the course of the disease. The present study focused on two aspects: (i) determining whether SN+ values differ between the sides, mirroring the asymmetric character of the disease; and (ii) determining whether age has an influence on SN echogenicity. This cross-sectional study included 300 PD patients and 200 healthy controls. SN+ was measured planimetrically by transcranial sonography. Echogenicity was analyzed separately for onset and non-onset sides, with onset side defined as the SN contralateral to the side of the body that first manifested PD-related motor impairment. Age of the patients and healthy controls at study time was used for correlation. We found that the onset SN+ contralateral to the side of initial motor symptoms was on average 17.6% larger than its counterpart. However, we also found that contrary to the control group, where an increase in age was associated with an increase in size of SN+, age of PD patients was associated with a decline in size of the onset SN+. Furthermore, SN measured at the onset side of PD patients correlated significantly with patient age and Hoehn and Yahr stage, a scale that grades PD severity, although this was not the case for the non-onset side. The present study indicates that changes in SN echogenicity have a different dynamic depending on the onset side of the disease. The age at study time had a significantly negative effect on the size of onset SN+, the effect on the non onset side was non-significant. We conclude that for appropriate PD analysis, onset SN+ is a more important marker than the average of both sides of SN. Furthermore, we found that among healthy controls, the size of SN+ increases with age. PMID- 30482711 TI - Multiple-Exposure Drug Release from Stable Nanodroplets by High-Intensity Focused Ultrasound for a Potential Degenerative Disc Disease Treatment. AB - The combination of simvastatin and CF680 dye encapsulated by stable nanodroplets has been developed as a drug delivery carrier. Simvastatin has previously been found to be a potential degenerative disc disease treatment. Multiple exposures of the nanodroplets to high-intensity focused ultrasound induced release of simvastatin. Each ultrasound exposure yielded a consistent concentration of the drug and dye released. B-mode ultrasound image analysis data and cavitation data clearly indicated the release mechanism is phase transition of the liquid nanodroplets into gas bubbles. The nanodroplets were stably stored in ex vivo rabbit spinal discs for at least 14 days, and the contents responded to ultrasound exposure on demand. Lastly, nucleus pulposus cells harvested from rabbit spine discs and exposed to media with nanodroplets exhibited a decrease in cell viability (85%) relative to the cells only (96.7%) at 24 h, but no difference at 48 h. Thus, the system may be a potential degenerative disc disease treatment. PMID- 30482712 TI - Comparison of Longitudinal and Apical Foetal Speckle Tracking Echocardiography Using Tissue Motion Annular Displacement and Segmental Longitudinal Strain. AB - The aim of our prospective pilot study with exploratory analysis was to compare longitudinal and apical foetal speckle tracking echocardiography (STE) using tissue motion annular displacement (TMAD) and segmental longitudinal strain (SLS). We compared two different STE quantification tools in a longitudinal and apical four-chamber view in 57 normal foetuses between 20 and 40 wk of gestation. Myocardial mechanical dyssynchrony and strain were assessed using offline quantification software (QLab Version 10.3, Philips Medical Systems, Andover, MA, USA). We compared the dyssynchrony measurements with TMAD and SLS in longitudinal and apical four-chamber views. Furthermore, we examined the segmental strain values of both ventricles with SLS and compared the differences between longitudinal and apical measurements. Dyssynchrony measurements with TMAD and SLS and strain measurements with SLS were feasible in all cases. In the apical view, the dyssynchrony measurements with TMAD were systematically greater than those achieved with SLS (p < 0.001). For the longitudinal view, no differences were observed between tools (p = 0.153). The application of SLS provided similar results for dyssynchrony in both views (intra-class correlation coefficient [ICC] = 0.281, p = 0.623), but the strain measurements in the left and right ventricles differed significantly between views (ICC = -0.082, p = 0.011, and ICC = -0.061, p = 0.024, respectively). For TMAD, we found large differences in the dyssynchrony values between longitudinal and apical assessment (ICC = -0.060, p = 0.03). Furthermore, TMAD exhibited reduced accuracy in the system's automatic tracking algorithm, limiting the data quality. The dyssynchrony assessment is affected less by the foetal position in SLS than in TMAD. The strain readings in SLS varied depending on the view in which they were assessed. The application of TMAD cannot be recommended for foetal STE. PMID- 30482713 TI - Algorithm for the treatment of oral and peri-oral defects through local flaps. AB - PURPOSE: Local flaps are currently considered the main reconstructive option for medium-size oral and peri-oral defects; however, their indications are sometimes challenging to select. The aim of this study was to critically analyse their selection and to propose a therapeutic algorithm. MATERIALS AND METHODS: We performed a search on PubMed regarding the medium-size oral and peri-oral defects reconstruction, and we collected data on the aetiology, the location of the defect, the type of flap used and postoperative complications. The final proposed treatment algorithm was the product of this analysis. RESULTS: We found 111 articles and 2504 flaps (236 buccinator flaps, 60 masseter flaps, 466 facial artery myomucosal flaps, 285 tongue flaps, 95 palatal flap, 525 buccal fat pad flaps and 835 local lip flaps). The most frequent defect localizations included floor of mouth (203 flaps), cheek (242 flaps), anterior hard palate (418 flaps) and upper and lower lip (274 and 559 flaps). Partial flap necrosis and dehiscence occurred in 3% of cases whereas total necrosis in 1%. CONCLUSIONS: Local flaps are a good option for oral and perioral defect reconstruction. An appropriate choice of the flap to be used based on the location of the defect is essential for a correct reconstruction. PMID- 30482714 TI - Navigation-guided resection of maxillary tumors: Can a new volumetric virtual planning method improve outcomes in terms of control of resection margins? AB - INTRODUCTION: In the present study, our aim was to confirm the role of navigation guided surgery in reducing the percentage of positive margins in advanced malignant pathologies of the mid-face, by introducing a new volumetric virtual planning method for resection. MATERIALS AND METHODS: Twenty-eight patients were included in this study. Eighteen patients requiring surgery to treat malignant midface tumors were prospectively selected and stratified into two different study groups. Patients enrolled in the Reference Points Resection group (RPR - 10 patients) underwent resection planning using the anatomical landmarks on CT scan; patients enrolled in the Volume Resection group (VR - 8 patients) underwent resection using the new volumetric virtual planning method. The remaining 10 patients (Control group) were treated without the use of a navigation system. RESULTS: In total, 127 margins were pathologically assessed in the RPR group, 75 in the VR group, and 85 in the control group. In the control group, 16% of the margins were positive, while in the RPR group the value was 9%, and in the VR group 1%. CONCLUSIONS: The volumetric tumor resection planning associated to the navigation-guide resection appeared to be an improvement in terms of control of surgical margins in advanced tumors involving the mid-face. PMID- 30482715 TI - Immunohistochemical analysis of lymphatic vessel density and mast cells in oral tongue squamous cell carcinoma. AB - The aim of this study was to analyze lymphangiogenesis and the presence of mast cells in oral tongue squamous cell carcinoma (OTSCC), correlating the findings with clinicopathological parameters (clinical stage, tumor size, nodal metastasis, histological grade of malignancy, local recurrence, and clinical outcome). Fifty-six cases of primary OTSCC were selected. Lymphatic vessels and mast cells were identified by immunostaining with anti-podoplanin (D2-40) and anti-tryptase antibody, respectively. Lymphatic vessel density (LVD) and mast cell density (MCD) were determined in the intratumoral and peritumoral areas. Intratumoral LVD was higher in advanced clinical stages (III/IV) when compared to early-stage (p = 0.017) and in metastatic cases compared to non-metastatic tumors (p = 0.013). Peritumoral LVD and intratumoral or peritumoral MCD did not differ significantly according to the clinicopathological parameters of OTSCCs (p > 0.05). No significant correlations between LVD and MCD were observed at the intratumoral (r = -0.014; p = 0.918) or peritumoral level (r = 0.156; p = 0.251). Our findings suggest that intratumoral lymphatic vessels, compared to peritumoral lymphatic vessels, appear to be more related to the progression of OTSCC. MCD alone does not seem to be determinant for lymphangiogenesis or for the biological behavior of OTSCC, indicating multiple pro- and antitumor effects of these inflammatory cells. PMID- 30482716 TI - Is training in obstetric critical care adequate? An international comparison. AB - Obstetric critical care is an emerging discipline which cuts across speciality boundaries. We have analysed the training curricula in the three major specialities (obstetrics, anaesthesia and intensive care medicine) likely to be involved in the care of the critically-ill obstetric patient, to assess whether it is adequate to ensure effective training on this subject. PMID- 30482717 TI - Maternal critical care in resource-limited settings. Narrative review. AB - Maternal critical care reflects interdisciplinary care in any hospital area according to the severity of illness of the pregnant woman. The admission rate to intensive care units is below 1% (0.08-0.76%) of deliveries in high-income countries, and ranges from 0.13% to 4.6% in low middle-income countries. Mortality in these patients is high and varies from 0% to 4.9% of admissions in high-income countries, and from 2% to 43.6% in low middle-income countries. Obstetric haemorrhage, sepsis, preeclampsia, human immunodeficiency virus complications and tropical diseases are the main reasons for intensive care unit admission in low middle-income countries. Bedside assessment tools, such as early warning scores, may help to identify critically-ill patients and those at risk of deterioration. There is a lack of uniformity in definitions, identification and treatment of critically ill pregnant patients, especially in resource-limited settings. Our aims were to (i) propose a more practical definition of maternal critical care, (ii) discuss maternal mortality in the setting of limited accessibility of critical care units, (iii) provide some accessible tools to improve identification of obstetric patients who may become critically ill, and (iv) confront challenges in providing maternal critical care in resource-limited settings. To improve maternal critical care, training programmes should embrace modern technological educational aids and incorporate new tools and technologies that assist prediction of critical illness in the pregnant patient. The goal must be improved outcomes following early interventions, early initiation of resuscitation, and early transfer to an appropriate level of care, whenever possible. PMID- 30482718 TI - Coagulopathy in obstetric cholestasis in Wessex Deanery. PMID- 30482719 TI - A prospective observational study of the change in regional cerebral oxygen saturation during cesarean delivery in women receiving phenylephrine prophylaxis for spinal hypotension. AB - BACKGROUND: Spinal hypotension causes decreased regional cerebral oxygen saturation (ScO2) in women undergoing cesarean delivery. In this study we aimed to measure the change in ScO2 using near infrared spectroscopy in women receiving a prophylactic phenylephrine infusion during cesarean delivery under spinal anesthesia. METHODS: This was a prospective, observational cohort study. Fifty three women had ScO2 measurements at the following time points: preoperatively, in the supine position with 30 degrees of left lateral tilt; one and five minutes after spinal anesthesia; at the time of skin incision; immediately after delivery; one minute after commencing the oxytocin infusion; at completion of surgery, and one hour after surgery. Spinal anesthesia and a prophylactic phenylephrine infusion were administered according to a standard treatment protocol. Statistical analysis used the Wilcoxon Signed Rank test with Bonferroni's correction for multiple comparisons. RESULTS: Blood pressure was maintained within 20% of baseline throughout surgery. The baseline mean (range) ScO2 was 61.5% (54.0-66.3%). It decreased significantly at all subsequent measurement points. The maximum decrease was five minutes after spinal anesthesia. Thirty-four (64.2%) of the parturients exhibited ScO2 values <20% of baseline, or a decrease to below an absolute value of 50%. There was no significant correlation between systolic blood pressure and mean ScO2. CONCLUSION: Spinal anesthesia with phenylephrine infusion during cesarean delivery is associated with a significant decrease in ScO2 levels, maximal five minutes later. Further studies are required to establish the clinical significance of this finding. PMID- 30482720 TI - Prophylactic infusion of phenylephrine is effective in attenuating the decrease in regional cerebral blood volume and oxygenation during spinal anesthesia for cesarean section. AB - BACKGROUND: Hypotension induced by spinal anesthesia for cesarean section causes a decrease in maternal regional cerebral blood volume and oxygenation. We used near-infrared spectroscopy to determine whether prophylactic infusion of phenylephrine attenuates these decreases. METHODS: Sixty patients undergoing bupivacaine spinal anesthesia for cesarean section were randomly divided into one of three intravenous infusion groups: saline (P0), phenylephrine 25 (P25) or 50 ug/min (P50). Mean arterial pressure, heart rate and near-infrared spectroscopy measurements were made at one-minute intervals for 20 minutes, and oxyhemoglobin, deoxy-hemoglobin and total-hemoglobin concentrations and tissue oxygenation index were determined. Mean changes in the values between baseline and each measurement time after intrathecal injection were compared. RESULTS: Significant decreases in mean arterial pressure were seen in group P0 compared to P25 and P50 (P <0.01). Heart rate decreased in a dose-dependent manner during phenylephrine infusion (P0 vs. P25 and P50, P25 vs. P50; P <0.05). Significantly higher total-hemoglobin levels were observed in the phenylephrine groups versus the P0 group (P <0.01). The largest decrease in tissue oxygenation index was found in the P50, followed by P0 and P25 groups (P0 vs. P25 and P50, P25 vs. P50; P <0.05). CONCLUSION: Prophylactic infusion of phenylephrine, especially at 25 ug/min, can effectively suppress decreases in regional cerebral blood volume and regional cerebral blood oxygenation after induction of spinal anesthesia for cesarean section. PMID- 30482721 TI - Anaesthetic implications of a patient with cold-induced anaphylaxis presenting to the labour ward. AB - Cold contact urticaria is a well described condition, with reactions ranging from localised wheals to systemic and anaphylactic reactions. Case reports involving anaesthetic care are rare. This report describes a patient with cold-induced urticaria with systemic reactions who had been advised to carry an adrenaline autoinjector. She presented to the labour ward out-of-hours and in established labour requesting epidural analgesia. She subsequently had an uneventful instrumental delivery following an epidural 'top-up'. This report focuses on the anaesthetic implications of her condition. PMID- 30482722 TI - Organotypic microfluidic breast cancer model reveals starvation-induced spatial temporal metabolic adaptations. AB - BACKGROUND: Ductal carcinoma in situ (DCIS) is the earliest stage of breast cancer. During DCIS, tumor cells remain inside the mammary duct, growing under a microenvironment characterized by hypoxia, nutrient starvation, and waste product accumulation; this harsh microenvironment promotes genomic instability and eventually cell invasion. However, there is a lack of biomarkers to predict what patients will transition to a more invasive tumor or how DCIS cells manage to survive in this harsh microenvironment. METHODS: In this work, we have developed a microfluidic model that recapitulates the DCIS microenvironment. In the microdevice, a DCIS model cell line was grown inside a luminal mammary duct model, embedded in a 3D hydrogel with mammary fibroblasts. Cell behavior was monitored by confocal microscopy and optical metabolic imaging. Additionally, metabolite profile was studied by NMR whereas gene expression was analyzed by RT qPCR. FINDINGS: DCIS cell metabolism led to hypoxia and nutrient starvation; revealing an altered metabolism focused on glycolysis and other hypoxia associated pathways. In response to this starvation and hypoxia, DCIS cells modified the expression of multiple genes, and a gradient of different metabolic phenotypes was observed across the mammary duct model. These genetic changes observed in the model were in good agreement with patient genomic profiles; identifying multiple compounds targeting the affected pathways. In this context, the hypoxia-activated prodrug tirapazamine selectively destroyed hypoxic DCIS cells. INTERPRETATION: The results showed the capacity of the microfluidic model to mimic the DCIS structure, identifying multiple cellular adaptations to endure the hypoxia and nutrient starvation generated within the mammary duct. These findings may suggest new potential therapeutic directions to treat DCIS. In summary, given the lack of in vitro models to study DCIS, this microfluidic device holds great potential to find new DCIS predictors and therapies and translate them to the clinic. PMID- 30482723 TI - Circulating miRNAs as footprints for liver fibrosis grading in schistosomiasis. AB - BACKGROUND: Chronic infection with Schistosoma japonicum or S. mansoni results in hepatic fibrosis of the human host. Staging fibrosis is crucial for the prognosis and to determine the rapid need of treatment in patients with schistosomiasis. METHODS: To establish whether there is a correlation between circulating microRNA (miRNA) level and fibrosis progression in schistosomiasis, ten miRNAs were selected to assess their potential in grading schistosomiasis liver fibrosis. This was done firstly in two mouse strains (C57BL/6 and BALB/c) to determine the temporal expression profiles in serum over the course of S. japonicum infection, and then within a cohort of 163 schistosomiasis japonica patients with different grades of liver fibrosis. FINDING: Four miRNAs (miR-150-5p, let-7a-5p, let-7d-5p and miR-146a-5p) were able to distinguish patients with mild versus severe fibrosis. The level of serum miR-150-5p showed the most promising potential for grading hepatic fibrosis in schistosomiasis. The diagnostic performance of miR 150-5p in discriminating mild from severe fibrosis is comparable with that of the ELF test and serum HA level. In addition, the serum levels of the four miRNAs rebounded in infected C57BL/6 mice, after 6 months post treatment, following the regression of liver fibrosis, thereby providing further support for the utility of these miRNAs in grading schistosomal hepatic fibrosis. INTERPRETATION: Circulating miRNAs can be a supplementary tool for assessing hepatic fibrosis in human schistosomiasis. FUND: National Health and Medical Research Council (NHMRC) of Australia (APP1102926, APP1037304 and APP1098244). PMID- 30482724 TI - Calling in the test: Smartphone-based urinary sepsis diagnostics. PMID- 30482725 TI - Small-sized follicles could contribute to high-order multiple pregnancies: outcomes of 6552 intrauterine insemination cycles. AB - RESEARCH QUESTION: Can predictors of twin and high-order multiple pregnancy among women with multiple cycles of ovarian stimulation intrauterine insemination (IUI) be identified? DESIGN: Retrospective cohort study of IUI cycles carried out between January 2014 and December 2015 in a private clinic in Spain. The 4879 women and 6552 cycles analysed in this study include single IUI with ovarian stimulation using recombinant FSH. RESULTS: Number of follicles and follicle size were the only factors with a significant effect (P < 0.001) on the likelihood of achieving a twin or multifetal pregnancy. Follicles 12 mm or wider greatly increase the chances of achieving a twin or multifetal pregnancy. A total of 73 out of 127 (57.5%) twin pregnancies occurred in cycles with at least one additional follicle measuring 12 mm or wider, and 102 out of 127 twin pregnancies (80.3%) occurred in cycles with at least one additional follicle measuring 14 mm or wider. Cancellation criteria should consider the presence of follicles 12 mm or wider. CONCLUSION: Follicles measuring 12 mm or wider increase the risk of having a twin or a high-order multiple pregnancy rate. These data may help clinicians balance decision-making between cancelling and performing the cycle within an IUI procedure. PMID- 30482726 TI - Management of Localized Breast Angiosarcoma by North American Radiation and Medical Oncologists. AB - INTRODUCTION: Primary breast angiosarcoma is a rare malignancy with no clinical trials to guide management. The current use of surgery, chemotherapy, and radiotherapy among North American oncologists is unknown. PATIENTS AND METHODS: An institutional review board-approved anonymous electronic survey was distributed to 9660 practicing North American radiation and medical oncologists. Questions pertained to treatment recommendations for localized nonmetastatic primary breast angiosarcoma, as well as knowledge/use of beta-blockers in angiosarcoma. The Fisher exact test was used to compare responses of medical and radiation oncologists. RESULTS: Surgery was recommended by 95% of all respondents. Chemotherapy was recommended by over half of medical and radiation oncologists. Radiotherapy was recommended by 92% of radiation and 56% of medical oncologists. The most common treatment recommendation was a trimodal treatment, with up-front surgery followed by adjuvant chemotherapy, then by adjuvant radiotherapy. Twenty-two percent of respondents were aware of clinical data pertaining to the use of beta-blockers in management of angiosarcoma, and among these respondents 69% were comfortable incorporating this treatment into standard practice. CONCLUSION: Trimodal management of primary localized breast angiosarcoma is supported by North American radiation and medical oncologists, with the majority recommending up-front surgery followed by adjuvant chemotherapy and radiation. The recently published reports of successful use of beta-blockers are not yet known among North American clinicians, but there is a great enthusiasm to incorporate these commonly prescribed medications into standard practice. These findings may greatly influence the standard of care for breast angiosarcoma treatment, particularly given the absence of Level I-supported evidence. PMID- 30482728 TI - Intradomain Interactions in an NMDA Receptor Fragment Mediate N-Glycan Processing and Conformational Sampling. AB - The structural and functional roles of highly conserved asparagine-linked (N) glycans on the extracellular ligand-binding domain (LBD) of the N-methyl-D aspartate receptors are poorly understood. We applied solution- and computation based methods that identified N-glycan-mediated intradomain and interglycan interactions. Nuclear magnetic resonance (NMR) spectra of the GluN1 LBD showed clear signals corresponding to each of the three N-glycans and indicated the reducing end of glycans at N440 and N771 potentially contacted nearby amino acids. Molecular dynamics simulations identified contacts between nearby amino acids and the N440- and N771-glycans that were consistent with the NMR spectra. The distal portions of the N771-glycan also contacted the core residues of the nearby N471-glycan. This result was consistent with mass spectrometry data indicating the limited N471-glycan core fucosylation and reduced branch processing of the N771-glycan could be explained by interglycan contacts. We discuss a potential role for the GluN1 LBD N-glycans in interdomain contacts formed in NMDA receptors. PMID- 30482727 TI - High Conformational Variability in the GluK2 Kainate Receptor Ligand-Binding Domain. AB - The kainate family of ionotropic glutamate receptors (iGluRs) mediates pre- and postsynaptic neurotransmission. Previously computed conformational potentials of mean force (PMFs) for iGluR ligand-binding domains (LBDs) revealed subtype dependent conformational differences between alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) iGluR subfamilies. Here we report PMFs for the kainate receptor GluK2 in apo and glutamate-bound states. Apo and glutamate-bound GluK2 LBDs preferentially access closed-cleft conformations. Apo GluK2 exhibits a surprisingly high degree of conformational flexibility, accessing open and closed states. Comparing across iGluR subtypes, these results are similar to glycine-binding GluN1 and GluN3A NMDA subunits and differ from glutamate-binding GluA2 and GluN2A subunits. To test the contribution of cross-lobe interactions on closed-cleft LBD stability, we computed PMFs for two GluK2 mutants, D462A and D656S. D462A, but not D656S, weakens closed-cleft conformations of the glutamate-bound LBD. Theoretical Boltzmann-weighted small-angle X-ray scattering profiles improve agreement with experimental results compared with calculations from the LBD crystal structure alone. PMID- 30482729 TI - Structures of Ebola and Reston Virus VP35 Oligomerization Domains and Comparative Biophysical Characterization in All Ebolavirus Species. AB - The multifunctional virion protein 35 (VP35) of ebolaviruses is a critical determinant of virulence and pathogenesis indispensable for viral replication and host innate immune evasion. Essential for VP35 function is homo-oligomerization via a coiled-coil motif. Here we report crystal structures of VP35 oligomerization domains from the prototypic Ebola virus (EBOV) and the non pathogenic Reston virus (RESTV), together with a comparative biophysical characterization of the domains from all known species of the Ebolavirus genus. EBOV and RESTV VP35 oligomerization domains form bipartite parallel helix bundles with a canonical coiled coil in the N-terminal half and increased plasticity in the highly conserved C-terminal half. The domain assembles into trimers and tetramers in EBOV, whereas it exclusively forms tetramers in all other ebolavirus species. Substitution of coiled-coil leucine residues critical for immune antagonism leads to aberrant oligomerization. A conserved arginine involved in inter-chain salt bridges stabilizes the VP35 oligomerization domain and modulates between coiled-coil oligomeric states. PMID- 30482730 TI - The Effect of Medical Consultation on Patients' Concerns Regarding Vaginal Mesh Use in Pelvic Reconstructive Surgery. AB - OBJECTIVE: This study sought to determine patients' background knowledge and attitudes towards the use of mesh in pelvic floor reconstructive surgery (PFRS) and the effect of medical consultation on their knowledge and attitudes about mesh use. METHODS: New urogynecology patients seen for pelvic organ prolapse and/or stress urinary incontinence were asked to complete pre-consultation questionnaires involving 12 questions on demographics and knowledge, attitudes, and concerns about the use of vaginal mesh. If PFRS was discussed, a post consultation questionnaire was administered. RESULTS: A total of 202 new patients were surveyed. Of these patients, 73.8% had heard of vaginal mesh, and most of this information came from a media source followed by their health care provider. A total of 102 of 202 patients completed both the pre- and post-consultation questionnaire. Before medical consultation, patients' "level of concern" on a Likert scale (1 = not at all concerned, 10 = very concerned) was 5.98 +/- 3.04. After consultation, the level of concern decreased significantly to 4.25 +/- 2.68 (P = 0.00005). Before consultation, 33.3% of patients stated that they would be willing to proceed with surgery using mesh; however, after receiving standardized information on vaginal mesh risks and complications on the basis of the most current information available, 62.8% stated that they would be willing to proceed with mesh if required (P = 0.00001). CONCLUSION: Almost 75% of patients presenting for urogynecologic consultation had heard of vaginal mesh use, and 55.7% cited the media as their source of information. Medical consultation significantly reduced the patients' level of concern regarding the use of mesh in PFRS and significantly increased the proportion of patients willing to have mesh placed if appropriate. PMID- 30482732 TI - Individualized epilepsy management: Medicines, surgery, and beyond. PMID- 30482731 TI - Differential Prognostic Value of Galectin-3 According to Carbohydrate Antigen 125 Levels in Transcatheter Aortic Valve Implantation. AB - INTRODUCTION AND OBJECTIVES: Galectin-3 (Gal-3) and carbohydrate antigen 125 (CA125) have been associated with adverse outcomes after transcatheter aortic valve implantation (TAVI). Experimental data have suggested a potential molecular interaction. Therefore, we assessed the association of Gal-3 and CA125 with prognosis after TAVI. METHODS: A total of 439 patients were enrolled. The primary endpoint was a composite of all-cause mortality or readmission for worsening heart failure after TAVI. RESULTS: The primary endpoint occurred in 16.4%. Gal-3 was dichotomized at >= 8.71 ng/mL into elevated and not elevated. Gal-3 was elevated in 31.9% and was associated with a higher risk of the primary endpoint (25% vs 12.4%, HR, 2.26; P<.001). After multivariable adjustment, the association of elevated Gal-3 with the primary endpoint was borderline significant (HR, 1.59; P=.068). CA125 was dichotomized at >= 18.4 U/mL, accordingly. CA125 was elevated in 51.9% and was also associated with a higher risk of the primary endpoint (25.4% vs 6.6%, HR, 4.20; P<.001). After multivariable adjustment, elevated CA125 (HR, 2.83; P=.001) remained independently associated with the primary endpoint. A differential prognostic effect of Gal-3 was found across CA125 status (P for interaction=.048). Elevated Gal-3 was associated with a higher risk of the primary endpoint when CA125 was elevated (38.8% vs 18.2%, HR, 2.02; P=.015) but lacked significance when CA125 was not elevated (6.6% vs 6.7%, HR, 1.16; P=.981). CONCLUSIONS: In patients undergoing TAVI, Gal-3 predicted adverse clinical outcomes only when CA125 was elevated. PMID- 30482733 TI - Establishing Nonprofit Status for an Interventional Radiology Student Interest Group. PMID- 30482735 TI - Your Mother Is Ill. PMID- 30482734 TI - Achieving Joint Commission Regulatory Compliance: Quality Improvement Process for CT Protocol Review and Dose Alert Reduction. PMID- 30482736 TI - Patient-Centered Outcomes Related to Imaging Testing in US Primary Care. AB - BACKGROUND: Imaging tests are one of the most sophisticated types of diagnostic tools used in health care, yet there are concerns that imaging is overused. Currently, tests are typically evaluated and implemented based on their accuracy, and there is limited knowledge about the range of patient-centered outcomes (PCOs) that imaging tests may lead to. This study explores patients' experiences and subsequent outcomes of imaging tests most notable to patients. METHODS: Adult patients from four primary care clinics who had an x-ray, CT, MRI, or ultrasound in the 12 months before recruitment participated in a single semistructured interview to recount their imaging experience. Interview transcripts were analyzed thematically. RESULTS: Four themes related to PCOs were identified from 45 interviews. Participants' mean age was 53 years (25-83 years), 30 had undergone a diagnostic imaging test, and 15 underwent imaging for screening or monitoring. Themes included knowledge gained from the imaging test, its contribution to their overall health care journey, physical experiences during the test procedure, and impacts of the testing process on emotions. CONCLUSIONS: Patients identified various imaging test outcomes that were important to them. Measurement and reporting these outcomes should be considered more often in diagnostic research. Tools for providers and patients to discuss and utilize these outcomes may help promote shared decision making around the use and impact of imaging tests. PMID- 30482737 TI - CBCT assessment of gubernacular canals in relation to eruption disturbance and pathologic condition associated with impacted/unerupted teeth. AB - OBJECTIVES: The aim of this study was to demonstrate the imaging characteristics of gubernacular canals (GCs) in impacted/unerupted permanent teeth and to determine whether these characteristics differ as a result of the presence of eruption disturbances or pathologic conditions associated with impacted/unerupted teeth. STUDY DESIGN: GCs were retrospectively analyzed by using cone beam computed tomography in 250 patients with 753 impacted/unerupted permanent teeth (105 males, 145 females; mean age, 21.09 +/- 14.45 years; range 6-70 years). RESULTS: The rate of detection of GCs was significantly lower in cases with eruption disturbances than in those without eruption disturbances. An inverse correlation was observed between age and detection of GCs. Similarly, root resorption of adjacent teeth and resorption of impacted/unerupted teeth were associated with lower rates of detection of GCs. However, no association was found for widening of the follicular space. Regression analysis determined disturbed eruption pattern as the most important factor for the absence of GCs. CONCLUSIONS: The absence of GC may indicate a disturbed eruption pattern of the tooth and may increase the risk of complications related to impaction resulting in a tooth that is more likely to remain unerupted. PMID- 30482738 TI - Is infrared thermography effective in the diagnosis of temporomandibular disorders? A systematic review. AB - OBJECTIVE: The aim of this study was to systematically review the scientific efficacy of infrared thermography (IT) on the diagnosis of temporomandibular joint disorders (TMDs). STUDY DESIGN: An electronic search was performed in 8 databases for publications up to May 2018. Additionally, a hand search of the reference lists was conducted. There were no restrictions on language or on year of publication. Two independent reviewers selected the studies, reviewed the abstract information, and assessed the quality. The methodology of the included articles was evaluated by using the QUADAS-2 tool. RESULTS: Nine studies fulfilled the eligibility criteria and were included in the systematic review. Four studies concluded that IT presents low accuracy or is not an accurate instrument for TMD diagnosis, but there was substantial variation in sensitivity, specificity, and receiver operating characteristic curve values. Five studies concluded that IT appears to be promising or may be a complementary diagnostic aid in the evaluation of TMDs. These studies presented sensitivity values ranging from 70% to 90% and specificity values ranging from 62% to 92%. All studies were judged as being "at risk of bias" and as having "concerns regarding applicability." CONCLUSIONS: The literature is still lacking in sufficient number of studies regarding the reliability of IT for the diagnosis of TMDs. PMID- 30482739 TI - A Web-Based Telemanagement System for Improving Disease Activity and Quality of Life in Patients With Complex Inflammatory Bowel Disease: Pilot Randomized Controlled Trial. AB - BACKGROUND: The reported efficacy of telemedicine in patients with inflammatory bowel disease (IBD) is inconsistent among studies, and data for complex IBD are lacking. OBJECTIVE: We aimed to evaluate the impact of remote monitoring using a Web system-Telemonitorizacion de la Enfermedad de Crohn y Colitis Ulcerosa or Telemonitoring of Crohn's Disease and Ulcerative Colitis (TECCU)-as compared to standard care and telephone care on health outcomes and health care in patients with complex IBD. METHODS: We performed a 3-arm randomized controlled trial. Adult patients with IBD who received immunosuppressants and biological agents were recruited from the IBD Unit of a tertiary university hospital. The patients were randomized into groups to receive remote monitoring (G_TECCU), nurse assisted telephone care (G_NT), or standard care with in-person visits (G_control). All patients completed the study visits at baseline and at 12 and 24 weeks in addition to each type of intervention. The primary outcome was the percentage of patients in remission at 24 weeks. Secondary health outcomes were quality of life, medication adherence, adverse effects, satisfaction, and social activities. Data on the number of outpatient visits and telephone calls, emergency visits, hospitalizations, IBD-related surgeries, and corticosteroid courses were also collected. RESULTS: A total of 63 patients were selected (21 patients in each group). During the study, 90.5% (19/21) of patients in G_control, 95.2% (20/21) in G_NT, and 85.7% (18/21) in G_TECCU were compliant to the intervention. After 24 weeks, the percentage of patients in remission was higher in G_TECCU (17/21, 81%) than in G_NT (14/21, 66.7%) and G_control (15/21, 71.4%). A higher improvement in disease activity was observed in G_TECCU than in G_control in terms of the Harvey-Bradshaw/Mayo (odds ratio=0.12, 95% CI=0.003 2.162, P=.19) and Harvey-Bradshaw/Walmsley (odds ratio=0.11, 95% CI=0.004-1.55, P=.13) indexes. Improvement in disease activity was associated with a larger reduction in fecal calprotectin values in G_TECCU compared to G_control (estimated intervention effect: odds ratio=-0.90; 95% CI=-1.96 to 0.16, P=.11). All completers adhered to treatment in G_TECCU. In addition, the quality of life, social activities, and satisfaction improved in all 3 groups. Although the number of outpatient visits and telephone calls was lower in G_TECCU than in G_NT and G_control, the safety profile was similar in all 3 groups. CONCLUSIONS: This pilot clinical trial suggests that the TECCU Web-based system is a safe strategy for improving health outcomes in patients with complex IBD and reducing the use of health care resources. TRIAL REGISTRATION: ClinicalTrials.gov NCT02943538; https://clinicaltrials.gov/ct2/show/NCT02943538 (Archived by WebCite at http://www.webcitation.org/746CRRtDN). PMID- 30482740 TI - A Rapid Process for Identifying and Prioritizing Technology-Based Tools for Health System Implementation. AB - BACKGROUND: Health system decisions to put new technologies into clinical practice require a rapid and trustworthy decision-making process informed by best evidence. OBJECTIVE: This study aimed to present a rapid evidence review process that can be used to inform health system leaders and clinicians seeking to implement new technology tools to improve patient-clinician decision making and patient-oriented outcomes. METHODS: The rapid evidence review process we pioneered involved 5 sequential subprocesses: (1) environmental scan, (2) expert panel recruitment, (3) host evidence review panel, (4) analysis, and (5) local validation panel. We conducted an environmental scan of health information technology (IT) literature to identify relevant digital tools in oncology care. We synthesized the recent literature using current evidence review methods, creating visual summaries for use by a national panel of experts. Panelists were taken through a 6-hour modified Delphi process to prioritize tools for implementation. Findings from the rapid evidence review panel were taken to a local validation panel for further rapid review during a 3-hour session. RESULTS: Our rapid evidence review process shows promise for informing decision making by reducing the amount of time and resources needed to identify and prioritize adoption of IT tools. Despite evidence of improved patient outcomes, panelists had substantial concerns about implementing patient-reported outcome tracking tools, voicing concerns about liability, lack of familiarity with new technology, and additional time and workflow changes such tools would require. Instead, clinicians favored technologies that did not require clinician involvement. CONCLUSIONS: Health system leaders can use the rapid evidence review process presented here to usefully inform local technology adoption, implementation, and use in practice. PMID- 30482741 TI - Predictive Modeling of 30-Day Emergency Hospital Transport of Patients Using a Personal Emergency Response System: Prognostic Retrospective Study. AB - BACKGROUND: Telehealth programs have been successful in reducing 30-day readmissions and emergency department visits. However, such programs often focus on the costliest patients with multiple morbidities and last for only 30 to 60 days postdischarge. Inexpensive monitoring of elderly patients via a personal emergency response system (PERS) to identify those at high risk for emergency hospital transport could be used to target interventions and prevent avoidable use of costly readmissions and emergency department visits after 30 to 60 days of telehealth use. OBJECTIVE: The objectives of this study were to (1) develop and validate a predictive model of 30-day emergency hospital transport based on PERS data; and (2) compare the model's predictions with clinical outcomes derived from the electronic health record (EHR). METHODS: We used deidentified medical alert pattern data from 290,434 subscribers to a PERS service to build a gradient tree boosting-based predictive model of 30-day hospital transport, which included predictors derived from subscriber demographics, self-reported medical conditions, caregiver network information, and up to 2 years of retrospective PERS medical alert data. We evaluated the model's performance on an independent validation cohort (n=289,426). We linked EHR and PERS records for 1815 patients from a home health care program to compare PERS-based risk scores with rates of emergency encounters as recorded in the EHR. RESULTS: In the validation cohort, 2.22% (6411/289,426) of patients had 1 or more emergency transports in 30 days. The performance of the predictive model of emergency hospital transport, as evaluated by the area under the receiver operating characteristic curve, was 0.779 (95% CI 0.774-0.785). Among the top 1% of predicted high-risk patients, 25.5% had 1 or more emergency hospital transports in the next 30 days. Comparison with clinical outcomes from the EHR showed 3.9 times more emergency encounters among predicted high-risk patients than low-risk patients in the year following the prediction date. CONCLUSIONS: Patient data collected remotely via PERS can be used to reliably predict 30-day emergency hospital transport. Clinical observations from the EHR showed that predicted high-risk patients had nearly four times higher rates of emergency encounters than did low-risk patients. Health care providers could benefit from our validated predictive model by targeting timely preventive interventions to high-risk patients. This could lead to overall improved patient experience, higher quality of care, and more efficient resource utilization. PMID- 30482742 TI - A Mobile App for the Self-Report of Psychological Well-Being During Pregnancy (BrightSelf): Qualitative Design Study. AB - BACKGROUND: Maternal mental health impacts both parental well-being and childhood development. In the United Kingdom, 15% of women are affected by depression during pregnancy or within 1 year of giving birth. Suicide is a leading cause of perinatal maternal mortality, and it is estimated that >50% of perinatal depression cases go undiagnosed. Mobile technologies are potentially valuable tools for the early recognition of depressive symptoms, but complex design challenges must be addressed to enable their use in public health screening. OBJECTIVE: The aim of this study was to explore the issues and challenges surrounding the use of mobile phones for the self-report of psychological well being during pregnancy. METHODS: This paper presents design research carried out as part of the development of BrightSelf, a mobile app for the self-report of psychological well-being during pregnancy. Design sessions were carried out with 38 participants, including pregnant women, mothers, midwives, and other health professionals. Overall, 19 hours of audio were fully transcribed and used as the basis of thematic analysis. RESULTS: The study highlighted anxieties concerning the pregnancy journey, challenges surrounding current approaches to the appraisal of well-being in perinatal care, and the midwife-patient relationship. Designers should consider the framing of perinatal mental health technologies, the experience of self-report, supporting self-awareness and disclosure, providing value to users through both self-report and supplementary features, and designing for longitudinal engagement. CONCLUSIONS: This study highlights the needs, motivations, and anxieties of women with respect to technology use in pregnancy and implications for the design of mobile health technologies. PMID- 30482744 TI - How Self-Directed e-Learning Contributes to Training for Medical Licentiate Practitioners in Zambia: Evaluation of the Pilot Phase of a Mixed-Methods Study. AB - BACKGROUND: Zambia faces a severe shortage of health workers, particularly in rural areas. To tackle this shortage, the Medical Licentiate program was initiated at Chainama College of Health Sciences in the capital, Lusaka, in 2002. The objective of the program was to alleviate the shortage of human resources in curative care. On-the-job training is conducted in decentralized teaching hospitals throughout Zambia. However, the program faces significant challenges such as shortages of senior medical instructors and learning materials. OBJECTIVE: Our aim was to address these challenges by introducing a self directed, e-learning platform with an offline tablet as part of a collaborative blended-learning intervention to supplement local teaching and training. METHODS: The pilot phase of the e-learning platform was evaluated using a mixed-methods approach with a convergent parallel design. Various methods were employed to test the data's adequacy and potential for generating valid results. Methods included questionnaires according to the technology acceptance model and information system success model by DeLone and McLean, semistructured interviews, learner diaries, pretesting, the collection of usage data, exam results, demographics, and informal feedback. Outcome measures included usage, adoption, efficiency, acceptance, user-friendliness, and gained knowledge and skills. RESULTS: In total, 52 students and 17 medical instructors participated in the pilot evaluation. The questionnaire results showed a high acceptance of the technology (>80%) and high agreement (>75%) with the e-learning platform. Semistructured interview results showed an overall appreciation of the e-learning intervention, but the need for more e-learning materials. Respondents identified a need for multimedia materials that transfer skills such as medical procedure visualization and interactive exercises to practice procedural knowledge. The learning diaries identified the lack of specific learning materials and potential shortcomings of existing learning materials. However, students were satisfied with the current e learning content. The majority of students used the e-learning platform offline on their tablets; online e-learning was underutilized. CONCLUSIONS: The pilot phase of the tablet-based e-learning platform to support the self-directed learning intervention was well received and appreciated by students and medical instructors of Chainama College of Health Sciences. E-learning for knowledge acquisition appears to be adequate and feasible for this low-resource educational environment. Our evaluation results guide the further development of the full implementation of the e-learning platform in this educational setting. E-learning materials should reflect curriculum requirements, and additional multimedia and interactive content is needed, as well as improved integration and active participation from medical instructors in the e-learning processes. PMID- 30482745 TI - BATF3-dependent genes control tumor rejection induced by dendritic cells independently of cross-presentation. AB - The BATF3-dependent cDC1 lineage of conventional dendritic cells (cDCs) is required for rejection of immunogenic sarcomas and for rejection of progressive sarcomas during checkpoint blockade therapy. One unique function of the cDC1 lineage is the efficient cross-presentation of tumor-derived neoantigens to CD8+ T cells, but it is not clear that this is the only unique function of cDC1 required for tumor rejection. We previously showed that BATF3 functions during cDC1 lineage commitment to maintain IRF8 expression in the specified cDC1 progenitor. However, since cDC1 progenitors do not develop into mature cDC1s in Batf3-/- mice, it is still unclear whether BATF3 has additional functions in mature cDC1 cells. A transgenic Irf8-Venus reporter allele increases IRF8 protein concentration sufficiently to allow autonomous cDC1 development in spleens of Batf3-/- mice. These restored Batf3-/- cDC1s are transcriptionally similar to control wild-type cDC1s, but have reduced expression of a restricted set of cDC1 specific genes. Restored Batf3-/- cDC1s are able to cross-present cell-associated antigens both in vitro and in vivo. However, Batf3-/- cDC1 exhibit altered characteristics in vivo and are unable to mediate tumor rejection. These results show that BATF3, in addition to regulating Irf8 expression to stabilize cDC1 lineage commitment, also controls expression of a small set of genes required for cDC1-mediated tumor rejection. These BATF3-regulated genes may be useful targets in immunotherapies aimed at promoting tumor rejection. PMID- 30482743 TI - Feasibility of Using a Commercial Fitness Tracker as an Adjunct to Family-Based Weight Management Treatment: Pilot Randomized Trial. AB - BACKGROUND: Fitness trackers can engage users through automated self-monitoring of physical activity. Studies evaluating the utility of fitness trackers are limited among adolescents, who are often difficult to engage in weight management treatment and are heavy technology users. OBJECTIVE: We conducted a pilot randomized trial to describe the impact of providing adolescents and caregivers with fitness trackers as an adjunct to treatment in a tertiary care weight management clinic on adolescent fitness tracker satisfaction, fitness tracker utilization patterns, and physical activity levels. METHODS: Adolescents were randomized to 1 of 2 groups (adolescent or dyad) at their initial weight management clinic visit. Adolescents received a fitness tracker and counseling around activity data in addition to standard treatment. A caregiver of adolescents in the dyad group also received a fitness tracker. Satisfaction with the fitness tracker, fitness tracker utilization patterns, and physical activity patterns were evaluated over 3 months. RESULTS: A total of 88 adolescents were enrolled, with 69% (61/88) being female, 36% (32/88) black, 23% (20/88) Hispanic, and 63% (55/88) with severe obesity. Most adolescents reported that the fitness tracker was helping them meet their healthy lifestyle goals (69%) and be more motivated to achieve a healthy weight (66%). Despite this, 68% discontinued use of the fitness tracker by the end of the study. There were no significant differences between the adolescent and the dyad group in outcomes, but adolescents in the dyad group were 12.2 times more likely to discontinue using their fitness tracker if their caregiver also discontinued use of their fitness tracker (95% CI 2.4-61.6). Compared with adolescents who discontinued use of the fitness tracker during the study, adolescents who continued to use the fitness tracker recorded a higher number of daily steps in months 2 and 3 of the study (mean 5760 vs 4148 in month 2, P=.005, and mean 5942 vs 3487 in month 3, P=.002). CONCLUSIONS: Despite high levels of satisfaction with the fitness trackers, fitness tracker discontinuation rates were high, especially among adolescents whose caregivers also discontinued use of their fitness tracker. More studies are needed to determine how to sustain the use of fitness trackers among adolescents with obesity and engage caregivers in adolescent weight management interventions. PMID- 30482747 TI - Cuba begins pulling 8300 doctors out of Brazil following Bolsonaro's comments. PMID- 30482746 TI - Leveraging TCR affinity in adoptive immunotherapy against shared tumor/self antigens. AB - Adoptive cellular therapy (ACT) using T-cell receptor (TCR)-engineered lymphocytes holds promise for eradication of disseminated tumors, but also an inherent risk of pathologic autoimmunity if targeted antigens or antigenic mimics are expressed by normal tissues. We evaluated whether modulating TCR affinity could allow CD8+ T cells to control tumor outgrowth without inducing concomitant autoimmunity in a preclinical murine model of ACT. RIP-mOVA mice express a membrane-bound form of chicken ovalbumin (mOVA) as a self-antigen in kidney and pancreas. Such mice were implanted with OVA-expressing ID8 ovarian carcinoma cells and subsequently treated with CD8+ T lymphocytes (CTLs) expressing either a high-affinity (OT-I) or low-affinity (OT-3) OVA-specific TCR. The effects on tumor growth versus organ-specific autoimmunity were subsequently monitored. High affinity OT-I CTLs underwent activation and proliferation in both tumor-draining and pancreatic lymph nodes, leading to both rapid eradication of ID8-OVA tumors and autoimmune diabetes in all treated mice. Remarkably, the low-affinity OT-3 T cells were only activated by tumor-derived antigen and mediated transient regression of ID8-OVA tumors without concomitant autoimmunity. The OT-3 cells eventually upregulated inhibitory receptors PD-1, TIM-3, and LAG-3 and became functionally unresponsive, however, allowing the tumors in treated mice to reestablish progressive growth. Antibody-mediated blockade of the inhibitory receptors prevented exhaustion and allowed tumor clearance, but these mice also developed autoimmune diabetes. The findings reveal that low-affinity TCRs can mediate tumor regression and that functional avidity can discriminate between tumor-derived and endogenous antigen, while highlighting the risks involved in immune checkpoint blockade on endogenous self-reactive T cells. PMID- 30482748 TI - Confidentiality has limits in domestic abuse cases. PMID- 30482750 TI - FDA recommends "modernizing" review of devices in wake of global investigation. PMID- 30482751 TI - Disease-modifying therapies for multiple sclerosis. PMID- 30482749 TI - Diagnostic routes and time intervals for patients with colorectal cancer in 10 international jurisdictions; findings from a cross-sectional study from the International Cancer Benchmarking Partnership (ICBP). AB - OBJECTIVE: International differences in colorectal cancer (CRC) survival and stage at diagnosis have been reported previously. They may be linked to differences in time intervals and routes to diagnosis. The International Cancer Benchmarking Partnership Module 4 (ICBP M4) reports the first international comparison of routes to diagnosis for patients with CRC and the time intervals from symptom onset until the start of treatment. Data came from patients in 10 jurisdictions across six countries (Canada, the UK, Norway, Sweden, Denmark and Australia). DESIGN: Patients with CRC were identified via cancer registries. Data on symptomatic and screened patients were collected; questionnaire data from patients' primary care physicians and specialists, as well as information from treatment records or databases, supplemented patient data from the questionnaires. Routes to diagnosis and the key time intervals were described, as were between-jurisdiction differences in time intervals, using quantile regression. PARTICIPANTS: A total of 14 664 eligible patients with CRC diagnosed between 2013 and 2015 were identified, of which 2866 were included in the analyses. PRIMARY AND SECONDARY OUTCOME MEASURES: Interval lengths in days (primary), reported patient symptoms (secondary). RESULTS: The main route to diagnosis for patients was symptomatic presentation and the most commonly reported symptom was 'bleeding/blood in stool'. The median intervals between jurisdictions ranged from: 21 to 49 days (patient); 0 to 12 days (primary care); 27 to 76 days (diagnostic); and 77 to 168 days (total, from first symptom to treatment start). Including screen-detected cases did not significantly alter the overall results. CONCLUSION: ICBP M4 demonstrates important differences in time intervals between 10 jurisdictions internationally. The differences may justify efforts to reduce intervals in some jurisdictions. PMID- 30482752 TI - Government cuts to NHS drug services. PMID- 30482754 TI - David Oliver: Top healthcare words of 2018. PMID- 30482753 TI - What should GPs stop doing? PMID- 30482755 TI - Serum Uromodulin Predicts Less Coronary Artery Calcification and Diabetic Kidney Disease Over 12 years in Adults With Type 1 Diabetes: The CACTI Study. AB - OBJECTIVE: Novel biomarkers are needed to better predict coronary artery calcification (CAC), a marker of subclinical atherosclerosis, and diabetic kidney disease (DKD) in type 1 diabetes. We evaluated the associations between serum uromodulin (SUMOD [a biomarker associated with anti-inflammatory and renal protective properties]), CAC progression and DKD development over 12 years. RESEARCH DESIGN AND METHODS: Participants (n = 527, 53% females) in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study were examined during 2002 2004, at a mean age of 39.6 +/- 9.0 years and a median duration of diabetes of 24.8 years. Urine albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) determined by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation were measured at baseline and after a mean follow-up period of 12.1 +/- 1.5 years. Elevated albumin excretion was defined as ACR >=30 mg/g, rapid GFR decline (>3 mL/min/1.73 m2/year), and impaired GFR as eGFR <60 mL/min/1.73 m2. SUMOD was measured on stored baseline plasma samples (Meso Scale Diagnostics). CAC was measured using electron beam computed tomography. CAC progression was defined as a change in the square root transformed CAC volume of >=2.5. RESULTS: Higher baseline SUMOD level conferred lower odds of CAC progression (odds ratio 0.68; 95% CI 0.48-0.97) per 1 SD increase in SUMOD (68.44 ng/mL), incident elevated albumin excretion (0.37; 0.16 0.86), rapid GFR decline (0.56, 0.35-0.91), and impaired GFR (0.44; 0.24-0.83) after adjustment for baseline age, sex, systolic blood pressure, LDL, albuminuria/GFR. The addition of SUMOD to models with traditional risk factors also significantly improved the prediction performance for CAC progression and incident DKD. CONCLUSIONS: Higher baseline SUMOD level predicted lower odds of both CAC progression and incident DKD over 12 years in adults with type 1 diabetes. PMID- 30482756 TI - A common molecular logic determines embryonic stem cell self-renewal and reprogramming. AB - During differentiation and reprogramming, new cell identities are generated by reconfiguration of gene regulatory networks. Here, we combined automated formal reasoning with experimentation to expose the logic of network activation during induction of naive pluripotency. We find that a Boolean network architecture defined for maintenance of naive state embryonic stem cells (ESC) also explains transcription factor behaviour and potency during resetting from primed pluripotency. Computationally identified gene activation trajectories were experimentally substantiated at single-cell resolution by RT-qPCR Contingency of factor availability explains the counterintuitive observation that Klf2, which is dispensable for ESC maintenance, is required during resetting. We tested 124 predictions formulated by the dynamic network, finding a predictive accuracy of 77.4%. Finally, we show that this network explains and predicts experimental observations of somatic cell reprogramming. We conclude that a common deterministic program of gene regulation is sufficient to govern maintenance and induction of naive pluripotency. The tools exemplified here could be broadly applied to delineate dynamic networks underlying cell fate transitions. PMID- 30482757 TI - Public prescription drug plan coverage for antiretrovirals and the potential cost to people living with HIV in Canada: a descriptive study. AB - BACKGROUND: Antiretrovirals are expensive and people living with HIV may experience a range of financial burdens when accessing these medications. Our aim was to describe the policy of all Canadian public drug insurance programs for antiretroviral drugs and illustrated how these policies might affect patients' annual out-of-pocket expenditures. METHODS: In December 2017, we reviewed public drug programs offering antiretroviral coverage in Canada using government websites to summarize eligibility criteria. We estimated the annual out-of-pocket costs incurred by people living with HIV by applying the cost-sharing rules to 2 hypothetical cases, a single man and a married woman with a net household income of $39 000 and $80 000, respectively, receiving identical prescriptions in different jurisdictions. RESULTS: We observed substantial variation in the subsidy provided based mainly on geography, income and age. All 5 federal programs and 6 of 13 provincial and territorial jurisdictions offered universal coverage. In the remaining regions, patients spend up to several thousand dollars annually depending on income (Manitoba), age and income (Ontario, Saskatchewan) and age, income and drug costs (Quebec and Newfoundland and Labrador). We found the greatest variation for our higher income case, with out-of-pocket expenses ranging from 0 to over 50% of the antiretroviral cost. INTERPRETATION: There is considerable inter- and intra-jurisdiction heterogeneity in the cost-sharing policies for antiretrovirals across Canada's public drug programs. Policy reforms that either eliminate or set national standards for copayments, deductibles or premiums would minimize variation and could reduce the risk of cost-associated non-adherence to HIV therapy. PMID- 30482759 TI - Patients in Wales wait longest out of 10 regions to begin bowel cancer treatment. PMID- 30482758 TI - Readmission following hypoxic ischemic brain injury: a population-based cohort study. AB - BACKGROUND: Readmission to acute care is common and is associated with indicators of suboptimal care and health system inefficiencies. The objective of this study was to identify independent determinants of readmission following survival of hypoxic ischemic brain injury. METHODS: We conducted a population-based retrospective cohort study using Ontario's administrative health data. Survivors of hypoxic ischemic brain injury aged 20 years or more discharged from acute care between fiscal years 2002/03 and 2010/11 were included. Multivariable negative binomial regression was used to identify independent determinants of both number of readmissions and cumulative duration of hospital stay(s) within 1 year after the index discharge. RESULTS: Of the 593 patients with hypoxic ischemic brain injury, 233 (39.3%) were readmitted within 1 year of the index acute care discharge. The number of readmissions was associated with age (35-49 yr v. 65-79 yr: rate ratio [RR] 0.57, 95% confidence interval [CI] 0.38-0.85; >= 80 yr v. 65 79 yr: RR 0.58, 95% CI 0.34-0.97) and higher comorbidity score (Johns Hopkins Aggregated Diagnosis Groups score > 30 v. < 10: RR 1.60, 95% CI 1.11-2.31). Cumulative readmission stay was associated with increased index acute care length of stay (31-90 d v. >= 90 d: RR 4.17, 95% CI 1.38-12.64), prior use of health care services (minimal v. very high: RR 0.15, 95% CI 0.05-0.49) and discharge disposition (home v. continuing/long-term care: RR 0.44, 95% CI 0.21-0.91). INTERPRETATION: The findings indicate a high readmission rate in the first year after the index acute care admission for survivors of hypoxic ischemic brain injury, reflecting care gaps and system inefficiencies. This suggests that bolstered discharge and home care planning and support are needed to address the specific needs of those with hypoxic ischemic brain injury. PMID- 30482761 TI - Comment on model-based meta-analysis to evaluate optimal doses of direct oral factor Xa inhibitors in atrial fibrillation patients. PMID- 30482760 TI - IL-15/IL-15Ralpha/CD80-expressing AML cell vaccines eradicate minimal residual disease in leukemic mice. AB - Engineered autologous acute myeloid leukemia (AML) cells present multiple leukemia-associated and patient-specific antigens and as such hold promise as immunotherapeutic vaccines. However, prior vaccines have not reliably induced effective antileukemic immunity, in part because AML blasts have immune inhibitory effects and lack expression of the critical costimulatory molecule CD80. To enhance induction of leukemia-specific cytolytic activity, 32Dp210 murine AML cells were engineered to express either CD80 alone, or the immunostimulatory cytokine interleukin-15 (IL-15) with its receptor alpha (IL 15Ralpha), or heterodimeric IL-15/IL-15Ralpha together with CD80 and tested as irradiated cell vaccines. IL-15 is a gammac-chain cytokine, with unique properties suited to stimulating antitumor immunity, including stimulation of both natural killer and CD8+ memory T cells. Coexpression of IL-15 and IL 15Ralpha markedly increases IL-15 stability and secretion. Non-tumor-bearing mice vaccinated with irradiated 32Dp210-IL-15/IL-15Ralpha/CD80 and challenged with 32Dp210 leukemia had greater survival than did mice treated with 32Dp210-CD80 or 32Dp210-IL-15/IL-15Ralpha vaccines, whereas no unvaccinated mice inoculated with leukemia survived. In mice with established leukemia, treatment with 32Dp210-IL 15/IL-15Ralpha/CD80 vaccination stimulated unprecedented antileukemic immunity enabling 80% survival, an effect that was abrogated by anti-CD8 antibody-mediated depletion in vivo. Because, clinically, AML vaccines are administered as postremission therapy, we established a novel model in which mice with high leukemic burdens were treated with cytotoxic therapy to induce remission (<5% marrow blasts). Postremission vaccination with 32Dp210-IL-15/IL-15Ralpha/CD80 achieved 50% overall survival in these mice, whereas all unvaccinated mice achieving remission subsequently relapsed. These studies demonstrate that combined expression of IL-15/IL-15Ralpha and CD80 by syngeneic AML vaccines stimulates effective and long-lasting antileukemic immunity. PMID- 30482762 TI - The value of clinical practice guidelines in hematology. PMID- 30482763 TI - American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. AB - BACKGROUND: Venous thromboembolism (VTE) is the third most common vascular disease. Medical inpatients, long-term care residents, persons with minor injuries, and long-distance travelers are at increased risk. OBJECTIVE: These evidence-based guidelines from the American Society of Hematology (ASH) intend to support patients, clinicians, and others in decisions about preventing VTE in these groups. METHODS: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and adult patients. The Grading of Recommendations Assessment, Development and Evaluation approach was used to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 19 recommendations for acutely ill and critically ill medical inpatients, people in long-term care facilities, outpatients with minor injuries, and long-distance travelers. CONCLUSIONS: Strong recommendations included provision of pharmacological VTE prophylaxis in acutely or critically ill inpatients at acceptable bleeding risk, use of mechanical prophylaxis when bleeding risk is unacceptable, against the use of direct oral anticoagulants during hospitalization, and against extending pharmacological prophylaxis after hospital discharge. Conditional recommendations included not to use VTE prophylaxis routinely in long-term care patients or outpatients with minor VTE risk factors. The panel conditionally recommended use of graduated compression stockings or low-molecular-weight heparin in long-distance travelers only if they are at high risk for VTE. PMID- 30482764 TI - American Society of Hematology 2018 guidelines for management of venous thromboembolism: diagnosis of venous thromboembolism. AB - BACKGROUND: Modern diagnostic strategies for venous thromboembolism (VTE) incorporate pretest probability (PTP; prevalence) assessment. The ability of diagnostic tests to correctly identify or exclude VTE is influenced by VTE prevalence and test accuracy characteristics. OBJECTIVE: These evidence-based guidelines are intended to support patients, clinicians, and health care professionals in VTE diagnosis. Diagnostic strategies were evaluated for pulmonary embolism (PE), deep vein thrombosis (DVT) of the lower and upper extremity, and recurrent VTE. METHODS: The American Society of Hematology (ASH) formed a multidisciplinary panel including patient representatives. The McMaster University GRADE Centre completed systematic reviews up to 1 October 2017. The panel prioritized questions and outcomes and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess evidence and make recommendations. Test accuracy estimates and VTE population prevalence were used to model expected outcomes in diagnostic pathways. Where modeling was not feasible, management and accuracy studies were used to formulate recommendations. RESULTS: Ten recommendations are presented, by PTP for patients with suspected PE and lower extremity DVT, and for recurrent VTE and upper extremity DVT. CONCLUSIONS: For patients at low (unlikely) VTE risk, using D-dimer as the initial test reduces the need for diagnostic imaging. For patients at high (likely) VTE risk, imaging is warranted. For PE diagnosis, ventilation-perfusion scanning and computed tomography pulmonary angiography are the most validated tests, whereas lower or upper extremity DVT diagnosis uses ultrasonography. Research is needed on new diagnostic modalities and to validate clinical decision rules for patients with suspected recurrent VTE. PMID- 30482766 TI - American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism. AB - BACKGROUND: Despite an increasing incidence of venous thromboembolism (VTE) in pediatric patients in tertiary care settings, relatively few pediatric physicians have experience with antithrombotic interventions. OBJECTIVE: These guidelines of the American Society of Hematology (ASH), based on the best available evidence, are intended to support patients, clinicians, and other health care professionals in their decisions about management of pediatric VTE. METHODS: ASH formed a multidisciplinary guideline panel that included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews (up to April of 2017). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 30 recommendations, covering symptomatic and asymptomatic deep vein thrombosis, with specific focus on management of central venous access device-associated VTE. The panel also addressed renal and portal vein thrombosis, cerebral sino venous thrombosis, and homozygous protein C deficiency. CONCLUSIONS: Although the panel offered many recommendations, additional research is required. Priorities include understanding the natural history of asymptomatic thrombosis, determining subgroup boundaries that enable risk stratification of children for escalation of treatment, and appropriate study of newer anticoagulant agents in children. PMID- 30482769 TI - No free rides: management of toxicities of novel immunotherapies in ALL, including financial. AB - Therapeutic options for acute lymphoblastic leukemia, especially in the relapsed/refractory setting, have expanded significantly in recent times. However, this comes at the cost of toxicities: medical as well as financial. We highlight some of the unique toxicities associated with the novel agents to apprise our readers about what to expect, how to recognize them, and how to manage these toxicities. One of the toxicities seen with inotuzumab, a CD22 antibody drug conjugate, is sinusoidal obstruction syndrome, which can be fatal in >80% of patients if associated with multiorgan failure. Blinatumomab, a monoclonal antibody targeting CD19, is associated with cytokine release syndrome (CRS) and neurotoxicity, both of which require prompt recognition and management primarily with corticosteroids. CRS and neurotoxicity are more common and more severe with chimeric antigen receptor T-cell therapy (CAR-T). The fact that CAR-T cannot be discontinued on demand adds a layer of complexity to the management of related toxicities of this therapy. Tocilizumab, an interleukin-6 receptor blocker, is used to treat severe CRS from CAR-T, whereas corticosteroids remain the mainstay for neurotoxicity management. Although effective, these drugs carry a high price tag, and we review the available data on cost-effectiveness of these agents, keeping in mind that median follow-up on most of these studies is limited and that long-term data on durability of response remain to be seen. PMID- 30482772 TI - STING promotes homeostasis via regulation of cell proliferation and chromosomal stability. AB - Given the integral role of Stimulator of interferon genes (STING, TMEM173) in the innate immune response, its loss or impairment in cancer is thought to primarily affect antitumor immunity. Here we demonstrate a role for STING in the maintenance of cellular homeostasis through regulation of the cell cycle. Depletion of STING in human and murine cancer cells and tumors resulted in increased proliferation compared to wild-type controls. Microarray analysis revealed genes involved in cell cycle regulation are differentially expressed in STINGko compared to WT MEFs. STING-mediated regulation of the cell cycle converged on NF-kappaB- and p53-driven activation of p21. The absence of STING led to premature activation of cyclin-dependent kinase 1 (CDK1), early onset S phase and mitosis, and increased chromosome instability, which was enhanced by ionizing radiation (IR). These results suggest a pivotal role for STING in maintaining cellular homeostasis and response to genotoxic stress. PMID- 30482770 TI - Clinical consequences of clonal hematopoiesis of indeterminate potential. AB - Clonally restricted hematopoiesis is a common aging-associated biological state that predisposes to subsequent development of a hematological malignancy or cardiovascular death. Clonal expansion driven by leukemia-associated somatic mutations, such as DNMT3A, ASXL1, or TET2, is best characterized, but oligoclonality can also emerge without recognized leukemia-driver mutations, perhaps as a result of stochastic neutral drift. Murine models provide compelling evidence that a major mechanism of increased cardiovascular mortality in the context of clonal hematopoiesis is accelerated atherogenesis driven by inflammasome-mediated endothelial injury, resulting from proinflammatory interactions between endothelium and macrophages derived from circulating clonal monocytes. Altered inflammation likely influences other biological processes as well. The rate of development of overt neoplasia in patients with clonal hematopoiesis of indeterminate potential (CHIP), as currently defined, is 0.5% to 1% per year. Contributing factors to clonal progression other than acquisition of secondary mutations in hematopoietic cells (ie, stronger leukemia drivers) are incompletely understood. Disordered endogenous immunity in the context of increased proliferative pressure, short telomeres leading to chromosomal instability, an unhealthy marrow microenvironment that favors expansion of clonal stem cells and acquisition of new mutations while failing to support healthy hematopoiesis, and aging-associated changes in hematopoietic stem cells, including altered DNA damage response, an altered transcriptional program, and consequences of epigenetic alterations, are all potential contributors to clonal progression. Clinical management of patients with CHIP includes monitoring for hematological changes and reduction of modifiable cardiovascular risk factors; eventually, it will also likely include anti-inflammatory therapies and targeted approaches to prune emergent dangerous clones. PMID- 30482768 TI - American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. AB - BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction mediated by platelet-activating antibodies that target complexes of platelet factor 4 and heparin. Patients are at markedly increased risk of thromboembolism. OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about diagnosis and management of HIT. METHODS: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 33 recommendations. The recommendations address screening of asymptomatic patients for HIT, diagnosis and initial management of patients with suspected HIT, treatment of acute HIT, and special situations in patients with acute HIT or a history of HIT, including cardiovascular surgery, percutaneous cardiovascular intervention, renal replacement therapy, and venous thromboembolism prophylaxis. CONCLUSIONS: Strong recommendations include use of the 4Ts score rather than a gestalt approach for estimating the pretest probability of HIT and avoidance of HIT laboratory testing and empiric treatment of HIT in patients with a low-probability 4Ts score. Conditional recommendations include the choice among non-heparin anticoagulants (argatroban, bivalirudin, danaparoid, fondaparinux, direct oral anticoagulants) for treatment of acute HIT. PMID- 30482765 TI - American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. AB - BACKGROUND: Clinicians confront numerous practical issues in optimizing the use of anticoagulants to treat venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians and other health care professionals in their decisions about the use of anticoagulants in the management of VTE. These guidelines assume the choice of anticoagulant has already been made. METHODS: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 25 recommendations and 2 good practice statements to optimize management of patients receiving anticoagulants. CONCLUSIONS: Strong recommendations included using patient self-management of international normalized ratio (INR) with home point-of-care INR monitoring for vitamin K antagonist therapy and against using periprocedural low-molecular-weight heparin (LMWH) bridging therapy. Conditional recommendations included basing treatment dosing of LMWH on actual body weight, not using anti-factor Xa monitoring to guide LMWH dosing, using specialized anticoagulation management services, and resuming anticoagulation after episodes of life-threatening bleeding. PMID- 30482771 TI - GVHD: biology matters. AB - Acute graft-versus-host disease (GVHD) targets the crypts in the gastrointestinal (GI) tract that are responsible for the self-renewal of the intestinal mucosa. Recent advances in the identification and culture of intestinal stem cells have improved our understanding of the interactions between the microbiome and the immune system (both innate and adaptive) that are key to the pathophysiology of GVHD. The identification of serum biomarkers that best predict long-term GVHD outcomes derive from the GI tract and have focused attention on cellular elements that act as shields against GVHD as well as its targets. These biomarkers have illuminated new mechanisms of crypt biology and provided insights that should prove useful both in the design of clinical trials and as guides to GVHD prevention and treatment. PMID- 30482774 TI - PARPi triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCAness. AB - Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have shown remarkable therapeutic efficacy against BRCA1/2 mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of single-stranded DNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring BRCA1/2 mutations. Here we show that PARPi mediated modulation of the immune response contributes to their therapeutic effects independently of BRCA1/2 mutations. PARPi promoted accumulation of cytosolic DNA fragments due to unresolved DNA lesions, which in turn activated the DNA sensing cGAS-STING pathway and stimulated production of type I interferons to induce antitumor immunity independent of BRCAness. These effects of PARPi were further enhanced by immune checkpoint blockade. Overall, these results provide a mechanistic rationale for using PARPi as immunomodulatory agents to harness the therapeutic efficacy of immune checkpoint blockade. PMID- 30482773 TI - Super-enhancer-associated long non-coding RNA HCCL5 is activated by ZEB1 and promotes the malignancy of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most dominant causes of neoplasm related deaths worldwide. In this study, we identify and characterize HCCL5, a novel cytoplasmic lncRNA, as a crucial oncogene in HCC. HCCL5 promoted cell growth, G1/S transition, invasion, and metastasis while inhibiting apoptosis of HCC cells both in vitro and in vivo. Moreover, HCCL5 was upregulated in TGF-beta1 induced classical epithelial-mesenchymal transition (EMT) models, and this lncRNA in turn accelerated the EMT phenotype by upregulating the expression of transcription factors Snail, Slug, ZEB1, and Twist1. HCCL5 was transcriptionally driven by ZEB1 via a super-enhancer and was significantly and frequently overexpressed in human HCC tissues, correlating with worse overall survival of HCC patients. Together, this study characterizes HCCL5 as a super-enhancer-driven lncRNA promoting HCC cell viability, migration, and EMT. Our data also suggest that HCCL5 may serve as a novel prognostic biomarker and therapeutic target in HCC. PMID- 30482775 TI - Use of a single CAR T cell and several bispecific adapters facilitates eradication of multiple antigenically different solid tumors. AB - Most solid tumors are comprised of multiple clones that express orthogonal antigens, suggesting that novel strategies must be developed in order to adapt CAR T cell therapies to treat heterogeneous solid tumors. Here we utilized a cocktail of low molecular weight bispecific adapters, each comprised of fluorescein linked to a different tumor-specific ligand, to bridge between an anti-fluorescein CAR on the engineered T cell and a unique antigen on the cancer cell. This formation of an immunological synapse between the CAR T cell and cancer cell enabled use of a single anti-fluorescein CAR T cell to eradicate a diversity of antigenically different solid tumors implanted concurrently in NSG mice. Based on these data, we suggest that a carefully designed cocktail of bispecific adapters in combination with anti-fluorescein CAR T cells can overcome tumor antigen escape mechanisms that lead to disease recurrence following many CAR T cell therapies. PMID- 30482767 TI - American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. AB - BACKGROUND: Venous thromboembolism (VTE) complicates ~1.2 of every 1000 deliveries. Despite these low absolute risks, pregnancy-associated VTE is a leading cause of maternal morbidity and mortality. OBJECTIVE: These evidence based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians and others in decisions about the prevention and management of pregnancy-associated VTE. METHODS: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations. RESULTS: The panel agreed on 31 recommendations related to the treatment of VTE and superficial vein thrombosis, diagnosis of VTE, and thrombosis prophylaxis. CONCLUSIONS: There was a strong recommendation for low molecular-weight heparin (LWMH) over unfractionated heparin for acute VTE. Most recommendations were conditional, including those for either twice-per-day or once-per-day LMWH dosing for the treatment of acute VTE and initial outpatient therapy over hospital admission with low-risk acute VTE, as well as against routine anti-factor Xa (FXa) monitoring to guide dosing with LMWH for VTE treatment. There was a strong recommendation (low certainty in evidence) for antepartum anticoagulant prophylaxis with a history of unprovoked or hormonally associated VTE and a conditional recommendation against antepartum anticoagulant prophylaxis with prior VTE associated with a resolved nonhormonal provoking risk factor. PMID- 30482776 TI - Ribosomal lesions promote oncogenic mutagenesis. AB - Ribosomopathies are congenital disorders caused by mutations in ribosomal proteins (RP) or assembly factors and are characterized by cellular hypo proliferation at an early stage. Paradoxically, many of these disorders have an elevated risk to progress to hyper-proliferative cancer at a later stage. Additionally, somatic RP mutations have recently been identified in various cancer types e.g. the recurrent RPL10-R98S mutation in T-cell acute lymphoblastic leukemia (T-ALL) and RPS15 mutations in chronic lymphocytic leukemia (CLL). We previously showed that RPL10-R98S promotes expression of oncogenes but also induces a proliferative defect due to elevated oxidative stress. In this study, we demonstrate that this proliferation defect is eventually rescued by RPL10-R98S mouse lymphoid cells that acquire 5-fold more secondary mutations than RPL10-WT cells. The presence of RPL10-R98S and other RP mutations also correlated with a higher mutational load in T-ALL patients, with an enrichment in NOTCH1-activating lesions. RPL10-R98S-associated cellular oxidative stress promoted DNA damage and impaired cell growth. Expression of NOTCH1 eliminated these phenotypes in RPL10 R98S cells, in part via downregulation of PKC-theta, with no effect on RPL10-WT cells. RP-mutant CLL patients also demonstrated a higher mutational burden, enriched for mutations that may diminish oxidative stress. We propose that oxidative stress due to ribosome dysfunction causes hypo-proliferation and cellular insufficiency in ribosomopathies and RP-mutant cancer. This drives surviving cells, potentiated by genomic instability, to acquire rescuing mutations which ultimately promote transition to hyper-proliferation. PMID- 30482778 TI - Tumor-contacted Neutrophils Promote Metastasis by a CD90-TIMP-1 Juxtacrine Paracrine Loop. AB - PURPOSE: The different prognostic values of tumor-infiltrating neutrophils (TINs) in different tissue compartments are unknown. In this study, we investigated their different prognostic roles and the underlying mechanism. EXPERIMENTAL DESIGN: We evaluated CD66b+ neutrophils in primary tumors from 341 breast cancer patients from Sun Yat-Sen Memorial Hospital by immunohistochemistry. The association between stromal and parenchymal neutrophil counts and clinical outcomes was assessed in training set (170 samples), validated in internal validation set (171 samples), and further confirmed in external validation set (105 samples). In addition, we isolated TINs from clinical samples and screened the cytokine profile by antibody microarray. The interaction between neutrophils and tumor cells was investigated in transwell and 3D-matrigel co-culture systems. The therapeutic potential of indicated cytokines was evaluated in tumor-bearing immunocompetent mice. RESULTS: We observed neutrophils in tumor parenchyma, rather than those in stroma, was an independent poor prognostic factor in training (95%CI HR=2.88-8.68, p<0.001), internal validation (95%CI HR=2.07-6.14, p<0.001) and external validation set (95%CI HR=2.27-11.33, p<0.001). The mechanistic study revealed that neutrophils induced breast cancer epithelial mesenchymal transition (EMT) via TIMP-1. Reciprocally, breast cancer cells undergoing EMT enhanced neutrophils TIMP-1 secretion by CD90 in a cell-contact manner. In vivo, TIMP-1 neutralization or CD90 blockade significantly reduced metastasis. More importantly, TIMP-1 and CD90 were positively correlated in breast cancer (r2=0.6079, p<0.001) and associated with poor prognosis of patients. CONCLUSIONS: Our findings unravel a location-dictated interaction between tumor cells and neutrophils and provide a rationale for new anti metastasis treatments. PMID- 30482777 TI - Variability of outcome measures in trials of intravenous therapy in acute severe paediatric asthma: a systematic review. AB - OBJECTIVE: To determine the variability of primary and secondary outcomes used in trials of intravenous bronchodilators in children with acute severe paediatric asthma. METHODS: Systematic search of MEDLINE, EMBASE, Cochrane CENTRAL and the WHO International Clinical Trials Registry Platform for randomised trials in children (less than18 years) with acute severe paediatric asthma comparing intravenous bronchodilator therapy to another treatment. Initial search was performed on 7 January 2016 with an updated search performed on 6 September 2018. Primary and secondary outcomes were collated. RESULTS: We identified 35 published papers and four registered study protocols. 56 primary outcomes were found, the most common being a clinical asthma score (23/56; 41%). Other identified primary outcomes included bedside tests of respiratory function (11/56; 20%) and measures of length of stay (9/56; 16%). There were a total of 60 different secondary outcomes, the most common were various length of stay measures (24/60; 40%) and adverse events (11/60; 18%). CONCLUSION: Studies comparing intravenous treatment modalities for children with acute severe paediatric asthma exhibit great variation in the type, number and timing of outcome measures used. There are no patient or family-specific outcomes reported. There is a need to develop international consensus. TRIAL REGISTRATION NUMBER: CRD42017055331. PMID- 30482780 TI - Rebuilding the excitement of surgery: five minutes with . . . Michael Griffins. PMID- 30482779 TI - Serum miRNA-based prediction of axillary lymph node metastasis in breast cancer. AB - PURPOSE: Sentinel lymph node biopsy (SLNB) is the gold-standard procedure for evaluating axillary lymph node (ALN) status in patients with breast cancer. However, the morbidity of SLNB is not negligible, and the procedure is invasive for patients without ALN metastasis. Here, we developed a diagnostic model for evaluating ALN status using a combination of serum microRNAs (miRNAs) and clinicopathological factors as a novel less-invasive biomarker. EXPERIMENTAL DESIGN: Pre-operative serum samples were collected from patients who underwent surgery for primary breast cancer or breast benign diseases between 2008 and 2014. A total of 958 serum samples (921 cases of primary breast cancer, including 630 cases in the no ALN metastasis group and 291 cases in the ALN metastasis group, and 37 patients with benign breast diseases) were analyzed by miRNA microarray. Samples were randomly divided into training and test sets. Logistic LASSO regression analysis was used to construct diagnostic models in the training set, which were validated in the test set. RESULTS: An optimal diagnostic model was identified using a combination of two miRNAs (miR-629-3p and miR-4710) and three clinicopathological factors (T stage, lymphovascular invasion, and ultrasound findings), which showed a sensitivity of 0.88 (0.84-0.92), a specificity of 0.69 (0.61-0.76), an accuracy of 0.818, and an area under the receiver operating characteristic curve of 0.86 in the test set. CONCLUSIONS: Serum miRNA profiles may be useful for the diagnosis of ALN metastasis before surgery in a less-invasive manner than SLNB. PMID- 30482781 TI - Movement for Movement: a practical insight into embedding physical activity into the undergraduate medical curriculum exemplified by Lancaster Medical School. PMID- 30482782 TI - Clinical research and the AMSSM Collaborative Research Network. PMID- 30482783 TI - When Parents Have Misunderstandings About the Risks and Benefits of Palliative Surgery. AB - When a child needs surgery, both the surgeon and the anesthesiologist must obtain informed consent from the parents. In theory, each specialist obtains permission for their respective portion of the procedure, with the anesthesiologist only obtaining informed consent for the administration of anesthesia and management in the operating room and recovery room. However, he or she may occasionally realize that the parents have misunderstandings about what the surgery and perioperative course entail. In such cases, he or she must decide whether their role is only to discuss the issues related to anesthesia care or whether he or she should also clarify the range of expected outcomes and the postoperative course after surgery. We present a case in which such a dilemma arose and on which we sought experts in anesthesia and ethics to comment. PMID- 30482784 TI - Transition to immediate open access publishing under Plan S will be smooth, promise backers. PMID- 30482785 TI - Air pollution and cognition. PMID- 30482786 TI - Tau accumulation in clinically normal older adults is associated with hippocampal hyperactivity. AB - Animal studies demonstrate that hyperactive neurons facilitate early accumulation and spread of tau and amyloid-beta proteins in the pathological cascade of Alzheimer's disease (AD). Human neuroimaging studies have linked hippocampal hyperactivity to amyloid-beta accumulation, apolipoprotein epsilon4 (APOE4) and clinical progression from prodromal AD to clinical dementia. The relationship between hippocampal hyperactivity and early AD molecular pathology (amyloid-beta and tau accumulation) prior to clinical symptoms remains to be elucidated. Here, we studied 120 clinically normal older humans (80 females/40 males) enrolled in the Harvard Aging Brain Study. We measured functional magnetic resonance imaging (fMRI) activity during successful memory encoding and amyloid-beta accumulation with PiB-PET imaging. Additionally, we measured tau accumulation using AV1451 PET imaging in a subset of 87 participants. In this subset, we found that inferior temporal tau accumulation was associated with increased fMRI activity in the hippocampus, but showed no clear association with amyloid. Together, the findings support a hypothetical model of the evolution of preclinical AD that place hippocampal hyperactivity concurrent with spread of tau pathology to neocortical regions prior to clinical impairment.SIGNIFICANCE STATEMENTThe circumstances under which the hippocampus becomes hyperactive in preclinical stages of Alzheimer's disease (AD) have thus far remained elusive. Recent advances in positron emission tomography (PET) tracers now enable in-vivo characterization of amyloid-beta and tau accumulation. Here, we combine amyloid and tau PET with functional magnetic resonance imaging (fMRI) to examine the association between Alzheimer's disease pathology and memory-related brain activity in clinically normal older adults. We found an association between increased hippocampal activity and tau accumulation in the inferior temporal cortex. These data suggest that the pathogenesis of hippocampal hyperactivity occurs concurrent with the spread of tau pathology from the entorhinal cortex to the neocortex, prior to the clinical manifestations of Alzheimer's disease. PMID- 30482787 TI - BZR1 mediates brassinosteroid-induced autophagy and nitrogen starvation tolerance in tomato. AB - Autophagy, an innate cellular destructive mechanism, plays crucial roles in plant development and responses to stress. Although autophagy can be stimulated or suppressed by multiple molecular processes, the role of phytohormone signaling in autophagy is unclear. Here, we demonstrate that the transcripts of autophagy related genes (ATGs) and the formation of autophagosomes are triggered by enhanced levels of brassinosteroid (BR). Furthermore, the BR-activated transcription factor brassinazole resistant 1 (BZR1), a positive regulator of the BR signaling pathway, was involved in BR-induced autophagy. Treatment with BR enhanced the formation of autophagosomes and the transcripts of ATGs in BZR1 overexpressing plants, while the effects of BR were compromised in BZR1-silenced plants. Yeast one-hybrid and chromatin immunoprecipitation coupled with qPCR analysis revealed that BZR1 bound to the promoters of ATG2 and ATG6. BR-induced formation of autophagosomes was decreased in ATG2- and ATG6-silenced plants. Moreover, exogenous application of BR enhanced chlorophyll content and autophagosomes formation, and decreased accumulation of ubiquitinated proteins under nitrogen starvation. Leaf chlorosis and chlorophyll degradation were exacerbated in BZR1-silenced plants and the BR biosynthetic mutant d^im, but alleviated in BZR1- and BZR1-1D-overexpressing plants under nitrogen starvation. Meanwhile, nitrogen starvation-induced ATGs expression and autophagosome formation were compromised in both BZR1-silenced and d^im plants, but increased in BZR1- and BZR1-1D-overexpressing plants. Taken together, our results suggest that BZR1-dependent BR signaling upregulates ATGs expression and autophagosome formation, which plays a critical role in plant response to nitrogen starvation in tomato. PMID- 30482788 TI - The plastidic sugar transporter pSuT influences flowering and affects cold responses. AB - Sucrose is one of the most important types of sugars in plants serving inter alia as a long-distance transport molecule, a carbon and energy storage compound, an osmotically active solute, and fuel for many anabolic reactions. Sucrose biosynthesis and degradation pathways are well known; however, regulation of sucrose intracellular distribution is poorly understood. In particular, the cellular function of chloroplast sucrose reserves and the transporters involved in accumulating these substantial sucrose levels remain uncharacterized. Here, we characterize the plastidic sugar transporter, pSuT, in Arabidopsis thaliana, which belongs to a subfamily of the monosaccharide transporter-like family. Transport analyses with yeast cells expressing a truncated, vacuolar-targeted version of pSuT indicate that both glucose and sucrose act as substrates, and non aqueous fractionation supports a role for pSuT in sucrose export from the chloroplast. The latter process is required for a correct transition from vegetative to reproductive growth and influences inflorescence architecture. Moreover, pSuT activity affects freezing-induced electrolyte release. These data further underline the central function of the chloroplast for plant development and modulation of stress tolerance. PMID- 30482790 TI - Length of Stay and Complications Associated With Febrile Infants <90 Days of Age Hospitalized in the United States, 2000-2012. AB - OBJECTIVES: It is not known how changes in the epidemiology of serious bacterial infection (SBI) and greater availability of rapid viral diagnostic tests have impacted the hospital length of stay (LOS) and associated complications among young infants with suspected SBI. METHODS: We used national administrative data from the Healthcare Cost and Utilization Project Kids' Inpatient Database and other state-specific data to identify febrile infants <90 days of age hospitalized in 2000, 2003, 2006, 2009, and 2012. We used multivariate analysis to determine LOS, risk factors for prolonged LOS, and complications of care among infants with isolated fever or viral respiratory disease, without concomitant serious infection. RESULTS: We identified 44 875 infants. LOS for each clinical group did not change over time in a clinically significant way. Mean LOS was <=2 days for approximately two-thirds of all infants and >=4 days for 11% in each clinical group. Factors associated with longer LOS included age <31 days, critical clinical status, concomitant chronic disease, and the presence of complications (P < .05). We identified 289 (0.8%) infants with 351 complications of care, 18 (6%) of whom had >1. These infants had longer LOS (P < .001), and those with chronic disease and older age were at increased risk (P < .01). CONCLUSIONS: Despite the changing epidemiology of SBI and increased availability of viral diagnostic testing, we did not detect a clinically significant change in LOS for febrile infants with suspected SBI. Complications associated with hospitalization of these infants was associated with increased LOS. PMID- 30482791 TI - Length of Stay and Complications Associated With Febrile Infants <90 Days of Age Hospitalized in the United States, 2000-2012: A Commentary. PMID- 30482792 TI - Phosphofructokinase controls the acetaldehyde induced phase shift in isolated yeast glycolytic oscillators. AB - The response of oscillatory systems to external perturbations is crucial for emergent properties such as synchronization and phase locking, and can be quantified in a phase response curve. In individual, oscillating yeast cells, we characterized experimentally the phase response of glycolytic oscillations for external acetaldehyde pulses, and followed the transduction of the perturbation through the system. Subsequently, we analyzed the control of the relevant system components in a detailed mechanistic model. The observed responses are interpreted in terms of the functional coupling and regulation in the reaction network. We find that our model quantitatively predicts the phase dependent phase shift observed in the experimental data. The phase shift is in agreement with an adaptation leading to synchronization with an external signal. Our model analysis establishes that phosphofructokinase plays a key role in the phase shift dynamics as shown in the phase response curve, and adaptation time to external perturbations. Specific mechanism-based interventions, made possible through such analyses of detailed models, can improve upon standard trial and error methods, e.g. melatonin supplementation to overcome jet-lag, which are error prone, specifically, since the effects are phase and dose dependent. PMID- 30482793 TI - BCAS2 is essential for hematopoietic stem and progenitor cell maintenance during zebrafish embryogenesis. AB - Hematopoietic stem and progenitor cells (HSPCs) originate from the hemogenic endothelium via the endothelial-to-hematopoietic transition, are self-renewing, and replenish all lineages of blood cells throughout life. BCAS2 (breast carcinoma amplified sequence 2) is a component of the spliceosome and is involved in multiple biological processes. However, its role in hematopoiesis remains unknown. We established a bcas2 knockout zebrafish model by using transcription activator-like effector nucleases (TALENs). The bcas2-/- zebrafish showed severe impairment of HSPCs and their derivatives during definitive hematopoiesis. We also observed significant signs of HSPC apoptosis in the CHT of bcas2-/- zebrafish, which may be rescued by suppression of p53. Furthermore, we show that the bcas2 deletion induces an abnormal alternative splicing of Mdm4 that predisposes cells to undergo p53-mediated apoptosis, providing a mechanistic explanation of the deficiency observed in HSPC. Our findings revealed a novel and vital role for BCAS2 during HSPC maintenance in zebrafish. PMID- 30482794 TI - Molecular mechanisms of Carfilzomib-induced cardiotoxicity in mice and the emerging cardioprotective role of Metformin. AB - Carfilzomib (Cfz), an irreversible proteasome inhibitor licensed for relapsed/refractory myeloma, is associated with cardiotoxicity in humans. We sought to establish the optimal protocol of Cfz-induced cardiac dysfunction, to investigate the underlying molecular-signaling and based on the findings, to evaluate the cardioprotective potency of Metformin (Met). Mice were randomized into: Protocols 1 and 2 (Control and Cfz for 1 and 2 consecutive days, respectively); Protocols 3 and 4 (Control and alternate doses of Cfz for 6 and 14 days, respectively); Protocols 5 A, B (Control and Cfz, intermittent doses on days 0, 1 and 7, 8 for 13 days); Protocols 6 A, B (pharmacological intervention; Control, Cfz, Cfz+Met and Met for 2 and 6 days, respectively) and Protocol 7 (bortezomib). Cfz was administered at 8 mg/kg(ip) and Met at 140 mg/kg(po). Cfz resulted in significant reduction of proteasomal activity in heart and PBMCs in all protocols except protocols 5. Echocardiography demonstrated that Cfz led to a significant fractional shortening (FS) depression in protocols 2 and 3, a borderline dysfunction in protocols 1 and 4 and had no detrimental effect on protocols 5. Molecular analysis revealed that Cfz inhibited AMPKalpha/mTORC1 pathways derived from increased PP2A activity in Protocol 2, whereas it additionally inhibited PI3K/Akt/eNOS pathway in Protocol 3. Co-administration of Met prevented Cfz-induced FS reduction and restored AMPKalpha phosphorylation and autophagic signaling. Conclusively, Cfz decreased left ventricular function through increased PP2A activity and inhibition of AMPKalpha and its downstream autophagic targets, while Met represents a novel promising intervention against Cfz-induced cardiotoxicity. PMID- 30482789 TI - Dynamic control of endogenous metabolism with combinatorial logic circuits. AB - Controlling gene expression during a bioprocess enables real-time metabolic control, coordinated cellular responses, and staging order-of-operations. Achieving this with small molecule inducers is impractical at scale and dynamic circuits are difficult to design. Here, we show that the same set of sensors can be integrated by different combinatorial logic circuits to vary when genes are turned on and off during growth. Three Escherichia coli sensors that respond to the consumption of feedstock (glucose), dissolved oxygen, and by-product accumulation (acetate) are constructed and optimized. By integrating these sensors, logic circuits implement temporal control over an 18-h period. The circuit outputs are used to regulate endogenous enzymes at the transcriptional and post-translational level using CRISPRi and targeted proteolysis, respectively. As a demonstration, two circuits are designed to control acetate production by matching their dynamics to when endogenous genes are expressed (pta or poxB) and respond by turning off the corresponding gene. This work demonstrates how simple circuits can be implemented to enable customizable dynamic gene regulation. PMID- 30482795 TI - Development of human target validation classification that predicts future clinical efficacy. AB - Fewer new medicines have become available to patients during the last decades. Clinical efficacy failures in late phase development have been identified as a common cause of this decline. Improved ways to ensure early selection of the right drug targets when it comes to efficacy is therefore a highly desirable goal. The aim of this work was to develop a strategy to facilitate selection of novel targets already in the discovery phase which later on in clinical development would demonstrate efficacy. A cross-functional team at AstraZeneca with extensive experience of drug discovery and development participated in several workshops to identify the critical elements that contribute to building human target validation (HTV; the relevance of the target from a human perspective). The elements were consolidated into a ten-point HTV classification system that was ranked from lowest to highest in terms of perceived impact on future clinical efficacy. Using fifty years of legacy research and development (R&D) data the ability of the ten-point HTV classification to predict future clinical efficacy was evaluated. Drug targets were classified as having low, medium or high HTV at the time of candidate drug (CD) selection. Comparing this HTV classification with later clinical development efficacy data showed that HTV classification was highly predictive of future clinical efficacy success. This new strategy for HTV assessment provides a novel approach to early prediction of clinical efficacy and a better understanding of portfolio risk. PMID- 30482796 TI - Left atrial pressure is associated with iatrogenic atrial septal defect after mitral valve clip. AB - OBJECTIVES: Mitral valve (MV) clip procedure requires interatrial trans-septal puncture to access the left atrium (LA). Iatrogenic atrial septal defect (iASD) is not uncommon and may remain for a while. However, haemodynamic and echocardiographic determinants of persistent iASD are not well investigated. We sought to find haemodynamic and echocardiographic determinants of iASD after MV clip. METHODS: A total of 131 patients with grades 3 to 4+ mitral regurgitation who underwent MitraClip and completed invasive haemodynamic measurement, baseline, 1 month and approximately 12 months of transthoracic echocardiography (TTE) follow-up were retrospectively reviewed. RESULTS: TTE at 1 month showed persistent iASD in 57% (1M-iASD). Mean LA pressure after clip was significantly higher in patients with 1M-iASD than patients without 1M-iASD (17+/-6 mm Hg vs 15+/-5 mm Hg, p=0.01). Among patients with 1M-iASD, 24 patients (35%) had persistent iASD at 12 months (12M-iASD). Mean LA pressure after clip was significantly higher in patients with 12M-iASD than patients without 12M-iASD (19+/-6 mm Hg vs 16+/-6 mm Hg, p=0.04). Patients with 12M-iASD did not significantly differ from patients without 12M-iASD in terms of right heart enlargement, estimated systolic pulmonary artery pressure, New York Heart Association functional class and brain natriuretic peptide at 12 months. Logistic regression analysis, however, showed that mean LA pressure after clip was significantly associated with persistent iASD at 12 months in patients with 1M iASD even after adjustment for cardiac index after clip and the prevalence of mitral regurgitation >=3+ at 12 months (OR 1.10 per 1 mm Hg, 95% CI 1.01 to 1.21, p=0.04). CONCLUSIONS: Elevated LA pressure after MV clip was associated with persistent iASD. PMID- 30482797 TI - Myocardial infarction with non-obstructive coronary arteries: a humbling diagnosis in 2018. PMID- 30482798 TI - Medaka Population Genome Structure and Demographic History Described via Genotyping-by-Sequencing. AB - Medaka is a model organism in medicine, genetics, developmental biology and population genetics. Lab stocks composed of more than 100 local wild populations are available for research in these fields. Thus, medaka represents a potentially excellent bioresource for screening disease-risk- and adaptation-related genes in genome-wide association studies. Although the genetic population structure should be known before performing such an analysis, a comprehensive study on the genome wide diversity of wild medaka populations has not been performed. Here, we performed genotyping-by-sequencing (GBS) for 81 and 12 medakas captured from a bioresource and the wild, respectively. Based on the GBS data, we evaluated the genetic population structure and estimated the demographic parameters using an approximate Bayesian computation (ABC) framework. The genome-wide data confirmed that there were substantial differences between local populations and supported our previously proposed hypothesis on medaka dispersal based on mitochondrial genome (mtDNA) data. A new finding was that a local group that was thought to be a hybrid between the northern and the southern Japanese groups was actually an origin of the northern Japanese group. Thus, this paper presents the first population-genomic study of medaka and reveals its population structure and history based on chromosomal genetic diversity. PMID- 30482799 TI - OCMA: Fast, Memory-Efficient Factorization of Prohibitively Large Relationship Matrices. AB - Matrices representing genetic relatedness among individuals (i.e., Genomic Relationship Matrices, GRMs) play a central role in genetic analysis. The eigen decomposition of GRMs (or its alternative that generates fewer top singular values using genotype matrices) is a necessary step for many analyses including estimation of SNP-heritability, Principal Component Analysis (PCA), and genomic prediction. However, the GRMs and genotype matrices provided by modern biobanks are too large to be stored in active memory. To accommodate the current and future "bigger-data", we develop a disk-based tool, Out-of-Core Matrices Analyzer (OCMA), using state-of-the-art computational techniques that can nimbly perform eigen and Singular Value Decomposition (SVD) analyses. By integrating memory mapping (mmap) and the latest matrix factorization libraries, our tool is fast and memory-efficient. To demonstrate the impressive performance of OCMA, we test it on a personal computer. For full eigen-decomposition, it solves an ordinary GRM (N=10,000) in 55 seconds. For SVD, a commonly used faster alternative of full eigen-decomposition in genomic analyses, OCMA solves the top 200 singular values (SVs) in half an hour, top 2,000 SVs in 0.95 hour, and all 5,000 SVs in 1.77 hours based on a very large genotype matrix (N=1,000,000, M=5,000) on the same personal computer. OCMA also supports multi-threading when running in a desktop or HPC cluster. Our OCMA tool can thus alleviate the computing bottleneck of classical analyses on large genomic matrices, and make it possible to scale up current and emerging analytical methods to big genomics data using lightweight computing resources. PMID- 30482800 TI - Dosage Compensation and Gene Expression of the X Chromosome in Sheep. AB - Ohno's hypothesis predicts that the expression of the single X chromosome in males needs compensatory upregulation to balance its dosage with that of the diploid autosomes. Additionally, X chromosome inactivation ensures that quadruple expression of the two X chromosomes is avoided in females. These mechanisms have been actively studied in mice and humans but lag behind in domestic species. Using RNA sequencing data, we analyzed the X chromosome upregulation in sheep fetal tissues from day 135 of gestation under control, over or restricted maternal diets (100%, 140% and 60% of National Research Council Total Digestible Nutrients), and in conceptuses, juvenile, and adult somatic tissues. By computing the mean expression ratio of all X-linked genes to all autosomal genes (X:A), we found that all samples displayed some levels of X chromosome upregulation. The degrees of X upregulation were not significant (P-value = 0.74) between ovine females and males in the same somatic tissues. Brain, however, displayed complete X upregulation. Interestingly, the male and female reproduction-related tissues exhibited divergent X dosage upregulation. Moreover, expression upregulation of the X chromosome in fetal tissues was not affected by maternal diets. Maternal nutrition, however, did change expression levels of several X-linked genes, such as sex determination genes SOX3 and NR0B1 In summary, our results showed that X chromosome upregulation occurred in nearly all sheep somatic tissues analyzed, thus support Ohno's hypothesis in a new species. However, the levels of upregulation differed by different subgroups of genes such as those that are house-keeping and "dosage-sensitive". PMID- 30482801 TI - High Efficiency Targeting of Non-coding Sequences Using CRISPR/Cas9 System in Tilapia. AB - The CRISPR/Cas9 has been successfully applied for disruption of protein coding sequences in a variety of organisms. The majority of the animal genome is actually non-coding sequences, which are key regulators associated with various biological process. In this study, to understand the biological signifi-cance of these sequences, we used one or dual gRNA guided Cas9 nuclease to achieve specific deletion of non-coding sequences including microRNA and 3' untranslated region (UTR) in tilapia, which is an important fish for studying sex determination and evolution. Co-injection of fertilized eggs with single gRNA targeting seed region of miRNA and Cas9 mRNA resulted in indel mutations. Further, co-injection of fertilized eggs with dual gRNAs and Cas9 mRNA led to the removal of the fragment between the two target loci, yielding maximum efficiency of 11%. This highest genomic deletion efficiency was further improved up to 19% using short ssDNA as a donor. The deletions can be transmitted through the germline to the next generation at average efficiency of 8.7%. Cas9-vasa 3'-UTR was used to increase the efficiency of germline transmission of non-coding sequence deletion up to 14.9%. In addition, the 3'-UTR of the vasa gene was successfully deleted by dual gRNAs. Deletion of vasa 3'-UTR resulted in low expression level of vasa mRNA in the gonad when compared with the control. To summarize, the improved CRISPR/Cas9 system provided a powerful platform that can assist to easily generate desirable non-coding sequences mutants in non-model fish tilapia to discovery their functions. PMID- 30482802 TI - An Evaluation of the Glass Vial Hydrolytic Resistance Method. AB - The European Pharmacopeia (Ph. Eur.) hydrolytic resistance method for glass vials is routinely used to screen pharmaceutical glass vial supply. Due to reliance on this method to reduce the risk of glass vial delamination in pharmaceutical drug products, it is important that the sources of method variability be understood and controlled. Several potential sources of variability in the Ph. Eur. alkalinity method have been studied for 3cc glass vials. Method parameters including vial rinsing, fill volume determination, vial covering, autoclave cycle execution, sample hold times, and titration procedure were evaluated in this study. The results of this study indicate the method parameters which require stringent control in order to achieve acceptable method precision and robustness. PMID- 30482803 TI - The relation between the load, duration and steam penetration capacity of a surface steam sterilization process; a case study. AB - BACKGROUND: In practice it is claimed that the characteristics of a load influence a surface steam sterilization process. [Rev#2 Com#1] 'Limited and mainly qualitative' information on this topic has been found in the literature. AIM: To find if a load influences the duration and the related characteristics of a surface steam sterilization process. METHOD: In a case study 30 days of every load monitoring with an objective, quantifying steam penetration test has been performed. This resulted in 98 production processes with load monitoring. The acquired data was analyzed. FINDINGS: A relation is found between the weight of a load and the duration of a surface steam sterilization process. CONCLUSIONS: It is demonstrated in this case study that the heavier a sterilizer load the longer the process will take. Additionally, it is concluded that when the duration of a process is longer, diffusion will have more effect and steam penetration increases. PMID- 30482804 TI - Entrectinib Effective across NTRK Fusion-Positive Cancers. AB - Entrectinib may be an effective therapy for patients with NTRK fusion-positive solid tumors, regardless of tumor type. In a combined analysis of phase I and phase II trials, more than half of patients responded to the drug, with a similar response rate in patients whose cancer had spread to the brain. PMID- 30482805 TI - Lysophospholipases Cooperate to Mediate Lipid Homeostasis and Lysophospholipid Signaling. AB - Lysophospholipids (LysoPL) are bioactive lipid species involved in cellular signaling processes and the regulation of cell membrane structure. LysoPLs are metabolized through the action of lysophospholipases, including lysophospholipase A1 (LYPLA1) and lysophospholipase A2 (LYPLA2). A new X-ray crystal structure of LYPLA2 compared to a previously published structure of LYPLA1 demonstrated near identical folding of the two enzymes; however, LYPLA1 and LYPLA2 have displayed distinct substrate specificities in recombinant enzyme assays. To determine how these in vitro substrate preferences translate into a relevant cellular setting and better understand the enzymes' role in LysoPL metabolism, CRISPR-Cas9 technology was utilized to generate stable knockouts of Lypla1 and/or Lypla2 in neuro2A cells. Using these cellular models in combination with a targeted lipidomics approach, LysoPL levels were quantified and compared between cell lines to determine the effect of losing lysophospholipase activity on lipid metabolism. This work suggests that LYPLA1 and LYPLA2 are each able to account for the loss of the other to maintain lipid homeostasis in cells; however, when both are deleted, LysoPL levels are dramatically increased, causing phenotypic and morphological changes to the cells. PMID- 30482806 TI - The role of X-box binding protein 1 in the hepatic response to refeeding in mice. AB - Refeeding mice after a prolonged fast is a potent stimulus of hepatic lipogenesis but is also associated with induction of the hepatic unfolded protein response (UPR). The X-box binding protein 1 (Xbp1), a key regulator of the adaptive UPR, transcriptionally activates hepatic lipogenesis genes. We therefore determined whether hepatic Xbp1 mediates the hepatic lipogenic response to refeeding. Mice bearing a hepatocyte-specific deletion of Xbp1 and littermate controls were fasted overnight followed by refeeding for up to 6 hours. Among control mice, refeeding induced hepatic expression of activated Xbp1 and, as expected, induced hepatic expression of genes controlling de novo lipogenesis of fatty acids. Unexpectedly, deletion of hepatic Xbp1 allowed for normal induction of hepatic lipogenesis genes yet impaired translation of SREBP1c and its targets in response to refeeding. Impaired protein translation was associated with enhanced postprandial activation of the global translational arrest protein, eIF2alpha, among mice lacking hepatic Xbp1. Deletion of hepatic Xbp1 prevented postprandial induction of genes regulating protein folding and processing and shifted the pattern of postprandial UPR activation to favor pro-apoptotic signals. We conclude that activation of hepatic Xbp1 in the postprandial states serves the dual roles of restoring postprandial hepatic lipogenesis and proteostasis. PMID- 30482808 TI - Heartbeat: The worldwide burden of atrial fibrillation. PMID- 30482807 TI - Profiling and quantification of aminophospholipids based on chemical derivatization coupled with HPLC-MS. AB - In this study, a novel strategy based on acetone stable-isotope derivatization coupled with high performance liquid chromatography-mass spectrometry (HPLC-MS) for profiling and accurate quantification of aminophospholipid (phosphatidylethanilamine (PE) and phosphatidylserine (PS)) in biological samples was developed. Acetone derivatization leads to alkylation of the primary amino groups of aminophospholipid with an isopropyl moiety, the use of deuterium labeled acetone (d6-acetone) introduced a 6 Da mass shift that was ideally suited for profiling and quantification analysis with high selectivity and accuracy. After derivatization, significantly increased column efficiency for chromatographic separation and detection sensitivity for MS analysis of aminophospholipid was observed. Furthermore, an accuracy quantification method was developed. Aminophospholipids in biological samples were derivatized with d0 acetone; while more than two aminophospholipid standards were selected for each class of aminophospholipid and derivatized with d6-acetone, which were then used as the internal standards to typically construct a calibration curve for each class to normalize the non-uniformity response caused by the differential fragmentation kinetics resulting from the distinct chemical constitution of individual aminophospholipid species in the biological samples. Its excellent applicability was validated by profiling and quantification of aminophospholipids presented in liver samples from rats fed with different diets. PMID- 30482809 TI - Time to stop using 'non-valvular AF' inappropriately: letter in response to review article. PMID- 30482810 TI - Response to: 'Current recommendations for anticoagulant therapy in patients with valvular heart disease and atrial fibrillation: the ACC/AHA and ESC/EACTS Guidelines in Harmony...but not Lockstep!' PMID- 30482811 TI - Serum high-sensitive cardiac troponin for the risk assessment of cardiovascular events. PMID- 30482812 TI - Editor's note: global outreach. PMID- 30482813 TI - Inclusion, access and social justice: the rhizomic evolution of a field across a continent. PMID- 30482814 TI - Critical orientations for humanising health sciences education in South Africa. AB - In this article, the authors make a case for the 'humanisation' and 'decolonisation' of health sciences curricula in South Africa, using integration as a guiding framework. Integration refers to an education that is built on a consolidated conceptual framework that includes and equally values the natural or biomedical sciences as well as the humanities, arts and social sciences, respecting that all of this knowledge has value for the practice of healthcare. An integrated curriculum goes beyond add-on or elective courses in the humanities and social sciences. It is a curriculum that includes previously marginalised sources of knowledge (challenging knowledge hierarchies and decolonising curricula); addresses an appropriate intellectual self-image in health sciences education (challenging the image of the health professional); promotes understanding of history and social context, centring issues of inclusion, access and social justice (cultivating a social ethic) and finally, focuses on care and relatedness as an essential aspect of clinical work (embedding relatedness in practice) The article offers a brief historical overview of challenges in health and health sciences education in South Africa since 1994, followed by a discussion of contemporary developments in critical health sciences pedagogies and the medical and health humanities in South Africa. It then draws on examples from South Africa to outline how these four critical orientations or competencies might be applied in practice, to educate health professionals that can meet the challenges of health and healthcare in contemporary South Africa. PMID- 30482815 TI - Biomedicine and the humanities: growing pains. AB - In this article, we discuss the challenges facing humanities researchers approaching studies in clinical and community health settings. This crossing of disciplines has arguably been less often explored in the countries we discuss Kenya, Tanzania and South Africa-but our experiences also speak to broader trouble with disciplinary 'ethnocentrism' that hampers the development of knowledge. After a brief contextualising overview of the structures within our universities that separate or link the humanities, medicine and social science, we use case studies of our experiences as an arts researcher, an anthropologist and a historian to draw attention to the methodological clashes that can hobble research between one disciplinary area and another, whether this manifests in the process of applying for ethical clearance or a professional wariness between healthcare practitioners and humanities scholars in health spaces. We argue overall for the great potential of humanities in the health 'space'-as well as the need for improved dialogue between the disciplines to bring a diverse community of knowledge to bear on our understandings of experiences of health. And we suggest the need for a robust awareness of our own positions in relation to medicine, as humanities scholars, as well as a patient persistence on both sides of the humanities-health science equation to create a broader and ultimately more effective research system. PMID- 30482816 TI - Community engagement with HIV drug adherence in rural South Africa: a transdisciplinary approach. AB - Digital storytelling (DST) is an emerging participatory visual method which combines storytelling traditions with computer and video production technology. In this project, at the heart of the HIV epidemic in KwaZulu-Natal, South Africa, we used DST to create a culturally grounded community engagement intervention. Our aim was to use narratives of people living with HIV on antiretroviral therapy (ART) to stimulate dialogue among the wider community and to encourage reflection on the contextual factors that influence ART adherence in this setting. We also wanted to explore whether exposure to the personal narratives might influence health literacy around HIV and ART. We ran two DST workshops, where 20 community participants were supported to create short digital stories about personal experiences of adherence. We then hosted 151 screenings of the digital stories at seven local health facilities and evaluated the impact of the intervention using a three-tiered mixed methods approach. We conducted two independent quantitative surveys of healthcare users (852 respondents during the preintervention round and 860 people during the postintervention round), five focus group discussions and observation of practice. Exposure to the digital stories did stimulate rich dialogue among community members, which broadened from the focus on ART adherence to other aspects around the impact of HIV and its treatment on individuals and the community. In the independently conducted surveys, we found no clear difference in knowledge or understanding of HIV and ART between the people exposed to the digital stories and those who were not exposed. Our findings provide support for the use of DST as an engagement intervention, but highlight some of the challenges in delivering this type of intervention and in evaluating the impact of this approach. PMID- 30482817 TI - Pharmaceuticals and modern statecraft in South Africa: the cases of opium, thalidomide and contraception. AB - This article provides a history of three pharmaceuticals in the making of modern South Africa. Borrowing and adapting Arthur Daemmrich's term 'pharmacopolitics', we examine how forms of pharmaceutical governance became integral to the creation and institutional practices of this state. Through case studies of three medicaments: opium (late 19th to early 20th century), thalidomide (late 1950s to early 1960s) and contraception (1970s to 2010s), we explore the intertwining of pharmaceutical regulation, provision and consumption. Our focus is on the modernist imperative towards the rationalisation of pharmaceutical oversight, as an extension of the state's bureaucratic and ideological objectives, and, importantly, as its obligation. We also explore adaptive and illicit uses of medicines, both by purveyors of pharmaceuticals, and among consumers. The historical sweep of our study allows for an analysis of continuities and changes in pharmaceutical governance. The focus on South Africa highlights how the concept of pharmacopolitics can usefully be extended to transnational-as well as local-medical histories. Through the diversity of our sources, and the breadth of their chronology, we aim to historicise modern pharmaceutical practices in South Africa, from the late colonial era to the Post-Apartheid present. PMID- 30482818 TI - Reflections on a field across time and space: the emergent medical and health humanities in South Africa. AB - In this paper, we draw on our own cross-cultural experience of engaging with different incarnations of the medical and health humanities (MHH) in the UK and South Africa to reflect on what is distinct and the same about MHH in these locations. MHH spaces, whether departments, programmes or networks, have espoused a common critique of biomedical dualism and reductionism, a celebration of qualitative evidence and the value of visual and performative arts for their research, therapeutic and transformative social potential. However, there have also been differences, and importantly a different 'identity' among some leading South African scholars and practitioners, who have felt that if MHH were to speak from the South as opposed to the North, they would say something quite different. We seek to contextualise our personal reflections on the development of the field in South Africa over recent years within wider debates about MHH in the context of South African academia and practice, drawing in part on interviews conducted by one of the authors with South African researchers and practitioners and our own reflections as 'Northerners' in the 'South'. PMID- 30482819 TI - Walking up hills, through history and in-between disciplines: MHH and Health Sciences Education at the tip of Africa. AB - Celebration, frustration, contestation and imagination all manifest themselves when examining the evolution of the field of Medical and Health Humanities (MHH) at the University of Cape Town (UCT). That this field has been growing at the same time as access to, inclusion in, and social justice issues linked to higher education have come under the spotlight has the potential to shape how we think and plan for the future of the field. Doing this will require treks up hills, journeys through difficult histories and dynamic dances in-between disciplines.This article examines MHH at UCT broadly, referring to projects and programmes that are underway primarily in the humanities and health sciences faculties. From this overview, the article specifically examines the curricula changes introduced in the Faculty of Health Sciences inspired by MHH and the author's interest in historical consciousness. It describes current points of intervention in physiotherapy and MBChB undergraduate curricula; and through short-term special study modules that have allowed those interested in MHH to explore relationships between health and healing and art, music, writing, yoga, PhotoVoice, drama, drawing and complex histories.It discusses some of the challenges of introducing humanities teaching into health sciences curricula; and some of the tensions that result from the meeting of divergent epistemologies and pedagogies. The article considers if, and how, MHH might engage with social (in)justice, and inclusions and exclusions and potentially offer a balm to soothe the bruising effects of oppressive histories and a hegemonically hierarchical present. PMID- 30482820 TI - Representing disability and development in the global south. AB - I reflect on two aesthetics which are at play in the presentation of critical disability and development work in the global south. On the one hand, authors of critical texts commonly use very complex and abstruse language, which may make such texts relatively inaccessible to some disabled people in the global south. On the other hand, the ways in which development work in the south is portrayed sometimes emphasises methods of engagement which may seen to be infantilising. Drawing on my own experience in such engagement activities, I suggest that it is important to understand, and to subvert, dominant forms of representation. PMID- 30482821 TI - Beyond the lab: Eh!woza and knowing tuberculosis. AB - Eh!woza is a public engagement initiative that explores the biomedical and social aspects of tuberculosis (TB) in South Africa. The project is a collaboration between scientists based in an infectious disease research institute, a local conceptual/visual artist, a youth-based educational non-governmental organization (NGO) and young learners from a high-burden TB community. The learners participate in a series of interactive science and media production workshops: initially presented with biomedical knowledge about TB and, in later sessions, are trained in creating documentary films and engage with ideas around visual representation. The participants are encouraged to make use of this newly acquired knowledge to tell stories from their chosen communities in Khayelitsha, a township in Cape Town. Through its engagement with the complex manner in which TB is experienced, framed and understood by biomedical scientists, young people, and those who have been affected by the disease, Eh!woza presents alternative ways of exploring the complexities of human illness. The integration and interrogation of biomedical understandings, lay narratives and the young participants' framing of the disease poses questions about 'knowing', and the meanings people attribute to ways of 'knowing' and the actions they impel. The project also presents contrasting reflections on cure-from a biomedical perspective, and care-from the perspective of TB-affected young people and community members. In this article, we describe the Eh!woza project, present thoughts from the participating students on the science and media workshops, and detail the narratives of ill-health and disease from people within their neighbourhoods. We conclude with a critical analysis of the complexities of knowledge communication, notions of cure versus care, and a consideration of the potential contribution of this project to the growth of medical humanities in Africa. PMID- 30482822 TI - Field notes in the clinic: on medicine, anthropology and pedagogy in South Africa. AB - This commentary is about medicine, anthropology and pedagogy: about the ways of knowing that different disciplinary orientations permit. I draw on a field note taken in the clinic to illustrate how cultures of healthcare and health sciences training in South Africa bracket the historical, social and political contexts of health and illness in this setting, at the expense of patient care and physician wellbeing. I consider what anthropological inquiry can offer to clinical practice, and advocate for critical orientations to clinical work and teaching that extend humanity to patients and providers. PMID- 30482823 TI - Challenging perceptions of disciplinary divide: an ethnographer's experience of collegiality, collaboration and crisis. AB - Warned by social scientists about 'the disciplinary divide' and the hostility of medical professionals to qualitative research, I was pleasantly surprised by the collegiality I experienced while conducting fieldwork among clinician-researchers in South Africa. This commentary is a challenge to common discourse, historically dominant in a global (north) anthropology, that biomedical practitioners are necessarily antagonistic to the humanities. Drawing on my field experiences, I propose an optimistic outlook for collaboration and inclusivity in developing medical and health humanities in Africa. While conducting anthropological fieldwork among doctors producing medical research, I gained access to elite professional spaces, even presenting anthropological work in medical research forums. I established relationships with leading figures in various clinical departments and research institutes. There were, unsurprisingly, times when I had to rigorously defend my methodology. I had to revise my methodological knowledge including on quantitative methods to explain varying epistemologies to both sympathetic and doubtful medical colleagues. But, I was often treated as a fellow researcher, a colleague. Some clinician-researchers accepted me as having different, valuable expertise to analyse human complexity and proposed opportunities for possible collaboration. I argue that these clinicians appreciated this expertise because of their pervasive perceptions of crisis in healthcare and an awareness of the complexities of biomedicine in an African context of social heterogeneity, medical pluralism and legacies of social injustice. These concerns around crisis and complexity may be points of leverage for expanding interdisciplinary collaboration and facilitating access to research sites and research forums. PMID- 30482824 TI - High-Grade Gastrointestinal Neuroendocrine Carcinoma Management and Outcomes: A National Cancer Database Study. AB - BACKGROUND: High-grade neuroendocrine carcinomas are rare in the gastrointestinal tract. However, treatment patterns and outcomes have not been well described. SUBJECTS, MATERIALS, AND METHODS: The National Cancer Database was analyzed. The primary objective was to describe the clinical outcomes and identify prognostic factors. Univariate and multivariate analyses were done to identify factors associated with patient outcome. RESULTS: A total of 1,861 patients were identified between 2004 and 2013. The mean age was 63 years (standard deviation +/-13). The majority of the patients (78.1%) were non-Hispanic whites. The most common primary sites were pancreas (pancreatic neuroendocrine tumor [PNET] = 19.4%), large intestine (18.1%), esophagus (17.8%), and rectum (15.5%). Stage at presentation was I (6.6%), II (10.5%), III (18%) and IV (64.6%). Only 1.6% of the patients had brain metastases. Surgical resection was the primary therapy in 27.9%, and their median overall survival (OS) was 13.3 months. Patients treated with palliative chemotherapy had a median OS of 11.2 months, compared with 1.7 months for untreated patients. The median OS for high-grade PNET was 6 months, compared with 9.9 months for other high-grade gastrointestinal neuroendocrine carcinomas (HG GI NEC). On univariable analysis, age < 65 years (hazard ratio [HR] 0.72; 0.66-0.8; p < .001) and treatment at an academic center (HR 0.88; 0.79 0.99; p < .034) were associated with improved survival. Multivariable analysis confirmed prognostic advantage of treatment at an academic center. CONCLUSION: This is the largest series of HG GI NEC. Most patients present with metastatic disease, and overall survival remains poor. Treatment at an academic center, younger age, and use of chemotherapy were associated with improved survival. Multiagent chemotherapy was found to be associated with superior survival compared with single-agent chemotherapy, which was superior to no chemotherapy. Temporal sequences of chemotherapy, surgery, and radiation administration were not found to be associated with survival differences on multivariable analysis. IMPLICATIONS FOR PRACTICE: Management of patients with high-grade gastrointestinal neuroendocrine carcinomas (HG GI NEC) is based on experience with small-cell lung cancer. In this retrospective review, most patients had advanced disease and pancreatic primary had worse outcomes. Treatment at an academic center, younger age, and use of chemotherapy are associated with improved survival. Patients with early-stage disease treated with resection alone had inferior outcomes compared with patients who received neoadjuvant or adjuvant therapy, suggesting that micrometastases contribute to poor surgical outcomes. The relatively high proportion of positive surgical margin favors downstaging with neoadjuvant therapy to improve resection and lower the risk of systemic recurrence. PMID- 30482825 TI - Diagnosis and Management of Immune Checkpoint Inhibitor-Associated Neurologic Toxicity: Illustrative Case and Review of the Literature. AB - Immune checkpoint inhibitors (ICIs) initiate antitumor immunity by blocking the action of immune inhibitor-signaled cytotoxic proteins, such as cytotoxic T lymphocyte-associated protein 4, programmed cell death protein 1, and programmed cell death ligand 1. However, in rare cases (~1%-12% of patients), ICI treatment causes neurologic immune-related adverse events (irAEs). These include, but are not limited to, headache, encephalitis, neuropathies, myasthenia gravis, and myositis. The symptoms associated with irAEs can range from mild (grade 1-2) to severe (grade 3-4); however, they are often challenging to diagnose because they may present as generalized symptoms, such as fatigue and weakness, that can also be caused by the cancer itself. Here, we present an illustrative case of a 67 year-old woman who presented with signs of a neurologic irAE, including progressive dysphagia and weakness leading to falls, which started during treatment with pembrolizumab and worsened following initiation of ipilimumab. Following neurological and pathological evaluation, she was diagnosed with myositis. She was treated with steroids and improved rapidly. In this article, we review previous literature to provide guidance to frequently asked questions concerning the diagnosis and management of neurologic irAEs in patients with advanced cancer. With prompt and effective treatment, most patients will achieve a complete recovery. KEY POINTS: Neurologic immune-related adverse events (irAEs) affect approximately 1% of patients treated with immune checkpoint inhibitor (ICI) monotherapy and 2%-3% treated with combination therapy. These irAEs can affect any portion of the nervous system, although peripheral nerve system manifestations are most common. Overlap syndromes with multiple neurologic irAEs or other affected organ systems frequently exist.Diagnosis of neurologic irAEs can be challenging. Routine testing may be unremarkable and symptoms frequently mimic those from cancer or side effects of other therapies. Optimal management is currently unknown. A systematic, highly coordinated, and multidisciplinary approach is critical.Outcomes from neurologic irAEs are typically favorable with the current practice of holding the ICI and starting corticosteroids. Some patients are even successfully retreated with an ICI. A subset of patients, however, have a fulminant and potentially fatal course.Improved risk assessments and targeted therapies are needed. PMID- 30482826 TI - Bacillus subtilis Biofilms: a Matter of Individual Choice. AB - Bacillus subtilis has the capacity to choose between two mutually exclusive lifestyles: biofilm formation and flagellum-mediated swimming motility. Interestingly, this choice is made at the individual cell level, with bacterial cells in a population expressing genes required for biofilm formation or genes required for swimming motility but not both. A bistable switch controls the biofilm-versus-swimming decision, resulting in an evolutionarily favorable strategy known as "bet hedging" that ensures that subpopulations of bacteria continue to grow as conditions change and/or become unfavorable. In a recent issue of mBio, J. Kampf and colleagues (mBio 9:e01464-18, 2018, https://doi.org/10.1128/mBio.01464-18) reported the use of a combination of genetics and microfluidics to reveal that the interplay that occurs between the SinR and YmdB proteins underlies the B. subtilis choice between biofilm formation and swimming motility. Their report suggests that B. subtilis experiences selective pressure to form biofilms while maintaining reserve cell subpopulations with the capacity to swim away. PMID- 30482827 TI - Roles of Cholesteryl-alpha-Glucoside Transferase and Cholesteryl Glucosides in Maintenance of Helicobacter pylori Morphology, Cell Wall Integrity, and Resistance to Antibiotics. AB - Infection of the human stomach caused by Helicobacter pylori is very common, as the pathogen colonizes more than half of the world's population. It is associated with varied outcomes of infection, such as peptic ulcer disease, gastric ulcers, and mucosa-associated lymphoid tissue lymphoma, and is generally considered a risk factor for the development of gastric adenocarcinoma. Cholesteryl glucosides (CGs) constitute a vital component of the cell wall of H. pylori and contribute to its pathogenicity and virulence. The hp0421 gene, which encodes cholesteryl alpha-glucoside transferase (CGT), appears critical for the enzymatic function of integrating unique CGs into the cell wall of H. pylori, and deletion of this gene leads to depletion of CGs and their variants. Herein, we report that the deletion of hp0421 and consequent deficiency of cholesterol alter the morphology, shape, and cell wall composition of H. pylori cells, as demonstrated by high-resolution confocal microscopy and flow cytometry analyses of two different type strains of H. pylori, their isogenic knockouts as well as a reconstituted strain. Moreover, measurement of ethidium bromide (EtBr) influx by flow cytometry showed that lack of CGs increased cell wall permeability. Antimicrobial susceptibility testing revealed that the hp0421 isogenic knockout strains (Hp26695Delta421 and Hp76Delta421) were sensitive to antibiotics, such as fosfomycin, polymyxin B, colistin, tetracycline, and ciprofloxacin, in contrast to the wild-type strains that were resistant to the above antibiotics and tended to form denser biofilms. Lipid profile analysis of both Hp76 and Hp76Delta421 strains showed an aberrant profile of lipopolysaccharides (LPS) in the Hp76Delta421 strain. Taken together, we herein provide a set of mechanistic evidences to demonstrate that CGs play critical roles in the maintenance of the typical spiral morphology of H. pylori and its cell wall integrity, and any alteration in CG content affects the characteristic morphological features and renders the H. pylori susceptible to various antibiotics.IMPORTANCE Helicobacter pylori is an important cause of chronic gastritis leading to peptic ulcer and is a major risk factor for gastric malignancies. Failure in the eradication of H. pylori infection and increasing antibiotic resistance are two major problems in preventing H. pylori colonization. Hence, a deeper understanding of the bacterial survival strategies is needed to tackle the increasing burden of H. pylori infection by an appropriate intervention. Our study demonstrated that the lack of cholesteryl glucosides (CGs) remarkably altered the morphology of H. pylori and increased permeability of the bacterial cell wall. Further, this study highlighted the substantial role of CGs in maintaining the typical H. pylori morphology that is essential for retaining its pathogenic potential. We also demonstrated that the loss of CGs in H. pylori renders the bacterium susceptible to different antibiotics. PMID- 30482828 TI - The Chaperone and Redox Properties of CnoX Chaperedoxins Are Tailored to the Proteostatic Needs of Bacterial Species. AB - Hypochlorous acid (bleach), an oxidizing compound produced by neutrophils, turns the Escherichia coli chaperedoxin CnoX into a powerful holdase protecting its substrates from bleach-induced aggregation. CnoX is well conserved in bacteria, even in non-infectious species unlikely to encounter this oxidant, muddying the role of CnoX in these organisms. Here, we found that CnoX in the non-pathogenic aquatic bacterium Caulobacter crescentus functions as a holdase that efficiently protects 50 proteins from heat-induced aggregation. Remarkably, the chaperone activity of Caulobacter CnoX is constitutive. Like E. coli CnoX, Caulobacter CnoX transfers its substrates to DnaK/J/GrpE and GroEL/ES for refolding, indicating conservation of cooperation with GroEL/ES. Interestingly, Caulobacter CnoX exhibits thioredoxin oxidoreductase activity, by which it controls the redox state of 90 proteins. This function, which E. coli CnoX lacks, is likely welcome in a bacterium poorly equipped with antioxidant defenses. Thus, the redox and chaperone properties of CnoX chaperedoxins were fine-tuned during evolution to adapt these proteins to the specific needs of each species.IMPORTANCE How proteins are protected from stress-induced aggregation is a crucial question in biology and a long-standing mystery. While a long series of landmark studies have provided important contributions to our current understanding of the proteostasis network, key fundamental questions remain unsolved. In this study, we show that the intrinsic features of the chaperedoxin CnoX, a folding factor that combines chaperone and redox protective function, have been tailored during evolution to fit to the specific needs of their host. Whereas Escherichia coli CnoX needs to be activated by bleach, a powerful oxidant produced by our immune system, its counterpart in Caulobacter crescentus, a bacterium living in bleach-free environments, is a constitutive chaperone. In addition, the redox properties of E. coli and C. crescentus CnoX also differ to best contribute to their respective cellular redox homeostasis. This work demonstrates how proteins from the same family have evolved to meet the needs of their hosts. PMID- 30482829 TI - Physiological Studies of Chlorobiaceae Suggest that Bacillithiol Derivatives Are the Most Widespread Thiols in Bacteria. AB - Low-molecular-weight (LMW) thiols mediate redox homeostasis and the detoxification of chemical stressors. Despite their essential functions, the distribution of LMW thiols across cellular life has not yet been defined. LMW thiols are also thought to play a central role in sulfur oxidation pathways in phototrophic bacteria, including the Chlorobiaceae Here we show that Chlorobaculum tepidum synthesizes a novel LMW thiol with a mass of 412 +/- 1 Da corresponding to a molecular formula of C14H24N2O10S, which suggests that the new LMW thiol is closely related to bacillithiol (BSH), the major LMW thiol of low G+C Gram-positive bacteria. The Cba. tepidum LMW thiol structure was N-methyl bacillithiol (N-Me-BSH), methylated on the cysteine nitrogen, the fourth instance of this modification in metabolism. Orthologs of bacillithiol biosynthetic genes in the Cba. tepidum genome and the CT1040 gene product, N-Me-BSH synthase, were required for N-Me-BSH synthesis. N-Me-BSH was found in all Chlorobiaceae examined as well as Polaribacter sp. strain MED152, a member of the Bacteroidetes A comparative genomic analysis indicated that BSH/N-Me-BSH is synthesized not only by members of the Chlorobiaceae, Bacteroidetes, Deinococcus-Thermus, and Firmicutes but also by Acidobacteria, Chlamydiae, Gemmatimonadetes, and Proteobacteria. Thus, BSH and derivatives appear to be the most broadly distributed LMW thiols in biology.IMPORTANCE Low-molecular-weight thiols are key metabolites that participate in many basic cellular processes: central metabolism, detoxification, and oxidative stress resistance. Here we describe a new thiol, N-methyl-bacillithiol, found in an anaerobic phototrophic bacterium and identify a gene that is responsible for its synthesis from bacillithiol, the main thiol metabolite in many Gram-positive bacteria. We show that the presence or absence of this gene in a sequenced genome accurately predicts thiol content in distantly related bacteria. On the basis of these results, we analyzed genome data and predict that bacillithiol and its derivatives are the most widely distributed thiol metabolites in biology. PMID- 30482830 TI - Supragingival Plaque Microbiome Ecology and Functional Potential in the Context of Health and Disease. AB - To address the question of how microbial diversity and function in the oral cavities of children relates to caries diagnosis, we surveyed the supragingival plaque biofilm microbiome in 44 juvenile twin pairs. Using shotgun sequencing, we constructed a genome encyclopedia describing the core supragingival plaque microbiome. Caries phenotypes contained statistically significant enrichments in specific genome abundances and distinct community composition profiles, including strain-level changes. Metabolic pathways that are statistically associated with caries include several sugar-associated phosphotransferase systems, antimicrobial resistance, and metal transport. Numerous closely related previously uncharacterized microbes had substantial variation in central metabolism, including the loss of biosynthetic pathways resulting in auxotrophy, changing the ecological role. We also describe the first complete Gracilibacteria genomes from the human microbiome. Caries is a microbial community metabolic disorder that cannot be described by a single etiology, and our results provide the information needed for next-generation diagnostic tools and therapeutics for caries.IMPORTANCE Oral health has substantial economic importance, with over $100 billion spent on dental care in the United States annually. The microbiome plays a critical role in oral health, yet remains poorly classified. To address the question of how microbial diversity and function in the oral cavities of children relate to caries diagnosis, we surveyed the supragingival plaque biofilm microbiome in 44 juvenile twin pairs. Using shotgun sequencing, we constructed a genome encyclopedia describing the core supragingival plaque microbiome. This unveiled several new previously uncharacterized but ubiquitous microbial lineages in the oral microbiome. Caries is a microbial community metabolic disorder that cannot be described by a single etiology, and our results provide the information needed for next-generation diagnostic tools and therapeutics for caries. PMID- 30482831 TI - The Phosphohistidine Phosphatase SixA Targets a Phosphotransferase System. AB - SixA, a well-conserved protein found in proteobacteria, actinobacteria, and cyanobacteria, is the only reported example of a bacterial phosphohistidine phosphatase. A single protein target of SixA has been reported to date: the Escherichia coli histidine kinase ArcB. The present work analyzes an ArcB independent growth defect of a sixA deletion in E. coli A screen for suppressors, analysis of various mutants, and phosphorylation assays indicate that SixA modulates phosphorylation of the nitrogen-related phosphotransferase system (PTSNtr). The PTSNtr is a widely conserved bacterial pathway that regulates diverse metabolic processes through the phosphorylation states of its protein components, EINtr, NPr, and EIIANtr, which receive phosphoryl groups on histidine residues. However, a mechanism for dephosphorylating this system has not been reported. The results presented here suggest a model in which SixA removes phosphoryl groups from the PTSNtr by acting on NPr. This work uncovers a new role for the phosphohistidine phosphatase SixA and, through factors that affect SixA expression or activity, may point to additional inputs that regulate the PTSNtr IMPORTANCE One common means to regulate protein activity is through phosphorylation. Protein phosphatases exist to reverse this process, returning the protein to the unphosphorylated form. The vast majority of protein phosphatases that have been identified target phosphoserine, phosphotheronine, and phosphotyrosine. A widely conserved phosphohistidine phosphatase was identified in Escherichia coli 20 years ago but remains relatively understudied. The present work shows that this phosphatase modulates the nitrogen-related phosphotransferase system, a pathway that is regulated by nitrogen and carbon metabolism and affects diverse aspects of bacterial physiology. Until now, there was no known mechanism for removing phosphoryl groups from this pathway. PMID- 30482832 TI - Mycobacterium tuberculosis Type VII Secretion System Effectors Differentially Impact the ESCRT Endomembrane Damage Response. AB - Intracellular pathogens have varied strategies to breach the endolysosomal barrier so that they can deliver effectors to the host cytosol, access nutrients, replicate in the cytoplasm, and avoid degradation in the lysosome. In the case of Mycobacterium tuberculosis, the bacterium perforates the phagosomal membrane shortly after being taken up by macrophages. Phagosomal damage depends upon the mycobacterial ESX-1 type VII secretion system (T7SS). Sterile insults, such as silica crystals or membranolytic peptides, can also disrupt phagosomal and endolysosomal membranes. Recent work revealed that the host endosomal sorting complex required for transport (ESCRT) machinery rapidly responds to sterile endolysosomal damage and promotes membrane repair. We hypothesized that ESCRTs might also respond to pathogen-induced phagosomal damage and that M. tuberculosis could impair this host response. Indeed, we found that ESCRT-III proteins were recruited to M. tuberculosis phagosomes in an ESX-1-dependent manner. We previously demonstrated that the mycobacterial effectors EsxG/TB9.8 and EsxH/TB10.4, both secreted by the ESX-3 T7SS, can inhibit ESCRT-dependent trafficking of receptors to the lysosome. Here, we additionally show that ESCRT III recruitment to sites of endolysosomal damage is antagonized by EsxG and EsxH, both within the context of M. tuberculosis infection and sterile injury. Moreover, EsxG and EsxH themselves respond within minutes to membrane damage in a manner that is independent of calcium and ESCRT-III recruitment. Thus, our study reveals that T7SS effectors and ESCRT participate in a series of measures and countermeasures for control of phagosome integrity.IMPORTANCE Mycobacterium tuberculosis causes tuberculosis, which kills more people than any other infection. M. tuberculosis grows in macrophages, cells that specialize in engulfing and degrading microorganisms. Like many intracellular pathogens, in order to cause disease, M. tuberculosis damages the membrane-bound compartment (phagosome) in which it is enclosed after macrophage uptake. Recent work showed that when chemicals damage this type of intracellular compartment, cells rapidly detect and repair the damage, using machinery called the endosomal sorting complex required for transport (ESCRT). Therefore, we hypothesized that ESCRT might also respond to pathogen-induced damage. At the same time, our previous work showed that the EsxG-EsxH heterodimer of M. tuberculosis can inhibit ESCRT, raising the possibility that M. tuberculosis impairs this host response. Here, we show that ESCRT is recruited to damaged M. tuberculosis phagosomes and that EsxG EsxH undermines ESCRT-mediated endomembrane repair. Thus, our studies demonstrate a battle between host and pathogen over endomembrane integrity. PMID- 30482833 TI - The Widely Conserved ebo Cluster Is Involved in Precursor Transport to the Periplasm during Scytonemin Synthesis in Nostoc punctiforme. AB - Scytonemin is a dimeric indole-phenol sunscreen synthesized by some cyanobacteria under conditions of exposure to UVA radiation. While its biosynthetic pathway has been elucidated only partially, comparative genomics reveals that the scytonemin operon often contains a cluster of five highly conserved genes (ebo cluster) of unknown function that is widespread and conserved among several bacterial and algal phyla. We sought to elucidate the function of the ebo cluster in the cyanobacterium Nostoc punctiforme by constructing and analyzing in-frame deletion mutants (one for each ebo gene and one for the entire cluster). Under conditions of UVA induction, all ebo mutants were scytoneminless, and all accumulated a single compound, the scytonemin monomer, clearly implicating all ebo genes in scytonemin production. We showed that the scytonemin monomer also accumulated in an induced deletion mutant of scyE, a non-ebo scytonemin gene whose product is demonstrably targeted to the periplasm. Confocal autofluorescence microscopy revealed that the accumulation was confined to the cytoplasm in all ebo mutants but that that was not the case in the scyE deletion, with an intact ebo cluster, where the scytonemin monomer was also excreted to the periplasm. The results implicate the ebo cluster in the export of the scytonemin monomer to the periplasm for final oxidative dimerization by ScyE. By extension, the ebo gene cluster may play similar roles in metabolite translocation across many bacterial phyla. We discuss potential mechanisms for such a role on the basis of structural and phylogenetic considerations of the ebo proteins.IMPORTANCE Elucidating the biochemical and genetic basis of scytonemin constitutes an interesting challenge because of its unique structure and the unusual fact that it is partially synthesized in the periplasmic space. Our work points to the ebo gene cluster, associated with the scytonemin operon of cyanobacteria, as being responsible for the excretion of scytonemin intermediates from the cytoplasm into the periplasm during biosynthesis. Few conserved systems have been described that facilitate the membrane translocation of small molecules. Because the ebo cluster is well conserved among a large diversity of bacteria and algae and yet insights into its potential function are lacking, our findings suggest that translocation of small molecules across the plasma membrane may be its generic role across microbes. PMID- 30482834 TI - Mechanistic Basis for Decreased Antimicrobial Susceptibility in a Clinical Isolate of Neisseria gonorrhoeae Possessing a Mosaic-Like mtr Efflux Pump Locus. AB - Recent reports suggest that mosaic-like sequences within the mtr (multiple transferable resistance) efflux pump locus of Neisseria gonorrhoeae, likely originating from commensal Neisseria sp. by transformation, can increase the ability of gonococci to resist structurally diverse antimicrobials. Thus, acquisition of numerous nucleotide changes within the mtrR gene encoding the transcriptional repressor (MtrR) of the mtrCDE efflux pump-encoding operon or overlapping promoter region for both along with those that cause amino acid changes in the MtrD transporter protein were recently reported to decrease gonococcal susceptibility to numerous antimicrobials, including azithromycin (Azi) (C. B. Wadsworth, B. J. Arnold, M. R. A. Satar, and Y. H. Grad, mBio 9:e01419-18, 2018, https://doi.org/10.1128/mBio.01419-18). We performed detailed genetic and molecular studies to define the mechanistic basis for why such strains can exhibit decreased susceptibility to MtrCDE antimicrobial substrates, including Azi. We report that a strong cis-acting transcriptional impact of a single nucleotide change within the -35 hexamer of the mtrCDE promoter as well gain-of-function amino acid changes at the C-terminal region of MtrD can mechanistically account for the decreased antimicrobial susceptibility of gonococci with a mosaic-like mtr locus.IMPORTANCE Historically, after introduction of an antibiotic for treatment of gonorrhea, strains of N. gonorrhoeae emerge that display clinical resistance due to spontaneous mutation or acquisition of resistance genes. Genetic exchange between members of the Neisseria genus occurring by transformation can cause significant changes in gonococci that impact the structure of an antibiotic target or expression of genes involved in resistance. The results presented here provide a framework for understanding how mosaic-like DNA sequences from commensal Neisseria that recombine within the gonococcal mtr efflux pump locus function to decrease bacterial susceptibility to antimicrobials, including antibiotics used in therapy of gonorrhea. PMID- 30482835 TI - Development of Thermostable Lyophilized Sabin Inactivated Poliovirus Vaccine. AB - As oral poliovirus vaccine (OPV) causes vaccine-associated paralytic poliomyelitis, the polio endgame strategy introduced by the Global Polio Eradication Initiative calls for a phased withdrawal of OPV and an introduction of inactivated poliovirus vaccine (IPV). The introduction of IPV creates challenges in maintaining the cold chain for vaccine storage and distribution. Recent advances in lyophilization have helped in finding a temperature-stable formulation for multiple vaccines; however, poliovirus vaccines have yet to capture a stable, safe formula for lyophilization. In addition, efficient in vitro methods for antigen measurement are needed for screening stable vaccine formulations. Here, we report size exclusion high-performance liquid chromatography (SE-HPLC) as a reliable means to identify the leading lyophilized formulation to generate thermostable Sabin inactivated poliovirus vaccine (sIPV). High-throughput screening and SE-HPLC determined the leading formulation, resulting in 95% D-antigen recovery and low residual moisture content of sIPV following lyophilization. Furthermore, the lyophilized sIPV remained stable after 4 weeks of incubation at ambient temperature and induced strong neutralizing antibodies and full protection of poliovirus receptor transgenic mice against the in vivo challenge of wild-type poliovirus. Overall, this report describes a novel means for the high-throughput evaluation of sIPV antigenicity and a thermostable lyophilized sIPV with in vivo vaccine potency.IMPORTANCE Poliomyelitis is a highly contagious disease caused by the poliovirus. While the live attenuated OPV has been the vaccine of choice, a major concern is its ability to revert to a form that can cause paralysis, so-called vaccine-associated paralytic poliomyelitis. Therefore, the new endgame strategy of the Global Polio Eradication Initiative includes the introduction of an IPV. However, the feasibility of the use of current IPV formulations in developing countries is limited, because IPV is insufficiently stable to be purified, transported, and stored under unrefrigerated conditions. We successfully designed the sIPV for use in the dry state that maintains the full vaccine potency in animal models after incubation at ambient temperature. This report provides, for the first time, candidate formulations of sIPV that are stable at elevated temperatures. PMID- 30482836 TI - Salmonella enterica Phylogeny Based on Whole-Genome Sequencing Reveals Two New Clades and Novel Patterns of Horizontally Acquired Genetic Elements. AB - Using whole-genome sequence (WGS) data from the GenomeTrakr network, a globally distributed network of laboratories sequencing foodborne pathogens, we present a new phylogeny of Salmonella enterica comprising 445 isolates from 266 distinct serovars and originating from 52 countries. This phylogeny includes two previously unidentified S. enterica subsp. enterica clades. Serovar Typhi is shown to be nested within clade A. Our findings are supported by both phylogenetic support, based on a core genome alignment, and Bayesian approaches, based on single-nucleotide polymorphisms. Serovar assignments were refined by in silico analysis using SeqSero. More than 10% of serovars were either polyphyletic or paraphyletic. We found variable genetic content in these isolates relating to gene mobilization and virulence factors which have different distributions within clades. Gifsy-1- and Gifsy-2-like phages appear more prevalent in clade A; other viruses are more evenly distributed. Our analyses reveal IncFII is the predominant plasmid replicon in S. enterica Few core or clade-defining virulence genes are observed, and their distributions appear probabilistic in nature. Together, these patterns demonstrate that genetic exchange within S. enterica is more extensive and frequent than previously realized, which significantly alters how we view the genetic structure of the bacterial species.IMPORTANCE Rapid improvements in nucleotide sequencing access and affordability have led to a drastic increase in availability of genetic information. This information will improve the accuracy of molecular descriptions, including serovars, within S. enterica Although the concept of serovars continues to be useful, it may have more significant limitations than previously understood. Furthermore, the discrete absence or presence of specific genes can be an unstable indicator of phylogenetic identity. Whole-genome sequencing provides more rigorous tools for assessing the distributions of these genes. Our phylogenetic and genetic content analyses reveal how active genetic elements are dynamically distributed within a species, allowing us to better understand genetic reservoirs and underlying bacterial evolution. PMID- 30482837 TI - Origins and Evolution of the Global RNA Virome. AB - Viruses with RNA genomes dominate the eukaryotic virome, reaching enormous diversity in animals and plants. The recent advances of metaviromics prompted us to perform a detailed phylogenomic reconstruction of the evolution of the dramatically expanded global RNA virome. The only universal gene among RNA viruses is the gene encoding the RNA-dependent RNA polymerase (RdRp). We developed an iterative computational procedure that alternates the RdRp phylogenetic tree construction with refinement of the underlying multiple sequence alignments. The resulting tree encompasses 4,617 RNA virus RdRps and consists of 5 major branches; 2 of the branches include positive-sense RNA viruses, 1 is a mix of positive-sense (+) RNA and double-stranded RNA (dsRNA) viruses, and 2 consist of dsRNA and negative-sense (-) RNA viruses, respectively. This tree topology implies that dsRNA viruses evolved from +RNA viruses on at least two independent occasions, whereas -RNA viruses evolved from dsRNA viruses. Reconstruction of RNA virus evolution using the RdRp tree as the scaffold suggests that the last common ancestors of the major branches of +RNA viruses encoded only the RdRp and a single jelly-roll capsid protein. Subsequent evolution involved independent capture of additional genes, in particular, those encoding distinct RNA helicases, enabling replication of larger RNA genomes and facilitating virus genome expression and virus-host interactions. Phylogenomic analysis reveals extensive gene module exchange among diverse viruses and horizontal virus transfer between distantly related hosts. Although the network of evolutionary relationships within the RNA virome is bound to further expand, the present results call for a thorough reevaluation of the RNA virus taxonomy.IMPORTANCE The majority of the diverse viruses infecting eukaryotes have RNA genomes, including numerous human, animal, and plant pathogens. Recent advances of metagenomics have led to the discovery of many new groups of RNA viruses in a wide range of hosts. These findings enable a far more complete reconstruction of the evolution of RNA viruses than was attainable previously. This reconstruction reveals the relationships between different Baltimore classes of viruses and indicates extensive transfer of viruses between distantly related hosts, such as plants and animals. These results call for a major revision of the existing taxonomy of RNA viruses. PMID- 30482838 TI - Correction: Size-dependent physiological responses of the branching coral Pocillopora verrucosa to elevated temperature and P CO2 (doi:10.1242/jeb.146381). PMID- 30482839 TI - Tissue-specific kinase expression and activity regulates flux through the pyruvate dehydrogenase complex. AB - The pyruvate dehydrogenase complex (PDC) is a multienzyme assembly that converts pyruvate to acetyl-CoA. As pyruvate and acetyl-CoA play central roles in cellular metabolism, understanding PDC regulation is pivotal to understanding the larger metabolic network. The activity of mammalian PDC is regulated through reversible phosphorylation governed by at least four isozymes of pyruvate dehydrogenase kinase (PDK). Deciphering which kinase regulates PDC in organisms at specific times or places has been challenging. In this study, we analyzed mouse strains carrying targeted mutations of individual isozymes to explore their role in regulating PDC activity. Analysis of protein content of PDK isozymes in major metabolic tissues revealed that PDK1 and PDK2 were ubiquitously expressed, while PDK3 and PDK4 displayed a rather limited tissue distribution. Measurement of kinase activity showed that PDK1 is the principal isozyme regulating hepatic PDC. PDK2 was largely responsible for inactivation of PDC in tissues of muscle origin and BAT. PDK3 was the principal kinase regulating pyruvate dehydrogenase activity in kidney and brain. In well-fed state, the tissue levels of PDK4 protein were fairly low. In most tissues tested, PDK4 ablation had little effect on the overall rates of inactivation of PDC in kinase reaction. Taken together, these data strongly suggest that the activity of PDC is regulated by different isozymes in different tissues. Furthermore, it appears that the overall flux through PDC in a given tissue largely reflects the properties of PDK isozyme that is principally responsible for the regulation of PDC activity in that tissue. PMID- 30482840 TI - The bacterial lipid II flippase MurJ functions by an alternating-access mechanism. AB - The peptidoglycan (PG) cell wall is an essential extracytoplasmic glycopeptide polymer that safeguards bacteria against osmotic lysis and determines cellular morphology. Bacteria use multi-protein machineries for the synthesis of the PG cell wall during cell division and elongation that can be targeted by antibiotics such as the beta-lactams. Lipid II, the lipid-linked precursor for PG biogenesis, is synthesized in the inner leaflet of the cytoplasmic membrane and then translocated across the bilayer, where it is ultimately polymerized into PG. In Escherichia coli, MurJ, a member of the MOP exporter superfamily, has been recently shown to have lipid II flippase activity that is dependent on membrane potential. Because of its essentiality, MurJ could potentially be targeted by much needed novel antibiotics. Recent structural information suggests that a central cavity in MurJ alternates between inward- and outward-open conformations to flip lipid II, but how these conformational changes occur are unknown. Here, we utilized structure-guided cysteine cross-linking and proteolysis-coupled gel analysis to probe the conformational changes of MurJ in E. coli cells. We found that paired cysteine substitutions in transmembrane domains 2 and 8, and periplasmic loops of MurJ could be cross-linked with homobifunctional cysteine cross-linkers, indicating that MurJ can adopt both inward- and outward-facing conformations in vivo. Furthermore, we show that dissipating the membrane potential with an ionophore decreases the prevalence of the inward-facing, but not the outward-facing state. Our study provides in vivo evidence that MurJ uses an alternating-access mechanism during the lipid II transport cycle. PMID- 30482841 TI - Sodium channel TRPM4 and sodium/calcium exchangers (NCX) cooperate in the control of Ca2+-induced mucin secretion from goblet cells. AB - Regulated mucin secretion is essential for the formation of the mucus layer that protects the underlying epithelial cells from foreign particles. Alterations in the quantity or quality of secreted mucins are therefore detrimental to airway and colon physiology. Based on various biochemical assays in several human cell lines, we report here that Na+/Ca2+ exchanger 2 (NCX2) works in conjunction with transient receptor potential cation channel subfamily M member 4 (TRPM4), and perhaps TRPM5, Na+ channels to control Ca2+-mediated secretion of both mucin 2 (MUC2) and MUC5AC from HT29-18N2 colonic cancer cells. Differentiated normal bronchial epithelial (NHBE) cells and tracheal cells from patients with cystic fibrosis (CFT1-LC3) expressed only TRPM4 and all three isoforms of NCXs. Blocking the activity of TRPM4 or NCX proteins abrogated MUC5AC secretion from NHBE and CFT1-LC3 cells. Altogether, our findings reveal that NCX and TRPM4/TRPM5 are both required for mucin secretion. We therefore propose that these two proteins could be potential pharmacological targets to control mucus-related pathologies such as cystic fibrosis. PMID- 30482842 TI - The recombination mediator proteins RecFOR maintain RecA* levels for maximal DNA polymerase V Mut activity. AB - DNA template damage can potentially block DNA replication. Cells have therefore developed different strategies to repair template lesions. Activation of the bacterial lesion bypass DNA polymerase V (Pol V) requires both the cleavage of the UmuD subunit to UmuD' and the acquisition of a monomer of activated RecA recombinase, forming Pol V Mut. Both of these events are mediated by the generation of RecA* via the formation of a RecA-ssDNA filament during the SOS response. Formation of RecA* is itself modulated by competition with the single stranded DNA-binding protein (SSB) for binding to ssDNA. Previous observations have demonstrated that RecA filament formation on SSB-coated DNA can be favored in the presence of the recombination mediator proteins RecF, RecO, and RecR. We show here using purified proteins that in the presence of SSB and RecA a stable RecA-ssDNA filament is not formed, although sufficient RecA* is generated to support some activation of Pol V. The presence of RecFOR increased RecA* generation and allowed Pol V to synthesize longer DNA products and to elongate from an unpaired primer terminus opposite template damage, also without the generation of a stable RecA-ssDNA filament. PMID- 30482843 TI - Cooperative actions of Tbc1d1 and AS160/Tbc1d4 in GLUT4 trafficking activities. AB - AS160 and Tbc1d1 are key Rab GTPase-activating proteins (RabGAPs) that mediate release of static GLUT4 in response to insulin or exercise-mimetic stimuli, respectively, but their cooperative regulation and its underlying mechanisms remain unclear. By employing GLUT4 nanometry with cell-based reconstitution models, we herein analyzed the functional cooperative activities of the RabGAPs. When both RabGAPs are present, Tbc1d1 functionally dominates AS160 and stimuli inducible GLUT4 release relies on Tbc1d1-evoking proximal stimuli such as AICAR and intracellular Ca2+. Detailed functional assessments with varying expression ratios revealed that AS160 modulates sensitivity to external stimuli in Tbc1d1 mediated GLUT4 release. For example, Tbc1d1-governed GLUT4 release triggered by Ca2+plus insulin occurred more efficiently than that in cells with little or no AS160. Series of mutational analyses revealed that these synergizing actions rely on phosphotyrosine-binding (PTB) 1 and calmodulin-binding domains of Tbc1d1 as well as key phosphorylation sites of both AS160 (T642) and Tbc1d1 (S237, T596). Thus, the emerging cooperative governance relying on the multiple regulatory nodes of both Tbc1d1 and AS160, functioning together, play a key role in properly deciphering biochemical signals into a physical GLUT4 release process in response to insulin, exercise and the two in combination. PMID- 30482844 TI - Targeting BCL-xL improves the efficacy of bromodomain and extra-terminal protein inhibitors in triple-negative breast cancer by eliciting the death of senescent cells. AB - Inhibitors of bromodomain and extra-terminal proteins (BETi) suppress oncogenic gene expression and have been shown to be efficacious in many in vitro and murine models of cancer, including triple-negative breast cancer (TNBC), a highly aggressive disease. However, in most cancer models, responses to BETi can be highly variable. We previously reported that TNBC cells either undergo senescence or apoptosis in response to BETi, but the specific mechanisms dictating these two cell fates remain unknown. Using six human TNBC cell lines, we show that the terminal response of TNBC cells to BETi is dictated by the intrinsic expression levels of the anti-apoptotic protein B-cell lymphoma-extra large (BCL-xL). BCL-xL levels were higher in cell lines that senesce in response to BETi compared to lines that primarily die in response to these drugs. Moreover, BCL-xL expression was further reduced in cells that undergo BETi-mediated apoptosis. Forced BCL-xL overexpression in cells that normally undergo apoptosis following BETi treatment shifted them to senescence without affecting the reported mechanism of action of BETi in TNBC, that is, mitotic catastrophe. Most importantly, pharmacological or genetic inhibition of BCL-xL induced apoptosis in response to BETi, and inhibiting BCL-xL, even after BETi-induced senescence had already occurred, still induced cell death. These results indicate that BCL-xL provides a senescent cell death-inducing or senolytic target that may be exploited to improve therapeutic outcomes of TNBC in response to BETi. They also suggest that the basal levels of BCL-xL should be predictive of tumor responses to BETi in current clinical trials. PMID- 30482846 TI - Integrated identification and quantification error probabilities for shotgun proteomics. AB - Protein quantification by label-free shotgun proteomics experiments is plagued by a multitude of error sources. Typical pipelines for identifying differential proteins use intermediate filters in an attempt to control the error rate. However, they often ignore certain error sources and, moreover, regard filtered lists as completely correct in subsequent steps. These two indiscretions can easily lead to a loss of control of the false discovery rate (FDR). We propose a probabilistic graphical model, Triqler, that propagates error information through all steps, employing distributions in favor of point estimates, most notably for missing value imputation. The model outputs posterior probabilities for fold changes between treatment groups, highlighting uncertainty rather than hiding it. We analyzed 3 engineered datasets and achieved FDR control and high sensitivity, even for truly absent proteins. In a bladder cancer clinical dataset we discovered 35 proteins at 5?% FDR, whereas the original study discovered 1 and MaxQuant/Perseus 4 proteins at this threshold. Compellingly, these 35 proteins showed enrichment for functional annotation terms, whereas the top ranked proteins reported by MaxQuant/Perseus showed no enrichment. The model executes in minutes and is freely available at https://pypi.org/project/triqler/. PMID- 30482845 TI - Surface loops in a single SH2 domain are capable of encoding the spectrum of specificity of the SH2 family. AB - Src homology 2 (SH2) domains play an essential role in cellular signal transduction by binding to proteins phosphorylated on Tyr residue. Although Tyr phosphorylation (pY) is a prerequisite for binding for essentially all SH2 domains characterized to date, different SH2 domains prefer specific sequence motifs C-terminal to the pY residue. Because all SH2 domains adopt the same structural fold, it is not well understood how different SH2 domains have acquired the ability to recognize distinct sequence motifs. We have shown previously that the EF and BG loops that connect the secondary structure elements on an SH2 domain dictates its specificity. In this study, we investigated if these surface loops could be engineered to encode diverse specificities. By characterizing a group of SH2 variants selected by different pY peptides from phage-displayed libraries, we show that the EF and BG loops of the Fyn SH2 domain are capable of encoding a wide spectrum of specificities, including all three major specificity classes (P+2, P+3 and P+4) of the SH2 domain family. Furthermore, we found that the specificity of a given variant correlates with the sequence feature of the bait peptide used for its isolation, suggesting that an SH2 domain may acquire specificity by co-evolving with its ligand. Intriguingly, we found that the SH2 variants can employ a variety of different mechanisms to confer the same specificity, suggesting the EF and BG loops are highly flexible and adaptable. Our work provides a plausible mechanism for the SH2 domain to acquire the wide spectrum of specificity observed in nature through loop variation with minimal disturbance to the SH2 fold. It is likely that similar mechanisms may have been employed by other modular interaction domains to generate diversity in specificity. PMID- 30482847 TI - Dynamic phosphoproteomics uncovers signaling pathways modulated by anti neoplastic sphingolipid analogs. AB - The anti-neoplastic sphingolipid analog SH-BC-893 starves cancer cells to death by down-regulating cell surface nutrient transporters and blocking lysosomal trafficking events. These effects are mediated by the activation of protein phosphatase 2A (PP2A). To identify putative PP2A substrates, we used quantitative phosphoproteomics to profile the temporal changes in protein phosphorylation in FL5.12 cells following incubation with SH-BC-893 or the specific PP2A inhibitor LB-100. These analyses enabled the profiling of more than 15,000 phosphorylation sites, of which 958 sites on 644 proteins were dynamically regulated. We identified 114 putative PP2A substrates including several nutrient transporter proteins, GTPase regulators (e.g. Agap2, Git1), and proteins associated with actin cytoskeletal remodeling (e.g. Vim, Pxn). To identify SH-BC-893-induced cell signaling events that disrupt lysosomal trafficking, we compared phosphorylation profiles in cells treated with SH-BC-893 or C2-ceramide, a non-vacuolating sphingolipid that does not impair lysosomal fusion. These analyses combined with functional assays uncovered the differential regulation of Akt and Gsk3b by SH-BC 893 (vacuolating) and C2-ceramide (non-vacuolating). Dynamic phosphoproteomics of cells treated with compounds affecting PP2A activity thus enabled the correlation of cell signaling with phenotypes to rationalize their mode of action. PMID- 30482848 TI - Thinking through acidic Ca2+ stores. AB - Glutamate signaling regulates neuronal activity and synaptic plasticity, which underlies learning and memory. In this issue of Science Signaling, Foster et al found that metabotropic glutamate receptors mediate long-term potentiation in hippocampal neurons by mobilizing acidic endolysosomal Ca2+ stores through the intracellular messenger NAADP. PMID- 30482849 TI - beta-Barrel outer membrane proteins suppress mTORC2 activation and induce autophagic responses. AB - The outer membranes of Gram-negative bacteria and mitochondria contain proteins with a distinct beta-barrel tertiary structure that could function as a molecular pattern recognized by the innate immune system. Here, we report that purified outer membrane proteins (OMPs) from different bacterial and mitochondrial sources triggered the induction of autophagy-related endosomal acidification, LC3B lipidation, and p62 degradation. Furthermore, OMPs reduced the phosphorylation and therefore activation of the multiprotein complex mTORC2 and its substrate Akt in macrophages and epithelial cells. The cell surface receptor SlamF8 and the DNA protein kinase subunit XRCC6 were required for these OMP-specific responses in macrophages and epithelial cells, respectively. The addition of OMPs to mouse bone marrow-derived macrophages infected with Salmonella Typhimurium facilitated bacterial clearance. These data identify a specific cellular response mediated by bacterial and mitochondrial OMPs that can alter inflammatory responses and influence the killing of pathogens. PMID- 30482850 TI - Aspirin ameliorates experimental autoimmune encephalomyelitis through interleukin 11-mediated protection of regulatory T cells. AB - Multiple sclerosis (MS) is a human disease that results from autoimmune T cells targeting myelin protein that is expressed within the central nervous system. In MS, the number of FoxP3-expressing regulatory T cells (Tregs) is reduced, which facilitates the activation of autoreactive T cells. Because aspirin (acetylsalicylic acid) is the most widely used nonsteroidal anti-inflammatory drug, we examined its immunomodulatory effect in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We found that low-dose aspirin suppressed the clinical symptoms of EAE in mouse models of both relapsing remitting and chronic disease. Aspirin reduced the development of EAE driven by myelin basic protein (MBP)-specific T cells and the associated perivascular cuffing, inflammation, and demyelination. The effects of aspirin required the presence of CD25+FoxP3+ Tregs Aspirin increased the amounts of Foxp3 and interleukin-4 (IL-4) in T cells and suppressed the differentiation of naive T cells into T helper 17 (TH17) and TH1 cells. Aspirin also increased the transcription of Il11 mediated by the transcription factor CREB, which was necessary for the generation of Tregs Neutralization of IL-11 negated the effects of aspirin on Treg development and exacerbated EAE. Furthermore, we found that IL 11 alone was sufficient to maintain the percentage of FoxP3+ Tregs and protect mice from EAE. These results identify a previously uncharacterized mode of action of aspirin. PMID- 30482851 TI - Hippocampal mGluR1-dependent long-term potentiation requires NAADP-mediated acidic store Ca2+ signaling. AB - Acidic organelles, such as endosomes and lysosomes, store Ca2+ that is released in response to intracellular increases in the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP). In neurons, NAADP and Ca2+ signaling contribute to synaptic plasticity, a process of activity-dependent long-term potentiation (LTP) [or, alternatively, long-term depression (LTD)] of synaptic strength and neuronal transmission that is critical for neuronal function and memory formation. We explored the function of and mechanisms regulating acidic Ca2+ store signaling in murine hippocampal neurons. We found that metabotropic glutamate receptor 1 (mGluR1) was coupled to NAADP signaling that elicited Ca2+ release from acidic stores. In turn, this released Ca2+-mediated mGluR1-dependent LTP by transiently inhibiting SK-type K+ channels, possibly through the activation of protein phosphatase 2A. Genetically removing two-pore channels (TPCs), which are endolysosomal-specific ion channels, switched the polarity of plasticity from LTP to LTD, indicating the importance of specific receptor store coupling and providing mechanistic insight into how mGluR1 can produce both synaptic potentiation and synaptic depression. PMID- 30482852 TI - Inhibition of MERTK promotes suppression of tumor growth in BRAF mutant and BRAF wild-type melanoma. AB - Molecularly-targeted agents have improved outcomes for a subset of patients with BRAF-mutated melanoma, but treatment of resistant and BRAF wild-type tumors remains a challenge. The MERTK receptor tyrosine kinase is aberrantly expressed in melanoma and can contribute to oncogenic phenotypes. Here we report the effect of treatment with a MERTK-selective small molecule inhibitor, UNC2025, in preclinical models of melanoma. In melanoma cell lines, treatment with UNC2025 potently inhibited phosphorylation of MERTK and downstream signaling, induced cell death, and decreased colony formation. In patient-derived melanoma xenograft models, treatment with UNC2025 blocked or significantly reduced tumor growth. Importantly, UNC2025 had similar biochemical and functional effects in both BRAF mutated and BRAF wild-type models and irrespective of NRAS mutational status, implicating MERTK inhibition as a potential therapeutic strategy in tumors that are not amenable to BRAF-targeting and for which there are limited treatment options. In BRAF-mutated cell lines, combined treatment with UNC2025 and the BRAF inhibitor vemurafenib provided effective inhibition of oncogenic signaling through ERK, AKT, and STAT6, increased induction of cell death, and decreased colony forming potential. Similarly, in NRAS-mutated cell lines, addition of UNC2025 to cobimetinib therapy increased cell death and decreased colony-forming potential. In a BRAF-mutated patient-derived xenograft, treatment with combined UNC2025 and vemurafenib was well-tolerated and significantly decreased tumor growth compared to vemurafenib alone. These data support the use of UNC2025 for treatment of melanoma, irrespective of BRAF or NRAS mutational status, and suggest a role for MERTK and targeted combination therapy in BRAF and NRAS mutated melanoma. PMID- 30482854 TI - Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation. AB - PIEZO1 is a cation channel that is activated by mechanical forces such as fluid shear stress or membrane stretch. PIEZO1 loss-of-function mutations in patients are associated with congenital lymphedema with pleural effusion. However, the mechanistic link between PIEZO1 function and the development or function of the lymphatic system is currently unknown. Here, we analyzed two mouse lines lacking PIEZO1 in endothelial cells (via Tie2Cre or Lyve1Cre) and found that they exhibited pleural effusion and died postnatally. Strikingly, the number of lymphatic valves was dramatically reduced in these mice. Lymphatic valves are essential for ensuring proper circulation of lymph. Mechanical forces have been implicated in the development of lymphatic vasculature and valve formation, but the identity of mechanosensors involved is unknown. Expression of FOXC2 and NFATc1, transcription factors known to be required for lymphatic valve development, appeared normal in Tie2Cre;Piezo1 cKO mice. However, the process of protrusion in the valve leaflets, which is associated with collective cell migration, actin polymerization, and remodeling of cell-cell junctions, was impaired in Tie2Cre;Piezo1 cKO mice. Consistent with these genetic findings, activation of PIEZO1 by Yoda1 in cultured lymphatic endothelial cells induced active remodeling of actomyosin and VE-cadherin+ cell-cell adhesion sites. Our analysis provides evidence that mechanically activated ion channel PIEZO1 is a key regulator of lymphatic valve formation. PMID- 30482853 TI - Targeting the sphingosine 1-phosphate axis exerts potent antitumor activity in BRAFi-resistant melanomas. AB - BRAF inhibitors (BRAFi) are used to treat melanoma patients harboring the V600E mutation. However, resistance to BRAFi is inevitable. Here, we identified sphingosine-1-phosphate (S1P) receptors as regulators of BRAFV600E-mutant melanoma cell-autonomous resistance to BRAFi. Moreover, our results reveal a distinct sphingolipid profile, i.e. a tendency for increased very long-chain ceramide species, in the plasma of melanoma patients who achieve a response to BRAFi therapy as compared to patients with progressive disease. Treatment with BRAFi resulted in a strong decrease in S1PR1/3 expression in sensitive but not in resistant cells. Genetic and pharmacologic interventions, that increase ceramide/S1P ratio, downregulated S1PR expression and blocked BRAFi-resistant melanoma cell growth. This effect was associated with a decreased expression of MITF and Bcl-2. Moreover, the BH3 mimetic ABT-737 improved the antitumor activity of approaches targeting S1P-metabolizing enzymes in BRAFi-resistant melanoma cells. Collectively, our findings indicate that targeting the S1P/S1PR axis could provide effective therapeutic options for melanoma patients who relapse after BRAFi therapy. PMID- 30482855 TI - Metabolic network-based stratification of hepatocellular carcinoma reveals three distinct tumor subtypes. AB - Hepatocellular carcinoma (HCC) is one of the most frequent forms of liver cancer, and effective treatment methods are limited due to tumor heterogeneity. There is a great need for comprehensive approaches to stratify HCC patients, gain biological insights into subtypes, and ultimately identify effective therapeutic targets. We stratified HCC patients and characterized each subtype using transcriptomics data, genome-scale metabolic networks and network topology/controllability analysis. This comprehensive systems-level analysis identified three distinct subtypes with substantial differences in metabolic and signaling pathways reflecting at genomic, transcriptomic, and proteomic levels. These subtypes showed large differences in clinical survival associated with altered kynurenine metabolism, WNT/beta-catenin-associated lipid metabolism, and PI3K/AKT/mTOR signaling. Integrative analyses indicated that the three subtypes rely on alternative enzymes (e.g., ACSS1/ACSS2/ACSS3, PKM/PKLR, ALDOB/ALDOA, MTHFD1L/MTHFD2/MTHFD1) to catalyze the same reactions. Based on systems-level analysis, we identified 8 to 28 subtype-specific genes with pivotal roles in controlling the metabolic network and predicted that these genes may be targeted for development of treatment strategies for HCC subtypes by performing in silico analysis. To validate our predictions, we performed experiments using HepG2 cells under normoxic and hypoxic conditions and observed opposite expression patterns between genes expressed in high/moderate/low-survival tumor groups in response to hypoxia, reflecting activated hypoxic behavior in patients with poor survival. In conclusion, our analyses showed that the heterogeneous HCC tumors can be stratified using a metabolic network-driven approach, which may also be applied to other cancer types, and this stratification may have clinical implications to drive the development of precision medicine. PMID- 30482856 TI - Emergent elasticity in the neural code for space. AB - Upon encountering a novel environment, an animal must construct a consistent environmental map, as well as an internal estimate of its position within that map, by combining information from two distinct sources: self-motion cues and sensory landmark cues. How do known aspects of neural circuit dynamics and synaptic plasticity conspire to accomplish this feat? Here we show analytically how a neural attractor model that combines path integration of self-motion cues with Hebbian plasticity in synaptic weights from landmark cells can self-organize a consistent map of space as the animal explores an environment. Intriguingly, the emergence of this map can be understood as an elastic relaxation process between landmark cells mediated by the attractor network. Moreover, our model makes several experimentally testable predictions, including (i) systematic path dependent shifts in the firing fields of grid cells toward the most recently encountered landmark, even in a fully learned environment; (ii) systematic deformations in the firing fields of grid cells in irregular environments, akin to elastic deformations of solids forced into irregular containers; and (iii) the creation of topological defects in grid cell firing patterns through specific environmental manipulations. Taken together, our results conceptually link known aspects of neurons and synapses to an emergent solution of a fundamental computational problem in navigation, while providing a unified account of disparate experimental observations. PMID- 30482857 TI - Mechanism of the E2 to E1 transition in Ca2+ pump revealed by crystal structures of gating residue mutants. AB - Ca2+-ATPase of sarcoplasmic reticulum (SERCA1a) pumps two Ca2+ per ATP hydrolyzed from the cytoplasm and two or three protons in the opposite direction. In the E2 state, after transferring Ca2+ into the lumen of sarcoplasmic reticulum, all of the acidic residues that coordinate Ca2+ are thought to be protonated, including the gating residue Glu309. Therefore a Glu309Gln substitution is not expected to significantly perturb the structure. Here we report crystal structures of the Glu309Gln and Glu309Ala mutants of SERCA1a under E2 conditions. The Glu309Gln mutant exhibits, unexpectedly, large structural rearrangements in both the cytoplasmic and transmembrane domains, apparently uncoupling them. However, the structure definitely represents E2 and, together with the help of quantum chemical calculations, allows us to postulate a mechanism for the E2 -> E1 transition triggered by deprotonation of Glu309. PMID- 30482858 TI - Contact mechanics between the human finger and a touchscreen under electroadhesion. AB - The understanding and control of human skin contact against technological substrates is the key aspect behind the design of several electromechanical devices. Among these, surface haptic displays that modulate the friction between the human finger and touch surface are emerging as user interfaces. One such modulation can be achieved by applying an alternating voltage to the conducting layer of a capacitive touchscreen to control electroadhesion between its surface and the finger pad. However, the nature of the contact interactions between the fingertip and the touchscreen under electroadhesion and the effects of confined material properties, such as layering and inelastic deformation of the stratum corneum, on the friction force are not completely understood yet. Here, we use a mean field theory based on multiscale contact mechanics to investigate the effect of electroadhesion on sliding friction and the dependency of the finger touchscreen interaction on the applied voltage and other physical parameters. We present experimental results on how the friction between a finger and a touchscreen depends on the electrostatic attraction between them. The proposed model is successfully validated against full-scale (but computationally demanding) contact mechanics simulations and the experimental data. Our study shows that electroadhesion causes an increase in the real contact area at the microscopic level, leading to an increase in the electrovibrating tangential frictional force. We find that it should be possible to further augment the friction force, and thus the human tactile sensing, by using a thinner insulating film on the touchscreen than used in current devices. PMID- 30482859 TI - TOR and RPS6 transmit light signals to enhance protein translation in deetiolating Arabidopsis seedlings. AB - Deetiolation is an essential developmental process transforming young plant seedlings into the vegetative phase with photosynthetic activities. Light signals initiate this important developmental process by triggering massive reprogramming of the transcriptome and translatome. Compared with the wealth of knowledge of transcriptional regulation, the molecular mechanism underlying this light triggered translational enhancement remains unclear. Here we show that light enhanced translation is orchestrated by a light perception and signaling pathway composed of photoreceptors, CONSTITUTIVE PHOTOMORPHOGENESIS 1 (COP1), the phytohormone auxin, target of rapamycin (TOR), and ribosomal protein S6 (RPS6). In deetiolating Arabidopsis seedlings, photoreceptors, including phytochrome A and cryptochromes, perceive far-red and blue light to inactivate the negative regulator COP1, which leads to activation of the auxin pathway for TOR-dependent phosphorylation of RPS6. Arabidopsis mutants defective in TOR, RPS6A, or RPS6B exhibited delayed cotyledon opening, a characteristic of the deetiolating process to ensure timely vegetative development of a young seedling. This study provides a mechanistic view of light-triggered translational enhancement in deetiolating Arabidopsis. PMID- 30482860 TI - NETSeq reveals heterogeneous nucleotide incorporation by RNA polymerase I. AB - DNA sequence motifs that affect RNA polymerase transcription elongation are well studied in prokaryotic organisms and contribute directly to regulation of gene expression. Despite significant work on the regulation of eukaryotic transcription, the effect of DNA template sequence on RNA polymerase I (Pol I) transcription elongation remains unknown. In this study, we examined the effects of DNA sequence motifs on Pol I transcription elongation kinetics in vitro and in vivo. Specifically, we characterized how the spy rho-independent terminator motif from Escherichia coli directly affects Saccharomyces cerevisiae Pol I activity, demonstrating evolutionary conservation of sequence-specific effects on transcription. The insight gained from this analysis led to the identification of a homologous sequence in the ribosomal DNA of S. cerevisiae We then used native elongating transcript sequencing (NETSeq) to determine whether Pol I encounters pause-inducing sequences in vivo. We found hundreds of positions within the ribosomal DNA (rDNA) that reproducibly induce pausing in vivo. We also observed significantly lower Pol I occupancy at G residues in the rDNA, independent of other sequence context, indicating differential nucleotide incorporation rates for Pol I in vivo. These data demonstrate that DNA template sequence elements directly influence Pol I transcription elongation. Furthermore, we have developed the necessary experimental and analytical methods to investigate these perturbations in living cells going forward. PMID- 30482861 TI - Quantifying the risk of hemiplasy in phylogenetic inference. AB - Convergent evolution-the appearance of the same character state in apparently unrelated organisms-is often inferred when a trait is incongruent with the species tree. However, trait incongruence can also arise from changes that occur on discordant gene trees, a process referred to as hemiplasy. Hemiplasy is rarely taken into account in studies of convergent evolution, despite the fact that phylogenomic studies have revealed rampant discordance. Here, we study the relative probabilities of homoplasy (including convergence and reversal) and hemiplasy for an incongruent trait. We derive expressions for the probabilities of the two events, showing that they depend on many of the same parameters. We find that hemiplasy is as likely-or more likely-than homoplasy for a wide range of conditions, even when levels of discordance are low. We also present a method to calculate the ratio of these two probabilities (the "hemiplasy risk factor") along the branches of a phylogeny of arbitrary length. Such calculations can be applied to any tree to identify when and where incongruent traits may be due to hemiplasy. PMID- 30482862 TI - Molecular mechanism of fusion pore formation driven by the neuronal SNARE complex. AB - Release of neurotransmitters from synaptic vesicles begins with a narrow fusion pore, the structure of which remains unresolved. To obtain a structural model of the fusion pore, we performed coarse-grained molecular dynamics simulations of fusion between a nanodisc and a planar bilayer bridged by four partially unzipped SNARE complexes. The simulations revealed that zipping of SNARE complexes pulls the polar C-terminal residues of the synaptobrevin 2 and syntaxin 1A transmembrane domains to form a hydrophilic core between the two distal leaflets, inducing fusion pore formation. The estimated conductances of these fusion pores are in good agreement with experimental values. Two SNARE protein mutants inhibiting fusion experimentally produced no fusion pore formation. In simulations in which the nanodisc was replaced by a 40-nm vesicle, an extended hemifusion diaphragm formed but a fusion pore did not, indicating that restricted SNARE mobility is required for rapid fusion pore formation. Accordingly, rapid fusion pore formation also occurred in the 40-nm vesicle system when SNARE mobility was restricted by external forces. Removal of the restriction is required for fusion pore expansion. PMID- 30482863 TI - PYL8 mediates ABA perception in the root through non-cell-autonomous and ligand stabilization-based mechanisms. AB - The phytohormone abscisic acid (ABA) plays a key role regulating root growth, root system architecture, and root adaptive responses, such as hydrotropism. The molecular and cellular mechanisms that regulate the action of core ABA signaling components in roots are not fully understood. ABA is perceived through receptors from the PYR/PYL/RCAR family and PP2C coreceptors. PYL8/RCAR3 plays a nonredundant role in regulating primary and lateral root growth. Here we demonstrate that ABA specifically stabilizes PYL8 compared with other ABA receptors and induces accumulation of PYL8 in root nuclei. This requires ABA perception by PYL8 and leads to diminished ubiquitination of PYL8 in roots. The ABA agonist quinabactin, which promotes root ABA signaling through dimeric receptors, fails to stabilize the monomeric receptor PYL8. Moreover, a PYL8 mutant unable to bind ABA and inhibit PP2C is not stabilized by the ligand, whereas a PYL85KR mutant is more stable than PYL8 at endogenous ABA concentrations. The PYL8 transcript was detected in the epidermis and stele of the root meristem; however, the PYL8 protein was also detected in adjacent tissues. Expression of PYL8 driven by tissue-specific promoters revealed movement to adjacent tissues. Hence both inter- and intracellular trafficking of PYL8 appears to occur in the root apical meristem. Our findings reveal a non-cell autonomous mechanism for hormone receptors and help explain the nonredundant role of PYL8-mediated root ABA signaling. PMID- 30482865 TI - Recognizing the Top 25 Peer Reviewers for the Journal of Virology. PMID- 30482866 TI - Acknowledgment of Ad Hoc Reviewers. PMID- 30482864 TI - Integrating host response and unbiased microbe detection for lower respiratory tract infection diagnosis in critically ill adults. AB - Lower respiratory tract infections (LRTIs) lead to more deaths each year than any other infectious disease category. Despite this, etiologic LRTI pathogens are infrequently identified due to limitations of existing microbiologic tests. In critically ill patients, noninfectious inflammatory syndromes resembling LRTIs further complicate diagnosis. To address the need for improved LRTI diagnostics, we performed metagenomic next-generation sequencing (mNGS) on tracheal aspirates from 92 adults with acute respiratory failure and simultaneously assessed pathogens, the airway microbiome, and the host transcriptome. To differentiate pathogens from respiratory commensals, we developed a rules-based model (RBM) and logistic regression model (LRM) in a derivation cohort of 20 patients with LRTIs or noninfectious acute respiratory illnesses. When tested in an independent validation cohort of 24 patients, both models achieved accuracies of 95.5%. We next developed pathogen, microbiome diversity, and host gene expression metrics to identify LRTI-positive patients and differentiate them from critically ill controls with noninfectious acute respiratory illnesses. When tested in the validation cohort, the pathogen metric performed with an area under the receiver operating curve (AUC) of 0.96 (95% CI, 0.86-1.00), the diversity metric with an AUC of 0.80 (95% CI, 0.63-0.98), and the host transcriptional classifier with an AUC of 0.88 (95% CI, 0.75-1.00). Combining these achieved a negative predictive value of 100%. This study suggests that a single streamlined protocol offering an integrated genomic portrait of pathogen, microbiome, and host transcriptome may hold promise as a tool for LRTI diagnosis. PMID- 30482867 TI - beta-RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9 R239X mice. AB - Coenzyme Q (CoQ) deficiency has been associated with primary defects in the CoQ biosynthetic pathway or to secondary events. In some cases, the exogenous CoQ supplementation has limited efficacy. In the Coq9 R239X mouse model with fatal mitochondrial encephalopathy due to CoQ deficiency, we have tested the therapeutic potential of beta-resorcylic acid (beta-RA), a structural analog of the CoQ precursor 4-hydroxybenzoic acid and the anti-inflammatory salicylic acid. beta-RA noticeably rescued the phenotypic, morphological, and histopathological signs of the encephalopathy, leading to a significant increase in the survival. Those effects were due to the decrease of the levels of demethoxyubiquinone-9 (DMQ9) and the increase of mitochondrial bioenergetics in peripheral tissues. However, neither CoQ biosynthesis nor mitochondrial function changed in the brain after the therapy, suggesting that some endocrine interactions may induce the reduction of the astrogliosis, spongiosis, and the secondary down-regulation of astrocytes-related neuroinflammatory genes. Because the therapeutic outcomes of beta-RA administration were superior to those after CoQ10 supplementation, its use in the clinic should be considered in CoQ deficiencies. PMID- 30482869 TI - The Brief Case: Retropharyngeal Abscess in a 14-Year-Old Caused by Fusobacterium necrophorum. PMID- 30482868 TI - CSF progranulin increases in the course of Alzheimer's disease and is associated with sTREM2, neurodegeneration and cognitive decline. AB - Progranulin (PGRN) is predominantly expressed by microglia in the brain, and genetic and experimental evidence suggests a critical role in Alzheimer's disease (AD). We asked whether PGRN expression is changed in a disease severity-specific manner in AD We measured PGRN in cerebrospinal fluid (CSF) in two of the best characterized AD patient cohorts, namely the Dominant Inherited Alzheimer's Disease Network (DIAN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). In carriers of AD causing dominant mutations, cross-sectionally assessed CSF PGRN increased over the course of the disease and significantly differed from non-carriers 10 years before the expected symptom onset. In late-onset AD, higher CSF PGRN was associated with more advanced disease stages and cognitive impairment. Higher CSF PGRN was associated with higher CSF soluble TREM2 (triggering receptor expressed on myeloid cells 2) only when there was underlying pathology, but not in controls. In conclusion, we demonstrate that, although CSF PGRN is not a diagnostic biomarker for AD, it may together with sTREM2 reflect microglial activation during the disease. PMID- 30482871 TI - Photo Quiz: A Bacterium Better Known by Surgical Pathologists than by Clinical Microbiologists. PMID- 30482870 TI - Closing the Brief Case: Retropharyngeal Abscess in a 14-Year-Old Caused by Fusobacterium necrophorum. PMID- 30482872 TI - Answer to December 2018 Photo Quiz. PMID- 30482873 TI - Air pollution moves up the global health agenda. PMID- 30482875 TI - The Detroit Research on Cancer Survivors (ROCS) Pilot Study: A focus on outcomes after cancer in a racially-diverse patient population. AB - BACKGROUND: African Americans are often diagnosed with advanced stage cancer and experience higher mortality compared with whites in the United States. Contributing factors, like differences in access to medical care and the prevalence of comorbidities, do not entirely explain racial differences in outcomes. METHODS: The Detroit Research on Cancer Survivors (ROCS) pilot study was conducted to investigate factors related to short and long term outcomes among cancer patients. Participants completed web-based surveys and mailed saliva specimens were collected for future genetic studies. RESULTS: We recruited 1,000 participants with an overall response rate of 68%. Thirty-one percent completed the survey without any interviewer support and the remaining participated in an interviewer-administered survey. Seventy-four percent provided a saliva specimen and 64% consented for tumor tissue retrieval. African American survivors required more interviewer support (p<0.001), however their response rate (69.6%) was higher than non-Hispanic whites (65.4%). African Americans reported poorer overall cancer-related quality of life compared with non-Hispanic whites, measured by FACT-G score (p<0.001), however , this relationship was reversed after controlling for socioeconomic factors, marital status, and the presence of comorbidities. CONCLUSIONS: In this pilot study, we demonstrated that a web-based survey supplemented with telephone interviews and mailed saliva kits are cost effective methods to collect patient-reported data and DNA for large studies of cancer survivors with a high proportion of minority patients. IMPACT: The preliminary data collected reinforces differences by race in factors affecting cancer outcomes. Our efforts continue as we expand this unique cohort to include more than 5,000 African American cancer survivors. PMID- 30482876 TI - Selenium and sex steroid hormones in a US nationally representative sample of men: A role for the link between selenium and estradiol in prostate carcinogenesis? AB - BACKGROUND: Given the recent findings from pooled studies about a potential inverse association between selenium levels and prostate cancer risk, the current cross-sectional study aimed to investigate the association between serum selenium and serum concentrations of sex steroid hormones including estradiol in a nationally representative sample of US men to investigate one mechanism by which selenium may influence prostate cancer risk. METHODS: The study included 1,420 men aged 20 years or older who participated in the Third National Health and Nutrition Examination Survey (NHANES III) between 1988 and 1994. We calculated age/race-ethnicity-adjusted and multivariable-adjusted geometric mean serum concentrations of total and estimated free testosterone and estradiol, androstanediol glucuronide (AAG), and sex hormone binding globulin (SHBG) and compared them across quartiles of serum selenium. RESULTS: Adjusting for age, race/ethnicity, smoking status, serum cotinine, household income, physical activity, alcohol consumption and percent body fat, mean total estradiol (e.g. Q1:38.00 pg/mL (95%CI:36.03-40.08) vs Q4:35.29 pg/mL (33.53-37.14); Ptrend=0.050)and free estradiol [e.g.Q1: 0.96 pg/mL (95%CI: 0.92-1.01) vs Q4: 0.90 (95%CI:0.85-0.95); Ptrend=0.065] concentrations decreased over quartiles of selenium. Stratification by smoking and alcohol consumption, showed that the latter observation was stronger for never smokers (Pinteraction=0.073) and those with limited alcohol intake (Pinteraction=0.017). No associations were observed for the other sex steroid hormones studied. CONCLUSION: Our findings suggests that a possible mechanism by which selenium may be protective for prostate cancer is related to estrogen. IMPACT: Further studies of longitudinal measurements of serum and toenail selenium in relation to serum measurements of sex steroid hormones are needed. PMID- 30482877 TI - Inner Workings: Mapping the microbiome location helps elucidate its role. PMID- 30482874 TI - Aspirin, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), and Glioma Risk: Original Data from the Glioma International Case-Control Study and a Meta Analysis. AB - BACKGROUND: There have been few studies of sufficient size to address the relationship between glioma risk and the use of aspirin or non-steroidal anti inflammatory drugs (NSAIDs), and results have been conflicting. The purpose of this study was to examine the associations between glioma and aspirin/NSAID use, and to aggregate these findings with prior published studies using meta-analysis. METHODS: The Glioma International Case-Control Study (GICC) consists of 4,533 glioma cases and 4,171 controls recruited from 2010-2013. Interviews were conducted using a standardized questionnaire to obtain information on aspirin/NSAID use. We examined history of regular use for >=6 months and duration response. Restricted maximum likelihood meta-regression models were used to aggregate site-specific estimates, and to combine GICC estimates with previously published studies. RESULTS: A history of daily aspirin use for >=6 months was associated with a 38% lower glioma risk, compared to not having a history of daily use (adjusted meta-OR=0.62, 95% CI=0.54-0.70). There was a significant duration-response trend (p=1.67x10-17), with lower ORs for increasing duration of aspirin use. Duration-response trends were not observed for NSAID use. In the meta-analysis aggregating GICC data with five previous studies, there was a marginally significant association between use of aspirin and glioma (mOR=0.84, 95% CI=0.70-1.02), but no association for NSAID use. CONCLUSION: Our study suggests that aspirin may be associated with a reduced risk of glioma. IMPACT: These results imply that aspirin use may be associated with decreased glioma risk. Further research examining the association between aspirin use and glioma risk is warranted. PMID- 30482879 TI - Patterns and trends in OSHA occupational noise exposure measurements from 1979 to 2013. AB - OBJECTIVES: Noise is one of the most common exposures, and occupational noise induced hearing loss (NIHL) is highly prevalent. In addition to NIHL, noise is linked to numerous non-auditory health effects. The Occupational Safety and Health Administration (OSHA) maintains the Integrated Management Information System (IMIS) database of compliance-related measurements performed in various industries across the USA. The goal of the current study was to describe and analyse personal noise measurements available through the OSHA IMIS, identifying industries with elevated personal noise levels or increasing trends in worker exposure over time. METHODS: Through a Freedom of Information Act request, we obtained OSHA's noise measurements collected and stored in IMIS between 1979 and 2013 and analysed permissible exposure limit (PEL) and action level (AL) criteria measurements by two-digit industry code. RESULTS: The manufacturing industry represented 87.8% of the 93 920 PEL measurements and 84.6% of the 58 073 AL measurements. The highest mean noise levels were found among the agriculture, forestry, fishing and hunting industry for PEL (93.1 dBA) and the mining, quarrying and oil and gas extraction group for AL (93.3 dBA). Overall, measurements generally showed a decreasing trend in noise levels and exceedances of AL and PEL by year, although this was not true for all industries. CONCLUSIONS: Our results suggest that, despite reductions in noise over time, further noise control interventions are warranted both inside and outside of the manufacturing industry. Further reductions in occupational noise exposures across many industries are necessary to continue to reduce the risk of occupational NIHL. PMID- 30482880 TI - COPD, airflow limitation and chronic bronchitis in farmers: a systematic review and meta-analysis. AB - INTRODUCTION: The current definition of chronic obstructive pulmonary disease (COPD) associates persistent airflow limitation and chronic respiratory symptoms. Agricultural work has been associated with an increased risk of developing COPD, but the prevalence and definition of the disease vary greatly between studies. This meta-analysis aimed to assess the association between agricultural work and COPD using the most widely used definitions of the disease. METHODS: Inclusion criteria were: (1) design: cross-sectional or longitudinal, (2) groups: at least one group of farmers and a control group of non-farmers, (3) outcome: prevalence or unadjusted OR of COPD, airflow limitation and/or chronic bronchitis, (4) study subjects: groups of exposed subjects comprising >=30 individuals and with a mean age >=40 years and (5) language: English and French language, full-length, original publications in peer-reviewed journals. RESULTS: In total, 22 manuscripts were included in the meta-analysis. Eight studies assessed only the prevalence of airflow limitation, nine assessed only the prevalence of chronic bronchitis and four assessed the prevalence of both these parameters. Only one assessed the prevalence of COPD according to its current definition, and this study also provided the prevalence of airflow limitation. Ten studies showed a positive association between farming exposure and airflow limitation or chronic bronchitis, and 12 showed no association (OR (95% CI)=1.77 (1.50 to 2.08), p<0.001). Cattle, swine, poultry and crop farming were associated with either airflow limitation or chronic bronchitis. CONCLUSION: Although some features of COPD are associated with some agricultural work, well-designed studies with appropriate diagnostic criteria should be conducted to draw strong conclusions about the relationship between COPD and farming. PMID- 30482881 TI - Transforming growth factor-beta1 up-regulates connexin43 expression in osteocytes via canonical Smad-dependent signaling pathway. AB - Connexin 43 (Cx43)-mediated gap junctional intercellular communication (GJIC) has been shown to be important in regulating multiple functions of bone cells. Transforming growth factor-beta1 (TGF-beta1) exhibited controversial effects on the expression of Cx43 in different cell types. To date, the effect of TGF-beta1 on the Cx43 expression of osteocytes is still unknown. In this study, we detected the expression of TGF-beta1 in osteocytes and bone tissue, and then used recombinant mouse TGF-beta1 to elucidate its effect on gap junctions of osteocytes. Our data indicated that TGF-beta1 up-regulated both mRNA and protein expression of Cx43 in osteocytes. Together with down-regulation of Cx43 expression after being treated with TGF-beta type I receptor inhibitor Repsox, we deduce that TGF-beta1 can positively regulate Cx43 expression in osteocytes. Thus we next focused on the downstream signals of TGF-beta and found that TGF-beta1 mediated smads, Smad3 and Smad4, to translocate into nucleus. These translocated signal proteins binds to the promoter of Gja1 which was responsible for the changed expression of Cx43. This study provides evidence that TGF-beta1 can enhance GJIC between osteocytes through up-regulating Cx43 expression and the underlying mechanism which involves in the activation of Smad-dependent pathway. PMID- 30482882 TI - Armc8 is a evolutionarily conserved armadillo protein involved in cell-cell adhesion complexes through multiple molecular interactions. AB - Armadillo-repeat-containing protein 8 (Armc8) belongs to the family of armadillo repeat containing proteins, which have been found to be involved in diverse cellular functions including cell-cell contacts and intracellular signaling. By comparative analyses of armadillo repeat protein structures and genomes from various premetazoan and metazoan species, we identified orthologs of human Armc8 and analyzed in detail the evolutionary relationship of Armc8 genes and their encoded proteins. Armc8 is a highly ancestral armadillo protein although not present in yeast. Consequently, Armc8 is not the human ortholog of yeast Gid5/Vid28.Further, we performed a candidate approach to characterize new protein interactors of Armc8. Interactions between Armc8 and specific delta-catenins (plakophilins-1, -2, -3 and p0071) were observed by the yeast two-hybrid approach and confirmed by co-immunoprecipitation and colocalization. We also showed that Armc8 interacts specifically with alphaE-catenin but neither with alphaN-catenin nor with alphaT-catenin. Degradation of alphaE-catenin has been reported to be important in cancer and to be regulated by Armc8. A similar process may occur with respect to plakophilins in desmosomes. Deregulation of desmosomal proteins has been considered to contribute to tumorigenesis. PMID- 30482883 TI - MiR-155 is involved in major depression disorder and antidepressant treatment via targeting SIRT1. AB - Major depressive disorder (MDD) is a common mood disorder and the treatment of MDD requires a variety of biopsychosocial approaches. The role of Silent information regulator 1 (SIRT1) in the regulation of MDD has recently been implicated. Here we aimed to explore and elucidate the therapeutic effects of a microRNA, miR-155, in treatment of MDD. With quantitative real-time PCR (qRT-PCR) analysis, we confirmed that cellular and serum levels of miR-155 were upregulated in individuals with depression compared with those in healthy controls. TargetScan analysis indicated that SIRT1 is a target of miR-155, which was confirmed by dual-luciferase assay, qRT-PCR and western blot analyses. Treatment of human neural progenitor cells with the antidepressant drug citalopram downregulated miR-155 expression and upregulated SIRT1 expression. These results suggest that miR-155 is an important factor in pathophysiology of depression. miR 155 is a potential target for the development of new antidepressant treatments. PMID- 30482884 TI - Title. AB - Epilepsy is defined as drug-resistant after failure of two adequate trials of appropriately chosen and administered antiepileptic drugs. Approximately 30% of patients with epilepsy have drug-resistant epilepsy. Reasons for treatment failure include failure to recognise epilepsy syndrome, poor drug compliance, and lifestyle factors. Patients with drug-resistant epilepsy should be encouraged to have early referral to a tertiary epilepsy centre for presurgical evaluation. Comprehensive neurophysiology, structural neuroimaging, neuropsychological, and psychiatric assessments are regarded as essential for determining suitability for epilepsy surgery. Epilepsy surgery, whether resection, disconnection, or neuromodulation, should be recommended only after multidisciplinary consensus agreement based on these assessments. PMID- 30482885 TI - Cell and tissue type independent age-associated DNA methylation changes are not rare but common. AB - Age-associated DNA methylation changes have been widely reported across many different tissue and cell types. Epigenetic 'clocks' that can predict chronological age with a surprisingly high degree of accuracy appear to do so independently of tissue and cell-type, suggesting that a component of epigenetic drift is cell-type independent. However, the relative amount of age-associated DNAm changes that are specific to a cell or tissue type versus the amount that occurs independently of cell or tissue type is unclear and a matter of debate, with a recent study concluding that most epigenetic drift is tissue-specific. Here, we perform a novel comprehensive statistical analysis, including matched multi cell-type and multi-tissue DNA methylation profiles from the same individuals and adjusting for cell-type heterogeneity, demonstrating that a substantial amount of epigenetic drift, possibly over 70%, is shared between significant numbers of different tissue/cell types. We further show that ELOVL2 is not unique and that many other CpG sites, some mapping to genes in the Wnt and glutamate receptor signaling pathways, are altered with age across at least 10 different cell/tissue types. We propose that while most age-associated DNAm changes are shared between cell-types that the putative functional effect is likely to be tissue-specific. PMID- 30482886 TI - TGF-beta induces corneal endothelial senescence via increase of mitochondrial reactive oxygen species in chronic corneal allograft failure. AB - The corneal endothelium (CE) dysfunction impairs optical transparency and leads to corneal allograft failure. Morphologically, CE cells are characterized by premature senescence at the late stage of corneal graft. However, the detailed molecular mechanisms are largely unknown. Here we found that transforming growth factor-beta (TGF-beta) is elevated in the CE of late graft failure. In addition, senescence-associated gene p21 and p16 are increased as well, which is consistent with their elevation upon TGF-beta treatment in human corneal endothelial cell B4G12. Furthermore, TGF-beta treatment leads to high positive ratio of SA-beta gal, indicating B4G12 cells undergo cellular senescence. Mechanistically, we demonstrated that TGF-beta could induce mitochondrial ROS (mtROS) production and mtROS scavenger could rescue CE cell senescence upon TGF-beta treatment. Our study provides new evidence that elevated TGF-beta plays a crucial role in the CE cell senescence and loss in chronic corneal graft failure, which could be potential targets for clinical treatment. PMID- 30482887 TI - Suppression of mTORC1 activity in senescent Ras-transformed cells neither restores autophagy nor abrogates apoptotic death caused by inhibition of MEK/ERK kinases. AB - Autophagy is conservative catabolic process that degrades organelles, in particular, mitochondria, and misfolded proteins within the lysosomes, thus maintaining cellular viability. Despite the close relationship between mitochondrial dysfunction and cellular senescence, it is unclear how mitochondria damage can induce autophagy in senescent cells. We show that MEK/ERK suppression induces mitochondria damage followed by apoptosis of senescent Ras-expressing cells. To understand the role of persistent mTORC1 signaling in breaking the cAMPK-induced autophagy caused by mitochondrial damage, we inhibited mTORS1 with low concentrations of pp242. mTORC1 suppression neither restores the AMPK-induced autophagy nor decreases the level of apoptosis upon MEK/ERK inhibition. We discovered the existence of an alternative autophagy-like way that partially increases the viability of senescent cells under suppressed mTORC1. The pp242 treated cells survive due to formation of the non-autophagous LC3-negative vacuoles, which contain the damaged mitochondria and lysosomes with the following excretion the content from the cell. MEK/ERK activity is required to implement this process in senescent cells. Senescent cells exhibit distinctive spatial distribution of organelles and proteins that provides uncoupling of final participants of autophagy. We show that this feature stops the process of cytoprotective autophagy in response to MEK/ERK suppression, thus allowing selective elimination of senescent Ras-expressing cells. PMID- 30482888 TI - Recycling the LDL receptor to combat atherosclerosis. PMID- 30482889 TI - The chiggers (Acari: Trombiculidae) on wild birds in Honduras. AB - The chiggers (Acari: Trombiculidae) Blankaartia sinnamaryi (Floch et Fauran, 1956), Parasecia soucouyanti (Brennan et Yunker, 1966), Eutrombicula lipovskyana (Wolfenbarger, 1952) and Neoschoengastia dalmati Brennan, 1951 were found in Honduras on a total of twelve bird species. Parasecia soucouyanti was recorded parasitising birds for the first time. All these mites are here reported from Honduras for the first time. PMID- 30482890 TI - Anomalous Fusion of Right Pulmonary Artery to Aortic Arch: Case Report of a Rare and Fatal Congenital Malformation in a Newborn and a Literature Review. AB - BACKGROUND We present a report of a rare cardiac malformation case as well as a review of the literature. In addition, the diagnostic features are discussed. CASE REPORT The case of a female newborn who died on her third day of life was studied at the Institute of Legal Medicine, University of Chieti-Pescara (Italy). The investigations around her death revealed a cardiac congenital malformation, seen as a rare variant of a common arterial trunk, in which the aorta was fused with the right branch of the pulmonary artery. The ascending aorta showed hypoplasia, while the coronary arteries were free of any pathological findings. The atrial septum showed a closed foramen ovale and the ventricular septum did not show any defect. Only an isolated right ventricular hypertrophy and dilation with no other cardiac abnormalities was found. The cause of death was acute respiratory failure on the third day of extrauterine life when the ductus Botalli closed. The karyotype analysis performed in this case was normal, and the fluorescent in situ hybridization analysis did not show the 22q11.2 microdeletion suggestive of the DiGeorge syndrome. CONCLUSIONS These findings underline the value of 3-dimensional/4-dimensional ultrasound imaging when added to a fetal cardiology screening program, and the need for improvements in postnatal screening routines by using pulse oximetry in order to discover isolated vascular defects before circulatory collapse occurs, as well as to reduce the medico-legal disputes in cases of missed diagnosis. We found the relevant literature search lacked a description of this congenital malformation, which supports our deeper perinatal investigation. PMID- 30482891 TI - Antimicrobial Resistance Profiles of Nosocomial Pathogens in Regional China: A Brief Report from Two Tertiary Hospitals in China. AB - BACKGROUND Antimicrobial resistance of nosocomial pathogens has become a worldwide problem that leads to major healthcare and economic burdens. Regional antimicrobial resistance profiles are needed to inform selection of proper antimicrobial agents. MATERIAL AND METHODS In collaboration with the Hospital Infection Control Office at our hospitals, we analyzed the constitution of nosocomial pathogens and the corresponding drug-resistance profiles. We paid particular attention to characteristics of pathogens that were derived from the bloodstream, and summarized the drug-resistance tendency of 2 specific bacteria within the most recent decade to reflect the development of resistance in regional China. RESULTS The most common types of nosocomial pathogens were Escherichia coli (859 isolates, 14.3%), Staphylococcus aureus (763 isolates, 12.7%), Acinetobacter baumannii (681 isolates, 11.3%), Klebsiella pneumonia (660 isolates, 11.0%), and Pseudomonas aeruginosa (654 isolates, 10.9%). The most common types of bloodstream-derived pathogens were K. pneumoniae (125 isolates, 16.3%), E. coli (118 isolates, 15.3%), A. baumanii (81 isolates, 10.5%), Candida albians (57 isolates, 7.4%), S. aureus (45 isolates, 5.9%), P. aeruginosa (44 isolates, 5.7%), and Enterobacterium spp. (42 isolates, 5.5%). Distinct antimicrobial resistance profiles were observed between different pathogens as well as between bloodstream-derived and other sources of pathogens. The resistant rates of A. baumanii and P. aeruginosa to antimicrobial agents have been increasing during the most recent 10 years at our hospital. CONCLUSIONS Our data demonstrated the characteristics of nosocomial infections and antibiotic resistance in regional China. The distinct resistance profile of each pathogen can help to tailor individual antimicrobial strategy. The emerging resistant rates to antimicrobials require reinforced actions for infection prevention and control. PMID- 30482892 TI - [Socioeconomic health inequalities in the Catalan population aged 50+ during the last economic crisis]. AB - OBJECTIVE: The short- and medium-term consequences of the economic crisis since 2008 has become a cause of concern for population health. The study's objective was to analyse health inequalities according to the socioeconomic profile of the Catalan population aged 50 year and older. METHODS: Cross-sectional study using data from the Catalan Health Survey (ESCA) for the periods 2006 (N=6667), 2010-12 (N=4458) y 2013-15 (N=5469). The dependent variables were self-perceived health, mental health, medication intake and sedentary lifestyle and the independent variables: labour force activity status, educational level, health care coverage, household social class and household monthly income. On each dependent variable multivariate logistic analysis was conducted using Stata 14, adjusting for the remaining socioeconomic factors and other demographic variables, and estimating the average marginal effects for each socioeconomic category in the three observation moments. RESULTS: Between 2006 and 2013-15 the difference in the probability of having less than good self-perceived health among the population with or without double health coverage reduced from 0.06 to 0.04; between the most and least educated from 0.12 to 0.08; but did not reduce between workers and non-workers. The gap according to employment status, educational levels and income in the risk of poor mental health increased between 2006 and 2010-12 from 0.08 to 0.10, from 0.10 to 0.12 and from 0.10 to 0.13, although subsequently, inequality decreased. Difference in medication intake increased by employment status (from 0.07 to 0.10) and educational level (from -0.01 to 0.03) and in sedentary lifestyles between workers and non-workers (from 0, 05 to 0.06). Socioeconomic conditions had more impact on 50-64 year olds, especially women, while social inequality declined among men. CONCLUSIONS: Despite the crisis health generally improved, while socioeconomic health inequalities remained or reduced, barring few exceptions. PMID- 30482893 TI - Experimental transmission of Zika virus by Aedes japonicus japonicus from southwestern Germany. AB - The invasive mosquito species Aedes japonicus japonicus (Ae. japonicus) is widely distributed in Central Europe and is a known vector of various arboviruses in the laboratory, including flaviviruses such as Japanese Encephalitis virus or West Nile virus. However, the vector competence of Ae. japonicus for the recently emerging Zika virus (ZIKV) has not been determined. Therefore, field-caught Ae. japonicus from Germany were orally infected with ZIKV and incubated at 21, 24, or 27 degrees C to evaluate the vector competence under climate conditions representative of the temperate regions (21 degrees C) in the species' main distribution area in Europe and of Mediterranean regions (27 degrees C). Aedes japonicus was susceptible to ZIKV at all temperatures, showing infection rates between 10.0% (21 degrees C) and 66.7% (27 degrees C). However, virus transmission was detected exclusively at 27 degrees C with a transmission rate of 14.3% and a transmission efficiency of 9.5%. Taking into account the present distribution of Ae. japonicus in the temperate regions of Central Europe, the risk of ZIKV transmission by the studied Ae. japonicus population in Central Europe has to be considered as low. Nevertheless, due to the species' vector competence for ZIKV and other mosquito-borne viruses, in combination with the possibility of further spread to Mediterranean regions, Ae. japonicus must be kept in mind as a potential vector of pathogens inside and outside of Europe. PMID- 30482894 TI - Filamentation in Candida auris, an emerging fungal pathogen of humans: passage through the mammalian body induces a heritable phenotypic switch. AB - Morphological plasticity has historically been an indicator of increased virulence among fungal pathogens, allowing rapid adaptation to changing environments. Candida auris has been identified as an emerging multidrug resistant human pathogen of global importance. Since the discovery of this species, it has been thought that C. auris is incapable of filamentous growth. Here, we report the discovery of filamentation and three distinct cell types in C. auris: typical yeast, filamentation-competent (FC) yeast, and filamentous cells. These cell types form a novel phenotypic switching system that contains a heritable (typical yeast-filament) and a nonheritable (FC-filament) switch. Intriguingly, the heritable switch between the typical yeast and the FC/filamentous phenotype is triggered by passage through a mammalian body, whereas the switch between the FC and filamentous phenotype is nonheritable and temperature-dependent. Low temperatures favor the filamentous phenotype, whereas high temperatures promote the FC yeast phenotype. Systemic in vivo and in vitro investigations were used to characterize phenotype-specific variations in global gene expression, secreted aspartyl proteinase (SAP) activity, and changes in virulence, indicating potential for niche-specific adaptations. Taken together, our study not only sheds light on the pathogenesis and biology of C. auris but also provides a novel example of morphological and epigenetic switching in fungi. PMID- 30482895 TI - Detection of distinct MERS-Coronavirus strains in dromedary camels from Kenya, 2017. PMID- 30482897 TI - The DEVD motif of Crimean-Congo hemorrhagic fever virus nucleoprotein is essential for viral replication in tick cells. PMID- 30482896 TI - Evidence of a fixed internal gene constellation in influenza A viruses isolated from wild birds in Argentina (2006-2016). AB - Wild aquatic birds are the major reservoir of influenza A virus. Cloacal swabs and feces samples (n = 6595) were collected from 62 bird species in Argentina from 2006 to 2016 and screened for influenza A virus. Full genome sequencing of 15 influenza isolates from 6 waterfowl species revealed subtypes combinations that were previously described in South America (H1N1, H4N2, H4N6 (n = 3), H5N3, H6N2 (n = 4), and H10N7 (n = 2)), and new ones not previously identified in the region (H4N8, H7N7 and H7N9). Notably, the internal gene segments of all 15 Argentine isolates belonged to the South American lineage, showing a divergent evolution of these viruses in the Southern Hemisphere. Time-scaled phylogenies indicated that South American gene segments diverged between ~ 30 and ~ 140 years ago from the most closely related influenza lineages, which include the avian North American (PB1, HA, NA, MP, and NS-B) and Eurasian lineage (PB2), and the equine H3N8 lineage (PA, NP, and NS-A). Phylogenetic analyses of the hemagglutinin and neuraminidase gene segments of the H4, H6, and N8 subtypes revealed recent introductions and reassortment between viruses from the Northern and Southern Hemispheres in the Americas. Remarkably and despite evidence of recent hemagglutinin and neuraminidase subtype introductions, the phylogenetic composition of internal gene constellation of these influenza A viruses has remained unchanged. Considering the extended time and the number of sampled species of the current study, and the paucity of previously available data, our results contribute to a better understanding of the ecology and evolution of influenza virus in South America. PMID- 30482898 TI - Potential of Aedes albopictus as a bridge vector for enzootic pathogens at the urban-forest interface in Brazil. AB - The invasive species Aedes albopictus is present in 60% of Brazilian municipalities, including at the interfaces between urban settings and forests that are zoonotic arbovirus hotspots. We investigated Ae. albopictus colonization, adult dispersal and host feeding patterns in the anthropic-natural interface of three forested sites covering three biomes in Brazil in 2016. To evaluate whether an ecological overlap exists between Ae. albopictus and sylvatic yellow fever virus (YFV) in forests, we performed similar investigations in seven additional urban-forest interfaces where YFV circulated in 2017. We found Ae. albopictus in all forested sites. We detected eggs and adults up to 300 and 500 m into the forest, respectively, demonstrating that Ae. albopictus forest colonization and dispersal decrease with distance from the forest edge. Analysis of the host identity in blood-engorged females indicated that they fed mainly on humans and domestic mammals, suggesting rare contact with wildlife at the forest edge. Our results show that Ae. albopictus frequency declines as it penetrates into the forest and highlight its potential role as a bridge vector of zoonotic diseases at the edge of the Brazilian forests studied. PMID- 30482900 TI - Intellectual synthesis in mentorship determines success in academic careers. AB - As academic careers become more competitive, junior scientists need to understand the value that mentorship brings to their success in academia. Previous research has found that, unsurprisingly, successful mentors tend to train successful students. But what characteristics of this relationship predict success, and how? We analyzed an open-access database of 18,856 researchers who have undergone both graduate and postdoctoral training, compiled across several fields of biomedical science with an emphasis on neuroscience. Our results show that postdoctoral mentors were more instrumental to trainees' success compared to graduate mentors. Trainees' success in academia was also predicted by the degree of intellectual synthesis between their graduate and postdoctoral mentors. Researchers were more likely to succeed if they trained under mentors with disparate expertise and integrated that expertise into their own work. This pattern has held up over at least 40 years, despite fluctuations in the number of students and availability of independent research positions. PMID- 30482899 TI - The importance of study duration and spatial scale in pathogen detection-evidence from a tick-infested island. AB - Ticks (Acari: Ixodoidea) are among the most common vectors of zoonotic pathogens worldwide. While research on tick-borne pathogens is abundant, few studies have thoroughly investigated small-scale spatial differences in their occurrence. Here, we used long-term cloth-dragging data of Ixodes ricinus and its associated, known and putative pathogens (Borrelia burgdorferi s.l., Borrelia miyamotoi, Anaplasma phagocytophilum, Rickettsia spp., Candidatus Neoehrlichia mikurensis, Bartonella spp., Babesia spp., and tick-borne encephalitis virus, TBEV) from a small, well-studied island in southwestern Finland to analyze potential temporal and spatial differences in pathogen prevalence and diversity between and within different biotopes. We found robust evidence indicating significant dissimilarities in B. burgdorferi s.l., A. phagocytophilum, Rickettsia, and Ca. N. mikurensis prevalence, even between proximal study areas on the island. Moreover, during the 6 years of the ongoing study, we witnessed the possible emergence of TBEV and Ca. N. mikurensis on the island. Finally, the stable occurrence of a protozoan pathogen that has not been previously reported in Finland, Babesia venatorum, was observed on the island. Our study underlines the importance of detailed, long-term tick surveys for public health. We propose that by more precisely identifying different environmental factors associated with the emergence and upkeep of enzootic pathogen populations through rigorous longitudinal surveys, we may be able to create more accurate models for both current and future pathogen distributions. PMID- 30482901 TI - Rapid and robust restoration of breathing long after spinal cord injury. AB - There exists an abundance of barriers that hinder functional recovery following spinal cord injury, especially at chronic stages. Here, we examine the rescue of breathing up to 1.5 years following cervical hemisection in the rat. In spite of complete hemidiaphragm paralysis, a single injection of chondroitinase ABC in the phrenic motor pool restored robust and persistent diaphragm function while improving neuromuscular junction anatomy. This treatment strategy was more effective when applied chronically than when assessed acutely after injury. The addition of intermittent hypoxia conditioning further strengthened the ventilatory response. However, in a sub-population of animals, this combination treatment caused excess serotonergic (5HT) axon sprouting leading to aberrant tonic activity in the diaphragm that could be mitigated via 5HT2 receptor blockade. Through unmasking of the continuing neuroplasticity that develops after injury, our treatment strategy ensured rapid and robust patterned respiratory recovery after a near lifetime of paralysis. PMID- 30482902 TI - Author Correction: Imaging and clinical data archive for head and neck squamous cell carcinoma patients treated with radiotherapy. AB - In the original version of the Data Descriptor the surname of author Hesham Elhalawani was misspelled. This has now been corrected in the HTML and PDF versions. PMID- 30482904 TI - Response to: Comment on 'Are patients with poorer vision more polite? A study examining door closing tendencies in patients with poor vision'. PMID- 30482905 TI - Comment on: 'Are patients with poorer vision more polite? A study examining door closing tendencies in patients with poor vision'. PMID- 30482903 TI - Genetic characterization and molecular epidemiological analysis of novel enterovirus EV-B80 in China. AB - Enterovirus B80 (EV-B80) is a newly identified serotype belonging to the enterovirus B species. To date, only two full-length genomic sequences of EV-B80 are available in GenBank, and few studies on EV-B80 have been conducted in China or worldwide. More information and research on EV-B80 is needed to assess its genetic characteristics, phylogenetic relationships, and association with enteroviral diseases. In this study, we report the phylogenetic characteristics of three Xinjiang EV-B80 strains and one Tibet EV-B80 strain in China. The full length genomic sequences of four strains show 78.8-79% nucleotide identity and 94 94.2% amino acid identity with the prototype of EV-B80, indicating a tendency for evolution. Based on a maximum likelihood phylogenetic tree based on the entire VP1 region, three genotypes (A-C) were defined, revealing the possible origin of EV-B80 strains in the mainland of China. Recombination analysis revealed intraspecies recombinations in all four EV-B80 strains in nonstructural regions along with two recombination patterns. Due to the geographic factor, the coevolution of EV-B strains formed two different patterns of circulation. An antibody seroprevalence study against EV-B80 in two Xinjiang prefectures also showed that EV-B80 strains were widely prevalent in Xinjiang, China, compared to other studies on EV-B106 and EV-B89. All four EV-B80 strains are not temperature sensitive, showing a higher transmissibility in the population. In summary, this study reports the full-length genomic sequences of EV-B80 and provides valuable information on global EV-B80 molecular epidemiology. PMID- 30482906 TI - Bevacizumab: a new way of doing business. Part 2. PMID- 30482907 TI - From axolotl to zebrafish: a comparative approach to the study of thyroid involvement in ocular development. AB - While discussion of interactions between the thyroid gland and the eye mostly focus on thyroid eye disease, the involvement of the thyroid and its hormones on development of the eye before birth is also an important perspective that should not be forgotten. Experimental models involving amphibians and fish are valuable both because the developing larvae are not constrained within the adult but can be observed and manipulated as they grow autonomously and also because they metamorphose with substantial morphological changes driven by the hypothalamo pituitary-thyroid axis occurring as they develop from eggs to adults. In this paper we will first discuss changes seen in the axolotl, a naturally occurring neotonous hypothyroid salamander and the Xenopus toad a widely used laboratory amphibian. Secondly we will document ocular changes in flatfish which exhibit remarkable anatomical alterations during their change from a pelagic to benthic lifestyle. Finally we will evaluate ocular changes in developing zebrafish when subjected to thyroid-disrupting chemicals. These experiments show the influence of the thyroid on ocular development when thyroid function is altered which may be of value in determining changes in human hypothyroid infants but are also important to note as these chemicals are widely used in plastics and also as flame retardants used to control wildfires. Run-off into water courses can damage both wildlife and humans consuming contaminated water and thyroid disruption may have significant effects on reproduction and development, although influences on ocular morphology have yet to be investigated. PMID- 30482908 TI - Synthesis and antimicrobial activity of 3,4-bis(arylthio)maleimides. AB - A series of 3,4-bis(arylthio)maleimides were synthesized and their antimicrobial activity was evaluated against Gram-positive and Gram-negative bacteria, including multidrug resistant (MDR) strains and some fungi. Most compounds turned out to be highly active, activity being dependent on substituents on phenyl rings. PMID- 30482909 TI - Publisher Correction: Associations between subjective well-being and subcortical brain volumes. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30482910 TI - The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. AB - Nonalcoholic fatty liver disease (NAFLD) and its inflammatory and often progressive subtype nonalcoholic steatohepatitis (NASH) are becoming the leading cause of liver-related morbidity and mortality worldwide, and a primary indication for liver transplantation. The pathophysiology of NASH is multifactorial and not yet completely understood; however, innate immunity is a major contributing factor in which liver-resident macrophages (Kupffer cells) and recruited macrophages play a central part in disease progression. In this Review, we assess the evidence for macrophage involvement in the development of steatosis, inflammation and fibrosis in NASH. In this process, not only the polarization of liver macrophages towards a pro-inflammatory phenotype is important, but adipose tissue macrophages, especially in the visceral compartment, also contribute to disease severity and insulin resistance. Macrophage activation is mediated by factors such as endotoxins and translocated bacteria owing to increased intestinal permeability, factors released from damaged or lipoapoptotic hepatocytes, as well as alterations in gut microbiota and defined nutritional components, including certain free fatty acids, cholesterol and their metabolites. Reflecting the important role of macrophages in NASH, we also review studies investigating drugs that target macrophage recruitment to the liver, macrophage polarization and their inflammatory effects as potential treatment options for patients with NASH. PMID- 30482911 TI - Global epidemiology and holistic prevention of pancreatitis. AB - Knowledge of pancreatitis in the 20th century was shaped predominantly by animal data and clinical trials. Several large general population-based cohort studies and comprehensive systematic literature reviews in the 21st century have had a major effect on our understanding of pancreatitis and its sequelae. This Review provides precise and up-to-date data on the burden of acute pancreatitis, chronic pancreatitis and post-pancreatitis diabetes mellitus. Exocrine pancreatic insufficiency and altered bone metabolism following pancreatitis are also discussed. Furthermore, the article introduces a framework for the holistic prevention of pancreatitis with a view to providing guidance on strategies and intervention objectives at primary, secondary and tertiary levels. Concerted efforts by not only gastroenterologists and surgeons but also primary care physicians, endocrinologists, radiologists, pain specialists, dietitians, epidemiologists and public health specialists will be required to reduce meaningfully the burden of pancreatitis and its sequelae over the ensuing decades. PMID- 30482912 TI - B1 B cells link gut dysbiosis and insulin resistance. PMID- 30482913 TI - Increased risk of second cancers at sites associated with HPV after a prior HPV associated malignancy, a systematic review and meta-analysis. AB - BACKGROUND: High-risk human papilloma viruses (HPV) are a causative agent of anogenital and oropharyngeal cancers. Patients treated for a preinvasive or invasive HPV-associated cancer may be at increased risk of a second such malignancy. METHODS: We performed a systematic review and random effects meta analysis to estimate the risk of HPV-associated cancer after prior diagnosis. Studies reporting second cancers at anogenital and oropharyngeal sites after prior diagnoses (preinvasive/invasive HPV-associated cancer) were identified. Studies reporting standardised incidence ratios (SIRs) were included in formal meta-analyses of second cancer risk. (PROSPERO ID: CRD42016046974). RESULTS: Searches returned 5599 titles, including 60 unique, eligible studies. Thirty-two (98 comparisons) presented SIRs for second cervical, anal, vulvo-vaginal, penile, and/or oropharyngeal cancers, included in the meta-analyses. All studies (and 95/98 comparisons) reported increased cancers in the population with previous HPV associated cancer when compared to controls. Pooled SIRs for second primary cancers ranged from 1.75 (95% CI 0.66-4.67) for cervical cancer after primary anal cancer, to 13.69 (95% CI 8.56-21.89) for anal cancer after primary vulvo vaginal cancer. CONCLUSIONS: We have quantified the increased risk of second HPV associated cancer following diagnosis and treatment for initial cancer or preinvasive disease. This has important implications for follow-up, screening, and future therapeutic trials. PMID- 30482915 TI - Boosting a bad signal. PMID- 30482914 TI - Dasatinib sensitises triple negative breast cancer cells to chemotherapy by targeting breast cancer stem cells. AB - BACKGROUND: Patients with triple negative breast cancer (TNBC) exhibit poor prognosis and are at high risk of tumour relapse, due to the resistance to chemotherapy. These aggressive phenotypes are in part attributed to the presence of breast cancer stem cells (BCSCs). Therefore, targeting BCSCs is a priority to overcoming chemotherapy failure in TNBCs. METHODS: We generated paclitaxel (pac) resistant TNBC cells which displayed higher sphere forming potential and percentage of BCSC subpopulations compared to the parental cells. A screen with various kinase inhibitors revealed dasatinib, a Src kinase family inhibitor, as a potent suppressor of BCSC expansion/sphere formation in pac-resistant TNBC cells. RESULTS: We found dasatinib to block pac-induced BCSC enrichment and Src activation in both parental and pac-resistant TNBC cells. Interestingly, dasatinib induced an epithelial differentiation of the pac-resistant mesenchymal cells, resulting in their enhanced sensitivity to paclitaxel. The combination treatment of dasatinib and paclitaxel not only decreased the BCSCs numbers and their sphere forming capacity but also synergistically reduced cell viability of pac-resistant cells. Preclinical models of breast cancer further demonstrated the efficiency of the dasatinib/paclitaxel combination treatment in inhibiting tumour growth. CONCLUSIONS: Dasatinib is a promising anti-BCSC drug that could be used in combination with paclitaxel to overcome chemoresistance in TNBC. PMID- 30482916 TI - Safety and efficacy of sacubitril?valsartan in acute heart failure. PMID- 30482918 TI - Skull-collecting ants slay with acid. PMID- 30482917 TI - Publisher Correction: Enhancers active in dopamine neurons are a primary link between genetic variation and neuropsychiatric disease. AB - In the version of this article initially published, the legends for Supplementary Figs. 4-8 and 10-14 contained errors. The Supplementary Figure legends have been corrected in the HTML and PDF versions of the article. PMID- 30482919 TI - Termite mounds dating back millennia can be seen from space. PMID- 30482920 TI - A simple gadget nudges people to save energy in the shower. PMID- 30482921 TI - A switch by China's home cooks helps to save millions of lives. PMID- 30482922 TI - A synthetic flower that unfolds in the dark. PMID- 30482923 TI - A bacterium's enemy isn't your friend. PMID- 30482924 TI - A nation where millions barely move. PMID- 30482926 TI - The party drug that helps to patch over betrayal. PMID- 30482925 TI - 'Marsquake' hunter prepares to land on the red planet. PMID- 30482927 TI - AI peer reviewers unleashed to ease publishing grind. PMID- 30482928 TI - Frustrated Alzheimer's researchers seek better lab mice. PMID- 30482929 TI - Genome-edited baby claim provokes international outcry. PMID- 30482930 TI - Can a major AI conference shed its reputation for hosting sexist behaviour? PMID- 30482931 TI - Statistical pitfalls of personalized medicine. PMID- 30482932 TI - Thanks for opening an overdue discussion on GWAS of BMI: a reply to Prof. Speakman et al. PMID- 30482933 TI - Niacin induces miR-502-3p expression which impairs insulin sensitivity in human adipocytes. AB - MicroRNAs have been involved in insulin resistance (IR). As the mechanism whereby niacin, an anti-dyslipidemic agent, leads to IR remains elusive, we sought to identify differentially expressed microRNAs in adipose tissue (AT) of individuals receiving niacin and to explore the link between microRNAs, niacin and IR in human adipocytes.In a double-blind controlled study, 22 obese men received extended-release niacin or placebo over 8 weeks. Bioclinical data and subcutaneous AT biopsies were obtained before and after treatment. AT microRNA expression profiles were determined using RTqPCR for 758 human-specific microRNAs. hMADS adipocytes were treated with niacin, or acipimox (a niacin-like drug without effect on IR), or transfected with miR-502-3p. Glucose uptake and Western blotting were performed.In obese men, insulin sensitivity decreased after niacin treatment. In AT, the expression of 6 microRNAs including miR-502-3p was up-regulated. Treatment of hMADS adipocytes with niacin specifically increased miR-502-3p expression. Acipimox had no effect. Overexpression of miR-502-3p in adipocytes led to reduced insulin-induced glucose uptake and lower insulin stimulated AKT phosphorylation.Long term niacin treatment altered microRNA expression levels in human AT. Increased miR-502-3p expression may play a role in the mediation of IR due to niacin in adipocytes.The study is registered in Clinical Trials NCT01083329 and EudraCT 2009-012124-85. PMID- 30482934 TI - Relationship between monetary delay discounting and obesity: a systematic review and meta-regression. AB - BACKGROUND AND OBJECTIVES: Previous studies have documented that high rates of delay discounting are associated with obesity. However, studies utilizing monetary reward experiments typically report no associations, as opposed to positive associations apparent in studies utilising food-reward experiments. Our objective was to investigate the reasons behind the mixed evidence from a methodological perspective using systematic review and meta-analytic methodologies. METHODS: Seven databases (EMBASE, MEDLINE, PsycINFO, Scopus, Web of Science, Econlit and IBSS) were systematically searched. Logistic meta regression was applied to identify the determinants of a significant association and risk of bias was assessed using a modified form of the Newcastle Ottawa cohort scale. RESULTS: A total of 59 studies were identified, among which 29 studies (49.2%) found a significant positive association and 29 (49.2%) reported no association. A higher proportion of significant and positive associations was reported in those studies utilizing 'best-practice' methods (i.e. appropriate measurement models) to estimate monetary delay discounting (15/27; 55.6%) and incentive-compatible experiments (10/16; 62.5%) than those using non-'best practice' methods (14/34; 41.2%) and hypothetical experiments (19/43; 44.2%). All five studies utilizing both 'best-practice' methods and incentive-compatible experiments generated a positive and significant relationship. Results from a logistic meta-regression also suggested that studies employing incentive compatible experiments (OR: 4.38, 95% CI = 1.05-18.33, p value: 0.04), 'best practice' methods (OR: 4.40, 95% CI = 0.88-22.99, p value: 0.07), parametric methods (OR: 3.36, 95% CI = 0.83-13.57, p value: 0.04), those conducted in children/adolescent populations (OR: 3.90, 95% CI = 0.85-17.88, p value: 0.08), and those with larger sample size (OR: 1.91, 95% CI = 1.15-3.18, p value: 0.01) tended to show positive and significant associations between delay discounting and obesity. CONCLUSIONS: This review suggests that the mixed evidence to date is a result of methodological heterogeneity, and that future studies should utilise 'best practice' methods. PMID- 30482935 TI - Exposure to per-fluoroalkyl and polyfluoroalkyl substances leads to immunotoxicity: epidemiological and toxicological evidence. AB - In this perspective, we evaluate key and emerging epidemiological and toxicological data concerning immunotoxicity of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) and seek to reconcile conflicting conclusions from two reviews published in 2016. We summarize ways that immunosuppression and immunoenhancement are defined and explain how specific outcomes are used to evaluate immunotoxicity in humans and experimental animals. We observe that different approaches to defining immunotoxicological outcomes, particularly those that do not produce clinical disease, may lead to different conclusions from epidemiological and toxicological studies. The fundamental point that we make is that aspects of epidemiological studies considered as limitations can be minimized when data from toxicological studies support epidemiological findings. Taken together, we find that results of epidemiological studies, supported by findings from toxicological studies, provide strong evidence that humans exposed to PFOA and PFOS are at risk for immunosuppression. PMID- 30482936 TI - Per and polyfluoroalkyl substances (PFAS) blood levels after contamination of a community water supply and comparison with 2013-2014 NHANES. AB - INTRODUCTION: Per and polyfluoroalkyl substances (PFAS), including perfluorononanoic acid (PFNA) and perfluorooctanoic acid (PFOA), were detected in the community water supply of Paulsboro New Jersey in 2009. METHODS: A cross sectional study enrolled 192 claimants from a class-action lawsuit, not affiliated with this study, who had been awarded a blood test for 13 PFAS. Study participants provided their blood test results and completed a survey about demographics; 105 participants also completed a health survey. Geometric means, 25th, 50th, 75th, and 95th percentiles of exposure of PFNA blood serum concentrations were compared to that of the 2013-2014 NHANES, adjusted for reporting level. Associations between PFNA, PFOA, PFOS, and PFHxS and self reported health outcomes were assessed using logistic regression. RESULTS: PFNA serum levels were 285% higher in Paulsboro compared with U.S. residents. PFNA serum levels were higher among older compared with younger, and male compared to female, Paulsboro residents. After adjustment for potential confounding, there was a significant association between increased serum PFNA levels and self reported high cholesterol (OR: 1.15, 95% CI: 1.02, 1.29). DISCUSSION/CONCLUSION: Further investigation into possible health effects of PFAS exposure in Paulsboro and other community settings is warranted. Since exposure has ceased, toxicokinetics of PFAS elimination should be explored. PMID- 30482937 TI - Correlation over time of toenail metals among participants in the VA normative aging study from 1992 to 2014. AB - BACKGROUND: Scientists use biomarkers to evaluate metal exposures. One biomarker, toenails, is easily obtained and minimally invasive, but less commonly used as a biomarker of exposure. Their utility will depend on understanding characteristics of their variation in a population over time. The objective of our study is to describe the correlation of toenail metal levels many years apart among participants in the VA Normative Aging Study (NAS). METHODS: Toenail clippings from 825 participants of the NAS from year 1992 to 2014 were analyzed for lead (Pb), Arsenic (As), Cadmium (Cd), Manganese (Mn), and Mercury (Hg). We utilized linear mixed models to assess correlation between toenail metal concentrations in multiple toenail samples from the same subject collected years apart and identified the optimal covariance pattern by likelihood ratio tests and Akaike's information criterion (AIC). Correlations among different metals were described using Spearman correlations. RESULTS: The average number of times toenail samples were collected from each subject ranged from 1.63 (Hg) to 2.04 (As). The average number of years between toenails collected per subject ranged from 4.73 (SD = 2.44) (Mn) to 5.35 (SD = 2.69) (Hg). Metal concentrations had slightly different correlation patterns over time, although for all metals correlations decreased with increasing time between samples. Estimated correlations over a 3-year span were highest for toenail Pb (0.68) and Hg (0.67), while As, Cd, and Mn had lower correlations of 0.49, 0.44, and 0.47, respectively. Even across a 6-year span, the lowest correlation was 0.35 (Cd). CONCLUSIONS: Our results suggest that Pb, As, Cd, Mn, and Hg levels from toenail clippings can reasonably reflect exposures over several years in elderly men in the NAS. Even across 6 years, toenail metal levels were generally well correlated among NAS participants. As such, they may be useful as biomarkers of exposure in epidemiological studies of similar populations. PMID- 30482939 TI - TBK1 and IKKepsilon restrain cell death. PMID- 30482940 TI - Targeting BAF-perturbed cancers. PMID- 30482942 TI - Social media for scientists. PMID- 30482941 TI - Autophagy and the cell biology of age-related disease. AB - Macroautophagy (autophagy) is a conserved lysosomal degradation process essential for cellular homeostasis and adaption to stress. Accumulating evidence indicates that autophagy declines with age and that impaired autophagy predisposes individuals to age-related diseases, whereas interventions that stimulate autophagy often promote longevity. In this Review, we examine how the autophagy pathway restricts cellular damage and degeneration, and the impact of these functions towards tissue health and organismal lifespan. PMID- 30482943 TI - Tumour heterogeneity and metastasis at single-cell resolution. AB - Tumours comprise a heterogeneous collection of cells with distinct genetic and phenotypic properties that can differentially promote progression, metastasis and drug resistance. Emerging single-cell technologies provide a new opportunity to profile individual cells within tumours and investigate what roles they play in these processes. This Review discusses key technological considerations for single-cell studies in cancer, new findings using single-cell technologies and critical open questions for future applications. PMID- 30482944 TI - Practice makes plasticity. PMID- 30482938 TI - Publisher Correction: Very-high-energy particle acceleration powered by the jets of the microquasar SS 433. AB - In this Letter, owing to a production error, the penultimate version of the PDF was published. The HTML version was always correct. The PDF has been corrected online. PMID- 30482945 TI - Midbrain activity can explain perceptual decisions during an attention task. AB - We introduce a decision model that interprets the relative levels of moment-by moment spiking activity from the right and left superior colliculus to distinguish relevant from irrelevant stimulus events. The model explains detection performance in a covert attention task, both in intact animals and when performance is perturbed by causal manipulations. This provides a specific example of how midbrain activity could support perceptual judgments during attention tasks. PMID- 30482946 TI - Loss of neuronal network resilience precedes seizures and determines the ictogenic nature of interictal synaptic perturbations. AB - The mechanism of seizure emergence and the role of brief interictal epileptiform discharges (IEDs) in seizure generation are two of the most important unresolved issues in modern epilepsy research. We found that the transition to seizure is not a sudden phenomenon, but is instead a slow process that is characterized by the progressive loss of neuronal network resilience. From a dynamical perspective, the slow transition is governed by the principles of critical slowing, a robust natural phenomenon that is observable in systems characterized by transitions between dynamical regimes. In epilepsy, this process is modulated by synchronous synaptic input from IEDs. IEDs are external perturbations that produce phasic changes in the slow transition process and exert opposing effects on the dynamics of a seizure-generating network, causing either anti-seizure or pro-seizure effects. We found that the multifaceted nature of IEDs is defined by the dynamical state of the network at the moment of the discharge occurrence. PMID- 30482947 TI - Large-scale associations between the leukocyte transcriptome and BOLD responses to speech differ in autism early language outcome subtypes. AB - Heterogeneity in early language development in autism spectrum disorder (ASD) is clinically important and may reflect neurobiologically distinct subtypes. Here, we identified a large-scale association between multiple coordinated blood leukocyte gene coexpression modules and the multivariate functional neuroimaging (fMRI) response to speech. Gene coexpression modules associated with the multivariate fMRI response to speech were different for all pairwise comparisons between typically developing toddlers and toddlers with ASD and poor versus good early language outcome. Associated coexpression modules were enriched in genes that are broadly expressed in the brain and many other tissues. These coexpression modules were also enriched in ASD-associated, prenatal, human specific, and language-relevant genes. This work highlights distinctive neurobiology in ASD subtypes with different early language outcomes that is present well before such outcomes are known. Associations between neuroimaging measures and gene expression levels in blood leukocytes may offer a unique in vivo window into identifying brain-relevant molecular mechanisms in ASD. PMID- 30482950 TI - Phosphatases start shedding their stigma of undruggability. PMID- 30482952 TI - RNAi deal flow heats up. PMID- 30482949 TI - Motor primitives in space and time via targeted gain modulation in cortical networks. AB - Motor cortex (M1) exhibits a rich repertoire of neuronal activities to support the generation of complex movements. Although recent neuronal-network models capture many qualitative aspects of M1 dynamics, they can generate only a few distinct movements. Additionally, it is unclear how M1 efficiently controls movements over a wide range of shapes and speeds. We demonstrate that modulation of neuronal input-output gains in recurrent neuronal-network models with a fixed architecture can dramatically reorganize neuronal activity and thus downstream muscle outputs. Consistent with the observation of diffuse neuromodulatory projections to M1, a relatively small number of modulatory control units provide sufficient flexibility to adjust high-dimensional network activity using a simple reward-based learning rule. Furthermore, it is possible to assemble novel movements from previously learned primitives, and one can separately change movement speed while preserving movement shape. Our results provide a new perspective on the role of modulatory systems in controlling recurrent cortical activity. PMID- 30482951 TI - Metabolic disease: Safely mimicking cold exposure to reverse obesity. PMID- 30482953 TI - Cancer: Redirecting T cell activity in solid tumours. PMID- 30482954 TI - Expanding the medicinal chemistry synthetic toolbox. AB - This corrects the article DOI: 10.1038/nrd.2018.116. PMID- 30482955 TI - Market watch: The industry's biggest drug launches. PMID- 30482956 TI - Anticancer therapy: Complementing tumour macrophage reprogramming. PMID- 30482957 TI - Anti-inflammatory cardiovascular therapies take another hit. PMID- 30482958 TI - Aging: Promoting NAD+ production. PMID- 30482959 TI - Drug repurposing: Heart failure drug effective in medulloblastoma. PMID- 30482961 TI - Samantha Du. PMID- 30482960 TI - Anticancer drugs: Translational target for checkpoint inhibitors. PMID- 30482948 TI - Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders. AB - Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 * 10-13) and African ancestries (rs2066702; P = 2.2 * 10-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors. PMID- 30482962 TI - Trial watch: The clinical trial landscape for PD1/PDL1 immune checkpoint inhibitors. PMID- 30482963 TI - FDA approves first new flu drug in 20 years. PMID- 30482964 TI - Type 2 diabetes: Microbial metabolite impairs insulin signaling. PMID- 30482965 TI - Antifungal drugs: Small molecules targeting a tertiary RNA structure fight fungi. PMID- 30482966 TI - A review on antifungal activity and mode of action of essential oils and their delivery as nano-sized oil droplets in food system. AB - An escalated demand of minimally processed food and increased negative perception for synthetic preservative has led to a lookout for a natural preservative. Essential oils (EOs) are volatile and aromatic secondary metabolites of plants that have been tapped mainly for its flavour and fragrances and various biological properties such as antimicrobial and antioxidant. The constituents and antifungal potential of EOs have been reported widely in the present scientific literature. Moreover, the current scientific research dealing with the mode of action of EOs on fungal spores and mycelial cells are very scarce, unlike bacteria. The antimicrobial efficacy of EO in real food system may alter due to interaction with food matrix components. Besides, minimum alteration in sensory qualities while retaining its maximum activity is the most sought-after criteria for food preservation with EOs. If the oil is applied in excess to have better antimicrobial activity, it may end up having an unacceptable organoleptic impact on the food. Appropriate edible delivery systems of EOs as an emulsion is a probable approach to retain the maximum efficacy of EOs in the food system. Nano emulsification of EO could increase its bioactivity due to increased bioavailability in the food matrix. The basis of this review is to provide an overview of current knowledge about the antifungal properties and antifungal mode of action of EOs, and to recognize the application of EO as nano-sized oil droplets in the food system. PMID- 30482967 TI - Honey authentication using rheological and physicochemical properties. AB - The aim of this study was to evaluate the influence of honey botanical origins on rheological parameters. In order to achieve the correlation, fifty-one honey samples, of different botanical origins (acacia, polyfloral, sunflower, honeydew, and tilia), were investigated. The honey samples were analysed from physicochemical (moisture content, fructose, glucose and sucrose content) and rheological point of view (dynamic viscosity-loss modulus G", elastic modulus G', complex viscosity eta*, shear storage compliance-J' and shear loss compliance J"). The rheological properties were predicted using the Artificial Neural Networks based on moisture content, glucose, fructose and sucrose. The models which predict better the rheological parameters in function of fructose, glucose, sucrose and moisture content are: MLP-1 hidden layer is predicting the G", eta* and J", respectively, MLP-2 hidden layers the J', while MLP-3 hidden layers the G', respectively. The physicochemical and rheological parameters were submitted to statistical analysis as follows: Principal component analysis (PCA), Linear discriminant analysis (LDA) and Artificial neural network (ANN) in order to evaluate the usefulness of the parameters studied for honey authentication. The LDA was found the suitable method for honey botanical authentication, reaching a correct cross validation of 94.12% of the samples. PMID- 30482968 TI - Effect of clove extract on lipid oxidation, antioxidant activity, volatile compounds and fatty acid composition of salted duck eggs. AB - Antioxidant activity, lipid oxidation, fatty acid composition and volatile compounds of duck eggs supplemented with clove extract were monitored over the salting period. The results indicated that application of clove extracts significantly reduced 2-thiobarbituric acid reactive substances and anisidine values as well as the conjugated dienes levels during curing. Clove extracts along with salting time had significant effects on the fatty acid composition. The predominant fatty acid in salted duck eggs supplemented with clove extracts for 14 day of the salting process was oleic acid, followed by palmitic acid and arachidonic acid. Additionally, treated eggs exhibited a higher docosahexaenoic acid content than that of control. The results of SPME GC-MS showed the presence of 46 and 37 volatiles in the treated eggs. Eugenol, as the primary bioactive component of clove, was detected in salted eggs supplemented with clove extracts. In addition, analyzing the results obtained through electronic nose showed that clove extract brought significant changes in salted eggs flavor components. PMID- 30482969 TI - Effects of temperature and pectin edible coatings with guava by-products on the drying kinetics and quality of dried red guava. AB - With the objective of utilizing agro-industrial by-products and enhancing the quality attributes of dehydrated fruits, this study evaluated the effects of edible pectin-based coatings containing disintegrated guava by-products (up to 50% concentration) and drying temperatures (46-74 degrees C) on the drying kinetics and nutritional properties of dried red guava. Coatings were applied to guava slices prior to hot-air drying. A central composite rotatable design was used to optimize carotenoid and phenolic compound retention. The effects of the edible coating compositions combined with the drying temperatures affected the effectiveness of the film as a barrier to carotenoid oxidation. Total phenolic compound retention, however, was affected only by temperature. Responses were simultaneously optimized, and high carotenoid and total phenolic retentions were obtained at approximately 60 degrees C with 25% by-product concentration. The effective water diffusivities were mainly affected by temperature. Consequently, the coatings improved nutritional quality without having a major impact on drying times. PMID- 30482970 TI - Characterization of Aloe vera-chitosan composite films and their use for reducing the disease caused by fungi in papaya Maradol. AB - Composite films with Aloe vera (A), chitosan (Ch) and essential oils (EOs) were formulated. Six of the twelve combinations tested formed films: A70Ch30, A70Ch30 15, A60Ch40, A60Ch40-15, A50Ch50, and A50Ch50-15. The A60Ch40-15 film showed the best physicochemical characteristics as well as the greatest in vitro antifungal activity. Although the A90Ch10 and A80Ch20-15 mixtures did not form films, their solutions showed high antifungal activity in vitro. Based on multivariate analysis of the data, A60Ch40-15, A90Ch10 and A80Ch20-15 films were selected as coating treatments for papaya during storage at 30 +/- 2 degrees C and 80% RH. Uncoated fruits (control 1) and treated with synthetic fungicide (control 2) were used as control. Coated fruits showed lower respiration rate, greater firmness and fewer changes in external coloration compared to control. Furthermore, these coatings reduced the incidence and severity of fungal disease by 40-50% compared to control 2. Aloe vera-chitosan films (A90Ch10 and A60Ch40-15), enriched with the EOs of cinnamon (10 mL L-1) and thyme (10 mL L-1), improved quality of the fruit (higher firmness, lower CO2 content, less internal color change) with 50% less disease incidence during storage at room temperature. PMID- 30482971 TI - Effects of inclusion of porcine blood hydrolysate on physico-chemical quality, oxidative and microbial stability of pork batter stored at (4 +/- 1 degrees C). AB - Present study was conducted to evaluate the anti-oxidant and anti-microbial efficiency of porcine blood hydrolysate (PBH) in refrigerated pork batter. PBH produced by alcalase was included into pork batter at different levels viz. PBH1 0.03, PBH2-0.06 and PBH3-0.09% (w/w) and compared with control (C-0%) and positive control (PC-0.02% BHT w/w). The pH increased, whereas water activity, extract release volume and emulsion stability decreased during storage; however, all these parameters were better maintained in the treated groups. Anti-oxidant efficacy of treatments improved in a concentration dependent manner. Peroxide, thiobarbituric acid reacting substances and free fatty acid values were significantly lower than control throughout storage. The colour and microbial quality was better maintained in treatments than C and PC. In microbial challenge test, counts of tested microbes in treatment batter reduced up to 4th day but increased thereafter. Results suggest that PBH can be utilized as a potential component to improve physico-chemical quality, colour, oxidative and microbial stability of meat batter during refrigerated storage. PMID- 30482972 TI - Microbiological and chemical properties of wet tarhana produced by different dairy products. AB - This study investigated the use of kefir, yogurt and their combination in the production of wet tarhana with an aim to increase the nutritional value of the end product. Along with microbiological and chemical properties, the volatile compound composition of wet tarhana was also evaluated. Wet tarhana revealed an increase in the lactic acid bacteria count (LAB) with the addition of kefir. After fermentation, counts of total yeast, LAB, and total mesophilic aerobic bacteria were 7.57, 8.26 and 7.64 log CFU/g, respectively. The values of pH and titratable acidity were measured as 4.78 and 4.68% in terms of lactic acid, respectively, at the end of fermentation. Lactic acid content increased from 3.31 to 10.82 g/kg throughout fermentation. A total of 72 volatile compounds were recorded during fermentation and 44 of these were identified by GC-MS. The most abundant compounds identified in the tarhana samples were hexadecanoic acid and 9,12-octadecadienoic acid. Moreover, ABTS antioxidant activity results of all formulations were measured in the range of 15.86 and 19.31 umol TE/g at the end of fermentation and it was independent of the fermentation period. PMID- 30482973 TI - Phenolic profile, free amino acids composition and antioxidant potential of dried longan fermented by lactic acid bacteria. AB - In this study, dried longan pulp (DLP) was subjected to fermentation using selected strains of lactic acid bacteria (Lactobacillus plantarum subsp. Plantarum and Leuconostoc mesenteroides). We then studied changes in the free and bound phytochemical profile, antioxidant activity, free amino acid, and organic acid composition. Fermentation exhibited a 17.4% and 5.7% increase in the amount of free and total phenolic contents of DLP. Phenolic composition determined by HPLC revealed significant changes due to fermentation that were primarily in the contents of gallic acid, vanillic acid, 4-methylcatechol and p-coumaric acid, resulting in a 37.9% and 25.7% increase in free gallic acid and 4-methylcatechol, respectively. Fermentation was also found to enhance the ferric reducing antioxidant power of both free and total and the oxygen radical absorbance capacity of free phenolic fraction by 18.3%, 11.8%, and 37.4%, respectively. In addition, fermentation was observed to reduce the contents of free amino acids with bitter taste (phenylalanine, tyrosine and leucine), and increase amino acids (taurine, aspartic acid, cysteine, cysteine thiazoline and gamma-amino-butyric acid) having antioxidant potential. Therefore, this study provides basis for the production of fermented longan-based functional products with improved antioxidant activity. PMID- 30482974 TI - Phytochemical components and amino acid profile of brown seaweed Durvillaea antarctica as affected by air drying temperature. AB - The effects of different drying temperatures between 40 and 80 degrees C on bioactive constituents and antioxidant activity of edible sub Antarctic brown seaweed, Durvillaea antarctica were studied. Dietary fibre, amino acids profile, pigments (chlorophyll and carotenoids), vitamin E, total phenolics and total flavonoids as well as antioxidant activity were determined, beside a measurement of the chromatic coordinates. The brown seaweed D. antarctica had a high content of dietary fibre and was rich in essential amino acids and drying between 40 and 80 degrees C did not influence significantly dietary fibre content nor the level of essential amino acids that remained around 44%. However, a significant degradation of the chlorophyll pigments was observed with the lowest level of the initial chlorophyll content occurring at 60 degrees C (59%). Total carotenoids content was stable during drying between 50 and 70 degrees C. Vitamin E showed no significant loss during drying at any of the assayed temperatures, which could be due to its occurrence within the lipid fraction. Drying at 40 degrees C imparted a darker brown colour to the seaweed, while a lighter brown colour was acquired as drying temperature increased. The greatest loss in total phenolics content occurred at 60 degrees C, while total flavonoids content showed a significant reduction, which declined as drying temperature increased. According to the experimental results, phenolics and flavonoids could be considered as an important source of bioactive compounds with relatively high antioxidant activity. Thus D. antarctica may satisfy the requirements for development of functional foods. PMID- 30482975 TI - Effect of clove bud and curry leaf essential oils on the anti-oxidative and anti microbial activity of burfi, a milk-based confection. AB - With scientific advancement in the field of food science and technology, there has been an increased availability of innovative ingredients that can be utilized towards value addition, quality enhancement, natural preservation, shelf life enhancement and adding novelty to traditional Indian dairy products. Here a scientific attempt has been made to increase the anti-oxidative and anti microbial potential of burfi, a popular confection of Indian sub-continent with low shelf life using herbal essential oils (EOs) (natural preservative, antioxidant and antimicrobial) such as curry leaf (CRYF) (0.05-0.15 ppm) and clove bud (CLVB) (0.15-0.25 ppm) EO. Samples were subjected to physico-chemical, sensory, anti-oxidant and microbiological analysis and the results revealed that increasing the herbal EOs levels in burfi led to increase in anti-microbial and anti-oxidative attributes but simultaneously decreased the sensory attributes. Physico-chemical attributes remained unaffected upon EOs incorporation. Principal component analysis revealed 81.5% relation between the burfi samples and its quality attributes (DPPH activity, ABTS activity, total phenolic content, sensory attributes, standard plate count, yeast and mould count, moisture content, water activity, lightness, L* value, redness, a* value and yellowness, b* value). Herbal EOs i.e. CRYF@0.10 ppm and CLVB@0.20 ppm on khoa basis were found optimum for incorporation into burfi for enhancing storage stability without compromising the sensory acceptability. PMID- 30482976 TI - Shelf stability of low glycemic index noodles: its physico-chemical evaluation. AB - Noodles are popularising among all age groups and all region throughout the World. To cater the demand of consumer noodles should be shelf-stable. Noodles prepared from chemically modified ingredients were studied for their keeping quality at two different conditions namely, ambient (27 degrees C, 65% RH) and accelerated (37 degrees C, 92% RH) for the period of 180 days (6 months). Samples were withdrawn at regular intervals and analysed for their physico chemical and nutritional parameters. Results showed that Maximum cooking loss was observed in GP-OCT (180 days) 5.9% and was with in the acceptable range (8%). Firmness of noodles increased on storage up to 60 days later reduced. Starch digestibility increased 5-8% in all the samples upon storage. EGI of samples increased 10-15% on storage. Samples prepared with chemically modified ingredients were acceptable till the end of 180 days (2 samples) with good acceptability and low EGI without affecting its quality. Hence, it can be concluded that noodles prepared with modified ingredients using chemicals are shelf-stable up to 6 months at ambient condition. PMID- 30482977 TI - Process kinetics on physico-chemical and peroxidase activity for different blanching methods of sweet corn. AB - Blanching was performed to inactivate the enzyme using microwave, steam and hot water blanching methods and effect on the enzymatic activity, chemical properties and physical properties of the sweet corn were studied. The effectiveness of each blanching process was evaluated by measuring the loss of peroxidase activity, which was lost after 60, 90 and 120 s with k-values 0.016, 0.024 and 0.028 s-1 following first order kinetics for microwave, steam and hot water blanching respectively. The total sugar, ascorbic acid, moisture content, kernel mass and geometric diameter changed from 8.40 to 6.30, 7.20 and 7.50 g/100 g; 7.15 to 5.70, 6.10 and 6.60 mg/100 g; 76 to 79.20, 78.20 and 75.30%; 0.47 to 0.53, 0.50 and 0.42 g; 8.00 to 8.50, 8.30 and 7.20 mm at optimum level of blanching during microwave, steam and hot water blanching respectively, indicating higher retention of total sugar and ascorbic acid in microwave blanching. The change in colour, especially increase in brownness was observed during blanching processes. The average R2 for zero-order model was 0.945, suggesting use of model for prediction of physico-chemical parameters during blanching process of sweet corn. PMID- 30482978 TI - Physico-chemical composition and oxidative stability of South African beef, game, ostrich and pork droewors. AB - Droewors are traditional South African salted and dried sausages, made without nitrites/nitrates and non- fermented. Different meat sources (beef, game and ostrich) are traditionally used in droewors processing, while the use of pork is uncommon, as it is said to lead to rancidity. The first part of the study analysed the physico-chemical composition of commercially available beef, game and ostrich meat droewors (n = 20). On average, they were composed of 26.3-29.2 g/100 g moisture, 41.3-44.0 g/100 g protein, 26.2-33.1 g/100 g fat and 5.9-6.5 g/100 g ash and 5.0-5.4 pH. Water activity (0.76-0.82) was sufficiently low to ensure shelf stability at ambient temperatures. In the second part beef and pork droewors were formulated in accordance with these results and with similar fat content, dried for 2 days (30 degrees C, 40% relative humidity) and stored for 26 days (25 degrees C, 50% relative humidity); measuring moisture, water activity, pH and lipid oxidative stability (thiobarbituric acid reactive substances (TBARS)) weekly. At day 5, moisture and thus water activity of pork droewors was slightly higher compared to beef ones and fat and ash content slightly lower (P <= 0.05) despite similar weight loss. Even with slightly less fat, TBARS in pork droewors were significantly higher after drying and throughout storage (3.83 vs 0.99 mg MDA equivalents/kg dry matter at a maximum). PMID- 30482979 TI - Gliadin protein antigenicity and health benefitting potential of Indian bread wheat (Triticum aestivum L.) varieties. AB - Health benefitting potential of twenty leading wheat varieties was assessed for grain nutritional quality status in relation to antigenic reactivity level of gluten protein fractions. Among the nutritional parameters, macronutrients viz. starch, total sugar, total protein and gluten content were observed maximum in the varieties RAJ4120, RAJ4083, RAJ3077, and WH1021 respectively. Micronutrients- zinc and iron and phytochemicals- total phenolics and flavonoids were observed to be maximum in RAJ4083. Among the four protein fraction, albumin and globulin contents were the highest in RAJ3077, whereas gliadin and gluten content was maximum in GW322 and minimum in RAJ4120. The varieties were also characterized by SDS-PAGE and the results revealed significant polymorphism in all of the four protein fractions. The antigenic properties of flour gliadin proteins as evaluated by ELISA revealed that all the varieties possessed antigenicity with highest level in GW322 (0.217 OD). However, all the varieties possessed good baking qualities as studied by rheological measurements. PMID- 30482980 TI - Characterization of the kefir beverage produced from yam (Colocasia esculenta L.), sesame seed (Sesamum indicum L.) and bean (Phaseolus vulgaris L.) extracts. AB - The objective of this study was to evaluate the characteristics of kefir beverages made from yam, sesame and bean extracts after fermentation of the extracts with water kefir grains. Formulations were prepared with raw and boiled yams. To the yam extract, sesame and different percentages of white bean extract were added. The fermentation kinetics, the chemical composition and color of the extracts were analyzed. To determine the fermentation kinetic parameters, pH and titratable acidity were evaluated. The chemical composition and color of all extracts were determined before and after fermentation process. The decrease in pH and increase in titratable acidity were affected both by raw or boiler yam. The addition of bean extract favored the decrease in pH of formulations containing extracts of raw or boiled yams. Chemical composition and color of the beverages were altered after fermentation. The kefir beverage made from yam and sesame enriched with 50% beans proved to be an excellent fermentation substrate. In addition, it is a new way of consuming vegetable products, especially fermented products, which have limited diversity to serve vegan consumers and also people with certain allergies to dairy products. PMID- 30482981 TI - Impact of a commercially available ion-exchange resin used in red wines to reduce toxic compounds: effect on pH, oxidation-reduction potential, color, and sensory attributes. AB - This research was performed to evaluate the impact of a novel ion-exchange treatment on the organoleptic, pH, color (hue and intensity), and oxidation reduction potential (ORP) properties of commercial red wines. The ion-exchange treatment used in this study is a commercially available device containing a double cation-anion exchange resin. The device is applied, directly by the consumer, to finished bottled wines with the purpose of mitigating the effects of potentially noxious compounds such as biogenic amines and sulfites. Sensory evaluation tests included discriminative, affective, and Quantitative Descriptive Analysis sensory tests were employed to evaluate the impact on the perceived taste of treated wines. The pH, ORP and color parameters (hue and intensity) of wines were measured to assess any physicochemical alterations that may help to explain the results of the sensory evaluation. While no significant changes in color hue or intensity were found, the results showed a reduction in pH (0.07 0.12) and an increase in ORP (2.667-6.666 mV). However, the changes in pH and ORP did not result in a detectable change in wine taste for the sensory panelists. These findings have important implications for the wine industry, where many consumers select wines for their characteristic taste qualities. Thus, any treatment to potentially remove noxious compounds should not impact the characteristic organoleptic properties of a chosen wine. PMID- 30482982 TI - Quality assessment of fresh tea leaves by estimating total polyphenols using near infrared spectroscopy. AB - This paper reports on the development of an integrated leaf quality inspecting system using near infrared reflectance (NIR) spectroscopy for quick and in situ estimation of total polyphenol (TP) content of fresh tea leaves, which is the most important quality indicator of tea. The integrated system consists of a heating system to dry the fresh tea leaves to the level of 3-4% moisture, a grinding and sieving system fitted with a 250 micron mesh sieve to make fine powder from the dried leaf. Samples thus prepared are transferred to the NIR beam and TP is measured instantaneously. The wavelength region, the number of partial least squares (PLS) component and the choice of preprocessing methods are optimized simultaneously by leave-one-sample out cross-validation during the model calibration. In order to measure polyphenol percentage in situ, the regression model is developed using PLS regression algorithm on NIR spectra of fifty-five samples. The efficacy of the model developed is evaluated by the root mean square error of cross-validation, root mean square error of prediction and correlation coefficient (R2) which are obtained as 0.1722, 0.5162 and 0.95, respectively. PMID- 30482983 TI - Nutritional composition and total collagen content of two commercially important edible bivalve molluscs from the Sea of Japan coast. AB - The study aimed to evaluate the chemical composition and nutraceutical potential of two commercially significant edible bivalve mollusc species (Anadara broughtonii and Mactra chinensis). The edible parts (motor muscle, mantle and adductor) of these molluscs were analyzed for their proximate composition, collagen content, amino acid profile, chemical score and elemental constituents. Both molluscs had low fat content (2.43-6.91 g/100 g dry weight), and protein (55.36-68.01 g/100 g dry weight) and carbohydrates (11.36-20.37 g/100 g dry weight) were their main components. Total collagen content of the edible bivalve molluscs varied from 30.5 to 39 mg/g wet weight, accounting for approximately half of their total protein content. Among amino acids, glycine, glutamate, aspartic acid, alanine, leucine, lysine and arginine were present at high levels in the edible parts of both bivalve molluscs, while the major elements present were sodium, potassium, magnesium, calcium, iron, zinc and nickel. Having high quality protein content, edible bivalve molluscs could be excellent sources of nutritive ingredients and, after further study, may find applications in nutricosmetics and functional foods. PMID- 30482984 TI - Optimization and multivariate accelerated shelf life testing (MASLT) of a low glycemic whole jamun (Syzygium cumini L.) confection with tailored quality and functional attributes. AB - An optimization and multivariate accelerated shelf-life testing (MASLT) was demonstrated to develop a low glycemic (GI) whole jamun (Syzygium cumini L.) confection (WJC) with soft texture and fruity hedonics targeted for diabetic strata. The hydrocolloids viz., agar (1-3 g), pectin (1-3 g), and polydextrose (24-28 g) were optimized [mixture design (MD)] to obtain hydrocolloid mix (HM) with a soft texture. Next, whole jamun ingredients viz, jamun pulp (JP) (20-30 g), seed powder (JSP) (1-5 g), and HM (25-35 g) were optimized (MD + PCA) for satisfactory texture, total polyphenolic content (TPC), and fruity hedonics. The optimized WJC was assayed for GI and modelled by univariate kinetics and MASLT (10-45 degrees C/75% humidity/120 days). Using MASLT, the collated effects of quality attributes (anthocyanin content, TPC, moisture, hardness, and total color change) were extracted as principal components to estimate new stability parameters viz, multivariate rate constants (k m), acceleration factors ( alphamT ), activation energy (E am), and cut-off criterion. The optimized WJC contains 2.3 g agar, 1.9 g pectin, 27.2 g polydextrose, 26.4 g JP, and 2 g JSP and had satisfactory hardness (1007 g), TPC (2.8 mg gallic acid equivalents/g), and low GI value (48.6). The zero-order kinetic fitting of univariate versus MASLT resulted in alpha(45,10)T , E a, and shelf life (10 degrees C) of 7.8 versus 6.2, 43.81 versus 39.22 kJ/mol and 175 versus 186 days, respectively. MASLT simplified the kinetic interpretations to a single variable by collating the useful information from critical quality parameters and predicted shelf life precisely than univariate kinetics. PMID- 30482985 TI - High intensity ultrasound assisted decaffeination process of coffee beans in aqueous medium. AB - The purpose of this study was to determine the influence of ultrasound intensity, pulse and temperature on extraction of caffeine, from Arabica coffee beans using water as solvent, and ultrasound frequency of 24 kHz. A central composite design was used, using ultrasound intensity (31.5-105 W cm-2), pulse (0.30-1) and extraction temperature of the extraction (30-60 degrees C) as independent factor. The caffeine recovery and caffeine diffusion coefficient were response variables. The ultrasound intensity and extraction temperature significantly influenced the caffeine recovery rate and the diffusion coefficient of caffeine. Activation energy of 48.95 kJ mol-1 for the caffeine diffusion coefficient in ultrasound assisted extraction was observed. The best results were obtained at 68.25-105 W cm-2 ultrasound intensity and 60 degrees C temperature, corresponding to caffeine recovery of 58.4-69.4% and diffusion coefficient of 8.92-10.57 * 10-11 m2 s-1. The pulse effect was not significant in the range of the studied variables. PMID- 30482986 TI - Optimization of AOT reversed micelle forward extraction of 7S globulin subunits from soybean proteins. AB - The work attempted to study on separating the alpha', alpha and beta subunits of 7S globulin from soybean proteins by reverse micelles. The effects of six single factors (W0, time, temperature, pH, surfactant concentration and salt solution species) on three subunit partitioning were discussed. The main influence factors (time, temperature and surfactant concentration) were optimized by the response surface test (Box-Behnken design, three factor three level) in order to optimize the forward extracting three subunits of 7S globulin. It was observed that the independent factor had substantial effect on the forward extraction yield of three subunits of 7S globulin. The statistical analysis showed that the reverse micelles could significantly affect the forward extraction efficiency of protein subunits. The highest forward extraction efficiency of alpha', alpha and beta subunits achieved 78.21, 63.65 and 61.34%, respectively. The proposed method also showed that the forward extraction efficiency of subunits with larger molecular weight was higher than low molecular weight. PMID- 30482987 TI - Development of functional cookies using saffron extract. AB - Saffron extracts of two different concentrations were prepared and used as a source of natural antioxidants in whole wheat flour cookies. The effect on the color, texture and sensory properties of the product was also studied over a storage period of 9 months. Results revealed that spread ratio and hardness of cookies reduced non-significantly with the addition of saffron extract (SE). Color values 'L' and 'b' of cookies increased significantly from 50.7 to 53.9 and 36.5 to 47.0, respectively with the addition of SE while 'a' value decreased non significantly (p > 0.05). DPPH radical scavenging activity, reducing power and inhibition of lipid peroxidation of dough and cookie samples containing SE were enhanced in comparison to control. The concentration of crocins, safranal and picrocrocin in DS50 and DS100 dough samples was found as 28.30, 48.30, 104.6 ug/g and 35.14, 62.38, 118.2 ug/g, respectively. Sensory scores of cookies containing SE were high as compared to control. All the quality parameters of cookies reduced during the storage period (0-9 months). However, the cookies with added SE revealed significantly higher quality attributes up to 6 months of storage without any significant loss in quality. PMID- 30482988 TI - Physicochemical, morphological and functional properties of protein isolates obtained from four fish species. AB - In this study, we investigated the physicochemical, morphological and functional characteristics of fish protein isolates (FPIs) prepared from four fish species through alkali solubilization and isoelectric precipitation. Significant differences were observed in the protein content, physicochemical, morphological and functional characteristics among FPIs. Morphology and particle size analysis revealed a significant difference in the shape and size of FPIs. Lipid oxidation of FPIs varied between 0.206 and 0.305 mg MDA/kg. Furthermore, all FPIs exhibited two broad diffraction peaks at ~ 8.6 degrees and 19.3 degrees , revealing their amorphous nature. A significant difference was observed in the thermal properties of selected samples, including T0, TP, TC, and DeltaH values. T0, TP, TC, and DeltaH of the endothermic transition varied in the range of 40.9-43.0 degrees C, 64.1-66.2 degrees C, 99.1-100.6 degrees C, and 237.1-267.2 J/g, respectively. All FPIs exhibited high water/oil absorption capacity, emulsifying capacity, foam stability and foaming capacity, signifying proteins potential to act as functional ingredients in the food industry. PMID- 30482989 TI - Effect of heat treatment on rheological properties of red kidney bean gluten free cake batter and its relationship with cupcake quality. AB - Legumes and cereals complement their nutritional quality and there is a need of convenience products made with these grains. The objectives of this study were to determine the rheological and functional properties of precooked red kidney bean (RKB) flours and their effect on viscoelastic properties of gluten free cake batter and cupcake quality including consumer acceptance. RKB flours were thermally processed by boiling at 100 degrees C (0, 20, 30 and 40 min) and drying at 80 degrees C (3 and 4 h). Rheological properties of cake batter containing 100% RKB flour were tested by creep-recovery and dynamic frequency tests. Batter of RKB flour boiled for 20 min was significantly stiffer with 100 times less deformable character compared to the control. Increase in batter modulus ranged from 2000 times elastic component (G'), 988 times viscous component (G") and 1805 times complex viscosity (eta*) at 20 min boiling. Drying did not have a significant effect on viscoelastic properties. Firmness and height of gluten free RKB cupcake were not affected by heat treatment. RKB gluten free cake after heat-moisture treatment had improved consumer acceptance scores compared to the control. Our findings showed that 20 min boiling and 3 h drying process is adequate for precooked RKB flour. PMID- 30482990 TI - Quality and sensory acceptability of fish fillet (Oreochromis niloticus) with alginate-based coating containing essential oils. AB - The quality and sensory acceptability of fish fillet (Oreochromis niloticus) with alginate-based coating containing ginger and oregano essential oils (EO) were evaluated. The antioxidant activity of essential oil, coating, and fish were also investigated. In relation to lipid oxidation, a decrease was observed in fish with the edible coatings compared to the control being the coating with oregano EO the most effective and also with the highest antioxidant activity. Loss in color and weight were significantly lower with coating. Fish with coating maintained firmness whereas fish without coating became softer. Fish with edible coating and oregano essential oils showed higher sensory acceptability regarding to odor evaluated by consumers. Thus, edible coatings with essential oils as natural antioxidant improved the product quality and sensory acceptability. PMID- 30482991 TI - Application of ohmic heating for concentration of milk. AB - The concentration of milk through evaporation is the most commonly employed unit operation for the production of a wide array of traditional and industrial dairy products. Major problems associated with thermal evaporation are a loss of aroma, flavor and color change. Ohmic heating (OH) has an immense potential for rapid and uniform heating of liquid, semi-solid and particulate foods, yielding microbiologically safe and high-quality product. The effect of ohmic heating on physico-chemical, rheological, sensorial and microbial properties during concentration of cow milk, buffalo milk and mixed milk (50:50) was studied and compared to conventional evaporation. OH significantly increased free fatty acids (FFA), apparent viscosity, hydroxymethylfurfural (HMF) content, instrumental color values i.e. redness (a*) and yellowness (b*) values. However, pH value and whiteness (L*) of the concentrated milk decreased significantly. OH caused a drastic reduction in microbiological counts and treated milk can be kept for a longer period. PMID- 30482992 TI - Rheology, acceptability and texture of wheat flour tortillas supplemented with soybean residue. AB - Dry soybean (Glycine max) residue (SBR) is a byproduct rich in dietary fibre and protein with high levels of essential amino acids. The effects due to the substitution of refined wheat flour with 5% or 10% SBR in dough rheology and hot press tortilla texture, dimensions, colour, protein and dietary fibre contents were studied. Substitution of 10% SBR improved flour in terms of gluten strength and sedimentation without significantly affecting dough hardness, cohesiveness, adhesiveness, and extensibility. The dimensions, colour and sensory acceptance of the supplemented tortillas were not affected by the addition of the SBR. The 10% SBR tortillas contained 1.77 times more insoluble dietary fibre, protein content of 9.3%, in vitro protein digestibility of 84% and protein digestibility corrected amino acid score (PDCAAS) of 52.63%. Results indicated that wheat flour tortillas with 10% SBR an excellent alternative to regular counterparts owing to their higher dietary fibre and protein quantity and quality. PMID- 30482993 TI - Design and development of technology for walnut cracking. AB - The aim of the present study was to design, develop and evaluate hand operated and power driven crackers for walnuts. Kaghazi (thin shelled) and medium shelled walnuts after subjecting to pre-optimized soaking conditions were cracked by developed crackers. Different parameters were evaluated to check the performance of the power operated cracker and hand operated cracker in comparison to manual cracking. 100% shelling coefficient and cracking coefficient value of 1 were recorded in manual and hand operated cracking methods in both Kaghazi and medium shelled walnuts. The coefficient of wholeness was recorded highest in hand operated cracking method in both Kaghazi and medium shelled walnuts. The throughput capacity and effective throughput capacity was highest and labour requirement was least in power operated walnut cracking method followed by manual cracking and hand operated cracking methods in both Kaghazi and medium shelled walnuts. In both Kaghazi and medium shelled walnuts, the butter ball + kernel halve recovery and cracking efficiency was recorded maximum in hand operated cracking method. The economic analysis reveals that both hand operated and power operated crackers can be useful for small to medium scale walnut growers and processing industries. PMID- 30482994 TI - Quantification of species-specific meat proteins in cooked and smoked sausages using infusion mass spectrometry. AB - Label-free quantification combined with high-resolution infusion-based mass spectrometry (MS) was evaluated to authenticate 'horse sausages' made from horse meat and pork. Four types of industrially processed sausages, including cooked horse meat, pork and beef, and their mixtures were analysed. Quantitation and evaluation of the species composition were based on a set of 11 species-specific meat proteins and 14 unique heat-stable peptide markers. Using infusion MS, the highest distinguishing value was found in four proteins, namely, horse myosin-7 (MYH7_HORSE) and horse myoglobin (MYG_HORSE), porcine myosin-4 (MYH4_PIG) and bovine myoglobin (MYG_BOVIN). The limit of detection was 5% (w/w) for pork and beef in the three-component matrix and 1% (w/w) for horse meat. The proteins' abundance was computed using a peak intensity measurement technique for precursor ions, based on the extracted ion currents/intensities of precursor ions. The procedure enabled discrimination between horse meat, pork and beef proteins, as well as estimation of the relative changes in protein abundance in all the examined samples. Substantial differences in the abundance of specific proteins were obtained from the pure meat samples, three-component mixtures and commercial sausages. The method may be useful in the preliminary screening of protein-rich food samples, aimed at fraud detection and estimation of the overall level of adulteration. PMID- 30482995 TI - Estimation of polyphenols by using HPLC-DAD in red and white wine grape varieties grown under tropical conditions of India. AB - Grapes are well known for their high content of phenolic compounds. Polyphenols are classified into flavonoids and non-flavonoids by their primary chemical structures of hydroxybenzene. Flavonoids mainly consist of anthocyanins, flavonoids, and flavonols whereas non-flavonoids include hydroxycinnamic and hydroxybenzoic acids. In the present study, sixteen phenolic compounds from ten red and nine white grape wine varieties were quantified using high-performance liquid chromatography. Gallic acid, Vanillic acid, Rutin hydrate, Ellagic acid, Chlorogenic acid, Sorbic acid, Catechin hydrate, Epicatechin, p-coumaric acid, Quercetin, Myricetin, Kaempferol, Piceatannol, and Resveratrol were major compounds found in red wine grapes. Among the varieties, Petit Verdot, Cabernet Franc showed maximum quantitative phenolics, whereas Cabernet Sauvignon, Niellucio, Cinsaut, and Syrah showed least quantitative phenolics in grape berries. Phenolic profile of white wine grapes showed lower concentration of phenolics than that of red wine grapes. The variety Gros Meseng showed maximum phenolics followed by Sauvignon, while the variety Colombard and Chenin Blanc showed least phenolics. PMID- 30482996 TI - Effect of extrusion conditions on the physicochemical and phytochemical properties of red rice and passion fruit powder based extrudates. AB - The passion fruit powder blended rice flour based extrudate was developed and investigated in terms of physicochemical and phytochemical properties. The extrusion process was performed using a twin screw extruder and optimized using rotatable central composite design followed by response surface methodology. The effect of process parameters such as temperature (80-150 degrees C), screw speed (200-400 rpm), moisture content (20-30%) and passion fruit powder (0-15%) on product quality was investigated. The optimum extrusion conditions of temperature, screw speed, feed moisture content, and passion fruit powder were 97.50 degrees C, 250 rpm, 25.20% and 11.25%, respectively. At optimum condition, the predicted values of responses were expansion ratio 8.05, water absorption index 2.77, total phenolic content 129.492 mg GAE/100 g and DPPH scavenging activity 65.79%. A comparison between optimized and control extrudates revealed that thermal, crystallinity and morphological properties of extrudates differed significantly. The comparison was also conducted in terms of FT-IR, SEM-EDS and HPLC analysis. The phytochemical properties showed that beta-carotene, cyanidin-3 glucoside, peonidin-3-D-glucoside chloride were higher in control whereas the optimized sample evinced more (+/-)-alpha-tocopherol and D-alpha-tocopherol. PMID- 30482997 TI - Preparation and characterization of nanoemulsion based beta-carotene hydrogels. AB - The aim of this study was to develop beta-carotene hydrogels using nanoemulsions, with increased beta-carotene aqueous solubility, bioavailability and improved physical and chemical stabilities. The nanoemulsion of beta-carotene was prepared using a solvent-displacement technique and converted into hydrogels using sodium alginate as stabilizer and calcium chloride as cross-linker. The effects of formulation parameters, mainly, the effects sodium alginate and calcium chloride concentrations on the physicochemical properties of hydrogels were evaluated using a surface response methodology. The second order polynomial equations, subsequently, were suggested to predict the changes of studied physicochemical characteristics of hydrogels, with relatively high regression of coefficients values. Based on numerical multiple optimization, it was concluded that using 4.1 g/l sodium alginate and 5.7 g/l calcium chloride, resulted in a hydrogel with the most desired physicochemical characteristics. No significant differences between the measured and predicted data, reconfirmed the accuracy of the models. PMID- 30482998 TI - The effect of rosemary extract and lactic acid on the quality of refrigerated broiler fillets. AB - The current study investigated the effect of rosemary extract (0.2% RE) and lactic acid (1% LA) on some freshness, bacterial parameters and formation of biogenic amines during refrigeration of broiler fillets. Ninety broiler fillet samples were divided into three groups (each 30). The control group was dipped in sterile distilled water, while the RE and LA groups were dipped in rosemary extract 0.2% (w/v) and lactic acid 1% (w/v), respectively. Sensory evaluation, pH, total volatile basic nitrogen (TVB-N), thiobarbituric acid reactive substances (TBARS), total psychrotrophic and Enterobacteriaceae counts were performed at zero time and at 3 days interval until the group were rejected from sensory analysis. Organoleptic scores were unacceptable after the 9th, 12th and 15th day of refrigeration in control, RE and LA groups, respectively. TVB-N was the lowest in LA group (3rd day; 4.36 +/- 0.12, 6th day; 5.62 +/- 0.7 and 9th day; 10.13 +/- 0.98) when compared with the RE and control groups. Moreover, TBARS was the highest in the control group (3rd day; 0.22 +/- 0.06, 6th day; 0.39 +/- 0.07 and 9th day; 0.78 +/- 0.09) when compared with the RE and LA groups. LA group showed the lowest number of psychrotrophic bacteria during refrigeration period when compared with the other groups. Enterbacteriaceae was detected at zero, 3rd and 6th day in control, RE and LA groups, respectively. This study concluded that dipping in LA 1% or RE 0.2% reduce the psychrotrophic and Enterobacteriaceae bacteria of broiler fillet and increased the acceptability of refrigerated fillet, decreased the biogenic amines formation and rancidity. Therefore, broiler fillets dipped in RE 0.2% or LA 1% can be used up to 12 or 15 days when refrigerated at 4 degrees C. PMID- 30482999 TI - Effect of exogenous gamma-aminobutyric acid treatment on the enzymatic browning of fresh-cut potato during storage. AB - The aim of this study was to evaluate the effect of gamma-aminobutyric acid (GABA) treatment on the enzymatic browning of fresh-cut potatoes. The browning index and activities of browning and defense-related enzymes were analyzed after 0, 1, 2, 3, 4, 5, and 6 days of storage at 4 degrees C. The results showed that the treatment with 20 g/L GABA for 10 min significantly retarded the browning of fresh-cut potatoes. GABA inhibited the browning of fresh-cut potatoes by enhancing the activities of catalase and superoxide dismutase, and decreasing the activities of polyphenol oxidase and reactive oxygen species. The results suggest that GABA plays an important role in reducing the browning of fresh-cut potatoes. Hence, GABA treatment is a promising approach for reducing the browning and maintaining the quality of fresh-cut potatoes. PMID- 30483000 TI - LC-ESI-MS based characterisation of isoflavones in soybean (Glycine max (L.) Merr.) from India. AB - A total of twenty-one soybean varieties were screened for their morphological characteristics followed by isoflavone content analysis by HPLC. The total isoflavone (TI) content was found within a wide range of 140.9-1048.6 MUg/g of soy in different varieties. The highest isoflavone content was found in MAUS-2 followed by DS_2613 and lowest in Karunae (140.9 MUg/g of soy). Various isoflavone forms were identified by LC-ESI+ MS. Significant differences in the isoflavone content were observed for all the aglycones and their glucoside conjugates as well as total daidzein, total genistein, total glycitein, and TI. A positive correlation between TI content and growth stages was found during the progression of seed development. An increase of 5.4-fold and 5.3-fold of TI concentration was observed for JS 335 and MAUS-2 respectively, from early to green mature (R5-R8) stage of bean development. PMID- 30483001 TI - Effect of edible coatings based on alginate/pectin on quality preservation of minimally processed 'Espada' mangoes. AB - The aims of the study were to develop and apply alginate and pectin-based edible coatings on minimally processed mango (Mangifera indica L.) variety 'Espada'. A full experimental design was performed using alginate, pectin and glycerol concentrations as independent variables and total soluble solids as response variable. Minimally processed mango was immersed in each film forming solution, calcium chloride and glycerol solutions pretreated with 1% (w/v) solution of ascorbic acid, dried at 25 +/- 2 degrees C for 24 h and then refrigerated at 8 +/- 1 degrees C for 14 d. Based on the results of the experimental design, the following formulations were evaluated: 2% (w/v) alginate/3% (w/v) pectin (with and without glycerol) and 3% (w/v) alginate/0.5% (w/v) pectin (with and without glycerol). Fruits coated with biopolymers had lower total soluble solids content and titratable acidity compared to the control group. The formulation containing 2% (w/v) alginate, 3% (w/v) pectin and 5.5% (w/v) glycerol showed the best performance for long-term refrigerated storage of minimally processed mango for a period of 16 d. PMID- 30483002 TI - Development and storage stability of buckwheat chips using response surface methodology (RSM). AB - Processing conditions (potato level, frying temperature and frying time) were optimized for the development of buckwheat based chips using response surface methodology (RSM). Moisture content, oil uptake, color values, hardness and overall acceptability (OAA) were used as indices of product quality. The polynomial regression model was fitted with R2 values of 0.983, 0.982, 0.98, 0.996, 0.973, 0.984 and 0.985 for moisture content, oil uptake, L, a*, b* values, hardness, and OAA respectively indicating fitness of the models. Potato level and frying temperature showed a significant effect on all responses at linear and quadratic levels except frying temperature for OAA at the linear level and hardness at quadratic level. Frying time showed significant effect on a* value, b* value, hardness and OAA at linear level. Interaction between all processing variables had a significant effect on a* value. Interaction between potato level and frying temperature had significant negative effect on moisture content of buckwheat chips. Potato level (30%), frying temperature (169 degrees C) and frying time (51 s) were found to be the optimum processing conditions with maximum OAA (8.36). 0.33 aw was established as the water activity at which maximum stability of chips was shown. Buckwheat chips packed in both polypropylene (PP) and metallised polyester (MP) remained stable and acceptable for 6 months at RT whereas for 3 and 6 months in PP and MP films respectively at 37 degrees C. PMID- 30483004 TI - Isolation and identification of hyper-ammonia-producing bacteria from commercial fermented skates (Raja kenojei). AB - Ammonia-producing bacteria were isolated and identified from five commercial fermented skates (A1, A2, A3, A4, and A5). In addition, the pH, ammonia nitrogen, total volatile nitrogen (TVBN), trimethylamine nitrogen (TMAN), and amino nitrogen contents of skate samples were also determined. A total of 88 strains of ammonia-producing bacteria was isolated and seven hyper-ammonia-producing bacteria isolates (A2-2, A2-3, A2-12, A2-18, A2-20, A3-6 and A3-14) were selected based on ammonia nitrogen producing ability. Those isolates were identified as Proteus hauseri (three strains), Providencia rustigianii (three strains), and Kurthia gibsonii. The pH and ammonia nitrogen content in skate samples were ranged from 8.63 to 9.03, and 4.86 to 7.31 g/kg, respectively. No significant difference of pH values was observed in skate samples A2, A3, A4 and A5. While, skate samples A3, A4 and A5 showed similar level of TVBN and TMAN content. Skate sample A2 showed the highest amino nitrogen content among all samples, which indicated the highest degree of protein degradation of skate muscle during fermentation. Bivariate cluster analysis showed that skate samples A3, A4, and A5 clustered together at a relatively high level, implying a similar microbial environment during fermentation. The cluster analysis allowed different commercial fermented skates to be clearly differentiated based on the characteristics determined in this study. This study can provide important information for investigating the mechanisms underlying ammonia flavor formation in skate muscle during fermentation. PMID- 30483003 TI - Essential oils and ethanol extract from Camellia nitidissima and evaluation of their biological activity. AB - Camellia nitidissima, a well-known species of yellow Camellia, has undergone commercial cultivation as a new tea resource recently. Herein, the composition, antioxidant and antimicrobial activities of the essential oil and ethanol extract of C. nitidissima were investigated. The essential oils from the leaves and flowers of C. nitidissima were obtained by hydro-distillation. A total of 56 and 34 constituents accounting for 77.5 and 96.8% of the oils were identified by GC MS. Linalool (35.8%), phytol (7.9%), cis-geranyl acetone (7.3%) and methyl salicylate (6.8%) were found to be the primary components in the leaf oil, while the flower oil was rich in alpha-eudesmol (34.3%), gamma-eudesmol (31.5%) and linalool (11.1%). The ethanol extract of C. nitidissima leaves contained 281.04 mg gallic acid equivalent/g of total phenols. The antioxidant activities of the two oils and extract were evaluated by DPPH and ABTS radical-scavenging assays. The IC50 values varied from 17.4 (extract) to 720.3 MUg/mL (flower oil) for DPPH and from 28.8(extract) to 889.6 MUg/mL (flower oil) for ABTS. Both essential oils exhibited moderate antioxidant activities, and the extract possessed strong effects close to ascorbic acid. Additionally, the antimicrobial activities of the oils and extract against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa were evaluated by agar dilution assay. No considerable bactericidal activities were observed for either essential oil or extract compared with ampicillin and tobramycin standards. The results indicated the extract was more efficient than the two essential oils against S. aureus (MIC = 0.625 mg/mL) and B. subtilis (MIC = 1.25 mg/mL). PMID- 30483005 TI - Effects on the quality and health-enhancing properties of industrial onion waste powder on bread. AB - Industrial onion waste powder (IOWP) was used as an additive in wheat flour at different levels: 0, 1, 2, 3, 4 and 5%. The effect of onion waste addition on the mixing properties of the dough and quality of bread was investigated. The mixing properties of the dough were determined by farinograph. The bread were characterized and evaluated for crumb hardness, crumb porosity, sensory properties, dietary fiber, total phenolic content and total flavonoids. DPPH and FRAP assays were carried out to measure antioxidant activity in vitro. The results indicated that IOWP could be used as a potential health-enhancing functional ingredient up to 3% level to produce bread enriched with dietary fiber, total phenolic compounds and total flavonoids, and characterized by high antioxidant activity and acceptable quality. PMID- 30483006 TI - Ultrasound pre-treatment prior to unripe banana air-drying: effect of the ultrasonic volumetric power on the kinetic parameters. AB - Aiming to decrease the water content during the air-drying process of unripe banana slices, ultrasound (US) pre-treatments (25 degrees C) for 20 and 25 min at 9.38 and 25.63 W/L ultrasonic volumetric power were evaluated. Air-drying was performed at 50 and 60 degrees C for 360 min. Unripe banana slices pretreated at 25.63 W/L did not improve water migration, under either air-drying temperature, while slices pretreated at 9.38 W/L resulted in an increase in water effective diffusivity of 4.8 and 13.7% at 20 min US + air-drying at 50 degrees C and 25 min US + air-drying at 60 degrees C, respectively. The drying time saving of 7% and 9%, respectively, was achieved, showing that these treatments were alternative for processing unripe banana slices. Thus, ultrasound and air-drying operational parameters required accurately defined to achieve desirable results. Experimental data were adjusted to four models and the Midilli model resulted in the best experimental data fit, with r 2 > 0.9988, RMSE < 0.0873 and chi2 < 0.00996. PMID- 30483008 TI - Quality changes in high hydrostatic pressure and thermal pasteurized grapefruit juice during cold storage. AB - This study evaluated the effects of high hydrostatic pressure (HHP) and thermal pasteurization (TP) on microbial counts, physicochemical properties, antioxidant characteristics, naringin and naringenin contents, and naringinase activity of grapefruit juice during 21 days cold storage period. Results showed that HHP and TP significantly decreased the total microbial, coliform, and yeast counts. No significant differences between HHP-treated grapefruit juice (600 MPa/5 min) and untreated fruit juice with respect to physicochemical properties such as total titratable acidity, pH, and total soluble solids was observed after 21 days of storage. Although HHP affected the colour and antioxidant characteristics of grapefruit juice, the extent of effect was significantly lower than that for TP treated fruit juice. This demonstrated that HHP could better maintain the original flavour and quality of grapefruit juice compared to TP. In addition, 92% naringinase activity was maintained in HHP-600 group on Day 21, which increased the degradation of bitter naringin into non-bitter naringenin during the cold storage of grapefruit juice. In summary, HHP can simultaneously maintain the microbiological safety of grapefruit juice along with its original quality characteristics. HHP can effectively extend the storage period and safety during cold chain transport, and hence highly applicable in the grapefruit juice industry. PMID- 30483007 TI - Antioxidant capacity and UPLC-PDA ESI-MS polyphenolic profile of Citrus aurantium extracts obtained by ultrasound assisted extraction. AB - This study aimed to evaluate different pre-treatments and solvent ratios on the total phenolic content and antioxidant activity of Citrus aurantium (sour orange) peel extracted by ultrasound. A two-factor (2 * 3) factorial design was implemented, with fresh and dry peels as pre-treatment conditions, and water (100%), 50% aqueous ethanol (v/v) and 96% aqueous ethanol (v/v) as the solvents. The phenolic compounds were identified and quantified by ultra-performance liquid chromatography-photodiode array and electrospray ionisation-mass spectrometry, respectively. The compounds were partially purified by advanced automated flash purification. The results indicated that the maximal phenolic content (40.95 +/- 3.44 mg gallic acid equivalents/g dry weight) was obtained when fresh sour orange peels were extracted with 50% (v/v) aqueous ethanol while the maximal antioxidant activity (730.04 +/- 28.60 MUmol Trolox equivalents/g dry weight) was achieved from aqueous extraction of dry sour orange peels. Nine phenolic compounds were identified and quantified. Naringin and neohesperidin predominated in sour peel extracts, whereas, caffeic and chlorogenic acids were the least abundant. Evaluation of the antioxidant activity in the fractions suggested that this activity might be attributed to the synergistic effect of the nine phenolic compounds present in the crude extract. Accordingly, sour orange peel is a potential source of phenolic compounds with antioxidant activity. PMID- 30483009 TI - Inhibitory effects of acetophenone or phenylethyl alcohol as fumigant to protect soybean seeds against two aflatoxin-producing fungi. AB - The antifungal activity of acetophenone and phenylethyl alcohol prevents seed contamination by Aspergillus flavus TISTR 3041 and A. parasiticus TISTR 3276. Their effects on seed germination were investigated. In vitro results showed that 100 uL L-1 acetophenone completely inhibited (by 100%) growth, conidial germination, and sporulation of the two aflatoxin-producing fungi, while phenylethyl alcohol showed only weak inhibitory activity even at 1000 uL L-1. Exposure to acetophenone at 100 uL L-1 for 6 h could completely kill (100% death) both fungal strains, while phenylethyl alcohol showed much lower efficacy (53.12%). In vivo results revealed that fumigation with 100 uL L-1 acetophenone for 24 h completely controlled (100%) A. flavus TISTR 3041 on soybean seeds during a 14-day test but exhibited weak efficacy on A. parasiticus TISTR 3276 (31.77%). Phenylethyl alcohol (1000 uL L-1) demonstrated weak inhibitory effect against both strains. The two volatile compounds had no adverse effects on seed germination. SEM confirmed that acetophenone could completely inhibit conidia germination, and abnormal growth of both fungal strains was observed. Thus, acetophenone has high potential to protect soybean seeds against aflatoxin producing fungi. PMID- 30483011 TI - The compositional, physicochemical and functional properties of germinated mung bean flour and its addition on quality of wheat flour noodle. AB - Despite sprouted grains have high nutritional and functional properties, their exploration in mung bean and application in traditional foods are limited. The effects of germination of mung bean for 12, 24, 36, 48, 60 and 72 h on compositional, physicochemical and functional properties of its flour were investigated. The effects of incorporation of germinated mung bean flour at different levels (0, 10, 20 and 30%) on noodles making properties of wheat flour were evaluated 0. The protein content increased while the amylose increased initially and then decreased with increase in germination time. Water absorption index, oil binding capacity and water retention capacity increased, while water soluble index initially increased and then decreased. The germinated mung bean flour became darker with increase in germination time. The protein bound to starch in noodlesed to increase in hardness, cohesiveness, gumminess, chewiness, resilience and cooking time of noodles. Additionally, the water absorption, cooking loss, adhesiveness and springiness of raw noodles and springiness, cohesiveness and chewiness of cooked noodles decreased with the addition of germinated flour. PMID- 30483010 TI - Oxidative stability, affective and discriminative sensory test of high oleic and regular peanut oil with addition of oregano essential oil. AB - Peanut oil is widely used in food but is susceptible to oxidation. This study investigated the antioxidant stability of high oleic (HO: 78.85 g/100 g oleic acid) and regular (C: 43.85 g/100 g oleic acid) peanut oils with oregano essential oil (OEO) added as a natural antioxidant. OEO contained gamma-terpinene (25.71%), carvacrol (16.73%) and terpinen-4-ol (16.17%) as the principal compounds. Thermal processing (60 degrees C for 28 days) of OEO increased the carvacrol and o-cymene contents and decreased the terpinen-4-ol, linalool and gamma-terpinene levels. Thus, carvacrol was the major compound with high oxidative stability. Thermal processing of the peanut oils showed that HO peanut oil developed less oxidation than C peanut oil. OEO provided antioxidant activity, which increased as its concentration increased (at 0.02 and 0.10% p/p of OEO, the peroxide value decreased by 18 and 46%, respectively). OEO displayed 54.7% free radical scavenging activity and 9.2 mg/g total phenolic content, explaining its antioxidant activity. Sensory analysis showed that OEO was detected in all samples, but consumer acceptance was greater when OEO was present (hedonic values of 7.4 and 6.8 for OEO at 0.02 and 0.10 g/100 g, respectively) compared to the peanut oil only control (hedonic value of 6.0). PMID- 30483012 TI - Thermal, structural and textural properties of amaranth and buckwheat starches. AB - Starches isolated from amaranth and buckwheat were analysed for thermal characteristics, crystallinity, gel textural properties and light transmittance. Buckwheat starch gels were harder with higher chewiness and springiness than amaranth starch gels. Starch from common buckwheat produced the hardest gel and amaranth starch from VL-44 cultivar produced the softest gel. Gelatinisation temperatures of amaranth and buckwheat starches differed significantly and tartary buckwheat starch showed the highest values for TP and TC. Buckwheat starches showed lower enthalpy change values than amaranth starches of both the cultivars. X-ray diffractometry confirmed 'A' type crystalline pattern for all tested starch samples and higher relative crystallinity was noticed in amaranth starches than buckwheat starches. Tartary buckwheat exhibited the lowest value of relative crystallinity and amaranth starch of Durga cultivars showed the highest value of relative crystallinity. FTIR spectrums showed band at similar wavenumbers (cm-1) with varying intensities. A declining order of paste clarity during storage at refrigeration temperature was observed for all starches. PMID- 30483013 TI - Dielectric properties for selected wall material in the development of microwave encapsulation-drying. AB - Dielectric properties study is important in understanding the interaction between materials within electromagnetic field. By knowing and understanding the dielectric properties of materials, an efficient and effective microwave heating process and products can be designed. In this study, the dielectric properties of several encapsulation wall materials were measured using open-ended coaxial probe method. This method was selected due to its simplicity and high accuracy. All materials exhibited similar behavior. The result inferred that beta-cyclodextrin (BC), starch (S), Arabic (GA) and maltodextrin (M) with various dextrose equivalent exhibited effective encapsulation wall materials in microwave encapsulation-drying technique owing to loss tangent values which were higher than 0.1 at general application frequency of 2.45 GHz. Thus, these were found to be suitable as wall material to encapsulate the selected core material in this microwave encapsulation-drying method. On contrary, sodium caseinate showed an ineffective wall material to be used in microwave encapsulation-drying. The differences in the values of dielectric constant, loss factor and loss tangent were found to be contributed by frequency, composition and bulk density. PMID- 30483014 TI - Optimizing and predicting degree of hydrolysis of ultrasound assisted sodium hydroxide extraction of protein from tea (Camellia sinensis L.) residue using response surface methodology. AB - Response surface methodology was employed to investigate the effect of sodium hydroxide concentration (X 1: 0.05-0.15 M), sonication time (X 2: 5-15 min), ultrasonic power (X 3: 150-450 W/L), and solid-liquid ratio (X 4: 20-60 g/L) on the optimization of protein extraction from tea residue. Single frequency countercurrent ultrasound (SFCU) was employed to assist the extraction and subsequent hydrolysis of the protein. Optimal extraction conditions were established and response surfaces were generated using mathematical models. There were positive linear and negative quadratic effects of extraction variables on protein yield. The optimal predicted protein yield of 138.9 mg/g was obtained under the optimum conditions of concentration of 0.13 M, extraction time of 13 min, ultrasonic power of 377 W/L and solid-liquid ratio of 51.5 g/L. A model for the degree of hydrolysis of the extraction process was also obtained which gave a predicted and experimental value of 8.4% and 7.5% respectively. Essential amino acid content of 36.7% was obtained under optimal conditions. PMID- 30483015 TI - Gelatin production using fish wastes by extracted alkaline protease from Bacillus licheniformis. AB - An effort was made to produce gelatin from Common carp wastes using extracted alkaline protease from Bacillus licheniformis PTCC 1595. Fermentation was performed by submerged media for 48 h and 72 h. The hydrolyzing enzyme was added in 5, 10, 15, 20, and 25 units per gram of wastes powder for hydrolysis. The produced gelatin was compared with commercial bovine gelatin with regard to some rheological and physicochemical properties. The yield of gelatin production was also determined as a result of hydroxyproline extraction from fish wastes. SDS PAGE was performed for enzyme and gelatins. For enzyme, two bands were achieved with 39 and 10.5 kDa molecular weight which were separated passing through a 15 kDa UF filter. Both gelatins showed beta, alpha1, and alpha2 chains as basic components, but the fish waste gelatin showed narrow bands. In conclusion, foam expansion and water holding capacity were approximately equal in both gelatin types used for food industry application. The results indicated that using 20 units of enzyme per gram of waste powder was the optimum amount of enzyme application. Further, fish wastes were concluded to be a practical source for gelatin production. PMID- 30483016 TI - Predatory Journals-A Looming Menace. PMID- 30483017 TI - Assessment of Dorsal Subluxation in Thumb Carpometacarpal Osteoarthritis. AB - Background Although dorsal subluxation is a typical finding for osteoarthritis of the thumb carpometacarpal (CMC) joint, it is difficult to evaluate the subluxation after trapeziectomy and the significance of its surgical correction combined with trapeziectomy is still controversial. The purpose of this study was to develop a method to evaluate dorsal subluxation without using landmarks on the trapezium. Methods Thirty patients with thumb CMC arthritis and 13 normal patients were included in this study. Dorsal subluxation of the CMC joint was evaluated by measuring the distance between the volar tip of the thumb metacarpal base and dorsoradial border of the index metacarpal base (M1M2 overlap) on the X ray true lateral view of the thumb as well as previously reported methods. Intraclass correlation coefficient (ICC) was used to assess inter- and intraobserver reliability for the measurement of M1M2 overlap by six examiners of different level of expertise. Dorsal subluxation was also evaluated after trapeziectomy with ligament reconstruction. Results There were almost perfect interobserver (ICC = 0.94) and intraobserver (ICC = 0.95 for an expert and 0.97 for a novice) reliabilities for the measurement of M1M2 overlap. There was a weak correlation between our method and previously reported methods. M1M2 overlap of the normal patients and the patients were 4.6 +/- 1.2 mm and 2.3 +/- 2.3 mm (mean +/- SD), respectively. M1M2 overlap was corrected significantly after trapeziectomy with ligament reconstruction. Conclusion Dorsal subluxation of the thumb CMC joint could be evaluated by M1M2 overlap before and after trapeziectomy. PMID- 30483018 TI - Reliability of Diagnosis of Partial Union of Scaphoid Waist Fractures on Computed Tomography. AB - Computed tomography (CT) is increasingly used not just to diagnose union but also to estimate the percentage of the fracture gap that is bridged by healing bone. This study tested the primary null hypothesis that there is no agreement between observers on the extent of union of a scaphoid waist fracture on CT. CT scans of 13 nondisplaced scaphoid waist fractures treated nonoperatively were rated by 145 observers. CT scans were done 10 to 12 weeks after injury. Observers were asked to "eyeball" measure percentage of union. We found that there was a moderate agreement on the categorical degree of partial union of a scaphoid waist fracture on CT (k = 0.34). Agreement on the location of bony bridging was slight (k = 0.31). We concluded that there is limited reliability of diagnosis of partial union of a scaphoid waist fracture on CT and that this should be taken into account in both patient care and research. This is a Level III, diagnostic study. PMID- 30483019 TI - Distal Radius Fractures: Evaluation of Closed Reduction and Percutaneous Kirschner Wire Pinning. AB - Objective Closed reduction and percutaneous pinning (CRPP) is losing popularity as a treatment modality for distal radius fractures. However, in select cases, CRPP may have advantages relative to open reduction and internal reduction. We aimed to retrospectively assess the outcomes after CRPP for the treatment of distal radius fractures. Study Design This is a retrospective cohort study. Methods We used billing records to identify all skeletally mature patients with a distal radius fracture who were treated with CRPP by a single surgeon at a level I trauma center in an urban city in the United States. We assessed the medical charts and recorded demographics, trauma and treatment characteristics, radiographic characteristics, and outcomes. Results All patients had a good or excellent range of motion regarding forearm rotation, and almost 80% had good or excellent range of motion regarding flexion or extension of their wrist. One patient had a concern for pin tract infection, and one had subcutaneous migration of a pin, which were both treated by pin removal. Conclusion CRPP is a good option in patients with few and sizeable fracture fragments in patients with a distal radius fracture, and it should be considered as an effective tool to restore radiographic parameters and functional outcomes. PMID- 30483020 TI - Surgical Implications of Innervation Pattern of the Triceps Muscle: A Cadaveric Study. AB - The innervation pattern of triceps is complex and not fully comprehended. Anomalous innervations of triceps have been described by various authors. We have attempted to delineate the nerve supply of the triceps and documented the anomalous innervations of its different heads. The brachial plexus and its major branches (in the region of the axilla and arm) and triceps were dissected in 36 embalmed cadaver upper limbs. Long head received one branch from radial nerve in 31 (86%) specimens. Four (11%) specimens received two branches including one that had dual innervation from the radial and axillary nerves, and one (3%) specimen had exclusive innervation from a branch of the axillary nerve. Medial head received two branches arising from the radial nerve in 34 (94%) specimens. One (3%) specimen received three branches from the radial nerve whereas one (3%) had dual supply from the radial and ulnar nerves. Lateral head received multiple branches exclusively from the radial nerve, ranging from 2 to 5, in all (100%) specimens. Knowledge of the variations in innervation of the triceps would not only help the surgeon to avoid inadvertent injury to any of the nerve branches but also offers new options for nerve and free functional muscle transfers. PMID- 30483021 TI - Epidermal Inclusion Cyst following Percutaneous Trigger Finger Release. AB - Epidermal inclusion cyst is a benign lesion that commonly occurs due to inclusion of epidermal cells into the dermal or deeper layers in a trauma event. Percutaneous release is a minimally invasive technique, and good surgical outcomes can be achieved. However, the percutaneous procedure is a puncture injury, and the epidermal inclusion cyst is reasonable to become a possible complication. In this article, we presented a case of trigger finger in left middle finger. The patient underwent percutaneous release as the treatment and a second percutaneous release 5 months later due to recurrence of the symptoms. An epidermal inclusion cyst was noted 5 months thereafter, and it was treated with excision. With this case, we need to be more aware of this possibility if a mass lesion without infection signs occurs in the released area and recommend sonography if there is a mass lesion a few months after the procedure. PMID- 30483022 TI - Lunate Reconstruction Using Osteochondral Vascularized Graft in Kienbock's Disease. AB - There is a general consensus that the pathogenesis for Kienbock's disease remains uncertain, though it is probably related to nonphysiologic stress transmission across the lunate, acting in concert with one of several possible vascular abnormalities. Most surgical treatments focus on mechanical aspects rather than real physiopathology, but in the recent years several articles have shown the utility of vascularized grafts in the treatment of Kienbock's disease, especially in its early stages. The authors present a case of a successfully reconstruction of a IIIA stage Kienbock's disease with an osteochondral vascularized graft from medial femoral condyle. PMID- 30483023 TI - A Rare Case of Complex Carpal Injury: Divergent Trapezium-Trapezoid Fracture Dislocation. AB - Background Divergent trapezium-trapezoid fracture dislocation is a rare and complex injury. The authors present an unusual case of dislocation of the trapezium-trapezoid complex with scaphoid fracture. Case Description A 25-year old man suffered a road traffic accident leading to complex carpal injury due to axial and rotation forces (steer wheel injury) on the left wrist. X-rays and computed tomographic (CT) scan were done showing trapezium-trapezoid dissociation with fracture of distal pole of scaphoid and ulna styloid. The second metacarpal base was fractured with many ligamentous injuries in the wrist. Methods Volar flexor carpi radialis (FCR) approach was used to reduce and fix scaphoid fracture with 2.7-mm cannulated screw. Dorsal approach was used to fix fracture of second metacarpal base and perform reduction in trapezium-trapezoid complex with help of 0.8-mm K-wires, and suspension wiring of first to second and second to third metacarpal was done using 1.5-mm K-wires. The transverse flexor retinaculum (TFR) in this case was avulsed. Discussion The divergent trapezium-trapezoid joint with scaphoid fracture is not described in the literature yet. The authors implicate steering wheel injury pattern for such complex carpal fracture dislocations. CT scan is imperative to diagnose and plan treatment of such fracture morphology. Early fracture reduction and stabilization of carpal dislocations are essential for proper functioning of wrist. PMID- 30483024 TI - Extended Hueston Flap: New Solution for Primary Closure. AB - Thumb tip injuries are very common in hand trauma, and several flaps are available to restore the defect. One of them is the Hueston flap. It is very simple and quick to harvest, but it could lead to donor site problems. The variant "radial extended" of this flap, proposed in this article, allows a primary closure of donor site avoiding making scar on contact areas subject to frequent use. We performed this technique in a clinical case that presented a distal thumb amputation with good aesthetic result and satisfactory function. PMID- 30483025 TI - Giant Cell Tumor of the Capitate Bone. AB - This case report describes a 16-year-old female patient with a giant cell tumor in her right capitate bone. The tumor was removed by intralesional curettage. A high-speed burr was used to extend the margins of the curettage, and alcohol irrigation was used for adjuvant therapy. The cavity of the capitate was filled with allogenic bone graft. There was no recurrence after 2 years of follow-up, and the right wrist radiographs demonstrated healing of the lesion. PMID- 30483026 TI - Volar Resurfacing of the Thumb with a Superficial Circumflex Iliac Artery Perforator Flap after Hydrofluoric Acid Burn. AB - A right-hand-dominant 55-year-old male automotive mechanic presented 24 hours following a hydrofluoric acid burn to the volar left thumb. Despite the severity of soft tissue injury, the neurovascular bundles were intact. Although a free toe pulp flap is often described to cover volar digit defects, the resultant 6- * 4 cm full-thickness injury of the thumb was too large to be adequately covered by a toe-pulp flap or other commonly used local flaps from the ipsilateral hand. The authors used a superficial circumflex iliac artery perforator (SCIP) flap to reconstruct the volar surface of the thumb from the tip to the metacarpophalangeal joint. They used an arterial anastomosis with the princeps pollicis artery so that the anastomosis was well outside the zone of injury. The patient recovered from the procedure without event and was discharged home on postoperative day 5. At his 2-week postoperative visit, protective sensation with diminished light touch was intact. The authors conclude that the SCIP flap is a technically challenging but versatile, thin flap with minimal donor site morbidity that can be used to resurface the volar aspect of the thumb. The SCIP flap is a valuable resource for the hand surgeon confronted with larger soft tissue defects of the hand. PMID- 30483027 TI - Triceps Tendon Anatomic Repair Utilizing the "Suture Bridge" Technique. AB - Triceps tendon ruptures are uncommon injuries, but they typically require surgical repair. Multiple primary repair techniques are available, including transosseous, suture anchor, and anatomic repairs. The technique described here, the "suture bridge" repair, provides an anatomic repair of the distal triceps tendon to its footprint. It has the potential advantages of increased load to failure, better footprint coverage, higher load resistance, and allows for early motion. PMID- 30483029 TI - The Importance of Clinical Examination in Traumatic Brachial Plexus Injuries. PMID- 30483028 TI - The Use of Dynamic Assist Orthosis for Muscle Reeducation following Brachial Plexus Injury and Reconstruction. AB - Therapeutic management of brachial plexus injuries remains complex. The impact of brachial plexus injuries on everyday human functioning should not be underestimated. Early active-assisted range of motion following such injuries may prevent myostatic contractures, minimize muscle atrophy, facilitate muscle fiber recruitment, and enable a faster return to baseline strength levels. The dynamic assist elbow flexion orthosis proposed is designed to provide patients with a graded system for muscle reeducation and function. No clinical data are currently available on the use of this orthosis design; however, this article presents a treatment option based on sound clinical reasoning to facilitate rehabilitation following this devastating injury. PMID- 30483030 TI - Challenges Faced in the Management of Radial Shaft Nonunion and Implant Failure on a Background of Distal Radius Malunion. PMID- 30483031 TI - Splitting Echinocactus: morphological and molecular evidence support the recognition of Homalocephala as a distinct genus in the Cacteae. AB - Molecular phylogenetic studies of the six currently accepted species in the genus Echinocactus have partially clarified certain aspects of its phylogeny. Most of the studies lack a complete sampling of Echinocactus and are based only in one source of data. Phylogenetic uncertainties in Echinocactus, such as the recognition of Homalocephala as a different genus from Echinocactus, the exclusion of E.grusonii or the affinities of E.polycephalus, are here resolved. Phylogenetic relationships of Echinocactus were reconstructed with a maximum parsimony, a maximum likelihood and a Bayesian approach including 42 morphological characters, four chloroplast markers (atpB-rbcL, trnH-psbA, trnL trnF and trnK/matK) and two nuclear genes. The utility of these two nuclear regions related to the betalain cycles (DODA and 5GT) are explored and discussed in relation to their potential as phylogenetic markers. Concatenated analyses with morphological and molecular data sets, plus 13 indels (2847 characters and 26 taxa), show general agreement with previous independent phylogenetic proposals but with strong support in order to propose the recognition of a reduced Echinocactus and the recognition of Homalocephala at the generic level. These results recovered a polyphyletic Echinocactus as currently defined. The here named HEA clade, recovers the species of Homalocephala, Echinocacuts and Astrophytum as a monophyletic group with strong internal support. The Homalocephala (H.texensis, H.parryi and H.polycephala), was recovered as sister to the Echinocactus clade (E.platyacanthus and E.horizonthalonius), plus the Astrophytum clade. Consequently, we propose here to recognise a monophyletic Echinocactus and a monophyletic Homalocephala as two distinct genera with their own molecular and morphological synapomorphies. The evolution of some morphological characters supporting these clades are discussed, the necessary new taxonomic combinations for Homalocephala are proposed and an identification key for the genera, the species and the subspecies of the HEA clade are presented. PMID- 30483032 TI - Bulbophyllumchrysolabium (Orchidaceae, Epidendroideae, Malaxideae), a new species from Yunnan, China. AB - Bulbophyllumchrysolabium, a new species belonging to section Racemosae from Yunnan, China is described and illustrated. The species is related to B.orientale and B.morphologorum, but differs by having the following set of characters: obliquely broadly-based triangular petals with a long filiform apex; lip densely glandular papillose and conspicuously ciliolate along margins; lip auricles well developed, narrowly falcate, tapering to a long sharp point at the apex; stelidia subulate and twisted inwards, slightly exceeding operculum. The conservation status of B.chrysolabium is assessed and taxonomic notes are provided. PMID- 30483033 TI - Co-Design and Co-Delivery: The Benefits of Integration From the Family Caregiver's Perspective. PMID- 30483034 TI - The Patient Experience of Integrated Care Scale: A Validation Study among Patients with Chronic Conditions Seen in Primary Care. AB - Introduction: Valid and comprehensive instruments to measure integrated care are required to capture patient experience and improve quality of patient care. This study aimed to validate the Patient Experience of Integrated Care Scale (PEICS), among patients with chronic conditions seen in primary care. Methods: One hundred and fifty-nine (159) French-speaking adults with at least one chronic condition were recruited in two family medicine clinics in Quebec (Canada) and completed the 17-item PEICS (T1). Fifty (50) participants completed it a second time 2 weeks later (T2). The internal consistency of the scale was assessed using Cronbach's alpha, the test-retest reliability with the intraclass correlation coefficient (ICC), and concurrent validity using three dimensions of the Continuity of Care from Multiple Clinicians (CC-MC), with Spearman's rank correlation coefficients. Results: Cronbach's alpha for the questionnaire was 0.88 (95% CI: 0.85 to 0.91). The intraclass correlation coefficient was 0.81 (95% CI: 0.64 to 0.90) and Spearman's rank correlation coefficient with the three dimensions of the CC-MC varied from 0.44 to 0.54. Conclusions and discussion: The PEICS showed good psychometric properties. This scale could be used in a population with chronic conditions followed in primary care to measure patient experience of integrated care. PMID- 30483035 TI - The Effectiveness of Shared Care in Cancer Survivors-A Systematic Review. AB - Objectives: To determine whether the shared care model during the follow-up of cancer survivors is effective in terms of patient-reported outcomes, clinical outcomes, and continuity of care. Methods: Using systematic review methods, studies were searched from six electronic databases-MEDLINE (n = 474), British Nursing Index (n = 320), CINAHL (n = 437), Cochrane Library (n = 370), HMIC (n = 77), and Social Care Online (n = 210). The review considered all health-related outcomes that evaluated the effectiveness of shared care for cancer survivors. Results: Eight randomised controlled trials and three descriptive papers were identified. The results showed the likelihood of similar effectiveness between shared care and usual care in terms of quality of life, mental health outcomes, unmet needs, and clinical outcomes in cancer survivorship. The reviewed studies indicated that shared care overall is highly acceptable to cancer survivors and primary care practitioners, and shared care might be cheaper than usual care. Conclusions: The results from this review suggest that the patient satisfaction of shared care is higher than usual care, and the effectiveness of shared care is similar to usual care in cancer survivorship. Interventions that formally involve primary care and improve the communication between primary care and hospital care could support the PCPs in the follow-up. PMID- 30483036 TI - The Luohu Model: A Template for Integrated Urban Healthcare Systems in China. AB - Introduction: Emerging from the epidemiological transition and accelerated aging process, China's fragmentated healthcare systems struggle to meet the demands of the population. On Sept 1st 2017, China's National Health and Family Planning Commission encouraged all cities to learn from the Luohu model of integration adopted in Luohu as an approach to meeting these challenges. In this paper, we study the integration process, analyze the core mechanisms, and conduct preliminary evaluations of integrated policy development in the Luohu model. Policy development: The Luohu hospital group was established in Aug 2015, consists of five district hospitals, 23 community health stations and an institute of precision medicine. The group adopted a series of professional, organizational, system, functional and normative strategies for integrated care, which was provided for the residents of Luohu, especially for the elderly population and patients with chronic conditions. According to a preliminary evaluation of the past two years, the Luohu model showed improvement in the structure and process towards integrated care. New preventive programs conducted in the hospital group resulted in changes of disease incidence. Residents were more satisfied with the Luohu model. However, spending exceeded the global budget for health insurance because of short-term increases in the demand for health care. Lessons learned: First, engagement of multiple stakeholders is essential for the design and implementation of reform. Second, organizational integration is a prerequisite for integrated care in China. Third, effective care integration requires alignment with payment reforms. Fourth, normative integration could promote collaboration in an integrated healthcare system. Conclusion: Core strategies and mechanisms of the Luohu model will promote integrated care in urban China and other countries facing the same challenges. However, it is necessary to study the effects of the Luohu model over the long term and continue to strive for integrated care. PMID- 30483037 TI - Implementation of Integrated Care in Singapore: A Complex Adaptive System Perspective. AB - Background: Integrated care that focuses on organising healthcare services around people and their communities rather than their diseases is promoted as the strategy to overcome the challenges associated with growing complexity in healthcare needs, demand for healthcare services and inadequate supply of services due to fragmentation in the provision of services. While conceptually appears to be simple, integrated care is made up of multicomponent delivery strategies targeting various levels of the healthcare system while engaging various stakeholders in their execution. Methods: We applied the complex adaptive system (CAS) perspective to two different initiatives that exemplify approaches towards integrating care in Singapore: the Regional Health System (RHS) model, implemented across healthcare institutions at the national level, and CARITAS Integrated Dementia Care implemented in the northern region of Singapore. We adopted an inductive approach in our analysis in which we studied the RHS and CARITAS Integrated Dementia Care according to the components of the CAS. We applied the typical characteristics of CAS: (i) diverse, interdependent and semi autonomous actors (ii) self-organizing capacity and simple rules (iii) relationship with the bigger system, emergent behaviour and non-linearity in our analysis of key drivers behind the implementation of both the RHS and CARITAS integrated dementia care. Results: By considering the RHS and CARITAS as whole networks each comprising of interacting and adaptive components instead of separate entities within a bigger system, the CAS provided a new mind-set in surfacing issues associated to the implementation of these integrated care networks. In addition to important actors, systems, it informed understanding of relationships and dependencies between different parts of the network - revealing the lack of homogeneity, conformity and difficulties in designing any optimal system in advance given the many moving parts. Conclusions: Drawing on the two examples of integrated care networks, this paper highlights the significance of effective collaboration built on a common focus, responsiveness to emergent behaviours, simple rules, the ability to self-organize and adapt in response to unexpected situations in further development of integrated care in the Singapore context and beyond. PMID- 30483038 TI - Anti-TNF Exposure during Pregnancy in Crohn's Disease Patients. AB - Inflammatory bowel disease (IBD) affects young people of reproductive age. Therefore, a broad discussion is needed about the possible disease effects in pregnancy, as well as the risks of fetal exposure to the medications used, especially biological therapy. This study aimed to describe the management of 4 Crohn's disease patients who received anti-TNF therapy during pregnancy and present a literature review. We reported 4 cases composed of young women who became pregnant while receiving anti-TNF agents. The patients presented a satisfactory response to the clinical treatment and the pregnancies progressed without complications. We did not observe maternal or embryonic toxicity, or unfavorable outcomes. The available data point to inflammatory activity as the main risk factor for unfavorable gestational evolution to date, and showed anti TNF therapy to be safe during pregnancy and breastfeeding. However, the benefits and risks must be discussed with the patient and management decisions should be taken on an individual basis. PMID- 30483039 TI - Severe de novo Ulcerative Colitis following Ixekizumab Therapy. AB - Ixekizumab is a selective monoclonal antibody targeting interleukin-17A, approved for the treatment of chronic plaque psoriasis. It has rarely been associated with inflammatory bowel disease (IBD) in randomized trials only. We report a unique case of severe new-onset ulcerative colitis in a young male complicated by cytomegalovirus infection who was on ixekizumab therapy for plaque psoriasis. We recommend that clinicians should exercise caution before prescribing ixekizumab as it seems to induce and exacerbate IBD. PMID- 30483041 TI - Successful Treatment of Hepatitis C Virus by Ledipasvir/Sofosbuvir in a Cirrhotic Patient with Sickle Cell Disease and Thalassemia Minor. AB - Around 8% of patients diagnosed with sickle cell disease (SCD) are hepatitis C virus (HCV) carriers. Previously, HCV treatment was seldom considered in SCD patients, as the ribavirin-induced hemolysis and interferon-induced cytopenias could lead to more profound anemia. Nowadays, several oral direct-acting antiviral drugs have been developed and approved by the FDA for hepatitis C treatment. While direct-acting antivirals mitigate many of these risks, their safety and efficacy in SCD patients remains insufficiently explored. Here, we report on successfully treating HCV with ledipasvir/sofosbuvir in a compensated cirrhotic patient with SCD and thalassemia minor. PMID- 30483040 TI - A Successfully Treated Case of Intrahepatic Cholangiocarcinoma with Exacerbation of Dermatomyositis. AB - Dermatomyositis (DM) is often found in conjunction with malignant tumors such as lung, cervical, and breast cancer. However, the association with intrahepatic cholangiocarcinoma (ICC) is extremely rare. Moreover, to our knowledge, there have been no previous reports of DM discovered because of exacerbation of DM. Our case was a 44-year-old female with dry cough, myalgia, and arthralgia. We performed hepatic resection for intrahepatic ICC. She was diagnosed with DM, and combination treatment with prednisolone and tacrolimus was started. During outpatient visits, her symptoms worsened, and she was hospitalized due to deterioration of her primary disease. On detailed examination, a malignant lesion in the liver was discovered. After operation, the symptoms of DM remain stable by taking prednisolone and tacrolimus. The patient was suspected to have paraneoplastic syndrome, which was discovered due to the exacerbation of the DM that was caused by the intrahepatic ICC. PMID- 30483042 TI - Clostridium difficile Causing Empyema. AB - Extraintestinal Clostridium difficile infection (CDI) is extremely uncommon. High mortality and poor outcomes have been observed among individuals with this rare medical condition. Empyema is one of the extraintestinal manifestations of CDI. Possible mechanisms to develop this parapneumonic effusion are aspiration and contamination of the chest tube. We present a 42-year-old Hispanic male with C. difficile empyema without any prior history of CDI. PMID- 30483043 TI - A Rare Cause of Dysphagia and Weight Loss. AB - Mixed connective tissue disease (MCTD) is a rare connective tissue disorder with clinical features that overlap with systemic lupus erythematous, systemic sclerosis, and polymyositis. We report the case of a patient who presented with dysphagia, 25-lb weight loss, difficulty opening her mouth, and joint pain. Dysphagia workup showed a normal barium swallow and normal-appearing EGD but esophageal manometry consistent with severe dysmotility. Through further laboratory and imaging studies, the patient met the diagnostic criteria for MCTD. She had marked improvement in her dysphagia with steroids, biologic therapy, and intravenous immunoglobulin. PMID- 30483044 TI - Effects of Coil Orientation on Motor Evoked Potentials From Orbicularis Oris. AB - This study aimed to characterize effects of coil orientation on the size of Motor Evoked Potentials (MEPs) from both sides of Orbicularis Oris (OO) and both First Dorsal Interosseous (FDI) muscles, following stimulation to left lip and left hand Primary Motor Cortex. Using a 70 mm figure-of-eight coil, we collected MEPs from eight different orientations while recording from contralateral and ipsilateral OO and FDI using a monophasic pulse delivered at 120% active motor threshold. MEPs from OO were evoked consistently for six orientations for contralateral and ipsilateral sites. Contralateral orientations 0 degrees , 45 degrees , 90 degrees , and 315 degrees were found to best elicit OO MEPs with a likely cortical origin. The largest FDI MEPs were recorded for contralateral 45 degrees , invoking a posterior-anterior (PA) current flow. Orientations traditionally used for FDI were also found to be suitable for eliciting OO MEPs. Individuals vary more in their optimal orientation for OO than for FDI. It is recommended that researchers iteratively probe several orientations when eliciting MEPs from OO. Several orientations likely induced direct activation of facial muscles. PMID- 30483045 TI - Statistical Shape Analysis of Large Datasets Based on Diffeomorphic Iterative Centroids. AB - In this paper, we propose an approach for template-based shape analysis of large datasets, using diffeomorphic centroids as atlas shapes. Diffeomorphic centroid methods fit in the Large Deformation Diffeomorphic Metric Mapping (LDDMM) framework and use kernel metrics on currents to quantify surface dissimilarities. The statistical analysis is based on a Kernel Principal Component Analysis (Kernel PCA) performed on the set of initial momentum vectors which parametrize the deformations. We tested the approach on different datasets of hippocampal shapes extracted from brain magnetic resonance imaging (MRI), compared three different centroid methods and a variational template estimation. The largest dataset is composed of 1,000 surfaces, and we are able to analyse this dataset in 26 h using a diffeomorphic centroid. Our experiments demonstrate that computing diffeomorphic centroids in place of standard variational templates leads to similar shape analysis results and saves around 70% of computation time. Furthermore, the approach is able to adequately capture the variability of hippocampal shapes with a reasonable number of dimensions, and to predict anatomical features of the hippocampus, only present in 17% of the population, in healthy subjects. PMID- 30483046 TI - Complexity of Wake Electroencephalography Correlates With Slow Wave Activity After Sleep Onset. AB - Sleep electroencephalography (EEG) provides an opportunity to study sleep scientifically, whose chaotic, dynamic, complex, and dissipative nature implies that non-linear approaches could uncover some mechanism of sleep. Based on well established complexity theories, one hypothesis in sleep medicine is that lower complexity of brain waves at pre-sleep state can facilitate sleep initiation and further improve sleep quality. However, this has never been studied with solid data. In this study, EEG collected from healthy subjects was used to investigate the association between pre-sleep EEG complexity and sleep quality. Multiscale entropy analysis (MSE) was applied to pre-sleep EEG signals recorded immediately after light-off (while subjects were awake) for measuring the complexities of brain dynamics by a proposed index, CI1-30. Slow wave activity (SWA) in sleep, which is commonly used as an indicator of sleep depth or sleep intensity, was quantified based on two methods, traditional Fast Fourier transform (FFT) and ensemble empirical mode decomposition (EEMD). The associations between wake EEG complexity, sleep latency, and SWA in sleep were evaluated. Our results demonstrated that lower complexity before sleep onset is associated with decreased sleep latency, indicating a potential facilitating role of reduced pre sleep complexity in the wake-sleep transition. In addition, the proposed EEMD based method revealed an association between wake complexity and quantified SWA in the beginning of sleep (90 min after sleep onset). Complexity metric could thus be considered as a potential indicator for sleep interventions, and further studies are encouraged to examine the application of EEG complexity before sleep onset in populations with difficulty in sleep initiation. Further studies may also examine the mechanisms of the causal relationships between pre-sleep brain complexity and SWA, or conduct comparisons between normal and pathological conditions. PMID- 30483048 TI - MicroRNA-210-5p Contributes to Cognitive Impairment in Early Vascular Dementia Rat Model Through Targeting Snap25. AB - Vascular dementia (VD) is the most common form of dementia in elderly people. However, little is understood about the role of microRNAs (miRNAs) involved in cognitive impairment in early VD. Here, a VD model induced by chronic cerebral ischemia and fetal bovine serum (FBS)-free cell model that detects synapse formation was established to investigate the function of miRNAs in early VD. The microarray analysis and real-time reverse transcription polymerase chain reaction (RT-PCR) showed that miR-210-5p increased significantly in the hippocampus of rats with 4 weeks of ischemia. The VD model rats also displayed significant cognitive deficits and synaptic loss. The overexpression of miR-210-5p decreased the synaptic number in primary hippocampal neurons, whereas specific suppression of miR-210-5p resulted in the formation of more synapses. Additionally, intracerebroventricular (ICV) injection of miR-210-5p agomir to VD rats aggravated phenotypes of cognitive impairment and synaptic loss. These VD-induced phenotypes were effectively attenuated by miR-210-5p antagomir. Moreover, bioinformatic prediction revealed that synaptosomal-associated protein of 25 KDa (Snap25) mRNA is targeted by miR-210-5p. The miR-210-5p decreased the luciferase activities of 3' untranslated region (3'UTR) of Snap25 mRNA. Mutation of predicted miR-210-5p binding sites in the 3' UTR of Snap25 mRNA abolished the miR 210-5p-induced decrease in luciferase activity. Western blot and immunofluorescence staining confirmed that miR-210-5p targets Snap25. Finally, RT quantitative PCR (qPCR) and immunofluorescence staining detected that miR-210-5p agomir downregulated Snap25 expression in the cornu ammonis1 (CA1) region of hippocampi in VD rats, whereas miR-210-5p antagomir upregulated Snap25 expression. Altogether, miR-210-5p contributes to cognitive impairment in chronic ischemia-induced VD model through the regulation of Snap25 expression, which potentially provides an opportunity to develop a new therapeutic strategy for VD. PMID- 30483050 TI - PINK1 Protects Against Gentamicin-Induced Sensory Hair Cell Damage: Possible Relation to Induction of Autophagy and Inhibition of p53 Signal Pathway. AB - Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) is a gatekeeper of mitochondrial quality control. The present study was aimed to examine whether PINK1 possesses a protective function against gentamicin (GM) induced sensory hair cell (HC) damage in vitro. The formation of parkin particles (a marker revealing the activation of PINK1 pathway which is a substrate of PINK1 and could signal depolarized mitochondria for clearance) and autophagy were determined by immunofluorescence staining. The expressions of PINK1, LC3B, cleaved-caspase 3 and p53 were measured by Western blotting. The levels of reactive oxygen species (ROS) and apoptosis were respectively evaluated by DCFH DA staining, Annexin V Apoptosis Detection Kit and TUNEL staining. Cell viability was tested by a CCK8 kit. We found that treatment of 400 MUM GM elicited the formation of ROS, which, in turn, led to PINK1 degradation, parkin recruitment, autophagy formation, an increase of p53 and cleaved-caspase 3 in HEI-OC1 cells and murine HCs. In contrast, co-treatment with ROS scavenger N-acetyl-L-cysteine (NAC) inhibited parkin recruitment, alleviated autophagy and p53 pathway-related damaged-cell elimination. Moreover, PINK1 interference contributed to a decrease of autophagy but an increase of p53 level in HEI-OC1 cells in response to GM stimulus. Findings from this work indicate that PINK1 alleviates the GM-elicited ototoxicity via induction of autophagy and resistance the increase of p53 in HCs. PMID- 30483049 TI - Human Calmodulin Mutations. AB - Fluxes of calcium (Ca2+) across cell membranes enable fast cellular responses. Calmodulin (CaM) senses local changes in Ca2+ concentration and relays the information to numerous interaction partners. The critical role of accurate Ca2+ signaling on cellular function is underscored by the fact that there are three independent CaM genes (CALM1-3) in the human genome. All three genes are functional and encode the exact same CaM protein. Moreover, CaM has a completely conserved amino acid sequence across all vertebrates. Given this degree of conservation, it was long thought that mutations in CaM were incompatible with life. It was therefore a big surprise when the first CaM mutations in humans were identified six years ago. Today, more than a dozen human CaM missense mutations have been described, all found in patients with severe cardiac arrhythmias. Biochemical studies have demonstrated differential effects on Ca2+ binding affinities for these CaM variants. Moreover, CaM regulation of central cardiac ion channels is impaired, including the voltage-gated Ca2+ channel, CaV1.2, and the sarcoplasmic reticulum Ca2+ release channel, ryanodine receptor isoform 2, RyR2. Currently, no non-cardiac phenotypes have been described for CaM variant carriers. However, sequencing of large human cohorts reveals a cumulative frequency of additional rare CaM mutations that raise the possibility of CaM variants not exclusively causing severe cardiac arrhythmias. Here, we provide an overview of the identified CaM variants and their known consequences for target regulation and cardiac disease phenotype. We discuss experimental data, patient genotypes and phenotypes as well as which questions remain open to understand this complexity. PMID- 30483047 TI - Heat Shock Proteins Regulatory Role in Neurodevelopment. AB - Heat shock proteins (Hsps) are a large family of molecular chaperones that are well-known for their roles in protein maturation, re-folding and degradation. While some Hsps are constitutively expressed in certain regions, others are rapidly upregulated in the presence of stressful stimuli. Numerous stressors, including hyperthermia and hypoxia, can induce the expression of Hsps, which, in turn, interact with client proteins and co-chaperones to regulate cell growth and survival. Such interactions must be tightly regulated, especially at critical points during embryonic and postnatal development. Hsps exhibit specific patterns of expression consistent with a spatio-temporally regulated role in neurodevelopment. There is also growing evidence that Hsps may promote or inhibit neurodevelopment through specific pathways regulating cell differentiation, neurite outgrowth, cell migration, or angiogenesis. This review will examine the regulatory role that these individual chaperones may play in neurodevelopment, and will focus specifically on the signaling pathways involved in the maturation of neuronal and glial cells as well as the underlying vascular network. PMID- 30483051 TI - Transcriptome Profiling of Layer 5 Intratelencephalic Projection Neurons From the Mature Mouse Motor Cortex. AB - The mature cortex contains hugely diverse populations of pyramidal projection neurons (PNs), critical to normal forebrain circuits. In order to understand the healthy cortex, it is essential to characterize this neuronal complexity. We recently demonstrated different identities for Fezf2-positive (Fezf2+ve) and Fezf2-negative (Fezf2-ve) intratelencephalic-PNs (IT-PNs) from layer 5 of the motor cortex (M1). Comparatively, each IT-PN type has a distinct electrophysiological phenotype and the Fezf2+ve IT-PNs display a unique apical dendritic tuft. Here, we aimed to expand our understanding of the molecular underpinnings defining these unique IT-PN types. Using a validated Fezf2-GFP reporter mouse, retrograde labeling techniques and fluorescence activated cell sorting (FACS), combined with a novel approach for low-input RNA-sequencing, we isolated mature Fezf2+ve and Fezf2-ve IT-PNs for transcriptome profiling. Through the comparison of Fezf2+ve and Fezf2-ve IT-PN gene expression profiles, we identified significant enrichment of 81 genes in the Fezf2+ve IT-PNs and 119 genes in the Fezf2-ve IT-PNs. Term enrichment analysis of these enriched genes demonstrated significant overrepresentation of the calcium-binding EF-hand domain in Fezf2+ve IT-PNs, suggesting a greater importance for calcium handling in these neurons. Of the Fezf2-ve IT-PN enriched genes an unexpected and unique enrichment of genes, previously associated with microglia were identified. Our dataset identifies the molecular profiles of two unique IT-PN types in the mature M1, providing important targets to investigate for their maintenance in the healthy mature brain. PMID- 30483052 TI - The Development of an AAV-Based CRISPR SaCas9 Genome Editing System That Can Be Delivered to Neurons in vivo and Regulated via Doxycycline and Cre-Recombinase. AB - The RNA-guided Cas9 nuclease, from the type II prokaryotic clustered regularly interspersed short palindromic repeats (CRISPR) adaptive immune system, has been adapted by scientists to enable site specific genome editing of eukaryotic cells both in vitro and in vivo. Previously, we reported the development of an adeno associated virus (AAV)-mediated CRISPR Streptococcus pyogenes (Sp) Cas9 system, in which the genome editing function can be regulated by controlling the expression of the guide RNA (sgRNA) in a doxycycline (Dox)-dependent manner. Here, we report the development of an AAV vector tool kit utilizing the Cas9 from Staphylococcus aureus (SaCas9). We demonstrate in vitro genome editing in human derived 293FT cells and mouse derived Neuro2A (N2A) cells and in vivo in neurons of the mouse brain. We also demonstrate the ability to regulate the induction of genome editing temporally with Dox and spatially with Cre-recombinase. The combination of these systems enables AAV-mediated CRISPR/Cas9 genome editing to be regulated both spatially and temporally. PMID- 30483054 TI - Developmental Changes in the Inhibition of Glycinergic Synaptic Currents by Niflumic Acid in Hypoglossal Motoneurons. AB - Mammalian brainstem hypoglossal motoneurones (HMs) receive powerful synaptic glycinergic inputs and are involved in a variety of motor functions, including respiration, chewing, sucking, swallowing, and phonation. During the early postnatal development, subunit composition of chloride-permeable glycine receptors (GlyRs) changes leading to a decrease of "fetal" alpha2 and elevation of "adult" alpha1 GlyR subunits. It has been recently demonstrated that niflumic acid (NFA), a member of the fenamate class of non-steroidal anti-inflammatory drugs, is an efficient subunits-specific blocker of GlyRs. At a heterologous expression of different GlyR subunits it has been shown that blocking potency of NFA is more than one order higher for alpha2 GlyRs than for receptors formed by alpha1 subunit. To reveal the action of NFA on the synaptic activity we analyzed here the effects of NFA on the glycinergic inhibitory post-synaptic currents in the HMs from mouse brainstem slices. In the whole-cell patch clamp configuration, the amplitude and the frequency of glycinergic synaptic currents from two age groups have been analyzed: "neonate" (P2-P4) and "juvenile" (P7-P12). Addition of NFA in the presence of antagonists of glutamate and GABA receptors caused a decrease in the mean amplitude and frequency of synaptic events. The degree of the inhibition induced by NFA decreased with the postnatal development, being higher on the motoneurons from "neonate" brainstem slices in comparison with the "juvenile" age group. Analysis of the pair-pulse facilitation suggests the post synaptic origin of NFA action. These observations provide evidence on the developmental changes in the inhibition by NFA of glycinergic synaptic transmission, which reflects increase in the alpha1 and decrease in the alpha2 GlyR subunits expression in synapses to hypoglossal motoneurons during the early stages of postnatal life. PMID- 30483056 TI - Tacrine(10)-Hupyridone Prevents Post-operative Cognitive Dysfunction via the Activation of BDNF Pathway and the Inhibition of AChE in Aged Mice. AB - Post-operative cognitive dysfunction (POCD) could cause short-term or long-term cognitive disruption lasting weeks or months after anesthesia and surgery in elderly. However, no effective treatment of POCD is currently available. Previous studies indicated that the enhancement of brain-derived neurotrophic factor (BDNF) expression, and the elevation the cholinergic system, might be effective to prevent POCD. In this study, we have discovered that tacrine(10)-hupyridone (A10E), a novel acetylcholinesterase (AChE) inhibitor derived from tacrine and huperzine A, could prevent surgery-induced short-term and long-term impairments of recognition and spatial cognition, as evidenced by the novel object recognition test and Morris water maze (MWM) tests, in aged mice. Moreover, A10E significantly increased the expression of BDNF and activated the downstream Akt and extracellular regulated kinase (ERK) signaling in the surgery-treated mice. Furthermore, A10E substantially enhanced choline acetyltransferase (ChAT) positive area and decreased AChE activity, in the hippocampus regions of surgery treated mice, indicating that A10E could prevent surgery-induced dysfunction of cholinergic system, possibly via increasing the synthesis of acetylcholine and the inhibition of AChE. In conclusion, our results suggested that A10E might prevent POCD via the activation of BDNF pathway and the inhibition of AChE, concurrently, in aged mice. These findings also provided a support that A10E might be developed as a potential drug lead for POCD. PMID- 30483055 TI - RAB7L1-Mediated Relocalization of LRRK2 to the Golgi Complex Causes Centrosomal Deficits via RAB8A. AB - Mutations in the LRRK2 gene cause autosomal-dominant Parkinson's disease (PD), and both LRRK2 as well as RAB7L1 have been implicated in increased susceptibility to idiopathic PD. RAB7L1 has been shown to increase membrane-association and kinase activity of LRRK2, and both seem to be mechanistically implicated in the same pathway. Another RAB protein, RAB8A, has been identified as a prominent LRRK2 kinase substrate, and our recent work demonstrates that aberrant LRRK2 mediated phosphorylation of RAB8A leads to centrosomal alterations. Here, we show that RAB7L1 recruits LRRK2 to the Golgi complex, which causes accumulation of phosphorylated RAB8A in a pericentrosomal/centrosomal location as well as centrosomal deficits identical to those observed with pathogenic LRRK2. The centrosomal alterations induced by wildtype LRRK2 in the presence of RAB7L1 depend on Golgi integrity. This is in contrast to pathogenic LRRK2 mutants, which cause centrosomal deficits independent of Golgi integrity or largely independent on RAB7L1 expression. Furthermore, centrosomal alterations in the presence of wildtype LRRK2 and RAB7L1 are at least in part mediated by aberrant LRRK2 mediated RAB8A phosphorylation, as abolished by kinase inhibitors and reduced upon knockdown of RAB8A. These results indicate that pathogenic LRRK2, as well as increased levels of RAB7L1, cause centrosomal deficits in a manner dependent on aberrant RAB8A phosphorylation and centrosomal/pericentrosomal accumulation, suggesting that centrosomal cohesion deficits may comprise a useful cellular readout for a broader spectrum of the disease. PMID- 30483053 TI - Metabotropic Glutamate Receptors in Glial Cells: A New Potential Target for Neuroprotection? AB - Neurodegenerative disorders are characterized by excitotoxicity and neuroinflammation that finally lead to slow neuronal degeneration and death. Although neurons are the principal target, glial cells are important players as they contribute by either exacerbating or dampening the events that lead to neuroinflammation and neuronal damage. A dysfunction of the glutamatergic system is a common event in the pathophysiology of these diseases. Metabotropic glutamate (mGlu) receptors belong to a large family of G protein-coupled receptors largely expressed in neurons as well as in glial cells. They often appear overexpressed in areas involved in neurodegeneration, where they can modulate glutamatergic transmission. Of note, mGlu receptor upregulation may involve microglia or, even more frequently, astrocytes, where their activation causes release of factors potentially able to influence neuronal death. The expression of mGlu receptors has been also reported on oligodendrocytes, a glial cell type specifically involved in the development of multiple sclerosis. Here we will provide a general overview on the possible involvement of mGlu receptors expressed on glial cells in the pathogenesis of different neurodegenerative disorders and the potential use of subtype-selective mGlu receptor ligands as candidate drugs for the treatment of neurodegenerative disorders. Negative allosteric modulators (NAM) of mGlu5 receptors might represent a relevant pharmacological tool to develop new neuroprotective strategies in these diseases. Recent evidence suggests that targeting astrocytes and microglia with positive allosteric modulators (PAM) of mGlu3 receptor or oligodendrocytes with mGlu4 PAMS might represent novel pharmacological approaches for the treatment of neurodegenerative disorders. PMID- 30483059 TI - How Prediction Based on Sequence Detection in the Cerebellum Led to the Origins of Stone Tools, Language, and Culture and, Thereby, to the Rise of Homo sapiens. AB - This article extends Leiner et al.'s watershed position that cerebellar mechanisms played prominent roles in the evolution of the manipulation and refinement of ideas and language. First it is shown how cerebellar mechanism of sequence-detection may lead to the foundational learning of a predictive working memory in the infant. Second, it is argued how this same cerebellar mechanism may have led to the adaptive selection toward the progressively predictive phonological loop in the evolution of working memory of pre-humans. Within these contexts, cerebellar sequence detection is then applied to an analysis of leading anthropologists Stout and Hecht's cerebral cortex-based explanation of the evolution of culture and language through the repetitious rigors of stone-tool knapping. It is argued that Stout and Hecht's focus on the roles of areas of the brain's cerebral cortex is seriously lacking, because it can be readily shown that cerebellar sequence detection importantly (perhaps predominantly) provides more fundamental explanations for the origins of culture and language. It is shown that the cerebellum does this in the following ways: (1) through prediction enhancing silent speech in working memory, (2) through prediction in observational learning, and (3) through prediction leading to accuracy in stone tool knapping. It is concluded, in agreement with Leiner et al. that the more recently proposed mechanism of cerebellar sequence-detection has played a prominent role in the evolution of culture, language, and stone-tool technology, the earmarks of Homo sapiens. It is further concluded that through these same mechanisms the cerebellum continues to play a prominent role in the relentless advancement of culture. PMID- 30483057 TI - Cell-Biological Requirements for the Generation of Dentate Gyrus Granule Neurons. AB - The dentate gyrus (DG) receives highly processed information from the associative cortices functionally integrated in the trisynaptic hippocampal circuit, which contributes to the formation of new episodic memories and the spontaneous exploration of novel environments. Remarkably, the DG is the only brain region currently known to have high rates of neurogenesis in adults (Andersen et al., 1966, 1971). The DG is involved in several neurodegenerative disorders, including clinical dementia, schizophrenia, depression, bipolar disorder and temporal lobe epilepsy. The principal neurons of the DG are the granule cells. DG granule cells generated in culture would be an ideal model to investigate their normal development and the causes of the pathologies in which they are involved and as well as possible therapies. Essential to establish such in vitro models is the precise definition of the most important cell-biological requirements for the differentiation of DG granule cells. This requires a deeper understanding of the precise molecular and functional attributes of the DG granule cells in vivo as well as the DG cells derived in vitro. In this review we outline the neuroanatomical, molecular and cell-biological components of the granule cell differentiation pathway, including some growth- and transcription factors essential for their development. We summarize the functional characteristics of DG granule neurons, including the electrophysiological features of immature and mature granule cells and the axonal pathfinding characteristics of DG neurons. Additionally, we discuss landmark studies on the generation of dorsal telencephalic precursors from pluripotent stem cells (PSCs) as well as DG neuron differentiation in culture. Finally, we provide an outlook and comment critical aspects. PMID- 30483060 TI - Evidence of Muller Glia Conversion Into Retina Ganglion Cells Using Neurogenin2. AB - Degenerative retinopathies are the leading causes of irreversible visual impairment in the elderly, affecting hundreds of millions of patients. Muller glia cells (MGC), the main type of glia found in the vertebrate retina, can resume proliferation in the rodent adult injured retina but contribute weakly to tissue repair when compared to zebrafish retina. However, postnatal and adult mouse MGC can be genetically reprogrammed through the expression of the transcription factor (TF) Achaete-scute homolog 1 (ASCL1) into induced neurons (iNs), displaying key hallmarks of photoreceptors, bipolar and amacrine cells, which may contribute to regenerate the damaged retina. Here, we show that the TF neurogenin 2 (NEUROG2) is also sufficient to lineage-reprogram postnatal mouse MGC into iNs. The efficiency of MGC lineage conversion by NEUROG2 is similar to that observed after expression of ASCL1 and both TFs induce the generation of functionally active iNs. Treatment of MGC cultures with EGF and FGF2 prior to Neurog2 or Ascl1 expression enhances reprogramming efficiencies, what can be at least partially explained by an increase in the frequency of MGCs expressing sex determining region Y (SRY)-box 2 (SOX2). Transduction of either Neurog2 or Ascl1 led to the upregulation of key retina neuronal genes in MGC-derived iNs, but only NEUROG2 induced a consistent increase in the expression of putative retinal ganglion cell (RGC) genes. Moreover, in vivo electroporation of Neurog2 in late progenitors from the neonatal rat retina, which are transcriptionally similar to MGCs, also induced a shift in the generation of retinal cell subtypes, favoring neuronal differentiation at the expense of MGCs and resuming the generation of RGCs. Altogether, our data indicate that NEUROG2 induces lineage conversion of postnatal rodent MGCs into RGC-like iNs in vitro and resumes the generation of this neuronal type from late progenitors of the retina in vivo. PMID- 30483061 TI - Sympathetic Hyperactivity and Age Affect Segregation and Expression of Neurotransmitters. AB - Sympathetic neurons of the rat superior cervical ganglion (SCG) can segregate their neurotransmitters and co-transmitters to separate varicosities of single axons. We have shown that transmitter segregation is a plastic phenomenon and that it is correlated with the strength of synaptic transmission. Here, we determined whether sympathetic dysfunction occurring in stress and hypertension was correlated with plastic changes of neurotransmitter segregation. We characterized the expression of the markers, L-glutamic acid decarboxylase of 67 kDa (GAD67) and vesicular acetylcholine (ACh) transporter (VAChT) in the SCG of cold stressed and spontaneously hypertensive rats (SHR). Considering that the SCG comprises a heterogeneous neuronal population, we explored whether the expression and segregation of neurotransmitters would also have an intraganglionic heterogeneous distribution in ganglia of stressed and hypertensive rats. Furthermore, since hypertension in SHR is detected around 8-10 weeks, we evaluated expression and segregation of ACh and GABA in adult hypertensive (12 week old (wo)) and young pre-hypertensive (6-wo) SHR. We found an increase in segregation of ACh and GABA with no change in transmitter expression in ganglia of stressed animals. In contrast, in SHR, there was an increase in GABA expression, although segregation did not vary. Segregation showed a caudo-rostral gradient in controls but not in the ganglia of stressed animals. GABA expression showed a rostro-caudal gradient in adult SHR, which was not present in young 6-wo rats. In young SHR, ACh increased and, unexpectedly, segregation of ACh and GABA was higher than in adults. Data suggest that ACh and GABA segregation increases in acute sympathetic hyperactivity like stress, but does not vary in chronic hyperactivity such as in hypertension. Changes in segregation are age-dependent and might be involved in the mechanisms underlying stress and hypertension. PMID- 30483058 TI - Immune Dysfunction and Autoimmunity as Pathological Mechanisms in Autism Spectrum Disorders. AB - Autism spectrum disorders (ASD) are a group of heterogeneous neurological disorders that are highly variable and are clinically characterized by deficits in social interactions, communication, and stereotypical behaviors. Prevalence has risen from 1 in 10,000 in 1972 to 1 in 59 children in the United States in 2014. This rise in prevalence could be due in part to better diagnoses and awareness, however, these together cannot solely account for such a significant rise. While causative connections have not been proven in the majority of cases, many current studies focus on the combined effects of genetics and environment. Strikingly, a distinct picture of immune dysfunction has emerged and been supported by many independent studies over the past decade. Many players in the immune-ASD puzzle may be mechanistically contributing to pathogenesis of these disorders, including skewed cytokine responses, differences in total numbers and frequencies of immune cells and their subsets, neuroinflammation, and adaptive and innate immune dysfunction, as well as altered levels of immunoglobulin and the presence of autoantibodies which have been found in a substantial number of individuals with ASD. This review summarizes the latest research linking ASD, autoimmunity and immune dysfunction, and discusses evidence of a potential autoimmune component of ASD. PMID- 30483062 TI - Clemastine Alleviates Depressive-Like Behavior Through Reversing the Imbalance of Microglia-Related Pro-inflammatory State in Mouse Hippocampus. AB - Backgrounds: Abundant reports indicate that neuroinflammatory signaling contributes to behavioral complications associated with depression and may be related to treatment response. The glial cells, especially microglia and astrocytes in brain regions of hippocampus and medial prefrontal cortex (mPFC), are major components of CNS innate immunity. Moreover, purinergic receptor P2X, ligand-gated ion channel 7 (P2X7R) was recently reckoned as a pivotal regulator in central immune system. Besides, it was pointed out that clemastine, a first generation histamine receptor H1 (HRH1) antagonist with considerable safety profile and pharmacological effect, may suppress immune activation through modulating P2X7R. Herein, we investigated the potential anti-neuroinflammatory effects of clemastine on chronic unpredictable mild stress (CUMS)-induced depressive-like behavior in a mouse model. Methods: Male BALB/c mice were subjected to CUMS for 4 weeks, some of them were injected with clemastine fumarate solution. After the stress procedure, behavioral tests including Sucrose Preference Tests (SPTs), Tail Suspension Tests (TSTs) and locomotor activities were performed to evaluate depressive-like phenotype. Subsequently, expression of cytokines and microglia-related inflammatory biomarkers were assessed. Results: In the present research, we found that clemastine significantly reversed both the declination of SPT percentage and the extension of TST immobility durations in depression mouse model without affecting locomotor activity. Also, we observed that clemastine regulated the imbalance of pro-inflammatory cytokines including interleukin-1 beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) in the hippocampus and serum of depressive-like mice. Additionally, clemastine significantly suppressed microglial M1-like activation specifically in the hippocampus, and also improved hippocampal astrocytic loss. Furthermore, clemastine downregulated hippocampal P2X7R without interfering with the expression of HRH1. Conclusion: As a safe and efficient anti-allergic agent, clemastine could impressively alleviate stress-related depressive-like phenotype in mice. Further evidence supported that it was because of the potential function of clemastine in modulating the expression of P2X7 receptor possibly independent of HRH1, therefore suppressing the microglial M1-like activation and pro inflammatory cytokines release in brain regions of hippocampus rather than mPFC. PMID- 30483064 TI - The Multifarious Role of Microglia in Brain Metastasis. AB - The immune landscape in brain metastasis is a very heterogeneous framework. Amongst a broad plethora of cells within the tumor microenvironment, the presence of activated microglia has been perfectly described. The innate role of microglial cells is to detect and eliminate any insults that may disturb the regular behavior of the brain. As part of its defensive role, it releases pro- and anti-inflammatory cytokines that aim to modulate the inflammatory scenario at the metastatic foci. However, the long term effects that these cells may exert on the metastatic progression is not clear. One of the biggest challenges in the field is to distinguish between brain resident microglial cells and infiltrated bone-marrow derived macrophages. Part of this issue is the fact that both cell types share similar phenotypes. Current studies are based on the modulation of the immune response against cancer cells (immunotherapy). However, most of current clinical trials and newly developed drugs focus on the adaptive immune response (e.g., immune blockade check-points). Additionally, the unique structure of the central nervous system with the presence of the blood-brain barrier have hindered a significant advance in novel therapies against brain metastasis. In this manuscript, we describe current advances in characterization of tumor associated microglia and macrophages, the importance of microglia during the anti cancerous response, and the future direction for the development of new strategies against this complex disease. PMID- 30483065 TI - Commentary: MagR Alone Is Insufficient to Confer Cellular Calcium Responses to Magnetic Stimulation. PMID- 30483063 TI - Patient-Derived Induced Pluripotent Stem Cells and Organoids for Modeling Alpha Synuclein Propagation in Parkinson's Disease. AB - Parkinson's disease (PD) is an age-associated, progressive neurodegenerative disorder characterized by motor impairment and in some cases cognitive decline. Central to the disease pathogenesis of PD is a small, presynaptic neuronal protein known as alpha synuclein (a-syn), which tends to accumulate and aggregate in PD brains as Lewy bodies or Lewy neurites. Numerous in vitro and in vivo studies confirm that a-syn aggregates can be propagated from diseased to healthy cells, and it has been suggested that preventing the spread of pathogenic a-syn species can slow PD progression. In this review, we summarize the works of recent literature elucidating mechanisms of a-syn propagation, and discussed the advantages in using patient-derived induced pluripotent stem cells (iPSCs) and/or induced neurons to study a-syn transmission. PMID- 30483066 TI - Large Volume Electron Microscopy and Neural Microcircuit Analysis. AB - One recent technical innovation in neuroscience is microcircuit analysis using three-dimensional reconstructions of neural elements with a large volume Electron microscopy (EM) data set. Large-scale data sets are acquired with newly-developed electron microscope systems such as automated tape-collecting ultramicrotomy (ATUM) with scanning EM (SEM), serial block-face EM (SBEM) and focused ion beam SEM (FIB-SEM). Currently, projects are also underway to develop computer applications for the registration and segmentation of the serially-captured electron micrographs that are suitable for analyzing large volume EM data sets thoroughly and efficiently. The analysis of large volume data sets can bring innovative research results. These recently available techniques promote our understanding of the functional architecture of the brain. PMID- 30483067 TI - Different Subgroups of Cholinergic Neurons in the Basal Forebrain Are Distinctly Innervated by the Olfactory Regions and Activated Differentially in Olfactory Memory Retrieval. AB - The mammalian basal forebrain (BF), a heterogenous structure providing the primary cholinergic inputs to cortical and limbic structures, plays a crucial role in various physiological processes such as learning/memory and attention. Despite the involvement of the BF cholinergic neurons (BFCNs) in olfaction related memory has been reported, the underlying neural circuits remain poorly understood. Here, we combined viral trans-synaptic tracing systems and ChAT-cre transgenic mice to systematically reveal the relationship between the olfactory system and the different subsets of BFCNs. The retrograde adeno-associated virus and rabies virus (AAV-RV) tracing showed that different subregional BFCNs received diverse inputs from multiple olfactory cortices. The cholinergic neurons in medial and caudal horizontal diagonal band Broca (HDB), magnocellular preoptic area (MCPO) and ventral substantia innominate (SI; hereafter HMS complex, HMSc) received the inputs from the entire olfactory system such as the olfactory bulb (OB), anterior olfactory nucleus (AON), entorhinal cortex (ENT), basolateral amygdala and especially the piriform cortex (PC) and hippocampus (HIP); while medial septum (MS/DB) and a part of rostral HDB (hereafter MS/DB complex, MS/DBc), predominantly from HIP; and nucleus basalis Meynert (NBM) and dorsal SI (hereafter NBM complex, NBMc), mainly from the central amygdala. The anterograde vesicular stomatitis virus (VSV) tracing further validated that the major target of the OB to the BF is HMSc. To correlate these structural relations between the BFCNs and olfactory functions, the neurons activated in the BF during olfaction related task were mapped with c-fos immunostaining. It was found that some of the BFCNs were activated in go/no-go olfactory discrimination task, but with different activated patterns. Interestingly, the BFCNs in HMSc were more significantly activated than the other subregions. Therefore, our data have demonstrated that among the different subgroups of BFCNs, HMSc is more closely related to the olfactory system, both structurally and functionally. This work provides the evidence for distinct roles of different subsets of BFNCs in olfaction associated memory. PMID- 30483068 TI - NeuTu: Software for Collaborative, Large-Scale, Segmentation-Based Connectome Reconstruction. AB - Reconstructing a connectome from an EM dataset often requires a large effort of proofreading automatically generated segmentations. While many tools exist to enable tracing or proofreading, recent advances in EM imaging and segmentation quality suggest new strategies and pose unique challenges for tool design to accelerate proofreading. Namely, we now have access to very large multi-TB EM datasets where (1) many segments are largely correct, (2) segments can be very large (several GigaVoxels), and where (3) several proofreaders and scientists are expected to collaborate simultaneously. In this paper, we introduce NeuTu as a solution to efficiently proofread large, high-quality segmentation in a collaborative setting. NeuTu is a client program of our high-performance, scalable image database called DVID so that it can easily be scaled up. Besides common features of typical proofreading software, NeuTu tames unprecedentedly large data with its distinguishing functions, including: (1) low-latency 3D visualization of large mutable segmentations; (2) interactive splitting of very large false merges with highly optimized semi-automatic segmentation; (3) intuitive user operations for investigating or marking interesting points in 3D visualization; (4) visualizing proofreading history of a segmentation; and (5) real-time collaborative proofreading with lock-based concurrency control. These unique features have allowed us to manage the workflow of proofreading a large dataset smoothly without dividing them into subsets as in other segmentation based tools. Most importantly, NeuTu has enabled some of the largest connectome reconstructions as well as interesting discoveries in the fly brain. PMID- 30483069 TI - Analyzing Image Segmentation for Connectomics. AB - Automatic image segmentation is critical to scale up electron microscope (EM) connectome reconstruction. To this end, segmentation competitions, such as CREMI and SNEMI, exist to help researchers evaluate segmentation algorithms with the goal of improving them. Because generating ground truth is time-consuming, these competitions often fail to capture the challenges in segmenting larger datasets required in connectomics. More generally, the common metrics for EM image segmentation do not emphasize impact on downstream analysis and are often not very useful for isolating problem areas in the segmentation. For example, they do not capture connectivity information and often over-rate the quality of a segmentation as we demonstrate later. To address these issues, we introduce a novel strategy to enable evaluation of segmentation at large scales both in a supervised setting, where ground truth is available, or an unsupervised setting. To achieve this, we first introduce new metrics more closely aligned with the use of segmentation in downstream analysis and reconstruction. In particular, these include synapse connectivity and completeness metrics that provide both meaningful and intuitive interpretations of segmentation quality as it relates to the preservation of neuron connectivity. Also, we propose measures of segmentation correctness and completeness with respect to the percentage of "orphan" fragments and the concentrations of self-loops formed by segmentation failures, which are helpful in analysis and can be computed without ground truth. The introduction of new metrics intended to be used for practical applications involving large datasets necessitates a scalable software ecosystem, which is a critical contribution of this paper. To this end, we introduce a scalable, flexible software framework that enables integration of several different metrics and provides mechanisms to evaluate and debug differences between segmentations. We also introduce visualization software to help users to consume the various metrics collected. We evaluate our framework on two relatively large public groundtruth datasets providing novel insights on example segmentations. PMID- 30483070 TI - Innervation of the Nose and Nasal Region of the Rat: Implications for Initiating the Mammalian Diving Response. AB - Most terrestrial animals demonstrate an autonomic reflex that facilitates survival during prolonged submersion under water. This diving response is characterized by bradycardia, apnea and selective increases in peripheral vascular resistance. Stimulation of the nose and nasal passages is thought to be primarily responsible for providing the sensory afferent signals initiating this protective reflex. Consequently, the primary objective of this research was to determine the central terminal projections of nerves innervating the external nose, nasal vestibule and nasal passages of rats. We injected wheat germ agglutinin (WGA) into specific external nasal locations, into the internal nasal passages of rats both with and without intact anterior ethmoidal nerves (AENs), and directly into trigeminal nerves innervating the nose and nasal region. The central terminations of these projections within the medulla were then precisely mapped. Results indicate that the internal nasal branch of the AEN and the nasopalatine nerve, but not the infraorbital nerve (ION), provide primary innervation of the internal nasal passages. The results also suggest afferent fibers from the internal nasal passages, but not external nasal region, project to the medullary dorsal horn (MDH) in an appropriate anatomical way to cause the activation of secondary neurons within the ventral MDH that express Fos protein during diving. We conclude that innervation of the anterior nasal passages by the AEN and nasopalatine nerve is likely to provide the afferent information responsible for the activation of secondary neurons within MDH during voluntary diving in rats. PMID- 30483071 TI - Neurophilic Descending Migration of Dorsal Midbrain Neurons Into the Hindbrain. AB - Stereotypic cell migrations in the developing brain are fundamental for the proper patterning of brain regions and formation of neural networks. In this work, we uncovered in the developing rat, a population of neurons expressing tyrosine hydroxylase (TH) that migrates posteriorly from the alar plate of the midbrain, in neurophilic interaction with axons of the mesencephalic nucleus of the trigeminal nerve. A fraction of this population was also shown to traverse the mid-hindbrain boundary, reaching the vicinity of the locus coeruleus (LC) in rhombomere 1 (r1). This migratory population, however, does not have a noradrenergic (NA) phenotype and, in keeping with its midbrain origin, expresses Otx2 which is down regulated upon migration into the hindbrain. The interaction with the trigeminal mesencephalic axons is necessary for the arrangement and distribution of migratory cells as these aspects are dramatically altered in whole embryo cultures upon disruption of trigeminal axon projection by interfering with DCC function. Moreover, in mouse embryos in an equivalent developmental stage, we detected a cell population that also migrates caudally within the midbrain apposed to mesencephalic trigeminal axons but that does not express TH; a fraction of this population expresses calbindin instead. Overall, our work identified TH-expressing neurons from the rat midbrain alar plate that migrate tangentially over long distances within the midbrain and into the hindbrain by means of a close interaction with trigeminal mesencephalic axons. A different migratory population in this region and also in mouse embryos revealed diversity among the cells that follow this descending migratory pathway. PMID- 30483074 TI - Pharmacological Modulation of the Psychiatric Risk Factor FKBP51 Alters Efficiency of Common Antidepressant Drugs. AB - Despite a growing body of research over the last few decades, mental disorders, including anxiety disorders or depression, are still one of the most prevalent and hardest to treat health burdens worldwide. Since pharmacological treatment with a single drug is often rather ineffective, approaches such as co-medication with functionally diverse antidepressants (ADs) have been discussed and tried more recently. Besides classical ADs, there is a growing number of candidate targets identified as potential starting points for new treatment methods. One of these candidates, the FK506 binding protein 51 (FKBP51) is linked to a number of psychiatric disorders in humans. In this study, we used SAFit2-a newly developed modulator of FKBP51, which has shown promising results in rodent models for stress-related disorders delivered in a depot formulation. We combined SAFit2 with the commonly prescribed selective serotonin reuptake inhibitor (SSRI) escitalopram and performed basic behavioral characterization in a mouse model. Remarkably, co-application of SAFit2 lowered the efficacy of escitalopram in anxiety-related tests but improved stress coping behavior. Given the fact that mental diseases such as anxiety disorders or depression can be divided into different sub-categories, some of which more or less prone to stress, SAFit2 could indeed be a highly beneficial co-medication in very specific cases. This study could be a first, promising step towards the use of FKBP51 modulators as potent and specific enhancers of AD efficiency for subclasses of patients in the future. PMID- 30483072 TI - Pre-reproductive Parental Enriching Experiences Influence Progeny's Developmental Trajectories. AB - While the positive effects of environmental enrichment (EE) applied after weaning, in adulthood, during aging, or even in the presence of brain damage have been widely described, the transgenerational effects of pre-reproductive EE have been less examined. And yet, this issue is remarkable given that parental environmental experience may imprint offspring's phenotype over generations through many epigenetic processes. Interactions between individual and environment take place lifelong even before conception. In fact, the environment pre-reproductively experienced by the mother and/or the father exerts a substantial impact on neural development and motor and cognitive performances of the offspring, even if not directly exposed to social, cognitive, physical and/or motor enrichment. Furthermore, pre-reproductive parental enrichment exerts a transgenerational impact on coping response to stress as well as on the social behavior of the offspring. Among the effects of pre-reproductive parental EE, a potentiation of the maternal care and a decrease in global methylation levels in the frontal cortex and hippocampus of the progeny have been described. Finally, pre-reproductive EE modifies different pathways of neuromodulation in the brain of the offspring (involving brain-derived neurotrophic factor, oxytocin and glucocorticoid receptors). The present review highlights the importance of pre reproductive parental enrichment in altering the performances not only of animals directly experiencing it, but also of their progeny, thus opening the way to new hypotheses on the inheritance mechanisms of behavioral traits. PMID- 30483075 TI - Behavioral Effect of Plant Volatiles Binding to Spodoptera littoralis Larval Odorant Receptors. AB - Phytophagous insects use volatile organic compounds (VOC) emitted by plants to orient towards their hosts. In lepidopteran pests, crop damages are caused by larval stages-the caterpillars-that feed extensively on leaves or other plant tissues. However, larval host plant choice has been poorly studied, and it is generally admitted that caterpillars feed on the plant where the female laid the eggs. The mobility of caterpillars has been generally overlooked even though several studies showed that they can orient towards odors and change host plant. Recently, a large number of odorant receptors (ORs) tuned to plant volatiles have been characterized in the model pest moth Spodoptera littoralis (Noctuidae). In the present work, we identified nine of these deorphanized ORs as expressed in S. littoralis caterpillars. In order to understand whether these ORs are involved in host searching, we tested the behavioral significance of their ligands using a larval two-choice assay. This OR-guided approach led to the identification of nine plant volatiles, namely 1-hexanol, benzyl alcohol, acetophenone, benzaldehyde, (Z)3-hexenol, (E)2-hexenol, indole, DMNT and (Z)3-hexenyl acetate, which are active on S. littoralis caterpillar behavior, increasing our knowledge on larval olfactory abilities. To further explore the link between OR activation and behavioral output induced by plant volatiles we used a modeling approach, thereby allowing identification of some ORs whose activation is related to caterpillar attraction. These ORs may be promising targets for future plant protection strategies. PMID- 30483073 TI - Sex-Dependent Motor Deficit and Increased Anxiety-Like States in Mice Lacking Autism-Associated Gene Slit3. AB - Altered neuronal connectivity has been implicated in the pathophysiology of Autism Spectrum Disorder (ASD). SLIT/ROBO signaling plays an important role in developmental processes of neuronal connectivity, including axon guidance, neuronal migration, and axonal and dendritic branching. Genetic evidence supports that SLIT3, one of the genes encoding SLITs, is associated with ASD. Yet the causal link between SLIT3 mutation and autism symptoms has not been examined. Here we assessed ASD-associated behaviors in Slit3 knockout (KO) mice. Our data showed that Slit3-KO mice exhibited reduced marble burying behaviors but normal social behaviors. In addition, Slit3-KO mice displayed hypolocomotion in the open field test and impaired motor coordination in the rotarod test. Anxiety-like behaviors were mainly observed in female KO mice assessed by three types of behavioral tests, namely, the open field test, elevated plus maze test, and light/dark box test. No differences were observed between KO and wildtype mice in recognition memory in the novel object recognition test or depression-like behavior in the tail suspension test. Taken together, loss of Slit3 may result in disrupted neural circuits related to motor function and increased anxiety-like states, which are co-occurring symptoms in ASD. PMID- 30483076 TI - Cocaine-Evoked Locomotor Activity Negatively Correlates With the Expression of Neuromedin U Receptor 2 in the Nucleus Accumbens. AB - Cocaine use disorder (CUD) is characterized by repeated cycles of drug seeking and drug taking. Currently, there are no available pharmacotherapies to treat CUD, partially due to a lack of a mechanistic understanding of cocaine-evoked alterations in the brain that drive drug-related behaviors. Repeated cocaine use alters expression of numerous genes in addiction-associated areas of the brain and these alterations are in part driven by inter-subject genetic variability. Recent findings have shown the neuropeptide neuromedin U (NMU) and its receptor NMU receptor 2 (NMUR2) decrease drug-related behaviors, but it is unknown if substances of abuse alter NMU or NMUR2 expression. Here, rats were given twice daily saline or cocaine (15 mg/kg, intraperitoneal (IP)) for 5 days and then 7 days with no treatment. All rats were then given a single cocaine treatment and locomotor activity was measured in the acute (non-sensitized) and repeated drug exposure (sensitized) groups. Immediately following locomotor assay, tissue was taken and we demonstrate that accumbal NMUR2 mRNA expression, but not NMU mRNA expression, is negatively correlated with non-sensitized cocaine-evoked locomotor activity, but the correlation is lost following cocaine sensitization. Furthermore, in a separate cohort NMUR2 protein levels also negatively correlated with cocaine-evoked locomotor activity based on immunohistochemical stereology for NMUR2 protein expression. These findings are the first to demonstrate that repeated cocaine exposure causes dysregulated expression of NMUR2 and highlight the deleterious effects of repeated cocaine exposure on neurobiological receptor systems. Restoring the normal function of NMUR2 could be beneficial to the treatment of CUD. PMID- 30483077 TI - Effects of a Dehydroevodiamine-Derivative on Synaptic Destabilization and Memory Impairment in the 5xFAD, Alzheimer's Disease Mouse Model. AB - Carboxy-dehydroevodiamine.HCl (cx-DHED) is a derivative of DHED, which improves memory impairment. Carboxyl modification increases solubility in water, indicating that its bioavailability is higher than that of DHED. Cx-DHED is expected to have better therapeutic effects on Alzheimer's disease (AD) than DHED. In this study, we investigated the therapeutic effects of cx-DHED and the underlying mechanism in 5xFAD mice, transgenic (Tg) mouse model of AD model mice. In several behavioral tests, such as Y-maze, passive avoidance, and Morris water maze test, memory deficits improved significantly in cx-DHED-treated transgenic (Tg) mice compared with vehicle-treated Tg mice. We also found that AD-related pathologies, including amyloid plaque deposition and tau phosphorylation, were reduced after the treatment of Tg mice with cx-DHED. We determined the levels of synaptic proteins, such as GluN1, GluN2A, GluN2B, PSD-95 and Rabphilin3A, and Rab3A in the brains of mice of each group and found that GluN2A and PSD-95 were significantly increased in the brains of cx-DHED-treated Tg mice when compared with the brains of Tg-vehicle mice. These results suggest that cx-DHED has therapeutic effects on 5xFAD, AD model mice through the improvement of synaptic stabilization. PMID- 30483078 TI - Prolonged Voluntary Running Negatively Affects Survival and Disease Prognosis of Male SOD1G93A Low-Copy Transgenic Mice. AB - Amyotrophic Lateral Sclerosis (ALS) is a disease in which physical activity plays a controversial role. Epidemiological studies indicate an association between intense exercise and risk of developing ALS. To study the impact of physical activity on ALS, mouse models rely mostly on forced exercise. In this study we hypothesized that voluntary wheel running could represent a better model of the influence of exercise in the pathogenesis of ALS. We used an automated home-cage running-wheel system that enables individual monitoring of performance. To verify the effect of voluntary running on disease progression, prognosis and survival as well as motor functions, we challenged SOD1G93A low-copy male and female mice on one (1 RW, at age 24 weeks) or multiple (3 RW) running sessions at age 13, 18, and 24 weeks. In parallel we measured performance on Rotarod and Grip strength tests at different ages. Several parameters were analyzed through Principal Component Analysis in order to detect what indices correlate and may be useful for deeper understanding of the relation between exercise and disease development. We found mutant male mice more negatively affected than females by prolonged and repeated exercise. SOD1G93A low-copy male mice showed shorter survival, increased body weight loss and poorer disease prognosis when exposed to multiple running sessions. These findings could encourage the investigation of the pathogenetic mechanisms underlying the supposedly increased risk to develop ALS in humans engaged in specific and intense exercise activities. PMID- 30483079 TI - Extinction of Fear Memory Attenuates Conditioned Cardiovascular Fear Reactivity. AB - Post-traumatic stress disorder (PTSD) is characterized by a heightened emotional and physiological state and an impaired ability to suppress or extinguish traumatic fear memories. Exaggerated physiological responses may contribute to increased cardiovascular disease (CVD) risk in this population, but whether treatment for PTSD can offset CVD risk remains unknown. To further evaluate physiological correlates of fear learning, we used a novel pre-clinical conditioned cardiovascular testing paradigm and examined the effects of Pavlovian fear conditioning and extinction training on mean arterial pressure (MAP) and heart rate (HR) responses. We hypothesized that a fear conditioned cardiovascular response could be detected in a novel context and attenuated by extinction training. In a novel context, fear conditioned mice exhibited marginal increases in MAP (~3 mmHg) and decreases in HR (~20 bpm) during CS presentation. In a home cage context, the CS elicited significant increases in both HR (100 bpm) and MAP (20 mmHg). Following extinction training, the MAP response was suppressed while CS-dependent HR responses were variable. These pre-clinical data suggest that extinction learning attenuates the acute MAP responses to conditioned stimuli over time, and that MAP and HR responses may extinguish at different rates. These results suggest that in mouse models of fear learning, conditioned cardiovascular responses are modified by extinction training. Understanding these processes in pre-clinical disease models and in humans with PTSD may be important for identifying interventions that facilitate fear extinction and attenuate hyper physiological responses, potentially leading to improvements in the efficacy of exposure therapy and PTSD-CVD comorbidity outcomes. PMID- 30483080 TI - Brain Network Changes in Fatigued Drivers: A Longitudinal Study in a Real-World Environment Based on the Effective Connectivity Analysis and Actigraphy Data. AB - The analysis of neurophysiological changes during driving can clarify the mechanisms of fatigue, considered an important cause of vehicle accidents. The fluctuations in alertness can be investigated as changes in the brain network connections, reflected in the direction and magnitude of the information transferred. Those changes are induced not only by the time on task but also by the quality of sleep. In an unprecedented 5-month longitudinal study, daily sampling actigraphy and EEG data were collected during a sustained-attention driving task within a near-real-world environment. Using a performance index associated with the subjects' reaction times and a predictive score related to the sleep quality, we identify fatigue levels in drivers and investigate the shifts in their effective connectivity in different frequency bands, through the analysis of the dynamical coupling between brain areas. Study results support the hypothesis that combining EEG, behavioral and actigraphy data can reveal new features of the decline in alertness. In addition, the use of directed measures such as the Convergent Cross Mapping can contribute to the development of fatigue countermeasure devices. PMID- 30483081 TI - The Effect of High-Definition Transcranial Direct Current Stimulation of the Right Inferior Frontal Gyrus on Empathy in Healthy Individuals. AB - Empathy, including cognitive and emotional empathy, refers to the ability to infer the mental states of others and to the capacity to share emotions. The neural mechanisms involved in empathy are complex and not yet fully understood, and previous studies have shown that both cognitive and emotional empathy are closely associated with the inferior frontal gyrus (IFG). In this study, we examined whether empathy can be modulated by high-definition transcranial direct current stimulation (HD-tDCS) of the right IFG. Twenty-three healthy participants took part in all three experimental conditions (i.e., anodal, cathodal and sham stimulation) in a randomized order. Participants then completed the Chinese version of the Multifaceted Empathy Test (MET), which assesses both cognitive and emotional empathy. The results show that scores obtained for cognitive empathy following cathodal stimulation are significantly lower than those obtained following sham stimulation. In addition, scores obtained for cognitive empathy following anodal stimulation are higher than those obtained following sham stimulation, though the difference is only marginally significant. However, the results fail to show whether the stimulation of the right IFG via HD-tDCS plays a role in emotional empathy. Our results suggest that the right IFG plays a key role in cognitive empathy and indicate that HD-tDCS can regulate cognitive empathy by inducing excitability changes in the right IFG. PMID- 30483082 TI - Moderating Effects of Harm Avoidance on Resting-State Functional Connectivity of the Anterior Insula. AB - As an index of behavioral inhibition and an individual's propensity to avoid, rather than seek, potentially dangerous situations, harm avoidance has been linked to internalizing psychopathology. Altered connectivity within intrinsic functional neural networks (i.e., default mode [DMN], central executive [CEN] and salience networks [SN]) has been related to internalizing psychopathology; however, less is known about the effects of harm avoidance on functional connectivity within and between these networks. Importantly, harm avoidance may be distinguishable from trait anxiety and have clinical relevance as a risk factor for internalizing psychopathology. A sample of young adults (n = 99) completed a resting state functional magnetic resonance imaging (fMRI) scan and self-report measures of harm avoidance and trait anxiety. Whole brain seed-to voxel and seed-to-network connectivity analyses were conducted using anterior insula seeds to examine associations between harm avoidance/trait anxiety and connectivity. After adjusting for sex and age, there was a significant negative effect of harm avoidance on connectivity between the anterior insula and clusters in the precuneus/posterior cingulate cortex (PCC) left superior/middle frontal gyrus, dorsal anterior cingulate cortex (dACC) and bilateral inferior parietal lobule (IPL)/angular gyrus. Seed-to-network analyses indicated a negative effect of harm avoidance on connectivity between the right anterior insula and anterior and posterior DMN. There were no effects of trait anxiety on functional connectivity of the anterior insula. Overall, the results indicate that individual differences in harm avoidance relate to disruptions in internetwork connectivity that may contribute to deficits in appropriately modulating attentional focus. PMID- 30483083 TI - Does Meditation Alter Brain Responses to Negative Stimuli? A Systematic Review. AB - Background: Despite several attempts to review and explain how meditation alters the brain and facilitates emotion regulation, the extent to which meditation and emotion regulation strategies share the same neural mechanisms remains unclear. Objective: We aim to understand the influence of meditation on the neural processing of negative emotional stimuli in participants who underwent meditation interventions (naive meditators) and long-term meditators. Methodology: A systematic review was conducted using standardized search operators that included the presence of terms related to emotion, meditation and neuro-imaging techniques in PsycInfo, PubMed, Scopus, and Web of Science databases. Results: Searches identified 882 papers, of which 11 were eligible for inclusion. Results showed a predominance of greater prefrontal/frontal activity related to meditation, which might indicate the increased recruitment of cognitive/attentional control resources in naive and long-term meditators. This increased frontal activity was also observed when participants were asked to simply react to negative stimuli. Findings from emotion-related areas were scarce but suggested increased insular activity in meditators, potentially indicating that meditation might be associated with greater bodily awareness. Conclusions: Meditation practice prompts regulatory mechanisms when participants face aversive stimuli, even without an explicit request. Moreover, some studies reported increased insular activity in meditators, consistent with the hypothesis that meditation helps foster an interoceptive awareness of bodily and emotional states. PMID- 30483084 TI - Aberrant Cerebellar-Cerebral Functional Connectivity in Children and Adolescents With Autism Spectrum Disorder. AB - The cerebellum, which forms widespread functional networks with many areas in the cerebral cortices and subcortical structures, is one of the brain regions most consistently reported to exhibit neuropathological features in patients with autism spectrum disorder (ASD). However, cerebellar functional connectivity (FC) studies in patients with ASD have been very sparse. Using resting state functional connectivity (rsFC) analysis, we investigated the FC of the hemispheric/vermal subregions and the dentate nucleus of the cerebellum with the cerebral regions in 36 children and adolescents [16 participants with ASD, 20 typically developing (TD) participants, age: 6-15 years]. Furthermore, an independent larger sample population (42 participants with ASD, 88 TD participants, age: 6-15 years), extracted from the Autism Brain Imaging Data Exchange (ABIDE) II, was included for replication. The ASD group showed significantly increased or decreased FC between "hubs" in the cerebellum and cerebral cortices, when compared with the TD group. Findings of aberrant FCs converged on the posterior hemisphere, right dentate nucleus, and posterior inferior vermis of the cerebellum. Furthermore, these aberrant FCs were found to be related to motor, executive, and socio-communicative functions in children and adolescents with ASD when we examined correlations between FC and behavioral measurements. Results from the original dataset were partially replicated in the independent larger sample population. Our findings suggest that aberrant cerebellar-cerebral FC is associated with motor, socio-communicative, and executive functions in children and adolescents with ASD. These observations improve the current knowledge regarding the neural substrates that underlie the symptoms of ASD. PMID- 30483086 TI - Wearable Neurophysiological Recordings in Middle-School Classroom Correlate With Students' Academic Performance. AB - The rapid development of wearable bio-sensing techniques has made it possible to continuously record neurophysiological signals in naturalistic scenarios such as the classroom. The present study aims to explore the neurophysiological correlates of middle-school students' academic performance. The electrodermal signals (EDAs) and heart rates (HRs) were collected via wristband from 100 Grade seven students during their daily Chinese and math classes for 10 days in 2 weeks. Significant correlations were found between the academic performance as reflected by the students' final exam scores and the EDA responses. Further regression analyses revealed significant prediction of the academic performance mainly by the transient EDA responses (R 2 = 0.083, p < 0.05, with Chinese classes only; R 2 = 0.030, p < 0.05, with both Chinese and math classes included). By combining the self-report data about session-based general statuses and the neurophysiological data, the explained powers of the regression models were further improved (R 2 = 0.095, p < 0.05, with Chinese classes only; R 2 = 0.057, p < 0.05, with both Chinese and math classes included), and the neurophysiological data were shown to have independent contributions to the regression models. In addition, the regression models became non-significant by exchanging the academic performances of the Chinese and math classes as the dependent variables, suggesting at least partly distinct neurophysiological responses for the two types of classes. Our findings provide evidences supporting the feasibility of predicting educational outputs by wearable neurophysiological recordings. PMID- 30483085 TI - Functional Connectivity During Handgrip Motor Fatigue in Older Adults Is Obesity and Sex-Specific. AB - The prevalence of obesity in older adults, particularly in females, is increasing rapidly and is associated with declines in both the brain and physical health. Both the obese and the female populations have shown greater motor fatigue than their counterparts, however, the central neural mechanisms for fatigue are unclear. The present study measured fatigue-related functional connectivity across frontal and sensorimotor areas using functional near-infrared spectroscopy (fNIRS). Fifty-nine older adults (30 non-obese and 29 obese) performed submaximal handgrip motor fatigue until voluntary exhaustion. Functional connectivity and cerebral hemodynamics were compared across eight cortical areas during motor fatigue and across obesity and sex groups along with neuromuscular fatigue outcomes (i.e., endurance time, strength loss, and force steadiness). Both obesity- and sex-specific functional architecture and mean activation differences during motor fatigue in older adults were observed, which were accompanied by fatigue-related changes in variability of force steadiness that differed between groups. While primary indicators of fatigue, i.e., endurance and strength loss, did not differ between groups, the motor steadiness changes indicated different neural adaptation strategies between the groups. These findings indicate that obesity and sex differences exist in brain function in older adults, which may affect performance during motor fatigue. PMID- 30483087 TI - Musical Creativity and Depth of Implicit Knowledge: Spectral and Temporal Individualities in Improvisation. AB - It has been suggested that musical creativity is mainly formed by implicit knowledge. However, the types of spectro-temporal features and depth of the implicit knowledge forming individualities of improvisation are unknown. This study, using various-order Markov models on implicit statistical learning, investigated spectro-temporal statistics among musicians. The results suggested that lower-order models on implicit knowledge represented general characteristics shared among musicians, whereas higher-order models detected specific characteristics unique to each musician. Second, individuality may essentially be formed by pitch but not rhythm, whereas the rhythms may allow the individuality of pitches to strengthen. Third, time-course variation of musical creativity formed by implicit knowledge and uncertainty (i.e., entropy) may occur in a musician's lifetime. Individuality of improvisational creativity may be formed by deeper but not superficial implicit knowledge of pitches, and that the rhythms may allow the individuality of pitches to strengthen. Individualities of the creativity may shift over a musician's lifetime via experience and training. PMID- 30483089 TI - Web-Based Interfaces for Virtual C. elegans Neuron Model Definition, Network Configuration, Behavioral Experiment Definition and Experiment Results Visualization. AB - The Si elegans platform targets the complete virtualization of the nematode Caenorhabditis elegans, and its environment. This paper presents a suite of unified web-based Graphical User Interfaces (GUIs) as the main user interaction point, and discusses their underlying technologies and methods. The user-friendly features of this tool suite enable users to graphically create neuron and network models, and behavioral experiments, without requiring knowledge of domain specific computer-science tools. The framework furthermore allows the graphical visualization of all simulation results using a worm locomotion and neural activity viewer. Models, experiment definitions and results can be exported in a machine-readable format, thereby facilitating reproducible and cross-platform execution of in silico C. elegans experiments in other simulation environments. This is made possible by a novel XML-based behavioral experiment definition encoding format, a NeuroML XML-based model generation and network configuration description language, and their associated GUIs. User survey data confirms the platform usability and functionality, and provides insights into future directions for web-based simulation GUIs of C. elegans and other living organisms. The tool suite is available online to the scientific community and its source code has been made available. PMID- 30483090 TI - A Linear Approach to Optimize an EMG-Driven Neuromusculoskeletal Model for Movement Intention Detection in Myo-Control: A Case Study on Shoulder and Elbow Joints. AB - The growing interest of the industry production in wearable robots for assistance and rehabilitation purposes opens the challenge for developing intuitive and natural control strategies. Myoelectric control, or myo-control, which consists in decoding the human motor intent from muscular activity and its mapping into control outputs, represents a natural way to establish an intimate human-machine connection. In this field, model based myo-control schemes (e.g., EMG-driven neuromusculoskeletal models, NMS) represent a valid solution for estimating the moments of the human joints. However, a model optimization is needed to adjust the model's parameters to a specific subject and most of the optimization approaches presented in literature consider complex NMS models that are unsuitable for being used in a control paradigm since they suffer from long lasting setup and optimization phases. In this work we present a minimal NMS model for predicting the elbow and shoulder torques and we compare two optimization approaches: a linear optimization method (LO) and a non-linear method based on a genetic algorithm (GA). The LO optimizes only one parameter per muscle, whereas the GA-based approach performs a deep customization of the muscle model, adjusting 12 parameters per muscle. EMG and force data have been collected from 7 healthy subjects performing a set of exercises with an arm exoskeleton. Although both optimization methods substantially improved the performance of the raw model, the findings of the study suggest that the LO might be beneficial with respect to GA as the latter is much more computationally heavy and leads to minimal improvements with respect to the former. From the comparison between the two considered joints, it emerged also that the more accurate the NMS model is, the more effective a complex optimization procedure could be. Overall, the two optimized NMS models were able to predict the shoulder and elbow moments with a low error, thus demonstrating the potentiality for being used in an admittance based myo-control scheme. Thanks to the low computational cost and to the short setup phase required for wearing and calibrating the system, obtained results are promising for being introduced in industrial or rehabilitation real time scenarios. PMID- 30483091 TI - Primary Gastrointestinal Kaposi's Sarcoma in a Patient with Human Immunodeficiency Virus. AB - Gastrointestinal bleeding in HIV patients secondary to coinfection by HHV8 and development of Kaposi's sarcoma (KS) is a rare complication even if no skin lesions are detected on physical examination. This article indicates which patients might develop this type of clinical sign and also tries to recall that absence of skin lesions never rules out the presence of KS, especially if gastrointestinal involvement is documented. Gastrointestinal bleeding in terms of hematemesis has rarely been reported in the literature. We review some important clinical findings, diagnosis, and treatment approach. We present the case of an HIV patient who presented to the emergency department with hematemesis and gastrointestinal signs of KS on upper gastrointestinal endoscopy without any dermatological involvement. PMID- 30483088 TI - The Anatomy of Inference: Generative Models and Brain Structure. AB - To infer the causes of its sensations, the brain must call on a generative (predictive) model. This necessitates passing local messages between populations of neurons to update beliefs about hidden variables in the world beyond its sensory samples. It also entails inferences about how we will act. Active inference is a principled framework that frames perception and action as approximate Bayesian inference. This has been successful in accounting for a wide range of physiological and behavioral phenomena. Recently, a process theory has emerged that attempts to relate inferences to their neurobiological substrates. In this paper, we review and develop the anatomical aspects of this process theory. We argue that the form of the generative models required for inference constrains the way in which brain regions connect to one another. Specifically, neuronal populations representing beliefs about a variable must receive input from populations representing the Markov blanket of that variable. We illustrate this idea in four different domains: perception, planning, attention, and movement. In doing so, we attempt to show how appealing to generative models enables us to account for anatomical brain architectures. Ultimately, committing to an anatomical theory of inference ensures we can form empirical hypotheses that can be tested using neuroimaging, neuropsychological, and electrophysiological experiments. PMID- 30483092 TI - Thromboembolic Events Related to Treatment with Checkpoint Inhibitors: Report of Two Cases. AB - Despite the significant clinical benefits, checkpoint inhibition is associated with a unique spectrum of immune-related adverse events. It is sometimes difficult to distinguish some rare adverse effects from a cancer progression; thus, such effects should be reported in clinical trials to be diagnosed by physicians. Only a few cases of arterial embolic events have been described in studies related to patients treated by immunotherapy. In this article, we report the cases of 2 patients who presented rare and severe thromboembolic events after using checkpoint inhibitors. The first case describes multiple organ embolism at the same time, associated with other autoimmune symptoms. In the second case, distal digital necrosis emerged after the initiation of immunotherapy. There is insufficient data about the real incidence of thromboembolic and rheumatological events related to checkpoint inhibition. Future trials should be done to establish preventive strategies. PMID- 30483093 TI - Capecitabine-Associated Terminal Ileitis. AB - Capecitabine is an oral fluoropyrimidine used as adjuvant and palliative chemotherapy in patients with colorectal cancer. Diarrhea is a well-known side effect of capecitabine and 5-fluorouracil agents. We present a case with terminal ileitis as a rare adverse event of capecitabine treatment. Capecitabine-induced terminal ileitis is likely to be underreported. It should be considered more often as a cause of severe and atypical complaints of diarrhea during treatment with capecitabine or other 5-fluorouracil agents. PMID- 30483094 TI - Breast Cancer Metastasis in the Skin with Hyperkeratotic Pigmentation Caused by Melanocyte Colonization. AB - Pigmented breast cancer in the skin caused by nonneoplastic melanocytes of epidermal origin is a rare condition of metastasis from breast cancer, but the pathogenesis of this phenomenon is almost unknown. In this report, we describe a case of breast cancer metastasis in the skin with prominent hyperkeratotic pigmentation caused by nonneoplastic melanocyte colonization. Immunohistochemical staining revealed that the metastatic tumor cells produced IL-23, which is reported not only to induce IL-17 but also to inhibit cell apoptosis in breast cancer cells, which affects tumor progression. In addition to IL-23, substantial numbers of IL-17-producing cells were detected at the peritumoral area, suggesting that IL-17 might induce not only melanogenesis but also keratinocyte proliferation and tumorigenesis. Our report suggests possible mechanisms of hyperkeratotic pigmentation of breast cancer metastasis in the skin. PMID- 30483095 TI - Large Cell Neuroendocrine Carcinoma of the Cervix with Sequential Metastasis to Different Sites: A Case Report. AB - Neuroendocrine carcinoma of the cervix is rare, and prognosis is very poor. Because of its rarity, effective treatment of neuroendocrine carcinoma of the cervix has not been established. It has distinct patterns of metastasis, but can be successfully treated with radical surgery and platinum-based chemotherapy. We report a 50-year-old woman who was diagnosed with large cell neuroendocrine carcinoma of the cervix and underwent radical surgery followed by adjuvant chemoradiation therapy. She experienced recurrence several times and to different sites, with sequential metastasis to the lung, breast, and retroperitoneum, but nevertheless survived more than 5 years. PMID- 30483096 TI - Keratoacanthoma Centrifugum Marginatum with Spontaneous Regression and Its Possible Differential Diagnosis. AB - Keratoacanthoma centrifugum marignatum (KCM) is a rare variant of keratoacanthoma, which is characterized by the dense infiltration of inflammatory cells throughout the dermis, especially around the keratinocytic islands. Therefore, it is sometimes difficult to differentiate between KCM and cutaneous T cell lymphomas. In this report, we describe a case of KCM with spontaneous regression that showed dense infiltration of CD3+CD8+ T cells. Our present case suggested the importance of investigating tumor-infiltrating lymphocytes to avoid the misdiagnosis of KCM as cutaneous T-cell lymphoma. PMID- 30483097 TI - Poorly Differentiated Small-Cell-Type Neuroendocrine Carcinoma of the Prostate: A Case Report and Literature Review. AB - Neuroendocrine cells are widespread throughout the body and can give rise of neuroendocrine tumors due to abnormal growth of the chromaffin cells. Neuroendocrine tumors divide into many subtypes based on tumor grade (Ki-67 index and mitotic count) and differentiation. These tumors can be further divided into secretory and nonsecretory types based on the production of peptide hormone by tumor cells. Poorly differentiated small-cell-type neuroendocrine tumors are one of the subtypes of neuroendocrine tumors. These tumors are less common; however, they tend to be locally invasive and aggressive in behavior with poor overall median survival. Treatment of the nonsecretory small-cell type is modeled to small-cell lung cancer with a regimen consisting of platinum-based chemotherapy and etoposide with variable response. Here, we present a case of poorly differentiated small-cell neuroendocrine tumor originating from the prostate. PMID- 30483098 TI - Hydrogen Sulfide-Synthesizing Enzymes Are Altered in a Case of Oral Cavity Mucoepidermoid Carcinoma. AB - Mucoepidermoid carcinoma (MEC) is the most common malignant epithelial neoplasm of the salivary glands. MECs of the mouth floor are rare, with only a few cases reported. Here we report a MEC of the mouth floor in a 55-year-old woman. Since several studies have shown that hydrogen sulfide (H2S)-synthesizing enzymes are often increased in malignant tumors compared to benign counterpart tissues, we used western blotting to compare the protein levels of cystathionine-beta synthase (CBS), cystathionine gamma-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) in a mouth floor MEC to adjacent benign oral mucosae. We also used high-performance liquid chromatography to quantify possible differences in tissue sulfur fraction concentrations between the two biopsy types. Last, we used western blotting to examine nicotinamide phosphoribosyl transferase (Nampt), mitoNEET, and phospho-ser727-Stat3 levels in the biopsies. We found that all the proteins and phospho-ser727-Stat3 are increased in the MEC compared to benign mucosae. Interestingly, free H2S levels, acid-labile, and the sulfane sulfur factions were essentially the same between the MEC and benign tissue. Although limited to a single and unusual tumor type, to our knowledge this is only the third time H2S concentrations were directly quantified inside a human tumor. Last, our results replicate those of two previous studies where the H2S-synthesizing enzymes are increased in a malignant tumor, while free H2S is either not increased or only slightly increased, suggesting that malignant tumors rapidly metabolize H2S as part of tumor maintenance and growth. PMID- 30483099 TI - Successful Use of Pembrolizumab to Treat Refractory Thymic Carcinoma with High PD L1 Expression. AB - Thymic carcinoma is a relatively rare and aggressive thymic epithelial tumor. Herein, we report successful treatment of thymic carcinoma with pembrolizumab. A 68-year-old woman was admitted to our hospital for evaluation of chest pain. Chest computed tomography showed a mass in the anterior mediastinum and lymphadenopathy in the left cervical lymph node. Analysis of biopsy specimens detected squamous cell carcinoma in the left cervical lymph node, and immunohistochemical analysis showed 100% expression of programmed death-ligand 1 (PD-L1). Masaoka-Koga stage IVb thymic carcinoma was ultimately diagnosed. Since 3 cycles of first-line chemotherapy did not result in improvement, pembrolizumab was administered as second-line treatment every 3 weeks at a dosage of 200 mg. After 3 cycles of pembrolizumab treatment, the size of the anterior mediastinal tumor and metastatic lesions had notably decreased. Pembrolizumab may prove to be an effective therapy for thymic carcinoma with high PD-L1 expression. PMID- 30483100 TI - The Smallest Reported Malignant Struma Ovarii: A Case Report. AB - Introduction: Malignant struma ovarii is a rare neoplasm. It is usually asymptomatic and not commonly diagnosed preoperatively. In addition, there is currently no established diagnostic and therapeutic approach for malignant struma ovarii. Case Report: A 66-year-old asymptomatic female was referred to our hospital. Computed tomography showed the presence of a well-defined mass with enhancement in the internal and peripheral areas. The patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and partial omentectomy. Histopathology revealed the presence of a papillary thyroid carcinoma arising from a 2.5-cm-diameter struma ovarii (malignant struma ovarii). According to the criteria of the International Federation of Gynecology and Obstetrics, the patient had stage IA disease. Subsequently, she underwent a thyroid scan with normal findings. At the 3-month follow-up, the patient was alive, in good clinical condition, and disease free. Conclusion: In this report, we present the smallest malignant struma ovarii reported so far in the literature. Because of the rarity of these tumors and the lack of firm prognostic factors, the treatment decision should be customized for each patient according to the pathological and clinical parameters. PMID- 30483101 TI - Acute Liver Failure with Diffuse Liver Metastasis from Breast Cancer, Not Detected by Computed Tomography: 2 Case Reports. AB - Diffuse liver metastasis is a rare pattern of liver metastasis that is associated with hepatic failure and poor prognosis. We experienced 2 cases of acute liver failure due to diffuse metastasis that could not be detected using computed tomography. In case 1, it was difficult to differentiate diffuse metastasis from alcoholic hepatitis. In case 2, it was difficult to diagnose diffuse liver metastasis because the patient had no history of malignancy. When liver enzyme levels are elevated, it is necessary to consider liver metastasis as a potential cause, regardless of computed tomography findings. PMID- 30483102 TI - A Case of Multiple Myeloma Presenting as Streptococcus pneumoniae Meningitis with Candida auris Fungemia. AB - Multiple myeloma (MM), a plasma cell neoplasm, has a typical presenting pattern consisting of bone pain, renal failure, anemia, and/or hypercalcemia. Even though MM is a cancer that impairs the immune system, rarely is a systemic infection the first sign of disease. In this case report, our patient presented with altered mental status due to meningitis and was later diagnosed with MM. Furthermore, we display a case of a rare but emerging and serious fungus, Candida auris, that the patient developed during his inpatient stay. This is the first such record of C. auris in an MM patient. PMID- 30483103 TI - Factors Affecting Therapeutic Effects in 17 Patients with Advanced Hepatocellular Carcinoma Who Were Treated with Sorafenib for More than 12 Months. AB - Background and Objective: Sorafenib is recommended for treating advanced hepatocellular carcinoma. However, it is frequently discontinued because of adverse events, which greatly affects its therapeutic effects. Furthermore, because patients treated with sorafenib for a long period can presumably tolerate adverse events, this study aimed to identify their characteristics and analyze factors affecting the therapeutic effects of the drug. Subjects and Methods: Seventeen patients with hepatocellular carcinoma who received sorafenib for 12 months or longer at our hospital between January 2009 and October 2015 were included. In these 17 patients, factors affecting the time to untreatable progression were analyzed using a Cox proportional hazards model, Kaplan-Meier curve, and log-rank test. Results: In the 17 patients, the mean sorafenib dose was 433 mg/day. The drug was discontinued in 12 patients, 9 (75%) of whom discontinued it because of progressive disease. The median time to untreatable progression was 23.1 months. The contributors to favorable therapeutic effects included administration of at least two sessions of concomitant therapy after initiating sorafenib therapy, a low neutrophil-to-lymphocyte ratio, and a decreased total bilirubin level. Conclusion: Achieving favorable therapeutic effects of sorafenib requires strict dose adjustment that allows better control of adverse events and long-term administration of the drug. Furthermore, combining sorafenib with other therapies, a low neutrophil-to-lymphocyte ratio, and a decreased total bilirubin level are useful predictors of favorable effects. PMID- 30483104 TI - A Modified Surgical Technique for Transposition of the Vertebral Artery to the Common Carotid Artery. AB - A proximal occluded vertebral artery (VA) with reconstitution by muscular collateral vessels is a relatively common finding. However, due to inadequate intracranial anastomosis and hypoplasia or stenosis of the opposite VA, a number of patients develop symptoms of brain ischemia. In the current case, a 63-year old man presented with repeat neurological symptoms such as dizziness, nausea, vomiting, dysarthria, left hemiparesis, and right hemianopsia. Magnetic resonance imaging revealed multiple posterior infarctions. Angiography revealed the VA to be occluded and reconstituted by collateral vessels. Considering the above results, we performed vertebral carotid artery transposition. However, several technical difficulties were encountered due to space limitations in the operative field and the limited length of the vessels to be anastomosed. To overcome such situations, we introduced a modified posterior wall end-to-side anastomosis technique. PMID- 30483105 TI - Diffusion Tensor Imaging in a Case of Pontine Bleeding Showing Hypertrophic Olivary Degeneration and Cerebellar Ataxia. AB - We present diffusion tensor tractography (DTT) findings in a case of hypertrophic olivary degeneration (HOD) and cerebellar ataxia. A 56-year-old man presented with abnormal ataxic gait and dysarthria. MRI 5 months after onset showed chronic pontine hematoma and enlarged bilateral inferior olivary nuclei. DTT showed decreased volume of the bilateral central tegmental tract, in accordance with the conventional hypothesis that HOD is associated with neurologic insult to the Guillain-Mollaret triangle. The patient's cerebellar ataxia was speculated to be due to decreased decussating fibers of the superior cerebellar peduncle, and this was confirmed by DTT. PMID- 30483106 TI - Human Chronic Necrotizing Granulomatous Meningoencephalitis: A Novel Case Report. AB - Necrotizing and granulomatous meningoencephalitis are common central nervous system diseases known to affect canines. To date, necrotizing granulomatous meningoencephalitis has yet to be described in humans. Current studies of presumed pathogenesis and possible treatment options have only been described in canines. This is a case report of a 55-year-old female patient who was diagnosed with necrotizing granulomatous meningoencephalitis in the setting of new-onset neurological symptoms without any infectious or malignant source. PMID- 30483108 TI - Detection of Candida Endophthalmitis in a Newborn Using Handheld Spectral-Domain Optical Coherence Tomography. AB - In a newborn with candidemia, two retinal lesions were seen without external inflammatory signs or reaction in the anterior chamber or vitreous. However, handheld spectral domain-optical coherence tomography (HH SD-OCT) images show that one of the retinal lesions had a "firework display" projecting to the vitreous that was not identified in indirect ophthalmoscopy. This finding suggested a Candida endophthalmitis. HH SD-OCT findings allowed us to make an accurate diagnosis and, therefore, modified the decision-making process in the treatment of the pathology. PMID- 30483109 TI - Bilateral Spontaneous Hyphemas in a Patient with Aplastic Anemia. AB - Bilateral spontaneous hyphemas are a rare ophthalmic event. Aplastic anemia is a hematologic condition with well-documented manifestations in the posterior segment but not the anterior segment. We present a patient with aplastic anemia without obvious risk factors for hyphema who developed bilateral spontaneous hyphemas. To our knowledge, this is the first reported case of bilateral spontaneous hyphemas in a patient with aplastic anemia. PMID- 30483107 TI - Development of a Donor Tissue Holding Technique for Descemet's Membrane Endothelial Keratoplasty Using a 25-Gauge Graft Manipulator. AB - Purpose: To report a modified surgical technique called the "donor tissue holding technique for Descemet's membrane endothelial keratoplasty (DMEK)" using a newly developed 25-gauge graft manipulator. Methods: Six consecutive patients exhibiting endothelial dysfunction were enrolled and treated by DMEK. In brief, after insertion of a DMEK donor into the anterior chamber, the edge of the roll was grasped using a graft manipulator and this grasp was maintained throughout the centering and opening of the roll (holding technique). The following parameters were evaluated in comparison to the previous 10 consecutive DMEK cases in which the no touch technique was used: time of graft unfolding, incidence of intra-/postoperative complications, and best spectacle-corrected visual acuity (BCVA) and endothelial cell density (ECD) 6 months after the procedure. Results: In both technique groups, neither intra- nor postoperative complications were noted in any case. No differences were observed between the two groups in postoperative BCVA (p = 0.88). Also, no differences were observed between the two groups in postoperative ECD (holding technique group: 2,108.3 cells/mm2, no touch technique group: 1,491.7 cells/mm2) (p = 0.08) Most notably, the time of graft unfolding prior to filling with air was significantly reduced in the holding technique group (305.5 s) compared to that of the no touch technique group (1,310.0 s; p = 0.01). Conclusions: This donor tissue holding technique enabled rapid and safe DMEK in a reproducible manner, even in Asian eyes with shallow anterior chambers with high vitreous pressure. PMID- 30483110 TI - Iris Morphological Features in Patients with 360 degrees Angle-Closure Neovascular Glaucoma: An Anterior Segment Optical Coherence Tomography Study. AB - Purpose: To investigate iris morphological features in 360 degrees angle-closure neovascular glaucoma (NVG) by swept-source anterior segment optical coherence tomography (ASOCT). Patients and Methods: In this retrospective, clinic-based, comparative study, 14 patients with 360 degrees angle-closure NVG and 14 healthy age-matched control subjects were enrolled. All patients enrolled had no prior glaucoma surgery but underwent cataract surgery with intraocular lens implantation. Horizontal scanning images of swept-source ASOCT were analyzed using software calipers in temporal and nasal angle areas. The iris thickness at 1 and 2 mm from the pupil edge, iris length, trabecular meshwork length, peripheral anterior synechia (PAS) length, PAS height ratio (PAS length/trabecular meshwork length), and pupil diameter were measured. Results: Between the groups, there were no statistically significant differences in iris length, trabecular meshwork length, and pupil diameter (p > 0.05). However, the iris thickness was significantly reduced in the NVG group compared with the control group in the temporal and nasal areas (0.306 vs. 0.563 mm/0.326 vs. 0.645 mm at 1 mm, 0.278 vs. 0.523 mm/0.282 vs. 0.546 mm at 2 mm, respectively) (mean, all p < 0.001). In the NVG group, PAS height ratios were 1.55 +/- 0.45 (mean +/- standard deviation) (range, 0.58-2.30) and 1.55 +/- 0.78 (range, 0.68-3.68) at the temporal and nasal angles, respectively. Conclusions: In patients with 360 degrees angle-closure NVG, the iris thickness decreased to about 50% of that in healthy subjects, and the PAS length exceeded the trabecular meshwork length by about 1.5 times. PMID- 30483112 TI - Relationship Between Sulcal Characteristics and Brain Aging. AB - This study aimed to determine whether sulcal morphology differs between middle age (MA) and older healthy individuals. Furthermore, we sought to determine whether age-related differences in sulcal characteristics were more strongly associated with differences in local or global cortical volumes. Participants (age 44-50, N = 403; age 64-70, N = 390) from the Personality and Total Health Through Life (PATH) study were included. Sulci were 17.3% wider, on average, in old age (OA) compared to MA participants, with the largest difference in the left superior frontal sulcus. Differences in sulcal width were generally higher in males than females. Differences in the width of the superior frontal and central sulci were significantly associated with differences in the volume of adjacent local gyri, while age-related differences in the width of lateral and superior temporal sulci were associated with differences in whole brain cortical volume. These findings suggest that sulcal characteristics provide unique information about changes in local and global brain structure in aging. PMID- 30483111 TI - Hippocampal Long-Term Depression in the Presence of Calcium-Permeable AMPA Receptors. AB - The GluA2 subunit of AMPA glutamate receptors (AMPARs) has been shown to be critical for the expression of NMDA receptor (NMDAR)-dependent long-term depression (LTD). However, in young GluA2 knockout (KO) mice, this form of LTD can still be induced in the hippocampus, suggesting that LTD mechanisms may be modified in the presence of GluA2-lacking, Ca2+ permeable AMPARs. In this study, we examined LTD at the CA1 synapse in GluA2 KO mice by using several well established inhibitory peptides known to block LTD in wild type (WT) rodents. We showed that while LTD in the KO mice is still blocked by the protein interacting with C kinase 1 (PICK1) peptide pepEVKI, it becomes insensitive to the N ethylmaleimide-sensitive factor (NSF) peptide pep2m. In addition, the effects of actin and cofilin inhibitory peptides were also altered. These results indicate that in the absence of GluA2, LTD expression mechanisms are different from those in WT animals, suggesting that there are multiple molecular processes enabling LTD expression that are adaptable to physiological and genetic manipulations. PMID- 30483114 TI - "Liquid Biopsy" of White Matter Hyperintensity in Functionally Normal Elders. AB - Background and Objective: In the aging brain, increased blood-brain barrier (BBB) leakage and white matter hyperintensity (WMH) on MRI are frequently presumed secondary to cerebral small vessel disease (cSVD) or endotheliopathy. We investigate this association in vivo by quantifying protein cargo from endothelial-derived exosomes (EDE), and comparing levels between two groups of functionally normal elders with and without WMH. In addition, we study associations of EDE proteins with upstream and downstream factors, such as inflammation and neurodegenerative changes, respectively. Methods: Twenty six neurologically normal older adults completed general health questionnaires, neuropsychological and physical examinations, and brain MRI. WMH was visually graded with modified Fazekas score of 2 or greater used to classify 11 subjects as cases, and 15 without WMH as controls. Plasma total exosomes were precipitated and EDEs enriched by sequential immuno-precipitations. In addition, we quantified three inflammatory cytokines from plasma and imaging variables on MRI. Group means were compared, the discriminant functions of biomarkers calculated, and the association of EDE biomarkers with plasma inflammatory markers, cognition, and imaging outcomes assessed via regression modeling. Results: Plasma levels of EDE cargo proteins GLUT1, LAT1, P-GP, and NOSTRIN were significantly higher in subjects with WMH in comparison to those without. In contrast, EDE levels of the marker with low expression in brain (VCAM1) were equal between groups. The effect sizes for each of the brain-expressed cargo proteins (GLUT1, LAT1, and P-GP) were such that age-adjusted logistic regressions revealed areas under the curve (AUC) with range of 0.82-0.89, differentiating subjects with WMH from those without. VCAM1 poorly discriminated between groups (AUC:0.55). Higher levels of all brain expressed EDE proteins were also associated with lower cognitive function, unrelated to burden of WMH. Levels of LAT1 and P-GP were significantly inversely associated with global gray matter volumes, and EDE GLUT1, LAT-1, and P-GP concentrations were significantly associated with systemic IL-6 levels. Conclusion: In a case control study of clinically normal adults with and without WMH, concentrations of EDE proteins were significantly higher in subjects with WMH in comparison to controls. This work is a first step toward in vivo dissection of molecular changes in endothelia of functionally normal subjects with radiographic evidence of age-associated white matter disease. PMID- 30483115 TI - Alteration of Metabosensitive Afferent Response With Aging: Exercised versus Non exercised Rats. AB - This study was designed to evaluate the effect of aging on the activity of metabosensitive afferent fibers (thin muscle afferents from group III and IV) and to determine if physical activity performed at old age may influence the afferent discharge. Afferents from tibialis anterior and soleus muscles were recorded on non-exercised rats aged of 3, 6, 12, and 20 months and on animals aged of 12 and 20 months performing a daily incremental treadmill exercise protocol during the last 8 weeks preceding the recordings. Metabosensitive afferent fibers were activated with potassium chloride (KCl) and lactic acid (LA) injections into the blood stream or by muscle electrically-induced fatigue (EIF). Results indicated that aging is associated to a decrease in the magnitude of the responses to chemical injections and EIF. Unfortunately, physical activity did not allow restoring the metabosensitive afferents responses. These results indicate an alteration of the thin afferent fibers with aging and should be taken into account regarding the management of muscle fatigue and potential alterations of exercise pressor reflex (EPR) occurring with aging. PMID- 30483113 TI - Cognitive and Brain Activity Changes After Mnemonic Strategy Training in Amnestic Mild Cognitive Impairment: Evidence From a Randomized Controlled Trial. AB - Background: Mnemonic strategy training (MST) has been shown to improve cognitive performance in amnestic mild cognitive impairment (a-MCI), however, several questions remain unresolved. The goal of the present study was to replicate earlier pilot study findings using a randomized controlled design and to evaluate transfer effects and changes in brain activation. Methods: Thirty patients with a MCI were randomized into MST or education program. At baseline, participants completed clinical and neuropsychological assessments as well as structural and functional magnetic resonance imaging (fMRI). Interventions were administered individually and comprised four sessions, over 2 weeks. MST taught patients to use a three-step process to learn and recall face-name associations. Post treatment assessment included fMRI, a separate face-name association task, neuropsychological tests, and measures of metamemory. Behavioral (i.e., non-fMRI) measures were repeated after one and 3-months. Results: Participants in the MST condition showed greater improvement on measures of face-name memory, and increased associative strategy use; effects that were accompanied by increased fMRI activation in the left anterior temporal lobe. While all participants reported greater contentment with their everyday memory following intervention, only the MST group reported significant improvements in their memory abilities. There was no clear indication of far-transfer effects to other neuropsychological tests. Conclusion: Results demonstrate that patients with a-MCI not only show stimulus specific benefits of MST, but that they appear capable of transferring training to at least some other cognitive tasks. MST also facilitated the use of brain regions that are involved in face processing, episodic and semantic memory, and social cognition, which are consonant with the cognitive processes engaged by training. PMID- 30483116 TI - Speech Analysis by Natural Language Processing Techniques: A Possible Tool for Very Early Detection of Cognitive Decline? AB - Background: The discovery of early, non-invasive biomarkers for the identification of "preclinical" or "pre-symptomatic" Alzheimer's disease and other dementias is a key issue in the field, especially for research purposes, the design of preventive clinical trials, and drafting population-based health care policies. Complex behaviors are natural candidates for this. In particular, recent studies have suggested that speech alterations might be one of the earliest signs of cognitive decline, frequently noticeable years before other cognitive deficits become apparent. Traditional neuropsychological language tests provide ambiguous results in this context. In contrast, the analysis of spoken language productions by Natural Language Processing (NLP) techniques can pinpoint language modifications in potential patients. This interdisciplinary study aimed at using NLP to identify early linguistic signs of cognitive decline in a population of elderly individuals. Methods: We enrolled 96 participants (age range 50-75): 48 healthy controls (CG) and 48 cognitively impaired participants: 16 participants with single domain amnestic Mild Cognitive Impairment (aMCI), 16 with multiple domain MCI (mdMCI) and 16 with early Dementia (eD). Each subject underwent a brief neuropsychological screening composed by MMSE, MoCA, GPCog, CDT, and verbal fluency (phonemic and semantic). The spontaneous speech during three tasks (describing a complex picture, a typical working day and recalling a last remembered dream) was then recorded, transcribed and annotated at various linguistic levels. A multidimensional parameter computation was performed by a quantitative analysis of spoken texts, computing rhythmic, acoustic, lexical, morpho-syntactic, and syntactic features. Results: Neuropsychological tests showed significant differences between controls and mdMCI, and between controls and eD participants; GPCog, MoCA, PF, and SF also discriminated between controls and aMCI. In the linguistic experiments, a number of features regarding lexical, acoustic and syntactic aspects were significant in differentiating between mdMCI, eD, and CG (non-parametric statistical analysis). Some features, mainly in the acoustic domain also discriminated between CG and aMCI. Conclusions: Linguistic features of spontaneous speech transcribed and analyzed by NLP techniques show significant differences between controls and pathological states (not only eD but also MCI) and seems to be a promising approach for the identification of preclinical stages of dementia. Long duration follow-up studies are needed to confirm this assumption. PMID- 30483117 TI - Can Blood Oxygenation Level Dependent Functional Magnetic Resonance Imaging Be Used Accurately to Compare Older and Younger Populations? A Mini Literature Review. AB - A wealth of research has investigated the aging brain using blood oxygenation level dependent functional MRI [Blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI)]. However, many studies do not consider the aging of the cerebrovascular system, which can influence the BOLD signal independently from neural activity, limiting what can be inferred when comparing age groups. Here, we discuss the ways in which the aging neurovascular system can impact BOLD fMRI, the consequences for age-group comparisons and possible strategies for mitigation. While BOLD fMRI is a valuable tool in this context, this review highlights the importance of consideration of vascular confounds. PMID- 30483118 TI - Different Patterns of Neurodegeneration and Glia Activation in CA1 and CA3 Hippocampal Regions of TgCRND8 Mice. AB - We investigated the different patterns of neurodegeneration and glia activation in CA1 and CA3 hippocampal areas of TgCRND8 mice. The main feature of this transgenic model is the rapid development of the amyloid pathology, which starts already at 3 months of age. We performed immunohistochemical analyses to compare the different sensibility of the two hippocampal regions to neurodegeneration. We performed qualitative and quantitative evaluations by fluorescence immunohistochemistry with double or triple staining, followed by confocal microscopy and digital image analysis in stratum pyramidale (SP) and stratum radiatum (SR) of CA1 and CA3, separately. We evaluated time-dependent Abeta plaques deposition, expression of inflammatory markers, as well as quantitative and morphological alterations of neurons and glia in transgenic mice at 3 (Tg 3M) and 6 (Tg 6M) months of age, compared to WT mice. In CA1 SR of Tg 6M mice, we found significantly more Medium and Large plaques than in CA3. The pattern of neurodegeneration and astrocytes activation was different in the two areas, indicating higher sensitivity of CA1. In the CA1 SP of Tg 6M mice, we found signs of reactive astrogliosis, such as increase of astrocytes density in SP, increase of GFAP expression in SR, and elongation of astrocytes branches. We found also common patterns of glia activation and neurodegenerative processes in CA1 and CA3 of Tg 6M mice: significant increase of total and reactive microglia density in SP and SR, increased expression of TNFalpha, of iNOS, and IL1beta in astrocytes and increased density of neurons-astrocytes-microglia triads. In CA1 SP, we found decrease of volume and number of pyramidal neurons, paralleled by increase of apoptosis, and, consequently, shrinkage of CA1 SP. These data demonstrate that in TgCRND8 mice, the responses of neurons and glia to neurodegenerative patterns induced by Abeta plaques deposition is not uniform in the two hippocampal areas, and in CA1 pyramidal neurons, the higher sensitivity may be related to the different plaque distribution in this area. All these modifications may be at the basis of memory loss, the peculiar symptom of AD, which was demonstrated in this transgenic mouse model of Abeta deposition, even at early stages. PMID- 30483119 TI - Biodegradable Nanoparticles Mediated Co-delivery of Erlotinib (ELTN) and Fedratinib (FDTN) Toward the Treatment of ELTN-Resistant Non-small Cell Lung Cancer (NSCLC) via Suppression of the JAK2/STAT3 Signaling Pathway. AB - Background: Erlotinib (ELTN)-based targeted therapy as first-line treatment for epidermal growth factor receptor (EGFR)-mutant lung cancers suffers from insufficient selectivity, side effects, and drug resistance, which poses critical challenges in the clinical setting. Acquired resistance of ELTN results in extremely poor prognoses of non-small cell lung cancer (NSCLC) patients, wherein activation of the JAK2/STAT3 signaling pathway has been proven to induce acquired ELTN resistance. Methods: In this study, we developed a nanoparticle (NP) delivery system based on Food and Drug Administration (FDA)-approved poly(ethylene glycol) (PEG)-poly(lactic acid) (PLA) for the co-delivery of ELTN and fedratinib (FDTN, a small-molecular, highly selective JAK2 inhibitor). Both ELTN and FDTN could be encapsulated into the PEG-PLA NPs via optimization of the encapsulation method. The effect of NPs on NSCLC cells was evaluated by MTT assay. Western blotting was performed to study the molecular mechanisms of NPs inhibiting the downstream pathways of EGFR in vitro. The histological analysis and protein expression in vivo were assessed by hematoxylin/eosin (H&E) staining and immunohistochemistry, respectively. Results: The drug cargoes exhibited great stability, and could be released more efficiently in the acidic tumorous condition. Mechanistic study showed that FDTN notably down-regulated the expression levels of proteins in the JAK2/STAT3 signaling pathway, including p EGFR, p-JAK2, p-STAT3 and Survivin, therefore reversing the ELTN resistance. As a result, synergistic anti-cancer effect was achieved by PEG-PLA NPs encapsulating both ELTN and FDTN in ELTN-resistant NSCLC tumors both in vitro and in vivo, and lower systemic side effect was noted for the co-delivery NPs compared to free drugs. Conclusion: This study provides a promising approach to overcome the ELTN resistance in the treatment of NSCLC, and the use of FDA-approved materials with clinically applied/investigated chemical drugs may facilitate the translation of the current delivery system. PMID- 30483120 TI - TRPM8 Activation via 3-Iodothyronamine Blunts VEGF-Induced Transactivation of TRPV1 in Human Uveal Melanoma Cells. AB - In human uveal melanoma (UM), tumor enlargement is associated with increases in aqueous humor vascular endothelial growth factor-A (VEGF-A) content that induce neovascularization. 3-Iodothyronamine (3-T1AM), an endogenous thyroid hormone metabolite, activates TRP melastatin 8 (TRPM8), which blunts TRP vanilloid 1 (TRPV1) activation by capsaicin (CAP) in human corneal, conjunctival epithelial cells, and stromal cells. We compare here the effects of TRPM8 activation on VEGF induced transactivation of TRPV1 in an UM cell line (92.1) with those in normal primary porcine melanocytes (PM) since TRPM8 is upregulated in melanoma. Fluorescence Ca2+-imaging and planar patch-clamping characterized functional channel activities. CAP (20 MUM) induced Ca2+ transients and increased whole-cell currents in both the UM cell line and PM whereas TRPM8 agonists, 100 MUM menthol and 20 MUM icilin, blunted such responses in the UM cells. VEGF (10 ng/ml) elicited Ca2+ transients and augmented whole-cell currents, which were blocked by capsazepine (CPZ; 20 MUM) but not by a highly selective TRPM8 blocker, AMTB (20 MUM). The VEGF-induced current increases were not augmented by CAP. Both 3-T1AM (1 MUM) and menthol (100 MUM) increased the whole-cell currents, whereas 20 MUM AMTB blocked them. 3-T1AM exposure suppressed both VEGF-induced Ca2+ transients and increases in underlying whole-cell currents. Taken together, functional TRPM8 upregulation in UM 92.1 cells suggests that TRPM8 is a potential drug target for suppressing VEGF induced increases in neovascularization and UM tumor growth since TRPM8 activation blocked VEGF transactivation of TRPV1. PMID- 30483122 TI - Ethnopharmacological Field Study of Three Q'eqchi Communities in Guatemala. AB - Mesoamerica is well known for the Mayan civilization, which flourished in this region during pre-Columbian times and made use of plant diversity for medicinal purposes. Currently, there are 21 Mayan ethnic groups in Guatemala, including the Q'eqchi'. The use of medicinal plants is still prevalent among them, they have been an important medicinal source for the population. The present study aims to compile traditional knowledge of the use of medicinal plants from three Q'eqchi' communities in Alta Verapaz, Guatemala and identify the important medicinal plants that are currently being used to treat relevant diseases. The study also aims to determine the relative importance of the identified species to propose new species for further pharmacological studies. Based on the cultural richness and the low level of perturbation of the vegetation, we selected the Q'eqchi' communities of Sanimtaqa, Santo Domingo de las Cuevas, and Chirrepec in Alta Verapaz, Guatemala. There, semi-structured interviews were conducted between June 2013 and December 2014 with common people. Plant-related questions and certain sociocultural contexts of the informants were included. Herbarium specimens for identification were collected with the help of the informants in their gardens with people from each community. The data were analyzed in two forms, the first non-quantitative based on the interpretation of the interviews (emic concepts of diseases) the second by following quantitative methods: informant consensus factor (Fic), Friedman's fidelity index (Fl), and use-reports (Ur). A total of 169 interviews were conducted. One hundred thirty-seven species of plants with medicinal uses were identified, which were described 2,055 times. These species belong to 59 families and 117 genera. Gastrointestinal conditions and pain/fever had the highest number of plant species uses for treatment. The main gastrointestinal conditions included diarrhea (Nume'sa'), stomach pain and worms (Luqum), while the pain/fever classification included headaches (rail jolom), and fevers (Tiq'). The most important cultural condition is called Chaquiq'yaj, the symptoms of the disease; diarrhea, vomiting, fever, lack of appetite, and thirst could be associated with a gastrointestinal. Conclusions: After analyzing the data, we can conclude that; Ageratina ligustrina, Catopheria chiapensis, Baccharis inamoena, Peperomia maculosa, Baccharis salicina, Clinopodium brownei, Calea integrifolia, and Smallanthus maculatus var. maculatus are the most culturally relevant species. PMID- 30483121 TI - Heteromerization Modulates mu Opioid Receptor Functional Properties in vivo. AB - Mu opioid receptors modulate a large number of physiological functions. They are in particular involved in the control of pain perception and reward properties. They are also the primary molecular target of opioid drugs and mediate their beneficial analgesic effects, euphoric properties as well as negative side effects such as tolerance and physical dependence. Importantly, mu opioid receptors can physically associate with another receptor to form a novel entity called heteromer that exhibits specific ligand binding, signaling, and trafficking properties. As reviewed here, in vivo physical proximity has now been evidenced for several receptor pairs, subsequent impact of heteromerization on native mu opioid receptor signaling and trafficking identified and a link to behavioral changes established. Selective targeting of heteromers as a tool to modulate mu opioid receptor activity is therefore attracting growing interest and raises hopes for innovative therapeutic strategies. PMID- 30483124 TI - Reimbursement of Orphan Drugs in Europe in Relation to the Type of Authorization by the European Medicines Agency and the Decision Making Based on Health Technology Assessment. AB - Objective: To assess shares of reimbursed orphan drugs and agreement in reimbursement decision-making in different European Union member states as well as to define odds for reimbursement influenced by the presence of conditional approval or exceptional circumstances granted by the European Medicines Agency (EMA) or by type of the disease. Methods: The list of authorized drugs with current orphan designations was collected from the website of the EMA. For each drug, the information regarding conditional approval or approval under exceptional circumstances was collected. The reimbursement statuses were available on national reimbursement or HTA agencies websites. The agreement for reimbursement decisions between selected countries was assessed using the kappa coefficient for the measurement of agreement. The impact of the EMA's conditional approval as well as approval under exceptional circumstances was assessed using the logistic regression and presented as odds ratio. Results: The percentage of reimbursed orphan drugs varied significantly from 27% in Poland to 88% in Denmark, with an average value of 51% (p < 0.0001). Regarding the reimbursement status, the highest, substantial agreement was observed between Spain and Italy, and the lowest agreement was observed between Germany and England, with kappa of 0.64 and 0.01, respectively. Conditional approval status significantly decreased the chance for reimbursement in France, Italy, and Spain by 77-80%; however, approval granted under exceptional circumstances had significant impact only in Germany with 85% decrease in chances for reimbursement. The type of the disease (oncology or metabolic) was significantly associated with both conditional approval (p of 0.03-oncology drugs were more likely to be conditionally approved then the rest of analyzed drugs) and exceptional circumstances (p of 0.02-drugs for metabolic diseases were more likely to be approved under exceptional circumstances). Conclusions: Access to reimbursed orphan drugs varies significantly across EU countries. The highest, substantial agreement in reimbursement decisions was observed between Italy and Spain and the lowest between Germany and England. Conditional approval and approval under exceptional circumstances were significant negative predictors of reimbursement in some countries and they were significantly associated with the type of the disease (oncology or metabolic). PMID- 30483125 TI - Cutaneous Leukemic Infiltrates Successfully Treated With Biomodulatory Therapy in a Rare Case of Therapy-Related High Risk MDS/AML. AB - Cutaneous manifestations in hematologic malignancies, especially in leukemia, are not common and may be very variable. Here we report a very unusual case of a patient (female, 70 years old) who was admitted to the hospital in 2016 because of skin lesions on the face, the trunk of the body and the extremities. She had a history of breast cancer in the year 2004 (pT1b, pN0, cM0, L0, V0, R0) which had been resected and treated with adjuvant radiation and chemotherapy (cyclophosphamide, methotrexate, 5-fluorouracile) as well as psoriasis treated with methotrexate and cyclosporine. Because of mild cytopenia a bone marrow aspirate/biopsy was performed showing myelodysplastic syndrome (MDS) with multilineage dysplasia. Cytogenetic review revealed a complex aberrant karyotype denoting adverse outcome. Simultaneously, a skin biopsy could confirm leukemic skin infiltration. Consequently, a therapy with azacitidine was started. After the first cycle the patient developed severe pancytopenia with a percentage of 13% peripheral blasts (previously 0-2%) as well as fever without evidence for infection which was interpreted as progressive disease. Therefore, the therapeutic regimen was changed to a biomodulatory therapy consisting of low-dose azacitidine 75 mg/day (given sc d1-7 of 28), pioglitazone 45 mg/day per os, and all-trans-retinoic acid (ATRA) 45 mg/m2/day per os. After cycle 1 of this combined biomodulatory therapy the patient showed hematologic recovery; besides a mild anemia (hemoglobin 11.1 g/dl) she developed a normal blood count. Moreover, the cutaneous leukemic infiltrates which had been unaffected by the azacitidine ameliorated tremendously after 2 cycles resulting in a complete remission of the skin lesions after cycle 6. In conclusion, we report a very unusual case with cutaneous infiltrates being the first clinical manifestation of hematologic disease, preceding the development of acute myeloid leukemia. While azacitidine alone was ineffective, a combined biomodulatory approach resulted in a complete remission of the cutaneous manifestation. PMID- 30483123 TI - Updates in Anthracycline-Mediated Cardiotoxicity. AB - Cardiotoxicity is one of the main adverse effects of chemotheraphy, affecting the completion of cancer therapies and the short- and long-term quality of life. Anthracyclines are currently used to treat many cancers, including the various forms of leukemia, lymphoma, melanoma, uterine, breast, and gastric cancers. World Health Organization registered anthracyclines in the list of essential medicines. However, anthracyclines display a major cardiotoxicity that can ultimately culminate in congestive heart failure. Taking into account the growing rate of cancer survivorship, the clinical significance of anthracycline cardiotoxicity is an emerging medical issue. In this review, we focus on the key progenitor cells and cardiac cells (cardiomyocytes, fibroblasts, and vascular cells), focusing on the signaling pathways involved in cellular damage, and the clinical biomarkers in anthracycline-mediated cardiotoxicity. PMID- 30483126 TI - Low Expression of miR-466f-3p Sustains Epithelial to Mesenchymal Transition in Sonic Hedgehog Medulloblastoma Stem Cells Through Vegfa-Nrp2 Signaling Pathway. AB - High-throughput analysis has improved the knowledge of medulloblastoma (MB), the leading cause of cancer related death in children, allowing a better comprehension of the key molecular pathways in MB pathogenesis. However, despite these advances, 30% of patients still die from the disease and survivors face severe long-term side effects. Cancer stem cells (CSCs) represent a subset of cells that not only drive tumorigenesis, but are also one of the main determinants of chemoresistance. Epithelial mesenchymal transition (EMT) is a hallmark of cancer and up to now few data is available in MB. To give insight into the role of the EMT process in maintaining the mesenchymal phenotype of CSCs, we analyzed the expression of EMT related transcripts and microRNAs in these cells. We firstly isolated CSCs from Sonic Hedgehog (SHH) MB derived from Ptch1 heterozygous mice and compared their expression level of EMT-related transcripts and microRNAs with cerebellar NSCs. We identified two molecules linked to SHH and EMT, Vegfa and its receptor Nrp2, over-expressed in SHH MB CSCs. Inhibition of Vegfa showed impairment of cell proliferation and self renewal ability of CSCs concurrent with an increase of the expression of the EMT gene, E-cadherin, and a decrease of the EMT marker, Vimentin. Moreover, among deregulated microRNAs, we identified miR-466f-3p, a validated inhibitor of both Vegfa and Nrp2. These results allowed us to describe a new EMT molecular network, involving the down-regulation of miR-466f-3p together with the concordant up regulation of Vegfa and Nrp2, that sustains the mesenchymal phenotype of SHH MB CSCs. PMID- 30483127 TI - Notch1 Inhibits Rosiglitazone-Induced Adipogenic Differentiation in Primary Thymic Stromal Cells. AB - Adipocyte deposition is believed to be a primary characteristic of age-related thymic involution. Herein, we cultured primary thymic stromal cells (TSCs), used rosiglitazone, a potent peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, to induce adipogenic differentiation, and investigated the differentially expressed genes during adipogenic differentiation by using RNA sequencing analysis. Furthermore, the effects of Notch1 on rosiglitazone-induced adipogenic differentiation of TSCs as well as the underlying mechanisms were also investigated. As a result, we identified a total of 1737 differentially expressed genes, among which 965 genes were up-regulated and 772 genes were down-regulated in rosiglitazone-treated cells compared with control cells. Gene ontology (GO) enrichment analysis showed that the GO terms were enriched in metabolic process, intracellular, and protein binding. Kyoto encyclopedia of genes and genomes (KEGG) analysis showed that a number of pathways, including ubiquitin mediated proteolysis, PPAR signaling pathway, and mammalian target of rapamycin (mTOR) signaling pathway were predominantly over-represented. Meanwhile, overexpression of Notch1 suppressed and inhibition of Notch1 promoted rosiglitazone-induced adipogenic differentiation in TSCs, and the pro-adipogenic effects of the Notch inhibitor DAPT were associated with the activation of autophagy. Taken together, our results suggest that Notch1 is a key regulator in thymic adipogenesis and may serve as a potential target to hinder thymic adiposity in age-related thymic involution. PMID- 30483128 TI - Effects of Taxifolin on Osteoclastogenesis in vitro and in vivo. AB - Osteoporosis is a highly prevalent disease which has been a major public health problem and considered to be associated with chronic low-grade systemic inflammation and oxidative damage. Taxifolin is a natural flavonoid and possesses many pharmacological activities including antioxidant and anti-inflammatory. Because flavonoids have been confirmed to fight osteoporosis and promote bone health, the aim of this study was to investigate the effects of taxifolin on the formation and function of osteoclast. In this study, we examined the effects of taxifolin on osteoclast using both in vitro and in vivo studies. Taxifolin suppressed the activation of nuclear factor-kappaB, C-Fos and mitogen-activated protein kinase, and also decreased osteoclast-specific genes expression, including Trap, Mmp-9, Cathepsin K, C-Fos, Nfatc1, and Rank. Taxifolin also prevented reactive oxygen species (ROS) production following RANKL stimulation. In addition, taxifolin alleviated ovariectomized-induced bone loss by repressing osteoclast activity and decreasing serum levels of tumor necrosis factor-alpha, interleukin-1beta, interleukin-6 and receptor activator of nuclear factor-kappaB ligand (RANKL) in vivo. Our results indicated that taxifolin inhibits osteoclastogenesis via regulation of modulation of several RANKL signaling pathways. Therefore, taxifolin may be considered as a potential alternative therapeutic agent for treating osteoclast-related diseases. PMID- 30483129 TI - Combined Pharmacological Inhibition of Cyclophilins, FK506-Binding Proteins, Hsp90, and Hsp70 Protects Cells From Clostridium botulinum C2 Toxin. AB - The Clostridium botulinum C2 toxin is an exotoxin causing severe enterotoxic symptoms. The C2 toxin consists of the binding/translocation component C2II, and the enzymatic active component C2I. After proteolytic activation, C2IIa forms heptamers that bind C2I. The C2IIa/C2I complex is taken up into mammalian target cells via receptor-mediated endocytosis. Acidification of endosomes leads to conformational changes in both components. C2IIa heptamers form a pore into the endosomal membrane, and C2I becomes unfolded and translocates through the narrow C2IIa pores into the cytosol of the cell. Here, C2I covalently transfers an ADP ribose moiety from its co-substrate NAD+ onto G-actin, which leads to depolymerization of F-actin resulting in rounding up of adherent cells. Translocation of C2I into the cytosol depends on the activity of the chaperones Hsp90 and Hsp70 and peptidyl-prolyl cis/trans isomerases of the cyclophilin (Cyp) and FK506-binding protein (FKBP) families. Here, we demonstrated that C2I is detected in close proximity with Hsp90, Cyp40, and FKBP51 in cells, indicating their interaction. This interaction was dependent on the concentration of C2 toxin and detected in mammalian Vero and human HeLa cells. Moreover, the present study reveals that combination of radicicol, VER-155008, cyclosporine A, and FK506, which are specific pharmacological inhibitors of Hsp90, Hsp70, Cyps, and FKBPs, respectively, resulted in a stronger inhibition of intoxication of cells with C2 toxin compared to application of the single inhibitors. Thus, the combination of inhibitors showed enhanced protection of cells against the cytotoxic effects of C2 toxin. Cell viability was not significantly impaired by application of the inhibitor combination. Moreover, we confirmed that the combination of radicicol, VER-155008, CsA, and FK506 in particular inhibit the membrane translocation step of C2I into the cytosol whereas receptor binding and enzyme activity of the toxin were not affected. Our findings further characterize the mode of action of Hsp90, Hsp70, Cyps, and FKBPs during membrane translocation of bacterial toxins and furthermore supply starting points for developing of novel therapeutic strategies against diseases caused by bacterial toxins that depend on Hsp90, Hsp70, Cyps, and FKBPs. PMID- 30483130 TI - Screening and Identification of Cardioprotective Compounds From Wenxin Keli by Activity Index Approach and in vivo Zebrafish Model. AB - Wenxin Keli (WXKL) is a widely used Chinese botanical drug for the treatment of arrhythmia, which is consisted of four herbs and amber. In the present study, we analyzed the chemical composition of WXKL using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) to tentatively identify 71 compounds. Through typical separate procession, the total extract of WXKL was divided into fractions for further bioassays. Cardiomyocytes and zebrafish larvae were applied for assessment. In vivo arrhythmia model in Cmlc2-GFP transgenic zebrafish was induced by terfenadine, which exhibited obvious reduction of heart rate and occurrence of atrioventricular block. Dynamic beating of heart was recorded by fluorescent microscope and sensitive camera to automatically recognize the rhythm of heartbeat in zebrafish larvae. By integrating the chemical information of WXKL and corresponding bioactivities of these fractions, activity index (AI) of each identified compound was calculated to screen potential active compounds. The results showed that dozens of compounds including ginsenoside Rg1, ginsenoside Re, notoginsenoside R1, lobetyolin, and lobetyolinin were contributed to cardioprotective effects of WXKL. The anti-arrhythmic activities of five compounds were further validated in larvae model and mature zebrafish by measuring electrocardiogram (ECG). Our findings provide a successful example for rapid discovery of bioactive compounds from traditional Chinese medicine (TCM) by activity index based approach coupled with in vivo zebrafish model. PMID- 30483132 TI - Peptides/Proteins Encoded by Non-coding RNA: A Novel Resource Bank for Drug Targets and Biomarkers. AB - Non-coding RNAs (ncRNAs) are defined as RNA molecules that do not encode proteins, but recent evidence has proven that peptides/proteins encoded by ncRNAs do indeed exist and usually contain less than 100 amino acids. These peptides/proteins play an important role in regulating tumor energy metabolism, epithelial to mesenchymal transition of cancer cells, the stability of the c-Myc oncoprotein, and the ubiquitination and degradation of proliferating cell nuclear antigen (PCNA). These peptides/proteins represent promising drug targets for fighting against tumor growth or biomarkers for predicting the prognosis of cancer patients. In this review, we summarize the characteristics of peptides/proteins that have recently been identified as putative ncRNA translation products and their outlook for small molecule peptide drugs, drug targets, and biomarkers. PMID- 30483131 TI - The Role of G-proteins and G-protein Regulating Proteins in Depressive Disorders. AB - Progress toward new antidepressant therapies has been relatively slow over the past few decades, with the result that individuals suffering from depression often struggle to find an effective treatment - a process often requiring months. Furthermore, the neural factors that contribute to depression remain poorly understood, and there are many open questions regarding the mechanism of action of existing antidepressants. A better understanding of the molecular processes that underlie depression and contribute to antidepressant efficacy is therefore badly needed. In this review we highlight research investigating the role of G proteins and the regulators of G-protein signaling (RGS) proteins, two protein families that are intimately involved in both the genesis of depressive states and the action of antidepressant drugs. Many antidepressants are known to indirectly affect the function of these proteins. Conversely, dysfunction of the G-protein and RGS systems can affect antidepressant efficacy. However, a great deal remains unknown about how these proteins interact with antidepressants. Findings pertinent to each individual G-protein and RGS protein are summarized from in vitro, in vivo, and clinical studies. PMID- 30483133 TI - N-myristoylation of Antimicrobial Peptide CM4 Enhances Its Anticancer Activity by Interacting With Cell Membrane and Targeting Mitochondria in Breast Cancer Cells. AB - Development of antimicrobial peptides (AMPs) as highly effective and selective anticancer agents would represent great progress in cancer treatment. Here we show that myristoyl-CM4, a new synthetic analog generated by N-myristoylation of AMPs CM4, had anticancer activity against MCF-7, MDA-MB-231, MX-1 breast cancer cells (IC50 of 3-6 MUM) and MDA-MB-231 xenograft tumors. The improved activity was attributed to the effect of myristoyl on the cell membrane. Flow cytometry and confocal laser scanning microscopy results showed that N-myristoylation significantly increased the membrane affinity toward breast cancer cells and also effectively mediated cellular entry. Despite increasing cytotoxicity against HEK293 and NIH3T3 cells and erythrocytes associated with its anticancer activity, myristoyl-CM4 maintained a certain selectivity toward breast cancer cells. Accordingly, the membrane affinity toward breast cancer cells was two to threefold higher than that of normal cells. Glycosylation analysis showed that sialic acid-containing oligosaccharides (including O-mucin and gangliosides) were important targets for myristoyl-CM4 binding to breast cancer cells. After internalization, co-localization analysis revealed that myristoyl-CM4 targeted mitochondria and induced mitochondrial dysfunction, including alterations in mitochondrial transmembrane potential, reactive oxygen species (ROS) generation and cytochrome c release. Activation of caspase 9, caspase 3 and cleavage of PARP were observed in MX-1, MCF-7, and MDA-MB-231 cells after myristoyl-CM4 treatment. The current work indicates that increasing hydrophobicity by myristoylation to modulate peptide-membrane interactions and then target mitochondria is a good strategy to develop AMPs as anticancer agents in the future. PMID- 30483134 TI - Strong Inhibitory Effect, Low Cytotoxicity and High Plasma Stability of Steroidal Inhibitors of N-Methyl-D-Aspartate Receptors With C-3 Amide Structural Motif. AB - Herein, we report the synthesis, structure-activity relationship study, and biological evaluation of neurosteroid inhibitors of N-methyl-D-aspartate receptors (NMDARs) receptors that employ an amide structural motif, relative to pregnanolone glutamate (PAG) - a compound with neuroprotective properties. All compounds were found to be more potent NMDAR inhibitors (IC50 values varying from 1.4 to 21.7 MUM) than PAG (IC50 = 51.7 MUM). Selected compound 6 was evaluated for its NMDAR subtype selectivity and its ability to inhibit AMPAR/GABAR responses. Compound 6 inhibits the NMDARs (8.3 receptors (8.3 +/- 2.1 MUM) more strongly than it does at the GABAR and AMPARs (17.0 receptors (17.0 +/- 0.2 MUM and 276.4 +/- 178.7 MUM, respectively). In addition, compound 6 (10 MUM) decreases the frequency of action potentials recorded in cultured hippocampal neurons. Next, compounds 3, 5-7, 9, and 10 were not associated with mitotoxicity, hepatotoxicity nor ROS induction. Lastly, we were able to show that all compounds have improved rat and human plasma stability over PAG. PMID- 30483136 TI - Analgesic Effects of Triterpenoid Saponins From Stauntonia chinensis via Selective Increase in Inhibitory Synaptic Response in Mouse Cortical Neurons. AB - Triterpenoid saponins from Stauntonia chinensis (TSS) are potential therapeutic agents because of its analgesic properties. However, the underlying mechanisms of the anti-nociceptive activity of TSS are largely unclear, especially in CNS. The present study confirmed the analgesic effect of TSS using four models of acute pain based on thermal or chemical stimuli. TSS treatment specifically impaired the threshold of thermal- and chemical-stimulated acute pain. Naloxone did not block the anti-nociceptive effects of TSS, which showed no participation of the opioid system. We investigated the electrical signal in cultured cortical neurons to explore whether TSS treatment directly affected synaptic transmission. TSS treatment selectively increased spontaneous inhibitory synaptic release and GABA induced charge transfer in mouse cortical neurons. The effects of TSS were maintained for at least 8 h in cultured neurons and in injected mice. Taken together, our results suggest that the analgesic role of TSS in cortex occurs via a particular increase in the inhibitory synaptic response at resting state, which supports TSS as a potential candidate for inflammatory pain relief. PMID- 30483137 TI - mGlu5 Receptor Blockade Within the Nucleus Accumbens Shell Reduces Behavioral Indices of Alcohol Withdrawal-Induced Anxiety in Mice. AB - Withdrawal from binge-drinking increases negative affect, coinciding with increased expression of the metabotropic glutamate receptor 5 (mGlu5) within the shell of the nucleus accumbens (AcbSh). Supporting a causal-effect relationship, systemic treatment with the mGlu5 receptor antagonist MTEP [3-((2-Methyl-4 thiazolyl)ethynyl)pyridine] is anxiolytic in binge-drinking adult and adolescent mice. Here, we employed neuropharmacological approaches to examine the functional relevance of AcbSh mGlu5 for behavioral indices of alcohol withdrawal-induced hyper-anxiety. Adult (PND 56) and adolescent (PND 28) male C57BL/6J mice consumed alcohol under modified Drinking-in-the-Dark procedures (10, 20, and 40% alcohol v/v) for 14 days. At an alcohol withdrawal time-point when mice manifest robust behavioral signs of hyper-anxiety (1 and 28 days withdrawal for adults and adolescents, respectively), mice were infused intra-AcbSh with 0, 1 or 10 MUg MTEP and then affect was assayed in the light-dark shuttle box, marble-burying and forced swim tests. Brain tissue was collected to evaluate changes in Egr1 (early growth response protein 1) induction to index AcbSh neuronal activity. As expected, alcohol-experienced mice exhibited behavioral signs of hyper emotionality. The anxiolytic effects of intra-AchSh MTEP were modest, but dose dependent, and varied with age of drinking-onset. In adult-onset mice, only the 1 MUg MTEP dose reduced withdrawal-induced hyper-anxiety, whereas only the higher dose was effective in adolescent-onset animals. MTEP reduced Egr1 expression within the AcbSh, irrespective of alcohol drinking history or age of drinking onset. However, only the high MTEP dose reduced Egr1 expression in adolescent onset binging mice. These results implicate AcbSh mGlu5 in modulating alcohol withdrawal-induced negative affect and suggest age differences in the neurobiological effects of alcohol withdrawal and behavioral responsiveness to mGlu5 blockade within the AcbSh. PMID- 30483138 TI - Lowering Etoposide Doses Shifts Cell Demise From Caspase-Dependent to Differentiation and Caspase-3-Independent Apoptosis via DNA Damage Response, Inducing AML Culture Extinction. AB - Cytotoxic chemotherapy, still the most widely adopted anticancer treatment, aims at eliminating cancer cells inducing apoptosis with DNA damaging agents, exploiting the differential replication rate of cancer vs. normal cells; efficiency is evaluated in terms of extent of induced apoptosis, which depends on the individual cell sensitivity to a given drug, and on the dose. In this in vitro study, we report that the concentration of etoposide, a topoisomerase II poison widely used in clinics, determines both the kinetics of cell death, and the type of apoptosis induced. We observed that on a set of myeloid leukemia cell lines, etoposide at high (50 uM) dose promoted a rapid caspase-3-mediated apoptosis, whereas at low (0.5 uM) dose, it induced morphological and functional granulocytic differentiation and caspase-2-dependent, but caspase-3-independent, cell death, displaying features consistent with apoptosis. Both differentiation and caspase-2- (but not 3)-mediated apoptosis were contrasted by caffeine, a well known inhibitor of the cellular DNA damage response (DDR), which maintained cell viability and cycling, indicating that the effects of low etoposide dose are not the immediate consequence of damage, but the result of a signaling pathway. DDR may be thus the mediator responsible for translating a mere dosage-effect into different signal transduction pathways, highlighting a strategic action in regulating timing and mode of cell death according to the severity of induced damage. The evidence of different molecular pathways induced by high vs. low drug doses may possibly contribute to explain the different effects of cytotoxic vs. metronomic therapy, the latter achieving durable clinical responses by treating cancer patients with stable, low doses of otherwise canonical cytotoxic drugs; intriguingly caspase-3, a major promoter of wounded tissue regeneration, is also a key factor of post-therapy cancer repopulation. All this suggests that cancer control in response to cytotoxic drugs arises from complex reprogramming mechanisms in tumor tissue, recently described as anakoinosis. PMID- 30483139 TI - Proteomic Responses Under Cold Stress Reveal Unique Cold Tolerance Mechanisms in the Pacific White Shrimp (Litopenaeus vannamei). AB - The Pacific white shrimp (Litopenaeus vannamei), one of the most widely cultured shrimp species in the world, often suffers from cold stress. To understand the molecular mechanism of cold tolerance in Pacific white shrimp, we conducted a proteomic analysis on two contrasting shrimp cultivars, namely, cold-tolerant Guihai2 (GH2) and cold-sensitive Guihai1 (GH1), under normal temperature (28 degrees C), under cold stress (16 degrees C), and during recovery to 28 degrees C. In total, 3,349 proteins were identified, among which 2,736 proteins were quantified. Based on gene ontology annotations, differentially expressed proteins largely belonged to biological processes, cellular components, and molecular functions. KEGG pathway annotations indicated that the main changes were observed in the lysosome, ribosomes, and oxidative phosphorylation. Subcellular localization analysis showed a significant increase in proteins present in cytosol, extracellular regions, and mitochondria. Combining enrichment-based clustering analysis and qRT-PCR analysis, we found that glutathione S transferase, zinc proteinase, m7GpppX diphosphatase, AP2 transcription complex, and zinc-finger transcription factors played a major role in the cold stress response in Pacific white shrimp. Moreover, structure proteins, including different types of lectin and DAPPUDRAFT, were indispensable for cold stress tolerance of the Pacific white shrimp. Results indicate the molecular mechanisms of the Pacific white shrimp in response to cold stress and provide new insight into breeding new cultivars with increased cold tolerance. PMID- 30483135 TI - Evolution of Cancer Pharmacological Treatments at the Turn of the Third Millennium. AB - The medical history of cancer began millennia ago. Historical findings of patients with cancer date back to ancient Egyptian and Greek civilizations, where this disease was predominantly treated with radical surgery and cautery that were often ineffective, leading to the death of patients. Over the centuries, important discoveries allowed to identify the biological and pathological features of tumors, without however contributing to the development of effective therapeutic approaches until the end of the 1800s, when the discovery of X-rays and their use for the treatment of tumors provided the first modern therapeutic approach in medical oncology. However, a real breakthrough took place after the Second World War, with the discovery of cytotoxic antitumor drugs and the birth of chemotherapy for the treatment of various hematological and solid tumors. Starting from this epochal turning point, there has been an exponential growth of studies concerning the use of new drugs for cancer treatment. The second fundamental breakthrough in the field of oncology and pharmacology took place at the beginning of the '80s, thanks to molecular and cellular biology studies that allowed the development of specific drugs for some molecular targets involved in neoplastic processes, giving rise to targeted therapy. Both chemotherapy and target therapy have significantly improved the survival and quality of life of cancer patients inducing sometimes complete tumor remission. Subsequently, at the turn of the third millennium, thanks to genetic engineering studies, there was a further advancement of clinical oncology and pharmacology with the introduction of monoclonal antibodies and immune checkpoint inhibitors for the treatment of advanced or metastatic tumors, for which no effective treatment was available before. Today, cancer research is always aimed at the study and development of new therapeutic approaches for cancer treatment. Currently, several researchers are focused on the development of cell therapies, anti-tumor vaccines, and new biotechnological drugs that have already shown promising results in preclinical studies, therefore, in the near future, we will certainly assist to a new revolution in the field of medical oncology. PMID- 30483140 TI - Molecular Evidence for the Fitness of Cotton Aphid, Aphis gossypii in Response to Elevated CO2 From the Perspective of Feeding Behavior Analysis. AB - Rising atmospheric carbon dioxide (CO2) concentration is likely to influence insect-plant interactions. Aphid, as a typical phloem-feeding herbivorous insect, has shown consistently more positive responses in fitness to elevated CO2 concentrations than those seen in leaf-chewing insects. But, little is known about the mechanism of this performance. In this study, the foliar soluble constituents of cotton and the life history of the cotton aphid Aphis gossypii and its mean relative growth rate (MRGR) and feeding behavior were measured, as well as the relative transcript levels of target genes related appetite, salivary proteins, molting hormone (MH), and juvenile hormone, to investigate the fitness of A. gossypii in response to elevated CO2 (800 ppm vs. 400 ppm). The results indicated that elevated CO2 significantly stimulated the increase in concentrations of soluble proteins in the leaf and sucrose in seedlings. Significant increases in adult longevity, lifespan, fecundity, and MRGR of A. gossypii were found under elevated CO2 in contrast to ambient CO2. Furthermore, the feeding behavior of A. gossypii was significantly affected by elevated CO2, including significant shortening of the time of stylet penetration to phloem position and significant decrease in the mean frequency of xylem phase. It is presumed that the fitness of A. gossypii can be enhanced, resulting from the increases in nutrient sources and potential increase in the duration of phloem ingestion under elevated CO2 in contrast to ambient CO2. In addition, the qPCR results also demonstrated that the genes related to appetite and salivary proteins were significantly upregulated, whereas, the genes related to MH were significantly downregulated under elevated CO2 in contrast to ambient CO2, this is in accordance with the performance of A. gossypii in response to elevated CO2. In conclusion, rise in atmospheric CO2 concentration can enhance the fitness of A. gossypii by increasing their ingestion of higher quantity and higher quality of host plant tissues and by simultaneously upregulating the transcript expression of the genes related to appetite and salivary proteins, and then this may increase the control risk of A. gossypii under conditions of climate change in the future. PMID- 30483142 TI - Cholesterol Protects Against Acute Stress-Induced T-Tubule Remodeling in Mouse Ventricular Myocytes. AB - Efficient excitation-contraction coupling in ventricular myocytes depends critically on the presence of the t-tubular network. It has been recently demonstrated that cholesterol, a major component of the lipid bilayer, plays an important role in long-term maintenance of the integrity of t-tubular system although mechanistic understanding of underlying processes is essentially lacking. Accordingly, in this study we investigated the contribution of membrane cholesterol to t-tubule remodeling in response to acute hyposmotic stress. Experiments were performed using isolated left ventricular cardiomyocytes from adult mice. Depletion and restoration of membrane cholesterol was achieved by applying methyl-beta-cyclodextrin (MbetaCD) and water soluble cholesterol (WSC), respectively, and t-tubule remodeling in response to acute hyposmotic stress was assessed using fluorescent dextran trapping assay and by measuring t-tubule dependent IK1 tail current (IK1,tail). The amount of dextran trapped in t-tubules sealed in response to stress was significantly increased when compared to control cells, and reintroduction of cholesterol to cells treated with MbetaCD restored the amount of trapped dextran to control values. Alternatively, application of WSC to normal cells significantly reduced the amount of trapped dextran further suggesting the protective effect of cholesterol. Importantly, modulation of membrane cholesterol (without osmotic stress) led to significant changes in various parameters of IK1, tail strongly suggesting significant but essentially hidden remodeling of t-tubules prior to osmotic stress. Results of this study demonstrate that modulation of the level of membrane cholesterol has significant effects on the susceptibility of cardiac t-tubules to acute hyposmotic stress. PMID- 30483141 TI - Short-Term Cardiovascular Response to Short-Radius Centrifugation With and Without Ergometer Exercise. AB - Artificial gravity (AG) has often been proposed as an integrated multi-system countermeasure to physiological deconditioning associated with extended exposure to reduced gravity levels, particularly if combined with exercise. Twelve subjects underwent short-radius centrifugation along with bicycle ergometry to quantify the short-term cardiovascular response to AG and exercise across three AG levels (0 G or no rotation, 1 G, and 1.4 G; referenced to the subject's feet and measured in the centripetal direction) and three exercise intensities (25, 50, and 100 W). Continuous cardiovascular measurements were collected during the centrifugation sessions using a non-invasive monitoring system. The cardiovascular responses were more prominent at higher levels of AG and exercise intensity. In particular, cardiac output, stroke volume, pulse pressure, and heart rate significantly increased with both AG level (in most of exercise group combinations, showing averaged increments across exercise conditions of 1.4 L/min/g, 7.6 mL/g, 5.22 mmHg/g, and 2.0 bpm/g, respectively), and workload intensity (averaged increments across AG conditions of 0.09 L/min/W, 0.17 mL/W, 0.22 mmHg/W, and 0.74 bpm/W respectively). These results suggest that the addition of AG to exercise can provide a greater cardiovascular benefit than exercise alone. Hierarchical regression models were fitted to the experimental data to determine dose-response curves of all cardiovascular variables as a function of AG-level and exercise intensity during short-radius centrifugation. These results can inform future studies, decisions, and trade-offs toward potential implementation of AG as a space countermeasure. PMID- 30483143 TI - Association Between c-Myc and Colorectal Cancer Prognosis: A Meta-Analysis. AB - Background: There is debate as to whether c-Myc predicts prognosis in colorectal cancer (CRC). In this study, we aimed to review the association between c-Myc and CRC prognosis. Methods: Pertinent studies were identified by searching electronic databases and carefully reviewing the reference lists of pertinent studies until March 2016. The summary hazard ratio (HR) and corresponding 95% confidence interval (CI) were calculated to study the association between c-Myc and CRC prognosis. Results: Eight cohort studies (including seven studies about overall survival [OS] and one study about disease free survival [DFS]) were included. The pooled HR of OS was 1.13 (95% CI: 0.66-1.95). In subgroup analysis, no significant association between c-Myc and CRC prognosis was found in the studies either from Western countries (HR: 0.87, 95% CI: 0.68-1.10) or Asian countries (HR: 1.89, 95% CI: 0.62-5.77). HRs were 0.86 (95% CI: 0.38-1.94) and 1.57 (95% CI: 0.73-3.39) for the studies using univariate analysis and multivariate analysis, respectively. HR from the studies that examined DNA level was significantly different (HR: 2.05, 95% CI: 1.22-3.46); while that about RNA level or protein level was not significantly different. Conclusion: c-Myc was not associated with CRC prognosis in this meta-analysis. However, the conclusion is preliminary and should be examined in future studies. PMID- 30483145 TI - The Effects of Physical Training on Quality of Life, Aerobic Capacity, and Cardiac Function in Older Patients With Heart Failure: A Meta-Analysis. AB - Aim: The purposes of this meta-analysis were to quantify the effectiveness of physical training on quality of life (QoL), aerobic capacity, and cardiac functioning in older patients with heart failure (HF) and evaluate dose-response relationships of training variables (frequency, volume, and duration). Methods: Scholarly databases (e.g., PubMed/MEDLINE, Google Scholar, and Scopus) were searched, identifying randomized controlled trials that investigated the effectiveness of different training modes on QoL (assessed by the Minnesota Living with Heart Failure Questionnaire), aerobic capacity (assessed by the 6 min walk test) and cardiac function (assessed by left ventricular ejection fraction). Results: Twenty five studies were included with a total of 2,409 patients. Results showed that exercise training improved total QoL (small ES = -0.69; 95% CI -1.00 to 0.38; p < 0.001), aerobic capacity (small ES = 0.47; 95% CI 0.15 0.71; p = 0.002) and cardiac function (moderate ES = 0.91; 95% CI 0.37-1.45; p = 0.001). In addition, univariate analyses revealed the moderating variable 'training mode' significantly influenced aerobic capacity (Q = 9.97; p = 0.007), whereby, resistance training had the greatest effect (ES = 1.71; 95% CI 1.03 2.39; p < 0.001), followed by aerobic training (ES = 0.51; 95% CI 0.30-0.72; p < 0.001), and combined training (ES = 0.15; 95% CI -0.24 to 0.53; p = 0.45). Meta regression analysis showed that only the duration of an intervention predicted the effect of physical training on QoL (coefficient = -0.027; p = 0.006), with shorter training durations (12 weeks) showing larger improvements. Conclusion: The present meta-analysis showed that physical training has positive effects on QoL, aerobic capacity, and cardiac function in older patients with HF. Practitioners should consider both training volume and mode when designing physical training programs in order to improve QoL and aerobic capacity in older patients with HF. PMID- 30483146 TI - Circadian Rhythms in Fractal Features of EEG Signals. AB - Time-of-day modulations affect both performance on a wide range of cognitive tasks and electrical activity of the brain, as recorded by electroencephalography (EEG). The aim of this work was to identify fluctuations of fractal properties of EEG time series due to circadian rhythms. In twenty-one healthy volunteers (all males, age between 20 and 30 years, chronotype: neutral type) high density EEG recordings at rest in open and closed eyes conditions were acquired in 4 times of the day (8.00 a.m., 11.30 a.m., 2.30 p.m., 7.00 p.m.). A vigilance task (Psychomotor Vigilance Test, PVT) was also performed. Detrended fluctuation Analysis (DFA) of envelope of alpha, beta and theta rhythms was performed, as well as Highuchi fractal dimension (HFD) of the whole band EEG. Our results evidenced circadian fluctuations of fractal features of EEG at rest in both eyes closed and eyes open conditions. Lower values of DFA exponent were found in the time T1 in closed eyes condition, likely effect of the sleep inertia. An alpha DFA exponent reduction was found also in central sensory-motor areas at time T3, the day time in which the sleepiness can be present. In eyes open condition, HFD lowered during the day. In eyes closed condition, an HFD increase was observed in central and frontal regions at time T2, the time in which alertness reaches its maximum and homeostatic sleep pressure is low. Complexity and the persistence of temporal correlations of brain rhythms change during daytime, parallel to changes in alertness and performance. PMID- 30483144 TI - Recent Progress in Space Physiology and Aging. AB - Astronauts coming back from long-term space missions present with different health problems potentially affecting mission performance, involving all functional systems and organs and closely resembling those found in the elderly. This review points out the most recent advances in the literature in areas of expertise in which specific research groups were particularly creative, and as they relate to aging and to possible benefits on Earth for disabled people. The update of new findings and approaches in space research refers especially to neuro-immuno-endocrine-metabolic interactions, optic nerve edema, motion sickness and muscle-tendon-bone interplay and aims at providing the curious - and even possibly naive young researchers - with a source of inspiration and of creative ideas for translational research. PMID- 30483148 TI - Regulation by Dietary Carbohydrates of Intermediary Metabolism in Liver and Muscle of Two Isogenic Lines of Rainbow Trout. AB - Rainbow trout (Oncorhynchus mykiss) is recognized as a typical "glucose intolerant" fish, and the limits of dietary carbohydrate utilization have been investigated for many years. In this study, the objective was to test the molecular effects of dietary carbohydrates on intermediary metabolism in two major metabolic tissues, liver and muscle. Another objective was also to study if the response to carbohydrate intake depended on the genetic background. We fed two isogenic lines of rainbow trout (named A22h and N38h) with high carbohydrate diet (carbohydrate, 22.9%) or low carbohydrate diet (carbohydrate, 3.6%) for 12 weeks. Carbohydrates were associated with higher feed utilization owned by the well-known protein-sparing effect, with better fish growth performance. However, atypical regulation of glycolysis and gluconeogenesis in liver and absence of hk and glut4 induction in muscle, were also observed. Regarding the effects of carbohydrates on other metabolism, we observed an increased, at a molecular level, of hepatic cholesterol biosynthesis, fatty acid oxidation and mitochondrial energy metabolism. Genetic variability (revealed by the differences between the two isogenic lines) was observed for some metabolic genes especially for those involved in the EPA and DHA biosynthetic capacity. Finally, our study demonstrates that dietary carbohydrate not only affect glucose metabolism but also strongly impact the lipid and energy metabolism in liver and muscle of trout. PMID- 30483147 TI - Whole-Body Electromyostimulation Improves Performance-Related Parameters in Runners. AB - The aim of this study was to study the effects of a 6-session (one per week) WB EMS training intervention on maximum oxygen uptake, aerobic and gas exchange thresholds, running economy, and muscular power in male recreational runners. Twelve men were randomized into WB-EMS intervention (n = 6; 27.0 +/- 7.5 years; 70.1 +/- 11.1 kg; 1.75 +/- 0.5 m) or control (n = 6; 27.0 +/- 6.1 years; 73.6 +/- 3.4 kg; 1.77 +/- 0.3 m). The WB-EMS group reduced the running training frequency to one per week and followed one WB-EMS training session per week during 6 weeks. Participants in the control group maintained their usual running endurance training. Each participant completed four assessments: physiological parameters [(i) VO2max, aerobic and gas exchange threshold values, and (ii) running economy at two intensities], muscular power (vertical jump), and anthropometric parameters both at baseline and after the intervention. Participants in the WB EMS group improved VO2max, aerobic and gas exchange threshold values, running economy, and vertical jump (p < 0.05) compared to the control group. There, WB EMS seems to be an effective training methodology leading to improvements in performance during endurance training volume reduction in male recreational runners. PMID- 30483149 TI - Genome-Wide Profiling of Cardinium-Responsive MicroRNAs in the Exotic Whitefly, Bemisia tabaci (Gennadius) Biotype Q. AB - Although the bacterial symbiont Cardinium has profound effects on the ecological adaptation of its host, the whitefly Bemisia tabaci (Gennadius) biotype Q (hereafter referred to as B. tabaci Q), the molecular mechanism underlying interactions between these two organisms is not yet fully understood. In this study, sRNA libraries were constructed, amplified, and sequenced for Cardinium infected (C+) and uninfected (C*-) B. tabaci Q with identical genetic backgrounds. Subsequently, the genes targeted by the differentially expressed miRNAs were predicted by integrating the B. tabaci Q genome data. A total of 125 known and 100 novel miRNAs were identified, among which 23 significant differentially expressed miRNAs were identified in both libraries. It is noteworthy that an analysis of target genes showed that Cardinium-responsive miRNA-regulated genes were functional in apoptosis, reproduction, development, immune response, thermotolerance and insecticide resistance. GO and KEGG pathway analysis revealed that some miRNA-target genes are closely associated with energy metabolism. A major finding of this study was the identification of several miRNAs that may be involved in physiological processes in response to environmental stress, i.e., insecticides and high temperatures. This information will provide a foundation to help further elucidate the functions of Cardinium in B. tabaci Q. PMID- 30483152 TI - Effects of Acute Cold Stress After Long-Term Cold Stimulation on Antioxidant Status, Heat Shock Proteins, Inflammation and Immune Cytokines in Broiler Heart. AB - To investigate the effects of acute cold stress (ACS) on chicken heart after cold stimulation, female broilers were raised in either normal (C) or gradually decreasing temperatures (CS I and CS II) for 34 days followed by a 24 h ACS at 7 degrees C. Cardiac tissues were collected from the pre-ACS and ACS time points to analyze the histopathological changes, antioxidant status and the expression of heat shock proteins, inflammatory factors and immune-related cytokines. The CS II heart tissues showed shrunken cell membranes and nuclei, disordered or ruptured myocardial fibers, higher MDA content and upregulation in HSP27, HSP40, HSP70, NF kappaB, COX-2, PTGEs, iNOS, TNF-alpha and IL-4 mRNAs, and in protein levels of HSP40, NF-kappaB and iNOS and reduction in CAT, GSH-px and SOD activity, as well as HSP90 and IFN-gamma levels compared to the control tissues before ACS. In contrast, the HSPs were significantly increased, and the inflammatory and immune related factors were unaltered prior to the ACS in the CS I compared to the C group. Following ACS, MDA content was significantly increased and antioxidant activity was significantly decreased in the CS I and CS II groups compared to the C group. The levels of HSP27, HSP70, HSP90, inflammatory factors and IL-4 were significantly reduced and that of IFN-gamma was significantly increased in CS I broiler hearts; the reverse trends were seen in CS II relative to CS I. Compared to the pre-ACS levels, that of HSP27, HSP40, HSP60, inflammatory factors and IL-4 were increased and IFN-gamma was decreased in the C and CS II groups after ACS. Therefore, cold stimulation at drastically lower temperatures induced cardiac damage, which was further aggravated by ACS. In contrast, cold stimulation at only 3 degrees C lower than normal temperature improved the adaptability of the broilers to ACS. PMID- 30483150 TI - Intestinal in vitro and ex vivo Models to Study Host-Microbiome Interactions and Acute Stressors. AB - The gut microbiome is extremely important for maintaining homeostasis with host intestinal epithelial, neuronal, and immune cells and this host-microbe interaction is critical during times of stress or disease. Environmental, nutritional, and cognitive stress are just a few factors known to influence the gut microbiota and are thought to induce microbial dysbiosis. Research on this bidirectional relationship as it pertains to health and disease is extensive and rapidly expanding in both in vivo and in vitro/ex vivo models. However, far less work has been devoted to studying effects of host-microbe interactions on acute stressors and performance, the underlying mechanisms, and the modulatory effects of different stressors on both the host and the microbiome. Additionally, the use of in vitro/ex vivo models to study the gut microbiome and human performance has not been researched extensively nor reviewed. Therefore, this review aims to examine current evidence concerning the current status of in vitro and ex vivo host models, the impact of acute stressors on gut physiology/microbiota as well as potential impacts on human performance and how we can parlay this information for DoD relevance as well as the broader scientific community. Models reviewed include widely utilized intestinal cell models from human and animal models that have been applied in the past for stress or microbiology research as well as ex vivo organ/tissue culture models and new innovative models including organ-on-a chip and co-culture models. PMID- 30483155 TI - Applying the Optimized CO Rebreathing Method for Measuring Blood Volumes and Hemoglobin Mass in Heart Failure Patients. AB - Introduction: Determination of blood volume, red cell volume, and plasma volume contributes to the understanding of the pathophysiology in heart failure, especially concerning anemia and volume load. The optimized carbon monoxide (CO) rebreathing method (oCORM) is used to determine these parameters and hemoglobin mass (Hbmass) in exercise physiology. The applicability of oCORM to determine the intravascular volumes and Hbmass in heart failure patients is currently undetermined because assumptions concerning CO kinetics with oCORM rely on healthy subjects with a normal ejection fraction. Therefore, the aim of the present study is to determine the applicability and the systematic error of oCORM arising from a reduced EF when oCORM is used for measurement of intravascular volumes and Hbmass in heart failure patients. Methods: oCORM was performed in 21 patients with heart failure and a reduced ejection fraction (EF) of < 30% (EFsev) and 25 controls (CONT). CO kinetics in capillary blood was studied 3-15 min after commencement of CO rebreathing. Differences in CO kinetics between the groups were assessed using a generalized linear model. The systematic error for determination of Hbmass with oCORM arising from differences in CO kinetics was assessed using the Monte Carlo method. Results: The CO kinetics was significantly different between EFsev and CONT. In both groups, exposure to CO led to a COHb increase to 6.0 +/- 1.0% 3 min after CO rebreathing. There were no CO related side effects or any clinical symptoms. Monte Carlo simulation quantifies the systematic error for determination of Hbmass arising from an impaired ejection fraction to be -0.88%. Conclusion: Our results indicate an impaired vascular mixing of CO when EF is severely reduced. When Hbmass is determined using the original oCORM protocol in heart failure patients with a reduced EF, the systematic underestimation of about 1% should be considered. However, the error arising from this impaired vascular mixing appears small and clinically negligible. Furthermore, application of oCORM was safe and not related to any side effects resulting from CO exposure. In conclusion, oCORM can be used for assessing intravascular volumes and Hbmass in patients with a reduced EF. PMID- 30483153 TI - Increased Abundance of Lactobacillales in the Colon of Beta-Adrenergic Receptor Knock Out Mouse Is Associated With Increased Gut Bacterial Production of Short Chain Fatty Acids and Reduced IL17 Expression in Circulating CD4+ Immune Cells. AB - Emerging evidence suggests an associative link between gut dysbiosis, the autonomic nervous system (ANS) and the immune system in pathophysiology of neurogenic hypertension (HTN). However, the close interplay between these three systems presents us with difficulties in deciphering the cause-effect relationship in disease. The present study utilized beta 1 and 2 adrenergic receptor knock out (AdrB1tm1BkkAdrB2tm1Bkk/J KO) mice to isolate the effects of reduced overall sympathetic drive on gut microbiota and systemic immune system. We observed the following: (i) Diminished beta adrenergic signaling mainly reflects in shifts in the Firmicutes phyla, with a significant increase in abundance of largely beneficial Bacilli Lactobacillales in the KO mice; (ii) This was associated with increased colonic production of beneficial short chain fatty acids (SCFAs) butyrate, acetate and propionate, confirming functional microbiota shifts in the KO mice; (iii) Dampened systemic immune responses in the KO mice reflected in reduction on circulating CD4+.IL17+ T cells and increase in young neutrophils, both previously associated with shifts in the gut microbiota. Taken together, these observations demonstrate that reduced expression of beta adrenergic receptors may lead to beneficial shifts in the gut microbiota and dampened systemic immune responses. Considering the role of both in hypertension, this suggests that dietary intervention may be a viable option for manipulation of blood pressure via correcting gut dysbiosis. PMID- 30483151 TI - Regulation of Renal Differentiation by Trophic Factors. AB - Classically, trophic factors are considered as proteins which support neurons in their growth, survival, and differentiation. However, most neurotrophic factors also have important functions outside of the nervous system. Especially essential renal growth and differentiation regulators are glial cell line-derived neurotrophic factor (GDNF), bone morphogenetic proteins (BMPs), and fibroblast growth factors (FGFs). Here we discuss how trophic factor-induced signaling contributes to the control of ureteric bud (UB) branching morphogenesis and to maintenance and differentiation of nephrogenic mesenchyme in embryonic kidney. The review includes recent advances in trophic factor functions during the guidance of branching morphogenesis and self-renewal versus differentiation decisions, both of which dictate the control of kidney size and nephron number. Creative utilization of current information may help better recapitulate renal differentiation in vitro, but it is obvious that significantly more basic knowledge is needed for development of regeneration-based renal therapies. PMID- 30483154 TI - Klotho and Aminopeptidases as Early Biomarkers of Renal Injury in Zucker Obese Rats. AB - The aim of this study was to investigate if urinary glutamyl aminopeptidase (GluAp), alanyl aminopeptidase (AlaAp), Klotho and hydroxyproline can be considered as potential biomarkers of renal injury and fibrosis in an experimental model of obesity. Male Zucker lean (ZL) and obese (ZO) rats were studied from 2 to 8 months old. Kidneys from ZO rats at the end of the study (8 months old) developed mild focal and segmental glomerulosclerosis as well as moderate tubulointerstitial injury. Urinary excretion of Klotho was higher in ZO rats at 2, 5, and 8 months of study, plasma Klotho levels were reduced and protein abundance of Klotho in renal tissue was similar in ZL and ZO rats. GluAp and AlaAp urinary activities were also increased in ZO rats throughout the time course study. ZO rats showed an augmentation of hydroxyproline content in renal tissue and a significant increase of tubulointerstitial fibrosis. Correlation studies demonstrated that GluAp, AlaAp, and Klotho are early diagnostic markers of renal lesions in Zucker obese rats. Proteinuria and hydroxyproline can be considered delayed diagnostic markers because their contribution to diagnosis starts later. Another relevant result is that GluAp, AlaAp, and Klotho are related not only with diagnosis but also with prognosis of renal lesions in Zucker obese rats. Moreover, strong predictive correlations of aminopeptidasic activities with the percentage of renal fibrosis or with renal hydroxyproline content at the end of the experiment were observed, indicating that an early increased excretion of these markers is related with a higher later extent of fibrosis in Zucker obese rats. In conclusion, GluAp, AlaAp, and Klotho are early diagnostic markers that are also related with the extent of renal fibrosis in Zucker obese rats. Therefore, they have a potential use not only in diagnosis, but also in prognosis of obesity-associated renal lesions. PMID- 30483156 TI - Glycemic Threshold as an Alternative Method to Identify the Anaerobic Threshold in Patients With Type 2 Diabetes. AB - Purpose: To analyze the agreement between the velocity, heart rate, and oxygen uptake values corresponding to second ventilatory threshold and glycemic threshold in patients with type 2 diabetes. Methods: Twenty-four untrained patients (55.1 +/- 8.9 years) were evaluated. Three different parameters of training intensity corresponding to anaerobic threshold, one mechanical (velocity) and two physiological (heart rate and oxygen uptake) parameters, were identified by a classical method (second ventilatory threshold) and by an alternative method (glycemic threshold). To determine the threshold values, patients performed an incremental treadmill test, with an initial velocity of 3 km.h-1 for 3 min, that was then increased by 1 km.h-1 every 2 min. Comparisons between mean values and the degree of agreement between second ventilatory threshold and glycemic threshold were analyzed using the paired t-test and Bland Altman test, respectively. Results: All patients performed the tests appropriately, and no adverse effects were recorded. Patients demonstrated similar mean velocity (p = 0.25), heart rate (p = 0.97) and oxygen uptake (p = 0.71) between the ventilatory threshold (6.4 +/- 0.6 km.h-1, 130.1 +/- 18.7 bpm, 15.2 +/- 3.5 ml.kg.min-1) and the glycemic threshold (6.2 +/- 0.9 km.h-1, 130.2 +/- 12.8 bpm, 15.0 +/- 3.8 ml.kg.min-1). Conclusion: The present study indicates an agreement between the glycemic and second ventilatory methods in determination of the anaerobic threshold of patients with type 2 diabetes; and thus, either method may be used for these patients. PMID- 30483158 TI - Combination of Agility and Plyometric Training Provides Similar Training Benefits as Combined Balance and Plyometric Training in Young Soccer Players. AB - Introduction: Studies that combined balance and resistance training induced larger performance improvements compared with single mode training. Agility exercises contain more dynamic and sport-specific movements compared with balance training. Thus, the purpose of this study was to contrast the effects of combined balance and plyometric training with combined agility and plyometric training and an active control on physical fitness in youth. Methods: Fifty-seven male soccer players aged 10-12 years participated in an 8-week training program (2 * week). They were randomly assigned to a balance-plyometric (BPT: n = 21), agility plyometric (APT: n = 20) or control group (n = 16). Measures included proxies of muscle power [countermovement jump (CMJ), triple-hop-test (THT)], muscle strength [reactive strength index (RSI), maximum voluntary isometric contraction (MVIC) of handgrip, back extensors, knee extensors], agility [4-m * 9-m shuttle run, Illinois change of direction test (ICODT) with and without the ball], balance (Standing Stork, Y-Balance), and speed (10-30 m sprints). Results: Significant time * group interactions were found for CMJ, hand grip MVIC force, ICODT without a ball, agility (4 m * 9 m), standing stork balance, Y-balance, 10 and 30-m sprint. The APT pre- to post-test measures displayed large ES improvements for hand grip MVIC force, ICODT without a ball, agility test, CMJ, standing stork balance test, Y-balance test but only moderate ES improvements with the 10 and 30 m sprints. The BPT group showed small (30 m sprint), moderate (hand grip MVIC, ICODTwithout a ball) and large ES [agility (4 m * 9 m) test, CMJ, standing stork balance test, Y-balance] improvements, respectively. Conclusion: In conclusion, both training groups provided significant improvements in all measures. It is recommended that youth incorporate balance exercises into their training and progress to agility with their strength and power training. PMID- 30483157 TI - Behavioral Evidence and Olfactory Reception of a Single Alarm Pheromone Component in Halyomorpha halys. AB - Halyomorpha halys is a major herbivore insect in the fruit orchards of China that has become a devastating invasive pest in North America and Europe since its accidental introductions in the 1990s and 2000s, respectively. Like other hemipteran insects, H. halys releases defensive chemicals against natural enemies, including (E)-2-decenal, which is an aldehyde associated with alarm pheromones. In this study, a series of electrophysiological and behavioral tests were conducted to characterize the alarm functions of (E)-2-decenal among H. halys adults and nymphs. An antennal transcriptome was obtained from a Chinese H. halys population, and 44 odorant-binding protein (OBP) genes were annotated. Among them, five putative alarm pheromone-binding proteins were screened and were extremely consistent with their homologs from US populations. These five OBPs were later expressed in a heterologous expression system, harvested, and then challenged with (E)-2-decenal in a binding assay. All five OBPs showed high binding activities to (E)-2-decenal, which demonstrated its behavioral significance as a defensive component in H. halys, as well as being the first report of its olfactory reception. These findings will help develop behavioral mediating tools as part of integrated pest management approaches to control this invasive pest. PMID- 30483159 TI - Selection and Validation of Reference Genes for RT-qPCR Analysis of the Ladybird Beetle Henosepilachna vigintioctomaculata. AB - Reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) is a momentous technique for quantifying expression levels of the targeted genes across various biological processes. Selection and validation of appropriate reference genes for RT-qPCR analysis are a pivotal precondition for reliable expression measurement. Henosepilachna vigintioctopunctata is one of the most serious insect pests that attack Solanaceae plants in Asian countries. Recently, the transcriptomes of H. vigintioctopunctata were sequenced, promoting gene functional studies of this insect pest. Unfortunately, the reference genes for H. vigintioctopunctata have not been selected and validated. Here, a total of 7 commonly used reference genes, namely, Actin, GAPDH, RPL13, RPL6, RPL32, RPS18, and ATPB, were selected and assessed for suitability under four experimental conditions, namely, developmental stage, tissue, temperature, and host plant, using RefFinder, which integrates four different analytical tools (Normfinder, geNorm, the DeltaCt method, and BestKeeper). The results displayed that RPL13 and RPS18 were the best suitable reference genes for each experimental condition. The relative transcript levels of 2 target genes, lov and TBX1, varied greatly according to normalization with the two most- and least-suited reference genes. Our results will be helpful for improving the accuracy of the RT-qPCR analysis for future functional investigations of target gene expression in H. vigintioctopunctata. PMID- 30483161 TI - Patterns of Management of Patients With Dual Disorder (Psychosis) in Italy: A Survey of Psychiatrists and Other Physicians Focusing on Clinical Practice. AB - Patients with severe psychotic disorders such as schizophrenia, schizoaffective, and bipolar disorders frequently suffer from concomitant substance use disorders (SUDs)-Dual Disorder (DD) patients. In order to better understand current practices for management of patients with psychotic episodes and concomitant SUD in Italy, we carried out a survey of psychiatrists on current routine practice among prescribers. These aspects can help to identify at-risk patients, improve current prescribing practices, and favor early intervention. An ad hoc survey of 17 questions was administered to psychiatrists via electronic polling and on-line distribution; 448 completed questionnaires were collected. Comorbid substance abuse was most frequently diagnosed within the context of anxiety disorder (46%), followed by bipolar disorder (25%), and schizophrenia/schizoaffective disorder (12%). The vast majority of respondents felt that patient management was becoming more complex due to substance abuse. The areas reported to be most affected in patients with SUD were functioning, interpersonal relations, and impulsivity, while sensory perception disorders, ideation, agitation, and impulsivity were the most frequently reported symptoms. In the acute setting, haloperidol was used as the first-line agent of choice followed by aripiprazole and olanzapine. In the maintenance phase, aripiprazole was the dominantly used first-line agent, followed by olanzapine. Almost half of respondents used long-acting agents, while about one-third did not. Among those prescribing long-acting agents, efficacy, control of impulsivity, and control of specific symptoms were cited as motivators, while in the maintenance phase, better adherence, and tolerability were mainly cited. From the responses to the present survey, it is clear that the respondents are aware of the problem of SUD in psychotic patients. While treatment be optimized in terms of the choice and formulation of antipsychotics, greater emphasis should be placed on efficacy, tolerability, and the negative metabolic consequences of some antipsychotics. When considering the ideal antipsychotic, long-acting agents were considered to be superior in reducing relapse, even if current treatment guidelines often give preference to oral formulations. PMID- 30483160 TI - Fragile X-Associated Neuropsychiatric Disorders (FXAND). AB - Fragile X syndrome (FXS) is caused by the full mutation (>200 CGG repeats) in the Fragile X Mental Retardation 1 (FMR1) gene. It is the most common inherited cause of intellectual disability (ID) and autism. This review focuses on neuropsychiatric disorders frequently experienced by premutation carriers with 55 to 200 CGG repeats and the pathophysiology involves elevated FMR1 mRNA levels, which is different from the absence or deficiency of fragile X mental retardation protein (FMRP) seen in FXS. Neuropsychiatric disorders are the most common problems associated with the premutation, and they affect approximately 50% of individuals with 55 to 200 CGG repeats in the FMR1 gene. Neuropsychiatric disorders in children with the premutation include anxiety, ADHD, social deficits, or autism spectrum disorders (ASD). In adults with the premutation, anxiety and depression are the most common problems, although obsessive compulsive disorder, ADHD, and substance abuse are also common. These problems are often exacerbated by chronic fatigue, chronic pain, fibromyalgia, autoimmune disorders and sleep problems, which are also associated with the premutation. Here we review the clinical studies, neuropathology and molecular underpinnings of RNA toxicity associated with the premutation. We also propose the name Fragile X-associated Neuropsychiatric Disorders (FXAND) in an effort to promote research and the use of fragile X DNA testing to enhance recognition and treatment for these disorders. PMID- 30483162 TI - COMT, 5-HTR2A, and SLC6A4 mRNA Expressions in First-Episode Antipsychotic-Naive Schizophrenia and Association With Treatment Outcomes. AB - Background: Dopaminergic and serotonergic systems play crucial roles in the pathophysiology of schizophrenia and modulate response to antipsychotic treatment. However, previous studies of dopaminergic and serotonergic genes expression are sparse, and their results have been inconsistent. In this longitudinal study, we aim to investigate the expressions of Catechol-O methyltransferase (COMT), serotonin 2A receptor (5-HTR2A), and serotonin transporter gene (SLC6A4) mRNA in first-episode antipsychotic-naive schizophrenia and to test if these mRNA expressions are associated with cognitive deficits and treatment outcomes or not. Method: We measured COMT, 5-HTR2A, and SLC6A4 mRNA expressions in 45 drug-naive first-episode schizophrenia patients and 38 health controls at baseline, and repeated mRNA measurements in all patients at the 8 week follow up. Furthermore, we also assessed antipsychotic response and cognitive improvement after 8 weeks of risperidone monotherapy. Results: Patients were divided into responders (N = 20) and non-responders groups (N = 25) according to the Remission criteria of the Schizophrenia Working Group. Both patient groups have significantly higher COMT mRNA expression and lower SLC6A4 mRNA expression when compared with healthy controls. Interestingly, responder patients have significantly higher levels of COMT and 5-HTR2A mRNA expressions than non-responder patients at baseline. However, antipsychotic treatment has no significant effect on the expressions of COMT, 5-HTR2A, and SLC6A4 mRNA over 8 week follow up. Conclusion: Our findings suggest that dysregulated COMT and SLC6A4 mRNA expressions may implicate in the pathophysiology of schizophrenia, and that COMT and 5-HTR2A mRNA may be potential biomarkers to predict antipsychotic response. PMID- 30483164 TI - Does Fruit and Vegetable Consumption During Adolescence Predict Adult Depression? A Longitudinal Study of US Adolescents. AB - The relationship between better diet quality and decreased depression across the life span is consistent and compelling. Fruit and vegetable consumption has been of particular interest. The nutritional benefits from the consumption of fruits and vegetables may mitigate non-communicable diseases and promote brain and mental health. This study aimed to determine whether fruit and vegetable consumption during adolescence was associated with a reduced risk of developing depression in adulthood in a large, representative sample of US individuals. Data from the Add Health Study were analyzed, which included 3,696 participants who were aged approximately 17 years at baseline (1994-1995), and 29 years at follow up (2007-2008). The Center for Epidemiologic Studies Depression Scale was used to assess depression and a self-report item asked how many times the participant consumed fruit/vegetables on the previous day. Individuals who were depressed at both times points had the highest proportion who failed to consume any fruit (31%) or vegetables (42%) on the previous day. Fruit and vegetable consumption did not predict of adult depression in fully adjusted models. Cross sectional associations existed for diet and adolescent depression only. Our initial findings supported fruit and vegetable consumption as being protective against adult depression, but this association was subsequently attenuated on adjustment for other relevant factors. Future research will benefit from more precise measures of dietary intakes. PMID- 30483165 TI - CBI-20: Psychometric Properties for the Coping Behaviors Inventory for Alcohol Abuse in Brazil. AB - For any professional, it is of crucial importance to know not only how coping styles and strategies are present in an individual, but to know about its role to the treatment of alcohol abuse. Moreover, new approaches have emerged in this area in terms of relapse prevention and the counseling by phone can be an alternative. The aim of this study is to examine the factor structure of the Coping Behaviors Inventory (CBI) and to test its invariance across groups face-to face and phone counseling in Brazil. For this purpose, two studies were carried out: study I, the factor structure was revisited in terms of exploratory factor analysis. Study II, face-to-face and phone counseling were examined through confirmatory factor analysis and multigroup analysis. The results confirmed the 4 factor solution with a revised model for the removal of 16 items. Thus presented, a reduced version with better indexes than the previous versions developed over the last 30 years that was ones reformulated from 60 items. The Internal consistency for study I presented alpha = 0.90 and homogeneity was between 0.17 and 0.5). In addition the KMO = 0.9 = 0.932, X(df=630)2 = 6091.94, p < 0.0 < 0.001. In study II, cronbach's alpha = 0.91 and homogeneity 0.23-0.61 (telemedicine treatment) and alpha = 0.90 0.17 to 0.63 (face-to-face treatment). In the CFA, the examination of the current version has better fit than the that the traditional model. Moreover, the new version showed convergent validity with the IDHEA questionnaire. In the multigroup analysis no significant changes between groups to a metric level. Finally, the Brazilian version of inventory showed no differences between the phone counseling and face-to-face participants in a metric level after a multigroup analysis. PMID- 30483166 TI - Why Do People With Schizophrenia Exercise? A Mixed Methods Analysis Among Community Dwelling Regular Exercisers. AB - Individuals with schizophrenia have reduced rates of physical activity, yet substantial proportions do engage in independent and regular exercise. Previous studies have shown improvement in symptoms and cognitive function in response to supervised exercise programs in people with schizophrenia. There is little data on motivations of individuals who exercise independently, or their chosen type, duration, or setting of exercise. This study explores motivational parameters and subjective experiences associated with sustained, independent exercise in outpatients with a diagnosis of schizophrenia or schizoaffective disorder. Participants completed a semi-structured interview and then were given a prospective survey containing visual analog scales of symptom severity and the Subjective Exercise Experiences Scales to complete immediately before and after three sessions of exercise. Results from the semi-structured interview were analyzed by modified content analysis. The most important reason for exercise was self-image, followed closely by psychological and physical health. Among psychological effects, participants reported exercise was most helpful for mood and cognitive symptoms. The prospective ratings demonstrated 10-15% average improvements in global well-being, energy, and negative, cognitive and mood symptoms, with almost no change in psychosis, after individual exercise sessions. This suggests that non-psychotic parameters are more susceptible to inter-session decay of exercise effects, which may reinforce continued exercise participation. PMID- 30483167 TI - The Direct Testing Effect Is Pervasive in Action Memory: Analyses of Recall Accuracy and Recall Speed. AB - Successful retrieval from memory is a desirably difficult learning event that reduces the recall decrement of studied materials over longer delays more than restudying does. The present study was the first to test this direct testing effect for performed and read action events (e.g., "light a candle") in terms of both recall accuracy and recall speed. To this end, subjects initially encoded action phrases by either enacting them or reading them aloud (i.e., encoding type). After this initial study phase, they received two practice phases, in which the same number of action phrases were restudied or retrieval-practiced (Exp. 1-3), or not further processed (Exp. 3; i.e., practice type). This learning session was ensued by a final cued-recall test both after a short delay (2 min) and after a long delay (1 week: Exp. 1 and 2; 2 weeks: Exp. 3). To test the generality of the results, subjects retrieval practiced with either noun-cued recall of verbs (Exp. 1 and 3) or verb-cued recall of nouns (Exp. 2) during the intermediate and final tests (i.e., test type). We demonstrated direct benefits of testing on both recall accuracy and recall speed. Repeated retrieval practice, relative to repeated restudy and study-only practice, reduced the recall decrement over the long delay, and enhanced phrases' recall speed already after 2 min, and this independently of type of encoding and recall test. However, a benefit of testing on long-term retention only emerged (Exp. 3), when prolonging the recall delay from 1 to 2 weeks, and using different sets of phrases for the immediate and delayed final tests. Thus, the direct testing benefit appears to be highly generalizable even with more complex, action-oriented stimulus materials, and encoding manipulations. We discuss these results in terms of the distribution based bifurcation model. PMID- 30483163 TI - Is It Possible to Predict the Future in First-Episode Psychosis? AB - The outcome of first-episode psychosis (FEP) is highly variable, ranging from early sustained recovery to antipsychotic treatment resistance from the onset of illness. For clinicians, a possibility to predict patient outcomes would be highly valuable for the selection of antipsychotic treatment and in tailoring psychosocial treatments and psychoeducation. This selective review summarizes current knowledge of prognostic markers in FEP. We sought potential outcome predictors from clinical and sociodemographic factors, cognition, brain imaging, genetics, and blood-based biomarkers, and we considered different outcomes, like remission, recovery, physical comorbidities, and suicide risk. Based on the review, it is currently possible to predict the future for FEP patients to some extent. Some clinical features-like the longer duration of untreated psychosis (DUP), poor premorbid adjustment, the insidious mode of onset, the greater severity of negative symptoms, comorbid substance use disorders (SUDs), a history of suicide attempts and suicidal ideation and having non-affective psychosis-are associated with a worse outcome. Of the social and demographic factors, male gender, social disadvantage, neighborhood deprivation, dysfunctional family environment, and ethnicity may be relevant. Treatment non-adherence is a substantial risk factor for relapse, but a small minority of patients with acute onset of FEP and early remission may benefit from antipsychotic discontinuation. Cognitive functioning is associated with functional outcomes. Brain imaging currently has limited utility as an outcome predictor, but this may change with methodological advancements. Polygenic risk scores (PRSs) might be useful as one component of a predictive tool, and pharmacogenetic testing is already available and valuable for patients who have problems in treatment response or with side effects. Most blood-based biomarkers need further validation. None of the currently available predictive markers has adequate sensitivity or specificity used alone. However, personalized treatment of FEP will need predictive tools. We discuss some methodologies, such as machine learning (ML), and tools that could lead to the improved prediction and clinical utility of different prognostic markers in FEP. Combination of different markers in ML models with a user friendly interface, or novel findings from e.g., molecular genetics or neuroimaging, may result in computer-assisted clinical applications in the near future. PMID- 30483168 TI - Gene Expression in the Hippocampus in a Rat Model of Premenstrual Dysphoric Disorder After Treatment With Baixiangdan Capsules. AB - Objective: To explore the targets, signal regulatory networks and mechanisms involved in Baixiangdan (BXD) capsule regulation of premenstrual dysphoric disorder (PMDD) at the gene transcription level, since the etiology and pathogenesis of PMDD are not well understood. Methods: The PMDD rat model was prepared using the resident-intruder paradigm. The rats were tested for aggressive behavior, and those with scores in the lowest 30% were used as controls, while rats with scores in the highest 30% were divided into a PMDD model group, BXD administration group and fluoxetine administration group, which were evaluated with open-field tests and aggressive behavior tests. We also analyzed gene expression profiles in the hippocampus for each group, and verified differential expression of genes by real-time PCR. Results: Before and after BXD or fluoxetine administration, scores in the open-field test exhibited no significant differences. The aggressive behavior of the PMDD model rats was improved to a degree after administration of both substances. Gene chip data indicated that 715 genes were differentially expressed in the control and BXD groups. Other group-to-group comparisons exhibited smaller numbers of differentially expressed genes. The effective targets of both drugs included the Htr2c, Cdh3, Serpinb1a, Ace, Trpv4, Cacna1a, Mapk13, Mapk8, Cyp2c13, and Htr1a genes. The results of real-time PCR tests were in accordance with the gene chip data. Based on the target genes and signaling pathway network analysis, we have elaborated the impact and likely mechanism of BXD in treating PMDD and premenstrual irritability. Conclusion: Our work contributes to the understanding of PMDD pathogenesis and the mechanisms of BXD treatment. We speculate that the differentially expressed genes could participate in neuroactive ligand-receptor interactions, mitogen-activated protein kinase, calcium, and gamma-aminobutyric acid signal transduction. PMID- 30483170 TI - Domestic Violence and Education: Examining the Impact of Domestic Violence on Young Children, Children, and Young People and the Potential Role of Schools. AB - This article examines how domestic violence impacts the lives and education of young children, children, and young people and how they can be supported within the education system. Schools are often the service in closest and longest contact with a child living with domestic violence; teachers can play a vital role in helping families access welfare services. In the wake of high profile cases of child abuse and neglect, concerns have been raised about the effectiveness of multi-agency responses to children living with abuse. In the United Kingdom, the case of 4-year-old Daniel Pelka who died in 2012 following abuse and starvation by his mother, who experienced domestic violence, and her partner, led to a serious case review. It found recording systems in Daniel's school were not used consistently, and details held by different agencies were not collated to enable the formation of a coherent assessment. The lack of integrated working cited in the report echoes findings from previous serious case reviews. A strong correlation exists between domestic abuse and child abuse, with approximately half of all domestic violence situations involving direct child abuse. Children can also be affected indirectly by violence occurring in their home by seeing or hearing it taking place. This article examines the impact of domestic violence on the mental health of children, and the impact on their education. Violence in children's lives often causes disruption to their schooling and harms the quality of their educational experiences and outcomes. The abuse children experience can result in emotional trauma, physical and psychological barriers to learning, and disruptive behavior in school, while the underlying causes of these problems remain hidden. Knowing when and how to seek advice from multi-agency professionals is an essential part of effective practice among school staff. Despite their vital role in identifying signs of abuse and signposting referral pathways, research indicates teachers often lack confidence and knowledge for such work. The article examines how the professional learning and professional confidence of teachers can be developed, and how recent policy and practice developments in the United Kingdom have the potential to influence work in this area. PMID- 30483169 TI - Using Hierarchical Linear Models to Examine Approximate Number System Acuity: The Role of Trial-Level and Participant-Level Characteristics. AB - The ability to intuitively and quickly compare the number of items in collections without counting is thought to rely on the Approximate Number System (ANS). To assess individual differences in the precision of peoples' ANS representations, researchers often use non-symbolic number comparison tasks in which participants quickly choose the numerically larger of two arrays of dots. However, some researchers debate whether this task actually measures the ability to discriminate approximate numbers or instead measures the ability to discriminate other continuous magnitude dimensions that are often confounded with number (e.g., the total surface area of the dots or the convex hull of the dot arrays). In this study, we used hierarchical linear models (HLMs) to predict 132 adults' accuracy on each trial of a non-symbolic number comparison task from a comprehensive set of trial-level characteristics (including numerosity ratio, surface area, convex hull, and temporal and spatial variations in presentation format) and participant-level controls (including cognitive abilities such as visual-short term memory, working memory, and math ability) in order to gain a more nuanced understanding of how individuals complete this task. Our results indicate that certain trial-level characteristics of the dot arrays contribute to our ability to compare numerosities, yet numerosity ratio, the critical marker of the ANS, remains a highly significant predictor of accuracy above and beyond trial-level characteristics and across individuals with varying levels of math ability and domain-general cognitive abilities. PMID- 30483171 TI - Measuring Burnout Among University Students: Factorial Validity, Invariance, and Latent Profiles of the Italian Version of the Maslach Burnout Inventory Student Survey (MBI-SS). AB - Burnout has a long tradition of studies in the workplace and recently researchers suggested burnout is also rising among university students. The Maslach Burnout Inventory (MBI) is considered a valid measure of burnout. However, the student version of the MBI (MBI-SS) has received limited empirical support. The aim of this paper is to analyze the factorial validity, invariance, and latent profiles of the Italian version of the MBI-SS in a sample university students. A total of 7757 Italian university students participated in an online cross-sectional survey. Results from explorative and confirmatory factor analyses showed acceptable fits for the Italian version of the MBI-SS. In addition, multigroup analyses supported full-metric invariance of MBI-SS within gender and academic level (bachelor vs. master). Finally, results from latent profile analysis showed that a three latent profile model was the better solution for the data: (a) burned-out (high levels of exhaustion, cynicism (CY), and low professional efficacy (PE); n = 2665, 34.2%); (b) overextended (high levels of exhaustion, moderate other, n = 3953, 51.0%); and (c) engaged (moderate exhaustion, low CY, and high PE, n = 1149, 14.8%). The resulting three-profile solution in the present study partially agrees with a prior study as it replicated three of the five-profile solution identified. In sum, we suggest that the MBI-SS is valid and reliable and represents a robust instrument for the measurement of burnout among Italian speaking university students. PMID- 30483172 TI - No Effect of the Right Posterior Parietal Cortex tDCS in Dual-Target Visual Search. AB - "Subsequent search misses" represent a decrease in accuracy at detecting a second target in a visual search task. In this study, we tested the possibility to modulate this effect via inhibition of the right posterior parietal cortex trough transcranial direct current stimulation (tDCS). The target stimuli were T-shapes presented among L-shaped distractors. The participant's task was to detect targets or to report their absence. For each trial, targets could be represented by one high-salient target, one low-salient target, two different targets (one high salient and one low salient), two high salient targets, two low salient targets, or no targets at all (catch-trials). Offline tDCS was applied over the right (target site) or left (control site) posterior parietal cortex. Sham stimulation over the right posterior parietal cortex was included as a control (placebo). Stimulation lasted for 10 min. Afterward, participants were asked to perform the experiment. Our findings suggest that stimulation did not modulate any of the task conditions, suggesting potential limitation of the study: either tDCS was not enough powerful to modulate the task performance or the task was too easy to be modulated by stimulation. PMID- 30483173 TI - Effects of Musical Tempo on Musicians' and Non-musicians' Emotional Experience When Listening to Music. AB - Tempo is an important musical element that affects human's emotional processes when listening to music. However, it remains unclear how tempo and training affect individuals' emotional experience of music. To explore the neural underpinnings of the effects of tempo on music-evoked emotion, music with fast, medium, and slow tempi were collected to compare differences in emotional responses using functional magnetic resonance imaging (fMRI) of neural activity between musicians and non-musicians. Behaviorally, musicians perceived higher valence in fast music than did non-musicians. The main effects of musicians and non-musicians and tempo were significant, and a near significant interaction between group and tempo was found. In the arousal dimension, the mean score of medium-tempo music was the highest among the three kinds; in the valence dimension, the mean scores decreased in order from fast music, medium music, to slow music. Functional analyses revealed that the neural activation of musicians was stronger than those of non-musicians in the left inferior parietal lobe (IPL). A comparison of tempi showed a stronger activation from fast music than slow music in the bilateral superior temporal gyrus (STG), which provided corresponding neural evidence for the highest valence reported by participants for fast music. Medium music showed stronger activation than slow music in the right Heschl's gyrus (HG), right middle temporal gyrus (MTG), right posterior cingulate cortex (PCC), right precuneus, right IPL, and left STG. Importantly, this study confirmed and explained the connection between music tempo and emotional experiences, and their interaction with individuals' musical training. PMID- 30483174 TI - Walking in a Patient's Shoes: An Evaluation Study of Immersive Learning Using a Digital Training Intervention. AB - Objectives: Evidence suggests that immersive learning increases empathy and understanding of the patient experience of illness. This study evaluated a digital training intervention 'In Their Shoes' which immerses participants in the experience of living with inflammatory bowel disease (IBD), highlighting the biopsychosocial impact. The simulation program uses a mobile application to deliver time-based tasks and challenges over 36 h, supplemented with telephone role-play and 'kit' items to open and use. This study investigated changes in IBD understanding and connection to patients, empathy and perception of job value in a group of pharmaceutical employees. Additionally, it explored experiences and impact of taking part in the intervention. Methods: A mixed methods pre-post design was utilized, with an opportunity sample of employees taking part in the training. 104 participants from sites in 12 countries completed measures at baseline and 97 post-intervention. Measures included the Toronto Empathy Questionnaire, Prosocial Job Characteristics Scale, and structured questions around IBD understanding and connection to patients. Two focus groups (N = 14) were conducted regarding participants experiences of the intervention to complement an open-response question in the questionnaire (N = 75). Qualitative data was analyzed using thematic analysis. Results: Following the intervention, there were statistically significant increases in IBD understanding and connection to patients (p < 0.00025), evaluation of organizational innovation (p < 0.00025), empathy (d = 0.45) and prosocial job perceptions (d = 0.28). Qualitative analysis revealed more fully the transformative personal journey undertaken by participants which provided 'eye opening' insight into the psychosocial impact of living and working with IBD. This insight encouraged patient perspective-taking and a strong desire to promote patient advocacy and reduce stigma around chronic illness. Finally, greater organizational pride and connectivity was evident for some participants. Conclusions: An immersive training program, focussing on the lived experience of illness, led to significant increases in disease understanding and empathy. These findings align with other literature evaluating immersive learning and the potential for increasing knowledge, empathy and motivation. The present study offers opportunities to extend this outside of the body of work focussing on healthcare practitioners and explores the benefits of using this type of learning experience within an organizational setting. PMID- 30483175 TI - Power of Cognition: How Dysfunctional Cognitions and Schemas Influence Eating Behavior in Daily Life Among Individuals With Eating Disorders. AB - Eating disorders (EDs) are characterized by marked cognitive distortions and maladaptive schemas. Cognitive models of EDs highlight the direct impact of cognitive dysfunctions on eating-related disturbances, insofar as specific cognitive contents such as thoughts about diet rules and food or loss of control may trigger disturbed eating behavior. Moreover, early maladaptive schemas that reflect perfectionist standards and relate to achievement and performance seem to be associated with disturbed eating, e.g., via their impact on situation-specific appraisals. However, so far, no study has investigated these assumptions. Hence, the present study sought to demonstrate whether and how cognitive content exerts an impact on eating behavior in daily life, and whether maladaptive core schemas impact the occurrence of binge eating via dysfunctional ED cognitions in eating related contexts. N = 29 females with bulimia nervosa (BN), n = 31 females with binge eating disorder (BED) and n = 30 female controls without EDs (NC) participated in the study. All participants received a handheld computer for a 48 h period to capture antecedents of disturbed eating behavior in daily life. Event sampling (meals, binge eating, purging, stressful situations) and signal-sampling (five times a day) methods were applied. EMA included a short questionnaire to assess dysfunctional cognitions and level of craving and to capture information about situational contexts. Early maladaptive schemas were assessed using a short version of the Young Schema Questionnaire at baseline. The main results showed specific patterns of dysfunctional eating-related cognitions for BED and BN. Binge eating was predicted by thoughts about loss of control (positively) and dietary restraint (negatively). For meal situations, no significant differences between the two ED groups emerged. All three domains exerted indirect effects on craving via thoughts about 'eating/loss of control,' whereas neither a direct nor an indirect effect emerged regarding thoughts about 'dietary restraint.' These results fit well with previous studies and support cognitive models of EDs; schema therapeutic approaches may be a valuable contribution to enhance treatment of EDs. Further studies should explore whether the findings from emerging adulthood can be generalized to younger age groups. PMID- 30483176 TI - Imagining Others' Minds: The Positive Relation Between Children's Role Play and Anthropomorphism. AB - Children's role playing, whether personifying toys or imagining invisible friends, involves imagining others' minds and internal states. Similarly, anthropomorphism - the attribution of internal states to non-human others (e.g., animals, inanimate nature, or technologies) - also involves imagining others' minds and internal states. We propose that the imaginative process of simulating and projecting internal states is common to both role play and anthropomorphism. The current study investigated the relation between children's role play and anthropomorphism. Ninety children (5, 7, and 9 years) were administered Individual Differences in Anthropomorphism Questionnaire - Child Form (IDAQ-CF), comprised of the technology-inanimate nature and animal subscales, and the Role Play Scale, which assessed (a) impersonation of animals, people, and/or machines and (b) imaginary companions (ICs), including invisible friends and personified toys. Results indicated that the imaginative act of impersonating an animal, person, and/or machine was positively related to anthropomorphism, and specifically anthropomorphism of inanimate nature and technology. Second, anthropomorphism of animals was highest amongst children with invisible ICs, followed by those with toy ICs and those who impersonated. Finally, children who frequently engaged with an invisible ICs more readily anthropomorphized in general and technology and inanimate nature in particular relative to all other children. Results are discussed in terms of the differing degrees of imagination involved in anthropomorphism of animals versus technology and inanimate nature. PMID- 30483177 TI - The Primacy-of-Warmth Effect on Spontaneous Trait Inferences and the Moderating Role of Trait Valence: Evidence From Chinese Undergraduates. AB - Research has shown that warmth and competence are the fundamental content dimensions underlying social judgment, and warmth judgments are primary. However, the overwhelming majority of research concerning "primacy-of-warmth" rests on trait judgment or lexical recognition, and little attention has been paid to spontaneous trait inferences (STIs) that are made on exposure to trait-implying behaviors. Two studies were performed to examine the primacy-of-warmth effect on STIs and to further explore whether trait valence moderates the effect. Consistent with our expectations, the results of Experiments 1 and 2 (for spontaneous trait activation and spontaneous trait binding, respectively) consistently demonstrated the primacy-of-warmth on STIs. Participants were more likely to draw STIs from behaviors implying warmth traits than those implying competence traits. Moreover, the primacy-of-warmth effect on STIs was moderated by trait valence. In concrete terms, participants were more likely to draw STIs from negative warmth behavioral sentences than negative competence behavioral sentences, whereas participants draw STIs from positive warmth behavioral sentences and from positive competence behavioral sentences equally. An original contribution made by our study is that we obtained the primacy-of-warmth effect on STIs, providing further evidence for the primacy-of-warmth effect in the domain of implicit social cognition. PMID- 30483179 TI - The "g" in Faking: Doublethink the Validity of Personality Self-Report Measures for Applicant Selection. AB - The meta-analytic finding that faking does not affect the criterion validity of self-report measures in applicant selection suggests cognitive abilities are crucial to fake personality to an expected optimal profile in self-report measures. Previous studies in this field typically focus on how the extent of faking changes self-report measurement. However, the effect of faking ability is rarely considered. In Study 1 (n = 151), we link two questionnaires, the WSQ and the NEO-PI-R, to use them for later faking ability tasks. With O*NET expert ratings and the linked questionnaires, we establish veridical responses of optimal personality profiles for both questionnaires. Based on this, in Study 2, we develop six faking ability task employing both questionnaires and three common jobs to fake for. To score the tasks, we introduce profile similarity metrics that compare faked response vectors to optimal profile vectors. The faking ability tasks were administered to a community sample (n = 210) who additionally completed measures of cognitive abilities, namely general mental ability, crystallized intelligence, and interpersonal abilities. For all, based on previous research, it can be argued that they should predict individual differences in faking ability. We establish a measurement model of faking ability and its relation to the other cognitive abilities. Using structural equations modeling, we find the strongest effect for crystallized intelligence and weaker effects for general mental ability and interpersonal abilities, all positively predicting faking ability. We show for the first time that we can measure faking ability with psychometrically sound techniques, establish a confirmatory factor model of faking ability and that it is largely explained by other cognitive abilities. We conclude that research supporting a positive link between self reported personality and job performance is presumably confounded by cognitive abilities, because they are predictive of both faking self-reported personality and job performance. We recommend researchers to broaden their measurements with assessments of faking ability or other cognitive abilities (besides general mental ability) in research regarding applicant selection. PMID- 30483178 TI - Democratic Systems Increase Outgroup Tolerance Through Opinion Sharing and Voting: An International Perspective. AB - Democracy may contribute to friendly attitudes and positive attitudes toward outgroups (i.e., outgroup tolerance) because members of democratic societies learn to exercise their rights (i.e., cast a vote) and, in the process, listen to different opinions. Study 1 was a survey study with representative samples from 33 countries (N = 45,070, 53.6% female) and it showed a positive association between the levels of democracy and outgroup tolerance after controlling for gender, age and the rate of immigrants influx from 2010 to 2013. Study 1 demonstrated that members in countries with higher political participation and civil liberty showed greater tolerance toward immigrants. In Study 2, we conducted an experimental study in Taiwan (N = 93, 67.7% female) to further examine two potential mediators (opinion sharing and voting) of the effect of democratic system on tolerance toward outgroups (i.e., attitudes toward mental patients) after controlling for gender and age. We found that when individuals were allowed to share opinions and vote, they had the highest positive other oriented emotions toward mental patients, which in turn led to greater tolerance toward outgroups compared to those who were not allowed to share opinions or vote. In general, these results demonstrated that the democratic system plays a critical role in increasing outgroup tolerance. Limitations of the two studies and implications regarding opinion sharing, voting, democratic systems, and effects on outgroup tolerance are discussed. PMID- 30483180 TI - Creating Art Together as a Transformative Process in Parent-Child Relations: The Therapeutic Aspects of the Joint Painting Procedure. AB - The relationships between parents and children contain implicit aspects, which are non-conscious and non-verbal, in addition to explicit ones. Both explicit and implicit aspects are central to understanding the dyadic dynamics and are implicated in psychotherapy processes and outcomes. Visual symbolization has a unique value as a channel of expression that can capture the implicit characteristics of relationships. Creating art together goes even further because it allows the presence of implicit representations of the relations in vivo. These representations can then be transformed through the joint process of creation, which has a unique potential to unleash reflective capacities when it is experienced in a playful and safe context. This paper presents a qualitative study that is part of larger mixed-methods research with 87 mother-child dyads (with children 9 to 12 years old). Dyads were administered the Joint Painting Procedure (JPP), which includes dyadic painting by the parent and child on the same paper and is used for evaluation and treatment in the field of parent-child therapy and art therapy. The study's objectives were to uncover and better understand the unique therapeutic aspects that such method allows and its potential to impact parent-child relationships. The findings of the qualitative study indicated that the JPP enabled several dynamic processes such as pleasure and fun, bi-directionality, mutual regulation, mentalization, and mutual recognition, which together created a salient positive transformation in the relationship. Through the JPP, a new transformative aspect of relations emerges and enables new and different modes of communication and interactions in about half of the dyads and a lesser and partial positive transformation in about a third of them. PMID- 30483181 TI - SPALEX: A Spanish Lexical Decision Database From a Massive Online Data Collection. PMID- 30483182 TI - Hypothesis: Clues From Mammalian Hibernation for Treating Patients With Anorexia Nervosa. AB - This hypothesis is that anorexia nervosa (AN) is a biologically driven disorder, and mammalian hibernation may offer clues to its pathogenesis. Using this approach, this hypothesis offers suggestions for employing heart rate variability as an early diagnostic test for AN; employing the ketogenic diet for refeeding patients, attending to omega 3:6 ratio of polyunsaturated fatty acids (PUFAs) in the refeeding diet; and exploring clinical trials of the endocannabinoid-like agent, palmitoylethanolamde for patients with AN. This hypothesis also explores the role of lipids and autoimmune phenomena in AN, and suggest a lipodomics study to search for antibodies in the serum on patients with AN. PMID- 30483183 TI - Conversational Time Travel: Evidence of a Retrospective Bias in Real Life Conversations. AB - We examined mental time travel reflected onto individuals' utterances in real life conversations using a naturalistic observation method: Electronically Activated Recorder (EAR, a portable audio recorder that periodically and unobtrusively records snippets of ambient sounds and speech). We introduced the term conversational time travel and examined, for the first time, how much individuals talked about their personal past versus personal future in real life. Study 1 included 9,010 sound files collected from 51 American adults who carried the EAR over 1 weekend and were recorded every 9 min for 50 s. Study 2 included 23,103 sound files from 33 young and 48 healthy older adults from Switzerland who carried the EAR for 4 days (2 weekdays and 1 weekend, counterbalanced). 30-s recordings occurred randomly throughout the day. We developed a new coding scheme for conversational time travel: We listened to all sound files and coded each file for whether the participant was talking or not. Those sound files that included participant speech were also coded in terms of their temporal focus (e.g., past, future, present, time-independent) and autobiographical nature (i.e., about the self, about others). We, first, validated our coding scheme using the text analysis tool, Linguistic Inquiry and Word Count. Next, we compared the percentages of past- and future-oriented utterances about the self (to tap onto conversational time travel). Results were consistent across all samples and showed that participants talked about their personal past two to three times as much as their personal future (i.e., retrospective bias). This is in contrast to research showing a prospective bias in thinking behavior, based on self-report and experience-sampling methods. Findings are discussed in relation to the social functions of recalling the personal past (e.g., sharing memories to bond with others, to update each other, to teach, to give advice) and to the directive functions of future-oriented thought (e.g., planning, decision making, goal setting that are more likely to happen privately in the mind). In sum, the retrospective bias in conversational time travel seems to be a functional and universal phenomenon across persons and across real-life situations. PMID- 30483184 TI - The Form of Morphemes: MEG Evidence From Masked Priming of Two Hebrew Templates. AB - Studies of lexical access have benefited from comparisons between languages like English, which shows concatenative morphology, and Semitic languages showing non concatenative morphology of roots and patterns. Morphological decomposition in Semitic has previously been probed using masked priming, originally developed to investigate concatenative morphology. However, studies conducted on Semitic languages have often targeted Semitic-specific questions, such as whether the root and the verbal template prime lexical access. The overall consequence of these studies for our understanding of lexical access remains unclear. In two experiments on Hebrew using MEG, we demonstrate that a verbal form which is orthographically and phonologically indistinguishable from non-verbal forms is primed by other verbs in the same template but not by similar nouns and adjectives. These results suggest that masked priming taps into more than just visual forms but reflects morphological content, even if this content is abstract, showing no distinct orthographic or phonological marking. PMID- 30483187 TI - Application of Asymmetric IRT Modeling to Discrete-Option Multiple-Choice Test Items. AB - Asymmetric IRT models have been shown useful for capturing heterogeneity in the number of latent subprocesses underlying educational test items (Lee and Bolt, 2018a). One potentially useful practical application of such models is toward the scoring of discrete-option multiple-choice (DOMC) items. Under the DOMC format, response options are independently and randomly administered up to the (last) keyed response, and thus the scheduled number of distractor response options to which an examinee may be exposed (and consequently the overall difficulty of the item) can vary. In this paper we demonstrate the applicability of Samejima's logistic positive exponent (LPE) model to response data from an information technology certification test administered using the DOMC format, and discuss its advantages relative to a two-parameter logistic (2PL) model in addressing such effects. Application of the LPE in the context of DOMC items is shown to (1) provide reduced complexity and a superior comparative fit relative to the 2PL, and (2) yield a latent metric with reduced shrinkage at high proficiency levels. The results support the potential use of the LPE as a basis for scoring DOMC items so as to account for effects related to key location. PMID- 30483186 TI - Can Simulated Green Exercise Improve Recovery From Acute Mental Stress? AB - This exploratory study enhances previous research into green exercise and addresses a gap in the research by exploring the contribution of individual and combined senses in the recovery of mood and stress after a psychological stressor, whilst rigorously controlling exercise intensity. The hypotheses were: (i) recovery of mood and stress from a state of psychological stress would be greater following simulated green exercise compared to rest, (ii) green exercise would facilitate better recovery than exercise alone, (iii) these effects would remain 10 min following intervention, and (iv) visual stimuli alone would enhance recovery from a state of psychological stress compared to sound. Fifty participants were randomly assigned to one of five groups: REST, exercise, exercise with nature sounds, exercise with nature visual and exercise with nature sound and visual. An initial visit to obtain predicted peak power output values and to familiarize participants with the equipment being used was followed by a second visit, where participants experienced one test condition. Baseline measures of heart rate, blood pressure, total mood disturbance (TMD), and perceived stress were taken, before participants completed a stressor based on the Trier Social Stress test. Measures of heart rate and blood pressure were recorded in the last 30 s of the stressor to assess efficacy of the stressor. Immediately post stressor, measures of mood and perceived stress were taken followed by the intervention assigned (one of five described above). Measures of mood and perceived stress were taken again immediately post intervention and 10 min post intervention. Results showed that green exercise improved mood and stress scores more than exercise alone or REST. For both TMD and perceived stress, improvements in all simulated nature conditions were significantly improved compared to REST or exercise alone immediately post intervention. There were no significant changes 10 min post intervention in either mood or perceived stress compared to immediately post intervention values in any of the groups. This study suggests that environmental exercise settings including nature sounds, visual or both combined should be considered as important in the use of exercise as a therapeutic activity or recovery from acute psychological stress. PMID- 30483185 TI - Insight and Dissociation in Lucid Dreaming and Psychosis. AB - Dreams and psychosis share several important features regarding symptoms and underlying neurobiology, which is helpful in constructing a testable model of, for example, schizophrenia and delirium. The purpose of the present communication is to discuss two major concepts in dreaming and psychosis that have received much attention in the recent literature: insight and dissociation. Both phenomena are considered functions of higher order consciousness because they involve metacognition in the form of reflective thought and attempted control of negative emotional impact. Insight in dreams is a core criterion for lucid dreams. Lucid dreams are usually accompanied by attempts to control the dream plot and dissociative elements akin to depersonalization and derealization. These concepts are also relevant in psychotic illness. Whereas insightfulness can be considered innocuous in lucid dreaming and even advantageous in psychosis, the concept of dissociation is still unresolved. The present review compares correlates and functions of insight and dissociation in lucid dreaming and psychosis. This is helpful in understanding the two concepts with regard to psychological function as well as neurophysiology. PMID- 30483188 TI - A Daily Diary Study on the Consequences of Networking on Employees' Career Related Outcomes: The Mediating Role of Positive Affect. AB - Although researchers have shown that networking is positively associated with numerous long-term outcomes (e. g., salary, promotion) investigations of proximal outcomes of networking are still scarce. Building on Conservation of Resources theory (COR; Hobfoll, 2001, 2011) and conducting a daily diary study over five consecutive working days (N = 160 academics), we investigated short-term effects of networking on employees' career-related outcomes (i.e., career optimism and career satisfaction), job attitudes (i.e., job satisfaction), and well-being (i.e., emotional exhaustion). Further, we suggested that positive affect would act as a mediator. Results from hierarchical linear modeling (HLM) showed that daily networking relates to all four outcome variables. Moreover, positive affect mediated three of four hypothesized relationships, with a marginally significant effect for career satisfaction. By providing evidence for valuable short-term benefits of networking, our study extends existing research on positive long-term effects (for example on salary, promotions). Findings broaden the scope by integrating networking research with a positive organizational behavior perspective. We discuss practical implications with regard to career intervention strategies, study limitations, and prospects for future research. PMID- 30483189 TI - It Takes Two: The Round-Robin Methodology for Investigative Interviewing Research. AB - Investigative interviews are complex, dyadic, and social interactions typically studied by evaluating interviewers' questioning strategies. In field settings, interviewers naturally vary in their interviewing practice. Thus, it is important to conduct research reflective of idiosyncrasies in witnesses, interviewers, and the resulting unique pairings. This study explored sources of variation in an interview by using a "round-robin" design. Each session of the study involved five witnesses observing five separate events. Witnesses were then simultaneously, but independently interviewed by four different interviewers, or completed a self-administered written interview. This sequence was repeated until each witness had seen every event and had been interviewed by each interviewer. Over nine sessions (N = 45) this produced 225 total interviews. Individual interview performance (accuracy and level of detail) as well as experience (subjective ratings) were then analyzed in relation to the typical performance of the interviewer, the witness, the event, and the unique paring. We found that witnesses and interviewers could have an effect on statement quality; however, the unique interview experience variance had the greatest influence on interview performance. This study presents the round-robin methodology as a useful tool to study realistic variation in interviewer, witness, and dyad behavior. The preprint of this paper is available at psyarxiv.com/tv5gz/, and materials and data are available at osf.io/ef634/files/. PMID- 30483191 TI - Problematic Gaming and Internet Use but Not Gambling May Be Overrepresented in Sexual Minorities - A Pilot Population Web Survey Study. AB - Background: Substance-related addictive disorders are known to be overrepresented in non-heterosexual individuals, but it is largely unknown whether this is also the case for behavioral addictions such as problem gaming and gambling. This study aimed, in a pilot web survey design, to assess whether problematic gambling, gaming and internet use may be more common in individuals with a non heterosexual orientation. Methods: An online survey was distributed through media and social media, and answered by 605 individuals (51% women and 11% non heterosexual). Problem gambling, problem gaming and problematic internet use were measured through structured screening instruments (the CLiP, the GAS and the PRIUSS, respectively). Results: Problem gaming and problematic internet use were significantly more prevalent in non-heterosexual subjects. Instead, problem gambling did not differ between heterosexual and non-heterosexual respondents. Psychological distress and social media use for more than 3 h daily were significantly more common in non-heterosexual respondents. In the overall sample, gaming and gambling were associated statistically. Conclusion: Based on the present pilot online survey, problematic gaming and internet use, but not problem gambling, may be more common in non-heterosexual populations. This area merits more and larger studies, and potentially preventive efforts aimed for non heterosexual individuals in the population. Possible explanations and study limitations are discussed in the paper. PMID- 30483190 TI - Variability of the Prevalence of Depression in Function of Sociodemographic and Environmental Factors: Ecological Model. AB - Major depression etiopathogenesis is related to a wide variety of genetics, demographic and psychosocial factors, as well as to environmental factors. The objective of this study is to analyze sociodemographic and environmental variables that are related to the prevalence of depression through correlation analysis and to develop a regression model that explains the behavior of this disease from an ecological perspective. This is an ecological, retrospective, cross-sectional study. The target population was 1,148,430 individuals over the age of 16 who were registered in Aragon (Spain) during 2010, with electronic medical records in the community's primary health care centers. The spatial unit was the Basic Health Area (BHA). The dependent variable was the diagnosis of Depression and the ecological independent variables were: Demographic variables (gender and age), population distribution, typology of the entity, population structure by sex and age, by nationality, by education, by work, by salary, by marital status, structure of the household by number of members, and state of the buildings. The results show moderate and positive correlations with higher rates of depression in areas having a higher femininity index, higher population density, areas with a higher unemployment rate and higher average salary. The results of the linear regression show that aging +75 and rural entities act as protective factors for depression, while urban areas and deficient buildings act as risk factors. In conclusion, the ecological methodology may be a useful tool which, together with the statistical epidemiological analysis, can help in the political decision making process. PMID- 30483192 TI - Concise, Simple, and Not Wrong: In Search of a Short-Hand Interpretation of Statistical Significance. AB - One challenge when communicating science to practitioners and the general public is accurately representing statistical results. In particular, describing the meaning of statistical significance to a non-scientific audience is especially difficult given the technical nature of a correct definition. Correct interpretations of statistical significance can be unintuitive, nuanced, and use unfamiliar technical language. As a result, when researchers are tasked with providing short and understandable interpretations of statistical significance it can be tempting to default to convenient but incorrect interpretations. In the current paper, we offer a concise, simple, and correct interpretation of statistical significance that is suitable for communications targeting a general audience. PMID- 30483193 TI - The Changing Educators' Work Environment in Contemporary Society. AB - In this paper, we are going to address job satisfaction and perceived self efficacy withinthe context of residential child-care. A joint report from the European Foundation for the Improvement on Living and Working Conditions and the European Agency for Safety and Health at Work revealed that managers in the field of health and education were the most concerned about the psychosocial risk of their employees, although concern is not automatically translated into tools to face the risk and to manage it. So, measuring and improving employees' job satisfaction and self-efficacy can be an important means for organizations to prevent the outcomes of psychosocial risk, and supporting high quality performance of workers. But profound changes are affecting the nature of work at large, and specifically social educator's in the field of residential care with minors. Globalization, radical technological and communication developments, as well as the pressure to frame care as a commodity, are quickly changing procedures and praxis at work, and even the meaning of job itself. All these changes are highly demanding for this category of professionals, as much as the fact that the organizational setting is vanishing as a resource to sustain their professional attitudes and behaviors. Under these circumstances, job satisfaction and self-efficacy can be hard to experience, and isolating their precursors is essential to develop healthy and effective work environments. This paper means to highlight the process of supporting self-efficacy and job satisfaction in the educational work in residential youth care that is still underrepresented in research. It presents data emerging from two studies, study 1 involving 268 educators and study 2 involving 472 educators belonging to different Italian residential child-care services. Study 1 consists of a quantitative study including the following measures: attachment style, job satisfaction, work related self-efficacy, and length of service. Study 2 consist of a qualitative exploration deepening the sources of educators' work-satisfaction. Quantitative data support the identification of attachment style and length of service as antecedents of work-related self-efficacy and job satisfaction. Qualitative data show the importance of relational issues in shaping the educators' satisfaction at work. PMID- 30483194 TI - Parenting Styles and Parent-Adolescent Relationships: The Mediating Roles of Behavioral Autonomy and Parental Authority. AB - The parent-adolescent relationship has been a classic research topic, and researchers have found that parenting styles (e.g., authoritative, authoritarian) are closely related to various qualities of parent-adolescent relationships (e.g., cohesion, conflict). However, little empirical work has addressed how these variables correlate with each other in mainland China, nor has prior research addressed internal psychological mechanisms. The present study investigated the associations between parenting styles and parent-adolescent relationship factors, examined the mediating effects of adolescents' expectations of behavioral autonomy and beliefs about parental authority, and explored whether adolescent gender moderated these effects. Results from a sample of 633 Chinese adolescents (7th grade: M age = 13.50 +/- 0.62 years, 9th grade: M age = 15.45 +/ 0.67 years, 11th grade: M age = 17.30 +/- 0.75 years) suggested similar levels of parent-adolescent conflict frequency for all parenting styles. However, for parent-adolescent conflict intensity, youth of neglectful and authoritarian parents reported higher levels compared to those with indulgent parents. The highest levels of cohesion with both parents were reported by adolescents with authoritative parents, followed by indulgent, authoritarian and neglect parenting styles. Cohesion with mothers for youth with authoritative or indulgent mothers was higher for girls than boys. Adolescents' expectation for behavioral autonomy mediated the links between parenting style and conflict, whereas adolescents' beliefs about the legitimacy of parental authority mediated the links between parenting style and cohesion; some of these mediating effects differed by gender. Findings highlight the importance of studying potential effects of adolescents' values and attitudes within the family system in specific cultural contexts. PMID- 30483195 TI - Exogenous Testosterone Increases Decoy Effect in Healthy Males. AB - There is increasing interest in the role played by testosterone in economic decision-making and social cognition. However, despite the growing body of findings in this field of research, no empirical study to date has tested whether testosterone modulates decision-making when an asymmetrically dominated decoy option is introduced in a choice set. Within a choice set that comprises two options, an asymmetrically dominated decoy option is a third option that, when introduced in the choice set, is much worse than one of the existing options, but comparable to the other existing option. Introduction of a decoy option leads to a preference toward the dominating option (i.e., decoy effect). Healthy male participants (n = 63) received a single-dose of 150 mg testosterone gel in a double-blind, placebo-controlled, between-subjects design. At 180 min post administration, participants took part in a decision-making task to elicit decoy effect. Results showed that participants in the testosterone group made less consistent choices and more target choices (i.e., decoy effect) than participants in the placebo group. These findings are interpreted in light of the dual-process theory and are in line with existing evidence suggesting that testosterone promotes more intuitive and automatic judgments in human decision-making. PMID- 30483196 TI - Why Can't We Accurately Predict Others' Decisions? Prediction Discrepancy in Risky Decision-Making. AB - Individuals often fail to accurately predict others' decisions in a risky environment. In this paper, we investigate the characteristics and causes of this prediction discrepancy. Participants completed a risky decision-making task mixed with different domains (gain vs. loss) and probabilities (small vs. large), with some participants making decisions for themselves (the actor) and the others predicting the actors' decisions (the predictor). The results demonstrated a prediction discrepancy: predictions were more risk-averse than the actual decisions over small-probability gains and more risk-seeking over large probability gains, while these patterns were reversed in the loss domain. Reported and predicted levels of emotional stimulation revealed a pattern that is consistent with the notion of risk-as-feelings and empathy gaps. Mediation analysis provided strong evidence that such prediction discrepancy is driven mainly by the predictor's underestimate of the intensity (not the impact) of the actor's emotional state. PMID- 30483197 TI - Theory of Mind and Sociometric Peer Status: The Mediating Role of Social Conduct. AB - The present study aimed at investigating the mediating role of social conduct in the relation between theory of mind (ToM) and sociometric peer status. One hundred and seventy-seven 8- to 11-year-olds filled out a battery encompassing advanced ToM skill, verbal ability and sociometric peer status, expressed in terms of social preference and social impact. A questionnaire on students' externalizing, internalizing and prosocial behaviors was administered to teachers. Only externalizing behavior mediated the link between ToM and social impact, controlling for age, gender, and verbal ability. Implications and suggestions for future research were discussed. PMID- 30483198 TI - Let's Chat: On-Screen Social Responsiveness Is Not Sufficient to Support Toddlers' Word Learning From Video. AB - Joint engagement with a speaker is one cue children may use to establish that an interaction is relevant to them and worthy of attention. People on pre-recorded video cannot engage contingently with a viewer in shared experiences, possibly leading to deficits in learning from video relative to learning from responsive face-to-face encounters. One hundred and thirty two toddlers (24 and 30 months old) were offered referential social cues disambiguating a novel word's meaning in one of four conditions: responsive live (a speaker was present and engaged with children); unresponsive video (a speaker on video looked at the camera and smiled at scripted times); unresponsive live (although present, the speaker behaved as she did on the unresponsive video), and responsive video (a speaker on closed-circuit video engaged with children, as in video chat). Children of both ages reliably learned the word in the responsive live condition, and older children (30 months) learned in the unresponsive live condition. Neither group learned in the responsive or unresponsive video conditions. The results show that the addition of communicative social cues to the video presentation via video chat was not sufficient to support learning in this case. Rather, toddlers' transfer and generalization of words presented on video chat may depend on other contextual factors, such as co-viewers who scaffold their learning. Live, responsive video as implemented in this and prior studies is compared, with implications for the use of video chat via the Internet with young children. PMID- 30483199 TI - Visual Perspectives in Episodic Memory and the Sense of Self. AB - The connection between memory and self-consciousness has been a central topic in philosophy of memory. When remembering an event we experienced in the past, not only do we experience being the subject of the conscious episode, but we also experience being the protagonist in the memory scene. This is the "phenomenal presence of self." To explore this special sense of self in memory, this paper focuses on the issue of how one identifies oneself in episodic simulation at the retrieval of memory and draws attention to the field and observer perspectives in episodic memory. Metzinger (2013a,b, 2017) recently introduced the concept of the phenomenal unit of identification (UI) to characterize the phenomenal property that gives rise to the conscious experience of "I am this." This paper shows how observer-perspective remembering provides an interesting opportunity for studying the sense of self. It is argued that observer-perspective remembering is a stable state of consciousness that is distinct from autoscopic phenomena with respect to the dimensions of minimal phenomenal self (MPS). Together, the notion of UI and the particular style of remembering offer a way of understanding the phenomenal presence of self, and three possible ways in which phenomenal properties constitute UI in memory are raised. The study of perspectives in episodic simulation may prompt new empirical and conceptual issues concerning both the sense of identity and the relationship between MPS and extended self. PMID- 30483200 TI - Independent Mobility and Social Affordances of Places for Urban Neighborhoods: A Youth-Friendly Perspective. AB - Meaning of place is usually approached as slow social cognitive construction. However, grounded on the theory of affordances, it may also stem from direct perception-action processes, which enable the formation of immediate perceived functional, social or symbolic meaning of place (Raymond et al., 2017b). In the present study, affordances of places, which are perceived by a specific perceiver in a specific place, were mapped using a web-map survey. Each place offers opportunities for interaction, behavior, use, feeling or meaning, which is directly perceived and actualized there. This paper aims at identifying the degree of youth-friendliness of urban neighborhoods using the hypothetical intertwined model of independent mobility and actualized affordances (Kytta, 2004) combined with place use and meaning (Broberg et al., 2013a). SoftGISchildren methodology (Broberg et al., 2013a) was adopted to carry out a cross-sectional research, involving 145 sixth to ninth graders of the Great Lisbon area. SoftGIS integrates Public Participation Geographic Information Systems (PPGIS), enabling collection and place mapping of daily subjective environmental experiences in the physical environment, consequently allowing for individuals to be actively engaged in public processes of participation (Brown and Kytta, 2014). A place based web survey called "Ideal City: a game of graphic imagination" was adopted. Participants were asked to map their home place, select and mark social, functional, leisure and emotional place transactions, and report actual and ideal mobility to these places. Findings on mobility showed that shorter distances to meaningful affordances of places promote active and independent travel; ideally, youths would like to be more frequently active and more frequently autonomous. As for meaningful places, a total of 1632 affordances were localized, with a higher number on social category. Neighborhood area (500 m around home place) was assessed as youth-friendly, where active and independent travel occurred more frequently, and social affordances were the most expressive type. Relational and affectional experience in the neighborhood places was meaningful for youth. Municipalities should consider these features when planning, designing and managing residential areas aiming for the well-being and health of young citizens; and include youths as specialists of space (spatialists) in planning participatory processes (PPGIS). PMID- 30483201 TI - Hemispheric Asymmetries in Radial Line Bisection: Role of Retinotopic and Spatiotopic Factors. AB - Previous studies showed that healthy individuals bisect radial lines oriented along the midsagittal plane farther than the true center (distal bisection bias). It was proposed that the distal bisection bias depended on the presence of an attention bias directed toward far space (distal attention bias) and that this bias is related to the activity of the occipitotemporal visual processing stream. Other studies have also suggested that a similar distal attention bias is linked to the activity of the right hemisphere. In the present experiment we investigated whether distal bisection bias increased when radial lines were placed in the left hemispace. Furthermore, we also examined whether the bisection bias was enhanced by the use of the left hand, as left hand movements are mainly controlled by the right hemisphere. Right-handed participants were asked to bisect radial lines presented below eye level along the midsagittal plane (central lines), or laterally and parallel to the midsagittal plane, in the left or right hemispace (left and right lines, respectively). Participants used their right or left hand. The results showed that participants consistently bisected left and central radial lines farther than (i) the true center and (ii) the subjective midpoint of right radial lines. Conversely, they bisected accurately right radial lines. The hand did not influence bisection error. The present study suggests that the distal bisection bias found in the bisection of left radial lines might depend on the presence of a distal attention bias related to right hemisphere activity. The relative contribution of retinotopic and spatiotopic factors in producing the distal bisection bias is discussed. PMID- 30483202 TI - A Dual Route Model of Empathy: A Neurobiological Prospective. PMID- 30483203 TI - Different Strokes for Different Folks: The BodyMind Approach as a Learning Tool for Patients With Medically Unexplained Symptoms to Self-Manage. AB - Medically unexplained symptoms (MUS) are common and costly in both primary and secondary health care. It is gradually being acknowledged that there needs to be a variety of interventions for patients with MUS to meet the needs of different groups of patients with such chronic long-term symptoms. The proposed intervention described herewith is called The BodyMind Approach (TBMA) and promotes learning for self-management through establishing a dynamic and continuous process of emotional self-regulation. The problem is the mismatch between the patient's mind-set and profile and current interventions. This theoretical article, based on practice-based evidence, takes forward the idea that different approaches (other than cognitive behavioural therapy) are required for people with MUS. The mind-set and characteristics of patients with MUS are reflected upon to shape the rationale and design of this novel approach. Improving services for this population in primary care is crucial to prevent the iterative spiraling downward of frequent general practitioner (GP) visits, hospital appointments, and accident and emergency attendance (A&E), all of which are common for these patients. The approach derives from embodied psychotherapy (authentic movement in dance movement psychotherapy) and adult models of learning for self-management. It has been developed from research and practice-based evidence. In this article the problem of MUS in primary care is introduced and the importance of the reluctance of patients to accept a psychological/mental health referral in the first instance is drawn out. A description of the theoretical underpinnings and philosophy of the proposed alternative to current interventions is then presented related to the design, delivery, facilitation, and educational content of the program. The unique intervention is also described to give the reader a flavor. PMID- 30483205 TI - Association Between Serum Vitamin D Levels and Parkinson's Disease: A Systematic Review and Meta-Analysis. AB - Background: Vitamin D is an important secosteroid which is involved the development and regulation of brain activity. Several studies have focused on exploring the relationship between serum vitamin D levels and Parkinson's disease (PD), but the conclusion remains ambiguous. Methods: We searched observational studies that explored the association between serum vitamin D levels and PD based on PubMed, EMBASE and Cochrane library from inception through to January 2018. The quality of included studies was evaluated by using Newcastle-Ottawa Scale (NOS). Statistical analysis of this meta-analysis was performed by Stata version 12.0 and R software. Results: Twenty studies with a total of 2,866 PD patients and 2,734 controls were included. Compared with controls, PD patients had lower serum vitamin D levels (WMD -3.96, 95%CI -5.00, -2.92), especially in higher latitude regions (WMD -4.20, 95%CI -5.66, -2.75). Assay methods contributed significantly to high heterogeneity. Furthermore, PD patients with deficient vitamin D levels had advanced risk (OR 2.08, 95%CI 1.35, 3.19) than those patients with insufficient ones (OR = 1.73, 95%CI 1.48, 2.03). In addition, serum vitamin D levels were also related to the severity of PD (WMD -5.27, 95%CI -8.14, -2.39) and the summary correlation coefficient showed strongly negative correlation (r = -0.55, 95%CI -0.73, -0.29). Moreover, the pooled correlation coefficient revealed that serum vitamin D levels were also negatively correlated to the Unified Parkinson's Disease Rating Scale III (UPDRS III) (r = -0.36, 95%CI -0.53, -0.16), but did not correlate with the duration of PD (P = 0.37) and age of patients (P = 0.49). Conclusion: Serum vitamin D levels are inversely associated with the risk and severity of PD. Our results provided an updated evidence of association between low vitamin D levels and PD and prompt the adjunctive therapeutic decisions about vitamin D replacement in PD. PMID- 30483204 TI - Determining the Quantitative Threshold of High-Frequency Oscillation Distribution to Delineate the Epileptogenic Zone by Automated Detection. AB - Objective: We proposed an improved automated high frequency oscillations (HFOs) detector that could not only be applied to various intracranial electrodes, but also automatically remove false HFOs caused by high-pass filtering. We proposed a continuous resection ratio of high order HFO channels and compared this ratio with each patient's post-surgical outcome, to determine the quantitative threshold of HFO distribution to delineate the epileptogenic zone (EZ). Methods: We enrolled a total of 43 patients diagnosed with refractory epilepsy. The patients were used to optimize the parameters for SEEG electrodes, to test the algorithm for identifying false HFOs, and to calculate the continuous resection ratio of high order HFO channels. The ratio can be used to determine a quantitative threshold to locate the epileptogenic zone. Results: Following optimization, the sensitivity, and specificity of our detector were 66.84 and 73.20% (ripples) and 69.76 and 66.13% (fast ripples, FRs), respectively. The sensitivity and specificity of our algorithm for removing false HFOs were 76.82 and 94.54% (ripples) and 72.55 and 94.87% (FRs), respectively. The median of the continuous resection ratio of high order HFO channels in patients with good surgical outcomes, was significantly higher than in patients with poor outcome, for both ripples and FRs (P < 0.05 ripples and P < 0.001 FRs). Conclusions: Our automated detector has the advantage of not only applying to various intracranial electrodes but also removing false HFOs. Based on the continuous resection ratio of high order HFO channels, we can set the quantitative threshold for locating epileptogenic zones. PMID- 30483206 TI - No Gain No Pain: Relations Between Vestibulo-Ocular Reflexes and Motion Sickness in Mice. AB - Motion sickness occurs when the vestibular system is subjected to conflicting sensory information or overstimulation. Despite the lack of knowledge about the actual underlying mechanisms, several drugs, among which scopolamine, are known to prevent or alleviate the symptoms. Here, we aim at better understanding how motion sickness affects the vestibular system, as well as how scopolamine prevents motion sickness at the behavioral and cellular levels. We induced motion sickness in adult mice and tested the vestibulo-ocular responses to specific stimulations of the semi-circular canals and of the otoliths, with or without scopolamine, as well as the effects of scopolamine and muscarine on central vestibular neurons recorded on brainstem slices. We found that both motion sickness and scopolamine decrease the efficacy of the vestibulo-ocular reflexes and propose that this decrease in efficacy might be a protective mechanism to prevent later occurrences of motion sickness. To test this hypothesis, we used a behavioral paradigm based on visuo-vestibular interactions which reduces the efficacy of the vestibulo-ocular reflexes. This paradigm also offers protection against motion sickness, without requiring any drug. At the cellular level, we find that depending on the neuron, scopolamine can have opposite effects on the polarization level and firing frequency, indicating the presence of at least two types of muscarinic receptors in the medial vestibular nucleus. The present results set the basis for future studies of motion sickness counter-measures in the mouse model and offers translational perspectives for improving the treatment of affected patients. PMID- 30483207 TI - Blood-Brain Barrier Dysfunction in Small Vessel Disease Related Intracerebral Hemorrhage. AB - Background and Purpose: Hypertensive vasculopathy and cerebral amyloid angiopathy are the two most common forms of cerebral small vessel disease. Both forms are associated with the development of primary intracerebral hemorrhage, but the pathophysiological mechanisms underlying spontaneous vessel rupture remain unknown. This work constitutes a systematic review on blood-brain barrier dysfunction in the etiology of spontaneous intracerebral hemorrhage due to cerebral small vessel disease. Methods: We searched Medline (1946-2018) and Embase (1974-2018) for animal and human studies reporting on blood-brain barrier dysfunction associated with intracerebral hemorrhage or cerebral microbleeds. Results: Of 26 eligible studies, 10 were animal studies and 16 were in humans. The authors found indications for blood-brain barrier dysfunction in all four animal studies addressing hypertensive vasculopathy-related intracerebral hemorrhage (n = 32 hypertensive animals included in all four studies combined), and in four of six studies on cerebral amyloid angiopathy-related intracerebral hemorrhage (n = 47). Of the studies in humans, five of six studies in patients with cerebral amyloid angiopathy-related intracerebral hemorrhage (n = 117) and seven out of nine studies examining intracerebral hemorrhage with mixed or unspecified underlying etiology (n = 489) found indications for blood-brain barrier dysfunction. One post-mortem study in hypertensive vasculopathy-related intracerebral hemorrhage (n = 82) found no evidence for blood-brain barrier abnormalities. Conclusions: Signs of blood-brain barrier dysfunction were found in 20 out of 26 studies. Blood-brain barrier integrity deserves further investigation with a view to identification of potential treatment targets for spontaneous intracerebral hemorrhage. PMID- 30483208 TI - Examination of Current Treatments and Symptom Management Strategies Used by Patients With Mal De Debarquement Syndrome. AB - Introduction: Mal de Debarquement Syndrome (MdDS) is a neurological disorder which affects the vestibular system pathways, manifesting as a constant sensation of movement in the form of rocking, bobbing, or swaying. The mechanism of MdDS is poorly understood and there is a lack of awareness amongst medical professionals about the condition. This study aimed to examine treatments and symptom management strategies used by MdDS patients and evaluate their self-reported effectiveness. Method: Motion-Triggered and Spontaneous/Other onset MdDS patients responded to a set of comprehensive questions as a retrospective survey regarding epidemiological details, diagnostic procedures, onset, and symptom triggers, hormonal influences as well as treatments and symptom management strategies used to reduce symptoms. The Motion-Triggered questionnaire was made available through Survey Monkey and the Spontaneous/Other Onset questionnaire through Qualtrics. The link for each questionnaire was made available on online MdDS support groups and on various research websites. Descriptive statistics were used for epidemiological data and Pearson's Chi Square tests were used for comparisons between and within both subtype groups. Results: A total of 370 patients participated in the surveys, with 287 valid responses collected for the section regarding treatment and symptom management strategies. The success of the treatments and symptom management strategies did not vary between subtypes Benzodiazepines/Antidepressants were reported as being most beneficial in reducing symptoms in both groups. Conclusion: This was the first attempt to evaluate the reported success of treatments and symptom management strategies in MdDS patients by assessing the patients' perceived helpfulness. The treatments and symptom management strategies reported to be the most helpful in managing and/or reducing symptoms are proposed to be effective due to their stress reducing capacities. We hope this study will broaden MdDS awareness and that this study will increase patient knowledge regarding treatments and symptom management strategies that other patients found helpful. PMID- 30483210 TI - Macroscale White Matter Alterations Due to Traumatic Cerebral Microhemorrhages Are Revealed by Diffusion Tensor Imaging. AB - With the advent of susceptibility-weighted imaging (SWI), the ability to identify cerebral microbleeds (CMBs) associated with mild traumatic brain injury (mTBI) has become increasingly commonplace. Nevertheless, the clinical significance of post-traumatic CMBs remains controversial partly because it is unclear whether mTBI-related CMBs entail brain circuitry disruptions which, although structurally subtle, are functionally significant. This study combines magnetic resonance and diffusion tensor imaging (MRI and DTI) to map white matter (WM) circuitry differences across 6 months in 26 healthy control volunteers and in 26 older mTBI victims with acute CMBs of traumatic etiology. Six months post-mTBI, significant changes (p < 0.001) in the mean fractional anisotropy of perilesional WM bundles were identified in 21 volunteers, and an average of 47% (sigma = 21%) of TBI related CMBs were associated with such changes. These results suggest that CMBs can be associated with lasting changes in perilesional WM properties, even relatively far from CMB locations. Future strategies for mTBI care will likely rely on the ability to assess how subtle circuitry changes impact neural/cognitive function. Thus, assessing CMB effects upon the structural connectome can play a useful role when studying CMB sequelae and their potential impact upon the clinical outcome of individuals with concussion. PMID- 30483211 TI - The Accumulation of Key Stroke Risk Factors and Its Association With the Characteristics of Subjects: A Population Based Cross Sectional Study. AB - Background: Evidence has shown that the greater the accumulation of risk factors for stroke, the greater the risk of stroke. Early intervention in the accumulation of risk factors for stroke can effectively reduce the incidence of stroke. The study aimed to investigate the distribution of the number of certain risk factors for stroke (hypertension, hyperlipidemia, overweight and obesity, and diabetes) and to explore the cause of the accumulation of certain stroke risk factors. Methods: A total of 4,052 participants aged 40 years or older were selected by the multistage stratified cluster sampling method in Dehui City in Jilin province, China. Descriptive data analyses were conducted. Multiple regression analyses were used to explore the adjusted association between the accumulation of key stroke risk factors and subjects' lifestyle and demographic characteristics. Results: Overall, 84.1% of the participants in this study had one or more of the four certain risk factors for stroke. The odds ratios (ORs) and 95% confidence intervals (CIs) of having >=1, >=2, and >=3 key stroke risk factors were 1.627 (1.258, 2.103), 1.446 (1.209, 1.728), and 1.394 (1.164, 1.670), respectively, for males compared to females. Similarly, the ORs and 95% CIs of having >=1, >=2, and >=3 key stroke risk factors were 1.227 (1.009, 1.492), 1.256 (1.096, 1.442), and 1.450 (1.262, 1.667), respectively, for partially salty diets compared to normal diets. Compared to people who did not exercise regularly, the ORs and 95% CIs of having >=1, >=2, and >=3 key stroke risk factors were 0.693 (0.544, 0.883), 0.800 (0.679, 0.944), and 0.775 (0.659, 0.913), respectively, for people who regularly exercised. Compared to people who without a family history of cerebrovascular diseases, the ORs and 95% CIs were 1.418 (1.162, 1.732), 1.327 (1.154, 1.525), and 1.209 (1.050, 1.393), for people who with it. Conclusions: Male, partially salty diets, and family history of cerebrovascular diseases were risk factors for the accumulation of certain stroke risk factors while regular physical exercise was a protective factor. PMID- 30483209 TI - Potential Mechanisms of Sensory Augmentation Systems on Human Balance Control. AB - Numerous studies have demonstrated the real-time use of visual, vibrotactile, auditory, and multimodal sensory augmentation technologies for reducing postural sway during static tasks and improving balance during dynamic tasks. The mechanism by which sensory augmentation information is processed and used by the CNS is not well understood. The dominant hypothesis, which has not been supported by rigorous experimental evidence, posits that observed reductions in postural sway are due to sensory reweighting: feedback of body motion provides the CNS with a correlate to the inputs from its intact sensory channels (e.g., vision, proprioception), so individuals receiving sensory augmentation learn to increasingly depend on these intact systems. Other possible mechanisms for observed postural sway reductions include: cognition (processing of sensory augmentation information is solely cognitive with no selective adjustment of sensory weights by the CNS), "sixth" sense (CNS interprets sensory augmentation information as a new and distinct sensory channel), context-specific adaptation (new sensorimotor program is developed through repeated interaction with the device and accessible only when the device is used), and combined volitional and non-volitional responses. This critical review summarizes the reported sensory augmentation findings spanning postural control models, clinical rehabilitation, laboratory-based real-time usage, and neuroimaging to critically evaluate each of the aforementioned mechanistic theories. Cognition and sensory re-weighting are identified as two mechanisms supported by the existing literature. PMID- 30483212 TI - Axonal Degeneration of the Vagus Nerve in Parkinson's Disease-A High-Resolution Ultrasound Study. AB - Background: Recent histopathological studies revealed degeneration of the dorsal motor nucleus early in the course of Parkinson's disease (PD). Degeneration of the vagus nerve (VN) axons following neurodegeneration of brainstem vagal nuclei should be detectable by high-resolution ultrasound (HRUS) as a thinning of the VNs. Methods: We measured both VNs cross-sectional area (VN-CSA) of 35 patients with PD and 35 age- and sex-matched healthy controls at the level of the thyroid gland using HRUS. Results: On both sides, the VN-CSA was significantly smaller in PD patients than in controls (right: 2.1 +/- 0.4 vs. 2.3 +/- 0.5 mm2, left 1.5 +/ 0.4 vs. 1.8 +/- 0.4 mm2; both p < 0.05). There was no correlation between the right or left VN-CSA and age, the Hoehn & Yahr stage, disease duration, the motor part of the Unified Parkinson's Disease Rating Scale score, the Montreal Cognitive Assessment score, or the Non-motor Symptoms Questionnaire, and Scale for Parkinson's disease score including its gastrointestinal domain. Conclusions: These findings provide evidencethat atrophy of the VNs in PD patients can be detected in-vivo by HRUS. PMID- 30483213 TI - High Low-Density Lipoprotein Cholesterol Inversely Relates to Dementia in Community-Dwelling Older Adults: The Shanghai Aging Study. AB - Background: The relationship between cholesterol and cognitive function is unclear from the previous studies. This study was conducted to explore this association in older Chinese adults. Methods: Data were from the Shanghai Aging Study, comprising 3,836 residents aged 50 years or over in an urban community. Diagnoses of dementia and mild cognitive impairment were established according to the fourth edition of diagnostic and statistical manual of mental disorders (DSM IV) and Petersen criteria. Multivariate logistic regression models, non-matched and propensity score (PS) matched, were used to examine the association between cholesterol levels and cognitive function. Results: There was a significantly higher proportion of participants with low levels of total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) in the dementia group than in groups without dementia (P < 0.05). High LDL-C level was inversely associated with dementia, with a negative trend in the PS matched model. TC and high density lipoprotein cholesterol (HDL-C) were not significantly related to dementia in either non-matched models or PS matched models. Conclusion: Our result indicates that high level of LDL-C is inversely associated with dementia. High level of LDL C may be considered as a potential protective factor against cognition decline. PMID- 30483214 TI - Neurologists' Assessment of Mental Comorbidity in Patients With Vertigo and Dizziness in Routine Clinical Care-Comparison With a Structured Clinical Interview. AB - Background: Mental health comorbidities are frequent in patients with vertigo and dizziness. The current study was conducted in a specialized interdisciplinary university center for vertigo and dizziness. Clinical routines consist of a structured work-up in which neuro-otological and neurological tests are performed to first detect possible organic vestibular deficits. In addition, psychiatric disorders and comorbidities are considered. The study aimed to evaluate neurologists' awareness of psychiatric next to somatic disorders within patients' first examination in terms of diagnostic congruence between neurologists' diagnoses and structured clinical assessment of mental disorders. Methods: The study involved 392 patients. Diagnostic evaluation included (a) structured history-taking (including psychosocial anamnesis), neurological, and neuro otological diagnostics conducted by neurologists and (b) a structured clinical interview for mental disorders (SCID-I) conducted by psychologists and final-year medical or psychology students. Cohen's Kappa was calculated to determine agreement rates regarding depression and anxiety disorders; additionally, sensitivity and specificity were evaluated. Results: Neurologists' assessments led to at least one psychiatric diagnosis among the main diagnoses in 40 (10.2 %) patients, whereas the structured clinical interview led to at least one DSM-IV psychiatric diagnosis in 174 (44.4%) of the patients. Agreement was low (kappa < 0.2); sensitivity was low (15%) but specificity was high (98%). Conclusions: Agreement between the diagnosis of neurologists and structured clinical interviews for psychiatric disorders is low. Since psychiatric disorders are frequent in vertigo and dizziness and tend to take a chronic course, improving early recognition and implementing appropriate care concepts is vital. PMID- 30483215 TI - Inverse Association Between Metabolic Syndrome and Altitude: A Cross-Sectional Study in an Adult Population of Ecuador. AB - Background: Metabolic syndrome (MetS) is characterized by the clustering of hyperglycemia, hypertension, hypertriglyceridemia, low high-density lipoprotein cholesterol levels and central adiposity. Altitude has been proposed as a protective factor to prevent the development of MetS and its components. Aim: To determine whether living at geographical elevation is associated with MetS and its individual components after adjustment for potential confounders in an Ecuadoran population. Methods: The study included 260 Ecuadoran university graduates over 20 years of age, from the coastal or the Andean Altiplano region. The altitude of residence was imputed with the postal code of each participant residence according to the data of the Ecuadoran Geophysical Institute of the National Polytechnic School. MetS was defined according to the harmonizing definition. Logistic regression models were fitted to assess the relationship between altitude level and the prevalence of MetS and its individual components. To test the internal validity, re-sampling techniques were used (1,000 bootstrap samples). Results: Living at high altitude was associated with less hypercholesterolemia (OR = 0.24; p < 0.001), hyperglycemia (OR = 0.25; p < 0.05) and MetS (OR = 0.24; p < 0.05), after adjusting for potential confounders. At high altitude the bootstrapped logistic regression models showed lower prevalence of hypercholesterolemia (OR = 0.30; p < 0.05), hyperglycemia (OR = 0.22; p < 0.001) and MetS (OR = 0.28; p < 0.05). The MetS score (0-5 points) showed a reduction in the number of MetS components at high altitude compared to sea level (B = -0.34; p = 0.002). A statistically significant lower self-reported energy intake was found in high altitude compared to sea level after adjustment for potential confounders (p < 0.001). Conclusion: In the present study concerning a small Ecuadoran population composed of highly educated adults living at the coast and the Andean Altiplano, living at high altitude (2,758-2,787 m) was associated with a lower prevalence of MetS, hypercholesterolemia and hyperglycemia, compared to the participants at sea level (4-6 m). In addition, an inverse association between altitude and self-reported energy intake was found after adjusting for covariates, suggesting a physiological role of appetite at high altitude even in acclimated subjects. PMID- 30483216 TI - Hypothalamus-Pituitary-Adrenal Dysfunction in Cholestatic Liver Disease. AB - The Hypothalamic-Pituitary-Adrenal (HPA) axis has an important role in maintaining the physiological homeostasis in relation to external and internal stimuli. The HPA axis dysfunctions were extensively studied in neuroendocrine disorders such as depression and chronic fatigue syndrome but less so in hepatic cholestasis, cirrhosis or other liver diseases. The HPA axis controls many functions of the liver through neuroendocrine forward signaling pathways as well as negative feedback mechanisms, in health and disease. This review describes cell and molecular mechanisms of liver and HPA axis physiology and pathology. Evidence is presented from clinical and experimental model studies, demonstrating that dysfunctions of HPA axis are correlated with liver cholestatic disorders. The functional interactions of HPA axis with the liver and immune system in cases of bacterial and viral infections are also discussed. Proinflammatory cytokines stimulate glucocorticoid (GC) release by adrenals but they also inhibit bile acid (BA) efflux from liver. Chronic hepatic inflammation leads to cholestasis and impaired GC metabolism in the liver, so that HPA axis becomes depressed. Recently discovered interactions of GC with self-oscillating transcription factors that generate circadian rhythms of gene expression in brain and liver, in the context of GC replacement therapies, are also outlined. PMID- 30483217 TI - How to Contribute to the Progress of Neuroendocrinology: Discovery of GnIH and Progress of GnIH Research. AB - It is essential to discover novel neuropeptides that regulate the functions of pituitary, brain and peripheral secretory glands for the progress of neuroendocrinology. Gonadotropin-releasing hormone (GnRH), a hypothalamic neuropeptide stimulating gonadotropin release was isolated and its structure was determined by Schally's and Guillemin's groups at the beginning of the 1970s. It was subsequently shown that GnRH is highly conserved among vertebrates. GnRH was assumed the sole hypothalamic neuropeptide that regulates gonadotropin release in vertebrates based on extensive studies of GnRH over the following three decades. However, in 2000, Tsutsui's group isolated and determined the structure of a novel hypothalamic neuropeptide, which inhibits gonadotropin release, in quail, an avian species, and named it gonadotropin-inhibitory hormone (GnIH). Following studies by Tsutsui's group demonstrated that GnIH is highly conserved among vertebrates, from humans to agnathans, and acts as a key neuropeptide inhibiting reproduction. Intensive research on GnIH demonstrated that GnIH inhibits gonadotropin synthesis and release by acting on gonadotropes and GnRH neurons via GPR147 in birds and mammals. Fish GnIH also regulates gonadotropin release according to its reproductive condition, indicating the conserved role of GnIH in the regulation of the hypothalamic-pituitary-gonadal (HPG) axis in vertebrates. Therefore, we can now say that GnRH is not the only hypothalamic neuropeptide controlling vertebrate reproduction. In addition, recent studies by Tsutsui's group demonstrated that GnIH acts in the brain to regulate behaviors, including reproductive behavior. The 18 years of GnIH research with leading laboratories in the world have significantly advanced our knowledge of the neuroendocrine control mechanism of reproductive physiology and behavior as well as interactions of the HPG, hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes. This review describes how GnIH was discovered and GnIH research progressed in this new research era of reproductive neuroendocrinology. PMID- 30483220 TI - Differentiated Mechanisms of Biochar Mitigating Straw-Induced Greenhouse Gas Emissions in Two Contrasting Paddy Soils. AB - Straw returns to the soil is an effective way to improve soil organic carbon and reduce air pollution by straw burning, but this may increase CH4 and N2O emissions risks in paddy soils. Biochar has been used as a soil amendment to improve soil fertility and mitigate CH4 and N2O emissions. However, little is known about their interactive effect on CH4 and N2O emissions and the underlying microbial mechanisms. In this study, a 2-year pot experiment was conducted on two paddy soil types (an acidic Utisol, TY, and an alkaline Inceptisol, BH) to evaluate the influence of straw and biochar applications on CH4 and N2O emissions, and on related microbial functional genes. Results showed that straw addition markedly increased the cumulative CH4 emissions in both soils by 4.7- to 9.1-fold and 23.8- to 72.4-fold at low (S1) and high (S2) straw input rate, respectively, and significantly increased mcrA gene abundance. Biochar amendment under the high straw input (BS2) significantly decreased CH4 emissions by more than 50% in both soils, and increased both mcrA gene and pmoA gene abundances, with greatly enhanced pmoA gene and a decreased mcrA/pmoA gene ratio. Moreover, methanotrophs community changed distinctly in response to straw and biochar amendment in the alkaline BH soil, but showed slight change in the acidic TY soil. Straw had little effect on N2O emissions at low input rate (S1) but significantly increased N2O emissions at the high input rate (S2). Biochar amendment showed inconsistent effect on N2O emissions, with a decreasing trend in the BH soil but an increasing trend in the TY soil in which high ammonia existed. Correspondingly, increased nirS and nosZ gene abundances and obvious community changes in nosZ gene containing denitrifiers in response to biochar amendment were observed in the BH soil but not in the TY soil. Overall, our results suggested that biochar amendment could markedly mitigate the CH4 and N2O emissions risks under a straw return practice via regulating functional microbes and soil physicochemical properties, while the performance of this practice will vary depending on soil parent material characteristics. PMID- 30483219 TI - Comparison of the Prevalence of Metabolic Disease Between Two Types of Urbanization in China. AB - Objective: China is experiencing the world's largest urbanization. There are two primary types of urbanization in China: rural-to-urban migration and in situ urbanization, represented by Zhejiang Shangyu (SY) and Jiangsu Nanjing (NJ), respectively. Our aim is to compare changes in the prevalence of metabolic disease between these two types of urbanization in China. Methods: This is a cross-sectional study derived from the SPECT-China 2014 study. This study includes subjects and metabolic parameters from SY and NJ. Furthermore, biochemical and anthropometric indexes were taken into consideration and compared between the areas of interest. Results: The prevalence rates of diabetes, prediabetes and healthy subjects were 6.5, 17.9, and 75.7% in SY and 16.0, 31.0, and 53.0% in NJ, respectively. Industrial and agricultural jobs accounted for 77.9% and 32.0% of employment in SY and NJ, respectively. Fasting plasma glucose (FPG) was higher in SY than in NJ; however, HbA1c was lower in SY than in NJ. There was a significant difference in nonalcoholic fatty liver disease (NAFLD) and healthy subjects between SY and NJ (P < 0.05). Significant differences were also found with respect to body mass index (BMI), waist circumference (WC) and hip circumference (HC) between these two locations (P < 0.001). Logistic regression analysis revealed that the prevalence of prediabetes, diabetes, overweight, obesity and dyslipidemia was higher in NJ than in SY. Conclusions: In situ urbanization has notably changed occupational distribution. The prevalence rates of diabetes, obesity, and NAFLD were increased in rapidly urbanized areas. Thus, more attention should be paid to rapidly urbanizing areas to reduce the prevalence of metabolic disease. PMID- 30483221 TI - Siroheme Is Essential for Assimilation of Nitrate and Sulfate as Well as Detoxification of Nitric Oxide but Dispensable for Murine Virulence of Aspergillus fumigatus. AB - The saprophytic mold Aspergillus fumigatus is the most common airborne fungal pathogen causing severe invasive fungal infections in immunocompromised patients. Siroheme is a heme-like prosthetic group used by plants and microorganisms for sulfate and nitrate assimilation but is absent in higher eukaryotes. Here, we investigated the role of siroheme in A. fumigatus by deletion of the gene encoding the bifunctional dehydrogenase/ferrochelatase enzyme Met8. Met8 deficiency resulted in the inability to utilize sulfate and nitrate as sulfur and nitrogen sources, respectively. These results match previous data demonstrating that siroheme is an essential cofactor for nitrite and sulfite reductases. Moreover, Met8-deficiency caused significantly decreased resistance against nitric oxide (NO) underlining the importance of nitrite reductase in NO detoxification. Met8-deficiency did not affect virulence in murine models for invasive aspergillosis indicating that neither NO-detoxification nor assimilation of sulfate and nitrate play major roles in virulence in this host. Interestingly, Met8-deficiency resulted in mild virulence attenuation in the Galleria mellonella infection model revealing differences in interaction of A. fumigatus with G. mellonella and mouse. PMID- 30483218 TI - Maternal Diabetes and Fetal Programming Toward Neurological Diseases: Beyond Neural Tube Defects. AB - The purpose of this review was to search for experimental or clinical evidence on the effect of hyperglycemia in fetal programming to neurological diseases, excluding evident neural tube defects. The lack of timely diagnosis and the inadequate control of diabetes during pregnancy have been related with postnatal obesity, low intellectual and verbal coefficients, language and motor deficits, attention deficit with hyperactivity, problems in psychosocial development, and an increased predisposition to autism and schizophrenia. It has been proposed that several childhood or adulthood diseases have their origin during fetal development through a phenomenon called fetal programming. However, not all the relationships between the outcomes mentioned above and diabetes during gestation are clear, well-studied, or have been related to fetal programming. To understand this relationship, it is imperative to understand how developmental processes take place in health, in order to understand how the functional cytoarchitecture of the central nervous system takes place; to identify changes prompted by hyperglycemia, and to correlate them with the above postnatal impaired functions. Although changes in the establishment of patterns during central nervous system fetal development are related to a wide variety of neurological pathologies, the mechanism by which several maternal conditions promote fetal alterations that contribute to impaired neural development with postnatal consequences are not clear. Animal models have been extremely useful in studying the effect of maternal pathologies on embryo and fetal development, since obtaining central nervous system tissue in humans with normal appearance during fetal development is an important limitation. This review explores the state of the art on this topic, to help establish the way forward in the study of fetal programming under hyperglycemia and its impact on neurological and psychiatric disorders. PMID- 30483222 TI - Altered Gut Microbiota in Myasthenia Gravis. AB - Myasthenia gravis (MG) is an autoimmune-mediated disorder, the etiology of which involves both environmental factors and genetics. While the exact factors responsible for predisposition to MG remain elusive, it is hypothesized that gut microbiota play a critical role in the pathogenesis of MG. This study investigated whether gut microbiota are altered in MG patients by comparing the fecal microbiota profiles of MG patients to those of age- and sex-matched healthy controls. Phylotype profiles of gut microbial populations were generated using hypervariable tag sequencing of the V4 region of the 16S ribosomal RNA gene. Fecal short-chain fatty acids (SCFAs) were assessed by gas chromatographic analyses. The results demonstrated that, compared to the healthy cohort, the gut microbiota of the MG group was changed in terms of the relative abundances of bacterial taxa, with sharply reduced microbial richness, particularly in the genus Clostridium. The fecal SCFA content was significantly lower in the MG group. Furthermore, microbial dysbiosis was closely related to the levels of inflammatory biomarkers in the sera of MG patients. PMID- 30483223 TI - Overexpression of luxS Promotes Stress Resistance and Biofilm Formation of Lactobacillus paraplantarum L-ZS9 by Regulating the Expression of Multiple Genes. AB - Probiotics have evoked great interest in the past years for their beneficial effects. The aim of this study was to investigate whether luxS overexpression promotes the stress resistance of Lactobacillus paraplantarum L-ZS9. Here we show that overexpression of luxS gene increased the production of autoinducer-2 (AI-2, quorum sensing signal molecule) by L. paraplantarum L-ZS9. At the same time, overexpression of luxS promoted heat-, bile salt-resistance and biofilm formation of the strain. RNAseq results indicated that multiple genes encoding transporters, membrane proteins, and transcriptional regulator were regulated by luxS. These results reveal a new role for LuxS in promoting stress resistance and biofilm formation of probiotic starter. PMID- 30483225 TI - Phenotypic and Genomic Properties of a Novel Deep-Lineage Haloalkaliphilic Member of the Phylum Balneolaeota From Soda Lakes Possessing Na+-Translocating Proteorhodopsin. AB - Stable development of a heterotrophic bacterial satellite with a peculiar cell morphology has been observed in several enrichment cultures of haloalkaliphilic benthic filamentous cyanobacteria from a hypersaline soda lake in Kulunda Steppe (Altai, Russia). The organism was isolated in pure culture (strain Omega) using sonicated cyanobacterial cells as substrate and it was identified as a deep phylogenetic lineage within the recently proposed phylum Balneolaeota. It is an obligately aerobic heterotroph utilizing proteins and peptides for growth. The cell morphology significantly varied from semicircles to long filaments depending on the growth conditions. The cultures are red-orange colored due to a presence of carotenoids. The isolate is an obligate alkaliphile with a pH range for growth from 8.5 to 10.5 (optimum at 9.5-10) and moderately salt-tolerant with a range from 0.3 to 3 M total Na+ (optimum at 1 M). The genome analysis of strain Omega demonstrated a presence of gene, encoding a proteorhodopsin forming a separate branch in the sodium-translocating proteorhodopsin family. Experiments with washed cells of Omega confirmed light-dependent sodium export. A possible physiological role of the sodium proteorhodopsin in strain Omega is discussed. Phylogenomic analysis demostrated that strain Omega forms an deep, independent branch of a new genus and family level within a recently established phylum Balneolaeota. PMID- 30483226 TI - Enterovirus D68 - The New Polio? AB - Enterovirus D68 (EV-D68) has emerged over the recent years, with large outbreaks worldwide. Increased occurrence has coincided with improved clinical awareness and surveillance of non-polio enteroviruses. Studies showing its neurotropic nature and the change in pathogenicity have established EV-D68 as a probable cause of Acute Flaccid Myelitis (AFM). The EV-D68 storyline shows many similarities with poliovirus a century ago, stimulating discussion whether EV-D68 could be ascertaining itself as the "new polio." Increasing awareness amongst clinicians, incorporating proper diagnostics and integrating EV-D68 into accessible surveillance systems in a way that promotes data sharing, will be essential to reveal the burden of disease. This will be a necessary step in preventing EV-D68 from becoming a threat to public health. PMID- 30483227 TI - Ice Nucleation Activity and Aeolian Dispersal Success in Airborne and Aquatic Microalgae. AB - Microalgae are common members of the atmospheric microbial assemblages. Diverse airborne microorganisms are known to produce ice nucleation active (INA) compounds, which catalyze cloud and rain formation, and thus alter cloud properties and their own deposition patterns. While the role of INA bacteria and fungi in atmospheric processes receives considerable attention, the numerical abundance and the capacity for ice nucleation in atmospheric microalgae are understudied. We isolated 81 strains of airborne microalgae from snow samples and determined their taxonomy by sequencing their ITS markers, 18S rRNA genes or 23S rRNA genes. We studied ice nucleation activity of airborne isolates, using droplet freezing assays, and their ability to withstand freezing. For comparison, we investigated 32 strains of microalgae from a culture collection, which were isolated from polar and temperate aqueous habitats. We show that ~17% of airborne isolates, which belonged to taxa Trebouxiphyceae, Chlorophyceae and Stramenopiles, were INA. A large fraction of INA strains (over 40%) had ice nucleation activity at temperatures >=-6 degrees C. We found that 50% of aquatic microalgae were INA, but the majority were active at temperatures <-12 degrees C. Most INA compounds produced by microalgae were proteinaceous and associated with the cells. While there were no deleterious effects of freezing on the viability of airborne microalgae, some of the aquatic strains were killed by freezing. In addition, the effect of desiccation was investigated for the aquatic strains and was found to constitute a limiting factor for their atmospheric dispersal. In conclusion, airborne microalgae possess adaptations to atmospheric dispersal, in contrast to microalgae isolated from aquatic habitats. We found that widespread taxa of both airborne and aquatic microalgae were INA at warm, sub-zero temperatures (>-15 degrees C) and may thus participate in cloud and precipitation formation. PMID- 30483224 TI - The Different Tactics of Foot-and-Mouth Disease Virus to Evade Innate Immunity. AB - Like all pathogens, foot-and-mouth disease virus (FMDV) is recognized by the immune system inducing a heightened immune response mainly mediated by type I and type III IFNs. To overcome the strong antiviral response induced by these cytokines, FMDV has evolved many strategies exploiting each region of its small RNA genome. These include: (a) inhibition of IFN induction at the transcriptional and translational level, (b) inhibition of protein trafficking; (c) blockage of specific post-translational modifications in proteins that regulate innate immune signaling; (d) modulation of autophagy; (e) inhibition of stress granule formation; and (f) in vivo modulation of immune cell function. Here, we summarize and discuss FMDV virulence factors and the host immune footprint that characterize infection in cell culture and in the natural hosts. PMID- 30483228 TI - Alterations of Gut Microbiota in Cholestatic Infants and Their Correlation With Hepatic Function. AB - Cholestasis is a major hepatic disease in infants, with increasing morbidity in recent years. Accumulating evidence has revealed that the gut microbiota (GM) is associated with liver diseases, such as non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. However, GM alterations in cholestatic infants and the correlation between the GM and hepatic functions remain uninvestigated. In this study, 43 cholestatic infants (IC group) and 37 healthy infants (H group) were enrolled to detect GM discrepancies using 16S rDNA analysis. The diversity in the bacterial community was significantly lower in the IC group than that in the H group (P = 0.013). After determining the top 10 abundant genera of microbes in the IC and H groups, we found that 13 of them were differentially enriched, including Bifidobacterium, Bacteroides, Streptococcus, Enterococcus, and Staphylococcus. As compared with the H group, the IC group had a more complex GM co-occurrence network featured by three core nodes: Phyllobacterium, Ruminococcus, and Anaerostipes. In addition, the positive correlation between Faecalibacterium and Erysipelatoclostridium (r = 0.689, P = 0.000, FDR = 0.009) was not observed in the IC patients. Using the GM composition, the cholestatic patients can be distinguished from healthy infants with high accuracy [areas under receiver operating curve (AUC) > 0.97], wherein Rothia, Eggerthella, Phyllobacterium, and Blautia are identified as valuable biomarkers. Using KEGG annotation, we identified 32 functional categories with significant difference in enrichment of the GM of IC patients, including IC-enriched functional categories that were related to lipid metabolism, biodegradation and metabolism of xenobiotics, and various diseases. In contrast, the number of functions associated with amino acid metabolism, nucleotide metabolism, and vitamins metabolism was reduced in the IC patients. We also identified significant correlation between GM composition and indicators of hepatic function. Megasphaera positively correlated with total bilirubin (r = 0.455, P = 0.002) and direct bilirubin (r = 0.441, P = 0.003), whereas gamma-glutamyl transpeptidase was positively associated with Parasutterella (r = 0.466, P = 0.002) and negatively related to Streptococcus (r = -0.450, P = 0.003). This study describes the GM characteristics in the cholestatic infants, illustrates the association between the GM components and the hepatic function, and provides a solid theoretical basis for GM intervention for the treatment of infantile cholestasis. PMID- 30483229 TI - Transcriptome-Stable Isotope Probing Provides Targeted Functional and Taxonomic Insights Into Microaerobic Pollutant-Degrading Aquifer Microbiota. AB - While most studies using RNA-stable isotope probing (SIP) to date have focused on ribosomal RNA, the detection of 13C-labeled mRNA has rarely been demonstrated. This approach could alleviate some of the major caveats of current non-target environmental "omics." Here, we demonstrate the feasibility of total RNA-SIP in an experiment where hydrocarbon-degrading microbes from a BTEX-contaminated aquifer were studied in microcosms with 13C-labeled toluene under microoxic conditions. From the total sequencing reads (~30 mio. reads per density-resolved RNA fraction), an average of 1.2% of reads per sample were identified as non rRNA, including mRNA. Members of the Rhodocyclaceae (including those related to Quatrionicoccus spp.) were most abundant and enriched in 13C-rRNA, while well known aerobic degraders such as Pseudomonas spp. remained unlabeled. Transcripts related to cell motility, secondary metabolite formation and xenobiotics degradation were highly labeled with 13C. mRNA of phenol hydroxylase genes were highly labeled and abundant, while other transcripts of toluene-activation were not detected. Clear labeling of catechol 2,3-dioxygenase transcripts supported previous findings that some of these extradiol dioxygenases were adapted to low oxygen concentrations. We introduce a novel combination of total RNA-SIP with calculation of transcript-specific enrichment factors (EFs) in 13C-RNA, enabling a targeted approach to process-relevant gene expression in complex microbiomes. PMID- 30483230 TI - A Strain of an Emerging Indian Xanthomonas oryzae pv. oryzae Pathotype Defeats the Rice Bacterial Blight Resistance Gene xa13 Without Inducing a Clade III SWEET Gene and Is Nearly Identical to a Recent Thai Isolate. AB - The rice bacterial blight pathogen Xanthomonas oryzae pv. oryzae (Xoo) injects transcription activator-like effectors (TALEs) that bind and activate host "susceptibility" (S) genes important for disease. Clade III SWEET genes are major S genes for bacterial blight. The resistance genes xa5, which reduces TALE activity generally, and xa13, a SWEET11 allele not recognized by the cognate TALE, have been effectively deployed. However, strains that defeat both resistance genes individually were recently reported in India and Thailand. To gain insight into the mechanism(s), we completely sequenced the genome of one such strain from each country and examined the encoded TALEs. Strikingly, the two strains are clones, sharing nearly identical TALE repertoires, including a TALE known to activate SWEET11 strongly enough to be effective even when diminished by xa5. We next investigated SWEET gene induction by the Indian strain. The Indian strain induced no clade III SWEET in plants harboring xa13, indicating a pathogen adaptation that relieves dependence on these genes for susceptibility. The findings open a door to mechanistic understanding of the role SWEET genes play in susceptibility and illustrate the importance of complete genome sequence-based monitoring of Xoo populations in developing varieties with effective disease resistance. PMID- 30483231 TI - High Prevalence of bla NDM Variants Among Carbapenem-Resistant Escherichia coli in Northern Jiangsu Province, China. AB - The continuous emergence of carbapenem-resistant Escherichia coli (CRECO) presents a great challenge to public health. New Delhi metallo-lactamase (NDM) variants are widely disseminated in China, so the research on the prevalence and transmission of diverse bla NDM variants is urgently needed. In the present study, 54 CRECO isolates were collected from 1,185 Escherichia coli isolates in five hospitals in Northern Jiangsu Province, China from September 2015 to August 2016. Antimicrobial susceptibility tests, PCR detection of resistance determinants, multi-locus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) were performed to characterize these strains. Plasmid conjugation experiments were carried out to determine the transferability of resistant genes from selected isolates. PCR-based replicon typing (PBRT), S1 nuclease-PFGE, and Southern blotting were conducted for plasmid profiling. Carbapenemase genes were detectable in all CRECO isolates, among which thirty-one CRECO isolates were found to carry bla NDM-5 (54.7%), while, bla NDM-1, bla NDM 7, bla NDM-4, bla NDM-9, and bla KPC-2 were identified in 14, five, two, one, and one isolates, respectively. MLST results revealed 15 different STs and four new STs were first reported to be linked with NDM-producing isolates. PFGE typing showed that no more than two isolates with the same ST appeared to the same band pattern except three ST410 isolates. Twenty-six selected NDM-producing isolates were successfully transferred to E. coli J53 by conjugation experiments. Notably, 50.0% (13/26) of blaNDM variants were found to be carried by ~55 kb IncX3 plasmid. Our study reported a high prevalence of blaNDM variants, especially bla NDM-5, in Northern Jiangsu province, China. Diverse bla NDM variants were mainly carried by ~55 kb IncX3 plasmids, suggesting that the fast evolution and high transferability of this kind of plasmid promote the high prevalence of bla NDM variants. Therefore, large-scale surveillance and effective infection control measures are also urgently needed to prevent diverse bla NDM variants from becoming epidemic in the future. PMID- 30483232 TI - Lectin-Like Bacteriocins. AB - Bacteria produce a diverse array of antagonistic compounds to restrict growth of microbial rivals. Contributing to this warfare are bacteriocins: secreted antibacterial peptides, proteins and multi-protein complexes. These compounds typically eliminate competitors closely related to the producer. Lectin-like bacteriocins (LlpAs) constitute a distinct class of such proteins, produced by Pseudomonas as well as some other proteobacterial genera. LlpAs share a common architecture consisting of two B-lectin domains, followed by a short carboxy terminal extension. Two surface-exposed moieties on susceptible Pseudomonas cells are targeted by the respective lectin modules. The carboxy-terminal domain binds D-rhamnose residues present in the lipopolysaccharide layer, whereas the amino terminal domain interacts with a polymorphic external loop of the outer-membrane protein insertase BamA, hence determining selectivity. The absence of a toxin immunity module as found in modular bacteriocins and other polymorphic toxin systems, hints toward a novel mode of killing initiated at the cellular surface, not requiring bacteriocin import. Despite significant progress in understanding the function of LlpAs, outstanding questions include the secretion machinery recruited by lectin-like bacteriocins for their release, as well as a better understanding of the environmental signals initiating their expression. PMID- 30483233 TI - Roots and Panicles of the C4 Model Grasses Setaria viridis (L). and S. pumila Host Distinct Bacterial Assemblages With Core Taxa Conserved Across Host Genotypes and Sampling Sites. AB - Virtually all studied plant tissues are internally inhabited by endophytes. Due to their relevance for plant growth and health, bacterial microbiota of crop plants have been broadly studied. In plant microbiome research the root is the most frequently addressed environment, whereas the ecology of microbiota associated with reproductive organs still demands investigation. In this work, we chose the model grasses Setaria viridis and Setaria pumila to better understand the drivers shaping bacterial communities associated with panicles (representing a reproductive organ) as compared to those associated with roots. We collected wild individuals of both grass species from 20 different locations across Austria and investigated the bacterial assemblages within roots and ripe grain-harboring panicles by 16S rRNA gene-based Illumina sequencing. Furthermore, plant samples were subjected to genotyping by genetic diversity-focused Genotyping by Sequencing. Overall, roots hosted more diverse microbiota than panicles. Both the plant organ and sampling site significantly shaped the root and panicle associated microbiota, whereas the host genotype only affected root communities. In terms of community structure, root-specific assemblages were highly diverse and consisted of conserved bacterial taxa. In contrast, panicle-specific communities were governed by Gammaproteobacteria, were less diverse and highly origin-dependent. Among OTUs found in both plant tissues, relative abundances of Gammaproteobacteria were higher in panicles, whereas Rhizobiales dominated root communities. We further identified core and non-core taxa within samples of both Setaria species. Non-core taxa included members of the Saccharibacteria and Legionelalles, while core communities encompassed eleven OTUs of seven bacterial orders, together with a set of ten panicle-enriched OTUs. These communities were widespread across root and panicle samples from all locations, hinting toward an evolved form of mutualism through potential vertical transmission of these taxa within Setaria species. PMID- 30483234 TI - Aerobic Anoxygenic Phototrophic Bacteria Promote the Development of Biological Soil Crusts. AB - Chlorophyll-containing oxygenic photoautotrophs have been well known to play a fundamental role in the development of biological soil crusts (BSCs) by harvesting solar radiations and providing fixed carbon to the BSCs ecosystems. Although the same functions can be theoretically fulfilled by the widespread bacteriochlorophyll-harboring aerobic anoxygenic phototrophic bacteria (AAnPB), whether AAnPB play a role in the formation of BSCs and how important they are to this process remain largely unknown. To address these questions, we set up a microcosm system with surface sands of the Hopq desert in northern China and observed the significant effects of near-infrared illumination on the development of BSCs. Compared to near-infrared or red light alone, the combined use of near infrared and red lights for illumination greatly increased the thickness of BSCs, their organic matter contents and the microalgae abundance by 24.0, 103.7, and 1447.6%, respectively. These changes were attributed to the increasing abundance of AAnPB that can absorb near-infrared radiations. Our data suggest that AAnPB is a long-overlooked driver in promoting the development of BSCs in drylands. PMID- 30483236 TI - Chaperones, Membrane Trafficking and Signal Transduction Proteins Regulate Zaire Ebola Virus trVLPs and Interact With trVLP Elements. AB - Ebolavirus (EBOV) life cycle involves interactions with numerous host factors, but it remains poorly understood, as does pathogenesis. Herein, we synthesized 65 siRNAs targeting host genes mostly connected with aspects of the negative-sense RNA virus life cycle (including viral entry, uncoating, fusion, replication, assembly, and budding). We produced EBOV transcription- and replication-competent virus-like particles (trVLPs) to mimic the EBOV life cycle. After screening host factors associated with the trVLP life cycle, we assessed interactions of host proteins with trVLP glycoprotein (GP), VP40, and RNA by co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP). The results demonstrate that RNAi silencing with 11 siRNAs (ANXA5, ARFGAP1, FLT4, GRP78, HSPA1A, HSP90AB1, HSPA8, MAPK11, MEK2, NTRK1, and YWHAZ) decreased the replication efficiency of trVLPs. Co-IP revealed nine candidate host proteins (FLT4, GRP78, HSPA1A, HSP90AB1, HSPA8, MAPK11, MEK2, NTRK1, and YWHAZ) potentially interacting with trVLP GP, and four (ANXA5, GRP78, HSPA1A, and HSP90AB1) potentially interacting with trVLP VP40. Ch-IP identified nine candidate host proteins (ANXA5, ARFGAP1, FLT4, GRP78, HSPA1A, HSP90AB1, MAPK11, MEK2, and NTRK1) interacting with trVLP RNA. This study was based on trVLP and could not replace live ebolavirus entirely; in particular, the interaction between trVLP RNA and host proteins cannot be assumed to be identical in live virus. However, the results provide valuable information for further studies and deepen our understanding of essential host factors involved in the EBOV life cycle. PMID- 30483237 TI - The Sheaths of Methanospirillum Are Made of a New Type of Amyloid Protein. AB - The genera Methanospirillum and Methanosaeta contain species of anaerobic archaea that grow and divide within proteinaceous tubular sheaths that protect them from environmental stressors. The sheaths of Methanosaeta thermophila PT are composed of the 60.9 kDa major sheath protein MspA. In this study we show that sheaths purified from Methanospirillum hungatei JF-1 are regularly striated tubular structures with amyloid-like properties similar to those of M. thermophila PT. Depolymerizing the sheaths from M. hungatei JF-1 allowed us to identify a 40.6 kDa protein (WP_011449234.1) that shares 23% sequence similarity to MspA from M. thermophila PT (ABK14853.1), indicating that they might be distant homologs. The genome of M. hungatei JF-1 encodes six homologs of the identified MspA protein. Several homologs also exist in the related strains Methanospirillum stamsii Pt1 (7 homologs, 28-66% sequence identity), M. lacunae Ki8-1 C (15 homologs, 29-60% sequence identity) and Methanolinea tarda NOBI-1 (2 homologs, 31% sequence identity). The MspA protein discovered here could accordingly represent a more widely found sheath protein than the MspA from M. thermophila PT, which currently has no homologs in the NCBI Reference Sequence database (RefSeq). PMID- 30483238 TI - Vanillin Alleviates High Fat Diet-Induced Obesity and Improves the Gut Microbiota Composition. AB - Vanillin, a simple phenolic compound, exists marginally in some plants and can be produced by microbes. This study uses high-fat-diet (HFD) induced obese mice to study the effect of vanillin on obesity and obtain positive results. First, both body and adipose tissue weight are reduced. Second, the blood properties signaling certain disorders such as ALT, LDH, glucose, cholesterol, LDL-C, TG and HDL-C are ameliorated and both insulin sensitivity, and glucose tolerance are improved. Third, vanillin reduced elevated levels of inflammatory factors including LPS, IL-6, and TNF-alpha in plasma and liver tissue resulting from obesity. Finally, the production of short chain fatty acids (SCFAs) is enhanced. Additionally, study results demonstrate that vanillin significantly alleviates obesity-related gut microbiota (GM) disorders including the decrease of alpha- and beta-diversity. Furthermore, vanillin reduces the abundance of Firmicutes phylum, increases the richness of Bacteroidetes and Verrucomicrobiota phyla, and inhibits the expansion of the lipopolysaccharide (LPS)-producing bacteria Bilophila genus and the H2S-producing bacteria Desulfovibrio genus. PMID- 30483235 TI - Factors Contributing to the Evolution of mecA-Mediated beta-lactam Resistance in Staphylococci: Update and New Insights From Whole Genome Sequencing (WGS). AB - The understanding of the mechanisms of antibiotic resistance development are fundamental to alert and preview beforehand, the large scale dissemination of resistance to antibiotics, enabling the design of strategies to prevent its spread. The mecA-mediated methicillin resistance conferring resistance to broad spectrum beta-lactams is globally spread in staphylococci including hospitals, farms and community environments, turning ineffective the most widely used and efficient class of antibiotics to treat staphylococcal infections. The use of whole genome sequencing (WGS) technologies at a bacterial population level has provided a considerable progress in the identification of key steps that led to mecA-mediated beta-lactam resistance development and dissemination. Data obtained from multiple studies indicated that mecA developed from a harmless core gene (mecA1) encoding the penicillin-binding protein D (PbpD) from staphylococcal species of animal origin (S. sciuri group) due to extensive beta-lactams use in human created environments. Emergence of the resistance determinant involved distortion of PbpD active site, increase in mecA1 expression, addition of regulators (mecR1, mecI) and integration into a mobile genetic element (SCCmec). SCCmec was then transferred into species of coagulase-negative staphylococci (CoNS) that are able to colonize both animals and humans and subsequently transferred to S. aureus of human origin. Adaptation of S. aureus to the exogenously acquired SCCmec involved, deletion and mutation of genes implicated in general metabolism (auxiliary genes) and general stress response and the adjustment of metabolic networks, what was accompanied by an increase in beta lactams minimal inhibitory concentration and the transition from a heterogeneous to homogeneous resistance profile. Nowadays, methicillin-resistant S. aureus (MRSA) carrying SCCmec constitutes one of the most important worldwide pandemics. The stages of development of mecA-mediated beta-lactam resistance described here may serve as a model for previewing and preventing the emergence of resistance to other classes of antibiotics. PMID- 30483239 TI - EGFR as a Negative Regulatory Protein Adjusts the Activity and Mobility of NHE3 in the Cell Membrane of IPEC-J2 Cells With TGEV Infection. AB - Transmissible gastroenteritis (TGE) has caused devastating economic losses to the swine industry worldwide, despite extensive research focusing on the pathogenesis of virus infection. The molecular pathogenic mechanism of TGEV-induced diarrhea in piglets is unknown. Intestinal diarrhea is closely related to the function of the Na+/H+ exchanger protein NHE3 in the brush border membrane of small intestine epithelial cells. The epidermal growth factor receptor (EGFR) may act to regulate NHE3 expression. In addition, EGFR may promote viral invasion of host cells. The present study aimed to determine whether NHE3 activity is regulated by altering EGFR expression to affect Na+ absorption in TGEV-infected intestinal epithelial cells. Porcine intestinal epithelial cells were used as models for TGEV infection. The results showed that Na+ absorption and NHE3 expression levels decreased in TGEV-infected cells. Proliferation of TGEV within IPEC-J2 cells could be inhibited by treatment with the EGFR inhibitor AG1478 and knockdown; resulting in recovery of Na+ absorption in TGEV infected cells and increasing the activity and expression of NHE3. Moreover, we demonstrated that NHE3 activity was regulated through the EGFR/ERK pathway. Importantly, NHE3 mobility on the plasma membrane of TGEV infected cells was significantly weaker than that in normal cells, and EGFR inhibition and knockdown recovered this mobility. Our research indicated that NHE3 activity was negatively regulated by EGFR in TGEV-infected intestinal epithelial cells. PMID- 30483240 TI - Soil Bacteria Isolated From Tunisian Arid Areas Show Promising Antimicrobial Activities Against Gram-Negatives. AB - Arid regions show relatively fewer species in comparison to better-watered biomes, but the competition for the few nutrients is very distinct. Here, in total 373 bacterial strains were isolated from rhizospheric soils obtained from three different sampling sites in Tunisia. Their potential for the production of antimicrobial compounds was evaluated. Bacterial strains, showing antibacterial activity against pathogenic bacteria, were isolated from all three sites, one strain from the Bou-Hedma national park, 15 strains from Chott-Djerid, and 13 strains from Matmata, respectively. The dominant genus was Bacillus, with 27 out of 29 strains. Most interestingly, 93% of the isolates showed activity against Gram-positive and Gram-negative test bacteria. Strain Bacillus sp. M21, harboring high inhibitory potential, even against clinical isolates of Gram-negative bacteria, was analyzed in detail to enable purification and identification of the bioactive compound responsible for its bioactivity. Subsequent HPLC-MS and NMR analyses resulted in the identification of 1-acetyl-beta-carboline as active component. Furthermore, fungicides of the bacillomycin and fengycin group, which in addition show antibiotic effects, were identified. This work highlights the high potential of the arid-adapted strains for the biosynthesis of specialized metabolites and suggest further investigation of extreme environments, since they constitute a promising bioresource of biologically active compounds. PMID- 30483241 TI - Electrode Potential Dependency of Single-Cell Activity Identifies the Energetics of Slow Microbial Electron Uptake Process. AB - Electrochemical measurements have been widely applied to study microbial extracellular electron transport processes. However, because electrochemistry detects not only microbial electron transport but also other reactions, background signals comparable to or larger than microbial ones hamper the identification of microbial electrochemical properties. This problem is crucial especially for the detection of electron uptake processes by slow-growing microbes in low-energy subsurface sediments, as the environmental samples contain electrochemically active humus and mineral particles. In this study, we report a cell-specific stable isotope analysis to quantify the electrode potential dependency of anabolic activity in individual cells for identifying the electron uptake energetics of slow-growing bacteria. Followed by the incubation of Desulfovibrio ferrophilus IS5 cells with isotopic 15N-ammonium as the sole N source on electrodes poised at potentials of -0.2, -0.3, -0.4, and -0.5 V [vs. standard hydrogen electrode (SHE)], we conducted nanoscale secondary ion mass spectroscopy (NanoSIMS) to quantify 15N assimilation in more than 100 individual cells on the electrodes. We observed significant 15N assimilation at potentials of -0.4 and more 15N assimilation at -0.5 V, which is consistent with the onset potential for electron uptake via outer-membrane cytochromes (OMCs). The activation of cell energy metabolism was further examined by transcriptome analysis. Our results showed a novel methodology to study microbial electron uptake energetics. The results also serve as the first direct evidence that energy acquisition is coupled to the electron uptake process in sulfate-reducing bacteria that are ubiquitous in the subsurface environments, with implications on the electron-fueled subsurface biosphere hypothesis and other microbial processes, such as anaerobic iron corrosion and anaerobic methane oxidation. PMID- 30483242 TI - Nipah Virus Infection of Immature Dendritic Cells Increases Its Transendothelial Migration Across Human Brain Microvascular Endothelial Cells. AB - Nipah virus (NiV) can infect multiple organs in humans with the central nervous system (CNS) being the most severely affected. Currently, it is not fully understood how NiV spreads throughout the body. NiV has been shown to infect certain leukocyte populations and we hypothesized that these infected cells could cross the blood-brain barrier (BBB), facilitating NiV entry into the CNS. Here, three leukocyte types, primary immature dendritic cells (iDC), primary monocytes (pMO), and monocytic cell line (THP-1), were evaluated for permissiveness to NiV. We found only iDC and THP-1 were permissive to NiV. Transendothelial migration of mock-infected and NiV-infected leukocytes was then evaluated using an in vitro BBB model established with human brain microvascular endothelial cells (HBMEC). There was approximately a threefold increase in migration of NiV-infected iDC across endothelial monolayer when compared to mock-infected iDC. In contrast, migration rates for pMO and THP-1 did not change upon NiV infection. Across TNF alpha-treated endothelial monolayer, there was significant increase of almost twofold in migration of NiV-infected iDC and THP-1 over mock-infected cells. Immunofluorescence analysis showed the migrated NiV-infected leukocytes retained their ability to infect other cells. This study demonstrates for the first time that active NiV infection of iDC and THP-1 increased their transendothelial migration activity across HBMEC and activation of HBMEC by TNF-alpha further promoted migration. The findings suggest that NiV infection of leukocytes to disseminate the virus via the "Trojan horse" mechanism is a viable route of entry into the CNS. PMID- 30483243 TI - Whole Genome Sequencing of Influenza A and B Viruses With the MinION Sequencer in the Clinical Setting: A Pilot Study. AB - Introduction: Whole genome sequencing (WGS) of influenza viruses is important for preparing vaccines and coping with newly emerging viruses. However, WGS is difficult to perform using conventional next-generation sequencers in developing countries, where facilities are often inadequate. In this study, we developed a high-throughput WGS method for influenza viruses in clinical specimens with the MinION portable sequencer. Methods: Whole genomes of influenza A and B viruses were amplified by multiplex RT-PCR from 13 clinical specimens collected in Tokyo, Japan. Barcode tags for multiplex MinION sequencing were added with each multiplex RT-PCR amplicon by nested PCR with custom barcoded primers. All barcoded amplicons were mixed and multiplex sequencing using the MinION sequencer with 1D2 sequencing kit. In addition, multiplex RT-PCR amplicons generated from each clinical specimen were sequenced using the Illumina MiSeq platform to validate the performance of MinION sequencer. The accuracy, recall, and precision rates of MinION sequencing were calculated by comparing the results of variant calling in the Illumina MiSeq platform and MinION sequencer. Results: Whole genomes of influenza A and B viruses were successfully amplified by multiplex RT PCR from 13 clinical samples. We identified 6 samples as influenza type A virus H3N2 subtype and 7 as influenza B virus Yamagata lineage using the Illumina MiSeq platform. The overall accuracy, recall, and precision rates of the MinION sequencer were, respectively 99.95%, 89.41%, and 97.88% from 1D reads and 99.97%, 93.28%, and 99.86% from 1D2 reads. Conclusion: We developed a novel WGS method for influenza A and B viruses. It is necessary to improve read accuracy and analytical tools in order to better utilize the MinION sequencer for real-time monitoring of genetic rearrangements and for evaluation of newly emerging viruses. PMID- 30483245 TI - Misregulation of the IgH Locus in Thymocytes. AB - Functional antigen receptor genes are assembled by somatic rearrangements that are largely lymphocyte lineage specific. The immunoglobulin heavy chain (IgH) gene locus is unique amongst the seven antigen receptor loci in undergoing partial gene rearrangements in the wrong lineage. Here we demonstrate that breakdown of lineage-specificity is associated with inappropriate activation of the EMU enhancer during T cell development by a different constellation of transcription factors than those used in developing B cells. This is reflected in reduced enhancer-induced epigenetic changes, eRNAs, formation of the RAG1/2-rich recombination center, attenuated chromatin looping and markedly different utilization of DH gene segments in CD4+CD8+ (DP) thymocytes. Additionally, CTCF dependent VH locus compaction is disrupted in DP cells despite comparable transcription factor binding in both lineages. These observations identify multiple mechanisms that contribute to lineage-specific antigen receptor gene assembly. PMID- 30483244 TI - Temporal Effects of High Fishmeal Diet on Gut Microbiota and Immune Response in Clostridium perfringens-Challenged Chickens. AB - Necrotic enteritis (NE) caused by Clostridium perfringens is responsible for huge financial losses in the poultry industry annually. A diet highly supplemented with fishmeal is one factor predisposing chickens to the development of clinical NE. However, the effects of fishmeal-rich diets on the gut microbiota and immune response in chickens with C. perfringens challenge over the long-term are not well-understood. Here, a chicken NE model was established in which chickens were fed high fishmeal diet and subsequently infected with C. perfringens (FM/CP). Two control groups of chickens, one that was not infected and had a high fishmeal feeding (FM) and another group only infected with C. perfringens with basic diets (CP), were used as comparators. We analyzed the gut microbiota and immune response of the three groups at the age of 20, 24 [1 day post-infection (dpi)] and 30 days (7 dpi) using 16S rDNA sequencing and real-time PCR, respectively. We found that the composition of the gut microbiota had significant shifted in both the CP and FM/CP groups, although the CP group did not have intestinal lesions. The structure of the gut microbiota in C. perfringens-challenged chickens, independent of a high fishmeal diet, had the tendency to return to their non infection state if the chickens no longer received C. perfringens challenge. Gut microbiota variation with time in challenged chickens with high fishmeal diet feeding was superimposed upon that of non-infected chickens with high fishmeal feeding. For the immune response, the relative expression of IL-8 in the ileum was significantly higher in infected chickens independent of high fishmeal feeding than in non-infected chickens. However, the expression of alpha 1-acid glycoprotein (AGP) and serum amyloid A (SAA) genes in chicken liver were significantly increased in FM/CP compared to the other groups. In conclusion, high fishmeal feeding induced significant changes to the structure of chicken gut microbiota over time and such changes provided an opening for C. perfringens infection to progress to NE. The relative expression of AGP and SAA in liver tissue may be used as diagnostic biomarkers for poultry NE but such an indication requires further investigation. PMID- 30483248 TI - Immunoproteomics and Surfaceomics of the Adult Tapeworm Hymenolepis diminuta. AB - In cestodiasis, mechanical and molecular contact between the parasite and the host activates the immune response of the host and may result in inflammatory processes, leading to ulceration and intestinal dysfunctions. The aim of the present study was to identify antigenic proteins of the adult cestode Hymenolepis diminuta by subjecting the total protein extracts from adult tapeworms to 2DE immunoblotting (two-dimensional electrophoresis combined with immunoblotting) using sera collected from experimentally infected rats. A total of 36 protein spots cross-reacting with the rat sera were identified using LC-MS/MS. As a result, 68 proteins, including certain structural muscle proteins (actin, myosin, and paramyosin) and moonlighters (heat shock proteins, kinases, phosphatases, and glycolytic enzymes) were identified; most of these were predicted to possess binding and/or catalytic activity required in various metabolic and cellular processes, and reported here as potential antigens of the adult cestode for the first time. As several of these antigens can also be found at the cell surface, the surface-associated proteins were extracted and subjected to in-solution digestion for LC-MS/MS identification (surfaceomics). As a result, a total of 76 proteins were identified, from which 31 proteins, based on 2DE immunoblotting, were predicted to be immunogenic. These included structural proteins actin, myosin and tubulin as well as certain moonlighting proteins (heat-shock chaperones) while enzymes with diverse catalytic activities were found as the most dominating group of proteins. In conclusion, the present study shed new light into the complexity of the enteric cestodiasis by showing that the H. diminuta somatic proteins exposed to the host possess immunomodulatory functions, and that the immune response of the host could be stimulated by diverse mechanisms, involving also those triggering protein export via yet unknown pathways. PMID- 30483246 TI - Unraveling SSc Pathophysiology; The Myofibroblast. AB - Systemic sclerosis (SSc) is a severe auto-immune disease, characterized by vasculopathy and fibrosis of connective tissues. SSc has a high morbidity and mortality and unfortunately no disease modifying therapy is currently available. A key cell in the pathophysiology of SSc is the myofibroblast. Myofibroblasts are fibroblasts with contractile properties that produce a large amount of pro fibrotic extracellular matrix molecules such as collagen type I. In this narrative review we will discuss the presence, formation, and role of myofibroblasts in SSc, and how these processes are stimulated and mediated by cells of the (innate) immune system such as mast cells and T helper 2 lymphocytes. Furthermore, current novel therapeutic approaches to target myofibroblasts will be highlighted for future perspective. PMID- 30483249 TI - Natural Killer Cells Adapt to Cytomegalovirus Along a Functionally Static Phenotypic Spectrum in Human Immunodeficiency Virus Infection. AB - Events related to HCMV infection drive accumulation of functionally enhanced CD57posNKG2Cpos adapted NK cells. We investigated NK cell adaptation to HCMV along a proposed continuum progressing from acute activation through maturation and memory formation towards functional exhaustion. Acute exposure to conditioned medium collected 24 h after HCMV infection (HCMVsn) increased NK cell cytotoxicity for all HCMV-seronegative and seropositive donors tested, with mean 38 and 29% boosts in natural and antibody-dependent cell-mediated cytotoxicity (ADCC), respectively. Increases in NK cell cytotoxicity were completely abrogated by blocking type I interferon (IFN) receptors and equivalent responses occurred with exposure to IFN-alpha2 alone at the same concentration present in HCMVsn. To study longer term effects of HCMV infection, we focused on three groups of human immunodeficiency virus (HIV)-infected subjects distinguished as HCMV-seronegative or HCMV-seropositive with either high (>20%) or low (<6%) fractions of their NK cells expressing NKG2C. The NK cells of all three HIV-infected groups responded to HCMVsn and IFN-alpha2 in a manner similar to the NK cells of either HCMV seronegative or seropositive controls. Neither HCMV status, nor the extent of phenotypic evidence of adaptation to HCMV infection significantly affected mean levels of ADCC or CD16-mediated NK cell degranulation and IFN-gamma production compared between the HIV-infected groups. Levels of IFN-gamma production correlated significantly with the fraction of NK cells lacking FcepsilonRIgamma (FcRgamma), but not with the fraction of NK cells expressing NKG2C. There was negligible expression of exhaustion markers Lag-3 and PD-1 on NK cells in any of the groups and no significant difference between groups in the fraction of NK cells expressing Tim-3. The fraction of NK cells expressing Tim-3 was unaffected by CD16 stimulation. Relative to the total NK cell population, responses of Tim-3 expressing cells to CD16 stimulation were variably compromised in HCMV seronegative and seropositive groups. In general, NK cell function in response to signaling through CD16 was well preserved in HIV infection and although HCMV had a clear effect on NK cell FcRgamma and NKG2C expression, there was little evidence that the level of adaptation to HCMV infection affected CD16-dependent NK cell signaling in HIV infection. PMID- 30483251 TI - Distinct Role of IL-27 in Immature and LPS-Induced Mature Dendritic Cell-Mediated Development of CD4+ CD127+3G11+ Regulatory T Cell Subset. AB - Interleukin-27 (IL-27) plays an important role in regulation of anti-inflammatory responses and autoimmunity; however, the molecular mechanisms of IL-27 in modulation of immune tolerance and autoimmunity have not been fully elucidated. Dendritic cells (DCs) play a central role in regulating immune responses mediated by innate and adaptive immune systems, but regulatory mechanisms of DCs in CD4+ T cell-mediated immune responses have not yet been elucidated. Here we show that IL 27 treated mature DCs induced by LPS inhibit immune tolerance mediated by LPS stimulated DCs. IL-27 treatment facilitates development of the CD4+ CD127+3G11+ regulatory T cell subset in vitro and in vivo. By contrast, IL-27 treated immature DCs fail to modulate development of the CD4+CD127+3G11+ regulatory T cell sub-population in vitro and in vivo. Our results suggest that IL-27 may break immune tolerance induced by LPS-stimulated mature DCs through modulating development of a specific CD4+ regulatory T cell subset mediated by 3G11 and CD127. Our data reveal a new cellular regulatory mechanism of IL-27 that targets DC-mediated immune responses in autoimmune diseases such as multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). PMID- 30483250 TI - Regulatory Networks Involving STATs, IRFs, and NFkappaB in Inflammation. AB - Cells engaging in inflammation undergo drastic changes of their transcriptomes. In order to tailor these alterations in gene expression to the requirements of the inflammatory process, tight and coordinate regulation of gene expression by environmental cues, microbial or danger-associated molecules or cytokines, are mandatory. The transcriptional response is set off by signal-regulated transcription factors (SRTFs) at the receiving end of pathways originating at pattern recognition- and cytokine receptors. These interact with a genome that has been set for an appropriate response by prior activity of pioneer or lineage determining transcription factors (LDTFs). The same types of transcription factors are also critical determinants of the changes in chromatin landscapes and transcriptomes that specify potential consequences of inflammation: tissue repair, training, and tolerance. Here we focus on the role of three families of SRTFs in inflammation and its sequels: signal transducers and activators of transcription (STATs), interferon regulatory factors (IRFs), and nuclear factor kappaB (NFkappaB). We describe recent findings about their interactions and about their networking with LDTFs. Our aim is to provide a snapshot of a highly dynamic research area. PMID- 30483252 TI - Inflammasome-Independent Role of NLRP3 Mediates Mitochondrial Regulation in Renal Injury. AB - The NOD-like receptor family, pyrin domain containing-3 (NLRP3) inflammasome has been implicated in renal inflammation and fibrosis. However, the biological function of inflammasome-independent NLRP3 in non-immune cells is still unclear. We evaluated the role of inflammasome-independent NLRP3 in renal tubular cells and assessed the value of NLRP3 as a therapeutic target for acute kidney injury (AKI). Various renal tubular cell lines and primary cultured tubular cells from NLRP3 knockout (KO) mice were used for in vitro studies. We also tested the role of tubular NLRP3 in AKI with a unilateral ureter obstruction model (UUO). Hypoxia induced significant increase of NLRP3 independent of ASC, caspase-1, and IL 1beta. NLRP3 in renal tubular cells relocalized from the cytosol to the mitochondria during hypoxia and bound to mitochondrial antiviral signal protein (MAVS). The deletion of NLRP3 or MAVS in renal tubular cells attenuated mitochondrial reactive oxygen species (ROS) production and depolarization of the mitochondrial membrane potentials under hypoxia. In response to UUO, NLRP3 KO mice showed less fibrosis, apoptosis, and ROS injury than wild type (WT) mice. Compared with WT kidney, mitophagy was up-regulated in NLRP3 KO kidney relative to the baseline and it was protective against AKI. Our results indicate that inflammasome-independent NLRP3 in renal tubular cells plays important role in mitochondrial ROS production and injury by binding to MAVS after hypoxic injury. This mitochondrial regulation in the absence of NLRP3 increases autophagy and attenuates apoptosis after UUO. We suggest that inflammasome-independent NLRP3 could be a therapeutic target of AKI to prevent the progression of chronic kidney disease. PMID- 30483253 TI - In vitro and in vivo Effects of Lactate on Metabolism and Cytokine Production of Human Primary PBMCs and Monocytes. AB - Lactate, the end product of anaerobic glycolysis, is produced in high amounts by innate immune cells during inflammatory activation. Although immunomodulating effects of lactate have been reported, evidence from human studies is scarce. Here we show that expression of genes involved in lactate metabolism and transport is modulated in human immune cells during infection and upon inflammatory activation with TLR ligands in vitro, indicating an important role for lactate metabolism in inflammation. Extracellular lactate induces metabolic reprogramming in innate immune cells, as evidenced by reduced glycolytic and increased oxidative rates of monocytes immediately after exposure to lactate. A short-term infusion of lactate in humans in vivo increased ex vivo glucose consumption of PBMCs, but effects on metabolic rates and cytokine production were limited. Interestingly, long-term treatment with lactate ex vivo, reflecting pathophysiological conditions in local microenvironments such as tumor or adipose tissue, significantly modulated cytokine production with predominantly anti inflammatory effects. We found time- and stimuli-dependent effects of extracellular lactate on cytokine production, further emphasizing the complex interplay between metabolism and immune cell function. Together, our findings reveal lactate as a modulator of immune cell metabolism which translates to reduced inflammation and may ultimately function as a negative feedback signal to prevent excessive inflammatory responses. PMID- 30483247 TI - Advances in Designing and Developing Vaccines, Drugs and Therapeutic Approaches to Counter Human Papilloma Virus. AB - Human papillomavirus (HPV) is a viral infection with skin-to-skin based transmission mode. HPV annually caused over 500,000 cancer cases including cervical, anogenital and oropharyngeal cancer among others. HPV vaccination has become a public-health concern, worldwide, to prevent the cases of HPV infections including precancerous lesions, cervical cancers, and genital warts especially in adolescent female and male population by launching national programs with international alliances. Currently, available prophylactic and therapeutic vaccines are expensive to be used in developing countries for vaccination programs. The recent progress in immunotherapy, biotechnology, recombinant DNA technology and molecular biology along with alternative and complementary medicinal systems have paved novel ways and valuable opportunities to design and develop effective prophylactic and therapeutic vaccines, drugs and treatment approach to counter HPV effectively. Exploration and more researches on such advances could result in the gradual reduction in the incidences of HPV cases across the world. The present review presents a current global scenario and futuristic prospects of the advanced prophylactic and therapeutic approaches against HPV along with recent patents coverage of the progress and advances in drugs, vaccines and therapeutic regimens to effectively combat HPV infections and its cancerous conditions. PMID- 30483254 TI - Lack of Adipocytes Alters Hematopoiesis in Lipodystrophic Mice. AB - Adult hematopoiesis takes place in the perivascular zone of the bone cavity, where endothelial cells, mesenchymal stromal/stem cells and their derivatives such as osteoblasts are key components of bone marrow (BM) niches. Defining the contribution of BM adipocytes to the hematopoietic stem cell niche remains controversial. While an excess of medullar adiposity is generally considered deleterious for hematopoiesis, an active role for adipocytes in shaping the niche has also been proposed. We thus investigated the consequences of total adipocyte deletion, including in the BM niche, on adult hematopoiesis using mice carrying a constitutive deletion of the gene coding for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma). We show that Pparg Delta/Delta lipodystrophic mice exhibit severe extramedullary hematopoiesis (EMH), which we found to be non-cell autonomous, as it is reproduced when wild-type donor BM cells are transferred into Pparg Delta/Delta recipients. This phenotype is not due to a specific alteration linked to Pparg deletion, such as chronic inflammation, since it is also found in AZIPtg/+ mice, another lipodystrophic mouse model with normal PPARgamma expression, that display only very moderate levels of inflammation. In both models, the lack of adipocytes alters subpopulations of both myeloid and lymphoid cells. The CXCL12/CXCR4 axis in the BM is also dysregulated in an adipocyte deprived environment supporting the hypothesis that adipocytes are required for normal hematopoietic stem cell mobilization or retention. Altogether, these data suggest an important role for adipocytes, and possibly for the molecular interactions they provide within the BM, in maintaining the appropriate microenvironment for hematopoietic homeostasis. PMID- 30483255 TI - Extracellular Vesicles in Joint Disease and Therapy. AB - The use of extracellular vesicles (EVs) as a potential therapy is currently explored for different disease areas. When it comes to the treatment of joint diseases this approach is still in its infancy. As in joint diseases both inflammation and the associated articular tissue destruction are important factors, both the immune-suppressive and the regenerative properties of EVs are potentially advantageous characteristics for future therapy. There is, however, only limited knowledge on the basic features, such as numerical profile and function, of EVs in joint articular tissues in general and their linking medium, the synovial fluid, in particular. Further insight is urgently needed in order to appreciate the full potential of EVs and to exploit these in EV-mediated therapies. Physiologic joint homeostasis is a prerequisite for proper functioning of joints and we postulate that EVs play a key role in the regulation of joint homeostasis and hence can have an important function in re-establishing disturbed joint homeostasis, and, in parallel, in the regeneration of articular tissues. In this mini-review EVs in the joint are explained from a historical perspective in both health and disease, including the potential niche for EVs in articular tissue regeneration. Furthermore, the translational potential of equine models for human joint biology is discussed. Finally, the use of MSC-derived EVs that is recently gaining ground is highlighted and recommendations are given for further EV research in this field. PMID- 30483256 TI - Schistosoma mansoni Infection-Induced Transcriptional Changes in Hepatic Macrophage Metabolism Correlate With an Athero-Protective Phenotype. AB - Hepatic macrophages play an essential role in the granulomatous response to infection with the parasitic helminth Schistosoma mansoni, but the transcriptional changes that underlie this effect are poorly understood. To explore this, we sorted the two previously recognized hepatic macrophage populations (perivascular and Kupffer cells) from naive and S. mansoni-infected male mice and performed microarray analysis as part of the Immunological Genome Project. The two hepatic macrophage populations exhibited remarkably different genomic profiles. However, this diversity was substantially reduced following infection with S. mansoni, and in fact, both populations demonstrated increases in transcripts of the monocyte lineage, suggesting that both populations may be replenished by monocytes following infection. Pathway analysis showed a profound alteration in global metabolic pathways, including changes to phospholipid and cholesterol metabolism, as well as amino acid biosynthesis and glucagon signaling. These changes suggest a possible mechanism for the previously reported athero-protective effects of S. mansoni infection. Indeed, we find that male ApoE null mice fed a high-fat diet in combination with S. mansoni infection have reduced plaque area and increased glucose tolerance as compared to control mice. Transcript analysis of infected and control high-fat diet fed ApoE-/- mice confirm that ApoC1, Psat1, and Gys1 are all altered by infection, suggesting that altered hepatic macrophage metabolism is associated with S. mansoni- induced protection from hyperlipidemia, atherosclerosis, and glucose intolerance. These results suggest a previously unknown and unreported role of hepatic macrophages in the modulation of whole body lipid and glucose metabolism during infection and provide a template for examining the role of immunomodulation on the long-term metabolism of the host. PMID- 30483259 TI - A Preliminary Study of a Lettuce-Based Edible Vaccine Expressing the Cysteine Proteinase of Fasciola hepatica for Fasciolosis Control in Livestock. AB - Oral vaccination with edible vaccines is one of the most promising approaches in modern vaccinology. Edible vaccines are an alternative to conventional vaccines, which are typically delivered by injection. Here, freeze-dried transgenic lettuce expressing the cysteine proteinase of the trematode Fasciola hepatica (CPFhW) was used to orally vaccinate cattle and sheep against fasciolosis, which is the most important trematode disease due to the parasite's global distribution, wide spectrum of host species and significant economic losses of farmers. In the study, goals such as reducing the intensity of infection, liver damage and F. hepatica fecundity were achieved. Moreover, we demonstrated that the host sex influenced the outcome of infection following vaccination, with female calves and male lambs showing better protection than their counterparts. Since differences occurred following vaccination and infection, different immunization strategies should be considered for different sexes and host species when developing new control methods. The results of the present study highlight the potential of oral vaccination with plant-made and plant-delivered vaccines for F. hepatica infection control. PMID- 30483258 TI - Contribution of Dendritic Cell Responses to Sepsis-Induced Immunosuppression and to Susceptibility to Secondary Pneumonia. AB - Dendritic cells (DCs) are bone marrow derived cells which continuously seed in peripheral tissue. During infection, DCs play an essential interface between innate and adaptive immunity. Pneumonia is a lung inflammation triggered by pathogens and is characterized by excessive release of inflammatory cytokines that activate innate and acquired immunity. Pneumonia induces a rapid and protracted state of susceptibility to secondary infection, a state so-called sepsis-induced immunosuppression. In this review, we focus on the role of DCs in the development of this state of immunosuppression. Early during inflammation, activated DCs are characterized by decreased capacity of antigen (cross)- presentation of newly encountered antigens and decreased production of immunogenic cytokines, and sepsis-induced immunosuppression is mainly explained by a depletion of immature DCs which had all become mature. At a later stage, newly formed respiratory immature DCs are locally programmed by an immunological scare left-over by inflammation to induce tolerance. Tolerogenic Blimp1+ DCs produce suppressive cytokines such as tumor growth factor-B and participate to the maintenance of a local tolerogenic environment notably characterized by accumulation of Treg cells. In mice, the restoration of the immunogenic functions of DCs restores the mucosal immune response to pathogens. In humans, the modulation of inflammation by glucocorticoid during sepsis or trauma preserves DC immunogenic functions and is associated with resistance to secondary pneumonia. Finally, we propose that the alterations of DCs during and after inflammation can be used as biomarkers of susceptibility to secondary pneumonia and are promising therapeutic targets to enhance outcomes of patients with secondary pneumonia. PMID- 30483260 TI - Crispr/Cas Mediated Deletion of PTPN22 in Jurkat T Cells Enhances TCR Signaling and Production of IL-2. AB - A single nucleotide polymorphism, C1858T, in the gene encoding the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) results in one of the strongest genetic traits associated with autoimmune disease outside of the Major Histocompatibility Complex (MHC) genes. However, the consequences of this polymorphism, which introduces an arginine to tryptophan substitution at amino acid 620, for the function of PTPN22 protein is unclear and conflicting results have been obtained in human compared to mouse cells expressing this variant phosphatase. In mouse the variant appears to be a loss-of-function allele resembling a milder form of the null allele, while studies in human cells have reported it to be a gain-of-function mutation. To address whether the phosphatase has distinct functions in mouse vs. human T cells, we used CRISPR gene-editing to generate the first example of human PTPN22-KnockOut (KO) T cells. By comparing isogenic human T cells which express or lack PTPN22, we showed that PTPN22 KO T cells displayed enhanced expression of IL-2 and CD69 upon stimulation with cognate antigen. PTPN22 KO cells also showed increased Erk phosphorylation upon stimulation with weak antigen, but the difference was diminished in response to strong antigen, indicating that PTPN22 plays a more critical role in regulating weak-antigen responses. These data are in keeping with a role for PTPN22 in determining the threshold of stimulation required to activate T cells, a critical function of autoimmune pathogenesis. Our data indicate that PTPN22 has comparable functions in mouse and human T cells, and that the conflicting results in the literature regarding the impact of the point mutation are not due to differences in the activity of PTPN22 itself, but may be related to interactions with other proteins or splice variation. PMID- 30483257 TI - Single-Cell Transcriptomics in Cancer Immunobiology: The Future of Precision Oncology. AB - Cancer is a heterogeneous and complex disease. Tumors are formed by cancer cells and a myriad of non-cancerous cell types that together with the extracellular matrix form the tumor microenvironment. These cancer-associated cells and components contribute to shape the progression of cancer and are deeply involved in patient outcome. The immune system is an essential part of the tumor microenvironment, and induction of cancer immunotolerance is a necessary step involved in tumor formation and growth. Immune mechanisms are intimately associated with cancer progression, invasion, and metastasis; as well as to tumor dormancy and modulation of sensitivity to drug therapy. Transcriptome analyses have been extensively used to understand the heterogeneity of tumors, classifying tumors into molecular subtypes and establishing signatures that predict response to therapy and patient outcomes. However, the classification of the tumor cell diversity and specially the identification of rare populations has been limited in these transcriptomic analyses of bulk tumor cell populations. Massively parallel single-cell RNAseq analysis has emerged as a powerful method to unravel heterogeneity and to study rare cell populations in cancer, through unsupervised sampling and modeling of transcriptional states in single cells. In this context, the study of the role of the immune system in cancer would benefit from single cell approaches, as it will enable the characterization and/or discovery of the cell types and pathways involved in cancer immunotolerance otherwise missed in bulk transcriptomic information. Thus, the analysis of gene expression patterns at single cell resolution holds the potential to provide key information to develop precise and personalized cancer treatment including immunotherapy. This review is focused on the latest single-cell RNAseq methodologies able to agnostically study thousands of tumor cells as well as targeted single-cell RNAseq to study rare populations within tumors. In particular, we will discuss methods to study the immune system in cancer. We will also discuss the current challenges to the study of cancer at the single cell level and the potential solutions to the current approaches. PMID- 30483262 TI - Age at Menarche and Risk of Multiple Sclerosis: Current Progress From Epidemiological Investigations. AB - Multiple sclerosis (MS) is a chronic autoimmune inflammatory disorder of the brain and spinal cord in which focal lymphocytic infiltration leads to the damage of myelin and axons. As a multi-factorial complex trait, both genetic background and environmental factors are involved in MS etiology. The disease is more prevalent among women, and an overall female-to-male sex ratio of around 3 is usually reported. The fact that the female preponderance is only apparent among patients with disease onset after age 12 points toward a role of puberty in MS. A key marker of female pubertal development is menarche, however, evidence from previous epidemiological investigations has been sparse and conflicting: although some studies have linked earlier age at menarche (AAM) to an increased risk of MS, others have found no association or an inverse association. Understanding the effect of AAM in MS could increase our knowledge to the disease etiology, as well as deliver meaningful implication to patients' care by aiding clinical diagnosis. Therefore, we reviewed all the currently available epidemiological studies conducted for AAM and risk of MS in adult human populations. We found evidence supporting a possible favorable role of late AAM on MS risk, but this should be further confirmed by well-designed large-scale epidemiological studies and meta analysis. Future work may be focused on Mendelian randomization analysis incorporating genetic markers to provide additional evidence of a putative causal relationship between AAM and MS. More work should be conducted for non-European populations to increase generalizability, and among the males to complementary with results from females. Future work may also be conducted focusing on hormonal reproductive factors other than menarche, and their effects in MS prognosis, severity, and drug response. PMID- 30483264 TI - Importance of EMT Factor ZEB1 in cDC1 "MutuDC Line" Mediated Induction of Th1 Immune Response. AB - The role of Epithelial to Mesenchymal Transition (EMT) factor Zeb1 is well defined in metastasis and cancer progression but it's importance in dendritic cells (DCs) is unexplored until now. For the first time we report here that Zeb1 controls immunogenic responses of CD8alpha+ conventional Type-I (cDC1) DCs. We found that ZEB1 expression increases significantly after TLR9 stimulation and its depletion impairs activation, co-stimulation and secretion of important cytokines like IL-6, IL-10 and IL-12 in cDC1 MutuDC line. We further confirmed our findings in primary cDC1 DCs derived from bone marrow. Co-culture of these Zeb1 knock down (KD) DCs with OT-II CD4+ T helper cells skewed their differentiation toward Th2 subtype. Moreover, adoptive transfer of activated Zeb1 KD DCs cleared intestinal worms in helminth infected mice by increasing Th2 responses in vivo. Integrative genomic analysis showed Zeb1 as an activator of immune response genes in cDC1 MutuDCs as compared to other pathway genes. In addition, differentially regulated genes in Zeb1 KD RNA-seq showed significant enrichment of Th2 activation pathways supporting our in vitro findings. Mechanistically, we showed that decreased IL-12 secreted by Zeb1 KD DCs is the plausible mechanism for increased Th2 differentiation. Collectively our data demonstrate that Zeb1 could be targeted in DCs to modulate T-cell mediated adaptive immune responses. PMID- 30483265 TI - Pentraxins and Fc Receptor-Mediated Immune Responses. AB - C-reactive protein (CRP) is a member of the pentraxin family of proteins. These proteins are highly conserved over the course of evolution being present as far back as 250 million years ago. Mammalian pentraxins are characterized by the presence of five identical non-covalently linked subunits. Each subunit has a structurally conserved site for calcium-dependent ligand binding. The biological activities of the pentraxins established over many years include the ability to mediate opsonization for phagocytosis and complement activation. Pentraxins have an important role in protection from infection from pathogenic bacteria, and regulation of the inflammatory response. It was recognized early on that some of these functions are mediated by activation of the classical complement pathway through C1q. However, experimental evidence suggested that cellular receptors for pentraxins also play a role in phagocytosis. More recent experimental evidence indicates a direct link between pentraxins and Fc receptors. The Fc receptors were first identified as the major receptors for immunoglobulins. The avidity of the interaction between IgG complexes and Fc receptors is greatly enhanced when multivalent ligands interact with the IgG binding sites and activation of signaling pathways requires Fc receptor crosslinking. Human pentraxins bind and activate human and mouse IgG receptors, FcgammaRI and FcgammaRII, and the human IgA receptor, FcalphaRI. The affinities of the interactions between Fc receptors and pentraxins in solution and on cell surfaces are similar to antibody binding to low affinity Fc receptors. Crystallographic and mutagenesis studies have defined the structural features of these interactions and determined the stoichiometry of binding as one-to-one. Pentraxin aggregation or binding to multivalent ligands increases the avidity of binding and results in activation of these receptors for phagocytosis and cytokine synthesis. This review will discuss the structural and functional characteristics of pentraxin Fc receptor interactions and their implications for host defense and inflammation. PMID- 30483263 TI - The Pleiotropic Immunomodulatory Functions of IL-33 and Its Implications in Tumor Immunity. AB - Interleukin-33 (IL-33) is a IL-1 family member of cytokines exerting pleiotropic activities. In the steady-state, IL-33 is expressed in the nucleus of epithelial, endothelial, and fibroblast-like cells acting as a nuclear protein. In response to tissue damage, infections or necrosis IL-33 is released in the extracellular space, where it functions as an alarmin for the immune system. Its specific receptor ST2 is expressed by a variety of immune cell types, resulting in the stimulation of a wide range of immune reactions. Recent evidences suggest that different IL-33 isoforms exist, in virtue of proteolytic cleavage or alternative mRNA splicing, with potentially different biological activity and functions. Although initially studied in the context of allergy, infection, and inflammation, over the past decade IL-33 has gained much attention in cancer immunology. Increasing evidences indicate that IL-33 may have opposing functions, promoting, or dampening tumor immunity, depending on the tumor type, site of expression, and local concentration. In this review we will cover the biological functions of IL-33 on various immune cell subsets (e.g., T cells, NK, Treg cells, ILC2, eosinophils, neutrophils, basophils, mast cells, DCs, and macrophages) that affect anti-tumor immune responses in experimental and clinical cancers. We will also discuss the possible implications of diverse IL-33 mutations and isoforms in the anti-tumor activity of the cytokine and as possible clinical biomarkers. PMID- 30483261 TI - Regulation of Placental Extravillous Trophoblasts by the Maternal Uterine Environment. AB - During placentation invasive extravillous trophoblasts (EVTs) migrate into the maternal uterus and modify its vessels. In particular, remodeling of the spiral arteries by EVTs is critical for adapting blood flow and nutrient transport to the developing fetus. Failures in this process have been noticed in different pregnancy complications such as preeclampsia, intrauterine growth restriction, stillbirth, or recurrent abortion. Upon invasion into the decidua, the endometrium of pregnancy, EVTs encounter different maternal cell types such as decidual macrophages, uterine NK (uNK) cells and stromal cells expressing a plethora of growth factors and cytokines. Here, we will summarize development of the EVT lineage, a process occurring independently of the uterine environment, and formation of its different subtypes. Further, we will discuss interactions of EVTs with arteries, veins and lymphatics and illustrate how the decidua and its different immune cells regulate EVT differentiation, invasion and survival. The present literature suggests that the decidual environment and its soluble factors critically modulate EVT function and reproductive success. PMID- 30483267 TI - PRL2 Controls Phagocyte Bactericidal Activity by Sensing and Regulating ROS. AB - Although it is well-recognized that inflammation enhances leukocyte bactericidal activity, the underlying mechanisms are not clear. Here we report that PRL2 is sensitive to oxidative stress at inflamed sites. Reduced PRL2 in phagocytes causes increased respiratory burst activity and enhances phagocyte bactericidal activity. PRL2 (Phosphatase Regenerating Liver 2) is highly expressed in resting immune cells, but is markedly downregulated by inflammation. in vitro experiments showed that PRL2 was sensitive to hydrogen peroxide (H2O2), a common damage signal at inflamed sites. In response to infection, PRL2 knockout (KO) phagocytes were hyper activated, produced more reactive oxygen species (ROS) and exhibited enhanced bactericidal activity. Mice with PRL2 deficiency in the myeloid cell compartment were resistant to lethal listeria infection and cleared the bacteria more rapidly and effectively. Moreover, in vitro experiments demonstrated that PRL2 binds to GTPase Rac and regulates ROS production. Rac GTPases were more active in PRL2 (KO) phagocytes than in wild type cells after bacterium infection. Our findings indicate that PRL2 senses ROS at inflamed sites and regulates ROS production in phagocytes. This positive feedback mechanism promotes bactericidal activity of phagocytes and may play an important role in innate anti-bacterial immunity. PMID- 30483266 TI - Maternal High Fat Diet Alters Gut Microbiota of Offspring and Exacerbates DSS Induced Colitis in Adulthood. AB - Background: Accumulating evidence shows that high fat diet is closely associated with inflammatory bowel disease. However, the effects and underlying mechanisms of maternal high fat diet (MHFD) on the susceptibility of offspring to colitis in adulthood lacks confirmation. Methods: C57BL/6 pregnant mice were given either a high fat (60 E% fat, MHFD group) or control diet [10 E% fat, maternal control diet (MCD) group] during gestation and lactation. The intestinal development, mucosal barrier function, microbiota, and mucosal inflammation of 3-week old offspring were assessed. After weaning all mice were fed a control diet until 8 weeks of age when the microbiota was analyzed. Offspring were also treated with 2% DSS solution for 5 days and the severity of colitis was assessed. Results: The offspring in MHFD group were significantly heavier than those in MCD group only at 2-4 weeks of age, while no differences were found in the body weight between two groups at other measured time points. Compared with MCD group, MHFD significantly inhibited intestinal development and disrupted barrier function in 3-week old offspring. Although H&E staining showed no obvious microscopic inflammation in both groups of 3-week old offspring, increased production of inflammatory cytokines indicated low-grade inflammation was induced in MHFD group. Moreover, fecal analysis of the 3-week old offspring indicated that the microbiota compositions and diversity were significantly changed in MHFD group. Interestingly after 5 weeks consumption of control diet in both groups, the microbiota composition of offspring in MHFD group was still different from that in MCD group, although the bacterial diversity was partly recovered at 8 weeks of age. Finally, after DSS treatment in 8-week old offspring, MHFD significantly exacerbated the severity of colitis and increased the production of proinflammatory cytokine. Conclusions: Our data reveal that MHFD in early life can inhibit intestinal development, induce dysbiosis and low-grade inflammation and lead to the disruption of intestinal mucosal barrier in offspring, and enhance DSS-induced colitis in adulthood. PMID- 30483268 TI - A Role for MK2 in Enhancing Neutrophil-Derived ROS Production and Aggravating Liver Ischemia/Reperfusion Injury. AB - Increased inflammatory responses and enhanced reactive oxygen species contribute to hepatic ischemia/reperfusion (I/R) injury, however the modulatory mechanisms haven't been completely unveiled. Here, we report that genetic deficiency of MAPK activated protein kinase 2 (MK2) protected against hepatic I/R injury and decreased hepatic neutrophil accumulation in MK2-/- mice. Depletion of neutrophil attenuated hepatic I/R injury in wide type mice. In response to C5a stimulation, MK2-/- neutrophils generated less superoxide in which both NADPH oxidase activation and p47phox phosphorylation were decreased. Furthermore, Ser329 of p47phox was identified for enhancement of superoxide production. The Ser329 phosphorylation was reduced in MK2-/- neutrophils. To determine whether MK2 modulates hepatic I/R injury via activating neutrophils, we generated myeloid specific MK2 deletion mice (MK2Lyz2-KO) and liver I/R injury was reduced in MK2Lyz2-KO mice. Our results indicate that MK2 augments hepatic I/R injury and induces ROS production with increased p47phox phosphorylation and MK2 is a potential drug target for treating hepatic I/R injury. PMID- 30483269 TI - HVEM and CD160: Regulators of Immunopathology During Malaria Blood-Stage. AB - CD8+ T cells are key players during infection with the malaria parasite Plasmodium berghei ANKA (PbA). While they cannot provide protection against blood stage parasites, they can cause immunopathology, thus leading to the severe manifestation of cerebral malaria. Hence, the tight control of CD8+ T cell function is key in order to prevent fatal outcomes. One major mechanism to control CD8+ T cell activation, proliferation and effector function is the integration of co-inhibitory and co-stimulatory signals. In this study, we show that one such pathway, the HVEM-CD160 axis, significantly impacts CD8+ T cell regulation and thereby the incidence of cerebral malaria. Here, we show that the co-stimulatory molecule HVEM is indeed required to maintain CD8+ T effector populations during infection. Additionally, by generating a CD160-/- mouse line, we observe that the HVEM ligand CD160 counterbalances stimulatory signals in highly activated and cytotoxic CD8+ T effector cells, thereby restricting immunopathology. Importantly, CD160 is also induced on cytotoxic CD8+ T cells during acute Plasmodium falciparum malaria in humans. In conclusion, CD160 is specifically expressed on highly activated CD8+ T effector cells that are harmful during the blood-stage of malaria. PMID- 30483270 TI - Evolutionary Regression and Species-Specific Codon Usage of TLR15. AB - Toll-like receptors (TLRs) form an ancient family of innate immune receptors that detect microbial structures and activate the host immune response. Most subfamilies of TLRs (including TLR3, TLR5, and TLR7) are highly conserved among vertebrate species. In contrast, TLR15, a member of the TLR1 subfamily, appears to be unique to birds and reptiles. We investigated the functional evolution of TLR15. Phylogenetic and synteny analyses revealed putative TLR15 orthologs in bird species, several reptilian species and also in a shark species, pointing to an unprecedented date of origin of TLR15 as well as large scale reciprocal loss of this TLR in most other vertebrates. Cloning and functional analysis of TLR15 of the green anole lizard (Anolis carolinensis), salt water crocodile (Crocodylus porosus), American alligator (Alligator mississippiensis), and chicken (Gallus gallus) showed for all species TLR15 specific protease-induced activation of NF kappaB, despite highly variable TLR15 protein expression levels. The variable TLR15 expression was consistent in both human and reptilian cells and could be attributed to species-specific differences in TLR15 codon usage. The species specific codon bias was not or barely noted for more evolutionarily conserved TLRs (e.g., TLR3). Overall, our results indicate that TLR15 originates before the divergence of chondrichthyes fish and tetrapods and that TLR15 of both avian and reptilian species has a conserved function as protease activated receptor. The species-specific codon usage and large scale loss of TLR15 in most vertebrates suggest evolutionary regression of this ancient TLR. PMID- 30483272 TI - The Immunogenetic Conundrum of Preeclampsia. AB - Pregnancy is an immunological challenge to the mother. The fetal tissues including the placenta must be protected from activation of the maternal immune system. On the other hand, the placental tissue sheds into the maternal circulation and must be adequately identified and phagocytized by the maternal immune system. During a healthy pregnancy, numerous immunosuppressive processes take place that allow the allograft fetus to thrive under exposure to humoral and cellular components of the maternal immune system. Breakdown of immune tolerance may result in sterile inflammation and cause adverse pregnancy outcomes such as preeclampsia, a vascular disease of the pregnancy with unpredictable course and symptoms from several organs. Immunological incompatibility between mother and fetus is strongly indicated in preeclampsia. Recently, genetic factors linking immunological pathways to predisposition to preeclampsia have been identified. In this mini-review genetic variation in immunological factors are discussed in the context of preeclampsia. Specifically, we explore immunogenetic and immunomodulary mechanisms contributing to loss of tolerance, inflammation, and autoimmunity in preeclampsia. PMID- 30483271 TI - Targeting Macrophage-Recruiting Chemokines as a Novel Therapeutic Strategy to Prevent the Progression of Solid Tumors. AB - Solid tumors are initiated by genetic mutations in non-hematopoietic cells and progress into invasive malignant tumors. This tumor progression often culminates in metastatic disease that is largely refractory to current therapeutic modalities and thus dramatically reduces survival of tumor patients. As solid tumors account for more than 80% of cancer-related deaths, it is necessary to develop novel therapeutic strategies to treat the diseases. An attractive strategy is to target macrophages in both primary tumors [known as tumor associated macrophages (TAMs)] and metastatic tumors [called metastasis associated macrophages (MAMs)]. TAMs and MAMs are abundant in most solid tumors and can promote tumor metastasis. Several studies in various models of solid tumors suggest that the accumulation of TAMs, MAMs, and their progenitor cells is regulated by chemokine ligands released by tumor and stromal cells. Consequently, these macrophage-recruiting chemokines could be potential therapeutic targets to prevent malignant tumor development through disruption of the accumulation of pro metastatic macrophages. This review will discuss the role of chemokine ligands and their receptors in TAM and MAM accumulation in primary and secondary tumor sites, and finally discuss the therapeutic potential of inhibitors against these macrophage-recruiting chemokines. PMID- 30483275 TI - Whole-Plant Water Use in Field Grown Grapevine: Seasonal and Environmental Effects on Water and Carbon Balance. AB - Water scarcity is a main challenge in vineyards sustainability in most of the grapevine areas now and even more in near future due to climatic change perspectives. In consequence, water use efficiency (WUE) measurements are of the highest interest to improve the sustainability of this crop. The vast majority of WUE measurements relays on measurements of leaf carbon and water fluxes at leaf level. However, less data are available at the whole-plant level, and for the moment those data are not totally coincident with conclusions reached at leaf scale. In this study, we used whole-plant chambers able to enclose an entire plant of 12 years old to measure at the same time water and carbon fluxes under realistic field grown conditions. The main objectives were to identify the technical issues interfering the whole-plant measurements and track the environmental and other abiotic factors that can affect water and carbon balance, i.e., WUE at the whole-plant scale. To achieve those objectives, we measured whole-plant water and carbon fluxes in grapevine exposed to two different water regimes at three phenological stages [pea size (July), ripening (August), and harvest (September)]. In September, measurements were repeated under high CO2 to also check its effect at the whole-plant scale. The results indicate that water and carbon fluxes are well coordinated under both water availability treatments. Under drought conditions, both fluxes were drastically reduced, but surprisingly the estimated WUE resulted not improved but decreased, contrarily to what is shown at the leaf scale. The phenology (September) also strongly decreased both water and carbon fluxes when compared to measurements in July. We hypostatized that harvest load respiration rates could have an important weight on the whole plant net carbon exchange (NCE). Finally, high CO2 measurements, after correction for leaks, indicated an increase of whole-plant NCE as well as increased whole plant WUE, as expected. Several technical issues were identified, like 1/instability of [CO2] during the night period that prevent robust estimation of whole-plant respiration and 2/condensation during last night and sun-rise hours which may affect the estimation of daily plant transpiration. PMID- 30483273 TI - Inflammatory Links Between High Fat Diets and Diseases. AB - In recent years, chronic overnutrition, such as consumption of a high-fat diet (HFD), has been increasingly viewed as a significant modifiable risk factor for diseases such as diabetes and certain types of cancer. However, the mechanisms by which HFDs exert adverse effects on human health remains poorly understood. Here, this paper will review the recent scientific literature about HFD-induced inflammation and subsequent development of diseases and cancer, with an emphasis on mechanisms involved. Given the expanding global epidemic of excessive HFD intake, understanding the impacts of a HFD on these medical conditions, gaining great insights into possible underlying mechanisms, and developing effective therapeutic strategies are of great importance. PMID- 30483274 TI - Functional Analysis of Four Terpene Synthases in Rose-Scented Pelargonium Cultivars (Pelargonium * hybridum) and Evolution of Scent in the Pelargonium Genus. AB - Pelargonium genus contains about 280 species among which at least 30 species are odorant. Aromas produced by scented species are remarkably diverse such as rose, mint, lemon, nutmeg, ginger and many others scents. Amongst odorant species, rose scented pelargoniums, also named pelargonium rosat, are the most famous hybrids for their production of essential oil (EO), widely used by perfume and cosmetic industries. Although EO composition has been extensively studied, the underlying biosynthetic pathways and their regulation, most notably of terpenes, are largely unknown. To gain a better understanding of the terpene metabolic pathways in pelargonium rosat, we generated a transcriptome dataset of pelargonium leaf and used a candidate gene approach to functionally characterise four terpene synthases (TPSs), including a geraniol synthase, a key enzyme responsible for the biosynthesis of the main rose-scented terpenes. We also report for the first time the characterisation of a novel sesquiterpene synthase catalysing the biosynthesis of 10-epi-gamma-eudesmol. We found a strong correlation between expression of the four genes encoding the respective TPSs and accumulation of the corresponding products in several pelargonium cultivars and species. Finally, using publically available RNA-Seq data and de novo transcriptome assemblies, we inferred a maximum likelihood phylogeny from 270 pelargonium TPSs, including the four newly discovered enzymes, providing clues about TPS evolution in the Pelargonium genus. Notably, we show that, by contrast to other TPSs, geraniol synthases from the TPS-g subfamily conserved their molecular function throughout evolution. PMID- 30483276 TI - Intraspecific Trait Variation and Phenotypic Plasticity Mediate Alpine Plant Species Response to Climate Change. AB - In a rapidly changing climate, alpine plants may persist by adapting to new conditions. However, the rate at which the climate is changing might exceed the rate of adaptation through evolutionary processes in long-lived plants. Persistence may depend on phenotypic plasticity in morphology and physiology. Here we investigated patterns of leaf trait variation including leaf area, leaf thickness, specific leaf area, leaf dry matter content, leaf nutrients (C, N, P) and isotopes (delta13C and delta15N) across an elevation gradient on Gongga Mountain, Sichuan Province, China. We quantified inter- and intra-specific trait variation and the plasticity in leaf traits of selected species to experimental warming and cooling by using a reciprocal transplantation approach. We found substantial phenotypic plasticity in most functional traits where delta15N, leaf area, and leaf P showed greatest plasticity. These traits did not correspond with traits with the largest amount of intraspecific variation. Plasticity in leaf functional traits tended to enable plant populations to shift their trait values toward the mean values of a transplanted plants' destination community, but only if that population started with very different trait values. These results suggest that leaf trait plasticity is an important mechanism for enabling plants to persist within communities and to better tolerate changing environmental conditions under climate change. PMID- 30483278 TI - Proteomics of Heat-Stress and Ethylene-Mediated Thermotolerance Mechanisms in Tomato Pollen Grains. AB - Heat stress is a major cause for yield loss in many crops, including vegetable crops. Even short waves of high temperature, becoming more frequent during recent years, can be detrimental. Pollen development is most heat-sensitive, being the main cause for reduced productivity under heat-stress across a wide range of crops. The molecular mechanisms involved in pollen heat-stress response and thermotolerance are however, not fully understood. Recently, we have demonstrated that ethylene, a gaseous plant hormone, plays a role in tomato (Solanum lycopersicum) pollen thermotolerance. These results were substantiated in the current work showing that increasing ethylene levels by using an ethylene releasing substance, ethephon, prior to heat-stress exposure, increased pollen quality. A proteomic approach was undertaken, to unravel the mechanisms underlying pollen heat-stress response and ethylene-mediated pollen thermotolerance in developing pollen grains. Proteins were extracted and analyzed by means of a gel LC-MS fractionation protocol, and a total of 1,355 proteins were identified. A dataset of 721 proteins, detected in three biological replicates of at least one of the applied treatments, was used for all analyses. Quantitative analysis was performed based on peptide count. The analysis revealed that heat-stress affected the developmental program of pollen, including protein homeostasis (components of the translational and degradation machinery), carbohydrate, and energy metabolism. Ethephon-pre-treatment shifted the heat stressed pollen proteome closer to the proteome under non-stressful conditions, namely, by showing higher abundance of proteins involved in protein synthesis, degradation, tricarboxylic acid cycle, and RNA regulation. Furthermore, up regulation of protective mechanisms against oxidative stress was observed following ethephon-treatment (including higher abundance of glutathione-disulfide reductase, glutaredoxin, and protein disulfide isomerase). Taken together, the findings identified systemic and fundamental components of pollen thermotolerance, and serve as a valuable quantitative protein database for further research. PMID- 30483277 TI - Unified Transcriptomic Signature of Arbuscular Mycorrhiza Colonization in Roots of Medicago truncatula by Integration of Machine Learning, Promoter Analysis, and Direct Merging Meta-Analysis. AB - Plant root symbiosis with Arbuscular mycorrhizal (AM) fungi improves uptake of water and mineral nutrients, improving plant development under stressful conditions. Unraveling the unified transcriptomic signature of a successful colonization provides a better understanding of symbiosis. We developed a framework for finding the transcriptomic signature of Arbuscular mycorrhiza colonization and its regulating transcription factors in roots of Medicago truncatula. Expression profiles of roots in response to AM species were collected from four separate studies and were combined by direct merging meta-analysis. Batch effect, the major concern in expression meta-analysis, was reduced by three normalization steps: Robust Multi-array Average algorithm, Z-standardization, and quartiling normalization. Then, expression profile of 33685 genes in 18 root samples of Medicago as numerical features, as well as study ID and Arbuscular mycorrhiza type as categorical features, were mined by seven models: RELIEF, UNCERTAINTY, GINI INDEX, Chi Squared, RULE, INFO GAIN, and INFO GAIN RATIO. In total, 73 genes selected by machine learning models were up-regulated in response to AM (Z-value difference > 0.5). Feature weighting models also documented that this signature is independent from study (batch) effect. The AM inoculation signature obtained was able to differentiate efficiently between AM inoculated and non-inoculated samples. The AP2 domain class transcription factor, GRAS family transcription factors, and cyclin-dependent kinase were among the highly expressed meta-genes identified in the signature. We found high correspondence between the AM colonization signature obtained in this study and independent RNA seq experiments on AM colonization, validating the repeatability of the colonization signature. Promoter analysis of upregulated genes in the transcriptomic signature led to the key regulators of AM colonization, including the essential transcription factors for endosymbiosis establishment and development such as NF-YA factors. The approach developed in this study offers three distinct novel features: (I) it improves direct merging meta-analysis by integrating supervised machine learning models and normalization steps to reduce study-specific batch effects; (II) seven attribute weighting models assessed the suitability of each gene for the transcriptomic signature which contributes to robustness of the signature (III) the approach is justifiable, easy to apply, and useful in practice. Our integrative framework of meta-analysis, promoter analysis, and machine learning provides a foundation to reveal the transcriptomic signature and regulatory circuits governing Arbuscular mycorrhizal symbiosis and is transferable to the other biological settings. PMID- 30483280 TI - Seed Transmission of Epichloe Endophytes in Lolium perenne Is Heavily Influenced by Host Genetics. AB - Vertical transmission of symbiotic Epichloe endophytes from host grasses into progeny seed is the primary mechanism by which the next generation of plants is colonized. This process is often imperfect, resulting in endophyte-free seedlings which may have poor ecological fitness if the endophyte confers protective benefits to its host. In this study, we investigated the influence of host genetics and environment on the vertical transmission of Epichloe festucae var. lolii strain AR37 in the temperate forage grass Lolium perenne. The efficiency of AR37 transmission into the seed of over 500 plant genotypes from five genetically diverse breeding populations was determined. In Populations I-III, which had undergone previous selection for high seed infection by AR37, mean transmission was 88, 93, and 92%, respectively. However, in Populations IV and V, which had not undergone previous selection, mean transmission was 69 and 70%, respectively. The transmission values, together with single-nucleotide polymorphism data obtained using genotyping-by-sequencing for each host, was used to develop a genomic prediction model for AR37 seed transmission. The predictive ability of the model was estimated at r = 0.54. While host genotype contributed greatly to differences in AR37 seed transmission, undefined environmental variables also contributed significantly to seed transmission across different years and geographic locations. There was evidence for a small host genotype-by-environment effect; however this was less pronounced than genotype or environment alone. Analysis of endophyte infection levels in parent plants within Populations I and IV revealed a loss of endophyte infection over time in Population IV only. This population also had lower average tiller infection frequencies than Population I, suggesting that AR37 failed to colonize all the daughter tillers and therefore seeds. However, we also observed that infection of seed by AR37 may fail during or after initiation of floral development from plants where all tillers remained endophyte-infected over time. While the effects of environment and host genotype on fungal endophyte transmission have been evaluated previously, this is the first study that quantifies the relative impacts of host genetics and environment on endophyte vertical transmission. PMID- 30483279 TI - Artificial Intelligence Understands Peptide Observability and Assists With Absolute Protein Quantification. AB - Targeted mass spectrometry has become the method of choice to gain absolute quantification information of high quality, which is essential for a quantitative understanding of biological systems. However, the design of absolute protein quantification assays remains challenging due to variations in peptide observability and incomplete knowledge about factors influencing peptide detectability. Here, we present a deep learning algorithm for peptide detectability prediction, d::pPop, which allows the informed selection of synthetic proteotypic peptides for the successful design of targeted proteomics quantification assays. The deep neural network is able to learn a regression model that relates the physicochemical properties of a peptide to its ion intensity detected by mass spectrometry. The approach makes use of experimentally detected deviations from the assumed equimolar abundance of all peptides derived from a given protein. Trained on extensive proteomics datasets, d::pPop's plant and non-plant specific models can predict the quality of proteotypic peptides for not yet experimentally identified proteins. Interrogating the deep neural network after learning from ~76,000 peptides per model organism allows to investigate the impact of different physicochemical properties on the observability of a peptide, thus providing insights into peptide observability as a multifaceted process. Empirical evaluation with rank accuracy metrics showed that our prediction approach outperforms existing algorithms. We circumvent the delicate step of selecting positive and negative training sets and at the same time also more closely reflect the need for selecting the top most promising peptides for targeting a protein of interest. Further, we used an artificial QconCAT protein to experimentally validate the observability prediction. Our proteotypic peptide prediction approach not only facilitates the design of absolute protein quantification assays via a user-friendly web interface but also enables the selection of proteotypic peptides for not yet observed proteins, hence rendering the tool especially useful for plant research. PMID- 30483281 TI - Rice Soluble Starch Synthase I: Allelic Variation, Expression, Function, and Interaction With Waxy. AB - Starch, which is composed of amylose and amylopectin, is the key determinant of rice quality. Amylose is regulated by the Waxy (Wx) gene, whereas amylopectin is coordinated by various enzymes including eight soluble starch synthases (SSSs), of which SSSI accounts for ~70% of the total SSS activity in cereal endosperm. Although great progress has been made in understanding SSSI gene expression and function, allelic variation and its effects on gene expression, rice physicochemical properties and qualities, and interactions with the Wx gene remain unclear. Herein, SSSI nucleotide polymorphisms were analyzed in 165 rice varieties using five distinct molecular markers, three of which reside in an SSSI promoter and might account for a higher expression of the SSSIi allele in indica ssp. than of the SSSIj allele in japonica ssp. The results of SSSI promoter-Beta Glucuronidase (beta-GUS) analysis were consistent with the expression results. Moreover, analysis of near isogenic lines (NILs) in the Nipponbare (Nip) background showed that Nip (SSSIi ) and Nip (SSSIj ) differed in their thermal properties, gel consistency (GC), and granule crystal structure. Knockdown of SSSI expression using the SSSI-RNA interference (RNAi) construct in both japonica and indica backgrounds caused consistent changes in most tested physicochemical characteristics except GC. Moreover, taste value analysis (TVA) showed that introduction of the SSSI allele in indica or knockdown of SSSI expression in japonica cultivars significantly reduced the comprehensive taste value, which was consistent with the superior taste of japonica against indica. Furthermore, to test the potential interaction between SSSI and different Wx alleles, three NILs within the Wx locus were generated in the indica cv. Longtefu (LTF) background, which were designated as LTF (Wxa ), LTF (Wxb ), and LTF (wx). The SSSI-RNAi construct was also introduced into these three NILs, and physiochemical analysis confirmed that the knockdown of SSSI significantly increased the rice apparent amylose content (AAC) only in the Wxa and Wxb background and caused different changes in GC in the NILs. Therefore, the effect of SSSI variation on rice quality also depends on its crosstalk with other factors, especially the Wx gene. These findings provide fundamental knowledge for future breeding of rice with premium eating and cooking qualities. PMID- 30483282 TI - Response of Wheat to a Multiple Species Microbial Inoculant Compared to Fertilizer Application. AB - Microbial inoculants, including those formed from multiple species, may have dual functions as biostimulants and/or biocontrol agents, and claimed agricultural benefits are instrumental for regulatory categorisation. Biostimulants include commercial products containing substances or microorganisms that stimulate plant growth. Biostimulant microbes can be involved in a range of processes that affect N and P transformations in soil and thus influence nutrient availability, and N and P fertilizers can influence soil microbial diversity and function. A glasshouse experiment was conducted to investigate the effect of a multiple species microbial inoculant relative to a rock-based mineral fertilizer and a chemical fertilizer on wheat growth and yield, and on microbial diversity in the rhizosphere. The microbial inoculant was compared to the mineral fertilizer (equivalent to 5.6 kg N ha-1 and 5.6 kg P ha-1), and to the chemical fertilizer applied at three rates equivalent to: (i) 7.3 kg N ha-1 and 8.4 kg P ha-1 as recommended for on-farm use, (ii) 5.6 kg N ha-1 and 6.5 kg P ha-1 which matched the N in the mineral fertilizer, and (iii) 4.9 kg N ha-1 and 5.6 kg P ha-1 which matched P content in the mineral fertilizer. Despite an early reduction in plant growth, the microbial inoculant treatment increased shoot growth at maturity compared to the control. Similarly, grain yield was higher after application of the microbial inoculant when compared to control, and it was similar to that of plants receiving the fertilizer treatments. Using 16S rRNA sequencing, the microbial inoculant and fertilizer treatments were shown to influence the diversity of rhizosphere bacteria. The microbial inoculant increased the relative abundance of the phylum Actinobacteria. At tillering, the proportion of roots colonized by arbuscular mycorrhizal (AM) fungi increased with the microbial inoculant and mineral fertilizer treatments, but decreased with the chemical fertilizer treatments. At maturity, there were no treatment effects on the proportion of wheat roots colonized by AM fungi. Overall, the multiple species microbial inoculant had beneficial effects in terms of wheat yield relative to the commercial mineral and chemical fertilizers applied at the level recommended for on-farm use in south-western Australia. PMID- 30483283 TI - Genome Editing for Crop Improvement - Applications in Clonally Propagated Polyploids With a Focus on Potato (Solanum tuberosum L.). AB - Genome-editing has revolutionized biology. When coupled with a recently streamlined regulatory process by the U.S. Department of Agriculture and the potential to generate transgene-free varieties, genome-editing provides a new avenue for crop improvement. For heterozygous, polyploid and vegetatively propagated crops such as cultivated potato, Solanum tuberosum Group Tuberosum L., genome-editing presents tremendous opportunities for trait improvement. In potato, traits such as improved resistance to cold-induced sweetening, processing efficiency, herbicide tolerance, modified starch quality and self-incompatibility have been targeted utilizing CRISPR/Cas9 and TALEN reagents in diploid and tetraploid clones. However, limited progress has been made in other such crops including sweetpotato, strawberry, grapes, citrus, banana etc., In this review we summarize the developments in genome-editing platforms, delivery mechanisms applicable to plants and then discuss the recent developments in regulation of genome-edited crops in the United States and The European Union. Next, we provide insight into the challenges of genome-editing in clonally propagated polyploid crops, their current status for trait improvement with future prospects focused on potato, a global food security crop. PMID- 30483284 TI - Dissecting the Physiological Function of Plant Glyoxalase I and Glyoxalase I-Like Proteins. AB - The Arabidopsis genome annotation include 11 glyoxalase I (GLXI) genes, all encoding for protein members of the vicinal oxygen chelate (VOC) superfamily. The biochemical properties and physiological importance of three Arabidopsis GLXI proteins in the detoxification of reactive carbonyl species has been recently described. Analyses of phylogenetic relationships and conserved GLXI binding sites indicate that the other eight GLXI genes (GLXI-like) do not encode for proteins with GLXI activity. In this perspective article we analyse the structural features of GLXI and GLXI-like proteins, and explore splice forms and transcript abundance under abiotic stress conditions. Finally, we discuss future directions of research on this topic with respect to the substrate identification of GLXI and GLXI-like proteins and the need of reliable quantitative measurements of reactive carbonyl species in plant tissues. PMID- 30483285 TI - Integrative Analysis of Three RNA Sequencing Methods Identifies Mutually Exclusive Exons of MADS-Box Isoforms During Early Bud Development in Picea abies. AB - Recent efforts to sequence the genomes and transcriptomes of several gymnosperm species have revealed an increased complexity in certain gene families in gymnosperms as compared to angiosperms. One example of this is the gymnosperm sister clade to angiosperm TM3-like MADS-box genes, which at least in the conifer lineage has expanded in number of genes. We have previously identified a member of this sub-clade, the conifer gene DEFICIENS AGAMOUS LIKE 19 (DAL19), as being specifically upregulated in cone-setting shoots. Here, we show through Sanger sequencing of mRNA-derived cDNA and mapping to assembled conifer genomic sequences that DAL19 produces six mature mRNA splice variants in Picea abies. These splice variants use alternate first and last exons, while their four central exons constitute a core region present in all six transcripts. Thus, they are likely to be transcript isoforms. Quantitative Real-Time PCR revealed that two mutually exclusive first DAL19 exons are differentially expressed across meristems that will form either male or female cones, or vegetative shoots. Furthermore, mRNA in situ hybridization revealed that two mutually exclusive last DAL19 exons were expressed in a cell-specific pattern within bud meristems. Based on these findings in DAL19, we developed a sensitive approach to transcript isoform assembly from short-read sequencing of mRNA. We applied this method to 42 putative MADS-box core regions in P. abies, from which we assembled 1084 putative transcripts. We manually curated these transcripts to arrive at 933 assembled transcript isoforms of 38 putative MADS-box genes. 152 of these isoforms, which we assign to 28 putative MADS-box genes, were differentially expressed across eight female, male, and vegetative buds. We further provide evidence of the expression of 16 out of the 38 putative MADS-box genes by mapping PacBio Iso-Seq circular consensus reads derived from pooled sample sequencing to assembled transcripts. In summary, our analyses reveal the use of mutually exclusive exons of MADS-box gene isoforms during early bud development in P. abies, and we find that the large number of identified MADS-box transcripts in P. abies results not only from expansion of the gene family through gene duplication events but also from the generation of numerous splice variants. PMID- 30483286 TI - Combinations of Independent Dominant Loci Conferring Clubroot Resistance in All Four Turnip Accessions (Brassica rapa) From the European Clubroot Differential Set. AB - Clubroot disease is devastating to Brassica crop production when susceptible cultivars are planted in infected fields. European turnips are the most resistant sources and their resistance genes have been introduced into other crops such oilseed rape (Brassica napus L.), Chinese cabbage and other Brassica vegetables. The European clubroot differential (ECD) set contains four turnip accessions (ECD1-4). These ECD turnips exhibited high levels of resistance to clubroot when they were tested under controlled environmental conditions with Canadian field isolates. Gene mapping of the clubroot resistance genes in ECD1-4 were performed and three independent dominant resistance loci were identified. Two resistance loci were mapped on chromosome A03 and the third on chromosome A08. Each ECD turnip accession contained two of these three resistance loci. Some resistance loci were homozygous in ECD accessions while others showed heterozygosity based on the segregation of clubroot resistance in 20 BC1 families derived from ECD1 to 4. Molecular markers were developed linked to each clubroot resistance loci for the resistance gene introgression in different germplasm. PMID- 30483287 TI - Coffee Somatic Embryogenesis: How Did Research, Experience Gained and Innovations Promote the Commercial Propagation of Elite Clones From the Two Cultivated Species? AB - Since the 1990s, somatic embryogenesis (SE) has enabled the propagation of selected varieties, Arabica F1 hybrid and Robusta clones, originating from the two cultivated coffee species, Coffea arabica and Coffea canephora, respectively. This paper shows how mostly empirical research has led to successful industrial transfers launched in the 2000s in Latin America, Africa, and Asia. Coffee SE can be considered as a model for other woody perennial crops for the following reasons: (i) a high biological efficiency has been demonstrated for propagated varieties at all developmental stages, and (ii) somaclonal variation is understood and mastered thanks to intensive research combining molecular markers and field observations. Coffee SE is also a useful model given the strong economic constraints that are specific to this species. In brief, SE faced four difficulties: (i) the high cost of SE derived plants compared to the cost of seedlings of conventional varieties, (ii) the logistic problems involved in reaching small-scale coffee growers, (iii) the need for certification, and (iv) the lack of solvency among small-scale producers. Nursery activities were professionalized by introducing varietal certification, quality control with regard to horticultural problems and somaclonal variation, and sanitary control for Xylella fastidiosa. In addition, different technology transfers were made to ensure worldwide dissemination of improved F1 Arabica hybrids and Robusta clones. Innovations have been decisive for successful scaling-up and reduction of production costs, such as the development of temporary immersion bioreactors for the mass production of pre-germinated embryos, their direct sowing on horticultural soil, and the propagation of rejuvenated SE plants by rooted mini cuttings. Today, SE is a powerful tool that is widely used in coffee for biotechnological applications including propagation and genetic transformation. Basic research has recently started taking advantage of optimized SE protocols. Based on -omics methodologies, research aims to decipher the molecular events involved in the key developmental switches of coffee SE. In parallel, a high throughput screening of active molecules on SE appears to be a promising tool to speed-up the optimization of SE protocols. PMID- 30483288 TI - Symbiotic Effectivity of Dual and Tripartite Associations on Soybean (Glycine max L. Merr.) Cultivars Inoculated With Bradyrhizobium japonicum and AM Fungi. AB - Soybean (Glycine max L. Merr.) is regarded worldwide as indisputably one of the most important crops for human food and animal feed. The presence of symbiotic bacteria and fungi is essential for soybean breeding, especially in low-input agricultural systems. Research on the cooperation between different microbial symbionts is a key to understanding how the health and productivity of the plant is supported. The symbiotic effectivity of dual and tripartite symbiotic agents was investigated in two pot experiments on different soybean cultivars with special regard to compatibility. In the Selection experiment, two out of sixteen soybean cultivars (Aliz, Emese) were chosen on the basis of their drought tolerance and used in all the other investigations. In the Compatibility experiment, the compatible coupling of symbiotic partners was selected based on the efficiency of single and co-inoculation with two Bradyrhizobium japonicum strains and two commercial arbuscular mycorrhizal fungal (AMF) products. Significant differences were found in the infectivity and effectivity of the microsymbionts. The rhizobial and AMF inoculation generally improved plant production, photosynthetic efficiency and root activity, but this effect depended on the type of symbiotic assotiation. Despite the low infectivity of AMF, inocula containing fungi were more beneficial than those containing only rhizobia. In the Drought Stress (DS) experiment, co-inoculated and control plants were grown in chernozem soil originating from organic farms. Emese was more resistant to drought stress than Aliz and produced a bigger root system. Under DS, the growth parameters of both microbially inoculated cultivars were better than that of control, proving that even drought tolerant genotypes can strengthen their endurance due to inoculation with AMF and nitrogen fixing bacteria. Root electrical capacitance (CR) showed a highly significant linear correlation with root and shoot dry mass and leaf area. The same root biomass was associated with higher CR in inoculated hosts. As CR method detects the absorptive surface increasing due to inoculation, it may be used to check the efficiency of the microbial treatment. PMID- 30483289 TI - Integrated QTL and eQTL Mapping Provides Insights and Candidate Genes for Fatty Acid Composition, Flowering Time, and Growth Traits in a F2 Population of a Novel Synthetic Allopolyploid Brassica napus. AB - Brassica napus (B. napus, AACC), is an economically important allotetraploid crop species that resulted from hybridization between two diploid species, Brassica rapa (AA) and Brassica olereacea (CC). We have created one new synthetic B. napus genotype Da-Ae (AACC) and one introgression line Da-Ol-1 (AACC), which were used to generate an F2 mapping population. Plants in this F2 mapping population varied in fatty acid content, flowering time, and growth-related traits. Using quantitative trait locus (QTL) mapping, we aimed to determine if Da-Ae and Da-Ol 1 provided novel genetic variation beyond what has already been found in B. napus. Making use of the genotyping information generated from RNA-seq data of these two lines and their F2 mapping population of 166 plants, we constructed a genetic map consisting of 2,021 single nucleotide polymorphism markers that spans 2,929 cM across 19 linkage groups. Besides the known major QTL identified, our high resolution genetic map facilitated the identification of several new QTL contributing to the different fatty acid levels, flowering time, and growth related trait values. These new QTL probably represent novel genetic variation that existed in our new synthetic B. napus strain. By conducting genome-wide expression variation analysis in our F2 mapping population, genetic regions that potentially regulate many genes across the genome were revealed. A FLOWERING LOCUS C gene homolog, which was identified as a candidate regulating flowering time and multiple growth-related traits, was found underlying one of these regions. Integrated QTL and expression QTL analyses also helped us identified candidate causative genes associated with various biological traits through expression level change and/or possible protein function modification. PMID- 30483290 TI - Variability in DNA Methylation and Generational Plasticity in the Lombardy Poplar, a Single Genotype Worldwide Distributed Since the Eighteenth Century. AB - In the absence of genetic diversity, plants rely on the capacity of phenotypic plasticity to cope with shifts in environmental conditions. Understanding the mechanisms behind phenotypic plasticity and how local phenotypic adjustments are transferred to clonal offspring, will provide insight into its ecological and evolutionary significance. Epigenetic changes have recently been proposed to play a crucial role in rapid environmental adaptation. While the contribution of epigenetic changes to phenotypic plasticity has been extensively studied in sexual reproducing model organisms, little work has been done on vegetative generations of asexual reproducing plant species. We studied the variability of DNA methylation and bud set phenology of the Lombardy poplar (Populus nigra cv. Italica Duroi), a cultivated tree representing a single genotype worldwide distributed since the eighteenth century. Bud set observations and CpG methyl polymorphisms were studied on vegetative offspring resulting from cuttings grown for one season in a common glasshouse environment. The cuttings were collected from 60 adult Lombardy poplars growing in different environments. The physiological condition of the cuttings was determined by measuring weight and nutrient condition. Methylation sensitive amplified polymorphisms were used to obtain global patterns of DNA methylation. Using logistic regression models, we investigated correlations among epigenotype, bud phenology, and the climate at the home site of the donor trees, while accounting for physiological effects. We found significant epigenetic variation as well as significant variation in bud phenology, in the absence of genetic variation. Remarkably, phenology of bud set observed at the end of the growing season in the common environment was significantly correlated with climate variables at the home site of the mother trees, specifically the average temperature of January and monthly potential evapotranspiration. Although we could not directly detect significant effects of epigenetic variation on phenology, our results suggest that, in the Lombardy poplar, epigenetic marks contribute to the variation of phenotypic response that can be transferred onto asexually reproduced offspring resulting in locally adapted ecotypes. This contributes to the growing evidence that epigenetic-based transgenerational inheritance might be relevant for adaptation and evolution in contrasting or rapidly changing environments. PMID- 30483291 TI - Clustering Field-Based Maize Phenotyping of Plant-Height Growth and Canopy Spectral Dynamics Using a UAV Remote-Sensing Approach. AB - Phenotyping under field environmental conditions is often considered as a bottleneck in crop breeding. Unmanned aerial vehicle high throughput phenotypic platform (UAV-HTPP) mounted with multi-sensors offers an efficiency, non invasive, flexible and low-cost solution in large-scale breeding programs compared to ground investigation, especially where measurements are time sensitive. This study was conducted at the research station of the Xiao Tangshan National Precision Agriculture Research Center of China. Using the UAV-HTPP, RGB and multispectral images were acquired during four critical growth stages of maize. We present a method of extracting plant height (PH) at the plot scale using UAV-HTPP based on the spatial structure of the maize canopy. The core steps of this method are segmentation and spatial Kriging interpolation based on multiple neighboring maximum pixels from multiple plants in a plot. Then, the relationships between the PH extracted from imagery collected using UAV-HTPP and the ground truth were examined. We developed a semi-automated pipeline for extracting, analyzing and evaluating multiple phenotypic traits: canopy cover (CC), normalized vegetation index (NDVI), PH, average growth rate of plant height (AGRPH), and contribution rate of plant height (CRPH). For these traits, we identify genotypic differences and analyze and evaluate dynamics and development trends during different maize growth stages. Furthermore, we introduce a time series data clustering analysis method into breeding programs as a tool to obtain a novel representative trait: typical curve. We classified and named nine types of typical curves of these traits based on curve morphological features. We found that typical curves can detect differences in the genetic background of traits. For the best results, the recognition rate of an NDVI typical curve is 59%, far less than the 82.3% of the CRPH typical curve. Our study provides evidence that the PH trait is among the most heritable and the NDVI trait is among the most easily affected by the external environment in maize. PMID- 30483292 TI - Glutathione S-Transferases in the Biosynthesis of Sulfur-Containing Secondary Metabolites in Brassicaceae Plants. AB - Plants in the Brassicaceae family have evolved the capacity to produce numerous unique and structurally diverse sulfur-containing secondary metabolites, including constitutively present thio-glucosides, also known as glucosinolates, and indole-type phytoalexins, which are induced upon pathogen recognition. Studies on the glucosinolate and phytoalexin biosynthetic pathways in the model plant Arabidopsis thaliana have shown that glutathione donates the sulfur atoms that are present in these compounds, and this further suggests that specialized glutathione S-transferases (GSTs) are involved in the biosynthesis of glucosinolates and sulfur-containing phytoalexins. In addition, experimental evidence has shown that GSTs also participate in glucosinolate catabolism. Several candidate GSTs have been suggested based on co-expression analysis, however, the function of only a few of these enzymes have been validated by enzymatic assays or with phenotypes of respective mutant plants. Thus, it remains to be determined whether biosynthesis of sulfur-containing metabolites in Brassicaceae plants requires specific or nonspecific GSTs. PMID- 30483293 TI - Differential Diel Translation of Transcripts With Roles in the Transfer and Utilization of Iron-Sulfur Clusters in Arabidopsis. AB - Iron-sulfur (Fe-S) clusters are evolutionarily ancient ubiquitous protein cofactors which have mostly catalytic functions but can also have structural roles. In Arabidopsis thaliana, we presently know a total of 124 Fe-S metalloproteins that are encoded in the genome. Fe-S clusters are highly sensitive to oxidation. Therefore, we hypothesized that Fe-S cluster protein biogenesis is adjusted following the daily rhythms in metabolism driven by photosynthesis at the whole-plant, organ, cellular and sub-cellular levels. It had been concluded previously that little such regulation occurs at the transcript level among the genes functioning in Fe-S cluster assembly. As an initial step toward testing our hypothesis, we thus addressed the diel time course of the translation state of relevant transcripts based on publicly available genome-wide microarray data. This analysis can answer whether the translation of the pool of transcripts of a given gene is temporarily either enhanced or suppressed, and when during the day. Thirty-three percent of the transcripts with functions in Fe-S cluster assembly exhibited significant changes in translation state over a diurnal time course, compared to 26% of all detected transcripts. These transcripts comprised functions in all three steps of cluster assembly including persulfide formation, Fe-S cluster formation and Fe-S cluster transfer to target apoproteins. The number of Fe-S cluster carrier/transfer functions contributed more than half of these transcripts, which reached maxima in translation state either during the night or the end of the night. Similarly, translation state of mitochondrial frataxin and ferredoxin, which are thought to contribute Fe and electrons during cluster formation, peaked during the night. By contrast, translation state of chloroplast SUFE2 in persulfide formation and cytosolic Fe-S cluster formation scaffold protein NBP35 reached maxima in translation state during the day. Among the transcripts encoding target Fe-S cluster-utilizing proteins, 19% exhibited diurnal variation in translation state. Day-time maxima of translation state were most common among these transcripts, with none of the maxima during the night (ZT18). We conclude that diurnal regulation of translation state is important in metalloprotein biogenesis. Future models of Fe-S protein biogenesis require more comprehensive data and will have to accommodate diurnal dynamics. PMID- 30483294 TI - The Spanish Core Collection of Common Beans (Phaseolus vulgaris L.): An Important Source of Variability for Breeding Chemical Composition. AB - The Iberian Peninsula is considered as a secondary center of diversity for the common bean, and the Spanish National Plant Genetic Resources Centre's germplasm bank holds more than 3,000 Spanish accessions of Phaseolus vulgaris L. from which a core collection of 202 landraces has been selected. In order to encourage the use of this abundant resource, this study aimed to characterize genetic diversity, by measuring chemical composition in these core collections (in both the seed coat and cotyledon) using previously developed near infrared spectroscopy models. Crucially, these landraces in question all originated under similar agroclimatic conditions, allowing these field trials to be conducted in a single location without significantly altering the agronomic behavior of individual accessions. Using previously reported data, we also explored the correlations between chemical composition and culinary/sensory traits, as well as possible associations between chemical composition and seed coat color or gene pool (Middle American or Andean). The general Mahalanobis distance was >3 in only 11 of 1,950 estimations, confirming the robustness of the regression models previously developed. Variability was greater in seed coat than in cotyledon compounds and ranges for all compounds were wide: ash 34-94 g/kg, Ca 5-31 g/kg, dietary fiber 554-911 g/kg, Mg 2-4.4 g/kg, uronic acid 95-155 g/kg, protein 192 304 g/kg, starch 339-446 g/kg, amylose 208-291 g/kg, amylopectin 333-482 g/kg, and apparent amylose 241-332 g/kg. Accessions with white seed coats tended to be richer in ash, dietary fiber, uronic acid, and Ca, and accessions of the Middle American gene pool had on average 65% more Ca than the Andean gene pool. Strong genetic correlations were not identified between chemical and culinary/sensory traits. This is particularly positive with regards to plant breeding, as it means that synchronic improvement of nutritional composition and sensory traits is possible. The genetic diversity of chemical composition described in the Spanish core collection of beans therefore represents a promising opportunity to develop cultivars with superior nutritional profiles. PMID- 30483295 TI - Detection of Cistanches Herba (Rou Cong Rong) Medicinal Products Using Species Specific Nucleotide Signatures. AB - Cistanches Herba is a medicinal plant that has tonification properties and is commonly used in Asia. Owing to the imbalance between supply and demand, adulterants are frequently added for profit. However, there is no regulatory oversight because quality control tools are not sufficient for identifying heavily processed products. Thus, a novel molecular tool based on nucleotide signatures and species-specific primers was developed. The ITS2 regions from 251 Cistanches Herba and adulterant samples were sequenced. On the basis of SNP sites, four nucleotide signatures within 30~37 bp and six species-specific primers were developed, and they were validated by artificial experimental mixtures consisting of six different species and different ratios. This method was also applied to detect 66 Cistanches Herba products on the market, including extracts and Chinese patent medicines. The results demonstrated the utility of nucleotide signatures in identifying adulterants in mixtures. The market study revealed 36.4% adulteration: 19.7% involved adulteration with Cynomorium songaricum or Cistanche sinensis, and 16.7% involved substitution with Cy. songaricum, Ci. sinensis, or Boschniakia rossica. The results also revealed that Cy. songaricum was the most common adulterant in the market. Thus, we recommend the use of species-specific nucleotide signatures for regulating adulteration and verifying the quality assurance of medicinal product supply chains, especially for processed products whose DNA is degraded. PMID- 30483297 TI - High Grazing Pressure of Geese Threatens Conservation and Restoration of Reed Belts. AB - Reed (Phragmites australis (Cav.) Trin. ex Steud.) beds are important habitat for marsh birds, but are declining throughout Europe. Increasing numbers of the native marsh bird, the Greylag goose (Anser anser L.), are hypothesized to cause reed bed decline and inhibit restoration of reed beds, but data are largely lacking. In this study, we experimentally tested the effect of grazing by Greylag geese on the growth and expansion of reed growing in belts along lake shorelines. After 5 years of protecting reed from grazing with exclosures, reed stems were over 4-fold denser and taller than in the grazed plots. Grazing pressure was intense with 50-100% of the stems being grazed among years in the control plots open to grazing. After 5 years of protection we opened half of the exclosures and the geese immediately grazed almost 100% of the reed stems. Whereas this did not affect the reed stem density, the stem height was strongly reduced and similar to permanently grazed reed. The next year geese were actively chased away by management from mid-March to mid-June, which changed the maximum amount of geese from over 2300 to less than 50. As a result, reed stem density and height increased and the reed belt had recovered over the full 6 m length of the experimental plots. Lastly, we introduced reed plants in an adjacent lake where no reed was growing and geese did visit this area. After two years, the density of the planted reed was six to nine-fold higher and significantly taller in exclosures compared to control plots where geese had access to the reed plants. We conclude that there is a conservation dilemma regarding how to preserve and restore reed belts in the presence of high densities of Greylag geese as conservation of both reed belts and high goose numbers seems infeasible. We suggest that there are three possible solutions for this dilemma: (1) effects of the geese can be mediated by goose population management, (2) the robustness of the reed marshes can be increased, and (3) at the landscape level, spatial planning can be used to configure landscapes with large reed bed reserves surrounded by unmown, unfertilized meadows. PMID- 30483296 TI - The Arabidopsis thaliana K+-Uptake Permease 5 (AtKUP5) Contains a Functional Cytosolic Adenylate Cyclase Essential for K+ Transport. AB - Potassium (K+) is the most abundant cation in plants, and its uptake and transport are key to growth, development and responses to the environment. Here, we report that Arabidopsis thaliana K+ uptake permease 5 (AtKUP5) contains an adenylate cyclase (AC) catalytic center embedded in its N-terminal cytosolic domain. The purified recombinant AC domain generates cAMP in vitro; and when expressed in Escherichia coli, increases cAMP levels in vivo. Both the AC domain and full length AtKUP5 rescue an AC-deficient E. coli mutant, cyaA, and together these data provide evidence that AtKUP5 functions as an AC. Furthermore, full length AtKUP5 complements the Saccharomyces cerevisiae K+ transport impaired mutant, trk1 trk2, demonstrating its function as a K+ transporter. Surprisingly, a point mutation in the AC center that impairs AC activity, also abolishes complementation of trk1 trk2, suggesting that a functional catalytic AC domain is essential for K+ uptake. AtKUP5-mediated K+ uptake is not affected by cAMP, the catalytic product of the AC, but, interestingly, causes cytosolic cAMP accumulation. These findings are consistent with a role for AtKUP5 as K+ flux sensor, where the flux-dependent cAMP increases modulate downstream components essential for K+ homeostasis, such as cyclic nucleotide gated channels. PMID- 30483299 TI - Varying Auxin Levels Induce Distinct Pluripotent States in Callus Cells. PMID- 30483298 TI - Functional Roles of Starch Binding Domains and Surface Binding Sites in Enzymes Involved in Starch Biosynthesis. AB - Biosynthesis of starch is catalyzed by a cascade of enzymes. The activity of a large number of these enzymes depends on interaction with polymeric substrates via carbohydrate binding sites, which are situated outside of the catalytic site and its immediate surroundings including the substrate-binding crevice. Such secondary binding sites can belong to distinct starch binding domains (SBDs), classified as carbohydrate binding modules (CBMs), or be surface binding sites (SBSs) exposed on the surface of catalytic domains. Currently in the Carbohydrate Active enZYmes (CAZy) database SBDs are found in 13 CBM families. Four of these families; CBM20, CBM45, CBM48, and CBM53 are represented in enzymes involved in starch biosynthesis, namely starch synthases, branching enzymes, isoamylases, glucan, water dikinases, and alpha-glucan phosphatases. A critical role of the SBD in activity has not been demonstrated for any of these enzymes. Among the well-characterized SBDs important for starch biosynthesis are three CBM53s of Arabidopsis thaliana starch synthase III, which have modest affinity. SBSs, which are overall less widespread than SBDs, have been reported in some branching enzymes, isoamylases, synthases, phosphatases, and phosphorylases active in starch biosynthesis. SBSs appear to exert roles similar to CBMs. SBSs, however, have also been shown to modulate specificity for example by discriminating the length of chains transferred by branching enzymes. Notably, the difference in rate of occurrence between SBDs and SBSs may be due to lack of awareness of SBSs. Thus, SBSs as opposed to CBMs are not recognized at the protein sequence level, which hampers their identification. Moreover, only a few SBSs in enzymes involved in starch biosynthesis have been functionally characterized, typically by structure-guided site-directed mutagenesis. The glucan phosphatase Like SEX4 2 from A. thaliana has two SBSs with weak affinity for beta-cyclodextrin, amylose and amylopectin, which were indicated by mutational analysis to be more important than the active site for initial substrate recognition. The present review provides an update on occurrence of functional SBDs and SBSs in enzymes involved in starch biosynthesis. PMID- 30483300 TI - Synergistic Biostimulatory Action: Designing the Next Generation of Plant Biostimulants for Sustainable Agriculture. AB - Over the past 10 years, interest in plant biostimulants (PBs) has been on the rise compelled by the growing interest of scientists, extension specialists, private industry, and growers in integrating these products in the array of environmentally friendly tools that secure improved crop performance and yield stability. Based on the new EU regulation PBs are defined through claimed agronomic effects, such as improvement of nutrient use efficiency, tolerance to abiotic stressors and crop quality. This definition entails diverse organic and inorganic substances and/or microorganisms such as humic acids, protein hydrolysates, seaweed extracts, mycorrhizal fungi, and N-fixing bacteria. The current mini-review provides an overview of the direct (stimulatory on C and N metabolism) and indirect (enhancing nutrient uptake and modulating root morphology) mechanisms by which microbial and non-microbial PBs improve nutrient efficiency, plant performance, and physiological status, resilience to environmental stressors and stimulate plant microbiomes. The scientific advances underlying synergistic and additive effects of microbial and non-microbial PBs are compiled and discussed for the first time. The review identifies several perspectives for future research between the scientific community and private industry to design and develop a second generation of PBs products (biostimulant 2.0) with specific biostimulatory action to render agriculture more sustainable and resilient. PMID- 30483301 TI - Importance of Ecological Variables in Explaining Population Dynamics of Three Important Pine Pest Insects. AB - Climate change challenges forest vitality both directly by increasing drought and heat periods and indirectly, e.g., by creating favorable conditions for mass outbreaks of phyllophagous insects. The large forests dominated by Scots pine (Pinus sylvestris L.) that cover the lowland regions in northeast Germany have already been affected regularly by cyclic mass propagations of defoliating insect species in the past with climate projections implying an even more advantageous environment for devastating outbreaks in the future. To improve predictive and responsive capacities we have investigated a wide range of ecological parameters to identify those most strongly related to past outbreak waves of three central species. In total, we analyzed 3,748 variables covering stand and neighborhood properties, site quality, and climatic conditions for an area of roughly 750,000 ha of pine forests in the period 2002-2016. To reflect sensitivity against varying climate, we computed "floating windows" in relation to critical phenological phases of the respective insects. The parameters with the highest explanatory power resulted from the variable importance measures of the Random Forest (RF) methodology and have been evaluated by a 10-fold cross-validation process. Our findings closely reflect the known specific gradation patterns and show that relative variable importance varies with species. While Lymantria monacha L. feeding was mainly dependent on the surroundings of the respective stand, Diprion pini L. proved to be almost exclusively susceptible to climatic effects in its population dynamics. Dendrolimus pini L. exhibited a mixed pattern of variable importance involving both climatic and forest structure parameters. In many cases the obtained statistical results support well-known ecological cause-effect relations and long-term population change dynamics. The RF delivered very high levels of sensitivity and specificity in the developed classifications and proved to be an excellent tool to handle the large amounts of data utilized for this study. While the presented classification approach may already support a better prognosis of the amplitude during the outbreak culmination, the obtained (most important) variables are proposed as preferable covariates for modeling population dynamics of the investigated insect species. PMID- 30483302 TI - Older Adults' Attitudes towards Cognitive Testing: Moving towards Person Centeredness. AB - Background: Research on person-centered cognitive testing is beginning to emerge. The current study is the first to focus on eliciting concrete preferences around the test experience. Methods: Adults >=50 years old completed the Attitudes Around Cognitive Testing (AACT) questionnaire on mturk.com. AACT elicits preferences for cognitive tests, the importance attributed to having choices, and willingness to engage in testing. Results: Data are reported for 289 respondents. The proportion of participants expressing preferences varied by domain (modality [49.5%], location [47.2%], company [80.1%], result delivery [78.3-89.7%]). Importance ratings for all domains had a median of 4 and a range of 1-5 using a Likert scale of agreement. Most participants (85.5%) were willing to engage in testing. Conclusion: Older adults have preferences for cognitive tests, especially with delivery of results. PMID- 30483304 TI - Psychometric Properties of a Flanker Task in a Sample of Patients with Dementia: A Pilot Study. AB - Background/Aims: Reliable and valid neuropsychological tests for patients with dementia are scarce. To improve the assessment of attention and inhibitory control in dementia, we determined the feasibility, test-retest reliability, and validity of a Flanker task. Methods: Participants with all-cause diagnosed dementia (n = 22, mean age 84 years; mean Mini-Mental State Examination [MMSE] score = 19.4) performed a computerized Flanker task twice within 7 days. The Flanker task required participants to indicate the direction of target arrows flanked by congruent or incongruent arrows. Number of completed trials, accuracy, and reaction times (RTs) were recorded, and interference scores were calculated from basic scores. We examined the psychometric properties of the Flanker task and its relationship with the MMSE and Stroop test. Results: The Flanker task was feasible. Test-retest reliability was good for number of correct answers and RTs, and fair to poor for accuracy and the interference scores. The correlation of the Flanker task with Stroop and MMSE performance was fair to poor. Conclusion: The Flanker task appears to be feasible, and a reliable and valid measure of selective attention. Although the test-retest reliability for the Flanker RT interference measure was fair, future studies need to confirm its validity to measure inhibitory control in patients with dementia. PMID- 30483305 TI - A Longitudinal Study of Peripheral and Central Auditory Function in Alzheimer's Disease and in Mild Cognitive Impairment. AB - Background/Aim: Central auditory processing disorder (CAPD) might precede the onset of Alzheimer's disease (AD). A method of evaluating CAPD is the dichotic digits test (DDT). The aim was to address this in a longitudinal setting. Methods: A total of 136 individuals were assessed with peripheral and central hearing tests at baseline and at 5-year follow-up. Results: Subjects with AD showed a significant decline in DDT scores of the right ear from baseline to follow-up. The other groups retained high DDT scores. Peripheral auditory function declined as expected according to age. Conclusions: Our study indicates that DDT performance reflects an ongoing process resulting in dementia. PMID- 30483306 TI - Demographics, Clinical Characteristics, and Therapeutic Approaches among Older Adults Referred to Mobile Psychiatric Crisis Intervention Teams: A Retrospective Study. AB - Background / Aims: The advent of mobile old age psychiatry intervention teams supports policies maintaining older adults in their habitual living environments, even those who are very old and suffering from acute cognitive and psychiatric impairments. Analyzing sociodemographic data, clinical and health characteristics, reasons for crisis-oriented psychiatric consultations, and other therapeutic suggestions for supporting home- or nursing home-dwelling older adult patients suffering from an onset of a psychiatric crisis. Methods: Reviews of the medical records and discharge letters of home- or nursing home-dwelling older adults who had undergone a consultation with the Lausanne region's Mobile Old Age Psychiatry Teams (MOAPTs), between May 2016 and December 2017. Results: Of 570 older adult patients referred for consultation with MOAPTs, 333 had medical records and discharge letters eligible for retrospective analysis (59%). The majority of these older adult patients were women aged over 80 years suffering from dementia, mood disorders with and without a risk of suicide, and delirium. Challenging behaviors related to different stages of cognitive impairment were the most important clinical reason for crisis consultations. Nonpharmacological and pharmacological treatments were delivered concurrently in 68% of crisis consultations. Conclusion: Appropriate responses by dual nurse-psychiatrist teams using crisis-oriented nonpharmacological and pharmacological interventions decreased hospitalization. PMID- 30483307 TI - Genetic Variation in Coat Colour Genes MC1R and ASIP Provides Insights Into Domestication and Management of South American Camelids. AB - The domestication of wild vicuna and guanaco by early pre-Inca cultures is an iconic example of wildlife management and domestication in the Americas. Although domestic llamas and alpacas were clearly selected for key, yet distinct, phenotypic traits, the relative patterns and direction of selection and domestication have not been confirmed using genetic approaches. However, the detailed archaeological records from the region suggest that domestication was a process carried out under significant control and planning, which would have facilitated coordinated and thus extremely effective selective pressure to achieve and maintain desired phenotypic traits. Here we link patterns of sequence variation in two well-characterised genes coding for colour variation in vertebrates and interpret the results in the context of domestication in guanacos and vicunas. We hypothesise that colour variation in wild populations of guanacos and vicunas were strongly selected against. In contrast, variation in coat colour variation in alpaca was strongly selected for and became rapidly fixed in alpacas. In contrast, coat colour variants in llamas were of less economic value, and thus were under less selective pressure. We report for the first time the full sequence of MC1R and 3 exons of ASIP in 171 wild specimens from throughout their distribution and which represented a range of commonly observed colour patterns. We found a significant difference in the number of non-synonymous substitutions, but not synonymous substitutions among wild and domestics species. The genetic variation in MC1R and ASIP did not differentiate alpaca from llama due to the high degree of reciprocal introgression, but the combination of 11 substitutions are sufficient to distinguish domestic from wild animals. Although there is gene flow among domestic and wild species, most of the non-synonymous variation in MC1R and ASIP was not observed in wild species, presumably because these substitutions and the associated colour phenotypes are not effectively transmitted back into wild populations. Therefore, this set of substitutions unequivocally differentiates wild from domestic animals, which will have important practical application in forensic cases involving the poaching of wild vicunas and guanacos. These markers will also assist in identifying and studying archaeological remains pre- and post-domestication. PMID- 30483303 TI - Current Perspectives and Mechanisms of Relationship between Intestinal Microbiota Dysfunction and Dementia: A Review. AB - Background: Accumulating data suggest a crucial role of the intestinal microbiota in the development and progression of neurodegenerative diseases. More recently, emerging reports have revealed an association between intestinal microbiota dysfunctions and dementia, a debilitating multifactorial disorder, characterized by progressive deterioration of cognition and behavior that interferes with the social and professional life of the sufferer. However, the mechanisms of this association are not fully understood. Summary: In this review, I discuss recent data that suggest mechanisms of cross-talk between intestinal microbiota dysfunction and the brain that underlie the development of dementia. Potential therapeutic options for dementia are also discussed. The pleiotropic signaling of the metabolic products of the intestinal microbiota together with their specific roles in the maintenance of both the intestinal and blood-brain barriers as well as regulation of local, distant, and circulating immunocytes, and enteric, visceral, and central neural functions are integral to a healthy gut and brain. Key Messages: Research investigating the effect of intestinal microbiota dysfunctions on brain health should focus on multiple interrelated systems involving local and central neuroendocrine, immunocyte, and neural signaling of microbial products and transmitters and neurohumoral cells that not only maintain intestinal, but also blood brain-barrier integrity. The change in intestinal microbiome/dysbiome repertoire is crucial to the development of dementia. PMID- 30483308 TI - Weighted Gene Correlation Network Analysis (WGCNA) Reveals Novel Transcription Factors Associated With Bisphenol A Dose-Response. AB - Despite Bisphenol-A (BPA) being subject to extensive study, a thorough understanding of molecular mechanism remains elusive. Here we show that using weighted gene correlation network analysis (WGCNA), which takes advantage of a graph theoretical approach to understanding correlations amongst genes and grouping genes into modules that typically have co-ordinated biological functions and regulatory mechanisms, that despite some commonality in altered genes, there is minimal overlap between BPA and estrogen in terms of network topology. We confirmed previous findings that ZNF217 and TFAP2C are involved in the estrogen pathway, and are implicated in BPA as well, although for BPA they appear to be active in the absence of canonical estrogen-receptor driven gene expression. Furthermore, our study suggested that PADI4 and RACK7/ZMYNDB8 may be involved in the overlap in gene expression between estradiol and BPA. Lastly, we demonstrated that even at low doses there are unique transcription factors that appear to be driving the biology of BPA, such as SREBF1. Overall, our data is consistent with other reports that BPA leads to subtle gene changes rather than profound aberrations of a conserved estrogen signaling (or other) pathways. PMID- 30483309 TI - Use of Mendelian Randomization for Identifying Risk Factors for Brain Tumors. AB - Gliomas are a group of primary brain tumors, the most common and aggressive subtype of which is glioblastoma. Glioblastoma has a median survival of just 15 months after diagnosis. Only previous exposure to ionizing radiation and particular inherited genetic syndromes are accepted risk factors for glioma; the vast majority of cases are thought to occur spontaneously. Previous observational studies have described associations between several risk factors and glioma, but studies are often conflicting and whether these associations reflect true casual relationships is unclear because observational studies may be susceptible to confounding, measurement error and reverse causation. Mendelian randomization (MR) is a form of instrumental variable analysis that can be used to provide supporting evidence for causal relationships between exposures (e.g., risk factors) and outcomes (e.g., disease onset). MR utilizes genetic variants, such as single nucleotide polymorphisms (SNPs), that are robustly associated with an exposure to determine whether there is a causal effect of the exposure on the outcome. MR is less susceptible to confounding, reverse causation and measurement errors as it is based on the random inheritance during conception of genetic variants that can be relatively accurately measured. In previous studies, MR has implicated a genetically predicted increase in telomere length with an increased risk of glioma, and found little evidence that obesity related factors, vitamin D or atopy are causal in glioma risk. In this review, we describe MR and its potential use to discover and validate novel risk factors, mechanistic factors, and therapeutic targets in glioma. PMID- 30483313 TI - Risk Factors for Acute Kidney Injury in Coronary Artery Bypass Graft Surgery Patients Based on the Acute Kidney Injury Network Criteria. AB - Background: Acute kidney injury (AKI) after coronary artery bypass graft surgery (CABG) is a common complication. The present study sought to determine AKI risk factors based on the Acute Kidney Injury Network (AKIN) classification. Methods: In a cross-sectional study, performed from March 2010 to April 2012 at Tehran Heart Center, affiliated with Tehran University of Medical Sciences, 29 independent risk factors for AKI based on the AKIN criteria were examined in isolated post-CABG patients. The patients' demographic data and risk factors were extracted from the Electronic Database of Tehran Heart Center. According to restricted inclusion and exclusion criteria as well as a creatinine rise to AKI Stage 1, the patients were divided into 2 groups of AKI-negative and AKI-positive and the risk factors were compared between these groups. Results: Out of 3473 included patients at a mean age of 60.78 (+/-9.46) years, the majority (2474 [71.23%]) were male. Totally, 958 (27.7%) patients had AKI, according to a creatinine rise to AKI Stage 1. Logistic regression analysis demonstrated that higher age (OR=1.021; P<0.001), higher body mass index (OR=1.035; P<0.001), lower preoperative creatinine level (OR=0.417; P<0.001), longer cardiopulmonary bypass time (OR=1.004; P=0.007), blood transfusion in the ICU (OR=1.408; P=0.001), and lack of intraoperative blood transfusion (OR=0.823; P=0.044) were the independent risk factors for AKI after CABG. Conclusion: Based on the findings of the current study, older age, higher body mass index, lower preoperative creatinine level, more blood transfusion in the intensive care unit (ICU), lack of intraoperative blood transfusion, and high cardiopulmonary bypass time may serve as risk factors for the development of AKI in CABG patients. PMID- 30483310 TI - The Spectrum of Neurological and White Matter Changes and Premutation Status Categories of Older Male Carriers of the FMR1 Alleles Are Linked to Genetic (CGG and FMR1 mRNA) and Cellular Stress (AMPK) Markers. AB - The fragile X premutation (PM) allele contains a CGG expansion of 55-200 repeats in the FMR1 gene's promoter. Male PM carriers have an elevated risk of developing neurological and psychiatric changes, including an approximately 50% risk of the fragile X-associated tremor/ataxia syndrome (FXTAS). The aim of this study was to assess the relationships of regional white matter hyperintensities (wmhs) semi quantitative scores, clinical status, motor (UPDRS, ICARS, Tremor) scales, and cognitive impairments, with FMR1-specific genetic changes, in a sample of 32 unselected male PM carriers aged 39-81 years. Half of these individuals were affected with FXTAS, while the non-FXTAS group comprised subcategories of non affected individuals and individuals affected with non-syndromic changes. The dynamics of pathological processes at the cellular level relevant to the clinical status of PM carriers was investigated using the enzyme AMP-activated protein kinase (AMPK), which is a highly sensitive cellular stress-sensing alarm protein. This enzyme, as well as genetic markers - CGG repeat number and the levels of the FMR1 mRNA - were assessed in blood lymphoblasts. The results showed that the repeat distribution for FXTAS individuals peaked at 85-90 CGGs; non-FXTAS carriers were distributed within the lowest end of the PM repeat range, and non syndromic carriers assumed an intermediate position. The size of the CGG expansion was significantly correlated, across all three categories, with infratentorial and total wmhs and with all motor scores, and the FMR1 mRNA levels with all the wmh scores, whilst AMPK activity showed considerable elevation in the non-FXTAS combined group, decreasing in the FXTAS group, proportionally to increasing severity of the wmhs and tremor/ataxia. We conclude that the size of the CGG expansion relates to the risk for FXTAS, to severity of infratentorial wmhs lesions, and to all three motor scale scores. FMR1 mRNA shows a strong association with the extent of wmhs, which is the most sensitive marker of the pathological process. However, the AMPK activity findings - suggestive of a role of this enzyme in the risk of FXTAS - need to be verified and expanded in future studies using larger samples and longitudinal assessment. PMID- 30483311 TI - Function and Regulation of Human Terminal Uridylyltransferases. AB - RNA uridylylation plays a pivotal role in the biogenesis and metabolism of functional RNAs, and regulates cellular gene expression. RNA uridylylation is catalyzed by a subset of proteins from the non-canonical terminal nucleotidyltransferase family. In human, three proteins (TUT1, TUT4, and TUT7) have been shown to exhibit template-independent uridylylation activity at 3'-end of specific RNAs. TUT1 catalyzes oligo-uridylylation of U6 small nuclear (sn) RNA, which catalyzes mRNA splicing. Oligo-uridylylation of U6 snRNA is required for U6 snRNA maturation, U4/U6-di-snRNP formation, and U6 snRNA recycling during mRNA splicing. TUT4 and TUT7 catalyze mono- or oligo-uridylylation of precursor let-7 (pre-let-7). Let-7 RNA is broadly expressed in somatic cells and regulates cellular proliferation and differentiation. Mono-uridylylation of pre-let-7 by TUT4/7 promotes subsequent Dicer processing to up-regulate let-7 biogenesis. Oligo-uridylylation of pre-let-7 by TUT4/7 is dependent on an RNA-binding protein, Lin28. Oligo-uridylylated pre-let-7 is less responsive to processing by Dicer and degraded by an exonuclease DIS3L2. As a result, let-7 expression is repressed. Uridylylation of pre-let-7 depends on the context of the 3'-region of pre-let-7 and cell type. In this review, we focus on the 3' uridylylation of U6 snRNA and pre-let-7, and describe the current understanding of mechanism of activity and regulation of human TUT1 and TUT4/7, based on their crystal structures that have been recently solved. PMID- 30483312 TI - Are Twenty-Four Sessions of Aerobic Exercise Sufficient for Improving Cardiac Parameters in Diabetes Mellitus? A Randomized Controlled Trial. AB - Background: Diabetes is a chronic disease that reduces cardiorespiratory fitness and increases systolic and diastolic blood pressures as well as resting heart rate due to the activity level of the sympathetic nervous system. The aim of this study was to assess the effectiveness of 2 types of aerobic exercise, with and without external loading, on cardiac parameters in diabetic patients. Methods: This randomized controlled trial was carried out on 45 volunteers. These individuals were randomly divided into aerobic, weighted vest, and control groups. The aerobic protocol comprised 24 sessions of aerobic exercise. The exercise program for the weighted vest group was identical to that of the aerobic group, except that the subjects wore a weighted vest. The parameters were measured before and after the 24 sessions. Results: The mean age of the study population was 48.30+/-5.02 years in the aerobic group, 48.33+/-5.74 years in the weighted vest group, and 48.60+/-4.79 years in the control group. Males comprised 7 (53.8%) patients in the aerobic group, 7 (58.3%) in the weighted vest group, and 8 (53.3%) in the control group. After 8 weeks, maximum oxygen consumption in the aerobic group (mean+/-SD=37.54+/-8.02 mL/kg/min, 95% CI: 5.48 to 11.60; P<0.001) and the weighted vest group (mean+/-SD=35.92+/-3.96 mL/kg/min, 95% CI: 4.36 to 9.64; P<0.001) was increased, similar to metabolic equivalent of task in the aerobic group (mean+/-SD=11.60+/-1.62 kcal/kg*h, 95% CI: 1.48 to 2.72; P<0.001) and the weighted vest group (mean+/-SD=11.21+/-1.11 kcal/kg*h, 95% CI: 1.23 to 2.28; P<0.001). Furthermore, resting heart rate decreased significantly in the aerobic group (mean +/- SD=90.23+/-8.90 bpm, 95% CI: -13.93 to -1.29; P=0.022) and the weighted vest group (mean+/-SD=90.58+/-9.19 bpm, 95% CI: -0.16 to - 12.33; P=0.045). Conclusion: These findings suggest that 24 aerobic exercise sessions might improve cardiac parameters in type 2 diabetes. PMID- 30483314 TI - Association between Serum Kalirin Levels and the KALRN gene rs9289231 Polymorphism in Early-Onset Coronary Artery Disease. AB - Background: Recently, rs9289231 genetic variations of kalirin (KALRN) have been introduced as potential genetic markers for coronary artery disease (CAD). However, the influence of KALRN single-nucleotide polymorphisms (SNPs) on serum kalirin levels has not been investigated in CAD patients so far. Thus, the present study aimed to survey whether SNP T>G (rs9289231) was associated with the risk of early-onset CAD and serum kalirin levels among the study subjects. Methods: The rs9289231 polymorphism of the KALRN was genotyped in 512 subjects (61.5% male, mean age=46.3+/-7.1 y), comprising 268 subjects with angiographically diagnosed CAD and 244 controls using an HRM assay. Also, the levels of serum kalirin were compared between 133 CAD subjects and 123 controls using a sandwich ELISA assay. Results: The CAD subjects had more frequently GG genotypes than the controls. The odds ratio (OR) remained significant after adjustment for known CAD risk factors (OR=4.13, 95% CI: 2.48-9.10; P<0.001). A significant difference was also observed in that the G allele was more frequent among the CAD subjects. The G allele at the rs9289231 polymorphism was associated with a higher risk of CAD (OR=2.11, 95% CI: 1.27-2.59; P=0.001). The mean kalirin level of the CAD patients was higher than that of the controls (P=0.041). No significant correlation was seen in the different genotypes with serum kalirin levels. Conclusion: The KALRN rs9289231 T>G variant was considerably related with an increased risk of early-onset CAD. High kalirin levels were found in young CAD patients compared to the control subjects, with the levels not affected by the different genotypes of rs9289231. PMID- 30483316 TI - Upper Limb Deep Vein Thrombosis: A Case Report of an Increasingly Common Condition. AB - Upper limb deep vein thrombosis (DVT) is a less common phenomenon than lower limb DVT. Repeated trauma secondary to sport- or job-related arm movements and positions has been recognized as the predisposing factor for upper limb DVT. We describe a 38-year-old male computer programmer admitted with swelling and pain in his left upper limb. Venous duplex ultrasound confirmed the presence of axillary vein thrombosis. Coagulation studies for secondary thrombosis were unremarkable. The patient was treated with full anticoagulation using low molecular weight heparin and warfarin. On subsequent follow-up at 3 months, the patient was symptom free and duplex sonography showed no evidence of thrombosis. PMID- 30483315 TI - Prevalence, Awareness, Treatment, and Control of Hypertension in an Isfahan State Institution Sample. AB - Background: Hypertension is a major risk factor for premature disability and death and is the leading risk factor for global disease burden. The present study aimed to assess the rates of prevalence, awareness, treatment, and control of hypertension in a sample of teachers, staff, and students at Isfahan University of Medical Sciences (IUMS). Methods: This cross-sectional survey was conducted from January to September 2015 on the staff, teachers, and students at IUMS. A total of 1500 subjects were randomly selected and were invited to participate in the survey. Hypertension was defined as an average of 2 blood pressure measurements of at least 140/90 mmHg. The rate of awareness was determined based on self-reports, treatment was defined as the regular use of blood pressure lowering medications, and control was defined as the maintenance of blood pressure below 140/90 mmHg. Results: The study population comprised 1317 individuals (45.9% female) at a mean age of 41.4+/-9.5 years. The prevalence rate of hypertension was 17.5% (231 of 1317 participants), and the rate of awareness was 54.5% (126 of 231 hypertensive patients). Seventy-nine (62.7%) patients were undergoing treatment, and 51.9% (41 of 79) controlled their disease. Institutional position (P<0.017), age (P<0.001), body mass index (P<0.001), education level (P<0.001), smoking status (P<0.001), and history of diabetes mellitus (P<0.001) were the most frequent risk factors associated with hypertension. Conclusion: The percentage of the hypertensive subjects who were aware, treated, and controlled was unacceptably low in our sample at IUMS. Hypertension is, therefore, a major health problem in this state institution. PMID- 30483318 TI - Multipolar Left Ventricular Lead Implantation in a Unique Coronary Sinus: Direct Drainage of the Posterior Vein into the Right Atrium. AB - The coronary sinus, whose electrical features play an important role in cardiac arrhythmias, is the integral part of the cardiac venous system. Here we describe a 67-year-old male patient with congestive heart failure who was referred to our hospital after the failure of the first cardiac resynchronization therapy defibrillator (CRT-D) implantation. During the cannulation of the coronary sinus, the separate orifice of the posterior cardiac vein was demonstrated by the retrograde filling of the coronary sinus via contrast injection into the posterior cardiac vein. Due to the serious tortuosity of the coronary venous sinus, a multipolar left ventricular lead was implanted using the separate ostium of the posterior cardiac vein. In our patient, the posterior cardiac vein directly drained into the right atrium. At 3 months' follow-up with the CRT-D, he was asymptomatic (New York Heart Association functional class I). PMID- 30483317 TI - Anesthetic Management of an Infant Presenting with an Intrapericardial Tumor: A Case Report. AB - Intrapericardial teratomas are rare primary cardiac tumors. These tumors, albeit benign in essence, can be fatal if they exert pressure on the cardiovascular and/or respiratory system. We describe a 34-day-old infant, who needed emergent surgery due to cardiovascular structure compromise. Proper anesthetic and surgical techniques conferred an uneventful postoperative course. Histologic examination confirmed the tumor as an intrapericardial teratoma. At 8 months' postoperative follow-up, the child had a good developmental status and a normal echocardiogram. PMID- 30483319 TI - Left Atrial Drainage of the Right Superior Vena Cava: A Case Report. AB - An isolated right superior vena cava (RSVC) draining into the left atrium represents a very rare congenital malformation, especially in the absence of a partial anomalous pulmonary venous return. This condition leads to hypoxemia, cyanosis, and clubbing without any other signs of heart defects. We describe an 8 year-old girl, who was referred to our hospital due to unexplained cyanosis. Segmental approach in transthoracic echocardiography showed left atrial drainage of the RSVC, which was subsequently confirmed by contrast echocardiography and angiography. Surgical repair via trans-section and anastomosis of the superior vena cava to the right atrium was performed to prevent the complications of right to-left shunting and cyanosis. During a 4-year follow-up, the patient remained in very good clinical status and her serial echocardiography was normal except for very mild left atrial and left ventricular enlargement. PMID- 30483320 TI - Fenestrated Endovascular Aortic Aneurysm Repair (FEVAR) for Complex Thoracoabdominal and Abdominal Aortic Aneurysms: First Iranian FEVAR Series Report with Mid-Term Follow-Up. AB - Endovascular treatment of aortic diseases has improved in recent years. More complex thoracoabdominal and juxtarenal abdominal aortic aneurysms can now be treated with new stent grafts and techniques. Fenestrated endovascular aortic aneurysm repair (FEVAR) with fenestrated stent grafts was commenced in our center after hundred cases of endovascular aortic repair, and so far 4 serial complex cases deemed inoperable (2 juxtarenal abdominal aortic aneurysms, 1 thoracoabdominal aneurysm, and 1 thoracoabdominal pseudoaneurysm) have been treated with FEVAR. All these patients needed custom-made stent grafts, which were designed and implanted successfully under general anesthesia in the catheterization laboratory. They were followed up for more than 1 year, with a median follow-up period of 23.0 months. There were no major in-hospital or short term complications. Only 1 patient had midterm unilateral iliac artery thrombosis, which was successfully managed interventionally. Computed tomography angiography at 1 year's follow-up showed that the stent grafts were patent and their visceral branch cover stents had no endoleak. PMID- 30483321 TI - Left Atrial Thrombus Presenting with Acute Coronary Syndrome and Cerebrovascular Event. PMID- 30483322 TI - Repair of the Isolated Mitral Valve P3 by "Resect-and-Respect" Combination. PMID- 30483324 TI - Epidemiology and Control of Leishmaniasis in the Former USSR: A Review Article. AB - Background: All types of the Old World's leishmaniasis were endemic on the territory of the South regions of ex-USSR. Epidemiological situation was well under control during the USSR era, due to implementation of complex anti leismaniasis measures. These interventions were dramatically stopped as a result of the collapse of the USSR. Methods: Most relevant publications on epidemiology and control of leishmaniases in the Republics of Central Asia and Transcaucasia of the ex-USSR were screened. Results: Within the endemic area, the foci of different kinds of leishmaniasis are often overlapped thus calling for deployment of integrated measures. The anthroponotic cutaneous leishmaniasis (ACL) was reported in settlements and towns of Central Asia and Transcaucasia of the ex USSR. The natural foci of cutaneous leishmaniasis were widespread in the desert of Turkmenistan, Uzbekistan, Kazakhstan and Tajikistan. The northern boundary of the zoonotic cutaneous leishmaniasis (ZCL) area coincided with the northern boundary of the distribution of great gerbils - the main reservoir of this infection in the ex-USSR. Visceral leishmaniasis (VL) occurred in the Central Asian Republics and in the republics of the Transcaucasia. Holistic approach was adopted by the programs targeting the source of infection, vector(s) and man. Conclusion: The presence rise in the number of cases of different types of leishmaniasis in the ex-USSR strongly necessitates that health authorities should consider these diseases as an important public health problem. The immediate task would be rebuilding a comprehensive surveillance system consisting of active and passive case detection mechanism along with immediate treatment of the patients. PMID- 30483323 TI - Immunodiagnosis of Visceral Leishmaniasis: Current Status and Challenges: A Review Article. AB - Background: Diagnosis of Visceral Leishmaniasis (VL) is still challenging. This review highlighted current status and challenges in the serological diagnosis of VL. Furthermore, the drawback of currently available serological tests and the most recent advancement in the designing and application of these assays for the diagnosis of VL are addressed. Methods: All the published literature cited within PubMed, ISI Web of Science, Google Scholar, Scopus, and IranMedex, regarding the immunodiagnosis of VL in human were sought from 2000 till Mar 2017. The search terms were "visceral leishmaniasis", or "kala-azar" subsequently combined with the search terms "diagnosis", "serodiagnosis", "human", "serological", "antigen detection" or "antibody detection". Data were extracted from literature which fulfilled our eligibility criteria. Results: Direct agglutination test (DAT) and rk39 dipstick have made a great improvement in the serological diagnosis of VL. Besides, other kinesin-related protein including K26, K28, and KE16 provided promisingly diagnostic accuracy in the diagnosis of VL. The Latex Agglutination Test for the diagnosis of VL (KAtex), with moderate sensitivity but high specificity, made a substantial contribution to the field. Moreover, a range of protein antigens has recently been detected in the urine of VL patients with encouraging diagnostic value. Conclusion: The suboptimal diagnostic accuracy of the currently available serological assays for the diagnosis of human VL necessitates further research and development in this field. Outcomes of immunodiagnostic tests based on recombinant antigens are favorable. These proteins might be the most appropriate antigens to be further evaluated and utilized for the diagnosis of human VL. PMID- 30483325 TI - Molecular Identification and Phylogenetic Classification of Leishmania spp. Isolated from Human Cutaneous Leishmaniasis in Iran: A Cross-sectional Study. AB - Background: In Iran, both forms of cutaneous (CL) and visceral leishmaniasis (VL) have been reported; so the accurate species identification of the parasite(s) and the analysis of genetic diversity are necessary. Methods: The smears were collected from lesions samples of 654 patients with CL, who attended local health centers in 12 provinces of Iran during 2013-2015. The smears were checked for the presence of amastigotes by light microscopy. DNA of 648 Leishmania isolates, amplified by targeting a partial sequence of ITS (18S rRNA-ITS1-5.8S rRNA-ITS2) gene. Twenty-five of all the amplicons were sequenced and analyzed with restriction fragment length polymorphism (RFLP) using the Taq1 enzyme. Results: All the smears were positive microscopically. The PCR-RFLP analysis revealed that 176 (27%) CL patients were infected with L. tropica and, 478 (73%) with L. major. The dominant species in all over Iran is L. major. The sequencing results of all CL patients and RFLP analysis confirmed each other. Based on our phylogenetic tree, 25 ITS DNA sequences were grouped into two clusters representing L. major and L. tropica species. Phylogenetic tree derived from the ITS sequences supports a clear divergence between L. major from the other species. Conclusion: Discrimination of Iranian Leishmania isolates using ITS gene gives us this opportunity to detect, identify, and construct the phylogenetic relationship of Iranian isolates. PMID- 30483326 TI - New Nodule Type Found in the Lungs of Pomacea canaliculata, an Intermediate Host of Angiostrongylus cantonensis. AB - Background: Pomacea canaliculata (P.canaliculata) lung nodules, were commonly caused by Angiostrongylus cantonensis infection. Here, we found a new nodule type without any parasites. Methods: Overall, 447 P. canaliculata snails were collected in Ning Bo, Zhe Jiang, China in 2018. In order to exhibit the similarities and differences between two nodules types (2018, Huzhou Zhejiang, China), both types were collected in formalin for tissue pathological sectioning. Besides, to obtain the microbial community of the new nodule, the 18S ribosomal RNA (rRNA) gene of it was amplified and analyzed using the Illumina second generation sequencing platform. Results: Although two nodules were found in the lungs of P. canaliculata, they were different in shape and pathology. Illumina sequencing indicated Poterioochromonas sp., a species of golden algae, might be the causing agent of the new nodule. Conclusion: We firstly found a new pathological nodule type in the lungs of P. canaliculata, and this nodule might be induced by golden algae infection, however, the direct link between the golden algae and the new nodules, as well as the nodules' impact on the snails' physiology and A. cantonensis infection require further study. PMID- 30483327 TI - An Experimental Model of Primary Amoebic Meningoence phalitis Due to Naegleria australiensis in Iran. AB - Background: The main aim of the present research was to develop the experimental meningo encephalitis due to Naegleria australiensis isolated from geothermal water sources in mice model, November 2017 in Iran. Methods: Naegleria australiensis was isolated from geothermal water sources in northern Iran. The number of amoebae was adjusted to be 1*104/ml amoebae. The experimental infection was done using 3 wk old male (BALB/c) mice. Seven animals were used for experimental amebic infection and one animal was selected for the control. Intranasal (IN) and intracerebral (IC) inoculation of amoebae were done. The mice were then monitored on daily observation and as soon as they present any brain involvement they sacrificed. The brain of all animals was then dislocated and passaged in non-nutrient agar. Results: One mouse out of seven infected mice were showed clinical symptoms of meningoencephalitis. Within few hours of culture of the brain, many vegetative forms of amoebae were detected in plate culture. The other infected animals and control mice showed no clinical symptoms until day 14. After 14 d all the animals sacrificed. The culture was negative up to one month. Conclusion: The lack of brain involvement of other animals in the present study could be due to animal immune system or it may be possible that the amoebae did not reach to olfactory bulb of nostrils. PMID- 30483328 TI - Detection of Toxoplasma gondii in Acute and Chronic Phases of Infection in Immunocompromised Patients and Pregnant Women with Real-time PCR Assay Using TaqMan Fluorescent Probe. AB - Background: Toxoplasma gondii, cause severe medical complications in infants and immune-compromised individuals. As using early, sensitive and rapid technique has major in diagnosis of toxoplasmosis, the present study was aimed to detect parasite by using from repetitive element (RE) and B1genes, in blood samples of seropositive immuno-compromised patients and pregnant women. Methods: A total of 110 peripheral blood samples were collected from seropositive cases with anti-T. gondii antibodies, including immunocompromised patients and pregnant women. DNA was extracted by a commercial kit and subjected to TaqMan probe-based real-time PCR assay by using primers and probes specific for RE and B1 genes, separately. The data were analyzed by Kappa test and SPSS-22 software. Results: In the pregnant women, 17 (68%) and 14 (56%) samples from 25 IgM+/ IgG+ cases and, 7 (25%) and 6 (21.4%) samples from 28 IgG+/IgM- cases were positive by RE and B1 real time PCR, respectively. Likewise, in immunocompromised group, 20 (66.6%) and 17 (56.6%) samples from 30 IgM+/ IgG+ cases and 2 (7.4%) and 2 (7.4%) samples from 27 IgG+/ IgM- cases were positive by RE and B1 real time PCR, respectively. Conclusion: Probe-based real time PCR assay is a quantitative approach for early diagnosis of T. gondii infection in clinical samples. Moreover, this method can be more appropriate in diagnosis of acute and reactivated toxoplasmosis. In addition our results indicated that RE gene is more sensitive than B1 gene. PMID- 30483329 TI - The First Survey of Isolation and Molecular Typing of Toxoplasma gondii by Bioassay and PCR Method in BALB/c Mice in Camels (Camelus dromedarius) from Eastern Iran. AB - Background: We isolated Toxoplasma gondii from camels by bioassay method in mice model and detect parasitic DNA in brain mice by molecular methods. Methods: One hundred tissue samples including heart (n=50), and diaphragm (n=50) were collected from camels (n=50) slaughtered in abattoirs from Feb to Oct 2015 in three provinces located in eastern Iran. In first, blood sample from 50 camels was assayed for anti-Toxoplasma antibodies by modified agglutination test (MAT) test. Bioassay method was done in positive MAT blood camels in BALB/c mice and Nested PCR performed in seropositive tissue samples to amplify the B1 and GRA6 genes. The existence of polymorphic restriction sites for endonuclease MseI was used with PCRRFLP method and Sequencing analysis to evaluate the prevalence of type strains (I, II and III). Results: Overall, 13 (26%) of camels were positive with titer of 1:20 for toxoplasmosis and 13(26%) tissue samples of camels were found positive for the T. gondii B1 gene, including 7(14%) diaphragm, 6(12%) heart. Moreover, 3(6%) tissue samples of camels were found positive with GRA6 gene for T. gondii. There are three genotypes and mix genotype using MseI enzyme among all positive samples. Conclusion: The obtained results from serological and molecular tests demonstrated the infection of T. gondii with previously recognized genotypes in the tissues of camels for first time from Iran. Since consumption of meat camels are raising in Iran, there may be a high risk of toxoplasmosis through consumption of products from these hosts due to their susceptibility to the infection. PMID- 30483330 TI - Expression of Plasmid Encoded GRA4 Gene of Toxoplasma gondii RH Strain in CHO Eukaryotic Cells. AB - Background: Toxoplasmosis is a common infection all around the world. During pregnancy; it may lead to congenital disorders or abortion in human and animals. Severe damage of toxoplasmosis indicates to require effective vaccine. One of dense granules antigen is GRA4 that secrete from tachyzoite and bradyzoite. GRA4 genome is unique without intron and is one of the major immunogenic proteins from Toxoplasma gondii. Methods: We confirmed the cloning of GRA4 gene into pcDNA3 by restriction enzyme and PCR of GRA4 gene with pcGRA4 plasmids as template. Then with using calcium-phosphate method we transfected the pcGRA4 into CHO (Chinesehamster ovary) cells. The yielded protein was separated by SDS-PAGE and moved by electroblotting to nitrocellulose paper. Results: Result of SDS-PAGE analysis showed the appearance of band approximately 42 kDa which was absent in the negative control, that was able to identify toxoplasmosis antibody IgM+ serum in western blot analysis. Conclusion: pcGRA4 plasmid is able to synthesis of antigenic protein in CHO cells. The ability of pcGRA4 for induction of protective immune response against toxoplasmosis will be evaluated in mouse model. PMID- 30483331 TI - Comparative Efficacy of Diethylcarbamazine, Nitazoxanide and Nanocomposite of Nitazoxanide and Silver Nanoparticles on the Dehydrogenases of TCA Cycle in Setaria cervi, in Vitro. AB - Background: Bovine filariid, Setaria cervi may cause serious pathological condition such as cerebrospinal nematodiasis in sheep, goat and horses. Since TCA cycle enzymes have certain biological functions that make them essential for the survival of parasite and therefore, efficacy of diethylcarbamazine (DEC), nitazoxanide (NTZ) and a nanocomposite of nitazoxanide and silver nanoparticles (NTZ+AgNPs) was assessed on succinate, malate and isocitrate dehydrogenases in the microfilariae (mf) and adult S. cervi worms. Methods: This study was conducted in the Department of Zoology, Aligarh Muslim University, Aligarh, India during 2015-2016. Adult and microfilariae of S. cervi were incubated in 100 MUg/ml of DEC, NTZ, and NTZ+AgNPs for 24 and 6 h, respectively at 37 degrees C. Succinate, malate and isocitrate dehydrogenases were localized by putting the mf and adult worms in the incubating medium containing their respective substrates at 37 degrees C for 2 h followed by counterstaining in 2% methylene green for 15 min. Results: Maximum inhibition of TCA cycle enzymes was observed in both microfilariae and adult worms treated with nanocomposite of NTZ-AgNPs. Ruptured sheath along with nanoparticles sticking to the body surface was noticed in NTZ+AgNPs treated microfilariae. Conclusion: NTZ+AgNPs proved most effective synergistic combination against TCA cycle enzymes which blocked the isocitrate and malate dehydrogenase almost completely, and succinate dehydrogenase to large extent in both microfilariae as well as adult worms of S. cervi. AgNPs ruptured the sheath and allowed the NTZ to attach and penetrate the main body to exert maximum effect on the enzymes. PMID- 30483332 TI - Induction of Apoptosis in Toxoplasma gondii Infected Hela Cells by Cisplatin and Sodium Azide and Isolation of Apoptotic Bodies and Potential Use for Vaccination against Toxoplasma gondii. AB - Background: Toxoplasma gondii can infect a wide range of mammalians, especially humans. It controls several intracellular signals for the inhibition of apoptosis. This study aimed to investigate the apoptogenic effect of cisplatin and sodium azide on T. gondii infected HeLa cells and isolate apoptotic bodies (blebs) as a potent stimulator of the immune system. Methods: The cytotoxic properties of cisplatin and sodium azide (NaN3) on HeLa cells were evaluated by MTT assay. Moreover, the apoptogenic activity of cisplatin and NaN3 was studied using flow cytometry (Annexin V/PI double staining) and scanning electron microscopy (SEM). Finally, apoptotic bodies were separated by centrifugation. Results: MTT assay data showed that the survival rate of cells treated with different concentration of NaN3 was significantly reduced, compared to negative control groups. Concerning cisplatin, only concentration of 20 MUM had not a significant impact on the cell viability; however, the other concentration of cisplatin significantly reduced cell viability, compared to negative control groups. The level of early apoptosis in uninfected HeLa cells was higher compared to infected HeLa cells treated with cisplatin and NaN3. Finally, apoptotic bodies were separated from T. gondii infected HeLa cells treated with cisplatin. Conclusion: Apoptosis was induced in both uninfected and infected HeLa cells with T. gondii and apoptotic bodies were isolated from infected cells. Therefore, further studies on apoptotic bodies are required in order to find a proper candidate for vaccine preparation against T. gondii infections. PMID- 30483333 TI - Parasitic Helminths in Wild Boars (Sus scrofa) in Mazandaran Province, Northern Iran. AB - Background: Wild boars (Sus scrofa) are distributed worldwide and found in many parts of Iran. Although S. scrofa is reservoirs for many parasites, there is little data on helminthic prevalence in them. We aimed to survey the status of helminthic infections in S. scrofa in the Mazandaran Province of northern Iran. Methods: Twenty-one wild boars were captured and examined for helminth infection during Dec 2012-Mar 2014. Adult worms such as Macracanthorhynchus hirudinaceus were identified by helminth size and shape, and the arrangement of the proboscis hooks. The sedimentation and flotation techniques were used to detect parasite eggs and larvae in faecal samples. Muscle samples were also surveyed for Trichinella larvae by artificial digestion method. Results: Of the 21 samples, 13 (61.9%) were infected with one or more helminth species. Seven helminth types were identified in the alimentary track, comprising 5 nematodes, 1 trematode, and 1 acanthocephalan, with prevalence rates of Macracanthorhynchus hirudinaceus (57.14%), Globocephalus spp. (33.33%), Trichuris suis (19.04), Gongylonema pulchrum (14.28%), Fasciola hepatica (14.28%), Dioctophyma renale (4.76%), and Ascaris suum (4.76%). Conclusion: Wild boars might be involved in transmitting zoonotic parasites to humans. The abundance of these animals near human habitation creates favorable conditions for infection. So the risk of parasitic helminth diseases increases in other animals and humans. PMID- 30483334 TI - Genetic Identification of Echinococcus granulosus Isolates in Hamadan, Western Iran. AB - Background: Cystic echinococcosis is a zoonotic infection and considered as a major economic and public health concern worldwide. This research was conducted to determine genotypic characteristics of livestock and human hydatid cyst isolates from Hamadan area, western Iran. Methods: Sampling was conducted in Hamadan industrial slaughterhouse and Beast Hospital of Hamadan City, western Iran, from 2015 to 2016. Overall, 74 livestock isolates including 69 sheep, 3 cattle and 2 goats and 9 human hydatid cysts were genotyped by PCR amplification of the rDNA ITS1 region and followed restriction fragment length polymorphism (RFLP) analysis with four restriction endonuclease enzymes, RsaI, HpaII, AluI, and TaqI, and sequencing. Results: The PCR amplicon size of each isolate was approximately 1 kb which was the same with that of sheep strain. According to the RFLP patterns, the isolates belonged to a single species, E. granulosus sensu stricto (G1-G3 complex). Furthermore, sequencing of representative amplicons confirmed that the RFLP-genotyped isolates corresponded to E. granulosus sensu stricto. Conclusion: E. granulosus sensu stricto is the prevailing species of E. granulosus sensu lato in the region and pointed out the importance of sheep/dog cycle in human transmission. PMID- 30483335 TI - Molecular and Serological Detection of Toxoplasma gondii in Stray Cats in Shiraz, South-central, Iran. AB - Background: Toxoplasmosis is a global zoonotic disease that causes critical medical complications in neonates and immunocompromised persons. Infection rates in cats, specifically stray cats, are believed to be the best sentry of the level of Toxoplasma gondii in the environment. Therefore, in this study, we surveyed T. gondii infection in stray cats of Shiraz, one of the metropolises of Iran. Methods: The appearance of antibodies and DNA of T. gondii in samples from 145 stray cats was determined in order to appraise the prevalence of T. gondii infection, by MAT and Nested-PCR. Results: The rate of T. gondii infection in the cats was 69% by PCR and 82.8% by MAT. Besides, the highest rate of infection was discerned in diaphragm (37.9%) and intercostal muscle (34.5%), while the lowest rate was related to ileum (6.9%). Moreover, the similarity between MAT with titers 1:20, 1:40 and PCR were 79.2% and 86.2%, respectively (P=0.02 and P=0.0001). Conclusion: Nested-PCR and MAT are valuable techniques for molecular and serological detection of T. gondii. The prevalence of T. gondii infection in stray cats in Shiraz is high. PMID- 30483336 TI - Genetic Diversity in C-terminal of SERA5 Gene in the Blood Stage of Human Isolates of Plasmodium vivax in Sistan and Baluchistan, Iran. AB - Background: Vivax malaria is more prevalent in the malarious areas of Iran, which makes vaccine research a high priority. Serine Repeat Antigens (SERA) have essential role in the parasite life cycle and high expression profiles of PvSERA5 make it suitable vaccine candidates. This study aimed to evaluate the genetic diversity of C-terminal region of PvSERA5 in Iranian isolates of Plasmodium vivax in Sistan and Baluchistan. Methods: Totally, 49 blood samples were taken from symptomatic malaria patients in Sistan and Baluchistan Province in 2016. Mono infection to P. vivax was confirmed by 18srRNA-Nested-PCR. Genomic DNA was extracted and C-terminal region of PvSERA5 was amplified by specific primers. PCR products have been sequenced and analysis was done by using bioinformatics software, mainly DnaSP & MEGA5. Results: Genetic diversity was calculated 14.8% in C-terminal region of PvSERA5 in Iranian isolates, 19 different sequences and 4 haplotypes existed. The amount of Tajima's D (0.3805) and ratio of non-synonymous to synonymous mutation (1.82) showed that C-terminal region of PvSERA5 is under positive natural selection; also intragenic recombination could interfere. Conclusion: Results could be helpful in any research, regarding this antigen as vaccine candidate in Iran or worldwide. PMID- 30483337 TI - Oxidant/Antioxidant Status, PON1 and ARES Activities, Trace Element Levels, and Histological Alterations in Sheep with Cystic Echinococcosis. AB - Background: Total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI), nitric oxide (NO), zinc (Zn), copper (Cu) levels, paraoxonase (PON1), arylesterase (ARES) activities, and biochemical changes were studied on sheep with cystic echinococcosis. Methods: The materials were taken from 2-3 yr old sheep slaughtered in Van Province, Turkey in 2017. Before the slaughter, blood samples were collected from the healthy sheep, while various organs of animals were examined for hydatid cysts after the slaughter. Thirty sheep were protoscolex positive, hydatic group, while 30 sheep that did not have any pathological lesions in organ examinations were accepted as the control group. TOS levels, PON1 and ARES activities, and Zn levels were determined by commercial kits, while Cu levels were determined by atomic absorption spectrophotometer. The collected data were then statistically analyzed. Results: Serum TOS and OSI levels were significantly higher in sheep with cystic echinococcosis compared to the control group (P<0.001). TAS levels (P<0.01), PON1 and ARES activities, on the other hand, were significantly higher in control group compared to the cystic echinococcosis group (P<0.001). There were no significant differences in Zn, NO and Cu levels between the groups. Conclusion: PON1 and ARES activities increased in sheep infected with cyst hydatid. The decline of antioxidant reserves in the metabolism results in excessive amounts of free radicals, along with alterations of the normal histological structure of the cystic organ and changes in trace element metabolism. PMID- 30483338 TI - Genotypes of Enterocytozoon bieneusi in Dogs and Cats in Eastern China. AB - Background: Enterocytozoon bieneusi is a common opportunistic pathogen found in both humans and animals. As companion animals live in close contact with human being, they may act as a zoonotic reservoir and play an important role in transmitting this parasite to humans. We evaluated the prevalence, genotypic diversity and zoonotic potential of E. bieneusi in dogs and cats in eastern China during Apr to Dec 2013. Methods: Fecal specimens from 315 dogs and 143 cats from veterinary hospitals in eastern China were examined in 2015 by internal transcribed spacer (ITS)-based PCR. Results: E. bieneusi was detected in 8.6% of canine and in 1.4% of feline samples. Seven genotypes of E. bieneusi were identified, including four known genotypes (PtEb IX, EbpC, Type IV and D) and three novel genotypes, named CHD1, CHD2 and CHD3. The dominant genotype in dogs was PtEbIX (59.3%; n=16/27). Five (CHD1, EbpC, CHD2, D and Type IV) of the seven genotypes were in the so-called zoonotic group 1, whereas genotypes PtEbIX belonged to the dog-specific group and genotypes CHD3 were placed in group 2. Conclusion: Dogs are predominately infected with host-specific genotypes of E. bieneusi, and the finding of several zoonotic genotypes in dogs and cats reminds us of potentially zoonotic transmission of microsporidiosis. PMID- 30483339 TI - Exploration of Sarcoptes scabiei Antigenic Protein Which Play Roles in Scabies Pathogenesis in Goats and Rabbits. AB - Background: Scabies or mange is an infectious skin disease caused by the mite Sarcoptes scabiei. This skin disease affects various livestock such as goats, sheep, swine, cattle, other animals like dogs, cats, wild animals and also affect human. This research aimed to explore the protein in mites S. scabiei which has antigenic character and play roles in scabies pathogenesis in goats and rabbits. Methods: S.scabiei mites were isolated from goats and rabbits, and characterized using SDS-PAGE. In addition the protein was also analysed using Western Blot assay. The isolation and identification were carried out in 2015 at the Parasitology Laboratory of Veterinary Medicine Faculty, Universitas Airlangga, Surabaya, Indonesia. Results: The identification results using SDS-PAGE of mites S. scabiei var. caprae expressed 12 protein bands between 26,7 kDa and 205,8 kDa, continued by Western Blot showed 3 protein bands, after being reacted with blood serum from scabies infected goat, it could be identified antigenic protein with molecule weight 205.8 kDa, 57.3 kDa, and 43 kDa. While protein in mites S. scabiei var. cuniculi identified 9 protein bands between 24 kDa and 75 kDa by SDS PAGE, and the Western Blot assay identified antigenic protein with molecule weight 62 kDa and 51 kDa. Conclusion: The antigenic protein of S. scabiei var. caprae and S. scabiei var. cuniculi showed that they are probably involved in the scabies pathogenesis in goats and rabbits. PMID- 30483340 TI - Allelic Variations of Plasmodium vivax Apical Membrane Antigen-1 (Pv AMA-1) in Malarious Areas of Southeastern Iran Using PCR-RFLP Technique. AB - Background: Although Plasmodium vivax is usually known as benign malaria, some variations of the parasite can result in acute and sever infection. In this study we tried to determine some genetic variations in PvAMA-1 antigen among the samples were collected form southeastern Iran. Methods: About two ml blood samples were collected into EDTA pre-dosed tubes from 30 P. vivax-infected patients individually between 2011 and 2013. A Giemsa stained thick and thin blood film was prepared from each of the patients. A PCR-RFLP technique was employed using EcoR-1, Pvu-II and Hind3 restriction enzymes to determine the allelic variations of the antigen. Results: A 1300bp gene corresponding to PvAMA 1 was selected for the amplification process. Among the total cases identified in this study 90% showed similar bounds when exposed to the restriction enzymes. Nine isolates (accession numbers: KF435081-KF435083 and JF682785-JF682790) were identified and registered in Gene bank. Identity among isolates was more than 96% in nucleotide level. Dendrogram clarified a close relationship among the clusters in spite of geographical distribution of the parasite. Conclusion: This study increased our data about prevalence and variation of PvAMA-1 alleles amongst P. vivax isolates in southeastern parts of Iran where besides native population bears considerable Afghan and Pakistani immigrants. PMID- 30483341 TI - Endoparasites of Jungle Cats (Felis chaus) and Their Pathologic Lesions. AB - Background: The jungle cats (Felis chaus) are native to Asia, and found in Iran. Although north of Iran has a wide distribution of jungle cats, there is not any data about prevalence of parasitic infections in the population of these cats. Methods: From 2012 to 2015, seven specimens of the wild jungle cat (Felis chaus) from north of Iran, Mazandaran Province, northern Iran were collected and examined for their endoparasites and pathological lesions which were caused by the parasites. Results: Parasitological evaluations showed several species of endoparasites in the small intestine of cats including nematode (Toxocara cati), trematode (Alaria alata), and cestode (Mesocestoides lineatus). All of the examined jungle cats were infected to parasitic infections. From the total number of 7 jungle cats T. cati was found in 6 cats, A. alata in 1 cat, and M. lineatus was recovered from 3 cats. Histopathological samples displayed necrosis, vacuolar degeneration, atrophy, destruction of tissue, hyperemia, and infiltration of inflammatory cells in the intestine tissue. Conclusion: This study for the first reported T. cati, A. alata, and M. lineatus and their pathologic effects in the small intestine of jungle cat. PMID- 30483342 TI - Effect of Origanum vulgare Hydroalcoholic Extract on Giardia lamblia Cysts Compared with Metronidazole in Vitro. AB - Background: Giardiasis, an intestinal infection, is made by the flagellate protozoan and on the other hand, positive effects of plants derivatives, especially phenolic derivatives, against giardiasis. The effect of Origanum vulgare (OV) hydroalcoholic extract is still uninvestigated. Thus, this study was conducted to evaluate the effect of OV hydroalcoholic extract on Giardia lamblia cysts compared with metronidazole in vitro. Methods: The present experimental study was conducted in 2015-2016 in the Laboratory of Department of Parasitology of Islamic Azad University (Abhar Branch, Abhar, Iran). Cysts separated from feces by Bingham procedure were calculated by using the Hemusytumetr method. Five hundred MUl of concentrations of 10, 100 and 200 mg/ml of OV hydroalcoholic extract and also125 mg/kg of metronidazole were added to the purified cysts of giardia. Control group was treated with normal saline. Anti-Giardia activity was calculated by using the light microscope for 30, 60 and 120 min and after exposure to eosin stain. Results: The results indicated anti-Giardia activity of OV hydroalcoholic extract and the best response was achieved at higher levels so that there were no significant differences among OV groups at levels of 200 mg/kg with metronidazole (P>0.05). Conclusion: The anti-Giardia activity of Origanum vulgare extract is may due to the presence of phenolic compounds present in it. PMID- 30483344 TI - Ovarian Cancer or Hydatidosis? A Case Report. AB - Echinococcus granulosus has been described as the common etiology of hydatid cysts in many parts of the world. A 54-yr-old female with lower abdominal pain referred to Gynecology Ward of Sari Imam Khomeini Hospital, Iran in 2016. Sonography was carried out and cysts in ovaries and liver were observed. The cysts of liver seemed to be hydatidosis but physicians were suspected about ovarian cystic mass. Anti-Echinococcus antibodies (ELISA) screen was positive. The operation was done on her and treatment by albendazole started one week before surgery and continued after discharge from the hospital. Pathology confirmed hydatidosis in ovary, also patient follow-up was performed for three months by abdominal CT scan that showed peritoan full of many small hydatid cysts. Uncommon locations for constitution of hydatid cysts such as ovary and peritoan often make the diagnosis very difficult. Hydatidosis is considered in differential diagnosis of any cysts of the entire body, especially in endemic countries such as Iran. PMID- 30483343 TI - Morphometric Analysis of the Intestine in Experimental Coccidiosis in Broilers Treated with Anticoccidial Drugs. AB - Background: Coccidiosis causes morphologic alteration in intestinal mucosa resulting in reduction of absorptive surface. Anticoccidials used as feed additives may induce changes in the intestinal mucosa. This study was designed to assess intestinal morphometry in broilers infected with Eimeria under different anticoccidial treatments. Methods: To evaluate the effect of salinomycin and amprolium+ethopabate on intestinal morphometry in broilers experimental coccidiosis, in Tehran, Iran in May 2015, fifty-four Ross 308 birds were randomly divided into two challenged and unchallenged groups at the age of 12 days. The birds were challenged with Eimeria field isolate at day 14. Different growth and parasitological parameters including weight gain, feed consumption, FCR, macroscopic lesion score and oocyst score were recorded 7 d post-inoculation. Histological sections from four main parts of intestine (anterior, middle, lower intestines and cecum) were prepared and analyzed. Villus width and length and total mucosal thickness were measured microscopically. Results: Amprolium+ethopabate and salinomycin significantly reduced coccidiosis gross lesions in infected birds. Microscopically anticoccidial administration in the presence of infection has significantly increased the villus length while the presence of amprolium+ethopabate in the absence of infection has greatly increased the mucosal thickness and villi height in comparison to the control group. Conclusion: Anticoccidials may induce some histological changes in the mucosa when there is no parasite to be affected. Some of these effects may be advantageous for the intestinal epithelium integrity and hence the birds' performance. PMID- 30483346 TI - Extracellular Vesicles: A More Layer of the Complexity of Hydatid Fluid Contents and Functions. PMID- 30483347 TI - Comment on "Zoonotic and Non-zoonotic Parasites of Wild Rodents in Turkman Sahra, Northeastern Iran". PMID- 30483345 TI - Can Giardia Infection Impair the Diagnostic Level of Fecal Calprotectin in Patients with Inflammatory Bowel Disease? A Case Report. AB - Inflammatory bowel disease (IBD) is attributed to complex conditions of gastrointestinal tract that is frequently reported all over the world. Fecal calprotectin evaluation is described as a primary tool to screen IBD patients. There are reports showing the confounding role of some microbial agents in diagnostic levels of calprotectin. A 32-yr-old woman with symptoms like IBD/IBS (irritable bowel syndrome); admitted to IBD Clinic of Behbood Research Center for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran, Jan 2017 for evaluation of the level of fecal calprotectin. In spite of high level of calprotectin, trophozoite of Giardia intestinalis was observed in direct examination of stool sample. Microbial pathogens can lead to false elevation of fecal calprotectin and misdiagnosis of gastrointestinal patients suspected to IBD. PMID- 30483348 TI - Intracerebral Adenosine During Sleep Deprivation: A Meta-Analysis and New Experimental Data. AB - The neuroregulator adenosine is involved in sleep-wake control. Basal forebrain (BF) adenosine levels increase during sleep deprivation. Only a few studies have addressed the effect of sleep deprivation on extracellular adenosine concentrations in other brain regions. In this paper, we describe a microdialysis experiment as well as a meta-analysis of published data. The 64 h microdialysis experiment determined the extracellular adenosine and adenosine monophosphate (AMP) concentrations in the medial prefrontal cortex of rats before, during and after 12 h of sleep deprivation by forced locomotion. The meta-analysis comprised published sleep deprivation animal experiments measuring adenosine by means of microdialysis. In the animal experiment, the overall median adenosine concentration was 0.36 nM and ranged from 0.004 nM to 27 nM. No significant differences were observed between the five conditions: 12 h of wash-out, baseline light phase, baseline dark phase, 12 h of sleep deprivation and 12 h of subsequent recovery. The overall median AMP concentration was 0.10 nM and ranged from 0.001 nM to 7.56 nM. Median AMP concentration increased during sleep deprivation (T = 47; p = 0.047) but normalised during subsequent recovery. The meta-analysis indicates that BF dialysate adenosine concentrations increase with 74.7% (95% CI: 54.1-95.3%) over baseline during sleep deprivation. Cortex dialysate adenosine concentrations during sleep deprivation were so far only reported by 2 publications. The increase in adenosine during sleep deprivation might be specific to the BF. At this stage, the evidence for adenosine levels in other brain regions is based on single experiments and insufficient for generalised conclusions. Further experiments are currently still warranted. PMID- 30483349 TI - A Systematic Search and Mapping Review of Studies on Intracerebral Microdialysis of Amino Acids, and Systematized Review of Studies on Circadian Rhythms. AB - Background: Microdialysis can be used to measure amino acids in the extracellular space in vivo, based on the principle of diffusion. Variations in experimental set-up result in variations in baseline levels of the compounds measured. Variations may also be due to circadian rhythms. Method: We systematically searched and mapped the literature on all studies reporting baseline microdialysis measurements of histamine and the amino acids asparagine, aspartate, GABA, glutamate, glutamine, glycine, proline and taurine. We fully reviewed the studies describing circadian rhythms for histamine and the selected amino acids. Results: We retrieved 2331 papers describing baseline measurements of one or more of the compounds of interest. We provide a numerical summary and lists of the publications by compound. We retrieved 11 references describing studies on the circadian rhythms of the compounds of interest. Aspartate, glutamate and histamine are generally higher during the dark than during the light phase in nocturnal rodents. For glutamine, no rhythmicity was observed. For GABA, the results were too inconsistent to generalise. For asparagine, glycine, proline and taurine, insufficient data are available. Conclusion: The literature on intracerebral microdialysis measurements of the amino acids is vast, but certain primary studies are still warranted. Future systematic reviews on the individual compounds can shed light on the effects of experimental variations on baseline concentrations. PMID- 30483350 TI - The metabolic model of heart failure: the role of sodium glucose co-transporter-2 (SGLT-2) inhibition. AB - Heart failure (HF) is one of the leading causes of hospital readmissions and health care expenditures. With a vast degree of advancements in the clinical approach and diagnosis, its management protocol is limited in terms of enhancing quality of life and prognosis. Type 2 diabetes mellitus (T2DM) is considered as one of the commonly associated comorbid conditions in the HF population. The understanding of the molecular and metabolic models of HF has led to the utilization of therapeutic goals of T2DM in improving HF-related complications. In the recent era, SGLT-2 inhibitors have shown success in decreasing cardiovascular mortality in the T2DM population. This article will help the reviewer to comprehend the pathophysiology of HF and the potential role of SGLT-2 inhibitors in the management algorithm of HF and its associated risk factors in T2DM. PMID- 30483352 TI - Use of PEG-asparaginase in a case of Hepatosplenic gammadelta T-cell lymphoma with long-term remission after stem cell transplantation. AB - Hepatosplenic gammadelta T-cell lymphoma (HSTCL) is a rare aggressive peripheral T-cell lymphoma. Prognosis is usually poor with a median survival between 8 and 16 months after traditional chemotherapy. Stem cell transplantation (SCT) is promising and with a more intense induction regimen, has yielded positive results. We report the use of pegylated-asparaginase (PEG-asparaginase) along with a conventional anthracycline-containing regimen in a 51-year-old male who was diagnosed with HSTCL, achieved a complete remission, and subsequently underwent peripheral blood SCT and remained in remission at the time of this case report. PMID- 30483351 TI - Impact of adalimumab on clinical outcomes, healthcare resource utilization, and sick leave in patients with ankylosing spondylitis: an observational study from five Central and Eastern European countries. AB - Background: Patients with ankylosing spondylitis (AS) are substantial users of healthcare resources due to chronic and potentially disabling disease. This study assessed the impact of adalimumab on clinical outcomes, healthcare resource utilization, and sick leave in patients with AS in five Central and Eastern Europe (CEE) countries. Methods: This was an observational study in the routine clinical setting. Patients diagnosed with AS and starting treatment with originator adalimumab were followed for 12 months by assessing disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] and Ankylosing Spondylitis Disease Activity Score [ASDAS]) and physical function (Bath Ankylosing Spondylitis Functional Index [BASFI]). Data on healthcare resource utilization and sick leave were collected prospectively and compared with historical data before adalimumab initiation, as well as between treatment responders and non-responders defined by BASDAI-50. Results: The total effectiveness population comprised 450 patients with on average long-standing AS, high disease activity, and functional impairment. At 12 months of adalimumab therapy, mean ASDAS and BASFI scores were in the range of low disease activity and normal physical function, respectively. The mean number of hospital admissions, hospital inpatient days, and healthcare provider visits were decreased by 67.9, 83.0, and 46.3%, respectively. The number and length of sick leaves were decreased by 65.6 and 81.4%, respectively. Reductions were higher in treatment responders than non-responders. Conclusion: Originator adalimumab in routine clinical practice in five CEE countries produced clinically meaningful improvements in disease activity and physical function, and it was associated with reductions in healthcare resource utilization and sick leave. PMID- 30483353 TI - What information do cancer patients want and how well are their needs being met? AB - The goal of this study is to determine the type of information cancer patients need and to measure the extent to which these information needs are met by measuring patients' levels of satisfaction. A self-administered questionnaire developed through extensive literature reviews was pilot tested on 11 cancer patients using convenience sampling in a large ambulatory cancer centre in Singapore. All eligible patients attending the centre during a 5-month period were invited to complete the 76-item survey that had been designed to evaluate self-reported information needs and level of satisfaction with the information received while undergoing cancer treatment. The importance of information and the level of satisfaction with needs being met were assessed with the 5-point Likert scale. A total of 411 patients (50%) completed the survey. Almost all patients wanted information about the disease, tests and investigations, treatment, side effects, sexuality, psychosocial support and financial matters, and most items listed in the questions in each selection were rated as important or very important. Responses indicate that patients were generally satisfied with the information provided especially on diagnosis and diagnostic tests, treatment and overall experience but there are information needs that need to be addressed more efficiently and effectively. The findings of this study support previous research which indicates that cancer patients who are receiving treatment have many information needs. Respondents were generally satisfied with the information provided, although some discrepancies were noted which reflect the complexities associated with cancer patient education. PMID- 30483355 TI - Regorafenib adjusted dose for Chilean patients with chemoresistant metastatic colorectal cancer: a case series. AB - Background: Regorafenib is a therapeutic alternative for patients with metastatic colorectal cancer (MCRC) resistant to conventional therapies. The reported toxicity is relevant and there is no data on Latin American patients. The objective was to evaluate the overall survival (OS), progression-free survival (PFS) and quality of life (QoL) in a prospective cohort of Latin American patients treated with an adjusted dose of regorafenib. Methods: We prospectively recruited patients with MCRC that progressed to standard therapy. A dose escalation algorithm was used. OS, PFS, response rate and QoL were evaluated. Results: We recruited 13 patients between June and November 2015. The median age was 60 years. Median OS was 8.6 months and median PFS was 2.2 months. The response rate was 8%. Grade 3-4 toxicities included grade 3 palmoplantar erythrodysesthesia in 23% and grade 3 fatigue in 12% of patients. Conclusion: Regorafenib treatment is effective in Latin American patients with conventional therapy resistant MCRC. PMID- 30483354 TI - Clinical decision making in postmastectomy radiotherapy in node negative breast cancer. AB - For decades, postmastectomy radiotherapy (PMRT) has been recommended for node positive [N(+)] breast cancer patients; nevertheless, the beneficial effect of PMRT for treatment of node negative [N(-)] disease remains under discussion. Nowadays, the biology of breast cancer and the risk factors (RFs) for locoregional failure (LRF) must be included in the decision on whether or not to carry out PMRT. For these reasons, the present review aims to evaluate the rationale use of PMRT in N(-) patients and discuss which subgroups may further benefit from the treatment in present times where the decision must be personalised, according to the RFs of locoregional recurrence (LRR). To perform the analysis, we ponder that LRR of over 10% should be considered unacceptable due to the fact that LRRs generate great morbidity in patients. For this purpose, we consider that routine RT in these patients is not recommended, although there are subgroups of patients with high LRR, in which PMRT could be beneficial. PMID- 30483357 TI - From science to real-life oncology-the ECCO 2018 European Cancer Summit, 7-9 September 2018, Vienna, Austria. AB - The European CanCer Organisation (ECCO) held its first European Cancer Summit in Vienna, Austria, from 7-9 September 2018. The summit, 'From Science to Real-life Oncology', attracted over 370 participants from across the globe. The aim of the event was connecting science with real life through policy evolution. A broad range of stakeholders attended the event including representatives of ECCO Member Societies, healthcare professionals, pharmaceutical company representatives, patient organisations including patient advocates, commercial providers to the healthcare sector, EU and national/regional government officials as well as academic researchers and regulatory professionals. The summit provided the opportunity to discuss some challenging issues including a European agenda on cancer, the use of big data and putting a price on cancer medicines. One of the objectives of the summit was to gather stakeholder decisions on resolutions looking at efficiency in cancer care, integration of services and quality. The result was a highly interactive well-attended meeting which permitted networking opportunities across stakeholder groups and giving direction to European cancer care. PMID- 30483356 TI - Thromboembolic events in patients with advanced stage non-small cell lung cancer treated with platinum-based chemotherapy: a prospective observational study. AB - Objectives: Cancer is frequently complicated by thromboembolic events (TEs). We aimed to determine the incidence of TEs in lung cancer patients treated with platinum-based chemotherapy and study patients' baseline and treatment attributes correlating with its onset. Materials and methods: Advanced lung cancer patients started on platinum-based chemotherapy were evaluated at baseline and during routine visits for the development of TEs. The duration of follow-up was 4 weeks from the last chemotherapy. A TE occurring between the first dose of chemotherapy and 4 weeks after the last dose was considered to be chemotherapy associated. Results: Of the 165 patients on platinum chemotherapy who completed follow-up, TEs occurred in 4.8% (8 out of 165) patients. Among these, three patients had developed venous pulmonary thromboembolism and five patients had developed cerebral infarction, out of which four had arterial cerebral infarction and one patient had a superior sagittal sinus thrombosis. The majority of events (7 out of 8) occurred within 100 days of starting platinum chemotherapy. Overall, the median time until occurrence of TE was 48 days (range, 10-130 days). None of the presumed risk factors were found be associated with the occurrence of TEs on univariate analysis. Conclusions: Advanced lung cancer patients on platinum chemotherapy are predisposed to thromboembolism due to many factors. Despite its lower incidence in our study, exclusion of patients with prior thrombosis suggests the incidence of de novo thrombosis, and hence raises a valid question of the need of thromboprophylaxis in a selected group of patients. PMID- 30483358 TI - Identifying barriers and finding solutions to implement best practices for cancer surgery at Maputo Central Hospital, Mozambique. AB - Purpose: The aim of this study was to assess the surgical resources and surgical oncology team skills at the Surgical Department of Maputo Central Hospital (MCH) in Mozambique in order to define an educational program to support surgical oncology practice. Methods: From January 2017 to December 2017, a general evaluation of the resources of MCH was carried out, as well as its offerings in oncological care in different services. Data were obtained by reviewing documents, visiting surgical services and interviewing key-informants and others informally. In addition, a group of seven surgeons of the Surgical Department of MCH answered a questionnaire about the quality of the cancer units (The Cancer Units Assessment Checklist for low- or middle-income African countries). Subsequently, surgical, anaesthesiology and intensive care facilities were evaluated according to the Portuguese-speaking African Countries Assessment of Surgical Oncology Capacity Survey (PSAC-Surgery). All the data were triangulated in order to identify gaps, develop an action plan and define an educational program. Results: Breast, oesophagus and colorectal cancers were the most commonly treated neoplasms in MCH. A range of technical and resource needs as well as the gaps in knowledge and skills were identified. All surgeons recognised the need to create a training program in oncology at the undergraduate level, specific training for residents and continuing oncological education for general surgeons to improve the practice of surgical oncology. It was evident that all these interventions needed to be formalised, appropriately certified and count for professional career progression. Based on the local epidemiological data and on these study findings, oncology education programs were developed for surgeons. Conclusions: The findings of this study contributed to the development of an educational program in surgical oncology, considered essential to the training of surgeons at MCH. The cancer educational programs and the mobilisation of adequate resources will ensure the provision of adequate surgical oncology treatments for MCH. The training requirements should be tailored to suit the local needs based on the most prevalent malignancies diagnosed in the region. In our view, this methodology may apply to other countries with similar realities in the formation of surgical oncologists. PMID- 30483359 TI - High tumour burden, delayed diagnosis and history of cardiovascular disease may be associated with carcinoid heart disease. AB - Background: Patients with carcinoid syndrome (CS) may present carcinoid heart disease (CHD) but prognostic factors are not entirely understood. Patients and Methods: Retrospective study of patients with metastatic neuroendocrine tumours (NETs) and CS and/or abnormal 24-hour-urinary 5-hydroxiindolacetic acid. CHD was defined as moderate to severe tricuspid or pulmonary regurgitation in the echocardiogram. Results: The frequency of CHD among 42 patients was 38% (95% confidence interval [CI]: 23%-54%). CHD was associated with higher volume of liver metastases (odds ratio [OR] 13.86, 95% CI: 2.57-74.68, p = 0.002). Time from CS symptoms to NET diagnosis was borderline significant (p = 0.08). When CHD was defined as at least mild tricuspide regurgitation, the frequency of CHD was 45% and it was associated with cardiovascular comorbidities (OR: 6.58, 95% CI: 1.09; 39.78, p = 0.040). Conclusion: CHD was frequent among patients with CS, significantly associated with high liver tumour burden, and likely linked to the history of cardiovascular disease and longer time of CS. PMID- 30483360 TI - Information sources and online information seeking behaviours of cancer patients in Singapore. AB - The aim of this study was to investigate the prevalence of Internet usage among cancer patients in seeking health-related information and the type of information sought. Sources of information received from, preferences for information sources and the perceived usefulness of information from these sources were also examined in this study. A self-administered questionnaire was used to evaluate the information needs of patients undergoing cancer treatment. The questionnaire also evaluated the current source and preferred source of information as well as their online information seeking behaviours. A total of 411 patients with cancer were recruited from an ambulatory cancer centre. The patients' physicians and healthcare specialists comprised a large majority of the patients' information sources; they were also the most preferred source of information. 59.1% of the respondents used the Internet to search for cancer-related information, namely diagnosis and treatment options, side effects of treatment and complementary and alternative therapy; demonstrating the importance of the above information. Physicians (60.3%) and healthcare specialists (26.5%) were the largest and most preferred sources of information for cancer patients in our study. It was not uncommon for cancer patients to use the Internet to search for additional information demonstrating the need to integrate this tool more effectively for knowledge transfer for those patients who want it. It is important for healthcare professionals to help cancer patients by directing them to sources of quality information (including websites). In addition, the provision of guidelines on how to evaluate health information on the Internet would be helpful to cancer patients. PMID- 30483361 TI - The impact of tobacco tax/law implementation on pancreatic cancer mortality in Mexico, 1999-2015. AB - Among the multiple aetiologies identified for pancreatic cancer (PC), cigarette smoking and diabetes are considered "moderate risk factors". Analysis of PC mortality trends is important as changes in incidence and mortality of this tumour can be partially attributable to changes in smoking patterns. A recent Mexican study examined PC mortality trends and showed a favourable trend from 2000 to 2014 [1]. However, the impact of new tobacco tax/laws which were implemented in Mexico in 2007/2008 was not assessed in this study. In this re analysis we assessed their impact on PC mortality and found a non-statistically significant trend from 1999 to 2008 - however, PC mortality statistically decreased from 2008 with an annual percent change or APC of -1.27, -1.23 and 1.17 in both sexes, females and males respectively, p < 0.05. These declines are likely resulting in part from new tobacco tax/laws which are likely contributing to the decrease over time of smoking prevalence and environmental tobacco smoke exposure. PMID- 30483362 TI - A feature-based neurocomputational model of semantic memory. AB - According with a featural organization of semantic memory, this work is aimed at investigating, through an attractor network, the role of different kinds of features in the representation of concepts, both in normal and neurodegenerative conditions. We implemented new synaptic learning rules in order to take into account the role of partially shared features and of distinctive features with different saliency. The model includes semantic and lexical layers, coding, respectively for object features and word-forms. Connections among nodes are strongly asymmetrical. To account for the feature saliency, asymmetrical synapses were created using Hebbian rules of potentiation and depotentiation, setting different pre-synaptic and post-synaptic thresholds. A variable post-synaptic threshold, which automatically changed to reflect the feature frequency in different concepts (i.e., how many concepts share a feature), was used to account for partially shared features. The trained network solved naming tasks and word recognition tasks very well, exploiting the different role of salient versus marginal features in concept identification. In the case of damage, superordinate concepts were preserved better than the subordinate ones. Interestingly, the degradation of salient features, but not of marginal ones, prevented object identification. The model suggests that Hebbian rules, with adjustable post synaptic thresholds, can provide a reliable semantic representation of objects exploiting the statistics of input features. PMID- 30483363 TI - Comparing advanced graph-theoretical parameters of the connectomes of the lobes of the human brain. AB - Deep, classical graph-theoretical parameters, like the size of the minimum vertex cover, the chromatic number, or the eigengap of the adjacency matrix of the graph were studied widely by mathematicians in the last century. Most researchers today study much simpler parameters of braingraphs or connectomes which were defined in the last twenty years for enormous networks-like the graph of the World Wide Web with hundreds of millions of nodes. Since the connectomes, describing the connections of the human brain, typically contain several hundred vertices today, one can compute and analyze the much deeper, harder-to-compute classical graph parameters for these, relatively small graphs of the brain. This deeper approach has proven to be very successful in the comparison of the connectomes of the sexes in our earlier works: we have shown that graph parameters, deeply characterizing the graph connectivity are significantly better in women's connectomes than in men's. In the present contribution we compare numerous graph parameters in the three largest lobes-frontal, parietal, temporal-and in both hemispheres of the human brain. We apply the diffusion weighted imaging data of 423 subjects of the NIH-funded Human Connectome Project, and present some findings, never described before, including that the right parietal lobe contains significantly more edges, has higher average degree, density, larger minimum vertex cover and Hoffman bound than the left parietal lobe. Similar advantages in the deep graph connectivity properties are held for the left frontal versus the right frontal and the right temporal versus the left temporal lobes. PMID- 30483364 TI - Aging-related changes of EEG synchronization during a visual working memory task. AB - Differences of EEG synchronization between normal old and young people during a working memory (WM) task were investigated. The synchronization likelihood (SL) is a novel method to assessed synchronization in multivariate time series for non stationary systems. To evaluate this method to study the mechanisms of WM, we calculated the SL values in brain electrical activity for both resting state and task state. EEG signals were recorded from 14 young adults and 12 old adults during two different states, respectively. SL was used to measure EEG synchronization between 19 electrodes in delta, theta, alpha1, alpha2 and beta frequency bands. Bad task performance and significantly decreased EEG synchronization were found in old group compared to young group in alpha1, alpha2 and beta frequency bands during the WM task. Moreover, significantly decreased EEG synchronization in beta band in the elder was also detected during the resting state. The findings suggested that reduced EEG synchronization may be one of causes for WM capacity decline along with healthy aging. PMID- 30483365 TI - Graph analysis of functional brain network topology using minimum spanning tree in driver drowsiness. AB - A large number of traffic accidents due to driver drowsiness have been under more attention of many countries. The organization of the functional brain network is associated with drowsiness, but little is known about the brain network topology that is modulated by drowsiness. To clarify this problem, in this study, we introduce a novel approach to detect driver drowsiness. Electroencephalogram (EEG) signals have been measured during a simulated driving task, in which participants are recruited to undergo both alert and drowsy states. The filtered EEG signals are then decomposed into multiple frequency bands by wavelet packet transform. Functional connectivity between all pairs of channels for multiple frequency bands is assessed using the phase lag index (PLI). Based on this, PLI weighted networks are subsequently calculated, from which minimum spanning trees are constructed-a graph method that corrects for comparison bias. Statistical analyses are performed on graph-derived metrics as well as on the PLI connectivity values. The major finding is that significant differences in the delta frequency band for three graph metrics and in the theta frequency band for five graph metrics suggesting network integration and communication between network nodes are increased from alertness to drowsiness. Together, our findings also suggest a more line-like configuration in alert states and a more star-like topology in drowsy states. Collectively, our findings point to a more proficient configuration in drowsy state for lower frequency bands. Graph metrics relate to the intrinsic organization of functional brain networks, and these graph metrics may provide additional insights on driver drowsiness detection for reducing and preventing traffic accidents and further understanding the neural mechanisms of driver drowsiness. PMID- 30483367 TI - EEG classification of driver mental states by deep learning. AB - Driver fatigue is attracting more and more attention, as it is the main cause of traffic accidents, which bring great harm to society and families. This paper proposes to use deep convolutional neural networks, and deep residual learning, to predict the mental states of drivers from electroencephalography (EEG) signals. Accordingly we have developed two mental state classification models called EEG-Conv and EEG-Conv-R. Tested on intra- and inter-subject, our results show that both models outperform the traditional LSTM- and SVM-based classifiers. Our major findings include (1) Both EEG-Conv and EEG-Conv-R yield very good classification performance for mental state prediction; (2) EEG-Conv-R is more suitable for inter-subject mental state prediction; (3) EEG-Conv-R converges more quickly than EEG-Conv. In summary, our proposed classifiers have better predictive power and are promising for application in practical brain-computer interaction . PMID- 30483366 TI - Higher-order spectral analysis of spontaneous speech signals in Alzheimer's disease. AB - An early and accurate diagnosis of Alzheimer's disease (AD) has been progressively attracting more attention in recent years. One of the main problems of AD is the loss of language skills. This paper presents a computational framework for classifying AD patients compared to healthy control subjects using information from spontaneous speech signals. Spontaneous speech data are obtained from 30 AD patients and 30 healthy controls. Because of the nonlinear and dynamic nature of speech signals, higher order spectral features (specifically bispectrum) were used for analysis. Four classifiers (k-Nearest Neighbor, Support Vector Machine, Naive Bayes and Decision tree) were used to classify subjects into three different levels of AD and healthy group based on their performance in terms of the HOS-based features. Ten-fold cross-validation method was used to test the reliability of the classifier results. The results showed that the proposed method had a good potential in AD diagnosis. The proposed method was also able to diagnose the earliest stage of AD with high accuracy. The method has the great advantage of being non-invasive, cost-effective, and associated with no side effects. Therefore, the proposed method can be a spontaneous speech directed test for pre-clinical evaluation of AD diagnosis. PMID- 30483368 TI - Complex dynamics of a neuron model with discontinuous magnetic induction and exposed to external radiation. AB - The last two decades have seen many literatures on the mathematical and computational analysis of neuronal activities resulting in many mathematical models to describe neuron. Many of those models have described the membrane potential of a neuron in terms of the leakage current and the synaptic inputs. Only recently researchers have proposed a new neuron model based on the electromagnetic induction theorem, which considers inner magnetic fluctuation and external electromagnetic radiation as a significant missing part that can participate in neural activity. While the flux coupling of the membrane is considered equivalent to a memductance function of a memristor, standard memductance model of alpha+3betaphi2 has been used in the literatures, but in this paper we propose a new memductance function based on discontinuous flux coupling. Various dynamical properties of the neuron model with discontinuous flux coupling are studied and interestingly the proposed model shows hyperchaotic behavior which was not identified in the literatures. Furthermore, we consider a ring network of the proposed model and investigate whether the chimera state can emerge. The chimera state relates to the state with simultaneously coherence and incoherence in oscillatory networks and has received much attention in recent years. PMID- 30483369 TI - Simulation of retinal ganglion cell response using fast independent component analysis. AB - Advances in neurobiology suggest that neuronal response of the primary visual cortex to natural stimuli may be attributed to sparse approximation of images, encoding stimuli to activate specific neurons although the underlying mechanisms are still unclear. The responses of retinal ganglion cells (RGCs) to natural and random checkerboard stimuli were simulated using fast independent component analysis. The neuronal response to stimuli was measured using kurtosis and Treves Rolls sparseness, and the kurtosis, lifetime and population sparseness were analyzed. RGCs exhibited significant lifetime sparseness in response to natural stimuli and random checkerboard stimuli. About 65 and 72% of RGCs do not fire all the time in response to natural and random checkerboard stimuli, respectively. Both kurtosis of single neurons and lifetime response of single neurons values were larger in the case of natural than in random checkerboard stimuli. The population of RGCs fire much less in response to random checkerboard stimuli than natural stimuli. However, kurtosis of population sparseness and population response of the entire neurons were larger with natural than random checkerboard stimuli. RGCs fire more sparsely in response to natural stimuli. Individual neurons fire at a low rate, while the occasional "burst" of neuronal population transmits information efficiently. PMID- 30483370 TI - Suppressing bursting synchronization in a modular neuronal network with synaptic plasticity. AB - Excessive synchronization of neurons in cerebral cortex is believed to play a crucial role in the emergence of neuropsychological disorders such as Parkinson's disease, epilepsy and essential tremor. This study, by constructing a modular neuronal network with modified Oja's learning rule, explores how to eliminate the pathological synchronized rhythm of interacted busting neurons numerically. When all neurons in the modular neuronal network are strongly synchronous within a specific range of coupling strength, the result reveals that synaptic plasticity with large learning rate can suppress bursting synchronization effectively. For the relative small learning rate not capable of suppressing synchronization, the technique of nonlinear delayed feedback control including differential feedback control and direct feedback control is further proposed to reduce the synchronized bursting state of coupled neurons. It is demonstrated that the two kinds of nonlinear feedback control can eliminate bursting synchronization significantly when the control parameters of feedback strength and feedback delay are appropriately tuned. For the former control technique, the control domain of effective synchronization suppression is similar to a semi-elliptical domain in the simulated parameter space of feedback strength and feedback delay, while for the latter one, the effective control domain is similar to a fan-shaped domain in the simulated parameter space. PMID- 30483371 TI - Bacteriological profile of intra-abdominal infections in a tertiary care hospital. AB - Background and Objectives: Intra-abdominal infections (IAIs) include a wide spectrum of pathological conditions, ranging from uncomplicated appendicitis to fecal peritonitis .The resulting infections should be diagnosed early and treated based on the organism isolated and its susceptibility. In this study the bacteriological profile and antimicrobial resistance pattern of intra-abdominal infections was analyzed. Materials and Methods: A retrospective analysis of samples received from 119 cases of intra-abdominal infections in our Institute from January 2015 to December 2017 was analyzed. Patients with primary peritonitis from cirrhosis or ascites were not included in the study. The specimens were primarily processed, as per standard methods. Identification and antimicrobial susceptibility testing was done by the Vitek-2 system. Anaerobic culture was performed on 5% sheep blood agar plates and incubated in GEN bag anaerobic pouches. Results: In our study perforative peritonitis 43/119 (36.1%) was predominant IAI followed by acute pancreatitis 14/119 (11.7%) and pancreatic necrosis 12/119 (10%). Microbial growth was observed in 66.3% (79/119) of the cases and combined infections were observed in14/119 (11.7%) of the cases. Escherichia coli was the predominant organism isolated in 58/119 (40.8%), out of which 41/58 (70.6%) were ESBL producers and 16/58 (27.5%) were multi drug resistant isolates. Klebsiella pneumoniae was isolated from 11/119 (9.2%) cases out of which 8/11 (72.7%) were ESBL and 3/11 (27.2%) were multidrug resistant isolates. Post-operative complications was observed in 12/119 (10%) patients with mortality in 15/119 (12.6%) patients. Conclusion: Early diagnosis and appropriate management of the infections will help to prevent the morbidity and mortality associated with these infections. PMID- 30483372 TI - Detection of methicillin-resistant Staphylococcus aureus (MRSA) in clinical samples of patients with external ocular infection. AB - Background and Objectives: Staphylococcus aureus is the main Gram-positive bacteria isolated from patients with ocular infections. Herein, we describe the pattern of antibiotic resistance, presence of resistance genes including ermA, ermB, ermC, msrA, mecA and the pvl cytotoxin gene in S. aureus isolates collected from patients with external ocular infection. Materials and Methods: In this study, 8 S. aureus isolates were collected from 81 patients that suffered from eye damage. Antibacterial susceptibility of isolates was determined using the Kirby-Bauer disk diffusion method. Resistance genes including ermA, ermB, ermC, msrA, mecA and the pvl virulence gene were detected by PCR method. Staphylococcal cassette chromosome mec (SCCmec) in MRSA isolates were detected by the multiplex PCR method. Results: Three isolates were resistant to cefoxitin which is considered MRSA. The mecA gene was identified in MRSA isolates. SCCmec type IV and the pvl gene were detected in one of the MRSA isolates that was recovered from a diabetic patient. Conclusion: The emergence of S. aureus isolates belonging to SCCmec type IV and pvl gene among patients with ocular infection is very serious; therefore, identify genetic characterization of MRSA isolates for empirical therapy and infection control is very important. PMID- 30483373 TI - Prevalence of Coxiella burnetii in unpasteurized dairy products using nested PCR assay. AB - Background and Objectives: Q fever is a worldwide disease which is common between humans and livestock. This disease is created by an obligate intracellular Rickettsia called Coxiella burnetii (C. burnetii). The aim of this study was to determine the prevalence of C. burnetii in unpasteurized dairy products in Shiraz. Materials and Methods: In this study (from summer 2016 to winter 2016), 238 non-pasteurized dairy products, (48 raw milk, 48 yogurt, 46 cheese, 48 dough and 48 ice cream samples) were collected from the retail market and analyzed using a nested PCR assay. Results: This study showed that 20 samples (8.4%), out of the 238 unpasteurized dairy products, were positive for C. burnetii as follows: 13 out of 48 (27.08%) raw milk, 3 out of 48 (6.25%) yogurt, 2 out of 46 (4.35%) cheese, 2 out of 48 (4.16%) dough, and 0 out of 48 ice cream samples. Conclusion: The present study suggests that unpasteurized dairy products are the main sources of C. burnetii in Shiraz, Southern Iran; thus, the consumption of pasteurized milk and dairy products is a valuable method to prevent the disease in humans. PMID- 30483374 TI - Prevalence of dengue and leptospirosis co-infection in a tertiary care hospital in south India. AB - Background and Objectives: Dengue and Leptospirosis were often discussed separately with rash being more common in dengue and jaundice in leptospirosis. But with increasing reports of co-infection, the situation has become worse. The main objective of this study was to look for the presence of both Dengue and Leptospira IgM antibodies in serum samples of patients, presenting with acute febrile illness. Medical records of the co-infected patients were examined to analyse the clinical features and laboratory findings. Materials and Methods: Serum samples of patients presenting with acute febrile illness were screened for the presence of Dengue IgM antibodies and Leptospira antibodies. Clinical features and laboratory parameters of patients with co-infection were compared with patients having dengue alone. Rainfall data was obtained to look for an association between rainfall and Dengue, leptospirosis and co-infected cases. Results: Co-infection was seen in 33 (3.4%) samples. There was a statistically significant association between clinical features like rashes, bleeding gums and co-infection. There was a statistically significant association between various laboratory parameters like thrombocytopenia and co-infection. There was positive correlation between rainfall and development of dengue, leptospirosis, and co infection but it was not statistically significant. Conclusion: The overall prevalence of co-infection was 3.4%. This study re-emphasizes the fact that dengue and leptospirosis are widely prevalent in south India and clinicians should be aware that co-infection with dengue and leptospirosis is not uncommon. PMID- 30483375 TI - Molecular diagnosis of genital tract infections among HIV-positive women in Iran. AB - Background and Objectives: Human immunodeficiency virus (HIV)-infected women are usually at a higher risk of sexually transmitted infections (STIs) than others. The objective of this study was to characterize the prevalence of human papilloma virus (HPV), herpes simplex virus (HSV), Chlamydia trachomatis (CT), and Neisseria gonorrhoeae (NG), and associated risk factors among HIV-infected women in Fars province, Iran. Materials and Methods: In this cross-sectional study, cervical swab samples were collected from 71 HIV-infected women, aged 17-45 years (mean +/- standard deviation: 31.11 +/- 6.58 years), and tested for HPV, HSV, CT, and NG using PCR assays. Results: Overall, 77.5% of patients were positive for the tested STIs with the following distribution: 36 (50.7%) HPV, 7 (9.9%) HSV, 4 (5.6%) NG, and 27 (38%) CT. From those, 39 (55%) were positive for only one infection, while 16 (22.5%) were positive for multiple infections. We observed that the prevalence of all tested STIs increased by age, except for HSV which showed a slight decrease, although not statistically significant. Socio-economic factors such as low educational level, multiple sex partners, and being a sex worker significantly correlated with higher positive prevalence of STIs in the studied population. Conclusion: A high prevalence of STIs was observed among HIV infected women in this region. These data might prompt policy makers and STI experts to focus on providing a comprehensive sex education, including participation in screening programs for STIs among high-risk groups. PMID- 30483377 TI - A case report of human tularemia from Iran. AB - Tularemia is one of the most contagious bacterial infections. Here, we report a human case of glandular tularemia in Iran following the first report in 1980. The patient was a 6-year-old girl who had consumed a hunted hare in Kurdistan Province in western Iran. PMID- 30483376 TI - Characterization of gyrA and parC mutations in ciprofloxacin-resistant Pseudomonas aeruginosa isolates from Tehran hospitals in Iran. AB - Background and Objectives: Pseudomonas aeruginosa, a major cause of several infectious diseases, has become a hazardous resistant pathogen. One of the factors contributing to quinolone resistance in P. aeruginosa is mutations occurring in gyrA and parC genes encoding the A subunits of type II and IV topoisomerases, respectively, in quinolone resistance determining regions (QRDR) of the bacterial chromosome. Materials and Methods: Thirty seven isolates from patients with burn wounds and 20 isolates from blood, urine and sputum specimen were collected. Minimum Inhibitory Concentrations (MICs) of ciprofloxacin were determined by agar diffusion assay. Subsequently, QRDRs regions of gyrA and parC were amplified from resistant isolates and were assessed for mutations involved in ciprofloxacin resistance after sequencing. Results: Nine isolates with MIC>=8 MUg/ml had a mutation in gyrA (Thr83->Ile). Amongst these, seven isolates also had a mutation in parC (Ser87-> Leu or Trp) indicating that the prevalent mutation in gyrA is Thr83Ile and Ser87Leu/Trp in parC. No single parC mutation was observed. Conclusion: It seems that mutations in gyrA are concomitant with mutations in parC which might lead to high-level ciprofloxacin resistance in P. aeruginosa isolates from patients with burn wounds and urinary tract infections. PMID- 30483378 TI - The antibacterial effect of aquatic and methanolic extract of Myrtus communis on Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis and Prevotella intermedia. AB - Background and Objectives: Anaerobic Gram negative bacteria are the main cause of periodontal destruction. It has been shown that Myrtus communis have anti bacterial activity on Gram positive and Gram negative bacteria. The aim of this study was to determine the antibacterial effect of aquatic and methanolic extract of Myrtus communis on some of the oral Gram-negative bacteria. Materials and Methods: The antibacterial effect of aquatic and methanolic extracts of Myrtus communis was determined using disk diffusion method at different concentrations from 10 to 500 mg/ml. The diameter of inhibition zones were determined. The MIC was defined using the standard broth macrodilution method. The results of the study were reported descriptively. Results: The aquatic extract of Myrtus communis from 20 to 500 mg/ml had antibacterial effect on Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis and Prevotella intermedia. The methanolic extract from 10 to 500 mg/ml had antibacterial effect on A. actinomycetemcomitans, P. gingivalis and P. intermediate. The MIC was achieved at 10 mg/ml, 10 mg/ml and 10 mg/ml for aquatic and methanolic extracts of Myrtus communis on A. Actinomycetemcomitans, P. Gingivalis and P. Intermediate, respectively. Conclusion: Aquatic and methanolic extracts of Myrtus communis had antibacterial effect on P. gingivalis, A. actinomycetemcomitans and P. intermediate. Most concentrations of aqueous extract were effective on bacteria, so, providing an alcoholic extract, that is a time consuming and costly method, does not seem necessary. PMID- 30483379 TI - Echovirus 30 and coxsackievirus A9 infection among young neonates with sepsis in Iran. AB - Background and Objectives: Human enteroviruses (EV) are the most common causes of neonatal sepsis-like disease. The frequencies of EV including coxsackievirus A, coxsackievirus B and Echovirus serotypes have been studied in young infants (younger than three months) with sepsis. So far, the role of enteroviruses among neonates with sepsis was not determined in Ahvaz, Iran. Therefore, this study was aimed to evaluate the frequency of EV among hospitalized young infants with clinical signs and symptoms of sepsis in Ahvaz. Materials and Methods: Blood specimens from 128 neonates (younger than 90 days), including 56 (43.75%) girls and 72 (56.25%) boys, were collected from hospitalized neonates with clinical signs and symptoms of sepsis-like symptoms. All blood samples were negative for bacterial culture. RNA was extracted from all sera and tested for detection of 5'UTR (Untranslated Region) of the EV by RT-PCR. To determine specific strains of EV, positive 5'UTR samples were further tested for detection of the VP1 region of EV by RT-PCR. Results: Overall, 50/128 (39.06%) specimens, including 24 (48%) girls and 26 (52%) boys, were positive for EV. 21/50 (42%) specimens were positive for the VP1 region. Randomly, 8 positive VP1 were selected and sequenced. Analysis of sequencing data showed 7/21 (33.33%) samples were positive for Echovirus 30 and 1/21 (4.76%) samples were positive for CVA9. Conclusion: The results of this survey indicate high prevalence of 39.06% of EV among young neonates with sepsis. A high prevalence of 33.3% Echoviruses 30 and a low rate of 4.76% coxsackievirus A9 infection has been observed in neonatal patients with viral sepsis. This outbreak is probably one of the first Enterovirus outbreaks to be reported in Ahvaz, Iran. The results of this survey will help to minimize unneeded use of antimicrobial drugs and reduce unnecessary hospitalization. PMID- 30483380 TI - Detection of JC Polyomavirus tumor antigen in gastric carcinoma: a report from Iran. AB - Background and Objectives: Factors contributing to development of gastric cancer are still under investigation. The JC Virus (JCV), as an oncogenic virus, has been indicated to play a possible role in gastric carcinogenesis. Theoretically, tumor antigen (T-Ag), the viral transforming protein, is capable of binding and inactivating tumor suppressor proteins p53 and pRb, there by promoting cancer development although such a role in gastric cancer is still controversial and additional data is needed to reach a definite conclusion. The prevalence of the virus varies in different geographic regions, therefore, we aimed to investigate JCV presence in cancerous gastric tissues of Iranian patients. Materials and Methods: Thirty-one paired samples were included in this study (total of 62 samples). T-Ag sequences were investigated using real-time PCR in formalin fixed paraffin embedded (FFPE) tissue samples from the tumor site and relevant adjacent non-cancerous tissues (ANCT). In positive samples, JCV copy number (viral load) was also measured using real-time PCR. To evaluate T-Ag protein expression, immunohistochemistry examination was performed using an anti-T-Ag specific antibody. Results: JCV sequences were detected in 17 out of 31 gastric cancer tissue samples (54.84%) and in 10 out of 31 of the non-cancerous adjacent gastric mucosa (32.25%) (Odds ratio of 2.4). Viral load in tumoral and adjacent tissue samples was not statistically different (p=0.88). Immunohistochemical study confirmed presence of JC T-Ag in the nuclear compartment. Conclusion: We showed the presence of the JC virus in gastric carcinoma tissue samples in our geographic region. This finding provides supportive data for a possible contribution of JCV in gastric cell transformation to malignancy. However, we highly recommend additional investigations to further explore JC virus and gastric cancer in order to reach a conclusion. PMID- 30483381 TI - Saffron (Crocus sativus) petal as a new pharmacological target: a review. AB - Saffron petal is the main by-product of saffron processing which produced at high level but it is not applied and thrown out. Saffron petal is containing of several compounds such as mineral agents, anthocyanins, flavonoids, glycosides, alkaloids and kaempferol. As saffron petal is cheaper and produces in large amounts compared to saffron stigma, so, it can be considered as an appropriate source for different purposes. In this review different pharmacological properties of saffron petal such as anti-bacterial, anti-spasmodic, immunomodulatory, anti-tussive, anti-depressant, anti-nociceptive, hepato protective, reno-protective, anti-hypertensive, anti-diabetic and anti-oxidant activity have been introduced. According to these properties, saffron petal can be used as an alternative or supplementary medicine in some diseases. PMID- 30483382 TI - Formation of therapeutic phage cocktail and endolysin to highly multi-drug resistant Acinetobacter baumannii: in vitro and in vivo study. AB - Objectives: Phage therapy is a potential alternative treatment for infections caused by Acinetobacter baumannii, a significant nosocomial pathogen, which has evolved resistance to almost all conventional antimicrobial drugs in poor hygiene and conflicts areas such as Iraq. Materials and Methods: Bacteriophages were isolated to highly resistant isolates of A. baumannii to form therapeutic phage cocktail, and to extract and evaluate native endolysin activity. Bacterial samples were collected in Al-Imamein Al-kadhimein Medical City Hospital. Phages were isolated from different regions in Baghdad city including (soil, sewage, irrigation channels). Phage endolysin was extracted from highly lytic phages that produced halo-like appearance around inhibition zone. Results: Up to 23 isolates of extensive- and pan- drug resistant (XDR, PDR) A. baumannii were isolated from patients with various infections, and 136 lytic phages specific to A. baumannii were isolated. Each bacterial isolate was sensitive to at least one lytic phage. Accordingly, a phage cocktail was formulated which remarkably minimized bacterial resistance to lysis by phages when compared to individual lytic phages. And, the phage cocktail succeeded in treating and saving life of all bacteremic mice with A. baumannii versus the non-treated group. In addition, the endolysin native activity to A. baumannii was evaluated in this study; endolysin revealed a potent antibacterial activity (> 1 log) reduction of bacterial density in just one hour of endolysin treatment. Conclusion: The phage therapy assessed in this study showed an ability to efficiently solve the problems of "superbug" bacteria by lysing effectively most XDR, PDR bacteria in vitro and in vivo. And, phage cocktail was shown to be superior over single-phage preparations in treating A. baumannii with much less resistance rate to therapeutic phages. Furthermore, intrinsic activity of native endolysin revealed promising results to tackling superbug pathogens. PMID- 30483383 TI - Effects of assisted oocyte activation with calcium- ionophore and strontium chloride on in vitro ICSI outcomes. AB - Objectives: Failed fertilization after intra-cytoplasmic sperm injection (ICSI) is mainly attributed to failed oocyte activation and can be overcome by artificial oocyte activation (AOA). The present study aims to compare in vitro outcomes of ICSI following two different assisted oocyte activation chemical procedures (SrCl2 and Ionomycin) in sibling oocytes of ICSI candidates. Materials and Methods: From March 2015 until February 2016, 105 infertile men with 99-100% abnormal sperm morphology, irrespective of sperm motility, concentration, or origin (semen or testicular) were included in this study. Out of these, 66 couples accepted to be included in the study group (Ionomycin/ SrCl2) and 39 couples requested routine AOA procedure (Ionomycin) as external control group. Primary outcomes of this study (fertilization, embryo quality, and post implantation development) were compared between these groups. Results: Significantly higher oocyte activation (67.90+/-3.6% vs. 51.16+/-3.6%, P=0.004) and fertilization (65.23+/-3.63% vs. 49.65+/-3.63%, P=0.008) rates were observed in sibling oocytes treated with Ionomycin in comparison to the SrCl2 sibling group. Percentage of top quality embryos was insignificantly higher in SrCl2 groups compared to the Ionomycin group (29.90+/-4.27 vs. 20.65+/-4.05%, P=0.26). Conclusion: Ionomycin may be superior to SrCl2 for inducing oocyte activation. However, SrCl2 may be a more efficient means to support the development of better quality embryos following ICSI. PMID- 30483385 TI - Immunohistochemical characterization of pancreatic duodenal homeobox protein-1, neurogenin-3, and insulin protein expressions in islet-mesenchymal cell in vitro: a morphochronological evaluation. PMID- 30483384 TI - The effects of bortezomib on the ovariectomy applied rat uterus: A histopathological, stereological, and immunohistochemical study. AB - Objectives: In this study, potential protective effects of Bortezomib (Bort), as a proteasome inhibitor, were investigated on the uterus of ovariectomized rats by histological, morphometric and immunohistochemical methods. Materials and Methods: In this study, 18 Sprague dawley strain female rats (12 weeks old, 250 300 g body weight) were used. Animals in the control group (Cont, n=6) were not exposed to any treatment. Ovariectomy was performed on the experimental groups. They (n=12) were divided into ovariectomy (Ovt, n=6) and Bortezomib (Bort, n=6) subgroups. Twelve weeks later, the rats were perfused. Then, uterine tissues were removed and examined by morphometrical, and light and electron microscopy methods. In addition, immunoreactivity of nuclear factor-kappa (NF-kappaB) was evaluated. Results: Morphometric and histopathological evaluations showed that Bort was effective in the uterus and protects the layer structures and the cells. Conclusion: In the light of these findings, we suggest that for proteasome inhibitor particularly Bort is thought to be useful through proteasome inhibition and NF-kappaB pathway. PMID- 30483386 TI - The application of titanium dioxide (TiO2) nanoparticles in the photo-thermal therapy of melanoma cancer model. AB - Objectives: Photo-thermal therapy (PTT) is a therapeutic method in which photon energy is converted into heat to induce hyperthermia in malignant tumor cells. In this method, energy conversion is performed by nanoparticles (NPs) to enhance induced heat efficacy. The low-cytotoxicity and high optical absorbance of NPs used in this technique are very important. In the present study, titanium dioxide (TiO2) NPs were used as agents for PTT. For increasing water dispersibility and biocompatibility, polyethylene glycol (PEG)-TiO2 NPs (PEGylated TiO2 NPs) were synthesized and the effect of these NPs on reducing melanoma tumor size after PTT was experimentally assessed. Materials and Methods: To improve the dispersibility of TiO2 NPs in water, PEG was used for wrapping the surface of TiO2 NPs. The formation of a thin layer of PEG around the TiO2 NPs was confirmed through thermo gravimetric analysis and transmission electron microscopy techniques. Forty female cancerous mice were divided into four equal groups and received treatment with NPs and a laser diode (lambda = 808 nm, P = 2 W & I = 2 W/cm2) for seven min once in the period of the treatment. Results: Compared to the mice receiving only the laser therapy, the average tumor size in the mice receiving TiO2-PEG NPs with laser excitation treatment sharply decreased. Conclusion: The results of animal studies showed that PEGylated TiO2 NPs were exceptionally potent in destroying solid tumors in the PTT technique. PMID- 30483387 TI - Serum-based metabolic alterations in patients with papillary thyroid carcinoma unveiled by non-targeted 1H-NMR metabolomics approach. AB - Objectives: As the most prevalent endocrine system malignancy, papillary thyroid carcinoma had a very fast rising incidence in recent years for unknown reasons besides the fact that the current methods in thyroid cancer diagnosis still hold some limitations. Therefore, the aim of this study was to improve the potential molecular markers for diagnosis of benign and malignant thyroid nodules to prevent unnecessary surgeries for benign tumors. Materials and Methods: In this study, 1H-NMR metabolomics platform was used to seek the discriminating serum metabolites in malignant papillary thyroid carcinoma (PTC) compared to benign multinodular goiter (MNG) and healthy subjects and also to better understand the disease mechanisms using bioinformatics analysis. Multivariate statistical analysis showed that PTC and MNG samples could be successfully discriminated in PCA and OPLS-DA score plots. Results: Significant metabolites that differentiated malignant and benign thyroid lesions included citrate, acetylcarnitine, glutamine, homoserine, glutathione, kynurenine, nicotinic acid, hippurate, tyrosine, tryptophan, beta-alanine, and xanthine. The significant metabolites in the PTC group compared to healthy subjects also included scyllo- and myo inositol, tryptophan, propionate, lactate, homocysteine, 3-methyl glutaric acid, asparagine, aspartate, choline, and acetamide. The metabolite sets enrichment analysis demonstrated that aspartate metabolism and urea cycle were the most important pathways in papillary thyroid cancer progression. Conclusion: The study results demonstrated that serum metabolic fingerprinting could serve as a viable method for differentiating various thyroid lesions and for proposing novel potential markers for thyroid cancers. Obviously, further studies are needed for the validation of the results. PMID- 30483388 TI - Interaction of aquaporin 4 and N-methyl-D-aspartate NMDA receptor 1 in traumatic brain injury of rats. AB - Objectives: methyl-D-aspartate NMDA receptor (NMDAR) and aquaporin 4 (AQP4) are involved in the molecular cascade of edema after traumatic brain injury (TBI) and are potential targets of studies in pharmacology and medicine. However, their association and interactions are still unknown. Materials and Methods: We established a rat TBI model in this study. The cellular distribution patterns of AQP4 after inhibition of NMDAR were determined by Western blotting and immunoreactive staining. Furthermore, the regulation of NMDA receptor 1 by AQP4 was studied by injection of a viral vector targeting AQP4 by RNAi into the rat brain before TBI. Results: The results suggest that AQP4 protein expression increased significantly (P<0.05) after TBI and was down-regulated by the NMDAR inhibitor MK801. This decrease could be partly reversed using the NMDAR agonist NMDA. This indicated that AQP4 mRNA levels and protein expression are regulated by the NMDA signaling pathway. By injection of AQP4 RNAi viral vector into the brain of TBI rat models, we found that the mRNA and protein levels of NMDAR decreased significantly (P<0.05). This suggested that NMDAR is also regulated by AQP4. Conclusion: These data suggested that the inhibition of AQP4 down-regulates NMDAR expression, which might be one of the mechanisms involved in edema after TBI. PMID- 30483389 TI - Generation of motor neurons from human amygdala-derived neural stem-like cells. AB - Objectives: Among several cell sources, adult human neural stem/progenitor cells (hNS/PCs) have been considered outstanding cells for performing mechanistic studies in in vitro and in vivo models of neurological disorders as well as for potential utility in cell-based therapeutic approaches. Previous studies addressed the isolation and culture of hNS/PCs from human neocortical and hippocampal tissues. However, little data are available on hNS/PCs obtained from the adult human amygdala. Materials and Methods: The present study explored the capacity of the amygdala harvested from resected brain tissues of patients with medically refractory epilepsy to generate neurosphere-like bodies and motor neuron-like cells. Results: Although the proliferation process was slow, a considerable amount of cells was obtained after the 3rd passage. In addition, the cells could generate motor neuron-like cells under appropriate culture conditions. Conclusion: Isolation and culture of these cells enable us to improve our knowledge of the role of the amygdala in some neurological and psychological disorders and provide a novel source for therapeutic cell transplantation. PMID- 30483390 TI - Silencing of rhomboid domain containing 1 to inhibit the metastasis of human breast cancer cells in vitro. AB - Objectives: A growing body of evidence indicates that rhomboid domain containing 1 (RHBDD1) plays an important role in a variety of physiological and pathological processes, including tumorigenesis. We aimed to determine the function of RHBDD1 in breast cancer cells. Materials and Methods: In this study, we used the OncomineTM database to determine the expression patterns of RHBDD1 in normal and breast cancer tissues. We performed lentiviral transfection of RHBDD1-specific small interfering RNA into the breast cancer cell lines ZR-75-30 and MDA-MB-231 in order to investigate the effects of RHBDD1 deficiency on breast cancer metastasis. Results: We found that knockdown of RHBDD1 inhibited breast cancer cell migration and invasion in vitro. Moreover, knockdown of RHBDD1 promoted epithelial-mesenchymal transition (EMT) by suppressing the expression of MPP2, MPP9, fibronectin 1, vimentin, SRY-box 2, zinc finger E-box binding homeobox 1, and snail family transcriptional repressor 1, and promoting the expression of cadherin 1. Additionally, knockdown of RHBDD1 inhibited the protein expression and phosphorylation of Akt. Conclusion: Our data indicate that RHBDD1 overexpression may promote breast cancer metastasis via the regulation of EMT, suggesting that RHBDD1 may be an important regulator of breast cancer metastasis. PMID- 30483391 TI - Combination of metformin and phenformin synergistically inhibits proliferation and hTERT expression in human breast cancer cells. AB - Objectives: Breast cancer remains a global challenge, and further chemopreventive therapies are still immediately required. Emerging evidence has revealed the potent anti-cancer effects of biguanides, Metformin (MET) and phenformin (PHE). Thus, to explore an efficient chemopreventive strategy for breast cancer, the antiproliferative effects of the combination of MET and PHE against breast cancer cells were assessed. Materials and Methods: Cytotoxicity of the drugs individually and in combination against T47D and MDA-MB-231 breast cancer cells were assessed using MTT assay and the median-effect method was used to analyze the precise nature of the interaction between MET and PHE. Besides, the expression levels of hTERT after 48 hr drug exposure were determined using qRT PCR. Results: Based on the cytotoxicity assay, both MET and PHE further inhibited the growth of MDA-MB-231 cells compared with T47D cells. It was found that MET+PHE reduced the IC50s of MET and PHE in both cells drastically more than the single treatments in a synergistic manner. Importantly, MET+PHE showed higher antiproliferative effect with smaller IC50 values against MDA-MB-231 cells than against T47D cells. Real-time PCR results revealed that hTERT expression was significantly reduced in both breast cancer cell lines treated with MET+PHE than the single treatments. In comparison between two types of breast cancer cells, it was detected that MET+PHE could further decline hTERT expression in MDA-MB 231cells than in T47D cells (P<0.001). Conclusion: It is speculated that the combination of MET and PHE may be a promising and convenient approach to improve the efficiency of breast cancer treatment.speculated that the combination of MET and PHE may be a promising and convenient approach to improve the efficiency of breast cancer treatment. PMID- 30483392 TI - Paeoniflorin has anti-inflammation and neurogenesis functions through nicotinic acetylcholine receptors in cerebral ischemia-reperfusion injury rats. AB - Objectives: Paeoniflorin (PF) has anti-oxidation, anti-inflammation, anti apoptosis, and neuroprotection pharmacological effects against ischemic injury. The aim of the present study was to investigate the neuroprotection mechanisms of PF in cerebral ischemia-reperfusion injury rats. Materials and Methods: We established an animal model of cerebral infarct by occlusion of the middle cerebral artery for 15 min, followed by reperfusion, and PF was administered 24 hr later (20 mg/kg, intraperitoneally for 6 days) after reperfusion. Results: Treatment with PF reduced the neurological deficit score, improved motor function, decreased cell counts of nicotinic acetylcholine receptor (nAChR) alpha4beta2 immunoreactive cells, and increased cell counts of nAChR alpha7. Furthermore, PF administration suppressed neuronal apoptosis and promoted neurogenesis. Conclusion: PF rescued neurological deficit and underlying mechanisms were inhibition of neurological apoptosis and inflammation by nAChRs. PMID- 30483393 TI - Iranian crack induces hepatic injury through mitogen-activated protein kinase pathway in the liver of Wistar rat. AB - Objectives: Iranian crack (IC) is a heroin-based substance manifesting various pathologic side effects. Herein, we aimed to investigate the mechanism of IC induced liver injuries in Wistar rats. Materials and Methods: Twenty male Wistar rats were randomly divided into two groups: control, and IC (0.9 mg/kg/day/IP, for 30 days). Mitochondrial reactive oxygen species (ROS) production was measured by DCF fluorescence staining. The expression of tumor necrosis factor-alpha (TNF alpha), interleukin 1beta (IL-1beta), and phosphorylation of p38 mitogen activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (c-JNK) were assessed by immunoblotting assay. The intensity of collagen fiber in the liver was also determined by Trichrome-Masson staining. Furthermore, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) activities were measured using colorimetric methods. Results: Our results showed that ROS production, p38 MAPK, c-JNK phosphorylation levels, and expression of TNF-alpha and IL-1beta were significantly elevated in the liver tissue of IC group as compared to the control group. Moreover, collagen fiber and ALT activity were increased in the liver tissue of IC group compared to the control group. However, there was no statistically significant difference in the levels of ALP between two groups. In addition, there was a positive correlation between the intensity of collagen fiber and the ALT activity, and the levels of TNF-alpha and IL-1beta and liver enzymes activities including ALP, ALT, and AST. Conclusion: Our findings revealed that IC-induced liver cells injury is partially mediated by MAPK stress kinases. Therefore, regular liver examination in substance abuse is strongly recommended. PMID- 30483394 TI - CircRNA_0109291 regulates cell growth and migration in oral squamous cell carcinoma and its clinical significance. AB - Objectives: Circular RNAs (circRNAs), a new class of non-coding RNAs, have emerged as important regulators during tumorigenesis. However, the functions of circRNAs have not been completely clarified in the progression of cancers. In our study, a novel circRNA hsa_circ_0109291 was investigated in oral squamous cell carcinoma (OSCC) tissues and cell lines. Materials and Methods: The expression profile of circRNAs in OSCC tumor tissues was performed by high-throughput sequencing. The CCK-8 wound healing and apoptosis assay were measured in OSCC cell lines after transfection with si-0109291 or si-NC. Results: We discovered that hsa_circ_0109291 was significantly increased in OSCC tissues and cell lines compared with their corresponding control group. Knockdown of hsa_circ_0109291 inhibited proliferation and migration of OSCC cell lines in vitro. In addition, inhibition of hsa_circ_0109291 dramatically induced apoptosis of OSCC cells. We further found that high hsa_circ_0109291 levels in OSCC patients resulted in a poorer prognosis than in patients with low hsa_circ_0109291 levels. Conclusion: These findings indicated that hsa_circ_0109291 correlated with the progression of OSCC and might be a new therapeutic target for the treatment of OSCC. PMID- 30483395 TI - The effects of crocetin, extracted from saffron, in chemotherapy against the incidence of multiple drug resistance phenotype. AB - Objectives: Crocetin, one of the main substances of saffron extract, has anti cancer effects. Drug resistance proteins (e.g. MRP1 and MRP2) are important reasons for the failure of cancer therapy. We intended to investigate the efficacy of crocetin on MRP1 and MRP2 activity in human ovarian cisplatin resistant carcinoma cell line (A2780-RCIS). Materials and Methods: The cytotoxic effect of crocetin was evaluated by the MTT assay. The efficacy of crocetin on MRP1 and MRP2 expression at mRNA level was studied by real-time RT-PCR. The effect of crocetin on the activity of MRP transporters was determined by drug efflux assay. Results: Crocetin decreased cell proliferation in the A2780 (IC50: 183+/-7 uM) and A2780-RCIS (IC50: 316+/-9 uM). Crocetin decreased the expression level of MRP1 (22+/-2 %) and MRP2 (48+/-8 %) in A2780-RCIS and inhibited MRP pumps function directly in A2780 (44+/-1 %) and A2780-RCIS (88+/-10 %) and indirectly in A2780 (32+/-2 %) and A2780-RCIS (48+/-15 %) respectively. Conclusion: Our findings showed that crocetin could quench drug resistance through modulation of MRP transporters in the drug resistant human ovarian cancer cells. PMID- 30483396 TI - Prolapsing mucosal fold: largest reported, presenting with major haemorrhage. AB - Prolapsing mucosal folds are uncommon benign colonic lesions that when inflamed may macroscopically resemble, and be confused with, an adenomatous or hyperplastic polyp. They are usually small and rarely cause symptoms. We report the case of a 55-year-old female admitted to hospital following six episodes of significant rectal bleeding. A colonoscopy revealed a 45 * 12 * 5 mm3 pedunculated polyp in the sigmoid colon. There was no evidence of haemorrhoids, colitis or diverticulosis. The polyp was resected by electrosurgical snare at 40 cm and a resolution clip was used to prevent postoperative bleeding. Histology of the polyp demonstrated a polypoid prolapsed mucosal fold with a core of fibrovascular submucosal tissue and normal overlying mucosa. In an extensive review of available literature, no polyp of this size has been reported. PMID- 30483397 TI - Clinical course of the untreated calcified big cerebellar liponeurocytoma. AB - Cerebellar liponeurocytoma (CLN) is a very rare tumor of central nervous system, classified as glioneuronal tumor by the latest classification of World Health Organization (WHO) in 2016. There are limited data in the literature about biologic behavior, growth pattern and radiological features of this tumor. In this case report, we operated a big calcified CLN patient who had denied any surgical procedures suggested by an another institute and had been followed for 4 years. PMID- 30473775 TI - Computational assessment of stomach tumor volume from multi-slice computerized tomography images in presence of type 2 cancer. AB - Background: The multi-slice computerized tomography (MSCT) is a medical imaging modality that has been used to determine the size and location of the stomach cancer. Additionally, MSCT is considered the best modality for the staging of gastric cancer. One way to assess the type 2 cancer of stomach is by detecting the pathological structure with an image segmentation approach. The tumor segmentation of MSCT gastric cancer images enables the diagnosis of the disease condition, for a given patient, without using an invasive method as surgical intervention. Methods: This approach consists of three stages. The initial stage, an image enhancement, consists of a method for correcting non homogeneities present in the background of MSCT images. Then, a segmentation stage using a clustering method allows to obtain the adenocarcinoma morphology. In the third stage, the pathology region is reconstructed and then visualized with a three dimensional (3-D) computer graphics procedure based on marching cubes algorithm. In order to validate the segmentations, the Dice score is used as a metric function useful for comparing the segmentations obtained using the proposed method with respect to ground truth volumes traced by a clinician. Results: A total of 8 datasets available for patients diagnosed, from the cancer data collection of the project, Cancer Genome Atlas Stomach Adenocarcinoma (TCGASTAD) is considered in this research. The volume of the type 2 stomach tumor is estimated from the 3-D shape computationally segmented from the each dataset. These 3-D shapes are computationally reconstructed and then used to assess the morphopathology macroscopic features of this cancer. Conclusions: The segmentations obtained are useful for assessing qualitatively and quantitatively the stomach type 2 cancer. In addition, this type of segmentation allows the development of computational models that allow the planning of virtual surgical processes related to type 2 cancer. PMID- 30473780 TI - Using zebrafish larval models to study brain injury, locomotor and neuroinflammatory outcomes following intracerebral haemorrhage. AB - Intracerebral haemorrhage (ICH) is a devastating condition with limited treatment options, and current understanding of pathophysiology is incomplete. Spontaneous cerebral bleeding is a characteristic of the human condition that has proven difficult to recapitulate in existing pre-clinical rodent models. Zebrafish larvae are frequently used as vertebrate disease models and are associated with several advantages, including high fecundity, optical translucency and non protected status prior to 5 days post-fertilisation. Furthermore, other groups have shown that zebrafish larvae can exhibit spontaneous ICH. The aim of this study was to investigate whether such models can be utilised to study the pathological consequences of bleeding in the brain, in the context of pre clinical ICH research. Here, we compared existing genetic (bubblehead) and chemically inducible (atorvastatin) zebrafish larval models of spontaneous ICH and studied the subsequent disease processes. Through live, non-invasive imaging of transgenic fluorescent reporter lines and behavioural assessment we quantified brain injury, locomotor function and neuroinflammation following ICH. We show that ICH in both zebrafish larval models is comparable in timing, frequency and location. ICH results in increased brain cell death and a persistent locomotor deficit. Additionally, in haemorrhaged larvae we observed a significant increase in macrophage recruitment to the site of injury. Live in vivo imaging allowed us to track active macrophage-based phagocytosis of dying brain cells 24 hours after haemorrhage. Morphological analyses and quantification indicated that an increase in overall macrophage activation occurs in the haemorrhaged brain. Our study shows that in zebrafish larvae, bleeding in the brain induces quantifiable phenotypic outcomes that mimic key features of human ICH. We hope that this methodology will enable the pre-clinical ICH community to adopt the zebrafish larval model as an alternative to rodents, supporting future high throughput drug screening and as a complementary approach to elucidating crucial mechanisms associated with ICH pathophysiology. PMID- 30483400 TI - Automated emergency paramedical response system. AB - With the evolution of technology, the fields of medicine and science have also witnessed numerous advancements. In medical emergencies, a few minutes can be the difference between life and death. The obstacles encountered while providing medical assistance can be eliminated by ensuring quicker care and accessible systems. To this effect, the proposed end-to-end system-automated emergency paramedical response system (AEPRS) is semi-autonomous and utilizes aerial distribution by drones, for providing medical supplies on site in cases of paramedical emergencies as well as for patients with a standing history of diseases. Security of confidential medical information is a major area of concern for patients. Confidentiality has been achieved by using decentralised distributed computing to ensure security for the users without involving third party institutions. AEPRS focuses not only on urban areas but also on semi-urban and rural areas. In urban areas where access to internet is widely available, a healthcare chatbot caters to the individual users and provides a diagnosis based on the symptoms provided by the patients. In semi-urban and rural areas, community hospitals have the option of providing specialised healthcare in spite of the absence of a specialised doctor. Additionally, object recognition and face recognition by using the concept of edge AI enables deep neural networks to run on the edge, without the need for GPU or internet connectivity to connect to the cloud. AEPRS is an airborne emergency medical supply delivery system. It uses the data entered by the user to deduce the best possible solution, in case of an alerted emergency situation and responds to the user accordingly. PMID- 30483402 TI - Physiological condition of nestling great tits Parus major in response to experimental reduction in nest micro- and macro-parasites. AB - Most passerines use nests as the exclusive place to lay and incubate eggs and bring nestlings up to fledging. Nests of secondary cavity nesters, like tits, provide a moist, warm and protected habitat for reproduction of blood parasites. Offspring fitness depends on interactions between parental care and environmental constraints. Life-history theory suggests that macro- and micro-parasites may generate selection pressures by affecting host health. In the present study, we replaced natural great tit Parus major nests in two, structurally and floristically contrasting sites (an urban parkland and a rich deciduous forest, located 10 km apart in Lodz, central Poland), with fresh, sterilized, artificial moss-cotton wool nests, twice, on the fifth and tenth day of nestlings life. We then examined haematological condition indicators (haemoglobin and glucose concentrations) of about 14-day-old nestlings. Nestlings that were developing in treated nests improved their health status in comparison with control nestlings. The mean haemoglobin and glucose concentrations (treated and control) also varied between both study areas. Our study confirms that the level of haemoglobin and especially the level of glucose may be treated as reliable indicator of environmental characteristics in great tits. PMID- 30483401 TI - Seawater acclimation affects cardiac output and adrenergic control of blood pressure in rainbow trout (Oncorhynchus mykiss)-implications for salinity variations now and in the future. AB - Greater salinity variations resulting from ongoing climate change requires consideration in conservation management as this may impact on the performance of aquatic organisms. Euryhaline fish exhibit osmoregulatory flexibility and can exploit a wide range of salinities. In seawater (SW), they drink and absorb water in the intestine, which is associated with increased gastrointestinal blood flow. Yet, detailed information on other cardiovascular changes and their control across salinities is scant. Such knowledge is fundamental to understand how fish are affected during migrations between environments with different salinities, as well as by increased future salinity variability. We used rainbow trout (Oncorhynchus mykiss) as a euryhaline model species and determined dorsal aortic blood pressure, cardiac output and systemic vascular resistance in vivo after chronic freshwater-or SW-acclimation. We also assessed alpha-adrenergic control of blood pressure using pharmacological tools. Dorsal aortic blood pressure and systemic vascular resistance were reduced, whereas cardiac output increased in SW. alpha-Adrenergic stimulation with phenylephrine caused similar dose-dependent increases in resistance and pressure across salinities, indicating unaltered alpha-adrenoceptor sensitivity. alpha-Adrenergic blockade with prazosin decreased resistance and pressure across salinities, but the absolute reduction in resistance was smaller in SW. Yet, both pressure and resistance after prazosin remained consistently lower in SW. This shows that SW-acclimation lowers systemic resistance through reduced vascular alpha-adrenergic tone, along with other unknown vasodilating factors. The marked changes in adrenergic regulation of the vasculature across salinities discovered here may have implications for cardiovascular and aerobic performance of fishes, with possible impacts on fitness-related traits like digestion and exercise capacity. Moreover, the evolution of more complex circulatory control systems in teleost fishes compared with elasmobranchs and cyclostomes may have been an important factor in the evolution of euryhalinity, and may provide euryhaline teleosts with competitive advantages in more variable salinity environments of the future. PMID- 30483404 TI - Secular trends in the prevalence of female genital mutilation/cutting among girls: a systematic analysis. AB - Background: Current evidence on the decline in the prevalence of female genital mutilation or cutting (FGM/C) has been lacking worldwide. This study analyses the prevalence estimates and secular trends in FGM/C over sustained periods (ie, 1990 2017). Its aim is to provide analytical evidence on the changing prevalence of FGM/C over time among girls aged 0-14 years and examine geographical variations in low-income and middle-income countries. Methods: Analysis on the shift in prevalence of FGM/C was undertaken using the Demographic Health Survey (DHS) and Multiple Indicator Cluster Survey (MICS) data sets from Africa and Middle East. A random-effects model was used to derive overall prevalence estimates. Using Poisson regression models, we conducted time trends analyses on the FGM/C prevalence estimates between 1990 and 2017. Findings: We included 90 DHS and MICS data sets for 208 195 children (0-14 years) from 29 countries spread across Africa and two countries in Western Asia. The prevalence of FGM/C among children varied greatly between countries and regions and also within countries over the survey periods. The percentage decline in the prevalence of FGM/C among children aged 0-14 years old was highest in East Africa, followed by North and West Africa. The prevalence decreased from 71.4% in 1995 to 8.0% in 2016 in East Africa. In North Africa, the prevalence decreased from 57.7% in 1990 to 14.1% in 2015. In West Africa, the prevalence decreased from 73.6% in 1996 to 25.4% in 2017. The results of the trend analysis showed a significant shift downwards in the prevalence of FGM/C among children aged 0-14 years in such regions and subregions of East Africa, North Africa and West Africa. East Africa has experienced a much faster decrease in the prevalence of the practice (trend= 7.3%, 95% CI -7.5% to -7.1%) per year from 1995 to 2014. By contrast, the decline in prevalence has been much slower in North Africa (trend=-4.4%, 95% CI -4.5% to 4.3%) and West Africa (trend=-3.0%, 95% CI -3.1% to -2.9%). Conclusion: The prevalence of FGM/C among children aged 0-14 years varied greatly between countries and regions and also within countries over the survey periods. There is evidence of huge and significant decline in the prevalence of FGM/C among children across countries and regions. There is a need to sustain comprehensive intervention efforts and further targeted efforts in countries and regions still showing high prevalence of FGM/C among children, where the practice is still pervasive. PMID- 30483403 TI - Relational concurrency, stages of infection, and the evolution of HIV set point viral load. AB - HIV viral load (VL) predicts both transmission potential and rate of disease progression. For reasons that are still not fully understood, the set point viral load (SPVL) established after acute infection varies across individuals and populations. Previous studies have suggested that population mean SPVL (MSPVL) has evolved near an optimum that reflects a trade-off between transmissibility and host survival. Sexual network structures affect rates of potential exposure during different within-host phases of infection marked by different transmission probabilities, and thus affect the number and timing of transmission events. These structures include relational concurrency, which has been argued to explain key differences in HIV burden across populations. We hypothesize that concurrency will alter the fitness landscape for SPVL in ways that differ from other network features whose impacts accrue at other times during infection. To quantitatively test this hypothesis, we developed a dynamic, stochastic, data-driven network model of HIV transmission, and evolution to assess the impact of key sexual network phenomena on MSPVL evolution. Experiments were repeated in sensitivity runs that made different assumptions about transmissibility during acute infection, SPVL heritability, and the functional form of the relationship between VL and transmissibility. For our main transmission model, scenarios yielded MSPVLs ranging from 4.4 to 4.75 log10 copies/ml, covering much of the observed empirical range. MSPVL evolved to be higher in populations with high concurrency and shorter relational durations, with values varying over a clinically significant range. In linear regression analyses on these and other predictors, main effects were significant (P < 0.05), as were interaction terms, indicating that effects are interdependent. We also noted a strong correlation between two key emergent properties measured at the end of the simulations-MSPVL and HIV prevalence-most clearly for phenomena that affect transmission networks early in infection. Controlling for prevalence, high concurrency yielded higher MSPVL than other network phenomena. Interestingly, we observed lower prevalence in runs in which SPVL heritability was zero, indicating the potential for viral evolution to exacerbate disease burden over time. Future efforts to understand empirical variation in MSPVL should consider local HIV burden and basic sexual behavioral and network structure. PMID- 30483406 TI - Strategic purchasing for universal health coverage: examining the purchaser provider relationship within a social health insurance scheme in Nigeria. AB - Background: In an attempt to achieve universal health coverage, Nigeria introduced a number of health insurance schemes. One of them, the Formal Sector Social Health Insurance Programme (FSSHIP), was launched in 2005 to provide health cover to federal government and formal private sector employees. It operates with two levels of purchasers, the National Health Insurance Scheme (NHIS) and health maintenance organisations (HMOs). This study critically assesses purchasing arrangements between NHIS, HMOs and healthcare providers and determines how the arrangements function from a strategic purchasing perspective within the FSSHIP. Methods: A qualitative study undertaken in Enugu state, Nigeria, data were gathered through reviews of documents, 17 in-depth interviews (IDIs) with NHIS, HMOs and healthcare providers and two focus group discussions (FGDs) with FSSHIP enrolees. A strategic purchasing lens was used to guide data analysis. Results: The purchasing function was not being used strategically to influence provider behaviour and improve efficiency and quality in healthcare service delivery. For the purchaser-provider relationship, these actions are: accreditation of healthcare providers; monitoring of HMOs and healthcare providers and use of appropriate provider payment mechanisms for healthcare services at every level. The government lacks resources and political will to perform their stewardship role while provider dissatisfaction with payments and reimbursements adversely affected service provision to enrolled members. Underlying this inability to purchase, health services strategically is the two tiered purchasing mechanism wherein NHIS is not adequately exercising its stewardship role to monitor and guide HMOs to fulfil their roles and responsibilities as purchasing administrators. Conclusions: Purchasing under the FSSHIP is more passive than strategic. Governance framework requires strengthening and clarity for optimal implementation so as to ensure that both levels of purchasers undertake strategic purchasing actions. Additional strengthening of NHIS is needed for it to have capacity to play its stewardship role in the FSSHIP. PMID- 30483407 TI - Disability status, intimate partner violence and perceived social support among married women in three districts of the Terai region of Nepal. AB - Introduction: Women living with disabilities are disproportionately vulnerable to intimate partner violence (IPV). Existing research on the topic largely takes place in high-income settings and treats disability as a dichotomous experience an individual either has a disability or does not. Disability experiences, however, are diverse such that some individuals face minimal impairment, while for others impairment can be severe. With this spectrum in mind, this study sought to examine the associations between severity of disability impairment, past-year IPV, past-year in-law violence and perceived social support among married women in Nepal. Methods: Baseline data (2016) from a randomised controlled trial aiming to reduce IPV among women aged 18-49 (n=1800) were analysed using generalised estimating equations logistic regressions to assess associations. Results: Women with severe impairment reported higher levels of physical and/or sexual, emotional, economic and in-law violence than women without a disability (adjusted OR (AOR)=1.68, 95% CI 1.04 to 2.72; AOR=1.65, 95% CI 1.03 to 2.65; AOR=1.75, 95% CI 1.02 to 3.02; AOR=2.80, 95% CI 2.53 to 5.11, respectively). Differences in IPV between women reporting some impairment versus no disability were observed for economic (AOR=1.47, 95% CI 1.11 to 1.94) and in law violence (AOR=1.50, 95% CI 1.07 to 2.10). Women with severe or some impairment versus no disability were less likely to perceive their in-laws as supportive. Conclusion: Disability status was associated with increased vulnerability to IPV. A gradient was observed; the highest levels of IPV were experienced by women with severe impairment, followed by some impairment. Future research should examine the mechanisms driving such observations. PMID- 30483405 TI - Traditional, complementary and alternative medicine use in Sub-Saharan Africa: a systematic review. AB - Background: The WHO estimates that a considerable number of people in Sub-Saharan Africa (SSA) rely on traditional, complementary and alternative medicine (TCAM) to meet their primary healthcare needs, yet there remains a dearth of research evidence on the overall picture of TCAM utilisation in the region. Methods: We conducted a literature search of original articles examining TCAM use in SSA between 1 January 2006 and 28 February 2017, employing Medline, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, Scopus, ProQuest, PubMed, Embase and African Journals Online databases. A critical appraisal of relevant articles reporting a quantitative or mixed method design was undertaken. Results: Despite the heterogeneity and general low quality of the identified literature, the review highlights a relatively high use of TCAM alone or in combination with orthodox medicine, in both general population and in specific health conditions in SSA. TCAM users compared with non TCAM users are more likely to be of low socioeconomic and educational status, while there were inconsistencies in age, sex, spatial location and religious affiliation between TCAM users and non-TCAM users. Most TCAM users (55.8%-100%) in SSA fail to disclose TCAM use to their healthcare providers, with the main reasons for non-disclosure being fear of receiving improper care, healthcare providers' negative attitude and a lack of enquiry about TCAM use from healthcare providers. Conclusion: TCAM use in SSA is significant, although most studies emerge from a few countries. Factors associated with TCAM use in SSA are similar to those observed in other regions, but further research may be required to further elucidate challenges and opportunities related to TCAM use specific to SSA. PMID- 30483410 TI - The legitimacy of modelling the impact of an intervention based on important intermediate outcomes in a trial. PMID- 30483409 TI - Girls' hidden penalty: analysis of gender inequality in child mortality with data from 195 countries. AB - Introduction: Gender inequality has been associated with child mortality; however, sex-specific mortalities have yet to be explored. The aim of this study is to assess the associations between gender inequality and the child mortality sex ratio at country level, worldwide and to infer on possible mechanisms. Methods: Data on sex-specific under-five mortality rates (U5MR) and the corresponding sex ratio (U5MSR) for the year 2015, by country, were retrieved from the Unicef database. Excess under-five female mortality was derived from previous published work. Gender inequality was measured using the Gender Inequality Index (GII). Additional biological and social variables have been included to explore potential mechanistic pathways. Results: A total of 195 countries were included in the analysis. In adjusted models, GII was significantly negatively associated with the U5MSR (beta=-0.29 (95% CI -0.42 to 0.16), p<0.001) and borderline significantly positively associated with excess under-five female mortality (beta = 3.25 (95% CI -0.28 to 6.67, p=0.071). The association between GII and U5MSR was strong and statistically significant only in low-income and middle-income countries and in the Western Pacific area. Conclusion: The more gender unequal a society is, the more girls are penalised in terms of their survival chances, in particular in low-income and middle-income countries. In order to decrease child mortality and excess girl mortality, global policy should focus on reducing gender inequality surrounding measures of reproductive health, women's political empowerment, educational attainment and participation in the workforce. PMID- 30483408 TI - 'They care rudely!': resourcing and relational health system factors that influence retention in care for people living with HIV in Zambia. AB - Introduction: Despite access to free antiretroviral therapy (ART), many HIV positive Zambians disengage from HIV care. We sought to understand how Zambian health system 'hardware' (tangible components) and 'software' (work practices and behaviour) influenced decisions to disengage from care among 'lost-to-follow-up' patients traced by a larger study on their current health status. Methods: We purposively selected 12 facilities, from 4 provinces. Indepth interviews were conducted with 69 patients across four categories: engaged in HIV care, disengaged from care, transferred to another facility and next of kin if deceased. We also conducted 24 focus group discussions with 158 lay and professional healthcare workers (HCWs). These data were triangulated against two consecutive days of observation conducted in each facility. We conducted iterative multilevel analysis using inductive and deductive reasoning. Results: Health system 'hardware' factors influencing patients' disengagement included inadequate infrastructure to protect privacy; distance to health facilities which costs patients time and money; and chronic understaffing which increased wait times. Health system 'software' factors related to HCWs' work practices and clinical decisions, including delayed opening times, file mismanagement, drug rationing and inflexibility in visit schedules, increased wait times, number of clinic visits, and frustrated access to care. While patients considered HCWs as 'mentors' and trusted sources of information, many also described them as rude, tardy, careless with details and confidentiality, and favouring relatives. Nonetheless, unlike previously reported, many patients preferred ART over alternative treatment (eg, traditional medicine) for its perceived efficacy, cost free availability and accompanying clinical monitoring. Conclusion: Findings demonstrate the dynamic effect of health system 'hardware' and 'software' factors on decisions to disengage. Our findings suggest a need for improved: physical resourcing and structuring of HIV services, preservice and inservice HCWs and management training and mentorship programmes to encourage HCWs to provide 'patient-centered' care and exercise 'flexibility' to meet patients' varying needs and circumstances. PMID- 30483412 TI - Estimating health opportunity costs in low-income and middle-income countries: a novel approach and evidence from cross-country data. AB - The economic evaluation of healthcare interventions requires an assessment of whether the improvement in health outcomes they offer exceeds the improvement in health that would have been possible if the additional resources required had, instead, been made available for other healthcare activities. Therefore, some assessment of these health opportunity costs is required if the best use is to be made of the resources available for healthcare. This paper provides a framework for generating country-specific estimates of cost per disability-adjusted life year (DALY) averted 'thresholds' that reflect health opportunity costs. We apply estimated elasticities on mortality, survival, morbidity and a generic measure of health, DALYs, that take account of measures of a country's infrastructure and changes in donor funding to country-specific data on health expenditure, epidemiology and demographics to determine the likely DALYs averted from a 1% change in expenditure on health. The resulting range of cost per DALY averted 'threshold' estimates for each country that represent likely health opportunity costs tend to fall below the range previously suggested by WHO of 1-3* gross domestic product (GDP) per capita. The 1-3* GDP range and many other previous and existing recommendations about which interventions are cost-effective are not based on an empirical assessment of the likely health opportunity costs, and as a consequence, the health effects of changes in health expenditure have tended to be underestimated, and there is a risk that interventions regarded as cost effective reduce rather than improve health outcomes overall. PMID- 30483411 TI - Is the single self-rated health item reliable in India? A construct validity study. AB - Introduction: In high-income countries, the self-rated health (SRH) item is used in health surveys to capture the population's general health because of its simplicity and satisfactory validity and reliability. Despite scepticism about its use in low-income and middle-income countries, India implemented the SRH item in many of its demographic and population health surveys, but evidence of its validity is lacking. The objective was to assess the construct validity of the SRH item in India. Methods: Data for 4492 men and 4736 women from the Indian sample of the World Health Survey (2003) were used. Overall, 43 health status indicators were grouped into health dimensions (physical, mental and functional health, chronic diseases, health behaviours) and the SRH item was regressed on these indicators by using sex-stratified multivariable linear regressions, adjusted with demographic and socioeconomic variables. Results: Respondents (participation rate 95.6%; mean age 38.9 years) rated their health as very good (21.8%), good (36.4%), moderate (26.6%), bad (13.2%) or very bad (2.0%). Among men, the adjusted explained SRH variance by health dimensions ranged between 18% and 41% (physical 33%, mental 32%, functional health 41%, chronic diseases 23%, health behaviours 18%). In multivariable models, the overall explained variance increased to 45%. The 43 health status indicators were associated with SRH and their effect sizes were in the expected direction. Among women, results were similar (overall explained variance 48%). Conclusion: The SRH item has satisfactory construct validity and may be used to monitor health status in demographic and population health surveys of India. PMID- 30483413 TI - Towards global health security: response to the May 2018 Nipah virus outbreak linked to Pteropus bats in Kerala, India. PMID- 30483414 TI - Task-shifting for cardiovascular risk factor management: lessons from the Global Alliance for Chronic Diseases. AB - Task-shifting to non-physician health workers (NPHWs) has been an effective model for managing infectious diseases and improving maternal and child health. There is inadequate evidence to show the effectiveness of NPHWs to manage cardiovascular diseases (CVDs). In 2012, the Global Alliance for Chronic Diseases funded eight studies which focused on task-shifting to NPHWs for the management of hypertension. We report the lessons learnt from the field. From each of the studies, we obtained information on the types of tasks shifted, the professional level from which the task was shifted, the training provided and the challenges faced. Additionally, we collected more granular data on 'lessons learnt ' throughout the implementation process and 'design to implementation' changes that emerged in each project. The tasks shifted to NPHWs included screening of individuals, referral to physicians for diagnosis and management, patient education for lifestyle improvement, follow-up and reminders for medication adherence and appointments. In four studies, tasks were shifted from physicians to NPHWs and in four studies tasks were shared between two different levels of NPHWs. Training programmes ranged between 3 and 7 days with regular refresher training. Two studies used clinical decision support tools and mobile health components. Challenges faced included system level barriers such as inability to prescribe medicines, varying skill sets of NPHWs, high workload and staff turnover. With the acute shortage of the health workforce in low-income and middle-income countries (LMICs), achieving better health outcomes for the prevention and control of CVD is a major challenge. Task-shifting or sharing provides a practical model for the management of CVD in LMICs. PMID- 30483415 TI - Using a mentorship model to localise the Practical Approach to Care Kit (PACK): from South Africa to Brazil. AB - Brazil's Sistema Unico de Saude, or Unified Health System policy, has delivered major improvements in health coverage and outcomes, but challenges remain, including the rise of non-communicable diseases (NCDs) and variations in quality of care across the country. Some of these challenges may be met through the adaptation and implementation of a South African primary care strategy, the Practical Approach to Care Kit (PACK). Developed by the University of Cape Town's Knowledge Translation Unit (KTU), PACK is intended for in-country adaptation by employing a mentorship model. Using this approach, the PACK Adult guide and training materials were localised for use in Florianopolis, Santa Catarina, Brazil, as part of an initiative to reform primary care, expand care for NCDs and make services more accessible and equitable. The value of the collaboration between the KTU and Florianopolis municipality is the transfer of skills and avoidance of duplication of effort involved in de-novo guide development, while ensuring that materials are locally acceptable and applicable. The collaboration has informed the development of the KTU's PACK mentorship package and led to a relationship between the groups of developers, ensuring ongoing learning and research, with the potential of assisting the further scale-up of PACK in Brazil. PMID- 30483417 TI - Back to the future with PACK. PMID- 30483416 TI - Crossing borders: the PACK experience of spreading a complex health system intervention across low-income and middle-income countries. AB - Developing a health system intervention that helps to improve primary care in a low-income and middle-income country (LMIC) is a considerable challenge; finding ways to spread that intervention to other LMICs is another. The Practical Approach to Care Kit (PACK) programme is a complex health system intervention that has been developed and adopted as policy in South Africa to improve and standardise primary care delivery. We have successfully spread PACK to several other LMICs, including Botswana, Brazil, Nigeria and Ethiopia. This paper describes our experiences of localising and implementing PACK in these countries, and our evolving mentorship model of localisation that entails our unit providing mentorship support to an in-country team to ensure that the programme is tailored to local resource constraints, burden of disease and on-the-ground realities. The iterative nature of the model's development meant that with each country experience, we could refine both the mentorship package and the programme itself with lessons from one country applied to the next-a 'learning health system' with global reach. While not yet formally evaluated, we appear to have created a feasible model for taking our health system intervention across more borders. PMID- 30483418 TI - A comparison of dry and wet aging on physicochemical and sensory characteristics of pork loin with two aging times. AB - This study investigated the effects of aging methods (wet aging and dry aging) and aging times (7 and 14 days) on the physicochemical and sensory characteristics of meat quality using pork loin. Dry-aged loin (DA) had significantly lower moisture content and higher crude fat protein content than wet-aged loin (WA). The pH of DA was significantly higher than that of WA and it increased with the aging time. DA showed lower cooking loss and higher aging loss than WA (p < 0.001). Lipid oxidation and metmyoglobin content of DA were higher than those of WA (p < 0.001). Shear force in DA was lower than that in WA (p < 0.001) and myofibril protein index (MFI) increased in DA. In addition, DA recorded higher scores of roast color, flavor and overall acceptability compared to WA. These results suggested that the application of dry-aging on pork improved physicochemical, textural and sensory characteristics. PMID- 30483419 TI - Interaction between rice bran albumin and epigallocatechin gallate and their physicochemical analysis. AB - Epigallocatechin gallate (EGCG) is sensitive to heat thus its application in food industry is limited. In this work, rice bran albumin protein (RAP) was used as a carrier for EGCG. RAP-EGCG complexes (RAPE) were prepared with the binding number n of 0.0505:1 (EGCG: RAP, w/w) and binding constant K of (0.74 +/- 0.002) * 104 M 1, which suggests that hydrogen bond/van der Waals forces played important roles in such binding. FTIR analysis demonstrated that EGCG could induce the secondary structure changes of RAP above the ratio of 1.92:1 (EGCG:RAP, w/w). Dynamic light scattering and scanning electron microscope results showed that EGCG could trigger RAP association. Furthermore, the EGCG stability in RAPE was significantly improved than that of free EGCG in 10-60 degrees C. The antioxidant ability of EGCG in RAPE was partially retained. These findings prove that RAP is a potential carrier for polyphenols and is beneficial for mechanism investigation between protein and polyphenols. PMID- 30483420 TI - Oxidative stability of oil-in-water emulsions with alpha-tocopherol, charged emulsifier, and different oxidative stress. AB - alpha-Tocopherol is known to show different activity depending on the concentration and food matrix. Effects of alpha-tocopherol at the concentrations of 0, 0.1, 0.5, and 1.0 mM were determined in oil-in-water (O/W) emulsions containing anionic, neutral, and cationic emulsifiers under different types of oxidative stress including riboflavin photosensitization, photooxidation, and autoxidation. Headspace oxygen depletion, lipid hydroperoxides, and conjugated dienes were analyzed to determine the oxidative stability of O/W emulsions. alpha Tocopherol served as an antioxidant in O/W emulsion with a cationic emulsifier irrespective of oxidative stress. alpha-Tocopherol acted as an antioxidant in O/W emulsion with a neutral emulsifier at riboflavin photosensitization while a prooxidant at photooxidation. However, in samples with an anionic emulsifier, alpha-tocopherol activity differed from the concentration and types of oxidative stress. Therefore, cationic transition metals or reactive oxygen species generated from RF photosensitization could play key roles of alpha-tocopherol in O/W emulsion. PMID- 30483421 TI - Synergistic interaction of Auricularia auricula-judae polysaccharide with yam starch: effects on physicochemical properties and in vitro starch digestibility. AB - Thermal stable polysaccharides from Auricularia auricula-judae (AP) have unique molecularstructures and multiple bioactivities. The effects of AP on the physicochemical properties and in vitro starch digestibility of yam starch (YS) were studied. The addition of AP induced a significant increase in the swelling power, solubility, mean volume diameter and adhesiveness as well as a dramatic decrease in the hardness and gumminess (p < 0.05). AP showed a strong suppressive effect on in vitro starch digestibility. Higher modulus (G', G") and stiffness parameters (Aalpha), and lower order of relaxation function (alpha), were observed in oscillatory rheological measurements, indicating that the gels were more elastic-like and had higher pseudoplasticity in the presence of AP. Furthermore, AP remarkably decreased the syneresis and storage modulus (G'), and also retarded the retrogradation process of YS gel at 4 degrees C, revealing a synergistic interaction between AP and YS, which could also be demonstrated by scanning electron microscopy. PMID- 30483422 TI - Application of alginate and gelatin-based edible coating materials as alternatives to traditional coating for improving the quality of pastirma. AB - This research was conducted to study the efficacy of sodium alginate and gelatin coating materials in improving the quality of pastirma. Pastirma was coated with traditional, alginate or gelatin coatings, stored at 4 degrees C for 4 weeks and examined weekly. Alginate and gelatin coated-pastirma revealed lower TBARS values which was within the acceptable limit (0.67 and 0.86 mg/kg) until the end of storage, however, the TBARS values of traditionally coated pastirma reached 1.33 by the end of storage. Edible coating delayed respiration rate with improvement of the color when compared with traditionally coated one. Oxygen concentration increased from 4.21 mg/kg/h in traditionally coated pastirma to 12.56 and 9.79 in alginate and gelatin coated ones, respectively. Meanwhile, CO2 concentration decreased from 10.40 mg/kg/h in traditionally coated pastirma to 4.89 and 6.07 mg/kg/h in alginate and gelatin coated ones, respectively. Moreover, a distinct improvement in all sensory attributes has been observed. PMID- 30483423 TI - Effect of isomaltulose used for osmotic extraction of Prunus mume fruit juice substituting sucrose. AB - This study evaluated the applicability of isomaltulose as a sucrose substitute in the osmotic extraction of Prunus mume fruit juice. Isomaltulose (20 mM) significantly reduced the uptake of a fluorescent tracer-2-[N-(7-nitrobenz-2-oxa 1,3-diaxol-4-yl) amino]-2-deoxyglucose. Juice extracted by isomaltulose had similar pH and titratable acidity values to those of the other sugars. Citric and malic acids were the main organic acids in the extracted juices. The radical scavenging ability of the plum juice extracted by isomaltulose was significantly higher than in juices extracted by other sugars (p < 0.05) and polyphenols content of the juice was also significantly higher than those of other sugars. The blood glucose level of P. mume juice extracted by fructose or isomaltulose was increased slowly compared to the juice extracted by sucrose. Therefore, the use of isomaltulose or an isomaltulose mixture in the manufacture of P. mume juice will help maintain health by reducing sugar intake. PMID- 30483424 TI - Optimization of green extraction methods for cinnamic acid and cinnamaldehyde from Cinnamon (Cinnamomum cassia) by response surface methodology. AB - The major compounds of cinnamon are cinnamic acid and cinnamaldehyde, for which the conditions of microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE), and reflux extraction (RE) were optimized using response surface methodology for comparing their efficiencies in terms of extraction yield, consumption of time and energy, and CO2 emission. The results indicated MAE superiority to UAE and RE owing to the highest yield of target compounds (total yield: 0.89%, cinnamic acid: 6.48 mg/100 mL, and cinnamaldehyde: 244.45 mg/100 mL) at optimum MAE conditions: 59% ethanol, 147.5 W microwave power and 3.4 min of extraction time. RE resulted in comparable yields with the highest consumption of time, energy, and solvent, and least CO2 emission. Therefore, it is concluded that MAE is the most efficient method for green extraction of cinnamic acid and cinnamaldehyde from cinnamon powder compared to UAE and RE. PMID- 30483425 TI - Systematical characterization of functional and antioxidative properties of heat induced polymerized whey proteins. AB - Effects of pH (6-8), protein concentration (6-11%, w/v), heating temperature (70 95 degrees C) and time (5-30 min) on functional and antioxidative properties of heat-induced polymerized whey protein were systematically investigated. All samples were determined for solubility at pH 4.6, emulsion capacity and stability, and antioxidative properties involving 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azinobis(2-ethylbenzothiazoline-6-sulfonate) (ABTS) scavenging abilities. Heating resulted in significant loss in solubility, emulsion capacity and stability for whey protein, p < 0.05. Heating decreased DPPH but enhanced ABTS scavenging ability for whey protein significantly, p < 0.05. Changes caused by pH variation were much stronger than those observed for other factors. Both protein concentration and heating time had negative effects while heating temperature had positive effect on emulsion capacity of whey protein. Data indicates that functional and antioxidative properties of whey protein could be altered by factors including pH, protein concentration, heating temperature and time. PMID- 30483426 TI - Textural character of sweet potato root of Korean cultivars in relation to chemical constituents and their properties. AB - A relationship between chemical constituents and physicochemical and textural properties of different Korean sweet potato (SP) cultivars were investigated in terms of the hardness of raw and cooked root, alcohol insoluble solid (AIS), starch and amylose content, amylase activities, and pasting properties. Correlation coefficients were analyzed and principal component analysis was performed. The hardness of cooked root was found to correlate with the hardness ratio of cooked/raw SP, AIS content (0.75**), starch content (0.64**), and peak viscosity of SP powder (0.56*). It was discovered that SP cultivars could be classified into mealy (Sincheonmi, Daeyumi, Sinyulmi), intermediate (Dahomi, Sinjami, Geonhwangmi, Yeonjami, Pungwonmi), and waxy (Juhwangmi, Sinhwangmi) types depending on the first principal component (PC1, 68%). Therefore, it was found that the texture types of SP cultivars could be predicted from hardness of cooked root and are in relation to AIS and starch contents, and peak viscosity of raw powder. PMID- 30483427 TI - Exploring the applicability of tamarind gum for making gluten-free rice bread. AB - The present study explored the applicability of tamarind gum in making gluten free rice bread. Hydration properties of gums and pasting properties of rice flour with the gums were analyzed with Rapid ViscoAnalyzer. Batter properties and bread quality characteristics of rice bread containing gums were analyzed. Except for guar and xanthan gum, the final viscosity after hydration of other gums and the pasting properties of rice flour with the gums were similar. The batter properties and the quality of rice bread containing tamarind gum were equivalent or superior to those containing other gums. Cross-sections of rice bread showed that addition of tamarind gum and pectin resulted in a fine appearance, but pectin may not be preferred due to its lower pH causing unpleasant sour taste and smell of the rice bread containing the gum. Therefore, tamarind gum can be a useful gum for applying to make gluten-free rice bread. PMID- 30483428 TI - Coating Satsuma mandarin using grapefruit seed extract-incorporated carnauba wax for its preservation. AB - Grapefruit seed extract (GSE)-incorporated carnauba wax (CW) coating was developed to preserve Satsuma mandarins (Citrus unshiu Marc.). GSE (1.00%, w/w) incorporated CW (GSE-CW) coating emulsions and GSE (0.50%)-oregano oil (OO, 0.50%)-incorporated CW (GSE-OO-CW) coating emulsions reduced Penicillium italicum disease incidence (%) on mandarin surfaces by 23.6 +/- 3.6 and 25.0 +/- 5.0%, respectively, relative to that on uncoated mandarin samples (100%). GSE (1.00%) CW coating emulsions exhibited a higher colloidal stability than GSE (0.50%)-OO (0.50%)-CW coating emulsions. During storage at 25 degrees C, GSE (1.00%)-CW coating was superior to CW coating in reducing P. italicum disease incidence. CW coating significantly reduced weight loss, respiration rate, and firmness loss during storage at 4 and 25 degrees C (P < 0.05). The ascorbic acid concentration and peel color were not affected by GSE-CW coating (P > 0.05). These results suggest that GSE-CW coating can extend the post-harvest shelf life of mandarins by inhibiting the growth of P. italicum. PMID- 30483429 TI - Spirulina sp. biomass dried/disrupted by different methods and their application in biofilms production. AB - Arthrospira Spirulina biomass is a source of intracellular compounds with great commercial interest, such as phycocyanin and phenolic compounds. In this work, different cell disruption methods of the microalgae biomass dried in spouted bed and in conventional tray were performed, aiming lead to the better extraction yields of these compounds. The samples of both drying techniques with the most suitable cell disruption were used to biofilms production. FTIR, DSC, and SEM for all samples were performed. The samples dried in spouted bed with cell disruption by milling and by microwave showed the best results for the powder products, with phycocyanin contents of 75.0 and 85.4 mg g-1, and total phenolic compounds of 41.6 and 41.9 mg g-1, respectively. However, the tray drying/milling produced the biofilms with the best characteristics (tensile strength of 3.69 MPa and water vapor permeability of 1.67 * 10-11 g m s-1 m-2 Pa-1) and the highest thermal stability. PMID- 30483430 TI - Changes in secondary structure of myofibrillar protein and its relationship with water dynamic changes during storage of battered and deep-fried pork slices. AB - Fourier transform infrared spectroscopy was used to analyze the changes of secondary structure of myofibrillar proteins in short-term storage of battered and deep-fried pork slices. These changes were combined with low-field NMR analysis results to analyze the correlation between secondary structure and dynamic changes of water content. The results showed that the number of alpha helix and beta-sheet decreased by 22.90 and 16.54% respectively, and the orderly structure changed to the disorder structure. The correlation results show that NMR spin-spin relaxation time (T21) has a high negative correlation with alpha helix, beta-sheet, and has a high positive correlation with irregular curl and beta-turn. The population of immobile water (P22) has a very high positive correlation with alpha-helix, beta-sheet, and has a relatively high negative correlation with irregular curl and beta-turn. The immobilized water plays an important role in maintaining the secondary structure. PMID- 30483431 TI - Phytochemical composition of everbearing strawberries and storage quality of strawberry fruit treated by precooling. AB - This study was conducted to investigate the nutrient composition of everbearing strawberry cultivar grown on highlands of Gangwon province after harvest. Various phytochemical compositions such as ascorbic acid, anthocyanin, malondialdehyde, and phenolic compounds were analyzed in strawberry fruits from five different cultivars (cv. Albion, Flamenco, Goha, San Andreas, and Seascape). Ascorbic acid content was similar among five cultivars at 20 mg 100 g-1, whereas major pigment anthocyanin in Seascape was higher than in any other cultivars. Goha and San Andreas showed higher total phenolic compound contents. The effect of room or forced-air precooling on Flamenco and Goha was studied. Higher weight loss was observed in Flamenco treated with forced-air cooling, while in Goha both precooling treatments induced weight loss. Both precooling treatments were effective to maintain firmness in two strawberry cultivars. Forced air cooling maintained total phenolic contents until 12 days of storage, and the efficiency accelerated by low temperature storage. PMID- 30483432 TI - Migration study of caprolactam from polyamide 6 sheets into food simulants. AB - Caprolactam, used in manufacturing polyamide (PA) 6, may threaten human health. Here, PA 6 sheets were produced by using a twin-screw extruder to evaluate its safety. Caprolactam migration concentrations from the PA 6 sheets into food simulants were evaluated according to the standard migration test conditions under the Korean Food Standards Codex (KFSC). Concentrations were investigated under various food simulants (distilled water, 4% acetic acid, 20 and 50% ethanol, and heptane) and storage conditions (at 25, 60, and 95 degrees C). Caprolactam migration concentrations into food simulants were determined as follows: 4% acetic acid (0.982 mg/L), distilled water (0.851 mg/L), 50% ethanol (0.624 mg/L), 20% ethanol (0.328 mg/L), and n-heptane (not detected). Migrations were determined to be under the regulatory concentration (15 mg/L) according to the KFSC test conditions. Taken together, these results verified that the standard migration test conditions by KFSC were reliable to evaluate the safety of PA 6. PMID- 30483433 TI - Pulsed electric field (PEF) technology for microbial inactivation in low-alcohol red wine. AB - The decontamination of spoilage-related microbes in low-alcohol red wine was performed using a serial multiple electrode pulsed electric field (PEF) treatment system. The system consisted of seven electrodes connected in series, and it has been designed to produce square-wave high-voltage pulses of 1 MUs duration at various electric field strengths and frequencies for decontamination. The initial counts of aerobic bacteria, yeast and lactic acid bacteria (spoilage-associated microbes) in the wine were 5.56, 5.61 and 5.22 log CFU/mL, respectively. The pattern of decontamination of the spoilage microorganisms followed first-order kinetics and the decontamination effect increased as the field strength and frequency increases. DHz and DPEF values were inversely related to the electric field strength of the PEF treatment. The yeast exhibited relatively low DPEF value than the aerobic and lactic acid bacteria. The lowest ZPEF-value was observed for the lactic acid bacteria (24.6 kV/cm) among the spoilage microbes. PMID- 30483434 TI - Effects of newly developed waxy rice flour on the quality characteristics and oxidative stability of Korean traditional fried cookie, Yakgwa. AB - The effects of waxy rice flour (WRF) in substitution for wheat flour (WF) on the oil absorption, structure, texture and oxidative stability of traditional Korean fried cookies, Yakgwa, were investigated. Fried cookie prepared with WF showed the greatest oil absorption (20.66%), however, the oil absorption reduced as the ratio of WRF substitution increased. The fried cookies prepared with WRF in substitution for WR showed the reduced oil absorption and increased oxidation stability. In addition, the cookies still maintained a layered structure with crispiness and softness. Also, when white WRF was used, the fried cookie showed the increased oxidative stability and reduced oil absorption decreased compared to when brown WRF was used. WRF can be used as a substitute for WF at a percentage of up to 75% and can improve the structure and oxidative stability of Yakgwa during storage. Substitution of WRF for WF significantly improves the structure and oxidative stability of Yakgwa. PMID- 30483435 TI - Application of lipase bearing dead mycelia as biocatalyst for octyl-octanoate synthesis. AB - Abstract: The present study scrutinizes lipases of different origins, immobilization methods, carriers, and reaction solvents to accelerate the octyl octanoate synthesis. The acylation reaction parameters including temperature, moisture level, shaking speed and enzyme dose were subsequently investigated and optimized following fully rotatable central composite design. The initial screening revealed that lipases of Rhizopus arrhizus, when applied as a biocatalyst (lipase bearing dead mycelia) furnished the highest acylation activity (147 MUM L-1 min-1). Validation of reaction conditions disclosed that 250 I.U. of lipase based biocatalyst when incubated with 850 mM of acylating agent and 750 mM of the substrate at 35 degrees C, 3% moisture level and 150 RPM shaking speed produced 70% acylation yield with an acylation activity higher than 147 MUM L-1 min-1. The observed results certify that lipase bearing dead mycelia of R. arrhizus might be an intelligent biocatalyst to manipulate the yield of acylation reactions encountered in the food industry. Graphical Abstract: PMID- 30483436 TI - Antioxidant properties of a vegetable-fruit beverage fermented with two Lactobacillus plantarum strains. AB - Fermented vegetable-fruit beverages are a popular fermented food, with many potential health benefits. In this study, two commercial Lactobacillus plantarum strains were selected to ferment a beverage containing apples, pears, and carrots. The metabolites and antioxidant activities were examined during the fermentation process. Results showed that lactic acid and acetic acid accumulated gradually, whereas malic acid decreased. Glucose and fructose increased from 0.48 and 14.8 g/L to 7.7 and 20.8 g/L, respectively, while sucrose decreased slightly. Ascorbic acid also increased continuously during the fermentation to 90.74 mg/100 mL. DPPH and ABTS radical scavenging activity and FRAP reached their maximum value after 4-8 days. The accumulation of TPC, TFC, and SOD reached their maximum value on the 8th day of fermentation. Our study revealed that the L. plantarum fermented vegetable-fruit beverage showed significant antioxidant activity, which is helpful in evaluating the fermentation end-point and developing a high-quality fermented beverage. PMID- 30483437 TI - Biotransformation of propolis phenols by L. plantarum as a strategy for reduction of allergens. AB - Propolis is a natural product produced by honeybees. It has antioxidant effects as well as antimicrobial, antiseptic, antibacterial, anti-inflammatory and antimutagenic properties. Except these important healthy properties some cytotoxic effects causing allergies also have been reported. In this study have been evaluated changes of phenolic compounds including allergens molecules found in propolis. Before biotransformation, propolis samples were treated with different solvent (ethanol and polyethylene glycol) to facilitate solvation of solid samples. Biotransformation was done by three different strains of Lactobacillus plantarum (10, 8014, ATCC). Results demonstrated the importance of used solvent/treatment for extraction procedure and strains of L. plantrum. The lowest values of main allergens were determined as 321 ng/mL for BCAFE, 320 ng/mL for 1.1 DMAECAFE and 8.02 ng/mL for CAPE. The study is the first work deal with evaluation of bioconversion of propolis by different L. plantarum strains and their effects on phenolic profile. PMID- 30483438 TI - Exopolysaccharide from Pantoea sp. BCCS 001 GH isolated from nectarine fruit: production in submerged culture and preliminary physicochemical characterizations. AB - Exopolysaccharide (EPS), as potential microbial base polysaccharide source, has plenty of applications due to its unique physicochemical structure. A Pantoea sp. BCCS 001 GH bacterium with the ability to produce a high amount of EPS was identified by 16S rRNA gene sequencing and biochemical tests. The synthesis of EPS by Pantoea sp. BCCS 001 GH was 13.50 g/L in 48 h when sucrose was used as substrate. The proposed protocol was desirably rapid for massive prodcution of EPS and showed the remarkable impact of sucrose and disodium hydrogen phosphate, peptone, Triton x-100 and 2% (v/v) inoculum size on the yields of EPS production. The EPS was mainly composed of glucose and galactose in a relative molar ration (glucose/galactose) of 85.18:14.82, respectively. The preliminary characterization showed the average molecular-weight of EPS is about 2.522 * 106 Da. The microscopics morphology of polymer was formed irregularly shaped structures. PMID- 30483439 TI - Characterization of Lactobacillus plantarum strains isolated from black raspberry and their effect on BALB/c mice gut microbiota. AB - The objective of this study was to evaluate probiotic effects of two Lactobacillus plantarum strains (GBL16 and 17) isolated from black raspberry. Results revealed that the number of GBL16 was gradually decreased as bile salt concentration was increased from 0.3 to 1%. However, GBL17 did not show any difference when GBL17 was applied to 1% bile salt, and it indicates that GBL17 is more tolerant to bile salt than GBL16. GBL17 exhibited higher heat resistance and adhesion ability to Caco-2 cells than GBL16. Regarding gut microbiome, no significant change in the number of total bacteria in intestines of mice after treatment with GBLs was determined. However, the combination of GBL16 and GBL17 significantly increased the number of total bacteria in intestines of mice after they were orally administered. Therefore, the results suggest that both GBL16 and 17 strains could be one of major probiotics that can improve human gut health. PMID- 30483440 TI - Analysis of Leuconostoc citreum strains using multilocus sequence typing. AB - The objective of this study was to perform genetic diversity analysis of 13 strains isolated from South Korean foods by multilocus sequence typing (MLST). For typing, seven housekeeping loci (atpA, dnaA, dnaK, gyrB, pheS, pyrG, and rpoA) were selected, amplified and analyzed. Fifty-one polymorphic sites varying from 1 to 22 in each species were identified. Thirteen sequence types were generated with allele numbers ranged from 2 to 10. The overall relationship between strains was assessed by unweighted pair group method with arithmetic mean dendrogram and minimum spanning tree. In addition, combined spits tree analysis revealed intragenic recombination. No clear relationship was observed between the isolation sources and strains. The developed MLST scheme enhanced our knowledge of the population diversity of Leu. citreum strains and will be used further for the selection of industrially important strain. PMID- 30483441 TI - Antioxidant and anti-inflammatory functionality of ten Sri Lankan seaweed extracts obtained by carbohydrase assisted extraction. AB - Enzyme-assisted extraction is a cost-effective, safe, and efficient method to obtain bioactives from plant materials. During this study, 10 different marine algae from Sri Lanka were individually extracted by using five commercial food grade carbohydrases. The enzymatic and water extracts of the seaweeds were analyzed for their antioxidant and anti-inflammatory activities. The highest DPPH, hydrogen peroxide (H2O2) and intracellular H2O2 scavenging abilities were observed from the Celluclast extract of Sargassum polycystum (CSp). CSp exerted protective effects against oxidative stress-induced cell death in hydrogen peroxide-induced Chang cells and in model zebrafish. The Celluclast extract of Chnoospora minima (CCm) showed the strongest anti-inflammatory activity against lipopolysaccharide (LPS)-induced NO production in RAW 264.7 macrophages (IC50 = 44.47 ug/mL) and in model zebrafish. CCm inhibited the levels of iNOS, COX-2, PGE2, and TNF-alpha in LPS stimulated RAW 264.7 macrophages. Hence, CSp and CCm could be utilized in developing functional ingredients for foods, and cosmeceuticals. PMID- 30483442 TI - Hypoglycemic effect of standardized Chrysanthemum zawadskii ethanol extract in high-fat diet/streptozotocin-induced diabetic mice and rats. AB - Chrysanthemum zawadskii (CZ) is a perennial herb belonging to the Asteraceae family. CZ is used medicinally to treat inflammatory and uterine diseases in Asia. CZ was extracted with 50% ethanol and CZ extract (CZE; at 125, 250, and 500 mg/kg body weight) was administered orally every day for 5 or 6 weeks to investigate the anti-diabetic effects in streptozotocin (STZ)-induced rats and STZ + high-fat diet (HFD)-fed mice. CZE significantly decreased fasting blood glucose levels in STZ- and STZ + HFD-induced diabetic models. In addition, glucose tolerance and insulin tolerance were improved in the STZ + HFD + CZE group by increasing insulin levels and decreasing hemoglobin A1c (HbA1c) levels in serum. Furthermore, CZE supplements decreased components of the serum lipid profile such as triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels. These results suggest that CZE may be a potential candidate for controlling hyperglycemia. PMID- 30483443 TI - Antihypertensive peptides from whey proteins fermented by lactic acid bacteria. AB - In this study, whey proteins were fermented with 34 lactic acid bacteria for 48 h at 37 degrees C and their ability to inhibit angiotensin 1-converting enzyme (ACE) activity were compared. All the lactic acid bacteria displayed varying proteolytic abilities in whey. Their fermentates also displayed varying abilities to inhibit ACE in vitro. Seven fermentates showed strong ACE inhibitory abilities between 84.70 +/- 0.67 and 52.40 +/- 2.1% with IC50 values between 19.78 +/- 1.73 and 2.13 +/- 0.7 mg/ml. Pediococcus acidilactici SDL1414 showed the strongest ACE inhibitory activity of 84.7 +/- 0.67% (IC50 = 19.78 +/- 1.73 MUg/ml). Mass spectrometry revealed that more than half (57.7%) of the low molecular weight peptides (< 7 kDa) in the P. acidilactici SDL1414 fermented samples were ACE inhibitory peptides. Our results show that P. acidilactici SDL1414 could be used as a starter culture in the dairy industry to develop antihypertensive functional foods for hypertension management. PMID- 30483444 TI - Oligopeptide derived from solid-state fermented cottonseed meal significantly affect the immunomodulatory in BALB/c mice treated with cyclophosphamide. AB - In this study, the immunomodulatory activity of oligopeptide (CP) derived from solid-state fermented cottonseed meal were investigated in immunosuppressed BALB/c mice models by treatment with cyclophosphamide (CY). Results indicated that oligopeptide increased the thymus and spleen indices of CY-treated mice. The count of plague forming cells (PFC) and the content of half serum hemolysis (HC50) in immunosuppressive mice were restored to the normal level in CP-10 and CP-20 groups while the cytokines interleukin (IL)-2, IL-6, and tumor necrosis factor alpha (TNF-alpha) were increased significantly in CP-20 group. Similar increasing the immunoglobulin of IgG and IgM content in the serum of CP-10 group were also observed. These findings indicated that oligopeptide derived from solid state fermented cottonseed meal had a strong immune-enhancing activity as well as a protective effect against immunosuppression induced by cyclophosphamide in mice. PMID- 30483445 TI - Protective effects of citrus based mixture drinks (CBMDs) on oxidative stress and restraint stress. AB - In the current study investigated the protective effects of citrus based mixture drinks (CBMDs) using oxidative stress in human dermal fibroblast (HDF) cells and restraint-stressed rats. The CBMDs contained citrus bioflavonoids including narirutin and hesperidin. The cell viability of HDF cells treated with H2O2 was observed at 53.9% but treated with CBMD-1 and CBMD-2 (500 MUg/mL) on H2O2 exposed HDF cells significantly increased the relative cell viability at 65.0 and 72.2%, respectively. In the treadmill test, the time spent on the electrode plate in the restraint-stressed group was analyzed 24.1 s, but restraint-stressed rats with administered CBMDs (300 mg/kg) had significantly decreased the time at 2.4 (CBMD 1) and 4.7 (CBMD-2) s, respectively. In addition, number of touches the electrode plate in restraint-stressed group was observed at 42.4 ea, but, restraint stressed rats with administered CBMD-1 and CBMD-2 (300 mg/kg) were significantly decreased at 7.0 and 10.2 ea, respectively. PMID- 30483446 TI - Repressive effects of red bean, Phaseolus angularis, extracts on obesity of mouse induced with high-fat diet via downregulation of adipocyte differentiation and modulating lipid metabolism. AB - Obesity is generally caused by quantitative changes in adipocyte differentiation and fat metabolism. Only a few studies have been determined the effect of red beans extract on obesity and plasma cholesterol concentration. We have been studied the functional activities of red-bean extracts including anti-oxidative effect against DNA and cell damages. Histological study including micro CT analysis showed that the accumulation of fat in hepatocytes and intestines was significantly decreased in red bean extract treated group. In addition, plasma cholesterol and triglyceride levels were decreased in blood samples. In addition, it was confirmed that the red bean extract inhibited the expression of PPARgamma, Fabp4 and RETN genes, which regulate total adipocyte differentiation and lipid metabolism. Red bean extract inhibits the expressions of transcription factors associated with adipocyte differentiation in a dose-dependent manner, thereby inhibiting fat accumulation and decreasing blood lipid levels in obese mice induced by high fat diet. PMID- 30483447 TI - Glycoproteins isolated from Atractylodes macrocephala Koidz improve protective immune response induction in a mouse model. AB - This study examined the efficacy of Atractylodes macrocephala Koidz (AMK) protein and polysaccharide extracts as adjuvant or adjuvant booster when given together with porcine pleuropneumonia vaccine. Experimental mice (n = 5/group) were subcutaneously immunized with 25 MUg ApxIIA #3 antigen, a target protein against A. pleuropneumoniae, together with alum and/or various concentrations (0-500 MUg) of the AMK extracts, while the control group received PBS only. Immunization with ApxIIA #3 antigen increased the antigen-specific IgG titer and this increase was enhanced in the immunization together with AMK protein, but not polysaccharide extract. Supplementation of AMK protein extract exhibited dose-dependent increases in the antigen-induced protective immunity against A. pleuropneumoniae challenge and in the lymphocyte proliferation specific to the antigen. Glycoproteins present in the AMK extract were the active components responsible for immune response induction. Collectively, the present findings suggest that AMK glycoproteins are useful as immune stimulating adjuvant or adjuvant booster. PMID- 30483449 TI - Determination and risk characterization of polycyclic aromatic hydrocarbons of tea by using the Margin of Exposure (MOE) approach. AB - Tea is one of the most frequently consumed drinks due to its favourite taste and the health benefit. Tea is produced by several processes and drying is very important step to develop the flavour and destroys the enzymes in tea. However, during drying tea, polycyclic aromatic hydrocarbons some of which are carcinogen and genotoxin are naturally produced. The risk of PAHs by drinking tea was characterized by determining contents of 4 PAHs in tea. 4 PAHs including Benz(a)anthracene (BaA), Chrysene (CHR), Benzo(b)fluoranthene (BbF) and Benzo(a)pyrene (BaP) were investigated by GC-MS in total 468 tea products, which were contaminated up to 4.63 ng g-1. Mate tea was the most highly contaminated by BaA, CHR, BbF and BaP and followed by Solomon's seal and Chrysanthemum. The Margin of Exposures calculated by the concentration of BaA, CHR, BbF and BaP and consumption amount of tea were higher than 10,000, and the risk of PAHs in tea were low concern to public health. PMID- 30483450 TI - Supercritical fluid extraction effectively removes phthalate plasticizers in spores of Ganoderma lucidum. AB - Phthalate plasticizers residue in food is a serious threat to public health. Spores of Ganoderma lucidum are easy to be contaminated with phthalates during collection and processing. In this study, supercritical fluid extraction (SFE) was performed to remove phthalates in spores of G. lucidum, and the effects on acid and peroxide values of spores' oil were also evaluated. The results showed SFE removed 100% of the residual di-iso-butyl phthalate, di-n-butyl phthalate and di-2-ethylhexyl phthalate in the spores of G. lucidum. No significant differences in polysaccharides content and fatty acid composition were observed between SFE and control spores. However, the triterpenoid extracts of SFE spores had a 7.45% increase, significantly higher than that in control spores. Accelerated oxidation tests further implied that SFE could improve the stability of spores' oil. Our results suggested SFE is a potential approach to remove phthalate from food related products. PMID- 30483448 TI - Isolation of a sleep-promoting compound from Polygonatum sibiricum rhizome. AB - The aim of this study was to identify sleep-promoting substance from Polygonatum sibiricum rhizome extract (PSE) with the regulation of sleep architecture. PSE showed a decrease in sleep latency time and an increase in the sleeping time. In the electroencephalography analysis of rats, PSE (150 mg/kg) showed an increase of non-rapid eye movement by 38% and a decrease of rapid eye movement by 31% compared to the control. This sleep-promoting activity was found to be involved in the GABAA-BDZ receptor. The chemical structure of the pure compound was determined by the 1H and 13C nuclear magnetic resonance spectroscopy and gas chromatography mass spectrometry analysis; active compound was glyceryl-1 monolinoleate. The commercial standard glyceryl-1-monolinoleate showed a similar inhibitory concentration on [3H]-flumazenil binding to GABAA-BDZ receptors with final active fraction of PSE. The results indicate that glyceryl-1-monolinoleate is a major active compound responsible for the PSE-derived sleep promotion. PMID- 30483451 TI - Population changes and growth modeling of Salmonella enterica during alfalfa seed germination and early sprout development. AB - This study examined the effects of alfalfa seed germination on growth of Salmonella enterica. We investigated the population changes of S. enterica during early sprout development. We found that the population density of S. enterica, which was inoculated on alfalfa seeds was increased during sprout development under all experimental temperatures, whereas a significant reduction was observed when S. enterica was inoculated on fully germinated sprouts. To establish a model for predicting S. enterica growth during alfalfa sprout development, the kinetic growth data under isothermal conditions were collected and evaluated based on Baranyi model as a primary model for growth data. To elucidate the influence of temperature on S. enterica growth rates, three secondary models were compared and found that the Arrhenius-type model was more suitable than others. We believe that our model can be utilized to predict S. enterica behavior in alfalfa sprout and to conduct microbial risk assessments. PMID- 30483452 TI - Effect of pepper tree (Schinus molle) essential oil-loaded chitosan bio nanocomposites on postharvest control of Colletotrichum gloeosporioides and quality evaluations in avocado (Persea americana) cv. Hass. AB - Preventive and curative activity of postharvest treatments with chitosan nanoparticles (CS) and chitosan biocomposites loaded with pepper tree essential oil (CS-PEO) against anthracnose were evaluated on Avocado (Persea americana) cv. Hass artificially inoculated in rind wounds. After 10 days of storage significant preventive and curative activity against Colletotrichum gloeosporioides was observed with the absence of internal damage by applying CS and CS-PEO. Quality parameters like water losses and firmness changes were assessed on fruit treated. CS and CS-PEO were effective to reduce water losses and firmness losses. PMID- 30483454 TI - Malignant Pheochromocytoma with Widespread Bony and Pulmonary Metastases. AB - Pheochromocytoma is a rare benign tumor of the adrenal gland. A select few cases may be malignant, and metastatic cases are exceedingly rare. It often presents with symptoms of catecholamine excess, such as sweating, palpitations, headaches, and characteristic paroxysmal hypertension. Due to its diffuse symptoms, it is difficult to diagnose and is often diagnosed late. We describe the unique case of a 44-year-old female patient who presented with uncontrolled hypertension and vomiting, accompanied by lower back pain. She was diagnosed with malignant pheochromocytoma with multiple metastases to the lungs, vertebrae, scapulae, and skull. Because of the advanced state of her disease, the patient was started on treatment with the chemotherapeutic combination of cyclophosphamide, vincristine, and dacarbazine. However, she had a complicated hospital course and died because of aspiration pneumonia and sepsis. PMID- 30483453 TI - Patient-Specific Pose Estimation in Clinical Environments. AB - Reliable posture labels in hospital environments can augment research studies on neural correlates to natural behaviors and clinical applications that monitor patient activity. However, many existing pose estimation frameworks are not calibrated for these unpredictable settings. In this paper, we propose a semi automated approach for improving upper-body pose estimation in noisy clinical environments, whereby we adapt and build around an existing joint tracking framework to improve its robustness to environmental uncertainties. The proposed framework uses subject-specific convolutional neural network models trained on a subset of a patient's RGB video recording chosen to maximize the feature variance of each joint. Furthermore, by compensating for scene lighting changes and by refining the predicted joint trajectories through a Kalman filter with fitted noise parameters, the extended system yields more consistent and accurate posture annotations when compared with the two state-of-the-art generalized pose tracking algorithms for three hospital patients recorded in two research clinics. PMID- 30483455 TI - Extrapyramidal Symptoms with Administration of Lenalidomide Maintenance Therapy for Multiple Myeloma. AB - Lenalidomide is commonly used as induction or maintenance therapy in multiple myeloma. We report a case of 71-year-old female presenting with tardive dyskinesia-like symptoms one month after starting her lenalidomide maintenance therapy after high-dose chemotherapy and autologous hematopoietic stem cell rescue. Her symptoms evolved over days to pronounced uncontrollable limb movements, tongue smacking, lip-smacking, abnormal sounds, and tongue biting. The patient categorically denied any exposure to other drugs which are known to cause symptoms of tardive dyskinesia. The patient underwent a thorough evaluation, stopped the lenalidomide, and received therapy to control her symptoms with a gradual improvement over a six-week period. There is a paucity of literature on the association of lenalidomide with tardive dyskinesia. Common central nervous system-related side effects include peripheral neuropathy, dizziness, dysgeusia, headache, tremor, somnolence, and memory impairment. Very few studies in the existing literature have reported an association of tardive dyskinesia with lenalidomide therapy. Here, we present a case of an elderly female with multiple myeloma who developed severe tardive dyskinesia while she was on lenalidomide maintenance therapy. PMID- 30483456 TI - Posterior Reversible Encephalopathy Syndrome in a Patient with Variegate Porphyria: A Case Report. AB - Variegate porphyria (VP) is one of the groups of rare inherited disorders of hemoglobin synthesis called Porphyria. It has two distinct manifestations, that is, those of cutaneous and nervous system. Posterior reversible encephalopathy syndrome (PRES) is a rare complication of porphyria. It occurs due to vasogenic edema in white matter of predominantly parieto-occipital lobes, characterized by headache, visual disturbances, altered mental state, hypertension, and seizures. We report a child diagnosed with VP who presents with clinical signs and radiological manifestations suggestive of PRES. To our knowledge this has never been reported in a case of VP and only twice been reported in another type of porphyria. A 12-year-old pre-pubertal boy already diagnosed with VP presents with seizure, visual disturbance, altered mental status, headache, and hypertension. Initial brain magnetic resonance imaging (MRI) revealed bilateral increased signal intensity in parieto-occipital region. Neurological opinion suggested that the symptoms experienced by the patient seem to be a complication of porphyria. Treatment was to control hypertension and prevent use of any aggravating agents. Follow-up MRI after two weeks revealed interval reduction in disease process. Diagnosis of PRES was thus confirmed. PRES should be considered in patients presenting with symptoms typical of encephalitis/meningitis/acute disseminated encephalomyelitis in a patient suffering from porphyria. Early diagnosis is key to quick improvement and prevention of complications. Though rare in pre-pubertal patients, it should be kept as a possibility especially when patients present with hypertension. Care should be taken to not use any drugs that can trigger PRES. PMID- 30483457 TI - Giant Cell Tumor of the Frontal Bone: A Case Report and Literature Review. AB - Giant cell tumors are rare benign lesions that typically occur at the epiphyses of long bones in the extremities and present with pain or swelling. These lesions very seldom occur in the skull, where they preferentially affect the sphenoid and temporal bones that develop by endochondral ossification. We report a rare case of a giant cell tumor of the frontal bone and review the literature on these lesions. A 21-year-old woman presented with localized swelling and tenderness over the left frontal bone. Imaging revealed a lytic lesion involving the left frontal bone, which was managed via left frontal craniectomy with resection of the bone and epidural mass. Histopathology revealed a giant cell tumor of bone (GCTB). Most data on giant cell tumors in the skull consist of case reports, with many large series of giant cell tumors having no examples in the skull. This report contributes to the scarce literature on these tumors in the skull. PMID- 30483458 TI - Tear production and intraocular pressure values in clinically normal eyes of whooper swans (Cygnus cygnus). AB - The objective of this study was to determine the normal range of tear production and values of intraocular pressure (IOP) in clinically normal eyes of whooper swans (Cygnus cygnus). A total of 86 birds: 81 cygnets (6-10 weeks old) and 5 moulting - adult swans (3-6 years old) were examined in this study. Both eyes of all birds underwent a complete ophthalmic examination, including evaluation of tear production with the phenol red thread test (PRTT) and the assessment of the IOP by rebound tonometry, employing the TonoVet(r) device. The mean +/- standard deviation of PRTT values were as follows: all cygnets (81) 22.59+/-3.48 mm/15s, male cygnets (45) 22.64+/-3.54 mm/15s, female cygnets (36) 22.53+/-3.44 mm/15s. IOP was as follows: all cygnets 11.30+/-3.55 mmHg, male cygnets 10.93+/-3.56 mmHg, female cygnets 11.74+/-3.50 mmHg. No statistically significant differences between right and left eye and between female and male cygnets were found for IOP and PRTT values. This study provides the reference values for the PRTT and IOP in healthy whooper swan cygnets, showing that PRTT determination of the tear production and rebound tonometry to evaluate the IOP methods are practical methods for ophthalmic examination in swans. PMID- 30483459 TI - Capripoxvirus antibodies detection: Relationship between the two methods alpha and beta of virus neutralisation test. AB - Virus neutralisation test (VNT) of capripoxvirus (CaPVs) was studied to assess the post-vaccination (vaccine effectiveness) or post-infection antibodies level using two methods: alpha-VNT and beta-VNT which are generally carried out to measure the Neutralising Index (N.I.) and the serum Antibody titre (TAb) respectively. The authors have demonstrated that a positive correlation exists between N.I. and TAb values, this study aimed to add more evidence to this correlation by establishing a graph and its mathematical equations. We found that: N.I. = (1.489 Log TAb) + 1.331; this serves as a base to calculate N.I. using TAb values measured by beta-VNT without going through alpha-VNT and vice versa. At the end of this study, we evaluated the equation accuracy by two parameters; the deviation (d) and the error percentage, which were d = 0.2 and error (%) = 8%, respectively. PMID- 30483460 TI - Intravenous pathogenicity of influenza virus A/H5N1/2014 isolated from pig in Ogbomoso, Nigeria. AB - Understanding the pathogenicity of avian influenza viruses in poultry is an important scientific and public health challenge because of antigenic shift/drift and a source of novel, potentially human-pathogenic strains. We have previously isolated an influenza A strain (H5N1/2014/Ogbomoso) from an outbreak among pig and have now aimed to assess its pathogenicity in an avian host and to categorize it as a low or high pathogenic strain. Intravenous pathogenicity index of the isolated virus was assayed using experimental infection of 6 weeks old pathogen specific free chicken. The peak of clinical signs was on day three post infection, and one death was observed on day eight. The intravenous pathogenicity index of this isolate was 0.08. This results classify this isolate as a low pathogenic avian influenza strain. PMID- 30483461 TI - Effects of the exposure site on histological pulpal responses after direct capping with 2 calcium-silicate based cements in a rat model. AB - Objectives: Direct pulp capping is a treatment for mechanically exposed pulp in which a biocompatible capping material is used to preserve pulpal vitality. Biocompatibility tests in animal studies have used a variety of experimental protocols, particularly with regard to the exposure site. In this study, pulp exposure on the occlusal and mesial surfaces of molar teeth was investigated in a rat model. Materials and Methods: A total of 58 maxillary first molars of Wistar rats were used. Forty molars were mechanically exposed and randomly assigned according to 3 factors: 1) the exposure site (occlusal or mesial), 2) the pulp capping material (ProRoot White MTA or Bio-MA), and 3) 2 follow-up periods (1 day or 7 days) (n = 5 each). The pulp of 6 intact molars served as negative controls. The pulp of 12 molars was exposed without a capping material (n = 3 per exposure site for each period) and served as positive controls. Inflammatory cell infiltration and reparative dentin formation were histologically evaluated at 1 and 7 days using grading scores. Results: At 1 day, localized mild inflammation was detected in most teeth in all experimental groups. At 7 days, continuous/discontinuous calcified bridges were formed at exposure sites with no or few inflammatory cells. No significant differences in pulpal response according to the exposure site or calcium-silicate cement were observed. Conclusions: The location of the exposure site had no effect on rat pulpal healing. However, mesial exposures could be performed easily, with more consistent results. The pulpal responses were not significantly different between the 2 capping materials. PMID- 30483462 TI - Endocrown restorations for extensively damaged posterior teeth: clinical performance of three cases. AB - The restoration of endodontically treated teeth (ETT) with more than one cusp missing and thin remaining walls is challenging for the general practitioner. The use of posts combined with full coverage restorations is a well-established approach, yet not following the minimal invasive principles of adhesive dentistry. Endocrowns are indirect monoblock restorations that use the pulp chamber of the ETT for retention. In this study the fabrication of 4 endocrowns and their clinical performance will be discussed. Two clinical cases include computer-aided design/computer-aided manufacturing manufactured molar endocrowns (one feldspathic ceramic and one hybrid composite-ceramic restoration) and the other two are dental laboratory manufactured resin composite premolar endocrown restorations. The modified United States Public Health Service criteria were used to assess the clinical behavior of the restorations at different follow up periods. Endocrown restorations present a satisfactory clinical alternative, either by the use of resin composite or glass ceramic and hybrid materials. Specific guidelines with minimal alterations should be followed for an endocrown restoration to be successful. Due to limited evidence regarding the long term evaluation of this restorative technique, a careful selection of cases should be applied. PMID- 30483463 TI - Unwanted effects due to interactions between dental materials and magnetic resonance imaging: a review of the literature. AB - Magnetic resonance imaging (MRI) is an advanced diagnostic tool used in both medicine and dentistry. Since it functions based on a strong uniform static magnetic field and radiofrequency pulses, it is advantageous over imaging techniques that rely on ionizing radiation. Unfortunately, the magnetic field and radiofrequency pulses generated within the magnetic resonance imager interact unfavorably with dental materials that have magnetic properties. This leads to unwanted effects such as artifact formation, heat generation, and mechanical displacement. These are a potential source of damage to the oral tissue surrounding the affected dental materials. This review aims to compile, based on the current available evidence, recommendations for dentists and radiologists regarding the safety and appropriate management of dental materials during MRI in patients with orthodontic appliances, maxillofacial prostheses, dental implants, direct and indirect restorative materials, and endodontic materials. PMID- 30483464 TI - Microtensile bond strength of CAD/CAM-fabricated polymer-ceramics to different adhesive resin cements. AB - Objectives: This study evaluated the microtensile bond strength (uTBS) of polymer ceramic and indirect composite resin with 3 classes of resin cements. Materials and Methods: Two computer-aided design/computer-aided manufacturing (CAD/CAM) fabricated polymer-ceramics (Enamic [ENA; Vita] and Lava Ultimate [LAV; 3M ESPE]) and a laboratory indirect composite resin (Gradia [GRA; GC Corp.]) were equally divided into 6 groups (n = 18) with 3 classes of resin cements: Variolink N (VAR; Vivadent), RelyX U200 (RXU; 3M ESPE), and Panavia F2 (PAN; Kuraray). The MUTBS values were compared between groups by 2-way analysis of variance and the post hoc Tamhane test (alpha = 0.05). Results: Restorative materials and resin cements significantly influenced uTBS (p < 0.05). In the GRA group, the highest MUTBS was found with RXU (27.40 +/- 5.39 N) and the lowest with VAR (13.54 +/- 6.04 N) (p < 0.05). Similar trends were observed in the ENA group. In the LAV group, the highest MUTBS was observed with VAR (27.45 +/- 5.84 N) and the lowest with PAN (10.67 +/- 4.37 N) (p < 0.05). PAN had comparable results to those of ENA and GRA, whereas the MUTBS values were significantly lower with LAV (p = 0.001). The highest bond strength of RXU was found with GRA (27.40 +/- 5.39 N, p = 0.001). PAN showed the lowest uTBS with LAV (10.67 +/- 4.37 N; p < 0.001). Conclusions: When applied according to the manufacturers' recommendations, the uTBS of polymer ceramic CAD/CAM materials and indirect composites is influenced by the luting cements. PMID- 30483465 TI - Comparison of the ability of Reciproc and Reciproc Blue instruments to reach the full working length with or without glide path preparation. AB - Objectives: The purpose of the present study was to compare the mean preparation times and frequency with which Reciproc and Reciproc Blue instruments reached the full working length in mandibular molars, with or without glide path preparation. Materials and Methods: Previously untreated mesiobuccal and mesiolingual canals with completely formed apices were randomly divided into 6 groups (n = 50) depending on the usage of Reciproc (RC; VDW), Reciproc Blue (RC Blue; VDW), C Pilot (CP; VDW), and R-Pilot (RP; VDW) files: RC, RC Blue, RC + C-Pilot (RC-CP), RC-Blue + C-Pilot (RC Blue-CP), RC+R-Pilot (RC-RP), and RC Blue + R-Pilot (RC Blue-RP). A glide path was prepared using the hand-operated C-Pilot or the machine-operated R-Pilot instruments, respectively. The chi2 test, analysis of variance, and the Tukey post hoc test were used for statistical comparisons. Results: No statistically significant differences were observed in the distribution of the frequency of reaching the full working length in the RC (94%), RC Blue (88%), RC-CP (94%), RC Blue-CP (90%), RC-RP (96%), and RC Blue-RP (92%) groups (p > 0.05). Conclusions: Preparation of a glide path did not have a significant effect on reaching the full working length using these systems. PMID- 30483467 TI - Statistical notes for clinical researchers: analysis of covariance (ANCOVA). PMID- 30483466 TI - C-shaped root canals of mandibular second molars in a Korean population: a CBCT analysis. AB - Objectives: The purpose of this study was to investigate the C-shaped root canal anatomy of mandibular second molars in a Korean population. Materials and Methods: A total of 542 teeth were evaluated using cone-beam computed tomography (CBCT). The canal shapes were classified according to a modified version of Melton's method at the level where the pulp chamber floor became discernible. Results: Of the 542 mandibular second molars, 215 (39.8%) had C-shaped canals, 330 (53%) had 3 canals, 17 (3.3%) had 2 canals, 12 (2.2%) had 4 canals, and 8 (1.7%) had 1 canal. The prevalence of C-shaped canals was 47.8% in females and 28.4% in males. Seventy-seven percent of the C-shaped canals showed a bilateral appearance. The prevalence of C-shaped canals showed no difference according to age or tooth position. Most teeth with a C-shaped canal system presented Melton's type II (45.6%) and type III (32.1%) configurations. Conclusions: There was a high prevalence of C-shaped canals in the mandibular second molars of the Korean population studied. CBCT is expected to be useful for endodontic diagnosis and treatment planning of mandibular second molars. PMID- 30483468 TI - Endodontic management of central incisor associated with large periapical lesion and fused supernumerary root: a conservative approach. AB - Fusion and gemination are developmental anomalies of teeth that may require endodontic treatment. Fusion may cause various clinical problems related to esthetics, tooth spacing, and other periodontal complications. Additional diagnostic tools are required for the diagnosis and the treatment planning of fused tooth. The present case report describes a case of unilateral fusion of a supernumerary root to an upper permanent central incisor with large periapical lesion in which a conservative approach was used without extraction of supernumerary tooth and obturated with mineral trioxide aggregate to reach a favorable outcome. PMID- 30483469 TI - Effect of casein phosphopeptide-amorphous calcium phosphate on fluoride release and micro-shear bond strength of resin-modified glass ionomer cement in caries affected dentin. AB - Objectives: This study was conducted to evaluate fluoride release and the micro shear bond strength of resin-modified glass ionomer cement (RMGIC) in casein phosphopeptide-amorphous calcium phosphate (CPP-ACP)-remineralized caries affected dentin (CAD). Materials and Methods: Exposed dentin surfaces of 30 human third molar teeth were divided into 2 equal groups for evaluating fluoride release and the micro-shear bond strength of RMGIC to CAD. Each group was subdivided into 3 equal subgroups: 1) control (sound dentin); 2) artificially demineralized dentin (CAD); 3) CPP-ACP remineralized dentin (remineralized CAD). To measure fluoride release, 15 disc-shaped specimens of RMGIC (4 mm in diameter and 2 mm in thickness) were bonded on one flat surface of the dentin discs of each group. Fluoride release was tested using ion chromatography at different intervals; 24 hours, 3, 5, 7 days. RMGIC micro-cylinders were built on the flat dentin surface of the 15 discs, which were prepared according to the assigned group. Micro-shear bond strength was measured after 24 hours water storage. Data were analyzed using 1- and 2-way analysis of variance and the post hoc least significant difference test (alpha = 0.05). Results: Fluoride detected in solutions (at all intervals) and the micro-shear bond strength of RMGIC bonded to CPP-ACP-remineralized dentin were significantly higher than those bonded to artificial CAD (p < 0.05). Conclusions: Demineralized CAD consumes more fluoride released from RMGIC into the solution for remineralization than CPP-ACP mineralized dentin does. CPP-ACP increases the micro-shear bond strength of RMGIC to CAD. PMID- 30483470 TI - Improved dentin disinfection by combining different-geometry rotary nickel titanium files in preparing root canals. AB - Objectives: This study was to evaluate the antibacterial effect of different instrumentation and irrigation techniques using confocal laser scanning microscopy (CLSM) after root canal inoculation with Enterococcus faecalis (E. faecalis). Materials and Methods: Mesiobuccal and mesiolingual canals of extracted mandibular molars were apically enlarged up to a size 25 hand K-file, then autoclaved and inoculated with E. faecalis. The samples were randomly divided into 4 main groups according to the system of instrumentation and irrigation: an XP-endo Shaper (XPS) combined with conventional irrigation (XPS/C) or an XP-endo Finisher (XPF) (XPS/XPF), and iRaCe combined with conventional irrigation (iRaCe/C) or combined with an XPF (iRaCe/XPF). A middle-third sample was taken from each group, and then the bacterial reduction was evaluated using CLSM at a depth of 50 um inside the dentinal tubules. The ratio of red fluorescence (dead cells) to green-and-red fluorescence (live and dead cells) represented the percentage of bacterial reduction. The data were then statistically analyzed using the Kruskal-Wallis test for comparisons across the groups and the Dunn test was used for pairwise comparisons. Results: The instrumentation and irrigation techniques had a significant effect on bacterial reduction (p < 0.05). The iRaCe/XPF group showed the strongest effect, followed by the XPS/XPF and XPS/C group, while the iRaCe/C group had the weakest effect. Conclusions: Combining iRaCe with XPF improved its bacterial reduction effect, while combining XPS with XPF did not yield a significant improvement in its ability to reduce bacteria at a depth of 50 um in the dentinal tubules. PMID- 30483471 TI - Influence of thickness and incisal extension of indirect veneers on the biomechanical behavior of maxillary canine teeth. AB - Objectives: To analyze the influence of thickness and incisal extension of indirect veneers on the stress and strain generated in maxillary canine teeth. Materials and Methods: A 3-dimensional maxillary canine model was validated with an in vitro strain gauge and exported to computer-assisted engineering software. Materials were considered homogeneous, isotropic, and elastic. Each canine tooth was then subjected to a 0.3 and 0.8 mm reduction on the facial surface, in preparations with and without incisal covering, and restored with a lithium disilicate veneer. A 50 N load was applied at 45 degrees to the long axis of the tooth, on the incisal third of the palatal surface of the crown. Results: The results showed a mean of 218.16 ustrain of stress in the in vitro experiment, and 210.63 ustrain in finite element analysis (FEA). The stress concentration on prepared teeth was higher at the palatal root surface, with a mean value of 11.02 MPa and varying less than 3% between the preparation designs. The veneers concentrated higher stresses at the incisal third of the facial surface, with a mean of 3.88 MPa and a 40% increase in less-thick veneers. The incisal cover generated a new stress concentration area, with values over 48.18 MPa. Conclusions: The mathematical model for a maxillary canine tooth was validated using FEA. The thickness (0.3 or 0.8 mm) and the incisal covering showed no difference for the tooth structure. However, the incisal covering was harmful for the veneer, of which the greatest thickness was beneficial. PMID- 30483472 TI - Cancer in an Historic Washington DC African American Population and Its Geospatial Distribution. AB - Background: Cancer continues to be a major cause of morbidity and mortality in the African American community but insights into the types and incidence of cancer 85 years ago have been virtually non-existent and little is known of its geospatial distribution. Historical information on cancer can shed light on current health disparities, particularly among African Americans. Objective: The aims of this study were to: (1) assess the frequencies of the cancer types present among Cobb Collection individuals; (2) compare these data with current research on cancer in African Americans; and (3) evaluate the pattern of cancer expression, including its geospatial distributions, as a cause of death between 1931 and 1969 in an historic African American subgroup and compare this pattern with the historic and contemporary patterns of cancer etiology and incidence. Methods: Systematic assessments of the existing clinical, demographic, and anatomical records in the Cobb Research Laboratory were made of individuals identified as dying from specific cancers from 1931 to 1969. These were compared with the national profiles of cancer during the historic time an individual died as well as the contemporary patterns of cancer deaths. Analysis of their residential addresses just prior to death were assessed using a commercial geographic information system. Each location was assigned a geospatial location and proximity between each site and clusters of sites were investigated. Results: Seventeen different cancer types were found within 28 individuals of the Cobb Collection between 1931 and 1969. The cancer types with the highest frequencies were carcinoma of stomach, lung, esophagus, larynx and bronchogenic carcinoma. Eighty-four percent of all cancer incidents occurred in males and 76% were among individuals identified as African American. Seventy-one percent of the highest incidence cancers were among African American males. Geospatial clustering was observed most noticeably in the redistribution of carcinoma of the esophagus. Conclusion: Our results provide historical depth to our knowledge of the common cancer causes of morbidity among African Americans of Washington DC from 1931 to 1969. We contrast these findings with national historical data on cancer etiology and ethnic disparities in incidence. Our study suggests that historic data can provide longitudinal depth to our understanding of the persistence of cancer susceptibilities in a vulnerable subgroup. PMID- 30483474 TI - Enhanced Cytotoxic Activity of Mitochondrial Mechanical Effectors in Human Lung Carcinoma H520 Cells: Pharmaceutical Implications for Cancer Therapy. AB - Cancer cell mitochondria represent an attractive target for oncological treatment as they have unique hallmarks that differ from their healthy counterparts, as the presence of a stronger membrane potential that can be exploited to specifically accumulate cytotoxic cationic molecules. Here, we explore the selective cytotoxic effect of 10-N-nonyl acridine orange (NAO) on human lung carcinoma H520 cells and compare them with healthy human lung primary fibroblasts. NAO is a lipophilic and positively charged molecule that promotes mitochondrial membrane adhesion that eventually leads to apoptosis when incubated at high micromolar concentration. We found an enhanced cytotoxicity of NAO in H520 cancer cells. By means Fluorescence lifetime imaging microscopy (FLIM) we also confirmed the formation of H-dimeric aggregates originating from opposing adjacent membranes that interfere with the mitochondrial membrane structure. Based on our results, we suggest the mitochondrial membrane as a potential target in cancer therapy to mechanically control the cell proliferation of cancer cells. PMID- 30483476 TI - Immunotherapy and Epigenetic Pathway Modulation in Glioblastoma Multiforme. AB - Glioblastoma Multiforme (GBM) is the most common malignant primary brain tumor. Despite aggressive multimodality treatment it remains one of the most challenging and intractable cancers (1]. While current standard of care treatment for GBM is maximal safe surgical resection, systemic chemotherapy with Temozolimide (TMZ), and radiation therapy, the current prognosis of GBM patients remains poor, with a median overall survival of 12-15 months (2, 3). Therefore, other treatments are needed to provide better outcomes for GBM patients. Immunotherapy is one of the most promising new cancer treatment approaches. Immunotherapy drugs have obtained regulatory approval in a variety of cancers including melanoma (4), Hodgkin lymphoma (5), and non-small cell lung cancer (6). The basis of immunotherapy in cancer treatment is linked to stimulating the immune system to recognize cancer cells as foreign, thereby leading to the eventual elimination of the tumor. One form of immunotherapy utilizes vaccines that target tumor antigens (7), while other approaches utilize T-cells in patients to stimulate them to attack tumor cells (8). Despite intensive efforts all approaches have not been overtly successful (9), suggesting that we need to better understand the underlying biology of tumor cells and their environment as they respond to immunotherapy. Recent studies have elucidated epigenetic pathway regulation of GBM tumor expansion (10), suggesting that combined epigenetic pathway inhibition with immunotherapy may be feasible. In this review, we discuss current GBM clinical trials and how immune system interactions with epigenetic pathways and signaling nodes can be delineated to uncover potential combination therapies for this incurable disease. PMID- 30483475 TI - High Therapeutic Efficacy of a New Survivin LSP-Cancer Vaccine Containing CD4+ and CD8+ T-Cell Epitopes. AB - The efficacy of an antitumoral vaccine relies both on the choice of the antigen targeted and on its design. The tumor antigen survivin is an attractive target to develop therapeutic cancer vaccines because of its restricted over-expression and vital functions in most human tumors. Accordingly, several clinical trials targeting survivin in various cancer indications have been conducted. Most of them relied on short peptide-based vaccines and showed promising, but limited clinical results. In this study, we investigated the immunogenicity and therapeutic efficacy of a new long synthetic peptide (LSP)-based cancer vaccine targeting the tumor antigen survivin (SVX). This SVX vaccine is composed of three long synthetic peptides containing several CD4+ and CD8+ T-cell epitopes, which bind to various HLA class II and class I molecules. Studies in healthy individuals showed CD4+ and CD8+ T-cell immunogenicity of SVX peptides in human, irrespective of the individual's HLA types. Importantly, high frequencies of spontaneous T-cell precursors specific to SVX peptides were also detected in the blood of various cancer patients, demonstrating the absence of tolerance against these peptides. We then demonstrated SVX vaccine's high therapeutic efficacy against four different established murine tumor models, associated with its capacity to generate both specific cytotoxic CD8+ and multifunctional Th1 CD4+ T cell responses. When tumors were eradicated, generated memory T-cell responses protected against rechallenge allowing long-term protection against relapses. Treatment with SVX vaccine was also found to reshape the tumor microenvironment by increasing the tumor infiltration of both CD4+ and CD8+ T cells but not Treg cells therefore tipping the balance toward a highly efficient immune response. These results highlight that this LSP-based SVX vaccine appears as a promising cancer vaccine and warrants its further clinical development. PMID- 30483477 TI - Evaluation of Proton Therapy Accuracy Using a PMMA Phantom and PET Prediction Module. AB - Purpose: Positron emission tomography (PET) scanning is a widely used method of proton therapy verification. In this study, a proton radiotherapy accuracy verification process was developed by comparing predicted and measured PET data to verify the correctness of PET prediction and was tested at the Shanghai Proton and Heavy Ion Center. Method: Irradiation was performed on a polymethyl methacrylate (PMMA) phantom. There were two dose groups, to which 2 and 4 Gy doses were delivered, and each dose group had different designed dose depths ranging from 5 to 20 cm. The predicted PET results were obtained using a PET prediction calculation module. The measured data were collected with a PET/computed tomography device. The predicted and measured PET data were normalized to similar PET amplitude values before comparison and were compared using depth and lateral profiles for the position error. The error was evaluated at the position corresponding to 50% of the maximum on the PET curves. The mean and standard deviation were calculated based on the data sampled in the scoring area. Gamma index analysis is also applied in the comparison. Results: In the depth comparison, the 2 and 4 Gy dose cases yielded similar mean depth errors between 1 and -1 mm, and the deviation was <2 mm. In the lateral comparison, the 2 Gy cases had a mean lateral error around 1 mm, and the 4 Gy cases had a mean lateral error <1 mm, with a standard deviation <1 mm for both the 2 and 4 Gy cases. All the cases have a gamma passing rate over 95%. Conclusion: The comparison of these PMMA phantom cases revealed good agreement between the predicted and measured PET data, with depth and lateral position errors <2 mm in total, considering the uncertainty. The comparison results demonstrate that the PET predictions obtained in PMMA phantom tests for single proton beam therapy verification are reliable and that the research can be extended to verification in human body treatment with further investigation. PMID- 30483473 TI - Carbohydrate Targets for CAR T Cells in Solid Childhood Cancers. AB - Application of the CAR targeting strategy in solid tumors is challenged by the need for adequate target antigens. As a consequence of their tissue origin, embryonal cancers can aberrantly express membrane-anchored gangliosides. These are carbohydrate molecules consisting of a glycosphingolipid linked to sialic acids residues. The best-known example is the abundant expression of ganglioside GD2 on the cell surface of neuroblastomas which derive from GD2-positive neuroectoderm. Gangliosides are involved in various cellular functions, including signal transduction, cell proliferation, differentiation, adhesion and cell death. In addition, transformation of human cells to cancer cells can be associated with distinct glycosylation profiles which provide advantages for tumor growth and dissemination and can serve as immune targets. Both gangliosides and aberrant glycosylation of proteins escape the direct molecular and proteomic screening strategies currently applied to identify further immune targets in cancers. Due to their highly restricted expression and their functional roles in the malignant behavior, they are attractive targets for immune engineering strategies. GD2-redirected CAR T cells have shown activity in clinical phase I/II trials in neuroblastoma and next-generation studies are ongoing. Further carbohydrate targets for CAR T cells in preclinical development are O-acetyl-GD2, NeuGc-GM3 (N-glycolyl GM3), GD3, SSEA-4, and oncofetal glycosylation variants. This review summarizes knowledge on the role and function of some membrane expressed non-protein antigens, including gangliosides and abnormal protein glycosylation patterns, and discusses their potential to serve as a CAR targets in pediatric solid cancers. PMID- 30483478 TI - Monitoring the Process of Endostar-Induced Tumor Vascular Normalization by Non contrast Intravoxel Incoherent Motion Diffusion-Weighted MRI. AB - Tumor vascular normalization has been proposed as a new concept in anti-tumor angiogenesis, and the normalization window is considered as an opportunity to increase the effect of chemoradiotherapy. However, there is still a lack of a non invasive method for monitoring the process of tumor vascular normalization. Intravoxel incoherent motion diffusion-weighted magnetic resonance imaging (IVIM DW-MRI) is an emerging approach which can effectively assess microperfusion in tumors, without the need for exogenous contrast agents. However, its role in monitoring tumor vascular normalization still needs further study. In this study, we established a tumor vascular normalization model of CT26 colon-carcinoma bearing mice by means of Endostar treatment. We then employed IVIM DW-MRI and immunofluorescence to detect the process of tumor vascular normalization at different times after treatment. We found that the D* values of the Endostar group were significantly higher than those of the control group on days 4, 6, 8, and 10 after treatment, and the f values of the Endostar group were significantly higher than those of the control group on days 6 and 8. Furthermore, we confirmed through analysis of histologic parameters that Endostar treatment induced the CT26 tumor vascular normalization window starting from day 4 after treatment, and this window lasted for 6 days. Moreover, we found that D* and f values were well correlated with pericyte coverage (r = 0.469 and 0.504, respectively; P < 0.001, both) and relative perfusion (r = 0.424 and 0.457, respectively; P < 0.001, both). Taken together, our findings suggest that IVIM DW-MRI has the potential to serve as a non-invasive approach for monitoring Endostar-induced tumor vascular normalization. PMID- 30483479 TI - A Wor1-Like Transcription Factor Is Essential for Virulence of Cryptococcus neoformans. AB - Gti1/Pac2 transcription factors occur exclusively in fungi and their roles vary according to species, including regulating morphological transition and virulence, mating and secondary metabolism. Many of these functions are important for fungal pathogenesis. We therefore hypothesized that one of the two proteins of this family in Cryptococcus neoformans, a major pathogen of humans, would also control virulence-associated cellular processes. Elimination of this protein in C. neoformans results in reduced polysaccharide capsule expression and defective cytokinesis and growth at 37 degrees C. The mutant loses virulence in a mouse model of cryptococcal infection and retains only partial virulence in the Galleria mellonella alternative model at 30 degrees C. We performed RNA-Seq experiments on the mutant and found abolished transcription of genes that, in combination, are known to account for all the observed phenotypes. The protein has been named Required for cytokinesis and virulence 1 (Rcv1). PMID- 30483480 TI - Cellular Markers of Active Disease and Cure in Different Forms of Leishmania infantum-Induced Disease. AB - Increased numbers of peripheral blood mononucleocytes (PBMC) and increased IFN gamma secretion following in vitro challenge of blood samples with soluble Leishmania antigen (SLA), have been proposed as biomarkers of specific cell mediated immunity, indicating that treatment of visceral leishmaniasis (VL) has been successful. However, Leishmania infantum infection may manifest as cutaneous leishmaniasis (CL), and less commonly as localized leishmanial lymphadenopathy (LLL) or mucosal leishmaniasis (ML). The present work examines the value of these biomarkers as indicators of cured leishmaniasis presenting in these different forms. Blood samples were collected before and after treatment from patients living in Fuenlabrada (Madrid, Spain), an L. infantum-endemic area recently the center of a leishmaniasis outbreak. All samples were subjected to Leishmania specific PCR, serological tests (IFAT and rK39-ICT), and the SLA-cell proliferation assay (SLA-CPA), recording PBMC proliferation and the associated changes in IFN-gamma production. Differences in the results recorded for the active and cured conditions were only significant for VL. PCR returned positive results in 67% of patients with active VL and in 3% of those with cured leishmaniasis. Similarly, rK39-ICT returned a positive result in 77% of active VL samples vs. 52% in cured VL samples, and IFAT in 90% vs. 56%; in the SLA-CPA, PBMC proliferation was seen in 16% vs. 90%, and an associated increase in IFN gamma production of 14 and 84%, respectively. The present findings reinforce the idea that PBMC proliferation and increased IFN-gamma production in SLA-stimulated PBMC provide biomarkers of clinical cure in VL. Other tests are urgently needed to distinguish between the cured and active forms of the other types of clinical leishmaniasis caused by L. infantum. PMID- 30483481 TI - Histological Disorganization of Spleen Compartments and Severe Visceral Leishmaniasis. AB - The spleen is a secondary lymphoid organ responsible for immune surveillance against blood-circulating pathogens. Absence of the spleen is associated with increased susceptibility to systemic spread and fatal infection by different pathogens. Severe forms of visceral leishmaniasis are associated with disorganization of spleen compartments where cell interactions essential for splenic immunological function take place. White pulp atrophies, secondary lymphoid follicles and marginal zones vanish, and the boundaries separating white and red pulp blur. Leukocyte populations are reduced or disappear or are replaced by plasma cells. In this paper, we review the published data on spleen disorganization in severe forms of visceral leishmaniasis and propose a histological classification to help the exchange of information among research groups. PMID- 30483482 TI - Immunity Against Leishmania major Infection: Parasite-Specific Granzyme B Induction as a Correlate of Protection. AB - Zoonotic cutaneous leishmaniasis (ZCL) caused by Leishmania (L.) major infection is characterized by different clinical presentations which depend in part on the host factors. In attempt to investigate the impact of the host's immune response in the outcome of the disease, we conducted a prospective study of 453 individuals living in endemic foci of L. major transmission in Central Tunisia. Several factors were assessed at the baseline including (i) the presence of typical scars of ZCL, (ii) in vivo hypersensitivity reaction to leishmanin, and (iii) the in vitro release of granzyme B (Grz B) by peripheral blood mononuclear cells (PBMC) in response to stimulation with live L. major promastigotes. After one season of parasite's transmission, repeated clinical examinations allowed us to diagnose the new emerging ZCL cases. Heterogeneity was observed in terms of number of lesions developed by each individual as well as their size and spontaneous outcome, which led us to establish the parameter "severity of the disease." The efficacy of the presence of typical ZCL scar, the leishmanin skin test (LST) positive reactivity and the high levels of Grz B (>=2 ng/ml), in the protection against the development of ZCL were 29, 15, and 22%, respectively. However, these factors were more efficient against development of intermediate or severe forms of ZCL. Levels of Grz B >2 ng/ml showed the best efficacy of protection (equals to 72.8%) against development of these forms of ZCL. The association of such parameter with the positivity of the LST exhibited a better efficacy (equals to 83.6%). In conclusion, our results support the involvement of Leishmania-specific cytotoxic cellular immune response in host protection against Leishmania-infection. This factor could be of great interest in monitoring the success of vaccination against human leishmaniasis. PMID- 30483484 TI - Methionine Antagonizes para-Aminosalicylic Acid Activity via Affecting Folate Precursor Biosynthesis in Mycobacterium tuberculosis. AB - para-Aminosalicylic acid (PAS) is a second-line anti-tubercular drug that is used for the treatment of drug-resistant tuberculosis (TB). PAS efficacy in the treatment of TB is limited by its lower potency against Mycobacterium tuberculosis relative to many other drugs in the TB treatment arsenal. It is known that intrinsic metabolites, such as, para-aminobenzoic acid (PABA) and methionine, antagonize PAS and structurally related anti-folate drugs. While the basis for PABA-mediated antagonism of anti-folates is understood, the mechanism for methionine-based antagonism remains undefined. In the present study, we used both targeted and untargeted approaches to identify factors associated with methionine-mediated antagonism of PAS activity. We found that synthesis of folate precursors as well as a putative amino acid transporter, designated MetM, play crucial roles in this process. Disruption of metM by transposon insertion resulted in a >=30-fold decrease in uptake of methionine in M. bovis BCG, indicating that metM is the major facilitator of methionine transport. We also discovered that intracellular biotin confers intrinsic PAS resistance in a methionine-independent manner. Collectively, our results demonstrate that methionine-mediated antagonism of anti-folate drugs occurs through sustained production of folate precursors. PMID- 30483485 TI - Iron and Virulence in Stenotrophomonas Maltophilia: All We Know So Far. AB - Stenotrophomonas maltophilia is a multi-drug-resistant global opportunistic nosocomial pathogen, which possesses a huge number of virulence factors and antibiotics resistance characteristics. Iron has a crucial contribution toward growth and development, cell growth and proliferation, and pathogenicity. The bacterium found to acquire iron for its cellular process through the expression of two iron acquisition systems. Two distinct pathways for iron acquisition are encoded by the S. maltophilia genome-a siderophore-and heme-mediated iron uptake system. The entAFDBEC operon directs the production of the enterobactin siderophore of catecholate in nature, while heme uptake relies on hgbBC and potentially hmuRSTUV operon. Fur and sigma factors are regulators of S. maltophilia under iron-limited condition. Iron potentially act as a signal which plays an important role in biofilm formation, extracellular polymeric substances (EPS), extracellular enzymes production, oxidative stress response, diffusible signal factor (DSF) and siderophore production in S. maltophilia. This review summarizes the current knowledge of iron acquisition in S. maltophilia and the critical role of iron in relation to its pathogenicity. PMID- 30483483 TI - Cellular Targets for the Treatment of Flavivirus Infections. AB - Classical antiviral therapy targets viral functions, mostly viral enzymes or receptors. Successful examples include precursor herpesvirus drugs, antiretroviral drugs that target reverse transcriptase and protease, influenza virus directed compounds as well as more recent direct antiviral agents (DAA) applied in the treatment of hepatitis C virus (HCV). However, from early times, the possibility of targeting the host cell to contain the infection has frequently re-emerged as an alternative and complementary antiviral strategy. Advantages of this approach include an increased threshold to the emergence of resistance and the possibility to target multiple viruses. Major pitfalls are related to important cellular side effects and cytotoxicity. In this mini-review, the concept of host directed antiviral therapy will be discussed with a focus on the most recent advances in the field of Flaviviruses, a family of important human pathogens for which we do not have antivirals available in the clinics. PMID- 30483486 TI - Growth Hormone Receptor Gene Expression Increase Reflects Nutritional Status Improvement in Patients Affected by Crohn's Disease. AB - Background: We proposed to verify the role of growth hormone receptor gene expression in growth failure of children with Crohn's disease (CD). Methods: We measured serum levels of growth hormone binding protein (GHBP) and insulin-like growth factor-I (IGF-I), and growth hormone receptor (GHR) gene expression in peripheral blood mononuclear cells of 21 patients with CD (before and after therapy) and in 27 age-sex-matched controls. Results: At diagnosis, significantly lower insulin-like growth factor-I and growth hormone binding protein levels were found in the CD group compared to the controls. Growth hormone receptor mRNA expression was lower in patients at diagnosis compared to the controls, even though the difference did not reach statistical significance, and significantly increased in patients in the following year. Insulin-like growth factor-I levels showed significant improvements 1 year after diagnosis compared to basal levels. On the contrary, growth hormone binding protein values had not significantly changed after 1 year of therapy. Conclusion: Our study raises the hypothesis of another mechanism through which cytokines interact with the growth hormone/insulin-like growth factor-I (GH/IGF-I) axis. PMID- 30483487 TI - Is It Beneficial to Patients to Include Congenital Adrenal Hyperplasia (CAH) Among the Disorders of Sex Development (DSD)? PMID- 30483488 TI - A Socio-Ecological Framework for Cancer Control in the Pacific: A Community Case Study of the US Affiliated Pacific Island Jurisdictions 1997-2017. AB - The United States Affiliated Pacific Island Jurisdictions (USAPIJ) are politically associated to the United States (US) as US Territories (Guam, American Samoa), a US Commonwealth (Commonwealth of the Northern Mariana Islands), and as sovereign nations linked to the US through Compacts of Free Association [Federated States of Micronesia (FSM), Republic of the Marshall Islands (RMI), Republic of Palau (ROP)]. Cervical cancer incidence in the RMI is the highest in the world, mammography services are not available in the FSM and only Guam has on-island oncology services. Cancer risk factors such as obesity, tobacco, and Hepatitis B are prevalent. Twelve years of nuclear testing in the RMI adds to the cancer burden. A community-based, multi-national coalition with multi-system external partners the Pacific Regional Cancer Control Partnership (PRCP) was developed to address cancer prevention and control in the USAPIJ. Through the PRCP, local cancer coalitions, a regional cancer registry, 12 years of regional cancer control plans, and cancer prevention programs and research has been implemented. Methods: The PRCP is the subject of this community case study. The PRCP is analyzed through a socio-ecological theoretical framework to contextualize its typology, building blocks, and management. The respective roles and work of each partner and organization will be described and aligned with the levels of the socio-ecological framework. Results: The USAPIJs evolved a community-focused internal and external regional cancer prevention and control network over 20 years. The function and structure of the PRCP fits within a socio ecological framework for cancer control. An adaptive management strategy has been used within the PRCP to manage its multi-national, multi-level, and multi-system partners. Conclusion: The PRCP has been able to advance cancer prevention and control programs with a community-centric model that functions in a multi national, multi-cultural, low-resource, geographically dispersed environment over the last 20 years. The PRCP operates with a structure and management style that is consistent with a socio-ecological framework for cancer control. This case study provides a blueprint for the PRCP organizational structure and a mechanism for its function. The PRCP concept, a community-centric model for cancer control in multi-national resource-limited environments, may be scaled to other global environments. PMID- 30483489 TI - Exploring the Role of Sex and Sexual Experience in Predicting American Indian Adolescent Condom Use Intention Using Protection Motivation Theory. AB - Introduction: American Indian (AI) youth experience poor sexual health outcomes. Research indicates the Protection Motivation Theory (PMT) is a robust model for understanding how sexual risk and protective behaviors are associated with condom use intention (CUI). Studies indicate the constructs of the PMT which influence CUI vary by sex and sexual experience. This analysis explores associations between PMT constructs and CUI by sex and sexual experience among AI youth who participated in the Respecting the Circle of Life (RCL) trial, a sexual and reproductive health intervention. Methods: We analyzed baseline data from the sample of 267 AIs, ages 13-19, who participated in the evaluation. We examined CUI and PMT construct scores by sex and sexual experience utilizing generalized estimated equations and multiple regression models to test which PMT constructs were associated with CUI across sex and sexual experience. Results: Twenty-two percentage of participants were sexually experienced; 56.8% reported CUI at baseline. We found several differences in scores in PMT constructs by sex and sexual experience including self-efficacy, response efficacy, vulnerability, severity, and extrinsic rewards. We also found constructs varied that were associated with CUI varied across sex and sexual experience. No PMT constructs were associated with CUI among sexually experienced youth. Conclusion: Results provide support for developing, selecting and delivering sexual health programs by sex and sexual experience in American Indian communities. Girls programs should focus on internal satisfaction and self-worth while boys should focus on negative impacts of not using condoms. Programs for youth who are not sexually active should focus on negative impacts of not using condoms. Programs for sexually inactive youth should work to change peer norms around condom use and improve knowledge about the efficacy of condom use. PMID- 30483490 TI - The Associations Between Cultural Identity and Mental Health Outcomes for Indigenous Maori Youth in New Zealand. AB - Objectives: To explore the relationships between Maori cultural identity, ethnic discrimination and mental health outcomes for Maori youth in New Zealand. Study Design: Nationally representative, anonymous cross-sectional study of New Zealand secondary school students in 2012. Methods: Secondary analysis of Maori students (n = 1699) from the national Youth'12 secondary school students survey was undertaken. Theoretical development and exploratory factor analysis were undertaken to develop a 14-item Maori Cultural Identity Scale (MCIS). Maori students reporting > 8 items were classified as having a strong MCIS. Prevalence of indicators were reported and logistic regression models were used to explore how wellbeing (WHO-5), depressive symptoms (Reynolds Adolescent Depression Scale SF), and suicide attempts were associated with the MCIS. Results: After adjusting for age, sex, ethnic discrimination and NZ Deprivation Index (NZDep), a strong Maori cultural identity (MCIS) was associated with improved wellbeing scores (OR 1.53, 95% CI 1.18-2.01) and fewer depressive symptoms (OR 0.53, 95% CI 0.38 0.73). Experiencing discrimination was associated with poorer wellbeing scores (OR 0.50, 95% CI 0.39-0.65), greater depressive symptoms (OR 2.2, 95% CI 1.55 3.18), and a previous suicide attempt (OR 2.47, 95% CI 1.71-3.58). Females less frequently reported good (WHO-5) wellbeing (OR 0.33, 95% CI 0.26-0.42), increased (RADS-SF) depressive symptoms (2.61, 95% CI 1.86-3.64) and increased suicide attempts [OR 3.35 (2.07-5.41)] compared to males. Wellbeing, depressive symptoms and suicide attempts did not differ by age or neighborhood level socio-economic deprivation, except those living in neighborhoods characterized as having medium level incomes, were less likely to have made a suicide attempt (OR 0.49, 95% CI 0.27-0.91). Conclusions: Maori youth who have a strong cultural identity were more likely to experience good mental health outcomes. Discrimination has a serious negative impact on Maori youth mental health. Our findings suggest that programmes, policies and practice that promote strong cultural identities and eliminate ethnic discrimination are required to improve mental health equity for Maori youth. PMID- 30483491 TI - Local Organizations Supporting Implementation of Graphic Health Warnings for Tobacco in Underserved Communities: A Qualitative Inquiry. AB - Background: Graphic health warnings (GHWs) on cigarette packages offer the potential to support tobacco cessation and prevention of initiation. Guidance for supporting implementation at the local level is limited, which can lead to missed opportunities to amplify the health impact of GHWs. This study examines the potential for local organizations engaged in tobacco control in underserved communities to support GHW implementation. Materials and Methods: Key informant interviews were conducted with 20 leaders in the three partner communities of Boston, Lawrence, and Worcester, Massachusetts. Data were analyzed using a combination of inductive and deductive methods, grounded in a framework analysis approach. Results: First, participants expected local organizations to play a diverse range of roles to support GHW policy implementation, ranging from convening local actors to offering complementary health education activities. Second, there is a need for external agencies to actively support local organizations during the pre-implementation and implementation phases, e.g., by engaging local organizations and providing resources and technical assistance. Finally, participants noted concerns about potential disconnects between the GHWs and the needs of underserved populations. Discussion: With the necessary supports, local community organizations can be important implementation partners to maximize the impact of GHWs and ensure that benefits accrue to members of underserved communities. PMID- 30483492 TI - Traditional Calibration Methods in Atomic Spectrometry and New Calibration Strategies for Inductively Coupled Plasma Mass Spectrometry. AB - Applications, advantages, and limitations of the traditional external standard calibration, matrix-matched calibration, internal standardization, and standard additions, as well as the non-traditional interference standard method, standard dilution analysis, multi-isotope calibration, and multispecies calibration methods are discussed. PMID- 30483493 TI - Water-Tolerant Trifloaluminate Ionic Liquids: New and Unique Lewis Acidic Catalysts for the Synthesis of Chromane. AB - The first example of triflometallate ionic liquids, named in analogy to chlorometallate ionic liquids, is reported. Trifloaluminate ionic liquids, synthesized from 1-alkyl-3-methylimidazolium triflates and aluminum triflate, were characterized by multinuclear NMR spectroscopy and FT-IR spectroscopy, revealing the existence of oligonuclear, multiply-charged trifloaluminate anions, with multiple bridging triflate modes. Acceptor numbers were determined to quantify their Lewis acidity, rendering trifloaluminate ionic liquids as medium strength Lewis acids (AN = ca. 65). Used as acidic catalysts in the cycloaddition of 2,4-dimethylphenol and isoprene (molar ratio 2:1) to prepare chromane, trifloaluminate systems outperformed literature systems, showing high activity (conversions 94-99%, selectivities 80-89%) and at low loadings (0.2 mol%) at 35 degrees C. Using these new systems as supported ionic liquid phase (SILP) on multi-walled carbon nanotubes (ionic liquid loading 16 wt%) delivered a recyclable catalytic system, with activity enhanced with respect to the homogenous regime. PMID- 30483494 TI - Anomalous Lattice Dynamics in AgC4N3: Insights From Inelastic Neutron Scattering and Density Functional Calculations. AB - We have performed temperature dependent inelastic neutron scattering measurements to study the anharmonicity of phonon spectra of AgC4N3. The analysis and interpretation of the experimental spectra is done using ab-initio lattice dynamics calculations. The calculated phonon spectrum over the entire Brillouin zone is used to derive linear thermal expansion coefficients. The effect of van der Waals interaction on structure stability has been investigated using advanced density functional methods. The calculated isothermal equation of states implies a negative linear compressibility along the c-axis of the crystal, which also leads to a negative thermal expansion along this direction. The role of elastic properties inducing the observed anomalous lattice behavior is discussed. PMID- 30483495 TI - Facile Preparation of Stereoblock PLA From Ring-Opening Polymerization of rac Lactide by a Synergetic Binary Catalytic System Containing Ureas and Alkoxides. AB - Ring-opening polymerization (ROP) of cyclic esters/lactones by efficient catalysts is a powerful method for synthesis of biodegradable and biocompatible polyesters with well-defined structures. To develop catalytic systems that are fast, selective and controlled is a persistent effort of chemists. In this contribution, we report a binary urea/alkoxide catalytic system that could catalyze ROP of rac-LA in a fast (over 90% conversion within 1-2 min), stereoselective (P i up to 0.93) and controlled manner, indicated by narrow MW distributions, linear relationship between the monomer conversions and M ns, end group fidelity, and chain extension experiments. Remarkably, the catalytic system described here is simple, easily prepared, and structurally tunable and thus has versatile catalytic performances. PMID- 30483496 TI - Ion Selectivity and Stability Enhancement of SPEEK/Lignin Membrane for Vanadium Redox Flow Battery: The Degree of Sulfonation Effect. AB - A membrane of high ion selectivity, high stability, and low cost is desirable for vanadium redox flow battery (VRB). In this study, a composite membrane is formed by blending the sulfonated poly (ether ether ketone) with lignin (SPEEK/lignin), and optimized by tailoring the degree of sulfonation. The incorporation of lignin into the SPEEK matrix provides more proton transport pathway and meanwhile adjusts the water channel to repulse vanadium ions. The VRB cells assembled with the composite membranes exhibit high coulombic efficiency (~99.27%) and impressive energy efficiency (~82.75%). The cells maintain a discharge capacity of ~95% after 100 cycles and ~85% after 200 cycles at 120 mA cm-2, much higher than the commercial Nafion 212. The SPEEK/lignin composite membranes are promising for application in VRB system. PMID- 30483497 TI - Field-Induced Dysprosium Single-Molecule Magnet Based on a Redox-Active Fused 1,10-Phenanthroline-Tetrathiafulvalene-1,10-Phenanthroline Bridging Triad. AB - Tetrathiafulvalene and 1,10-phenanthroline moieties present, respectively remarkable redox-active and complexation activities. In this work, we investigated the coordination reaction between the bis(1,10-phenanthro[5,6 b])tetrathiafulvalene triad (L) and the Dy(hfac)3.2H2O metallo precursor. The resulting {[Dy2(hfac)6(L)].CH2Cl2.C6H14}3 (1) dinuclear complex showed a crystal structure in which the triad L bridged two terminal Dy(hfac)3 units and the supramolecular co-planar arrangement of the triads is driven by donor-acceptor interactions. The frequency dependence of the out-of-phase component of the magnetic susceptibility highlights three distinct maxima under a 2000 Oe static applied magnetic field, a sign that 1 displays a Single-Molecule Magnet (SMM) behavior with multiple magnetic relaxations. Ab initio calculations rationalized the Ising character of the magnetic anisotropy of the DyIII ions and showed that the main anisotropy axes are perpendicular to the co-planar arrangement of the triads. Single-crystal rotating magnetometry confirms the orientation of the main magnetic axis. Finally combining structural analysis and probability of magnetic relaxation pathways through Quantum Tunneling of the Magnetization (QTM) vs. excited states (Orbach), each DyIII center has been attributed to one of the three observed magnetic relaxation times. Such coordination compound can be considered as an ideal candidate to perform redox-magnetic switching. PMID- 30483499 TI - Enhanced Metabolite Productivity of Escherichia coli Adapted to Glucose M9 Minimal Medium. AB - High productivity of biotechnological strains is important to industrial fermentation processes and can be constrained by precursor availability and substrate uptake rate. Adaptive laboratory evolution (ALE) of Escherichia coli MG1655 to glucose minimal M9 medium has been shown to increase strain fitness, mainly through a key mutation in the transcriptional regulator rpoB, which increases flux through central carbon metabolism and the glucose uptake rate. We wanted to test the hypothesis that a substrate uptake enhancing rpoB mutation can translate to increased productivity in a strain possessing a heterologous metabolite pathway. When engineered for heterologous mevalonate production, we found that E. coli rpoB E672K strains displayed 114-167% higher glucose uptake rates and 48-77% higher mevalonate productivities in glucose minimal M9 medium. This improvement in heterologous mevalonate productivity of the rpoB E672K strain is likely mediated by the elevated glucose uptake rate of such strains, which favors overflow metabolism toward acetate production and availability of acetyl CoA as precursor. These results demonstrate the utility of adaptive laboratory evolution (ALE) to generate a platform strain for an increased production rate for a heterologous product. PMID- 30483498 TI - Computational Modeling and Reverse Engineering to Reveal Dominant Regulatory Interactions Controlling Osteochondral Differentiation: Potential for Regenerative Medicine. AB - The specialization of cartilage cells, or chondrogenic differentiation, is an intricate and meticulously regulated process that plays a vital role in both bone formation and cartilage regeneration. Understanding the molecular regulation of this process might help to identify key regulatory factors that can serve as potential therapeutic targets, or that might improve the development of qualitative and robust skeletal tissue engineering approaches. However, each gene involved in this process is influenced by a myriad of feedback mechanisms that keep its expression in a desirable range, making the prediction of what will happen if one of these genes defaults or is targeted with drugs, challenging. Computer modeling provides a tool to simulate this intricate interplay from a network perspective. This paper aims to give an overview of the current methodologies employed to analyze cell differentiation in the context of skeletal tissue engineering in general and osteochondral differentiation in particular. In network modeling, a network can either be derived from mechanisms and pathways that have been reported in the literature (knowledge-based approach) or it can be inferred directly from the data (data-driven approach). Combinatory approaches allow further optimization of the network. Once a network is established, several modeling technologies are available to interpret dynamically the relationships that have been put forward in the network graph (implication of the activation or inhibition of certain pathways on the evolution of the system over time) and to simulate the possible outcomes of the established network such as a given cell state. This review provides for each of the aforementioned steps (building, optimizing, and modeling the network) a brief theoretical perspective, followed by a concise overview of published works, focusing solely on applications related to cell fate decisions, cartilage differentiation and growth plate biology. Particular attention is paid to an in-house developed example of gene regulatory network modeling of growth plate chondrocyte differentiation as all the aforementioned steps can be illustrated. In summary, this paper discusses and explores a series of tools that form a first step toward a rigorous and systems level modeling of osteochondral differentiation in the context of regenerative medicine. PMID- 30483500 TI - Investigating the Effect of Selected Non-Saccharomyces Species on Wine Ecosystem Function and Major Volatiles. AB - Natural alcoholic fermentation is initiated by a diverse population of several non-Saccharomyces yeast species. However, most of the species progressively die off, leaving only a few strongly fermentative species, mainly Saccharomyces cerevisiae. The relative performance of each yeast species is dependent on its fermentation capacity, initial cell density, ecological interactions as well as tolerance to environmental factors. However, the fundamental rules underlying the working of the wine ecosystem are not fully understood. Here we use variation in cell density as a tool to evaluate the impact of individual non-Saccharomyces wine yeast species on fermentation kinetics and population dynamics of a multi species yeast consortium in synthetic grape juice fermentation. Furthermore, the impact of individual species on aromatic properties of wine was investigated, using Gas Chromatography-Flame Ionization Detector. Fermentation kinetics was affected by the inoculation treatment. The results show that some non Saccharomyces species support or inhibit the growth of other non-Saccharomyces species in the multi-species consortium. Overall, the fermentation inoculated with a high cell density of Starmerella bacillaris displayed the fastest fermentation kinetics while fermentation inoculated with Hanseniaspora vineae showed the slowest kinetics. The production of major volatiles was strongly affected by the treatments, and the aromatic signature could in some cases be linked to specific non-Saccharomyces species. In particular, Wickerhamomyces anomalus at high cell density contributed to elevated levels of 2-Phenylethan-1 ol whereas Starm. bacillaris at high cell density resulted in the high production of 2-methylpropanoic acid and 3-Hydroxybutanone. The data revealed possible direct and indirect influences of individual non-Saccharomyces species within a complex consortium, on wine chemical composition. PMID- 30483504 TI - Editorial: Molecular Mechanisms of Proteinuria. PMID- 30483501 TI - Selective Autophagy and Xenophagy in Infection and Disease. AB - Autophagy, a cellular homeostatic process, which ensures cellular survival under various stress conditions, has catapulted to the forefront of innate defense mechanisms during intracellular infections. The ability of autophagy to tag and target intracellular pathogens toward lysosomal degradation is central to this key defense function. However, studies involving the role and regulation of autophagy during intracellular infections largely tend to ignore the housekeeping function of autophagy. A growing number of evidences now suggest that the housekeeping function of autophagy, rather than the direct pathogen degradation function, may play a decisive role to determine the outcome of infection and immunological balance. We discuss herein the studies that establish the homeostatic and anti-inflammatory function of autophagy, as well as role of bacterial effectors in modulating and coopting these functions. Given that the core autophagy machinery remains largely the same across diverse cargos, how selectivity plays out during intracellular infection remains intriguing. We explore here, the contrasting role of autophagy adaptors being both selective as well as pleotropic in functions and discuss whether E3 ligases could bring in the specificity to cargo selectivity. PMID- 30483505 TI - Effect of Bronchoscopy on Gas Exchange and Respiratory Mechanics in Critically Ill Patients With Atelectasis: An Observational Cohort Study. AB - Background: Atelectasis frequently develops in critically ill patients and may result in impaired gas exchange among other complications. The long-term effects of bronchoscopy on gas exchange and the effects on respiratory mechanics are largely unknown. Objective: To evaluate the effect of bronchoscopy on gas exchange and respiratory mechanics in intensive care unit (ICU) patients with atelectasis. Methods: A retrospective, single-center cohort study of patients with clinical indication for bronchoscopy because of atelectasis diagnosed on chest X-ray (CXR). Results: In total, 101 bronchoscopies were performed in 88 ICU patients. Bronchoscopy improved oxygenation (defined as an increase of PaO2/FiO2 ratio > 20 mmHg) and ventilation (defined as a decrease of > 2 mmHg in partial pressure of CO2 in arterial blood) in 76 and 59% of procedures, respectively, for at least 24 h. Patients with a low baseline value of PaO2/FiO2 ratio and a high baseline value of PaCO2 were most likely to benefit from bronchoscopy. In addition, in intubated and pressure control ventilated patients, respiratory mechanics improved after bronchoscopy for up to 24 h. Mild complications, and in particular desaturation between 80 and 90%, were reported in 13% of the patients. Conclusions: In selected critically ill patients with atelectasis, bronchoscopy improves oxygenation, ventilation, and respiratory mechanics for at least 24 h. PMID- 30483502 TI - Role of Metabolism in Hepatic Stellate Cell Activation and Fibrogenesis. AB - Activation of hepatic stellate cell (HSC) involves the transition from a quiescent to a proliferative, migratory, and fibrogenic phenotype (i.e., myofibroblast), which is characteristic of liver fibrogenesis. Multiple cellular and molecular signals which contribute to HSC activation have been identified. This review specially focuses on the metabolic changes which impact on HSC activation and fibrogenesis. PMID- 30483503 TI - Emerging Roles of Cellular Metabolism in Regulating Dendritic Cell Subsets and Function. AB - Dendritic cells (DCs) are the bridge between innate and T cell-dependent adaptive immunity and are promising therapeutic targets for cancer and immune-mediated disorders. Upon stimulation by pathogen or danger-sensing receptors, DCs become activated and poised to induce T cell priming. Recent studies have identified critical roles of metabolic pathways, including glycolysis, oxidative phosphorylation, and fatty acid metabolism, in orchestrating DC function. In this review, we discuss the shared and distinct metabolic programs shaping the functional specification of different DC subsets, including conventional DCs, bone marrow-derived DCs, and plasmacytoid DCs. We also briefly discuss the signaling networks that tune metabolic programs in DC subsets. PMID- 30483506 TI - Macrophage Exposure to Polycyclic Aromatic Hydrocarbons From Wood Smoke Reduces the Ability to Control Growth of Mycobacterium tuberculosis. AB - Use of solid fuels for cooking or home heating has been related to various diseases of the respiratory tract. Woodsmoke contains a mixture of carcinogenic polycyclic aromatic hydrocarbons (PAHs) and volatile organic compounds. Inhalation of these materials induces local and systemic changes in the immune system which may impair critical cell defense mechanisms; however, few studies have investigated the early effects that PAH exposures have on immune cells as macrophages. The aim of this study was to analyze if the pre-exposure to PAHs derived from woodsmoke deteriorates macrophage ability to control the intracellular growth of Mycobacterium tuberculosis. By using an in vitro experimental model, we analyzed the phenotype and some metabolic changes on THP-1 and monocyte-derived macrophages. Our results demonstrated that exposure to PAHs leads to cell activation and deteriorates mitochondrial function of the macrophage thus facilitating growth of M. tuberculosis. PMID- 30483507 TI - Publications Are Not the Finish Line: Focusing on Societal Rather Than Publication Impact. PMID- 30483509 TI - Editorial: Intestinal Inflammation. PMID- 30483511 TI - The Impact of Manuscript Learning vs. Video Learning on a Surgeon's Confidence in Performing a Difficult Procedure. AB - Introduction: Operative surgical videos are a popular educational resource, not commonly a part of a peer-reviewed article. We wanted to evaluate the impact of either reading a peer-reviewed manuscript or watching an operative video on a surgeon's confidence in performing a complex case. Methods: Pediatric surgeons and fellows were asked to complete an initial questionnaire to assess their confidence (formulated as a score) in the diagnosis and operative repair of anal stenosis and rectal atresia. Results: Of 101 pediatric surgeons and fellows, 52 (51%) were randomized into a "manuscript" group and 49 (49%) into a "video" group. The mean confidence before the intervention was the same in the two groups (6.4 vs. 6.6). Attending surgeons started with more confidence than trainees (7.1 vs. 5.3, p < 0.001). In the manuscript group, the average confidence increased to 7.7 (p = 0.005), and in the video group the average confidence increased to 7.9 (p = 0.001) globally. Trainees in the video group significantly improved their confidence to a score of 6.6 (p = 0.035), as did attending surgeons to 8.5 (p = 0.01). In the manuscript group, only attendings significantly improved their confidence by 1.5-8.3 (p < 0.001), whereas trainees did not with a difference of 1.3 (p = 0.194). When considering experience level, physicians who reported never having performed this surgery improved only by reading the manuscript (3.9-6.2) (p = 0.004), not by watching the video (5.4-6.6) (p = 0.106). Surgeons with experience doing this operation (>5 times) did not improve their confidence by reading the manuscript (p = 0.10), nor by watching the video (p = 0.112). Conclusion: Reviewing either a detailed manuscript or operative video on the surgical management of rectal atresia and anal stenosis demonstrated a significant increase in self-reported confidence. Trainees benefitted the most from operative videos, whereas experienced surgeons did not improve their confidence by reading the manuscript nor watching the video. PMID- 30483508 TI - The Platelet Response to Tissue Injury. AB - In recent years, various studies have increasingly explained platelet functions not only in their central role as a regulator in cellular hemostasis and coagulation. In fact, there is growing evidence that under specific conditions, platelets act as a mediator between the vascular system, hemostasis, and the immune system. Therefore, they are essential in many processes involved in tissue remodeling and tissue reorganization after injury or inflammatory responses. These processes include the promotion of inflammatory processes, the contribution to innate and adaptive immune responses during bacterial and viral infections, the modulation of angiogenesis, and the regulation of cell apoptosis in steady state tissue homeostasis or after tissue breakdown. All in all platelets may contribute to the control of tissue homeostasis much more than generally assumed. This review summarizes the current knowledge of platelets as part of the tissue remodeling network and seeks to provide possible translational implications for clinical therapy. PMID- 30483510 TI - The Failure to Measure Dietary Intake Engendered a Fictional Discourse on Diet Disease Relations. AB - Controversies regarding the putative health effects of dietary sugar, salt, fat, and cholesterol are not driven by legitimate differences in scientific inference from valid evidence, but by a fictional discourse on diet-disease relations driven by decades of deeply flawed and demonstrably misleading epidemiologic research. Over the past 60 years, epidemiologists published tens of thousands of reports asserting that dietary intake was a major contributing factor to chronic non-communicable diseases despite the fact that epidemiologic methods do not measure dietary intake. In lieu of measuring actual dietary intake, epidemiologists collected millions of unverified verbal and textual reports of memories of perceptions of dietary intake. Given that actual dietary intake and reported memories of perceptions of intake are not in the same ontological category, epidemiologists committed the logical fallacy of "Misplaced Concreteness." This error was exacerbated when the anecdotal (self-reported) data were impermissibly transformed (i.e., pseudo-quantified) into proxy-estimates of nutrient and caloric consumption via the assignment of "reference" values from databases of questionable validity and comprehensiveness. These errors were further compounded when statistical analyses of diet-disease relations were performed using the pseudo-quantified anecdotal data. These fatal measurement, analytic, and inferential flaws were obscured when epidemiologists failed to cite decades of research demonstrating that the proxy-estimates they created were often physiologically implausible (i.e., meaningless) and had no verifiable quantitative relation to the actual nutrient or caloric consumption of participants. In this critical analysis, we present substantial evidence to support our contention that current controversies and public confusion regarding diet-disease relations were generated by tens of thousands of deeply flawed, demonstrably misleading, and pseudoscientific epidemiologic reports. We challenge the field of nutrition to regain lost credibility by acknowledging the empirical and theoretical refutations of their memory-based methods and ensure that rigorous (objective) scientific methods are used to study the role of diet in chronic disease. PMID- 30483513 TI - How Important Is Protein Diffusion in Prokaryotes? AB - That diffusion is important for the proper functioning of cells is without question. The extent to which the diffusion coefficient is important is explored here for prokaryotic cells. We discuss the principles of diffusion focusing on diffusion-limited reactions, summarize the known values for diffusion coefficients in prokaryotes and in in vitro model systems, and explain a number of cases where diffusion coefficients are either limiting for reaction rates or necessary for the existence of phenomena. We suggest a number of areas that need further study including expanding the range of organism growth temperatures, direct measurements of diffusion limitation, expanding the range of cell sizes, diffusion limitation for membrane proteins, and taking into account cellular context when assessing the possibility of diffusion limitation. PMID- 30483512 TI - The PII-NAGK-PipX-NtcA Regulatory Axis of Cyanobacteria: A Tale of Changing Partners, Allosteric Effectors and Non-covalent Interactions. AB - PII, a homotrimeric very ancient and highly widespread (bacteria, archaea, plants) key sensor-transducer protein, conveys signals of abundance or poorness of carbon, energy and usable nitrogen, converting these signals into changes in the activities of channels, enzymes, or of gene expression. PII sensing is mediated by the PII allosteric effectors ATP, ADP (and, in some organisms, AMP), 2-oxoglutarate (2OG; it reflects carbon abundance and nitrogen scarcity) and, in many plants, L-glutamine. Cyanobacteria have been crucial for clarification of the structural bases of PII function and regulation. They are the subject of this review because the information gathered on them provides an overall structure based view of a PII regulatory network. Studies on these organisms yielded a first structure of a PII complex with an enzyme, (N-acetyl-Lglutamate kinase, NAGK), deciphering how PII can cause enzyme activation, and how it promotes nitrogen stockpiling as arginine in cyanobacteria and plants. They have also revealed the first clear-cut mechanism by which PII can control gene expression. A small adaptor protein, PipX, is sequestered by PII when nitrogen is abundant and is released when is scarce, swapping partner by binding to the 2OG-activated transcriptional regulator NtcA, co-activating it. The structures of PII-NAGK, PII PipX, PipX alone, of NtcA in inactive and 2OG-activated forms and as NtcA-2OG PipX complex, explain structurally PII regulatory functions and reveal the changing shapes and interactions of the T-loops of PII depending on the partner and on the allosteric effectors bound to PII. Cyanobacterial studies have also revealed that in the PII-PipX complex PipX binds an additional transcriptional factor, PlmA, thus possibly expanding PipX roles beyond NtcA-dependency. Further exploration of these roles has revealed a functional interaction of PipX with PipY, a pyridoxal-phosphate (PLP) protein involved in PLP homeostasis whose mutations in the human ortholog cause epilepsy. Knowledge of cellular levels of the different components of this PII-PipX regulatory network and of KD values for some of the complexes provides the basic background for gross modeling of the system at high and low nitrogen abundance. The cyanobacterial network can guide searches for analogous components in other organisms, particularly of PipX functional analogs. PMID- 30483514 TI - Conformational Change Induced by Putidaredoxin Binding to Ferrous CO-ligated Cytochrome P450cam Characterized by 2D IR Spectroscopy. AB - The importance of conformational dynamics to protein function is now well appreciated. An outstanding question is whether they are involved in the effector role played by putidaredoxin (Pdx) in its reduction of the O2 complex of cytochrome P450cam (P450cam), an archetypical member of the cytochrome P450 superfamily. Recent studies have reported that binding of Pdx induces a conformational change from a closed to an open state of ferric P450cam, but a similar conformational change does not appear to occur for the ferrous, CO ligated enzyme. To better understand the effector role of Pdx when binding the ferrous, CO-ligated P450cam, we applied 2D IR spectroscopy to compare the conformations and dynamics of the wild-type (wt) enzyme in the absence and presence of Pdx, as well as of L358P P450cam (L358P), which has served as a putative model for the Pdx complex. The CO vibrations of the Pdx complex and L358P report population of two conformational states in which the CO experiences distinct environments. The dynamics among the CO frequencies indicate that the energy landscape of substates within one conformation are reflective of the closed state of P450cam, and for the other conformation, differ from the free wt enzyme, but are equivalent between the Pdx complex and L358P. The two states co populated by the Pdx complex are postulated to reflect a loosely bound encounter complex and a more tightly bound state, as is commonly observed for the dynamic complexes of redox partners. Significantly, this study shows that the binding of Pdx to ferrous, CO-ligated P450cam does perturb the conformational ensemble in a way that might underlie the effector role of Pdx. PMID- 30483516 TI - Roll-Back Eradication of Bovine Tuberculosis (TB) From Wildlife in New Zealand: Concepts, Evolving Approaches, and Progress. AB - The New Zealand government and agricultural industries recently jointly adopted the goal of nationally eradicating bovine tuberculosis (TB) from livestock and wildlife reservoirs by 2055. Only Australia has eradicated TB from a wildlife maintenance host. Elsewhere the disease is often self-sustaining in a variety of wildlife hosts, usually making eradication an intractable problem. The New Zealand strategy for eradicating TB from wildlife is based on quantitative assessment using a Bayesian "Proof of Freedom" framework. This is used to assess the probability that TB has been locally eradicated from a given area. Here we describe the framework (the concepts, methods and tools used to assess TB freedom and how they are being applied and updated). We then summarize recent decision theory research aimed at optimizing the balance between the risk of falsely declaring areas free and the risk of overspending on disease management when the disease is already locally extinct. We explore potential new approaches for further optimizing the allocation of management resources, especially for places where existing methods are impractical or expensive, including using livestock as sentinels. We also describe how the progressive roll-back of locally eradicated areas scales up operationally and quantitatively to achieve and confirm eradication success over the entire country. Lastly, we review the progress made since the framework was first formally adopted in 2011. We conclude that eradication of TB from New Zealand is feasible, and that we are well on the way to achieving this outcome. PMID- 30483515 TI - The Hypervariable Loops of Free TCRs Sample Multiple Distinct Metastable Conformations in Solution. AB - CD4+ and CD8+ alphabeta T cell antigen recognition is determined by the interaction between the TCR Complementarity Determining Region (CDR) loops and the peptide-presenting MHC complex. These T cells are known for their ability to recognize multiple pMHC complexes, and for a necessary promiscuity that is required for their selection and function in the periphery. Crystallographic studies have previously elucidated the role of structural interactions in TCR engagement, but our understanding of the dynamic process that occurs during TCR binding is limited. To better understand the dynamic states that exist for TCR CDR loops in solution, and how this relates to their states when in complex with pMHC, we simulated the 2C T cell receptor in solution using all-atom molecular dynamics in explicit water and constructed a Markov State Model for each of the CDR3alpha and CDR3beta loops. These models reveal multiple metastable states for the CDR3 loops in solution. Simulation data and metastable states reproduce known CDR3beta crystal conformations, and reveal several novel conformations suggesting that CDR3beta bound states are the result of search processes from nearby pre existing equilibrium conformational states. Similar simulations of the invariant, Type I Natural Killer T cell receptor NKT15, which engages the monomorphic, MHC like CD1d ligand, demonstrate that iNKT TCRs also have distinct states, but comparatively restricted degrees of motion. PMID- 30483517 TI - Hypocoagulability and Platelet Dysfunction Are Exacerbated by Synthetic Colloids in a Canine Hemorrhagic Shock Model. AB - Background: Hemorrhagic shock and volume replacement can alter coagulation. Synthetic colloids, hydroxyethyl starch (HES), and gelatin, may enhance hypocoagulability. Our primary objective was to describe the effect of four fluid products on coagulation in canine hemorrhagic shock. Our secondary objective was to compare measurements of coagulation during shock to baseline in all dogs. Methods: Anesthetized greyhounds subjected to atraumatic hemorrhage for 60 min were administered 20 mL kg-1 of either fresh whole blood (FWB), 6% HES 130/0.4, 4% succinylated gelatin (GELO), or 80 mL kg-1 of isotonic crystalloid over 20 min (n = 6 per group). Platelet closure time (PCT), rotational thromboelastometry (ROTEM) and plasma coagulation assays were measured at baseline, end of hemorrhage (shock), and 40 (T60), and 160 (T180) min after study fluid. ROTEM parameters included clotting time (CT), clot formation time (CFT), alpha angle, maximum clot firmness (MCF), lysis index at 60 min (LI60), and thrombodynamic potential index (TPI) for INTEM, EXTEM, FIBTEM (MCF only), and APTEM (LI60 only) profiles. Plasma coagulation assays included prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen concentration and activities of factor VII (FVII), factor VIII (FVIII), and von Willebrand Factor antigen (vWF). Between-group differences were tested using linear mixed models with post-hoc between-group comparisons (Bonferroni-Holm corrected). Differences between baseline and shock were tested using paired t-tests. Significance was set at P < 0.05. Results: GELO showed longer PCT at T60, compared with FWB and CRYST, and at T180, compared with all other groups. HES showed longer EXTEM CT at T60, compared with all other groups. HES showed lower INTEM and EXTEM MCF at T60 and lower INTEM MCF at T180, compared with FWB. Some plasma coagulation assays showed greater hypocoagulability with HES. Comparing shock to baseline, EXTEM CT, INTEM CFT, EXTEM CFT, PT, and FVIII significantly increased and PCT, INTEM CT, INTEM MCF, EXTEM MCF, EXTEM LI60, EXTEM TPI, FIBTEM MCF, APTT, fibrinogen, FVII, and vWF significantly decreased. Conclusions: In dogs with hemorrhagic shock, volume replacement with GELO caused mild platelet dysfunction and HES was associated with coagulation changes consistent with hypocoagulability, beyond effects of hemodilution. Shock alone produced some evidence of hypocoagulability. PMID- 30483518 TI - Capsular Switching and ICE Transformation Occurred in Human Streptococcus agalactiae ST19 With High Pathogenicity to Fish. AB - Although Streptococcus agalactiae (GBS) cross-infection between human and fish has been confirmed in experimental and clinical studies, the mechanisms underlying GBS cross-species infection remain largely unclear. We have found different human GBS ST19 strains exhibiting strong or weak pathogenic to fish (sGBS and wGBS). In this study, our objective was to identify the genetic elements responsible for GBS cross species infection based on genome sequence data and comparative genomics. The genomes of 11 sGBS strains and 11 wGBS strains were sequenced, and the genomic analysis was performed base on pan-genome, CRISPRs, phylogenetic reconstruction and genome comparison. The results from the pan-genome, CRISPRs analysis and phylogenetic reconstruction indicated that genomes between sGBS were more conservative than that of wGBS. The genomic differences between sGBS and wGBS were primarily in the Cps region (about 111 kb) and its adjacent ICE region (about 106 kb). The Cps region included the entire cps operon, and all sGBS were capsular polysaccharide (CPS) type V, while all wGBS were CPS type III. The ICE region of sGBS contained integrative and conjugative elements (ICE) with IQ element and erm(TR), and was very conserved, whereas the ICE region of wGBS contained ICE with mega elements and the variation was large. The capsular switching (III-V) and transformation of ICE adjacent to the Cps region occurred in human GBS ST19 with different pathogenicity to fish, which may be related to the capability of GBS cross-infection. PMID- 30483519 TI - Protective roles of ginseng against bacterial infection. AB - Ginseng (Panax ginseng Meyer) is a well-known traditional herbal medicine that plays a protective role against microbial attack. Several studies have revealed its anti-cancer, anti-inflammatory, and immune-modulatory effects. Ginseng contains several components that vary according to the year of cultivation and the processing method used, such as heating, drying, and steaming, which induce different degrees of pharmacological activities. This review discusses the antibacterial effects of ginseng against pathogenic bacterial infections. We describe how ginseng regulates pathogenic factors that are harmful to the host and discuss the therapeutic potential of ginseng as a natural antibacterial drug to combat bacterial infectious disease, which is a global public health challenge. The components of ginseng could be novel alternatives to solve the growing problem of antibiotic resistance and toxicity. PMID- 30483521 TI - A chemical genetic screen reveals a role for proteostasis in capsule and biofilm formation by Cryptococcus neoformans. AB - Pathogenic microorganisms employ specialized virulence factors to cause disease. Biofilm formation and the production of a polysaccharide capsule are two important virulence factors in Cryptococcus neoformans, the fungal pathogen that causes meningoencephalitis. Here, we show that the bipolar disorder drug lithium inhibits formation of both virulence factors by a mechanism involving dysregulation of the ubiquitin/proteasome system. By using a chemical genetics approach and bioinformatic analyses, we describe the cellular landscape affected by lithium treatment. We demonstrate that lithium affects many different pathways in C. neoformans, including the cAMP/protein kinase A, inositol biosynthesis, and ubiquitin/proteasome pathways. By analyzing mutants with defects in the ubiquitin/proteasome system, we uncover a role for proteostasis in both capsule and biofilm formation. Moreover, we demonstrate an additive influence of lithium and the proteasome inhibitor bortezomib in inhibiting capsule production, thus establishing a link between lithium activity and the proteasome system. Finally, we show that the lithium-mimetic drug ebselen potently blocks capsule and biofilm formation, and has additive activity with lithium or bortezomib. In summary, our results illuminate the impact of lithium on C. neoformans, and link dysregulation of the proteasome to capsule and biofilm inhibition in this important fungal pathogen. PMID- 30483523 TI - A comparative approach to decipher intestinal animal-microbe associations. AB - Mammalian guts harbor indigenous microbes that are integral to host health. Microbiome research using sophisticated model organisms has provided insights into intricate interactions between microbiota and host animals. However, it remains unclear how these animal-microbe associations developed. We have recently addressed this question via comparative analyses of chordates, given that complex biological systems can be resolved into ancestral and derived elements when examined in an evolutionary framework (Nat Commun 9: 3402). Results support the view that microbial colonization of the mucus layer that overlies mammalian gastrointestinal epithelium was established upon loss of ancestral chitin-based barrier immunity. Comparative approaches enable us to arrange ongoing biological processes into host natural history for better understanding of intestinal animal microbe associations. PMID- 30483522 TI - Nutritional and meiotic induction of transiently heritable stress resistant states in budding yeast. AB - Transient exposures to environmental stresses induce altered physiological states in exposed cells that persist after the stresses have been removed. These states, referred to as cellular memory, can even be passed on to daughter cells and may thus be thought of as embodying a form of epigenetic inheritance. We find that meiotically produced spores in the budding yeast S. cerevisiae possess a state of heightened stress resistance that, following their germination, persists for numerous mitotic generations. As yeast meiotic development is essentially a starvation response that a/alpha diploid cells engage, we sought to model this phenomenon by subjecting haploid cells to starvation conditions. We find also that haploid cells exposed to glucose withdrawal acquire a state of elevated stress resistance that persists after the reintroduction of these cells to glucose-replete media. Following release from lengthy durations of glucose starvation, we confirm that this physiological state of enhanced stress resistance is propagated in descendants of the exposed cells through two mitotic divisions before fading from the population. In both haploid starved cells and diploid produced meiotic spores we show that their cellular memories are not attributable to trehalose, a widely regarded stress protectant that accumulates in these cell types. Moreover, the transiently heritable stress resistant state induced by glucose starvation in haploid cells is independent of the Msn2/4 transcription factors, which are known to program cellular memory induced by exposure of cells to NaCl. Our findings identify new developmentally and nutritionally induced states of cellular memory that exhibit striking degrees of persistence and mitotic heritability. PMID- 30483520 TI - Conventional and emerging roles of the energy sensor Snf1/AMPK in Saccharomyces cerevisiae. AB - All proliferating cells need to match metabolism, growth and cell cycle progression with nutrient availability to guarantee cell viability in spite of a changing environment. In yeast, a signaling pathway centered on the effector kinase Snf1 is required to adapt to nutrient limitation and to utilize alternative carbon sources, such as sucrose and ethanol. Snf1 shares evolutionary conserved functions with the AMP-activated Kinase (AMPK) in higher eukaryotes which, activated by energy depletion, stimulates catabolic processes and, at the same time, inhibits anabolism. Although the yeast Snf1 is best known for its role in responding to a number of stress factors, in addition to glucose limitation, new unconventional roles of Snf1 have recently emerged, even in glucose repressing and unstressed conditions. Here, we review and integrate available data on conventional and non-conventional functions of Snf1 to better understand the complexity of cellular physiology which controls energy homeostasis. PMID- 30483524 TI - JGH Open: The dawn of a new era in publishing! PMID- 30483525 TI - Positive relationship between infliximab and adalimumab trough levels at completion of induction therapy with clinical response rates, at a tertiary referral center. AB - Background and Aim: Anti-tumor necrosis factor alpha (TNFalpha) therapies have improved outcomes for patients with inflammatory bowel disease. The aim of this study was to explore the relationship between infliximab (IFX) and adalimumab (ADL) trough and antibody levels with clinical response rates at the end of induction. Methods: This was a prospective, single-center study. Patients were recruited from July 2015 to August 2016. Inclusion criteria were all inflammatory bowel disease patients older than 17 years who started treatment with IFX or ADL. Baseline clinical disease activity indexes were performed. Clinical response was defined as HBI <=3 or partial Mayo score <=4% or <30% reduction from baseline. Anti-TNFalpha trough and antibody levels were measured using standard ELISA techniques. Results: Thirty-five patients were recruited, of whom 23 had Crohn's disease and 12 had ulcerative colitis. Eighteen were treated with ADL and 17 with IFX. The mean age of the cohort was 40.3 years, 62.9% were females, 34.3% were on concomitant thiopurines, and 25.7% had prior anti-TNFalpha exposure. Overall response rate was 51.4%, 33.3% for ADL and 70.6% for IFX.Mean trough levels were 12.5 MUg/mL for IFX and 4.4 MUg/mL for ADL. There was a clear link between higher anti-TNFalpha trough levels at the end of induction with clinical response rates. For IFX, mean trough level was 16.4 MUg/mL for responders versus 5.3 MUg/mL for non-responders (P = 0.026). Area under the curve for association of IFX level at induction with clinical response was 0.864 (P = 0.0001). Similar link was present between higher ADL levels with clinical response, although not statistically significant. Conclusion: Higher trough levels at the end of induction are associated with improved response. Ongoing work will define optimal targets at this key timeframe. PMID- 30483526 TI - Comparing swallowing of capsule to endoscopic placement of capsule endoscopy in children. AB - Background and Aim: Capsule endoscopy (CE) offers a method of directly visualizing areas of the small bowel not accessible by conventional endoscopy. Some children are unable to swallow the capsule requiring endoscopic placement under general anesthesia. The aim of the present study was to identify any differences between children requiring endoscopic placement and those able to swallow the capsule. Methods: Retrospective chart review of consecutive CE in a tertiary pediatric center was conducted. Patient demographics, outcomes, and complications between the two groups were noted. Paired t-test comparing continuous variables and Fisher exact test for categorical data were used. Results: A total of 104 CEs were performed in 88 patients, median age 12.8 (range: 1.6-18.5) years. Almost half, 49% (51/104), swallowed the capsule. Children requiring endoscopic placement were significantly younger (9.8 vs 14.2 years; P < 0.001), lighter (34.5 vs 54.9 kg; P < 0.0001), and had longer small intestinal transit time (308 vs 229 min; P < 0.0001). Positive findings were more likely in those who swallowed the capsule (50% vs 30%, P = 0.017), likely a reflection of the indications for procedure. Poor views were found in 30% (16/53) of patients in the endoscopic placement group due to iatrogenic bleeding from biopsies taken from concurrent procedures but did not affect outcome or subsequent patient management. Conclusions: CE is safe and well tolerated in children. Children requiring endoscopic placement were significantly younger, lighter, had longer small intestine transit time, and less likely to have positive findings. Concurrent biopsies during capsule placement increase the likelihood of inadequate views but did not affect outcome or management. PMID- 30483527 TI - Impact of dietary beliefs and practices on patients with inflammatory bowel disease: An observational study from India. AB - Background and Aim: Patients with inflammatory bowel disease (IBD) are at a risk of nutritional deficits because of poor dietary beliefs and practices. There are no data on this aspect from Asia, which is experiencing a rise in IBD incidence. We aimed to establish dietary beliefs and practices in patients of IBD from India. Methods: Patients with ulcerative colitis (UC) and Crohn's disease (CD) followed up between November 2016 and March 2017 were included. A questionnaire extracted information on the patients' sociodemographic, nutritional and disease profile, smoking and drinking habits, dietary beliefs and practices, current dietary preferences, intake and avoidance, dietary changes made after diagnosis of IBD, dietary changes made during relapse, frequency of consumption of major food groups, and the attitudes toward dietary advice. Results: A total of 316 patients (218 UC and 98 CD; mean age: 38.5 +/- 12.2 years) were included. Forty four percent patients perceived food as a risk factor for IBD, 52% felt dietary habits to have a more important role than medicines in disease control, 77% reported certain foods improve symptoms during relapse, 86% had modified their diet since the diagnosis of IBD (UC > CD, P = 0.04), 90% imposed food restrictions, and <50% had received dietary counseling. About 40% of patients could not meet their dietary requirements and 66% had decreased their dietary intake since diagnosis, which further decreased during relapse (85%). Conclusion: Dietary beliefs and practices play a central role in perception of disease in IBD patients. A large majority of them make dietary changes which can lead to undernutrition. Proper dietary counseling is required in these patients to prevent malnutrition. PMID- 30483528 TI - Drug resistance in intestinal tuberculosis: A reason to worry? AB - Background and Aim: Emergence of drug resistance in intestinal tuberculosis (ITB) makes the treatment of this condition challenging. While there is growing evidence of multiple and extensive drug resistance in pulmonary and glandular tuberculosis (TB), literature regarding susceptibility and resistance patterns in ITB is scarce. The aim of the current paper was to study the prevalence of drug resistance in patients with ITB. Methods: Among patients presenting to a tertiary care hospital in Mumbai between 2008 and 2016, records of all patients with ITB, whose mucosal biopsy (obtained at ileocolonoscopy) tissue culture was positive for Mycobacterium tuberculosis and in whom drug sensitivity testing was performed, were retrospectively analyzed. Sensitivity and resistance to single or multiple anti-TB drugs were noted. Results: A total of 43 patients were included, of whom 10 (23.2%) patients were diagnosed to have resistance to at least one first-line anti-TB drug. Resistance to isoniazid was the most common (nine patients), followed by rifampicin (six), pyrazinamide (five), streptomycin and ethionamide (four each), ethambutol, moxifloxacin and ofloxacin (three each), and p-amino salicylic acid (one). Six patients (13.9%) had multidrug-resistant TB and needed second-line anti-TB therapy as per drug sensitivity pattern. There was no patient with extensive drug-resistant TB. Conclusion: Twenty-three percent of our patients with ITB tested for drug resistance had drug resistance, 13.9% being multidrug resistant and needing second-line anti-TB therapy. PMID- 30483529 TI - Thiopurine metabolite level and toxicity in Indians with inflammatory bowel disease. AB - Background and Aim: A lower dose requirement and higher toxicity of thiopurine is reported in Asian patients with inflammatory bowel disease (IBD) as compared with Caucasian patients. These reports are based on thiopurine methyltransferase measurement studies rather than metabolite estimation.We studied the utility of thiopurine metabolite estimation in Indian patients with IBD and compared dose and toxicity with Asian and Caucasian patients. Methods: In this prospective study, 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine levels were determined by HPLC in 76 IBD patients treated with thiopurines. The levels were correlated with dose, disease activity, and toxicity. The dose-related metabolite levels and toxicity were compared with Caucasian and Asian patients reported in literature. Results: Of the 76 patients (32 women, mean age: 35.9 [SD: 14.54] years, 36 Crohn's disease and 40 ulcerative colitis), 1 non-compliant patient had undetectable level of metabolites. Of the 75 patients, 21(28%) had therapeutic level of 6-TGN, 37(49%) had subtherapeutic level and 17(23%) had supratherapeutic level. The 6-methylmercaptopurine levels ranged up to 4971 pmol/8 * 108 red blood cells. Six (8%) patients showed toxicity. Thiopurine dose was optimized in 20 (26.31%) patients. Dose-based metabolite levels were comparable to Asian and Caucasian patients. The toxicity (8%) observed in our patients was less than that reported (12-39%). Conclusion: Half of the patients in this study had low and a quarter had high 6-TGN levels. One-fourth of the patients needed dose modification. The dose-based metabolite levels were comparable and the toxicity was less than that reported in Asian and Caucasian patients. PMID- 30483530 TI - Pulmonary function in patients with ulcerative colitis and its relationship with disease severity. AB - Background and Aim: Ulcerative colitis (UC) patients have several extraintestinal and systemic manifestations. As studies on the frequency and predictors of pulmonary involvement in patients with UC are inconsistent, we undertook this prospective study. Methods: Eighty-seven patients with UC (in remission 49, 56.3%, active disease 38, 43.6%, median age: 40 years, range: 16-66, 55, 62.2% males) and 50 healthy controls (median age: 38 years, range: 14-69, 34, 68% males) underwent pulmonary function tests (PFTs) including forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), Tiffeneau value (FEV1/FVC), mid-expiratory flow rate, and diffusion lung capacity for carbon monoxide with spirometer. Results: Subjects with UC and control were comparable in age and gender. PFT was abnormal in 24 (27.5%) patients (active disease 15/38, 39.4%, remission 9/49, 18.4%) and 1 (2%) control (P < 0.005). Of the 24 patients with abnormal PFT, small airway, restrictive, and obstructive defects were detected in 12 (50%), 11 (45.8%), and 1 (4.2%) patients, respectively. Patients with abnormal PFT more often had active disease (15/24, 62.5% vs 23/63, 36.5%; P = 0.03). No relation of PFT abnormalities was found with age, sex, duration of disease, body mass index, serum albumin, and hemoglobin levels, and other extraintestinal manifestation (arthritis/arthralgia) and drugs used to treat UC. Conclusion: UC patients with active disease have abnormal pulmonary functions with predominant involvement of small airways. Active UC was more often associated with abnormal PFT than the disease in remission. PMID- 30483531 TI - White Diet with split-dose Picosalax is preferred, better tolerated, and non inferior to day-before clear fluids with polyethylene glycol plus sodium picosulfate-magnesium citrate for morning colonoscopy: A randomized, non inferiority trial. AB - Background and Aim: Bowel preparations with polyethylene glycol (PEG) and clear fluids are often poorly tolerated. We compared an innovative low-residue White Diet and low-volume, split-dose Picosalax with the standard preparation at our institution of day-before clear fluids and combination PEG plus sodium picosulfate/magnesium citrate (SPMC). Methods: Adults undergoing morning colonoscopy were randomized to either the White Diet and split-dose, two sachets of Picosalax (WD/PICO) or day-before clear fluids and 1-L PEG plus two sachets of SPMC (CF/PEG + SPMC). The primary endpoint was successful bowel preparation defined by an Ottawa bowel preparation score <= 6. An intention-to-treat analysis with a predefined non-inferiority margin of 15% was used to compare efficacy. Results: A total of 250 patients were randomized (125 WD/PICO and 125 CF/PEG + SPMC). WD/PICO was non-inferior to CF/PEG + SPMC for successful bowel preparation by intention-to-treat analysis (58% WD/PICO vs 62% CF/PEG + SPMC, 95%CI: -14.2 to 6.2%) and per-protocol analysis (64% WD/PICO vs 65% CF/PEG + SPMC, 95%CI: -11.3 to 9.4%). Patients in the WD/PICO group reported greater satisfaction with the diet (P < 0.001), greater ease of following the diet (P < 0.001), and improved experience compared with prior colonoscopy (P < 0.0001), less bloating (P = 0.02), less weakness (P = 0.046), less hunger (P < 0.0001), and less interference with daily activities (P = 0.001). Procedure/withdrawal times and adenoma detection rates were similar between groups. Conclusion: Bowel preparation with the White Diet and low-volume, split-dose Picosalax was preferred and better tolerated without detriment to bowel preparation success compared with clear fluids and combination PEG plus SPMC for morning colonoscopy. PMID- 30483533 TI - Editorial. PMID- 30483534 TI - The history and profile of JGH. PMID- 30483532 TI - Liver stiffness measurement predicts hepatocellular carcinoma development in patients treated with direct-acting antivirals. AB - Background and Aim: Predictive factors for hepatocarcinogenesis following eradication of hepatitis C virus by direct-acting antivirals (DAAs) are unknown. The aim of the study was to investigate the relationships between liver stiffness (LS) using acoustic radiation force impulse (ARFI) erastograghy and the development of hepatocellular carcinoma (HCC) in patients who achieved sustained virological response (SVR) treated with DAA. Methods: In this prospective study, we enrolled 263 hepatitis C patients with SVR who underwent ARFI before DAA treatment. Thirty patients had previous HCC. Results: The median LS value according to ARFI measurements was 1.34 m/s (range: 0.67-4.35). During the follow up period (median: 18.1 months), development of HCC occurred in 19 patients (7.2%; HCC occurrence in 7 patients and HCC recurrence in 12 patients). By multivariate Cox regression analysis, HCC history (hazard ratio [HR]: 10.634; 95% confidence interval [CI]: 4.13-27.37; P = 0.001), older age (HR: 4.638; 95% CI: 1.63-13.61; P = 0.004) and higher total bilirubin levels (HR: 4.189; 95% CI: 1.66 10.60; P = 0.002) were independent predictors for the development of HCC, and higher LS value (>=1.73 m/s) at baseline was an independent predictor for HCC occurrence (HR: 8.350; 95% CI: 1.62-43.09; P = 0.011). The cumulative recurrence of HCC was statistically similar according to the degree of LS in patients who were previously treated for HCC. Conclusion: The LS value at baseline is useful for predicting HCC occurrence. Thus, even if SVR is achieved, patients with higher LS at baseline must be followed carefully for HCC occurrence. PMID- 30483535 TI - Outcome and validation of a new clinically based staging system for predicting survival of perihilar cholangiocarcinoma patients. AB - Background and Aim: Currently available staging systems for cholangiocarcinoma (CCA) are not applicable to patients with unresectable stage. A new clinical staging system for perihilar CCA (pCCA) subtype has been recently developed in a US cohort, with a good performance in predicting survival of all pCCA patients. We aimed to determine outcomes of pCCA patients and evaluate predictive performance of this staging system in an Asian population. Methods: All 141 patients diagnosed with pCCA between 2003 and 2012 were identified. Clinical information was retrospectively abstracted. Patients were classified into four stages based on the new staging system. Survival predictors were analyzed using the Cox proportional hazard analysis. Results: Of the 141 pCCA patients, 38 (27%), 101 (72%), and 2 (1%) received resection, palliative biliary drainage +/- chemotherapy, and best supportive care, respectively. Survival predictors included resectable disease, tumor size, distant metastasis, and cancer antigen 19-9 >= 1000 U/mL. When classified by clinical stages, 13, 4, 99, and 25 patients were in stages I, II, III, and IV, with median survivals of 18.4, 7.3, 6.3, and 2.6 months; and hazard ratio (95% confidence interval) of 1.0 (reference), 1.7 (0.5-5.5), 3.2 (1.5-6.7), and 10.8 (4.6-25.0), respectively. Conclusion: The clinical staging system has a limited performance in differentiating stage II pCCA patients from stage III patients in the Thai cohort. This can be due to differences in patient characteristics and treatment modalities between the Asian and White pCCA populations. However, the median survivals of patients with other stages are significantly different. PMID- 30483536 TI - Vitamin D supplementation in patients with nonalcoholic fatty liver disease: A randomized controlled trial. AB - Background and Aim: Deficiency of vitamin D may be related to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The aim of the present study was to evaluate the effect of vitamin D supplementation in patients with NAFLD. Methods: A total of 81 patients with NAFLD with normal or raised (n = 47) serum alanine aminotransferase (ALT) having vitamin D deficiency were randomized prospectively. Group 1 (n = 51) received lifestyle modifications and a single injection of vitamin D (600 000 U) (standard medical treatment [SMT] + vitamin D) and group 2 (n = 30) received lifestyle modifications (SMT) for 6 months. The primary objective of this study was to assess the improvement in insulin resistance (IR) and serum ALT (in patients with raised ALT) and the secondary objective was to assess the change in cytokine profile in the SMT + vitamin D group. Results: After 6 months, significant improvement in serum levels of ALT was observed in the SMT + vitamin D group when compared to the SMT group (ALT [87 +/- 48 and 59 +/- 32 IU/mL, P < 0.001] vs [64 +/- 35 and 62 +/- 24 IU/mL, P = 0.70]). Mean insulin levels and homeostasis model assessment-IR remained unchanged at 6 months in the SMT + vitamin D group while there was a significant increase in mean insulin and homeostasis model assessment-IR in the SMT group. SMT + vitamin D group had significant increase in mean serum levels of adiponectin (836 +/- 309 and 908 +/- 312 (pg/mL), P = 0.018) compared with the baseline; tumor necrosis factor-alpha levels decreased from baseline but the change was not significant. Conclusion: Patients with NAFLD given vitamin D in addition to lifestyle modifications have significant improvement in serum ALT and serum adiponectin levels. PMID- 30483537 TI - Risk stratifying the screening of Barrett's esophagus: An Asian perspective. AB - Background and Aim: Barrett's esophagus (BE) is a premalignant condition for esophageal adenocarcinoma. Although risk factors exist for screening patients in the West, we aimed to determine the factors in terms of demographics and symptoms for patients in an Asian setting. Methods: We recruited 1378 patients over a 7 year period as part of an ongoing gastric cancer screening program. An appropriately designed questionnaire was utilized to determine the necessary risk factors and symptoms with endoscopic analysis and subsequent histological confirmation as the gold standard. We utilized the existence of intestinal metaplasia of the distal esophagus as the primary diagnostic pathology. Results: We demonstrated that no symptoms were indicative of BE in an Asian setting. Age (odds ratio 1.081, 95% confidence interval 1.022-1.143) and male gender (odds ratio 4.808, 95% confidence interval 1.727-13.33) proved significant demographic factors for the presence of intestinal metaplasia (P 0.007, 0.003, respectively). Conclusions: We advocate the utilization of increasing age and male gender as the primary risk factors for patients at risk of BE. We also recommend astute examination of the distal esophagus whilst patients undergo simultaneous gastric cancer screening. PMID- 30483539 TI - Misdiagnosing hepatic inflammatory pseudotumor as hepatocellular carcinoma: A case report. AB - A 61-year-old Chinese male was found to have a lesion in the left liver during a routine body check-up. Laboratory tests revealed no abnormalities except for a rise in C-reactive protein. Computed tomography showed features suggestive of hepatocellular carcinoma. The patient underwent liver IVb segmentectomy and cholecystectomy. Histopathology showed features of hepatic inflammatory pseudotumor. The C-reactive protein decreased to close to normal on postoperative day 9. A patient with hepatic inflammatory pseudotumor who presented with features mimicking hepatocellular carcinoma was reported. A preoperatively raised C-reactive protein was the only hint which suggested that our patient might have had hepatic inflammatory pseudotumor instead of hepatocellular carcinoma. PMID- 30483538 TI - A case of small invasive gastric cancer arising from Helicobacter pylori-negative gastric mucosa: Fundic gland-type adenocarcinoma. AB - This study showed that we need to bear in mind the possibility of gastric adenocarcinoma of the fundic gland type upon encounter with such elevated lesions originating from Helicobacter pylori (H. pylori)-negative gastric mucosa. We believe that our study makes a significant contribution to the literature because small invasive gastric adenocarcinoma of the fundic gland type is a rare disease entity, which exhibits a submucosal tumor-like or superficial flat-type elevated lesion on H. pylori-negative gastric mucosa in the endoscopic examinations. PMID- 30483540 TI - Editorial. PMID- 30483541 TI - Advancing gastroenterology and hepatology in the Asian Pacific region. PMID- 30483542 TI - Referrals to a tertiary hospital: A window into clinical management issues in functional gastrointestinal disorders. AB - Background and Aim: To investigate the quality of and reasons for referrals of patients with likely functional gastrointestinal disorders (FGID) and explore patients' experience of clinical management. Methods: A cross sectional, mixed methods study was undertaken. Referrals (July 2013-2015) to one gastroenterology outpatient department triaged as "likely FGID", the referred patients and their referring primary healthcare providers were examined. Results: A total of 69% of patients reported not yet receiving an initial diagnosis, 52% reported persistent/distressing symptoms or reduced quality of life, 24% feared missed or worsening pathology, and 35% were seeking repeat specialist consultation. Most patients were dissatisfied (40%) or only partially satisfied (36%) with current management. Dissatisfaction was significantly related to the lack of provision of a diagnosis and effective treatment options (P < 0.001). Referral quality was poor and with the reason for referral clearly communicated in only 25%. Common referral reasons included repeat presentations (n = 32), diagnostic uncertainty (n = 19), to ensure nothing is missed (n = 19), patient request (n = 17), no response to treatment (n = 16), and to allay patient fears (n = 14). A total of 28/60 primary healthcare providers were confident that their patient had a FGID, yet sought confirmation (n = 16), second opinion (n = 8), or advice (n = 4). Conclusion: Current management of FGID in usual care is suboptimal, as evidenced by the tertiary referral load, patient dissatisfaction, and the lack of provision of diagnoses and effective treatment options. Some clinicians lack confidence in effectively identifying and managing these conditions. Resources and supports to equip and assist clinicians to identify and manage FGID successfully may enhance patient care. PMID- 30483543 TI - Aggressive nutrition intervention reduces ascites and frequency of paracentesis in malnourished patients with cirrhosis and ascites. AB - Background and Aim: Alterations in nutrient metabolism, nutritional requirements, and reduced dietary intakes are common in chronic liver disease (CLD). These result in malnutrition, sarcopenia, and exacerbate progression to decompensation and ascites. We aimed to investigate the effects of continuous tube feeding (TF) on nutritional status and levels of ascites in malnourished individuals with decompensated cirrhosis. Methods: Fourteen malnourished patients with decompensated cirrhosis and ascites who failed to respond to standard oral nutritional interventions received supplementary continuous nasogastric TF for 7 +/- 1 weeks. Liver disease severity was assessed by model for end-stage liver disease (MELD) and Child-Turcotte-Pugh (CTP) scores. Results: Continuous TF occurred at home for 7 weeks (1.5-12 weeks). Prior to feeding, 12 patients had severe ascites, 10 required paracentesis, and 13 were severely malnourished. At completion of TF, five patients did not have ascites, four had mild ascites, four had moderate ascites, and only one had severe ascites and 10 no longer required paracentesis (P < 0.001). Median patient survival was 26 +/- 7 months. Five survived to transplantation and three remained transplant-free at 8, 1.9, and 1.7 years. Seven patients were moderately malnourished at completion of TF with an overall improvement in hand grip strength from 51% to 65% of predicted (P = 0.02). Conclusion: Supplementary continuous TF may help to reduce ascites and paracentesis requirements and improve nutritional status. Supplementary continuous TF should be considered as a treatment for malnourished patients with decompensated cirrhosis and refractory ascites. PMID- 30483544 TI - Blood biomarkers reflect integration of severity and extent of endoscopic inflammation in ulcerative colitis. AB - Background and Aim: Blood markers are not always regarded as satisfactory surrogate biomarkers for predicting endoscopic activity in ulcerative colitis (UC). However, those biomarkers have been evaluated solely based on endoscopic activity at the most severe colorectal location, taking no account of the extent of inflammation. This study aimed to examine whether integrated evaluation of severity and extent of endoscopic activity improves the performance of blood biomarkers for UC. Methods: We performed a retrospective study of UC patients who underwent colonoscopy and blood tests in our hospital. Blood tests were C reactive protein (CRP), serum albumin (ALB), and platelet count (PLT). We compared blood markers with two versions of endoscopic activity assessed by Mayo endoscopic subscore (MES): the maximum score of MES in the colorectum (mMES, range: 0-3) and the cumulative score of MES of six colorectal regions (cMES, range: 0-18). Results: All three blood markers correlated well with both mMES and cMES, and each marker showed better correlation with cMES than mMES (Spearman rank correlation coefficient: PLT: 0.54 vs 0.47, ALB: -0.65 vs -0.52, and CRP: 0.52 vs 0.38, respectively). The predictability, including sensitivity and specificity, of each marker for endoscopic activity was also better for cMES, resulting in higher degrees of area under the curve (mMES vs cMES: PLT: 0.75 vs 0.83, ALB: 0.77 vs 0.90, and CRP: 0.75 vs 0.90, respectively). Conclusion: When incorporating the extent of inflammation, blood markers are better at predicting endoscopic activity of UC than previously considered and could be used as a reliable biomarker in clinical practice. PMID- 30483545 TI - Study of the protective effect of ischemic and pharmacological preconditioning on hepatic ischemic reperfusion injury induced in rats. AB - Background and Aim: Hepatic ischemia reperfusion injury is the main cause of liver failure following liver surgery, so an effective method is needed to prevent or reduce this hepatic injury. The aim of the present study is to investigate the potential effect of ischemic preconditioning versus pharmacological preconditioning with lisinopril or verapamil for protection against hepatic ischemia reperfusion injury induced in rats. Methods: Rats were divided into six groups. Group I served as control untreated. Rats of group II were subjected to laparotomy without induction of ischemia reperfusion. Ischemia reperfusion by ligation of the portal trait for 30 min, followed by reperfusion for 2 h, was performed in rats of groups III-VI. Ischemic preconditioning was performed for rats of group IV before induction of ischemia reperfusion. Lisinopril and verapamil was given daily for 3 days before induction of ischemia reperfusion in groups V and VI, respectively. Serum level of liver transaminases and liver malondialdehyde content were measured, and hepatic histopathological examination was assessed. Results: Induction of ischemia reperfusion resulted in significant elevation of liver transaminases and liver malondialdehyde content associated with significant hepatic histopathological injury that were significantly improved by ischemic preconditioning, lisinopril, or verapamil treatment. Verapamil showed the most significant improvement compared with ischemic preconditioning or lisinopril treatment. Conclusion: Ischemic preconditioning and pharmacological preconditioning by lisinopril or verapamil can protect against hepatic ischemia reperfusion probably through inhibition of oxidative stress and neutrophil infiltration. The most potent protection is demonstrated by verapamil treatment. PMID- 30483547 TI - Editorial. PMID- 30483546 TI - Serum ferritin as a non-invasive marker in the prediction of hepatic fibrosis among Egyptian patients with non-alcoholic fatty liver disease. AB - Background and Aim: Many studies have found a relationship between hepatic iron, serum ferritin, and non-alcoholic fatty liver disease (NAFLD) or its progress. The aim of this study is to assess the value of serum ferritin as a non-invasive marker in the prediction of hepatic fibrosis in NAFLD. Methods: This study included 113 subjects who were classified into three groups. Group I included 30 healthy subjects as control with no clinical, radiological, and histological features of NAFLD. Group II included 31 NAFLD patients without hepatic fibrosis. Group III included 52 patients with hepatic fibrosis on top of NAFLD. Results: Serum ferritin was determined using ferritin ELISA kit. Fibrosis 4 score was calculated. Liver biopsy was conducted for included patients. Significantly higher levels of serum ferritin were found in patients with hepatic fibrosis on top of NAFLD than controls. Receiver operating characteristic curve analysis revealed that an optimum cutoff level of 51.95 ng/mL was the best to predict fibrosis on top of NAFLD with diagnostic sensitivity and specificity of 65% and 60%, respectively, and area under the curve = 0.658. Conclusion: Higher serum ferritin was found in patients with hepatic fibrosis on top of NAFLD. Serum ferritin was found to be a predictor of fibrosis on top of NAFLD with moderate sensitivity and specificity. PMID- 30483548 TI - Eradicating gastric cancer. PMID- 30483549 TI - Balloon-occluded retrograde transvenous obliteration as a procedure to improve liver function in patients with decompensated cirrhosis. AB - Aim: Portosystemic shunts aggravate liver function by decreasing portal blood flow. The usefulness of balloon-occluded retrograde transvenous obliteration (B RTO), a standardized therapeutic procedure for gastric fundal varices (GFV), for the improvement of liver function was evaluated in cirrhotic patients with or without varices. Methods: The subjects were 161 patients with portosystemic shunts. A balloon catheter was inserted into the shunts, followed by the injection of 5% ethanolamine oleate through the catheter under balloon inflation. The balloon was kept inflated for 6 to 48 h. Results: B-RTO was performed as a therapy for GFV in 112 patients and for the improvement of liver function in 49 patients. The targets were splenorenal shunts in 104 patients (93.6%) in the former group and 33 patients (67.3%) in the latter group, and the procedures were successfully completed in 109 (97.3%) and 39 (79.6%) patients, respectively. In both groups, the serum albumin levels were increased and the serum ammonia levels were decreased at more than 1 month after the procedures, compared with the baseline levels, whereas significant improvements in the Child-Pugh scores and prothrombin times were only seen in the latter group. In these patients, the portal blood flows evaluated using Doppler ultrasound were increased at 1 week after the procedures, compared with the baseline levels. Conclusions: B-RTO is a useful therapeutic procedure for improving liver function even in patients without GFV by increasing the portal venous flow with successfully targeted, uncommon portosystemic shunts. PMID- 30483550 TI - Left-sided colitis and extensive colitis have similar colectomy rates after index episode of acute severe colitis: A long-term follow-up study. AB - Background and Aim: The extent of disease of ulcerative colitis (UC) has been found to be a predictor of acute severe colitis (ASC), but it is unclear whether the extent of disease at the index episode of ASC is a predictor of long-term outcome. Methods: Hospitalized patients satisfying Truelove and Witts' criteria under follow-up at a single center from January 2003 to December 2016 were included. The extent of disease at index ASC was classified according to the Montreal classification as left-sided or extensive colitis. Extent was used to predict the long-term risk of colectomy or steroid dependence following an index episode of ASC. Results: Of 2076 patients with ulcerative colitis, 241 (12%) had an index episode of ASC. In total, 34 (14%) patients underwent a colectomy at index admission and 53 (26%) over a median follow-up of 48(1-172) months. Left sided colitis and extensive colitis did not differ in the rate of colectomy at index admission (12% vs 15%, P = 0.4) and colectomy in follow-up (31% vs 23%, P = 0.17). Readmission due to ASC was also similar between the two groups (28% vs 32%, P = 0.6). Conclusion: Extent of disease at index ASC does not predict colectomy at admission and over the long term. PMID- 30483553 TI - Mesenchymal stem cell therapy for advanced liver cirrhosis: A case report. AB - Mesenchymal stem cell (MSC) transplant may offer an alternative to liver transplantation in patients with end-stage liver disease. However, its efficacy remains uncertain. MSC was performed on a 50-year-old male with decompensated (Child-Turcotte-Pugh grade C) alcoholic liver cirrhosis due to an absence of donors for adult-deceased and living-related liver transplantation. Autologous bone marrow-derived MSCs were harvested from the patient and cultured using standard protocols. The MSCs were subsequently re-administrated into the liver via hepatic intra-arterial infusion on two separate occasions. After infusion, there was an improvement in biochemical parameters (serum total bilirubin, serum albumin), and a reduction of diuretic use for ascites for up to 8 weeks. However, all biochemical and clinical parameters deteriorated on long-term follow-up without any further infusions. The patient eventually succumbed to his disease. MSC transplantation may have a clinical benefit on adult patients with end-stage liver cirrhosis, but this appears to be transitory. PMID- 30483551 TI - Association of interferon gamma gene polymorphism and susceptibility to hepatitis C virus infection in Egyptian patients: A multicenter, family-based study. AB - Background and Aim: Polymorphisms in some genes may influence the persistence of hepatitis C virus (HCV) infection, clinical outcome, HCV replication, and liver damage. This study was conducted to investigate the role of the interferon gamma (IFN-gamma) gene at (+874 T/A, -764 G/C, -179 C/A) single-nucleotide polymorphisms (SNPs) and its receptor (IFN-gammaR2) at (rs 2786067 A/C) SNP in the susceptibility of Egyptian families to HCV infection with high-resolution techniques. Methods: In total, 517 Egyptian families, with 2246 subjects, were recruited to this study from the Upper and Lower Egypt governorates and were classified into three groups: 1034 patients with chronic hepatitis C virus, 108 subjects with spontaneous virus clearance (SVC), and 1104 subjects as a healthy control group. All subjects were genotyped for (+874 T/A, rs2430561, -764 G/C, rs2069707, -179 C/A, rs2069709, and rs 27860067, A/C) SNPs of the IFN-gamma gene using the allelic discrimination real-time polymerase chain reaction technique and were confirmed using sequence-based typing. Results: The carriage of T allele of (+874) IFN-gamma is a risky allele and was significantly higher in chronic hepatitis C more than other two groups (odds ratio [OR]: 2.6646, P < 0.0002). On the other hand, the C allele of (-764, rs2069707) is a protective allele and was higher in SVC than the other two groups (OR: 0.2709, P < 0.0001). However, both ( 179 C/A, rs 2069709) and (rs 27860067, A/C) SNPs are not polymorphic enough to be studied in the Egyptian population. Conclusions: HCV infection is associated with the T allele of (+874 rs2430561), while SVC of HCV is associated with the C allele of (-764, rs2069707) of the IFN-gamma gene. PMID- 30483554 TI - Editor's note. PMID- 30483552 TI - Asunaprevir and daclatasvir in hemodialysis patients with chronic hepatitis C virus genotype 1b infection. AB - Background and Aim: Patients requiring hemodialysis show high morbidity with hepatitis C virus (HCV) infection, but there are difficulties associated with interferon-based therapies. Asunaprevir and daclatasvir could help patients with HCV genotype 1b because the drugs have a nonrenal metabolism and show good viral eradication. We evaluated the efficacy and safety of combined asunaprevir and daclatasvir therapy. Methods: This was a multicenter prospective trial of patients with chronic hepatitis or compensated cirrhosis from HCV genotype 1b who had end-stage renal disease requiring chronic hemodialysis. Asunaprevir and daclatasvir were administered orally (100 mg twice daily and 60 mg once daily, respectively) for 24 weeks. The primary end-point was the proportion of patients achieving sustained virological response 12, defined as HCV RNA <15 IU/mL undetectable at 12 weeks after completion of asunaprevir and daclatasvir treatment. Results: Between December 2014 and December 2015, 23 dialysis patients were enrolled, and 22 patients completed the protocol therapy. Sustained virological response 12 rates were 91.3% (95% confidence interval: 72.0-98.9) in the intention-to-treat and 95.5% (95% confidence interval: 77.2-99.9) in the per protocol populations. Serum aminotransferase significantly decreased after initiation of asunaprevir and daclatasvir (P < 0.01), although the level was low at baseline. Asunaprevir and daclatasvir were well tolerated; however, one patient could not continue because of infective endocarditis and cerebral infarction. Conclusions: Asunaprevir and daclatasvir could help patients with chronic hepatitis C receiving hemodialysis. Close collaboration with dialysis physicians is important when treating these patients because hemodialysis carries life-threatening risks. PMID- 30483555 TI - Non-alcoholic fatty pancreas disease as a risk factor for pancreatic cancer based on endoscopic ultrasound examination among pancreatic cancer patients: A single center experience. AB - Background and Aim: Non-alcoholic fatty pancreas disease (NAFPD) is a disease that ranges from simple steatosis and can further lead to chronic pancreatitis and possible pancreatic cancer development. Its exact pathogenesis and impact on clinical practice are still largely unknown. Pancreatic cancer is still the most lethal malignancy in the world. Studies about the relationship between NAFPD and pancreatic cancer are still lacking. This study aims to find the possible role of endoscopic ultrasound (EUS) examination as a screening tool in NAFPD patients based on EUS examination among pancreatic cancer patients. Methods: EUS hospital data were collected within a 2-year period, and all patients who underwent EUS procedures were analyzed. Pancreatic malignancy was diagnosed based on imaging and tumor markers and cytopathology using the endoscopic ultrasound fine needle aspiration (EUS-FNA) procedure. Patients with pre-existing pancreatic diseases, significant alcohol consumption, or other primary cancer with metastasis to the pancreas were excluded. Statistical analysis was performed using SPSS version 23.0. Results: In total, 162 patients (75 females and 87 males) were recruited for database analysis.^ Pancreatic malignancy was found in 43 (26.5%) patients, whereas fatty pancreas was found in 53 (32.7%) patients, and this was commonly found among pancreatic cancer patients.^ Based on logistic regression analysis, factors such as age, gender, diabetes, and chronic pancreatitis were not found to be significant risk factors for pancreatic malignancy where fatty pancreas is the only significant risk factor for pancreatic cancer (odds ratio: 18.027 [95% CI: 7.288-44.588]). Conclusion: Prevalence of NAFPD among pancreatic cancer patients is high. Future studies can be conducted to show whether EUS can be considered a screening tool for the early detection of pancreatic malignancy in NAFPD patients; a cohort prospective study might also be needed to show clear causality between fatty pancreas and pancreatic cancer. PMID- 30483556 TI - Patchy colitis, and young age at diagnosis and at the time of surgery predict subsequent development of Crohn's disease after ileal pouch-anal anastomosis surgery for ulcerative colitis. AB - Background and Aim: A proportion of patients having total proctocolectomy and ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) are later diagnosed with Crohn's disease (CD). The aim of this study was to identify preoperative and perioperative predictors for the subsequent development of CD in patients who had IPAA for presumed UC. Methods: A retrospective case-control study of patients undergoing IPAA surgery for presumed UC was undertaken. Cases were patients who had a revised diagnosis of CD after surgery. Preoperative and perioperative variables were examined and analyzed. Results: Fifteen cases were compared with 39 controls. Patients aged <=25 years at initial UC diagnosis were more likely to develop CD compared to those aged >25 years (odds ratio, OR [95% confidence interval, CI]: 7.1 [1.6-31.3]; P = 0.01). Patients aged <=30 years at the time of colectomy had an increased risk of subsequent development of CD compared to those aged >30 years (OR [95% CI]: 4.5 [1.3-16.0]; P = 0.02). Cases were more likely to have patchy colitis on their colectomy specimen (OR [95% CI]: 6.7 [1.1-41.8]; P = 0.04). There was no significant difference between groups regarding transmural inflammation, ileitis, or fissuring ulcers on colectomy specimens, or preoperative C-reactive protein (CRP), albumin, family history, and smoking status. Conclusion: Predictors of the development of CD in the pouch include young age at diagnosis and at the time of surgery, and patchy colitis in the resected colon. PMID- 30483557 TI - Low FODMAP diet in Egyptian patients with Crohn's disease in remission phase with functional gastrointestinal symptoms. AB - Background and Aim: Despite being in remission, functional gastrointestinal disease (FGID) in Crohn's disease (CD) patients can reduce their quality of life. The Egyptian daily diet contains a high amount of FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides, And Polyols). As the low FODMAP diet has been proven to be effective in irritable bowel syndrome worldwide, it was reasonable to take a step further and begin to study the effect of low FODMAP in Egyptian CD patients with FGID. The outcomes were assessed in terms of improvement in symptoms and hence the quality of life, and the factors that led to this improvement were also recorded. Methods: In total, 100 CD patients with FGID in the remission stage who were already on a low-fiber diet (+/- lactose free diet) were selected to follow the low FODMAP diet. A structured interview was performed after 3 months with a number of scored-scale questionnaires comparing symptoms before and after the diet and the impact on quality of life. Evaluation of the adherence, satisfaction, palatability, and affordability of the diet was performed. Different demographic data were also evaluated in correspondence with improvements in the quality of life. Results: The mean score of FGID improvement was 38.45 +/- 21.56%. The quality of life was significantly improved; 90% of female patients versus 49.4% males had a better quality of life. The households (not working) as well as those with morning jobs (6 hours) reported an increase in quality of life. Although the Egyptian low FODMAP diet was expensive (in terms of gluten-free wheat), 67% were adherent to it (18.16 +/- 6.85). Conclusion: As a first step in Egypt, the low FODMAP diet was effective in improving the quality of life of CD patients with FGID. PMID- 30483558 TI - Adiponectin level changes among Egyptians with gastroesophageal reflux disease. AB - Background and Aim: Visceral fat is an important endocrine organ that secretes different bioactive substances such as adipocytokines. The aim of this study was to investigate the adiponectin level changes among patients with erosive gastroesophageal reflux disease (GERD)and its consequence on pathogenesis. Methods: In this study, 150 subjects were selected and divided into four groups: Group I (n = 40) were healthy individuals with an average body mass index and had no gastrointestinal tract symptoms; Group II (n = 50) were patients with mild to moderate erosive esophagitis; Group III (n = 40) were patients with severe erosive esophagitis; and finally, Group IV (n = 20) were patients with Barrett's esophagus. Upper gastrointestinal endoscopy was performed for Groups II, III, and IV only, and histopathological assessment was conducted for the suspicious cases of Barrett's esophagus. The measurement of serum adiponectin was performed for all groups using the ELISA test. Results: Our results revealed that the serum level of adiponectin was significantly lower in patients with different grades of GERD as well Barrett's esophagus as compared to healthy controls (P-value < 0.001). Additionally, the serum level of adiponectin was correlated with different grades of GERD as the highest level of the adiponectin was found in the control group (11.05 +/- 2.58) followed by mild to moderate GERD (6.39 +/- 1.64) and then severe GERD (2.42 +/- 1.00); finally, the lowest level was detected in the Barrett's esophagus group (1.99 +/- 0.47). Our study showed significant correlation between body mass index, waist circumference, and waist-hip ratio on one hand and serum adiponectin level on the other hand, with a statistically significant difference (P-value < 0.001). The best cut-off value for serum adiponectin was 7.7 (MUg/mL), with a sensitivity of 91.8% and specificity of 97.5%. Conclusions: Low serum adiponectin level appears to be associated with an increased risk of erosive esophagitis, and visceral fat accumulation is related to the impaired secretion of adiponectin, which may have an influence on the pathogenesis of GERD. PMID- 30483559 TI - Non-liquid as initial meal in mild acute pancreatitis: Renewed meta-analysis. AB - In this study, we first evaluated that all of the studies included were randomized controlled trials (RCTs). Second, the number of patients in the present meta-analysis is larger than before, so the conclusion is more convincing. PMID- 30483560 TI - Editor's note. PMID- 30483561 TI - Esophageal tuberculosis: Uncommon of common. AB - Background and Aim: Esophageal involvement in tuberculosis (TB) is rare and is usually secondary. Data on esophageal TB are scarce. We aimed to analyze clinical and endoscopic features and outcomes of treatment in esophageal TB. Methods: We retrospectively identified patients with esophageal TB from January 2014 to December 2016 at GB Pant Hospital. Well-defined granuloma with or without caseation and/or acid-fast bacilli on staining either from esophageal biopsy or the adjacent mediastinal lymph node fine-needle aspiration cytology (FNAC) specimen, along with clinical features and response to antitubercular therapy (ATT), were collectively considered to diagnose definite TB. Treatment received and response to therapy were documented and analyzed. Results: A total of 19 patients had definite esophageal TB, and the median age of patients was 39 years (14-65 years) and 10 (52.6%) patients were female. The most common presenting symptom was dysphagia (n = 16, 84%) followed by odynophagia (n = 8, 42%). On endoscopy, the mid-esophagus was the most common site of involvement, and findings included ulcers (n = 17), elevated lesions (n = 9), and fistulae (n = 4) in patients. The mediastinal lymphadenopathy was present in all patients, with parenchymal lesions seen in three patients. The endoscopic mucosal biopsies were diagnostic in 11 patients, and in the remaining 8 patients, endoscopic ultrasound guided FNAC from the mediastinal lymph nodes was diagnostic. A total of 18 patients completely responded to ATT, and 1 patient had partial response with persistent fistulae requiring additional treatment. Conclusion: Esophagus involvement is rare in TB; endoscopic mucosal biopsy and EUS-guided FNAC is diagnostic, and the response to ATT is excellent. PMID- 30483562 TI - Prevalence and risk factors of non-alcoholic fatty liver disease in Bangladesh. AB - Background and Aim: Non-alcoholic fatty liver disease (NAFLD) is a significant cause of hepatic dysfunction and liver-related mortality. As there is a lack of population-based prevalence data in a representative sample of general population, we aimed to estimate the prevalence and risk factors of NAFLD in Bangladesh. Methods: A cross-sectional study was conducted both in urban and rural areas of Bangladesh from December 2015 to January 2017. Data were collected using a pretested structured questionnaire followed by ultrasonography of hepatobiliary system for screening of NAFLD. Multivariate logistic regression was used to estimate the risk factors of NAFLD. Results: A total of 2782 (1694 men and 1088 women) participants were included in the study, with a mean age of 34.21 (+/-12.66) years. The overall prevalence of NAFLD was 33.86% (95% confidence interval [CI]: 32.12, 35.64). Females living in the rural areas and midlife adults (45-54 years) had the highest prevalence of NAFLD (P < 0.05). Multivariable logistic regression model demonstrated that increasing age, diabetes, elevated body mass index, and married individuals are significantly associated with NAFLD. Individuals with diabetes (adjusted odds ratio: 2.71, 95% CI: 1.85, 3.97) and hypertension were at a higher risk of having NAFLD. The odds of having NAFLD were 4.51 (95% CI: 3.47, 5.86) and 10.71 (95% CI: 7.80, 14.70) times higher among overweight and obese participants, respectively, as compared to normal-weight participants. Conclusions: About one-third of the population of Bangladesh is affected by NAFLD. Individuals with higher body mass index (overweight and obese), diabetics, midlife adults, married individuals, and rural women were more at risk of having NAFLD than others. PMID- 30483563 TI - Risk of small intestinal bacterial overgrowth in patients receiving proton pump inhibitors versus proton pump inhibitors plus prokinetics. AB - Background and Aim: Intestinal dysmotility is considered a risk factor for small intestinal bacterial overgrowth (SIBO). Prokinetics improve intestinal motility and are often prescribed with proton pump inhibitors (PPIs) in patients with gastroesophageal reflux disease (GERD) and/or functional dyspepsia. The present study aimed to evaluate the prevalence of SIBO and the orocecal transit time (OCTT) in patients taking PPI compared with those taking PPI plus prokinetics. Methods: The study is a single-center, cross-sectional study. Enrolled patients (with age > 12 years) were divided into two groups: patients taking PPIs for more than 3 months (Group A) and those taking PPIs with prokinetics for more than 3 months (Group B) for various indications. Lactulose breath test (LBT) for OCTT and glucose breath test (GBT) for SIBO were conducted for all patients. Results: Of the 147 enrolled patients, SIBO was documented in 13.2% patients in Group A versus 1.8% in Group B, P = 0.018. Median OCTT in Group A was 130 (105-160) min compared with 120 (92.5-147.5) min in Group B (P = 0.010). Median OCTT among SIBO positive patients was 160 (140-172.5) min compared with SIBO-negative patients, where it was 120 (103.75-150) min (P = 0.002). The duration and type of PPI used were not associated with the occurrence of SIBO in our study. Conclusion: The use of prokinetics in patients on PPI may reduce the risk of SIBO by enhancing intestinal motility and may reduce SIBO risk associated with long-term PPI use. PMID- 30483564 TI - Non-alcoholic fatty liver disease in patients with autoimmune hepatitis. AB - Background and Aim: The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing all over the world. NAFLD develops in patients with liver disease, including patients with autoimmune hepatitis (AIH). NAFLD and AIH have some similar laboratory and histological findings. The aim of this study was to elucidate the characteristics of AIH patients with NAFLD. Methods: We re evaluated the nationwide survey performed in Japan in 2015 of AIH patients diagnosed between 2009 and 2013. Results: A total of 1151 subjects (144 men and 1007 women) were enrolled in the present study. The overall prevalence of NAFLD was 17.0%. Compared to AIH without NAFLD, AIH patients with NAFLD had the following characteristics: (i) low female-to-male ratio, (ii) older age, (iii) mild elevation in hepatobiliary enzymes, (iv) histologically progressive fibrosis and mild plasma cell infiltration or mild lobular hepatitis, (v) lower prevalence of prednisolone administration and higher prevalence of ursodeoxycholic acid administration, (vi) higher levels of hepatic enzymes and immunoglobulin G after treatment, and (vii) similar prevalence of autoimmune and malignant complications. Conclusion: AIH patients with NAFLD have many features that are different from AIH patients without NAFLD. Understanding these differences is essential for the proper diagnosis and treatment of AIH patients with NAFLD. PMID- 30483566 TI - Gastroduodenal involvement in disseminated strongyloidiasis. AB - Here, we report the case of a 57-year-old Peruvian man on long-term corticosteroid therapy for a drug allergy and proton pump inhibitors for chronic dyspepsia symptoms. Upper gastrointestinal endoscopy showed multiple white granular lesions and widespread erosions in the stomach. Our findings indicate that gastric strongyloidiasis should be carefully considered in high-risk patients even if endoscopic findings are nonspecific. PMID- 30483565 TI - Is non-alcoholic fatty liver disease a reflection of what we eat or simply how much we eat? AB - Non-alcoholic fatty liver disease (NAFLD) is an increasingly common and potentially serious condition, which has emerged with the obesity epidemic. This disease can progress to cirrhosis and hepatocellular cancer. Associated comorbidities, such as cardiovascular disease and type 2 diabetes, are common. Obesity is the key risk factor and diet appears to be a critical factor in the pathogenesis of NAFLD. We reviewed studies undertaken on human subjects investigating which dietary components initiate excess hepatic triglyceride deposition. Most experimental diets used high-calorie excesses, or extreme proportions of fat or carbohydrate, not typical of current dietary patterns. Hypercaloric diets, where the additional calories were predominantly either fat or carbohydrates, increased intrahepatocellular lipids. The type of fat appeared important, with diets high in saturated fatty acids favoring hepatic fat accumulation which was substantially lower with polyunsaturated fatty acids. The effect of dietary fructose on markers of NAFLD did not appear to be worse than that of glucose. The initiation of excess hepatic triglycerides is likely to be a complex interaction of energy and nutrients with more than one dietary factor involved. It was not possible to disentangle the hepatic effects of excess energy from that of different macronutrient distributions in current literature. Further investigation is needed to determine the type of diet that is likely to lead to the development of NAFLD. A better understanding of the contribution of diet to pathogenesis of NAFLD would better inform prevention strategies. PMID- 30483567 TI - Editor's note. PMID- 30483568 TI - Nodular gastritis in association with gastric cancer development before and after Helicobacter pylori eradication. AB - Background and Aim: Nodular gastritis is caused by Helicobacter pylori infection and is associated with the development of diffuse-type gastric cancer. This study examined the clinical characteristics of patients with nodular gastritis, including cancer incidence before and after H. pylori eradication. Methods: This was a retrospective study of patients who underwent upper endoscopy and were positive for H. pylori infection. We examined the clinical findings and follow-up data after H. pylori eradication in patients with and without nodular gastritis. Results: Of the 674 patients with H. pylori infections, nodular gastritis was observed in 114 (17%). It was more prevalent in women (69%) and young adults. Among patients with nodular gastritis, six (5%) had gastric cancer, all of which were of the diffuse type. Among the 19 (4%) patients with gastric cancer and no nodular gastritis, 16 had intestinal-type cancer. White spot aggregates in the corpus, a specific finding in patients with nodular gastritis, were more frequently observed in patients with gastric cancer than in those without (83% vs 26%, P = 0.0025). Of 82 patients with nodular gastritis who had H. pylori eradicated successfully, none developed gastric cancer over a 3-year follow-up period, while 7 (3%) of 220 patients without nodular gastritis developed gastric cancer after H. pylori eradication. Conclusions: In patients with nodular gastritis, white spot aggregates in the corpus may indicate a higher risk of developing diffuse-type gastric cancer. Nodular gastritis may be an indication for eradication therapy to reduce the risk of cancer development after H. pylori eradication. PMID- 30483570 TI - Colonization of Helicobacter pylori in the gastric cardia: A comparison between the UFT300 and CLO tests. AB - Background and aim: To assess the detection rates of Helicobacter pylori colonization in the gastric cardia with two commercial kits of rapid urease test: 5 min UFT300 and 24 h CLO test in H. pylori-infected patients. Methods: Eighty consecutive dyspeptic patients with confirmed H. pylori infection (serology and 13C-urea breath test) were prospectively studied. During endoscopy, tissue samples using separate biopsy forceps from the cardia were taken for the UFT300 and CLO tests. The results of the UFT300 were read at 5 and 30 min, and those of the CLO test were read at 24 h. Results: Of 80 enrolled patients, 17 (21.3%) and 44 (55%) had positive findings with the UFT300 at 5 and 30 min, respectively, while 72 (90%) had positive findings with the CLO test at 24 h. The CLO test is significantly more sensitive than the UFT300 in evaluating H. pylori status in the cardia. On comparing patients with and without carditis, the detection rates of the CLO test were similar (91.1% vs 88.6%; P = 0.724), and the rates of the UFT300 were also similar at 5 and 30 min. Conclusions: The rate of H. pylori colonization in the gastric cardia was 90% in H. pylori-infected patients detected with the CLO test. Although the UFT300 provides a more rapid reading of H. pylori status, the diagnostic yield of the CLO test is much higher than that of the UFT300. However, a positive result of the UFT300 may indicate a higher bacterial load in the cardia, which warrants a more effective therapeutic strategy. PMID- 30483569 TI - Daclatasvir and asunaprevir improves health-related quality of life in Japanese patients infected with hepatitis C virus. AB - Aims: Interferon-free direct-acting antiviral agent (DAA) regimens for chronic hepatitis C virus (HCV) patients have improved their health-related quality of life (HRQOL). Currently, there are no published data assessing the impact of DAAs regimens without sofosbuvir on HRQOL. The aim of this study was to investigate the improvement of HRQOL in Japanese HCV patients treated with a protease inhibitor and a nonstructural protein 5A inhibitor. Methods and Results: A total of 123 Japanese genotype 1b HCV patients receiving daclatasvir (DCV) and asunaprevir (ASV) for 24 weeks were enrolled. HRQOL was assessed using the Japanese version of the Chronic Liver Disease Questionnaire (CLDQ) at baseline; weeks 4, 12, and 24; and post-24 weeks. Changes in CLDQ scores were calculated by subtracting the CLDQ score at each time point from the baseline value. Improvement in the mean change of the Japanese version of the CLDQ score became statistically significant as early as week 4 after the initiation of treatment (+9.3%; P < 0.0001) and was sustained during and after DCV/ASV treatment. The changes of CLDQ at posttreatment week 24 in patients with sustained virological responses (SVR) were significantly higher than those in patients without SVR (0.4% and -4.1%, respectively; P < 0.05). Conclusions: This study of DCV/ASV treatment for Japanese HCV patients in a clinical setting demonstrated that HRQOL can improve as early as at the initiation of treatment and can continue during and after treatment, regardless of the classes of DAAs regimens and race. Moreover, SVR are needed to continue HRQOL improvement. PMID- 30483573 TI - Editor's note. PMID- 30483571 TI - Differential characteristics in drug-induced autoimmune hepatitis. AB - Background and Aim: Drug-induced autoimmune hepatitis (DIAIH) is an adverse effect associated with several drugs that usually occurs acutely, with variable latency, and it may potentially be mortal. There are a few reports and studies about DIAIH. Methods: This was an analytical study of a retrospective cohort of patients, discriminated according to idiopathic or drug-induced etiology, followed up for a 7-year period until 31 December 2016. Results: A total of 190 patients were selected for the analysis, 12 (6.3%) with DIAIH. The two main drugs related to DIAIH were nitrofurantoin, n = 8 (67%), and NSAID, n = 2 (17%), constituting 84% of the cases. There were no significant differences in seropositivity between AIH with DIAIH in antinuclear antibodies (ANA) and anti smooth muscle antibodies (ASMA) antibodies, with 82.6% versus 82.6% and 34% versus 16%, respectively. The fibrosis stages were similar, except for the F4 stage, in a greater proportion in AIH. None of the patients with DIAIH had cirrhosis or developed it during follow-up, but it was present in 42.1% of the AIH cases at diagnosis (P = 0.003). Biochemical remission with management was higher in DIAIH but not significant (91.7% vs 80.9%, P = 0.35). The definitive interruption of immunosuppression was successfully performed in 25% of those with DIAIH without relapses but was only possible in 2.8% in AIH (P < 0.001) with 32 cases of relapses. Conclusion: DIAIH constitutes a minor proportion of AIH. The clinical and histological characteristics may be similar; DIAIH patients have a greater chance of having treatment suspended with a low risk of relapse, progression to cirrhosis, or need for liver transplant. PMID- 30483574 TI - Fecal microbiota transplantation: Current status and challenges in China. PMID- 30483572 TI - Postpolypectomy prophylactic clip closure for the prevention of delayed postpolypectomy bleeding: A systematic review. AB - Delayed postpolypectomy bleeding (DPPB) is the most common complication of colonoscopic polypectomy. Prophylactic clipping after an uncomplicated polypectomy is increasingly used, but it is unclear if this results in the prevention of DPPB. This study aimed to review prophylactic clip use and its effect on the rates of DPPB. MEDLINE, Embase, and the Cochran Library were systematically searched for studies (1995-March 2017) that used prophylactic hemoclips and assessed DPPB as an outcome. Of 1402 articles identified, nine papers were eligible for inclusion, evaluating 4311 patients and 7783 polyps; 118 patients experienced a DPPB, and 49 of these patients received prophylactic clips. There was no significant difference in DPPB rates in patients who received prophylactic clipping compared to those who did not (odd ratio: 0.8; 95% confidence interval: 0.36-1.77; P = 0.56). There was also no significant difference in the DPPB of polyps <20 mm compared with polyps >=20 mm. Clip application for prophylactic management of an uncomplicated polypectomy has not been demonstrated to reduce the risk of DPPB, casting doubt on the use of this costly practice. PMID- 30483576 TI - Quality of life in celiac disease and the effect of gluten-free diet. AB - Background and Aim: Patients with celiac disease (CD) have a poor health-related quality of life (HR-QOL). We assessed the QOL in patients with CD using both generic (SF-12) and specific (CD-QOL) questionnaires, and the effect of gluten free diet (GFD) on HR-QOL. Methods: We conducted a prospective follow-up study based on consecutive patients of suspected CD between June 2014 and November 2015. After taking a detailed history, all patients were subjected to laboratory investigations (including complete blood count, biochemistry, and the IgA tTG antibody), followed by endoscopy and duodenal biopsies for histopathology. The HR QOL was assessed using SF-12 and CD-QOL questionnaires. Patients who were strictly adherent to GFD were re-assessed at the end of 6 months for laboratory parameters and QOL. Results: Sixty adult patients of CD, with mean age of 28.85 +/- 12.43 years, and a M:F ratio of 1.3:1, were enrolled in the study. The mean PCS (physical health composite scale score) and MCS (mental health composite scale score) at baseline were 37.20 +/- 11.09 and 41.88 +/- 8.39, which showed a statistically significant improvement after GFD to 50.30 +/- 9.88 and 50.22 +/- 9.04, respectively. Though there was no significant difference in the total CD QOL score after GFD, there was a significant improvement in the dysphoria and health-concern subscales. We also found a negative correlation of the pre-GFD symptom score (based on number of positive symptoms) with PCS and MCS and a positive correlation with the CD-QOL score. Conclusion: This study has shown a reduced HR-QOL in adult CD patients, which improves significantly on GFD, and is associated with a higher symptom number. PMID- 30483577 TI - Epidemiology and clinical course of inflammatory bowel disease in the Central Province of Sri Lanka: A hospital-based study. AB - Background and Aim: There is increasing prevalence of inflammatory bowel disease (IBD) in Asia, but Sri Lankan data on the state of epidemiology and clinical course of IBD are scarce. Methods: A hospital-based study was done by recruiting IBD patients who permanently reside in the Central Province (population 2.57 million, 12.6% of Sri Lankan population) of Sri Lanka. Cases were confirmed by standard criteria and data were collected from health records and patient interviews at clinic visits and hospital admissions. Results: There were 200 cases of IBD; (ulcerative colitis [UC]-140, Crohn's disease [CD]-60, microscopic colitis-7). The crude prevalence rate of UC was 5.44/100 000 (95% CI 5.41 5.47/100 000) and CD was 2.33/100 000 (95% CI 2.31-2.35/100 000). Female to male ratios were 1:0.8 for UC but 1:1.5 for CD.Mean age at diagnosis was 42.0 and 31.9 years for UC and CD, respectively. One UC and one CD patient had positive family history of IBD. Among the UC patients, 60.7%, 24.3%, and 15% had proctitis, left sided, and extensive disease, respectively. At presentation, 62.1% of the UC patients have had moderately severe disease. 60% of the CD patients had only large bowel involvement and 80% had nonstricturing and nonpenetrating disease. Extra intestinal manifestations were present in 45.7% and 60.0% of UC and CD patients, respectively, in which peripheral arthralgia and arthritis being the commonest. 6.4% of UC and 23.3% of the CD patients (total of 23) required infliximab for induction of remission. Conclusion: The prevalence of IBD in the Central Province of Sri Lanka is lower than other Asian and Western populations. There is a predominance of male gender and isolated colonic disease in CD patients. UC patients have an equal gender distribution and a higher proportion of proctitis. CD needed induction with infliximab than UC. PMID- 30483575 TI - Antifibrogenic effect of melatonin in rats with experimental liver cirrhosis induced by carbon tetrachloride. AB - Background and Aim: Liver diseases are a major public health problem, accounting for a significant number of hospital visits and admissions and an increasing mortality rate. Melatonin (MLT) is a powerful antioxidant molecule that has been shown to be beneficial under various conditions. The objective was to evaluate the effect of MLT on experimental liver cirrhosis induced by carbon tetrachloride (CCl4) in rats. Methods: Twenty male Wistar rats (230-250 g) were divided into four groups. I: control group (CO); II: CO + MLT; III: CCl4; and IV: CCl4 + MLT. CCl4 was administered intraperitoneally (i.p.) as follows: 10 doses every 5 days, 10 doses every 4 days, and 7 doses every 3 days. MLT was administered i.p. at a dose of 20 mg/kg from the 10th week to the end of the experiment (16th week). Results: In the CCl4 + MLT group, we found that MLT caused a decrease in the level of F2-isoprostanes and NQO1 expression. We also found that MLT reduced the inflammatory process as shown by decreased expressions of NF-KB/p65 and inducible nitric oxide synthase (iNOS) and a smaller amount of inflammatory infiltrate. MLT reduced the expression of transforming growth factor beta1 (TGF-beta1), alpha smooth muscle actin (alpha-SMA), and vascular endothelial growth factor (VEGF). Picrosirius staining showed that MLT decreases fibrosis. Conclusion: MLT has a potent antifibrogenic effect, modulating the parameters of oxidative stress, angiogenesis, and inflammation. PMID- 30483578 TI - Differences between the outcome of recurrent acute pancreatitis and acute pancreatitis. AB - Background and aim: Overall, a handful of studies are available on the outcomes of recurrent acute pancreatitis (RAP), in comparison to the first episode of acute pancreatitis (AP). We aimed to provide a more complete and updated picture of RAP and how it is different from the initial episode of AP. Methods: Consecutive patients admitted with an episode of AP over 8 years were divided into two groups on the basis of prior episodes: AP and RAP. Primary outcome measures were for surgical necrosectomy and mortality. Results: Of the 724 patients (age 39.22 +/- 13.25 years, 68% male) with an episode of pancreatitis, 632 (87.3%) had presented with a first episode (AP) and 92 (12.7%) with at least one prior episode (RAP). The incidence of severe pancreatitis was significantly less in RAP patients (10.9%) in comparison to AP patients (48.6%). The requirement of surgical intervention and mortality were less in patients with RAP (1.1 and 2.2%, respectively) compared to patients with AP (9.3 and 18%, respectively). The mean number of episodes per RAP patients was 2.97 +/- 1.66 (range 2-10), and 64.1% had only two episodes. Regarding the etiology of RAP patients, biliary etiology (32.6%) and alcohol (30.4%) were the two most frequent factors, and no etiology could be identified in 19.6%. Conclusion: Patients with RAP had milder disease course and lesser mortality when compared to the initial episode of AP. Appropriate evaluation and dealing with etiological factors at the initial episode of AP can prevent a majority of RAP. PMID- 30483579 TI - Design and methodology of a study on colorectal cancer in Johannesburg, South Africa. AB - Background and Aim: Cancer is one of the foremost causes of morbidity and mortality worldwide. Globally, colorectal cancer (CRC) is the third most diagnosed and fourth most important cause of cancer death. A total of 70% of all CRC-related deaths occur in low- and middle-income countries. In Sub-Saharan Africa (SSA), estimating the burden of CRC is difficult. Only 27 of 43 SSA countries have formalized cancer registration systems; data quality is variable and national coverage rare. Methods: This is a multidisciplinary, longitudinal cohort study started in January 2016. Patients >18 years with histologically confirmed primary adenocarcinoma of the colon and rectum, diagnosed within the previous 12 months, are eligible. Participants were assessed and were followed up for 3 years. Baseline information, including demographics, socioeconomic status, family history, medical and surgical non-cancer-related history, dietary history, colonoscopic findings, staging at presentation, treatment, and disease recurrence, is collected, as well as blood tests and histology results. Outcomes include disease recurrence (local and metastatic) and survival. Results and Conclusion: This study aims to describe the clinical presentation, management, and outcomes of adults with CRC in a multiethnic, urban South African population. It will be the first prospective study to describe clinical presentation, demographics, risk factors, treatment, and outcomes according to population group, from both private and state health-care facilities in Johannesburg, South Africa. The results of this study will be relevant not only to South Africa but also to other SSA countries undergoing similar rates of rapid urbanization and epidemiological transition. PMID- 30483580 TI - Treatment of fecal impaction in children using combined polyethylene glycol and sodium picosulphate. AB - Background and Aim: Polyethylene glycol (PEG) is the gold standard for fecal disimpaction in constipation. A regimen of PEG combined with the stimulant laxative sodium picosulphate (SPS) produced fecal disimpaction in chronically constipated children in the community, but it is unknown if it is effective for more severe constipation. To determine the stool output and effect of a combined PEG and SPS regimen on fecaloma in children with severe constipation and impaction. Methods: Children with symptoms for a duration of >=2 years, a palpable fecaloma, and enlarged rectum on X-ray (rectal: pelvic ratio > 0.6) were recruited from a tertiary hospital. Daily diaries recorded laxative dose, stool frequency, volume, and consistency (Bristol stool scale, BSS). Abdominal X-rays were taken on day 1 and day 8, and stool loading was assessed using the Leech score. Laxative doses were based on the child's age. The dose of PEG with electrolytes taken was 2-8 sachets (14.7 g/sachet) on days 1-2, reducing to 2-6 sachets on day 3. The SPS dose was 15-20 drops on days 2-3. Results: Eighty-nine children (4-18 years) produced a large volume of soft stool (median/inter quartile-range: 2.2/1.6-3.1 L) over 7 days. Stool volume on X-rays decreased significantly in the colon (P < 0.001). Fecalomas resolved in 40 of 89 children, while 49 needed a second high dose. Rectal:pelvic ratios did not change. Conclusions: A combined high dose of PEG and SPS on days 1 and 2 was effective in removing the fecaloma in half of the children. Administering high doses for a longer period should be tested to provide outpatient disimpaction for severe fecalomas. Rectums remained flaccid after emptying. PMID- 30483581 TI - Is obesity rather than the dietary supplement used for weight reduction the cause of liver injury? AB - Acute liver injury has been attributed to dietary supplements (DS) used for weight loss, but their causal role was much questioned, and obesity as an alternative cause of the liver injury remained unclear. A comprehensive search of the Medline database was conducted with terms that included "DS," "liver injury," "obesity," "obesity-related liver diseases," and "nonalcoholic steatohepatitis." For each term, we focused on the first 50 publications. We undertook a manual search to identify additional reports. Underlying liver diseases and other health issues are common in patients taking DS for weight reduction. These include obesity or morbid obesity, as well as complex metabolic disorders complicated by excess morbidity and mortality due to associated liver diseases. Among these are nonalcoholic fatty liver disease with potential progression to nonalcoholic steatohepatitis and cirrhosis, often classified as cryptogenic with a rare risk of hepatocellular carcinoma. With the exception of hepatocellular carcinoma, these obesity-related liver diseases were observed to varying degrees in patients, and some even required a liver transplant. This raises the question whether the liver injury that occurred in these patients is due to DS consumed for weight loss or to the underlying obesity-related liver diseases. This analysis showed that, in many instances, the causal role of obesity has been neglected. Obesity-associated liver diseases should be considered as differential diagnosis of liver injury in obese patients using DS. PMID- 30483583 TI - Histoplasmosis-induced ileal perforation in a patient with acquired immune deficiency syndrome: Case report. AB - Intestinal involvement with disseminated histoplasmosis is common in some populations infected with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), especially in those who come from tropical zones. We report the case of a 29-year-old male patient, from a tropical zone, with HIV infection and a CD4 value less than 50 cells/mm3, with a history of abdominal pain, fever, diarrhea, and weight loss. On presentation, he was pale, sweaty, and had abdominal rebound tenderness. Laboratory findings demonstrated microcitic hipocromic anemia, azoemia, and hypoalbuminemia. Abdominal-X-rays revealed pneumoperitoneum and air fluid levels. He underwent surgery, and a 1-cm perforation proximal to ileocecal valve was found. A resection and an ileostomy were performed. Histopathology identified caseating granulomas with yeast, compatible with histoplasmosis. He was treated with anfotericin B plus itraconazol with clinical improvement. PMID- 30483584 TI - Editor's note. PMID- 30483582 TI - Systematic review of histological remission criteria in eosinophilic esophagitis. AB - Elemental diets, dietary elimination, and steroid therapies are the most common therapies in the clinical trials for eosinophilic esophagitis (EoE). Histological findings (usually reported as eosinophils per microscopic high-powered field [hpf]) remain the most common end-point used to define response. Yet, the threshold for defining "response" and "remission" are ill-defined among consensus guidelines and may vary from study to study. We conducted a systematic literature review of articles on eosinophilic esophagitis, published between January 2007 and November 2017, considering histological remission as the primary outcome. We abstracted treatment information and definitions of histological remission or response. A comparison of definitions of histological remission across and within institutions was performed. A total of 61 articles were included in this review, with approximately 60% of the studies published from centers in the United States. Histological definitions of remission of EoE ranged from 0 to <=20 eosinophils/hpf. The most stringent criteria, ranging from 0 to <=5 eosinophils/hpf, were commonly used in interventional trial studies that examined the effects of new treatments. We found remarkable variability in definitions between studies, treatment types, and regions. Age or epidemiological distribution of study subjects did not influence the criteria for histological remission. Clinical and histological improvements are important measures of the effects of treatment. Histological findings, the most objective measure of treatment, should provide an optimal method for comparing the effectiveness of various treatments. Yet, our findings suggest a lack of consistent remission criteria in published studies. Considering these inconsistencies, it is difficult to compare the effectiveness of various treatments. PMID- 30483585 TI - Changes in transient elastography in early cirrhotic patients after receiving nonselective B-blocker for primary variceal bleeding prophylaxis: Three-month follow up. AB - Background and Aim: A nonselective B-blocker (NSBB) is recommended for primary prophylaxis of variceal bleeding. The impact of treatment with NSBB on modulating transient elastography (TE) has not been reported. The aim of the study is to investigate the effect of NSBB treatment on TE in early cirrhotic patients. Methods: In this prospective study, we enrolled all early cirrhotic patients who underwent esophagogastroduodenoscopy (EGD) and showed small esophageal varices (EV) at our institute for a period of 1 year. The TE and heart rate (HR) of all participants were measured before and 3 months after receiving NSBB. Results: Thirty-nine patients receiving propanolol for 3 months were analyzed. There were 16 patients in the HR responder group (41%) and 23 patients in the HR nonresponder group (59%). The reduction of TE was preferably found in the HR responder group compared with the HR nonresponder group, in which mean changes in TE were -5.6 and -0.7 kPa, respectively (P = 0.23). In addition, we categorized the patients using their TE responses. Twenty-five patients (64.1%) showed reduced TE during the follow-up period, in which the mean TE value change was 2.94 kPa. Using correlation analysis, TE and HR responses were insignificantly correlated (r = 0.23, P = 0.15). Conclusion: The NSBB administered for 3 months mainly improved TE value in early cirrhotic patients even though the changes of HR and TE did not correlate. Further study is needed to confirm whether the monitoring of TE change may be a better predictor for pharmacological response than the HR response. PMID- 30483586 TI - Early experience with a low FODMAP diet in Asian patients with irritable bowel syndrome. AB - Background: The efficacy and acceptance of a low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet in Asian adults with irritable bowel syndrome (IBS) remain uncertain. We aimed to describe our early experience in a single center with a dedicated gastroenterology dietetic service. Methods: Consecutive patients with IBS referred to our dedicated Dietetic Gastroenterology Clinic between February 2016 and May 2016 were screened. A low FODMAP diet was instituted as per standard protocol. Data on demographic and clinical variables were obtained from patients' records and prospective telephone interviews. Results: A total of 16 patients, with a median age of 67 +/- 13.57 years; female gender n = 10 (62.5%); ethnicity: Chinese n = 8 (50%), Indian n = 5 (31.25%), and Malay n = 3 (18.75%) with IBS, were included in the study. Compliance with the low FODMAP diet was complete in 8 of 16 (50%) patients, partial in 4 of 16 (25%), and 4 of 16 (25%) could not comply with the diet at all. Improvement in symptoms were reported in 11 of 16 (68.8%) patients. Among patients who complied (complete/partial) with the low FODMAP diet, predominant symptom improvement was reported as follows: abdominal pain 3 of 5 (60%), abdominal bloating/distension 7 of 10 (70%), and flatulence 7 of 8 (87.5%). Patients with the IBS-D subtype appeared to have the greatest improvement in stool consistency (87.5% IBS-D vs 12.5% non-IBS-D, P = 0.009). Conclusion: Based on our pilot observational study of a relatively small sample of Asian IBS patients, compliance with a low FODMAP diet appears to be low. Further larger studies are required to verify our observation. PMID- 30483587 TI - Risk factors for postoperative infection after gastrointestinal surgery among adult patients with inflammatory bowel disease: Findings from a large observational US cohort study. AB - Background and Aim: Postoperative infection (POI) is a major source of morbidity and prolongation of hospitalization in inflammatory bowel disease (IBD) patients. This large observational study was conducted to further describe risk factors and to quantify the proportion of POIs that are preventable. Methods: We conducted a retrospective cohort analysis of the Optum US health insurance claims database. The study population included adults with ulcerative colitis (UC) or Crohn's disease (CD) who underwent lower gastrointestinal (GI) surgery of small intestine, colon, rectum, or anus during September 2014 to September 2016. Multiple logistic regression was used to identify and quantify risk factors and determine the proportion of infections that are preventable. Results: A total of 3360 adult IBD patients with lower GI surgery were included in the study. Their mean age was 51 years, 52.5% were women, and 59.5% had CD. The 30-day POI incidence was 15.1% (95% confidence interval: 14.0-16.4%). We identified the following nonmodifiable or procedural risk factors: history of POI, open procedure, red blood cell transfusion within 6 months, preoperative hospital stay of at least 4 days, lower GI ostomy surgery, lower GI resection surgery, and a history of chronic obstructive pulmonary disease. Modifiable risk factors included corticosteroid use and anemia prior to surgery, but few infections were attributable to these modifiable factors. Conclusions: This large, observational, real-world evidence study from the US found that the majority of the observed risk factors were nonmodifiable or procedure-related. Corticosteroid use and anemia before surgery were identified as modifiable risk factors. PMID- 30483588 TI - Value of routine duodenal mucosal biopsies in the evaluation of anemia in a large Australian referral centre. AB - Background and Aim: Small bowel mucosal biopsies (SBBx) are routinely performed to investigate unexplained anemia; however, previous studies have demonstrated a low yield in diagnosing celiac disease. Our aim was to determine the yield of routine SBBx in a large cohort of patients who underwent gastroscopy for the investigation of anemia. Methods: Data from consecutive patients who underwent gastroscopy for the investigation of anemia in a tertiary hospital, from January 2008-December 2011, were prospectively collected. Measured outcomes were the prevalence of celiac disease, the yield of duodenal biopsies, and the correlation between celiac serology and diagnosis. Results: Over 4 years, 987 patients (385 M:602 F; 48.27 +/- 15.89 years) underwent endoscopy for anemia, of which 534 (54.1%) had proven iron deficiency anemia (IDA). Abnormal SBBx consistent with celiac disease were found in 2% (22/987), with a higher prevalence in females (3.2%, n = 19 vs 0.8%, n = 3 in males) and in those with IDA (3.6%, n = 19 vs 0.7%, n = 3 in non-IDA). Macroscopic endoscopic abnormalities were present in 86% (19/22) of patients with celiac disease. Of the 178 patients who had celiac serology, tissue transglutaminase antibody had the highest sensitivity (80%) and specificity (99%). Combined serology had a sensitivity of 85.7%. Conclusion: Only 2% of patients with unexplained anemia had abnormal SBBx consistent with celiac disease and even fewer patients in non-IDA. Given the availability and high sensitivity of celiac serology and macroscopic changes on endoscopy, SBBx should not be routine during endoscopy but should be limited to those with positive celiac serology, abnormal endoscopic appearance, or females with IDA. PMID- 30483589 TI - Anemia in celiac disease is multifactorial in etiology: A prospective study from India. AB - Background and Aims: Anemia is one of the most common extraintestinal manifestations of celiac disease (CD), with iron deficiency anemia (IDA) being the predominant cause. However, anemia in CD can have varied etiologies, including mixed nutritional deficiency. We aimed to study the prevalence and etiology of anemia in CD in a north Indian population. Methods: In this prospective observational study, consecutive patients with documented CD between January 2012 and December 2013 were included, and all patients underwent detailed clinical assessment; hematological investigations including iron profile, serum folate, and vitamin B12 levels; and esophageoduodenoscopy with duodenal biopsies for histopathological examination. Prevalence of anemia and different deficiencies were calculated, and a correlation between hematological parameters and histological findings was found. Results: Of the 103 patients studied, anemia was detected in 96 patients, giving a prevalence of 93.2% with a baseline hemoglobin of 8.94 +/- 2.54 g/dL. Overall, iron deficiency was seen in 84 (81.5%) patients, followed by vitamin B12 deficiency in 14 (13.6%) and folate deficiency in 11 (10.7%) patients; 17 (16.5%) patients had anemia due to mixed nutritional deficiencies, and 4 (3.9%) patients had anemia of chronic disease. The mean hemoglobin and median ferritin levels were significantly lower in patients with severe villous atrophy compared to those with mild atrophy. Conclusion: Anemia in patients with CD is multifactorial. Even though iron deficiency is the most common cause, other nutrient deficiencies should always be explored. PMID- 30483590 TI - Fecal calprotectin correlates with active colonic inflammatory bowel disease but not with small intestinal Crohn's disease activity. AB - Background: The utility of fecal calprotectin (FC) in small intestinal Crohn's disease (CD) is unclear. We examined how reliably FC reflects clinical and mucosal disease activity in small intestinal CD, colonic CD, and ulcerative colitis (UC). Methods: A total of 72 Inflammatory Bowel Disease (IBD) patients (23 colonic CD, 14 isolated small intestinal CD, and 35 UC) were included. Clinical activity was assessed using the Harvey-Bradshaw Index (HBI) (CD) and Mayo score (UC). Inflammatory activity was assessed through ileocolonoscopy, cross-sectional imaging, C-reactive protein (CRP), and FC. Clinical activity was defined as HBI > 4 or Mayo clinical score >= 3. Endoscopy activity was defined as Mayo endoscopic subscore >= 1, SES-CD score >= 3, and Rutgeerts > i1. Results: In UC, FC was correlated with the Mayo clinical score (P < 0.0001) and was highly correlated with the total Mayo score (P < 0.0001). A cut-off value of FC 100 MUg/g provided sensitivity of 88% and specificity 100% for endoscopic activity. FC was lower for patients with endoscopic and clinical remission compared to active endoscopic disease (median 100 vs 1180 MUg/g, P < 0.0001). In colonic CD, there was a significant correlation between FC and endoscopic activity (P < 0.001). For an FC cut-off value of 100 MUg/g, sensitivity was 100%, and specificity was 67%. In contrast, for isolated small intestinal CD, there was no significant correlation between FC and objective disease activity measured by either endoscopy or imaging (AUC 0.52, P = 0.58). Conclusion: FC is reliable for the detection of colonic mucosal inflammation in both UC and CD but is less sensitive and reliable in the detection of small intestinal CD. PMID- 30483591 TI - Optimal cut-off value of fecal calprotectin for the evaluation of ulcerative colitis: An unsolved issue? AB - Introduction: There is variability in the fecal calprotectin (FCP) cut-off level for the prediction of ulcerative colitis (UC) disease activity and differentiation from irritable bowel disease (IBS-D). The FCP cut-off levels vary from country to country. Aims: We aimed to assess FCP as a marker of disease activity in patients with UC. We determined the optimal FCP cut-off value for differentiating UC and IBS-D. Methods: In a prospective study, we enrolled 76 UC and 30 IBS-D patients. We studied the correlation of FCP with disease activity/extent as well as its role in differentiating UC from IBS-D. We also reviewed literature regarding the optimal FCP cut-off level for the prediction of disease activity and differentiation from IBS-D patients. Results: Sensitivity, specificity, positive predictive value, and negative predictive value of FCP (cut off level, 158 MUg/g) for the prediction of complete mucosal healing (using Mayo endoscopic subscore) were 90, 85, 94.7, and 73.3%, respectively. Sensitivity, specificity, positive predictive value, and negative predictive value of FCP (cut off level, 425 MUg/g) for the prediction of inactive disease (Mayo Score <= 2) were 94.3, 88.7, 86.2, and 95.4%, respectively. We also found a FCP cut-off value of 188 MUg/g for the differentiation of UC from IBS-D. Conclusions: The study reveals the large quantitative differences in FCP cut-off levels in different study populations. This study demonstrates a wide variation in FCP cut-off levels in the initial diagnosis of UC as well as in follow-up post-treatment. Therefore, this test requires validation of the available test kits and finding of appropriate cut-off levels for different study populations. PMID- 30483592 TI - The incidence of esophageal cancer and dysplasia in a Chinese population with nondysplastic Barrett's esophagus. AB - Aim: The aim of this study was to investigate the incidence of dysplastic transformation of Barrett's esophagus (BE) in a Chinese population. Method: Data from nondysplastic BE patients at Taichung Veterans General Hospital were collected from May 2008 to June 2017. The enrolled individuals received regular upper gastrointestinal (UGI) endoscopy during follow up. The pathological transformations, including low-grade dysplasia (LGD), high-grade dysplasia (HGD), or esophageal adenocarcinoma (EAC), were collected prospectively until June 2017. Rates of progression were calculated in cases with a diagnosis of dysplasia or EAC. Results: There were 51 subjects who met the inclusion criteria, with a mean follow up of 3.71 years (SD, 1.61) and a total follow up of 189.1 patient-years. Eight cases (15.7%) developed LGD, with a calculated incidence rate of 2.9% per year. The mean time to development of LGD was 3.26 years (SD, 2.68-3.84). One subject (2%) developed EAC, with a calculated incidence rate of 0.4% per year. No case with HGD was detected. Conclusion: In a Chinese population with nondysplastic BE, 15.7% of cases developed LGD, with an incidence rate of 2.9% per year, and 2% of cases developed EAC, with an incidence rate of 0.4% per year. PMID- 30483593 TI - Characterization of ulcerative colitis-associated constipation syndrome (proximal constipation). AB - Background: The syndrome of constipation with other abdominal symptoms ("proximal constipation") in ulcerative colitis (UC) is commonly recognized by practitioners but is poorly described, with no recognized definition and little understanding with regard to prevalence and effect of therapies on disease outcomes. This study aimed to address these issues in a cross-sectional, consecutive series of patients with UC. Methods: A working definition of proximal constipation was established. Consecutive patients were recruited, and their disease activity, recent medications, and investigations plus abdominal symptoms were assessed at a study visit. Relevant clinical data were also extracted from medical records. Results: Of 125 patients with UC, (mean age 47, range 14-84 years, 61 male), 58 (46%) fulfilled the definition of proximal constipation. The main symptoms were reduced stool frequency (69%), hard stools (43%), abdominal pain (40%), excessive flatus (29%), straining (24%), and sensation of incomplete emptying (14%). Proximal constipation was associated with female gender (OR 3.45 [1.45-8.24]), left-sided (OR 2.84 [1.14-7.11]) and concurrently active disease (OR 5.56 [1.96 16.67]), but not age, disease duration or therapy. A total of 88% had an increase in anti-inflammatory therapy, with the use of laxatives or fiber supplements in 63% compared with 1.4% of those without proximal constipation. Conclusions: Proximal constipation is common, and its risk increases in active and distal disease, especially in women. Validation of its definition and evaluation of therapeutic strategies are needed. A new term "ulcerative colitis-associated constipation syndrome" is proposed to more accurately depict its nature. PMID- 30483595 TI - Epidemiology of non-alcoholic fatty liver disease-related hepatocellular carcinoma and its implications. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related mortality worldwide. Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver pathology that is characterized by the excessive accumulation of fat in the liver attributable to overnutrition and is strongly associated with the metabolic syndrome. Non-alcoholic steatohepatitis is the more severe form of NAFLD that is defined histologically by the presence of lobular inflammation and hepatocyte ballooning. Non-alcoholic steatohepatitis patients have a greater tendency to develop advanced liver fibrosis, cirrhosis, and HCC. This review focuses on the epidemiology of NAFLD related HCC and its implications. NAFLD has been estimated to contribute to 10 12% of HCC cases in Western populations and 1-6% of HCC cases in Asian populations. NAFLD-related HCC is expected to increase in Asian populations, in line with the increased prevalence of NALFD similar to that of Western populations in recent years. The increasing burden of NAFLD-related HCC over time has been demonstrated in studies from both Western and Asian populations. Certain factors such as ethnicity, obesity, and diabetes mellitus appear to have an incremental effect on the risk of developing HCC among NAFLD patients. The difficulty in identifying NAFLD patients with cirrhosis and the possibility of HCC developing in noncirrhotic NAFLD patients are challenges that need to be addressed. Further understanding of these gaps may contribute to better surveillance strategies for the early detection of HCC in NAFLD patients to reduce the mortality and improve the survival of these patients. PMID- 30483594 TI - A review of vedolizumab and ustekinumab for the treatment of inflammatory bowel diseases. AB - Recent advancement in the understanding of the pathophysiology of inflammatory bowel disease has seen an expansion in therapeutic options. Vedolizumab, a selective alpha4beta7 inhibitor, and ustekinumab, an IL 12/23 p40 inhibitor, have provided the much-awaited out-of-class alternatives for patients who have failed or who are intolerant to anti-Tumor Necrosis Factor (TNF) therapy. However, questions remain as to how we may best use these novel therapeutic agents. We evaluate the evidence available from randomized controlled trials and postmarketing cohort studies and discuss their safety, efficacy, and limitations, in relation to anti-TNF therapy, in optimizing the treatment outcomes. PMID- 30483596 TI - Kombiglyze (metformin and saxagliptin)-induced hepatotoxicity in a patient with non-alcoholic fatty liver disease. AB - A 33-year-old man was referred with hyperosmotic symptoms of 4 weeks. Clinical examination showed palpable hepatomegaly and no stigmata of liver disease. Findings were random glucose 16.6 mmol/L, HbA1c 12.4%, triglyceride 6.2 mmol/L, normal LFTs and ultrasound liver: increased echogenicity. Management consisted of dietician referral and commencement of metformin 500 mg bd, diamicron MR 60 mg od, and fenofibrate 145 mg od. He was non-compliant, complaining of "heaviness of head" after consuming oral diabetic agents, without symptoms of hypoglycemia. Treatment was switched to Kombiglyze XR (saxaglipitin 5 mg + metformin 1000 mg) and empagliflozin 25 mg od. He presented 1 week later with generalised pruritus with ALT 307 IU/L and serum GGT 808 IU/L. Following this, a percutaneous liver biopsy was performed, revealing steatohepatitis and marked intra-hepatic cholestasis. Kombiglyze XR was withheld, with resolution of LFTs to baseline. Phenotypes of liver injury are categorised according to R value, defined as ratio ALT/ULN:ALP/ULN. R value of >=5:hepatocellular injury, <=2:cholestatic injury, 2 5:mixed-type injury. Here, R value points toward mixed type (R = 3.203). Hepatotoxicity in patients with NASH is difficult to diagnose, based on laboratory parameters. Liver histology was useful in indicating additional changes apart from NASH, causing liver derangement. The Rousal Uclaf Causality Assessment Method is a scoring method to determine the probability of drug induced liver injury. RUCAM score for this case was 6 (probable adverse drug reaction). Hepatotoxicity from saxagliptin not been reported prior. Clinicians need to be more vigilant, particularly in patients with NASH. PMID- 30483597 TI - Evaluating the performance of tools used to call minority variants from whole genome short-read data. AB - Background: High-throughput whole genome sequencing facilitates investigation of minority sub-populations from virus positive samples. Minority variants are useful in understanding within and between host diversity, population dynamics and can potentially help to elucidate person-person transmission chains. Several minority variant callers have been developed to describe the minority variants sub-populations from whole genome sequence data. However, they differ on bioinformatics and statistical approaches used to discriminate sequencing errors from low-frequency variants. Methods: We evaluated the diagnostic performance and concordance between published minority variant callers used in identifying minority variants from whole-genome sequence data. The ART-Illumina read simulation tool was used to generate three artificial short-read datasets of varying coverage and error profiles from an RSV reference genome. The datasets were spiked with nucleotide variants at predetermined positions and frequencies. Variants were called using FreeBayes, LoFreq, Vardict, and VarScan2. The variant callers' agreement in identifying known variants was quantified using two measures; concordance accuracy and the inter-caller concordance. Results: The variant callers reported differences in identifying minority variants from the datasets. Concordance accuracy and inter-caller concordance were positively correlated with sample coverage. FreeBayes identified majority of the variants although it was characterised by variable sensitivity and precision in addition to a high false positive rate relative to the other minority variant callers and which varied with sample coverage. LoFreq was the most conservative caller. Conclusions: We conducted a performance and concordance evaluation of four minority variant calling tools used to identify and quantify low frequency variants. Inconsistency in the quality of sequenced samples impact on sensitivity and accuracy of minority variant callers. Our study suggests that combining at least three tools when identifying minority variants is useful in filtering errors when calling low frequency variants. PMID- 30483598 TI - A blind spot? Confronting the stigma of hepatitis B virus (HBV) infection - A systematic review. AB - Background: The Global Hepatitis Health Sector Strategy is aiming for the elimination of viral hepatitis as a public health threat by 2030. Successful diagnostic, treatment and preventive strategies can reduce incidence and morbidity; it is important to ensure that these interventions and services are not only available, but also accessible. Stigma, poverty, and lack of knowledge may present a substantial barrier, especially in resource limited settings. We therefore set out to assimilate evidence for the nature and impact of stigma on the lives of people with HBV infection and on the community, and to suggest ways to tackle stigma and discrimination. Methods: We carried out a literature search in PubMed using the search terms 'hepatitis B', 'stigma' to identify relevant papers published between 2007 and 2017 (inclusive), with a particular focus on Africa. Results: We identified a total of 34 articles, of which only one study was conducted in Africa. Lack of knowledge on HBV was consistently identified: there were misconceptions about HBV transmission among the public, healthcare workers (HCWs) provided inaccurate information to individuals diagnosed with HBV, and poor understanding resulted in lack of preventive precautions. Stigma negatively impacted on health behaviour such as help-seeking, screening, disclosure, prevention of transmission, and adherence to treatment. Conclusion: Stigma is a potentially major barrier to the successful implementation of preventive, diagnostic and treatment strategies for HBV infection, and yet there is very limited recognition of the magnitude of this challenge, especially in Africa. There is a need for more research in this area, to identify and evaluate interventions that can be used effectively to tackle stigma in HBV, and to inform collaborative efforts between policy makers, HCWs, traditional healers, religious leaders, charity organisations and support groups, to improve awareness and tackle stigma in HBV in Africa. PMID- 30483599 TI - Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapse. AB - Background: Mutations of the common cytokine receptor gamma chain (gammac) cause Severe Combined Immunodeficiency characterized by absent T and NK cell development. Although stem cell therapy restores these lineages, residual immune defects are observed that may result from selective persistence of gammac deficiency in myeloid lineages. However, little is known about the contribution of myeloid-expressed gammac to protective immune responses. Here we examine the importance of gammac for myeloid dendritic cell (DC) function. Methods: We utilize a combination of in vitro DC/T-cell co-culture assays and a novel lipid bilayer system mimicking the T cell surface to delineate the role of DC-expressed gammac during DC/T-cell interaction. Results: We observed that gammac in DC was recruited to the contact interface following MHCII ligation, and promoted IL 15Ralpha colocalization with engaged MHCII. Unexpectedly, trans-presentation of IL-15 was required for optimal CD4+T cell activation by DC and depended on DC gammac expression. Neither recruitment of IL-15Ralpha nor IL-15 trans-signaling at the DC immune synapse (IS), required gammac signaling in DC, suggesting that gammac facilitates IL-15 transpresentation through induced intermolecular cis associations or cytoskeletal reorganization following MHCII ligation. Conclusions: These findings show that DC-expressed gammac is required for effective antigen-induced CD4+ T cell activation. We reveal a novel mechanism for recruitment of DC IL-15/IL-15Ralpha complexes to the IS, leading to CD4+ T cell costimulation through localized IL-15 transpresentation that is coordinated with antigen-recognition. PMID- 30483600 TI - ICR142 Benchmarker: evaluating, optimising and benchmarking variant calling using the ICR142 NGS validation series. AB - Evaluating, optimising and benchmarking of next generation sequencing (NGS) variant calling performance are essential requirements for clinical, commercial and academic NGS pipelines. Such assessments should be performed in a consistent, transparent and reproducible fashion, using independently, orthogonally generated data. Here we present ICR142 Benchmarker, a tool to generate outputs for assessing variant calling performance using the ICR142 NGS validation series, a dataset of exome sequence data from 142 samples together with Sanger sequence data at 704 sites. ICR142 Benchmarker provides summary and detailed information on the sensitivity, specificity and false detection rates of variant callers. ICR142 Benchmarker also automatically generates a single page report highlighting key performance metrics and how performance compares to widely-used open-source tools. We used ICR142 Benchmarker with VCF files outputted by GATK, OpEx and DeepVariant to create a benchmark for variant calling performance. This evaluation revealed pipeline-specific differences and shared challenges in variant calling, for example in detecting indels in short repeating sequence motifs. We next used ICR142 Benchmarker to perform regression testing with versions 0.5.2 and 0.6.1 of DeepVariant. This showed that v0.6.1 improves variant calling performance, but there was evidence of some minor changes in indel calling behaviour that may benefit from attention in future updates. The data also allowed us to evaluate filters to optimise DeepVariant calling, and we recommend using 30 as the QUAL threshold for base substitution calls when using DeepVariant v0.6.1. Finally, we used ICR142 Benchmarker with VCF files from two commercial variant calling providers to facilitate optimisation of their in-house pipelines and to provide transparent benchmarking of their performance. ICR142 Benchmarker consistently and transparently analyses variant calling performance based on the ICR142 NGS validation series, using the standard VCF input and outputting informative metrics to enable user understanding of pipeline performance. ICR142 Benchmarker is freely available at https://github.com/RahmanTeamDevelopment/ICR142_Benchmarker/releases. PMID- 30483603 TI - Forensic science: defending justice. PMID- 30483602 TI - Human rhinovirus spatial-temporal epidemiology in rural coastal Kenya, 2015-2016, observed through outpatient surveillance. AB - Background: Human rhinovirus (HRV) is the predominant cause of upper respiratory tract infections, resulting in a significant public health burden. The virus circulates as many different types (~160), each generating strong homologous, but weak heterotypic, immunity. The influence of these features on transmission patterns of HRV in the community is understudied. Methods: Nasopharyngeal swabs were collected from patients with symptoms of acute respiratory infection (ARI) at nine out-patient facilities across a Health and Demographic Surveillance System between December 2015 and November 2016. HRV was diagnosed by real-time RT PCR, and the VP4/VP2 genomic region of the positive samples sequenced. Phylogenetic analysis was used to determine the HRV types. Classification models and G-test statistic were used to investigate HRV type spatial distribution. Demographic characteristics and clinical features of ARI were also compared. Results: Of 5,744 NPS samples collected, HRV was detected in 1057 (18.4%), of which 817 (77.3%) were successfully sequenced. HRV species A, B and C were identified in 360 (44.1%), 67 (8.2%) and 390 (47.7%) samples, respectively. In total, 87 types were determined: 39, 10 and 38 occurred within species A, B and C, respectively. HRV types presented heterogeneous temporal patterns of persistence. Spatially, identical types occurred over a wide distance at similar times, but there was statistically significant evidence for clustering of types between health facilities in close proximity or linked by major road networks. Conclusion: This study records a high prevalence of HRV in out-patient presentations exhibiting high type diversity. Patterns of occurrence suggest frequent and independent community invasion of different types. Temporal differences of persistence between types may reflect variation in type-specific population immunity. Spatial patterns suggest either rapid spread or multiple invasions of the same type, but evidence of similar types amongst close health facilities, or along road systems, indicate type partitioning structured by local spread. PMID- 30483601 TI - Novel Wolbachia strains in Anopheles malaria vectors from Sub-Saharan Africa. AB - Background: Wolbachia, a common insect endosymbiotic bacterium that can influence pathogen transmission and manipulate host reproduction, has historically been considered absent from the Anopheles (An.) genera, but has recently been found in An. gambiae s.l. populations. As there are numerous Anopheles species that have the capacity to transmit malaria, we analysed a range of species to determine Wolbachia prevalence rates, characterise novel Wolbachia strains and determine any correlation between the presence of Plasmodium, Wolbachia and the competing endosymbiotic bacterium Asaia. Methods: Anopheles adult mosquitoes were collected from five malaria-endemic countries: Guinea, Democratic Republic of the Congo (DRC), Ghana, Uganda and Madagascar, between 2013 and 2017. Molecular analysis of samples was undertaken using quantitative PCR, Sanger sequencing, Wolbachia multilocus sequence typing (MLST) and high-throughput amplicon sequencing of the bacterial 16S rRNA gene. Results: Novel Wolbachia strains were discovered in five species: An. coluzzii, An. gambiae s.s., An. arabiensis, An. moucheti and An. species 'A', increasing the number of Anopheles species known to be naturally infected. Variable prevalence rates in different locations were observed and novel strains were phylogenetically diverse, clustering with Wolbachia supergroup B strains. We also provide evidence for resident strain variants within An. species 'A'. Wolbachia is the dominant member of the microbiome in An. moucheti and An. species 'A', but present at lower densities in An. coluzzii. Interestingly, no evidence of Wolbachia/Asaia co-infections was seen and Asaia infection densities were also shown to be variable and location dependent. Conclusions: The important discovery of novel Wolbachia strains in Anopheles provides greater insight into the prevalence of resident Wolbachia strains in diverse malaria vectors. Novel Wolbachia strains (particularly high-density strains) are ideal candidate strains for transinfection to create stable infections in other Anopheles mosquito species, which could be used for population replacement or suppression control strategies. PMID- 30483605 TI - Accident or crime? About the meaning of face injuries inflicted by blunt force. AB - Injuries caused by blunt force are seen frequently in daily forensic casework. Sometimes, especially when there is less information about the surrounding circumstances, it might become difficult to figure out the cause and background of injuries: accident, criminal violence or self-infliction? In the study presented, face injuries caused by blunt force in 694 cases were analyzed comparing the injury patterns in accidents to those in crimes. It turned out injuries of the ear and retroauricular region clearly indicate a crime. Also, soft tissue injuries of nose, upper jaw, and lower jaw point towards a criminal violence, whereas tooth injuries occur with a similar frequency in both crimes and accidents. PMID- 30483607 TI - An approach to quantifying the plausibility of the inadvertent download defence. AB - A table of 95% confidence limits on the probabilities for randomly downloading relatively small numbers of illegal images or sensitive documents amongst a relatively large number of other images or documents has been computed. It is anticipated that these data will assist prosecution officials in arriving at a decision as to whether or not there is a reasonable likelihood of a successful criminal prosecution when the inadvertent download defence is employed in cases of possession of child pornography, terrorist material or espionage-related documents. The same data can also be used by defence counsels to assess the strength of the prosecution's case. PMID- 30483604 TI - Research progress in the estimation of the postmortem interval by Chinese forensic scholars. AB - The determination of time since death or the postmortem interval (PMI) is one of the most important and frequently asked questions in forensic medicine. Medicolegal scholars and forensic pathologists around the world have studied the estimation of PMI extensively in the past, and many novel methods and advanced technologies have now been applied in the field. For several centuries, Chinese forensic examiners have also worked on the estimation of the PMI, and there are a large number of excellent studies published in Chinese rather than in English, and these are not easily accessible or known internationally. Therefore we have conducted a review of relevant studies published by Chinese forensic scholars in the last few decades. The scope of this review is to provide a concise summary of the current progress in the estimation of PMI by Chinese forensic researchers using molecular biology, spectroscopic technology, entomological methods, energy changes, thanatochemistry and other methods. PMID- 30483606 TI - Anticoagulant rodenticide intoxication in east China: a three-year analysis. AB - The study was designed to analyze the incidence and pattern of anticoagulant rodenticide intoxication in east China and to discuss strategies of diagnosis based on laboratory analysis experience. A total of 117 patients with anticoagulant rodenticide poisoning confirmed by toxicological analysis in east China were included in this study from 2011 to 2013. The mean concentration of anticoagulant rodenticide, age, and gender of these patients, as well as the mode and type of poisoning, were discussed. The age ranged from less than 1 to 80 years with the feeble preponderance of males (M = 53.0%, F = 47.0%). The 0-9 age group covered the largest ratio of these anticoagulant rodenticide poisoning patients. Accidental or voluntary ingestion seems to be the most common cause of intoxication, with still the poisoning cause being unknown for a large number of positive analyses. Bromadiolone was the most commonly observed anticoagulant rodenticide found in the biological samples, followed by brodifacoum. The concentrations of bromadiolone and brodifacoum that were detected in the first collected whole blood from each patient ranged from 1 to 878 ng/mL (mean 97.9 ng/mL) and from 0.5 to 1566 ng/mL (mean 225.1 ng/mL), respectively. The data analysis shows a high incidence of anticoagulant rodenticide poisoning without awareness of the poisoned subjects, clearly emphasizing the need for toxicological analysis in patients with vitamin K-dependent coagulation disorder and restriction on availability of anticoagulant rodenticide. PMID- 30483608 TI - Analytical data supporting the "theoretical" postmortem redistribution factor (Ft ): a new model to evaluate postmortem redistribution. AB - The concepts of postmortem redistribution (PMR, F) factor, and "theoretical" PMR (Ft ) - based upon a drug's characteristic L/P ratio - have been defined to express the direct relationship between postmortem peripheral blood and the corresponding antemortem whole-blood concentration. This paper applies recent data describing liver/peripheral blood (L/P) ratios for many commonly detected drugs to assess these models, and provide a ranking of drugs' propensity for (and degree of) PMR. PMID- 30483609 TI - Wildlife forensic examination in Russia: the practice and perspectives. AB - Two case studies are described which show application of forensic expertise to establish important circumstances related to the investigation of the crimes against wildlife flora and fauna. Forensic study of the animal hair is a method for investigation of the crimes against wildlife objects which is used more frequently during the recent years. The perspectives of development of the new branch of forensic research in Russia are formulated, and the proposals and recommendations for developing the Eurasian wildlife flora and fauna network are formulated in this article. PMID- 30483610 TI - Guidelines for Collection of Biological Samples for Clinical and Forensic Toxicological Analysis. AB - This article aims to review general procedures for sampling of routinely collected as well as on alternative samples that may provide additional information regarding intoxication. These approaches may be applied whenever sample collection for clinical and forensic toxicology is required and should be considered as general guidelines that must be adapted to each specific case. It is expected that this article will help toxicologists and other forensic experts to accomplish their mission, since the toxicological result is first influenced by the quality and quantity of the sample available for analysis. These guidelines were approved by the European Council of Legal Medicine. PMID- 30483611 TI - Systemic air embolism complicating upper gastrointestinal endoscopy: a case report with post-mortem CT scan findings and review of literature. AB - Endoscopy of the gastrointestinal and biliary tract is a common procedure and is routinely performed for therapeutic and diagnostic purposes. Perforation, bleeding and infection are some of the more common reported side effects. Air embolism on the other hand, is a rare complication of gastrointestinal endoscopy. We report a 77-year-old African-American female with a history of pancreatic cancer, which was resected with a Whipple procedure. As part of diagnostic and therapeutic procedure, an endoscopic retrograde cholangiopancreatography was planned several months after the surgery. The patient's heart rate suddenly slowed to 40 bpm during the procedure and she became cyanotic and difficult to oxygenate after the endoscope was introduced and CO2 gas was insufflated. A forensic autopsy was performed with post-mortem computed tomography (PMCT) and revealed extensive systemic air embolism. The detailed PMCT and autopsy findings are presented and current literature is reviewed. PMID- 30483612 TI - Forensic Sciences Research: from dream to reality. PMID- 30483614 TI - Violent offences of methamphetamine users and dilemmas of forensic psychiatric assessment. AB - Methamphetamine (MA), an extremely addictive synthetic stimulant, has quickly spread to become the most frequently used illicit drug in China. People with a history of chronic and heavy MA use have a high possibility of exhibiting schizophrenia-like psychotic symptoms, mainly delusions of reference, auditory hallucinations and cognitive deficits. These emerging findings suggest MA use increases aggression and violence and that there is a correlation between MA use and violence. However, it is unclear how to assess the capacity of criminal responsibility in "MA-induced" psychosis and how to set clear boundaries between schizophrenia and MA-induced psychosis when only limited and inconsistent evidence is available. Furthermore, a final persuasive differential diagnostic method based on improved understanding of schizophrenia and MA-induced psychotic disorders has yet to be developed. This paper will evaluate the epidemiology, social harm, and forensic psychiatric assessment of MA users, propose a future direction for the differential diagnosis between MA-induced psychotic disorders and schizophrenia, and put forward some practical solutions to assess the capacity of criminal responsibility of defendants with drug-induced psychotic disorder. PMID- 30483615 TI - Quantitative analysis of opioids and cannabinoids in wastewater samples. AB - Wastewater-based epidemiology is an innovative approach that uses the analysis of human excretion products in wastewater to obtain information about exposure to drugs in defined population groups. We developed and validated an analytical method for the simultaneous determination of opioids (morphine, oxycodone, hydrocodone, oxymorphone and hydromorphone), and cannabinoids (Delta9 tetrahydrocannabinol, 11-nor-9-carboxy-tetrahydrocannabinol (THCCOOH) and THCCOOH glucuronide) in raw-influent wastewater samples by ultra-high performance liquid chromatography-tandem mass spectrometry. Method validation included linearity (5 1 000 ng/L for opioids, 10-1 000 ng/L for cannabinoids), imprecision (<21.2%), accuracy (83%-131%), matrix effect (from -35.1% to -14.7%) and extraction efficiency (25%-84%), limit of detection (1-5 ng/L) and quantification (5-10 ng/L) and auto-sampler stability (no loss detected). River and wastewater samples were collected in triplicate from different locations in New York City and stored at -20 degrees C until analysis. Water from sewage overflow location tested positive for morphine (10.7 ng/L), oxycodone (4.2-23.5 ng/L), oxymorphone (4.8 ng/L) and hydromorphone (4.2 ng/L). Raw influent wastewater samples tested positive for morphine (133.0-258.3 ng/L), oxycodone (31.1-63.6 ng/L), oxymorphone (16.0-56.8 ng/L), hydromorphone (6.8-18.0 ng/L), hydrocodone (4.0-12.8 ng/L) and THCCOOH (168.2-772.0 ng/L). This method is sensitive and specific for opioids and marijuana determination in wastewater samples. PMID- 30483613 TI - Metabolism and metabolomics of ketamine: a toxicological approach. AB - Ketamine is a phencyclidine derivative and a non-competitive antagonist of N methyl-D-aspartate (NMDA) receptor for which glutamate is the full agonist. It produces a functional dissociation between the thalamocortical and limbic systems, a state that has been termed as dissociative anaesthesia. Considerable variability in the pharmacokinetics and pharmacodynamics between individuals that can affect dose-response and toxicological profile has been reported. This review aims to discuss pharmacokinetics of ketamine, namely focusing on all major and minor, active and inactive metabolites. Both ketamine optical isomers undergo hepatic biotransformation through the cytochrome P450, specially involving the isoenzymes 3A4 and 2B6. It is first N-demethylated to active metabolite norketamine. Different minor pathways have been described, namely hydroxylation of the cyclohexanone ring of ketamine and norketamine, and further conjugation with glucuronic acid to increase renal excretion. More recently, metabolomics data evidenced the alteration of several biological pathways after ketamine administration such as glycolysis, tricarboxylic acid cycle, amino acids metabolism and mitochondrial beta-oxidation of fatty acids. It is expected that knowing the metabolism and metabolomics of ketamine may provide further insights aiming to better characterize ketamine from a clinical and forensic perspective. PMID- 30483616 TI - Massively parallel sequencing of 231 autosomal SNPs with a custom panel: a SNP typing assay developed for human identification with Ion Torrent PGM. AB - The custom-designed single nucleotide polymorphism (SNP) panel amplified 231 autosomal SNPs in one PCR reaction and subsequently sequenced with massively parallel sequencing (MPS) technology and Ion Torrent personal genome machine (PGM). SNPs were chosen from SNPforID, IISNP, HapMap, dbSNP, and related published literatures. Full concordance was obtained between available MPS calling and Sanger sequencing with 9947A and 9948 controls. Ten SNPs (rs4606077, rs334355, rs430046, rs2920816, rs4530059, rs1478829, rs1498553, rs7141285, rs12714757 and rs2189011) with low coverage or heterozygote imbalance should be optimized or excluded from the panel. Sequence data had sufficiently high coverage and gave reliable SNP calling for the remaining 221 loci with the custom MPS-SNP panel. A default DNA input amount of 10 ng per reaction was recommended by Ampliseq technology but sensitivity testing revealed positive results from as little as 1 ng input DNA. Mixture testing with this panel is possible through analysis of the F MAR (frequency of major allele reads) values at most loci with enough high coverage depth and low level of sequencing noise. These results indicate the potential advantage of the custom MPS-SNP assays and Ion Torrent PGM platform for forensic study. PMID- 30483617 TI - Multiple regression analysis of the craniofacial region of Chinese Han people using linear and angular measurements based on MRI. AB - The purpose of this study was to measure the craniofacial region of Chinese Han people in the linear and angular dimensions, and to analyse the effects on sex, age and body parameters (height and weight). All 250 individuals (86 males, 164 females) underwent a three-dimensional magnetic resonance imaging (MRI) scan, and the MRI data were imported into VG Studio MAX 2.2 software. Each linear and angular measurement in the craniofacial region was processed directly. Using SPSS 20.0 software, nine multiple regression equations were constructed, and all the adjusted R 2 values were statistically significant (0.031-0.311). Multiple regression analysis showed that most craniofacial measurements of Chinese people were significantly correlated with height, weight or age. The multiple regression equations constructed will be helpful in anthropometric analysis and forensic inference. PMID- 30483618 TI - Determination of five endosulfan pesticides in the fish pond water by dispersive liquid-liquid microextraction combined with GC-MS. AB - A simple and rapid dispersive liquid-liquid microextraction (DLLME) technique coupled with gas chromatography-ion trap mass spectrometry (GC-MS) was developed for the extraction and analysis of five endosulfan pesticides from the fish pond water. In this work, different parameters affecting the extraction process such as the type and volume of extraction solvent, type and volume of disperser solvent, and extraction time were studied and optimized. Under optimized conditions, the enrichment factor ranged from 189 to 269 and the relative recovery ranged from 88.5% to 94.9%. The linear range was 2.0-80.0 ug/L; the limits of detection and quantitation were in the range 0.04-1.06 ug/L and 0.12 3.53 ug/L, respectively. The relative standard deviations were in the range 0.94% 2.08% (n = 5). The obtained results show that DLLME combined with GC-MS is a fast and simple method for the determination of endosulfan pesticides in fish pond water. PMID- 30483620 TI - Forensic imaging. PMID- 30483619 TI - Intramedullary schwannoma of the upper cervical spinal cord: a case study of identification in pathologic autopsy. AB - Intramedullary schwannoma of the upper cervical spinal cord is rarely reported in forensic medicine. We herein report a case involving a patient who died of compression from an intramedullary schwannoma in the upper cervical spinal cord. A 30-year-old man initially presented with a five-day history of pain in the left chest that progressed to weakening in the left arm. Although the patient was treated with analgesic poultices, he developed inspiratory dyspnoea and died while working the next day without having undergone any medical imaging examination or surgical treatment. Anatomical and histopathological examinations revealed an intramedullary schwannoma in the left cervical spinal cord (C3-C5) underneath the spinal nerve root. The cause of death might have been asphyxia secondary to the tumour, which interfered with the nerve function in the respiratory muscles. This finding suggests that an autopsy is essential for pathologists and medicolegists to comprehensively undertake their due obligation to obtain "the first evidence", especially when there is a lack of directly related evidence. As part of the central nervous system, the spinal cord could be systematically included in a routine pathological autopsy in some cases. PMID- 30483622 TI - Clinical forensic imaging and fundamental rights in Austria. AB - Clinical forensic imaging encompasses the diverse application of imaging procedures that serve the same purpose: to enable the analysis and investigation of criminal activities and consequences of a crime. All kinds of imaging techniques and their corresponding images can be subsumed under "forensigraphy", a more comprehensive term for forensic imaging created by the Ludwig Boltzmann Institute for Clinical Forensic Imaging in Graz, Austria. As the word forensigraphy suggests, criminal imaging material should be of use in forensic investigations. Ideally, this can lead to new findings that would not have been revealed without the application of imaging techniques and are moreover admissible as evidence in criminal proceedings. However, the admissibility of evidence can only be facilitated through the implementation of clinical forensic imaging techniques into the forensic routine case work, which requires a precise pre-analysis of the corresponding legal framework. Because taking and displaying internal images of a person's body touches upon various aspects of one's physical and psychological integrity, imaging methods in general and clinical forensic imaging methods especially have a strong impact on and interfere regularly with the fundamental rights of the concerned person. Particularly with regard to a possible medical context, certain legal regulations have to be taken into account. Therefore, this paper examines forensic imaging in the field of radiological forensigraphy, specifically its in vivo (i.e. clinical) application. It is designed to enlighten readers as to the great significance of legal barriers that emerge from fundamental rights, as laid down in the European Convention on Human Rights (ECHR), when dealing with clinical forensic imaging. As a result, the legal framework of clinical forensic imaging procedures are comprehensively described, the relevant fundamental rights, especially the right to respect for private and family life, the right to data protection and certain procedural guarantees, are concisely presented to further raise awareness regarding the importance of fundamental rights. PMID- 30483621 TI - Modern post-mortem imaging: an update on recent developments. AB - Modern post-mortem investigations use an increasing number of digital imaging methods, which can be collected under the term "post-mortem imaging". Most methods of forensic imaging are from the radiology field and are therefore techniques that show the interior of the body with technologies such as X-ray or magnetic resonance imaging. To digitally image the surface of the body, other techniques are regularly applied, e.g. three-dimensional (3D) surface scanning (3DSS) or photogrammetry. Today's most frequently used techniques include post mortem computed tomography (PMCT), post-mortem magnetic resonance imaging (PMMR), post-mortem computed tomographic angiography (PMCTA) and 3DSS or photogrammetry. Each of these methods has specific advantages and limitations. Therefore, the indications for using each method are different. While PMCT gives a rapid overview of the interior of the body and depicts the skeletal system and radiopaque foreign bodies, PMMR allows investigation of soft tissues and parenchymal organs. PMCTA is the method of choice for viewing the vascular system and detecting sources of bleeding. However, none of those radiological methods allow a detailed digital view of the body's surface, which makes 3DSS the best choice for such a purpose. If 3D surface scanners are not available, photogrammetry is an alternative. This review article gives an overview of different imaging techniques and explains their applications, advantages and limitations. We hope it will improve understanding of the methods. PMID- 30483624 TI - Analysis of size and shape differences between ancient and present-day Italian crania using metrics and geometric morphometrics based on multislice computed tomography. AB - The Museum of Human Anatomy in Naples houses a collection of ancient Graeco-Roman crania. The aim of this study was to use multislice computed tomography (MSCT) to evaluate and objectively quantify potential differences in cranial dimensions and shapes between ancient Graeco-Roman crania (n = 36) and modern-day southern Italian crania (n = 35) and then to characterize the cranial changes occurring over more than 2000 years, known as secular change. The authors used traditional metric criteria and morphometric geometry to compare shape differences between the sets of crania. Statistically significant differences in size between the ancient and modern crania included shorter facial length, narrower external palate, smaller minimum cranial breadth, shorter right and left mastoid processes, and wider maximum occipital and nasal breadth. The shape changes from the ancient to modern crania included a global coronal enlargement of the face and cranial diameters, with more anterior projection of the face at the anterior nasal spine, but also posterior projection at the glabella and the nasion. It is not possible to determine whether these differences result exclusively from secular changes in the cranium or from other factors, including a mix of secular change and other unknown factors. To the best of our knowledge, this is the first MSCT-based study to compare ancient Graeco-Roman and modern-day southern Italian crania and to characterize shape and size differences. PMID- 30483625 TI - CT-scan vs. 3D surface scanning of a skull: first considerations regarding reproducibility issues. AB - Three-dimensional surface scanning (3DSS) and multi-detector computed tomography (MDCT) are two techniques that are used in legal medicine for digitalizing objects, a body or body parts such as bones. While these techniques are more and more commonly employed, surprisingly little information is known about the quality rendering of digitalized three-dimensional (3D) models provided by each of them. This paper presents findings related to the measurement precision of 3D models obtained through observation of a study case, where a fractured skull reconstructed by an anthropologist was digitalized using both post-mortem imaging methods. Computed tomography (CT) scans were performed using an 8-row MDCT unit with two different slice thicknesses. The variability of 3D CT models superimposition allowed to assess the reproducibility and robustness of this digitalization technique. Furthermore, two 3D surface scans were done using a professional high resolution 3D digitizer. The comparison of 3D CT-scans with 3D surface scans by superimposition demonstrated several regions with significant differences in topology (average difference between +1.45 and -1.22 mm). When comparing the reproducibility between these two digitalizing techniques, it appeared that MDCT 3D models led in general to greater variability for measurement precision between scanned surfaces. Also, the reproducibility was better achieved with the 3D surface digitizer, showing 3D models with fewer and less pronounced differences (from +0.32 to -0.31 mm). These experiments suggest that MDCT provides less reproducible body models than 3D surface scanning. But further studies must be undertaken in order to corroborate this first impression, and possibly explain the reason for these findings. PMID- 30483623 TI - State of the art in post-mortem forensic imaging in China. AB - The autopsy and histopathologic examination are traditional and classic approaches in forensic pathology. In recent years, with the tremendous progresses of computer technology and medical imaging technology, the developed post-mortem computer tomography, post-mortem magnetic resonance imaging and other new methods provide non-invasive, intuitive, high-precision examining methods and research tools for the forensic pathology. As a result, the reconstruction of the injury as well as the analysis of injury mechanism has been essentially achieved. Such methods have become popular in the research field of forensic science and related work has also been carried out in China. This paper reviews the development and application of abovementioned post-mortem forensic imaging methods in China based on the relevant literature. PMID- 30483626 TI - A fatal case of oxygen embolism in a hospital. AB - This case reports on a 68-year-old man who was found dead in hospital next to his bed. Before this, he had been treated with intravenous antibiotics for pneumonia. The body was found with a peripheral venous catheter connected to a nasal cannula delivering oxygen (O2) from the wall. Extensive medico-legal examinations were performed, including post-mortem computed tomography (CT), complete conventional autopsy, histological and immunohistochemistry analysis, toxicological analysis and post-mortem chemistry. Additionally, CT-guided gas sampling was performed at multiple sites to collect samples for gas analysis. During the external examination, massive subcutaneous emphysema was visible over the entire surface of the body. The CT scan revealed the presence of gas throughout the vascular system, and in the subcutaneous and muscular tissues. The autopsy confirmed the presence of lobar pneumonia and multiple gas bubbles in the vascular system. The gas analysis results showed a subnormal concentration of oxygen, confirming the suspected pure O2 embolism. Moreover, the carbon dioxide (CO2) concentration in the gas sample from the heart was elevated to a level similar to those found in scuba diving fatalities. This could come from degassing of dissolved CO2 that accumulated and was trapped in the cardiac cavity. Based on the results of the different exams performed, and especially the gas analysis results, it was concluded that the cause of death was O2 embolism. PMID- 30483627 TI - Diagnosis of coronary artery disease using targeted post-mortem computed tomography coronary angiography: a case report. AB - Targeted post-mortem computed tomography (PMCT) combined with coronary angiography has the potential to play a significant role in the investigation of sudden cardiac death. The authors utilized a targeted PMCT coronary angiography in a case involving a 53-year-old man who died from acute myocardial ischemia and cardiac decompensation which may result from coronary artery disease (CAD). The victim collapsed suddenly at work and died soon after arrival to hospital. The body was examined using PMCT and targeted PMCT coronary angiography. The left anterior descending coronary artery exhibited 75%-100% stenosis in the middle segment; however, the distal segment could not be clearly visualized. In addition, the left circumflex and right coronary artery exhibited calcification, atherosclerosis and an area of 50% stenosis. Signs of cardiogenic pulmonary oedema were also identified. The imaging results suggested that this individual had coronary atherosclerosis and probably died from CAD. The autopsy and histological examination revealed acute myocardial ischemia and myocardial scarring, confirming the cause of death while excluding other probabilities. In summary, targeted post-mortem computed tomography angiography (PMCTA) can visualize the arteries and estimate the degree of principal pathological changes. This method is a simple, reliable and sensitive technique for identifying the presence of coronary atherosclerosis. It is a valuable post-mortem forensic imaging method and should be recommended in the investigation of suspicious cardiac deaths. PMID- 30483628 TI - A new challenge for expert witnesses relying on subjective information. PMID- 30483630 TI - Metabolic risk factors associated with sudden cardiac death (SCD) during acute myocardial ischemia. AB - Sudden cardiac death (SCD) is the leading cause of death worldwide. Myocardial ischemia (MI) is the most common underlying causal disorder for SCD. Metabolic risks leading to SCD during acute MI are still not fully understood. Here, using tissue metabolomics, we aimed to investigate myocardial metabolic alterations relevant to SCD events in an acute MI rat model induced by coronary artery ligation (CAL). Thirty-four rats were successfully performed CAL, of which 13 developed lethal ventricular tachyarrhythmia (LVTA)-SCD and 7 developed severe atrioventricular block (AB)-SCD. Fourteen rats that survived within 70 min after the ligation were served as peer controls. The partial least squares-discriminant analysis plots demonstrated clear separations between the SCD rats and controls, indicating obvious differences in myocardial metabolome between these rats. The levels of isoleucine, lactate, glutamate choline, phosphorylcholine, taurine and asparagine in ischemic myocardia were positively associated with LVTA-SCD events; in contrast, the levels of alanine, urea, phenylalanine, linoleic acid, elaidic acid and stearic acid were inversely correlated with LVTA-SCD events. The levels of glutamate and urea were positively and negatively relevant to AB-SCD events, respectively. The dangerous metabolites indicated that lower levels of energy substrates, severe hypoxia, the inhibition of transamination and hyper sympathetic excitement and reactive oxygen species in myocardia were vulnerable to SCD during acute MI. The results suggest fatal metabolic alterations correlated with SCD events during acute MI, which could offer novel clues for the prevention or treatment of acute MI-related SCD. PMID- 30483631 TI - Microscopic examination of pituitary glands in cases of fatal accidental hypothermia. AB - In cases of death caused by hypothermia, histological analysis can be used to determine the cause of death. Certain histological alterations of the pituitary glands in hypothermia have been reported in the literature, including haemorrhage, hyperaemia and cellular vacuolization of cells in the anterior lobe. In the present study, the validity of these morphological alterations as markers for fatal accidental hypothermia was investigated in autopsy material. A total of 34 pituitary glands in cases of verified fatal accidental hypothermia were examined histologically (haematoxylin and eosin, ferric, azan) and immunohistochemically (LCA, ACTH, C5b-9). The findings were compared with 61 cases in a control group. Hyperaemia was found in 50.0% of the study group cases and 59.0% of the control group cases. Cellular vacuolization was observed in one case (2.9%) in the study group and one case (1.6%) in the control group. Acute or recent haemorrhage in the glandular tissue was never detected. In our study, the histopathological characteristics described in the literature as pathognomonic for hypothermia could not be confirmed. Furthermore, histological differences in the pituitary glands between fatal hypothermia cases and control group cases were not observed. PMID- 30483629 TI - Brugada syndrome: a fatal disease with complex genetic etiologies - still a long way to go. AB - Brugada syndrome (BrS) is an arrhythmogenic disorder which was first described in 1992. This disease is a channelopathy characterized by ST-segment elevations in the right precordial leads and is susceptible to sudden death. BrS is a fatal disease with gender and age preferences. It occurs mainly in young male subjects with a structurally normal heart and silently progresses to sudden death with no significant symptoms. The prevalence of BrS has been reported in the ranges of 5 20 per 10 000 people. The disease is more prevalent in Asia. Nowadays, numerous variations in 23 genes have been linked to BrS since the first gene SCN5A has been associated with BrS in 1998. Not only can clinical specialists apply these discoveries in risk assessment, diagnosis and personal medicine, but also forensic pathologists can make full use of these variations to conduct death cause identification. However, despite the progress in genetics, these associated genes can only account for approximately 35% of the BrS cases while the etiology of the remaining BrS cases is still unexplained. In this review, we discussed the prevalence, the genes associated with BrS and the application of molecular autopsy in forensic pathology. We also summarized the present obstacles, and provided a new insight into the genetic basis of BrS. PMID- 30483632 TI - Astrocytic clasmatodendrosis in the cerebral cortex of methamphetamine abusers. AB - Postmortem investigation of methamphetamine (MA) abuse is an important task in forensic pathology. The present study investigated morphological changes in the astrocytes in the parietal cerebral cortex of MA abusers. Glial fibrillary acidic protein immunoreactivity in the cerebral cortex was examined in forensic autopsy cases for MA-detected group and control group. Clasmatodendrotic astrocytes (including those with swollen cell bodies and disintegrating distal processes) were frequently observed in the cerebral cortex of MA abusers. Quantitative analysis using a colour image processor showed a concomitant increase in the astrocyte area and astrocyte-to-vessel area ratio (size and number of astrocytes) in the grey matter in acute MA fatality and other MA-involved cases, although the astrocyte area (size) was also increased in cases of asphyxiation. The total astrocyte area (size) in the white matter was significantly higher in MA fatalities and asphyxia than in the other groups involving MA abusers. Those indices were independent of blood MA level, age, sex, survival or postmortem time. These observations suggest the increasing number and hypertrophic changes of astrocytes in the grey matter in MA abusers can be the outcome of long-term abuse, while disintegrating distal processes may exist only in acute fatal MA intoxication. PMID- 30483633 TI - Anatomical changes correlated with chronic pain in forensic medicine. AB - This study was performed to determine the relationships between chronic pain and anatomic changes that may occur in the body. Autopsies were performed on fatalities that required death investigation in Linn County, IA, or adjacent and nearby areas. Persons with chronic pain were older than the control population at the time of death. Diabetes, hypertension and depression were more common in persons with chronic pain. Certain causes of death may also have been related to chronic pain. The heart, lungs, liver, spleen and kidneys were significantly heavier in persons with chronic pain; emphysema and pleural and abdominal adhesions were more common in persons with chronic pain. There appear to have been diffuse changes in the body related to chronic pain. These changes may have been mediated by a number of systemic mechanisms that are involved with chronic pain, including cardiovascular activity, the immune system, the neuroendocrine system and others. PMID- 30483635 TI - The increase of firearm-related violence in Sweden. AB - Firearm-related violence is common in our contemporary world and causes serious harm to humans as well as to the society. One of the countries in which firearm related violence is increasing is Sweden and its most southern region, Skane, in which Malmo, Sweden's third largest city, is highly affected. If not contained and limited, Sweden risks becoming more and more violent. PMID- 30483634 TI - Influence of functional polymorphism in MIF promoter on sudden cardiac death in Chinese populations. AB - Sudden cardiac death (SCD) is defined as an unexpected natural death without any obvious non-cardiac causes that occurs within 1 h with witnessed symptom onset or within 24 h without witnessed symptom onset. Genetic studies conducted during the past decade have markedly illuminated the genetic basis of the cardiac disorders associated with SCD. Macrophage migration inhibitory factor (MIF) is an upstream immunoregulatory cytokine associated with the pathogenesis of many inflammatory diseases including atherosclerosis and myocardial infarction. Previous studies have reported that the functional -794(CATT)5-8 polymorphism in MIF is unrelated to sudden infant death syndrome susceptibility. However, there are no reports concerning the association between the polymorphism and adult SCD susceptibility. In the current study, we investigated the association between the -794(CATT)5-8 polymorphism and adult SCD susceptibility using 79 adult SCD cases and 313 healthy controls. All samples were analysed using a conventional polymerase chain reaction (PCR) technique. We found that CATT6 and 5-6 were the most common allele and genotype in both groups, respectively, while no significant association was found between the -794(CATT)5-8 polymorphism and SCD susceptibility. We also summarized the allele frequencies of -794(CATT)5-8 in cohorts of healthy people from different countries and found that the allele frequency distributions of the polymorphism in Chinese populations were quite different from that of American and European populations (P = 0.005, P = 0.0001, respectively), but similar to Japanese populations (P = 0.827). In conclusion, this study indicates that the 794(CATT)5-8 polymorphism may not be associated with adult SCD susceptibility in Chinese populations. Different allele frequency distributions of the polymorphism in multiple populations may provide a useful reference for further genetic association studies. PMID- 30483636 TI - Unexpected sudden death in pregnancy - arrhythmogenic right ventricular cardiomyopathy/dysplasia: a case report. AB - Cardiovascular disease is an important contributor to maternal mortality in both developing and developed countries. Systematic search for cardiac disease is usually not performed during pregnancy despite hypertensive disease, undiagnosed pulmonary hypertension and cardiomyopathies being recognized as major health problems in these settings. This article reported a 27-year-old female who was normal on clinical examination and basic investigations, and on an antenatal visit was found collapsed in the toilet of her house and was pronounced dead on admission to hospital. She was found to be in the 11th week of pregnancy and had no history of significant illness in the past. Autopsy did not reveal any obvious macroscopic pathology except for a significant amount of epicardial fat infiltrating into myocardium of right ventricle. Detailed histopathological examination of the heart demonstrated fibro-fatty replacement of the heart muscle. The cause of death was arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). ARVC/D can cause unexpected sudden death during pregnancy. Therefore, it is recommended that an ECG and echocardiogram be included as screening tests during antenatal follow-up to minimize preventable cardiac deaths like ARVC/D. PMID- 30483639 TI - Forensic application of comet assay: an emerging technique. AB - Postmortem interval (PMI) estimation is a recurring problem in the field of forensic medicine. Conventional methods are effective but are insufficient to estimate accurate and precise time of death or PMI. In addition, degradation of biological samples is another major problem in forensic science which affects the investigation process and misleads the result. Some previous studies reported that DNA fragmentation has strong correlation with PMI. DNA fragmentation increased with prolonged PMI. Comet assay is a rapid sensitive, versatile, reliable and cost effective technique that is specifically used for qualitative and quantitative estimation of nuclear DNA fragmentation. Due to this attribute, comet assay can help to estimate accurate and precise time of death for some extent that is for early PMI estimation. In addition, two confounding factors are responsible for DNA fragmentation: (1) micro-organism; (2) environmental condition. Here, comet assay plays a dual role: (1) partially degraded samples get repaired using repair enzyme; (2) accurate time since deposition can be measured without using repair enzyme. Furthermore, this assay can also help to identify potential exposures of environmental-released chemicals/toxicants and its deleterious effects on human population. In this way, comet assay shows its versatile applications that could be useful for forensic investigation. Therefore, with the help of this review, an attempt was made to explore the versatility of comet assay technique for forensic applications and its future perspective. PMID- 30483637 TI - Virtual anthropology - a brief review of the literature and history of computed tomography. AB - Computed tomography (CT) has influenced numerous fields since its inception in the 1970s. The field of palaeoanthropology significantly benefited from this efficient and non-invasive medium in terms of the conservation, reconstruction and analysis of fossil human remains. Over the past decade, there has been a steady increase in the number of forensic anthropological studies incorporating virtual osteological analyses. Because of the increasing importance of these modern cross-sectional imaging techniques and the requirement for standardized parameters in forensic science, we deemed it important to outline the history and development of CT applications in these related academic areas. The present paper outlines the history of "virtual anthropology" and osteological multi-detector CT in the context of palaeoanthropology and forensic anthropology. PMID- 30483640 TI - Predictive models for the assessment of bodily harm. AB - The Spanish scale to quantify or qualify bodily harm resulting from any unintentional traffic accident prior to 1 January 2016 is established by Royal Legislative Decree (RDL) 8/2004. This scale assigns points to the sequelae, which are converted into Euros using a table that is updated annually. The objective of this study is to develop a predictive model of sequelae points that will enable the estimation of compensation a short time after the accident. This will facilitate the calculation of the money reserve and rapid access to compensation for the injured party. To conduct this study, we developed a database with information from 999 individuals who had suffered car crash injuries which were evaluated according to the scale contained in RDL 8/2004 for medical experts. Predictive models based on logistic regression models were designed on this database. To choose the best model, we calculated Mallow's Cp. The use of hurdle models made it possible to predict the points received by an injured party within a relatively short period of time after the accident. Once these points are known, it is a simple matter to calculate the corresponding compensation. The prediction models developed provide an easy way to predict the compensation to be awarded to the injured party. These models use days of hospitalization, sex, age and the results of international scales based on the Abbreviated Injury Scale. These variables can be used soon after the occurrence of the crash. PMID- 30483638 TI - Assessment of cognitive dysfunction in traumatic brain injury patients: a review. AB - Traumatic brain injury (TBI) is one of the major causes of human mortality and morbidity in the world. Brain injury could affect the core of a person's being - their thinking, memory, personality and behaviour. Electrophysiological markers from the human electroencephalogram and brain imaging provide a rich source of data which helps to elucidate specific processing impairments in TBI patients. To assess the cognitive and social function in traumatic brain injury patients, this review will focus on some of methods for assessing the disabling cognitive and social function deficits induced by TBI. There are many new technologies available to address TBI and recognition related questions. Integration of the various techniques will help to facilitate our comprehending of TBI, cognitive function and social function, and improve treatment and rehabilitation. PMID- 30483641 TI - Screening for volatile sulphur compounds in a fatal accident case. AB - Acute fatal poisoning due to the inhalation of toxic gas frequently occurs in China. Volatile sulphur compounds (VSCs) are toxic to humans. In fatal poisoning investigations, such as those in industrial settings, a number of VSCs, including methanethiol (MT), dimethyl sulphide (DMS), dimethyl disulphide (DMDS) and dimethyl trisulphide (DMTS), can coexist. To date, there is limited data regarding these compounds in post-mortem cases. In the present study, we report toxicological findings in a fatal accident case with two victims. Headspace gas chromatography/flame ionization detector with two columns of different polarities was utilized to screen MT, DMS, DMDS and DMTS in blood. The limits of detection in both methods were 0.05 mg/mL. No sulphur compounds were detected in the blood samples of the two victims. DMS and DMDS were detected in the lungs at concentrations of 0.5 and 1.3 mg/g and 2.2 and 4.1 mg/g, respectively. DMDS liver concentrations were 2.5 and 6.5 mg/g. In addition to hydrogen sulphide, screening for additional VSCs could help establish the cause of death. PMID- 30483642 TI - The mechanical properties of plastic evidence bags used for collection and storage of drug chemicals relevant to clandestine laboratory investigations. AB - The effectiveness of three types of plastic bags used by the New South Wales Police Force for the storage of clandestine drug evidence has been investigated through a comparison of mechanical properties. The tensile and tear properties of "as received" low-density polyethylene (LDPE) and poly(vinyl chloride) (PVC) bags do not show major differences such that one type would be favoured over the other. However, the mechanical properties of the bags once exposed to a range of chemicals routinely collected as drug evidence have been shown to be influenced as a result of different chemical interactions. Although an interaction of reagents/solvents with an additive within the LDPE bags is proposed to influence the mechanical properties of the bags, the change in properties has been shown to be less severe than that observed for the PVC bag, where softening and damage of the bags results due to absorption of reagents. PMID- 30483643 TI - Accuracy and reliability of feature selection by Chinese fingerprint examiners. AB - The selection of minutiae is a critical part of the analysis phase within the fingerprint identification methodology, known as analysis-comparison-evaluation verification. This study assessed the accuracy and reliability of the minutiae selections of 92 Chinese fingerprint examiners during the analysis phase, absent an exemplar print, of the fingerprint identification process. Specifically, we measured the accuracy (trueness) of their annotation of minutiae, and we measured their reliability which is the reproducibility and repeatability in their annotations in one complex mark by using R software. We observed significant variation within inter- and intra-examiner annotations of the minutiae. We saw no statistically significant differences for the variability of minutiae annotations based on the participant's sex or years of experience. PMID- 30483644 TI - The Humanitarian and Human Rights Resource Center: support to address global forensic issues. PMID- 30483645 TI - Intrauterine fetal death in triplet gestation caused by feto-fetal transfusion syndrome - a case report. AB - Feto-fetal transfusion syndrome (FFTS) severely affects monochorionic (MC) multiple pregnancies and affects 1 in 1600 pregnancies overall. The number of increasing disputed obstetrics cases in China is related to unavailability of prompt diagnosis of FFTS. We present here a woman with a MC triplet pregnancy with intrauterine fetal death at 33 weeks of gestation due to FFTS. Subsequent pathological anatomy showed that the MC placenta contained vascular anastomoses, including arterio-arterial anastomosis and arterio-venous anastomosis. These anastomoses led to unidirectional blood flow with the absence of adequate compensatory counter-transfusion and bi-directional flow. When encountering such challenging conditions, medical practitioners should discreetly compare the fetuses' characteristics with features of placental blood vessels and consult morphological and pathological findings. Furthermore, they should perform ultrasound examinations, particularly focussing on fetal size differences and the maximum vertical pocket in the diagnosis of FFTS, especially in MC multiple pregnancies with abdominal symptoms. PMID- 30483646 TI - Forensic entomology. PMID- 30483647 TI - The uses of Chrysomya megacephala (Fabricius, 1794) (Diptera: Calliphoridae) in forensic entomology. AB - Chrysomya megacephala (Fabricius, 1794) occurs on every continent and is closely associated with carrion and decaying material in human environments. Its abilities to find dead bodies and carry pathogens give it a prominence in human affairs that may involve prosecution or litigation, and therefore forensic entomologists. The identification, geographical distribution and biology of the species are reviewed to provide a background for approaches that four branches of forensic entomology (urban, stored-product, medico-criminal and environmental) might take to investigations involving this fly. PMID- 30483649 TI - Delayed reception of live blowfly (Calliphora vicina and Chrysomya rufifacies) larval samples: implications for minimum postmortem interval estimates. AB - Forensic entomology evidence collected by police and mortuary staff may be delayed in getting to the entomologist. Live samples may continue developing and alter minimum postmortem interval (PMImin) estimates. This study investigated development of simulated evidential samples of Calliphora vicina Robineau Desvoidy and Chrysomya rufifacies (Macquart) (Diptera: Calliphoridae) maggots. Maggots of each species were studied in three developmental classes: "small" (late second/early third instar), "mid" (mid third instar) and "large" (late third instar). Seven replicates of 11 maggots in each class were assigned without food to four treatments: (1) 24 h at 20 degrees C; (2) 24 h at 4 degrees C; (3) 48 h at 20 degrees C and (4) 48 h at 4 degrees C. There was a significant difference in absolute length change across treatments, reflecting size for C. vicina, and interaction between size, time and temperature for Ch. rufifacies. Calliphora vicina maggots showed minimal mortality, and most second instar larvae moulted by the experiment's end. Chrysomya rufifacies showed heavy mortality and minimal moulting from the second to third instar. Only "large" Ch. rufifacies maggots kept at room temperature for 48 h pupariated. Since these results confirm that development can continue in live unfed maggot samples after their collection, it is not advisable to delay their preservation. PMID- 30483650 TI - Histological age estimation of the eggs of Calliphora vicina Robineau Desvoidy (Diptera: Calliphoridae). AB - Aging blow fly eggs can be critical to a forensic investigation, but there are currently no forensically useful timelines describing internal anatomical changes in embryological development. This is partly due to the lack of an economical, rapid and technically simple histological technique to allow mass production of slides for research and casework. We present a histological method that uses a slightly modified standard laboratory processing run with 1 h fixation in 10% formalin, 2 h softening in Molliflex and Haemotoxylin and Eosin (H&E) staining. We also present a summary of the internal anatomical changes that can be visualized using our technique in the developing eggs of Calliphora vicina Robineau-Desvoidy (Diptera: Calliphoridae). We examined eggs from at least three different females grown at 15 degrees C and sampled at 6 h intervals, and eggs grown at 20 degrees C and sampled at 3 h intervals. Blind aging trials demonstrated that it is possible to accurately age material grown at 20 degrees C to within 6 h (but attempts to further narrow this interval resulted in errors in one-third of cases). It was also possible to see sufficient anatomical detail to age eggs preserved for forensic casework 5, 8, 9, 10 and 11 years previously. Additionally, we determined that section quality was improved by 5 s fixation in hot water prior to preservation in ethanol. However, hot water fixation for longer than this increased the level of section artefact. PMID- 30483648 TI - A brief review of forensically important flesh flies (Diptera: Sarcophagidae). AB - Forensic entomology could provide valuable data for the minimum postmortem interval (PMImin) estimation and other relevant information, such as causes and circumstances of death. Some representatives of flesh flies are one of the dominant necrophagous insects during early stages of decomposition, demonstrating unique biological characteristics compared with other necrophagous flies. Moreover, they lead to global health concerns as carriers of various pathogenic micro-organisms, and dominantly result in the traumatic myiasis. Thus, sarcophagid flies are considered important in decomposition processes for PMImin estimation. However, the utility of sarcophagid flies has been seriously hampered by limited ecological, biological and taxonomic knowledge of them. The aim of this paper is to provide a brief review on the species, distribution and biological habit of forensically important sarcophagid flies. In addition, the relation between traumatic myiasis and flesh flies, molecular identification methods and developmental pattern of flesh flies are summarized. PMID- 30483651 TI - Effect of low temperature in the development cycle of Lucilia sericata (Meigen) (Diptera, Calliphoridae): implications for the minimum postmortem interval estimation. AB - Knowledge of necrophagous insects' developmental data is necessary for the forensic entomologist to estimate a reliable minimum postmortem interval (PMImin). Among the most represented necrophagous species, Lucilia sericata (Diptera, Calliphoridae) is particularly interesting. It is regularly identified in samples, with a predominance in summer, and is commonly used by analysts of our entomology department (Institut de Recherche Criminelle de la Gendarmerie Nationale) to estimate the PMImin with the accumulated degree days (ADD) method. This method requires the mathematical lower thermal threshold to be known. This value dictates the quality of the applied ADD method but cannot be considered as fixed, especially when insect development occurs at temperatures close to the biological threshold. In such conditions, it is necessary to study the influence of such temperatures on development rate, as well as the consequences of estimating the period of first oviposition on cadavers, when using the ADD method. Seven replicate rearings were conducted at six different temperatures: 30 degrees C, 24 degrees C, 18 degrees C, 15 degrees C, 12 degrees C and 10 degrees C. Time of development and time of emergence were recorded. The effect of low temperature on the development cycle and the reliability of the ADD method under this entire temperature spectrum were studied using different linear regression models. Calculated durations of total insect time development and experimental rearing duration were then compared. A global linear model cannot be used on the whole temperature spectrum experienced by L. sericata without resulting in an overestimation at some temperatures. We found a combination of two linear regression models to be suitable for the estimation of the total development time, depending on the temperature experienced by L. sericata. This approach allowed us to obtain a variation lower than 2% at 12 degrees C and 10 degrees C between the calculated duration and experimental duration of development. In comparison, the results obtained with a global model show a variation higher than 3% at 12 degrees C and 10% at 10 degrees C. PMID- 30483652 TI - Amplified fragment length polymorphism analysis supports the valid separate species status of Lucilia caesar and L. illustris (Diptera: Calliphoridae). AB - Common DNA-based species determination methods fail to distinguish some blow flies in the forensically and medically important genus Lucilia Robineau Desvoidy. This is a practical problem, and it has also been interpreted as casting doubt on the validity of some morphologically defined species. An example is Lucilia illustris and L. caesar, which co-occur in Europe whilst only L. illustris has been collected in North America. Reports that these species shared both mitochondrial and nuclear gene sequences, along with claims that diagnostic morphological characters are difficult to interpret, were used to question their separate species status. We report here that amplified fragment length polymorphism profiles strongly support the validity of both species based on both assignment and phylogenetic analysis, and that traditional identification criteria based on male and female genital morphology are more reliable than has been claimed. PMID- 30483653 TI - Diversity of the Formicidae (Hymenoptera) carrion communities in Lisbon (Portugal): preliminary approach as seasonal and geographic indicators. AB - The value of the Formicidae (Insecta, Hymenoptera) community in forensic investigations is poorly studied in Portugal. In order to better understand the structure and dynamics of this group of insects in cadavers and their putative value in forensic investigations, studies were carried out in Lisbon area during one year. Piglet carcasses were used as a model of human decomposition. The entomofauna attracted to the carcasses was collected over a period of about 2 months in each season of the year. The collection of ants was performed at regular intervals, daily in the first 23 days and then with intervals of 2, 3 or 5 days until the end of the experiment. Five stages of cadaveric decomposition were recognized with the ants being present in all of them. Three hundred and nine specimens were captured: 7 in autumn, 6 in winter, 90 in spring and 206 in summer. These specimens belong to three subfamilies and seven different species. Four of them had never been mentioned before as being associated to cadavers in this geographical area. Spring and summer had the greater diversity of species and a larger number of individuals. Temnothorax luteus was the dominant species in spring and Tapinoma nigerrimum in summer. Corroborating the information of other similar studies carried out in the Iberian Peninsula, the sarcosaprophagous Formicidae community found in Lisbon is unique and different from other studied locations, which supports the need to perform regional studies. Our results shown that ants do not present a definite pattern of succession, but some species have the potential to be seasonal or geographic indicators. PMID- 30483654 TI - Development of Chrysomya megacephala at constant temperatures within its colony range in Yangtze River Delta region of China. AB - Chrysomya megacephala (Fabricius, 1794) is the most abundant and predominant species which arrives and colonizes a cadaver first in most parts of China. Therefore, its growth and development patterns have great implications in the estimation of the minimum postmortem interval (PMImin). In this study, C. megacephala was collected from the Yangtze River Delta region and reared at seven constant temperatures ranging from 16 degrees C to 34 degrees C. The developmental duration and accumulated degree hours, larval body length and morphological changes of C. megacephala were examined. Furthermore, we constructed three developmental models, isomorphen diagram, isomegalen diagram and thermal summation model, which can be used for estimating PMImin. The developmental durations of C. megacephala at 16 degrees C, 19 degrees C, 22 degrees C, 25 degrees C, 28 degrees C, 31 degrees C and 34 degrees C are (794.8 +/- 14.7), (533.2 +/- 10.1), (377.8 +/- 16.8), (280.8 +/- 15.1), (218.9 +/ 8.5), (190.8 +/- 10.1) and (171.8 +/- 6.8) h, respectively. The developmental threshold temperature D 0 is (11.41 +/- 0.32) degrees C, and the thermal summation constant K is (3 418.7 +/- 137.0) degree hours. Regression analysis was conducted to obtain equations of the variation in larval body length with time after hatching, and variation in time after hatching with body length. Moreover, our study divides the intra-puparial morphological changes of C. megacephala into 11 sub-stages, and provides the time range experienced by each sub-stage. The results of this study provide fundamental development data for the use of C. megacephala in PMImin estimations. PMID- 30483655 TI - Chrysomya chani Kurahashi (Diptera: Calliphoridae), a blow fly species of forensic importance: morphological characters of the third larval instar and a case report from Thailand. AB - Blow flies are worldwide the most important insects from a forensic point of view. In Thailand, aside from the two most common species, Chrysomya megacephala (F.) and Chrysomya rufifacies (Macquart), Chrysomya chani Kurahashi was also found to be of forensic importance. We present a case of a human female cadaver in its bloated stage of decomposition, discovered at Pachangnoi Subdistrict, northern Thailand. Entomological sampling during the autopsy displayed an assemblage of numerous dipteran larvae. Macroscopic observations showed the coexistence of third instar larvae of the three blow flies C. megacephala, Chrysomya villeneuvi Patton, an unknown blow fly species and one muscid, Hydrotaea sp. The minimum post-mortem interval was estimated to be six days, based on the developmental rate of C. megacephala. The ID of the unknown larva, which is the focus of this report, was revealed later as C. chani by DNA sequencing, using a 1205 bp of cytochrome c oxidase subunit I (COI). The occurrence of C. chani on a human body revealed the need to analyse and describe the morphology of its immature stage, to enable forensic entomologists to identify this fly species in future cases. The morphological examination of the third instar was performed, revealing peculiar characteristics: protuberant tubercles encircling abdominal segments; 9-11 lobes on the anterior spiracle; six prominent pairs of tubercles along the peripheral rim of the eighth abdominal segment; a heavily sclerotized complete peritreme of the posterior spiracles. A key to differentiate the third instar of blow flies of forensic importance in Thailand is provided. PMID- 30483656 TI - Decomposition pattern and insect colonization in two cases of suicide by hanging. AB - Hanging is one of the most common methods of suicide worldwide. Despite the high incidence, only a little knowledge about the pattern of cadaver colonization by insects on hanging corpse is available. Different types of hanging can alter the body decomposition process as well as the pattern and rate of insect colonization. Two case studies where the hanging occurred with a similar postmortem interval of 34 days are described. The two bodies showed different patterns of insect colonization and decomposition scored using the Total Body Score (TBS) and the TBS for hanging (TBShang). The first case was about the body of a 24-years-old male, with mummification of the unclothed upper anatomical parts. A TBS of 14 and a TBShang of 18 were assigned. The second body, belonging to a 15-years-old male, was found pre-skeletonized lying on the ground with the skull disarticulated. A TBS of 31 and a TBShang of 32 were assigned. Average temperatures of (21.5 +/- 2.5) degrees C for the first body and (25.1 +/- 2.7) degrees C for the second body were recorded in the 34 days preceding the bodies' discovery for a total of 731 and 853 Accumulated Degree Days (ADD) respectively. According to previous studies, the different decomposition patterns were related to temperatures of exposition and to the diversity of arthropod community found on the bodies because of the different types of hanging: totally suspended vs. in contact with the soil. The limited insect activity caused by hanging explains the delay in decomposition of hanging bodies in which mummification can take place, especially on the upper body parts. In vertical body position, the body fluids accumulated in the lower body parts accelerating the desiccation of soft tissues on the upper parts. The effect of gravity can also explain the decrease of internal maggot mass as larvae easily fall from the hanging body to the drip zones below where they are unable to recolonize the body if totally suspended. Furthermore, in a hanging body a greater surface is exposed to wind and sun with a quicker skin drying preventing the additional Diptera colonization. This paper shows the weaknesses of scoring scales and regression models developed to predict ADD when irregular decomposition and mummification have not taken into account. PMID- 30483657 TI - Forensic genetics. PMID- 30483658 TI - Thanatomicrobiome composition profiling as a tool for forensic investigation. AB - Thanatomicrobiome, or the postmortem microbiome, has been recognized as a useful microbial marker of the time and location of host death. In this mini-review, we compare the experimental methods commonly applied to thanatomicrobiome studies to the state-of-the-art methodologies in the microbiome field. Then, we review present findings in thanatomicrobiome studies, focusing on the diversity of the thanatomicrobiome composition and prediction models that have been proposed. Finally, we discuss potential improvements and future directions of the field. PMID- 30483661 TI - PowerPlex(r) fusion 6C system: internal validation study. AB - This work is aimed at describing the proceedings and parameters used to validate PowerPlex(r) Fusion 6C System, the polymerase chain reaction (PCR) amplification kit by Promega, for posterior implementation in the laboratorial routine of the Forensic Genetic Service. The PowerPlex(r) Fusion 6C System allows multiplex PCR, through simultaneous amplification and posterior detection by fluorescence of 27 loci. Characterization of the kit was made according to the laboratory's internal validation procedure based on validation guidelines from Scientific Working Group on DNA Analysis Methods. Some parameters were evaluated, such as specificity, analytical thresholds, sensitivity, precision, mixture studies, DNA control samples, a proficiency test and changes in the PCR-based procedures: final reaction volume and cycle number, changes in the reaction mixture for direct amplification. This kit proved to be very robust and the results are in concordance with previous developmental validation by the manufacturer. In some parameters, the results were better than expected. PMID- 30483660 TI - Polymorphism study of nine SNPs associated with subjective response to alcohol in Chinese Han, Hui, Tibetan, Mongolian and Uygur populations. AB - Heavy alcohol drinking is a major public health problem, causing a large disease, social and economic burden in societies. Subjective response (SR) to alcohol is an intermediate characteristic of heavy drinking. A variety of candidate genes have been reported to be associated with SR to alcohol. In this study, we investigated nine single nucleotide polymorphisms (SNPs) related to SR to alcohol in healthy individuals from five Chinese ethnic groups, the Han, Hui, Tibetan, Mongolian and Uygur populations, and a total of 584 bloodstain samples were collected. The nine SNPs included four SNPs in alcohol-metabolizing genes (ADH1B, ADH1C, ALDH2 and CYP2E1*5B) and five SNPs in genes of neurobiological pathways (GABRA2, OPRM1, CHRNA3, HYKK and SLC6A4). A SNaPshot analysis method was developed to type these SNPs simultaneously, and all samples were typed successfully. Statistical analyses of the allele frequencies indicated that the frequencies of all SNPs, except for ADH1C, showed varying degrees of difference in the five studied ethnic groups. Tibetans showed the highest frequencies of risk alleles for heavy drinking at most loci. The genetic polymorphic differences found in this study revealed the variation in genetic susceptibility to heavy drinking in the studied populations. PMID- 30483659 TI - Sequencing of 231 forensic genetic markers using the MiSeq FGxTM forensic genomics system - an evaluation of the assay and software. AB - The MiSeq FGxTM Forensic Genomics System types 231 genetic markers in one multiplex polymerase chain reaction (PCR) assay. The markers include core forensic short tandem repeats (STRs) as well as identity, ancestry and phenotype informative short nucleotide polymorphisms (SNPs). In this work, the MiSeq FGxTM Forensic Genomics System was evaluated by analysing reproducibility, sensitivity, mixture identification and forensic phenotyping capabilities of the assay. Furthermore, the genotype calling of the ForenSeqTM Universal Analysis Software was verified by analysing fastq.gz files from the MiSeq FGxTM platform using the softwares STRinNGS and GATK. Overall, the performance of the MiSeq FGxTM Forensic Genomics System was high. However, locus and allele drop-outs were relatively frequent at six loci (two STRs and four human identification SNPs) due to low read depth or skewed heterozygote balances, and the stutter ratios were larger than those observed with conventional STR genotyping methods. The risk of locus and allele drop-outs increased dramatically when the amount of DNA in the first PCR was lower than 250 pg. Two-person 50:1 mixtures were identified as mixtures, whereas 100:1 and 1 000:1 mixtures were not. Y-chromosomal short tandem repeats (Y-STRs) alleles were detected in the 100:1 and 1 000:1 female/male mixtures. The ForenSeqTM Universal Analysis Software provided the data analyst with useful alerts that simplified the analysis of the large number of markers. Many of the alerts were due to user-defined, locus-specific criteria. The results shown here indicated that the default settings should be altered for some loci. Also, recommended changes to the assay and software are discussed. PMID- 30483662 TI - Forensic investigation of 23 autosomal STRs and application in Han and Mongolia ethnic groups. AB - A forensic validation study of the Early Access HuaxiaTM Platinum Polymerase Chain Reaction (PCR) kit was completed to document the performance capabilities and limitations. The genotyping of DNA samples was consistent across a large range of template DNA concentrations, with complete profiles obtained at 0.125 ng; however, no more than 2 mm * 1.2 mm punches of samples would be recommended for direct amplification. The size precision and accuracy test revealed the genotyping ability; while consistent results were obtained when comparing the kit with other commercially available systems. In addition, the whole PCR amplification can finish within approximately 45 min, making the system suitable for fast-detection. However, only partial profiles may be obtained with challenging samples, including DNA stored on Foam-Tipped Applicators (FTA) cards or some case samples. For the forensic application in ethnic groups, a total of 282 and 229 alleles were obtained in Han and Mongolia, respectively. Since the 23 short tandem repeats were independent from each other, the cumulative power of exclusion in duos was 0.999 999 157 188 and the cumulative power of exclusion in trios was 0.999 999 999 859 in the Han group while the cumulative power of exclusion in duos (CPEduo) was 0.999 998 848 26 and cumulative power of exclusion in trios (CPEtrio) was 0.999 999 999 79 in the Mongolia group. And good internal consistency was found between the two investigated groups and the Sichuan Han, Hui, Tibetan and Uygur according to available reference data. PMID- 30483663 TI - Genetic and structural characterization of 20 autosomal short tandem repeats in the Chinese Qinghai Han population and its genetic relationships and interpopulation differentiations with other reference populations. AB - China is a multinational country composed of 56 ethnic groups of which the Han Chinese accounts for 91.60%. Qinghai Province is located in the northeastern part of the Qinghai-Tibet Plateau, has an area of 72.12 km2, and is the fourth largest province in China. In the present study, we investigated the genetic polymorphisms of 20 short tandem repeat (STR) loci in a Qinghai Han population, as well as its genetic relationships with other populations. A total of 273 alleles were identified in 2 000 individuals at 20 loci, and the allelic frequency ranged from 0.000 2 to 0.532 7. The 20 STR loci showed a relatively high polymorphic rate in the studied group. Observed and expected heterozygosities ranged 0.613 0-0.907 5 and 0.614 8-0.920 0, respectively. The combined power of discrimination, and the probability of exclusion in duo and trio cases were 0.999 999 999 999 999 999 999 999 34, 0.999 996 0 and 0.999 999 996 5, respectively. Analyses of interpopulation differentiation revealed that the most significant differences were found between the Qinghai Han and Malaysian, while no significant differences were found between the Qinghai Han and Han people from Shaanxi and Jiangsu. The results of principal component analysis, multidimensional scaling analysis and phylogenetic reconstructions also suggested the close relationships between the Qinghai Han and other two Han populations. The present results, therefore, indicated that these 20 STR loci could be used for paternity testing and individual identification in forensic applications, and may also provide information for the studies of genetic relationships between Qinghai Han and other groups. PMID- 30483664 TI - RNA-seq profiling reveals differentially expressed genes as potential markers for vital reaction in skin contusion: a pilot study. AB - Detection of the vitality of wounds is essential in forensic practice. The present study used Illumina RNA-seq technology to determine gene expression profiles in contused mouse skin. In obtained high quality sequencing reads, the reads were mapped onto a reference transcriptome (Mus_musculus.GRCm38.83). The results revealed that there were 659 up-regulated and 996 down-regulated differentially expressed genes (DEGs) in contused mouse skin. The DEGs were further analyzed using the Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes databases. Genes from different functional categories and signalling pathways were enriched, including the immune system process, immune response, defense response, cytokine-cytokine receptor interaction, complement and coagulation cascades and chemokine signalling pathway. Expression patterns of 11 DEGs were verified by RT-qPCR in mice skins. In addition, alterations of five DEGs were also analyzed in postmortem human wound samples. The results were in concordance with the results of RNA-seq. These findings suggest that RNA-seq is a powerful tool to reveal DEGs as potential markers for vital reaction in terms of forensic practices. PMID- 30483665 TI - Disubstituted piperazine analogues of trifluoromethylphenylpiperazine and methylenedioxybenzylpiperazine: analytical differentiation and serotonin receptor binding studies. AB - A series of N,N-disubstituted piperazines were synthesized containing the structural elements of both methylenedioxybenzylpiperazine (MDBP) and trifluoromethylphenylpiperazine (TFMPP) in a single molecule. These six potential designer drug molecules having a regioisomeric relationship were compared in gas chromatography-mass spectrometry (GC-MS), gas chromatography-infrared spectroscopy and serotonin receptor affinity studies. These compounds were separated by capillary gas chromatography on an Rxi(r)-17Sil MS stationary phase film and the elution order appears to be determined by the position of aromatic ring substitution. The majority of electron ionization mass spectral fragment ions occur via processes initiated by one of the two nitrogen atoms of the piperazine ring. The major electron ionization mass spectrometry (EI-MS) fragment ions observed in all six of these regioisomeric substances occur at m/z = 364, 229, 163 and 135. The relative intensity of the various fragment ions is also equivalent in each of the six EI-MS spectra. The vapour phase infrared spectra provide a number of absorption bands to differentiate among the six individual compounds on this regioisomeric set. Thus, the mass spectra place these compounds into a single group and the vapour phase infrared spectra differentiate among the six regioisomeric possibilities. All of the TFMPP-MDBP regioisomers displayed significant binding to 5-HT2B receptors and in contrast to 3-TFMPP, most of these TFMPP-MDBP isomers did not show significant binding at 5-HT1 receptor subtypes. Only the 3-TFMPP-3,4-MDBP (Compound 5) isomer displayed affinity comparable to 3 TFMPP at 5-HT1A receptors (Ki = 188 nmol/L). PMID- 30483666 TI - Glycated haemoglobin (HbA1c) for postmortem diagnosis of diabetes. AB - The study was conducted at the Estonian Forensic Science Institute in 2008-2014 as continuous part of our previous study of alcohol and premature death in Estonian men. Autopsy data from 504 cases of male deaths (ages 19-79) were collected and blood and urine samples for glycated haemoglobin (HbA1c), liver enzymes and alcohol concentration were analysed. The aim of our research was to find undiagnosed diabetes and diabetes risk cases postmortem on the basis of increased values of HbA1c. HbA1c was within the reference value 4.8%-5.9% (29-42 mmol/mol), in 88.1% (n = 444) of cases, below reference value in 2.4% (n = 12), in the risk group of diabetes, HbA1c 6.0%-6.4% (42-46 mmol/mol) was within 5.8% (n = 29), and HbA1c result of >=6.5% (48 mmol/mol) manifested in 3.8% (n = 19) of cases. The higher the age, the more cases with HbA1c value >=6.0% (42 mmol/mol) occurred. In the group of external causes of death (n = 348), the HbA1c value of >=6.5% (48 mmol/mol) HbA1c occurred in four cases. The HbA1c value was >=6.5% (48 mmol/mol) in 78.9% of 156 cases when the cause of death was disease, of which 58% were cardiovascular diseases. The prevalence of diabetes and diabetes risk was found lower compared to population-based study, as majority of the deceased were young and middle-aged males and no females were included. In the case of poisoning with narcotic substances, HbA1c was within the reference range. A negative correlation occurred between alcohol intoxication and HbA1c value. A positive correlation between ALT and HbA1c was found - the higher stage of liver damage correlated with the higher HbA1c level. PMID- 30483667 TI - Digital, big data and computational forensics. PMID- 30483668 TI - Critical review of the use and scientific basis of forensic gait analysis. AB - This review summarizes the scientific basis of forensic gait analysis and evaluates its use in the Netherlands, United Kingdom and Denmark, following recent critique on the admission of gait evidence in Canada. A useful forensic feature is (1) measurable, (2) consistent within and (3) different between individuals. Reviewing the academic literature, this article found that (1) forensic gait features can be quantified or observed from surveillance video, but research into accuracy, validity and reliability of these methods is needed; (2) gait is variable within individuals under differing and constant circumstances, with speed having major influence; (3) the discriminative strength of gait features needs more research, although clearly variation exists between individuals. Nevertheless, forensic gait analysis has contributed to several criminal trials in Europe in the past 15 years. The admission of gait evidence differs between courts. The methods are mainly observer-based: multiple gait analysts (independently) assess gait features on video footage of a perpetrator and suspect. Using gait feature databases, likelihood ratios of the hypotheses that the observed individuals have the same or another identity can be calculated. Automated gait recognition algorithms calculate a difference measure between video clips, which is compared with a threshold value derived from a video gait recognition database to indicate likelihood. However, only partly automated algorithms have been used in practice. We argue that the scientific basis of forensic gait analysis is limited. However, gait feature databases enable its use in court for supportive evidence with relatively low evidential value. The recommendations made in this review are (1) to expand knowledge on inter- and intra-subject gait variabilities, discriminative strength and interdependency of gait features, method accuracies, gait feature databases and likelihood ratio estimations; (2) to compare automated and observer-based gait recognition methods; to design (3) an international standard method with known validity, reliability and proficiency tests for analysts; (4) an international standard gait feature data collection method resulting in database(s); (5) (inter)national guidelines for the admission of gait evidence in court; and (6) to decrease the risk for cognitive and contextual bias in forensic gait analysis. This is expected to improve admission of gait evidence in court and judgment of its evidential value. Several ongoing research projects focus on parts of these recommendations. PMID- 30483669 TI - Review of the accreditation of digital forensics in China. AB - As a result of the many developments in information technology, digital evidence plays an increasingly important role in criminal and civil litigation. Because digital evidence is necessary for litigation, the judicial system must be assured of its accuracy, reliability, and verifiability, which can be assured by accreditation. This paper focuses on a comparison of the evolution of the accreditation of digital forensics internationally and domestically, discusses the existing problems that such accreditation encounters, and proposes the corresponding solutions. Moreover, this paper discusses the future of digital forensic laboratory accreditation and its implementation. PMID- 30483670 TI - Evaluating OpenFace: an open-source automatic facial comparison algorithm for forensics. AB - This article studies the application of models of OpenFace (an open-source deep learning algorithm) to forensics by using multiple datasets. The discussion focuses on the ability of the software to identify similarities and differences between faces based on images from forensics. Experiments using OpenFace on the Labeled Faces in the Wild (LFW)-raw dataset, the LFW-deep funnelled dataset, the Surveillance Cameras Face Database (SCface) and ForenFace datasets showed that as the resolution of the input images worsened, the effectiveness of the models degraded. In general, the effect of the quality of the query images on the efficiency of OpenFace was apparent. Therefore, OpenFace in its current form is inadequate for application to forensics, but can be improved to offer promising uses in the field. PMID- 30483671 TI - Camera recognition with deep learning. AB - In this paper, camera recognition with the use of deep learning technique is introduced. To identify the various cameras, their characteristic photo-response non-uniformity (PRNU) noise pattern was extracted. In forensic science, it is important, especially for child pornography cases, to link a photo or a set of photos to a specific camera. Deep learning is a sub-field of machine learning which trains the computer as a human brain to recognize similarities and differences by scanning it, in order to identify an object. The innovation of this research is the use of PRNU noise patterns and a deep learning technique in order to achieve camera identification. In this paper, AlexNet was modified producing an improved training procedure with high maximum accuracy of 80%-90%. DIGITS showed to have identified correctly six cameras out of 10 with a success rate higher than 75% in the database. However, many of the cameras were falsely identified indicating a fault occurring during the procedure. A possible explanation for this is that the PRNU signal is based on the quality of the sensor and the artefacts introduced during the production process of the camera. Some manufacturers may use the same or similar imaging sensors, which could result in similar PRNU noise patterns. In an attempt to form a database which contained different cameras of the same model as different categories, the accuracy rate was low. This provided further proof of the limitations of this technique, since PRNU is stochastic in nature and should be able to distinguish between different cameras from the same brand. Therefore, this study showed that current convolutional neural networks (CNNs) cannot achieve individualization with PRNU patterns. Nevertheless, the paper provided material for further research. PMID- 30483673 TI - Finding Dutch natives in online forums. AB - Law enforcement agencies have a restricted area in which their powers apply, which is called their jurisdiction. These restrictions also apply to the Internet. However, on the Internet, the physical borders of the jurisdiction, typically country borders, are hard to discover. In our case, it is hard to establish whether someone involved in criminal online behavior is indeed a Dutch citizen. We propose a way to overcome the arduous task of manually investigating whether a user on an Internet forum is Dutch or not. More precisely, we aim to detect that a given English text is written by a Dutch native author. To develop a detector, we follow a machine learning approach. Therefore, we need to prepare a specific training corpus. To obtain a corpus that is representative for online forums, we collected a large amount of English forum posts from Dutch and non Dutch authors on Reddit. To learn a detection model, we used a bag-of-words representation to capture potential misspellings, grammatical errors or unusual turns of phrases that are characteristic of the mother tongue of the authors. For this learning task, we compare the linear support vector machine and regularized logistic regression using the appropriate performance metrics f 1 score, precision, and average precision. Our results show logistic regression with frequency-based feature selection performs best at predicting Dutch natives. Further study should be directed to the general applicability of the results that is to find out if the developed models are applicable to other forums with comparable high performance. PMID- 30483672 TI - Clothing identification via deep learning: forensic applications. AB - Attribute-based identification systems are essential for forensic investigations because they help in identifying individuals. An item such as clothing is a visual attribute because it can usually be used to describe people. The method proposed in this article aims to identify people based on the visual information derived from their attire. Deep learning is used to train the computer to classify images based on clothing content. We first demonstrate clothing classification using a large scale dataset, where the proposed model performs relatively poorly. Then, we use clothing classification on a dataset containing popular logos and famous brand images. The results show that the model correctly classifies most of the test images with a success rate that is higher than 70%. Finally, we evaluate clothing classification using footage from surveillance cameras. The system performs well on this dataset, labelling 70% of the test images correctly. PMID- 30483674 TI - Google timeline accuracy assessment and error prediction. AB - Google Location Timeline, once activated, allows to track devices and save their locations. This feature might be useful in the future as available data for evidence in investigations. For that, the court would be interested in the reliability of this data. The position is presented in the form of a pair of coordinates and a radius, hence the estimated area for tracked device is enclosed by a circle. This research focuses on the assessment of the accuracy of the locations given by Google Location History Timeline, which variables affect this accuracy and the initial steps to develop a linear multivariate model that can potentially predict the actual error with respect to the true location considering environmental variables. The determination of the potential influential variables (configuration of mobile device connectivity, speed of movement and environment) was set through a series of experiments in which the true position of the device was recorded with a reference Global Positioning System (GPS) device with a superior order of accuracy. The accuracy was assessed measuring the distance between the Google provided position and the de facto one, later referred to as Google error. If this Google error distance is less than the radius provided, we define it as a hit. The configuration that has the largest hit rate is when the mobile device has GPS available, with a 52% success. Then the use of 3G and 2G connection go with 38% and 33% respectively. The Wi-Fi connection only has a hit rate of 7%. Regarding the means of transport, when the connection is 2G or 3G, the worst results are in Still with a hit rate of 9% and the best in Car with 57%. Regarding the prediction model, the distances and angles from the position of the device to the three nearest cell towers, and the categorical (non-numerical) variables of Environment and means of transport were taking as input variables in this initial study. To evaluate the usability of a model, a Model hit is defined when the actual observation is within the 95% confidence interval provided by the model. Out of the models developed, the one that shows the best results was the one that predicted the accuracy when the used network is 2G, with 76% of Model hits. The second model with best performance had only a 23% success (with the mobile network set to 3G). PMID- 30483675 TI - A facial reconstruction method based on new mesh deformation techniques. AB - This article presents a new numerical method for facial reconstruction. The problem is the following: given a dry skull, reconstruct a virtual face that would help in the identification of the subject. The approach combines classical features as the use of a skulls/faces database and more original aspects: (1) an original shape matching method is used to link the unknown skull to the database templates; (2) the final face is seen as an elastic 3D mask that is deformed and adapted onto the unknown skull. In this method, the skull is considered as a whole surface and not restricted to some anatomical landmarks, allowing a dense description of the skull/face relationship. Also, the approach is fully automated. Various results are presented to show its efficiency. PMID- 30483676 TI - Emphysematous Cystitis. PMID- 30483677 TI - Panner's Disease: The Vacuum Phenomenon Revisited. PMID- 30483678 TI - Air Embolism into Superior Mesenteric Artery Following Replacement of Ascending Aorta for Aortic Dissection - A Rare and Fatal Case. AB - We report an unusual case of fatal air embolism into the superior mesenteric artery in a patient, who underwent replacement of the ascending aorta for aortic dissection type A. CT performed twice on the first postoperative day showed abundant air in the superior mesenteric artery and its branches (but not in the portal-venous system) indicating air embolism with no signs of bowel necrosis. On the second postoperative day, the patient underwent extensive bowel resection due to bowel ischemia and died on the third postoperative day on MODS/SIRS. PMID- 30483679 TI - First-principle study of seven allotropes of arsenene and antimonene: thermodynamic, electronic and optical properties. AB - Recently, Group-V monolayer elements, especially the novel allotropes of arsenene and antimonene, have attracted significant attention. Motivated by this, we employed first principles to systemically investigate the properties of seven new allotropes of arsenene and antimonene. Through analysis of cohesive energy and phonon mode dispersion, we proved their high dynamical stability. Thermodynamics were also considered with Debye temperature, heat capacity and Gibb's free energy, which revealed their basic thermal properties and thermo-dynamic stability at ambient temperature. By calculating the band structures, we found that gamma-type, delta-type, epsilon-type and zeta-type for both arsenene and antimonene are semiconductors with direct band gaps, but eta-type, theta-type and iota-type for both arsenene and antimonene are semiconductors with indirect bandgaps. Furthermore, by studying optical absorptions, we discovered that these arsenene and antimonene allotropes exhibit absorption from visible to ultraviolet region with clear linear dichroism in x and y directions; particularly, gamma type and zeta-type have stronger optical absorption than others. PMID- 30483680 TI - An ultratrace assay of arsenite based on the synergistic quenching effect of Ru(bpy)32+ and arsenite on the electrochemiluminescence of Au-g-C3N4 nanosheets. AB - A novel ratiometric electrochemiluminescence (ECL) indicator has been constructed for ultratrace As(iii) detection based on the synergistic quenching of ECL emission of Au-g-C3N4 NSs using As(iii) and Ru(bpy)32+, meanwhile generating a new ECL signal of Ru(bpy)32+ with an increased intensity. Due to the dual quenching effect of As(iii) and Ru(bpy)32+ coupled with the generation of the second ECL signal of Ru(bpy)32+, the sensitivity and selectivity for detecting As(iii) are vastly enhanced. PMID- 30483681 TI - Facile dual doping strategy via carbonization of covalent organic frameworks to prepare hierarchically porous carbon spheres for membrane capacitive deionization. AB - For the first time, N,B dual-doped porous carbon spheres (denoted as PCSs) were prepared through direct carbonization of covalent organic frameworks (COFs) and used as an electrode material for membrane capacitive deionization (MCDI). Due to their high accessible surface area and defect-abundant structure offered by N,B co-doping, the nanostructured PCSs exhibit high desalination ability and are expected to be promisingly applied in MCDI. PMID- 30483682 TI - Understanding the mechanism and stereoselectivity of NHC-catalyzed [3 + 2] cycloaddition of 3-bromoenals and isatin N-Boc ketimines. AB - The mechanism and origin of stereoselectivities in N-heterocyclic carbine (NHC) catalyzed [3 + 2] cycloaddition of 3-bromoenals and isatin N-Boc ketimines have been studied using density functional theory (DFT) calculations. Various possible reaction pathways were examined and analyzed. Our calculation results reveal that the catalytic cycle can be characterized by six steps: nucleophilic attack of a catalyst on 3-bromoenal (step I); [1,2]-proton transfer (step II); addition to the other reactant isatin N-Boc ketimine (step III); debromination (step IV); intramolecular cycloaddition concerted with hydrogen-elimination (step V) and elimination of the NHC catalyst (step VI). For step II, besides the direct [1,2] proton transfer, the mediator (base and water)-assisted proton transfer has been investigated, and the DFT results show that the 2H2O cluster-mediated proton transfer is most energy favorable. The carbon-carbon bond formation step (step III) is calculated to be the stereoselectivity-determining step and the S configuration product is the predominant product, which are in good agreement with the experimental observations. The mechanistic insights gained in this work should be helpful for other NHC-catalyzed reactions. PMID- 30483683 TI - Continuous flow chemistry: where are we now? Recent applications, challenges and limitations. AB - A general outlook of the changing face of chemical synthesis is provided in this article through recent applications of continuous flow processing in both industry and academia. The benefits, major challenges and limitations associated with the use of this mode of processing are also given due attention as an attempt to put into perspective the current position of continuous flow processing, either as an alternative or potential combinatory technology for batch processing. PMID- 30483684 TI - Atom-economical selenation of electron-rich arenes and phosphonates with molecular oxygen at room temperature. AB - Organoselenium and selenophosphorus compounds are ubiquitously found in biologically active compounds, agrochemicals, functionalized materials etc. Although selenium is a micronutrient and an essential trace element, its contamination/consumption in higher concentrations is extremely dangerous. However, most of the previous selenation reactions generate toxic selenium waste as a by-product. Thus development of green synthetic protocols of these compounds is in high demand. We report herein a mild base-catalyzed cross-dehydrogenative coupling (CDC) between electron-rich arenes and phenylselenol to afford 3 selenylindole or selenylated phenols under air at room temperature. Interestingly, in the presence of a base and oxygen, the phenylselenol is converted into the diphenyldiselenide and provides almost quantitative yield. Similarly, a mild synthesis of selenophosphates was also achieved from the corresponding diorganyldiselenide or phenylselenols and nucleophilic phosphonates in a "dump and stir" manner under an oxygen balloon without a base or catalyst. From the preliminary mechanistic studies for selenation of indoles and phosphonates with TEMPO and EPR of the reaction mixture, it was evident that the reaction proceeds through the anionic pathway, which is in sharp contrast to the previous literature. The present reactions proceed smoothly under the mild conditions, furnishing high to almost quantitative yields in several cases. The reaction is easily scaled up to gram scale and has been demonstrated for the synthesis of an anti-HIV zidovudine (AZT) analogue. PMID- 30483685 TI - Commemorative issue in honour of Jan van der Leun, 14 June 1928-6 July 2016. PMID- 30483686 TI - B(C6F5)3-catalyzed Markovnikov addition of indoles to aryl alkynes: an approach toward bis(indolyl)alkanes. AB - The first example of the metal- and solvent-free B(C6F5)3-catalyzed Markovnikov addition of indoles to aryl alkynes was disclosed. Both N-H and N-protected indoles were tolerated, leading to a wide spectrum of versatile bis(indolyl)alkanes in moderate to good yields with high regioselectivities. PMID- 30483687 TI - Hydrophilic azaspiroalkenes as robust bioorthogonal reporters. AB - Two hydrophilic spiroalkenes, azaspiro[2.3]hex-1-ene and azaspiro[2.4]hept-1-ene, were designed and synthesized. Compared to the previously reported spiro[2.3]hex 1-ene, the azaspiroalkenes exhibited greater water solubility and reactivity as dipolarophiles in the photoinduced tetrazole-alkene cycloaddition reaction. In addition, an azaspiro[2.3]hex-1-ene-containing amino acid, AsphK, was found to be charged by an engineered pyrrolysyl-tRNA synthetase into proteins via amber codon suppression in E. coli as well as in mammalian cells. PMID- 30483688 TI - Emerging applications of peptide-oligonucleotide conjugates: bioactive scaffolds, self-assembling systems, and hybrid nanomaterials. AB - Peptide-oligonucleotide conjugates (POCs) are covalent constructs that link a molecule like DNA to a synthetic peptide sequences. These materials merge the programmable self-assembly of oligonucleotides with the bioactivity and chemical diversity of polypeptides. Recent years have seen the widespread use of POCs in a range of fields, driven the by relative advantages of each molecular type. In this review, we will present an overview of the synthesis and application of POCs, with an emphasis on emerging areas where these molecules will have a unique impact. We first discuss two main strategies for synthesizing POCs from synthetic monomers such as phosphoramidites and functionalized amino acids. We then describe four key fields of research in POCs: (1) biomaterials for interfacing with, and controlling the behavior of cells; (2) hybrid self-assembling systems that balance peptide and oligonucleotide intermolecular forces; (3) template enhanced coupling of POCs into larger molecules; and (4) display of peptides on self-assembled oligonucleotide scaffolds. We also highlight several promising areas for future applications in each of these four directions, and anticipate ever increasing uses of POCs in interdisciplinary research. PMID- 30483689 TI - Comparing the molecular and global rheology of a fluid under high pressures. AB - The viscosity of liquids is a strong function of pressure. While viscosity is relatively easy to measure at low pressure, high-pressure rheology presents significant experimental challenges. As a result, rheological models are often used to extrapolate viscosity from low pressure measurements to higher pressures. Techniques to obtain data over a wide range of pressures and shear rates, as well as understanding the validity and limitations of methods to fill the gaps in the available data, are therefore of crucial practical and theoretical importance. This work examines the viscosity of polyalphaolefin (PAO) by combining average global area averaged measurements at high pressure and local molecular viscosity measurements at moderate pressures. Viscosities spanning five orders of magnitude are examined at pressures up to 720 MPa. High pressure results were obtained with friction measurements where the fluid is sheared between two surfaces in a loaded point contact. The local molecular microviscosity at medium and low pressures was measured by applying a technique based on fluorescence anisotropy, which probes the rotational motion of dye molecules in a nanoscale film under shear. Both sets of measurements are taken in the same configuration, an elastohydrodynamic (EHD) contact. This is the first set of quantitative local viscosity measurements that have been verified against both friction and high pressure rheometry measurements. Commonly used rheological models were compared to experimental results. Our work shows that fluorescence anisotropy and friction measurements can be used to determine the viscosity of liquids over a wide range of conditions from a single experimental setup. The results obtained match results from low- and high-pressure rheometry for PAO. The importance of correcting friction data for pressure non-uniformity, temperature and shear thinning is also highlighted. PMID- 30483690 TI - Transformations of ferrates(iv,v,vi) in liquids: Mossbauer spectroscopy of frozen solutions. AB - The kinetics and mechanism of ferrate(iv), (v) and (vi) transformations in water and in polar organic solvents (namely ethanol and tetrahydrofuran) have been investigated by the method of 57Fe Mossbauer spectroscopy of frozen solutions. Ethanol with a very limited amount of water under an inert atmosphere, significantly slows down the transformation reactions of ferrates(iv and v) and provides direct proof of the existence of intermediate states. Simultaneously, ethanol is oxidized to caboxylates in the close vicinity of the surface of ferrate crystallites as proven by X-ray photoelectron spectroscopy. On the contrary, any transformation of ferrate(vi) in pure ethanol (with a very limited amount of water) was not observed. Mossbauer spectroscopy of frozen solutions enabled us to experimentally identify and quantify intermediates of ferrate(iv) and ferrate(v) transformations for the first time. Sodium ferrate(iv) in its tetrahedral form, Na4FeO4, undergoes a two-step charge disproportionation to Fe(iii) and Fe(vi) via a Fe(v) intermediate without any evolution of oxygen in polar protic and aprotic solvents, specifically 2Fe(iv) -> Fe(iii) + Fe(v), and Fe(iv) + Fe(v) -> Fe(iii) + Fe(vi), i.e. in sum 3Fe(iv) -> 2Fe(iii) + Fe(vi). Ferrate(v) (K3FeO4) transforms to Fe(iii) and Fe(vi) without any indication of the Fe(iv) intermediate within the detection limit of the method. In addition to a charge disproportionation reaction proceeding in polar liquids, 3Fe(v) -> Fe(iii) + 2Fe(vi), a competitive reduction of Fe(v) directly to Fe(iii) accompanied by oxygen evolution takes place in water. Oxygen evolution was also measured for ferrate(iv and vi) transformations in water, but to a higher and a smaller extent compared to ferrate(v), respectively. The thermodynamics of the suggested ferrate(iv) and ferrate(v) transformation pathways was examined by DFT calculations. PMID- 30483691 TI - Differentiating human pluripotent stem cells into vascular smooth muscle cells in three dimensional thermoreversible hydrogels. AB - Vascular smooth muscle cells (VSMCs) are of great value and are needed in large quantities for tissue engineering, drug screening, disease modeling and cell based therapies. However, getting high quantity VSMCs remains a challenge. Here, we report a method for the scalable manufacturing of VSMCs from human pluripotent stem cells (hPSCs). hPSCs are expanded and differentiated into VSMCs in a three dimensional (3D) thermoreversible hydrogel. The hydrogel not only acts as a 3D scaffold for cells to grow, but also protects cells from hydrodynamic stresses in the culture vessel and prevents cells from excessive aggregation. Together, the hydrogel creates a cell-friendly microenvironment, leading to high culture efficiency. We show that VSMCs can be generated in 10 days with high viability (>90%), high purity (>80%) and high yield (~2.0 * 107 cells per mL hydrogel) in the hydrogel scaffold. The generated VSMCs have normal functions. Genome-wide gene expression analysis shows VSMCs made in the hydrogel (i.e. 3D-VSMCs) have higher expression of genes related to vasculature development and glycolysis compared to VSMCs made in the conventional 2D cultures (i.e. 2D-VSMCs), while 2D VSMCs have higher expression of genes related to cell proliferation. This simple, defined and efficient method is scalable for manufacturing hPSC-VSMCs for various biomedical applications. PMID- 30483692 TI - Direct and highly stereoselective synthesis of quinolizidine iminosugars promoted by l-proline-Et3N. AB - A mild and effective method for the synthesis of polyhydroxylated quinolizidine iminosugars is described. The Mannich-type reaction of iminosugar C-glycosides with aldehyde in the presence of l-proline-Et3N provides polyhydroxylated quinolizidine iminosugars, and desired products as the potential glucosidase inhibitors were obtained in good to excellent yields with excellent stereoselectivity. PMID- 30483693 TI - Proton transfer from pinene stabilizes water clusters. AB - We ionize small mixed pinene-water clusters by electron impact or by using photons after sodium doping and analyze the products by mass spectrometry. Electron ionization results in the formation of pure pinene, mixed pinene-water and protonated water cluster cations. The "fragmentation free" photoionization after sodium doping results into the formation of only water-Na+ clusters with a mean cluster size below that observed after electron ionization. We show that protonated water clusters are formed both directly and indirectly via pinene ionziation. The latter pathway is detailed by ab intio calculations, demonstrating the feasibility of proton transfer from pinene for larger water clusters. In small clusters, the proton transfer reaction is controlled by proton solvation energy and we can thus estimate its value for finite size clusters. The observed stabilization mechanism of water clusters may contribute to the formation of cloud condensation nuclei in the atmosphere. PMID- 30483694 TI - StnK2 catalysing a Pictet-Spengler reaction involved in the biosynthesis of the antitumor reagent streptonigrin. AB - Streptonigrin (STN, 1) is a highly functionalized aminoquinone alkaloid antibiotic with broad and potent antitumor activity. Previous isotope-labelling and genetic studies suggested that a beta-carboline alkaloid should be a key intermediate of STN biosynthesis and formed via a Pictet-Spengler (PS) reaction. Herein, StnK2 was biochemically characterized to be a Pictet-Spenglerase (PSase) catalysing the formation of a tetrahydro-beta-carboline (TH-betaC) scaffold from (2S,3S)-beta-methyl tryptophan and d-erythrose-4-phosphate. StnK2 can tolerate the alteration of tryptophan but only accept d-erythrose-4-phosphate as the aldehyde substrate, and StnK2 was identified to be R-specific for the newly formed chiral center. This work increases the diversities of Pictet-Spenglerase in nature and set a stage for the generation of streptonigrin derivatives by precursor-directed pathway engineering based on the flexible substrate selectivity of StnK2. PMID- 30483695 TI - Unconventional ionic ring-deconstruction pathways of a three-membered heterocycle. AB - Two different ionic deconstructions of a three-membered COP ring have been discovered. The first involves displacement of the C[double bond, length as m dash]O unit (aldehyde elimination) induced by base whilst the second involves acid-initiated extrusion of the ring-carbon (2-methyl-2-butene). Insight into the latter deconstruction was obtained by quantum chemical calculations. PMID- 30483696 TI - An enantioselective synthesis of alpha-alkylated pyrroles via cooperative isothiourea/palladium catalysis. AB - Herein we describe the direct enantioselective Lewis base/Pd catalysed alpha allylation of pyrrole acetic acid esters. This provides high isolated yields of highly enantioenriched products and exhibits broad reaction scope with respect to both reaction partners. The products can be readily elaborated in a manner which points towards potential applications in target directed synthesis. PMID- 30483697 TI - [Effect of cyclic tensile stress on expression of type II collagen and Sox9 in rat cranial base synchondrosis]. AB - PURPOSE: To establish an in vitro mechanical stimulation model of cranial base synchondrosis chondrocytes, and to study the effect of cyclic tensile stress on the main extracellular matrix of rat cranial base synchondrosis. METHODS: Cyclic tensile stress was imposed to the second passage of cranial base synchondrosis chondrocytes for 3, 6, 12 and 24 hours respectively by using a Flexcell Strain Unit-5000T(10% surface elongation, 1 Hz). After mechanical loading, the total RNA of the cells harvested from six-well BioFlex was extracted. Real-time quantitative RT-PCR was performed to quantify the mRNA levels of type II collagen and Sox9. The data were analyzed with SPSS 17.0 software package. RESULTS: Compared with the control group(0 h group), the mRNA expression of type II collagen was decreased after 3 hours of loading, but not statistically significant; While the expression of Sox9 decreased significantly (P<0.05). In the 6 h group, the expression of Col-II and Sox9 decreased significantly (P<0.01 and 0.05, respectively). The expression of Col-II and Sox9 increased in the 12 h group. The 24 h group showed significant increase in both type II collagen and Sox9 (P<0.05). CONCLUSIONS: The results illustrate that cyclic tensile stress can affect the synthesis of the main extracellular matrix of cranial base synchondrosis in vitro. Expression of type II collagen and Sox9 can be inhibited during early stage of mechanical loading. However, when loading time extends, the mechanical stimuli greatly promotes the expression of type II collagen and Sox9. The reaction of Sox9 in this in vitro mechanical stimulation model happens earlier than that of type II collagen. PMID- 30483698 TI - [Effect of exogenous ATP on NLRP3 inflammasome activation in gingival fibroblasts cells]. AB - PURPOSE: To investigate exogenous ATP-dependent activation of NLRP3 inflammasome and interleukin-1beta ( IL-1beta) secretion in P.gingivalis infected and heat killed P.gingivalis induced gingival fibroblasts cells ( hGFs) in vitro. METHODS: Gingival tissues were obtained from healthy patients and hGFs were cultured in vitro with tissue block method to harvest primary cells. HGFs was simulated by being treated with 100 MOI live P.gingivalis or 100 MOI heat-killed P.gingivalis (HP.gingivalis) after 5 mmol/L ATP pre-treatment. Real-time PCR was carried out to assess mRNA expression of NLRP3, ASC, caspase-1 and IL-1beta. The protein level of NLRP3 , caspase-1 and IL-1beta was evaluated by Western blot. IL-1beta secretion was measured using ELISA. Statistical analysis was performed using Graphpad prism 6 statistical package and the measurement data were analyzed by t test or one-way ANOVA. RESULTS: Compared with the control group, P.gingivalis downregulated NLRP3 mRNA and ASC mRNA while upregulated IL-1beta mRNA. Moreover, the protein expression of NLRP3 and IL-1beta was decreased. The gene and protein expression of NLRP3, ASC and IL-1beta was induced by HP.gingivalis, while caspase 1mRNA and IL-1betasecretion was free from P.gingivalis or HP.gingivalis stimulus. All those genes as well as intracellular protein expression and IL-1betasecretion were significantly potentiated with ATP/P.gingivalis or ATP/HP.gingivalis stimuli in hGFs. CONCLUSIONS: Exogenous ATP may be a potential stimulus signal in favour of NLRP3 inflammasome activation of hGFs and mediated inflammatory factor IL 1beta secretion. PMID- 30483699 TI - [Evaluation of the filling quality of different root canal obturation techniques using micro-CT]. AB - PURPOSE: The aim of this study was to evaluate the quality of different root canal obturation techniques by micro-CT. METHODS: Forty single-canal upper incisors were collected and decoronated to obtain 12 mm root segments. The root canals were prepared by using ProTaper rotary files and allocated into 4 groups randomly(n=10), then obturated with gutta-percha and(or) iRoot SP by cold lateral compaction (CLC), continuous wave condensation (CWC), single core (SC), sealer only buckfill (SoB) techniques, respectively. Each tooth was then scanned with micro-CT, and the percentage of 3D volume and 2D slices of voids and gaps were calculated 1 week later. The data were analyzed using SPSS 22.0 software package. RESULTS: Percentage of cross-sections with voids and gaps in CWC group was significantly less than others (P<0.05) , and it had a significantly greater filling area in 3D volume in whole root canal, middle third and coronal third levels (P<0.05), while SOB group had the largest filling quality in apical third levels (P<0.05). CONCLUSIONS: No filling technology can avoid voids. CWC technology provides the best filling performance. PMID- 30483700 TI - [Effect of 17beta-estradiol or resveratrol dimer on hypoxia inducible factor 1alpha in genioglossus myoblasts and its mechanism]. AB - PURPOSE: To investigate the role of 17beta-estradiol (E2) and resveratrol dimer (RD) on HIF-1alpha and the underlying mechanism. METHODS: Mice genioglossus myoblasts were isolated and cultured, and the estrogen receptor-alpha (ERalpha) shRNA lentivirus was used for gene knockdown. Cells in different groups were treated with different agents (E2, or RD, or E2 and LY294002), then incubated in normoxia or hypoxia for 24 h, the expressions of HIF-1alpha, ERalpha, ERbeta, total-Akt and phospho-Akt were detected using qRT-PCR and Western blot. Statistical analysis was completed with SPSS 17.0 software package. RESULTS: Both E2 and RD inhibited the overexpression of HIF-1alpha induced by hypoxia at mRNA and protein levels, and these effects were eliminated by genetic silencing of ERalpha by RNAi. Mechanically, E2 activated PI3K/Akt pathways to induce HIF 1alpha expression. CONCLUSIONS: ERalpha may be responsible for down-regulation of HIF-1alpha by E2 or RD via activation of downstream PI3K/Akt pathways. PMID- 30483701 TI - [Investigation of the micromorphological differences of the implant-abutment junction]. AB - PURPOSE: The aim of this pilot study was to investigate the morphological micro features of 3 commercially available implant-abutment joints, using compatible and original prosthetic components and to explore the correlation between the micromorphology and potential functional complications. METHODS: Three abutments (one original and two compatibles) were torqued on original Straumann RN implants, according to the manufacturer's instructions. The implant-abutment units were sliced in the microtome and photographed under different magnifications through a scanning electron microscope. Calibration measurements were conducted under magnification corresponding to the area under assessment. RESULTS: Major dimensional differences were identified between all studied contact areas of the three units. The tight contact in the implant shoulder was similar in all three units, but engagement of the internal connection and, in particular, the anti-rotation elements were seriously compromised in the compatible abutments. One compatible abutment demonstrated compromised engagement of the abutment screw as well. CONCLUSIONS: Compatible abutments can present critical morphological differences from the original ones. The differences in the cross-sectional geometry result in large differences in the overall contact areas, both in terms of quality and quantity which could have serious implications from the long-term stability of the prosthesis. PMID- 30483702 TI - [Human umbilical cord mesenchymal stem cells co-cultured with dental pulp cells in vitro and its effect on cell biological behaviors]. AB - PURPOSE: To investigated the effect of human umbilical cord mesenchymal stem cells (hUCMSCs) and human dental pulp cells (hDPCs) on cell biological behaviors by co-culture system in vitro. METHODS: hUCMSCs and hDPCs were obtained by primary culture. A culture system of hUCMSCs and hDPCs induced by BMP2 was established in vitro. hUCMSCs and hDPCs were co-cultured at the ratio of 1:1, 1:5 and 5:1. The optimum ratio of each group was selected to further experiment. The formation of calcium nodule was stained by alizarin red staining at 21 day. The expression of DSPP,ALP,DMP1,OCN,VEGF,HGF and Nanog gene was detected by real-time quantitative PCR at 7 day and 14 day. 1:1 group and hUCMSCs, hDPCs group were selected for alizarin red staining at 21 day according to PCR results. Statistical analysis was performed using SPSS 21.0 software package. RESULTS: Calcified nodules formation in 1:1 group was significantly higher than in hUCMSCs group (P<0.05), close to that in hDPCs. qPCR showed that the mRNA expression of DSPP, ALP, DMP1, OCN, VEGF and HGF in 1:1 group was significantly higher than that in hUCMSCs (P<0.05); mRNA expression of Nanog in 1:1 group was significantly lower than in hUCMSCs group (P<0.05). The results of alizarin red staining showed that the OD value of 1:1 group was significantly higher than that of hUCMSCs group (P<0.05). CONCLUSIONS: The cells can be induced to differentiate into odontoblastoid-like cells and the mRNA expression of angiogenic factors was stimulated by hUCMSCs co-culure wih hDPCs. PMID- 30483703 TI - [Safe zones of the maxillary posterior area for mini-implant insertion in adolescents with skeletal Class II malocclusion]. AB - PURPOSE: The purpose of this study was to measure the interradicular spaces between the maxillary second premolar and first molar in adolescents with skeletal Class II malocclusion, so as to obtain scientific knowledge for placing mini-implants. METHODS: Forty four cone-beam computed tomography(CBCT) images were selected, which consisted of 23 males and 21 females (average age, 14.07 years) with skeletal Class II malocclusion. CBCT was used to measure the closest interradicular distance and the shortest distance from cortical bone surface to the narrowest interradicular space apically at 1-mm intervals in 9 axial images from the cementoenamel junction(CEJ). SPSS 20.0 software package was used for statistical analysis. RESULTS: There was no significant difference in the closest interradicular distance and the shortest distance from cortical bone surface to the narrowest interradicular space between the left and right side (P>0.05), and no significant difference was found between males and females (P>0.05); The shortest distance from cortical bone surface to the narrowest interradicular space of the left apical area had positive correlation with SNA angle; The closest interradicular distance became wider toward the apical area,and the average distance of the shortest distance from cortical bone surface to the narrowest interradicular space was over 5mm in all sections. CONCLUSIONS: The distribution of interradicular spaces between the maxillary second premolar and first molar of adolescents with skeletal Class II malocclusion is learned using CBCT. These data might provide a reference for placing mini-implants. PMID- 30483704 TI - [Evaluation of dental and craniofacial characteristics in patients with mild skeletal facial asymmetry]. AB - PURPOSE: The purpose of this study was to investigate the dental and craniofacial morphological characteristics in patients with mild skeletal facial asymmetry, and to investigate the relationship between mild skeletal facial asymmetry and dental anomalies. METHODS: Thirty patients with mild skeletal facial asymmetry (experimental group) and 30 patients with normal faces (control group) were selected. All patients were scanned by cone-beam computed tomography (CBCT) and X ray machine, Winceph software was used to measure the posteroanterior cephalometric radiographs, NNT software was used to measure the CBCT data. The results were analyzed by Chi-square test, paired t test and independent sample t test using SPSS 19.0 software package. RESULTS: There were significant differences between the left and right sides of faces, teeth and alveolar bone of the first molar in the experimental group. The angle of mandibular dental midline and facial midline, the inclination of the frontal mandibular plane, the inclination of the first molar, the inclination of alveolar bone of the mandibular first molar, the width of alveolar bone of the mandibular first molar showed significant differences between the experimental group and the control group (P<0.05). There are some correlations among menton deviation, inclination of the first molar and alveolar bone of the first molar. CONCLUSIONS: Patients with mild skeletal facial asymmetry showed some specific skeletal and dental characteristics. There could be some correlations between these features.. PMID- 30483705 TI - [Impact assessment on enamel remineralization after orthodontic treatment with casein phosphopeptide calcium phosphate complex]. AB - PURPOSE: To compare the effect on enamel demineralization following fluoride rinse or casein phosphopeptide calcium phosphate complex (CPP-ACP) after fixed appliance orthodontic treatment. METHODS: The study population consisted of 21 post-orthodontic patients (13 females, 8 males, 84 affected teeth) with white spot lesions (WSL). They were divided into 3 groups with 28 affected teeth in each group. Participants in the control group were brushed with fluoride toothpaste twice a day. Participants in the fluoride group were instructed to rinse the mouth with 20mL 0.01% sodium fluoride rinse in addition to brushing twice a day. Participants in CPP-ACP group were instructed to use tooth moss after brushing their teeth twice a day for 6 months. SPSS 17.0 software package was used to analyze the data. RESULTS: Within 6 months after orthodontic treatment, white spot lesions areas of the three groups caused by enamel demineralization were all reduced in different degrees, and the differences of success rate were significant among three groups (P<0.05). CPP-ACP group achieved the highest success rate (51%) than the other group, the fluoride group (44%) and the control group (42%). CONCLUSIONS: Brushing teeth, fluoride rinse and CPP-ACP have certain effect on remineralization of demineralized teeth in 6 months after orthodontic treatment. Compared with brushing and fluoride rinse, CPP-ACP can reduce the area of enamel demineralization more effectively. PMID- 30483706 TI - [Influence on the condyle position by decreasing posterior occlusal plane angle in Class II high angle cases]. AB - PURPOSE: To investigate the changes of condyle position by decreasing posterior occlusal plane angle in Class II high angle cases. METHODS: Fifteen Class II high angle patients, aged from 15 to 30, were treated. Before treatment, ANB>5 degrees , FH-MP>32 degrees , molar relationship was Class II bilaterally. The treatment began with aligning and leveling the upper and lower dental arch, then the upper arch was expanded when necessary. Multiloop edgewise arch wire (MEAW) was used to guide the mandible forward and flatten the posterior occlusal plane. Cone-beam CT(CBCT) was taken for each patient before and after treatment. The anterior, superior and posterior spaces of temporomandibular joint(TMJ) were measured respectively, and the posterior occlusal plane angle was also measured. Paired t test was used to evaluate the changes of condyle position and posterior occlusal plane angle, and pearson correlation coefficients was used to determine the correlation between changes of condyle position and posterior occlusal plane angle using SPSS 19 software package. RESULTS: Class II molar relationship of all patients was improved to Class I, and the profile was improved. Posterior and superior space of TMJ increased by 0.88 mm+/-0.17 mm and 0.45 mm+/-0.20 mm on average respectively, and both increases were significant. Posterior occlusal plane was flattened, POP-SN and POP-FH decreased by 3.59 degrees +/-2.31 degrees and 2.31 degrees +/-3.62 degrees , respectively, and the decreases were significant. Pearson's correlation test showed no significant correlation between changes of condyle position and posterior occlusal plane angle. CONCLUSIONS: In orthodontic treatment of Class II high angle cases, the condyle can be changed to anterior and inferior position by decreasing posterior occlusal plane angle. PMID- 30483707 TI - [Dentists' knowledge and practice of revascularization in Shanghai: a cross sectional study]. AB - PURPOSE: To evaluate dentists' knowledge and practice of revascularization in Shanghai. METHODS: Using multistage, cluster and random sampling method, 5 districts from Shanghai urban and suburban areas were randomly selected, covering class-three and class-two hospitals, dental center, private hospitals and clinics, and 3 class-three authoritative dental special hospitals (nonrandom). A questionnaire survey was conducted among the endodontists, pedodontists and general dentists. SAS 9.13 software package was used for data analysis. RESULTS: A total of 834 dentists were investigated, and 588 valid questionnaires (75.3%) were collected. 401 (68.2%) dentists were familiar with revascularization, 20% of them treated patients with revascularization. The most common source of learning revascularization was continuing dental education (33.3%) and 85.8% dentists showed interest in revascularization. The most important reason for not using revascularization was unfamiliar with the operational procedure (41.5%). CONCLUSIONS: The middle-aged endodontic and pediatric specialists with higher education have better understanding and motion to apply revascularization, and are more interested in continuing dental education. In continuing education courses, lectures of revascularization with practical training should be increased, in order to promote revascularization application in dental practice. PMID- 30483708 TI - [The influence of the age of deep caries on eruption of premolars]. AB - PURPOSE: To evaluate the influence of the time of deep caries on eruption of premolars. METHODS: Children in kindergarten in 2010 was selected to check caries of deciduous molars, then baseline data of population and personal oral health records were established. After data collection, from 2010 to 2017, according to the age of deep caries in deciduous molars, they were divided into 4 groups: four year, five-year, six-year and seven-year. SPSS 20.0 software package was applied to analyze the results. RESULTS: Between 2010 and 2017, 994 children were investigated, including 528 boys and 466 girls. A total of 1220 maxillary first deciduous molars, 1307 maxillary second deciduous molars ,1244 mandibular first deciduous molars and 1253 mandibular second deciduous molars were investigated. At the age of 4 to 7, when the maxillary and mandibular deciduous molars suffered from deep caries, the replacement time of the premolars was earlier than cases with no caries. The difference was statistically significant (P<0.05); When deciduous molar decay occurred in young children, premolars had a tendency to erupt earlier, especially deciduous molars developed deep caries before 5 years, the difference was statistically significant (P<0.05). CONCLUSIONS: Prevention and intervention of dental caries in children is very important. Especially for children under 5 years old, caries in children's molars need early treatment, in order to decrease the impact on normal replacement of permanent teeth. PMID- 30483709 TI - [Clinical evaluation of short implants in atrophic posterior region]. AB - PURPOSE: To evaluate the clinical effect of short implants in atrophic posterior region. METHODS: A total of 38 Bicon short implants (<=8 mm) were placed in 30 patients with 3-10 mm of bone height in the posterior region from January to December 2012. The follow-up period was 4 years, radiographic, clinical examination(improved plaque index, improved bleeding index, probing depth)were conducted and patient satisfactions were investigated with Oral Health Impact Profile (OHIP-I). Statistical analysis was performed using SPSS17.0 software package. RESULES: Implant survival rate of short implants was 100% and implant success rate was 94.7%. The mean peri-implant bone resorption value was (0.25+/ 0.65) mm,the change of mesial and distal marginal bone was (-0.23+/-0.74) mm and (-0.27+/-0.59) mm, respectively. Crown to implant ratio (C/I)= 1.77+/-0.34, the implants were divided into 3 groups according to C/I<=1,12,there was no significant difference in marginal bone changes and no correlation between C/I and bone resorption. Through clinical examination,improved plaque index was 1.08+/-0.88,improved bleeding index was 1.11+/-0.83 and the average probing depth was (3.08+/-1.19) mm. OHIP-I score was 2.66+/-0.88, there was significant difference compared with preoperative OHIP-I score. CONCLUSIONS: Short implants are feasible and the success rate is high in the posterior region with insufficient bone height. The soft tissue around the short implants is in good health.While avoiding complex surgical procedures, reducing trauma, shortening the duration of treatment,short implants have a high degree of acceptance and the patient satisfactions are excellent.At the same time, regular preventive maintenance is important to maintain the long-term stability of implant dentures. PMID- 30483710 TI - [Comparison of the effect of three nickel-titanium instruments on molar root canal curvature]. AB - PURPOSE: To evaluate the influence of ProTaper, Mtwo, and M3 nickel-titanium instruments on root canal curvature during root canal preparation. METHODS: Forty five molars with root canal therapy were randomly divided into 3 groups. The root canals were prepared by using ProTaper, Mtwo and M3 nickel-titanium instruments. The qualified rate and change of root canal curvature before and after preparation were compared using SPSS22.0 software package. RESULTS: There was no significant difference between the three groups in the qualification rate after root canal preparation and the effect of different preparatory devices on root canal curvature(P>0.05), but there was significant difference in the change of root canal curvature before and after preparation (P<0.05). CONCLUSIONS: The three kinds of nickel-titanium instruments can effectively form root canal and have no difference in root canal curvature, but the curvature of root canal is changed after preparation. It is important to prevent complications during curved root canal preparation. PMID- 30483711 TI - [Clinical treatment and prognosis of 52 cases of neurinoma in parotid region]. AB - PURPOSE: To investigate the clinical features, diagnosis, and treatment, as well as prognosis of neurinoma in parotid region, in order to provide references for clinical treatment. METHODS: Fifty-two cases of neurinoma in parotid region treated between June 2000 to December 2013 were retrospectively investigated, including their clinical characteristics, imaging examination, diagnosis, therapies and prognosis. SPSS13.0 software package was used for Fisher's exact test. RESULTS: Nine cases (17.31%) in all had facial paralysis, discomfort and other neural symptoms before operation. Eleven cases(21.15%) was preoperatively diagnosed. All patients were treated with surgery, pathologically diagnosed and followed up for 42 months to 206 months. No recurrence and malignant transformation were found. Twenty-eight cases (53.85%) had symptoms of facial nerve injury postoperatively, but 18 cases (64.29%) were improved functionally. When there was no obvious correlation between the tumor and facial nerve, no facial nerve paralysis was found. When the tumor was located on the facial nerve, the rate of preserving facial nerve function was 22.22%, the rate of intracapsular enucleation of the neurinoma was 85.71%, and the effective rate of excision followed by facial nerve reconstruction was 85.71%. CONCLUSIONS: The diagnosis of neurinoma in parotid region is difficult and needed to be confirmed by postoperative pathology. The preservation of facial nerve function should be the utmost procedure during operation while intracapsular enucleation is the first choice. However, in order to restore the function of facial nerve, nerve reconstruction should be performed as soon as possible. PMID- 30483712 TI - [Expression and significance of YAP and TAZ proteins in oral squamous cell carcinoma]. AB - PURPOSE: To investigate the expression and significance of YAP and TAZ proteins in oral squamous cell carcinoma. METHODS: From February 2014 to March 2017, 113 oral squamous cell carcinoma specimens were selected, and the adjacent tissues (away from carcinoma >2 cm) were selected as the control. Immunohistochemical staining was used to detect the expression of YAP and TAZ protein, and its relationship with clinicopathological features were evaluated with SPSS 19.0 software package. RESULTS: The positive rate of YAP and TAZ protein in cancer tissues was 65.49% and 61.95%, respectively, which was significantly higher than that in the adjacent tissues (P<0.05). The positive expression of YAP protein in patients with low differentiation, cervical lymph node metastasis, stage III, tumor diameter>4 cm were 83.64%, 80.33%, 82.35% and 82.61%, significantly higher than that inpatients with high differentiation, without cervical lymph node metastasis, stage I-II, tumor diameter <=4 cm (P<0.05). The positive expression rate of TAZ protein in patients with low differentiation, stage III, tumor diameter >4 cm was 80%, 85.29% and 82.61%, significantly higher than that in patients with high differentiation, stage I-II, tumor diameter <=4 cm (P<0.05). The expression of YAP protein was positively correlated with the expression of TAZ protein (rs=0.571, P<0.05). CONCLUSIONS: YAP and TAZ proteins are strongly expressed in oral squamous cell carcinoma, closely related to the clinical and pathological features such as the degree of differentiation and the diameter of the tumor, suggesting that Hippo signaling pathway may be involved in the development of oral squamous cell carcinoma. PMID- 30483713 TI - [Effect of maximum anchorage extraction on upper airway in adolescent patients with bimaxillary protrusion]. AB - PURPOSE: To investigate the effect of maximum anchorage on upper airway in adolescent patients with bimaxillary protrusion and extraction from three dimensional direction on cone-beam computed tomography(CBCT). METHODS: A retrospective evaluation was carried out on pre- and post-orthodontic treatment records of 50 adolescents with bimaxillary protrusion treated by maximum anchorage extraction. The changes on upper airway pre- and post-treatment were measured. The data were analyzed using SPSS 17.0 software package. RESULTS: It was found that the volume, mean cross-section area, minimum cross-section area of oropharyngeal and hypopharyngeal airway were significantly decreased after treatment (P<0.001). The cross-section morphology of oropharyngeal and hypopharyngeal airway showed more ellipsoid(P<0.001). Pearson's correlation analysis indicated that the lower incisor retraction and hyoid retraction was correlated with mean cross-section area of hypopharyngeal airway (P<0.05). There was significant correlation in the upper and lower incisor retraction and hyoid retraction(P<0.01). CONCLUSIONS: The upper airway dimension should be given serious consideration on the decision when closing the space with maximum anchorage in adolescent patients. PMID- 30483714 TI - [Application of double miniscrews for extraction of horizontally impacted wisdom tooth with high risk of injury to inferior alveolar nerve]. AB - PURPOSE: To study the clinical effect of double miniscrews for extraction of horizontally impacted wisdom tooth adjacent to the inferior alveolar nerve canal. METHODS: Eight horizontally impacted wisdom teeth requiring extraction because of orthodontic treatment were proven to be adjacent to the inferior alveolar nerve canal by means of cone-beam CT scan. The treatment began with double miniscrews traction under the help of cantilever beam. After 6~9 months, they left the canal and then were extracted. RESULTS: After extraction, no patient developed lip numbness. CONCLUSIONS: Application of double miniscrews traction is an efficient and reliable method for extraction of horizontally impacted wisdom tooth that is adjacent to the inferior alveolar nerve canal. PMID- 30483715 TI - [Effect of diode laser in the treatment of 78 patients with sinus chronic apical abscess]. AB - PURPOSE: To explore the effect of diode laser in the treatment of sinus chronic apical abscess. METHODS: A total of 78 patients with sinus chronic apical abscess were randomly divided into experimental group and control group, 39 cases in each group. Patients in the control group were treated with conventional root canal preparation and calcium hydroxide sealant. After conventional root canal preparation, the canals in the experimental group were disinfected with diode laser and then calcium hydroxide sealant. SPSS 19.0 software package was used for data analysis. RESULTS: Of 39 patients in the experimental group, only 1 sinus was not healed,the total effective rate was 97.44%;Of 39 patients in the control group,9 sinuses were not healed, the total effective rate was 76.92%. The difference between the two groups was statistically significant. CONCLUSIONS: The results show that the effect of diode laser in the treatment of sinus chronic apical abscess is better, which is worthy of wide application. PMID- 30483716 TI - [Long-term effect of intruded upper molars and dental implant restoration in 24 patients]. AB - PURPOSE: To evaluate the long-term effectiveness of intruded upper molar with orthodontic mini-screw and the long-term stability of the lower molar restored with dental implant. METHODS: Twenty-four patients with excessive growing upper molar were chosen. The upper molars were intruded by orthodontic mini-screw to increase the bite distance, and then restored with dental implant. The height of molar and the height of bone around the implant were measured on the lateral cephalometric films and panoramic films to analyze the long-term effect of molar intrusion and implantation. The data were analyzed with SPSS18.0 software package. RESULTS: There was significant difference between the length of upper molar before and after intrusion, the upper molars were intruded (2.7+/-0.3)mm 3.5 months after orthodontic mini-screw; there was no significant difference after 1 year with retainer and implant restoration. The height of bone around the implant decreased 1.2 mm but without significant difference. CONCLUSIONS: With the upper molar intruded by orthodontic mini-screw , more bite space can be obtained to restore lower molar with dental implant, and the long-term effect of upper molar intrusion and lower molar implant are stable. PMID- 30483717 TI - [Practice and effect of one-stop service of dental clinic for old people]. AB - PURPOSE: To evaluate the effect of one-stop service of dental clinic for old people. METHODS: Before and after the implementation of one-stop service in the First Dental Clinic,120 elderly patients were selected as the study subjects. SPSS19.0 software was used to compare the average time and payment time of the two groups of patients, and the patients' satisfaction with the service. RESULTS: After one-stop service, the average clinical time and payment time were significantly decreased, which had statistical significance (P<0.01). The satisfaction degree from one-stop service was improved significantly (from 90% to 98%). CONCLUSIONS: The results indicated that one-stop service, by optimizing the treating process of oral diseases and improving clinical experience of aged patients, might be a more advanced service pattern to meet the demand of oral diseases and improve oral health level of the aged patients. PMID- 30483718 TI - [Evaluation of using Proplan virtual software in teaching of orthognathic surgery]. AB - PURPOSE: Using Proplan virtual software to construct a virtual teaching platform for orthognathic surgery, and to explore an effective teaching model for orthognathic surgery. METHODS: One-hundred grade four students of stomatology in Fujian Medical University were divided into two groups. Traditional orthognathic surgery teaching method and Proplan virtual software teaching method were employed to teach the two groups of students, respectively. Orthognathic-surgery related paper test was used to evaluate how the two groups of students understand orthognathic surgery; then the students were switched to the other teaching method, respectively. A follow-up questionnaire survey was conducted to further evaluate students' acceptance of the two teaching methods. Finally, a comprehensive statistical analysis was performed for students understanding of orthognathic surgery using SPSS 11.0 software package. RESULTS: According to the test scores, students in the experimental group scored higher than the control group, the difference was significant (P<0.01). The acceptance of different teaching methods displayed remarkable difference between the two groups. Token together, our finding showed that virtual model surgery teaching was an easier teaching method for students to understand and accept. CONCLUSIONS: Proplan virtual software teaching improves the teaching efficiency of orthognathic surgery and deserves further promotion. PMID- 30483719 TI - [Study on the incentive strategy of "double guidance" way and "1+2" mode in the cultivation of master's degree postgraduates-A case study of Zhejiang Chinese Medical University]. AB - With the degree of enrollment of postgraduates in medical specialty expanding year by year, medical colleges have been exposed the deficiencies in the education of professional degree, which is paying more attention to clinic but less to scientific research. Postgraduate students have weak scientific awareness and less enthusiasm. This study forward on reforming the teaching model and incentive strategy based on the questionnaire survey. The purpose was to encourage the professional degree postgraduate students to be involved in scientific research initiative, innovation ability, and improve the quality of postgraduate education. PMID- 30483720 TI - [McCune-Albright syndrome with hyperthyroidism: report of one case and review of literature]. AB - McCune-Albright Syndrome(MAS) is a rare disease characterized by triad of polyostotic fibrous dysplasia of bone(FD), precocious puberty, and cafe-au-lait skin pigmentation. This paper reported a case of McCune-Albright syndrome with hyperthyroidism, and discussed the pathogenesis, clinical manifestations, diagnosis and treatment of MAS. PMID- 30483721 TI - Clinical practice guidelines for the management of brain tumours: A rehabilitation perspective. AB - OBJECTIVE: To critically appraise published clinical practice guidelines (CPGs) for brain tumours, and to synthesize evidence-based recommendations from a rehabilitation perspective. METHODS: A comprehensive literature search included: health science databases, CPG clearinghouse/developer websites, and grey literature up to March 2018. All brain tumour CPGs that reported systematic methods for evidence search, and clearly defined recommendations supporting evidence for rehabilitation interventions were included. Three authors independently selected potential CPGs and assessed their methodological quality using the Appraisal of Guidelines, Research and Evaluation (AGREE-II) Instrument. Recommendations from included CPGs were categorized from a rehabilitation perspective. RESULTS: Of the 11 CPGs identified, only 2, developed by the National Institute for Health and Clinical Excellence (NICE) and the Australian Cancer Network (ACN), included rehabilitation components for the management of brain tumours. Both CPGs were of moderate quality. The recommendations reported were generic, and only the ACN guidelines provided detailed recommendations for rehabilitation interventions. Both guidelines recommend a comprehensive multi disciplinary care approach. Detailed comparison, however, was not possible due to inconsistent recommendations, making it difficult to summarize rehabilitative care. CONCLUSION: Despite rehabilitation being an integral component of the management of brain tumours, only a limited number of CPGs have incorporated recommendations for specific rehabilitation interventions. In order to improve clinical outcomes in this population future CPGs should incorporate rehabilitation interventions. PMID- 30483722 TI - Early physical and psycho-educational rehabilitation in patients with coronary artery bypass grafting: A randomized controlled trial. AB - OBJECTIVES: Rehabilitation of patients following coronary artery bypass grafting (CABG) has been widely studied; however, research into early rehabilitation after CABG is sparse. The aim of this trial was to assess the impact of early rehabilitation, compared with usual care in patients following CABG. DESIGN: Randomized controlled trial. PATIENTS: A total of 326 patients treated with CABG. METHODS: Patients treated with CABG were randomized 1:1 to 4 weeks of comprehensive early rehabilitation or usual care. The primary outcome was the Six Minute Walk Test (6MWT). Secondary outcomes were mental health and physical activity (Medical Outcome Study Short Form; SF-12); anxiety and depression (Hospital Anxiety and Depression Scale; HADS); physical and emotional scores; sleep (Pittsburgh Sleep Quality Index; PSQI); pain (Orebro Musculoskeletal Screening Questionnaire; OMSQ) and muscle endurance (Sit-To-Stand test). RESULTS: Sixteen patients dropped out. No significant differences between groups in the primary outcome (6MWT) were found after 4 weeks (p = 0.27). For secondary outcomes the odds ratio of HADS-D >= 8 decreased in favour of the experimental intervention (p = 0.04). There was non-adherence to parts of the intervention. Per-protocol analysis showed differences between groups for the 6MWT (p = 0.02) and the Sit-To-Stand test (p = 0.046). CONCLUSION: In general, the intervention had no effect on the 6MWT, or secondary outcomes, except for depressive symptoms. However, in adherent participants, the intervention had a positive effect for the primary and several secondary outcomes. PMID- 30483723 TI - Inter- and intra-rater variability of testing velocity when assessing lower limb spasticity. AB - OBJECTIVE: To establish the variability of fast testing velocity and joint range of motion and position when assessing lower-limb spasticity in individuals following neurological injury. DESIGN: Observational study of people with lower limb spasticity. SUBJECTS: Patients with an upper motor neurone lesion (n = 35) and clinicians experienced in spasticity assessment (n = 34) were included. METHODS: The Modified Tardieu scale (MTS) was completed on the quadriceps, hamstrings (2 positions), gastrocnemius and soleus for each participant's more affected lower limb by 3 assessors. Mean absolute differences (MADs) were used to calculate variability as a measure of reliability. RESULTS: Variability of peak testing velocity was greater at the ankle joint compared with the knee joint. The greatest MAD for V3 (fast) inter-rater testing velocity was 119 degrees /s in the soleus, representing 29.4% of the mean variable value, and least for the quadriceps (64.3 degrees /s; 18.5%). Inter-rater variability was higher than intra-rater variability for all testing parameters. The MAD for joint end angle ranged from 2.6 degrees to 10.7 degrees and joint start angle from 1.2 degrees to 14.4 degrees . CONCLUSION: There was a large degree of inter- and intra-rater variability in V3 testing velocity when using the MTS to assess lower limb spasticity. The inter-rater variability was approximately double the intra-rater variability. PMID- 30483724 TI - Manually assisted body-weight supported locomotor training does not re-establish walking in non-walking subjects with chronic incomplete spinal cord injury: A randomized clinical trial. AB - OBJECTIVE: To assess the effects of manually assisted body-weight supported locomotor training in subjects with chronic incomplete spinal cord injury. DESIGN: Randomized controlled clinical trial. SUBJECTS: Twenty subjects with American Spinal Injury Association Impairment Scale grades C or D and > 2 years post-injury. METHODS: Random allocation to 60 days of body-weight supported locomotor training, or usual care, which might include over-ground walking. Walking function, lower extremity muscle strength and balance were blindly evaluated pre-/post-intervention. RESULTS: A small, non-significant improvement in walking function was observed (0.1 m/s (95% confidence interval (95% CI) -0.2, 0.4)), but subjects without baseline gait function, did not re-establish walking. The effect on lower extremity muscle strength was 2.7 points (95% CI -1.4, 6.8). No difference was observed in balance measures. CONCLUSION: Subjects with chronic incomplete spinal cord injury without baseline walking function were unable to re establish gait with manually assisted body-weight supported locomotor training. A modest, non-significant, improvement was found in strength and walking speed. However, due to study recruitment problems, an effect size that was smaller than anticipated, and large functional heterogeneity among study subjects, the effect of late-onset body-weight supported locomotor training is not clear. Future studies should include larger numbers of subjects with less functional loss and greater functional homogeneity. Intensive training should probably start earlier post-injury. PMID- 30483725 TI - Isorhamnetin alleviates lipopolysaccharide-induced inflammatory responses in BV2 microglia by inactivating NF-kappaB, blocking the TLR4 pathway and reducing ROS generation. AB - Isorhamnetin, which is a flavonoid predominantly found in fruits and leaves of various plants, including Hippophae rhamnoides L. and Oenanthe javanica (Blume) DC, is known to possess various pharmacological effects. However, the anti inflammatory potential of isorhamnetin remains poorly studied. Therefore, the present study aimed to investigate the inhibitory potential of isorhamnetin against inflammatory responses in lipopolysaccharide (LPS)-stimulated BV2 microglia. To measure the effects of isorhamnetin on inflammatory mediators and cytokines, and reactive oxygen species (ROS) generation, the following methods were used: cell viability assay, griess assay, ELISA, reverse transcriptase polymerase chain reaction, flow cytometry, western blotting and immunofluorescence staining. The results revealed that isorhamnetin significantly suppressed LPS-induced secretion of pro-inflammatory mediators, including nitric oxide (NO) and prostaglandin E2, without exhibiting significant cytotoxicity. Consistent with these results, isorhamnetin inhibited LPS-stimulated expression of regulatory enzymes, including inducible NO synthase and cyclooxygenase-2 in BV2 cells. Isorhamnetin also downregulated LPS-induced production and expression of pro-inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-1beta. The mechanism underlying the anti-inflammatory effects of isorhamnetin was subsequently evaluated; this flavonoid inhibited the nuclear factor (NF)-kappaB signaling pathway by disrupting degradation and phosphorylation of inhibitor kappaB-alpha in the cytoplasm and blocking translocation of NF-kappaB p65 into the nucleus. In addition, isorhamnetin effectively suppressed LPS-induced expression of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88. It also suppressed the binding of LPS with TLR4 in BV2 cells. Furthermore, isorhamnetin markedly reduced LPS-induced generation of ROS in BV2 cells, thus indicating a strong antioxidative effect. Collectively, these results suggested that isorhamnetin may suppress LPS-mediated inflammatory action in BV2 microglia through inactivating the NF-kappaB signaling pathway, antagonizing TLR4 and eliminating ROS accumulation. Further studies are required to fully understand the anti-inflammatory effects associated with the antioxidant capacity of isorhamnetin; however, the findings of the present study suggested that isorhamnetin may have potential benefits in inhibiting the onset and treatment of neuroinflammatory diseases. PMID- 30483726 TI - Physiological function of myocilin and its role in the pathogenesis of glaucoma in the trabecular meshwork (Review). AB - Myocilin is highly expressed in the trabecular meshwork (TM), which plays an important role in the regulation of intraocular pressure (IOP). Myocilin abnormalities may cause dysfunction of the TM, potentially leading to increased IOP. High IOP is a well-known primary risk factor for glaucoma. Myocilin mutations are common among glaucoma patients, and they are implicated in juvenile onset open-angle glaucoma (JOAG) and adult-onset primary open-angle glaucoma (POAG). Aggregation of aberrant mutant myocilins is closely associated with glaucoma pathogenesis. The aim of the present review was to discuss the recent findings regarding the major physiological functions of myocilin, such as intra- and extracellular proteolytic processes. We also aimed to discuss the risk factors associated with myocilin and the development of glaucoma, such as misfolded/mutant myocilin, imbalance of myocilin and extracellular proteins, and instability of mutant myocilin associated with temperature. Finally, we further outlined certain issues that are yet to be resolved, which may represent the basis for future studies on the role of myocilin in glaucoma. PMID- 30483727 TI - Molecular targets of curcumin in breast cancer (Review). AB - Curcumin (diferuloylmethane), an orange-yellow component of turmeric or curry powder, is a polyphenol natural product isolated from the rhizome of Curcuma longa. For centuries, curcumin has been used in medicinal preparations and as a food colorant. In recent years, extensive in vitro and in vivo studies have suggested that curcumin possesses activity against cancer, viral infection, arthritis, amyloid aggregation, oxidation and inflammation. Curcumin exerts anticancer effects primarily by activating apoptotic pathways in cancer cells and inhibiting pro-cancer processes, including inflammation, angiogenesis and metastasis. Curcumin targets numerous signaling pathways associated with cancer therapy, including pathways mediated by p53, Ras, phosphatidylinositol-3-kinase, protein kinase B, Wnt-beta catenin and mammalian target of rapamycin. Clinical studies have demonstrated that curcumin alone or combined with other drugs exhibits promising anticancer activity in patients with breast cancer without adverse effects. In the present review, the chemistry and bioavailability of curcumin and its molecular targets in breast cancer are discussed. Future research directions are discussed to further understand this promising natural product. PMID- 30483728 TI - Therapeutic effects of a liquid bandage prepared with cellulose powders from Styela clava tunics and Broussonetia kazinoki bark: Healing of surgical wounds on the skin of Sprague Dawley rats. AB - Cellulose in different forms has extensively been applied in biomedical treatments, including scaffolding, tissue engineering and tissue formation. To evaluate the therapeutic effects of a liquid bandage (LB) prepared with cellulose powders from Styela clava tunics (SCT) and Broussonetia kazinoki bark (BSLB) for healing cutaneous wounds, the remedial effects of a low concentration (LoBSLB) and a high concentration (HiBSLB) of BSLB on skin regeneration and toxicity in Sprague Dawley rats. Results indicated that the total area of skin involved in the surgical wound was lower in the BSLB-treated group compared with the Vehicle treated group at days 4-12, although some variations were observed in the HiBSLB treated group. In addition, the BSLB-treated group showed significantly enhanced width of the re-epithelialization region and epidermal thickness when compared with the Vehicle-treated group. Furthermore, significant stimulation in the expression level of collagen-1 and the signaling pathway of VEGF after topical application of BSLB was indicated. No liver or kidney toxicities were detected for either doses of BSLB. Overall, the results of the present study suggest that BSLB accelerates the process of wound healing in surgical skin wounds of Sprague Dawley rats through stimulation of re-epithelialization and connective tissue formation, without any accompanying significant toxicity. PMID- 30483729 TI - Rosiglitazone attenuates cell apoptosis through antioxidative and anti-apoptotic pathways in the hippocampi of spontaneously hypertensive rats. AB - Oxidative stress serves an important role in hypertensive brain damage. Peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists possess antioxidative and anti-apoptotic effects. The present study verified the possibility that rosiglitazone serves a neuroprotective role by alleviating oxidative stress and cell apoptosis in the hippocampi of spontaneously hypertensive rats (SHRs). SHRs and age-matched Wistar-Kyoto (WKY; both 56 weeks old) rats received gavage administration of vehicle or rosiglitazone (5 mg/kg/day) for eight weeks. Systolic blood pressure (SBP) was measured by the indirect tail-cuff method. The expression ratio of activated astrocytes was analyzed by glial fibrillary acidic protein immunohistochemistry. PPAR-gamma, inducible nitric oxide synthase (iNOS), gp47phox, B-cell lymphoma 2 (Bcl-2), Bcl 2-associated X protein (Bax) and caspase-3 expression were investigated by quantitative polymerase chain reaction and western blot analysis. The number of apoptotic cells in the hippocampus of four groups was detected using the terminal deoxynucleotidyl transferase-mediated dUTP end-labeling (TUNEL) method. Compared with the WKY group, the SHR group exhibited decreased Bcl-2 and PPAR-gamma expression, increased SBP, increased ratio of activated astrocytes and TUNEL positive cells, increased expression of iNOS, gp47phox, caspase-3 and Bax. Rosiglitazone administration increased Bcl-2 and PPAR-gamma expression, decreased the ratio of activated astrocytes and TUNEL-positive cells, decreased iNOS, gp47phox, caspase-3 and Bax expression in the hippocampi of SHRs. However, rosiglitazone did not significantly decreased SBP in the SHR group. Therefore, rosiglitazone exerts neuroprotective effect through antioxidative and anti apoptotic pathways, which was independent of blood pressure control. PMID- 30483730 TI - IL-18 promotes the secretion of matrix metalloproteinases in human periodontal ligament fibroblasts by activating NF-kappaB signaling. AB - Chronic periodontitis is the most common periodontal disease and is characterized by progressive degeneration of periodontal tissue. Periodontal-specific pathogens can induce the expression of various inflammatory cytokines in periodontal ligament cells and their secretion into peripheral blood. These inflammatory cytokines have an important role in the occurrence and development of chronic periodontitis. ELISA was used to detect the expression of interleukin-18 (IL-18) protein in the serum and saliva of 30 healthy volunteers and 30 patients with chronic periodontitis. The clinical parameters that were assessed included plaque index, gingival index, periodontal probing depth and attachment loss. The effect of IL-18 on the viability of human periodontal ligament fibroblasts (hPDLFs) was examined using a Cell Counting Kit-8 assay. The effects of IL-18 on mRNA expression and secretion of matrix metalloproteinase (MMP)1, MMP2, MMP3 and MMP9 in hPDLFs were detected by reverse transcription-quantitative polymerase chain reaction and ELISA, respectively. The effect of IL-18 on the phosphorylation of nuclear factor-kappaB (NF-kappaB) p65 protein and the protein expression of MMP1, MMP2, MMP3 and MMP9 in hPDLF cells was detected by western blotting. The expression level of IL-18 in the serum of patients with chronic periodontitis was significantly higher than that of healthy volunteers, and the expression level of IL-18 in saliva was positively correlated with the periodontal destruction. However, IL-18 did not have a significant effect on the viability ability of hPDLFs. IL-18 promoted phosphorylation of NF-kappaB p65 protein in hPDLF, and increased the mRNA expression and protein secretion of MMP1, MMP2, MMP3 and MMP9. These findings indicate that IL-18 promotes the secretion of MMP1, MMP2, MMP3, and MMP9 in hPDLFs by activating the NF-kappaB signaling pathway, which has a key role in the development of chronic periodontitis. Therefore, targeting IL-18 may be a new research direction for the treatment of chronic periodontal disease. PMID- 30483731 TI - Potential four-miRNA signature associated with T stage and prognosis of patients with pancreatic ductal adenocarcinoma identified by co-expression analysis. AB - With a 5-year survival rate of only 8%, pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-associated mortality worldwide. Unfortunately, even following radical surgery, patient outcomes remain poor. Emerging as a new class of biomarkers in human cancer, microRNAs (miRNAs/miRs) have been reported to have various tumor suppressor and oncogenic functions. In the present study, miRNA expression profiles of patients with PDAC and corresponding clinical data with survival profiles were obtained from The Cancer Genome Atlas database. A co-expression network was constructed to detect the modules significantly associated with clinical features by weighted gene co expression network analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed on the hub miRNAs in the module of interest for functional annotation. A prognosis model consisting of hub miRNAs was generated using the R package 'rbsurv' and validated in survival analysis. The expression data of 523 miRNAs in 124 patients with PDAC were analyzed in a co-expression network. The turquoise module containing 131 miRNAs was identified to be associated with pathological T stage (cor=-0.21; P=0.02). The 39 hub miRNAs of the turquoise module were then detected using the 'networkScreening' function in R. These miRNAs were predominantly involved in biological processes including 'regulation of transcription', 'apoptotic process', 'TGF-beta receptor signaling pathway', 'Ras protein signal transduction' and significantly enriched in 'cell cycle', 'adherens junction', 'FoxO', 'Hippo' and 'PI3K-Akt signaling' pathways. A prognostic signature consisting of four hub miRNAs (miR-1197, miR-218-2, miR-889 and miR-487a) associated with pathological T stage was identified to stratify the patients with early-stage PDAC into high and low risk groups. The signature may serve as a potential prognostic biomarker for patients with early-stage PDAC who undergo radical resection. PMID- 30483732 TI - Astragaloside IV ameliorates high glucose-induced renal tubular epithelial mesenchymal transition by blocking mTORC1/p70S6K signaling in HK-2 cells. AB - Astragaloside IV (AST) is the major active saponin in Astragalus membranaceus and, reportedly, has a variety of pharmacological activities. However, the potential of AST to ameliorate high glucose-mediated renal tubular epithelial mesenchymal transition (EMT) remains undetermined. The aim of the present research was to explore the effect and mechanism of AST in EMT of renal tubular epithelial cells, as an underlying mechanism of renal fibrosis and a vital feature involved in diabetic nephropathy. The effect of AST on the EMT of renal tubular epithelial cells (HK-2) stimulated by high glucose was investigated and it was attempted to elucidate the potential underlying mechanism. The expression of E-cadherin and alpha-smooth muscle actin were determined by western blotting and immunofluorescence assays. The expression of the mammalian target of rapamycin complex 1 (mTORC1)/ ribosomal protein S6 kinase beta-1 (p70S6K) signaling pathway and protein levels of four transcriptional factors (snail, slug, twist and zinc finger E-box-binding homeobox 1) were also determined by western blotting. Additionally, extracellular matrix components, including fibronectin (FN) and collagen type IV (Col IV) were detected by ELISA. The results suggested that the EMT of HK-2 cells and the mTORC1/p70S6K pathway were activated by high glucose. The expression of snail and twist in HK-2 cells was elevated by high glucose. Furthermore, extracellular matrix components, FN and Col IV, were increased in HK-2 cells cultured with high glucose. In turn, treatment with AST reduced EMT features in HK-2 cells, inhibited mTORC1/p70S6K pathway activation, downregulated expression of snail and twist, and reduced secretion of FN and Col IV. In summary, the findings suggested that AST ameliorates high glucose-mediated renal tubular EMT by blocking the mTORC1/p70S6K signaling pathway in HK-2 cells. PMID- 30483733 TI - Hyaluronic acid-chitosan nanoparticles encoding CrmA attenuate interleukin-1beta induced inflammation in synoviocytes in vitro. AB - Osteoarthritis (OA) is a common degenerative joint disease characterized by inflammation of synoviocytes and degradation of cartilage. In the present study, hyaluronic acid/chitosan (HA/CS) nanoparticles were used as a vehicle for gene therapy of OA, and the cytokine response modifier A (CrmA) pDNA was proposed as the target gene. The HA/CS/pCrmA nanoparticles were prepared and the characteristics of the nanoparticles were examined. The nanoparticles were spherical, and the smallest size was obtained with the HA:CS weight ratio of 1:4. The release analysis exhibited a constant release over 29 days. The pDNA was completely combined with HA/CS nanoparticles and the HA/CS nanoparticles protected pDNA from degradation. Subsequently, rat synoviocytes were transfected with HA/CS/pDNA nanoparticles, and the results demonstrated that the HA/CS nanoparticles were able to improve the transfection capacity of pDNA. The cytotoxicity of the HA/CS/pDNA nanoparticles was additionally detected using a MTS assay to ensure that the HA/CS nanoparticle was a safe carrier. To additionally investigate the effects of HA/CS/pCrmA nanoparticles on synoviocytes in OA, the MMP-3 and MMP-13 gene expression levels were detected at the gene and protein expression levels. These results indicated that the HA/CS/pCrmA nanoparticles attenuated interleukin-1beta-mediated inflammation in synoviocytes. It was concluded that the HA/CS/pCrmA nanoparticles may provide a novel approach to the treatment of OA. PMID- 30483734 TI - HSP90 interacts with HMGCR and promotes the progression of hepatocellular carcinoma. AB - Heat shock protein 90 (HSP90) has been reported to promote the growth and inhibit apoptosis of hepatocellular carcinoma (HCC) cells. However, the underlying mechanisms are not fully understood. Immunostaining of the tissue array demonstrated that HSP90 was upregulated in HCC clinical samples and was associated with clinical features. HSP90 interacted with 3-hydroxy-3 methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of mevalonate pathway, in the immunoprecipitation assay and regulated its protein expression level by inhibiting protein degradation. In addition, lovastatin, an inhibitor of HMGCR, impaired the oncogenic functions of HSP90 in the cell growth, migration and colony formation assays. Taken together, this study demonstrated that HSP90 promoted the progression of HCC by positively regulating the mevalonate pathway and indicated that HSP90 may be a promising therapeutic target. PMID- 30483735 TI - Dioscin attenuates high-fat diet-induced insulin resistance of adipose tissue through the IRS-1/PI3K/Akt signaling pathway. AB - Insulin resistance, as a common metabolic disorder, may be caused by diet-induced obesity. The aim of the present study is to investigate the effects of dioscin on regulating insulin resistance of adipose tissue induced by a high-fat diet (HFD). An animal model was established successfully using C57BL/6J mice with high-fat feeding, followed by treatment with 5, 10 and 20 mg/kg dioscin through gavage for 18 weeks, and randomly divided into a control group, a HFD model group and a dioscin group treated with 5, 10 and 20 mg/kg/day dioscin for 12 weeks. Histopathological changes in adipose tissues were examined using hematoxylin and eosin staining. Biochemical parameters of the serum were also monitored, including glucose, insulin, total triglyceride, homeostasis model assessment of insulin resistance (HOMA-IR) and adipose insulin resistance (Adipo-IR) levels. Expression of the mRNA and associated proteins of the insulin receptor substrate 1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathways were determined using reverse transcription-quantitative polymerase chain reaction (RT qPCR) and western blot analysis, respectively. HOMA-IR and Adipo-IR values of mice fed with a HFD were significantly higher compared with those in the control group (P<0.01). However, dioscin administration significantly decreased HOMA-IR and Adipo-IR values in a dose-dependent manner (P<0.05), suggesting the effects of dioscin on attenuating insulin resistance. RT-qPCR results indicated that the associated genes of the IRS-1/PI3K/Akt pathway were significantly downregulated by HFD compared with the control group (P<0.05), while dioscin significantly increased the expression of those genes compared with the control group (P<0.05). Similarly, the significant increase in phosphorylated (p-)IRS-1/IRS-1 (P<0.05) and p-Akt/Akt (P<0.05) values were substantially reversed by dioscin treatment. Dioscin pronouncedly mitigated insulin resistance in adipose tissues through the IRS-1/PI3K/Akt pathway and has potential to be used as a novel therapeutic agent for the therapy of HFD-induced insulin resistance in adipose tissue. PMID- 30483736 TI - Attenuation of autophagy flux by 6-shogaol sensitizes human liver cancer cells to TRAIL-induced apoptosis via p53 and ROS. AB - Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily and is an antitumor drug that induces apoptosis in tumor cells with minimal or no effects on normal cells. Here, it is demonstrated that 6 shogaol (6-sho), a bioactive component of ginger, exerted anti-inflammatory and anticancer properties, attenuated tumor cell propagation and induced TRAIL mediated cell death in liver cancer cells. The current study identified a potential pathway by revealing that TRAIL and 6-sho or chloroquine acted together to trigger reactive oxygen species (ROS) production, to upregulate tumor suppressor protein 53 (p53) expression and to change the mitochondrial transmembrane potential (MTP). Treatment with N-acetyl-L-cysteine reversed these effects, restoring the MTP and attenuated ROS production and p53 expression. Interestingly, treatment with 6-sho increased p62 and microtubule-associated proteins 1A/1B light chain 3B-II levels, indicating an inhibited autophagy flux. In conclusion, attenuation of 6-sho-induced autophagy flux sensitized cells to TRAIL-induced apoptosis via p53 and ROS, suggesting that the administration of TRAIL in combination with 6-sho may be a suitable therapeutic method for the treatment of TRAIL-resistant Huh7 liver cells. PMID- 30483738 TI - A SIRT1 agonist reduces cognitive decline in type 2 diabetic rats through antioxidative and anti-inflammatory mechanisms. AB - Sirtuin 1 (SIRT1) is an NAD+-dependent protein deacetylase that is involved in cell differentiation, aging, apoptosis, physiological rhythms, metabolic regulation, oxidative stress and numerous other important biological processes. In the present study, the ability of a sirtuin-1 (SIRT1) agonist, SRT1720, to reduce cognitive decline in type 2 diabetes mellitus (T2DM) was investigated. Streptozotocin-induced male Sprague-Dawley rats were used to establish a T2DM model and the protective effect of SRT1720 and its underlying mechanisms were investigated. Body weight and fasting blood glucose (FBG) were recorded and cognitive function was measured with the Morris water maze. Levels of oxidative stress, inflammation, caspase-3 activity and nuclear factor kappaB (NF-kappaB) mRNA expression were detected with a series of commercial assay kits and reverse transcription-quantitative polymerase chain reaction, respectively. Western blot analysis was performed to determine the protein expression of NF-kappaB, endothelial nitric oxide synthase (eNOS), peroxisome proliferator-activated receptor gamma (PPARgamma), AMP-activated protein kinase (AMPK), heat shock 70 kDa protein (HSP70), SIRT1, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1). The results revealed that SRT1720 significantly increased body weight, decreased FBG, improved cognitive function and reduced the levels of proteins associated with oxidative stress and inflammation damage in T2DM rats. Additionally, SRT1720 significantly decreased NF-kappaB p65 mRNA expression and increased eNOS and PPARgamma expression. SRT1720 significantly reduced caspase-3 activity and HSP70 protein expression, and increased p-AMPK, SIRT1, Nrf2 and HO-1 protein expression. Collectively, the results indicate that SRT1720 may reduce cognitive decline in T2DM rats through antioxidative and anti inflammatory action via NF-kappaB and AMPK-dependent mechanisms. PMID- 30483737 TI - Rosuvastatin protects against oxidized low-density lipoprotein-induced endothelial cell injury of atherosclerosis in vitro. AB - Atherosclerosis-induced cardiovascular diseases (CVDs) are accompanied by substantial morbidity and mortality. The loss and injury of endothelial cells is the primary cause of atherosclerosis. Rosuvastatin is an alternative agent used to reduce the risk of cardiovascular disease. Subsequently, the present study aimed to investigate the protective effects of rosuvastatin on oxidized-low density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cell (HUVEC) injury. The viability of ox-LDL-cultured HUVECs with or without rosuvastatin (0.01, 0.1 and 1 umol/l) pretreatment, and pretreatment at different time points (3, 6, 12 and 24 h) was determined using an MTT assay. Morphological changes and the extent of apoptosis were detected; the anti-oxidase activity, including superoxide dismutase (SOD) and catalase (CAT), was examined, and the contents of malondiahdehyde (MDA) and nitric oxide (NO) were measured. The phosphorylation levels of endothelial nitric oxide synthase (eNOS), protein kinase B (Akt) and phosphoinositide 3 kinase (PI3K) were detected using western blot analysis. The results demonstrated that pretreatment with 0.01-1 umol/l rosuvastatin decreased cell apoptosis caused by ox-LDL. Notably, pretreatment with 1 umol/l rosuvastatin for >12 h increased cell viability. Additionally, DAPI staining revealed that rosuvastatin inhibited HUVEC apoptosis. Rosuvastatin treatment also resulted in increased SOD and CAT activities and decreased MDA content in ox-LDL-stimulated HUVECs. Furthermore, pretreatment with 0.01-1 umol/l rosuvastatin significantly increased' the NO content compared with HUVECs treated with ox-LDL alone. Western blot analyses demonstrated that rosuvastatin upregulated the phosphorylation of eNOS, Akt and PI3K. These findings indicated that rosuvastatin could protect HUVECs against ox-LDL-induced injury through its anti-oxidant effect and its ability to upregulate the expression of vascular endotheliocyte-protecting factors. PMID- 30483739 TI - Potential functions of long non-coding RNAs in the osteogenic differentiation of human bone marrow mesenchymal stem cells. AB - Long non-coding RNAs (lncRNAs) are a specific group of RNA molecules that do not encode proteins. They have been shown to serve important regulatory functions in various biological and cell differentiation processes. However, the potential functions and regulatory mechanisms of lncRNAs that are associated with the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) remain to be elucidated. The present study aimed to investigate lncRNAs that are differentially expressed during the osteogenic differentiation of hBMSCs, along with the potential functions of those lncRNAs. To this end, three groups of hBMSCs were stimulated to undergo osteogenic differentiation for 7 days. Known lncRNAs, unknown lncRNAs and mRNAs that demonstrated differential expression prior to and following the osteogenic differentiation of hBMSCs were screened using lncRNA high-throughput sequencing. In addition, 12 lncRNAs were selected for reverse transcription-quantitative polymerase chain reaction (RT-qPCR) validation of the accuracy of the sequencing results. The potential functions and possible targets of the differentially expressed lncRNAs were analyzed using bioinformatics technologies (gene ontology, Kyoto Encyclopedia of Genes and Genomes and gene co-expression network analysis). In total, 64 lncRNAs were differentially expressed by at least two-fold in hBMSCs prior to and following osteogenic differentiation; these included seven known lncRNAs (two upregulated and five downregulated lncRNAs) and 57 unknown lncRNAs (35 upregulated and 22 downregulated lncRNAs). In addition, 409 mRNAs (257 upregulated and 152 downregulated mRNAs) were differentially expressed by at least two-fold. The RT qPCR results obtained for 12 selected differentially expressed lncRNAs were consistent with the sequencing results. The gene co-expression network analysis of lncRNAs and mRNAs demonstrated that four lncRNAs (ENSG00000238042, lnc_1269, lnc_1369 and lnc_1708) may serve important roles in the osteogenic differentiation of hBMSCs. In conclusion, during the osteogenic differentiation of hBMSCs, the lncRNA expression profile changed significantly; certain of the observed differentially expressed lncRNAs may be derived from protein-coding genes and may serve important roles in osteogenic differentiation. PMID- 30483740 TI - Characterization of circRNA-associated ceRNA networks in patients with nonvalvular persistent atrial fibrillation. AB - Circular RNAs (circRNAs) are non-coding RNAs forming closed-loop structures, and their aberrant expression may lead to disease. However, the potential network of circRNA-associated competing endogenous RNA (ceRNA) involved in nonvalvular persistent atrial fibrillation (NPAF) has not been previously reported. In the present study, four left atrial appendages (LAA) of patients with NPAF and four normal LAAs were examined via RNA sequencing, and their potential functions were investigated via bioinformatics analysis. The circRNA-enriched genes were analyzed using Gene Ontology (GO) categories, while the enrichment of circRNAs was detected via the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. A total of 296 significantly dysregulated circRNA transcripts were obtained, with 238 upregulated and 58 downregulated. A number of circRNAs were further confirmed using reverse transcription-quantitative polymerase chain reaction analysis. Furthermore, the more comprehensive circRNA-associated ceRNA networks were examined in patients with NPAF. GO categories and KEGG annotation analysis of circRNAs revealed that the circRNA-associated ceRNA networks were likely to influence AF though alterations in calcium and cardiac muscle contraction. The circRNA-associated ceRNA networks revealed that dysregulated circRNAs in NPAF may be involved in regulating hsa-microRNA (miR)-208b and hsa-miR-21. To the best of our knowledge, this study presents the circRNA-associated ceRNA networks in NPAF for the first time, which may have potential implications for the pathogenesis of AF. This study reveals a potential perspective from which to investigate circRNAs in circRNA-associated ceRNA networks (hsa_circRNA002085, hsa_circRNA001321) in NPAF, and provides a potential biomarker for AF. PMID- 30483741 TI - Establishment of microRNA, transcript and protein regulatory networks in Alport syndrome induced pluripotent stem cells. AB - Alport syndrome (AS) is an inherited progressive disease caused by mutations in genes encoding for the alpha3, alpha4 and alpha5 chains, which are an essential component of type IV collagen and are required for formation of the glomerular basement membrane. However, the underlying etiology of AS remains largely unknown, and the aim of the present study was to examine the genetic mechanisms in AS. Induced pluripotent stem cells (iPSCs) were generated from renal tubular cells. The Illumina HiSeqTM 2000 system and iTRAQ-coupled 2D liquid chromatography-tandem mass spectrometry were used to generate the sequences of microRNAs (miRNAs), transcripts and proteins from AS-iPSCs. Integration of miRNA, transcript and protein expression data was used to construct regulatory networks and identify specific miRNA targets amongst the transcripts and proteins. Relative quantitative proteomics using iTRAQ technology revealed 383 differentially abundant proteins, and high-throughput sequencing identified 155 differentially expressed miRNAs and 1,168 differentially expressed transcripts. Potential miRNA targets were predicted using miRanda, TargetScan and Pictar. All target proteins and transcripts were subjected to network analysis with miRNAs. Gene ontology analysis of the miRNAs and their targets revealed functional information on the iPSCs, including biological process and cell signaling. Kyoto Encyclopedia of Genes and Genomes pathways analysis revealed that the transcripts and proteins were primarily enriched in metabolic and cell adhesion molecule pathways. In addition, the network maps identified hsa-miRNA (miR)-4775 as a prominent miRNA that was associated with a number of targets. Similarly, the prominent ELV-like protein 1-A and epidermal growth factor receptor (EGFR) associated transcripts were identified. Reverse transcription-quantitative polymerase chain reaction analysis was used to confirm the upregulation of hsa miR-4775 and EGFR. The integrated approach used in the present study provided a comprehensive molecular characterization of AS. The results may also further understanding of the genetic pathogenesis of AS and facilitate the identification of candidate biomarkers for AS. PMID- 30483742 TI - Tunicamycin enhances the suppressive effects of cisplatin on lung cancer growth through PTX3 glycosylation via AKT/NF-kappaB signaling pathway. AB - Long pentraxin-3 (PTX3) is an inflammatory molecule related to cancer proliferation, invasion, and metastasis. Many studies have highlighted the significance of glycosylated molecules in immune modulation, inflammation and cancer progression. Moreover, aberrant glycosylation of cancer cells is linked to chemoresistance. This study aimed to develop effective therapeutic strategies for deglycosylation of PTX3 (dePTX3) in order to enhance chemosensitivity to cisplatin (Cis) in lung cancer treatment. The A549 and SPCA1 cells were used to determine the role of PTX3 glycosylation in lung cancer growth. Our results revealed that PTX3 was higher in both human lung cancer tissues and serum in comparison with control. Furthermore, we found that deglycosylated PTX3 (dePTX3) by tunicamycin (TM), which is N-glycan precursor biosynthesis blocker, and PNGase F significantly reduced the survival and migration of lung cancer cells. To further confirm this, we also generated glycosylation-site mutant of PTX3 (mPTX3) to characterize the loss of glyco-function. dePTX3 and TM enhanced the suppressive effects of Cis on lung cancer cell growth, migration and invasion compared to individual treatment. Treatment with a combination of TM and Cis significantly inactivated AKT/NF-kappaB signaling pathway and induced apoptosis. In conclusion, these findings suggest that PTX3 is an important mediator of lung cancer progression, and dePTX3 by TM enhances the anticancer effects of Cis. The deglycosylation in chemotherapy may represent a potential novel therapeutic strategy against lung cancer. PMID- 30483743 TI - Magnetization transfer contrast MRI in GFP-tagged live bacteria. AB - Green fluorescent protein (GFP) is a widely utilized molecular reporter of gene expression. However, its use in in vivo imaging has been restricted to transparent tissue mainly due to the tissue penetrance limitation of optical imaging. Magnetization transfer contrast (MTC) is a magnetic resonance imaging (MRI) methodology currently utilized to detect macromolecule changes such as decrease in myelin and increase in collagen content. MTC MRI imaging was performed to detect GFP in both in vitro cells and in an in vivo mouse model to determine if MTC imaging could be used to detect infection from Pseudomonas aeruginosa in murine tissues. It was demonstrated that the approach produces values that are protein specific and concentration dependent. This method provides a valuable, non-invasive imaging tool to study the impact of novel antibacterial therapeutics on bacterial proliferation and perhaps viability within the host system, and could potentially suggest the modulation of bacterial gene expression within the host when exposed to such compounds. PMID- 30483744 TI - MicroRNA-3666 suppresses the growth and migration of glioblastoma cells by targeting KDM2A. AB - MicroRNAs (miRNAs) are acknowledged as essential regulators in human cancer types, including glioblastoma (GBM). However, the functions of microRNA-3666 (miR 3666) in GBM remain unclear. In the present study, it was identified that the expression of miR-3666 was significantly downregulated in GBM tissues compared with adjacent normal tissues by reverse transcription-quantitative polymerase chain reaction. Additionally, miR-3666 was downregulated in GBM cell lines. Furthermore, it was observed that the miR-3666 expression level in patients with GBM was associated with prognosis. With functional experiments, it was identified that overexpression of miR-3666 significantly inhibited the proliferation, migration and invasion of GBM cells in vitro by Cell Counting kit-8 and Transwell assays. Ectopic expression of miR-3666 significantly arrested GBM cells in the G0 phase by fluorescence activated cell sorting. In terms of the underlying mechanism, it was identified that lysine-specific demethylase 2A (KDM2A) is a direct target of miR-3666 in GBM cells. Overexpression of miR-3666 significantly decreased the expression of KDM2A in GBM cells. Furthermore, it was observed that knockdown of KDM2A significantly suppressed the proliferation, migration and invasion of GBM cells. Collectively, the present results demonstrated that the miR-3666/KDM2A axis serves an important role in the progression of GBM, which provides novel insight into the development of therapeutic strategies for GBM treatment. PMID- 30483745 TI - AT-101 induces G1/G0 phase arrest via the beta-catenin/cyclin D1 signaling pathway in human esophageal cancer cells. AB - AT-101, an orally available and well-tolerated natural pan-Bcl-2 family protein inhibitor, has been reported to be effective against a variety of cancers. However, the mechanisms whereby AT-101 exhibits anticancer activity have not been fully elucidated. In this study, we demonstrated that AT-101 reduced the cell viability of human esophageal cancer cells by inducing G1/G0 phase arrest and apoptosis. Apoptotic cell death occurred later than cell cycle arrest, as evidenced by an increase in the proportion of Annexin V-positive cells and cleaved caspase-3, -9 and PARP protein levels. AT-101 markedly downregulated the protein levels of phospho-retinoblastoma (Ser 780) and cyclin D1, whereas it elevated protein levels of p53 and p21Waf1/Cip1, contributing to the inhibition of cell cycle progression. Moreover, AT-101 substantially reduced beta-catenin expression. XAV-939, a small molecule that inhibits the Wnt/beta-catenin signaling pathway by facilitating beta-catenin degradation, lowered beta-catenin and cyclin D1 protein expression to an extent similar to AT-101. XAV-939 alone resulted in G1/G0 phase arrest and further induced cell cycle arrest in combination with AT-101, suggesting that the beta-catenin/cyclin D1 signaling pathway mediated, at least in part, the cell cycle arrest induced by AT-101. The present study may shed new light on the anticancer activity of AT-101 in relation to cell cycle arrest as well as apoptosis in human esophageal cancer cells. PMID- 30483746 TI - Human adipose-derived mesenchymal stem cells promote breast cancer MCF7 cell epithelial-mesenchymal transition by cross interacting with the TGF-beta/Smad and PI3K/AKT signaling pathways. AB - The influence and underlying mechanisms of human adipose-derived stem cells (Hu ADSCs) on breast cancer cells in the tumor microenvironment remain unclear. Understanding the association between Hu-ADSCs and cancer cells may provide targets for breast cancer treatment and reference for the clinical application of stem cells. Therefore, a Hu-ADSC and breast cancer MCF7 cell coculture system was established to investigate the paracrine effects of Hu-ADSCs on MCF7 cell migration and invasion, in addition to the potential mechanism of action by reverse transcription-quantitative polymerase chain reaction and western blotting. Hu-ADSCs enhanced MCF7 cell migration and invasion by decreasing the expression of epithelial marker E-cadherin, and increasing the expression of interstitial marker N-cadherin and epithelial-mesenchymal transition (EMT) transcription factors in vitro. The EMT effect of cocultured MCF7 cells was inhibited with the addition of anti-transforming growth factor (TGF)-beta1 or phosphoinositide 3-kinase (PI3K) inhibitor LY294002, accompanied by a significant decrease in phosphorylated (p)-mothers against decapentaplegic homolog (Smad) and p-protein kinase B (AKT) expression. The data suggested that the paracrine effect of Hu-ADSCs in the tumor microenvironment promoted the EMT of MCF7 cells by cross interacting with the TGF-beta/Smad and PI3K/AKT pathways. PMID- 30483747 TI - Knockdown of long non-coding RNA HOST2 inhibits the proliferation of triple negative breast cancer via regulation of the let-7b/CDK6 axis. AB - The upregulation of long non-coding RNA (lncRNA) human ovarian cancer-specific transcript 2 (HOST2) has been identified in breast cancer. The present study aimed to investigate whether lncRNA HOST2 regulated the proliferation of triple negative breast cancer (TNBC) cells, and the underlying molecular mechanism. In total, 30 patients with primary TNBC, who were treated at Wuhai People's Hospital (Wuhai, China), were recruited for the present study. Reverse transcription quantitative polymerase chain reaction analysis was used for the examination of gene expression levels. A Cell Counting kit-8 (CCK-8) assay was used for the detection of cell proliferation. Phases of the cell cycle were evaluated by flow cytometry. Western blot analysis was performed to detect protein expression levels. A dual luciferase activity assay was performed to examine the interaction between microRNA (miRNA) and the 3' untranslated region (UTR) of target mRNA. The results revealed increased expression levels of HOST2 in tumor tissues from patients with TNBC. A positive correlation was identified between the expression of HOST2 and cyclin-dependent kinase 6 (CDK6) in tumor tissues. The silencing of HOST2 induced cell proliferation inhibition and cell cycle redistribution in MDA MB-231 and MDA-MB-468 TNBC cells. In these two cell lines, HOST2 silencing caused a decrease in the phosphorylation of RB1 and CDK6, which was observed at the mRNA and protein levels. However, the silencing of CDK6 did not alter the expression of HOST2. It was hypothesized and confirmed that let-7b, a previously reported target miRNA of HOST2, was able to directly bind to the 3'UTR of CDK6 and repress its expression. The expression of let-7b was negatively correlated with the expression of HOST2 and CDK6 in tumor tissues. Overall, the data suggested that lncRNA HOST2 acts as an oncogene in TNBC via the upregulation of CDK6. PMID- 30483748 TI - HOXA5 inhibits the proliferation and induces the apoptosis of cervical cancer cells via regulation of protein kinase B and p27. AB - Homeobox A5 (HOXA5) is a member of the homeobox gene (HOX) family, which plays an important role in the development of various malignant tumors. Here, we speculated that HOXA5 has an effect on cervical cancer development. In our study, we aimed to explore the role and molecular mechanism of HOXA5 in regards to the cell proliferation and apoptosis in cervical cancer. We found that expression levels of HOXA5 measured by RT-qPCR and western blot assays in cervical cancer cell lines and tissues were both significantly downregulated. We performed a gain of-function experiment by the transfection with pcDNA.3.1-HOXA5 in ME-180 and HT 3 cells to overexpress HOXA5, and the caspase-3 activity measured by caspase-3 activity assay kit and cell apoptosis detected by flow cytometry were obviously promoted. Meanwhile, cell proliferation tested by BrdU assay, invasion determined by Transwell and cell viability tested by MTT were inhibited. Moreover, protein kinase B (AKT) was activated by incubation with SC79 (AKT activator; 1 ug/ml) after HOXA5 overexpression, and reversed the effect of HOXA5 overexpression on p27 expression. Additionally, significant elevation of AKT activation measured by western blot analysis abrogated the effect of HOXA5 on caspase-3 activity, cell apoptosis, proliferation, invasion and cell viability. Taken together, this study revealed that HOXA5 inhibits cervical cancer progression by regulating AKT/p27, proposing the potential role of HOXA5 in the prevention and treatment of cervical cancer. PMID- 30483749 TI - Dexmedetomidine attenuates the toxicity of beta-amyloid on neurons and astrocytes by increasing BDNF production under the regulation of HDAC2 and HDAC5. AB - Cytotoxicity of beta-Amyloid (Abeta) is a major contributor to the pathogenesis of Alzheimer's disease. Dexmedetomidine (Dex) has been revealed to have multiple neuroprotective actions as a clinical anesthetic agent. The aim of the present study was to investigate the protection of Dex against Abeta in neurons and astrocytes, and the possible protective mechanisms. Primary neurons and astrocytes were isolated respectively from the hippocampus and cerebral cortex of neonatal Sprague Dawley rats. The neurons and astrocytes were incubated with Abeta in the presence or absence of Dex, which was followed by evaluation of the cell viability and apoptosis. Reverse transcription-quantitative polymerase chain reaction, western blotting and ELISA assays were performed to assess the levels of specific genes or proteins. The results revealed that Abeta decreased the viabilities of neurons and astrocytes in a dose-dependent manner, and elevated the rate of apoptosis. However, Dex attenuated the detrimental effects of Abeta. Abeta caused deacetylation of histone H3 by promoting the accumulation of histone deacetylase (HDAC)-2 and HDAC5 in the cell nucleus, resulting in the reduced production of brain-derived neurotrophic factor (BDNF). However, Dex reversed the Abeta-induced deacetylation of histone H3 and thus, increased BDNF production. Using a HDAC inhibitor or recombinant BDNF protein also protected the neurons and astrocytes against Abeta cytotoxicity. These results suggested that the protective effect of Dex against Abeta is particularly relevant to BDNF. Thus, the present study provides a foundation for the further study of Dex protection against Abeta in animal models and pre-clinical researches. PMID- 30483750 TI - SETDB1 induces epithelial-mesenchymal transition in breast carcinoma by directly binding with Snail promoter. AB - SET domain bifurcated 1 (SETDB1) is a histone H3 lysine 9 methyltransferase that is highly expressed in various tumor types, including breast cancer. However, how SETDB1 functions in breast cancer is unclear. In the present study, proliferation, migration and invasion assays were performed to explore the role of SETDB1 in breast cancer cells. SETDB1 downregulation in BT549 and MDA-MB-231 cells reduced cell proliferation, whereas upregulation in MCF7 and T47D cells enhanced proliferation. Depletion of SETDB1 suppressed cell migration and invasion in vitro and reduced lung metastasis in vivo. By contrast, SETDB1 overexpression enhanced cell migration and invasiveness. Notably, SETDB1 overexpression appeared to induce epithelial-mesenchymal transition (EMT) in MCF7 cells. Mechanistic investigations indicated that SETDB1 acts as an EMT inducer by binding directly to the promoter of the transcription factor Snail. Thus, SETDB1 is involved in breast cancer metastasis and may be a therapeutic target for treating patients with breast cancer. PMID- 30483751 TI - (+)-pinoresinol-O-beta-D-glucopyranoside from Eucommia ulmoides Oliver and its anti-inflammatory and antiviral effects against influenza A (H1N1) virus infection. AB - Eucommia ulmoides Oliver (Du-Zhong) is an ancient Chinese herbal remedy used for the treatment of various diseases. To date, the effects of its constituent lignans on influenza viruses remain to be elucidated. In the present study, a lignan glycoside was isolated and purified from Eucommia ulmoides Oliver. Its structures were identified via extensive spectroscopic analysis, and its antiviral and anti-inflammatory activities, specifically against influenza viruses, were determined via a cytopathic effect (CPE) assay, plaque-reduction assays, a progeny virus yield reduction assay, reverse transcription-quantitative polymerase chain reaction analysis and a Luminex assay. Additionally, western blot analysis was performed to investigate the underlying mechanisms of its effects against influenza viruses. The chemical and spectroscopic methods determined the structure of lignan glycoside to be (+)-pinoresinol-O-beta-D glucopyranoside. The CPE assay showed that (+)-pinoresinol-O-beta-D glucopyranoside exerted inhibitory activities with 50% inhibition concentration values of 408.81+/-5.24 and 176.24+/-4.41 ug/ml against the influenza A/PR/8/34 (H1N1) and A/Guangzhou/GIRD07/09 (H1N1) strains, respectively. Its antiviral properties were confirmed by plaque reduction and progeny virus yield reduction assays. Additional mechanistic analyses indicated that the anti-H1N1 virus induced effects of (+)-pinoresinol-O-beta-D-glucopyranoside were likely due to inactivation of the nuclear factor-kappaB, p38 mitogen-activated protein kinase and AKT signaling pathways. Furthermore, (+)-pinoresinol-O-beta-D-glucopyranoside exhibited pronounced inhibitory effects on the expression of influenza H1N1 virus induced pro-inflammatory mediators, including tumor necrosis factor-alpha, interleukin (IL)-6, IL-8 and monocyte chemoattractant protein 1. The data obtained suggest that (+)-pinoresinol-O-beta-D-glucopyranoside may be a candidate drug for treating influenza H1N1 virus infection. PMID- 30483752 TI - Aging, rather than Parkinson's disease, affects the responsiveness of PBMCs to the immunosuppression of bone marrow mesenchymal stem cells. AB - Whether aging or Parkinson's disease (PD) affects the responses of peripheral blood mononuclear cells (PBMCs) to immunosuppression by bone marrow-derived mesenchymal stem cell (BM-MSCs) and which cytokines are more effective in inducing BM-MSCs to be immunosuppressive remains to be elucidated. PBMCs were isolated from healthy young (age 26-35), healthy middle-aged (age 56-60) and middle-aged PD-affected individuals. All the recruits were male. The mitogen stimulated PBMCs and proinflammatory cytokine-pretreated BM-MSCs were co cultured. The PBMC proliferation was measured using Cell Counting Kit-8, while the cytokine secretion was assayed by cytometric bead array technology. The immunosuppressive ability of BM-MSCs was confirmed in young healthy, middle-aged healthy and middle-aged PD-affected individuals. Among the three groups, the PBMC proliferation and cytokine secretion of the young healthy group were suppressed more significantly compared with those of the middle-aged healthy and middle-aged PD-affected group. No significant differences were identified in the PBMC proliferation and cytokine secretion between the patients with PD and the middle aged healthy subjects. Interferon (IFN)-gamma synergized with tumor necrosis factor (TNF)-alpha, interleukin (IL)-1alpha or IL-1beta was more effective than either one alone, and the combinations of IFN-gamma + IL-1alpha and IFN-gamma + IL-1beta were more effective than IFN-gamma + TNF-alpha in inducing BM-MSCs to inhibit PBMC proliferation. The results of the present study suggested that aging, rather than PD, affects the response of PBMCs toward the suppression of BM MSC, at least in middle-aged males. Patients with PD aged 56-60 remain eligible for anti-inflammatory BM-MSC-based therapy. Treatment of BM-MSCs with IFN-gamma + IL-1alpha or IFN-gamma + IL-1beta prior to transplantation may result in improved immunosuppressive effects. PMID- 30483753 TI - MicroRNA-140-5p aggravates hypertension and oxidative stress of atherosclerosis via targeting Nrf2 and Sirt2. AB - In the present study, the function of microRNA (miR)-140-5p on oxidative stress in mice with atherosclerosis was investigated. A reverse transcription quantitative polymerase chain reaction assay was used to determine the expression of miR-140-5p. Oxidative stress kits and reactive oxygen species (ROS) kits were used to analyze alterations in oxidative stress and ROS levels. The alterations in protein expression were determined using western blot analysis and an immunofluorescence assay. miR-140-5p expression was increased in mice with atherosclerosis with hypertension. Consistently, miR-140-5p expression was also increased in mice with atherosclerosis. Upregulation of miR-140-5p increased oxidative stress and ROS levels by suppressing the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), sirtuin 2 (Sirt2), Kelch-like enoyl CoA hydratase-associated protein 1 (Keap1) and heme oxygenase 1 (HO-1) in vitro. By contrast, downregulation of miR-140-5p decreased oxidative stress and ROS levels by activating the protein expression of Nrf2, Sirt2, Keap1 and HO-1 in vitro. Sirt2 agonist or Nrf2 agonist inhibited the effects of miR-140-5p on oxidative stress in vitro. Collectively, these results suggested that miR-140-5p aggravated hypertension and oxidative stress of mice with atherosclerosis by targeting Nrf2 and Sirt2. PMID- 30483754 TI - Oncological hyperthermia: The correct dosing in clinical applications. AB - The problem with the application of conventional hyperthermia in oncology is firmly connected to the dose definition, which conventionally uses the concept of the homogeneous (isothermal) temperature of the target. Its imprecise control and complex evaluation is the primary barrier to the extensive clinical applications. The aim of this study was to show the basis of the problems of the misleading dose concept. A clear clarification of the proper dose concept must begin with the description of the limitations of the present doses in conventional hyperthermia applications. The surmounting of the limits the dose of oncologic hyperthermia has to be based on the applicability of the Eyring transition state theory on thermal effects. In order to avoid the countereffects of thermal homeostasis, the use of precise heating on the nanoscale with highly efficient energy delivery is recommended. The nano-scale heating allows for an energy-based dose to control the process. The main aspects of the method are the following: i) It is not isothermal (no homogeneous heating); ii) malignant cells are heated selectively; and iii) it employs high heating efficacy, with less energy loss. The applied rigorous thermodynamical considerations show the proper terminology and dose concept of hyperthermia, which is based on the energy-absorption (such as in the case of ionizing radiation) instead of the temperature-based ideas. On the whole, according to the present study, the appropriate dose in oncological hyperthermia must use an energy-based concept, as it is well-known in all the ionizing radiation therapies. We propose the use of Gy (J/kg) in cases of non ionizing radiation (hyperthermia) as well. PMID- 30483755 TI - miR-381 and miR-489 suppress cell proliferation and invasion by targeting CUL4B via the Wnt/beta-catenin pathway in gastric cancer. AB - Accumulating evidence has highlighted the critical role of cullin 4B (CUL4B) in driving tumourigenesis in several malignancies, including gastric cancer (GC); however, the mechanisms underlying CUL4B upregulation remain unclear. The dysregulation of microRNAs (miRNAs or miRs) is known to be involved in tumourigenesis. In this study, we report that the expression of miR-381 and miR 489 is downregulated and is negatively correlated with that of CUL4B in GC tissues and cell lines. Further analysis verified that miR-381 and miR-489 directly targeted CUL4B. CUL4B silencing inhibited cell proliferation, migration and invasion by inactivating the Wnt/beta-catenin pathway. miR-381/miR-489 overexpression recapitulated the effects of CUL4B silencing, while CUL4B restoration negated the suppressive effects induced by the ectopic expression of miR-381/miR-489. Furthermore, miR-381/miR-489 exerted tumour suppressive functions by inactivating the Wnt/beta-catenin pathway through the targeting of CUL4B. Taken together, the findings of this study suggest that the miR-381/miR 489-mediated expression of CUL4B modulates the proliferation and invasion of GC cells via the Wnt/beta-catenin pathway, which indicates that the miR-381/miR-489 CUL4B axis is critical in the control of GC tumourigenesis. PMID- 30483756 TI - An integrative theory for cancer (Review). AB - In the integrative theory, chronic irritations induce tumors with genetic alterations and rapid proliferative ability. Tumor cells reprogram the metabolism and employ aerobic glycolysis to sustain rapid growth. The host provides both the nutrients and exhaust system to support tumor growth via the tumor microenvironment. Under certain conditions, such as aging, diabetes, obesity and a high-fat diet, the exhaust system is impaired, triggering a metabolic imbalance between the tumor and host. This is similar to a problematic car with an advanced motor with an out-of-date exhaust system. The metabolic imbalance causes a metabolic catastrophe, making tumor cells reside in a dismal environment and forcing them to invade, metastasize and undergo necrosis. Tumor necrosis, particularly in metastases, leads to non-specific systemic inflammation, which is the major cause of cancer-related mortality. On the whole, the integrative theory views cancer in an integrative manner and proposes that both genetic alterations and tumor-host interaction as regards metabolism and immunology determine the destiny of the tumor and host. Although cancer is a genetic disease, tumor biology is basically the nature of the host. PMID- 30483758 TI - The association of changes in RAD51 and survivin expression levels with the proton beam sensitivity of Capan-1 and Panc-1 human pancreatic cancer cells. AB - Fewer than 20% of patients diagnosed with pancreatic cancer can be treated with surgical resection. The effects of proton beam irradiation were evaluated on the cell viabilities in Panc-1 and Capan-1 pancreatic cancer cells. The cells were irradiated with proton beams at the center of Bragg peaks with a 6-cm width using a proton accelerator. Cell proliferation was assessed with the MTT assay, gene expression was analyzed with semi-quantitative or quantitative reverse transcription-polymerase chain reaction analyses and protein expression was evaluated by western blotting. The results demonstrated that Capan-1 cells had lower cell viability than Panc-1 cells at 72 h after proton beam irradiation. Furthermore, the cleaved poly (ADP-ribose) polymerase protein level was increased by irradiation in Capan-1 cells, but not in Panc-1 cells. Additionally, it was determined that histone H2AX phosphorylation in the two cell lines was increased by irradiation. Although a 16 Gy proton beam was only slightly up-regulated cyclin-dependent kinase inhibitor 1 (p21) protein expression in Capan-1 cells, p21 expression levels in Capan-1 and Panc-1 cells were significantly increased at 72 h after irradiation. Furthermore, it was observed that the expression of DNA repair protein RAD51 homolog 1 (RAD51), a homogenous repair enzyme, was decreased in what appeared to be a dose-dependent manner by irradiation in Capan-1 cells. Contrastingly, the transcription of survivin in Panc-1 was significantly enhanced. The results suggest that RAD51 and survivin are potent markers that determine the therapeutic efficacy of proton beam therapy in patients with pancreatic cancer. PMID- 30483757 TI - OxLDL promotes lymphangiogenesis and lymphatic metastasis in gastric cancer by upregulating VEGF-C expression and secretion. AB - Gastric cancer is one of the most malignant tumor types, and its metastasis is a notable cause of mortality. Among the methods of tumor metastasis, lymphatic metastasis is the predominant one in gastric cancer. A previous study reported that the plasma oxidized low-density lipoprotein (oxLDL) is the risk factor associated with the development of tumors in patients with abnormal lipid metabolism, but the influence of plasma oxLDL in the lymphatic metastasis of gastric cancer remains unclear. In the present study, the concentration of plasma oxLDL from patients with gastric cancer was detected with an ELISA kit, and the lymphatic vessel density in gastric cancer tissues was determined by D2-40 staining. The correlation analysis of oxLDL concentration and lymphatic vessel density demonstrated that plasma oxLDL was positively correlated with lymphatic metastasis in patients with gastric cancer. Subsequently, the popliteal lymph node metastasis animal experiment with nude mice confirmed that oxLDL could promote the lymphatic metastasis of gastric cancer. Following this, the western blotting and ELISA data demonstrated that oxLDL promoted the expression and secretion of vascular endothelia growth factor (VEGF)-C in gastric cancer cell lines. Finally, blocking the lectin-like oxLDL-1 (LOX-1) receptor, a specific receptor for oxLDL, and the nuclear factor (NF)-kappaB signaling pathway following oxLDL (50 ug/ml) treatment in HGC-27 cells revealed that oxLDL could activate the NF-kappaB signaling pathway mediated by LOX-1, with subsequent upregulation of VEGF-C expression, and secretion in and from gastric cancer cells, and finally that it could promote the lymphatic metastasis of gastric cancer. These data indicate the association between the plasma oxLDL and the lymphatic metastasis of gastric cancer, and indicate that oxLDL elimination may be a potential therapeutic target for the prevention and intervention of early lymph node metastasis in gastric cancer. PMID- 30483759 TI - EphA3 inhibits migration and invasion of esophageal cancer cells by activating the mesenchymal-epithelial transition process. AB - Eph receptor tyrosine kinases are critical for cell-cell communication during normal and oncogenic development. Eph receptor A3 (EphA3) expression is associated with tumor promotion in certain types of cancer; however, it acts as a tumor suppressor in others. The expression levels of EphA3 and its effects on tumor progression in esophageal squamous cell carcinoma (ESCC) cell lines were determined using reverse transcription-quantitative polymerase chain reaction analysis and a Transwell invasion assay. The present study demonstrated that EphA3 expression was decreased in ESCC tissues and cell lines. Treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine increased the mRNA expression levels of EphA3 in the ESCC cell lines KYSE510 and KYSE30. In addition, overexpression of EphA3 in KYSE450 and KYSE510 cells inhibited cell migration and invasion. EphA3 overexpression also decreased RhoA GTPase. Furthermore, EphA3 overexpression induced mesenchymal-epithelial transition, as demonstrated by epithelial-like morphological alterations, increased expression of epithelial proteins (E-cadherin and the tight junction protein 1 zonula occludens-1) and decreased expression of mesenchymal proteins (Vimentin, N-cadherin and Snail). Conversely, silencing EphA3 in KYSE410 cells triggered epithelial-mesenchymal transition, and promoted cell migration and invasion. These results suggested that EphA3 may serve a tumor-suppressor role in ESCC. PMID- 30483761 TI - Dynamic expression of SMAD3 is critical in osteoblast differentiation of PDMCs. AB - Human pluripotent stem cells have the potential assist in the identification of genes involved in mammalian development. The human placenta is considered a repository of stem cells, termed placenta-derived multipotent cells (PDMCs), which are able to differentiate into cells with an osteoblastic phenotype. This plasticity of PDMCs maybe applied clinically to the understanding of osteogenesis and osteoporosis. In the presentstudy, osteoblasts were generated by culturing PDMCs in osteogenic medium. Reverse transcription quantitative polymerase chain reactionand the degree of osteoblast calcification were used to evaluate the efficacy of osteogenesis. The results suggestedthat the expression of mothers against decapentaplegic homolog 3 (SMAD3) increased in the initial stages of osteogenic differentiation but decreased in the later stages. However, osteogenesis was inhibitedwhen the PDMCs overexpressed SMAD3 throughout the differentiation period. In addition, the rate of osteogenic differentiation was decreased when SMAD3 signaling was impaired. In conclusion, SMAD3 serves an important role in osteoblast differentiation and bone formation in a time dependent manner. The data from the present study indicate that arapid increase in SMAD3 expression is crucial for osteogenesis and suggest a role for PDMCs in the treatment of patients with osteoporosis. PMID- 30483760 TI - The oncometabolite d-2-hydroxyglutarate induces angiogenic activity through the vascular endothelial growth factor receptor 2 signaling pathway. AB - The mutation of isocitrate dehydrogenase (IDH)1 (R132H) and IDH2 (R172K) and the induction of hypoxia in various solid tumors results in alterations in metabolic profiles, including the production of the d- or l-forms of 2-hydroxyglutarate (2HG) from alpha-ketoglutarate in aerobic metabolism in the tricarboxylic acid (TCA) cycle. However, it is unclear whether the oncometabolite d-2HG increases angiogenesis in endothelial cells. Therefore, in this study, we analyzed the levels of various metabolites, including d-2HG, under hypoxic conditions and in IDH2R172K mutant breast cancer cells by mass spectrometry. We then further evaluated the effects of this metabolite on angiogenesis in breast cancer cells. The results revealed that treatment with d-2HG increased the levels of secreted vascular endothelial growth factor (VEGF) in cancer cells and enhanced endothelial cell proliferation in a concentration-dependent manner. Wound healing and cell migration (examined by Transwell assay) were significantly increased by d-2HG to a level similar to that induced by VEGF. Tube formation was significantly stimulated by d-2HG, and chick chorioallantoic membrane angiogenesis was also enhanced by d-2HG. d-2HG activated VEGF receptor (VEGFR)2 and VEGFR2 downstream signaling, extracellular signal-regulated kinase 1/2, focal adhesion kinase, AKT and matrix metalloproteinase (MMP)2. Taken together, the findings of this study suggested that d-2HG induced angiogenic activity via VEGFR2 signaling and increased MMP2 activity. PMID- 30483762 TI - MicroRNA-30e inhibits adhesion, migration, invasion and cell cycle progression of prostate cancer cells via inhibition of the activation of the MAPK signaling pathway by downregulating CHRM3. AB - Prostate cancer (PCa) testing is currently based on measurement of serum prostate specific antigen levels and digital rectal examination, which are limited by a low predictive value and the adverse effects associated with overdiagnosis and overtreatment. Recent studies have reported that the abnormal expression of microRNAs (miRNAs) is associated with the mechanism underlying the development of PCa. Thus, the aim of the present study was to investigate the effects of miR-30e and its target gene, M3 muscarinic acetylcholine receptor (CHRM3), on the adhesion, migration, invasion and cell cycle distribution of PCa cells via the mitogen-activated protein kinase (MAPK) signaling pathway. The differentially expressed genes were screened in the Gene Expression Omnibus database from a gene expression microarray (GSE55945) of PCa. PCa tissues and adjacent tissues were collected from patients with PCa. The PC-3 and DU145 human PCa cell lines were treated with activator, inhibitor and siRNAs. The effects of miR-30e on cell adhesion, migration, invasion and cell cycle distribution with the involvement of CHRM3 and the MAPK signaling pathway were investigated. The bioinformatics results demonstrated that the CHRM3 gene and the MAKP signaling pathway were involved in the progression of PCa, and has-miR-30e was selected for further study. The levels of miR-30e were significantly downregulated, while the levels of CHRM3 were obviously upregulated in PCa. CHRM3 was verified as a target gene of miR-30e. Upregulation of miR-30e and downregulation of CHRM3 decreased the levels of p-P38, p-extracellular signal-regulated kinase, p-c-Jun N-terminal kinase, p-c-fos and p-c-JUN, cell adhesion, migration and invasion ability, and the number of cells in the S phase, while they increased the number of cells in the G0 and G1 phases. The findings of the present study suggest that miR-30e inhibited the adhesion, migration, invasion and cell cycle entry of PCa cells by suppressing the activation of the MAPK signaling pathway and inhibiting CHRM3 expression. Thus, miR-30e may serve as a candidate target for the treatment of PCa. PMID- 30483763 TI - Fe3O4-solamargine induces apoptosis and inhibits metastasis of pancreatic cancer cells. AB - Fe3O4-magnetic liposome (MLP) can deliver drugs to target tissues and can increase drug efficacy. The present study aimed to investigate the effects of solamargine (SM) and Fe3O4-SM in pancreatic cancer (PC). Cell viability was detected using a Cell Counting kit-8 assay. Apoptosis and cell cycle progression was tested using a flow cytometry assay. A scratch assay was used to examine cell metastasis. Quantitative polymerase chain reaction, western blot analysis or immunohistochemical analysis were performed to determine the expression of target factors. Magnetic resonance imagining (MRI) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling were conducted to detect tumor growth and apoptosis in vivo, respectively. It was demonstrated that Fe3O4-SM inhibited cancer cell growth via a slow release of SM over an extended period of time. SM was revealed to induce apoptosis and cell cycle arrest. Furthermore, SM decreased the expression of X-linked inhibitor of apoptosis, Survivin, Ki-67, proliferating cell nuclear antigen and cyclin D1, but increased the activity of caspase-3. It was also observed that SM inhibited tumor cell metastasis by modulating the expression of matrix metalloproteinase (MMP)-2 and TIMP metallopeptidase inhibitor-2. Furthermore, the phosphorylation of protein kinase B and mechanistic target of rapamycin was suppressed by SM. Notably, the effect of SM was enhanced by Fe3O4-SM. The malignant growth of PC was decreased by SM in vivo. Furthermore, the expression of Ki-67 was decreased by SM and Fe3O4-SM. Additionally, cell apoptosis was increased in the Fe3O4-SM group, compared with the SM group. The present study illustrated the antitumor effect and action mec hanism produced by SM. Additionally, it was demonstrated that Fe3O4-SM was more effective than SM in protecting against PC. PMID- 30483764 TI - Mitogen-activated kinase kinase kinase 1 inhibits hedgehog signaling and medulloblastoma growth through GLI1 phosphorylation. AB - The aberrant activation of hedgehog (HH) signaling is a leading cause of the development of medulloblastoma, a pediatric tumor of the cerebellum. The FDA approved HH inhibitor, Vismodegib, which targets the transmembrane transducer SMO, has shown limited efficacy in patients with medulloblastoma, due to compensatory mechanisms that maintain an active HH-GLI signaling status. Thus, the identification of novel actionable mechanisms, directly affecting the activity of the HH-regulated GLI transcription factors is an important goal for these malignancies. In this study, using gene expression and reporter assays, combined with biochemical and cellular analyses, we demonstrate that mitogen activated kinase kinase kinase 1 (MEKK1), the most upstream kinase of the mitogen activated protein kinase (MAPK) phosphorylation modules, suppresses HH signaling by associating and phosphorylating GLI1, the most potent HH-regulated transcription factor. Phosphorylation occurred at multiple residues in the C terminal region of GLI1 and was followed by an increased association with the cytoplasmic proteins 14-3-3. Of note, the enforced expression of MEKK1 or the exposure of medulloblastoma cells to the MEKK1 activator, Nocodazole, resulted in a marked inhibitory effect on GLI1 activity and tumor cell proliferation and viability. Taken together, the results of this study shed light on a novel regulatory mechanism of HH signaling, with potentially relevant implications in cancer therapy. PMID- 30483765 TI - AngiomiRs: MicroRNAs driving angiogenesis in cancer (Review). AB - Angiogenesis is an important hallmark of cancer serving a key role in tumor growth and metastasis. Therefore, tumor angiogenesis has become an attractive target for development of novel drug therapies. An increased amount of anti angiogenic compounds is currently in preclinical and clinical development for personalized therapies. However, resistance to current angiogenesis inhibitors is emerging, indicating that there is a need to identify novel anti-angiogenic agents. In the last decade, the field of microRNA biology has exploded revealing unsuspected functions in tumor angiogenesis. These small non-coding RNAs, which have been dubbed as angiomiRs, may target regulatory molecules driving angiogenesis, such as cytokines, metalloproteinases and growth factors, including vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, epidermal growth factor, hypoxia inducible factor-1, as well as mitogen-activated protein kinase, phosphoinositide 3-kinase and transforming growth factor signaling pathways. The present review discusses the current progress towards understanding the functions of miRNAs in tumor angiogenesis regulation in diverse types of human cancer. Furthermore, the potential clinical application of angiomiRs towards anti-angiogenic tumor therapy was explored. PMID- 30483766 TI - Insulin gene enhancer binding protein 1 induces adipose tissue-derived stem cells to differentiate into pacemaker-like cells. AB - Hybrid approaches combining gene- and cell-based therapies to make biological pacemakers are a promising therapeutic avenue for bradyarrhythmia. The present study aimed to direct adipose tissue-derived stem cells (ADSCs) to differentiate specifically into cardiac pacemaker cells by overexpressing a single transcription factor, insulin gene enhancer binding protein 1 (ISL-1). In the present study, the ADSCs were transfected with ISL-1 or mCherry fluorescent protein lentiviral vectors and co-cultured with neonatal rat ventricular cardiomyocytes (NRVMs) in vitro for 5-7 days. The feasibility of regulating the differentiation of ADSCs into pacemaker-like cells by overexpressing ISL-1 was evaluated by observation of cell morphology and beating rate, reverse transcription-quantitative polymerase chain reaction analysis, western blotting, immunofluorescence and analysis of electrophysiological activity. In conclusion, these data indicated that the overexpression of ISL-1 in ADSCs may enhance the pacemaker phenotype and automaticity in vitro, features which were significantly increased following co-culture induction. PMID- 30483767 TI - Downregulation of Blimp1 inhibits the maturation of bone marrow-derived dendritic cells. AB - Modulation of differentiation of dendritic cells (DCs), which are derived from bone marrow cells, may influence their maturation and consequently regulate their ability to present antigens to alloreactive T lymphocytes. B lymphocyte-induced maturation protein-1 (Blimp1) is a master regulator of immunocyte differentiation, which has been investigated for its effect on DCs. In the present study, a lentivirus was used as a vector to transduce Blimp1-short hairpin (sh)RNA into primary bone marrow cells during their differentiation to DCs. Lentiviral-mediated Blimp1-shRNA (lenti-shRNA-Blimp1) had a transduction efficiency of >60% in DC precursors. Lenti-shRNA-Blimp1 significantly downregulated the expression levels of Blimp1 and modulated the expression of its target proteins, including class II major histocompatibility complex (MHC) transactivator, c-myc and interleukin-6. Although lenti-shRNA-Blimp1 did not interfere with the differentiation of bone marrow cells to DCs, it inhibited DC maturation by decreasing the expression of surface MHC-II molecules, but not the expression of MHC-I molecules and co-stimulatory molecules [cluster of differentiation (CD)80/CD86]. Subsequently, alloreactive T cell proliferation was alleviated and regulatory T cells were expanded in response to lenti-shRNA Blimp1. A toxicity assay indicated that the morphology and proliferation of cultured DCs were mildly influenced by the lentiviral vector, indicating that the use of alternative vectors with minimal or no toxicity could be investigated in future studies. In conclusion, transduction with lenti-shRNA-Blimp1 modulated the maturation of DCs via MHC-II molecule suppression and inhibited alloreactive T cell activation. The present findings supported the application of Blimp1-based intervention as a novel approach to induce immature DCs for further immunological research. PMID- 30483769 TI - IKBKB expression in clear cell renal cell carcinoma is associated with tumor grade and patient outcomes. AB - Inhibitor of nuclear factor kappa B kinase subunit B (IKBKB or IKKbeta) is a key activator of the nuclear factor kappaB transcription factor pathway. Increased expression and/or aberrant activity of IKBKB have been observed in various types of human cancer. Three independent techniques, reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemistry, were used to demonstrate that IKBKB expression is decreased in clear cell renal cell carcinoma (ccRCC). Notably, the patients with upregulated IKBKB protein expression were characterized by higher nuclear grade tumors and significantly shorter survival. The findings indicate that IKBKB protein may be of clinical relevance in ccRCC, serving as a marker of poor prognosis and as potential target for adjuvant chemotherapies. Further studies are required to validate the prognostic and predictive value of IKBKB. PMID- 30483768 TI - Exosomal lncRNA-ATB activates astrocytes that promote glioma cell invasion. AB - Glioma invasion is a main cause of a poor prognosis and relapse in patients suffering from the disease. However, the molecular mechanisms responsible for glioma cell invasion remain poorly understood. In this study, the characteristics of exosomes were identified using electron microscope (TEM), and western blot analysis. The potential mechanism of long non-coding RNA (lncRNA) activated by TGF-beta (lncRNA-ATB) was demonstrated using luciferase reporter assays and RNA immunoprecipitation. We found that glioma cell-derived exosomes promoted the activation of astrocytes and had the ability to shuttle long non-coding RNA (lncRNA) activated by TGF-beta (lncRNA-ATB) to astrocytes. More importantly, lncRNA-ATB activated astrocytes through the suppression of microRNA (miRNA or miR)-204-3p in an Argonaute 2 (Ago2)-dependent manner. Furthermore, astrocytes activated by lncRNA-ATB in turn promoted the migration and invasion of glioma cells. Taken together, the findings of this study suggest that lncRNA-ATB may play an important role in modulating glioma microenvironment through exosomes. Thus, a better understanding of this process may provide implications for the prevention of highly invasive glioma. PMID- 30483770 TI - Evaluation of chemotherapeutic and cancer-protective properties of sphingosine and C2-ceramide in a human breast stem cell derived carcinogenesis model. AB - The overall goal of the present study was to evaluate the chemotherapeutic and cancer-protective properties of D-erythro-sphingosine (sphingosine) and C2 ceramide using a human breast epithelial cell (HBEC) culture system, which represents multiple-stages of breast carcinogenesis. The HBEC model includes Type I HBECs (normal stem), Type II HBECs (normal differentiated) and transformed cells (immortal/non-tumorigenic cells and tumorigenic cells, which are transformed from the same parental normal stem cells). The results of the present study indicate that sphingosine preferentially inhibits proliferation and causes death of normal stem cells (Type I), tumorigenic cells, and MCF7 breast cancer cells, but not normal differentiated cells (Type II). In contrast to the selective anti-proliferative effects of sphingosine, C2-ceramide inhibits proliferation of normal differentiated cells as well as normal stem cells, tumorigenic cells, and MCF7 cancer cells with similar potency. Both sphingosine and C2-ceramide induce apoptosis in tumorigenic cells. Among the sphingosine stereoisomers (D-erythro, D-threo, L-erythro, and L-threo) and sphinganine that were tested, L-erythro-sphingosine most potently inhibits proliferation of tumorigenic cells. The inhibition of breast tumorigenic/cancer cell proliferation by sphingosine was accompanied by inhibition of telomerase activity. Sphingosine at non-cytotoxic concentrations, but not C2-ceramide, induces differentiation of normal stem cells (Type I), thereby reducing the number of stem cells that are more susceptible to neoplastic transformation. To the best of our knowledge, the present study demonstrates one of the first results that sphingosine can be a potential chemotherapeutic and cancer-protective agent, whereas C2-ceramide is not an ideal chemotherapeutic and cancer-protective agent due to its anti proliferative effects on Type II HBECs and its inability to induce the differentiation of Type I to Type II HBECs. PMID- 30483771 TI - miR-122 promotes proliferation and invasion of clear cell renal cell carcinoma by suppressing Forkhead box O3. AB - MicroRNAs (miRNAs) serve an important role in renal cancer, but renal cancer miRNA expression data remains inconsistent. Therefore, there is a requirement for integrated analysis of these data. An increasing number of studies demonstrate that miR-122 is dysregulated in numerous cancer types, including liver, lung and breast cancer, yet its role in clear cell renal cell carcinoma (ccRCC) remains unclear. In the present study, an integrated analysis of four ccRCC miRNAs expression datasets was performed and the expression of miR-122 in the present cohort was validated. The effects of cell proliferation, colony formation, migration and invasion of ccRCC cells in vitro were assayed following transfection with miR-122 mimics and inhibitor. The target gene of miR-122 was confirmed using a luciferase reporter assay, and a xenograft mouse model was used to determine the effect of miR-122 in ccRCC tumorigenicity in vivo. The present results demonstrated that patients with ccRCC with an increased miR-122 level in tumor tissues had a shortened metastasis-free survival time as indicated by The Cancer Genome Atlas-Kidney Renal Clear Cell Carcinoma dataset and the present ccRCC cohort. Overexpression of miR-122 in 786-O cells improved cell proliferation, colony formation, migration and invasion, while knockdown of miR 122 in SN12-PM6 cells inhibited cell growth, colony formation, migration and invasion. Western blot analysis and luciferase reporter assays were used to identify FOXO3 as a direct target of miR-122. The present results indicate that miR-122 serves a tumor-promoting role by direct targeting FOXO3 in ccRCC. PMID- 30483772 TI - Silencing of caveolin-1 in fibroblasts as opposed to epithelial tumor cells results in increased tumor growth rate and chemoresistance in a human pancreatic cancer model. AB - Caveolin-1 (Cav-1) expression has been shown to be associated with tumor growth and resistance to chemotherapy in pancreatic cancer. The primary aim of this study was to explore the significance of Cav-1 expression in pancreatic cancer cells as compared to fibroblasts in relation to cancer cell proliferation and chemoresistance, both in vitro and in vivo, in an immunodeficient mouse model. We also aimed to evaluate the immunohistochemical expression of Cav-1 in the epithelial and stromal component of pancreatic cancer tissue specimens. The immunohistochemical staining of poorly differentiated tissue sections revealed a strong and weak Cav-1 expression in the epithelial tumor cells and stromal fibroblasts, respectively. Conversely, the well-differentiated areas were characterized by a weak epithelial Cav-1 expression. Cav-1 downregulation in cancer cells resulted in an increased proliferation in vitro; however, it had no effect on chemoresistance and growth gain in vivo. By contrast, the decreased expression of Cav-1 in fibroblasts resulted in a growth advantage and the chemoresistance of cancer cells when they were co-injected into immunodeficient mice to develop mixed fibroblast/cancer cell xenografts. On the whole, the findings of this study suggest that the downregulation of Cav-1 in fibroblasts is associated with an increased tumor proliferation rate in vivo and chemoresistance. Further studies are warranted to explore whether the targeting of Cav-1 in the stroma may represent a novel therapeutic approach in pancreatic cancer. PMID- 30483773 TI - Functional role of RBM10 in lung adenocarcinoma proliferation. AB - Lung cancer is one of the most common causes of morbidity and mortality among malignant tumors worldwide. The poor prognosis of patients with lung adenocarcinomas is primarily due to its strong ability to invade and metastasize. Recent research has indicated that RNA-binding protein 10 (RBM10) is mutated in lung adenocarcinoma, and is closely associated with tumor proliferation and apoptosis; however, the precise role of RBM10 in lung adenocarcinoma remains unclear. Our preliminary experiments (unpublished data) revealed that RBM10 expression was upregulated in lung adenocarcinoma cell lines and tissues. In this study, we first detected the protein expression level of RBM10 in lung adenocarcinoma cells and tissues, and we then examined the effects of RBM10 overexpression and downregulation (via small interfering RNA) on the proliferation and apoptosis of stable lung adenocarcinoma cells, along with its possible mechanisms of action. We also used clinical samples of lung adenocarcinomas to verify our results. We found that RBM10 protein was overexpressed in lung adenocarcinoma cells and tissues, and it reduced p53 expression (as detected by immunofluorescence assay and western blot analysis) in A549 cells and inhibited apoptosis (as shown by flow cytometric assay). RBM10 also promoted cell growth and proliferation in vitro and increased cell migration in a cell wound scratch assay. Furthermore, we found that RBM10 activated key proliferative signaling pathways [such as the epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)-AKT pathways] and inhibited apoptotic pathways. In addition, we demonstrated that a high expression of RBM10 protein in patient tissue samples was associated with a shorter overall survival time and a poor prognosis. On the whole, the findings of this study indicate that RBM10 may function as an oncogene in lung cancer, and may thus prove to be a novel therapeutic target for the prophylaxis and treatment of lung adenocarcinomas. PMID- 30483774 TI - MYCN is amplified during S phase, and c-myb is involved in controlling MYCN expression and amplification in MYCN-amplified neuroblastoma cell lines. AB - Neuroblastoma derived from primitive sympathetic neural precursors is a common type of solid tumor in infants. MYCN proto-oncogene bHLH transcription factor (MYCN) amplification and 1p36 deletion are important factors associated with the poor prognosis of neuroblastoma. Expression levels of MYCN and c-MYB proto oncogene transcription factor (c-myb) decline during the differentiation of neuroblastoma cells; E2F transcription factor 1 (E2F1) activates the MYCN promoter. However, the underlying mechanism of MYCN overexpression and amplification requires further investigation. In the present study, potential c Myb target genes, and the effect of c-myb RNA interference (RNAi) on MYCN expression and amplification were investigated in MYCN-amplified neuroblastoma cell lines. The mRNA expression levels and MYCN gene copy number in five neuroblastoma cell lines were determined by quantitative polymerase chain reaction. In addition, variations in potential target gene expression and MYCN gene copy number between pre- and post-c-myb RNAi treatment groups in MYCN amplified Kelly, IMR32, SIMA and MHH-NB-11 cell lines, normalized to those of non MYCN-amplified SH-SY5Y, were examined. To determine the associations between gene expression levels and chromosomal aberrations, MYCN amplification and 1p36 alterations in interphases/metaphases were analyzed using fluorescence in situ hybridization. Statistical analyses revealed correlations between 1p36 alterations and the expression of c-myb, MYB proto-oncogene like 2 (B-myb) and cyclin dependent kinase inhibitor 1A (p21). Additionally, the results of the present study also demonstrated that c-myb may be associated with E2F1 and L3MBTL1 histone methyl-lysine binding protein (L3MBTL1) expression, and that E2F1 may contribute to MYCN, B-myb, p21 and chromatin licensing and DNA replication factor 1 (hCdt1) expression, but to the repression of geminin (GMNN). On c-myb RNAi treatment, L3MBTL1 expression was silenced, while GMNN was upregulated, indicating G2/M arrest. In addition, MYCN gene copy number increased following treatment with c-myb RNAi. Notably, the present study also reported a 43.545% sequence identity between upstream of MYCN and Drosophila melanogaster amplification control element 3, suggesting that expression and/or amplification mechanisms of developmentally-regulated genes may be evolutionarily conserved. In conclusion, c-myb may be associated with regulating MYCN expression and amplification. c-myb, B-myb and p21 may also serve a role against chromosome 1p aberrations. Together, it was concluded that MYCN gene is amplified during S phase, potentially via a replication-based mechanism. PMID- 30483775 TI - Cabazitaxel liposomes with aptamer modification enhance tumor-targeting efficacy in nude mice. AB - The present study investigated the feasibility of improving the tumor-targeting efficacy and decreasing the toxicity of liposomal cabazitaxel (Cab) with aptamer modification. The process involved preparing aptamer (TLS1c)-modified liposomes and studying the behavior of the liposomes in vitro and in vivo. TLS1c as an aptamer, which has high specificity for BNL 1ME A.7R.1 (MEAR) cells, was conjugated with Cab liposomes (Cab/lipo) to enhance MEAR tumor tissue targeting. Confocal laser scanning microscopy and flow cytometry analyses demonstrated that the fluorescence of the liposomes modified with the aptamer was notably stronger compared with that of the unmodified liposomes. Furthermore, the biodistribution data of the modified liposomes tested in tumor-bearing mice revealed high specificity of biotinylated TLS1c-modified Cab/lipo (BioTL-Cab/lipo) for tumor tissues. Furthermore, the modified liposomes demonstrated decreased cytotoxicity and simultaneously retained potent inhibition against tumor growth. It is likely that the specific binding of the aptamer (TLS1c) to the targeted cells (MEAR) facilitates the binding of the liposomes to the targeted cells. Therefore, BioTL Cab/lipo may be considered as a promising delivery system to improve cell targeting and reduce drug toxicity in the treatment of cancer. PMID- 30483776 TI - Roles of the inflammasome in the gut-liver axis (Review). AB - The gut-liver axis connects the liver with the intestine via bile acid metabolism. Bile acid dysregulation leads to intestinal dysbiosis, that allows enterogenous pathogenic bacteria, including Gram-negative bacteria and their products lipopolysaccharide (LPS), into the liver via the portal vein, triggering inflammation in the liver. The inflammasome serves as an intracellular pattern recognition receptor that detects pathogens or danger signals and mediates innate immunity in the liver or gut. Specifically, the NACHT, LRR and PYD domains containing protein (NLRP)6 inflammasome maintains intestinal microbial balance, by promoting interleukin (IL)-18-dependent antimicrobial peptide synthesis and mucus secretion from goblet cells. The NLRP3 inflammasome, in contrast, primarily induces IL-1beta and aggravates inflammatory liver injury. Furthermore, the NLRP3 inflammasome affects the epithelial integrity of cholangiocytes by inducing the production of pro-inflammatory cytokines. In addition, bile acids, including deoxycholic acid and chenodeoxycholic acid, are able to activate the NLRP3 inflammasome in macrophages; however, bile acids have the potential to exert the opposite role by interacting with the membrane-bound Takeda G-protein receptor 5 or by activating nuclear farnesoid-X receptor. Therefore, further investigation of the molecular mechanisms underlying the inflammasome, involved in the gut liver axis, may provide important insights into the identification of a potential therapeutic target for the treatment of liver and gut diseases. The present review discusses the roles of the inflammasome in the gut-liver axis, and the emerging associations between the inflammasome and the intestinal microbiota or the bile acids in the gut-liver axis. PMID- 30483777 TI - UBIAD1 expression is associated with cardiac hypertrophy in spontaneously hypertensive rats. AB - The present study investigated the potential role of UbiA prenyltransferase domain-containing 1 (UBIAD1) in the pathogenesis of hypertensive cardiac hypertrophy. Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats at 8, 16 and 28 weeks of age were used. Blood pressure was measured using a non invasive tail cut-off system. Cardiac functional index was assessed by arterial catheterization. Myocardial structure and cell apoptosis were evaluated by hematoxylin and eosin staining, and terminal deoxynucleotidyl-transferase mediated dUTP nick end labeling assays, respectively. Myocardial expression of UBIAD1, coenzyme Q10 (CoQ10), endothelial nitric oxide synthase (eNOS) and atrial natriuretic peptide were evaluated by immunohistochemistry, western blotting and reverse transcription-quantitative polymerase chain reaction. Circulating and myocardial expression of nitric oxide (NO) were measured using the Griess method. SHRs exhibited increased blood pressure and cardiomyocyte apoptosis, as well as cardiac hypertrophy, compared with age-matched WKY rats. Myocardial expression of UBIAD1 was significantly decreased in SHRs in an age-dependent manner. Similarly, myocardial CoQ10 and eNOS expression were significantly reduced in SHR compared to age-matched WKY rats, and these expression levels additionally decreased further with aging. Serum and myocardial NO expression was additionally decreased in SHRs. Decreased UBIAD1 expression in SHR hearts was associated with decreased levels of CoQ10, eNOS and NO. Given the well-established role of UBIAD1 in the regulation of NO signaling, reduced expression of UBIAD1 in SHR hearts potentially contributed to the pathogenesis of hypertensive cardiac hypertrophy. Therefore, UBIAD1 may represent a potential therapeutic target for clinical treatment of hypertensive cardiac hypertrophy. PMID- 30483778 TI - Platelet-derived growth factor D promotes the angiogenic capacity of endothelial progenitor cells. AB - Neovascularization and re-endothelialization rely on endothelial progenitor cells (EPCs). However, the recruitment and angiogenic roles of EPCs are subject to regulation through the vascular microenvironment, which remains largely unknown. Platelet-derived growth factor D (PDGF-D) is a new member of the PDGF family that binds the PDGFR-beta homodimer. However, it remains unknown whether and how it affects the angiogenic capacity of EPCs and participates in tube-like formation. EPCs were derived from rat bone marrow cells, and the gain-of-function approach was used to study the effects of PDGF-D on the biological activities of EPCs. EPCs that stably express PDGF-D were generated by lentiviral-mediated transduction, and the expression levels were evaluated by western blotting and reverse transcription, followed by real-time quantitative polymerase chain reaction (RT-qPCR). The biological activities of EPCs evaluated in the present study included proliferation, adhesion, migration, tube formation and senescence. Furthermore, the downstream signaling of PDGF-D was explored by western blot analysis. The results revealed that the lentiviral-mediated expression of PDGF-D in the microenvironment promoted the migration, proliferation, adhesion and tube formation of EPCs. In addition, PDGF-D suppressed the senescence of EPCs. Mechanistically, PDGF-D induced the phosphorylation of several signaling molecules, including STAT3, AKT, ERK1/2, mTOR and GSK-3beta, suggesting that PDGF D enhanced the angiogenic function of EPCs through PDGF receptor-dependent and independent signaling pathways. In conclusion, PDGF-D promotes the angiogenic capacity of EPCs, including proliferation, migration, adhesion and tube formation, and thereby contributes to angiogenesis. PMID- 30483779 TI - Visfatin is regulated by interleukin-6 and affected by the PPAR-gamma pathway in BeWo cells. AB - Visfatin, an adipocytokine and cytosolic enzyme with nicotinamide phosphoribosyltransferase (Nampt) activity, is involved in the pathogenesis of numerous metabolic disorders. In addition, the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) serves important roles in anti inflammatory reactions and regulates glucose and lipid metabolism. The aim of the present study was to investigate the effect of interleukin-6 (IL-6) on the expression and secretion of visfatin in BeWo cells, and to determine whether the PPAR-gamma pathway is involved in the regulation of visfatin by IL-6. Therefore, BeWo cells were stimulated with serial concentrations of IL-6 or pioglitazone, and the expression levels of visfatin and PPAR-gamma were determined by reverse transcription-quantitative polymerase chain reaction and western blotting. The results of the present study demonstrated that IL-6 downregulated the mRNA levels of visfatin and PPAR-gamma, which were strongly associated. Activation of PPAR gamma by pioglitazone resulted in significantly increased expression of visfatin, which abrogated the inhibitory effect of IL-6 on visfatin in BeWo cells. Furthermore, treatment using pioglitazone alone increased the expression and secretion of the visfatin protein, compared with the control or IL-6 alone group. In summary, the findings of the present study suggested that IL-6 inhibited the expression of visfatin and PPAR-gamma at the transcriptional level; in addition, activation of PPAR-gamma upregulated visfatin at the mRNA and protein expression levels. Therefore, the PPAR-gamma signaling pathway may be involved in the regulation of visfatin by IL-6 in BeWo cells. These results may provide novel insight into the roles of visfatin in trophoblastic cells. Furthermore, thiazolidinedione pioglitazone, by upregulating visfatin expression, may promote the energy metabolism of trophoblastic cells, maintain the function of the placenta and improve the outcome of pregnancy. PMID- 30483780 TI - Inhibition of lactate dehydrogenase A suppresses inflammatory response in RAW 264.7 macrophages. AB - Lactate is an important metabolite in cellular metabolism and fluctuates in certain disease conditions including cancer and immune diseases. It was hypothesized that a decrease in lactate would modulate the inflammatory response elicited by lipopolysaccharides (LPS) in macrophages. When RAW 264.7 macrophages were treated with FX11, a specific lactate dehydrogenase (LDHA) inhibitor, the expression of the cytokines, inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) was downregulated due to reduced cellular lactate levels. Genetic suppression of LDHA by small interfering RNA (siRNA) downregulated the LPS-activated expression of interleukin (IL)-6, iNOS, and COX 2, and reduced the production of IL-6 and nitrites. Pharmacological and genetic suppression of LDHA inhibited the phosphorylation of p38 mitogen-activated protein kinase. Microarray gene expression profile demonstrated that the genes involved in cell proliferation and inflammation were mainly altered by siRNA mediated LDHA suppression. Collectively, the present observations suggest that lactate may be an important metabolite and implicated in regulation of inflammatory response. PMID- 30483781 TI - Rapamycin-induced autophagy attenuates hormone-imbalance-induced chronic non bacterial prostatitis in rats via the inhibition of NLRP3 inflammasome-mediated inflammation. AB - Chronic non-bacterial prostatitis (CNBP) is a common urinary disease and no standard treatments are available at present. Although autophagy serves an important role in a variety of chronic diseases, its role in CNBP is yet to be fully elucidated. Therefore, the present study aimed to investigate the effects of rapamycin-induced autophagy on CNBP by establishing a rat model. In the present study, a total of 30 male Sprague-Dawley rats were randomly divided into three groups (n=10 per group): i) Control, in which rats underwent a sham operation; ii) the model (CNBP), in which rats were castrated and administered 17beta-estradiol (0.25 mg/kg via subcutaneous injection) for 30 consecutive days; and iii) rapamycin treatment, in which rats were employed in accordance with the CNBP model, but also received a daily intraperitoneal injection of rapamycin (1 mg/kg) from the 16th day post-surgery for 15 days. Alterations in histology and the levels of autophagy-associated markers, and components of the NLRP3 inflammasome, were measured in the prostate tissues of the rats. The levels of molecules located further downstream of the NLRP3 inflammasome pathway, including interleukin (IL)-1beta and IL-18, were also measured. The results demonstrated that, compared with the control group, increased infiltration levels of inflammatory cells and glandular epithelial degeneration were observed in the prostate tissues of rats with CNBP. Furthermore, a significant increase in the concentration of IL-1beta and IL-18 in the serum, as well as the increased expression levels of NLRP3, ASC and caspase-1 in prostate tissues were also observed. In addition, reductions in the number of autophagosomes and the expression levels of autophagy-associated, including microtubule-associated protein 1 light chain 3beta (LC3B) and Beclin 1, were also detected in the CNBP group; however, treatment with rapamycin reversed these effects. Collectively, the findings of the present study indicated that the NLRP3 inflammasome-mediated inflammatory response was activated by a hormonal imbalance in the prostate glands of rats; however, these effects may be suppressed via rapamycin-induced autophagy. PMID- 30483782 TI - Nicotinamide induces liver regeneration and improves liver function by activating SIRT1. AB - Nicotinamide (Nam) has recently been characterized as an agent for tissue regeneration due to the observed pro-proliferation effects. However, the effect of Nam on liver regeneration remains undetermined. In the present study, the potency of Nam as a regimen to promote liver regeneration and restore liver function was evaluated following partial hepatectomy (PH) on C57BL/6 mice. Ki-67 immunohistochemical and cell cycle analyses demonstrated that exogenous Nam supplementation promoted the proliferation of hepatocytes and accelerated the recovery of liver tissue. The addition of Nam protected liver function following PH, as evidenced by hematoxylin and eosin staining of liver tissue morphology and measurement of serum liver injury markers. Notably, immunoblotting results revealed that the expression and activity of NAD-dependent protein deacetylase sirtuin-1 (SIRT1) were significantly upregulated following treatment with Nam, suggesting that Nam may promote liver regeneration through activation of SIRT1. The present study demonstrated that Nam regulated the process of liver regeneration and improved liver function by activating SIRT1, suggesting that Nam has the potency to be used for promoting liver regeneration following surgical resection. PMID- 30483783 TI - MG132 selectively upregulates MICB through the DNA damage response pathway in A549 cells. AB - Natural killer (NK) cells recognize stress-activated NK group 2, member D (NKG2D) ligands in tumors. In the present study, the expression levels of NKG2D ligands were examined in four lung cancer cell lines (A549, PLA801D, NCI-H157 and NCI H520). In the A549 cells, the expression of MHC class I polypeptiderelated sequence (MIC)A/B and UL16 binding protein (ULBP)1 was weak, the expression of ULBP2 was typical, and neither ULBP3 nor ULBP4 were expressed. The mechanism underlying the regulatory effect of a cancer treatment agent on the expression of NKG2D ligands was investigated using the proteasome inhibitor MG132. Following treatment for 8 h with MG132, the transcription levels of MICB and ULBP1 were upregulated 10.62- and 11.09-fold, respectively, and the expression levels of MICB and ULBP1 were increased by 68.18 and 23.65%, respectively. Notably, MICB exhibited significant time-dependent change. MG132 increased the transcription of MICB by acting at a site in the 480-bp MICB upstream promoter. The activity of the MICB promoter was upregulated 1.77-fold following treatment with MG132. MG132 treatment improved the cytotoxicity of NK cells, which was partially blocked by an antibody targeting NKG2D, and more specifically the MICB molecule. The expression of MICB induced by MG132 was inhibited by KU-55933 [ataxia telangiectasia mutated (ATM) kinase inhibitor], wortmannin (phosphoinositide 3 kinase inhibitor) and caffeine (ATM/ATM-Rad3-related inhibitor). The phosphorylation of checkpoint kinase 2 (Chk2), an event associated with DNA damage, was observed following treatment with MG132. These results indicated that MG132 selectively upregulates the expression of MICB in A549 cells, and increases the NKG2D-mediated cytotoxicity of NK cells. The regulatory effect of MG132 may be associated with the activation of Chk2, an event associated with DNA damage. The combination of MG132 with NK cell immunotherapy may have a synergistic effect that improves the therapeutic effect of lung cancer treatment. PMID- 30483784 TI - Puerarin promotes DUSP1 expression by regulating miR-133a-3p in breast cancer. AB - Previous studies demonstrated that puerarin represents a potential therapeutic drug for breast cancer treatment, due to its ability to inhibit the migration of MCF-7 and MDA-MB-231 cell lines. In order to investigate the mechanism of puerarin in breast cancer cells, the aim of the present study was to examine whether puerarin regulated the dual specificity phosphatase 1 (DUSP1) expression level by promoting the microRNA-133a-3p (miR-133a-3p) expression level in breast cancer. Cell viability and apoptosis were assessed in HCC38 cells by Cell Counting Kit-8 assays and a flow cytometry assay, respectively. In total, four treatment groups were considered: Puerarin treatment, miR-133a-3p mimics transfection, puerarin + miR-133a-3p mimics and negative control. miR-133a-3p expression and DUSP1 mRNA expression levels were analyzed by reverse transcription-quantitative polymerase chain reaction, and western blotting was used to detect the protein expression level. Furthermore, a luciferase reporter gene assay was used to test whether DUSP1 mRNA was a direct target of miR-133a 3p. The present results suggested that treatment with puerarin or miR-133a-3p mimics transfection affected the miR-133a-3p expression level and the activity of the DUSP1/p38 pathway, leading to inhibition of HCC38 cell viability and an increase in apoptosis. miR-133a-3p overexpression enhanced the drug action of peurarin. In conclusion, puerarin may increase DUSP1 expression by promoting the miR-133a-3p expression level in HCC38 breast cancer cells. Therefore, miR-133a-3p may represent a novel molecular marker for diagnosis and treatment of breast cancer, and puerarin may represent a promising clinical drug for treatment of patients with breast cancer. PMID- 30483785 TI - Function of BRD4 in the pathogenesis of high glucose-induced cardiac hypertrophy. AB - Diabetic cardiomyopathy is one of the major complications of diabetes, and due to the increasing number of patients with diabetes it is a growing concern. Diabetes induced cardiomyopathy has a complex pathogenesis and histone deacetylase mediated epigenetic processes are of prominent importance. The olfactory bromodomain-containing protein 4 (BRD4) is a protein that recognizes and binds acetylated lysine. It has been reported that the high expression of BRD4 is involved in the process of cardiac hypertrophy. The aim of the present study was to investigate the function of BRD4 in the process of high glucose (HG)-induced cardiac hypertrophy, and to clarify whether epigenetic regulation involving BRD4 is an important mechanism. It was revealed that BRD4 expression levels were increased in H9C2 cells following 48 h of HG stimulation. This result was also observed in a diabetic rat model. Furthermore, HG stimulation resulted in the upregulation of the myocardial hypertrophy marker, atrial natriuretic peptide, the cytoskeletal protein alpha-actin and fibrosis-associated genes including transforming growth factor-beta, SMAD family member 3, connective tissue growth factor and collagen, type 1, alpha1. However, administration of the specific BRD4 inhibitor JQ1 (250 nM) for 48 h reversed this phenomenon. Furthermore, protein kinase B (AKT) phosphorylation was activated by HG stimulation and suppressed by JQ1. In conclusion, BRD4 serves an important role in the pathogenesis of HG induced cardiomyocyte hypertrophy through the AKT pathway. PMID- 30483786 TI - (R)-dehydroxyabscisic alcohol beta-D-apiofuranosyl-(1?->6')-beta-D glucopyranoside enhances the osteoblastic differentiation of ST2 cells via the BMP/WNT pathways. AB - Lonicera japonica has been used in traditional Chinese medicine as an important medicinal plant, with the ability to inhibit osteoclast development and bone loss. However, it is not clear which active ingredient exerts these effects. (R) dehydroxyabscisic alcohol beta-D-apiofuranosyl-(1?->6')-beta-D-glucopyranoside (DAG) is an active constituent isolated from Lonicera japonica. In the present study, the ST2 bone marrow stromal cell line was treated by DAG at different concentrations and the osteoblastic differentiation was explored by ELISA assay, Von Kossa staining, Alizarin Red S staining, reverse transcription-quantitative polymerase chain reaction and western blot analysis. The results revealed that DAG promoted osteoblastic differentiation, as evidenced by increasing mineralization and alkaline phosphatase (ALP) activity, as well as the expression of genes encoding bone differentiation markers, including Alp, osteopontin (Opn) and osteocalcin (Ocn). In addition, DAG upregulated the gene expression of bone morphogenetic protein (Bmp)-2, Bmp4, Wnt family member (Wnt)-1, Wnt3 and runt related transcription factor 2 (Runx2), as well as the protein expression of phosphorylated-mothers against decapentaplegic homolog (Smad) 1, Smad5 Smad8, beta-catenin and Runx2 in ST2 cells. The osteogenic effects induced by DAG were attenuated by the BMP antagonist Noggin and the WNT signaling pathway inhibitor Dickkopf related protein-1. The data indicated that DAG promoted the osteoblastic differentiation of ST2 cells, at least partially through regulating the BMP/WNT signaling pathways. This provides scientific rationale for the development of DAG as a treatment for bone loss-associated diseases, such as osteoporosis. PMID- 30483787 TI - Expression of FKBP52 in the ovaries of PCOS rats. AB - The present study aimed to examine the expression of FK-506 binding protein 52 (FKBP52) in the ovary tissues of rats with polycystic ovarian syndrome (PCOS) and its action on mediating androgen receptor (AR) through the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. PCOS model rats were established by dehydroepiandrosterone injection. Enzyme-linked immunosorbent assay (ELISA) measured serum sex hormones. Hematoxylin and eosin (H&E) staining was used to examine histological changes of the ovarian tissues. The expression levels of FKBP52 were detected by immunohistochemical (IHC) staining, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis and western blotting (WB). In addition, RT-qPCR analysis was used to detect the mRNA expression of AR, and WB was used to detect the protein expression levels of AR, ERK1/2 and phosphorylated (p-)ERK1/2. In granulosa cell (GC) experiments, primary GCs were extracted and cultured. FKBP4 is the FKBP52 encoding gene, therefore, adenovirus vectors Ad-Oe-FKBP4-EGFP and Ad-siRNA-FKBP4 EGFP were constructed to examine the association among the above factors using the RT-qPCR and WB methods. In the animal experiment, the vaginal smear, H&E staining and ELISA results showed that the PCOS model was successfully established. The IHC staining revealed that the expression of FKBP52 in the GCs of the PCOS model group was higher than the remaining groups (P<0.01). The mRNA and expression levels of FKBP52 and AR in the PCOS model rats were significantly increased, when compared with levels in the other rats (P<0.05). The expression level of p-ERK1/2 was also higher (P<0.05). In the GC experiment, following overexpression of the FKBP4 gene, the mRNA and expression levels of FKBP52 and AR were increased (P<0.05). The expression level of p-ERK1/2 was also increased (P<0.05). Following FKBP4 gene silencing, the mRNA and expression levels of FKBP52 and AR were decreased (P<0.05). The expression level of ERK1/2 was also decreased (P<0.05). However, the expression level of p-ERK1/2 was increased (P<0.05). In conclusion, the upregulation of co-chaperone FKBP52 may mediate the activation of AR through the MAPK/ERK pathway. PMID- 30483788 TI - Microarray analysis of the molecular mechanisms associated with age and body mass index in human meniscal injury. AB - The aim of the present study was to identify genes and functional pathways associated with meniscal injuries affected by age or body mass index (BMI) using microarray analysis. The GSE45233 gene expression dataset with 12 injured meniscus samples associated with age and BMI and GSE66635 dataset with 12 injured and 12 normal meniscus samples were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified based on age or BMI in GSE45233. DEGs between injured and normal meniscus samples in GSE66635 were also identified. Common DEGs between GSE45233 and GSE66635 were identified as feature genes associated with age or BMI, followed by protein-protein interaction (PPI) network and functional pathway enrichment analyses for the feature genes. Finally, the GSE51588 genome-wide expression profile was then downloaded from the GEO database to validate the results. A total of 1,328 DEGs were identified. Of these, 28 age-associated and 20 BMI-associated meniscal injury genes were obtained. B-cell lymphoma-2 (Bcl-2) and matrix metalloproteinase-14 were identified as hub genes in the PPI networks. Functional pathway enrichment analysis revealed that vascular endothelial growth factor A (VEGFA), transferrin (TF) and Bcl-2 were involved in the hypoxia-inducible factor 1 signaling pathway. TF was involved in the mineral absorption function pathway associated with BMI. Additionally, TF and VEGFA were identified to be overlapping candidate genes of GSE45233 and GSE66635, and DEGs in GSE51588. Therefore, VEGFA, TF, and Bcl-2 may be important genes for human meniscal injuries. Additional evaluations of these results are required. PMID- 30483789 TI - Identification of potential biomarkers for differential diagnosis between rheumatoid arthritis and osteoarthritis via integrative genome-wide gene expression profiling analysis. AB - The present study aimed to identify potential novel biomarkers in synovial tissue obtained from patients with Rheumatoid Arthritis (RA) and Osteoarthritis (OA) for differential diagnosis. The genome-wide expression profiling datasets of synovial tissues from RA and OA cohorts, including GSE55235, GSE55457 and GSE55584 datasets, were retrieved and used to identify differentially expressed genes (DEGs; P<0.05; false discovery rate <0.05 and Fold Change >2) between RA and OA using R software. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of DEGs were performed to determine molecular and biochemical pathways associated with the identified DEGs, and a protein-protein interaction (PPI) network of the DEGs was constructed using Cytoscape software. Significant modules in the PPI network and candidate driver genes were screened using the Molecular Complex Detection Algorithm. Potential biomarkers were evaluated by receiver operating characteristic and logistic regression analyses. Large numbers of DEGs were detected, including 273, 205 and 179 DEGs in the GSE55235, GSE55457 and GSE55584 datasets, respectively. Among them, 80 DEGs exhibited identical expression trends in all the three datasets, including 49 upregulated and 31 downregulated genes in patients with RA. DEGs in patients suffering from RA compared with patients suffering from OA were predominantly associated with the primary immunodeficiency pathway, including interleukin 7 receptor (IL7R) and signal transducer activator of transcription 1 (STAT1). The sensitivity of IL7R + STAT1 to differentiate RA from OA was 93.94% with a specificity of 80.77%. The results generated from analyses of the GSE36700 dataset were closely associated with results generated from analyses of GSE55235, GSE55457 and GSE55584 datasets, which further verified the reliability of the aforementioned results. The results of the present study suggested that increased expression of IL7R and STAT1 in synovial tissue as well as in the primary immunodeficiency may be associated with RA occurrence. These identified novel biomarkers may be used to predict disease occurrence and clinically differentiate RA from OA. PMID- 30483790 TI - Dynamic Nestin expression during hair follicle maturation and the normal hair cycle. AB - Nestin, a type-VI intermediate filament protein, serves as a marker for neural stem cells, and is also known to be expressed in follicle stem cells. Hair follicles go through repeated cycles of anagen (growth), catagen (regression) and telogen (quiescence) throughout the life of mammals following morphogenesis. In the present study it was demonstrated that in mice, the maturation of hair follicles includes the period between morphogenesis and the first anagen (4 weeks of age). Skin samples from Nestin-green fluorescent protein (GFP)+ mice at different hair follicle stages were collected, and immunostaining for Nestin and Ki67 was performed. It was identified that during morphogenesis, Nestin-GFP expression was rarely detected and it gradually increased during maturation (0-4 weeks) in hair follicle dermal cells. In mature hair follicle dermal cells, Nestin and the proliferation marker Ki67 were highly expressed in anagen, while during telogen, they were markedly decreased. Additionally, lineage tracing data demonstrated that peri-follicular Nestin+ cells during morphogenesis differentiated into cluster of differentiation 31+ cells. PMID- 30483791 TI - Differential expression profiles of long non-coding RNAs during the mouse pronuclear stage under normal gravity and simulated microgravity. AB - Pronuclear migration, which is the initial stage of embryonic development and the marker of zygote formation, is a crucial process during mammalian preimplantation embryonic development. Recent studies have revealed that long non-coding RNAs (lncRNAs) serve an important role in early embryonic development. However, the functional regulation of lncRNAs in this process has yet to be elucidated, largely due to the difficulty of assessing gene expression alterations during the very short time in which pronuclear migration occurs. It has previously been reported that migration of the pronucleus of a zygote can be obstructed by simulated microgravity. To investigate pronuclear migration in mice, a rotary cell culture system was employed, which generates simulated microgravity, in order to interfere with murine pronuclear migration. Subsequently, lncRNA sequencing was performed to investigate the mechanism underlying this process. In the present study, a comprehensive analysis of lncRNA profile during the mouse pronuclear stage was conducted, in which 3,307 lncRNAs were identified based on single-cell RNA sequencing data. Furthermore, 52 lncRNAs were identified that were significantly differentially expressed. Subsequently, 10 lncRNAs were selected for validation by reverse transcription-quantitative polymerase chain reaction, in which the same relative expression pattern was observed. The results revealed that 12 lncRNAs (lnc006745, lnc007956, lnc013100, lnc013782, lnc017097, lnc019869, lnc025838, lnc027046, lnc005454, lnc007956, lnc019410 and lnc019607), with tubulin beta 4B class IVb or actinin alpha 4 as target genes, may be associated with the expression of microtubule and microfilament proteins. Binding association was confirmed using a dual-luciferase reporter assay. Finally, Gene Ontology analysis revealed that the target genes of the differentially expressed lncRNAs participated in cellular processes associated with protein transport, binding, catalytic activity, membrane-bounded organelle, protein complex and the cortical cytoskeleton. These findings suggested that these lncRNAs may be associated with migration of the mouse pronucleus. PMID- 30483792 TI - Epithelial-mesenchymal transition phenotype of circulating tumor cells is associated with distant metastasis in patients with NSCLC. AB - Circulating tumor cells (CTCs) are closely associated with cancer metastasis in preclinical models and patients with cancer. However, to the best of the authors knowledge, it remains unknown which type of CTCs may serve the key role in cancer metastasis. The present study investigated the association between the epithelial mesenchymal transition (EMT) phenotype of CTCs from the peripheral blood and distant metastasis in patients with non-small cell lung cancer (NSCLC). Expression of EMT markers in CTCs from a cohort of patients was detected using CanpatrolTM CTC assays. A total of 110 patients (85 patients with NSCLC and 25 patients with benign diseases) were recruited. Among the 110 patients, 88 (80.0%) were characterized as CTC positive with EMT markers. Receiver operating characteristic curves revealed that E+/M+ CTCs exhibited the highest area under the curve (AUC) value of 0.876 [95% confidence interval (CI), 0.805-0.948; P<0.001) in distinguishing between patients with NSCLC and benign pulmonary diseases, and M+ CTCs had the highest AUC value of 0.723 (95% CI, 0.612-0.833; P<0.001) in differentiating patients with NSCLC with distant metastasis from those with non-distant metastasis. The results indicate the potential predictive value of distant metastasis of the EMT phenotype of CTCs in the peripheral blood of patients with NSCLC. PMID- 30483793 TI - Doxorubicin-loaded dual-functional hyaluronic acid nanoparticles: Preparation, characterization and antitumor efficacy in vitro and in vivo. AB - A novel GHH copolymer was synthesized using hyaluronic acid modified with glycyrrhetinic acid and L-histidine (His), and doxorubicin-loaded GHH nanoparticles (DOX/GHH) were prepared for liver-targeted drug delivery and pH responsive drug release. In the present study, GHH nanoparticles were characterized, and their pH-responsive behaviors were evaluated at different pH levels. The antitumor effect of the DOX/GHH nanoparticles was investigated in vitro and in vivo. Results showed that the DOX/GHH nanoparticles were spherical, and the particle sizes ranged from 238.1 to 156.7 nm with an increase in the degree of substitution of His. The GHH nanoparticles were obviously internalized into human hepatoblastoma cells. In vitro cytotoxicity assay results showed that the DOX/GHH nanoparticles exhibited a dose-dependent antitumor effect. Compared with free DOX, the DOX/GHH nanoparticles displayed higher antitumor efficacy. These results indicate that GHH nanoparticles could be a promising nano-delivery carrier of hydrophobic drugs for liver-targeted therapy. PMID- 30483794 TI - miR-1271-5p inhibits cell proliferation and induces apoptosis in acute myeloid leukemia by targeting ZIC2. AB - MicroRNAs (miRNAs) have been demonstrated to regulate the progression of numerous types of cancer, including acute myeloid leukemia (AML). Previous studies demonstrated that miR-1271-5p functions as a tumor suppressor; however, the roles of miR-1271-5p in AML remain unknown. In the present study, miR-1271-5p was significantly downregulated in AML tissues compared with normal tissues by reverse transcription-quantitative polymerase chain reaction analysis. Furthermore, the expression levels of miR-1271-5p in patients with AML may function as a prognostic marker. In addition, overexpression of miR-1271-5p significantly suppressed the proliferation and induced apoptosis of AML cells by Cell Counting kit-8 and fluorescence activated cell sorter assays; miR-1271-5p downregulation exhibited opposing effects. Additionally, transcription factor ZIC2 may be a direct target of miR-1271-5p in AML cells, which was demonstrated by a luciferase reporter assay and RNA pulldown assay. Overexpression of miR-1271 5p significantly reduced the mRNA and protein expression levels of ZIC2 in AML193 and OCI-AML2 cells by reverse transcription-quantitative polymerase chain reaction analysis and western blotting. Furthermore, an inverse correlation between miR-1271-5p and ZIC2 expression in AML samples was observed. In summary, ZIC2 was upregulated in AML tissues, and restoration of ZIC2 expression was able to promote the proliferation and reduce the apoptosis of AML cells transfected with miR-1271-5p mimics. The results of the present study demonstrated that miR 1271-5p inhibited the progression of AML by targeting ZIC2. PMID- 30483795 TI - Dual blockade of EGFR tyrosine kinase using osimertinib and afatinib eradicates EGFR-mutant Ba/F3 cells. AB - Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are efficacious drugs for non-small cell lung cancers (NSCLCs) with EGFR-activating mutations. Afatinib, a second-generation EGFR-TKI and osimertinib, a third generation EGFR-TKI, are both standard therapies for patients with these types of cancer. Each drug possesses distinct binding sites for the tyrosine kinase domain of EGFR. The present study examined the efficacy of single and combination TKI therapy using in vitro growth inhibition assays of Ba/F3 cells with an EGFR activating Del19 mutation. Afatinib or osimertinib treatment alone markedly inhibited cell proliferation in Ba/F3 cells, although drug-resistant cells eventually appeared with secondary EGFR mutations (either T790M or C797S, respectively) as determined by direct sequencing. Notably a combination of afatinib and osimertinib eradicated Ba/F3 cells with no development of resistance. We also evaluated the efficacy of afatinib, osimertinib, and a combination of the two, using drug-resistant cells with T790M or C797S mutations. Osimertinib was effective for treating Ba/F3 cells with the T790M mutation, whereas afatinib was moderately effective against C797S Ba/F3 cells. However, subsequent treatment, even when both drugs were used in combination, could not completely eradicate the Ba/F3 population and doubly resistant cells with a variety of triple mutations were generated, including Del19/T790M/C797S. In conclusion, an initial treatment with a combination of osimertinib and afatinib is potentially more effective for eradicating mutant EGFR-dependent cells than sequential drug use. This should be tested in future clinical trials to establish whether such a combination would be effective for the treatment of NSCLC. PMID- 30483796 TI - Lysine demethylase 2A promotes the progression of ovarian cancer by regulating the PI3K pathway and reversing epithelial-mesenchymal transition. AB - Metastasis is the most common cause of death in ovarian cancer patients but remains largely untreated. Epithelial-mesenchymal transition (EMT) is critical for the conversion of early-stage ovarian tumors into metastatic malignancies. Thus, investigating the signaling pathways promoting EMT may identify potential targets for the treatment of metastatic ovarian cancer. Lysine demethylase 2A (KDM2A), also known as FBXL11 and JHDM1A, is a histone H3 lysine 36 (H3K36) demethylase that regulates EMT and the metastasis of ovarian cancer. However, the function and underlying mechanisms of EMT suppression in ovarian cancer have not been thoroughly elucidated to date. In the present study, we used Gene Expression Omnibus (GEO) databases to determine that KDM2A is significantly upregulated in human ovarian cancers. KDM2A expression was assessed by immunohistochemistry of epithelial ovarian cancer (EOC) borderline ovarian tumors and normal ovary tissues. Seven fresh EOC tissues and 3 fresh normal ovary tissues were collected for western blot analysis. Kaplan-Meier survival curves were constructed to identify genes related to EOC prognosis from the TCGA data portal. Stable KDM2A knockdown cell lines were established to study the biological functions and underlying mechanisms of KDM2A in EMT in vitro. GEO database analysis revealed that KDM2A was highly upregulated in EOC tissues; this analysis was accompanied by immunochemistry and western blot analysis using samples of human tissues. High expression of KDM2A was associated with poor survival in EOC patients. KDM2A knockdown promoted apoptosis and suppressed the proliferation, migration and invasion of tumor cells in vitro. EMT and the PI3K/AKT/mTOR signaling pathway were suppressed in KDM2A-silenced cells. Inactivation of the PI3K/AKT/mTOR signaling pathway in A2780 cells induced EMT inhibition. Our data revealed that KDM2A functions as a tumor oncogene, and the downregulation of KDM2A expression regulates EMT and EOC progression, providing a valuable prognostic marker and potential target for the treatment of EOC patients. PMID- 30483797 TI - Carvedilol suppresses malignant proliferation of mammary epithelial cells through inhibition of the ROS-mediated PI3K/AKT signaling pathway. AB - Reactive oxygen species (ROS) cause oncogenic mutations through direct interaction with DNA. Carvedilol (CAR) exhibits antioxidative activity, and pre clinical studies have identified that CAR may prevent malignant transformation in certain carcinogenic models. This suggests that CAR may be a potential agent in cancer prevention. In the present study, non-cancerous MCF-10A cells were used as a model to investigate the chemopreventive effect of CAR on benzo(a)pyrene (BaP) induced cellular carcinogenesis. It was identified that CAR had the ability to eliminate BaP-induced ROS production and subsequent DNA damage. CAR/BaP activated the ROS-mediated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)Thr308 signaling pathway, whereas the effectors of the PI3K/AKT signaling pathway, murine double minute 2 (MDM2) and p53Ser15, served important functions in the BaP/CAR-mediated MCF10A cellular transformation. The results of the present study indicated that CAR may be a novel chemopreventive agent, notably in the prevention of estrogen receptor-negative breast cancer. The antioxidant effects of CAR may contribute to its chemopreventive activity. PMID- 30483798 TI - Tumor p16INK4 gene expression and prognosis in colorectal cancer. AB - Hypermethylation of the tumor suppressor gene p16INK4 (p16) promoter is associated with worse prognosis in colorectal cancer (CRC). In the present study, it was investigated whether p16 mRNA expression correlates with the methylation of its promoter, and whether it influences prognosis in patients with CRC. DNA and RNA were extracted from 101 resected tumor specimens. A MethyLight assay was used to quantify p16 methylation in terms of percentage of methylated reference (PMR), and the expression of p16 mRNA was measured using reverse transcription polymerase chain reaction. Associations between p16 methylation or mRNA expression and patient survival were evaluated using Kaplan-Meier analysis and Cox proportional hazards regression. p16 methylation was detected in 67 cases (66.3%) and the median PMR value was 0.344 (range, 0.00-468.6). Using a cut-off PMR value of 4, high p16 methylation was observed in 18 cases (17.8%). No significant association was observed between p16 methylation level and patient prognosis. As expected, a significant inverse association was observed between p16 methylation and mRNA expression (P=0.034). Amongst the 83 cases with low p16 methylation, a significantly worse outcome was identified in patients expressing high p16 mRNA expression levels (P=0.026). Multivariate analysis identified that p16 mRNA expression was an independent prognostic factor for worse survival (P=0.011). These results suggested a paradoxical association between high levels of p16 mRNA expression in the tumor and worse prognosis in patients with CRC. PMID- 30483799 TI - Erythropoietin promotes expression of survivin via STAT3 activation and reduces sensitivity to cisplatin in cervical cancer cells. AB - Erythropoietin (Epo) is used for the treatment of cancer-associated anaemia. However, certain studies have identified that the administration of Epo mediates the acquisition of resistance to cisplatin, which is widely used to treat cervical cancer. Our group previously reported that cervical cancer cells express Epo receptor and that exogenous Epo induces cell proliferation and migration. However, the effect of Epo on cervical cancer cell death mediated by chemotherapeutic agents has not yet been evaluated. Thus, the aim of the present study was to assess the potential effect of Epo on the cytotoxic activity of cisplatin in cervical cancer cells. The effect of Epo was assessed in 3 cervical cancer-derived cell lines. It was observed that pre-incubation with Epo induced a significant reduction of cisplatin-induced apoptosis in vitro and in vivo. Incubation with Epo induced the expression and activation of the transcriptional factor signal transducer and activator of transcription 3 (STAT3), which in turn stimulated the expression and activation of the anti-apoptotic protein survivin. The cytotoxicity of cisplatin was partially restored by treating the cells with MY155, an inhibitor of survivin. Conversely, inhibition of STAT3 activation using sub-lethal doses of WP1066, completely abolished the cytoprotective effect of Epo. These observations indicated that Epo was able to hinder the cytotoxic effect of cisplatin in cervical cancer cells by activating anti-apoptotic responses regulated by STAT3. PMID- 30483800 TI - Silencing of the transcriptional factor ZEB1 alters the steroidogenic pathway, and increases the concentration of testosterone and DHT in DU145 cells. AB - Prostate cancer (PCa) is the second most common type of male malignancy worldwide. The transcription factor zinc finger E-box binding homeobox 1 (ZEB1) is associated with epithelial-mesenchymal transition and is also involved in regulation of androgen receptor (AR) expression, the main ligands of which are testosterone and dihydrotestosterone (DHT). These androgens are synthesized through the steroidogenic pathway within the prostate, and their synthesis is altered in PCa. The present study aimed to determine the ZEB1-induced alterations in androgen synthesis and AR expression in the DU145 PCa cell line. Reverse transcription-quantitative polymerase chain reaction, western blotting and immunocytochemistry were used to determine the mRNA and protein expression levels, and cellular localization of steroidogenic pathway enzymes in the DU145 cell line in response to ZEB1 silencing. Furthermore, the concentrations of testosterone and DHT were detected in cell culture medium using ELISA. ZEB1 silenced cells exhibited an increase in testosterone and DHT production, an increase in AR expression and an alteration in the steroidogenic pathway. In particular, steroidogenic acute regulatory protein and 5alpha-reductase 2 expression levels were decreased, whereas cytochrome P450 family 17 subfamily A member 1, 5alpha-reductase 1, aldo-keto reductase family 1 member D1 and aldo keto reductase family 1 member C2 expression levels were increased. In conclusion, the present study provided novel information regarding the regulation of intratumoral androgen production in PCa, which is relevant for the progression of the disease to a castration-resistant form. PMID- 30483801 TI - FOXN3 is downregulated in osteosarcoma and transcriptionally regulates SIRT6, and suppresses migration and invasion in osteosarcoma. AB - Forkhead box N3 (FOXN3) has been reported to be downregulated in numerous cancers, including laryngeal, oral squamous cell and hepatocellular carcinomas, and diffuse large B-cell lymphoma. FOXN3 was proposed to serve as a tumor suppressor; however, the function of FOXN3 in osteosarcoma (OS) remains unknown. The present study suggested that FOXN3 was notably downregulated in OS tissues compared with in adjacent normal tissues, and the expression of FOXN3 was negatively correlated with tumor size, metastasis and tumor, node and metastasis stage. Additionally, low expression levels of FOXN3 predicted a poor prognosis of patients with OS. Additionally, the present study revealed that FOXN3 was also downregulated in OS cells. Numerous functional experiments, including colony formation, Cell Counting Kit-8, wound healing and Transwell invasion assays, were performed. The results of the present study revealed that FOXN3 suppressed the proliferation, migration and invasion of OS cells. SIRT6 has been reported to serve a key role in OS; chromatin-immunoprecipitation (ChIP) and quantitative ChIP, as well as a luciferase reporter assay, demonstrated that SIRT6 was transcriptionally regulated by FOXN3. Furthermore, FOXN3 also regulated matrix metalloproteinase-9 secretion via the regulation of SIRT6 expression. The findings of the present study indicated that FOXN3 serves as a tumor suppressor in OS and proposed FOXN3 as a prognostic predictor and a therapeutic target for patients with OS. PMID- 30483802 TI - Identification of long non-coding RNA expression patterns useful for molecular based classification of type I endometrial cancers. AB - Endometrial cancer is the most frequently diagnosed gynecologic malignant disease. Although several genetic alterations have been associated with the increased risk of endometrial cancer, to date, the diagnosis and prognosis still rely on morphological features of the tumor, such as histological type, grading and invasiveness. As molecular-based classification is desirable for optimal treatment and prognosis of these cancers, we explored the potential of lncRNAs as molecular biomarkers. To this end, we first identified by RNA sequencing (RNA Seq) a set of lncRNAs differentially expressed in cancer vs. normal endometrial tissues, a result confirmed also by analysis of normal and cancerous endometrium RNA-Seq data from TCGA (The Cancer Genome Atlas). A significant association of a subset of these differentially expressed lncRNAs with tumor grade was then determined in 405 TCGA endometrial cancer profiles. Integrating endometrial cancer-specific expression profiles of long and small non-coding RNAs, a functional association network was then identified. These results describe for the first time a functional ?core? network, comprising small and long RNAs, whose deregulation is associated with endometrial neoplastic transformation, representing a set of cancer biomarkers that can be monitored and targeted for diagnosis, follow-up and therapy of these tumors. PMID- 30483803 TI - MEK inhibition prevents TGF-beta1-induced myofibroblast transdifferentiation in human tenon fibroblasts. AB - Subconjunctival fibrosis represents the primary cause of postoperative failure of trabeculectomy, and at present there is a lack of effective intervention strategies. The present study aimed to investigate the effect of the mitogen activated protein kinase kinase (MEK) inhibitor U0126 on human tenon fibroblast (HTF) myofibrosis transdifferentiation, and to illuminate the underlying molecular mechanisms involved. It was demonstrated that U0126 significantly inhibited the proliferation, migration and collagen contraction of HTFs stimulated with TGF-beta1. In addition, U0126 largely attenuated the TGF-beta1 induced conversion of HTFs into myofibroblasts, as indicated by a downregulation of the mRNA and protein expression of alpha-smooth muscle actin and zinc finger protein SNAI1, and by ameliorating the 3D-collagen contraction response. Mechanistically, U0126 suppressed the TGF-beta1-stimulated phosphorylation of mothers against decapentaplegic homolog 2/3, P38 mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2, indicating that U0126 may inhibit HTF activation through the canonical and non-canonical signaling pathways of TGF beta1. Therefore, U0126 exhibits a potent anti-fibrotic effect among HTFs, and the inhibition of MEK signaling may serve as an alternative intervention strategy for the treatment of trabeculectomy-associated fibrosis. PMID- 30483804 TI - Docetaxel promotes cell apoptosis and decreases SOX2 expression in CD133 expressing hepatocellular carcinoma stem cells by suppressing the PI3K/AKT signaling pathway. AB - Docetaxel is a front-line standard-of-care chemotherapeutic drug for the treatment of cancers. However, the underlying function and mechanism of docetaxel in human hepatocellular carcinoma (HCC) are uncertain. Therefore, the present study aimed to determine the effects of docetaxel on cell apoptosis and SOX2 expression in cultured human HCC stem cells. After human HCC stem cells were treated with docetaxel, cell proliferation was assessed by methyl thiazolyl tetrazolium (MTT) method, the cell apoptotic rate was evaluated by flow cytometry, the expression of CD133 and sex determining region Y-box 2 (SOX2) was determined by RT-PCR and immunohistochemistry, and the protein levels of CD133, SOX2, phosphoinositide 3-kinases (PI3K), AKT and phosphorylated AKT (p-AKT) were analyzed by western blotting. The results indicated that SOX2 and CD133 were highly expressed in patients with HCC while their expression was significantly decreased after patients with HCC were treated with docetaxel. In vitro, docetaxel inhibited the proliferation while it enhanced the apoptosis of human CD133-expressing HCC stem cells. Furthermore, lower expression of p-AKT and SOX2 were revealed in the presence of docetaxel. Notably, docetaxel-inhibited SOX2 expression and growth of human CD133-expressing HCC stem cells were partially restricted following the block of the PI3K/AKT signaling pathway using the inhibitor LY294002. The present study collectively indicated that docetaxel promoted apoptosis and upregulated SOX2 expression of human HCC stem cells through the suppression of the PI3K/AKT signaling pathway. PMID- 30483805 TI - BAI1-associated protein 2-like 2 is a potential biomarker in lung cancer. AB - Lung cancer is the leading cause of cancer-related death worldwide. The underlying molecular mechanisms that trigger this disease remain largely unknown. The I-BAR family is involved in regulating cell membrane formation and some members, such as BAIAP2L1, IRSp53 and MIM have been shown to participate in tumorigenic progression. However, the role of BAI1-associated protein 2-like 2 (BAIAP2L2) in cancer development is unclear. In the present study, we determined that BAIAP2L2 was upregulated in lung adenocarcinoma tissues and various lung cancer cell lines. In vitro, BAIAP2L2 silencing resulted in decreased viability and colony formation capacity of both A549 and H1299 cells. By contrast, BAIAP2L2 overexpression promoted the proliferation and growth of 95D cells. These results indicated that BAIAP2L2 was essential for lung cancer cell proliferation and growth. We also found that BAIAP2L2 knockdown increased the apoptosis of A549 and H1299 cells. At the molecular level, BAIAP2L2 knockdown led to dysregulation of numerous genes, among which the Estrogen-mediated S-phase Entry pathway was significantly suppressed. Collectively, our findings revealed BAIAP2L2 as a novel biomarker and potential therapeutic target for lung cancer. PMID- 30483806 TI - Overexpression of MUC1 predicts poor prognosis in patients with breast cancer. AB - Breast cancer is the most commonly diagnosed cancer in females; thus, there is an urgent requirement to identify precise biomarkers for the diagnosis and treatment of the disease. Mucin 1 (MUC1) is a glycoprotein that has been demonstrated to be involved in the metastasis and invasion of multiple tumor types. Bioinformatics analyses were conducted to indicate the prognostic value of MUC1 in breast cancer. Additionally, the expression level of MUC1 was assessed using Oncomine analysis. Furthermore, PrognoScan was used to analyze the prognostic value of MUC1 in breast cancer. Mutations of MUC1 were analyzed by the Catalogue of Somatic Mutations in Cancer and cBioPortal databases. In addition, University of California, Santa Cruz (UCSC) was used to examine the methylation status of MUC1. Co-expression of MUC1 mRNA was detected with the cBioPortal, UCSC and Breast Cancer Gene-Expression Miner v4.0 datasets. The results demonstrated that MCU1 is frequently overexpressed in breast cancer and is negatively associated with CpG sites. Furthermore, pooled data indicated that abnormally high expression of MUC1 indicates poor prognosis. Additionally, upregulation of MUC1 expression is associated with estrogen receptor- and progesterone receptor-positive disease, aging and increased Scarff, Bloom and Richardson grade, but is not associated with triple-negative and basal-like status. Subsequent data mining across multiple large databases demonstrated a positive association between MUC1 mRNA expression and cyclic AMP-responsive element-binding protein 3-like 4 (CREB3L4) in breast cancer tissues. The present data indicated that the overexpression of MUC1 indicates a poor prognosis in patients with breast cancer and is associated with MUC1 promoter methylation status. Additionally, MUC1 positively correlated with CREB3L4 and may serve as a potential prognostic factor and therapy target for breast cancer. PMID- 30483807 TI - MicroRNA-154 functions as a tumor suppressor in bladder cancer by directly targeting ATG7. AB - Aberrant expression of miR-154 is usually found in cancer studies; however, the role of miR-154 has seldom been reported in bladder cancer (BCa). In this study, we observed that miR-154 expression was significantly downregulated in BCa tissues and cell lines, and was associated with several clinicopathological characteristics, including advanced T stage, lymphatic invasion, and distant metastasis. Low expression level of miR-154 was associated with poor survival outcomes in BCa patients. Overexpression of miR-154 led to significant decrease in the proliferation, migration, and invasion of BCa cells, while knockdown of miR-154 yielded the opposite effect. ATG7 was identified as a direct target of miR-154. ATG7 expression was negatively correlated with miR-154 expression in BCa tissues. Silencing of ATG7 achieved a similar effect to miR-154 overexpression; overexpression of ATG7 reversed the inhibitory effect of miR-154 on BCa cell proliferation, migration and invasion. A xenograft study revealed that miR-154 inhibited BCa cell growth in vivo, and suppressed ATG7 expression. Altogether, this study demonstrated that miR-154 may function as a tumor suppressor in BCa and indicated that miR-154 may be a potential therapeutic target for BCa patients. PMID- 30483808 TI - NADH dehydrogenase complex I is overexpressed in incipient metastatic murine colon cancer cells. AB - Colon cancer is one of the most frequently occurring types of cancers in the world. Primary tumours are treated very efficiently, but the metastatic cases are known to have severe outcomes. Therefore, the aim of the present study was to obtain a greater understanding of the transformation of primary colon cancer cells into metastatic phenotypes. Small changes in protein expression provoke the metastatic phenotype transformation. More sensitive methods to detect small variations are required. A murine colon cancer cell line with metastatic characteristics in a very early phase was created in order to investigate the first steps of transformation using a murine liver metastasis model. The protein expression patterns of metastatic and non-metastatic cells were compared using the stable isotope labelling by amino acids in cell culture method in combination with mass spectrometry. Quantitative proteomics data indicated that nicotinamide adenine dinucleotide hydride (NADH) dehydrogenase complex I was overexpressed in metastatic cells with respect to non-metastatic cells. Since the NADH dehydrogenase complex catalyses the oxidation of NADH to NAD+, the functionality of the complex was studied by measuring the amount of NADH. The results revealed that metastatic cells accumulate more NADH and reactive oxygen species. In addition, the mitochondrial membrane potential of metastatic cells was lower than that of non-metastatic cells, indicating that the activity of NADH dehydrogenase and the mitochondrial oxidative chain were decreased in metastatic cells. During the incipient transformation of primary cancer cells, NADH dehydrogenase complex I was overexpressed but then became inactive due to the Warburg effect, which inhibits mitochondrial activity. In the first step of transformation, the high energy demand required in an adverse environment is fulfilled by overexpressing components of the respiratory chain, a fact that should be considered for future anti-metastatic therapies. PMID- 30483809 TI - Chemokine profiling in serum from patients with ovarian cancer reveals candidate biomarkers for recurrence and immune infiltration. AB - The management of advanced ovarian cancer is challenging due to the high frequency of recurrence, often associated with the development of resistance to platinum-based chemotherapy. Molecular analyses revealed the complexity of ovarian cancer with particular emphasis on the immune system, which may contribute to disease progression and response to treatment. Cytokines and chemokines mediate the cross-talk between cancer and immune cells, and therefore, present as potential biomarkers, reflecting the tumor microenvironment. A panel of circulating C-C motif chemokine ligand (CCL) and C-X-C motif chemokine ligand (CXCL) chemokines were examined in the serum of 40 high-grade patients with ovarian cancer prior to primary surgery. The level of immune infiltration in tumors was also analyzed. The preoperative levels of chemokines differ between patients. Elevated levels of circulating CXCL4 + CCL20 + CXCL1 combination can discriminate patients with shorter recurrence-free survival and overall survival. The presence of tumor-infiltrating T lymphocytes was detected in half of the patients. The mRNA expression analysis suggests the presence of antitumoral and immunosuppressive elements in the tumor microenvironment. The combination of circulating CXCL9 + CXCL10 can distinguish immune-infiltrated tumors that will lead to shorter recurrence-free survival. The results suggest that preoperative profiling of circulating chemokines in patients with ovarian cancer may provide valuable information regarding tumor recurrence and immune infiltration. The findings demonstrate that combinations have better prognostic utility than single chemokines, and may serve as patient stratification tools. PMID- 30483810 TI - Involvement of the glutamine RF-amide peptide and its cognate receptor GPR103 in prostate cancer. AB - Glutamine RF-amide peptide (QRFP) belongs to the RFamide neuropeptide family, which is involved in a wide spectrum of biological activities, ranging from food intake and cardiovascular functioning to analgesia, aldosterone secretion, locomotor activity and reproduction. Recently, QRFP has been demonstrated to exert its effects by activating the G protein-coupled receptor GPR103. QRFP is expressed in the brain and peripherally in the adipose tissue, bladder, colon, testis, parathyroid and thyroid gland, as well as in the prostate gland. Following lung cancer, prostate cancer constitutes the second most frequently diagnosed cancer among men, whilst obesity appears to be a contributing factor for aggressive prostate cancer. In the present study, we sought to investigate the role of QRFP in prostate cancer, using two androgen-independent human prostate cancer cell lines (PC3 and DU145) as in vitro experimental models and clinical human prostate cancer samples. The expression of both QRFP and GPR103 at the gene and protein level was higher in human prostate cancer tissue samples compared to control and benign prostatic hyperplasia (BHP) samples. Furthermore, in both prostate cancer cell lines used in the present study, QRFP treatment induced the phosphorylation of ERK1/2, p38, JNK and Akt. In addition, QRFP increased cell migration and invasion in these in vitro models, with the increased expression of MMP2. Furthermore, we demonstrated that the pleiotropic adipokine, leptin, increased the expression of QRFP and GPR103 in PC3 prostate cancer cells via a PI3K- and MAPK-dependent mechanism, indicating a novel potential link between adiposity and prostate cancer. Our findings expand the existing evidence and provide novel insight into the implication of QRFP in prostate cancer. PMID- 30483811 TI - Molecular mechanism of LKB1 in the invasion and metastasis of colorectal cancer. AB - The occurrence of colorectal cancer (CRC) is associated with a variety of oncogenes and tumor-suppressor genes. As a tumor-suppressor gene, the liver kinase B1 gene (LKB1, also known as serine/threonine kinase 11, STK11) is closely related to tumor angiogenesis, invasion and metastasis, but its molecular mechanisms remain unclear. The aim of the present study was to investigate the effects of LKB1 on the invasion and metastasis of CRC, and to explore its molecular mechanisms. By detecting the expression of LKB1 in CRC, we can provide a reference index for diagnosing the depth of invasion and lymph node metastasis. Immunohistochemistry results indicated that LKB1 expression was strongly positive in normal colon tissue and that it inhibited the production of CRC. Immunocytochemical staining showed that the expression of LKB1 was significantly decreased in adenocarcinoma and mucinous adenocarcinoma tissues, and this reduced expression induced the invasion and metastasis of CRC. In the present study, LKB1 small interfering RNA (LKB1 siRNA) was transfected into LoVo cells to observe the effect of LKB1 on the invasion and metastasis of CRC. LKB1 silencing decreased the phosphorylation of AMP-activated protein kinase (p-AMPK) in its downstream pathway, which increased the phosphorylation of protein kinase B (p-AKT) and promoted tumor cell proliferation, enhancing the migration and invasion of CRC. The present study also explored the role of metformin in the LKB1 signaling pathway. Metformin inhibits the invasion and metastasis of CRC by activating p AMPK, thereby inhibiting the activation of p-AKT. These results suggest that LKB1 plays an important role in the invasion and metastasis of CRC by activating AMPK, negatively regulating the AKT signaling pathway and regulating gene expression. Mutation or deletion of LKB1 is expected to be a novel therapeutic target or clinical biomarker for the prevention of the invasion and metastasis of CRC. PMID- 30483812 TI - Levistolide A synergistically enhances doxorubicin-induced apoptosis of k562/dox cells by decreasing MDR1 expression through the ubiquitin pathway. AB - Multidrug resistance (MDR) is one of the main reasons underlying failure of cancer chemotherapy. Certain natural compounds may help prevent MDR, and may be used in combination with chemotherapeutic agents to enhance their efficacy. Levistolide A is a natural product that is extracted from the rhizome of Angelicae sinensis (Oliv.), which has been used as an essential component of antitumor formulas since ancient times in China. The present study conducted the following experiments: MTT assay, apoptosis analysis, cellular doxorubicin accumulation assay, immunoblotting and reverse transcription-quantitative polymerase chain reaction, to investigate whether levistolide A enhance doxorubicin-induced apoptosis of k562/dox cells and to determine the molecular mechanisms involved. When combined with doxorubicin, levistolide A exhibited a synergistic effect and induced cytotoxicity in k562/dox cells. Drug accumulation studies revealed that levistolide A increased the intracellular concentration of doxorubicin in a dose-dependent manner. Cell apoptosis experiments indicated that levistolide A increased the sensitivity of k562/dox cells to doxorubicin. Furthermore, detection of reactive oxygen species (ROS) revealed that levistolide A enhanced doxorubicin-induced cell death by increasing the levels of ROS. Mitochondrial potential detection with JC-1 staining also indicated that levistolide A synergistically enhanced doxorubicin-induced cell death. Immunoblotting demonstrated that levistolide A enhanced doxorubicin-induced cell death by decreasing the expression levels of B-cell lymphoma 2 and increasing caspase 3 expression. Furthermore, multidrug resistance protein 1 (MDR1) expression in k562/dox cells was downregulated by levistolide A in a dose dependent manner, thus suggesting that levistolide A may modulate MDR1 during cancer therapy. Therefore, the combination of levistolide A with doxorubicin could result in more effective and less toxic anticancer regimens. PMID- 30483813 TI - Biological role of metabolic reprogramming of cancer cells during epithelial mesenchymal transition (Review). AB - Epithelial-mesenchymal transition (EMT) is required for the distant metastasis of tumors. The degree of tumor malignancy increases as EMT progresses. Notably, the biology of tumor cells differs from that of normal cells, with regards to characteristics and energy metabolism mechanisms; abnormal glucose metabolism, excessive accumulation of fatty acids and other metabolic disorders occur in metastatic tumors. Previous studies have confirmed that the regulation of tumor cell metabolism can affect tumor metastasis and some findings have resulted in novel clinical applications. The present review aimed to provide a basis for treatments targeting the tumor EMT process and metabolic reprogramming. PMID- 30483814 TI - Leukocyte-associated immunoglobulin-like receptor 1 promotes tumorigenesis in RCC. AB - Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, responsible for approximately 90-95% of cases. We previously reported a novel method that enables direct extraction of extracellular vesicles (EVs) from surgically resected viable tissues, yielding what we term tissue-exudative extracellular vesicles (Te-EVs). Quantitative LC/MS analysis identified 3,871 proteins in Te-EVs, among which leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) was highly enriched in tumor Te-EVs. In the present study, we found that LAIR1 was significantly upregulated in clinical specimens of human RCC tumor tissues compared to that noted in adjacent non-cancerous renal tissues as determined by quantitative PCR analysis. LAIR1 overexpression resulted in accelerated cell proliferation and tumor growth in RCC cells. Moreover, knockdown of LAIR1 using siRNA significantly inhibited cell proliferation in RCC cells. Mechanistically, LAIR1 upregulated the phosphorylation status of Akt, which in turn increased cell proliferation in RCC cells. In clinical RCC specimens, RCC patients with high LAIR1 mRNA expression showed poor progression-free survival compared to those with low LAIR1 expression. These findings indicate that LAIR1 promotes tumorigenesis in RCC. PMID- 30483815 TI - Sex-specific aortic root anatomy in patients with bicuspid aortic valve undergoing TAVR in a Chinese cohort. AB - OBJECTIVES: The aim of this study is to investigate the sex-specific aortic root anatomy in patients with bicuspid aortic valve (BAV). PATIENTS AND METHODS: This retrospective study includes 73 consecutive patients with BAV who underwent CT evaluation before transcatheter aortic valve replacement (TAVR) between July 2013 and April 2017 in the Second Affiliated Hospital of Zhejiang University. RESULT: The size of the annulus, diameter and height of the sinotubular junction (STJ), height of the coronary artery ostia, and dimension of the aorta were measured. Women had significantly smaller annulus parameters (mean diameter: 23.4 +/- 1.8 vs. 26.1 +/- 2.1 mm; area: 425.3 +/- 59.4 vs. 527.4 +/- 84.6 mm2; perimeter: 74.3 +/- 5.2 vs. 83.2 +/- 6.4 mm), and STJ diameter (29.7 +/- 3.1 vs. 32.6 +/- 4.5 mm) than men (p < 0.01 for all), even after adjustment for their smaller body surface area (BSA). Dimension of aorta and height of right coronary artery were also significantly smaller in women, although not when indexing for the BSA. The left ventricular ejection fraction of women is significantly higher than that of men before discharge (60.2 +/- 9.7% vs. 53.7 +/- 13.6%, p = 0.01). There were no differences between women and men in the all-cause 30-day and 1-year mortality. CONCLUSION: Women with BAV had smaller annulus and STJ diameter after indexing for BSA, reflecting a sex-specific difference. There were no differences in 30 day and 1-year mortality between the two groups. PMID- 30483816 TI - Efficacy and safety of rosuvastatin vs. atorvastatin in lowering LDL cholesterol : A meta-analysis of trials with East Asian populations. AB - BACKGROUND: The VOYAGER meta-analysis reported on the low-density lipoprotein cholesterol (LDL-C)-lowering effect of commonly used statins in Caucasian subjects. As there is limited literature available on the efficacy of statins in Asian populations, the current meta-analysis compared the effects of rosuvastatin and atorvastatin on LDL-C levels in an East Asian population. METHODS: The MEDLINE, PubMed, Embase, Cochrane Library, and Web of Science databases were searched for randomized controlled trials comparing lipid-lowering effects of rosuvastatin and atorvastatin in an East Asian population. Data on the study design, participant characteristics, and outcomes were extracted. Odds ratios (OR), weighted mean differences (WMD), or standardized mean differences were calculated using the random-effects model. RESULTS: The meta-analysis comprised 16 randomized controlled trials with 5930 participants. Compared with atorvastatin, patients treated with rosuvastatin had a significant reduction in LDL-C: WMD = -7.15 mg/dl (95% confidence intervals [CI]: -10.71--3.60) mg/dl, p < 0.0001. Meta-regression analyses revealed no significant association between the superior benefits of rosuvastatin and other variables including age, sex, baseline LDL-C level, and follow-up duration. Additionally, the rosuvastatin group of patients, who were treated with half the dose of atorvastatin, achieved a significantly greater reduction in LDL-C levels (WMD = -3.57; 95% CI: -5.40- 1.74 mg/dl, p < 0.001). Both rosuvastatin and atorvastatin were well tolerated, with similar incidences of adverse events. CONCLUSION: Similar to the VOYAGER meta-analysis, which reported a greater efficacy of rosuvastatin in comparison with atorvastatin and simvastatin in Caucasian patients, we found that the efficacy of rosuvastatin was superior to atorvastatin in East Asian patients with hypercholesterolemia. PMID- 30483817 TI - Targeting autophagy using metallic nanoparticles: a promising strategy for cancer treatment. AB - Despite the extensive genetic and phenotypic variations present in the different tumors, they frequently share common metabolic alterations, such as autophagy. Autophagy is a self-degradative process in response to stresses by which damaged macromolecules and organelles are targeted by autophagic vesicles to lysosomes and then eliminated. It is known that autophagy dysfunctions can promote tumorigenesis and cancer development, but, interestingly, its overstimulation by cytotoxic drugs may also induce cell death and chemosensitivity. For this reason, the possibility to modulate autophagy may represent a valid therapeutic approach to treat different types of cancers and a variety of clinical trials, using autophagy modulators, are currently employed. On the other hand, recent progress in nanotechnology offers plenty of tools to fight cancer with innovative and efficient therapeutic agents by overcoming obstacles usually encountered with traditional drugs. Interestingly, nanomaterials can modulate autophagy and have been exploited as therapeutic agents against cancer. In this article, we summarize the most recent advances in the application of metallic nanostructures as potent modulators of autophagy process through multiple mechanisms, stressing their therapeutic implications in cancer diseases. For this reason, we believe that autophagy modulation with nanoparticle-based strategies would acquire clinical relevance in the near future, as a complementary therapy for the treatment of cancers and other diseases. PMID- 30483818 TI - Manipulation of crossover frequency and distribution for plant breeding. AB - The crossovers (COs) that occur during meiotic recombination lead to genetic diversity upon which natural and artificial selection can act. The potential of tinkering with the mechanisms of meiotic recombination to increase the amount of genetic diversity accessible for breeders has been under the research spotlight for years. A wide variety of approaches have been proposed to increase CO frequency, alter CO distribution and induce COs between non-homologous chromosomal regions. For most of these approaches, translational biology will be crucial for demonstrating how these strategies can be of practical use in plant breeding. In this review, we describe how tinkering with meiotic recombination could benefit plant breeding and give concrete examples of how these strategies could be implemented into breeding programs. PMID- 30483819 TI - Development and use of chromosome segment substitution lines as a genetic resource for crop improvement. AB - KEY MESSAGE: CSSLs are a complete library of introgression lines with chromosomal segments of usually a distant genotype in an adapted background and are valuable genetic resources for basic and applied research on improvement of complex traits. Chromosome segment substitution lines (CSSLs) are genetic stocks representing the complete genome of any genotype in the background of a cultivar as overlapping segments. Ideally, each CSSL has a single chromosome segment from the donor with a maximum recurrent parent genome recovered in the background. CSSL development program requires population-wide backcross breeding and genome wide marker-assisted selection followed by selfing. Each line in a CSSL library has a specific marker-defined large donor segment. CSSLs are evaluated for any target phenotype to identify lines significantly different from the parental line. These CSSLs are then used to map quantitative trait loci (QTLs) or causal genes. CSSLs are valuable prebreeding tools for broadening the genetic base of existing cultivars and harnessing the genetic diversity from the wild- and distant-related species. These are resources for genetic map construction, mapping QTLs, genes or gene interactions and their functional analysis for crop improvement. In the last two decades, the utility of CSSLs in identification of novel genomic regions and QTL hot spots influencing a wide range of traits has been well demonstrated in food and commercial crops. This review presents an overview of how CSSLs are developed, their status in major crops and their use in genomic studies and gene discovery. PMID- 30483820 TI - [Left atrial appendage occlusion in patients with nonvalvular atrial fibrillation : Present evidence, ongoing studies, open questions]. AB - About every fifth ischemic stroke is caused by atrial fibrillation. Oral anticoagulation is highly effective in secondary stroke prevention, but a relevant portion of patients with atrial fibrillation is not (permanently) anticoagulated for a variety of reasons. Based on present evidence, no general recommendation can be given for left atrial appendage occlusion in patients with nonvalvular atrial fibrillation. However, left atrial appendage occlusion is a treatment option after severe anticoagulation-related bleeding, if the cause of bleeding is not treatable. Left atrial appendage occlusion is critical in patients with a relative contraindication for oral anticoagulation or lack of adherence to given medication. It seems to be important that further randomized studies confirm a benefit of left atrial appendage occlusion in selected patients with nonvalvular atrial fibrillation. In addition, it is vital to clarify whether discontinuation of antiplatelets is feasible after catheter-based left atrial appendage occlusion, as antiplatelets are associated with a risk of bleeding. Within this review article, we discuss present evidence, gaps of knowledge and provide an overview on ongoing clinical studies. In addition, we summarize the design of the CLOSURE-AF study. This randomized multicenter study will start recruitment soon and is funded by the German Center for Cardiovascular Research e. V. PMID- 30483821 TI - Interleukin-23 receptor signaling mediates cancer dormancy and radioresistance in human esophageal squamous carcinoma cells via the Wnt/Notch pathway. AB - In the tumor microenvironment, inflammatory cells and molecules influence almost every process; among them, interleukin-23 (IL-23) is a pro-inflammatory molecule that exhibits pro- or anti-tumor properties, but both activities remain poorly understood. In this study, we investigated the effect of extracellular IL-23 in IL-23 receptor-positive (IL-23R+) esophageal squamous cell carcinoma (ESCC) and explored the mechanisms underlying this effect. We analyzed ESCC tumor tissues by immunohistochemical and immunofluorescence staining and found that IL-23, which was highly expressed, co-localized with Oct-4A in IL-23R+ ESCC cells. In addition, IL-23 treatment significantly increased the accumulation of CD133+ cells and activated the Wnt and Notch signaling pathways in CD133-IL-23R+ ESCC cell lines. Consistently, CD133-IL-23R+ cells pretreated with IL-23 showed stronger anti-apoptosis activity when exposed to radiation and higher survival than untreated groups. Moreover, the inhibition of Wnt/Notch signaling by a small molecule inhibitor or siRNA abolished the effect of IL-23-induced dormancy and consequent radioresistance. Taken together, these results suggested that IL-23 facilitates radioresistance in ESCC by activating Wnt/Notch-mediated G0/1 phase arrest, and attenuating these detrimental changes by blocking the formation of dormancy may prove to be an effective pretreatment for radiotherapy. KEY MESSAGES: IL-23/IL-23R is correlated with the acquisition of stem-like potential in ESCC. CD133-IL-23R+ ESCCs acquired dormancy via IL-23. Radioresistance depends on IL-23-mediated Wnt/Notch pathway activation in vitro and vivo. PMID- 30483822 TI - Coexpression of FOXK1 and vimentin promotes EMT, migration, and invasion in gastric cancer cells. AB - In human gastric cancer (GC), the upregulation of FOXK1 and vimentin is frequently observed in cancer cells and correlates with increased malignancy. We report that FOXK1 synergizes with vimentin to promote GC invasion and metastasis via the induction of epithelial-mesenchymal transition (EMT). We showed that higher expression levels of FOXK1 were significantly associated with GC development. FOXK1 can physically interact with and stabilize vimentin. Moreover, a positive correlation between the expression of FOXK1 and vimentin was found in GC cells. Higher expression levels of these two proteins were significantly associated with differentiation, lymph node metastasis, AJCC stage, and poorer prognosis. Furthermore, the coexpression of FOXK1 and vimentin enhances cell metastasis through the induction of EMT in GC cells. However, the siRNA-mediated repression of vimentin in FOXK1-overexpressing cells reversed the EMT-like phenotype and reduced GC cell migration and invasion in vitro and in vivo. Altogether, our findings suggest that the vimentin-FOXK1 axis provides new insights into the molecular mechanisms underlying EMT regulation during GC progression and metastasis. PMID- 30483823 TI - ? PMID- 30483824 TI - Reduction of the dislocated hips with the Tubingen hip flexion splint in infants. AB - PURPOSE: Early detection and conservative treatment are essential for a successful outcome in developmental dysplasia of the hip (DDH). The aim of this study was to evaluate the efficacy of Tubingen hip flexion splint treatment on dislocated hips of type D, 3, and 4 according to the Graf classification. METHODS: A total of 104 dislocated hips in 92 patients were treated with Tubingen splints. Splint treatment was applied to patients with dislocated hips as diagnosed under ultrasonographic evaluation. After four to six weeks of treatment, the hips were re-evaluated according to the Graf classification under ultrasonography. The success of Tubingen splinting was determined as follows: hips initially diagnosed as Graf type 3 and 4 were upgraded to type 2c, 2b, or 1 after treatment, and hips initially diagnosed as Graf type D were upgraded to type 2b or 1 after treatment. RESULTS: The mean age at treatment initiation was 11.91 +/- 5.16 (range, 4-32) weeks. There were no statistically significant relationships between success rates and sex, bilateral hip involvement, or initial physical examination findings (p > 0.05). The age at the start of treatment was found to be statistically significant in terms of the success of the splint (p = 0.03). CONCLUSIONS: For successful treatment with Tubingen splints, the cut-off point of starting initial treatment was defined as the 15th week, with sensitivity of 84.62% and specificity of 62.50%. The success rate was 75% with a successful outcome in 78 hips. In view of these results, Graf type D, 3, and 4 dislocated hips can be successfully treated with Tubingen splints. PMID- 30483826 TI - [Muscle-tendon tears]. PMID- 30483825 TI - [Surgical treatment of chronic pectoralis major rupture]. AB - OBJECTIVE: Reconstruction of the chronic pectoralis major rupture with reconstruction of the anatomy and the original initial length of the muscle tendon unit as well as the full strength. INDICATIONS: Basically all chronic tears of the pectoralis major, causing discomfort. CONTRAINDICATIONS: Infections and tumors in the operation area. SURGICAL TECHNIQUE: Skin incision medial to the anterior axillary line about 6 cm long in the split lines of the skin. Locate and sharply mobilize the muscle stump. Preparation of the crest of the greater tubercle and positioning 2-4 JuggerKnots(r) (Zimmer Biomet, Warsaw, IN, USA). In adduction and internal rotation, reinsert the muscle. In case of chronic tears possibly interposition or augmentation of a tendon auto- or allograft. POSTOPERATIVE MANAGEMENT: Immobilization in a sling for 6 weeks without mobilization. From week 7, no-load mobilization. Weight load building from week 13. RESULTS: In a prospective study, 25 patients with chronic pectoralis major tears were reconstructed with 18 allografts and 7 autografts. According to Bak et al. the clinical outcome was good and very good in 92% of cases, but the complication rate was high at 24%. The secondary reconstruction of the chronic tear shows good and very good results even after years. PMID- 30483828 TI - [Report from the 12th Congress of the European Laryngological Society : London, 16-19 May 2018]. PMID- 30483827 TI - Diltiazem used as a tacrolimus-sparing agent for treatment of pediatric patients with refractory nephrotic syndrome: a case report and retrospective analysis. PMID- 30483829 TI - Attentional cost in additional visual feedback protocols in healthy young subjects. AB - Additional visual feedback (VFB) is a technique allowing improved postural stability in young healthy individuals despite an increased muscular activity, the two trends being assessed through center-of-gravity (CGv) and differences between CGv and center-of-pressure (CP) movements (CP-CGv), respectively. These two opposing effects are likely explained by the respective contribution of automatic and voluntary controls and in turn the neural circuits involved. To specify these specific contributions, a dual-task protocol was set up, consisting in adding to VFB a navigation task performed at the maximum cognitive capacities of the subjects who were evaluated beforehand. Overall, the protocol comprises six conditions: three visual tasks (eyes open without VFB, VFBBW based on body weight distribution, VFBCP based on CP displacements) associated with or without a cognitive task. Variances of CP-CGv and CGv movements, along the mediolateral (ML) and anteroposterior (AP) axes, and parameters from fractional Brownian motion modeling (transition point coordinates and scaling regimes to assess the level of deterministic or stochastic activity) were used to assess the postural behaviors. The results show that during VFBCP, the dual tasks protocol infers a decreased contribution of deterministic activity in CP-CGv movements, inducing decreased variances, and alters the correction of the CGv over the longest Deltat but nonetheless without changing CGv variances. Disturbing the subject's attention during the VFBBW condition induces decreased CP-CGv and CGv movements along the ML and AP axes, respectively. These data demonstrate the high level of attention induced by VFB protocols. If the tonic postural activity, expressed through CP-CGv movements, decreases whatever VFB condition along both the ML and AP axes, the effects on CGv movement appear to be mostly related to the additional information (BW or CP) provided. Overall, if too much voluntary control in upright stance maintenance is detrimental for the magnitudes of the CP CGv movements, it appears beneficial for those of the CGv movements. By emphasizing the role of automatic and voluntary controls in VFB protocols, these insights document the neural circuits involved in such protocols and specify their conditions of use. PMID- 30483830 TI - Where is my mind? Examining mind-wandering and vigilance performance. AB - Vigilance is the ability to sustain attention to information for prolonged periods of time, particularly in environments where critical signals may be rare. Recent research in the domain of mind-wandering has suggested that processes associated with mind-wandering may underpin the typical decline in vigilance task performance. Current methods for measuring mind-wandering either disrupt vigils by asking probe questions throughout the task, or, require observers to reflect on how much mind-wandering occurred during the task upon conclusion of the vigil. Across three experimental studies, we treat mind-wandering as an individual difference, which was measured pre- and post-vigil. We argue this technique is a more holistic representation of mind-wandering and is less intrusive than probe measures, which serve to disrupt the vigil. The results of our first experiment challenge previous results in the literature: higher rates of mind-wandering were associated with improved correct detection performance. Interestingly, the second experiment suggests that increases in mind-wandering were not linked to vigilance performance deficits. However, significant differences in global workload emerged in the second experiment, implying individuals low in mind-wandering report greater workload. In a third experiment, wherein we manipulated event rate, mind wandering typology had no significant effect on vigilance performance. We conclude with a discussion of the relevance of individual differences in mind wandering in vigilance research considering the present findings. PMID- 30483831 TI - The correlation of crystalline and elemental composition of urinary stones with a history of bacterial infections: TXRF, XRPD and PCR-DGGE studies. AB - The aim of this study was to analyze the correlation between past bacterial infections and the type and chemical composition of urinary stones experienced by human patients. Bacteria have been recognized to contribute to urinary stones; however, the role of uropathogens in the development of specific stones has not been extensively investigated. The detection of past bacterial infection (eleven different bacterial species) in urinary stones from 83 patients was made on a DNA level using polymerase chain reaction (PCR) and denaturing gradient gel electrophoresis (DGGE) and correlated with the chemical composition of urinary stones measured using X-ray powder diffraction (XPRD) technique and their elemental composition by total reflection X-ray fluorescence (TXRF). In this study, two scenarios of urinary stones formation mediated by Proteus sp. or Escherichia coli are presented. The first one is associated with Proteus spp. which dominated in 84% of infectious urinary stones and is strongly correlated with struvite and calcium phosphate, in whose matrix additionally strontium, phosphorus, potassium, nickel and zinc are detected. The formation of these stones is closely correlated with urease activity. The second scenario for urinary stone mineralization is associated with E. coli identified in weddellite stones, in which matrix iron was detected. In conclusion, the statistical correlations of bacterial infections with crystalline and elemental composition showed that in mixed bacterial infections, one scenario dominated and excluded the second one. PMID- 30483833 TI - Effect of menthol on nicotine intake and relapse vulnerability in a rat model of concurrent intravenous menthol/nicotine self-administration. AB - RATIONALE: Epidemiological data suggest that menthol may increase vulnerability to cigarette/nicotine use and relapse. While menthol's sensory properties are often attributed as the underlying cause of the enhanced vulnerability, an alternative possibility is that they are mediated via pharmacological interactions with nicotine. OBJECTIVE: This study addressed the possibility that menthol enhances nicotine intake and relapse vulnerability via pharmacological interactions with nicotine using a concurrent intravenous menthol/nicotine self administration procedure. METHODS: Following acquisition, adolescent rats were given 23-h/day access to nicotine (0.01 mg/kg/infusion), nicotine plus menthol (0.16, 0.32, or 0.64 mg/kg/infusion), or menthol alone (0.16, 0.32, 0.64 mg/kg/infusion) for a total of 10 days. Nicotine-seeking was assessed using an extinction/cue-induced reinstatement procedure following 10 days of forced abstinence. We also assessed the effect of menthol (0.32 mg/kg/infusion) on progressive ratio responding for nicotine (0.01 mg/kg/infusion). RESULTS: Menthol decreased PR responding for nicotine but did not affect self-administration under extended access conditions. The low dose of menthol tended to decrease subsequent extinction responding, and was not different from menthol alone, whereas the high dose decreased reinstatement responding. Although not significant, the highest levels of extinction responding were observed in a minority of rats in the moderate and high menthol-nicotine groups; rats in these groups also took longer to extinguish. CONCLUSIONS: Taken together, these results demonstrate that pharmacological interactions of menthol with nicotine reduce, rather than increase, nicotine's reinforcing effects and some measures of relapse vulnerability. Importantly, however, moderate and high menthol doses may increase some aspects of relapse vulnerability in a minority of individuals. PMID- 30483832 TI - Lateral retinacular release is not recommended in association to MPFL reconstruction in recurrent patellar dislocation. AB - PURPOSE: Reconstruction of the medial patellofemoral ligament (MPFL) has become the gold standard for the treatment of the recurrent patellar dislocation (RPD). Lateral retinacular release can be performed in association with MPFL reconstruction, but the effect on outcomes is not clear. To evaluate the effect of lateral release on outcomes following MPFL reconstruction is the aim of this study. It is hypothesized that isolated MPFL reconstruction was not inferior to MPFL reconstruction and lateral retinacular release in terms of IKDC subjective score and patellar tilt (PT). METHODS: Patients between ages 18 and 45 scheduled to undergo MPFL reconstruction without an associated bony procedure (tibial tubercle osteotomy or trochleoplasty) were randomized to isolated MPFL reconstruction or MPFL reconstruction (no LRR group) and arthroscopic LRR (LRR group). Evaluation criteria were subjective IKDC score as the primary outcome and PT evaluated with a CT-scan. PT was evaluated with the quadriceps relaxed (PTQR) and contracted (PTQC). RESULTS: Of 43 patients included in the trial, 7 were lost of follow-up, 3 were not able to complete evaluation because of medical reasons, and 33 patients were evaluated with a minimum of 12 months and a median follow-up of 24 (12-60) months. The average subjective IKDC score was at 86 +/- 20 (29-94) in the LRR group and 82 +/- 15 (39-95) in the no LRR group (p = 0.45). The PTQR was at 22 degrees +/- 7 degrees (13-37) in the LRR group and 21 +/- 10 (4-37) in the no LRR group (n.s.). The PTQC was at 27 degrees +/- 9 degrees (12-40) in the LRR group and 25 +/- 12 (5-45) in the no LRR group (n.s.). No complications were noted in either group. CONCLUSIONS: No significant differences were found in subjective IKDC score or patellar tilt based on the addition of an arthroscopic LRR to an MPFL reconstruction in patients with RPD not undergoing associated bony procedures. There is no indication to a systematic lateral retinacular release in association with MPFL reconstruction in the treatment of RPD. LEVEL OF EVIDENCE: II. PMID- 30483835 TI - High-flow nasal cannula flow rate in young infants with severe viral bronchiolitis: the question is still open. PMID- 30483834 TI - Tumor-infiltrating immune cell subpopulations and programmed death ligand 1 (PD L1) expression associated with clinicopathological and prognostic parameters in ependymoma. AB - Ependymomas are biologically and clinically heterogeneous tumors of the central nervous system that have variable clinical outcomes. The status of the tumor immune microenvironment in ependymoma remains unclear. Immune cell subsets and programmed death ligand 1 (PD-L1) expression were measured in 178 classical ependymoma cases by immunohistochemistry using monoclonal antibodies that recognized tumor-infiltrating lymphocyte subsets (TILs; CD3, CD4, CD8, FOXP3, and CD20), tumor-associated macrophages (TAMs; CD68, CD163, AIF1), indoleamine 2,3 dioxygenase (IDO)+ cells and PD-L1-expressing tumor cells. Increases in CD3+ and CD8+ cell numbers were associated with a prolonged PFS. In contrast, increased numbers of FOXP3+ and CD68+ cells and a ratio of CD163/AIF1+ cells were significantly associated with a shorter PFS. An increase in the IDO+ cell number was associated with a significantly longer PFS. To consider the quantities of TILs, TAMs, and IDO+ cells together, the cases were clustered into 2 immune cell subgroups using a k-means clustering analysis. Immune cell subgroup A, which was defined by high CD3+, low CD68+ and high IDO+ cell counts, predicted a favorable PFS compared to subgroup B by univariate and multivariate analyses. We found six ependymoma cases expressing PD-L1. All these cases were supratentorial ependymoma, RELA fusion-positive (ST-RELA). PD-L1 expression showed no prognostic significance. This study showed that the analysis of tumor-infiltrating immune cells could aid in predicting the prognosis of ependymoma patients and in determining therapeutic strategies to target the tumor microenvironment. PD-L1 expression in the ST-RELA subgroup suggests that this marker has a potential added value for future immunotherapy treatments. PMID- 30483836 TI - Prediction of optimal outcomes in organ transplantation. PMID- 30483837 TI - Persistence of piperacillin concentrations after treatment discontinuation: in cauda venenum? PMID- 30483838 TI - Allelopathic Effects on Microcystis aeruginosa and Allelochemical Identification in the Cuture Solutions of Typical Artificial Floating-Bed Plants. AB - Cyperus alternifolius (C. alternifolius) and Canna generalis (C. generalis) are widely used as artificial floating-bed (AFB) plants for water pollution control. This study evaluated the release of anti-cyanobacterial allelochemicals from both plants in AFB systems. A series of cyanobacterial assays using pure culture solutions and extracts of culture solutions of C. alternifolius and C. generalis demonstrated allelopathic growth inhibition of a cyanobacterium M. aeruginosa. After 45 days of incubation by the culture solutions, both final inhibitory rates of M. aeruginosa were more than 99.6% compared with that of the control groups. GC/MS analyses indicated the presence of a total of 15 kinds of compounds, including fatty acids and phenolic compounds, in both plants' culture solutions, which are are anti-cyanobacterial. These findings provide a basis to apply artificial floating-bed plants for cyanobacterial inhibition using allelopathic effects. PMID- 30483839 TI - Bacterial Communities in Areas of Oil and Methane Seeps in Pelagic of Lake Baikal. AB - We have assessed the diversity of bacteria near oil-methane (area I) and methane (area II) seeps in the pelagic zone of Lake Baikal using massive parallel sequencing of 16S rRNA, pmoA, and mxaF gene fragments amplified from total DNA. At depths from the surface to 100 m, sequences belonging to Cyanobacteria dominated. In the communities to a depth of 200 m of the studied areas, Proteobacteria dominated the deeper layers of the water column. Alphaproteobacteria sequences were predominant in the community near the oil methane seep, while the community near the methane seep was characterized by the prevalence of Alpha- and Gammaproteobacteria. Among representatives of these classes, type I methanotrophs prevailed in the 16S rRNA gene libraries from the near-bottom area, and type II methanotrophs were detected in minor quantities at different depths. In the analysis of the libraries of the pmoA and mxaF functional genes, we observed the different taxonomic composition of methanotrophic bacteria in the surface and deep layers of the water column. All pmoA sequences from area I were type II methanotrophs and were detected at a depth of 300 m, while sequences of type I methanotrophs were the most abundant in deep layers of the water column of area II. All mxaF gene sequences belonged to Methylobacterium representatives. Based on comparative analyses of 16S rRNA, pmoA, and mxaF gene fragment libraries, we suggest that there must be a wider spectrum of functional genes facilitating methane oxidation that were not detected with the primers used. PMID- 30483840 TI - Exploring sex differences in human health risk assessment for PFNA and PFDA using a PBPK model. AB - Perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA), which are classified as perfluoroalkyl and polyfluoroalkyl substances (PFASs), have been widely used in industrial applications as a surface protectant. PFASs have been detected in wildlife and in humans around the globe. The purposes of this study are to develop and validate a physiologically based pharmacokinetic (PBPK) model for detecting PFNA and PFDA in male and female rats, and to apply the model to a human health risk assessment regarding the sex difference. A PBPK model of PFNA and PFDA was established based on an in vivo study in male and female rats. Analytes in biological samples (plasma, nine tissues, urine, and feces) were determined by ultra-liquid chromatography coupled tandem mass spectrometry (UPLC MS/MS) method. PFNA and PFDA showed a gender differences in the elimination half life and volume of distribution. The tissue-plasma partition coefficients were the highest in the liver in both male and female rats. The predicted rat plasma and urine concentrations simulated and fitted were in good agreement with the observed values. The PBPK models of PFNA and PFDA in male and female rats were then extrapolated to a human PBPK model based on human physiological parameters. The external doses were calculated at 3.35 ng/kg/day (male) and 17.0 ng/kg/day (female) for PFNA and 0.530 ng/kg/day (male) and 0.661 ng/kg/day (female) for PFDA. Human risk assessment was estimated using Korean biomonitoring values considering the gender differences. This study provides valuable insight into human health risk assessment regarding PFNA and PFDA exposure. PMID- 30483841 TI - Roseovarius ponticola sp. nov., a novel lipolytic bacterium of the family Rhodobacteraceae isolated from seawater. AB - A lipolytic, Gram-negative, aerobic, non-motile and pleomorphic bacterial strain, designated W-SW3T, was isolated from seawater around Wando, an island of South Korea, and its taxonomic position was determined using a polyphasic approach. Its optimal growth occurred at 30 degrees C, pH 7.0-8.0 and 2.0-4.0% (w/v) NaCl. Neighbour-joining phylogenetic tree of 16S rRNA gene sequences showed that strain W-SW3T belonged to the genus Roseovarius of the family Rhodobacteraceae, by showing the highest 16S rRNA gene sequence similarity value (97.3%) to the type strain of Roseovarius nanhaiticus. Strain W-SW3T exhibited 16S rRNA gene sequence similarities of 93.2-95.6% to the type strains of the other Roseovarius species. Ubiquinone-10 was found as the predominant ubiquinone and C18:1 omega7c and C16:0 were found as the major fatty acids. Phosphatidylcholine, phosphatidylglycerol, diphosphatidylglycerol, one unidentified lipid and one unidentified aminolipid were major polar lipids detected. The DNA G + C content of strain W-SW3T was 63.9 mol%. Mean DNA-DNA relatedness values of strain W-SW3T with the type strains of R. nanhaiticus and R. antarcticus were 18 and 9%, respectively. The phenotypic properties, together with the phylogenetic and genetic data, made it possible strain W-SW3T to be separated from other recognized species of the genus Roseovarius. On the basis of the data presented, strain W-SW3T represents a novel species of the genus Roseovarius, for which the name Roseovarius ponticola sp. nov. is proposed. The type strain is W-SW3T (= KCTC 62424T = KACC 19615T = NBRC 113186T). PMID- 30483842 TI - Biochemical characterization of a Kunitz inhibitor from Inga edulis seeds with antifungal activity against Candida spp. AB - We describe the characterization of IETI, the first trypsin inhibitor purified from Inga edulis, a tree widely distributed in Brazil. Two-step chromatography was used to purify IETI, a protein composed of a single peptide chain of 19,685.10 Da. Amino-terminal sequencing revealed that IETI shows homology with the Kunitz family, as substantiated by its physical-chemical features, such as its thermal (up to 70 degrees C) and wide-range pH stability (from 2 to 10), and the value of its dissociation constant (6.2 nM). IETI contains a single reactive site for trypsin, maintained by a disulfide bridge; in the presence of DTT, its inhibitory activity was reduced in a time- and concentration-dependent manner. IETI presented activity against Candida ssp., including C. buinensis and C. tropicalis. IETI inhibitory activity triggered yeast membrane permeability, affecting cell viability, thus providing support for the use of IETI in further studies for the control of fungal infections. PMID- 30483843 TI - Magnetic resonance imaging performed before and after preoperative chemoradiotherapy in rectal cancer: predictive factors of recurrence and prognostic significance of MR-detected extramural venous invasion. AB - PURPOSE: To evaluate the role of magnetic resonance imaging (MRI) performed before and after neoadjuvant chemoradiotherapy (nCRT) in predicting risk of recurrence in rectal cancer and to investigate the prognostic significance of MR detected extramural venous invasion (mr-EMVI) and of its regression after nCRT. METHODS: During 2005-2016, 87 patients with rectal cancer underwent pre- and post nCRT MRI before surgery. Two radiologists independently reviewed MR examinations retrospectively, assessing T stage, nodal involvement, circumferential resection margin (CRM) status, and mr-EMVI. All four parameters assessed in pre- and post nCRT MRI were correlated with the risk of recurrence. Correlation with disease free survival (DFS) was investigated for significant predictive factors in pre nCRT MRI and for mr-EMVI and its possible regression in post-nCRT MRI. RESULTS: 15 of 87 patients developed recurrence, with a relapse-rate of 17.2%. Statistical analysis showed a significant correlation between CRM involvement and mr-EMVI assessed in pre-nCRT MRI and the risk of recurrence; 3 years-DFS in patients positive for these two parameters was significantly shorter compared with negatives. In post-nCRT MRI, all four parameters correlated significantly with recurrence: mr-EMVI affected significantly 3 years-DFS and its regression after nCRT correlated with a trend toward improvement of survival outcomes, although not statistically significant. CONCLUSIONS: CRM involvement and mr-EMVI assessed in pre-nCRT MRI should be considered early predictive factors of recurrence in rectal cancer. MRI performed after nCRT has a significant value in predicting risk of recurrence: mr-EMVI confirmed to be a poor prognosis predictor and its regression or persistence after nCRT could have influences on treatment and follow-up strategies. PMID- 30483844 TI - Abdominal and pelvic imaging findings associated with sex hormone abnormalities. AB - Hormones are substances that serve as chemical communication between cells. They are unique biological molecules that affect multiple organ systems and play a key role in maintaining homoeostasis. In this role, they are usually produced from a single organ and have defined target organs. However, hormones can affect non target organs as well. As such, biochemical and hormonal abnormalities can be associated with anatomic changes in multiple target as well as non-target organs. Hormone-related changes may take the form of an organ parenchymal abnormality, benign neoplasm, or even malignancy. Given the multifocal action of hormones, the observed imaging findings may be remote from the site of production, and may actually be multi-organ in nature. Anatomic findings related to hormone level abnormalities and/or laboratory biomarker changes may be identified with imaging. The purpose of this image-rich review is to sensitize radiologists to imaging findings in the abdomen and pelvis that may occur in the context of hormone abnormalities, focusing primarily on sex hormones and their influence on these organs. PMID- 30483845 TI - The "zebra spleen". PMID- 30483846 TI - Habitat-specificity and diversity of culturable cold-adapted yeasts of a cold based glacier in the Tianshan Mountains, northwestern China. AB - Asian cold-based glacier yeasts with respect to their abundance, distribution, and taxonomy, in contrast to other continental cryosphere areas, have been little investigated. The present study reports the diversity and phylogeny of culturable cold-adapted yeasts in six cold habitats of the Glacier No.1 in the Tianshan Mountains (northwestern China). Of the total 591 yeast isolates, 401 were identified as basidiomycetous yeasts represented by 41 species of 15 genera, while 190 ascomycetous yeast isolates were assigned to the 8 species of 7 genera. The most prevalent species was Candida akabanensis with a 19.8% frequency of occurrence, followed by Vishniacozyma victoriae (16.4%) and Diutina rugosa (9.98%), of which V. victoriae was the only yeast species common to all six glacial habitats. Variability on the component and abundance of yeast taxa among glacial habitats primarily displayed in four dominant yeast genera, namely Candida, Vishniacozyma, Filobasidium, and Naganishia. However, network analysis illustrated that most of 32 rare yeast populations were habitat-specific, implying that the low-abundance yeast population was more easily influenced by the local habitat conditions (species sorting). Based on indicator species analyses, the subglacial habitat was characterized by psychrotolerant and/or psychrophilic yeast taxa. PMID- 30483847 TI - Towards the biofilm characterization and regulation in biological wastewater treatment. AB - There is an increasing need for application of biofilm process in the upcycling of wastewater treatment plants all around the world in recent years, yet there are few literatures on summarizing wastewater biofilm during the life cycle. In particular, there is a vacancy on characterization at various stages of biofilm and its regulation. This review provided a whole look at biofilm formation and its development, accompanied by microbial physiology, ecology, and activity, where the initialization of biofilm formation and its characterization were stressed. The new progresses on biofilm physio-ecology analysis and methods on evaluating microbial activity were summarized, while it is worth mentioning that the concept of aging biofilm was also presented. Furthermore, regulations methods of biofilm were reviewed and future research trends on biofilm control were prospected, aiming at guiding biofilm control in biofilm-based wastewater treatment. PMID- 30483848 TI - Fracture Risk in Women with Dysglycaemia: Assessing Effects of Baseline and Time Varying Risk Factors. AB - Although individuals with diabetes appear to have a higher fracture risk compared to those without diabetes, fracture risk in impaired fasting glucose (IFG) has not been thoroughly explored. This study determined associations between glycaemia status and fracture risk. Women (n = 575, aged 50 + years) enrolled in the Geelong Osteoporosis Study, were followed from baseline (1993-1997), to date of first fracture, death or December 31, 2010, whichever occurred first (median 13.7 years, IQR 7.4-14.8). Hazard ratios (HRs) for any fracture (excluding fingers, toes, skull/face), as well as major osteoporotic fracture (MOF, clinical spine, hip, proximal humerus, wrist), in diabetes (n = 69), IFG (n = 250) and normoglycaemia (n = 256), were calculated using a Cox proportional hazards model. Normoglycaemia was set as the reference category. A Cox proportional hazards model with time-varying covariates was also used to assess change in baseline risk factors at the 10-year follow-up visit (2004-2008). During follow-up (6433 person-years), 162 women sustained any fracture and 104 had a MOF. Unadjusted fracture risk was higher in diabetes (HR 1.64; 95% CI 1.02-2.63) compared to normoglycaemia, but IFG and normoglycaemia had similar risk (HR 1.06; 95% CI 0.76 1.47). Age- and BMD-adjusted any-fracture risk in diabetes compared to normoglycaemia was greater (HR 1.59; 95% CI 0.98-2.58); IFG was similar to normoglycaemia (HR 1.01; 95% CI 0.72-1.41). For MOF, unadjusted and age- and BMD adjusted fracture risk in IFG was similar to normoglycaemia HR 1.02; 95% CI 0.74 1.40 and HR 0.95; 95% CI 0.69-1.32, respectively, but diabetes was higher compared to normoglycaemia (unadjusted HR 1.64; 95% CI 1.04-2.60; adjusted HR 1.57; 95% CI 0.98-2.51). In the time-varying model, there was no difference between IFG in either the unadjusted or adjusted models, for both any fracture and MOF (p > 0.05). For diabetes, there was a significant difference between normoglycaemia in the adjusted model for any fracture (p = 0.046), but not for MOF (p = 0.103). An increased risk of fracture for women with diabetes was observed after accounting for time-varying risk factors. There was no difference in fracture risk detected for women with IFG. PMID- 30483849 TI - Multiple vitamin deficiencies additively increase the risk of incident fractures in Japanese postmenopausal women. AB - : The associations of multiple vitamin deficiencies on incident fractures were uncertain, the relationships between serum vitamin markers and incident bone fractures were investigated in Japanese postmenopausal women. The number of deficiencies was additively associated with incident fracture after adjustment for possible confounding factors including the treatment of osteoporosis. INTRODUCTION: To evaluate the associations of multiple vitamin deficiencies on incident fractures, the relationships between serum vitamin markers and incident bone fractures were investigated in Japanese postmenopausal women. METHODS: This analysis used a subset of the ongoing cohort maintained by a primary care institution. Inclusion criteria of the present study were postmenopausal women aged >= 50 years, without vitamin supplementation and secondary osteoporosis. Baseline serum concentrations of 25-hydroxyvitamin D (25(OH)D), undercarboxylated osteocalcin (ucOC), and homocysteine (Hcy) were measured to assess vitamin D, vitamin K, and vitamin B, respectively. Since 25(OH) D positively relates to vitamin D, ucOC and Hcy negatively relate to vitamin K and vitamin B nutrients, respectively, the subjects with lower (25(OH)D) or higher (ucOC or Hcy) values than each median value was defined as subjects with the corresponding vitamin deficiency. Subjects were divided into four groups according to the number of deficiency: no deficiency, single deficiency, double deficiencies, and triple deficiencies. Relationships between the vitamin deficiencies and incident fractures were evaluated by Cox regression analysis. RESULTS: A total of 889 subjects were included in this analysis; their mean and SD age was 68.3 +/- 9.5 years, and the follow-up period was 6.3 +/- 5.1 years. The numbers of subjects in the four groups were 139 (15.6%), 304 (34.2%), 316 (35.5%), and 130 (14.6%) for the groups with no, single, double, and triple deficiencies, respectively. Incident fractures were observed in 264 subjects (29.7%) during the observation period. The number of deficiencies was significantly associated with incident fracture (hazard ratio 1.25, 95% confidence interval 1.04-1.50, P = 0.018) after adjustment for possible confounding factors including the treatment of osteoporosis. CONCLUSION: Accumulation of vitamin deficiencies was related to incident fractures. PMID- 30483850 TI - [Clavicular fractures : Diagnostics, management and treatment]. AB - Clavicular fractures account for approximately 6% of bony injuries of the shoulder girdle. Patients suffering from this type of injury show 2 peaks (at the 2nd and 8th decades of life) where the majority occur in young active patients during recreational and sports activities. Besides an accurate patient history with a focus on the trauma mechanism, the clinical and radiological investigations are the cornerstones of the diagnostics. Slightly displaced fractures in a pediatric population as well as non-displaced fractures in adults can be treated conservatively. In cases of shortening and/or displacement and high functional demands, operative treatment of clavicular fractures, stable fixation and the possibility of early mobilization and therapy can be achieved; however, the indications for the procedure also depend on other factors. Surgical stabilization can substantially reduce the danger of non-union, which is why it is becoming more important. PMID- 30483851 TI - Linked factors to access to sexual health checkups of female sex workers in the metropolitan region of Chile. AB - OBJECTIVES: To describe and compare the profile of female sex workers (FSWs) that access or do not access sexual health checkups (SHC). The research question was what are the factors linked to access to SHC for FSWs in the metropolitan region (RM) of Chile? METHODS: A cross-sectional study was conducted in the RM with FSWs over the age of 18. A sample of 370 FSWs was selected by using the time-location sampling method in closed venues and at street-level locations. A survey was applied, validated, and included clinical-epidemiological, behavioral and socio demographic variables. RESULTS: 38.6% (n = 140) of FSWs that answered the question never used SHC and 37.6% (n = 84) received checkups in a specialized health center for FSWs. FSWs with no SHC were younger, prone to have more group sex, preferably with occasional or no stable partner, and did not know where to get an HIV test. CONCLUSIONS: FSWs have had uncertain access to sexual health controls. FSWs with no SHC and young FSWs presented higher-risk behaviors. PMID- 30483852 TI - Reducing postoperative catheterisation after anterior colporrhaphy from 48 to 24 h: a randomised controlled trial. AB - INTRODUCTION AND HYPOTHESIS: There is a distinct lack of literature on postoperative management after anterior colporrhaphy (AC). Our traditional postoperative protocol consisted of 24 h of indwelling catheterisation followed by 24 h of self-intermittent catheterisation. We hypothesised that a new protocol consisting of only 24 h of indwelling catheterisation might produce better results without additional complications. METHODS: From April 2014 to July 2017, all candidates for AC were randomised to catheter removal 24 or 48 h after surgery. The primary outcome was the postoperative urinary retention (POUR) rate. Secondary outcomes included: asymptomatic bacteriuria (AB), urinary tract infection (UTI) and postoperative pain after 24 h. RESULTS: A total of 79 patients were recruited. Thirty-seven and 40 patients were randomised to follow the 48-h protocol and the 24-h protocol respectively. There were no significant differences in relation to the POUR rate: 3 patients (8.1%) vs 1 (2.5%) in the 48 h vs the 24-h group respectively (p = 0.346). The UTI rate was 2 (8.1%) vs 0 patients respectively (p = 0.139) and the postoperative AB rate was 3 (9.1%) vs 0 patients (p = 0.106). In the postoperative pain evaluation, the visual analogue scale score was significantly higher in the 48 h group (0.35 vs 0.13, p = 0.02). CONCLUSIONS: According to our results, reducing the catheterisation from 48 to 24 h after AC does not increase the risk of POUR and decreases the rate of UTI, AB and postoperative pain. This new postoperative management protocol of pelvic floor surgery would improve postoperative outcomes and shorten the stay in hospital. PMID- 30483853 TI - Evaluation of COLIA1-1997 G/T polymorphism as a related factor to genital prolapse. AB - INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse has a multifactorial etiology. There is increasing evidence that genetic factors greatly impact its development. This study aimed to evaluate the possible relation of the collagenous polymorphism -1997 G/T with genital prolapse in Brazilian women. METHODS: A cohort study of 180 women with stage 0 or I (group A) pelvic organ prolapse disorder and 112 women with stage III or IV (group B) was conducted. Blood DNA was isolated, and the -1997 G/T polymorphism was identified by amplifying a region of the COLIA1 gene starting prior to the protein's coding sequence. RESULTS: No significant difference in the prevalence of genotypes TG and TT was found between groups (p = 0.67); differences were not found even when patients were grouped by the presence of 0 or >= 1 polymorphic alleles (p = 0.46). Age and home birth were found to be independent risk factors for prolapse. CONCLUSIONS: Our study could not find any association between the -1997G/T polymorphism and genital prolapse in Brazilian women. PMID- 30483854 TI - Quantification of DEET and neonicotinoid pesticide biomarkers in human urine by online solid-phase extraction high-performance liquid chromatography-tandem mass spectrometry. AB - Neonicotinoid insecticides are widely used replacements for organophosphate and carbamate insecticides, but the extent of human exposure is largely unknown. On the other hand, based on urinary concentrations of DEET metabolites, human exposure to N,N-diethyl-m-toluamide (DEET) appears to be widespread. We developed a fast online solid-phase extraction high-performance liquid chromatography isotope dilution tandem mass spectrometry (HPLC-MS/MS) method to measure in 200 MUL of human urine the concentrations of six neonicotinoid biomarkers (acetamiprid, N-desmethyl-acetamiprid, clothianidin, imidacloprid, 5-hydroxy imidacloprid, thiacloprid), and two DEET biomarkers (3-diethyl-carbamoyl benzoic acid, 3-ethyl-carbamoyl benzoic acid). Limits of detection ranged from 0.01 to 0.1 MUg/L, depending on the biomarker. Accuracy ranged from 91 to 116% and precision ranged from 3.7 to 10 %RSD. The presented method can be used to increase our understanding of exposure to neonicotinoid insecticides and DEET, and to evaluate the potential health effects from such exposures. PMID- 30483855 TI - A novel fluorescent probe for ascorbic acid based on seed-mediated growth of silver nanoparticles quenching of carbon dots fluorescence. AB - A novel, economic, and eco-friendly method of detecting ascorbic acid (AA) with excellent sensitivity was developed. The method took advantage of the fluorescence of carbon quantum dots (CDs) decreasing as the AA concentration increased through interactions between AA and Ag(I) in the presence of silver nanoparticle (AgNP) seeds, producing more AgNPs and allowing fluorescence resonance energy transfer between the AgNPs and the CDs. The change in the fluorescence intensity when AA was added was proportional to the AA concentration over the range 0-9.0 MUM. The AA detection limit was 0.2 MUM. This approach is a new method for determining the concentration of AA. PMID- 30483856 TI - Luminescent nanomaterials for droplet tracking in a microfluidic trapping array. AB - The use of high-throughput multiplexed screening platforms has attracted significant interest in the field of on-site disease detection and diagnostics for their capability to simultaneously interrogate single-cell responses across different populations. However, many of the current approaches are limited by the spectral overlap between tracking materials (e.g., organic dyes) and commonly used fluorophores/biochemical stains, thus restraining their applications in multiplexed studies. This work demonstrates that the downconversion emission spectra offered by rare earth (RE)-doped beta-hexagonal NaYF4 nanoparticles (NPs) can be exploited to address this spectral overlap issue. Compared to organic dyes and other tracking materials where the excitation and emission is separated by tens of nanometers, RE elements have a large gap between excitation and emission which results in their spectral independence from the organic dyes. As a proof of concept, two differently doped NaYF4 NPs (europium: Eu3+, and terbium: Tb3+) were employed on a fluorescent microscopy-based droplet microfluidic trapping array to test their feasibility as spectrally independent droplet trackers. The luminescence tracking properties of Eu3+-doped (red emission) and Tb3+-doped (green emission) NPs were successfully characterized by co-encapsulating with genetically modified cancer cell lines expressing green or red fluorescent proteins (GFP and RFP) in addition to a mixed population of live and dead cells stained with ethidium homodimer. Detailed quantification of the luminescent and fluorescent signals was performed to confirm no overlap between each of the NPs and between NPs and cells. Thus, the spectral independence of Eu3+-doped and Tb3+ doped NPs with each other and with common fluorophores highlights the potential application of this novel technique in multiplexed systems, where many such luminescent NPs (other doped and co-doped NPs) can be used to simultaneously track different input conditions on the same platform. Graphical abstract ?. PMID- 30483857 TI - High-throughput detection of low abundance sialylated glycoproteins in human serum by TiO2 enrichment and targeted LC-MS/MS analysis: application to a prostate cancer sample set. AB - Glycopeptide enrichment can be a strategy to allow the detection of peptides belonging to low abundance proteins in complex matrixes such as blood serum or plasma. Though several glycopeptide enrichment protocols have shown excellent sensitivities in this respect, few reports have demonstrated the applicability of these methods to relatively large sample cohorts. In this work, a fast protocol based on TiO2 enrichment and highly sensitive mass spectrometric analysis by Selected Reaction Monitoring (SRM) has been applied to a cohort of serum samples from prostate cancer and benign prostatic hyperplasia patients in order to detect low abundance proteins in a single LC-MS/MS analysis in nanoscale format, without immunodepletion or peptide fractionation. A peptide library of over 700 formerly N-glycosylated peptides was created by data dependent analysis. Then, 16 medium to low abundance proteins were selected for detection by single injection LC MS/MS based on selected-reaction monitoring. Results demonstrated the consistent detection of the low-level proteins under investigation. Following label-free quantification, four proteins (Adipocyte plasma membrane-associated protein, Periostin, Cathepsin D and Lysosome-associated membrane glycoprotein 2) were found significantly increased in prostate cancer sera compared to the control group. Graphical abstract ?. PMID- 30483858 TI - Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989-2013: a multicentre prospective registration study. AB - AIMS/HYPOTHESIS: Against a background of a near-universally increasing incidence of childhood type 1 diabetes, recent reports from some countries suggest a slowing in this increase. Occasional reports also describe cyclical variations in incidence, with periodicities of between 4 and 6 years. METHODS: Age/sex standardised incidence rates for the 0- to 14-year-old age group are reported for 26 European centres (representing 22 countries) that have registered newly diagnosed individuals in geographically defined regions for up to 25 years during the period 1989-2013. Poisson regression was used to estimate rates of increase and test for cyclical patterns. Joinpoint regression software was used to fit segmented log-linear relationships to incidence trends. RESULTS: Significant increases in incidence were noted in all but two small centres, with a maximum rate of increase of 6.6% per annum in a Polish centre. Several centres in high incidence countries showed reducing rates of increase in more recent years. Despite this, a pooled analysis across all centres revealed a 3.4% (95% CI 2.8%, 3.9%) per annum increase in incidence rate, although there was some suggestion of a reduced rate of increase in the 2004-2008 period. Rates of increase were similar in boys and girls in the 0- to 4-year-old age group (3.7% and 3.7% per annum, respectively) and in the 5- to 9-year-old age group (3.4% and 3.7% per annum, respectively), but were higher in boys than girls in the 10- to 14-year old age group (3.3% and 2.6% per annum, respectively). Significant 4 year periodicity was detected in four centres, with three centres showing that the most recent peak in fitted rates occurred in 2012. CONCLUSIONS/INTERPRETATION: Despite reductions in the rate of increase in some high-risk countries, the pooled estimate across centres continues to show a 3.4% increase per annum in incidence rate, suggesting a doubling in incidence rate within approximately 20 years in Europe. Although four centres showed support for a cyclical pattern of incidence with a 4 year periodicity, no plausible explanation for this can be given. PMID- 30483859 TI - Maternal metabolites during pregnancy are associated with newborn outcomes and hyperinsulinaemia across ancestries. AB - AIMS/HYPOTHESIS: We aimed to determine the association of maternal metabolites with newborn adiposity and hyperinsulinaemia in a multi-ethnic cohort of mother newborn dyads. METHODS: Targeted and non-targeted metabolomics assays were performed on fasting and 1 h serum samples from a total of 1600 mothers in four ancestry groups (Northern European, Afro-Caribbean, Mexican American and Thai) who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, underwent an OGTT at ~28 weeks gestation and whose newborns had anthropometric measurements at birth. RESULTS: In this observational study, meta-analyses demonstrated significant associations of maternal fasting and 1 h metabolites with birthweight, cord C-peptide and/or sum of skinfolds across ancestry groups. In particular, maternal fasting triacylglycerols were associated with newborn sum of skinfolds. At 1 h, several amino acids, fatty acids and lipid metabolites were associated with one or more newborn outcomes. Network analyses revealed clusters of fasting acylcarnitines, amino acids, lipids and fatty acid metabolites associated with cord C-peptide and sum of skinfolds, with the addition of branched-chain and aromatic amino acids at 1 h. CONCLUSIONS/INTERPRETATION: The maternal metabolome during pregnancy is associated with newborn outcomes. Maternal levels of amino acids, acylcarnitines, lipids and fatty acids and their metabolites during pregnancy relate to fetal growth, adiposity and cord C peptide, independent of maternal BMI and blood glucose levels. PMID- 30483860 TI - CCR2 and CCR5 promote diclofenac-induced hepatotoxicity in mice. AB - Liver injury, one of the major side effects of diclofenac (DIC), plagues thousands of patients who treated with it. Although involvements of metabolic factors, oxidative stress, and mitochondrial injury have been characterized, the exact immunomolecular mechanism of the hepatotoxicity of DIC still remains ambiguous. In this study, we investigated the role of chemokine receptors CCR2 and CCR5 in this progression. Ccr2, Ccr5, and Tnfr1/2-deficient mice, as well as wild type littermates, were administrated DIC or vehicle for 24 h, receptively. Hepatic expression of CCR2, CCR5, and their ligands were upregulated after DIC treatment. DIC-induced liver injury was augmented in Ccr2+/+ mice than Ccr2-/- mice, a similar phenotype was observed in Ccr5-deficient mice. In addition, antagonists of CCR2 or CCR5 protected liver damage caused by diclofenac. Besides, the number of neutrophils present in the liver was gradually increased from 0 to 12 h after drug administration. However, the recruitment of neutrophils was dramatically lessened after blocking CCR2 or CCR5 signaling. Furthermore, TNF alpha level in the liver was decreased in Ccr2-/- mice compared with Ccr2+/+ mice. Intriguingly, in line with this, TNF receptor 1 and 2 double knockout mice showed markedly attenuated hepatotoxicity of DIC. These suggested that CCR2 and CCR5 mediated hepatotoxicity induced by diclofenac, TNF-alpha was responsible, at least in part, for it, and the pharmacological inhibition of CCR2 or CCR5 might serve as a novel therapeutic approach for DIC-induced hepatotoxicity. PMID- 30483861 TI - Gadolinium chloride attenuates acetic acid-evoked colitis in mice by reducing neutrophil infiltration and pro-oxidative enzyme activity. AB - This study investigated the potential of gadolinium chloride (GdCl3), an inhibitor of kupffer cells on the myeloperoxidase (MPO) function, both in vivo on colon inflammation model and in vitro on thioglycollate-elicited peritoneal neutrophils. Colon inflammation was induced in mice (n = 7) by 4% acetic acid (AA) enema. GdCl3 (10 mg/kg) treatment was given 24 h before AA challenge. Clinical changes during the protocol were scored. Colons were segmented into distal and proximal parts for histological and biochemical assessment. Furthermore, myeloperoxidase (MPO) enzymes were extracted and analyzed by western blot. Short-term GdCl3 treatment inhibited dose-dependently superoxide anion (O2. ), alkaline phosphatase (ALP), and MPO release and promoted neutrophil apoptosis. In vivo, low-dose GdCl3 improved colitis scores and inhibited acute phagocyte recruitment and colon damage within the mucosa as revealed by the decrease in MPO, nitric oxide (NO), and malondialdehyde (MDA) levels. At the same time, GdCl3 restored catalase (CAT), superoxide dismutase (SOD) activities, and reduced glutathione (GSH) levels, thus reversing the MDA/GSH ratio in both distal and proximal colons. Compared to proximal, distal colon was more altered and displayed higher pathological manifestations. Lastly, the induction of apoptosis and regulation of the major nitrosative and oxidative functions of neutrophils by GdCl3 suggests its consideration as a beneficial tool in attenuating colon inflammation. PMID- 30483862 TI - Retrospective evaluation of bone marrow cell morphology in a cohort of patients with isolated idic(20q-) karyotypic abnormalities. AB - Isochromosome 20q- (i(20q-)), as a rare reproducible chromosomal anomaly formed on the basis of 20q-, has not been commonly reported. Due to the rarity of this karyotypic anomaly, the bone marrow morphological characteristics of the patients with i(20q-) have not been clarified until now. In this study, the bone marrow cell morphology from MDS patients with isolated i(20q-), isolated 20q-, and normal karyotype was retrospectively compared and statistically analyzed. The results indicated that the isolated i(20q-) was mostly detected in MDS-MLD patients. The frequency and proportion dysplasia of cytoplasmic vacuolization in erythoid cells and small or unusually large size in myeloid cells of isolated i(20q-) MDS patients were significantly higher than those of normal karyotype MDS patients respectively (P < 0.05); the frequency and proportion dysplasia of decreased granules/agranularity in myeloid cells of isolated i(20q-) MDS patients were higher than those of isolated 20q- MDS patients (P < 0.05). The incidence of some specific morphological manifestations, such as deeply lobulated and hyperlobulated megakaryocytes and hypogranular and vacuolized eosinophils, may be an important morphological implication for the anomaly of isolated i(20q-). These morphological features of dysplasia may be helpful in distinguishing MDS with isolated i(20q-) from those with isolated 20q- and normal karyotype. PMID- 30483863 TI - Interaction of host and Staphylococcus aureus protease-system regulates virulence and pathogenicity. AB - Staphylococcus aureus causes various health care- and community-associated infections as well as certain chronic TH2 driven inflammatory diseases. It is a potent pathogen with serious virulence and associated high morbidity. Severe pathogenicity is accredited to the S. aureus secreted virulence factors such as proteases and host protease modulators. These virulence factors promote adhesion and invasion of bacteria through damage of tight junction barrier and keratinocytes. They inhibit activation and transmigration of various immune cells such as neutrophils (and neutrophil proteases) to evade opsono-phagocytosis and intracellular bacterial killing. Additionally, they protect the bacteria from extracellular killing by disrupting integrity of extracellular matrix. Platelet activation and agglutination is also impaired by these factors. They also block the classical as well as alternative pathways of complement activation and assist in spread of infection through blood and tissue. As these factors are exquisite factors of S. aureus mediated disease development, we have focused on review of diversification of various protease-system associated virulence factors, their structural building, diverse role in disease development and available therapeutic counter measures. This review summarises the role of protease associated virulence factors during invasion and progression of disease. PMID- 30483864 TI - The effect of pasireotide on intestinal anastomotic healing with and without whole-body irradiation in a rat model. AB - OBJECTIVE: To examine pasireotide's effect on intestinal anastomotic healing under physiological conditions and following preoperative whole-body irradiation. MATERIAL AND METHODS: Forty-five male Wistar rats received an ileoileal end-to end anastomosis. Group 1 (Co, n = 9) served as control. Group 2 (SOM, n = 10) received pasireotide (60 mg/kg) 6 days preoperatively. Group 3 (R-Co, n = 13) was subjected to 8 Gy whole-body irradiation 4 days preoperatively. Finally, group 4 (R-SOM, n = 13) received pasireotide 6 days preoperatively and whole-body irradiation 4 days preoperatively. On postoperative day 4, anastomotic bursting pressure, histology, IGF-1 staining, and collagen density were examined. RESULTS: Mortality was higher in irradiated animals (30.8% vs. 5.3%, p = 0.021), and anastomotic bursting pressure was significantly lower (median, R-Co = 83 mmHg; R SOM = 101 mmHg; Co = 149.5 mmHg; SOM = 169 mmHg). Inflammation measured by leukocyte infiltration following irradiation was reduced (p = 0.023), and less collagen was observed, though this was not statistically significant. Bursting pressure did not significantly differ between Co and SOM and between R-Co and R SOM animals respectively. Semi-quantitative scoring of IGF-1, fibroblast bridging, or collagen density did not reveal significant differences among the groups. CONCLUSION: Whole-body irradiation decreases the quality of intestinal anastomotic wound healing and increases mortality. Pasireotide does not significantly lessen this detrimental effect. PMID- 30483865 TI - [Circulating tumor cells in pancreatic cancer : Results of morphological and molecular analyses and comparisons with the primary tumor]. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a disease with a poor prognosis. PDAC shows characteristic mutations within codon 12/13. Circulating tumor cells (CTC) detected in blood samples of patients with cancer are hypothesized as the means of systemic tumor spread. But less is known about morphological/molecular characteristics or the pathophysiological meaning of PDAC CTC. OBJECTIVES: The aim of the study was a cytomorphological and genetic analysis of CTC from patients with PDAC followed by the correlation of the results with those of the corresponding tumor in the pancreas. MATERIAL AND METHODS: Blood samples of 58 patients with PDAC and 10 "normal" control donors were processed through a size-based CTC isolation. KRAS-mutation analyses were performed for CTC and the primary tumor and the results were compared. Furthermore, their potential as a prognostic marker was evaluated. RESULTS: In patients with different UICC stages CTC were detected, but not in normal control patients. There was a trend for a worse median overall survival (OS) for patients with >3 CTC/ml. Patients with a KRASG12V mutation showed a trend for a better median OS compared to those with other KRAS mutations (10 months) or even without KRAS mutation. Fifty-eight percent of the patients presented concordant KRAS mutations in the primary tumor and corresponding CTC, while 42% were discordant. The median OS for both groups was similar. CONCLUSIONS: Detection and characterization of CTC (for example by KRAS mutation analysis) may be useful for prognosis. Furthermore, it expands our knowledge of tumor biology and may detect possible tumor heterogeneity regarding the mutation profile of some cancer types. PMID- 30483866 TI - Trifurcated external carotid artery and complete gamma-loop of its maxillary branch. AB - The external carotid artery (ECA) normally bifurcates terminally with the superficial temporal artery (STA) and the maxillary artery (MA). From the horizontally coursing, mandibular segment of the MA leaves the middle meningeal artery (MMA). We hereby report a previously unknown anatomic possibility, incidentally found during an angio-CT scan in an adult female patient. Unilaterally, the ECA was terminally trifurcated, sending off the MA, STA, and MMA. On that side, the mandibular segment of the MA had a gamma-loop and the contralateral one had a U-loop; both these loops were inferior to the lateral pterygoid muscle, closely approaching the respective lingula of the mandible. These findings are relevant during surgery of the parotid gland and infratemporal fossa, approaches of the MMA, and inferior alveolar nerve blocks. The modified origin of the MMA could be explained by an altered development of the primitive stapedial artery. PMID- 30483867 TI - Examining changes in acromial morphology in relation to spurs at the anterior edge of acromion. AB - BACKGROUND: Although acromial morphology is classified as flat, curved, and hooked, whether the morphology is primary or acquired is debated. There have been no investigations on the effect of acromial spurs on acromial morphology. This study therefore aimed to evaluate acromial morphology in relation to spur formation at the anterior edge of the acromion. MATERIALS AND METHODS: Acromial morphology was investigated in 40 scapulae taken from 20 cadavers (10 male and 10 female), with a median age of 82 years (range 62-97 years). Ink prints of the anteroposterior aspect of the acromion were used to evaluate acromial slope angle and curvature height in relation to spur incidence, length, and shape at the anterior edge of the acromion. RESULTS: Differences were observed in acromial morphology and acromial curvature in relation to acromial spurs (incidence, size, and shape). A hooked acromion was observed as a primary structure in 25% of specimens, which increased to 43% when acromial spurs were involved. No differences were observed in relation to sex or side, while a significant correlation was observed between acromial curvature and the age of the specimens. CONCLUSION: Acromial spurs increase acromial curvature and therefore change acromion morphology. Nevertheless, it is concluded that a hooked acromion occurs as a primary formed structure. LEVEL OF EVIDENCE: Basic science study, anatomy, cadaver dissection. PMID- 30483868 TI - Progressive programmed cell death inwards across the anther wall in male sterile flowers of the gynodioecious plant Plantago lanceolata. AB - MAIN CONCLUSION: A cell death signal is perceived and responded to by epidermal cells first before being conveyed inwards across the anther wall in male sterile Plantago lanceolata flowers. In gynodioecious plants, floral phenotype is determined by an interplay between cytoplasmic male sterility (CMS)-promoting factors and fertility-restoring genes segregating in the nuclear background. Plantago lanceolata exhibits at least four different sterilizing cytoplasms. MS1, a "brown-anther" male sterile phenotype, segregates with a CMSI cytoplasm and a non-restoring nuclear background in P. lanceolata populations. The aim of this study was to investigate the cytology of early anther development in segregating hermaphrodite and male sterile flowers sharing the same CMSI cytoplasm, and to determine if the sterility phenotype correlates with any changes to the normal pattern of programmed cell death (PCD) that occurs during anther development. Cytology shows cellular abnormalities in all four anther wall layers (epidermis, endothecium, middle layer and tapetum), the persistence and enlargement of middle layer and tapetal cells, and the failure of microspore mother cells to complete meiosis in male sterile anthers. In these anthers, apoptotic-PCD occurs earlier than in fertile anthers and is detected in all four cell layers of the anther wall before the middle layer and tapetal cells become enlarged. PCD is separated spatially and temporally within the anther wall, occurring first in epidermal cells before extending radially to cells in the inner anther wall layers. This is the first evidence of a cell death signal being perceived and responded to by epidermal cells first before being conveyed inwards across the anther wall in male sterile plants. PMID- 30483869 TI - Environmental factors influencing flight activity of forensically important female blow flies in Central Europe. AB - In forensic entomology, evaluation of a possible delay between a person's death and insect colonization is crucial. We monitored the seasonal flight activities of the most abundant blow flies in an urban habitat in Frankfurt/Germany based on 152 sampling days between April and October 2017. Thirty-six thousand female specimens of 12 necrophagous taxa were sampled as a possible groundwork for establishing a prediction tool for the activity of certain forensically relevant taxa. The most abundant taxon was Lucilia sericata (n = 19,544), followed by Lucilia caesar (n = 8025), Calliphora vicina (n = 5224), and Lucilia ampullacea (n = 1834). Up to six environmental parameters were statistically significant predictors of fly presence, leading to unique patterns of seasonal and daily activity for all four species. In detail, our analysis proved that L. sericata is a sun-loving, high-summer species that dominates the warmer months and is mostly influenced by mean day temperature. In contrast, L. caesar seems to be a shade loving species that dominates in autumn resp. late-season and is mainly influenced by mean day temperature and wind speed. The activity of L. ampullacea was highly related to mean day temperature and relative humidity. In contrast to all other species, C. vicina behaved differently, particularly due to its occurrence throughout the entire sampling interval and the higher tolerance limits for the measured abiotic parameters, especially temperature. The present study is groundwork for establishing a prediction tool for the flight and oviposition activity of forensically relevant taxa. PMID- 30483870 TI - Correction to: Oceanisphaera aquimarina sp. nov., Isolated from Oil-Contaminated Sediment of Ocean Coastal Area from South Korea. AB - The original version of this article unfortunately contained a mistake in the provided KEMB accession number. PMID- 30483871 TI - Genome Comparisons of Wild Isolates of Caulobacter crescentus Reveal Rates of Inversion and Horizontal Gene Transfer. AB - Since previous interspecies comparisons of Caulobacter genomes have revealed extensive genome rearrangements, we decided to compare the nucleotide sequences of four C. crescentus genomes, NA1000, CB1, CB2, and CB13. To accomplish this goal, we used PacBio sequencing technology to determine the nucleotide sequence of the CB1, CB2, and CB13 genomes, and obtained each genome sequence as a single contig. To correct for possible sequencing errors, each genome was sequenced twice. The only differences we observed between the two sets of independently determined sequences were random omissions of a single base in a small percentage of the homopolymer regions where a single base is repeated multiple times. Comparisons of these four genomes indicated that horizontal gene transfer events that included small numbers of genes occurred at frequencies in the range of 10-3 to 10-4 insertions per generation. Large insertions were about 100 times less frequent. Also, in contrast to previous interspecies comparisons, we found no genome rearrangements when the closely related NA1000, CB1, and CB2 genomes were compared, and only eight inversions and one translocation when the more distantly related CB13 genome was compared to the other genomes. Thus, we estimate that inversions occur at a rate of one per 10 to 12 million generations in Caulobacter genomes. The inversions seem to be complex events that include the simultaneous creation of indels. PMID- 30483872 TI - Correction to: Loktanella aquimaris sp. nov., Isolated from Seawater. AB - The original version of this article unfortunately contained a mistake in the species name description. Also the accession number was published incorrectly. PMID- 30483873 TI - Why are we not flooded by involuntary thoughts about the past and future? Testing the cognitive inhibition dependency hypothesis. AB - In everyday life, involuntary thoughts about future plans and events occur as often as involuntary thoughts about the past. However, compared to involuntary autobiographical memories (IAMs), such episodic involuntary future thoughts (IFTs) have become a focus of study only recently. The aim of the present investigation was to examine why we are not constantly flooded by IFTs and IAMs given that they are often triggered by incidental cues while performing undemanding activities. One possibility is that activated thoughts are suppressed by the inhibitory control mechanism, and therefore depleting inhibitory control should enhance the frequency of both IFTs and IAMs. We report an experiment with a between-subjects design, in which participants in the depleted inhibition condition performed a 60-min high-conflict Stroop task before completing a laboratory vigilance task measuring the frequency of IFTs and IAMs. Participants in the intact inhibition condition performed a version of the Stroop task that did not deplete inhibitory control. To control for physical and mental fatigue resulting from performing the 60-min Stroop tasks in experimental conditions, participants in the control condition completed only the vigilance task. Contrary to predictions, the number of IFTs and IAMs reported during the vigilance task, using the probe-caught method, did not differ across conditions. However, manipulation checks showed that participants' inhibitory resources were reduced in the depleted inhibition condition, and participants were more tired in the experimental than in the control conditions. These initial findings suggest that neither inhibitory control nor physical and mental fatigue affect the frequency of IFTs and IAMs. PMID- 30483874 TI - Adult attention-deficit/hyperactivity disorder, risky substance use and substance use disorders: a follow-up study among young men. AB - We investigated whether adult attention-deficit/hyperactivity disorder (ADHD) predicts risky substance use and substance use disorders (SUDs), and its impact on the course of these problematic substance use patterns. Our sample included 4975 Swiss men (mean age 20 +/- 1.2 years) who participated in the baseline and 15-month follow-up assessments of the Cohort Study on Substance Use Risk Factors. We examined: (1) the contribution of ADHD, as assessed at baseline, on the risky use of alcohol, nicotine and cannabis, and their corresponding use disorders (AUD, NUD, CUD) at follow-up; and (2) the association between ADHD and the course of outcomes (i.e., absence, initiation, maturing out, persistence) over 15 months. All analyses were adjusted for socio-demographics and co-morbidity. Men with ADHD were more likely to exhibit persistent risky alcohol and nicotine use, and to mature out of risky cannabis use. ADHD at baseline was positively linked to AUD and negatively to CUD at follow-up, but not to NUD. For all SUDs, ADHD had a positive association with use persistence and maturing out. Comparing these two trajectories revealed that early age of alcohol use initiation distinguished between persistence and maturing out of AUD, while the course of NUD and CUD was related to ADHD symptoms and SUD severity at baseline. Already in their early twenties, men with ADHD are especially likely to exhibit persistent problematic substance use patterns. Substance-specific prevention strategies, particularly implemented before early adulthood, may be crucial to reducing the development and persistence of pathological patterns in such individuals. PMID- 30483875 TI - Prevalence of sleep-disordered breathing among women working in the aged care services in Japan. AB - OBJECTIVES: The aim of this study was to examine the prevalence of sleep disordered breathing (SDB) in women working in the field of aged care in Japan. METHODS: A cross-sectional study was conducted for female employees aged 18-60 years in aged care facilities in Japan. The analyzed set consisted of 712 participants with complete data. SDB was determined by respiratory disturbance index (RDI), measured using an ambulatory airflow monitor with a polyvinylidene fluoride film sensor to detect nasal and oral airflow overnight at home. Based on the findings of previous studies, RDI 10 was considered equivalent to apnea hypopnea index (AHI) 15. RESULTS: The prevalence of moderate-to-severe SDB (RDI >= 10) was 22.8%. The mean age was 38.1 years, and mean sleeping time of participants was 6.1 h. The median body mass index (BMI) was 22.0. Women with moderate-to-severe SDB (RDI >= 10) had a higher age, neck circumference, neck height ratio, BMI, systolic blood pressure, and increased prevalence of hypertension, short sleepers (amount of sleep on the SDB testing day < 6 h), and habitual snorers, compared to women with no or mild SDB (RDI < 10). CONCLUSIONS: Our study found that women working in the aged care services in Japan were heavily burdened by SDB even though they were relatively young and slim. To prevent CVD from developing in the future, programs through which workplaces can help their employees improve their lifestyle, and early diagnosis and treatment of SDB are highly recommended. PMID- 30483876 TI - Assessment of coronary flow reserve predicts long-term outcome of responders to cardiac resynchronization therapy. AB - Cardiac resynchronization therapy (CRT) has been established as a treatment for patients with chronic heart failure (HF). We tested the hypothesis that assessment of coronary flow reserve (CFR) predicts the long-term outcome of CRT. The study consisted of 114 HF patients implanted with a CRT device for the treatment of advanced HF between April 2010 and April 2018. After excluding patients that withdrew from long-term follow-up and patients missing a baseline CFR measurement, we enrolled 53 eligible patients. CFR was determined non invasively by transthoracic echocardiography. Based on the ROC curve for predicting the appearance of major adverse cerebral and cardiovascular events (MACCE), the level of preserved CFR was set at >1.35 in responders. Accurate follow-up information (mean 873 +/- 498 days) was obtained in 23 patients with a preserved CFR (16 females; mean age 71 +/- 7.9 years) and 11 patients with a depressed CFR (5 females; mean age, 73 +/- 7.6 years) in responders. Kaplan-Meier survival analysis demonstrated that the depressed CFR group had a higher prevalence of MACCE than the preserved CFR group (log rank, 9.83; p = 0.0021). Multivariate analysis revealed that depressed CFR was associated with MACCE (hazard ratio 4.88, 95% confidence interval 1.13-26.5, p = 0.0329). Our results suggest that the assessment of CFR predicts the outcome in responders to CRT. Preservation of coronary circulation flow might underlie one of the mechanisms for a better response to CRT in responders. PMID- 30483877 TI - The role of PI3K/AKT/FOXO signaling in psoriasis. AB - Phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling pathway play a central role in multiple cellular functions such as cell proliferation and survival. The forkhead box O (FOXO) transcription factors are negatively regulated by the PI3K/AKT signaling pathway and considered to have inhibitory effect on cell proliferation. Psoriasis is a multifactorial disease with a strong genetic background and characterized by hyperproliferative keratinocyte. PI3K signaling regulates proliferation of keratinocyte by activating AKT and other targets, and by inducing FOXO downregulation. The amplification of PI3K and AKT and the loss of the FOXO are gradually being recognized in psoriatic lesions. The upstream and downstream of PI3K/AKT signaling molecules such as tumor suppressor phosphatase and tensin homolog (PTEN) and mammalian target of Rapamycin (mTOR), respectively, are also frequently altered in psoriasis. In this review, we highlight the recent studies on the roles and mechanisms of PI3K and AKT in regulating hyperproliferation of keratinocyte, and the roles of the downstream targets FOXO in psoriasis. Finally, we summarized that PI3K/AKT/FOXO signaling and its upstream and downstream molecule which could be underlying therapeutic target for psoriasis. This article is part of a special issue entitled: PI3K-AKT FOXO axis in psoriasis. PMID- 30483878 TI - CXCL12 regulates differentiation of human immature melanocyte precursors as well as their migration. AB - Melanocyte stem cells (McSCs) are localized in the bulge region of hair follicles and supply melanocytes, which determine hair color by synthesizing melanin. Ectopic differentiation of McSCs, which are usually undifferentiated in the bulge region, causes depletion of McSCs and results in hair graying. Therefore, to prevent hair graying, it is essential to maintain McSCs in the bulge region, but the mechanism of McSC maintenance remains unclear. To address this issue, we investigated the role of CXCL12, a chemokine which was previously suggested to induce migration of melanocyte lineage cells, as a niche component of McSCs. Immunohistological analysis revealed that CXCL12 was highly expressed in the bulge region of human hair follicles. CXCL12 mRNA expression level was significantly lower in white hairs plucked from human scalps than in black hairs. CXCL12 attracted the migration of early-passage normal human epidermal melanocytes (eNHEMs), an in vitro model of McSCs, which had characteristics of immature melanocyte precursors. We also found that CXCL12 suppressed their differentiation. These results suggest that CXCL12 regulates differentiation of McSCs as well as their proper localization, and maintaining McSCs by regulating CXCL12 expression level in the bulge region may be a key to preventing hair graying. PMID- 30483879 TI - Out-of-position telomeres in meiotic leptotene appear responsible for chiasmate pairing in an inversion heterozygote in wheat (Triticum aestivum L.). AB - Chromosome pairing in meiosis usually starts in the vicinity of the telomere attachment to the nuclear membrane and congregation of telomeres in the leptotene bouquet is believed responsible for bringing homologue pairs together. In a heterozygote for an inversion of a rye (Secale cereale L.) chromosome arm in wheat, a distal segment of the normal homologue is capable of chiasmate pairing with its counterpart in the inverted arm, located near the centromere. Using 3D imaging confocal microscopy, we observed that some telomeres failed to be incorporated into the bouquet and occupied various positions throughout the entire volume of the nucleus, including the centromere pole. Rye telomeres appeared ca. 21 times more likely to fail to be included in the telomere bouquet than wheat telomeres. The frequency of the out-of-bouquet rye telomere position in leptotene was virtually identical to the frequency of telomeres deviating from Rabl's orientation in the nuclei of somatic cells, and was similar to the frequency of synapsis of the normal and inverted chromosome arms, but lower than the MI pairing frequency of segments of these two arms normally positioned across the volume of the nucleus. Out-of-position placement of the rye telomeres may be responsible for reduced MI pairing of rye chromosomes in hybrids with wheat and their disproportionate contribution to aneuploidy, but appears responsible for initiating chiasmate pairing of distantly positioned segments of homology in an inversion heterozygote. PMID- 30483880 TI - The role of non-invasive imaging techniques in detecting intra-abdominal adhesions: a systematic review. AB - BACKGROUND: Intra-abdominal adhesions after surgery are highly prevalent. Adhesions implicate complications during subsequent surgery and can cause chronic abdominal pain. The objective of this review was to investigate the usefulness of non-invasive diagnostic methods for detection of adhesions. METHODS: We searched the electronic databases: MEDLINE, Embase, and The Cochrane Central Register of Controlled Trials for studies investigating the use of non-invasive diagnostic imaging techniques for detecting adhesions. Main outcome was the sensitivity and specificity of each technique. We used the Quality Assessment of Diagnostic Accuracy studies tool to assess bias. RESULTS: In total, 25 studies were included: 18 using ultrasound (US), 5 using magnetic resonance imaging (MRI), 1 using computed tomography (CT), and 1 using both US and MRI. A total of 2195 patients were included. Overall accuracy ranged between 76 and 100% for US studies and between 79 and 90% for MRI and was 66% for CT. Sensitivity ranged between 21 and 100% for US and between 22 and 93% for MRI and was 61% for CT. Specificity was 32-100% for US, 25-93% for MRI, and 63% for CT. Bias analysis revealed that in most studies, investigators were blinded to the reference standard but not to the index test and 11 of 25 studies had a high risk of selection bias. CONCLUSIONS: Currently, abdominal US can be used to determine the presence of adhesions between bowel and the abdominal wall. MRI is also an accurate diagnostic modality and can in addition visualize adhesions between viscera, however, with a tendency to over diagnose adhesions. There is insufficient evidence to support CT as a diagnostic modality for adhesions. PMID- 30483881 TI - Association between the missense alcohol dehydrogenase rs1229984T variant with the risk for Parkinson's disease in women. AB - BACKGROUND/OBJECTIVE: Several meta-analyses including retrospective case-control studies have shown that the risk of developing Parkinson's disease (PD) correlates inversely with alcohol consumption and (PD), although the results of prospective longitudinal studies are far from being conclusive. The reasons for this inverse association are not well-known. Because alcohol dehydrogenase is one of the most important alcohol-detoxification enzymes, we tried to replicate a putative association of the risk of developing PD with two missense gene variations affecting the alcohol dehydrogenase 1B (ADH1B) gene (one of them related with aversive effects to alcohol). METHODS: In a cohort composed of 629 PD patients and 865 age- and gender-matched healthy individuals, we analyzed genotypes and allele frequencies for two common missense ADH1B single nucleotide polymorphisms (SNPs), namely rs1229984 (His48Arg) and rs6413413 (Thr60Ser) using specifically designed TaqMan assays. RESULTS: The frequency of individuals carrying rs1229984T alleles in homozygosity or in heterozygosity was higher in PD than in controls in the whole study cohort (P < 0.001 and P = 0.005, respectively), and in women (P < 0.001 and P < 0.001, respectively). The genotypes for rs6413413 were similar in PD patients and control subjects. Age at onset of PD patients was not statistically related to rs1229984 or rs6413413 genotypes. CONCLUSIONS: The missense variant rs1229984T is statistically associated with the risk of developing PD mainly in women, which could explain differences in alcohol consumption in this gender. PMID- 30483882 TI - Update on opsoclonus-myoclonus syndrome in adults. AB - Opsoclonus-myoclonus syndrome in adults is a rare and heterogeneous disorder with the clinical features of opsoclonus, myoclonus, ataxia, and behavioral and sleep disturbances. The pathophysiology is thought to be immunological on the basis of paraneoplastic or infectious etiologies. Immunomodulatory therapies should be performed although the response may be incomplete. A number of autoantibodies have been identified against a variety of antigens, but no diagnostic immunological marker has yet been identified. This review focuses on underlying mechanisms of opsoclonus-myoclonus syndrome, including findings that have been identified recently, and provides an update on the clinical features and treatments of this condition. PMID- 30483883 TI - Rapid Relief: Thyroidectomy is a Quicker Cure than Radioactive Iodine Ablation (RAI) in Patients with Hyperthyroidism. AB - BACKGROUND: Time to hormonal control after definitive management of hyperthyroidism is unknown but may influence patient and physician decision making when choosing between treatment options. The hypothesis is that the euthyroid state is achieved faster after thyroidectomy than RAI ablation. METHODS: A retrospective review of all patients undergoing definitive therapy for hyperthyroidism was performed. Outcomes after thyroidectomy were compared to RAI. RESULTS: Over 3 years, 217 patients underwent definitive therapy for hyperthyroidism at a county hospital: 121 patients received RAI, and 96 patients underwent thyroidectomy. Age was equivalent (p = 0.72). More males underwent RAI (25% vs 15%, p = 0.05). Endocrinologists referred for both treatments equally (p = 0.82). Both treatments were offered after a minimum 1-year trial of medical management (p = 0.15). RAI patients mostly had Graves (93%), versus 73% of thyroidectomy patients (p < 0.001). Thyroidectomy patients more frequently had eye symptoms (35% vs 13%, p < 0.001), compressive symptoms (74% vs 15%, p < 0.001), or were pregnant/nursing (14% vs 0, p < 0.001). While the thyroidectomy patients had a documented discussion of all treatment modalities, 79% of RAI patients did not have a documented discussion regarding the option of surgical management (p < 0.001). Both treatment groups achieved an euthyroid state (71% vs 65%, p = 0.39). Thyroidectomy patients became euthyroid faster [3 months (2-7 months) versus 9 months (4-14 months); p < 0.001]. CONCLUSIONS: Thyroidectomy for hyperthyroidism renders a patient to an euthyroid state faster than RAI. This finding may be important for patients and clinicians considering definitive options for hyperthyroidism. PMID- 30483884 TI - Anastomotic Leakage After Stoma Reversal Combined with Incisional Hernia Repair. AB - BACKGROUND: Stoma reversal in patients with an incisional hernia represents a clinical dilemma, as it remains unknown whether hernia repair should be concomitantly employed. We aimed at examining postoperative complications and mortality in patients undergoing stoma reversal with or without concomitant hernia repair. METHODS: This study included all patients subjected to stoma reversal between 2010 and 2016 at our institution. Patients were grouped according to conductance of concomitant incisional hernia repair or not. The primary outcome was anastomotic leak (AL). Secondary outcomes were surgical site occurrences (SSO), overall surgical complications, 90-day mortality and overall survival. RESULTS: In total, 142 patients were included of whom 18 (13%) underwent concomitant hernia repair. The incidence of AL was significantly higher in patients subjected to concomitant hernia repair (four out of 18 [22.2%]) compared with patients undergoing stoma reversal alone (three out of 124 [2.4%], P = 0.002). Additional variables associated with AL were duration of surgery (P < 0.001) and ischemic heart disease (P = 0.039). Twenty-two patients (15.5%) developed a SSO: eight (44.4%) in the hernia repair group and 14 (11.3%) in the non-hernia repair group (P < 0.001). In the multivariable analysis, concomitant hernia repair remained significantly associated with development of postoperative complications (OR = 5.92, 95% CI = 1.54-25.96, P = 0.012). CONCLUSIONS: Compared with stoma reversal alone, incisional hernia repair concomitant with stoma reversal was associated with a higher incidence of AL and other complications. PMID- 30483885 TI - A helicase links upstream ORFs and RNA structure. AB - Upstream open reading frames (uORFs) in 5' UTRs of eukaryotic mRNAs are increasingly recognized as important elements that regulate cellular protein synthesis. Since uORFs can start from non-AUG codons, an enormous number of potential uORF initiation sites exists in 5'UTRs. However, only a subset of these sites is used and it has been unclear how actual start sites are selected. Studies of the DEAD-box helicase Ded1p from S. cerevisiae show that translation of uORFs with non-AUG initiation codons occurs upstream of mRNA structures that emerge with defective Ded1p. The data designate mRNA structure as important determinant for non-AUG initiation sites of uORFs. Ded1p can control this RNA structure and thereby regulate uORF translation. PMID- 30483886 TI - The ion channel, TRPM2, contributes to the pathogenesis of radiodermatitis. AB - Radiodermatitis is a painful side effect for cancer patients undergoing radiotherapy. Irradiation of the skin causes inflammation and breakdown of the epidermis and can lead to significant morbidity and mortality in severe cases, as seen in exposure from accidents or weapons such as "dirty bombs" and ultimately leads to tissue fibrosis. However, the pathogenesis of radiodermatitis is not fully understood. Using a mouse model of radiodermatitis, we showed that the Transient Receptor Potential Melastatin 2 (TRPM2) ion channel plays a significant role in the development of dermatitis following exposure to ionizing radiation. Irradiated TRPM2-deficient mice developed less inflammation, fewer severe skin lesions and decreased fibrosis when compared to wild type mice. The TRPM2 deficient mice also showed a faster recovery period as seen by their increased weight gain post irradiation. Finally, TRPM2-deficient mice exhibited lower systemic inflammation with a reduction in inflammatory cytokines present in the serum. These findings suggest that TRPM2 may be a potential therapeutic target for reducing the severity of radiodermatitis. PMID- 30483887 TI - Bologna criteria are predictive for ovarian response and live birth in subsequent ovarian stimulation cycles. AB - PURPOSE: The ESHRE Working Group on Poor Ovarian Response defined a set of variables to define poor responders, named as the Bologna Criteria, but several concerns have been raised regarding their applicability and prognostic significance. In order to evaluate the clinical relevance of the criteria, we retrospectively analyzed the ovarian response and live birth rates in women who had consecutive IVF attempts, according to their fulfillment of the criteria. METHODS: The study group comprised 1153 and 288 women who had two and three consecutive ovarian stimulation (OS) cycles between May 2010 and January 2017, respectively. We compared the ovarian response and live birth rates in subsequent IVF attempts of Bologna criteria-defined poor responder women and women who did not fulfill the Bologna criteria. RESULTS: Women who fulfilled the criteria achieved higher rates of poor ovarian response (76.2% vs 14.3% and 60.3% vs 13.4%) and lower live birth rates (14.6% vs 33.3% and 12.9% vs 34.3%) in their second and third OS cycles, respectively (both p < 0.001) compared to women who did not fulfill the criteria. The former group also had lower number of oocytes and lower likelihood of having embryo transfer in their subsequent OS cycles. The criteria were able to predict both ovarian response and clinical outcome in the subsequent cycle in < 40-year-old women, whereas they were predictive only for the ovarian response but not for the clinical outcome in women over 40 years of age, who exhibited very low live birth rates regardless of the fulfillment of the criteria. CONCLUSIONS: The results of this study show that the Bologna criteria are clinically relevant in terms of prediction of ovarian response and clinical outcome in subsequent OS cycles. PMID- 30483888 TI - Influence of amino acids and vitamins on the growth of gdhA derivative Pasteurella multocida B:2 for use as an animal vaccine. AB - Pasteurella multocida serotype B:2 is the causative agent of haemorrhagic septicaemia, a fatal disease in cattle and buffaloes. For use as a vaccine in the treatment of HS disease, an efficient cultivation of attenuated gdhA derivative P. multocida B:2 (mutant) for mass production of viable cells is required. In this study, the role of amino acids and vitamins on the growth of this particular bacterium was investigated. Initially, three basal media (Brain-heart infusion, Terrific broth, and defined medium YDB) were assessed in terms of growth performance of P. multocida B:2. YDB medium was selected and redesigned to take into account the effects of amino acids (glutamic acid, cysteine, glycine, methionine, lysine, tyrosine, and histidine) and vitamins (vitamin B1, nicotinic acid, riboflavin, pyridoxine, pantothenic acid, and biotin). High viable cell number was largely affected by the availability of micronutrient components and macronutrients. Histidine was essential for the growth whereby a traceable amount (20 mM) was found to greatly enhance the growth of gdhA derivative P. multocida B:2 mutant (6.6 * 109 cfu/mL) by about 19 times as compared to control culture (3.5 * 108 cfu/mL). In addition, amongst the vitamins added, riboflavin exhibited the highest impact on the viability of gdhA derivative P. multocida B:2 mutant (5.3 * 109 cfu/mL). Though the combined histidine and riboflavin in the culture eventually did not promote the stacking impact on cell growth and cell viability, nonetheless, they were still essential and important in either growth medium or production medium. PMID- 30483889 TI - Mechanical assessment of tripled hamstring tendon graft when using suspensory fixation for cruciate ligament reconstruction. AB - BACKGROUND: Tripling semitendinosus tendon for ACL graft preparation facilitates creation of longer and thicker grafts. Our objective was to evaluate the mechanical difference between tripled tendon grafts, prepared by three methods, by comparing with quadrupled tendon graft. METHODS: Bovine hind-foot hoof extensors were allocated to four groups. Group I had quadrupled graft construct. Tripled graft constructs were prepared by passing the tendon to the Endobutton CL loop and stitching the third strand to (i) the loop (in Group II) or (ii) to one strand(in Group III) or (iii)to loop and both tendon strands (in Group IV). The constructs were preloaded from 10 to 50 N at 0.1 Hz for 10 cycles, followed by 1000 cycles of sinusoidal loading between 50 and 250 N at a frequency of 0.5 Hz. The specimens were then subjected to load to failure test at the rate of 50 mm/min. Displacement with cyclic loading, load at failure and the mode of failure were noted. RESULTS: The load at failure was 957 +/- 23.30 N (Mean +/- Standard Deviation) in Group I, 590.8 +/- 24.40 N in Group II, 682.6 +/- 59.28 N in Group III and 963.4 +/- 21.72 N in Group IV. The displacement with cyclic loading was 1.13 +/- 0.11 mm in Group I, 4.908 +/- 0.55 mm in Group II, 1.822 +/- 0.55 mm in Group III and 1. 126 +/- .018 mm in Group IV. There was no significant difference between the Groups I and IV with respect to the load at failure and displacement (p > 0.05). The values were significantly different in Group II and Group III (p < 0.01), when compared to groups I and IV. CONCLUSIONS: Tripled grafts have mechanical properties equivalent to quadrupled grafts only when the three strands are sutured together. Caution may be warranted when using suspensory fixation device with tripled tendons and the third strand must be securely attached to the loop of fixation device and to the other two strands. PMID- 30483890 TI - Zoonotic and genetically diverse subtypes of Blastocystis in US pre-weaned dairy heifer calves. AB - Blastocystis is an emerging zoonotic pathogen with global distribution. However, limited data exist on the prevalence and genetic diversity of Blastocystis in the USA and in food animals. We conducted the first large-scale molecular investigation of Blastocystis in the USA by testing 2539 fecal samples from dairy heifer calves from 13 states. Blastocystis was detected in 73 (2.9%) fecal samples and in 10 of the 13 tested states. Molecular characterization showed a wide diversity of subtypes. Eleven subtypes were identified, seven previously reported (ST-3, ST-4, ST-5, ST-10, ST-14, ST-17, and ST-21) and four potentially novel subtypes (named ST-23 to ST-26). Zoonotic subtypes 3, 4, and 5 were found in 67% (49) of the positive specimens in this population. Our results suggest that cattle could serve as reservoirs of infection for humans and other domestic animals highlighting the potential risk of zoonotic transmission for Blastocystis. PMID- 30483891 TI - Correction to: Monogenean parasites infect ornamental fish imported to Australia. AB - The phylogenetic tree (Figure 7) in the published document has incorrect Bayesian analysis posterior probabilities. This error prevents accurate analysis by future research in parasitology. The figure is therefore replaced by the corrected figure below. PMID- 30483892 TI - The Assessment of Quality Attributes for Biosimilars: a Statistical Perspective on Current Practice and a Proposal. AB - Establishing comparability of the originator and its biosimilar at the structural and functional level, by analyzing so-called quality attributes, is an important step in biosimilar development. The statistical assessment of quality attributes is currently in the focus of attention because both the FDA and the EMA are working on regulatory documents for advising companies on the use of statistical approaches for strengthening their comparability claim. In this paper, we first discuss "comparable" and "not comparable" settings and propose a shift away from the usual comparison of the mean values: we argue that two products can be considered comparable if the range of the originator fully covers the range of the biosimilar. We then introduce a novel statistical testing procedure (the "tail-test") and compare the operating characteristics of the proposed approach with approaches currently used in practice. In contrast to the currently used approaches, we note that our proposed methodology is compatible with the proposed understanding of comparability and has, compared to other frequently applied range-based approaches, the advantage of being a formal statistical testing procedure which controls the patient's risk and has reasonable large-sample properties. PMID- 30483894 TI - Formulation and Manufacturing of Solid Dosage Forms. PMID- 30483895 TI - Transcriptome analysis of adipose tissue from pigs divergent in feed efficiency reveals alteration in gene networks related to adipose growth, lipid metabolism, extracellular matrix, and immune response. AB - Adipose tissue is hypothesized to play a vital role in regulation of feed efficiency (FE; efficiency in converting energy and nutrients into tissue), of which improvement will simultaneously reduce environmental impact and feed cost per pig. The objective of the present study was to sequence the subcutaneous adipose tissue transcriptome in FE-divergent pigs (n = 16) and identify relevant biological processes underpinning observed differences in FE. We previously demonstrated that high-FE pigs were associated with lower fatness when compared to their counterparts. Here, ontology analysis of a total of 209 annotated genes that were differentially expressed at a p < 0.01 revealed establishment of a dense extracellular matrix and inhibition of capillary formation as one underlying mechanism to achieve suppressed adipogenesis. Moreover, mechanisms ensuring an efficient utilization of lipids in high-FE pigs might be orchestrated by upstream regulators including CEBPA and EGF. Consequently, high-FE adipose tissue could exhibit more efficient cholesterol disposal, whilst inhibition of inflammatory and immune response in high-FE pigs may be an indicator of an optimally functioning adipose tissue. Taken together, adipose tissue growth, extracellular matrix formation, lipid metabolism and inflammatory and immune response are key biological events underpinning the differences in FE. Further investigations focusing on elucidating these processes would assist the animal production industry in optimizing strategies related to nutrient utilization and product quality. PMID- 30483893 TI - Anti-CD20 Directed Therapy of B Cell Lymphomas: Are New Agents Really Better? AB - PURPOSE OF REVIEW: Since its initial approval in 1997, rituximab has revolutionized the treatment of CD20-positive lymphoproliferative disorders. Now, over two decades later, second-generation molecules are emerging that may have key biological advantages compared to rituximab, as well as biosimilars that may be more cost-effective. Clinicians, health policy makers, and payers will now need to critically appraise the available evidence for these competitors and decide which anti-CD20 to use. RECENT FINDINGS: Evidence has emerged directly comparing rituximab IV to a subcutaneous preparation, and head-to-head comparisons of rituximab versus next-generation anti-CD20 monoclonal antibodies have also been published. Trials comparing rituximab with newly developed biosimilars have also allowed for registration of these agents. In this review, we will present an overview of anti-CD20 monoclonal antibody development, discuss the mechanistic and clinical evidence for rituximab, as well as the novel compounds, and provide commentary on the possible advantages and limitations of these agents. PMID- 30483896 TI - Reduced thiamine binding is a novel mechanism for TPK deficiency disorder. AB - Thiamine pyrophosphokinase (TPK) converts thiamine (vitamin B1) into thiamine pyrophosphate (TPP), an essential cofactor for many important enzymes. TPK1 mutations lead to a rare disorder: episodic encephalopathy type thiamine metabolism dysfunction. Yet, the molecular mechanism of the disease is not entirely clear. Here we report an individual case of episodic encephalopathy, with familial history carrying a novel homozygous TPK1 mutation (p.L28S). The L28S mutation leads to reduced enzymatic activity, both in vitro and in vivo, without impairing thiamine binding and protein stability. Thiamine supplementation averted encephalopathic episodes and restored the patient's developmental progression. Biochemical characterization of reported TPK1 missense mutations suggested reduced thiamine binding as a new disease mechanism. Importantly, many disease mutants are directly or indirectly involved in thiamine binding. Thus, our study provided a novel rationale for thiamine supplementation, so far the major therapeutic intervention in TPK deficiency. PMID- 30483897 TI - Preoperative continuation of aspirin administration in patients undergoing major abdominal malignancy surgery. AB - PURPOSE: In contrast to that in a nonoperative setting, it has been shown that perioperative administration of aspirin did not decrease the rate of death or myocardial infarction but increased major bleeding risk. Since these conflicting results might be due to concurrent use of anticoagulants and a lower thrombotic risk of patients, this cohort study was carried out for patients at a high thrombotic risk without concurrent use of anticoagulants. METHODS: Medical records for patients who underwent major abdominal malignancy surgery and who were on a preoperative antiplatelet regimen were reviewed. The patients were divided into two groups according to perioperative antiplatelet management: administration of all preoperative antiplatelet agent-suspended (no aspirin) group and only aspirin administration-continued (aspirin) group. The incidence of symptomatic thromboembolic events, frequency of exogenous blood transfusion within 30 days after surgery and the amount of intraoperative bleeding were compared between the two groups. RESULTS: After propensity score matching, 105 patients of each group were matched. The incidence of perioperative thromboembolic events in the no-aspirin group was significantly higher than that in the aspirin group [7/105 (6.7%) vs 0/105 (0%), 95% CI 1.44-infinity, P = 0.016]. In contrast, neither the frequency of exogenous transfusion [21.0% vs 11.4%, 95% CI 0.88-4.38 P = 0.110] nor the amount of intraoperative bleeding [median (interquartile range), ml: 230 (70-500) vs 208 (50-500), P = 0.325] was different between the two groups. CONCLUSION: Although the sample size is relatively small, our findings suggest that continuation of aspirin administration is likely to reduce the thrombotic risk but unlikely to increase the bleeding risk of patients who undergo major abdominal surgery for malignancy. PMID- 30483898 TI - Effects of VEGFR1+ hematopoietic progenitor cells on pre-metastatic niche formation and in vivo metastasis of breast cancer cells. AB - The pre-metastatic niche has been shown to play a critical role in tumor metastasis, and its formation is closely related to the tumor microenvironment. However, the underlying molecular mechanisms remain unclear. In the present study, we successfully established a mouse model of lung metastasis using luciferase-expressing MDA-MB-435s cells. In this model, recruitment of vascular endothelial growth factor receptor-1 (VEGFR1)+CD133+ hematopoietic progenitor cells (HPCs) was gradually increased in lung but gradually decreased after the formation of tumor colonies in lung. We also established a highly metastatic MDA MB-435s (MDA-MB-435s-HM) cell line from the mouse model. Changes in protein profiles in different culture conditions were investigated by protein microarray analysis. The levels of CXC chemokine ligand 16, interleukin (IL)-2Ralpha, IL 2Rgamma, matrix metalloproteinase (MMP)-1, MMP-9, platelet-derived growth factor receptor (PDGFR)-alpha, stromal cell-derived factor (SDF)-1alpha, transforming growth factor (TGF)-beta, platelet endothelial cell adhesion molecule (PECAM)-1 and vascular endothelial (VE)-cadherin were significantly greater (> fivefold) in the culture medium from MDA-MB-435s-HM cells than in that from MDA-MB-435s cells. Moreover, the levels of MMP-9, PDGFR-alpha, and PECAM-1 were significantly greater in the co-culture medium of MDA-MB-435s-HM cells and CD133+ HPCs than in that from MDA-MB-435s-HM cells. Differentially expressed proteins were validated by enzyme-linked immunosorbent assay, and expression of their transcripts was confirmed by quantitative real-time polymerase chain reaction. Moreover, inhibition of MMP-9, PDGFR-alpha, and PECAM-1 by their specific inhibitors or antibodies significantly decreased cell migration, delayed lung metastasis, and decreased recruitment of VEGFR1+CD133+ HPCs into lung. Intra-hepatic growth of HPCs enhanced the invasive growth of MDA-MB-435s-HM cells in the liver. Our data indicate that VEGFR1+CD133+ HPCs contribute to lung metastasis. PMID- 30483901 TI - Social Withdrawal in Adolescence and Early Adulthood: Measurement Issues, Normative Development, and Distinct Trajectories. AB - Social withdrawal during adolescence and early adulthood is particularly problematic due to the increasing importance of social interactions during these ages. Yet little is known about the changes, trajectories, or correlates of being withdrawn during this transition to adulthood. The purpose of this study was to examine the normative change and distinct trajectories of withdrawal in order to identify adolescents and early adults at greatest risk for maladjustment. Participants were from a Dutch population-based cohort study (Tracking Adolescents' Individual Lives Survey), including 1917 adolescents who were assessed at four waves from the age of 16 to 25 years. Five items from the Youth Self Report and Adult Self Report were found to be measurement invariant and used to assess longitudinal changes in social withdrawal. Overall, participants followed a U-shaped trajectory of social withdrawal, where withdrawal decreased from ages 16 to 19 years, remained stable from 19 to 22 years, and increased from 22 to 25 years. Furthermore, three distinct trajectory classes of withdrawal emerged: a low-stable group (71.8%), a high-decreasing group (12.0%), and a low curvilinear group (16.2%). The three classes differed on: shyness, social affiliation, reduced social contact, anxiety, and antisocial behaviors. The high decreasing group endorsed the highest social maladjustment, followed by the low curvilinear group, and the low-stable group was highly adjusted. We discuss the potential contribution of the changing social network in influencing withdrawal levels, the distinct characteristics of each trajectory group, and future directions in the study of social withdrawal in adolescence and early adulthood. PMID- 30483899 TI - Impact of image guidance on toxicity and tumour outcome in moderately hypofractionated external-beam radiotherapy for prostate cancer. AB - To report toxicity and efficacy outcome of moderately hypofractionated image guided external-beam radiotherapy in a large series of patients treated for prostate cancer (PCa). Between 10/2006 and 12/2015, 572 T1-T3N0M0 PCa patients received 70.2 Gy in 26 fractions at 2.7 Gy/fraction: 344 patients (60%) with three-dimensional conformal radiotherapy (3D-CRT) and 228 (40%) with intensity modulated radiotherapy (IMRT). Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria and Houston definition (nadir + 2) were used for toxicity and biochemical failure evaluation, respectively. Median age was 74 years (interquartile range 69-77). Compared with 3D-CRT, in IMRT group more high-risk patients (29% vs 18%; P = 0.002) and more high-volume target (75% vs 60%; P < 0.001) were included. Acute gastro-intestinal (GI) toxicity G > 1 were registered in 8% and in 11% IMRT and 3D-CRT patients, respectively, whereas late GI G > 1 were observed in 2% and 16% IMRT and 3D-CRT patients, respectively. Acute genito-urinary (GU) toxicity G > 1 were registered in 26% and 40% IMRT and 3D-CRT patients, respectively, whereas late GU G > 1 occurred in 5% IMRT and 15% 3D-CRT patients. Multivariate proportional hazard Cox models confirmed significantly greater risk of late toxicity with 3D-CRT compared to IMRT for GU > 1 (P = 0.004) and for GI > 1 (P < 0.001). With a median 4-year follow-up, overall survival (OS), clinical progression-free survival (cPFS) and biochemical PFS (bPFS) for the whole series were 91%, 92% and 91%, respectively. cPFS and bPFS were significantly different by risk groups. Multivariate Cox models for bPFS and cPFS showed no difference between irradiation techniques and a significant impact of risk group and initial PSA. Moderately hypofractionated radiotherapy is a viable treatment option for localized PCa with excellent tumour control and satisfactory toxicity profile. IMRT seems associated with a reduction in toxicity, whereas tumour control was equal between IMRT and 3D-CRT patients and depended mainly on the risk category. PMID- 30483900 TI - Proton Therapy in Non-small Cell Lung Cancer. AB - OPINION STATEMENT: Non-small cell lung cancer (NSCLC) accounts for 85% of new lung cancer cases and has 5-year survival rates ranging from 92% in early-stage disease to as low as 13% in locally advanced cases. Radiation therapy is a key component in the treatment repertoire for NSCLC, where it is currently used alone or in combinations with chemotherapy and surgery. Despite the broad use of modern photon radiation techniques, as many as 25% of patients experience isolated locoregional recurrences, and toxicity has been proven to be a limiting factor in many cases. Proton beam therapy (PBT) has emerged as a potential solution to improve upon clinical outcomes in both early-stage and locally advanced disease. The proton beam allows for a sharp dose build-up and drop-off, which is particularly important in lung cancer where nearby structures include the heart, spinal cord, esophagus, and uninvolved lung. There are now numerous studies showing dosimetric advantages of PBT in early and locally advanced NSCLC, particularly in the heart and lung doses. Randomized data comparing clinical outcomes between proton and photon radiation are limited to a small number of studies. Despite early results suggesting improvements or at least comparable outcomes with PBT, the most recent randomized comparisons have failed to show significant differences in toxicity and local control between photon and proton therapy. As newer PBT techniques (e.g., intensity-modulated proton therapy) are increasingly utilized, more dramatic improvements in tumor control and toxicity may be demonstrated. It is also important to recognize that there may be certain subpopulations in which the benefits of proton therapy are greater, such as central early-stage tumors, previously irradiated tumors, and locally advanced tumors, while others may best be treated with traditional photon techniques. As immunotherapy becomes more prevalent in the treatment of NSCLC, improving local control and limiting the toxicity contributed by radiation will be increasingly important. The unique dosimetric advantages of PBT may allow for tumor dose escalation while maintaining normal tissue doses to improve local control, or treating the tumor to the standard dose while decreasing normal tissue doses to improve toxicity. Finally, given the high costs of proton therapy, where low insurance approval rates have limited trial enrollment, it will be important to determine the overall cost-benefit ratio. PMID- 30483903 TI - Transanal extended rectal surgery with lateral pelvic lymph node dissection. PMID- 30483902 TI - Anger, Sympathy, and Children's Reactive and Proactive Aggression: Testing a Differential Correlate Hypothesis. AB - This study tested the theoretical assertion that anger and sympathy would be differentially associated with "hot-blooded" reactive and "cold-blooded" proactive aggression in an ethnically diverse community sample of 4- and 8-year olds from Canada (N = 300; n = 150 in each age group; 50% female). We conducted structured interviews with children to elicit their self-reported anger in response to social conflicts (anger reactivity), ability to effectively manage feelings of frustration (anger regulation), and the degree to which they felt concern for others in need (sympathy). Caregivers completed questionnaires assessing the degree to which children engaged in reactive and proactive overt aggression. Across ages, dysregulated anger was more strongly associated with reactive aggression, whereas lower sympathy was more strongly linked to proactive aggression. Anger reactivity did not predict children's aggressive behavior, with one exception: lower anger reactivity in 8-year-old males was associated with higher levels of proactive aggression. These findings support the hypotheses that anger and sympathy are differentially involved in reactive and proactive aggression, and that these distinct affective correlates are evident by the preschool years. PMID- 30483904 TI - Dual integrin alphavbeta 3 and NRP-1-Targeting Paramagnetic Liposome for Tumor Early Detection in Magnetic Resonance Imaging. AB - Enhanced MRI (magnetic resonance imaging) plays a vital role in the early detection of tumor but with low specificity. Molecular imaging of angiogenesis could efficiently deliver contrast agents to the tumor site by specific targeted carriers. We designed and synthesized dual-targeted paramagnetic liposomes functionalized with two angiogenesis-targeting ligands, the alphaVbeta3 integrin specific RGD (Arg-Gly-Asp) and the neuropilin-1 (NRP-1) receptor-specific ATWLPPR (Ala-Thr-Trp-Leu-Pro-Pro-Arg) (A7R). These liposomes were proved to be in the nanoparticle range and demonstrated to effectively encapsulate paramagnetic MRI contrast agents Gd-DTPA (gadolinium-diethylenetriamine pentaacetic acid). T1 relaxivity of various liposome formulations was lower than pure Gd-DTPA but with no statistically significant difference. In vitro cellular uptake and competitive inhibition assay showed the higher binding affinity of dual-targeted liposomes to HUVECs (human umbilical vein endothelial cells) and A549 cells compared with pure Gd-DTPA, non-targeted, and single-targeted liposomes, which was proved to be mediated by the binding of RGD/alphanubeta3-integrin and A7R/NRP1. For MR imaging of mice bearing A549 cells in vivo, dual-targeted liposomes reached the highest SER (signal enhancement rate) value with a significant difference at all experimental time points. It was about threefold increase compared to pure Gd DTPA and non-targeted liposomes and was 1.5-fold of single-targeted liposomes at 2 h post injection. The SER was lowered gradually and decreased only by 40% of the peak value in 6 h. Dual-targeted liposomes were likely to exert a synergistic effect and the specificity of delivering Gd-DTPA to the tumor site. Therefore, dual-alphanubeta3-integrin-NRP1-targeting paramagnetic liposome with a RGD ATWLPPR heterodimeric peptide might be a potent system for molecular imaging of tumor. PMID- 30483905 TI - Determination of Ondansetron by Spectrofluorimetry: Application to Forced Degradation Study, Pharmaceuticals and Human Plasma. AB - The current manuscript describes a validated, responsive and rapid spectrofluorimetric method for quantifying ondansetron (OND) in authentic form, spiked human plasma and dosage forms. This is the first reported fluorescence study of Ondansetron in Triton X 100 system. Various variables affecting fluorescence response were studied precisely and optimised. The described method involved the fluorescence measurement in Triton X 100 system at lambdaem/lambdaex 354/317 nm. The calibration plot attained linearity over concentration range of 0.2 - 2 MUg/mL. The developed method has been extensively applied to degradation studies of OND as per International Conference on Harmonisation (ICH) guidelines by exposing to oxidative, thermal, photo, acidic and alkaline conditions and also the degradation pathway has been proposed. PMID- 30483906 TI - A differential k-mer analysis pipeline for comparing RNA-Seq transcriptome and meta-transcriptome datasets without a reference. AB - Next-generation DNA sequencing technologies, such as RNA-Seq, currently dominate genome-wide gene expression studies. A standard approach to analyse this data requires mapping sequence reads to a reference and counting the number of reads which map to each gene. However, for many transcriptome studies, a suitable reference genome is unavailable, especially for meta-transcriptome studies which assay gene expression from mixed populations of organisms. Where a reference is unavailable, it is possible to generate a reference by the de novo assembly of the sequence reads. However, the high cost of generating high-coverage data for de novo assembly hinders this approach and more importantly the accurate assembly of such data is challenging, especially for meta-transcriptome data, and resulting assemblies frequently suffer from collapsed regions or chimeric sequences. As an alternative to the standard reference mapping approach, we have developed a k-mer-based analysis pipeline (DiffKAP) to identify differentially expressed reads between RNA-Seq datasets without the requirement for a reference. We compared the DiffKAP approach with the traditional Tophat/Cuffdiff method using RNA-Seq data from soybean, which has a suitable reference genome. We subsequently examined differential gene expression for a coral meta-transcriptome where no reference is available, and validated the results using qRT-PCR. We conclude that DiffKAP is an accurate method to study differential gene expression in complex meta-transcriptomes without the requirement of a reference genome. PMID- 30483907 TI - Glycine supplementation to breast-fed piglets attenuates post-weaning jejunal epithelial apoptosis: a functional role of CHOP signaling. AB - This study was conducted to test the hypothesis that preweaning glycine supplementation to breast-fed piglets alleviated the post-weaning apoptosis of jejunal epithelium through CHOP signaling. Seven-day-old sow-reared piglets were orally administrated with 0, 50, 100, or 200% of glycine intake from sow's milk twice daily for 14 days and then were weaned at 21 days of age. Tissue samples were collected at 28 days of age for determining intestinal morphology, serum diamine oxidase (DAO) activity, abundances of proteins involved in ER stress and apoptosis. Glycine (100-200%) administration increased villus height, the ratio of villus height to crypt depth in the jejunum. Glycine supplementation (200%) enhanced average daily weight gain during the first 2 weeks post-weaning. Serum DAO activity and jejunal epithelium apoptosis were decreased, but the number of goblet cells in the jejunum was increased. Western blot analysis showed that 100 200% glycine enhanced the protein levels of occludin, claudin-1, and zonula occludens (ZO)-1 without affecting those of claudin-3, ZO-2, and ZO-3. Further studies showed that protein abundances of glucose-regulated protein 78 (BiP/GRP78) and p-IRE1alpha, instead of ATF6alpha, were reduced by glycine. Among the proteins related to apoptosis, abundances of CHOP and p53 were reduced, whereas those of Bcl-2 and Bcl-xL were enhanced in the jejunum of 100-200% glycine-supplemented piglets. Collectively, our results indicated that preweaning glycine supplementation improved the intestinal development of post-weaning piglets. The beneficial effect of glycine was associated with improved intestinal mucosal barrier and reduced apoptosis of enterocytes through CHOP signaling. PMID- 30483909 TI - Awareness and Knowledge of Nonalcoholic Fatty Liver Disease Among Office Employees in Beijing, China. AB - BACKGROUND: Prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing in China; however, awareness and knowledge of NAFLD is lacking among the Chinese public. AIMS: We investigated knowledge about NAFLD and the impact of a brief educational seminar among office employees in Beijing. METHODS: Educational seminar on knowledge about NAFLD and recommendations on diet and physical activity and a pre- and a post-survey in 8 offices in Beijing. RESULTS: A total of 420 participants (24.7% with a diagnosis of NAFLD) completed both the pre- and post-surveys. Median age was 42, 39.1% were men, 93.9% participants had some college education, 50.5% were overweight/obese, and 74.9% were inactive/minimally active. Only 31.2% had awareness of NAFLD. Median baseline knowledge score (of a total of 25) was 17 in participants with and 16 in those without a diagnosis of NAFLD. After the seminar, 30.9% of participants with and 50.8% without a diagnosis of NAFLD increased their knowledge score by >= 3 points, and 92.9% indicated they will improve their diet and physical activity. Multivariate logistic regression analyses found baseline knowledge score was associated with personal diagnosis of NAFLD and family history of dyslipidemia while improvement in knowledge was associated with lower baseline knowledge score and absence of a personal diagnosis of NAFLD. CONCLUSION: We found a high prevalence but a low awareness of NAFLD among office employees in Beijing. A brief educational seminar improved knowledge about NAFLD and motivated lifestyle changes. More educational efforts are needed to decrease the burden of NAFLD in China. PMID- 30483908 TI - Capecitabine Versus Continuous Infusion Fluorouracil for the Treatment of Advanced or Metastatic Colorectal Cancer: a Meta-analysis. AB - OPINION STATEMENT: Nowadays, systemic chemotherapy with intravenous (IV) 5 fluorouracil (5-FU) remains the most commonly prescribed treatment for metastatic colorectal cancers (CRC), in combination with other cytotoxic drugs. 5-FU can be administered through a bolus injection or continuous infusion (cIV), with the latter becoming the preferred administration method and standard of care in recent years. Oral fluoropyrimidines were developed to overcome challenges associated with the IV administration of 5-FU, among which capecitabine has become the most widely used one. However, although capecitabine and other oral fluoropyrimidine-based regimens are more convenient to administer, their efficacy and safety in comparison with IV 5-FU are not well understood. Results from recent randomized controlled trials, observational studies, and meta-analyses have been inconsistent. Safety, in particular, remains controversial. Our review, a first comprehensive meta-analysis comparing the efficacy and safety of cIV 5-FU with capecitabine, the two most widely used fluorouracil modalities in CRC, showed that cIV 5-FU-based regimens are associated with greater response rates compared with capecitabine-based regimens, with no difference in progression-free survival, time to treatment failure, overall survival, or disease-free survival between the two. Furthermore, cIV 5-FU-based regimens showed an improved safety profile compared with capecitabine-based regimens. Our findings suggest that cIV 5-FU remains a more effective and safer modality of fluorouracil administration than capecitabine, thus providing supporting evidence to guide clinical practice in the management of colorectal cancer. PMID- 30483910 TI - Up-regulation of PCSK9 gene expression and diminished level of LDL-receptor in rat liver as a potential cause of post-lipectomy hypercholesterolemia. AB - Studies designed to examine effects of fat mass reduction (including lipodystrophy and lipectomy) on human serum total and LDL-cholesterol concentrations are inconsistent. The purpose of this study was to examine effect of partial lipectomy in rats (as an experimental model of fat mass reduction in humans) on (1) circulating total cholesterol, LDL-cholesterol + VLDL-cholesterol and HDL-cholesterol concentrations, and (2) factors which may affect serum cholesterol concentrations such as: (a) liver LDL-receptor level, (b) expression of liver PCSK9 and (c) circulating PCSK9 concentration. Reduction of rat adipose tissue mass resulted in an increase in circulating total and LDL + VLDL cholesterol concentrations, which was associated with (a) decrease in liver LDL-R level, (b) increase in liver PCSK9 expression, and (c) increase in circulating PCSK9 concentration as compared with sham controls. These changes were accompanied by elevated liver HNF1alpha (and HNF4alpha) mRNA levels. Silencing HNF1alpha in HepG2 cells by siRNA led to decrease in PCSK9 mRNA levels. This suggests that overexpression of HNF1alpha gene in liver of lipectomized rats can lead to overproduction of PCSK9. In conclusion, up-regulation of PCSK9, due to overexpression of HNF1alpha gene in liver of lipectomized rats and subsequently increase in circulating PCSK9 concentration lead to decrease in liver LDL-R level. This may contribute, at least in part, to an increase in the concentration of circulating cholesterol in rats with reduced fat mass. These findings provide a possible explanation for the molecular mechanism of hypercholesterolemia observed sometimes after reduction of fat mass in human. PMID- 30483911 TI - Rare genetic variants potentially involved in ovarian hyperstimulation syndrome. AB - PURPOSE: We aim to investigate whether there is a genetic predisposition in women who developed ovarian hyperstimulation syndrome (OHSS) after GnRH antagonist protocol with GnRH agonist trigger and freeze-all approach. METHODS: Four patients with OHSS after GnRH agonist trigger and freeze-all approach were gathered from the worldwide patient population. These patients were analyzed through Whole Exome Sequencing. In this study known causes of OHSS were investigated and new causes present in at least two individuals were searched for. RESULTS: In the first part of the study, we evaluated the presence of mutations in genes already known to be involved in OHSS. In PGR and TP53, heterozygous alterations were detected. PGR is predicted to be involved in progesterone resistance with a recessive inheritance pattern and is, therefore, not considered as being causal. The consequences of the variant detected in TP53 currently remain unknown. In part 2 of the study, we assessed the clinical significance of variants in genes previously not linked to OHSS. We especially focused on genes with variants present in >= 2 patients. Two patients have variants in the FLT4 gene. Mutations in this gene are linked to hereditary lymphedema, but no link to OHSS has been described. CONCLUSIONS: Defining a genetic predisposition for OHSS is essential in view of prevention. In this study, a potential link between the FLT4 gene and OHSS has been suggested. Future functional studies are essential to define a more precise involvement of the detected variants in the development of OHSS. PMID- 30483912 TI - Iterative simulations to estimate the elastic properties from a series of MRI images followed by MRI-US validation. AB - The modeling of breast deformations is of interest in medical applications such as image-guided biopsy, or image registration for diagnostic purposes. In order to have such information, it is needed to extract the mechanical properties of the tissues. In this work, we propose an iterative technique based on finite element analysis that estimates the elastic modulus of realistic breast phantoms, starting from MRI images acquired in different positions (prone and supine), when deformed only by the gravity force. We validated the method using both a single modality evaluation in which we simulated the effect of the gravity force to generate four different configurations (prone, supine, lateral, and vertical) and a multi-modality evaluation in which we simulated a series of changes in orientation (prone to supine). Validation is performed, respectively, on surface points and lesions using as ground-truth data from MRI images, and on target lesions inside the breast phantom compared with the actual target segmented from the US image. The use of pre-operative images is limited at the moment to diagnostic purposes. By using our method we can compute patient-specific mechanical properties that allow compensating deformations. Graphical Abstract Workflow of the proposed method and comparative results of the prone-to-supine simulation (red volumes) validated using MRI data (blue volumes). PMID- 30483913 TI - Quantitative evaluation of fiber tractography with a Delaunay triangulation-based interpolation approach. AB - The recent challenge in high angular resolution diffusion imaging (HARDI) is to find a tractography process that provides information about the neural architecture within the white matter of the brain in a clinically feasible measurement time. The great success of the HARDI technique comes from its capability to overcome the problem of crossing fiber detection. However, it requires a large number of diffusion-weighted (DW) images which is problematic for clinical time and hardware. The main contribution of this paper is to develop a full tractography framework that gives an accurate estimate of the crossing fiber problem with the aim of reducing data acquisition time. We explore the interpolation in the gradient direction domain as a method to estimate the HARDI signal from a reduced set of DW images. The experimentation was performed in a first time on simulated data for a quantitative evaluation using the Tractometer system. We used, also, in vivo human brain data to demonstrate the potential of our pipeline. Results on both simulated and real data illustrate the effectiveness of our approach to perform the brain connectivity. Overall, we have shown that the proposed approach achieves competitive results to other tractography methods according to Tractometer connectivity metrics. Graphical Abstract ?. PMID- 30483914 TI - Selective suppression of excipient signals in 2D 1H-13C methyl spectra of biopharmaceutical products. AB - While the use of 1H-13C methyl correlated NMR spectroscopy at natural isotopic abundance has been demonstrated as feasible on protein therapeutics as large as monoclonal antibodies, spectral interference from aliphatic excipients remains a significant obstacle to its widespread application. These signals can cause large baseline artifacts, obscure protein resonances, and cause dynamic range suppression of weak peaks in non-uniform sampling applications, thus hampering both traditional peak-based spectral analyses as well as emerging chemometric methods of analysis. Here we detail modifications to the 2D 1H-13C gradient selected HSQC experiment that make use of selective pulsing techniques for targeted removal of interfering excipient signals in spectra of the NISTmAb prepared in several different formulations. This approach is demonstrated to selectively reduce interfering excipient signals while still yielding 2D spectra with only modest losses in protein signal. Furthermore, it is shown that spectral modeling based on the SMILE algorithm can be used to simulate and subtract any residual excipient signals and their attendant artifacts from the resulting 2D NMR spectra. PMID- 30483915 TI - Long-term effects of various types of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on changes in glomerular filtration rate in Korea. AB - Few long-term follow-up studies have compared the changes in renal function according to the type of statin used in Korea. We compared the long-term effects of statin intensity and type on the changes in the glomerular filtration rate (GFR). We extracted data of patients who took statin for the first time. We analyzed whether or not different statins affect the changes in GFR at 3 months after baseline and 4 years after. We included 3678 patients and analyzed the changes in GFR. The GFR decreased by 3.2%+/-0.4% on average 4 years after the first statin prescription, indicating statistically significant deterioration (from 83.5+/-0.4 mL/min/1.73 m2 to 79.9 0.4 mL/min/1.73 m2, P < 0.001). When comparing the GFR among different statins, significant differences were observed between atorvastatin and fluvastatin (-5.3%+/-0.7% vs. 1.2%+/-2.2%, P < 0.05) and between atorvastatin and simvastatin (-5.3%+/-0.7% vs.-0.7%+/-0.8%, P < 0.05). In pitavastatin (odds ratio [OR]= 0.64, 95% confidence interval [CI]= 0.46-0.87, P < 0.005) and simvastatin (OR = 0.69, 95% CI = 0.53-0.91, P < 0.008), the GFR rate that decreased by < 60 mL/min/1.73 m2 was significantly lower than that of atorvastatin. Regarding long-term statin intake, GFR changed with the type of statin. This work is the first in Korea to compare each statin in terms of changes in the GFR after the statin prescription. PMID- 30483916 TI - Does surgeon volume influence the outcome after hip hemiarthroplasty for displaced femoral neck fractures; early outcome, complications, and survival of 752 cases. AB - INTRODUCTION: Surgeon volume of hip arthroplasties is of importance with regard to complication and revision rates in total hip arthroplasty. For hip hemiarthroplasty, the effect of surgeon volume on outcome is far less studied. We analyzed the outcome of hip hemiarthroplasties performed by orthopedic surgeons in a retrospective cohort in different volume categories, focusing on early survival of the prosthesis and complications. METHODS: Between March 2009 and January 2014, 752 hemiarthroplasties were performed for intracapsular femoral neck fracture by 27 orthopedic surgeons in a large Dutch teaching hospital. Surgeons were divided into four groups, a resident group and three groups based on the number of total hip arthroplasties and hemiarthroplasties performed per year: a low-volume (< 10 arthroplasties per year), moderate-volume (10-35 arthroplasties per year), and high-volume groups (> 35 arthroplasties per year). Outcome measures were stem survival using a competing risk analysis, complication rates, and mortality. Chi-square tests were used to compare complication rates and mortality between groups. RESULTS: Patients were followed for a minimum of 2 years or until revision or death. Overall 60% of the patients included had died at time of follow-up. We found comparable stem survival rates in the low-volume group (n = 48), moderate-volume group (n = 201), high-volume group (n = 446), and resident group (n = 57). There were no significant differences between the groups with regard to dislocation rate, incidence of periprosthetic fracture, infection, and mortality. CONCLUSION: Surgeon volume and experience did not influence early outcome and complication rates in hip hemiarthroplasty. Hemiarthroplasty can safely be performed by both experienced hip surgeons and low-volume surgeons. PMID- 30483917 TI - Suboptimal patellofemoral alignment is associated with poor clinical outcome scores after primary total knee arthroplasty. AB - BACKGROUND: Proper patellofemoral alignment is an important goal in total knee arthroplasty (TKA). Acceptable patellar alignment is defined as patellar tilt less than or equal to 5 degrees and patellar displacement less than or equal to 5 mm. Previous studies reported an incidence of post-operative patellar malalignment in TKA from 7 to 35%. However, correlation between patellar malalignment and clinical outcome after TKA remains unclear. The purpose of the present study was to evaluate the effect of patellar tilt and displacement on the clinical outcome of TKA. METHODS: A retrospective review of 138 primary TKAs with a minimum of 2 year follow-up is reported. Pre-operative and post-operative mechanical axis, patellar tilting angle and patellar displacement were measured. Clinical outcomes were evaluated by the knee functional scores including the Knee Society Score (KSS), Knee injury and Osteoarthritis Outcome Score (KOOS), and Western Ontario McMaster University Osteoarthritis Index (WOMAC) at final follow up. RESULTS: Forty-two (30%) primary TKAs had suboptimal patellofemoral alignment with a patellar tilt angle greater than 5 degrees or lateral patellar displacement of more than 5 mm. There was no statistical difference in pre operative mechanical axis, pre-operative patellar tilt angle, or pre-operative lateral patellar displacement between the primary TKAs with proper patellofemoral alignment and those with suboptimal alignment. Patients with post-operative patellar tilt or displacement had clinically significant reductions in KSS, KOOS, and WOMAC when compared with patients without post-operative patellar tilt or displacement. The odds of having a fair or poor post-operative result, an odds ratio of 3.4 (95% CI 1.6-7.2) for KSS, 6.4 (95% CI 2.9-14.2) for KOOS, and 5.9 (95% CI 2.6-13.5) for WOMAC, were associated with suboptimal patellofemoral alignment. CONCLUSION: Establishing proper patellofemoral alignment remains an essential goal of primary TKA. There is a strong association between suboptimal post-operative patellofemoral alignment and poor clinical outcome scores after primary TKA. PMID- 30483918 TI - Cell specific interaction of pasireotide: review of preclinical studies in somatotroph and corticotroph pituitary cells. AB - BACKGROUND: Pasireotide is a second-generation somatostatin (SRIF) receptor ligand (SRL), approved for medical treatment of acromegaly and Cushing's disease (CD). The molecule is a stable cyclohexapeptide synthetized based on SRIF structure. Differently from first-generation SRLs (e.g. octreotide), preferentially binding somatostatin receptor (SST) subtype 2 (SST2), pasireotide has high affinity for multiple SSTs (SST5 > SST2 > SST3 > SST1). Interestingly, early preclinical studies demonstrated that pasireotide shows distinct functional properties compared to SRIF and first-generation SRLs when binding SSTs. METHODS: We aimed to highlight the differential receptor-targeted action of pasireotide in the treatment of somatotroph and corticotroph adenomas, throughout the critical revision of preclinical studies carried out on acromegaly and CD models. RESULTS: Different authors demonstrated that the antisecretory effect of pasireotide in somatotroph adenoma cell cultures is comparable to that of the SST2-preferential agonist octreotide. Some reports even show a direct correlation between SST2 mRNA expression and GH reduction after pasireotide treatment, thus laying for a predominant role of SST2 in driving pasireotide efficacy in somatotropinomas in vitro. On the other hand, the inhibitory effect of pasireotide on ACTH secretion in corticotropinoma cells seems to be mainly mediated by SST5. Indeed, most reports show a higher potency and efficacy of pasireotide compared to SST2 preferential agonists, while functional studies confirm the pivotal role of SST5 targeting in corticotroph cells. CONCLUSIONS: The analysis of preclinical studies carried out in somatotroph and corticoph adenomas points out that pasireotide shows a cell-specific activity, exerting its biological effects via different SSTs in the different adenoma histotypes. PMID- 30483919 TI - A neurosurgical approach to traumatic brain injury and post-traumatic hypopituitarism. AB - PURPOSE: Traumatic brain injury (TBI) is a common cause of mortality and major disability worldwide. The initial management often depends on the severity of the injury. Pituitary dysfunction can develop as a sequela of TBI, and can have long term, debilitating impact on the patients. Early identification and prompt intervention of post-traumatic hypopituitarism (PTHP) is essential to prevent or minimize the adverse consequences of this condition. We hereby provide an overview of the current management of TBI from a neurosurgical standpoint. We then review the pathophysiology and risk factors of developing PTHP, as well as our recommendations for its management. METHODS: A review of current literature on TBI and PTHP, including primary research articles, reviews and clinical guidelines. RESULTS: The current neurosurgical approach to the management of TBI is presented, followed by the pathophysiology and risk factors of PTHP, as well as our recommendations for its management. CONCLUSIONS: Post-traumatic hypopitutiarism is a serious and potentially debilitating condition that is likely under-recognised and under-diagnosed. From a neurosurgical perspective, we advocate a pragmatic approach, i.e. screening those considered at high risk of developing PTHP based on clinical features and biochemical/endocrinological testings; and referring them to a specialist endocrinologist for further management as indicated. PMID- 30483921 TI - Preface. PMID- 30483920 TI - Brick tea consumption is a risk factor for dental caries and dental fluorosis among 12-year-old Tibetan children in Ganzi. AB - Brick tea contains high concentration of fluoride. The aim of the present work was to explore whether and how the brick tea is a risk factor for dental caries and dental fluorosis among Tibetan children in Ganzi. A cross-sectional study was conducted with 368 12-year-old Tibetan children in Ganzi. Dental caries was measured by DMFT index, and dental fluorosis severity was measured by Dean's Index. Community Fluorosis Index was used to estimate public health significance of dental fluorosis. Oral health-related behaviors and awareness, dietary habits and socioeconomic status were determined by a questionnaire. Bivariate and multivariate analyses were used to determine risk factors associated with dental caries and dental fluorosis. Dental caries prevalence was 37.50%, mean DMFT was 0.84 +/- 1.53, while dental fluorosis prevalence was 62.23%. Community Fluorosis Index was 1.35, indicating a medium prevalent strength of dental fluorosis. Dental fluorosis was associated with mother's regular consumption of brick tea and residence altitude, and dental caries was associated with mother's regular consumption of brick tea. Mother's regular consumption of brick tea was a risk factor for both dental fluorosis and dental caries among children. Reducing mother's brick tea consumption during pregnancy and lactation may improve oral health status of their children. PMID- 30483922 TI - Latinx Youth in First Contact with the Justice System: Trauma and Associated Behavioral Health Needs. AB - This study examines the prevalence of trauma exposure and its association with psychiatric symptoms, substance use, and sexual activity among First-Time Offending, Court-Involved Non-Incarcerated (FTO-CINI) Latinx youth. Latinx youth (N = 181), ages 12-18, were recruited from a family court in the Northeastern region of the United States as part of a longitudinal cohort study of 423 FTO CINI youth. Baseline data on trauma exposure and symptoms, psychiatric symptoms, substance use (alcohol/marijuana), and sexual activity among the Latinx sample were analyzed by age, gender, and offense type (status versus delinquent). Almost three-quarters of Latinx FTO-CINI youth reported lifetime trauma exposure. Almost half of Latinx youth reported lifetime marijuana use, 30% reported lifetime alcohol use, and 33% reported lifetime sexual activity. Females reported higher rates of internalizing symptoms and greater affect dysregulation. Trauma-exposed youth were more likely than their non-exposed peers to have reported more externalizing symptoms; trauma-exposed females compared to trauma-exposed males reported more severe internalizing symptoms. Latinx FTO-CINI females may have different behavioral health needs than their male counterparts. Court-based screening and assessment practices should attend to the specific behavioral needs of this unique, underserved population. PMID- 30483923 TI - A Simple Method for Comparing Complex Models: Bayesian Model Comparison for Hierarchical Multinomial Processing Tree Models Using Warp-III Bridge Sampling. AB - Multinomial processing trees (MPTs) are a popular class of cognitive models for categorical data. Typically, researchers compare several MPTs, each equipped with many parameters, especially when the models are implemented in a hierarchical framework. A Bayesian solution is to compute posterior model probabilities and Bayes factors. Both quantities, however, rely on the marginal likelihood, a high dimensional integral that cannot be evaluated analytically. In this case study, we show how Warp-III bridge sampling can be used to compute the marginal likelihood for hierarchical MPTs. We illustrate the procedure with two published data sets and demonstrate how Warp-III facilitates Bayesian model averaging. PMID- 30483924 TI - Semi-sparse PCA. AB - It is well known that the classical exploratory factor analysis (EFA) of data with more observations than variables has several types of indeterminacy. We study the factor indeterminacy and show some new aspects of this problem by considering EFA as a specific data matrix decomposition. We adopt a new approach to the EFA estimation and achieve a new characterization of the factor indeterminacy problem. A new alternative model is proposed, which gives determinate factors and can be seen as a semi-sparse principal component analysis (PCA). An alternating algorithm is developed, where in each step a Procrustes problem is solved. It is demonstrated that the new model/algorithm can act as a specific sparse PCA and as a low-rank-plus-sparse matrix decomposition. Numerical examples with several large data sets illustrate the versatility of the new model, and the performance and behaviour of its algorithmic implementation. PMID- 30483925 TI - Tests of Matrix Structure for Construct Validation. AB - Psychologists and other behavioral scientists are frequently interested in whether a questionnaire measures a latent construct. Attempts to address this issue are referred to as construct validation. We describe and extend nonparametric hypothesis testing procedures to assess matrix structures, which can be used for construct validation. These methods are based on a quadratic assignment framework and can be used either by themselves or to check the robustness of other methods. We investigate the performance of these matrix structure tests through simulations and demonstrate their use by analyzing a big five personality traits questionnaire administered as part of the Health and Retirement Study. We also derive rates of convergence for our overall test to better understand its behavior. PMID- 30483926 TI - [Modern surgery for rheumatic diseases]. PMID- 30483928 TI - ? PMID- 30483927 TI - ? PMID- 30483929 TI - ? PMID- 30483930 TI - Alteration in branchial NKA and NKCC ion-transporter expression and ionocyte distribution in adult hilsa during up-river migration. AB - Hilsa (Tenualosa ilisha) is a clupeid that migrates from the off-shore area through the freshwater river for spawning. The purpose of this study was to investigate the involvement of branchial Na+/K+-ATPase (NKA) and Na+/K+/2Cl- cotransporter (NKCC) in maintaining ionic homeostasis in hilsa while moving across the salt barriers. Hilsa, migrating through marine and brackish waters, did not show any significant decline in NKA activity, plasma osmolality, and plasma ionic concentration. In contrast, all the parameters declined significantly, after the fish reached in freshwater zone of the river. Immunoblotting with NKA alpha antibody recognized two bands in gill homogenates. The intensity of the higher molecular NKA band decreased, while the other band subsequently increased accompanying the movement of hilsa from marine water (MW) to freshwater. Nevertheless, total NKA expression in marine water did not change prior to freshwater entry. NKCC expression was down-regulated in gill, parallel with NKA activity, as the fish approached to the freshwater stretch of river. The NKA alpha-1 and NKCC1 protein abundance decreased in freshwater individuals by 40% and 31%, respectively, compared to MW. NKA and NKCC1 were explicitly localized to branchial ionocytes and immunoreactive signal appeared throughout the cytoplasm except for the nucleus and the most apical region indicates a basolateral/tubular distribution. Immunoreactive ionocytes were distributed on the filaments and lamellae; lamellar ionocytes were more in number irrespective of habitat salinity. The decrease in salinity caused a slight reduction in ionocyte number, but not in size and the underlying distribution pattern did not alter. The overall results support previously proposed models that both the ion transporters are involved in maintaining ionic homeostasis and lamellar ionocytes may have the function in hypo-osmoregulation in migrating hilsa, unlike other anadromous teleosts. PMID- 30483931 TI - Acute temperature effects on metabolic rate, ventilation, diffusive water exchange, osmoregulation, and acid-base status in the Pacific hagfish (Eptatretus stoutii). AB - The Pacific hagfish (Eptatretus stoutii) is a representative of the most basal extant craniates, and is a marine osmoconformer with an extremely low metabolic rate (MO2 = 475 umol O2/kg/h at 12 degrees C). We investigated potential physiological trade-offs associated with compensatory changes in gill ventilation and perfusion when 12 degrees C-acclimated hagfish were acutely exposed to 7 degrees C or 17 degrees C, as reflected in diffusive unidirectional water flux ([Formula: see text], measured with tritiated water: 3H2O), net ammonia flux (Jamm), and plasma ion and acid-base status. [Formula: see text] was high (~ 1.4 L/kg/h at 12 degrees C) in comparison to marine teleosts and elasmobranchs. MO2 increased linearly with temperature (R2 = 0.991), and was more sensitive (Q10 = 3.22) in the 12-7 degrees C range than either Jamm (1.86) or [Formula: see text] (1.35), but the pattern reversed from 12 to 17 degrees C (Q10s: MO2 = 2.77, Jamm = 2.88, [Formula: see text] = 4.01). Heart rate, ventilatory index (a proxy for total ventilation), and coughing frequency also increased but with different patterns. At 17 degrees C, plasma [Ca2+] and [Mg2+] decreased, although osmolality increased, associated with elevations in plasma [Na+] and [Cl-]. Blood pH and PCO2 were unaffected by acute temperature changes while [HCO3-] increased. Hyperoxia (PO2 > 300 Torr) attenuated the increase in [Formula: see text] at 17 degrees C, did not affect Jamm, and had diverse effects on plasma ion and acid base status. Our results suggest a clear osmorespiratory compromise occurring for the diffusive water fluxes as a result of acute temperature changes in this osmoconformer. PMID- 30483932 TI - Meta-Analysis Should be Done in a Normative Manner. PMID- 30483933 TI - High- and Extra-High-Profile Round Implants in Breast Augmentation: Guidelines to Prevent Rippling and Implant Edge Visibility. AB - BACKGROUND: Rippling and implant edge visibility after breast augmentation depends on several factors. Among the most relevant are breast soft tissue thickness, particularly the retroareolar mammary parenchyma, and implant profile. They were correlates to prevent these occurrences. METHODS: Thirty patients underwent breast augmentation through subfascial dissection involving the pectoralis, serratus, external oblique, and rectus abdominis fascias. The thickness of the retroareolar mammary parenchyma distributed patients into two groups. Group I: patients with thickness equal to or greater than 4.0 cm received high-profile 85% fill round implants. Group II: patients with thickness up to 3.9 cm received extra-high-profile 100% fill round implants. MRI was performed preoperatively and 5 years after augmentation to evaluate breast tissue changes and implant contouring. RESULTS: Seventeen patients with high-profile implants and thirteen patients with extra-high-profile implants had noticeable improvement of the breasts without the occurrence of rippling or implant edge visibility. A natural appearance of the breast, increased mammary cone, balanced upper and lower pole contouring was maintained at 5 years postoperatively. MRI performed 5 years after breast augmentation validated patient clinical outcomes not evidencing implant deformities, or soft tissue thinning, parenchymal atrophy or chest wall deformities. CONCLUSIONS: The adequate correlation between retroareolar mammary parenchyma thickness with high-profile 85% fill and extra high-profile 100% fill textured round implants was of utmost importance in preventing rippling and implant edge visibility. The wide fascial support, width of the implant smaller than the breast diameter, and soft cohesive gel-filled implants were co-adjuvant factors in preventing rippling and implant edge visibility. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 30483934 TI - Evaluation of Glandular Liposculpture as a Single Treatment for Grades I and II Gynecomastia. PMID- 30483935 TI - Fat Grafting in Composite Breast Augmentation with Round Implants: A New Concept for Breast Reshaping. PMID- 30483936 TI - Levator Pull-Out Suture Technique for Immediate Postoperative Correction of Eyelid Asymmetry After Ptosis Surgery in Asians. AB - BACKGROUND: Postoperative eyelid asymmetry is the most common complaint of patients after undergoing blepharoplasty and ptosis correction surgery. Calibrating eyelid asymmetry during ptosis correction surgery is still difficult for surgeons despite the development of innovative procedures. Our levator pull out suture technique for correcting postoperative eyelid asymmetry after ptosis surgery is introduced. METHODS: A total of 330 patients who underwent ptosis correction surgery with upper blepharoplasty from 2016 to 2017 were enrolled in our study. All surgeries were performed using the levator pull-out suture technique, and the postoperative eyelid asymmetry was corrected in the outpatient clinic at 2-3 days after the operation. Patient satisfaction was evaluated preoperatively and at 1 week and 2 months postoperatively using a questionnaire. Visual acuity, marginal reflex distance 1 (MRD1), and vertical palpebral fissure length asymmetry were measured preoperatively and compared to values taken postoperatively. RESULTS: Patient satisfaction regarding asymmetry increased from 2.7/5 (preoperatively) to 4.1/5 points (postoperatively). MRD1 and vertical palpebral fissure length increased from 1.1/1.2 and 6.8/6.8 mm (preoperatively), respectively, to 2.8/2.9 and 8.5/8.6 mm (postoperatively), respectively. The asymmetry of MRD1 and vertical palpebral fissure length before and after surgery were corrected from 0.45/1.81 to 0.01/0.19 mm (p < 0.01). CONCLUSION: Our innovative surgical method of using the levator pull-out suture technique is relatively simple and allows for finer suture adjustments postoperatively to effectively correct eyelid asymmetry, with satisfactory results. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 30483937 TI - Photobiomodulation Improved the First Stages of Wound Healing Process After Abdominoplasty: An Experimental, Double-Blinded, Non-randomized Clinical Trial. AB - BACKGROUND: Photobiomodulation is widely studied for its potential benefits in the wound healing process. Numerous scientific studies have highlighted its effect on various phases of wound repair, but clinical validations are few. This comparative trial aims to evaluate the influence of photobiomodulation on the post-abdominoplasty healing process. METHODS: Seventeen Caucasian women (aged 18 55) who underwent an abdominoplasty were enrolled in this double-blinded, controlled clinical trial. The postoperative scars were divided into two areas; the right side of the scars was treated with ten sessions of photobiomodulation (consisting in three types of wavelengths). The other part of the scars was used as control and did not receive any additional treatment. Clinical assessments of both parts of the scars were scheduled at 1, 6 and 12 months postoperative. RESULTS: Within six months following surgery, significantly improved quality of the scars on the treated side compared with the untreated side was reported by patients and experienced professionals according to Vancouver Scar Scale, Patient and Observer Scar Assessment Scale (p < 0.05) and standardized photographs (p < 0.05). At 1 year of follow-up, patients observed no differences between the treated and untreated sides of the scars. This suggests that photobiomodulation appears to play an early role in the wound healing process, accelerating the first stages of cicatrization. CONCLUSION: This study statistically validates the positive impact of photobiomodulation treatment on the first stages of the postoperative healing process. Carried out on Caucasians participants only, this study should, however, be performed on a more heterogeneous population to definitively confirm these effects on an international population. CLINICAL TRIAL REGISTRY: Registro Brasileiro de ensaios clinicos: http://www.ensaiosclinicos.gov.br , Trial RBR-49PK78. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 30483938 TI - Secondary Breast Augmentation: Is there a Trend for Bigger Implants? PMID- 30483939 TI - Functional Annotation and Analysis of Dual Oxidase 1 (DUOX1): a Potential Anti pyocyanin Immune Component. AB - Dual Oxidase 1 (DUOX1) is a prominent immune system component primarily expressed in esophagus, lungs, skin, and urinary bladder including others. DUOX1 is involved in lactoperoxidase-mediated innate immunity at mucosal surfaces by generation of antimicrobial hypothiocyanite at the apical surface of epithelial lining. Upon detection of bacterial pathogens mainly Pseudomonas aeruginosa, DUOX1 is activated in bronchial epithelial cells. Both the host and pathogen enter a redox dual with DUOX1 and hypothiocyanite from host and Pyocyanin (PCN) as a redox active virulence factor from P. aeruginosa. The synergy of the both enzymes permanently oxidizes PCN and thus holds the potential to prevent PCN induced virulence, which otherwise paves the way for establishment of persistent chronic infection. In this study, we structurally and functionally annotated the DUOX1, predicted its 3d structure, physio-chemical properties, post-translational modifications, and genetic polymorphism analysis with subsequent disease associated single-nucleotide variations and their impact on DUOX1 functionality by employing in silico approaches. DUOX1 holds greater homology with gorilla and chimpanzee than other primates. The localization signal peptide was present at the beginning of the peptide with cleavage site at 22 aa position. Three distinct functional domains were observed based on homology: An_peroxidase, FRQ1, and oxido-reductase domains. Polymorphism analysis revealed > 60 SNPs associated with different cancers with probable damaging effects. No cancer-associated methylated island was observed for DUOX1. Three-dimensional structure was developed via homology modeling strategy. The proper annotation will help in characterization of DUOX1 and enhance our knowledge of its functionality and biological roles. PMID- 30483940 TI - The significance of selected prognostic factors in pediatric tympanoplasty. AB - OBJECTIVES: The aim of this study was to determine the importance of selected prognostic factors on outcomes of tympanoplasty in children. MATERIALS AND METHODS: 241 children classified into three age groups (3-7, 8-12 and 13-18), had undergone tympanoplasty between 2001 and 2007 and were subsequently observed for at least 2 years. Prognostic factors were assessed with regard to their impact on the functional and anatomical outcome of the tympanoplasty defined, respectively, as postoperative air-bone gap and state of the middle ear. RESULTS: In 85% of children, a tympanic membrane reconstruction was performed. An unchanged TM was achieved in 85% of the patients in early results and in 76% in later results. Air bone gap closure was observed in 66% of cases. The earlier preventive retraction pocket tympanoplasty was performed, the better anatomical results were obtained ranging from 91% in the 3-7 age group versus 75-70% in 8-12 and 13-18 age groups. The results of total or subtotal perforation reconstructions were worse than for small perforation with closure rates of 76.5% vs 94.5%, respectively. CONCLUSION: Age is not a factor determining the success rate in pediatric tympanoplasty. A better surgical outcome can be achieved in children with a dry ear, and better middle ear condition, because of previously performed surgeries. Preventive tympanoplasty is also advantageous. The hearing results in type 2 and 3 tympanoplasty are similar, but type 1 tympanoplasty has superior efficacy to the former two types. PMID- 30483941 TI - Odontogenic rhinosinusitis and sinonasal complications of dental disease or treatment: prospective validation of a classification and treatment protocol. AB - PURPOSE: Odontogenic sinusitis and sinonasal complications of dental disease or treatment (SCDDT) represent a heterogeneous group of conditions that often require multidisciplinary care. The present study aims to prospectively validate a classification and treatment protocol for SCDDT patients. METHODS: One hundred twenty-eight consecutive patients (73 females and 45 males, mean age 52.4 years) affected by SCDDT not responding to dental and medical therapy were classified and surgically treated according to the proposed protocol. The protocol classified patients into three aetiology-based groups (preimplantologic, implantologic, and related to traditional dental diseases and procedures, respectively). The groups were further divided into classes according to the presence of oro-antral communications and/or dislocated dental hardware. Each condition was treated according to the class-related, protocol-defined treatment, by either a transnasal or combined transnasal/transoral approach. All patients were successfully classified according to our protocol. None of the proposed classes were redundant, and no condition fell outside the definitions. RESULTS: The surgical treatment protocol proved to be adequate and effective, in that 125 of the 128 patients completely recovered after surgical treatment. CONCLUSIONS: The term SCDDT and the consequent classification proposed by the authors appear, therefore, to be nosologically correct. Furthermore, the protocol-related proposed treatment appears to be clinically sound, with a success rate nearing 98%. PMID- 30483942 TI - The relationship between endoscopic and radiologic findings and olfactory status of patients with chronic rhinosinusitis with nasal polyps before and after the endoscopic sinus surgery. AB - INTRODUCTION: This study was attempted to investigate the relationship between radiologic and endoscopic findings and pre- and post-operative olfactory scores in chronic rhinosinusitis with nasal polyps. MATERIALS AND METHODS: In this study, 40 patients aged 19-64 years with chronic rhinosinusitis with nasal polyps (CRSwNP) undergoing endoscopic sinus surgery were involved. The patients' olfactory status was evaluated using Smell Identification Test (Iran SIT) before and 3 months after the surgery. Patients' nasal endoscopic signs were recorded using Modified Lund-Kennedy scoring system before and 3 months after the surgery and radiological symptoms were recorded based on Lund-Mackay CT scoring before the surgery. Then the relationship between olfactory status and endoscopic and radiological findings was investigated. RESULTS: With respect to mean of olfactory score, a significant difference was observed before and after the surgery (p value = 0.001). There was a significant difference between means of pre- and post-operative endoscopy scores (p value = 0.001). Pre-operative endoscopic and CT scan scores had a negative correlation with pre- and post operative olfactory scores (p value < 0.05). Pre-op. olfactory scores had negative correlation with post-op. endoscopy scores (p value = 0.02). Post-op. olfactory scores had negative correlation with post-op. endoscopy scores but was not statistically significant (p value = 0.22). CONCLUSION: Our results revealed that pre-operative endoscopy and radiology findings were consistent with the olfactory status of patients with CRSwNP before and after endoscopic sinus surgery. PMID- 30483943 TI - Glottic configuration changes and outcomes of endoscopic arytenoid abduction lateropexy. AB - INTRODUCTION: Endoscopic arytenoid abduction lateropexy (EAAL) is an effective glottis enlarging procedure for the treatment of bilateral vocal cord palsy (BVCP). The postoperative glottic configuration changes can be evaluated by modern, high-resolution, 3D image reconstructions. Functional results are described by spirometry as well as objective and subjective phoniatric tests. METHODS: Unilateral EAAL was performed in ten malignant thyroid gland tumor patients (eight women, two men), who had BVCP after thyroid surgery. Slicer 3D(r) software was used for morphometric analysis. Pre- and postoperative peak inspiratory flow (PIF) and standard phoniatric parameters were compared. RESULTS: The glottic gap improved significantly (+ 60%). Significant improvement of PIF was found in all cases. Phoniatric tests revealed better quality of voice and patient satisfaction. Their voices changed from a severely impaired to a socially acceptable, almost normal, quality. CONCLUSION: The results support our clinical observations that the ideal position of the lateralization sutures is the one which provides a physiological abduction position of the arytenoid cartilage. Considering these good results, the surgical indications for minimally invasive endoscopic arytenoid lateropexy may be extended. PMID- 30483944 TI - Renewed assessment of the risk of emergent advanced cell therapies to transmit neuroproteinopathies. AB - The inadvertent transmission of long incubating, untreatable and fatal neurodegenerative prionopathies, notably iatrogenic Creutzfeldt-Jakob disease, following transplantation of cadaver-derived corneas, pituitary growth, hormones and dura mater, constitutes a historical precedent which has underpinned the application of precautionary principles to modern day advanced cell therapies. To date these have been reflected by geographic or medical history risk-based deferral of tissue donors. Emergent understanding of other prion-like proteinopathies, their potential independence from prions as a transmissible agent and the variable capability of scalably manufacturable stem cells and derivatives to take up and clear or to propagate prions, substantiate further commitment to qualifying neurodegenerative proteinopathy transmission risks. This is especially so for those involving direct or facilitated access to a recipient's brain or connected visual or nervous system such as for the treatment of stroke, retinal and adult onset neurodegenerative diseases, treatments for which have already commenced. In this review, we assess the prospective global dissemination of advanced cell therapies founded on transplantation or exposure to allogeneic human cells, recap lessons learned from the historical precedents of CJD transmission and review recent advances and current limits in understanding of prion and other neurodegenerative disease prion-like susceptibility and transmission. From these we propose grounds for a reassessment of the risks of emergent advanced cell therapies to transmit neuroproteinopathies and suggestions to ACT developers and regulators for risk mitigation and extension of criteria for deferrals. PMID- 30483945 TI - Post-stroke inflammation-target or tool for therapy? AB - Inflammation is currently considered a prime target for the development of new stroke therapies. In the acute phase of ischemic stroke, microglia are activated and then circulating immune cells invade the peri-infarct and infarct core. Resident and infiltrating cells together orchestrate the post-stroke inflammatory response, communicating with each other and the ischemic neurons, through soluble and membrane-bound signaling molecules, including cytokines. Inflammation can be both detrimental and beneficial at particular stages after a stroke. While it can contribute to expansion of the infarct, it is also responsible for infarct resolution, and influences remodeling and repair. Several pre-clinical and clinical proof-of-concept studies have suggested the effectiveness of pharmacological interventions that target inflammation post-stroke. Experimental evidence shows that targeting certain inflammatory cytokines, such as tumor necrosis factor, interleukin (IL)-1, IL-6, and IL-10, holds promise. However, as these cytokines possess non-redundant protective and immunoregulatory functions, their neutralization or augmentation carries a risk of unwanted side effects, and clinical translation is, therefore, challenging. This review summarizes the cell biology of the post-stroke inflammatory response and discusses pharmacological interventions targeting inflammation in the acute phase after a stroke that may be used alone or in combination with recanalization therapies. Development of next-generation immune therapies should ideally aim at selectively neutralizing pathogenic immune signaling, enhancing tissue preservation, promoting neurological recovery and leaving normal function intact. PMID- 30483946 TI - Influence of biofilms on morbidity associated with short-term indwelling ureteral stents: a prospective observational study. AB - PURPOSE: To evaluate the influence of biofilms on morbidity associated with short term ureteral stenting using contemporary methods of biofilm examination and validated assessment of symptoms. METHODS: Patients undergoing temporary ureteral stenting for secondary ureterorenoscopy due to urinary calculi were prospectively included. The German Ureteral Stent Symptoms Questionnaire (USSQ) was used to assess stent-associated morbidity. Biofilms were removed from stents using 'pinhole extraction', a novel, validated, abrasion-based technique. Extracted biofilms were analyzed for total mass, bacterial load and mineral components. Correlation between total biofilm mass and USSQ total score was the primary outcome variable analyzed using Spearman correlation. Secondary outcomes included correlations between various biofilm characteristics and symptoms. RESULTS: 94 patients were included in the analysis. Extracted biofilm mass had a median of 37.0 mg (0-310.2 mg) per stent. No correlation between total biofilm mass and USSQ total score was found (Spearman r = 0.012; p = 0.911). Correlations between biofilm characteristics and morbidity were generally weak and not significant. Significant correlations could be found between biofilm mass and hematuria (r = 0.280; p = 0.007), and between the number of bacteria (qPCR) and the USSQ subscore for pain (r = 0.243; p = 0.019) and the intake of analgesics (r = 0.259; p = 0.012). CONCLUSION: Based on elaborated biofilm examination methods and validated self-reported outcome measures, our findings indicate that biofilms might aggravate some lower urinary tract symptoms but are not the main trigger for stent-associated morbidity in short-term ureteral stenting. PMID- 30483947 TI - Is time from diagnosis to radical prostatectomy associated with oncological outcomes? AB - PURPOSE: To study the association between time from diagnosis to radical prostatectomy (RP-interval) and prostate cancer-specific mortality (PCSM), histological findings in the RP-specimen and failure after RP (RP-failure). METHODS: Patients diagnosed with non-metastatic prostate cancer (PCa) in 2001 2010 and prostatectomized within 180 days of biopsy were identified in the Cancer Registry of Norway and the Norwegian Prostate Cancer Registry. Patients were stratified according to risk groups and RP-intervals of 0-60, 61-90, 91-120 and 121-180 days. Aalen-Johansen and Kaplan-Meier methods estimated curves for PCSM, RP-failure and overall mortality. Multivariable Cox regressions and Chi-square tests were used to evaluate the impact of RP-interval on outcomes. RESULTS: In 5163 eligible patients, the median time from diagnosis to RP was 93 days (range 1 180). Risk group distribution was similar in all RP-interval groups. With almost eight years of observation, no association was found between RP-interval and PCSM in the intermediate-or high-risk groups. Increasing RP-interval did not increase the rate of adverse histological outcomes or incidence of RP-failure. CONCLUSIONS: Increasing RP-interval up to 180 days was not associated with adverse oncological outcomes at eight years follow-up. These findings should be considered when planning for prostatectomy. PMID- 30483948 TI - Factors associated with lamina cribrosa displacement after trabeculectomy measured by optical coherence tomography in advanced primary open-angle glaucoma. PMID- 30483949 TI - Visual impairment and blindness in institutionalized elderly in Germany. AB - PURPOSE: To determine the prevalence of and identify factors associated with visual impairment and blindness in institutionalized elderly in Germany. METHODS: In this prospective multicenter cross-sectional study, ophthalmic health care need and provision were investigated in institutionalized elderly in 32 nursing homes in Germany. All participants underwent a standardized examination including medical and ocular history, refraction, visual acuity testing, tonometry, biomicroscopy, and dilated funduscopy. A standardized questionnaire was used to identify factors associated with eye healthcare utilization, visual impairment and/or blindness. RESULTS: Visual acuity of 566 (94.3%; 413 women and 153 men) of a total of 600 institutionalized elderly was determined. Mean age of the included patients was 82.9 years (+/- 9.8). Of all participants, 30 (5.3%; 95% CI 3.4 7.2%) were blind and 106 (18.7%; 95% CI 15.5-21.9%) were moderately or severely visually impaired according to the World Health Organization definition. The 136 blind and moderately or severely visually impaired participants were older (OR, Odds Ratio = 1.1, 95% CI 1.0-1.1; p < 0.001), and more likely to have reduced mobility (OR = 12.6, 95% CI 2.8-57.6; p = 0.001). CONCLUSION: A high proportion of blindness and visual impairment was found amongst nursing home residents. Age and reduced mobility were factors associated with an increased likelihood of blindness and visual impairment. Any surveys of blindness and visual impairment excluding nursing homes may considerably underestimate the prevalence of visual impairment and blindness. PMID- 30483950 TI - Impact of ab-interno trabeculectomy on Bruch's membrane opening-based morphometry of the optic nerve head for glaucoma progression analysis. AB - PURPOSE: To analyze the longitudinal change in Bruch's membrane opening minimal rim width (BMO-MRW) and circumpapillary retinal nerve fiber layer (RNFL) thickness using spectral domain optical coherence tomography (SD-OCT) after glaucoma surgery via ab-interno trabeculectomy in adult glaucoma patients. METHODS: Retrospective audit of 65 eyes of 65 participants undergoing ab-interno trabeculectomy using electroablation of the trabecular meshwork. In 53 eyes, surgery was combined with phacoemulsification and posterior chamber lens implantation. Pre- and postoperative SD-OCT examinations of the optic nerve head (ONH), intraocular pressure (IOP), and visual field data were analyzed. Longitudinal change in morphometric SD-OCT parameters of the ONH was compared and correlated to change in IOP and visual field function. RESULTS: BMO-MRW increased significantly between baseline (BL) and follow-up (FU) within the first 6 months after surgery (BL = 167.85 +/- 90 MUm; FU = 175.59 +/- 89 MUm; p = 0.034). This increase correlated with postoperative lowering of IOP (rho = - 0.41; p = 0.016). Nine months after surgery (range, 7-12 months), there was no significant change in BMO-MRW (BL = 196.79 +/- 79; FU = 196.47 +/- 85 MUm; p = 0.95), while in later follow-up, a decrease of BMO-MRW was found (BL = 175.18 +/- 78; FU = 168.65 +/- 72; p = 0.05). RNFL thickness was unchanged in early (p > 0.16) and significantly decreased in later follow-up (p = 0.009). Mean deviation (MD) of visual field function did not show a significant change before and after surgery. CONCLUSION: Electroablative ab-interno trabeculectomy leads to a significant transient mild increase in BMO-MRW. This increase was shown to correlate with IOP lowering. Significant loss of BMO-MRW in later follow-up may reflect insufficient IOP reduction by surgery. The parameters RNFL thickness and MD seem less impacted directly by surgery. PMID- 30483951 TI - The application of defunctioning stomas after low anterior resection of rectal cancer. AB - Defunctioning stomas are frequently used by colorectal surgeons after unsatisfactory anastomosis. The primary purpose of constructing a defunctioning stoma is to prevent an anastomotic leakage or to alleviate the detrimental consequences of it. However, the construction of defunctioning stomas is not free and is associated with adverse impacts on the patient. Stoma-related complications can develop in different stages and can impair a patient's quality of life. Furthermore, one in every four to six defunctioning stomas turns into a non-closure stoma. Since no definite indications for the creation of a defunctioning stoma are available, surgeons have to carefully weigh their benefits against their adverse effects. Thus, the precise selection of patients who should undergo the creation of a defunctioning stoma is of great importance, and an alternative method for preventing anastomotic leakage is needed. PMID- 30483952 TI - Living donor liver transplantation: looking back at my 30 years of experience. AB - Since I moved from the National Cancer Center to Shinshu University, I have been performing living donor liver transplantation (LDLT), which is the only way to save the life of patients with end-stage liver disease. In June 1990, we performed the first LDLT that case was the first successful case in Japan. The patient remains healthy and is enjoying a normal life still 28 years after the transplant. In 1993, we successfully performed adult-to-adult LDLT, which was the first successful case in the world. The patient enjoyed a normal life for 17 years until she died at 70 years of age. For small children, the left liver of adult donors is too large to close the abdomen. However, in adolescents or adults, even when the whole right liver is used, the volume of the graft is too small. The concept of the standard liver volume (SLV) has proven very important for this procedure and is calculated as follows: 706.2 * body surface area + 2.4. We proposed a method for evaluating the congestion of the liver by Doppler ultrasound. In addition, we devised the right lateral sector graft. Over the years, we have contributed to LDLT in many ways and published many papers. We feel that our findings are quite useful not only for LDLT but also for other hepatectomy procedures. PMID- 30483953 TI - The Effect of Linagliptin versus Metformin Treatment-Related Quality of Life in Patients with Type 2 Diabetes Mellitus. AB - INTRODUCTION: There have been no studies directly comparing the effect of dipeptidyl peptidase-4 inhibitors with that of metformin on treatment-related quality of life (QOL) when used as first-line therapy in patients with type 2 diabetes mellitus (T2DM). METHODS: This study is a prospective, randomized, open label, multicenter, parallel-group, comparative study. Forty-four participants who failed to achieve target glycemic control with diet and exercise therapy were randomly allocated to receive linagliptin or metformin therapy. We compared treatment-related QOL among the two groups using the Oral Hypoglycemic Agent Questionnaire, version 2 (OHA-Q version 2) and the self-administered Diabetes Therapy-Related QOL (DTR-QOL) questionnaire. RESULTS: After randomization, 21 patients in the linagliptin group and 22 patients in the metformin treatment group were included in the full analysis set. Biochemical parameters, incidence of adverse effects, and rate of adherence to medication were comparable between the two groups. Over the 24-week treatment period, no significant differences in overall OHA-Q scores between the groups were observed, although the subscale 1 (treatment convenience) score was significantly higher in the linagliptin group than in the metformin group. The overall DTR-QOL score did not differ between the two groups; however, the DTR-QOL scores significantly improved after 24 weeks of linagliptin treatment, but not after metformin treatment. CONCLUSION: We did not find significantly better treatment-related QOL with linagliptin among Japanese patients with T2DM. In terms of treatment convenience, our data showed that linagliptin was superior to metformin. FUNDING: This study was financially supported by Nippon Boehringer Ingelheim Co., Ltd. and Eli Lilly and Company. The journal's article processing fees were covered by a research fund from Juntendo University. CLINICAL TRIAL REGISTRATION: UMIN000022953. PMID- 30483954 TI - Analysis of the prognostic relevance of sex-steroid hormonal receptor mRNA expression in muscle-invasive urothelial carcinoma of the urinary bladder. AB - Muscle-invasive urothelial carcinoma of the urinary bladder (UCB) often recurs following radical cystectomy (RC). An altered expression of sex-steroid hormone receptors has been associated with oncological outcomes of UCB and may represent therapeutic targets. Here the expression of different hormone receptors was measured on mRNA levels in patients treated by RC and associated with outcomes. Androgen receptor (AR), estrogen receptor 1 (ESR1), and progesterone receptor (PGR) mRNA expression was assessed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in RC samples of 87 patients with a median age of 66 (39-88) years. Univariate and multivariate analyses were performed to test associations with pathological and clinical characteristics as well as recurrence-free (RFS) and disease-specific survival (DSS). AR mRNA expression was lower in comparison with ESR1 and PGR expression (p < 0.0001). In univariate analysis, high expression levels of AR were associated with reduced RFS (HR 2.8, p = 0.015) and DSS (HR 2.8, p = 0.010). High AR mRNA expression and a positive lymph node status were independent predictors for reduced RFS (HR 2.5, p = 0.0049) and DSS (HR 3.4, p = 0.009). In patients with low AR mRNA expression, an increased ESR1 and PGR mRNA expression were associated with reduced RFS and DSS. High expression levels of AR are significantly associated with adverse outcome in patients with muscle-invasive UCB following RC. ESR1 and PGR expression status can further stratify patients with low AR expression into subgroups with significantly reduced RFS and DSS. Therapeutic targeting of AR may influence outcomes in patients with UCB. PMID- 30483955 TI - Evaluation of tumor-infiltrating lymphocytes in osteosarcomas of the jaws: a multicenter study. AB - The aim of the present study was to investigate the profile of tumor-infiltrating lymphocytes (TIL) in osteosarcomas of the jaws (OSJ). A total of 21 OSJ samples were analyzed in a retrospective and cross-sectional multicenter study. Immunohistochemistry was performed to determine the recognition of TIL such as CD4+, CD8+, granzyme B+ (GrB), programmed cell death protein+ (PD-1), and cytotoxic T lymphocyte-associated antigen 4+ (CTLA-4) in intratumoral and peripheral (stromal) regions. Positivity was determined based on the percentage and density of TIL+ per square millimeter [1 = absent (< 25 cells/mm2), 2 = low (25 to 130 cells/mm2), and 3 = high (> 130 cells/mm2)]. The association of TIL density with clinicopathologic data was determined by the Mann-Whitney test (p < 0.05). OSJ were positive for CD8+ cells in 45% (n = 9) of cases, for CD4+ cells in 30% (n = 6) of cases, and for CTLA-4+ in 4.8% (n = 1) of cases, with a score of 2 (low TIL) in all cases. All cases were negative for GrB and PD-1 (score 1). No association was observed between immune infiltrate and clinicopathologic findings. OSJ showed a microenvironment with low TIL, including failure of effectiveness of the antitumor immune response (absence of GrB+ cells), and few cells exhibited immunotherapeutic targets, such as CTLA-4 and PD-1. PMID- 30483956 TI - Measurement of blood flow in myocardial layers: A step toward comprehensive physiological evaluation. PMID- 30483957 TI - Assessing severity of cardiac sarcoid: Is SUV the answer? PMID- 30483959 TI - What is this image? 2018: Image 4 result : PET-CT appearance of benign lipomatous hypertrophy of inter-atrial septum. PMID- 30483958 TI - Safety of regadenoson positon emission tomography stress testing in orthotopic heart transplant patients. AB - OBJECTIVES: We sought to determine the safety of regadenoson (REG) stress testing in patients who have undergone orthotopic heart transplantation (OHT). BACKGROUND: Routine screening for cardiac allograft vasculopathy (CAV) is necessary after OHT. Adenosine stress is contraindicated after heart transplantation due to supersensitivity in denervated hearts. Safety of regadenoson stress following OHT has not been well studied. METHODS: We retrospectively reviewed data from OHT patients (N = 123) who were referred to REG stress testing. Medical records were reviewed to determine hemodynamic and ECG response to regadenoson and to identify adverse reactions. RESULTS: No serious adverse events occurred. No life-threatening arrhythmias or hemodynamic changes occurred. Common side-effects related to regadenoson were observed, dyspnea being the most frequent (66.7%). On average the heart rate rose from 82.8 +/- 12 to 95.7 +/- 13.4 bpm (P < 0.001), systolic blood pressure decreased from 138.7 +/- 20.9 to 115.9 +/- 23.9 mmHg (P < 0.001) and mean arterial pressure decreased from 103.5 +/- 14.1 to 84.72 +/- 15.90 mmHg (P < 0.001) during stress protocol. There was no sustained ventricular tachycardia, ventricular fibrillation, or second-or third-degree atrioventricular block. CONCLUSION: Regadenoson stress testing appears to be well tolerated and safe in OHT patients. PMID- 30483960 TI - A novel ISLR2-linked autosomal recessive syndrome of congenital hydrocephalus, arthrogryposis and abdominal distension. AB - ISLR2 (immunoglobulin superfamily containing leucine-rich repeat 2), encodes a protein involved in axon guidance in brain development (hence the other name leucine-rich repeat domain- and immunoglobulin domain-containing axon extension proteins; LINX). A recently described mouse knockout displays hydrocephalus. However, the corresponding phenotype in humans is unknown. Here, we describe a multiplex consanguineous family in which a homozygous truncating variant in ISLR2 segregates with severe congenital hydrocephalus, arthrogryposis multiplex congenita and abdominal distension. We suggest this syndrome may represent the human "knockout" phenotype for ISLR2. PMID- 30483962 TI - New sagittal classification of AIS: validation by 3D characterization. AB - INTRODUCTION AND AIM: In order to improve surgical planning of sagittal correction in AIS, we proposed a new sagittal classification-Abelin-Genevois et al. Eur Spine J (27(9):2192-2202, 2018. https://doi.org/10.1007/s00586-018-5613-1 ). The main criticism is related to the fact that 2D lateral view results from the projection of the 3D deformity. The aim of this study is to show that the new sagittal classification system is a reliable system to describe the different sagittal scenarios that AIS could create both in 2D and 3D. METHODS: We performed retrospective radiograph analysis of prospectively collected data from 93 consecutive AIS patients who underwent an examination of the whole spine using the EOS(r) imaging system. 2D (Keops(r)) and 3D analyses (sterEOS(r)) provided frontal and sagittal spinal and spinopelvic parameters. In addition, 3D analysis provided apical vertebra rotation (AVR). RESULTS: Comparing 2D and 3D measurements for the general cohort, excellent correlation can be found for all parameters, but only fairly good for T10L2 and L1S1 angles. The highest variability was observed for T10L2, differences between 2D and 3D measurements being greater when the Cobb angle increased. AVR did not influence concordance between 2D and 3D measurements. Eighty-two percent were similarly classified in 2D and 3D according to the new classification. Misclassified patients were all AIS sagittal type 3 in 3D analysis, thoracolumbar junction (TLJ) lordosis being underestimated on 2D view. DISCUSSION: In conclusion, for the majority of cases (82%), 2D analysis may provide enough information for decision making when using a semi-automated 2D measurement system. However, in severe cases, especially when Cobb angle exceeds 55 degrees , 3D analysis should be used to get a more accurate view on the thoracolumbar junction behavior. These slides can be retrieved under Electronic Supplementary Material. PMID- 30483961 TI - Characteristics of deformity surgery in patients with severe and rigid cervical kyphosis (CK): results of the CSRS-Europe multi-centre study project. AB - INTRODUCTION AND PURPOSE: Little information exists on surgical characteristics, complications and outcomes with corrective surgery for rigid cervical kyphosis (CK). To collate the experience of international experts, the CSRS-Europe initiated an international multi-centre retrospective study. METHODS: Included were patients at all ages with rigid CK. Surgical and patient specific characteristics, complications and outcomes were studied. Radiographic assessment included global and regional sagittal parameters. Cervical sagittal balance was stratified according to the CSRS-Europe classification of sagittal cervical balance (types A-D). RESULTS: Eighty-eight patients with average age of 58 years were included. CK etiology was ankylosing spondlitis (n = 34), iatrogenic (n = 25), degenerative (n = 9), syndromatic (n = 6), neuromuscular (n = 4), traumatic (n = 5), and RA (n = 5). Blood loss averaged 957 ml and the osteotomy grade 4.CK correction and blood loss increased with osteotomy grade (r = 0.4/0.6, p < .01). Patients with different preop sagittal balance types had different approaches, preop deformity parameters and postop alignment changes (e.g. C7-slope, C2-7 SVA, translation). Correction of the regional kyphosis angle (RKA) was average 34 degrees (p < .01). CK-correction was increased in patients with osteoporosis and osteoporotic vertebrae (POV, p = .006). 22% of patients experienced a major long term complication and 14% needed revision surgery. Patients with complications had larger preop RKA (p = .01), RKA-change (p = .005), and postop increase in distal junctional kyphosis angle (p = .02). The POV-Group more often experienced postop complications (p < .0001) and revision surgery (p = .02). Patients with revision surgery had a larger RKA-change (p = .003) and postop translation (p = .04). 21% of patients had a postop segmental motor deficit and the risk was elevated in the POV-Group (p = .001). CONCLUSIONS: Preop patient specific, radiographic and surgical variables had a significant bearing on alignment changes, outcomes and complication occurrence in the treatment of rigid CK. PMID- 30483963 TI - Refeeding in anorexia nervosa. AB - Refeeding in anorexia nervosa is a collaborative enterprise involving multidisciplinary care plans, but clinicians currently lack guidance, as treatment guidelines are based largely on clinical confidence rather than more robust evidence. It seems crucial to identify reproducible approaches to refeeding that simultaneously maximize weight recovery and minimize the associated risks, in addition to improving long-term weight and cognitive and behavioral recovery and reducing relapse rates. We discuss here various approaches to refeeding, including, among others, where, by which route, how rapidly patients are best refed, and ways of choosing between them, taking into account the precautions or the potential effects of medication or of psychological care, to define better care plans for use in clinical practice.Conclusion: The importance of early weight gain for long-term recovery has been demonstrated by several studies in both outpatient and inpatient setting. Recent studies have also provided evidence to support a switch in current care practices for refeeding from a conservative approach to higher calorie refeeding. Finally, the risks of undernutrition/"underfeeding syndrome" and a maintenance of weight suppression are now better identified. Greater caution should still be applied for more severely malnourished < 70% average body weight and/or chronically ill, adult patients. What is Known: * Refeeding is a central part of the treatment in AN and should be a multidisciplinary and collaborative enterprise, together with nutritional rehabilitation and psychological support, but there are no clear guidelines on the management of refeeding in clinical practice. * The risk of a refeeding syndrome is well known and well managed in severely malnourished patients ("conservative approaches"). What is New: * There is evidence that early weight restoration has an impact on outcome, justifying an aggressive approach to refeeding in the early stages of the illness. * The risks of "underfeeding syndrome" and of a maintenance of weight suppression are now better identified and there is sufficient evidence to support a switch in current care practices for refeeding from a conservative approach to higher calorie refeeding. Graphical abstract ?. PMID- 30483964 TI - Polyphosphoinositide-Binding Domains: Insights from Peripheral Membrane and Lipid Transfer Proteins. AB - Within eukaryotic cells, biochemical reactions need to be organized on the surface of membrane compartments that use distinct lipid constituents to dynamically modulate the functions of integral proteins or influence the selective recruitment of peripheral membrane effectors. As a result of these complex interactions, a variety of human pathologies can be traced back to improper communication between proteins and membrane surfaces; either due to mutations that directly alter protein structure or as a result of changes in membrane lipid composition. Among the known structural lipids found in cellular membranes, phosphatidylinositol (PtdIns) is unique in that it also serves as the membrane-anchored precursor of low-abundance regulatory lipids, the polyphosphoinositides (PPIn), which have restricted distributions within specific subcellular compartments. The ability of PPIn lipids to function as signaling platforms relies on both non-specific electrostatic interactions and the selective stereospecific recognition of PPIn headgroups by specialized protein folds. In this chapter, we will attempt to summarize the structural diversity of modular PPIn-interacting domains that facilitate the reversible recruitment and conformational regulation of peripheral membrane proteins. Outside of protein folds capable of capturing PPIn headgroups at the membrane interface, recent studies detailing the selective binding and bilayer extraction of PPIn species by unique functional domains within specific families of lipid-transfer proteins will also be highlighted. Overall, this overview will help to outline the fundamental physiochemical mechanisms that facilitate localized interactions between PPIn lipids and the wide-variety of PPIn-binding proteins that are essential for the coordinate regulation of cellular metabolism and membrane dynamics. PMID- 30483965 TI - Endovascular intervention in the maintenance and rescue of paediatric arteriovenous fistulae for hemodialysis. AB - BACKGROUND: Arteriovenous fistulae (AVF) provide superior primary vascular access for children on chronic dialysis compared to central venous catheters (CVC). However, AVFs inevitably develop complications and will require some intervention to maintain long-term functional patency. METHODS: We report an 'endovascular first' approach to the maintenance and rescue of paediatric AVFs. Thirty interventions targeting 46 lesions in 18 children (median age 11 years [range 5 17]) were performed. Sixty-eight percent of the AVFs were brachio-cephalic fistulae, 26% brachio-basilic fistulae and 5% radio-cephalic fistulae. Immediate functional success was 86% with good dialysis adequacy (mean urea reduction ratio > 70%) at 3 months post procedure. RESULTS: There was one significant complication, consisting of an AVF rupture which was managed with a covered stent. CONCLUSIONS: Repeated interventions may be necessary to maintain AVF patency and avoid central venous catheters. This is the largest series reported to date. PMID- 30483966 TI - Filicide research in the twenty-first century. PMID- 30483967 TI - Traumatic upper plexus palsy: Is the exploration of brachial plexus necessary? AB - Brachial plexus injuries are major injuries of the upper limb resulting in severe dysfunction usually in young patients. Upper trunk injuries of the brachial plexus account for approximately 45% of brachial plexus injuries. Treatment options for upper trunk brachial plexus injuries include exploration of the plexus and microsurgical repair using nerve grafts or nerve transfers. Several published studies presented the results of both techniques, but there are few studies which compared these two techniques. This article summarizes the treatment options for upper trunk brachial plexus injuries, discusses the merits and demerits of each technique, and presents authors' proposed treatment for these injuries. PMID- 30483968 TI - Current concepts in peripheral nerve surgery. AB - The injuries of the peripheral nerves are relatively frequent. Some of them may lead to defects which cannot be repaired with direct end-to-end repair without tension. These injuries may cause function loss to the patient, and they consist a challenge for the treating microsurgeon. Autologous nerve grafts remain the gold standard for bridging the peripheral nerve defects. Nevertheless, there are selected cases where alternative types of nerve reconstruction can be performed in order to cover the peripheral nerve defects. In all these types of reconstruction, the basic principles of microsurgery are necessary and the surgeon should be aware of them in order to achieve a successful reconstruction. The purpose of the present review was to present the most current data concerning the surgical options available for bridging such defects. PMID- 30483969 TI - Clinicopathological features and prognosis of 276 cases of primary small (<= 2 cm) gastric gastrointestinal stromal tumors: a multicenter data review. AB - BACKGROUND: Till present, there are still controversies over the epidemiology, pathological features, types of surgical treatment, and prognoses of primary small gastric GISTs (gGISTs). METHODS: From January 1998 to January 2015, patients with primary small gGIST admitted from four high-volume medical centers of the Southern China were enrolled and their data were analyzed to evaluate their clinicopathological features, treatment and prognostic factors to provide evidence-based medical experience for clinical practice. RESULTS: A total of 276 primary small gGIST cases over a period of 18 years were investigated and had a median age of 60 years (range 27-91 years old). Regarding the tumor sites, 24 (8.7%) cases were in the cardia of the stomach, 107 (38.8%) in the fundus, 117 (42.4%) in the gastric body, and 28 (10.1%) in the gastric antrum. Eleven patients (4.0%) underwent a preoperative biopsy. A total of 137 (49.6%), 75 (27.2%), and 64 (23.2%) patients underwent laparoscopic, open resection, and endoscopic resection, respectively. Sixty-four patients (23.2%) had local endoscopic resection, 172 (62.3%) had wedge resection, 7 (2.5%) had proximal gastrectomy, 19 (6.9%) had distal gastrectomy, and 14 (5.1%) had total gastrectomy. Mitotic counts were <= 5/50, (5-10)/50, and > 10/50 per HPF in 259 (93.8%), 7 (2.5%), and 10 (3.6%) cases, respectively. There were 259 cases (97.1%) of spindle cell type, 7 (2.5%) epithelial cell types and one case (0.4%) of mixed type. Immunohistochemistry showed 74.6% (206/276), 98.2% (271/276), and 97.4% (269/276) of the patients had co-expression of CD34+, CD117+, and DOG-1+, respectively. Thirty-nine patients underwent genetic testing (39/276, 14.1%). Three patients (1.1%) had positive resection margin. Five high-risk patients received follow-up treatment with imatinib with a median follow-up time of 38 months (range 3-156 months). The overall 1-, 3-, and 5-year overall survival rates were 100%, 99.6%, and 99.1%, respectively. CONCLUSION: Though the incidence of primary small gGISTs increased per annum, the overall survival prognoses were high. Surgery or endoscopic resection was the primary mode of treatment. Pathological features of primary small gGISTs were similar to large gGISTs, and to achieve a timely surgical intervention, the identification of intermediate- and high-risk cases should be a future focus of study. PMID- 30483970 TI - The learning curve for a surgeon in robot-assisted laparoscopic pancreaticoduodenectomy: a retrospective study in a high-volume pancreatic center. AB - BACKGROUND: Pancreaticoduodenectomy (PD) is one of the most technically difficult abdominal operations. Recent advances have allowed surgeons to attempt PD using minimally invasive surgery techniques. This retrospective study aimed to analyze the learning curve of a single surgeon who had carried out his first 100 robot assisted laparoscopic pancreaticoduodenectomy (RPD) in a high-volume pancreatic center. METHODS: The data on consecutive patients who underwent RPD for malignant or benign pathologies were prospectively collected and retrospectively analyzed. The data included the demographic data, operative time, estimated blood loss, postoperative length of hospital stay, morbidity rate, mortality rate, and final pathological results. The cumulative sum (CUSUM) analysis was used to identify the inflexion points which corresponded to the learning curve. RESULTS: Between 2012 and 2016, 100 patients underwent RPD by a single surgeon. From the CUSUM operation time (CUSUM OT) learning curve, two distinct phases of the learning process were identified (early 40 patients and late 60 patients). The operation time (mean, 418 min vs. 317 min), hospital stay (mean, 22 days vs. 15 days), and estimated blood loss (mean, 227 ml vs. 134 ml) were significantly lower after the first 40 patients (P < 0.05). The pancreatic fistula, postoperative hemorrhage, delayed gastric emptying, and reoperation rates also decreased in the late 60 patients group (P < 0.05). Non-significant reductions were observed in the incidences of major (Clavien-Dindo Grade II or higher) morbidity, postoperative death, bile leakage, gastric fistula, wound infection, and open conversion. CONCLUSIONS: RPD was technically feasible and safe in selected patients. The learning curve was completed after 40 RPD. Further studies are required to confirm the long-term oncological outcomes of RPD. PMID- 30483971 TI - Randomized trial of a web-based survivor intervention on melanoma prevention behaviors of first-degree relatives. AB - OBJECTIVES: Melanoma can be prevented through reducing sun exposure and detected early by increasing examination of skin for lesions. First-degree relatives of melanoma cases have higher risk than the general population and, therefore, could be targets of behavioral interventions through families. We tested the effects of a family-based web delivered intervention to melanoma families on the melanoma risk reduction behaviors of first-degree relatives of melanoma cases. METHODS: A total of 313 families that included one first-degree relative were recruited to join this randomized trial. All intervention families received access to the Suntalk website developed to promote family communication and behavioral risk reduction among families of melanoma survivors. RESULTS: First degree relatives in the intervention arm significantly increased their yearly performance of both skin self examination and thorough provider examination from baseline to 12-month follow-up while the control FDRs decreased their yearly performance of both of those behaviors (p's = 0.006 and 0.005, respectively). Several sun protection behaviors increased significantly in FDRs in the intervention arm but not the control arm, including wearing a covering on the head (p = 0.005), staying in available shade (p = 0.008), and avoiding sun exposure during peak hours (p = 0.010). Some of these changes were mediated by perceptions of risk and other process variables. CONCLUSIONS: A web-based intervention can reduce risk of melanoma through changes in relevant behaviors among first-degree relatives of melanoma survivors. Future research should identify methods for making this type of intervention accessible to more families and for broadening the reach to other types of cancer families. PRACTICE IMPLICATIONS: This program can be provided to melanoma families to improve their sun protection and screening behaviors, at the point of diagnosis. PMID- 30483972 TI - The potential toxic impact of different gadolinium-based contrast agents combined with 7-T MRI on isolated human lymphocytes. AB - BACKGROUND: To investigate a potentially amplifying genotoxic or cytotoxic effect of different gadolinium-based contrast agents (GBCAs) in combination with ultra high-field 7-T magnetic resonance imaging (MRI) exposure in separated human peripheral blood lymphocytes. METHODS: This in vitro study was approved by the local ethics committee and written informed consent was obtained from all participants. Isolated lymphocytes from twelve healthy donors were incubated with gadobutrol, gadoterate meglumine, gadodiamide, gadopentetate dimeglumine, or gadoxetate either alone or combined with 7-T MRI (1 h). Deoxyribonucleic acid (DNA) double-strand breaks were assessed 15 min after MRI exposure by automated gammaH2AX foci quantification. Cytotoxicity was determined at later endpoints by Annexin V/propidium iodide apoptosis assay (24 h) and [3H]-thymidine proliferation test (72 h). As a reference, lymphocytes from four different donors were exposed analogously to iodinated contrast agents (iomeprol, iopromide) in combination with computed tomography. RESULTS: Baseline gammaH2AX levels (0.08 +/ 0.02 foci/cell) were not significantly (p between 0.135 and 1.000) enhanced after administration of GBCAs regardless of MRI exposure. In contrast to the two investigated macrocyclic GBCAs, lymphocytes exposed to the three linear GBCAs showed a dose-dependent increase in apoptosis (maximum 186% of unexposed control, p < 0.001) and reduced proliferation rate (minimum 0.7% of unexposed control, p < 0.001). However, additional 7-T MRI co-exposure did not alter GBCA-induced cytotoxicity. CONCLUSIONS: Exposure of lymphocytes to different GBCAs did not reveal significant induction of gammaH2AX foci, and enhanced cytotoxicity was only observed in lymphocytes treated with the linear GBCAs used in this study, independent of additional 7-T MRI co-exposure. PMID- 30483974 TI - ASO Author Reflections: Low-grade Appendiceal Mucinous Neoplasia (LAMN): Which Criteria for a "Watch and Wait" Strategy? PMID- 30483973 TI - Intradural "limited drill" technique of anterior clinoidectomy and optic canal unroofing for microneurosurgical management of ophthalmic segment and PCOM aneurysms-review of surgical results. AB - To evaluate the safety and efficacy of intradural "limited drill" technique (ILDT) of anterior clinoidectomy (AC) and optic canal unroofing (OCU) for microneurosurgical management of ophthalmic segment and posterior communicating artery (PCOM) aneurysms. All the patients with ophthalmic segment and PCOM aneurysms who underwent AC and OCU by ILDT for microneurosurgical management of ophthalmic segment and PCOM aneurysms during 4-year period (2013-2016) at our Institute were included in this study. In ILDT of AC and OCU, the use of power drill is restricted to AC only and OCU is done exclusively with 1-mm Kerrison punch. AC and OCU by ILDT were done in 24 patients with 29 ophthalmic segment and 7 PCOM aneurysms. AC and OCU by ILDT helped in mobilization of optic nerve/internal carotid artery (ICA) and provided excellent exposure for all these aneurysms. There was no injury to ICA or optic nerve during drilling. AC and OCU facilitated clip ligation of 34 of these aneurysms. Remaining 2 aneurysms were considered not suitable for clipping. Check angiogram done for 33 aneurysms revealed complete obliteration of 26 aneurysms, very small residual neck in 5 aneurysms, and small residual aneurysm in 2 aneurysms. Deterioration in vision was noted in 1 patient (4.1%). In 6 patients with preoperative visual deficits, significant improvement in vision was noted in 4 patients (4/6-66.6%) after surgery. Good outcome (MRS < 2) was noted in 91.6% (22/24) of these patients. ILDT is a safe and effective technique of AC and OCU which provide good exposure for ophthalmic segment and PCOM aneurysms. PMID- 30483975 TI - Management of Regional Lymph Nodes in Patients with Merkel Cell Carcinoma Following a Positive Sentinel Node Biopsy: Less May be More, But is Either Enough? PMID- 30483976 TI - Higher Tumor Burden Neutralizes Negative Margin Status in Hepatectomy for Colorectal Cancer Liver Metastasis. AB - OBJECTIVE: The aim of this study was to examine if the prognostic significance of margin status in hepatectomy for colorectal cancer liver metastasis (CRLM) varies for different levels of tumor burden because hepatectomy indications for CRLM have been recently expanded to include patients with a higher tumor burden in whom achieving an R0 resection is difficult. METHODS: Clinicopathological variables in an exploration cohort of 290 patients receiving hepatectomy in Japan for CRLM were investigated. R0 resection was defined as a margin width > 0 mm. Tumor burden was assessed using the recently introduced Tumor Burden Score (TBS), which was calculated as TBS2 = (maximum tumor diameter in cm)2 + (number of lesions)2. The principal findings were validated using a cohort from the United States. RESULTS: R1 resection rates significantly increased as TBS increased: 4/86 (4.7%) in patients with TBS < 3, 29/171 (17.0%) in patients with TBS >= 3 and < 9, and 9/33 (27.3%) in patients with TBS >= 9 (p < 0.001). R0 resection was significantly superior to R1 resection in patients with TBS >= 5; however, this was not the case for TBS >= 6, as confirmed by both univariate and multivariate analyses. Furthermore, prehepatectomy chemotherapy was associated with significantly improved survival for patients with TBS >= 8. Analysis of the validation cohort yielded similar results. CONCLUSIONS: R0 resection appeared to have a positive impact on prognosis among patients with low tumor burden; however, this was not the case for patients with high tumor burden. As such, systemic treatment, in addition to surgery, may be central to achieving satisfactory outcomes in the latter patient population. PMID- 30483977 TI - Using body mass index to estimate individualised patient radiation dose in abdominal computed tomography. AB - BACKGROUND: The size-specific dose estimate (SSDE) is a dose-related metrics that incorporates patient size into its calculation. It is usually derived from the volume computed tomography dose index (CTDIvol) by applying a conversion factor determined from manually measured anteroposterior and lateral skin-to-skin patient diameters at the midslice level on computed tomography (CT) localiser images, an awkward, time-consuming, and not highly reproducible technique. The objective of this study was to evaluate the potential for the use of body mass index (BMI) as a size-related metrics alternative to the midslice effective diameter (DE) to obtain a size-specific dose (SSDE) in abdominal CT. METHODS: In this retrospective study of patients who underwent abdominal CT for the investigation of inflammatory bowel disease, the DE was measured on the midslice level on CT-localiser images of each patient. This was correlated with patient BMI and the linear regression equation relating the quantities was calculated. The ratio between the internal and the external abdominal diameters (DRATIO) was also measured to assess correlation with radiation dose. Pearson correlation analysis and linear regression models were used. RESULTS: There was good correlation between DE and patient BMI (r = 0.88). An equation allowing calculation of DE from BMI was calculated by linear regression analysis as follows: DE = 0.76 (BMI) + 9.4. A weak correlation between radiation dose and DRATIO was demonstrated (r = 0.45). CONCLUSIONS: Patient BMI can be used to accurately estimate DE, obviating the need to measure anteroposterior and lateral diameters in order to calculate a SSDE for abdominal CT. PMID- 30483978 TI - Incidence and risk factors of new-onset hypertrophic pachymeningitis in patients with anti-neutrophil antibody-associated vasculitis: using logistic regression and classification tree analysis. AB - OBJECTIVES: Hypertrophic pachymeningitis (HP) is a rare complication in patients with anti-neutrophil antibody-associated vasculitis (AAV); its clinical features, incidence, and risk factors remain unknown. We aimed to clarify the prevalence, clinical features, and factors associated with new-onset HP in patients with AAV. METHOD: A retrospective cohort study involving 93 patients with AAV was conducted. HP incidence between patients with granulomatosis with polyangiitis (GPA) and those with microscopic polyangiitis (MPA) was compared to investigate risk factors associated with HP. We performed only univariate analysis using logistic regression and classification tree (CART) analysis due to the small number of HP cases. RESULTS: Among the 93 patients (76 with MPA and 17 with GPA), only 6 patients developed HP (1 with MPA, 5 with GPA) over an average observation period of 4 years; all patients who developed HP were positive for myeloperoxidase anti-neutrophil antibody. HP incidence was significantly higher in patients with GPA than in those with MPA (60.2 versus 3.3 persons per 1000 person-years, respectively, P = 0.002). The univariate analysis revealed that otitis media (P < 0.001) and sinusitis (P = 0.014) were associated with new-onset HP. Univariate CART analysis grouped the patients into patients with HP who have otitis media (33%) and patients with HP who have sinusitis (21%). The odds ratio of otitis media adjusted by age and first diagnosis of AAV was 38.1 (95% confidence interval, 3.08-331.4; P = 0.004). CONCLUSIONS: Although only in the univariate analysis, otitis media was the most discriminating factor to predict new-onset HP in patients with AAV. PMID- 30483979 TI - Impact of cardiac resynchronization therapy on circulating IL-17 producing cells in patients with advanced heart failure. AB - PURPOSE: IL-17-producing T cells have been implicated in the inflammatory milieu of chronic heart failure (CHF), which implies a dismal prognosis in affected patients. The aim of this study was to evaluate the impact of cardiac resynchronization therapy (CRT) on the frequency and functional activity of Th17 and Tc17 cells, as well as, on IL-17 mRNA expression in patients with CHF. METHODS: Twenty-eight patients with CHF, analyzed before CRT (T0) and 6 months later (T6), and 15 healthy controls (HC) were enrolled in this study. Circulating Th17 and Tc17 cells were evaluated by flow cytometry. The quantification of IL 17A mRNA expression was performed by real-time PCR. RESULTS: Circulating Tc17 cells tended to be higher in CHF patients submitted to CRT than in HC (0.92% (0.24-3.32) versus 0.60% (0.09-3.68), although not reaching statistical significance. The frequency of Tc17 cells in CHF patients significantly decreases after CRT reaching levels similar to those of HC (0.92% (0.24-3.32) at T0 versus 0.56% (0.21-4.20) at T6, P < 0.05), mainly due to responders to CRT. Additionally, the expression of IL-17 mRNA was detected in a few number of responder patients at T0 (27%) and only detected in one responder at T6 (7%). Conversely, in non-responders, the proportion of patients exhibiting IL-17 mRNA expression increases from baseline (17%) to T6 (42%). No significant differences were observed in Th17 cells between HC, CHF patients in T0 and patients in T6. CONCLUSION: The inflammatory response mediated by circulating IL-17 producing cells seems to be suppressed by CRT, particularly in responders. PMID- 30483980 TI - Multipoint left ventricular pacing improves response to cardiac resynchronization therapy with and without pressure-volume loop optimization: comparison of the long-term efficacy of two different programming strategies. AB - PURPOSE: Cardiac resynchronization therapy (CRT) with multipoint left ventricular (LV) pacing (MultiPointTM Pacing [MPP]) improves long-term LV reverse remodeling, though questions persist about how to program LV pacing vectors and delays. We evaluated if an empirical method of programming MPP vectors and delays between pacing pulses improved CRT response similar to pressure-volume loop (PVL) optimized MPP programming. METHODS: Patients undergoing CRT implant (Quadra Assura MPTM CRT-D and QuartetTM LV lead) received MPP with programmed settings optimized either by PVL measurements at implant (PVL-OPT group) or empirically determined by maximizing the spatial separation between the two cathodes and minimal delays between the three ventricular pacing pulses (MAX-SEP group). CRT response was prospectively defined as a reduction in end-systolic volume (ESV) of >= 15% relative to baseline at 6 months as determined by a blinded observer. RESULTS: Patient characteristics at baseline (NYHA II-III, ejection fraction [EF] 27 +/- 6%, QRS 151 +/- 17 ms) were not significantly different between the PVL OPT (n = 27) and MAX-SEP (n = 26) groups. During the follow-up period, there were no differences in the number of patients requiring reprogramming due to phrenic nerve stimulation or a high threshold for PVL-OPT vs. MAX-SEP (5/27 [19%] vs. 7/26 [27%], p = 0.53). After 6 months, ESV reduction, EF increase, and CRT response rate (RR) were similar for PVL-OPT vs. MAX-SEP (ESV - 20 +/- 11 vs. - 22 +/- 11%, p = 0.59; EF + 10 +/- 4 vs. + 9 +/- 7%, p = 0.53; RR 20/27 [74%] vs. 21/26 [81%], p = 0.74), while fewer patients in the PVL-OPT group experienced NYHA class reduction >= 2 (4/27 [15%] vs.15/26 [58%], p = 0.002). CONCLUSIONS: Both evaluated methods of MPP programming resulted in similar CRT outcomes. Empirical MPP programming by maximum spatial separation of LV cathodes may be an effective, simple, and non-invasive alternative to pressure-volume optimization. PMID- 30483981 TI - Incidence, depth, and severity of surgical site infections after neurosurgical interventions. AB - BACKGROUND: Today, there are only few reports on the incidence of surgical site infections (SSIs) in neurosurgery. The objective of this work was to determine the rate of SSI at a tertiary neurosurgical department for benchmarking purpose. METHODS: Data of consecutive patients undergoing neurosurgical treatment between January 2013 and December 2016 were prospectively entered into a registry. SSIs were diagnosed according to the 2017 Centers for Disease Control and Prevention criteria, with severity graded according to the Clavien-Dindo grade (CDG). We analyzed type and length of surgery (LOS), time to SSI, responsible microorganisms, and its association with the functional status (Karnofsky Performance Status = KPS). RESULTS: Of n = 5463 procedures, a SSI occurred in n = 106 (1.94%). The highest rates of SSI occurred after vascular (3.4%) and cerebrospinal fluid (CSF) diversion procedures (3%), as well as after procedures performed to treat a previous complication (2.9%). There was no difference in LOS across procedures with and without SSI. The median time between the index procedure and SSI was 15.5 days. SSIs were most frequently diagnosed after hospital discharge (55%). The most common microorganisms were coagulase-negative staphylococci, Staphylococcus aureus, and Escherichia coli. In 62.3% of cases, SSI required invasive treatment (surgical revision). Patients with SSI in the in- and out-patient setting (SSI occurring after hospital discharge) presented both with a median KPS of 80. CONCLUSIONS: The current report provides an overview on SSI in a contemporary, unselected, large series of patients undergoing modern neurosurgical care for benchmarking purposes. The overall rate of SSI was about 2%, but subpopulations with higher risks were identified where additional measures could be taken to prevent SSI and monitor patients at risk more closely for SSI. PMID- 30483982 TI - Use of intraoperative intracavitary (direct-contact) ultrasound for resection control in transsphenoidal surgery for pituitary tumors: evaluation of a microsurgical series. AB - BACKGROUND: Perisellar infiltration may be responsible for incomplete removal of pituitary tumors. Since intraoperative visualization of parasellar structures is difficult during transsphenoidal surgery, we are describing the use of intraoperative direct contact ultrasound (IOUS). METHODS: Within 5 years, in 113 transsphenoidal operations (58 male, 55 female, age 14-81 years, 110 pituitary adenomas (mean diameter 26.6 mm, 69 non-secreting adenomas, 41 secreting adenomas), and 1 of each Rathke's cleft cyst, craniopharyngioma, and xanthogranuloma), IOUS was applied. After wide opening of the sellar floor and removal of the intrasellar tumor portions, a commercially available side fire ultrasound probe is introduced, and in direct contact to the sellar envelope, the perisellar space is scanned perpendicular to the axis of the working channel. We compared the results of IOUS to postoperative MRI after 3-6 months. RESULTS: Identification of the intracavernous ICA, the anterior optic pathway, and the ACA, was possible, it was safe to operate close to them. In 65 operations (58%), further resection of tumor remnants was performed after IOUS. In this selected series, complete resection of tumors (stated by postoperative MRI after 3-6 months) was achieved in 75 operations (66%) and remission was achieved in 18 operations of secreting adenomas (44%). Compared to MRI after 3 to 6 months, the sensitivity of IOUS was 0.568 and the specificity was 0.907. No complications related to IOUS were seen. CONCLUSIONS: Visualization of the perisellar compartments by IOUS is easy and fast to perform. It allows the surgeon to identify resectable tumor remnants intraoperatively, which otherwise could be missed. PMID- 30483983 TI - Transferring of femoral nerve motor branches for high-level sciatic nerve injury: a cadaver feasibility study. AB - BACKGROUND: Sciatic nerve injuries cause significant disability. We propose here a novel reconstructive procedure of transferring the motor branches of the femoral nerve as donor nerves to reconstruct both the peroneal and tibial nerve function as a novel approach to treat high sciatic nerve injury. METHODS: The autopsies of donor nerves (vastus lateralis nerve branch (VLN), vastus medialis nerve branch (VMN), saphenous nerve (SAN)) and respective recipient nerves (deep peroneal nerve branch (DPN), medial gastrocnemius nerve branch (MGN), sural nerve (SN)) were conducted in six fresh-frozen lower limbs. The distance between the origin or bifurcation points of the nerves to the head of fibula and the diameter of the end at the coaptation site were measured. The feasibility of tensionless direct suturing or grafting between the donor nerves and the recipient was evaluated. Finally, the nerve end at the coaptation site was harvested for observation with toluidine blue staining and nerve fiber count. RESULTS: The mean diameter of the VMN, VLN, MGN, DPN, SAN, and SN nerves were 1.5 +/- 0.1, 1.4 +/- 0.1, 1.3 +/- 0.1, 2.3 +/- 0.1, 2.1 +/- 0.3, and 1.3 +/- 0.2 mm, respectively. Histological observation showed that the abovementioned six nerve bundles had a respective nerve fiber number of 392 +/- 27, 205 +/- 520, 219 +/- 67, 394 +/- 50, 308 +/- 77, and 335 +/- 49. A total of 5/6 specimens needed grafting for a length ranging from 5 to 15 cm to bridge the VMN-MGN, 6/6 needed a graft length of 10-20 cm for VLN-DPN bridging, and 2/6 needed a graft length of 0-4 cm for SAN-SN bridging. CONCLUSION: The study demonstrated the feasibility of the transferring femoral nerve branches to sciatic nerve branches to restore the function for sciatic injury. PMID- 30483984 TI - Hearing preservation after removal of small vestibular schwannomas by retrosigmoid approach: comparison of two different ABR neuromonitoring techniques. AB - BACKGROUND AND OBJECTIVE: Goals of small vestibular schwannoma (VS) microneurosurgery are as follows: radical resection, facial nerve (FN) preservation, and hearing preservation (HP). Microsurgical advances make HP possible in many patients with preoperative socially useful hearing (SUH). We evaluated postoperative HP in VS with maximum diameter < 2 cm monitored with two different auditory brainstem response (ABR) techniques. MATERIALS AND METHODS: Twenty-eight consecutive non-randomized patients with SUH suffering from small VS underwent keyhole microneurosurgery by retrosigmoid (RS) approach. Selection criteria are as follows: speech discrimination > 50%, pure tone audiogram < 50 dB loss (50/50 criterion; AAO-HNS classes A-B), maximum diameter < 2 cm. HP was attempted with intraoperative ABR, evoked by classical Click (16 cases, group 1) and LS-CE-Chirp(r) stimulus (12, group 2). RESULTS: Mean age was 47.5 years (16 75); average maximum diameter was 1.35 cm (0.5-1.9 mm). Total and nearly total resection (> 95%) was obtained in all, as confirmed by 24-48-h postoperative enhanced MRI. Mortality and major morbidity were 0. In all cases, FN was preserved; in 3, incomplete deficit recovered within few weeks. Socially useful HP (pre- and postoperatively) was 64.3% (18 of 28): 56.25% group 1 and 75% group 2 (p = NS). Postoperative ipsilateral deafness was observed in 5 cases of group 1 (p < 0.0001). Preoperative tinnitus had negative impact on HP (p < 0.05). CONCLUSIONS: Microsurgery can cure small growing VS with SUH. Our limited experience confirms that keyhole RS removal assisted by intraoperative ABR monitoring leads to valuable rates of SUH. LS-CE-Chirp-evoked ABRs allow a safe, effective, and clear neurophysiological feedback and are faster and, thus, more useful than the Click-ABR. PMID- 30483986 TI - Neoadjuvant chemoradiotherapy or chemotherapy for gastroesophageal junction adenocarcinoma: A systematic review and meta-analysis. AB - OBJECTIVE: The preferred neoadjuvant treatment for gastroesophageal junction (GEJ) adenocarcinoma is still matter of debate. We conducted a meta-analysis to assess the different impact of neoadjuvant combined chemotherapy and radiotherapy (CTRT) versus chemotherapy (CT) alone. METHODS: A comprehensive search was performed in EMBASE, PubMed, and Cochrane Library databases from inception to 30th June 2018. Studies comparing survival of patients who underwent CTRT or CT alone before surgery for GEJ adenocarcinoma were included. Hazard ratio (HR) for overall survival (OS) was extracted, and a random-effects model was used for pooled analysis. Median OS, 5-year OS, complete pathologic response (pCR), locoregional and distant failure rates were also calculated. RESULTS: 22 studies including 18,260 patients were considered for the final analysis. The pooled results demonstrated that combined CTRT do not significantly reduce the risk of death (HR 0.95, 95% CI 0.84-1.07; P = 0.41) but has a positive impact on the risk of relapse (HR 0.85, 95% CI 0.75-0.97; P = 0.01) compared to CT alone. Addition of RT to CT alone significantly increased the odds of pCR by 2.8 (95% CI 2.27 3.47; P < 0.001) and reduced the risk of locoregional failure (OR 0.6, 95% CI 0.39-0.91; P = 0.01) but not the risk of distant metastases (OR 0.81, 95% CI 0.59 1.11; P = 0.19). CONCLUSIONS: In this systematic review and meta-analysis comparing neoadjuvant CTRT with CT for adenocarcinoma of GEJ, we found no difference in terms of median OS, despite a higher pCR rate and a reduced risk of locoregional recurrences for the combined approach. Further studies, preferably large randomized clinical trials, are needed to confirm these results. PMID- 30483985 TI - Number of retrieved lymph nodes is an independent prognostic factor after total gastrectomy for patients with stage III gastric cancer: propensity score matching analysis of a multi-institution dataset. AB - BACKGROUND: The prognostic significance of the number of retrieved lymph nodes (RLNs) in gastric cancer remains controversial. Therefore, we designed a multicenter collaborative database to investigate the correlation between the number of RLNs and prognosis of patients with advanced gastric cancer after curative resection. METHODS: We retrospectively analyzed 1103 patients who underwent gastrectomy for stage II/III gastric cancer between 2010 and 2014. Lymph nodes, which were retrieved by surgeons from surgically resected specimens, were validated by pathologists. A target population and the optimal cutoff were determined using receiver operating characteristic (ROC) curve analysis. After propensity score matching of eight variables, including splenectomy and adjuvant chemotherapy, the prognostic significance of RLNs was evaluated. RESULTS: According to ROC curve analysis, the optimum cutoff score for predicting postoperative survival was 40. After matching, the backgrounds of patients in the RLN < 40 and RLN >= 40 groups (n = 87 each) became well-balanced. The RLN < 40 group experienced significantly shorter relapse-free and overall survival. The prevalence of peritoneal recurrence was significantly increased in the RLN < 40 group. RLN < 40 was an independent prognostic factor in multivariable analysis, although pathological N status was not. A forest plot revealed that the RLN < 40 group was at greater risk of recurrence in most subgroups. CONCLUSIONS: RLN < 40 was associated with an adverse prognosis of patients with stage III gastric cancer who underwent total gastrectomy. PMID- 30483987 TI - Thoracic Lymph Node Map App Review. PMID- 30483988 TI - A Platform Integrating Acquisition, Reconstruction, Visualization, and Manipulator Control Modules for MRI-Guided Interventions. AB - This work presents a platform that integrates a customized MRI data acquisition scheme with reconstruction and three-dimensional (3D) visualization modules along with a module for controlling an MRI-compatible robotic device to facilitate the performance of robot-assisted, MRI-guided interventional procedures. Using dynamically-acquired MRI data, the computational framework of the platform generates and updates a 3D model representing the area of the procedure (AoP). To image structures of interest in the AoP that do not reside inside the same or parallel slices, the MRI acquisition scheme was modified to collect a multi-slice set of intraoblique to each other slices; which are termed composing slices. Moreover, this approach interleaves the collection of the composing slices so the same k-space segments of all slices are collected during similar time instances. This time matching of the k-space segments results in spatial matching of the imaged objects in the individual composing slices. The composing slices were used to generate and update the 3D model of the AoP. The MRI acquisition scheme was evaluated with computer simulations and experimental studies. Computer simulations demonstrated that k-space segmentation and time-matched interleaved acquisition of these segments provide spatial matching of the structures imaged with composing slices. Experimental studies used the platform to image the maneuvering of an MRI-compatible manipulator that carried tubing filled with MRI contrast agent. In vivo experimental studies to image the abdomen and contrast enhanced heart on free-breathing subjects without cardiac triggering demonstrated spatial matching of imaged anatomies in the composing planes. The described interventional MRI framework could assist in performing real-time MRI-guided interventions. PMID- 30483989 TI - Detecting delirium in elderly medical emergency patients: validation and subsequent modification of the German Nursing Delirium Screening Scale. AB - Detecting delirium in elderly emergency patients is critical to their outcome. The Nursing Delirium Screening Scale (Nu-DESC) is a short, feasible instrument that allows nurses to systematically screen for delirium. This is the first study to validate the Nu-DESC in a German emergency department (ED). The Nu-DESC was implemented in a high-volume, interdisciplinary German ED. A consecutively recruited sample of medical patients aged >= 70 years was screened by assigned nurses who performed the Nu-DESC as part of their daily work routine. The results were compared to a criterion standard diagnosis of delirium. According to the criterion standard diagnosis, delirium was present in 47 (14.9%) out of the 315 patients enrolled. The Nu-DESC shows a good specificity level of 91.0% (95% CI 87.0-94.2), but a moderate sensitivity level of 66.0% (95% CI 50.7-79.1). Positive and negative likelihood ratios are 7.37 (95% CI 4.77-11.36) and 0.37 (95% CI 0.25-0.56), respectively. In an exploratory analysis, we find that operationalizing the Nu-DESC item "disorientation" by specifically asking patients to state the day of the week and the name of the hospital unit would raise Nu-DESC sensitivity to 77.8%, with a specificity of 84.6% (positive and negative likelihood ratio of 5.05 and 0.26, respectively). The Nu-DESC shows good specificity but moderate sensitivity when performed by nurses during their daily work in a German ED. We have developed a modified Nu-DESC version, resulting in markedly enhanced sensitivity while maintaining a satisfactory level of specificity. PMID- 30483990 TI - Drug-drug interactions in patients with acute coronary syndrome across phases of treatment. AB - The objective of this study is to evaluate potential drug-drug interactions (pDDIs) and risk factors for pDDIs in three phases of an acute coronary syndrome (ACS) treatment: from the point of first medical contact to the coronary angiography (first phase), after coronary angiography to the last day of hospitalization (second phase), and at discharge from hospital (third phase). This retrospective observational cohort clinical study was conducted at the Clinic for Cardiology of the Clinical Centre Kragujevac, a public tertiary care hospital in Kragujevac, Serbia. Micromedex(r) interaction checker was used to detect pDDIs. This study included 245 ACS patients. All patients were exposed to at least one pDDI in all the phases of treatment. Mean total number of pDDIs was 9.47 +/- 6.07, 10.11 +/- 6.92, and 6.29 +/- 3.66 in first, second, and third phases, respectively. Age, > 6 h from the beginning of the symptoms to admission, primary PCI, STE-ACS, COPD, delirium, hyperlipidemia, hypertension, obesity, systolic blood pressure at admission, TIMI risk score at admission, ALT, LDL, number of physicians who prescribed drugs to a single patient, number of prescribed drugs, and various pharmacological classes increased risk of pDDIs. Mechanical ventilation, dementia, and drug allergy noted in the medical documentation protected against them. Effects of heart failure, diabetes, and aPTT depended on phase of treatment and severity of pDDI. In conclusion, physicians should be vigilant to the possibility of pDDIs in patients harbouring factors that may increase their rate. PMID- 30483991 TI - American Association of Community Psychiatrists Position Statement: Putting Patients First by Improving Treatment Planning and Reducing Administrative and Clinical Burden of Treatment Plan Documentation. AB - This paper represents a position statement of the American Association of Community Psychiatrists (AACP) regarding treatment plans. We regard treatment plans, a documentation requirement, in this position statement, as distinct from the process of treatment planning. The AACP is concerned that treatment plan documentation in its current state, creates unnecessary administrative burden for physicians, without evidence of benefit for patients, reducing direct patient contact time, thereby negatively impacting quality of care. In this position, we echo the statements made by the American College of Physicians in their position paper entitled "Putting Patients First by Reducing Administrative Tasks in Health Care". We recommend a review of the treatment plan documentation requirement across the nation, engaging consumers, providers, regulatory agencies in all states, as well as national reimbursement and regulatory agencies, in order to promote the process of quality driven care and documentation. PMID- 30483992 TI - Efficacy and safety of edaravone in treatment of amyotrophic lateral sclerosis-a systematic review and meta-analysis. AB - BACKGROUND: Based on the results of randomized, double-blind, placebo-controlled trials, the benefit and safety of edaravone in the treatment of amyotrophic lateral sclerosis remain controversial. We performed a meta-analysis to evaluate the efficacy and safety of edaravone in the treatment of this disease. METHODS: We searched PubMed, the Cochrane Library, and Embase from the inception of electronic data to April 2018. We included randomized, double-blind, placebo controlled trials reporting amyotrophic lateral sclerosis patients receiving 60 mg intravenous edaravone or intravenous saline placebo for 24 weeks. The primary efficacy evaluation was changed in Amyotrophic Lateral Sclerosis Functional Rating Scale score from baseline to after the trial. Measure of safety was the frequency of investigated adverse events and serious adverse events. Data synthesis and analysis and evaluation of risk of bias were performed using RevMan 5.3 software. Heterogeneity among studies was evaluated with the I2 statistic. RESULTS: A total of 367 patients were analyzed across three randomized controlled trials (183 patients receiving intravenous edaravone; 184 receiving placebo). A difference in ALSFRS-R score between groups at 24 weeks was found (mean difference [MD] = 1.63, 95% confidence interval [CI] 0.26-3.00, P = .02). No differences in the frequency of adverse events (odds ratio [OR] = 1.22, 95% CI 0.68-2.19, P = .50) or serious adverse events (OR = 0.71, 95% CI 0.43-1.19, P = .20) were found. CONCLUSION: Intravenous edaravone is efficacious in amyotrophic lateral sclerosis patients, with no severe adverse effects. Additional reliable randomized controlled trials with larger sample sizes will further assess the efficacy and safety of edaravone in amyotrophic lateral sclerosis. CLINICAL TRIAL REGISTRATION: The systematic review and meta-analysis was registered in the international prospective register of systematic reviews. (PROSPERO registration number: CRD42018096191; http://www.crd.york.ac.uk/PROSPERO .). PMID- 30483993 TI - A new neurobehavioral phenotype of familial Creutzfeldt-Jakob disease: impaired theory of mind. PMID- 30483995 TI - Highlights of the Issue 12, 2018. PMID- 30483994 TI - Sports, physical activity and headache in the classical age: historical descriptions from the first sports textbook, "De arte gymnastica", by Girolamo Mercuriale. AB - BACKGROUND AND OBJECTIVES: The relationship between physical activity, sports and headache presents a growing interest, testified by numerous papers recently published. The correlation between headache and sporting activities or physical exercise dates back to the classical age. We aim at promoting the development of more studies focused on the relationship between headache and physical activity. METHODS: We analysed the book "De arte gymnastica", written by Girolamo Mercuriale (Forli, Italy, 1530-1606), and considered the first "sports medical textbook". We discuss these classical literature findings in the light of the International Classification of Headache Disorders, 3rd edition. RESULTS: The Author's work derives from the systematic revision of Greek, Roman and Arabic literatures about the matter. Despite some references to inveterate headaches or cold-related pains, Mercuriale does not gather specific clinical characterisations of different types of headache. However, interestingly, he reports detailed descriptions of how the same sport, or the same physical activity, could cause or give relief from head pain, depending on the precise way of practising. Mercuriale summarises 18 sports or physical activities that can give relief from headache; conversely, running or heavy activities, such as boxing, appear among the 12 contraindicated sports for people suffering from headache. CONCLUSIONS: "De arte gymnastica", by Girolamo Mercuriale, is the first textbook on sports medicine. Headache if often cited along the treatise: different sports and physical activities, or various ways of practising the same action could produce opposite effects for people suffering from headache. PMID- 30483996 TI - Influence of environmental temperature, heat-treatment and design on the cyclic fatigue resistance of three generations of a single-file nickel-titanium rotary instrument. AB - The aim of the present study was to evaluate the effect of environmental temperature, heat-treatment*** and design on the cyclic fatigue resistance of OneShape (OS), OneShape new generation (OSNG) and One Curve (OC) NiTi rotary single-file instruments. Cyclic fatigue testing of NiTi instruments was performed in an artificial canal with a 5-mm radius of curvature and a 60 degrees angle of curvature located 5 mm from the tip of the instrument. During the experiment 3 different temperatures were used in a thermostatic bath with electronic and infrared controls: 0 degrees , 20 degrees and 35 degrees C. Sixty OneShape, 60 OneShape new generation and 60 One Curve instruments were rotated in the artificial canal until fracture occurred and the number of cycles to fracture (NCF) and the length of the fractured fragment (FL) was recorded. Data were analyzed by one-way ANOVA test at the 5% significance level. Fatigue resistance was significantly higher as the environmental temperature decreased, with differences ranging from 61 to 791%. OC instruments were significantly more resistant to cyclic fatigue than OS and OSNG instruments at all the temperatures tested (P < 0.05). There was no significant difference with respect to the length of the fractured file fragments for all the instruments tested at all the temperatures tested (P > 0.05). Within the limitation of the present study, fatigue resistance of the files was significantly increased when the environmental temperature decreased. OC instruments were significantly more resistant to cyclic fatigue than OS and OSNG instruments at all the temperatures tested. PMID- 30483997 TI - Fourier transform infrared spectroscopy: unlocking fundamentals and prospects for bacterial strain typing. AB - The need to identify highly related bacterial strains is ancient in clinical, industrial, or environmental microbiology. Strategies based on different phenotypic and genotypic principles have been used since the early 1930s with variable outcomes and performances, accompanying the evolution of bacterial features' knowledge as well as technologies, instruments, and data analysis tools. Today, more than ever, the implementation of bacterial typing methods that combine a high reliability and accuracy with a rapid, low-cost, and user-friendly performance is highly desirable, especially for clinical microbiology. FT-IR developments for bacterial discrimination at the infra-species level settled on the identification of bacterial groups previously defined by phenotypic or genotypic typing methods. Therefore, this review provides a brief historical overview of main bacterial strain typing methods, and a comprehensive analysis of the fundamentals and applications of Fourier transform infrared spectroscopy, a phenotypic-based method with potential for routine strain typing. The different studies on FT-IR-based strain typing of diverse Gram-negative and Gram-positive bacterial species are discussed in light of genotypic, phenotypic, and biochemical aspects, in order to definitively give this methodology credit to be widely accepted by microbiologists. Importantly, the discriminatory biochemical fingerprints observed on FT-IR spectra have been consistently correlated with sugar-based coating structures that besides reflecting strain variation are also of high relevance for the specificity in pathogen-host interactions. Thus, FT-IR based bacterial typing might not only be useful for quick and reliable strain typing but also to help understanding the diversity, evolution, and host adaptation factors of key bacterial pathogens or subpopulations. PMID- 30483998 TI - Iclaprim activity against wild-type and corresponding thymidine kinase-deficient Staphylococcus aureus in a mouse protection model. AB - The in vitro and in vivo antimicrobial activities of dihydrofolate reductase (DHFR) inhibitors are inhibited in the presence of free thymidine in the growth milieu and in rodent efficacy models. However, for thymidine kinase (TK) deficient mutant bacteria, the presence of free thymidine does not impact the activity of DHFR inhibitors, and these mutants were used to assess the in vivo efficacy of the DHFR inhibitor, iclaprim. The efficacies of iclaprim, trimethoprim, and vancomycin were evaluated in a systemic mouse infection model. Female CD-1 mice were infected intraperitoneally (IP) with wild-type Staphylococcus aureus ATCC 25923 (MSSA) or AW 6 (MRSA) or their corresponding isogenic TK-deficient mutant S. aureus strains AH 1246 and AH 1252. Iclaprim showed potent antibacterial activity against both the TK-deficient mutant S. aureus strains, with PD50 values of 1.8 and < 0.5 mg/kg, respectively, for strains AH 1246 and AH 1252. In contrast, poor antibacterial activity was observed against corresponding wild-type (TK competent) S. aureus strains, with PD50 values of 10.8 and 2.2 mg/kg, respectively, for strains ATCC 25923 and AW 6. This study confirms that thymidine plays an important antagonistic role when determining the efficacy of DHFR inhibitors in vivo. This is the first study to show that iclaprim is active against TK-deficient S. aureus strains in a systemic mouse infection model, and that TK-deficient mutants may be used to evaluate iclaprim's activity in rodent models in vivo. PMID- 30483999 TI - Kidney fibrosis induced by various irrigation pressures in mouse models of mild and severe hydronephrosis. AB - OBJECTIVE: We want to study whether the degree of fibrosis in the mild and severe hydronephrosis is different, and whether the irrigation pressure will affect the fibrosis of the hydronephrosis. METHODS: Animal models of mild and severe hydronephrosis in the left kidney were established: 72 healthy C57BL/6 mice were randomly divided into nine groups (eight in each group). The N group was used as a control group, and 0 mmHg pressure perfusion was given. The M and S groups were used as mild and severe hydronephrosis groups, respectively. The mild and severe hydronephrosis groups were subdivided into eight subgroups, M0-M3 and S0-S3. Among them, groups 0, 1, 2, and 3 were perfused with 0 mmHg, 20 mmHg, 60 mmHg, and 100 mmHg, respectively. We investigated the effects of irrigation pressures on renal fibrosis in mild (group M) and heavy (group S) hydronephrosis by quantitative real-time polymerase chain reaction, Western blot analysis, Masson staining and immunohistochemistry staining in mouse models. RESULTS: Compared with group N, EMT and ECM deposits were significantly aggravated in both the mild and severe hydronephrosis groups, TGF-beta signaling pathway-related molecules significantly changed too. In terms of ECM deposition, S2 and S3 are significantly increased compared to S0.The EMT of M2 and M3 changed significantly compared with M0; the EMT of S1, S2 and S3 changed significantly compared with S0.The molecules related to TGF-beta signaling pathway also changed: M0 and S0 changed significantly compared with N; M1, M2 and M3 changed significantly compared with M0; compared with S0, S1, S2 and S3 changed significantly. CONCLUSION: Compared with mild hydronephrosis, renal fibrosis in severe hydronephrosis is more severe and its tolerance to perfusion pressure is lower. These changes may be related to the TGF-beta signalling pathway. PMID- 30484000 TI - Drivers of Overweight/Obesity in 4-11 Year Old Children of Australians and Immigrants; Evidence from Growing Up in Australia. AB - Despite high overweight/obesity rates in children of Australian immigrants, the risk factors are unknown. We investigated behavioural risk factors and their association with overweight/obesity in 4-11 year-old children by immigrant status. We conducted cross-sectional and longitudinal analysis of 8 years data from the longitudinal study of Australian children. Immigrant children from low and-middle-income-countries had higher overweight/obesity rates across all ages. These children had higher vegetables and sugar-sweetened-beverages intake, higher sedentary activities and lower organized-sports participation than immigrant children from high-income-countries or Australian-children. Organized-sports participation and screen-time converged to the Australian norms in 10-11 year-old boys, but not in girls. Preference for sedentary activities and screen-time explained the differences in overweight/obesity by maternal immigrant status in boys but not in girls. The difference in drivers of overweight/obesity amongst immigrant children from low-and-middle-income-countries suggest more nuanced age, sex and culturally sensitive preventive health messages for immigrants. PMID- 30484001 TI - Does Gender Influence Outcome in Schizophrenia? AB - Good outcome of schizophrenia has several meanings and most of these meanings carry both positive and negative undertones depending on perspective. Currently, a person's subjective sense that illness has been partly overcome and that life is meaningful has come to be viewed as the most valid signpost of a good outcome. A review of the literature shows that women have certain advantages over men in that their illness starts at a later age and that their symptoms respond more quickly and more completely to available treatments. These advantages serve women well at the outset of illness but benefits appear to dissipate over time. Gender differences in outcome thus vary depending on the age of the patient. They also vary with the social and cultural background of the study population. Neither sex, therefore, has a monopoly on good outcome. The hope is that studying gender differences will uncover critical elements of good outcome that lead to interventions that will benefit both women and men. PMID- 30484002 TI - Enacting Homebirth Bodies: Midwifery Techniques in Germany. AB - Building on insights from science and technology studies-inspired anthropological research on reproduction, this paper uses a praxiographic approach to analyze homebirth midwifery practices in Germany. I show that such practices are syncretic, and that techniques of routinizing and multiplying obstetrical interventions are combined in more or less coherent ways to configure pregnancies and births as physical, emotional, and social becomings. In the process of attending, homebirth bodies learn to co-respond to each other, to the midwifery techniques, and to the homebirth environment. Understanding how and with which aims midwives and women invest in those longterm engagements specific to homebirth surroundings may inform clinical practices. PMID- 30484003 TI - Language and Culture in the Caregiving of People with Dementia in Care Homes - What Are the Implications for Well-Being? A Scoping Review with a Welsh Perspective. AB - The loss of language skills is one of the most challenging aspects of living with dementia. This is particularly true for bilingual individuals, who have difficulty in maintaining fluency in more than one language. Language and culture overlap greatly, with potential implications for the well-being of people with dementia (PWD) being cared for in their 'second' language or culture. Our aim was to review the available relevant literature, together with an examination of the potential effects of linguistic incongruity on healthcare in general for Welsh speakers in Wales. A literature search yielded 50 articles, which were analysed using the scoping review methodological framework. We found that the presence of cultural and linguistic congruity was beneficial for PWD living in care homes, and that their absence was detrimental. The absence of linguistic congruity is a strong predictor for decreased well-being in people in such settings, due to communication barriers between residents and carers, which result mainly from the loss of PWD's second language skills. Such barriers may lead to inappropriate care, e.g. being unable to obtain help to self-care, as well as social isolation. This review suggests that strategies need to be developed across the world to accommodate bilingual individuals requiring a care home for their dementia needs. There is a particular dearth of research regarding the influence of bilingualism on the experience of dementia care in those areas of the UK where the indigenous population are most likely to be bilingual (i.e. parts of Wales). PMID- 30484004 TI - Metabolomics Analysis Reveals Therapeutic Effects of alpha-Mangostin on Collagen Induced Arthritis in Rats by Down-regulating Nicotinamide Phosphoribosyltransferase. AB - alpha-Mangostin (MAN) is a bioactive compound isolated from pericarp of mangosteen (Garcinia mangostana Linn.) with significant anti-rheumatic potentials. The purpose of this study was to explore the mechanisms underlying its therapeutic effects on collagen-induced arthritis (CIA) in rats with metabolomics approaches. Therapeutic effects of MAN on CIA were assessed by radiographic, histological, and immunohistochemical methods. Metabolic profiles of rats were characterized based on UPLC-MS/MS analysis of urine samples, followed by verification in HFLS-RA cells using a variety of toxicological and biochemical assays. We found that MAN treatment protected joint structures in CIA rats and caused a decrease of nicotinamide mononucleotide (NMN) in urine. The levels of nicotinamide phosphoribosyltransferase (NAMPT) were reduced in fibroblast-like synoviocytes by MAN both in vivo and in vitro, which was accompanied with a decline in nicotinamide adenine dinucleotide (NAD) production. Secretion of extracellular NAMPT (eNAMPT) in HFLS-RA cells was also decreased upon MAN treatment, which lagged behind the changes of its intracellular counterpart (iNAMPT). Co-treatment with NMN raised the secretion of eNAMPT and restored the decline of p-p65 and TNF-alpha induced by MAN in vitro. Sirt1 expression was down-regulated under MAN treatments too. These results suggest that MAN treatment suppressed NAD production by inhibiting iNAMPT expression, which in turn decreased eNAMPT secretion and alleviated NF-kappaB-mediated inflammations in CIA rats. PMID- 30484005 TI - Interleukin (IL)-35 Suppresses IL-6 and IL-8 Production in IL-17A-Stimulated Human Periodontal Ligament Cells. AB - Interleukin (IL)-35 is a novel anti-inflammatory cytokine that is produced by regulatory T cells. IL-35 is reported to suppress IL-17A-producing helper T (Th17) cell activation. IL-17A is related to progression of periodontitis. Furthermore, IL-35 and IL-17A are detected in human gingival crevicular fluid. However, the effect of IL-35 and interaction between IL-35 and IL-17A on pro inflammatory cytokine production in human periodontal resident cells are still unclear. The aim of this study was to clarify the effect of IL-35 on IL-6 and IL 8 production in human periodontal ligament cells (HPDLCs) stimulated with IL-17A. IL-35 inhibited IL-6 and IL-8 production in IL-17A-stimulated HPDLCs. Moreover, western blot analysis showed that IL-35 suppressed extracellular signal-regulated kinase (ERK) and nuclear factor (NF)-kappaB p65 phosphorylation in IL-17A stimulated HPDLCs. Our findings suggested that IL-35 produced from regulatory T cells might inhibit progression of periodontitis by decreasing IL-17A-induced levels of IL-6 and IL-8. PMID- 30484006 TI - Degradation Products of Polydopamine Restrained Inflammatory Response of LPS Stimulated Macrophages Through Mediation TLR-4-MYD88 Dependent Signaling Pathways by Antioxidant. AB - Polydopamine (PDA) has a promising application as coating of biomaterials due to its favorable degradability and bioadaptability. However, its bioactivity, such as anti-inflammatory capacity, was still little known. Herein, we investigated whether degradable products of PDA could affect inflammatory response in lipopolysaccharide (LPS)-stimulated human THP-1-derived macrophages. The supernatants containing degradation products of PDA, annotated as PDA extracts, were collected after PDA being immersed in cell culture medium for 3 days. Wherein, the composition of the degradation products was analyzed by HPLC assay. Collected PDA extracts were diluted into 100%, 50%, and 25% of original concentration, respectively, to evaluate their anti-inflammatory ability on LPS induced macrophages from the expression levels of pro-inflammatory cytokines to associated molecular mechanism. Our results showed that the PDA extracts were mainly composed of dopamine, quinine, and PDA segments. Furthermore, macrophages showed no cytotoxicity after PDA extract treatment with or without LPS, while the release levels of TNF-alpha and IL-6 by LPS-induced macrophages were decreased in dose-dependent by PDA extract treatment. Additionally, TLR-4 and MYD88 expression in protein and RNA level were downregulated by PDA extracts in LPS-induced macrophages. Similarly, PDA extracts effectively inhibited LPS-induced NF-kappaB trans-locating into nuclear by inactivation of the phosphorylation of IKK alpha/beta and IKbeta-alpha. Of note, the production of LPS-induced ROS was reduced by PDA extracts in macrophages, while HO-1 expression, a critical protein of antioxidant signaling pathway, was increased. Based on these results, we proposed a potential mechanism by which degradation products of PDA suppressed inflammation of macrophages via downregulation TLR-4-MYD88-NFkappaB pathway and simultaneous activation HO-1 pathway, which might be a possible therapeutic target. PMID- 30484007 TI - Tackling tumor heterogeneity and phenotypic plasticity in cancer precision medicine: our experience and a literature review. AB - The predominant cause of cancer mortality is metastasis. The major impediment to cancer cure is the intrinsic or acquired resistance to currently available therapies. Cancer is heterogeneous at the genetic, epigenetic, and metabolic levels. And, while a molecular-targeted drug may be pathway-precise, it can still fail to achieve wholesome cancer-precise toxicity. In the current review, we discuss the strategic differences between targeting the strengths of cancer cells in phenotypic plasticity and heterogeneity and targeting shared vulnerabilities of cancer cells such as the compromised integrity of membranous organelles. To better recapitulate subpopulations of cancer cells in different phenotypic and functional states, we developed a schematic combination of 2-dimensional culture (2D), 3-dimmensional culture in collagen I (3D), and mammosphere culture for stem cells (mammosphere), designated as Scheme 2D/3D/mammosphere. We investigated how the tumor suppressor maspin may limit carcinoma cell plasticity and affect their context-dependent response to drugs of different mechanisms including docetaxel, histone deacetylase (HDAC) inhibitor MS-275, and ionophore antibiotic salinomycin. We showed that tumor cell phenotypic plasticity is not an exclusive attribute to cancer stem cells. Nonetheless, three subpopulations of prostate cancer cells, enriched through Scheme 2D/3D/mammosphere, show qualitatively different drug responses. Interestingly, salinomycin was the only drug that effectively killed all three cancer cell subpopulations, irrespective of their capacity of stemness. Further, Scheme 2D/3D/mammosphere may be a useful model to accelerate the screening for curative cancer drugs while avoiding costly characterization of compounds that may have only selective toxicity to some, but not all, cancer cell subpopulations. PMID- 30484008 TI - A Systematic Review Assessing the Current State of Automated Pupillometry in the NeuroICU. AB - The aim of this study was to assess the current state of automated pupillometry technology and its application in the neurointensive care unit (neuroICU). We performed a literature search using the PubMed, MEDLINE, and EMBASE databases from database inception through a search end date of October 18, 2018, to identify studies reporting on the use of automated pupillometry in the care of critically ill patients with neurological impairment. Two independent reviewers reviewed all titles and abstracts in two filtering phases. Data were extracted independently. One hundred and forty-one articles/abstracts have been published on the use of automated pupillometry in critical care since inception of the PubMed, MEDLINE, and EMBASE databases. We selected and reviewed 22 full-text articles and 8 abstracts, of which 26 were prospective, 2 were retrospective, and 2 were larger case series. Automated pupillometry increased precision, reliability, and reproducibility compared with the manual pupillary examination; detected subtle and early pupillary changes; detected pupillary changes that indicate a rise, or impending rise, in intracranial pressure detected level of analgesia and depth of sedation; served as a prognostic indicator; estimated the clinical severity of aneurysmal subarachnoid hemorrhage; and served as a noninvasive monitor of response to osmotic therapy. At present, no consensus guidelines exist endorsing routine use of automated pupillometry in the neuroICU. However, an increasing quantity of research supports the usefulness of automated pupillometry in this setting. Further large-scale prospective studies are needed before updated consensus guidelines recommending widespread adoption of automated pupillometry are produced. PMID- 30484009 TI - Cardiac Dysfunction in Neurocritical Care: An Autonomic Perspective. AB - A number of neurologic disorders can cause cardiac dysfunction by involving the conductive system and contractile apparatus of the heart. This is especially prominent in the neurocritical care setting where the spectrum of cardiac dysfunction due to acute neurologic injury ranges from trivial and isolated electrocardiographic changes to malignant arrhythmias and sudden death (Table 1). The mechanism of these cardiac complications is complex and not fully understood. An understanding of the neuroanatomical structures and pathways is of immense importance to comprehend the underlying pathophysiology that culminates as cardiac damage and dysregulation. Once the process is initiated, it can complicate and adversely affect the outcome of primary neurologic conditions commonly seen in the neurocritical care setting. Not only are these cardiac disorders under-recognized, there is a paucity of data to formulate evidence based guidelines regarding early detection, acute management, and preventive strategies. However, certain details of clinical features and their course combined with location of primary neurologic lesion on neuroimaging and data obtained from laboratory investigations can be of great value to develop a strategy to appropriately manage these patients and to prevent adverse outcome from these cardiac complications. In this review, we highlight the mechanisms of cardiac dysfunction due to catastrophic neurologic conditions or due to stress of critical illness. We also address various clinical syndromes of cardiac dysfunction that occur as a result of the neurologic illness and in turn may complicate the course of the primary neurologic condition. PMID- 30484010 TI - The Feasibility, Safety and Effectiveness of a Ketogenic Diet for Refractory Status Epilepticus in Adults in the Intensive Care Unit. AB - BACKGROUND: Status, refractory status and super refractory status epilepticus are common neurologic emergencies. The objective of this study is to investigate the feasibility, safety and effectiveness of a ketogenic diet (KD) for refractory status epilepticus (RSE) in adults in the intensive care unit (ICU). METHODS: We performed a retrospective, single-center study of patients between ages 18 and 80 years with RSE treated with a KD treatment algorithm from November 2016 through April 2018. The primary outcome measure was urine ketone body production as a biomarker of feasibility. Secondary measures included resolution of RSE and KD related side effects. RESULTS: There were 11 adults who were diagnosed with RSE that were treated with the KD. The mean age was 48 years, and 45% (n = 5) of the patients were women. The patients were prescribed a median of three anti-seizure medications before initiating the KD. The median duration of RSE before initiation of the KD was 1 day. Treatment delays were the result of Propofol administration. 90.9% (n = 10) of patients achieved ketosis within a median of 1 day. RSE resolved in 72.7% (n = 8) of patients; however, 27.3% (n = 3) developed super-refractory status epilepticus. Side effects included metabolic acidosis, hypoglycemia and hyponatremia. One patient (20%) died. CONCLUSIONS: KD may be feasible, safe and effective for treatment of RSE in the ICU. A randomized controlled trial (RCT) may be indicated to further test the safety and efficacy of KD. PMID- 30484011 TI - Changes in thromboinflammatory profiles across the generations of transcatheter aortic heart valves. AB - The transcatheter aortic valve replacement (TAVR) procedure was developed to provide patients with severe aortic stenosis an alternative to the surgical aortic valve replacement. Since the approval of the original SAPIEN the technology has rapidly evolved. While several approaches can be used for valve deployment, as delivery systems have become smaller and more flexible, the transfemoral approach has become the dominant technique for valve deployment. One hundred and forty five patients undergoing TAVR receiving one of four valve types (Sapien, Sapien XT, Sapien3 or CoreValve) via the femoral artery were included in this study. Platelet count, white blood cells count (WBC), Interleukin-6 (IL-6), and Serum Amyloid A (SAA) were determined before and after TAVR. Platelet counts declined after the procedure regardless of the valve type and were dependent upon the baseline platelet count. Use of conscious sedation blunted the decline in platelet count. With the newer generation valves, the rise in WBC post-TAVR was lower than observed with the Sapien, in keeping with less systemic inflammation. Consistent with WBC, IL-6 levels were lower following deployment of the newer generation valves. Elevations in plasma SAA, which occur following myocardial injury, were not reduced with the newer valves. Evolution of the TAVR technology has occurred rapidly over the last 5 years. The newer devices and smaller delivery systems are associated with less systemic inflammation, as reflected in WBC and plasma IL-6 levels. However, the acute phase reactant SAA remains unchanged, possibly reflecting different triggers for SAA following TAVR. PMID- 30484012 TI - Frailty and health-related quality of life in older women with breast cancer. AB - PURPOSE: In older women, breast cancer and its treatment can have profound impact on their physical, mental, and social health, especially in frail patients. This study evaluated the association between frailty and long-term health-related quality of life (HRQOL) in older women undergoing breast cancer treatment. METHODS: Using the Carolina Senior Registry (CSR), participants with breast cancer were contacted to complete a follow-up HRQOL questionnaire (median 4 years). Baseline Geriatric Assessment (GA) variables were used to calculate the Carolina Frailty Index (CFI) and categorize participants as robust, pre-frail, or frail. Outcomes included HRQOL domains of physical function, social roles, fatigue, depression, anxiety, pain, and sleep disturbance assessed using PROMIS(r) instruments. Regression modeling compared outcomes between frailty groups using adjusted mean differences (AMD). RESULTS: Of 190 eligible patients, 63 completed follow-up HRQOL survey. Mean age was 70 years (range 65-86) and 91% were white. Based on the CFI, 49 (78%) patients were robust, 11 (18%) pre-frail, and 3 (5%) frail. After controlling for age and cancer stage, patients identified as pre-frail/frail reported worse physical function (AMD - 9.2, p < 0.001) and social roles (AMD - 7.2, p = 0.002) and more fatigue (AMD 7.6, p = 0.008), depression (AMD 5.6, p = 0.004), and sleep disturbance (AMD 6.9, p = 0.008) compared to robust patients at follow-up. CONCLUSIONS: Frailty in older women with breast cancer was associated with worse long-term HRQOL outcomes. Further research is needed to develop interventions for frail patients at-risk for reduced HRQOL. PMID- 30484013 TI - Evaluation of quality of care in relation to health-related quality of life of patients diagnosed with brain tumor: a novel clinic for proton beam therapy. AB - PURPOSE: Patients with brain tumors constitute a vulnerable group, and it is important that they receive the highest quality of care (QoC). The study aim was to describe the perceptions of QoC and its association with health-related quality of life in brain tumor patients undergoing proton beam therapy in a newly established clinic. METHOD: Data were collected at the start of treatment and after 3 and 6 weeks. Adult patients (>= 18 years old) with brain tumors (n = 186) completed two self-administered questionnaires: a modified Quality from the Patients' Perspective, which measures perceived reality and subjective importance of care, and the EORTC QLQ-C30. Data were analyzed using parametric and non parametric statistical tests. RESULTS: The perceived QoC was highest for treatment information and lowest for dietician and smoking information, whereas interaction with doctors and nurses was rated as the most important aspect of quality of care. Subjective importance ratings were significantly higher than perceived reality ratings for 60% of items. A better global health was moderately correlated with a higher perceived support for fatigue. CONCLUSIONS: A need for quality improvement was identified for several aspects of patient care. Greater symptom distress during the treatment period led to greater perceived importance of symptom support. Ensuring QoC is complex and collaboration with other health care professionals is essential. RELEVANCE TO CLINICAL PRACTICE: The clinic could improve QoC regarding information about possible symptoms, adjust care according to patient perceptions of importance, and involve patients in care decisions. PMID- 30484014 TI - Pre-to-post diagnosis weight trajectories in colorectal cancer patients with non metastatic disease. AB - PURPOSE: Previous studies have shown that > 50% of colorectal cancer (CRC) patients treated with adjuvant chemotherapy gain weight after diagnosis. This may affect long-term health. Therefore, prevention of weight gain has been incorporated in oncological guidelines for CRC with a focus on patients that undergo adjuvant chemotherapy treatment. It is, however, unknown how changes in weight after diagnosis relate to weight before diagnosis and whether weight changes from pre-to-post diagnosis are restricted to chemotherapy treatment. We therefore examined pre-to-post diagnosis weight trajectories and compared them between those treated with and without adjuvant chemotherapy. METHODS: We included 1184 patients diagnosed with stages I-III CRC between 2010 and 2015 from an ongoing observational prospective study. At diagnosis, patients reported current weight and usual weight 2 years before diagnosis. In the 2 years following diagnosis, weight was self-reported repeatedly. We used linear mixed models to analyse weight trajectories. RESULTS: Mean pre-to-post diagnosis weight change was -0.8 (95% CI -1.1, -0.4) kg. Post-diagnosis weight gain was + 3.5 (95% CI 2.7, 4.3) kg in patients who had lost >= 5% weight before diagnosis, while on average clinically relevant weight gain after diagnosis was absent in the groups without pre-diagnosis weight loss. Pre-to-post diagnosis weight change was similar in patients treated with (-0.1 kg (95%CI -0.8, 0.6)) and without adjuvant chemotherapy (-0.9 kg (95%CI -1.4, -0.5)). CONCLUSIONS: Overall, hardly any pre to-post diagnosis weight change was observed among CRC patients, because post diagnosis weight gain was mainly observed in patients who lost weight before diagnosis. This was observed independent of treatment with adjuvant chemotherapy. PMID- 30484015 TI - Obstructive sleep apnea as a risk factor for preeclampsia-eclampsia. AB - PURPOSE: Preeclampsia-eclampsia remains one of the leading causes of maternal and perinatal morbidity and mortality. Emerging evidence suggests that obstructive sleep apnea (OSA), which has been linked to hypertension in the general population, may play role in hypertensive disorders in pregnancy, including preeclampsia-eclampsia. However, little research has been conducted in Asia (no data in Thailand) on the effects of OSA on preeclampsia-eclampsia. We aimed to examine the association between OSA and preeclampsia-eclampsia among Thai pregnant women. METHODS: We conducted a large prospective cohort study among Thai pregnant women who were in the second trimester of singleton pregnancy. The Berlin Questionnaire was administered to evaluate the risk for OSA. Preeclampsia eclampsia was diagnosed by standard clinical assessment. Multivariate models were applied in adjustment for confounding factors. RESULTS: Enrolled were 1345 pregnant women. The overall prevalence of high risk for OSA was 10.1% (95% confidence intervals [CIs] 8.5-11.7), and it was significantly associated with pre-pregnancy body mass index and score on the Perceived Stress Scale. An adjusted odds ratio (OR) for preeclampsia-eclampsia in women with high risk for OSA was 2.72 (95% CI 1.33-5.57). CONCLUSIONS: Pregnant women with high risk for OSA are at increased risks for preeclampsia-eclampsia compared to those with low risk for OSA. Our results support a role for screening for OSA by BQ during antenatal care. PMID- 30484016 TI - Acupoint Catgut Embedding Alleviates Insomnia in Different Chinese Medicine Syndrome Types: A Randomized Controlled Trial. AB - OBJECTIVE: To investigate the effects and safety of catgut embedding on alleviating insomnia. METHODS: Totally 510 patients with insomnia were divided into 5 Chinese medicine (CM) syndrome types: Xin (Heart) and Pi (Spleen) deficiency, yin deficiency with excess fire, Xin and gut qi deficiency, Wei (Stomach) disorder, and qi and blood deficiency, respectively. These 5 types of patients were randomly assigned to a catgut embedding group, an acupuncture group or a medication group (30 cases in Xin and Pi deficiency type, Wei disorder type, Xin and gut qi deficiency type, respectively; 40 cases in yin deficiency with excess fire type and qi and blood deficiency type, respectively). In the catgut embedding group, patients were treated by implanting catgut into acupoints once every 10 days for a total of 30 days. In the acupuncture group, patients were treated with acupuncture once per day over 30 days (excluding weekends); and patients in the medication group took 1 mg Eurodin Tablet orally every night for 30 days. Pittsburgh Sleep Quality Index (PSQI) was evaluated before treatment, on 30 and 60 days after the first treatment, respectively. The International Unified Sleep Efficiency Value (IUSEV) was measured at 30 and 60 days. The safety was evaluated after treatment and adverse events were analyzed. RESULTS: The objective PSQI scores including subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbance, daytime dysfunction, and total scores at 30 days were significantly improved compared with pre-treatment in the catgut embedding and acupuncture groups (P<0.01 or P<0.05). At 30 days, the PSQI scores in catgut embedding group were superior to the medication group in the patients with each type of insomnia, with the exception of sleep duration (P<0.01 or P<0.05). At 60 days, significant differences were found between the catgut embedding group and the medication group (P<0.01 for all indices). The IUSEV scores in the catgut embedding group were significantly higher than the acupuncture group at 60 days, and the scores in acupuncture group were higher than the medication group at 30 days (P<0.05 for all types). No severe adverse events were found in this study. CONCLUSIONS: Acupoint catgut embedding and acupuncture were more effective than medication in alleviating insomnia syndrome in different Chinese medicine syndrome type. However, the sustained effects of acupoint catgut embedding were superior to acupuncture. PMID- 30484017 TI - Classical Chinese Herbal Formulas in the Treatment of Coronary Heart Disease: A Narrative Review. AB - OBJECTIVE: To summarize the current evidence for 8 frequently prescribed Chinese herbal formulas (CHF) as treatments for angina pectoris in patients with coronary heart disease (CHD) and the associated adverse reactions. METHODS: Seven electronic databases were screened from their inception through July 2018 for all evidence related to classical CHF for the treatment of patients with CHD. RESULTS: CHF improves CHD outcomes in terms of angina pectoris, electrocardiogram results, Chinese medicine syndromes and biomarkers iomarkers. The combination of CHF and Western medicine (WM) is more effective on CHD than WM alone. The use of CHF to treat CHD shows the same or better clinical effects as the use of WM alone. The 8 investigated CHF do not induce hepatic and renal toxicity or other serious adverse effects. CONCLUSIONS: The safety and efficacy of 8 frequently prescribed herbal formulas for treating CHD have been confirmed in many studies. The findings of these studies are positive but should be interpreted cautiously due to the poor methodological quality of the randomized controlled trials (RCTs) and meta-analyses. Additional high-quality, multi-center, large-sample RCTs should be performed to confirm these results. PMID- 30484018 TI - Chinese Herbal Medicine for Osteosarcoma in the Mouse: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To summarize and critically assess the inhibitory effects of Chinese herbal medicine (CHM) on tumor volume and tumor weight for the treatment of osteosarcoma (OS) in mouse models. METHODS: PubMed, Embase, Web of Science, China Knowledge Resource Integrated Database (CNKI), Wanfang Database, VIP Database, and Chinese BioMedical (CBM) were searched since their inception dates to March 10, 2016. Two reviewers independently selected the controlled studies estimating effects of CHM on mouse OS by administration in vivo. A pair-wise meta-analysis was performed. Twenty-five studies with adequate randomization were included in the systematic review. RESULTS: CHM may significantly inhibit OS growth in mice, as assessed using the tumor weight [20 studies, n=443; 290 for CHM and 153 for the control; pooled mean difference (MD)=-2.90; 95% confidence interval (CI): 3.50 to-2.31; P<0.01], tumor volume (16 studies, n=382; 257 for CHM and 125 for the control; pooled MD =-2.57; 95% CI:-3.33 to-1.80; P<0.01) and tumor growth inhibition rate. CONCLUSION: CHM could significantly inhibit the growth of OS in mouse models, which might be supportive for the design of preclinical and clinical trials in future. PMID- 30484019 TI - Development of Improved Version of Quality of Life Assessment Instrument for Lung Cancer Patients Based on Traditional Chinese Medicine (QLASTCM-Lu). AB - OBJECTIVE: To develop an improved version of the Quality-of-Life Assessment instrument for Lung Cancer Patients Based on Traditional Chinese Medicine (QLASTCM-Lu) and to evaluate its psychometric property. METHODS: The structured group method and the theory in developing rating scale were employed to revise the preliminary scale. The psychometric property (reliability, validity, and responsiveness) of the established QLASTCM-Lu (modified) were evaluated by quality of life data measured in 100 lung cancer patients. Statistical analyses were made accordingly by way of correlation analysis, factor analysis and paired t-test. RESULTS: The internal consistency reliability of the overall scale and all domains was from 0.80 to 0.94. Correlation and factor analyses demonstrated that the scale was good in construct validity. The criterion validity was formed with European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-Lung Cancer (EORTC QLQ-LC43) as the criterion. Statistically significant changes were found apart from such domain as "mental condition" and "social function", with the standardized response means being close to those of QLQ-LC43. CONCLUSION: QLASTCM-Lu (modified) could be used to measure the quality of life of lung cancer patients with good reliability, validity and a certain degree of responsiveness. PMID- 30484020 TI - Curcumin Reverses 5-Fluorouracil Resistance by Promoting Human Colon Cancer HCT 8/5-FU Cell Apoptosis and Down-regulating Heat Shock Protein 27 and P Glycoprotein. AB - OBJECTIVE: To investigate the potential mechanisms that curcumin reverses 5 fluorouracil (5-FU) multidrug resistance (MDR). METHODS: Cell growth and the inhibitory rate of curcumin (2-25 MUg/mL) and/or 5-FU (0.05-1000 MUg/mL) on human colon cancer HCT-8 and HCT-8/5-FU (5-FU-resistant cell line) were determined using cell counting kit-8 (CCK-8) assay. Apoptosis and cell cycle after 5-FU and/or curcumin treatment were detected by flflow cytometry (FCM) and transmission electron microscopy (TEM). The expression of the multidrug resistance related factors p-glycoprotein (P-gp) and heat shock protein 27 (HSP 27) genes and proteins were analyzed by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting (WB), respectively. RESULTS: The inhibitory rate of curcumin or 5-FU on HCT-8 and HCT-8/5-FU cells proliferation at exponential phase were in a dosedependent manner, HCT-8 cell line was more sensitive to curcumin or 5-FU when compared the inhibitory rate of HCT-8/5-FU. The 50% inhibitory concentration (IC50) of combination 5-FU and curcumin (4.0 MUg/mL) in HCT-8/5-FU was calculated as 179.26 MUg/mL, with reversal fold of 1.85. Another IC50 of combination 5-FU and curcumin (5.5 MUg/mL) in HCT-8/5-FU was calculated as 89.25 MUg/mL, with reversal fold of 3.71. Synergistic effect of 5-FU and curcumin on HCT-8 and HCT-8/5-FU cells were found. The cell cycle analysis performed by FCM showed that HCT-8 and HCT-8/5-FU cells mostly accumulated at G0/G1 phase, which suggested a synergistic effect of curcumin and 5-FU to induce apoptosis. FCM analysis found that the percentage of apoptosis of cells treated with curcumin, 5-FU and their combination were significantly increased compared to the control group (P<0.05), and the percentage of apoptosis of the combination groups were slightly higher than other groups (P<0.05). The mRNA levels of P-gp (0.28+/-0.02) and HSP-27 (0.28+/-0.09) in HCT-8/5-FU cells treated with combination drugs were lower than cells treated with 5-FU alone (P gp, 0.48+/-0.07, P=0.009; HSP-27, 0.57+/-0.10, P=0.007). The protein levels of P gp (0.25+/-0.06) and HSP-27 (0.09+/-0.02) in HCT-8/5-FU cells treated with combination drugs were decreased when compared to 5-FU alone (P-gp, 0.46+/-0.02, P=0.005; HSP-27, 0.43+/-0.01, P=0.000). CONCLUSIONS: Curcumin can inhibit the proliferation of human colon cancer cells. Curcumin has the ability of reversal effects on the multidrug resistance of human colon cancer cells lines HCT-8/5-FU. Down-regulation of P-gp and HSP-27 may be the mechanism of curcumin reversing the drug resistance of HCT-8/5-FU to 5-FU. PMID- 30484021 TI - Wet-Cupping Is Effective on Persistent Nonspecific Low Back Pain: A Randomized Clinical Trial. AB - OBJECTIVE: To compare the possible effects of wet-cupping therapy with conventional therapy on persistent nonspecific low back pain (PNSLBP). METHODS: In this randomized clinical trial, 180 participants with the mean age of 45+/-10 years old, who had been suffering from PNSLBP were randomly assigned to wetcupping and conventional groups. The wet-cupping group was treated with two separate sessions (4 weeks in total) on the inter-scapular and sacrum area. In the conventional group, patients were conservatively treated using rest (6 weeks) and oral medications (3 weeks). The primary and the secondary outcome were the quantity of disability using Oswestry Disability Index (ODI), and pain intensity using Visual Analogue Scale (VAS), respectively. RESULTS: There was no significant difference in demographic characteristics (age, gender, and body mass index) between the two groups (P>0.05). Therapeutic effect of wet-cupping therapy was comparable to conventional treatment in the 1st month follow-up visits (P<0.05). The functional outcomes of wet-cupping at the 3rd and 6th month visits were significantly increased compared to the conventional group. Final ODI scores in the wet-cupping and conventional groups were 16.7+/-5.7 and 22.3+/-4.5, respectively (P<0.01). CONCLUSION: wet-cupping may be a proper method to decrease PNSLBP without any conventional treatment. The therapeutic effects of wet-cupping can be longer lasting than conventional therapy. (Registration No. IRCT2013021672741)). PMID- 30484022 TI - Standard Protocol Items for Clinical Trials with Traditional Chinese Medicine 2018: Recommendations, Explanation and Elaboration (SPIRIT-TCM Extension 2018). AB - Traditional Chinese Medicine (TCM) is one of the oldest systems of medicine. More and more attention has been paid to TCM application, but the variable quality of clinical trials with TCM impedes its widespread acceptance. The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement has established guidelines for designing clinical trials to ensure that the trial results are accurate and reliable. However, there are difficulties when applying SPIRIT 2013 Statement to trials with TCM, due to the unique theory and the characteristic of TCM intervention. An Extension to the original SPIRIT was developed to ensure the quality of trial design with TCM. As Chinese herbal formulae, acupuncture and moxibustion are common and representative interventions in TCM practice, the executive working group determined that the SPIRIT-TCM Extension focus on these three interventions. Extension was developed through initiation, 3 rounds of Delphi consensus survey, and finalizing expert meeting. Seven items from the SPIRIT 2013 Statement were modified, namely, "title", "background and rationale", "objectives", "eligibility criteria", "interventions", "outcomes", and "data collection methods". The Extension includes the introduction of the concept of TCM pattern and 3 major TCM interventions, with examples and explanations. The SPIRIT-TCM Extension 2018 provides suggestion for investigators in designing high quality TCM clinical trials. It is expected that wide dissemination and application of this extension ensure continuous improvement of TCM trial quality throughout the world. PMID- 30484023 TI - Three-dimensional descriptors for aminergic GPCRs: dependence on docking conformation and crystal structure. AB - Three-dimensional descriptors are often used to search for new biologically active compounds, in both ligand- and structure-based approaches, capturing the spatial orientation of molecules. They frequently constitute an input for machine learning-based predictions of compound activity or quantitative structure activity relationship modeling; however, the distribution of their values and the accuracy of depicting compound orientations might have an impact on the power of the obtained predictive models. In this study, we analyzed the distribution of three-dimensional descriptors calculated for docking poses of active and inactive compounds for all aminergic G protein-coupled receptors with available crystal structures, focusing on the variation in conformations for different receptors and crystals. We demonstrated that the consistency in compound orientation in the binding site is rather not correlated with the affinity itself, but is more influenced by other factors, such as the number of rotatable bonds and crystal structure used for docking studies. The visualizations of the descriptors distributions were prepared and made available online at http://chem.gmum.net/vischem_stability , which enables the investigation of chemical structures referring to particular data points depicted in the figures. Moreover, the performed analysis can assist in choosing crystal structure for docking studies, helping in selection of conditions providing the best discrimination between active and inactive compounds in machine learning-based experiments. PMID- 30484024 TI - Imaging findings of intraosseous traumatic neuroma of the mandible. AB - A traumatic neuroma is an uncommon pseudotumor associated with peripheral nerves and occurs following surgery or trauma. It mostly occurs in the extraosseous soft tissue; traumatic neuromas of intraosseous origin are extremely rare. We herein report an unusual case of an intraosseous traumatic neuroma associated with the inferior alveolar nerve that was incidentally found on a panoramic image. In this report, we place special emphasis on the imaging features of traumatic neuroma, including the computed tomography and magnetic resonance imaging findings. PMID- 30484025 TI - Multiple microlithiasis in bilateral parotid glands as the initial clinical manifestation of primary Sjogren's syndrome. AB - We report a rare case of Sjogren's syndrome (SS) with multiple microliths in the bilateral parotid glands. A 41-year-old man presented to our department with mild pain in the region of the right parotid gland. The dental examination was negative except for the parotid regions. The right region was moderately swollen and the left mildly swollen. Plain radiography revealed multiple calculi in the bilateral parotid glands. Ultrasonography showed heterogenic parenchyma, with microliths and cystic lesions in the parotid glands and heterogenic echotexture in the submandibular glands. Immunologic tests and the Schirmer test confirmed the diagnosis of SS. As the patient had no classic symptoms of SS, the bilateral multiple microliths were the first sign, facilitating the final diagnosis. Early diagnosis of SS is highly relevant because the proper therapy can be initiated. Adequate follow-up and, especially, control of the disease activity by identifying the predictive factors, are the primary objectives of SS management, enabling personalized treatment of this malignant disease. This case is a good example of how detection of calcifications in the bilateral parotid glands by plain radiography can help diagnose SS at an early stage. PMID- 30484026 TI - Hemifacial spasm secondary to vascular loop compression: a rare case report. AB - Hemifacial spasm (HFS) is characterised by brief, persistent, involuntary paroxysmal contractions of the facial muscles innervated by the facial nerve. Broadly its aetiology is portrayed as primary and secondary. Primary HFS is a result of vascular compression of the ipsilateral facial nerve at its root exit zone, and secondary HFS can occur after any injury to the facial nerve from the internal auditory canal to the stylomastoid foramen, which may be a result of a cerebellopontine angle tumour, schwannoma, fusiform aneurysm, or demyelinating lesion such as multiple sclerosis. We report a rare case of HFS in a 40-year-old female patient, who presented with a 4-year history of twitching of the left eye and deviation of the mouth towards the left side. An MRI of the brain revealed a vascular anomaly at the root exit zone of the left facial nerve. The present report aims to highlight MRI as a single, non-invasive diagnostic investigation to confirm the diagnosis of HFS. PMID- 30484027 TI - Radiological manifestations of renal osteodystrophy in the orofacial region: a case report and literature review. AB - Renal osteodystrophy (ROD) is a metabolic skeletal pathology that frequently affects the orofacial region and presents with characteristic radiological manifestations. This paper reports a case of ROD causing diffused orofacial bone alterations in a female patient with end-stage chronic kidney disease. The radiological features on panoramic, posteroanterior and lateral skull and computed tomography radiographs are described for this case. Previous reports in the literature are reviewed and discussed with a focus on radiological characteristics and differential diagnoses. PMID- 30484028 TI - Comparison of periodontal evaluation by cone-beam computed tomography, and clinical and intraoral radiographic examinations. AB - OBJECTIVES: Cone-beam computed tomography (CBCT) has been widely used in many fields of dentistry. However, little is known about the accuracy of CBCT for evaluation of periodontal status. The objective of this study was to compare and correlate periodontal assessments among CBCT, clinical attachment loss (CAL) measurement, and periapical (PA)/bitewing (BW) radiography. METHODS: Eighty patients (28 males, 52 females; age range, 19-84 years) from the University of Texas School of Dentistry at Houston were evaluated retrospectively. Measurements were taken on the central incisors, canines, and first molars of the right maxilla and left mandible. CAL was extracted from periodontal charts. The radiographic distance from the cementum-enamel junction (CEJ) to the alveolar crest was measured for tooth mesial and distal sites on PA/BW and CBCT images using MiPacs software and Anatomage Invivo software, respectively. One-way ANOVA and Pearson analysis were performed for statistical analyses. RESULTS: The CEJ crest distances for CBCT, PA/BW, and CAL were 2.56 +/- 0.12, 2.04 +/- 0.12, and 2.08 +/- 0.17 mm (mean +/- SD), respectively. CBCT exhibited larger values than the other two methods (p < 0.05). There were highly significant positive correlations among CBCT, PA/BW, and CAL measurements at all examined sites (p < 0.001). The Pearson correlation coefficient was higher for CBCT with CAL relative to PA/BW with CAL, but the difference was not significant (r = 0.64 and r = 0.55, respectively, p > 0.05). CONCLUSIONS: This study validates the suitability of CBCT for periodontal assessment. Further studies are necessary to optimize the measurement methodology with CBCT. PMID- 30484030 TI - Age-related changes in the pulp chamber of maxillary and mandibular molars on cone-beam computed tomography images. AB - OBJECTIVES: Secondary dentine is laid on pulp chamber walls with increasing age, and decreases pulp chamber size. This study aimed to investigate age estimation on cone-beam computed tomography (CBCT) images for forensic science, and the relationship between age and pulp chamber area of maxillary and mandibular molars. METHODS: We reviewed the CBCT images of 316 first molars in 87 patients with dental lesions. The 87 patients were classified into three groups: younger, 11-28 years; middle-aged, 34-59 years; and older, 60-74 years. The relationship between age and pulp chamber area of maxillary and mandibular molars was evaluated. RESULTS: The mean pulp chamber area of maxillary molars was 8.4 +/- 2.0, 4.4 +/- 1.7, and 2.9 +/- 0.9 mm2 in the younger, middle-aged, and older groups, respectively, (p = 0.028). The mean pulp chamber area of mandibular molars was 10.5 +/- 2.3, 6.7 +/- 2.2, and 3.7 +/- 1.5 mm2 in the younger, middle aged, and older groups, respectively, (p = 0.000). The mean pulp chamber area of mandibular molars was larger than that of maxillary molars in the younger (p = 0.000), middle-aged (p = 0.000), and older (p = 0.094) groups. The mean pulp chamber area of maxillary and mandibular molars was significantly correlated with age [Y = -0.142X + 11.582 (R 2 = 0.586, p = 0.000) and Y = -0.163X + 14.249 (R 2 = 0.609, p = 0.000), respectively]. CONCLUSIONS: These findings should be useful for diagnosis and treatment planning in dental practice and age estimation in forensic science. PMID- 30484029 TI - Dense cancellous bone as evidenced by a high HU value is predictive of late implant failure: a preliminary study. AB - OBJECTIVES: The mechanism of late implant failure is unclear. This study examined the association between sclerosing cancellous bone images and the risk of late implant failures using multi-detector row computed tomography (CT) imaging data. METHODS: We performed a case-control study. The study group consisted of consecutive patients with implant failures treated at Kyushu Dental University between 2001 and 2016. CT data for late failure of 36 implants in 16 patients were available. The study cohort consisted of 16 patients with 36 late failed implants and 28 patients with 113 successful implants. RESULTS: The mean survival rate was 6.9 months for early implant failure, 76.6 months for late failure with marginal bone resorption, inflammation symptoms, and so-called peri-implantitis, and 95.0 months for late failure caused by implant fracture. The mean HU value for cases in the control group was 507 compared with 1231 for cases with late failure implants. Logistic regression was used for analysis. There were signs of high radiodensity of peri-implant cancellous bone when comparing adjusted radiodensity per 100 HU using CT data (OR 2.35; 95% CI 1.73-3.20; p < 0.001). CONCLUSIONS: Within the limits of our study, the presence of high radiodensity and cancellous bone consolidation on imaging may be related to risk factors for late implant failure. Therefore, CT images of the host cancellous bone status for observation of visible sclerosis could be a useful diagnostic indicator for late implant failure. PMID- 30484031 TI - Diffusion-weighted magnetic resonance imaging in oral and maxillofacial lesions: preliminary study on diagnostic ability of apparent diffusion coefficient maps. AB - OBJECTIVES: The aim of this study was to investigate the usefulness of diffusion weighted magnetic resonance imaging (DWI) in oral and maxillofacial lesions, especially the utility of apparent diffusion coefficient (ADC) maps for differential diagnosis of these lesions. METHODS: Fifty-seven patients who underwent magnetic resonance imaging for diagnosis of oral and maxillofacial lesions were included in this prospective study. DWI was performed on a 1.5 T unit with b-factors of 0 and 800 s/mm2, and ADC maps were generated. ADC values were measured for all 57 oral and maxillofacial lesions (19 squamous cell carcinoma, 10 medication-related osteonecrosis of the jaw, 6 odontogenic abscess, 4 ranula, 4 osteoradionecrosis, 4 hemangioma, 3 pleomorphic adenoma, 3 odontogenic keratocyst, 2 nasopalatine duct cyst, 1 malignant melanoma, and 1 basal cell carcinoma). RESULTS: The mean ADC values for ranula (2.69 +/- 0.59 * 10-3 mm2/s) and nasopalatine duct cyst (2.34 +/- 0.12 * 10-3 mm2/s) were significantly higher than those for the other oral and maxillofacial lesions (p = 0.000). In contrast, the mean ADC value for odontogenic abscess (0.67 +/- 0.36 * 10-3 mm2/s) was significantly lower than those for the other oral and maxillofacial lesions (p = 0.000). CONCLUSIONS: The present study suggests the usefulness of DWI in oral and maxillofacial lesions, especially the utility of ADC maps for differential diagnosis of these lesions. PMID- 30484032 TI - Multiple mandibular static bone depressions attached to the three major salivary glands. AB - A Stafne bone defect is a static bone depression in the mandible that is commonly observed in cortical bone near the mandibular angle. We herein present a rare case in which static bone depressions attached to the three major salivary glands were observed on panoramic radiography and computed tomography (CT). The three static bone depressions in the mandible were visualized on a panoramic radiograph and CT as oval radiolucent masses in a 68-year-old man. The CT numbers in the bone depressions ranged from 10 to 50 HU, and they were close to those of the respective salivary glands. Based on the CT numbers, the areas in the bone depressions were determined to be a normal parotid gland, sublingual gland, and submandibular gland. The patient underwent a follow-up examination and did not request further consultation. PMID- 30484033 TI - Case-control study of mandibular canal branching and tooth-related inflammatory lesions. AB - OBJECTIVES: Morphological variations of mandibular canals increase the risk of neurovascular damage and bleeding during surgical procedures by decreasing the predictability of the inferior alveolar neurovascular bundle location. To improve the predictability with such variations, the present study aimed to verify the possibility of a relationship between mandibular canal branches (MCBs) and tooth related inflammatory lesions, using trough cone-beam computed tomography (CBCT) examinations. METHODS: The sample comprised 150 age and sex-matched examinations (50 cases and 100 controls) from two databases. The CBCT examinations were grouped by the presence of MCBs starting in the mandibular body regions as the outcome variable. Tooth-related inflammatory lesions and measurements of gray levels in the posterior region of the alveolar ridge were assessed in both groups. A multiple logistic regression analysis was applied to verify the relationships between MCBs and independent variables (p < 0.05). RESULTS: Occurrence of tooth-related inflammatory lesions increased the risk of MCBs in the mandibular body regions (p < 0.001; OR 11.640; 95% CI 4.327-31.311). High contrast images had a weaker association with MCBs (p = 0.002; OR 1.002; 95% CI 1.002-1.003). The most frequent tooth-related inflammatory lesions in both groups were endodontic (34 lesions; 45.94% of the total lesions). Most of the tooth related inflammatory lesions related to MCBs were endodontic (20 cases) and combined endodontic and periodontal inflammation (20 cases). CONCLUSIONS: An association was observed between MCBs in the mandibular body regions and tooth related inflammatory lesions. Inflammatory lesions of endodontic origin are most often associated with MCBs. PMID- 30484035 TI - A case of sublingual adenoid cystic carcinoma involving the mandible presenting as a "skip lesion". AB - Adenoid cystic carcinoma (ACC) is a slowly growing malignant neoplasm with a propensity for perineural invasion. Microscopic invasion of ACC often prevents its detection on computed tomography (CT) or magnetic resonance imaging (MRI). We herein report a rare case of sublingual ACC presenting as a "skip lesion" that rapidly infiltrated the mandible after tumor resection. A 64-year-old man presented to Okayama University Hospital with an 18-month history of swelling in the right floor of the mouth. Clinical examination displayed an ulcerated swollen mass in that region. An enhanced mass was detected in the right sublingual space on CT and MRI. Bone surface erosion was observed at the inferior border of the mandible, but continuity with the sublingual mass or mass around that lesion was not detected by imaging. Sublingual tumor resection and selective neck dissection were performed by the pull-through method. Histopathologically, the surgical margins were free of cancer cells, and the tumor was diagnosed as ACC. Continuity with the sublingual mass and mandibular bone was not detected intraoperatively. However, marked bone resorption was detected in the anterior mandible 3 months after the operation. Biopsy was performed, and the findings indicated the same histological type of sublingual ACC. This case suggests that a malignant tumor close to the jaw bone requires the clinician to consider the possibility of bone invasion and to observe a wide region surrounding the tumor using imaging examination. PMID- 30484034 TI - Cone-beam computed tomography and anatomical observations of normal variants in the mandible: variant dentists should recognize. AB - Many types of cone-beam computed tomography (CBCT) have recently been developed and are being used in many dental clinics. CBCT has significantly changed imaging diagnosis in dentistry by showing detailed structures in multiple dimensions with high spatial resolution. This allows dentists to confirm what cannot be recognized with conventional two-dimensional images, such as small neurovascular canals, the buccolingual location of structures/lesions, and the three dimensional shapes of hard tissue structures. The aim of this study was to review the normal variants of detailed anatomical structures in relation with the mandibular canal by comparing the previous reports and anatomical evaluations. These structures are likely to be observed on CBCT images by dental practitioners prior to dental procedures involving the mandibular teeth and bone. Understanding the relationship of these structures is useful for dental practitioners and oral surgeons to reduce the possibility of causing damage and patient discomfort during dental procedures. PMID- 30484036 TI - Impact of statistical reconstruction and compressed sensing algorithms on projection data elimination during X-ray CT image reconstruction. AB - OBJECTIVES: To examine the effect of incomplete, or total elimination of, projection data on computed tomography (CT) images subjected to statistical reconstruction and/or compressed sensing algorithms. METHODS: Multidetector row CT images were used. The algebraic reconstruction technique (ART) and the maximum likelihood-expectation maximization (ML-EM) method were compared with filtered back-projection (FBP). Effects on reconstructed images were studied when the projection data of 360 degrees (360 projections) were decreased to 180 or 90 projections by reducing the collection angle or thinning the image data. The total variation (TV) regularization method using compressed sensing was applied to images processed by the ART. Image noise was subjectively evaluated using the root-mean-square error and signal-to-noise ratio. RESULTS: When projection data were reduced by one-half or three-quarters, ART and ML-EM produced better image quality than FBP. Both ART and ML-EM resulted in high quality at a spread of 90 projections over 180 degrees rotation. Computational loading was high for statistical reconstruction, but not for ML-EM, compared with the ART. TV regularization made it possible to use only 36 projections while still achieving acceptable image quality. CONCLUSIONS: Incomplete projection data-accomplished by reducing the angle to collect image data or thinning the projection data without reducing the angle of rotation over which it is collected-made it possible to reduce the radiation dose while retaining image quality with statistical reconstruction algorithms and/or compressed sensing. Despite heavier computational calculation loading, these methods should be considered for reducing radiation doses. PMID- 30484037 TI - Differences in signal intensities of temporomandibular joint (TMJ) effusion on fluid-attenuated inversion recovery (FLAIR) images. AB - OBJECTIVES: Joint effusion is demonstrated by high signal intensity in the upper and lower temporomandibular joint (TMJ) spaces on T2-weighted images. The fluid attenuated inversion recovery (FLAIR) technique can be applied to analyze joint effusion in the TMJ. FLAIR signal intensity can be more sensitively influenced by the contents of joint effusion than T2-weighted signal intensity. The purpose of this study was to analyze the signal intensity of joint effusion on FLAIR images and to investigate the changes in joint effusion contents according to the status of TMJ disorders. METHODS: A total of 48 joints (45 patients) with joint effusion were investigated by magnetic resonance (MR) imaging. Regions of interest were placed over the joint effusion and gray matter on FLAIR images. The joints were categorized as normal disk position (NL), disk displacement with reduction (DWR), disk displacement without reduction (DWOR), and osteoarthritis (OA). The signal intensity ratio of joint effusion was calculated using gray matter as the reference point. The Kruskal-Wallis test and Steel test were applied. A probability of less than 0.05 was considered statistically significant. RESULTS: The median signal intensity ratios of joint effusion differed significantly among the four joint categories (p = 0.02, Kruskal-Wallis test). The median signal intensity ratio of joint effusion in the OA category was significantly higher than that in the NL category (p = 0.04, Steel test). CONCLUSIONS: The present findings suggest that FLAIR images can demonstrate the changes in joint effusion contents according to the status of TMJ disorders. PMID- 30484038 TI - CBCT-based bone quality assessment in decompression of large odontogenic cystic lesions. AB - OBJECTIVES: Bone quality comprises bone mineral density and trabecular microstructure. The aim of this study was to explore the effectiveness of cone beam computed tomography (CBCT) in evaluating bone quality of large odontogenic cystic lesions after decompression using CBCT and BoneJ software, and to determine whether secondary definitive surgery can be guided using CBCT data. METHODS: Twenty-seven patients with large odontogenic cystic lesions treated by decompression were evaluated by CBCT. Medical history and perioperative details were analyzed. RESULTS: The [Formula: see text]CT values for all patients with cystic lesions decreased after decompression, with no differences for age, sex, and histology (p > 0.05). Bone volume fraction and trabecular number of new cancellous bone (0.012%, 0.17/mm3) were lower than those of normal cancellous bone (0.189%, 0.47/mm3) (p < 0.05), while new cancellous bone trabecular separation (11.344 +/- 2.556 mm) was stronger than normal cancellous bone trabecular separation (4.833 +/- 2.232 mm) (p < 0.05). There were no differences in trabecular thickness between new cancellous bone (3.812 +/- 1.593 mm) and normal cancellous bone (4.598 +/- 3.573 mm) (p = 0.746). The [Formula: see text]CT values of five patients with favorable osteogenesis were - 72, -86, - 86, -47, and - 55, those of three patients with moderate osteogenesis were - 107, 120, and - 71, and those of two patients with poor osteogenesis were - 165 and - 127 during secondary definitive surgery. CONCLUSIONS: CBCT is considered beneficial for evaluating bone quality of large odontogenic cystic lesions after decompression, while providing potentially useful information for referral to secondary definitive surgery. PMID- 30484039 TI - A Mathematical Model of Fluid Transport in an Accurate Reconstruction of Parotid Acinar Cells. AB - Salivary gland acinar cells use the calcium ([Formula: see text]) ion as a signalling messenger to regulate a diverse range of intracellular processes, including the secretion of primary saliva. Although the underlying mechanisms responsible for saliva secretion are reasonably well understood, the precise role played by spatially heterogeneous intracellular [Formula: see text] signalling in these cells remains uncertain. In this study, we use a mathematical model, based on new and unpublished experimental data from parotid acinar cells (measured in excised lobules of mouse parotid gland), to investigate how the structure of the cell and the spatio-temporal properties of [Formula: see text] signalling influence the production of primary saliva. We combine a new [Formula: see text] signalling model [described in detail in a companion paper: Pages et al. in Bull Math Biol 2018, submitted] with an existing secretion model (Vera-Siguenza et al. in Bull Math Biol 80:255-282, 2018. https://doi.org/10.1007/s11538-017-0370-6 ) and solve the resultant model in an anatomically accurate three-dimensional cell. Our study yields three principal results. Firstly, we show that spatial heterogeneities of [Formula: see text] concentration in either the apical or basal regions of the cell have no significant effect on the rate of primary saliva secretion. Secondly, in agreement with previous work (Palk et al., in J Theor Biol 305:45-53, 2012. https://doi.org/10.1016/j.jtbi.2012.04.009 ) we show that the frequency of [Formula: see text] oscillation has no significant effect on the rate of primary saliva secretion, which is determined almost entirely by the mean (over time) of the apical and basal [Formula: see text]. Thirdly, it is possible to model the rate of primary saliva secretion as a quasi-steady-state function of the cytosolic [Formula: see text] averaged over the entire cell when modelling the flow rate is the only interest, thus ignoring all the dynamic complexity not only of the fluid secretion mechanism but also of the intracellular heterogeneity of [Formula: see text]. Taken together, our results demonstrate that an accurate multiscale model of primary saliva secretion from a single acinar cell can be constructed by ignoring the vast majority of the spatial and temporal complexity of the underlying mechanisms. PMID- 30484040 TI - A Growth-Fragmentation Approach for Modeling Microtubule Dynamic Instability. AB - Microtubules (MTs) are protein filaments found in all eukaryotic cells which are crucial for many cellular processes including cell movement, cell differentiation, and cell division. Due to their role in cell division, they are often used as targets for chemotherapy drugs used in cancer treatment. Experimental studies of MT dynamics have played an important role in the development and administration of many novel cancer drugs; however, a complete description of MT dynamics is lacking. Here, we propose a new mathematical model for MT dynamics, that can be used to study the effects of chemotherapy drugs on MT dynamics. Our model consists of a growth-fragmentation equation describing the dynamics of a length distribution of MTs, coupled with two ODEs that describe the dynamics of free GTP- and GDP-tubulin concentrations (the individual dimers that comprise of MTs). Here, we prove the well-posedness of our system and perform a numerical exploration of the influence of certain model parameters on the systems dynamics. In particular, we focus on a qualitative description for how a certain class of destabilizing drugs, the vinca alkaloids, alter MT dynamics. Through variation of certain model parameters which we know are altered by these drugs, we make comparisons between simulation results and what is observed in in vitro studies. PMID- 30484041 TI - Towards an Algebra of Existence and Development of Unique Subjects with Unique Minds: a Commentary to Jens Mammen's Book. AB - In the commentary to Jens Mammen's book A New Logical Foundation for Psychology (2017), three issues are discussed. The first one concerns possible interrelations of: (a) others' irreplaceability and existential irretrievability rigorously proved by Mammen; and (b) morality and attitudes to the others. Lem's criticism of Heidegger's existential philosophy, which paradoxically ignores mass homicide, is discussed in the context of topology of being. Different attitudes to the other as irreplaceable and irretrievable (e.g., in case of apprehension and execution of a murderer) are analyzed. The second issue concerns the possibility of true duplicates of the same person. The paradox of copied complexity is introduced. The third issue concerns reductionism (including brain reductionism) and opportunities to deduce various phenomena of development (mental development, actual genesis of creative thinking, etc.) from the new logical foundation for psychology built by Mammen. PMID- 30484042 TI - Zinc oxide nanostructures as a control strategy of bacterial speck of tomato caused by Pseudomonas syringae in Egypt. AB - This study was conducted to evaluate the ability of zinc oxide nanoparticles (ZONPs) with unique properties to protect tomato against the bacterial speck pathogen, caused by Pseudomonas syringae pv. tomato DC3000 (Pst). Protection of tomato against bacterial speck using ZONPS was evaluated by its direct antibacterial activity and its ability for inducing resistance in tomato plants. The results revealed that ZONPs showed significant direct antibacterial activity against Pseudomonas syringae pv. tomato under laboratory conditions. Moreover, tomato plants treated with ZONPs showed a significant reduction in disease severity and bacterial proliferation relative to non-treated plants. Furthermore, tomato plants treated with ZONPs showed higher self-defense enzyme activity relative to untreated plants. The regulatory and defense genes, LePR-1a and Lipoxygenase (LOX), involved in the salicylic acid (SA) and (JA) signaling pathways, respectively, were highly expressed in tomato plants treated with ZONPs compared to untreated plants. Growth characters of tomato plants treated with ZONPs were significantly enhanced relative to untreated plants. The control of bacterial speck pathogen of tomato using ZONPs through its direct antibacterial and by developing of systemic resistance in treated tomatoes against the pathogen is considered the first report. PMID- 30484043 TI - Performance and autopsy of nanofiltration membranes at an oil-field wastewater desalination plant. AB - In this study, the long-term operational performance of an on-site NF facility at a full-scale oil-field wastewater desalination plant was monitored. The NF facility with poor permeability due to membrane fouling enables efficient multivalent salt removal (rejections of Mg2+, Ca2+, Fe3+, and Al3+ were approximately 100%). Moreover, a comparison of the cleaning efficiencies of two on-site cleaning modes indicated that PL-007 cleaning helped to improve the effectiveness of subsequent acid cleaning in the removal of inorganic foulants. Furthermore, a spiral-wound NF membrane module harvested from the plant was unfolded and autopsied. The results showed that both anionic polyacrylamide (APAM) and crude oil were identified as the predominant organic matter on the membrane surface and collectively accounted for a substantial fraction (86.3%) in terms of dry weight. Additionally, dissolved organics with a high molecular weight were prone to accumulation on the membrane surface. Multivalent elements, including Mg, Ca, Al, Fe, and Si, were the primary inorganic species in the fouling layer. Among the inorganic elements, Si occupied a high proportion and existed in the form of SiO2 in the fouling layer. According to the autopsy results, organic fouling combined with inorganics was responsible for the decline in the flux. PMID- 30484044 TI - Efficiency of maternal-fetal transfer of perfluoroalkyl and polyfluoroalkyl substances. AB - Perfluoroalkyl and polyfluoroalkyl substances (PFASs) can be transferred from a mother to her fetus during pregnancy and adversely affect fetal development. However, the efficiency and influencing factors of PFASs maternal-fetal transfer remain unclear. We measured the levels of six perfluoroalkylcarboxylates, three perfluoroalkylsulfonates, and one sulfonamide in 369 pairs of maternal and umbilical cord serum and examined the transplacental transfer efficiency (TTE) of PFASs by the functional group and carbon chain length in a prospective birth cohort in Shandong, China. All ten PFASs were detected in both maternal and umbilical cord serum in nearly all samples. Maternal and cord levels were closely correlated (the correlation coefficient [r] ranging from 0.485 to 0.908) in most PFASs except perfluorobutane sulfonic acid (PFBS) (r = 0.159). TTE was significantly affected by the functional group and carbon chain length. Compared to perfluoroalkylcarboxylates, perfluoroalkylsulfonates had a lower ratio of maternal to fetal transfer. A U-shaped relationship between carbon chain length and TTE was observed for perfluoroalkylcarboxylates while a monotonic descending trend was identified between TTE and the increasing carbon chain length for perfluoroalkylsulfonates. PFASs can readily pass through the placenta. The functional group and carbon chain length are important determinants for the TTE of PFASs. PMID- 30484045 TI - The effects of urbanization and globalization on CO2 emissions: evidence from the Sub-Saharan Africa (SSA) countries. AB - Ecological modernization theories suggest that it is hard to determine a priori the environmental effects of urbanization, while neoliberal doctrine advocates a positive role of globalization in developing economies especially in terms of reducing poverty and inequality. Yet, the environmental effect of globalization is not unanimous. This study employs second-generation panel regression techniques that account for heterogeneous slope coefficients and cross-sectional dependence to estimate the impacts that urbanization and globalization have on CO2 emissions for a panel of 44 Sub-Saharan Africa (SSA) countries for the period 1984-2016. Also, a causality test that considers both these issues is performed. The estimated coefficient of urbanization is positive, statistically significant, and highly consistent across different estimation techniques. The magnitude of the coefficient and level of significance are different in different econometric estimations. In most specifications, the estimated coefficient on the globalization variable is statistically insignificant. Urbanization is found to cause emissions. The environmental implications of these results are discussed with a set of policy recommendations for an environmentally better SSA region. PMID- 30484046 TI - Enhancement of ciprofloxacin degradation in aqueous system by heterogeneous catalytic ozonation. AB - Fluoroquinolones are extensively used in medicine due to their antimicrobial activity. Their presence in water inhibits microorganism activity in conventional wastewater treatment plants. This study aims to evaluate the technical feasibility of applying heterogeneous catalytic ozonation to eliminate ciprofloxacin (CIP) as a representative of fluoroquinolone antibiotics normally present in municipal wastewater discharges. Experiments were conducted in a semi batch stirred slurry reactor, using 0.7 L of 100 mg L-1 CIP aqueous solution, at pH 3 and 30 degrees C. Experimental results show that single ozonation can easily oxidise CIP molecules (68%) within the first 5 min, leading to the generation of refractory oxidation by-products. However, when heterogeneous catalytic ozonation is applied using iron oxide supported on MFI synthetic zeolite, total degradation of CIP is observed at 5 min and a higher mineralisation rate is obtained. A novel sequential process is developed for CIP mineralisation. In a first step, a flash single ozonation is applied and CIP molecules are broken down. Then, a catalytic ozonation step is conducted by adding the Fe/MFI catalyst into the reactor. As a result of catalyst addition, 44% of Total Organic Carbon (TOC) is eliminated within the first 15 min, compared to single ozonation where only 13% of TOC removal is reached in the same time. The application of this sequential process to a real wastewater effluent spiked with CIP leads to 52% of TOC removal. PMID- 30484047 TI - Monitoring metal pollution on coastal lagoons using Cerastoderma edule-a report from a moderately impacted system in Western Portugal (Obidos Lagoon). AB - The main goal of this monitoring program was to evaluate the contamination in the intertidal environment of Obidos Lagoon by the metals Cd, Pb, and Ni on water, sediments, and on biological samples, using the bivalve Cerastoderma edule (common name: cockle) as a biomonitor. Since C. edule is an edible mollusc, the risk of their consumption by humans from this lagoon was also evaluated. The study was performed in a restricted area of the lagoon-the ML station-where human activities, such as shellfish harvesting, intersect with the natural processes occurring in this system. The results obtained revealed that the water samples were polluted with Cd and Pb with concentrations (0.00025 mg l-1 and 0.0072 mg l 1) above the maximum legislated on the Directive 2008/105/EC, while for Ni, this occurred only on one of the seasons sampled (summer 2010: 0.029 mg l-1). The sediments were not contaminated with Cd and Ni, and the contamination detected for the metal Pb, allowed the classification of this station as an unpolluted site ([Pbmin] = 7.477 mg.kg-1 and [Pbmax] = 19.875 mg.kg-1). On biological samples, comparing the results of metal contaminations with the values of the maximum levels fixed by European Commission Regulation (EC) No 1881/2006 and USFDA, all the results were below the legal value. Therefore, during the period of study, the consumption of this bivalve by humans was safe. Also, BAF and CF calculations suggest that C. edule can be used as a biomonitor to determine the source of the contaminations. This study supported the use of C. edule as a biomonitor to assess the contamination by the metals Pb and Ni at the Obidos Lagoon and allowed to predict the potential transfer of metals to higher trophic levels with potential impacts on the natural and human communities. PMID- 30484048 TI - Biochar as low-cost sorbent of volatile fuel organic compounds: potential application to water remediation. AB - Pyrolysis of waste materials to produce biochar is an excellent and suitable alternative supporting a circular bio-based economy. One of the properties attributed to biochar is the capacity for sorbing organic contaminants, which is determined by its composition and physicochemical characteristics. In this study, the capacity of waste-derived biochar to retain volatile fuel organic compounds (benzene, toluene, ethylbenzene and xylene (BTEX) and fuel oxygenates (FO)) from artificially contaminated water was assessed using batch-based sorption experiments. Additionally, the sorption isotherms were established. The results showed significant differences between BTEX and FO sorption on biochar, being the most hydrophobic and non-polar contaminants those showing the highest retention. Furthermore, the sorption process reflected a multilayer behaviour and a relatively high sorption capacity of the biochar materials. Langmuir and Freundlich models were adequate to describe the experimental results and to detect general differences in the sorption behaviour of volatile fuel organic compounds. It was also observed that the feedstock material and biochar pyrolysis conditions had a significant influence in the sorption process. The highest sorption capacity was found in biochars produced at high temperature (> 400 degrees C) and thus rich in aromatic C, such as eucalyptus and corn cob biochars. Overall, waste-derived biochar offers a viable alternative to be used in the remediation of volatile fuel organic compounds from water due to its high sorption capacity. PMID- 30484049 TI - Camera sensor-based contamination detection for water environment monitoring. AB - Water environment monitoring is of great importance to human health, ecosystem sustainability, and water transport. Unlike traditional water quality monitoring problems, this paper focuses on visual perception of water environment. We first introduce the development of a customized aquatic sensor node equipped with an embedded camera sensor. Based on this platform, we present an efficient and holistic contamination detection approach, which can automatically adapt to the detection of floating debris in dynamic waters or the identification of salient regions in static waters. Our approach is specifically designed based on compressed sensing theory to give full consideration to the unique challenges in water environment and the resource constraints on sensor nodes. Both laboratory and field experiments demonstrate the proposed method can fast and accurately detect various types of water pollutants and is a better choice for camera sensor based water environment monitoring compared with other methods. PMID- 30484050 TI - Amorphous iron sulfide nanowires as an efficient adsorbent for toxic dye effluents remediation. AB - Environmental and health concerns arising from the toxicity of organic dye effluents is still the issue of the twenty-first century. In that regard, this study presents iron sulfide (FeS2) for its use in environmental remediation application. Amorphous phase FeS2 nanowires were synthesized by PVP-assisted solvothermal reaction and were characterized using XRD, XPS, BET, FE-SEM, and EDS techniques. The amorphous phase FeS2 is attractive from material synthesis point of view as its synthesis does not require delicate control over the process parameters, unlike the crystalline phase. The 1-D nanowire FeS2 had a high surface-to-volume ratio with negative zeta potential within a wide pH range. Having those surface and microstructural properties, these nanowires exhibited excellent adsorption property towards model organic dyes, Congo red (anionic), and methylene blue (cationic), with theoretical adsorption capacity of 118.86 and 48.82 mg g-1, respectively. Adsorption kinetics and isotherm models were implemented to study the adsorption processes at different adsorption conditions (pH, adsorbent loading, initial adsorbate concentration). The pH dependence of the adsorption and FT-IR analysis evidenced the prevalence of both physisorption and chemisorption during the adsorption of Congo red. Recyclability test proved the excellent performance of this amorphous FeS2 nanowire adsorbent for three consecutive cycles. Considering its ease of synthesis, excellent adsorption property, and cyclic performance, the as-prepared adsorbent could be a promising material for dye effluents treatment. PMID- 30484051 TI - The zoocenosis of the Aral Sea: six decades of fast-paced change. AB - During the last six decades, the water level of the Aral Sea, once one of the largest lakes in the world, has experienced a major human-driven regression followed by significant changes in salinity. These fast-paced alterations were initiated by the diversion of two rivers-the Amu Darya and Syr Darya-key players in the regulation of the water balance of the Aral Sea. Consequently, biological modifications took place leading to severe changes of the zoocenosis. This paper reviews the changes that have affected communities of fish and aquatic invertebrates in the Aral Sea since the 1950s. The reported alterations in biodiversity not only represent a natural response to a decrease in water level and a subsequent increase in salinity but also effects of non-native species introduction. The future prospects for invertebrates and fish in the Aral Sea, assuming that initiated restoration work is continued, are also discussed in this paper. PMID- 30484052 TI - Inter-species and inter-colony differences in elemental concentrations in eggshells of sympatrically nesting great cormorants Phalacrocorax carbo and grey herons Ardea cinerea. AB - We compared the concentrations of 17 heavy metals and essential elements in post hatching eggshells of two waterbirds, the obligate piscivorous great cormorant Phalacrocorax carbo (GCM) and the more omnivorous grey heron Ardea cinerea (GHR), breeding sympatrically in eight mixed colonies in Poland. We found significant inter-species and inter-colony differences in the levels of most of the elements. GHR had significantly higher concentrations of Al, which can be explained by its very low stomach pH: an acidic environment favours the release of Al compounds. Differences in Mn, Ni, Cu, Se and Hg concentrations can be attributed to the various contributions of fish and other aquatic organisms to the diet, and to the exploration of different habitats (GCM exclusively aquatic, GHR a wider range) and microhabitats (GCM, in contrast to wading GHR, dive for food, exploring the whole depth range of water bodies), differently exposed to contamination by those elements from sediments. Inter-colony differences were related to the level of industrialisation. We recorded higher levels of some elements in the eggshells (Fe, Mn in both species and Cr, Ni and Zn in GCM) collected in industrialised areas, which may be associated with the negative environmental impact of industrial areas. PMID- 30484053 TI - Bioconversion of lignin into bioplastics by Pandoraea sp. B-6: molecular mechanism. AB - Lignin is a byproduct in the pulp and paper industry and is considered as a promising alternative for the provision of energy and chemicals. Currently, the efficient valorization of lignin is a challenge owing to its polymeric structure complexity. Here, we present a platform for bio-converting Kraft lignin (KL), to polyhydroxyalkanoate (PHA) by Pandoraea sp. B-6 (hereafter B-6). Depolymerization of KL by B-6 was first confirmed, and > 40% KL was degraded by B-6 in the initial 4 days. Characterization of PHA showed that up to 24.7% of PHA accumulated in B-6 grown in 6-g/L KL mineral medium. The composition, structure, and thermal properties of the produced PHA were analyzed, revealing that 3-hydroxybutyrate was the only monomer and that PHA was comparable with the commercially available bioplastics. Moreover, the genomic analysis illustrated three core enzymatic systems for lignin depolymerization including laccases, peroxidases, and Fenton reaction enzymes; five catabolic pathways for LDAC degradation and a gene cluster consisting of bktB, phaR, phaB, phaA, and phaC genes involved in PHA biosynthesis. Accordingly, a basic model for the process from lignin depolymerization to PHA production was constructed. Our findings provide a comprehensive perspective for lignin valorization and bio-material production from waste. PMID- 30484054 TI - Membrane fouling and performance of anaerobic ceramic membrane bioreactor treating phenol- and quinoline-containing wastewater: granular activated carbon vs polyaluminum chloride. AB - Although anaerobic membrane bioreactor (AnMBR) has been proposed for the treatment of phenolic wastewater, the membrane fouling is still a major obstacle. The effects of dosing of granular activated carbon (GAC) and polyaluminum chloride (PACl) on the treatment performance and membrane fouling of anaerobic ceramic membrane bioreactor were investigated for treating phenol- and quinoline containing wastewater. The results suggested that the one-off dosing of GAC resulted in a decrease of protein/carbohydrate ratio, which might account for the aggravation of membrane fouling alongside with the decreased flocs size. Nevertheless, the substrate uptake rates (SUR) of phenol and quinoline, and the specific methanogenic activity of sludge at the GAC dosing stage of experimental reactor (R1) were 8.79 +/- 0.63 mg phenol g-1 MLVSS d-1, 7.01 +/- 0.09 mg quinoline g-1 MLVSS d-1 and 0.27 +/- 0.01 g CODCH4 g-1 MLVSS d-1, which were 1.69, 3.59 and 1.93 times higher than that of the control reactor (R2). The dosing of PACl reduced the membrane fouling rate by changing the floc structure of sludge, as well as the component of SMP and EPS. However, the substrate uptake rate of quinoline was declined. This work provides a comprehensive evaluation on the effect of GAC and PACl dosing on membrane fouling and performance of anaerobic ceramic membrane bioreactor treating phenol-and quinoline-containing wastewater. PMID- 30484055 TI - Marine litter in stomach content of small pelagic fishes from the Adriatic Sea: sardines (Sardina pilchardus) and anchovies (Engraulis encrasicolus). AB - Marine litter impacts oceans and affects marine organisms, representing a potential threat for natural stocks of pelagic fish species located at the first levels of the marine food webs. In 2013-2014, on a seasonal basis, marine litter and microplastics in stomach contents from Sardinia pilchardus and Engraulis encrasicolus were evaluated. Selected species are plankitivores of great ecological and commercial importance in the Adriatic Sea. Collected data were correlated to possible factors able to affect ingested levels as well as species, season of sampling, biometry and sex of animals. Almost all tested samples (80 organisms for each species) contained marine litter (over 90% of samples from both species) and also microplastics; while any meso- or macroplastics were recorded. On average, recorded items were as follows: 4.63 (S. plichardus) and 1.25 (E. encrasicolus) per individual. Sardines evidenced a higher number of microplastics characterised by a smaller size than those recorded in anchovies. For sardines, sex, Gastro Somatic Index and sampling season showed negligible effects on the number of ingested litter; conversely, anchovies showed differences related with both sex of animals and dominant colour of ingested materials with prevalence for black and blue colours. PMID- 30484056 TI - Polyphenolic extracts from the xerophyte Rhamnus lycioides as a radiation biodosimeter. AB - The majority of dosimeters currently in use are synthetic and very expensive. Therefore, the study of the dosimetric characteristics of polyphenolic extracts of xerophytes is useful because drought stress causes an increase in the production of these cheap and natural compounds containing benzene rings. Here, the polyphenolic compounds were extracted from Rhamnus lycioides which was collected from Bou-Hedma National Park in Tunisia and identified using liquid chromatography-mass spectrometry (LC-MS). We investigated the impact of cobalt-60 (60Co) irradiation (0-30 kilogray (kGy)) on the color parameters of polyphenolic extracts of R. lycioides using the Konica Minolta CR 300 portable colorimeter and UV-Visible spectroscopy. The structural and morphological characteristics of the irradiated extracts were assessed using Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD) technique and scanning electron microscopy (SEM). Overall, our results suggest that exposure to ionizing radiation (IR) of the polyphenolic components of the xerophyte R. lycioides has produced significant dose-dependent changes in their optical and morphological properties. Thus, these extracts can be valorized as biodosimeters in the dose range from 5 to 25 kGy. PMID- 30484057 TI - Antimicrobial activity of X zeolite exchanged with Cu2+ and Zn2+ on Escherichia coli and Staphylococcus aureus. AB - The biocidal cations of Cu2+ and Zn2+ were hosted on the surfaces and in the cavities of X zeolite via ion exchange. The microstructure and interface properties of the exchanged zeolite X samples were analyzed by XRD, SEM, XPS, and XRF. The as-prepared samples showed excellent antimicrobial activity towards gram negative bacteria of Escherichia coli and gram-positive bacteria of Staphylococcus aureus. Furthermore, the batch antimicrobial experiments showed that the bacterial disinfection process fitted well with the first order model. The Cu2+-zeolite showed excellent and better antibacterial performance on S. aureus than on E. coli, and the mortalities of E. coli and S. aureus were almost 100% after 1 h with the initial Cu2+-zeolite concentrations of 1000 ppm and 100 ppm, respectively. However, the Zn2+-zeolites were found to be less effective on S. aureus than on E. coli, and the mortalities of E. coli and S. aureus were almost 100% after 1 h with the initial Zn2+-zeolite concentrations of 500 ppm and 1000 ppm, respectively. In addition, the relationships between the apparent rate constant (k) and reagent concentration (C) were also systematically investigated. The present results suggest that the as-prepared samples could be promising antibacterial materials for the efficient disinfection of contaminated water with bacteria. PMID- 30484058 TI - The effect of command-and-control regulation on environmental technological innovation in China: a spatial econometric approach. AB - Combining with the spatial variations in environmental technological innovation cross-province in China, this study employs the spatial econometric model to explore how environmental technological innovation responds to changes in command and-control regulation and three other traditional determinants (the environmental R&D investments, the environmental labor force inputs, and the provincial economic development level) during the study period from 2004 to 2016.The results indicate that there is a clear sign of spatial correlation in the environmental technological innovation according to the global and local indicators of spatial association. Then, considering the spatial interdependence of environmental technological innovation and holding other variables constant, evidence shows that command-and-control regulation has a significant adverse effect on environmental technological innovation in the whole country and the Eastern region, while the effect is statistically positive in the Western region and non-significant in the Central region. We also find that the effects in two sub-periods of 2004-2010 and 2011-2016 are obvious differences because some new command-and-control regulation instruments were formulated and implemented in 2010. In addition, environmental technological innovation is also directly catalyzed by the environmental R&D investments, the environmental labor force inputs, and the provincial economic development level. PMID- 30484059 TI - Nationwide outcomes and costs of laparoscopic and robotic vs. open hepatectomy. AB - The safety of hepatectomy continues to improve and it holds a key role in the management of benign and malignant hepatic lesions. Laparoscopic and robotic approaches to hepatectomy are increasingly utilized. The purpose of this study was to compare outcomes and costs of laparoscopic and robotic vs. open approaches to hepatectomy and to determine the national nonelective postoperative readmission rate, including readmission to other hospitals. The Nationwide Readmission Database from 2013 to 2014 was queried for all patients undergoing hepatectomy. Patients undergoing laparoscopic and robotic hepatectomies were compared to patients undergoing open hepatectomy. Multivariate logistic regression was implemented to determine the odds ratios (OR) for non-elective readmission within 45 days. There were 10,870 patients who underwent hepatectomy from 2013 to 2014 and 724 (6.7%) were approached with laparoscopic or robotic technique. The robotic cohort had lower mean cost of the index admission ($24,983 +/- $18,329 vs. open $32,391 +/- $31,983, p < 0.001, 95% CI - 18,292 to 534), shorter LOS (4.5 +/- 3.8 vs. lap 6.8 +/- 6.0 vs. open 7.6 +/- 7.7 days, p < 0.01), and were less likely to be readmitted within 45 days (7.9% vs. 13.0% lap vs. 13.8% open, p = 0.05). The robotic cohort was slightly younger (mean age 57.5 +/- 13.5 vs. lap 60.1 +/- 13.8 vs. open 58.9 +/- 13.7, p < 0.05), and no significant differences were seen by Charlson Comorbidity Index. Anastomosis of hepatic duct to GI tract carried higher odds of mortality (OR 2.87, p < 0.01) and higher odds of readmission (OR 1.40, p < 0.01). LOS above 7 days increased odds of readmission (OR 2.24, p < 0.01). Nearly one-fifth of patients readmitted after hepatectomy present to a different hospital. Robotic hepatectomy was associated with favorable cost and readmission outcomes compared to laparoscopic and open hepatectomy patients, despite similar patient comorbid burdens and patient's age. Length of stay over 7 days and anastomosis of hepatic duct to GI tract are strong risk factors for readmission and mortality. PMID- 30484060 TI - Unrestricted Somatic Stem Cells Loaded in Nanofibrous Conduit as Potential Candidate for Sciatic Nerve Regeneration. AB - Motor and sensory recovery following critical size peripheral nerve defects is often incomplete. Although nerve grafting has been proposed as the gold standard, it is associated with several disadvantages. Here we report a novel approach to peripheral nerve repair using Human Unrestricted Somatic Stem Cells (USSC) delivered through an electrospun neural guidance conduit. Conduits were produced from PCL and gelatin blend. Several in vitro methods were utilized to investigate the conduit's physicochemical and biological characteristics. Nerve regeneration was studied across a 10-mm sciatic nerve gap in Wistar rats. For functional analysis, the conduits were seeded with 3 * 104 USSCs and implanted into a 10-mm sciatic nerve defect. After 14 weeks, the results of functional recovery analysis and histopathological examinations showed that animals implanted with USSC containing conduits exhibited improved functional and histopathological recovery which was more close to the autograft group compared to other groups. Our results support the potential applicability of USSCs to treat peripheral nerve injury in the clinic. PMID- 30484061 TI - Non-invasive Vagus Nerve Stimulation Protects Against Cerebral Ischemia/Reperfusion Injury and Promotes Microglial M2 Polarization Via Interleukin-17A Inhibition. AB - Microglia play an essential role during cerebral an ischemia/reperfusion (I/R) related inflammatory process. Because the M2 phenotype of microglia exhibits anti inflammation activity, it has become a promising target for anti-inflammatory therapy. Vagus nerve stimulation (VNS) reportedly has neuroprotective effects against cerebral I/R injuries via its anti-inflammatory action. The aim of this study was to investigate the ability of non-invasive VNS (nVNS) to alleviate cerebral I/R in mice by promoting microglial M2 polarization. Neurological scoring and cerebral infarct volume assessments were performed 72 h after a middle cerebral artery occlusion (MCAO)-induced stroke. M2 phenotype microglia were identified by immunohistochemistry staining using Arg-1 and Iba-1 antibodies. The protein expressions of Arg-1, IL-17A, IL-10, Bax, and Bcl-2 were detected by Western blot. Apoptotic cells were detected using TUNEL staining. According to our results, nVNS decreased infarct volume, improved neurological outcomes, reduced apoptotic neurons (TUNEL+NeuN+ cells), and promoted microglial M2 polarization as indicated by elevated Arg-1 protein expression and increased Arg-1+ cells after MCAO. Moreover, nVNS attenuated the increased levels of IL-17A protein expression after MCAO. To test the possible involvement of IL-17A in nVNS induced neuroprotection and microglial M2 polarization, 1-MUg recombinant IL-17A (rIL-17A) was intranasally administered once daily for three consecutive days after reperfusion. We found that the intranasal administration of rIL-17A nullified the nVNS-induced promotion of microglial M2 polarization. Furthermore, rIL-17A administration abolished the neuroprotective effect of nVNS. In conclusion, our study identifies microglial M2 polarization as an important mechanism underlying the nVNS-mediated neuroprotection against cerebral I/R. This effect of nVNS could be attributed to the inhibition of IL-17A expression. PMID- 30484062 TI - Early surgery with aggressive surgical approach to improve 6-month outcomes in patients with active infective endocarditis: contribution of cerebral preoperative magnetic resonance imaging. AB - OBJECTIVES: We investigated the hypothesis that early surgery for infective endocarditis (IE) attenuates the rate of death or embolic events and does not increase the rate of relapse or postoperative valvular dysfunction (PVD) at 6 months. METHODS: 21 consecutive patients who underwent surgical treatment of IE were prospectively included. We assessed 6-month postoperative clinical outcomes by comparing early surgery (Group E, surgery within 72 h) and conventional treatment (Group C). Nine patients (43%) were assigned to Group E based on a combination of preoperative evaluation parameters, including the findings of cerebral magnetic resonance imaging (MRI), which was performed in all patients with left-sided IE. RESULTS: Six surgical plans (5 advancements and 1 postponement) were modified by routine MRI. Although preoperative echocardiography did not confirm all annular invasions, the rate of periannular infection, which was treated by pericardial annular patch plasty (56%) in patients with native-valve IE, was higher in Group E than C (P = 0.006). Early surgery based on MRI findings resulted in no postoperative embolic events or cerebral bleeding. The 6-month mortality rate was 0% in both groups, although the calculated 6-month IE mortality rate was 49.2 +/- 25% and 28.8 +/- 18%, respectively. No recurrence of IE or PVD occurred in Group E. The 6-month rate of freedom from composite events was 100% in Group E. CONCLUSIONS: Aggressive treatment (periannular resection and disuse of a prosthetic annuloplasty ring) and optimal antibiotic therapy based on intraoperative microorganisms, even in patients who underwent early surgery, reduced the 6-month relapse and PVD rates. PMID- 30484063 TI - Primary Tumor Resection for Stage IV Colorectal Cancer in the Era of Targeted Chemotherapy. AB - BACKGROUND: In the current era of targeted therapies, the benefits of resection of primary tumors in patients with unresectable stage IV colorectal cancer, specifically with regard to overall survival, are unknown. METHODS: Our study population comprised 208 consecutive patients with unresectable stage IV colorectal cancer who received chemotherapy containing at least one molecular target agent, bevacizumab, cetuximab, and panitumumab, at the National Cancer Center Hospital from 2006 to 2013. To lessen the effects of confounding factors between two treatment groups (resection versus non-resection) such as performance status, presence of severe symptoms, M subcategories (M1a versus M1b, M1c) according to the TNM classification, primary tumor site, and CEA value, we conducted three different propensity score analyses (regression adjustment, stratification, and matching). RESULTS: Of the 208 patients, 108 (52%) underwent resection of the primary tumor, while 100 (48%) did not. Regression adjustment revealed that resection was not associated with longer overall survival (hazard ratio of 0.70 (95% CI [0.49-1.00]; p = 0.051)). Stratification analysis of five strata revealed inconsistent results (hazard ratios ranged from 0.50 to 1.58); specifically, resection was associated with longer overall survival in four strata, but with shorter survival in one stratum. The propensity score-matched cohort (64 matched pairs) yielded a hazard ratio of 0.76 (95% CI [0.51-1.15]; p = 0.197). CONCLUSIONS: All three analyses revealed that, in the current era of chemotherapy with target agents, primary tumor resection was only marginally influential and did not significantly improve overall survival over chemotherapy alone. PMID- 30484064 TI - Bidirectional regulation of Ca2+ in exo-endocytosis coupling. PMID- 30484065 TI - Medicinal and Aromatic Plants Used in Traditional Treatment of the Oral Pathology: The Ethnobotanical Survey in the Economic Capital Casablanca, Morocco (North Africa). AB - In order to identify the medicinal and aromatic plants most requested for the treatment of the most common oral pathology, an ethnobotanical survey was carried out in the economic capital Casablanca, Morocco. The data basis was obtained draw selected traditional herbalists based on the semi-structured questionnaire. Quantitative indices such as use value (UV), family UV (FUV), fidelity level and informant consensus factor (ICF) were intended to evaluate the importance of plant species. A total of 46 plants species belonging to 22 families that were used. Juglandaceae family showed the highest significance (FUV = 0.75). We identified 40 species used for gum disease (gingivitis, periodontal abscess), 15 for dental pain (toothache, tooth sensitivity), 14 for halitosis, 12 for oral ulcers (aphtous, mouth ulcers and herpes), 3 for dental stain (teeth cleaning, sparkling and bleaching) and only 2 for tooth decay. The used plants are mainly prepared as decoction (80.4%). Syzygium aromaticum (UV = 0.94) was the specie most commonly prescribed by local herbalists. The higher ICF (0.75) was registered for the use gum disease. PMID- 30484066 TI - The drivers and extent of poison use by Namibia's communal farmers: Implications for averting the African vulture crisis. AB - The use of poison by farmers to control livestock predators is a major threat to vulture populations across Eurasia and Africa. While there is now some understanding of poison use on freehold farmland regions in southern Africa, the prevalence and drivers of this practice are still unknown in communal farmlands. We surveyed 353 communal farmers in Namibia to assess the prevalence of reported poison use and intended poison use and the factors associated with both. We used the Randomised Response Technique, a method deemed to yield more robust estimates of the prevalence of sensitive behaviours compared to direct questioning. We found 1.7% of communal farmers admitted to using poison in the last year. Furthermore, across the study region, predicted poison use was the highest (up to 7%) in areas of the upper north-west. The identified 'hotspots' of poison use will assist conservation practitioners to focus their poison-mitigation efforts centred in the areas of the highest need. PMID- 30484067 TI - Fluid and electrolyte balance-establishing the knowledge base of Foundation Year One doctors. AB - BACKGROUND: Fluid and electrolyte management for hospital inpatients has been identified by multiple reports to be suboptimal, with delegation of this task to the most junior members of a medical team, Foundation Year One (FY1) doctors, also known as interns or house officers, being identified as a contributing factor. METHODS: An online survey was distributed nationally via social media to FY1 doctors between 21st August 2018 and 19th September 2018. Questions focused around cohort characteristics, team behaviours around fluid and electrolyte prescribing, as well as teaching and knowledge. RESULTS: Two hundred eighty-six doctors participated. 67.13% knew the daily water requirement of a healthy adult. 58.39 and 79.72% knew the daily requirements of potassium and sodium, respectively. 41.26 and 33.57% knew the potassium and sodium composition of Hartmann's solution (1 L), respectively, with only 31.12% of candidates knowing the correct sodium content of 1 L of normal saline 0.9%. FY1 doctors were the principle prescribers of fluid therapy (97.55%); senior house officers, registrars, and consultants were only actively involved in the process 51.75, 20.98, and 5.59% of the time, respectively. 30.77 and 23.43% of FY1s received guidelines and/or teaching on the topic within their firms or as part of their foundation teaching, respectively. At undergraduate level, 52.44% of doctors reported the teaching to be "neither poor or good," "poor," or "very poor." CONCLUSION: The principle knowledge base underlying fluid and electrolyte management is still poorly understood by FY1 doctors, with poor teaching of the subject at both undergraduate and post-graduate level potentially contributing. PMID- 30484068 TI - Moving from peripheral blood to local uterine immunophenotype analysis in patients with poor reproductive history: pilot study of a novel technique. AB - BACKGROUND: A complete reproductive immunophenotype is poorly described, with most focus on peripheral blood natural killer cells rather than uterine populations. There is debate regarding normal endometrial levels, with no consensus, and much controversy on correlation with implantation/miscarriage. AIMS: Development and validation of a rapid endometrial assessment flow cytometry (FCM) technique, allowing determination of local lymphocyte subset ranges, comparison to peripheral blood, and patient subgroup analysis. METHODS: Prospective pilot, assessing patients with prior implantation, failure offered endometrial biopsy before subsequent ART cycle, functioning as therapeutic scratch. HRT regime administered to standardise environment, and progesterone primed mid-luteal biopsy (five completed days progestogen, P+5) analysed using comprehensive flow panel to identify lymphocyte subsets. RESULTS: Two hundred patients were recruited in a tertiary university-affiliated ART centre. FCM identified differing lymphocyte ranges between peripheral blood and biopsy. Uterine/decidual natural killer cells are the dominant endometrial subtype. Patients with repeated implantation failure had higher uNK levels (52.4 vs 43.7%, p = 0.01). Conversely, B lymphocytes (0.87 vs 0.72%, p = 0.032), pNK (1.21 vs 0.8%, p = 0.041), and NK-T (2.68 vs 2.26, p = 0.031) cells were higher in recurrent pregnancy loss. CONCLUSION: FCM is widely used to assess cellular populations, but not typically employed for endometrial evaluation. FCM provides a rapid, detailed, and quantitative analysis and reduces inter-observer subjectivity bias. Detailed understanding of the normal endometrial immunophenotype, and associated deviations, may provide insight into the aetiology of infertile patients labelled "unexplained". Failure despite transfer of high grade, or proven euploid blastocysts, is a difficult problem, and endometrial profiling may help identify research areas to determine potential future therapeutic interventions for this difficult to treat population. PMID- 30484069 TI - Sinonasal Myxoma: A Distinct Lesion of Infants. AB - An 11 month old Caucasian male presented with swelling of the right side of the nose and buccal vestibule of unknown duration. Radiographic images revealed a well-circumscribed, hypodense soft tissue mass with a peripheral hyperdense circumference involving the anterior aspect of the right maxilla. The lesion extended from the inferior aspect of the orbital rim superiorly to the maxillary bone inferiorly without invading any nearby structures. The lesion was completely resected via combined extraoral and intraoral approach. The clinical, radiographic, histologic and immunohistochemical features of a sinonasal myxoma in an infant are discussed. PMID- 30484070 TI - Acantholytic Squamous Cell Carcinoma and Salivary Duct Carcinoma Ex-pleomorphic Adenoma of the Submandibular Gland: A Report of Two Extremely Rare Cases with an Immunohistochemical Analysis. AB - Carcinoma ex pleomorphic adenoma (CXPA) is a malignant tumor of the salivary gland that arises from pleomorphic adenoma (PA). Squamous cell carcinoma (SCC) is extremely rare in the salivary glands. We report two cases of acantholytic SCC (ASCC) ex PA. Case 1 involved a 72-year-old female, and case 2 involved a 67-year old male. Histologically, both cases involved PA, and salivary duct carcinoma (SDC) components, which were positive for androgen receptor (AR) and gross cystic disease fluid protein (GCDFP)-15 but negative for HER2, were seen in the intracapsular regions. The invasive components consisted of ASCC, which were positive for cytokeratin 5/6 and p63 but negative for AR and GCDFP-15. The SDC and ASCC components were positive for the epidermal growth factor receptor. In both cases, the cytoplasmic localization or decreased expression of E-cadherin was observed in the ASCC. In the early phase, CXPA might emerge as SDC, and it might change into SCC as it invades beyond the capsule due to changes in microenvironment. Also, the aberrant expression of E-cadherin is related to acantholysis in SCC. PMID- 30484071 TI - Mycotoxins in poultry feed and feed ingredients in Nigeria. AB - Mycotoxins are toxic secondary fungal metabolites that can negatively affect animal productivity when ingested through feed. In order to assess mycotoxin contamination of poultry feed and feed ingredients vis-a-vis source tracking of feed contamination in Nigeria, 102 samples of feed (n = 30) and feed ingredients (n = 72) were collected from in-house mills of poultry farms across 12 states of Nigeria and analyzed for multiple mycotoxins using LC/MS-MS. One hundred and forty microbial metabolites were detected in the feed and feed ingredients. The most frequent mycotoxin in the feed was fumonisin B1, occurring in 97% of the samples at mean concentration of 1014 MUg kg-1. AFB1 occurred in 83% of the feed samples at mean concentration of 74 MUg kg-1 and in all feed ingredients except fish meal and other cereals (millet and rice). Feed samples analyzed in this study were contaminated with at least four mycotoxins: aflatoxins and fumonisin co-occurring in 80% of the samples. Peanut cake and maize contributed the most to the levels of aflatoxin and fumonisin, respectively, in the feed. Consequently, there is a need to explore other cereal- and protein-based ingredients for compounding feeds in order to reduce the risk associated with high mycotoxin (e.g. aflatoxin) intake in poultry. PMID- 30484073 TI - e-Health in cardiology: How to cure the infarcted innovation implementation. PMID- 30484072 TI - Serious Adverse Events Associated with Off-Label Use of Azithromycin or Fentanyl in Children in Intensive Care Units: A Retrospective Chart Review. AB - OBJECTIVES: Half of prescription drugs commonly given to children lack product labeling on pediatric safety, efficacy, and dosing. Two drugs most widely used off-label in pediatrics are azithromycin and fentanyl. We sought to determine the risk of serious adverse events (SAEs) when oral azithromycin or intravenous/intramuscular fentanyl are used off-label compared to on-label in pediatric intensive care units (ICUs). STUDY DESIGN: Six pediatric hospitals participated in a retrospective chart review of patients administered oral azithromycin (n = 241) or intravenous/intramuscular fentanyl (n = 367) between January 5, 2013 and December 26, 2014. Outcomes were SAEs by drug and labeling status: off-label compared to on-label by Food and Drug Administration (FDA) approved age and/or indication. Statistical analysis was performed using logistic regression to estimate odds ratios (ORs) and Cox regression to estimate hazard ratios (HRs). RESULTS: Twenty-one (9%) children receiving azithromycin experienced SAEs. Off-label use of azithromycin was not associated with a higher risk of SAE (OR 0.87, 95% CI 0.27-2.71, p = 0.81). Ninety-five (26%) children receiving fentanyl experienced SAEs. Fentanyl off-label use by both age and indication was not associated with a higher risk of overall SAEs compared to on label use (OR 1.99, 95% CI 0.94-4.19, p = 0.07). However, the risk of the SAE respiratory depression was significantly greater when fentanyl was used off-label by both age and indication (OR 5.05, 95% CI 1.08-23.56, p = 0.044). Results based on HRs were similar. CONCLUSIONS: Azithromycin off-label use in pediatric ICUs does not appear to be associated with an increased risk of SAEs. Off-label use of fentanyl appears to be more frequently associated with respiratory depression when used off-label by both age and indication in pediatric ICUs. Prospective studies should be undertaken to assess the safety and efficacy of fentanyl in the pediatric population so that data can be added to the FDA labeling. PMID- 30484074 TI - Two causes of palpitations, detected by photoplethysmography on a mobile phone. PMID- 30484075 TI - Myotonic dystrophy presenting as severely dilated cardiomyopathy with out-of hospital cardiac arrest. PMID- 30484076 TI - Two causes of palpitations, detected by photoplethysmography on a mobile phone. PMID- 30484077 TI - Protein-Ligand Interaction by Ligand Titration, Fast Photochemical Oxidation of Proteins and Mass Spectrometry: LITPOMS. AB - We report a novel method named LITPOMS (ligand titration, fast photochemical oxidation of proteins and mass spectrometry) to characterize protein-ligand binding stoichiometry, binding sites, and site-specific binding constants. The system used to test the method is melittin-calmodulin, in which the peptide melittin binds to calcium-bound calmodulin. Global-level measurements reveal the binding stoichiometry of 1:1 whereas peptide-level data coupled with fitting reveal the binding sites and the site-specific binding affinity. Moreover, we extended the analysis to the residue level and identified six critical binding residues. The results show that melittin binds to the N-terminal, central linker, and C-terminal regions of holo-calmodulin with an affinity of 4.6 nM, in agreement with results of previous studies. LITPOMS, for the first time, brings high residue-level resolution to affinity measurements, providing simultaneously qualitative and quantitative understanding of protein-ligand binding. The approach can be expanded to other binding systems without tagging the protein to give high spatial resolution. Graphical Abstract. PMID- 30484078 TI - Imaging of thoracic hernias: types and complications. AB - Thoracic hernias are characterised by either protrusion of the thoracic contents outside their normal anatomical confines or extension of the abdominal contents within the thorax. Thoracic hernias can be either congenital or acquired in aetiology. They can occur at the level of the thoracic inlet, chest wall or diaphragm. Thoracic hernias can be symptomatic or fortuitously discovered on imaging obtained for other indications. Complications of thoracic hernias include incarceration, trauma and strangulation with necrosis. Multiple imaging modalities are available to evaluate thoracic hernias. Radiographs usually offer the first clue to the diagnosis. Upper gastrointestinal radiography can identify bowel herniation and associated complications. CT and occasionally MR can be useful for further evaluation of these abnormalities, accurately identifying the type of hernia, its contents, associated complications, and provide a roadmap for surgical planning. In this article, we review the different types of thoracic hernias and the role of imaging in the evaluation of these hernias. TEACHING POINTS: * Protrusion of lung contents beyond the anatomic confines of the thorax constitutes a hernia. * Complications of thoracic hernias include incarceration, trauma and strangulation with necrosis. * Multiple imaging modalities are available to evaluate thoracic hernias. * CT is the imaging modality of choice for identifying thoracic hernias and their complications. * Imaging can provide a roadmap for surgical planning. PMID- 30484079 TI - Fibrous dysplasia for radiologists: beyond ground glass bone matrix. AB - Fibrous dysplasia (FD) is a congenital disorder arising from sporadic mutation of the alpha-subunit of the Gs stimulatory protein. Osseous changes are characterised by the replacement and distortion of normal bone with poorly organised, structurally unsound, fibrous tissue. The disease process may be localised to a single or multiple bones. In McCune-Albright syndrome (MAS), fibrous dysplasia is associated with hyperfunction of endocrine organs and overproduction of melanin in the skin, while Mazabraud syndrome FD is associated with intramuscular myxomas. In radiology, FD is very often automatically associated with the term "ground glass matrix". However, FD is a complex disease, and knowledge of its unique pathogenesis and course are crucial to understanding imaging findings and potential complications. This article aims to not only summarise the spectrum of radiological findings of osseous and extra-osseous abnormalities associated with FD but also to highlight the pathological base of the disease evolution, corresponding imaging changes and complications based on the disease distribution. We also have provided current recommendations for clinical management and follow-up of patients with FD. TEACHING POINTS: * FD is often a part of complex disease, involving not only bone but also multiple other organs. * FD lesions are characterised by age-related histological, radiographical and clinical transformations. * Radiologists play a crucial role in the identification of osseous complications associated with FD. * The craniofacial form of the disease is the most common type of FD and the most difficult form to manage. * Patients with McCune-Albright syndrome may have different extra-skeletal abnormalities, which often require follow-up. PMID- 30484080 TI - Acknowledgement to Authors, Referees, and Readers. PMID- 30484081 TI - Typicality: Stable structures and flexible functions. AB - Some research suggests typicality is stable, other research suggests it is malleable, and some suggests it is unstable. The two ends of this continuum stability and instability-make somewhat contradictory claims. Stability claims that typicality is determined by our experience of decontextualized feature correlations in the world and is therefore fairly consistent. Instability claims that typicality depends on context and is therefore extremely inconsistent. After reviewing evidence for these two claims, we argue that typicality's stability and instability are not contradictory but rather complementary when they are understood as operating on two different levels. Stability reflects how information gets encoded into semantic memory-what we call structural typicality. Instability reflects the task-dependent recruitment of semantic knowledge-what we call functional typicality. Finally, we speculate on potential factors that may mediate between the recruitment of structural or functional typicality. PMID- 30484082 TI - Beyond one's body parts: Remote object movement with sense of agency involuntarily biases spatial attention. AB - Humans' own body postures and/or actions bias visual attention. This study examined whether an object controlled remotely with a sense of agency (SoA) can bias attentional allocation, even if the mappings of body movement and object movement do not correspond (i.e., with a less extended body representation). In the experiments, participants shifted a circle toward an instructed direction via keypress. On some trials, the task changed to identification of visual characters instead of the circle shift. Strength of SoA was manipulated based on the probability that the circle actually moved to the participant's intended location, with high probability producing a strong SoA. Results showed that visual identification performance became higher for appearance of the target at the intended location than at the unintended location, but only when observers felt a strong SoA. This suggests that the object's movement attracts attention when the observer feels a strong SoA over its control. PMID- 30484083 TI - Organizational Justice and Refraining from Seeking Medical Care Among Japanese Employees: A 1-Year Prospective Cohort Study. AB - BACKGROUND: Using a 1-year prospective design, we examined the association of organizational justice (i.e., procedural justice and interactional justice) with refraining from seeking medical care (RSMC) among Japanese employees. METHODS: We surveyed 2695 employees (1994 men and 701 women) from two factories of a manufacturing company in Japan. A self-administered questionnaire comprising scales for measuring organizational justice (Organizational Justice Questionnaire) and potential confounders (i.e., demographic and socioeconomic characteristics as well as health-related behaviors) was administered at baseline (from April to June 2011). At 1-year follow-up (from April to June 2012), a single-item question was used to measure RSMC during the follow-up period. Multiple logistic regression analysis was conducted by gender. RESULTS: After adjusting for potential confounders, low procedural justice and low interactional justice at baseline were found to be significantly associated with higher odds of RSMC during the 1-year follow-up for male employees (odds ratio = 1.33 [95% confidence interval = 1.16-1.52], p < 0.001 and 1.15 [95% confidence interval = 1.02-1.29], p = 0.019, respectively). Similar patterns were observed for female employees (odds ratio = 1.37 [95% confidence interval = 1.08-1.74], p = 0.009 and 1.23 [95% confidence interval = 1.02-1.50], p = 0.035 for low procedural justice and low interactional justice, respectively). CONCLUSIONS: The present study provided evidence that the lack of organizational justice is positively associated with RSMC among Japanese employees, independently of demographic and socioeconomic characteristics as well as of health-related behaviors. PMID- 30484084 TI - High Proportion of Subjective Component to the Disease Activity Score is Associated with Favorable Response to Abatacept in Rheumatoid Arthritis. AB - BACKGROUND: Response prediction of certain biologic agents for the treatment of rheumatoid arthritis (RA) remains an unmet need in real-world clinical practice. The contribution of patient-reported components to the 28-joint Disease Activity Score (DAS28) was termed DAS28-P and investigated as a predictor of response to biologic agents, mostly tumor necrosis factor inhibitors. We aimed to evaluate DAS28-P as a predictor of the European League Against Rheumatism (EULAR) response to abatacept in patients with RA. METHODS: The study population was a prospective, observational, multicenter cohort of Korean patients with RA, who were followed up for a nationwide post-marketing surveillance study of abatacept. Correlation of DAS28-P with DAS28, change of DAS28, and EULAR response groups were evaluated. Logistic regression analysis was used to predict good-to-moderate EULAR response to abatacept in the study population. RESULTS: A total of 341 patients were involved in the analysis stratified on the EULAR response criteria. Presence of comorbidities, previous exposure to biologic agents, baseline DAS28, three of its components (tender joint counts, global health visual analog scale, erythrocyte sedimentation rate), and baseline DAS28-P were significantly associated with EULAR response to abatacept at 6 months. Stratified upon EULAR response, a group with good-to-moderate response had a higher baseline value and lower interval change for DAS28-P. Logistic regression analysis showed that a DAS28-P cut-off of > 0.44 was more positively associated with good-to-moderate EULAR response with abatacept treatment than naivety to biologic agents. CONCLUSIONS: The DAS28-P could be predictive of response to abatacept. A higher baseline DAS28-P is associated with a favorable therapeutic response to abatacept. TRIAL REGISTRATION: Trial name, Korean Post-marketing Surveillance for Orencia(r). Trial registration number, NCT01583244. Registered on April 20, 2012. PMID- 30484085 TI - Magnetic resonance perfusion and diffusion characteristics of granulomatous diseases mimic those of malignant lesions: six case reports. AB - The perfusion and diffusion properties of a tumor are important clues in evaluating its growth potential and predicting its histological type, such as benign or malignant. Tumor perfusion can be estimated by assessing time-dependent changes in the intratumoral levels of the contrast agent during dynamic contrast enhanced magnetic resonance (MR) imaging, whereas tumor diffusion can be estimated by assessing intratumoral water diffusivity on diffusion-weighted MR imaging. Granulomatous diseases with different etiologies occur in various head and neck regions, including the mandible, maxillary sinus, salivary glands, and lymph nodes. However, the perfusion and diffusion properties of granulomatous diseases in the head and neck regions are not well documented. In this study, we assessed the time-signal intensity curves and apparent diffusion coefficients of six granulomatous diseases of various histological types that appeared in the soft tissues of the head and neck. Our data show that the perfusion and diffusion characteristics of granulomatous diseases mimic those of malignant diseases, highlighting the need for careful interpretation of MR perfusion and diffusion findings to distinguish between granulomatous diseases and cancers of the head and neck region. Clinicians should pay particular attention to blood examination and biopsy results when interpreting imaging findings. PMID- 30484086 TI - Comparative cone-beam computed tomography evaluation of the osseous morphology of the temporomandibular joint in temporomandibular dysfunction patients and asymptomatic individuals. AB - OBJECTIVE: We examined the bone components of the temporomandibular joint (TMJ) in asymptomatic individuals and patients with temporomandibular dysfunction (TMD) using cone-beam computed tomography (CBCT). METHODS: Two hundred asymptomatic individuals and 200 patients with TMD were included in this study. Condyle position, eminence height, eminence inclination, condyle shape, and fossa shape were assessed on CBCT images of the 800 temporomandibular joints. RESULTS: The eminence inclination (P < 0.05), eminence height (P < 0.0001), mediolateral width of condyle (P < 0.0001), and anterior joint space (P < 0.0001) were significantly greater in male subjects compared with female subjects in both the asymptomatic group and TMD group. Comparisons of the asymptomatic group and TMD group revealed significant differences in the anterior joint space (P < 0.0001), ratio of anterior joint space to posterior joint space (P < 0.001), posterior joint space (P < 0.05), eminence inclination (P < 0.05), eminence height (P < 0.05), condyle shape (P < 0.0001), and fossa shape (P < 0.05). CONCLUSIONS: The present analyses suggest that a steeper articular eminence inclination may be risk factor for TMD. The presence of TMD was associated with the condyle position in the TMJ. PMID- 30484087 TI - Gas gangrene in the deep spaces of the head and neck visualized on computed tomography images. AB - Cellulitis accompanied by gas gangrene is a rapidly-spreading and potentially fatal infection. Here, we present a case of gas gangrene in the deep spaces of the head and neck in an elderly woman, diagnosed by computed tomography (CT). An 86-year-old woman with Alzheimer's disease, hypertension, hyperlipidemia, and osteoporosis was referred to our institute by her local dentist. The patient exhibited trismus caused by severe swelling in the left submandibular area. CT images of the head and neck area showed swelling of the cervical tissue with air in the parapharyngeal and masticator spaces. She was treated with antibiotics, followed by drainage. Although the therapy was continued, the patient died from a cardiac complication on hospital day 42. Our case highlights the usefulness of CT for diagnosing gas gangrene in the deep spaces of the head and neck in a woman with Alzheimer's disease. PMID- 30484088 TI - Fusion imaging: a bipartite approach. AB - Image fusion is the process of registering and combining multiple images from single or multiple imaging modalities to improve the imaging quality and applicability. It reduces randomness and redundancy to increase the diagnostic value of images for better assessment of medical problems. Fusion imaging was designed to overcome the disadvantages of morphological and/or functional imaging, and attempts to provide inputs that improve treatment planning, resulting in better prognostication. This review attempts to summarize the techniques and their applications in head and neck imaging. PMID- 30484089 TI - Evaluation of lateral pterygoid muscles in painful temporomandibular joints by signal intensity on fluid-attenuated inversion recovery images. AB - OBJECTIVES: Pathological changes of the lateral pterygoid muscle (LPM) have been investigated using various modalities, including magnetic resonance (MR) imaging and electromyography. Fluid-attenuated inversion recovery (FLAIR) is an MR sequence that we hypothesized can be used to evaluate abnormalities of the LPM. The purpose of this study was to analyze the FLAIR signal intensity of the LPM in painful temporomandibular joints (TMJs) and investigate the pathological changes of the muscle. METHODS: The study was based on 149 TMJs of 77 patients who were referred for MR imaging of the TMJ. Patients rated their degree of pain during chewing and mouth opening using a visual analog scale (VAS). Regions of interest were placed over the superior and inferior heads of the LPM and gray matter on FLAIR sagittal images. Using the signal intensity of gray matter as a reference, the signal intensity ratio (SIR) of the LPM was calculated. Spearman's rank correlation coefficient was used to analyze the correlation between the SIR and the VAS score (p < 0.05). RESULTS: A significant correlation was present between the SIR on FLAIR images and the VAS score. CONCLUSIONS: These results suggest that the FLAIR signal intensity of the superior and inferior heads of the LPM significantly increases as TMJ pain becomes more severe. Thus, FLAIR could be useful in assessing the relationship between the MR signals of the LPM and clinical symptoms. PMID- 30484090 TI - Non-contrast computed tomography and magnetic resonance imaging features of mucoepidermoid carcinoma in the salivary glands. AB - BACKGROUND: Use of contrast-enhanced cross-sectional imaging is considered standard practice for investigating mucoepidermoid carcinoma (MEC) in the salivary glands. The purpose of this study was to present the common features of MEC on computed tomography (CT) and magnetic resonance imaging (MRI) without contrast enhancements, and to investigate the possibility of discriminating between MEC and pleomorphic adenoma based on the features observed on both modalities. METHODS: Twenty cases of biopsy-confirmed MEC originating in the salivary glands were reviewed and characterized by two oral and maxillofacial radiologists with regard to the following aspects: detectability, margin, border, encapsulation, content, contrast between lesion and masticator muscle, and bone changes. RESULTS: Ninety percent of bone changes caused by MEC were detected by CT and sixty-nine percent of tumor existences were detected by MRI. The lesion border could provide a clue to distinguish MEC from pleomorphic adenoma. CONCLUSIONS: Observation of MEC features was possible by both CT and MRI. Among the features, the lesion border could be a clue to distinguish MEC from pleomorphic adenoma. PMID- 30484092 TI - Anatomical study of the maxillary tuberosity using cone beam computed tomography. AB - OBJECTIVES: To examine the dimensions (width, length, and height) of the maxillary tuberosity (MT) and their correlations with age and sex, and to identify different anatomical types for adequate positioning of miniscrews in this area. METHODS: The study enrolled 39 patients attending the University of Valencia. The patients comprised 21 males and 18 females with a mean age of 39.7 +/- 8.4 years. The dimensions of all 78 MTs were measured on cone beam computed tomography (CBCT) images using Invivo Dental 5 software. RESULTS: The intraobserver and interobserver errors were good for all measurements. A total of 858 MT measurements were taken. The widths were greater in men than in women, with significant differences. The MT dimensions showed correlations with patient age, whereby older patients presented with greater widths and lengths, but reduced heights. Three different anatomical types were detected according to patient age. CONCLUSIONS: The dimensions (width, length, and height) of the MT vary according to patient age and sex. The MT dimensions conform to particular anatomical types, which should be taken into account when placing miniscrews in this region. PMID- 30484091 TI - Incidental findings on cone-beam computed tomographic images: paranasal sinus findings and nasal septum variations. AB - OBJECTIVE: CBCT applications have received widespread acceptance in dentistry. CBCT scans provide three-dimensional information on anatomic structures and characteristics of pathologies, rather than the two-dimensional information obtained with the conventional techniques. The purpose of this study was to evaluate incidental findings in out-of-interest areas on CBCT images and to reveal their frequency and characteristics. METHODS: A total of 691 CBCT scans from 691 patients were assessed. Demographic data, CBCT indications, and incidental findings outside the primary area of interest, such as anatomical variations and pathologies, were noted. The incidental findings were categorized and analyzed using descriptive statistics. RESULTS: In total, 1109 incidental findings in paranasal sinuses were noted on 548 of the 691 CBCT scans. The highest rate of incidental findings was maxillary sinus findings, followed by concha bullosa and septum deviation. The most frequently observed pathology was mucosal thickening, followed by polypoid mucosal thickening in the maxillary sinus. CONCLUSIONS: While most incidental findings require no treatment, some conditions will necessitate modification of the treatment plan. Therefore, dental practitioners should be aware of incidental findings and anatomical variations. Correct identification of these findings will reduce unnecessary further diagnostic assessments and allow selection of more appropriate treatment plans. PMID- 30484093 TI - Is the buccal compartment a masticatory space extension or an anatomic space in itself? Evidence based on medical images and human cadaver dissection. AB - OBJECTIVES: According to some authors, the buccal space is incompletely closed with no real anatomical separation from the masticator space, and also has no fascial limit toward the cranial and caudal regions. However, several other authors consider this anatomic area to be a separated space. The goal of this study was to provide a detailed description of the normal anatomy using medical images and human cadaveric head material dissection of this facial anatomic region, to precisely clarify its condition as an extension of the masticator space or an independent space. METHODS: The buccomasseteric area in 25 male and female patients aged 14-68 years, who were referred for various head and neck disorders that did not compromise the masticatory and buccal area, was analyzed by magnetic resonance imaging on the axial and coronal planes. The region was further examined by dissection of the buccomasseteric area in four heads of fresh adult male and female human cadavers aged 30-65 years. RESULTS: The findings demonstrated that the buccal compartment should be considered part of the masticator space, rather than a space in itself. This was mainly because a corridor was positioned medially to the tendon of the masseter muscle that communicated the infratemporal region of the masticator space with the buccal region, with no fascial barrier at this level that could separate it from the masticator space. CONCLUSIONS: The present study suggests that the buccal compartment is part of the masticator space, rather than a space in itself. PMID- 30484094 TI - Three-dimensional evaluation of angular, linear, and resorption features of maxillary impacted canines on cone-beam computed tomography. AB - OBJECTIVES: The aim of this study was to evaluate the localization, angulation, and resorption features of maxillary impacted canines on cone-beam computed tomography (CBCT). METHODS: This retrospective study examined the CBCT scans of 140 maxillary impacted canines in 102 patients (43 males, 59 females; mean age: 16.25 +/- 6.31 years). The following impacted canine-related parameters were analyzed on the CBCT images: impaction side; location; root resorption levels of adjacent teeth; occlusal plane and midline distances of impacted canines; and angulations of impacted canines to midline, lateral incisor, and occlusal plane. RESULTS: Bilateral canine impaction was found in 38 subjects, and unilateral canine impaction was present in 64 subjects. Severe resorption was found in 14 canines. There were no significant differences between the occlusal plane and midline distances to the impacted canine cusp tip and root apex (p > 0.05). The midline angulation of right maxillary impacted canines was significantly higher than that of left maxillary impacted canines (p < 0.05), while the occlusal plane angulation of left maxillary impacted canines was significantly higher than that of right maxillary impacted canines (p < 0.05). CONCLUSIONS: Maxillary canine impaction was more frequently seen in female subjects than in male subjects. Lateral incisors were more frequently affected than first premolars, and slight resorption was more frequently seen in adjacent teeth. CBCT assessment of maxillary impacted canines can provide accurate measurements of angular, linear, and resorption parameters. PMID- 30484096 TI - Vitamin D basis of Alzheimer's disease: from genetics to biomarkers. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder seen mostly in the elderly population. While to date AD research has focused on either neurochemical disruptions, genetic studies, or the pathological hallmarks, little has been done to establish a novel approach that would encompass all three aspects, one that would overcome the current barriers in AD research and determine the cause of AD and, eventually, discover a treatment. Meanwhile, there have been strong indications in recent years that vitamin D, a secosteroid hormone, and its receptors are fundamentally involved in neurodegenerative mechanisms. Observational studies have pointed to vitamin D deficiency as a genetic risk factor for AD, Parkinson's disease (PD), vascular dementia, and multiple sclerosis (MS), as well as other neurological disorders, brought about by alterations in genes involved in metabolism, transportation, and actions of vitamin D. Molecular studies have demonstrated that vitamin D treatments prevent amyloid production while also increasing its clearance from the brain in AD. Finally, recent vitamin D intervention studies have reported significant improvement in cognitive performance in subjects with senile dementia, mild cognitive impairment, and AD. This review aims to describe how a vitamin D research strategy, fully integrating all aspects of present-day AD research, would elucidate the genetic, molecular, and biochemical background of the disease. PMID- 30484095 TI - Magnetic resonance imaging in endodontics: a literature review. AB - OBJECTIVES: Magnetic resonance imaging (MRI) has recently been used for the evaluation of dental pulp anatomy, vitality, and regeneration. This study reviewed the recent use of MRI in the endodontic field. METHODS: Literature published from January 2000 to March 2017 was searched in PubMed using the following Medical Subject Heading (MeSH) terms: (1) MRI and (dental pulp anatomy or endodontic pulp); (2) MRI and dental pulp regeneration. Studies were narrowed down based on specific inclusion criteria and categorized as in vitro, in vivo, or dental pulp regeneration studies. The MRI sequences and imaging findings were summarized. RESULTS: In the in vitro studies on dental pulp anatomy, T1-weighted imaging with high resolution was frequently used to evaluate dental pulp morphology, demineralization depth, and tooth abnormalities. Other sequences such as apparent diffusion coefficient mapping and sweep imaging with Fourier transformation were used to evaluate pulpal fluid and decayed teeth, and short-T2 tissues (dentin and enamel), respectively. In the in vivo studies, pulp vitality and reperfusion were visible with fat-saturated T2-weighted imaging or contrast enhanced T1-weighted imaging. In both the in vitro and in vivo studies, MRI could reveal pulp regeneration after stem cell therapy. Stem cells labeled with superparamagnetic iron oxide particles were also visible on MRI. Angiogenesis induced by stem cells could be confirmed on enhanced T1-weighted imaging. CONCLUSION: MRI can be successfully used to visualize pulp morphology as well as pulp vitality and regeneration. The use of MRI in the endodontic field is likely to increase in the future. PMID- 30484097 TI - Molecular basis of vitamin D action in neurodegeneration: the story of a team perspective. AB - Vitamin D, a secosteroid hormone, has, over the years, mainly been known for its classic role in the maintenance of calcium homeostasis of the human body. However, there is increasing understanding that vitamin D contributes to the regulation of Ca2+ homeostasis, especially via voltage-gated calcium channels, in another major organ that uses calcium, the brain. Almost 30 years ago, the role of dysregulation in the aging brain and in Alzheimer's disease (AD) gave rise to the Ca2+ hypothesis of brain aging and dementia. We thus made calcium homeostasis the starting point of our studies, proposing the notion that the consequences of long-term deficiency and/or inefficient utilization of vitamin D may cause the disruption of calcium homeostasis in neurons, this creating a vulnerability of neurons to aging and neurodegeneration. In this mini-review, we aim to describe the potential of vitamin D (cholecalciferol) as a neurosteroid based on our findings and conclusions. PMID- 30484098 TI - From the Editor's Desk: on the Nature of Scientific Progress. PMID- 30484099 TI - Rising Mortality Rate of Cervical Cancer in Younger Women in Urban China. AB - BACKGROUND: In recent decades, much effort has been made in China to reduce the burden of cervical cancer. OBJECTIVE: Our study's purpose was to examine trends of cervical cancer mortality in each 5-year age group for urban and rural Chinese women, respectively. DESIGNS: Retrospective analysis of cervical cancer mortality from 1987 to 2015 from the World Health Organization Cancer Mortality Database and China Health Statistical Yearbooks. PARTICIPANTS: Chinese women. MAIN MEASURES: Trends were examined using annual percent change (APC) and average annual percent change (AAPC) via Joinpoint regression models for each 5-year age group in urban and rural areas, respectively. RESULTS: In urban China, mortality rate of cervical cancer increased significantly among urban women aged 25-54 years (AAPC 2.12~5.49%), in contrast to a decline trend among urban women older than 60 years (AAPC - 3.61~- 5.35%). In rural China, cervical cancer rates declined in all age groups, but the magnitude was smaller in women aged 30-54 years (AAPC - 0.59~- 2.20%) compared to women older than 55 years (AAPC - 3.06~- 4.33%). CONCLUSION: Mortality rate of cervical cancer is rising at an alarming rate in younger women in urban China. Timely intervention is required for these vulnerable populations. PMID- 30484100 TI - Predictors Associated with Survival Among Elderly In-Patients Who Receive Cardiopulmonary Resuscitation in Japan: An Observational Cohort Study. AB - BACKGROUND: Little is known about the outcomes of in-hospital cardiopulmonary resuscitation (CPR) in Asian populations including elderly patients in Japan. OBJECTIVE: To determine the survival outcome of in-hospital CPR among elderly patients in Japan, and to identify predictors associated with survival. DESIGN: Retrospective cohort study in 81 Japanese hospitals from April 1, 2010 to March 31, 2016. PATIENTS: We included elderly patients (age >= 65 years) who received CPR after 2 days of hospitalization. MAIN MEASURES: The primary outcome was survival at hospital discharge and the secondary outcomes were the discharge disposition and consciousness level of patients who survived to hospital discharge. To determine predictors associated with survival after in-hospital CPR, we fit multivariable models for patient-level and institutional-level factors. KEY RESULTS: Among the 5365 patients who received CPR, 595 (11%) survived to discharge. Of those who survived to discharge, 46% of patients were discharged home, and 10% of patients were comatose at discharge. Older age and higher burden of comorbidities were associated with reduced survival. The adjusted OR was 0.35 (95% CI, 0.22-0.55) for age >= 90 years compared to age 65 69 years, and 0.68 (95% CI, 0.48-0.97) for Charlson Comorbidity Index score of >= 4 compared with score of 0. Other predictors of reduced survival included receiving CPR on weekends compared to weekdays (AOR, 0.63; 95% CI, 0.51-0.77) and in small hospitals compared to large hospitals (AOR, 0.58; 95% CI, 0.40-0.83). CONCLUSIONS: Among elderly patients in Japan, the survival rate of in-hospital CPR was approximately one in ten, and less than half of these patients were discharged home. In addition to older age and higher illness burden, receiving CPR on weekends and/or in small hospitals were significant predictors of reduced survival. These findings should be considered in advanced care planning discussions with elderly patients to avoid subjecting patients to CPR that are likely futile. PMID- 30484101 TI - Rates and Impact of Adherence to Recommended Care for Unhealthy Alcohol Use. AB - BACKGROUND: Unhealthy alcohol use is a major worldwide health problem. Yet few studies have assessed provider adherence to the alcohol-related care recommended in clinical practice guidelines, nor links between adherence to recommended care and outcomes. OBJECTIVES: To describe quality of care for unhealthy alcohol use and its impacts on drinking behavior RESEARCH DESIGN: Prospective observational cohort study of quality of alcohol care for the population of patients screening positive for unhealthy alcohol use in a large Veterans Affairs health system. PARTICIPANTS: A total of 719 patients who screened positive for unhealthy alcohol use at one of 11 primary care practices and who completed baseline and 6-month telephone interviews. MAIN MEASURES: Using administrative encounter and medical record data, we assessed three composite and 21 individual process-based measures of care delivered across primary and specialty care settings. We assessed self reported daily alcohol use using telephone interviews at baseline and 6-month follow-up. KEY RESULTS: The median proportion of patients who received recommended care across measures was 32.8% (range < 1% for initiating pharmacotherapy to 93% for depression screening). There was negligible change in drinking for the study population between baseline and 6 months. In covariate adjusted analyses, no composites were significantly associated with changes in heavy drinking days or drinks per week, and just one of nine individual measures tested was significantly associated. In a subsample of patients drinking above recommended weekly limits prior to screening, two of nine individual measures were significantly associated. CONCLUSIONS: This study shows wide variability in receipt of recommended care for unhealthy alcohol use. Receipt of recommended interventions for reducing drinking was frequently not associated with decreased drinking. Results suggest deficits in provision of comprehensive alcohol care and in understanding how to improve population-based drinking outcomes. PMID- 30484102 TI - Uncertainty as a Key Influence in the Decision To Admit Patients with Transient Ischemic Attack. AB - BACKGROUND: Patients with transient ischemic attacks (TIA) are at high risk of subsequent vascular events. Hospitalization improves quality of care, yet admission rates for TIA patients vary considerably. OBJECTIVES: We sought to identify factors associated with the decision to admit patents with TIA. DESIGN: We conducted a secondary analysis of a prior study's data including semi structured interviews, administrative data, and chart review. PARTICIPANTS: We interviewed multidisciplinary clinical staff involved with TIA care. Administrative data included information for TIA patients in emergency departments or inpatient settings at VA medical centers (VAMCs) for fiscal years (FY) 2011 and 2014. Chart reviews were conducted on a subset of patients from 12 VAMCs in FY 2011. APPROACH: For the qualitative data, we focused on interviewees' responses to the prompt: "Tell me what influences you in the decision to or not to admit TIA patients." We used administrative data to identify admission rates and chart review data to identify ABCD2 scores (a tool to classify stroke risk after TIA). KEY RESULTS: Providers' decisions to admit TIA patients were related to uncertainty in several domains: lack of a facility TIA-specific policy, inconsistent use of ABCD2 score, and concerns about facilities' ability to complete a timely workup. There was a disconnect between staff perceptions about TIA admission and facility admission rates. According to chart review data, staff at facilities with higher admission rates in FY 2011 reported consistent reliance on ABCD2 scores and related guidelines in admission decision-making. CONCLUSIONS: Many factors contributed to decisions regarding admitting a patient with TIA; however, clinicians' uncertainty appeared to be a key driver. Further quality improvement interventions for TIA care should focus on facility adoption of TIA protocols to address uncertainty in TIA admission decision-making and to standardize timely evaluation of TIA patients and delivery of secondary prevention strategies. PMID- 30484103 TI - Plasma exosomes stimulate breast cancer metastasis through surface interactions and activation of FAK signaling. AB - PURPOSE: The interaction between malignant cells and surrounding healthy tissues is a critical factor in the metastatic progression of breast cancer (BC). Extracellular vesicles, especially exosomes, are known to be involved in inter cellular communication during cancer progression. In the study presented herein, we aimed to evaluate the role of circulating plasma exosomes in the metastatic dissemination of BC and to investigate the underlying molecular mechanisms of this phenomenon. METHODS: Exosomes isolated from plasma of healthy female donors were applied in various concentrations into the medium of MDA-MB-231 and MCF-7 cell lines. Motility and invasive properties of BC cells were examined by random migration and Transwell invasion assays, and the effect of plasma exosomes on the metastatic dissemination of BC cells was demonstrated in an in vivo zebrafish model. To reveal the molecular mechanism of interaction between plasma exosomes and BC cells, a comparison between un-treated and enzymatically modified exosomes was performed, followed by mass spectrometry, gene ontology, and pathway analysis. RESULTS: Plasma exosomes stimulated the adhesive properties, two dimensional random migration, and transwell invasion of BC cells in vitro as well as their in vivo metastatic dissemination in a dose-dependent manner. This stimulatory effect was mediated by interactions of surface exosome proteins with BC cells and consequent activation of focal adhesion kinase (FAK) signaling in the tumor cells. CONCLUSIONS: Plasma exosomes have a potency to stimulate the metastasis-promoting properties of BC cells. This pro-metastatic property of normal plasma exosomes may have impact on the course of the disease and on its prognosis. PMID- 30484104 TI - A mouse model featuring tissue-specific deletion of p53 and Brca1 gives rise to mammary tumors with genomic and transcriptomic similarities to human basal-like breast cancer. AB - PURPOSE AND METHODS: In human basal-like breast cancer, mutations and deletions in TP53 and BRCA1 are frequent oncogenic events. Thus, we interbred mice expressing the CRE-recombinase with mice harboring loxP sites at TP53 and BRCA1 (K14-Cre; p53f/f Brca1f/f) to test the hypothesis that tissue-specific deletion of TP53 and BRCA1 would give rise to tumors reflective of human basal-like breast cancer. RESULTS: In support of our hypothesis, these transgenic mice developed tumors that express basal-like cytokeratins and demonstrated intrinsic gene expression features similar to human basal-like tumors. Array comparative genomic hybridization revealed a striking conservation of copy number alterations between the K14-Cre; p53f/f Brca1f/f mouse model and human basal-like breast cancer. Conserved events included MYC amplification, KRAS amplification, and RB1 loss. Microarray analysis demonstrated that these DNA copy number events also led to corresponding changes in signatures of pathway activation including high proliferation due to RB1 loss. K14-Cre; p53f/f Brca1f/f also matched human basal like breast cancer for a propensity to have immune cell infiltrates. Given the long latency of K14-Cre; p53f/f Brca1f/f tumors (~ 250 days), we created tumor syngeneic transplant lines, as well as in vitro cell lines, which were tested for sensitivity to carboplatin and paclitaxel. These therapies invoked acute regression, extended overall survival, and resulted in gene expression signatures of an anti-tumor immune response. CONCLUSION: These findings demonstrate that this model is a valuable preclinical resource for the study of human basal-like breast cancer. PMID- 30484105 TI - Effect of tris(2-carboxyethyl)phosphine and tertiary butyl alcohol on the performance of convection polymerase chain reaction. AB - Rapid and on-site DNA-based molecular detection has become increasingly important for sensitive, specific, and timely detection and treatment of various diseases. To prepare and store biomolecule-containing reagents stably, reducing agents are used during protein preparation, and freeze-drying technology has been applied to the protein reagents. Some of the additives used during these processes may affect subsequent processes such as polymerase chain reaction (PCR). In this study, we evaluated the impact of TCEP, a reducing agent, and TBA, a freeze drying medium, on the performance of convection PCR (cPCR) using a battery operable PCR device. Singleplex cPCR detection of a 249 bp amplicon from human genomic DNA suggested that approximately 82% of performance was achieved in the presence of 0.1 mM TCEP and 1% TBA. The limit of detection and the minimum number of cycles at which amplicons began to appear was a little lower (~ 82% efficiency) or higher (20 vs 15 cycles), respectively, in the chemical-treated group than in the control group. With larger amplicons of 500 bp, the chemical treated group revealed approximately 78% of performance and amplicons started to appear at 20 cycles of cPCR in both groups. Similar results were obtained with multiplex cPCR amplification. PMID- 30484106 TI - Study of the mechanism underlying hsa-miR338-3p downregulation to promote fibrosis of the synovial tissue in osteoarthritis patients. AB - Osteoarthritis (OA) is a degenerative joint disease characterized by the degradation of joint cartilage, the formation of osteophyma at joint margins, and synovial changes. Whereas lesions of the joint cartilage were the key point of the research and treatment of osteoarthritis before, a recent study showed that the synovium plays a crucial role in the pathological progress of OA. The inflammatory environment in the joints of OA patients always results in the overactivation of fibroblast-like synoviocytes (FLSs), which produce a multitude of inflammatory factors and media, not only leading to the degradation and injury of the cartilage tissue and promoting the development of osteoarthritis but also resulting in synovial fibrosis and joint stiffness. Therefore, the synovium has attracted increasing attention in the research of OA, and the study of the mechanism of activation of FLSs and the fibrosis of joint synovium may shed new light on OA treatment. By using high-throughput screening, we have identified that hsa-miR338-3p is significantly downregulated in the synovial tissue and joint effusion from OA patients. A functional study showed that overexpression of hsa-miR338-3p in the FLSs inhibited the TGF-beta1-induced overactivation of the TGF-beta/Smad fibrosis regulation pathway by suppressing TRAP-1 expression and thus reducing the TGF-beta1-induced activation of the FLSs and the expression of vimentin and collagen I, two fibrosis markers. Meanwhile, a mechanism study also showed that the upregulation of hsa-miR338-3p reduced Smad2/3 phosphorylation by suppressing TRAP-1 and thus inhibited the TGF-beta/Smad pathway and TIMP1, a downstream protein. The present study, for the first time, illustrates the role of hsa-miR338-3p in synovial fibrosis in OA patients and the related mechanism, which is of importance to the treatment of OA and its complications by targeting the FLSs and synovial tissue. Hsa-miR338-3p not only has the potential to be a target for the gene therapy of OA but also has the potential to be a new marker for the diagnosis of clinical progression in OA patients. PMID- 30484107 TI - Mesenchymal stem cell dysfunction in diabetes. AB - Diabetes mellitus (DM) is a chronic disease that results in a variety of systemic complications. Recently, stem cell-based therapies have been proposed as potential modalities to manage DM related complications. Mesenchymal stem cell (MSC) based therapies are often considered as an ideal stem cell-based treatment for DM management due to their immunosuppressive characteristics, anti inflammatory properties and differentiation potential. While MSCs show tremendous promise, the underlying functional deficits of MSCs in DM patients is not well understood. Using the MEDLINE database to define these functional deficits, our search yielded 1826 articles of which 33 met our inclusion criteria. This allowed us to review the topic and illuminate four major molecular categories by which MSCs are compromised in both Type 1 DM and Type II DM models which include: (1) changes in angiogenesis/vasculogenesis, (2) altered pro-inflammatory cytokine secretion, (3) increased oxidative stress markers and (4) impaired cellular differentiation and decreased proliferation. Knowledge of the deficits in MSC function will allow us to more clearly assess the efficacy of potential biologic therapies for reversing these dysfunctions when treating the complications of diabetic disease. PMID- 30484108 TI - Expression of long non-coding RNA CCHE1 in colorectal carcinoma: correlations with clinicopathological features and ERK/COX-2 pathway. AB - Colorectal cancer (CRC) is among the leading causes of cancer-related mortality worldwide. Compelling evidence suggests that long non-coding RNA (lncRNAs) can control carcinogenesis by regulating various aspects of cell biology. However, limited number of CRC-related lncRNAs has been well characterized. This study was undertaken to investigate the expression pattern of the novel lncRNA-CCHE1 in CRC patients and to examine its correlation with clinicopathological features, ERK/COX-2 pathway and some cell proliferation markers in order to gain biological insights on its role in CRC pathogenesis. Colon cancer specimens with their adjacent non-cancerous tissues were taken from 60 patients with primary CRC. LncRNA-CCHE1 relative expression was assessed using quantitative real-time RT PCR. P-ERK 1/2 and cyclin D1 levels were estimated by ELISA. COX-2 and proliferating cell nuclear antigen (PCNA) expression were assessed immunohistochemically. lncRNA-CCHE1 expression was upregulated in CRC tissues compared to adjacent non-cancerous tissues, and was significantly associated with larger tumor size, less differentiated histology, advanced dukes' stage, positive lymph node involvement and vascular invasion. It also showed a significant positive correlation with the expression of p-ERK1/2, COX-2 as well as cyclin D1and PCNA (as markers for cell proliferation). These findings signify that lncRNA-CCHE1 is a key oncogene possibly involved in CRC development and progression by modulating ERK/COX-2 pathway and cell proliferation activity. Our study also provides a rationale for potential use of lncRNA-CCHE1 as a novel prognostic marker, and opens the door for the development of lncRNA-CCHE1 directed therapeutic approaches for CRC patients. PMID- 30484109 TI - Improving oxidative damage, photosynthesis traits, growth and flower dropping of pepper under high temperature stress by selenium. AB - Pepper is mostly produced in greenhouses and fields in spring up to the end of summer. The reproductive stage coincides with high temperature of summer, which causes flowers to drop, leading to reduction in the yield, Se as a beneficial element can improved some stress indices. Control randomized design experiment was conducted to investigate the effect(s) of Se on heat stresses of pepper in control environment. Se in three concentrations of SeCl2 (4 (Se1), 6 (Se2) and 8 (Se3) mg L-1) was used at 35 +/- 2 degrees C for 4 h a day, matching the high afternoon temperature. Growth, photosynthesis traits (Photosynthesis rate, transpiration and stomatal conductance), flower dropping and antioxidant changes were all measured. Results showed that Se1 decreased deleterious effects of heat stresses on vegetative traits (fresh and dry weight of fruit). Including dry weight of shoot, fresh and dry weight of root, and reproductive growth, such as Fresh weight and dry weight of fruit, flowers and fruit number. Photosynthesis rate, fruit antioxidant and phenol improved with the application of Se to heat stresses. POD and SOD activity increased, and MDA content decreased with Se application at the high temperature. Se also improved the P and S uptake. Generally, using 4 and 6 mg L-1 of Se could improve growth and physiological and phytochemical parameters of pepper and decrease the flower dropping at high temperature. PMID- 30484111 TI - Kainate Receptor Activation Enhances Amyloidogenic Processing of APP in Astrocytes. AB - Kainic acid (KA) is an analogue of the excitatory neurotransmitter glutamate that, when injected systemically into adult rats, can trigger seizures and progressive neuronal loss in a manner that mirrors the neuropathology of human mesial temporal lobe epilepsy. However, biomolecular mechanisms responsible for the neuronal loss that occurs as a consequence of this treatment remains elusive. We have recently reported that toxicity induced by KA can partly be mediated by astrocyte-derived amyloid beta (Abeta) peptides, which are critical in the development of Alzheimer's disease (AD). Nonetheless, little is known how KA can influence amyloid precursor protein (APP) levels and processing in astrocytes. Thus, in the present study using human U-373 astrocytoma and rat primary astrocytes, we evaluated the role of KA on APP metabolism. Our results revealed that KA treatment increased the levels of APP and its cleaved products (alpha /beta-CTFs) in cultured U-373 astrocytoma and primary astrocytes, without altering the cell viability. The cellular and secretory levels of Abeta1 40/Abeta1-42 were markedly increased in KA-treated astrocytes. We also demonstrated that the steady-state levels of APP-secretases were not altered but the activity of gamma-secretase is enhanced in KA-treated U-373 astrocytoma. Furthermore, using selective receptor antagonists, we showed that the effects of KA is mediated by activation of kainate receptors and not NMDA or AMPA receptors. These results suggest that KA can enhance amyloidogenic processing of APP by activating its own receptor leading to increased production/secretion of Abeta related peptides from activated astrocytes which may contribute to the pathogenesis of temporal lobe epilepsy. PMID- 30484110 TI - Correction to: International experience in the development of patient-derived xenograft models of diffuse intrinsic pontine glioma. AB - There are two errors and one omission in the original article. Author Gottardo's correct name is Nicholas G. Gottardo, author Hulleman's correct affiliation is no. 3 (VUMC, Amsterdam), and the Acknowledgements should include the following sentence: "We would like to thank Dr Angel Montero Carcaboso (Hospital Sant Joan de Deu, Barcelona, Spain) for generously supplying the HSJD-DIPG007 cells." PMID- 30484112 TI - Riluzole Attenuates L-DOPA-Induced Abnormal Involuntary Movements Through Decreasing CREB1 Activity: Insights from a Rat Model. AB - Chronic administration of L-DOPA, the first-line treatment of dystonic symptoms in childhood or in Parkinson's disease, often leads to the development of abnormal involuntary movements (AIMs), which represent an important clinical problem. Although it is known that Riluzole attenuates L-DOPA-induced AIMs, the molecular mechanisms underlying this effect are not understood. Therefore, we studied the behavior and performed RNA sequencing of the striatum in three groups of rats that all received a unilateral lesion with 6-hydroxydopamine in their medial forebrain bundle, followed by the administration of saline, L-DOPA, or L DOPA combined with Riluzole. First, we provide evidence that Riluzole attenuates AIMs in this rat model. Subsequently, analysis of the transcriptomics data revealed that Riluzole is predicted to reduce the activity of CREB1, a transcription factor that regulates the expression of multiple proteins that interact in a molecular landscape involved in apoptosis. Although this mechanism underlying the beneficial effect of Riluzole on AIMs needs to be confirmed, it provides clues towards novel or existing compounds for the treatment of AIMs that modulate the activity of CREB1 and, hence, its downstream targets. PMID- 30484113 TI - In Schizophrenia, Deficits in Natural IgM Isotype Antibodies Including those Directed to Malondialdehyde and Azelaic Acid Strongly Predict Negative Symptoms, Neurocognitive Impairments, and the Deficit Syndrome. AB - Schizophrenia is characterized by an interrelated activation of the immune inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS), which downregulates the IRS. Deficit schizophrenia is characterized by a deficit in IgM-mediated autoimmune responses to tryptophan catabolites. The presence and correlates of IgM isotype antibodies to oxidative-specific epitopes (OSEs), nitroso (NO), and nitro (NO2) adducts in schizophrenia remain unknown. This study measured IgM antibodies to malondialdehyde (MDA), azelaic acid, phosphatidylinositol, oleic acid, NO-tryptophan, NO-albumin, NO-cysteinyl, and NO2-tyrosine in a sample of 80 schizophrenia patients, divided into those with and those without deficit schizophrenia, and 38 healthy controls. Deficit schizophrenia was characterized by significantly lower IgM antibody levels to all OSEs as compared with non-deficit schizophrenia and controls. Lowered IgM antibodies to MDA coupled with increased IgM levels to NO-cysteinyl and NO2 tyrosine strongly predict deficit schizophrenia versus non-deficit schizophrenia with an area under the ROC curve of 0.913. A large part of the variance (21.2 42.2%) in the negative symptoms of schizophrenia and excitation is explained by IgM antibody titers to MDA (inversely) and NO-cysteinyl and/or NO2-tyrosine (both positively). Lower IgM antibodies to MDA are significantly associated with impairments in episodic memory including direct and delayed recall. These findings further indicate that deficit schizophrenia is a distinct phenotype of schizophrenia, which is characterized by lower natural IgM antibody levels to OSEs and relative increments in nitrosylation and nitration of proteins. It is concluded that deficits in natural IgM attenuate CIRS functions and that this impairment may drive negative symptoms and impairments in episodic memory and thus deficit schizophrenia. PMID- 30484114 TI - The Stanley Neuropathology Consortium Integrative Database (SNCID) for Psychiatric Disorders. PMID- 30484115 TI - Deep-learned placental vessel segmentation for intraoperative video enhancement in fetoscopic surgery. AB - INTRODUCTION: Twin-to-twin transfusion syndrome (TTTS) is a potentially lethal condition that affects pregnancies in which twins share a single placenta. The definitive treatment for TTTS is fetoscopic laser photocoagulation, a procedure in which placental blood vessels are selectively cauterized. Challenges in this procedure include difficulty in quickly identifying placental blood vessels due to the many artifacts in the endoscopic video that the surgeon uses for navigation. We propose using deep-learned segmentations of blood vessels to create masks that can be recombined with the original fetoscopic video frame in such a way that the location of placental blood vessels is discernable at a glance. METHODS: In a process approved by an institutional review board, intraoperative videos were acquired from ten fetoscopic laser photocoagulation surgeries performed at Yale New Haven Hospital. A total of 345 video frames were selected from these videos at regularly spaced time intervals. The video frames were segmented once by an expert human rater (a clinician) and once by a novice, but trained human rater (an undergraduate student). The segmentations were used to train a fully convolutional neural network of 25 layers. RESULTS: The neural network was able to produce segmentations with a high similarity to ground truth segmentations produced by an expert human rater (sensitivity = 92.15% +/- 10.69%) and produced segmentations that were significantly more accurate than those produced by a novice human rater (sensitivity = 56.87% +/- 21.64%; p < 0.01). CONCLUSION: A convolutional neural network can be trained to segment placental blood vessels with near-human accuracy and can exceed the accuracy of novice human raters. Recombining these segmentations with the original fetoscopic video frames can produced enhanced frames in which blood vessels are easily detectable. This has significant implications for aiding fetoscopic surgeons-especially trainees who are not yet at an expert level. PMID- 30484116 TI - Automated anatomical labeling of coronary arteries via bidirectional tree LSTMs. AB - PURPOSE: Automated anatomical labeling facilitates the diagnostic process for physicians and radiologists. One of the challenges in automated anatomical labeling problems is the robustness to handle the large individual variability inherited in human anatomy. A novel deep neural network framework, referred to Tree Labeling Network (TreeLab-Net), is proposed to resolve this problem in this work. METHODS: A multi-layer perceptron (MLP) encoder network and a bidirectional tree-structural long short-term memory (Bi-TreeLSTM) are combined to construct the TreeLab-Net. Vessel spatial locations and directions are selected as features, where a spherical coordinate transform is utilized to normalize vessel spatial variations. The dataset includes 436 coronary computed tomography angiography images. Tenfold cross-validation is performed for evaluation. RESULTS: The precision-recall curve of TreeLab-Net shows that the four main branch classes, LM, LAD, LCX and RCA, have the area under the curve (AUC) higher than 97%. Other major side branch classes, D, OM, and R-PLB, also have AUC higher than 90%. Comparing with four other methods (i.e., AdaBoost, MLP, Up-to-Down and Down-to-Up TreeLSTM), the TreeLab-Net achieves higher F1 scores with less topological errors. CONCLUSION: The TreeLab-Net is able to capture the characteristics of tree structures by learning the spatial and topological dependencies of blood vessels effectively. The results demonstrate that TreeLab Net is able to yield competitive performances on a large dataset with great variance among subjects. PMID- 30484117 TI - IncobotulinumtoxinA Efficacy and Safety in Adults with Upper-Limb Spasticity Following Stroke: Results from the Open-Label Extension Period of a Phase 3 Study. AB - INTRODUCTION: The objective of the study was to investigate the efficacy and safety of repeated incobotulinumtoxinA injections for the treatment of upper-limb post-stroke spasticity in adults. METHODS: Adults 18-80 years of age with post stroke upper-limb spasticity who completed the 12-week randomized, double-blind, placebo-controlled main period (MP) of a phase 3 trial (NCT01392300) were eligible to enrol in the 36-week open-label extension period (OLEX). The OLEX included three treatment cycles at fixed 12-week injection intervals; subjects were injected with 400 U incobotulinumtoxinA into the affected upper limb. Efficacy assessments included evaluation of muscle tone using the Ashworth Scale (AS) and the Global Impression of Change Scale (GICS) assessed by the investigator, subject, and caregiver. The incidence of adverse events (AEs) was monitored throughout the OLEX. RESULTS: A total of 296 of 299 subjects (99.0%) who completed the MP received incobotulinumtoxinA in the OLEX, and 248 subjects completed the 36-week OLEX. The proportion of subjects with at least a 1-point improvement in AS score from each incobotulinumtoxinA treatment to the respective 4-week post-injection visit ranged by cycle from 52.3% to 59.2% for wrist flexors, 49.1% to 52.3% for elbow flexors, 59.8% to 64.5% for finger flexors, 35.5% to 41.2% for thumb flexors, and 37.4% to 39.9% for forearm pronators (P < 0.0001 for all). Over 90% of subjects were assessed by the investigator to be at least minimally improved (4 weeks post-injection) on the GICS during each injection cycle; 61.0% in the 1st cycle, 58.2% in the 2nd cycle, and 57.4% in the 3rd cycle were considered much improved or very much improved on the GICS. Three percent of subjects (9/296) reported treatment-related AEs; the most frequently reported were pain in the extremity (n = 2, 0.7%) and constipation (n = 2, 0.7%). Serious AEs were reported by 22 subjects (7.4%); however, none were considered treatment-related. CONCLUSIONS: Repeated injections of incobotulinumtoxinA for the treatment of post-stroke upper-limb spasticity led to significant improvements in muscle tone and investigator's global impression of change. Treatment was well tolerated, with no serious treatment-related AEs. FUNDING: Merz Pharmaceuticals GmbH. PMID- 30484118 TI - Transcriptional mechanism of IRF8 and PU.1 governs microglial activation in neurodegenerative condition. AB - Microglial activation occurs in divergent neuropathological conditions. Such microglial event has the key involvement in the progression of CNS diseases. However, the transcriptional mechanism governing microglial activation remains poorly understood. Here, we investigate the microglial response to traumatic injury-induced neurodegeneration by the 3D fluorescence imaging technique. We show that transcription factors IRF8 and PU.1 are both indispensible for microglial activation, as their specific post-developmental deletion in microglia abolishes the process. Mechanistically, we reveal that IRF8 and PU.1 directly target the gene transcription of each other in a positive feedback to sustain their highly enhanced expression during microglial activation. Moreover, IRF8 and PU.1 dictate the microglial response by cooperatively acting through the composite IRF-ETS motifs that are specifically enriched on microglial activation related genes. This action of cooperative transcription can be further verified biochemically by the synergetic binding of IRF8 and PU.1 proteins to the composite-motif DNA. Our study has therefore elucidated the central transcriptional mechanism of microglial activation in response to neurodegenerative condition. PMID- 30484119 TI - To bin or not to bin? A comparison of symptom frequency response formats in the assessment of health-related quality of life. AB - PURPOSE: The goal of this study is to compare three different types of retrospective frequency response formats on the Healthy Days Symptoms Module (HDSM). Responses are compared in terms of intra-individual consistency, psychometric value, and participant feedback about each type of response format. METHODS: Respondents each completed three versions of the HDSM, where items were framed to elicit an open-ended frequency, a fixed choice frequency, or a vague quantifier response. Traditional reliability statistics were used to evaluate intra-individual consistency. Differential item functioning (DIF) was used to test for response format effects, and item response theory (IRT) scale scores and standard errors were computed across the three forms to compare psychometric value. Linear mixed modeling was used to examine the associations of IRT scale scores across response formats with respondent characteristics. RESULTS: People are largely consistent in how they respond to items about their health, regardless of the response format, and no DIF was detected between response formats. The IRT scores computed from the "# of days" frequency response formats tend to have better measurement precision than those from vague quantifiers. Open ended frequencies capture a greater span of individual differences for people reporting fewer symptoms; however, little measurement precision is lost in collapsing the frequencies into categories. CONCLUSIONS: Both the open-ended and fixed choice frequency response formats offer more measurement precision than vague quantifiers. While the open-ended frequency response format may capture more individual differences, respondents tend to report more difficulty with exact frequency recall, and thus, prefer the fixed choice frequency format. PMID- 30484120 TI - Measurement invariance of the Satisfaction with Life Scale by gender, age, marital status and educational level. AB - INTRODUCTION: The Satisfaction with Life Scale (SWLS) has shown strong evidence of acceptability, reliability, validity and invariance for gender, whereas there is mixed evidence of invariance by culture and age and the literature has not explored the roles of marital status and educational level. The SWLS should be invariant by marital status and educational level to be able to compare scores between groups. We aimed to explore the invariance of the SWLS by marital status and educational level. METHOD: A convenience sample of 726 Spanish adults participated in a survey. We tested a one-factor model using confirmatory factor analysis. We tested the configural, metric and scalar invariance of the factorial structure of the SWLS by gender, age, marital status and level of education. RESULTS: The results show a scalar invariance by gender and educational level and a partial scalar invariance by marital status. Women and individuals in a relationship show greater subjective well-being while no differences are observed among people with different educational levels. DISCUSSION: The SLWS is valid for comparisons between genders, age, educational levels but not for marital status. It is essential to verify its invariance to interpret mean differences and significance values appropriately. PMID- 30484121 TI - Sensitivity of EQ-5D-3L, HUI2, HUI3, and SF-6D to changes in speech reception and tinnitus associated with cochlear implantation. AB - PURPOSE: There is concern that some generic preference-based measures (GPMs) of health-related quality of life may be insensitive to interventions that improve hearing. Establishing where sensitivity arises could contribute to the design of improved measures. Accordingly, we compared the sensitivity of four widely used GPMs to a clinically effective treatment-cochlear implantation-which restores material degrees of hearing to adults with little or no functional hearing. METHODS: Participants (N = 147) received implants in any of 13 hospitals in the UK. One month before implantation and 9 months after, they completed the HUI2, HUI3, EQ5D3L, and SF-6D questionnaires, together with the EuroQoL visual-analogue scale as a direct measure of health, a performance test of speech reception, and a self-report measure of annoyance due to tinnitus. RESULTS: Implantation was associated with a large improvement in speech reception and a small improvement in tinnitus. HUI2 and HUI3 were sensitive to the improvement in speech reception through their Sensation and Hearing dimensions; EQ5D3L was sensitive to the improvement in tinnitus through its Anxiety/Depression dimension; SF-6D was sensitive to neither. Participants reported no overall improvement in health. Variation in health was associated with variation in tinnitus, not variation in speech reception. CONCLUSIONS: None of the four GPMs was sensitive to the improvements in both speech reception and tinnitus that were associated with cochlear implantation. To capture fully the benefits of interventions for auditory disorders, developments of current GPMs would need to be sensitive to both the health-related and non-health-related aspects of auditory dysfunction. PMID- 30484122 TI - Discovery of caerulomycin/collismycin-type 2,2'-bipyridine natural products in the genomic era. AB - 2,2'-Bipyridine (2,2'-BP) is the unique molecular scaffold of the bioactive natural products represented by caerulomycins (CAEs) and collismycins (COLs). CAEs and COLs are highly similar in the chemical structures in which their 2,2' BP cores typically contain a di- or tri-substituted ring A and an unmodified ring B. Here, we summarize the CAE and COL-type 2,2'-BP natural products known or hypothesized to date: (1) isolated using methods traditional for natural product characterization, (2) created by engineering the biosynthetic pathways of CAEs or COLs, and (3) predicted upon bioinformatics-guided genome mining. The identification of these CAE and COL-type 2,2'-BP natural products not only demonstrates the development of research techniques and methods in the field of natural product chemistry but also reflects the general interest in the discovery of CAE and COL-type 2,2'-BP natural products. PMID- 30484123 TI - CylA is a sequence-specific protease involved in toxin biosynthesis. AB - CylA is a subtilisin-like protein belonging to a recently expanded serine protease family related to class II lanthipeptide biosynthesis. As a leader peptidase, CylA is responsible for maturation of the enterococcal cytolysin, a lantibiotic important for Enterococcus faecalis virulence. In vitro reconstitution of CylA reveals that it accepts both linear and modified cytolysin peptides with a preference for cyclized peptides. Further characterization indicates that CylA activates itself by removing its N-terminal 95 amino acids. CylA achieves sequence-specific traceless cleavage of non-cognate peptides even if they are post-translationally modified, which makes the peptidase a powerful tool for mining novel lanthipeptides by providing a general strategy for leader peptide removal. Knowledge about the substrate specificity of CylA may also facilitate the development of protease inhibitors targeting cytolysin biosynthesis as a potential therapeutic approach for enterococcal infections. PMID- 30484124 TI - Natural product drug discovery in the genomic era: realities, conjectures, misconceptions, and opportunities. AB - Natural product discovery from microorganisms provided important sources for antibiotics, anti-cancer agents, immune-modulators, anthelminthic agents, and insecticides during a span of 50 years starting in the 1940s, then became less productive because of rediscovery issues, low throughput, and lack of relevant new technologies to unveil less abundant or not easily detected drug-like natural products. In the early 2000s, it was observed from genome sequencing that Streptomyces species encode about ten times as many secondary metabolites as predicted from known secondary metabolomes. This gave rise to a new discovery approach-microbial genome mining. As the cost of genome sequencing dropped, the numbers of sequenced bacteria, fungi and archaea expanded dramatically, and bioinformatic methods were developed to rapidly scan whole genomes for the numbers, types, and novelty of secondary metabolite biosynthetic gene clusters. This methodology enabled the identification of microbial taxa gifted for the biosynthesis of drug-like secondary metabolites. As genome sequencing technology progressed, the realities relevant to drug discovery have emerged, the conjectures and misconceptions have been clarified, and opportunities to reinvigorate microbial drug discovery have crystallized. This perspective addresses these critical issues for drug discovery. PMID- 30484125 TI - Systematic investigation of CRISPR-Cas9 configurations for flexible and efficient genome editing in Corynebacterium glutamicum NRRL-B11474. AB - This study details a reliable and efficient method for CRISPR-Cas9 genome engineering in the high amino acid-producing strain of Corynebacterium glutamicum, NRRL-B11474. Our investigation demonstrates that a plasmid-encoded single-guide RNA paired with different edit-encoding fragments is sufficient to generate edits without the addition of an exogenous recombinase. This approach leverages a genome-integrated copy of the cas9 gene for reduced toxicity, in combination with a single plasmid carrying the targeting guide RNA and matching edit fragment. Our study systematically investigated the impact of homology arm length on editing efficiency and demonstrates genome editing with homology arm lengths as small as 25 bp for single-nucleotide polymorphisms and 75 bp for 100 bp sequence swaps. These homology arm lengths are smaller than previously reported for other strains of C. glutamicum. Our study finds that C. glutamicum NRRL-B11474 is not amenable to efficient transformation with plasmids containing the BL1, NG2, or CC1 origins of replication. This finding differs from all previously reported approaches to plasmid-based CRISPR-Cas9 or Cpf1 editing in other strains of C. glutamicum. Two alternative origins of replication (CG1 and CASE1) can be used to successfully introduce genome edits; furthermore, our data demonstrate improved editing efficiency when guide RNAs and edit fragments are encoded on plasmids carrying the CASE1 origin of replication (compared to plasmids carrying CG1). In addition, this study demonstrates that efficient editing can be done using an integrated Cas9 without the need for a recombinase. We demonstrate that the specifics of CRISPR-Cas9 editing configurations may need to be tailored to enable different edit types in a particular strain background. Refining configuration parameters such as edit type, homology arm length, and plasmid origin of replication enables robust, flexible, and efficient CRISPR-Cas9 editing in differing genetic strain contexts. PMID- 30484126 TI - Gorham's disease of the mandible: radiological features. AB - The most conspicuous element of Gorham's disease is its radiographic features, wherein massive disappearance of the mandible is observed. We report a case of an adolescent boy with massive osteolysis of the mandible in whom the diagnosis of Gorham's disease was made. A 14-year-old boy was referred to the Department of Oral and Maxillofacial Surgery, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, for the management of a massive mandibular deformity. He was diagnosed with a hemangioma-like lesion at 1 year of age. The disease had progressed for an unknown number of years. Plain X-rays and computed tomography images were examined for reconstructive surgery planning. Gorham's disease is self-limiting, but has catastrophic results. The role of imaging is huge, particularly for reconstructive surgery planning. PMID- 30484127 TI - Current status of oral and maxillofacial radiology in West Africa. AB - BACKGROUND: Oral and maxillofacial radiology became the ninth dental specialty recognized by the American Dental Association (ADA) in 1999. This came about following the discovery of X-rays by Wilhelm Conrad Roentgen in 1895 and, 14 days later, the application of X-rays to making dental radiographs by Otto Walkhoff. The purpose of this narrative study was to review the evolution of oral and maxillofacial radiology as a dental specialty in the USA and its recognition as a program of training by the West African College of Surgeons. METHODS: This study was conceptualized as a narrative review of the literature focusing on the history and development of oral and maxillofacial radiology in the USA. It builds a synthesis that describes the recognition of oral and maxillofacial radiology as a specialty of dentistry in West Africa, UK, Japan, and Australia. RESULTS: The main finding was that oral and maxillofacial radiology became the ninth specialty recognized by the American Dental Association, ADA, in October 13, 1999. On March 20, 2014, the West African College of Surgeons recognized this specialty and granted accreditation for postgraduate training. In the UK, Japan, and Australia, the postgraduate education in oral and maxillofacial radiology has two patterns, namely professional training and academic training. CONCLUSIONS: The primary goal of the postgraduate training curriculum is to train radiologists who are competent to deliver care to patients in any clinical setting, including a dental school, hospital radiology practice, or private practice. PMID- 30484128 TI - Associations between mandibular symphysis form and craniofacial structures. AB - OBJECTIVES: This study aimed to (1) analyze the relationships between mandibular symphysis characteristics (height, prominence, inclination, concavity, and convexity) and facial pattern, skeletal class, lower incisor position, and sex, and (2) determine the associations between the symphysis soft tissue dimensions and the underlying osseous structures. METHODS: Cone-beam computed tomography (CBCT) images were selected for 385 patients (206 women and 179 men). The patients were classified according to their skeletal class and vertical pattern. The lower incisor inclination (IMPA) was recorded. Twelve measurements were taken for each mandibular symphysis using Invivo5 software (Anatomage, San Jose, CA, USA). RESULTS: Symphyseal measurements were larger in males than in females. Skeletal Class II and III hyperdivergent patients showed the highest symphysis height values. Hypodivergent individuals showed lower symphysis convexity angles. Concavity of the symphysis was greater for Class II hyperdivergent patients. Lower incisor inclination showed a positive correlation with symphysis concavity and inclination. Moderate and weak correlations were found between hard tissue and soft tissue parameters. CONCLUSIONS: Only a few characteristics of symphysis morphology depend on sex, incisor position, skeletal class, and vertical pattern. More significant relationships are found when the vertical pattern and skeletal class are analyzed in combination. The shape of the symphysis soft tissue is not directly correlated with the underlying skeletal structures. PMID- 30484129 TI - Craniofacial cephalometric morphologies in different cleft types: a retrospective cross-sectional study of 212 patients. AB - OBJECTIVE: The aim of this study was to evaluate and compare the craniofacial cephalometric morphologies among different cleft types in a Spanish population. METHODS: A retrospective cross-sectional study was carried out on 212 patients. The patients were subdivided into four groups according to their cleft types: unilateral cleft lip and palate; bilateral cleft lip and palate; cleft lip; and cleft palate. Angular and linear cephalometric measurements were taken on lateral radiographs. RESULTS: Unilateral cleft lip and palate was associated with a dolichofacial growth pattern, skeletal Class III with correct maxillary position, and lingual incisor inclination. Bilateral cleft lip and palate was associated with a mesofacial growth pattern, skeletal Class I with protruded maxillary position, and lingual incisor inclination. Cleft palate was associated with a mesofacial growth pattern, skeletal Class III with correct maxillary position, and lingual incisor inclination. Cleft lip was associated with a brachyfacial growth pattern, skeletal Class I with protruded maxillary position, lingual upper incisor inclination, and corrects lower incisor inclination. Significant correlations were observed between cleft types and their craniofacial cephalometric measurements. CONCLUSIONS: The present information can be used for the determination of orthodontic treatment and even future orthognathic surgery planning, a requirement in most cleft patients. PMID- 30484130 TI - Panoramic radiographic features that predict the development of bisphosphonate related osteonecrosis of the jaw. AB - OBJECTIVES: The purpose of this study was to clarify which panoramic radiographic features can predict the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ). METHODS: Participants included 24 patients treated with bisphosphonates (BP) for osteoporosis who developed osteonecrosis of the jaw (ONJ+ group). Controls included 179 patients treated with BP who did not have osteonecrosis (ONJ- group) and 200 patients with no history of BP administration (unmedicated group). The mandibular cortical width, mandibular cortical index (MCI), sclerosis of trabecular bone, and thickening of the lamina dura were evaluated on panoramic radiographs. RESULTS: The mandibular cortical width was significantly smaller in the ONJ- group than in the other groups. Class II MCI (semilunar defects of endosteal margin) was frequently noted on the affected and contralateral sides in the ONJ+ group but not in the ONJ- or unmedicated groups. Sclerosis of the trabecular bone was significantly more frequently observed on the affected side in the ONJ+ group than in the other groups. Thickening of the lamina dura was observed significantly more frequently in the BP-treated groups than in the unmedicated group. CONCLUSIONS: Class II MCI may be an indicator to predict the development of BRONJ. Sclerosis of trabecular bone was a characteristic imaging feature of BRONJ. Thickening of the lamina dura may be an imaging feature caused by BP administration. PMID- 30484131 TI - Root and canal morphology of mandibular premolars using cone-beam computed tomography in a Chilean and Belgian subpopulation: a cross-sectional study. AB - OBJECTIVE: To describe mandibular premolar root and canal morphology and its variability in Chilean and Belgian samples using cone-beam computed tomography. METHODS: A cross-sectional and descriptive study was conducted. A total of 402 mandibular premolars were examined using cone-beam computed tomography images of Chilean and Belgian patients. Premolars that met the inclusion criteria were studied in relation to the number of roots, number of canals, root canal configuration, presence of C-shaped configuration, tooth length, and root length. RESULTS: The mandibular first premolar frequently presented with one root (94% Chilean; 100% Belgian), as did the mandibular second premolar (99% Chilean; 98% Belgian). One canal was present in 69% of Chilean, and 83% of Belgian mandibular first premolars, and in 95% of Chilean and 91% of Belgian second premolars. A type I root canal configuration was found in 69% of Chilean and 83% of Belgian first premolars and in 95% of Chilean and 92% of Belgian second premolars. CONCLUSIONS: The anatomical parameters analyzed in the Chilean and Belgian samples are similar. However, it should be noted that there are anatomical variations in mandibular premolars. PMID- 30484132 TI - Evaluation of renal osteodystrophy in the dental clinic by assessment of mandibular and phalangeal cortical indices. AB - OBJECTIVES: Secondary hyperparathyroidism (SHPT) is a disease that affects patients with chronic kidney disease, and is characterized by mineral disturbance and bone loss, known as renal osteodystrophy. The aim of this study was to assess the validity of using intraoral phosphor storage plates to take radiographs of the middle phalanges to evaluate bone loss resulting from SHPT during follow-up of these patients. METHODS: The sample consisted of 24 patients with chronic kidney disease, 12 with parathyroid hormone (PTH) levels >=500 pg/ml, and 12 with PTH levels <500 pg/ml, who underwent hemodialysis weekly. For each patient, a panoramic radiograph and digital radiographs of the ring, index, and middle fingers of both hands were taken. The Mandibular Cortical Index (MCI) and the Trabecular Bone Pattern Index (TBP) were applied to the panoramic radiographs, while the Phalangeal Cortical Index (PCI) was applied to the digital radiographs of the phalanges. Three evaluators performed all analyses. RESULTS: Significant correlations were found between the PTH levels and the MCI (p = 0.023), the PCI (p = 0.039) and the TBP index (p = 0.032). These parameters were also significantly interrelated (MCI * PCI = 0.001; MCI * TBP = 0.004 and PCI * TBP = 0.009). The PCI was shown to have the highest correlation with PTH levels. CONCLUSION: In patients with chronic renal disease, it is clinically relevant to use panoramic and digital radiographs using intraoral storage plates to assess a number of quantitative parameters that can be linked to PTH levels. PMID- 30484134 TI - Correction to: Extranodal lymphoma arising within the maxillary alveolus: a systematic review. AB - OBJECTIVES: Extranodal lymphomas affecting the head and neck infrequently arise within the jaw bones. Although clinical examination and conventional radiography may initially suffice for such lesions arising within the mandible, those arising within the maxillary alveolus generally require cross-sectional imaging because of the complex anatomy of this region. This study was performed to determine the prevalence, demographic characteristics, and clinical presentations of these lesions and the imaging modalities used for their diagnosis. STUDY DESIGN: A systematic review (SR) on case series and another SR on case reports were performed to investigate the demographic, clinical, and radiological features of extranodal lymphomas arising within the maxillary alveolus. RESULTS: Most case series were derived from just four nations, whereas the case reports were derived from a wider range of ethnicities. The more detailed case reports significantly reported at least one imaging modality. Most patients were aware of their lesions for nearly 2 months before presentation. The most frequent symptom was swelling. Most case reports included a provisional diagnosis, the most frequent of which was dental infection followed by squamous cell carcinoma. DISCUSSION: Extranodal lymphomas arising within the maxillary alveolus were sufficiently frequent in four communities to be reported in two or more case series, and the occasional single case report indicated that such lesions are more widespread globally. Although the SR on case series revealed differences in the relative period prevalence and maxillary/mandibular ratio, the SR on case reports revealed details of the clinical presentation and imaging modalities used. PMID- 30484136 TI - Acknowledgment to reviewers 2017. PMID- 30484135 TI - Correction to: Comparative cone-beam computed tomography evaluation of the osseous morphology of the temporomandibular joint in temporomandibular dysfunction patients and asymptomatic individuals. AB - In the original publication of the article in "Abstract", the sentence that reads as "The present analyses suggest that a steeper articular eminence inclination may be risk factor" should read as "As a result of our analysis, we concluded that a low eminence angle may be risk factor". PMID- 30484133 TI - Clinical guidelines for dental cone-beam computed tomography. AB - Dental cone-beam computed tomography (CBCT) received regulatory approval in Japan in 2000 and has been widely used since being approved for coverage by the National Health Insurance system in 2012. This imaging technique allows dental practitioners to observe and diagnose lesions in the dental hard tissue in three dimensions (3D). When performing routine radiography, the examination must be justified, and optimal protection should be provided according to the ALARA (as low as reasonably achievable) principles laid down by the International Commission on Radiological Protection. Dental CBCT should be performed in such a way that the radiation exposure is minimized and the benefits to the patient are maximized. There is a growing demand for widespread access to cutting-edge health care through Japan's universal health insurance system. However, at the same time, people want our limited human, material, and financial resources to be used efficiently while providing safe health care at the least possible cost to society. Japan's aging population is expected to reach a peak in 2025, when most of the baby boomer generation will be aged 75 years or older. Comprehensive health care networks are needed to overcome these challenges. Against this background, we hope that this text will contribute to the nation's oral health by encouraging efficient use of dental CBCT. PMID- 30484137 TI - Enhanced Properties and Lactose Hydrolysis Efficiencies of Food-Grade beta Galactosidases Immobilized on Various Supports: a Comparative Approach. AB - In this study, a fungal and two yeast beta-galactosidases were immobilized using alginate and chitosan. The biochemical parameters and lactose hydrolysis abilities of immobilized enzymes were analyzed. The pH optima of immobilized fungal beta-galactosidases shifted to more acidic pH compared to free enzyme. Remarkably, the optimal temperature of chitosan-entrapped yeast enzyme, Maxilact, increased to 60 degrees C, which is significantly higher than that of the free Maxilact (40 degrees C) and other immobilized forms. Chitosan-immobilized A. oryzae beta-galactosidase showed improved lactose hydrolysis (95.7%) from milk, compared to the free enzyme (82.7%) in 12 h. Chitosan-immobilized Maxilact was the most efficient in lactose removal from milk (100% lactose hydrolysis in 2 h). The immobilized lactases displayed excellent reusability, and chitosan immobilized Maxilact hydrolyzed > 95% lactose in milk after five reuses. Compared to free enzymes, the immobilized enzymes are more suitable for cost-effective industrial production of low-lactose milk due to improved thermal activity, lactose hydrolysis efficiencies, and reusability. PMID- 30484138 TI - Clinicopathological Criteria Defining Mucinous Appendiceal Tumors from 2476 Appendectomies: a Single-Center Retrospective Study. AB - OBJECTIVES: Mucinous appendiceal tumors (MATs) constitute 0.2-0.3% of appendectomies. This retrospective chart review study determines the incidence of MATs among appendectomies at King Abdul-Aziz Specialist Hospital, Taif City, Saudi Arabia, from January 2009 to December 2014. The clinicopathological features, histopathological criteria, management, outcomes of patients, and the impact of histopathological classification on the follow-up period and recurrence are evaluated. METHODS: Demographic and clinicopathological data were collected from medical records. Microscopic slides from 2476 appendectomies were re examined to diagnose and classify MATs into low-grade mucinous neoplasms (LAMNs) and mucinous adenocarcinomas (MACAs). CK20, CK7, and cdx2 immunohistochemistry was applied for evaluating pseudomyxoma peritonei. Data were expressed as numbers, percentages, and mean +/- standard deviation. RESULTS: Nine MATs were diagnosed with an incidence of 0.36% of appendectomies, a male:female ratio of 1.25:1 and a mean age of 57.2 years. Acute appendicitis was the commonest clinical presentation. About 66.7% were LAMNs and 33.3% MACAs. Beside appendectomy, MACAs were managed with right hemicolectomy and chemotherapy. The median follow-up was 34 months with recurrence and liver metastases in two MACAs. No recurrences for LAMNs. CONCLUSIONS: MATs constitute 0.36% of all appendectomies. Classifying MATs into LAMNs and MACAs is more applicable for both clinical and pathology practices as compared to the three- or four-tiered classification schemes. PMID- 30484139 TI - The Problematic Use of Dietary Reference Intakes to Assess Magnesium Status and Clinical Importance. AB - Determination of the public health concern about magnesium (Mg) in health and disease has been confounded by the lack of a practical measure of status. This has resulted in a lack of consistency in associating Mg deficiency with specific pathological conditions. Some attempts at associating Mg with a chronic disease have used the Dietary Reference Intakes (DRIs) as a status assessment measure. Use of current DRIs for Mg is problematic because recent evidence suggests that they should be updated and based on body weight. An evidence-based suggested Estimated Average Requirement (EAR) and Recommended Dietary Allowance (RDA) for a 70-kg individual is 175 and 250 mg/day, respectively. However, numerous dietary and physiological factors can affect the need for Mg and thus affect the use of the current or suggested new DRIs to assess Mg status. Calcium intakes above normal requirements can decrease Mg balance and exacerbate signs of Mg deficiency. Mg deficiency apparently occurs often in obesity because of increased need to counteract the inflammatory stress induced by adipose tissue dysfunction. Deficiency in anti-oxidant nutrients such as vitamin E and selenium can exacerbate a response to low dietary Mg indicated by increased oxidative stress which can lead to chronic disease. Dietary modifiers of Mg absorption and excretion affect balance and thus the need for Mg. Factors decreasing Mg balance include low dietary protein and non-fermentable fiber, while factors that can increase balance include fructose and fermentable fiber and fructose-containing oligosaccharides. Use of the DRIs to assess the Mg status of a population or group needs to consider their physiological characteristics and dietary habits and be aware that the DRIs may need updating. The DRIs only can be considered a component of a toolbox that presently includes serum Mg concentration and the daily urinary Mg excretion to assess the Mg status of an individual. PMID- 30484140 TI - Financial Impact of Alternative Pricing Benchmarks for Physician-Dispensed Drugs in the California Workers' Compensation System. AB - BACKGROUND: Pricing drugs in the California Workers' Compensation System (CAWCS) has become more difficult as there are increasingly fewer drugs listed in the Medi-Cal primary fee schedule, which is used as the source for CAWCS drug prices. This presents a challenge of providing timely and accurate CAWCS reimbursement. The objectives of this study are (1) to explore any trends in physician-dispensed drug prices; (2) to compare the proportion of drugs with and without a price and to determine the financial implications of repricing CAWCS physician-dispensed drugs with five alternative pricing benchmarks; and (3) to offer recommendations for the pricing benchmark to maximize pricing coverage and to remain budget neutral. METHODS: We evaluated physician-dispensed drugs at the transaction level, reimbursed in the CAWCS. Frequency, reimbursement rate, and total and average paid costs were reported. We matched each claim line in the CAWCS to the corresponding unit price of an alternative price benchmark including average wholesale price, wholesale acquisition cost, direct prices, national average drug acquisition cost, and Federal Upper Limit. RESULTS: Average wholesale price provided prices for 99.9% of physician-dispensed drug claims, while Medi-Cal, the current primary physician-dispensed drug benchmark provided prices for a lower percentage (92.7%) of claims. The CAWCS prices were equivalent to 49% of the average wholesale price, 95.5% of Medi-Cal, 126.7% of the wholesale acquisition cost, 266% of the Federal Upper Limit, 64.4% of direct prices, and 197% of national average drug acquisition cost-estimated prices. CONCLUSIONS: The CAWCS current Medi-Cal pricing for physician-dispensed drugs is better than all alternatives in terms of price availability, transparency, and budget neutrality, but pricing availability may decrease over time as Medi-Cal moves to managed care. National average drug acquisition cost is the next best alternative, but it requires combinations of pricing benchmarks to maximize its price availability. PMID- 30484141 TI - Prenatal and postnatal urinary tract dilation: advantages of a standardized ultrasound definition and classification. AB - Urinary tract dilatation is identified sonographically in 1-2% of fetuses and reflects a spectrum of possible nephro-uropathies. There is significant variability in the clinical management of individuals with prenatal urinary tract dilatation to postnatal urinary pathologies, because of a lack of consensus and uniformity in defining and classifying urinary tract dilation. Ultrasonography is the first step to screen and diagnose kidneys and the urinary tract diseases of the children. The need for a correct ultrasound approach led to the realization of algorithms aimed at standardizing the procedures, the parameters and the classifications. Our objective was to highlight the strengths of the Classification of Urinary Tract Dilation (UTD) suggested by the Consensus Conference which took place in 2014 with the participation of eight Scientific Societies and was subsequently published on the Journal of Pediatric Urology. Before its spread out, the definition of UTD was not uniform and the ultrasonographic measurements were not clearly defined, leading to misunderstandings between physicians. The Classification by the Consensus Conference of 2014 represents a revolutionary tool for the diagnosis and management of UTD. Furthermore, the parameters suggested by the classification proposed are applicable for both prenatal and postnatal classification, ensuring a correct follow-up in children with UTD whose diagnosis had been already made during pregnancy. PMID- 30484142 TI - Analysis of Fatal Attraction and Gone Girl to Teach Personality Clusters. PMID- 30484143 TI - Assessing the Safety and Efficacy of Lactobacillus plantarum MTCC 5690 and Lactobacillus fermentum MTCC 5689 in Colitis Mouse Model. AB - Probiotic lactobacilli have an unprecedented history of safe use, although some cases of infections have raised concerns about their safety, and hence, a rigorous screening of any new strain even of Lactobacillus is a must in order to study possible adverse interactions with the host, particularly under unhealthy conditions. The present study was, therefore, undertaken to investigate the safety as well as therapeutic efficacy of probiotic Lactobacillus plantarum MTCC 5690 and L. fermentum MTCC 5689 strains in dextran sodium sulfate (DSS)-induced colitis mouse model. Both MTCC 5690 and MTCC 5689 did not induce any detrimental effect on the colitic mice, as was reflected by normal colon and caecum length, blood biochemistry, hematology, and absence of inflammation. Although translocation of both the strains was observed in extraintestinal organs, probiotic-fed mice had significantly improved intestinal permeability and decreased myeloperoxidase (MPO) activity. Probiotic interventions also led to an improved health index and better growth of colitis mice compared to colitis animals with no probiotic intervention. These results point towards the safe use of L. plantarum MTCC 5690 and L. fermentum MTCC 5689 as biotherapeutics for amelioration of inflammatory conditions after establishing their efficacy in human clinical trials. PMID- 30484144 TI - Strategies for the Construction of Cassava Brown Streak Disease Viral Infectious Clones. AB - Cassava brown streak disease (CBSD) has major impacts on yield and quality of the tuberous roots of cassava in Eastern and Central Arica. At least two Potyviridae species cause the disease: Cassava brown streak virus (CBSV) and Ugandan cassava brown streak virus (UCBSV). Cloned viral genome sequences known as infectious clones (ICs) have been important in the study of other viruses, both as a means of standardising infectious material and characterising viral gene function. IC construction is often technically challenging for Potyviridae due to sequence instability in E. coli. Here, we evaluate three methods for the construction of infectious clones for CBSD. Whilst a simple IC for in vitro transcription was made for UCBSV isolate 'Kikombe', such an approach failed to deliver full-length clones for CBSV isolates 'Nampula' or 'Tanza', necessitating more complex approaches for their construction. The ICs successfully generated symptomatic infection in the model host N. benthamiana and in the natural host cassava. This shows that whilst generating ICs for CBSV is still a technical challenge, a structured approach, evaluating both in vitro and in planta transcription systems should successfully deliver ICs, allowing further study into the symptomology and virulence factors in this important disease complex. PMID- 30484145 TI - The Effect of Methyl Jasmonate and Temperature on the Transient Expression of Recombinant Proteins in Cucurbita pepo L. AB - The aim of this study is to assess the effect of methyl jasmonate (MeJA) and temperature on the valuable pharmaceuticals expression in a virus-mediated transient expression system, and so the Zuchini Yellow Mosaic Virus (ZYMV) based vector was used for transferring the GFP reporter gene and recombinant tissue plasminogen activator (rtPA) gene (K2S) to cucurbit (Cucurbita pepo L.). MeJA, temperature and time (days after inoculation), were evaluated as a factorial experiment in a completely randomized design (CRD). At first, the effect of all treatment combinations on GFP expression was assessed. At this step, the ELISA test was used to select the optimum treatment combination. ELISA method revealed the significant difference between applied treatments. The optimized treatment significantly increased the expression of rtPA compared to the control. The Real Time PCR reaction for both GFP and rtPA genes showed no significant differences between optimum and control treatments, however, transcripts of the small subunit of RuBisCO were extremely down-regulated in optimum treatment condition. Reduction in RuBisCO expression at protein level was tangible under treatment condition based on the ELISA test. Therefore, it can be inferred that suppressing the expression of RuBisCO, probably resulted in higher access of expression system to free amino acids inside the cell. In this study, MeJA has been shown to be a positive factor, but the low temperature (17 degrees C), unlike previous studies, suppressed the expression of recombinant protein unexpectedly, probably due to the incompatibility of the viral construct with low temperature. In conclusion, the use of a suitable gene construct, which is not sensitive to temperature, is likely to result in a more favorable outcome. PMID- 30484146 TI - Adipogenic and Osteogenic Differentiation of In Vitro Aged Human Mesenchymal Stem Cells. AB - Multipotent mesenchymal stem cells (MSCs) are an attractive candidate for regeneration of damaged cells, tissues, and organs. Due to limited availabilities, MSC populations must be rapidly expanded to satisfy clinical needs. However, senescence attributed to extensive in vitro expansion compromises the regenerative and therapeutic potential of MSCs. In this chapter, we describe a step-by-step protocol that aims to induce adipogenic and osteogenic differentiation of in vitro aged human MSCs and highlight noteworthy issues that may arise during the process. PMID- 30484147 TI - Analytical Grade Purification of Phycocyanin from Cyanobacteria. AB - Phycocyanin is a blue-colored pigment-protein complex that exhibits numerous biofunctions such as anti-inflammation, antioxidation, antitumor, neuroprotective effect, and immunological enhancement. Purified phycocyanin has pharmaceutical and nutraceutical applications. In addition, as a nontoxic and non-carcinogenic natural coloring agent, phycocyanin has many applications in the food and cosmetic industries. This chapter describes a protocol for extraction and analytical grade purification of phycocyanin from cyanobacteria. The purification steps include (1) extraction of phycocyanin from biomass, (2) ammonium sulfate precipitation of phycocyanin and dialysis, and (3) purification of phycocyanin by gel filtration and ion-exchange chromatography. PMID- 30484148 TI - Effect of mcl-PHA synthesis in flax on plant mechanical properties and cell wall composition. AB - The high demand for new biomaterials makes synthesis of polyhydroxyalkanoates (PHA) in plants an interesting and desirable achievement. Production of polymers in plants is an example of application of biotechnology for improving the properties of plants, e.g. industrial properties, but it can also provide knowledge about plant physiology and metabolism. The subject of the present study was an industrially important plant: flax, Linum usitatissimum L., of a fibre cultivar (cv Nike). In the study the gene encoding PHA synthase from Pseudomonas aeruginosa, fused to a peroxisomal targeting signal, was expressed in flax plants with the aim of modifying the mechanical properties of plants. Medium-chain length (mcl) hydroxy acids in flax plants from tissue cultures were detected by GC-FID and FTIR method. The introduced changes did not affect fatty acid content and composition in generated flax plants. Since mcl-PHA are known as elastomers, the mechanical properties of created plants were examined. Modified plants showed increases in the values of all measured parameters (except strain at break evaluated for one modified line). The largest increase was noted for tensile stiffness, which was 2- to 3-fold higher than in wild-type plants. The values estimated for another parameter, Young's modulus, was almost at the same level in generated flax plants, and they were about 2.7-fold higher when compared to unmodified plants. The created plants also exhibited up to about 2.4-fold higher tensile strength. The observed changes were accompanied by alterations in the expression of selected genes, related to cell wall metabolism in line with the highest expression of phaC1 gene. Biochemical data were confirmed by spectroscopic methods, which also revealed that crystallinity index values of cellulose in modified flax plants were increased in comparison to wild-type flax plants and correlated with biomechanical properties of plants. PMID- 30484149 TI - Functional Contributions of Prefoldin to Gene Expression. AB - Prefoldin is a co-chaperone that evolutionarily originates in archaea, is universally present in all eukaryotes and acts as a co-chaperone by facilitating the supply of unfolded or partially folded substrates to class II chaperonins. Eukaryotic prefoldin is known mainly for its functional relevance in the cytoplasmic folding of actin and tubulin monomers during cytoskeleton assembly. However, the role of prefoldin in chaperonin-mediated folding is not restricted to cytoskeleton components, but extends to both the assembly of other cytoplasmic complexes and the maintenance of functional proteins by avoiding protein aggregation and facilitating proteolytic degradation. Evolution has favoured the diversification of prefoldin subunits, and has allowed the so-called prefoldin like complex, with specialised functions, to appear. Subunits of both canonical and prefoldin-like complexes have also been found in the nucleus of yeast and metazoan cells, where they have been functionally connected with different gene expression steps. Plant prefoldin has also been detected in the nucleus and is physically associated with a gene regulator. Here we summarise information available on the functional involvement of prefoldin in gene expression, and discuss the implications of these results for the relationship between prefoldin structure and function. PMID- 30484150 TI - Prefoldins in Archaea. AB - Molecular chaperones promote the correct folding of proteins in aggregation-prone cellular environments by stabilizing nascent polypeptide chains and providing appropriate folding conditions. Prefoldins (PFDs) are molecular chaperones found in archaea and eukaryotes, generally characterized by a unique jellyfish-like hexameric structure consisting of a rigid beta-barrel backbone with protruding flexible coiled-coils. Unlike eukaryotic PFDs that mainly interact with cytoskeletal components, archaeal PFDs can stabilize a wide range of substrates; such versatility reflects PFD's role as a key element in archaeal chaperone systems, which often lack general nascent-chain binding chaperone components such as Hsp70. While archaeal PFDs mainly exist as hexameric complexes, their structural diversity ranges from tetramers to filamentous oligomers. PFDs bind and stabilize nonnative proteins using varying numbers of coiled-coils, and subsequently transfer the substrate to a group II chaperonin (CPN) for refolding. The distinct structure and specific function of archaeal PFDs have been exploited for a broad range of applications in biotechnology; furthermore, a filament forming variant of PFD has been used to fabricate nanoscale architectures of defined shapes, demonstrating archaeal PFDs' potential applicability in nanotechnology. PMID- 30484151 TI - Role of the PAQosome in Regulating Arrangement of Protein Quaternary Structure in Health and Disease. AB - The PAQosome, formerly known as the R2TP/PFDL complex, is an eleven-subunit cochaperone complex that assists HSP90 in the assembly of numerous large multisubunit protein complexes involved in essential cellular functions such as protein synthesis, ribosome biogenesis, transcription, splicing, and others. In this review, we discuss possible mechanisms of action and role of phosphorylation in the assembly of client complexes by the PAQosome as well as its potential role in cancer, ciliogenesis and ciliopathies. PMID- 30484152 TI - The Multiple Functions of the PAQosome: An R2TP- and URI1 Prefoldin-Based Chaperone Complex. AB - The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92. The R2TP complex is conserved among eukaryotes and has been comprehensively studied over the last 13 years. The R2TP complex is known for its involvement in the assembly and stabilization of L7Ae ribonucleoproteins, U5 small nuclear ribonucleoprotein, RNA polymerase II, phosphatidylinositol-3-kinase related proteins (PIKKs), and the tuberous sclerosis complex (TSC1-TSC2). By contrast, the URI1 prefoldin complex has evolved exclusively in higher metazoans. Although the URI1 prefoldin complex was initially reported more than 15 years ago, little is known about its function and its role within the PAQosome. Given that URI1 is overexpressed in many types of cancer, it is surprising that the URI1 prefoldin complex has been overlooked. This chapter provides an update on the recent progress uncovering the physiological roles of each PAQosome subunit and provides an overview of the potential functions of the URI1 prefoldin complex. PMID- 30484153 TI - Advances on the Structure of the R2TP/Prefoldin-like Complex. AB - Cellular stability, assembly and activation of a growing list of macromolecular complexes require the action of HSP90 working in concert with the R2TP/Prefoldin like (R2TP/PFDL) co-chaperone. RNA polymerase II, snoRNPs and complexes of PI3 kinase-like kinases, a family that includes the ATM, ATR, DNA-PKcs, TRAPP, SMG1 and mTOR proteins, are among the clients of the HSP90-R2TP system. Evidence links the R2TP/PFDL pathway with cancer, most likely because of the essential role in pathways commonly deregulated in cancer. R2TP forms the core of the co cochaperone and orchestrates the recruitment of HSP90 and clients, whereas prefoldin and additional prefoldin-like proteins, including URI, associate with R2TP, but their function is still unclear. The mechanism by which R2TP/PFLD facilitates assembly and activation of such a variety of macromolecular complexes is poorly understood. Recent efforts in the structural characterization of R2TP have started to provide some mechanistic insights. We summarize recent structural findings, particularly how cryo-electron microscopy (cryo-EM) is contributing to our understanding of the architecture of the R2TP core complex. Structural differences discovered between yeast and human R2TP reveal unanticipated complexities of the metazoan R2TP complex, and opens new and interesting questions about how R2TP/PFLD works. PMID- 30484155 TI - Roles and Functions of the Unconventional Prefoldin URI. AB - Almost 15 years ago, the URI prefoldin-like complex was discovered by Krek and colleagues in immunoprecipitation experiments conducted in mammalian cells with the aim of identifying new binding partners of the E3 ubiquitin-protein ligase S phase kinase-associated protein 2 (SKP2) (Gstaiger et al. Science 302(5648):1208 1212, 2003). The URI prefoldin-like complex is a heterohexameric chaperone complex comprising two alpha and four beta subunits (alpha2beta4). The alpha subunits are URI and STAP1, while the beta subunits are PFDN2, PFDN6, and PFDN4r, one of which is probably present in duplicate. Elucidating the roles and functions of these components in vitro and in vivo will help to clarify the mechanistic behavior of what appears to be a remarkably important cellular machine. PMID- 30484154 TI - Role of the Unconventional Prefoldin Proteins URI and UXT in Transcription Regulation. AB - The Unconventional prefoldin RPB5 interacting protein (URI), also known as RPB5 Mediating Protein (RMP) has been shown to play several regulatory roles in different cellular compartments including the mitochondria, as a phosphatase binding protein; in the cytoplasm, as a chaperone-like protein; and in the nucleus, as a transcriptional regulator through binding to RPB5 and RNA polymerase II (polII). This chapter focuses on the role URI plays in transcriptional regulation in the prostate cell. In prostate cells, URI is tightly bound to another prefoldin-like protein called UXT, a known androgen receptor (AR) cofactor. Part of a multiprotein complex, URI and UXT act as transcriptional repressors, and URI regulates KAP1 through PP2A phosphatase activity. The discovery of the interaction of URI and UXT with KAP1, AR, and PP2A, as well as the numerous interactions between URI and components of the R2TP/prefoldin-like complex, RPB5, and nuclear proteins involved in DNA damage response, chromatin remodeling and gene transcription, reveal a pleiotropic effect of the URI/UXT complex on nuclear processes. The mechanisms by which URI/UXT affect transcription, chromatin structure and regulation, and genome stability, remain to be elucidated but will be of fundamental importance considering the many processes affected by alterations of URI/UXT and other prefoldins and prefoldin-like proteins. PMID- 30484156 TI - The Yeast Prefoldin Bud27. AB - Bud27 and its human orthologue URI (unconventional prefoldin RPB5-interactor) are members of the prefoldin (PFD) family of ATP-independent molecular chaperones binding the Rpb5 subunit to all three nuclear eukaryotic RNA polymerases (RNA pols). Bud27/URI are considered to function as a scaffold protein able to assemble additional members of the prefoldin (PDF) family in both human and yeast. Bud27 and URI are not subunits of the canonical PFD/GimC complex and not only the composition but also other functions independent of the PFD/GimC complex have been described for Bud27 and URI. Bud27 interacts only with Pfd6 but no other components of the R2TP/PFDL. Furthermore previously reported interaction between Bud27 and Pfd2 was not later confirmed. These results point to major differences in the prefoldin-like complex composition between yeast and other organisms, suggesting also important differences in functions. Furthermore, this assumption could be extended to the R2TP/PFDL complex, which has been shown to differ between different organisms and has not been identified in yeast. This casts doubt on whether Bud27 cooperation with prefoldin and other components of the R2TP/PFDL modules are required for its action. This could be extended to URI and point to a role of Bud27/URI in cell functions more relevant than this previously proposed as co-prefoldin. PMID- 30484157 TI - Structure and Function of the Cochaperone Prefoldin. AB - Molecular chaperones are key players in proteostasis, the balance between protein synthesis, folding, assembly and degradation. They are helped by a plethora of cofactors termed cochaperones, which direct chaperones towards any of these different, sometime opposite pathways. One of these is prefoldin (PFD), present in eukaryotes and in archaea, a heterohexamer whose best known role is the assistance to group II chaperonins (the Hsp60 chaperones found in archaea and the eukaryotic cytosolic) in the folding of proteins in the cytosol, in particular cytoskeletal proteins. However, over the last years it has become evident a more complex role for this cochaperone, as it can adopt different oligomeric structures, form complexes with other proteins and be involved in many other processes, both in the cytosol and in the nucleus, different from folding. This review intends to describe the structure and the many functions of this interesting macromolecular complex. PMID- 30484158 TI - Comparative analysis of the gut microbiota in distinct statin response patients in East China. AB - Statin response shows great interindividual variations. Recently, emerging studies have shown that gut microbiota is linked to therapeutic responses to drugs, including statins. However, the association between the gut bacteria composition and statin response is still unclear. In this study, gut microbiota of 202 hyperlipidemic patients with statin sensitive (SS) response and statin resistant (SR) response in East China were investigated by high throughput sequencing to compare the gut bacteria composition and biodiversity in distinct statin response patients. Higher biodiversity was detected in Group SS than Group SR. Specifically, group SS showed significantly increased proportion of genera Lactobacillus (P = 0.001), Eubacterium (P = 0.004), Faecalibacterium (P = 0.005), and Bifidobacterium (P = 0.002) and decreased proportion of genus Clostridium (P = 0.001) compared to Group SR. The results indicated that higher gut biodiversity was associated with statin sensitive response. The increased genera Lactobacillus, Eubacterium, Faecalibacterium, Bifidobacterium, and decreased genus Clostridium in patient gut microbiota may predict patient's statin response, and hence may guide statin dosage adjustments. PMID- 30484159 TI - Water-based extracts of Zizania latifolia inhibit Staphylococcus aureus infection through the induction of human beta-defensin 2 expression in HaCaT cells. AB - Zizania latifolia is a perennial herb belonging to the family Gramineae that has been used as a health food in Asian countries. In this study, we investigated the antimicrobial effect of Z. latifolia, which increased human beta-defensin 2 (hBD2) expression in HaCaT cells. hBD2 expression was further increased in cells treated with Z. latifolia extracts and subsequently infected with Staphylococcus aureus. Inversely, S. aureus infection decreased after treatment. The induction of hBD2 in HaCaT cells was mediated by the Toll-like receptor 2 (TLR2) signaling pathway, including the activation of extracellular signal-regulated kinase (ERK) and activator protein 1 (AP-1). Further study using siRNA revealed that hBD2 played an important role in the inhibition of S. aureus infection in HaCaT cells. Our data suggest that Z. latifolia extracts can be used as an antimicrobial ingredient for skin treatment formulas. PMID- 30484160 TI - Prevalence of human Norovirus by genotype in contaminated groundwater in Korea over the last decade (2007-2016). AB - This study investigated the occurrence of human Norovirus (HuNoV) by genotype in 1,486 groundwater samples collected from 843 groundwater wells suspected of contamination during 2007-2016, in South Korea. We identified and genotyped 186 HuNoV sequences in 178 HuNoV-positive samples using the RIVM-NoroNet norovirus genotyping tool (NGT) and phylogenetic tree analysis based on RIVM-NoroNet reference sequences. HuNoV GII was more prevalent than GI. The major genotypes detected were HuNoV GII.4 (43.0%), GII.22 (15.6%), GI.5 (10.2%), and GI.1 (8.6%); several genotypes accounted for < 5.0% of all HuNoVs, including GII.17, GI.6, GI.4, GII.6, GI.8, GII.3, GII.13, GI.3, GI.7, GI.2, GI.9, GII.1, GII.8, and GII.10. The prevalence of HuNoVs and number of genotypes detected has drastically decreased over the last decade. HuNoV GII.17, the emerging genotype worldwide including Europe and Asia, appeared in Korean groundwater from 2010, dominated in 2013-2014, and continued to be observed. HuNoV GII.4, the major type occurred last decade from Korean groundwater except 2013-2014, continued to be detected and prevalent similar to HuNoV GII.17 in 2016. PMID- 30484161 TI - Revisiting pollinating Cyclocephala scarab beetles (Coleoptera: Melolonthidae: Dynastinae) associated with the soursop (Annona muricata, Annonaceae). AB - The soursop (Annona muricata L., Annonaceae) is an important fruit crop in several countries of South America, including Brazil, and the presence of the scarab beetles in this orchads can reduce pollination deficits and increase the productivity. For this reason, we report Cyclocephala celata Dechambre, 1980 as a flower visitor and potential pollinator of the soursop. Additionally, this work presents an updated list of Cyclocephala species found on A. muricata, corrects some misidentifications, and provides comments and an identification key for all taxa cited as floral visitors of this crop. PMID- 30484162 TI - A Research Note on the Prevalence of Housing Eviction Among Children Born in U.S. Cities. AB - A growing body of research suggests that housing eviction is more common than previously recognized and may play an important role in the reproduction of poverty. The proportion of children affected by housing eviction, however, remains largely unknown. We estimate that one in seven children born in large U.S. cities in 1998-2000 experienced at least one eviction for nonpayment of rent or mortgage between birth and age 15. Rates of eviction were substantial across all cities and demographic groups studied, but children from disadvantaged backgrounds were most likely to experience eviction. Among those born into deep poverty, we estimate that approximately one in four were evicted by age 15. Given prior evidence that forced moves have negative consequences for children, we conclude that the high prevalence and social stratification of housing eviction are sufficient to play an important role in the reproduction of poverty and warrant greater policy attention. PMID- 30484163 TI - Nonlabor Income and Age at Marriage: Evidence From China's Heating Policy. AB - We exploit China's heating policy to investigate how nonlabor income affects marriage. From the mid-1950s, the policy gave substantial subsidies to urban residents north of the Huai River. Applying geographic regression discontinuity, we find that with the policy, urban men in the north married 15 months earlier than men in the south. The difference is substantial given that the average age at first marriage is 24.9 years for urban men in the south. The effect is larger for later birth cohorts, which is consistent with the progressive implementation of the policy. The effect is smaller among women, consistent with women having less power in the household than men. There is no effect among rural residents, who did not benefit from the heating policy. PMID- 30484164 TI - A survey of mentor gender preferences amongst anesthesiology residents at the University of British Columbia. PMID- 30484165 TI - A friend in need: evaluating the impact of Lifebox in Burkina Faso. PMID- 30484166 TI - Evaluation de l'impact du projet Lifebox au Burkina Faso sur la pratique de l'oxymetrie pulsee et la check-list de l'organisation mondiale de la sante pour la securite du patient au bloc operatoire. PMID- 30484167 TI - The perioperative patient on buprenorphine: a systematic review of perioperative management strategies and patient outcomes. AB - BACKGROUND: An increasing number of patients with opioid use disorder (OUD) are treated with opioid agonist-antagonists such as buprenorphine/naloxone. Perioperative management of patients on buprenorphine/naloxone is inconsistent and remains a controversial topic with mismanagement posing a significant risk to the long-term health of these patients. METHODS: We performed a systematic literature search involving Medline, Medline In-Process, Embase, Cochrane Central, Cochrane Database of Systematic Reviews, PsycINFO, Web of Science (Clarivate), Scopus (Elsevier), CINAHL (EbscoHosst), and PubMed (NLM). RESULTS: Eighteen studies were included in the final sample, including one controlled study and four observational studies . Neither the controlled study nor the observational studies assessed addiction treatment retention, harm reduction, or long-term mortality rates as primary or secondary outcomes. Of the observational studies, authors showed equivalent peri- and postoperative pain control among buprenorphine continued patients. All but one authors described adequate analgesia among the case reports in which buprenorphine <= 16 mg sublingually (SL) daily was continued during the perioperative period. Long-term harm reduction was not reported with only three case reports including any long-term abstinence or relapse rates. CONCLUSIONS: The current understanding of the risks and benefits of continuing or stopping buprenorphine perioperatively is limited by a lack of high-quality evidence. Observational studies and case reports indicate no evidence against continuing buprenorphine perioperatively, especially when the dose is < 16 mg SL daily. In patients with significant potential for relapse, such as those with a recent history of OUD, the discontinuation of buprenorphine should have a strong rationale supported by patient and surgical preferences. Future studies require standardized reporting of median doses, details on the route of delivery, dosing schedules and any dosing changes, and rates of addiction relapse, including long-term morbidity and mortality where possible. PMID- 30484168 TI - The need to collect, aggregate, and analyze global anesthesia and surgery data. AB - In the Sustainable Development Goals era, there is a new awareness of the need for an integrated approach to healthcare interventions and a strong commitment to Universal Health Coverage. To achieve the goal of strengthening entire health systems, surgery, as a crosscutting treatment modality, is indispensable. For any health system strengthening exercise, baseline data and longitudinal monitoring of progress are necessary. With improved data capabilities, there are unparalleled possibilities to map out and understand systems, integrating data from many sources and sectors. Nevertheless, there is also a need to prioritize among indicators to avoid information overload and data collection fatigue. There is a similar need to define indicators and collection methodology to create standardized and comparable data. Finally, there is a need to establish data pathways to ensure clear responsibilities amongst national and international institutions and integrate surgical metrics into existing mechanisms for sustainable data collection. This is a call to collect, aggregate, and analyze global anesthesia and surgery data, with an account of existing data sources and a proposed way forward. PMID- 30484169 TI - Alstrom Syndrome Presenting as Isolated Dilated Cardiomyopathy. AB - Cardiomyopathy is an etiologically heterogeneous condition, and non-syndromic as well as syndromic genetic causes are identified in a significant proportion of cases without a known acquired cause. The present report describes a 2-mo-old boy who presented initially with a referral diagnosis of isolated dilated cardiomyopathy, without any associated dysmorphism or malformations, and with history of similar cardiac disease and early infantile death in an elder male sibling. Next generation sequencing (NGS) based multigene panel testing of the cardiomyopathy-associated genes was done which revealed the diagnosis of Alstrom syndrome, based on which appropriate management and surveillance could be planned for the child and accurate genetic counseling could be provided to the parents. This report reiterates the fact that genetic testing for cardiomyopathy without an obvious acquired cause helps in identification of the underlying etiology, appropriate management, early diagnosis of syndromic forms, and monitoring and pre-symptomatic intervention for associated extracardiac complications. PMID- 30484170 TI - Correction to: A Practical Guide to Molecular Dynamics Simulations of DNA Origami Systems. AB - Correction to: Chapter 15 in: Giampaolo Zuccheri (ed.), DNA Nanotechnology: Methods and Protocols, Methods in Molecular Biology, vol. 1811, https://doi.org/10.1007/978-1-4939-8582-1_15. PMID- 30484171 TI - Correction to: Optimised isolation method for RNA extraction suitable for RNA sequencing from feline teeth collected in a clinical setting and at post mortem. AB - The authors regret that the original version of the above article contained errors in the Figs. 3, 4 and Tables 3 legends. The errors has been corrected. PMID- 30484172 TI - A Letter to the Editor: Boerhave Syndrome After BIB Gastric Baloon Implantation-a Unique Complication. PMID- 30484173 TI - Revisional Gastric Bypass After Failed Adjustable Gastric Banding-One-Stage or Two-Stage Procedure? AB - BACKGROUND: Revisional laparoscopic Roux-en-Y gastric bypass (R-LRYGB) is the preferred procedure after failed adjustable gastric banding. Little is known about whether a one-stage procedure (one surgery for band removal and R-LRYGB) or a two-stage procedure (first band removal and later R-LRYGB) is superior. Aim of this study is to compare early- and long-term results of both methods at our institution. METHODS: Retrospective analysis of 165 (m 26/f 139) consecutive patients (98 one-stage, 67 two-stage) with R-LRYGB. Mean follow-up time was 50.1 +/- 38.8 months. Indications for one-stage vs. two-stage procedures, operating time, peri- and postoperative complications, morbidity, mortality, and length of stay (LOS) were analyzed. Data are reported as total numbers (%) and mean +/- standard deviation. RESULTS: Mean age at R-LRYGB was 43.9 +/- 10.7 vs. 44.3 +/- 10.7 years with a BMI of 37.1 +/- 6.8 vs. 39.8 +/- 7.1 (one-stage vs. two-stage). In the one-stage group, the main indication for revisional surgery was weight regain (57.1%), followed by dilatation of the esophagus or pouch (37.7%) and gastroesophageal reflux disease (GERD) (36.7%), whereas in the two-stage group, it was band erosion (52.2%) and dilatation of the esophagus or pouch (17.9%) and GERD (11.9%). There was no significant difference in operative time (208.5 +/- 61.2 vs. 206.3 +/- 73.5 min), LOS (8.6 +/- 3.4 vs. 9.3 +/- 5.7 days) or mortality (0% overall). Major complications (Clavien-Dindo >= IIIa) occurred similarly often in both groups: 15.3% vs. 16.9% (one-stage vs. two-stage). CONCLUSION: Both approaches achieve good results. However, the one-stage R-LRYGB is the preferable procedure because it reduces costs and LOS by doing without an additional surgical procedure. PMID- 30484174 TI - Safety and Efficacy of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Used for Analgesia After Bariatric Surgery: A Retrospective Case-Control Study. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are cornerstone in multimodal analgesia protocols. This point is of great value in morbidly obese patients due to the high prevalence of restrictive pulmonary disease and obstructive sleep apnea. The aim of this study was to test the hypothesis that NSAIDs do not increase acute bariatric surgery complications while optimizing postoperative analgesia. METHODS: Databases of two medical centers were retrospectively reviewed to find all patients who underwent bariatric surgery between 1 January 2017 and 31 December 2017. Inclusion criteria were BMI greater than 30 kg/m2 and age of 16-75 years old. Patients who suffered from severe organ failure or coagulation disorders were excluded. Patient's demographics, obesity related diseases (diabetes, hypertension, dyslipidemia), postoperative pain scores, and morphine consumption in PACU, as well as early and late surgical complications, were collected. Patients included from the first institution (where NSAIDs analgesia was prohibited: control group) were compared to patients from the second institution (where NSAIDs analgesia was mandatory: case group). RESULTS: The study population included 270 patients, 134 in the control group, and 136 in the case group. NSAIDs usage produced better analgesia with significant reduction in morphine consumption and PACU length of stay. Also, incidence of surgical complications was the same in the two groups. CONCLUSIONS: NSAIDs administration do not increase postoperative complication rate after bariatric surgery. Although NSAID administration provided better analgesia and shorter PACU stay, future prospective studies are needed to confirm these encouraging results and to evaluate their impact on postoperative rehabilitation. PMID- 30484175 TI - Diagnosis of ethmoid sinolith by cone-beam computed tomography: case report and literature review. AB - INTRODUCTION: The aim of this study was to report the first case of diagnosis of a rare ethmoid sinolith by cone-beam computed tomography (CBCT) and discuss the importance of carefully assessing the entire volume of the images regardless of the region of interest. CASE PRESENTATION: A 22-year-old woman underwent CBCT examination to assess the upper permanent canine teeth. Analysis of the entire volume of CBCT revealed an oval-shaped hyperdense, homogeneous, expansive formation with defined boundaries located in the ethmoid bone. The differential diagnosis of a sinolith in the ethmoid sinus was confirmed after removal of the lesion by nasoendoscopy and histopathological examination. CONCLUSION: The diagnosis of lesions in the ethmoid sinus is challenging because of the complex anatomy of this region. Considering the limitations of two-dimensional X-ray examination, CBCT examination has become an important imaging modality for the diagnosis of these calcifications. In addition, the ability of the dental surgeon to assess the entire volume of the CBCT images and the knowledge of imaging features of these calcifications allows for recognition of incidental findings, facilitating early diagnosis and appropriate treatment. PMID- 30484176 TI - Prediction of malignancy of submandibular gland tumors with apparent diffusion coefficient. AB - OBJECTIVE: This study was performed to predict malignancy of submandibular gland tumors using the apparent diffusion coefficient (ADC). METHODS: In total, 31 patients (19 male, 12 female; age, 16-71 years) with solid submandibular gland tumors were retrospectively analyzed. All patients underwent single-shot echo planar diffusion-weighted magnetic resonance imaging of the submandibular gland region. ADC maps of the submandibular gland were reconstructed. The ADC value of the submandibular gland tumors was calculated. A freehand region of interest encompassing the homogenous tumor and solid part of the heterogeneous tumor was established. RESULTS: The mean ADC for submandibular gland malignancy (1.15 +/- 0.09 * 10-3 mm2/s) was significantly lower than that for benignancy (1.55 +/- 0.25 * 10-3 mm2/s, P = 0.001). An ADC of 1.26 * 10-3 mm2/s could predict malignancy of submandibular gland tumors with an area under the curve of 0.869, accuracy of 84%, sensitivity of 88%, and specificity of 81%. CONCLUSION: The ADC is a noninvasive imaging parameter that can be used for prediction of malignancy of submandibular gland tumors. PMID- 30484177 TI - Foreign body removal assisted by an intraoral ultrasound probe. AB - Ultrasonography has recently been applied to the field of oral and maxillofacial surgery because of its noninvasiveness and ease of use. However, traditional transducers are not used in the intraoral area because of their large size. A novel intraoral transducer was introduced with size, volume, and axis modifications. This new transducer allows the surgeon to approach the intraoral region during dental procedures. This report describes a case of successful removal of a foreign body using the newly developed intraoral ultrasound probe. Precise localization and minimally invasive removal of the foreign body using the intraoral transducer were simultaneously conducted. Because of its many advantages, this intraoral ultrasound transducer has the potential to be applied in oral and maxillofacial surgery. PMID- 30484178 TI - Evaluation of permanent and primary enamel and dentin mineral density using micro computed tomography. AB - OBJECTIVES: The present study was performed to investigate the mineral density distribution in enamel and dentin for both permanent and primary teeth and to establish the standard density per tooth type using micro-computed tomography (CT). METHODS: Fifty-seven extracted human teeth (37 permanent, 20 primary) were evaluated in the present study. The enamel and dentin mineral densities in the extracted teeth were measured using micro-CT. Cubic regression curves were used to determine the mineral density distribution in the enamel and dentin for each tooth type. RESULTS: The mean values, distributions, and regression equations of the mineral densities were obtained. The mean mineral density values for permanent enamel and dentin were significantly higher than those for their primary counterparts for each tooth type. CONCLUSIONS: In the present study, we demonstrated the distribution of mineral density in sound enamel and dentin and attempted to determine the standard mineral density for each tooth type using micro-CT. The mineral density distributions found in this study contribute to our understanding of the mechanical properties of enamel and dentin. A positive correlation suggests that the systemic bone mineral density could be predicted based on the analysis of exfoliated teeth, such as in patients with hypophosphatasia. The present results may be useful in establishing a numerical standard for the mechanism involved in root fracture and for early detection of root fracture risk. PMID- 30484179 TI - Evaluation of trabecular pattern of mandible using fractal dimension, bone area fraction, and gray scale value: comparison of cone-beam computed tomography and panoramic radiography. AB - OBJECTIVE: This study was performed to compare the fractal dimension (FD), bone area fraction (BAF), and gray scale value (GSV) on digital panoramic radiography (DPR) and cross-sectional cone-beam computed tomography (CBCT) using image analysis and to determine whether a relationship exists among parameters associated with bone quality. METHODS: Thirty edentulous human hemimandibles were scanned by DPR and CBCT. Ninety regions of interest (ROIs) were evaluated on DPR and CBCT images to calculate the FD and BAF. The GSV of the ROI on CBCT was also calculated. RESULTS: Statistically significant differences were observed in the FD values of the ROIs between DPR and CBCT (p = 0.002) and in the BAF values of ROIs between DPR and CBCT (p = 0.017). The Spearman's correlation test revealed a statistically significant high correlation between the FD and BAF values of the ROIs on DPR and between the FD and BAF values of the ROIs on CBCT (p < 0.01). No significant correlations were observed between the GSVs of ROIs on CBCT and the FD values of ROIs on DPR, the BAF values of ROIs on DPR, the FD values of ROIs on CBCT, and the BAF values of ROIs on CBCT (p > 0.05). CONCLUSIONS: The GSV did not support the FD and BAF. Additionally, DPR and CBCT did not have similar image quality for assessing the FD, BAF, and GSV. In evaluating the trabecular structure, the use of panoramic radiographs should be continued because the image resolution of CBCT is lower and its generalized dose is higher than that of panoramic radiography. These results may serve as a reference for clinical practitioners using dental CBCT to analyze the trabecular structures of alveolar bones. PMID- 30484180 TI - Retrograde superselective intra-arterial chemoradiotherapy combined with hyperthermia and cetuximab for carcinoma of the buccal mucosa with N3 lymph node metastasis: a case report. AB - We herein report a case of squamous cell carcinoma of the buccal mucosa with N3 cervical lymph node metastasis in a 63-year-old man. The patient was treated with combination therapy comprising radiotherapy (2 Gy/day, total of 70 Gy), superselective intra-arterial chemotherapy via a superficial temporal artery (docetaxel, total of 70 mg/m2 and cisplatin, total of 175 mg/m2), cetuximab (initial dose of 400 mg/m2 with subsequent weekly doses of 250 mg/m2 intravenously), and four sessions of hyperthermia for cervical lymph node metastases. The patient responded well to the therapy, with a complete response of the primary tumor. Radical neck dissection was performed with reconstructive surgery, including resection of the overlying skin. A pathologic complete response was achieved for the N3 and all other cervical lymph node metastases. The patient showed no evidence of recurrence in the 3 years following treatment. Based on the findings in the present case, the use of retrograde superselective intra-arterial chemoradiotherapy combined with hyperthermia and cetuximab seems to be a promising modality for patients with N3 cervical lymph node metastasis of oral cancer. PMID- 30484181 TI - Trabecular structure designation using fractal analysis technique on panoramic radiographs of patients with bisphosphonate intake: a preliminary study. AB - OBJECTIVE: This study was performed to evaluate the trabecular pattern of patients with cancer taking bisphosphonates on panoramic images using fractal dimension (FD) analysis by comparison with healthy subjects and to assess whether any difference exists between regions. METHODS: FD analysis was conducted using ImageJ 1.3 software (National Institutes of Health, Bethesda, MD, USA) with the box-counting method on panoramic radiographs of 33 patients taking bisphosphonates (13 males and 20 females) and 33 healthy sex- and age-matched individuals. RESULTS: FD values were higher (1.39 +/- 0.14) in the study group than control group (1.38 +/- 0.07) (p <= 0.05). No difference was detected in the FD values among the tested regions. The mean FD values in the control and study groups were as follows: region 1, 1.49 and 1.41 (p = 0.54); region 2, 1.36 and 1.37 (p = 0.84); region 3, 1.35 and 1.42 (p = 0.11); and region 4, 1.39 and 1.39 (p = 0.90), respectively. Female patients showed significantly lower values above the mandibular canal on the distal side of the second premolar and anterior to the mental foramen than did male patients (p <= 0.05). Age was unrelated to the FD in the study group (p >= 0.05). CONCLUSIONS: The FD values of the patients with cancer taking bisphosphonates were higher than those of the controls. FD analysis showed the potential for examining bone structure in panoramic radiographs. Studies with a larger sample size are necessary to confirm these results. PMID- 30484182 TI - Assessment of aging characteristics of female condylar trabecular structure by cone-beam computed tomography. AB - OBJECTIVES: This study was performed to analyze the aging-related changes of the female condylar bone mineral density (BMD) and trabecular structure by cone-beam computed tomography (CBCT), and determine whether the condylar structure shows obvious changes after menopause. METHODS: The CBCT images of 160 female patients who met the inclusion criteria for the study were collected and divided into four groups by age (20-29 years, 30-39 years, premenopausal, and postmenopausal groups). Computer processing software CT-Analyser (Version 1.15.2.2+; SkyScan, Antwerp, Belgium) was used to measure the condylar BMD and related indexes, namely the bone volume/tissue volume ratio (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), trabecular structure model index (SMI), and bone surface area/volume ratio (BS/BV). SPSS 12.0 (SPSS Inc., Chicago, IL, USA) was used to analyze the radiographic findings and statistical differences. RESULTS: No significant differences were found between the bilateral condyles in each group (P > 0.05). BV/TV, Tb.N, and Tb.Th of the condyle decreased with age, and the postmenopausal group showed significantly different values for each index compared with the other groups (P < 0.01). Tb.Sp, SMI, and BS/BV of the condyle increased with age, and the postmenopausal group showed significantly different values for each index compared with the other groups (P < 0.01). CONCLUSIONS: With increasing age, the female condylar bone volume decreases, the Tb.N and Tb.Th decrease, the gap between the trabecular bone increases, and plate-like trabecular bone gradually transforms into a rod like form. These changes are much more obvious in postmenopausal women. PMID- 30484183 TI - Evaluation of cone-beam computed tomography diagnostic image quality using cluster signal-to-noise analysis. AB - OBJECTIVES: (1) We sought to assess correlation among four representative parameters from a cluster signal-to-noise curve (true-positive rate [TPR] corresponding to background noise, accuracy corresponding to background noise, maximum TPR, and maximum accuracy) and the diagnostic accuracy of the identification of the mandibular canal using data from observers in a previous study, under the same exposure conditions. (2) We sought to clarify the relationship between the hole depths of a phantom and diagnostic accuracy. METHODS: CBCT images of a Teflon plate phantom with holes of decreasing depths from 0.7 to 0.1 mm were analyzed using the FindFoci plugin of ImageJ. Subsequently, we constructed cluster signal-to-noise curves by plotting TPRs against false-positive rates. The four parameters were assessed by comparing with the diagnostic accuracy calculated from the observers. To analyze image contrast ranges related to detection of mandibular canals, we determined five ranges of hole depths, to represent different contrast ranges-0.1-0.7, 0.1-0.5, 0.2-0.6, 0.2-0.7 and 0.3-0.7 mm-and compared them with observers' diagnostic accuracy. RESULTS: Among the four representative parameters, accuracy corresponding to background noise had the highest correlation with the observers' diagnostic accuracy. Hole depths of 0.3-0.7 and 0.1-0.7 mm had the highest correlation with observers' diagnostic accuracy in mandibles with distinct and indistinct mandibular canals, respectively. CONCLUSIONS: The accuracy corresponding to background noise obtained from the cluster signal-to-noise curve can be used to evaluate the effects of exposure conditions on diagnostic accuracy. PMID- 30484184 TI - Evaluation of condyle position in patients with Angle Class I, II, and III malocclusion using cone-beam computed tomography panoramic reconstructions. AB - OBJECTIVES: This study was performed to compare the positions of the right and left condyles between male and female patients with different Angle malocclusions using cone-beam computed tomography (CBCT) panoramic reconstructions. METHODS: The CBCT images of 60 patients (age of 18-37 years) were retrospectively evaluated. The patients were divided according to their Angle malocclusion classifications (Angle Classes I, II, and III). The condyle-to-eminence, condyle to-fossa, and condyle-to-meatus distances were measured digitally using i-CAT software. RESULTS: The left and right condyle-to-fossa distances were the most variable parameters among the Angle classes. The right condyle-to-eminence and right condyle-to-fossa distances were significantly different among the classes. Male patients seemed to have a greater condyle-to-fossa distance on the right side in both the Class I and III groups. The mean distance from the condyle to eminence, condyle to fossa, and condyle to meatus on the right side was the greatest in the Angle Class II group. CONCLUSIONS: In all three types of malocclusion (Angle Classes I, II, and III), the condyles on both the right and left sides were not exactly symmetric or centrally located within the glenoid fossa. This work emphasizes the differences in the condyle position between male and female patients. Furthermore, the symmetry and centricity of the condyles are not dependent on the patient's sex or type of malocclusion. PMID- 30484185 TI - Trabecular structural changes in the mandibular condyle caused by degenerative osteoarthritis: a comparative study by cone-beam computed tomography imaging. AB - OBJECTIVES: Temporomandibular osteoarthritis causes pain and loss of function. In advanced cases, it may also result in destruction of joint cartilage surfaces and bone structure. METHODS: This study was performed to examine the potential changes in the condylar trabecular bone structure in patients with temporomandibular osteoarthritis. Condylar trabecular structures were compared between 35 healthy patients and 35 patients with temporomandibular osteoarthritis by a box-counting method using fractal dimensional analysis on cone-beam computed tomography images. RESULTS: The average fractal dimensions of patients with temporomandibular osteoarthritis and healthy patients were 1.18 and 1.23, respectively. This difference was statistically significant (p <= 0.05). CONCLUSIONS: Our results add to the existing preliminary knowledge regarding the osteoporotic changes that occur in the trabecular structure under the subchondral bone, which is normally not seen on radiographic images, as well as the destruction and remodeling that occur on the condyle surface, which is visible on radiographic images. PMID- 30484186 TI - Morphology, incidence of bridging, and dimensions of sella turcica in different racial groups. AB - OBJECTIVES: This study was performed to assess the morphological appearance, incidence of bridging, and linear dimensions of the sella turcica (ST) in Bosnian and Iraqi subjects, and to identify associations of sex, age, and racial group with the size of the ST. METHODS: The digital standardised lateral cephalograms of 360 Bosnian and Iraqi patients (116 female, 64 male; age range 8-28 years) were retrospectively analysed. The following ST-related parameters were analysed on the lateral cephalograms: sella morphology, sella bridging, and sella size. The data were correlated with sex, age, and race. RESULTS: The ST exhibited a normal morphology in most subjects of both races (86.7%). The frequency of partial bridging was found in 38.9 and 37.2% of Bosnian and Iraqi subjects, respectively. A significant correlation was detected between the length of the ST and sex in both the Bosnian and Iraqi subjects (p < 0.05). A direct correlation was present between patient age and the size of the ST in both races at the 0.01 and 0.001 levels for depth, length, and diameter. When race was compared with sella size, a significant difference was found in the length and depth of the ST (p < 0.001). CONCLUSIONS: Similarities were found between Bosnian and Iraqi subjects in the morphology, incidence of bridging, and linear dimensions of the ST. Length was the only parameter significantly associated with sex, age, and racial group. These findings could be used as reference standards for studying the ST in both races. PMID- 30484187 TI - Incidental findings during head and neck MRI screening in 1717 patients with temporomandibular disorders. AB - OBJECTIVE: Magnetic resonance imaging (MRI) plays an important role in the evaluation of temporomandibular disorders (TMDs). At our institution, we perform additional head and neck screening using head coils when performing MRI screening of the temporomandibular joint (TMJ) to detect lesions in areas other than the TMJ (lesions discovered by chance, or incidental findings; IFs) and to conduct a diagnosis of exclusion. The objective of this study was to determine the number and frequency of IFs detected during head and neck screening, according to sites and diseases. MATERIALS AND METHODS: The study evaluated 1717 patients with clinically suspected TMDs who underwent MRI of the TMJ. IFs were assessed on horizontal sections of images of the craniofacial region obtained by the short tau inversion recovery imaging technique. RESULTS: The patients undergoing MRI of the TMJ comprised 433 males and 1284 females. Among the patients, at least one IF was detected on images in 461 patients. The most common IF site was the maxillary sinus. Based on diagnostic imaging, there were 21 IFs (1.2%) associated with TMD symptoms, or for which an association with TMD symptoms could not be ruled out. CONCLUSIONS: Combination of conventional MRI imaging of the TMJ with craniofacial MRI screening may allow detection of lesions other than TMDs, thereby confirming the usefulness of MRI. Detection of IFs may require development of different therapeutic strategies than those for TMDs. PMID- 30484188 TI - Improvement of region of interest extraction and scanning method of computer aided diagnosis system for osteoporosis using panoramic radiographs. AB - OBJECTIVES: Patients undergoing osteoporosis treatment benefit greatly from early detection. We previously developed a computer-aided diagnosis (CAD) system to identify osteoporosis using panoramic radiographs. However, the region of interest (ROI) was relatively small, and the method to select suitable ROIs was labor-intensive. This study aimed to expand the ROI and perform semi-automatized extraction of ROIs. The diagnostic performance and operating time were also assessed. METHODS: We used panoramic radiographs and skeletal bone mineral density data of 200 postmenopausal women. Using the reference point that we defined by averaging 100 panoramic images as the lower mandibular border under the mental foramen, a 400 * 100-pixel ROI was automatically extracted and divided into four 100 * 100-pixel blocks. Valid blocks were analyzed using program 1, which examined each block separately, and program 2, which divided the blocks into smaller segments and performed scans/analyses across blocks. Diagnostic performance was evaluated using another set of 100 panoramic images. RESULTS: Most ROIs (97.0%) were correctly extracted. The operation time decreased to 51.4% for program 1 and to 69.3% for program 2. The sensitivity, specificity, and accuracy for identifying osteoporosis were 84.0, 68.0, and 72.0% for program 1 and 92.0, 62.7, and 70.0% for program 2, respectively. Compared with the previous conventional system, program 2 recorded a slightly higher sensitivity, although it occasionally also elicited false positives. CONCLUSIONS: Patients at risk for osteoporosis can be identified more rapidly using this new CAD system, which may contribute to earlier detection and intervention and improved medical care. PMID- 30484189 TI - Ultrasound-guided sialo-irrigation with a saline-air mixture as the contrast medium. AB - Ultrasound (US)-guided salivary gland irrigation is a popular conservative treatment method that improves the success rate and reduces complications of the sialo-irrigation procedure. US is routinely used for evaluation of various salivary gland diseases because of its easy accessibility and absence of ionizing radiation. US also allows dynamic studies with real-time imaging during diagnostic or surgical procedures. However, conventional US images have limitations in salivary duct visualization. Although US images acquired with saline irrigation have improved visualization because of ductal system dilation by the pulling effect, the resultant image quality remains insufficient for diagnosis. Therefore, contrast agents are required during US-guided sialo irrigation procedures to produce diagnostic image quality. Air bubbles in saline solution have high echogenicity and enhance image quality by acting as a US contrast agent. The aim of this study was to assess the clinical significance of US-guided sialo-irrigation with a saline-air contrast medium, to estimate its diagnostic and treatment efficacy, and to examine the procedure in two patients. In the study, two patients underwent US-guided salivary gland irrigation with air bubble mixed saline solution. During the procedure, we were able to visualize the salivary gland duct and subsequently irrigate and clean the inside of the duct. As a result, the patients' symptoms were relieved and saline solution mixed with air bubbles was confirmed to be an effective contrast agent. PMID- 30484190 TI - Schwannoma assumedly originating from the submandibular ganglion or glandular branches radiologically mimicking a submandibular gland tumor. AB - Schwannoma is a benign nerve sheath tumor composed of Schwann cells. Schwannomas originating from ganglia are rare, and schwannomas of the submandibular ganglion or glandular branches have not been reported to date. We present a case of a Japanese woman in her sixties with a submandibular schwannoma originating from the submandibular ganglion, mimicking a submandibular gland tumor on radiological findings. As the radiological findings were nonspecific, the key finding in the present case may be the characteristic location of the tumor suspended from the undersurface of the lingual nerve and situated above the deep portion of the submandibular gland. PMID- 30484191 TI - Prevalence and characteristics of pneumatizations of the articular eminence and roof of the glenoid fossa on cone-beam computed tomography. AB - OBJECTIVE: The aim of this study was to determine the prevalence and characteristics of pneumatization of the articular tubercle (PAT) and pneumatization of the roof of the glenoid fossa (PRGF) in a large population using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: This study was designed to evaluate the CBCT images of 1000 patients. The prevalences of the pneumatizations by age, sex, locularity, and laterality were determined. The significance of differences between variables was evaluated by the Chi-square test and analysis of variance. RESULTS: PAT was detected in 28.4% of the zygomatic bone sides and PRGF in 29.6%. Bilateral PAT was detected in 176 (17.6%) patients and bilateral PRGF in 195 (19.5%). The mean age of patients with PAT was 47.33 years and that of patients with PRGF was 45.62 years. Multilocular appearance was observed significantly more often than unilocular type for both pneumatizations (p < 0.01). Unilateral PAT cases were slightly, but significantly, higher than bilateral PAT cases (p = 0.047), while no significant difference was observed between unilateral and bilateral PRGF cases. CONCLUSIONS: In conclusion, PAT and PRGF can be assessed more accurately on CBCT images than on plain radiographs. During routine radiological investigations, maxillofacial radiologists should be aware of zygomatic air cells. PMID- 30484192 TI - A case of venous malformation of the mandible. AB - OBJECTIVE: Vascular malformations occur more rarely in bones than in soft tissue, with 0.5-1.0% of all intraosseous tumors occurring in the mandible. We report a diagnostically challenging case of unilocular venous malformation of the mandible. CASE REPORT: A 76-year-old man presented with a heterogeneous, unilocular, radiolucent lesion with a well-defined border. Panoramic radiography and computed tomography imaging revealed a continuous white line on the cortical bone at the inferior border of the left mandibular molar region. A spherical lesion with a well-defined border and a clear round region in the left mandible were revealed on magnetic resonance imaging. The lesion had the same signal intensity as muscles on T1-weighted imaging, a homogeneous high-intensity signal on short T1-inversion recovery imaging, and a well-defined low-signal intensity region surrounded by a high-intensity signal region on T2-weighted imaging. Pathological findings indicated that the lesion was a venous malformation. DISCUSSION: Although many studies have reported that venous malformations have a multilocular appearance, few have described the occurrence of unilocular lesions. Future investigations using magnetic resonance imaging and computed tomography are needed to increase the diagnostic accuracy for unilocular central vascular malformations of the jaw bone. PMID- 30484193 TI - Comparison of cone-beam computed tomography with bitewing radiography for detection of periodontal bone loss and assessment of effects of different voxel resolutions: an in vitro study. AB - OBJECTIVE: The aim of the study was to compare intraoral radiographs and CBCT images for detection of horizontal periodontal bone loss, and to investigate the diagnostic effect of different voxel resolutions in CBCT imaging. METHODS: A total of 240 sites with horizontal bone loss were measured on the buccal, lingual, mesial, and distal surfaces of 60 posterior teeth in four maxillary and six mandibular bones obtained from cadavers (dry skulls). Direct measurements on the dry skulls were accepted as the gold standard values. Measurements on CBCT images at two different voxel resolutions (0.250 and 0.160 mm3) and intraoral bitewing radiographs were compared with one another and with the gold standard values. RESULTS: The measurements on the CBCT images at two voxel resolutions and bitewing radiographs did not differ significantly (p > 0.05) from the direct measurements on the dry skulls. No significant difference was found between the bitewing radiographs and CBCT images for measurements in the mesial and distal regions (p > 0.05). There was no significant difference between the measurements on the buccal and lingual surfaces at the two different voxel resolutions (p > 0.05). CONCLUSIONS: CBCT scans are recommended for evaluation of buccal and lingual bone loss to avoid intraoral radiographs that exceed routine examination of interproximal alveolar bone loss. Furthermore, instead of basing the voxel size on the required CBCT scans, it is recommended to select the smallest possible field of view to reduce the dose of radiation. PMID- 30484194 TI - Radiological analysis of the sella turcica and its correlations with body mass index in a North Indian population. AB - OBJECTIVES: The sella turcica is an important component situated in the mid-third of the cranial fossa. Knowledge about its normal morphologies and dimensions may play a crucial role in diagnosing underlying pathologies. The present study aimed to analyze the principal morphological shapes of the sella turcica, measure its linear dimensions, and determine whether any correlations exist between its dimensions and body mass index (BMI) in subjects in a North Indian population. METHODS: The study was conducted on 100 subjects (50 men; 50 women) who underwent cone-beam computed tomography scans at our Oral Medicine and Radiology Department. The subjects had an age range of 20-60 years. The morphology of the sella turcica was examined according to age and various measurements were taken to determine its size. Possible correlations between the dimensions of the sella turcica and BMI were evaluated by statistical analysis. RESULTS: In the present study, 69% of the subjects had a normal morphology. No uniform increases in length, width, and depth of the sella turcica were observed with aging. When Pearson correlation coefficients were calculated, no strong correlations were found between the dimensions of the sella turcica and BMI. A mild correlation was seen between the length and width of the sella turcica. CONCLUSION: No significant correlations were found between the dimensions of the sella turcica and BMI in the present study. These findings may have arisen through the small sample size, and thus further studies with larger groups of subjects are warranted. PMID- 30484195 TI - Protection evaluation of non-lead radiation-shielding fabric: preliminary exposure-dose study. AB - OBJECTIVES: The aim of this study was to evaluate the effectiveness and shielding performance of a novel recently developed non-lead radiation-shielding fabric containing bismuth oxide (BO-fabric). METHODS: BO-fabric was fabricated using urethane resin and bismuth nanopowder. A dose-measurement method was employed to evaluate the radiation-attenuation characteristics of the shielding fabric in accordance with the Korean Standards standard. The shielding performances (%) were calculated by measuring the radiation doses after lamination with increasing layers of fabric (1-10 layers). The physical performance of the fabric in terms of flexural and abrasion resistances was evaluated by the Korea Apparel Testing and Research Institute (KATRI). RESULTS: The radiation-attenuation capabilities of one layer of BO-fabric were 58.5, 49.9, and 43.0% at tube voltages of 60, 80, and 100 kVp, respectively. The radiation-shielding performance upon lamination of BO-fabric gradually increased as the number of layers increased. Excellent flexural and abrasion resistances were observed in the KATRI evaluation. CONCLUSIONS: A non-lead radiation-shielding fabric based on urethane resin and bismuth was fabricated and examined, revealing an excellent shielding performance. Owing to the flexibility and simple operation of the fabric, it can be employed for various designs of clothing and protective apparel with many purposes. PMID- 30484196 TI - Correction to: Extranodal lymphoma arising within the maxillary alveolus: a systematic review. AB - Owing to an unfortunate mistake at Springer's end, the original article was published with errors which are corrected with this erratum as suggested by the author. The authors are not responsible for this procedural lapse. PMID- 30484197 TI - Buccal bifurcation cyst (paradental cyst) defined by ultrasonography and cone beam computed tomography. AB - Buccal bifurcation cyst (BBC) is an uncommon inflammatory odontogenic cyst that generally occurs at the buccal region of the permanent mandibular first molars in children aged 6-8 years. The diagnosis of BBC cannot be made from the histopathologic features; therefore, diagnosis is primarily based on specific clinical and radiographic findings. In this case report, we present the clinical and radiological findings, including ultrasonography (USG) and cone-beam computed tomography (CBCT) images, of a 10-year-old boy who was referred with a complaint of swelling on the lower right jaw. According to the radiographic and clinical findings, the differential diagnosis of this lesion included lateral radicular cyst, lateral periodontal cyst, dentigerous cyst, eruption cyst, and others. Recently, in addition to classical radiographies and CBCT, USG has been considered important for diagnosis. In particular, if a cyst produces a perforation in the cortical bone, it is helpful to make a pre-diagnosis with USG. PMID- 30484198 TI - Reproducibility of CBCT image analysis: a clinical study on intrapersonal and interpersonal errors in bone structure determination. AB - OBJECTIVE: For correct implant planning based on cone-beam computed tomography (CBCT), the bone contour must be accurately determined. Identification of the contour is difficult in bones with incomplete mineralization. In this clinical study, we investigated the intrapersonal and interpersonal reproducibilities of manual bone contour determination on CBCT images using a semi-automated computerized process. METHODS: The bone surface level in the area of the socket in 20 patients who had undergone tooth extraction from the upper jaw at 10 +/- 1 weeks previously was determined on CBCT images. Two investigators with different levels of experience determined the bone structure initially (T0) and repeated the procedure after 3 months (T1). The bone structure marked on CBCT images was converted into a surface data set. The resulting data sets were superimposed on one another. In the analyses, the shortest distances between the datasets were identified and measured. The average deviations were statistically evaluated. RESULTS: The intrapersonal evaluation resulted in an average deviation of 0.18 mm across both investigators. The interpersonal analysis comparing the two investigators resulted in average deviations of 0.15 mm at T0 and 0.26 mm at T1. Significant differences were not found. CONCLUSIONS: The low intrapersonal deviation indicates that the procedure has satisfactory reproducibility. All deviations were within the range of the selected resolution of the CBCT device. Application of a semi-automated procedure to detect the bone border in areas with incomplete mineralization is a predictable process. TRIAL REGISTRATION: The study was registered in the German Clinical Trials Register and the International Clinical Trials Registry Platform of the WHO: DRKS00004769, date of registration: 28 February 2013; and DRKS00005978, date of registration: 09 November 2015. PMID- 30484199 TI - Swallowing function in advanced tongue cancer patients before and after bilateral neck dissection following superselective intra-arterial chemoradiotherapy for organ preservation: a case-control study. AB - OBJECTIVE: This study aimed to evaluate swallowing function in advanced tongue cancer patients before and after bilateral neck dissection following superselective intra-arterial chemoradiotherapy (CRT). METHODS: A videofluoroscopic swallowing study (VFSS) was used to evaluate swallowing function in 10 patients with advanced tongue cancer before and after bilateral neck dissection. RESULTS: Laryngeal penetration increased in the postoperative VFSS. Temporal analysis comparing two time points revealed that, after surgery, oral transit time increased significantly, but there was no difference in pharyngeal delay time or pharyngeal transit time. Spatial analysis revealed significant decreases after surgery in the maximum distance of upper esophageal sphincter (UES) opening, the maximum distance of hyoid bone movement in both the anterior and superior direction, and the maximum velocity of hyoid bone movement. CONCLUSIONS: Laryngeal penetration and aspiration increased as a result of limited hyoid movement and diminished UES opening after bilateral neck dissection following superselective intra-arterial CRT for advanced tongue cancer. PMID- 30484200 TI - Radiological features of synovial chondromatosis affecting the temporomandibular joint: report of three cases. AB - Synovial chondromatosis is a benign nodular cartilaginous proliferation that mainly occurs in large joints. The temporomandibular joint is considered to be rarely affected. Several cases of synovial chondromatosis of the temporomandibular joint have been reported with clinical and histological features. People with this disease may present with swelling, pain, intracapsular sounds, and limitation of mandibular movement. Radiographs are an important component in the diagnostic process for synovial chondromatosis. In this article, we report three cases of synovial chondromatosis occurring in the temporomandibular joint with a focus on the radiological features, including those on plain films, cone-beam computed tomography (CT) images, and conventional CT images. The three cases had totally different radiological features. The imaging differences were analyzed and compared to create combined diagnostic methods based on clinical features and examination techniques. The role of cone beam CT examination in the diagnosis of the disease is discussed. PMID- 30484202 TI - Ultrasonographic evaluation of masseter muscle thickness in patients with disk displacement with reduction. AB - OBJECTIVES: This study was performed to ultrasonographically assess the masseter muscle thicknesses of individuals with disk displacement with reduction. METHODS: The thickness of the masseter muscle in 100 patients (28 male, 72 female; average age 34 years) who presented with one-sided temporomandibular joint pain and a clicking sound and were diagnosed with disk displacement with reduction was measured in relaxation and at maximum contraction using ultrasonography. RESULTS: In the contracted position, the difference in the masseter muscle thickness between the healthy side and the side with disk displacement with reduction was statistically significant (p < 0.05). However, no statistically significant difference was found between the two sides in the relaxed position. CONCLUSIONS: Obvious ultrasonographic changes of the masseter muscle were found in patients with temporomandibular disk displacement with reduction, and these changes might be related to unilateral chewing. Individuals with anterior disc displacement probably chew unilaterally because of pain and clicking. PMID- 30484201 TI - Comparison of temporomandibular joint shape and size in patients with facial asymmetry. AB - OBJECTIVE: To examine the morphologic similarities and differences in mandibular condyle and glenoid fossa between the deviated and non-deviated sides in patients with facial asymmetry using statistical analysis. METHODS: One hundred eighty four patients (95 men, 89 women; mean age, 22.30 +/- 3.87 years) with facial asymmetry were examined with cone-beam computed tomography (CBCT). Shape analysis was performed to compare the shapes and sizes of the condyle and fossa between the deviated and non-deviated sides in the frontal and lateral aspects. Ordinary Procrustes analysis (OPA) was used to determine shape variations of the fossa and condyle. RESULTS: Shape variations derived from ordinary sum of squares (OSS) suggested that, in the frontal aspect, there was a difference between the two sides in both the fossa and condyle (P < 0.05). In the lateral aspect, there was no difference in fossa shape between the two sides (P > 0.05); however, the shape of condyle was different between the non-deviated and deviated sides (P < 0.05). Size comparison in OPA matching and centroid size (CS) in the frontal aspect demonstrated that the non-deviated side was larger than the deviated side. In the lateral aspect, fossa showed no difference in CS between the two sides (P > 0.05); however, the non-deviated side was larger than the deviated side for condyle (P < 0.05). CONCLUSIONS: Morphometric differences in condyle and fossa between the deviated and non-deviated sides were observed. Structures of the non deviated side were relatively larger than those of the deviated side, except for fossa in the lateral aspect. PMID- 30484203 TI - Relationship between sella turcica bridging and cephalometric parameters in adolescents and young adults. AB - OBJECTIVES: Sella turcica bridging occurs with fusion or calcification of the anterior and posterior clinoid processes in the middle cranial region. This study aimed to compare the cephalometric parameters among normal shape, partial bridge, and total bridge of the sella turcica in adolescent and young adult subjects. METHODS: This retrospective study was performed on the lateral cephalometric radiographs of 410 Turkish adolescent and young adult subjects. The subjects were divided into three groups: normal sella turcica shape (128 females, 32 males; mean age: 17.7 +/- 1.54 years), partial sella turcica bridge (129 females, 32 males; mean age: 17.8 +/- 2.15 years), and total sella turcica bridge (66 females, 23 males; mean age: 18.2 +/- 1.82 years). Thirteen angular and eight linear cephalometric measurements were performed using a cephalometric software program. The data were analyzed by one-way analysis of variance, and the Kruskal Wallis test with the Bonferroni correction. RESULTS: Significant differences were found for Nperp-A distance, Nperp-Pg distance, and palatal plane-to-anterior cranial base angle among the groups (p < 0.016). There were no significant differences in the cephalometric parameters between the partial and total sella turcica bridging groups (p > 0.05). CONCLUSIONS: This study evaluated a large amount of data for cephalometric measurements focusing on the degree of calcification of the sella turcica in adolescent and young adult subjects. The maxilla and mandible were located in a sagittally retrusive position in the partial and total sella turcica bridge subjects compared with the normal sella turcica shape subjects. PMID- 30484204 TI - Principles of the magnetic resonance imaging movie method for articulatory movement. AB - Magnetic resonance imaging (MRI) has become a critical tool for dental examination. MRI has many advantages over radiographic examination methods, including the lack of a requirement for patient exposure and the ability to capture high-contrast images of various tissue and organ types. However, MRI also has several limitations, including long examination times and the existence of metallic or motion artifacts. A cardiac imaging method using cine sequences was developed in the 1990s. This technique allows for analysis of heart movement and functional blood flow. Moreover, this method has been applied in dentistry. Recent research involving 3 T MRI has led to the achievement of a temporal resolution of < 10 ms, surpassing the frame rate of typical video recording. The current review introduces the history and principles of the cine sequence method and its application to the oral and maxillofacial regions. PMID- 30484205 TI - Determination of optimum exposure parameters for dentoalveolar structures of the jaws using the CB MercuRay system with cluster signal-to-noise analysis. AB - OBJECTIVE: To determine the optimum cone beam computed tomography exposure parameters for specific diagnostic tasks. METHODS: A Teflon phantom attached to a half-mandible in a large container was scanned in dental (D), implant (I), and panoramic (P) modes. An identical phantom in a small container was scanned in D mode. Both were scanned at 60, 80, 100, and 120 kV. We evaluated the image quality of five anatomical structures [dentinoenamel junction (1), lamina dura and periodontal ligament space (2), trabecular pattern (3), cortex-spongy bone junction (4), and pulp chamber and root canal (5)] and analyzed the diagnostic image quality with cluster signal-to-noise analysis. We then evaluated correlations between the two image qualities and calculated the threshold of acceptable diagnostic image quality. Optimum exposure parameters were determined from images with acceptable diagnostic image quality. RESULTS: For the small container, the optimum exposure parameters were D mode, 80 kV for (1), (3), and (4) and D mode, 100 kV for (5). For the large container, they were D mode, 120 kV for (1), (3), and (5) and D mode, 100 kV for (4). I mode, 120 kV reached the acceptable level for (4). No images reached the acceptable level for (2). CONCLUSIONS: No optimum exposure parameters were identified for the evaluation of the lamina dura and periodontal ligament space. D mode was sufficient for the other structures; however, the tube voltage required for each structure differed. Smaller patients required lower tube voltage. I mode, 120 kV may be used for larger lesions. PMID- 30484206 TI - Twenty classic signs in oral and maxillofacial radiology. AB - Teachers of radiology often employ the use of classic signs to help learners identify the typical appearance of various pathologies. This article is a compendium of simply-described classic signs in oral and maxillofacial radiology, including their use in differential diagnoses. PMID- 30484207 TI - Comparability of dental implant site ridge measurements using ultra-low-dose multidetector row computed tomography combined with filtered back-projection, adaptive statistical iterative reconstruction, and model-based iterative reconstruction. AB - OBJECTIVE: To assess the linear measurements of edentulous ridges recorded from multidetector row computed tomography (MDCT) images obtained by a previously untested ultra-low dose in combination with filtered back-projection (FBP), adaptive statistical iterative reconstruction (ASIR), and model-based iterative reconstruction (MBIR). METHODS: Three cadavers were imaged using a reference protocol with a standard dose and FBP (volume CT dose index (CTDIvol): 29.4 mGy) and two ultra-low-dose protocols, LD1 and LD2 (CTDIvol: 0.53 and 0.29 mGy). All test examinations were reconstructed with FBP, ASIR 50, ASIR 100, and MBIR. Linear measurements from the images of the edentulous ridges recorded from the test protocols were compared with those from the reference using a one-sample t test, Bland-Altman plots, and linear regression. Statistical significance was set at a p value of 0.05. RESULTS: The one-sample t test demonstrated a statistically significant difference between the measurements from the reference protocol and all test protocols. The difference was not clinically significant for the following three test protocols: LD1/FBP, LD1/ASIR 50, and LD2/FBP. Bland-Altman plots with linear regression showed no systematic variation between the measurements obtained with the reference protocol and these three test protocols. CONCLUSIONS: The lowest-dose protocol to demonstrate comparable measurements with a standard MDCT dose was CTDIvol 0.29 mGy with FBP. These results must be considered with caution for areas of the jaws with thin cortication. The results in areas of thin cortication should be verified by studies with larger sample sizes at such areas and comparison with true gold standard measurements. PMID- 30484208 TI - Evaluating the mandibular condyles of patients with osteoarthritis for bone marrow abnormalities using magnetic resonance T2 mapping. AB - OBJECTIVES: This study investigated whether erosion and osteophyte correlates with condyle bone marrow abnormalities (BMA), as detected with quantitative T2 mapping. METHODS: Fifty-six joints (in 44 patients) that demonstrated evidence of bony erosion (ER) or osteophytes (OS) related to disc displacement without reduction were studied with MR images. A control group of 50 joints (in 50 patients) was included. The subjects were divided into five groups; noAR (control), noBMA-ER, BMA-ER, noBMA-OS, and BMA-OS. T2 mapping was performed and the regions of interest were placed over the bone marrow at the top of the condyle. The mean T2 values of the bone marrow of the mandibular condyle were calculated for all mapping images. After assessing age-related changes in T2 values of noAR group using Pearson's product-moment, differences in median T2 values of five groups were analyzed using Kruskal-Wallis test, and Steel-Dwass test (p < 0.05). RESULTS: There was no significant correlation between age and T2 value in noAR group. The median T2 values of noBMA-ER and BMA-ER groups were significantly higher than those of noAR, noBMA-OS and BMA-OS groups. Those of noBMA-OS and BMA-OS groups were significantly lower than those of noAR, noBMA-ER and BMA-ER groups. There was no significant difference between noBMA and BMA groups. CONCLUSIONS: It is suggested that erosion and osteophyte of the condyle may correlate with bone marrow abnormalities. T2 mapping could be show slight marrow changes of the arthritic condyle. PMID- 30484209 TI - Abnormal positioning of the common carotid artery clinically diagnosed as a submandibular mass. AB - The common carotid artery (CCA) usually runs along the long axis of the neck, although it is occasionally found in an abnormal position or is displaced. We report a case of an 86-year-old woman in whom the CCA was identified in the submandibular area. The patient visited our clinic and reported soft tissue swelling in the right submandibular area. It resembled a tumor mass or a swollen lymph node. Computed tomography showed that it was the right CCA that had been bent forward and was running along the submandibular subcutaneous area. Ultrasonography verified the diagnosis. No other lesions were found on the diagnostic images. Consequently, the patient was diagnosed as having abnormal CCA positioning. Although this condition generally requires no treatment, it is important to follow-up the abnormality with diagnostic imaging because of the risk of cerebrovascular disorders. PMID- 30484210 TI - Radiculomegaly of canines in oculofaciocardiodental syndrome. AB - Oculofaciocardiodental (OFCD) syndrome is a rare genetic disease, first reported by Hayward in 1980. This syndrome presents with various ocular, facial, cardiac, and dental symptoms, including congenital cataract, dysmorphic facial features, congenital heart disease, and enlarged roots, respectively. The most important criteria for the diagnosis of OFCD syndrome are dental abnormalities, especially extreme elongation of canine roots. Here, we report detailed analysis of the dentofacial region, as well as ocular, facial, cardiac, and dental findings in a female with OFCD syndrome. To the best of our knowledge, the patient in this case is the first such patient reported in South Korea. PMID- 30484211 TI - Diagnostic usefulness of panoramic imaging of the pterygopalatine fossa: case of a schwannoma causing pterygopalatine fossa expansion. AB - The pterygopalatine fossa is a small area between the posterior wall of the maxillary sinus and the anterior surface of the pterygoid process of the sphenoid bone. The pterygopalatine fossa can be seen clearly on panoramic imaging. We present the case of a 57-year-old man who exhibited right pterygopalatine fossa expansion on panoramic imaging. Computed tomography (CT), magnetic resonance imaging (MRI), and panoramic imaging all showed a tumor at the right pterygopalatine fossa in this patient. CT indicated that the tumor replaced right retromaxillary fat and displaced the posterior wall of the maxillary sinus. On MRI, the tumor showed intermediate signal intensity at the paranasal area on T1 weighted images, and variable intermediate and high signal intensities on fat suppressed T2-weighted images. It was eventually diagnosed as a schwannoma. Thus, panoramic imaging can be used for disease screening at the posterior border of the maxilla. Our conclusion is based on this report of a patient with a schwannoma at the posterior wall of the maxillary sinus, which panoramic imaging revealed to have pterygopalatine fossa expansion. PMID- 30484212 TI - Sonographic diagnosis in the head and neck region: from an educational lecture presented at the 56th General Assembly and Annual Scientific Congress of the Japanese Society for Oral and Maxillofacial Radiology. AB - Sonography is a simple, inexpensive, and non-invasive diagnostic modality. Although tissues behind bony structures and deep tissues are not delineated, sonography can depict superficial soft tissues very clearly. In the head and neck region, however, it has not yet been used widely, as the anatomical structures are complicated, and considerable experience is needed both to perform an examination and to make a diagnosis. To perform examinations efficiently, operators must be familiar with the sonographic system in use, and take images at standard planes. To make a correct diagnosis, operators require knowledge of the sonographic anatomy on standard planes, representative sonographic signs and artifacts, and common diseases and their typical sonographic findings. In this paper, we have explained the sonographic anatomy on standard planes, and the sonographic findings of common diseases in the oral and maxillofacial region. PMID- 30484213 TI - Effect of bisphosphonate treatment on the jawbone: an exploratory study using periapical and panoramic radiographic evaluation. AB - OBJECTIVE: This cross-sectional study aimed to explore potential jawbone changes secondary to bisphosphonate (BP) treatment of osteoporosis using digital panoramic and periapical radiography. METHODS: Thirty-nine women, previously examined with dual-energy X-ray absorptiometry, were radiographed by digital panoramic and/or periapical radiography. On periapical radiographs, trabecular bone structure and fractal dimension analyses of the mandibular first molar and edentulous regions were performed. On panoramic radiographs, the mandibular cortical width (MCW) was calculated, and trabecular bone structure and fractal dimension analyses of the trabecular bone in the alveolar and basal bones were performed. The results were compared between patients treated or not treated with BP using linear regression analysis to adjust for potential confounding factors. RESULTS: The analyses of periapical and panoramic radiological images showed no statistical differences in the jawbones between groups after bisphosphonate use for mean intervals of 4.3 and 5 years; respectively. Although the mandibular cortical width on panoramic radiography was correlated with BP use, it was not noted to be statistically significant. CONCLUSIONS: The trabecular parts of the alveolar and basal bones and the MCW were not significantly altered by BP treatment in patients with osteoporosis over 4.3-5 years, as detected by digital periapical and panoramic radiography. The low dosages of bisphosphonates used in the treatment of osteoporosis may explain this lack of change in MCW. Dental radiographs should not be considered as a method to monitor BP-induced jaw bone alterations among osteoporotic patients. PMID- 30484214 TI - Caries detection enhancement using texture feature maps of intraoral radiographs. AB - OBJECTIVES: Dental caries are caused by tooth demineralization due to bacterial plaque formation. However, the resulting lesions are often discrete and thus barely recognizable in intraoral radiography images. Therefore, more advanced detection techniques are in great demand among dentists and radiographers. This study was performed to evaluate the performance of texture feature maps in the recognition of discrete demineralization related to caries plaque formation. METHODS: Digital intraoral radiology image analysis protocols incorporating first order features (FOF), co-occurrence matrices, gray tone difference matrices, run length matrices (RLM), local binary patterns (LBP), and k-means clustering (CLU) were used to transform the digital intraoral radiology images of 10 patients with confirmed caries, which were retrospectively reviewed in a dental clinic. The performance of the resulting texture feature maps was compared with that of radiographic images by radiologists and dental specialists. RESULTS: Significantly improved detection of caries spots was achieved by employing the CLU and FOF texture feature maps. The caries-affected area with sharp margins was well defined using the CLU approach. A pseudo-three-dimensional effect was observed in outlining the demineralization zones inside the cavity with the FOF 5 protocol. In contrast, the LBP and RLM techniques produced less satisfactory results with unsharp edges and less detailed depiction of the lesions. CONCLUSIONS: This study illustrated the applicability of texture feature maps to the recognition of demineralized spots on the tooth surface debilitated by caries and identified the best performing techniques. PMID- 30484215 TI - Oropharyngeal adenoid cystic carcinoma invading the mandibular bone through the mandibular foramen. AB - Adenoid cystic carcinoma (ACC) is a rare epithelial tumor of the head and neck region, and one of the most common malignant tumors of the salivary glands. ACC is a slow-growing tumor characterized by perineural invasion and often has a high recurrence rate. We describe a case of oropharyngeal ACC invading the mandibular bone through the mandibular foramen that showed a rare pattern of origin and invasion. A 70-year-old woman complained of noise and pain around the right temporomandibular joint. Osteomyelitis was suspected on the initial imaging examinations, although the findings were slightly atypical. However, a mass was observed in the right oropharyngeal wall on subsequent imaging examinations, and mandibular bone invasion, rather than osteomyelitis, was additionally suspected. The mass in the right oropharyngeal wall and right mandible was surgically excised. On postoperative histopathological examination, the mass was finally diagnosed as ACC. As tumor cells were also observed around the inferior alveolar nerve, mandibular bone invasion through the mandibular foramen was suspected. An oropharyngeal ACC invading the mandibular bone through the mandibular foramen is extremely rare. The present case suggests that bone invasion should be considered carefully with several imaging examinations when a malignant tumor such as ACC is observed around the jaw bone. PMID- 30484216 TI - Investigation of maxillary sinus volume relationships with nasal septal deviation, concha bullosa, and impacted or missing teeth using cone-beam computed tomography. AB - OBJECTIVES: The aim of this retrospective study was to investigate the correlations of maxillary sinus volume with nasal septal deviation, concha bullosa, impacted teeth, and missing teeth in the maxillary posterior region on maxillary sinus volume using cone-beam computed tomography (CBCT) images. METHODS: The study cohort comprised 252 CBCT images of 252 patients retrospectively selected from the records in our CBCT archive. All CBCT images were exported to 3D modeling software for calculation of maxillary sinus volumes. Nasal septal deviation cases were grouped as mild, moderate, and severe. Concha bullosa was classified as lamellar, bulbous, and extensive. Maxillary sinus volume differences were evaluated by comparing the bilateral sinus volumes in patients with nasal septal deviation, unilateral concha bullosa, and unilateral impacted or missing maxillary posterior teeth. RESULTS: The findings revealed that males had a significantly higher mean sinus volume than females (p < 0.01) and that sinus volume tended to decrease with age (p < 0.05). In moderate and severe nasal septal deviation cases, the maxillary sinus volume was significantly smaller on the same side as the deviation than on the contralateral side (p < 0.05). There were no significant correlations between maxillary sinus volume and concha bullosa, unilateral impacted teeth, or unilateral missing teeth (p > 0.05). CONCLUSIONS: The present findings suggest that maxillary sinus volume is smaller on the same side as the deviation in moderate and severe septal deviation cases and that the maxillary sinus volume tends to decrease with increasing age. PMID- 30484217 TI - A simple location-tracking app for psychological research. AB - Location data gathered from a variety of sources are particularly valuable when it comes to understanding individuals and groups. However, much of this work has relied on participants' active engagement in regularly reporting their location. More recently, smartphones have been used to assist with this process, but although commercial smartphone applications are available, these are often expensive and are not designed with researchers in mind. To overcome these and other related issues, we have developed a freely available Android application that logs location accurately, stores the data securely, and ensures that participants can provide consent or withdraw from a study at any time. Further recommendations and R code are provided in order to assist with subsequent data analysis. PMID- 30484218 TI - Quantifying sensorimotor experience: Body-object interaction ratings for more than 9,000 English words. AB - Ratings of body-object interaction (BOI) measure the ease with which the human body can interact with a word's referent. Researchers have studied the effects of BOI in order to investigate the relationships between sensorimotor and cognitive processes. Such efforts could be improved, however, by the availability of more extensive BOI norms. In the present work, we collected BOI ratings for over 9,000 words. These new norms show good reliability and validity and have extensive overlap with the words used both in other lexical and semantic norms and in the available behavioral megastudies (e.g., the English Lexicon Project, Balota, Yap, Cortese, Hutchison, Kessler, & Loftis in Behavior Research Methods, 39, 445-459, 2007; and the Calgary Semantic Decision Project, Pexman, Heard, Lloyd, & Yap in Behavior Research Methods, 49, 407-417, 2017). In analyses using the new BOI norms, we found that high-BOI words tended to be more concrete, more graspable, and more strongly associated with sensory, haptic, and visual experience than are low-BOI words. When we used the new norms to predict response latencies and accuracy data from the behavioral megastudies, we found that BOI was a stronger predictor of responses in the semantic decision task than in the lexical decision task. These findings are consistent with a dynamic, multidimensional account of lexical semantics. The norms described here should be useful for future research examining the effects of sensorimotor experience on performance in tasks involving word stimuli. PMID- 30484219 TI - Extrapolating baseline trend in single-case data: Problems and tentative solutions. AB - Single-case data often contain trends. Accordingly, to account for baseline trend, several data-analytical techniques extrapolate it into the subsequent intervention phase. Such extrapolation led to forecasts that were smaller than the minimal possible value in 40% of the studies published in 2015 that we reviewed. To avoid impossible predicted values, we propose extrapolating a damping trend, when necessary. Furthermore, we propose a criterion for determining whether extrapolation is warranted and, if so, how far out it is justified to extrapolate a baseline trend. This criterion is based on the baseline phase length and the goodness of fit of the trend line to the data. These proposals were implemented in a modified version of an analytical technique called Mean phase difference. We used both real and generated data to illustrate how unjustified extrapolations may lead to inappropriate quantifications of effect, whereas our proposals help avoid these issues. The new techniques are implemented in a user-friendly website via the Shiny application, offering both graphical and numerical information. Finally, we point to an alternative not requiring either trend line fitting or extrapolation. PMID- 30484220 TI - A new nonparametric test for the race model inequality. AB - The race model inequality (RMI), as first introduced by Miller (Cognitive Psychology, 14, 247-279, 1982), entails an upper bound on the amount of statistical facilitation for reaction times (RTs) attainable by a race model within the redundant-signals paradigm. A violation of RMI may be considered as empirical evidence for a coactivation model rather than a race model. Here, we introduce a novel nonparametric procedure for evaluating the RMI for single participant analysis. The statistical procedure is based on a new probabilistic representation that highlights some neglected, but important distributional features of the RMI. In particular, we show how the reconstructed distribution function under maximal statistical facilitation for a race model is characterized by a specific truncated-type property. The results of two Monte Carlo simulation studies suggest that our procedure efficiently controls for type I error with reasonable power. Finally, unlike previous proposals for single participant analysis (e.g., Maris and Maris (Journal of Mathematical Psychology 47, 507-514, 2003)), our approach is also more consistent with the typical way to collect RT data in experimental works. R script functions for running the statistical analysis on single participant data are made freely available to the readers on a dedicated web server. PMID- 30484221 TI - The Muse Cell Discovery, Thanks to Wine and Science. AB - Multilineage-differentiating stress-enduring (Muse) cells, identified as cells positive for the pluripotent marker stage-specific embryonic antigen (SSEA-3+), were discovered as stress-tolerant pluripotent stem cells from among mesenchymal stem cells (MSCs) and fibroblasts, as well as from the adult human bone marrow mononucleated fraction. MSCs are a crude population of cells that differentiate into multiple cell types covering all three germ layers in low proportion and were thus deduced to contain a genuine pluripotent stem cell subpopulation. Muse cells constitute several percent of MSCs and 1 of ~3000 bone marrow mononucleated cells. They exhibit pluripotent gene expression as well as trilineage differentiation and self-renewal capabilities at the single-cell level, while, in contrast, MSC cells other than Muse cells do not exhibit these characteristics. These characteristics indicate that Muse cells correspond to the subpopulation of MSC cells responsible for the pluripotent aspect of MSCs. In addition to their pluripotency, Muse cells play an important role in vivo as endogenous stem cells that contribute to tissue homeostasis through daily reparative maintenance and to tissue reconstruction through their unique reparative functions following serious tissue damage. This chapter describes how my research team discovered Muse cells. PMID- 30484222 TI - Basic Characteristics of Muse Cells. AB - Multilineage-differentiating stress-enduring (Muse) cells exhibit the core characteristics of pluripotent stem cells, namely, the expression of pluripotency markers and the capacity for trilineage differentiation both in vitro and in vivo and self-renewability. In addition, Muse cells have unique characteristics not observed in other pluripotent stem cells such as embryonic stem cells, control of pluripotency by environmental switch of adherent suspension, symmetric and asymmetric cell division, expression of factors relevant to stress tolerance, and distinctive tissue distribution. Pluripotent stem cells were recently classified into two discrete states, naive and primed. These two states have multiple functional differences, including their proliferation rate, molecular properties, and growth factor dependency. The properties exhibited by Muse cells are similar to those of primed pluripotent stem cells while with some uniqueness. In this chapter, we provide a comprehensive description of the basic characteristics of Muse cells. PMID- 30484223 TI - Muse Cells Are Endogenous Reparative Stem Cells. AB - The dynamics and actions of Muse cells at a time of physical crisis are unique and highly remarkable compared with other stem cell types. When the living body is in a steady state, low levels of Muse cells are mobilized to the peripheral blood, possibly from the bone marrow, and supplied to the connective tissue of nearly every organ. Under conditions of serious tissue damage, such as acute myocardial infarction and stroke, Muse cells are highly mobilized to the peripheral blood, drastically increasing their numbers in the peripheral blood within 24 h after the onset of tissue injury. The alerting signal, sphingosine-1 phosphate, attracts Muse cells to the damaged site mainly via the sphingosine-1 phosphate receptor 2, enabling them to preferentially home to site of injury. After homing, Muse cells spontaneously differentiate into tissue-compatible cells and replenish new functional cells for tissue repair. Because Muse cells have pleiotropic effects, including paracrine, anti-inflammatory, anti-fibrotic, and anti-apoptotic effects, these cells synergistically deliver long-lasting functional and structural recovery. This chapter describes how Muse cells exert their reparative effects in vivo. PMID- 30484224 TI - Protocols for Isolation and Evaluation of Muse Cells. AB - This chapter provides the detailed method for isolation of Muse cells and evaluation of their pluripotency. The basic population of Muse cells is cultured mesenchymal stem cells such as bone marrow-mesenchymal stem cells, fibroblasts, and adipose-derived stem cells. The detailed method for handling mesenchymal stem cells is also provided in this protocol. PMID- 30484225 TI - Stem Cells and DNA Repair Capacity: Muse Stem Cells Are Among the Best Performers. AB - Stem cells persist for long periods in the body and experience many intrinsic and extrinsic stresses. For this reason, they present a powerful and effective DNA repair system in order to properly fix DNA damage and avoid the onset of a degenerative process, such as neoplastic transformation or aging. In this chapter, we compare the DNA repair ability of pluripotent stem cells (ESCs, iPSCs, and Muse cells) and other adult stem cells. We also describe personal investigations showing a robust and effective capacity of Muse cells in sensing and repairing DNA following chemical and physical stress. Muse cells can repair DNA through base and nucleotide excision repair mechanisms, BER and NER, respectively. Furthermore, they present a pronounced capacity in repairing double strand breaks by the nonhomologous end joining (NHEJ) process. The studies addressing the role of DNA damage repair in the biology of stem cells are of paramount importance for comprehension of their functions and, also, for setting up effective and safe stem cell-based therapy. PMID- 30484226 TI - Immunomodulatory Properties and Potential Therapeutic Benefits of Muse Cells Administration in Diabetes. AB - It is well established the link between inflammation and the development of insulin resistance and pathogenesis of type 2 diabetes. Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing pancreatic beta cells mediated by autoreactive T lymphocytes and pro-inflammatory agents. Therefore, developing new strategies to efficiently control dysregulated inflammation could have substantial benefits in the treatment of diabetes. Recently, a novel population of non-tumorigenic pluripotent stem cells, named multilineage-differentiating stress-enduring (Muse) cells, was discovered. Muse cells secrete significant amounts of TGF-beta1, a key cytokine governing down modulation of T lymphocytes and macrophages. In this chapter, we discuss the immunomodulatory properties of Muse cells as well as the molecular mechanism of TGF-beta1 as mediator of Muse cell action. We also describe the role of certain cytokines/growth factors highly expressed in Muse cells as potential mediators of their effects. Finally, we provide evidence of the beneficial effects of adipose tissue-derived Muse cells in an experimental mice model of type 1 diabetes. PMID- 30484227 TI - The Role of the Mitochondria in the Evolution of Stem Cells, Including MUSE Stem Cells and Their Biology. AB - From the transition of single-cell organisms to multicellularity of metazoans, evolutionary pressures selected new genes and phenotypes to cope with the oxygenation of the Earth's environment, especially via the symbiotic acquisition of the mitochondrial organelle. There were many new genes and phenotypes that appeared, namely, stem cells, low-oxygen-micro-environments to house these genes ("niches"), new epigenetic mechanisms to regulate , selectively, the gene repertoire to control proliferation, differentiation, apoptosis, senescence and DNA protection mechanisms, including antioxidant genes and DNA repair. This transition required a critical regulation of the metabolism of glucose to produce energy for both the stem cell quiescent state and the energy-requiring differentiated state. While the totipotent-, embryonic-, pluripotent-, and a few adult organ-specific stem cells were recognized, only relatively recently, because of the isolation of somatic cell nuclear transfer (SCNT) stem cells and "induced pluripotent stem" cells, challenges to the origin of these "iPS" cells have been made. The isolation and characterization of human MUSE stem cells and more adult organ-specific adult stem cells have indicated that these MUSE cells have many shared characteristics of the "iPS" cells, yet they do not form teratomas but can give rise to the trigeminal cell layers. While the MUSE cells are a subset of human fibroblastic cells, they have not been characterized, yet, for the mitochondrial metabolic genes, either in the stem cell state or during their differentiation processes. A description of other human adult stem cells will be made to set future studies of how the MUSE stem cells compare to all other stem cells. PMID- 30484228 TI - Acute Myocardial Infarction, Cardioprotection, and Muse Cells. AB - Acute myocardial infarction (AMI) is a common cause of morbidity and mortality worldwide. Severe MI leads to heart failure due to a marked loss of functional cardiomyocytes. First-line treatment for AMI is to reperfuse the occluded coronary artery by PCI as soon as possible. Besides PCI, there are several therapies to reduce the infarct size and improve the cardiac function and remodeling. These are drug therapies such as pharmacological pre- and postconditioning, cytokine therapies, and stem cell therapies. None of these therapies have been clinically developed as a standard treatment for AMI. Among many cell sources for stem cell therapies, the Muse cell is an endogenous non tumorigenic pluripotent stem cell, which is able to differentiate into cells of all three germ layers from a single cell, suggesting that the Muse cell is a potential cell source for regenerative medicine. Endogenous Muse cell dynamics in the acute phase plays an important role in the prognosis of AMI patients; AMI patients with a higher number of Muse cells in the peripheral blood in the acute phase show more favorable improvement of the cardiac function and remodeling in the chronic phase, suggesting their innate reparative function for the heart. Intravenously administered exogenous Muse cells engrafted preferentially and efficiently to infarct border areas via the S1P-S1PR2 axis and differentiated spontaneously into working cardiomyocytes and vessels, showed paracrine effects, markedly reduced the myocardial infarct size, and delivered long-lasting improvement of the cardiac function and remodeling for 6 months. These findings suggest that Muse cells are reparative stem cells, and thus their clinical application is warranted. PMID- 30484229 TI - Application of Muse Cell Therapy to Stroke. AB - Stroke is defined as a sudden onset of neurologic deficits arising from cerebrovascular complications. It is the second common cause of death around the world and the major cause of disability. Because brain is an organ with complicated neural networks and neurons are highly differentiated, it has been traditionally considered to possess a limited potential for regeneration. The number of stroke patients is increasing, and stroke represents a serious problem from the viewpoint of the national medical economy. Even with the current sophisticated treatments, more than half of stroke patient survivors remain disabled. Therefore, it is imperative to develop a new treatment for promoting functional recovery and repair of the lost neurological circuit. Multilineage differentiating stress-enduring (Muse) cells are endogenous non-tumorigenic stem cells with pluripotency. After transplantation, Muse cells recognize the injured site through their specific receptor for damage signal, home preferentially into these tissues and spontaneously differentiate into tissue-compatible cells to replace the lost cells, and repair the tissue, delivering functional and structural regeneration. These properties are desirable for the treatment of strokes and advantageous compared to other stem cell therapies. Here, we describe the current status of stem cell therapies for stroke and future possibilities of Muse cell therapy. PMID- 30484230 TI - Muse Cell: A New Paradigm for Cell Therapy and Regenerative Homeostasis in Ischemic Stroke. AB - Multilineage-differentiating stress enduring (Muse) cells are one of the most promising donor cells for cell therapy against ischemic stroke, because they can differentiate into any type of cells constructing the central nervous system (CNS), including the neurons. They can easily be isolated from the bone marrow stromal cells (BMSCs), which may also contribute to functional recovery after ischemic stroke as donor cells. In this chapter, we concisely review their biological features and then future perspective of Muse cell transplantation for ischemic stroke. In addition, we briefly refer to the surprising role of Muse cells to maintain the homeostasis in the living body under both physiological and pathological conditions. PMID- 30484231 TI - Application of Muse Cell Therapy for Kidney Diseases. AB - The kidney plays an essential role in the maintenance of homeostasis in healthy individuals, e.g., by regulating the amount of water and concentration of electrolyte in the body. Owing to the structural complexity, renal dysfunction is caused by a myriad of diseases and conditions, and in severe cases, it progresses to end-stage renal disease in which patients require renal replacement therapy, i.e., maintenance dialysis or kidney transplantation. The currently available therapeutic modalities, with the exception of renal transplantation, cannot recover severely deteriorated renal function. Thus, regenerative medicine holds considerable promise as a potential means for developing next-generation renal therapeutics. Mesenchymal stem cell (MSC) transplantation has been investigated in acute kidney injury and chronic kidney disease models, and clinical studies have already been started for some kinds of kidney diseases. However, most of these studies concluded that the main underlying mechanism of therapeutic effect of MSC transplantation was paracrine. Recently, we reported that Muse cell therapy in a murine model of chronic kidney disease resulted in differentiation of intravenously injected Muse cells into glomerular cells after preferential homing to damaged glomerulus and improvement in renal function. The result suggested the potentiality of Muse cell therapy for glomerular regeneration. Muse cells are a promising cell source for regenerative therapy for kidney diseases. PMID- 30484232 TI - Liver Regeneration Supported by Muse Cells. AB - Cellular compensation from extrahepatic resources is expected to improve the prognosis of liver diseases. Currently, liver dysfunction is treated by a variety of modalities including drugs, cytokines, vascular interventions, energy devices, surgery, and liver transplantation; however, in recent years there have been few significant advancements in treatment efficacy. A next-generation therapeutic strategy for liver disease, cellular compensatory therapy (i.e., cell therapy), is now being considered for clinical practice. Liver dysfunction is attributed to a lack of sufficient functional cells. However, processes involved in recovery of liver function are not fully elucidated, which has complicated the interpretation of treatment effects at the cellular level. Our genotyping study of living donor liver transplantation revealed that a variety of graft liver tissues contained the donor genotype, indicating that extrahepatic cells had differentiated into liver component cells during liver regeneration. Multilineage-differentiating stress-enduring (Muse) cells appear to be a strong candidate for extrahepatic resources that can contribute to liver regeneration. Muse cells are defined as stage-specific embryonic antigen 3-expressing cells that contribute to tissue regeneration and have the potential to differentiate into three germ layers. The significant advantage of Muse cells over other "pluripotent cells" is that Muse cells are present in bone marrow/blood as well as a variety of connective tissues, which provides safety and ethical advantages for clinical applications. Here, we review current therapeutic topics in liver diseases and discuss the potential for cell therapy using Muse cells based on our recent studies of Muse cell administration in a mouse model of physical partial hepatectomy. PMID- 30484233 TI - Current Cell-Based Therapies in the Chronic Liver Diseases. AB - Liver diseases account for one of the leading causes of deaths in global health care. Furthermore, chronic liver failure such as liver cirrhosis is, namely, responsible for these fatal conditions. However, only liver transplantation is an established treatment for this end-stage condition, although the availability of this salvage treatment option is quite limited. Thus, the novel therapy such as artificial liver devices or cellular administration has been regarded as feasible. Especially cellular therapies have been proposed in decades. The technical advancement and progress of understanding of cellular differentiation have contributed to the development of basis of cellular therapy. This attractive therapeutic option has been advanced from original embryonic stem cells to more effective cellular fractions such as Muse cells. Indeed several cellular therapies including bone marrow-derived stem cells or peripheral blood-derived stem cells were initiated; the recent most organized clinical trials could not demonstrate its efficacy. Thus, truly innovative cellular therapy is needed to meet the scientific demands, and Muse cell administration is the remaining approach to this. In this article, we will discuss the current development and status of cellular therapy toward chronic liver failure. PMID- 30484234 TI - Artificial Pigmented Human Skin Created by Muse Cells. AB - The skin composes physiological and chemical barrier and renews skin component cells throughout the human life. Melanocytes locate in the basal layer of the epidermis and produce melanin to protect the skin from ultraviolet. Melanin plays key roles in determining human skin and hair color. Melanocyte dysfunction observed in albinism and vitiligo not only causes cosmetic problems but also increases risk of skin cancer. As rejuvenate therapy, embryonic stem (ES) cells and induced pluripotent stem (iPS) cells have been reported to generate melanocytes. Other than ES and iPS cells, human skin tissues maintain pluripotent stem cells, named multilineage-differentiating stress-enduring (Muse) cells. We employ Muse cells isolated from human fibroblasts and adipose tissue to differentiate into melanocytes (Muse-MC). Muse-MC express melanocyte-related molecules, such as tyrosinase and DCT, and show tyrosinase activity. We also succeeded to differentiate Muse cells into fibroblasts and keratinocytes and created three-dimensional (3D) reconstituted skin with Muse cell-derived melanocytes, fibroblasts, and keratinocytes. The 3D reconstituted skin of Muse cell-derived cells coordinately showed epidermis layers and Muse-MC localized in the basal layer of the epidermis. Thus Muse cells in the human skin can be a source of rejuvenation medicine for the skin reconstruction. PMID- 30484235 TI - Muse Cells and Aortic Aneurysm. AB - The aorta is a well-organized, multilayered structure comprising several cell types, namely, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and fibroblasts, as well as an extracellular matrix (ECM), which includes elastic and collagen fibers. Aortic aneurysms (AAs) are defined as progressive enlargements of the aorta that carries an incremental risk of rupture as the diameter increases over time. The destruction of the aortic wall tissue is triggered by atherosclerosis, inflammation, and oxidative stress, leading to the activation of matrix metalloproteinases (MMPs), and inflammatory cytokines and chemokines, resulting in the loss of the structural back bone of VSMCs, ECM, and ECs. To date, cell-based therapy has been applied to animal models using several types of cells, such as VSMCs, ECs, and mesenchymal stem cells (MSCs). Although these cells indeed deliver beneficial outcomes for AAs, particularly by paracrine and immunomodulatory effects, the attenuation of aneurysmal dilation with a robust tissue repair is insufficient. Meanwhile, multilineage-differentiating stress enduring (Muse) cells are known to be endogenous non-tumorigenic pluripotent-like stem cells that are included as several percent of MSCs. Since Muse cells are pluripotent-like, they have the ability to differentiate into cells representative of all three germ layers from a single cell and to self-renew. Moreover, Muse cells are able to home to the site of damage following simple intravenous injection and repair the tissue by replenishing new functional cells through spontaneous differentiation into tissue-compatible cells. Given these unique properties, Muse cells are expected to provide an efficient therapeutic efficacy for AA by simple intravenous injection. In this chapter, we summarize several studies on Muse cell therapy for AA including our recent data, in comparison with other kinds of cell therapies. PMID- 30484236 TI - Muse Cells and Ischemia-Reperfusion Lung Injury. AB - Ischemia-reperfusion injury (IRI) is one of the main causes of primary graft dysfunction that accounts for 25% of mortality after lung transplantation. Disruption of blood supply and subsequent reperfusion result in organ damage with activating innate and adaptive immune response, leading to inflammatory insults. The IRI after lung transplantation is primarily manifested by permeability pulmonary edema on the basis of pulmonary vascular endothelial cell injury as seen in acute respiratory distress syndrome (ARDS). Stem cells have potent anti inflammatory and immunomodulatory properties through local paracrine mechanisms. The application of mesenchymal stem cells (MSCs) for ARDS as well as IRI in various organs, therefore, has been interested and extensively investigated in animal models with promising results. Furthermore, two recent clinical randomized, placebo-controlled pilot studies demonstrated that treatment of ARDS with MSCs appears to be safe and feasible.Muse cells are stress-tolerant and non tumorigenic endogenous pluripotent-like stem cells. They comprise small proportions of cultured fibroblasts and MSCs and can be isolated from these populations. Muse cells are known to migrate to the damaged tissue after local or systemic administration, spontaneously differentiate into the tissue-compatible cells, and also secrete factors related to immunomodulation and tissue repair. We have recently shown the effect of Muse cells on ameliorating lung IRI in a rat model. With 2 h of warm ischemia and subsequent reperfusion on the left lung, the lung showed severe pulmonary edema. Administration of Muse cell through the left pulmonary artery immediately after reperfusion more significantly improved lung oxygenation capacity, compliance, and histological damage on days 1 and 3 after reperfusion compared with MSCs, and this was associated with higher expression levels of proteins related with anti-inflammation and tissue repair in the lung. Encouraging results of this study advocate further investigation of the ability of Muse cells to prevent and treat IRI after lung transplantation. PMID- 30484237 TI - Clinical Trials of Muse Cells. AB - Among many kinds of somatic stem cells, hematopoietic stem cells are the cells that have been successfully applied to treating leukemia patients as forms of bone marrow and cord blood transplantation. Mesenchymal stem cells, collectable from several sources including the bone marrow and adipose tissue, are also widely applied to clinical trials for their easy accessibility and low risks of tumorigenesis, while their outcomes were shown to be not clinically relevant in several target diseases. The most important issue for the stem cells is whether the cells are safe and effective for curing diseases. In this chapter, the outline of the clinical trial in Muse cells is discussed. PMID- 30484238 TI - Future of Muse Cells. AB - Discovered nearly 10 years ago by Professor Mari Dezawa and her colleagues, Muse cells are entering clinical trials faster than any other stem cell for three reasons. First, Muse cells have multiple fail-safe mechanisms to keep themselves from growing out of control and do not form tumors. In contrast, embryonic stem cells and induced pluripotent stem cells form tumors and must be differentiated before transplantation. Second, Muse cells possess potent anti-immune mechanisms, including human leukocyte antigen G and indoleamine 2,3-dioxygenase that prevent both cellular and humoral immunity. Muse cells engraft even though they do not match HLA antigens with the host. Third, Muse cells are able to determine what kind and how many cells they need to make for tissue repair. While the mechanisms responsible for these traits are not well understood, Muse cells are able to enter severely injured tissues of all kinds and repair them. Study of mechanisms underlying these traits of Muse cells is likely to yield new therapies for cancer prevention, autoimmune diseases, and repair of injured tissues. The future is bright for Muse cells. PMID- 30484239 TI - Relation Between Delirium and Anticholinergic Drug Burden in a Cohort of Hospitalized Older Patients: An Observational Study. AB - BACKGROUND: Delirium is a neuropsychiatric syndrome which occurs on average in one out of five hospitalized older patients. It is associated with a number of negative outcomes, including worsening of cognitive and functional status, increasing the burden on patients and caregivers, and elevated mortality. Medications with anticholinergic effect have been associated with the clinical severity of delirium symptoms in older medical inpatients, but this association is still debated. OBJECTIVE: The aim was to assess the association between delirium and anticholinergic load according to the hypothesis that the cumulative anticholinergic burden increases the risk of delirium. METHODS: This retrospective, cross-sectional study was conducted in a sample of older patients admitted to the Acute Geriatric Unit (AGU) of the San Gerardo Hospital in Monza (Italy) between June 2014 and January 2015. Delirium was diagnosed on admission using the 4 'A's Test (4AT), a validated screening tool for delirium diagnosis, which has shown good sensitivity and specificity to detect this condition in elderly patients admitted to an AGU. Each patient's anticholinergic burden was measured with the Anticholinergic Cognitive Burden (ACB) scale, a ranking of anticholinergic medications to predict the risk of adverse effects on the central nervous system in older patients. RESULTS: Of the 477 eligible for the analysis, 151 (31.7%) had delirium. According to the ACB scale, 377 patients (79.0%) received at least one anticholinergic drug. Apart from quetiapine, which has a strong anticholinergic effect, the most commonly prescribed anticholinergic medications had potential anticholinergic effects but unknown clinically relevant cognitive effects according to the ACB scale (score 1). Patients with delirium had a higher anticholinergic burden than those without delirium, with a dose effect relationship between total ACB score and delirium, which was significant at univariate analysis. A plateau risk was found in patients who scored 0-2, but patients who scored 3 or more had about three or six times the risk of delirium than those not taking anticholinergic drugs. The dose-response relationship was maintained in the multivariate model adjusted for age and sex [odds ratio (OR) 5.88, 95% confidence interval (CI) 2.10-16.60, p = 0.00007], while there was only a non-significant trend in the models adjusted also for dementia and Mini Nutritional Assessment (OR 2.73, 95% CI 0.85-8.77, p = 0.12). CONCLUSIONS: Anticholinergic drugs may influence the development of delirium due to the cumulative effect of multiple medications with modest antimuscarinic activity. However, this effect was no longer evident in multivariable logistic regression analysis, after adjustment for dementia and malnutrition. Larger, multicenter studies are required to clarify the complex relationship between drugs, anticholinergic burden and delirium in various categories of hospitalized older patients, including those with dementia and malnutrition. PMID- 30484240 TI - Aging in Primary Systemic Vasculitis: Implications for Diagnosis, Clinical Manifestations, and Management. AB - Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) usually affect adults and older populations. The well recognized clinical (i.e., granulomatosis with polyangiitis [GPA], microscopic polyangiitis, and eosinophilic GPA) and serological phenotypes (i.e., anti-MPO-ANCA, anti-PR3-ANCA and ANCA negative) within AAV differ substantially for clinical, demographic, and epidemiological features, including age at presentation. Whether and how aging could contribute to the clinical expression of these disease phenotypes is intriguing and still overlooked. In addition, despite being predominantly a disease of the elderly, most of the studies analyzing drug interventions and the clinical trials on AAV explicitly excluded older patients, limiting the understanding of the disease in this subset of patients. In elderly patients induced with cyclophosphamide, a lower dose of treatment for patients aged 60 years or older and with reduced renal function has been recommended. Giant cell arteritis (GCA) and Takayasu's arteritis (TAK) are two primary systemic vasculitides involving large vessels that differ in age at presentation, with GCA patients being at least 10 years older than TAK patients. Different treatment approaches are effective in these conditions. However, a few authors have suggested that they might be considered expressions of the same clinical syndrome, rather than two different diseases. Novel insights into the role of senescence-related immunological and vascular processes might help to interpret the link between these two conditions. Overall, the impact of aging on all these vasculitides is complex and not easy to analyze. So far, few studies focusing on this topic have been published. We reviewed data on the clinical presentation, epidemiology, therapy, and disease- and treatment-related complications in patients affected by these vasculitides, highlighting the differences in young versus elderly subjects. PMID- 30484241 TI - Effects of N-Glycans on Glycoprotein Folding and Protein Dynamics. AB - This chapter describes the folding of synthetic homogeneous glycosylpolypeptides into glycoproteins depending on the position and number of glycosylation sites and oligosaccharide structures. To evaluate the role of oligosaccharides in protein folding, we synthesized small glycoprotein models, homogeneous misfolded glycoproteins, and erythropoietins. In addition to these chemical syntheses, this chapter introduces a unique method for 15N-labeling of synthetic glycoproteins to enable structural analysis. Based on experimental results, it can be suggested that N-glycans stabilize the structure of glycoproteins. PMID- 30484242 TI - Synthesis of Glycosylated Metal Complexes for Probing Carbohydrate-Carbohydrate Interactions. AB - Densely packed carbohydrate clusters on cell surfaces play essential roles in varieties of bioprocesses. Little information has been, however, accumulated so far concerning their structural/functional details. In this chapter, we discuss artificial systems to investigate carbohydrate-carbohydrate interactions within/between the carbohydrate cluster(s). Among such artificial systems, much attention will be especially placed on glycosylated tris-bipyridine ferrous complexes for monitoring not only carbohydrate-carbohydrate interactions within the glycocluster but also their resultant conformational changes. PMID- 30484243 TI - Unraveling of Lipid Raft Organization in Cell Plasma Membranes by Single-Molecule Imaging of Ganglioside Probes. AB - Ganglioside s are involved in a variety of physiological roles and particularly in the formation and function of lipid rafts in cell membranes. However, the dynamic behaviors of gangliosides have not been investigated in living cells owing to the lack of fluorescent probes that behave like their parental molecules. This has recently been resolved by developing new fluorescent ganglioside analogues that act similarly to their parental molecules, synthesized by only chemical methods. We performed single fluorescent-molecule imaging and revealed that ganglioside probes dynamically enter and exit rafts containing CD59, a glycosylphosphatidylinositol (GPI)-anchored protein, both before and after stimulation. The residency time of our ganglioside probes in CD59 oligomers was 48 ms after stimulation. The residency times in CD59 homodimer and monomer rafts were 40 and 12 ms, respectively. These results reveal the first direct evidence that GPI-anchored receptors and gangliosides interact in a cholesterol dependent manner. Furthermore, they demonstrate that gangliosides continually move in and out of rafts that contain CD59 in an extremely dynamic manner and at a much higher frequency than expected. In this chapter, we review methods for the development and single-molecule imaging of new fluorescent ganglioside analogues and discuss how raft domains are formed, both before and after receptor engagement. PMID- 30484244 TI - MALDI Mass Spectrometry Imaging of N-Linked Glycans in Tissues. AB - Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been used for two decades to profile the glycan constituents of biological samples. An adaptation of the method to tissues, MALDI mass spectrometry imaging (MALDI-MSI), allows high-throughput spatial profiling of hundreds to thousands of molecules within a single thin tissue section. The ability to profile N-glycans within tissues using MALDI-MSI is a recently developed method that allows identification and localization of 40 or more N glycans. The key component is to apply a molecular coating of peptide-N glycosidase to tissues, an enzyme that releases N-glycans from their protein carrier. In this chapter, the methods and approaches to robustly and reproducibly generate two-dimensional N-glycan tissue maps by MALDI-MSI workflows are summarized. Current strengths and limitations of the approach are discussed, as well as potential future applications of the method. PMID- 30484245 TI - Isomeric Separation and Characterisation of Glycoconjugates. AB - Individual monosaccharides can be linked in a variety of different combinations to form complex glycoconjugates. In contrast to DNA and proteins, glycoconjugate synthesis does not follow any template but is the consequence of the concerted action of various enzymes such as transferases and glycosidases . Thus, tools for glycoconjugate sequencing need to differentiate individual monosaccharide identity, linkage and anomericity to investigate and understand glycoconjugate function. In this chapter we provide a concise overview on the most commonly used and robust tools to separate and characterise glycoconjugate isomers. PMID- 30484246 TI - Synchrotron-Radiation Vacuum-Ultraviolet Circular-Dichroism Spectroscopy for Characterizing the Structure of Saccharides. AB - Circular-dichroism (CD) spectroscopy is a powerful tool for analyzing the structures of chiral molecules and biomolecules. The development of CD instruments using synchrotron radiation has greatly expanded the utility of this method by extending the spectra to the vacuum-ultraviolet (VUV) region below 190 nm and thereby yielding information that is unobtainable by conventional CD instruments. This technique is especially advantageous for monitoring the structure of saccharides that contain hydroxy and acetal groups with high-energy transitions in the VUV region. Combining VUVCD spectra with theoretical calculations provides new insight into the contributions of anomeric hydroxy groups and rotational isomers of hydroxymethyl groups to the dynamics, intramolecular hydrogen bonds, and hydration of saccharides in aqueous solution. PMID- 30484247 TI - Biophysical Analyses for Probing Glycan-Protein Interactions. AB - Glycan-protein interactions occur at many physiological events, and the analyses are of considerable importance for understanding glycan-dependent mechanisms. Biophysical approaches including 3D structural analysis are essential for revealing glycan-protein interactions at the atomic level. The inherent diversity of glycans suits them to function as identification tags, e.g., distinguish self from the nonself components of pathogens. However, the complexity of glycans and poor affinities for interaction partners limit the usefulness of conventional analyses. To cope with such troublesome glycans, a logical sequence of biophysical analyses need to be developed. In this chapter, we introduce a workflow of glycan-protein interaction analysis consisting of six steps: preparation of lectin and glycan, screening of glycan ligand, determination of binding epitope, quantitative interaction analysis, 3D structural analysis, and molecular dynamics simulation. Our increasing knowledge and understanding of lectin-glycan interactions will hopefully lead to the design of glyco-based medicines and vaccines. PMID- 30484248 TI - Structural Aspects of ER Glycoprotein Quality-Control System Mediated by Glucose Tagging. AB - N-linked oligosaccharides attached to proteins act as tags for glycoprotein quality control, ensuring their appropriate folding and trafficking in cells. Interactions with a variety of intracellular lectins determine glycoprotein fates. Monoglucosylated glycoforms are the hallmarks of incompletely folded glycoproteins in the protein quality-control system, in which glucosidase II and UDP-glucose/glycoprotein glucosyltransferase are, respectively, responsible for glucose trimming and attachment. In this review, we summarize a recently emerging view of the structural basis of the functional mechanisms of these key enzymes as well as substrate N-linked oligosaccharides exhibiting flexible structures, as revealed by applying a series of biophysical techniques including small-angle X ray scattering, X-ray crystallography, high-speed atomic force microscopy , electron microscopy , and computational simulation in conjunction with NMR spectroscopy. PMID- 30484249 TI - Structural Basis of Protein Asn-Glycosylation by Oligosaccharyltransferases. AB - Glycosylation of asparagine residues is a ubiquitous protein modification. This N glycosylation is essential in Eukaryotes, but principally nonessential in Prokaryotes (Archaea and Eubacteria), although it facilitates their survival and pathogenicity. In many reviews, Archaea have received far less attention than Eubacteria, but this review will cover the N-glycosylation in the three domains of life. The oligosaccharide chain is preassembled on a lipid-phospho carrier to form a donor substrate, lipid-linked oligosaccharide (LLO). The en bloc transfer of an oligosaccharide from LLO to selected Asn residues in the Asn-X-Ser/Thr (X?Pro) sequons in a polypeptide chain is catalyzed by a membrane-bound enzyme, oligosaccharyltransferase (OST). Over the last 10 years, the three-dimensional structures of the catalytic subunits of the Stt3/AglB/PglB proteins, with an acceptor peptide and a donor LLO, have been determined by X-ray crystallography, and recently the complex structures with other subunits have been determined by cryo-electron microscopy . Structural comparisons within the same species and across the different domains of life yielded a unified view of the structures and functions of OSTs. A catalytic structure in the TM region accounts for the amide bond twisting, which increases the reactivity of the side-chain nitrogen atom of the acceptor Asn residue in the sequon. The Ser/Thr-binding pocket in the C terminal domain explains the requirement for hydroxy amino acid residues in the sequon. As expected, the two functional structures are formed by the involvement of short amino acid motifs conserved across the three domains of life. PMID- 30484250 TI - Visualization of Functional Structure and Kinetic Dynamics of Cellulases. AB - Cellulose is the most abundant carbohydrate on earth and hydrolyzed by cellulases in nature. During catalysis, cellulase transfers protons to and from the oxygen atoms of the glycosidic bond and a water molecule. Since cellulose is an insoluble polymer, some kinds of cellulases, with high activity toward crystalline cellulose, move on the crystal surface with continuous hydrolysis of the molecular chain. In addition, binding and dissociation on/from the crystal surface are also important elementary steps of the reaction cycle. Recently, these interesting features of cellulases can be directly analyzed, due to the development of visualization techniques. In this chapter, we introduce (1) visualization of the protonation state of the catalytic residue by neutron crystallography, (2) visualization of processive movement on the crystal surface by high-speed atomic force microscopy , and (3) visualization of binding and dissociation events by single-molecule fluorescence microscopy. PMID- 30484251 TI - Structure and Dynamics of Immunoglobulin G Glycoproteins. AB - Immunoglobulin G (IgG) is a major serum glycoprotein that exerts the role of antibody in the immune system. This multifunctional glycoprotein couples antigen recognition with a variety of effector functions promoted via interactions with various IgG-binding proteins. Given its versatile functionality, IgG has recently been used for therapeutic interventions. Evidence indicates that the carbohydrate moieties of IgG glycoproteins critically affect their antibody functions, particularly the effector functions mediated by the interactions with Fcgamma receptors (FcgammaRs). N-glycans at specific positions of FcgammaR also contribute both positively and negatively to the interactions with IgG. The integration of multilateral biophysical approaches, including X-ray crystallography, nuclear magnetic resonance spectroscopy, and molecular dynamics simulations, has provided structural insights into the mechanisms underlying the glycofunctions of this interacting system. The N-glycans of IgG and FcgammaR mediate their interactions by either strengthening or weakening the affinity on the basis of their glycoforms. Moreover, the N-glycosylation of IgG-Fc is a prerequisite to maintain the integrity of the quaternary structure of the sites interacting with the effector molecules and can also control functionally relevant local conformations. The biopharmaceutical significance of these glycan functions is discussed from a structural point of view. PMID- 30484253 TI - Quantifying Weak Glycan-Protein Interactions Using a Biolayer Interferometry Competition Assay: Applications to ECL Lectin and X-31 Influenza Hemagglutinin. AB - This chapter introduces two formats using bio-layer interferometry competition assays to determine the solution K D values of weak glycan-protein interactions. This approach overcomes the challenge of determining weak interactions while minimizing the amount of reagents required. Accurate solution K D values aid in understanding the complex relationships between monomeric versus multimeric interactions and affinity versus avidity. The assays have been applied to a well studied lectin (Erythrina crista-galli lectin) and influenza hemagglutinin (X 31). The solution K D values determined from this approach are in good agreement with previous reported literature values from isothermal titration calorimetry and NMR. Additionally, this approach appears robust and precise. PMID- 30484252 TI - Biophysical Approaches to Solve the Structures of the Complex Glycan Shield of Chloroviruses. AB - The capsid of Paramecium bursaria chlorella virus (PBCV-1) contains a heavily glycosylated major capsid protein, Vp54. The capsid protein contains four glycans, each N-linked to Asn. The glycan structures are unusual in many aspects: (1) they are attached by a beta-glucose linkage, which is rare in nature; (2) they are highly branched and consist of 8-10 neutral monosaccharides; (3) all four glycoforms contain a dimethylated rhamnose as the capping residue of the main chain, a hyper-branched fucose residue and two rhamnose residues ''with opposite absolute configurations; (4) the four glycoforms differ by the nonstoichiometric presence of two monosaccharides, L-arabinose and D-mannose ; (5) the N-glycans from all of the chloroviruses have a strictly conserved core structure; and (6) these glycans do not resemble any structures previously reported in the three domains of life.The structures of these N-glycoforms remained elusive for years because initial attempts to solve their structures used tools developed for eukaryotic-like systems, which we now know are not suitable for this noncanonical glycosylation pattern. This chapter summarizes the methods used to solve the chlorovirus complex glycan structures with the hope that these methodologies can be used by scientists facing similar problems. PMID- 30484254 TI - Strength training is associated with better functional fitness and perceived healthy aging among physically active older adults: a cross-sectional analysis of the Canadian Longitudinal Study on Aging. AB - BACKGROUND: Regular participation in strength exercise is important to promote healthy aging. However, much of the available evidence on physical activity and older adults has focused on aerobic activity, while there is less research on the benefits of exercise that is performed specifically to strengthen muscles. AIMS: Using cross-sectional data from the Canadian Longitudinal Study on Aging, the purpose of this study was to determine if strength training is associated with better functional fitness and health among older adults who meet the minimum guidelines for aerobic physical activity. METHODS: Older adults who met guidelines for aerobic physical activity (>= 60 years, N = 9100) completed performance-based assessments of physical function and self-reported their physical activity, perceived health, and chronic conditions. Body fat was determined using DEXA. Logistic regression analyses were used to determine whether strength training was associated with better functional fitness, body composition, and health. RESULTS: 32.5% of active older adults reported engaging in strength training 1-7 days per week. Participating in any strength training was associated with better scores on measures of balance (OR 1.17, CI 1.04, 1.32), mobility (OR 1.32, CI 1.18, 1.47), body fatness (OR 1.58, CI 1.38, 1.81), and better perceived health (OR 1.34, CI 1.19, 1.51), and healthy aging (OR 1.26, CI 1.12, 1.42). DISCUSSION: These results suggest that all older adults, even those who are active and have good mobility, may benefit from strength training. CONCLUSION: Physical activity guidelines should place a greater emphasis on strength training for older adults. PMID- 30484255 TI - Resveratrol and 1,25-dihydroxyvitamin D co-administration protects the heart against D-galactose-induced aging in rats: evaluation of serum and cardiac levels of klotho. AB - The current study investigates the cooperative cardioprotective effect of calcitriol (active form of vitamin D) combined with resveratrol in a rat model of D-galactose (D.gal)-induced aging. Male Wistar rats received resveratrol (D.gal + Res), calcitriol (D.gal + Cal), or a combination of them (D.gal + Res + Cal). Intact animals served as control (Ctl). Blood pressure (BP) was recorded by cannulation of the left carotid artery. Fibrosis and cell size were assessed by Masson's trichrome and hematoxylin-eosin staining, respectively. Cardiac and serum level of antiaging protein, klotho, was measured by ELISA assay method. Gene expression was evaluated by real-time RT-PCR. Biochemical tests were performed according to the standardized method. In D.gal + Res + Cal group, BP, heart weight-to-body weight ratio, and cardiomyocytes size decreased significantly compared with D-gal group. The cardiac transcription levels of catalase and superoxide dismutase 1 and 2 were upregulated in D.gal + Res + Cal compared to the D.gal group (P < 0.001, P < 0.05, P < 0.05, respectively). Increased level of malondialdehyde was observed in D.gal group (P < 0.01 vs. Ctl) which was normalized partially in D.gal + Res + Cal group (P < 0.05). Catalase and superoxide dismutase activity also increased in D.gal + Res + Cal group (P < 0.01 vs. D.gal). Cardiac Klotho, as the antiaging protein, remained unchanged at mRNA and protein levels among the experimental groups. The serum level of Klotho did not change significantly in D.gal group; however, in D.gal + Res + Cal group, serum klotho concentration was increased (P < 0.05 vs. D.gal). It could be concluded that co-administration of resveratrol and vitamin D protects the heart against aging-induced damage by the modulation of hemodynamic parameters and antioxidant status of the heart. Furthermore, increased serum level of klotho could be a novel mechanism for antiaging effects of resveratrol and vitamin D. PMID- 30484256 TI - Amphotericin B-loaded nanoparticles for local treatment of cutaneous leishmaniasis. AB - Cutaneous leishmaniasis (CL) is an infectious, parasitic disease caused by the protozoan Leishmania. Amphotericin B (AMB) is a macrolide polyene antibiotic presenting potent antifungal and antileishmanial activity, but due to poor water solubility at physiological pH, side effects, and toxicity, its therapeutic efficiency is limited. In the present study, poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with AMB were generated to reduce drug toxicity and facilitate localized delivery over a prolonged time. AMB NPs were characterized for particle size, zeta potential, polydispersity index, and degree of aggregation. In vitro assessments demonstrated its sustained activity against Leishmania major promastigotes and parasite-infected macrophages. A single intralesional administration to infected BALB/c mice revealed that AMB NPs were more effective than AMB deoxycholate in terms of reducing lesion area. Taken together, these findings suggest that AMB NPs improve AMB delivery and can be used for local treatment of CL. PMID- 30484257 TI - Newly synthesized surfactants for surface mannosylation of respirable SLN assemblies to target macrophages in tuberculosis therapy. AB - The present study reports about new solid lipid nanoparticle assemblies (SLNas) loaded with rifampicin (RIF) surface-decorated with novel mannose derivatives, designed for anti-tuberculosis (TB) inhaled therapy by dry powder inhaler (DPI). Mannose is considered a relevant ligand to achieve active drug targeting being mannose receptors (MR) overexpressed on membranes of infected alveolar macrophages (AM), which are the preferred site of Mycobacterium tuberculosis. Surface decoration of SLNas was obtained by means of newly synthesized functionalizing compounds used as surfactants in the preparation of carriers. SLNas were fully characterized in vitro determining size, morphology, drug loading, drug release, surface mannosylation, cytotoxicity, macrophage internalization extent and ability to bind MR, and intracellular RIF concentration. Moreover, the influence of these new surface functionalizing agents on SLNas aerodynamic performance was assessed by measuring particle respirability features using next generation impactor. SLNas exhibited suitable drug payload, in vitro release, and more efficient ability to enter macrophages (about 80%) compared to bare RIF (about 20%) and to non-functionalized SLNas (about 40%). The involvement of MR-specific binding has been demonstrated by saturating MR of J774 cells causing a decrease of RIF intracellular concentration of about 40%. Furthermore, it is noteworthy that the surface decoration of particles produced a poor cohesive powder with an adequate respirability (fine particle fraction ranging from about 30 to 50%). Therefore, the proposed SLNas may represent an encouraging opportunity in a perspective of an efficacious anti TB inhaled therapy. PMID- 30484258 TI - Pectin-encrusted gold nanocomposites containing phytic acid and jacalin: 1,2 dimethylhydrazine-induced colon carcinogenesis in Wistar rats, PI3K/Akt, COX-2, and serum metabolomics as potential targets. AB - Phytic acid (PA) has momentous chemotherapeutic potential. Due to the chelate formation and rapid elimination, it is not popular in cancer treatment. The present work was inquested to develop a surface-modified nanoformulation of PA which prevents its speedy elimination and maximizes chemotherapeutic action. Chloroauric acid was reduced with pectin to produce pectin-gold nanoparticles (PGNPs). PGNPs were incubated with PA and jacalin for drug loading and surface modifications, respectively, to form PA-loaded jacalin-pectin-gold nanoparticles (PA-J-PGNPs). Formulation(s) were assessed for various pharmaceutical/pharmacological parameters. To validate the efficacy against colon carcinogenesis, formulation(s) were assessed in 1,2-dimethylhydrazine (DMH) treated Wistar rats. DMH treatment distorted colonic architecture, oxidative, and hemodynamic parameters, which were favorably restored by PA-J-PGNP administration. To further confirm our deliberations, formulation(s) were also examined against DMH-altered metabolic changes and expression of markers pertaining to cellular proliferation, which was reinstated by PA-J-PGNPs. Our findings establish PA formulation(s) as a promising approach for suppression of colon carcinogenesis. PMID- 30484259 TI - Investigation of the relation between administered dose and image quality for pediatric 99mTc-DMSA renal scintigraphy: clinical study applying the JSNM (Japanese Society of Nuclear Medicine) pediatric dosage card : The Japanese Society of Nuclear Medicine Technology (JSNMT), the Optimization of Imaging Technique Committee for Pediatric Nuclear Medicine Studies. AB - PURPOSE: In 2013, the Japanese Society of Nuclear Medicine (JSNM) announced consensus guidelines for pediatric nuclear medicine. These JSNM guidelines proposed use of lower administered doses compared with traditionally determined doses, which were estimated from age, weight or body surface area (BSA) based on the administered dose for adults in Japan. When the JSNM guidelines are used, the relationship between this recommended administered dose and image quality remains unclear. In this study, we clarified the relationship between administered dose and image quality for pediatric 99mTc-DMSA renal scan retrospectively, and verified the diagnosable image quality with the recommended administered dose of the JSNM guidelines. MATERIALS AND METHODS: Data from 7 pediatric patients who underwent 99mTc-DMSA dynamic renal scans according to the guidelines' recommended doses were collected. Scan frame rate was 1 frame/min, and scan time was up to 8 min. Eight images, which had different acquired time periods from 1 min to 8 min were prepared by adding each frame. Nine nuclear medicine specialists determined 8 images with different acquired times as diagnosable or undiagnosable. A region of interest (ROI) with 50% thresholds was placed on each kidney of every image. Coefficient of variation (CV) was calculated by dividing the standard deviation (sigma) by the mean counts (u) of each ROI (CV = sigma/u * 100). 99mTc-DMSA renal scans (total of 2821 cases) that were performed previously in collaboration with 6 hospitals were collected, and CVs of these images were calculated in all cases. These 2821 cases were separated into 5 groups for every 10 kg weight; i.e., (1) less than 10 kg, (2) 10-19.9 kg, (3) 20-29.9 kg, (4) 30-39.9 kg, and (5) above 40 kg. Regression line of each group was analyzed in relation to the CV and administered dose. The CV at the point of intersection with the recommended dose range from the guideline was determined for each group. This CV value was considered as the estimated CV of the image obtained when the recommended dose of the guideline was used. Thus, if the CV was equal to or less than the estimated CV value, then the diagnostic image quality was deemed satisfactory. RESULTS: Average CV of the lower limit of diagnosable images in 7 cases as determined by 9 nuclear medicine specialists was 19.9%. Estimated CV was 21.2-24.2% in the group weighing < 10 kg (group 1), 19.9-20.6% in the group weighing > 10 kg and < 20 kg (group 2), 19.6% in group weighing > 20 kg and < 30 kg (group 3), 19.4-19.5% in the group weighing > 30 kg and < 40 kg (group 4), and 19.8% in the group weighing > 40 kg (group 5). The estimated CVs from groups 1 and 2 with weight < 20 kg exceeded 19.9%. CONCLUSIONS: Although 99mTc-DMSA renal scan can be carried out using the guidelines' recommended dose with conventional image acquisition time in patients weighing 20 kg or more, those < 20 kg need consideration for a longer image acquisition time to obtain diagnosable images. PMID- 30484260 TI - Introduction of the targeted alpha therapy (with Radium-223) into clinical practice in Japan: learnings and implementation. AB - Radium-223 dichloride (Ra-223) is the first targeted alpha therapy approved for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastasis. Ra-223 improved overall survival in the international Phase III ALSYMPCA (ALpharadin in SYMPtomatic Prostate Cancer) study. Ra-223 was also demonstrated to be efficacious and safe in Japanese patients in Phase I and Phase II clinical trials. Ra-223 was approved in Japan for the treatment of patients with CRPC with bone metastasis in 2016. The conduct of clinical studies with radionuclides in Japan involves mandatory compliance with local and international regulations pertaining to radiation protection. Without an existing Japanese framework for the handling of alpha-emitters in clinical practice, we encountered many challenges to initiate the clinical studies. Therefore, we started on a project to determine best practice on the use of Ra-223 in clinical studies. For this project, we evaluated all applicable laws and regulations on the use of radionuclides in medicine, then examined whether and how the alpha-emitter Ra-223 could meet these legal and regulatory requirements. This included how to approach the matter of discharging patients administered Ra-223 from hospital and radiation protection for caregivers, general public and medical care professionals. Subsequently, we published Manual on the proper use of radium-223 dichloride injection in clinical trials that summarized the essential requirements necessary to allow the safe use of Ra-223 in clinical trials in Japan. As the result, we succeeded in demonstrating that clinical trials of an alpha-emitter, Ra-223, could be implemented safely in Japan. Our experience in Japan highlights the importance of a multidisciplinary team-based approach and continued professional training in a clinical setting. This article summarizes the rationale behind the development of this manual. We hope that by sharing our experience and information, we can help other countries considering the introduction of radionuclides for clinical use, and support the future development of radionuclide therapies in a safe and effective manner. PMID- 30484261 TI - Precursor Lesions of the Vocal Cord: a Study on the Diagnostic Role of Histomorphology, Histometry and Ki-67 Proliferation. AB - The precise typing of precursor lesions of squamous cell carcinoma of vocal cord is of vital importance since it determines the line of therapy and prognosis. The aim of the present study is to evaluate the possible value of the types of dyskeratosis, histometry and cell proliferation rate in discriminating these lesions. The present retrospective study was based on 145 patients, classified according to the updated 2017 WHO system and included: Low-grade dysplasia (24 cases), high -grade dysplasia (53 cases), carcinoma insitu (33 cases) and microinvasive carcinomas (35 cases). Cell proliferation was assessed by immunoreactivity to Ki-67. For histometry and quantitation of Ki-67 proliferation rate, an image analysis system was used (Leica LAS, Wetzlar, Germany). Epithelial pearls (cell nests) were commonly observed in microinvasive carcinoma (82.9%) than high-grade dysplasia (5.9%). The median epithelial thickness, as well as, proliferation rate showed a significant increase according to the grade of the lesion. It is concluded that dyskeratosis pattern, histometry and Ki 67proliferation rate are valuable parameters to characterize precursor lesions. The presence of epithelial pearls, thickness > 450 MUm and Ki-67 > 40% denote high risk lesions that require adequate excision and/or radiotherapy. PMID- 30484262 TI - Patterns of Regression in Breast Cancer after Primary Systemic Treatment. AB - Despite national guidelines, the evaluation of effects of primary systemic treatment (PST) in breast cancer is a complex challenge. Our aims were to evaluate the response patterns focusing on correlations of radiological and pathological tumor size, regression heterogeneity in different molecular subtypes, cellularity changes and the incidence of enlarged, multinucleated neoplastic cells related to therapy. Slides of pretreatment biopsies and resection specimens of consecutive cases were reevaluated focusing on heterogeneity of regression per whole slide, and 40x or 100x magnification fields. Alteration in cellularity and the presence of multinucleated tumor giant cells were noted. The correlation of pathological and radiological sizes and their alterations were analyzed by Spearman rank correlation. The present study included 106 tumors. A decrease in size (84.9%) and cellularity (76.4%) was noted in all molecular subtypes. Inhomogeneous regression was found in 45.3%, with minor inhomogeneity in the majority. Scatter pattern regression was seen only in 8 cases (7.5%). Significant correlations were found between the pathological and radiological sizes (p = 0.02), and between the alterations of cellularity and pathological and radiological size (p = 0.04; p = 0.03, respectively). Multinucleated tumor giant cells were noted in 17.9% (n = 19), nearly exclusively in cases treated with PST including taxanes. Regression inhomogeneity following PST is present in about half of the cases, and is not related to molecular subtypes. The evaluation of the maximum area of the tumor bed is recommended for the proper evaluation of regression. Multinucleated tumor giant cells are related to PST including taxane derivate, and may cause upgrading. PMID- 30484263 TI - Expression and Significance of TRIM 28 in Squamous Carcinoma of Esophagus. AB - Tripartite motif-containing protein 28 (TRIM28) has been proved to accelerate cell proliferation and metastasis in a variety of human cancers. However, the role of TRIM28 in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, to compare the biological effect and significance of TRIM28 expression in ESCC, immunohistochemistry (streptavidin-perosidase, S-P) method was used firstly to examine the expression of TRIM28 in 136 cases of ESCC, 35 cases of high grade intraepithelial neoplasia (HGIN), 29 cases of low grade intraepithelial neoplasia (LGIN) and 37 cases of normal esophageal epithelium (NEE). Then the associations of TRIM28 expression with clinicopathological data and overall survival (OS) were also analyzed. Western blot was performed to evaluate TRIM28 protein in a total of 20 matched human ESCC and NEE tissues. Moreover, the localization of TRIM28 protein in ESCC and NEE tissues was also detected by immunofluorescence. TRIM28 protein was mainly distributed in the nucleus of ESCC. The expression of TRIM28 increased progressively from NEE to LGIN, to HGIN, and to ESCC, and it was also related to invasive depth, pTNM stage and lymph node metastasis in ESCC (P < 0.05). The results of western blot and immunofluorescence all showed that the relative expression of TRIM28 protein was markedly upregulated in ESCC compared with the NEE tissues (P < 0.01). However, prognostic analysis showed that TRIM28 may not be a prognostic factor of patients with ESCC. In conclusion, the overexpression of TRIM28 may play an important role for development and metastasis in ESCC. PMID- 30484264 TI - Oxidative Stress in beta-Thalassemia. AB - Cell oxidative status, which represents the balance between oxidants and antioxidants, is involved in normal functions. Under pathological conditions, there is a shift toward the oxidants, leading to oxidative stress, which is cytotoxic, causing oxidation of cellular components that result in cell death and organ damage. Thalassemia is a hereditary hemolytic anemia caused by mutations in globin genes that cause reduced or complete absence of specific globin chains (commonly, alpha or beta). Although oxidative stress is not the primary etiology of thalassemia, it mediates several of its pathologies. The main causes of oxidative stress in thalassemia are the degradation of the unstable hemoglobin and iron overload-both stimulate the production of excess free radicals. The symptoms aggravated by oxidative stress include increased hemolysis, ineffective erythropoiesis and functional failure of vital organs such as the heart and liver. The oxidative status of each patient is affected by multiple internal and external factors, including genetic makeup, health conditions, nutrition, physical activity, age, and the environment (e.g., air pollution, radiation). In addition, oxidative stress is influenced by the clinical manifestations of the disease (unpaired globin chains, iron overload, anemia, etc.). Application of personalized (theranostics) medicine principles, including diagnostic tests for selecting targeted therapy, is therefore important for optimal treatment of the oxidative stress of these patients. We summarize the role of oxidative stress and the current and potential antioxidative therapeutics in beta-thalassemia and describe some methodologies, mostly cellular, that might be helpful for application of a theranostics approach to therapy. PMID- 30484265 TI - Low molecular weight heparin in surgical valve procedures: When and how much for an optimal prophylaxis? AB - BACKGROUND: Periprocedural antithrombotic prophylaxis in patients undergoing surgical valve procedures (SVP) is insufficiently investigated. Low molecular weight heparin (LMWH) has been considered as an alternative to unfractionated heparin (UFH). However, safety and efficacy of this prophylaxis strategy is unknown. This study aimed to investigate safety and efficacy of periprocedural LMWH prophylaxis and determine optimal dosage and timing for periprocedural cessation and initiation. METHODS: The present study is a retrospective, single center observational analysis of 388 patients who underwent SVP (valve replacement or valvuloplasty) between 2015 and 2016. In-hospital endpoints were bleeding, transfusions, reoperation due to bleeding, and thromboembolic events. RESULTS: Giving the first dose of LMWH on the day of SVP was a risk factor for bleeding (OR 1.07; 95% CI 1.04-1.10; p < 0.001), transfusions (OR 1.04; 95% CI 1.01-1.07; p = 0.008) and reoperation due to bleeding (OR 1.20; 95% CI 1.12-1.28; p < 0.001), with > 40 mg/day as a predictor. A higher dosage of LMWH premedication was an independent risk factor for bleeding (OR 1.02; 95% CI 1.00 1.04; p = 0.03) and transfusion (OR 1.03; 95% CI 1.01-1.05; p = 0.01), with > 60 mg/day as a predictor for these events. LMWH dosed within 24 h prior to SVP increased the risk of transfusion (AUC 0.636; 95% CI 0.496-0.762; p = 0.04). CONCLUSIONS: Bleeding is an important early concern after surgical valve procedures. Safety and efficacy of periprocedural prophylaxis with LMWH depends on dosage and the timing of its administration. The most optimal periprocedural prophylaxis in the SVP population appears to be LMWH in dosage of 40-60 mg/day, which is recommended for deep vein thrombosis prophylaxis, ceased at least one day before SVP. PMID- 30484267 TI - Predictors for early mortality and arrhythmic events in patients with a CRT-D: A two center cohort study. AB - BACKGROUND: Guidelines of heart failure therapy include cardiac resynchronization as standard of care in patients with severely depressed left ventricular function and wide QRS complex. It has been shown that patients benefit regarding mortality and morbidity. However, early mortality precludes long-term benefits from the device. The aim of the study was to identify predictors for early occurrence of both death and first-ever implantable cardioverter-defibrillator (ICD) therapy using a large combined database of patients with cardiac resynchronization therapy with defibrillator (CRT-D). METHODS: From two registries (tertiary care centres) 904 patients were identified, no single patient was excluded. Early death was defined as death occurring within the 3 years after implantation whereas early ICD therapy as such occurring within the first year. 33 baseline parameters were compared using uni- and multivariate analysis with the Cox model and binary logistic regression. RESULTS: The population was predominantly male (77%), with mean age of 63 +/- 11 years and primary prevention indication in 80%. Mean follow-up was 55 +/- 38 months. 256 (28%) patients had ICD therapies whereof the first-ever event occurred early in 52%. 270 (30%) patients died after 41 +/- 31 months, mostly from advancing heart failure (41%), 141 (52%) patients of them early. Independent predictors for early ICD therapy were secondary prevention and renal failure. Independent predictors for early mortality were a history of percutaneous coronary intervention and of peripheral vascular disease. CONCLUSIONS: Predictors for early mortality after CRT-D implantation were a history of percutaneous coronary intervention and peripheral vascular disease, present in only a minority of patients, thus limiting their use in clinical practice. PMID- 30484266 TI - Peak systolic velocity of tricuspid annulus is inferior to tricuspid annular plane systolic excursion for 30 days prediction of adverse outcome in acute pulmonary embolism. AB - BACKGROUND: Tricuspid annular plane systolic excursion (TAPSE) is an established index of right ventricular (RV) systolic function and a significant predictor in normotensive patients with pulmonary embolism (PE). Recently, Doppler tissue imaging-derived tricuspid annular systolic velocity (TV S'), a modern parameter of RV function was reported to be useful in the diagnosis and prognosis of a broad spectrum of heart diseases. Therefore, herein, is an analysis of the prognostic value of both parameters in normotensive PE patients. METHODS: 139 consecutive PE patients (76 female, age 56.4 +/- 19.5 years) were included in this study. All patients were initially anticoagulated. Transthoracic echocardiography was performed on admission. The study endpoint (SE) was defined as PE-related 30-day mortality and/or need for rescue thrombolysis. RESULTS: Seven (5%) patients who met the criteria for SE presented more severe RV dysfunction at echocardiography. Univariable Cox regression analysis showed that RV/LV ratio predicted SE with hazard risk (HR) 10.6 (1.4-80.0; p = 0.02); TAPSE and TV S' showed HR 0.77 (0.67-0.89), p < 0.001, and 0.71 (0.52-0.97), p = 0.03, respectively. Area under the curve for TAPSE in the prediction of SE was 0.881; 95% CI 0.812-0.932, p = 0.0001, for TV S' was 0.751; 95% CI 0.670-0.820, p = 0.001. Multivariable analysis showed that the optimal prediction model included TAPSE and systolic blood pressure (SBP showed HR 0.89 95% CI 0.83-0.95, p < 0.001 and TAPSE HR 0.67, 95% CI 0.52-0.87, p<0.03). Kaplan-Meier analysis showed that initially PE patients with TAPSE > 18 mm had a much more favorable prognosis that patients with TAPSE < 18 mm (p < 0.01), while analysis of S' was only of borderline statistical significance. CONCLUSIONS: It seems that TV S' is inferior to TAPSE for 30 day prediction of adverse outcome in acute pulmonary embolism. PMID- 30484268 TI - Kinetics of selected serum markers of fibrosis in patients with dilated cardiomyopathy and different grades of diastolic dysfunction of the left ventricle. AB - BACKGROUND: Fibrosis of the extracellular matrix (ECM) in dilated cardiomyopathy (DCM) is common and compromises both systolic and diastolic function. The aim of this study was to investigate the kinetics of ECM fibrosis markers over a 12 month follow-up in patients with DCM based on the severity of diastolic dysfunction (DD). METHODS: Seventy consecutive DCM patients (48 +/- 12.1 years, ejection fraction 24.4 +/- 7.4%) were included in the study. The grade of DD was determined using the ASE/EACVI algorithm. Markers of ECM fibrosis were measured at baseline and at 3 and 12 month follow-ups: collagen type I and III (PICP, PINP, PIIICP, PIIINP), tumor growth factor beta-1 (TGF1-beta), connective tissue growth factor (CTGF) and galectin-3 were measured. RESULTS: Patients were divided into three groups according to DD severity: 30 patients with grade I, 18 with grade II and 22 with grade III of DD. Levels of PICP, PINP were increased over a 12-month period, while PIIINP decreased and PIIICP unchanged. Levels of TGF1-beta decreased from the 3 to the 12-month points in grade I and II DD, and in grade III they remained unchanged. Levels of CTGF decreased over 12 months in grade III DD but were unchanged in grades I and II. Galectin-3 levels remained the same over all observation periods, irrespective of DD grade. CONCLUSIONS: Regardless of the DD grade, markers of collagen type I synthesis increased, markers of collagen type III decreased. Levels of TGF and CTGF had a tendency to decrease. Galectin-3 was revealed not to be a marker discriminating the severity of DD. PMID- 30484269 TI - The effect of acetylsalicylic acid dosed at bedtime on the anti-aggregation effect in patients with coronary heart disease and arterial hypertension: A randomized, controlled trial. AB - BACKGROUND: Acetylsalicylic acid (ASA) is one of the basic drugs used in the secondary prevention of coronary heart disease (CAD), and in most cases it is taken in the morning in one daily dose.. It is suggested that the morning peak of platelet aggregation is responsible for the occurrence of myocardial infarctions and strokes. Hence, the aim of the study was to observe the effect of ASA (morning vs. evening) dosing on the anti-aggregative effect of platelets in patients with CAD and arterial hypertension (AH). METHODS: The study involved 175 patients with CAD and AH. Patients were randomly assigned to one of two study groups, taking ASA in the morning or in the evening. The patients had two visits, one baseline and another after 3 months from changing the time of ASA dosage. The platelet aggregation was determined using the VerifyNow analyzer. RESULTS: In the ASA evening group, a significant reduction in platelet aggregation was obtained. In the ASA morning group, a significant difference in response to ASA was observed, depending on sex. In men, the reactivity of platelets decreased, but in women it increased. CONCLUSIONS: In the group of patients with CAD and AH, bedtime ASA dosing is associated with a significant reduction in platelet aggregation. The response to ASA may differ between sexes. The benefit gained by changing the drug administration from the morning to the evening is greater in women. PMID- 30484270 TI - Sex prediction by metric and non-metric analysis of the hard palate and the pyriform aperture. AB - BACKGROUND: Analysis of the bones and bone fragments of the cranium may be a useful tool for sex diagnosis in the identification of human remains which have been exposed to adverse conditions. The object of the present study was to evaluate sex prediction through metric and non-metric analysis of the hard palate (HP) and the pyriform aperture (PA), using macerated skulls of adult individuals. MATERIALS AND METHODS: We analysed 312 dry skulls of adult individuals of both sexes, studying the metric and non-metric characteristics of the hard palate and pyriform aperture. The accuracy, sensitivity, specificity and positive and negative predictive values were evaluated. A binary logistic regression and a linear regression were performed. The ROC curve was constructed to analyse the performance of sex diagnosis. Measurements of the HP and the PA were analysed by ANOVA and Tukey's test. The SPSS v.20.0 software was used, with a significance threshold of 5%. RESULTS: The shape of the PA presented 61.9% accuracy, 54.4% sensitivity and 65.7% specificity. The shape of the HP presented 51.5% accuracy, 65.6% sensitivity and 44.7% specificity. Only the height of the PA functioned as a good predictor of sex. CONCLUSIONS: The height of the PA produced good diagnostic performance (area under curve=0.764). The height of the PA was the most reliable indicator for sex prediction, and could be used by forensic scientists to identify sex. PMID- 30484271 TI - Morphometric study of inferior peroneal retinaculum and contents of inferior peroneal tunnel. AB - The aims of this study are to investigate the inferior peroneal retinaculum (IPR) regarding morphometric parameters, and contents in the inferior peroneal tunnel (IP tunnel). One hundred and nine embalmed cadaveric legs were dissected in prone position. The extension band of the IPR was found in 31.19% of cases. The mean of length, width at the origin, width at the middle part, width at the insertion, and thickness of the IPR were 23.42 +/- 3.54 (17.05-33.68), 13.29 +/- 2.56 (5.83 20.92), 14.50 +/- 2.37 (6.68-21.34), 10.10 +/- 2.63 (4.59-19.17) and 0.48 +/- 0.16 (0.20-0.87) mm, respectively. The angle of the IPR to the horizontal axis was 38.51 +/- 7.07 (11.67-54.00) degrees. The IP tunnel was divided into the upper and lower tunnels. The normal contents were the tendons of peroneus brevis (PB) and peroneus longus (PL) in the upper and lower tunnels, respectively. However, additional contents were found in the upper tunnel in two cases. One was the tendon of peroneus digiti quinti (PDQ), and peroneus quartus (PQ) in the other one. Moreover, an unusual accessory peroneal muscle coursed into the lower tunnel and inserted on the peroneal tubercle. Tears of the PB tendon were observed in two cases. These morphometric data might be beneficial in surgical repair for IPR injury. PMID- 30484272 TI - A classical model of educational cooperation in Human Anatomy: the Table Chieftains. AB - This project has been developed for many years in the Human Anatomy courses. Its good outcomes have been confirmed by years of evidence of excellent results obtained through the learning of Human Anatomy. This method of teaching and learning as one, allows students who are taking Human Anatomy classes to receive practical training in small groups, and transmit it to their colleagues in the practical training established in the Medical degree. Table Leaders feel rewarded as they learn to speak in public, regularly transmitting the knowledge obtained, and by having to be up to date with their studies. These are all aspects that help, not only the table's chief process of learning, but also that of their colleagues, who see closely and carefully anatomical details that help them understand the subject. This method of supporting practical training is always under the supervision of the teacher who develops the practical classes. These chief used to pass the test without additional problems. Thus the note was significantly increased versus the class colleagues. PMID- 30484273 TI - ["Apuntes en Neurologia" (Notes in Neurology): a synthesis of the evidence on common paroxysmal neurological disorders and on neurodegenerative disorders]. AB - "Apuntes en Neurologia" is an initiative in which prominent national and international leaders, with broad academic recognition, came together to synthesise the most outstanding clinical aspects within their area of interest and to discuss the latest developments in a more accessible language. Understanding the factors that affect the onset and progression of any neurological disease through a review is important to be able to develop strategies to reduce the burden of these diseases. Moreover, knowledge of the clinical aspects is essential to solve the problems of daily clinical practice. The data collected here reflect the weight of evidence and some of them anticipate a promising future in the treatment of these diseases. This first edition focuses on common paroxysmal neurological disorders such as migraine, epilepsy and sleep disorders, as well as neurodegenerative disorders such as Parkinson's disease and cognitive impairment. These are clearly different pathologies, although some of them such as migraine and epilepsy, may share clinical symptoms. Sleep disorders, however, are important manifestations of neurodegenerative diseases that are sometimes clinically apparent long before the onset of other neurological symptoms. After recalling pathophysiology and diagnosis, the current review focuses on bringing together the main advances in five of the major neurological diseases. PMID- 30484274 TI - [Appraisal of cerebral atrophy in multiple sclerosis by means of the corpus callosum index]. AB - INTRODUCTION: The course of multiple sclerosis is characterised by the development of cerebral atrophy. It is of interest to monitor it in order to evaluate the treatment response, and the preferred technique consists in performing brain volume analyses, which are currently restricted to the field of research. AIM: To analyse the corpus callosum index (CCI) as a possible alternative to the methods based on brain segmentation. SUBJECTS AND METHODS: Our sample was made up of 109 patients with recently diagnosed demyelinating diseases (90 relapsing-remitting multiple sclerosis, 7 primary progressive forms and 12 isolated demyelinating syndromes), and the CCI was calculated in their first magnetic resonance brain scan, together with 101 healthy controls. The sequences of the patients were submitted to a volumetric analysis using the software package MSmetrix. RESULTS: The mean value of the CCI was 0.377 in patients and 0.411 in the controls, and the difference was statistically significant (p < 0.001). The CCI also showed a statistically significant correlation with the brain volume (p < 0.001; r = 0.444) and with the lesional volume in the FLAIR sequence (p < 0.001; r = -0.521), while no association was observed with the volume of grey matter (p = 0.058). CONCLUSIONS: The CCI is related to the overall brain volume obtained by volumetric techniques and may reflect the presence of atrophy in the initial stages of demyelinating diseases, which makes it a fast and easy to calculate alternative. PMID- 30484275 TI - [Spanish translation and validation of the Neuromuscular Module of the Pediatric Quality of Life Inventory (PedsQL): evaluation of the quality of life perceived by 8-18 years old children with neuromuscular diseases and by their parents]. AB - INTRODUCTION: The quality of life related to health of children with pediatric neuromuscular diseases is studied from the perspective of self-perception and parent-perception. It is therefore essential to dispose valid scales such as Pediatric Quality of Life inventory (PedsQL) Neuromuscular Module for its correct assessment. AIM: To assess the validity and reliability of the Spanish version of PedsQL Neuromuscular Module for self-perceived and parent-perceived quality of life of children aged 8-18 with neuromuscular disorders. SUBJECTS AND METHODS: The cognitive validity of the Spanish version of PedsQL was carried out with Mapi Research Trust permission. Subsequently, a test-retest was performed with 90 children volunteers with neuromuscular diseases, 50 aged 8-12 and 40 aged 13-18, and 85 of those children's parents. This allowed an evaluation of PedsQL intra observer concordance and internal consistency. Finally, construct validity was evaluated through factor analysis. RESULTS: The Cronbach alpha and all correlation intra-observer coefficients were higher than 0.8, indicating excellent validity and reliability and a higher internal consistency. The construct validity analysis suggested that a new construct with more might be a better fit than three and it will be able to explain a higher percentage of variability. CONCLUSIONS: The Spanish version of PedsQL Neuromuscular Module for self-perceived and parent-perceived quality of life of children aged 8-18 presented excellent validity and reliability. PMID- 30484276 TI - [Behavioural variant of frontotemporal dementia as the presenting symptom of corticobasal degeneration]. AB - INTRODUCTION: The behavioural variant of frontotemporal dementia is characterised by progressive social, cognitive and personality deterioration associated with several molecular pathologies of frontotemporal lobar dementia (FTLD): FTLD-tau, FTLD-TDP and FTLD-FUS. Its diagnosis requires pathological studies. CASE REPORT: A 61-year-old male, with a three-year progressive history of behavioural disorder, apathy, poor language skills, perseveration, lack of empathy, bulimia and executive dysfunction. Neuroimaging revealed right-dominant frontal cortical atrophy, and a single-photon emission tomography brain scan showed bilateral frontal hypoperfusion with thalamic and caudate involvement. Clinically, he was diagnosed with probable frontotemporal dementia, behavioural variant. On his death, his brain was donated to the Neurological Tissue Bank and the neuropathological diagnosis was corticobasal degeneration. CONCLUSIONS: Corticobasal degeneration is one of the FTLD-tau tauopathies. The 2013 diagnostic criteria for corticobasal degeneration include executive dysfunction and behavioural and personality disorders similar to those of this patient as a clinical phenotype. The anatomoclinical case presented illustrates the absence of any correlation between the clinical phenotype and the underlying neuropathological diagnosis in frontotemporal dementia, and the need to conduct a histopathological study in order to reach a definitive diagnosis. PMID- 30484277 TI - [Major neurological complications of genitourinary cancers]. AB - INTRODUCTION: Genitourinary cancers constitute a heterogeneous and increasingly frequent group of malignant tumors that have the potential to derive directly, or indirectly from the treatment applied, in a series of neurological complications that negatively impact on the quality of life of the patients who suffer them. AIMS: To report the most relevant data on the main neurological complications of genitourinary cancers. DEVELOPMENT: We conducted a PubMed search for articles, latest books, leading clinical practice guidelines, and scientific societies, regarding the appearance of such complications. CONCLUSIONS: Neurological complications of genitourinary cancers generate a significant burden of morbidity and mortality in cancer patients. In a paradoxical manner, owing to the raised survival of these patients, the likelihood of metastatization at the nervous system level and/or adverse effects related to the treatment received, especially due to chemotherapy, is also increased. Currently, diagnosis and management of neurological complications associated with genitourinary cancers represent a very important area of growing interest for the development of research projects that allow to improve the prognosis and quality of life genitourinary cancers subjects and their relatives and/or caregivers. For this purpose, it is necessary to know more about the etiopathogenesis and pathophysiology that leads to the occurrence of these type of complications in genitourinary cancers individuals, in particular paraneoplastic syndromes. Moreover, on the other hand, to carry out further well-designed randomized controlled clinical trials that expand the therapeutic arsenal with new chemotherapeutic drugs that possess a better antineoplastic effectiveness and improve the safety related to the neurotoxic side effects. PMID- 30484278 TI - [Synaptic plasticity as a substrate of resilience]. AB - INTRODUCTION: Adverse life experiences promote the development of mental illness such as depression, anxiety or schizophrenia. However, some individuals are capable to overcome adversity, achieving a physical and psychological normal development; this process is known as resilience. AIM: To discuss the neuronal substrates of resilience. DEVELOPMENT: We propose that resilience at neuronal level needs systems for representing and evaluating the context (adverse situation) in order to display an adequate behavioural output, and for reorganizing memory associated to the adverse situation in order to tell a new story using the same elements of experience; this is, a system that allows to reorganize neuronal ensembles associated to the adverse memory. In this sense, it is not coincidence that neuronal substrates involving in resilience include the reward-guided behavior system (nucleus accumbens-ventral tegmental area), the emotional system (amygdala-hippocampus), the stress system (hypothalamus pituitary-adrenal) and the system for context evaluation, representation and discrimination (prefrontal cortex-hippocampus). We emphasize that each adverse experience shapes both the activity of the resilience neuronal system and the behavioral output. CONCLUSIONS: We propose that synaptic plasticity in structures for representing and evaluating context is the neuronal substrate of resilience. Specifically, cortico-hippocampal interactions would allow to re-build adverse experiences through the reorganization of neuronal ensembles. PMID- 30484279 TI - [Acute parainfectious transverse myelitis with radiculitis in a child with closed spinal dysraphism]. PMID- 30484280 TI - [Guillain-Barre syndrome in times of arbovirosis]. PMID- 30484281 TI - [Guillain-Barre syndrome in times of arbovirosis. Reply]. PMID- 30484282 TI - Polyunsaturated fatty acids for the primary and secondary prevention of cardiovascular disease. AB - BACKGROUND: Evidence on the health effects of total polyunsaturated fatty acids (PUFA) is equivocal. Fish oils are rich in omega-3 PUFA and plant oils in omega-6 PUFA. Evidence suggests that increasing PUFA-rich foods, supplements or supplemented foods can reduce serum cholesterol, but may increase body weight, so overall cardiovascular effects are unclear. OBJECTIVES: To assess effects of increasing total PUFA intake on cardiovascular disease and all-cause mortality, lipids and adiposity in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to April 2017 and clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to September 2016, without language restrictions. We checked trials included in relevant systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing higher with lower PUFA intakes in adults with or without cardiovascular disease that assessed effects over 12 months or longer. We included full texts, abstracts, trials registry entries and unpublished data. Outcomes were all-cause mortality, cardiovascular disease mortality and events, risk factors (blood lipids, adiposity, blood pressure), and adverse events. We excluded trials where we could not separate effects of PUFA intake from other dietary, lifestyle or medication interventions. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts, assessed trials for inclusion, extracted data, and assessed risk of bias. We wrote to authors of included trials for further data. Meta-analyses used random-effects analysis, sensitivity analyses included fixed-effects and limiting to low summary risk of bias. We assessed GRADE quality of evidence. MAIN RESULTS: We included 49 RCTs randomising 24,272 participants, with duration of one to eight years. Eleven included trials were at low summary risk of bias, 33 recruited participants without cardiovascular disease. Baseline PUFA intake was unclear in most trials, but 3.9% to 8% of total energy intake where reported. Most trials gave supplemental capsules, but eight gave dietary advice, eight gave supplemental foods such as nuts or margarine, and three used a combination of methods to increase PUFA.Increasing PUFA intake probably has little or no effect on all-cause mortality (risk 7.8% vs 7.6%, risk ratio (RR) 0.98, 95% confidence interval (CI) 0.89 to 1.07, 19,290 participants in 24 trials), but probably slightly reduces risk of coronary heart disease events from 14.2% to 12.3% (RR 0.87, 95% CI 0.72 to 1.06, 15 trials, 10,076 participants) and cardiovascular disease events from 14.6% to 13.0% (RR 0.89, 95% CI 0.79 to 1.01, 17,799 participants in 21 trials), all moderate-quality evidence. Increasing PUFA may slightly reduce risk of coronary heart disease death (6.6% to 6.1%, RR 0.91, 95% CI 0.78 to 1.06, 9 trials, 8810 participants) andstroke (1.2% to 1.1%, RR 0.91, 95% CI 0.58 to 1.44, 11 trials, 14,742 participants, though confidence intervals include important harms), but has little or no effect on cardiovascular mortality (RR 1.02, 95% CI 0.82 to 1.26, 16 trials, 15,107 participants) all low-quality evidence. Effects of increasing PUFA on major adverse cardiac and cerebrovascular events and atrial fibrillation are unclear as evidence is of very low quality.Increasing PUFA intake probably slightly decreases triglycerides (by 15%, MD -0.12 mmol/L, 95% CI -0.20 to -0.04, 20 trials, 3905 participants), but has little or no effect on total cholesterol (mean difference (MD) -0.12 mmol/L, 95% CI -0.23 to -0.02, 26 trials, 8072 participants), high-density lipoprotein (HDL) (MD -0.01 mmol/L, 95% CI -0.02 to 0.01, 18 trials, 4674 participants) or low-density lipoprotein (LDL) (MD -0.01 mmol/L, 95% CI -0.09 to 0.06, 15 trials, 3362 participants). Increasing PUFA probably has little or no effect on adiposity (body weight MD 0.76 kg, 95% CI 0.34 to 1.19, 12 trials, 7100 participants).Effects of increasing PUFA on serious adverse events such as pulmonary embolism and bleeding are unclear as the evidence is of very low quality. AUTHORS' CONCLUSIONS: This is the most extensive systematic review of RCTs conducted to date to assess effects of increasing PUFA on cardiovascular disease, mortality, lipids or adiposity. Increasing PUFA intake probably slightly reduces risk of coronary heart disease and cardiovascular disease events, may slightly reduce risk of coronary heart disease mortality and stroke (though not ruling out harms), but has little or no effect on all-cause or cardiovascular disease mortality. The mechanism may be via TG reduction. PMID- 30484283 TI - Interventions for preventing intensive care unit delirium in adults. AB - BACKGROUND: Delirium is defined as a disturbance in attention, awareness and cognition with reduced ability to direct, focus, sustain and shift attention, and reduced orientation to the environment. Critically ill patients in the intensive care unit (ICU) frequently develop ICU delirium. It can profoundly affect both them and their families because it is associated with increased mortality, longer duration of mechanical ventilation, longer hospital and ICU stay and long-term cognitive impairment. It also results in increased costs for society. OBJECTIVES: To assess existing evidence for the effect of preventive interventions on ICU delirium, in-hospital mortality, the number of delirium- and coma-free days, ventilator-free days, length of stay in the ICU and cognitive impairment. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, BIOSIS, International Web of Science, Latin American Caribbean Health Sciences Literature, CINAHL from 1980 to 11 April 2018 without any language limits. We adapted the MEDLINE search for searching the other databases. Furthermore, we checked references, searched citations and contacted study authors to identify additional studies. We also checked the following trial registries: Current Controlled Trials; ClinicalTrials.gov; and CenterWatch.com (all on 24 April 2018). SELECTION CRITERIA: We included randomized controlled trials (RCTs) of adult medical or surgical ICU patients receiving any intervention for preventing ICU delirium. The control could be standard ICU care, placebo or both. We assessed the quality of evidence with GRADE. DATA COLLECTION AND ANALYSIS: We checked titles and abstracts to exclude obviously irrelevant studies and obtained full reports on potentially relevant ones. Two review authors independently extracted data. If possible we conducted meta-analyses, otherwise we synthesized data narratively. MAIN RESULTS: The electronic search yielded 8746 records. We included 12 RCTs (3885 participants) comparing usual care with the following interventions: commonly used drugs (four studies); sedation regimens (four studies); physical therapy or cognitive therapy, or both (one study); environmental interventions (two studies); and preventive nursing care (one study). We found 15 ongoing studies and five studies awaiting classification. The participants were 48 to 70 years old; 48% to 74% were male; the mean acute physiology and chronic health evaluation (APACHE II) score was 14 to 28 (range 0 to 71; higher scores correspond to more severe disease and a higher risk of death). With the exception of one study, all participants were mechanically ventilated in medical or surgical ICUs or mixed. The studies were overall at low risk of bias. Six studies were at high risk of detection bias due to lack of blinding of outcome assessors. We report results for the two most commonly explored approaches to delirium prevention: pharmacologic and a non-pharmacologic intervention.Haloperidol versus placebo (two RCTs, 1580 participants)The event rate of ICU delirium was measured in one study including 1439 participants. No difference was identified between groups, (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.87 to 1.17) (moderate-quality evidence). Haloperidol versus placebo neither reduced or increased in-hospital mortality, (RR 0.98, 95% CI 0.80 to 1.22; 2 studies; 1580 participants (moderate-quality evidence)); the number of delirium- and coma-free days, (mean difference (MD) -0.60, 95% CI -1.37 to 0.17; 2 studies, 1580 participants (moderate-quality of evidence)); number of ventilator-free days (mean 23.8 (MD -0.30, 95% CI -0.93 to 0.33) 1 study; 1439 participants, (high quality evidence)); length of ICU stay, (MD 0.18, 95% CI -0.60 to 0.97); 2 studies, 1580 participants; high-quality evidence). None of the studies measured cognitive impairment. In one study there were three serious adverse events in the intervention group and five in the placebo group; in the other there were five serious adverse events and three patients died, one in each group. None of the serious adverse events were judged to be related to interventions received (moderate-quality evidence).Physical and cognitive therapy interventions (one study, 65 participants)The study did not measure the event rate of ICU delirium. A physical and cognitive therapy intervention versus standard care neither reduced nor increased in-hospital mortality, (RR 0.94, 95% CI 0.40 to 2.20, I2 = 0; 1 study, 65 participants; very low-quality evidence); the number of delirium- and coma-free days, (MD -2.8, 95% CI -10.1 to 4.6, I2 = 0; 1 study, 65 participants; very low-quality evidence); the number of ventilator-free days (within the first 28/30 days) was median 27.4 (IQR 0 to 29.2) and 25 (IQR 0 to 28.9); 1 study, 65 participants; very low-quality evidence, length of ICU stay, (MD 1.23, 95% CI -0.68 to 3.14, I2 = 0; 1 study, 65 participants; very low quality evidence); cognitive impairment measured by the MMSE: Mini-Mental State Examination with higher scores indicating better function, (MD 0.97, 95% CI -0.19 to 2.13, I2 = 0; 1 study, 30 participants; very low-quality evidence); or measured by the Dysexecutive questionnaire (DEX) with lower scores indicating better function (MD -8.76, 95% CI -19.06 to 1.54, I2 = 0; 1 study, 30 participants; very low-quality evidence). One patient experienced acute back pain accompanied by hypotensive urgency during physical therapy. AUTHORS' CONCLUSIONS: There is probably little or no difference between haloperidol and placebo for preventing ICU delirium but further studies are needed to increase our confidence in the findings. There is insufficient evidence to determine the effects of physical and cognitive intervention on delirium. The effects of other pharmacological interventions, sedation, environmental, and preventive nursing interventions are unclear and warrant further investigation in large multicentre studies. Five studies are awaiting classification and we identified 15 ongoing studies, evaluating pharmacological interventions, sedation regimens, physical and occupational therapy combined or separately, and environmental interventions, that may alter the conclusions of the review in future. PMID- 30484284 TI - Autologous platelet concentrates for treating periodontal infrabony defects. AB - BACKGROUND: Periodontal disease is a condition affecting tooth-supporting tissues (gingiva, alveolar bone, periodontal ligament, and cementum), with the potential of introducing severe adverse effects on oral health. It has a complex pathogenesis which involves the combination of specific micro-organisms and a predisposing host response. Infrabony defects are one of the morphological types of alveolar bone defects that can be observed during periodontitis. Recent approaches for the treatment of infrabony defects, combine advanced surgical techniques with platelet-derived growth factors. These are naturally synthesized polypeptides, acting as mediators for various cellular activities during wound healing. It is believed that the adjunctive use of autologous platelet concentrates to periodontal surgical procedures produces a better and more predictable outcome for the treatment of infrabony defects. OBJECTIVES: To assess the effects of autologous platelet concentrates (APC) used as an adjunct to periodontal surgical therapies (open flap debridement (OFD), OFD combined with bone grafting (BG), guided tissue regeneration (GTR), OFD combined with enamel matrix derivative (EMD)) for the treatment of infrabony defects. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 27 February 2018); the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 1) in the Cochrane Library (searched 27 February 2018); MEDLINE Ovid (1946 to 27 February 2018); Embase Ovid (1980 to 27 February 2018); and LILACS BIREME Virtual Health Library (from 1982 to 27 February 2018). The US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials on 27 February 2018. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of both parallel and split-mouth design, involving patients with infrabony defects requiring surgical treatment. Studies had to compare treatment outcomes of a specific surgical technique combined with APC, with the same technique when used alone. DATA COLLECTION AND ANALYSIS: Two review authors independently conducted data extraction and risk of bias assessment, and analysed data following Cochrane methods. The primary outcomes assessed were: change in probing pocket depth (PD), change in clinical attachment level (CAL), and change in radiographic bone defect filling (RBF). We organised all data in four groups, each comparing a specific surgical technique when applied with the adjunct of APC or alone: 1. APC + OFD versus OFD, 2. APC + OFD + BG versus OFD + BG, 3. APC + GTR versus GTR, and 4. APC + EMD versus EMD. MAIN RESULTS: We included 38 RCTs. Twenty-two had a split-mouth design, and 16 had a parallel design. The overall evaluated data included 1402 defects. Two studies were at unclear overall risk of bias, while the remaining 36 studies had a high overall risk of bias.1. APC + OFD versus OFD alone Twelve studies were included in this comparison, with a total of 510 infrabony defects. There is evidence of an advantage in using APC globally from split-mouth and parallel studies for all three primary outcomes: PD (mean difference (MD) 1.29 mm, 95% confidence interval (CI) 1.00 to 1.58 mm; P < 0.001; 12 studies; 510 defects; very low-quality evidence); CAL (MD 1.47 mm, 95% CI 1.11 to 1.82 mm; P < 0.001; 12 studies; 510 defects; very low-quality evidence); and RBF (MD 34.26%, 95% CI 30.07% to 38.46%; P < 0.001; 9 studies; 401 defects; very low-quality evidence).2. APC + OFD + BG versus OFD + BG Seventeen studies were included in this comparison, with a total of 569 infrabony defects. Considering all follow ups, as well as 3 to 6 months and 9 to 12 months, there is evidence of an advantage in using APC from both split-mouth and parallel studies for all three primary outcomes: PD (MD 0.54 mm, 95% CI 0.33 to 0.75 mm; P < 0.001; 17 studies; 569 defects; very low-quality evidence); CAL (MD 0.72 mm, 95% CI 0.43 to 1.00 mm; P < 0.001; 17 studies; 569 defects; very low-quality evidence); and RBF (MD 8.10%, 95% CI 5.26% to 10.94%; P < 0.001; 11 studies; 420 defects; very low quality evidence).3. APC + GTR versus GTR alone Seven studies were included in this comparison, with a total of 248 infrabony defects. Considering all follow ups, there is probably a benefit for APC for both PD (MD 0.92 mm, 95% CI -0.02 to 1.86 mm; P = 0.05; very low-quality evidence) and CAL (MD 0.42 mm, 95% CI -0.02 to 0.86 mm; P = 0.06; very low-quality evidence). However, given the wide confidence intervals, there might be a possibility of a slight benefit for the control. When considering a 3 to 6 months and a 9 to 12 months follow-up there were no benefits evidenced, except for CAL at 3 to 6 months (MD 0.54 mm, 95% CI 0.18 to 0.89 mm; P = 0.003; 3 studies; 134 defects). No RBF data were available.4. APC + EMD versus EMDTwo studies were included in this comparison, with a total of 75 infrabony defects. There is insufficient evidence of an overall advantage of using APC for all three primary outcomes: PD (MD 0.13 mm, 95% CI -0.05 to 0.30 mm; P = 0.16; 2 studies; 75 defects; very low-quality evidence), CAL (MD 0.10 mm, 95% CI -0.13 to 0.32 mm; P = 0.40; 2 studies; 75 defects; very low-quality evidence), and RBF (MD -0.60%, 95% CI -6.21% to 5.01%; P = 0.83; 1 study; 49 defects; very low-quality evidence).All studies in all groups reported a survival rate of 100% for the treated teeth. No complete pocket closure was reported. No quantitative analysis regarding patients' quality of life was possible. AUTHORS' CONCLUSIONS: There is very low-quality evidence that the adjunct of APC to OFD or OFD + BG when treating infrabony defects may improve probing pocket depth, clinical attachment level, and radiographic bone defect filling. For GTR or EMD, insufficient evidence of an advantage in using APC was observed. PMID- 30484285 TI - Baclofen for alcohol use disorder. AB - BACKGROUND: Alcohol use disorder (AUD) and alcohol-related impairments belong to the most widespread psychiatric disorders leading to specific psychophysical, affective and cognitive symptoms and consequences for psychosocial well-being and health. Alcohol consumption is increasingly becoming a problem in many developing regions and AUD prevalence is estimated at 4.1% worldwide, with highest prevalence in European countries (7.5%), and the North America (6.0%). Therapeutic approaches, including pharmacotherapy, play an important role in treating patients with AUD. OBJECTIVES: To assess the efficacy and safety of baclofen for treating people with AUD, who are currently drinking, with the aim of achieving and maintaining abstinence or reducing alcohol consumption. SEARCH METHODS: We searched the Cochrane Drugs and Alcohol Specialised Register, CENTRAL, MEDLINE, Embase, two further databases and two clinical trials registries, conference proceedings, and the reference lists of retrieved articles. The date of the most recent search was 30 January 2018. SELECTION CRITERIA: Randomised controlled trials (RCTs) of at least four weeks' treatment duration and 12 weeks' overall study duration comparing baclofen for relapse prevention of AUD with placebo, no treatment or other treatments. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 12 RCTs (1128 participants). All studies but three recruited fewer than 100 participants. Participants had a diagnosis of alcohol dependence according the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV or the International Classification of Diseases (ICD)-10 criteria who were currently drinking. The mean age of participants was 48 years, and there were more men (69%), than women. All studies compared baclofen to placebo, except for one study that evaluated baclofen versus acamprosate. The included studies considered baclofen at different doses (range 10 mg a day to 150 mg a day). In all but one of the studies, participants in both the baclofen and placebo groups received psychosocial treatment or counselling of various intensity.We judged most of the studies at low risk of selection, performance, detection (subjective outcome), attrition and reporting bias.We did not find any difference between baclofen and placebo for the primary outcomes: relapse-return to any drinking (RR 0.88, 95% CI 0.74 to 1.04; 5 studies, 781 participants, moderate certainty evidence); frequency of use by percentage of days abstinent (MD 0.39, 95% CI 11.51 to 12.29; 6 studies, 465 participants, low certainty evidence) and frequency of use by percentage of heavy drinking days at the end of treatment (MD 0.25, 95% CI -1.25 to 1.76; 3 studies, 186 participants, moderate certainty evidence); number of participants with at least one adverse event (RR 1.04, 95% CI 0.99 to 1.10; 4 studies, 430 participants, high certainty evidence); the dropout rate at the end of treatment (RR 0.98, 95% CI 0.77 to 1.26, 8 studies, 977 participants, high certainty evidence) and dropout due to adverse events (RR 1.11, 95% CI 0.59 to 2.07; 7 studies, 913 participants, high certainty evidence).We found evidence that baclofen increases amount of use (drink per drinking days), (MD 1.55, 95% CI 1.32 to 1.77; 2 studies, 72 participants, low certainty evidence).Among secondary outcomes, there was no difference on craving (MD 1.38, 95% CI -1.28 to 4.03, 5 studies, 469 participants), and anxiety (SMD 0.07, 95% CI -0.14 to 0.28; 5 trials, 509 participants). We found that baclofen increased depression (SMD 0.27, 95% CI 0.05 to 0.48; 3 studies, 387 participants).Concerning the specific adverse events we found that baclofen increased: vertigo (RR 2.16, 95% CI 1.24 to 3.74; 7 studies, 858 participants), somnolence/sedation (RR 1.48, 95%CI 1.11 to 1.96; 8 studies, 946 participants), paraesthesia (RR 4.28, 95% CI 2.11 to 8.67; 4 studies, 593 participants), and muscle spasms/rigidity (RR 1.94, 95%CI 1.08 to 3.48; 3 studies, 551 participants). For all the other adverse events we did not find significant differences between baclofen and placebo.For the comparison baclofen versus acamprosate, we were only able to extract data for one outcome, craving. For this outcome, we found that baclofen increased craving compared with acamprosate (MD 14.62, 95% CI 12.72 to 16.52; 1 study, 49 participants). AUTHORS' CONCLUSIONS: None of the primary or secondary outcomes of the review showed evidence of a difference between baclofen and placebo. The high heterogeneity among primary studies results limits the interpretation of the summary estimate, the identification of moderators and mediators of baclofen's effects on alcohol use remains a challenge for further research. Even though some results from RCTs are promising, current evidence remains uncertain regarding the use of baclofen as a first-line treatment for people with AUDs. PMID- 30484286 TI - Oral isotretinoin for acne. AB - BACKGROUND: Acne vulgaris, a chronic inflammatory disease of the pilosebaceous unit associated with socialisation and mental health problems, may affect more than 80% of teenagers. Isotretinoin is the only drug that targets all primary causal factors of acne; however, it may cause adverse effects. OBJECTIVES: To assess efficacy and safety of oral isotretinoin for acne vulgaris. SEARCH METHODS: We searched the following databases up to July 2017: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and LILACS. We updated this search in March 2018, but these results have not yet been incorporated in the review. We also searched five trial registries, checked the reference lists of retrieved studies for further references to relevant trials, and handsearched dermatology conference proceedings. A separate search for adverse effects of oral isotretinoin was undertaken in MEDLINE and Embase up to September 2013. SELECTION CRITERIA: Randomised clinical trials (RCTs) of oral isotretinoin in participants with clinically diagnosed acne compared against placebo, any other systemic or topical active therapy, and itself in different formulation, doses, regimens, or course duration. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 31 RCTs, involving 3836 participants (12 to 55 years) with mild to severe acne. There were twice as many male participants as females.Most studies were undertaken in Asia, Europe, and North America. Outcomes were generally measured between eight to 32 weeks (mean 19.7 weeks) of therapy.Assessed comparisons included oral isotretinoin versus placebo or other treatments such as antibiotics. In addition, different doses, regimens, or formulations of oral isotretinoin were assessed, as well as oral isotretinoin with the addition of topical agents.Pharmaceutical companies funded 12 included trials. All, except three studies, had high risk of bias in at least one domain.Oral isotretinoin compared with oral antibiotics plus topical agentsThese studies included participants with moderate or severe acne and assessed outcomes immediately after 20 to 24 weeks of treatment (short-term). Three studies (400 participants) showed isotretinoin makes no difference in terms of decreasing trial investigator assessed inflammatory lesion count (RR 1.01 95% CI 0.96 to 1.06), with only one serious adverse effect found, which was Stevens-Johnson syndrome in the isotretinoin group (RR 3.00, 95% CI 0.12 to 72.98). However, we are uncertain about these results as they were based on very low-quality evidence.Isotretinoin may slightly improve (by 15%) acne severity, assessed by physician's global evaluation (RR 1.15, 95% CI 1.00 to 1.32; 351 participants; 2 studies), but resulted in more less serious adverse effects (67% higher risk) (RR 1.67, 95% CI 1.42 to 1.98; 351 participants; 2 studies), such as dry lips/skin, cheilitis, vomiting, nausea (both outcomes, low-quality evidence).Different doses/therapeutic regimens of oral isotretinoinFor our primary efficacy outcome, we found three RCTs, but heterogeneity precluded meta-analysis. One study (154 participants) reported 79%, 80% and 84% decrease in total inflammatory lesion count after 20 weeks of 0.05, 0.1, or 0.2 mg/kg/d of oral isotretinoin for severe acne (low-quality evidence). Another trial (150 participants, severe acne) compared 0.1, 0.5, and 1 mg/kg/d oral isotretinoin for 20 weeks and, respectively, 58%, 80% and 90% of participants achieved 95% decrease in total inflammatory lesion count. One RCT, of participants with moderate acne, compared isotretinoin for 24 weeks at (a) continuous low dose (0.25 to 0.4 mg/kg/day), (b) continuous conventional dose (0.5 to 0.7 mg/kg/day), and (c) intermittent regimen (0.5 to 0.7 mg/kg/day, for one week in a month). Continuous low dose (MD 3.72 lesions; 95% CI 2.13 to 5.31; 40 participants; one study) and conventional dose (MD 3.87 lesions; 95% CI 2.31 to 5.43; 40 participants; one study) had a greater decrease in inflammatory lesion counts compared to intermittent treatment (all outcomes, low-quality evidence).Fourteen RCTs (906 participants, severe and moderate acne) reported that no serious adverse events were observed when comparing different doses/therapeutic regimens of oral isotretinoin during treatment (from 12 to 32 weeks) or follow-up after end of treatment (up to 48 weeks). Thirteen RCTs (858 participants) analysed frequency of less serious adverse effects, which included skin dryness, hair loss, and itching, but heterogeneity regarding the assessment of the outcome precluded data pooling; hence, there is uncertainty about the results (low- to very-low quality evidence, where assessed).Improvement in acne severity, assessed by physician's global evaluation, was not measured for this comparison.None of the included RCTs reported birth defects. AUTHORS' CONCLUSIONS: Evidence was low-quality for most assessed outcomes.We are unsure if isotretinoin improves acne severity compared with standard oral antibiotic and topical treatment when assessed by a decrease in total inflammatory lesion count, but it may slightly improve physician assessed acne severity. Only one serious adverse event was reported in the isotretinoin group, which means we are uncertain of the risk of serious adverse effects; however, isotretinoin may result in more minor adverse effects.Heterogeneity in the studies comparing different regimens, doses, or formulations of oral isotretinoin meant we were unable to undertake meta analysis. Daily treatment may be more effective than treatment for one week each month. None of the studies in this comparison reported serious adverse effects, or measured improvement in acne severity assessed by physician's global evaluation. We are uncertain if there is a difference in number of minor adverse effects, such as skin dryness, between doses/regimens.Evidence quality was lessened due to imprecision and attrition bias. Further studies should ensure clearly reported long- and short-term standardised assessment of improvement in total inflammatory lesion counts, participant-reported outcomes, and full safety accounts. Oral isotretinoin for acne that has not responded to oral antibiotics plus topical agents needs further assessment, as well as different dose/regimens of oral isotretinoin in acne of all severities. PMID- 30484287 TI - Remineralization of artificial carious lesions using a novel fluoride incorporated bioactive glass dentifrice. AB - BACKGROUND: Remineralization potential of dentifrices with novel compositions that can restore minerals back into incipient carious lesions has not been extensively studied so far. OBJECTIVES: The aim of this study was to assess the efficacy of a dentifrice based on novel fluoride incorporated bioactive glass in remineralizing artificial carious lesions in human enamel, and compare it with a standard fluoride-containing dentifrice. MATERIAL AND METHODS: Twenty-four human extracted teeth were sectioned at the cementoenamel junction to obtain enamel blocks. These blocks (n = 24) were randomly divided into 3 groups, with each group containing 8 specimens: group 1 (negative control group; distilled water), group 2 (positive control group; fluoride toothpaste) and group 3 (test group; BioMinTM F toothpaste). Artificial carious lesions were produced in the enamel surfaces by exposing them to a demineralization solution (6% citric acid, pH 2.2) for 96 h. After demineralization, the specimens were brushed with manual toothbrushes in a toothbrush simulation machine (each sample received 800 strokes). For brushing the specimens from group 1, 20 mL of distilled water was used, for group 2 - 20 mL of slurry of toothpaste mixed with artificial saliva, and for group 3 - 20 mL of slurry of toothpaste (BioMin F) mixed with artificial saliva. The micro-hardness data (VHN - Vickers hardness number) was collected at baseline (sound enamel), post-demineralization and post-remineralization. RESULTS: The biggest difference between the post-remineralization and post demineralization values was observed in group 3 (mean VHN = 118.73), followed by group 2 (mean VHN = 60.54) and group 1 (mean VHN = 47.44). All the groups revealed significant differences (p < 0.05) when the post-demineralization and post-remineralization values were compared to baseline values within each group. CONCLUSIONS: The BioMin F group outperformed the other 2 groups in terms of remineralizing the demineralized enamel structure. PMID- 30484288 TI - [Study of the structure of contact lenses using PALS, MIR and Raman spectroscopy in the regard of safety of persons exposed to ionizing radiation]. AB - Among patients and health professionals who are exposed to ionizing radiation during diagnostic and therapeutic procedures, refractive errors are common and soft contact lenses are widely used to correct them. Changes in the inner structure of contact lens may influence the safety of its usage through modification of its water content or oxygen accessibility to cornea. Therefore, analysis of impact of external factors, therein ionizing radiation used in medicine, on contact lenses parameters is necessary, particularly to compare the presence of free volume gaps in the structure of the polymer soft contact lenses. Possible change in dimensions or quantity of free volume gaps in the structure of the material caused by the exposure to ionizing radiation may have negative influence on oxygen permeability. To prevent such process, different means could be used, i.a., positron annihilation lifetime spectroscopy (PALS), Raman spectroscopy and mid-infrared spectroscopy (MIR). Use of contact lenses which reduce transport of oxygen to cornea increases the risk of corneal hypoxia - one of the possible complications of using contact lenses. Research on effects of different types of ionizing radiation (X-ray, gamma, beta) on materials used in production of contact lenses is vital because of the connection of this issue with the safety of contact lenses wearers. Such research can also shed light on the problem of safe use of contact lenses by persons exposed to ionizing radiation. PMID- 30484289 TI - A study of the effect of X-ray irradiation on the structure of Narafilcon A biopolymer soft contact lenses. AB - BACKGROUND: The effects of external factors such as X-ray irradiation on the structure and physical properties of contact lenses are very important for both the patients using contact lenses and medical personnel. OBJECTIVES: The aim of the study was to investigate the effect of X-rays on the structure of Narafilcon A silicone-hydrogel contact lenses. MATERIAL AND METHODS: In order to study the structural changes caused by X-rays in Narafilcon A polymer contact lenses, the following spectroscopy methods were used: positron annihilation lifetime spectroscopy (PALS), Fourier transform middle infrared spectroscopy (FTIR) and Raman spectroscopy (RS). Irradiation of the investigated sample was carried out using an Elekta Synergy accelerator. The contact lenses were irradiated with the following total doses of X-rays: 0.05 Gy, 0.5 Gy, 0.8 Gy, and 1.0 Gy. RESULTS: The PALS measurements showed that X-ray irradiation caused slight changes in the size of the free volume and the fractional free volume in the structure of the polymer contact lenses examined. However, the FTIR and RS measurements showed that X-rays did not break the monomer bonds in the polymeric structure of the sample. CONCLUSIONS: The changes revealed by the PALS method may be related to possible displacement of monomer chains, resulting in changes in the dimensions and numbers of free volumes. The finding that X-ray radiation does not affect or damage polymer bonds can in the future contribute to the use of X-ray and gamma radiation to sterilize contact lenses. PMID- 30484290 TI - Preoperative Th1/Th2 and related cytokines: Prediction value in postoperative febrile UTI after ureteroscopy in patients with ureteral calculi. AB - BACKGROUND: The topic of whether preoperative Th1/Th2 cells and their related factors have a predictive value for postoperative febrile urinary tract infection (UTI) in patients with ureteral calculi has not been explored. OBJECTIVES: The objective of this study was to investigate the role of preoperative Th1/Th2 cells and related cytokines in the prediction of postoperative febrile UTI after ureteroscopy in patients with ureteral calculi. MATERIAL AND METHODS: One hundred sixty patients who underwent ureteroscopic pneumatic lithotripsy in the Affiliated Hospital of Hangzhou Normal University (China) were recruited and divided into febrile UTI group (n = 78) and non-UTI group (n = 82). Flow cytometry was used to detect the proportions of Th1 and Th2 cells (Th1% and Th2%). Detection of Th1/Th2 cell-related cytokines was conducted using enzyme linked immunosorbent assay (ELISA). Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to measure the expression of T-bet and GATA3. RESULTS: Compared with patients in non-UTI group, those in febrile UTI group had significantly increased proportions of Th2 cells, levels of Th2 cytokines (interleukin (IL)-4, IL-10 and IL-5), and mRNA expression of Th2-associated transcription factor GATA3 (all p < 0.05). In addition, the Th1/Th2 ratio of febrile UTI group was significantly lower than that of non-UTI group (p < 0.001). Receiver operating characteristic (ROC) curve analysis showed that the accuracy rate of Th2%, Th1/Th2 ratio, and IL-4, IL-10 and IL-5 levels for the diagnosis of postoperative febrile UTI in patients with ureteral calculi was 90.63%, 85.00%, 72.50%, 87.50%, and 91.88%, respectively, and their combined diagnostic sensitivity was 97.4% with specificity as high as 100%. CONCLUSIONS: Perioperative Th2 dominance was correlated with the risk of postoperative febrile UTI after ureterscopy in patients with ureteral calculi, which can provide clinical guidance for the development of individualized treatment. PMID- 30484291 TI - The effect of anakinra to nephrotoxicity with cisplatin induced in rats: Biochemical, gene expression and histopathological evaluation. AB - BACKGROUND: Oxidative stress and interleukin-1 beta (IL-1beta) have been reported to play a role in the pathogenesis of nephrotoxicity induced by cisplatin. OBJECTIVES: The objective of this study was to investigate the effect of anakinra, which is an IL-1beta receptor antagonist, on cisplatin-induced nephrotoxicity in rats, through biochemical, gene expression and histopathological analyses. MATERIAL AND METHODS: The study was designed with 4 groups. For 1 week, the control group (C) and the cisplatin (Cis) group received distilled water, while the cisplatin + anakinra 50 (Cis + ANA50) group and the cisplatin + anakinra 100 (Cis + ANA100) group were intraperitoneally administered 50 mg/kg and 100 mg/kg of anakinra, respectively. The Cis, Cis + ANA50 and Cis + ANA100 groups were intraperitoneally injected with a 2.5 mg/kg dose of cisplatin for 7 days. After sacrifice, the kidney tissue of each rat was extracted for the assessment of the malondialdehyde (MDA) and total glutathione (tGSH) levels, and for gene expression analyses of IL-1beta. The kidney tissues were histopathologically evaluated. Statistical analyses of the data were performed using one-way analysis of variance (ANOVA). RESULTS: The administration of cisplatin (the Cis group) yielded a higher level of MDA (4.75 +/-0.25 nmol/mL; p < 0.001) and lower levels of tGSH (1.80 +/-0.35 mg/L; p < 0.001) compared to other groups. Cisplatin also increased IL-1beta gene expression (6.33 +/-0.27 gene expression levels; p < 0.001) compared to other groups. The impact of anakinra on the MDA and tGSH levels, and on IL-1beta gene expression induced by cisplatin was observed as a reversal of these findings (p < 0.05). Anakinra better prevented an increase of the levels of MDA and IL-1beta at a dose of 100 mg/kg compared to a 50 mg/kg dose. CONCLUSIONS: Anakinra prevents oxidative kidney damage induced by cisplatin, in a dose-dependent manner. This result suggests that anakinra may be useful in the treatment of cisplatin-induced kidney damage. PMID- 30484292 TI - The phospholipid fraction obtained from egg yolk reduces blood pressure increase induced by acute stress in spontaneously hypertensive rats. AB - BACKGROUND: Despite continuous research, an improved understanding of the pathophysiology of hypertension and the development of new antihypertensive therapies, hypertension is still the most prevalent chronic cardiovascular disease (CVD) among adults in Western societies. Stress is a common factor related to cardiovascular morbidity. An increase in blood pressure is one of the most common reactions to stress. Chronic and acute stress have also been related to cardiovascular disorders. Polyunsaturated fatty acids (PUFAs) have attracted considerable interest as potential complementary therapy for the treatment of CVD, including hypertension. Egg yolk, rich in PUFAs and phospholipids, might be a good source of phospholipids and PUFAs. OBJECTIVES: The current study was aimed at investigating the potential effect of the phospholipid fraction of eggs on blood pressure changes in spontaneously hypertensive rats (SHRs) as a response to acute stress. MATERIAL AND METHODS: Male, 7-week-old SHRs received dietary phospholipid fraction for 12 weeks. The control animals received standard feed. At the end of the treatment, they were exposed to 40 min of white noise in order to induce acute stress. Then, blood pressure measurements were carried out under normal conditions for 12 h before and during the acute stress procedure. Blood pressure was measured by telemetry. RESULTS: Diastolic, systolic and mean blood pressure were significantly lower in the SHRs treated with phospholipid fraction than in the control group. The acute stressor caused a significant increase in diastolic, systolic and mean blood pressure in both the treated and untreated animals, but the increase in blood pressure as a response to the stressor was significantly less pronounced in the rats treated with phospholipid fraction than in control rats. These results show that egg phospholipids can limit a stress induced rise in blood pressure. CONCLUSIONS: The results of this research show that phospholipid fraction derived from egg yolk reduces stress-induced increases in blood pressure. PMID- 30484293 TI - Penetration model for chemical reactivation for resin-embedded green fluorescent protein imaging. AB - In the so-called surface microscopy, serial block-face imaging is combined with mechanic sectioning to obtain volumetric imaging. While mapping a resin-embedded green fluorescent protein (GFP)-labeled specimen, it has been recently reported that an alkaline buffer is used to chemically reactivate the protonated GFP molecules, and thus improve the signal-to-noise ratio. In such a procedure, the image quality is highly affected by the penetration rate of a solution. We propose a reliable penetration model to describe the penetration process of the solution into the resin. The experimental results are consistent with the parameters predicted using this model. Thus, this model provides a valuable theoretical explanation and aids in optimizing the system parameters for mapping resin-embedded GFP biological samples. PMID- 30484294 TI - Combining fluorescence-based image segmentation and automated microfluidics for ultrafast cell-by-cell assessment of biomarkers for HER2-type breast carcinoma. AB - Immunohistochemistry (IHC) is one of the main clinical techniques for biomarker assessment on tissue biopsies. It consists in chromogenic labeling with specific antibodies, followed by optical imaging, and it is used for diagnosis and therapeutic targeting. A well-known drawback of IHC is its limited robustness, which often precludes quantitative biomarker assessment. We combine microfluidic immunostaining, fluorescence imaging, and image-based cell segmentation to create an ultrafast procedure for accurate biomarker assessment via IHC. The experimental protocol is very simple and based on fast delivery of reagents in a microfluidic chamber created by clamping a half-chamber patterned in a silicon chip on top of a tumor tissue section. Also, the imaging procedure simply requires a standard fluorescence microscope, already widely used in clinical practice. The image processing is based on local-contrast enhancement and thresholding of the obtained fluorescence image, with subsequent Voronoi segmentation. To assess the experimental and analytical procedure on robust biological controls, we apply our method to well-characterized cell lines, which guarantee higher reproducibility than whole-tissue samples and therefore enable to disentangle the technical variability from the biological variability. To increase the potential translationality, we address the detection and quantification of the human epidermal growth factor receptor 2 (HER2) protein, which is a biomarker for HER2-type breast carcinoma diagnosis and therapy. We report both ultrafast immunofluorescence staining (5 min per sample) of two breast cancer biomarkers and ultrafast cell segmentation (1 min per sample = processing of thousands of cells). This provides a quantitative, cell-based immunofluorescent signal, with which we propose a potential diagnostic criterion to separate HER2-positive and HER2-negative breast cancer cells at high sensitivity and specificity. PMID- 30484295 TI - Multimodal imaging and high-throughput image-processing for drug screening on living organisms on-chip. AB - A major step for the validation of medical drugs is the screening on whole organisms, which gives the systemic information that is missing when using cellular models. Caenorhabditis elegans is a soil worm that catches the interest of researchers who study systemic physiopathology (e.g., metabolic and neurodegenerative diseases) because: (1) its large genetic homology with humans supports translational analysis; (2) worms are much easier to handle and grow in large amounts compared with rodents, for which (3) the costs and (4) the ethical concerns are substantial. Here, we demonstrate how multimodal optical imaging on such an organism can provide high-content information relevant to the drug development pipeline (e.g., mode-of-action identification, dose-response analysis), especially when combined with on-chip multiplexing capability. After designing a microfluidic array to select small separated populations of C. elegans, we combine fluorescence and bright-field imaging along with high throughput feature recognition and signal detection to enable the identification of the mode-of-action of an antibiotic. For this purpose, we use a genetically encoded fluorescence reporter of mitochondrial stress, which we studied in living specimens during their entire development. Furthermore, we demonstrate real-time, very large field-of-view capability on multiplexed motility assays for the assessment of the dose-response relation of an anesthetic. PMID- 30484296 TI - Keeping support and clinical supervision on your agenda. AB - Support and clinical supervision can benefit staff and service users. Inquiries have highlighted lack of support and clinical supervision as potential contributory factors for adverse care events. For support and clinical supervision to be embedded effectively, leaders and managers must value and promote them in their organisations. This article describes practical steps to support implementation of clinical supervision. By examining the main stages of supervision and preparation, evaluation of process and outcomes, and practical considerations, the article supports healthcare managers to encourage staff engagement and to implement a clinical supervision process. PMID- 30484297 TI - Pelvic plexus (PP) block; a new sonographic technique for acute pelvic pain. PMID- 30484298 TI - Intravenous dexmedetomidine: can it modulate the effects of inflammation, or is it only an antinociceptive agent? PMID- 30484299 TI - More salutary effects of intraoperative dexmedetomidine. PMID- 30484300 TI - Biomarkers in sepsis: towards precision medicine for the prevention of adverse outcomes. PMID- 30484301 TI - Erector spinae block for parathyroidectomy. PMID- 30484302 TI - Perioperative management of the patient on direct oral anticoagulants: is it time to measure ? PMID- 30484303 TI - Bright Stretchable Electroluminescent Devices based on Silver Nanowire Electrodes and High-k Thermoplastic Elastomers. AB - Stretchable electroluminescent device is a compliant form of light emitting device to expand the application areas of conventional optoelectronics on rigid wafers. Currently, practical implementations are impeded by the high operating voltage required to achieve sufficient brightness. In this study, we report the fabrication of an intrinsically stretchable electroluminescent device based on silver nanowire electrodes and high-k thermoplastic elastomer. The device exhibit bright emission with low driving voltage by using polar elastomer as the dielectric matrix of the electroluminescent layer. Highly stretchable silver nanowire electrodes contribute to the exceptional elasticity and durability of the device in spite of bending, stretching, twisting, puncturing and cutting. Stretchable electroluminescent devices developed here may find potential uses in wearable displays, deformable lightings, and soft robotics. PMID- 30484304 TI - Simple molecular-engineering approach for enhancing orientation and out-coupling efficiency of thermally activated delayed fluorescent emitters without red shifting emission. AB - The inclusion of a tetraphenylbenzene (4Ph) unit in thermally activated delayed fluorescence (TADF) emitters is demonstrated as a novel strategy for greatly enhancing the horizontally oriented alignment of the emitters without shifting the emission spectrum to longer wavelengths. Doping of blue-emitting 4PhOXDDMAC or greenish-blue-emitting 4PhOXDPXZ into o-DiCbzBz host layers yielded much higher degrees of horizontally oriented alignment for the emitter (up to 92%) compared to when the 4Ph unit was excluded (69% and 75%, respectively). The enhanced alignment results in high out-coupling efficiencies of 24% and 35% in organic light-emitting diodes based on 4PhOXDDMAC and 4PhOXDPXZ, respectively, and boosts the external quantum efficiencies to values (8.8% and 29.2%, respectively) that are higher than would be expected for randomly oriented emitters (out-coupling efficiency of 20%). These enhancements are achieved while avoiding the red-shift that often occurs using the common strategy of increasing molecular length, and, thereby, conjugation, to increase orientation. PMID- 30484305 TI - Light and flexible composite nanofibrous membranes for high-efficiency electromagnetic absorption in a broad frequency. AB - With the fast advancement of up-to-date communication technologies, electromagnetic wave (EMW) absorption materials are widely required for various applications. However, it is still a big challenge to produce lightweight, flexible and high efficiency EMW absorption materials in a broad-ranging frequency. Herein, we designed to fabricate the magnetic and dielectric nanofibrous membranes which can be effectively used as EMW absorption materials by facile electrospinning process. The as-fabricated composite carbon nanofibers (CNFs), which combined the components of nickel, cobalt antioxidant nanoparticles and carbon nanotubes, exhibited outstanding magnetic, dielectric properties and strong absorption ability in a wide frequency range. These nanoparticles encapsulated in CNFs are extremely beneficial to the electrical conductivity of the composites through decreasing the contact loss within the CNFs by formation the metal-metal interfaces. Correspondingly, the RL value of -46.60 dB was reached at 4.88 GHz frequency range with a layer thickness of 5.5 mm for these mechanically light and flexible membranes. The enhanced absorption performance (< 10 dB) in the wide frequency band (4.16-18 GHz) can be achieved by selecting a suitable thickness of the material. Results demonstrate that the permittivity and permeability of developed samples have been largely improved due to the integrated interaction of all introduced components in the structure. The composite membranes are a promising candidate for scalable, lightweight and high performance EMW absorption materials in the frequency range from C band to Ku band (4-18 GHz). PMID- 30484306 TI - Excitons and Biexciton Dynamics in Single CsPbBr3 Perovskite Quantum Dots. AB - Colloidal lead halide perovskite quantum dots, due to their optical versatility and facile solution processability, have been recently recognized as components of various optoelectronic devices. Detailed understanding of their exciton recombination dynamics at the single-particle level is necessary for utilizing their full potential. We conducted spectroscopic studies of the excitons and biexciton dynamics in single CsPbBr3 perovskite quantum dots. It was found that while the rates of radiative recombination remain essentially constant, the overall relaxation process is dominated by non-radiative recombination of single excitons and biexcitons. The radiative lifetime scaling is determined to be ~1.0 for single exciton and ~4.4 for biexcitons. A linear dependence of fluorescence lifetime vs. intensity distribution agrees well with the prediction of the model of multiple recombination centers. The blinking mechanism of CsPbBr3 quantum dots is addressed by considering the trion states under higher excitation powers. PMID- 30484307 TI - Dye-assembled Upconversion Nanocomposite for Luminescence Ratiometric In-Vivo Bioimaging of Copper ions. AB - Overdose of Cu2+ is associated with multiple diseases, such as Wilson disease, Parkinson disease and Alzheimer disease. Therefore, the detections of Cu2+ in vivo and in vitro are meaningful. Near-infrared fluorescent probes are commonly applied for the detection of Cu2+ in real time. With mono detection signal provided, these probes are not persuasive when applied to complicated biological environments, such as cells and animals. In this report, we conjugated the organic fluorescent probe CYDAC16 with the UCNPs (Lanthanide-doped upconversion nanoparticles) to develop a ratiometric luminescent probe for Cu2+. The composite material UCNPs-CYDAC16 provides ratiometric signal based on UCL (Upconversion luminescent) 660 nm and 800 nm. With good sensitivity and selectivity for Cu2+, it works well in vivo and in vitro for detection of Cu2+. We believe it is promising in further biological applications. PMID- 30484308 TI - Directly converting syngas to linear alpha-olefins over core-shell Fe3O4@MnO2 catalysts. AB - Converting syngas to value-added chemicals via Fischer-Tropsch synthesis (FTS) has attracted much attention, whereas the direct hydrogenation of CO to heavy olefins, especially linear alpha-olefins (LAOs), remains a challenge. In this study, we designed a core-shell Fe3O4@MnO2 catalyst to realize the direct conversion of syngas to LAOs with high efficiency. This catalyst exhibited an enhanced selectivity of 79.60% for total alkenes and 64.95% for C4+ alkenes, 91% of which are LAOs, at a CO conversion of approximately 75%. Promotion of the electron transfer from MnO2 to Fe3O4 inside the core-shell Fe3O4@MnO2 catalyst facilitated the dissociative adsorption of CO molecules on Fe3O4 and the spillover of H atoms therein, which enhanced C-C coupling, weakened the hydrogenation activity of the catalyst, and improved the production of LAOs. A superior stability over 100 h was observed, demonstrating the promising potential of this catalyst for industrial applications. PMID- 30484309 TI - Combining High Porosity with High Surface Area in Flexible Interconnected Nanowire Meshes for Hydrogen Generation and Beyond. AB - Nanostructured metals with large surface area have a great potential for multiple device applications. Although various metal architectures based on metal nanoligaments and nanowires are well known, they typically show a tradeoff between mechanical robustness, high surface area and high (macro)porosity, which, when combined, could significantly improve the performance of devices such as batteries, electrolyzers or sensors. In this work we rationally designed templated networks of interconnected metal nanowires, combining for the first time high porosity of metal foams, narrowly-distributed macropores and a very high surface area of nanoporous dealloyed metals. Thanks to their structural uniformity, the few-micron thick nanowire meshes are also remarkably flexible and durable. We show how the textural properties of the material can be precisely tuned to optimize the nanowire networks for applications in different devices. In an exemplary application in electrolytic production of hydrogen, thanks to its high surface area, a few-micron thick nanomesh outperformed a 300 times thicker nickel foam. Furthermore, thanks to its high porosity, the Pt-doped nanomesh surpassed a microporous Pt/C cloth, demonstrating benefits of the optimally designed nanowire structure for a simultaneous improvement and miniaturization of electrochemical devices. This work extends the potential of interconnected nanowires to multiple new research and industrial applications requiring highly porous and flexible conductive materials with high surface-to-volume ratio. PMID- 30484310 TI - Folic Acid Reduced Triglycerides Deposition in Primary Chicken Hepatocytes. AB - Abdominal fat or fatty liver cause huge economic loss in poultry industry and nonalcoholic fatty liver disease (NAFLD) is also a global health issue in human. More than 90% of de novo lipogenesis in human and chickens is undertaken by the liver which is proved to be full of lipid in new-born chickens. Folic acid was thought to have correlation with lipid metabolism. Primary hepatocytes from new born chickens were employed as a natural fatty liver model in vitro and further to explore whether folic acid could relieve fatty liver in the current study. We found that folic acid addition reduced triglyceride deposition by suppressing de novo fatty acid synthesis and coordinately promoting triglyceride hydrolysis and exportation in primary chicken hepatocytes from new-born chickens. In addition, lipogenesis suppression was through PI3K/AKT/SREBP pathway mediated by weakening insulin/IGF signal. Our data suggested that folic acid may be considered as a precautionary or therapeutic strategy for abdominal fat deposition and fatty liver. In addition, mechanism regulation also implied that IGF2 inhibitor and PI3K inhibitor may be used for the NAFLD therapy to relieve TG deposition. PMID- 30484311 TI - Synthesis of (+/-)-Naphthacemycin A9. AB - Naphthacemycin A9 was synthesized in nine steps by a sequence featuring a Diels Alder reaction of a hindered aryl butadiene and a Hauser-Kraus annulation reaction. PMID- 30484312 TI - Photochemical aging of guaiacol by Fe(III)-oxalate complexes in atmospheric aqueous phase. AB - Fe(III)-oxalate complexes are likely abundant in clouds, fogs and aerosol water. They are photoreactive and can act as an important source of reactive oxygen species (.OH, H2O2 and HO2.) in tropospheric aqueous phases. Although the mechanisms involved in ferrioxalate photolysis have been investigated extensively, few kinetic and mechanistic information is available on the aging of dissolved organic compounds by this photochemical system. In this work, the Fe(III)-oxalate mediated photooxidation of guaiacol (GUA), a model for phenolic compounds emitted from biomass burning, was investigated under typical pH conditions of the atmospheric water. The effect of Fe(III) concentration, oxalate concentration and pH on the photooxidation of GUA was studied in detail. Our results revealed that oxalate can inhibit the oxidation of GUA by Fe(III) under the dark condition. However, the iron-catalyzed photooxidation of GUA can be strongly promoted in the presence of oxalate due to the formation of photoactive Fe(III)-oxalate complexes. GUA was rapidly oxidized to form a number of polymeric, functionalized and open-ring products with low volatility. Detailed reaction pathways for the photooxidation of GUA by Fe(III)-oxalate complexes were proposed based on the results of high-resolution mass spectrometry. This work suggests that ferrioxalate photochemistry can play an important role in the transformation of dissolved organics in atmospheric aqueous phases. PMID- 30484313 TI - Heterogeneous Acetylation of Plant Fibers into Micro- and Nanocelluloses for the Synthesis of Highly-stretchable, Tough and Water-Resistant Co-continuous Filaments via Wet-Spinning. AB - Heterogeneous acetylation of wood fibers is proposed for weakening their interfibrillar hydrogen bonding, which facilitates their processing into micro- and nanocelluloses that can be further used to synthesize filaments via wet spinning. The structural (SEM, WAXD), molecular (SEC) and chemical (FTIR, titration) properties of the system are used to propose the associated reaction mechanism. Unlike the homogeneous acetylation, this method does not alter the main morphological features of cellulose fibrils. Thus, we show for the first time, the exploitation of synergies of compositions simultaneously comprising dissolved cellulose esters and suspended cellulose micro- and nanofibrils. Such colloidal suspension forms a co-continuous assembly with a matrix that interacts strongly with the micro- and nanofibrils in the dispersed phase. This facilitates uninterrupted and defect-free wet-spinning. Upon contact with an anti-solvent (water), filaments are easily formed and display a set of properties that set them apart from those reported so far for nanocelluloses: a remarkable stretch ability (30 % strain) and ultra-high toughness (33 MJ/m3), both surpassing the values of all reported nanocellulose-based filaments. All the while, they also exhibit competitive stiffness and strength (6 GPa and 143 MPa, respectively). Most remarkably, they retain 90% of these properties after-long term immersion in water, solving the main challenge of the lack of wet-strength that is otherwise observed for filaments synthesized from nanocelluloses. PMID- 30484314 TI - Formal Total Synthesis of Hybocarpone Enabled by Visible-Light-Promoted Benzannulation. AB - The formal total synthesis of hybocarpone was achieved in eight steps from commercially available 1,2,4-trimethoxybenzene. Key transformations include a visible-light-promoted benzannulation to construct the key alpha-naphthol intermediate, and a modified CAN-mediated dimerization/hydration cascade sequence to generate the vicinal all-carbon quaternary centers in a stereocontrolled manner. The total synthesis of boryquinone was also achieved in seven steps. PMID- 30484315 TI - Tunable Copper-Catalyzed Reaction of C60 with 2-Ethoxycarbonylacetamides and Subsequent BF3*Et2O-Mediated Isomerization of the Generated Dihydrofuran-Fused Fullerenes to Fulleropyrrolidinones. AB - A tunable copper-catalyzed reaction of C60 with 2-ethoxycarbonylacetamides using air as the oxidant has been explored, which selectively affords methanofullerenes (2) and dihydrofuran-fused fullerenes (3) under CuI/DMAP and CuCl/NMI catalytic systems, respectively. Furthermore, the generated dihydrofuran-fused fullerenes could be transformed to fulleropyrrolidinones (4 and 5) upon treating with BF3?Et2O. PMID- 30484316 TI - DNA-Stabilized Silver Nanoclusters for Label-Free Fluorescence Imaging of Cell Surface Glycans and Fluorescence Guided Photothermal Therapy. AB - A multifunctional nanoplatform that enables the integration of biological detection, imaging diagnosis, and synergistic therapy into a single nanostructure holds great promise for nanoscience and nanomedicine. Herein, a novel theranostic platform was presented for label-free imaging of cell surface glycans based on DNA/silver nanoclusters (AgNCs) via hybridization chain reac-tion (HCR) and fluorescence guided photothermal therapy (PTT). In this strategy, a dibenzocyclooctyne (DBCO)-functionalized DNA and two hairpin structures of DNA/AgNCs probes were involved. Following metabolic glycan labeling, the binding of DBCO-functionalized DNA to cell surface initiated HCR, and then cell surface glycans were specifically labeled by DNA/AgNCs fluorescent probes. Furthermore, this signal amplification strategy was adopted in quantitative analysis, and the detection limit could be achieved as low as 20 cells in 200 MUL binding buffer. Moreover, the remarkable photothermal proper-ties of DNA/AgNCs via HCR, led to efficient killing of cancer cell and inhibited the tumor growth under imaging guide. In this strategy, DNA/AgNCs were utilized to detect the cellular glycans, which aided in overcoming the high cost and instability of fluorescent dyes. Simultaneously, the HCR process avoided the introduction of excessive azido sugars under the precondition of ensuring apparent fluorescence. These results indicated that the developed nanoplatform has great potential for specific cell surface glycans imaging and fluorescence guided PTT. PMID- 30484317 TI - Rubbing-Induced Site-Selective Growth (RISS) of MoS2 Device Patterns. AB - The superior electronic and mechanical properties of 2D-layered transition metal dichalcogenides could be exploited to make a broad range of devices with attractive functionalities. However, the nanofabrication of such layered-material based devices still needs resist-based lithography and plasma etching processes for patterning layered materials into functional device features. Such patterning processes lead to unavoidable contaminations, to which the transport characteristics of atomically-thin layered materials are very sensitive. More seriously, such lithography-introduced contaminants cannot be safely eliminated by conventional semiconductor cleaning approaches. This challenge seriously retards the manufacturing of large arrays of layered-material-based devices with consistent characteristics. Towards addressing this challenge, we introduce a rubbing-induced site-selective growth method capable of directly generating few layer MoS2 device patterns without need of any additional patterning processes. This method consists of two critical steps: (i) a damage-free mechanical rubbing process for generating microscale triboelectric charge patterns on a dielectric surface, and (ii) site-selective deposition of MoS2 within rubbing-induced charge patterns. Our microscopy characterizations in combination with finite element analysis indicate that the field magnitude distribution within triboelectric charge patterns determines the morphologies of grown MoS2 patterns. In addition, the MoS2 line patterns produced by the presented method have been implemented for making arrays of working transistors and memristors. These devices exhibit a high yield and a good uniformity in their electronic properties over large areas. The presented method could be further developed into a cost-efficient nanomanufacturing approach for producing functional device patterns based on various layered materials. PMID- 30484318 TI - Correction to "Efficacy and Safety Profiles of Oral Atorvastatin-Loaded Nanoparticles: Effect of Size Modulation on Biodistribution". PMID- 30484319 TI - In situ characterization of the microstructural evolution of biopharmaceutical solid-state formulations with implications for protein stability. AB - Lyophilized and spray-dried biopharmaceutical formulations are used to provide long-term stability for storage and transport, but questions remain about the molecular structure in these solid formulations and how this structure may be responsible for protein stability. Small-angle neutron scattering with a humidity control environment is used to characterize protein-scale microstructural changes in such solid-state formulations as they are humidified and dried in situ. The findings indicate that irreversible protein aggregates of stressed formulations do not form within the solid-state, but do emerge upon reconstitution of the formulation. After plasticization of the solid-state matrix by exposure to humidity, the formation of reversibly self-associating aggregates can be detected in situ. The characterization of the protein-scale microstructure in these solid state formulations facilitates further efforts to understand the underlying mechanisms that promote long-term protein stability. PMID- 30484320 TI - Aldolase does not show enhanced diffusion in dynamic light scattering experiments. AB - Recent experimental studies have measured a 30-80% increase of the diffusion coefficient when various enzymes, including aldolase, are catalytically active. This observation has been supported by several theoretical explanations, but other theoretical studies argue against the possibility of enhanced diffusion, and two of them ascribe the experimental observations to potential artifacts arising in fluorescence correlation spectroscopy (FCS) measurements. Here, we utilized dynamic light scattering (DLS) to measure the diffusion coefficient of aldolase in the absence and presence of its substrate. The DLS measurements have an experimental error of 3%, and do not find a statistically significant change of the aldolase diffusion coefficient even at a saturating substrate concentration. This finding lends support to the contention that photophysical artifacts may have affected the FCS measurements and challenges the idea that enzymes can be self-propelled by their catalytic activity. PMID- 30484321 TI - Porous Zero-Mode Waveguides for Picogram-Level DNA Capture. AB - We have recently shown that nanopore zero-mode waveguides are effective tools for capturing picogram levels of long DNA fragments for single-molecule DNA sequencing. Despite these key advantages, manufacturing of large arrays is not practical due to the need for serial nanopore fabrication. To overcome this challenge, we have developed an approach for wafer-scale fabrication of waveguide arrays on low-cost porous membranes, which are deposited using molecular layer deposition. The membrane at each waveguide base contains a network of serpentine pores that allows efficient electrophoretic DNA capture at picogram levels while eliminating the need for prohibitive serial pore milling. Here, we show that loading efficiency of these porous waveguides is up to two orders of magnitude greater than their nanopore predecessors. This new device facilitates scaling up the process, greatly reducing the cost and effort of manufacturing. Further, the porous zero-mode waveguides can be used for applications which benefit from low input single molecule real-time (SMRT) sequencing. PMID- 30484322 TI - Bright and Ultrafast Photoelectron Emission from Aligned Single-Wall Carbon Nanotubes through Multiphoton Exciton Resonance. AB - Ultrashort bunches of electrons, emitted from solid surfaces through excitation by ultrashort laser pulses, are an essential ingredient in advanced X-ray sources and ultrafast electron diffraction spectroscopy. Multiphoton photoemission using a noble metal as the photocathode material is typically used, but more brightness is desired. Artificially structured metal photocathodes have been shown to enhance optical absorption via surface plasmon resonance, but such an approach severely reduces the damage threshold in addition to requiring state-of-the-art facilities for photocathode fabrication. Here, we report ultrafast photoelectron emission from sidewalls of aligned single-wall carbon nanotubes. We utilized strong exciton resonances, inherent in this prototypical one-dimensional material, as well as the high damage threshold owing to their excellent thermal conductivity and mechanical rigidity. We obtained unambiguous evidence for resonance-enhanced multiphoton photoemission processes with definite power-law behaviors. In addition, we observed strong polarization dependence and ultrashort photoelectron response time, both of which can be quantitatively explained by our model. These results firmly establish aligned single-wall carbon nanotube films as a novel and promising ultrafast photocathode material. PMID- 30484323 TI - Isosteviol protects free fatty acid- and high fat diet-induced hepatic injury via modulating PKC-beta/p66Shc/ROS and ER stress pathways. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases. The prevalence of NAFLD is continuously rising as the prevalence of obesity and metabolic syndrome is increasing. However, there are no approved pharmacotherapies for the treatment of NAFLD other than managing life style and controlling diets. Extensive studies have demonstrated that multiple mechanisms are involved in free fatty acid (FFA)- and high fat diet (HFD)-induced hepatic injury, including mitochondrial dysfunction, activation of oxidative stress and endoplasmic reticulum (ER) stress and lysosome dysfunction. A previous study reported that Isosteviol (ISV), a derivative of stevioside, prevents HFD-induced hepatic injury. However, the underlying mechanisms remain unclear. In the current study, we examined the potential cellular/molecular mechanisms underlying ISV mediated protective effect against FFA-/HFD-induced hepatic lipotoxicity using both in vitro primary rat hepatocytes and the in vivo rat NAFLD model. The results indicated that ISV inhibits FFA-/HFD-induced hepatic injury via reducing oxidative and ER stress. Specifically, ISV inhibited the expression, activation and mitochondrial translocation of Src-homology-2-domain-containing transforming protein 1 (p66Shc), an adapter protein, which mediates oxidative stress-induced injury and is a substrate of protein kinase C-beta (PKC-beta), via inhibition of PKC-beta activity. However, ISV had no effect on the expression and activity of peptidyl-prolyl cis-trans isomerase and phosphatase A2, isomerase and phosphorylase of p66Shc. In addition, ISV also inhibited FFA-induced ER stress and decreased ER-mitochondrial interaction. Conclusion: ISV prevents FFA/HFD induced hepatic injury through modulating PKC-beta/p66Shc/oxidative and ER stress pathways. ISV represents a promising therapeutic agent for NAFLD in the future. PMID- 30484324 TI - Atomic layout of an orthodontic titanium mini-implant in human tissue: Insights into the possible mechanisms during osseointegration. AB - OBJECTIVES:: To evaluate nanoscale molecular interactions in the interface between human bone and orthodontic titanium implants. MATERIALS AND METHODS:: An orthodontic implant (sandblasted with large grit and with an acid-etched surface treated with Ti6A14V alloy) retrieved from the mandible of human after 2 months of healing was used to analyze the molecular interactive mechanism between the implant and the surrounding bone tissue. To preserve the natural state of the sample as much as possible, cryofixation and scanning electron microscope/focused ion beam milling without any chemical treatment were used during sample preparation. Atom probe tomography was used to investigate the chemical composition and structure at the interface between the implant and human bone tissue. RESULTS:: Three-dimensional (3D) reconstruction of the whole sample revealed a 20 * 50-nm2 plate-like bony element diffusion layer in the sample. The iso concentration analysis of the diffusion layer indicated that the bony element, calcium, and the implant element, titanium oxide, were interspersed with each other. Detailed ionic distribution was illustrated by 3D reconstruction with partial region of interest and one-dimensional concentration profiles of the implant-bone interface. CONCLUSIONS:: The study results advance nanoscale understanding of osseointegration and suggest a potential nanostructure for increasing bond strength of biomaterials to bone. PMID- 30484325 TI - Long-term stability of maxillary protraction therapy in Class III patients with complete unilateral cleft lip and palate. AB - OBJECTIVES:: This study evaluated the long-term stability of maxillary protraction (MP) in patients with complete unilateral cleft lip and palate (UCLP) and identified factors influencing relapse and long-term outcomes. MATERIALS AND METHODS:: Twenty-three adolescents with UCLP who underwent MP therapy were recalled when craniofacial growth was close to completion. Subjects exhibiting reverse/positive overjets were assigned to unstable/stable groups. Lateral cephalometric measurements were made before treatment (T0), after active treatment (T1), and at the end of the growth spurt (T2). RESULTS:: About 63% of the subjects exhibited positive overjets during follow-up. The unstable group demonstrated higher B-x and Co-Gn distances than the stable group (both P < .05) at T0. More short-term (T0-T1) sagittal advancement of point A (A-y) was evident in the unstable group than in the stable group ( P < .05), but no long-term difference was apparent between the two groups ( P = .481). During the posttreatment period (T1-T2), the SNA angle and maxillary incisor protrusion (U1 SN angle) were considerably lower in the unstable group than in the stable group (both P < .05). Overall, the unstable group exhibited a lower increase in the vertical extent of point A (A-x) than the stable group from T0 to T2 ( P < .05). CONCLUSIONS:: In the long term, MP affords favorable maxillary advancement in patients with UCLP. A mandibular excess at T0 and vertical maxillary hypoplasia may contribute to the long-term relapse of a reverse overjet. PMID- 30484326 TI - Contact of the incisive canal and upper central incisors causing root resorption after retraction with orthodontic mini-implants: A CBCT study. AB - OBJECTIVES:: To explore risk factors for contact between the incisive canal (IC) and upper central incisors (U1) and to evaluate the relationship between contact and root resorption using cone-beam computer tomography (CBCT). MATERIALS AND METHODS:: This retrospective study used CBCT data of 33 patients treated by a senior orthodontist. Anterior teeth were retracted with mini-implants, and CBCT scans were taken before and after retraction. IC height and width, U1 lingual movement, and U1-IC distance and root length decrease were compared between contact and noncontact groups. RESULTS:: Sixteen U1 roots in 11 patients touched the IC. The contact group had lower positioned ICs (2.86 +/- 1.10 mm) than the noncontact group (4.07 +/- 1.72 mm). The middle of the U1 roots showed more lingual movement to ICs in the contact group (2.30 +/- 1.20 mm) than in the noncontact group (1.07 +/- 1.16 mm). Right central incisors were closer to the IC than were the left. Root length decreased significantly more in the contact group (2.63 +/- 0.93 mm) than in the noncontact group (1.14 +/- 0.83 mm). CONCLUSIONS:: There is a risk for the U1 root to contact the IC during anterior retraction when the IC is lower positioned. This contact might cause external apical root resorption. PMID- 30484327 TI - Guideposts for Inserting Intercuneiform Joint Arthrodesis Screws: Analysis Using Multiplanar Reconstructed Computed Tomography. AB - Intercuneiform arthrodesis is often required for various midfoot pathologies; however, intercuneiform screw insertion is not easy due to the complicated anatomical structure of cuneiforms. This study aimed to determine the advisable screw entry point and direction using intraoperatively detectable landmarks. The computed tomography (CT) scan data of feet were reformatted using OsiriX software multiplanar reconstruction. First, based on the data of 10 CT scans of normal feet, we determined the advisable screw entry point at the upper one-third in the dorsoplantar direction and center in the anteroposterior direction on the medial aspect of the medial cuneiform and insertion direction toward the outermost point of the base of the fifth metatarsal in the axial plane and parallel to the plantar surface in the coronal plane. Second, we examined the accuracy of these newly designed guideposts in the simulation using other CT scan data of the other 27 normal feet and 12 flat feet. The simulated screw trajectory penetrated the mid three-fifths of all three cuneiforms in 97% of the normal feet and 92% of the flat feet with no cases of cortical wall violation. Levels of Evidence: Level V: Expert opinion. PMID- 30484328 TI - Immune responses elicited by the recombinant Erp, HspR, LppX, MmaA4, and OmpA proteins from Mycobacterium tuberculosis in mice. AB - Immunogenic potency of the recombinant Erp, HspR, LppX, MmaA4, and OmpA proteins from Mycobacterium tuberculosis (MTB), formulated with Montanide ISA 720 VG adjuvant, was evaluated in BALB/c mice for the first time in this study. The five vaccine formulations, adjuvant, and BCG vaccine were subcutaneously injected into mice, and the sera were collected at days 0, 15, 30, 41, and 66. The humoral and cellular immune responses against vaccine formulations were determined by measuring serum IgG and serum interferon-gamma (IFN-gamma) and interleukin-12 (IL 12) levels, respectively. All formulations significantly increased IgG levels post-vaccination. The highest increase in IFN-gamma level was provided by MmaA4 formulation. The Erp, HspR, and LppX formulations were as effective as BCG in enhancement of IFN-gamma level. The most efficient vaccine boosting the IL-12 level was HspR formulation, especially at day 66. Erp formulation also increased the IL-12 level more than BCG at days 15 and 30. The IL-12 level boosted by MmaA4 formulation was found to be similar to that by BCG. OmpA formulation was inefficient in enhancement of cellular immune responses. This study showed that MmaA4, HspR, and Erp proteins from MTB are successful in eliciting both humoral and cellular immune responses in mice. PMID- 30484330 TI - Radiation safety goggles are more important than Holmium laser safety goggles. PMID- 30484329 TI - Effects of isokinetic muscle strengthening on muscle strength, mobility, and gait in post-stroke patients: a systematic review and meta-analysis. AB - OBJECTIVE:: To investigate whether isokinetic muscle strengthening improves muscle strength, mobility, and gait in post-stroke patients. METHODS:: We searched for randomized controlled trials at PubMed/Medline, SciELO, PEDro, and Cochrane Central Register of Controlled Trials, from the earliest date available to June 2018. Randomized controlled trials that examined the effects of isokinetic muscle strengthening versus other rehabilitation interventions or control in post-stroke patients were included. Study quality was evaluated using the PEDro scale. Weighted mean difference (WMD) and 95% confidence intervals (CIs) were calculated, and heterogeneity was assessed using the I2 test. RESULTS:: In total, 13 studies (347 patients) focusing on the use of isokinetic in rehabilitation following stroke were included. All trials were of low-to moderate quality. Isokinetic muscle strengthening improved muscle strength WMD 0.8 (95% CI: 0.2, 1.4; N = 96), mobility WMD -2.03 seconds (95% CI: -2.9, -1.1; N = 111) and gait speed WMD 0.9 m/s (95% CI: 0.05, 1.8; N = 87). CONCLUSION:: Isokinetic muscle strengthening seems to be a useful strategy for improving muscle strength, mobility, and gait in post-stroke patients. PMID- 30484331 TI - Evaluation of Optimal Timing of Expert Feedback in a Simulated Flexible Ureteroscopy Course. AB - Introduction Simulation-based training (SBT) has become an increasingly popular modality to train novice surgical residents in the face of rapidly increasing innovative surgical techniques across all surgical disciplines. Recent studies have already demonstrated SBT to be effective in helping overcome the learning curve associated with new surgical techniques, especially in junior residents and endoscopic procedures. Additionally, it is known that trainees benefit significantly from expert feedback; however, there is a paucity of data looking into the optimal timing of this feedback during SBT. To address this knowledge deficit, a SBT curriculum was developed for junior urology residents to assess optimal timing of feedback during SBT for flexible ureteroscopy (fURS). Methods The SBT course consisted of a pre-training assessment, 3 independent practice sessions, and a post-training assessment, with residents receiving expert feedback right after their pre-training assessment (early feedback (EF)) or after their final independent training session (late feedback [LF]). Results Fifteen trainees with similar baseline fURS experience and pre-course fURS task performance scored participated in the study. There was a significant difference between the pre- and post- task completion times overall (15.2 min vs. 9.1 min, p<0.001), with no difference between the early or late feedback (LF) groups (p=0.884). The mean performance scores improved for both groups (18.2 vs. 24.2, p<0.001) with the EF group having a more statistically significant improvement in performance scores compared to the LF group (p=0.05), and most (73%) of residents preferred EF. Conclusions This study demonstrates that a SBT curriculum for fURS is effective for technical skills development among junior trainees, and that EF resulted in marginally better overall scores and was preferred by residents. PMID- 30484332 TI - IMPACT OF COMBINATION OF LOCAL ANAESTHETIC WOUNDS INFILTRATION AND ULTRASOUND TRANSVERSUS ABDOMINAL PLAN (US-TAP) BLOCK IN PATIENTS UNDERGOING ROBOT-ASSISTED RADICAL PROSTATECTOMY: PERIOPERATIVE RESULTS OF A DOUBLE-BLIND RANDOMIZED CONTROLLED TRIAL. AB - OBJECTIVE To determinate benefits of the combination of local anaesthetic wounds infiltration and Ultrasound Transversus Abdominal Plane (US-TAP) block with ropivacaine on postoperative pain, early recovery and hospital stay in patients undergoing robot assisted radical prostatectomy (RARP). METHODS The study is double-blinded randomized controlled trial. Our hypothesis was that the combination of wound infiltration and US-TAP block with Ropivacaine would decrease immediate post-operative pain and opioids use. Primary outcomes included postoperative pain and opioids demand during the hospital stay. Secondary outcomes were nausea/vomiting rate, stool passing time, use of pro-kinetics, length of hospital stay and 30-days readmission to the hospital for pain or other US-TAP-block related complications. RESULTS A total of 100 patients who underwent RARP were eligible for the analysis; 57 received the US-TAP block with 20 ml of 0.35% Ropivacaine (US-TAP-block group) and 43 did not receive US-TAP block (no-US TAP group). All the patients received the local wound anaesthetic infiltration with 20 ml of 0.35% Ropivacaine. US-TAP block group showed a decreased mean NRS within 12h after surgery (1.5 vs 2.6; p=0.02) and mean NRS (1.8 vs 2.7; p=0.04) with lesser n. of patients who used of opioid (3.5% vs 18.6%; p=0.01) during the first 24 h. Moreover, we found a shorter mean length of hospital stay (LOS, 4.27 vs 4.72, days; p= 0.04) with a lower requirement of pro-kinetics administration during the hospital stay (21% vs 72%; p<0.001). No US-TAP-block related complications were reported. CONCLUSION Combination of anaesthetic wound infiltration and US-TAP block with Ropivacaine as part of a multimodal analgesic regimen can be safely offered to patients undergoing RARP and ePLND. It improves the immediate post-operative pain control, reducing opioids administration and is associated to a decreased use of pro-kinetics and shorter hospital stay. PMID- 30484333 TI - Emerging drugs for migraine treatment: an update. AB - INTRODUCTION: Migraine is a very frequent and disabling neurological disorder. The current treatment options are old, generally poorly tolerated and not migraine-specific, reflecting the low priority of migraine research and highlighting the vast unmet need in its management. Areas covered: Advancement in the understanding of migraine pathophysiological mechanisms and identification of novel potentially meaningful targets have resulted in a multitude of emerging acute and preventive treatments. Here we review the known putative migraine pathophysiological mechanisms in order to understand the rationale of the most promising novel treatments targeting the Calcitonin-Gene-Related Peptide (CGRP) receptor and ligand and the 5 hydroxytryptamine (5-HT)1F receptor. Key findings on the phase II and phase III clinical trials on these treatments will be summarised. Furthermore a critical analysis on failed trials of potentially meaningful targets such the nitric oxide and the orexinergic pathways will be conducted. Future perspective will be outlined. Expert opinion: The recent approval of Erenumab and Fremanezumab is a major milestone in the therapy of migraine since the approval of triptans. Several more studies are needed to fully understand the clinical potential, long-term safety and cost-effectiveness of these therapies. This paramount achievement should stimulate the development of further research in the migraine field. PMID- 30484334 TI - HEME OXYGENASE-1 HAS AN ANTITUMOR ROLE IN BREAST CANCER. AB - AIMS: Heme Oxygenase-1 (HO-1) is an enzyme involved in cellular responses to oxidative stress and has also been shown to regulate processes related to cancer progression. In this regard, HO-1 has been shown to display a dual effect with either antitumor or protumor activity, being this also true for breast cancer (BC). In this work we intended to address this discrepancy regarding the role of HO-1 in BC. RESULTS: HO-1 was detected in human breast cancer tissues, and its protein levels correlated with reduced tumor size and longer overall survival time of patients, thus suggesting the clinical importance of HO-1 in this type of cancer. Contrariwise, nuclear localization of HO-1 correlated with higher tumor grade suggesting that the effect of HO-1 is dependent on its cellular localization. In vivo experiments showed that both pharmacological activation and genetic overexpression of HO-1 reduce the tumor burden in two different animal models of BC. Furthermore, the pharmacological and genetic activation of HO-1 in several BC cell lines both reduce the cellular viability by inducing apoptosis and cell cycle arrest and decrease the cellular migration and invasion rates by modulating pathways involved in the epithelial-mesenchymal transition. Furthermore, HO-1 activation impaired in vivo the metastatic dissemination. Innovation and conclusions: by using various BC cell lines and animal models as well as human tumor samples we demonstrated that total HO-1 displays antitumor activities in BC. Furthermore, our studies suggest that HO-1 subcellular localization may explain the differential effects observed for the protein in different tumor types. PMID- 30484335 TI - Applicability of tumor spheroids for in vitro chemosensitivity assays. AB - INTRODUCTION: Drug screening assays employing 2D-cultures of cancer cells have been largely replaced by 3D multicellular tumor spheroid (MCTS) models which more closely represent patient's tumors. The predictive power of the different MCTSs depends on source of the cells, techniques of preparation and characteristics of the aggregates. Areas covered: The preparation of MCTSs and a comparison of the spheroids assembled from permanent cancer and patient-derived cell lines in respect to the correlation of their chemosensitivity to clinical responses are discussed. Spheroids formed in in vivo in pleural effusion and blood of cancer patients are presented as interesting sources for drug screening. Expert opinion: 3D tumor models for drug screening were adopted to increase the predictive power of assays for success in clinical trials. Cell lines which form dense spheroids differ in physical properties, gene expression and chemosensitivity from 2D cultures. Still, most of these MCTS models lack characteristics of complex tumor tissues and have not been validated for their adequacy to select clinically useful drugs. Patient-derived spheroids from pleural effusion or blood, namely tumorospheres of circulating tumor cells, are MCTS models most similar to patient's tumors. PMID- 30484336 TI - From pharmaceuticals to nutraceuticals: bridging disease prevention and management. AB - INTRODUCTION: Nutraceuticals, up today, do not have a specific definition distinct from those of other food-derived categories, e.g. food supplements, herbal products, pre and probiotics, functional foods, etc. They have, however, a pharmacological beneficial effect on health. Many studies have been recently addressed to assess their safety, efficacy, and regulation since they are getting growing attention by market and research, with the aim to clear the difference between them and other market available food-derived products that claim beneficial effect on health. Areas covered: The understanding of the potential mechanisms of action of pharmaceutically active substances contained in nutraceuticals that may improve health and reduce the risk of pathological conditions while enhancing overall well-being is the challenge for nutraceuticals to be considered as a preventive and therapeutic efficient tool in facing some diseases. Expert commentary: It is of utmost importance to have a proper and unequivocal definition of nutraceuticals and a shared regulation. Nevertheless, there is a lack of clear information and, often, the claimed health benefits may not be properly substantiated by safety and by efficacy in vivo data, which can induce false expectations and miss the target for a product to be effective, as claimed. PMID- 30484337 TI - Advances in distributed computing with modern drug discovery. AB - INTRODUCTION: Computational chemistry dramatically accelerates the drug discovery process and high-performance computing (HPC) can be used to speed up the most expensive calculations. Supporting a local HPC infrastructure is both costly and time consuming and therefore many research groups are moving from in-house solutions to remote distributed computing platforms. Areas covered: The authors focus on the use of distributed technologies, solutions and infrastructures to gain access to HPC capabilities, software tools and datasets to run the complex simulations required in computational drug discovery. Expert opinion: The use of computational tools can decrease the time to market of new drugs. HPC has a crucial role in handling the complex algorithms and large volumes of data required to achieve specificity and avoid undesirable side-effects. Distributed computing environments have clear advantages over in-house solutions in terms of cost and sustainability. The use of infrastructures relying on virtualization reduces set-up costs. Distributed computing resources can be difficult to access, although web-based solutions are becoming increasingly available. There is a trade-off between cost effectiveness and accessibility in using on-demand computing resources rather than free/academic resources. Graphics processing unit computing, with its outstanding parallel computing power, is becoming increasingly important. PMID- 30484338 TI - Mitral valve prolapse. AB - INTRODUCTION: Mitral valve prolapse is a common valve pathology with a spectrum of disease from isolated prolapse to myxomatous, multi-scallop Barlow's disease. The main complications relate to progression of mitral regurgitation, endocarditis, sudden death and stroke. The timing of intervention in patients with asymptomatic severe mitral regurgitation is controversial. Areas covered: This article reviews the pathophysiology, genetics, clinical features, diagnostic imaging, complications, long term outcomes and indications for intervention in mitral valve prolapse. Expert commentary: Several key dilemmas in the management of mitral valve prolapse remain. Factors which influence progression of mitral regurgitation are unclear and therefore we have no therapeutic targets to prevent progression. Evidence-based methods to reduce the risk of sudden death, stroke and endocarditis have not been identified. In symptomatic patients with severe mitral regurgitation valve surgery is recommended. In asymptomatic patients, careful risk stratification incorporating markers of left ventricular dysfunction, atrial fibrillation, pulmonary hypertension and valve reparability is required to identify the optimal timing of intervention. PMID- 30484339 TI - Current perspectives of physical activity in cystic fibrosis. AB - INTRODUCTION: Regular exercise and physical activity participation are recommended in guideline-based care for individuals with cystic fibrosis (CF) across the spectrum of age and disease severity. However, the best training methods to improve physical function and encourage ongoing exercise and activity participation are not clear, which is an ongoing challenge for clinicians. Areas covered: This perspective provides an overview of current evidence for exercise and physical activity relative to clinical outcomes and healthcare utilisation in people with CF, and highlights areas of future research need. Expert commentary: What kind, how much, how often and how best to support people with CF to be physically active is uncertain. Whether new methods of training, the use of technology, or pharmaceutical developments, could best deliver increased activity and physiological benefit without increased therapeutic burden is unclear. At present, if people with CF are going to be physically active, seemingly they should aim to perform this activity in the way most likely to confer some health benefit i.e. concerted exercise bouts of at least ten minutes in addition to any incidental (habitual) activity performed during the course of daily life. PMID- 30484340 TI - A decade of nutraceutical patents: where are we now in 2018? AB - INTRODUCTION: In the last 10 years, nutraceuticals have grown in interest to researchers, industry, and consumers and are now familiar in the collective imagination as a tool for preventing the onset of a disease. Often nutraceuticals are confused with biologically active phytochemicals/botanicals which can have health benefits. This is a misunderstanding however as the term nutraceutical refers to a product that must have a beneficial effect on health proven by clinical testing. Areas covered: A search has been performed on both recent patents and the literature regarding nutraceuticals focusing on the beneficial and proven health effects on pathological conditions to give an overview of the state-of-the-art developments in this area. Patents and literature data addressing specific pathological conditions are discussed. Expert opinion: Nutraceuticals represent a challenge for the future of drug-based pharmacotherapy, and, at the same time, are a powerful tool for the prevention of chronic disease. They are not proposed as an alternative to drugs, but instead, can be helpful to complement a pharmacological therapy and prevent the onset of chronic diseases in subjects who do not qualify for conventional pharmacological treatment. PMID- 30484341 TI - The COX-2/prostanoid signaling cascades in seizure disorders. AB - Introduction:A robust neuroinflammatory response is a prevalent feature of multiple neurological disorders, including epilepsy and acute status epilepticus. One component of this neuroinflammatory reaction is the induction of cyclooxygenase-2 (COX-2), synthesis of several prostaglandins and endocannabinoid metabolites, and subsequent activation of prostaglandin and related receptors. Neuroinflammation mediated by COX-2 and its downstream effectors has received considerable attention as a potential target class to ameliorate the deleterious consequences of neurological injury. Area covered: Here we describe the roles of COX-2 as a major inflammatory mediator. In addition, we discuss the receptors for prostanoids PGE2, PGD2, and PGF2alpha as potential therapeutic targets for inflammation-driven diseases. The consequences of prostanoid receptor activation after seizure activity are discussed with an emphasis on the utilization of small molecules to modulate prostanoid receptor activity. Expert opinion: Limited clinical trial experience is supportive but not definitive for a role of the COX signaling cascade in epileptogenesis. The cardiotoxicity associated with chronic coxib use, and the expectation that COX-2 inhibition will influence the levels of endocannabinoids, leukotrienes and lipoxins as well as the prostaglandins and their endocannabinoid metabolite analogs, is shifting attention towards downstream synthases and receptors that mediate inflammation in the brain. PMID- 30484343 TI - Motor performance is preserved in healthy aged adults following severewhole-body hyperthermia. AB - Healthy aging is associated with a progressive decline in motor performance and thermoregulatory efficiency. Functional consequences of severe whole-body hyperthermia on neurophysiological functions in healthy aged men have not been investigated. To determine whether severe whole-body hyperthermia (increase in rectal temperature of about 2.5 degrees C) induced by lower-body heating in older men (64-80 years, n = 9) would suppress excitability of reflexes, voluntarily and electrically induced ankle plantar flexor contractile properties were compared with those in young men (19-21 years, n = 11). Though no aging effect on hyperthermia-induced reflex amplitudes was observed, a decrease in maximal H-reflex and V-wave latencies was found to be greater in older than in young men. In older men, lower-body heating was accompanied by a significant increase in twitch and tetani test torque in parallel with a greater decrease in muscle contraction time. There was no temperature-depended aging effect on the voluntary activation and maximal voluntary torque production. Despite delayed and weakened thermoregulation and age-related decline in neuromuscular function, motor performance in whole-body severe hyperthermia is apparently preserved in healthy aging. PMID- 30484344 TI - A new microwave applicator for laparoscopic and robotic liver resection. AB - PURPOSE: Bleeding from parenchyma transection during a robotic hepatic surgery remains the most critical point affecting postoperative recovery and long-term survival. Various robotic devices with different types of energies have been proposed; however, each of these lack in steerability, efficacy, or accuracy. The aim of this work is to evaluate the feasibility and performance of a new steerable microwave resection device intended for minimizing intraoperative blood loss during laparoscopic and robotic liver resections. METHODS: The new device operating at 2.45 GHz was designed to accommodate the engineering constraints derived from its use for robotic surgery or laparoscopy, in which a steerable head is required and the internal cooling of forced gas or water is undesirable. The device design, analysis, and optimization were addressed using the most advanced commercial electromagnetic and thermal solvers to achieve the best results. To experimentally validate the results of the numerical analysis, many ablations were performed on a freshly explanted bovine liver by using a single device prototype with three levels of energy supplied to the tissue. During the ablation procedures, the time, temperature, and shape of the thermal lesion were recorded using thermocouples and an infra-red thermos camera. SUMMARY: Ex vivo tests showed good agreement with the numerical simulations, demonstrating the validity of the simplifications adopted to deal with the complex phenomena involved in the extreme hyperthermia of a living tissue. The high performance, thermal reliability, and robustness of the developed device were also demonstrated along with the possibility of reducing operation time and blood loss. PMID- 30484345 TI - Patients with hypokalemia develop WNK bodies in the distal convoluted tubule of the kidney. AB - Hypokalemia contributes to the progression of chronic kidney disease, while a definitive pathophysiogical theory to explain this remains to be established. K+ deficiency results in profound alterations of renal epithelial transport. These include an increase of salt reabsorption via the Na+,Cl--cotransporter (NCC) of the distal convoluted tubule (DCT), which minimizes electroneutral K+ loss in downstream nephron segments. In experimental conditions of dietary K+ depletion, punctate structures in the DCT containing crucial NCC-regulating kinases have been discovered in the murine DCT and termed "WNK bodies", referring to their component, with no lysine (WNK) kinases. We hypothesized that in humans, WNK bodies occur as well in hypokalemia. Renal needle biopsies of patients with chronic hypokalemic nephropathy and appropriate controls were examined by histological stains and immunofluorescence. Segment- and organelle-specific marker proteins were used to characterize the intrarenal and subcellular distribution of established WNK body constituents, namely WNK and Ste20-related proline-alanine-rich (SPAK) kinases. In both hypokalemic patients, WNKs and SPAK concentrated in non-membrane bound cytoplasmic regions in the DCT, consistent with prior descriptions of WNK bodies. The putative WNK bodies were located in the perinuclear region close to, but not within, the endoplasmic reticulum. They were closely adjacent to microtubules but not clustered in aggresomes. Notably, we provide the first report of WNK bodies, which are functionally challenging structures associated with K+ deficiency, in human patients. PMID- 30484346 TI - Furosemide Reduces BK-alphabeta4-mediated K+ Secretion in Mice on an Alkaline High K+ Diet. AB - Special high K diets have cardio-protective effects and are often warranted in conjunction with diuretics such as furosemide for treating hypertension. However, it is not understood how a high K diet (HK) influences the actions of diuretics on renal K+ handling. Furosemide acidifies the urine by increasing acid secretion via the Na+-H+ exchanger 3 (NHE3) in TAL and vacuolar H+-ATPase (V-ATPase) in the distal nephron. We previously found that an alkaline urine is required for BK alphabeta4-mediated K+ secretion in mice on HK. We therefore hypothesized that furosemide could reduce BK-alphabeta4-mediated K+ secretion by acidifying the urine. Treating with furosemide (drinking water) for 11 days led to decreased urine pH in both WT and BK-beta4 knockout mice (BK-beta4 KO) with increased V ATPase expression and elevated plasma aldosterone levels. However, furosemide decreased renal K+ clearance and elevated plasma [K+] in WT but not BK-beta4 KO. Western blotting and immunofluorescence staining showed that furosemide treatment decreased cortical expression of BK-beta4 and reduced apical localization of BK alpha in connecting tubules (CNT). Addition of the carbonic anhydrase inhibitor, acetazolamide, to furosemide water restored urine pH along with renal K+ clearance and plasma [K+] to control levels. Acetazolamide plus furosemide also restored the cortical expression of BK-beta4 and BK-alpha in connecting tubules (CNT). These results indicate that in mice adapted to HK, furosemide reduces BK alphabeta4-mediated K+ secretion by acidifying the urine. PMID- 30484347 TI - Moderate aging does not exacerbate cisplatin-induced kidney injury or fibrosis despite altered inflammatory cytokine expression and immune cell infiltration. AB - Aging is a risk factor for certain forms of kidney injury due to normal physiological changes, but the role aging plays in cisplatin-induced kidney injury is not well-defined in humans or animal models of the disease. To improve on current knowledge in this field, we treated eight and forty week old FVB/n mice with either one, high dose of cisplatin as a model of acute kidney injury (AKI) or with repeated, low doses of cisplatin (7 mg/kg cisplatin once a week for four weeks) as a clinically relevant model of chronic kidney disease (CKD) to determine if aging exacerbates cisplatin-induced kidney injury. Eight and forty week old mice had comparable levels of AKI. Forty week old mice had an elevation of fibrotic markers basally, but treatment with cisplatin did not exacerbate fibrosis. We concluded that this may be the result of a decreased inflammatory response in forty week old cisplatin-treated mice compared to eight week old mice. In spite of a decreased inflammatory response, forty week old treated mice had more immune cell infiltration than eight week old mice. Our data highlight the importance of examining age as a risk factor for cisplatin-induced kidney injury. PMID- 30484348 TI - 'Overruled': the kidneys' judgement of sodium balance versus stabilization of renal function. PMID- 30484349 TI - Periostin and polycystic kidney disease: more pieces in the puzzle. PMID- 30484350 TI - Renal Olfactory Receptor 1393 Contributes to the Progression of Type II Diabetes in a Diet-Induced Obesity Model. AB - Olfactory receptors (ORs) are G protein-coupled receptors which serve to detect odorants in the nose. Additionally, these receptors are expressed in other tissues where they have functions outside of the canonical smell response. Olfactory Receptor 1393 (Olfr1393) was recently identified as a novel regulator of sodium glucose co-transporter 1 (Sglt1) localization in the renal proximal tubule. Glucose reabsorption in the proximal tubule (via Sglt1 and Sglt2) has emerged as an important contributor to the development of diabetes. Inhibition of Sglt2 is now accepted as a viable therapeutic treatment option for patients with type II diabetes and has been shown to delay development of diabetic kidney disease. We hypothesized that Olfr1393 may contribute to the progression of type II diabetes, particularly the development of hyperfiltration which has been linked to increased Na+ reabsorption in the proximal tubule via the Sglts. To test this, Olfr1393 wildtype (WT) and knockout (KO) mice were challenged with a high fat diet (HFD) to induce early stage type II diabetes. After 16 weeks on the HFD, WT male mice displayed increased fasting blood glucose values and impaired glucose tolerance. Both of these effects were significantly blunted in the male KOs. In addition, both male and female WT mice developed diabetes-induced hyperfiltration which was attenuated in the Olfr1393 KO mice and corresponded with a reduction in Sglt2 luminal expression. Collectively, this data indicates that renal Olfr1393 can contribute to the progression of type II diabetes, likely as a regulator of sodium-glucose co-transport in the proximal tubule. PMID- 30484351 TI - A Best Evidence Medical Education (BEME) systematic review of: What works best for health professions students using mobile (hand-held) devices for educational support on clinical placements? BEME Guide No. 52. AB - BACKGROUND: Ingrained assumptions about clinical placements (clerkships) for health professions students pursuing primary basic qualifications might undermine best educational use of mobile devices. QUESTION: What works best for health professions students using mobile (hand-held) devices for educational support on clinical placements? METHODS: A Best Evidence Medical Education (BEME) effectiveness-review of "justification" complemented by "clarification" and "description" research searched: MEDLINE, Educational Resource Information Center, Web of Science, Cumulative Index to Nursing and Allied Health Literature, PsycInfo, Cochrane Central, Scopus (1988-2016). Reviewer-pairs screened titles/abstracts. One pair coded, extracted, and synthesized evidence, working within the pragmatism paradigm. SUMMARY OF RESULTS: From screening 2279 abstracts, 49 articles met inclusion-criteria, counting four systematic reviews for context. The 45 articles of at least Kirkpatrick K2 primary research mostly contributed K3 (39/45, 86.7%), mixed methods (21/45, 46.7%), and S3-strength (just over one-half) evidence. Mobile devices particularly supported student: assessment; communication; clinical decision-making; logbook/notetaking; and accessing information (in about two-thirds). Informal and hidden curricula included: concerns about: disapproval; confidentiality and privacy; security; distraction by social connectivity and busy clinical settings; and mixed messages about policy. DISCUSSION AND CONCLUSION: This idiosyncratic evidence-base of modest robustness suggested that mobile devices provide potentially powerful educational support on clinical placement, particularly with student transitions, metalearning, and care contribution. Explicit policy must tackle informal and hidden curricula though, addressing concerns about transgressions. PMID- 30484352 TI - Higher risk of hospitalized infection, cardiovascular disease, and fracture in patients with rheumatoid arthritis determined using the Japanese health insurance database. AB - OBJECTIVE: To evaluate the risk of hospitalized infection (HI), cardiovascular disease (CVD), stroke, and fracture in rheumatoid arthritis (RA) patients compared with non-RA patients using the Japanese health insurance database. METHOD: Among individuals aged >=18 years, RA cases were defined to have one RA diagnostic code and receiving >=1 disease-modifying antirheumatic drug between 2005 and 2013 (n = 6,712). Age-, sex-, calendar year of the observation start-, and observation length-matched non-RA cases were selected at 1:5 (n = 33,560). Hazard ratios (HRs) were calculated using the time-dependent Cox regression analysis. RESULTS: Median age of the patients was 52.0 years. The incidence rates of HI, CVD, and fracture in the RA group were 2.42/100 person-years (PY), 4.94/1,000 PY, and 10.59/1,000 PY. The crude incidence rate ratios (95% CI) (RA vs. non-RA) for HI, CVD, and fracture were 2.47 (2.20-2.77), 1.89 (1.49-2.41), and 3.35 (2.80-4.02). The adjusted HR (95% CI) (RA vs. non-RA) was significantly elevated (HI, 1.74 [1.52-1.99], CVD, 1.38 [1.04-1.85], and fracture, 1.88 (1.54 2.31)]. CONCLUSION: The relatively young RA population had significantly higher risks of these complications than the non-RA, indicating importance of prevention of them even at young ages in clinical settings. PMID- 30484353 TI - Cost-utility analysis of levodopa carbidopa intestinal gel (Duodopa) in the treatment of advanced Parkinson's Disease in patients in Scotland and Wales. AB - AIMS: To carry out a cost-utility analysis comparing the cost-effectiveness of levodopa carbidopa intestinal gel (LCIG) with standard of care (SOC) in patients with advanced Parkinson's Disease (aPD) unsuitable for apomorphine or deep brain stimulation (DBS). LCIG is the only treatment option in this small, but clinically important, population. METHODS: A Markov model with 25 disease states based on disease stage and off-time status plus death. Patients enter the model with aPD spending >50% of their waking day in the off state. Patients progress through the model in 6-monthly cycles for 20 years to approximate lifetime treatment and capture long-term costs and effects of therapy. Inputs are based on LCIG clinical trials for clinical outcomes and health state utilities, the literature for health state transitions and use UK-based input data wherever possible (drug costs, disease/adverse event management costs, discontinuation rates, mortality rates). LIMITATIONS: Data collection can be challenging in this small, elderly population with advanced disease, therefore some model inputs were estimated, rather than collected directly. We assumed a reduction in off-time was the only benefit after the first year of treatment with LCIG, this is a conservative approach, since there may be additional clinical benefits. RESULTS: There is a considerable incremental gain in quality adjusted life years (QALYs) for patients treated with LCIG of 1.26 QALY with associated incremental cost effectiveness ratio (ICER) of L52,110. If the impact on caregivers is included the ICER reduces to L47,266. CONCLUSIONS: In cases where there is an orphan population, with no alternative treatment options, HTA assessments have a broader decision-making framework and the ICER is interpreted in this context. In the setting of a very small population, with considerable unmet need, LCIG represents value for money, as reflected by funding approval across the UK. PMID- 30484354 TI - Body Part Removal: A Thematic Exploration of U.K. Homicide Offenses. AB - Body part removal (BPR) is a rare homicide phenomena, which emerges as a result of a variety of motives. Fifty-eight BPR U.K. homicide cases were analyzed. Findings indicated key characteristics within BPR murder offenses, with most offenders males; aged around 31 years; knew their victims; with presence of alcohol, drugs, and mental health issues; and more than two thirds of the sample had previous convictions, more than 50% for theft. Offense behaviors showed "multiple wounds" and "victim naked" as highest frequency, with the head as the most frequently removed body part. Smallest space analysis (SSA) identified two behavioral themes (expressive and instrumental) with 62.1% of cases classified as one of these. The study has provided the largest U.K. sample of BPR homicide, furthering understanding this type of offense and the offenders who commit it. PMID- 30484355 TI - Violent Motherhood: Prevalence and Factors Affecting Violence Against Pregnant Women in India. AB - Violence against women is widely recognized as a serious public health problem in the world. Especially violence against pregnant women has more severe health consequences for both women and child. The objective of this study is to examine the prevalence and factors affecting violence during pregnancy in India. Data from the National Family Health Survey (NFHS)-4 are used to analyze this study. NFHS is a series of demographic health surveys conducted in India. Information on violence against pregnant women was collected for the first time in NFHS-4. Univariate and multivariate analyses are used to show the factors affecting violence during pregnancy. Study results reveal that the prevalence of violence varied among states from 0.5% to 9%, and women in South India were at a greater risk of abuse during pregnancy than that of women in other parts of India. Women with no education, women in poor household, women having three and more children, and women from rural area are at greater risk of being victims of violence during motherhood. Effective strategies such as responsive health care system, effective implementation of legal measures, and educating and engaging men in preventing violence are urgently needed. PMID- 30484356 TI - Client-Perpetrated Violence Among Frontline Child Welfare Workers. AB - Client-perpetrated violence against child protective services (CPS) workers is common and detrimental to worker wellbeing with consequences including physical injury and psychological illnesses. Despite the impacts of violence, few studies capture violence in a representative sample of CPS workers. This study examines prevalence and applies a structural inequality framework to consider who among CPS workers is most susceptible. This article used the Florida Study of Professionals for Safe Families dataset, a longitudinal panel study of newly hired CPS workers ( N = 1,501) to examine the prevalence of violence in the first 6 months of employment and consider the influence of individual characteristics. CPS workers experienced high levels of non-physical violence (75%), threats (37%), and physical violence (2.3%). Age and race were significantly related to instances of violence as were college major and position. Relationships were nuanced and did not uniformly follow a structural inequality framework. The high prevalence of violence within the first months on the job illustrates the importance of conflict and violence training before workers acquire independent caseloads. In addition, institutionalized mandatory reporting procedures with definitions of non-physical violence, threats, and physical violence may promote a culture of safety rather than an attitude that violence is part of the job. Finally, supervisors and peers can benefit from opportunities to support one other. The high prevalence of violence within certain subgroups of workers coupled with its wide-ranging consequences call for additional theoretical and empirical research and responsive policy to prioritize worker safety and wellbeing. PMID- 30484357 TI - Treatment-Related Costs of Childhood Epilepsy in Mainland China: A Preliminary Study in a Tertiary Pediatric Epilepsy Center. AB - This study aimed to investigate the treatment-related annual cost of childhood epilepsy and its related factors in mainland China. A total of 244 cases were collected at the outpatient clinics of Peking University First Hospital Pediatrics from April 2010 to August 2013. The median annual epilepsy treatment related costs per patient were estimated to be RMB7822 (US$1160), accounting for 43.72% (median) of urban residents' disposable income in China. Those who lived far away or with uncontrolled seizures yielded much higher costs. This study concluded that the treatment of children with epilepsy produces a heavy burden on both families and society in mainland China. The constitution ratio of antiepileptic drugs and travel expenses are much higher than those of other countries. Adjusting medical insurance coverage, balancing medical resource distribution, and taking good control of seizures might be effective in reducing the economic burden of childhood epilepsy in China. PMID- 30484358 TI - Examining Commonly Reported Sex Trafficking Indicators From Practitioners' Perspectives: Findings From a Pilot Study. AB - Commonly reported sex trafficking indicators have been disseminated widely by government and non-governmental organizations in trainings aimed to increase identification and referral to resources. However, very little research evaluates such indicators. Drawing from survey responses of 86 social service providers, health care practitioners, and justice system officials in a Midwestern City, this pilot study aimed to examine: (a) the pervasiveness of the commonly reported indicators, (b) the salience of domains of indicators, and (c) the extent to which indicators differ across service populations (U.S.-born minors, U.S.-born adults, foreign born minors, and foreign born adults). The most commonly identified indicators included mental health symptoms of depression ( M = 3.82); low self-esteem ( M = 3.59); anxiety ( M = 3.55); low levels of interpersonal trust ( M = 3.52); sense of fear ( M = 3.36); feelings of shame or guilt ( M =3.34); isolation from family, friends, and communities ( M = 3.3); and fear/distrust of law enforcement ( M = 3.80). The least commonly identified indicators included exhibiting low English proficiency ( M = 1.62), previous history of loitering charges ( M = 1.74), presenting false documents ( M = 1.85), presence of tattoos or branding ( M = 1.89), presenting delayed cognitive development ( M = 1.91), being unaware of one's location ( M = 1.94), owing large debt ( M = 1.95), previous history of prostitution or drug charges ( M = 1.98, M = 2.01), and physical evidence of torture ( M = 2.07). The mental health domain was identified as especially common among U.S.-born adults ( M = 3.07). Criminal justice involvement was identified as less common among foreign-born minors ( M = 1.82) and foreign-born adults ( M = 1.96). The most commonly identified indicators, according to the service providers, health care workers, and justice system officials who work with them, are inconsistent with many of the indicators that are used frequently across governmental and community trainings. Trainings focusing on diverse case examples of trafficking may be important in strengthening identification of sex trafficked individuals, as well as accounting for regional contexts. PMID- 30484359 TI - Stent Frame Movement Following Endovascular Aneurysm Sealing in the Abdominal Aorta. AB - PURPOSE: To investigate the incidence and extent of stent frame movement after endovascular aneurysm sealing (EVAS) in the abdominal aorta and its relationships to aneurysm growth and the instructions for use (IFU) of the Nellix endograft. METHODS: A retrospective single-center study was conducted to review the clinical data and computed tomography (CT) images of 75 patients (mean age 76+/-7.6 years; 57 men) who underwent infrarenal EVAS and had a minimum 1-year follow-up. The first postoperative CT scan at 1 month and the subsequent scans were used to measure the distances between the proximal end of the stent frames and a reference visceral vessel using a previously validated technique. Device migration was based on the Society of Vascular Surgery definition of >10-mm downward movement of either Nellix stent frame in the proximal landing zone; a more conservative proximal displacement measure (downward movement ?4 mm) was also recorded. Patients were categorized according to adherence to the old (2013) or new (2016) Nellix IFU. Aneurysm diameter was measured for each scan; a change ?5 mm was deemed indicative of aneurysm growth. RESULTS: Over a median follow-up of 24 months (range 12-48), proximal displacement ?4 mm occurred in 42 (56%) patients and migration >10 mm in 16 (21%), with similar incidences in the right and left stent frames. Proximal displacement was significantly more frequent among patients whose anatomy did not conform to any IFU (p=0.025). Presence of aneurysm growth ?5 mm was observed in 14 (19%) patients and was significantly associated with proximal displacement ?4 mm (p=0.03). CONCLUSION: Infrarenal EVAS may be complicated by proximal displacement and migration, particularly when performed outside the IFU. The definition of migration used for endovascular aneurysm repair may be inappropriate for EVAS; a new consensus on definition and measurement technique is necessary. PMID- 30484360 TI - Building a New Intimate Relationship After Experiencing Intimate Partner Violence in Victim-Survivors of South Korea. AB - Intimate partner violence (IPV) refers to harmful acts occurring among members of an intimate relationship. Many studies have explored individuals' experiences of IPV as well as its consequences; however, so far, few studies have explored the lives of IPV victim-survivors after escaping from the violent relationship and the experiences of building new intimate relationships. Thus, the purpose of this study was to understand the young female adults' experience of building a new intimate relationship after ending their abusive relationship. This study used a qualitative phenomenological design to understand the women's lived experiences in their own voices, as suggested by Giorgi. In total, 13 young female adults in South Korea were recruited and interviewed. All interviews were audio-recorded and transcribed. Drawing on the interview data, we constructed the structure of their experiences through identifying five themes: (I) having difficulty in meeting new people, (II) starting to build a new relationship based on trauma, (III) struggling to escape the boundaries of the abuser, (IV) learning about healthy intimate relationships, and (V) something's wrong again. The findings were meaningful in that they showed how victim-survivors clearly needed care and support even after they escaped from their abusive relationships and began new ones. In addition, we found that some of them entered into another abusive relationship with their new partners. Finally, this study informs researchers and health professionals across the world about the experiences of IPV victims within specific cultural background. We hope that the findings of this study will contribute to building various interventions and programs for victim-survivors of IPV. PMID- 30484361 TI - Anemoside A3 rapidly reverses depression-like behaviors and weakening of excitatory synaptic transmission in mouse models of depression. AB - BACKGROUND AND AIM:: Developing fast-acting antidepressants attracts considerable attention. Anemoside A3, a natural triterpenoid glycoside isolated from Pulsatillae Radix, has been reported to produce antidepressant-like action in the forced swim test. We herein explore the fast-onset antidepressant-like potentials and antidepressant mechanisms of anemoside A3. METHODS:: The forced swim test and tail suspension test were used to determine the acute antidepressant-like action of anemoside A3. This action of anemoside A3 was confirmed in chronic mild stress and chronic social defeat stress models. In vitro extracellular field potential recordings were conducted to investigate the impact of anemoside A3 on chronic stress-induced alterations at temporoammonic-CA1 synapses. Western blot, whole cell patch-clamp recordings, and microinjections of alpha-amino-3-hydroxyl-5 methyl-4-isoxazole-propionate receptor antagonists into the stratum lacunosum moleculare were performed to unravel the contribution of stratum lacunosum moleculare alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors to anemoside A3's antidepressant-like activity. In vivo microdialysis and pharmacological depletion of serotonin were implemented to examine the role of the serotonin system in the antidepressant-like effect of anemoside A3. RESULTS:: Anemoside A3 administered intraperitoneally displayed acute antidepressant-like effects in the mouse forced swim test and tail suspension test and anemoside A3 treatment (intraperitoneally) for five days was sufficient to reverse depression related behaviors of mice subjected to chronic stress. Accordingly, chronic social defeat stress-induced weakening of alpha-amino-3-hydroxyl-5-methyl-4 isoxazole-propionate receptor-mediated neurotransmission in the temporoammonic CA1 pathway and downregulation of synaptic GluA2-lacking alpha-amino-3-hydroxyl-5 methyl-4-isoxazole-propionate receptor expression in the stratum lacunosum moleculare could both be normalized by five days of anemoside A3 treatment (intraperitoneally). Moreover, intra-stratum lacunosum-moleculare infusion of GluA2-lacking alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor antagonist abolished anemoside A3's antidepressant-like effect. Lastly, serotonin system was not implicated in anemoside A3's antidepressant-like effect. CONCLUSIONS:: Our results suggest that anemoside A3 induces a rapid antidepressant-like response by a stratum lacunosum-moleculare GluA2-lacking alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor-dependent mechanism. In view of this, anemoside A3 represents a promising agent for depression treatment. PMID- 30484362 TI - Biophysical modeling suggests optimal drug combinations for improving the efficacy of GABA agonists after traumatic brain injuries. AB - Traumatic brain injuries (TBI) lead to dramatic changes in the surviving brain tissue. Altered ion concentrations, coupled with changes in the expression of membrane-spanning proteins, create a post-TBI brain state that can lead to further neuronal loss due to secondary excitotoxicity. Several GABA receptor agonists have been tested in the search for neuroprotection immediately after an injury, with paradoxical results. These drugs not only fail to offer neuroprotection, but can also slow down functional recovery after TBI. Here, using computational modeling, we provide a biophysical hypothesis to explain these observations. We show that the accumulation of intracellular chloride ions due to a transient upregulation of Na+-K+-2Cl- (NKCC1) co-transporters as observed following TBI, causes GABA receptor agonists to lead to excitation and depolarization block, rather than the expected hyperpolarization. The likelihood of prolonged, excitotoxic depolarization block is further exacerbated by the extremely high levels of extracellular potassium seen after TBI. Our modeling results predict that the neuroprotective efficacy of GABA receptor agonists can be substantially enhanced when they are combined with NKCC1 co-transporter inhibitors. This suggests a rational, biophysically principled method to identify drug combinations for neuroprotection after TBI. PMID- 30484363 TI - Communication Challenges at the Crossroads of Oncology and Palliative Care: Finding a Way Forward When Clinicians Differ on Prognosis. AB - In this article, we present a dialogue between a junior and a seasoned palliative care attending on approaching situations in which clinicians have differing opinions about patients' prognoses. In such situations, we may find a way forward by identifying common ground and exploring patients' and clinicians' values. Specifically, we can ask what constitutes a reasonable quality of life for our patients, and we can explore our colleagues' hopes, worries, and values using familiar communication techniques. Ultimately, we can support and align with both our patients and colleagues and work toward reframing a difficult situation. PMID- 30484364 TI - Downstream TRPM4 Polymorphisms are associated with Intracranial Hypertension and Statistically Interact with ABCC8 Polymorphisms in a Prospective Cohort of Severe Traumatic Brain Injury. AB - Sulfonylurea-receptor-1(SUR1) and its associated Transient-Receptor-Potential cation channel subfamily-M(TRPM4) channel are key contributors to cerebral edema and intracranial hypertension in traumatic brain injury (TBI) and other neurological disorders. Channel inhibition by glyburide is clinically promising. ABCC8 (encoding SUR1) single-nucleotide polymorphisms (SNPs) are reported as predictors of raised intracranial-pressure (ICP). This project evaluated whether TRPM4 SNPs predicted ICP and TBI outcome. DNA was extracted from 435 consecutively enrolled severe-TBI patients. Without a priori selection, all eleven TRPM4 SNPs available on the multiplex platform (Illumina:Human-Core-Exome v1.0) were genotyped spanning the 25-exon gene. 385 patients were analyzed after quality control. Outcomes included ICP and 6-month Glasgow-outcome scale (GOS) score. Proxy-SNPs, spatial-modeling, and functional predictions were determined using established software-programs. rs8104571 (intron-20) and rs150391806 (exon 24) were predictors of ICP. rs8104571 heterozygotes predicted higher average-ICP (beta=10.3, p=0.00000029), peak-ICP (beta=19.6, p=0.0007), and proportion ICP>25mmHg (beta=0.16 p=0.004). rs150391806 heterozygotes had higher mean (beta=7.2, p=0.042) and peak (beta=28.9, p=0.0015) ICPs. rs8104571, rs150391806 and 34 associated proxy-SNPs in linkage-disequilibrium clustered downstream. This region encodes TRPM4's channel pore and a region postulated to juxtapose SUR1 sequences encoded by an ABCC8 DNA segment containing previously identified relevant SNPs. There was an interaction effect on ICP between rs8104571 and a cluster of predictive ABCC8 SNPs (rs2237982, rs2283261, rs11024286). While not significant in univariable or a basic multivariable model, in an expanded model additionally accounting for injury pattern, CT appearance, and intracranial hypertension, heterozygous rs8104571 was associated with favorable 6 month GOS (OR=16.7, p=0.007951). This trend persisted in a survivor-only subcohort (OR=20.67, p=0.0168). In this cohort, two TRPM4 SNPs predicted increased ICP with large effect sizes. Both clustered downstream, spanning a region encoding the channel pore and interacting with SUR1. If validated, this may guide risk stratification and eventually inform treatment-responder classification for SUR1 TRPM4 inhibition in TBI. Larger studies are warranted. PMID- 30484365 TI - Effects of adolescent caffeine consumption on cocaine self-administration and reinstatement of cocaine seeking. AB - BACKGROUND:: Caffeine consumption by children and adolescents has risen dramatically in recent years, yet the lasting effects of caffeine consumption during adolescence remain poorly understood. AIM:: These experiments explore the effects of adolescent caffeine consumption on cocaine self-administration and seeking using a rodent model. METHODS:: Sprague-Dawley rats consumed caffeine for 28 days during the adolescent period. Following the caffeine consumption period, the caffeine solution was replaced with water for the remainder of the experiment. Age-matched control rats received water for the duration of the study. Behavioral testing in a cocaine self-administration procedure occurred during adulthood (postnatal days 62-82) to evaluate how adolescent caffeine exposure influenced the reinforcing properties of cocaine. Cocaine seeking was also tested during extinction training and reinstatement tests following cocaine self-administration. RESULTS:: Adolescent caffeine consumption increased the acquisition of cocaine self-administration and increased performance on different schedules of reinforcement. Consumption of caffeine in adult rats did not produce similar enhancements in cocaine self-administration. Adolescent caffeine consumption also produced an upward shift in the U-shaped dose response curve on cocaine self-administration maintained on a within-session dose-response procedure. Adolescent caffeine consumption had no effect on cocaine seeking during extinction training or reinstatement of cocaine seeking by cues or cocaine. CONCLUSIONS:: These findings suggest that caffeine consumption during adolescence may enhance the reinforcing properties of cocaine, leading to enhanced acquisition that may contribute to increased addiction vulnerability. PMID- 30484366 TI - Examining Reading Comprehension Profiles of Grade 5 Monolinguals and English Language Learners Through the Lexical Quality Hypothesis Lens. AB - This study set out to compare patterns of relationships among phonological skills, orthographic skills, semantic knowledge, listening comprehension, and reading comprehension in English as a first language (EL1) and English language learners (ELL) students and to test the applicability of the lexical quality hypothesis framework. Participants included 94 EL1 and 178 ELL Grade 5 students from diverse home-language backgrounds. Latent profile analyses conducted separately for ELLs and EL1s provided support for the lexical quality hypothesis in both groups, with the emergence of two profiles: A poor comprehenders profile was associated with poor word-reading-related skills (phonological awareness and orthographic processing) and with poor language-related skills (semantic knowledge and, to a lesser extent, listening comprehension). The good comprehenders profile was associated with average or above-average performance across the component skills, demonstrating that good reading comprehension is the result of strong phonological and orthographic processing skills as well as strong semantic and listening comprehension skills. The good and poor comprehenders profiles were highly similar for ELL and EL1 groups. Conversely, poor comprehenders struggled with these same component skills. Implications for assessment and future research are discussed. PMID- 30484367 TI - The Mediating Role of Coping Style: Associations Between Intimate Partner Violence and Suicide Risks Among Chinese Wives of Men Who Have Sex With Men. AB - The wives of men who have sex with men, known as " Tongqi" in China, have increasingly attracted public attention due to their potential risks of suicide and sexually transmitted infections and HIV. However, few studies have explored the association between intimate partner violence (IPV) and suicide risk or the mediating effect of coping style on these associations among Tongqi in China. To describe these relationships, a cross-sectional online survey was conducted in China from February 2016 to February 2017. A questionnaire, which consisted of the Revised Conflict Tactics Scales, the Simplified Coping Style Questionnaire, the Beck Scale for Suicidal Ideation, and reports of suicide attempts, was completed by 178 Chinese Tongqi. Bootstrap tests were performed to determine the mediating role of coping styles on the association between IPV and suicide risks. The median IPV score was 14 (range: 0-50), with the domain of negotiation ranking highest. The average coping style score was .37+/-.73; 61.2% of Tongqi have had suicidal ideation, and 11.8% had attempted suicide. IPV was significantly correlated with suicidal ideation ( rs = .19, p < .01) and suicide attempts ( rs = .29, p < .001). Participants with a negative coping style had higher suicidal ideation ( rs = -.39, p < .01) and suicide attempts ( rs = -.22, p < .01). Coping style had a full mediating effect on the association between IPV and suicidal ideation and a partial mediating effect on suicide attempts. Chinese Tongqi experienced high level of IPV and suicide risks. IPV contributed to the suicide risks of Chinese Tongqi, but these associations were mediated by coping style. Therefore, interventions to improve mental health and prevent suicide risks of Chinese Tongqi should focus on helping them develop a positive coping style to achieve the goal of Healthy China in 2030. PMID- 30484368 TI - Comparison of the inhibition potential of parthenolide (PTL) and micheliolide (MCL) on various UDP-Glucuronosyltransferase (UGT) isoforms. AB - 1. Parthenolide (PTL) and micheliolide (MCL) are sesquiterpene lactones with similar structures, and both of them have been reported to exhibit multiple biochemical and pharmacological activities. This study aims to investigate the inhibition of these two compounds on the activity of UDP-glucuronosyltransferases (UGTs). 2. In vitro incubation mixture for recombinant UGTs-catalyzed glucuronidation metabolism of 4-methylumbelliferone (4-MU) was utilized to investigate the inhibition potential. Inhibition kinetics (including inhibition type and parameters) were determined, and in silico docking was employed to elucidate the inhibition difference between PTL and MCL on UGT1A1. 3. MCL showed no inhibition towards all the UGT isoforms, and PTL showed strong inhibition towards UGT1A1. The half-maximal inhibitory concentration (IC50) of PTL on the activity of UGT1A1 was determined to be 64.4 MUM. Inhibition kinetics determination showed that PTL exerted noncompetitive inhibition towards UGT1A1, and the inhibition kinetic constant (Ki) was determined to be 12.1 MUM. In silico docking method has been employed to show that hydrogen bonds between PTL and the activity cavity of UGT1A1 contributed to the stronger inhibition of PTL on the activity of UGT1A1 than MCL. In conclusion, PTL can more easily induce drug-drug interaction (DDI) with clinical drugs mainly undergoing UGT1A1-catalyzed glucuronidation. PMID- 30484369 TI - Bullying Perpetration and Victimization: A Test of Traditional and Cyber Behaviors as Latent Constructs. AB - The current investigation hypothesized and tested latent bully/victim traits for physical, verbal, or relational bullying/victimization, both cyber and traditional behaviors. Data were collected from 1,356 German students who attended Grades 5 to 10: 48.4% males, 49.3% females from eight different schools in Northern Germany. Based on two samples for cross-validation ( Ntraining set = 525, Nvalidation set = 525), study findings provided strong evidence of adequate model fit, both for traditional and cyber behaviors. Consistent with the current state of knowledge, bullying and victimization latent traits highly associated, more so for cyber behaviors than traditional ones. Thus, both the theoretical plausibility as well as statistical evidence support the application of latent modeling to these behaviors. Further research is needed to replicate the applied measurement models proposed in this work and to reveal moderators or measurement invariance across diverse populations. Nevertheless, the current evidence substantiates the importance of the application of a latent modeling approach to overcome known psychometric challenges of reliability and validity in bullying research. PMID- 30484370 TI - Dysregulation of Transcription Factors: A Key Culprit Behind Neurodegenerative Disorders. AB - Neurodegenerative diseases (NDs) are considered heterogeneous disorders characterized by progressive pathological changes in neuronal systems. Transcription factors are protein molecules that are important in regulating the expression of genes. Although the clinical manifestations of NDs vary, the pathological processes appear similar with regard to neuroinflammation, oxidative stress, and proteostasis, to which, as numerous studies have discovered, transcription factors are closely linked. In this review, we summarized and reviewed the roles of transcription factors in NDs, and then we elucidated their functions during pathological processes, and finally we discussed their therapeutic values in NDs. PMID- 30484371 TI - Proteomic Analysis and Biochemical Correlates of Mitochondrial Dysfunction following Low-Intensity Primary Blast Exposure. AB - Service members during military actions or combat training are frequently exposed to primary blasts by weaponry. Most studies have investigated moderate or severe brain injuries from blasts generating overpressures over 100-kPa, while understanding the pathophysiology of low-intensity blast (LIB)-induced mild traumatic brain injury (mTBI) leading to neurological deficits remains elusive. Our recent studies, using an open-field LIB-induced mTBI mouse model with an peak overpressure at 46.6-kPa, demonstrated behavioral impairments and brain nanoscale damages, notably mitochondrial and axonal ultrastructural changes. In this study, we used tandem mass tagged (TMT) quantitative proteomics and bioinformatics analysis to seek insights into the molecular mechanisms underlying ultrastructural pathology. Changes in global- and phospho-proteomes were determined at 3 and 24 hours, 7 and 30 days post injury (DPI), in order to investigate the biochemical and molecular correlates of mitochondrial dysfunction. Results showed striking dynamic changes in a total of 2216 proteins and 459 phosphorylated proteins at vary time points after blast. Disruption of key canonical pathways included evidence of mitochondrial dysfunction, oxidative stress, axonal / cytoskeletal / synaptic dysregulation, and neurodegeneration. Bioinformatic analysis identified blast induced trends in networks related to cellular growth / development / movement / assembly and cell-to-cell signaling interactions. With observations of proteomic changes, we found LIB-induced oxidative stress associated with mitochondrial dysfunction mainly at 7 and 30 DPI. These dysfunctions included impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated respiration relevant enzyme activities. Insights on the early pathogenesis of primary LIB induced brain damage provide a template for further characterization of its chronic effects, identification of potential biomarkers and targets for intervention. PMID- 30484372 TI - Equine cord blood mesenchymal stromal cells have greater differentiation and similar immunosuppressive potential to cord tissue mesenchymal stromal cells. AB - Mesenchymal stromal cells (MSCs) are the most common cell population studied for therapeutic use in veterinary medicine. MSCs obtained from neonatal sources such as umbilical cord tissue (CT-MSCs) or cord blood (CB-MSCs) are appealing due to the non-invasive nature of procurement and the time allowed for characterization of cells prior to use. However, it remains unclear whether CB- or CT-MSCs have equivalent progenitor and non-progenitor functions. CB-MSCs have been shown to have superior chondrogenic potential to MSCs from other sources, whereas their immunomodulatory capacity does not seem to vary significantly. Using equine CB MSCs and CT-MSCs from the same donor, we hypothesized that MSCs from both sources would have a similar immunophenotype, that CB-MSCs would be more amenable to differentiation, and that they can equally suppress lymphocyte proliferation. We evaluated cells from both sources for "classic" equine MSC markers CD90, CD105, CD29, and CD44, as well as pericyte markers CD146, NG2 and alpha-SMA. Contrary to our hypothesis, CB-MSCs showed mid- to high expression of pericyte surface markers CD146 and NG2, while expression in CT-MSCs was absent. Upon trilineage differentiation, CB-MSCs were more osteogenic and chondrogenic based on ALP activity and glycosaminoglycan content, respectively. Finally, using a mononuclear cell suppression assay, we determined that CB-MSCs and CT-MSCs are both capable of suppressing stimulated mononuclear cell proliferation to a similar degree. We have determined that choice of MSC tissue source should be made with the intended application in mind. This appears to be particularly relevant if pursuing a progenitor-based treatment strategy. PMID- 30484373 TI - Prosocial behavior toward estranged persons modulates the interaction between midline cortical structures and the reward system. AB - Good reputation enhances positive self-image, which motivates prosocial behavior, a phenomenon known as indirect reciprocity. Thus, good reputation should promote prosocial behavior toward estranged people to whom affective responses leading to direct reciprocity are suppressed. We predicted that such behaviors involve an interrelationship between self-image, processed in the medial prefrontal cortex (mPFC) and precuneus, and social reward, processed in the reward system. To test our hypothesis, we performed fMRI on 21 participants during a virtual ball-toss game after subjects formed negative impressions (estrangement) or neutral impressions of other players. During some blocks of the game, the other players did not receive tosses, and participants could increase tosses to them (i.e., engage in prosocial behavior). Participants significantly increased tosses to all isolated players; therefore, prosocial behavior occurred irrespective of estrangement. Prosocial behavior toward estranged players enhanced positive self image and increased activation of the anterior mPFC and precuneus. The precuneus exhibited enhanced functional connectivity with the striatum. Thus, a positive self-image, represented by an interaction between the midline cortical structures and striatum, plays key roles in prosocial behavior toward estranged people. PMID- 30484374 TI - "We Were Totally Supportive, of Course": How People Talk About Supporting a Significant Other to Stop or Reduce Their Drinking. AB - Despite the strong influence our significant others have on health behaviors such as alcohol consumption, little is known about when they are willing to provide support for changing such behaviors. We conducted interviews with 13 Australian adults who had a partner, friend, or family member who stopped or significantly reduced their alcohol consumption within the past 2 years, to understand how these significant others accounted for providing support for this behavior change as reasonable. Through thematic discourse analysis, we identified three types of accounts: (a) deontological, referring to duty or obligation to support others; (b) consequentialist, where costs for providing support were minimized or balanced; and (c) relational, attending to the importance of maintaining relationships. By identifying the principles people draw on to justify supporting a significant other who changes their alcohol consumption, this study enhances our understanding about when significant others are likely to support health behavior changes. PMID- 30484375 TI - A Data-driven Approach to Unlikely, Possible, Probable, and Definite Acute Concussion Assessment. AB - Kutcher and Giza suggested incorporating levels of certainty in concussion diagnosis decisions. These guidelines were based on clinical experience rather than objective data. Therefore, we combined data-driven optimization with predictive modeling to identify which athletes are Unlikely to have concussion and classify remaining athletes as Possible, Probable, or Definite concussion by diagnostic certainty. We developed and validated our framework using data from the Concussion Assessment, Research, and Education (CARE) Consortium. Acute concussions consisted of assessments at <6 hours (n=1085) and 24-48 hours post injury (n=1413). Normal performances consisted of assessments at baseline (n=1635) and the time of unrestricted return-to-play (n=1345). We evaluated the distribution of acute concussions and normal performances across risk categories and identified interclass and intraclass differences in demographics, time-of injury characteristics, the Standard Assessment of Concussion (SAC), Sport Concussion Assessment Tool (SCAT) symptom assessments, and Balance Error Scoring System (BESS). Our algorithm accurately classified concussions as Probable or Definite (sensitivity=91.07-97.40%). Definite and Probable concussions had higher SCAT symptom scores compared to Unlikely and Possible concussions (p<0.05). Definite concussions had lower SAC and higher BESS scores (p<0.05). Baseline to post-injury change scores for the SAC, SCAT symptoms, and BESS were significantly different between acute Possible or Probable concussions and normal performances (p<0.05). There were no consistent patterns in demographics across risk categories, although a greater proportion of concussions classified as Unlikely were reported immediately compared to Definite concussions (p<0.05). While clinical interpretation is still needed, our data-driven approach to concussion risk stratification provides a promising step towards evidence-based concussion assessment. PMID- 30484376 TI - Where Patients With Cancer Die: A Population-Based Study, 1990 to 2012. AB - AIMS:: To describe changes in the place of death of patients with cancer from 1990 to 2012, and to identify issues for their end-of-life care. MATERIALS AND METHODS:: Population-based descriptive study, with analyses of place of death patterns, using the South Australian Cancer Registry records of 86 257 patients with cancer who died from 1990 to 2012. RESULTS:: From 1990 to 2012, the proportion of cancer deaths in hospital decreased from 63.4% to 50.9%, and in nursing homes increased from 8.2% to 22.5%. After the year 2000, the proportions in hospices and at home were both below 15%. Multivariate analyses showed that young patients with cancer were more likely to die in a hospice or at home, compared to elderly patients with cancer who were more likely to die in a nursing home; the likelihood of dying in a hospice increased with socioeconomic status; patients with a short survival time or a hematological malignancy were more likely to die in a metropolitan hospital. CONCLUSIONS:: Compared to most other countries, the proportion of cancer deaths at home was low, and many patients would not have died at their preferred place. The trend for more cancer deaths to occur in nursing homes is likely to continue, but nursing homes generally lack the resources and skilled staff to provide quality palliative care. Models of palliative care delivery should take account of patient preferences, the growth of terminal cancer care in nursing homes, and apparent inequities. PMID- 30484377 TI - Is the absence of alpha-helix 2 in the appendant structure region the major contributor to structural instability of human cystatin C? PMID- 30484378 TI - SOX-6, 9-Transfected Adipose Stem Cells to Treat Surgically-induced Osteoarthritis in Goats. AB - The authors developed SOX-6, 9-transfected human adipose stem cells (SOX-6, 9ASCs) to treat osteoarthritis (OA) and tested their effectiveness in arresting OA progression when injected intra-articularly (IA) in a surgically-induced OA caprine model. SOX-6, 9ASCs demonstrated similar in vitro chondrogenic potential, as determined by proteoglycan production, to ASCs treated with TGF-beta2 and BMP-7 (positive controls). On the other hand, the mRNA expressions of COL2A1 and aggrecan were 3.5-fold (p = 0.004) and 1.4-fold (p = 0.058) higher, respectively, in SOX-6, 9ASCs than in positive controls. In vivo tracking of injected SOX-6, 9ASCs in rats demonstrated that these cells disappear from the joint cavity within 2 weeks, suggesting paracrine mode of action. In a surgically-induced goat model of OA, IA SOX-6, 9ASCs at a dose of 0.6 x 107 best preserved articular cartilage and produced significantly better macroscopic and microscopic scores than negative controls in femoral and tibial articular surfaces. In conclusion, SOX-6, 9-transfection led to in vitro chondrogenesis of ASCs comparable to that achieved by growth factor treatment. IA injection of SOX-6, 9ASCs in optimal dose reduced the progression of surgically-induced OA in goats. We suggest that SOX-6, 9ASCs offer a novel potential strategy to treat OA. PMID- 30484379 TI - Are we getting it wrong? Perspectives on the future of palliative care in hospitals. PMID- 30484380 TI - Intensification of Nickel recovery from water using an electrically driven hybrid process: Continuous Electropermutation. AB - Process intensification through the combined use of electrodialysis (ED) and ion exchange resin (IER) hybrid process, called continuous electropermutation (CEP), was employed to remove Ni(II) cations from water. To carry out this process, Amberjet 1200 H cation-exchange resin was introduced into the feed compartment of the ED cell. The applied electrical field improves the mobility of species and ensures a continuous resin activation which is a main drawback in IER process. Furthermore, the IER incorporated in the ED cell enhances the conductivity of the feed water, therefore it extends the range of ED which could be applied for the recovery of ions from very low concentration wastewaters. The effects of some factors such as the type of regenerating electrolyte, current density, quantity of resin incorporated in the conducting space and concentration of Ni(II) at the inlet were investigated. The efficiency of CEP and ED for Ni(II) removal was expressed in terms of recovery rate and concentration factor. In CEP process, recovery rates of 99% were found with a 40 ppm Ni(II) concentration and an applied current density of 2 mA.cm-2 resulting in an outlet Ni(II) concentration lower than 1 ppm, against 73.69% in conventional ED. Moreover, in CEP Ni(II) cation was recovered in receiver compartment more than the feed solution with concentration factor more than 10 against 0.39 in ED. On the other hand, the voltage of ED cell was found to increase due to the lower conductivity in the feed compartment compared with that of CEP. In CEP, the highest concentration factor was found at an applied current density of 2.7 mA.cm-2 which reached 41.26. Finally, with increasing Ni(II) feed inlet concentration, there was a trade-off between obtaining a high Ni(II) concentration in the receiver compartment and a low Ni(II) concentration at the outlet of feed compartment. PMID- 30484381 TI - Lesbians in work settings: Identity, visibility, and strategy. AB - This is the foreward to this special issue of the Journal of Lesbian Studies on Lesbians in Work Settings: Identity, Visibility, and Strategy. The article briefly provides a context for the issue, and includes the proposed questions for consideration that were included in its call for papers. There is a need for continued research on lesbians in work settings, and this special issue contains articles that interrogate issues of lesbian presence, rights, access, identity, and visibility. PMID- 30484382 TI - A Multimodality Navigation System for Endoscopic Fetal Surgery: A Phantom Case Study for Congenital Diaphragmatic Hernia. AB - This article presents a multi-modality tracking and navigation system achieved by merging optical tracking and ultrasound imaging into a novel navigation software to help in surgical pre-planning and real-time target setting and guidance. Fetal surgeries require extensive experience in coordination of hand-eye-ultrasound surgical equipment, knowledge, and precise assessment of relative anatomy. While there are navigation systems available for similar constrained working spaces in arthroscopic and cardiovascular procedures, fetal minimally invasive surgery does not yet have a dedicated navigation platform capable of supporting robotic instruments that can be adapted to the set of unique procedures. This article discusses the testing of the novel multi-modality navigation system in a phantom environment developed for this purpose. The outcomes suggest that the subjects demonstrated an increase in average reaching accuracy by about 60% and an overall reduction in time taken by 33.6%. They also showed higher levels of confidence in reaching the targets, which was visualised from the pattern of trajectory of movements during the procedure. To evaluate the navigation system, a phantom surgical environment was found necessary. Therefore, the article also discusses the details of the development of a fetal phantom environment for congenital diaphragmatic hernia for surgical testing, evaluation, and training. A surgical procedure was conducted on the phantom using the proposed tracking navigation system and using only ultrasound. PMID- 30484383 TI - Cochlear implantation in a 10-year old boy with Pendred syndrome and extremely enlarged endolymphatic sacs. AB - A 10-year-old boy with fluctuating sensorineural hearing loss (SNHL) and biallelic mutations in the SLC26A4 gene and with inner ear anomalies received a cochlear implantation. SLC26A4 mutations are associated with variable degrees of SNHL and enlarged vestibular aqueducts (EVA), identified either as non-syndromic EVA or classic Pendred syndrome; the latter also associated with thyroid dysfunction. The inner ear malformations in this group of patients have been considered a relative contraindication against cochlear implantation because of the potential per- and postoperative complications such as peroperative cerebrospinal fluid leak or postoperative vestibular symptoms. In the current case there were no surgical or postoperative complications, indicating that extremely enlarged endolymphatic sacs are not as such a contraindication for cochlear implantation. This case also illustrates the management dilemma of an appropriate timing for cochlear implantation. PMID- 30484384 TI - Chemoradiation in female patients with anal cancer: Patient-reported outcome of acute and chronic side effects. AB - INTRODUCTION:: We evaluated acute and chronic side effects of 3D conformal radiotherapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) in female patients with anal carcinoma and accessed correlations between dosimetric parameters and the considered toxicities. METHODS:: For 70 women with anal cancer treated at our department, acute and chronic side effects and quality of life (QoL) were evaluated with questionnaires using the Common Terminology Criteria for Adverse Events (CTCAE v. 4.0.) and Late Effects in Normal Tissue, Subjective, Objective Management and Analytic Scales (LentSoma) before, during, and after the treatment. RESULTS:: Forty-seven out of 70 (67%) patients completed the questionnaire and were enrolled in the study. Only poor urinary stream, loss of pubic hair during chemoradiation, and chronic vaginal dryness were observed more frequently in the 3D-CRT group compared to the IMRT group (univariable logistic regression p = .032, p = .04, p = .049, respectively). After the treatment, 43% in the 3D-CRT group and 29% in the IMRT group reported a severe loss of QoL. A higher proportion among the patients receiving a genital V20 ?35% showed grade 1 3 side effects such as chronic dyspareunia ( p = .035; Fisher exact test). CONCLUSION:: Our results suggest that the use of IMRT decreases acute and chronic adverse effects although reduced QoL also occurred in the IMRT group. These effects are likely to be underreported in retrospective studies using physician reported outcome measures. PMID- 30484385 TI - Unexpected postpneumonectomy exertion-induced acute right heart failure. AB - INTRODUCTION:: Thoracic surgery can have serious side effects. Accurate preoperative evaluation to assess which patients with anatomically resectable disease are suitable candidates for surgery is mandatory. CASE DESCRIPTION:: A 58 year-old man, scheduled for left pneumonectomy for lung cancer, passed all the preoperative examinations suggested by guidelines and underwent the surgery. Three days after pneumonectomy, he experienced hemorrhagic shock and subsequent acute respiratory distress syndrome. Fifteen days after left pneumonectomy, he experienced exertional acute right heart failure (ARHF). We administered sildenafil and he improved, clinically and echocardiographically. During the following 2 years of follow-up, he was asymptomatic at rest but under exercise test, he developed pulmonary hypertension with echocardiographic signs of right ventricular impairment. CONCLUSIONS:: In patients scheduled for major lung resections, preoperative stress echocardiography may give an adjunctive value to cardiopulmonary exercise test, quantifying the exercise-induced reduction in right ventricle ejection fraction and identifying asymptomatic patients at risk for postoperative ARHF. PMID- 30484386 TI - Contrasting Effects of Pressure Compensation on TEOAE and DPOAE in Children With Negative Middle Ear Pressure. AB - In children with normal cochlear acuity, middle ear fluid often abolishes otoacoustic emissions (OAEs), and negative middle ear pressure (NMEP) reduces them. No convincing evidence of beneficial pressure compensation on distortion product OAE (DPOAE) has yet been presented. Two studies aimed to document effects of NMEP on transient OAE (TEOAE) and DPOAE. In Study 1, TEOAE and DPOAE pass/fail responses were analyzed before and after pressure compensation in 50 consecutive qualifying referrals having NMEP from -100 to -299 daPa. Study 2 concentrated on DPOAE, recording both amplitude (distortion product amplitude) and signal-to noise ratio (SNR) before and after pressure compensation. Of the 20 participants, 5 had both ears qualifying. An effect of compensation on meeting a pass criterion was present in TEOAE for both left and right ear data in Study 1 but not demonstrable in DPOAE. In Study 2, the distortion product amplitude compensation effect was marginal overall, and depended on recording frequency band. SNR values improved moderately after pressure compensation in the two (overlapping) sets of single-ear data. In the five cases with both ears qualifying, a stronger compensation effect size, over 3 dB, was seen. The absolute dependence of SNR on frequency was also strongly replicated, but in no analysis, the frequency * compensation interaction was significant. Independent of particular frequency range, the data support a limited SNR improvement in 2 to 3 dB for compensation in DPOAE, with slightly larger effects in ears giving SNRs between 0 dB and +6 dB, where pass/fail cutoffs would generally be located. PMID- 30484387 TI - Development and Evaluation of Context-based Assessment System for Visualization Enhanced Construction Safety Education. AB - Construction jobsites remain among the most dangerous workplaces, with fatalities, accidents and injuries still plaguing the industry. Safety education is critical in fostering graduates capable of ensuring safe construction work; however current learner assessment methods in pedagogy fail to ascertain the possession of safety knowledge and skills as they would be required in practice. This paper aims to address this problem by proposing context-based learner assessment in construction safety education. A novel assessment system is developed and deployed with final-year construction management students, with learner testing through visualization-enhanced: (1) Safety Theory Questions (STQ); (2) Site Inspection Scenario (SIS) questions; and (3) Job Safety Analysis Review (JSA) questions. The cognitive impact of the assessment approach is investigated through the NASA Task Load Index (NASA-TLX), and its effectiveness is verified through educator and learner trials. Results demonstrate that the proposed system has significant potential as an innovative assessment tool for safety education. PMID- 30484388 TI - Substrate Elasticity Governs Differentiation of Renal Tubule Cells in Prolonged Culture. AB - End-stage renal disease afflicts nearly 750,000 Americans and claims over 100,000 lives annually in the United States. Kidney transplantation is associated with longest survival and least cost but is limited by scarcity of donor organs. Most patients are treated with hemodialysis. Each hemodialysis treatment consumes over 160 liters of water and anchors the patient to a machine for 12-15 hours per week. Cultured tubule cells can reduce the obligate fluid requirements of a bioengineered artificial kidney by concentrating wastes and reabsorbing filtered salt and water. Primary tubule epithelial cells rapidly dedifferentiate in culture and form a flattened epithelium lacking the brush border essential to apicobasal transport. We hypothesized that substrate mechanical properties t have a strong influence on differentiation in primary cell culture. We cultured primary renal tubule cells on polyacrylamide hydrogels of varying elasticity and measured expression of key transporter proteins essential to renal tubule cell function. Primary tubule cells cultured on soft substrates for extended periods showed increased expression of key transporters characteristic of differentiated proximal tubule cells. These data support the hypothesis that scaffold elasticity is a critical factor in cell culture, and, unexpectedly, that prolonged culture of primary cells was essential to observing this difference. PMID- 30484389 TI - A reductionist approach to understanding the nervous system: the Harold Atwood legacy. PMID- 30484390 TI - Strong stimulation triggers full fusion exocytosis and very slow endocytosis of the small dense core granules in carotid glomus cells. AB - Chemosensory glomus cells of the carotid bodies release transmitters, including ATP and dopamine mainly via the exocytosis of small dense core granules (SDCGs, vesicular diameter of ~100 nm). Using carbon-fiber amperometry, we showed previously that with a modest uniform elevation in cytosolic Ca2+ concentration ([Ca2+]i of ~0.5 uM), SDCGs of rat glomus cells predominantly underwent a "kiss and-run" mode of exocytosis. Here, we examined whether a larger [Ca2+]i rise influenced the mode of exocytosis. Activation of voltage-gated Ca2+ channels by a train of voltage-clamped depolarizations which elevated [Ca2+]i to ~1.6 MUM increased the cell membrane capacitance by ~2.5%. At 30 s after such a stimulus, only 5% of the added membrane was retrieved. Flash photolysis of caged-Ca2+ (which elevated [Ca2+]i to ~16 MUM) increased cell membrane capacitance by ~13%, and only ~30% of the added membrane was retrieved at 30 s after the UV flash. When exocytosis and endocytosis were monitored using the two-photon excitation and extracellular polar tracer (TEP) imaging of FM1-43 fluorescence in conjunction with photolysis of caged Ca2+, almost uniform exocytosis was detected over the cell's entire surface and it was followed by slow endocytosis. Immunocytochemistry showed that the cytoplasmic densities of dynamin I, II and clathrin (key proteins that mediate endocytosis) in glomus cells were less than half of those in adrenal chromaffin cells, suggesting that a lower expression of endocytotic machinery may underlie the slow endocytosis in glomus cells. An analysis of the relative change in the signals from two fluorescent dyes that simultaneously monitored the addition of vesicular volume and plasma membrane surface area, suggested that with an intense stimulus, SDCGs of glomus cells underwent full fusion without any significant "compound" exocytosis. Therefore, during a severe hypoxic challenge, glomus granules undergo full fusion for a more complete release of transmitters. PMID- 30484391 TI - BK channels and a cGMP-dependent protein kinase (PKG) function through independent mechanisms to regulate the tolerance of synaptic transmission to acute oxidative stress at the Drosophila larval neuromuscular junction. AB - A cGMP-dependent protein kinase (PKG) has previously been shown to regulate synaptic transmission at the Drosophila neuromuscular junction (NMJ) during acute oxidative stress, potentially through modulation of downstream K+ channel kinetics; however, the specific K+ channels through which PKG functions remains unclear. In this study, we hypothesized that PKG may be acting on calcium activated large-conductance Slo K+ channels, or BK channels. We found that genetic elimination and pharmacological inhibition of BK channel conductance increases synaptic transmission tolerance to acute H2O2-induced oxidative stress. Furthermore, we discovered that activation of PKG in BK channel loss-of-function (Slo4) mutants significantly decreases time to stimulus-induced synaptic failure, providing the first evidence of PKG and BK channels functioning independently to control synaptic transmission tolerance to acute oxidative stress. PMID- 30484392 TI - Child Harold. PMID- 30484393 TI - Human Wharton's Jelly Mesenchymal Stem Cells Show Unique Gene Expression Compared to Bone Marrow Mesenchymal Stem Cells Using Single-Cell RNA-Sequencing. AB - Human Wharton's jelly stem cells (hWJSCs) isolated from the human umbilical cord are a unique population of mesenchymal stem cells with significant clinical utility. Their broad differentiation potential, high rate of proliferation, ready availability from discarded cords, and prolonged maintenance of stemness properties in culture make them an attractive alternative source of MSCs with therapeutic value compared to bone marrow MSCs (hBMMSCs). We aimed to characterise the differences in gene expression profiles between these two stem cell types using single-cell RNA sequencing (scRNA-Seq) to determine which pathways are involved in conferring hWJSCs with their unique properties. We identified 436 significantly differentially expressed genes between the two cell types, playing roles in processes including immunomodulation, angiogenesis, wound healing, apoptosis, anti-tumour activity, and chemotaxis. Expression of immune molecules is particularly high in hWJSCs compared to hBMMSCs. These differences in gene expression may help to explain many of the advantages that hWJSCs have over hBMMSCs for clinical application. Although cell-surface protein marker expression indicates that isolated hWJSCs and hBMMSCs are both homogenous populations, using scRNA-Seq we can clearly identify extreme variability in expression levels between individual cells within a certain cell type. If the cells are examined as bulk populations, it is not possible to appreciate that a single cell may be making a major unique contribution to the apparent overall expression level. We demonstrated how the fine tuning of expression within hWJSCs and hBMMSCs may be achieved by expression of molecules with opposing function between two cells. We hypothesise that a greater understanding of these differences in gene expression between the two cell types may aid in development of new therapies using hWJSCs. PMID- 30484395 TI - GHB Pharmacology and Toxicology: From Metabolism and Pharmacokinetics to Applications: In Clinical and Forensic Toxicology. PMID- 30484394 TI - European perspective on the 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Proceedings of an interactive international symposium. AB - BACKGROUND: The American Thyroid Association (ATA) Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer (DTC) are highly influential practice recommendations. The latest revision appeared in 2015 ("ATA 2015"). These guidelines were developed predominantly by North American experts. European experts frequently have different perspectives, given epidemiological, technological/methodological, practice organization, and medicolegal differences between the respective regions. SUMMARY: Divergent viewpoints were the focus of an invited symposium organized by the European Association of Nuclear Medicine involving 17 European thyroidologists, 4 ATA Guidelines Taskforce members, and an audience of 200 international experts. The group discussed "preoperative assessment of thyroid nodules," "surgery and role of pathology," "radioiodine therapy (RAIT)," "assessment of initial therapy and dynamic risk stratification," and "treatment of persistent disease, recurrences, and advanced thyroid cancer." The dialogue resulted in this position paper contrasting European and ATA 2015 perspectives on key issues. One difference pertains to ATA 2015's permissiveness of lobectomy for primary tumors <=4 cm. European panelists cited preclusion of RAIT, potential need for completion thyroidectomy, frequent inability to avoid chronic thyroid hormone replacement, and limitations of supportive evidence as arguments against widely applying lobectomy. Significant divergence involved ATA 2015's guidance regarding RAIT. European panelists favored wider use of post operative RAIT than does ATA 2015. Rationales included the modality's association with favorable patient outcomes and generally limited toxicity, and lack of high quality evidence supporting withholding RAIT. Additionally, European panelists favored recombinant human thyrotropin in more settings than does ATA 2015, citing avoidance of hypothyroid morbidity and quality-of-life impairment, without apparent sacrifice in oncologic outcomes. Based on clinicial evidence plus theoretical advantages, European experts advocated dosimetric versus fixed activity RAIT approaches for advanced DTC. European panelists noted that the ATA 2015 risk stratification system requires information sometimes unavailable in everyday practice. ATA 2015 recommendations regarding radioiodine-refractory DTC should consider potential palliative benefits of RAIT in patients who also have radioiodine-susceptible lesions. CONCLUSIONS: European panelists suggested modifications to approximately one-third of ATA 2015 recommendations. Varying European and ATA 2015 perspectives can stimulate analysis and discussion of literature and performance of primary research to resolve discrepant recommendations and potentially improve patient outcomes. PMID- 30484396 TI - Current Trends in Biotherapeutic Higher Order Structure Characterization by Irreversible Covalent Footprinting Mass Spectrometry. AB - BACKGROUND: Biotherapeutics, particularly monoclonal antibodies (mAbs), are a maturing class of drugs capable of treating a wide range of diseases. Therapeutic function and solution-stability are linked to the proper three-dimensional organization of the primary sequence into higher order structure (HOS) as well as the timescales of protein motions (dynamics). Methods that directly monitor protein HOS and dynamics are important for mapping therapeutically relevant protein-protein interactions and assessing properly folded structures. Irreversible covalent protein footprinting mass spectrometry (MS) tools, such as site-specific amino acid labeling and hydroxyl radical footprinting are analytical techniques capable of monitoring the side chain solvent accessibility influenced by tertiary and quaternary structure. Here we discuss the methodology, examples of biotherapeutic applications, and the future directions of irreversible covalent protein footprinting MS in biotherapeutic research and development. CONCLUSION: Bottom-up mass spectrometry using irreversible labeling techniques provide valuable information for characterizing solution-phase protein structure. Examples range from epitope mapping and protein-ligand interactions, to probing challenging structures of membrane proteins. By paring these techniques with hydrogen-deuterium exchange, spectroscopic analysis, or static phase structural data such as crystallography or electron microscopy, a comprehensive understanding of protein structure can be obtained. PMID- 30484397 TI - Development of Synchrotron Footprinting at NSLS and NSLS-II. AB - X-ray synchrotron footprinting is a rapidly growing technique ideal for the analysis of solution-state structure and dynamics of macromolecules. First developed in the 1990's at the National Synchrotron Light Source, instrumentation to expand the technology has continuously pushed the boundaries of biological systems that can be studied using the technique. Dedicated synchrotron beamlines, first X28C at NSLS, then XFP (17-BM) at NSLS-II provide an important resource for examining fundamental biological mechanisms of folding, ligand binding, catalysis, splicing, transcription, translation, and macromolecular assembly. PMID- 30484398 TI - Expression and Purification of Tag-removed Human IL37 by Digestion on Beads in Escherichia Coli. AB - Human interleukin 37 (IL37), a unique anti-inflammatory cytokine of IL1 family member, plays critical roles in innate and adaptive immunity and inflammation. Preparation of high purity and tag-removed recombinant IL37 protein (rIL37) is critical for its clinical application. In this study, we constructed an N terminal cleavable GST-fused IL37 expression vector. Subsequent to transformation and optimization of the induction temperature, the soluble expression level of rIL37 was 306.5 mg/L of culture medium at 18 degrees C induction in Escherichia coli. Meanwhile, rIL37 was digested on beads by GST-HRV3C protease during GST affinity chromatography. After further purification, the purity of rIL37 was higher than 99 %. Finally, the anti-inflammatory activity of tag-removed protein was verified by the results showing that rIL37 suppressed IL1beta production in PBMCs. In a word, this work presents a protocol to produce high purity and tag removed rIL37 with anti-inflammatory activity, which provides the firm basis for advancing clinical application in human IL37-related inflammatory diseases. PMID- 30484399 TI - Fast Photochemical Oxidation of Proteins Coupled with Mass Spectrometry. AB - Structural proteomics approaches coupled with mass spectrometry are increasingly used in biology to examine the composition and structure of macromolecules. Hydroxyl radical-mediated protein footprinting using mass spectrometry has recently been developed to define structure, assembly, and conformational changes of macromolecules in solution based on measurements of reactivity of amino-acid side chains with reagents that irreversibly modify a protein side chain. Generating the hydroxyl radicals by laser irradiation, Hambly and Gross developed fast photochemical oxidation of proteins (FPOP), which labels proteins on the millisecond or shorter time scale. Quantitative mass spectrometric analysis of the modified protein fragments provide a footprinting approach that has been used to probe protein structure and protein-ligand and protein-protein interactions. In this review, we discuss the fundamentals of the FPOP method and review its application in protein footprinting. We also will highlight the future directions of FPOP. PMID- 30484400 TI - Protein Footprinting with Radical Probe Mass Spectrometry - Two Decades of Achievement. AB - BACKGROUND: Radical Probe Mass Spectrometry (RP-MS) describes a pioneering methodology in structural biology that enables the study of protein structures, their interactions, and dynamics on fast timescales (down to sub-milliseconds). Hydroxyl radicals (*OH) generated directly from water within aqueous solutions induce the oxidation of reactive, solvent accessible amino acid side chains that are then analyzed by mass spectrometry. Introduced in 1998 at the American Society for Mass Spectrometry annual conference, RP-MS was first published on in 1999. OBJECTIVE: This review article describes developments and applications of the RP-MS methodology over the past two decades. METHOD: The RP-MS method has been variously referred to as synchrotron X-ray radiolysis footprinting, Hydroxyl Radical Protein Footprinting (HRPF), X-ray Footprinting with Mass Spectrometry (XF-MS), Fast Photochemical Oxidation of Proteins (FPOP), oxidative labelling, covalent oxidative labelling, and even the Stability of Proteins from Rates of Oxidation (SPROX). RESULTS: The article describes the utility of hydroxyl radicals as a protein structural probe, the advantages of RP-MS in comparison to other MS-based approaches, its proof of concept using ion mobility mass spectrometry, its application to protein structure, folding, complex and aggregation studies, its extension to study the onset of protein damage, its implementation using a high throughput sample loading approach, and the development of protein docking algorithms to aid with data analysis and visualization. CONCLUSION: RP-MS represents a powerful new structural approach that can aid in our understanding of the structure and functions of proteins, and the impact of sustained oxidation on proteins in disease pathogenesis. PMID- 30484401 TI - Recent Advances in X-Ray Hydroxl Radical Footprinting at the Advanced Light Source Synchrotron. AB - Efforts in the field of synchrotron footprinting are progressing rapidly, with two major footprinting centers in the United States, one on the east coast at the National Synchrotron Light Source II, and one on the west coast at the Advanced Light Source. This article describes recent technical advances in the technique at the Advanced Light Source, and describes the types of biological problems that can be addressed using the new methods and instrumentation. PMID- 30484402 TI - Using X-ray Footprinting and Mass Spectrometry to study the structure and function of membrane proteins. AB - Membrane proteins are crucial for cellular sensory cascades and metabolite transport, and hence are key pharmacological targets. Structural studies by traditional high-resolution techniques are limited by the requirements for high purity and stability when handled in high concentration and nonnative buffers. Hence, there is a growing requirement for the use of alternate methods in a complementary but orthogonal approach to study the dynamic and functional aspects of membrane proteins in physiologically relevant conditions. In recent years, significant progress has been made in the field of X-ray radiolytic labeling in combination with mass spectroscopy, commonly known as X-ray Footprinting and Mass Spectrometry (XFMS), which provide residue-specific information on the solvent accessibility of proteins. In combination with both low-resolution biophysical methods and high-resolution structural data, XFMS is capable of providing valuable insights into structure and dynamics of membrane proteins, which have been difficult to obtain by standalone high-resolution structural techniques. The XFMS method has also demonstrated a unique capability for identification of structural waters and their dynamics in protein cavities at both a high degree of spatial and temporal resolution, and thus capable of identifying conformational hot-spots in transmembrane proteins. Here, we provide a perspective on the place of XFMS amongst other structural biology methods and showcase some of the latest developments in its usage for studying conformational changes in membrane proteins. PMID- 30484403 TI - Activation of AMPK by Medicinal Plants and Natural Products: Its Role in Type 2 Diabetes Mellitus. AB - Type-2 diabetes (T2D) is a metabolic disease characterized by permanent hyperglycemia, whose development can be prevented or delayed by using therapeutic agents and implementing lifestyle changes. Some therapeutic alternatives include regulation of glycemia through modulation of different mediators and enzymes, such as AMP-activated protein kinase (AMPK), a highly relevant cellular energy sensor for metabolic homeostasis regulation, with particular relevance in the modulation of liver and muscle insulin sensitivity. This makes it a potential therapeutic target for antidiabetic drugs. In fact, some of them are standard drugs used for treatment of T2D, such as biguanides and thiazolidindiones. In this review, we compile the principal natural products that are activators of AMPK and their effect on glucose metabolism, which could make them candidates as future antidiabetic agents. Phenolics such as flavonoids and resveratrol, alkaloids such as berberine, and some saponins are potential natural activators of AMPK with a potential future as antidiabetic drugs. PMID- 30484404 TI - 9.4T Magnetic Resonance Imaging of the Mouse Circle of Willis Enables Serial Characterization of Flow-Induced Vascular Remodeling by Computational Fluid Dynamics. AB - BACKGROUND: The neurovasculature dynamically responds to changes in cerebral blood flow by vascular remodeling processes. Serial imaging studies in mouse models could help to characterize pathologic and physiologic flow-induced remodeling of the Circle of Willis (CoW). METHOD: We induced flow-driven pathologic cerebral vascular remodeling in the CoW of mice (n=3) by ligation of the left common carotid artery (CCA), and the right external carotid and pterygopalatine arteries, increasing blood flow through the basilar and the right internal carotid arteries. One additional mouse was used as a wild-type control. Magnetic resonance imaging (MRI) at 9.4 Tesla(T) was used to serially image the mouse CoW over three months, and to obtain three-dimensional images for use in computational fluid dynamic (CFD) simulations. Terminal vascular corrosion casting and scanning electron microscope imaging were used to identify regions of macroscopic and microscopic arterial damage. RESULTS: We demonstrated the feasibility of detecting and serially measuring pathologic cerebral vascular changes in the mouse CoW, specifically in the anterior vasculature. These changes were characterized by bulging and increased vessel tortuosity on the anterior cerebral artery and aneurysm-like remodeling at the right olfactory artery origin. The resolution of the 9.4T system further allowed us to perform CFD simulations in the anterior CoW, which showed a correlation between elevated wall shear stress and pathological vascular changes. CONCLUSION: In the future, serial high-resolution MRI could be useful for characterizing the flow environments corresponding to other pathologic remodeling processes in the mouse CoW, such as aneurysm formation, subarachnoid hemorrhage, and ischemia. PMID- 30484405 TI - Blood pressure and the risk of dementia: a dose-response meta-analysis of prospective studies. AB - BACKGROUND: A number of epidemiological studies have revealed a controversial correlation between blood pressure (BP) and the risk of dementia, hindering translation of reseach into preventative practice. OBJECTIVE: To meta-analyze the dose-response relationship of dementia and its subtypes to BP. METHOD: Relevant studies were identified via a systematic retrieval analysis in electronic databases from inception to May 1, 2017. Linear and non-linear dose-response meta analyses were conducted to evaluate the effects of BP on dementia risk. RESULTS: Twenty-three studies from 17 articles with 830631 participants and 4384 cases for all dementia, 17 studies from 12 articles with 1707445 participants and 3481 cases for Alzheimer's disease (AD) and 11 studies from 8 articles with 1693690 participants and 1067 cases for vascular dementia (VD) were included. We identified that the associations between BP and dementia varied with population characteristics. A nonlinear relationship was found between systolic blood pressure (SBP) and all dementia risk in population aged >= 65 years (pnonlinearity <0.05). SBP between 110 and 120mmHg played a protective role in population aged 62 to 82, while SBP above 162 mmHg would significantly increase the risk in those aged 70 to 86.5. It is also noteworthy that there is a linear association between diastolic blood pressure (DBP) and AD risk in the population aged >= 65 years, such that the risk decreased by 3% for per 10 mmHg increase in a specific range of DBP. CONCLUSION: These findings indicate that BP management strategy for dementia prevention might be tailored according to specific population characteristics. PMID- 30484406 TI - Gender-specific relationship between uric acid levels and prognosis after cerebral venous thrombosis. AB - BACKGROUND: Uric acid (UA) has been known to play a neuroprotective role in ischemic stroke patients. However, the relationship between UA levels and prognosis in patients with cerebral venous thrombosis (CVT) has not been investigated. METHOD: A total of 228 CVT patients were retrospectively identified and were divided into three groups according to UA levels. Functional outcome was evaluated by modified Rankin Scale (mRS). Multivariate logistic regression analysis was conducted to evaluate the relation between UA levels and functional outcome after CVT. RESULTS: UA levels were significantly higher in male than female patients (274.5+/-125.9 vs. 197.4+/-81.6, P < 0.001). The association between UA levels and mortality was modified by sex (P-interaction = 0.010). Multivariate logistic regression analysis indicated that a higher UA level was associated with a decreased risk of mRS of 3 to 6 in female patients (odds ratio [OR] = 0.204; 95% confidence interval [CI], 0.044-0.938), but not in male patients (OR= 0.441; 95% CI, 0.033-5.339). Similarly, a high UA level was associated with a decreased risk of mortality in female patients (OR= 0.058; 95% CI, 0.008-0.437), but not in male patients (OR= 2.309; 95% CI, 0.057-93.308). In addition, each 1 μmol/L increase in UA levels was also associated with a lower risk of poor clinical outcome and mortality for female patients, but not in male patients. CONCLUSION: Our study demonstrated that there might be a gender specific relationship between UA levels and clinical outcome in patients with CVT. Higher UA levels were associated with better prognosis in female patients, but not in male patients. PMID- 30484407 TI - Sirtuins: Developing Innovative Treatments for Aged-Related Memory Loss and Alzheimer's Disease. AB - The world's population continues to age at a rapid pace. By the year 2050, individuals over the age of 65 will account for sixteen percent of the world's population and life expectancy will increase well over eighty years of age. Accompanied with the aging of the global population is a significant rise in non communicable diseases (NCDs). Neurodegenerative disorders will form a significant component for NCDs. Currently, dementia is the 7th leading cause of death and can be the result of multiple causes that include diabetes mellitus, vascular disease, and Alzheimer's disease (AD). AD may represent at least sixty percent of these cases. Current treatment for these disorders is extremely limited to provide only some symptomatic relief at present. Sirtuins and in particular, the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), represent innovative strategies for the treatment of cognitive loss. New work has revealed that SIRT1 provides protection against memory loss through mechanisms that involve oxidative stress, A? toxicity, neurofibrillary degeneration, vascular injury, mitochondrial dysfunction, and neuronal loss. In addition, SIRT1 relies upon other avenues that can include trophic factors, such as erythropoietin, and signaling pathways, such as Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4). Yet, SIRT1 can have detrimental effects as well that involve tumorigenesis and blockade of stem cell differentiation and maturation that can limit reparative processes for cognitive loss. Further investigations with sirtuins and SIRT1 should be able to capitalize upon these novel targets for dementia and cognitive loss. PMID- 30484408 TI - One-year outcome of Shanghai mild cognitive impairment cohort study. AB - BACKGROUND & OBJECTIVE: The purpose of this study is to identify the risk factors associated with the conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia for the early detection of AD. METHODS: The study comprised a prospective cohort study that included 400 MCI subjects with annual follow-ups for 3 years. RESULTS: During the first 12 months' follow-up, 42 subjects converted to Alzheimer's dementia (21 probable AD and 21 possible AD), two subjects converted to other types of dementia and 56 subjects lost follow. The factors associated with a greater risk of conversion from MCI to AD included gender, whole brain volume, and right hippocampal volume (rt. HV), as well as scores on the Revised Chinese version of the Alzheimer's Disease Assessment Scale Cognitive subscale 13 (ADAS-Cog-C), clock drawing test (CDT), symbol digit modalities test (SDMT), and Rey-Osterrieth complex figure test (ROCFT). The risk classification of the combined ADAS-Cog-C and Alzheimer Cognitive Composite (ACC) score with the rt. HV and left entorhinal cortex volume (lt. ECV) showed a conversion difference among the groups. CONCLUSION: Early detection of AD and potential selection for clinical trial design should utilize the rt. HV, as well as neuropsychological test scores, including those of the ADAS-Cog-C and ACC. PMID- 30484409 TI - Identification, Prediction and Data Analysis of Non Coding RNAs: A Review. AB - BACKGROUND: Non coding RNAs (ncRNAs) which play an important role in various cellular processes are important in medicine as well as drug design strategies. Different studies have shown that ncRNAs are dis-regulated in cancer cells and play an important role in human tumorigenesis. Therefore, it is important to identify and predict such molecules by experimental and computational methods, respectively. However, to avoid expensive experimental methods, computational algorithms have been developed for accurately and fast prediction of ncRNAs. OBJECTIVE: The aim of this review was to introduce the experimental and computational methods to identify and predict ncRNAs structure. Also, we were explained the ncRNAs roles in cellular processes and drugs design, briefly. METHODS: In this survey, we will introduce ncRNAs and their roles in biological and medicinal processes. Then, some important laboratory techniques will be studied to identify ncRNAs. Finally, the state-of-the-art models and algorithms will be introduced along with important tools and databases. RESULTS: The results showed that the integration of experimental and computational approaches improves to identify ncRNAs. Moreover, the high accurate databases, algorithms and tools were compared to predict the ncRNAs. CONCLUSION: ncRNAs prediction is an exciting research field, but there are different difficulties. It requires to accurate and reliable algorithms and tools. Also, it is should be mentioned that computational costs of such algorithm including running time and usage memory is very importance. Finally, some suggestions were presented to improve computational methods of ncRNAs gene and structural prediction. PMID- 30484410 TI - Cytarabine and Ferric Carboxymaltose (Fe+3) Increase Oxidative Damage and Alter Serotonergic Metabolism in Brain. AB - BACKGROUND & OBJECTIVE: The purpose of this study was to measure the effect on brain biomarkers after treatment with anticancer compounds - cytarabine (CT) and ferric carboxymaltose (FC) (Fe+3) in Wistar rats. The Wistar rats were treated as follows: group 1 (control), NaCl 0.9%; group 2, CT (25 mg/k), group 3, FC(Fe+3) (50 mg/k) and group 4, CT + FC(Fe+3). The animals were sacrificed and their brains were obtained and used to measure lipoperoxidation (TBARS), H2O2, Na+, K+ ATPase, glutathione (GSH), serotonin metabolite (5-HIAA) and dopamine. The results indicated an enhancement of lipid peroxidation in the cortex and striatum of groups treated with FC(Fe+3) and CT, while GSH decreased in the cortex of group treated with CT + FC(Fe+3). Dopamine decreased in the cortex of the rats that received CT, while in the striatum, 5HIAA increased in all groups. RESULTS & CONCLUSION: These results suggest that the treatment with CT and FC(Fe+3) boosted oxidative stress and led to an alteration in momoamine concentrations in the brain. PMID- 30484411 TI - Identification of novel pancreatic lipase inhibitors using structure based virtual screening, docking and simulations studies. AB - BACKGROUND: Obesity is well known multifactorial disorder towards the public health concern in front of the world. Increasing rates of obesity has characterized with liver diseases, chronic diseases, diabetes mellitus, hypertension, and stroke, hearts improper function, reproductive and gastrointestinal, gallstones. An essential enzyme pancreatic lipase recognized for the digestion and absorption of lipids, can be a pleasing drug target towards the future development of anti-obesity therapeutics in cure of obesity disorders. OBJECTIVE: The purpose of present study is to identify an effective potential therapeutic agent for the inhibition of pancreatic lipase. METHOD: Using trio of in-silico procedure of HTVS, SP and XP in Glide module, Schrodinger with default parameters, were applied on Specs databases to identify a best potential compound based on receptor grid. Finally, based on binding interaction, docking score and glide energy, selected compounds were taken forward into the platform of IFD, ADME, MMGBSA, DFT, and MDS for analyzing the ligands behavior into the protein binding site. RESULTS: Using in silico protocol of structure based virtual screening on pancreatic lipase were reported top two compounds AN-465/43369242 & AN-465/43384139 from Specs database. Result suggested both the compounds are competitive inhibitors with higher docking score and greatest binding affinity than reported inhibitor. CONCLUSION: Thus, we anticipate that results could be future therapeutic agents and may present an idea toward the experimental studies against the inhibition of pancreatic lipase. PMID- 30484412 TI - Phytochemical Profiling, GC-MS Analysis and alpha-Amylase Inhibitory Potential of Ethanolic Extract of Cocos nucifera Linn. Endocarp. AB - Drugs with post-prandial action constitute one of the main course of treatments for diabetes. In the present investigation, we have explored the alpha-amylase inhibitory potential of ethanolic extract of Cocos nucifera endocarp. DNS based alpha-amylase assay indicated that IC50 value of extract lies in the range of 63 126 ug/ml and at higher doses, i.e. above 250 ug/ml, it is having better alpha amylase inhibition than the standard drug, acarbose. Phytochemical screening indicated that ethanolic extract is rich in alkaloids, tannins, flavonoids, saponins, triterpenes, glycosides, carbohydrates, terpenoids, quinones and lactones. Further, GC-MS analysis (where Similarity Index was > 90) predicted that the probable phytoconstituents present in the ethanolic extract are myristic acid, syringaldehyde, eugenol, vanillin, 2,4-di-tert-butylphenol, lauric acid, palmitic acid methyl ester and gamma-sitosterol. In silico docking studies were done using VLife MDS 4.6 software and the probable molecules, predicted after GC MS analysis, were docked with the co-crystallized (acarbose) tracked active site and rest all cavities of porcine pancreatic alpha-amylase (1OSE). gamma Sitosterol have shown the strong affinity towards the active site which was tracked by co-crystallized ligand along with cavity 1 and 2 while significant interactions were observed in case of co-crystallized tracked active site as well as cavity 4 of 1OSE. ADMET analysis was done using StarDrop 6.4, Derek Nexus and P450 Modules from Optibrium Ltd. and LHASA Ltd. Ethanolic extract of C. nucifera has no haemolytic effect. Its ability to effectively inhibit alpha-amylase may be attributed to the presence of the above probable molecules, which will be explored further. PMID- 30484413 TI - Plant derived glycosides with alpha-glucosidase inhibitory activity: current standing and future prospects. AB - The alpha-glucosidase (EC 3.2.1.20), a calcium-containing intestinal enzyme which is positioned in the cells which cover the intestinal microvilli brush border. The carbohydrates require metabolism by alpha-glucosidase before being absorbed into the small intestine, and as a result this enzyme represents a significant drug target for the effective management of diabetes. There are few alpha glucosidase inhibitors in the clinical practice that are challenged by several limitations. Thus, new effective and safe therapeutic agents in this class are required. In this regard, plant secondary metabolites are a very promising source to be investigated. Herein in this review, we have focused on the preclinical studies on various glycosides with in vitro alpha-glucosidase inhibitory activity. The surveyed literature revealed marked inhibitory profile of various glycosides, and some of them were extremely potent relatively to the standard, acarbose. Therefore, these glycosides are strong candidates for further more detailed studies to ascertain their clinical potential and for effective contribution in effective management of diabetes, where multiple targets are required to address. PMID- 30484415 TI - The Association of Serum Vitamin D Levels with Pseudoexfoliation Glaucoma/Syndrome. AB - OBJECTIVE: To investigate whether serum vitamin D levels have an effect on pseudoexfolation (PEX) glaucoma/syndrome development and on the control of glaucoma in these cases. METHOD: A total of 31 cases with PEX glaucoma, 34 cases with the PEX syndrome and 43 control subjects of similar age and sex were included in the study. Vitamin D levels were compared between the groups and also between the cases where glaucoma surgery was performed or not. RESULTS: PEX glaucoma group consisted of 17 males and 14 females, PEX syndrome group of 27 males and 7 females, and the control group of 27 males and 16 females. The mean age was 70.9+/-8.9 years, 72.1+/-7.3 years, and 67.9+/-9.1 years in PEX glaucoma, syndrome and control group, respectively. Mean vitamin D levels were 9.4+/-7.7 ng/mL, 7.9+/-6,1 ng/mL, 11.5+/-14.2 ng/mL in PEX glaucoma, syndrome and control group respectively (p?0.05). The mean serum vitamin D level was 8.04+/-4.7 ng/mL in those who underwent glaucoma surgery and 10.1+/-8.7 ng/mL in those who didn't undergo glaucoma surgery in PEX glaucoma group (p?0.05). No difference was found between the PEX glaucoma subgroups in terms of the mean deviation when classified according to vitamin D levels (?10 ng/mL, >=10 ng/mL) (p?0.05). CONCLUSION: Although we found no statistically significant difference between the PEX syndrome/glaucoma, and control group in terms of serum vitamin D levels, serum vitamin D levels was lower in PEX syndrome and glaucoma group than control group. Our results indicate that serum vitamin D levels have no effect on the development of PEX glaucoma/syndrome or the control of the disorder in cases with PEX glaucoma. However these results need to be supported with further studies on a larger number of patients and with longer follow-up. PMID- 30484414 TI - Prevalence of Extended Spectrum beta-Lactamases in Multi-drug Resistant Pseudomonas aeruginosa from Diabetic Foot Patients. AB - BACKGROUND: Pseudomonas aeruginosa is one of the major pathogen associated with acute tissue damage in patients with diabetic foot ulcer (DFU). Antibiotic resistance in P. aeruginosa often bodes unpredictable and unfavourable clinical outcomes, owing to a variety of intrinsic and acquired molecular mechanisms. The study aimed to determine the frequency of ESBLs in Multi-drug resistant P. aeruginosa from diabetic foot patients. METHOD: Present study's duration was one year and 100 patients with DFU were enrolled. All the pus samples were subjected to the bacterial culture, gram staining, catalase test, oxidase test and antimicrobial susceptibility pattern was ascertained using the phenotypic method. The presences of genes encoding extended spectrum beta-lactamase enzyme were determined by PCR. RESULT: Of 23 positive isolates of P. aeruginosa, Polymxin B showed greater susceptibility of all antibiotics used. 10 isolates were ESBLs positive as detected by double disk diffusion test. The positive ESBL strain showed an increase of >=5mm in the zone of inhibition of the combination discs in comparison to the alone ceftazidime disc. The PCR-based ESBLs positivity was also tested for TEM-1, SHV-1, PER-1, and VEB-1. Where: (07/10) strains carried SHV-1, (05/10) strains were positive for TEM-1, while none of the isolates were PCR positive for PER-1 and VEB-1. CONCLUSION: P. aeruginosa isolates shows a difference in pattern of ESBL genes compared to that of other such endeavours. Polymxin B was found to be most effective against the tested P. aeruginosa isolates and SHV-1 was most common ESBL among these strains. PMID- 30484416 TI - Delay discounting and its association with food purchasing considerations and food availability in the home in south-east Alabama, USA. AB - OBJECTIVE: Certain factors, such as food quality, label content and grocery characteristics, may be considered when purchasing foods. Food availability in the home has been shown to influence dietary behaviours, also associated with delay discounting (DD). The present study sought to characterize the relationships between DD, food purchasing considerations and healthfulness of foods in the home. DESIGN: A cross-sectional, online survey of adults (n 477) was conducted with the following measures: DD, consideration of food quality (nutrition, taste) and grocery characteristics (price, ease of preparation, shelf life) while shopping, use of food labels and food availability in the home. DD was assessed by the area under the delay discounting curve (AUC) using a binary choice task. Greater AUC reflects lower DD. Structural equation modelling was used to allow AUC to simultaneously predict purchasing considerations and foods in the home. SETTING: Online survey.ParticipantsAdult employees in south-east Alabama, USA. RESULTS: DD was negatively associated with food label use and emphasis on food quality when shopping (P<0.001). In the final model, DD was associated with availability of healthful foods in the home and emphasis on food quality and grocery characteristics. About 33 % of the variance in shopping behaviours, 5 % in food label use, 7 % in availability of healthful foods and 4 % in availability of unhealthful foods was explained by DD. CONCLUSIONS: Individuals with lower DD appear to be more thoughtful in making food purchasing decisions and have healthful foods available in the home more frequently than individuals with higher DD. PMID- 30484417 TI - Study Design and Rationale for the Mood and Methylation Study: A Platform for Multi-Omics Investigation of Depression in Twins. AB - Major depression is a complex disorder with no single, direct causal mechanism. Morbidity has been linked to genetic processes, developmental history, and unique environmental exposures. Epigenetic mechanisms, especially DNA methylation, are also likely important factors in the pathogenesis of major depressive disorder (MDD). A community-based twin sample has many advantages for epigenetic studies, given the shared genetic and developmental histories of same-sex twin pairs. This article describes the rationale and study design for the Mood and Methylation Study in which 133 twin pairs (101 monozygotic and 32 dizygotic), both discordant and concordant for lifetime history of MDD, were evaluated on a large number of variables related to MDD. The twins also provided blood samples for an epigenome wide association study of differentially methylated regions (DMR) relevant to MDD. Although MDD is typically considered a disorder of the central nervous system, it is unfeasible to obtain a large sample of brain tissues. However, epigenetic variation is not limited to the affected tissue but can also be detected in peripheral blood leukocytes. Thus, this study focused on monocytes for the major analyses. Additional plans for the study include gene expression analysis from the same set of twins using RNA-seq and validation of significant DMRs in postmortem brain tissues from a separate sample. Moreover, sufficient samples have been collected to perform future 'multi-omic' analyses, including metabolome, microbiome, and transcriptome. Our long-term goal is to understand how epigenomic and other 'omic' factors can be manipulated for diagnostic, preventive, and therapeutic purposes for MDD and its related conditions. PMID- 30484418 TI - Continuity of genetic and environmental influences on clinically assessed major depression from ages 18 to 45. AB - BACKGROUND: Studies on the stability of genetic risk for depression have relied on self-reported symptoms rather than diagnoses and/or short follow-up time. Our aim is to determine to what degree genetic and environmental influences on clinically assessed major depressive disorder (MDD) are stable between age 18 and 45. METHODS: A population-based sample of 11 727 twins (6875 women) born between 1967 and 1991 was followed from 2006 to 2015 in health registry data from primary care that included diagnoses provided by treating physicians. Individuals with schizophrenia or bipolar disorder (n = 163) were excluded. We modelled genetic and environmental risk factors for MDD in an accelerated longitudinal design. RESULTS: The best-fitting model indicated that genetic influences on MDD were completely stable from ages 18 to 45 and explained 38% of the variance. At each age, the environmental risk of MDD was determined by the risk at the preceding observation, plus new environmental risk, with an environmental correlation of +0.60 over 2 years. The model indicated no effects of shared environment and no environmental effects stable throughout the observational period. All long-term stability was therefore explained by genetic factors. CONCLUSIONS: Different processes unfolded in the genetic and environmental risk for MDD. The genetic component is stable from later adolescence to middle adulthood and accounted for nearly all long-term stability. Therefore, molecular genetic studies can use age heterogenous samples when investigating genetic risk variants of MDD. Environmental risk factors were stable over a short span of years with associations rapidly decreasing and no evidence of permanent environmental scarring. PMID- 30484419 TI - Letter in response to: "CJEM Debate Series: #ChoosingWisely - The Choosing Wisely campaign will not impact physician behaviour and choices". PMID- 30484420 TI - Safety and clinically important events in PCP-initiated STEMI bypass in Ottawa. AB - CLINICIAN'S CAPSULE What is known about the topic? Transport of STEMI patients directly to the cath lab (STEMI bypass) by advanced care paramedics (ACPs) is common practice. The safety of this practice with primary care paramedics (PCPs) is unknown. What did this study ask? What is the prevalence and breakdown of events during PCP STEMI bypass? What did this study find? Clinically important events are common in STEMI bypass patients. A smaller proportion of events would be addressed differently by ACP compared to PCP protocols. Why does this study matter to clinicians? This study adds to the evidence that PCP STEMI bypass is safe. PMID- 30484422 TI - You don't need a mentor; you need a board of directors. PMID- 30484421 TI - CJEM Debate Series#PhysicianProductivity - Measuring and understanding causes of variability in emergency physician performance are essential to improve emergency department efficiency. PMID- 30484423 TI - ST-segment elevation myocardial infarction (STEMI) bypass: The importance of paramedics in an integrated STEMI system of care. PMID- 30484424 TI - Delirium in older emergency department patients. PMID- 30484425 TI - FOAMed and social media - innovation or disruption? PMID- 30484427 TI - Diagnostic guidelines for IPF: when art meets science. PMID- 30484426 TI - Plant diversity maintains multiple soil functions in future environments. AB - Biodiversity increases ecosystem functions underpinning a suite of services valued by society, including services provided by soils. To test whether, and how, future environments alter the relationship between biodiversity and multiple ecosystem functions, we measured grassland plant diversity effects on single soil functions and ecosystem multifunctionality, and compared relationships in four environments: ambient conditions, elevated atmospheric CO2, enriched N supply, and elevated CO2 and N in combination. Our results showed that plant diversity increased three out of four soil functions and, consequently, ecosystem multifunctionality. Remarkably, biodiversity-ecosystem function relationships were similarly significant under current and future environmental conditions, yet weaker with enriched N supply. Structural equation models revealed that plant diversity enhanced ecosystem multifunctionality by increasing plant community functional diversity, and the even provision of multiple functions. Conserving local plant diversity is therefore a robust strategy to maintain multiple valuable ecosystem services in both present and future environmental conditions. PMID- 30484428 TI - Fish smoking in Lagos. PMID- 30484430 TI - Blood testing in the diagnosis of pulmonary alveolar proteinosis. PMID- 30484429 TI - Extracorporeal carbon dioxide removal for lowering the risk of mechanical ventilation: research questions and clinical potential for the future. AB - As a result of technical improvements, extracorporeal carbon dioxide removal (ECCO2R) now has the potential to play an important role in the management of adults with acute respiratory failure. There is growing interest in the use of ECCO2R for the management of both hypoxaemic and hypercapnic respiratory failure. However, evidence to support its use is scarce and several questions remain about the best way to implement this therapy, which can be associated with serious side effects. This Review reflects the consensus opinion of an international group of clinician scientists with expertise in managing acute respiratory failure and in using ECCO2R therapies in this setting. We concisely review clinically relevant aspects of ECCO2R, and provide a series of recommendations for clinical practice and future research, covering topics that include the practicalities of ECCO2R delivery, indications for use, and service delivery. PMID- 30484431 TI - Blood testing in the diagnosis of pulmonary alveolar proteinosis - Authors' reply. PMID- 30484432 TI - Fast calculation of nanodosimetric quantities in treatment planning of proton and ion therapy. AB - Details of the pattern of ionization formed by particle tracks extends knowledge of dose effects on the nanometer scale. Ionization detail (ID), frequently characterized by ionization cluster size distributions (ICSD), is obtained through time-consuming Monte Carlo (MC) track-structure simulations. In this work, TOPAS-nBio was used to generate a highly precise database of biologically significant ID quantities, sampled with randomly oriented 2.3 nm diameter cylinders, 3.4 nm (10 base pairs) long, inside a chromatin-size cylinder, irradiated by 1-1000 MeV/u ions of Z = 1-8. A macroscopic method developed to utilize the database using condensed-history MC was used to calculate distributions of the ICSD first moment [Formula: see text] and cumulative probability [Formula: see text] in a 20 * 20 * 40 cm3 water phantom irradiated with proton and carbon spread-out Bragg peak (SOBP) of 10.5 cm range, 2 cm width. Results were verified against detailed MC track-structure simulations using phase space scored at several depths. ID distributions were then obtained for intensity modulated proton and carbon radiotherapy plans in a digitized anthropomorphic phantom of a base of skull tumor to demonstrate clinical application of this approach. The database statistical uncertainties were 0.5% (3 standard deviations). Fluence-averaged ID as implemented proved unsuitable for macroscopic calculation. E dep-averaged ID agreed with track-structure results within 0.8% for protons. For carbon, maximum absolute differences of 2.9% +/- 1.6% and 5.6% +/- 1.9% for [Formula: see text], 1.7% +/- 0.8% and 1.9% +/- 0.4% (1 standard deviation) for [Formula: see text], were found in the plateau and SOBP, respectively, up to 11.5% +/- 5.6% in the tail region. Macroscopic ID calculation was demonstrated for a realistic treatment plan. Computation times with or without ID calculation were comparable in all cases. Pre-calculated nanodosimetric data may be used for condensed-history MC for nanodosimetric ID based treatment planning in ion radiotherapy in the future. The macroscopic approach developed has the calculation speed of condensed-history MC while approaching the accuracy of full track structure simulations. PMID- 30484433 TI - Computational design of hepatitis C virus immunogens from host-pathogen dynamics over empirical viral fitness landscapes. AB - Hepatitis C virus (HCV) afflicts 170 million people and kills 700 000 annually. Vaccination offers the most realistic and cost effective hope of controlling this epidemic, but despite 25 years of research, no vaccine is available. A major obstacle is HCV's extreme genetic variability and rapid mutational escape from immune pressure. Coupling maximum entropy inference with population dynamics simulations, we have employed a computational approach to translate HCV sequence databases into empirical landscapes of viral fitness and simulate the intrahost evolution of the viral quasispecies over these landscapes. We explicitly model the coupled host-pathogen dynamics by combining agent-based models of viral mutation with stochastically-integrated coupled ordinary differential equations for the host immune response. We validate our model in predicting the mutational evolution of the HCV RNA-dependent RNA polymerase (protein NS5B) within seven individuals for whom longitudinal sequencing data is available. We then use our approach to perform exhaustive in silico evaluation of putative immunogen candidates to rationally design tailored vaccines to simultaneously cripple viral fitness and block mutational escape within two selected individuals. By systematically identifying a small number of promising vaccine candidates, our empirical fitness landscapes and host-pathogen dynamics simulator can guide and accelerate experimental vaccine design efforts. PMID- 30484434 TI - Sparsity-induced dynamic guided filtering approach for sparse-view data toward low-dose x-ray computed tomography. AB - Iterative reconstruction (IR) methods that can incorporate filtering or regularization techniques have received widespread attention in many situations. Total variation (TV) regularization has proven to be a powerful tool to suppress streak artifacts and noise for sparse-view computed tomography (CT) reconstruction over 360 degrees . However, with under-sampled projection data from limited-view (e.g. half-view) CT scanning, where the projections are further reduced, the edge structures are partly blurred, and some artifacts (such as blocky artifacts) are not effectively suppressed in TV-based results. To further improve the quality of the reconstructed image, a sparsity-induced dynamic guided image filtering reconstruction (SIDGIFR) method is proposed. Intermediate reconstruction results constrained by total difference (TD) minimization are taken as the guidance image to filter the results of projection onto convex sets (POCS) by guided image filtering (GIF). In the SIDGIFR algorithm, the guidance image is dynamically updated, which can transfer the important features (such as edge and small details) to the filtered image during the iterative process. To confirm the efficiency and feasibility of the SIDGIFR algorithm, simulated experiments and real data studies are performed. The quantitative evaluation shows that the proposed SIDGIFR method has better performance than other classical IR methods. What's more, the proposed SIDGIFR algorithm can better preserve the edge structures, and suppress noise and artifacts, than the existing IR methods. PMID- 30484435 TI - Hypo-fractionated boost in locally advanced non-small cell lung cancer: temporal distribution of boost fractions. AB - To propose new schemas for radiation boosting of primary tumors, in locally advanced non-small cell lung cancers (NSCLC), in conjunction with standard chemoradiotherapy. To investigate the effect of temporal distributions of the boost fractions on tumor control. NSCLC cases, previously treated with 60 Gy in 30 fractions, were retrospectively planned by adding a radiation boost (25 Gy in 5 fractions) to the primary tumor. Several integrated and sequential boosting schedules were considered. Biological doses were calculated for targets and organs at risk (OAR). Tumor control probabilities (TCP) were calculated using an empirical model and a stochastic model that accounts more systematically for tumor growth kinetics and cell kill. For heterogeneous patient populations, the TCPs for different boost schedules ranged from 82% to 84% and from 73% to 74% for integrated and sequential boosting respectively. For individual tumors with specific growth parameters, the TCP varied by up to 19% between the different schedules. The TCP for sequential boosting was expected to be up to 67% lower than front integrated boosting. The gap in TCP between schedules was higher for tumors with higher clonogenic cell numbers, lower radio-sensitivity, shorter doubling times and lower cell loss. The proposed boosting schemas are dosimetrically feasible and biologically effective. We suggest that the boosts are most effective when given during the first week of treatment and least effective when given sequentially after the end of treatment. The effect of boost scheduling and the effectiveness of front boosting are expected to be most significant for tumors with high clonogenic cell numbers, fast growing rates, low cell loss and low radio-sensitivity. Ultimately, animal studies and clinical trials, guided by biology modeling as presented in the present work, will be needed to verify the effectiveness of fine tuning temporal distributions of radiotherapy fractions. PMID- 30484436 TI - Receiver array design for sonothrombolysis treatment monitoring in deep vein thrombosis. AB - High intensity focused ultrasound (HIFU) can disintegrate blood clots through the generation and stimulation of bubble clouds within thrombi. This work examined the design of a device to image bubble clouds for monitoring cavitation-based HIFU treatments of deep vein thrombosis (DVT). Acoustic propagation simulations were carried out on multi-layered models of the human thigh using two patient data sets from the Visible Human Project. The design considerations included the number of receivers (32, 64, 128, 256, and 512), their spatial positioning, and the effective angular array aperture (100 degrees and 180 degrees about geometric focus). Imaging array performance was evaluated for source frequencies of 250, 750, and 1500 kHz. Receiver sizes were fixed relative to the wavelength (pistons, diameter = lambda/2) and noise was added at levels that scaled with receiver area. With a 100 degrees angular aperture the long axis size of the -3 dB main lobe was ~1.2lambda-i.e. on the order of the vessel diameter at 250 kHz (~7 mm). Increasing the array aperture to span 180 degrees about the geometric focus reduced the long axis by a factor of ~2. The smaller main lobe sizes achieved by imaging at higher frequencies came at the cost of increased levels of sensitivity to phase aberrations induced during acoustic propagation through the intervening soft tissue layers. With noise added to receiver signals, images could be reconstructed with peak sidelobe ratios < -3 dB using single-cycle integration times for source frequencies of 250 and 750 kHz (NRx ? 128). At 1500 kHz, longer integration times and/or higher element counts were required to achieve similar peak sidelobe ratios. Our results suggest that a modest number of receivers(i.e. NRx = 128) arranged on a semi-cylindrical shell may be sufficient to enable passive acoustic imaging with single-cycle integration times (i.e. volumetric rates up to 0.75 MHz) for monitoring cavitation-based HIFU treatments of DVT. PMID- 30484437 TI - Viscoelasticity measurement of ex vivo bovine cartilage using Lamb wave method. AB - Cartilage viscoelasticity changes with cartilage degeneration. Therefore, measurement of cartilage viscoelasticity could offer an alternative to traditional imaging methods for early diagnosis of osteoarthritis. In previous studies, we confirmed the feasibility of using the Lamb wave method (LWM) to assess the elasticity within a simulated cartilage-bone structures. The objective of the present study was to test the suitability of the LWM for measuring viscoelastic properties of ex vivo bovine tibial plateau cartilage. Theoretical and numerical analyses were performed to understand the viscoelastic Lamb wave propagation in cartilage and a suitable measurement range and loading frequency for the LWM were determined. The viscoelasticity of bovine cartilage was experimentally estimated to be 32.8 +/- 0.50, 30.9 +/- 0.50, and 31.9 +/- 1.85 Pa . s for cartilage samples with thicknesses of 2.84 +/- 0.02, 2.32 +/- 0.03, and 2.01 +/- 0.08 mm, respectively, which showed good repeatability during LWM measurements. However, cartilage elasticity was not sensitive to the viscoelastic Lamb wave speed. Indentation tests were also performed and cartilage elasticities were 0.88 +/- 0.09, 1.03 +/- 0.12, and 0.93 +/- 0.09 MPa, respectively. This study validates the use of the LWM for measuring the viscoelasticity of ex vivo cartilage and provides a critical step toward the ultimate goal of measuring the viscoelasticity of cartilage in vivo. PMID- 30484438 TI - Three-Dimensional Soft-Tissue Evaluation in Patients with Cleft Lip and Palate. AB - BACKGROUND In cleft lip and palate (CLP) patients, the shape of the facial soft tissues shows variety in 3 dimensions (3D). Two-dimensional (2D) photographs and radiographs are insufficient in the examination of these anomalies. The aim of this retrospective study was to examine the soft tissue and craniofacial characteristics of individuals with nonsyndromic unilateral cleft lip and palate (UCLP), bilateral cleft lip and palate (BCLP), skeletal Class III malocclusions, or skeletal Class I malocclusions using 3D facial imaging. MATERIAL AND METHODS The entire study group consisted of a total of 158 patients, aged 8-32 years: 29 of the patients had UCLP, 22 BCLP, 54 had skeletal Class III malocclusions, and 53 had skeletal Class I malocclusions. 3D stereophotogrammetric soft-tissue recordings of all patients were analyzed. ANOVA and the Kruskal-Wallis test were performed to compare the groups. RESULTS Statistically significant differences were observed among the groups in terms of linear, angular, proportional. and volumetric measurements. While nasal differences were not observed in the Class III group, nose and upper-lip deformities were common in the CLP groups. Upper lip projection was reduced in all 3 groups. In the Class III patients, the lower lip and chin were more prominent than in the other groups. The facial convexity angle was increased in the CLP and Class III groups. The upper-lip volume was decreased in the BCLP, the UCLP, and the Class III groups. CONCLUSIONS Patients with skeletal Class III or CLP anomalies showed significantly different soft tissue characteristics than the Class I control group. 3D stereophotogrammetric facial imaging is an easy and noninvasive method that can be used in examination and recording of these facial deformities. It is possible to make volumetric measurements using this method. PMID- 30484439 TI - Association of sports and physical activity with obesity among teenagers in Poland. AB - OBJECTIVES: The purpose of the study was to assess the relationship between the body mass index and sports and physical activities in an unbiased, simple, random sample of teenagers from mid-northeastern Poland. MATERIAL AND METHODS: Children and adolescents aged 10-19 years old were surveyed. The Internet-based survey was conducted to collect information on physical activity, leisure time, studying hours, weight, and height. RESULTS: Obesity was found to be low in the study population. The overall prevalence of overweight was not higher than 8%. Only 0.6% of participants were underweight. Overall, 68% of them confirmed participating in sports. Boys were frequently more active than girls (> 70% boys and > 60% girls). Participants mostly played soccer, volleyball, handball, or basketball (30.5%); 7% of them practiced martial arts and 16.5% of them participated in swimming. Sports activity significantly influenced body mass index. Obesity was not related to the lack of participation for physical activity in girls but a significant relationship was observed in boys (p < 0.02). The risk of obesity or overweight for inactive teenagers increased 2-fold (p < 0.01). CONCLUSIONS: We report the overall participation of teenagers from 2 cities in mid-northeastern Poland in sports and physical activities and demonstrate that the lack of statistically significant differences in the body mass index and obesity and overweight is prevalent among boys and girls. Obesity was significantly related to less physical activity in boys, and the likelihood of obesity or overweight increased in inactive teenagers. Thus, we suggest that the importance of overweight and obesity prevention programs should be emphasized. PMID- 30484440 TI - Low frequency electromagnetic waves increase human sperm motility - A pilot study revealing the potent effect of 43 khz radiation. AB - OBJECTIVES: Abnormalities in the timing and course of spermatozoa capacitation and hyperactivation underlie common pathologies related to male infertility. Recent data shows that low frequency electromagnetic waves may influence cell membrane potential and permeability. It is therefore possible that low frequency electromagnetic waves could affect the maturation and motility processes of spermatozoa. The 43-kHz wave generator was used for modeling the impact of environmental exposure to low frequency electromagnetic radiation on human sperm. MATERIAL AND METHODS: Sperm samples were gathered from 103 fertile, healthy men aged 25-30 years old and performed computer-assisted sperm analysis. After initial examination, each participant's semen sample was divided into 2 aliquots (control and experimental) and placed in separate automated incubators. The samples constituting the experimental group were placed into the exposure system that emitted 43-kHz electromagnetic waves. Sperm motility was assessed at 3 h, 12 h and 24 h. RESULTS: Exposure to a 43-kHz radio frequency increased the percentage of sperm in progressive motility by up to 5.8% and the velocity of said sperm by up to 2 MUm/s. Moreover, the total number of hyperactivated spermatozoa was significantly increased in the semen exposed to the electromagnetic signal. CONCLUSIONS: In vivo environmental exposure to 43 kHz waves may promote the development of infertility related to premature capacitation outside of the vaginal tract. Exposing semen to this particular frequency may also boost the capacitation and hyperactivation of spermatozoa in vitro, prior to conducting assisted reproductive therapies. PMID- 30484441 TI - Subsecond detection of guanosine using fast-scan cyclic voltammetry. AB - Guanosine is an important neuromodulator and neuroprotector in the brain and is involved in many pathological conditions, including ischemia and neuroinflammation. Traditional methods to detect guanosine in the brain, like HPLC, offer low limits of detection and are robust; however, subsecond detection is not possible. Here, we present a method for detecting rapid fluctuations of guanosine concentration in real-time using fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes. The optimized waveform scanned from -0.4 V to 1.3 V and back at a rate of 400 V s-1 and application frequency of 10 Hz. Potential limits were chosen to increase selectivity of guanosine over the structurally similar interferent adenosine. Two oxidation peaks were detected with the optimized waveform: the primary oxidation reaction occurred at 1.3 V and the secondary oxidation at 0.8 V. Guanosine detection was stable over time with a limit of detection of 30 +/- 10 nM, which permits its use to monitor low nanomolar fluctuations in the brain. To demonstrate the feasibility of the method for in-tissue detection, guanosine was exogenously applied and detected within live rat brain slices. This paper demonstrates the first characterization of guanosine using FSCV, and will be a valuable method for measuring signaling dynamics during guanosine neuromodulation and protection. PMID- 30484442 TI - Reactivity and energy level of a localized hole in liquid water. AB - We study the reactivity and the energy level associated with the reduction of the H2O+ radical cation in liquid water by combining ab initio molecular dynamics simulations at the hybrid functional level, a grand-canonical formulation of solutes in aqueous solution, and nudge-elastic-band calculations. We demonstrate that this extremely oxidative solute promptly dissociates and calculate an energy barrier for the reaction of 0.06 eV, consistent with the short measured lifetimes. We calculate the energy level related to the H2O+/H2O redox couple with respect to the vacuum level and to the computational standard hydrogen electrode (SHE), using the thermodynamic integration method. This energy level is found to lie at 3.8 +/- 0.1 eV above the SHE level, in remarkable agreement with a previous estimate based on thermodynamical data. The implications of the present results for the mechanism of water splitting at the heterogenous semiconductor-water interface are discussed. PMID- 30484443 TI - Ring-opening polymerization of trimethylene carbonate to poly(trimethylene carbonate) diol over a heterogeneous high-temperature calcined CeO2 catalyst. AB - CeO2 calcined at 1273 K showed higher activity per surface area than other metal oxides in the ring-opening polymerization of trimethylene carbonate under neat conditions without any additives, providing metal-free and additive-free poly(trimethylene carbonate) diols with no ether bonds with high selectivity. It was demonstrated that CeO2 was a robust and reusable heterogeneous catalyst. PMID- 30484444 TI - Paper-based SERS analysis with smartphones as Raman spectral analyzers. AB - SERS (Surface Enhanced Raman Spectroscopy) can realize fingerprint recognition of molecular samples with high detection accuracy and sensitivity. However, rapid and convenient measurement of the Raman spectra of analytes for a point-of-care test (POCT) has put forward a high demand for portable Raman spectrometers, as well as reliable SERS substrates. Hereby, we first utilize a smartphone as a miniaturized Raman spectral analyzer, which has the revolutionary advantages of a friendly human-machine interface, fast measurement time, and good sensitivity. Meanwhile, a paper-based SERS chip was prepared based on commonly used filter paper and silver nanoparticles (AgNP), which was successfully used to detect low concentrations of typical SERS analyte model molecules including rhodamine 6G and crystal violet. The current method of smartphone-based SERS spectroscopy as a POCT device will greatly promote the application of Raman technology in a variety of scenarios, such as safety inspections, pesticide residue detection, water pollution monitoring, and so on. Coupled with paper-based SERS chips with advantages of facile preparation, low cost and good reliability, the current work proves to have a great potential for industrial production and for meeting the vast marketing demand of Raman based POCT technology. PMID- 30484445 TI - Degradable vinyl copolymers through thiocarbonyl addition-ring-opening (TARO) polymerization. AB - The radical copolymerization of the thionolactone dibenzo[c,e]oxepane-5-thione with acrylates, acrylonitrile, and N,N-dimethylacrylamide afforded copolymers containing a controllable amount of backbone thioesters which could be selectively cleaved. The process is compatible with RAFT polymerization and promising for the development of advanced degradable polymers. PMID- 30484446 TI - Bi-directional alkyne tandem isomerization via Pd(0)/carboxylic acid joint catalysis: expedient access to 1,3-dienes. AB - An in situ formed palladium hydride catalyst enables the sequential dual isomerization of propargylamide derivatives to 1-amido-1,3-dienes with high chemo and regioselectivity. The reaction shows ample functional group tolerance, delivering a valuable class of products, including highly deuterated ones, from readily available reagents. The reaction occurs through a complex mechanism studied by DFT modelling. PMID- 30484448 TI - Potential application of 2D monolayer beta-GeSe as an anode material in Na/K ion batteries. AB - Sodium-ion batteries (NIBs) and potassium-ion batteries (KIBs) have attracted increasing attention due to the high cost and finite abundance of lithium. Here, by using first-principles calculations, monolayer beta-GeSe has been found to be a promising anode material with a capacity of 353.65 mA h g-1 for both NIBs and KIBs. Additionally, the diffusions of Na and K over the monolayer beta-GeSe are ultrafast with small energy barriers of 0.080/0.125 eV and 0.052/0.047 eV for the Ge/Se side, respectively, indicating excellent rate performance. Monolayer beta GeSe has low open circuit voltages of 0.219 V (vs. Na/Na+) and 0.030 V (vs. K/K+), which implies that the NIBs and KIBs could have high energy densities due to the high working voltages between the anode and cathode. Therefore, monolayer beta-GeSe as an anode material for NIBs and KIBs with excellent performance shows tremendous potential in the energy field. PMID- 30484447 TI - Mapping the ultrafast vibrational dynamics of all-trans and 13-cis retinal isomerization in Anabaena Sensory Rhodopsin. AB - Discrepancies in the isomerization dynamics and quantum yields of the trans and cis retinal protonated Schiff base is a well-known issue in the context of retinal photochemistry. Anabaena Sensory Rhodopsin (ASR) is a microbial retinal protein that comprises a retinal chromophore in two ground state (GS) conformations: all-trans, 15-anti (AT) and 13-cis, 15-syn (13C). In this study, we applied impulsive vibrational spectroscopic techniques (DFWM, pump-DFWM and pump-IVS) to ASR to shed more light on how the structural changes take place in the excited state within the same protein environment. Our findings point to distinct features in the ground state structural conformations as well as to drastically different evolutions in the excited state manifold. The ground state vibrational spectra show stronger Raman activity of the C14-H out-of-plane wag (at about 805 cm-1) for the 13C isomer than that for the AT isomer, which hints at a pre-distortion of 13C in the ground state. Evolution of the Raman frequency after interaction with the actinic pulse shows a blue-shift for the C[double bond, length as m-dash]C stretching and CH3 rocking mode for both isomers. For AT, however, the blue-shift is not instantaneous as observed for the 13C isomer, rather it takes more than 200 fs to reach the maximum frequency shift. This frequency blue-shift is rationalized by a decrease in the effective conjugation length during the isomerization reaction, which further confirms a slower formation of the twisted state for the AT isomer and corroborates the presence of a barrier in the excited state trajectory previously predicted by quantum chemical calculations. PMID- 30484449 TI - Reactive messengers for digital molecular communication with variable transmitter receiver distance. AB - Molecular communication exploits functional molecular systems travelling along fluid media to deliver messages encoded as concentration pulses, e.g. molecular bits. As the bits are naturally broadened by diffusion, limiting the distance along which information can be transferred, by careful design and optimization of the molecular messengers, is required. A new paradigm, exploiting the chemical reactivity of a suitable molecular messenger, has been developed to achieve long range information transfer with variable transmitter-receiver distances. The experimental results and theoretical simulations, carried out by using fluorescent molecules switched by pH-driven hydrolysis, are reported here. In particular, we simulated the information transport process by using numerical solutions of differential equations governing information swapping and we show that by exploiting the reactivity of the chemical messenger, a stable signal at the receiver is maintained within a wide range of distance. This theoretical prediction was fully experimentally verified by using a prototypal molecular communication platform. PMID- 30484450 TI - A genomic characterisation of monometallic nanoparticles. AB - Because size and shape can affect the chemo-physical properties of nanoparticles, we extend the use of geometrical descriptors to sequence a genome of monometallic nanoparticles. Selecting the generalised coordination number as a descriptor, the derived geometrical genome distinguishes, catalogues, and counts the variety of adsorption sites available on each isomer with a diameter up to 10 nm, therefore it depends on the nanoparticle size and shape. This procedure allows us to elucidate the effects of morphological diversity within a sample and those of thermally activated structural rearrangements among isomers on nanocatalyst activity. By screening the geometrical genome of archetypal shapes, we forecast Pt stellated twinned nanoparticles, elongated along their five-fold axis and with their shortest diameter of ~2 nm, as optimal candidates for the electro-reduction of molecular oxygen at room temperature, in agreement with available experimental data. PMID- 30484451 TI - Reversible hydrogen storage in pristine and Li decorated 2D boron hydride. AB - Motived by the recent experimental fabrication of two-dimensional boron hydride (BH) sheets (Nishino et al., J. Am. Chem. Soc. 2017, 139, 13761), we explore the feasibility of pristine and Li doped BH sheets as a hydrogen storage medium within the framework of density functional theory. BH shows an unexpected high affinity to Li with a binding energy of -2.38 eV in comparison to other alkali and alkaline earth metals (Na, K, Ca, Mg and Al), much larger than its bulk cohesive energy (-1.63 eV). Energy barriers of Li diffusion on BH are also determined to be around 1.12 eV, showing both high dynamic and thermodynamic stability without the issue of cluster formation. Moreover, Li decorated BH is expected to achieve a high theoretical gravimetric density of 11.57 wt% with an average H2 adsorption energy of -0.17 eV, holding great potential in massive hydrogen storage. In addition to the storage, thermodynamic analysis on the desorption behaviors of H2 molecules is performed via N-P-T diagram, which demonstrates that most of the H2 molecules (8.30 wt%) could be released at 3 atm/100 degrees C. Thus, the Li-decorated BH sheets are expected to be applied as an efficient medium for hydrogen storage under ambient conditions. PMID- 30484452 TI - Coupled double triplet state in singlet fission. AB - The highly unusual state, 1(TT), is a coupled, double triplet state that has recently garnered significant attention. This multiexcitonic state can be formed by a quantum transition from a single-photon bright state in a variety of organic semiconducting materials. 1(TT)'s transient nature and similarity to independent triplets, however, has led to significant difficulties in characterization and prediction of its properties. Recent progress describing 1(TT) from theory and experiment are breaking through these difficulties, and have greatly advanced our comprehension of this state. Starting from the early description of 1(TT) in polyenes, this perspective discusses formation mechanisms, spectroscopic signatures, and the scope of intertriplet interactions. When employing singlet fission to generate charge carriers in a solar cell, 1(TT) has a central role. Due to the variety of coupling strengths between triplet states in 1(TT) amongst different chromophores, two different strategies are discussed to enable efficient charge carrier extraction. Continued growth in our understanding of 1(TT) may lead to control over complex quantum states for intriguing applications beyond high-efficiency, organic solar cells. PMID- 30484455 TI - Health functions and structure-activity relationships of natural anthraquinones from plants. AB - Anthraquinone compounds with the anthraquinone ring structure are widely found in traditional Chinese medicines and they are attracting a lot of attention due to their good pharmacological activity. Diversities of anthraquinones depend on their chemical structures, such as the number of anthraquinone rings and the substituents; what's more, the difference in chemical structure determines the difference in physiological activity. Based on results of previous studies, this review summarizes several natural anthraquinones identified from Chinese herbal medicines and their physiological activities including anti-cancer, anti pathogenic microorganisms, anti-inflammatory, anti-oxidation, anti-osteoporosis, anti-depression, and anti-constipation. The source, effect, model, and action mechanism of the active anthraquinones are described in detail, from which their structure-activity relationship is summarized. By analyzing the relationship between anthraquinone structure and function, we found that, on the whole structure, the anthraquinone ring and anthraquinone glycosides have significant anticancer activity and anti-constipation activity, while for their substituents, anthraquinones substituted by alizarin have significant antioxidant activity and the polarity of the substituents is closely related to their antibacterial activities. PMID- 30484456 TI - Plasmonic hot carrier-driven oxygen evolution reaction on Au nanoparticles/TiO2 nanotube arrays. AB - The use of hot carriers generated from the decay of localized surface plasmon resonance in noble metal nanoparticles is a promising concept for photocatalysis. Here, we report the enhancement of photocatalytic activity by the flow of hot electrons on TiO2 nanotube arrays decorated with 5-30 nm Au nanoparticles as photoanodes for photoelectrochemical water splitting. This enhanced photocatalytic activity is correlated to the size of the Au nanoparticles, where higher oxygen evolution was observed on the smaller nanoparticles. Conductive atomic force microscopy and ultraviolet photoelectron spectroscopy were used to characterize the Schottky barrier between Au and TiO2, which reveals a reduction in the Schottky barrier with the smaller Au nanoparticles and produces an enhanced transfer of photoinduced hot carriers. This study confirms that the higher photocatalytic activity was indeed driven by the hot electron flux generated from the decay of localized surface plasmon resonance. PMID- 30484459 TI - A tetranuclear CuDy coordination cluster as a Suzuki (C-C) coupling reaction promoter. AB - The air-stable tetranuclear coordination cluster [CuII2DyIII2L4(NO3)2(CH3CN)2].2(CH3CN), which can be obtained in high yield, promotes the Suzuki coupling reaction of phenylboronic acid with substituted aryl halides under environmentally benign conditions. PMID- 30484460 TI - Synthesis of 2-substituted benzo[b]thiophenes via gold(i)-NHC-catalyzed cyclization of 2-alkynyl thioanisoles. AB - Benzo[b]thiophene heterocycles are important components of many important small molecule pharmaceuticals and drug candidates as well as organic semiconducting materials. Many methods have been developed for the construction of a benzo[b]thiophene core via cyclization reaction of alkynes. Although few catalytic reactions were disclosed, most methods rely on stoichiometric activation of alkynes. Here we report an efficient method for the synthesis of 2 substituted benzo[b]thiophenes from 2-alkynyl thioanisoles catalyzed by a gold(i) IPr hydroxide that is applicable to a wide range of substrates with diverse electronic and steric properties. Additionally, we demonstrate experimentally that the acid additive and its conjugate base are essential to catalyst turnover. PMID- 30484461 TI - Template-free synthesis of nanoparticle-built MgO and Zn-doped MgO hollow microspheres with superior performance for Congo red adsorption from water. AB - Nanoparticle-built MgO hollow microspheres were synthesized through a template free hydrothermal route using citrate as a structural director. Zn was introduced into MgO to improve the surface charge. Pure MgO and Zn-doped MgO samples were characterized by X-ray diffraction (XRD), energy-dispersive X-ray spectrometry (EDX), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and a zeta-potential analyzer. The as-prepared microspheres showed outstanding performance for the removal of Congo red (CR, anionic dye) from solutions. The maximum adsorption capacities of pure MgO and Zn-doped MgO samples were 3022.02 and 2953.39 mg g-1, respectively. The Zn-loaded sample only required 45 min to reach equilibrium, which was much shorter than that of pure MgO sample (120 min) and most previously reported adsorbents. The high adsorption capacity and efficiency for CR removal resulted from the samples' unique porous structures and positive surface charges at pH 7. The adsorption process followed Langmuir isotherm and pseudo-second-order model. Regeneration assessment was conducted by a method of calcining for four times, and the observed steady adsorption efficiency indicated a bright prospect for the two samples in wastewater treatment. PMID- 30484462 TI - Automated high-content phenotyping from the first larval stage till the onset of adulthood of the nematode Caenorhabditis elegans. AB - The nematode Caenorhabditis elegans is increasingly used as a model for human biology. However, in vivo culturing platforms for C. elegans allowing high content phenotyping during their life cycle in an automated fashion are lacking so far. Here, a multiplexed microfluidic platform for the rapid high-content phenotyping of populations of C. elegans down to single animal resolution is presented. Nematodes are (i) reversibly and regularly confined during their life inside tapered channels for imaging fluorescence signal expression and to measure their growth parameters, and (ii) allowed to freely move in microfluidic chambers, during which the swimming behavior was video-recorded. The obtained data sets are analyzed in an automated way and 19 phenotypic parameters are extracted. Our platform is employed for studying the effect of bacteria dilution, a form of dietary restriction (DR) in nematodes, on a worm model of Huntington's disease and demonstrates the influence of DR on disease regression. PMID- 30484463 TI - Curcumin-loaded nanoemulsion: a new safe and effective formulation to prevent tumor reincidence and metastasis. AB - Curcumin is widely considered beneficial to human health, but insolubility and instability greatly hamper reproducible exploitation of the advantageous traits. Here we report on the development, characterization and evaluation of a curcumin loaded nanoemulsion (CUR-NEM) that is highly effective in preventing post-surgery tumor reincidence and metastasis. The method of fabrication utilized safe excipients and generated particles of 200 nm (PDI <= 0.2) with negative zeta potential (-30 mV) and a high yield of curcumin (95%), which can be converted by lyophilization to a dry powder. In vitro assays showed that CUR-NEM is safe in non-cancerous human cells (HEK-293T) and preferentially cytotoxic in gastric (AGS), colon (HT29-ATCC, HT29-US), breast (MDA-MB-231) and melanoma (B16F10) cells. In addition, in melanoma cells the nanoformulation increases intracellular curcumin accumulation and reactive oxygen species (ROS) formation, while preventing cell-migration and invasion. In vivo studies in C57BL/6 mice demonstrated that a single dose, applied topically to the wounded area after surgical excision of primary tumors formed upon subcutaneous injection of syngeneic B16F10 cells, was sufficient to completely prevent reincident tumor growth and spontaneous lung metastasis, while in untreated animals 70% reincidence and metastasis were observed. In vivo experiments also showed that the fluorescence signal due to curcumin was maintained at least 15 days after topical application of CUR-NEM, while when administered in DMSO the curcumin signal disappeared within 4 days. Importantly, the administration of a dose 22 times larger than that applied topically to animals after tumor surgery did not alter biochemical parameters. Due to the safety and efficacy of the formulation, we envisage it as ideal for topical application in cancer patients following surgery, to prevent tumor reincidence and metastasis. In addition, other routes of administration/protocols could also be proposed to treat/prevent malignant tumors in patients. PMID- 30484464 TI - Magnetic on-off switching in redox non-innocent ligand bridged binuclear cobalt complexes. AB - The redox non-innocent ligand 2,2'-bipyrimidine (bpym) reacted with two molar equivalents of LCo(tol) (L = CH(MeC[double bond, length as m-dash]NAr)2, Ar = 2,6 iPr2C6H3) to afford the binuclear CoII complex (LCo)2(MU-bpym) (1), in which the bpym moiety accepts two electrons from the metal centers and in the dianion state. Complex 1 readily underwent one-electron oxidation when treated with [Cp2Fe]+[BPh4]- affording the cation salt [(LCo)2(MU-bpym)][BPh4] (2) with the bpym moiety in the radical anion state. Meanwhile, complex 2 could be converted back to 1 with elemental potassium. The magnetic studies revealed that complex 2 is a single molecular magnet (SMM) under a small external field, while 1 has no SMM activity. This represents a new example of a SMM exhibiting a fully reversible 'on/off' switching ability in anodic and neutral states. PMID- 30484465 TI - Double helical structure of the twist-bend nematic phase investigated by resonant X-ray scattering at the carbon and sulfur K-edges. AB - The mesogenic dimer displaying nematic and NTB phases was investigated by resonant X-ray scattering at both C and S absorption K-edges and supported by single X-ray crystallography. In the crystal resonant studies revealed the forbidden reflection in non-resonant diffraction similar to that found in the NTB phase. The lack of a second harmonic in both C and S resonant X-ray scattering supports the double helical structure of the twist-bend nematic phase. PMID- 30484467 TI - A supramolecular Cd(ii)-metallogel: an efficient semiconductive electronic device. AB - A sonication-based strategy for the synthesis of a functional supramolecular Cd(ii)-metallogel (CdA-OX) has been achieved through mixing cadmium(ii) acetate dihydrate and oxalic acid dihydrate, a low molecular weight gelator (LMWG), in N,N-dimethyl formamide solvent at room temperature under atmospheric pressure. The mechanical properties of the supramolecular Cd(ii)-metallogel were investigated through a rheological study. The pebble-like self-assembly hierarchical architecture of the supramolecular metallohydrogel was visualized through field emission scanning electron microscopy investigations. The electrical properties of the metallogel were thoroughly examined and indicate its semiconducting nature. Based on its conducting properties, the Cd(ii)-metallogel was successfully applied to a Schottky barrier diode. Overall, this work is a novel instance of technologically challenging electronic device application of a Cd(ii)-metallogel. PMID- 30484466 TI - Boosting reversible oxygen electrocatalysis with enhanced interfacial pyridinic-N Co bonding in cobalt oxide/mesoporous N-doped graphene hybrids. AB - A hybrid electrocatalyst CoO/r-NLG with a high density of pyridinic-N-Co bonds was synthesized via pyrolysis treatments of a mixture of cobalt iron precursors and laser-induced mesoporous N-doped graphene, which achieved superb reversible ORR/OER activities, offering a low efficiency loss (DeltaE) of 0.635 V in a 1.0 M KOH electrolyte. PMID- 30484468 TI - Close-packed polybutylcarbosilane dendrimers of higher generations. AB - Variation of generation number strongly affects the type of ordering found for polybutylcarbosilane dendrimers: G5 dendrimers are liquid-like, G6 are cubic liquid crystals and G7/G8 are disordered close-packed. It was revealed that G6 dendrimers are highly likely to form Im3[combining macron]m lattice structures with the parameter a = 5.15 nm, and a domain size that exceeds 100 nm. PMID- 30484469 TI - Remarkable pressure-induced emission enhancement based on intermolecular charge transfer in halogen bond-driven dual-component co-crystals. AB - A series of two-component co-crystals driven by IN interactions based on the bipyridine (BIPY) chromophore with one among three different co-former building blocks, iodopentafluorobenzene (IPFB), 1,4-diiodotetrafluorobenzene (DITFB) and 1,3,5-trifluoro-2,4,6-triiodobenzene (IFB), were prepared and analysed via infared spectroscopy and single-crystal X-ray diffraction. By comparing the IN distances in the co-crystal structures, we found that the higher the -F ratio in the building blocks the closer the contact of the IN bond, enhancing the intermolecular interactions in these co-crystals as well. That is, the positive electrostatic potential on the iodine atom(s) in the co-formers was enhanced by the presence of strong electron-withdrawing groups. The distinct spectroscopic behaviours (fluorescence and Raman spectra) among the two-component BIPY co crystal systems in response to hydrostatic pressure were also investigated. Interestingly, the fluorescence of BIPY-DITFB presented intriguing abnormal evolution from dark to bright, suggesting a new charge transfer state due to the decreased intermolecular distance and the enhanced IN interactions. Theoretical simulations by Materials Studio also showed the shortened IN distance and the increased angle of C-IN, evidencing the enhanced IN interactions. In contrast, BIPY-IFB showed only slightly enhanced fluorescence intensity at 550 nm consistent with BIPY-DITFB. Once the pressure was relieved, both the Raman and fluorescence spectra for BIPY co-crystal systems entirely self-recovered. Remarkable emission enhancement in a solid-state co-crystal has been rarely reported in previous publications and in fact, this study paves a unique way for designing and developing novel stimuli-responsive photo-functional materials. PMID- 30484470 TI - Nature and nurture: confluence of pathway determinism with metabolic and chemical serendipity diversifies Monascus azaphilone pigments. AB - Covering: up to June 2018Understanding the biosynthetic mechanisms that generate the astounding structural complexity and variety of fungal secondary metabolites (FSMs) remains a challenge. As an example, the biogenesis of the Monascus azaphilone pigments (MonAzPs) has remained obscure until recently despite the significant medical potential of these metabolites and their long history of widespread use as food colorants. However, a considerable progress has been made in recent years towards the elucidation of MonAzPs biosynthesis in various fungi. In this highlight, we correlate a unified biosynthetic pathway with the diverse structures of the 111 MonAzPs congeners reported until June 2018. We also discuss the origins of structural diversity amongst MonAzPs analogues and summarize new research directions towards exploring novel MonAzPs. The case of MonAzPs illuminates the various ways that FSMs metabolic complexity emerges by the interplay of biosynthetic pathway determinism with metabolic and chemical serendipity. PMID- 30484471 TI - Tunable 2D binary colloidal alloys for soft nanotemplating. AB - The realization of non-close-packed nanoscale patterns with multiple feature sizes and length scales via colloidal self-assembly is a highly challenging task. We demonstrate here the creation of a variety of tunable particle arrays by harnessing the sequential self-assembly and deposition of two differently sized microgel particles at the fluid-fluid interface. The two-step process is essential to achieve a library of 2D binary colloidal alloys, which are kinetically inaccessible by direct co-assembly. These versatile binary patterns can be exploited for a range of end-uses. Here we show that they can for instance be transferred to silicon substrates, where they act as masks for the metal assisted chemical etching of binary arrays of vertically aligned silicon nanowires (VA-SiNWs) with fine geometrical control. In particular, continuous binary gradients in both NW spacing and height can be achieved. Notably, these binary VA-SiNW platforms exhibit interesting anti-reflective properties in the visible range, in agreement with simulations. The proposed strategy can also be used for the precise placement of metallic nanoparticles in non-close-packed arrays. Sequential depositions of soft particles enable therefore the exploration of complex binary patterns, e.g. for the future development of substrates for biointerfaces, catalysis and controlled wetting. PMID- 30484473 TI - Systematic studies on the in vivo substance basis and the pharmacological mechanism of Acanthopanax Senticosus Harms leaves by UPLC-Q-TOF-MS coupled with a target-network method. AB - The leaves of Acanthopanax Senticosus Harms (ASL) can be used as a food ingredient and also as raw materials for making tea and wine. As a traditional Chinese medicine (TCM), ASL has demonstrated significant effects in the treatment of ischemic stroke, but the substance basis and the pharmacological mechanism of ASL are unclear. In this study, a sensitive and rapid method was constructed for the separation and identification of the absorbed prototype components and metabolites from ASL in rat plasma and brain using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q TOF-MS). A database of ASL active ingredients was established, which comprised 27 prototype ingredients and 20 metabolites from the rat plasma and 10 prototype ingredients and 7 metabolites from the rat brain. A comprehensive and effective target-network pharmacological method for tracing co-related targets and pathways between ASL and ischemic stroke was also set up. As a result, 34 targets and 30 pathways were obtained. TNF, NF-kappaB, IL-6, IL-1B, ICAM, and MMP-9 targets are all critical factors related to ischemic stroke, while the NF-kappaB signaling pathway, MAPK signaling pathway, TNF signaling pathway, and arachidonic acid metabolism play significant roles in the development of ischemic stroke. The visualized relationship between ASL and ischemic stroke was demonstrated by compound-target networks and compound-target-pathway networks, which revealed the therapeutic targets around the signaling pathways of ASL in the treatment of ischemic stroke. This research method will open a window for the mechanistic studies of TCM in the treatment of diseases. PMID- 30484474 TI - Correction: High pH promoting the synthesis of V-Silicalite-1 with high vanadium content in the framework and its catalytic performance in selective oxidation of styrene. AB - Correction for 'High pH promoting the synthesis of V-Silicalite-1 with high vanadium content in the framework and its catalytic performance in selective oxidation of styrene' by Jing Zhao et al., Dalton Trans., 2018, 47, 11375-11385. PMID- 30484475 TI - The National Health Surveillance Policy. PMID- 30484476 TI - Biochemical identification techniques and antibiotic susceptibility profile of lipolytic ambiental bacteria from effluents. AB - Different methodologies have been developed throughout the years to identify environmental microorganisms to improve bioremediation techniques, determine susceptibility profiles of bacteria in contaminated environments, and reduce the impact of microorganisms in ecosystems. Two methods of bacterial biochemical identification are compared and the susceptibility profile of bacteria, isolated from residential and industrial wastewater, is determined. Twenty-four bacteria were retrieved from the bacteria bank of the Environmental Microbiology Laboratory at the Institute of Biology (IB) of the Universidade Federal de Pelotas, Pelotas, Brazil. Bacteria were identified by conventional biochemical tests and by the VITEK (r)2 automated system. Further, the susceptibility profile to antibiotics was also determined by the automated system. Six species of bacteria (Raoutella planticola, K. pneumoniae ssp. pneumoniae , Serratia marcescens, Raoutella sp., E. cloacae and Klebsiella oxytoca) were identified by conventional biochemical tests, while three species of bacteria (K. pneumoniae ssp. pneumoniae, S. marcescens and K. oxytoca ) were identified by VITEK(r)2 automated system. VITEK (r)2 indicated agreement in 19 (79.17%) isolates and difference in five (20.83%) isolates when compared to results from conventional biochemical tests. Further, antibiotic susceptibility profile results showed that all isolates (100%) were resistant to at least one out of the 18 antibiotics tested by VITEK(r)2. Thus, no multi-resistant bacteria that may be used in effluent treatment systems or in bioremediation processes have been reported. Results indicate VITEK (r) 2 automated system as a potential methodology in the determination of susceptibility profile and identification of environmental bacteria. PMID- 30484477 TI - Trichospilus diatraeae (Hymenoptera: Eulophidae): development and reproduction in Lepidoptera palm oil pests. AB - Brazil is a leading palm oil producer, but the defoliating caterpillars Opsiphanes invirae Hubner Brassolis sophorae L. (Lepidoptera: Nymphalidae) can reduce the productivity of this crop. The aim of this study was to evaluate the development and reproduction of the parasitoid Trichospilus diatraeae Cherian & Margabandhu (Hymenoptera: Eulophidae) in pupae of these oil palm defoliators. Ten O. invirae or B. sophorae pupae with up to two days old were exposed each to 30 T. diatraeae females for 48 hours. Parasitism and emergence of the progeny of T. diatraeae were similar in pupae of both Lepidoptera defoliators. The life cycle of this parasitoid was shorter in O. invirae (21.50 +/- 0.42 days) pupae than with those of B. sophorae (27.60 +/- 1.80 days). The number of the progeny (669.00 +/- 89.62) and dead immature (217.13 +/- 58.18) of T. diatraeae were higher in B. sophorae pupae than in those of O. invirae with 447.83 +/- 51.52 and 13.50 +/- 5.23, respectively. The sex ratio and female and male longevity of T. diatraeae emerged from these hosts were similar. The reproductive traits, especially the number of individuals (offspring) of T. diatraeae were better with B. sophorae pupae than with those of O. invirae. PMID- 30484478 TI - Reproductive ecology of Otocinclus vittatus (Regan, 1904) in the Pantanal floodplain, upper Paraguay River basin. AB - We studied the reproductive biology of Otocinclus vittatus in the southern Pantanal, Brazil. A total of 1066 fishes were analyzed (490 males, 488 females and 88 individuals of undetermined sex), sampled with a rectangular sieve and a seine net from February/2009 to January/2011. Variations in the sex ratio, seasonality in reproduction, fecundity, and size at first maturity were estimated. No variations were detected in the total sex ratio for the study period as a whole; although ratio has varied over time. The gonadosomatic index varied according to the river level, but not according to water temperature and rainfall. The mean fecundity was estimated at 84.1 oocytes, with a positive correlation with standard length. The size at first maturity (L50) estimated was 18.7 mm for females and 20.1 mm for males. PMID- 30484479 TI - Cost-effectiveness analysis of natural birth and elective C-section in supplemental health. AB - OBJECTIVE: To conduct a cost-effectiveness analysis of natural childbirth and elective C-section for normal risk pregnant women. METHODS: The study was conducted from the perspective of supplemental health, a health subsystem that finances private obstetric care, represented in Brazil by health plan operators. The reference populations were normal risk pregnant women, who could undergo natural childbirth or elective C-section, subdivided into primiparous and multiparous women with previous uterine scar. A decision analysis model was constructed including choice of delivery types and health consequences for mother and newborn, from admission for delivery to maternity hospital discharge. Effectiveness measures were identified from the scientific literature, and cost data obtained by consultation with health professionals, health plan operators' pricing tables, and pricing reference publications of health resources. RESULTS: Natural childbirth was dominant compared with elective C-section for primiparous normal risk pregnant women, presenting lower cost (R$5,210.96 versus R$5,753.54) and better or equal effectiveness for all evaluated outcomes. For multiparous women with previous uterine scar, C-section presented lower cost (R$5,364.07) than natural childbirth (R$5,632.24), and better or equal effectiveness; therefore, C-section is more efficient for this population. CONCLUSIONS: It is necessary to control and audit C-sections without clinical indication, especially with regard to primiparous women, contributing to the management of perinatal care. PMID- 30484480 TI - Evidence-based decision making and promotion of physical activity among directors of local health departments. AB - OBJECTIVE: To describe the steps involved in evidence-based decision making for the implementation of programs aimed at the promotion of physical activity. METHODS: It is a descriptive, cross-sectional study with quali-quantitative approach, held with municipal health secretaries chosen deliberately by regional health representatives of the state of Parana. A total of 27 secretaries participated in a telephone interview consisting of 17 open questions. Content analysis was conducted according to the categories of an evidence-based decision making model consisting of seven steps. RESULTS: None of the participants employed every step of the evidence-based decision-making model. The steps that were most often mentioned included: evaluation of the program (33.3%), use of evidence from the literature (22.2%) and identification of the problem (22.2%). The steps that were reported the least included: quantification of the problem (14.8%), development and prioritization of actions (14.8%), development of the plan of action (14.8%) and evaluation of the community (3.7%). CONCLUSIONS: The use of evidence-based decision making in the context of the promotion of physical activity was shown to be incipient among the health secretaries of the state of Parana. We suggest widening dissemination and training on the use of evidence based decision making among municipal administrators to increase the effectiveness of actions for promotion of physical activity. PMID- 30484481 TI - Human visceral leishmaniasis and relationship with vector and canine control measures. AB - OBJECTIVE: Estimate the coverage of control measures of visceral leishmaniasis and relate them with the occurrence of human visceral leishmaniasis in endemic urban area. METHODS: Cases of human and canine visceral leishmaniasis were considered as study population and evaluated by a serological survey conducted in Aracatuba, state Sao Paulo, from 2007 to 2015. The cases of human visceral leishmaniasis were geocoded by the address of the patients and the canine disease by the address of the dogs' owners. The coverage of serological survey, euthanasia, and insecticide spraying was calculated, as well as the canine seroprevalence and the incidence rates of human visceral leishmaniasis. The relationship between human visceral leishmaniasis and control measures was evaluated, as well as the seroprevalence by comparing maps and by linear regression. The relationship between the canine and the human disease was also evaluated by the Ripley's K function. RESULTS: The incidence rates of human visceral leishmaniasis showed a period of decline (2007 to 2009) and a period of stability (2010 to 2015), a behavior similar to that of canine seroprevalence. In general, the coverage of control measures was low, and the non-association with the incidence of human visceral leishmaniasis can be a result of the period analyzed and of the small number of analyzed units (sectors of the Superintendence for the Control of Endemic Diseases). The distribution of human cases showed spatial dependence with the distribution of seropositive dogs from 2007 to 2009. CONCLUSIONS: This study reaffirmed the relationship between the occurrence of the disease in humans and dogs, it verified a decrease in the rates of visceral leishmaniasis in Aracatuba over time, even at low coverage of control activities. However, further studies are needed to determine if factors beyond monitoring and control measures are involved in the reduction of incidences. PMID- 30484483 TI - Implication of violence against women on not performing the cytopathologic test. AB - OBJECTIVE: To analyze the association between intimate partner violence and not performing the cytopathologic test in the last three years. METHODS: It is a transversal study, performed in 26 health units in the city of Vitoria, state Espirito Santo, from march to September 2014. The sample was constituted by 106 primary care female users, aging from 30 to 59 years-old. Data on cervical cancer screening were collected, besides the women's sociodemographic, behavior, obstetric, and gynecological characteristics by an interview, and the World Health Organization recommended tool for identifying violence experiences was applied. The analysis was performed through the chi-square test for association, linear trend for ordinal variables, and the Poisson regression analysis with robust variance. RESULTS: Among the participating women, 14% (95%CI 12.0-17.2) had overdue Pap tests. Most women who did not perform the test had lower schooling levels, lower income, were smokers, in an unmarried union, having had their sexual debut before 15 years-old, three or more pregnancies, and two or more partners in the last 12 months. Women who suffered intimate partner sexual and physical violence were, respectively, 1.64 (95%CI -1.03-2.62) and 1.94 (95%CI 1.28-2.93) times more delayed in the Pap tests than non-victims. CONCLUSIONS: Violence is a significant exacerbating factor and affects women's health negatively. Women who are physically or sexually victimized by their partners are more vulnerable to not performing Pap tests and, consequently, have fewer chances of early diagnosing cervical cancer. PMID- 30484482 TI - Cognitive screening test in primary care: cut points for low education. AB - OBJECTIVE: To establish the diagnostic accuracy of the Brazilian version of the General Practitioner Assessment of Cognition (GPCOG-Br) compared to the Mini Mental State Examination (MMSE) in individuals with low educational level. METHODS: Ninety-three patients (>= 60 years old) from Brazilian primary care units provided sociodemographic, cognitive, and functional data. Receiver operating characteristics, areas under the curve (AUC) and logistic regressions were conducted. RESULTS: Sixty-eight patients with 0-4 years of education. Cases (n = 44) were older (p = 0.006) and performed worse than controls (n = 49) on all cognitive or functional measures (p < 0.001). The GPCOG-Br demonstrated similar diagnostic accuracy to the MMSE (AUC = 0.90 and 0.91, respectively) and similar positive and negative predictive values (PPV/NPV, respectively: 0.79/0.86 for GPCOG-Br and 0.79/0.81 for MMSE). Adjusted cut-points displayed high sensitivity (all 86%) and satisfactory specificity (65%-80%). Lower educational level predicted lower cognitive performance. CONCLUSIONS: The GPCOG-Br is clinically well-suited for use in primary care. PMID- 30484484 TI - Obstetric practices in planned home births assisted in Brazil. AB - OBJECTIVE: To describe obstetric practices in planned home births, assisted by qualified professionals in Brazil. METHOD: This is a descriptive study, with data collected in an online bank maintained by 49 professionals from December 2014 to November 2015, in which the target population was women and newborns assisted in home births. Data were analyzed through descriptive statistics. RESULTS: A total of 667 women and 665 newborns were included. Most of the women gave birth at home (84.4%), in a nonlithotomic position (99.1%); none underwent episiotomy; 32.3% had intact perineum; and 37.8% had first-degree lacerations, some underwent amniotomy (5.4%), oxytocin administration (0.4%), and Kristeller's maneuver (0.2%); 80.8% of the women with a previous cesarean section had home birth. The rate of transfer of parturients was 15.6%, of puerperal women was 1.9%, and of neonates 1.6%. The rate of cesarean section in the parturients that started labor at home was 9.0%. CONCLUSION: The obstetric practices taken are consistent with the scientific evidence; however, unnecessary interventions are still performed. The rates of cesarean sections and maternal and neonatal transfers are low. Home can be a place of birth option for women seeking a physiological delivery. PMID- 30484485 TI - Self-care support for the management of type 1 diabetes during the transition from childhood to adolescence. AB - OBJECTIVE: To analyze the needs of pre-adolescents with type 1 diabetes regarding self-care support for disease management. METHOD: Qualitative study conducted between October and December 2016 with pre-adolescents seen at a hospital outpatient clinic and at Family Health Units; semi-structured interviews were used. Data were analyzed using a thematic analysis based on the theoretical basis of self-care support. RESULTS: Nine pre-adolescents participated in the study. It was identified that in order to build self-efficacy, pre-adolescents need to overcome the disease denial phase, know how to handle feelings triggered by the need for lifestyle changes, receive support from their families and social networks, and have the self-awareness and self-perception needed to feel secure in managing their diabetes. CONCLUSION: The intrinsic challenges of adolescence and the way pre-adolescents with diabetes handle the disease have an influence on diabetes management and create needs that must be appreciated by health care professionals in order to provide self-care support. PMID- 30484486 TI - Oral health of older people: tracking soft tissue injuries for the prevention of oral cancer. AB - OBJECTIVE: To detect oral soft tissue injuries in older people. METHOD: A quantitative analytical cross-sectional study conducted in Fortaleza, Ceara. Individual interviews addressed age, gender, marital status, income, and education. The community oral health indicator was used to detect oral soft tissue injuries and their location. RESULTS: Most of the 821 participants aged 60 100 years were women (580; 70.6%), attended school for up to 5 years (401; 48.8%), were illiterate (201; 24.5%), were retired (608; 74.1%), and received up to 2 wages (701; 85.4%). A total of 604 participants (73.6%) wore dentures. Injuries included red patches (152; 55.9%), blisters (58; 21.3%), lesions and/or wounds (39; 14.3%), and white patches (30; 11%). Locations of injuries were the roof of the mouth (167; 61.4%), gums (62; 22.8%), cheeks (39; 14.3%), tongue (15; 5.5%), lips (15; 5.5%), and the floor of the mouth (12; 4.4%). Injuries were associated with age (p<0.001), retirement (p=0.005), education (p=0.010), dentures (p<0.001) and red patches (p<0.001). CONCLUSION: Tracking soft tissue injuries and referring older adults with suspected malignant lesions to the health team should be included as oral cancer identification and prevention measures. Furthermore, health care providers should raise older adults' awareness of the importance of regular preventive examinations. PMID- 30484487 TI - Nursing diagnoses in the hemodynamics sector: an adaptive perspective. AB - OBJECTIVE: To identify nursing diagnoses of NANDA-I Taxonomy II in patients treated in the Hemodynamics Sector. METHOD: A descriptive, cross-sectional study with a quantitative approach conducted in a teaching hospital in the interior of Rio Grande do Sul. Data were collected through a sociodemographic characterization instrument and information regarding the problems of physical physiological adaptation. RESULTS: 100 patients participated in the study. Defining characteristics, risk factors and related factors were identified through adaptation problems. In all, 28 nursing diagnoses were identified, and 13 were considered for the discussion which presented frequency above 50% and represented the main adaptive problems. Protection, neurological and activity and rest components were the most frequent. CONCLUSION: The recognition of nursing diagnoses facilitates a connection between the main problems of adaptation and nursing interventions. PMID- 30484488 TI - Evaluation of non-attendance for Pap test through the Surveillance System by telephone survey. AB - OBJECTIVE: To estimate the prevalence of the Pap test and analyze the factors associated with its non-attendance by Brazilian women. METHOD: Cross-sectional, population-based study in which were used Vigitel (Surveillance System for Protective and Risk Factors for Chronic Diseases by Telephone Survey ) data and were included women in the target age range of the screening. The coverage and prevalence of non-screening were assessed according to sociodemographic, behavioral and health characteristics. RESULTS: Data from 22,580 women were included. About 17.1% of women did not take the Pap test in the three previous years. Women in the age groups of 35-44, 45-54 and 55-64 years showed a higher prevalence of having the test compared to those aged 25-34 years (p<0.05). The following factors were associated with the non-attendance: women with less than 12 years of study (p<0.05), who declared not having a partner (p<0.0001), residents of Northeast, Midwest and North regions (p<0.05), malnourished (p=0.017), who self-assessed their health as negative and presented at least one negative health behavior (p<0.0001). CONCLUSION: Despite the high coverage of this screening, it remains unsatisfactory in population subgroups, such as women living without a partner, with low educational level, malnourished, who self assessed their health status as negative, and with at least one negative health behavior. PMID- 30484489 TI - Analysis of the application values of different combination schemes of liquid based cytology and high-risk human papilloma virus test in the screening of high grade cervical lesions. AB - The aim of this study was to explore the value of different combination schemes of liquid-based cytology (LBC) and high-risk human papilloma virus (HPV) test in the screening of high-grade (>=CIN 2) cervical lesions. From 5727 women who had undergone examinations with LBC and high-risk HPV test, 1884 patients with positive results of either or both LBC and HPV test were included in this study and underwent cervical biopsy. Based on the pathological examination results, comparisons of the assessment indicators of all diagnostic tests were made, and the application values of LBC and high-risk HPV test and different combination schemes of the two in the screening of high-grade (>=CIN II) cervical lesions were estimated. Compared with the single test method, the sensitivity and negative predictive value of the combination scheme of LBC+HPV (with one positive result) were increased significantly (98.7% and 99.7%), but the specificity (60.8%) and accuracy rate (65.4%) dropped significantly (P<0.05). The sensitivity of LBC+HPV (with two positive results) was the lowest (80.7%), but the specificity and accuracy rate were the highest (83.5% and 83.1%, P<0.05). Z test showed that differences in the screening efficiency of four schemes were not statistically significant (P>0.05). Both LBC and HPV test were effective methods in the screening of high-grade cervical lesions; combination of the two tests did not improve the screening efficiency, but the scheme of LBC+HPV (with two positive results) significantly increased the sensitivity and negative predictive value, which was of better cost-benefit value. PMID- 30484490 TI - Glycoprotein nonmetastatic melanoma protein B accelerates tumorigenesis of cervical cancer in vitro by regulating the Wnt/beta-catenin pathway. AB - Cervical cancer is one of the most common cancers among women around the world. However, the underlying mechanism involved in cervical cancer progression is incompletely known. In the present study, we determined the role of glycoprotein nonmetastatic melanoma protein B (GPNMB) in tumorigenesis of cervical cancer. According to the GEO database, we found that GPNMB expression was significantly higher in cervical cancer than in normal cervix epithelium. A similar pattern was observed in GPNMB expression in cultured cervical cancer cells and normal cervical epithelial cells. Compared with the control, GPNMB knockdown significantly decreased the proliferation and migration capacity, but enhanced the apoptosis capacity of SiHa and HeLa cells. Additionally, the activity of MMP 2 and MMP-9 were aberrantly increased in SiHa and HeLa cells compared with normal cervical epithelial cells, whereas their activities were strongly inhibited by GPNMB siRNA. Furthermore, Wnt/beta-catenin signaling was activated by GPNMB in SiHa and HeLa cells. Increased MMP-2/MMP-9 expression was suppressed by Dkk-1, inhibitor of Wnt/beta-catenin signaling, while it was enhanced by stimulator BIO. The proliferation, migration, and apoptosis capacity of HeLa cells were found to be affected by Dkk-1 and BIO to different extents. In conclusion, we demonstrated that GPNMB contributed to the tumorigenesis of cervical cancer, at least in part, by regulating MMP-2/MMP-9 activity in tumor cells via activation of canonical Wnt/beta-catenin signaling. This might be a potential therapeutic target for treating human cervical cancer. PMID- 30484491 TI - HtrA1 suppresses the growth of pancreatic cancer cells by modulating Notch-1 expression. AB - Pancreatic cancer is well known to be the most deadly malignancy with the worst survival rate of all cancers. High temperature requirement factor A1 (HtrA1) plays an important role in cancer cell proliferation, migration, apoptosis, and differentiation. This study aimed to explore the function of HtrA1 in pancreatic cancer cell growth and its underlying mechanism. We found that the expression of HtrA1 was lower in pancreatic cancer tissue compared to the adjacent normal tissue. Consistently, HtrA1 levels were also decreased in two human pancreatic cancer cell lines, PANC-1 and BXPC-3. Moreover, enforced expression of HtrA1 inhibited cell viability and colony formation of PANC-1 and BXPC-3 cells. Overexpression of HtrA1 promoted apoptosis and suppressed migratory ability of tumor cells. On the contrary, siRNA-mediated knockdown of HtrA1 promoted the growth potential of pancreatic cancer cells. In addition, we found that up regulation of HtrA1 reduced the expression of Notch-1 in pancreatic cancer cells. On the contrary, knockdown of HtrA1 increased the expression levels of Notch-1. Furthermore, overexpression of Notch-1 abolished the anti-proliferative effect of HtrA1 on pancreatic cancer cells. Taken together, our findings demonstrated that HtrA1 could inhibit pancreatic cancer cell growth via regulating Notch-1 expression, which implied that HtrA1 might be developed as a novel molecular target for pancreatic cancer therapy. PMID- 30484492 TI - FGFR1 is an independent prognostic factor and can be regulated by miR-497 in gastric cancer progression. AB - Fibroblast growth factor receptor 1 (FGFR1) has been reported in gastric cancer to be a prognostic factor. However, miR-497-targeted FGFR1 has not been explored in the carcinogenesis of gastric cancer. The present study intended to revalidate the prognostic significance of FGFR1 in patients with gastric cancer, and the mechanism of miR-497-regulated FGFR1 was investigated in gastric cancer cell proliferation and apoptosis. The messenger RNA (mRNA) and protein levels were assayed by RT-qPCR and western blotting, respectively. The targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. Cell proliferation was analyzed by CCK-8 assay. Annexin V-FITC/PI staining was used to evaluate the apoptosis in AGS and SGC-7901 cells. FGFR1 was frequently up-regulated in gastric cancer tissues and associated with poor overall survival in patients with gastric cancer. Interestingly, FGFR1 loss-of function resulted in a significant growth inhibition and apoptosis in AGS and SGC 7901 cells. In addition, we found that miR-497 was inhibited in gastric cancer tissues and cell lines, while overexpression of miR-497 could suppress proliferation and induce apoptosis in AGS and SGC-7901 cells. Importantly, bioinformatics analysis and experimental data suggested that FGFR1 was a direct target of miR-497, which could inhibit FGFR1 expression when transfected with miR 497 mimics. Furthermore, we found that overexpression of FGFR1 reversed the growth inhibition and apoptosis of miR-497 mimics in AGS and SGC-7901 cells. These findings suggested that overexpression of miR-497 inhibited proliferation and induced apoptosis in gastric cancer through the suppression of FGFR1. PMID- 30484493 TI - Necroptosis occurs in osteoblasts during tumor necrosis factor-alpha stimulation and caspase-8 inhibition. AB - Necroptosis is a regulated cell death mechanism. However, it is unknown whether necroptosis is involved in the death of tumor necrosis factor-alpha (TNF-alpha) treated osteoblasts. Therefore, we conducted the study with TNF-alpha, Nec-1 (a specific inhibitor of necroptosis), and Z-IETD-FMK (a specific inhibitor of apoptosis) to determine whether necroptosis plays a role in the death of TNF alpha-treated osteoblast cell line MC3T3-E1. Cell viability, cell death, and lactate dehydrogenase (LDH) release were assayed to evaluate cytotoxicity. Specific marker proteins receptor interacting protein kinase (RIPK3) and phosphorylated mixed lineage kinase domain-like protein (p-MLKL) for necroptosis, and cleaved caspase 3 for apoptosis were detected by western blot, and mRNA was measured by quantitative real-time polymerase chain reaction (qRT-PCR). We found that TNF-alpha inhibited cell proliferation in a dose- and time-dependent manner. Nec-1 plus Z-IETD-FMK restored cell viability and significantly decreased LDH release. In addition, TNF-alpha alone increased the cell population of AV+PI-, while Z-IETD-FMK caused a shift in the cell population from AV+PI- to AV+PI+. Furthermore, TNF-alpha significantly increased protein cleaved caspase 3. TNF alpha plus Z-IETD-FMK significantly increased the proteins RIPK3 and MLKL phosphorylation in MC3T3-E1 cells, while the changes in mRNA levels of RIPK3, MLKL, and caspase 3 were not consistent with the changes in the corresponding protein expression levels. In conclusion, TNF-alpha induced preferentially apoptosis in osteoblast cell line and necroptosis played a decisive role when TNF alpha-induced death was inhibited by the inhibitor of apoptosis. Combined treatment with Nec-1 and Z-IETD-FMK protected mouse osteoblasts from death induced by TNF-alpha. PMID- 30484494 TI - YAP activation promotes the transdifferentiation of cardiac fibroblasts to myofibroblasts in matrix remodeling of dilated cardiomyopathy. AB - Yes-associated protein (YAP) is an important regulator of cellular proliferation and transdifferentiation. However, little is known about the mechanisms underlying myofibroblast transdifferentiation in dilated cardiomyopathy (DCM). We investigated the role of YAP in the pathological process of cardiac matrix remodeling. A classic model of DCM was established in BALB/c mice by immunization with porcine cardiac myosin. Cardiac fibroblasts were isolated from neonatal Sprague-Dawley rats by density gradient centrifugation. The expression levels of alpha-smooth muscle actin (alpha-SMA) and collagen volume fraction (CVF) were significantly increased in DCM mice. Angiotensin II (Ang II)-mediated YAP activation promoted the proliferation and transdifferentiation of neonatal rat cardiac fibroblasts, and this effect was significantly suppressed in the shRNA YAP + Ang II group compared with the shRNA Control + Ang II group in vitro (2.98+/-0.34 *105 vs 5.52+/-0.82 *105, P<0.01). Inhibition of endogenous Ang II stimulated YAP improved the cardiac function by targeting myofibroblast transdifferentiation to attenuate matrix remodeling in vivo. In the valsartan group, left ventricular ejection fraction and fractional shortening were significantly increased compared with the DCM group (52.72+/-5.51% vs 44.46+/ 3.01%, P<0.05; 34.84+/-3.85% vs 26.65+/-3.12%, P<0.01). Our study demonstrated that YAP was a regulator of cardiac myofibroblast differentiation, and regulation of YAP signaling pathway contributed to improve cardiac function of DCM mice, possibly in part by decreasing myofibroblast transdifferentiation to inhibit matrix remodeling. PMID- 30484495 TI - NOP14 inhibits melanoma proliferation and metastasis by regulating Wnt/beta catenin signaling pathway. AB - Malignant melanoma is an aggressive skin cancer with a high mortality rate. Nucleolar protein 14 (NOP14) has been implicated in cancer development. However, the role of NOP14 in malignant melanoma progression remains largely unclear. In this study, we observed that malignant melanoma tissue showed NOP14 down regulation compared to melanocytic nevi tissues. Moreover, we observed that NOP14 expression was significantly associated with melanoma tumor thickness and lymph node metastasis. NOP14 overexpression in melanoma cells suppressed proliferation, caused G1 phase arrest, promoted apoptosis, and inhibited melanoma cell migration and invasion. Further investigations revealed that NOP14 overexpression reduced the expression levels of Wnt3a, beta-catenin, and GSK-3beta of the Wnt/beta catenin pathway. In summary, we demonstrated that NOP14 inhibited melanoma cell proliferation and metastasis by regulating the Wnt/beta-catenin signaling pathway. PMID- 30484496 TI - Protective effects of Polygonatum sibiricum polysaccharide on acute heart failure in rats 1. AB - PURPOSE: To investigate the protective effects of Polygonatum sibiricum polysaccharide (PSP) on acute heart failure (AHF) in rats. METHODS: Sixty rats were randomly divided into control, model, and low-, middle- and high-dose PSP groups, 12 rats in each group. The low-, medium- and high-dose PSP groups were intragastrically administrated with 100, 200 and 400 mg/kg PSP for 5 days, respectively. On the sixth day, the AHF model was established by intraperitoneal injection of adriamycin. After 24h, the cardiac function, serum biochemical indexes, myocardial ATPase and succinate dehydrogenase levels and apoptosis related protein expressions were determined. RESULTS: Compared with model group, in high-dose PSP group the heart rate, left ventricular systolic pressure, +/ dp/dtmax, serum superoxide dismutase level, myocardial Na+-K+-ATPase, Ca2+-Mg2+ ATPase and succinate dehydrogenase levels and myocardial Bcl-2 and Caspase-3 protein expression levels were significantly increased (P<0.05), the left ventricular end diastolic pressure, serum cTnI, CK-MB, TNF-alpha, IL-6, malondialdehyde and nitric oxide levels and myocardial Bax and cleaved Caspase-3 protein expression levels were significantly decreased (P<0.05). CONCLUSIONS: Polysaccharide can prevent the acute heart failure induced by adriamycin. The mechanism may be related to its anti-oxidative stress, anti-inflammation and inhibition of cardiac myocyte apoptosis. PMID- 30484497 TI - Vascular and ventilatory mechanical responses in three different stages of pulmonary development in the rabbit model of congenital diaphragmatic hernia 1. AB - PURPOSE: To evaluate the vascular ventilatory response in different stages of lung development and to compare them to the neonates with congenital diaphragmatic hernia (CDH) in a rabbit model. METHODS: New Zealand rabbits were divided into 8 groups (n=5): E25, E27, E30, and CDH. All groups were ventilated on a FlexiVent (Scireq, Montreal, QC, Canada), compounding the other 4 groups. The CDH surgery was performed at E25 and the harvest at E30. Dynamic compliance (CRS), dynamic elastance (ERS) and dynamic resistance (RRS) were measured every 4 min/24 min. Median wall thickness (MWT) and airspace were measured. ANOVA Bonferroni tests were used to perform statistical analysis. Significance was considered when p<0.05. RESULTS: CRS was higher in E30 compared to all other groups (p<0.05). CRS and RRS of CDH and E27 were similar and were higher in E25 (p<0.05). MWT was decreased according to the gestational age, was increased in E27V and E30V (p<0.05) and decreased in CDHV (p<0.05), airspace was decreased in E25 and increased in all ventilated groups (p<0.05). CONCLUSIONS: The ventilation response of congenital diaphragmatic hernia is like the pseudoglandular stage of the lung development. These findings add information about the physiology of pulmonary ventilation in CDH. PMID- 30484498 TI - The role of the exogenous supply of adenosine triphosphate in the expression of Bax and Bcl2L1 genes in intestinal ischemia and reperfusion in rats 1. AB - PURPOSE: To investigate the role of the exogenous supply of adenosine triphosphate (ATP) in the expression of Bax and Bcl2L1 genes in intestinal ischemia and reperfusion (IR) in rats. METHODS: The study was designed as a randomized controlled trial with a blinded assessment of the outcome. Eighteen adult male Wistar-EPM1 rats were housed under controlled temperature and light conditions (22-23 degrees C, 12 h light/dark cycle). The animals were randomly divided into 3 groups: 1. Sham group (SG): no clamping of the superior mesenteric artery; 2. Ischemia and reperfusion group (IRG): 3. Ischemia and reperfusion plus ATP (IRG + ATP). ATP was injected in the femoral vein before and after ischemia. Afterwards, intestinal segments were appropriately removed and processed for Endothelial Cell Biology Rat RT2 Profiler PCR Array. RESULTS: ATP promoted the upregulation of Bcl2L1 gene expression, whereas it did not have significant effects on Bax gene expression. In addition, the relation of Bax/Bcl2L1 gene expression in the IRG group was 1.39, whereas it was 0.43 in the IRG + ATP group. Bcl2L1 plays a crucial role in protecting against intestinal apoptosis after ischemia and reperfusion. Increased Bcl2L1 expression can inhibit apoptosis while decreased Bcl2L1 expression can trigger apoptosis. CONCLUSION: Adenosine triphosphate was associated with antiapoptotic effects on the rat intestine ischemia and reperfusion by upregulating of Bcl2L1 gene expression. PMID- 30484499 TI - Apoptotic mechanisms in rabbits with blast-induced acute lung injury 1. AB - PURPOSE: To investigate the apoptotic mechanisms in rabbits with blast-induced acute lung injury (ALI). METHODS: A total of 40 rabbits were randomly divided into a blank control group (A, n=10) and an experimental group (EXP, n=30). Explosion-induced chest-ALI models were prepared and sampled at different time points (4, 12, and 24h after modeling, T1-T3) to test the lung dry weight/wet weight ratio (W/D) and arterial oxygen pressure (PaO2), apoptosis of lung tissue by the TUNEL assay, and Caspase-3, Bax, and Bcl-2 levels by immunohistochemical analysis. Furthermore, lung tissue was sampled to observe pathological morphology by microscopy. RESULTS: Under a light microscope, Group EXP exhibited obvious edema in the pulmonary interstitial substance and alveoli, a large number of red blood cells, inflammatory cells, and serous exudation in the alveolar cavity, as well as thickening of the pulmonary interstitial fluid. Compared to Group A, the W/D ratio was significantly increased in Group EXP (P<0.01), while PaO2 was significantly reduced (P<0.01). The apoptosis index was significantly increased (P<0.01), and caspase-3 and Bax/Bcl-2 levels were increased (P<0.01). CONCLUSION: Apoptosis plays an important role in the occurrence and development of acute lung injury in rabbits by participating in lung injury and promoting the progression of ALI. PMID- 30484500 TI - Stereological and morphological analysis of the effects of aging on spermatogenesis in rat testis 1. AB - PURPOSE: To quantify, through stereological and morphometric analysis, spermatogenesis in rats undergoing the natural aging process. METHODS: Seventy two male Wistar rats were divided into 6 equal groups according to age at the time of killing: 3, 6, 9, 12, 18, and 24 months. All the rats were subjected orchiectomy and collection of testicular parenchymal fragments for histological and morphometric analysis. The numerical density of spermatids was calculated using a stereological study, and morphometric analysis was conducted to measure the height of the germinal epithelium and the area of the seminiferous tubules. RESULTS: We found that the 18 and 24 months groups showed a significant reduction in the number of round spermatids. However, the height of the germinal epithelium was not significantly different between the groups. The area of seminiferous tubules was also significantly reduced in the elderly rats compared to that in the young ones. CONCLUSION: Aging of rats showed a significant reduction in the number of round spermatids and the area of the seminiferous tubules, more pronounced in the rats at 18 and 24 months of life. PMID- 30484501 TI - Rat models of high risk colorectal anastomoses 1. AB - PURPOSE: To evaluate the most frequent surgical techniques of high-risk colorectal anastomoses in rats. METHODS: Wistar rats were enrolled in three different models comprising inflammatory (TNBS enema), vascular (portal vein occlusion) or obstructive (a non-ischemic constricting ring) mechanisms associated with colonic anastomosis that had accomplished after these former lesions. Histological analyses (Hematoxylin and eosin and Picrosirius red) were performed. RESULTS: All anastomoses techniques were associated with risk factors and had complications, mainly anastomotic leakage. In Study 1, the use of a pharmacological agent, trinitrobenzene sulfonic acid (TNBS) mimicked an inflammatory bowel disease such as Crohn's disease with 50% of anastomosis leakage, the higher percentage among all models tested. In Study 2, after portal ischemia followed by reperfusion it was observed a dense neutrophil infiltrate in the midst of necrotic tissue and fibrin at the anastomotic site and 5 days after the anastomosis, no collagen was produced. In Study 3, 5 days after the mechanical obstruction some denuded areas of epithelium with marked oedema of mucosa and submucosa were seen, at the anastomotic site and anastomosis group showed some reduction of collagen density when compared with Control/Sham group. CONCLUSION: All the experimental surgical techniques tested in rats were associated with high-risk colorectal anastomoses and were useful to study colonic anastomotic healing and intestinal leakage. PMID- 30484502 TI - Topical hepatic hypothermia associated with ischemic preconditioning. Histopathological and biochemical analysis of ischemia reperfusion damage in a 24 hour model 1. AB - PURPOSE: To develop a new 24 hour extended liver ischemia and reperfusion (LIR) model analyzing the late biochemical and histopathological results of the isolated and combined application of recognized hepatoprotective mechanisms. In addition, we used a new stratification with zoning to classify the histological lesion. METHODS: A modified animal model of severe hepatic damage produced through 90 minutes of segmental ischemia (70% of the organ) and posterior observation for 24 hours of reperfusion, submitted to ischemic preconditioning (IPC) and topical hypothermia (TH) at 26oC, in isolation or in combination, during the procedure. Data from intraoperative biometric parameters, besides of late biochemical markers and histopathological findings, both at 24 hours evolution time, were compared with control (C) and normothermic ischemia (NI) groups. RESULTS: All groups were homogeneous with respect to intraoperative physiological parameters. There were no losses once the model was stablished. Animals subjected to NI and IPC had worse biochemical (gamma-glutamyl transpeptidase, alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, direct bilirubin, and total bilirubin) and histopathological scores (modified Suzuki score) compared to those of control groups and groups with isolated or associated TH (p < 0.05). CONCLUSION: The new extended model demonstrates liver ischemia and reperfusion at 24 hour of evolution and, in this extreme scenario, only the groups subjected to topical hypothermia, combined with ischemic preconditioning or alone, had better outcomes than those subjected to only ischemic preconditioning and normothermic ischemia, reaching similar biochemical and histopathological scores to those of the control group. PMID- 30484503 TI - Analysis of BMSCs-intervened viscoelasticity of sciatic nerve in rats with chronic alcoholic intoxication 1. AB - PURPOSE: To investigate the impact of bone mesenchymal stem cells (BMSCs) intervention on the viscoelasticity of sciatic nerve in rats with chronic alcohol intoxication (CAI). METHODS: The CAI rat models were prepared, divided into model groups, and treated with either BMSCs or basic fibroblast growth factor (bFGF). Then the rats underwent electrophysiological test and the serum levels of malondialdehyde (MDA), superoxide dismutase (SOD), and metallothionein (MT) were measured. Histological observation, stress relaxation test, and creep test were performed for the sciatic nerve of the CAI model in each group. RESULTS: The MDA level of group BMSC was significantly lower (p<0.05) than that of groups MOD (the CIA model) and bFGF. The SOD and MT levels were higher in group BMSC than in groups MOD and bFGF (p<0.05). The motor nerve conduction velocity and amplitude were higher in group BMSC than in groups MOD and bFGF (p<0.05). The amounts of 7200s stress reduction and 7200 s strain increase of the sciatic nerve in group BMSC were greater than those in groups bFGF and MOD (p<0.05). CONCLUSION: Bone mesenchymal stem cells can improve the metabolism of free radicals, restore the tissue morphology and viscoelasticity of the chronic alcohol intoxication animal model, and positively affect the repairing of the injured sciatic nerve. PMID- 30484504 TI - Structural Heart Interventional Imagers - The New Face of Cardiac Imaging. PMID- 30484505 TI - Gender Disparities and Outcomes Of Acute Coronary Syndromes In Brazil. PMID- 30484506 TI - Nonfunctioning Adrenal Incidentalomas: The Search for Subclinical Cardiac Alterations. PMID- 30484507 TI - Mortality for Critical Congenital Heart Diseases and Associated Risk Factors in Newborns. A Cohort Study. PMID- 30484508 TI - Anxiety and Depression after Myocardial Infarction: Can Inflammatory Factors be Involved? PMID- 30484509 TI - Reintervention in Artificial Cardiac Pacing Systems. PMID- 30484510 TI - High Intensity Exercises in Heart Failure with Preserved Ejection Fraction. PMID- 30484511 TI - Can We Consider PR Interval to Screen Patients for Cardiac Resynchronization Therapy? PMID- 30484512 TI - Cardiovascular Aggression by Doxorubicin: The Search for Mechanisms. PMID- 30484513 TI - Real World of Percutaneous Coronary Interventions in the Public Health System in Rio de Janeiro: How Can It Be Improved? PMID- 30484514 TI - Is it Possible to Easily Identify Metabolically Healthy Obese Women? AB - BACKGROUND: Obesity is recognized as a major risk factor for the development of several metabolic complications. However, some obese individuals have a favorable metabolic profile. OBJECTIVE: The aim of this study was to identify an easy parameter for recognizing metabolically healthy obese (MHO) women. METHODS: A total of 292 non-diabetic women with a body mass index (BMI) >= 30 kg/m2 were selected, and 239 composed the final cohort. We classified the participants according to their metabolic state determined by homeostasis model assessment (HOMA) into MHO or metabolically unhealthy obese (MUO). Both groups were compared regarding biochemical, anthropometric, and body composition characteristics. RESULTS: The average age of the cohort was 43.9 +/- 10.9 years and the average BMI was 37.2 +/- 5.3 kg/m2. In total, 75.7% of the participants were classified as MHO by HOMA. A cutoff of 108.2 cm for waist circumference (WC) identified MHO participants with a sensitivity of 72.4% (95% confidence interval [CI]: 59.8 82.3%), specificity of 66.9% (95% CI: 59.71-73.3%), and negative likelihood ratio of 0.41 (95% CI: 0.36-0.47). Additionally, a visceral adiposity index cutoff value of 99.2 identified MHO women with a sensitivity of 89.7% (95% CI: 79.2 95.2%), specificity of 48.6% (95% CI: 41.4-55.9%), and negative likelihood ratio of 0.21 (95% CI: 0.15-0.30). CONCLUSION: Women classified as MHO exhibited smaller WC measurements and lower body fat percentages, as well as lower blood glucose and insulin levels. WC emerged as an easy parameter for identifying MHO women. PMID- 30484516 TI - Flexibilization of Fasting for Laboratory Determination of the Lipid Profile in Brazil: Science or Convenience? PMID- 30484517 TI - Counterpoint: Flexibilization of Fasting for Laboratory Determination of the Lipid Profile in Brazil: Science or Convenience? PMID- 30484515 TI - Role of miRNAs on the Pathophysiology of Cardiovascular Diseases. AB - MiRNA (or microRNA) is a subclass of non-coding RNAs that is responsible for post transcriptional gene regulation. It has approximately 22 nucleotides and regulates gene expression in plants and animals at the post-transcriptional level, by the cleavage of a target mRNA or by suppression of its translation. Although many of the processes and mechanisms have not yet been fully elucidated, there is a strong association between miRNA expression and several diseases. It is known that miRNAs are expressed in the cardiovascular system, but their role in cardiovascular diseases (CVDs) has not been clearly established. In this non systematic review of the literature, we first present the definition of miRNAs and their action at the cellular level. Afterward, we discuss the role of miRNAs as circulating biomarkers of CVDs, and then their role in cardiac remodeling and atherosclerosis. Despite the complexity and challenges, it is crucial to identify deregulated miRNAs in CVDs, as it allows a better understanding of underlying cellular and molecular mechanisms and helps in the development of more accurate diagnostic and prognostic circulating biomarkers, and new therapeutic strategies for different stages of CVDs. PMID- 30484518 TI - Case 6 / 2018 - Percutaneous Occlusion of a Large Ductus Arteriosus in a Low Weight Infant, with Immediate Clinical and Radiographic Improvement. PMID- 30484519 TI - Rare Presentation of Dercum's Disease in a Child with Abnormalities in Lipoprotein Metabolism. PMID- 30484520 TI - How Echocardiographic Deformation Indices Can Distinguish Different Types of Left Ventricular Hypertrophy. PMID- 30484521 TI - Epstein-Barr virus and skin. AB - Epstein-Barr virus is a DNA virus infecting human beings and could affect 90% of human population. It is crucial to take in account that in Latin America, unlike what happens in developed countries, the exposure to the virus is very early and therefore people have a much longer interaction with the virus. The virus is related to many diseases, mainly the oncological ones, and when the onset is in cutaneous tissue, it can present many clinical variants, as well acute as chronic ones. Among the acute ones are infectious mononucleosis rash and Lipschutz ulcers; the chronic presentations are hypersensivity to mosquito bites, hydroa vacciniforme, hydroa vacciniforme-like lymphoma, its atypical variants and finally nasal and extra-nasal NK/T-cell lymphoma. Although they are not frequent conditions, it is crucial for the dermatologist to know them in order to achieve a correct diagnosis. PMID- 30484523 TI - Assessment of patch test results carried out during ten years in a city in southern Brazil. AB - BACKGROUND: Contact dermatitis affects up to 20% of the population. Patch testing for contact allergy may be needed to confirm the diagnosis. OBJECTIVES: To describe and discuss the results of patch tests performed in a city in southern Brazil. METHODS: A cross-sectional analysis was performed on all skin test results over ten years. Variables such as gender, age at the time of testing, and test results were evaluated. Triggering factors, duration of complain, and previous medications used related to the clinical history were retrieved for some patients by reviewing their medical records. RESULTS: The sample was composed of 539 patch tests, of which 411 (76.2%) were from women. The age of the tested subjects ranged from 5 to 87 years. The prevalence of positive reactions in the patch tests was 391 (72.5%). The most prevalent positive reaction was to nickel sulfate (196; 36.4%), which had statistical significance when associated with female gender (p<0,001). STUDY LIMITATIONS: Database obtained through secondary sources (the reports of the exams and the medical records), occurring the incomplete registration of some information. CONCLUSIONS: Data analysis at the local level is important to define preventive policies. PMID- 30484522 TI - Evaluation of the occurrence of sexual dysfunction and general quality of life in female patients with psoriasis. AB - BACKGROUND: Psoriasis has a significant impact on quality of life (QoL). Sexual life can also be affected, with sexual dysfunction being reported by 25-70% of patients. OBJECTIVES: To determine the occurrence of sexual dysfunction and evaluate QoL in women with psoriasis. METHODS: This case-control study included women aged 18-69 years. The validated Brazilian Portuguese versions of the Female Sexual Function Index (FSFI) and of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) were administered to all participants to assess sexual function and QoL, respectively. Patients with psoriasis underwent clinical evaluation for the presence of comorbidities, especially psoriatic arthritis and other rheumatic manifestations. Location of lesions and the extent of skin involvement were also assessed. RESULTS: The sample consisted of 150 women, 75 with diagnosis of psoriasis and 75 healthy controls. Prevalence of sexual dysfunction was high in women with psoriasis (58.6% of the sample). Prevalence was statistically higher in women with psoriasis than in controls (P = 0.014). The SF-36 domain scores were also lower in women with psoriasis, with role limitations due to physical health, limitations due to emotional problems, and mental health being the most affected domains. STUDY LIMITATIONS: Sample size was calculated to evaluate the association between the occurrence of sexual dysfunction and psoriasis, but it did not include the determination of the possible causes of this dysfunction. CONCLUSIONS: QoL and sexual function were altered in women with psoriasis and should be taken into consideration when assessing disease severity. PMID- 30484524 TI - Translation and validation of the Simplified Psoriasis Index (SPI) into Brazilian Portuguese. AB - BACKGROUND: The Simplified Psoriasis Index is a tool that assesses the current severity, psychosocial impact, past history and interventions in patients with psoriasis through separate components. Two versions are available, one in which the current severity of the disease is evaluated by the patient themselves and another by the physician. OBJECTIVES: Translate the Simplified Psoriasis Index into Brazilian Portuguese and verify its validity. METHODS: The study was conducted in two stages; the first stage was the translation of the instrument; the second stage was the instrument's validation. RESULTS: We evaluated 62 patients from Complexo Hospitalar Santa Casa de Porto Alegre and Hospital Universitario de Brasilia. The Simplified Psoriasis Index translated into Portuguese showed high internal consistency (Cronbach test 0.68). STUDY LIMITATIONS: Some individuals, because of poor education, might not understand some questions of the Simplified Psoriasis Index. CONCLUSIONS: The Brazilian Portuguese version of the Simplified Psoriasis Index was validated for our population and can be recommended as a reliable instrument to assess the patients with psoriasis. PMID- 30484525 TI - Impact of psoriasis in the quality of life of children, adolescents and their families: a cross-sectional study. AB - BACKGROUND: Psoriasis is a chronic and inflammatory disease that impairs quality of life and causes psychological symptoms. Despite the high prevalence of psoriasis in pediatric patients, studies investigating the impact of psoriasis in the quality of life of children, adolescents and families are sparse. OBJECTIVE: To investigate the impact of psoriasis in the quality of life of children and adolescents with psoriasis and their families and to determine depression and anxiety levels of the patients. METHODS: A total of 58 patients with psoriasis aged 7-18 years (median age: 11) and a family member of each patient were included in the study. Children's Dermatology Life Quality Index (CDLQI), Family Dermatology Life Quality Index (FDLQI), Children's Depression Inventory (CDI) and State-Trait Anxiety Inventory for Children (STAIC) were used in the study. RESULTS: The median PASI score of the patients included in the study was 1.8. The median CDLQI and FDLQI scores in the study groups were 5 and 10, respectively. The median CDI score, STAIC-state and STAIC-trait scores of the patients were 6, 28 and 32.5, respectively. STUDY LIMITATIONS: Lack of a control group and patient assessment of disease severity. Relatively mild disease severity of the subjects. CONCLUSIONS: Psoriasis has a negative impact in the quality of life of children, adolescents and their families, even in the presence of mild disease. Considering that impairment in quality of life may be associated with psychosocial morbidity, a combined approach with medical therapy, family counseling and quality of life assessment may be beneficial in this patient group. PMID- 30484526 TI - Leprosy: clinical and epidemiological study in patients above 60 years in Espirito Santo State - Brazil. AB - BACKGROUND: Leprosy is a chronic infectious disease that is endemic in Brazil and little studied in patients over 60 years old. OBJECTIVE: The aim of this study was the epidemiological and clinical description of cases of leprosy in individuals older than 60 years, notified in the State of Espirito Santo - Brazil. METHODS: It was an observational, descriptive and retrospective study of leprosy patients notified between 2001 and 2011. RESULTS: Out of 16,025 notifications, 2,510 (15.6%) were of patients over 60 years of age; the distribution among the period was egalitarian except in the last 2 years, when there was a mild reduction of cases; the average was 70 years of age (+/-7 years); 46% were women, being 62% of those paucibacillary cases; 1,145 (50.5%) were dark-skined people in particular among paucibacillary cases; 1,638 (72.9%) were illiterates or poorly instructed n particular among multibacillary cases (P=0.022); 59.9% patients were clinically multibacillary cases and 37.4% had positive bacilloscopy; 37.9% patients had clinical alterations on peripheral nerves, 36.7% of all the multibacillary cases were classified as grade I and 15.3% as grade in assessment of disability. STUDY LIMITATIONS: This was a retrospective study, which used secondary data generated by physicians and notified by other professionals, whar could have enabled possible errors on original data. CONCLUSIONS: Leprosy in this age group suggests a long incubation period with reactivation of latent focus or late infection. Men were more affected, as well as the afro descendent race was statistically significant in the paucibacillary cases (P=0.000) and illiterate/poor education in multibacillary cases (P=0.022). Nearly 40% of patients had positive bacilloscopy and grade I/II disability, demonstrating a late diagnosis. PMID- 30484527 TI - Evaluation of the profile of inflammatory cytokines, through immunohistochemistry, in the skin of patients with allergic contact dermatitis to nickel in the acute and chronic phases. AB - BACKGROUND: Allergic contact dermatitis to ion nickel (Ni+2) is an inflammatory dermatosis, common in industrialized countries. It involves the activation of nickel-specific T-cells, followed by proliferation and induction of a mixed profile of both proinflammatory and regulatory cytokines, suggesting that several T-cell subtypes (helper - Th and cytotoxic - Tc) are involved. A broader understanding of the cytokine profile may lead to new therapeutic approaches. OBJECTIVES: This study aimed to analyze the cytokines TNF-alpha, INF-gamma, IL-2, IL-4, IL-10, IL-13, IL-17 and IL-23 using the immunohistochemistry technique in order to try to identify their prevalence in chronic and acute eczema of patients with allergic contact dermatitis to Ni+2. METHODS: We performed an immunohistochemical study for eight cytokines in 20 patients with Ni+2 allergic contact dermatitis, biopsied at the site of chronic eczema, triggered by the patient's daily contact with Ni+2, and at the site of acute eczema caused by nickel sulfate, 48 hours after applying the contact test. RESULTS: The stained samples showed positive results for the eight cytokines studied. TNF-alpha, IFN gamma, IL-4, IL-13 and IL-17 had a higher prevalence in chronic eczema, IL-2 and IL-23 in acute eczema, and IL-10 presented a similar prevalence in both acute and chronic eczema. However, these prevalences were statistically significant only for IL-4 and IL-13. STUDY LIMITATIONS: Small sample size. CONCLUSIONS: In chronic and acute eczema, we observed the presence of a mixed cytokine profile of the T cell subtypes (Th/Tc), suggesting that the responses are expressed at the same time. PMID- 30484528 TI - Rosacea-specific quality of life questionnaire: translation, cultural adaptation and validation for Brazilian Portuguese. AB - BACKGROUND: Brazil does not have a rosacea-specific quality of life questionnaire. OBJECTIVES: translation into Brazilian Portuguese, development of cultural adaptation, and validation of the RosaQoL disease-specific questionnaire for rosacea of any subtype. METHODS: the recommended procedures for translation, cultural adaptation, and validation of an instrument were followed, and three interviews were conducted: baseline; seven to fourteen days after baseline; and at four to six months. The questionnaire was analyzed (with 95% confidence interval) for reliability by internal consistency (Cronbach's alpha); testretest reproducibility (intraclass correlation coefficient); responsiveness and validity. RESULTS: terms of the original questionnaire were replaced to guarantee cultural and semantic equivalence. Validity was demonstrated by expressive correlations between the RosaQoL domains and by significance in the Jonckheere Terpstra test (p<=0.05) between the scores of the RosaQoL domains and the participants' self-perception in relation to the disease. Reliability was acceptable; alpha coefficient ranged from 0.923 to 0.916 in the first and second applications of the RosaQoL, respectively, and the Intraclass Correlation Coefficient (ICC) ranged from 0.671 to 0.863 in the seven- to fourteen-day period. Responsiveness, measured by grouping participants into three categories based on self-perception of rosacea (better, worse or unchanged), was found for the "better" response group (p<=0.05). STUDY LIMITATIONS: small sample; limited variety of screening sources. CONCLUSIONS: RosaQoL-BR (Brazil) was demonstrated as a reliable, valid and responsive questionnaire, with limitations, for individuals with any subtype of rosacea. PMID- 30484529 TI - Evaluation of skin expression profiles of patients with vitiligo treated with narrow-band UVB therapy by targeted RNA-seq. AB - BACKGROUND: Vitiligo is characterized by a lack of pigmentation in the skin. To date, there are no studies that analyze the changes in gene expression in the skin of vitiligo patients in response to narrow-band ultraviolet B (nb-UVB) phototherapy treatment. OBJECTIVE: Explore the usefulness of new generation RNA sequencing in the identification of gene expression changes in the skin of vitiligo patients treated with nb-UVB phototherapy. METHODS: Four skin biopsies (4mm in diameter) were collected from 45 Mexican vitiligo vulgaris patients, 2 specimens before and 2 after treatment with nb-UVB phototherapy, obtained from pigmented and non-pigmented tissue. RNA extracted from the biopsies was analyzed using the Illumina TruSeq Targeted RNA Expression protocol to study the expression of genes that participate in pathways of skin homeostasis. The 2 groups were compared using Student's t-test and the Mann-Whitney U-test. RESULTS: The expression analysis identified differences in 12 genes included in this study after comparing the samples obtained before and after treatment: 5 genes involved in skin pigmentation, 2 genes involved in apoptosis, 2 genes involved in cell survival, 2 genes involved in oxidative stress responses and 1 gene involved in signal transduction mechanisms (p<0.05). STUDY LIMITATIONS: The small size of skin biopsies limits the amount of RNA obtained, the number of genes to be analyzed and the use of conventional techniques such as RT-qPCR. CONCLUSION: We demonstrated usefulness of new generation RNA sequencing in the identification of gene expression changes, in addition to identifying new targets in the study of vitiligo. PMID- 30484530 TI - Descriptive dermoscopy terminology in Portuguese language in Brazil: a reproducibility analysis of the 3rd consensus of the International Dermoscopy Society. AB - BACKGROUND: Dermoscopy is a noninvasive complementary diagnostic method largely used in dermatology. Feasibility, accuracy, and reproducibility are key elements for a diagnostic method to be useful, hence the importance of the terminology used to describe dermoscopic criteria. OBJECTIVE: To evaluate the reproducibility of the English descriptive terminology proposed for dermoscopic criteria at the 3rd Consensus Meeting of the International Dermoscopy Society in Brazilian Portuguese. METHODS: Nine Brazilian dermatologists independently analyzed the translation of sixty dermoscopic descriptive terms proposed at the 3rd Consensus Conference of the International Society of Dermoscopy. Interobserver agreement index was analyzed using the Fleiss' kappa test. RESULTS: The interobserver agreement of the descriptive terminology in Brazilian Portuguese was considered weak (kappa = 0.373;p < 0.05). The interobserver agreement of the descriptive terminology used to describe morphology and arrangement of vascular structures was considered moderate (kappa = 0.43; p < 0.05). STUDY LIMITATIONS: Our study limitations include the small number of participants and limited regional representation (only 2 out of 5 Brazilian regions were represented). CONCLUSIONS: The descriptive English terminology proposed at the 3rd Consensus Conference of the International Dermoscopy Society revealed weak reproducibility and the morphology and arrangement of vascular structures presented moderate reproducibility in Brazilian Portuguese. Despite small regional differences, metaphoric terminology in dermoscopy seems to be the most useful and reproducible system to be adopted in Brazilian Portuguese. PMID- 30484532 TI - Cutaneous T-cell lymphomas in the revised 4th edition of World Health Organization classification of tumors of hematopoietic and lymphoid tissues (2017). AB - Recently, the World Health Organization published the revised 4th edition of its classification of tumors of hematopoietic and lymphoid tissues. The present paper is a concise comparative review of the main primary cutaneous T-cell hematopoietic tumors, with emphasis on their immunohistochemical profiles. PMID- 30484531 TI - Fundamental aspects of the local approach to cutaneous ulcers. AB - Ulcers or wounds can be classified as acute or chronic. Their treatment involves overall assessment of the patient and choice of suitable local therapy, and the appropriate indication and use of products. Technological progress in the field of wound treatment has increased rapidly. Constant updating, with emphasis on available scientific evidence, is necessary to offer the best approaches to patients with acute and chronic wounds. A qualitative analysis of literature was conducted to identify scientific publications that update the concepts involved in local wound treatment, to present some resources that can aid the healing process and describe the different types of dressings available. This review includes wound assessment using the acronym TIME (tissue, infection/inflammation, moisture balance and edge of wound), cleaning and debridement, infection/inflammation control, exudate control, dressing types and main indications. PMID- 30484534 TI - Granuloma annulare on the palms in an elderly patient. AB - Granuloma annulare is a relatively common, idiopathic, benign inflammatory dermatosis, with a varied clinical presentation that often makes diagnosis difficult. It mainly affects the extremities, such as the dorsa of the hands and feet, forearms and legs. Palmar and plantar regions are generally spared. It occurs mainly in young female patients. The presentation of the palmar variant in an elderly patient is a rarity. PMID- 30484533 TI - Autoimmune progesterone dermatitis manifesting as generalized fixed drug eruption. AB - Autoimmune progesterone dermatitis is an uncommon, poorly recognized and under diagnosed catamenial dermatosis associated with hypersensitivity reactions to progestagens. Most cases manifest as urticaria, eczema or erythema multiforme like. A 26-year-old woman developed violaceous plaques on the groin and abdomen, 4 days after a spontaneous abortion resolved with uterine curettage. The lesions recurred once monthly at the same sites, mimicking a fixed drug eruption. Although the histopathology was compatible with fixed drug eruption, positive intradermal testing and symptomatic improvement after using oral contraceptive pills gave us a clue to the diagnosis. PMID- 30484535 TI - Thalidomide in plasma cell balanitis refractory to conventional topical treatment. AB - Zoon's plasma cell balanitis is a chronic genital inflammatory dermatosis that affects uncircumcised men, especially the elderly. It's characterized by painless erythematous plaques of orange hue, located on the glans penis and foreskin. Circumcision is the most effective treatment; however, it can be hard for patients to accept. As an alternative, topical calcineurin inhibitors are used, with good response. This article reports the case of a 32-year-old patient, HIV carrier, diagnosed with Zoon's plasma cell balanitis. Treatment with topical tacrolimus was administered, without improvement. A 6-week course of thalidomide resulted in complete remission of the lesions, without recurrence after eight months of follow-up. PMID- 30484536 TI - Cutaneous metastasis of colorectal cancer. AB - Cutaneous metastases from internal malignant neoplasms are a rare event and a late clinical finding that is associated with disseminated disease and a poor prognosis. Skin metastases from colon tumors occur in only 4% of cases of metastatic colorectal cancer. They are most often located on the abdominal skin. We report a case of 54-year-old male patient with a cutaneous metastatic focus on the lower abdomen as the initial presenting symptom of an underlying colon cancer. PMID- 30484537 TI - Nodular vasculitis associated with lung adenocarcinoma. AB - Nodular vasculitis is an uncommon type of panniculitis. It was firstly associated to the infection by Mycobacterium tuberculosis and named erythema induratum of Bazin, however nowadays it has been associated with several other underlying disorders and it is better described as nodular vasculitis. Concerning its relationship with malignant conditions, there is only one reported case, in association with metastatic colon adenocarcinoma. We report a case of nodular vasculitis as the first manifestation of lung adenocarcinoma. To the best of our knowledge, this is the first reported association of both diseases. PMID- 30484538 TI - Chagas disease reactivation: cutaneous manifestations in a transplanted patient. AB - Chagas disease is an endemic zoonosis caused by a protozoan agent called Trypanosoma cruzi. It is mainly transmitted by a hematophagous vector, and less frequently by blood transfusion, transplacental and solid organ transplant. In most cases, primary infection is not diagnosed and the disease progresses to a chronic phase. Immunosuppressed patients are a vulnerable population that may present an acute, atypical and severe reactivation of the chronic form of this disease. We hereby report a case of a female patient, who received a renal transplant with immunosuppressive treatment, who was diagnosed with a chagasic hypodermitis secondary to an acute reactivation of a chronic phase of this disease. We describe the clinical features, epidemiological and histopathological findings, treatment and course. PMID- 30484539 TI - Dermoscopy of squamoid eccrine ductal carcinoma: an aid for early diagnosis. AB - Squamoid eccrine ductal carcinoma is a cutaneous malignancy that originates from the eccrine sweat gland. A 76-year-old woman presented with an asymptomatic papule on her nose that had been present for one year. Dermoscopy showed pseudocysts, irregular linear crown vessels, and yellowish-brown globules surrounded by white halos. This is the first dermoscopic description of squamoid eccrine ductal carcinoma. Studies with more cases are needed to confirm the dermoscopic characterization of this tumor. PMID- 30484540 TI - Dermatoscopy: an auxiliary resource for the diagnosis of poroid neoplasms. AB - Poroid neoplasms are benign epithelial proliferations with eccrine sweat gland differentiation. They are a challenging diagnosis because of the clinical heterogeneity, being able to mimic several malignant neoplasms. They are classified into classic poroma, hidroacanthoma simplex, dermal duct tumor and poroid hidradenoma. Association of histological subtypes occurs in more than 25% of cases. We report a case of a combined poroid neoplasia of classical poroma and poroid hidradenoma, reviewing its dermatoscopic features. PMID- 30484541 TI - Vertical plane ex vivo dermoscopy: a novel dermoscopic technique. A preliminary study. AB - Dermoscopic examination allows visualization of horizontal images on the skin, showing well-defined patterns. The authors propose ex vivo dermoscopic visualization using a vertical view of skin sections. The new image clearly distinguishes the stratum corneum, epidermis, and dermis as well as the anatomical location of the pigment. Will this new approach be useful in dermoscopic diagnosis? Further studies are needed. PMID- 30484542 TI - Paracoccidioidomycosis manifested by sarcoidosis-like cutaneous lesions and caused by Paracoccidioides brasiliensis sensu stricto (S1a). AB - Molecular studies have shown more than one species of the genus Paracoccidioides to be the causal agent of paracoccidioidomycosis. Efforts have been made to correlate the identified species with epidemiological and clinical data of patients, aiming to determine the real meaning and impact of new species. Bearing this objective in mind, the authors report a clinical case of paracoccidioidomycosis, from Sao Paulo state, Brazil, that manifested as uncommon sarcoid-like cutaneous lesions and was caused by Paracoccidioides brasiliensis sensu stricto (S1a). The patient was treated with itraconazole 200mg/day for 12 months, with complete clinical remission. PMID- 30484543 TI - Case for diagnosis. Ulcerated intradermal nevus simulating Sister Mary Joseph's nodule. AB - We report a case of a 76-year-old patient with a history of recent weight loss and ulcerated umbilical nodular lesion. Initially, we considered the diagnostic hypothesis of Sister Mary Joseph's nodule. However, histopathological evaluation revealed that it was an ulcerated intradermal nevus. We perform a brief review of umbilical nodules. PMID- 30484544 TI - Report of 73 cases of cutaneous sporotrichosis in Mexico. AB - We report 73 cases of cutaneous sporotrichosis from the Community Dermatology program, at the central and mountain areas of the state of Guerrero, Mexico. A similar number of cases was found between children and adults, mostly peasants and school-age children with rural occupations. Upper limbs were the mostly affected and the predominant clinical form was lymphocutaneous (56.16%). All cultures corresponded to Sporothrix schenckii (sl). Treatment was done with potassium iodide in 54 patients, achieving clinical and mycological cure in all cases. PMID- 30484545 TI - Positive results of patch tests with fragrance markers: analysis of a 15-year period at a Brazilian dermatology center. AB - Fragrances may cause allergic contact dermatitis. Data on patients who were patch tested, between 2000 and 2015, with fragrance allergens included in the Brazilian baseline series (balsam of Peru, colophony and fragrance mix I), were collected and analyzed. Of these patients, 258 (13.8%) were positive for fragrance markers, 9.8% being positive for fragrance mix I. Among these 258 there was a predominance of women in their 40s, with hand eczema. The frequency of sensitization to fragrances, as well as the epidemiological profile, was supported by the literature. Fragrance mix I was the main marker. It is important to expand the fragrance markers used in the Brazilian baseline series of patch tests. PMID- 30484546 TI - No detection of c-kit gene mutations in exons 9, 11, 13 and 17 and low CD117 expression in plaque-stage mycosis fungoides. AB - The growth factor receptor c-kit (CD117) is expressed in immature T-cells and in some advanced forms of mycosis fungoides. c-kit gene mutation results in unrestricted neoplastic proliferation. We aimed to detect by PCR the most frequent exon mutations in seventeen plaque-stage MF patients, in their perilesional skin and in healthy skin donors. We secondarily evaluated CD117 expression by immunohistochemistry in plaque-stage and tumor-stage MF. We detected no mutation in c-kit gene and low CD117 expression was confirmed on atypical cells in one patient. Complete c-kit exon and intron sequences should be assessed and more sensitive sequencing method could be also applied. PMID- 30484548 TI - Analysis of the role of nail polish in the transmission of onychomycosis. PMID- 30484549 TI - Active search for cases of leprosy in the city of Manaus. PMID- 30484550 TI - Assessing the efficacy of a 10-point referral tool in the triaging of pigmented lesions to a Dermatology clinic. PMID- 30484547 TI - Profile of dermatological consultations in Brazil (2018). AB - BACKGROUND: Dermatological diseases are among the primary causes of the demand for basic health care. Studies on the frequency of dermatoses are important for the proper management of health planning. OBJECTIVES: To evaluate the nosological and behavioral profiles of dermatological consultations in Brazil. METHODS: The Brazilian Society of Dermatology invited all of its members to complete an online form on patients who sought consultations from March 21-26, 2018. The form contained questions about patient demographics, consultation type according to the patient's funding, the municipality of the consultation, diagnosis, treatments and procedures. Diagnostic and therapeutic decisions were compared between subgroups. RESULTS: Data from 9629 visits were recorded. The most frequent causes for consultation were acne (8.0%), photoaging (7.7%), nonmelanoma skin cancer (5.4%), and actinic keratosis (4.7%). The identified diseases had distinct patterns with regard to gender, skin color, geographic region, type of funding for the consultation, and age group. Concerning the medical conducts, photoprotection was indicated in 44% of consultations, surgical diagnostic procedures were performed in 7.3%, surgical therapeutic procedures were conducted in 19.2%, and cosmetic procedures were performed in 7.1%. STUDY LIMITATIONS: Nonrandomized survey, with a sample period of one week. CONCLUSION: This research allowed us to identify the epidemiological profiles of the demands of outpatients for dermatologists in various contexts. The results also highlight the importance of aesthetic demands in privately funded consultations and the significance of diseases such as acne, nonmelanoma skin cancer, leprosy, and psoriasis to public health. PMID- 30484552 TI - Conjunctival melanoma. PMID- 30484551 TI - Malignant subcutaneous PEComa on the cheek. PMID- 30484553 TI - Multiple spider telangiectasias in a breast cancer patient on T-DM1 treatment. PMID- 30484554 TI - Dermoscopic findings of pseudoxanthomatous mastocytosis localized on vulva. PMID- 30484555 TI - Toxic epidermal necrolysis after yellow fever vaccination. PMID- 30484556 TI - Contact dermatitis from Do-It-Yourself slime. PMID- 30484557 TI - [Leprosy trends following implementation of an intervention project in a state capital in the North of Brazil, 2002-2016]. AB - The project Palmas Free of Leprosy was implemented to improve indicators and deal with the disease, since the capital of Tocantins State is the most hyperendemic state capital in Brazil. This study measures the impact of the project's intervention through trend analysis of the priority indicators in Palmas, from 2002 to 2016. The study was based on an analysis of data from the Brazilian Information System for Notifiable Diseases (SINAN) and reports of applied training courses with problem-solving methodology. The indicators for new leprosy cases in Palmas residents were investigated, and the trends were identified by joinpoint regression analysis to assess the results. In the year the intervention project was implemented (2016), the detection rate for new cases in the overall population was 236.3/100,000 inhabitants, and this indicator showed a significant decrease of -7.5% from 2002 to 2014. From 2014 to 2016, there was a significant increase of 104.6% in overall detection. The detection rate in individuals under 15 years of age also showed a reduction of -4.6%, but in the years 2014, 2015, and 2016 there was an increase of 111.1%, together with detection rates for grades 0, 1, and 2, with 59.3%, 225.2%, and 121.7%, respectively. The proportion of cases detected by contact assessment showed a significant increase of 201.1% from 2014 to 2016. The data proved the effectiveness and potentiality of the project's intervention strategy for the diagnosis and control of leprosy in Palmas. The study provided evidence that timely diagnosis by primary care services results in indicators that reflect the real incidence of cases. PMID- 30484558 TI - Inequalities in multimorbidity among elderly: a population-based study in a city in Southern Brazil. AB - Lower socioeconomic level is positively related to multimorbidity and it is possible that the clustering of health conditions carries the same association. The aim of this study was to identify prevalence of multimorbidity and clusters of health conditions among elderly, as well the underlying socioeconomic inequalities. This was a cross-sectional population-based study carried out with 60-year-old individuals. Multimorbidity was defined as the presence of 2+, 3+, 4+ or 5+ health conditions in the same individual. Schooling levels and the National Economic Index were used to investigate inequalities in the prevalence of multimorbidities among elderly. Slope and concentration indexes of inequality were used to evaluate absolute and relative differences. A factorial analysis was performed to identify disease clusters. In every ten older adults, about nine, eight, seven and six presented, respectvely, 2+, 3+, 4+ and 5+ health conditions. Three clusters of health conditions were found, involving musculoskeletal/mental/functional disorders, cardiometabolic, and respiratory factors. Higher inequalities were found the higher amount of health conditions (5+), when considering economic level, and for 3+, 4+ and 5+, when considering educational level. These findings show high multimorbidity prevalence among elderly, highlighting the persistence of health inequalities in Southern Brazil. Strategies by the health services need to focus on elderly at lower socioeconomic levels. PMID- 30484559 TI - Cultural humility: a strategic concept for addressing refugee health in Brazil. PMID- 30484560 TI - Parallels between research in mental health in Brazil and in the field of Global Mental Health: an integrative literature review. AB - Global Mental Health is a field of teaching, research, and practice whose goal is to improve access to mental health and reduce inequalities in mental health outcomes for all people worldwide, especially proposing action in low- and middle income countries like Brazil. Given this global scenario and Brazil's progress in health and psychiatric reforms, it is important to investigate the current status of the Brazilian mental health literature and its relationship to Global Mental Health, describing how Brazilian research deals with key topics in the Global Mental Health field. The authors performed an integrative literature review using a qualitative and descriptive approach. The article search was performed for the years 2014 and 2015 in Portuguese and English, using the terms "mental health" and "Brazil", combined with key words corresponding to the principal themes addressed by authors in Global Mental Health. The search yielded 88 articles, which were analyzed according to authorship, periodicals and regions, and the analytical categories of access, primary care, community mental health services, social determinants of health, human rights, and equity. Brazil's mental health research revealed a rich and diverse body of studies, showing parallels with the literature on global mental health, but with limited systematization. Although the review revealed efforts to generate knowledge in this field within Brazil, some barriers may be limiting Brazil's participation in the international debate on Global Mental Health. PMID- 30484561 TI - Active aging: prevalence and gender and age differences in a population-based study. AB - The aim of this study was to analyze prevalence rates and gender and age differences in indicators of active aging in elders participating in the Campinas Municipal Health Survey in Campinas, Sao Paulo State, Brazil (2014-2015). We estimated prevalence rates for participation by the elderly in twelve activities pertaining to four dimensions and calculated the prevalence ratios with Poisson regression. The study population consisted of 986 elderly. The results showed that 40.2% of the elderly participated in sociocultural activities, 25.3% were physically active in their leisure time, 21.7% used the Internet, 22.1% performed paid work, and only 2.6% were taking courses. In the social dimension, the only gender difference was in religious practice, which was less prevalent in men (PR = 0.67). In the dimension of physical activity, men were more active at work (PR = 2.10), in commuting (PR = 1.61), and in their leisure time (PR = 1.44). There was no gender difference in the intellectual dimension, and men were more active in paid work, (PR = 1.78). The analyses by age brackets showed that in men, only physical activity at work and paid work presented lower prevalence in the group eighty years and older. Among the oldest elderly women, lower prevalence rates were seen in six activities, which suggests a possible differential effect of advanced age between the sexes. The results show important rates of participation by elderly in some indicators of active aging, besides challenges in activities that are performed rarely and gender differences in participation. PMID- 30484562 TI - Experiences and perceptions of people who use heroin: public health lessons from Hermosillo, Mexico. AB - Heroin consumption in Mexico is low compared with its use in the United States; however, this practice is more common in the northern region of Mexico than in the rest of the country, being documented only in cities that are located exactly at the Mexico-U.S. border. The Mexican legal framework is focused on rehabilitation, but its effects on the lives of users are unknown. The objective of this research was to analyze how the regulatory Mexican framework is conceptualized and practiced in the daily life of a group of heroin users from a northern city, where consumption has recently spread and has not been documented. We collected the official registered data from users and conducted a qualitative study in Hermosillo, Sonora. A research on the legal framework was conducted, as well as on the city's context. Data on heroin users can be found at HIV health center, as there is no other source of such records. The Mexican legal framework aims at rehabilitation and at avoiding criminalization; however, the daily life of users drives them towards crime circuits: people commit crimes to stay in prison, where they can control the addiction and get heroin, in case of abstinence. The Mexican State has no empirical information to improve its programs and laws related to the use of heroin. The daily practices of users become not only epidemiological but social risks to the community and to the users themselves. Also, the lack of access due to stigmatization, criminalization and violence, increases the inequities, creating a cycle that reproduces poverty and suffering as part of a social structure. Therefore, changes are needed in the justice system. PMID- 30484564 TI - [Why don't we take good care of our less gifted patients?] PMID- 30484563 TI - [Staff burnout and psychosocial risk factors in a long-stay hospital in Spain]. AB - The aim of this study was to assess the relationship between psychosocial risks and burnout syndrome in a long-stay hospital in Spain. A cross-sectional study was conducted in 2017, applying the Spanish version of the MBI-HSS and the F Psico 3.1 questionnaire of Spain's National Institute of Work Safety and Health. The predictive variables were sociodemographic characteristics, modulators, and psychosocial risk factors. The outcome variables were prevalence of burnout and the effects on his subscales. Associations between variables were measured by odds ratio. Burnout was directly associated with psychosocial risks related to workload, psychological demands, participation/supervision, role performance and social support, and consumption of anxiolytics. Meanwhile, protective factors were having children, feeling valued by patients and coworkers, satisfaction at work, optimism, and social support. The associations found on depersonalization were similar but weaker. Low personal fulfillment was directly associated with the psychosocial risks related to length of workweek, limited autonomy and variety/content of work, and role performance and social support. Low personal fulfillment was the subscale with the most modulating and protective sociodemographic variables included marital status, children, night shift, feeling valued by patients and family members, social support, self-efficacy, and optimism. According to our results, there is an association between psychosocial risks and burnout syndrome. Individuals with greater work satisfaction, self efficacy, and optimism cope better with stress and are less vulnerable to psychosocial risks and burnout. PMID- 30484565 TI - [Conversion disorder: for the neurologist, the psychiatrist or both?] PMID- 30484566 TI - [ROM in mental health care: treatment outcomes of both generic and disorder specific instruments in patients with anxiety disorders; a cohort study]. AB - BACKGROUND: In routine outcome monitoring (rom) generic instruments are often used to measure outcomes. This could hamper the clinical use of these instruments and lead to a possible underestimation of treatment outcomes.
AIM: To examine whether there are differences in the degree of progress between outcomes of disorder specific instruments measuring anxiety symptoms and the Symptomatic Distress subscale of the Outcome Questionnaire-45 (oq-45-sd).
METHOD: Data from 604 patients with an anxiety disorder were analyzed. The mean change scores, percentages of reliable change and effect sizes on the oq-45-sd were compared to the outcomes of seven commonly used instruments that specifically measure the symptoms of anxiety disorders.
RESULTS: The effect sizes on the oq-45-sd and the disorder specific instruments were 0.80 or higher. The correlation between the change scores was moderate, as was the correspondence between the degree to which patients improved reliably. In one third to half of the cases changes on the oq-45-sd and on the disorder specific instruments were not in agreement.
CONCLUSION: The treatment outcomes of the oq-45-sd are approximately as positive as those of the disorder specific instruments. However, discrepancies existed in the extent to which patients had improved. In accordance with the advice of the International Consortium for Health Outcomes Measurement, the use of both kinds of instruments is advised when evaluating the progress of the treatment. PMID- 30484567 TI - [Towards personalized child and adolescent psychiatry care by using routinely registered data from everyday clinical practice]. AB - BACKGROUND: Studying differences in the course and treatment effects of psychiatric disorders between subgroups of patients can provide suggestions to improve everyday clinical practice.
AIM: To illustrate how routinely registered data from child and adolescent psychiatry can be used to gain insight into differences in the development of patient groups.
METHOD: Multilevel analyses in four subgroups of youths with an autism spectrum disorder (asd; n = 1681; boys/girls, with/without comorbid psychiatric disorder) to investigate differences in the development of quality of life during the first six months of treatment.
RESULTS: Subgroups of youths with asd showed differences in development of quality of life, which can provide suggestions to establish personalized care.
CONCLUSION: Multicenter research in large samples is needed to investigate the robustness of our findings. The 'Research Data Infrastructure', containing routine outcome monitoring and electronic medical record data from more than 117.000 youths in child and adolescent psychiatry, offers a unique opportunity to perform large scale practice based research. PMID- 30484568 TI - [Brua and psychiatry: A pilot study among Dutch-Antillean patients in the Netherlands]. AB - BACKGROUND: Individuals native to Aruba, Bonaire, and Curacao, the abc islands of the former Netherlands Antilles, often attribute their complaints to brua, although they seldom discuss this with health professionals. This may have a negative influence on the therapeutic relationship and diagnostic processes.
AIM: To explore the role of brua in the illness perception of psychiatric patients in the Netherlands who were originally from the abc islands.
METHOD: A random sample of patients under treatment at Parnassia Psychiatric Institute in The Hague were interviewed with the aid of a semi-structured questionnaire.
RESULTS: Of the 18 psychiatric patients interviewed, 10 (56%) believed in brua, and 3 (17%) considered it the cause of their disease. Although none of the interviewees admitted to an active involvement in brua, 8 (44%) had been in touch with a traditional healer and 9 (50%) possessed artifacts meant to provide protection against evil. Regarding the usefulness of discussing brua with health professionals, opinions were divided.
CONCLUSION: Psychiatric patients in the Netherlands native to the abc islands are all knowledgeable of brua, with more than half of them believing in it. Despite the fear and shame that people often experience, making brua fit for discussion in clinical practice would improve the relationship between health professional and patient, yielding further opportunities for diagnosis and treatment. PMID- 30484569 TI - [rTMS for treatment resistant depression - proposal for a treatment protocol]. AB - BACKGROUND: At present, the use of repetitive transcranial magnetic stimulation (rtms) for treatment-resistant depression is sufficiently substantiated to be applied in clinical practice. In the Netherlands, it will be reimbursed when offered in combination with cognitive behavior therapy.
AIM: Proposal for a clinical treatment protocol for rtms in The Netherlands.
METHOD: A study of the literature and a critical appraisal of available international guidelines for rtms.
RESULTS: rtms is a safe treatment for patients suffering from a moderate to severe depressive disorder that is relatively treatment-resistant. The duration of the effect is still unknown. It is advised to stimulate the left dorsolateral prefrontal cortex using an intensity of 120% of the resting motor threshold, with a frequency of 10 Hz and using 3000 pulses per session during a total of 20-30 sessions.
CONCLUSION: The proposed treatment protocol is favored based on the available evidence when rtms is used as a treatment aimed to acutely decrease the severity of depressive symptoms. It is further proposed to systematically collect technical and outcome data on treatment with rtms to further improve treatment with rtms in clinical practice. PMID- 30484570 TI - [Vision on man, vision on addiction: a multiple view of problems and recovery]. AB - BACKGROUND: The way we look at addiction has changed dramatically over the past decades. Currently, the brain disease model is the leading model in the biomedical scientific literature. However, this model has been severely criticized and seems to apply mostly to people with a chronic form of addiction. When the ideas of the recovery movement are applied to the current understanding of addiction, the biopsychosocial (bps) model seems the most fitting. On the other hand, while 'meaningful existence' (or 'sense of meaning') is a focal element the model of recovery, this concept is not included in the bps model.
AIM: To explore whether addition of the concept of meaning to the bps model is usefull.
METHOD: Discussion of a case and evaluation of selected literature.
RESULTS: We advocate the addition of the concept 'sense of meaning' to the bps model, making it the bpsm model. A matter still to be resolved is whether this concept would become a fourth domain or considered either subjacent to or above the other three domains. We suggest that, while sense of meaning is not new in addiction care, adding this concept would underline the importance of the personal story behind the addiction.
CONCLUSION: Addition of the concept meaning to the bps model is Usefull in addiction care. PMID- 30484571 TI - [Discontinuing venlafaxine by switching to fluoxetine]. AB - Patients wanting to discontinue their antidepressant use may experience antidepressant discontinuation syndrome (ADS). This is characterized by symptoms such as nausea, vomiting, diarrhea, headaches and sweating. Withdrawal symptoms can discourage patients from permanently discontinuing antidepressants. We present the case of a 48-year-old visually impaired woman where, after a first attempt failed, venlafaxine was successfully discontinued after a switch to fluoxetine. Fluoxetine mediated discontinuation is a simple, effective and inexpensive method for patients who suffer from withdrawal symptoms when tapering off antidepressants. PMID- 30484572 TI - [Oppositional behavior in a 14-year-old boy as a first clinical symptom of Wilson's disease]. AB - A 14-year-old boy was referred to the child and adolescent psychiatry department due to an increase in oppositional behavior. The psychiatric history revealed that he was also suffering from dysarthria, excessive salivation and a decline in academic performance. Extensive diagnostic testing led to the diagnosis of Wilson's disease. The timely administration of appropriate treatment necessitates early recognition of the psychiatric symptoms associated with Wilson's disease. PMID- 30484573 TI - ? PMID- 30484574 TI - The Rationale for Selective Laser Trabeculoplasty in Africa. AB - Glaucoma is the leading cause of irreversible blindness in Africa. The condition is treatable but not curable. There are numerous obstacles to glaucoma care in Africa, including availability, accessibility and affordability of treatments, as well as medication nonadherence among patients. Medical therapy is costly relative to the average income in Africa and it requires daily self-dosing by patients. Surgery is of limited availability in many regions in Africa, and a high proportion of patients refuse surgery because it is expensive. Selective laser trabeculoplasty (SLT) proves to be a favorable alternative to medical or surgical care, as it is highly effective and safe in people of African descent, more cost-effective than medical therapy, quick and easy to perform, and portable. The procedure also requires no postoperative care, thus obviates the issue of nonadherence. In uncontrolled studies, SLT has a high response rate and it lowers intraocular pressure by 30-40%, which exceeds the goal in international guidelines for initial therapies. The African Glaucoma Consortium (AGC), a member driven stakeholder collective, has been formed in part to develop the infrastructure for continent-wide improvements in glaucoma care. It embraces SLT as a potential key tool in their development plans. The mission of AGC includes improving clinical care by educating existing and new health care professionals to expand the provider network, by conducting trials to identify optimal care strategies for glaucoma in Africa, and by facilitating the development of an integrated network of Centers of Excellence to bring SLT and other crucial glaucoma therapies to communities throughout Africa. PMID- 30484575 TI - [Epidemiological aspects of autism in mental health care structures in the district of Bamako, Mali]. AB - AIMS: Autism is a global and early developmental disorder that appears before the age 3 years old. It is characterized by a triad of symptoms affecting the following domains: social interaction, verbal and non-verbal communication, imagination and behaviors. This work aimed to determine the frequency of autism and to identify its risk factors in Malians aged 0-17 years old. METHOD: In a cross sectional and prospective study, we reviewed clinical data in 2068 medical charts dating from 1992 to 2012 from all the mental health care centers in Bamako. RESULTS: We found a frequency of 7.8% (162/2068). The age range 0-5 years old was the most represented. The sex ratio was 1.7. The autistic child was issued from a consanguineous marriage in 25.4% (41/162) of the cases. To have parents in divorce, being the first child, and male gender were associated with autism with statistical significance. Our data suggest an elevated number of autism cases in Mali. We plan to carry out a larger prospective study to determine other autism risk factors and importantly to identify autistic families for a molecular genetic study. PMID- 30484576 TI - [Epidemiological scope of traditional gold panning with trauma in emergency service at Gabriel Toure teaching hospital]. AB - INTRODUCTION: Traditional gold washing traumatism during traditional gold panningfalls within the scope of occupational accidents, which are common pathologies in developing countries such as Mali. Our work aimed to study traumatism during traditional gold panning. MATERIAL AND METHOD: A 1-year prospective study from November 2014 to November 2015 on the cases of traumatism during traditional gold washing (TOT) admitted to the emergency room(ER) of the University Hospital Gabriel Toure during the study period. Data were collected from outpatient visit records and medical charts. Data were collected on the survey sheets and analyzed with Epi-info version 7.1.1.0.fr software. Data entry was made with Windows 7 software. RESULTS: During the study period, 21,400 patients were admitted to the ER, of whom 445 patients were victims of traumatism, a frequency of 2.08% of all outpatient visits in the ER. The age group 21-40 years old was the most represented with 64.94% of the cases. The male gender was predominant with 77.08% of the cases with a sex ratio of 3.36. Mine landslides were the most common causality in 65.39% of the cases. Dorsal spine involvement was the most common with 41.80% of cases. Medullary vertebral fracture was the most frequent diagnosis with 43.82% of cases. In total, 79.55% of patients received medical treatment. Patients or were transferred to neurosurgery department in 58.20% of cases. CONCLUSION: Traumatism during traditional gold panning is common. Lesions most often fit in a context of polytraumatism. The rapidity of the diagnosis and management are crucial to the prognosis of the disease. PMID- 30484577 TI - [Urological Complications of Pelvic Surgery at Point-G Hospital, About 23 Cases]. AB - INTRODUCTION: Bladder and ureteral lesions are the most common urologic complications occurring during pelvic surgery with 1% and 0.5% to 3%, respectively. These lesions are rarely recognized intraoperatively and pose a major problem to urologists, gynecologists, and general surgeons. OBJECTIVE: To study the factors favoring urologic complications following pelvic surgery at the University Hospital Point-G. PATIENTS AND METHOD: We conducted a retrospective study at the University Hospital Point-G between 2006 and 2015. It involved 23 patients with a whole urological lesion following pelvic surgery. These patients underwent a clinical and para-clinical examination (intravenous urography, methylene blue test) to confirm the urological lesion and to determine its management. RESULTS: The average age of our patients was 32.00 years with extremes of 18 and 40 years old. The leakage of urine was found in 82.6% (19/23). Interventions that caused urologic injury were: caesarean section 52.2% (12/23), hysterectomy 30.4% (7/23), as well as a caesarean section and hysterectomy 17.4% (4/23). Methylene blue was performed in 19 patients, it was positive in 52.2% (12/23) and intravenous urography (IVU) in 7 patients. The lesions encountered were: retrotrigonal fistula vesico-vaginal 10 cases, vesico-vaginal fistula under trigonal 2 cases, uretero-vaginal fistula 7 cases, and bilateral ureteral ligation 4 cases. Fistulorraphy was performed in 52.2% followed by direct ureterovesical reimplantation. The postoperative outcome was satisfactory in 100% of cases with obtaining a good bladder tightness. The average duration of hospitalization was 12 days (+/- 4 days). CONCLUSION: Pelvic surgery results in urological injuries. Caesarean section and hysterectomy are contributing factors. Vesico-vaginal fistula or ureteral lesions are common. PMID- 30484578 TI - [Epidemiological and clinical aspects of prurigo in HIV infected patients in Fousseyni N'Daou hospital of Kayes, Mali]. AB - INTRODUCTION: Prurigo is one of the most common dermatological conditions during HIV infection and AIDS. It appears as an immunosuppression marker associated with HIV infection. The study objective was to determine the prevalence of prurigo in people living with the human immunodeficiency virus (PLHIV) in Fousseyni N'Daou Hospital of Kayes, and to describe the socio-demographic aspects of patients and lesions associated with prurigo among PLHIV. METHODS: It was a descriptive cross sectional study included all cases of HIV infected patients with prurigo in the Dermatology-Venomology Department of Fousseyni N'DAOU Hospital from January 1, 2015 to August 31, 2015. RESULTS: We collected 121 cases of prurigo. The hospital prevalence was 14.5% among PLHIV with 65% Female and the average age was 34.8 years old (SD: 15-81 years). The elementary lesions associated with prurigo were seropapules (40.2%), vesiculo-crusts (13%), excoriated papules (33.3%), lichenified papules (10.8%), and cicatricial lesions (2.7%). The prurigo was generalized in 68.5% of cases and localized in 31.24%. More than half of our patients had weight loss, fever, diarrhea and oral candidiasis in their medical history. Patients were infected with HIV1 in 60.03% and HIV1+ 2 in 24.3%. More than the half of our patients had a CD4 count inferior to 250 cells/mm3 at the time of prurigo diagnosis. CONCLUSION: In our study, prurigo remains a common condition in PLHIV, particularly in patients with low CD4 counts. Early detection and rapid antietroviral therapy can reduce the frequency of prurigo in PLHIV. PMID- 30484579 TI - [Pathologies of peritoneo-vaginal canal in pediatric surgery at the teaching hospital Gabriel Toure]. AB - : The closure anomalies of the peritoneal-vaginal canal include several clinical entities, which are at the origin of various symptomatology. OBJECTIVE: To study the anatomo-clinical and therapeutic aspects of pathologies of the peritoneal vaginal canal. MATERIALS AND METHOD: This was a prospective study from January 1st to December 31st, 2015 carried out in the pediatric surgery department of University Hospital Gabriel Toure. It covered all children aged 0-15 years old with a pathology of the peritoneal-vaginal canal operating in the department during the study period. This study did not include cases that were not operated on or not seen during the study period. RESULTS: During the study period, 2,699 children were treated in pediatric surgery, of which 150 cases of pathology of the peritoneal-vaginal canal had a hospital frequency of 5.5%. The average age was 3.25 +/- 9.63 years. The sex ratio was 14. The reason for consultation was intermittent or permanent inguinal or inguino-scrotal swelling in all children. The pathology was discovered by the parents during the pushing efforts in 46.7%. Inguino-scrotal swelling was found on physical examination in 40% of cases. The right side was reached in 60% of the cases. Hernia accounted for 80.6% of these pathologies. We recorded 31 cases of strangulation and 11 cases of craze. Immediate operative follow-up was simple in 92% of patients. This rate was 96% after 6 months. CONCLUSION: Pathologies of the peritoneal-vaginal canal are very common in pediatric surgical practice. The first place of these pathologies is occupied by hernia. They preferentially affect male infants. PMID- 30484580 TI - [Turner syndrome in the hopital du Mali, a case]. AB - Turner syndrome is a chromosomal aberration linked to the complete or partial absence of an X chromosome. Its prevalence is 1/2500 female newborns. We report a case in the department of internal medicine and endocrinology of the hospital of MALI. This was a 14-year old girl who consulted for stunting and puberty. She presented clinically a dysmorphic syndrome, TANNER stage1 secondary sexual characteristics, weight and height at -3 DS and a bone age estimated to 91/2 years old on the X-ray of the hand. The hormonal assessment showed an elevation of FSH and LH and the genetic study showed an iso chromosome Xq. This result was part of a Turner syndrome with Xq iso chromosome. PMID- 30484581 TI - [Vein of Galen aneurysmal malformation in a Neonate: a case report]. AB - The aneurysm of the Galen vein is a rare and complex congenital intracerabral vascular malformation. We report a case suspected by the obstetric ultrasound in the third trimester and confirmed by the transfontanellar Doppler ultrasound and brain CT-Scan in the asymptomatic 11-day old baby born at term. PMID- 30484582 TI - [Diagnosis and therapeutic aspects of the amoebic liver abscesses in the surgery at point "G" Hospital]. AB - AIM: Our aim was to evaluate the diagnosis and therapeutic aspects of the amoebic liver abscesses in the surgery "A" department of the University hospital Point "G". PATIENTS AND METHODS: Were included in this study, patients admitted to the surgery "A" department for amoebic liver abscess confirmed by a positive amoebic serology and the chocolate appearance of bacteria-free pus. Bacterial liver abscesses were not included into this study. RESULTS: Over a 10-year period, 52 cases of patients diagnosed with amoebic liver abscess were collected in the department. There were 41 men and 11 women, with a sex ratio of 3.7. The mean age was 37.8 years old with extremes of 15 and 66 years. The most represented professions were farmers (36.5%) followed by salesmen (26.7%) and students (11.5%). The average outpatient visit delay time was 18.5 days with the extremes of 5 and 34 days. The most frequent clinical signs were pain in the right hypochondrium (86.5%), fever (78.8%) and hepatomegaly (61.5%). Abdominal ultrasound showed a single located abscess in 44 patients (84.6%) and these abscesses were localized in the right hepatic lobe in 34 patients(65.4%). The average volume of the abscess was 366.5 cm3 with the extremes of 36 cm3 and 1580 cm3. Amoebic serology was positive in 38 patients (80.9%). Cytobacteriological analysis of pus in 37 patients (71%) was negative. Patients underwent an ultrasound assisted needle aspiration of pus in 65.4% he. Laparotomy and a laparoscopic approach were performed in 7.7% and in 5.8%, respectively. The clinical course was uneventfulin 94.2%. The mean hospital stay duration was 16.5 days with the extremes of 4 and 29 days. No death was recorded during hospitalization. CONCLUSION: Amoebic liver abscess is an uncommon pathology in a surgical setting. Abdominal ultrasound andechography guided liver puncture allowed the diagnosis. Laparoscopic approach minimizes the burden of the laparotomy. PMID- 30484583 TI - [Renal involvement during monoclonal gammopathies at the teaching hospital of Yopougon in Abidjan, from 2000 to 2016]. AB - BACKGROUND: Renal involvement is common during monoclonal gammopathies and their occurrence impacts the survival of the patients. Our objective was to describe the renal features during monoclonal gammopathies from 2004 to 2016 at the University Hospital of Yopougon in Abidjan. METHODS: Renal failure was defined as blood creatinine level > 20 mg/L and/or proteinuria > 500 mg/24 hours. RESULTS: We identified 42 cases of monoclonal gammopathiesincluding multiple myeloma (n=40) and monoclonal gammopathy of underdetermined significance (n=2). The rate of renal impairment was 57% (n=24) including tubular disease (n=20)and glomerular nephropathy (n=3). Two patients (one with cast nephropathy and another with Randall's disease) performed renal biopsy. The factors associated with renal impairment were mainly hyperuricemia (n=24)and hypercalcemia (n=23). Three cases were treated by hemodialysis. There were 6 (14.3%) deaths among patients with renal impairment. CONCLUSION: Tubular injury was common among patients with monoclonal gammopathy. It was associated with hypercalcemia and Hyperuricemia. PMID- 30484584 TI - [Prevalence of Malaria, Intestinal and Urinary parasite infections in Kalifabougou, Mali]. AB - : Soil transmitted helminthiasis and schistosomiasis are neglected tropical diseases (NTD), affecting the health status of endemic Malian populations. Mali has a national NTD elimination program using the mass drug administration (MDA) strategy combining Albendazole, Ivermectinand Praziquantel. Malaria still remains a public health problem in Mali. The Community health Center (CSCOM) in Kalifabougouvillage in the Kati health district has benefited from such MDA program since 2010. AIM: To evaluate the prevalence rate of malaria, intestinal and urinary parasite infections in the local population. MATERIEL AND METHODS: We conducted a nested cross sectional and cohort study in May 2011 on volunteers aged three months old to 25 years old. Blood smear (blood), Kato-Katz (Stools) and urine filtration techniques were used to evaluate parasite prevalence. Informed consent and assentment were obtained from the volunteers before their inclusion. All volunteers received treatment against the parasite diseases of interest according to the guidelines of national disease control programs. RESULTS: A total of 688 volunteers were included. The prevalence rates of parasitic infections were 22.1% [95% CI= 22.06 - 22.12] for Plasmodium falciparum, 9% [95% CI: 8.9-9.034] for Schistosoma haematobium; 3.5% [95% CI: 3.48-3.513] for Hymenolepis nana and 0.1% [95% CI : 0.093-0.107] for Schistoso mamansoni. The prevalence rate of the co-infection Plasmodium falciparum - Schistosoma haematobium was 2.18% [95% CI= 2.17 - 2.19] in Kalifabougou. CONCLUSION: Praziquantel and Albendazole-based MDA and Artemisinin based combined therapy (ACTs) could explain theobserved low prevalence of helminthiasis and malaria in Kalifabougou, Mali. PMID- 30484585 TI - [Analyze of the performance of procurement and distribution system of antiretroviral, antituberculosis and antimalarials drugs in Benin in 2016]. AB - OBJECTIVE: We aimed to analyze the performance of procurement and distribution system of antiretroviral, antituberculosis and antimalarial drugs in Benin. METHODS: We carried out a cross-sectional study in 2016. Data on the procurement, storage and distribution of drugs were collected by either individual interview or observation of storage sites at the central procurement center for essential medicines (CAME) in Benin. Compliance with the norms of the procurement and distribution of the products was appreciated. At the operational level, order satisfaction, drug expiry and stock status of the targeted health programs were measured based on the participants statements. RESULTS: Three workers of the CAME and 76 of health programs were surveyed. According to the norms, malfunctioning impaired the system of the procurement, storage and the distribution of the products. At the operational level, our study participants reported that antiretroviral drug orders were satisfied in 83%, drugs were distributed within three months of their expiration date in 26- 33%, and the CAME often ran out of antiretroviral drugs (stock-outs)in 69%. CONCLUSION: Malfunctioning impaired the system of the procurement, storage and the distribution of antiretroviral, antimalarial and antituberculosis drugs. These dysfunctions negatively affect the performance of the system. PMID- 30484586 TI - [Relationship between changes in the prevalence of HIV infection in pregnant women from 2006 to 2015 and place of residence in Benin]. AB - OBJECTIVE: We aimed to determine the relationship between changes in the prevalence of HIV infection in pregnant women from 2006 to 2015 and place of residence in Benin. METHODS: In a retrospective and analytical study, were viewed the reports of the annual surveys of HIV infection among pregnant women from 2006 to 2015 across the country. RESULTS: A total of 138,319 pregnant women participated in the annual HIV surveys from 2006 to 2015. The national prevalence of HIV infection among pregnant women between 2006 and 2015 was 2%. The prevalence of HIV infection from 2006 to 2015 in pregnant women increased significantly in departments of Mono (p = 0.001) and Donga (p = 0.001) and decreased in the departments of Collines (p = 0.000) and Couffo (p = 0.001) and in urban areas (p = 0.000). CONCLUSION: Changes in the prevalence of HIV infection among pregnant women between 2006 and 2015 varied across departments and according the urbanization of the residence. The National AIDS control program may take these results into account when planning interventions against HIV for optimal response against the pandemic infection. PMID- 30484587 TI - [Patients' satisfaction survey after tranvesical prostatectomy in the urology department of Gabriel Toure University Hospital]. AB - AIM: This study was aimed to evaluate patients' satisfaction with tranvesical prostatectomy in the Urology department of University Hospital Gabriel Toure according to the (International Prostate Symptoms Score (IPSS) and the quality of life scores. PATIENTS AND METHODS: We conducted a prospective descriptive study over a 12-month period including a consecutive cohort of patients who had transvesical prostatectomy. Each patient was evaluated before and six weeks after the surgery. We used the IPSS as an assessment tool, supplemented by the Quality of Life (SQ) questionnaire. RESULTS: One hundred and thirteen (113) patients aged 71 +/- 8 years old on average were evaluated. The mean duration of symptoms associated with benign prostatic hyperplasia was 19 months and 17% of patients had a mechanical complication. All patients had either moderate or severe lower urinary tract symptoms preoperatively, while 99% of them had an IPSS score <8 postoperatively. CONCLUSION: Transvesical prostatectomy allows an important improvement of the IPSS score of the patients and their satisfaction about their quality of life. PMID- 30484588 TI - [Morbidity of adolescents at the Kaya Regional Hospital Center (Burkina Faso)]. AB - AIM: This study aimed to determine the epidemiological and evolutionary profile of hospital-based adolescent disease in Kaya, Burkina Faso. PATIENTS AND METHODS: We conducted a cross-sectional descriptive studyall adolescents hospitalized from 2014 to 2015 at the regional hospital center (CHR) of Kaya. RESULTS: A total of 1,312 adolescents were hospitalized during the study period, an hospitalization rate of 7.21%. The mean age was 15.52 +/- 3 years with a sex ratio of 0.63. The services most frequently used were gynecology obstetrics (30.87%), surgery (29.72%) and pediatrics (24.16%). Disease states were dominated by the pregnancy, childbirth and the puerperium (24.08%), follow-up of traumatic lesions (19.43%), infectious and parasitic diseases (16.61%). Traumatic ailments were predominant in boys and were mainly due to road accidents (12.73%) and falling from trees. CONCLUSION: Teenagers giving births, traumatic injuries, infectious and parasitic diseases including malaria were the main causes of hospitalization in our study. The solution could come from sex education, use of bed nets and awareness of the driving code. PMID- 30484589 TI - [Hirsutism secondary to a luteal cyst of the right ovary at the department of internal medicine and endocrinology of the Mali Hospital]. AB - : The authors are reporting here for the first time a documented case of androgen secreting luteal cyst responsible for primary sterility in Mali. A 26-year married woman with a history of familial hyper androgenia of diabetes and high blood pressure who consulted for hyper androgen syndrome and primary infertility. Hirsutism with the presence of hairs on her chin, upper lips, thorax, forearms, arms, and her legs under waxing which made a Ferriman and Galloway scoreof10. A pelvic ultrasound coupled with a laparoscopy allowed us to retain the diagnosis of luteal cyst. CONCLUSION: Hyper androgenicity in women is rare and the luteal cystis one of its multiple etiologies. PMID- 30484590 TI - Efficacy of diclofenac mesotherapy for the treatment of chronic neck pain in spondylartrosis. PMID- 30484591 TI - Bioavailability of a fixed combination of intramuscular diclofenac 75 mg + thiocolchicoside 4 mg single dose vs. single components. PMID- 30484592 TI - Clinical use of cardiac troponin for acute cardiac care and emerging opportunities in the outpatient setting. AB - Cardiac troponin (cTn) testing has evolved significantly in recent times. Because of increased sensitivity, its use has shifted from a marker used solely to help diagnose acute myocardial infarction (MI) to a marker than can be used in the outpatient setting, as well as for both detection of myocardial injury and risk stratification. Its main role remains in the diagnosis of acute MI and the risk stratification of patients presenting with suspected acute coronary syndrome. The analytical improvements in assays leading to precise high-sensitivity cTn assays have contributed to the development of numerous strategies to identify patients at both low- and high-risk for acute MI within a few hours. These approaches should reduce overcrowding in the emergency room and expedite triaging. The ability of measuring cTn in most patients using high- sensitivity (hs) assays has allowed for the opportunity to examine its use in the detection of cardiotoxicity in patients undergoing chemotherapy, as well as exploring the application in both primary and secondary prevention of coronary artery disease. This particular field of research has become increasingly complex, partly due to the numerous cTn assays available (I and T; point- of-care, contemporary, hs) and an array of approaches in which one can use the test. Given these complexities, the purpose of this document is to summarize the analytical and clinical information relevant to cTn assays, in particular, hs-cTn assays, and describe present and future opportunities for use of cTn in acute cardiac care and in the outpatient setting. PMID- 30484593 TI - A clinical comparative study of effects of different corneal refractive surgeries on postoperative stability of tear film. PMID- 30484594 TI - Ex-PRESS glaucoma shunt implantation and trabeculectomy combined with mitomycin C in the treatment of uveitic glaucoma. PMID- 30484595 TI - ? AB - Summarizing paper contains short analysis of the publications resulting cell biological, molecular genetic and population genetic investigations devoted to studying of accute radiation exposure and chronic radiation contamination effects on biological systems after disaster on Chornobyl nuclear power station in 1986. PMID- 30484596 TI - ? AB - The main results of thirty-year period of repeated screening programs and observational studies in contaminated and non-contaminated regions of Belarus are analyzed. The possible reasons of discrepant and contradictory data about the consequences of Chernobyl catastrophe delivered by different study groups during early period after the accident are discussed. High incidence of thyroid nodular disease and cancer in children and adolescence after the catastrophe are described. The research shows high effectiveness of screening in early diagnosis thyroid disorders and radiation-induced thyroid cancer in different regions of Belarus and in various time points. PMID- 30484597 TI - ? AB - The review presents data on the basic molecular ge-netic mechanisms of formation of papillary thyroid carcinoma. The participation of ionizing radiation in the cancer pathogenesis was analyzed. The role of tu-mor microenvironment, inflammation and nuclear trans-cription factor NF-kappaB in the initiation and development of papillary thyroid carcinoma was shown. PMID- 30484598 TI - ? AB - In the last 60 years dramatically increased the content of nitrates in groundwater due to intensive use of nitrogen fertilizers in agriculture. Research in post-Chernobyl period has shown that a sharp increase in the incidence of thyroid cancer depends not only on the level of thyroid dose, but also on the level of nitrates in groundwater. PMID- 30484599 TI - ? AB - Recently, radiofrequency ablation has been increasingly used for the treatment of thyroid nodules. The widespread introduction of this method, however, hampered by the lack of data on efficacy and safety of different devices that are currently on the market, the selection of the optimal mode of procedure also remains to be elucidated. Experimental data obtained during the application of the original patented device is presented. The results make it possible to move from ex vivo experiments to clinical practice. PMID- 30484600 TI - The Video Consulting Emergency (VCE) protocol: a proposition from the World Society of Emergency Surgery members for the initial management of non traumatic acute abdomen. AB - BACKGROUND: Our aim is to present the Video-Consulting Emergency (VCE) protocol to improve the decision-making process between an on-site emergency physician and a remote acute care surgeon using a smart phone and the FaceTime application and the Acute Abdominal Decision Making (AADM) model proposed by World Society of Emergency Surgeons members. METHODS: VCE protocol involves emergency physician and the on-call emergency surgeon. Both must be provided a smart phone for 24 hours video-consulting with FaceTime application. AADM method is a simple, systematic, diagnostic methodology developed by WSES to guide and support the emergency physician (EM) throughout the management of acute abdominal pain in the emergency department (ED). The aim is to distinguish life-threatening abdominal diseases from non-specific abdominal pain. With FaceTime video consultations, EM can be supported and guided in his clinical reasoning. RESULTS: VCE protocol in ED could be fundamental for an effective first surgical screening and it is an interesting clinical tool with the potential to improve clinical evaluation of patients admitted for acute abdomen. CONCLUSIONS: Its application could decrease healthcare costs related to unnecessary exams, admissions, surgeries or transfers. PMID- 30484601 TI - Structured training program in colorectal surgery: the robotic surgeon as a new paradigm. AB - BACKGROUND: One major issue in general surgery is how to provide novice surgeons with a structured training program (STP). The aim of our study is to assess the efficacy of a STP in robotic colorectal surgery for young surgeons without prior experience in both open and laparoscopic colorectal surgery, who were autonomous in basic minimally-invasive surgical procedures. Right colectomy with intracorporeal anastomosis has been chosen as a model. METHODS: Between May 2015 and December 2017 two junior attending surgeons were trained through a STP. Right colectomy was divided into three main learning modules (colonic mobilization, vascular control, intracorporeal anastomosis) and each one was carried out by the trainees for at least two times under direct supervision of the senior surgeon. After the initial robotic cases completely performed under formal proctoring, they were privileged to perform robotic right colectomy independently without a mentor (20 procedures). Operative time, conversion rate, intra- and post operative complications, length of stay and pathological outcomes were the variables analyzed to assess the effectiveness of the STP. RESULTS: The mean operative time was 200 minutes and no conversion was required. Neither intraoperative nor major post-operative complications were recorded and the mean length of hospital stay was 6 days. Mean nodal yield was 21. CONCLUSIONS: A STP in robotic colorectal surgery is feasible and effective. Right colectomy represents a good model as first step of the program in order to develop multiple technical skills. Previous experience in open or laparoscopic colorectal surgery may not be necessary. PMID- 30484602 TI - ? AB - Thirty years after the Chernobyl explosion we still lack information regarding the genetic effects of radionuclide contamination on the plant population. For example, are plants adapting to the low dose of chronic ionising irradiation and showing improved resistance to radiation damage? Are they coping with changing/increased pathogenicity of fungi and viruses in the Chernobyl exclusion zone? Are plant populations rapidly accumulating mutational load and should we expect rapid microevolutionary changes in plants in the Chernobyl area? This review will try to summarise the current knowledge on these aspects of plant genetics and ecology and draw conclusions on the importance of further studies in the area around Chernobyl. PMID- 30484603 TI - ? AB - The paper discusses different methodological approaches to the study of transgenerational alterations of metabolic pathways in soybean and flax seeds in the process of adaptation to chronic irradiation in the Chernobyl alienation zone. A combination of general biological methods and novel approaches, such as genomics, proteomics, cytogenetics, and mutagenesis, allows researchers to analyze an organism's systemic response and identify the latent chronic irradiation effects in plants from the Chernobyl zone. The proteomic approaches are especially efficient, since they range from the identification of changes in abundance and folding of individual proteins to the characterization of posttranslational modifications, trends of qualitative changes during seed maturation, or protein-protein interactions during plant growth and development under permanent impacts of stress factors. The application of proteomics opens new horizons in the understanding of the hidden mechanisms behind the impact of chronic low-dose radiation on living cells and makes it possible to visualize metabolic network alterations regardless of their transcriptional, translational, or epigenetic nature. PMID- 30484604 TI - ? AB - It is known that the most suitable plant indicator targets for radiation pollution biomonitoring are conifers, because they have high radiosensitivity. In this review are briefly considered previously accumulated information about the genetic nature of morphological abnormalities in gymnosperms, induced by acute and chronic irradiation in the exclusion zone of the Chornobyl nuclear power plant. Since in the last decade appeared additional number of important research results, dedicated to the analysis of molecular biological and molecular genetic effects of chronic irradiation on the coniferous plants growing in the exclusion zone of the Chornobyl disaster, all these results are also analyzed in current review. PMID- 30484605 TI - ? AB - Development of RNAi-based therapeutics is a fast growing field of pharmaceutical industry. Using plants for production of pharmaceutically valuable siRNAs may have significant advantages of cost-effectiveness, scalability and low risk of contamination with human pathogens. If edible plant species are genetically engineered to synthesize siRNAs, the costly stage of target product purification may be omitted. We describe the establishment of transgenic lettuce plants producing shRNA targeting delta isoform of protein kinase C (PKC-delta), an effective target for RNAi-based treatment of arterial hypertension. Transgenic lettuce plants were obtained by Agrobacterium-mediated transformation with genetic constructs harboring antiPKC and scrambled (control) shRNA genes. The presence of transgenes was proved by PCR analysis, and the accumulation of antiPKC shRNA was estimated using RT-qPCR technique. Six transgenic lettuce lines showed varying levels of antiPKC shRNA expression with the highest value reaching 14 +/- 9 % of highly abundant endogenous lettuce micro RNA (miR156a), or 12.7 fmol/g dry weight. Plants carrying either antiPKC or scrambled shRNA genes flowered normally, but did not produce seeds. The described transgenic lettuce plants accumulating antiPKC siRNA are the subject for animal testing and can be considered as a raw material for the development of novel antihypertensive drugs. PMID- 30484606 TI - ? AB - The transcriptomes from different organs and tissues of western poplar, eucalyptus, soybean and common bean were studied. The expression level of cellulose synthase genes was notably different in different types of tissues and organs in studied plants. For common bean and eucalyptus transcriptome the domination of certain cellulose synthase genes was typical. These prevailing genes made up more than 50 % of the total expression pull of cellulose synthases. On the contrary, cellulose synthase expression pulls of wes-tern poplar and soybean were distributed between multiple genes. The different expression strategies of CesA-genes may reflect a phylogenetic processes that occurred in genomes studied. PMID- 30484607 TI - ? AB - The degree of dominance and the coefficient of heritability have been investigated as indicators of the allelic interaction at loci Rht8 and Rht-B1, which is characterized by the partial, complete or over dominance of greater plant height and by the low or medium heritability. Alleles with a weaker or without direct negative effect dominate under alleles reducing the plant height stronger. The impact of weather conditions on a change of the dominance is discussed. The line Kooperatorka has an additional allele (alleles), causing the greater heights of plants, with partially recessive mode of inheritance. An unidentified half-dominant dwarfing gene (genes) is present in a genotype of the line Odeska 3. The presence of a heterosis, caused by heterozygosity for genes, which are not critical in our research, distorts the evaluation of the allelic relationship characteristics studied. PMID- 30484608 TI - ? AB - Results of fluorescence microscopic research and quantitative luminescent analysis of pathogen induced callose accumulation in winter wheat seedlings of two cultivars different in resistance to eye spot causal agent are presented. Higher content of constitutive callose in intact seedlings of unsusceptible cultivar at the initial stages of vegetation was determined. It correlates with resistance of this cultivar to the eye spot causal agent. The increased pathogen induced accumulation of callose in seedlings of susceptible cultivar is revealed, but didn't influence it protection against pathogen. PMID- 30484609 TI - ? AB - The results of study interaction of genes CTR1, ALF3 and NPH4, IAR2 inheritance attributes of the root system Arabidopsis. It is set that there is a recession epistasis in the second generation of crossing of plants mutant lines ctr1-1 * alf3-1 (alf3-1 alf3-1 > CTR1_). At crossing of plants mutant lines nph4-1 * iar2 1 there is polymeric co-operation of genes NPH4 and IAR2 in the generation of F2. PMID- 30484610 TI - ? AB - ISSR-PCR markers were used to assess genetic diversity and to elucidate relatedness among 21 Ukrainian and 3 West European sweet cherry varieties, which are widely cultivated in Ukraine. The discriminatory potential was tested for 11 ISSR-PCR primers, which produced 193 amplicons. UBC 835, 836, 841 and 881 were identified as the best primers suitable for routine application. The studied cultivars appear to be genetically highly heterogenic and can be divided in two main groups. The first one includes closely related cultivars obtained by hybridization of Drogan's Yellow (Drogans gelbe Knorpelkirsche), Valerii Chkalov and some other forms. The second group comprises less similar cultivars derived from several West-European and unknown ancestors. Origin of several Ukrainian cultivars is discussed. PMID- 30484611 TI - ? AB - A novel AluI-polymorphism in the fourth intron of chicken growth hormone gene was shown. It was detected the cytosine to thymine transition in the restriction site for AluI. Primers, that flanking the 460 bp fragment of the fourth intron, containing a polymorphic restriction site for AluI, was designed. The nucleotide sequence fragments amplified polymorphic variants was determined. Using designed primers was analyzed the genetic structure of populations of White Plymouth Rock, Poltava Clay, Rhode Island Red and Borkovskaya Barvistaya chicken breeds. It was found that growth hormone gene (by AluI-polymorphism in the fourthintron) was polymorphic in all experimental populations. Frequencies of alleles C and T in chicken population of White Plymouth Rock breed were 0,14 and 0,86; Rhode Island Red - 0,3 and 0,7; Poltava Clay - 0,04 and 0,96; Borkovskaya Barvistaya - 0,08 and 0,92 respectively. The tendency to increase egg production and egg weight of chicken with C/C genotype, as well as meat quality (live weight, carcass weight, weight of pectoral muscles) of chickens with genotype T/T of Rhode Island Red chicken breed was shown. PMID- 30484612 TI - ? AB - Formaldehyde (FA) interacts with biological molecules such as DNA and it induces DNA-protein cross-links (DPCs), oxidative stress, reactive oxygen species (ROS), methylation, chromosomal damage, fragmentation, and adducts of DNA, which are considered the most important genotoxic effects caused by exposure to FA. The purpose of this study was to evaluate the percentage of DNA fragmentation on lymphocytes and spermatozoa from Wistar rats exposed to different doses of FA. The results about the percentage of fragmentation of DNA in lymphocytes and spermatozoa, were statistical different from controlled group versus treated groups respectively to (p < 0.05). Pathological changes were observed in the seminiferous tubules, especially in rats exposed to 30 mg/kg of FA. This study provided additional evidence supporting that FA induces DNA strand breaks in both cells and therefore genotoxic damage in Wistar rats. PMID- 30484613 TI - ? AB - Nuruozak (Salvia leriifolia Benth), is a perennial herbaceous plant that is endemic to Iran and has recently been introduced as a medicinal plant. Artificial polyploidy is an efficient method to increase the production of secondary metabolites and can result in a whole spectrum of genetic, molecular and physiological modifications. In order to produce an autotetraploid population of nuruozak, various concentrations of colchicine (0.00, 0.05, 0.10, 0.20 or 0.50 % w/v) were applied to the seeds and shoot apical meristems of young seedlings at the fourth leaf-stage. Microscopic studies, flow cytometry analysis and chromosome counting were conducted to select tetraploid nuruozak plants. Furthermore, the effects of ploidy level on the essential oil content and composition and biomass production of nuruozak plants, as well as selected structural and physiological characteristics were studied. Based on the number of the obtained tetraploids, treatment of shoot apical meristems was more efficient than seed treatment. Structural and phytochemical characteristics, chlorophyll content and photosynthetic rate were affected by the increase in ploidy level. In addition to the higher potential in biomass production, tetraploid plants produced eight new compounds which were absent in diploids. PMID- 30484614 TI - ? AB - The genotypic features of morphogenesis and regeneration in vitro for five maize inbreds of perspective breeding Lancaster heterotic group compared to representatives of others heterotic groups - PLS61, A188 and Chi31 were studied. It was identified that the ratio of such types of morphogenesis as organogenesis and embryoidogenesis in callus culture was determined by the explant genotype and the concentration of sucrose in the medium for callusogenesis. The frequency of embryoidogenesis as the most effective type of morphogenesis for further regeneration in Lancaster inbreds averaged about 40.0 +/- 12.8 %, while for other heterotic groups it was only 14.0 +/- 4.0 %. For Lancaster heterotic group sucrose at the concentration of 30 g/l in the medium for callusogenesis provided further regeneration through embryoidogenesis at the level of 26.5 +/- 15.4 %, but sucrose at the concentration of 60 g/l provided it at 57.7 +/- 19.8 %. For inbreds which represent other heterotic groups sucrose content in the medium for callusogenesis did not affect further regenaration, the level of embryoidogenesis at 30 and 60 g/l sucrose amounted 11.0 +/- 7.0 and 15.0 +/- 4.8 % correspondingly. PMID- 30484615 TI - ? AB - This survey paper contains a brief analysis of publications included in current issue of scientific journal "Cytology and Genetics" dedicated to its 50th anniversary. These papers reflect scientific achievements of their authors in the field of genetics and cell biology and underine the potential of these two biological disciplines, forming "double helix" of the journal. PMID- 30484616 TI - ? AB - The study of viruses lasts for more than a century since their discovery in 1892. In recent decades, viruses are also being actively exploited as a biotechnological tool. Plant-virus-driven transient expression of heterologous proteins is an actively developing production platform; it is the basis of several industrial processes that are currently being used for the production of multiple recombinant proteins. Viral vectors have also become useful tools for research. Viral vectors delivered by Agrobacterium (magnifection) provide for high pro-tein yield, rapid scale up and fast manufacturing. In this review, we explore modern approaches for bio technological production of recombinant proteins in plants using viral vectors. PMID- 30484618 TI - ? AB - An overview on the effects of real and simulated microgravity on certain cell components and processes, including new information obtained recently, is presented. Attention is focused on the influence of microgravity on the cytoplasmic membrane state, transcriptome and proteome, cell wall remodeling, and Ca2+-signaling in plant cells that are not specialised to gravity perception. It is emphasized the exceptional significance of the data on the organ-specific remodeling of the transcriptome and proteome in response to space flight, that discovers new advanced approaches to implement the fundamental and applied problems of plant space biology. PMID- 30484617 TI - ? AB - It has been described achievements of cell and genetic engineering that led to formation of new genetics chapter - transmission genetics. It has been analyzed results and showed new opportunities in the field of transgenomic somatic hybrids and cybrid obtaining, production of transgenic plants with agronomic pharmaceutical application, development of transplastomic plants, accu-mulation of recombinant proteins by using the transient expression of foreign genes in plants. PMID- 30484619 TI - ? AB - Diversity of Ukrainian winter common wheat varieties was studied with respect to the storage protein loci Gli-A1, Gli-B1, Gli-D1, Glu-A1, Glu-B1, Glu-D1, Gli-A3, Gli-B5, and Gli-A6 (362 varieties) and markers for the Lr34/Yr18/Pm38/Sr57/Bdv1 gene conferring moderate resistance to a number of biotrophic pathogens, the Tsn1 gene for sensitivity to the toxins A of the necrotrophic fungi Pyrenophora triticirepentis and Stagonospora nodorum, the Tsc2 gene for sensitivity to the toxin B of P. triticirepentis, and the TDF_076_2D gene for moderate resistance to Fusarium head blight (181 varieties). Significant differences in frequencies of alleles at these marker loci between groups of varieties developed in different soil and climatic zones were revealed. The retention of a set of predominant alleles of a certain zone in different periods of breeding was confirmed. At the same time, the appearance of new allele associations in the groups of varieties of the Steppe (in particular Gli-A1g and Glu-B1al) and the Central Forest-Steppe (1AL/1RS and Glu-B1d) in the last two decades has been noted. Nonrandom associations between alleles of disease resistance genes as well as alleles of disease resistance genes and storage protein alleles were revealed PMID- 30484620 TI - ? AB - A cross was made of Elymus repens onto the wheat cultivar Crocus and BC1 progeny advanced to BC1F7 by single seed descent. Sixteen lines were selected based on agronomic performance and evaluated in an FHB epiphytotic nursery. Eight lines with FHB resistance were selected. Based on GISH analysis, line P1142-3-1-5 had 42 chromosomes with one pair of chromosomes showing telomeric translocations on both arms. This chromosome was identified as 3D by using SSR markers. An evaluation of lines with single translocations revealed that FHB resistance was contributed by the translocation on the long arm of chromosome 3D. That line has minimal linkage drag and should be amenable to applications in breeding for disease resistance. PMID- 30484621 TI - ? AB - The influence of treatment with the donor of nitric oxide sodium nitroprusside (SNP - 0,5 mM) on the salt resistance of Arabidopsis plants of wild-type (Col-0) and transformant with the gene of bacterial salicylatehydroxylase (NahG) was compared. The basic resistance against the salt stress (200 mM of NaCl) in transformants NahG was higher. In the conditions of salt stress these plants differed in the higher activity of antioxidant enzymes and the raised content of carbohydrates and anthocyans. The treatment with NO donor increased the salt resistance of plants of both genotypes that expressed in the decrease of growth inhibition, reduction of oxidative damages and preservation of chlorophyll pool in the leaves. After the influence of salt stress the activity of superoxide dismutase and guaiacol peroxidase in treated with SNP wild type plants and transformants was higher, than in the appropriate untreated plants. In the wild type plants, treated with NO donor, the content of proline in leaves after the salt stress was lower, than in untreated. The treatment with SNP of transformants NahG, on the contrary, led to more essential increase of proline content in leaves under the salt stress. The conclusion is made that plants of wild type Col 0 and transformant NahG have differences in the functioning of protective systems under the salt stress, and the induction of protective systems in A. thaliana plants under the influence of nitric oxide can occur without salicylate participation. PMID- 30484622 TI - ? AB - MuDR exhibits the highest transposition activity and insertional mutagenesis frequency in Mutator (Mu) family. If we isolate the MuDR-insertion-specific flanking sequences (MuDRFs), it will be crucial for using Mu element-mediated mutants. The MuDR-TAIL-PCR system was constructed and optimized using a combination of MuDR-TIR-nested specific primers and 12 arbitrary degenerate (AD) primers, modified reaction system and procedure and mutant DNA templates of 87 genotypes from M2 or M2:3 families created by crossing the W22::Mu line (active MuDR donor parent) from the UniformMu population with the Zong31 (Z31) line (recipient parent). Here 129 different MuDRFs were acquired by MuDR-TAIL-PCR, accounting for 86.60 % of the total mutant-specific agarose gel bands. In addition, we confirmed the authenticity of the non-redundant flanking sequence amplifications. The amplified non-redundant flanking sequences accounted for 65.12 % of the total MuDRFs, and 88.00 % of the non-redundant MuDRFs were inserted inside the genes. These results show that the MuDR-TAIL-PCR system that we developed can be used for specifically isolating MuDRFs. PMID- 30484623 TI - Oligonucleotide Drugs for Transthyretin Amyloidosis. PMID- 30484624 TI - Oligonucleotide Drugs for Transthyretin Amyloidosis. PMID- 30484625 TI - Extender Unit Promiscuity and Orthogonal Protein Interactions of an Aminomalonyl ACP Utilizing Trans-Acyltransferase from Zwittermicin Biosynthesis. AB - Trans-acting acyltransferases (trans-ATs) are standalone enzymes that select and deliver extender units to polyketide synthase assembly lines. Accordingly, there is interest in leveraging trans-ATs as tools to regioselectively diversify polyketide structures. Yet, little is known regarding the extender unit and acyl carrier protein (ACP) specificity of trans-ATs, particularly those that utilize unusual ACP-linked extender units. For example, the biosynthesis of the antibiotic zwittermicin involves the trans-AT ZmaF, which is responsible for installing a rare ACP-linked aminomalonyl extender unit. Here, we developed a method to access a panel of non-natural and non-native ACP-linked extender units and used it to probe the promiscuity of ZmaF, revealing one of the most promiscuous ATs characterized to date. Furthermore, we demonstrated that ZmaF is highly orthogonal with respect to its ACP specificity, and the ability of ZmaF to trans-complement noncognate PKS modules was also explored. Together, these results set the stage for further engineering ZmaF as a tool for polyketide diversification. PMID- 30484626 TI - Monoamine biosynthesis via a noncanonical calcium-activatable aromatic amino acid decarboxylase in psilocybin mushroom. AB - Aromatic L-amino acid decarboxylases (AAADs) are a phylogenetically diverse group of enzymes responsible for the decarboxylation of aromatic amino acid substrates into their corresponding aromatic arylalkylamines. AAADs have been extensively studied in mammals and plants as they catalyze the first step in the production of neurotransmitters and bioactive phytochemicals, respectively. Unlike mammals and plants, the hallucinogenic psilocybin mushroom Psilocybe cubensis reportedly employs an unrelated phosphatidylserine-decarboxylase-like enzyme to catalyze L tryptophan decarboxylation, the first step in psilocybin biosynthesis. To explore the origin of this chemistry in psilocybin mushroom, we generated the first de novo transcriptomes of P. cubensis and investigated several putative L-tryptophan decarboxylase-like enzymes. We report the biochemical characterization of a noncanonical AAAD from P. cubensis (PcncAAAD) that exhibits substrate permissiveness towards L-phenylalanine, L-tyrosine, and L-tryptophan, as well as chloro-tryptophan derivatives. The crystal structure of PcncAAAD revealed the presence of a unique C-terminal appendage domain featuring a novel double-beta barrel fold. This domain is required for PcncAAAD activity and regulates catalytic rate and thermal stability through calcium binding. PcncAAAD likely plays a role in psilocybin production in P. cubensis and offers a new tool for metabolic engineering of aromatic-amino-acid-derived natural products. PMID- 30484627 TI - Photophysics at Unusually High Dye Concentrations. AB - The study of the interaction of light with systems at high dye concentrations implies a great challenge because several factors, such as emission reabsorption, dye aggregation, and energy trapping, hinder rationalization and interpretation of the involved photophysical processes. Space constraints induce dye interaction even in the absence of ground state stabilization of dimers and oligomers. At distances on the order of 1 nm, statistical energy traps are usually observed. At longer distances, excited state energy transfer takes place. Most of these factors do not result in ground state spectroscopic changes. Rather, fluorescence phenomena such as inner filter effects, concentration-dependent Stokes' shifts, and changes in quantum yields and decay times are evidenced. Photophysical studies are commonly carried out at high dilution, to minimize dye-dye interactions and emission reabsorption, and in the absence of light scattering. Under these conditions, the physical description of the system becomes rather simple. Fluorescence and triplet quantum yields become molecular properties and can be easily related to ratios of rate constants. However, many systems containing dyes able to fulfill specific functions, whether man-made or biological, are far from being dilute and scattering-free. The photosynthetic apparatus is a paradigmatic example. It is clear that isolation of components allows gathering relevant information about complex systems. However, knowledge of the photophysical behavior in the unaltered environment is essential in most cases. Complexity generally increases when light scattering is present. Despite that, our experience shows that light scattering, when correctly handled, may even simplify the task of unraveling molecular parameters. We show that methods and models aiming at the determination and interpretation of fluorescence and triplet quantum yields as well as energy transfer efficiencies can be developed on the basis of simple light-scattering theories. Photophysical studies were extended to thin films and layer-by-layer assemblies. Procedures are presented for the evaluation of fluorescence reabsorption in concentrated fluid solutions up to the molar level, which are being applied to ionic liquids, in which the emitting species are the bulk ions. Fluorescence reabsorption models proved to be useful in the interpretation of the photophysics of living organisms such as plant leaves and fruits. These new tools allowed the assessment of chlorophyll fluorescence at the chloroplast, leaf and canopy levels, with implications in remote sensing and the development of nondestructive optical methods. PMID- 30484628 TI - "Guide Star" Assisted Noninvasive Photoacoustic Measurement of Glucose. AB - A novel "guide star" assisted photoacoustic (GSPA) method for noninvasive glucose measurement has been proposed. Instead of receiving PA signals that are directly generated by tissue, a virtual photodiode is employed to amplify the PA signal difference regarding amplitude and peak arrival time caused by glucose concentration variations in an indirect way. Being different from traditional PA spectroscopy, this method can improve sensitivity and accuracy by optimizing optical path lengths (or tissue thickness). On the other hand, being superior to near-infrared (NIR) spectroscopy, it utilizes both optical absorption and acoustic propagation velocity information offered by PA signals. Theoretical analysis and simulation have been done to illustrate how the concentration change affects the PA waveform. In vitro experiments on aqueous glucose solution were conducted with concentrations varying in human physiological range (50~350 mg/dL). Performance of quartz cuvettes with 1-mm and 2-mm optical path lengths were compared in terms of correlation quality (R2), degree of agreement (Bland Altman plot) and clinical accuracy (Clarke's Error Grid analysis) to demonstrate the scalability of sensitivity provided by the indirect method. Longer optical length shows better sensitivity and accuracy in this case. Moreover, detection was also done on human blood serum to further prove the potential of the proposed method for clinical application.Our proposed method provides solution to enhance sensitivity, facilitating development of portable and low-cost PA sensors with low power laser diodes for noninvasive glucose monitoring and other applications. PMID- 30484629 TI - High sensitivity plasmonic sensing of hydrogen over a broad dynamic range using catalytic Au-CeO2 thin film nanocomposites. AB - Next-generation gas-sensor technologies are needed for diverse applications including environmental surveillance, occupational safety, and industrial process control. However, the dynamic range using existing sensors is often too narrow to meet demands. In this work plasmonic films of Au-CeO2 that detect hydrogen with 0.38% and 60% lower and upper detection limits in an oxygen-free atmosphere experiment are demonstrated. The observed 15nm peak shift was 4x stronger versus other plasmonic H2 sensors. The proposed sensing mechanism that involves H2 dissociation by Audelta+ nanoparticles, was validated using XPS, kinetics, and Arrhenius studies. Our understanding of this remarkable sensing behavior in oxygen-free conditions opens new horizons for packaging, art conservation, industrial process control and other applications where conventional oxygen dependent sensors lack broad dynamic range. PMID- 30484630 TI - Excited-state intramolecular proton transfer-based multifunctional solid-state emitter: a fluorescent platform with 'write-erase-write' function. AB - The excited-state intramolecular proton transfer (ESIPT)-based molecular probes have drawn significant attention owing to their environment-sensitive fluorescence properties, large Stokes shift and emerged as building blocks for the development of molecular sensors and switches. However, most of the ESIPT based fluorophores exhibit weak emission in the solid state limiting the scope of real-time applications. Addressing such issues, herein, we presented a C3 symmetric like molecular architecture employing a simple one-step Schiff base condensation between triaminoguanidinium chloride and 3,5-ditertbutyl-2 hydroxybenzaldehyde (TGHB). The temperature-dependent fluorescence studies including at 77 K indicated the strong emission from the keto tautomer compared to that of the enol. The facile ESIPT in TGHB in the solid-state led to a remarkable enhancement of fluorescence quantum yield of 1600-times compared to that of the solution (lambdaem = 545 nm) by restricting the intramolecular rotation and subsequently suppressing the nonradiative deactivation. The excited state processes were further elucidated through time-resolved fluorescence measurements. TGHB exhibited turn on-off fluorescence upon exposure to acid /base vapor in the form of powder as well as transparent, free-standing thin film. A rewritable and erasable fluorescent platform was demonstrated using TGHB as molecular ink, which offers potential testbed for performing multiple times 'write-erase-write' cycles. In addition, TGHB, possessing multiple binding sites (O and N donor) involving the central core of triaminoguanidinium cation, displayed selective turn-on fluorescence with Zn2+. The structure-property relationship revealed in the present study provides an insight towards the development of novel cost-effective multifunctional materials promising for stimuli-responsive molecular switches. PMID- 30484631 TI - DNA Origami as Seeds for Promoting Protein Crystallization. AB - This study reports the first experimental evidence of DNA origami as a seed resulting in the increase in probability of protein crystallization. Using DNA origami constructed from long single-stranded M13 DNA scaffolds folded with short single-stranded DNA staples, it was found that the addition of the DNA origami in concentrations of 2-6 nM to mixtures of a well-characterized protein (Catalase) solution (1.0-7.0 mg/mL) resulted in a higher proportion of mixtures with successful crystallization, up to 11x greater. The improvement to crystallization is evident particularly for mixtures with low concentrations of Catalase (< 5 mg/mL). DNA origami in different conformations: a flat rectangular sheet and a tubular hollow cylinder, were examined. Both conformations improved crystallization as compared to control experiments without M13 DNA or non-folded M13 DNA, but exhibited little difference in the extent of protein crystallization improvement. This work confirms predictions of the potential use of DNA origami to promote protein crystallization, with potential application to systems with limited protein available or difficult to crystallize. PMID- 30484632 TI - Structural and Metal Ion Effects on Human Topoisomerase IIalpha Inhibition by alpha-(N)-Heterocyclic Thiosemicarbazones. AB - Our previous research has shown that alpha-(N)-heterocyclic thiosemicarbazone (TSC) metal complexes inhibit human topoisomerase IIalpha (TopoIIalpha), while the ligands without metals do not. To find out the structural elements of TSC that are important for inhibiting TopoIIalpha, we have synthesized two series of alpha-(N)-heterocyclic TSCs with various substrate ring segments, side chain substitutions and metal ions, and we have examined their activities in TopoIIalpha-mediated plasmid DNA relaxation and cleavage assays. Our goal is to explore the structure-activity relationship of alpha-(N)-heterocyclic TSCs and their effect on TopoIIalpha. Our data suggest that, similar to Cu(II)-TSCs, Pd(II)-TSC complexes inhibit plasmid DNA relaxation mediated by TopoIIalpha. In TopoIIalpha-mediated plasmid DNA cleavage assay, the Cu(II)-TSC complexes induce higher levels of DNA cleavage than their Pd(II) counterparts. The Cu(II)-TSC complexes with methyl, ethyl and tert-butyl substitutions are slightly more effective than those with benzyl and phenyl groups. The alpha-(N)-heterocyclic ring substrates of the TSCs, including benzoylpyridine, acetylpyridine, and acetylthiazole, do not exhibit a significant difference in TopoIIalpha-mediated DNA cleavage. Our data suggests that the metal ion of TSC complexes plays a predominant role in inhibition of TopoIIalpha, the side chain substitution of the terminal nitrogen plays a secondary role, while the substrate ring segment has the least effect. Our molecular modeling data support the biochemical data, which together provide a mechanism by which Cu(II)-TSC complexes stabilize TopoIIalpha mediated cleavage complexes. PMID- 30484633 TI - Stable, Strain-Sensitivity Conductive Hydrogel with Anti-freezing Capable, Remoldability and Reusability. AB - Conductive hydrogels have important potential in biosensors, bioactuators and health recording electrodes, but they are often troubled by sensitivity, operating temperature range and whether they can be recycled or not. In this paper, conductive hydrogels polyvinyl alcohol/glycerol/polyaniline (PGA) were prepared by organic combination of low-cost polyvinyl alcohol (PVA), polyaniline (PANi)and glycerin. First, the effects of PVA, glycerol, aniline/phytic acid solution concentration on the mechanical properties, electrical properties and frost resistance of the PGA gel were discussed. Second, the interaction energies of PVA, PANi, phytic acid, glycerol and water molecules were analyzed by Materials Studio. Then, a simple biosensor fabricated using the PGA gel realized the detection of the conventional motion signal of the human body. The conductive gel has high sensitivity (GF=2.14), fast response time (230ms) and can be circulated several times (~540 cycles). Furthermore, the PGA conductive gel can maintain good electrical conductivity (0.32S/m) and mechanical properties even at -20 degrees C. Also, the gel can be recovered by heating injection, cooling and cyclic freeze-thaw three-step method. It is believed that the PGA conductive gel would be used as a novel multifunctional material at subzero temperatures in various fields, such as flexible electrode, sensors, and wearable devices. PMID- 30484634 TI - Fouling-resistant and Self-cleaning Aliphatic Polyketone Membrane for Sustainable Oil-Water Emulsion Separation. AB - The cost-effective treatment of emulsified oily wastewater discharged by many industries and human societies is a great challenge. Herein, based on an aliphatic polyketone (PK) polymer with good membrane formation ability and intrinsic intermediate hydrophilicity, a new class of reduced PK membranes (rPK) combining an all hydrophilic and electrically neutral surface chemistry comprising ketone and hydroxyl groups, and a fibril-like morphology featuring re entrant structure were facilely prepared by phase separation and following fast surface reduction. The synergetic cooperation of surface chemistry and surface geometry endowed the prepared membranes with excellent superhydrophilicity, underwater superoleophobicity, and underoil superhydrophilicity, in addition to anti-protein-adhesion property. Thus, fouling-resistant and self-cleaning filtrations of challenging oil-in-water emulsions containing adhesive oil, surfactant, high salinity and proteins were effortlessly realized with high flux (up to ~50000 Lm-2h-1bar-1), slow and reversible flux decline and low oil permeate (<20 ppm). In contrast, a commercial superhydrophilic microporous membrane made of mixed cellulose ester (MCE) suffered severe fouling gradually or immediately when carrying out the emulsion filtrations, due to its less than ideal surface properties. It is believed that this class of membranes with desirable superwettability, high flux and preparation simplicity can be a potential new benchmark for high performance and large-scale oil-water separation in complex environments. PMID- 30484635 TI - Effect of Defects on Diffusion Behaviors of Lithium-ion Battery Electrodes: In Situ Optical Observation and Simulation. AB - Lithium-ion batteries (LIBs) with high energy efficiency are urgently needed in various fields. For the LIBs electrodes, defects would be generated during manufacture processes and mechanical degradation, and the defects significantly impact the stability and performance of LIBs. However, the effects of electrode defects on the electrochemical processes are still not clear. Herein, an in situ optical observation system is developed for monitoring the Li diffusion around the pre-introduced defects in the commercial graphite electrodes. The experiments show the gas-filled defects vertical to the direction of the Li diffusion would obviously decelerate Li diffusion, while the electrolyte-filled defects parallel to the direction of the Li diffusion would accelerate Li diffusion. In addition, finite element analysis (FEA) suggests consistent with the experiments, showing nonuniform distribution of local Li concentration around the defect. The equivalent diffusivity obtained by FEA is also dependent on the configuration of the defects. The diffusivities of electrolyte-filled parallel defect and gas filled vertical defect are 12.6 % and 11.0 %, respectively. For the gas-filled defects, the size-effect calculation manifests that equivalent diffusivity would decrease with the enlarged defect size, and the shape of the defects would substantially impact the decrease rate. The results directly reveal the mechanisms of defect induced diffusion behavior change in the electrodes by the new equivalent 2D experiments, and the equivalent diffusivity would be useful for optimizing electrode designs in LIBs. PMID- 30484636 TI - Analyzing Solid-Phase Natural Organic Matter using Laser Desorption Ionization Ultrahigh Resolution Mass Spectrometry. AB - Extensive sample preparation procedures are required to analyze natural organic matter (NOM) in soil and sediment samples due to the mineral matrix. The preparation procedure not only requires a large amount of sample (typically more than 50 mg) but also incomplete extraction of the organic can be done. In this study, 2-5 MUg solid NOM or 500 MUg unprocessed soil samples were fixed on a metal plate using double adhesive tape and analyzed directly using laser desorption ionization (LDI) and ultrahigh resolution mass spectrometry (UHR-MS). Most of the peaks reported in previous LDI UHR-MS studies using NOM solutions were observed, and an additional ~2200 unique peaks were found by analyzing the fulvic acids direct solid phase. Differences among soils origin in their molecular compositions were seen clearly with minimum sample preparation. Lignin and tannin-type molecules were detected in both Elliott soil and topsoil from Kyungpook National University campus. The data presented in this study demonstrate a proof-of-principle that highly sensitive, direct, molecular level analysis of solid-phase NOM from unprocessed soil samples and minimum sample preparation is possible. PMID- 30484637 TI - Novel gas diffusion cloth bioanodes for high-performance methane powered microbial fuel cells. AB - Microbial fuel cells (MFCs) are a promising technology that converts chemical energy into electricity. However, up to now only few MFCs have been powered by gas fuels such as methane and their limited performance is still challenged by the low solubility and bioavailability of gases. Here we developed a gas diffusion cloth (GDC) anode to significantly enhance the performance of methane powered MFCs. The GDC anode was constructed by simply coating waterproof GORE-TEX cloth with conductive carbon cloth in one step. After biofilm enrichment, the GDC anodes obtained a methane-dependent current up to 1130.2 mA m-2, which was 165.2 times higher than conventional carbon cloth (CC) anodes. Moreover, MFCs equipped with GDC anodes generated a maximum power density of 419.5 mW m-2. Illumina high throughput sequencing revealed that the GDC anode biofilm was dominated mainly by Geobacter, in contrast with the most abundant Methanobacterium in planktonic cells. It is hypothesized that Methanobacterium reversed the methanogenesis process by transferring electrons to the anodes and Geobacter generated electricity via the intermediates (e.g. acetate) of anaerobic methane oxidation. Overall, this work provides an effective route in preparing facile and cost effective anodes for high-performance methane MFCs. PMID- 30484638 TI - Single Laboratory Validation of the Multiplex xMAP Food Allergen Detection Assay (xMAP FADA) with Incurred Food Samples. AB - An xMAP Food Allergen Detection Assay (xMAP FADA) was developed to meet analytical needs when responding to complaints by individuals with multiple food allergies and to address potential ambiguities associated with cross-reactive proteins. A Single Laboratory Validation (SLV) was conducted to examine the reliability of the xMAP FADA to detect 15 analytes individually, or as part of a mixture, at >=6 concentrations, in four foods. The xMAP FADA reliably detected the analytes despite the incurred dark chocolate and incurred baked muffins displaying recoveries of 10-20% and <60%, respectively. The high reliability for recoveries less than 60% in part reflects the statistical strength of the design of the xMAP FADA. Only crustacean, egg, and milk incurred in dark chocolate were not reliably detected using the PBST buffered-detergent protocol. Following the reduced-denatured protocol no problems were encountered detecting milk, though egg did not display a dynamic response in dark chocolate. The ruggedness of the xMAP FADA was ascertained by the ability of novice analysts to detect food allergens in baked rice cookies. Despite one analyst loosing >80% of the beads and the count for one bead set dropping to 7, the assay displayed only a decrease in precision (increased standard deviations) and a change in the ratios between complementary antibody pairs. PMID- 30484639 TI - Fragment-Based Approaches for Supramolecular Interaction Energies: Applications to Foldamers and Their Complexes with Anions. AB - We explore the application of our multilayer Molecules-in-Molecules (MIM) fragment-based method for the study of the energies in supramolecular systems, viz. foldamers and their anion bound complexes. The performance of five different density functional theory (DFT) methods in conjunction with the fragmentation based method is evaluated against the unfragmented energies for a test set of 5 foldamers (82 to 170 atoms). A systematic protocol has been developed to account for the pi...pi interactions in such systems in addition to the traditional fragmentation of the system along the backbone comprised of covalently bonded dimer (or trimer) units. We find a significant improvement in the performance of the method on going from a one-layer MIM1 model (errors >10 kcal/mol) to a two layer MIM2 model (errors 0-2 kcal/mol), due to the incorporation of long-range interactions in the latter approach. Furthermore, we extend the applicability of MIM2 models to determine accurate binding energies of macromolecular receptor anion complexes. For three different anion bound macrocycles, our MIM2 protocol provides total energies within 1.5 kcal/mol of the unfragmented energies for most of the DFT methods. The corresponding anion binding energies are calculated within 0.5 kcal/mol of the unfragmented binding energies due to systematic error cancellation between the macrocycle and the macrocycle-anion complex. Finally, we have calibrated the absolute accuracy in the calculated binding energies by comparison with unfragmented DLPNO-CCSD(T) calculations on three macromolecule chloride anion complexes. The most accurate results are obtained using a MIM2 model using DLPNO-CCSD(T) calculations on trimer units as the high level and DFT D3 (e.g., M06-2X-D3) as the low level of theory, yielding sub kcal/mol errors in the anion binding energies. Our protocol can be an accurate method to calculate anion binding energies for very large supramolecular systems. PMID- 30484640 TI - Understanding the Binding of a Bifunctional Amidoximate-Carboxylate Ligand With Uranyl in Seawater. AB - Extracting uranium from seawater remains a formidable challenge due to its extremely low concentration at 3.3 ppb. State-of-the-art polymeric sorbents employ both amidoximate and carboxylate groups on the side chains to achieve optimal U uptake and selectivity, but little is known about the synergistic effect between the two functional groups in binding with uranyl. Herein we simulated the binding of a model amidoxime-carboxylate bifunctional ligand with uranyl using a combination of theoretical methods. Gas-phase quantum-mechanical calculations showed a chelate binding of a eta2 amidoximate and a monodentate carboxylate binding to uranyl. Ab initio molecular dynamics (MD) simulation in an explicit water solvation confirmed the stability of the chelate mode. Classical MD and free-energy simulations in 0.5 M NaCl showed that the carboxylate group binds first to uranyl, leading to a loose intermediate state, and then the amidoximate group binds, resulting in a more stable and tight chelate state. Binding of the second bifunctional ligand follows a similar process and the two ligands prefer a trans-configuration around the uranyl group. The simulated free energies indicate that the two bifunctional ligands bind with uranyl 55 kJ/mol stronger than the two ligands with amidoximate groups only. This work suggests an important synergy between amidoximate and carboxylate groups in binding uranyl. PMID- 30484641 TI - Tuning Hydrogenated Si, Ge, and SiGe Nanocluster Properties Using Theoretical Calculations and a Machine Learning Approach. AB - There are limited studies available that predict the properties of hydrogenated silicon-germanium (SiGe) clusters. For this purpose, we conducted a computational study of 46 hydrogenated SiGe clusters (SixGeyHz, 1 tetrahydroxyisobacteriochlorin metal complexes > isobacteriochlorindilactone metal complexes or porphyrin -> tetrahydroxybacteriochlorin -> bacteriochlorindilactone (and related) pathways, respectively, are described. A major benefit of these complementary routes over established methods is the simplicity of the isolation of the dilactones because of the reduced number of side-products formed. In an alternative approach we also report the direct and selective conversion of free base meso tetrakis(pentafluorophenyl)porphyrin to all isomers of free base isobacteriodilactones using the oxidant cetyltrimethylN+MnO4-. The solid state structures of some of the isomers and their precursors are reported, providing data on the conformational modulation induced by the derivatizations. We also rationalize computationally their differing thermodynamic stability and electronic properties. In making new efficient routes toward these dilactone isomers available, we enable the further study of this diverse class of porphyrinoids. PMID- 30484651 TI - Modified polymer matrix in pharmaceutical hot melt extrusion by molecular interactions with a carboxylic co-former. AB - Hot melt extrusion (HME) has become an essential technology to cope with an increasing number of poorly soluble drug candidates. However, there is only limited choice of pharmaceutical polymers to obtain suitable amorphous solid dispersions (ASD). Considerations of miscibility, stability, and biopharmaceutical performance narrow the selection of excipients and further technical constraints arise from the needed pharmaceutical processing. The present work introduces the concept of molecularly targeted interactions of a co former with a polymer to design a new matrix for HME. Model systems of dimethylaminoethyl methacrylate copolymer, Eudragit E (EE) and bi-carboxylic acids were studied and pronounced molecular interactions were demonstrated by 1H, 13C NMR, FTIR spectroscopy as well as by different techniques of microscopic imaging. A difference was shown between new formulations exploiting specifically the targeted molecular interactions and a common drug-polymer formulation. More specifically, a modified matrix with malic acid exhibited a technical extrusion advantage over polymer alone and there was a benefit of improved physical stability revealed for the drug fenofibrate. This model compound displayed greatly enhanced dissolution kinetics from the ASD formulations. It can be concluded that harnessing molecularly designed polymer modifications by co formers has much potential in solid dispersion technology and in particular regarding HME processing. PMID- 30484652 TI - Enhancing nanoparticle diffusion on a unidirectional domain wall magnetic ratchet. AB - nanoscale magnetic devices is often limited by the presence of thermal fluctuations, while in micro-nanofluidic applications the same fluctuations may be used to spread reactants or drugs. Here we demonstrate the controlled motion and the enhancement of diffusion of magnetic nanoparticles that are manipulated and driven across a series of Bloch walls within an epitaxially grown ferrite garnet film. We use a rotating magnetic field to generate a traveling wave potential that unidirectionally transports the nanoparticles at a frequency tunable speed. Strikingly, we find an enhancement of diffusion along the propulsion direction and a frequency dependent diffusion coefficient that can be precisely controlled by varying the system parameters. To explain the reported phenomena, we develop a theoretical approach that shows a fair agreement with the experimental data enabling an exact analytical expression for the enhanced diffusivity above the magnetically modulated periodic landscape. Our technique to control thermal fluctuations of driven magnetic nanoparticles represents a versatile and powerful way to programmably transport magnetic colloidal matter in a fluid, opening the doors to different fluidic applications based on exploiting magnetic domain wall ratchets. PMID- 30484654 TI - Facilitating Tip-Enhanced Raman Scattering on Dielectric Substrates via Electrical Cutting of Silver Nanowire Probes. AB - TERS is a powerful tool for nanoscale optical characterization of surfaces. However, even after 20 years of development, the parameters for optimal TERS tips are still up for debate. As a result, routine measurements on bulk or dielectric substrates remain exceptionally challenging. Herein we help to alleviate this by using electrical cutting to strategically modify silver nanowire TERS probes. Following cutting, the tips present a large, spherical apex and are often nanostructured with numerous nanoparticles, which we argue improve light collection and optical coupling. This doubles TERS signals on a highly-enhancing, gap-mode substrate compared to our standard nanowire tips, whilst maintaining a high reproducibility and resolution. More interestingly, on a dielectric substrate (graphene on SiO2) the tips give ~7x higher signals than our standard tips. Further investigations point to the non-local nature of the enhancement using standard, smooth, TERS probes without gap-mode, making such nanostructuring highly beneficial in these cases. PMID- 30484653 TI - Reductive Cross-Coupling of Aldehydes and Imines Mediated by Visible Light Photoredox Catalysis. AB - Under photoredox catalysis conditions, the conventional electrophilic reactivity of ketimines is inverted to generate nucleophilic species. As a result, chemoselective cross-electrophile couplings between aldehydes and ketimines are achieved via umpolung reactivity of ketimines to furnish amino alcohols (44 examples with good to excellent yields). To illustrate the utility of the amino alcohol products, 1,2-dihydroindol-3-one-based fluorophores are easily synthesized using the coupling products. Finally, a plausible reaction pathway is discussed. PMID- 30484655 TI - The Bicyclo[2.2.2]octane Motif: A Class of Saturated Group 14 Quantum Interference Based Single-Molecule Insulators. AB - The electronic transmission through sigma-conjugated molecules can be fully suppressed by destructive quantum interference, which makes them potential candidates for single-molecule insulators. The first molecule with clear suppression of the single-molecule conductance due to sigma-interference was recently found in the form of a functionalized bicyclo[2.2.2]octasilane. Here we continue the search for potential single-molecule insulators based on saturated group 14 molecules. Using a high-throughput screening approach, we assess the electron transport properties of the bicyclo[2.2.2]octane class by systematically varying the constituent atoms between carbon, silicon, and germanium, thus exploring the full chemical space of 771 different molecules. The majority of the molecules in the bicyclo[2.2.2]octane class are found to be highly insulating molecules. Though the all-silicon molecule is a clear-cut case of sigma interference, it is not unique within its class and there are many potential molecules that we predict to be more insulating. The finding of this class of quantum interference based single-molecule insulators indicates that a broad range of highly insulating saturated group 14 molecules are likely to exist. PMID- 30484656 TI - Prediction of the Glass Transition Temperatures of Zeolitic Imidazolate Glasses through Topological Constraint Theory. AB - A topological constraint model is developed to predict the compositional scaling of glass transition temperature (Tg) in a metal-organic framework glass, agZIF-62 [Zn(Im2-xbImx)]. A hierarchy of bond constraints is established using a combination of experimental results and molecular dynamic simulations with ReaxFF. The model can explain the topological origin of Tg as a function of the benzimidazolate concentration with an error of 3.5 K. The model is further extended to account for the effect of 5-methylbenzimidazolate, enabling calculation of a ternary diagram of Tg with a mixture of three organic ligands in an as-yet un-synthesized, hypothetical framework. We show that topological constraint theory is an effective tool for understanding the properties of metal organic framework glasses. PMID- 30484657 TI - Decomposable PVA-based super-hydrophobic 3D porous material for effective water/oil separation. AB - The development of the oil industry brings the critical problem of the ocean pollution by oil spill or fossil fuels. The material for water/oil separation is one of the effective approaches to solve this crisis. Polyvinyl alcohol (PVA) has been used for water/oil separation material. Currently, glutaraldehyde was employed as the cross-linking agent which is well-known toxic and environmentally unfriendly. Moreover, the cross-linked material is difficult to deal with for disposing purpose. Here we propose a strategy of fabricating macro-porous material which was prepared by PVA and sodium silicate (Na2SiO3) in aqueous solution. Following through the one-step method of sol-gel reaction of hydroxyl groups with trimethoxy (octadecyl) silane (ODTMS), the low surface energy substance was grafted on the macro-porous material and a super-hydrophobic macro porous membrane for water/oil separation was prepared. As oil sorbent, the as prepared dried super-hydrophobic PVA/ Na2SiO3 porous materials (PSD6S) have the adsorption capacity of 1.8-7.0 g/g for oil uptake which depends on the type of oil liquid. Typically, the separation efficiency of this material could reach more than 99% even after 10 times without the help of ambient pressure. It is noteworthy that the as-prepared samples could be easily decomposable and dissolvable completely in acidic medium at a rapid rate. PMID- 30484658 TI - Hippocampal proteomic alteration in triple transgenic mouse model of Alzheimer's disease and implication of PINK 1 regulation in donepezil treatment. AB - BACKGROUND: Donepezil is a clinically approved acetylcholinesterase inhibitor (AChEI) for cognitive improvement in Alzheimer's disease (AD). Donepezil has been used as a first-line therapeutics for the symptomatic treatment of AD, but its ability to modify disease pathology and underlying mechanisms are not clear. METHODS: We investigated the protective effects and underlying mechanisms of donepezil in AD-related triple transgenic (APPSwe/PSEN1M146V/MAPTP301L) mouse model (3*Tg-AD). Mice (8-month old) were treated with donepezil (1.3 mg/kg) for 4 months and evaluated by behavioral tests for assessment of cognitive functions and the hippocampal tissues were examined by protein analysis and quantitative proteomics. RESULTS: Behavioral tests showed that donepezil significantly improved the cognitive capabilities of 3xTg-AD mice. The levels of soluble and insoluble amyloid beta proteins (Abeta1-40 and Abeta1-42) and senile plaques were reduced in the hippocampus. Golgi staining of the nervous tissue showed that donepezil prevented dendritic spine loss in hippocampal neurons of 3xTg-AD mice. Proteomic studies of the hippocampal tissues identified 3131 proteins with altered expression related to AD pathology, of which 262 could be significantly reversed with donepezil treatment. Bioinformatics with functional analysis and protein-protein interaction (PPI) network mapping showed that donepezil significantly elevated the protein levels of PINK 1, NFASC, MYLK2, and NRAS in the hippocampus, and modulated the biological pathways of axon guidance, mitophagy, mTOR and MAPK signaling. The substantial upregulation of PINK 1 with donepezil was further verified by western blotting. CONCLUSIONS: Donepezil exhibited neuroprotective effects via multiple mechanisms. In particular, PINK 1 is related to mitophagy and cellular protection from mitochondrial dysfunction, which might play important roles in AD pathogenesis and represent a potential therapeutic target. PMID- 30484659 TI - Does Local Structure Bias How a Crystal Nucleus Evolves? AB - The broad scientific and technological importance of crystallization has led to significant research probing and rationalizing crystal nucleation processes. Previous work has generally neglected the possibility of the molecular-level dynamics of individual crystal nuclei coupling to local structures. However, recent experimental work has conjectured that this can occur. Therefore, to address a deficiency in scientific understanding of crystallization, we have probed the nucleation of prototypical single and multi-component crystals (specifically, ice and mixed gas hydrates). We establish that local structures can bias the evolution of nascent crystal phases on a nanosecond timescale by, for example, promoting the appearance or disappearance of specific crystal motifs, and thus reveal a new facet of crystallization behaviour. Moreover, we demonstrate structural biases are likely present during crystallization processes beyond ice and gas hydrate formation. Structurally-biased dynamics are a lens for understanding existing computational and experimental results while pointing to future opportunities. PMID- 30484660 TI - Flueggeacosines A-C, Dimeric Securinine-Type Alkaloid Analogues with Neuronal Differentiation Activity from Flueggea suffruticosa. AB - Flueggeacosines A-C (1-3), three dimeric securinine-type alkaloid analogues with unprecedented skeletons, were isolated from Flueggea suffruticosa. Compounds 1 and 2 are the first examples of C-3-C-15' connected dimeric securinine-type alkaloids. Compound 3 is an unprecedented heterodimer of securinine-type and benzoquinolizidine alkaloids. Biosynthetic pathways for 1-3 were proposed on the basis of the coexisting alkaloid monomers as the precursors. Compound 2 exhibited significant activity in promoting neuronal differentiation of Neuro-2a cells. PMID- 30484661 TI - Salt Effect in Ion-Pair Dynamics after Bimolecular Photoinduced Electron Transfer in a Room-Temperature Ionic Liquid. AB - Bimolecular photoinduced electron transfer between perylene and two quenchers was investigated in an imidazolium room-temperature ionic liquid (RTIL) and in a dipolar solvent mixture of the same viscosity using transient absorption on the subpicosecond to submicrosecond timescales. Whereas charge separation dynamics were similar in both solvents, significant differences were observed in the temporal evolution of the ensuing radical ions: although small, the free ion yield is significantly larger in the RTIL, and recombination of the ion pair to the triplet state of perylene is more efficient in the dipolar solvent. The temporal evolution of reactant, ion and triplet state populations could be well reproduced using Unified Encounter Theory. This analysis reveals that the observed differences can be explained by the strong screening of the Coulomb potential in the ion pair by the ionic solvent. In essence, RTILs favor free ions compared to highly dipolar solvents of the same viscosity. PMID- 30484662 TI - Visible-Light-Mediated Synthesis of Unsymmetrical Diaryl Sulfides via Oxidative Coupling of Arylhydrazine with Thiol. AB - A metal-free visible-light-promoted oxidative coupling between thiols and arylhydrazines has been developed to afford diaryl sulfides using a catalytic amount of rose bengal as photocatalyst under aerobic conditions. A library of unsymmetrical diaryl sulfides with broad functionalities was synthesized in good yields at room temperature. The present methodology is also applicable to benzo[ d]thiazole-2-thiols, benzo[ d]oxazole-2-thiol, 1 H-benzo[ d]imidazole-2-thiols, and 1 H-imidazole-2-thiol. PMID- 30484663 TI - Ultraviolet Photodissociation of ESI and MALDI generated protein ions on a Q Exactive mass spectrometer. AB - The identification of molecular ions produced by MALDI or ESI strongly relies on their fragmentation to structurally informative fragments. The widely diffused fragmentation techniques for ESI multiply charged ions, are either incompatible (ECD and ETD) or show lower efficiency (CID, HCD), with the predominantly singly charged peptide and protein ions formed by MALDI. In source decay (ISD) has been successfully adopted to sequence MALDI generated ions, but it further increases spectral complexity and it is not compatible with Mass Spectrometry Imaging. Excellent UVPD performances, in terms of number of fragment ions and sequence coverage has been demonstrated for electrospray ionization for multiple proteomics applications. UVPD showed a much lower charge state dependence and so protein ions produced by MALDI may exhibit equal propensity to fragment. Here we report UVPD implementation on an Orbitrap Q-Exactive plus equipped with a ESI/EP MALDI. UVPD of MALDI generated ions was benchmarked against MALDI-ISD, MALDI-HCD and ESI-UVPD. MALDI-UVPD outperformed MALDI-HCD and ISD efficiently sequencing small proteins ions. Moreover, the singly charged nature of MALDI-UVPD avoids the bioinformatics challenges associated with highly congested ESI-UVPD mass spectra. Our results demonstrate the ability of UVPD to further improve tandem mass spectrometry capabilities for MALDI generated protein ions. Data are available via ProteomeXchange with identifier PXD011526. PMID- 30484664 TI - Palladium(II)-Catalyzed Asymmetric Tandem Cyclization of 2-Aminoaryl Alkynones: An Approach to Chiral 1,2,3,4-Tetrahydro-beta-carbolines. AB - A Pd(OAc)2-catalyzed asymmetric cyclization of 2-aminoaryl alkynones involving an intramolecular trans-aminopalladation of alkyne and 1,2-addition to the carbonyl group tandem processes was developed. This strategy represents the first example using palladium as the catalyst and 2-alkynylaniline derivatives as the starting material to allow facile access to chiral 1,2,3,4-tetrahydro-beta-carbolines in high yields and excellent enantioselectivities. PMID- 30484665 TI - Androgens in women - critical evaluation of the methods for their determination in diagnostics of endocrine disorders. AB - The androgens dehydroepiandrosterone sulfate, dehydro-epiandrosterone, androstenedione and testosterone are routinely assessed in women, and circulating levels of these androgens reflect their production. These androgens are measured in most laboratories using various immuno-analytical methods. Recently, however, androgen assays have begun to be performed using gas or liquid chromatography combined with mass spectrometry. To better understand the difficulties and issues of androgen laboratory diagnostics, it is important to assess each of the methods used, how and why they were introduced into practice, and their advantages, limits, historic milestones and current status. It is also necessary to understand how reference ranges are determined and specifics arising from the physiology of individual androgens. Here we present a summary and discussion of these issues. PMID- 30484666 TI - Impaired vitamin D sensitivity. AB - Resistance to vitamin D has been known for decades as vitamin D resistant rickets, caused by mutations of the gene encoding for vitamin D receptor (VDR). Findings of extra-skeletal effects of vitamin D and learning of the molecular mechanisms used by its biologically active metabolite calcitriol revealed other ways leading to its impaired sensitivity. Calcitriol takes advantage of both genomic and non-genomic mechanisms through its binding to vitamin D receptor, located not only in the cell nuclei but also in a perinuclear space. On the genomic level the complex of calcitriol bound to VDR binds to the DNA responsive elements of the controlled gene in concert with another nuclear receptor, retinoid X receptor, and expression of the VDR itself is controlled by its own ligand. These elements were found not only in the promotor region, but are scattered over the gene DNA. The gene expression includes a number of nuclear transcription factors which interact with the responsive elements and with each other and learning how they operate would further contribute to revealing causes of the impaired vitamin D sensitivity. Finally, the examples of major disorders are provided, associated with impairment of the vitamin D function and its receptor. PMID- 30484667 TI - Phytoestrogens and the intestinal microbiome. AB - The microflora of the digestive tract is composed of a unique set of bacteria, yeasts, viruses and other microorganisms, generally known as the microbiome. The microbiome exhibits considerable inter-individual variability, with up to two thirds of the microflora differing between individuals. Because of this, the variable intestinal microflora is responsible for many differences in metabolic, hormonal and immunological processes in humans and animals. Significant differences have been observed in the metabolism of phytoestrogens, naturally occurring substances that possess estrogenic or anti-estrogenic activity. These substances occur predominately in legumes, especially in soy and many soy products. Because of their effects, phytoestrogens are used as an alternative therapy for menopausal disorders and benign prostate hyperplasia. In connection with the worldwide expansion of soy products as part of healthy lifestyles including vegetarianism and veganism, phytoestrogens have become a regular part of everyday life. The activity of phytoestrogens is strongly dependent on the microbiome. Their metabolites have stronger estrogenic activity than the natural substances themselves, and because of the variability in microbiomes, there are large differences in the effects of phytoestrogens among individuals. PMID- 30484668 TI - Links between the circadian rhythm, obesity and the microbiome. AB - Obesity is linked to a wide range of serious illnesses. In addition to the important impact on the health of the individual, obesity also has a substantial impact on the economy. Disruption of physiological day-night cycles could contribute to the increased incidence of obesity. According to the American National Sleep Federation, the percentage of the people who reported a sleep duration of six hours or less increased from 12 to 37 % over ten years. Insufficient sleep leads not only to an increase of the total calorie intake but changes the meal preference in favor of palatable foods and meals with high carbohydrate content. A decrease of leptin and increase of ghrelin levels caused by sleep deficiency can also play a role. In addition to the higher caloric intake, the timing of food consumption should be taken into account. The same meal eaten during the night versus the day is associated with increased postprandial glucose and triglyceride levels. The gut microbiome has also been recently understood as an endocrine system, with links between the gut microbiome and circadian rhythm changes possibly influencing increased obesity. PMID- 30484669 TI - The evolution of taste and perinatal programming of taste preferences. AB - Taste is important for food intake. The fetus first experiences taste through amniotic fluid, and later via mother's milk. Early human experience with taste has a key importance for later acceptance of food. Dietary behavior is determined by the interaction of many different factors. The development of the olfactory and taste receptors begins at 7-8 weeks of gestation. An early sensitive period probably exists when flavor preference is established. Sweet taste is preferred in early childhood; this is the reason why children are at increased risk of over consuming saccharides. Gustatory sensitivity declines with age. The threshold for the perception of each basic taste differs, and is established genetically. In this review, we summarize published data on taste preferences and its development and changes during life. PMID- 30484670 TI - Genetic predictors of the development and recurrence of Graves' disease. AB - Graves' disease affects approximately 3 % of women and 0.5 % of men. The first choice therapy is based on the administration of thyrostatic drugs. However, approximately half of patients relapse within two years of discontinuation. These patients must then decide whether to re-initiate thyrostatics, which may have serious side effects, or to undergo surgery or radioiodine treatment. Familial forms of Graves' disease indicate a significant genetic component, with twin studies demonstrating a contribution of genetic factors up to 70-80 %. The autoimmune nature of the disease involves the human leukocyte antigen (HLA) complex, which has a decisive impact on each individual's immune response. Within HLA, some variants of the DRB1, DQA1 and DQB1 genes appear to be possible predictors of the development and recurrence of Graves' disease. Outside the HLA region, many variants of immunocompetent genes have also been identified as potential Graves' disease predictors. Apart from the immune system, some thyroid specific genes have been described in relation to the disease. Here, we present current knowledge regarding the genetic components involved in the development and recurrence of Graves' disease. Further, we present original pilot results from a cohort of Czech Graves' disease patients regarding the HLA variants. PMID- 30484671 TI - Osteoporosis complicating some inborn or acquired diseases. AB - Osteoporosis in chronic diseases is very frequent and pathogenetically varied. It complicates the course of the underlying disease by the occurrence of fractures, which aggravate the quality of life and increase the mortality of patients from the underlying disease. The secondary deterioration of bone quality in chronic diseases, such as diabetes of type 1 and type 2 and/or other endocrine and metabolic disorders, as well as inflammatory diseases, including rheumatoid arthritis - are mostly associated with structural changes to collagen, altered bone turnover, increased cortical porosity and damage to the trabecular and cortical microarchitecture. Mechanisms of development of osteoporosis in some inborn or acquired disorders are discussed. PMID- 30484672 TI - Endocrine disruptors of the bisphenol and paraben families and bone metabolism. AB - After menopause, when estrogen levels decrease, there is room for the activity of anthropogenic substances with estrogenic properties - endocrine disruptors (EDs) that can interfere with bone remodeling and changes in calcium-phosphate metabolism. Selected unconjugated EDs of the bisphenol group - BPA, BPS, BPF, BPAF, and the paraben family - methyl-, ethyl-, propyl-, butyl-, and benzyl parabens - were measured by high performance liquid chromatography-tandem mass spectrometry in the plasma of 24 postmenopausal women. Parameters of calcium phosphate metabolism and bone mineral density were assessed. Osteoporosis was classified in 14 women, and 10 women were put into the control group. The impact of EDs on calcium-phosphate metabolism was evaluated by multiple linear regressions. In women with osteoporosis, concentrations of BPA ranged from the lower limit of quantification (LLOQ) - 104 pg/ml and methyl paraben (MP) from LLOQ - 1120 pg/ml. The alternative bisphenols BPS, BPF and BPAF were all under the LLOQ. Except for MP, no further parabens were detected in the majority of samples. The multiple linear regression model found a positive association of BPA (beta=0.07, p<0.05) on calcium (Ca) concentrations. Furthermore, MP (beta=-0.232, p<0.05) was negatively associated with C-terminal telopeptide. These preliminary results suggest that these EDs may have effects on calcium-phosphate metabolism. PMID- 30484673 TI - Parabens and their relation to obesity. AB - Parabens are a group of chemicals used as preservatives in the food, cosmetic and pharmaceutical industries. They are known to possess estrogenic effects, and therefore have been classified as endocrine disruptors. In addition to the classical endocrine organs, other tissues have endocrine activity, including adipose tissue. Several chemicals are known to cause obesogenic effects, and parabens are currently being studied in this context. The aim of this study was to investigate the possible connections of paraben exposure and obesity. Blood plasma from 27 healthy women was collected during their menstrual cycle. Basal anthropometric measures, levels of parabens (methylparaben, ethylparaben and propylparaben), adipokines (adiponectin, adipsin, leptin, resistin and visfatin) and hormones affecting energy balance and metabolic health (c-peptide, ghreline, GIP, GLP-1, glucagon, insulin, PAI-1) were measured. A Kolmogorov-Smirnov test showed higher methylparaben and propylparaben levels in women with BMI 25-34.9 compared to those with BMI 18.5-24.9. Plasma levels of methylparaben as well as the sum of parabens were positively associated with the plasma adipsin levels. Negative associations for methylparaben were found for glucagon, leptin and PAI 1. In accordance with other experimental studies we observed important associations of methylparaben and hormones affecting energy balance and metabolic health, indicating its obesogenic potential. PMID- 30484674 TI - Phthalate metabolites in maternal and cord plasma and their relations to other selected endocrine disruptors and steroids. AB - Endocrine disruptors (EDs) are known to have harmful effects on the human endocrine system; special effort is actually given to the exposure during pregnancy. Humans are usually exposed to a mixture of EDs, which may potentiate or antagonize each other, and the combined effect may be difficult to estimate. The main phthalate monoesters monoethyl-, mono-n-butyl-, monoisobutyl-, monobenzyl-, mono-(2-ethylhexyl)-, mono-(2-ethyl-5-hydroxyhexyl)- and mono-(2 ethyl-5-oxohexyl) phthalate were determined in 18 maternal (37th week of pregnancy) and cord plasma samples using liquid chromatography-tandem mass spectrometry. Previously determined levels of selected bisphenols, parabens and steroids were also considered in this study. In cord blood, there were significantly higher mono-n-butyl phthalate levels than in maternal blood (p=0.043). The results of multiple regression models showed that maternal plasma phthalates were negatively associated with cord plasma androstenedione, testosterone and dehydroepiandrosterone and positively associated with estradiol and estriol. For estriol, a cumulative association was also observed for sumabisphenols. To the best of our knowledge, this is the first pilot study evaluating the effect of prenatal exposure by multiple EDs on newborn steroidogenesis. Our results confirmed phthalate accumulation in the fetal area and disruption of fetal steroidogenesis. This preliminary study highlights the negative impacts of in utero EDs exposure on fetal steroidogenesis. PMID- 30484675 TI - Steroid hormone levels in the peripartum period - differences caused by fetal sex and delivery type. AB - Progesterone, estrogens, androgens and glucocorticoids all play important roles during pregnancy, from implantation to delivery. Focusing on selected steroid hormones in the peripartum period, we defined reference ranges measured using LS MS/MS, and assessed relationships with maternal age, pregnancy weight gain, delivery type, and fetal sex. Samples were taken from 142 healthy women with physiological gravidity at the 37th week, during the first period of labor, and from newborn mixed cord blood. We found higher cortisol and 17-OH-pregnenolone plasma levels in mothers at the 37th week that carried male fetuses (p=0.03), but no significant differences in any studied hormones in newborns of different sex. Neither maternal age nor weight gain nor newborn birth weight had any relationships to any of the studied hormones. However, there were differences depending on vaginal versus planned cesarean section deliveries. In women carrying a male fetus we found significantly higher levels of 17-OH-pregnenolone, progesterone, cortisol, corticosterone and significantly lower levels of estradiol in those undergoing spontaneous vaginal delivery. However, we found no significant differences in the cord blood of newborn males from either delivery type. We established reference ranges for our analysis methods, which should be useful for further studies as well as in standard clinical practice. PMID- 30484676 TI - May circulating steroids reveal a predisposition to intrahepatic cholestasis of pregnancy in non-pregnant women? AB - Intrahepatic cholestasis of pregnancy (ICP) is a frequent liver disorder, mostly occurring in the third trimester. ICP is not harmful to the mothers but threatens the fetus. The authors evaluated steroid alterations in maternal and mixed umbilical blood to elucidate their role in the ICP development. Ten women with ICP were included in the study. Steroids in the maternal blood were measured by Gas Chromatography-Mass Spectrometry (GC-MS) (n=58) and RIA (n=5) at the diagnosis of ICP, labor, day 5 postpartum, week 3 postpartum and week 6 postpartum. The results were evaluated by ANOVA consisting of the subject factor, between subject factors ICP, gestational age at the diagnosis of ICP and gestational age at labor, within-subject factor Stage and ICP * Stage interaction. The 17 controls were firstly examined in the week 36 of gestation. ICP patients showed reduced CYP17A1 activity in the C17,20 lyase step thus shifting the balance between the toxic conjugated pregnanediols and harmless sulfated 5alpha/beta-reduced-17-oxo C19 steroids. Hence, more toxic metabolites originating in maternal liver from the placental pregnanes may penetrate backward to the fetal circulation. As these alterations persist in puerperium, the circulating steroids could be potentially used for predicting the predisposition to ICP even before next pregnancy. PMID- 30484677 TI - The quantitation of 7beta-hydroxy-epiandrosterone in the plasma and seminal plasma of men with different degrees of fertility. AB - 7beta-hydroxy-epiandrosterone (7beta-OH-EpiA) is an endogenous androgen metabolite that has been shown to exert neuroprotective, anti-inflammatory and anti-estrogenic effects. However, to the best of our knowledge no information is available about this androgen steroid in relation to sperm quality. We analyzed 7beta-OH-EpiA in plasma and seminal plasma using a newly developed isotope dilution ultra-high performance liquid chromatography - mass spectrometry method. Validation met the requirements of FDA guidelines. Levels of 7beta-OH-EpiA were measured in 191 men with different degrees of infertility. One-way analysis of variance followed by multiple comparison and correlation analysis adjusted for age, BMI and abstinence time were performed to evaluate the relationships between this steroid and sperm quality. Concentrations of 7beta-OH-EpiA in seminal plasma were significantly higher in severely infertile men in comparison with healthy men and slightly infertile men. The same trend was found when blood plasma was evaluated. Furthermore, plasma 7beta-OH-EpiA negatively correlated with sperm concentration (-0.215; p<0.01) and total count (-0.15; p<0.05). Seminal 7beta-OH EpiA was negatively associated with motility (-0.26; p<0.01), progressively motile spermatozoa (-0.233; p<0.01) and nonprogressively motile spermatozoa ( 0.188; p<0.05). 7beta-OH-EpiA is associated with lower sperm quality and deserves more research in that respect. PMID- 30484678 TI - Serum and intratesticular sex steroids in azoospermic men: how do they correlate? AB - Five intratesticular sex steroids (testosterone, dihydrotestosterone, androstenedione, estradiol and epitestosterone) along with six serum hormones (LH, FSH, prolactin, SHBG, testosterone and estradiol) were determined in 84 non obstructive azoospermic men, in order to evaluate to what extent serum and testicular tissue as well as individual hormones in the same material mutually correlate. With exception of androstenedione, tight correlations were found among tissue content of sex steroids, while only weak correlation was recorded between serum and testicular concentrations of major sex steroids testosterone and estradiol. It points to importance of measurement of intratesticular steroids in combination with examination of sperm parameters for assessment of testicular function and spermatogenesis. PMID- 30484679 TI - Physiological changes after spa treatment - a focus on endocrinology. AB - The paper presents the results of our effort to reveal objective parameters for evaluation of the spa treatment for patients with anxiety-depressive disorders. The study was based on our previous experience with neuroactive steroids and neurosteroids, which play a crucial role in the psychological well-being of patients by maintaining balance of the organism. A total number of 94 steroids were determinated in a group of 70 female patients diagnosed with anxiety depressive disorders. Patients underwent a month spa treatment while maintaining unchanged medication dosing with SSRI (selective serotonin reuptake inhibitors). The other investigated factors contributing to improving the health of treated subjects were amino-acid homocysteine and serotonin. The blood samples were collected at the beginning and the end of the spa treatment. Serotonin in all patients increased by a relative 23 % (results given as relative differences in percent), while homocysteine decreased by 17.1 %. Statistically significant increases were found in 21 steroids, which indicate activation of the adrenal cortex. It can be assumed, that the overall improvement in the mental condition of patients, which was proved by questionnaire from Knobloch and Hausner, the increase in immune suppressive substances and anti-autoimmune responses, will maintain for a longer time after the spa treatment. PMID- 30484680 TI - Changes in plasma concentrations and mRNA expression of hepatokines fetuin A, fetuin B and FGF21 in physiological pregnancy and gestational diabetes mellitus. AB - We measured plasma concentrations, adipose tissue and placental mRNA expression of hepatokines fetuin A, fetuin B and fibroblast growth factor 21 (FGF21) in 12 healthy pregnant women (P group), 12 pregnant women with gestational diabetes (GDM) and 10 healthy non-pregnant women (N group) to explore their potential role in the etiopathogenesis of GDM. GDM and P group had comparable BMI, C-reactive protein (CRP) and glycated hemoglobin levels while IL-10 and TNF-alpha levels were higher in GDM group. Fetuin A and fetuin B levels were higher in pregnancy as compared to N group and decreased after delivery with no apparent influence of GDM. In contrast, the pattern of changes of circulating FGF21 levels differed between GDM and P group. Fetuin A concentrations positively correlated with CRP, TNF-alpha mRNA expression in adipose tissue and IL-6 mRNA expression in placenta. Fetuin B positively correlated with CRP. FGF21 levels correlated positively with IFN-gamma mRNA in adipose tissue and inversely with IL-8 mRNA in the placenta. Taken together, fetuin A and fetuin B levels were increased during pregnancy regardless of the presence of GDM. In contrast, FGF21 patterns differed between healthy pregnant women and GDM patients suggesting a possible role of this hepatokine in the etiopathogenesis of GDM. PMID- 30484681 TI - Expression profiling of Nme7 interactome in experimental models of metabolic syndrome. AB - Nucleoside diphosphate kinase 7, non-metastatic cells 7 (NME7) is an acknowledged member of ciliome and is involved in the biogenesis or function of cilia. As obesity and diabetes are common in several ciliopathies, we aimed to analyze changes of gene expression within Nme7 interactome in genetically designed rat models of metabolic syndrome. We assessed the liver transcriptome by Affymetrix microarrays in adult males of 14 PXO recombinant inbred rat strains and their two progenitor strains, SHR-Lx and BXH2. In the strains with the lowest expression of Nme7, we have identified significant enrichment of transcripts belonging to Nme7 interactome. In the subsequent network analysis, we have identified three major upstream regulators - Hnf4a, Ppara and Nr1h4 and liver steatosis (p=0.0001) and liver necrosis/cell death (apoptosis of liver cells, p=0.0003) among the most enriched Tox categories. The mechanistic network reaching the top score showed substantial overlap with Assembly of non-motile cilium and Glucose metabolism disorder gene lists. In summary, we show in a genetic model of metabolic syndrome that rat strains with the lowest expression of Nme7 present gene expression shifts of Nme7 interactome that are perturbing networks relevant for carbohydrate and lipid metabolism as well as ciliogenesis. PMID- 30484682 TI - Parathyroid imaging by (18)F-fluorocholine PET/CT in patients with primary hyperparathyroidism and inconclusive conventional methods: clinico-pathological correlations. AB - (18)F-fluorocholine positron emission tomography/computed tomography (FCH) was performed after inconclusive neck ultrasound and (99)Tc-sestaMIBI SPECT (MIBI) scintigraphy in patients with primary hyperparathyroidism (PHPT) to localize abnormal parathyroid glands before surgery. The results were retrospectively evaluated and compared to postoperative histopathological findings. 13 patients with PHPT were enrolled (mean age 64.3 years, preoperative calcium 2.74 mmol/l and parathyroid hormone 114.6 ng/l). FCH localized hyperfunctioning parathyroid glands in 12 patients of 13 (per patient sensitivity 92 % and positive predictive value (PPV) 100 %). Fourteen parathyroid lesions (11 adenomas, 3 hyperplastic glands) were resected with a mean size of 11.9 mm (per lesion sensitivity 93 % and PPV 81 %). Four adenomas and one hyperplastic gland were composed of only chief cells, whereas five lesions contained both chief and oxyphil cells. In three patients an exclusively oxyphil adenoma was found, surprisingly with negative MIBI scintigraphy in spite of a high mitochondria content in the oxyphil parathyroid cells. 12 of 13 patients had thyroid disease. In our limited study sample, FCH correctly identified parathyroid adenomas and/or hyperplastic glands in 92 % of patients with previously inconclusive conventional imaging. Unlike MIBI, FCH successfully localized small, hyperplastic and multiple hyperfunctioning parathyroid glands, irrespective of their histopathological composition. PMID- 30484683 TI - Comparison of the Effect of Three Different Fortification Methods on Growth of Very Low Birth Weight Infants. AB - BACKGROUND: This study aimed to compare the effects of adjustable fortification (AF), targeted fortification (TF), and standard fortification (SF) methods on the early growth of very low birth weight infants. MATERIALS AND METHODS: Sixty infants <32 weeks of gestational age and weighing <1,500 g were selected. These infants were exclusively fed with breast milk and were randomized into three fortification groups: SF, AF, and TF. SF consists of adding a fixed amount of fortifier to maternal milk. Blood urea nitrogen levels are used to adjust fortifier in AF. In TF, breast milk is analyzed and fortified accordingly based on the macronutrient content to achieve the targeted intake. RESULTS: A total of 76 preterm infants were eligible for the study. Sixty infants were randomized into three groups. At the end of the fourth week of fortification period, median daily weight gain of the infants was similar in the AF [23.5 g/(kg.d)] and TF groups [25.5 g/(kg.d)], and significantly higher in both groups than in SF group [12 g/(kg.d)] (AF versus SF group, p < 0.001 and TF versus SF group, p < 0.001). Weight, head circumference, and length were compared across the three groups regarding percentile. Significant improvement in the percentile groups of weight and head circumference was observed in the AF and TF groups. In the SF group, a significant decline in the percentile groups of weight, head circumference, and length was detected. Daily protein and energy intakes in AF and TF groups were significantly higher than those in SF group (SF versus AF, p < 0.001 and SF versus TF, p < 0.001). CONCLUSIONS: Fortifying breast milk with AF and TF methods was found to improve body weight, length, and head circumference percentiles of preterm infants, whereas SF method was found unsatisfactory. To provide optimum growth for preterm babies, breast milk that has been fortified by using AF and TF strategies should be recommended in neonatal intensive care units. PMID- 30484684 TI - An avian influenza virus H6N1 outbreak in commercial layers: case report and reproduction of the disease. AB - An outbreak of low pathogenic avian influenza (LPAI) subtype H6N1 (intravenous pathogenicity index = 0.11) infection occurred in four productive brown layer flocks on three farms in the Netherlands within a period of two months. The farms were located at a maximum distance of 4.6 km from each other. The infections were associated with egg production drops up to 74%, pale eggshells and persisting high mortality up to 3.2% per week. Three flocks were slaughtered prematurely as they were not profitable anymore. Newcastle disease, infectious bronchitis, egg drop syndrome and Mycoplasma gallisepticum infections could very likely be excluded as cause of or contributor to the condition in the field. Also, the anticoccidial drug nicarbazin, which can cause egg production drops and eggshell decolouration was not detected in eggs from affected flocks. Furthermore, post mortem examinations revealed no lesions indicative of bacterial infection. Moreover, bacteriological analysis of hens was negative. The condition was reproduced in commercial brown layers after intratracheal inoculation with virus isolates from affected flocks. It is concluded that the LPAI H6N1 virus is very likely the only cause of the disease. An overview of main manuscripts published since 1976 describing non-H5 and non-H7 avian influenza (AI) virus infections in chickens and their biological significance is included in the present study, in which once more is shown that not only high pathogenic AI virus subtypes H5 and H7 can be detrimental to flocks of productive layers, but also non-H5 and non-H7 LPAI virus (H6N1 virus). PMID- 30484685 TI - Multimicrobial Kombucha Culture Tolerates Mars-Like Conditions Simulated on Low Earth Orbit. AB - A kombucha multimicrobial culture (KMC) was exposed to simulated Mars-like conditions in low-Earth orbit (LEO). The study was part of the Biology and Mars Experiment (BIOMEX), which was accommodated in the European Space Agency's EXPOSE R2 facility, outside the International Space Station. The aim of the study was to investigate the capability of a KMC microecosystem to survive simulated Mars-like conditions in LEO. During the 18-month exposure period, desiccated KMC samples, represented by living cellulose-based films, were subjected to simulated anoxic Mars-like conditions and ultraviolet (UV) radiation, as prevalent at the surface of present-day Mars. Postexposure analysis demonstrated that growth of both the bacterial and yeast members of the KMC community was observed after 60 days of incubation; whereas growth was detected after 2 days in the initial KMC. The KMC that was exposed to extraterrestrial UV radiation showed degradation of DNA, alteration in the composition and structure of the cellular membranes, and an inhibition of cellulose synthesis. In the "space dark control" (exposed to LEO conditions without the UV radiation), the diversity of the microorganisms that survived in the biofilm was reduced compared with the ground-based controls. This was accompanied by structural dissimilarities in the extracellular membrane vesicles. After a series of subculturing, the revived communities restored partially their structure and associated activities. PMID- 30484687 TI - Is a zero suicide target defensible and sensible? PMID- 30484686 TI - Preoperative Symptom Duration Is Associated With Outcomes After Hip Arthroscopy. AB - BACKGROUND:: Prolonged disease chronicity has been implicated as a cause of suboptimal clinical outcomes after hip arthroscopy for femoroacetabular impingement syndrome (FAIS), possibly due to disease progression, deconditioning, and the development of compensatory pathomechanics. PURPOSE:: To evaluate the effect of increasing duration of preoperative symptoms on patient-reported outcomes, reoperation, and clinical failure of hip arthroscopy for FAIS. STUDY DESIGN:: Cohort study; Level of evidence, 3. METHODS:: A retrospective cohort study was performed to identify all patients undergoing primary hip arthroscopy between January 1, 2012, and July 30, 2014, by a single surgeon, with minimum follow-up of 2 years. Patient demographics, comorbid medical conditions, and preoperative outcome scores were compared between patients with preoperative symptoms lasting less than 2 years and those with symptoms lasting 2 years or longer. Multivariate regressions were used to compare Hip Outcome Score Activities of Daily Living (HOS-ADL), Hip Outcome Score Sport-Specific (HOS-SS), and modified Harris Hip Score (mHHS) between the 2 cohorts at 2 years of follow up. RESULTS:: A total of 624 patients were included, with an average age of 34.0 +/- 13.5 years; 235 (37.7%) patients had experienced preoperative symptoms 2 years or longer. Patients with symptoms lasting less than 2 years had statistically significant higher outcome scores than those with symptoms lasting 2 or more years for the HOS-ADL (86.3 +/- 16.4 vs 80.3 +/- 19.9, respectively), HOS-SS (75.0 +/- 25.3 vs 65.1 +/- 29.0), and mHHS (79.1 +/- 16.6 vs 74.0 +/- 18.8), as well as higher satisfaction (82.1 +/- 30.7 vs 71.1 +/- 31.6) and lower pain scores (2.6 +/- 2.3 vs 3.5 +/- 2.6). On multivariate analysis, patients with symptoms 2 years or longer had significantly higher visual analog scale-Pain score (beta = 0.6, P = .039) and lower HOS-ADL (beta = -3.4, P = .033), HOS-SS (beta = -6.3, P = .012), and satisfaction (beta = -6.7, P = .028) at 2-year follow-up. Patients with longer duration of symptoms also demonstrated less improvement in HOS-SS (beta = -10.3, P = .001) at 2 years after surgery. Patients with symptoms for 2 years or longer were significantly less likely to achieve a patient acceptable symptomatic state for HOS-ADL (relative risk [RR] = 0.8, P = .024) and HOS-SS (RR = 0.8, P = .032) at 2 years of follow-up. Patients with symptoms 2 years or longer also demonstrated significantly higher rates of revision arthroscopy (RR = 10.1, P = .046). CONCLUSION:: Patients with untreated, FAIS-related symptoms lasting 2 years or longer before arthroscopic management had significantly worse patient-reported outcomes and higher rates of reoperation at 2 years after surgery when compared with those patients with a shorter duration of preoperative symptoms. PMID- 30484688 TI - PTSD - Inevitable or preventable? PMID- 30484689 TI - Pacific Medical Student Association (PMSA); a report from a RANZCP sponsored inaugural medical student camp. PMID- 30484691 TI - It's time to address the mental health needs of people with intellectual disability. PMID- 30484690 TI - From the President. PMID- 30484694 TI - College formally commits to Tri-nation Alliance. PMID- 30484692 TI - Upcoming RANZCP conferences. PMID- 30484696 TI - The primacy of person-centred care for patients with intellectual disability. PMID- 30484697 TI - Recurrence of Patellar Instability in Adolescents Undergoing Surgery for Osteochondral Defects Without Concomitant Ligament Reconstruction. AB - BACKGROUND:: First-time patellar dislocation with an associated chondral or osteochondral loose body is typically treated operatively to address the loose fragment. The incidence of recurrent instability in this patient population if the medial patellofemoral ligament (MPFL) is not reconstructed is unknown. PURPOSE:: To determine the recurrent instability rate in patients undergoing surgery for patellar instability with chondral or osteochondral loose bodies, as well as to identify and stratify risk factors for recurrent instability. STUDY DESIGN:: Case series; Level of evidence, 4. METHODS:: This was a retrospective analysis of adolescent patients treated operatively for acute patellar dislocation with associated chondral or osteochondral loose bodies between 2010 and 2016 at a single pediatric level I trauma center with minimum 2-year follow up. Potential demographic, injury-related, radiographic, and surgical risk factors were recorded. The primary outcome variable was recurrent subluxation and/or dislocation. Secondary outcome variables included need for additional procedures, Kujala score, Single Assessment Numerical Evaluation (SANE) score, and patient satisfaction. RESULTS:: Forty-one patients were included. In total, 61% experienced recurrent instability at a mean follow-up of 4.1 years and 39% required subsequent MPFL reconstruction. Tibial tubercle-trochlear groove (TT-TG) distance greater than 15 mm was a risk factor for recurrent instability ( P = .03). Patients with TT-TG distance greater than 15 mm and greater than 20 mm had recurrent instability rates of 75% and 86%, respectively. MPFL repair did not reduce the rate of recurrent instability ( P = .87). Recurrent instability was associated with significantly worse mean Kujala (93.9 vs 83.0; P = .01), SANE (88.9 vs 73.1; P = .01), and patient satisfaction scores (9.4 vs 7.3; P = .002). CONCLUSION:: If the MPFL is not reconstructed during index loose body treatment, children have a 61% recurrent instability rate. Patients with TT-TG distance greater than 15 mm, and particularly greater than 20 mm, are at highest risk for recurrent instability. PMID- 30484698 TI - An accurate regression of developmental stages for breast cancer based on transcriptomic biomarkers. AB - AIM: Breast cancers at different stages have tremendous differences on both phenotypic and molecular patterns. The developmental stage is an essential factor in the clinical decision of treatment plans, but was usually formulated as a classification problem, which ignored the consecutive relationships among them. MATERIALS & METHODS: This study proposed a regression-based procedure to detect the stage biomarkers of breast cancers. Biomarkers were detected by the Lasso and Ridge algorithms. RESULTS & CONCLUSION: A collaboration duet of Lasso and Ridge regression algorithms achieved the best performances, with classification accuracy (Acc) equal to 0.8294 and regression goodness-of-fit (R2) equal to 0.7810. The 265 biomarker genes were enriched with the signal peptide-based secretion function with the Bonferroni-corrected p-value equal to 6.9408e-3 and false discovery rate (FDR) equal to 1.1614e-2. PMID- 30484699 TI - Intramedullary versus extramedullary alignment guides on total knee arthroplasty: a meta-analysis. AB - AIM: A meta-analysis concentrated on the effect of intramedullary and extramedullary systems on total knee arthroplasty. METHOD: Potential academic articles were identified from Cochrane Library, Medline, PubMed, Embase, ScienceDirect, CNKI, WanFang, VIP and other databases. The STATA version was used to analyze the pooled data. RESULTS: There are obvious significant differences in drainage volume and transfusion rate. There was no significant difference in lower limb coronal alignment, coronal and sagittal alignment of the femoral component, operation time, postoperative knee score and complications. CONCLUSION: Our meta-analysis shows that the alignment of the extramedullary distal femur osteotomy is as accurate as intramedullary systems. Furthermore, extramedullary distal femur osteotomy without invading the femoral medullary cavity could reduce postoperative bleeding and the transfusion rate. Furthermore, research is required to test the robustness of our findings when more data is available and by undertaking both Bayesian and frequentist methods. When more data are available, the heterogeneity can be further explored through sensitivity analysis, and the available data can be combined to verify the hypothesis. PMID- 30484700 TI - Rare Pelvic Malignant Tumors in Adults: Treatment Features and Clinical Outcome in Nonmetastatic Disease (Single Institution Experience). AB - BACKGROUND: Nearly 200 cancers repertories are rare, and more than 20% are pelvic neoplasia. Diagnosis and treatment are challenging, even in reference centers, and survival is influenced by the aggressiveness of certain histologies and absence of a standard of care. PATIENTS AND METHODS: The authors report the results of a retrospective analysis of patients that attended the Institute of Oncology, Bucharest, between 2004 and 2015, for nonmetastatic pelvic malignant tumor treatment and follow-up. The outcomes are compared between the rare and common histology groups. RESULTS: Of the 60 cases analyzed, 17 patients (28.33%) bore a rare tumor, 33 (55%) were women, and the median age was 59 years. The majority was concerned by bladder (41.66%, 25 patients) and cervix (23.33%, 14 patients) neoplasms. For a median follow-up of 27.5 months, relapse was registered in 27 patients (45%), of whom 9 (33.33%) were from the rare group (53% of this subpopulation). The highest relapse rates were recorded in patients with rare bladder tumors (66.7%, 4 patients) compared with 42.1% (8 patients) in the common group (p = 0.294) and in prostate localization (66.7%, 2 patients) compared with 16.7% (1 patient) (p = 0.134). Estimated median relapse-free survival (RFS) was 60, 12 months in the rare group and 67 months for common tumors. CONCLUSIONS: In nonmetastatic rare pelvic tumor patients, the outcome was found to be poorer than in those concerned by common histologies stratified by organ. A higher rate of relapse and the lowest median RFS were observed in bladder and prostatic cancers. PMID- 30484702 TI - Applications of omega-3 polyunsaturated fatty acid supplementation for sport performance. AB - Omega-3 (n-3) polyunsaturated fatty acid (PUFA) supplementation has recently been proposed as an ergogenic aid for athletes. This claim is primarily based on mechanistic evidence that n-3PUFA's exert anti-inflammatory properties and act to change the functional capacity of the muscle cell by modifying the membrane fluidity of proteins and lipids within the cell membrane. In this review, we critically evaluate the scientific literature that examines the efficacy of n 3PUFA supplementation to improve athlete performance within the context of promoting muscle adaptation, energy metabolism, muscle recovery and injury prevention (e.g. muscle loss during immobilisation, or concussion). These findings have applications to athletes competing in strength/power-, endurance- and team-, based sports. Based on available information, there is some scientific evidence that n-3PUFA supplementation may improve endurance capacity by reducing the oxygen cost of exercise. Moreover, several studies report a benefit of n 3PUFA supplementation in promoting recovery from eccentric-based muscle damaging exercise. In contrast, there is insufficient evidence from studies in athletic populations to support the claim that n-3PUFA supplementation facilitates muscle growth during resistance training or preserves muscle mass during catabolic scenarios such as energy restriction or immobilisation. Moving forward, there remains ample scope to investigate context-specific applications of n-3PUFA supplementation for sport performance. PMID- 30484701 TI - Simultaneous Evaluation of the Preservative Effect of RNAlater on Different Tissues by Biomolecular and Histological Analysis. AB - A major concern in biomedical research is the quality of biological samples. RNAlater is a stabilizer, which was originally developed for RNA preservation in fresh tissues and is important for collection and transportation. However, this reagent lacks a comprehensive and systematic evaluation of its preservative effect on different mammalian tissues under consistent experimental conditions. In this study, we collected liver, kidney, testis, brain, and colon tissues from mice and divided the samples into the following respective groups: fresh, RNAlater preserved, and liquid nitrogen snap frozen. Biomolecules (RNA, DNA, and protein) were extracted from each tissue in each group, and samples were formalin fixed and paraffin embedded for quality assessment. Our results revealed that high-quality (yield, purity, and integrity) nucleic acids could be extracted from all samples. Gene expression determined by quantitative real-time polymerase chain reaction exhibited no major difference among the three groups. Notably, we observed significant protein degradation in brain tissue preserved by RNAlater compared with fresh and snap-frozen tissue. Protein expression of the other four tissues was similar among the three groups. Hematoxylin and eosin staining of all tissue types indicated no apparent difference among the three groups. We concluded that high-quality nucleic acids can be obtained and tissue morphology conserved when tissues are preserved with RNAlater. However, there are tissue specific differences in protein preservation when using RNAlater, which should be evaluated before extensive storage. PMID- 30484703 TI - miR-146a rs2910164 Polymorphism and Risk of Papillary Thyroid Carcinoma: A Meta Analysis. AB - AIMS: The presence of single nucleotide polymorphisms contributes to genetic diversity, and some are associated with cancer progression. Recent studies concerning the relationship between polymorphisms in miR-146a and the risk of papillary thyroid carcinoma (PTC) have produced conflicting results. Here, a meta analysis of previous studies was performed to evaluate this relationship. MATERIALS AND METHODS: Electronic databases, including PubMed, China National Knowledge Infrastructure, Cochrane Library, Embase, and Web of Science, were searched for studies concerning miR-146a and PTC published between January 1, 2000 and January 1, 2018. Fixed/random-effects models were used to calculate the pooled odds ratios (ORs) estimated in each study according to the level of heterogeneity. RESULTS: Eight studies involving 3993 cases and 9919 controls were assessed. Pooled results showed no association between the miR-146a rs2910164 polymorphism and PTC (OR = 1.001, 95% confidence interval [CI] 0.893-1.121). Subgroup analysis showed that the GG/GC genotype did not significantly increase PTC risk versus CC among Asians (OR = 0.939; 95% CI 0.828-1.066). Similarly, the combination of the GG and GC genotypes did not increase the risk of PTC for Caucasians (OR = 1.571, 95% CI 0.949-2.601). CONCLUSIONS: The results of our meta analysis indicated that the miR-146a rs2910164 variant genotype has no effect on susceptibility to PTC. PMID- 30484705 TI - A 10-year review of single medication double-dose ingestions in the nation's largest poison control system. AB - BACKGROUND: Most Americans take at least one medication on a daily basis. Inadvertently ingesting a double-dose of a medication with a narrow therapeutic index may lead to adverse effects. When a patient or medical professional contacts the local poison center after an overdose, a poison specialist fields the incoming information and, depending on the caller, provides specific recommendations. We sought to determine which medication classes were most likely to lead to significant adverse outcomes when an extra dose was ingested. METHODS: This was a retrospective review of all double-dose medication ingestions reported to the California Poison Control System (CPCS) between January 2006 and December 2015. Inclusion criteria were single-instance, single-medication ingestions where the dose was known. All ages and both sexes were included. We evaluated generalized outcomes per AAPCC criteria stratified as no effect, minor, moderate, major or death. We also documented specific symptoms and interventions noted by the poison control specialists. RESULTS: Out of 1286 cases, 876 ingestions met the inclusion criteria. Medications with antihypertensive and behavior modulating effects each accounted for over a third of all moderate and major effects. The medications/medication classes implicated in the 12 major outcomes included propafenone, beta blockers (betaBs), calcium channel blockers (CCBs), bupropion, and tramadol. Of these, vasoactive medications were associated with the most severe effects requiring cardiac pacing and vasopressor drips. Analgesics, antimicrobials, and anti-allergy medications were well tolerated. There were no deaths. CONCLUSIONS: Major adverse outcomes after a double dose ingestion were rare. Most double dose medication ingestions can be safely monitored at home, albeit with a few exceptions. Vigilance is warranted in cases of betaB and CCB ingestion due to the risk of hemodynamic collapse or seizures with tramadol and bupropion. PMID- 30484704 TI - Development of a Simple and Cost-Effective Method Based on T7 Endonuclease Cleavage for Detection of Single Nucleotide Polymorphisms. AB - AIMS: Single nucleotide polymorphisms (SNP) can be used as genetic markers and for risk assessment of allele-linked diseases, which may provide information for clinical diagnosis. Large-scale microarray and next-generation sequencing methods have made genome-wide SNP genotyping possible. However, in addition to their high cost, these techniques are dependent on having specialized equipment. Thus, there is a need for a simple genotyping method that can be implemented in a resource limited environment. METHODS: We developed a strategy for SNP genotyping based on T7 Endonuclease I cleavage and an enzyme-linked microparticle immune assay. Using this method, we genotyped two common SNP sites (rs11526468 and rs12979860). The quality of the genotyping process was validated. RESULTS: Although a 70% false negative rate was observed, no false-positive reactions were found. Therefore, multiple parallel repeat reactions can offset the possibility off time failed detection. DISCUSSION: As the method employs a duplicate reagent-dependent procedure, it has the potential for integration into a portable kit for field operation. PMID- 30484706 TI - Letter in reply to 'How to manage a spontaneous coronary artery dissection: reconsidering diagnosis and therapy'. PMID- 30484707 TI - Study of Karolinska Institutet and Washington University polyomaviruses in tonsil, adenoid, throat swab and middle ear fluid samples. AB - AIM: To study prevalence of Karolinska Institutet (KI) and Washington University (WU) polyomavirus (PyV) in 100 tonsils, 100 adenoids, 146 throat swab and 15 middle ear fluid samples collected from 146 patients (120 children and 26 adults), to analyze the sequence of noncoding control region (NCCR) and complete WUPyV genomes. MATERIALS & METHODS: Viruses were detected by quantitative real time PCR. The NCCRs and WUPyV genomes were sequenced and analyzed. RESULTS: The frequency of WUPyV and KIPyV DNA was 27 and 11% in adenoids, 4 and 3% in tonsils, 4.1 and 1.4% in throat swab samples, respectively. The WUPyV DNA was detected in one middle ear fluid sample as well. The WUPyV NCCRs showed mutations which may alter the putative transcription factor binding sites. Phylogenetic analysis revealed three clades of WUPyV. CONCLUSION: Tonsils and adenoids might be site of virus replication and/or persistence, and WUPyV may invade into the middle ear. PMID- 30484708 TI - Optimal regimen for treatment-naive hormone receptor-positive HER-2 negative metastatic breast cancer. PMID- 30484709 TI - Frequent Callers: "Good Care" with ICTs in Indian Transnational Families. AB - In the context of transnational family life, everyday information and communication technologies (ICTs) are key members of transnational care collectives. Through the approach of material semiotics to care as a relational practice between people and nonhuman entities, I explore frequent calling as one aspect of these collectives. I analyze the practice of frequent calling on phone and webcam between elderly parents living in Kerala, South India, and their adult children who work abroad as nurses. When family members are scattered around the world, frequent calling becomes a way to enact "good care" at a distance. PMID- 30484710 TI - Effects of Acute Exposure to Hypobaric Hypoxia on Mucosal Barrier Injury and the Gastrointestinal Immune Axis in Rats. AB - Khanna, Kunjan, K.P. Mishra, Sudipta Chanda, Malleswara Rao Eslavath, Lilly Ganju, Bhuvnesh Kumar, and Shashi Bala Singh. Effects of acute exposure to hypobaric hypoxia on mucosal barrier injury and the gastrointestinal immune axis in rats. High Alt Med Biol 00:000-000, 2018.-High altitude-induced gastrointestinal (GI) problems are potentially life-threatening. GI tract bleeding and inflammation are the major problems induced by hypobaric hypoxia (HH). In this study, effects of acute exposure to HH up to 14 days at 7620 m on GI immune function have been studied. To fulfill these objectives, Sprague-Dawley (SD) rats were divided into five groups namely Control and HH exposed (1, 3, 7, and 14 days). All groups except control were exposed to 7620 m of HH in an animal decompression chamber for the respective time intervals. Different degrees of intestinal mucosal damage in terms of increased mucosal permeability and disruption of intestinal villi were observed for different time intervals. HH exposure also upregulated secretory immunoglobulin A (sIgA) and proinflammatory cytokines in GI lavage along with proinflammatory markers such as toll-like receptor 4 (TLR4) and inducible nitric oxide synthase (iNOS). HH exposure of rats for 7 days significantly increased interleukin-17 (IL-17) and natural killer (NK) cell and dendritic cell populations compared with unexposed control rats. However, the number of naive T cells was significantly decreased in Peyer's patches. Our results connect HH to GI immune axis and highlight Th17 cells and proinflammatory molecules as potential therapeutic targets to counteract HH induced GI dysfunction. PMID- 30484711 TI - Prolonged coma resulting from massive levothyroxine overdose and the utility of N terminal prohormone brain natriuretic peptide (NT-proBNP). AB - INTRODUCTION: Levothyroxine overdose rarely results in systemic toxicity. We report a case of intentional levothyroxine overdose with a delayed onset coma and delirium lasting two weeks. CASE SUMMARY: A 72-year-old female ingested 12 mg levothyroxine. Initially, she was drowsy but quickly recovered and was well for the following two days. On day-3 post-overdose her mental state gradually deteriorated. She presented to the hospital with agitation, confusion and dyspnoea. Initial vital signs: P128 bpm, BP132/67 mmHg, temperature 38 degrees C and SpO2 97%RA. Features suggesting thyroid storm were present: fever >38 degrees C, tachycardia and persistent coma. Serum T4 and T3 were >150 pmol/L (normal: 8-16) and >30.8 pmol/L (normal: 3.2-6.1), respectively. These remained elevated for 11 days. She was treated with propranolol, propylthiouracil and cholestyramine. She remained intubated for two weeks without sedation. Her conscious state improved on day-13, coinciding with normalisation of serum T4. Normal cognition was regained four days later. N-terminal pro-brain natriuretic peptide (NT ProBNP) concentration was increased during coma and peaked 2 days prior to Glasgow Coma Score improving. DISCUSSION: Our case demonstrates features of thyrotoxicosis and thyroid storm with coma after massive levothyroxine overdose. Coma was associated with an increase in NT-proBNP concentration. This may be a potential marker for brain injury and recovery. PMID- 30484713 TI - An analytically confirmed non-fatal intoxication by carfentanil in Sweden. PMID- 30484712 TI - Erratum: "Prenatal Exposure to DDT and Pyrethroids for Malaria Control and Child Neurodevelopment: The VHEMBE Cohort, South Africa". PMID- 30484714 TI - Microbial Contamination of Organically and Conventionally Produced Fresh Vegetable Salads and Herbs from Retail Markets in Southwest Germany. AB - A total of 189 samples of fresh products (leafy salads, ready-to-eat mixed salads, and fresh herbs) bought in retail in Southwest Germany were investigated for their microbiological quality and the presence of pathogenic bacteria, including Salmonella spp., Listeria monocytogenes, and presumptive Bacillus cereus. Total aerobic mesophilic plate counts (TAC) ranged from 5.5 to 9.6 log colony-forming units (CFUs) per gram. Enterobacteria and pseudomonads were the predominant microorganisms and were detected in all samples with counts between 5.0 and 9.2 log CFU/g. Strains of Escherichia coli were detected in 9 salad (7.9%) and 25 herb samples (33.3%). Significant differences in bacterial counts were found between conventionally and organically-grown products: in herbs the counts of moulds were significantly higher in organically-grown products, while E. coli was only detected in conventionally-grown products. In conventionally grown salad samples, yeast counts were significantly higher. Salmonella Enteritidis was only detected in two conventionally- and in one organically produced salad samples (2.6%). No coagulase-positive staphylococci were detected in fresh salads as well as in herbs. High levels of B. cereus sensu lato (>=3 log CFU/g) were detected in 19 vegetable salads (16.7%) and even in 55 samples of fresh herbs (73.3%). Listeria monocytogenes could not be detected in fresh herbs; however, three L. monocytogenes strains were isolated from two conventionally produced salad samples and belonged to PCR serogroup IIa. Although our results indicate a high microbial load in fresh salads and herbs in Southwest Germany in 2015, the incidences of human pathogenic bacteria, that is, L. monocytogenes, Salmonella spp., and coagulase-positive staphylococci strains, were low. PMID- 30484716 TI - Editorial Acknowledgment of Ad Hoc Reviewers. PMID- 30484718 TI - Editors' Note: New Forum for the Leonard I. Pearlin Award Paper. PMID- 30484715 TI - Stress and the Mental Health of Populations of Color: Advancing Our Understanding of Race-related Stressors. AB - This article provides an overview of research on race-related stressors that can affect the mental health of socially disadvantaged racial and ethnic populations. It begins by reviewing the research on self-reported discrimination and mental health. Although discrimination is the most studied aspect of racism, racism can also affect mental health through structural/institutional mechanisms and racism that is deeply embedded in the larger culture. Key priorities for research include more systematic attention to stress proliferation processes due to institutional racism, the assessment of stressful experiences linked to natural or manmade environmental crises, documenting and understanding the health effects of hostility against immigrants and people of color, cataloguing and quantifying protective resources, and enhancing our understanding of the complex association between physical and mental health. PMID- 30484719 TI - Letter to the editor regarding quantitative dynamic contrast-enhanced ultrasound may help predict the outcome of hepatocellular carcinoma after microwave ablation. PMID- 30484720 TI - Precoagulation with microwave ablation for hepatic parenchymal transection during liver partial resection. AB - PURPOSE: To evaluate the feasibility of precoagulation with microwave ablation (MWA) for hepatic parenchymal transection during liver partial resection. METHODS: A total of 66 eligible patients were enrolled in this double-blind, randomized, controlled study. Patients were randomized to receive either the traditional clamp-crushing method (Control group) or the MWA precoagulation method (MWA group) for hepatic parenchymal transection during liver partial resection. The operative time, hepatic portal occlusion time, intraoperative blood loss and transfusion, postoperative complications and recovery outcomes were compared. RESULTS: Compared to the Control group, the MWA group had significantly less intraoperative blood loss. Fewer red blood cell transfusions were observed in the MWA group but without statistical significance. The MWA group showed significantly higher serum alanine aminotransferase and aspartate aminotransferase levels at day 1 postoperatively, but no differences between the MWA and Control groups were found at days 3 and 7. There were no significant differences in terms of operative time, hepatic portal occlusion time, postoperative total bilirubin levels, human albumin solution consumption or length of hospital stay. Postoperative complications such as impaired renal function, pyrexia, admission to ICU, abscess, biliary leakage, intrahepatic and distant tumor recurrence and in-hospital mortality were comparable between the two groups. CONCLUSION: Precoagulation with MWA reduced intraoperative blood loss with similar postoperative complications, providing a safe, effective, novel alternative for hepatic parenchymal transection during liver partial resection. Additional results from larger series are recommended to confirm these findings. PMID- 30484721 TI - Potential of curcumin and resveratrol as biochemical and biophysical modulators during lung cancer in rats. AB - The present study explored chemopreventive aspects of curcumin and resveratrol in the experimental model of lung carcinogenesis in rats. The main aim was to establish efficacy of combined phytochemicals treatment over individual treatments in rat cancer model. The study was performed in terms of both biophysical and biochemical parameters. The rats were segregated into five groups, which included normal control, benzo[a]pyrene (BP) treated, BP + curcumin treated, BP + resveratrol treated, and BP + curcumin + resveratrol treated groups. The results confirmed significant changes in the biochemical indices of the BP treated rats. Further, radiorespirometric studies showed significant rise in the 14C-glucose turnover and uptakes in BP treated rats. Also, a significant increase in the cell proliferation was noticed indirectly by recording uptakes of 3H-thymidine in the lung slices of BP treated rats. On the other hand, supplementation with curcumin and resveratrol in combination to BP treated rats significantly modulated both biophysical and biochemical indices. The histopathological studies also supported the efficacy of combined treatment of phytochemicals during lung carcinogenesis. The present study concluded that the combination of curcumin and resveratrol efficiently modulated lung carcinogenesis in rats. PMID- 30484722 TI - Future of nanomedicines for treating respiratory diseases. AB - INTRODUCTION: Nanoparticles are under discussion in drug delivery for more than 20 years now, but examples for nanoparticulate formulations in the treatment of respiratory diseases are rare and mostly limited to the administration of sub micron drug particles (ultrafine particles). However, nanoparticles may also carry specific benefits for respiratory treatment. Are nanoparticles the next generation drug carrier system to facilitate systemic delivery, sustained release and cancer treatment in the lungs? Areas covered: This review will look into the promises and opportunities of the use of nanoparticles in the treatment of respiratory diseases. Important aspects to discuss are the fate of nanoparticles in the lung and mechanisms for reproducible delivery of nanoparticulate formulations to the lungs. Examples are given where nanoparticles may be advantageous over for traditional formulations and further aspects to explore are mentioned. Expert opinion: The benefit of nanoparticulate systems for respiratory delivery adds to the portfolio of possible formulation strategies, depends on the intended functionality and needs more exploration. Advantages of such systems are only seen in special cases. PMID- 30484723 TI - KL-6 is a long-term disease-activity biomarker for interstitial lung disease associated with polymyositis/dermatomyositis, but is not a short-term disease activity biomarker. AB - OBJECTIVES: We aimed to evaluate the usefulness of serum KL-6 for interstitial lung disease (ILD) with polymyositis/dermatomyositis (PM/DM). METHODS: All consecutive and previously untreated adult patients with PM/DM who were admitted to our hospital from 2010 to 2015 were included. The associations between serum KL-6 levels and clinical information were retrospectively analyzed. RESULTS: Baseline serum KL-6 levels were significantly higher in patients with ILD than in those without (n = 41 and 15, respectively; p < 0.001). In the 14 patients whose ILD improved within 4 weeks post-treatment, their serum KL-6 levels did not significantly decrease at 2 weeks, 4 weeks, or 3 months post-treatment (p = 1.00, 1.00, and 0.83, respectively). Conversely, their serum KL-6 levels significantly decreased at 6, 9, and 12 months post-treatment (p = 0.01 in all comparisons). In the 12 patients whose ILD remained unchanged or deteriorated in 4 weeks post treatment, only the difference between their serum KL-6 levels at 3 and 12 months was significant (p = 0.003). CONCLUSIONS: The present study validated the serum KL-6 as a diagnostic marker for ILD in PM/DM. However, serum KL-6 is not a short term disease-activity biomarker for ILD with PM/DM, but it is a long-term disease activity biomarker. PMID- 30484724 TI - Factors associated with discontinuation of glucocorticoids after starting biological disease-modifying antirheumatic drugs in rheumatoid arthritis patients. AB - OBJECTIVES: Glucocorticoids (GCs) are effective treatments for rheumatoid arthritis (RA) but long-term use has adverse effects. This study aimed to elucidate whether GCs can be discontinued by introducing bDMARDs (biological disease-modifying antirheumatic drugs) and the factors influencing the outcome. METHOD: We included RA patients who had been orally taking GCs at the initiation of bDMARDs. The changes in GC dose after starting bDMARDs were evaluated and the GC discontinuation rate was analyzed using Kaplan-Meier analysis. The factors associated with discontinuation of GCs were assessed by Cox hazard models. RESULTS: Eighty RA patients were included in the study. The dosage of oral prednisolone (PSL) was significantly reduced from 5.0 to 3.0 mg/day by 3 months (p=0.01). GCs were discontinued in 31.3% of patients and the median time until GC discontinuation was 10.1 months. The GC discontinuation rate was significantly higher in patients with Class 1 and 2 (p = 0.024), with an initial PSL dose <5 mg/day (p = 0.040), and with low DAS28(ESR) (p = 0.038). In multivariate analyses, higher DAS28(ESR) (odds ratio, 0.200; p = 0.039), and higher PSL dose (odds ratio, 0.748; p = 0.029) were significantly associated with less frequent GC discontinuation. CONCLUSIONS: DAS28(ESR) high and PSL dose were factors associated with discontinuation of GC use after starting bDMARDs. PMID- 30484725 TI - SOCS3 control the activity of NF-kappaB induced by HSP70 via degradation of MyD88 adapter-like protein (Mal) in IPEC-J2 cells. AB - Hyperthermia in pigs induces suppressor of cytokine signaling (SOCS) 3 and SOCS4 expression in intestinal gut and causes disruption of inflammation cytokine production. These changes may affect the development of inflammatory bowel disease in heat-stressed pigs. However, the mechanisms are not well understood. Accordingly, in this study, we examined the roles of SOCS members in regulation of the nuclear factor (NF)-kappaB pathway and heat shock protein (HSP) 70 mediated cytokine induction in 293T human embryonic kidney cells and IPEC-J2 porcine small intestinal epithelial cells. Ectopic expression of HSP70 significantly modulated NF-kappaB activity (p <= .05). Moreover, co-expression of SOCS3 or SOCS4 with HSP70 reduced NF-kappaB activity, which was abolished by SOCS3 or SOCS4 knockdown with short hairpin RNA. Interestingly, MyD88-adaptor like (Mal) protein was downregulated in cells expressing SOCS3 but not in cells expressing SOCS4. In addition, SOCS3 but not SOCS4 negatively regulated the activity of NF-kappaB induced by HSP70 overexpression via degradation of Mal. These findings may facilitate the development of novel SOCS3-based therapeutic strategies to control heat stress-related disorders in pigs. PMID- 30484726 TI - Spontaneous remission in congenital leukemia. PMID- 30484727 TI - Adolescent cocaine exposure enhanced negative affect following drug re-exposure in adult rats: Attenuation of c-Fos activation. AB - BACKGROUND:: The goal of the present study was to utilize the adolescent drug experience as an emerging vulnerability factor for developing psychiatric comorbidities in adulthood that could, in turn, help to elucidate and/or hypothesize possible mechanisms contributing to higher relapse rates. OUTCOMES:: The current results showed that adolescent cocaine exposure (15 mg/kg, intraperitoneally, seven days) during early-mid adolescence (postnatal days 33 39) enhanced negative affect in adulthood, by increasing behavioral despair following drug re-exposure and by increasing anhedonia. Thus, these behavioral data provided a good model to further ascertain the long-term cellular and molecular adaptations that might take place in the brain in response to adolescent cocaine exposure as well as the impact of drug re-exposure in adulthood. In this regard, the results showed that adolescent cocaine exposure did not modulate cell proliferation (Ki-67+ cells) or c-Fos protein activation in the dentate gyrus region of the hippocampus, but attenuated c-Fos activation in the dorsal striatum. CONCLUSIONS:: These results proved that a history of cocaine exposure during adolescence increased the vulnerability to induce negative affect (i.e. emergence of psychiatric comorbidity) in adulthood while it decreased neuronal activation in the dorsal striatum. Interestingly, these effects were only observed following cocaine re-exposure in adulthood, suggesting that avoiding drug contact in adulthood could prevent the long-term negative effects induced by adolescent cocaine. PMID- 30484728 TI - Changes Over Time in the Oregon Physician Orders for Life-Sustaining Treatment Registry: A Study of Two Decedent Cohorts. AB - BACKGROUND: The Physician Orders for Life-Sustaining Treatment (POLST) began in Oregon in 1993 and has since spread nationally and internationally. OBJECTIVES: Describe and compare demographics and POLST orders in two decedent cohorts: deaths in 2010-2011 (Cohort 1) and in 2015-2016 (Cohort 2). DESIGN: Descriptive retrospective study. SETTING/SUBJECTS: Oregon decedents with an active form in the Oregon POLST Registry. MEASUREMENTS: Oregon death records were matched with POLST orders. Descriptive analysis and logistic regression models assess differences between the cohorts. RESULTS: The proportion of Oregon decedents with a registered POLST increased by 46.6% from 30.9% (17,902/58,000) in Cohort 1 to 45.3% (29,694/65,458) in Cohort 2. The largest increase (83.3%) was seen in decedents 95 years or older with a corresponding 78.7% increase in those with Alzheimer's disease and dementia, while the interval between POLST form completion and death in these decedents increased from a median of 9-52 weeks. Although orders for do not resuscitate and other orders to limit treatment remained the most prevalent in both cohorts, logistic regression models confirm a nearly twofold increase in odds for cardiopulmonary resuscitation and full treatment orders in Cohort 2 when controlling for age, sex, race, education, and cause of death. CONCLUSION: Compared with Cohort 1, Cohort 2 reflected several trends: a 46.6% increase in POLST Registry utilization most marked in the oldest old, substantial increases in time from POLST completion to death, and disproportionate increases in orders for more aggressive life-sustaining treatment. Based on these findings, we recommend testing new criteria for POLST completion in frail elders. PMID- 30484729 TI - Prevalence of Stress Urinary Incontinence in Women with Premature Ovarian Insufficiency. AB - BACKGROUND: To determine the prevalence of stress urinary incontinence (SUI) and associated factors in women with premature ovarian insufficiency (POI). MATERIALS AND METHODS: The study included 149 patients with POI and 303 control women without POI. Age, body mass index (BMI), gestational history, time since onset of POI, and status of hormone therapy (HT) for POI were recorded. RESULTS: There was no statistical difference in the mean age, BMI, and parity between the two groups. The prevalence of SUI in the POI group tended to be higher than that in the control group (20.9%, 30/149 vs. 16.2%, 49/303), although not significantly (p = 0.297). About 41.6% (62/149) of patients with POI received HT. Patients with POI and SUI were older (p = 0.018) and had higher BMI (p = 0.007) than women with POI without SUI (p = 0.007). Compared to nulliparas, primiparas were more likely to have SUI (p = 0.046). However, SUI developed irrespective of time since onset of oligomenorrhea/amenorrhea or HT use. Furthermore, regression analysis showed that the prevalence of SUI was higher in women 30-39 years of age (odds ratio [OR] = 3.27, p = 0.002) and older than 40 years (OR = 7.78, p = 0.001). Primiparas (OR = 2.89, p = 0.001) and vaginal delivery (OR = 2.58, p = 0.023) were associated with SUI. CONCLUSIONS: The prevalence of SUI was fairly high among patients with POI, and age, parity, and vaginal delivery were the main risk factors. However, duration of POI and HT use had no effect on SUI. Increasing awareness of the importance of urinary system health in this population will improve the quality of life for these women. PMID- 30484731 TI - A Correction to: Special Issue: Electromagnetic fields in biology and medicine. PMID- 30484730 TI - Cancer!? I Don't Have Time for That: Impact of a Psychosocial Intervention for Young Adults with Cancer. AB - PURPOSE: Young adult oncology has gained momentum in recognizing the unique medical and psychosocial needs of the population of adolescents and young adults with cancer (AYAC). However, many of their psychosocial needs remain unmet and we are yet to identify how clinical or research programs can be tailored to meet these needs. The aim of the study was to evaluate the impact of a cognitive behavioral intervention adapted to meet the psychosocial needs and issues of AYAC and delivered either through Skype or face-to-face sessions against a control condition. METHODS: A total of 113 AYAC aged between 18 and 39 years were randomly assigned to a brief three-session intervention or control/care-as-usual group. They were then assessed at three time points of baseline (time 1), post (time 2), and 3-month postintervention (time 3) using self-report questionnaires targeting overall outcomes of mood/emotional well-being and health-related quality of life (HRQOL) and specific outcomes of illness-related self-efficacy and family/social and sexual relationship well-being. RESULTS: Significant between-group differences were obtained from time 1 to time 2 on outcomes of social/family and sexual relationship well-being, whereas groups did not differ from time 2 to time 3. Within-group results from time 1 to time 2 showed significant improvements in sexual esteem for both groups, whereas only AYAC of the intervention group significantly improved on outcomes of anxiety, overall mood/emotional well-being and HRQOL. In addition, improvements in self-efficacy were obtained only for the intervention group from time 2 to time 3. CONCLUSION: When compared with a control/care-as-usual condition, the intervention had a positive impact on psychological and relationship well-being. Results suggested that the intervention was beneficial and clinically relevant to the population of AYAC. PMID- 30484732 TI - Changes in the diagnosis of glomerular diseases in east China: a 15-year renal biopsy study. AB - BACKGROUND: There have been some gradual changes in the distribution of renal biopsy pathological diagnoses during recent years. This study aimed to show changes in renal disease prevalence in China by investigating 10 patients diagnosed at our Kidney Disease Centre during the last 15 years. METHODS AND RESULTS: All patients aged 15-year-old or older who underwent renal biopsy at the First Affiliated Hospital, Zhejiang University, from 2001 to 2015 were enrolled. There were 5 common types of primary glomerulonephritis: IgA nephropathy (IgA N), membranous nephropathy (MN), mesangial progressive glomerulonephritis (MsPGN), minimal change disease (MCD), and focal segmental glomerulosclerosis (FSGS), which represented 50%, 16.8%, 15.9%, 8.1% and 2.5% of total cases, respectively. IgA nephropathy was the most common type of primary glomerulonephritis (PGN). CONCLUSIONS: Our results mostly showed a new trend that the diagnosis of IgA nephropathy was not increasing and the prevalence of membranous nephropathy had increased, becoming the second most common type of primary glomerulonephritis. Key POINTS Distinguished with other domestic studies, IgA nephropathy did not show a trend of continuous growth although it still had about the half proportion of PGN, whereas membranous nephropathy kept rising and became the second common PGN. Concerning SGN, LN peaked in the younger-age and middle-age groups with a significant female prevalence, DN, BANS and SV had a male predominance peaking in the middle-age and old-age groups. PMID- 30484733 TI - Subchronic treatment with St John's wort produces a positive shift in emotional processing in healthy volunteers. AB - BACKGROUND:: The neurocognitive model of antidepressant treatment in depression states that antidepressants work by producing relatively immediate positive shifts in emotional processing, which translate into clinical improvement with time. St John's Wort has shown antidepressant potential in randomised controlled trials; however, its pharmacological actions are broad and it is unknown whether treatment also produces changes in emotional processing. AIMS:: We investigated whether short-term treatment with St John's wort has similar effects on emotional processing to those reported with other antidepressants such as selective serotonergic reuptake inhibitors. METHODS:: Forty-eight healthy participants were given St John's wort or placebo treatment for seven days. On day 7 they completed a battery of tasks to measure emotional processing and other elements of cognition. RESULTS:: St John's wort treatment produced similar changes to other antidepressants, for example reducing recognition of disgusted faces and attention to fearful faces, while increasing memory for positive words. We failed to find evidence for an effect of St John's wort on other aspects of cognition including working memory. CONCLUSIONS:: These findings lend support to the theory that the production of early positive biases in emotional processing may be a common feature of all clinically effective antidepressants with diverse pharmacological mechanisms. PMID- 30484734 TI - Increased Incidence of Endometrial Cancer Following the Women's Health Initiative: An Assessment of Risk Factors. AB - BACKGROUND: The Surveillance, Epidemiology, and End Result (SEER) database shows a variable increase in endometrial cancer incidence over time. The objective of this review was to examine published endometrial cancer rates and potential etiologies. METHODS: Endometrial cancer incidence was obtained from the SEER Program database from 1975 through 2014, and a test for trend in incidence was calculated. Changes in risk factors thought to be associated with endometrial cancer, including age, obesity, diabetes, diet and exercise, reproductive factors, and medications (hormone therapy [HT] including Food and Drug Administration [FDA]-approved and non-FDA-approved [compounded] estrogens and progestogens, tamoxifen, and hormonal contraceptives) were found through PubMed searches. Temporal trends of risk factors were compared with endometrial cancer trends from SEER. RESULTS: Although endometrial cancer rates were constant from 1992 to 2002 (women 50-74 years of age), they increased 2.5% annually with a 10% increase from 2006 to 2012 (trend test 0.82). Use of approved prescription estrogen-progestogen combination products decreased after the publication of the Women's Health Initiative (WHI) data, whereas other risk factors either remained constant or decreased during the same time; however, compounded bioidentical HT (CBHT) use increased coincident with the endometrial cancer increase. CONCLUSION: Endometrial cancer rate increases after the first publication of WHI data in 2002 may be associated with the decreased use of approved estrogen-progestogen therapy, the increase in CBHT use, and the prevalence of obesity and diabetes; potential relationships require further evaluation. PMID- 30484736 TI - The Timing Hypothesis: Hormone Therapy for Treating Symptomatic Women During Menopause and Its Relationship to Cardiovascular Disease. AB - The risks and benefits of menopausal hormonal therapy (HT) have been evaluated extensively over the past three decades. While the efficacy of HT for management of menopausal symptoms, including vasomotor symptoms and vaginal dryness is well established, its relationship to cardiovascular outcomes is complex. The timing hypothesis, which posits that the cardiovascular effects of HT depend on the timing of initiation of HT in relation to menopause, has helped shape our understanding of the cardiovascular outcomes related to HT. Based on results from female monkey studies, the timing hypothesis provides a framework to explain discrepancies in results between multiple observation studies and the Women's Health Initiative (WHI) hormone therapy trials. The WHI trials closed early in 2002 in part because of increased cardiovascular events seen in women on treatment. Subanalysis of the WHI results by age group, and more recent randomized control studies, including the Kronos Early Estrogen and Prevention Study (KEEPS) and Early Versus Late Intervention Trial (ELITE), demonstrate that the risk of adverse cardiovascular events for HT are low for women <60 years of age or within 10 year from menopause. Although current data does not support using HT for primary prevention of cardiovascular disease, it does suggest that HT can be safely used to treat symptoms in appropriately selected women close to menopause. PMID- 30484735 TI - Biomarkers Associated with Lymphedema and Fibrosis in Patients with Cancer of the Head and Neck. AB - BACKGROUND: This study examined interrelationships of selected interleukins (ILs), tumor growth factors, matrix metalloproteinases (MMPs), and C-reactive protein, interferon-gamma (IFN-gamma), and tumor necrosis factor alpha (TNF alpha) with lymphedema/fibrosis in patients with head and neck cancer (HNC). METHODS AND RESULTS: Patients newly diagnosed with >=Stage II HNC (N = 100) were assessed for external/internal lymphedema and/or fibrosis before treatment, end of-treatment, and at regularly established intervals through 72 weeks posttreatment and blood was drawn. Data from 83 patients were analyzed. Group based trajectory modeling generated patient groups with similar longitudinal biomarker and lymphedema-fibrosis trajectories. Area-under-the-curve (AUC) values were also generated for each biomarker and severity of lymphedema-fibrosis. Associations among and between biomarkers and lymphedema-fibrosis trajectories and AUCs were tested (log-likelihood chi-square, correlations). The strongest evidence for the association of biomarkers with the overall and trajectory patterns and severity of lymphedema-fibrosis was observed for IL-6, IL-1beta, TNF alpha, TGF-beta1, and MMP-9 (all p < 0.05). Convergence of joint trajectory patterns and AUC were observed with IL-6 with all lymphedema-fibrosis trajectories and internal lymphedema AUC. IL-1beta trajectories converged with external lymphedema trajectories and all lymphedema-fibrosis AUCs. TNF-alpha and TGF-beta1 converged most strongly with fibrosis in terms of trajectory patterns. However TNF-alpha demonstrated stronger association with lymphedema-fibrosis AUC (fibrosis: rs = 0.49). MMP-9 demonstrated convergence with lymphedema-fibrosis AUCs (lymphedema: 0.43-0.42; fibrosis: 0.35). CONCLUSION: Systemic levels of selected mediators of proinflammatory processes track with acute and chronic clinical phenotypes of lymphedema/fibrosis in HNC patients suggesting their potential role in the pathogenesis of these conditions. PMID- 30484737 TI - Diminished responses to monoaminergic antidepressants but not ketamine in a mouse model for neuropsychiatric lupus. AB - BACKGROUND:: A significant proportion of patients suffering from major depression fail to remit following treatment and develop treatment-resistant depression. Developing novel treatments requires animal models with good predictive validity. MRL/lpr mice, an established model of systemic lupus erythematosus, show depression-like behavior. AIMS:: We evaluated responses to classical antidepressants, and associated immunological and biochemical changes in MRL/lpr mice. METHODS AND RESULTS:: MRL/lpr mice showed increased immobility in the forced swim test, decreased wheel running and sucrose preference when compared with the controls, MRL/MpJ mice. In MRL/lpr mice, acute fluoxetine (30 mg/kg, intraperitoneally (i.p.)), imipramine (10 mg/kg, i.p.) or duloxetine (10 mg/kg, i.p.) did not decrease the immobility time in the Forced Swim Test. Interestingly, acute administration of combinations of olanzapine (0.03 mg/kg, subcutaneously)+fluoxetine (30 mg/kg, i.p.) or bupropion (10 mg/kg, i.p.)+fluoxetine (30 mg/kg, i.p.) retained efficacy. A single dose of ketamine but not three weeks of imipramine (10 mg/kg, i.p.) or escitalopram (5 mg/kg, i.p.) treatment in MRL/lpr mice restored sucrose preference. Further, we evaluated inflammatory, immune-mediated and neuronal mechanisms. In MRL/lpr mice, there was an increase in autoantibodies' titers, [3H]PK11195 binding and immune complex deposition. There was a significant infiltration of the brain by macrophages, neutrophils and T-lymphocytes. p11 mRNA expression was decreased in the prefrontal cortex. Further, there was an increase in the 5-HT2aR expression, plasma corticosterone and indoleamine 2,3-dioxygenase activity. CONCLUSION:: In summary, the MRL/lpr mice could be a useful model for Treatment Resistant Depression associated with immune dysfunction with potential to expedite antidepressant drug discovery. PMID- 30484738 TI - Prevalence of Optimal Metabolic Health in American Adults: National Health and Nutrition Examination Survey 2009-2016. AB - BACKGROUND: Several guidelines for cardiometabolic risk factor identification and management have been released in recent years, but there are no estimates of current prevalence of metabolic health among adults in the United States. We estimated the proportion of American adults with optimal cardiometabolic health, using different guidelines. METHODS: Data from the National Health and Nutrition Examination Survey 2009-2016 were analyzed (n = 8721). Using the most recent guidelines, metabolic health was defined as having optimal levels of waist circumference (WC <102/88 cm for men/women), glucose (fasting glucose <100 mg/dL and hemoglobin A1c <5.7%), blood pressure (systolic <120 and diastolic <80 mmHg), triglycerides (<150 mg/dL), and high-density lipoprotein cholesterol (>=40/50 mg/dL for men/women), and not taking any related medication. RESULTS: Changing from ATP III (Adult Treatment Panel III) guidelines to more recent cut points decreased the proportion of metabolically healthy Americans from 19.9% (95% confidence interval [CI]: 18.3-21.5) to 12.2% (95% CI: 10.9-13.6). Dropping WC from the definition increased the percentage of adults with optimal metabolic health to 17.6%. Characteristics associated with greater prevalence of metabolic health were female gender, youth, more education, never smoking, practicing vigorous physical activity, and low body mass index. Less than one-third of normal weight adults were metabolically healthy and the prevalence decreased to 8.0% and 0.5% in overweight and obese individuals, respectively. CONCLUSIONS: Prevalence of metabolic health in American adults is alarmingly low, even in normal weight individuals. The large number of people not achieving optimal levels of risk factors, even in low-risk groups, has serious implications for public health. PMID- 30484739 TI - Medicaid Family Planning Expansions: The Effect of State Plan Amendments on Postpartum Contraceptive Use. AB - OBJECTIVE: To determine the effect of state Medicaid family planning (FP) programs transitioning from a Section 1115 waiver to a State Plan Amendment (SPA) on reproductive health outcomes. MATERIALS AND METHODS: Data were from the Pregnancy Risk Assessment Monitoring System on 75,082 women who had a live birth between 2007 and 2013 and were living in one of nine states. We performed a difference-in-differences analysis to quantify the effect of the transition on postpartum contraceptive (PPC) use and unintended births (UBs). RESULTS: Over 80% of the sample reported using PPC; half reported an UB. The odds of PPC use among women who were living in a study state and gave birth after the transition were 1.14 times that of women who were living in a comparison state and/or gave birth before the transition (95% confidence interval: 1.04-1.24). CONCLUSIONS: Findings suggest that women living in states that transitioned from a waiver to SPA experienced an increased likelihood of PPC compared with those living in comparison states. PMID- 30484740 TI - Influence of biomechanical models on joint kinematics and kinetics in baseball pitching. AB - In baseball pitching, biomechanical parameters have been linked to ball velocity and potential injury risk. However, although the features of a biomechanical model have a significant influence on the kinematics and kinetics of a motion, this influence have not been assessed for pitching. The aim of this study was to evaluate the choice of the trunk and shoulder features, by comparing two models using the same input. The models differed in thoraco-humeral joint definition (moving or fixed with the thorax), joint centre estimation, values of the inertial parameters and computational framework. One professional pitcher participated in the study. We found that the different features of the biomechanical models have a substantial influence on the kinematics and kinetics of the pitchers. With a fixed thoraco-humeral joint the peak average thorax angular velocity was delayed and underestimated by 17% and the shoulder internal rotation velocity was overestimated by 7%. The use of a thoraco-humeral joint fixed to the thorax will lead to an overestimation of the rotational power at the shoulder and will neglect the power produced by the forward and upward translation of the shoulder girdle. These findings have direct implications for the interpretation of shoulder muscle contributions to the pitch. PMID- 30484741 TI - Continuing war on pain: a personalized approach to the therapy with nonsteroidal anti-inflammatory drugs and opioids. AB - Successful pain management requires the delivery of analgesia with minimal risk of adverse drug reactions. Nonsteroidal anti-inflammatory drugs and opioids remain the mainstay of treatment for the majority of patients. Unfortunately, almost 50% of all patients experience inadequate pain relief and serious side effects. Allelic variants in genes coding for target proteins, transporters and enzymes, which govern analgesic drugs action and their fate in the organism, might explain inter-individual variability in pain severity and in drug-induced pain relief and toxicities. Additionally, it seems that epigenetic changes contribute to the highly variable response to pain treatment. Therefore, pharmacogenomic testing might be a valuable tool for personalization of pain treatment, with a multidisciplinary team approach involved. PMID- 30484742 TI - Increasing Prevalence of Group III Penicillin-Binding Protein 3 Mutations Conferring High-Level Resistance to Beta-Lactams Among Nontypeable Haemophilus influenzae Isolates from Children in Korea. AB - This study investigated the roles of beta-lactamase and penicillin-binding protein 3 (PBP3) alterations in the development of recent antimicrobial resistance in nontypeable Haemophilus influenzae (NTHi) isolated from Korean children. Nasopharyngeal NTHi isolates from children at a tertiary children's hospital were tested for antimicrobial susceptibility using E-test. beta lactamase production was screened by the paper disc test, and polymerase chain reaction amplification of blaTEM and blaROB-1 was performed. The ftsI gene was amplified to identify PBP3 alteration. Of the 53 NTHi isolates, 69.8% were ampicillin nonsusceptible. The nonsusceptibility rates for cefaclor were 81.1%, cefpodoxime 69.8%, and amoxicillin/clavulanate 32.1%. About 60.3% and 32.1% of the isolates were genetically beta-lactamase-nonproducing ampicillin-resistant (gBLNAR) and genetically beta-lactamase-producing amoxicillin/clavulanate resistant (gBLPACR) strains, respectively. Group III amino acid substitutions comprised 65.6% of the gBLNAR strains and 70.6% of the gBLPACR strains. MIC50 for amoxicillin/clavulanate, cefaclor, cefuroxime, cefpodoxime, and cefixime were more than 2-80 times higher in the gBLNAR and gBLPACR strains compared with gBLPAR strains. Group III gBLNAR strains had significantly higher ampicillin, amoxicillin/clavulanate, cefpodoxime, and cefixime minimum inhibitory concentrations than group II strains. Group III gBLNAR and gBLPACR NTHi strains are highly prevalent in Korea, raising the alarm about increasing beta-lactam resistance in NTHi. PMID- 30484743 TI - Feasibility and Acceptability of an Electronic Parenting Skills Intervention for Parents of Alcohol-Using Adolescent Trauma Patients. AB - BACKGROUND: Identifying problem drinkers and providing brief intervention (BI) for those who screen positive are required within all level I trauma centers. While parent-adolescent relationships impact adolescent alcohol use, parenting skills are rarely included in adolescent alcohol BIs within pediatric trauma centers. INTRODUCTION: The primary objective of this study was to examine the feasibility and acceptability of an electronic parenting skills intervention for parents of injured adolescents who report alcohol or drug use. MATERIALS AND METHODS: Across three pediatric level I trauma centers, admitted trauma patients 12-17 years of age, screening positive for alcohol or drug use, were consented along with one parent. Adolescent-parent dyads were enrolled and assigned to the intervention (Parenting Wisely web-based modules coupled with text messaging) or standard care conditions using a 2:1 allocation ratio. Teens completed 3- and 6 month follow-up surveys; parents completed 3-month follow-up surveys. RESULTS: Thirty-seven dyads were enrolled into the study. Only one-third of parents accessed the web-based Parenting Wisely after baseline. All parents completed the text message program. At 3-month follow-up, 78% of parents endorsed that they would recommend the program to others. There were no significant differences in adolescent substance use or parenting behaviors between groups at follow-up. DISCUSSION: A texting component is well received, but web-based components may be underutilized. Larger studies are necessary to determine if an electronic skills intervention has an effect on parenting skills and adolescent substance use. CONCLUSIONS: This study demonstrated accessibility and feasibility of an e parenting intervention with more utilization of text components than web-based. PMID- 30484744 TI - Prevalence and Clinical Features of Community-Acquired Pneumonia Caused by Macrolide-Resistant Mycoplasma pneumoniae Isolated from Adults in Jeju Island. AB - AIMS: Although the cases of macrolide-resistant Mycoplasma pneumoniae (MRMP) have been increasing substantially among children, there are very few studies that have focused on MRMP in adults. This study aimed to investigate the prevalence and clinical features of community-acquired pneumonia (CAP) caused by MRMP from adults in Jeju Island, Korea. METHODS: We retrospectively recruited adult patients with CAP in whom M. pneumoniae infections had been confirmed for a 7 year period. Macrolide resistance was determined by identifying a mutation in the 23S rRNA gene using PCR. RESULTS: In total, 70 subjects were included. Their mean age was 46.1 years and 36 (51.4%) were women. Only two isolates (2.9%) carried macrolide resistance mutations in the 23S rRNA gene, and all the mutations were A2063G transitions. No significant differences were observed in age, comorbidities, symptoms, duration of fever, and length of hospital stay between the MRMP and macrolide-sensitive Mycoplasma pneumoniae groups. The number of involved pulmonary lobes was greater in the MRMP group (3.50 vs. 1.44, p = 0.008). CONCLUSION: The prevalence of CAP caused by MRMP was relatively low in adults in Jeju Island. Patients with MRMP pneumonia tended to have multilobar pneumonic infiltrates. PMID- 30484745 TI - LED light use for the improvement of wastewater treatment in the hydroponic system. AB - Effective removal of nitrogen and phosphorus from sewage before its discharge to the receiving water body is now a key task for scientists and technologists around the world. The widespread problem of eutrophication in the watercourses as well as in the seas and oceans obliges to take actions leading to more effective protection of water resources and implementation of sustainable development principles. One of the methods of increased wastewater treatment from nutrients is the use of a third stage of treatment with the use of macrophytes for the uptake of nitrogen and phosphorus. These systems, called hydroponic, under moderate climate conditions show little effectiveness due to the lack of sufficient light intensifying the growth of aquatic plants. The aim of this study was to evaluate the reduction of biogenic compounds concentrations in wastewater where additional lighting of plants was provided by the use of LED (Light Emitting Diodes), in two different conditions of experiment: with aeration and with carbon dioxide supplementation. Analyses show that the effectiveness of purification was higher in the wastewater supplemented with CO2 and artificial lighting had no significant influence on the reduction of nitrogen forms concentrations. In wastewater with aeration, higher effectiveness of nitrogen removal was observed in the tank with artificial lighting. In both cases, aeration or CO2 supplementation as well as artificial lighting or its lack, had no influence on total phosphorus and phosphates removal. PMID- 30484746 TI - Over Half of Family Medicine Residency Program Directors Report Use of Telehealth Services. AB - BACKGROUND: Little is known about the adoption of telehealth services among family medicine residency programs. INTRODUCTION: Using the 2015 Council of Academic Family Medicine Educational Research Alliance Program Directors Fall Survey section on telehealth, the authors investigated how residency programs used telehealth services during calendar year 2015. MATERIALS AND METHODS: The authors used bivariate analyses to examine how family medicine residency program characteristics vary by telehealth usage. Services provided through telehealth (live interactive video or e-visits and store-and-forward services), clinical purpose of use, frequency of use, and number of patients served were characterized. RESULTS: Surveys reached 461 Family Medicine Residency program directors, and 207 surveys were eligible for analysis (44.9% response rate). Fifty-seven percent of family medicine residency director survey respondents reported that their residents used telehealth services in calendar year 2015. Most of the telehealth users reported providing only e-visits or store-and forward services (70.6%), with 78% of the 106 programs indicating that they served as the sending site for these services. Altogether 29% of users reported providing visits using live interactive video, with ~63% indicating that they served as the originating site for these services (i.e., where the patient is located). DISCUSSION: Increasing and enhancing the use of telehealth services in residency programs might help increase telehealth use in other settings. CONCLUSIONS: Although the majority of family medicine residency programs indicated that they used telehealth services, the reported use was limited, with those who did use telehealth services doing so infrequently. PMID- 30484747 TI - Occurrence of MYOC and CYP1B1 variants in juvenile open angle glaucoma Brazilian patients. AB - BACKGROUND: The purpose of this study was to screen juvenile open angle glaucoma (JOAG) patients from Brazil for variants within the MYOC and CYP1B1 genes. MATERIAL AND METHODS: In this study, we evaluated the coding regions of MYOC and CYP1B1 genes in 100 non-related patients with JOAG and 200 controls through Sanger sequencing. We also tested the most frequent single nucleotide variants of CYP1B1 for association with JOAG. RESULTS: Sixteen different sequence variants in the MYOC gene were observed in JOAG patients: eight variants were described as neutral and eight were identified in 34 out of 100 patients with JOAG and no controls, thus being considered damaging. In the CYP1B1 gene, nine neutral variants and two damaging alterations were found among JOAG patients. No association between CYP1B1 variants and JOAG was detected. CONCLUSION: While MYOC damaging alterations were highly prevalent (34%), CYP1B1 damaging variants were less frequent (2%) in this cohort of Brazilian JOAG patients. PMID- 30484749 TI - Statins as secondary preventives in patients with intracerebral hemorrhage. AB - BACKGROUND: Statins are important components of secondary stroke prevention, but there is a concern they may increase the risk of intracerebral hemorrhage. Although this risk may have been overestimated, there is still an open question whether statin therapy should be continued, or even initiated, in patients who have had a recent intracerebral hemorrhage. AIM: Our aim was to investigate the risk of statin use after an intracerebral hemorrhage with respect to recurrent intracerebral hemorrhage, stroke in general, and death. METHODS: This observational study was based on patients with a first intracerebral hemorrhage in 2004 through 2009. Clinical characteristics, index intracerebral hemorrhage, and recurrent intracerebral hemorrhages were identified by the Swedish Stroke Register; additional data on comorbidities and vital status were retrieved through record linkages to national registers. A propensity score for the likelihood of receiving statins at discharge was developed and used with other established risk factors in a multivariable analysis. RESULTS: Of 6082 intracerebral hemorrhage patients (mean age 69.6 years), 1097 (18%) were prescribed statins at discharge. During the follow-up (mean 3.1 years), 1434 (23.6%) deaths and 234 (3.8%) recurrent intracerebral hemorrhages were observed. Statin therapy was associated with a reduced risk of death (adjusted hazard ratio: 0.71; 95% confidence interval: 0.60-0.84) but not with the risk of recurrent intracerebral hemorrhage (adjusted hazard ratio: 0.82; 95% confidence interval: 0.55-1.22). CONCLUSIONS: This study provides some reassurance that statins may be safe to use, in at least some patients, after an intracerebral hemorrhage. In patients with intracerebral hemorrhage, statin use was associated with a reduced risk of death, without an increased risk of recurrent intracerebral hemorrhage. PMID- 30484750 TI - Mixed methods in public health research in Taiwan - Using visual diagrams to communicate complex design procedures. AB - Scholars introduce modern mixed methods research (MMR) and its application in public health research in Taiwan. Specifically, they showcase a multi-phased Taiwan cervical cancer screening mixed methods study using visual diagrams to communicate complex design procedures. While some previous researchers have incorporated quantitative and qualitative data in research, here we hope to provide significant clarity to guide those new to the MMR field. We have structured the article in the following way. First, we provide a brief overview of MMR. Second, we illustrate the compelling need for MMR from a public health perspective using cancer screenings as an example. Third, we introduce the Taiwan cervical cancer screening program as an exemplar of MMR application and the utility of visual diagrams. Study methodology can be applied to international researchers and scholars from interdisciplinary fields beyond public health. PMID- 30484751 TI - University efforts to address confidentiality issues for STI services. AB - OBJECTIVE: This study assessed university policies for addressing confidentiality issues for students seeking STI services. PARTICIPANTS: Universities with sponsored health insurance plans (SHIP) and/or wellness centers were selected from a university health services survey in 2017. METHODS: STI service coverage and polices for addressing confidentiality issues related to explanation of benefit (EOB) forms were stratified by institution type (4-year versus 2-year) and minority serving institution (MSI) status. Rao-Scott chi-square tests were used to assess for differences in STI service coverage and polices. RESULTS: More non-MSIs (61.6%) had SHIPs compared to MSIs (40.0%, p < .001). Only 40.8% of health centers had a policy for addressing EOB-related confidently issues. Of those, the most reported policy was that students could pay out-of-pocket to avoid generating an EOB (36.2%). CONCLUSIONS: Reducing confidentiality barriers are important for STI prevention in students. Universities may consider establishing policies for addressing EOB-related confidentiality concerns. PMID- 30484752 TI - Contextualising sexual health practices among lesbian and bisexual women in Jamaica: a multi-methods study. AB - Limited research has examined lesbian and bisexual women's sexual health practices in the Caribbean, where lesbian and bisexual women experience sexual stigma that may reduce sexual healthcare utilisation. We conducted a sequential multi-method research study, including semi-structured individual interviews (n = 20) and a focus group (n = 5) followed by a cross-sectional survey (n = 205) with lesbian and bisexual women in Kingston, Montego Bay, and Ocho Rios, Jamaica. Binary logistic analyses and ordinal logistic regression were conducted to estimate the odds ratios for social-ecological factors associated with lifetime STI testing, sex work involvement, and the last time of STI testing. Over half of participants reported a lifetime STI test and of these, 6.1% reported an STI diagnosis. One-fifth of the sample reported ever selling sex. Directed content analysis of women's narratives highlighted that stigma and discrimination from healthcare providers, in combination with low perceived STI risk, limited STI testing access and safer sex practices. Participants described how safer sex self efficacy increased their safer sex practices. Quantitative results revealed that a longer time since last STI test was positively associated with depression, sexual stigma, and forced sex, and negatively associated with residential location, perceived STI risk, safer sex self-efficacy, and LGBT connectedness. Selling sex was associated with perceived STI risk, relationship status, sexual stigma, food insecurity, and forced sex. Sexual health practices among lesbian and bisexual women in Jamaica are associated with intrapersonal, interpersonal, and structural factors, underscoring the urgent need for multi-level interventions to improve sexual health and advance sexual rights among lesbian and bisexual women in Jamaica. PMID- 30484753 TI - Colletotrichum acutatum and C. gloeosporioides Species Complexes Associated with Apple in Brazil. AB - Glomerella leaf spot (GLS) is an apple disease that concerns growers due to the increases in severity over the years and the difficulties in control. Species within the Colletotrichum acutatum and C. gloeosporioides species complexes cause GLS, but the proportion of species within each complex in Brazilian apple orchards is not known. The objectives of this study were to identify isolates of Colletotrichum causing GLS on apple orchards in the main Brazilian producing regions to the species level. Two hundred and seven isolates were obtained in orchards in Sao Paulo (SP), Parana (PR), Santa Catarina (SC), and Rio Grande do Sul (RS) states. Genomic DNA was extracted, and the ITS, GAPDH, CHS-1, and TUB2 genes were amplified and sequenced. The phylogenetic trees were generated using a concatenated alignment. One hundred and fourteen isolates were identified as belonging to the C. acutatum species complex (Cac) and 93 to the C. gloeosporioides species complex (Cgc). Five phylogenetic species were identified: C. melonis (1.9%), C. nymphaeae (47.4%), C. paranaense (2.4%), C. limetticola (3.4%), and C. fructicola (44.9%). In SC, Cgc predominates, but in the states of SP, PR, and RS, Cac was predominant. This is the first report of C. limetticola from apple. PMID- 30484754 TI - A Natural Reservoir and Transmission Vector of Grapevine Vein Clearing Virus. AB - Grapevine vein clearing virus (GVCV) is associated with a vein-clearing and vine decline disease. In this study, we surveyed wild Ampelopsis cordata from the Vitaceae family and found that 31% (35 of 113) of native A. cordata plants are infected with GVCV. The full-length genome sequence of one GVCV isolate from A. cordata shared 99.8% identical nucleotides with an isolate from a nearby cultivated 'Chardonel' grapevine, suggesting the occurrence of an insect vector. To identify a vector, we collected Aphis illinoisensis (common name: grape aphids) from wild A. cordata plants and detected GVCV in the aphid populations. We found that A. illinoisensis is capable of transmitting GVCV from infected A. cordata to Chardonel grapevines in the greenhouse. Upon transmission, GVCV caused severe symptoms on the infected Chardonel 45 days post transmission. We conclude that wild GVCV isolates from A. cordata are capable of inducing a severe disease on cultivated grapevines once they spread from native A. cordata to vineyards via grape aphids. The discovery of a natural reservoir and an insect vector of GVCV provides timely knowledge for disease management in vineyards and critical clues on viral evolution and epidemiology. PMID- 30484755 TI - Integrated Effects of Genetic Resistance and Prothioconazole + Tebuconazole Application Timing on Fusarium Head Blight in Wheat. AB - Integrated Fusarium head blight (FHB) management programs consisting of different combinations of cultivar resistance class and an application of the fungicide prothioconazole + tebuconazole at or after 50% early anthesis were evaluated for efficacy against FHB incidence (INC; percentage of diseased spikes), index (IND; percentage of diseased spikelets per spike), Fusarium damaged kernel (FDK), deoxynivalenol (DON) toxin contamination, grain yield, and test weight (TW) in inoculated field trials conducted in 11 U.S. states in 2014 and 2015. Mean log response ratios and corresponding percent control values for INC, IND, FDK, and DON, and mean differences in yield and TW relative to a nontreated, inoculated susceptible check (S_CK), were estimated through network meta-analyses as measures of efficacy. Results from the analyses were then used to estimate the economic benefit of each management program for a range of grain prices and fungicide applications costs. Management programs consisting of a moderately resistant (MR) cultivar treated with the fungicide were the most efficacious, reducing INC by 60 to 69%, IND by 71 to 76%, FDK by 66 to 72%, and DON by 60 to 64% relative to S_CK, compared with 56 to 62% for INC, 68 to 72% for IND, 66 to 68% for FDK, and 58 to 61% for DON for programs with a moderately susceptible (MS) cultivar. The least efficacious programs were those with a fungicide application to a susceptible (S) cultivar, with less than a 45% reduction of INC, IND, FDK, or DON. All programs were more efficacious under conditions favorable for FHB compared with less favorable conditions, with applications made at 50% early anthesis being of comparable efficacy to those made 2 to 7 days later. Programs with an MS cultivar resulted in the highest mean yield increases relative to S_CK (541 to 753 kg/ha), followed by programs with an S cultivar (386 to 498 kg/ha) and programs with an MR cultivar (250 to 337 kg/ha). Integrated management programs with an MS or MR cultivar treated with the fungicide at or after 50% early anthesis were the most likely to result in a 50 or 75% control of IND, FDK, or DON in a future trial. At a fixed fungicide application cost, these programs were $4 to $319/MT more economically beneficial than corresponding fungicide-only programs, depending on the cultivar and grain price. These findings demonstrate the benefits of combining genetic resistance with a prothioconazole + tebuconazole treatment to manage FHB, even if that treatment is applied a few days after 50% early anthesis. PMID- 30484756 TI - Homophobia in Health Professionals in Ankara, Turkey: Developing a Scale. AB - The aims of this study were to develop a sexual orientation attitude scale and use it to investigate the attitudes of psychiatrists, other physicians and first year medical students toward homosexuals and homosexuality in Ankara, Turkey. A cross-sectional study was performed with three groups including psychiatrists (n = 147), non-psychiatric physicians (n = 224) and first year medical students (n = 280). A scale with 43 items consisting of four subscales (heterosexism, homophobia, homonegativity, neutrality) was developed which showed high internal consistency, validity and reliability in this sample of Turkish individuals. The internal consistency coefficients (Cronbach's alpha) for the subscales were 0.85 0.86, 0.95-0.95, 0.95-0.95, and 0.85-0.86, respectively. Being male, single, a graduate of a religious (Imam Hatip) or vocational high school, of rural origin, a student, more religious, heterosexual and studying at university hospitals were found to be related to higher scores (indicating more negative attitudes) on all subscales and the total scale and these differences were significant. Students had the highest scores and psychiatrists had the lowest scores in all subscales and the total scale. The results of this study indicate that physicians and medical students have negative attitudes toward homosexuals and that medical training on sexual health issues should be improved in Turkey. PMID- 30484757 TI - Maternal protein intake during pregnancy is associated with child growth up to 5 years of age, but not through insulin-like growth factor-1: findings from the ROLO study. AB - Infant protein intake has been associated with child growth, however, research on maternal protein intake during pregnancy is limited. Insulin-like growth factors (IGF) play a role in early fetal development and maternal protein intake may influence child body composition via IGF-1. The aim of this study was to investigate the association of maternal protein intake throughout pregnancy on cord blood IGF-1 and child body composition from birth to 5 years of age. Analysis was carried out on 570 mother-child dyads from the Randomised cOntrol trial of LOw glycaemic index diet study. Protein intake was recorded using 3-d food diaries in each trimester of pregnancy and protein intake per kg of maternal weight (g/d per kg) was calculated. Cord blood IGF-1 was measured at birth. Infant anthropometry was measured at birth, 6 months, 2 and 5 years of age. Mixed modelling, linear regression, and mediation analysis were carried out. Birth weight centiles were positively associated with early-pregnancy protein intake (g/d per kg), while weight centiles from 6 months to 5 years were negatively associated (B=-21.6, P<0.05). These associations were not mediated by IGF-1. Our findings suggest that high protein intake in early-pregnancy may exert an in utero effect on offspring body composition with a higher weight initially at birth but slower growth rates into childhood. Further research is needed to elucidate the exact mechanisms by which dietary protein modulates fetal growth. PMID- 30484758 TI - Coffee intake, glucose metabolism and gene polymorphisms: response to Kawada. PMID- 30484759 TI - Engagement of cellular cholesterol in the life cycle of classical swine fever virus: its potential as an antiviral target. AB - Classical swine fever virus (CSFV), the etiological agent of classical swine fever in pigs, is a member of the Pestivirus genus within the Flaviviridae family. It has been proposed that CSFV infection is significantly inhibited by methyl-beta-cyclodextrin (MbetaCD) treatment. However, the exact engagement of cellular cholesterol in the life cycle of CSFV remains unclear. Here, we demonstrated that pretreatment of PK-15 cells with MbetaCD significantly decreased the cellular cholesterol level and resulted in the inhibition of CSFV infection, while replenishment of exogenous cholesterol in MbetaCD-treated cells recovered the cellular cholesterol level and restored the viral infection. Moreover, we found that depletion of cholesterol acted on the early stage of CSFV infection and blocked its internalization into the host cells. Furthermore, we showed that 25-hydroxycholesterol, a regulator of cellular cholesterol biosynthesis, exhibited a potent anti-CSFV activity by reducing cellular cholesterol level. Taken together, our findings highlight the engagement of cholesterol in the life cycle of CSFV and its potential use as an antiviral target. PMID- 30484760 TI - Oceanibium sediminis gen. nov., sp. nov., isolated from marine sediment. AB - A novel Gram-stain-negative, rod-shaped marine bacterium, designated as strain O448T, was isolated from the coastal area of Weihai, China (122 degrees 14' E, 36 degrees 54' N). Cells of strain O448T were non-motile, aerobic, approximately 0.4-0.6 um wide and 1.5-2.0 um long. Growth occurred at 20-40 degrees C (optimally between 33-37 degrees C), pH 6.5-8.0 (optimally at 7.0) and in the presence of 1.0-5.0 % (w/v) NaCl (optimally between 2.0-3.0 %). Phylogenetic analysis based on 16S rRNA gene sequence indicated that strain O448T belongs to family Rhodobacteraceae and exhibits 16S rRNA gene sequence similarities of 94.3, 94.1 and 93.8 % to the type strains of Pontivivens insulae, Halovulum dunhuangense and Maritimibacter alkaliphilus, respectively. The major cellular fatty acid was C18 : 1omega7c and the major polar lipids were phosphatidylethanolamine, phosphatidylcholine and phosphatidylglycerol. Strain O448T contained Q-10 as the sole respiratory quinone. The genomic DNA G+C content was 65.6 mol%. It is evident from phenotypic data and phylogenetic inference that strain O448T represents a novel species in a new genus, for which the name Oceanibiumsediminis gen. nov., sp. nov. is proposed. The type strain is O448T (=KCTC 62076T=MCCC 1H00233T). PMID- 30484761 TI - Kistimonas alittae sp. nov., a gammaproteobacterium isolated from the marine annelid Alitta succinea. AB - A novel Gram-stain-negative, rod-shaped, motile, non-spore-forming, facultatively anaerobic marine bacterium was isolated from the gastrointestinal tract of the sandworm Alitta succinea collected from Grice Cove, South Carolina, USA. The strain was arginine dihydrolase-positive, and oxidase- and catalase-positive. Growth occurred between 10 and 37 degrees C, with optimal growth occurring between 30 and 32 degrees C. Comparative 16S rRNA gene sequence analysis showed its nearest neighbours are members of the genus Kistimonas of the family Hahellaceae, which is found in the order Oceanospirillales, class Gammaproteobacteria. The closest related species was Kistimonas asteriae KMD 001T with 16S rRNA gene sequence similarity of 99.0 %. However, DNA-DNA hybridization between these strains revealed less than 70 % DNA-DNA relatedness, supporting the novel species status of the strain. The major fatty acids were C16 : 0, C18 : 0, C18 : 1omega7c and a summed feature that contained C16 : 1omega6c/C16 : 1omega7c. The major respiratory quinone was ubiquinone-9 and the predominant polar lipids were phosphatidylserine, phosphoethanolamine, phosphatidylglycerol and diphosphatidylglycerol. The genomic DNA G+C content was 52.5 mol%. Based on the data presented, strain BGP-2T is considered to represent a novel member of the genus Kistimonas , for which the name Kistimonas alittae sp. nov. is proposed. The type strain is BGP-2T (=CCUG 65711T=JCM 30010T). PMID- 30484762 TI - ICTV virus taxonomy profile: Birnaviridae. AB - Birnaviridae is a family of viruses with bi-segmented dsRNA genomes totalling about 6 kbp forming icosahedral, non-enveloped virions. The family includes four genera, members of three of which (Aquabirnavirus, Avibirnavirus and Blosnavirus) infect vertebrates (excluding mammals), whereas members of the fourth genus (Entomobirnavirus) infect insects. Each genus includes 1-3 species. Infectious pancreatic necrosis virus of salmonids and infectious bursal disease virus of poultry are two economically important birnaviruses. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of Birnaviridae, which is available at www.ictv.global/report/birnaviridae. PMID- 30484763 TI - ICTV virus taxonomy profile: Picobirnaviridae. AB - Picobirnaviridae is a family of viruses with bi-segmented (rarely unsegmented) dsRNA genomes comprising about 4.4 kbp in total, with small, non-enveloped spherical virions. The family includes one genus (Picobirnavirus) grouping three genetic clusters with high sequence variability, two defined by viruses infecting vertebrates and a third with viruses found in invertebrates. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of Picobirnaviridae, which is available at www.ictv.global/report/picobirnaviridae. PMID- 30484764 TI - Artificial urinary sphincter revision with Quick Connects(r) versus suture-tie connectors: does technique make a difference? AB - OBJECTIVE: To evaluate characteristics of artificial urinary sphincter (AUS) mechanical failures and compare outcomes based on the use of either suture-tied connections or Quick-Connects(r) (QC) for single-component revisions. MATERIAL AND METHODS: A total of 46 patients underwent single-component AUS revisions following primary AUS placement from January 1983 to January 2011 at our institute. Prior to 1996 all revision cases were performed with suture-tie connections and after that time we used QC for revisions. Device success was evaluated for a potential association with revision surgery including the type of connector used. RESULTS: Forty-six patients underwent single-component revision surgery for primary device malfunction. In these cases, the tubing connections were performed using suture-tie connectors in 34 (74%), and QC in 12 (26%) cases. The median age was 68.8 years for suture-tie vs 70.6 years for QC (p=0.52). The median follow-up period after revision surgery was 24 months (IQR 7.2, 55.2). There was no statistically significant difference in 5-year device survival rates between suture-tie and QC (36% vs. 61%; p=0.85) techniques. There were no cases of device infection or repeat mechanical failure at the connector among cases of revision performed using QC, as compared to five device infections and four repeat mechanical failures among the suture-tie cohort. CONCLUSION: The use of QC for single-component AUS revision for mechanical failures appears to be safe, efficient and reliable. There is not enough evidence supporting the presence of an association between connector type with the risk of overall device failure. PMID- 30484765 TI - Spectrum of urologic complications in obstetrics and gynecology: 13 years' experience from a tertiary referral center. AB - OBJECTIVE: To analyze the patterns of presentation and management for urologic complications of obstetrics and gynecology in the form of genitourinary fistulas at a tertiary referral center and highlight the social issues associated with them. MATERIAL AND METHODS: We conducted this retrospective study analyzing 311 patients with genitourinary fistulas after obstetric and gynecologic surgeries between January 2005 and January 2018. We recorded the patients' characteristics and area of residence and then analyzed the etiology, surgical management and success rates by grouping the patients into four types of genitourinary fistulas. The primary end point of success was patient being leak free. RESULTS: Majority of patients (90.4%) were from rural areas. The distribution of genitourinary fistulas in descending order was vesicovaginal (79.7%), ureterovaginal (11.8%), urethrovaginal (10.2%) and vesicouterine fistulas (2.6%). The mean time to presentation was 25.80+/-48.69 days with a wide range of 10 days to 360 months. The most common etiology was obstructed labour (58.5%) followed by abdominal hysterectomy (32.7%). For vesicovaginal fistulas the route to be used for repair depended on surgeon's preference and both transabdominal and transvaginal routes had almost equal success rates. The success rate of laparoscopic vesicovaginal fistula repair was 89.4% and all (100%) laparoscopic ureteroneocystostomies were successful. CONCLUSION: Genitourinary fistulas especially due to obstructed labour are still common in developing world showcasing the problem of inequitable distribution of healthcare. The surgical treatment approach depends on the surgeon's familiarity with the said procedure although versatility is required. PMID- 30484767 TI - Risk factors for subsequent urethral atrophy in patients undergoing artificial urinary sphincter placement. AB - OBJECTIVE: Artificial urinary sphincter (AUS) device failure or revision can be due to multiple etiologies including erosion, infection, mechanical malfunction, and urethral atrophy. However, few studies have evaluated factors that predispose patients to urethral atrophy. Here, we sought to identify preoperative and perioperative risk factors associated with urethral atrophy in men undergoing primary artificial urinary sphincter (AUS) placement for stress urinary incontinence. MATERIAL AND METHODS: From 1987 to 2013, 1829 AUS procedures were performed at our institution. A total of 1068 patients underwent primary AUS placement and were the focus of our study. Multiple clinical and surgical variables were evaluated for a potential association with revision for atrophy. Those found to be associated with atrophy and relevant competing risks were further evaluated on multivariable analysis. RESULTS: With a median follow-up of 4.2 years (IQR 1.3-8.1), 89 men (8.3%) had urethral atrophy requiring reoperation. Median time to revision was 4.5 years (IQR 1.9-7.6). On univariable analysis, only smaller cuff size (4.0-cm versus 4.5-cm; HR 3.1, p=0.04) was associated with an increased rate of urethral atrophy. Notably, patient age at the time of surgery (p=0.62), body mass index (0.22), and smoking status (p=1.00) were not associated with a risk of atrophy. On multivariable analysis smaller urethral cuff size remained significant (HR 2.8, 95% CI 1.1-7.1; p=0.01). CONCLUSION: Revision surgery for urethral atrophy was performed in approximately 8% of men undergoing primary AUS placement. Utilization of a smaller AUS cuff size appears to be an independent factor associated with increased rate of urethral atrophy. PMID- 30484766 TI - Readability and understandability of andrology questionnaires. AB - OBJECTIVE: Medical questionnaires, which enable collection, comparison and analysis of appropriate data as a means of written communication between a patient and a doctor, must be easily readable, and understandable. Here, we measure the readability and understandability of questionnaires used in andrology and examine the relationship between the educational status of the patients and the understandability of the forms. MATERIAL AND METHODS: Seven questionnaires used to diagnose andological diseases were selected from the European Association of Urology guidelines. The number of syllables per word, the number of words in a sentence, and the average word and sentence lengths were calculated for each Turkish validated form. Readability scores were calculated, and closet tests were used to measure the understandability of the texts. RESULTS: Three hundred and twenty-seven male volunteers participated in the study. Two hundred and sixteen of the participants (66%) had a high school or college education. The readability level of the seven forms was determined to be "Difficult" or "Very Difficult," and at least a high school education level was required to understand the forms. As education level and monthly income increased, the understandability of the forms increased; as the readability of the forms became more difficult, their understandability decreased (p<0.001). CONCLUSION: The readability levels of questionnaires used in andrology are well above the reading level of Turkey. Health providers can help patients to fill out forms to increase doctor-patient communication. PMID- 30484768 TI - Utility of Mitrofanoff as bladder draining tool: A single center experience in pediatric patients. AB - OBJECTIVE: Mitrofanoff procedure has been employed commonly as bladder draining tool in patients unable to do clean intermittent self catheterization through native urethera. Single centre experience of pediatric age group patients undergoing Mitrofanoff procedure has been presented here. MATERIAL AND METHODS: It was a retrospective study of 29 children who underwent continent catheterizable conduit (CCC), from January 2009 till March 2017. Charts were reviewed for age, gender, presenting complaints, need for augmentation cystoplasty, Mitrofanoff channel source such as appendix or ileal patch, duration of surgery in minutes, hospital stay in days, per operative and postoperative complications. Preoperative evaluation of the children was done by doing complete blood picture, serum electrolytes, and renal function tests. Radiological evaluation included ultrasound kidney,ureter and bladder, voiding cystourethrography, urodynamic analysis and a nuclear renal scan with 99m Technetium dimercapto-succinic acid or MAG-3 scan. The abdominal end of the conduit was brought through the abdominal wall, and a stoma was fashioned by the V-quadrilateral-Z technique. RESULTS: Twenty nine children having mean age of 9.54+/-4.88 years underwent CCC. There were 19 males (65.51%) and 10 females (34.48%). Children who underwent CCC included 18 children having neurogenic bladder, 2 cases of urethral trauma/stricture 3 patients with history of posterior uretheral valve and 6 patients with exstrophy bladder. Augmentation cystoplasty plus mitrofanoff was done in 18 children while only mitrofanoff in 11 children. Stuck catheter was seen in one patient which was removed successfully via normal urethral route under general anesthesia. Stomal stenosis in first year was noted in 4 patients (13.79%). CONCLUSION: Continent catheterizable conduit based on Mitrofanoff principle have durable outcome over long term follow up in terms of urinary continence and complications. PMID- 30484769 TI - Pericentromeric hypomethylation elicits an interferon response in an animal model of ICF syndrome. AB - : Pericentromeric satellite repeats are enriched in 5-methylcytosine (5mC). Loss of 5mC at these sequences is common in cancer and is a hallmark of Immunodeficiency, Centromere and Facial abnormalities (ICF) syndrome. While the general importance of 5mC is well-established, the specific functions of 5mC at pericentromeres are less clear. To address this deficiency, we generated a viable animal model of pericentromeric hypomethylation through mutation of the ICF-gene ZBTB24. Deletion of zebrafish zbtb24 caused a progressive loss of 5mC at pericentromeres and ICF-like phenotypes. Hypomethylation of these repeats triggered derepression of pericentromeric transcripts and activation of an interferon-based innate immune response. Injection of pericentromeric RNA is sufficient to elicit this response in wild-type embryos, and mutation of the MDA5 MAVS dsRNA-sensing machinery blocks the response in mutants. These findings identify activation of the innate immune system as an early consequence of pericentromeric hypomethylation, implicating derepression of pericentromeric transcripts as a trigger of autoimmunity. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter). PMID- 30484771 TI - Human-specific ARHGAP11B induces hallmarks of neocortical expansion in developing ferret neocortex. AB - The evolutionary increase in size and complexity of the primate neocortex is thought to underlie the higher cognitive abilities of humans. ARHGAP11B is a human-specific gene that, based on its expression pattern in fetal human neocortex and progenitor effects in embryonic mouse neocortex, has been proposed to have a key function in the evolutionary expansion of the neocortex. Here, we study the effects of ARHGAP11B expression in the developing neocortex of the gyrencephalic ferret. In contrast to its effects in mouse, ARHGAP11B markedly increases proliferative basal radial glia, a progenitor cell type thought to be instrumental for neocortical expansion, and results in extension of the neurogenic period and an increase in upper-layer neurons. Consequently, the postnatal ferret neocortex exhibits increased neuron density in the upper cortical layers and expands in both the radial and tangential dimensions. Thus, human-specific ARHGAP11B can elicit hallmarks of neocortical expansion in the developing ferret neocortex. PMID- 30484770 TI - Rat behavior and dopamine release are modulated by conspecific distress. AB - Rats exhibit 'empathy' making them a model to understand the neural underpinnings of such behavior. We show data consistent with these findings, but also that behavior and dopamine (DA) release reflects subjective rather than objective evaluation of appetitive and aversive events that occur to another. We recorded DA release in two paradigms: one that involved cues predictive of unavoidable shock to the conspecific and another that allowed the rat to refrain from reward when there were harmful consequences to the conspecific. Behavior and DA reflected pro-social interactions in that DA suppression was reduced during cues that predicted shock in the presence of the conspecific and that DA release observed on self-avoidance trials was present when the conspecific was spared. However, DA also increased when the conspecific was shocked instead of the recording rat and DA release during conspecific avoidance trials was lower than when the rat avoided shock for itself. PMID- 30484772 TI - Advancing the aging biology toolkit. AB - A new device for isolating large quantities of old yeast cells expands the experimental boundaries of aging research. PMID- 30484773 TI - Neural dynamics at successive stages of the ventral visual stream are consistent with hierarchical error signals. AB - Ventral visual stream neural responses are dynamic, even for static image presentations. However, dynamical neural models of visual cortex are lacking as most progress has been made modeling static, time-averaged responses. Here, we studied population neural dynamics during face detection across three cortical processing stages. Remarkably, ~30 milliseconds after the initially evoked response, we found that neurons in intermediate level areas decreased their responses to typical configurations of their preferred face parts relative to their response for atypical configurations even while neurons in higher areas achieved and maintained a preference for typical configurations. These hierarchical neural dynamics were inconsistent with standard feedforward circuits. Rather, recurrent models computing prediction errors between stages captured the observed temporal signatures. This model of neural dynamics, which simply augments the standard feedforward model of online vision, suggests that neural responses to static images may encode top-down prediction errors in addition to bottom-up feature estimates. PMID- 30484774 TI - The hydrophobic nature of a novel membrane interface regulates the enzyme activity of a voltage-sensing phosphatase. AB - Voltage-sensing phosphatases (VSP) contain a voltage sensor domain (VSD) similar to that of voltage-gated ion channels but lack a pore-gate domain. A VSD in a VSP regulates the cytoplasmic catalytic region (CCR). However, the mechanisms by which the VSD couples to the CCR remain elusive. Here we report a membrane interface (named 'the hydrophobic spine'), which is essential for the coupling of the VSD and CCR. Our molecular dynamics simulations suggest that the hydrophobic spine of Ciona intestinalis VSP (Ci-VSP) provides a hinge-like motion for the CCR through the loose membrane association of the phosphatase domain. Electrophysiological experiments indicate that the voltage-dependent phosphatase activity of Ci-VSP depends on the hydrophobicity and presence of an aromatic ring in the hydrophobic spine. Analysis of conformational changes in the VSD and CCR suggests that the VSP has two states with distinct enzyme activities and that the second transition depends on the hydrophobic spine. PMID- 30484775 TI - TAPBPR mediates peptide dissociation from MHC class I using a leucine lever. AB - Tapasin and TAPBPR are known to perform peptide editing on major histocompatibility complex class I (MHC I) molecules, however, the precise molecular mechanism(s) involved in this process remain largely enigmatic. Here, using immunopeptidomics in combination with novel cell-based assays that assess TAPBPR-mediate peptide exchange, we reveal a critical role for the K22-D35 loop of TAPBPR in mediating peptide exchange on MHC I. We identify a specific leucine within this loop that enables TAPBPR to facilitate peptide dissociation from MHC I. Moreover, we delineate the molecular features of the MHC I F pocket required for TAPBPR to promote peptide dissociation in a loop-dependent manner. These data reveal that chaperone-mediated peptide editing of MHC I can occur by different mechanisms dependent on the C-terminal residue that the MHC I accommodates in its F pocket and provide novel insights that may inform the therapeutic potential of TAPBPR manipulation to increase tumour immunogenicity. PMID- 30484776 TI - Readmissions after Pediatric Hospitalization for Suicide Ideation and Suicide Attempt. AB - OBJECTIVE: To inform resource allocation toward a continuum of care for youth at risk of suicide, we examined unplanned 30-day readmissions after pediatric hospitalization for either suicide ideation (SI) or suicide attempt (SA). METHODS: We conducted a retrospective cohort study of a nationally representative sample of 133,516 hospitalizations for SI or SA among 6- to 17-year-olds to determine prevalence, risk factors, and characteristics of 30-day readmissions using the 2013 and 2014 Nationwide Readmissions Dataset (NRD). Risk factors for readmission were modeled using logistic regression. RESULTS: We identified 95,354 hospitalizations for SI and 38,162 hospitalizations for SA. Readmission rates within 30 days were 8.5% for SI and SA hospitalizations. Among 30-day readmissions, more than one-third (34.1%) occurred within 7 days. Among patients with any 30-day readmission, 11% had more than one readmission within 30 days. The strongest risk factors for readmission were SI or SA hospitalization in the 30 days preceding the index SI/SA hospitalization (adjusted odds ratio [AOR]: 3.14, 95% CI: 2.73-3.61) and hospitalization for other indications in the previous 30 days (AOR: 3.18, 95% CI: 2.67-3.78). Among readmissions, 94.5% were for a psychiatric condition and 63.4% had a diagnosis of SI or SA. CONCLUSIONS: Quality improvement interventions to reduce unplanned 30-day readmissions among children hospitalized for SI or SA should focus on children with a recent prior hospitalization and should be targeted to the first week following hospital discharge. FUNDING: Dr. Zima received funding from the Behavioral Health Centers of Excellence for California (SB852). PMID- 30484777 TI - Healthcare Quality for Children and Adolescents with Suicidality Admitted to Acute Care Hospitals in the United States. PMID- 30484778 TI - Limitations of Using Pediatric Respiratory Illness Readmissions to Compare Hospital Performance. AB - BACKGROUND: Adult hospital readmission rates can reliably identify meaningful variation in hospital performance; however, pediatric condition-specific readmission rates are limited by low patient volumes. OBJECTIVE: To determine if a National Quality Forum (NQF)-endorsed measure for pediatric lower respiratory illness (LRI) 30-day readmission rates can meaningfully identify high- and low performing hospitals. DESIGN: Observational, retrospective cohort analysis. We applied the pediatric LRI measure and several variations to evaluate their ability to detect performance differences. SETTING: Administrative claims from all hospital admissions in California (2012-2014). PATIENTS: Children (age <18 years) with LRI (primary diagnosis: bronchiolitis, influenza, or pneumonia; or LRI as a secondary diagnosis with a primary diagnosis of respiratory failure, sepsis, bacteremia, or asthma). MEASUREMENTS: Thirty-day hospital readmission rates and costs. Hierarchical regression models adjusted for age, gender, and chronic conditions were used. RESULTS: Across all California hospitals admitting children (n = 239) using respiratory readmission rates, no outlier hospitals were identified with (1) the NQF-endorsed metric, (2) inclusion of primary asthma or secondary asthma exacerbation diagnoses, or (3) inclusion of 30-day emergency revisits. By including admissions for asthma, adding emergency revisits, and merging 3 years of data, we identified 9 outlier hospitals (2 high-performers, 7 low-performers). There was no association of hospital readmission rates with costs. CONCLUSIONS: Using a nationally-endorsed quality measure of inpatient pediatric care, we were unable to identify meaningful variation in hospital performance without broadening the metric definition and merging multiple years of data. Utilizers of pediatric-quality measures should consider modifying metrics to better evaluate the quality of pediatric care at low-volume hospitals. FUNDING: Supported by the Agency for Healthcare Research and Quality (K08 HS24592 to SVK and U18HS25297 to MDC and NSB) and the National Institute of Child Health and Human Development (K23HD065836 to NSB). The funding agency played no role in the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the manuscript for publication. PMID- 30484779 TI - The Adoption of an Online Journal Club to Improve Research Dissemination and Social Media Engagement Among Hospitalists. AB - BACKGROUND: Twitter-based journal clubs are intended to connect clinicians, educators, and researchers to discuss recent research and aid in dissemination of results. The Journal of Hospital Medicine (JHM) began producing a Twitter-based journal club, #JHMChat, in 2015. OBJECTIVE: To describe the implementation and assess the impact of a journal-sponsored, Twitter-based journal club on Twitter and journal metrics. INTERVENTION: Each #JHMChat focused on a recently published JHM article, was moderated by a social media editor, and included one study author or guest. MEASUREMENTS: The total number of participants, tweets, tweets/participant, impressions, page views, and change in the Altmetric score were assessed after each session. Thematic analysis of each article was conducted, and post-chat surveys of participating authors and participant responses to continuing medical education surveys were reviewed. RESULTS: Seventeen Twitter-based chats were held: seven (47%) focused on value, six (40%) targeted clinical issues, and four (27%) focused on education. On average, we found 2.17 (+/-0.583 SD) million impressions/session, 499 (+/- 129 SD) total tweets/session, and 73 (+/-24 SD) participants/session. Value-based care articles had the greatest number of impressions (2.61 +/- 0.55 million) and participants (90 +/- 12). The mean increase in the Altmetric score was 14 points (+/-12), with medical education-themed articles garnering the greatest change (mean increase of 32). Page views were noted to have increased similarly to levels of electronic Table of Content releases. Authors and participants believed #JHMChat was a valuable experience and rated it highly on post-chat evaluations. CONCLUSIONS: Online journal clubs appear to increase awareness and uptake of journal article results and are considered a useful tool by participants. PMID- 30484780 TI - Increasing Inpatient Consultation: Hospitalist Perceptions and Objective Findings. In Reference to: "Hospitalist Perspective of Interactions with Medicine Subspecialty Consult Services". AB - OBJECTIVE: DESIGN: SETTING: PATIENTS: MEASUREMENTS: RESULTS: CONCLUSIONS: PMID- 30484781 TI - Reply to "Increasing Inpatient Consultation: Hospitalist Perceptions and Objective Findings. In Reference to: 'Hospitalist Perspective of Interactions with Medicine Subspecialty Consult Services'". PMID- 30484782 TI - Diving Into Diagnostic Uncertainty: Strategies to Mitigate Cognitive Load: In Reference to: "Focused Ethnography of Diagnosis in Academic Medical Centers". PMID- 30484783 TI - In Reply to "Diving Into Diagnostic Uncertainty: Strategies to Mitigate Cognitive Load. In Reference to: 'Focused Ethnography of Diagnosis in Academic Medical Centers'". PMID- 30484784 TI - Manufacturing human pluripotent stem cell derived endothelial cells in scalable and cell-friendly microenvironments. AB - Human pluripotent stem cell derived endothelial cells (hPSC-ECs) are of great value for studying and treating vascular diseases. However, manufacturing high quantity and quality hPSC-ECs with current cell culture technologies remains very challenging. Here, we report a novel method that can manufacture hPSC-ECs in scalable and cell-friendly microenvironments to address this challenge. Using this method, hPSCs are expanded and differentiated into ECs in microscale alginate hydrogel tubes. The hydrogel tubes protect cells from the highly variable hydrodynamic conditions and critical hydrodynamic stresses in the culture vessel and limit the cell mass less than the diffusion limits (of human tissue) to ensure efficient mass transport. The hydrogel tubes provide uniform and friendly microenvironments for cells to grow. This novel design leads to extremely high production efficiency. We showed that hPSC-ECs could be produced in 10 days with high viability (>90%), high purity (>80%) and high yield (~5.0 * 108 cells per mL of microspace). The yield is about 250 times that of the current state-of-the-art. hPSC-ECs made in these hydrogel tubes had similar in vitro and in vivo functions to hPSC-ECs generated by conventional cell culture methods. This simple, scalable, efficient, defined and cost-effective technology will make hPSC-ECs broadly available and affordable for various biomedical applications. PMID- 30484785 TI - Recombinant human BMP-2 accelerates the migration of bone marrow mesenchymal stem cells via the CDC42/PAK1/LIMK1 pathway in vitro and in vivo. AB - Biomaterials are widely used for bone regeneration and fracture repair. The migration of bone marrow mesenchymal stem cells (BMSCs) into bone defect sites or material implantation sites, and their differentiation into osteoblasts, is central to the fracture healing process, and the directional migration of BMSCs depends on cytokines or chemokines at the defect site. BMP-2 can stimulate the migration of a variety of cells, but it remains unclear whether BMSC migration can be induced. To provide evidence for BMP-2-induced BMSC migration, we tested the cytoskeletal changes and migration ability of BMSCs after treatment with recombinant human BMP-2 (rhBMP-2). We also explored the recruitment of BMSCs from the circulatory system using a collagen sponge incorporating rhBMP-2 that was implanted in vivo. Furthermore, to understand the mechanism underlying this migration, we investigated the effect of rhBMP-2 on migration-related signal pathways. Here, we found that, rhBMP-2 treatment significantly increased the migration of BMSCs in vitro via activation of the CDC42/PAK1/LIMK1 pathway, and that this migration could be blocked by silencing CDC42. In vivo, collagen sponge material loaded with rhBMP-2 could recruit BMSCs injected into the circulatory system. Moreover, inhibition using the small interfering RNA for CDC42 led to a significant decrease in the number of BMSCs within the material. In conclusion, our data prove that rhBMP-2 can accelerate BMSC migration via the CDC42/PAK1/LIMK1 pathway both in vivo and in vitro, and therefore provides a foundation for further understanding and application of rhBMP-2-incorporated materials by enhancing BMSC recruitment. PMID- 30484786 TI - A perspective on quantum mechanics and chemical concepts in describing noncovalent interactions. AB - Since quantum mechanical calculations do not typically lend themselves to chemical interpretation, analyses of bonding interactions depend largely upon models (the octet rule, resonance theory, charge transfer, etc.). This sometimes leads to a blurring of the distinction between mathematical modelling and physical reality. The issue of polarization vs. charge transfer is an example; energy decomposition analysis is another. The Hellmann-Feynman theorem at least partially bridges the gap between quantum mechanics and conceptual chemistry. It proceeds rigorously from the Schrodinger equation to demonstrating that the forces exerted upon the nuclei in molecules, complexes, etc., are entirely classically coulombic attractions with the electrons and repulsions with the other nuclei. In this paper, we discuss these issues in the context of noncovalent interactions. These can be fully explained in coulombic terms, electrostatics and polarization (which include electronic correlation and dispersion). PMID- 30484787 TI - Analysing thermophoretic transport of water for designing nanoscale-pumps. AB - We propose a new design for thermally induced water pumping through carbon nanotubes by imposing a thermal gradient along the length of a carbon nanotube (CNT), which connects two water-filled reservoirs. We analyse the flow parameters by varying the imposed thermal gradient (4.62 to 20.98 K nm-1), the radius (0.81 to 1.89 nm) and the length (5 to 50 nm) of the CNT. Using molecular dynamics simulations, we compute the volumetric flow rate of the pump, velocity profiles of flow and thermophoretic forces acting on water molecules for various thermal gradients. The directed motion of water molecules is induced by the spatial variations of CNT-water energy interactions at the interface and the variations in the oscillation of the carbon atoms from hot to cold ends. The net flow and average velocity of water molecules are found to increase linearly with the applied thermal gradient, as well as with an increase in the radius and length of the CNT. We observe that nano-pumps with an increase in the radius and length of the CNT connecting the reservoirs perform better and also achieved higher efficiency levels. The analysis of the results indicates that the present design leads to a realistic system capable of providing continuous transportation of water leading to interesting practical applications in nanoscale devices. PMID- 30484788 TI - Facile fabrication of fluorescent Fe-doped carbon quantum dots for dopamine sensing and bioimaging application. AB - In this paper, we have presented a novel strategy to fabricate Fe-doped carbon quantum dots (Fe-CQDs) for dopamine sensing applications. The Fe-CQDs are obtained by one step hydrothermal carbonization, using ethylenediamine tetraacetic acid salts and ferric nitrate as the carbon and iron source, which simultaneously incorporates Fe (dopamine-bonding site) and luminescent carbon quantum dots (fluorophores). The added dopamine containing catechol groups might form complexes with Fe ions (doped in CQDs) due to coordination. Subsequently, dopamine was oxidized to generate dopamine-quinone (a known potent electron acceptor) species by ambient O2. Thus, the coordination induced dopamine in proximity to the CQDs, which provided favourable electron acceptors in close proximity to the CQDs and produced high quenching efficiencies. Such fluorescence responses can be used for well quantifying dopamine in the range of 0.01-50 MUM with a detection limit of 5 nM (S/N = 3). The proposed sensing system has been successfully used for the assay of dopamine in human urine samples. Preliminary cell image study indicates that the obtained Fe-CQDs possess high photostability and low cytotoxicity, which make them promising for biological applications. PMID- 30484789 TI - Disturbance of adhesomes by gold nanoparticles reveals a size- and cell type bias. AB - Gold nanoparticles (AuNP) have been thoroughly studied as multifunctional theranosis agents for cell imaging and cancer therapy as well as sensors due to their tunable physical and chemical properties. Although AuNP have proved to be safe in a wide concentration range, yet other important biological effects can arise in the sublethal window of treatment. This is especially pivotal to understand how AuNP can affect cell biology when labeling steps are needed for cell tracking in vivo, as nanoparticle loading can affect cell migratory/invasion ability, a function mediated by filamentous actin-rich nanometric structures collectively called adhesomes. It is noteworthy that, although numerous research studies have addressed the cell response to AuNP loading, yet none of them focuses on adhesome dynamics as a target of intracellular pathways affected by AuNP. We intend to study the collective dynamics of adhesive F-actin rich structures upon AuNP treatment as an approach to understand the complex AuNP triggered modulation of migration/invasion related cellular functions. We demonstrated that citrate-coated spherical AuNP of different sizes (3, 11, 16, 30 and 40 nm) disturbed podosome-forming rosettes and the resulting extracellular matrix (ECM) degradation in a murine macrophage model depending on core size. This phenomenon was accompanied by a reduction in metalloproteinase MMP2 and an increment in metalloproteinase inhibitors, TIMP-1/2 and SerpinE1. We also found that AuNP treatment has opposite effects on focal adhesions (FA) in endothelial and mesenchymal stem cells. While endothelial cells reduced their mature FA number and ECM degradation rate upon AuNP treatment, mouse mesenchymal stem cells increased the number and size of mature FA and, therefore, the ECM degradation rate. Overall, AuNP appear to disturb adhesive structures and therefore migratory/invasive cell functions measured as ECM degradation ability, providing new insights into AuNP-cell interaction depending on cell type. PMID- 30484790 TI - Design considerations for chiral frustrated Lewis pairs: B/N FLPs derived from 3,5-bicyclic aryl piperidines. AB - Herein, 3,5-bicyclic aryl piperidines are derivatized to generate chiral B/N FLPs. Initially, the twofold symmetric amine C6H2F2(C5H8NiPr) 1 was converted in a series of synthetic steps to the styrene-derivative C6HF2(C5H8NiPr)(CH[double bond, length as m-dash]CH2) 4. Efforts to hydroborate the vinyl fragment proved challenging as a result of the strongly basic nitrogen, although the species C6HF2(C5H8N(H)iPr)(CH2CH2B(OH)(C6F5)2) 5 was crystallographically characterized. Modification of the system was achieved by conversion of the amine C6H2F2(C5H8NH) 6 to C6HF2(C5H8NPh)(CH[double bond, length as m-dash]CH2) 9. Hydroboration of 9 with 9-BBN or HB(C6F5)2 gave C6HF2(C5H8NPh)(CH2CH2BBN) 10 or C6HF2(C5H8NPh)(CH2CH2B(C6F5)2) 11, respectively. The latter species was derivatized by complexation of PPh3 to give C6HF2(C5H8NPh)(CH2CH2B(C6F5)2)(PPh3) 12. The Lewis acidities of 10 and 11 were assessed by the Gutman-Beckett test and by computations of the FIA and GEI. While 10 did not effect HD scrambling or hydrogenation of N-phenylbenzylimine, 11 was effective in HD scrambling. Despite this, no reduction of N-t-butylbenzylimine or N-phenylbenzylimine was achieved. These data demonstrate that 10 lacks the threshold combination of Lewis acidity and basicity to activate H2, while 11 lacks the steric demands about boron to preclude classical Lewis acid-base bond formation with imine substrates. PMID- 30484791 TI - Insight into the chromophore of rhodopsin and its Meta-II photointermediate by 19F solid-state NMR and chemical shift tensor calculations. AB - 19F nuclei are useful labels in solid-state NMR studies, since their chemical shift and tensor elements are very sensitive to the electrostatic and space filling properties of their local environment. In this study we have exploited a fluorine substituent, strategically placed at the C-12-position of 11-cis retinal, the chromophore of visual rhodopsins. This label was used to explore the local environment of the chromophore in the ground state of bovine rhodopsin and its active photo-intermediate Meta II. In addition, the chemical shift and tensor elements of the chromophore in the free state in a membrane environment and the bound state in the protein were determined. Upon binding of the chromophore into rhodopsin and Meta II, the isotropic chemical shift changes in the opposite direction by +9.7 and -8.4 ppm, respectively. An unusually large isotropic shift difference of 35.9 ppm was observed between rhodopsin and Meta II. This partly originates in the light-triggered 11-cis to all-trans isomerization of the chromophore. The other part reflects the local conformational rearrangements in the chromophore and the binding pocket. These NMR data were correlated with the available X-ray structures of rhodopsin and Meta II using bond polarization theory. For this purpose hydrogen atoms have to be inserted and hereto a family of structures were derived that best correlated with the well-established 13C chemical shifts. Based upon these structures, a 12-F derivative was obtained that best corresponded with the experimentally determined 19F chemical shifts and tensor elements. The combined data indicate strong changes in the local environment of the C-12 position and a substantially different interaction pattern with the protein in Meta II as compared to rhodopsin. PMID- 30484792 TI - Scalable fabrication of nanopores in membranes via thermal annealing of Au nanoparticles. AB - Nanopores are promising candidates for versatile sensing of micro- and nanomaterials. However, the fabrication of isolated nanopores with optimal dimensions and distributions requires complex processes that involve the use of high-cost equipment. Herein, we report a scalable fabrication of isolated conical nanopores with adjustable dimensions and distribution densities on a Si3N4 membrane via thermal annealing of Au nanoparticles (AuNPs). The AuNP-dispersed solution was dropped and evaporated on the membrane, while the pH value and concentration of AuNPs controlled the zeta potential difference and the distribution density of the attached AuNPs. The optimized thermal annealing directly fabricated conical nanopores at the positions of the AuNPs because of the quasi-liquid state of the AuNPs and their interaction with the Si3N4 lattices. The 50, 100, and 200 nm AuNPs enabled one-step fabrication of 8-, 26-, and 63 nm nanopores, while the inter-distances and distribution densities were controllable over the membrane. The physicochemical analyses elucidated the underlying mechanisms of direct nanopore formation, and the precise adjustment of thermal annealing developed three unique nanopores that differently interacted with the AuNPs: (1) Au-residue-embedded nanopores, (2) isolated nanopores, and (3) nanopores with the remaining Au droplet. The AuNPs-driven fabrication of versatile nanopore membranes enables new applications for sensing and transporting small-scale materials. PMID- 30484793 TI - Femtosecond electronic relaxation and real-time vibrational dynamics in 2' hydroxychalcone. AB - Femtosecond ultrafast electronic relaxation and vibrational dynamics in 2' hydroxychalcone after deep ultraviolet (DUV) excitation were observed by two types of pump-probe spectroscopy experiments, i.e., DUV-pump pulse and visible broadband-probe pulse (DUV/Vis) experiments and DUV-pump and DUV-probe (DUV/DUV) pulse experiments. Time-dependent density functional theory (TDDFT) calculations were performed to elucidate relaxation dynamics from the third singlet electronic excited state S3. The DUV/Vis experiments and TDDFT calculations have disclosed the ultrafast dynamics of internal conversion from the initial S3 state (tau1 ~ 35 fs) to the S1 state via a rapid process through the S3/S2 conical intersection and proton transfer [OH: tau2(H) ~ 93 and OD: tau2(D) ~ 164 fs] before deactivation through the S1/S0 conical intersection (tau3 ~ 690 fs). Thanks to the ultrashort pump and probe pulses, real-time observation of vibrational modes coupled to the electronic excitation was realized providing both amplitudes and phases. Spectrogram analyses were performed based on the real-time spectra obtained by the DUV/Vis experiments, in which instantaneous vibrational frequencies reflecting molecular structural change after the impulsive excitation were visualized. The vibrational frequency of central C[double bond, length as m dash]C bond stretch decreases from ~1600 cm-1 to ~1560 cm-1 in about 200-500 fs and recovers in ~550 fs. Normal mode analyses along the decay path support the observed variation of the C[double bond, length as m-dash]C stretching frequency. The temporal weakening of the central C[double bond, length as m-dash]C bond is connected with the angle of the two aromatic rings which flip back to the initial conformation. PMID- 30484794 TI - Softening gold for elastronics. AB - Gold, one of the noble metals, has played a significant role in human society throughout history. Gold's excellent electrical, optical and chemical properties make the element indispensable in maintaining a prosperous modern electronics industry. In the emerging field of stretchable electronics (elastronics), the main challenge is how to utilize these excellent material properties under various mechanical deformations. This review covers the recent progress in developing "softening" gold chemistry for various applications in elastronics. We systematically present material synthesis and design principles, applications, and challenges and opportunities ahead. PMID- 30484795 TI - Mineral identity, natural organic matter, and repeated contaminant exposures do not affect the carbon and nitrogen isotope fractionation of 2,4-dinitroanisole during abiotic reduction. AB - The recent development of insensitive munitions, such as 2,4-dinitroanisole (DNAN), as components of military explosives has generated concern for potential subsurface contamination and created a need to fully characterize their transformation processes. Compound specific isotope analysis (CSIA) has proven to be a useful means of assessing transformation pathways according to characteristic stable isotope fractionation patterns. The C and N isotope fractionation of DNAN associated with abiotic and enzymatic hydrolysis was recently assessed. The extent to which DNAN isotope fractionation will be affected by other potentially competing transformation pathways known for nitroaromatic compounds (e.g., reduction) and if previous knowledge can be extrapolated to other environmental matrices remains to be understood. Here, we investigated the C and N isotope fractionation and reaction rate constants of DNAN during abiotic reduction mediated by mineral-associated Fe(ii) species as a function of mineral type, natural organic matter presence, and repeated exposures to DNAN. Though rate constants varied, N and C apparent kinetic isotope effects (AKIEs) remained consistent across all experiments (averaged values of 15N-AKIE = 1.0317 +/- 0.0064 and 13C-AKIE = 1.0008 +/- 0.0005) and revealed significant 15N- and minimal 13C-enrichment in agreement with previous work on nitroaromatic compounds. Moreover, the observed fractionation was clearly distinct from trends for abiotic and enzymatic hydrolysis. This study provides a strengthened basis for the use of CSIA as a robust tool for monitoring DNAN degradation in complex environmental matrices as a component of future remediation efforts. PMID- 30484796 TI - Controlling the distance of highly confined droplets in a capillary by interfacial tension for merging on-demand. AB - Droplet microfluidics is a powerful technology that finds many applications in chemistry and biomedicine. Among different configurations, droplets confined in a capillary (or plugs) present a number of advantages: they allow positional identification and simplify the integration of complex multi-steps protocols. However, these protocols rely on the control of droplet speed, which is affected by a complex and still debated interplay of various physico-chemical parameters like droplet length, viscosity ratio between droplets and carrier fluid, flow rate and interfacial tension. We present here a systematic investigation of the droplet speed as a function of their length and interfacial tension, and propose a novel, simple and robust methodology to control the relative distance between consecutive droplets flowing in microfluidic channels through the addition of surfactants either into the dispersed and/or into the continuous phases. As a proof of concept application, we present the possibility to accurately trigger in space and time the merging of two confined droplets flowing in a uniform cross section circular capillary. This approach is further validated by monitoring a conventional enzymatic reaction used to quantify the concentration of H2O2 in a biological sample, showing its potentialities in both continuous and stopped assay methods. PMID- 30484797 TI - Optimised spectral pre-processing for discrimination of biofluids via ATR-FTIR spectroscopy. AB - Pre-processing is an essential step in the analysis of spectral data. Mid-IR spectroscopy of biological samples is often subject to instrumental and sample specific variances which may often conceal valuable biological information. Whilst pre-processing can effectively reduce this unwanted variance, the plethora of possible processing steps has resulted in a lack of consensus in the field, often meaning that analysis outputs are not comparable. As pre-processing is specific to the sample under investigation, here we present a systematic approach for defining the optimum pre-processing protocol for biofluid ATR-FTIR spectroscopy. Using a trial-and-error based approach and a clinically relevant dataset describing control and brain cancer patients, the effects of pre processing permutations on subsequent classification algorithms were observed, by assessing key diagnostic performance parameters, including sensitivity and specificity. It was found that optimum diagnostic performance correlated with the use of minimal binning and baseline correction, with derivative functions improving diagnostic performance most significantly. If smoothing is required, a Sovitzky-Golay approach was the preferred option in this investigation. Heavy binning appeared to reduce classification most significantly, alongside wavelet noise reduction (filter length >=6), resulting in the lowest diagnostic performances of all pre-processing permutations tested. PMID- 30484802 TI - Geometric stabilisation of topological defects on micro-helices and grooved rods in nematic liquid crystals. AB - We demonstrate how the geometric shape of a rod in a nematic liquid crystal can stabilise a large number of oppositely charged topological defects. A rod is of the same shape as a sphere, both having genus g = 0, which means that the sum of all topological charges of defects on a rod has to be -1 according to the Gauss Bonnet theorem. If the rod is straight, it usually shows only one hyperbolic hedgehog or a Saturn ring defect with negative unit charge. Multiple unit charges can be stabilised either by friction or large length, which screens the pair interaction of unit charges. Here we show that the curved shape of helical colloids or the grooved surface of a straight rod create energy barriers between neighbouring defects and prevent their annihilation. The experiments also clearly support the Gauss-Bonnet theorem and show that topological defects on helices or grooved rods always appear in an odd number of unit topological charges with a total topological charge of -1. PMID- 30484803 TI - Correction: Icariin and icaritin recover UVB-induced photoaging by stimulating Nrf2/ARE and reducing AP-1 and NF-kappaB signaling pathways: a comparative study on UVB-irradiated human keratinocytes. AB - Correction for 'Icariin and icaritin recover UVB-induced photoaging by stimulating Nrf2/ARE and reducing AP-1 and NF-kappaB signaling pathways: a comparative study on UVB-irradiated human keratinocytes' by Eunson Hwang et al., Photochem. Photobiol. Sci., 2018, 17, 1396-1408. PMID- 30484804 TI - A new automated solar disc for water disinfection by pasteurization. AB - A new automated Solar Water Pasteurization Disc of double reflection of 3.8 and 1.3 m in diameter for the first and second reflectors has been erected and tested for performing microbiological disinfection of water in a simple, efficient, and continuous treatment in Brazil. The disc was constructed with a light weight aluminum frame and low-cost materials such as iron and small mirrors of 10 * 10 cm for easy assembly and replacement. The solar disc is automated for solar azimuth tracking and free of any connection to the electrical network. Experiments were conducted in summer and autumn with an average solar radiation of 150 W m-2, and the solar disc achieved a water flow of 60 litres per hour at temperatures above 60 degrees C. The water showed 100% disinfection effectiveness in tests with Escherichia coli. Therefore, this solar disc produces 315 litres of safe water between 10:00 and 15:00 h in the Brazilian Southeast. The solar disc's low relative weight, portability, and lack of connection to the electricity grid and production of drinking water for one family per day make it possible to consider its use in rural areas that are poor and difficult to access. PMID- 30484805 TI - A triply-responsive supramolecular vesicle fabricated by alpha-cyclodextrin based host-guest recognition and double dynamic covalent bonds. AB - The supramolecular construction of multi-stimuli assemblies is a challenging task for prospective use. In this work, a novel supramolecular amphiphile was fabricated by introducing molecules with dynamic covalent bonds into host-guest inclusion. The amphiphile formed a vesicle, which was characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), 1H NMR and UV-vis spectra. Furthermore, the vesicular structure could be regulated by pH, light and redox reagent, and thus the loaded dye in the vesicles could be released in a controlled manner. PMID- 30484809 TI - Selective separation of heavy metal ions from dilute aqueous solutions by foams and micelles of surfactants. AB - Traditional metal ion separation by surfactant foams is dependent on the interaction difference of various metal ions with surfactant monomers rather than surfactant aggregates, because the binding of metal ions with surfactant aggregates retains the metal ions in bulk solution. This kind of separation method is only effective for the metal ions with obvious differences in valence, size or coordination ability. The present study proposes a novel separation method based on the binding affinity difference of metal ions with micelles and monomers of two surfactants to selectively separate multivalent ions Cr3+, Ni2+ and Cu2+ from their dilute mixed aqueous solution. The two surfactants are single chain surfactant sodium dodecyl sulfate (SDS) and gemini surfactant 1,3-bis(N dodecyl-N-propanesulfonate sodium)-propane (C12C3C12(SO3)2), which show negligible synergism because they are both negatively charged and hold a significantly different self-assembling ability, thus allowing the coexistence of SDS/C12C3C12(SO3)2 micelles with SDS monomers. At first, Cr3+ ions were separated from Cu2+ and Ni2+ ions by the foam generated by the SDS monomers due to more intensive electrostatic interaction of Cr3+ ions with the SDS monomers. Afterwards Ni2+ ions were separated from Cu2+ ions by utilizing the high binding affinity of Cu2+ with the SDS/C12C3C12(SO3)2 micelles in the bulk solution and Ni2+ with the SDS monomers in the foam. This work has proved that micelles can assist the selective separation of "twin-like" metal ions Ni2+ and Cu2+ when the concentrations of monomers and micelles are properly adjusted. PMID- 30484812 TI - A ferronematic slab in external magnetic fields. AB - The behavior of a uniformly magnetized ferronematic slab is investigated numerically in a situation in which an external magnetic field is applied parallel and antiparallel, respectively, to its initial magnetization direction. The employed numerical method allows one to determine hysteresis curves from which a critical magnetic field strength (i.e., the one at which the ferronematic sample becomes distorted) as a function of the system parameters can be inferred. Two possible mechanisms of switching the magnetization by applying a magnetic field in the antiparallel direction are observed and characterized in terms of the coupling constant between the magnetization and the nematic director and in terms of the coupling strength of the nematic liquid crystal and the walls of the slab. Suitably prepared walls allow one to combine both switching mechanisms in one setup, such that one can construct a cell, the magnetization of which can be reversibly switched off. PMID- 30484813 TI - What Role Should Psychiatrists Have in Responding to the Opioid Epidemic? PMID- 30484814 TI - Quantifying the Added Value of Low-Molecular-Weight Heparin to Intermittent Pneumatic Compression for Preventing Venous Thromboembolic Events Under the Risk Benefit Perspective. PMID- 30484815 TI - Creating a Partnership Between Dermatologists and Geriatricians-Reply. PMID- 30484816 TI - Patch Testing and Allergen-Specific Inhibition in a Patient Taking Dupilumab. PMID- 30484817 TI - Creating a Partnership Between Dermatologists and Geriatricians. PMID- 30484818 TI - Association of Psychotic Experiences With Subsequent Risk of Suicidal Ideation, Suicide Attempts, and Suicide Deaths: A Systematic Review and Meta-analysis of Longitudinal Population Studies. AB - Importance: Recent research has highlighted that psychotic experiences are far more prevalent than psychotic disorders and associated with the full range of mental disorders. A particularly strong association between psychotic experiences and suicidal behavior has recently been noted. Objective: To provide a quantitative synthesis of the literature examining the longitudinal association between psychotic experiences and subsequent suicidal ideation, suicide attempts, and suicide deaths in the general population. Data Sources: We searched PubMed, Excerpta Medica Database, Cumulative Index to Nursing and Allied Health Literature, and PsycINFO from their inception until September 2017 for longitudinal population studies on psychotic experiences and subsequent suicidal ideation, suicide attempts, and suicide death. Study Selection: Two authors searched for original articles that reported a prospective assessment of psychotic experiences and suicidal ideation, suicide attempts, or suicide death in general population samples, with at least 1 follow-up point. Data Extraction and Synthesis: Two authors conducted independent data extraction. Authors of included studies were contacted for information where necessary. We assessed study quality using the Newcastle-Ottawa Quality Assessment Scale. We calculated pooled odds ratios using a random-effects model. A secondary analysis assessed the mediating role of co-occurring psychopathology. Main Outcomes and Measures: Psychotic experiences and subsequent suicidal ideation, suicide attempts, and suicide death. Results: Of a total of 2540 studies retrieved, 10 met inclusion criteria. These 10 studies reported on 84 285 participants from 12 different samples and 23 countries. Follow-up periods ranged from 1 month to 27 years. Individuals who reported psychotic experiences had an increase in the odds of future suicidal ideation (5 articles; n = 56 191; odds ratio [OR], 2.39 [95% CI,1.62-3.51]), future suicide attempt (8 articles; n = 66 967; OR, 3.15 [95% CI, 2.23-4.45]), and future suicide death (1 article; n = 15 049; OR, 4.39 [95% CI, 1.63-11.78]). Risk was increased in excess of that explained by co-occurring psychopathology: suicidal ideation (adjusted OR, 1.59 [95% CI, 1.09-2.32]) and suicide attempt (adjusted OR, 2.68 [95% CI, 1.71-4.21]). Conclusions and Relevance: Individuals with psychotic experiences are at increased risk of suicidal ideation, suicide attempts, and suicide death. Psychotic experiences are important clinical markers of risk for future suicidal behavior. PMID- 30484819 TI - Elimination of the Moratorium on Gun Research Is Not Enough: The Need for the CDC to Set a Budgetary Agenda. PMID- 30484820 TI - Patient Preferences for Bariatric Surgery: Findings From a Survey Using Discrete Choice Experiment Methodology. AB - Importance: Surgical options for weight loss vary considerably in risks and benefits, but the relative importance of procedure-associated characteristics in patient decision making is largely unknown. Objective: To identify patient preferences for risks, benefits, and other attributes of treatment options available to individuals who are candidates for bariatric surgery. Design, Setting, and Participants: This discrete choice experiment of weight loss procedures was performed as an internet-based survey administered to patients recruited from bariatric surgery information sessions in the State of Michigan. Each procedure was described by the following set of attributes: (1) treatment method, (2) recovery and reversibility, (3) time that treatment has been available, (4) expected weight loss, (5) effect on other medical conditions, (6) risk of complication, (7) adverse effects, (8) changes to diet, and (9) out-of pocket costs. Participants chose between surgical profiles by comparing attributes. Survey data were collected from May 1, 2015, through January 30, 2016, and analyzed from February 1 to June 30, 2016. Main Outcomes and Measures: Estimated relative value of risks and benefits for leading weight-loss surgical options and marginal willingness to pay for procedure attributes. A latent class analysis identified respondent subgroups. Results: Among the 815 respondents (79.9% women; mean [SD] age, 44.5 [12.0] years), profiles of hypothetical procedures that included resolution of medical conditions (coefficient for full resolution, 0.229 [95% CI, 0.177 to 0.280; P < .001]; coefficient for no resolution, -0.207 [95% CI, -0.254 to -0.159; P < .001]), higher total weight loss (coefficient for each additional 20% loss, 0.185 [95% CI, 0.166 to 0.205; P < .001]), and lower out-of-pocket costs (coefficient for each additional $1000, 0.034 [95% CI, -0.042 to -0.025; P < .001]) were most likely to be selected. Younger respondents were more likely than older respondents to choose treatments with higher weight loss (coefficient for loss of 80% excess weight 0.543 [95% CI, 0.435-0.651] vs 0.397 [95% CI, 0.315-0.482]) and were more sensitive to out-of pocket costs (coefficient for $100 out-of-pocket costs, 0.346 [95% CI, 0.221 0.470] vs 0.262 [95% CI, 0.174 to 0.350]; coefficient for $15 000 in out-of pocket costs, -0.768 [95% CI, -0.938 to -0.598] vs -0.384 [95% CI, -0.500 to 0.268]). Marginal willingness to pay indicated respondents would pay $5470 for losing each additional 20% of excess body weight and $12 843 for resolution of existing medical conditions, the most desired procedure attributes. Latent class analysis identified the following 3 unobserved subgroups: cost-sensitive (most concerned with costs); benefit-focused (most concerned with excess weight loss and resolution of medical conditions); and procedure-focused (most concerned with how the treatment itself worked, including recovery and reversibility). Conclusions and Relevance: Candidates for bariatric surgery identified costs, expected weight loss, and resolution of medical conditions as the most important characteristics of weight loss surgery decisions. Other information, such as risk of complications and adverse effects, were important to patients but less so. PMID- 30484821 TI - Association of Transient Palmoplantar Keratoderma With Clinical and Immunologic Characteristics of Bullous Pemphigoid. AB - Importance: Development of transient palmoplantar keratoderma (PPK) with bullous pemphigoid (BP) has only been described in 2 isolated case reports. The clinical significance and the pathophysiologic mechanisms of this association are unknown. Objective: To examine the clinical characteristics and immunological profile of patients with BP who develop transient PPK and analyze therapeutic options and outcomes. Design, Setting, and Participants: In this case series, patients with BP who developed acquired, transient PPK, and were treated at a single institution from January 1, 2015, through December 31, 2017, were studied. Main Outcomes and Measures: Clinical and immunological activity of BP, treatment administrated before and after PPK appearance, and patient outcomes. Results: Six patients with BP and transient PPK were identified and included in the study. There were 5 women and 1 man with a mean age of 72 years. At baseline, all patients had a generalized, multibullous BP and high serum anti-BP180 antibodies (mean, 130 U/mL; range, 73-150), whereas anti-BP230 antibodies were elevated in only 1 case. The PPK appeared a mean 6.2 (range, 2-12) months after BP diagnosis, following a prolonged period of disease activity with recurrent flares. When the PPK occurred, BP was uncontrolled on therapy (mean Bullous Pemphigoid Disease Activity Index [BPDAI] score, 57; range, 34-105; mean anti-BP180 antibodies titer, 122 U/mL; range, 81-150). On administration of additional systemic immunosuppressive therapies, the PPK healed progressively in a mean 4.3 months (range, 2-9), along with BP clinical remission in 4 of 6 patients. No relationship was found between PPK occurrence and anti-BP180/230 antibodies profiles. In contrast, blister fluids collected at the time of PPK displayed a much higher level of interleukin 1beta (IL-1beta) compared with those collected in the absence of PKK. Expression of IL-17A, IL-17F, and IL-22 was also enhanced in the blister fluid of patients with BP who had PPK. Conclusions and Relevance: To our knowledge, this is the first report of 6 cases of BP with transient PPK with extensive immunological investigation. The PPK appeared after a prolonged period of clinical BP activity punctuated with recurrent relapses, was transient, and healed after BP control with additional immunosuppressive therapy. Enhanced expression of a particular cytokine panel in the blister fluid at time of PPK could support keratinocyte proliferation as described in patients with psoriasis. Transient PPK could represent a clinical marker of severe, treatment-resistant BP. PMID- 30484822 TI - Expert-Level Diagnosis of Nonpigmented Skin Cancer by Combined Convolutional Neural Networks. AB - Importance: Convolutional neural networks (CNNs) achieve expert-level accuracy in the diagnosis of pigmented melanocytic lesions. However, the most common types of skin cancer are nonpigmented and nonmelanocytic, and are more difficult to diagnose. Objective: To compare the accuracy of a CNN-based classifier with that of physicians with different levels of experience. Design, Setting, and Participants: A CNN-based classification model was trained on 7895 dermoscopic and 5829 close-up images of lesions excised at a primary skin cancer clinic between January 1, 2008, and July 13, 2017, for a combined evaluation of both imaging methods. The combined CNN (cCNN) was tested on a set of 2072 unknown cases and compared with results from 95 human raters who were medical personnel, including 62 board-certified dermatologists, with different experience in dermoscopy. Main Outcomes and Measures: The proportions of correct specific diagnoses and the accuracy to differentiate between benign and malignant lesions measured as an area under the receiver operating characteristic curve served as main outcome measures. Results: Among 95 human raters (51.6% female; mean age, 43.4 years; 95% CI, 41.0-45.7 years), the participants were divided into 3 groups (according to years of experience with dermoscopy): beginner raters (<3 years), intermediate raters (3-10 years), or expert raters (>10 years). The area under the receiver operating characteristic curve of the trained cCNN was higher than human ratings (0.742; 95% CI, 0.729-0.755 vs 0.695; 95% CI, 0.676-0.713; P < .001). The specificity was fixed at the mean level of human raters (51.3%), and therefore the sensitivity of the cCNN (80.5%; 95% CI, 79.0%-82.1%) was higher than that of human raters (77.6%; 95% CI, 74.7%-80.5%). The cCNN achieved a higher percentage of correct specific diagnoses compared with human raters (37.6%; 95% CI, 36.6%-38.4% vs 33.5%; 95% CI, 31.5%-35.6%; P = .001) but not compared with experts (37.3%; 95% CI, 35.7%-38.8% vs 40.0%; 95% CI, 37.0%-43.0%; P = .18). Conclusions and Relevance: Neural networks are able to classify dermoscopic and close-up images of nonpigmented lesions as accurately as human experts in an experimental setting. PMID- 30484823 TI - Nationwide Incidence of Metastatic Cutaneous Squamous Cell Carcinoma in England. AB - Importance: Cutaneous squamous cell carcinoma (cSCC) is the most common skin cancer with metastatic potential, but epidemiologic data are poor. Changes to the National Cancer Registration and Analysis Service (NCRAS) in England have allowed more accurate data analysis of primary and metastatic cSCC since 2013. Objective: To assess the national incidence of cSCC and metastatic cSCC (mcSCC) in England from 2013 through 2015. Design, Setting, and Participants: This national population-based study identified a cohort of patients with cSCC and mcSCC in England from January 1, 2013, through December 31, 2015. Patients were identified using diagnostic codes derived from pathology reports in the NCRAS. Data were analyzed from March 1, 2017, through March 1, 2018. Main Outcomes and Measures: Incidence rates across sex and risk factors for cSCC were derived from the NCRAS data. Risk of occurrence of mcSCC among the population with cSCC was assessed with Cox proportional hazards regression analysis to determine indicators of mcSCC. Results: Among the 76 977 patients with first primary cSCC in 2013 through 2015 (62.7% male; median age, 80 years [interquartile range, 72-86 years]), the age-standardized rates for the first registered cSCC in England from 2013 through 2015 were 77.3 per 100 000 person-years (PY) (95% CI, 76.6-78.0) in male patients and 34.1 per 100 000 PY (95% CI, 33.7-34.5) in female patients. Increased primary cSCC tumor count was observed in older, white male patients in lower deprivation quintiles. After a maximum follow-up of 36 months, cumulative incidence of mcSCC developed in 1.1% of women and 2.4% of men with a primary cSCC. Significant increases in the risk of metastasis with adjusted hazard rates of approximately 2.00 were observed in patients who were aged 80 to 89 years (hazard ratio [HR], 1.23; 95% CI, 1.07-1.43), 90 years or older (HR, 1.35; 95% CI, 1.09-1.66), male (HR, 1.79; 95% CI, 1.52-2.10), immunosuppressed (HR, 1.99; 95% CI, 1.64-2.42), and in higher deprivation quintiles (HR for highest quintile, 1.64; 95% CI, 1.35 2.00). Primary cSCC located on the ear (HR, 1.70; 95% CI, 1.42-2.03) and lip (HR, 1.85; 95% CI, 1.29-2.63) were at highest risk of metastasis. Conclusions and Relevance: This study presents the first national study of the incidence of mcSCC. With limited health care resources and an aging population, accurate epidemiologic data are essential for informing future health care planning, identifying high-risk patients, and evaluating skin cancer prevention policies. PMID- 30484824 TI - Risk of Appendiceal Neoplasm in Periappendicular Abscess in Patients Treated With Interval Appendectomy vs Follow-up With Magnetic Resonance Imaging: 1-year Outcomes of the Peri-Appendicitis Acuta Randomized Clinical Trial. AB - Importance: The step after conservative treatment of periappendicular abscess arouses controversy, ranging from recommendations to abandon interval appendectomy based on low recurrence rates of the precipitating diagnosis to performing routine interval appendectomy owing to novel findings of increased neoplasm risk at interval appendectomy. To our knowledge, there are no randomized clinical trials with sufficient patient numbers comparing these treatments. Objective: To compare interval appendectomy and follow-up with magnetic resonance imaging after initial successful nonoperative treatment of periappendicular abscess. Design, Setting, and Participants: The Peri-Appendicitis Acuta randomized clinical trial was a multicenter, noninferiority trial conducted in 5 hospitals in Finland. All patients between age 18 and 60 years with periappendicular abscess diagnosed by computed tomography and successful initial nonoperative treatment from January 2013 to April 2016 were included. Data analysis occurred from April 2016 to September 2017. Interventions: Patients were randomized either to interval appendectomy or follow-up with magnetic resonance imaging; all patients underwent colonoscopy. Main Outcomes and Measures: The primary end point was treatment success, defined as an absence of postoperative morbidity in the appendectomy group and appendicitis recurrence in the follow-up group. Secondary predefined end points included neoplasm incidence, inflammatory bowel disease, length of hospital stay, and days of sick leave. Results: A total of 60 patients were included (36 men [60%]; median [interquartile range] age: interval appendectomy group, 49 [18-60] years; follow-up group, 47 [22-61] years). An interim analysis in April 2016 showed a high rate of neoplasm (10 of 60 [17%]), with all neoplasms in patients older than 40 years. The trial was prematurely terminated owing to ethical concerns. Two more neoplasms were diagnosed after study termination, resulting in an overall neoplasm incidence of 20% (12 of 60). On study termination, the overall morbidity rate of interval appendectomy was 10% (3 of 30), and 10 of the patients in the follow-up group (33%) had undergone appendectomy. Conclusions and Relevance: The neoplasm rate after periappendicular abscess in this small study population was high, especially in patients older than 40 years. If this considerable rate of neoplasms after periappendicular abscess is validated by future studies, it would argue routine interval appendectomy in this setting. Trial Registration: ClinicalTrials.gov identifier: NCT03013686. PMID- 30484825 TI - States Move to Substitute Opioids With Medical Marijuana to Quell Epidemic. PMID- 30484826 TI - Settling the Controversy-Appendectomy as the Criterion for Appendicitis Diagnosis. PMID- 30484827 TI - Erythematous Papule on the Glans Penis. PMID- 30484828 TI - High-Density Lipoprotein-Targeted Therapies-Not Dead Yet. PMID- 30484829 TI - Cardiovascular Disease Disparities: The Gap Remains. PMID- 30484830 TI - Aortic Stenosis-50 Years of Discovery. PMID- 30484831 TI - Quantifying the Added Value of Low-Molecular-Weight Heparin to Intermittent Pneumatic Compression for Preventing Venous Thromboembolic Events Under the Risk Benefit Perspective-Reply. PMID- 30484832 TI - High-Density Lipoprotein-Targeted Therapies-Not Dead Yet-Reply. PMID- 30484833 TI - Association of Race/Ethnicity With Oral Anticoagulant Use in Patients With Atrial Fibrillation: Findings From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II. AB - Importance: Black and Hispanic patients are less likely than white patients to use oral anticoagulants for atrial fibrillation. Little is known about racial/ethnic differences in use of direct-acting oral anticoagulants (DOACs) for atrial fibrillation. Objective: To assess racial/ethnic differences in the use of oral anticoagulants, particularly DOACs, in patients with atrial fibrillation. Design, Setting, and Participants: This cohort study used data from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II, a prospective, US-based registry of outpatients with nontransient atrial fibrillation 21 years and older who were followed up from February 2013 to July 2016. Data were analyzed from February 2017 to February 2018. Exposures: Self-reported race/ethnicity as white, black, or Hispanic. Main Outcomes and Measures: The primary outcome was use of any oral anticoagulant, particularly DOACs. Secondary outcomes included the quality of anticoagulation received and oral anticoagulant discontinuation at 1 year. Results: Of 12 417 patients, 11 100 were white individuals (88.6%), 646 were black individuals (5.2%), and 671 were Hispanic individuals (5.4%) with atrial fibrillation. After adjusting for clinical features, black individuals were less likely to receive any oral anticoagulant than white individuals (adjusted odds ratio [aOR], 0.75 [95% CI, 0.56, 0.99]) and less likely to receive DOACs if an anticoagulant was prescribed (aOR, 0.63 [95% CI, 0.49-0.83]). After further controlling for socioeconomic factors, oral anticoagulant use was no longer significantly different in black individuals (aOR, 0.78 [95% CI, 0.59-1.04]); among patients using oral anticoagulants, DOAC use remained significantly lower in black individuals (aOR, 0.73 [95% CI, 0.55 0.95]). There was no significant difference between white and Hispanic groups in use of oral anticoagulants. Among patients receiving warfarin, the median time in therapeutic range was lower in black individuals (57.1% [IQR, 39.9%-72.5%]) and Hispanic individuals (51.7% [interquartile range {IQR}, 39.1%-66.7%]) than white individuals (67.1% [IQR, 51.8%-80.6%]; P < .001). Black and Hispanic individuals treated with DOACs were more likely to receive inappropriate dosing than white individuals (black patients, 61 of 394 [15.5%]; Hispanic patients, 74 of 409 [18.1%]; white patients, 1003 of 7988 [12.6%]; P = .01). One-year persistence on oral anticoagulants was the same across groups. Conclusions and Relevance: After controlling for clinical and socioeconomic factors, black individuals were less likely than white individuals to receive DOACs for atrial fibrillation, with no difference between white and Hispanic groups. When atrial fibrillation was treated, the quality of anticoagulant use was lower in black and Hispanic individuals. Identifying modifiable causes of these disparities could improve the quality of care in atrial fibrillation. PMID- 30484834 TI - Bioactive Signaling in Next-Generation Pharmacotherapies for Heart Failure: A Review. AB - Importance: The standard pharmacotherapy for heart failure (HF), particularly HF with reduced ejection fraction (HFrEF), is primarily through the use of receptor antagonists, notably inhibition of the renin-angiotensin system by either angiotensin-converting enzyme inhibition or angiotensin II receptor blockade (ARB). However, the completed Prospective Comparison of ARNI With an ACE Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial identified that the use of a single molecule (sacubitril/valsartan), which is an ARB and the neutral endopeptidase inhibitor (NEPi) neprilysin, yielded improved clinical outcomes in HFrEF compared with angiotensin-converting enzyme inhibition alone. Observations: This review examined specific bioactive signaling pathways that would be potentiated by NEPi and how these would affect key cardiovascular processes relevant to HFrEF. It also addressed potential additive/synergistic effects of ARB. A number of biological signaling pathways that may be potentiated by sacubitril/valsartan were identified, including some novel candidate molecules, which will act in a synergistic manner to favorably alter the natural history of HFrEF. Conclusions and Relevance: This review identified that activation rather than inhibition of specific receptor pathways provided favorable cardiovascular effects that cannot be achieved by renin-angiotensin system inhibition alone. Thus, an entirely new avenue of translational and clinical research lies ahead in which HF pharmacotherapies will move beyond receptor antagonist strategies. PMID- 30484835 TI - Utility of Naltrexone Treatment for Chronic Inflammatory Dermatologic Conditions: A Systematic Review. AB - Importance: Dermatology is encountering increasing rates of autoimmune disease manifesting in primary skin conditions that are difficult to treat without a risk of immunosuppression. Naltrexone is an orally active opioid antagonist that influences a variety of systemic pathways, including the immune system, in low doses of 1.5 to 4.0 mg/d. This phenomenon has piqued the interest of researchers and practitioners in regard to low-dose naltrexone's potential in the treatment of several autoimmune conditions. Objective: To review the existing literature on naltrexone treatment for dermatologic conditions. Evidence Review: A primary literature search was conducted using PubMed in April 2018 for all articles published from 1971 to April 2018. Search terms consisted of naltrexone or low dose naltrexone or low-dose naltrexone and dermatology or skin or hair or nails. Reviews, animal studies, and nondermatologic and pharmacologic studies were excluded. Findings: From 1037 articles, 22 were deemed to be appropriate for inclusion in this review for a qualitative synthesis. The 22 articles included randomized clinical trials, case reports, and series. There were 7 articles on low-dose naltexone, 1 on topical naltrexone, and 14 on high-dose naltrexone use in dermatology. In high, low, and topical doses, naltrexone was effective in treating pruritus attributable to atopic dermatitis, prurigo nodularis, cholestatsis, burn injury, systemic sclerosis, Hailey-Hailey disease, and lichen planopilaris. High-dose naltrexone was ineffective in treating flushing and uremic pruritus most likely because of the lack of opioid involvement in the pathophysiologic mechanisms of these conditions. Conclusions and Relevance: The findings suggest that low-dose naltrexone is safe and effective in the treatment of Hailey-Hailey disease and lichen planopilaris and both low- and high-dose naltrexone successfully treat pruritus attributable to various pathologic conditions; however, more adverse effects occurred in those taking high doses. Low-dose naltrexone has the potential for the treatment of chronic inflammatory skin conditions; however, additional evidence is needed for dosing and long-term treatment guidelines. PMID- 30484836 TI - Association of Rankings With Cardiovascular Outcomes at Top-Ranked Hospitals vs Nonranked Hospitals in the United States. AB - Importance: The US News & World Report (USNWR) identifies the "Best Hospitals" for "Cardiology and Heart Surgery." These rankings may have significant influence on patients and hospitals. Objective: To determine whether USNWR top-ranked hospitals perform better than nonranked hospitals on mortality rates and readmission measures as well as patient satisfaction. Design, Setting, and Participants: This national retrospective cross-sectional study was conducted from 2017 to 2018 and included 3552 US hospitals. Exposures: US News & World Report ranking (top-ranked vs nonranked). Main Outcomes and Measures: Thirty-day risk-standardized mortality and readmission rates for 3 cardiovascular conditions: acute myocardial infarction (AMI), heart failure (HF), and coronary artery bypass grafting (CABG) as well as Hospital Consumer Assessment of Healthcare Providers and Systems patient satisfaction star ratings obtained from publicly available Centers for Medicaid and Medicare Services data, generated from Medicare fee-for-service beneficiaries age 65 years or older from 2014 to 2018. Results: Thirty-day mortality rates at top-ranked hospitals (n = 50), compared with nonranked hospitals (n = 3502), were lower for AMI (11.9% vs 13.2%, P < .001), HF (9.5% vs 11.9%; P < .001), and CABG (2.3%vs 3.3%; P < .001). Thirty day readmission rates at the top-ranked hospitals (n = 50) when compared with nonranked hospitals (n = 2841) were similar for AMI (16.7% vs 16.5%; P = .64) and CABG (14.1% vs 13.7%; P = .15) but higher for HF (21.0% vs 19.2%; P < .001), Finally, patient satisfaction was higher at top-ranked hospitals (n = 50) compared with nonranked hospitals (n = 3412) (3.9 vs 3.3; P < .001). Conclusions and Relevance: We found that USNWR top-ranked hospitals for cardiovascular care had lower 30-day mortality rates for AMI, HF, and CABG and higher patient satisfaction ratings compared with nonranked hospitals. However, 30-day readmission rates were either similar (for AMI and CABG) or higher (for HF) at top-ranked compared with nonranked hospitals. This discrepancy between readmissions and other performance measures raises concern that readmissions may not be an adequate metric of hospital care quality. PMID- 30484837 TI - Estimated 5-Year Number Needed to Treat to Prevent Cardiovascular Death or Heart Failure Hospitalization With Angiotensin Receptor-Neprilysin Inhibition vs Standard Therapy for Patients With Heart Failure With Reduced Ejection Fraction: An Analysis of Data From the PARADIGM-HF Trial. AB - Importance: The addition of neprilysin inhibition to standard therapy, including a renin-angiotensin system blocker, has been demonstrated to improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF) compared with standard therapy alone. The long-term absolute risk reduction from angiotensin receptor neprilysin inhibitor (ARNI) therapy, and whether it merits widespread use among diverse subpopulations, has not been well described. Objective: To calculate estimated 5-year number needed to treat (NNT) values overall and for different subpopulations for the Prospective Comparison of ARNI with Angiotensin Converting Enzyme Inhibitor (ACEI) to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) cohort. Design, Setting, and Participants: Overall and subpopulation 5-year NNT values were estimated for different end points using data from PARADIGM-HF, a double-blind, randomized trial of sacubitril-valsartan vs enalapril. This multicenter, international study included 8399 men and women with HFrEF (ejection fraction, <=40%). The study began in December 2009 and ended in March 2014. Analyses began in March 2018. Interventions: Random assignment to sacubitril-valsartan or enalapril. Main Outcomes and Measures: Cardiovascular death or HF hospitalization, cardiovascular death, and all-cause mortality. Results: The final cohort of 8399 individuals included 1832 women (21.8%) and 5544 white individuals (66.0%), with a mean (SD) age of 63.8 (11.4) years. The 5-year estimated NNT for the primary outcome of cardiovascular death or HF hospitalization with ARNI therapy incremental to ACEI therapy in the overall cohort was 14. The 5-year estimated NNT values were calculated for different clinically relevant subpopulations and ranged from 12 to 19. The 5-year estimated NNT for all-cause mortality in the overall cohort with ARNI incremental to ACEI was 21, with values ranging from 16 to 31 among different subgroups. Compared with imputed placebo, the 5-year estimated NNT for all-cause mortality with ARNI was 11. The 5-year estimated NNT values were also calculated for other HFrEF therapies compared with controls from landmark trials for all-cause mortality and were found to be 18 for ACEI, 24 for angiotensin receptor blockers, 8 for beta-blockers, 15 for mineralocorticoid antagonists, 14 for implantable cardioverter defibrillator, and 14 for cardiac resynchronization therapy. Conclusions and Relevance: The 5-year estimated NNT with ARNI therapy incremental to ACEI therapy overall and for clinically relevant subpopulations of patients with HFrEF are comparable with those for well-established HF therapeutics. These data further support guideline recommendations for use of ARNI therapy among eligible patients with HFrEF. PMID- 30484838 TI - Trends in Serious Psychological Distress and Outpatient Mental Health Care of US Adults. AB - Importance: Reports of a recent increase in US outpatient mental health care raise questions about whether it has been driven by rising rates of psychological distress and whether mental health treatment has become either more or less focused on people with higher levels of distress. Objective: To characterize national trends in serious psychological distress and trends in outpatient mental health service use by adults with and without serious psychological distress. Design, Setting, and Participants: The 2004-2005, 2009-2010, and 2014-2015 Medical Expenditure Panel Surveys (MEPS) were nationally representative surveys taken in US households. The analysis was limited to participants 18 years or older. Dates of this analysis were February 2018 to April 2018. Main Outcomes and Measures: Annual national trends in the percentages of adults with serious psychological distress (Kessler 6 scale score >=13), outpatient mental health service use (outpatient visit with a mental disorder diagnosis, psychotherapy visit, or psychotropic medication), and type of psychotropic medication use (antidepressants, anxiolytics/sedatives, antipsychotics, mood stabilizers, and stimulants). Age- and sex-adjusted odds ratios of the associations of survey period with the odds of serious psychological distress, outpatient mental health service use, and outpatient mental health service use were stratified by level of psychological distress. Results: The analysis involved 139 862 adult participants from the 2004-2005, 2009-2010, and 2014-2015 MEPS, including 51.67% women, 48.33% men, 67.11% white adults, and 32.89% nonwhite adults, with an overall mean (SE) age of 46.41 (0.14) years. Serious psychological distress declined overall from 4.82% (2004-2005) to 3.71% (2014-2015), including significant declines among young (3.94% to 3.07%), middle-aged (5.52% to 4.36%), and older adults (5.24% to 3.79%); men (3.94% to 3.09%) and women (5.64% to 4.29%); and major racial/ethnic groups (white, 4.52% to 3.82%; African American, 5.12% to 3.64%; Hispanic, 6.03% to 3.55%; and other, 5.22% to 3.26%). Overall, the percentage of adults receiving any outpatient mental health service increased from 19.08% (2004-2005) to 23.00% (2014-2015) (adjusted odds ratio, 1.25; 95% CI, 1.17-1.34). Although the proportionate increase in outpatient mental health service use for adults with serious psychological distress (54.17% to 68.40%) was larger than that for adults with less serious or no psychological distress (17.26% to 21.08%), the absolute increase in outpatient mental health service use was almost completely the result of growth in outpatient mental health service use by individuals with less serious or no psychological distress. Conclusions and Relevance: The recent increase in outpatient mental health service use occurred during a period of decline in serious psychological distress. Adults with less serious psychological distress accounted for most of the absolute increase in outpatient mental health service use, while adults with serious psychological distress experienced a greater relative increase in outpatient mental health service use. PMID- 30484839 TI - The Art and Science of Nursing. PMID- 30484843 TI - Care Plan Standardization for Older Adults: Opportunities for Nursing Leadership. AB - Care plans guide and document achievement of short- and long-term goals. However, most care plans are discipline oriented, document medical problems, and lack person-centered information such as care preferences. The current authors' goal was to explore the status of comprehensive care plans and the future application of sharing data among health care providers and settings. Semi-structured interviews were conducted among a variety of professionals in six geographically diverse settings to learn the status and performance of care plans. Various biases, regular and irregular omissions, and lack of long-term perspectives in the care plan generation processes were found. These deficits support the need for developing comprehensive standardized care plans to improve access, coordination, and quality of care for older adults. Nurses are in an ideal position to lead local, state, and national initiatives to drive policies for comprehensive care plans that will improve access to and quality of care delivery to older adults. [Journal of Gerontological Nursing, 44(12), 11-16.]. PMID- 30484844 TI - Older Smokers' Beliefs About e-Cigarettes and Intent to Quit Conventional Cigarettes. AB - To explore associations between older smokers' attitudes and beliefs about electronic cigarettes (e-cigarettes) and tobacco use behavior, descriptive and correlational analysis of a cross-sectional survey of a random national sample of current smokers (age >=45 years [considered "older" herein]) was performed. Of 498 older smokers, 75% wanted to quit smoking cigarettes and 60% had tried e cigarettes. The 108 current e-cigarette users believed e-cigarettes help quit cigarettes (p < 0.001), are safer than cigarettes (p = 0.002), and are acceptable to friends (p = 0.010) and family (p = 0.007). Smokers not considering cessation believed friends and family think it is okay to smoke cigarettes (p < 0.001). Among older smokers: (a) most want to quit cigarettes; (b) e-cigarette use is increasing; (c) most believe e-cigarettes are healthier than cigarettes and effective for cessation; and (d) perceived social acceptability modifies tobacco use behavior by influencing initiation and maintenance of conventional cigarette and e-cigarette use. [Journal of Gerontological Nursing, 44(12), 17-24.]. PMID- 30484845 TI - Development of a Comprehensive Geriatric Assessment Led by Geriatric Nurse Consultants: A Feasibility Study. AB - Hospitalized older adults are at high risk for complications, leading to negative outcomes such as longer lengths of stay, hospital readmissions, and functional and cognitive decline. Comprehensive Geriatric Assessment (CGA) models are effective in mitigating these syndromes but are not widespread. Nurses with expertise in gerontology who can provide consultation and care coordination can improve care processes and clinical outcomes. This pilot study capitalized on the role of the geriatric nurse consultant (GNC) to develop, implement, and test the feasibility, acceptability, and utility of a GNC-led CGA. Through repeated applications with hospitalized patients, this study demonstrated that GNCs could complete a CGA and identify clinically actionable findings. This study also uncovered clinical geriatric concerns that would not have otherwise been identified via traditional nursing assessments. The results highlight contribution of a GNC-led CGA as a mechanism to support care process improvements to address common geriatric concerns in the acute care setting. [Journal of Gerontological Nursing, 44(12), 25-34.]. PMID- 30484846 TI - Nurses' Recognition of Hospitalized Older Patients With Delirium and Cognitive Impairment Using the Delirium Observation Screening Scale: A Prospective Comparison Study. AB - The aim of the current study was to report findings about delirium detection when ward nurses screened for delirium in patients with cognitive impairment using the Delirium Observation Screening Scale (DOSS) in comparison to the Confusion Assessment Method (CAM). A secondary analysis was performed of research data collected in 2010 at a Swiss tertiary university hospital. During the first 5 days after admission, patients 70 and older with cognitive impairment were screened for delirium using the DOSS. Throughout patients' hospital stay, research assistants also completed the CAM on a daily basis. A total of 138 patients who did not have delirium initially participated in the study. Of these patients, 44 (32%) developed delirium with a median duration of 3 days (Q1 = 1.25; Q3 = 5.00). Ward nurses correctly identified delirium using the DOSS in 56% of cases (sensitivity) and no delirium in 92% of cases (specificity). Although the DOSS was 100% correct in detecting patients with hyperactive delirium, the identification rate decreased to 60% for patients with mixed delirium subtype and 38% for patients with hypoactive delirium. Delirium screening using observational methods may be insufficiently sensitive and should be supplemented with a formal attention test. [Journal of Gerontological Nursing, 44(12), 35-43.]. PMID- 30484847 TI - The Association Between Chronic Condition Symptoms and Treatment Burden in a Skilled Nursing Population. AB - The purpose of the current study was to determine the relationship between chronic condition symptoms and treatment burden in older adults transitioning from skilled nursing facilities to home. Treatment burden is defined as the burden associated with adhering to a prescribed chronic condition self-management regimen. Analysis of correlations between chronic condition symptoms and treatment burden revealed that symptoms and treatment burden are positively correlated (p < 0.05). Multivariate analysis (adjusted R2 = 0.40, F[10, 63] = 5.96, p < 0.001), controlling for other known antecedents of treatment burden, demonstrated that fatigue (standardized beta coefficient = 0.47, p < 0.001) predicted higher levels of treatment burden. Post hoc analysis revealed caregiver presence partially mediated the effect of fatigue on treatment burden, decreasing treatment burden during transition. Findings support existing transitional care literature suggesting that clinical assessment, including symptom screening, treatment of symptoms, and/or intervention reducing the impact of symptoms on patients' health and well-being, may lower treatment burden, thus improving self management adherence. [Journal of Gerontological Nursing, 44(12), 45-52.]. PMID- 30484848 TI - Overcoming Anterior Breaches in the Distal Femur During Long Gamma Nailing. AB - Anterior cortical penetration of distal femora when using long gamma nails is well established. To avoid this complication, using the appropriate entry point, a nail with a smaller radius of curvature, and intraoperative imaging is suggested. Despite this, there are times when the guidewire or the nail can abut or even perforate the anterior cortex. This is more likely to occur in patients with scalloped anterior distal femora and increased femoral anterior bowing. The authors overcome this potential problem during surgery by using a bent-tip guidewire. Their technique is cost neutral, safe, and quick. [Orthopedics. 201x; xx(x):xx-xx.]. PMID- 30484849 TI - Use of Continuous Passive Motion Reduces Rates of Arthrofibrosis After Anterior Cruciate Ligament Reconstruction in a Pediatric Population. AB - Joint immobilization after anterior cruciate ligament (ACL) reconstruction may lead to intra-articular adhesions and range of motion deficits. Some practitioners thus advocate for the use of postoperative continuous passive motion (CPM) machine protocols. However, previous studies have failed to show CPM to be effective in increasing postoperative range of motion. Continuous passive motion has, however, been shown to reduce rates of arthrofibrosis requiring manipulation under anesthesia (MUA) in adult populations. To date, there has been no study of the efficacy of CPM after ACL reconstruction in a pediatric population. This was a retrospective cohort study of pediatric patients (age <20 years) who underwent primary ACL reconstruction at an urban tertiary care children's hospital. Clinically significant arthrofibrosis was defined as reduced knee flexion requiring MUA within 6 months of surgery. The final dataset included 163 patients. There was no significant difference between cohorts in range of motion at the 1-week, 1-month, 3-month, and 6-month time points (P=.137, .695, .897, and .339, respectively). The 2 cohorts also did not differ significantly in pain scores at these time points (P=.684, .623, .507, and 1.000, respectively). At 3 and 6 months, neither quadriceps nor hamstrings strength differed significantly between cohorts. Four patients (7.4%) in the no-CPM cohort required MUA for arthrofibrosis within 6 months of surgery, while no patients in the CPM cohort required MUA (P=.023). This suggests that CPM use reduces arthrofibrosis requiring MUA in pediatric patients after ACL reconstruction. Future work may better define the clinical utility and cost-effectiveness of CPM in rehabilitation after these surgeries. [Orthopedics. 201x; xx(x):xx-xx.]. PMID- 30484850 TI - Projected Medicare Savings Associated With Lowering the Risk of Total Hip Arthroplasty Revision: An Administrative Claims Data Analysis. AB - In the United States, demand for total hip arthroplasty (THA) and THA revision procedures are increasing due to an aging population, a longer life expectancy, and an increasing prevalence of osteoarthritis. This retrospective cohort study identified patients 65 years and older in the Medicare 5% Standard Analytic Files who underwent THA for osteoarthritis between January 1, 2009, and September 30, 2010. The authors estimated the 5-year cumulative revision risk (CRR) using the Kaplan-Meier method, revision-related complications, and Medicare expenditures. Using a 6.22% compound annual growth rate from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality, the authors estimated the number of THAs that will be performed from 2018 to 2027 and calculated the 10-year projected savings to Medicare for a 1% reduction in CRR. Among 7820 patients, the mean age was 74.4 years, and 62.4% were female. Cumulative revision risk was 4.2% at 5 years (through September 30, 2015), with 30.8% of revisions occurring within 90 days of the THA. At least 24.4% of revision patients had a complication. Median revision inpatient stay and episode of care (through 90 days) expenditures were $23,847 and $36,157, respectively. With a 1% absolute reduction in CRR, Medicare could save $697 million over a 10 year period, or $985 million when including Medicare Advantage, which represented 29.2% of 2016 Medicare payments. Strategies to reduce the risk of THA revision, such as the use of implant constructs with lower CRR and value-based payment models, are needed to achieve Medicare payment reductions while maintaining or improving quality of care for Medicare beneficiaries. [Orthopedics. 201x; xx(x):xx-xx.]. PMID- 30484851 TI - Use of an Additional Nonlocking Screw in Olecranon Fracture Osteosynthesis Changes Failure Mechanism. AB - Hardware-related complications can occur when plate fixation is used to stabilize osteoporotic fractures involving the olecranon. The use of an additional nonlocking screw, placed retrograde into the proximal fracture segment, may improve stability under load. The purpose of this study was to conduct a biomechanical comparison of olecranon repair constructs with and without this additional retrograde screw. Nine matched pairs of elderly fresh-frozen cadaveric upper extremities were used. Two-part olecranon fractures were modeled, and fracture stabilization was performed. Olecranon plates were implanted either with the standard surgical technique (CTRL) or with an additional retrograde screw (EXPT). Dynamic extensions of increasingly loaded forearms were performed, and comparisons of sustained cycles, maximum load, and total work were made. Relative motion of bone segments was tracked, and modes of failure were assessed. Seventy eight percent of specimens from the CTRL group failed due to relative fragment displacement exceeding 3 mm, while 78% of EXPT specimens failed due to instantaneous catastrophic failure. There were no significant differences in terms of number of survived cycles, maximum load, or work performed between the groups. The addition of a retrograde screw in this plating technique changes the failure mode from fracture displacement to catastrophic failure. The use of a 3.5 mm retrograde screw in the relatively small proximal ulnar fragment should be avoided, but screws with a smaller diameter may still have potential to improve fixation. Further biomechanical and clinical research is necessary to improve strategies for plate fixation of olecranon fractures in the elderly population. [Orthopedics. 201x; xx(x):xx-xx.]. PMID- 30484852 TI - Chronic Morbidity of a Pilot Hole Burr Technique for Anterior Iliac Crest Autograft in Cervical Fusion. AB - Anterior cervical decompression and fusion is a commonly performed procedure for cervical pathology. Graft choices include autograft, allograft, xenograft, synthetic, or a combination. Autograft has been shown to increase fusion rate compared with allograft, yet high morbidity at the harvest site has been reported. Few studies have evaluated chronic graft site pain, and to the authors' knowledge, no study has evaluated morbidity of a pilot hole burr technique for anterior iliac crest harvest. The objective of this study was to evaluate chronic morbidity of anterior iliac crest harvest in anterior cervical decompression and fusion using a pilot hole burr technique. A phone survey was used to identify chronic morbidity. Number of levels fused, age, sex, and acute graft site complications were explored to evaluate impact of patient characteristics on chronic graft site pain. A total of 140 patients met inclusion criteria; 106 patients (76%) completed the phone survey. Mean follow-up was 38.9 months. Two patients (1.9%) reported current and constant graft site pain. Nine patients (8.5%) reported intermittent pain. Average numeric pain rating scale score for survey participants was 0.25 of 10. No patients were taking narcotics for graft site pain. Two patients (1.9%) reported functional impairment secondary to the graft site pain. There was no impact of number of levels fused, age, sex, or acute graft site complications on chronic graft site pain. The pilot hole burr technique resulted in low long-term morbidity and may offer an alternative to traditional methods for those wishing to use autologous graft in anterior cervical decompression and fusion. [Orthopedics. 201x; xx(x):xx-xx.]. PMID- 30484853 TI - Bone Scintigraphy: A Review of Technical Aspects and Applications in Orthopedic Surgery. AB - Due to its high sensitivity, low cost, accessibility, and ease of use, bone scintigraphy is used in orthopedic surgery for the diagnosis and management of varied pathology. It is commonly used for insufficiency fractures, metastatic neoplasia, staging and surveillance of sarcoma, and nonaccidental trauma. It augments diagnoses, including stress or occult fractures, musculoskeletal neoplasia or infection, and chronic regional pain syndrome, in patients presenting with normal results on radiographs. Bone scan images are resistant to metal-based implant artifact, allowing effective evaluation of failed total joint prostheses. Bone scintigraphy remains an underused tool in the evaluation and management of orthopedic patients. [Orthopedics. 201x; xx(x):xx-xx.]. PMID- 30484854 TI - Allogeneic Haematopoietic Cell Transplantation for Epidermolysis Bullosa: the Dutch Experience. PMID- 30484855 TI - Laparoscopic versus open surgery for suspected appendicitis. AB - BACKGROUND: The removal of the acute appendix is one of the most frequently performed surgical procedures. Open surgery associated with therapeutic efficacy has been the treatment of choice for acute appendicitis. However, in consequence of the evolution of endoscopic surgery, the operation can also be performed with minimally invasive surgery. Due to smaller incisions, the laparoscopic approach may be associated with reduced postoperative pain, reduced wound infection rate, and shorter time until return to normal activity.This is an update of the review published in 2010. OBJECTIVES: To compare the effects of laparoscopic appendectomy (LA) and open appendectomy (OA) with regard to benefits and harms. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE and Embase (9 February 2018). We identified proposed and ongoing studies from World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov and EU Clinical Trials Register (9 February 2018). We handsearched reference lists of identified studies and the congress proceedings of endoscopic surgical societies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing LA versus OA in adults or children. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed the risk of bias, and extracted data. We performed the meta-analyses using Review Manager 5. We calculated the Peto odds ratio (OR) for very rare outcomes, and the mean difference (MD) for continuous outcomes (or standardised mean differences (SMD) if researchers used different scales such as quality of life) with 95% confidence intervals (CI). We used GRADE to rate the quality of the evidence. MAIN RESULTS: We identified 85 studies involving 9765 participants. Seventy-five trials included 8520 adults and 10 trials included 1245 children. Most studies had risk of bias issues, with attrition bias being the largest source across studies due to incomplete outcome data.In adults, pain intensity on day one was reduced by 0.75 cm on a 10 cm VAS after LA (MD -0.75, 95% CI -1.04 to -0.45; 20 RCTs; 2421 participants; low quality evidence). Wound infections were less likely after LA (Peto OR 0.42, 95% CI 0.35 to 0.51; 63 RCTs; 7612 participants; moderate-quality evidence), but the incidence of intra-abdominal abscesses was increased following LA (Peto OR 1.65, 95% CI 1.12 to 2.43; 53 RCTs; 6677 participants; moderate-quality evidence).The length of hospital stay was shortened by one day after LA (MD -0.96, 95% CI -1.23 to -0.70; 46 RCTs; 5127 participant; low-quality evidence). The time until return to normal activity occurred five days earlier after LA than after OA (MD -4.97, 95% CI -6.77 to -3.16; 17 RCTs; 1653 participants; low-quality evidence). Two studies showed better quality of life scores following LA, but used different scales, and therefore no pooled estimates were presented. One used the SF-36 questionnaire two weeks after surgery and the other used the Gastro-intestinal Quality of Life Index six weeks and six months after surgery (both low-quality evidence).In children, we found no differences in pain intensity on day one (MD 0.80, 95% CI -1.65 to 0.05; 1 RCT; 61 participants; low-quality evidence), intra abdominal abscesses after LA (Peto OR 0.54, 95% CI 0.24 to 1.22; 9 RCTs; 1185 participants; low-quality evidence) or time until return to normal activity (MD 0.50, 95% CI -1.30 to 0.30; 1 RCT; 383 participants; moderate-quality evidence). However, wound infections were less likely after LA (Peto OR 0.25, 95% CI 0.15 to 0.42; 10 RCTs; 1245 participants; moderate-quality evidence) and the length of hospital stay was shortened by 0.8 days after LA (MD -0.81, 95% CI -1.01 to 0.62; 6 RCTs; 316 participants; low-quality evidence). Quality of life was not reported in any of the included studies. AUTHORS' CONCLUSIONS: Except for a higher rate of intra-abdominal abscesses after LA in adults, LA showed advantages over OA in pain intensity on day one, wound infections, length of hospital stay and time until return to normal activity in adults. In contrast, LA showed advantages over OA in wound infections and length of hospital stay in children. Two studies reported better quality of life scores in adults. No study reported this outcome in children. However, the quality of evidence ranged from very low to moderate and some of the clinical effects of LA were small and of limited clinical relevance. Future studies with low risk of bias should investigate, in particular, the quality of life in children. PMID- 30484856 TI - Effects of Tyr555 and Trp678 on the processivity of cellobiohydrolase A from Ruminiclostridium thermocellum: A simulation study. AB - Cellobiohydrolase A from Ruminiclostridium thermocellum (Cbh9A) is a processive exoglucanase from family 9 and is an important cellobiohydrolase that hydrolyzes cello-oligosaccharide into cellobiose. Residues Tyr555 and Trp678 considerably affect catalytic activity, but their mechanisms are still unknown. To investigate how the Tyr555 and Trp678 affect the processivity of Cbh9A, conventional molecular dynamics, steered molecular dynamics, and free energy calculation were performed to simulate the processive process of wild type (WT)-Cbh9A, Y555S mutant, and W678G mutant. Analysis of simulation results suggests that the binding free energies between the substrate and WT-Cbh9A are lower than those of Y555S and W678G mutants. The pull forces and energy barrier in Y555S and W678G mutants also reduced significantly during the steered molecular dynamics (SMD) simulation compared with that of the WT-Cbh9A. And the potential mean force calculations showed that the pulling energy barrier of Y555S and W678G mutants is much lower than that of WT-Cbh9A. PMID- 30484857 TI - Severe vitamin D deficiency is a prognostic biomarker in autoimmune hepatitis. AB - BACKGROUND: Vitamin D deficiency has been implicated in the outcome of chronic liver disease. AIM: To determine the frequency of severe vitamin D deficiency in autoimmune hepatitis (AIH), assess its association with treatment non-response, and evaluate the relationship between vitamin D status and liver-related mortality and need for transplantation. METHODS: Two hundred and nine patients were evaluated by liver tissue examination at presentation. Serum vitamin D levels were determined, and serum levels <25 nmol/L (10 ng/mL) were considered severely deficient. Treatment non-response was defined as non-normalised aspartate aminotransferase/alanine aminotransferase and immunoglobulin G levels during conventional immunosuppressive therapy. Univariate and multivariate analyses were performed using binary logistic regression and Cox proportional hazards model. RESULTS: The mean vitamin D level was 60 +/- 38 nmol/L (range, 3 263 nmol/L), and 42 patients (20%) had severe vitamin D deficiency. Treatment non response was more common in patients with severe vitamin D deficiency than in patients without (59% vs 41%, P = 0.04). Severe vitamin D deficiency was also independently associated with a higher risk of developing cirrhosis (HR 3.40; 95% CI 1.30-8.87, P = 0.01) and liver-related mortality or requirement for liver transplantation (LT; HR 5.26, 95% CI, 1.54-18.0, P = 0.008). Patients with persistent severe deficiency following vitamin D supplementation continued to have poor outcomes. CONCLUSIONS: Severe vitamin D deficiency is associated with treatment non-response, progression to cirrhosis, and liver-related death or need for LT. Severe vitamin D deficiency is a prognostic biomarker in AIH. PMID- 30484858 TI - Vocal motor control and central auditory impairments in unilateral vocal fold paralysis. AB - OBJECTIVES: To evaluate differences in vocal motor control and central auditory processing between treated unilateral vocal fold paralysis (UVFP) and healthy control cohorts. STUDY DESIGN: Cross-sectional. METHODS: Ten UVFP study patients treated by type I thyroplasty with stable voices were compared to 12 control subjects for vocal motor control using a pitch perturbation response task and central auditory processing performance using a battery of complex sound intelligibility assays that included adverse temporal and noise conditions. Standard clinical evaluations of voice production and peripheral audiometric sensitivity were performed. RESULTS: Vocal motor control was impaired in treated UVFP. The UVFP cohort exhibited a 32.5% reduction in the instantaneous, subconscious compensatory response to pitch feedback perturbation in the interval between 150 ms and 550 ms following onset (P < 0.0001, linear mixed effects model). This impairment cannot simply be ascribed to vocal motor capacity insufficiency in the UVFP cohort because both cohorts demonstrated comparable functional capacity to perform the vocal motor task. The UVFP cohort also showed greater propensity for central auditory processing impairment (P < 0.05), notably for temporal compression and added noise challenges. CONCLUSION: Combined central vocal motor control and auditory processing impairments in treated UVFP highlight reciprocal interdependency of sensory and motor systems. This pilot study suggests that peripheral motor impairment of the larynx can degrade central auditory processing, which in turn may contribute to vocal motor control impairment. A more complete restoration communicative function in UVFP will require deeper understanding of sensory, motor, and sensorimotor aspects of the human communication loop. LEVEL OF EVIDENCE: 3b Laryngoscope, 2018. PMID- 30484859 TI - Work Stress and the Risk of Cancer: a Meta-analysis of Observational Studies. AB - Epidemiological studies have explored the relationship between work stress and the risk of cancer, but it remains unclear on whether work stress could increase the risk of cancer, or by other factors such as smoking and physical activity. This study aimed to investigate the association between work stress and the risk of cancer and in relation to major potential confounding and modifying factors. We systematically searched three electronic databases, hand-searched references and citations of retrieved articles, and consulted experts to identify studies on assessing the association between work stress and the risk of cancer. The relative risks (RRs) of cancer associated with work stress were estimated using a random-effects model, and stratified by exposure measurement, study design, gender, study location, cancer site, smoking, drinking, body mass index, and physical activity. A total of 281,290 participants were included in this analysis. The significant association between work stress and the risk of colorectal (RR=1.36; 95%CI: 1.16-1.59), lung (RR=1.24; 95%CI: 1.02-1.49), and esophagus (RR=2.12; 95%CI: 1.30-3.47) cancers were found. A statistically significant effect of work stress on colorectal cancer risk was observed in North America (RR=1.51, 95% CI: 1.23-1.86, but not significant in Europe (RR= 1.16, 95% CI: 0.90-1.48). By contrast, a significant association between work stress and esophagus cancer was found in Europe, but not in North America. In addition, we did not observe any association between work stress and the risk of prostate, breast, or ovarian cancers. Findings of this study show that work stress is an important risk factor for colorectal, lung, and esophagus cancers. General public should be aware of the increased risk of cancer in employers with work stress. More efforts should be focused on understanding and studying the potential mechanisms which would help to identify employees at higher risk of these cancers. This article is protected by copyright. All rights reserved. PMID- 30484861 TI - Computer and internet-based technologies for psychotherapy, supervision, and supervision-of-supervision. PMID- 30484860 TI - CD99 expression is strongly associated with clinical outcome in children with B cell precursor acute lymphoblastic leukaemia. AB - Our study aimed to determine the expression pattern and clinical relevance of CD99 in paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). Our findings demonstrate that high expression levels of CD99 are mainly found in high risk BCP-ALL, e.g. BCR-ABL1 and CRLF2Re/Hi , and that high CD99 mRNA levels are strongly associated with a high frequency of relapse, high proportion of positive for minimal residual disease at day 29 and poor overall survival in paediatric cohorts, which indicate that CD99 is a potential biomarker for BCP-ALL. PMID- 30484862 TI - Establishment of a novel testicular cell line from sterlet Acipenser ruthenus and evaluation of its applications. AB - In this study, a cell line, designated as ART, was successfully established from testis tissues of the sterlet Acipenser ruthenus and characterized by studying and comparing the expression of specific genes between the cell line and the parent gonad tissues. The results suggested that the developed ART cell line was composed of a mixture of germ cells and somatic cells. Ploidy analysis indicated that the cell line exhibited a high degree of genetic stability and that the cells remained in a good proliferating state after being subcultured to passage 80. PMID- 30484863 TI - The histone deacetylase inhibitor panobinostat exerts anticancer effects on esophageal squamous cell carcinoma cells by inducing cell cycle arrest. AB - Esophageal squamous cell carcinoma (ESCC) is a common malignancy without effective therapy. Histone deacetylase inhibitors (HDACIs) have been demonstrated as an emerging class of anticancer drugs for a range of haematological and solid tumours. However, the effect of HDACIs has not yet been investigated on ESCC cells. In this study, HDACIs were initially considered to have anticancer activity for ESCC, due to the high expression of HDAC genes in ESCC cell lines by analysing expression data of 27 ESCC cell lines from the Broad-Novartis Cancer Cell Line Encyclopedia. Next, we used five ESCC cell lines and one normal immortalized esophageal epithelial cell line to screen three HDACIs, panobinostat (LBH589), vorinostat (SAHA), and trichostatin A (TSA), for the ability to inhibit growth. Here, we report that LBH589 more effectively suppressed cell proliferation of ESCC cell lines, in a dose-dependent manner, than TSA and SAHA, as well as had lower toxicity against the SHEE normal immortalized esophageal epithelial cell line. Further experiments indicated that LBH589 treatment significantly inhibited TP53 (mutated TP53) expression, both at the mRNA and protein level, and simultaneously increased p21 and decreased cyclin D1 expression. Taken together, we propose that LBH589 inhibits ESCC cell proliferation mainly through inducing cell cycle arrest by increasing p21 and decreasing cyclin D1 in a p53-independent manner. SIGNIFICANCE OF THE STUDY: In this study, the antitumor activity of HDACIs LBH589, SAHA, and TSA on ESCC was characterized, with LBH589 displaying the most potent anti-proliferative activity while not harming normal immortalized esophageal epithelial cells. Furthermore, we propose that LBH589 exerts its anti-proliferative effect by inducing cell cycle arrest. The ability to specifically target cancer cells indicates therapeutic potential for use of LBH589 in the treatment of ESCC. PMID- 30484864 TI - Correlating laryngoscopic appearance of laryngeal lesions with histopathology. AB - OBJECTIVES/HYPOTHESIS: Meticulous scrutiny of laryngeal lesions with laryngoscopes and microscopes often identify angiogenic activity, one of the hallmarks of neoplastic and preneoplastic lesions. The aim of this study was to determine if there is an association between laryngoscopic appearance and histopathology of laryngeal lesions based on operative biopsies. STUDY DESIGN: Retrospective case-control study. METHODS: One hundred forty-four laryngeal biopsies from 92 patients between 2015 and 2017 met inclusion criteria. Cases were patients who had biopsy-proven laryngeal dysplasia or malignancy. Controls were patients who had benign laryngeal pathology. All of the laryngeal lesions had either keratosis or vascular stippling, an indication of angiogenic activity. Medical records, videostroboscopies and operative findings of these patients were reviewed. Multivariable logistic regression was used to examine the correlation between laryngoscopic appearance of laryngeal lesions and presence or absence of dysplasia and invasive carcinoma. RESULTS: Fifty percent of the 144 laryngeal lesions were classified either as dysplastic or malignant by histopathology. Vascular stippling was present in 31% of all laryngeal lesions. On logistic regression, vascular stippling was significantly associated with dysplastic and malignant lesions (P = .0018). Overall sensitivity and specificity of vascular stippling and the presence of dysplasia and malignancy were 51% and 89%, respectively. CONCLUSIONS: Laryngoscopic and microscopic appearance of vascular stippling could inform clinicians on diagnostic sampling of suspicious laryngeal lesions that reduces delay in diagnosis. The low sensitivity of vascular stippling underlies the importance of maintaining high clinical suspicion and proceeding to the operating theater for adequate tissue sampling. LEVEL OF EVIDENCE: 3 Laryngoscope, 2018. PMID- 30484865 TI - When to replace legacy cochlear implants for technological upgrades: Indications and outcomes. AB - OBJECTIVE: To determine indications, surgical efficacy, and audiologic outcomes of replacing Advanced Bionics Clarion C1.2 internal devices (Advanced Bionics, LLC, Valencia, CA) as a means of technology upgrade. STUDY DESIGN: Retrospective review, case series. METHODS: Ten patients were initially implanted as a child (mean age = 3.87 years) and underwent cochlear implant reimplantation (CIR) with current Advanced Bionics internal device as a young adult (mean duration of implant use = 15.66 years). Demographic data and pre- and post-CIR speech perception scores were collected. RESULTS: Technology upgrade was the primary (9) or secondary (1) motivation for CIR. No surgical complications were noted, and full insertion was obtained in nine cases. Intraoperative impedance levels and neural response imaging measures were within normal limits for eight patients. At most recent post-CIR follow-up evaluation, all patients (100%) performed within or better than the 95% confidence interval of their pre-CIR word and sentence recognition scores; and 55.6%, 50.0%, and 50.0% of patients performed above the 95% confidence interval of their pre-CIR scores for the CNC words, sentences in quiet, and sentences in noise, respectively. CONCLUSION: Post-CIR audiological benefit was stable or improved compared to pre-CIR results in all categories by 3 months after reactivation. Given these results, patients who are unable to use the most current external processors due to incompatibility with a legacy internal device could consider reimplanation to optimize their overall performance with a cochlear implant. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018. PMID- 30484866 TI - SDHx gene detection and clinical Phenotypic analysis of multiple paraganglioma in the head and neck. AB - OBJECTIVES: The goal of this study was to detect and explore the mechanisms of the succinate dehydrogenase (SDH) complex subunit-related gene mutations in cases of multiple paraganglioma (PGL) in the head and neck. METHODS: In Beijing Tongren Hospital (Capital Medical University, Beijing, People's Republic of China) between January 2013 and February 2017, 23 cases of head and neck multiple PGL were evaluated by genetic sequencing. From these cases, four hereditary families and 10 cases with sporadic occurrences were found. Gene mutations, including SDHD, SDHB, SDHC, SDHAF2, VHL and RET in germ cells and somatic cells, were detected by gene capture and high throughput sequencing. RESULTS: In family 1, 12 instances of SDHD gene mutation were detected, eight of which manifested as bilateral carotid body tumor (CBT) with one bilateral malignant CBT. In family 2, three cases of SDHD mutation were found with one case of bilateral CBT and two cases of unilateral CBT. In family 3, two cases of SDHD gene mutation were found, both characterized by vagus PGL and pheochromocytoma. Of the 10 patients with sporadic manifestations, five cases of SDHD gene mutation and one case of RET gene mutation were detected. Two novel gene mutations, c.387_393del7 mutation of SDHD gene and c.3247A>G mutation of RET gene, were also detected. CONCLUSION: In patients with multiple PGL in the head and neck, these are accompanied by a genetic mutation of the germ cell. In this case study, this mutation was most commonly a mutation of the SDHD gene. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018. PMID- 30484867 TI - BICELLULAR POLLEN 1 is a modulator of DNA replication and pollen development in Arabidopsis. AB - During male gametogenesis in Arabidopsis, the haploid microspore undergoes an asymmetric division to produce a vegetative and a generative cell, the latter continues to divide symmetrically to form two sperms. This simple system couples cell cycle with cell fate specification. Here we addressed the role of DNA replication in male gametogenesis using a mutant bicellular pollen 1 (bice1) which produces bicellular, rather than tricellular pollen grains as in wild-type plant at anthesis. The mutation prolonged DNA synthesis of the generative cell, which resulted in about 40% pollen grains arrested at two nucleate stage. The extended S phase did not impact the cell fate of the generative cell as shown by cell-specific markers. BICE1 encodes a plant homolog of human D123 protein that is required for G1 progression, but the underlying mechanism is unknown. Here we showed that BICE1 interacts with MCM4 and MCM7 of the pre-replication complex. Consistently, double mutations in BICE1 and MCM4, or MCM7 also lead to bicellular pollen and condensed chromosomes. These suggest that BICE1 plays a role in modulating DNA replication via interaction with MCM4 and MCM7. This article is protected by copyright. All rights reserved. PMID- 30484868 TI - Comparing cognitive styles in social anxiety and major depressive disorders: An examination of rumination, worry, and reappraisal. AB - OBJECTIVE: Social anxiety disorder (SAD) and major depressive disorder (MDD) are commonly occurring and frequently comorbid disorders. Though individuals with SAD and MDD are more likely to engage in rumination and worry, relatively few studies have compared individuals with SAD, MDD, or both disorders on their use of these cognitive styles. Similarly, the extent to which the disorders differ in their use of reappraisal remains unclear. Thus, the current study sought to systematically examine rumination, worry, and reappraisal in individuals with and without SAD, MDD, or both disorders. METHODS: The study comprised 330 participants recruited from the community (n = 54 with SAD, n = 61 with MDD, n = 69 with comorbid SAD/MDD, and n = 146 healthy controls). Following confirmation of diagnostic status via clinical interview, participants completed measures of rumination, worry, and reappraisal. RESULTS: Healthy controls reported less use of rumination (i.e., brooding and reflection) and worry than individuals with a psychiatric diagnosis. Individuals with SAD or MDD did not differ from each other, but participants in both groups reported less rumination, particularly brooding, than individuals with comorbid SAD/MDD. Diagnostic group differences in reappraisal only emerged when reappraisal was considered alongside other cognitive styles. Further, moderation analyses indicated that reappraisal was only associated with SAD or MDD when participants also reported high levels of rumination and worry. CONCLUSIONS: Results support transdiagnostic conceptualizations of rumination and worry. They also suggest that reappraisal is only useful when it is used by people who experience frequent and habitual negative cognitions. PRACTITIONER POINTS: Individuals with SAD or MDD report more rumination and worry than healthy controls, but do not differ from each other in their reliance on these cognitive styles. Individuals with comorbid SAD/MDD endorse more rumination than individuals with SAD or MDD alone, even after adjusting for differences in symptom severity. Reappraisal may only predict diagnostic group status when considered alongside other cognitive styles. In particular, high reappraisal may be associated with reduced risk of psychiatric disorder, but only when rumination and worry are also high. LIMITATIONS: The study was limited by its cross-sectional design and reliance on self-report measures. Participants were diagnosed using DSM-IV-TR criteria for SAD and MDD. PMID- 30484869 TI - DRESS/DIHS caused by levofloxacin in a patient with systemic scleroderma, rheumatoid arthritis, and Sjogren syndrome. AB - Drug-induced hypersensitivity syndrome (DIHS) or drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, severe skin disease with manifestations such as fever, eosinophilia, lymphadenopathy and internal organ damage that typically develops 2 to 6 weeks after drug intake. DRESS/DIHS follows a prolonged course involving frequent flare-ups and relapses over weeks or months after treatment discontinuation. PMID- 30484870 TI - Rejecting, reframing, and reintroducing: trans people's strategic engagement with the medicalisation of gender dysphoria. AB - This article uses ethnographic methods to explore how transgender people engage the medicalisation of transgender experience in a U.S. context under the purview of the American Psychiatric Association. Building on sociological literature related to medicalisation, this paper argues that the lived experience of medicalisation is a non-linear, complex process whereby individual engagement with medical authority is both empowering and constraining in the lives of trans people. Inductive qualitative analysis of 158 hours of participant observation and 33 in-depth interviews with members of a transgender community organisation revealed that transgender individuals (i) reject a medical frame for gender dysphoria, (ii) embrace and stress the importance of gender-affirming medical technologies for individual identity development and social interaction and (iii) strategically reintroduce medical logics and embrace medical authority in order to facilitate medical and social recognition, validation and acceptance. PMID- 30484871 TI - Comparative multi-scale hierarchical structure of the tail, plantaris, and Achilles tendons in the rat. AB - Rodent tendons are widely used to study human pathologies such as tendinopathy and repair, and to address fundamental physiological questions about development, growth, and remodeling. However, how the gross morphology and multi-scale hierarchical structure of rat tendons, such as the tail, plantaris, and Achilles tendons, compare with that of human tendons are unknown. In addition, there remains disagreement about terminology and definitions. Specifically, the definitions of fascicle and fiber are often dependent on diameter sizes, not their characteristic features, and these definitions impair the ability to compare hierarchical structure across species, where the sizes of the fiber and fascicle may change with animal size and tendon function. Thus, the objective of the study was to select a single species that is commonly used for tendon research (rat) and tendons with varying mechanical functions (tail, plantaris, Achilles) to evaluate the hierarchical structure at multiple length scales using histology, SEM, and confocal imaging. With the exception of the specialized rat tail tendon, we confirmed that in rat tendons there are no fascicles and the fiber is the largest subunit. In addition, we provided a structurally based definition of a fiber as a bundle of collagen fibrils that is surrounded by elongated cells, and this definition was supported by both histologically processed and unprocessed samples. In all rat tendons studied, the fiber diameters were consistently between 10 and 50 MUm, and this diameter range appears to be conserved across larger species. Specific recommendations were made highlighting the strengths and limitations of each rat tendon as a research model. Understanding the hierarchical structure of tendon can advance the design and interpretation of experiments and development of tissue-engineered constructs. PMID- 30484872 TI - Design of Hedgehog pathway inhibitors for cancer treatment. AB - Hedgehog (Hh) signaling is involved in the initiation and progression of various cancers and is essential for embryonic and postnatal development. This pathway remains in the quiescent state in adult tissues but gets activated upon inflammation and injuries. Inhibition of Hh signaling pathway using natural and synthetic compounds has provided an attractive approach for treating cancer and inflammatory diseases. While the majority of Hh pathway inhibitors target the transmembrane protein Smoothened (SMO), some small molecules that target the signaling cascade downstream of SMO are of particular interest. Substantial efforts are being made to develop new molecules targeting various components of the Hh signaling pathway. Here, we have discussed the discovery of small molecules as Hh inhibitors from the diverse chemical background. Also, some of the recently identified natural products have been included as a separate section. Extensive structure-activity relationship (SAR) of each chemical class is the focus of this review. Also, clinically advanced molecules are discussed from the last 5 to 7 years. Nanomedicine-based delivery approaches for Hh pathway inhibitors are also discussed concisely. PMID- 30484873 TI - The use of cobalt chloride as a chemical hypoxia model. AB - The use of hypoxia models in cell culture has allowed the characterization of the hypoxia response at the cellular, biochemical and molecular levels. Although a decrease in oxygen concentration is the optimal hypoxia model, the problem faced by many researchers is access to a hypoxia chamber or a CO2 incubator with regulated oxygen levels, which is not possible in many laboratories. Several alternative models have been used to mimic hypoxia. One of the most commonly used models is cobalt chloride-induced chemical hypoxia because it stabilizes hypoxia inducible factors 1alpha and 2alpha under normoxic conditions. This model has several advantages, and currently, there is a substantial amount of scattered information about how this model works. This review describes the characteristics of the model, as well as the biochemical and molecular bases that support it. The regulation of hypoxia inducible factors by oxygen and the role of CoCl2 are explained to understand the most accepted bases of the CoCl2 -induced hypoxia model. The different current hypotheses that explain the establishment of hypoxic conditions using CoCl2 are also described. Finally, based on the different observations reported in the literature, we provide a critical review about the scope and limitations of this widely used chemical hypoxia model to be informative to all researchers interested in the field. PMID- 30484874 TI - We remember those who left us in the recent past. PMID- 30484875 TI - Hepatocellular carcinoma in otherwise sonographically normal liver. AB - PURPOSE: Hepatocellular carcinoma (HCC) on normal liver is very rare. The goal of this study was to determine the clinical manifestations and the role of ultrasonography (US) in the diagnosis of HCC arising in normal liver. METHODS: The clinical data and US findings in 12 cases of surgically resected HCC in normal liver were retrospectively analyzed. RESULTS: The patients were asymptomatic, had no hepatocarcinogenic factor, and hepatic function tests were almost normal in most cases. HCCs were large, encapsulated, and solitary, and there were predominantly well-differentiated or moderately differentiated in most cases. US showed a hypoechoic rim and lateral shadowing, suggestive of peritumoral capsule formation, and on contrast-enhanced US (CEUS), the tumor was hyperenhanced in arterial phase and washed out in postvascular phase, revealing typical HCC findings. CONCLUSIONS: US raises suspicion of HCC by showing lateral shadowing on grayscale ultrasound and hypervascularity on CEUS of the lesion. PMID- 30484877 TI - Gait parameters in children with bilateral spastic cerebral palsy: a systematic review of randomized controlled trials. AB - AIM: To identify the gait parameters used to assess gait disorders in children with bilateral spastic cerebral palsy (CP) and evaluate their responsiveness to treatments. METHOD: A systematic search within PubMed, Web of Science, and Scopus (in English, 2000-2016) for randomized controlled trials of children with bilateral spastic CP who were assessed by instrumented gait analysis (IGA) was performed. Data related to participants and study characteristics, risk of bias, and outcome measures were collected. A list of gait parameters responsive to clinical interventions was obtained. RESULTS: Twenty-one articles met the inclusion criteria. Eighty-nine gait parameters were identified, 56 of which showed responsiveness to treatments. Spatiotemporal and kinematic parameters were widely used compared to kinetic and surface electromyography data. The majority of responsive gait parameters were joint angles at the sagittal plane (flexion extension). INTERPRETATION: The IGA yields responsive outcome measures for the gait assessment of children with bilateral spastic CP. Spatiotemporal and kinematic (at sagittal plane) parameters are the gait parameters used most frequently. Further research is needed to establish the relevant gait parameters for each clinical problem. WHAT THIS PAPER ADDS: Fifty-six responsive gait parameters for children with bilateral spastic cerebral palsy were identified. Most responsive gait parameters belong to joint angles time-series at sagittal plane. Spatiotemporal and kinematic parameters are widely used compared to kinetic and surface electromyography parameters. PMID- 30484878 TI - Review article: emulsifiers in the food supply and implications for gastrointestinal disease. AB - BACKGROUND: Dietary emulsifiers are the latest food additives to be associated with intestinal, cardiovascular and metabolic health. Most recently, there are postulations around certain emulsifiers playing a role in the development of Crohn's disease. AIM: To review the use of food-based emulsifiers, their content in the food supply and mechanisms by which they might exert potentially detrimental biological effects. METHODS: Information on emulsifiers and thickeners relevant to human health was critically examined. RESULTS: The term, "emulsifier," has been used loosely and has included thickeners as well as agents that truly promote emulsions. These comprise proteins, phospholipids and carbohydrates, alone or in combination, and play roles in optimising food appearance, texture and mouthfeel, delivering or disguising flavours and achieving palatable low-fat foods. Their presence in the food supply is common, but not "ubiquitous" as frequently stated. Strict regulations limit the amount added to foods, but the lack of established methodologies to measure the actual food content of these diverse compounds limits our knowledge of consumption. Emulsifiers and thickeners have effects on the gut microbiota, mucosal barrier and inflammatory pathways, and can induce disease in experimental models. However, differentiating pharmacological from physiological effects and translating findings in experimental animals to humans raise uncertainties about the relevance of such effects. CONCLUSIONS: There is limited evidence to directly link emulsifiers and thickeners to human disease, but multiple potential pathogenic mechanisms. Knowledge of actual dietary intake and high-quality interventional studies is needed to enable the risks associated with their intake to be understood. PMID- 30484879 TI - Microorganisms in the ticks Amblyomma dissimile Koch 1844 and Amblyomma rotundatum Koch 1844 collected from snakes in Brazil. AB - Knowledge about ticks (Acari) and screening of ticks parasitizing various hosts are necessary to understand the epidemiology of tick-borne pathogens. The objective of this study was to investigate tick infestations on snakes (Reptilia: Squamata: Serpentes) arriving at the serpentarium at the Institute Vital Brazil, Rio de Janeiro. Some of the identified ticks were individually tested for the presence of bacteria of the genera Rickettsia (Rickettsiales: Rickettsiaceae), Borrelia (Spirochaetales: Spirochaetaceae), Coxiella (Legionellales: Coxiellaceae), Bartonella (Rhizobiales: Bartonellaceae), Ehrlichia (Rickettsiales: Anaplasmataceae), Anaplasma (Rickettsiales: Anaplasmataceae), and Apicomplexa protozoa of the genera Babesia (Piroplasmida: Babesiidae) and Hepatozoon (Eucoccidiorida: Hepatozoidae). A total of 115 hard ticks (Ixodida: Ixodidae) were collected from 17 host individuals obtained from four Brazilian states. Two species of tick were identified: Amblyomma dissimile Koch 1844 (four larvae, 16 nymphs, 40 adults), and Amblyomma rotundatum Koch 1844 (12 nymphs, 43 adults). Rickettsia bellii was found in A. rotundatum and A. dissimile ticks and Rickettsia sp. strain Colombianensi, Anaplasma-like and Hepatozoon sp. in A. dissimile ticks. Among the tested ticks, no DNA of Borrelia, Bartonella, Coxiella or Babesia was found. The present findings extend the geographic range of Rickettsia sp. strain Colombianensi in Brazil and provide novel tick-host associations. PMID- 30484876 TI - Disease-biased and shared characteristics of the immunoglobulin gene repertoires in marginal zone B cell lymphoproliferations. AB - The B cell receptor immunoglobulin (BcR IG) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n=488) i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL) as well as provisional entities (n=76) according to the World Health Organization classification. The most striking IG gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different IG gene distributions depending on the primary site of involvement. Cross-entity comparisons of the MZ IG sequence dataset with a large dataset of IG sequences (MZ-related or not; n=65,837) revealed four major clusters of cases sharing homologous ('public') heavy variable complementarity-determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia but also rheumatoid factors and non-malignant spleen MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen triggered, immune-mediated mechanisms, may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments. PMID- 30484880 TI - Lemierre's syndrome: One rare disease-Two case studies. AB - WHAT IS KNOWN AND OBJECTIVE: Lemierre's syndrome is often misdiagnosed as a common cold or viral infection. Fusobacterium necrophorum is the most common causative organism. The recommended treatment regimen is 6 weeks of a beta-lactam antibiotic along with metronidazole. CASE DESCRIPTION: We present two cases of Lemierre's syndrome with internal jugular vein thrombophlebitis and positive blood cultures for F. necrophorum. The first case was successfully treated with 6 weeks of a beta-lactam antibiotic and 4 weeks of metronidazole, while the second case was successfully treated with 4 weeks of a beta-lactam antibiotic and 2 weeks of metronidazole. WHAT IS NEW AND CONCLUSION: Two cases of Lemierre's syndrome were treated successfully with only 2-4 weeks of metronidazole therapy. Shorter duration of metronidazole therapy should be explored in future studies. PMID- 30484881 TI - Hepatitis B virus relapse rates in chronic hepatitis B patients who discontinue either entecavir or tenofovir. AB - BACKGROUND: Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are first line long-term monotherapy for treatment of chronic hepatitis B (CHB) infection. High virological relapse rates are found after cessation of either ETV or TDF in CHB patients. AIM: To compare hepatitis B virus (HBV) relapse rates in CHB patients without cirrhosis who discontinued ETV or TDF. METHODS: A retrospective prospective study was conducted in 342 CHB patients (108 hepatitis B e antigen (HBeAg)-positive and 234 HBeAg-negative) who received ETV and 165 (46 HBeAg positive, 119 HBeAg-negative) who received TDF were recruited. All patients had post-treatment follow-up for at least 6 months. All fulfilled the stopping criteria of the Asia-Pacific Association for the Study of the Liver of 2012. RESULTS: Patients who discontinued TDF had significantly higher rates and earlier times of virological and clinical relapse than those who discontinued ETV. This was also seen in propensity score (PS)-matched HBeAg-positive and HBeAg-negative patients. Multivariate analysis showed that being in the TDF group was an independent factor for virological and clinical relapse in all patients and PS matched HBeAg-positive and HBeAg-negative patients. The rate of off-therapy HBsAg loss was comparable between the ETV and TDF groups after 2-3 years follow-up. Clinical relapse tended to be more severe in the TDF group compared with the ETV group. CONCLUSION: HBV relapse occurs sooner and is more severe after cessation of TDF than after cessation of ETV. PMID- 30484882 TI - Sunscreen bans: Coral reefs and skin cancer. AB - WHAT IS KNOWN AND OBJECTIVE: Hawaii will ban two major ingredients of sunscreens. This article reviews the reasons and future directions. Hawaii recently enacted legislation that will ban the use of two major ingredients of the majority of commonly used sunscreens. The reason for the ban is the ingredients' putative deleterious impact on marine ecosystems, particularly coral reefs. But sunscreens also save lives by decreasing the risk of UV-induced skin cancers. We review both sides of the issue and potential implications for the healthcare system. COMMENT: Coral reefs consist of organisms in delicate equilibria that are susceptible to small changes in their surroundings. Recent natural and man-made disruptions, direct or indirect, such as changes in ocean temperature and chemistry, ingress of invasive species, pathogens, pollution and deleterious fishing practices, have been blamed for the poor health, or even the outright destruction, of some coral reefs. The most popular sunscreen products contain two ingredients-oxybenzone and octinoxate-that have also been implicated in coral toxicity and will be banned. This creates a healthcare dilemma: Will the protection of coral reefs result in an increase in human skin cancers? WHAT IS NEW AND CONCLUSION: Concentration estimates and mechanism studies support an association-direct or indirect (via promotion of viral infection)-of sunscreens with bleaching of coral reefs. A ban on the two most common sunscreen ingredients goes into effect in Hawaii on January 1, 2021. Proponents suggest that this is a trend, just the first of many such bans worldwide; opponents warn of a dire increase in human skin cancers. As a result, alternative sunscreen compounds are being sought. PMID- 30484883 TI - miR-30a-5p inhibition promotes interaction of Fas+ endothelial cells and FasL+ microglia to decrease pathological neovascularization and promote physiological angiogenesis. AB - Ischemia-induced angiogenesis contributes to various neuronal and retinal diseases, and often results in neurodegeneration and visual impairment. Current treatments involve the use of anti-VEGF agents but are not successful in all cases. In this study we determined that miR-30a-5p is another important mediator of retinal angiogenesis. Using a rodent model of ischemic retinopathy, we show that inhibiting miR-30a-5p reduces neovascularization and promotes tissue repair, through modulation of microglial and endothelial cell cross-talk. miR-30a-5p inhibition results in increased expression of the death receptor Fas and CCL2, to decrease endothelial cell survival and promote microglial migration and phagocytic function in focal regions of ischemic injury. Our data suggest that miR-30a-5p inhibition accelerates tissue repair by enhancing FasL-Fas crosstalk between microglia and endothelial cells, to promote endothelial cell apoptosis and removal of dead endothelial cells. Finally, we found that miR-30a levels were increased in the vitreous of patients with proliferative diabetic retinopathy. Our study identifies a role for miR-30a in the pathogenesis of neovascular retinal disease by modulating microglial and endothelial cell function, and suggests it may be a therapeutic target to treat ischemia-mediated conditions. PMID- 30484884 TI - Dual actions of the antioxidant chlorophyllin, a glutathione transferase P1-1 inhibitor, in tumorigenesis and tumor progression. AB - Glutathione (GSH) and enzymes related to this antioxidant molecule are often overexpressed in tumor cells and may contribute to drug resistance. Blockade of glutathione transferases (GSTs) has been proposed to potentiate the efficacy of chemotherapeutic drugs in cancer. The aim of this study was to evaluate the effect of chlorophyllin that has antioxidant properties, and also interferes with the activity of GST P1-1, on breast cancers in vitro and in vivo. The in vivo studies were conducted using an N-methyl- N-nitrosourea (MNU)-induced chemical carcinogenesis model in laboratory rats. DNA damage, GST activity, and GSH levels were determined in liver and tumor tissues. Treatment with chlorophyllin increased the GSH levels in the liver and significantly decreased DNA damage in the blood, liver, and tumor tissues. Even though tumorigenesis was delayed in rats receiving chlorophyllin before MNU injections, once the tumors emerged, the progression of tumor appeared to be faster than in the animals that received the carcinogen only. Out of nine breast cell lines, GST P1-1 expression was detected in MCF-12A, MDA-MB-231, and HCC38. Concomitant incubation with chlorophyllin and docetaxel did not significantly affect cell proliferation and viability. Chlorophyllin displayed genoprotective effects that initially delayed tumorigenesis. However, once the tumors were established, it may act as a promoter that facilitates tumor growth, potentially by a mechanism independent of cell proliferation and viability. Our results underline the pros and cons of antioxidant treatment in cancer, even if it has a capacity to inhibit GST P1-1. PMID- 30484885 TI - An unexpected cause of bilateral periorbital oedema. PMID- 30484887 TI - Bayesian adaptive group lasso with semiparametric hidden Markov models. AB - This paper presents a Bayesian adaptive group least absolute shrinkage and selection operator method to conduct simultaneous model selection and estimation under semiparametric hidden Markov models. We specify the conditional regression model and the transition probability model in the hidden Markov model into additive nonparametric functions of covariates. A basis expansion is adopted to approximate the nonparametric functions. We introduce multivariate conditional Laplace priors to impose adaptive penalties on regression coefficients and different groups of basis expansions under the Bayesian framework. An efficient Markov chain Monte Carlo algorithm is then proposed to identify the nonexistent, constant, linear, and nonlinear forms of covariate effects in both conditional and transition models. The empirical performance of the proposed methodology is evaluated via simulation studies. We apply the proposed model to analyze a real data set that was collected from the Alzheimer's Disease Neuroimaging Initiative study. The analysis identifies important risk factors on cognitive decline and the transition from cognitive normal to Alzheimer's disease. PMID- 30484886 TI - Comparative Study of Pattern-Based Versus Size Ratio Ultrasound Strain Elastographic Techniques on Breast Masses. AB - OBJECTIVES: The aim of this study was to compare the diagnostic performance of strain elastographic techniques involving pattern-based elastography versus size ratio elastography on breast masses. METHODS: Female patients presenting to the radiology department for ultrasound (US)-guided biopsies, fine-needle aspirations, or localizations of breast masses were invited to undergo US elastographic assessments of the lesions before the breast procedures. The masses were evaluated for color score and color map size ratio elastographic assessments with one US machine and size ratio and grayscale strain pattern elastographic assessments with another machine. With the histopathologic diagnosis as the reference standard, the sensitivity, specificity, and area under the receiver operating characteristic curve were compared among the 4 groups. RESULTS: A total of 154 breast masses from 139 women were assessed. The sensitivity and specificity were 0.615 (95% confidence interval, 0.470-0.747) and 0.824 (0.736 0.892), respectively for the color score, 0.962 (0.868-0.995) and 0.765 (0.670 0.843) for the size ratio, 0.904 (0.790-0.968) and 0.745 (0.649-0.826) for the color map size ratio, and 0.635 (0.490-0.764) and 0.422 (0.324-0.523) for the grayscale strain pattern. The areas under the receiver operating characteristic curve were 0.729 for the color score, 0.874 for the size ratio (P = .001 with the color score as a reference), 0.836 for the color map size ratio (P = .002), and 0.556 for the grayscale strain pattern (P < .001). CONCLUSIONS: Size ratio elastography had higher sensitivity and better diagnostic accuracy compared to color score elastography. This superiority was demonstrated on two different US systems, and size ratio elastography should thus be considered over color score elastography in the adjunctive US assessment of breast lesions. PMID- 30484888 TI - Facial comedonal acne in orofaciodigital syndrome type 1 caused by a novel frameshift variant in OFD1. PMID- 30484889 TI - Trimebutine Maleate Relaxes The Isolated Rat Thoracic Aorta: The Role of Nitric Oxide and L-Type Calcium Channels. AB - Trimebutine maleate (TMB), widely prescribed drug for functional gastrointestinal disorders, has been reported to regulate smooth muscle contractility by modulating multiple ion channels activities in the gastrointestinal tract. However, its action on isolated aorta has not yet been reported. The aim of the present study was to evaluate in vitro vasorelaxant properties and the underlying pharmacological mechanisms of TMB in isolated rat thoracic aortic rings. Vascular activity experiments were performed on thoracic aorta isolated from Sprague Dawley rats in-vitro, including endothelium-intact and endothelium-denuded aortic rings. TMB (10-10 -10-5 M) induced relaxation in endothelium-intact aortic rings precontracted by phenylephrine with a potency similar to that of carbachol. TMB induced relaxation was not altered by glibenclamide and atropine in endothelium intact aortic rings. However, L-NAME and endothelium denudation significantly reduced but not completely reversed the vasorelaxant effect of TMB. Also, TMB induced relaxation wasn't affected by diclofenac in endothelium-intact aortic rings. TMB at 10-5 M significantly reduced the CaCl2 -induced contractions in endothelium-intact aortic rings stimulated with KCl, but not stimulated with phenylephrine under Ca2+ free conditions. Moreover, TMB at 10-5 M effectively attenuated Bay-K8644-induced contractions in aortic rings. These results suggest that TMB-induced relaxation was mediated by both endothelium-dependent and endothelium-independent manner in isolated rat thoracic aorta. The mechanism of TMB-induced relaxation at low concentrations is partially related to NO- and endothelium-dependent but unrelated to prostanoids formation. However, inhibition of Ca2+ influx through voltage-operated calcium channels and L-type Ca2+ channel blocking effect appears to be involved in the mechanism of vasorelaxant effect of TMB at high concentrations. This article is protected by copyright. All rights reserved. PMID- 30484890 TI - The effect of long noncoding RNAs HOX transcript antisense intergenic RNA single nucleotide polymorphisms on breast cancer, cervical cancer, and ovarian cancer susceptibility: A meta-analysis. AB - Recent studies have shown that long noncoding RNAs (lncRNA) HOX transcript antisense intergenic RNA (HOTAIR) polymorphisms are associated with cancer susceptibility. The greatest threat to women's health among a variety of cancers is breast cancer (BC), cervical cancer (CC), and ovarian cancer (OC), and the incidence of it is increasing. We performed a meta-analysis to clarify the relationship between lncRNA HOTAIR expression and BC, CC, and OC susceptibility. We thoroughly searched PubMed, Embase, and the Cochrane Library to obtain the relevant literature. We extracted data from case groups and control groups for each single-nucleotide polymorphism (SNP) (rs4759314, rs920778, rs189663, rs12826786, rs7958904, and rs874945) and compared the relationship between alleles, codominance models, dominant and invisible models and BC, CC, and OC susceptibility. Our study included 11 studies with a total of 5322 patients. There was a significant association between the rs4759314 polymorphism of HOTAIR and susceptibility to BC, CC, and OC (codominant model: AG/AA odds ratio [OR] = 1.13 [95% confidence intervals [CI], 1.00-1.29], GG/AA OR = 1.54 [95% CI, 1.06 2.23]; dominant model: GG + AG/AA OR = 1.16 [95% CI, 1.02-1.32]; and recessive model: GG/AA + AG OR = 1.51 [95% CI, 1.05-2.19]). The association between the expression of rs920778 and BC, CC, and OC susceptibility was not clear (alleles T/C: OR = 1.28 [95% CI, 0.87-1.89]; in codominant model: CT/CC OR = 1.10, [95% CI, 0.71-1.71], TT/CC OR = 1.29 [95% CI, 0.59-2.80]; dominant model: TC + TT/CC OR = 1.16, [95% CI, 0.73-1.86]; and recessive model: TT/TC + CC OR = 1.43, [95% CI, 0.83-2.47]). HOTAIR polymorphism rs1899663 was associated with BC, CC, and OC susceptibility to a certain extent, (alleles T/G OR = 0.90 [95% CI, 0.69-1.16]; in the codominant model: GT/GG OR = 0.81 [95% CI, 0.50-1.30], TT/GG OR = 1.04 [95% CI, 0.63-1.72]; dominant model: GT + TT/GG OR = 0.82 [95% CI, 0.52-1.29]; and recessive model: TT/GT + GG OR = 1.21 [95% CI, 0.76-1.94]). The rs12826786, rs7958904, and rs874945 polymorphisms were associated with a certain degree of BC, CC, and OC susceptibility, but they were not statistically significant. HOTAIR rs4759314 increased susceptibility to BC, CC, and OC in some patients; rs029778 and rs1899663 also increased susceptibility to some extent. SNPs rs12826786, rs7958904, and rs874945 did not correlate with an effect on patient susceptibility to BC, CC, and OC. PMID- 30484891 TI - miR-203 accelerates apoptosis and inflammation induced by LPS via targeting NFIL3 in cardiomyocytes. AB - Myocarditis is an inflammatory disease of the myocardium. MicroRNA-203 (miR-203) is involved in various physiological and pathological processes. In this work, we aimed to explore the roles and potential mechanisms of miR-203 in myocarditis in vitro. Cardiomyocyte H9c2 was subjected to 10 MUg/mL lipopolysaccharide (LPS) for 24 hours. Real-time polymerase chain reaction analysis revealed that LPS upregulated miR-203 expression in H9c2 cells. Cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) assays demonstrated that inhibition of miR-203 reduced cell injury induced by LPS. The cell apoptosis rate, caspase 3 activity, caspase 3/7 activities, and the expression of cleaved-caspase 3 (c-caspase 3) were declined upon miR-203 depletion. In addition, miR-203 silencing attenuated the expression and production of inflammatory cytokines (tumor necrosis factor alpha, interleukin [IL]-6, and IL-8). On the contrary, overexpression of miR-203 showed the opposite trend in cell apoptosis and inflammation. Luciferase reporter assay confirmed that miR-203 could bind with the nuclear factor interleukin-3 (NFIL3) 3'-untranslated regions (3'-UTR), and miR-203 regulated the expression of NFIL3 negatively. Moreover, NFIL3 silencing partly abolished the myocardial protective functions of miR-203 inhibitor. Herein, we suggest that miR-203 promoted cell apoptosis and inflammation induced by LPS via targeting NFIL3. PMID- 30484892 TI - MicroRNA-338-3p inhibits tumor growth and metastasis in osteosarcoma cells by targeting RUNX2/CDK4 and inhibition of MAPK pathway. AB - Osteosarcoma (OS) is one of the most aggressive bone tumors. MicroRNAs (miRNAs) have been found to implicate in the pathogenesis of different types of cancers, including OS. This study aimed to explore the roles of miR-338-3p in OS and investigate the underlying mechanism. Human OS cell lines (MG-63 and U2OS) and osteoblast (hFOB) cell line were used in the study. The expression levels of miR 338-3p, runt-related transcription factor 2 (RUNX2) and cyclin-dependent kinase 4 (CDK4) were altered by transient transfection and determined by quantitative real time polymerase chain reaction/Western blot analysis. Cell viability, colony numbers, migration, and invasion, and apoptotic cells were measured by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay, transwell assay, and flow cytometry assay, respectively. Dual luciferase reporter assay was performed to identify the target gene of miR-338 3p. Western blot assay was carried to measure the protein expression levels involved in cell apoptosis, migration, and mitogen-activated protein kinases (MAPK) pathway. We found that the expression of miR-338-3p was downregulated in MG-63 cell and U2OS cells, compared with hFOB cells. MiR-338-3p suppression significantly increased cell viability and colony numbers, promoted cell migration, and invasion, but suppressed cell apoptosis in MG-63 and U2OS cells. Opposite results were observed in the miR-338-3p overexpression. Interestingly, RUNX2 and CDK4 were direct target genes of miR-338-3p. RUNX2 inhibition shared a similar effect of miR-338-3p mimic on MG-63 cells. Furthermore, miR-338-3p inhibited the activation of MAPK pathway in MG-63 cells. To conclude, these findings suggested that miR-338-3p functioned as a tumor suppressor in OS cells by targeting RUNX2 and CDK4, as well as inhibition of the MAPK pathway. PMID- 30484893 TI - LincRNA-p21 enhances the sensitivity of radiotherapy for gastric cancer by targeting the beta-catenin signaling pathway. AB - Long noncoding RNAs (lncRNAs) are a large and diverse class of transcribed RNA molecules with a length of more than 200 nucleotides that modulate the gene expression at the posttranscriptional or transcriptional level. LncRNAs played crucial roles in many biological processes, such as cell proliferation, metastasis, and migraton. In this study, we evaluated the role of lincRNA-p21 in the gastric cancer (GC). We demonstrated that the expression level of lincRNA-p21 was downregulated in the GC tissues and cell lines. Moreover, ectopic expression of lincRNA-p21 suppressed the GC cell growth, cell cycle, and migration. Furthermore, we demonstrated that the X-ray increased the expression level of lincRNA-p21 in both the HCG-27 and SGC7901 cells and elevated expression of lincRNA-p21 increased the radiotherapy sensitivity of the GC cell. In addition, we showed that ectopic expression of lincRNA-p21 suppressed the beta-catenin and c-myc expression. Overexpression of lincRNA-p21 inhibited the GC cell proliferation and increased the radiosensitivity of GC cells by regulating the beta-catenin signaling pathway. These data suggested that lincRNA-p21 acted as a tumor suppressor gene in the development of GC. PMID- 30484894 TI - MyD88 overexpression deteriorates Ang-II-induced ED via upregulating MPO and COX2 and downregulating eNOS in the corpus cavernosum of rats. AB - INTRODUCTION: Erectile dysfunction (ED) is a common sexual problem for men and the exploration of its treatment is still in mire demand. We aim to investigate the role of the Toll-like receptor 4 (TLR4)/myeloid differentiation primary response gene 88 (MyD88) signaling pathway in the pathogenesis of angiotensin II (Ang-II) induced ED. METHODS: Male Sprague-Dawlay rats were treated with Ang-II and intracavernous pressure (ICP) was measured to confirm the occurrence of ED. The corpus cavernosum penises of rats were transfected with plasmids to overexpressed MyD88. Inflammatory and vascular parameters including myeloperoxidase (MPO), cyclooxygenase2 (COX2), endothelial nitric oxide synthase (eNOS), malondialdehyde (MDA), superoxide dismutase (SOD), reactive oxygen species (ROS), and cytokines in treated and untreated ED rats were measured. Flow cytometry was used to determine the apoptosis of endothelial cells of corpus cavernosum penises of rats. RESULTS: Ang-II-induced ED rats were found to contain upregulated TLR4, MyD88, MPO, and COX2, and downregulated eNOS. MyD88 overexpression deteriorates cavernous structural damage, reduces ICP and ICP/MAP values and reverses the therapeutic effect of anti-TLR4 antibodies in rats with Ang-II-induced ED. Moreover, overexpression of MyD88 further upregulated MPO and COX2, downregulated eNOS, promoted oxidative stress, inflammation, and cell apoptosis rate via positively regulating the TLR4/MyD88 signaling pathway, while anti-TLR4 antibodies downregulated MPO and COX2, upregulated eNOS, suppressed oxidative stress, inflammation, and cell apoptosis rate via inactivating the TLR4/MyD88 signaling pathway in the rat corpus cavernosum penises. Furthermore, MyD88 overexpression promotes oxidative stress and inflammation and reverses the effect of anti-TLR4 antibodies in the penis of ED rats. CONCLUSION: MyD88 overexpression deteriorates Ang-II-induced ED via upregulating MPO and COX2 and downregulating eNOS in the corpus cavernosum rats. PMID- 30484895 TI - Using a panel of multiple tumor-associated antigens to enhance the autoantibody detection in the immunodiagnosis of ovarian cancer. AB - BACKGROUND: Ovarian cancer (OC) is a major malignancy affecting a large population over the world, and a biomarker that holds diagnostic potential is of critical importance. Recently, autoantibodies have been indicated as biomarkers in multiple cancer research. The current study was designed to explore the practice of using autoantibodies in diagnostic settings by the enzyme-linked immunosorbent assay of sera with a panel of tumor-associated antigens (TAAs). METHODS: A panel of 12 TAAs was selected to detect the corresponding autoantibodies in sera sampled from 132 OC patients as case group and 147 normal healthy individuals as the control group. The diagnostic potential of this panel was evaluated by conventional evaluation, receiver operating characteristic (ROC) curve analyses, and classification tree analysis. RESULTS: When the cutoff values were set as mean +/- 2 SD for normal healthy individuals, the positive rates of antibodies to any single TAA were less than 20% both in OC and in normal healthy individuals. In a parallel screening approach, a panel of nine TAAs (p53, C-myc, p90, p62, AHSG, 14-3-3zeta, RalA, Koc, and p16), obtained optimal diagnostic performance in OC with the sensitivity of 61.4% at the 85.0% specificity. In addition, when the nine TAAs were combined with CA125, the sensitivity and specificity were improved to 94.7% and 78.2%, respectively. The ROC curve analyses showed that only the area under the receiver operating characteristic curves (AUCs) of antibodies against C-myc, Koc, and RalA was beyond 0.6, which were 0.732, 0.668, and 0.665, respectively. The AUC of the combination was up to 0.914 (P < 0.05). Decision tree analysis showed that C-myc, HCC1.3, RalA, and CA125 held high potential in the detection of OC. The panel of nine TAAs also identified 78.8% of OC patients who had normal CA125 levels in their serum samples, indicating that elevated CA125 and anti-TAA antibodies appeared to be independent but supplementary biomarkers for diagnosing OC. CONCLUSIONS: In summary, the current study further supports that a customized TAA panel can serve as a promising and powerful tool for immunodiagnosis of OC and may be particularly useful in patients with normal CA125 levels. PMID- 30484897 TI - Pathogenesis-targeted therapeutic strategies in Parkinson's disease. PMID- 30484896 TI - A paradoxical relationship between family history, onset age, and genetic risk in Parkinson's disease. PMID- 30484898 TI - Oral tranexamic acid for the treatment of melasma. PMID- 30484899 TI - Hate and the Health of Populations. PMID- 30484900 TI - In Memoriam: Gerald Malcolm Stern (October 9, 1930-September 9, 2018). PMID- 30484901 TI - Impact of baseline left ventricular ejection fraction on outcome after transfemoral transcatheter aortic valve implantation in patients with and without low-gradient aortic stenosis. AB - OBJECTIVES: To evaluate the impact of baseline left ventricular ejection fraction (LVEF) and its interaction with low-gradient aortic stenosis (LGAS) on all-cause mortality after transfemoral aortic valve implantation (TF-TAVI). METHODS: We reviewed mortality data of 624 consecutive single center TF-TAVI patients and categorized LVEF according to current ASE/EACVI recommendations (normal, mildly-, moderately-, and severely abnormal). RESULTS: Baseline LVEF was normal in 336 (53.8%), mildly abnormal in 160 (25.6%), moderately abnormal in 91 (14.6%), and severely abnormal in 37 (5.9%) patients, and 1-year mortality was 19%, 17%, 23%, and 43% (P = 0.002), respectively. Patients with LGAS had a similar 1-year mortality compared to those without LGAS in groups with normal (19% vs 19%, P = 0.899) and mildly abnormal LVEF (16% vs 17%, P = 0.898). One-year mortality of patients with LGAS was significantly greater than in those without LGAS in presence of moderately abnormal LVEF (31% vs 11%, P = 0.022), and it was numerically greater than in those without LGAS in presence of severely abnormal LVEF (48% vs 25%, P = 0.219). In multivariate analysis, only the combination of moderately/severely abnormal LVEF and LGAS predicted increased 1-year mortality (HR: 2.12, 95% CI: 1.4-3.2, P < 0.001). Other variables, including EuroSCORE I did not affect this result. CONCLUSIONS: Moderately/severely abnormal LVEF (<=40%) at baseline is associated with increased mortality after TF-TAVI, especially when the mean transvalvular aortic gradient is <40 mm Hg (LGAS), while outcomes in patients with normal and mildly abnormal LVEF are comparable regardless of the pressure gradient across the native aortic valve. (DRKS00013729). PMID- 30484902 TI - Linear lipoatrophy following intra-articular triamcinolone acetonide injection mimicking linear scleroderma. AB - A 12-year-old female with oligoarticular juvenile inflammatory arthritis developed an atrophic linear plaque involving the left medial forearm and proximal arm 7 months after intra-articular triamcinolone injection for arthritis. The plaque spontaneously resolved without treatment over approximately one year. It is important to recognize this rare complication of intra-articular steroid injection in order to avoid potential misdiagnosis as linear scleroderma and subsequent immunosuppressive treatment. PMID- 30484903 TI - Potential of RNA interference in the study and management of the whitefly, Bemisia tabaci. AB - Whiteflies cause considerable losses to crops, directly by feeding, and indirectly by transmission of viruses. The current control methods consist of a combination of different control tactics, mainly still relying on unsafe and non ecofriendly chemical control. RNA interference (RNAi) is a post-transcriptional gene-silencing strategy in which double-stranded RNA (dsRNA), corresponding specifically to a target gene, is introduced in a target organism. Research on RNAi in the previous decade has shown its success as a potential insect control strategy, which can be highly species-specific and environment friendly. In whiteflies, the success of dsRNA delivery through the oral route opened possibilities for its management through plant-mediated RNAi. To date, several genes have been targeted in whiteflies through RNAi and these assays demonstrated its potential to manage whiteflies at lab level. However, further research and investments are needed to move toward an application at field level. In this review, for the first time, we collected the literature on genes targeted for silencing via RNAi in whiteflies and discuss the potential of RNAi in whitefly pest control. We also discuss likely delivery methods, including transgenic in planta delivery and symbiont-mediated delivery, and its potential for studying and interfering with insecticide resistance mechanisms and virus transmission by whiteflies. PMID- 30484904 TI - A multivariate discrete failure time model for the analysis of infant motor development. AB - We develop a multivariate discrete failure time model for the analysis of infant motor development. We use the model to jointly evaluate the time (in months) to achievement of three well-established motor milestones: sitting up, crawling, and walking. The model includes a subject-specific latent factor that reflects underlying heterogeneity in the population and accounts for within-subject dependence across the milestones. The factor loadings and covariate effects are allowed to vary flexibly across milestones, and the milestones are permitted to have unique at-risk intervals corresponding to different developmental windows. We adopt a Bayesian inferential approach and develop a convenient data-augmented Gibbs sampler for posterior computation. We conduct simulation studies to illustrate key features of the model and use the model to analyze data from the Nurture study, a birth cohort examining infant health and development during the first year of life. PMID- 30484905 TI - The formation of a glial scar does not prohibit remyelination in an animal model of multiple sclerosis. AB - The role of astrocytes in the pathophysiology of multiple sclerosis (MS) is discussed controversially. Especially the formation of the glial scar is often believed to act as a barrier for remyelination. At the same time, astrocytes are known to produce factors that influence oligodendrocyte precursor cell (OPC) survival. To explore these mechanisms, we investigated the astrocytic reaction in an animal model induced by immunization with myelin oligodendrocyte glycoprotein (MOG) in Dark Agouti (DA) rats, which mimics most of the histological features of MS. We correlated the astroglial reaction by immunohistochemistry (IHC) for glial fibrillary acidic protein (GFAP) to the remyelination capacity by in situ hybridization for mRNA of proteolipid protein (PLP), indicative of OPCs, over the full course of the disease. PLP mRNA peaked in early remyelinating lesions while the amount of GFAP positive astrocytes was highest in remyelinated lesions. In shadow plaques, we found at the same time all features of a glial scar and numbers of OPCs and mature oligodendrocytes, which were nearly equal to that in unaffected white matter areas. To assess the plaque environment, we furthermore quantitatively analyzed factors expressed by astrocytes previously suggested to influence remyelination. From our data, we conclude that remyelination occurs despite an abundant glial reaction in this animal model. The different patterns of astrocytic factors and the occurrence of different astrocytic phenotypes during lesion evolution furthermore indicate a finely regulated, balanced astrocytic involvement leading to successful repair. PMID- 30484906 TI - Lipid transporter Spns2 promotes microglia pro-inflammatory activation in response to amyloid-beta peptide. AB - Accumulating evidence indicates that neuroinflammation contributes to the pathogenesis and exacerbation of neurodegenerative disorders, such as Alzheimer's disease (AD). Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid that regulates many pathophysiological processes including inflammation. We present evidence here that the spinster homolog 2 (Spns2), a S1P transporter, promotes microglia pro-inflammatory activation in vitro and in vivo. Spns2 knockout (Spns2KO) in primary cultured microglia resulted in significantly reduced levels of pro-inflammatory cytokines induced by lipopolysaccharide (LPS) and amyloid beta peptide 1-42 oligomers (Abeta42) when compared with littermate controls. Fingolimod (FTY720), a S1P receptor 1 (S1PR1) functional antagonist and FDA approved drug for relapsing-remitting multiple sclerosis, partially blunted Abeta42-induced pro-inflammatory cytokine generation, suggesting that Spns2 promotes microglia pro-inflammatory activation through S1P-signaling. Spns2KO significantly reduced Abeta42-induced nuclear factor kappa B (NFkappaB) activity. S1P increased, while FTY720 dampened, Abeta42-induced NFkappaB activity, suggesting that Spns2 activates microglia inflammation through, at least partially, NFkappaB pathway. Spns2KO mouse brains showed significantly reduced Abeta42-induced microglia activation/accumulation and reduced levels of pro inflammatory cytokines when compared with age-matched controls. More interestingly, Spns2KO ameliorated Abeta42-induced working memory deficit detected by Y-Maze. In summary, these results suggest that Spns2 promotes pro inflammatory polarization of microglia and may play a crucial role in AD pathogenesis. PMID- 30484908 TI - Effects of Bacillus subtilis C-3102 on production, hatching performance, egg quality, serum antioxidant capacity and immune response of laying breeders. AB - To investigate the supplemental effects of Bacillus subtilis C-3102 on the production, hatching performance, egg quality, serum antioxidant capacity and immune response of laying breeders, a total of 480 Xuefeng black-bone (25-week old) hens were randomly assigned into four treatment groups: Hens fed the basal diets with 0 (CON), 3.0 * 105 (BS-1), 6.0 * 105 cfu/g (BS-2) and 9.0 * 105 (BS 3) cfu/g of B. subtilis C-3102. As the B. subtilis C-3102 level increased, egg weight (linear, p < 0.01; quadratic, p = 0.003), fertility (linear, p = 0.021; quadratic, p = 0.059), hatchability (linear, p = 0.038; quadratic, p = 0.119) and yolk colour (linear, p = 0.006; quadratic, p = 0.021) increased in a linear or quadratic manner. Yolk index increased quadratically (linear, p = 0.054; quadratic, p = 0.017), and eggshell thickness (linear, p = 0.036; quadratic, p = 0.128), the activity of GSH-Px (linear, p = 0.024; quadratic, p = 0.078), the concentration of IgM (linear, p = 0.016; quadratic, p = 0.056) and the level of AIV-Ab (linear, p = 0.034; quadratic, p = 0.103) in the serum increased linearly as dietary supplementation of B. subtilis C-3102 increased. The results showed that dietary treatments did not affect egg production, feed conversion ratio, egg mass, hatchability of fertile eggs, eggshell-breaking strength, egg-shape index, yolk percentage, Haugh unit, T-SOD, T-AOC, MDA, IgA and IgG concentrations and the level of NDV-Ab in the serum. In conclusion, dietary supplementation of 9.0 * 105 cfu/g B. subtilis C-3102 in laying breeders diets may be a feasible means of effectively increasing egg weight, fertility and hatchability, and improving egg quality such as eggshell thickness, yolk index and yolk colour. Besides, B. subtilis C-3102 can enhance the activity of GSH-Px, the concentration of IgM and the level of AIV-Ab in the serum. PMID- 30484907 TI - Proceeding report of the Second Symposium on Hidradenitis Suppurativa Advances (SHSA) 2017. AB - The 2nd Annual Symposium on Hidradenitis Suppurativa Advances (SHSA) took place on 03-05 November 2017 in Detroit, Michigan, USA. This symposium was a joint meeting of the Hidradenitis Suppurativa Foundation (HSF Inc.) founded in the USA, and the Canadian Hidradenitis Suppurativa Foundation (CHSF). This was the second annual meeting of the SHSA with experts from different disciplines arriving from North America, Europe and Australia, in a joint aim to discuss most recent innovations, practical challenges and potential solutions to issues related in the management and care of Hidradenitis Suppurativa patients. The last session involved clinicians, patients and their families in an effort to educate them more about the disease. This article is protected by copyright. All rights reserved. PMID- 30484909 TI - Acetaminophen pharmacokinetics in severely obese adolescents and young adults. AB - BACKGROUND: Intravenous acetaminophen is commonly administered as an adjunctive to opioids during major surgical procedures, but neither the correct pharmacokinetic size descriptor nor the dose is certain in severely obese adolescents undergoing bariatric surgery. METHODS: Adolescents, 14-20 years of age, with a body mass index (BMI) >=95th percentile for age and sex or BMI >=40 kg.m-2 , presenting for laparoscopic or robotic assisted or vertical sleeve gastrectomy were administered intravenous acetaminophen (1000 mg) following completion of the surgical procedure. Venous blood was drawn for acetaminophen assay at eight time points, starting 15 minutes after completion of the infusion and up to 12 hours afterward. Time-concentration data profiles were analyzed using nonlinear mixed effects models. Parameter estimates were scaled to a 70-kg person using allometry. Normal fat mass was used to assess the impact of obesity on pharmacokinetic parameters. RESULTS: The study cohort comprised 11 female patients, age 17 SD 2 years with a weight of 125 SD 19 kg and a mean BMI of 46 SD 5 kg.m-2 . The plasma acetaminophen serum concentration was 17 (SD 4) MUg.mL-1 at 10-20 minutes after completion of the infusion and 5 (SD 6) MUg.mL-1 at 80-100 minutes. A two-compartment model, used to investigate pharmacokinetics, estimated clearance 10.6 (CV 72%) L.h.70 kg-1 , intercompartment clearance 37.3 (CV 63%) L.h.70 kg-1 , central volume of distribution 20.4 (CV 46%) L.70 kg-1 , and peripheral volume of distribution 16.8 (CV 42%) L.70 kg-1 . Clearance was best described using total body weight. Normal fat mass with a parameter that accounts for fat mass contribution (Ffat) of 0.88 best described volumes. CONCLUSION: Current recommendations of acetaminophen to a maximum dose of 1000 mg resulted in serum concentrations below detection limits in all patients within 2 hours after administration. Dose is better predicted using total body mass with allometric scaling. PMID- 30484910 TI - Is bromelain effective in controlling the inflammatory parameters of pain, edema, and trismus after lower third molar surgery? A systematic review and meta analysis. AB - The aim of this systematic review was to evaluate the clinical evidences of the bromelain in minimizing inflammatory parameters such as pain, edema, and trismus after lower third molar surgeries. An electronic search was conducted in six databases through November 2017. The eligibility criteria included randomized and non-randomized clinical trials and/or comparative studies that used bromelain after lower third molar surgeries. The search strategy resulted in 117 articles. Following the selection process, seven studies were included in the systematic review and four in the meta-analysis. In terms of the risk of bias analysis, all the evaluated studies were classified as low or unclear risk of bias in the following criteria: selection bias, detection bias, and reporting bias. The final quantitative analysis of the variables showed that the use of bromelain resulted in greater reduction of pain levels (mean difference [MD]: -0.38; 95% confidence interval [CI; -0.66 to -0.09]), edema (MD: -0.34; 95% CI [ -0.68 to -0.01]), and trismus (MD: -2.01; 95% CI [ -3.99 to -0.02]) among the analyzed groups. The results suggest that the bromelain appears to be effective in the control of pain, edema, and trismus after lower third molar surgeries; however, further high quality studies are needed to confirm this finding. PMID- 30484911 TI - Mixed Lead-Tin Halide Perovskites for Efficient and Wavelength-Tunable Near Infrared Light-Emitting Diodes. AB - Near-infrared (NIR) light-emitting diodes (LEDs), with emission wavelengths between 800 and 950 nm, are useful for various applications, e.g., night-vision devices, optical communication, and medical treatments. Yet, devices using thin film materials like organic semiconductors and lead based colloidal quantum dots face certain fundamental challenges that limit the improvement of external quantum efficiency (EQE), making the search of alternative NIR emitters important for the community. In this work, efficient NIR LEDs with tunable emission from 850 to 950 nm, using lead-tin (Pb-Sn) halide perovskite as emitters are demonstrated. The best performing device exhibits an EQE of 5.0% with a peak emission wavelength of 917 nm, a turn-on voltage of 1.65 V, and a radiance of 2.7 W Sr-1 m-2 when driven at 4.5 V. The emission spectra of mixed Pb-Sn perovskites are tuned either by changing the Pb:Sn ratio or by incorporating bromide, and notably exhibit no phase separation during device operation. The work demonstrates that mixed Pb-Sn perovskites are promising next generation NIR emitters. PMID- 30484912 TI - Self-Assembly of a Monochromophore-Based Polymer Enables Unprecedented Ratiometric Tracing of Hypoxia. AB - The accuracy of traditional bischromophore-based ratiometric probes is always compromised by undesirable energy/charge transferring interactions between the internal reference moiety and the sensing chromophore. In this regard, ratiometric sensing with a monochromophore system is highly desirable. Herein, an unprecedented monochromophore-based ratiometric probe, which consists of a hydrophilic backbone poly(N-vinylpyrrolidone) (PVP) and single chromophore of platinum(II) tetraphenylporphyrin (Pt-TPP) is reported. Combination of the specific assembled clustering-triggered fluorescent emission (oxygen-insensitive) with the original Pt-TPP phosphorescence (oxygen-sensitive) enables successful construction of a monochromophore-based ratiometric nanosensor for directly tracing hypoxia in vivo, along with the preferable facilitation of enhanced permeation and retention effect and long excitation wavelength. The unique ratiometric signals enable the direct observation from normoxic to hypoxic environment in both living A549 cells and a tumor-bearing mice model, providing a significant paradigm of a monochromophore-based dual-emissive system with the specific assembled cluster emission. The work satisfactorily demonstrates a valuable strategy for designing monochromophore-based dual-emissive materials, and validates its utility for in vivo ratiometric biological sensing without the common energy/charge interference in bischromophore-based system. PMID- 30484913 TI - Total nutrient digestibility and small intestine starch digestion in Nellore and Angus young bulls fed a whole shelled corn diet. AB - Eighteen Nellore and 18 Angus young bulls with BW of 381 +/- 12 kg were randomly assigned into two feeding groups (whole shelled corn [WSC] or ground corn with silage [GC]) to evaluate the interaction of breed and diet on total nutrient digestibility, pancreatic alpha-amylase, and maltase activity and SLC5A1expression in the small intestine. Experimental diets (DM basis) included (a) a diet containing 30% corn silage and 70% GC and soya bean meal-based concentrate and (b) a diet containing 85% WSC and 15% of a soya bean meal- and mineral-based pelleted supplement. The treatments were Nellore fed GC diet; Nellore fed WSC diet; Angus fed GC diet; and Angus fed WSC diet. Total faecal collection for the digestibility trial occurred from day 48 until day 50 of the experimental period. Feeding the WSC diet reduced DM and NDF intake (p < 0.01). Angus had greater DM and nutrient intake in kg/day (p < 0.01). However, there was no breed effect on DM and nutrient intakes based on percentage of BW (p > 0.19). Angus had greater starch digestibility (p = 0.03) than Nellore. Cattle fed the WSC diet had greater DM, NDF and starch digestibility (p < 0.01) compared with those fed the GC diet. The activity of pancreatic alpha-amylase (U/g of protein) was greater in Nellore (p < 0.01) and was not affected by diet (p = 0.52). In duodenum, maltase activity (U/g of protein) was greater in bulls fed GC diet (p = 0.02). Expression of the gene SLC5A1was not affected by breed or diet (p > 0.05). In conclusion, Nellore had less capacity to digest starch. However, they did not have less pancreatic alpha-amylase and duodenal maltase activity compared to Angus. The use of the WSC diet increases DM and total nutrient digestibility. PMID- 30484914 TI - Approaching Ultrastable High-Rate Li-S Batteries through Hierarchically Porous Titanium Nitride Synthesized by Multiscale Phase Separation. AB - Porous architectures are important in determining the performance of lithium sulfur batteries (LSBs). Among them, multiscale porous architecutures are highly desired to tackle the limitations of single-sized porous architectures, and to combine the advantages of different pore scales. Although a few carbonaceous materials with multiscale porosity are employed in LSBs, their nonpolar surface properties cause the severe dissolution of lithium polysulfides (LiPSs). In this context, multiscale porous structure design of noncarbonaceous materials is highly required, but has not been exploited in LSBs yet because of the absence of a facile method to control the multiscale porous inorganic materials. Here, a hierarchically porous titanium nitride (h-TiN) is reported as a multifunctional sulfur host, integrating the advantages of multiscale porous architectures with intrinsic surface properties of TiN to achieve high-rate and long-life LSBs. The macropores accommodate the high amount of sulfur, facilitate the electrolyte penetration and transportation of Li+ ions, while the mesopores effectively prevent the LiPS dissolution. TiN strongly adsorbs LiPS, mitigates the shuttle effect, and promotes the redox kinetics. Therefore, h-TiN/S shows a reversible capacity of 557 mA h g-1 even after 1000 cycles at 5 C rate with only 0.016% of capacity decay per cycle. PMID- 30484915 TI - Local Electronic Structure of Molecular Heterojunctions in a Single-Layer 2D Covalent Organic Framework. AB - The synthesis of a single-layer covalent organic framework (COF) with spatially modulated internal potentials provides new opportunities for manipulating the electronic structure of molecularly defined materials. Here, the fabrication and electronic characterization of COF-420: a single-layer porphyrin-based square lattice COF containing a periodic array of oriented, type II electronic heterojunctions is reported. In contrast to previous donor-acceptor COFs, COF-420 is constructed from building blocks that yield identical cores upon reticulation, but that are bridged by electrically asymmetric linkers supporting oriented electronic dipoles. Scanning tunneling spectroscopy reveals staggered gap (type II) band alignment between adjacent molecular cores in COF-420, in agreement with first-principles calculations. Hirshfeld charge analysis indicates that dipole fields from oriented imine linkages within COF-420 are the main cause of the staggered electronic structure in this square grid of atomically-precise heterojunctions. PMID- 30484916 TI - Factors Affecting and Adjustments for Sex Differences in Current Perception Threshold With Transcutaneous Electrical Stimulation in Healthy Subjects. AB - OBJECTIVE: Current perception threshold (CPT) measurement is a noninvasive, easy, and semi-objective method for determining sensory function using transcutaneous electrical stimulation. Previous studies have shown that CPT is determined by physical characteristics, such as sex, age, physical sites, and presence of neuropathy. Although the CPT reported in males is clearly higher than that in females, the reason for this difference remains unclear. This study investigates the cause of sex-based differences in CPT and suggests an adjustment method, which may suppress the sex difference in CPT. MATERIALS AND METHODS: Electrical stimulation was applied with PainVision(r) via five sizes of circular surface electrodes. Seventy healthy participants were examined thrice under each electrode. The relationship among body water percentage, body fat percentage, and CPT was then analyzed. RESULTS: CPT values are higher in males than that in females, with statistically significant sex differences with each electrode pairs (EL 1: p < 0.001; EL 2: p = 0.006; EL 3: p < 0.001; EL 4: p < 0.001; EL 5: p < 0.001). By adjusting for body fat percentage or body water percentage, the log transformation values (CPT values) no longer exhibit sex differences with any electrode pairs (body fat: p = 0.09; body water: p = 0.08). CONCLUSION: We conclude that sensitivity for perceiving electrical stimulation can be influenced by the subjects' characteristics, such as body fat or body water percentages. PMID- 30484917 TI - Touch imprint cytology on endoscopic ultrasound fine-needle biopsy provides comparable sample quality and diagnostic yield to standard eus-fna specimens in the evaluation of solid pancreatic lesions. AB - OBJECTIVES: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is the gold standard for the diagnosis of solid pancreatic lesions (SPLs). Cytological samples can also be obtained using touch imprint cytology (TIC) on EUS fine needle biopsy (FNB) specimens. We aimed to compare sample quality and diagnostic yield of EUS-FNA-standard cytology (EUS-FNA-SC) to that of EUS-FNB-TIC in a series of patients with SPLs. METHODS: Thirty-two consecutive patients referred for EUS-tissue acquisition of SPLs who underwent rapid on-site evaluation (ROSE) of both EUS-FNA-SC and paired EUS-FNB-TIC during the same endoscopic session were retrospectively identified. Sample quality (evaluated in terms of blood contamination, presence of clots, tissue casts, cellularity, and necrosis) and diagnostic yield were compared between the techniques. RESULTS: The mean number of passes to reach diagnosis at ROSE was similar between EUS-FNA-SC and EUS-FNB TIC (1.09 +/- 0.3 vs 1.13 +/- 0.34, P = .711). EUS-FNA-SC scores of sample quality were comparable to those of EUS-FNB-TIC (blood contamination, 2.47 +/- 1.11 vs 2.25 +/- 1.14, P = .109; clots, 1.25 +/- 0.76 vs 1.19 +/- 0.69, P = .624; tissue casts, 3.56 +/- 0.88 vs 3.59 +/- 1.09, P = .872; cellularity, 2.84 +/- 1.11 vs 3.09 +/- 1.09, P = .244; necrosis, 2.25 +/- 1.08 vs 2.53 +/- 1.02 P = .059; total score, 12.38 +/- 2.88 vs 17.66 +/- 2.38, P = .536). Adequacy, sensitivity and diagnostic accuracy of the two sampling techniques were equal (93.7%, 90.6%, 90.6%, respectively). CONCLUSIONS: EUS-FNB-TIC provides comparable samples to those of EUS-FNA-SC and combines the benefits of cytology and histology for the evaluation of SPLs by employing a single needle during the same endoscopic procedure. This article is protected by copyright. All rights reserved. PMID- 30484918 TI - Oxygen-Dependent Regulation of SPI1 Type Three Secretion System by Small RNAs in Salmonella enterica serovar Typhimurium. AB - Salmonella Typhimurium induces inflammatory diarrhea and uptake into intestinal epithelial cells using the Salmonella pathogenicity island 1 (SPI1) type III secretion system (T3SS). Three AraC-like regulators, HilD, HilC, and RtsA, form a feed-forward regulatory loop that activates transcription of hilA, encoding the activator of the T3SS structural genes. Many environmental signals and regulatory systems are integrated into this circuit to precisely regulate SPI1 expression. A subset of these regulatory factors affect translation of hilD, but the mechanisms are poorly understood. Here, we identified two sRNAs, FnrS and ArcZ, which repress hilD translation, leading to decreased production of HilA. FnrS and ArcZ are oppositely regulated in response to oxygen, one of the key environmental signals affecting expression of SPI1. Mutational analysis demonstrates that FnrS and ArcZ bind to the hilD mRNA 5' UTR, resulting in translational repression. Deletion of fnrS led to increased HilD production under low aeration conditions, whereas deletion of arcZ abolished the regulatory effect on hilD translation aerobically. The fnrS arcZ double mutant has phenotypes in a mouse oral infection model consistent with increased expression of SPI1. Together, these results suggest that coordinated regulation by these two sRNAs maximizes HilD production at an intermediate level of oxygen. This article is protected by copyright. All rights reserved. PMID- 30484919 TI - Surface Atomic Regulation of Core-Shell Noble Metal Catalysts. AB - Core-shell noble metal catalysts have raised significantly attentions in the past decades, as they not only reduce the usage of noble metals effectively but also exhibit unique properties derived from synergistic effect between core and shell metals. In particular, regulating the surface structure of shells to maximize the atomic utilization efficiency of noble metals is critically important. Controlling the shell thickness of noble metal catalysts at the atomic-level as an efficient approach to realize this goal has been attracted great attentions, which involves the formation of ultrathin shell (typically 2-6 atomic layers), monolayer, or even atomically dispersed noble metal embedded in the host metal. These strategies drive the core/support metals to improve the number of active sites and the intrinsic activity of deposited noble metals remarkably, meanwhile minimize the usage of noble metals. Here, the recent advances regarding atomically control of the core-shell noble metal catalysts is reviewed, with focusing on the surface regulation. First, synthesis methods and surface structures are summarized, and then catalytic applications of these architectures are highlighted. PMID- 30484920 TI - Hysterotomy level at cesarean section and occurrence of large scar defects: a randomized single-blind trial. AB - OBJECTIVE: To study the effect of cesarean hysterotomy level on the occurrence of large uterine scar defects 6-9 months after delivery. METHODS: This was a two center, randomized, single-blind trial of a surgical procedure with masked assessment of the principal outcome under study. Women in active labor (cervix dilatation >=5 cm) were randomized into a high incision (HIGH) or a low incision (LOW) group. Hysterotomy was performed 2 cm above (HIGH) or 2 cm below (LOW) the plica vesicouterina. Women were examined with saline contrast sonohysterography to assess the appearance of the hysterotomy scar 6-9 months after delivery. The main outcome was occurrence of a large scar defect. A scar defect was defined as large if the remaining myometrial thickness over the defect was <=2.5 mm. Secondary outcomes were operative complications, perinatal- and long-term outcomes. RESULTS: 122 patients were included in the trial and 114 were assessed with ultrasound. Large scar defects were seen in 4 (7%) of 55 women in the high incision group and in 24 (41%) of 59 women in the low incision group (P< 0.001) odds ratio 8.7 (95% CI 2.8-27.4). CONCLUSION: The cesarean hysterotomy level in women in advanced labor is associated with the occurrence of large scar defects detected by transvaginal ultrasound 6-9 months after delivery. This article is protected by copyright. All rights reserved. PMID- 30484921 TI - Rare presentation of immunoglobulin A vasculitis as acute pancreatitis in a 10 year-old girl. PMID- 30484922 TI - Non-indicated acid-suppression prescribing in a tertiary paediatric hospital: An audit and costing study. AB - AIM: To quantify (i) indicated versus non-indicated prescribing of acid suppression therapies (AST) in a tertiary paediatric hospital; (ii) patient, provider and hospital factors associated with non-indicated prescribing; and (iii) medication costs. METHODS: This was a prospective, electronic medical audit conducted at The Royal Children's Hospital (RCH) Melbourne in August-September 2016. Proton pump inhibitor (PPI) and histamine-2 receptor antagonist (H2 RA) prescriptions were extracted, with relevant patient, provider and hospital data. Logistic regression analysis of variables associated with indicated and non indicated prescribing was undertaken. Costs of indicated and non-indicated prescriptions were estimated, with annual costs projected. RESULTS: There was more non-indicated than indicated prescribing across inpatient, outpatient and emergency department settings. Of the total 303 prescriptions analysed, 238 (78.5%) were non-indicated. Gastrostomy presence (odds ratio (OR) 5.51 (1.96 15.46), P = 0.001), consultant providers (OR 2.69 (1.23-5.87), P = 0.01) and inpatient setting (OR 2.35 (1.16-4.77), P = 0.02) were all associated with a higher likelihood of non-indicated prescribing. The child having a predisposing diagnosis was significantly associated with indicated prescribing (OR 0.41 (0.21 0.80), P = 0.009). A total of 75% of hospital and patient spending was for non indicated prescriptions. Annual costs of non-indicated AST for Melbourne's RCH were projected to be $15 493. CONCLUSIONS: Non-indicated acid-suppression prescribing is common in a tertiary paediatric hospital and associated with gastrostomy presence, consultant providers and inpatient status. Future research should use qualitative methods to understand clinician and patient drivers of prescribing and use this information to develop and test targeted solutions to reduce non-indicated AST prescribing. PMID- 30484923 TI - A Surface-Functionalized Ionovoltaic Device for Probing Ion-Specific Adsorption at the Solid-Liquid Interface. AB - Aqueous ion-solid interfacial interactions at an electric double layer (EDL) are studied in various research fields. However, details of the interactions at the EDL are still not fully understood due to complexity induced from the specific conditions of the solid and liquid parts. Several technical tools for ion-solid interfacial probing are experimentally and practically proposed, but they still show limitations in applicability due to the complicated measurements. Recently, an energy conversion device based on ion dynamics (called ionovoltaic device) was also introduced as another monitoring tool for the EDL, showing applicability as a novel probing method for interfacial interactions. Herein, a monitoring technique for specific ion adsorption (Cu2+ and Pb2+ in the range of 5 * 10-6 1000 * 10-6 m) in the solid-liquid interface based on the ionovoltaic device is newly demonstrated. The specific ion adsorption and the corresponding interfacial potentials profiles are also investigated to elucidate a working mechanism of the device. The results give the insight of molecular-level ion adsorption through macroscopic water-motion-induced electricity generation. The simple and cost effective detection of the device provides an innovative route for monitoring specific adsorption and expandability as a monitoring tool for various solid liquid interfacial phenomena that are unrevealed. PMID- 30484924 TI - Identification of a novel sperm class and its role in fertilization in Drosophila. AB - In many species, males have evolved to produce a sterile sperm (parasperm) in conjunction with fertilizing sperm (eusperm). Here, we document evidence of males depositing two morphologically distinct types of parasperm (1 and 2) into the female reproductive tract in Drosophila pseudoobscura. These parasperm differ in length, shape, amount produced, amount in long-term storage, and may have separate roles in ensuring male fertilization success. While both parasperm types protect eusperm from female spermicides, only parasperm 2, which has a corkscrew shape, is associated with sperm competition. Increased production of parasperm 2 is also negatively correlated with the eusperm and parasperm 1 production. Thus, selection may be acting on parasperm production in the presence of sperm competition. Our findings show how both sperm competition and cryptic female choice may be acting in conjunction to influence the evolution of ejaculate composition. Our identification and characterization of two distinct parasperm morphs will enhance the ability for further evaluation of parasperm's role in fertilization. This article is protected by copyright. All rights reserved. PMID- 30484925 TI - Association Between Early Implant Failure and Prosthodontic Characteristics. AB - PURPOSE: To identify associations between early implant failure and prosthodontic characteristics that could be used to guide subsequent continuous quality improvement efforts of patient care. MATERIALS AND METHODS: An implant-level analysis was performed in which data were abstracted from a prospective clinical database of all adult patients treated with implants and followed up from January 2000 through December 2014 at the Department of Dental Specialties at Mayo Clinic in Rochester, Minnesota. These data were used to determine time to implant failure. Associations between prosthodontic characteristics and early implant failure were evaluated with Cox proportional hazards regression models and summarized with hazard ratios (HRs) and 95% CIs. RESULTS: Among 8762 implants in 2787 patients, 395 (4.5%) failed within the first year of placement at a mean (SD) of 127 (97) days (range, 2-364 days). Univariable analysis showed no associations between early implant failure and use of a cover screw, prosthesis, or definitive or provisional prosthesis at implant placement. Three of 25 single crowns failed, and use of a single crown was significantly associated with early implant failure (HR, 3.94; 95% CI, 1.08-14.35; P = 0.04). This study identified no significant associations between prosthodontic characteristics identified after implant placement and early implant failure. CONCLUSIONS: Use of a prosthesis at implant placement, use of a definitive or provisional prosthesis, and early mechanical complications were not associated with increased risk of early implant failure. Quality improvement efforts should focus on aspects of decision making that aim to decrease surgical complications. This article is protected by copyright. All rights reserved. PMID- 30484926 TI - Patterns of transposable element variation and clinality in Drosophila. AB - Natural populations often exist in spatially diverse environments and may experience variation in the strength and targets of natural selection across their ranges. Drosophila provides an excellent opportunity to study the effects of spatially varying selection in natural populations, as both D. melanogaster and D. simulans live across a wide range of environments in North America. Here, we characterize patterns of variation in transposable elements (TEs) from six populations of D. melanogaster and nine populations of D. simulans sampled from multiple latitudes across North America. We find a nearly two-fold excess of TEs in D. melanogaster relative to D. simulans, with this difference largely driven by TEs segregating at the lowest and highest allele frequencies. We find no effect of latitude on either total TE abundance or average TE allele frequencies in either species. Moreover, we show that, as a class of mutations, the most common patterns of TE variation do not coincide with the sampled latitudinal gradient, nor are they consistent with local adaptation acting on environmental differences found in the most extreme latitudes. We also do not find a cline in ancestry for North American D. melanogaster-for either TEs or SNPs-suggesting a limited role for demography in shaping patterns of TE variation. Though we find little evidence for widespread clinality among TEs in Drosophila, this does not necessarily imply a limited role for TEs in adaptation. We discuss the need for improved models of adaptation to large-scale environmental heterogeneity, and how these might be applied to TEs. This article is protected by copyright. All rights reserved. PMID- 30484927 TI - Hospitalisation of adults with Down syndrome: lesson from a 10-year experience from a community hospital. AB - BACKGROUND: Life expectancy of individuals with Down syndrome (DS) has improved significantly over the past decades. However, there are sparse data documenting the co-morbidities and hospitalisation of adult patients with DS in the literature. The aim of this study was to characterise the co-morbidities and pattern of hospitalisation in adult patients with DS during a 10-year period at the community hospital as well as to compare hospitalisation parameters with the general adult population during the same years. METHOD: We reviewed the medical records of 81 hospitalisations from 37 patients with DS aged 21 to 68 years at Metrowest Medical Center during a 10-year period and compared with those of the general adult population during the same time. Co-morbidities were also described. RESULTS: Adults with DS had a mean age at admission of 48.6 +/- 8.8 years with the median length of stay of 3 days (interquartile range 4 days). Male patients were hospitalised longer than female patients (mean 5.0 vs. 2.8 days; P < 0.05), and patients who lived at home were admitted at earlier ages than those who came from residential healthcare facility (mean 41.5 vs. 52.2 years; P < 0.001). The most common cause of hospitalisation was pneumonia/aspiration syndrome (29.6%), and the most common co-morbidity was gastroesophageal reflux disease (GERD)/dysphagia (70.3%). Presence of GERD/dysphagia or seizure disorder was significantly associated with multiple admission and readmission within 1 month (P < 0.05). The mortality rate was 4.9%, and the rate of intensive care unit admission was 8.6%. CONCLUSIONS: Our cohort did not show statistically significant different hospitalisation parameters such as inpatient mortality and average length of stay when compared with general adult population hospitalised at the same years. The care of adult patients with DS presents challenges in internal medicine due to its unique co-morbid profile and signifies the importance of multidisciplinary approach. In order to improve the care of this patient population, their co-morbidities, particularly GERD/dysphagia and seizure disorder, should be optimally managed and comprehensively addressed when patients are hospitalised. PMID- 30484928 TI - Impaired generalization of reward but not loss in obsessive-compulsive disorder. AB - BACKGROUND: Generalizing from past experiences can be adaptive by allowing those experiences to guide behavior in new situations. Generalizing too much, however, can be maladaptive. For example, individuals with pathological anxiety are believed to overgeneralize emotional responses from past threats, broadening their scope of fears. Whether individuals with pathological anxiety overgeneralize in other situations remains unclear. METHODS: The present study (N = 57) used a monetary sensory preconditioning paradigm with rewards and losses to address this question in individuals with obsessive-compulsive disorder (OCD) and social anxiety disorder (SAD), comparing them to healthy comparison subjects (HC). In all groups, we tested direct learning of associations between cues and reward vs. loss outcomes, as well as generalization of learning to novel choice options. RESULTS: We found no differences between the three groups in the direct learning of stimuli with their outcomes: all subjects demonstrated intact stimulus-response learning by choosing rewarding options and avoiding negative ones. However, OCD subjects were less likely to generalize from rewards than either the SAD or HC groups, and this impairment was not found for losses. Additionally, greater deficits in reward generalization were correlated with severity of threat estimation, as measured by a subscale of the Obsessive Beliefs Questionnaire, both within OCD and across all groups. CONCLUSIONS: These findings suggest that a compromised ability to generalize from rewarding events may impede adaptive behavior in OCD and in those susceptible to high estimation of threat. PMID- 30484929 TI - Grain-Boundary-Induced Drastic Sensing Performance Enhancement of Polycrystalline Microwire Printed Gas Sensors. AB - The development of materials with high efficiency and stable signal output in a bent state is important for flexible electronics. Grain boundaries provide lasting inspiration and a promising avenue for designing advanced functionalities using nanomaterials. Combining bulk defects in polycrystalline materials is shown to result in rich new electronic structures, catalytic activities, and mechanical properties for many applications. However, direct evidence that grain boundaries can create new physicochemical properties in flexible electronics is lacking. Here, a combination of bulk electrosensitive measurements, density functional theory calculations, and atomic force microscopy technology with quantitative nanomechanical mapping is used to show that grain boundaries in polycrystalline wires are more active and mechanically stable than single-crystalline wires for real-time detection of chemical analytes. The existence of a grain boundary improves the electronic and mechanical properties, which activate and stabilize materials, and allow new opportunities to design highly sensitive, flexible chemical sensors. PMID- 30484930 TI - Analysis of 17 948 pediatric patients undergoing procedural sedation with a combination of intranasal dexmedetomidine and ketamine. AB - BACKGROUND: Intranasal procedural sedation using dexmedetomidine is well described in the literature. The combination of intranasal dexmedetomidine and ketamine is a novel approach for which there are little data on the rate of successful sedation or adverse events. OBJECTIVES: The aim of this study is to evaluate the rate of successful sedation and adverse events of intranasal procedural sedation using a combination of dexmedetomidine and ketamine for diagnostic examination in children. METHODS: This was a retrospective study and data were collected after ethics approval. A total of 17 948 pediatric patients (7718 females, 10 230 males) in a tertiary hospital in China were evaluated. Patients received a combination of 2 MUg kg-1 of dexmedetomidine and 1 mg kg-1 of ketamine intranasally for procedural sedation. The level of sedation and recovery was assessed by the Modified Observer Assessment of Alertness/Sedation scale and the Modified Aldrete Score. RESULTS: The rate of intranasal sedation success was 93% (16691/17948), intranasal sedation rescue was 1.8% (322/17948), and intranasal sedation failure was 5.2% (935/17948). Sedation success was defined as successful completed the diagnostic examination and obtained adequate diagnostic quality images and reports. Intranasal sedation success, rescue and failure were respectively defined as sedation success with intranasal a single dose, additional bolus dose and the need for intravenous (IV) medications/inhalation agents. Median sedation time was 62 min (interquartile range: 55-70 min), median time for onset of sedation was 15 min (interquartile range: 15-20 min), and median sedation recovery time was 45 min (interquartile range: 38-53 min). Incidence of adverse events was low (0.58%; 105/17948), with major and minor adverse event being reported in 0.02% (4/17948) and 0.56% (101/17948) patients, respectively. Postoperative nausea and vomiting was the most common (0.3%; 53/17948) minor adverse event. CONCLUSION: Procedural sedation using a combination of intranasal dexmedetomidine and ketamine is associated with acceptable effectiveness and low rates of adverse events. PMID- 30484931 TI - Neonatal Pain: Knowledge and Perception Among Pediatric Doctors in Malaysia. AB - BACKGROUND: Inadequate pain management is linked to potential neuro-developmental and behavioral problems. Sufficient knowledge in neonatal pain is required to facilitate optimal pain management. This study aimed to assess the knowledge and perception of pain experienced by neonates requiring intensive care among pediatric doctors working in a Level III neonatal intensive care unit in Malaysian hospitals. METHODS: This was a cross-sectional study conducted over a period of 18 months. A self-administered questionnaire assessing knowledge and perception on neonatal pain was used. RESULTS: Twenty-four hospitals participated in the study, with 423 respondents. The response rate was 85%. One-hundred and ninety-seven (47%) respondents were aware of available tools used for neonatal pain assessment. However, only 6% used them in daily practice. Doctors with >4 years of experience in neonatal care had better awareness of available pain assessment tool (59.4% vs 40.9%, p = 0.001). Sixteen statements regarding knowledge were assessed. Mean score obtained was 10.5(SD 2.5). Consultants/specialists obtained a higher mean score compared to medical officers (11.9 versus 10.4, p< 0.001]. More than 80% of respondents were able to discriminate painful from non-painful procedures. CONCLUSION: Clinicians involved in neonatal care, especially those with longer experience were, knowledgeable about neonatal pain. However, gaps between knowledge and its application remain. Implementation of clinical guidelines to improve the quality of assessment and adequate pain management in neonates is recommended. This article is protected by copyright. All rights reserved. PMID- 30484932 TI - What is the protective effect of krill oil on rat ovary against ischemia reperfusion injury? AB - AIM: In this study, we aimed to investigate the protective effect of krill oil (KO) against ischemia-reperfusion (I/R) injury on rat ovary. METHODS: This study was conducted with 32 Wistar Albino rats. Rats were divided into four groups, with eight rats in each group-as follows: Sham group, I/R group, I/R + low dose KO group (50 mg) and I/R + high dose KO group (500 mg). The histopathological and follicle counts were performed on the right ovary. The total antioxidant status, total oxidant status and oxidative stress index were evaluated on the left ovary. And also serum N-thiol level, serum T-thiol level, serum disulfide (SDS) level, serum disulfide/N-thiol and serum disulfide/T-thiol ratios were evaluated too. RESULTS: A statistically significant difference was determined between the I/R group and all the other groups for all parameters. There was significant difference between KO groups and the Sham group for the parameters of serum N thiol, serum T-thiol, SDS, serum disulfide/N-thiol and serum disulfide/T-thiol. SDS, total oxidant status and oxidative stress index were determined to be the highest in the I/R group and the lowest in the low dose KO group. The total antioxidant status values were found to be the highest in the high dose KO group and the lowest in the I/R group. Follicle counts and histological injury scores showed no significant difference between Sham and KO groups. CONCLUSION: This study demonstrated that KO has beneficial effects on decreasing the injury after I/R on rat ovary. PMID- 30484933 TI - Solitary colorectal liver metastasis after curative intent surgery: prognostic factors affecting outcomes and survival. AB - BACKGROUND: The aim of this study was to identify the prognostic factors affecting recurrence and survival in patients who underwent curative intent surgery for colorectal cancer (CRC) with a single liver metastasis. METHODS: Between January 2006 and August 2012, we retrospectively evaluated 141 patients for CRC with single liver metastasis underwent curative intent surgery for colon and liver simultaneously. Some patients (11.3%) had radiofrequency ablation as an option. RESULTS: The 5-year disease-free and overall survival (OS) rates were 38.9% and 59.6%, respectively. Recurrence occurred in 77 (54.6%) patients after surgery. Multivariate analysis identified node positivity and no adjuvant chemotherapy as independent risk factors for OS. We analyzed the OS risk factors in 76 recurred patients from the time of recurrence. Multivariate analysis revealed the following significant risk factors for OS after recurrence: a high serum carcinoembryonic antigen concentration at the time of recurrence, the treatment type after recurrence (chemotherapy or no treatment) and a left hepatic metastasis. CONCLUSION: Patients who underwent a curative resection for CRC with a single liver metastasis had a relatively favourable prognosis; in these patients, node positivity and no adjuvant chemotherapy were independent prognostic factors for OS. Furthermore, a high serum carcinoembryonic antigen concentration at the time of recurrence, the treatment type after recurrence (chemotherapy or no treatment) and a left hepatic metastasis may be independent prognostic factors for OS in patients with recurrence. The left hepatic metastasis group tended to have a multiple hepatic relapse more frequently than the right hepatic metastasis group in cases of isolated hepatic relapse. PMID- 30484934 TI - Preconditioning strategies for improving the survival rate and paracrine ability of mesenchymal stem cells in acute kidney injury. AB - Acute kidney injury (AKI) is a common, severe emergency case in clinics, with high incidence, significant mortality and increased costs. Despite development in the understanding of its pathophysiology, the therapeutic choices are still confined to dialysis and renal transplantation. Considering their antiapoptotic, immunomodulatory, antioxidative and pro-angiogenic effects, mesenchymal stem cells (MSCs) may be a promising candidate for AKI management. Based on these findings, some clinical trials have been performed, but the results are contradictory (NCT00733876, NCT01602328). The low engraftment, poor survival rate, impaired paracrine ability and delayed administration of MSCs are the four main reasons for the limited clinical efficacy. Investigators have developed a series of preconditioning strategies to improve MSC survival rates and paracrine ability. In this review, by summarizing these encouraging studies, we intend to provide a comprehensive understanding of various preconditioning strategies on AKI therapy and improve the prognosis of AKI patients by regenerative medicine. PMID- 30484935 TI - Effect of a computerized decision support system on potentially inappropriate medication prescriptions for elderly patients in Thailand. AB - RATIONALE, AIMS, AND OBJECTIVES: The prescription of potentially inappropriate medication (PIM) is a global issue associated with increased adverse drug events, mortality, and health care expenditure. Computerized decision support system (CDSS) for the detection of PIM is a novel alert system in Thailand for reducing PIM prescriptions. The aim of this study was to evaluate the effect of a CDSS on PIM prescriptions for elderly patients in Thai community hospitals. METHODS: The study design comprised two phases with a duration of 12 months each: pre-CDSS implementation (October 2015-March 2016) and post-CDSS implementation (October 2016-March 2017). Medical services and prescription claims data from four hospitals were used to calculate the prevalence of PIM prescriptions among elderly patients aged 60 years and older. Chi-square tests were used to analyse changes in PIM prescriptions across hospitals post CDSS. RESULTS: The overall prevalence of PIM prescriptions post-CDSS implementation significantly decreased from 87.7% to 74.4%. The severity of mild and moderate PIMs was significantly reduced from 71.9% to 49.0% and from 64.5% to 48.7%, respectively. All hospitals had only one severe PIM, which was hyoscine. It was reduced from 4.7% to 1.5%, but the change was not significant (P = 0.74). The proportion of frequently prescribed PIMs in all PIM levels was significantly decreased, regardless of existing alternative medications. CONCLUSIONS: Specific CDSS for PIM in community hospital setting was associated with a reduction of PIM prescription in elderly patients. This CDSS can change physician's prescription behaviour to avoid inappropriate medications. PMID- 30484936 TI - An interaction between climate change and infectious disease drove widespread amphibian declines. AB - Climate change might drive species declines by altering species interactions, such as host-parasite interactions. However, few studies have combined experiments, field data, and historical climate records to provide evidence that an interaction between climate change and disease caused any host declines. A recently proposed hypothesis, the thermal mismatch hypothesis, could identify host species that are vulnerable to disease under climate change because it predicts that cool- and warm-adapted hosts should be vulnerable to disease at unusually warm and cool temperatures, respectively. Here, we conduct experiments on Atelopus zeteki, a critically endangered, captively bred frog that prefers relatively cool temperatures, and show that frogs have high pathogen loads and high mortality rates only when exposed to a combination of the pathogenic chytrid fungus (Batrachochytrium dendrobatidis) and high temperatures, as predicted by the thermal mismatch hypothesis. Further, we tested various hypotheses to explain recent declines experienced by species in the amphibian genus Atelopus that are thought to be associated with B. dendrobatidis and reveal that these declines are best explained by the thermal mismatch hypothesis. As in our experiments, only the combination of rapid increases in temperature and infectious disease could account for the patterns of declines, especially in species adapted to relatively cool environments. After combining experiments on declining hosts with spatiotemporal patterns in the field, our findings are consistent with the hypothesis that widespread species declines, including possible extinctions, have been driven by an interaction between increasing temperatures and infectious disease. Moreover, our findings suggest that hosts adapted to relatively cool conditions will be most vulnerable to the combination of increases in mean temperature and emerging infectious diseases. PMID- 30484937 TI - International Journal of Clinical Practice: What was hot in 2018? AB - Last month we reported on a bibliometric experiment examining if articles in the International Journal of Clinical Practice designated as "Editor's Choice" are downloaded. This article is protected by copyright. All rights reserved. PMID- 30484938 TI - Spontaneous biliary peritonitis and retroperitoneal biloma: an unusual presentation of a common disease. PMID- 30484940 TI - Aortic saddle embolism following pneumonectomy for synovial sarcoma of lung. PMID- 30484939 TI - Fabrication and performance evaluation of blood compatible hemodialysis membrane using carboxylic multiwall carbon nanotubes and low molecular weight polyvinylpyrrolidone based nanocomposites. AB - This study focused to optimize the performance of polyethersulfone (PES) hemodialysis (HD) membrane using carboxylic functionalized multiwall carbon nanotubes (c-MWCNT) and lower molecular weight grade of polyvinylpyrrolidone (PVP k30). Initially, MWCNT were chemically functionalized by acid treatment and nanocomposites (NCs) of PVP-k30 and c-MWCNT were formed and subsequently blended with PES polymer. The spectra of FTIR of the HD membranes revealed that NCs has strong hydrogen bonding and their addition to PES polymer improved the capillary system of membranes as confirmed by Field Emission Scanning Electron Microscope (FESEM) and leaching of the additive decreased to 2% and hydrophilicity improved to 22%. The pore size and porosity of NCs were also enhanced and rejection rate was achieved in the establish dialysis range (<60 kDa). The antifouling studies had shown that NCs membrane exhibited 30% less adhesion of protein with 80% flux recovery ratio. The blood compatibility assessment disclosed that NCs based membranes showed prolonged thrombin and prothrombin clotting times, lessened production of fibrinogen cluster, and greatly suppressed adhesion of blood plasma than a pristine PES membrane. The results also unveiled that PVP-k30/NCs improved the surface properties of the membrane and the urea and creatinine removal increased to 72% and 75% than pure PES membranes. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2018. PMID- 30484941 TI - Surgical ultrasonography at the bedside: a comparison of surgical trainees with trained sonographers for symptomatic cholelithiasis - a first Australian experience. AB - BACKGROUND: Symptomatic cholelithiasis accounts for a significant burden of emergency general surgical presentations in Australia and the Western population. Access to hepatobiliary ultrasonography to facilitate diagnosis can lead to delays in timely treatment. Surgical ultrasonography at the bedside (SUB) can mitigate this barrier to patient care. This study assessed the diagnostic accuracy of SUB by trainees versus formal ultrasonographer or computed tomography examination for suspected symptomatic cholelithiasis. METHODS: A prospective non inferiority study of emergency patient admissions with abdominal pain in two tertiary referral hospitals during July 2017 to October 2018 was performed. Results of SUB were compared with accredited radiographer ultrasonography or computed tomography and histopathological assessment. Positive findings at SUB for symptomatic cholelithiasis included: cholelithiasis, gallbladder wall thickness ?3 mm, pericholecystic fluid or sonographic Murphy's sign. RESULTS: One hundred patients with epigastric or right upper quadrant pain underwent SUB. Mean patient age was 49 years (range 20-90 years), with 61 females and 39 males. Sensitivity and specificity for diagnosis of symptomatic cholelithiasis was 94.9% and 100% for SUB and 98.7% and 100% for accredited radiographers. Diagnostic accuracy was 96% for SUB and 99% for radiographer ultrasonography. Positive predictive value and negative predictive value were 100% and 84.6% for SUB and 100% and 96% for radiographers. The inter-rater reliability for features compatible with the diagnosis of symptomatic cholelithiasis was good with a kappa of 0.758 (95% confidence interval 0.587-0.929, P < 0.001). CONCLUSION: This first Australian experience demonstrates that general surgical trainees can accurately diagnose cholecystitis with SUB and this assessment is not inferior and has substantial agreement with accredited radiographer ultrasonography. PMID- 30484942 TI - Combined use of Kirschner wires and hinged external fixator for capitellar and trochlear fractures: a minimum 24-month follow-up. AB - BACKGROUND: Open reduction and internal fixation is the adequate treatment for capitellar and trochlear fractures. Given the low incidence of this type of fractures, it is difficult to constitute a universally accepted method for fixation. Thus, we hypothesised that combined use of Kirschner wires (K-wires), absorbable rods and sutures for fixation and post-operative hinged external fixator for early rehabilitation exercise can restore elbow joint function well. METHODS: This retrospective study included 20 patients with a mean age of 48.3 (range 16-76) years. According to the Dubberley classification, fractures were classified on plain radiographs, computed tomography images and intra-operative findings. All patients were evaluated by the range of motion of the elbow and the Broberg-Morrey score. RESULTS: All fractures had healed without non-union, and the average time was 13.6 (range 8-17) weeks. The mean follow-up was 42.5 (range 24-80) months. The mean flexion was 117.1 degrees (range 90 degrees -135 degrees ), and the mean extension was 17.5 degrees (range 0 degrees -45 degrees ). The mean pronation was 74.4 degrees (range 45 degrees -85 degrees ), and the mean supination was 84.3 degrees (range 60 degrees -90 degrees ). The average Broberg Morrey score was 86.2 (range 68-98) points with 10 excellent, 7 good and 3 fair results. CONCLUSION: K-wires, absorbable rods and sutures combined with hinged external fixator are feasible for fixation of capitellar and trochlear fractures. However, due to the absence of a control group (such as Herbert screw fixation), comparative studies are still needed to demonstrate the safety and reliability of K-wires for fixation. PMID- 30484943 TI - Sexual selection and its evolutionary consequences in female animals. AB - For sexual selection to act on a given sex, there must exist variation in the reproductive success of that sex as a result of differential access to mates or fertilisations. The mechanisms and consequences of sexual selection acting on male animals are well documented, but research on sexual selection acting on females has only recently received attention. Controversy still exists over whether sexual selection acts on females in the traditional sense, and over whether to modify the existing definition of sexual selection (to include resource competition) or to invoke alternative mechanisms (usually social selection) to explain selection acting on females in connection with reproduction. However, substantial evidence exists of females bearing characters or exhibiting behaviours that result in differential reproductive success that are analogous to those attributed to sexual selection in males. Here we summarise the literature and provide substantial evidence of female intrasexual competition for access to mates, female intersexual signalling to potential mates, and postcopulatory mechanisms such as competition between eggs for access to sperm and cryptic male allocation. Our review makes clear that sexual selection acts on females and males in similar ways but sometimes to differing extents: the ceiling for the elaboration of costly traits may be lower in females than in males. We predict that current and future research on female sexual selection will provide increasing support for the parsimony and utility of the existing definition of sexual selection. PMID- 30484945 TI - Diagnosis and Treatment of Asthma in Nonpregnant Women. AB - Asthma is a common condition affecting 8.3% of the adult population in the United States. The disease is characterized by chronic airway inflammation that leads to airway hyperresponsiveness and obstruction that results in coughing, wheezing, shortness of breath, and a feeling of chest tightness. The diagnosis and classification of asthma is based on reported symptoms, physical examination findings, and spirometry. Pharmacologic therapy is prescribed using a stepwise approach that begins with inhaled short-acting beta2 -agonists for intermittent asthma with the addition of daily inhaled corticosteroids for more persistent cases. Individuals with asthma are reevaluated on a regular basis to monitor symptoms, and pharmacologic treatments are adjusted as needed. Familiarity with the stepwise approach for asthma management and confidence in the efficacy and safety profiles of inhaled medications will assist clinicians in successful management of asthma in the primary care setting. PMID- 30484944 TI - Evolutionary history of fire-stimulated resprouting, flowering, seed release and germination. AB - Fire has shaped the evolution of many plant traits in fire-prone environments: fire-resistant tissues with heat-insulated meristems, post-fire resprouting or fire-killed but regenerating from stored seeds, fire-stimulated flowering, release of on-plant-stored seeds, and germination of soil-stored seeds. Flowering, seed release and germination fit into three categories of response to intensifying fire: fire not required, weakly fire-adapted or strongly fire adapted. Resprouting also has three categories but survival is always reduced by increasing fire intensity. We collated 286 records for 20 angiosperm and two gymnosperm families and 50 trait assignments to dated phylogenies. We placed these into three fire-adapted trait types: those associated with the origin of their clade and the onset of fire-proneness [primary diversification, contributing 20% of speciation events over the last 120 million years (My)], those originating much later coincident with a change in the fire regime (secondary diversification, 30%), and those conserved in the daughter lineage as already adapted to the fire regime (stabilisation, 50%). All four fire-response types could be traced to >100 My ago (Mya) with pyrogenic flowering slightly younger because of its dependence on resprouting. There was no evidence that resprouting was always an older trait than either seed storage or non-sprouting throughout this period, with either/both ancestral or derived in different clades and times. Fire-adapted traits evolved slowly in the Cretaceous, 120-65 Mya, and rapidly but fitfully in the Cenozoic, 65-0 Mya, peaking over the last 20 My. The four trait-types climaxed at different times, with the peak in resprouter speciation over the last 5 My attributable to fluctuating growing conditions and increasing savanna grasslands unsuitable for non-sprouters. All experienced a trough in the 40-30-Mya period following a reduction in world temperatures and oxygen levels and expected reduced fire activity. Thick bark and serotiny arose in the Mid-Cretaceous among extant Pinaceae. Heat-stimulated germination of hard seeds is ancestral in the 103-My-old Fabales. Smoke-(karrikin)-stimulated germination of non-hard seeds is even older, and includes the 101-My-old Restionaceae-Anarthriaceae. A smoke/karrikin response is detectable in some fire free lineages that prove to have a fire-prone ancestry. Among clades that are predominantly fire-prone, absence of fire-related traits is the advanced condition, associated either with increased fire frequency (loss of serotiny and soil storage), or migration to fire-free habitats (loss of thick bark, pyrogenic flowering, serotiny or soil storage). Protea (Africa) and Hakea (Australia) illustrate the importance of stabilisation processes between resprouting/non sprouting in accounting for speciation events over the last 20 My and highlight the frequent interchange possible between these two traits. Apart from Pinus, most ancestral trait reconstruction relative to fire has been conducted on predominantly Southern Hemisphere clades and this needs to be redressed. Despite these limitations, it is clear that fire has had a profound effect on fire related trait evolution worldwide, and set the platform for subsequent evolution of many non-fire-related traits. Genetics of the triggering mechanisms remain poorly understood, except the karrikin system for smoke-stimulated germination. We exhort biologists to include fire-proneness and fire-related traits in their thinking on possible factors controlling the evolution of plants. PMID- 30484946 TI - Sesquiterpenoids Produced by the Combination of Two Sesquiterpene Cyclases with Promiscuous Myxobacterial CYP260B1. AB - Sesquiterpenes represent a class of important terpenoids with high structural diversity and a wide range of applications. The cyclized core-skeletons are generated by sesquiterpene cyclases, and the structural diversity is further increased by a series of modification steps. Cytochromes P450 (P450s) are a class of monooxygenases and one of the main contributors for the structure diversity of natural products. Some of these P450s show a broad substrate range and might be promising candidates for the implementation of cascade reactions. In this study, a combinatorial biosynthesis strategy was utilized by the combination of a promiscuous myxobacterial P450 (CYP260B1) with two sesquiterpene cyclases (FgJ01056, FgJ09920) of filamentous fungi. Two oxygenated products, culmorin, culmorone, and a new compound, koraidiol, were successfully generated and characterized. This approach suggests the potential use of non-cognate P450s to produce novel oxygenated terpenoids, or to generate a novel biosynthetic route for known terpenoids by a combinatorial biosynthesis strategy. PMID- 30484947 TI - A head-to-head comparison of personal and professional continuous glucose monitoring systems in people with type 1 diabetes: hypoglycaemia remains the weak spot. AB - To compare the performance of a professional (proCGM) and a personal continuous glucose monitoring (persCGM) system worn in parallel under standardised conditions in individuals with type 1 diabetes (T1D). Two CGM systems (iPro2 - proCGM; Minimed 640G - persCGM) worn in parallel using the same sensor (Enlite 2) were compared. Ten people with T1D were included in this single-centre, open label study in which CGM performance was evaluated. The study consisted of a 24 hour inpatient phase (meals, exercise, glycaemic challenges) and a 4-day home phase. Analyses included fulfilment of ISO 15197:2013 criteria, mean absolute relative difference (MARD), Parkes Error Grid and Bland-Altman plots. During the inpatient stay ISO 15197:2013 criteria fulfilment was 58.4% (proCGM) and 57.8% (persCGM). At home the systems met ISO 15197:2013 criteria by 66.5% (proCGM) and 65.3% (persCGM). No difference of MARD in inpatient phase (19.1+/-16.7% vs. 19.0+/-19.6; p=0.83) and home-phase (18.6+/-26.8% vs. 17.4+/-21.3%, p=0.87) was observed. All sensors performed less accurate during hypoglycaemia. ProCGM and persCGM showed similar performance during day- and night-time for the inpatient and the home-phase. However, sensor performance was reduced during hypoglycaemia for both systems. This article is protected by copyright. All rights reserved. PMID- 30484948 TI - Ketogenic diet treatment in recurrent diffuse intrinsic pontine glioma in children: A safety and feasibility study. AB - BACKGROUND: The mean overall survival rate of children with diffuse intrinsic pontine glioma (DIPG) is 9-11 months, with current standard treatment with fractionated radiotherapy and adjuvant chemotherapy. So far, novel therapeutic strategies have not yet resulted in significantly better survival. The main source of energy for glioblastoma cells is glucose. Therefore, metabolic alterations induced by the use of the extremely carbohydrate-restricted ketogenic diet (KD) as adjuvant therapy are subject of interest in cancer research. PROCEDURE: This study explores the safety and feasibility of the KD in children with recurrent DIPG and no remaining treatment options. Safety was defined as the number of adverse effects. Feasibility was defined as the number of patients who were able to use the KD for three months. Coping of patients and parents was measured with questionnaires. RESULTS: Three of 14 children referred to our hospital between 2010 and 2015 were included. Two patients completed the study, and one died before the end of the study. Hospitalizations were needed for placing a nasogastric tube (n = 1) and epileptic seizures (n = 1). Adverse effects related to the diet were mild and transient. Parents were highly motivated during the study. CONCLUSION: Use of KD is safe and feasible, but the effect on survival has to be proven in a larger cohort of children who start the KD earlier after diagnosis, preferably as adjuvant therapy to fractionated radiotherapy. PMID- 30484949 TI - Reduction of routine radiographs in the follow-up of distal radius and ankle fractures: Barriers and facilitators perceived by orthopaedic trauma surgeons. AB - RATIONALE, AIMS, AND OBJECTIVES: Studies suggest that routine radiographs during follow-up of distal radius and ankle fractures result in increased radiation exposure and health care costs, without influencing treatment strategies. Encouraging clinicians to omit these routine radiographs is challenging, and little is known about barriers and facilitators that influence this omission. Therefore, this study aims to identify barriers and facilitators among orthopaedic trauma surgeons that might prove valuable towards the design of a deimplementation strategy. METHODS: A mixed-method approach was used. First, interviews were conducted with orthopaedic trauma surgeons and patients (n = 16). Subsequently, a questionnaire was developed. This questionnaire was presented to 228 orthopaedic trauma surgeons in the Netherlands. Regression analyses were performed in order to identify which variables were independently associated to the decision to stop performing routine radiographs 6 and 12 weeks after trauma if proven not effective in a large randomized controlled trial. RESULTS: In total, 130 (57%) respondents completed the questionnaire. Of these, 71% indicated they would stop ordering routine radiographs if they were proven not effective. Three facilitators were independent predictors for the intention to omit routine radiographs: This will "lead to lower health care costs" (Odds Ratio [OR]: 5.38 and 4.38), the need for "incorporation in the regional protocol" (OR: 3.66 and 2.66), and this will "result in time savings for the patient" (OR: 4.84). CONCLUSIONS: We identified three facilitators that could provide backing for a deimplementation strategy aimed at a reduction of routine radiographs for patients with distal radius and ankle fractures. PMID- 30484950 TI - O-GlcNAcylation promotes colorectal cancer progression by regulating protein stability and potential catcinogenic function of DDX5. AB - The RNA helicase p68 (DDX5), a key player in RNA metabolism, belongs to the DEAD box family and is involved in the development of colorectal cancer. Here, we found both DDX5 and O-GlcNAcylation are up-regulated in colorectal cancer. In addition, DDX5 protein level is significantly positively correlated with the expression of O-GlcNAcylation. Although it was known DDX5 protein could be regulated by post-translational modification (PTM), how O-GlcNAcylation modification regulated of DDX5 remains unclear. Here we show that DDX5 interacts directly with OGT in the SW480 cell line, which is the only known enzyme that catalyses O-GlcNAcylation in humans. Meanwhile, O-GlcNAcylation could promote DDX5 protein stability. The OGT-DDX5 axis affects colorectal cancer progression mainly by regulating activation of the AKT/mTOR signalling pathway. Taken together, these results indicated that OGT-mediated O-GlcNAcylation stabilizes DDX5, promoting activation of the AKT/mTOR signalling pathway, thus accelerating colorectal cancer progression. This study not only reveals the novel functional of O-GlcNAcylation in regulating DDX5, but also reveals the carcinogenic effect of the OGT-DDX5 axis in colorectal cancer. PMID- 30484951 TI - Identification of a 4-mRNA metastasis-related prognostic signature for patients with breast cancer. AB - Metastasis-related mRNAs have showed great promise as prognostic biomarkers in various types of cancers. Therefore, we attempted to develop a metastasis associated gene signature to enhance prognostic prediction of breast cancer (BC) based on gene expression profiling. We firstly screened and identified 56 differentially expressed mRNAs by analysing BC tumour tissues with and without metastasis in the discovery cohort (GSE102484, n = 683). We then found 26 of these differentially expressed genes were associated with metastasis-free survival (MFS) in the training set (GSE20685, n = 319). A metastasis-associated gene signature built using a LASSO Cox regression model, which consisted of four mRNAs, can classify patients into high- and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter MFS (hazard ratio [HR] 3.89, 95% CI 2.53-5.98; P < 0.001), disease-free survival (DFS) (HR 4.69, 2.93-7.50; P < 0.001) and overall survival (HR 4.06, 2.56-6.45; P < 0.001) than patients with low-risk scores. The prognostic accuracy of mRNAs signature was validated in the two independent validation cohorts (GSE21653, n = 248; GSE31448, n = 246). We then developed a nomogram based on the mRNAs signature and clinical-related risk factors (T stage and N stage) that predicted an individual's risk of disease, which can be assessed by calibration curves. Our study demonstrated that this 4-mRNA signature might be a reliable and useful prognostic tool for DFS evaluation and will facilitate tailored therapy for BC patients at different risk of disease. PMID- 30484953 TI - Disabled-1 is down-regulated in clinical breast cancer and regulates cell apoptosis through NF-kappaB/Bcl-2/caspase-9. AB - Disabled-1 (Dab1) is best known as an adaptor protein regulating neuron migration and lamination during development. However, the exact function of Dab1 in breast cancer is unknown. In this study, we examined the expression of Dab1 in 38 breast cancer paraffin sections, as well as 60 paired frozen breast cancer and their adjacent tissues. Our results showed that Dab1 was reduced in breast cancer, and its compromised expression correlated with triple negative breast cancer phenotype, poor differentiation, as well as lymph node metastasis. Functional analysis in breast cancer cell lines demonstrated that Dab1 promoted cell apoptosis, which, at least partially, depended on its regulation of NF-kappaB/Bcl 2/caspase-9 pathway. Our study strongly suggests that Dab1 may be a potential tumour suppressor gene in breast cancer. PMID- 30484952 TI - One method to establish Epstein-Barr virus-associated NK/T cell lymphoma mouse models. AB - Novel nude mice model of human NK/T cell lymphoma were established by subcutaneously injecting two NK/T cell lymphoma cell lines into the right axillary region of mice and successful passages were completed by injecting cell suspension which was obtained through a 70-MUm cell strainer. These mice models and corresponding cell clones have been successfully developed for more than 8 generations. The survival rates of both resuscitation and transplantation in NKYS and YT models were 90% and 70% correspondingly. Pathologically, the tumour cells in all passages of the lymphoma-bearing mice and cell lines obtained from tumours were parallel to initial cell lines. Immunologically, the tumour cells expressed the characteristics of the primary and essential NK/T lymphomas. The novel mice models maintained the essential features of human NK/T cell lymphoma, and they would be ideal tools in vivo for further research of human NK/T cell lymphoma. PMID- 30484954 TI - Exosomes from mesenchymal stem cells expressing miR-125b inhibit neointimal hyperplasia via myosin IE. AB - Intercellular communication between mesenchymal stem cells (MSCs) and their target cells in the perivascular environment is modulated by exosomes derived from MSCs. However, the potential role of exosome-mediated microRNA transfer in neointimal hyperplasia remains to be investigated. To evaluate the effects of MSC derived exosomes (MSC-Exo) on neointimal hyperplasia, their effects upon vascular smooth muscle cell (VSMC) growth in vitro and neointimal hyperplasia in vivo were assessed in a model of balloon-induced vascular injury. Our results showed that MSC-Exo were internalised by VSMCs and inhibited proliferation and migration in vitro. Further analysis revealed that miR-125b was enriched in MSC-Exo, and repressed the expression of myosin 1E (Myo1e) by targeting its 3' untranslated region. Additionally, MSC-Exo and exosomally transferred miR-125b repressed Myo1e expression and suppressed VSMC proliferation and migration and neointimal hyperplasia in vivo. In summary, our findings revealed that MSC-Exo can transfer miR-125b to VSMCs and inhibit VSMC proliferation and migration in vitro and neointimal hyperplasia in vivo by repressing Myo1e, indicating that miR-125b may be a therapeutic target in the treatment of vascular diseases. PMID- 30484955 TI - Bladder dysfunction does not affect long-term success rate of the retropubic suburethral sling procedure in women with stress urinary incontinence. AB - OBJECTIVE: This study investigated the long-term success rate of retropubic suburethral sling in the treatment of women with stress urinary incontinence (SUI) and different bladder function. METHODS: Surgical outcomes of women with SUI undergoing a retropubic suburethral sling procedure between October 1989 and November 2014 were analyzed retrospectively. Bladder function was evaluated in every patient preoperatively using videourodynamic studies. Patients were classified as having stable bladder, detrusor overactivity (DO), or detrusor underactivity (DU). Baseline urodynamic parameters were analyzed and long-term therapeutic outcomes were compared among these three groups. RESULTS: In all, 403 patients underwent sling procedure for SUI. Of these, 291 (72.2%) had a stable bladder, 78 (19.4%) had DO, and 34 (8.4%) had DU. Mean (+/- SD) patient age was 60.2 +/- 11.8 years, and the median follow-up was 97 months (interquartile range 24-325 months). Postoperatively, the overall continence rate was 83.4% (336/403). After surgery, 71 patients (17.6%) complained of dysuria, 14 (3.5%) complained of urgency incontinence, 25 (6.2%) had recurrent SUI requiring a secondary sling procedure, and urethrolysis was performed in 13 (3.2%). In the stable bladder, DO, and DU groups, the 5-year continence rates were 88.6%, 84.1%, and 79.4%, respectively (P = 0.59), whereas the 10-year continence rates were 83.8%, 72.9%, and 79.4%, respectively. Kaplan-Meier survival analysis indicated that the long term success rate was similar among the three groups (P = 0.39). CONCLUSIONS: The overall continence rate was 83.4% and the 10-year continence rate was satisfactory in all bladder function subgroups. Treatment outcomes were the same for women with SUI but different bladder function. PMID- 30484956 TI - The utility of nipple scraping in the diagnosis of Paget disease of the breast. PMID- 30484957 TI - A Salt-Templated Strategy toward Hollow Iron Selenides-Graphitic Carbon Composite Microspheres with Interconnected Multicavities as High-Performance Anode Materials for Sodium-Ion Batteries. AB - In this work, a facile salt-templated approach is developed for the preparation of hollow FeSe2 /graphitic carbon composite microspheres as sodium-ion battery anodes; these are composed of interconnected multicavities and an enclosed surface in-plane embedded with uniform hollow FeSe2 nanoparticles. As the precursor, Fe2 O3 /carbon microspheres containing NaCl nanocrystals are obtained using one-pot ultrasonic spray pyrolysis in which inexpensive NaCl and dextrin are used as a porogen and carbon source, respectively, enabling mass production of the composites. During post-treatment, Fe2 O3 nanoparticles in the composites transform into hollow FeSe2 nanospheres via the Kirkendall effect. These rational structures provide numerous conductive channels to facilitate ion/electron transport and enhance the capacitive contribution. Moreover, the synergistic effect between the hollow cavities within FeSe2 and the outstanding mechanical strength of the porous carbon matrix can effectively accommodate the large volume changes during cycling. Correspondingly, the composite microsphere exhibits high discharge capacity of 510 mA h g-1 after 200 cycles at 0.2 A g-1 with capacity retention of 88% when calculated from the second cycle. Even at a high current density of 5.0 A g-1 , a high discharge capacity of 417 mA h g-1 can be achieved. PMID- 30484958 TI - Up-regulation of SPINT2/HAI-2 by Azacytidine in bone marrow mesenchymal stromal cells affects leukemic stem cell survival and adhesion. AB - The role of tumour microenvironment in neoplasm initiation and malignant evolution has been increasingly recognized. However, the bone marrow mesenchymal stromal cell (BMMSC) contribution to disease progression remains poorly explored. We previously reported that the expression of serine protease inhibitor kunitz type2 (SPINT2/HAI-2), an inhibitor of hepatocyte growth factor (HGF) activation, is significantly lower in BMMSC from myelodysplastic syndromes (MDS) patients compared to healthy donors (HD). Thus, to investigate whether this loss of expression was due to SPINT2/HAI-2 methylation, BMMSC from MDS and de novo acute myeloid leukaemia (de novo AML) patients were treated with 5-Azacitidine (Aza), a DNA methyltransferase inhibitor. In MDS- and de novo AML-BMMSC, Aza treatment resulted in a pronounced SPINT2/HAI-2 levels up-regulation. Moreover, Aza treatment of HD-BMMSC did not improve SPINT2/HAI-2 levels. To understand the role of SPINT2/HAI-2 down-regulation in BMMSC physiology, SPINT2/HAI-2 expression was inhibited by lentivirus. SPINT2 underexpression resulted in an increased production of HGF by HS-5 stromal cells and improved survival of CD34+ de novo AML cells. We also observed an increased adhesion of de novo AML hematopoietic cells to SPINT2/HAI-2 silenced cells. Interestingly, BMMSC isolated from MDS and de novo AML patients had increased expression of the integrins CD49b, CD49d, and CD49e. Thus, SPINT2/HAI-2 may contribute to functional and morphological abnormalities of the microenvironment niche and to stem/progenitor cancer cell progression. Hence, down-regulation in SPINT2/HAI-2 gene expression, due to methylation in MDS-BMMSC and de novo AML-BMMSC, provides novel insights into the pathogenic role of the leukemic bone marrow microenvironment. PMID- 30484959 TI - Bisphosphonic acids and related compounds as inhibitors of nucleotide- and polyphosphate-processing enzymes: A PPK1 and PPK2 case study. AB - Bisphosphonic acids, which are structural analogs of pyrophosphate, constitute a class of compounds with very high potential for the construction of effective inhibitors of enzymes operating on oligo- and polyphosphates. The bisphosphonate based methodology was applied for the discovery of inhibitors of two families of polyphosphate kinases (PPK1 and PPK2). Screening of thirty-two structurally diverse bisphosphonic acids and related compounds revealed several micromolar inhibitors of both enzymes. Importantly, selectivity of bisphosphonates could be achieved by application of the appropriate side chain. PMID- 30484960 TI - Differences in cardiovascular safety with non-steroidal anti-inflammatory drug therapy - a nationwide study in patients with osteoarthritis. AB - Osteoarthritis (OA) and the non-steroidal anti-inflammatory drugs (NSAIDs) used to relieve OA-associated pain have been linked independently to increased cardiovascular risk. We examined the risk of cardiovascular events associated with NSAID use in patients with OA. We employed linked nationwide administrative registers to examine NSAID use between 1996 and 2015 by Danish patients with OA aged >=18 years. Using adjusted Cox proportional hazard analyses, we calculated the risk of the composite outcome of cardiovascular death, non-fatal myocardial infarction and non-fatal ischaemic stroke/TIA, and of each outcome separately, up to 5 years after OA diagnosis. Of 533,502 patients included, 64.3% received NSAIDs and 38,226 (7.2%) experienced a cardiovascular event during follow-up. Compared with non-use, all NSAIDs were associated with increased risk of the composite outcome: hazard ratio (HR) for rofecoxib, 1.90 [95% Confidence Interval, 1.74-2.08]; celecoxib, 1.47 [1.34-1.62]; diclofenac, 1.44 [1.36-1.54]; ibuprofen, 1.20 [1.15-1.25]; naproxen, 1.20 [1.04-1.39]. Similar results were seen for each outcome separately. When celecoxib was used as reference, ibuprofen (HRs 0.81 [CI 0.74-0.90]) and naproxen (HRs 0.81 [0.68-0.97]) exhibited a lower cardiovascular risk, even when low doses were compared. Low-dose naproxen and ibuprofen were associated with the lowest risks of the composite outcome compared to no NSAID use: HRs 1.12 [1.07-1.19] and 1.16 [0.92-1.42], respectively. In patients with OA, we found significant differences in cardiovascular risk among NSAIDs. Naproxen and ibuprofen appeared to be safer compared to celecoxib, also when we examined equivalent low doses. In terms of cardiovascular safety, naproxen and ibuprofen, at the lowest effective doses, may be the preferred first choices among patients with OA needing pain relief. This article is protected by copyright. All rights reserved. PMID- 30484961 TI - Retrotransposon insertion as a novel mutational event in Bardet-Biedl syndrome. AB - BACKGROUND: Bardet-Biedl syndrome (BBS) is an autosomal recessive pleiotropic disorder of the primary cilia that leads to severe visual loss in the teenage years. Approximately 80% of BBS cases are explained by mutations in one of the 21 identified genes. Documented causative mutation types include missense, nonsense, copy number variation (CNV), frameshift deletions or insertions, and splicing variants. METHODS: Whole genome sequencing was performed on a patient affected with BBS for whom no mutations were identified using clinically approved genetic testing of the known genes. Analysis of the WGS was done using internal protocols and publicly available algorithms. The phenotype was defined by retrospective chart review. RESULTS: We document a female affected with BBS carrying the most common BBS1 mutation (BBS1: Met390Arg) on the maternal allele and an insertion of a ~1.7-kb retrotransposon in exon 13 on the paternal allele. This retrotransposon insertion was not automatically annotated by the standard variant calling protocols used. This novel variant was identified by visual inspection of the alignment file followed by specific genome analysis with an available algorithm for transposable elements. CONCLUSION: This report documents a novel mutation type associated with BBS and highlights the importance of systematically performing transposon detection analysis on WGS data of unsolved cases. PMID- 30484962 TI - Lymphovascular invasion as an independent prognostic indicator in radically resected thoracic esophageal squamous cell carcinoma. AB - BACKGROUND: The prognostic value of lymphovascular invasion (LVI) in esophageal cancer remains controversial. This study investigated the impact of LVI on prognosis in thoracic esophageal squamous cell carcinoma (ESCC). METHODS: A total of 1586 patients who underwent radical esophagectomy were selected for the study. Correlations between LVI and clinicopathological features were evaluated by chi2 test. Univariate analysis of the survival curve was conducted using the Kaplan Meier method. Multivariate analysis was carried out by Cox regression. The Akaike information criterion (AIC) and the concordance index (c-index) were employed to assess model prognostic accuracy of different pN staging systems. RESULTS: The presence of LVI was detected in 406 of 1586 (25.6%) patients. LVI frequency was significantly higher in patients with higher pN classifications (P < 0.001). LVI had independent significant prognostic value in ESCC (P < 0.001). In subgroup analyses, the presence of LVI significantly decreased overall survival in pN0, pN2, and pN3 stage patients. The AIC value of the pN staging system modified by LVI was lower than that of the current pN staging system, while the c-index of the modified pN staging system was higher than that of the current pN staging system. CONCLUSION: Our results suggest that LVI is an independent prognostic indicator in radically resected thoracic ESCC. LVI could potentially supplement the pN ESCC staging system. ESCC patients with LVI could be staged at more advanced pN classifications. PMID- 30484963 TI - Adhesion of silicone oil and emulsification: an in vitro assessment using a microfluidic device and 'Eye-on-a-Chip'. AB - PURPOSE: Silicone oil (SiO) with additives of high-molecular-weight (HMW) SiO molecules, eases both the injection and removal. When used inside an eye, it remains unclear how increasing extensional viscosity of SiO might reduce emulsification. Using cell-lined models, this study aims to understand the reason why SiO with HMW is less prone to emulsification. METHODS: The adhesion of SiO was studied and recorded in a cell-coated microchannel by optical microscopy. The resistance of SiO against emulsification was tested on another cell-coated eye-on a-chip platform, which was subject to simulated saccadic eye movements, for 4 days. Silicone oil (SiO) candidates with HMW, SiOHMW 2000 and SiOHMW 5000 , and their counterparts SiO2000 and SiO5000 without HMW, were tested. The quantity of the SiO emulsified droplets formed was assessed daily by optical microscopy. RESULTS: When flowing in the microchannel, SiO adheres on the cell-coated substrate. The number of droplets is generally lower in SiO with HMW than their counterparts. At the end of the experiment, the average numbers of droplets in SiO2000 (29.1 +/- 41.0) and SiO5000 (9.1 +/- 19.5) are higher than those in SiOHMW 2000 (6.0 +/- 4.5) and SiOHMW 5000 (5.6 +/- 4.1). CONCLUSION: A new mechanism of emulsification of SiO is proposed: SiO adheres to ocular tissue to form emulsified droplets. The presence of HMW, which increases the extensional viscosity, may resist the break-up of SiO from the substrate to form emulsified droplets. When tested in a physiologically representative platform, the use of HMW in SiO generally reduces the number of droplets formed in vitro. PMID- 30484964 TI - Improved protein production and codon optimization analyses in Escherichia coli by bicistronic design. AB - Different codon optimization algorithms are available that aim at improving protein production by optimizing translation elongation. In these algorithms, it is generally not considered how the altered protein coding sequence will affect the secondary structure of the corresponding RNA transcript, particularly not the effect on the 5'-UTR structure and related ribosome binding site availability. This is a serious drawback, because the influence of codon usage on mRNA secondary structures, especially near the start of a gene, may strongly influence translation initiation. In this study, we aim to reduce the effect of codon usage on translation initiation by applying a bicistronic design (BCD) element. Protein production of several codon-optimized gene variants is tested in parallel for a BCD and a standard monocistronic design (MCD). We demonstrate that these distinct architectures can drastically change the relative performance of different codon optimization algorithms. We conclude that a BCD is indispensable in future studies that aim to reveal the impact of codon optimization and codon usage correlations. Furthermore, irrespective of the algorithm used, using a BCD does improve protein production compared with an MCD. The overall highest expression from BCDs for both GFP and RFP is at least twofold higher than the highest levels found for the MCDs, while for codon variants having very low expression from the MCD, even 10-fold to 100-fold increases in expression were achieved by the BCD. This shows the great potential of the BCD element for recombinant protein production. PMID- 30484965 TI - The new strategies to overcome challenges in protein production in bacteria. AB - Recombinant proteins are essential for biotechnology. Here we review some of the key points for improving the production of heterologous proteins, and what can be the future of the field. PMID- 30484966 TI - Promising clinical outcomes of sequential and "Sandwich" chemotherapy and extended involved-field intensity-modulated radiotherapy in patients with stage IE /IIE extranodal natural killer/T-cell lymphoma. AB - BACKGROUND: The optimal treatment for the rare subtype of non-Hodgkin lymphoma, extranodal natural killer/T-cell lymphoma (ENKTL), nasal-type, has not been clearly defined. The purpose of the study was to investigate the efficacy of sequential and "Sandwich" chemotherapy and extended involved-field intensity modulated radiotherapy (IMRT) in patients with stage IE /IIE extranodal ENKTL, nasal-type. METHODS: One hundred and fifty-five patients with stage IE /IIE nasal type ENKTL were enrolled in the study, including 99 patients treated with sequential chemotherapy and extended involved-field IMRT (SCRT) and 56 patients with "Sandwich" chemotherapy and extended involved-field IMRT and chemotherapy (SCRCT). All patients were treated with extended involved-field IMRT with median dose of 54.6 Gy to the primary tumor and positive lymph nodes. Ninety-four patients had Ann Arbor stage IE disease, and 61 patients had stage IIE disease. RESULTS: The 5-year rates of loco-regional recurrence (LRR), progression-free survival (PFS), and overall survival (OS) were 17.0%, 78.5%, and 84.7%, respectively. Univariate analysis revealed that EBV DNA copy after treatment (normal vs elevated level) was significant prognostic factor for LRR, PFS, and OS (P < 0.001); therapeutic method (SCRT vs SCRCT) was significant prognostic factor for PFS (71.0% vs 91.8%, P = 0.011), but there was no significant effect on 5 year LRR and OS (22.2% vs 8.2%, P = 0.051 for LRR; 80.9% vs 91.8%, P = 0.199 for OS). CONCLUSIONS: Compared with SCRT, SCRCT was significantly associated with higher PFS rates and showed a trend toward improved loco-regional control. EBV DNA copy after treatment is a good index for recurrence and prognosis for stage IE /IIE ENKTL patients. PMID- 30484967 TI - Epidemiological investigation of the novel genotype avian hepatitis E virus and co-infected immunosuppressive viruses in farms with hepatic rupture hemorrhage syndrome, recently emerged in China. AB - Since 2016, hepatic rupture hemorrhage syndrome (HRHS) appeared in chickens of China and caused huge economic loss. To assess the infection status of the avian HEV and co-infected viruses, including avian leukosis virus (ALV), reticuloendotheliosis virus (REV), fowl adenovirus (FAdV) and chicken infectious anemia virus (CIAV), in farms with HRHS, 180 liver samples were collected from 24 farms in different provinces and detected by strict molecular virology methods. Results showed that the positive rates of HEV, ALV, REV, FAdV and CIAV were 74.44%, 20.00%, 27.78%, 31.11% and 12.22%, respectively, while there are also 112 samples with co-infection, for a rate of 58%. Meanwhile, the positive rate of HEV decreased gradually with age; the lowest positive rate of ALV (5.76%) and REV (19.23%) appeared in 25-35 weeks age, during which the positive rate of CIAV was the highest (19.23%); the positive rate of HEV in layers (64.00%) was lower than that of broilers (83.33%), but the positive rates of ALV (38.46%) and CIAV (15.38%) in layers were higher than that of broilers (5.88%, 9.80%); the positive rates of HEV (75.88%) and CIAV (15.60%) in parental generation (PG) were higher than that of commodity generation (CG, 64.10%, 0.00%), while the positive rate of ALV showed inverse relationship (PG: 14.89%; CG: 38.46%). Additionally, phylogenetic analysis showed that all the avian HEV identified this study belong to a novel genotype, and found the close relationship between the wild strains (REV and CIAV) and corresponding isolates from contaminated vaccine. The data presented in this report will enhance the current understanding of the epidemiology characteristics in farms with HRHS in China. This article is protected by copyright. All rights reserved. PMID- 30484968 TI - Circular incision and cutting, a novel treatment for esophageal cancer patients with anastomotic stricture after esophagectomy. AB - OBJECTIVE: Endoscopic balloon dilation (EBD) is still considered as the standard treatment for patients with anastomotic strictures after esophagectomy. However, repeated dilation sessions are often required to maintain the lumen patency. We therefore developed a novel method called circular incision and cutting (CIC) and compared the efficacy of CIC and EBD among patients with anastomotic strictures after esophagectomy. METHODS: In this retrospective study, 71 consecutive esophageal cancer patients with anastomotic strictures after esophagectomy between January 2011 and December 2016 were included. Among these individuals, 22 patients received CIC therapy and 49 patients were treated with EBD. RESULTS: The dysphagia in all patients was immediately improved and no serious adverse events required further intervention were observed after CIC therapy. Compared with EBD, CIC exhibited greater points in the difference of dysphagia score before and after treatment (1.73 vs. 1.16, P = 0.03). Moreover, the interval of restenosis and 6-month lumen patency in CIC showed better effect than that in EBD (88.07 days vs. 62.76 days, P = 0.001; 0.63 vs. 1.44, P = 0.007). CONCLUSIONS: The CIC method may be an effective and safe option for esophageal cancer patients with anastomotic strictures after esophagectomy. PMID- 30484969 TI - Liver fluke (Fasciola hepatica) co-infection with bovine tuberculosis (bTB) in cattle: a retrospective animal-level assessment of bTB risk in dairy and beef cattle. AB - Bovine tuberculosis (bTB), caused by Mycobacterium bovis, remains a persistent problem for cattle industries in endemic countries. The frequency, quality, and performance of tests, and the presence of wildlife reservoirs, have been identified as impediments to eradication. Recently, exposure to helminth infection (Fasciola hepatica) has been associated negatively with the disclosure of bTB. Here, for the first time, we assess impact of concurrent infections of Fasciola hepatica and the disclosure of bTB at the animal-level using large surveillance datasets. We utilised a dataset of 138,566 animal records from an abattoir from Northern Ireland (2011-2013). The presence of F. hepatica infection was assessed from macroscopic tissue inspection at abattoir. Multivariable models were developed to assess co-infection associations with bTB status based on: Single Intradermal Comparative Tuberculin Test (SICTT), lesion, bacteriological confirmation, including either all animals, or only skin-test negative animals (lesions at routine slaughter; LRS; confirmed non-reactors at routine slaughter; cNRs) or positive (reactors) animals alone, respectively. The relationship between skin tuberculin reaction sizes and fluke status was also explored for a subset of animals with field recordings (n=24,680). Controlling for known risk factors (e.g. climatic, herd and individual level characteristics), we did not find significant associations between the SICTT (standard or severe interpretation), lesion, nor confirmation status of animals and their liver fluke status. The only exception was a negative association between liver fluke positivity, and LRS or cNRs, respectively; though effect-sizes were small (e.g. LRS Odds-Ratio: 0.87; 95%CI: 0.76-1.00). There was limited evidence of a relationship between tuberculin reaction sizes during SICTT testing and liver fluke infection status. These data do not support the contention that the detection of bTB using skin-tests or reactor post-mortem follow-up may be compromised by co-infection at a population level, but the relationship with lesion formation (pathogenesis) may indicate an impact for post-mortem surveillance. PMID- 30484970 TI - ? PMID- 30484971 TI - [Improved rehabilitation after major urological surgery : what role for the general practitioner ?] AB - Enhanced recovery after surgery (ERAS) is a multimodal concept aiming to reduce surgical stress and prevent postoperative complications. Once adapted to urologic patients in 2013, this protocol evolves continuously and many international centers have now implemented it. This article resumes ERAS key principles for general practitioners as they can have a significant impact on patient's optimization before surgery. PMID- 30484972 TI - [Augmented reality in urology : present and future]. AB - Minimally invasive surgery has recently gained popularity. This paradigm shift involves a series of potential difficulties from the surgeon's perspective. With recent developments these obstacles are gradually being overcomed. Recent navigation systems offer major improvements in the way information is acquired, displayed, and integrated into the surgical workflow through augmented reality. Finally, the progress of robotics has helped to improve the minimally invasive dexterity and competence of the surgeon. This article sumarizes the main and most recent developments in the areas mentionned above, analyzes the current limits that still need to be addressed, and suggests possible future directions. PMID- 30484973 TI - [Diagnosis and management of small solid renal masses]. AB - Discovery of small solid renal masses via echography, CT-scan or MRI is common in current medical practice, with more than 70 % found incidentally. Although they include benign lesions, most are renal cell carcinomas. A radiological assessment, associated if necessary with a percutaneous renal biopsy, leads to their diagnosis in the vast majority of cases. Minimally invasive partial nephrectomy has become the standard surgical technique in specialized centers. Ablative therapies (radiofrequency and cryotherapy) and active surveillance are other possible therapeutic approaches. A benefit-risk assessment of these treatments considering patient age, kidney function and comorbidities, is key in the management of these small solid renal masses. PMID- 30484974 TI - [Ambulatory surgery in urology]. AB - The volume of ambulatory surgery in urology increases every year. Successful ambulatory care is defined by low hospital (re)admission rates, insuring optimal oncologic and functional outcomes. New medical techniques such as minimally invasive surgical approaches and less side effects of anesthesia have helped the development of ambulatory surgery. Additionally, it is essential to lower the burden of healthcare systems financially, without compromising quality of care. Ambulatory surgery needs a multidisciplinary team involvement, where the general practitioner has a key role. PMID- 30484975 TI - [About the indications to urodynamic studies and to a prior antibioprophylaxy]. AB - In this review article, we refer to recent publications dealing with the indication to pressure-volume and pressure-flow studies using cystometry as well as the indication for antibioprophylaxis prior to these examinations. We conclude that despite various indications these examinations must be reserved for complex cases after exhaustive preliminary evaluation. Moreover, in case of complex urinary incontinence or neurogenic bladder videocystomanometry is recommended for a correct and complete diagnosis. In addition, antibiotic prophylaxis is no longer considered as necessary before these examinations, including for neurological patients. PMID- 30484977 TI - ? PMID- 30484976 TI - [Erectile dysfunction, an urologic and multidisciplinary approach]. AB - Erectile dysfunction (ED) is a common complaint, both in the general medicine and the urology out-patient clinic. The quite recent availability of effective treatments has profoundly changed the perception of sexual health in society, which has become more demanding. We should see erectile or sexual function as a health marker. Its causes are often diverse but we can classify them as somatic (vascular, neurological, endocrine, tissue-related, iatrogenic) or psychogenic. Management should be etiological if possible. It often goes first by reducing cardiovascular risk factors and then by prescribing a vasodilating agent functioning through the inhibition of phosphodiesterase 5. When modifiable cardiovascular risk factors are identified, we refer the patient to a specialized consultation. ED is to be seen as a warning sign of a preventable disease or cardiovascular event. PMID- 30484978 TI - ? PMID- 30484979 TI - ? PMID- 30484980 TI - ? PMID- 30484981 TI - ? PMID- 30484982 TI - ? PMID- 30484983 TI - ? PMID- 30484984 TI - Prognostic Value of NRAS Gene for Survival of Colorectal Cancer Patients: A Systematic Review and Meta-Analysis AB - Introduction: NRAS gene is associated with malignant proliferation and metastasis of colorectal cancer (CRC).But its prognostic value on CRC is still unknown. The objective of this study is to perform a meta-analysis to obtainits prognostic value on survival of CRC patients. Methods: The systematic review and meta analysis was designed,undertaken and reported using items from the PRISMA statement. Relevant articles were identified through PubMed(containing Medline), Embase, Web of Science databases and Google scholar search engines from their inception up toOctober 3, 2016. The articles about NRAS on prognosis of CRC patients were enrolled. The association between NRASand CRC survival time (including overall survival [OS], progression-free survival [PFS], and disease free survival[DFS]) was evaluated using hazard ratio (HR) with its corresponding 95% confidence interval (CI). Results: A totalof fifteen articles were included. High-expression of NRAS was significantly associated with poor OS (HR: 1.36, 95%CI: 1.15-1.61), and poor PFS (HR: 1.75, 95% CI: 1.04-2.94). The combined HR of NRAS on DFS was 0.87 (95% CI:0.37-2.03). Subgroup analysis showed that NRAS was significantly associated with poor OS for patients from Westerncountries (HR: 1.38, 95% CI: 1.09-1.73), but not for those from Asian countries. Conclusions: This meta-analysisdemonstrate that NRAS gene could predict the poor prognosis for the CRC patients. More large-sample cohort studiesare needed to further confirm this conclusion. PMID- 30484985 TI - Determining the Survival Rate of Colorectal Cancer in Iran: A Systematic Review and Meta-Analysis AB - Objective: Colorectal cancer is one of the most common causes of death in the world. Despite of remarkableadvances in medical sciences, cancer is an important disease and the second cause of death after cardiovascular diseases.The present study was aimed at determining the survival rate of colorectal cancer in Iran. Methods: The present studyis a systematic review of national and international electronic databases. Studies that had the inclusion criteria wereincluded in the study, electronically published articles over December 2007 and March 2015 were retrieved. The collecteddata were analyzed by meta-analytic method through stata 11.0 Software, and the survival rate was measured. Results:The 1-, 2-, 3-, 4-, and 5-year survival rates of colorectal cancer in Iran were respectively calculated as 85, 75.10, 65,55.40, and 52.The results indicated that there is a significant relationship between anatomic location of tumor andsurvival rate. According to the results of this examination, survival rate of the patients with rectal cancer was 41.9times higher than those with colorectal cancer. Conclusion: Due to the relative high prevalence of this cancer amongyoung people in Iran and the low survival rate, early diagnosis of colorectal neoplasms is necessary before they becomesymptomatic through more effective diagnosis programs of enhancing the patients' health and survival rate. Moreover,it is necessary to conduct more specialized and relevant studies in order to determine genetic or environmental causes ofcancer such as diet and cultural and behavioral habits at the national level and with different ethnicities. PMID- 30484986 TI - Overexpression of Regulatory T Cell-Related Markers (FOXP3, CTLA-4 and GITR) by Peripheral Blood Mononuclear Cells from Patients with Breast Cancer AB - Background: Regulatory T (Treg) cells are immunosuppressor lymphocytes that play a critical role in the establishmentand progression of cancers. A number of markers, especially FOXP3, CTLA-4 and GITR influence the function ofTreg cells. This investigation aimed to evaluate the expression of a number of important Treg cell-related markers byperipheral blood mononuclear cells (PBMCs) from newly diagnosed women with breast cancer. Methods: The freshPBMCs were obtained from 20 women with breast cancer and 20 healthy individuals. The PBMCs from both groupswere cultured for 32 hours in the presence or absence of PHA (10 MUg/ml). After total RNA extraction from culturedPBMCs, the expression of the FOXP3, CTLA 4 and GITR transcripts was assessed using real time-PCR. Results:The mRNA expression of FOXP3, CTLA-4 and GITR in unstimulated PBMCs from patients with breast cancer weresignificantly higher than healthy control group (P<0.05, P<0.03 and P<0.04, respectively). Similarly, the expression ofFOXP3, CTLA-4 and GITR transcripts in PHA-stimulated PBMCs from patients with breast cancer were significantlyincreased in comparison with healthy individuals (P<0.01, P<0.005 and P<0.01, respectively). Conclusion: The increasedexpression of FOXP3, CTLA-4 and GITR represent higher activity of Treg cells in patients with breast cancer that mayplay an important role in the tumor establishment and development. PMID- 30484987 TI - Effects of a Self-Monitoring Quality of Life Intervention for Patients with Cancer Receiving Palliative Care in Japan: Study Protocol for a Randomized Controlled Trial AB - Background: Previous studies suggest the use of patient-reported outcome measures in routine clinical practice hasimportant benefits for patients with cancer, particularly as feedback regarding patients' quality of life (QOL) improvesdoctor patient communication and clinical decision making. This study aimed to examine the effect of using the CareNotebook as a routine self-monitoring QOL intervention in clinical practice for patients with cancer receiving palliativecare. The results are expected to clarify the practical use of the Care Notebook in this population. Methods: Thisprospective randomized study is being undertaken at Toshima Hospital, Japan. Participating patients who are randomlyassigned to the intervention group will be asked to complete the shortened Care Notebook booklet for patients withcancer in palliative care once each day. A control group will receive usual care. The primary outcome is global healthstatus/QOL (Global QOL), as assessed by the European Organization for Research and Treatment of Cancer Quality ofLife Questionnaire Core 15 Palliative. Data will be collected at baseline (after allocation), and at 1 week and 3 weeksin both the control and intervention groups. The effects of the intervention will be evaluated with a mixed randomeffects model. The required sample size is 200 patients. We obtained approval from Toshima Hospital (No 26-11) andthe Tokyo Medical and Dental University Ethics Committee (No 1756). The findings will be disseminated throughpublications in peer-reviewed journals and attendance at domestic and international conferences. The trial was registeredwith the UMIN clinical trials registry (Trial registration number: UMIN000025322). Conclusions: This study willprovide evidence on whether medical staff can use the Care Notebook as a routine self-monitoring QOL intervention inclinical practice for patients with cancer receiving palliative care. We expect that a routine Care Notebook interventionfor patients with cancer will be recommended in healthcare facilities. PMID- 30484988 TI - Estimating Risk of Breast Cancer Occurrences at Different Ages: Application of Survival Techniques AB - Background: Awareness is the primary means to control breast cancer occurrence. The purpose of the present workis to study the risk of breast cancer occurrence in different age group, for the study area, Assam, India, by means ofsurvival analysis techniques. Methods: Survival and hazard functions are key concepts in survival analysis for describingthe distribution of event times. In the present research a new individialized model has been proposed for cumulativehazard function, taking gamma probability distribution as probability distribution of breast cancer occurrences. KaplanMeier Survival method has been applied to find out the probability of diseases occurrence in the early menarche andlate menarche group. The data used for implementation were collected from the Record Department of a prime localcancer institute, for the period 2010-2012. The information for the risk factor age at menarche were collected from thepatients registered during August 2011 to February 2012. Results: The study reveals that in the study area, cumulativehazard of the women belonging to 35 to 50 years is higher than the early and late aged women. The cumulative hazardplot with shape parameter 0.5, 1 and 10 shows that cumulative risk for early aged women are greater than the late agewomen but when this values is increased from 10, the opposite trend is observed. Further, the median age of diseaseoccurrence among early menarche group is 52 years and for late menarche it is 54 years. Conclusion: The modeldeveloped could successfully point out the age group for women lying at higher risk of breast cancer occurrence.Additionally the important risk factor, age at menarche, was effectively applied to supplement to this calculation. It ishoped that practical use of this method would enhance not only awareness but also early detection of the said disease. PMID- 30484989 TI - Can we reduce ischemic cholangiopathy rates in donation after cardiac death liver transplantation after 10 years of practice? Canadian single-centre experience AB - Background: Outcomes in liver transplantation with organs obtained via donation after cardiocirculatory death (DCD) have been suboptimal compared to donation after brain death, attributed mainly to the high incidence of ischemic cholangiopathy (IC). We evaluated the effect of a 10-year learning curve on IC rates among DCD liver graft recipients at a single centre. Methods: We analyzed all DCD liver transplantation procedures from July 2006 to July 2016. Patients were grouped into early (July 2006 to June 2011) and late (July 2011 to July 2016) eras. Those with less than 6 months of follow-up were excluded. Primary outcomes were IC incidence and IC-free survival rate. Results: Among the 73 DCD liver transplantation procedures performed, 70 recipients fulfilled the selection criteria, 32 in the early era and 38 in the late era. Biliary complications were diagnosed in 19 recipients (27%). Ischemic cholangiopathy was observed in 8 patients (25%) in the early era and 1 patient (3%) in the late era (p = 0.005). The IC-free survival rate was higher in the late era than the early era (98% v. 79%, p = 0.01). The warm ischemia time (27 v. 24 min, p = 0.049) and functional warm ischemia time (21 v. 17 min, p = 0.002) were significantly lower in the late era than the early era. Conclusion: We found a significant reduction in IC rates and improvement in ICfree survival among DCD liver transplantation recipients after a learning curve period that was marked by more judicious donor selection with shorter procurement times. PMID- 30485036 TI - Lung Cancer Screening Recommendations from the ACCP. PMID- 30485037 TI - Advance Care Planning Increases Execution of Advance Directives and Surrogate Decision-Maker Assignment. PMID- 30485038 TI - Crohn's Disease: Diagnosis and Management. AB - Crohn's disease is a chronic inflammatory condition that affects the gastrointestinal tract. It can cause lesions from mouth to anus and may result in extraintestinal complications. The prevalence of Crohn's disease is increasing in adults and children. Genetic predispositions to Crohn's disease have been identified, and specific environmental factors have been associated with its development. Common presenting symptoms include diarrhea, abdominal pain, rectal bleeding, fever, weight loss, and fatigue. Physical examination should identify unstable patients requiring immediate care, include an anorectal examination, and look for extraintestinal complications. Initial laboratory evaluation identifies inflammation and screens for alternative diagnoses. Measurement of fecal calprotectin has value to rule out disease in adults and children. Endoscopy and cross-sectional imaging are used to confirm the diagnosis and determine the extent of disease. Treatment decisions are guided by disease severity and risk of poor outcomes. Patients commonly receive corticosteroids to treat symptom flare ups. Patients with higher-risk disease are given biologics, with or without immunomodulators, to induce and maintain remission. For children, enteral nutrition is an option for induction therapy. All patients with Crohn's disease should be counseled on smoking avoidance or cessation. Patients with Crohn's disease are at increased risk of cancer, osteoporosis, anemia, nutritional deficiencies, depression, infection, and thrombotic events. Maximizing prevention measures is essential in caring for these patients. PMID- 30485039 TI - Dental Problems in Primary Care. AB - Oral health directly affects overall health and quality of life. More Americans lack dental insurance than medical insurance. Patients with poor oral health are more likely to have respiratory and cardiovascular diseases, adverse pregnancy outcomes, and diabetes mellitus. Early childhood caries is the most common chronic condition in American children. Certain illicit and prescription drugs increase the risk of enamel erosion and caries formation in adults. Incision and drainage is the treatment of choice for dental abscess. Risk factors for periodontal disease include smoking, diabetes, human immunodeficiency virus infection, use of certain medications, and genetic susceptibility. Patients with gingivitis typically present with swollen, erythematous gum tissue that bleeds easily with brushing or flossing. One in three children will have an injury to the primary teeth, and one in five 12-year-old children will have an injury to the permanent teeth. All dental fractures should be evaluated with imaging and managed in conjunction with a dental professional. Immediate reimplantation is the preferred treatment for avulsed permanent teeth. Primary care clinicians are well positioned to reduce rates of oral disease. Family physicians can incorporate oral health into routine practice through counseling about diet, oral hygiene, smoking cessation, and fluoride supplementation; application of fluoride varnish; and screening for dental disease. PMID- 30485040 TI - Deep Venous Thrombosis: Home vs. Inpatient Treatment. PMID- 30485042 TI - Mifepristone Pretreatment Improves Success Rate of Misoprostol for Early Pregnancy Loss. PMID- 30485041 TI - Pruritic Rash on the Hands and Feet. PMID- 30485043 TI - Faith in Subtraction: Deprescribing in Older Patient Facilitates Needed Surgery. PMID- 30485044 TI - Early Invasive Management of Acute Coronary Syndromes. PMID- 30485045 TI - Practical Considerations of Caring for Patients Abroad During Short-term Medical Trips. PMID- 30485047 TI - Direct Oral Anticoagulants Preferred Over Warfarin for Nonvalvular Atrial Fibrillation in Patients Also Taking Low-Dose Aspirin. PMID- 30485048 TI - Preventing or Delaying Type 2 Diabetes Mellitus with Diet and Exercise. PMID- 30485049 TI - Incidental Findings Are Common with Chest CT and MRI of the Spine and Brain. PMID- 30485051 TI - The Responsibility of Family Physicians to our Transgender Patients. PMID- 30485050 TI - Caring for Transgender and Gender-Diverse Persons: What Clinicians Should Know. AB - Persons whose experienced or expressed gender differs from their sex assigned at birth may identify as transgender. Transgender and gender-diverse persons may have gender dysphoria (i.e., distress related to this incongruence) and often face substantial health care disparities and barriers to care. Gender identity is distinct from sexual orientation, sex development, and external gender expression. Each construct is culturally variable and exists along continuums rather than as dichotomous entities. Training staff in culturally sensitive terminology and transgender topics (e.g., use of chosen name and pronouns), creating welcoming and affirming clinical environments, and assessing personal biases may facilitate improved patient interactions. Depending on their comfort level and the availability of local subspecialty support, primary care clinicians may evaluate gender dysphoria and manage applicable hormone therapy, or monitor well-being and provide primary care and referrals. The history and physical examination should be sensitive and tailored to the reason for each visit. Clinicians should identify and treat mental health conditions but avoid the assumption that such conditions are related to gender identity. Preventive services should be based on the patient's current anatomy, medication use, and behaviors. Gender-affirming hormone therapy, which involves the use of an estrogen and antiandrogen, or of testosterone, is generally safe but partially irreversible. Specialized referral-based surgical services may improve outcomes in select patients. Adolescents experiencing puberty should be evaluated for reversible puberty suppression, which may make future affirmation easier and safer. Aspects of affirming care should not be delayed until gender stability is ensured. Multidisciplinary care may be optimal but is not universally available. PMID- 30485052 TI - Wearable Devices for Weight Loss. PMID- 30485053 TI - Evidence Supporting Niacin Therapy Is More Nuanced Than Article States. PMID- 30485054 TI - Does Niacin Have Cardiovascular Benefits in Patients with Dyslipidemia? PMID- 30485055 TI - Crohn's Disease. PMID- 30485056 TI - Common Dental Infections. PMID- 30485057 TI - Quantitative single-cell-analysis of isolated cancer cells with microwell array. AB - The heterogeneous nature of tumor cell populations suggests that quantitative analysis at the single-cell level may provide better insights into cancer biology. Specifically, detection of multiple biomarkers from a single cell offers important initial information about cellular behavior. However, conventional approaches have limitations on biomarker detections in a single cell level. Here we fabricated a polymer microwell array to capture single cells from prostate cancer cell lines and quantitatively analyzed three different cancer-related biomarker expressions, CD44, EpCAM, and PSMA without protein extraction step. The resulting information of cell surface biomarker distribution was compared to other standard analytical techniques. Interestingly large variation of CD44 expression levels was observed when cell proliferation cycle is modulated. On the other hand, expression levels of EpCAM in three different cell lines are consistent throughout analytical methods except microarray where it has different substrate material to adhere with. This observation clearly emphasizes that biomarker choice and environmental control are critical to properly understand the single cell state. PMID- 30485058 TI - Traceless solid-phase synthesis of 1'H-spiro[pyrrolidine-3,2'-quinazolin]-2-ones and 1'H-spiro[piperidine-3,2'-quinazolin]-2-ones via lactamization of 1,2 dihydroquinazoline-2-carboxylates. AB - We present the solid-phase synthesis of 1,2-dihydroquinazoline-2-carboxylate derivatives with a quaternary carbon in position 2 and their subsequent cyclization in solution into compounds with unique 3D architectures and pharmacological relevance - spiroquinazolines, namely, 1'H-spiro[pyrrolidine-3,2' quinazolin]-2-ones and 1'H-spiro[piperidine-3,2'-quinazolin]-2-ones. Acyclic precursors were prepared from commercially available building blocks: protected amino acids (2,4-diaminobutyric acid and ornithine), 2-nitrobenzensulfonyl chlorides and alpha-bromoacetophenones. The crucial step of the synthesis was a base-mediated tandem reaction including C-arylation followed by cyclization into indazole oxides, and the formation of a 5-membered heterocycle was accomplished by ring expansion into quinazolines. These derivatives were cyclized into spiro compounds in solution after cleavage from the resin. PMID- 30485059 TI - Glutamate, glutamate transporters, and circadian rhythm sleep disorders in neurodegenerative diseases. AB - Glutamate, a primary excitatory neurotransmitter as well as an important intermediate of the cellular metabolism in the brain, has a widespread influence in the sleep-wake regulatory system. Glutamate transporters, including vesicular glutamate transporters and excitatory amino acid transporters, serve as the main force to control the extracellular concentration of glutamate in the brain. They are likely to be critical tools needed for the brain to modulate the sleep-wake cycle, and likely innervated by the circadian rhythm system in a day-night variant pattern either. Since nearly all patients with neurodegenerative diseases suffer rhythmic sleep disorders in the initial stages, which become aggravated with the development of disease and often exhibit glutamate uptake dysfunction either, we consider whether the glutamate transporters of both types could be used as the potential targets to help redress the circadian rhythm sleep disorders of patients with neurodegenerative diseases. Therefore, in this review, we sought to analyze the principles governing glutamate transmission and discuss whether the circadian rhythm regulatory properties of these processes endow glutamate transporters with unique functions in the sleep-wake shift of the brain. We attempt to provide a theoretical framework in this field for future studies, and to help in the exploration of potential therapeutic targets to delay or prevent the development of neurodegenerative diseases. PMID- 30485060 TI - Surface-Functionalized Silicon Nanoparticles as Anode Material for Lithium-ion Battery. AB - An epoxy group was successfully attached to the surface of silicon nano particle (SiNPs) via a silanization reaction between silanol-enriched SiNPs and functional silanes. The epoxy-functionalized SiNPs showed much improved cell performance compared with the pristine SiNPs due to the increased stability with electrolyte and the formation of a covalent bond between the epoxy group and the polyacrylic acid binder. Furthermore, the anode laminate made from epoxy-SiNPs showed much enhanced adhesion strength. Post-test analysis shed light on how the epoxy functional group affects the physical and electrochemical properties of the SiNPs anode. PMID- 30485061 TI - Investigation of the Physical Properties of Plasma Enhanced Atomic Layer Deposited Silicon Nitride as Etch Stopper. AB - Correlations between physical properties linking film quality with wet etch rate (WER), one of the leading figures of merit, in plasma-enhanced atomic layer deposition (PEALD) grown silicon nitride (SiNx) films remain largely unresearched. Achieving a low WER of a SiNx film is especially significant in its use as an etch stopper for technology beyond 7 nm node semiconductor processing. Herein, we explore the correlation between the hydrogen concentration, hydrogen bonding states, bulk film density, residual impurity concentration, and the WERs of PEALD SiNx using Fourier transform infrared spectrometry, X-ray reflectivity, and spectroscopic ellipsometry, etc. PEALD SiNx films for this study were deposited using hexachlorodisilane and hollow cathode plasma source under a range of process temperatures (270 degrees C - 360 degrees C) and plasma gas compositions (N2/NH3 or Ar/NH3) to understand the influence of hydrogen concentration, hydrogen bonding states, bulk film density, and residual impurity concentration on the WER. Varying hydrogen concentration and differences in the hydrogen bonding states resulted in different bulk film densities, and accordingly, a variation in WER. We observe a linear relationship between hydrogen bonding concentration and WER as well as a reciprocal relationship between bulk film density and WER. Analogous to the PECVD SiNx processes, a reduction in hydrogen bonding concentration arises from either (1) thermal activation or (2) plasma excited species. However, unlike the case with silane (SiH4)-based PECVD SiNx, PEALD SiNx WERs are affected by residual impurities of Si precursors (i.e., chlorine impurity). Thus, possible wet etching mechanisms in HF in which the WER is affected by hydrogen bonding states or residual impurities are proposed. The shifts of amine basicity in SiNx due to different hydrogen bonding states and the changes in Si electrophilicity due to Cl impurity content are suggested as the main mechanisms that influence WER in the PEALD processes. PMID- 30485062 TI - Controlled-Size Hollow Magnesium Sulfide Nanocrystals Anchored on Graphene for Advanced Lithium Storage. AB - Magnesium sulfide (MgS), representative of alkaline-earth metal chalcogenides (AEMCs), is a potential conversion/alloy-type electrode material for lithium ion batteries (LIBs), by virtue of its low potential voltage, high theoretical capacity and abundant magnesium resource. However, the limited capacity utilization and inferior rate performance still hinder its practical application, and the progress is rather slow due to the challenging fabrication technique for MgS. Herein, we report a series of controlled-size hollow MgS Nanocrystals (NCs) homogenously distributed on graphene (MgS@G), fabricated through a metal hydride framework (MHF) strategy, and its application as advanced electrode material for LIBs. The hollow structure of MgS NCs are mainly attributed to the Kirkendall effect and the escape of H atoms from metal hydride during sulfuration. The as synthesized MgS@G demonstrates robust nanoarchitecture and admirable interactions, which assure spatially confined lithiation/delithiation process, optimize the dynamics of two-steps conversion/alloying reactions, and induce a synergetic pseudocapacitive storage contribution. As the result, a representative MgS@G composite delivers a largely enhanced capacity of >1208 mAh g-1 at a current density of 100 mA g-1, and a remarkable long-term cycle stability at a high current density of 5 A g-1 with a capacity of 838 mAh g-1 over 3000 cycles, indicating well-sustained structural integrity. This work presents an effective route towards the development of high-performance magnesium-based material for energy storage. PMID- 30485063 TI - Electrochemical Polishing of Two-Dimensional Materials. AB - Two-dimensional (2D) layered materials demonstrate their exquisite properties such as high temperature superconductivity, superlubricity, charge density wave, piezotronics, flextronics, straintronics, spintronics, valleytronics, and optoelectronics, mostly, at the monolayer limit. Following initial breakthroughs based on micromechanically exfoliated 2D monolayers, significant progress has been made in recent years towards the bottom-up synthesis of large-area monolayer 2D materials such as MoS2 and WS2 using physical vapor deposition (PVD) and chemical vapor deposition (CVD) techniques in order to facilitate their transition into commercial technologies. However, the nucleation and subsequent growth of the secondary, tertiary, and greater numbers of vertical layers poses a significant challenge not only towards the realization of uniform monolayers, but also to maintain their consistent electronic and optoelectronic properties which change abruptly when transitioning from the monolayer to multilayer form. Chemical or physical techniques which can remove the unwarranted top layers without compromising the material quality will have tremendous consequence towards the development of atomically flat, large-area, uniform monolayers of 2D materials. Here, we report a simple, elegant, and self-limiting electrochemical polishing technique which can thin down any arbitrary thickness of 2D material, irrespective of whether these are obtained using powder vapor transport (PVT) or mechanical exfoliation, into their corresponding monolayer form at room temperature within a few seconds without compromising their atomistic integrity. The effectiveness of this electrochemical polishing technique is inherent to 2D transition metal dichalcogenides (TMDCs) owing to the stability of their basal planes, enhanced edge reactivity, and stronger-than-van der Waals (vdW) interaction with the substrate. Our study also reveals that 2D monolayers are chemically more robust and corrosion resistant compared to their bulk counterparts in similar oxidative environments which enables electrochemical polishing of such materials down to a monolayer. PMID- 30485064 TI - Blue-emitting Photostable Hybrid Films for High-efficiency Large-area Light Converter and Photonic Applications. AB - A blue fluorophore of Schiff base zinc complex is prepared by a hydrolysis-free solution-based synthetic method. Under UV excitation, the complex produces blue emission with a quantum yield (Q) of 42.6% in methylene chloride and 24.0% in standalone powder form. Quantum mechanical calculations show that the blue emission is generated by the change in the chemical state of the ligand associated with the complexation with Zn cations. Thin films of Zn complexes incorporated in polymethylmethacrylate (PMMA) and cellulose acetate butyrate (CAB) polymers are also prepared by dispersing the complexes into the polymer matrices. These hybrid polymer films exhibit several notable features, particularly enhanced luminescence efficiency (with maximum Q of 85.8% for PMMA and 30.0% for CAB) and scalability for fabrication over a large area while retaining the original properties of the host polymers. Light-emitting diodes are also fabricated using the CAB hybrid thin films, and they show a Q of 43.2% with excellent photostability. The complex and its hybrid films demonstrate their great potential for such applications as UV-to-blue conversion devices in photoelectronics, solar-cell concentrators, solid-state lighting and display, and green-house agriculture. PMID- 30485065 TI - Nanoscale Topography-Rigidity Correlation at the Surface of T Cells. AB - The mechanical properties of cells affect their function, in sensing, development and motility. However, the rigidity of the cell surface and its correlation to its local topography remain poorly understood. Here, we applied Quantitative Imaging AFM to capture high resolution force maps at the surface of non-adherent T cells. Using this method, we found a positive topography-rigidity correlation at the cells' surface, as opposed to a negative correlation at the surface of adherent cells. We then used 3D single molecule localization microscopy of the membrane and cortical actin, and an actin-perturbing drug, to implicate actin involvement in the positive rigidity-topography correlation in T cells. Our results shed new light on the variability of cell-surface rigidity and its underlying mechanism, showing a functional role for cortical actin in the PM protrusions of T cells, as they are locally more rigid than their surroundings. These findings suggest the possible functional role of the membrane protrusions as a mechanosensor. PMID- 30485066 TI - Nanochannel-Confined Graphene Quantum Dots for Ultrasensitive Electrochemical Analysis of Complex Samples. AB - Herein, we present an electrochemical sensing platform based on nanochannel confined graphene quantum dots (GQDs), which is able to detect a spectrum of small analytes in complex samples with high sensitivity. Vertically-ordered mesoporous silica-nanochannel film (VMSF) is decorated on the supporting electrode, conferring the electrode with excellent anti-fouling and anti interference properties through steric exclusion and electrostatic repulsion. The synthesized GQDs with different functionalities are confined in the nanochannels of VMSF through electrophoresis, serving as the recognition element and signal amplifier. Without the usual need of tedious pretreatment, ultrasensitive and fast detection of Hg2+, Cu2+ and Cd2+ (with limit of detection or LOD of 9.8 pM, 8.3 pM and 4.3 nM, respectively) and dopamine (LOD of 120 nM) in complex food (Hg2+-contaminated seafood), environmental (soil leaching solution), and biological (serum) samples are realized as the proof-of-concept demonstrations. PMID- 30485067 TI - Kinetics of Strand Displacement and Hybridization on Wireframe DNA Nanostructures: Dissecting the Roles of Size, Morphology, and Rigidity. AB - Dynamic wireframe DNA structures have gained significant attention in recent years, with research aimed towards using these architectures for sensing and encapsulation applications. For these assemblies to reach their full potential, however, knowledge on the rates of strand displacement and hybridization on these constructs is required. Herein, we report the use of single molecule fluorescence methodologies to observe the reversible switching between double- and single stranded forms of triangular wireframe DNA nanotubes. Specifically, by using fluorescently labeled DNA strands, we were able to monitor changes in intensity over time as we introduced different sequences. This allowed us to extract detailed kinetic information on the strand displacement and hybridization processes. Due to the polymeric NT structure, the ability to individually address each of the three sides, and the inherent polydispersity of our samples as a result of the step polymerization by which they are formed, a library of compounds could be studied independently yet simultaneously. Kinetic models relying on simple exponential decays, multi-exponential decays or sigmoidal behavior were adjusted to the different constructs to retrieve erasing and refilling kinetics. Correlations were made between the kinetic behavior observed, the site accessibility, the nanotube length, and the structural robustness of wireframe DNA nanostructures, including fully single-stranded analogs. Overall, our results reveal how the length, morphology, and rigidity of the DNA framework modulate the kinetics of strand displacement and hybridization, as well as the overall addressability and structural stability of the structures under study. PMID- 30485068 TI - Glutathione-Responsive Prodrug Nanoparticles for Effective Drug Delivery and Cancer Therapy. AB - Spurred by recent progress in medicinal chemistry, numerous lead compounds have sprung up in the past few years, while the majority are hindered by hydrophobicity, which greatly challenges druggability. In an effort to assess the potential of platinum (Pt) candidates, the nanosizing approach to alter the pharmacology of hydrophobic Pt(IV) prodrugs in discovery and development settings is described. The construction of a self-assembled nanoparticle (NP) platform, composed of amphiphilic lipid-PEG for effective delivery of Pt(IV) prodrugs capable of resisting thiol-mediated detoxification through a glutathione (GSH) exhausting effect, offers a promising route to synergistically improve safety and efficacy. After a systematic screening, the optimized NPs (referred to as P6 NPs) exhibited small particle size (99.3 nm), high Pt loading (11.24%), reliable dynamic stability (~7 days), and rapid redox-triggered release (~80% in 3 days). Subsequent experiments on cells support the emergence of P6 NPs as a highly effective means of transporting a lethal dose of cargo across cytomembranes through macropinocytosis. Upon reduction by cytoplasmic reductants, particularly GSH, P6 NPs under disintegration released sufficient active Pt(II) metabolites, which covalently bound to target DNA and induced significant apoptosis. The PEGylation endowed P6 NPs with in vivo longevity and tumor specificity, which were essential to successfully inhibit the growth of cisplatin-sensitive and resistant xenograft tumors, while effectively alleviating toxic side-effects associated with cisplatin. P6 NPs are, therefore, promising for overcoming the bottleneck in the development of Pt drugs for oncotherapy. PMID- 30485069 TI - Plasma-Assisted Synthesis of NiSe2 Ultrathin Porous Nanosheets with Selenium Vacancies for Supercapacitor. AB - Two-dimensional (2D) NiSe2 nanosheets with porous ultrathin structure and selenium vacancies (NiSe2 PNSvac) were synthesized via plasma-assisted dry exfoliation for supercapacitor. The specific capacitance of the NiSe2 PNSvac was 466 F g-1 in 1 M KOH electrolyte, which is much higher than those of NiSe2 ultrathin nanosheeets (328 F g-1) and NiSe2 particles (251 F g-1). After 1000 cycles, the specific capacitance of the NiSe2 PNSvac can be maintained well, indicating its high cycling stability. The superior performance arose from its high conductivity, short electrolyte diffusion distance and large specific surface area. PMID- 30485070 TI - Amphiphilic Drug Conjugates as Nanomedicines for Combined Cancer Therapy. AB - Chemotherapy suffers from some limitations such as poor bioavailability, rapid clearance from blood, poor cellular uptake, low tumor accumulation, severe side effects on healthy tissues and most importantly multidrug resistance (MDR) in cancer cells. Nowadays, a series of smart drug delivery system (DDS) based on amphiphilic drug conjugates (ADCs) has been developed to solve these issues, including polymer-drug conjugate (PDC), phospholipid-mimicking prodrugs, peptide drug conjugates (PepDCs), pure nanodrug (PND), amphiphilic drug-drug conjugate (ADDC), and Janus drug-drug conjugate (JDDC). These ADCs can self-assemble into nanoparticles (NPs) or microbubbles (MBs) for targeted drug delivery by minimizing the net amount of excipients, realizing great goals, such as stealth behavior and physical integrity, high drug loading content, no premature leakage, long blood circulation time, fixed drug combination, and controlled drug-release kinetics. Besides, these self-assembled systems can be further used to load additional therapeutic agents and imaging contrast agents for combined therapy, personalized monitoring of in vivo tumor targeting, and the pharmacokinetics of drugs for predicting the therapeutic outcome. In this review, we will summarize the latest progress in the development of ADCs based combination chemotherapy and discuss the important roles for overcoming the tumor MDR. PMID- 30485071 TI - Cyclic Hypervalent Iodine Reagents: Enabling Tools for Bond Disconnection via Reactivity Umpolung. AB - The efficient synthesis of organic compounds is an important field of research, which sets the basis for numerous applications in medicine or materials science. Based on the polarity induced by functional groups, logical bond disconnections can be deduced for the elaboration of organic compounds. Nevertheless, this classical approach makes synthesis rigid, as not all bond disconnections are possible. The concept of Umpolung has been therefore introduced: by inverting the normal polarity of functional groups, new disconnections become possible. Among the tools for achieving Umpolung, hypervalent iodine reagents occupy a privileged position. The electrophilicity of the iodine atom and the reactivity of the hypervalent bond allow access to electrophilic synthons starting from nucleophiles. Nevertheless, some classes of hypervalent iodine reagents can be too unstable for many applications, in particular involving metal catalysis. In this context, cyclic hypervalent iodine reagents, especially benziodoxolones (BXs), have been known for a long time to be more stable than their acyclic counterparts, yet their synthetic potential had not been fully exploited. In this Account, we report our efforts since 2008 on the use of BX reagents in the development of new transformations in organic synthesis, which showed for the first time their versatility as synthetic tools. Our work started with electrophilic alkynylation, as alkynes are one of the most important functional groups in organic chemistry, but are usually introduced as nucleophiles. We used ethynylbenziodoxolones (EBXs) in the direct alkynylation of nucleophiles, such as keto esters, thiols, or phosphines. The reagents could then be applied to the gold- and palladium-catalyzed alkynylation of C-H bonds on (hetero)arenes, leading to a more efficient alternative to the Sonogashira reaction. More complex reactions were then developed with formations of several bonds in a single transformation. Gold- and platinum-catalyzed cyclization/alkynylation domino processes gave access to new types of alkynylated heterocycles. Multifunctionalization of olefins became possible through intramolecular oxy- and amino-alkynylations. (Enantioselective) copper-catalyzed oxy-alkynylation of diazo compounds led to stereocenters with perfect atom economy. Finally, EBXs were also used for the alkynylation of radicals generated under photoredox conditions. Since 2013, we then extended the use of BX reagents to other transformations. Azidobenziodoxol(on)ess (ABXs) were used in the azidation of keto esters, enol silanes, and styrenes. New more stable derivatives were introduced. Cyanobenziodoxolones (CBXs) enabled the cyanation of stabilized enolates, thiols, and radicals. Finally, new BX reagents were developed for the Umpolung of indoles and pyrroles. They could be used in metal-catalyzed directed C-H functionalizations, as well as in Lewis acid mediated oxidative coupling to give functionalized bi(hetero)arenes. In the past decade, our group and others have shown that BX reagents are not only "structural beauties", but also extremely useful reagents in synthetic chemistry. A toolbox of cyclic hypervalent iodine reagents is now available to achieve Umpolung-based disconnections. We are convinced that the field is still in its infancy, and many new reagents and transformations still remain to be discovered. PMID- 30485072 TI - Self-Powered Ultraviolet Photodetector with Super High Photoresponsivity (3.05 A/W) Based on the GaN/Sn:Ga2O3 pn Junction. AB - Ultraviolet (UV) radiation has a variety of impacts including the health of humans, the production of crops and the lifetime of buildings. Based on the photovoltaic effect, self-powered UV photodetectors can measure and monitor UV radiation without any power consumption. However, the current low photoelectric performance of these detectors has hindered their practical use. In our study, a super-high performance self-powered UV photodetector based on GaN/Sn:Ga2O3 pn junction was generated by depositing a Sn doped n-type Ga2O3 thin film onto a p type GaN thick film. The responsivity at 254 nm reached up to 3.05 A/W without power supply and had a high UV/visible rejection ratio of R254 nm/R400 nm=5.9*103 and an ideal detectivity at 1.69*1013 cm.Hz1/2.W-1, which is well beyond the level of previous self-powered UV photodetectors. Moreover, our device also has a low dark current (1.8*10-11A), a high Iphoto/Idark ratio (~104), and a fast photoresponse time of 18 ms without bias. These outstanding performance results are attributed to the rapid separation of photo-generated electron-hole pairs driven by a high built-in electric field in the interface depletion region of the GaN/Sn: Ga2O3 pn junction. Our results provide an improved and easy route to constructing high performance self-powered UV photodetectors that can potentially replace traditional high energy consuming UV detection systems. PMID- 30485073 TI - Synthesis and Evaluation of Multifunctional Fluorescent Inhibitors with Synergistic Interaction of PSMA and Hypoxia for Prostate Cancer. AB - Prostate cancer is one of the most common cancers in the world. It is widely known that prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer, and hypoxia is a common characteristic of many solid tumors, including prostate cancer. In this study, we designed multifunctional fluorescent inhibitors to target PSMA and tumor hypoxia in order to increase the tumor uptake of inhibitors. Novel PSMA inhibitors were prepared using lysine as the backbone to connect three different functional groups: the glutamate-urea-lysine (GUL) structure for inhibiting PSMA, 2-nitroimidazole for the hypoxia-sensitive moiety, and a near-infrared fluorophore (sulfo-Cyanine 5.5). According to the in vitro PSMA binding assay, novel fluorescent inhibitors were demonstrated to have nanomolar binding affinities. Multifunctional inhibitor 2 with one 2 nitroimidazole had a similar inhibitory activity to inhibitor 1 that did not contain the hypoxia targeting moiety, but multifunctional inhibitor 3 with two 2 nitroimidazoles showed lower inhibitory activity than inhibitor 1 due to the bulky structure of the hypoxia-sensitive group. However, in vivo optical imaging and ex vivo biodistribution studies indicated that both multifunctional inhibitors 2 and 3 had higher accumulation in tumors than inhibitor 1 due to a synergistic combination of PSMA and hypoxia targeting moieties. These observations suggest that this novel multifunctional strategy might be a promising approach to improve the diagnosis and therapy of prostate cancer. PMID- 30485074 TI - Kinetic delay in partitioning and parallel particle pathways: under-appreciated aspects of environmental transport. AB - We outline the general conditions under which chemicals of high hydrophobicity or, more generally, high partition ratios (HPRs) in water or air, may experience unexpectedly long kinetic delays in approaching equilibrium conditions with organic media. Such a 'hydrophobic delay' in the case of KOW or an 'aerophobic' delay in the case of KOA, may be misinterpreted as being caused by a change in partitioning behavior or mechanism, resulting in development of non-linear regression models describing inter-media partitioning. In fact, the partitioning is fundamentally linear but is distorted by a kinetic delay in partitioning. To illustrate this concept, we first compile the fundamental equations describing the diffusive equilibration processes, including a complementary transport mechanism termed a Parallel Particle Pathway (PPP). Such a mechanism may occur simultaneously, shortening the HPR delay, and complicating interpretation. Second, we describe five examples in which the HPR delay explains the observed and occasionally difficult-to-interpret environmental behavior of chemicals, namely studies of air-aerosol partitioning, chemical accumulation in indoor dust and surfaces, air-vegetation partitioning, internal transport in organisms, and fish bioaccumulation and toxicity. We believe that the general HPR delay and PPP issues deserve exposure as a commonly occurring and often under-appreciated process. PMID- 30485075 TI - Visualizing Kinetically Robust CoIII4L6 Assemblies In Vivo: SPECT Imaging of the Encapsulated [99mTc]TcO4- Anion. AB - Non-covalent encapsulation is an attractive approach for modifying the efficacy and physiochemical properties of both therapeutic and diagnostic species. Abiotic self-assembled constructs have shown promise, yet many hurdles between in vitro and (pre)clinical studies remain, not least the challenges associated with maintaining the macromolecular, hollow structure under non-equilibrium conditions. Using a kinetically robust CoIII4L6 tetrahedron we now show the feasibility of encapsulating the most widely used precursor in clinical nuclear diagnostic imaging, the gamma emitting [99mTc]TcO4- anion, under conditions compatible with in vivo administration. Subsequent SPECT imaging of the caged anion reveals a marked change in the biodistribution compared to the thyroid accumulating free oxo-anion, thus moving clinical applications of (metallo)supramolecular species a step closer. PMID- 30485076 TI - Modeling atmospheric age distribution of elemental carbon using a regional age resolved particle representation framework. AB - The aging process of soot particles has significant implications when estimating their impacts on air quality and climate. In this study, the source-oriented UCD/CIT model with externally-mixed aerosol representation is expanded to track the age distribution of elemental carbon (EC) in Southeast Texas. EC with the age of 0-3 hours (i.e. emitted less than 3 hours ago) accounts for ~70-90% of total in urban Houston and 20-40% in rural areas of southeast Texas in August 2000. Significant diurnal variations in the mean age of EC are predicted, with higher contributions from fresh particles during the morning and early evening due to increased traffic emission and reduced atmospheric mixing. Spatially, the mean age of EC decreases with proximity to major sources. Ground-level EC with the age >6 hours are less than 20% of the first age group over land, and background EC accounts for majority over the Gulf of Mexico. Differences in EC spatial distribution indicate that age distribution could have regional impact on aerosol optical and hygroscopic properties, and thus potentially affect cloud formation and radiation balance. Appropriately accounting for the differential properties due to age distribution is needed to better evaluate aerosol direct and indirect effects. PMID- 30485077 TI - POLYMER CANCEROSTATICS TARGETED BY RECOMBINANT ANTIBODY FRAGMENTS TO GD2-POSITIVE TUMOR CELLS. AB - A water-soluble polymer cancerostatic actively targeted against cancer cells expressing a disialoganglioside antigen GD2 was designed, synthesized and characterized. A polymer conjugate of an anti-tumor drug doxorubicin with a N-(2 hydroxypropyl)methacrylamide-based copolymer was specifically targeted against GD2 antigen-positive tumor cells using a recombinant single chain fragment (scFv) of an anti-GD2 monoclonal antibody. The targeting protein ligand was attached to the polymer-drug conjugate either via a covalent bond between the amino groups of the protein using a traditional non-specific aminolytic reaction with a reactive polymer precursor or via a non-covalent but highly specific interaction between bungarotoxin covalently linked to the polymer and the recombinant scFv modified with a C-terminal bungarotoxin-binding peptide. The GD2 antigen binding activity and GD2-specific cytotoxicity of the targeted non-covalent polymer-scFv complex proved to be superior to the covalent polymer-scFv conjugate. PMID- 30485078 TI - Synthesis of Re(I) Rings Comprising Different Re(I) Units and Their Light Harvesting Abilities. AB - Trimethylamine N-oxide (Me3NO) could selectively remove only one CO ligand from fac-[Re(N^N)(CO)3(PR2R')]+ (N^N = diimine ligand), whereby only the CO ligand in the trans position to the phosphorus ligand was selectively removed to give cis,trans-[ReI(N^N)(CO)2(PR2R')(L)] n+ in good yields. This decarbonylation reaction using Me3NO was found to be especially useful for synthesizing biscarbonyl Re(I) complexes with electron-withdrawing groups in the diimine ligand, which could not be synthesized or were obtained only in low yields by the photochemical method. Me3NO also selectively removed the carbonyl ligands in the trans position to the phosphorus ligands from the edge Re(I) complex units, which have the fac-[Re(N^N)(CO)3(PR2R')]+ structure, in linear-shaped Re(I) multinuclear complexes. This reaction was successfully applied to synthesize a novel precursor with ring-shaped multinuclear Re complexes (Re-rings) comprising different kinds of Re(I) units. The newly synthesized Re-rings, which consist of one Re unit with a 4,4'-bis(trifluoromethyl)-2,2'-bipyridine (CF3bpy) ligand and one or two Re unit(s) with a 2,2'-bipyridine (bpy) ligand, showed almost quantitative excitation-energy harvesting ability from the Re unit(s) with bpy to that with CF3bpy. PMID- 30485079 TI - Rapid Dissolution of BaSO4 by Macropa, an 18-Membered Macrocycle with High Affinity for Ba2. AB - Insoluble BaSO4 scale is a costly and time-consuming problem in the petroleum industry. Clearance of BaSO4-impeded pipelines requires chelating agents that can efficiently bind Ba2+, the largest nonradioactive +2 metal ion. Due to the poor affinity of currently available chelating agents for Ba2+, however, the dissolution of BaSO4 remains inefficient, requiring very basic solutions of ligands. In this study, we investigated three diaza-18-crown-6 macrocycles bearing different pendent arms for the chelation of Ba2+ and assessed their potential for dissolving BaSO4 scale. Remarkably, the bis-picolinate ligand macropa exhibits the highest affinity reported to date for Ba2+ at pH 7.4 (log K' = 10.74), forming a complex of significant kinetic stability with this large metal ion. Furthermore, the BaSO4 dissolution properties of macropa dramatically surpass those of the state-of-the-art ligands DTPA and DOTA. Using macropa, complete dissolution of a molar equivalent of BaSO4 is reached within 30 min at room temperature in pH 8 buffer, conditions under which DTPA and DOTA only achieve 40% dissolution of BaSO4. When further applied for the dissolution of natural barite, macropa also outperforms DTPA, showing that this ligand is potentially valuable for industrial processes. Collectively, this work demonstrates that macropa is a highly effective chelator for Ba2+ that can be applied for the remediation of BaSO4 scale. PMID- 30485080 TI - Correction to "Quantitative Characterization of Bivalent Probes for a Dual Bromodomain Protein, Transcription Initiation Factor TFIID subunit 1". PMID- 30485081 TI - Reactivity toward Unsaturated Small Molecules of Thiolate-Bridged Diiron Hydride Complexes. AB - In the presence of 1 equiv of tBuNC, the homolytic cleavage of the FeIII-H bond in the diiron terminal hydride complex [Cp*Fe( t-H)(MU-eta2:eta4-bdt)FeCp*][BF4] (1[BF4]) smoothly took place to release 1/2 H2, followed by binding of a tBuNC group to the unsaturated FeII center. Interestingly, upon exposure of 1[BF4] to 1 atm of acetylene, the isomerization process of the hydride ligand from the terminal to bridging coordination site was unaffected. Upon treatment of the diiron hydride bridged complex 2[BF4] with acetylene at 30 degrees C, two FeIII H bonds were broken, and then an acetylene molecule was coordinated to the diiron centers in a novel MU-eta2:eta2 side-on fashion. In the above reaction system, the hydride ligands whether terminal or bridging all play a role as the electron donor for the reduction of the diiron centers from FeIIIFeIII to FeIIIFeII. These reaction patterns are reminiscent of the vital E4 state responsible for N2 binding and H2 liberation in the catalytic cycle of nitrogenase, which contains two {Fe-H-Fe} motifs as electron reservoirs for the reduction of the iron centers. Differently, when treating 1[BF4] with TMSN3, the terminal hydride ligand was inserted into the azide group to give a diiron amide complex 4[BF4] in moderate yield. PMID- 30485082 TI - Estimating the Individual Spectroscopic Properties of Three Unique EuIII Sites in a Coordination Polymer. AB - We isolated a coordination polymer with the formula [Eu3(3,5 dcba)9(H2O)(dmf)3].2dmf, with three unique EuIII coordination sites in the asymmetric unit, with the EuIII ions bridged by 3,5-dichlorobenzoato (3,5-dcba) ligands. The coordination polymer crystallized in the triclinic space group P1 with unit cell dimensions a = 12.4899(15), b = 16.326(2), and c = 25.059(3) A, alpha = 84.271(3) degrees , beta = 84.832(3) degrees , and gamma = 68.585(3) degrees and V = 4725.2(10) A3. The characteristic 5D0 -> 7F J ( J = 0-4) EuIII transitions were observed upon ligand-centered excitation. Emission lifetimes of 0.825 +/- 0.085 and 1.586 +/- 0.057 ms were observed and were attributed to the sites with coordination of water or dimethylformamide (dmf) molecules to each ion, respectively. Through a combination of spectroscopy and calculations, we determined the photophysical properties of each unique EuIII site. Energy transfer rates ligand -> EuIII were determined for each unique site using the overlapped polyhedra method. The rates depend on the coordinated water molecules and the different donor-acceptor distances. The two sites without coordinated water molecules and shortest donor-acceptor distance display the fastest energy transfer rate ligand -> EuIII, whereas the site with coordinated water molecules and longest donor-acceptor distance displays the slowest energy-transfer rate. Donor-acceptor distances were estimated computationally and were confirmed by calculating the frontier orbitals in the asymmetric units of the polymer using density functional theory. PMID- 30485083 TI - Understanding the Importance of Cu(I) Intermediates in Self-Reducing Molecular Inks for Flexible Electronics. AB - Fast and scalable low-temperature deposition of microscale metallic features is of utmost importance for the development of future flexible smart applications including sensors, wireless communication, and wearables. Recently, a new class of metal-organic decomposition (MOD) copper inks was developed, consisting of self-reducing copper formate containing amine complexes. From these novel inks, copper metal features with outstanding electrical conductivity (+/-105 S cm-1) are deposited at a temperature of 150 degrees C or less, which is well below the reduction temperature of orthorhombic alpha-copper formate (around 225 degrees C). However, the underlying principle of this reaction mechanism and the relationship between the corresponding temperature shift and the amine coordination are still under debate. The current study provides a full explanation for the shift in reduction temperatures via in situ characterization. The results clearly indicate that the structural resemblance and stability of the Cu(II) starting compound and the occurring Cu(I) intermediate during the in situ reduction are the two main variables that rationalize the temperature shift. As such, the thermal compatibility of copper MOD inks with conventional plastic substrates such as polyethylene terephthalate can be explained, based on metal organic complex properties. PMID- 30485084 TI - Nanoscale Metal-Organic Layers for Radiotherapy-Radiodynamic Therapy. AB - Nanoscale metal-organic layers (nMOLs) are an emerging class of 2D crystalline materials formed by reducing the dimensionality of nanoscale metal-organic frameworks (nMOFs). nMOLs hold significant potential in biomedical applications by combining the structural and compositional tunability of nMOFs and anisotropic properties of 2D nanomaterials. Here we report two novel nMOLs, Hf12-Ir and Hf6 Ir, based on Hf12 and Hf6 secondary building units (SBUs) and photosensitizing Ir(bpy)[dF(CF3)ppy]2+ derived ligands [bpy = 2,2'-bipyridine; dF(CF3)ppy = 2-(2,4 difluorophenyl)-5-(trifluoromethyl)pyridine] for radiotherapy (RT) and radiodynamic therapy (RDT). Upon X-ray irradiation, the Hf12 or Hf6 SBUs in the nMOLs efficiently absorb X-rays to enhance RT by producing hydroxyl radicals and to elicit RDT through the excitation of Ir(bpy)[dF(CF3)ppy]2+ derived ligands to generate singlet oxygen and superoxide anions. Hf12-Ir and Hf6-Ir promoted effective cell instant death through RDT and cell reproductive death through RT to elicit superb anticancer efficacy, resulting in >99% tumor regression at low X ray doses of 0.5 * 5 Gy. PMID- 30485085 TI - Efficient Modeling of Optical Excitations of Colloidal Core-Shell Semiconductor Quantum Dots by Using Symmetrized Orbitals. AB - An efficient method for the theoretical investigation of optical properties of semiconductor core-shell quantum dots (CSQDs) is introduced within the multi-band approach, which takes the advantage of the symmetry of the system. The heteroepitaxial strain and excitonic effect are included in the calculation of energy levels, envelope wave-functions, exciton binding energy, and linear absorption coefficient. The adoption of symmetrized orbitals allows improvement of the computation time significantly. To avoid appearance of spurious solutions caused by imbalance of basis functions adopted, we consider an 8-band model which is block-diagonalized into two conduction bands and six valence bands, that we call 2+6-band model. The band non-parabolicity effect is modeled by an energy dependent term, such that the density of states obtained can mimic the actual density of states of a full-band model. The simulated absorption spectra of ZnTe/ZnSe CSQD are in good agreement with those observed experimentally, including the high rise of absorption at energies far above the absorption edge. PMID- 30485086 TI - Using Nanospray Liquid Chromatography and Mass Spectrometry to Quantitate Shiga Toxin Production in Environmental Escherichia coli Recovered from a Major Produce Production Region in California. AB - A set of 45 environmental strains of Shiga toxin producing E. coli (STEC) from three California counties were analyzed for Shiga toxin production by nanospray liquid chromatography-mass spectrometry and Vero cell bioassay. The STEC in this set comprised six serotypes ((O113:H21, O121:H19, O157:H7, O6:H34, O177:H25, and O185:H7) each containing either the stx2a or stx2c operon. Six of the seven O113:H21 were found to contain two distinct stx2a operons. Eight strains of O157:H7 possessed a stx2c operon whose A subunit gene was interrupted by an insertion sequence (IS1203v). Shiga toxin production was induced by nutrient depletion and quantitated by mass spectrometry. The 37 strains produced Shiga toxins in a fifty-fold range (1.4 ng/ml to 49 ng/ml). The IS-interrupted strains expressed low but measurable amounts of the B subunits (0.5 -1.9 ng/ml). Another strain possessed an identical stx operon without an IS interruption and produced intact Stx2c (5.7 ng/ml). PMID- 30485087 TI - Simulating Powder X-ray Diffraction Patterns of Two-Dimensional Materials. AB - Powder X-ray diffraction (PXRD) is widely used to study atomic arrangements in ordered materials. The Bragg equation, which describes diffraction of a three dimensional crystal, fails in two-dimensional (2D) cases. Complete integration of diffraction signals from a continuum instead of discrete directions in the Bragg equation is thus required for proper data interpretation of 2D materials. Furthermore, modeling of preferred orientation of the 2D crystals as well as geometric disorders are also of vital importance. Here, we present a complete integration method in real space (CIREALS) for PXRD simulation of monolayer or multilayer 2D crystals, especially 2D metal-organic layers and 2D covalent organic frameworks. By working in real space instead of reciprocal space, we can readily capture the 2D geometry and preferred orientation of these materials. The predicted PXRD patterns by CIREALS facilitates structure analysis of these new types of 2D material. PMID- 30485088 TI - Prediction of CRISPR sgRNA activity using a deep convolutional neural network. AB - The CRISPR-Cas9 system derived from adaptive immunity in bacteria and archaea has been developed into a powerful tool for genome engineering with wide-ranging applications. Optimizing single guide RNA (sgRNA) design to improve efficiency of target cleavage is a key step for successful gene editing using the CRISPR-Cas9 system. Because not all sgRNAs that cognate to a given target gene are equally effective, computational tools have been developed based on experimental data to increase the likelihood of selecting effective sgRNAs. Despite considerable efforts to date, it still remains a big challenge to accurately predict functional sgRNAs directly from large-scale sequence data. We propose DeepCas9, a deep-learning framework based on convolutional neural network (CNN), to automatically learn the sequence determinants and further enable the identification of functional sgRNAs for the CRISPR-Cas9 system. We show that the CNN method outperforms previous methods in both, the ability to correctly identify highly active sgRNAs in experiments not used in the training and the ability to accurately predict the target efficacies of sgRNAs in different organisms. Besides, we further visualize the convolutional kernels and show the match of identified sequence signatures and known nucleotide preferences. We finally demonstrate the application of our method for the design of next generation genome-scale CRISPRi and CRISPRa libraries targeting human and mouse genomes. We expect that DeepCas9 will assist in reducing the numbers of sgRNAs that need to be experimentally validated to enable more effective and efficient genetic screens and genome engineering. DeepCas9 can be freely accessed at https://github.com/lje00006/DeepCas9. PMID- 30485089 TI - Towards a better understanding of starch-monoglyceride-protein interactions. AB - The aim of the present study was to investigate the interactions between maize starch (MS), beta-lactoglobulin (betaLG) and monoglycerides (MG) containing different fatty acids in a model system. Results from the Rapid Visco Analyzer (RVA) showed that MS-MGC14:0 and MS-MGC16:0 systems presented a viscosity peak during RVA cooling and/or holding stage, while MS-MGC18:0, MS-MGC18:1 and MS MGC18:2 systems did not show obvious changes in pasting profile. Addition of betaLG altered significantly the pasting profiles of MS-MG systems in different ways, with the most obvious change observed for MS-MGC18:0 system. Results from differential scanning calorimetry (DSC), Raman spectroscopy and X-ray diffraction showed that the complexes in ternary systems were more ordered than those in binary systems. The thermal transition temperatures of complexes in binary and ternary systems were similar, although the enthalpy changes were greater for ternary than for binary systems. From the above results, we concluded that addition of betaLG promoted the formation of MS-MG complexes rather than the involvement of formation of ternary MS-MG-betaLG complexes. PMID- 30485090 TI - A Pair of Enantiomeric Bis- seco-abietane Diterpenoids from Cryptomeria fortunei. AB - (+/-)-Cryptomeriolide, a pair of racemic bis- seco-abietane diterpenoids, were isolated from the bark of Cryptomeria fortunei. The separation of enantiomers was achieved by using chiral stationary phase HPLC. Their structures including the absolute configuration and conformations in solution and solid state were determined by extensive analysis of spectroscopic data, single-crystal X-ray diffraction, and comparison of calculated and experimental electronic circular dichroism data. A bioinspired one-pot enantiomeric synthesis of 1a and 1b was accomplished via a readily made intermediate orthoquinone from sugiol. All compounds including the synthetic intermediates were assayed for their cytotoxic activities on human cancer cell lines HL-60, A549, and SGC7901. PMID- 30485091 TI - Three-Dimensional Activity Landscape Models of Different Design and Their Application to Compound Mapping and Potency Prediction. AB - Activity landscapes (ALs) integrate structural and potency data of active compounds and provide graphical access to structure-activity relationships (SARs) contained in compound data sets. Three-dimensional (3D) ALs can be conceptualized as a two-dimensional (2D) projection of chemical space with an interpolated activity surface added as a third dimension. Such 3D AL models are particularly intuitive for SAR visualization. In this work, 3D ALs were generated on the basis of different projection methods and fingerprint descriptors and their topologies were compared. Moreover, going beyond qualitative analysis, the use of 3D AL models for semi-quantitative and quantitative potency predictions was investigated. Neuroscale, a neural network variant of multi-dimensional scaling (MDS), combined with Gaussian process regression (GPR) was identified as a preferred approach for generating 3D AL models that accounted with high accuracy for training compounds and their SAR characteristics. On the other hand, GPR induced overfitting generally limited the accuracy of potency value predictions, regardless of the projection methods that were applied. However, 3D AL models enabled reliable mapping of test compounds with varying potency levels to corresponding AL regions. Most accurate mapping was achieved with neuroscale models. Taken together, the results of our analysis indicate high potential of 3D AL models for graphical SAR exploration and the identification of potent test compounds. PMID- 30485092 TI - Electron-Spin Structure and Metal-Ligand Bonding in Open-Shell Systems from Relativistic EPR and NMR: A Case Study of Square-Planar Iridium Catalysts. AB - Electron and nuclear magnetic resonance spectroscopies are indispensable and powerful methods for investigating the molecular and electronic structures of open-shell systems. We demonstrate that the NMR and EPR parameters are extremely sensitive quantitative probes for the electronic spin density around heavy-metal atoms and the metal-ligand bonding. Using relativistic density-functional theory, we have analyzed the relation between the spin density and the EPR and NMR parameters in paramagnetic iridium(II/IV) complexes with a PNP pincer ligand. As the magnetic-response parameters for compounds containing 5d transition metal(s) are heavily affected by spin-orbit coupling, relativistic effects must be included in the calculations. We have used a recent implementation of the fully relativistic Dirac-Kohn-Sham (DKS) method employing the hybrid PBE0 functional and an implicit solvent model to calculate EPR parameters and hyperfine NMR shifts. The modulation of the metal-ligand bond by the trans substituent (-Cl or =N) and the electronic spin structure around the central metal atom and ligands are shown to be reflected in the "long-range" through-bond Fermi-contact (FC) contributions to the ligand 13C and 1H hyperfine couplings. Interestingly, the hyperfine coupling constant of the ligand atom L ( AL) bonded directly to the iridium center changes its sign because of the dominating role of the paramagnetic spin-orbit (PSO) term. Furthermore, the electronic g-shift and the PSO contribution to the ligand AL are shown to invert their signs when nitrogen is substituted for chlorine, reflecting the different formal metal oxidation states and the change in metal-ligand bond character. A full understanding of the substituent effects is provided by using chemical bond concepts in combination with a molecular-orbital (MO) theory analysis of the second-order perturbation theory expression for the EPR parameters. Our findings are easily transferable to other systems containing d-block elements and beyond. Relativistic DFT calculations of magnetic-resonance parameters are expected to frequently assist in future experimental observations and the characterization of hitherto unknown unstable or exotic species. PMID- 30485093 TI - Kinetics of Intramolecular Phenyl Migration and Fused Ring Formation in Hexylbenzene Radicals. AB - A combined ab initio/TST study was conducted to study the phenyl migration and fused ring formation of a series of 1-phenyl-hex-x-yl radicals. Phenyl shift proceeds through a two-step mechanism with a ring closure by ipso-cycloaddition, followed by a ring opening by beta-scission leading to x-phenyl-hex-1-yl radical isomers. Both steps involve a spirocyclic transition state connected by a spirocyclic intermediate. Barrier heights at the CBS-QB3 level range from 9.9 to 17.7 kcal mol-1 depending on the size of the newly formed ring. Formation of fused rings by peri-cycloaddition reactions occur through barrier heights that range from 8.8 to 28.8 kcal mol-1. The addition sites are the substituted and ortho carbons of the phenyl ring for the ipso and peri cycloadditions respectively. For both types of reaction, Arrhenius A factor decreases as the ring size increases. This is related to the number of internal rotors lost across the reaction. In addition, length of the side chain also impacts on the kinetics as longer side chains decrease the barrier height required to form a second cycle. Electrons in the cyclohexadienyl group of the spiro and fused rings are much more localized than expected, with the presence of two distinct pi bonds. Rate coefficients for each reaction are provided. The unimolecular reactions are fast at most conditions, implying that ring formation and/or ring opening processes will equilibrate 1-phenyl-hex-x-yl, x-phenyl-hex-1-yl radicals and the spiro and fused isomers. PMID- 30485094 TI - Morpholine-based Gemini surfactant: synthesis and its application for reverse froth flotation of carnallite ore in potassium fertilizer production. AB - Potassium fertilizer plays a critical role in increasing the food production. Carnallite is concentrated by reverse froth flotation and used as a raw material to produce potassium fertilizer (KCl) in agriculture. However, all the surfactants used in the carnallite reverse flotation process are conventional monomeric surfactants contain a single similar hydrophobic group in the molecule, which results in a low production efficiency. In this work, a new morpholine based Gemini surfactant, 1,4-bis (morpholinododecylammonio) butane dibromide (BMBD) was prepared, and originally recommended as a collector for reverse froth flotation separation of halite (NaCl) from carnallite ore. The flotation results indicated BMBD had higher flotation recovery and stronger affinity of halite against carnallite, compared with conventional monomeric surfactant N-(n-Dodecyl) morpholine (DDM). FTIR spectra suggested that BMBD molecules were adsorbed on halite surface rather than the carnallite surface. Additionally, BMBD molecules can strongly reduce the surface tension of NaCl saturated solution. Considering the BMBD's unique properties, such as double reactive centers to mineral surfaces, double hydrophobic groups, and stronger surface tension reducing ability, made it be a superior collector for reverse flotation desalination from carnallite ores than DDM. PMID- 30485095 TI - LC-MS-based metabolomics reveals the chemical changes of polyphenols during high temperature roasting of large-leaf yellow tea. AB - Large-leaf yellow tea (LYT) is made from mature tea leaves with stems and has unique sensory characteristics different from other teas. To study the chemical changes of LYT during processing, samples were collected from each step for quantitative and qualitative analyses by high performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). LC-MS based non targeted and targeted metabolomics analyses revealed that the tea sample after roasting was markedly different from samples before roasting, with the levels of epi-catechins and free amino acids significantly decreased, but the epimerized catechins increased dramatically. After accounting for common compounds in tea, N ethyl-2-pyrrolidinone-substituted flavan-3-ols were found to be the marker compounds responsible for the classification of all samples, as they rapidly rose with increasing processing temperature. These findings suggested that the predominant changes in the tea constituents during large-leaf yellow tea roasting were the thermally induced degradation and epimerization of catechins and the formation of N-ethyl-2-pyrrolidinone-substituted flavan-3-ols from L-theanine. PMID- 30485096 TI - Assessment of functionals for TDDFT calculations of one- and two-photon absorption properties of neutral and anionic fluorescent proteins chromophores. AB - Performance of DFT functionals with different percentage of exact Hartree-Fock exchange energy (EX) is assessed for recovery of the CC2 reference one- (OPA) and two-photon absorption (TPA) spectra of fluorescent proteins chromophores in vacuo. The investigated DFT functionals, together with their EX contributions are: BLYP (0%), B3LYP (20%), B1LYP (25%), BHandHLYP (50%) and CAM-B3LYP (19% at short range and 65% at long range). Our test set consists of anionic and neutral chromophores as naturally occuring in the fluorescent proteins. For the first time, we compare TDDFT and CC2 methods for higher excited states, than the S1 state, exhibiting relatively large TPA intensity. Our TDDFT results for neutral chromophores reveal an increase of excitation energies as well as TPA and OPA intensities errors, compared to CC2-derived results, as the DFT functional contains less exact exchange. The long-range-corrected CAM-B3LYP functional performs the best, closely followed by BHandHLYP, while BLYP usually significantly underestimates all investigated spectral properties, hence being the worst in reproducing the reference CC2 results. The hybrid B3LYP and B1LYP functionals can be roughly placed in between. We propose that TDDFT may underestimate the TPA intensities for neutral chromophores of fluorescent proteins due to underestimated oscillator strengths between some excited states. In case of anionic chromophores, we find that B3LYP and B1LYP functionals overcome others in terms of reproducing CC2 excitation energies. On the other hand, however, TPA intensity is usually significantly underestimated and in this respect CAM-B3LYP functional seems to be again superior. In contrast to the case of neutral chromophores, it seems that large magnitude of excited-state dipole moment or change in dipole moment upon excitation may be the driving force behind high TPA transition moments. PMID- 30485097 TI - A new approach for drug target and bioactivity prediction: the Multi-fingerprint Similarity Search aLgorithm (MuSSeL). AB - We present MuSSeL, a multi-fingerprint similarity search algorithm, able to predict putative drug targets for a given query small molecule as well as to return a quantitative assessment of its bioactivity in terms of Ki or IC50 values. Predictions are automatically made exploiting a large collection of high quality experimental bioactivity data available from ChEMBL (version 22.1) combining, in a consensus-like approach, predictions resulting from a similarity search performed using 13 different fingerprint definitions. Importantly, the herein proposed algorithm is also effective in detecting and handling activity cliffs. A calibration set including small molecules present in the last updated version of ChEMBL (version 23) was employed to properly tune the algorithm parameters. Three randomly built external sets were instead challenged for model performances. The potential use of MuSSeL was also challenged by a prospective exercise for the prediction of five bioactive compounds taken from articles published in Journal of Medicinal Chemistry just few months ago. The paper emphasizes the importance of implementing multi-fingerprint consensus strategies to increase the confidence in prediction of similarity search algorithms and provides a fast and easy-to-run tool for drug target and bioactivity prediction. PMID- 30485098 TI - 1,4-Benzodioxane Lignans: An Efficient, Asymmetric Synthesis of Flavonolignans and Study of Neolignan Cytotoxicity and Antiviral Profiles. AB - 1,4-Benzodioxane lignans are a class of bioactive compounds that have received much attention through the years. Herein research pertaining to both 1,4 benzodioxane flavonolignans and 1,4-benzodioxane neolignans is presented. A novel synthesis of both traditional 1,4-benzodioxane flavonolignans and 3 deoxyflavonolignans is described. The antiviral and cytotoxic activities of 1,4 benzodioxane neolignans were then investigated; eusiderins A, B, G, and M, deallyl eusiderin A, and nitidanin, which contain the 1,4-benzodioxane motif but lack the chromanone motif found in the known antiviral flavonolignans, were tested. Notably, it was found that all eusiderin 1,4-benzodioxane neolignans exhibited greater antiviral activity than the potent and well-known silybin flavonolignans. While most modifications of the C-1' side chain did not significantly alter the cytotoxicity or antiviral activity, eusiderin M and nitidanin, which contain an allylic alcohol side chain, had lower cytotoxicity. All the eusiderins had similar antiviral activities, with eusiderin B having the best selectivity index. These results show that the chromanone moiety of the flavonolignans is not essential for bioactivity. PMID- 30485099 TI - Fabrication and Characterization of Oleogel stabilized by Gelatin-Polyphenol Polysaccharides Nanocomplexes. AB - The development of oleogel has attracted growing attention due to its health benefits and promising potential to substitute saturated or trans-fat. The present work reports a type of oleogel using the emulsion stabilized by gelatin (GLT), tannic acid (TA) and flaxseed gum (FG) complexes (GLT-TA-FG) through freeze-drying and oven-drying. Results showed that the incorporation of TA and FG promoted the formation of nanoparticles, resulting in increased charge quantity and reduced oil-water surface tension. The structural integrity of oleogel largely depends on the drying method, FG incorporation as well as TA concentration. It was demonstrated that with oven drying, stable oleogel without oil leakage could only be fabricated in the presence of FG. The GLT-0.075 wt% TA FG complexes formed particles shell around the oil droplet, leading to the enhanced gel strength of the oleogel. In addition, the oleogel stabilized by GLT TA-FG complexes had high thixotropic recovery degree and rehydration ability, implying the stabilizing effect of TA and FG. Therefore, the interfacially adsorbed particles and the polymer gel network in bulk together contributed to the compact structure of oleogel. We believe that the oleogel based on GLT-TA-FG complexes has potential applications in food products with tunable rheological and textural properties. PMID- 30485100 TI - Visualization of Solar Cells Libraries Space by Dimension Reduction Methods. AB - Reliably projecting the high dimensional materials space into 2- or 3-dimensions allows for an intuitive grasp of the overall distribution of samples in this space. This in turn facilitates the identification of interesting trends including the formation of materials clusters and the presence of outliers as well as the rational navigation through this space in search for new materials. In this work we present the first application of four dimensionality reduction techniques to the visualization and analysis of part of the materials space populated by solar cells entirely made of metal oxides. For this purpose, we integrated five metal oxide-based solar cell libraries into a uniform database and subjected it to dimensionality reduction using four different techniques, namely, principal component analysis (PCA), kernel PCA, Isomap and Diffusion map. We demonstrate that all methods were able to maintain the local environment of samples in the low dimension space with PCA, the oldest of the methods, performing the best. In contrast, the non-linear Isomap technique performs best in maintaining the clustering structure of the data (although its performances are only marginally better than those of the other methods). We further show that the performances of all techniques improve upon the removal of outliers. We suggest that the methods introduced in this study could readily be extended to the study of other types of solar cells either alone or in combinations thereby setting the ground for big data analysis of the photovoltaic space. PMID- 30485101 TI - Structure and Chemical Order in S-Se Binary Glasses. AB - The compositional evolution of the structure and chemical order in binary SxSe100 x glasses (0 <= x <= 90) is investigated using a combination of high-resolution 2D 77Se isotropic-anisotropic correlation NMR and Raman spectroscopy. The results indicate that the structure of S-Se glasses consist of two types of topological elements, namely polymeric [Se,S]n chains and eight-membered SeyS8-y rings (0 <= y <= 8). The relative concentration of Se atoms monotonically decreases in the chain elements and concomitantly increases in the ring elements with increasing S concentration. Moreover, the Se speciation results are consistent with an average heterocyclic ring composition of Se1S7 at low S content (<=40 at.% S), while the composition shifts to Se1.5S6.5 at higher S content (>=60 at.% S), indicating increasing incorporation of multiple Se atoms in each ring element. The Raman spectra suggest that -Se-Se- association is favored, when more than one Se atoms is incorporated in chains and rings. As in their elemental forms, the S and Se atoms retain their preference of forming rings and chains in binary SxSe100-x glasses, which predicts a linear compositional variation in the relative fractions of these topological elements. This structural evolution is consistent with the corresponding variation in the Tg and molar volume, both of which exhibit a linear decrease with increasing S concentration. PMID- 30485102 TI - Visible-Light-Enabled Oxidative Alkylation of Unactivated Alkenes with Dimethyl Sulfoxide through Concomitant 1,2-Aryl Migration. AB - Metal-free oxidative radical 1,2-alkylarylation of unactivated alkenes with the alpha-C(sp3)-H bond of dimethyl sulfoxide has been developed. This study realizes a new, conceptually novel technology for convenient construction of a variety of alpha-aryl-gamma-methylsulfinyl ketones in good-to-excellent yields with the synergistic interactions of visible light irradiation, organic fluorophores 4CzIPN, and hypervalent iodine(III) reagent under transition-metal free conditions. A remarkable kinetic isotope effect was observed, which helped provide insight into the reaction's mechanistic course. PMID- 30485103 TI - Increase of the Charge Transfer Rate Coefficients for NO+ and O2+* Reactions with Isoprene Molecules at Elevated Interaction Energies. AB - Atmospheric concentrations of isoprene (2-methyl butadiene) in environmental research and in exhaled breath for medical research are usually measured by soft chemical ionization mass spectrometry that relies on a knowledge of the kinetics of the gas phase reactions of H3O+, NO+ or O2+* ions with isoprene molecules. Thus, we have carried out an experimental study of the rate coefficients, k, and product ions distributions for such reactions over a range of ion-molecule interaction energy, Er, (0.05-0.8 eV) in a helium-buffered selected ion flow drift tubem SIFDT. It is found that contrary to the ion-induced dipole capture model, k for the NO+ and O2+* charge transfer reactions almost doubled over the Er range, whilst k for the H3O+ proton transfer reaction did not significantly change with Er, as predicted. These results reveal that the reaction mechanism involving ion-molecule capture forming an intermediate complex does not properly describe charge transfer to isoprene molecules. It is important to account for this increase in k with Er in these isoprene charge transfer reactions, and probably for other such reactions, when using drift tube reactors for trace gas analysis. PMID- 30485104 TI - Is Inversion of Phosphorus Trihalides (PF3, PCl3, PBr3, and PI3) a Diradical Process? AB - This work explores possible reaction paths for the inversion of a series of trigonal pyramidal phosphorus trihalides, PF3, PCl3, PBr3, and PI3, and it especially addresses the question of whether and when the bonding of the lowest energy species along the inversion paths should be described as a hyper open shell diradical. The various paths for inversion are calculated using a single reference method within the framework of Kohn-Sham density functional theory and also with multi-reference wave function methods. Our calculated results using both kinds of methods show that, for all the halogens studied (F, Cl, Br, and I), the lowest-energy singlet path for the inversion occurs by the formation of a C2v transition structure rather than a D3h transition structure. This geometrical preference agrees with what has been inferred previously based on closed-shell singlet calculations. But in the present study, we examined not only closed-shell singlet transition states but also open-shell singlet states and triplet states for calculating stationary points and inversion paths, and for some of the phosphorus trihalides, we found that paths involving open-shell configurations are lower in energy than those restricted to closed-shell configurations. We analyzed the changes along the paths in terms of hybridization and orientation of the frontier orbitals and in terms of locally avoided crossings, and the extent of diradical character was quantified by calculating the effective number of unpaired electrons. Even for the singlet inversion path that goes via a D3h structure, the barrier for PF3, PCl3, and PBr3 is higher for a closed-shell singlet spin state than for the open-shell singlet configuration. Furthermore, the energy of the triplet D3h structure is below even the open-shell D3h singlet for PCl3, PBr3, and PI3. This necessitates rethinking the role of open-shell states in nominally closed-shell processes. PMID- 30485105 TI - Promising Fast Energy Transfer System Between Graphene Quantum Dots and the Application in Fluorescent Bio-imaging. AB - Tunable photoluminescence performance of graphene quantum dots (GQDs) is one of the most important topics for the development of GQDs. In this paper, we report lattice doped GQDs (boron doped GQDs, B-GQDs and phosphorus doped GQDs, P-GQDs). Due to the matched band structure, the fast energy transfer between blue emitted B-GQDs (emission wavelength: 460 nm) and orange emitted P-GQDs (emission wavelength: 630 nm) can induce an efficient fluorescence emission in P-GQDs once B-GQDs are excited under the optimal excitation wavelength of 460 nm. Moreover, with the effective energy transfer, the quantum yield of P-GQDs increased to 0.48 which is much higher than that of pure P-GQDs. We also demonstrated the potentials of this system for fluorescent bio-imaging in vitro. PMID- 30485106 TI - Chlorinated Wide Bandgap Donor Polymer Enabling Annealing Free Non-Fullerene Solar Cells with the Efficiency of 11.5. AB - Substituting the hydrogen atoms on the conjugated side chain of a wide bandgap polymer J52 with chlorine atoms can simultaneously increase the Jsc, Voc and FF of non-fullerene OSCs, leading to an efficiency boost from 3.78% to 11.53%, which is among the highest efficiency for as-cast OSCs reported to date. To illustrate the impressive 3-fold PCE enhancement, the chlorination effect on the optical properties and energy levels of polymers, film morphology, and underlying charge dynamics are systematically investigated. Grazing incident wide angle X-ray scattering studies show that chlorinated J52-2Cl exhibits strong molecule aggregation, the preferred face-on orientation and enhanced intermolecular pi-pi interactions, hence increase charge carrier mobility by one order of magnitude. Moreover, chlorination modifies the miscibility between donor and acceptor, and consequently optimizes the phase separation morphology of J52-2Cl:ITIC blend films. These results highlight chlorination as a promising approach to achieve highly efficient as-cast OSCs without any extra treatment. PMID- 30485107 TI - Surface-nanostructured single silver nanowire: a new one-dimensional microscale SERS interface. AB - One-dimensional microscale SERS-active interfaces have been intriguing as a newly emerging class of SERS interfaces compared to conventional macroscale SERS substrates. In this work, a stable surface-nanostructured single silver nanowire was fabricated. The nanostructures on the nanowire are formed by nanoscale silver crystal dots with diameters of 20-50 nm. The SERS signals of the crystal violet probe molecules adsorbed on the nanostructures are dramatically enhanced by both electromagnetic and chemical effects. The hot spots generated at the junctions of adjacent nanoscale dots yield highly efficient surface plasmon resonance. Simultaneously, the charge transfer on the atomic-scale silver cluster located at the nanostructured interface causes an enhancement similar to a Raman resonance. The intensity distributions of the SERS peaks on the surface-nanostructured single nanowire are characterized by SERS mapping. It is found that, although the intensities of the SERS peaks are different, their SERS mapping images show uniform SERS enhancement distributions, whereas the noticeable SERS intensity distributions on the single smooth silver nanowire are mainly located on the two ends of the nanowire. The large number of nanoscale crystal dots along with the atomic-scale silver clusters are uniformly and densely distributed on the surface of the single roughened nanowire; these structural attributes induce a uniform and large surface plasmon resonance and charge transfer enhancements on the entire surface of the nanowire. This work indicates that the surface nanostructured single silver nanowire, synthesized using a quite simple preparation method, performs as an excellent one-dimensional microscale SERS substrate with uniform and high enhancement characteristics, which shows high potential for applications as a new class of SERS-active substrates. Furthermore, the higher enhancement factor of the microscale SERS interfaces can be achieved by introducing other roughened nanowires to assemble a dimer and a trimer as micro SERS substrates, which is consistent with the dark field (DF) measurements. PMID- 30485108 TI - Probing Exciton Delocalisation in Organic Semiconductors: Insight from Time Resolved Electron Paramagnetic Resonance and Magnetophotoselection Experiments. AB - Delocalisation of excited states of organic semiconductors is directly related to their efficiency in devices. Time-resolved electron paramagnetic resonance spectroscopy provides unique capabilities in this respect, due to its high spectral resolution and capability to probe the geometry and extend of excitons. Using magnetophotoselection experiments, the mode of exciton delocalisation, along the backbone or parallel to the pi-pi stacking direction of the conjugated polymers, can be revealed. We demonstrate the robustness of this approach by applying it to building blocks of a prototypical conjugated polymer showing a symmetry of their excited states being far from ideal for this experiment. This renders magnetophotoselection superior to other approaches, being applicable to a wealth of other organic semiconductors. The insight gained into exciton delocalisation is crucial to the structure-function relationship of organic semiconductors and directly relevant for developing highly efficient materials. PMID- 30485109 TI - Facile Fabrication of Oxidation-Responsive Polymeric Nanoparticles for Effective Anticancer Drug Delivery. AB - Reactive oxygen species (ROS) are highly overproduced in cancerous tissues, and thus oxidation-responsive nanoparticles (NPs) have emerged as a promising drug carrier for cancer-targeted drug delivery. In this study, we successfully synthesized poly(vanillyl alcohol-co-oxalate) (PVAX) polymer with an excellent ROS-responsive capacity. A well-established emulsion-solvent evaporation method was used to fabricate PVAX-based curcumin (CUR)-loaded NPs (PVAX-NPs) and their counterparts (poly(lactic-co-glycolic acid)-based CUR-loaded NPs, PLGA-NPs). It was found that these NPs had a hydrodynamic particle size of approximately 245 nm, narrow size distribution (polydispersity index less than 0.1), negative zeta potential (around -18 mV), smooth surface appearance and high drug encapsulation efficiency. Moreover, we found that the CUR release rate of PVAX-NPs was greatly increased in the presence of hydrogen peroxide-rich environment due to the cleavage of polyoxalate ester bonds in PVAX polymer, resulting in the evenly distribution of CUR within the whole cancer cells. More importantly, PVAX-NPs exhibited much stronger anticancer activities and pro-apoptotic capacities than PLGA-NPs both in vitro and in vivo. These results clearly demonstrate that these ROS-responsive PVAX-NPs can be exploited as a robust anticancer drug delivery platform in chemotherapy. PMID- 30485110 TI - Stereoselective Synthesis of Diverse Lactones through a Cascade Reaction of Rhodium Carbenoids with Ketoacids. AB - A convergent cascade approach for the stereoselective synthesis of diverse lactones is described. The Rh2(TFA)4-catalyzed cascade reaction proceeds via a carboxylic acid O-H insertion/aldol cyclization with high chemo-, regio-, and diastereoselectivity. The cascade reaction provides quick access to highly functionalized gamma-butyro- and delta-valerolactones from readily accessible ketoacid and diazo synthons. To demonstrate the utility of this approach, a thermally induced oxy-Cope ring-expansion strategy has been incorporated in the cascade sequence to access medium-sized lactones, which can undergo a serendipitous rearrangement to form spiro-lactones through an intramolecular aldol/trans-lactonization sequence. The reaction has proven to be general, with a range of ketoacids and diazo carbonyls to provide functionalized lactones of varying ring sizes. PMID- 30485111 TI - Effects of Nanowire Length on Charge Transport in Vertically Aligned Gold Nanowire Array Electrodes. AB - In this study, we demonstrate that vertically aligned gold nanowire array electrodes provide rapid ion and electron transport to the electrode-electrolyte interface. The charge-transport properties of the nanowire electrodes were investigated through cyclic voltammetry, galvanostatic charge/discharge measurements, and electrochemical impedance spectroscopy under a constant-volume device configuration. The total charge stored in the corresponding devices increases monotonically with the length of the nanowires owing to the concomitant increase in the electroactive real surface area of the electrode. A remarkable feature of the electrodes is that the internal resistance associated with charge transport decreases with increasing nanowire length. The electric double-layer capacitance per unit electroactive surface area remains constant up to high charge/discharge rates. Our results demonstrate that charge migration occurs rapidly on the surfaces of the nanowires regardless of their length and the charge/discharge rate used. Thus, vertically aligned nanowire array electrodes show promise as current collectors for next-generation electrochemical energy storage devices. PMID- 30485112 TI - The role of PEG-40-stearate in the production, morphology and stability of microbubbles. AB - Phospholipid coated microbubbles are currently in widespread clinical use as ultrasound contrast agents and under investigation for therapeutic applications. Previous studies have demonstrated the importance of the coating nanostructure in determining microbubble stability and its dependence upon both composition and processing method. Whilst the influence of different phospholipids has been widely investigated, the role of other constituents such as emulsifiers has received comparatively little attention. Herein, we present an examination of the impact of polyethylene glycol (PEG) derivatives upon microbubble structure and properties. We present data using both pegylated phospholipids and a fluorescent PEG-40-stearate synthesised in house to directly observe its distribution in the microbubble coating. We examine microbubbles of clinically relevant sizes, investigating both their surface properties and population size distribution and stability. Domain formation was only observed on the surface of larger microbubbles, which were found to contain a higher concentration of PEG-40 stearate. Lipid analogue dyes were also found to influence domain formation compared with PEG-40-stearate alone. "Squeezing out" of PEG-40-stearate was not observed from any of the microbubble sizes investigated. At the ambient temperature, microbubbles formulated with DSPE-PEG(2000) were found to be more stable than those containing PEG-40-stearate. At 37 degrees C, however the stability in serum was found to be the same for both formulations and no difference in acoustic backscatter was detected. This could potentially reduce the cost of PEGylated microbubbles and facilitate simpler attachment of targeting or therapeutic species. However, whether PEG-40-stearate sufficiently shields microbubbles to inhibit physiological clearance mechanisms still requires investigation. PMID- 30485113 TI - Preparation and photochromic behavior of spiropyran-containing fluorinated polyacrylate hydrophobic coatings. AB - In this study, spiropyran (SP)-containing fluorinated polyacrylate (F-PA-SP) latex was prepared by emulsion polymerization using fluorinated and SP-based acrylic monomers as raw materials. FT-IR and 1H-NMR demonstrate that the F-PA-SP copolymer has been successfully synthesized, and DLS and TEM analyses indicate that the synthesized latex has presented a uniform particle size of approximately 200 nm. XPS, AFM and water contact angle (WCA) analysis were used to investigate the surface properties of the F-PA-SP coating and demonstrate that its hydrophobicity is enhanced by addition of a fluorinated acrylic monomer. The photochromic properties of the coating were investigated by UV-Vis spectroscopy, and the results reveal that the F-PA-SP coating possesses better photo responsiveness, fatigue resistance, and photo-reversibility under UV/Vis irradiation than the coating prepared using fluorinated polyacrylate/SP blended latex. Moreover, the WCA of the F-PA-SP coating subjected to UV/Vis irradiation shows minimal changes and retains its excellent hydrophobicity. Finally, the F-PA SP latex was applied to cellulosic paper, and the resulting photochromic paper exhibits outstanding reversible color changes and hydrophobicity. PMID- 30485114 TI - Nanocrevasse-rich Carbon Fibers for Stable Lithium and Sodium Metal Anodes. AB - The metallic lithium (Li) and sodium (Na) anodes have great attention as ideal anodes to meet the needs for high energy density batteries due to their highest theoretical capacities. Although many approaches have successfully improved the performances of Li or Na metal anodes, many of these methods are difficult to scale up and thus cannot be applied in the production of batteries in practice. In this work, we introduce nanocrevasses in a carbon fiber scaffold which can facilitate the penetration of molten alkali metal into a carbon scaffold by enhancing its wettability for Li/Na metal. The resulting alkali metal/carbon composites exhibit stable long-term cycling over hundreds of cycles. The facile synthetic method enables for scalable production using recycled metal waste. Thus, the addition of nanocrevasses to carbon fiber as a scaffold for alkali metals can generate environmentally friendly and cost-effective composites for practical electrode applications. PMID- 30485115 TI - Exercise training normalizes elevated firing rate of hypothalamic presympathetic neurons in heart failure rats. AB - Exercise training (ExT) normalizes elevated sympathetic nerve activity in heart failure (HF), but the underlying mechanisms are not well-understood. In this study, we examined the effects of 3 weeks of ExT on the electrical activity of the hypothalamic presympathetic neurons in the brain slice of HF rats. HF rats were prepared by ligating the left descending coronary artery. Electrophysiological properties of paraventricular nucleus neurons projecting to the rostral ventrolateral medulla (PVN-RVLM) was examined using slice patch-clamp technique. The neuronal firing rate was elevated in HF rats, and ExT induced a reduction in the firing rate (P<0.01). This ExT-induced decrease in the firing rate was associated with an increased frequency of spontaneous and miniature inhibitory postsynaptic current (IPSC, P<0.05). There was no significant change in excitatory postsynaptic current. Replacing Ca2+ with Mg2+ in the recording solution reduced the elevated IPSC frequency in HF rats with ExT (P<0.01), but not in those without ExT, indicating an increase in the probability of GABA release. In contrast, ExT did not restore the reduced GABAA receptor-mediated tonic inhibitory current in HF rats. A GABAA receptor blocker (bicuculline, 20 MUM) increased the firing rate in HF rats with ExT (P<0.01), but not in those without ExT. Collectively, these results show that ExT normalized the elevated firing activity by increasing synaptic GABA release in PVN-RVLM neurons in HF rats. Our findings provide a brain mechanism underlying the beneficial effects of ExT in HF, which may shed light on the pathophysiology of other diseases accompanied by sympathetic hyperactivation. PMID- 30485116 TI - Can the Sputum Microbiota Be a Biomarker that Predicts Mortality after Acute Exacerbations of COPD? PMID- 30485117 TI - No Association Between Risk of Anterior Cruciate Ligament Rupture and Selected Candidate Collagen Gene Variants in Female Elite Athletes From High-Risk Team Sports. AB - BACKGROUND:: Several single-nucleotide variants (SNVs) in collagen genes have been reported as predisposing factors for anterior cruciate ligament (ACL) tears. However, the evidence is conflicting and does not support a clear association between genetic variants and risk of ACL ruptures. PURPOSE:: To assess the association of previously identified candidate SNVs in genes encoding for collagen and the risk of ACL injury in a population of elite female athletes from high-risk team sports. STUDY DESIGN:: Cohort study; Level of evidence, 2. METHODS:: A total of 851 female Norwegian and Finnish elite athletes from team sports were included from 2007 to 2011. ACL injuries acquired before inclusion in the cohort were registered by interview. The participants were followed prospectively through 2015 to record new complete ACL injuries. Six selected SNVs were genotyped ( COL1A1: rs1800012, rs1107946; COL3A1: rs1800255; COL5A1: rs12722, rs13946; COL12A1: rs970547). RESULTS:: No associations were found between ACL rupture and the SNVs tested. CONCLUSION:: The study does not support a role of the 6 selected SNVs in genes encoding for collagen proteins as risk factors for ACL injury. CLINICAL RELEVANCE:: Genetic profiling to identify athletes at high risk for ACL rupture is not yet feasible. PMID- 30485118 TI - Changes in Perianchor Cyst Formation Over Time After Rotator Cuff Repair: Influential Factors and Outcomes. AB - BACKGROUND:: There is a lack of knowledge about the changes in perianchor cysts over time and the factors related to perianchor cysts. PURPOSE:: To evaluate the changes in perianchor cyst formation and anchor absorption over time after arthroscopic rotator cuff repair with a biocomposite suture anchor and to evaluate the factors affecting perianchor cyst persistence and their relationship with patient outcomes. STUDY DESIGN:: Case-control study; Level of evidence, 3. METHODS:: Forty consecutive patients (mean age, 61.10 +/- 5.79 years) who underwent arthroscopic repair for medium- to large-sized rotator cuff tears using a single type of biocomposite (poly-L-lactic acid/polyglycolic acid-beta tricalcium phosphate) medial-row anchor were prospectively enrolled. Postoperative magnetic resonance imaging (MRI) at 2 different time points (6 and 18 months) was performed, and perianchor cyst formation, anchor absorption, and healing failures were evaluated using postoperative MRI. Demographic and clinical data were collected, and functional outcomes at a minimum of 18 months after surgery were assessed. RESULTS:: Perianchor cysts were observed in 24 patients (60.0% total; grade 1: 35.0%; grade 2: 10.0%; grade 3: 7.5%; grade 4: 7.5%) at 6 months, and 7 patients (18.4% total; grade 1: 7.9%; grade 2: 5.3%; grade 3: 2.6%; grade 4: 2.6%) had a persistent perianchor cyst at 18 months after surgery. No anchors were absorbed at 6 months, but 73.7% of patients revealed complete or near-full absorption at 18 months. Patients with persistent perianchor cysts showed a significantly larger tear size in the anteroposterior dimension ( P = .002) and greater retraction ( P < .001). There were no differences in healing failures and functional outcomes between patients with and without persisting perianchor cysts (all P > .05). No differences were found in perianchor cyst formation and anchor absorption between anchors inserted in the greater tuberosity and the lesser tuberosity (all P > .05). CONCLUSION:: The incidence and severity of perianchor cysts decreased with time, and most biocomposite suture anchors were absorbed at 18 months after surgery. Persisting perianchor cysts correlated with a larger tear size in the anteroposterior dimension and greater retraction. PMID- 30485119 TI - Methylglyoxal induces retinopathy-type lesions in the absence of hyperglycemia: studies in a rat model. AB - The aim of this study was to evaluate whether damage to the neurovascular unit in diabetes depends on reactive metabolites such as methylglyoxal (MG), and to assess its impact on retinal gene expression. Male Wistar rats were supplied with MG (50 mM) by drinking water and compared with age-matched streptozotocin diabetic animals and untreated controls. Retinal damage was evaluated for the accumulation of MG-derived advanced glycation end products, changes in hexosamine and PKC pathway activation, microglial activation, vascular alterations (pericyte loss and vasoregression), neuroretinal function assessed by electroretinogram, and neurodegeneration. Retinal gene regulation was studied by microarray analysis, and transcription factor involvement was identified by upstream regulator analysis. Systemic application of MG by drinking water increased retinal MG to levels comparable with diabetic animals. Elevated retinal MG resulted in MG-derived hydroimidazolone modifications in the ganglion cell layer, inner nuclear layer, and outer nuclear layer, a moderate activation of the hexosamine pathway, a pan-retinal activation of microglia, loss of pericytes, increased formation of acellular capillaries, decreased function of bipolar cells, and increased expression of the crystallin gene family. MG mimics important aspects of diabetic retinopathy and plays a pathogenic role in microglial activation, vascular damage, and neuroretinal dysfunction. In response to MG, the retina induces expression of neuroprotective crystallins.-Schlotterer, A., Kolibabka, M., Lin, J., Acunman, K., Dietrich, N., Sticht, C., Fleming, T., Nawroth, P., Hammes, H.-P. Methylglyoxal induces retinopathy-type lesions in the absence of hyperglycemia: studies in a rat model. PMID- 30485120 TI - Associations between Ozone and Fine Particulate Matter and Respiratory Illness Found to Vary between Children and Adults: Implications for U.S. Air Quality Policy. PMID- 30485121 TI - Underdetection and Undertreatment of Dyspnea in Critically Ill Patients. AB - Rationale Dyspnea is a common and distressing physical symptom among patients in the intensive care unit, which may be underdetected and undertreated. Objective To determine the frequency of dyspnea relative to pain, the accuracy of nurses and personal caregiver dyspnea ratings relative to patient-reported dyspnea, and the relationship between nurse-detected dyspnea and treatment. Methods An observational study of patients (n=138) hospitalized in a medical intensive care unit (MICU). Nurses and patients' personal caregivers at the bedside reported on their perception of patients' symptoms. Measurements and Main Results Dyspnea was assessed by patients, caregivers, and nurses with a numerical rating scale. Across all three raters, the frequency of moderate-to-severe dyspnea was similar or greater than that of pain (p < .05 for caregiver and nurse ratings). Personal caregivers' ratings of dyspnea had substantial agreement with patient ratings (? = 0.65, p <0.001), but nurses' ratings were not significantly related to patient ratings (? = 0.19, p = 0.39). Nurse detection of moderate-to-severe pain was significantly associated with opioid treatment (OR = 2.70, 95% CI = 1.10 to 6.60, p = 0.03); however, nurse detection of moderate-to-severe dyspnea was not significantly associated with any assessed treatment. Conclusions Dyspnea was reported at least as frequently as pain among the sampled MICU patients. Personal caregivers had good agreement with patient reports of moderate-to-severe dyspnea. However, even when detected by nurses, dyspnea appeared to be undertreated. These findings suggest the need for improved detection and treatment of dyspnea in the MICU. PMID- 30485122 TI - Microbial degradation of low-density polyethylene and synthesis of polyhydroxyalkanoate polymers. AB - We have characterized the ability of eight bacterial strains to utilize powdered low-density polyethylene (LDPE) plastic (un-treated and without any additives) as a sole carbon source. Cell mass production on LDPE containing medium after 21 days of incubation varied between 0.083 +/- 0.015 g L-1 cell dry weight (cdw) for Micrococcus luteus IRN20 and 0.39 +/- 0.036 g L-1 for Cupriavidus necator H16. The percent decrease in LDPE mass ranged from 18.9% +/- 0.72 for M. luteus IRN20 to 33.7% +/- 1.2 for C. necator H16. Linear alkane hydrolysis products from LDPE degradation were detected in the culture media, and the carbon chain lengths of the hydrolysis products detected varied, depending on the species of bacteria. We also determined that C. necator H16 produced short chain length polyhydroxyalkanaote (scl-PHA) biopolymers, while Pseudomonas putida LS46 and Acinetobacter pitti IRN19 produced medium chain length (mcl-PHA) biopolymers while growing on PE powder. C. necator H16 accumulated poly (3-hydrodxybutyrate co-3-hydroxyvalerate) (PHB/V) polymers to 3.18 % +/- 0.4 of cdw. The monomer composition of the PHB/V was 94.9% +/- 0.61 3-hydrodxybutyrate and 5.03% +/- 0.56 3-hydroxyvalerate. This is the first report that provides direct evidence for simultaneous bioconversion of LDPE plastic to biodegradable polyhydroxyalkanoate polymers. PMID- 30485123 TI - A Randomized, Waiting-List-Controlled Study Shows That Brief, Mindfulness-Based Psychological Interventions Are Effective for Treatment of Women's Low Sexual Desire. AB - We evaluated two treatment conditions for low sexual desire in women: one where participants were administered a mindfulness-based treatment protocol and another with exercises focusing on scheduled sex and motivations for sex in addition to the aforementioned protocol. Seventy women (Mage 39.2, SD = 9.8) with complaints of low sexual desire were randomly allocated to one of these treatment conditions or a waiting-list condition. Participants attended four individual sessions and completed homework exercises. Questionnaire data were collected before and after treatment and at follow-ups three and six months later. Primary outcomes were the Female Sexual Function Index (FSFI) desire subdomain and the Sexual Interest and Desire Inventory-Female (SIDI-F). Secondary outcomes were the Female Sexual Distress Scale-Revised (FSDS-R), the Revised Dyadic Adjustment Scale (RDAS), the Perceived Relationship Quality Components Inventory (PRQC), and the Brief Symptom Inventory-18 (BSI-18). Women in both treatment conditions reported significantly higher sexual desire (FSFI desire d = 0.75 to 1.06) immediately following treatment, compared to the waiting list. Improvements were sustained at follow up, accompanied by improvements in some secondary outcomes. We found no significant differences between the treatment conditions in terms of treatment effectiveness. Our study adds to the literature suggesting that mindfulness-based treatments are suitable options for treating low sexual desire in women. PMID- 30485124 TI - Midterm Results of the Bony Bankart Bridge Technique for the Treatment of Bony Bankart Lesions. AB - BACKGROUND:: The arthroscopic "bony Bankart bridge" (BBB) repair technique was recently shown to successfully restore shoulder stability at short-term follow up, but longer-term outcomes have not yet been described. PURPOSE:: To report the outcomes at minimum 5-year follow-up after BBB repair for anterior shoulder instability with a bony Bankart lesion. STUDY DESIGN:: Case series; Level of evidence, 4. METHODS:: Patients were included if they sustained a bony Bankart lesion, were treated with a BBB technique, and were at least 5 years postoperative. Patients were excluded if they underwent concomitant rotator cuff repair or an open bone fragment reduction. All patients were assessed with the following measures preoperatively and at final evaluation: QuickDASH (Quick Disabilities of the Arm, Shoulder and Hand), American Shoulder and Elbow Surgeons, Single Assessment Numeric Evaluation, and 12-Item Short Form Health Survey (SF-12) Physical Component Summary. RESULTS:: From 2008 to 2012, 13 patients who underwent BBB met the inclusion criteria with a mean age of 39.6 years (range, 19.1-68.8 years) and a mean follow-up of 6.7 years (range, 5.1-9.0 years). Mean time from most recent injury to surgery was 6.3 months (range, 1 day 36 months). The mean glenoid bone loss was 22.5% (range, 9.1%-38.6%). Mean SF-12 scores demonstrated significant improvement from 45.8 (SD, 9.7) preoperatively to 55.1 (SD, 5.9) at a mean follow-up of 6.7 years. At final follow-up, the mean American Shoulder and Elbow Surgeons score was 93.1 (range, 68.3-100); the mean QuickDASH score, 6.2 (range, 0-25); and the mean Single Assessment Numeric Evaluation score, 92.8 (range, 69-99). None of the patients progressed to further shoulder surgery. Three of 13 patients (23%) reported subjective recurrent instability. At final follow-up, 9 of 12 (75%) patients indicated that their sports participation levels were equal to their preinjury levels. Median patient satisfaction at final follow-up was 10 of 10 points (range, 3-10). CONCLUSION:: The arthroscopic BBB technique for patients with anterior bony Bankart lesions can restore shoulder stability, yield durable improvements in clinical outcomes, and provide a high return-to-sport rate at a minimum 5-year follow-up. Three of 13 patients experienced postoperative symptoms of instability but did not undergo further stabilization surgery. PMID- 30485125 TI - Team type, team maturity and team effectiveness in specialist palliative home care: an exploratory questionnaire study. AB - To meet complex needs in persons and families within specialist palliative care, care team members are expected to work together in performing a comprehensive assessment of patient needs. Team type (how integrated team members work) and team maturity (group development) have been identified as components in team effectiveness and productivity. The aim of the study reported in this paper was to identify team types in specialist palliative care in Sweden, and to explore associations between team type, team maturity and team effectiveness in home care teams. A national web-based survey of team types, based on Thylefors questionnaire, and a survey of healthcare professionals using the Group Development Questionnaire (GDQ-SE3) to assess team developmental phase, effectiveness and productivity were used in an exploratory cross-sectional design. The participants were: Specialist palliative care teams in Sweden registered in the Palliative Care Directory (n = 77), and members of 11 specialist palliative home care teams. Teams comprised physicians, registered nurses, social workers, physiotherapists and/or occupational therapists, full-or part-time. Our national web survey results showed that the 77 investigated teams had existed from 7 to 21 years, were foremost of medium size and functioned as inter- or transprofessional teams. Results from the 61 HCPs, representing 11 teams, indicated that more mature teams tended to work in an integrated manner, rather than in parallel. The effectiveness ratio varied from 52% to 86% in teams. Recommendations arising from our findings include the need for clarification of team goals and professional roles together with prioritizing the development of desirable psychosocial traits and team processes in clinical settings. PMID- 30485126 TI - Mechanical loading mitigates osteoarthritis symptoms by regulating endoplasmic reticulum stress and autophagy. AB - Osteoarthritis (OA) is a disease characterized by cartilage damage and abnormal remodeling of subchondral bone. Our previous study showed that in the early stage of OA, knee loading exerts protective effects by suppressing osteoclastogenesis through Wnt signaling, but little is known about loading effects at the late OA stage. Endoplasmic reticulum (ER) stress and autophagy are known to be involved in the late OA stage. We determined the effects of mechanical loading on ER stress and autophagy in OA mice. One hundred seventy-four mice were used for a surgery-induced OA model. In the first set of experiments, 60 mice were devoted to evaluation of the role of ER stress and autophagy in the development of OA. In the second set, 114 mice were used to assess the effect of knee loading on OA. Histologic, cellular, microcomputed tomography, and electron microscopic analyses were performed to evaluate morphologic changes, ER stress, and autophagy. Mechanical loading increased phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha) and regulated expressions of autophagy markers LC3II/I and p62. Osteoarthritic mice also exhibited an elevated ratio of calcified cartilage to total articular cartilage (CC/TAC), and synovial hyperplasia with increased lining cells was found. At the early disease stage, subchondral bone plate thinning and reduced subchondral bone volume fraction (B.Ar/T.Ar) were observed. At the late disease stages, subchondral bone plate thickened concomitant with increased B.Ar/T.Ar. Mice subjected to mechanical loading exhibited resilience to cartilage destruction and a correspondingly reduced Osteoarthritis Research Society International score at 4 and 8 wk, as well as a decrease in synovitis and CC/TAC. While chondrocyte numbers in the OA group was notably decreased, mechanical loading restored chondrogenic differentiation. These results demonstrate that mechanical loading can retard the pathologic progression of OA at its early and late stages. The observed effects of loading are associated with the regulations of ER stress and autophagy.-Zheng, W., Li, X., Liu, D., Li, J., Yang, S., Gao, Z., Wang, Z., Yokota, H., Zhang, P. Mechanical loading mitigates osteoarthritis symptoms by regulating endoplasmic reticulum stress and autophagy. PMID- 30485127 TI - The Determination of Purine Crystal Structures; An Overlooked Prequel to the Discovery of The Double Helix. AB - N/A. PMID- 30485128 TI - Remittance or persistence of attention deficit-hyperactivity disorder (ADHD) and its impact on recidivism in risky driving behaviors. AB - OBJECTIVE: Recent data regarding the persistence or remittance of attention deficit-hyperactivity disorder (ADHD) diagnosis into adulthood raise the question of its possible role in crucial public health issues, including road safety, especially when neurocognitive capacities are challenged. METHODS: The study included 611 participants with serious traffic violations. The Spanish version of the Mini International Neuropsychiatric Interview (M.I.N.I.) was used to assess psychopathology. They were grouped into 3 diagnostic conditions: non-ADHD, persistent ADHD (ADHD-P), and remittent ADHD (ADHD-R). Several risky driving behaviors were analyzed. RESULTS: Although participants with ADHD have more driving violations relative to non-ADHD, ADHD-R, and ADHD-P drivers have similar profiles. ADHD-R and ADHD-P drivers are more prone to perform risky and recidivistic behaviors relative to non-ADHD counterparts (P = .044 and P = .047, respectively); ADHD-R and ADHD-P participants are statistically comparable in this proneness (P = .772). CONCLUSION: These results suggest that the underlying core deficits of ADHD-attention and other executive disabilities-persist despite the fact that some people no longer reach the threshold for clinical diagnosis. PMID- 30485129 TI - The many faces of mathematical modelling in oncology. AB - The application of modelling to solve problems in biology and medicine, and specifically in oncology and radiation therapy, is increasingly established and holds big promise. In this review, we provide an overview of the basic concepts of the field and its current state, along with new tools available and future directions for research. We will outline radiobiology models, examples of other anti cancer therapy models, multi-scale modelling and we will discuss the mechanistic and phenomenological approaches to modelling. PMID- 30485130 TI - Clinical Validation of Coexisting Activating Mutations Within EGFR, Mitogen Activated Protein Kinase, and Phosphatidylinositol 3-Kinase Pathways in Lung Cancers. AB - CONTEXT.-: Mutations within the same signature transduction pathway are redundant and, therefore, most are mutually exclusive. Laboratory errors, however, may introduce unexpected coexisting mutations. OBJECTIVE.-: To validate coexisting mutations within epidermal growth factor receptor (EGFR), mitogen-activated protein kinase, and phosphatidylinositol 3-kinase pathways. DESIGN.-: In this retrospective study for quality assessment of next-generation sequencing in a clinical diagnostics setting, coexisting mutations within EGFR, KRAS, NRAS, BRAF, AKT1, and PIK3CA genes were examined in 1208 non-small cell lung cancers. RESULTS.-: EGFR mutations did not coexist with BRAF mutations, neither kinase activated nor kinase-impaired mutations. There was a low but similar incidence (3.3%-5.1%) of PIK3CA mutations in BRAF-, EGFR-, and KRAS-mutated lung cancers and a rare incidence of coexisting KRAS and EGFR mutations detected in 1 of 1208 lung cancers (0.08%) or 1 of 226 EGFR-mutated lung cancers (0.4%). Coexisting BRAF p.V600E mutation was observed in 3 of 4 AKT1 p.E17K-mutated lung cancers. Mutational profiling of DNA reisolated from subareas with the same or different histomorphology, using an alternative assay, confirmed that coexisting mutations might present within the same (whole or subclonal) population or different populations and clarified that the so-called coexisting activating KRAS and BRAF mutations originally reported in a specimen were indeed present in separate lung nodules submitted in the same block. CONCLUSIONS.-: The results supported that EGFR and BRAF mutations are early driver mutations in lung cancers. Guidelines from official organizations to establish standard operating procedures are warranted to validate unexpected coexisting mutations and, if clinically indicated, to determine their presence in the same or different tumor populations. PMID- 30485131 TI - Alarmins at the maternal-fetal interface: involvement of inflammation in placental dysfunction and pregnancy complications. AB - Inflammation is known to be associated with placental dysfunction and pregnancy complications. Infections are well known to be a cause of inflammation but they are frequently undetectable in pregnancy complications. More recently, the focus has been extended to inflammation of non-infectious origin, namely caused by endogenous mediators known as "damage-associated molecular patterns - DAMPs" or alarmins. In this manuscript we review the mechanism by which inflammation; sterile or infectious can alter the placenta and its function. We discuss some classical DAMPs, such as: uric acid, high mobility group box 1 (HMGB1), cell free fetal deoxyribonucleic acid (cffDNA), S100 proteins, heat shock protein 70 (HSP70) and adenosine tri-phosphate (ATP), and their impact on the placenta. We focus on the main placental cells (i.e. trophoblast and Hofbauer cells) and describe the placental response to, and release of, DAMPs. We also covered the current state of knowledge about the role of DAMPs in pregnancy complications including preeclampsia, fetal growth restriction, preterm birth, and stillbirth and possible therapeutic strategies to preserve placental function. PMID- 30485132 TI - High-throughput data-driven analysis of myofiber composition reveals muscle specific disease and age-associated patterns. AB - Contractile properties of myofibers are dictated by the abundance of myosin heavy chain (MyHC) isoforms. MyHC composition designates muscle function, and its alterations could unravel differential muscle involvement in muscular dystrophies and aging. Current analyses are limited to visual assessments in which myofibers expressing multiple MyHC isoforms are prone to misclassification. As a result, complex patterns and subtle alterations are unidentified. We developed a high throughput, data-driven myofiber analysis to quantitatively describe the variations in myofibers across the muscle. We investigated alterations in myofiber composition between genotypes, 2 muscles, and 2 age groups. We show that this analysis facilitates the discovery of complex myofiber compositions and its dependency on age, muscle type, and genetic conditions.-Raz, V., Raz, Y., van de Vijver, D., Bindellini, D., van Putten, M., van den Akker, E. B. High-throughput data-driven analysis of myofiber composition reveals muscle-specific disease and age-associated patterns. PMID- 30485133 TI - Oxymatrine Attenuates Abeta1-42-Induced Neurotoxicity in Primary Neuronal Cells and Memory Impairment in Rats. AB - Abeta1-42-induced oxidative stress causes the death of neuronal cells, which is involved in the development of Alzheimer's disease (AD). Oxymatrine (OMT) inhibits oxidative stress. In this study, we investigated the effect of OMT on Abeta1-42-induced neurotoxicity in vivo and in vitro. In the Morris water maze test, OMT significantly decreased the escape latency and increased the number of platform crossings. In vitro, OMT markedly increased cell viability and superoxide dismutase activity. Moreover, OMT decreased the lactate dehydrogenase leakage, malondialdehyde content, and reactive oxygen species in a dose-dependent manner. OMT upregulated the ratio of Bcl-2/Bax and downregulated the level of caspase-3. Furthermore, OMT inhibited the activation of MAPK (ERK 1/2, JNK) and NF-kappaB. In summary, OMT may be a potential compound for the treatment of AD. PMID- 30485134 TI - Correlation between uterine artery Doppler and the sFlt-1/PlGF ratio in different phenotypes of placental dysfunction. AB - OBJECTIVE: To explore correlations between the sFlt-1/PlGF ratio and uterine arteries (UtA) Doppler indexes in placental dysfunction-related disorders (PDD). METHODS: We prospectively included women with a singleton pregnancy with preeclampsia (PE) only (n = 22), preeclampsia with fetal growth restriction (FGR) (n = 32), FGR only (n = 12), or normal pregnancy (n = 29). RESULTS: In PDDs, significantly positive correlations between the sFlt-1/PlGF ratio and the mean UtA pulsatility (mPI-UtA), as well as the resistance index (mRI-UtA) were found (p = 0.015, p = 0.019, respectively), but not in normal pregnancies. PDD with signs of impaired placentation, evidenced by the increased sFlt-1/PlGF ratio and mPI-UtA, was found in 50.0%, and, by the increased sFlt-1/PlGF ratio and mRI-UtA, in 65.2%. PDD without signs of impaired placentation, evidenced by the increased sFlt-1/PlGF ratio but normal mPI-UtA, was found in 24.2%, and, by the increased sFlt-1/PlGF ratio but normal mRI-UtA, in 7.6%. A substantial proportion of women with signs of impaired placentation were diagnosed with FGR with or without PE. CONCLUSION: In PDD, the sFlt-1/PlGF ratio and UtA Doppler indexes increase proportionally. Correlations between the sFlt-1/PlGF ratio and UtA Doppler indexes might help to distinguish between PDDs with and without impaired placentation. However, further studies are needed to explore the correlations in different phenotypes of PDD. PMID- 30485135 TI - Behind Closed Doors: Individual and Joint Pornography Use Among Romantic Couples. AB - Most previous research on the associations between pornography use and relational well-being has utilized individual data sets that have limited scholars' ability to truly understand the dyadic nature of pornography use within romantic couples. Using a dyadic data set of 240 committed heterosexual couples from the United States, we explored actor and partner associations between pornography use, sexual dynamics, and relational well-being. We also explored how couple pornography use and partner knowledge of pornography use were associated with well-being. Results suggested that female pornography use was associated with higher female sexual desire but no other dependent variables. Male pornography use was associated with a wide array of negative well-being indicators, including less male and female relationship satisfaction, lower female sexual desire, and lower male positive communication. Couple pornography use was associated with higher reported sexual satisfaction for both partners but no other well-being indicators. Partner knowledge of use had little direct association with well being, but some evidence suggested that unknown individual use may be associated with less sexual satisfaction but more relationship satisfaction. Results suggest that different configurations of use among heterosexual couples are associated with varying relational well-being indicators. PMID- 30485136 TI - Carnosine modulates the Sp1-Slc31a1/Ctr1 copper sensing system and influences copper homeostasis in murine CNS-derived cells. AB - Carnosine (CAR) is an endogenous dipeptide physiologically present in excitable tissues, such as CNS and muscle. CAR is acknowledged as a substrate involved in many homeostatic pathways and mechanisms and, due to its biochemical properties, as a molecule intertwined with the homeostasis of heavy metals such as copper (Cu). In CNS, Cu excess and dysregulation imply oxidative stress, free-radical production and functional impairment leading to neurodegeneration. Here, we report that CAR intercepts the regulatory routes of Cu homeostasis in nervous cells and tissues. Specifically, in a murine neuron-derived cell model, i.e. the B104 neuroblastoma cells, extracellular CAR exposure up to 24 hours influenced intracellular Cu entry and affected (down-regulated) the key Cu-sensing system consisting of the gene coding for the Slc31a1 transmembrane Cu importer (alias Ctr1) and the gene coding for the Cu-responsive transcription factor Sp1 ( Sp1). Also, CAR exposure upregulated CAR biosynthesis ( Carns1), extracellular degradation ( Cndp1) and transport ( Slc15a4 alias Pht1) genes, and elicited CAR intracellular accumulation, contributing to the outline of functional association between CAR and Cu within the cell. Interestingly, the same gene modulation scheme acting in vitro operates in vivo, in brains of mice undergoing dietary administration of CAR in drinking water for 2 weeks. Overall, our findings describe for the first time a regulatory interaction between CAR and Cu pathways in CNS and indicate CAR as a novel active molecule within the network of ligands and chaperones that physiologically regulate Cu homeostasis. PMID- 30485137 TI - ROS-induced autophagy regulates porcine trophectoderm cell apoptosis, proliferation and differentiation. AB - Significant embryo loss remains a serious problem in pig production. Reactive oxygen species (ROS) play a critical role in embryonic implantation and placentation. However, the potential mechanism of ROS on porcine trophectoderm (pTr) cell fate during peri-implantation period has not been investigated. This study aimed to elucidate the effects of ROS on pTr cell phenotypes and the regulatory role in cell attachment and differentiation. Herein, results showed that exogenous H2O2 inhibited pTr cell viability, arrested cell cycle at S and G2/M phase, increased cell apoptosis and autophagy protein light chain 3B (LC3B) and Beclin-1, while these effects were reversed by different concentrations of N acety-l-cysteine (NAC) post-treatment. In addition, NAC abolished H2O2-induced autophagic flux, inhibited intracellular and mitochondrial ROS, and restored expression of genes important for mitochondrial DNA and biogenesis, cell attachment and differentiation. NAC reversed H2O2-activated MAPK and Akt/mTOR pathways in dose-dependent manners. Furthermore, analyses with pharmacological and RNA interference approaches suggested that autophagy regulated cell apoptosis and gene expression of caudal-related homeobox 2 (Cdx2) and IL1beta. Collectively, these results provide new insights into the role of the ROS-induced autophagy in pTr cell apoptosis, attachment and differentiation, indicating a promising target for decreasing porcine conceptus loss during the peri implantation period. PMID- 30485138 TI - Blocking REDD1/TXNIP axis ameliorates LPS-induced vascular endothelial cell injury through repressing oxidative stress and apoptosis. AB - The aim of the present study was to investigate the potential role of REDD1 (Regulated in development and DNA damage response 1) on LPS-induced vascular endothelial injury by using human umbilical vein endothelial cells (HUVECs). We observed that REDD1 expression was apparently elevated in HUVECs after exposure to LPS. Additionally, elimination of REDD1 strikingly attenuated the secretion of pro-inflammatory cytokines TNF-alpha, IL-6, IL-1beta and MCP-1 and endothelial cell adhesion markers ICAM-1 and VCAM-1 that was induced by LPS stimulation. Subsequently, knockdown of REDD1 augmented cell viability but ameliorated LDH release in HUVECs stimulated with LPS. Meanwhile, depletion of REDD1 effectively restricted LPS-induced HUVEC apoptosis, as exemplified by reduced DNA fragmentation, and it also elevated anti-apoptotic Bcl-2 protein, concomitant with reduced levels of pro-apoptotic proteins Bax and C-caspase-3. Furthermore, repression of REDD1 remarkably alleviated LPS-trigged intracellular ROS generation accompanied by decreased MDA content and increased the activity of endogenous antioxidant enzymes SOD, CAT and GPx. Most important, depletion of REDD1 protected HUVECs against inflammation-mediated apoptosis and oxidative damage partly through TXNIP. Collectively, these findings indicate that the blocking REDD1/TXNIP axis repressed the inflammation-mediated vascular injury process, which may be closely related to oxidative stress and apoptosis in HUVECs, implying that REDD1/TXNIP axis may be a new target for preventing endothelial cell injury process. PMID- 30485139 TI - Correction. PMID- 30485140 TI - The Emergence of Canalization and Evolvability in an Open-Ended, Interactive Evolutionary System. AB - Many believe that an essential component for the discovery of the tremendous diversity in natural organisms was the evolution of evolvability, whereby evolution speeds up its ability to innovate by generating a more adaptive pool of offspring. One hypothesized mechanism for evolvability is developmental canalization, wherein certain dimensions of variation become more likely to be traversed and others are prevented from being explored (e.g., offspring tend to have similar-size legs, and mutations affect the length of both legs, not each leg individually). While ubiquitous in nature, canalization is rarely reported in computational simulations of evolution, which deprives us of in silico examples of canalization to study and raises the question of which conditions give rise to this form of evolvability. Answering this question would shed light on why such evolvability emerged naturally, and it could accelerate engineering efforts to harness evolution to solve important engineering challenges. In this article, we reveal a unique system in which canalization did emerge in computational evolution. We document that genomes entrench certain dimensions of variation that were frequently explored during their evolutionary history. The genetic representation of these organisms also evolved to be more modular and hierarchical than expected by chance, and we show that these organizational properties correlate with increased fitness. Interestingly, the type of computational evolutionary experiment that produced this evolvability was very different from traditional digital evolution in that there was no objective, suggesting that open-ended, divergent evolutionary processes may be necessary for the evolution of evolvability. PMID- 30485141 TI - Moving from Overwhelming to Actionable Complexity in Population Health Policy: Can ALife help? PMID- 30485142 TI - Erratum. PMID- 30485143 TI - Bringing ALife and Complex Systems Science to Population Health Research. AB - Despite tremendous advancements in population health in recent history, human society currently faces significant challenges from wicked health problems. These are problems where the causal mechanisms at play are obscured and difficult to address, and consequently they have defied efforts to develop effective interventions and policy solutions using traditional population health methods. Systems-based perspectives are vital to the development of effective policy solutions to seemingly intractable health problems like obesity and population aging. ALife in particular is well placed to bring interdisciplinary modeling and simulation approaches to bear on these challenges. This article summarizes the current status of systems-based approaches in population health, and outlines the opportunities that are available for ALife to make a significant contribution to these critical issues. PMID- 30485144 TI - Adaptation Is Not Just Improvement over Time. AB - The idea that an agent's actions can impact its actual long-term survival is a very appealing one, underlying influential treatments such as Di Paolo's (2005). However, this presents a tension with understanding the agent and environment as possessing specific objective physical microstates. More specifically, we show that such an approach leads to undesirable outcomes, for example, all organisms being maladaptive on average. We suggest that this problematic intuition of improvement over time may stem from Bayesian inference. We illustrate our arguments using a recent model of autopoietic agency in a model protocell, showing the limitations of previous approaches in this model and specific instantiations of Bayesian inference by ignorant observers in certain scenarios. PMID- 30485145 TI - Measuring Fitness Effects of Agent-Environment Interactions. AB - One important sense of the term "adaptation" is the process by which an agent changes appropriately in response to new information provided by environmental stimuli. We propose a novel quantitative measure of this phenomenon, which extends a little-known definition of adaptation as "increased robustness to repeated perturbation" proposed by Klyubin (2002). Our proposed definition essentially corresponds to the average value (relative to some fitness function) of state changes that are caused by the environment (in some statistical ensemble of environments). We compute this value by comparing the agent's actual fitness with its fitness in a counterfactual world where the causal links between agent and environment are disrupted. The proposed measure is illustrated in a simple Markov chain model and also using a recent model of autopoietic agency in a simulated protocell. PMID- 30485149 TI - Therapeutic drug monitoring of natalizumab. PMID- 30485148 TI - The First Decade of Web-Based Sports Injury Surveillance: Descriptive Epidemiology of Injuries in US High School Girls' Volleyball (2005-2006 Through 2013-2014) and National Collegiate Athletic Association Women's Volleyball (2004 2005 Through 2013-2014). AB - CONTEXT: : The advent of Web-based sports injury surveillance via programs such as the High School Reporting Information Online system and the National Collegiate Athletic Association Injury Surveillance Program has aided in the acquisition of girls' and women's volleyball injury data. OBJECTIVE: : To describe the epidemiology of injuries sustained in high school girls' volleyball in the 2005-2006 through 2013-2014 academic years and collegiate women's volleyball in the 2004-2005 through 2013-2014 academic years using Web-based sports injury surveillance. DESIGN: : Descriptive epidemiology study. SETTING: : Online injury surveillance from high school girls' (annual average = 100) and collegiate women's (annual average = 50) volleyball teams. PATIENTS OR OTHER PARTICIPANTS: : Girls' and women's volleyball players who participated in practices and competitions during the 2005-2006 through 2013-2014 academic years in high school and the 2004-2005 through 2013-2014 academic years in college. MAIN OUTCOME MEASURE(S): : Athletic trainers collected time-loss (>=24 hours) injury and exposure data. Injury rates per 1000 athlete-exposures (AEs), injury rate ratios (IRRs) with 95% confidence intervals (CIs), and injury proportions by body site and diagnosis were calculated. RESULTS: : The High School Reporting Information Online system documented 1634 time-loss injuries during 1 471 872 AEs; the National Collegiate Athletic Association Injury Surveillance Program documented 2149 time-loss injuries during 563 845 AEs. The injury rate was higher in college than in high school (3.81/1000 versus 1.11/1000 AEs; IRR = 3.43; 95% CI = 3.22, 3.66), and higher in high schools with <=1000 students than in those with >1000 students (IRR = 1.35; 95% CI = 1.23, 1.49). Injury rates did not vary by collegiate division. The injury rate was higher during competitions than practices for high school (IRR = 1.23; 95% CI = 1.12, 1.36) but not for college (IRR = 1.01; 95% CI = 0.92, 1.10). Ankle sprains were common in both the high school and collegiate setting. However, liberos had a high incidence of concussion. CONCLUSIONS: : Injury rates were higher among collegiate than high school players. However, injury rates differed by event type in high school, unlike college. Concussion injury patterns among liberos varied from those for other positions. These findings highlight the need for injury-prevention interventions specific to setting and position. PMID- 30485150 TI - Encoding prediction signals during appetitive and aversive Pavlovian conditioning in the primate lateral hypothalamus. AB - The lateral hypothalamus (LH), which plays a role in homeostatic functions like appetite regulation, is also linked to arousal and motivational behavior. However, little is known about how these components are encoded in the LH. Thus, cynomolgus monkeys were conditioned with two distinct contexts, i.e., an appetitive context with available rewards and an aversive context with predicted airpuffs. Different LH neuron groups encoded different degrees of expectation, predictability, and risks of rewards in a specific manner. A nearly equal number of one-third of the recorded LH neurons showed a positive or negative correlation between their response to visual conditioned stimuli (CSs) that predicted the probabilistic delivery of rewards (0%, 50%, and 100%) and the associative values. For another one-third of recorded neurons, a nearly equal number showed a positive or negative correlation between their responses to rewards (appetitive unconditioned stimulus [US]) and reward predictability. Some neurons exhibited their highest or lowest trace-period responses in the 50%-reward trials. These response modulations were represented independently and overlaid on a consistent excitatory or inhibitory response across the conditioning events. LH neurons also showed consistent responses in the aversive context. However, the responses to aversive conditioning events depending on the airpuff value and predictability were less common. The multifaceted modulation of consistent activity related to outcome predictions may reflect motivational and arousal signals. Further, it may underlie the role the LH plays in the integration and relay of signals to cortices for adaptive and goal-directed physiological and behavioral responses to environmental changes. PMID- 30485151 TI - TRPA1 - a molecular view. AB - The TRPA1 ion channel is expressed in pain sensing neurons and other tissues and has become a major target in the development of novel pharmaceuticals. A remarkable feature of the channel is its long list of activators, many of which we are exposed to in daily life. Many of these agonists induce pain and inflammation, making TRPA1 a major target for anti-inflammatory and analgesic therapies. Studies in human patients and in experimental animals have confirmed an important role for TRPA1 in a number of pain conditions. Over the recent years, much progress has been made in elucidating the molecular structure of TRPA1 and in discovering binding sites and modulatory sites of the channel. Since the list of published mutations and important molecular sites is steadily growing and since it has become difficult to see the forest for the trees, this review aims at summarizing the current knowledge about TRPA1, with a special focus on the molecular structure and the known binding or gating sites of the channel. PMID- 30485152 TI - Pilot study on the efficiency of water-only decontamination for firefighters' turnout gear. AB - Firefighters are exposed to toxic environments upon entering burning structures. Many structures contain synthetic materials which release toxic chemicals when on fire. These chemicals can enter the body through multiple routes of exposure, including inhalation and skin absorption. Thus, according to the fire departments included in this study, firefighters now conduct on-site decontamination procedures to remove hazardous chemicals, including polycyclic aromatic hydrocarbons from the surface of firefighter turnout gear. Several methods are being practiced at the local level, including decontamination with soap and water, and decontamination with water alone. The water-only decontamination method requires less time and supplies yet has not been investigated as a suitable method for removing polycyclic aromatic hydrocarbons from turnout gear. Therefore, we evaluated the efficiency of this method by measuring polycyclic aromatic hydrocarbon (PAH) concentration levels before and after water-only decontamination. The calculated efficiency displays the percentage of PAHs removed (or not removed) at post-decontamination in relation to the initial sample collected at pre-decontamination. The turnout gear was sampled after live residential structure fires. Firefighter turnout gear was worn throughout Attack, Overhaul Search and Rescue, and Rescue from Fire operations. All firefighters came to a central location for sampling after completing their job responsibilities. Water only decontamination did not appear to be effective, resulting in an overall 42% increase in PAH contamination. The unexpected increase may have been due to disparate pre- and post-decontamination sampling sites on turnout gear. PMID- 30485153 TI - Temporal resolution of single photon responses in primate rod photoreceptors and limits imposed by cellular noise. AB - Sensory receptor noise corrupts sensory signals, contributing to imperfect perception and dictating central processing strategies. For example, noise in rod phototransduction limits our ability to detect light and minimizing the impact of this noise requires precisely tuned nonlinear processing by the retina. But detection sensitivity is only one aspect of night vision: prompt and accurate behavior also requires that rods reliably encode the timing of photon arrivals. We show here that the temporal resolution of responses of primate rods is much finer than the duration of the light response and identify the key limiting sources of transduction noise. We also find that the thermal activation rate of rhodopsin is lower than previous estimates, implying that other noise sources are more important than previously appreciated. A model of rod single-photon responses reveals that the limiting noise relevant for behavior depends critically on how rod signals are pooled by downstream neurons. PMID- 30485154 TI - Unhealthy behavior clustering and mental health status in United States college students. AB - OBJECTIVE: Examine the association of health risk behavior clusters with mental health status among US college students. PARTICIPANTS: 105,781 US college students who completed the Spring 2011 National College Health Assessment. METHODS: We utilized the latent class analysis to determine clustering of health risk behaviors (alcohol binge drinking, cigarette/marijuana use, insufficient physical activity, and fruit/vegetable consumption), and chi-square and ANOVA analyses to examine associations between the class membership and mental health (mental health diagnoses, psychological symptoms, and self-injurious thoughts/behaviors). RESULTS: Three classes were identified with differing rates of binge drinking, substance use, and insufficient physical activity but similar rates of insufficient fruit/vegetable consumption. Students classified with the highest rates of binge drinking and cigarette/marijuana use had the highest rates across all mental health variables compared to other classes. CONCLUSIONS: Students who reported engaging in multiple health risk behaviors, especially high alcohol and cigarette/marijuana use, were also more likely to report poorer mental health. PMID- 30485155 TI - Ramping Up the Response to Ebola. PMID- 30485156 TI - Pregnant Women and the Ebola Crisis. PMID- 30485157 TI - Connections between sources of health and beauty information and indoor tanning behavior among college women. AB - OBJECTIVE: This study tested how media, family, and peer sources of health and beauty information predict indoor tanning (IT) beliefs and behavior. PARTICIPANTS: 210 undergraduate women at a state university in the southeastern United States. METHODS: Respondents completed a survey about sources of health and beauty information, IT beliefs, and IT behavior. Correlations and a path model were used to test associations between variables. RESULTS: Friends were positively and family were negatively associated with positive outcome expectations, with mood enhancement beliefs positively predicting behavior. Reliance on news positively predicted appearance damage and immediate risk, which both predicted behavior. Reliance on social media was negatively associated with beliefs about immediate risks. CONCLUSION: Health and beauty information from social media and from friends may promote beliefs about tanning, while information from news or one's family may reduce risky beliefs. Prevention efforts could leverage information sources to shift tanning beliefs and behavior. PMID- 30485158 TI - Prevalence of past-year mental disorders and its correlates among Chinese international students in US higher education. AB - OBJECTIVE: This study examined the prevalence of past-year mental disorders and its correlates among Chinese international students in US higher education. PARTICIPANTS: A total of 222 Chinese international students participated in the study. METHODS: Participants were recruited via a social marketing campaign and participated in an online survey. RESULTS: The majority of the participants were female (65.3%) and graduate students (84.7%) with a mean age of 23.75 years. Of the sample, 77.9 and 74.3% reported having experienced depression and anxiety symptoms in the past year, respectively. Predictors of a higher past-year global mental health status were: not having a steady partner; being more likely to return China after graduation; a higher level of stress about the returning plan; and, a lower rating of cultural humility of key college/university personnel. CONCLUSIONS: These results suggest that mental health is a pressing issue facing Chinese international students and correlated with other psychosocial factors. PMID- 30485159 TI - Fatty-acid Binding Protein 5 modulates the SAR1 GTPase cycle and enhances budding of large COPII cargos. AB - COPII coated vesicles are the primary mediators of ER-to-Golgi trafficking. Sar1, one of the five core COPII components, is a highly conserved small GTPase, which, upon GTP binding, recruits the other COPII proteins to the ER membrane. It has been hypothesized that the changes in the kinetics of SAR1 GTPase may allow for the secretion of large cargos. Here we developed a cell-free assay to recapitulate COPII-dependent budding of large lipoprotein cargos from the ER. We identified Fatty-acid Binding Protein 5 (FABP5) as an enhancer of this budding process. We found that FABP5 promotes the budding of particles ~150nm in diameter and modulates the kinetics of the SAR1 GTPase cycle. We further found that FABP5 enhances the trafficking of lipoproteins and of other cargos, including collagen. These data identify a novel regulator of SAR1 GTPase activity and highlight the importance of this activity for trafficking of large cargos. PMID- 30485160 TI - Multi-layered regulation of TORC1-body formation in budding yeast. AB - The Target of Rapamycin Kinase Complex 1 (TORC1) regulates cell growth and metabolism in eukaryotes. In Saccharomyces cerevisiae, TORC1 activity is known to be controlled by the conserved GTPases, Gtr1/2, and movement into and out of an inactive agglomerate/body. However, it is unclear if/how these regulatory steps are coupled. Here we show that active Gtr1/2 is a potent inhibitor of TORC1-body formation, but cells missing Gtr1/2 still form TORC1-bodies in a glucose/nitrogen starvation dependent manner. We also identify 13 new activators of TORC1-body formation and show that seven of these proteins regulate the Gtr1/2 dependent repression of TORC1-body formation, while the remaining proteins drive the subsequent steps in TORC1 agglomeration. Finally, we show that the conserved PI(3)P binding protein, Pib2, forms a complex with TORC1 and overrides the Gtr1/2 dependent repression of TORC1-body formation during starvation. These data provide a unified, systems-level model of TORC1 regulation in yeast. PMID- 30485161 TI - A rapid computational approach identifies SPICE1 as an Aurora kinase substrate. AB - Aurora kinases play a major role in mitosis by regulating diverse substrates. Defining their critical downstream targets is important to understand Aurora kinase function. Here we have developed an unbiased computational approach to identify new Aurora kinase substrates based on phosphorylation site clustering, protein localization, protein structure, and species conservation. We validate the microtubule-associated proteins Clasp2, Elys, TTLL4 and SPICE1 as Aurora A and B kinases substrates in vitro. We also demonstrate that SPICE1 localization is regulated by Aurora kinases during mitosis. In the absence of Aurora kinase activity, SPICE1 remains at centrioles but does not target to the spindle. Similarly a non-phosphorylatable SPICE1 mutant no longer localizes to the spindle. Finally, we show that misregulating SPICE1 phosphorylation results in abnormal centriole number, spindle multipolarity, and chromosome alignment defects. Overall, our work indicates that temporal and spatial Aurora kinase mediated regulation of SPICE1 is important for correct chromosome segregation. In addition, our work provides a database-search tool that enables rapid identification of Aurora kinase substrates. PMID- 30485162 TI - Emotional expressions manifested by pregnant women in the experience of the art of maternal womb painting. AB - The aim of the researchers was to identify the emotional expressions manifested by pregnant women in the experience of the Art of Maternal Womb Painting. It was an exploratory research, kind before and after, and qualitative approach, developed in Brazil between October 2015 and January 2016. The data were collected from interview, intervention, filming, photography and field diary on 10 pregnant women. The analysis involved coding of facial expressions by Facial Action Coding System. The measurement of the facial behavior allowed the identification of the six universal emotions, their characteristics and the order of appearance with relation to background of each pregnant. PMID- 30485163 TI - Protective effect of Schisandra chinensis lignans on hypoxia-induced PC12 cells and signal transduction. AB - It is well-known that hypoxia induces neuronal injury; however, the mechanisms underlying this observed effect remain to be determined. Schisandra chinensis lignans (SCL). The aim of this study was thus to examine the ability of Schisandra chinensis lignans (SCL) to prevent hypoxia-induced neuronal injury using a human adrenal pheochromocytoma cell line (PC12). Exposure to hypoxia significantly reduced cell survival rate in cultured PC12 cells. However, pretreatment with SCL at 10, 20 or 40 MUmol/L followed by hypoxia prevented loss of cellular viability. Flow cytometry demonstrated that the apoptotic rate in PC12 cells following hypoxia was significantly increased. Pretreatment with SCL 20 or 40 MUmol/L in hypoxia-exposed cells resulted in significantly reduced apoptotic rates compared to hypoxia. Immunocytochemical staining showed that protein expression of p-Akt was significantly diminished by hypoxia. Following pre-treatment with different concentrations of SCL, PC12 cells were markedly stimulated as evidenced by elevated protein expression of p-Akt in a concentration-dependent manner. The expression of p-Akt protein in the presence of PI3K/Akt signaling pathway inhibitor LY294002 and SCL was not markedly changed indicating that signal transduction was affected by this Chinese herb. There were no significant differences in total Akt protein expression following hypoxia or pretreatment with SCL. Western blot demonstrated that expression levels of caspase-3 protein were significantly increased while expression levels of Bcl-2 protein were decreased in hypoxic cells. Pretreatment with SCL followed by hypoxia significantly lowered expression levels of caspase-3 protein accompanied by elevated expression levels of Bcl-2 protein in a concentration-dependent manner. After co-incubation with LY29004 and SCL, down-regulation of expression of caspase-3 protein and up-regulation of the expression of Bcl-2 protein noted with SCL alone were suppressed. Data suggest that the protective effect exerted by SCL in hypoxia-induced PC12 cell injury involves enhanced cell proliferation and inhibition of apoptosis mediated by activation of PI3K/Akt signaling pathway. The increased protein Akt phosphorylation expression levels resulted in consequent reduced downstream caspase-3 expression and enhanced Bcl-2 expression. PMID- 30485164 TI - Use of Vitamin D Supplements in Osteoarthritis: An Observational Study in a Tertiary Health Care Facility. AB - OBJECTIVE: The purpose of the study was to assess impact of vitamin D supplements on the disease progression and overall health of osteoarthritis (OA) patients. METHODOLOGY: A cohort study was carried out for 8 months (August 2017-March 2018) in the Orthopedics Department of Kasturba Hospital, Manipal, India, a tertiary care hospital. One hundred and forty-two patients who were diagnosed with OA (grades 1-3) with low serum 25(OH)D levels (severely deficient, deficient, or insufficient) were selected for the study. These patients were categorized into two cohorts: a control cohort (CC) and a study cohort (SC). CC members were patients (n = 71) who had not received vitamin D supplements, and SC members were patients (n = 71) who had received vitamin D supplements. Severity grading of OA, pain score, and health assessment were performed using the Kellgren-Laurence grading score, visual analogue scale (VAS), and WOMAC, respectively, at baseline and after 3 months of follow-up. RESULTS: Subjects in the both CC and SC reported no statistically significant difference (similar in both group) in severity grade (p = 0.303), pain score (p = 0.099), parathyroid hormone (PTH) (p = 0.083), and health status (p = 0.76) at baseline. After 3 months of follow-up (post vitamin D supplementation), OA patients have shown statistically significant difference in severity grades, serum 25(OH)D status, PTH level (p < 0.001), and overall health status (p = 0.001) in the SC with respect to baseline. Likewise, percentage distribution of positive changes was significantly higher in severity grade, pain score, serum 25(OH)D level, overall health status (p < 0.001), and PTH (p = 0.040) of SC as compared to CC at follow-up. CONCLUSION: Vitamin D supplements have significantly improved serum 25(OH)D levels, PTH, severity grade, and pain score of OA patients. Most importantly, vitamin D supplements have shown improvement in the overall health of OA patients, emphasizing the place of vitamin D supplements in the management of OA. Clinical Trial Registry-India (CTRI) registration no: CTRI/2017/12/011031. PMID- 30485165 TI - Performance of the Tuberculin Skin Test in Mycobacterium bovis-Exposed and Unexposed African Lions ( Panthera leo). AB - Lion ( Panthera leo) populations, classified as vulnerable under the International Union for Conservation of Nature red list of threatened species, are facing a variety of threats, including tuberculosis (TB) caused by Mycobacterium bovis. The lack of knowledge on pathogenesis and diagnosis of TB, the prolonged course of the disease, the existence of subclinical infection, and nonspecific clinical signs hamper management of TB in both free-ranging and captive lion populations. Early and accurate antemortem diagnosis of M. bovis infections is important for disease management. In this study, we investigate the suitability of the single intradermal cervical test (SICT), developed with free ranging Kruger National Park (KNP) lions exposed to M. bovis, for use in other lion populations. Using the recommended interpretation, the specificity of the SICT was low in disease-free captive lions, leading to false-positive diagnoses in 54% of individuals in the present study. Alternative interpretations of the tuberculin skin test are proposed that significantly reduce false-positive diagnosis in the sampled captive lions without significantly affecting diagnoses in the KNP lions; these changes may facilitate screening for M. bovis infection regardless of the exposure status of the lion population being investigated. PMID- 30485166 TI - Rate of Cooling in a Moose ( Alces alces) Carcass. AB - Postmortem body temperature is used to estimate time of death in humans, but the available models are not validated for most nonhuman species. Here, we report that cooling in an adult female moose ( Alces alces) equipped with a rumen temperature monitor was extremely slow, with a rumen temperature of 27-28 C as late as 40 h postmortem. PMID- 30485167 TI - Transmission Dynamics of Toxoplasma gondii in Arctic Foxes ( Vulpes lagopus): A Long-term Mark-recapture Serologic Study at Karrak Lake, Nunavut, Canada. AB - Transmission dynamics of Toxoplasma gondii, a parasite of importance for wildlife and human health, are enigmatic in the Arctic tundra, where free-ranging wild and domestic felid definitive hosts are absent and rarely observed, respectively. Through a multiyear mark-recapture study (2011-2017), serosurveillance was conducted to investigate transmission of T. gondii in Arctic foxes ( Vulpes lagopus) in the Karrak Lake region, Nunavut, Canada. Sera from adult foxes and fox pups were tested for antibodies to T. gondii by using serologic methods, including the indirect fluorescent antibody test, direct agglutination test, and modified agglutination test. The overall seroprevalence was 39% in adults and 17% in pups. Mature foxes were more likely to be exposed (seroconvert) than young foxes (less than 1 yr old), with the highest level of seroprevalence in midaged foxes (2-4 yr old). Pups in two different litters were seropositive on emergence from the den, around 5 wk old, which could have been due to passive transfer of maternal antibody or vertical transmission of T. gondii from mother to offspring. The seropositive pups were born of seropositive mothers that were also seropositive the year before they gave birth, suggesting that vertical transmission might not be limited to litters from mothers exposed to T. gondii for the first time in pregnancy. All recaptured seropositive foxes remained seropositive on subsequent captures, suggesting that antibodies persist or foxes are constantly reexposed or a combination of both. The results of this study provided insights into how foxes were likely exposed to T. gondii, the dynamics of antibody persistence and immune response, and how the parasite was maintained in a terrestrial Arctic ecosystem in the absence of felid definitive hosts. PMID- 30485169 TI - Establishment of an Uncomplicated Radiation-delayed Wound Healing Model Using Irradiation in Pigs. AB - INTRODUCTION: Radiation-delayed wounds require diverse therapeutic strategies to achieve effective healing. However, the development of novel therapies with a radiation-delayed wound healing model is hindered by the lack of standardized animal models. OBJECTIVE: In this study, the authors propose and verify a procedure to establish a radiation-delayed wound healing model in pigs. MATERIALS AND METHODS: Two female pigs received a single 18-Gy dose of a 6-MeV electron beam per 18 cm x 8 cm area. Three areas were treated on the paraspinal dorsal skin surface of each pig, with 2 on the left side of the spine and 1 on the right. Wounds were periodically created on the 2 pigs at 1 of the following time points: (1) 2 weeks post radiation (PR2 group; n = 4), (2) 4 weeks post radiation (PR4 group; n = 4), and (3) 6 weeks post radiation (PR6 group; n = 4). A partial thickness wound was created by excising the skin, superficial fat layer, and superficial fascia while preserving the deep fat and deep fascia. Wound contraction was evaluated, and histological analysis was performed at 2 and 4 weeks after wounding. RESULTS: The control wounds displayed complete reepithelialization at week 4. However, the PR6 group showed delayed wound healing for the entire experimental period. Furthermore, compared with the control group, the PR6 group demonstrated excessive acute and chronic inflammation and exhibited incomplete reepithelialization at week 4. CONCLUSIONS: These findings suggest skin wounding 6 weeks after irradiation is most suitable for the induction of a delayed wound healing model. Using this protocol, the authors safely generated a delayed wound healing model without acute complications from irradiation. PMID- 30485170 TI - Use of Negative Pressure Wound Therapy With Instillation and a Novel Reticulated Open-cell Foam Dressing With Through Holes at a Level 2 Trauma Center. AB - INTRODUCTION: Current wound treatment options for complex wounds include advanced wound therapies. One such treatment, negative pressure wound therapy (NPWT), has evolved to include automated instillation of topical wound solutions with a user specified dwell time (NPWTi-d). A novel reticulated open-cell foam dressing with through holes (ROCF-CC) was developed to assist wound cleansing by removing thick wound exudate and infectious material. OBJECTIVE: The author's experience using NPWTi-d with ROCF-CC on complex wounds is presented. MATERIALS AND METHODS: Patients (N = 19) received antibiotics, pain medication (oral or intravenous), and debridement when applicable. The ROCF-CC contact layer with through holes was cut to fit the wound dimensions and placed in the wound bed. The cover layer (without holes) was placed over the contact layer to fill the remainder of the wound bed, including undermined areas. The foam layers were covered with a semi occlusive drape, and NPWTi-d was initiated by instilling saline or a hypochlorous solution with a 1-minute to 10-minute dwell time followed by 2 to 3.5 hours of negative pressure (-125 mm Hg or -150 mm Hg). Dressing changes were performed every 2 to 3 days. RESULTS: Mean patient age was 57.1 +/- 18.1 years. Common comorbidities included diabetes, obesity, and tobacco use. After an average of 9.0 +/- 6.9 days of therapy, all wounds displayed less malodor, less devitalized tissue, and improved granulation tissue formation. CONCLUSIONS: In all 19 cases, adjunctive use of NPWTi-d with ROCF-CC contributed to hospital discharge, wound closure, and successful limb salvage in this patient population. PMID- 30485172 TI - The search for a new test of early cancer detection. PMID- 30485171 TI - Provisional standardization of hepcidin assays: creating a traceability chain with a primary reference material, candidate reference method and a commutable secondary reference material. AB - Background Hepcidin concentrations measured by various methods differ considerably, complicating interpretation. Here, a previously identified plasma based candidate secondary reference material (csRM) was modified into a serum based two-leveled sRM. We validated its functionality to increase the equivalence between methods for international standardization. Methods We applied technical procedures developed by the International Consortium for Harmonization of Clinical Laboratory Results. The sRM, consisting of lyophilized serum with cryolyoprotectant, appeared commutable among nine different measurement procedures using 16 native human serum samples in a first round robin (RR1). Harmonization potential of the sRM was simulated in RR1 and evaluated in practice in RR2 among 11 measurement procedures using three native human plasma samples. Comprehensive purity analysis of a candidate primary RM (cpRM) was performed by state of the art procedures. The sRM was value assigned with an isotope dilution mass spectrometry-based candidate reference method calibrated using the certified pRM. Results The inter-assay CV without harmonization was 42.1% and 52.8% in RR1 and RR2, respectively. In RR1, simulation of harmonization with sRM resulted in an inter-assay CV of 11.0%, whereas in RR2 calibration with the material resulted in an inter-assay CV of 19.1%. Both the sRM and pRM passed international homogeneity criteria and showed long-term stability. We assigned values to the low (0.95+/-0.11 nmol/L) and middle concentration (3.75+/-0.17 nmol/L) calibrators of the sRM. Conclusions Standardization of hepcidin is possible with our sRM, which value is assigned by a pRM. We propose the implementation of this material as an international calibrator for hepcidin. PMID- 30485173 TI - Danger of false negative (exclusion) or false positive (diagnosis) for 'congenital thrombophilia' in the age of anticoagulants. AB - Background Most guidelines and experts recommend against performance of thrombophilia testing in general, and specifically against testing patients on pharmacological anticoagulants, due to substantially increased risk of false positive identification. For example, vitamin K antagonist (VKA) therapy affects protein C (PC) and protein S (PS), as well as some clotting assays (e.g. as used to investigate activated PC resistance [APCR]). Although heparin may also affect clotting assays, most commercial methods contain neutralisers to make them 'insensitive' to therapeutic levels. Direct oral anticoagulants (DOACs) also affect a wide variety of thrombophilia assays, although most reported data has employed artificial in vitro spiked samples. Methods In the current report, data from our facility for the past 2.5 years has been assessed for all 'congenital thrombophilia' related tests, as evaluated against patient anticoagulant status. We processed 10,571 'thrombophilia' related test requests, including antithrombin (AT; n=3470), PC (n=3569), PS (n=3585), APCR (n=2359), factor V Leiden (FVL; n=2659), and prothrombin gene mutation (PGM; n=2103). Results As expected, VKA therapy affected PC and PS, and despite manufacturer claims, also APCR. Most assays, as suggested by manufacturers, were largely resistant to heparin therapy. DOACs' use was associated with falsely low APCR ratios (i.e. FVL-like effect) and somewhat unexpectedly, anti-Xa agents apixaban and rivaroxaban were also associated with lower AT and higher PS values. Conclusions It is concluded that ex-vivo data appears to confirm the potential for both false positive and false negative 'thrombophilia' events in patients on anticoagulant (including DOAC) treatment. PMID- 30485174 TI - A new preanalytical factor: conveyor transport influences residual platelet concentrations. PMID- 30485175 TI - Electronic health records, communication, and data sharing: challenges and opportunities for improving the diagnostic process. AB - Background Diagnosis requires that clinicians communicate and share patient information in an efficient manner. Advances in electronic health records (EHRs) and health information technologies have created both challenges and opportunities for such communication. Methods We conducted a multi-method, focused ethnographic study of physicians on general medicine inpatient units in two teaching hospitals. Physician teams were observed during and after morning rounds to understand workflow, data sharing and communication during diagnosis. To validate findings, interviews and focus groups were conducted with physicians. Field notes and interview/focus group transcripts were reviewed and themes identified using content analysis. Results Existing communication technologies and EHR-based data sharing processes were perceived as barriers to diagnosis. In particular, reliance on paging systems and lack of face-to-face communication among clinicians created obstacles to sustained thinking and discussion of diagnostic decision-making. Further, the EHR created data overload and data fragmentation, making integration for diagnosis difficult. To improve diagnosis, physicians recommended replacing pagers with two-way communication devices, restructuring the EHR to facilitate access to key information and improving training on EHR systems. Conclusions As advances in health information technology evolve, challenges in the way clinicians share information during the diagnostic process will rise. To improve diagnosis, changes to both the technology and the way in which we use it may be necessary. PMID- 30485177 TI - Language lateralization with resting-state and task-based functional MRI in pediatric epilepsy. AB - OBJECTIVEDetermining language laterality in patients with intractable epilepsy is important in operative planning. Wada testing is the gold standard, but it has a risk of stroke. Both Wada and task-based functional MRI (tb-fMRI) require patient cooperation. Recently, resting-state fMRI (rs-fMRI) has been explored for language lateralization. In the present study, the correlation between rs-fMRI and tb-fMRI in language lateralization is estimated in a pediatric population with intractable epilepsy.METHODSrs-fMRI and tb-fMRI language lateralization testing performed as part of epilepsy surgery evaluation was retrospectively reviewed.RESULTSTwenty-nine patients underwent rs-fMRI and tb-fMRI; a total of 38 rs-fMRI studies and 30 tb-fMRI studies were obtained. tb-fMRI suggested left dominance in 25 of 30 cases (83%), right in 3 (10%), and in 2 (7%) the studies were nondiagnostic. In rs-fMRI, 26 of 38 studies (68%) suggested left dominance, 3 (8%) right dominance, 6 (16%) bilateral, and 3 (8%) were nondiagnostic. When tb fMRI lateralized to the left hemisphere (25 cases), rs-fMRI was lateralized to the left in 23 patients (92%) and it was bilateral/equal in 2 (8%). When tb-fMRI lateralized to the right (3 cases), rs-fMRI lateralized to the right in all cases (100%). The overall concordance rate was 0.93 (95% CI 0.76-0.99) when considering cases with tb-fMRI and rs-fMRI performed within 6 months of each other, and tb fMRI results were not nondiagnostic.CONCLUSIONSrs-fMRI significantly correlated with tb-fMRI in lateralizing language and suggests the potential role for identifying hemispheric dominance via rs-fMRI. Further investigation and validation studies are warranted. PMID- 30485176 TI - Cervical mismatch: the normative value of T1 slope minus cervical lordosis and its ability to predict ideal cervical lordosis. AB - OBJECTIVENumerous studies have attempted to delineate the normative value for T1S CL (T1 slope minus cervical lordosis) as a marker for both cervical deformity and a goal for correction similar to how PI-LL (pelvic incidence-lumbar lordosis) mismatch informs decision making in thoracolumbar adult spinal deformity (ASD). The goal of this study was to define the relationship between T1 slope (T1S) and cervical lordosis (CL).METHODSThis is a retrospective review of a prospective database. Surgical ASD cases were initially analyzed. Analysis across the sagittal parameters was performed. Linear regression analysis based on T1S was used to provide a clinically applicable equation to predict CL. Findings were validated using the postoperative alignment of the ASD patients. Further validation was then performed using a second, normative database. The range of normal alignment associated with horizontal gaze was derived from a multilinear regression on data from asymptomatic patients.RESULTSA total of 103 patients (mean age 54.7 years) were included. Analysis revealed a strong correlation between T1S and C0-7 lordosis (r = 0.886), C2-7 lordosis (r = 0.815), and C0-2 lordosis (r = 0.732). There was no significant correlation between T1S and T1S CL. Linear regression analysis revealed that T1S-CL assumed a constant value of 16.5 degrees (R2 = 0.664, standard error 2 degrees ). These findings were validated on the postoperative imaging (mean absolute error [MAE] 5.9 degrees ). The equation was then applied to the normative database (MAE 6.7 degrees controlling for McGregor slope [MGS] between -5 degrees and 15 degrees ). A multilinear regression between C2-7, T1S, and MGS demonstrated a range of T1S-CL between 14.5 degrees and 26.5 degrees was necessary to maintain horizontal gaze.CONCLUSIONSNormative CL can be predicted via the formula CL = T1S - 16.5 degrees +/- 2 degrees . This implies a threshold of deformity and aids in providing a goal for surgical correction. Just as pelvic incidence (PI) can be used to determine the ideal LL, T1S can be used to predict ideal CL. This formula also implies that a kyphotic cervical alignment is to be expected for individuals with a T1S < 16.5 degrees . PMID- 30485178 TI - Long-term follow-up of pediatric head trauma patients treated at Mulago National Referral Hospital in Uganda. AB - OBJECTIVEThere is a paucity of literature on long-term neurosurgical outcomes in sub-Saharan Africa, and as neurosurgical services expand in each country, it would be beneficial to understand the impact of these services on the national population. Since follow-up can be inconsistent, the authors here used the novel method of telephone surveys to conduct the first-ever long-term follow-up in Uganda to elucidate the outcomes of pediatric head trauma patients treated at the national referral hospital.METHODSA prospectively maintained database of pediatric head trauma patients treated at the Mulago National Referral Hospital (MNRH) between 2014 and 2015 included 232 patients eligible for this study. Quality of life was assessed through phone surveys conducted by a Ugandan collaborator on site who performed all interviews with the guardian listed at the time of hospital admission, using each participant's language.RESULTSPhone interviews were completed for 142 patients, resulting in a 61% response rate. Including inpatient deaths, the mortality rate was 10%. Almost half of the patients (48%) did not return to MNRH postdischarge, and 37% received no subsequent healthcare at all. Including inpatient deaths, the average Extended Glasgow Outcome Scale-Pediatric Revision (GOSE-Peds) scores for patients with severe, moderate, and mild head trauma were 5.68 +/- 2.85, 4.79 +/- 2.38, and 3.12 +/- 2.08, respectively, at 1 year postinjury and 5.56 +/- 2.58, 4.00 +/- 2.45, and 2.21 +/- 1.49, respectively, at 2 years postinjury.CONCLUSIONSThis first-ever long-term follow-up of pediatric head trauma patients in Uganda confirmed the feasibility of a novel phone follow-up method for patients throughout Uganda. The results at 2 years showed poor long-term recovery in patients who suffered moderate or severe head trauma but good recovery in patients who suffered mild head trauma. However, there was greater overall disability than that in comparable head trauma studies in the US. The current study lays the groundwork for phone follow-up in low- and middle-income countries as a viable way to obtain outcome data. PMID- 30485179 TI - Response to editorials. Resting-state brain functional MRI to complete the puzzle. PMID- 30485180 TI - Outcomes and prognostic stratification of patients with recurrent glioblastoma treated with salvage stereotactic radiosurgery. AB - OBJECTIVEGlioblastoma (GBM) is the most malignant form of astrocytoma. The average survival is 6-10 months in patients with recurrent GBM (rGBM). In this study, the authors evaluated the role of stereotactic radiosurgery (SRS) in patients with rGBMs.METHODSThe authors performed a retrospective review of their brain tumor database (1997-2016). Overall survival (OS) and progression-free survival (PFS) after salvage SRS were the primary endpoints evaluated. Response to SRS was assessed using volumetric MR images.RESULTSFifty-three patients with rGBM underwent salvage SRS targeting 75 lesions. The median tumor diameter and volume were 2.55 cm and 3.80 cm3, respectively. The median prescription dose was 18 Gy (range 12-24 Gy) and the homogeneity index was 1.90 (range 1.11-2.02). The median OS after salvage SRS was estimated to be 11.0 months (95% CI 7.1-12.2) and the median PFS after salvage SRS was 4.4 months (95% CI 3.7-5.0). A Karnofsky Performance Scale score >= 80 was independently associated with longer OS, while small tumor volume (< 15 cm3) and less homogeneous treatment plans (homogeneity index > 1.75) were both independently associated with longer OS (p = 0.007 and 0.03) and PFS (p = 0.01 and 0.002, respectively). Based on these factors, 2 prognostic groups were identified for PFS (5.4 vs 3.2 months), while 3 were identified for OS (median OS of 15.2 vs 10.5 vs 5.2 months).CONCLUSIONSSRS is associated with longer OS and/or PFS in patients with good performance status, small-volume tumor recurrences, and heterogeneous treatment plans. The authors propose a prognostic model to identify a cohort of rGBM patients who may benefit from SRS. PMID- 30485181 TI - Letter to the Editor. Upfront GKS for Cushing's disease and acromegaly: is it suitable? PMID- 30485182 TI - Letter to the Editor. The triangulation technique for localizing the lacerum ICA in endoscopic endonasal skull base surgery. PMID- 30485183 TI - Long-term pain outcomes for recurrent idiopathic trigeminal neuralgia after stereotactic radiosurgery: a prospective comparison of first-time microvascular decompression and repeat stereotactic radiosurgery. AB - OBJECTIVEMicrovascular decompression (MVD) and stereotactic radiosurgery (SRS) are common surgical treatments for trigeminal neuralgia (TN). Many patients who receive SRS have pain recurrence; the ideal second intervention is unknown. The authors directly compared pain outcomes after MVD and repeat SRS in a population of patients in whom SRS failed as their first-line procedure for TN, and they identified predictors of pain control.METHODSThe authors reviewed a prospectively collected database of patients undergoing surgery for TN between 1997 and 2014 at the University of California, San Francisco (UCSF). Standardized data collection focused on preoperative clinical characteristics, surgical characteristics, and postoperative outcomes. Patients with typical type 1, idiopathic TN with >= 1 year of follow-up were included.RESULTSIn total, 168 patients underwent SRS as their first procedure. Of these patients, 90 had residual or recurrent pain. Thirty of these patients underwent a second procedure at UCSF and had >= 1 year of follow-up; 15 underwent first-time MVD and 15 underwent repeat SRS. Patients undergoing MVD were younger than those receiving repeat SRS and were more likely to receive >= 80 Gy during the initial SRS. The average follow-up was 44.9 +/- 33.6 months for MVD and 48.3 +/- 45.3 months for SRS. All patients achieved complete pain freedom without medication at some point during their follow-up. At last follow-up, 80% of MVD-treated patients and 33.3% of SRS-treated patients had a favorable outcome, defined as Barrow Neurological Institute Pain Intensity scores of I-IIIa (p < 0.05). Percentages of patients with favorable outcome at 1 and 5 years were 86% and 75% for the MVD cohort and 73% and 27% for the SRS cohort, respectively (p < 0.05). Multivariate Cox proportional hazards analysis demonstrated that performing MVD was statistically significantly associated with favorable outcome (HR 0.12, 95% CI 0.02-0.60, p < 0.01). There were no statistically significant predictors of favorable outcome in the MVD cohort; however, the presence of sensory changes after repeat SRS was associated with pain relief (p < 0.01).CONCLUSIONSPatients who received MVD after failed SRS had a longer duration of favorable outcome compared to those who received repeat SRS; however, both modalities are safe and effective. The presence of post-SRS sensory changes was predictive of a favorable pain outcome in the SRS cohort. PMID- 30485184 TI - Case-matched comparative analysis of spinal deformity correction in arthrogryposis multiplex congenita versus adolescent idiopathic scoliosis. AB - OBJECTIVEAs scoliosis in arthrogryposis multiplex congenita (AMC) is unusual and the number of cases reviewed in previous studies is also relatively small, no previous study exists that has directly compared the results of spinal deformity correction between AMC and adolescent idiopathic scoliosis (AIS) patients. The aim of this study was to compare the radiographic and clinical outcomes of surgical correction of spinal deformity associated with AMC versus AIS.METHODSTwenty-four adolescents with AMC were matched with 48 AIS patients in terms of Cobb angle of main curve, curve pattern, sex, age at surgery, Risser grade, and length of follow-up. Patients in both groups underwent posterior-only spinal correction and fusion procedures. The surgical outcomes and complications were analyzed and compared between the 2 groups.RESULTSIn comparison to the AIS group, the AMC group had a significantly longer mean operation time (5.6 vs 4.4 hours, p = 0.002), more blood loss (1620 +/- 250 ml vs 840 +/- 260 ml, p < 0.001), and more fusion levels (14.1 +/- 2.3 levels vs 12.4 +/- 2.5 levels, p = 0.007) as well as a lower correction rate (44.3% +/- 11.1% vs 70.8% +/- 12.4%, p < 0.001) and a higher rate of loss of correction (5.0% +/- 3.1% vs 2.1% +/- 1.9%, p < 0.001). Nine patients in the AMC group had preoperative pelvic obliquity, which was corrected from a mean of 14.2 degrees +/- 8.4 degrees to a mean of 4.3 degrees +/- 3.2 degrees (p < 0.001) after the surgery. The thoracic lordosis and sagittal vertical axis were significantly improved in the AMC group. Notably, however, the AMC group was found to have higher rates of screw malpositioning (15.9% vs 9.5%, p = 0.002) and complications (8/24 [33.3%] vs 4/48 [8.3%], p = 0.016) as compared to the AIS group.CONCLUSIONSCorrection of AMC associated scoliosis tends to require a longer operating time and involve more fusion levels but results in less correction, more blood loss, and more complications, in comparison with AIS. In addition, more attention should be paid to pelvic obliquity and sagittal hyperlordosis in AMC patients. PMID- 30485185 TI - Endoscope- versus microscope-integrated near-infrared indocyanine green videoangiography in aneurysm surgery. AB - OBJECTIVEThe quality of surgical treatment of intracranial aneurysms is determined by complete aneurysm occlusion while preserving blood flow in the parent, branching, and perforating arteries. For a few years, there has been a nearly noninvasive and cost-effective technique for intraoperative flow evaluation: microscope-integrated indocyanine green videoangiography (mICG-VA). This method allows for real-time information about blood flow in the aneurysm and the involved vessels, but its limitations are seen in the evaluation of structures located in the depth of the surgical field, especially through small craniotomies. To compensate for these drawbacks, an endoscope-integrated ICG-VA (eICG-VA) was developed. The objective of the present study was to assess the use of eICG-VA in comparison with mICG-VA for intraoperative blood flow evaluation.METHODSIn the period between January 2011 and January 2015, 216 patients with a total of 248 intracranial saccular aneurysms were surgically treated in the Department of Neurosurgery of Saarland University Medical Center in Homburg/Saar, Germany. During 95 surgeries in 88 patients with a total of 108 aneurysms, intraoperative evaluation was performed with both eICG-VA and mICG-VA. After clipping, evaluation of complete aneurysm occlusion and flow in the parent, branching, and perforating arteries was performed using both methods. Intraoperative applicability of each technique was compared with the other and with postoperative digital subtraction angiography as a standard evaluation technique.RESULTSEvaluation of completeness of aneurysm occlusion and of flow in the parent, branching, and perforating arteries was more successful with eICG-VA than with mICG-VA, especially for aneurysm neck assessment (88.9% vs 69.4%). For 63.9% of the aneurysms (n = 69), both methods were equivalent, but in 30.6% of the cases (n = 33), the eICG-VA provided better results for evaluating the post clipping situation. In 4.6% of these aneurysms (n = 5), the information given by the additional endoscope considerably changed the surgical procedure. Thus, one residual aneurysm (0.9%), two neck remnants (1.9%), and two branch occlusions (1.9%) could be prevented. Nevertheless, two incomplete aneurysm occlusions (1.9%) and six neck remnants (5.6%) were revealed by postoperative digital subtraction angiography.CONCLUSIONSEndoscope-integrated ICG-VA seems to be an improvement that might increase the quality of aneurysm surgery by providing additional information. It offers higher illumination, magnification, and an extended viewing angle. Its main advantage is its ability to assess deep-seated aneurysms, especially through small craniotomies, but further studies are required. PMID- 30485186 TI - In vivo histotripsy brain treatment. AB - OBJECTIVEHistotripsy is an ultrasound-based treatment modality relying on the generation of targeted cavitation bubble clouds, which mechanically fractionate tissue. The purpose of the current study was to investigate the in vivo feasibility, including dosage requirements and safety, of generating well confined destructive lesions within the porcine brain utilizing histotripsy technology.METHODSFollowing a craniectomy to open an acoustic window to the brain, histotripsy pulses were delivered to generate lesions in the porcine cortex. Large lesions with a major dimension of up to 1 cm were generated to demonstrate the efficacy of histotripsy lesioning in the brain. Gyrus-confined lesions were generated at different applied dosages and under ultrasound imaging guidance to ensure that they were accurately targeted and contained within individual gyri. Clinical evaluation as well as MRI and histological outcomes were assessed in the acute (<= 6 hours) and subacute (<= 72 hours) phases of recovery.RESULTSHistotripsy was able to generate lesions with a major dimension of up to 1 cm in the cortex. Histotripsy lesions were seen to be well demarcated with sharp boundaries between treated and untreated tissues, with histological evidence of injuries extending <= 200 um from their boundaries in all cases. In animals with lesions confined to the gyrus, no major hemorrhage or other complications resulting from treatment were observed. At 72 hours, MRI revealed minimal to no edema and no radiographic evidence of inflammatory changes in the perilesional area. Histological evaluation revealed the histotripsy lesions to be similar to subacute infarcts.CONCLUSIONSHistotripsy can be used to generate sharply defined lesions of arbitrary shapes and sizes in the swine cortex. Lesions confined to within the gyri did not lead to significant hemorrhage or edema responses at the treatment site in the acute or subacute time intervals. PMID- 30485187 TI - US regional variations in rates, outcomes, and costs of spinal arthrodesis for lumbar spinal stenosis in working adults aged 40-65 years. AB - OBJECTIVEIt is important to identify differences in the treatment of common diseases over time and across geographic regions. Several studies have reported increased use of arthrodesis to treat lumbar spinal stenosis (LSS). The purpose of this study was to investigate geographic variations in the treatment of LSS by US region.METHODSThe authors reviewed inpatient and outpatient medical claims from 2010 to 2014 using the MarketScan Commercial Claims and Encounters database (Truven Health Analytics), which includes data on commercially insured members younger than 65 years. ICD-9 code 724.02 was used to identify patients aged >= 40 and < 65 years who underwent surgery for "spinal stenosis of the lumbar region" and for whom LSS was the only principal diagnosis. The primary outcome was the performance of spinal arthrodesis as part of the procedure. Geographic regions were based on patient residence and defined according to the US Census Bureau as the Northeast, Midwest, South, and West.RESULTSRates of arthrodesis, as opposed to decompression alone, varied significantly by region, from 48% in the South, to 42% in the Midwest, 36% in the Northeast, and 31% in the West. After controlling for patient age, sex, and Charlson Comorbidity Index values, the differences remained significant. Compared with patients in the Northeast, those in the South (OR 1.6, 95% CI 1.50-1.75) and Midwest (OR 1.3, 95% CI 1.18-1.41) were significantly more likely to undergo spinal arthrodesis. On multivariate analysis, patients in the West were significantly less likely to have a prolonged hospital stay (> 3 days) than those in the Northeast (OR 0.84, 95% CI 0.75-0.94). Compared with the rate in the Northeast, the rates of discharge to a skilled nursing facility were lower in the South (OR 0.41, 95% CI 0.31-0.55) and West (OR 0.72, 95% CI 0.53-0.98). The 30-day readmission rate was significantly lower in the West (OR 0.81, 95% CI 0.65-0.98) than in the Northeast and similar between the other regions. Mean payments were significantly higher in the Midwest (mean difference $5503, 95% CI $4279-$6762), South (mean difference $6187, 95% CI $5041 $7332), and West (mean difference $7732, 95% CI $6384-$9080) than in the Northeast.CONCLUSIONSThe use of spinal arthrodesis, as well as surgical outcomes and payments for the treatment of LSS, varies significantly by US region. This highlights the importance of developing national recommendations for the treatment of LSS. PMID- 30485188 TI - A wearable mixed-reality holographic computer for guiding external ventricular drain insertion at the bedside. AB - OBJECTIVEThe goal of this study was to explore the feasibility and accuracy of using a wearable mixed-reality holographic computer to guide external ventricular drain (EVD) insertion and thus improve on the accuracy of the classic freehand insertion method for EVD insertion. The authors also sought to provide a clinically applicable workflow demonstration.METHODSPre- and postoperative CT scanning were performed routinely by the authors for every patient who needed EVD insertion. Hologram-guided EVD placement was prospectively applied in 15 patients between August and November 2017. During surgical planning, model reconstruction and trajectory calculation for each patient were completed using preoperative CT. By wearing a Microsoft HoloLens, the neurosurgeon was able to visualize the preoperative CT-generated holograms of the surgical plan and perform EVD placement by keeping the catheter aligned with the holographic trajectory. Fifteen patients who had undergone classic freehand EVD insertion were retrospectively included as controls. The feasibility and accuracy of the hologram-guided technique were evaluated by comparing the time required, number of passes, and target deviation for hologram-guided EVD placement with those for classic freehand EVD insertion.RESULTSSurgical planning and hologram visualization were performed in all 15 cases in which EVD insertion involved holographic guidance. No adverse events related to the hologram-guided procedures were observed. The mean +/- SD additional time before the surgical part of the procedure began was 40.20 +/- 10.74 minutes. The average number of passes was 1.07 +/- 0.258 in the holographic guidance group, compared with 2.33 +/- 0.98 in the control group (p < 0.01). The mean target deviation was 4.34 +/- 1.63 mm in the holographic guidance group and 11.26 +/- 4.83 mm in the control group (p < 0.01).CONCLUSIONSThis study demonstrates the use of a head-mounted mixed-reality holographic computer to successfully perform hologram-assisted bedside EVD insertion. A full set of clinically applicable workflow images is presented to show how medical imaging data can be used by the neurosurgeon to visualize patient-specific holograms that can intuitively guide hands-on operation. The authors also provide preliminary confirmation of the feasibility and accuracy of this hologram-guided EVD insertion technique. PMID- 30485190 TI - Letter to the Editor. Local steroid application during anterior cervical discectomy and fusion. PMID- 30485189 TI - Association between payer status and patient-reported outcomes in adult patients with lumbar spinal stenosis treated with decompression surgery. AB - OBJECTIVEInsurance disparities can have relevant effects on outcomes after elective lumbar spinal surgery. The aim of this study was to evaluate the association between private/public payer status and patient-reported outcomes in adult patients who underwent decompression surgery for lumbar spinal stenosis.METHODSA sample of 100 patients who underwent surgery for lumbar spinal stenosis from 2012 to 2014 was evaluated as part of the prospectively collected Quality Outcomes Database at a single institution. Outcome measures were evaluated at 3 months and 12 months, analyzed in regard to payer status (private insurance vs Medicare/Veterans Affairs insurance), and adjusted for potential confounders.RESULTSAt baseline, patients had similar visual analog scale back and leg pain, Oswestry Disability Index, and EQ-5D scores. At 3 months postintervention, patients with government-funded insurance reported significantly worse quality of life (mean difference 0.11, p < 0.001) and more leg pain (mean difference 1.26, p = 0.05). At 12 months, patients with government funded insurance reported significantly worse quality of life (mean difference 0.14, p < 0.001). There were no significant differences at 3 months or 12 months between groups for back pain (p = 0.14 and 0.43) or disability (p = 0.19 and 0.15). Across time points, patients in both groups showed improvement at 3 months and 12 months in all 4 functional outcomes compared with baseline (p < 0.001).CONCLUSIONSBoth private and public insurance patients had significant improvement after elective lumbar spinal surgery. Patients with public insurance had slightly less improvement in quality of life after surgery than those with private insurance but still benefited greatly from surgical intervention, particularly with respect to functional status. PMID- 30485191 TI - Letter to the Editor. Reversal of low prealbumin with oral branched-chain amino acids: a simple solution to an expensive problem. PMID- 30485192 TI - A modern series of subdiaphragmatic craniopharyngiomas. AB - OBJECTIVEThe endoscopic endonasal approach has been proposed as a primary surgical strategy for select craniopharyngiomas. However, those tumors that arise from the sella have not been classified with the other craniopharyngioma subtypes in terms of surgical nuances, intraoperative findings, and postoperative outcomes. The authors describe their experience with a select subtype of craniopharyngioma arising within the sella subjacent to the diaphragma sellae and refer to these tumors as type 0.METHODSAfter obtaining IRB approval, three institutions retrospectively reviewed their data collected from 2005 to 2017. Patients eligible for inclusion in the study were those who had tumors that originated from the sella inferior to the diaphragma sellae. Demographic, clinical, radiological, surgical, and follow-up data were examined and analyzed.RESULTSTwenty-eight patients (average age 19.3 years, range 3-60 years) were included in this study. Sixteen patients (57%) were younger than 18 years of age. All patients had characteristic imaging features of an expanded sella. Seventy-five percent of the patients presented with some form of visual field deficit (89% had radiographic optic apparatus compression) and 39% with hypopituitarism. The average maximal tumor diameter in the axial, coronal, or sagittal plane was 3.1 cm. Gross-total resection was achieved in 82% of the patients. Twenty-one percent of patients experienced an iatrogenic complication, and there were only two cases (7%) of postoperative cerebrospinal fluid (CSF) leakage. Only two patients (7%) required the use of a nasoseptal flap as part of their original reconstruction. Pathology was uniformly the adamantinomatous subtype. Postoperative objective visual outcomes were improved in 71% of the patients with visual symptoms or visual field deficits on presentation and stable in 24%. Mean follow-up was 45.1 months (range 3-120 months) with an 18% recurrence rate at a mean of 44.4 months (range 10-84 months). One patient was lost to follow-up. Thirty-six percent of patients received postoperative radiation to treat recurrence or residual tumor. Endocrine data are also presented.CONCLUSIONSCraniopharyngiomas that originate within the sella below the diaphragma sellae are a select subtype characterized by 1) an enlarged sella, 2) an intact diaphragma sellae at surgery, and 3) an adamantinomatous pathology. These tumors can be treated transnasally without the absolute need for neurovascular flap reconstruction, as there is a low risk of CSF leakage. PMID- 30485193 TI - Repeat Gamma Knife radiosurgery versus microvascular decompression following failure of GKRS in trigeminal neuralgia: a systematic review and meta-analysis. AB - OBJECTIVEGamma Knife radiosurgery (GKRS) has emerged as a promising treatment modality for patients with classical trigeminal neuralgia (TN); however, considering that almost half of the patients experience post-GKRS failure or lesion recurrence, a repeat treatment is typically necessary. The existing literature does not offer clear evidence to establish which treatment modality, repeat GKRS or microvascular decompression (MVD), is superior. The present study aimed to compare the overall outcome of patients who have undergone either repeat GKRS or MVD after failure of their primary GKRS; the authors do so by conducting a systematic review and meta-analysis of the literature and analysis of data from their own institution.METHODSThe authors conducted a systematic review and meta analysis of the PubMed, Cochrane Library, Web of Science, and CINAHL databases to identify studies describing patients who underwent either repeat GKRS or MVD after initial failed GKRS for TN. The primary outcomes were complete pain relief (CPR) and adequate pain relief (APR) at 1 year. The secondary outcomes were rate of postoperative facial numbness and the retreatment rate. The pooled data were analyzed with R software. Bias and heterogeneity were assessed using funnel plots and I2 tests, respectively. A retrospective analysis of a series of patients treated by the authors who underwent repeat GKRS or MVD after post-GKRS failure or relapse is presented.RESULTSA total of 22 studies met the selection criteria and were included for final data retrieval and meta-analysis. The search did not identify any study that had directly compared outcomes between patients who had undergone repeat GKRS versus those who had undergone MVD. Therefore, the authors' final analysis included two groups: studies describing outcome after repeat GKRS (n = 17) and studies describing outcome after MVD (n = 5). The authors' institutional study was the only study with direct comparison of the two cohorts. The pooled estimates of primary outcomes were APR in 83% of patients who underwent repeat GKRS and 88% of those who underwent MVD (p = 0.49), and CPR in 46% of patients who underwent repeat GKRS and 72% of those who underwent MVD (p = 0.02). The pooled estimates of secondary outcomes were facial numbness in 32% of patients who underwent repeat GKRS and 22% of those who underwent MVD (p = 0.11); the retreatment rate was 19% in patients who underwent repeat GKRS and 13% in those who underwent MVD (p = 0.74). The authors' institutional study included 42 patients (repeat GKRS in 15 and MVD in 27), and the outcomes 1 year after retreatment were APR in 80% of those who underwent repeat GKRS and 81% in those who underwent MVD (p = 1.0); CPR was achieved in 47% of those who underwent repeat GKRS and 44% in those who underwent MVD (p = 1.0). There was no difference in the rate of postoperative facial numbness or retreatment.CONCLUSIONSThe current meta-analysis failed to identify any superiority of one treatment over the other with comparable outcomes in terms of APR, postoperative facial numbness, and retreatment rates. However, MVD was shown to provide a better chance of CPR compared with repeat GKRS. PMID- 30485194 TI - North American survey on the post-neuroimaging management of children with mild head injuries. AB - OBJECTIVEThere remains uncertainty regarding the appropriate level of care and need for repeating neuroimaging among children with mild traumatic brain injury (mTBI) complicated by intracranial injury (ICI). This study's objective was to investigate physician practice patterns and decision-making processes for these patients in order to identify knowledge gaps and highlight avenues for future investigation.METHODSThe authors surveyed residents, fellows, and attending physicians from the following pediatric specialties: emergency medicine; general surgery; neurosurgery; and critical care. Participants came from 10 institutions in the United States and an email list maintained by the Canadian Neurosurgical Society. The survey asked respondents to indicate management preferences for and experiences with children with mTBI complicated by ICI, focusing on an exemplar clinical vignette of a 7-year-old girl with a Glasgow Coma Scale score of 15 and a 5-mm subdural hematoma without midline shift after a fall down stairs.RESULTSThe response rate was 52% (n = 536). Overall, 326 (61%) respondents indicated they would recommend ICU admission for the child in the vignette. However, only 62 (12%) agreed/strongly agreed that this child was at high risk of neurological decline. Half of respondents (45%; n = 243) indicated they would order a planned follow-up CT (29%; n = 155) or MRI scan (19%; n = 102), though only 64 (12%) agreed/strongly agreed that repeat neuroimaging would influence their management. Common factors that increased the likelihood of ICU admission included presence of a focal neurological deficit (95%; n = 508 endorsed), midline shift (90%; n = 480) or an epidural hematoma (88%; n = 471). However, 42% (n = 225) indicated they would admit all children with mTBI and ICI to the ICU. Notably, 27% (n = 143) of respondents indicated they had seen one or more children with mTBI and intracranial hemorrhage demonstrate a rapid neurological decline when admitted to a general ward in the last year, and 13% (n = 71) had witnessed this outcome at least twice in the past year.CONCLUSIONSMany physicians endorse ICU admission and repeat neuroimaging for pediatric mTBI with ICI, despite uncertainty regarding the clinical utility of those decisions. These results, combined with evidence that existing practice may provide insufficient monitoring to some high-risk children, emphasize the need for validated decision tools to aid the management of these patients. PMID- 30485195 TI - Coping strategies used by caregivers of children with newly diagnosed brain tumors. AB - OBJECTIVEThe goal of this study was to determine what strategies caregivers use to cope with the stress of a child who has recently undergone surgical treatment for a newly diagnosed brain tumor. Results will be used to improve psychosocial assessments and treatments provided to these families during initial hospitalization.METHODSCaregivers of children with newly diagnosed brain tumors admitted to Children's of Alabama were enrolled during the child's initial hospitalization for surgical treatment from April 2016 to August 2017. The single item, National Comprehensive Cancer Network visual analog Distress Thermometer (DT) was administered. Clinical and demographic variables were collected from the medical record. Approximately 1 month after patients were discharged from the hospital, caregivers participated in a semistructured interview that included questions about parent and family coping strategies. Broad questions about stress management since diagnosis were followed by specific questions about individual coping strategies. Interviews were recorded, transcribed, and coded for common themes. Themes were broadly characterized as adaptive versus maladaptive coping. Analysis was then performed to determine if DT scores or clinical or demographic factors were associated with the presence of maladaptive coping using a concurrent triangulation mixed-methods design.RESULTSCaregivers identified several adaptive coping strategies, such as active coping, acceptance coping, emotion-focused coping, spiritual coping, social support, and posttraumatic growth. Maladaptive coping strategies were mostly categorized as avoidant coping. Caregivers endorsed multiple different coping strategies (mean of 4.59 strategies per caregiver). No clinical or demographic variables, whether the tumor was benign or malignant, or the DT score correlated with caregiver endorsement of maladaptive coping strategies.CONCLUSIONSCaregivers of children newly diagnosed with brain tumors employ a number of coping strategies, some of which are maladaptive. The authors have not identified any method for predicting who is at risk for maladaptive coping. Assessment of coping skills and education about coping have the potential to improve overall care delivery to these families. PMID- 30485196 TI - Comparative accuracies of electrodiagnostic and imaging studies in neonatal brachial plexus palsy. AB - OBJECTIVEThe incorporation of ancillary testing in the preoperative setting for patients with neonatal brachial plexus palsy (NBPP) remains controversial, but the recommendation for early nerve reconstruction when a baby has a preganglionic lesion at the lower nerve roots is generally accepted. At some specialty centers, nerve surgeons use preoperative electrodiagnostic testing (EDX) and imaging to aid in lesion localization and the preoperative planning of the nerve reconstruction. EDX and imaging have been evaluated for their abilities to detect pre- and postganglionic lesions, but their accuracies have never been compared directly in the same set of patients. The aim of the present study was to evaluate the accuracy of imaging and EDX in an NBPP population.METHODSA retrospective review was conducted of 54 patients with operative NBPP seen between 2007 and 2017. The patients underwent EDX and imaging: EDX was performed, and the results were reviewed by board-certified electrodiagnosticians, and imaging was reviewed by board-certified neuroradiologists. The gold standard was considered to be the findings at surgical exploration. Descriptive and analytical statistics were utilized to compare the accuracies of imaging and EDX.RESULTSThe mean age at surgery was 6.94 mos (+/- 4 mos). Fifteen patients (28%) were Narakas grade I-II, and 39 (72%) were Narakas grade III-IV. For all nerve roots, the overall accuracy of detecting preganglionic lesions was 74% for EDX and 69% for imaging. The overall sensitivity of detecting preganglionic lesions by EDX was 31%, but the specificity was 90%. The overall sensitivity of detecting preganglionic lesions by imaging was 66%, and the overall specificity was 70%. However, at C8, EDX was 37.5% sensitive and 87.5% specific, whereas imaging was 67.7% sensitive but only 29.4% specific.CONCLUSIONSEDX outperformed imaging with regard to specificity and accuracy of identifying preganglionic injuries. This finding is especially relevant in the lower nerve roots, given that lower plexus preganglionic lesions are an accepted indication for early intervention. PMID- 30485197 TI - Letter to the Editor. Prognostication in traumatic brain injury. PMID- 30485198 TI - Minimal PaO2 threshold after traumatic brain injury and clinical utility of a novel brain oxygenation ratio. AB - OBJECTIVEAvoiding decreases in brain tissue oxygenation (PbtO2) after traumatic brain injury (TBI) is important. How best to adjust PbtO2 remains unclear. The authors investigated the association between partial pressure of oxygen (PaO2) and PbtO2 to determine the minimal PaO2 required to maintain PbtO2 above the hypoxic threshold (> 20 mm Hg), accounting for other determinants of PbtO2 and repeated measurements in the same patient. They also explored the clinical utility of a novel concept, the brain oxygenation ratio (BOx ratio = PbtO2/PaO2) to detect overtreatment with the fraction of inspired oxygen (FiO2).METHODSA retrospective cohort study at an academic level 1 trauma center included 38 TBI patients who required the insertion of a monitor to measure PbtO2. Various determinants of PbtO2 were collected simultaneously whenever a routine arterial blood gas was drawn. A PbtO2/PaO2 ratio was calculated for each blood gas and plotted over time for each patient. All patients were managed according to a standardized clinical protocol. A mixed effects model was used to account for repeated measurements in the same patient.RESULTSA total of 1006 data points were collected. The lowest mean PaO2 observed to maintain PbtO2 above the ischemic threshold was 94 mm Hg. Only PaO2 and cerebral perfusion pressure were predictive of PbtO2 in multivariate analysis. The PbtO2/PaO2 ratio was below 0.15 in 41.7% of all measures and normal PbtO2 values present despite an abnormal ratio in 27.1% of measurements.CONCLUSIONSThe authors' results suggest that the minimal PaO2 target to ensure adequate cerebral oxygenation during the first few days after TBI should be higher than that suggested in the Brain Trauma Foundation guidelines. The use of a PbtO2/PaO2 ratio (BOx ratio) may be clinically useful and identifies abnormal O2 delivery mechanisms (cerebral blood flow, diffusion, and cerebral metabolic rate of oxygen) despite normal PbtO2. PMID- 30485199 TI - Letter to the Editor. Inter-rater agreement: a methodological issue. PMID- 30485201 TI - Letter to the Editor. Radiosurgery for cerebral cavernous malformations: a word of caution. PMID- 30485200 TI - Fivefold higher rate of pseudarthrosis with polyetheretherketone interbody device than with structural allograft used for 1-level anterior cervical discectomy and fusion. AB - OBJECTIVECommon interbody graft options for anterior cervical discectomy and fusion (ACDF) include structural allograft and polyetheretherketone (PEEK). PEEK has gained popularity due to its radiolucency and its elastic modulus, which is similar to that of bone. The authors sought to compare the rates of pseudarthrosis, a lack of solid bone growth across the disc space, and the need for revision surgery with the use of grafts made of allogenic bone versus PEEK.METHODSThe authors retrospectively reviewed 127 cases in which patients had undergone a 1-level ACDF followed by at least 1 year of radiographic follow-up. Data on age, sex, body mass index, tobacco use, pseudarthrosis, and the reoperation rate for pseudarthrosis were collected. These data were analyzed by performing a Pearson's chi-square test.RESULTSOf 127 patients, 56 had received PEEK implants and 71 had received allografts. Forty-six of the PEEK implants (82%) were stand-alone devices. There were no significant differences between the 2 treatment groups with respect to patient age, sex, or body mass index. Twenty nine (52%) of 56 patients with PEEK implants demonstrated radiographic evidence of pseudarthrosis, compared to 7 (10%) of 71 patients with structural allografts (p < 0.001, OR 9.82; 95% CI 3.836-25.139). Seven patients with PEEK implants required reoperation for pseudarthrosis, compared to 1 patient with an allograft (p = 0.01, OR 10.00; 95% CI 1.192-83.884). There was no significant difference in tobacco use between the PEEK and allograft groups (p = 0.586).CONCLUSIONSThe results of this study demonstrate that the use of PEEK devices in 1-level ACDF is associated with a significantly higher rate of radiographically demonstrated pseudarthrosis and need for revision surgery compared with the use of allografts. Surgeons should be aware of this when deciding on interbody graft options, and reimbursement policies should reflect these discrepancies. PMID- 30485202 TI - Letter to the Editor. Multiple sclerosis-related tremor and stereotactic radiosurgery. PMID- 30485203 TI - C2 neurofibromas in neurofibromatosis type 1: genetic and imaging characteristics. AB - OBJECTIVEC2 nerve root neurofibromas have been reported frequently in patients with neurofibromatosis type 1 (NF1), although their genetic and imaging characteristics are unexplored. The aim of this study was to characterize genetic and spinal imaging findings in a large cohort of NF1 patients with C2 neurofibromas.METHODSThe authors performed a review of national NF1 referrals between 2009 and 2016. Inclusion criteria were at least 1 C2 root neurofibroma and cervical-spine or whole-spine MRI scans available for analysis. Blinded imaging review was performed by a neuroradiologist with an interest in NF1.RESULTSFifty-four patients with 106 C2 neurofibromas were included. The median age was 32.5 years (range 15-61 years), and there were slightly more male patients (33 vs 21 female patients). Splice-site (30%) and missense (20%) variants were frequent. Spinal neurofibromas were distributed in all spine regions (65%) or in the cervical spine alone (22%). Most (93%) C2 neurofibromas were visible on MRI scans of the head. Intradural invasion and cord compression in the cervical spine included the C2 level in 95% and 80% of patients, respectively. Compared with all other cervical spine neurofibromas in these patients, C2 neurofibromas had higher rates of intraspinal extension (75% vs 32%; OR 6.20, 95% CI 3.85-9.97; p < 0.001), intradural invasion (53% vs 26%; OR 3.20, 95% CI 2.08-4.92; p < 0.001), and cord compression (25% vs 13%; OR 2.26, 95% CI 1.35-3.79; p = 0.002). However, C2 neurofibromas had lower rates of extraforaminal growth beyond the transverse process (12% vs 62%; OR 0.09, 95% CI 0.05-0.16; p < 0.001).CONCLUSIONSC2 neurofibromas are associated with an aggressive intraspinal phenotype, limited growth outside the spinal canal, and an uncommon genetic profile. These observations require future study. PMID- 30485204 TI - Intravenous infusion of mesenchymal stem cells for protection against brainstem infarction in a persistent basilar artery occlusion model in the adult rat. AB - OBJECTIVEMorbidity and mortality in patients with posterior circulation stroke remains an issue despite advances in acute stroke therapies. The intravenous infusion of mesenchymal stem cells (MSCs) elicits therapeutic efficacy in experimental supratentorial stroke models. However, since there are few reliable animal models of ischemia in the posterior circulation, the therapeutic approach with intravenous MSC infusion has not been tested. The objective of this study was to test the hypothesis that intravenously infused MSCs provide functional recovery in a newly developed model of brainstem infarction in rats.METHODSBasilar artery (BA) occlusion (BAO) was established in rats by selectively ligating 4 points of the proximal BA with 10-0 nylon monofilament suture. The intravenous infusion of MSCs was performed 1 day after BAO induction. MRI and histological examinations were performed to assess ischemic lesion volume, while multiple behavioral tests were performed to evaluate functional recovery.RESULTSThe MSC-treated group exhibited a greater reduction in ischemic lesion volume, while behavioral testing indicated that the MSC-infused group had greater improvement than the vehicle group 28 days after the MSC infusion. Accumulated infused MSCs were observed in the ischemic brainstem lesion.CONCLUSIONSInfused MSCs may provide neuroprotection to facilitate functional outcomes and reduce ischemic lesion volume as evaluated in a newly developed rat model of persistent BAO. PMID- 30485205 TI - Artificial disc replacement versus fusion in patients with cervical degenerative disc disease with radiculopathy: 5-year outcomes from the National Swedish Spine Register. AB - OBJECTIVEThe long-term efficacy of artificial disc replacement (ADR) surgery compared with fusion after decompression for the treatment of cervical degenerative disc disease and radiculopathy has not previously been investigated in a population-based setting.METHODSAll patients with cervical degenerative disc disease and radiculopathy who were in the national Swedish Spine Registry (Swespine) beginning in January 1, 2006, were eligible for the study. Follow-up information was obtained up to November 15, 2017. The authors compared, using propensity score matching, patients treated with anterior decompression and insertion of an ADR with patients who underwent anterior decompression combined with fusion surgery. The primary outcome was the Neck Disability Index (NDI), a patient-reported function score ranging from 0% to 100%, with higher scores indicating greater disability and a minimum clinically important difference of > 15%.RESULTSA total of 3998 patients (2018:1980 women/men) met the inclusion criteria, of whom 204 had undergone arthroplasty and 3794 had undergone fusion. After propensity score matching, 185 patients with a mean age of 49.7 years remained in each group. Scores on the NDI were approximately halved in both groups after 5 years, but without a significant mean difference in NDI (3.0%; 95% CI -8.4 to 2.4; p = 0.28) between the groups. There were no differences between the groups in EuroQol-5 Dimensions or in pain scores for the neck and arm.CONCLUSIONSIn patients with cervical degenerative disc disease and radiculopathy, decompression plus ADR surgery did not result in a clinically important difference in outcomes after 5 years, compared with decompression and fusion surgery. PMID- 30485206 TI - The impact of adding posterior instrumentation to transpsoas lateral fusion: a systematic review and meta-analysis. AB - OBJECTIVETranspsoas lateral interbody fusion is one of the lateral minimally invasive approaches for lumbar spine surgery. Most surgeons insert the interbody cage laterally and then insert pedicle or cortical screw and rod instrumentation posteriorly. However, standalone cages have also been used to avoid posterior instrumentation. To the best of the authors' knowledge, the literature on comparison of the two approaches is sparse.METHODSThe authors performed a systematic review and meta-analysis of the available literature on transpsoas lateral interbody fusion by an electronic search of the PubMed, EMBASE, and Scopus databases using PRISMA guidelines. They compared patients undergoing transpsoas standalone fusion (TP) with those undergoing transpsoas fusion with posterior instrumentation (TPP).RESULTSA total of 28 studies with 1462 patients were included. Three hundred and seventy-four patients underwent TPP, and 956 patients underwent TP. The mean patient age ranged from 45.7 to 68 years in the TP group, and 50 to 67.7 years in the TPP group. The incidence of reoperation was found to be higher for TP (0.08, 95% confidence interval [CI] 0.04-0.11) compared to TPP (0.03, 95% CI 0.01-0.06; p = 0.057). Similarly, the incidence of cage movement was found to be greater in TP (0.18, 95% CI 0.10-0.26) compared to TPP (0.03, 95% CI 0.00-0.05; p < 0.001). Oswestry Disability Index (ODI) and visual analog scale (VAS) scores and postoperative transient deficits were found to be comparable between the two groups.CONCLUSIONSThese results appear to suggest that addition of posterior instrumentation to transpsoas fusion is associated with decreased reoperations and cage movements. The results of previous systematic reviews and meta-analyses should be reevaluated in light of these results, which seem to suggest that higher reoperation and subsidence rates may be due to the use of the standalone technique. PMID- 30485207 TI - Three types of dural suturing for closure of CSF leak after endoscopic transsphenoidal surgery. AB - OBJECTIVETranssphenoidal surgery (TSS) is commonly used for anterior skull base surgery, especially in the sella turcica (sellar) region. However, because of its anatomical position, CSF leakage is a major complication of this approach. The authors introduced a new grading reconstruction strategy for anterior skull base surgery with continuous dural suturing in 2013. In this paper the authors report on their methods and results.METHODSAll patients with sellar or anterior skull base lesions that were removed with TSS or extended TSS by a single neurosurgeon between April 2013 and March 2017 at Nagoya University Hospital and several cooperating hospitals were retrospectively identified. Three methods of suturing dura were considered, depending on the dural defect.RESULTSThere were 176 TSS cases (141 conventional TSS cases and 35 extended endoscopic TSS cases) and 76 cases of Esposito's grade 2 or 3 intradural high-flow CSF leakage. In the high flow CSF leak group, there were 3 cases of CSF leakage after the operation. The rates of CSF leakage after surgery corresponding to grades 2 and 3 were 2.9% (1/34) and 4.7% (2/42), respectively.CONCLUSIONSDural suturing is a basic and key method for reconstruction of the skull base, and continuous suturing is the most effective approach. Using this approach, the frequency of cases requiring a nasoseptal flap and lumbar drainage can be reduced. PMID- 30485208 TI - Acute traumatic thoracolumbar paraspinal compartment syndrome: case report. AB - Although compartment syndrome can occur in any compartment in the body, it rarely occurs in the paraspinal musculature and has therefore only been reported in a few case reports. Despite its rare occurrence, acute paraspinal compartment syndrome has been shown to occur secondary to reperfusion injury and traumatic and atraumatic causes. Diagnosis can be based on clinical examination findings, MRI or CT studies, or through direct measurement of intramuscular pressures. Conservative management should only be used in the setting of chronic presentation. Operative decompression via fasciotomy in cases of acute presentation may improve the patient's symptoms and outcomes. When treating acute paraspinal compartment syndrome via surgical decompression, an important aspect is the anatomical consideration. Although grouped under one name, each paraspinal muscle is enclosed within its own fascial compartment, all of which must be addressed to achieve an adequate decompression. The authors present the case of a 43-year-old female patient who presented to the emergency department with increasing low-back and flank pain after a fall. Associated sensory deficits in a cutaneous distribution combined with imaging and clinical findings contributed to the diagnosis of acute traumatic paraspinal compartment syndrome. The authors discuss this case and describe their surgical technique for managing acute paraspinal compartment syndrome. PMID- 30485209 TI - Distress and psychosocial risk in families with newly diagnosed pediatric brain tumors. AB - OBJECTIVEHospitalization for a newly diagnosed pediatric brain tumor is an extremely stressful time for a family, but this period has not been the focus of rigorous study. The purpose of this study was to quantify distress and psychosocial risk in this population to improve psychosocial care delivery.METHODSThe authors administered the National Comprehensive Cancer Network Distress Thermometer (DT) and the Psychosocial Assessment Tool 2.0 (PAT) to primary caregivers of all children admitted to Children's of Alabama with a new brain tumor between April 2016 and August 2017. The DT is a single-item measure of distress (scale range 0-10). The PAT (range 0-7) stratifies families by risk level: a score less than 1.0 indicates universal risk level (risk typically experienced during hospitalization); a score of 1.0-2.0 indicates targeted risk (specific psychosocial difficulties that impact medical treatment); and a score higher than 2.0 indicates clinically significant risk. Demographic and clinical information was abstracted from each child's medical record. A correlation matrix using nonparametric statistics was created between abstracted data and the DT and PAT scores.RESULTSForty primary caregivers were enrolled (of 49 eligible), with the patient age ranging from newborn to 17 years (mean 7.7 years). Twenty-five (63%) of the children were male, and 24 (60%) were white, non Hispanic. Mean and median DT scores were 7.2 (SD 2.6) and 7, respectively. However, 12 (30%) rated their distress 10/10, and 85% rated distress 5 or greater. PAT scores ranged from 0.0 to 2.36 with mean and median scores of 0.89 (SD 0.50) and 0.86, respectively. PAT results for 16 (40%) families were in the targeted or clinical range, indicating psychosocial factors that have the potential to interfere with medical treatment. No clinical or demographic variable correlated significantly with the DT or PAT score.CONCLUSIONSFamilies of children with newly diagnosed brain tumors experience high levels of distress and psychosocial risk. This work will serve as the foundation for efforts to standardize psychosocial evaluation for newly diagnosed pediatric neurosurgical patients, and to create protocols that organize existing hospital-based psychosocial support services. These efforts have the potential to improve patient and family satisfaction as well as treatment outcomes. PMID- 30485210 TI - Intravenous infusion of mesenchymal stem cells promotes functional recovery in a rat model of chronic cerebral infarction. AB - OBJECTIVEIntravenous infusion of mesenchymal stem cells (MSCs) derived from adult bone marrow improves behavioral function in rat models of cerebral infarction. Although clinical studies are ongoing, most studies have focused on the acute or subacute phase of stroke. In the present study, MSCs derived from bone marrow of rats were intravenously infused 8 weeks after the induction of a middle cerebral artery occlusion (MCAO) to investigate whether delayed systemic injection of MSCs improves functional outcome in the chronic phase of stroke in rats.METHODSEight weeks after induction of the MCAO, the rats were randomized and intravenously infused with either MSCs or vehicle. Ischemic volume and behavioral performance were examined. Blood-brain barrier (BBB) integrity was assessed by quantifying the leakage of Evans blue into the brain parenchyma after intravenous infusion. Immunohistochemical analysis was also performed to evaluate the stability of the BBB.RESULTSMotor recovery was better in the MSC-treated group than in the vehicle treated group, with rapid improvement (evident at 1 week post-infusion). In MSC treated rats, reduced BBB leakage and increased microvasculature/repair and neovascularization were observed.CONCLUSIONSThese results indicate that the systemic infusion of MSCs results in functional improvement, which is associated with structural changes in the chronic phase of cerebral infarction, including in the stabilization of the BBB. PMID- 30485211 TI - Factors associated with venous thromboembolic events following ICU admission in patients undergoing spinal surgery: an analysis of 1269 consecutive patients. AB - OBJECTIVEVenous thromboembolic events (VTEs) are a common cause of morbidity and mortality after spine surgery. Patients admitted to the intensive care unit (ICU) following spine surgery exhibit high-risk clinical characteristics.METHODSThe authors retrospectively analyzed 1269 ICU patients who had undergone spine surgery between January 1, 2009, and May 31, 2015. Relevant demographic, procedural, and outcome variables were collected.RESULTSPatients admitted to the ICU postoperatively had a postoperative VTE rate of 10.2%, compared to 2.5% among all spine surgery patients during the study period. ICU patients had a higher comorbid disease burden (odds ratio [OR] 1.45, p < 0.001), and were more likely to have a history of a bleeding disorder (2.60% vs 0.46%, OR 2.85, p = 0.028), receive a transfusion (OR 4.81, p < 0.001), have a fracture repaired (OR 4.30, p < 0.001), have an estimated blood loss > 500 ml (OR 1.95, p = 0.009), have an osteotomy (OR 20.47, p = 0.006), or have a corpectomy (OR 3.48, p = 0.007) than patients not admitted to the ICU. There was a significant difference in time to VTE between patients undergoing osteotomy and patients undergoing scoliosis corrections without osteotomy (p = 0.0431), patients with fractures (p = 0.0113), and patients undergoing fusions for indications other than scoliosis or fracture (p = 0.0056). Patients who developed a deep vein thrombosis (DVT) during their ICU stay were more likely to have received a prophylactic inferior vena cava filter placement (OR 8.98, p < 0.001), have undergone an interbody fusion procedure (OR 2.38, p = 0.037), have a history of DVT (OR 3.25, p < 0.001), and have shorter surgery times (OR 0.30, p = 0.002). Patients who developed a pulmonary embolism (PE) during the ICU stay were more likely to have a history of PE (OR 12.68 p = 0.015), history of DVT (OR 5.11, p = 0.042), fracture diagnosis (OR 7.02, p = 0.040), and diagnosis of scoliosis (OR 7.78, p = 0.024). Patients with higher BMIs (OR 0.85, p = 0.036) and those who received anticoagulation treatment (OR 0.16, p = 0.031) were less likely to develop a PE during their ICU stay.CONCLUSIONSPatients admitted to the ICU following spine surgery have a higher rate of VTE than non-ICU patients. Time to VTE varied by pathology. Factors independently associated with VTE in the ICU are distinct from factors otherwise associated with VTE. Some factors are independently associated with VTE throughout the 30-day postoperative period, while others are associated with VTE specifically during the initial ICU stay or after leaving the ICU. PMID- 30485212 TI - Differences in fixation strength among constructs of atlantoaxial fixation. AB - OBJECTIVETo avoid jeopardizing an aberrant vertebral artery, there are three common options in placing a C2 screw, including pedicle, pars, and translaminar screws. Although biomechanical studies have demonstrated similar strength among these C2 screws in vitro, there are limited clinical data to address their differences in vivo. When different screws were placed in each side, few reports have compared the outcomes. The present study aimed to evaluate these multiple combinations of C2 screws.METHODSConsecutive adult patients who underwent posterior atlantoaxial (AA) fixation were retrospectively reviewed. Every patient uniformly had bilateral C1 lateral mass screws in conjunction with 2 C2 screws (1 C2 screw on each side chosen among the three options: pedicle, pars, or translaminar screws, based on individualized anatomical consideration). These patients were then grouped according to the different combinations of C2 screws for comparison of the outcomes.RESULTSA total of 63 patients were analyzed, with a mean follow-up of 34.3 months. There were five kinds of construct combinations of the C2 screws: 2 pedicle screws (the Ped-Ped group, n = 24), 2 translaminar screws (the La-La group, n = 7), 2 pars screws (the Pars-Pars group, n = 6), 1 pedicle and 1 pars screw (the Ped-Pars group, n = 7), and 1 pedicle and 1 translaminar screw (the Ped-La group, n = 19). The rate of successful fixation in each of the groups was 100%, 57.1%, 100%, 100%, and 78.9% (Ped-Ped, La-La, Par Par, Ped-Par, and Ped-La, respectively). The patients who had no translaminar screw had a higher rate of success than those who had 1 or 2 translaminar screws (100% vs 73.1%, p = 0.0009). Among the 5 kinds of construct combinations, 2 C2 pedicle screws (the Ped-Ped group) had higher rates of success than 1 C2 pedicle and 1 C2 translaminar screw (the Ped-La group, p = 0.018). Overall, the rate of successful fixation was 87.3% (55/63). There were 7 patients (4 in the Ped-La group and 3 in the La-La group) who lost fixation/reduction, and they all had at least 1 translaminar screw.CONCLUSIONSIn AA fixation, C2 pedicle or pars screws or a combination of both provided very high success rates. Involvement of 1 or 2 C2 translaminar screws in the construct significantly lowered success rates. Therefore, a C2 pars screw is recommended over a translaminar screw. PMID- 30485213 TI - Spindle cell oncocytoma of the pituitary gland. AB - OBJECTIVEThe authors report the diagnosis, management, and outcomes of 6 cases of spindle cell oncocytoma (SCO) in an effort to guide clinical diagnosis and management of these uncommon lesions.METHODSThis study is a retrospective review of cases involving adult patients who underwent resection of pituitary lesions at the authors' institutions between January 2000 and October 2017. The authors identified patients with histopathological confirmation of SCO and collected clinical data, including preoperative, perioperative, and postoperative management, complications, and outcomes.RESULTSSix patients with SCO were identified. Clinical findings at initial presentation included visual disturbances, dizziness, and headache. All patients underwent resection. Four resections were initially performed by the transsphenoidal approach, and 2 resections were performed by craniotomy at an outside institution with subsequent transsphenoidal reoperations. Neither necrosis nor increased mitotic activity was seen in the tumor samples. All samples stained positive for S100 protein and thyroid transcription factor 1 and negative for glial fibrillary acidic protein and pituitary hormones. Five of the samples stained positive for epithelial membrane antigen. The average MIB-1 index was 8.3% (range 2-17). Postoperatively, 3 of the 6 patients received further treatment for progression of residual tumor or for recurrence, 2 have stable residual tumor, and 1 has had no recurrence after gross-total resection. Two patients developed postoperative complications of transient sixth cranial nerve palsy and diplopia. There were no other complications.CONCLUSIONSSCO poses both a diagnostic and therapeutic challenge. These tumors are often initially misdiagnosed as nonfunctional pituitary adenomas because of their sellar location and nonspecific symptomatology. Postoperatively, SCO must also be distinguished from other neoplasms of the posterior pituitary gland through histopathological examination. Resection of SCO can be challenging, given its highly vascular and adherent nature. Long-term follow-up is critical, as the tumor is associated with higher recurrence and progression rates compared to other benign neoplasms of the sella. PMID- 30485214 TI - Hypoxia accelerates intraplaque neovascularization derived from endothelial progenitor cells in carotid stenosis. AB - OBJECTIVEThe relationship between intraplaque hypoxia and intraplaque hemorrhage (IPH) has been reported, but the details remain obscure. In this study, the authors aimed to clarify the relationship among intraplaque hypoxia, endothelial progenitor cells (EPCs), and neovascularization, which causes IPH. The histological findings of specimens obtained from carotid endarterectomy were assessed.METHODSThis study included 49 patients who underwent carotid endarterectomy. Magnetic resonance plaque imaging was performed to analyze the components of the carotid plaques, and surgical specimens were subjected to immunohistochemical analysis. The numbers of hypoxia-inducible factor-1 alpha (HIF-1alpha)-, CD34-, CD133-, and vascular endothelial growth factor receptor-2 (VEGFR-2)-positive cells in the carotid plaques were precisely quantified, as were the number and maximum diameter of CD31-positive microvessels.RESULTSPlaque components were judged as fibrous in 7 samples, lipid-rich in 22, and IPH in 20. The number of CD34-, VEGFR-2-, and CD133-positive cells as an EPC-specific marker was significantly correlated with the number of HIF-1alpha-positive cells (r = 0.9, r = 0.82, and r = 0.81, respectively). These numbers varied among the 3 plaque components (IPH > lipid-rich > fibrous). The number and maximum luminal diameter of CD31-positive microvessels were also significantly correlated with the number of HIF-1alpha-positive cells (r = 0.85 and r = 0.89, respectively) and varied among the 3 plaque components (IPH > lipid-rich > fibrous).CONCLUSIONSThe present findings suggest that intraplaque hypoxia may accelerate abnormal microvessel formation derived from EPCs, which in turn promotes IPH. The results also suggest that microvessel enlargement is a pivotal characteristic of IPH and these enlarged microvessels are immature endothelial tubes with disorganized branching and are fragile and prone to rupture. PMID- 30485215 TI - Location of correction within the lumbar spine impacts acute adjacent-segment kyphosis. AB - OBJECTIVEThe surgical correction of adult spinal deformity (ASD) often involves modifying lumbar lordosis (LL) to restore ideal sagittal alignment. However, corrections that include large changes in LL increase the risk for development of proximal junctional kyphosis (PJK). Little is known about the impact of cranial versus caudal correction in the lumbar spine on the occurrence of PJK. The goal of this study was to investigate the impact of the location of the correction on acute PJK development.METHODSThis study was a retrospective review of a prospective multicenter database. Surgically treated ASD patients with early follow-up evaluations (6 weeks) and fusions of the full lumbosacral spine were included. Radiographic parameters analyzed included the classic spinopelvic parameters (pelvic incidence [PI], pelvic tilt [PT], PI-LL, and sagittal vertical axis [SVA]) and segmental correction. Using Glattes' criteria, patients were stratified into PJK and noPJK groups and propensity matched by age and regional lumbar correction (DeltaPI-LL). Radiographic parameters and segmental correction were compared between PJK and noPJK patients using independent t tests.RESULTSAfter propensity matching, 312 of 483 patients were included in the analysis (mean age 64 years, 76% women, 40% with PJK). There were no significant differences between PJK and noPJK patients at baseline or postoperatively, or between changes in alignment, with the exception of thoracic kyphosis (TK) and DeltaTK. PJK patients had a decrease in segmental lordosis at L4-L5-S1 (-0.6 degrees vs 1.6 degrees , p = 0.025), and larger increases in segmental correction at cranial levels L1-L2-L3 (9.9 degrees vs 7.1 degrees ), T12-L1-L2 (7.3 degrees vs 5.4 degrees ), and T11-T12-L1 (2.9 degrees vs 0.7 degrees ) (all p < 0.05).CONCLUSIONSAlthough achievement of an optimal sagittal alignment is the goal of realignment surgery, dramatic lumbar corrections appear to increase the risk of PJK. This study was the first to demonstrate that patients who developed PJK underwent kyphotic changes in the L4-S1 segments while restoring LL at more cranial levels (T12-L3). These findings suggest that restoring lordosis at lower lumbar levels may result in a decreased risk of developing PJK. PMID- 30485216 TI - Daniel Ruge: the first neurosurgeon to serve as physician to the president. AB - The role of chief White House physician has traditionally been held by an individual with a background in a broad medical field, such as emergency medicine, family medicine, or internal medicine. Dr. Daniel Ruge, who served as the director of the Spinal Cord Injury Service for the Veterans Administration and was appointed during President Ronald Reagan's first term, was the first neurosurgeon to become the chief White House physician. Aside from being the first neurosurgeon to serve in this capacity, Dr. Ruge also stands apart from others who have held this esteemed position because of how he handled Reagan's care after an attempt was made on the then-president's life. Instead of calling upon leading medical authorities of the time to care for the president, Dr. Ruge instead decided that Reagan should be treated as any trauma patient would be treated. Dr. Ruge's actions after the assassination attempt on President Reagan resulted in the rapid, smooth recovery of the then-president. Daniel Ruge's background, his high-profile roles and heavy responsibilities, and his critical decision-making are characteristics that make his role in the history of medicine and of neurosurgery unique. PMID- 30485217 TI - Percutaneous endoscopic discectomy in adolescent lumbar disc herniation: a 3- to 5-year study. AB - OBJECTIVEThe authors sought to investigate the efficiency of percutaneous endoscopic discectomy (PED) in adolescent patients with lumbar disc herniation (LDH), compare PED outcomes in adolescent patients with those in young adult LDH patients as controls, and discuss relevant technical notes.METHODSThis was a retrospective study involving 19 adolescent LDH patients (age > 13 and < 18 years, 20 discectomies) and 38 young adults (age < 40 years, 38 discectomies) who also had LDH and were matched to the adolescent group for sex and body mass index. The combined cohort included 51 male patients (89.5%) and 6 female patients (10.5%), with an average age of 26.7 years (range 14-39 years). The operated levels included L3-4 in 1 patient (1.7%), L4-5 in 22 patients (37.9%), and L5-S1 in 35 patients (60.4%). Two adolescents (10.5%) exhibited apophyseal ring separation and one (5.3%) had had previous PED. All patients underwent PED under local anesthesia. Outcomes were evaluated through a visual analog scale (VAS), the Japanese Orthopaedic Association (JOA) scoring system, and the modified MacNab grading system.RESULTSThe mean duration of follow-up was 41.7 months (range 36-65 months). The outcomes in adolescents were satisfactory and comparable with previously reported outcomes of microsurgical discectomy (MD) and conventional open discectomy (COD). The adolescent patients had a faster and better recovery course than the adult patients (p < 0.01). One adolescent patient (5.3%) exhibited recurrence and 2 adults (5.3%) experienced transient dysesthesia; the complication rates were comparable in the 2 age groups (p = 0.47). Prolonged duration of symptoms (p < 0.01) and disc degeneration (p = 0.01) were correlated with lower postoperative JOA values; patients with extrusions had higher postoperative JOA values than those with protrusions (p = 0.01).CONCLUSIONSPED may yield favorable results in the treatment of adolescent LDH in terms of short- to medium-term follow-up; restricted discectomy and a conservative rehabilitation program might be advisable. Further long-term studies are warranted to address this rare disease entity. PMID- 30485218 TI - The effect of C2-3 disc angle on postoperative adverse events in cervical spondylotic myelopathy. AB - OBJECTIVEComplete radiographic and clinical evaluations are essential in the surgical treatment of cervical spondylotic myelopathy (CSM). Prior studies have correlated cervical sagittal imbalance and kyphosis with disability and worse health-related quality of life. However, little is known about C2-3 disc angle and its correlation with postoperative outcomes. The present study is the first to consider C2-3 disc angle as an additional radiographic predictor of postoperative adverse events.METHODSA retrospective chart review was performed to identify patients with CSM who underwent surgeries from 2010 to 2014. Data collected included demographics, baseline presenting factors, and postoperative outcomes. Cervical sagittal alignment variables were measured using the preoperative and postoperative radiographs. Univariable logistic regression analyses were used to explore the association between dependent and independent variables, and a multivariable logistic regression model was created using stepwise variable selection.RESULTSThe authors identified 171 patients who had complete preoperative and postoperative radiographic and outcomes data. The overall rate of postoperative adverse events was 33% (57/171), and postoperative C2-3 disc angle, C2-7 sagittal vertical axis, and C2-7 Cobb angle were found to be significantly associated with adverse events. Inclusion of postoperative C2-3 disc angle in the analysis led to the best prediction of adverse events. The mean postoperative C2-3 disc angle for patients with any postoperative adverse event was 32.3 degrees +/- 17.2 degrees , and the mean for those without any adverse event was 22.4 degrees +/- 11.1 degrees (p < 0.0001).CONCLUSIONSIn the present retrospective analysis of postoperative adverse events in patients with CSM, the authors found a significant association between C2-3 disc angle and postoperative adverse events. They propose that C2-3 disc angle be used as an additional parameter of cervical spinal sagittal alignment and predictor for operative outcomes. PMID- 30485219 TI - Letter to the Editor. Epidural blood patch in superficial siderosis caused by spontaneous intracranial hypotension. PMID- 30485220 TI - Letter to the Editor. Microsurgical rhizotomy as treatment for trigeminal neuralgia in patients with multiple sclerosis: turnpike or dirt road? PMID- 30485221 TI - ReStNeuMap: a tool for automatic extraction of resting-state functional MRI networks in neurosurgical practice. AB - OBJECTIVEResting-state functional MRI (rs-fMRI) represents a promising and cost effective alternative to task-based fMRI for presurgical mapping. However, the lack of clinically streamlined and reliable rs-fMRI analysis tools has prevented wide adoption of this technique. In this work, the authors introduce an rs-fMRI processing pipeline (ReStNeuMap) for automatic single-patient rs-fMRI network analysis.METHODSThe authors provide a description of the rs-fMRI network analysis steps implemented in ReStNeuMap and report their initial experience with this tool after performing presurgical mapping in 6 patients. They verified the spatial agreement between rs-fMRI networks derived by ReStNeuMap and localization of activation with intraoperative direct electrical stimulation (DES).RESULTSThe authors automatically extracted rs-fMRI networks including eloquent cortex in spatial proximity with the resected lesion in all patients. The distance between DES points and corresponding rs-fMRI networks was less than 1 cm in 78% of cases for motor, 100% of cases for visual, 87.5% of cases for language, and 100% of cases for speech articulation mapping.CONCLUSIONSThe authors' initial experience with ReStNeuMap showed good spatial agreement between presurgical rs-fMRI predictions and DES findings during awake surgery. The availability of the rs fMRI analysis tools for clinicians aiming to perform noninvasive mapping of brain functional networks may extend its application beyond surgical practice. PMID- 30485222 TI - Coil and Onyx embolization of a torcular herophili dural arteriovenous fistula in a full-term neonate with advanced heart failure using a transumbilical approach. AB - Neonatal dural arteriovenous fistulas (DAVFs) are rare, but if left untreated will advance to life-threatening neurological and cardiovascular compromise. Endovascular treatment is the preferred treatment modality for DAVFs. The goal of endovascular therapy is to obliterate feeding vasculature and prevent secondary complications. Endovascular access can be difficult to obtain in a neonate. The authors present the case of a full-term, normal birth weight neonate with severe congestive heart failure secondary to a congenital DAVF of the torcular herophili that was successfully treated with transumbilical arterial coil embolization and a liquid embolic agent. PMID- 30485223 TI - Management of hydrocephalus in infants with severe hemophilia A: report of 2 cases. AB - The authors report on the clinical course of two infants with severe hemophilia A (HA) and concomitant progressive hydrocephalus that required management with a ventriculoperitoneal shunt. The first child, with known HA, presented with a spontaneous intracranial hemorrhage and acquired hydrocephalus. He underwent cerebrospinal fluid diversion with a temporary external ventricular drain, followed by placement of a ventriculoperitoneal shunt. The second child had hydrocephalus secondary to a Dandy-Walker malformation and was diagnosed with severe HA during preoperative evaluation. He underwent placement of a ventriculoperitoneal shunt after progression of the hydrocephalus. The authors also review the treatment of hydrocephalus in patients with HA and describe the perioperative protocols used in their two cases. Treatment of hydrocephalus in infants with HA requires unique perioperative management to avoid complications. PMID- 30485224 TI - Does lumbar drainage reduce postoperative cerebrospinal fluid leak after endoscopic endonasal skull base surgery? A prospective, randomized controlled trial. AB - OBJECTIVEBased on a null hypothesis that the use of short-term lumbar drainage (LD) after endoscopic endonasal surgery (EES) for intradural pathology does not prevent postoperative CSF leaks, a trial was conducted to assess the effect of postoperative LD on postoperative CSF leak following standard reconstruction.METHODSA prospective, randomized controlled trial of lumbar drain placement after endoscopic endonasal skull base surgery was performed from February 2011 to March 2015. All patients had 3-month follow-up data. Surgeons were blinded to which patients would or would not receive the drain until after closure was completed. An a priori power analysis calculation assuming 80% of power, 5% postoperative CSF leak rate in the no-LD group, and 16% in the LD group determined a planned sample size of 186 patients. A routine data and safety check was performed with every 50 patients being recruited to ensure the efficacy of randomization and safety. These interim tests were run by a statistician who was not blinded to the arms they were evaluating. This study accrued 230 consecutive adult patients with skull base pathology who were eligible for endoscopic endonasal resection. Inclusion criteria (high-flow leak) were dural defect greater than 1 cm2 (mandatory), extensive arachnoid dissection, and/or dissection into a ventricle or cistern. Sixty patients were excluded because they did not meet the inclusion criteria. One hundred seventy patients were randomized to either receive or not receive a lumbar drain.RESULTSOne hundred seventy patients were randomized, with a mean age of 51.6 years (range 19-86 years) and 38% were male. The mean BMI for the entire cohort was 28.1 kg/m2. The experimental cohort with postoperative LD had an 8.2% rate of CSF leak compared to a 21.2% rate in the control group (odds ratio 3.0, 95% confidence interval 1.2-7.6, p = 0.017). In 106 patients in whom defect size was measured intraoperatively, a larger defect was associated with postoperative CSF leak (6.2 vs 2.9 cm2, p = 0.03). No significant difference was identified in BMI between those with (mean 28.4 +/- 4.3 kg/m2) and without (mean 28.1 +/- 5.6 kg/m2) postoperative CSF leak (p = 0.79). Furthermore, when patients were grouped based on BMI < 25, 25-29.9, and > 30 kg/m2, no difference was noted in the rates of CSF fistula (p = 0.97).CONCLUSIONSAmong patients undergoing intradural EES judged to be at high risk for CSF leak as defined by the study's inclusion criteria, perioperative LD used in the context of vascularized nasoseptal flap closure significantly reduced the rate of postoperative CSF leaks.Clinical trial registration no.: NCT03163134 (clinicaltrials.gov). PMID- 30485225 TI - Complications of spinal osteotomy for thoracolumbar kyphosis secondary to ankylosing spondylitis in 342 patients: incidence and risk factors. AB - OBJECTIVETo describe the incidence of complications in spinal osteotomy for thoracolumbar kyphosis caused by ankylosing spondylitis (AS) and to investigate the risk factors for these complications.METHODSFrom April 2000 to July 2017, 342 consecutive AS patients with a mean age (+/- SD) of 35.4 +/- 9.8 years (range 17 71 years) undergoing spinal osteotomy were enrolled. Patients with complications within the 1st postoperative year were identified. Demographic, radiological, and surgical data were compared between patients with and without complications. The complications were classified into intraoperative and postoperative complications.RESULTSA total of 310 consecutive pedicle subtraction osteotomy (PSO) and 37 multiple Smith-Petersen osteotomy (SPO) procedures were performed in 342 patients. Overall, 47 complications were identified in 47 patients (13.7%), including 31 intraoperative complications and 16 postoperative complications. Patients with complications were older than those without (p = 0.006). A significant difference was observed in preoperative global kyphosis (GK), lumbar lordosis (LL), sagittal vertical axis (SVA), and the correction of these radiographic parameters between patients with and without complications (p < 0.05). Two-level PSO (p = 0.022) and an increased number of instrumented vertebrae (p = 0.019) were significantly associated with an increased risk of complications.CONCLUSIONSThe overall incidence of complications was 13.7%. Age; preoperative GK, LL, and SVA; the correction of GK, LL, and SVA; 2-level PSO; and number of instrumented vertebrae were risk factors. Therefore, the potential risk of extensive surgeries with large correction and long fusion in older AS patients with severe GK should be seriously considered in surgical decision-making. PMID- 30485226 TI - Editorial. Resting-state fMRI for the masses. PMID- 30485227 TI - Letter to the Editor. Activity versus injury: further defining the risk/benefit ratio in the Neurosurgery Charity Softball Tournament. PMID- 30485228 TI - Erratum. The distribution, clearance, and brainstem toxicity of panobinostat administered by convection-enhanced delivery. PMID- 30485229 TI - Letter to the Editor. 3D-printed polymethylmethacrylate implant for cranioplasty. PMID- 30485230 TI - Updating superficial siderosis of the central nervous system: bleeding of a dorsal osteophyte into the subarachnoid space from a perforating artery. AB - Superficial siderosis of the central nervous system (SSCNS) is an uncommon and often unrecognized disorder that results from recurrent and persistent bleeding into the subarachnoid space. Currently, there is no effective treatment for SSCNS. The identification and surgical resolution of the cause of bleeding remains the most reliable method of treatment, but the cause of bleeding is often not apparent. The identified sources of recurrent bleeding have typically included neoplasms, vascular malformations, brachial plexus or nerve root injury or avulsion, and previous head and spinal surgery. An association between recurrent bleeding in the CNS and dural abnormalities in the spine has recently been suggested. Dural tears have been identified in relation to a protruding disc or osteophyte. Also in these patients, the exact mechanism of bleeding remains unknown because of a lack of objective surgical data, even in patients who undergo neurosurgical procedures.The present case concerns a 48-year-old man who presented with longstanding symptoms of mild hearing loss and mild gait ataxia. A diagnosis of SSCNS was made in light of the patient's history and the findings on physical examination, imaging, and laboratory testing. MRI and CT detected a small calcific osteophyte in the anterior epidural space of T8-9. The patient underwent surgical removal of the bone spur and dural tear repair. During the surgery, the authors detected a perforating artery, which was on the osteophyte, that was bleeding into the subarachnoid space. This case shows a possible mechanism of chronic bleeding from an osteophyte into the subarachnoid space. In the literature currently available, a perforating artery on an osteophyte bleeding into the subarachnoid space has never been described in SSCNS. PMID- 30485232 TI - Erratum. Intracranial pressure elevations in diffuse axonal injury: association with nonhemorrhagic MR lesions in central mesencephalic structures. PMID- 30485231 TI - Fusiform vertebral artery aneurysms involving the posterior inferior cerebellar artery origin associated with the sole angiographic anterior spinal artery origin: technical case report and treatment paradigm proposal. AB - Fusiform aneurysms of the vertebral artery (VA) involving the posterior inferior cerebellar artery (PICA) origin are uncommon and challenging. The anterior spinal artery (ASA) commonly originates from a unilateral ramus just distal to the PICA. Occlusion of an unpaired ASA can result in bilateral medial medullary syndrome. The authors propose a treatment paradigm for ASA preservation based on the artery's proximity to fusiform VA aneurysms, and they present 3 representative cases. In the first case, they performed a V3-PICA bypass using an interposition graft and then performed endovascular coil embolization of the parent VA. A complete occlusion of the aneurysm and VA was complicated by ASA thrombosis. The subsequent cases were treated with PICA-PICA bypass and subsequent endovascular embolization of the VA. Filling of the sole angiographic ASA remote from the aneurysm was preserved in both cases. The anatomy of the ASA is the most critical determinant of treatment recommendations for fusiform VA aneurysms involving PICA. When the ASA originates from the aneurysm, proximal occlusion with or without a PICA bypass is suggested. In cases in which the ASA is removed from the aneurysm, the authors recommend revascularization followed by endovascular sacrifice. When the aneurysm is immediately adjacent to the ASA, revascularization and open trapping should be considered. PMID- 30485233 TI - Rapid cardiac ventricular pacing to facilitate embolization of vein of Galen malformations: technical note. AB - OBJECTIVEVein of Galen aneurysmal malformations (VGAMs) in infancy have a poor natural history if left untreated. Their high-flow nature can preclude safe and accurate therapeutic vessel occlusion and the risk of inadvertent pulmonary embolism is predominant. The authors describe the technique of rapid cardiac ventricular pacing for inducing transient hypotension to facilitate the controlled embolization of VGAMs.METHODSInitial transjugular venous access was obtained for placing temporary pacing leads for rapid cardiac ventricular pacing immediately prior to embolization. Definitive transarterial embolization procedures for the VGAMs were then performed in the same setting in which liquid embolic agents or coils were used.RESULTSBeginning in 2010, a total of five procedures were performed in three infants. Transvenous rapid cardiac ventricular pacing was successfully achieved to induce systemic transient flow arrest in all but two attempts, and facilitated partial embolization with n-butyl cyanoacrylate (n-BCA) and coils in all procedures. Ventricular fibrillation occurred twice in one patient and was successfully reversed with defibrillation on both occasions. One patient failed to improve and died from refractory heart failure. Two patients stabilized following staged embolization.CONCLUSIONSRapid transvenous cardiac ventricular pacing can be considered to induce transient hypotension and facilitate controlled embolization in challenging high-flow VGAMs. PMID- 30485234 TI - Ventricle contact is associated with lower survival and increased peritumoral perfusion in glioblastoma. AB - OBJECTIVEThe purpose of this study was to prospectively investigate outcome and differences in peritumoral MRI characteristics of glioblastomas (GBMs) that were in contact with the ventricles (ventricle-contacting tumors) and those that were not (noncontacting tumors). GBMs are heterogeneous tumors with variable survival. Lower survival is suggested for patients with ventricle-contacting tumors than for those with noncontacting tumors. This might be supported by aggressive peritumoral MRI features. However, differences in MRI characteristics of the peritumoral environment between ventricle-contacting and noncontacting GBMs have not yet been investigated.METHODSPatients with newly diagnosed GBM underwent preoperative MRI with contrast-enhanced T1-weighted, FLAIR, diffusion-weighted, and perfusion-weighted sequences. Tumors were categorized into ventricle contacting or noncontacting based on contrast enhancement. Survival analysis was performed using log-rank for univariate analysis and Cox regression for multivariate analysis. Normalized perfusion (relative cerebral blood volume [rCBV]) and diffusion (apparent diffusion coefficient [ADC]) values were calculated in 2 regions: the peritumoral nonenhancing FLAIR region overlapping the subventricular zone and the remaining peritumoral nonenhancing FLAIR region.RESULTSOverall survival was significantly lower for patients with contacting tumors than for those with noncontacting tumors (434 vs 747 days, p < 0.001). Progression-free survival showed a comparable trend (260 vs 375 days, p = 0.094). Multivariate analysis confirmed a survival difference for both overall survival (HR 3.930, 95% CI 1.740-8.875, p = 0.001) and progression-free survival (HR 2.506, 95% CI 1.254-5.007, p = 0.009). Peritumoral perfusion was higher in contacting than in noncontacting tumors for both FLAIR regions (p = 0.04). There was no difference in peritumoral ADC values between the 2 groups.CONCLUSIONSPatients with ventricle-contacting tumors had poorer outcomes than patients with noncontacting tumors. This disadvantage of ventricle contact might be explained by higher peritumoral perfusion leading to more aggressive behavior. PMID- 30485235 TI - Assessment of costs in open surgery and stereotactic radiosurgery for vestibular schwannomas. AB - OBJECTIVEMicrosurgical resection and radiosurgery remain the most widely used interventions in the treatment of vestibular schwannomas. There is a growing demand for cost-effectiveness analyses to evaluate these two treatment modalities and delineate the factors that drive their total costs. Here, the authors evaluated specific cost drivers for microsurgical and radiosurgical management of vestibular schwannoma by using the Value Driven Outcomes system available at the University of Utah.METHODSThe authors retrospectively reviewed all cases involving microsurgical and radiosurgical treatment of vestibular schwannomas at their institution between November 2011 and September 2017. Patient and tumor characteristics, subcategory costs, and potential cost drivers were analyzed.RESULTSThe authors identified 163 vestibular schwannoma cases, including 116 managed microsurgically and 47 addressed with stereotactic radiosurgery (SRS). There were significant differences between the two groups in age, tumor size, and preoperative Koos grade (p < 0.05), suggesting that indications for treatment were markedly different. Length of stay (LOS) and length of follow-up were also significantly different. Facility costs were the most significant contributor to both microsurgical and SRS groups (58.3% and 99.4%, respectively); however, physician professional fees were not specifically analyzed. As expected, microsurgical treatment resulted in an average 4-fold greater overall cost of treatment than for SRS cases (p < 0.05), and there was a greater variation in costs for open cases as well. Costs remained stable over time for both open resection and SRS. Multivariable analysis showed that LOS (beta = 0.7, p = 0.0001), discharge disposition (beta = 0.2, p = 0.004), nonserviceable hearing (beta = 0.1, p = 0.02), and complications (beta = 0.2, p = 0.005) affected cost for open surgery, whereas no specifically examined factor could be identified as driving costs for SRS.CONCLUSIONSThis analysis identified the fact that facility utilization constitutes the majority of total costs for both microsurgery and SRS treatment modalities of vestibular schwannomas. LOS, discharge disposition, nonserviceable hearing, and complications contributed significantly to the total costs for the microsurgical group, whereas none of the factors could be identified as driving total costs for the SRS group. This information may be used to establish policies and protocols to reduce facility costs, with the goal of decreasing the total costs without jeopardizing patient care. PMID- 30485236 TI - Riskier-than-expected occlusive treatment of ruptured posterior communicating artery aneurysms: treatment and outcome of 620 consecutive patients. AB - OBJECTIVEOcclusive treatment of posterior communicating artery (PCoA) aneurysms has been seen as a fairly uncomplicated procedure. The objective here was to determine the radiological and clinical outcome of patients after PCoA aneurysm rupture and treatment and to evaluate the risk factors for impaired outcome.METHODSIn a retrospective clinical follow-up study, data were collected from 620 consecutive patients who had been treated for ruptured PCoA aneurysms at a single center between 1980 and 2014. The follow-up was a minimum of 1 year after treatment or until death.RESULTSOf the 620 patients, 83% were treated with microsurgical clipping, 8% with endovascular coiling, 2% with the two procedures combined, 1% with indirect surgical methods, and 6% with conservative methods. The most common procedural complications were treatment-related brain infarctions (15%). The occurrence of artery occlusions (10% microsurgical, 8% endovascular) was higher than expected. Most patients made a good recovery at 1 year after aneurysmal subarachnoid hemorrhage (modified Rankin Scale [mRS] score 0-2: 386 patients [62%]). A fairly small proportion of patients were left severely disabled (mRS score 4-5: 27 patients [4%]). Among all patients, 20% died during the 1st year. Independent risk factors for an unfavorable outcome, according to the multivariable analysis, were poor preoperative clinical condition, intracerebral or subdural hematoma due to aneurysm rupture, age over 65 years, artery occlusion on postoperative angiography, occlusive treatment-related ischemia, delayed cerebral vasospasm, and hydrocephalus requiring a shunt.CONCLUSIONSEven though most patients made a good recovery after PCoA aneurysm rupture and treatment during the 1st year, the occlusive treatment related complications were higher than expected and caused morbidity even among initially good-grade patients. Occlusive treatment of ruptured PCoA aneurysms seems to be a high-risk procedure, even in a high-volume neurovascular center. PMID- 30485237 TI - Circumferential wall enhancement in evolving intracranial aneurysms on magnetic resonance vessel wall imaging. AB - OBJECTIVERecent MR vessel wall imaging studies have indicated intracranial aneurysms in the active state could show circumferential enhancement along the aneurysm wall (CEAW). While ruptured aneurysms frequently show CEAW, CEAW in unruptured aneurysms at the evolving state (i.e., growing or symptomatic) has not been studied in detail. The authors quantitatively assessed the degree of CEAW in evolving unruptured aneurysms by comparing it separately to that in stable unruptured and ruptured aneurysms.METHODSA quantitative analysis of CEAW was performed in 26 consecutive evolving aneurysms using MR vessel wall imaging. Three-dimensional T1-weighted fast spin echo sequences were obtained before and after contrast media injection, and the contrast ratio of the aneurysm wall against the pituitary stalk (CRstalk) was calculated as the indicator of CEAW. Aneurysm characteristics of evolving aneurysms were compared with those of 69 stable unruptured and 67 ruptured aneurysms.RESULTSThe CRstalk values in evolving aneurysms were significantly higher than those in stable aneurysms (0.54 vs 0.34, p < 0.0001), and lower than those in ruptured aneurysms (0.54 vs 0.83, p < 0.0002). In multivariable analysis, CRstalk remained significant when comparing evolving with stable aneurysms (odds ratio [OR] 12.23, 95% confidence interval [CI] 3.53-42.41), and with ruptured aneurysms (OR 0.083, 95% CI 0.022 0.310).CONCLUSIONSThe CEAW in evolving aneurysms was higher than those in stable aneurysms, and lower than those in ruptured aneurysms. The degree of CEAW may indicate the process leading to rupture of intracranial aneurysms, which can be useful additional information to determine an indication for surgical treatment of unruptured aneurysms. PMID- 30485239 TI - Letter to the Editor. Temporary occlusion during clipping of ruptured intracranial aneurysms. PMID- 30485238 TI - Neural basis of episodic memory in the intermediate term after medial temporal lobe resection. AB - OBJECTIVEHow the brain supports intermediate-term preservation of memory in patients who have undergone unilateral medial temporal lobe resection (MTLR) has not yet been demonstrated. To understand the neural basis of episodic memory in the intermediate term after surgery for temporal lobe epilepsy (TLE), the authors investigated the relationship between the activation of the hippocampus (HIP) during successful memory encoding and individual memory capacity in patients who had undergone MTLR. They also compared hippocampal activation with other parameters, including structural volumes of the HIP, duration of illness, and age at seizure onset.METHODSThirty-five adult patients who had undergone unilateral MTLR at least 1 year before recruiting and who had a favorable seizure outcome were enrolled (17 left MTLR, 18 right MTLR; mean follow-up 6.31 +/- 2.72 years). All patients underwent a standardized neuropsychological examination of memory function and functional MRI scanning with a memory-encoding paradigm of words and figures. Activations of the HIP during successful memory encoding were calculated and compared with standard neuropsychological memory scores, hippocampal volumes, and other clinical variables.RESULTSGreater activation in the HIP contralateral to the side of the resection was related to higher postoperative memory scores and greater postoperative memory improvement than the preoperative baseline in both patient groups. Specifically, postoperative verbal memory performance was positively correlated with contralateral right hippocampal activation during word encoding in the left-sided surgery group. In contrast, postoperative visual memory performance was positively correlated with contralateral left hippocampal activation during figure encoding in the right-sided surgery group. Activation of the ipsilateral remnant HIP was not correlated with any memory scores or volumes of the HIP; however, it had a negative correlation with the seizure-onset age and positive correlation with the duration of illness in both patient groups.CONCLUSIONSFor the first time, a neural basis that supports effective intermediate-term episodic memory after unilateral MTLR has been characterized. The results provide evidence that engagement of the HIP contralateral rather than ipsilateral to the side of resection is responsible for effective memory function in the intermediate term (> 1 year) after surgery in patients who have undergone left MTLR and right MTLR. Engagement of the material-specific contralesional HIP, verbal memory in the left-sided surgery group, and visual memory in the right sided surgery group were observed. PMID- 30485240 TI - Using an artificial neural network to predict traumatic brain injury. AB - OBJECTIVEPediatric traumatic brain injury (TBI) is common, but not all injuries require hospitalization. A computational tool for ruling in patients who will have a clinically relevant TBI (CRTBI) would be valuable, providing an evidence based way to safely discharge children who are at low risk for a CRTBI. The authors hypothesized that an artificial neural network (ANN) trained on clinical and radiologist-interpreted imaging metrics could provide a tool for identifying patients likely to suffer from a CRTBI.METHODSThe authors used the prospectively collected, publicly available, multicenter Pediatric Emergency Care Applied Research Network (PECARN) TBI data set. All patients under the age of 18 years with TBI and admission head CT imaging data were included. The authors constructed an ANN using clinical and radiologist-interpreted imaging metrics in order to predict a CRTBI, as previously defined by PECARN: 1) neurosurgical procedure, 2) intubation > 24 hours as direct result of the head trauma, 3) hospitalization >= 48 hours and evidence of TBI on a CT scan, or 4) death due to TBI.RESULTSAmong 12,902 patients included in this study, 480 were diagnosed with CRTBI. The authors' ANN had a sensitivity of 99.73% with precision of 98.19%, accuracy of 97.98%, negative predictive value of 91.23%, false-negative rate of 0.0027%, and specificity for CRTBI of 60.47%. The area under the receiver operating characteristic curve was 0.9907.CONCLUSIONSThe authors are the first to utilize artificial intelligence to predict a CRTBI in a clinically meaningful manner, using radiologist-interpreted CT information, in order to identify pediatric patients likely to suffer from a CRTBI. This proof-of-concept study lays the groundwork for future studies incorporating iterations of this algorithm directly into the electronic medical record for real-time, data-driven predictive assistance to physicians. PMID- 30485241 TI - Intramedullary spinal cord ependymoma and astrocytoma: intraoperative frozen section diagnosis, extent of resection, and outcomes. AB - OBJECTIVEThe intraoperative differentiation of ependymomas from astrocytomas is important because neurosurgical strategies differ between these two tumor groups. Previous studies have reported that the diagnostic accuracy of intraoperative frozen sections of intracranial central nervous system (CNS) tumors is higher than 83%-97%, whereas that for spinal intramedullary tumors remains unknown. Herein, authors tested the hypothesis that intraoperative frozen-section diagnosis is the gold standard for a differential diagnosis of intramedullary spinal cord tumors.METHODSThe clinical characteristics, intraoperative histological diagnosis from frozen sections, extent of tumor resection, progression-free survival (PFS), and overall survival (OS) of 49 cases of intramedullary spinal cord ependymomas (n = 32) and astrocytomas (n = 17) were retrospectively evaluated.RESULTSThe frozen-section diagnosis and final diagnosis with permanent sections agreed in 23 (72%) of 32 cases of ependymoma. Of the 9 cases of ependymoma in which the frozen-section diagnosis disagreed with the final diagnosis, 4 were incorrectly diagnosed as astrocytoma and the other 5 cases had a nonspecific diagnosis, such as glioma. Nonetheless, gross-total resection was achieved in 6 of these 9 cases given the presence of a dissection plane. The frozen-section diagnosis and final diagnosis agreed in 12 (71%) of 17 cases of astrocytoma. Of the 5 cases of astrocytoma in which the frozen-section diagnosis disagreed with the final diagnosis, 1 was incorrectly diagnosed as ependymoma and the other 4 had a nonspecific diagnosis. Gross-total resection was achieved in only 1 of these 5 cases.A relationship between the size of tumor specimens and the diagnostic accuracy of frozen sections was not observed. Ependymal rosettes and perivascular pseudorosettes were observed in 30% and 57% of ependymomas, respectively, but were absent in astrocytomas.Progression-free survival and OS were both significantly longer in cases of ependymoma than in cases of astrocytoma (p < 0.001). Gross-total resection was achieved in 69% of ependymomas and was associated with longer PFS (p = 0.041). In the astrocytoma group, gross-total resection was achieved in only 12% and there was no relationship between extent of resection and OS. Tumor grades tended to correlate with OS in astrocytomas (p = 0.079).CONCLUSIONSThe diagnostic accuracy of intraoperative frozen sections was lower for intramedullary spinal cord ependymomas and astrocytomas in the present study than that for intracranial CNS tumors reported on in the literature. Surgical strategies need to be selected based on multiple factors, such as clinical characteristics, preoperative imaging, frozen-section diagnosis, and intraoperative findings of the tumor plane. PMID- 30485242 TI - Changes in the gray and white matter of patients with ischemic-edematous insults after traumatic brain injury. AB - OBJECTIVEGray matter (GM) and white matter (WM) are vulnerable to ischemic edematous insults after traumatic brain injury (TBI). The extent of secondary insult after brain injury is quantifiable using quantitative CT analysis. One conventional quantitative CT measure, the gray-white matter ratio (GWR), and a more recently proposed densitometric analysis are used to assess the extent of these insults. However, the prognostic capacity of the GWR in patients with TBI has not yet been validated. This study aims to test the prognostic value of the GWR and evaluate the alternative parameters derived from the densitometric analysis acquired during the acute phase of TBI. In addition, the prognostic ability of the conventional TBI prognostic models (i.e., IMPACT [International Mission for Prognosis and Analysis of Clinical Trials in TBI] and CRASH [Corticosteroid Randomisation After Significant Head Injury] models) were compared to that of the quantitative CT measures.METHODSThree hundred patients with TBI of varying ages (92 pediatric, 94 adult, and 114 geriatric patients) and admitted between 2008 and 2013 were included in this retrospective cohort study. The normality of the density of the deep GM and whole WM was evaluated as the proportion of CT pixels with Hounsfield unit values of 31-35 for GM and 26-30 for WM on CT images of the entire supratentorial brain. The outcome was evaluated using the Glasgow Outcome Scale (GOS) at discharge (GOS score <= 3, n = 100).RESULTSLower proportions of normal densities in the deep GM and whole WM indicated worse outcomes. The proportion of normal WM exhibited a significant prognostic capacity (area under the curve [AUC] = 0.844). The association between the outcome and the normality of the WM density was significant in adult (AUC = 0.792), pediatric (AUC = 0.814), and geriatric (AUC = 0.885) patients. In pediatric patients, the normality of the overall density and the density of the GM were indicative of the outcome (AUC = 0.751). The average GWR was not associated with the outcome (AUC = 0.511). IMPACT and CRASH models showed adequate and reliable performance in the pediatric and geriatric groups but not in the adult group. The highest overall predictive performance was achieved by the densitometry-augmented IMPACT model (AUC = 0.881).CONCLUSIONSBoth deep GM and WM are susceptible to ischemic-edematous insults during the early phase of TBI. The extent of the secondary injury was better evaluated by analyzing the normality of the deep GM and WM rather than by calculating the GWR. PMID- 30485243 TI - Transcortical insular glioma resection: clinical outcome and predictors. AB - OBJECTIVEInsular lobe gliomas continue to challenge neurosurgeons due to their complex anatomical position. Transcortical and transsylvian corridors remain the primary approaches for reaching the insula, but the adoption of one technique over the other remains controversial. The authors analyzed the transcortical approach of resecting insular gliomas in the context of patient tumor location based on the Berger-Sinai classification, achievable extents of resection (EORs), overall survival (OS), and postsurgical neurological outcome.METHODSThe authors studied 255 consecutive cases of insular gliomas that underwent transcortical tumor resection in their division. Tumor molecular pathology, location, EOR, postoperative neurological outcome for each insular zone, and the accompanying OS were incorporated into the analysis to determine the value of this surgical approach.RESULTSLower-grade insular gliomas (LGGs) were more prevalent (63.14%). Regarding location, giant tumors (involving all insular zones) were most prevalent (58.82%) followed by zone I+IV (anterior) tumors (20.39%). In LGGs, tumor location was an independent predictor of survival (p = 0.003), with giant tumors demonstrating shortest patient survival (p = 0.003). Isocitrate dehydrogenase 1 (IDH1) mutation was more likely to be associated with giant tumors (p < 0.001) than focal tumors located in a regional zone. EOR correlated with survival in both LGG (p = 0.001) and higher-grade glioma (HGG) patients (p = 0.008). The highest EORs were achieved in anterior-zone LGGs (p = 0.024). In terms of developing postoperative neurological deficits, patients with giant tumors were more susceptible (p = 0.038). Postoperative transient neurological deficit was recorded in 12.79%, and permanent deficit in 15.70% of patients. Patients who developed either transient or permanent postsurgical neurological deficits exhibited poorer survival (p < 0.001).CONCLUSIONSThe transcortical surgical approach can achieve maximal tumor resection in all insular zones. In addition, the incorporation of adjunct technologies such as multimodal brain imaging and mapping of cortical and subcortical eloquent brain regions into the transcortical approach favors postoperative neurological outcomes, and prolongs patient survival. PMID- 30485244 TI - Erratum. Intermediate-risk meningioma: initial outcomes from NRG Oncology RTOG 0539. PMID- 30485245 TI - Erratum. A prospective randomized trial of the optimal dose of mannitol for intraoperative brain relaxation in patients undergoing craniotomy for supratentorial brain tumor resection. PMID- 30485246 TI - Erratum. Phenytoin versus levetiracetam as prophylaxis for postcraniotomy seizure in patients with no history of seizures: systematic review and meta-analysis. PMID- 30485247 TI - Obituary. Charles B. Wilson, MD, 1929-2018. PMID- 30485248 TI - Positive association of familial longevity with the moderate-high HDL-C concentration in Bama Aging Study. AB - Familial longevity is characterized by beneficial metabolic phenotype in lipid metabolism and APOE genetic variation. Although effects of lipid metabolism and the genetic basis for human longevity remain largely unclear, the contribution of high-density lipoprotein cholesterol (HDL-C) and APOE epsilon2 allele has been repeatedly demonstrated. This study was designed to determine whether ApoE isoforms and HDL-C levels marked the familial longevity status in an offspring cohort with the age range of 20-89 years old and subsequently to explore the correlation between these two markers and the aging. In the Bama Aging Study (BAS), we recruited 312 offspring from longevity historical families and 298 controls from non-longevity historical families. Information on APOE genotype frequencies, lipid levels, and population characteristics were recorded. No evidence was found to support the association of APOE genotypes with HDL-C and age. HDL-C was significantly higher in longevity group (p < 0.0001). Scatter plot showed a moderately strong linear relationship between the HDL-C level and age in longevity group (r = 0.213, p < 0.001). We conclude that the variation of the APOE gene may not influence familial longevity status at a certain age but the moderate-high HDL-C level contributes to the familial longevity in Bama. PMID- 30485249 TI - Microfluidic DNA combing for parallel single-molecule analysis. AB - DNA combing is a widely used method for stretching and immobilising DNA molecules on a surface. Fluorescent labelling of genomic information enables high resolution optical analysis of DNA at the single-molecule level. Despite its simplicity, the application of DNA combing in diagnostic workflows is still limited, mainly due to difficulties in analysing multiple small-volume DNA samples in parallel. Here, we report a simple and versatile microfluidic DNA combing technology (MUDC), which allows manipulating, stretching and imaging of multiple, microliter scale DNA samples by employing a manifold of parallel microfluidic channels. Using DNA molecules with repetitive units as molecular rulers, we demonstrate that the MUDC technology allows uniform stretching of DNA molecules. The stretching ratio remains consistent along individual molecules as well as between different molecules in the various channels, allowing simultaneous quantitative analysis of different samples loaded into parallel channels. Furthermore, we demonstrate the application of MUDC to characterise UVB induced DNA damage levels in human embryonic kidney cells and the spatial correlation between DNA damage sites. Our results point out the potential application of MUDC for quantitative and comparative single-molecule studies of genomic features. The extremely simple design of MUDC makes it suitable for integration into other microfluidic platforms to facilitate high-throughput DNA analysis in biological research and medical point-of-care applications. PMID- 30485250 TI - Elastic wave propagation in smooth and wrinkled stratified polymer films. AB - Periodic materials with sub-micrometer characteristic length scale can provide means for control of propagation of hypersonic phonons. In addition to propagation stopbands for the acoustic phonons, distinct dispersive modes can reveal specific thermal and mechanical behavior under confinement. Here, we employ both experimental and theoretical methods to characterize the phonon dispersion relation (frequency versus wave vector). We employed Brillouin light scattering (BLS) spectroscopy to record the phonon dispersion in stratified multilayer polymer films. These films consist of 4-128 alternate polycarbonate (PC) and poly (methyl methacrylate) (PMMA) layers along and normal to the periodicity direction. The distinct direction-dependent phonon propagation was theoretically accounted for, by considering the polarization, frequency and intensity of the observed modes in the BLS spectra. Layer-guiding was also supported by the glass transition temperatures of the PC and PMMA layers. The number of phonon dispersion branches increased with the number of layers but only a few branches were observable by BLS. Introduction of an additional in-plane periodicity, through a permanent wrinkling of the smooth PC/PMMA films, had only subtle consequences in the phonon propagation. Using the frequencies of the periodicity induced modes and momentum conservation equation we were able to precisely back calculate the wrinkle periodicity. However, a wrinkling-induced acoustic stopband utilizing flexible layered materials is still a challenge. PMID- 30485251 TI - Heart rate variability, multifractal multiscale patterns and their assessment criteria. AB - OBJECTIVE: Both the central nervous system and the autonomic nervous system are complex physiological networks which modulate the heart rate. They are spatially extended, have built-in delays and work on many time scales simultaneously nonhomogeneous networks with multifractal dynamics. The object of our research was the analysis of human heart rate variability (HRV) using the nonlinear multiscale multifractal analysis (MMA) method for several cardiovascular diseases. The analysis of HRV (night-time recordings) involved six groups of patients: 61 healthy persons, 104 cases with aortic valve stenosis, 42 with hypertrophic cardiomyopathy, 36 with atrial fibrillation, 70 patients with coronary artery disease and 19 with congestive heart failure. 85% of patients formed a training data set (282 subjects) and 15% formed a test data set (50 subjects). APPROACH: Multiscale multifractal analysis allows one to analyze the complexity of HRV and find the scaling properties of its fluctuations. The main result of MMA is the Hurst surface, the shape of which changes depending on the medical case analyzed. We prepared six criteria to distinguish a multifractal pattern for healthy subjects. We also prepared additional criteria, enabling one to recognize atrial fibrillation. MAIN RESULTS: For the training data set, we obtained the following accuracy statistics in distinguishing the patients from the healthy: 68% for coronary artery disease, 67% for hypertrophic cardiomyopathy, 88% for atrial fibrillation, 74% for aortic valve stenosis and 83% for congestive heart failure. For the complete training data set we obtained an accuracy of 73%, and 80% for the test data set (mean for ten random selections of the test data set). SIGNIFICANCE: The results of MMA presented here provide an additional input into the diagnostic process and may help to create a paradigm for future studies on medical screening methods, especially in that MMA focuses on very low frequencies of HRV not easily accessible by standard medical techniques. Satisfactory statistics for screening using both MMA and the unfiltered version of LF/HF indicate that the nature of the complete network moderating heart rhythm needs to be studied and that sinus rhythm in clinical patients may not always be separated from arrhythmia when its incidence is large. PMID- 30485252 TI - Structural reconfiguration and stress relaxation in twisted epitaxial graphene by annealing. AB - The possibility to engineer the van der Waals interactions between graphene layers is crucial for controlling the electronic properties. Using epitaxial graphene with preferential orientations grown on the C-face 6H-SiC as a prototype, we have addressed the annealed structural reconfiguration of graphene layer in view of the evolutions of surface ripples and relative rotation angle (RRA) between lattices. It was found that the heat treatment of graphene layers under vacuum deformed the arcuate ripple surface and subsequently split one ripple into parallel twin pleats, which drastically increased the strains in the films. The originally oriented graphene layers, with small RRA between adjacent layers, were rearranged by the annealing resulting in disordered orientations and larger RRA. After a sufficient annealing, the compressive stress stored in the films was well released to give undistorted graphene lattices. The vacuum annealing is an effective treatment for irreversibly relaxing the graphene structure. PMID- 30485253 TI - Numerical study on spindle positioning using phase field method. AB - A method of numerical simulation of cell division using phase fields is presented. The cell division plane is obtained as a result of the spindle position and orientation considered with the spatial distribution of the activated cortical force generators and the dividing cell shape. To exemplify the application of the proposed method, numerical simulations of the development of cysts and early embryos are performed. The numerical results demonstrate that the activated cortical force generators that are localized at the lateral cortices of the epithelial cells lead to the formation of a single central lumen. It is additionally shown that the linear distribution of the activated cortical force generators along the animal-vegetal axis of a spherical cell engenders a similar cell proliferation of the divided embryo generated by the 32 cell period in a sea cucumber. PMID- 30485255 TI - Self-identified gadolinium toxicity: comparison of gadolinium in bone and urine to healthy gadolinium-based contrast agent exposed volunteers. AB - OBJECTIVE: To report additional gadolinium bone and urine data that can contribute to gaps in knowledge with respect to gadolinium uptake and retention in the body. APPROACH: In vivo measurements of gadolinium retention in the tibia bone were performed on individuals self-identified as exhibiting symptoms of gadolinium toxicity as a result of receiving GBCA, as well as on control individuals. Gadolinium urine measurements for controls, symptomatic exposed, and non-symptomatic exposed were conducted through Mayo Medical Laboratories. MAIN RESULTS: Gadolinium bone concentration in the exposed group is significantly higher than the control group (p < 0.01), with a significant difference between symptomatic and non-symptomatic (p < 0.01), using a one-tailed t test on variance weighted means. Gadolinium urine levels in both control subjects and non symptomatic exposed subjects are significantly lower than symptomatic exposed subjects (p <= 0.05). A linear regression analysis for gadolinium urine levels and GBCA dose resulted in a positive linear relationship (R 2 = 0.91, p < 0.01). Gadolinium levels in urine and gadolinium concentration in bone were found to have a non-significant relationship (R 2 = 0.11, p = 0.3). SIGNIFICANCE: Significant differences in gadolinium levels in bone and urine are observed between individuals experiencing symptoms of gadolinium toxicity and for those who are not exhibiting symptoms. No correlation was observed between gadolinium in bone and gadolinium excreted in urine, suggesting that the retention of gadolinium in the body is complicated, involving multiple long-term storage sites. PMID- 30485254 TI - Horizontal GaN nanowires grown on Si (111) substrate: the effect of catalyst migration and coalescence. AB - Here, we demonstrate the growth of horizontal GaN nanowires (NWs) on silicon (111) by a surface-directed vapor-liquid-solid growth. The influence of the Au/Ni catalysts migration and coalescence on the growth of the NWs has been systematically studied. 2D root-like branched NWs were gown spontaneously through catalyst migration. Furthermore, a novel phenomenon that a catalyst particle is embedded in a horizontal NW was observed and attributed the destruction of growth steady state due to the catalysts coalescence. The transmission electron microscopy and photoluminescence, cathodoluminescence measurement demonstrated that the horizontal NWs exhibit single crystalline structures and good optical properties. Our work sheds light on the horizontal NWs growth and should facilitate the development of highly integrated III-V nanodevices on silicon. PMID- 30485256 TI - Ultrafast measurements of the dynamics of single nanostructures: a review. AB - The ability to study single particles has revolutionized nanoscience. The advantage of single particle spectroscopy measurements compared to conventional ensemble studies is that they remove averaging effects from the different sizes and shapes that are present in the samples. In time-resolved experiments this is important for unraveling homogeneous and inhomogeneous broadening effects in lifetime measurements. In this report, recent progress in the development of ultrafast time-resolved spectroscopic techniques for interrogating single nanostructures will be discussed. The techniques include far-field experiments that utilize high numerical aperture (NA) microscope objectives, near-field scanning optical microscopy (NSOM) measurements, ultrafast electron microscopy (UEM), and time-resolved x-ray diffraction experiments. Examples will be given of the application of these techniques to studying energy relaxation processes in nanoparticles, and the motion of plasmons, excitons and/or charge carriers in different types of nanostructures. PMID- 30485257 TI - Required CPAP usage time to normalize AHI in obstructive sleep apnea patients: a simulation study. AB - OBJECTIVE: Adherence to continuous positive airway pressure (CPAP) is often limited. The aim of the current work was to create a simulation tool to enable determination of the individual CPAP therapy time required to normalize apnea hypopnea index (AHI) (<5 events h-1) in a cohort of OSA patients. APPROACH: Polygraphic studies of 1989 consecutive patients were analyzed. CPAP therapy was simulated in 5 min intervals starting from the beginning of the night and continuing until the end. In simulation, events inside the simulated CPAP therapy periods were considered to be prevented. The cutoff points where AHI reached a normal level of < 5 events h-1 were determined for mild, moderate and severe OSA categories. MAIN RESULTS: The median values of the required simulated CPAP usage times to normalize the AHI values were 3.3 h, 5.6 h and 6.5 h in the mild, moderate and severe OSA categories, respectively. However, there were great differences between individuals in the CPAP usage times required to normalize AHI. SIGNIFICANCE: An arbitrary threshold for CPAP adherence (e.g. 4 h) leaves many OSA patients with a significant residual AHI, which could explain why some clinical trials fail to show significant benefits. Thresholds for adherence should be adjusted based on the patient-specific distribution of obstruction events during the night. PMID- 30485258 TI - Soft Tissue Sarcoma of the Extremities: What Is the Value of Treating at High volume Centers? AB - BACKGROUND: For many cancer types, survival is improved when patients receive management at treatment centers that encounter high numbers of patients annually. This correlation may be more important with less common malignancies such as sarcoma. Existing evidence, however, is limited and inconclusive as to whether facility volume may be associated with survival in soft tissue sarcoma. QUESTIONS/PURPOSES: The purpose of this study was to examine the association between facility volume and overall survival in patients with soft tissue sarcoma of the extremities. In investigating this aim, we sought to (1) examine differences in the treatment characteristics of high- and low-volume facilities; (2) estimate the 5-year survival by facility volume; and (3) examine the association between facility volume and of traveling a further distance to a high volume center and overall survival when controlling for confounding factors. METHODS: The largest sarcoma patient registry to date is contained within the National Cancer Database (NCDB) and captures > 70% of new cancer diagnoses annually. We retrospectively analyzed 25,406 patients with soft tissue sarcoma of the extremities in the NCDB from 1998 through 2012. Patients were stratified based on per-year facility sarcoma volume and we used univariate comparisons and multivariate proportional hazards analyses to correlate survival measures with facility volume and various other patient-, tumor-, and treatment-related factors. First, we evaluated long-term survival for all variables using the Kaplan-Meier method with statistical comparisons based on the log-rank test. Multiple patient, tumor, and treatment characteristics were compared between the two facility-volume groups and then included them in the multivariate proportional hazards model. Of the 25,406 patients analyzed, 3310 were treated at high-volume centers (>= 20 patients annually) and 22,096 were treated at low volume centers. Patient demographics were generally not different between both patient cohorts, although patients treated at high-volume centers were more likely to have larger and higher grade tumors (64% versus 56% size >= 5 cm, 28% versus 14% undifferentiated grade, p < 0.001). RESULTS: When controlling for patient, tumor, and treatment characteristics in a multivariate proportional hazards analysis, patients treated at high-volume facilities had an overall lower risk of mortality than those treated at low-volume centers (hazard ratio, 0.81 [0.75-0.88], p < 0.001). Patients treated at high-volume centers were also less likely to have positive margins (odds ratio [OR], 0.59 [0.52-0.68], p < 0.001) and in patients who received radiation, those treated at high-volume centers were more likely to have radiation before surgery (40.5% versus 21.7%, p < 0.001); there was no difference in the type of surgery performed (resection versus amputation) (OR, 1.01 [0.84-1.23], p = 0.883). CONCLUSIONS: With the largest patient cohort to date, this database review suggests that certain patients with soft tissue sarcoma of the extremities, particularly those with large high-grade tumors, may benefit from treatment at high-volume centers. Further investigation is necessary to help improve the referral of appropriate patients to high-volume sarcoma centers and to increase the treatment capacity of and access to such centers. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 30485259 TI - Plasma Levels of microRNA-221 (miR-221) are Increased in Patients with Acute Pulmonary Embolism. AB - BACKGROUND The aim of this study was to measure and compare the plasma levels of the microRNA (miRNA), miR-221, in patients with acute pulmonary embolism (PE) with healthy individuals and to evaluate the potential role of miR-221 as a diagnostic biomarker for acute PE. MATERIAL AND METHODS In blood samples collected from 60 patients with acute PE and 50 healthy volunteers, plasma levels of microRNA were identified using a microRNA microarray, and miR-221 expression was detected using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). Brain natriuretic peptide (BNP) and troponin I were measured using an automated immunoassay analyzer. D-dimer levels were measured with an enzyme-linked immunosorbent assay (ELISA). RESULTS From the evaluation of 32 differentially expressed plasma miRNAs, miR-221 was significantly upregulated in the plasma of patients with acute PE compared with normal individuals (P<0.05). Correlation analysis showed that plasma miR-221 levels in patients with acute PE were positively correlated with levels of BNP (r=0.842, P<0.05), troponin I (r=0.853; P<0.05), and D-dimer (r=0.838; P<0.05). The receiver operating characteristic (ROC) area under the curve (AUC) for plasma miR-221 was 0.823 (95% CI, 0.757-0.906) (P<0.05), compared with the AUC for D-dimer of 0.768 (95% CI, 0.727-0.853), the AUC for troponin I of 0.713 (95% CI, 0.646-0.868), and the AUC for BNP of 0.648 (95% CI, 0.601-0.723). CONCLUSIONS Plasma levels of miR-221 were significantly increased in patients with acute PE when compared with healthy individuals. PMID- 30485260 TI - Building a local community of practice in scientific programming for life scientists. AB - In this paper, we describe why and how to build a local community of practice in scientific programming for life scientists who use computers and programming in their research. A community of practice is a small group of scientists who meet regularly to help each other and promote good practices in scientific programming. While most life scientists are well trained in the laboratory to conduct experiments, good practices with (big) data sets and their analysis are often missing. We propose a model on how to build such a community of practice at a local academic institution, present two real-life examples, and introduce challenges and implemented solutions. We believe that the current data deluge that life scientists face can benefit from the implementation of these small communities. Good practices spread among experimental scientists will foster open, transparent, and sound scientific results beneficial to society. PMID- 30485261 TI - Stress-responsive and metabolic gene regulation are altered in low S adenosylmethionine. AB - S-adenosylmethionine (SAM) is a donor which provides the methyl groups for histone or nucleic acid modification and phosphatidylcholine production. SAM is hypothesized to link metabolism and chromatin modification, however, its role in acute gene regulation is poorly understood. We recently found that Caenorhabditis elegans with reduced SAM had deficiencies in H3K4 trimethylation (H3K4me3) at pathogen-response genes, decreasing their expression and limiting pathogen resistance. We hypothesized that SAM may be generally required for stress responsive transcription. Here, using genetic assays, we show that transcriptional responses to bacterial or xenotoxic stress fail in C. elegans with low SAM, but that expression of heat shock genes are unaffected. We also found that two H3K4 methyltransferases, set-2/SET1 and set-16/MLL, had differential responses to survival during stress. set-2/SET1 is specifically required in bacterial responses, whereas set-16/MLL is universally required. These results define a role for SAM in the acute stress-responsive gene expression. Finally, we find that modification of metabolic gene expression correlates with enhanced survival during stress. PMID- 30485262 TI - Nucleosome positions establish an extended mutation signature in melanoma. AB - Ultraviolet (UV) light-induced mutations are unevenly distributed across skin cancer genomes, but the molecular mechanisms responsible for this heterogeneity are not fully understood. Here, we assessed how nucleosome structure impacts the positions of UV-induced mutations in human melanomas. Analysis of mutation positions from cutaneous melanomas within strongly positioned nucleosomes revealed a striking ~10 base pair (bp) oscillation in mutation density with peaks occurring at dinucleotides facing away from the histone octamer. Additionally, higher mutation density at the nucleosome dyad generated an overarching "translational curvature" across the 147 bp of DNA that constitutes the nucleosome core particle. This periodicity and curvature cannot be explained by sequence biases in nucleosomal DNA. Instead, our genome-wide map of UV-induced cyclobutane pyrimidine dimers (CPDs) indicates that CPD formation is elevated at outward facing dinucleotides, mirroring the oscillation of mutation density within nucleosome-bound DNA. Nucleotide excision repair (NER) activity, as measured by XR-seq, inversely correlated with the curvature of mutation density associated with the translational setting of the nucleosome. While the 10 bp periodicity of mutations is maintained across nucleosomes regardless of chromatin state, histone modifications, and transcription levels, overall mutation density and curvature across the core particle increased with lower transcription levels. Our observations suggest structural conformations of DNA promote CPD formation at specific sites within nucleosomes, and steric hindrance progressively limits lesion repair towards the nucleosome dyad. Both mechanisms create a unique extended mutation signature within strongly positioned nucleosomes across the human genome. PMID- 30485263 TI - A precipitation gradient drives change in macroinvertebrate composition and interactions within bromeliads. AB - Ecological communities change across spatial and environmental gradients due to (i) changes in species composition, (ii) changes in the frequency or strength of interactions or (iii) changes in the presence of the interactions. Here we use the communities of aquatic invertebrates inhabiting clusters of bromeliad phytotelms along the Brazilian coast as a model system for examining variation in multi-trophic communities. We first document the variation in the species pools of sites across a geographical climate gradient. Using the same sites, we also explored the geographic variation in species interaction strength using a Markov network approach. We found that community composition differed along a gradient of water volume within bromeliads due to the spatial turnover of some species. From the Markov network analysis, we found that the interactions of certain predators differed due to differences in bromeliad water volume. Overall, this study illustrates how a multi-trophic community can change across an environmental gradient through changes in both species and their interactions. PMID- 30485264 TI - Rhinovirus infections change DNA methylation and mRNA expression in children with asthma. AB - Human rhinovirus infection (HRVI) plays an important role in asthma exacerbations and is thought to be involved in asthma development during early childhood. We hypothesized that HRVI causes differential DNA methylation and subsequently differential mRNA expression in epithelial cells of children with asthma. Primary nasal epithelial cells from children with (n = 10) and without (n = 10) asthma were cultivated up to passage two and infected with Rhinovirus-16 (RV-16). HRVI induced genome-wide differences of DNA methylation in asthmatics (vs. controls) and resulting mRNA expression were analyzed by the HumanMethylation450 BeadChip Kit (Illumina) and RNA sequencing. These results were further verified by pyrosequencing and quantitative PCR, respectively. 471 CpGs belonging to 268 genes were identified to have HRVI-induced asthma-specifically modified DNA methylation and mRNA expression. A minimum-change criteria was applied to restrict assessment of genes with changes in DNA methylation and mRNA expression of at least 3% and least 0.1 reads/kb per million mapped reads, respectively. Using this approach we identified 16 CpGs, including HLA-B-associated transcript 3 (BAT3) and Neuraminidase 1 (NEU1), involved in host immune response against HRVI. HRVI in nasal epithelial cells leads to specific modifications of DNA methylation with altered mRNA expression in children with asthma. The HRVI induced alterations in DNA methylation occurred in genes involved in the host immune response against viral infections and asthma pathogenesis. The findings of our pilot study may partially explain how HRVI contribute to the persistence and progression of asthma, and aid to identify possible new therapeutic targets. The promising findings of this pilot study would benefit from replication in a larger cohort. PMID- 30485265 TI - Implementation science: Epidemiology and feeding profiles of the Chagas vector Triatoma dimidiata prior to Ecohealth intervention for three locations in Central America. AB - The Ecohealth strategy is a multidisciplinary data-driven approach used to improve the quality of people's lives in Chagas disease endemic areas, such as regions of Central America. Chagas is a vector-borne disease caused by the parasite Trypanosoma cruzi. In Central America, the main vector is Triatoma dimidiata. Because successful implementation of the Ecohealth approach reduced home infestation in Jutiapa department, Guatemala, it was scaled-up to three localities, one in each of three Central American countries (Texistepeque, El Salvador; San Marcos de la Sierra, Honduras and Olopa, Guatemala). As a basis for the house improvement phase of the Ecohealth program, we determined if the localities differ in the role of sylvatic, synanthropic and domestic animals in the Chagas transmission cycle by measuring entomological indices, blood meal sources and parasite infection from vectors collected in and around houses. The Polymerase Chain Reaction (PCR) with taxa specific primers to detect both, blood sources and parasite infection, was used to assess 71 T. dimidiata from Texistepeque, 84 from San Marcos de la Sierra and 568 from Olopa. Our results show that infestation (12.98%) and colonization (8.95%) indices were highest in Olopa; whereas T. cruzi prevalence was higher in Texistepeque and San Marcos de la Sierra (>40%) than Olopa (8%). The blood meal source profiles showed that in Olopa, opossum might be important in linking the sylvatic and domestic Chagas transmission cycle, whereas in San Marcos de la Sierra dogs play a major role in maintaining domestic transmission. For Texistepeque, bird was the major blood meal source followed by human. When examining the different life stages, we found that in Olopa, the proportion bugs infected with T. cruzi is higher in adults than nymphs. These findings highlight the importance of location-based recommendations for decreasing human-vector contact in the control of Chagas disease. PMID- 30485266 TI - Demographic characteristics of an avian predator, Louisiana Waterthrush (Parkesia motacilla), in response to its aquatic prey in a Central Appalachian USA watershed impacted by shale gas development. AB - We related Louisiana Waterthrush (Parkesia motacilla) demographic response and nest survival to benthic macroinvertebrate aquatic prey and to shale gas development parameters using models that accounted for both spatial and non spatial sources of variability in a Central Appalachian USA watershed. In 2013, aquatic prey density and pollution intolerant genera (i.e., pollution tolerance value <4) decreased statistically with increased waterthrush territory length but not in 2014 when territory densities were lower. In general, most demographic responses to aquatic prey were variable and negatively related to aquatic prey in 2013 but positively related in 2014. Competing aquatic prey covariate models to explain nest survival were not statistically significant but differed annually and in general reversed from negative to positive influence on daily survival rate. Potential hydraulic fracturing runoff decreased nest survival both years and was statistically significant in 2014. The EPA Rapid Bioassessment protocol (EPA) and Habitat Suitability Index (HSI) designed for assessing suitability requirements for waterthrush were positively linked to aquatic prey where higher scores increased aquatic prey metrics, but EPA was more strongly linked than HSI and varied annually. While potential hydraulic fracturing runoff in 2013 may have increased Ephemeroptera, Plecoptera, and Trichoptera (EPT) richness, in 2014 shale gas territory disturbance decreased EPT richness. In 2014, intolerant genera decreased at the territory and nest level with increased shale gas disturbance suggesting the potential for localized negative effects on waterthrush. Loss of food resources does not seem directly or solely responsible for demographic declines where waterthrush likely were able to meet their foraging needs. However collective evidence suggests there may be a shale gas disturbance threshold at which waterthrush respond negatively to aquatic prey community changes. Density-dependent regulation of their ability to adapt to environmental change through acquisition of additional resources may also alter demographic response. PMID- 30485267 TI - Dispositional mindfulness in daily life: A naturalistic observation study. AB - Mindfulness has seen an extraordinary rise as a scientific construct, yet surprisingly little is known about how it manifests behaviorally in daily life. The present study identifies assumptions regarding how mindfulness relates to behavior and contrasts them against actual behavioral manifestations of trait mindfulness in daily life. Study 1 (N = 427) shows that mindfulness is assumed to relate to emotional positivity, quality social interactions, prosocial orientation and attention to sensory perceptions. In Study 2, 185 participants completed a gold-standard, self-reported mindfulness measure (the FFMQ) and underwent naturalistic observation sampling to assess their daily behaviors. Trait mindfulness was robustly related to a heightened perceptual focus in conversations. However, it was not related to behavioral and speech markers of emotional positivity, quality social interactions, or prosocial orientation. These findings suggest that the subjective and self-reported experience of being mindful in daily life is expressed primarily through sharpened perceptual attention, rather than through other behavioral or social differences. This highlights the need for ecological models of how dispositional mindfulness "works" in daily life, and raises questions about the measurement of mindfulness. PMID- 30485268 TI - Trends in use of prescription stimulants in the United States and Territories, 2006 to 2016. AB - BACKGROUND: Stimulants are considered the first-line treatment for Attention Deficit Hyperactivity Disorder (ADHD) in the US and they are used in other indications. Stimulants are also diverted for non-medical purposes. Ethnic and regional differences in ADHD diagnosis and in stimulant use have been identified in earlier research. The objectives of this report were to examine the pharmacoepidemiological pattern of these controlled substances over the past decade and to conduct a regional analysis. METHODS: Data (drug weights) reported to the US Drug Enforcement Administration's Automation of Reports and Consolidated Orders System for four stimulants (amphetamine, methylphenidate, lisdexamfetamine, and methamphetamine) were obtained from 2006 to 2016 for Unites States/Territories. Correlations between state level use (mg/person) and Hispanic population were completed. RESULTS: Amphetamine use increased 2.5 fold from 2006 to 2016 (7.9 to 20.0 tons). Methylphenidate use, at 16.5 tons in 2006, peaked in 2012 (19.4 tons) and subsequently showed a modest decline (18.6 tons in 2016). The consumption per municipality significantly increased 7.6% for amphetamine and 5.5% for lisdexamfetamine but decreased 2.7% for methylphenidate (all p < .0005) from 2015 to 2016. Pronounced regional differences were also observed. Lisdexamfetamine use in 2016 was over thirty-fold higher in the Southern US (43.8 mg/person) versus the Territories (1.4 mg/person). Amphetamine use was about one third lower in the West (48.1 mg/person) relative to the Northeastern (75.4 mg/person, p < .05) or the Midwestern (69.9 mg/person, p <= .005) states. States with larger Hispanic populations had significantly lower methylphenidate (r(49) = -0.63), lisdexamfetamine (B, r(49) = -0.49), and amphetamine (r(49) = -0.43) use. CONCLUSIONS: Total stimulant usage doubled in the last decade. There were dynamic changes but also regional disparities in the use of stimulant medications. Future research is needed to better understand the reasons for the sizable regional and ethnic variations in use of these controlled substances. PMID- 30485269 TI - Would government compensation of living kidney donors exploit the poor? An empirical analysis. AB - Government compensation of kidney donors would likely increase the supply of kidneys and prevent the premature deaths of tens of thousands of patients with kidney failure each year. The major argument against it is that it would exploit the poor who would be more likely to accept the offers of compensation. This overlooks the fact that many poor patients desperately need a kidney transplant and would greatly benefit from an increased supply of kidneys. The objective of this study is to empirically test the hypothesis that government compensation of kidney donors would exploit the poor. Exploitation is defined by economists and several noted ethicists as paying donors less than the fair market value of their kidney. Exploitation is expressed in monetary terms and compared with the economic benefit recipients receive from a transplant. Data are from the Scientific Registry of Transplant Recipients and the United States Renal Data System annual data reports. Educational attainment is used as a proxy for income. We estimate that if the government rewards living donors with a package of non cash benefits worth $75,000 per kidney, donors would not be exploited. Much more important, this compensation would likely end the kidney shortage, enabling many more patients with kidney failure to obtain transplants and live longer and healthier lives. The value of kidney transplantation to a U.S. recipient is about $1,330,000, which is an order of magnitude greater than any purported exploitation of a living donor (zero to $75,000). Consequently, the aggregate net benefit to the poor alone from kidney transplantation would increase to about $12 billion per year from $1 billion per year currently. Most of the benefit would accrue to poor kidney recipients. But poor donors would receive the fair market value of their kidney, and hence would not be exploited. If the government wanted to ensure that donors also received a net benefit, it could easily do so by increasing the compensation above $75,000 per donor. PMID- 30485270 TI - A deep learning approach to automatic detection of early glaucoma from visual fields. AB - PURPOSE: To investigate the suitability of multi-scale spatial information in 30o visual fields (VF), computed from a Convolutional Neural Network (CNN) classifier, for early-glaucoma vs. control discrimination. METHOD: Two data sets of VFs acquired with the OCTOPUS 101 G1 program and the Humphrey Field Analyzer 24-2 pattern were subdivided into control and early-glaucomatous groups, and converted into a new image using a novel voronoi representation to train a custom designed CNN so to discriminate between control and early-glaucomatous eyes. Saliency maps that highlight what regions of the VF are contributing maximally to the classification decision were computed to provide classification justification. Model fitting was cross-validated and average precision (AP) score performances were computed for our method, Mean Defect (MD), square-root of Loss Variance (sLV), their combination (MD+sLV), and a Neural Network (NN) that does not use convolutional features. RESULTS: CNN achieved the best AP score (0.874+/ 0.095) across all test folds for one data set compared to others (MD = 0.869+/ 0.064, sLV = 0.775+/-0.137, MD+sLV = 0.839+/-0.085, NN = 0.843+/-0.089) and the third best AP score (0.986 +/-0.019) on the other one with slight difference from the other methods (MD = 0.986+/-0.023, sLV = 0.992+/-0.016, MD+sLV = 0.987+/ 0.017, NN = 0.985+/-0.017). In general, CNN consistently led to high AP across different data sets. Qualitatively, computed saliency maps appeared to provide clinically relevant information on the CNN decision for individual VFs. CONCLUSION: The proposed CNN offers high classification performance for the discrimination of control and early-glaucoma VFs when compared with standard clinical decision measures. The CNN classification, aided by saliency visualization, may support clinicians in the automatic discrimination of early glaucomatous and normal VFs. PMID- 30485271 TI - Zinc enhances hippocampal long-term potentiation at CA1 synapses through NR2B containing NMDA receptors. AB - The role of zinc (Zn2+), a modulator of N-methyl-D-aspartate (NMDA) receptors, in regulating long-term synaptic plasticity at hippocampal CA1 synapses is poorly understood. The effects of exogenous application of Zn2+ and of chelation of endogenous Zn2+ were examined on long-term potentiation (LTP) of stimulus-evoked synaptic transmission at Schaffer collateral (SCH) synapses in field CA1 of mouse hippocampal slices using whole-cell patch clamp and field recordings. Low micromolar concentrations of exogenous Zn2+ enhanced the induction of LTP, and this effect required activation of NMDA receptors containing NR2B subunits. Zn2+ elicited a selective increase in NMDA/NR2B fEPSPs, and removal of endogenous Zn2+ with high-affinity Zn2+ chelators robustly reduced the magnitude of stimulus evoked LTP. Taken together, our data show that Zn2+ at physiological concentrations enhances activation of NMDA receptors containing NR2B subunits, and that this effect enhances the magnitude of LTP. PMID- 30485272 TI - Deficiency of the pattern-recognition receptor CD14 protects against joint pathology and functional decline in a murine model of osteoarthritis. AB - OBJECTIVE: CD14 is a monocyte/macrophage pattern-recognition receptor that modulates innate inflammatory signaling. Soluble CD14 levels in knee OA synovial fluids are associated with symptoms and progression of disease. Here we investigate the role of this receptor in development of OA using a murine joint injury model of disease. METHODS: 10-week-old Male C57BL/6 (WT) and CD14 deficient (CD14-/-) mice underwent destabilization of the medial meniscus (DMM) surgery to induce OA. Joint histopathology was used to examine cartilage damage, and microCT to evaluate subchondral bone (SCB) remodeling at 6 and 19 weeks after surgery. Synovial and fat pad expression of macrophage markers (F4/80, CD11c, CD68, iNOS, CCR7, CD163 and CD206) was assessed by flow cytometry and droplet digital (dd)PCR. Changes in locomotive activity indicative of joint pain were evaluated longitudinally up to 16 weeks by automated behavioral analysis. RESULTS: Early cartilage damage scores 6 weeks post-DMM were similar in both strains (Mean score +/-SEM WT: 4.667+/-1.38, CD14-/-: 4.6+/-0.6), but at 19 weeks were less severe in CD14-/- (6.0+/-0.46) than in WT mice (13.44+/-2.5, p = 0.0002). CD14-/- mice were protected from both age-related and post-surgical changes in SCB mineral density and trabecular thickness. In addition, CD14-/- mice were protected from decreases in climbing activity (p = 0.015 vs. WT, 8 weeks) observed after DMM. Changes in synovial/fat pad expression of CCR7, a marker of M1 macrophages, were slightly reduced post-DMM in the absence of CD14, while expression of CD68 (pan-macrophage marker) and CD163 (M2 marker) were unchanged. CONCLUSION: CD14 plays an important role in progression of structural and functional features of OA in the DMM model, and may provide a new target for therapeutic development. PMID- 30485273 TI - Bi-objective inventory allocation planning problem with supplier selection and carbon trading under uncertainty. AB - Concern is growing that business enterprises focus primarily on their economic activities while disregarding the adverse environmental and social effects of these activities. To contribute to the literature on this matter, this study investigates a novel bi-objective inventory allocation planning problem with supplier selection and carbon trading across multiple periods under uncertainty. The concepts of a carbon credit price and a carbon cap are proposed to demonstrate the effect of carbon emissions costs on inventory allocation network costs. Demands of manufacturers, transport price, and defect rate of materials that should be rejected are set as random variables. We combine normalized normal constraint method, differential evolution algorithm, and uncertainty simulation to deal with the complex model. One representative case shows the effectiveness and practicability of this model and proposed method. The Pareto frontier is generated by solving the bi-objective model. We extend the results of numerical examples in large scale problems, and compare the solution method results with exact solutions. The environmental objective across the inventory allocation network varies with changes of the carbon cap and the carbon credit price. PMID- 30485274 TI - Welfare effects of weather variability: Multi-country evidence from Africa south of the Sahara. AB - Climate change and weather variability pose serious threats to food and nutrition security as well as ecosystems, especially when livelihoods depend heavily on natural resources. This study examines the effect of weather variability (shock) occurring up to three planting and growing season prior on per capita monthly household expenditure in rural Tanzania, Uganda, and Ghana. The analyses combine monthly temperature (1950-2013) and precipitation (1981-2013) data with data from several rounds of household surveys conducted between 1998 and 2013. Substantial spatial and temporal heterogeneity is documented in the incidence of shocks, with effects dependent on both the study and lag period considered. Analysis of short panel data shows the cumulative effect of above-average precipitation on expenditure to be negative in Uganda -while positive in Tanzania-, but the relationship does not persist when pooling survey data spanning over a decade. The evidence from pooled data suggests a positive association between above average temperature (heat wave) and expenditure in (historically cooler) Uganda, with the opposite effect observed in (the relatively warmer) Tanzania. For Ghana, the association between heat wave and expenditure is positive. There is no evidence of heterogeneous effects along several dimensions, except by agro ecological condition. Further research into the effects of shocks on more direct outcomes-such as agricultural practices, yields, and dietary intake-is therefore recommended to shed light on possible impact pathways and appropriate localized adaptation strategies. PMID- 30485275 TI - Deep-sea anthropogenic macrodebris harbours rich and diverse communities of bacteria and archaea. AB - The deep sea is the largest biome on earth, and microbes dominate in biomass and abundance. Anthropogenic litter is now almost ubiquitous in this biome, and its deposition creates new habitats and environments, including for microbial assemblages. With the ever increasing accumulation of this debris, it is timely to identify and describe the bacterial and archaeal communities that are able to form biofilms on macrodebris in the deep sea. Using 16S rRNA gene high throughput sequencing, we show for the first time the composition of bacteria and archaea on macrodebris collected from the deep sea. Our data suggest differences in the microbial assemblage composition across litter of different materials including metal, rubber, glass, fabric and plastic. These results imply that anthropogenic macrodebris provide diverse habitats for bacterial and archaeal biofilms and each may harbour distinct microbial communities. PMID- 30485276 TI - Latent human traits in the language of social media: An open-vocabulary approach. AB - Over the past century, personality theory and research has successfully identified core sets of characteristics that consistently describe and explain fundamental differences in the way people think, feel and behave. Such characteristics were derived through theory, dictionary analyses, and survey research using explicit self-reports. The availability of social media data spanning millions of users now makes it possible to automatically derive characteristics from behavioral data-language use-at large scale. Taking advantage of linguistic information available through Facebook, we study the process of inferring a new set of potential human traits based on unprompted language use. We subject these new traits to a comprehensive set of evaluations and compare them with a popular five factor model of personality. We find that our language-based trait construct is often more generalizable in that it often predicts non-questionnaire-based outcomes better than questionnaire-based traits (e.g. entities someone likes, income and intelligence quotient), while the factors remain nearly as stable as traditional factors. Our approach suggests a value in new constructs of personality derived from everyday human language use. PMID- 30485277 TI - Improving efficiency in neuroimaging research through application of Lean principles. AB - INTRODUCTION: "Lean" is a set of management principles which focus on increasing value and efficiency by reducing or avoiding waste (e.g., overproduction, defects, inventory, transportation, waiting, motion, over processing). It has been applied to manufacturing, education, and health care, leading to optimized process flow, increased efficiency and increased team empowerment. However, to date, it has not been applied to neuroimaging research. METHODS: Lean principles, such as Value stream mapping (e.g. a tool with which steps in the workflow can be identified on which to focus improvement efforts), 5S (e.g. an organizational method to boost workplace efficiency and efficacy) and Root-cause analysis (e.g. a problem-solving approach to identify key points of failure in a system) were applied to an ongoing, large neuroimaging study that included seven research visits per participant. All team members participated in a half-day exercise in which the entire project flow was visualized and areas of inefficiency were identified. Changes focused on removing obstacles, standardization, optimal arrangement of equipment and root-cause-analysis. A process for continuous improvement was also implemented. Total time of an experiment was recorded before implementation of Lean for two participants and after implementation of Lean for two participants. Satisfaction of team members was assessed anonymously on a 5 item Likert scale, ranging from much worsened to much improved. RESULTS: All team members (N = 6) considered the overall experience of conducting an experiment much improved after implementation of Lean. Five out of six team members indicated a much-improved reduction in time, with the final team member considering this somewhat improved. Average experiment time was reduced by 13% after implementation of Lean (from 142 and 147 minutes to 124 and 128 minutes). DISCUSSION: Lean principles can be successfully applied to neuroimaging research. Training in Lean principles for junior research scientists is recommended. PMID- 30485278 TI - powerTCR: A model-based approach to comparative analysis of the clone size distribution of the T cell receptor repertoire. AB - Sequencing of the T cell receptor repertoire is a powerful tool for deeper study of immune response, but the unique structure of this type of data makes its meaningful quantification challenging. We introduce a new method, the Gamma-GPD spliced threshold model, to address this difficulty. This biologically interpretable model captures the distribution of the TCR repertoire, demonstrates stability across varying sequencing depths, and permits comparative analysis across any number of sampled individuals. We apply our method to several datasets and obtain insights regarding the differentiating features in the T cell receptor repertoire among sampled individuals across conditions. We have implemented our method in the open-source R package powerTCR. PMID- 30485279 TI - Regeneration-associated cells improve recovery from myocardial infarction through enhanced vasculogenesis, anti-inflammation, and cardiomyogenesis. AB - BACKGROUND: Considering the impaired function of regenerative cells in myocardial infarction (MI) patients with comorbidities and associated risk factors, cell therapy to enhance the regenerative microenvironment was designed using regeneration-associated cells (RACs), including endothelial progenitor cells (EPCs) and anti-inflammatory cells. METHODS: RACs were prepared by quality and quantity control culture of blood mononuclear cells (QQMNCs). Peripheral blood mononuclear cells (PBMNCs) were isolated from Lewis rats and conditioned for 5 days using a medium containing stem cell factors, thrombopoietin, Flt-3 ligand, vascular endothelial growth factor, and interleukin-6 to generate QQMNCs. RESULTS: A 5.3-fold increase in the definitive colony-forming EPCs and vasculogenic EPCs was observed, in comparison to naive PBMNCs. QQMNCs were enriched with EPCs (28.9-fold, P<0.0019) and M2 macrophages (160.3-fold, P<0.0002). Genes involved in angiogenesis (angpt1, angpt2, and vegfb), stem/progenitors (c-kit and sca-1), and anti-inflammation (arg-1, erg-2, tgfb, and foxp3) were upregulated in QQMNCs. For in vivo experiments, cells were administered into syngeneic rat models of MI. QQMNC-transplanted group (QQ-Tx) preserved cardiac function and fraction shortening 28 days post-MI in comparison with PBMNCs-transplanted (PB-Tx) (P<0.0001) and Control (P<0.0008) groups. QQ-Tx showed enhanced angiogenesis and reduced interstitial left ventricular fibrosis, along with a decrease in neutrophils and an increase in M2 macrophages in the acute phase of MI. Cell tracing studies revealed that intravenously administered QQMNCs preferentially homed to ischemic tissues via blood circulation. QQ-Tx showed markedly upregulated early cardiac transcriptional cofactors (Nkx2-5, 29.8 fold, and Gata-4, 5.2-fold) as well as c-kit (4.5-fold) while these markers were downregulated in PB-Tx. In QQ-Tx animals, de novo blood vessels formed a "Biological Bypass", observed macroscopically and microscopically, while PB-Tx and Control-Tx groups showed severe fibrotic adhesion to the surrounding tissues, but no epicardial blood vessels. CONCLUSION: QQMNCs conferred potent angiogenic and anti-inflammatory properties to the regenerative microenvironment, enhancing myocardiogenesis and functional recovery of rat MI hearts. PMID- 30485280 TI - Tracking a serial killer: Integrating phylogenetic relationships, epidemiology, and geography for two invasive meningococcal disease outbreaks. AB - BACKGROUND: While overall rates of meningococcal disease have been declining in the United States for the past several decades, New York City (NYC) has experienced two serogroup C meningococcal disease outbreaks in 2005-2006 and in 2010-2013. The outbreaks were centered within drug use and sexual networks, were difficult to control, and required vaccine campaigns. METHODS: Whole Genome Sequencing (WGS) was used to analyze preserved meningococcal isolates collected before and during the two outbreaks. We integrated and analyzed epidemiologic, geographic, and genomic data to better understand transmission networks among patients. Betweenness centrality was used as a metric to understand the most important geographic nodes in the transmission networks. Comparative genomics was used to identify genes associated with the outbreaks. RESULTS: Neisseria meningitidis serogroup C (ST11/ET-37) was responsible for both outbreaks with each outbreak having distinct phylogenetic clusters. WGS did identify some misclassifications of isolates that were more distant from the outbreak strains, as well as those that should have been included based on high genomic similarity. Genomes for the second outbreak were more similar than the first and no polymorphism was found to either be unique or specific to either outbreak lineage. Betweenness centrality as applied to transmission networks based on phylogenetic analysis demonstrated that the outbreaks were transmitted within focal communities in NYC with few transmission events to other locations. CONCLUSIONS: Neisseria meningitidis is an ever changing pathogen and comparative genomic analyses can help elucidate how it spreads geographically to facilitate targeted interventions to interrupt transmission. PMID- 30485281 TI - Iodine status of children and knowledge, attitude, practice of iodised salt use in a remote community in Kerema district, Gulf province, Papua New Guinea. AB - Iodine deficiency is the single most common cause of preventable mental impairment in communities with suboptimal iodine intake. Objective of the present study was to assess in more detail the iodine status and knowledge, attitudes and practice (KAP) relating to use of iodised salt in a remote community in Kotidanga area, Kerema district, Gulf province, Papua New Guinea. This prospective school and community based cross-sectional study was carried out in 2017. Simple random sampling was used to select schools. Multistage sampling was used to randomly select 300 children aged 6 to 12 years, of which 289 consented to participate in the study. A single urine sample was collected from each of the consenting children, as well as a salt sample from their households. Discretionary salt intake was assessed in a sub-sample of the children's households. Salt iodine content and urinary iodine concentration (UIC) were analysed. A semi-structured modified Food and Agriculture Organisation questionnaire was used to assess KAP of three different community groups. Only 64% of households had salt on the day of data collection. Mean iodine content in household salt samples was 29.0 +/- 19.1 ppm. Iodine content was below 30.0 ppm in 54.8% and below 15.0 ppm in 31.2% of salt samples. Mean per capita discretionary intake of household salt was 2.9 +/- 1.8 g/day. Median UIC was 25.5 MUg/L and Interquartile Range was 15.0 to 47.5 MUg/L, indicating moderate status iodine nutrition. Median UIC was 34.3 MUg/L for children in households with salt, compared to 15.5 MUg/L for children in households without salt, indicating severe iodine deficiency in the latter group. The three community groups had limited knowledge about importance of using iodised salt and consequences of iodine deficiency on health outcomes. This remote community has limited access to adequately iodised household salt due to high cost, inappropriate packaging, storage and food preparation, resulting in iodine deficiency. Strategies to increase iodine intake are needed. PMID- 30485282 TI - Theaflavins, polyphenols of black tea, inhibit entry of hepatitis C virus in cell culture. AB - The treatment of hepatitis C virus (HCV) infection by combination of direct acting antivirals (DAA), with different mode of action, has made substantial progress in the past few years. However, appearance of resistance and high cost of the therapy is still an obstacle in the achievement of the therapy, more specifically in developing countries. In this context, search for affordable antivirals with new mechanisms of action is still needed. Tea, after water, is the most popular drink worldwide. Polyphenols extracted from green tea have already shown anti-HCV activity as entry inhibitors. Here, three different theaflavins, theaflavin (TF1), theaflavin-3'-monogallate (TF2), and theaflavin-3 3'-digallate (TF3), which are major polyphenols from black tea, were tested against HCV in cell culture. The results showed that all theaflavins inhibit HCV infection in a dose-dependent manner in an early step of infection. Results obtained with HCV pseudotyped virions confirmed their activity on HCV entry and demonstrated their pan-genotypic action. No effect on HCV replication was observed by using HCV replicon. Investigation on the mechanism of action of black tea theaflavins showed that they act directly on the virus particle and are able to inhibit cell-to-cell spread. Combination study with inhibitors most widely used in anti-HCV treatment regimen demonstrated that TF3 exerts additive effect. In conclusion, theaflavins, that are present in high quantity in black tea, are new inhibitors of HCV entry and hold promise for developing in therapeutic arsenal for HCV infection. PMID- 30485283 TI - The burden of dyslipidaemia and factors associated with lipid levels among adults in rural northern Ghana: An AWI-Gen sub-study. AB - Dyslipidaemia is a primary risk factor for cardiometabolic disease, causing over 17 million deaths globally in 2015. However, the burden of dyslipidaemia and factors associated with lipid levels remain unknown in many rural African populations. Therefore, this study evaluated the association of socio demographic, anthropometric and behavioural factors with lipid levels in rural Ghana. The prevalence of hypercholesterolaemia, hypertriglyceridaemia and elevated LDL-C in the total population of 1839 (846 men and 993 women) was 4.02%, 2.12%, and 5.55% respectively and did not differ between genders. The prevalence of low HDL-C levels was 60.30% and differed (p = 0.005) between men (56.86%) and women (63.24%). Subcutaneous abdominal fat was associated with TC (beta = 0.067, p = 0.015) and TG (beta = 0.137, p<0.001) among women and LDL-C (beta = 0.139, p = 0.006) and TC (beta = 0.071, p = 0.048) among men. Body mass index was associated with TC (beta = 0.010, p = 0.043) among men while waist circumference was associated with LDL-C (beta = 0.116, p<0.001) and TG (beta = 0.094, p<0.001) among women. Hip circumference was negatively associated (beta = -0.053, p = 0.043) while visceral fat was positively associated with TG (beta = 0.033, p = 0.022) among women. Socioeconomic status, education, being unmarried and employment were associated with HDL-C (beta = 0.081, p = 0.004), LDL-C (beta = 0.095, p = 0.004) and TG (beta = 0.095, p = 0.001) all among women, and TC (beta = 0.070, p = 0.010) among men, respectively. Nankana women had lower TC (beta = 0.069, p = 0.001), and men lower TG levels (beta = -0.084, p = 0.008) than the other ethnic groups. Tobacco smoking (beta = 0.066, p = 0.024) and alcohol intake (beta = 0.084, p = 0.001) were associated with HDL-C levels among men and women respectively. Further studies are required to investigate whether high prevalence of low HDL-C levels in this population presents with any adverse cardiovascular disease outcomes. Associations of education, employment and adiposity with lipid levels suggest that future societal advances and increases in the prevalence of obesity may lead to associated adverse health consequences. Monitoring and interventions are required to limit these effects. PMID- 30485285 TI - Reinterpretation of an endangered taxon based on integrative taxonomy: The case of Cynara baetica (Compositae). AB - The Strait of Gibraltar, the gateway between the Atlantic Ocean and the Mediterranean Sea, has a convulsive geological history, with recurring closing and opening events since the late Miocene. As a consequence, this region has played a major role in the evolutionary history of many species. Cynara baetica (Compositae) is a diploid perennial herb distributed in both sides of this strait. It is currently subdivided into two subspecies: C. baetica subsp. baetica for the Spanish populations, and C. baetica subsp. maroccana for the Moroccan ones. Following three different approximations of species delimitation, including phylogenetic and population genetic analyses (based on three AFLP primer combinations and two intergenic spacers of cpDNA), ecological niche modeling (ENM) and morphological studies, this taxon is investigated and reinterpreted. The results obtained showed a clear genetic, morphological and ecological differentiation between the two taxa and the important role played by the Strait of Gibraltar as a geographical barrier. Based on this evidence, the current taxonomic treatment is modified (both taxa should recover their specific rank) and specific conservation guidelines are proposed for the newly delimited taxa. PMID- 30485284 TI - Validation of the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) heart failure risk score and the effect of adding natriuretic peptide for predicting mortality after discharge in hospitalized patients with heart failure. AB - BACKGROUND: In clinical practice, a risk prediction model is an effective solitary program to predict prognosis in particular patient groups. B-type natriuretic peptide (BNP)and N-terminal pro-b-type natriuretic peptide (NT proBNP) are widely recognized outcome-predicting factors for patients with heart failure (HF).This study derived external validation of a risk score to predict 1 year mortality after discharge in hospitalized patients with HF using the Meta analysis Global Group in Chronic Heart Failure (MAGGIC)program data. We also assessed the effect of adding BNP or NT-proBNP to this risk score model in a Korean HF registry population. METHOD AND RESULTS: We included 5625 patients from the Korean acute heart failure registry (KorAHF) and excluded those who died in hospital. The MAGGIC constructed a risk score to predict mortality in patients with HF by using 13 routinely available patient characteristics (age, gender, diabetes, chronic obstructive pulmonary disorder (COPD), HF diagnosed within the last 18 months, current smoker, NYHA class, use of beta blocker, ACEI or ARB, body mass index, systolic blood pressure, creatinine, and EF). We added BNP or NT proBNP, which are the most important biomarkers, to the MAGGIC risk scoring system in patients with HF. The outcome measure was 1-year mortality. In multivariable analysis, BNP or NT-proBNP independently predicted death. The risk score was significantly varied between alive and dead groups (30.61 +/- 6.32 vs. 24.80 +/- 6.81, p < 0.001). After the conjoint use of BNP or NT-proBNP and MAGGIC risk score in patients with HF, a significant difference in risk score was noted (31.23 +/- 6.46 vs. 25.25 +/- 6.96, p < 0.001).The discrimination abilities of the risk score model with and without biomarker showed minimal improvement (C index of 0.734 for MAGGIC risk score and 0.736 for MAGGIC risk score plus BNP or NT-proBNP, p = 0.0502) and the calibration was found good. However, we achieved a significant improvement in net reclassification and integrated discrimination for mortality (NRI of 33.4%,p < 0.0001 and IDI of 0.002, p < 0.0001). CONCLUSION: In the KorAHF, the MAGGIC project HF risk score performed well in a large nationwide contemporary external validation cohort. Furthermore, the addition of BNP or NT proBNPto the MAGGIC risk score was beneficial in predicting more death in hospitalized patients with HF. PMID- 30485286 TI - LC-MS/MS analysis of the dog serum phosphoproteome reveals novel and conserved phosphorylation sites: Phosphoprotein patterns in babesiosis caused by Babesia canis, a case study. AB - Phosphorylation is the most commonly studied protein post-translational modification (PTM) in biological systems due to its importance in controlling cell division, survival, growth, etc. Despite the thorough research in phosphoproteomics of cells and tissues there is little information on circulating phosphoproteins. We compared serum from 10 healthy dogs and 10 dogs affected by B. canis-caused babesiosis with no organ dysfunctions by employing gel-free LC MS/MS analysis of individual samples and tandem mass tag (TMT) label-based quantitative analyses of pools, both supported by phosphopeptide enrichment. Results showed a moderate number of phosphorylated proteins (50-55), with 89 phosphorylation sites not previously published for dogs although a number of them matched phosphorylation sites found in mammalian orthologs. Three phosphopeptides showed significant variation in babesiosis-affected dog sera compared to controls: Serum amyloid A (SAA) phosphorylated at serine 101 (up-regulation), kininogen 1 phosphorylated at threonine 326, and fibrinogen alpha phosphorylated at both threonine 20 and serine 22 (down-regulation). 71.9% of the detected phosphorylated sites were phosphoserine, 16.8% phosphothreonine and only 11.2% phosphotyrosine residues. TMT label-based quantitative analysis showed alpha-2-HS glycoprotein / Fetuin A to be the most abundant phosphoprotein (50-70% of all phosphoproteins) followed by kininogen-1 (10-20%). The alterations of phosphorylated proteins observed in canine babesiosis caused by Babesia canis suggest new insights into the largely neglected role of extracellular protein phosphorylation in health and disease, encouraging urgent further research on this area. To the best of our knowledge the present study represents the first attempt to characterize canine serum phosphoproteome. PMID- 30485288 TI - An experimental examination of object-directed ritualized action in children across two cultures. AB - Ritualized actions are common in daily life, and prevalent across cultures. Adults have been shown, under experimental conditions, to treat objects subjected to ritualized action as special and different relative to objects subjected to non-ritualized action. Similarly, children as young as 4, are sensitive to ritualized actions-frequently reproducing such actions at high fidelity. The current cross-cultural experiment attempts to extend existing findings among two culturally distinct groups of children with regard to object-directed rituals. We predicted that children's preference for a reward would be influenced by ritualized action (but not non-ritualized action). Over two trials we presented children in Australia (N = 93; mean age = 6.03 years, SD = 2.07 years) and Vanuatu (N = 109; mean age = 6.13 years, SD = 1.96 years) with two identical rewards, which was either subjected to ritualized action or non-ritualized action. Contrary to previous findings among adults, ritualized action did not influence children's preference for a reward. We frame the current results in the context of socially relevant group rituals, and discuss the implications for both wider theory and methods. We conclude with a call for pre-registered replications. PMID- 30485287 TI - Fine Endmesolithic fish caviar meal discovered by proteomics in foodcrusts from archaeological site Friesack 4 (Brandenburg, Germany). AB - The role of aquatic resources in ancient economies and paleodiet is important for understanding the evolution of prehistorical societies. Charred food remains from ancient pottery are valuable molecular evidence of dietary habits in antiquity. However, conventional archaeometric approaches applied in their analysis lack organismal specificity, are affected by abundant environmental contaminants, do not elucidate food processing recipes and are limited in the inland regions where diverse dietary resources are available. We performed proteomics analysis of charred organic deposits adhered on early ceramics from Mesolithic-Neolithic inland site Friesack 4 (Brandenburg, Germany). One of pots-a small coarse bowl radiocarbon dated to the end of the 5th millennium BC-was attributed to Endmesolithic pottery. Proteomics of foodcrust from this vessel identified fine carp roe meal and revealed details of a prehistorical culinary recipe. Ancient proteins were unequivocally distinguished from contemporary contaminants by computing deamidation ratios of glutamine residues. These data paint a broader picture of the site-specific exploitation of aquatic resources and contribute to better understanding of the dietary context of Neolithic transition in European inland. PMID- 30485289 TI - Basic color categories and Mandarin Chinese color terms. AB - Basic color terms used in Mandarin Chinese have been controversial since first discussed by Berlin and Kay in 1969. Previous studies showed much inconsistency on what should be considered as basic color terms in Mandarin Chinese. In the present study, we investigated categories of color rather than merely the color terms used by Taiwanese native Mandarin speakers. Using samples conforming to the Berlin and Kay survey, various colors were chosen from a collection of Natural Color System (NCS) colored papers and mounted on a piece of neutral gray card. The card was then mounted on a touch-screen, under D65 illumination. Thirty-two single-character color related Mandarin terms were selected from a Chinese character database according to frequency of use. Participants were required to select the color sample that matched the term by pressing a virtual button on the touch screen. The results show that certain terms can be directly correlated to basic color terms in English, comparable with the results of Berlin and Kay's original study and those that followed. However, some terms, such as Mo ( ink), Tie ( iron), and Cai (vegetable), show a wide spread of term maps and inconsistent use among subjects. Principle component analysis (PCA) procedures were used to analysis the commodity of data among subjects. The findings suggest that the basic color categories among Mandarin Chinese speakers are similar to those found in the World Color Survey (WCS), but are represented by wide-spread and inconsistent color terms among speakers. PMID- 30485290 TI - Patterns of brown bear damages on apiaries and management recommendations in the Cantabrian Mountains, Spain. AB - Large carnivores are often persecuted due to conflict with human activities, making their conservation in human-modified landscapes very challenging. Conflict related scenarios are increasing worldwide, due to the expansion of human activities or to the recovery of carnivore populations. In general, brown bears Ursus arctos avoid humans and their settlements, but they may use some areas close to people or human infrastructures. Bear damages in human-modified landscapes may be related to the availability of food resources of human origin, such as beehives. However, the association of damage events with factors that may predispose bears to cause damages has rarely been investigated. We investigated bear damages to apiaries in the Cantabrian Mountains (Spain), an area with relatively high density of bears. We included spatial, temporal and environmental factors and damage prevention measures in our analyses, as factors that may influence the occurrence and intensity of damages. In 2006-2008, we located 61 apiaries, which included 435 beehives damaged in the study area (346 km2). The probability of an apiary being attacked was positively related to both the intensity of the damage suffered the year before and the distance to the nearest damaged apiary, and negatively related to the number of prevention measures employed as well as the intensity of the damage suffered by the nearest damage apiary. The intensity of damage to apiaries was positively related to the size of the apiary and to vegetation cover in the surroundings, and negatively related to the number of human settlements. Minimizing the occurrence of bear damages to apiaries seems feasible by applying and maintaining proper prevention measures, especially before an attack occurs and selecting appropriate locations for beehives (e.g. away from forest areas). This applies to areas currently occupied by bears, and to neighbouring areas where dispersing individuals may expand their range. PMID- 30485291 TI - Exploring the spatial heterogeneity in different doses of vaccination coverage in India. AB - BACKGROUND: Despite the universalization of immunization against the six vaccine preventable diseases (VPDs), the coverage of full immunization among the children under age five has remained a challenge globally. The 2015-16 National Family Health Survey (NFHS) indicated large disparity in the coverage of different vaccination doses (BCG, Polio, DPT and Measles) including full immunization across the districts of India. The spatial distribution of poor performing districts in terms of vaccination and the district level spatial, contextual determinants contributing to the low coverage have been poorly studied. Using the recent household survey (NFHS, 2015-16), this study examined the spatial heterogeneity and the factors associated with low vaccination coverage among the children aged 12-23 months across India. DATA AND METHODS: This study used the data from fourth round of National Family Health Survey conducted in 2015-16. District-level prevalence of each of the vaccination doses including full immunization, were analysed. Moran's I, Univariate and Bivariate LISA, Ordinary least square (OLS) and spatial models were employed to achieve the overall aim of the study. RESULTS: At the national level, the prevalence of full immunization was 62 percent. Specific vaccination coverage for BCG, three doses of polio, three doses of DPT and measles were 92, 73, 78 and 81 percent, respectively. The value of the bivariate Moran's I statistics confirmed the spatial dependence between specific vaccination and the set of independent variables. District-level prevalence of the specific vaccine and full immunization showed significant spatial clustering across India. The adjusted coefficients from the spatial error model confirmed that district-level proportion of utilization of post-natal care, institutional births, neonatal tetanus protection of the last birth, women's education and coverage of health insurance showed statistically significant association with every doses of vaccination coverage. CONCLUSION: The full and specific immunization coverage was considerably low in the geographical hotspots as compared to the national coverage. Maternal and child health care services utilization, financial assistance to the mothers through JSY scheme and mother's education were found to determine full immunization as well as the specific vaccination coverage. Appropriate intervention should be designed to reduce the geographical disparity in the coverage of specific and full immunization across India and thus safeguard child health protecting the children from the vaccine preventable diseases across the geography. PMID- 30485292 TI - Risk of poultry compartments for transmission of Highly Pathogenic Avian Influenza. AB - When outbreaks of Highly Pathogenic Avian Influenza (HPAI) occur in OIE member countries with until then disease-free status, member countries can use 'compartmentalisation'. A compartment may be defined as a subset of farms under a common management system, complying with certain stringent surveillance, control and biosecurity measures, and based on that may receive a disease-free status. Based on this disease-free status the compartment is exempted from certain transport restrictions coming into force in case of outbreaks occurring in the country. For deciding whether a candidate compartment is granted official compartment status, it is relevant to assess the additional HPAI transmission risks that would arise due to the exemptions granted. These risks consist of both additional local transmission risks as well as the additional risk of a 'jump' of HPAI infection from one poultry area, via the compartment, to another area. Here such risk assessment is carried out using a spatial mathematical model for between-farm transmission in the Netherlands, yielding insight in the roles of compartment composition and contact structure and identify relevant evaluation criteria for granting HPAI compartment status. At the core of this model are transmission probabilities associated with indirect between-farm contacts, e.g. through feed delivery, egg collection and professional visitors. These probabilities were estimated from Dutch epidemic outbreak data in earlier work. The additional risk of a jump of HPAI from one area, via the compartment, to another area is calculated relative to the direct jump risk. The results show that additional transmission risks caused by a compartment to other farms are mainly dependent on the distance of densely populated poultry areas (DPPAs) to the nearest compartment farm. Apart from conditions on these distances, we also recommend specific routing requirements for transport and other movements within the compartment. PMID- 30485293 TI - Gas injection and brine discharge in rock salt gas storage studied via numerical simulation. AB - Underground gas storage in rock salt is of great importance for peak-shaving and emergency gas supply. This paper addressed an actual rock salt underground gas storage facility in Jiangsu province, China, as the research project and carried out the following research centered on a detailed geological model, a salt cavern model and the process of gas injection and brine discharge. First, based on the theory of gas-liquid two-phase flow, the authors established a relationship between brine flow and natural gas bubbles under high pressure in the process of brine discharge. Second, the effect of pipe depth on the gas injection and brine discharge was simulated. The objective was mainly to choose the best combination of pipe depth and rate of brine discharge flow based on analysis of the relationship between the brine discharge pipe depth and the flow rate of the residual brine, and the optimal rate was given according to different distances. Third, the effect of residual brine on the gas injection and brine discharge was analyzed. The relationship curves between the maximum velocity on the surface of brine and the distance from the lower end of the brine discharge pipe to the bottom of the gas storage were obtained, and reasonable rates were suggested under different actual working conditions. PMID- 30485294 TI - Preservation potential of keratin in deep time. AB - Multiple fossil discoveries and taphonomic experiments have established the durability of keratin. The utility and specificity of antibodies to identify keratin peptides has also been established, both in extant feathers under varying treatment conditions, and in feathers from extinct organisms. Here, we show localization of feather-keratin antibodies to control and heat-treated feathers, testifying to the repeatability of initial data supporting the preservation potential of keratin. We then show new data at higher resolution that demonstrates the specific response of these antibodies to the feather matrix, we support the presence of protein in heat-treated feathers using ToF-SIMS, and we apply these methods to a fossil feather preserved in the unusual environment of sinter hot springs. We stress the importance of employing realistic conditions such as sediment burial when designing experiments intended as proxies for taphonomic processes occurring in the fossil record. Our data support the hypothesis that keratin, particularly the beta-keratin that comprises feathers, has potential to preserve in fossil remains. PMID- 30485295 TI - Dopamine production in Enterococcus faecium: A microbial endocrinology-based mechanism for the selection of probiotics based on neurochemical-producing potential. AB - The mechanisms by which probiotics may influence host physiology are still incompletely understood. Microbial endocrinology, a field representing the union of microbiology, endocrinology and neurobiology, has theorized that microorganisms have the capacity to serve as neurochemical delivery vehicles [1]. According to microbial endocrinology, neurochemicals can serve as a common language between host and bacterium, enabling bidirectional communication. We report herein the first demonstration that Enterococcus sp. has the capacity to produce dopamine in a gastrointestinal-like environment when supplied with the dopamine precursor L-3,4 dihydroxyphenylalanine (L-dopa). The results presented herein provide a means to select probiotics based on neurochemical-producing potential and suggest the possibility that probiotics containing E. faecium may serve to influence the host through dopaminergic pathways. PMID- 30485296 TI - Network assessment of demethylation treatment in melanoma: Differential transcriptome-methylome and antigen profile signatures. AB - BACKGROUND: In melanoma, like in other cancers, both genetic alterations and epigenetic underlie the metastatic process. These effects are usually measured by changes in both methylome and transcriptome profiles, whose cross-correlation remains uncertain. We aimed to assess at systems scale the significance of epigenetic treatment in melanoma cells with different metastatic potential. METHODS AND FINDINGS: Treatment by DAC demethylation with 5-Aza-2'-deoxycytidine of two melanoma cell lines endowed with different metastatic potential, SKMEL-2 and HS294T, was performed and high-throughput coupled RNA-Seq and RRBS-Seq experiments delivered differential profiles (DiP) of both transcriptomes and methylomes. Methylation levels measured at both TSS and gene body were studied to inspect correlated patterns with wide-spectrum transcript abundance levels quantified in both protein coding and non-coding RNA (ncRNA) regions. The DiP were then mapped onto standard bio-annotation sources (pathways, biological processes) and network configurations were obtained. The prioritized associations for target identification purposes were expected to elucidate the reprogramming dynamics induced by the epigenetic therapy. The interactomic connectivity maps of each cell line were formed to support the analysis of epigenetically re-activated genes. i.e. those supposedly silenced by melanoma. In particular, modular protein interaction networks (PIN) were used, evidencing a limited number of shared annotations, with an example being MAPK13 (cascade of cellular responses evoked by extracellular stimuli). This gene is also a target associated to the PANDAR ncRNA, therapeutically relevant because of its aberrant expression observed in various cancers. Overall, the non-metastatic SKMEL-2 map reveals post-treatment re-activation of a richer pathway landscape, involving cadherins and integrins as signatures of cell adhesion and proliferation. Relatively more lncRNAs were also annotated, indicating more complex regulation patterns in view of target identification. Finally, the antigen maps matched to DiP display other differential signatures with respect to the metastatic potential of the cell lines. In particular, as demethylated melanomas show connected targets that grow with the increased metastatic potential, also the potential target actionability seems to depend to some degree on the metastatic state. However, caution is required when assessing the direct influence of re-activated genes over the identified targets. In light of the stronger treatment effects observed in non metastatic conditions, some limitations likely refer to in silico data integration tools and resources available for the analysis of tumor antigens. CONCLUSION: Demethylation treatment strongly affects early melanoma progression by re-activating many genes. This evidence suggests that the efficacy of this type of therapeutic intervention is potentially high at the pre-metastatic stages. The biomarkers that can be assessed through antigens seem informative depending on the metastatic conditions, and networks help to elucidate the assessment of possible targets actionability. PMID- 30485297 TI - Does walking protect against decline in cognitive functioning among breast cancer patients undergoing chemotherapy? Results from a small randomised controlled trial. AB - BACKGROUND: Cancer related cognitive impairments have been subjectively reported and objectively detected in breast cancer patients treated with chemotherapy and are known to have a profound negative impact on productivity, psychosocial well being and overall quality of life. Moderate levels of walking are known to be of benefit to the psychosocial well-being of those affected by breast cancer and for managing cognitive impairment in healthy adults, children, and the elderly. The purpose of this study is to investigate the effects of a home-based, self managed, moderate intensity walking intervention on subjective and objective cognitive functioning in breast cancer patients undergoing chemotherapy. METHODS: A home-based, self-managed intervention that consisted of moderate levels of walking was compared to usual care among breast cancer patients treated with chemotherapy in a randomised controlled trial. Outcome measures included changes in subjective (CFQ) and objectively detected cognitive functioning (Stroop, SART and two subscales from the WAIS- Digit Span and Block Design). Fifty participants were randomised to either the intervention group (n = 25), who completed 12 weeks of moderate intensity walking, or to the control group (n = 25) mid-way through chemotherapy. RESULTS: Compared with the control group, the self-managed walking intervention had positive effects on perceived cognitive function but not on sustained attention, executive function, memory or visual spatial skills when assessed objectively using neuropsychological measures. CONCLUSION: This home based, self-managed intervention is beneficial for protecting against perceived cognitive decline in breast cancer patients treated with chemotherapy. There is a need for further research to objectively assess cognitive decline within this population with larger sample sizes of patients. TRIAL REGISTRATION: Current Controlled Trials ISRCTN50709297. PMID- 30485298 TI - Functional architecture of the foveola revealed in the living primate. AB - The primate foveola, with its high cone density and magnified cortical representation, is exquisitely specialized for high-resolution spatial vision. However, uncovering the wiring of retinal circuitry responsible for this performance has been challenging due to the difficulty in recording receptive fields of foveal retinal ganglion cells (RGCs) in vivo. In this study, we use adaptive optics scanning laser ophthalmoscopy (AOSLO) to image the calcium responses of RGCs in the living primate, with a stable, high precision visual stimulus that allowed us to localize the receptive fields of hundreds of foveal ganglion cells. This approach revealed a precisely radial organization of foveal RGCs, despite the many distortions possible during the extended developmental migration of foveal cells. By back projecting the line connecting RGC somas to their receptive fields, we have been able to define the 'physiological center' of the foveola, locating the vertical meridian separating left and right hemifields in vivo. PMID- 30485299 TI - Validity and reliability of the Beck Depression Inventory II (BDI-II) in family caregivers of children with chronic diseases. AB - BACKGROUND: Information on the psychometric properties of the Beck Depression Inventory II (BDI-II) in family caregivers of children with chronic diseases is currently unavailable, indicating a significant gap in the literature. Therefore, we investigated 1) which of the five evaluated measurement models had the best fit, 2) the scale's reliability, and 3) the scale's convergent validity. METHODS: In 2018, a cross-sectional ex post facto study with non-probability convenience sampling was conducted in 446 family caregivers of children with chronic diseases at the National Institute of Health in Mexico City; the family caregivers responded to the BDI-II and a battery of instruments measuring anxiety, caregiver burden, parental stress, well-being, and quality of life. A confirmatory factor analysis was conducted to determine the fit of the five models. Cronbach's alpha and composite reliability were calculated to assess the scale's reliability, and Spearman's rank correlation was used to investigate the scale's convergent validity. RESULTS: This study provided evidence that the two-factor somatic affective and cognitive model had the best fit. The BDI-II demonstrated adequate reliability and evidence of convergent validity, as the BDI-II factors were positively correlated with anxiety, caregiver burden, and parental stress and negatively correlated with well-being and quality of life. CONCLUSIONS: The findings reveal that the BDI-II is a valid, reliable, and culturally relevant instrument to measure depression in family caregivers of children with chronic diseases. PMID- 30485300 TI - Determining factors for the increase in self-referrals to the Emergency Department of a rural hospital in Huelva (Spain). AB - OBJECTIVE: To analyse the increase of self-referral patients at the Emergency Department of Riotinto District Hospital (in Huelva, Spain) during a short period. The study focused on patients' profiles to identify key factors that explained the increase of self-referrals. MATERIAL AND METHODS: Retrospective descriptive study using patient's data from a hospital emergency department between 2003-2015, excluding the period 2012-14 due to the lack of records. Socio demographic variables, type of referral, access to health services, hospital route, transfer time and organisational changes were analysed, among other factors. Descriptive statistics, chi-square test, and binary logistic regression analysis were used. RESULTS: Self-referral patients to the hospital emergency department revealed a growing trend. Logistic regression model showed that the variables that best predict its occurrence were the health system changes from 2008 and the time it takes to get to the Extra-hospital Emergency Services, where those changes act as modifiers of the effect. From 2008, the likelihood of self referral in towns with an Extra-hospital Emergency Service over 2 minutes away by car was of 76.43%. When including the triage level, the logistic regression model showed that 83.1% of patients referred themselves. CONCLUSIONS: Changes in the health system and in the time for patients to get to the reference hospital from their origin, affect the likelihood of self-referral to the emergency department. Once the patient's severity level was included, this variable, along with the time to get to the emergency department, modified the probability of self referral to the emergency department. We found an increase in hospital services together with a reduction of resources in the primary care emergency system. This may have led to inefficiencies in the public health system, together with an increase in self-referrals and greater problems to service users. PMID- 30485301 TI - Mark-release-recapture meets Species Distribution Models: Identifying micro habitats of grassland butterflies in agricultural landscapes. AB - Habitat demands and species mobility strongly determine the occurrence of species. Sedentary species with specific habitat requirements are assumed to occur more patchy than mobile habitat generalist species, and thus suffer stronger under habitat fragmentation and habitat deterioration. In this study we measured dispersal and habitat preference of three selected butterfly species using mark-release-recapture technique. We used data on species abundance to calculate Species Distribution Models based on high-resolution aerial photographs taken using RGB / NIR cameras mounted on a UAV. We found that microhabitats for species with specific habitat requirements occur spatially restricted. In contrast, suitable habitats are more interconnected and widespread for mobile habitat generalists. Our models indicate that even managed grassland sites have comparatively little habitat quality, while road verges provide high quality micro-habitats. In addition, dispersal was more restricted for specialist butterfly species, and higher for the two other butterfly species with less ecological specialisation. This study shows synergies arising when combining ecological data with high precision aerial pictures and Species Distribution Models, to identify micro-habitats for butterflies. This approach might be suitable to identify and conserve high quality habitats, and to improve nature conservation at the ground. PMID- 30485302 TI - Standardization of medical service indicators: A useful technique for hospital administration. AB - BACKGROUND: Many comparability problems appear in the process of the performance assessment of medical service. When comparing medical evaluation indicators across hospitals, or even within the same hospital, over time, the differences in the population composition such as types of diseases, comorbidities, demographic characteristics should be taken into account. This study aims to introduce a standardization technique for medical service indicators and provide a new insight on the comparability of medical data. METHODS: The medical records of 142592 inpatient from three hospitals in 2017 were included in this study. Chi square and Kruskal-Wallis tests were used to explore the compositions of confounding factors among populations. The procedure of stratified standardization technique was applied to compare the differences of the average length of stay and the average hospitalization expense among three hospitals. RESULTS: Age, gender, comorbidity, and principal diagnoses category were considered as confounding factors. After correcting all factors, the average length of stay of hospital A and C were increased by 0.21 and 1.20 days, respectively, while that of hospital B was reduced by 1.54 days. The average hospitalization expenses of hospital A and C were increased by 1494 and 660 Yuan, whilst that of hospital B was decreased by 810 Yuan. CONCLUSIONS: Standardization method will be helpful to improve the comparability of medical service indicators in hospital administration. It could be a practical technique and worthy of promotion. PMID- 30485303 TI - Relative robustness of NOEC and ECx against large uncertainties in data. AB - The relative ability of the NOEC (no-observed-effect concentration) and ECx (the effect concentration corresponding to x-percent response) to determine benchmark toxicant concentrations, which are expected to ensure environmental safety, when there are large uncertainties in data was investigated with Monte Carlo simulations. We assumed a hypothetical true concentration-response function, and examined how random fluctuations of responses around the true responses affected the NOEC and ECx values. For assessment of the relative performances of these endpoints, we adopted two criteria: how large uncertainties were allowed for the minimum requirement for safety to be met, and the probability with which the estimated endpoints exceeded the minimum requirement for safety. The results of simulations indicated that, when there were small uncertainties in the data, performance of the NOEC was comparable with or slightly better than the ECx (EC5 and EC10) in providing benchmark concentrations that satisfied the minimum requirement for safety. With larger random variation of data (the coefficient of variation in responses between replicates within treatments or in the control was noticeably larger than 10 percent), the NOEC performed considerably worse than the ECx in terms of the frequency of simulated runs in which the endpoints exceeded the minimum requirement of safety. We conclude that the NOEC is as relevant as the ECx for risk assessment of chemicals under limited situations. PMID- 30485304 TI - Real-world unexpected outcomes predict city-level mood states and risk-taking behavior. AB - Fluctuations in mood states are driven by unpredictable outcomes in daily life but also appear to drive consequential behaviors such as risk-taking. However, our understanding of the relationships between unexpected outcomes, mood, and risk-taking behavior has relied primarily upon constrained and artificial laboratory settings. Here we examine, using naturalistic datasets, how real-world unexpected outcomes predict mood state changes observable at the level of a city, in turn predicting changes in gambling behavior. By analyzing day-to-day mood language extracted from 5.2 million location-specific and public Twitter posts or 'tweets', we examine how real-world 'prediction errors'-local outcomes that deviate positively from expectations-predict day-to-day mood states observable at the level of a city. These mood states in turn predicted increased per-person lottery gambling rates, revealing how interplay between prediction errors, moods, and risky decision-making unfolds in the real world. Our results underscore how social media and naturalistic datasets can uniquely allow us to understand consequential psychological phenomena. PMID- 30485305 TI - What demographic attributes do our digital footprints reveal? A systematic review. AB - To what extent does our online activity reveal who we are? Recent research has demonstrated that the digital traces left by individuals as they browse and interact with others online may reveal who they are and what their interests may be. In the present paper we report a systematic review that synthesises current evidence on predicting demographic attributes from online digital traces. Studies were included if they met the following criteria: (i) they reported findings where at least one demographic attribute was predicted/inferred from at least one form of digital footprint, (ii) the method of prediction was automated, and (iii) the traces were either visible (e.g. tweets) or non-visible (e.g. clickstreams). We identified 327 studies published up until October 2018. Across these articles, 14 demographic attributes were successfully inferred from digital traces; the most studied included gender, age, location, and political orientation. For each of the demographic attributes identified, we provide a database containing the platforms and digital traces examined, sample sizes, accuracy measures and the classification methods applied. Finally, we discuss the main research trends/findings, methodological approaches and recommend directions for future research. PMID- 30485306 TI - Team reasoning-Experimental evidence on cooperation from centipede games. AB - Previous laboratory studies on the centipede game have found that subjects exhibit surprisingly high levels of cooperation. Across disciplines, it has recently been highlighted that these high levels of cooperation might be explained by "team reasoning", the willingness to think as a team rather than as an individual. We run an experiment with a standard centipede game as a baseline. In two treatments, we seek to induce team reasoning by making a joint goal salient. First, we implement a probabilistic variant of the centipede game that makes it easy to identify a joint goal. Second, we frame the game as a situation where a team of two soccer players attempts to score a goal. This frame increases the salience even more. Compared to the baseline, our treatments induce higher levels of cooperation. In a second experiment, we obtain similar evidence in a more natural environment-a beer garden during the 2014 FIFA Soccer World Cup. Our study contributes to understanding how a salient goal can support cooperation. PMID- 30485307 TI - CCN5 knockout mice exhibit lipotoxic cardiomyopathy with mild obesity and diabetes. AB - Obesity is associated with various human disorders, such as type 2 diabetes, cardiovascular diseases, hypertension, and cancers. In this study, we observed that knockout (KO) of CCN5, which encodes a matricellular protein, caused mild obesity in mice. The CCN5 KO mice also exhibited mild diabetes characterized by high fasting glucose levels and impaired insulin and glucose tolerances. Cardiac hypertrophy, ectopic lipid accumulation, and impaired lipid metabolism in hearts were observed in the CCN5 KO mice, as determined using histology, quantitative RT PCR, and western blotting. Fibrosis was significantly greater in hearts from the CCN5 KO mice both in interstitial and perivascular regions, which was accompanied by higher expression of pro-fibrotic and pro-inflammatory genes. Both systolic and diastolic functions were significantly impaired in hearts from the CCN5 KO mice, as assessed using echocardiography. Taken together, these results indicate that CCN5 KO leads to lipotoxic cardiomyopathy with mild obesity and diabetes in mice. PMID- 30485308 TI - Novelty upon novelty visualized by rotational scanning electron micrographs (rSEM): Laboulbeniales on the millipede order Chordeumatida. AB - Laboulbeniales are highly specific ectoparasitic fungi of arthropods (insects, millipedes, and arachnids). The first Laboulbeniales parasitizing the millipede order Chordeumatida (Diplopoda) were discovered and described as a new dioecious genus of Laboulbeniales, Thaxterimyces, to accommodate the new species T. baliensis. Also the millipede host is a new species and is described as Metopidiothrix sheari. This is the first time Laboulbeniales fungus and its millipede host are described as new together. Males of Metopidiothrix have the most extensive secondary sexual modifications in the entire class Diplopoda. Although nothing is known about the function of these modifications, the unique pattern of Laboulbeniales infection in the new millipede species is obviously related to host sexual behavior. Rotational Scanning Electron Micrographs (rSEM) are used to create a 3D comprehensive model to examine the fungal-host interaction, a more advanced visualization of the ectoparasitic fungus on its host. Laboulbeniales diversity on millipedes is still understudied, and a consistent effort is needed to unveil and understand the extent and diversity of this biological interaction. Due to their minute size and apparently non detrimental effect on their hosts, Laboulbeniales in general have been largely ignored by mycologists and neglected by generations of entomologists. As a result a significant component of global biodiversity has been strongly underestimated, and a wealth of new discoveries is still to be made both in the field and in existing museum collections. PMID- 30485309 TI - Behavioral thermoregulation in Locusta migratoria manilensis (Orthoptera: Acrididae) in response to the entomopathogenic fungus, Beauveria bassiana. AB - Insects such as locusts and grasshoppers can reduce the effectiveness of pathogens and parasites by adopting different defense strategies. We investigated the behavioral thermopreference of Locusta migratoria manilensis (Meyen) (Orthoptera: Acrididae) induced by the fungus Beauveria bassiana, and the impact this behavior had on the fungal mycosis under laboratory conditions. By basking in higher temperature locations, infected nymphs elevated their thoracic temperature to 30-32.6 degrees C, which is higher than the optimum temperature (25 degrees C) for B. bassiana conidial germination and hyphal development. A minimum thermoregulation period of 3 h/day increased survival of infected locusts by 43.34%. The therapeutic effect decreased when thermoregulation was delayed after initial infection. The fungus grew and overcame the locusts as soon as the thermoregulation was interrupted, indicating that thermoregulation helped the insects to cope with infection but did not completely rid them of the fungus. A significant enhancement in the number of haemocytes was observed in infected thermoregulating locusts, reaching levels that were even higher than those observed in the controls. In contrast, haemocyte concentration was severely reduced in infected insects that did not thermoregulate. In infected non thermoregulating locusts, the reduction in haemocyte number was accompanied by an increase in fungal blastospore concentration that was obvious in the haemolymph by day four. In contrast, no circulating blastospores were found in the haemolymph of infected thermoregulating locusts three days post-inoculation. We also examined the phagocytic activity of infected insects in vivo by using fluorescein isothiocyanate (FITC)-labelled silica beads. The proportion of beads that was engulfed by haemocytes in infected, thermoregulating insects was similar to that in the controls throughout the experiment, whereas the rate of phagocytosis in infected, non-thermoregulating insects progressively decreased after infection. These findings demonstrated that behavioural thermoregulation can adversely affect B. bassiana mycosis in infected L. migratoria manilensis, thereby limiting the development of lethal entomopathogenic fungi in locusts. This is apparently accomplished through an increase in the levels of haemocytes, leading to greater phagocytic activity under certain environmental conditions. PMID- 30485310 TI - How are different levels of knowledge about physical activity associated with physical activity behaviour in Australian adults? AB - People with knowledge of the benefits of physical activity tend to be more active; however, such knowledge is typically operationalized as a basic understanding that physical activity is 'good' for health. Therefore, the aim of this study was to investigate whether there are differences in how detailed a person's knowledge is about the benefits of physical activity. Participants (N = 615) completed an online survey to measure their current physical activity behaviour, as well as their level of knowledge of the benefits and risks of physical (in)activity. The majority of participants (99.6%) strongly agreed that physical activity is good for health, however on average, participants only identified 13.8 out of 22 diseases associated with physical inactivity and over half of participants (55.6%) could not identify how much physical activity is recommended for health benefits. Furthermore, 45% of the participants overestimated, 9% underestimated and 27% did not know the increased risk of disease resulting from inactivity as indicated by the Australian Department of Health. Participants were significantly more active when they correctly identified more diseases associated with physical inactivity and when they overestimated the risks associated with inactivity. Therefore, health promotion initiatives should increase knowledge of the types of diseases associated with inactivity. Low knowledge of physical activity guidelines suggest they should be promoted more, as this knowledge provides guidance on frequency, types and duration of physical activity needed for health. PMID- 30485311 TI - Stigma and Ebola survivorship in Liberia: Results from a longitudinal cohort study. AB - BACKGROUND: Survivors of the 2014-2016 West Africa Ebola epidemic have been reported to suffer high levels of stigmatization after return to their communities. We sought to characterize the stigma encountered by a cohort of Ebola survivors in Liberia over time. METHODS: Ebola-related stigma was assessed from June 2015 to August 2017 in 299 adolescent and adult Liberian Ebola Survivor Cohort participants at three month intervals using adapted HIV stigma scales scored from 0 to 10 according to the proportion of answers indicating stigmatization. FINDINGS: The median time from Ebola Virus Disease (EVD) to study entry was 393 days (IQR 336-492). Participants (43% female) had a median age of 31 (IQR 25-40) years. Mean self-reported stigma levels were greater at baseline (6.28 +/- 0.15 [IQR: 4.38-8.75]) compared to the first post-baseline visit (0.60 +/- 0.10 [IQR: 0-0]; p<0.0001). During follow-up, stigma levels were stable. Baseline stigma significantly increased during enrollment and following clusters of Ebola re-emergence in Liberia. Survivors encountered primarily enacted and perceived external stigma rather than internalized stigma. CONCLUSIONS: Ebola related stigma was prevalent among Liberian survivors more than a year after EVD recovery. Self-reported stigma was greater in the period before cohort enrollment; however, some degree of stigmatization persisted years after EVD. Transient rises in stigma were observed following episodic Ebola re-emergence of EVD in Liberia. During future EVD outbreaks, enhanced public health interventions designed to prevent and mitigate Ebola-related stigma that is enacted and external should be implemented to support survivor recovery and community re integration. PMID- 30485312 TI - A view to a kill? - Ambient bacterial load of frames and lenses of spectacles and evaluation of different cleaning methods. AB - Surfaces with regular contact with the human body are typically contaminated with microorganisms and might be considered as fomites. Despite spectacles being widespread across populations, little is known about their microbial contamination. Therefore, we swab-sampled 11 worn spectacles within a university setting as well as 10 worn spectacles in a nursing home setting. The microbial load was determined by aerobic cultivation. All spectacles were found to be contaminated with bacteria, with nose pads and ear clips having the highest density, i.e. at sites with direct skin contact. Summed over all sites, the median microbial load of the university spectacles (1.4 +/- 10.7 x 103 CFU cm-2) did not differ significantly from the spectacles tested in the nursing home (20.8 +/- 39.9 x 103 CFU cm-2). 215 dominant bacterial morphotypes were analyzed by MALDI biotyping. 182 isolates could be assigned to 10 genera, with Staphylococcus being the most common. On genus-level, bacterial diversity was greater on nursing home spectacles (10 genera) compared to the university environment (2 genera). Four cleaning methods were investigated using lenses artificially contaminated with Escherichia coli, Micrococcus luteus, a 1:2 mixture of E. coli and M. luteus, and Staphylococcus epidermidis (the dominant isolate in our study), respectively. Best cleaning results (99% -100% median germ reduction) were obtained using impregnated wipes; dry cleaning was less effective (85% -90% median germ reduction). Finally, 10 additional worn university spectacles were cleaned with wipes impregnated with an alcohol-free cleaning solution before sampling. The average bacterial load was significantly lower (0.09 +/- 0.49 x 103 CFU cm-2) compared to the uncleaned university spectacles previously investigated. Spectacles are significantly contaminated with bacteria of mostly human skin origin-including significant amounts of potentially pathogenic ones and may contribute to eye infections as well as fomites in clinical environments. PMID- 30485313 TI - The magnitude of Yo-Yo test improvements following an aerobic training intervention are associated with total genotype score. AB - Recent research has demonstrated that there is considerable inter-individual variation in the response to aerobic training, and that this variation is partially mediated by genetic factors. As such, we aimed to investigate if a genetic based algorithm successfully predicted the magnitude of improvements following eight-weeks of aerobic training in youth soccer players. A genetic test was utilised to examine five single nucleotide polymorphisms (VEGF rs2010963, ADRB2 rs1042713 and rs1042714, CRP rs1205 & PPARGC1A rs8192678), whose occurrence is believed to impact aerobic training adaptations. 42 male soccer players (17.0 +/- 1y, 176 +/- 6 cm, 69 +/- 9 kg) were tested and stratified into three different Total Genotype Score groups; "low", "medium"and "high", based on the possession of favourable polymorphisms. Subjects underwent two Yo-Yo tests separated by eight-weeks of sports-specific aerobic training. Overall, there were no significant differences between the genotype groups in pre-training Yo-Yo performance, but evident between-group response differentials emerged in post training Yo-Yo test performance. Subjects in the "high" group saw much larger improvements (58%) than those in the 'medium" (35%) and "low" (7%) groups. There were significant (p<0.05) differences between the groups in the magnitude of improvement, with athletes in the "high" and medium group having larger improvements than the "low" group (d = 2.59 "high" vs "low"; d = 1.32 "medium" vs "low"). In conclusion, the magnitude of improvements in aerobic fitness following a training intervention were associated with a genetic algorithm comprised of five single nucleotide polymorphisms. This information could lead to the development of more individualised aerobic training designs, targeting optimal fitness adaptations. PMID- 30485314 TI - Screening for osteogenic activity in extracts from Irish marine organisms: The potential of Ceramium pallidum. AB - Extracts and compounds derived from marine organisms have reportedly shown some osteogenic potential. As such, these bioactives may aid in the treatment of musculoskeletal conditions such as osteoporosis; helping to address inefficacies with current treatment options. In this study, 72 fractions were tested for their in vitro osteogenic activity using a human foetal osteoblast (hFOB) cell line and bone marrow derived mesenchymal stem cells (MSCs), focusing on their cytotoxic, proliferative and differentiation effects. Extracts dissolved in dimethyl sulfoxide and ethanol showed no significant osteogenic potential. However, two extracts derived from powder residues (left over from original organic extractions) caused a significant promotion of MSC differentiation. Bioactivity from powder residues derived from the epiphytic red algae Ceramium pallidum is described in detail to highlight its treatment potential. In vitro, C. pallidum was shown to promote MSC differentiation and extracellular matrix mineralisation. In vivo, this extract caused a significant increase in opercular bone growth of zebrafish larvae and a significant increase in bone density of regenerated adult caudal fins. Our findings therefore show the importance of continued screening efforts, particularly of novel extract sources, and the presence of bioactive compounds in C. pallidum extract. PMID- 30485315 TI - Online interest regarding violent attacks, gun control, and gun purchase: A causal analysis. AB - BACKGROUND: Increased interest about gun ownership and gun control are oftentimes driven by informational shocks in a common factor, namely violent attacks, and the perceived need for higher levels of safety. A causal depiction of the societal interest around violent attacks, gun control and gun purchase, both synchronous and over time, should be a stepping stone for designing future strategies regarding the safety concerns of the U.S. population. OBJECTIVE: Examine the causal relationships between unexpected increases in population interest about violent attacks, gun control, and gun purchase. METHODS: Relationships among online searches for information about violent attacks, gun control, and gun purchase occurring between 2004 and 2017 in the U.S. are explained through a novel structural vector autoregressive time series model to account for simultaneous causal relationships. RESULTS: More than 20% of the stationary variability in each of gun control and gun purchase interest can be explained by the remaining factors. Gun control interest appears to be caused, in part, by violent attacks informational shocks, yet violent attacks, although impactful, have a lesser effect than gun control debate on long-term gun ownership interests. CONCLUSIONS: The form in which gun control has been introduced in public debate may have further increased gun ownership interest. Reactive gun purchase interest may be an unintended side effect of gun control debate. U.S. policymakers may need to rethink current approaches to promotion of gun control, and whether societal policy debate without policy outcomes could be having unintended effects. PMID- 30485316 TI - Biomechanics of the peafowl's crest reveals frequencies tuned to social displays. AB - Feathers act as vibrotactile sensors that can detect mechanical stimuli during avian flight and tactile navigation, suggesting that they may also detect stimuli during social displays. In this study, we present the first measurements of the biomechanical properties of the feather crests found on the heads of birds, with an emphasis on those from the Indian peafowl (Pavo cristatus). We show that in peafowl these crest feathers are coupled to filoplumes, small feathers known to function as mechanosensors. We also determined that airborne stimuli with the frequencies used during peafowl courtship and social displays couple efficiently via resonance to the vibrational response of their feather crests. Specifically, vibrational measurements showed that although different types of feathers have a wide range of fundamental resonant frequencies, peafowl crests are driven near optimally by the shaking frequencies used by peacocks performing train-rattling displays. Peafowl crests were also driven to vibrate near resonance in a playback experiment that mimicked the effect of these mechanical sounds in the acoustic very near-field, reproducing the way peafowl displays are experienced at distances <= 1.5m in vivo. When peacock wing-shaking courtship behaviour was simulated in the laboratory, the resulting airflow excited measurable vibrations of crest feathers. These results demonstrate that peafowl crests have mechanical properties that allow them to respond to airborne stimuli at the frequencies typical of this species' social displays. This suggests a new hypothesis that mechanosensory stimuli could complement acoustic and visual perception and/or proprioception of social displays in peafowl and other bird species. We suggest behavioral studies to explore these ideas and their functional implications. PMID- 30485317 TI - Exploring attentional bias towards threatening faces in chimpanzees using the dot probe task. AB - Primates have evolved to rapidly detect and respond to danger in their environment. However, the mechanisms involved in attending to threatening stimuli are not fully understood. The dot-probe task is one of the most widely used experimental paradigms to investigate these mechanisms in humans. However, to date, few studies have been conducted in non-human primates. The aim of this study was to investigate whether the dot-probe task can measure attentional biases towards threatening faces in chimpanzees. Eight adult chimpanzees participated in a series of touch screen dot-probe tasks. We predicted faster response times towards chimpanzee threatening faces relative to neutral faces and faster response times towards faces of high threat intensity (scream) than low threat intensity (bared teeth). Contrary to prediction, response times for chimpanzee threatening faces relative to neutral faces did not differ. In addition, we found no difference in response times for faces of high and low threat intensity. In conclusion, we found no evidence that the touch screen dot probe task can measure attentional biases specifically towards threatening faces in our chimpanzees. Methodological limitations of using the task to measure emotional attention in human and non-human primates, including stimulus threat intensity, emotional state, stimulus presentation duration and manual responding are discussed. PMID- 30485318 TI - Effect of increasing heart rate on finger photoplethysmography fitness index (PPGF) in subjects with implanted cardiac pacemakers. AB - Finger photoplethysmography (PPG) is a noninvasive method that measures blood volume changes in the finger. The PPG fitness index (PPGF) has been proposed as an index of vascular risk and vascular aging. The objectives of the study were to determine the effects of heart rate (HR) on the PPGF and to determine whether PPGF is influenced by blood pressure (BP) changes. Twenty subjects (78+/-8 years, 3 female) with permanent cardiac pacemakers or cardioverter defibrillators were prospectively recruited. HR was changed by pacing, in a random order from 60 to 100 bpm and in 10 bpm increments. At each paced HR, the PPGF was derived from a finger photoplethysmogram. Cardiac output (CO), stroke volume (SV) and total peripheral resistance (TPR) were derived from the finger arterial pressure waveform. Brachial blood pressure (BP) was measured by the oscillometric method. This study found that as HR was increased from 60 to 100 bpm, brachial diastolic BP, brachial mean BP and CO were significantly increased (p<0.01), whilst the PPGF and SV were significantly decreased (p<0.001). The effects of HR on the PPGF were influenced by BP, with a decreasing HR effect on the PPGF that resulted from a higher BP. In conclusion, HR was a significant confounder for PPGF and it must be taken into account in analyses of PPGF, when there are large changes or differences in the HR. The magnitude of this effect was BP dependent. PMID- 30485319 TI - Timberline structure and woody taxa regeneration towards treeline along latitudinal gradients in Khangchendzonga National Park, Eastern Himalaya. AB - With main purpose of developing a coherent baseline information of timberline forests of Sikkim, Eastern Himalaya, we investigated, (i) forest structure and composition, (ii) regeneration status of dominant timberline tree species between timberline and treeline, (iii) influence of environmental variables in species composition, and (iv) relationship between environmental variables and ecological attributes. The study was conducted along the timberline stretch of Dzongri landscape nested within the Khangchendzonga National Park (UNESCO's World Heritage Site, 2016), a core zone of Khangchendzonga Biosphere Reserve (in UNESCO WNBRs, 2018), Sikkim, India. We employed quadrat method to sample 9 contiguous sites to capture all possible variations in timberline composition. Transect method was used to study the regeneration of woody taxa between timberline to treeline. In total, 20 woody species belonging to 10 genera and 6 families were recorded. Among these, Abies densa, Rhododendron lanatum and Sorbus microphylla exhibited higher dominance, comprising of 50% of the total importance value index (IVI) weightage. Betula utilis the common treeline species in much of the western and central parts of Himalaya was absent here. Tree density in studied timberline was significantly higher than its western Himalayan counterparts of Indian Himalayan region. Environmental variables viz., elevation, slope, and humus were observed determinants of species composition across the study area. The species dominance correlated negatively (p<0.01; n = 9) with species diversity and richness. We observed an irregular spatial pattern of timberline across the 9 study sites, and the extent of timberline elements (seedling; sapling; live tree or dead tree) ranged between 5.3m to 187.7m higher than the current timberline at different sites. The present trends suggest that upslope advancement is unlikely to occur in near future, while treeline densification is anticipated. Further investigations are suggested to develop a holistic understating of these timberline patterns across the Indian Himalayan region. PMID- 30485320 TI - Non-targeted metabolomics unravels a media-dependent prodiginines production pathway in Streptomyces coelicolor A3(2). AB - The genus Streptomyces is the best-known source of therapeutic secondary metabolites, especially antibiotics with pharmaceutical applications. Here, we performed a comparative study based on the time-resolved metabolic disparity in S. coelicolor A3(2) subjected to fermentative cultivation in two different types of media (R2YE and RSM3) in order to investigate secondary metabolite production pathways. The relative abundance of secondary metabolites, such as prodiginines, indoles, germicidins, and selected diketopiperazines, was increased in S. coelicolor A3(2) cultivated in R2YE medium compared to that in RSM3 medium, variably at the late-log and stationary phases of fermentative growth. Correlation analysis indicated that "antibiotic prodiginines" contributed maximally to the absorption maxima (A530) of culture supernatants, indicating their optimal production at 96 hours in R2YE medium. A higher abundance of L proline (48-72 hours) followed by prodiginines (96 hours) was evident, substantiating the intertwined links between precursor and activated prodiginines pathway. Similarly, the higher abundance of indoles was concurrent with tryptophan levels in the shikimate pathway, whereas diketopiperazines were synchronously abundant along with the levels of phenylalanine, leucine, and proline. Additionally, acetyl-CoA induced the acetate pathway, resulting in the production of germicidins. Thus, our results demonstrate that S. coelicolor A3(2) produces specific secondary metabolites by enhancing the dedicated metabolic pathway responsible for their production. In conclusion, our results from this study provide insight into the metabolic pathways of S. coelicolor A3(2), and can be applied to further optimize the production of prodiginines. PMID- 30485321 TI - A computational investigation of lift generation and power expenditure of Pratt's roundleaf bat (Hipposideros pratti) in forward flight. AB - The aerodynamic mechanisms of bat flight have been studied using a numerical approach. Kinematic data acquired using a high resolution motion capture system was employed to simulate the unsteady air flow around a bat's wings. A flapping bat wing contains many degrees of freedom, which make 3D motion tracking challenging. In order to overcome this challenge, an optical motion capture system of 21 cameras was used to reduce wing self-occlusion. Over the course of a meter-long flight, 108 discrete marker points on the bat's wings (Pratt's roundleaf bat, Hipposideros pratti) were tracked. The time evolution of the surface of each wing was computationally reconstructed in 3D space. The resulting kinematic model was interfaced with an unsteady incompressible flow solver using the immersed boundary method (IBM) and large eddy simulation (LES). Verification and validation of the flow simulation were conducted to establish accuracy. The aerodynamic forces calculated from the simulation compared well to the forces theoretically needed to sustain the observed flight trajectory. The transient flow field generated by the simulation allowed for the direct calculation of lift, drag, and power output of the bat during flight. The mean lift coefficient was found to be 3.21, and the flap cycle averaged aerodynamic power output was 1.05 W. Throughout the flap cycle, the planform area of the wings varied up to 46% between the largest and smallest values. During the upstroke, wing rotation was found to mitigate negative lift thereby improving overall flight efficiency. The high resolution motion capture and flow simulation framework presented here has the potential to facilitate the understanding of complex bat flight aerodynamics for both straight and maneuvering flight modes. PMID- 30485322 TI - A statistical framework for radiation dose estimation with uncertainty quantification from the gamma-H2AX assay. AB - Over the last decade, the gamma-H2AX focus assay, which exploits the phosphorylation of the H2AX histone following DNA double-strand-breaks, has made considerable progress towards acceptance as a reliable biomarker for exposure to ionizing radiation. While the existing literature has convincingly demonstrated a dose-response effect, and also presented approaches to dose estimation based on appropriately defined calibration curves, a more widespread practical use is still hampered by a certain lack of discussion and agreement on the specific dose response modelling and uncertainty quantification strategies, as well as by the unavailability of implementations. This manuscript intends to fill these gaps, by stating explicitly the statistical models and techniques required for calibration curve estimation and subsequent dose estimation. Accompanying this article, a web applet has been produced which implements the discussed methods. PMID- 30485323 TI - RORalpha controls inflammatory state of human macrophages. AB - ROR family of nuclear receptor transcription factors forms nodes connecting metabolic and inflammatory signaling pathways. The RORalpha members of the family have intrinsic transcriptional activity and they are involved in both activation and repression of a wide range of genes. The role of RORalpha in control of inflammation has been extensively studied using animal models but its function in human cells is not as well understood. To address this shortcoming, we analyzed how RORalpha is shaping the inflammatory state of human macrophages. Using CRISPR Cas9 system, we deleted RORA in THP-1 human monocytic cell line. In mutant cells we observed a dramatic increase in basal expression of a subset of NF-kappaB regulated genes, including TNF, IL-1beta and IL-6, at both transcriptional and translational levels. Furthermore, RORA-deletion cells produced notable amounts of pro-IL-1beta even in the absence of LPS stimulation. Subsequent LPS stimulation induced cleavage of pro-IL-1beta to mature form. Our RNAseq analysis further confirmed the key role of RORA in setting the inflammatory state of macrophages and defined the set of differentially regulated genes. Overall, our data provides evidence supporting the anti-inflammatory function of RORalpha in human macrophages. PMID- 30485324 TI - Zebrafish larvae show negative phototaxis to near-infrared light. AB - Zebrafish larvae (Danio rerio) are among the most used model species to test biological effects of different substances in biomedical research, neuroscience and ecotoxicology. Most tests are based on changes in swimming activity of zebrafish larvae by using commercially available high-throughput screening systems. These systems record and analyse behaviour patterns using visible (VIS) and near-infrared (NIR) light sources, to simulate day (VIS) and night (NIR) phases, which allow continuous recording of the behaviour using a NIR sensitive camera. So far, however, the sensitivity of zebrafish larvae to NIR has never been tested experimentally, although being a critical piece of information for interpreting their behaviour under experimental conditions. Here, we investigated the swimming activity of 96 hpf (hours post fertilization) and 120 hpf zebrafish larvae under light sources of NIR at 860 nm and at 960 nm wavelength and under VIS light. A thermal source was simultaneously presented opposite to one of the light sources as control. We found that zebrafish larvae of both larval stages showed a clear negative phototactic response towards 860 nm NIR light and to VIS light, but not to 960 nm NIR light. Our results demonstrated that zebrafish larvae are able to perceive NIR at 860 nm, which is almost identical to the most commonly used light source in commercial screening systems (NIR at 850 nm) to create a dark environment. These tests, however, are not performed in the dark from the zebrafish's point of view. We recommend testing sensitivity of the used test organism before assuming no interaction with the applied light source of commonly used biosensor test systems. Previous studies on biological effects of substances to zebrafish larvae should be interpreted with caution. PMID- 30485325 TI - The association between dengue immunoglobulin G titres with previous clinical dengue infection and white cell counts in Cuban children: A population-based study. AB - BACKGROUND: The prevalence of dengue infection is increasing globally. There are few prospective population-based surveillance studies of the immunological and inflammatory consequences of exposure to dengue virus in young children. OBJECTIVE: To study the association between serologically confirmed prior medical diagnosis of dengue infection and blood measures of systemic inflammation with dengue virus immunoglobulin G levels. METHODS: A population-based study of healthy three-year old children living in Havana, Cuba. RESULTS: 865 individuals provided a blood sample. Fourteen (1.6%) had a prior medical diagnosis of dengue infection, and 851 individuals had no prior medical diagnosis. There was no difference in the serum immunoglobulin G titres between these groups (Mann Whitney test, p = 0.49). Total white cell count, blood neutrophil and eosinophil counts were linearly associated with a dengue immunoglobulin G value above the median value. CONCLUSIONS: There was no difference between the dengue immunoglobulin G titres in young children who had previously had clinically proven dengue infection compared to those who had no diagnosis of prior infection. This may be a consequence of a relatively high prevalence of sub clinical infection. A higher dengue immunoglobulin G level was positively associated with a range of inflammatory biomarkers, although these data cannot demonstrate a causal association. PMID- 30485326 TI - Brain functional changes in patients with botulism after illegal cosmetic injections of botulinum toxin: A resting-state fMRI study. AB - BACKGROUND: Botulinum toxin type A (BoNT-A) is generally considered safe and is widely used to treat a variety of clinical conditions involving muscle hyperactivity and for cosmetic purposes. However, the effects of BoNT-A poisoning (botulism) on brain function are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Herein, we investigated brain functions in 9 patients who received illegal cosmetic injections of botulinum and 18 matched controls by combining the analysis methods of regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) based on resting-state fMRI. Compared with the controls, the patients with botulism exhibited significantly reduced ReHo values in the left posterior lobe of the cerebellum extending to the right anterior lobe of the cerebellum, as well as in the right anterior lobe of the cerebellum extending to the parahippocampal gyrus and right posterior lobe of the cerebellum. The patients with botulism also showed weakened ALFF values in the right anterior lobe of the cerebellum extending to the left anterior lobe of the cerebellum and right posterior lobe of the cerebellum, as well as in the right anterior lobe of the cerebellum. CONCLUSIONS/SIGNIFICANCE: The results indicate that BoNT-A may modulate cerebral activation in specific areas, which may play roles in both the adverse effects of botulism and the mechanism underlying clinical treatment with BoNT-A. PMID- 30485328 TI - Long-term responses of riparian plants' composition to water level fluctuation in China's Three Gorges Reservoir. AB - The water level fluctuation zone (WLFZ) has experienced a novel hydrological regime due to the anti-seasonal operation of China's Three Gorges Reservoir. Overall, hydrological change can significantly influence the riparian environment and shift the riparian vegetation. Although numerous studies have investigated the short-term responses of riparian plants to water level fluctuation in this zone, few have addressed long-term effects. In this study, four permanent plots in the WLFZ of the canyon landform area were chosen to evaluate the long-term responses of riparian plants to water level fluctuation from 2008 to 2015 and to screen candidate plants for ecological restoration. We recorded 146 species in 2008, 110 species in 2009, 68 species in 2012 and 69 species in 2015, indicating a conspicuous loss in riparian plants. Most of the remnant plants were annual and perennial herbs. Of the native species present in 2008, 82, 22 and 8 had disappeared in 2009, 2012 and 2015, respectively. Simultaneously, 45, 15 and 11 non-native species were first found, respectively. Additionally, over half of the native and the non-native species were not found after being subjected to a water level fluctuation. From 2008 to 2015, only 27 native species always presented; however, not all of them were chosen as candidates for ecological restoration because of their decreased importance values. In contrast, the importance value of Cynodon dactylon increased over time, suggesting its high tolerance to long term winter flooding. We concluded that riparian plants' composition of the canyon landform area dramatically declined after long-term water level fluctuation and their presence was determined by the novel hydrological condition. Our results also suggested that Cynodon dactylon or its combination with other species (i.e. Digitaria chrysoblephara, Setaria glauca, Setaria viridis) is a better candidate for ecological restoration in the WLFZ. PMID- 30485327 TI - Discriminating severe seasonal allergic rhinitis. Results from a large nation wide database. AB - Allergic rhinitis (AR) is a chronic disease affecting a large amount of the population. To optimize treatment and disease management, it is crucial to detect patients suffering from severe forms. Several tools have been used to classify patients according to severity: standardized questionnaires, visual analogue scales (VAS) and cluster analysis. The aim of this study was to evaluate the best method to stratify patients suffering from seasonal AR and to propose cut-offs to identify severe forms of the disease. In a multicenter French study (PollinAir), patients suffering from seasonal AR were assessed by a physician that completed a 17 items questionnaire and answered a self-assessment VAS. Five methods were evaluated to stratify patients according to AR severity: k-means clustering, agglomerative hierarchical clustering, Allergic Rhinitis Physician Score (ARPhyS), total symptoms score (TSS-17), and VAS. Fisher linear, quadratic discriminant analysis, non-parametric kernel density estimation methods were used to evaluate miss-classification of the patients and cross-validation was used to assess the validity of each scale. 28,109 patients were categorized into "mild", "moderate", and "severe", through the 5 different methods. The best discrimination was offered by the ARPhyS scale. With the ARPhyS scale, cut-offs at a score of 8-9 for mild to moderate and of 11-12 for moderate to severe symptoms were found. Score reliability was also acceptable (Cronbach's alpha coefficient: 0.626) for the ARPhyS scale, and excellent for the TSS-17 (0.864). The ARPhyS scale seems the best method to target patients with severe seasonal AR. In the present study, we highlighted optimal discrimination cut-offs. This tool could be implemented in daily practice to identify severe patients that need a specialized intervention. PMID- 30485329 TI - Asymmetrical effects of real exchange rate on the money demand in Saudi Arabia: A non-linear ARDL approach. AB - This present research investigates the money demand function of Saudi Arabia using a long period 1968-2016. In addition, the asymmetrical effects of real exchange rate changes have also been explored in the estimated money demand function. Our empirical results suggest that income and inflation have positive and negative effects on money demand respectively. Further, a real appreciation of US dollar has a positive effect but a real depreciation has a negative effect on the money demand. Furthermore, income and price homogeneity hypotheses do not hold for the estimated elasticities. Moreover, the estimated model is found stable with the theoretically expected effects of money demand's determinants. Therefore, we are suggesting money supply as a monetary policy instrument to the economy of Saudi Arabia. PMID- 30485330 TI - Evaluation of transcriptionally regulated genes identifies NCOR1 in hormone receptor negative breast tumors and lung adenocarcinomas as a potential tumor suppressor gene. AB - Regulation of transcription is a key process in cellular homeostasis. It depends on regulators that either repress or stimulate the transcription of genes, therefore controlling different biological functions. The Nuclear Receptor Corepressor 1 (NCOR1) is one of those co-repressors that regulate the transcription by facilitating the recruitment of HDAC1, 2, 3, 4, 5 and 7. In our article, by using an in silico approach, we evaluate the mutational status of NCOR1 in breast and lung tumors. We identified that NORC1 is mutated in more than 3% of breast tumors and lung adenocarcinomas and linked this fact with detrimental outcome in some subtypes, particularly in those that are hormone receptor negative. In addition to these findings, as mutations in this gene are deleterious, we confirmed that high levels of this gene were linked with good prognosis in the same tumor subtypes. Findings in the same direction were identified in lung adenocarcinomas, with mutations associated with detrimental prognosis and high expression with better outcome. In conclusion, hereby we describe the presence and prognostic role of mutations in the NCOR1 gene in hormone receptor negative breast and lung adenocarcinomas, and we also confirm that NCOR1 is a tumor suppressor gene. Further studies should be performed to explore therapeutic mechanisms to restore its function. PMID- 30485331 TI - Evaluation of flicker induced hyperemia in the retina and optic nerve head measured by Laser Speckle Flowgraphy. AB - PURPOSE: The coupling between neural activity and blood flow is a physiological key principle of ocular blood flow regulation. The current study was performed to investigate whether Laser speckle flowgraphy (LSFG), a commercially available technique for measuring blood flow, is capable to assess flicker-induced haemodynamic changes in the retinal and optic nerve head (ONH) circulation. METHODS: Twenty healthy subjects were included in this cross sectional study. A commercial LSFG instrument was used to measure blood flow at the ONH as well as in retinal vessels before and during stimulation with flickering light. Mean blur rate (MBR), a measure of relative blood flow velocity, was obtained for the ONH and relative flow volume (RFV) a measure of relative blood flow of the respective retinal vessels. RESULTS: Stimulation with flicker light increased ONH MBR by +17.5%+/-6.6% (p<0.01). In retinal arteries, flicker stimulation led an increase of +23.8+/-10.0% (p<0.05) in total RFV. For retinal veins, an increase of +23.1%+/-11.0 (p<0.05) in total RFV was observed during stimulation. A higher response was observed in nasal RFV compared to temporal RFV in retinal arteries (nasal: +28.9%+/-20.0%; temporal: +20.4%+/-17.6%, p<0.05) and veins (nasal: +28.3%+/-19.6%; temporal +17.8%+/-18.9%, p<0.05). CONCLUSION: As shown previously with other techniques, flicker stimulation leads to an increase in retinal and optic nerve head blood flow. Our results indicate that LSFG is an appropriate method for the quantification of retinal and ONH blood flow during visual stimulation and may be used as a non-invasive, easy to use tool to assess neuro vascular coupling in humans. PMID- 30485332 TI - Anti-saccades predict cognitive functions in older adults and patients with Parkinson's disease. AB - A major component of cognitive control is the ability to act flexibly in the environment by either behaving automatically or inhibiting an automatic behaviour. The interleaved pro/anti-saccade task measures cognitive control because the task relies on one's abilities to switch flexibly between pro and anti-saccades, and inhibit automatic saccades during anti-saccade trials. Decline in cognitive control occurs during aging or neurological illnesses such as Parkinson's disease (PD), and indicates decline in other cognitive abilities, such as memory. However, little is known about the relationship between cognitive control and other cognitive processes. Here we investigated whether anti-saccade performance can predict decision-making, visual memory, and pop-out and serial visual search performance. We tested 34 younger adults, 22 older adults, and 20 PD patients on four tasks: an interleaved pro/anti-saccade, a spatial visual memory, a decision-making and two types of visual search (pop-out and serial) tasks. Anti-saccade performance was a good predictor of decision-making and visual memory abilities for both older adults and PD patients, while it predicted visual search performance to a larger extent in PD patients. Our results thus demonstrate the suitability of the interleaved pro/anti-saccade task as a cognitive marker of cognitive control in aging and PD populations. PMID- 30485333 TI - Full reconstruction of large lobula plate tangential cells in Drosophila from a 3D EM dataset. AB - With the advent of neurogenetic methods, the neural basis of behavior is presently being analyzed in more and more detail. This is particularly true for visually driven behavior of Drosophila melanogaster where cell-specific driver lines exist that, depending on the combination with appropriate effector genes, allow for targeted recording, silencing and optogenetic stimulation of individual cell-types. Together with detailed connectomic data of large parts of the fly optic lobe, this has recently led to much progress in our understanding of the neural circuits underlying local motion detection. However, how such local information is combined by optic flow sensitive large-field neurons is still incompletely understood. Here, we aim to fill this gap by a dense reconstruction of lobula plate tangential cells of the fly lobula plate. These neurons collect input from many hundreds of local motion-sensing T4/T5 neurons and connect them to descending neurons or central brain areas. We confirm all basic features of HS and VS cells as published previously from light microscopy. In addition, we identified the dorsal and the ventral centrifugal horizontal, dCH and vCH cell, as well as three VSlike cells, including their distinct dendritic and axonal projection area. PMID- 30485334 TI - Pelagic shrimp play dead in deep oxygen minima. AB - Pelagic crustaceans are arguably the most abundant group of metazoans on Earth, yet little is known about their natural behavior. The deep pelagic shrimp Hymenopenaeus doris is a common decapod that thrives in low oxygen layers of the eastern Pacific Ocean. When first observed in situ using a remotely operated vehicle, most specimens of H. doris appeared dead due to inactivity and inverted orientation. Closer inspection revealed that these animals were utilizing small, subtle shifts in appendage position to control their orientation and sink rate. In this mode, they resembled molted shrimp exoskeletons. We hypothesize that these shrimp may avoid capture by visually-cued predators with this characteristic behavior. The low metabolic rates of H. doris (0.55-0.81 mg O2 kg 1 min-1) are similar to other deep-living shrimp, and also align with their high hypoxia tolerance and reduced activity. We observed similar behavior in another deep pelagic decapod, Petalidium suspiriosum, which transiently inhabited Monterey Canyon, California, during a period of anomalously warm ocean conditions. PMID- 30485335 TI - Cesarean delivery rate and staffing levels of the maternity unit. AB - OBJECTIVE: To investigate whether staffing levels of maternity units affect prelabor urgent, elective, and intrapartum cesarean delivery rates. METHODS: This population-based retrospective cohort study covers the deliveries of the 11 hospitals of a French perinatal network in 2008-2014 (N = 102 236). The independent variables were women's demographic and medical characteristics as well as the type, organization, and staffing levels for obstetricians, anesthesiologists, and midwives of each maternity unit. Bivariate and multivariate analyses were conducted with multilevel logistic models. RESULTS: Overall, 23.9% of the women had cesarean deliveries (2.4% urgent before labor, 10% elective, and 11.5% intrapartum). Independently of individual- and hospital level factors, the level of obstetricians, measured by the number of full-time equivalent persons (i.e., 35 working hours per week) per 100 deliveries, was negatively associated with intrapartum cesarean delivery (adjusted odds ratio, aOR 0.55, 95% confidence interval, CI 0.36-0.83, P-value = 0.005), and the level of midwives negatively associated with elective cesarean delivery (aOR 0.79, 95% CI 0.69-0.90, P-value < 0.001). Accordingly, a 10% increase in obstetrician and midwife staff levels, respectively, would have been associated with a decrease in the likelihood of intrapartum cesarean delivery by 2.5 percentage points and that of elective cesarean delivery by 3.4 percentage points. These changes represent decreases in intrapartum and elective cesarean delivery rates of 19% (from 13.1% to 10.6%) and 33% (from 10.3% to 6.9%), respectively. CONCLUSION: Staffing levels of maternity units affect the use of cesarean deliveries. High staffing levels for obstetricians and midwives are associated with lower cesarean rates. PMID- 30485336 TI - The influence of pitch feedback on learning of motor -timing and sequencing: A piano study with novices. AB - Audio-motor coordination is a fundamental requirement in the learning and execution of sequential actions such as music performance. Predictive motor control mechanisms determine the sequential content and timing of upcoming tones and thereby facilitate accurate performance. To study the role of auditory-motor predictions at early stages of acquiring piano performance skills, we conducted an experiment in which non-musicians learned to play a musical sequence on the piano in synchrony with a metronome. Three experimental conditions compared errors and timing. The first consisted of normal auditory feedback using conventional piano key-to-tone mappings. The second employed fixed-pitch auditory feedback consisting of a single tone that was given with each key stroke. In the third condition, for each key stroke a tone was randomly drawn from the set of tones associated with the normal sequence. The results showed that when auditory feedback tones were randomly assigned, participants produced more sequencing errors (i.e., a higher percentage of incorrect key strokes) compared to when auditory feedback was normal or consisted of a single tone of fixed pitch. Furthermore, synchronization with the metronome was most accurate in the fixed pitch single-tone condition. These findings suggest that predictive motor control mechanisms support sequencing and timing, and that these sensorimotor processes are dissociable even at early stages of acquiring complex motor skills such as music performance. PMID- 30485337 TI - Surgeons are deeply affected when patients are diagnosed with prosthetic joint infection. AB - Knee replacement is a common preference sensitive quality-of-life procedure that can reduce pain and improve function for people with advanced knee arthritis. While most patients improve, knee replacement surgery has the potential for serious complications. Prosthetic knee infection is an uncommon but serious complication. This study explored the impact of cases of prosthetic knee infection on surgeons' personal and professional wellbeing. Qualitative telephone interviews were conducted with consultant orthopaedic surgeons who treated patients for prosthetic knee infection in one of six high-volume NHS orthopaedic departments. Data was audio-recorded, transcribed and analysed thematically. Eleven surgeons took part. Analysis identified three overarching themes: (i) At some point infection is inevitable but surgeons still feel accountable; (ii) A profound emotional impact and (iii) Supporting each other. The occurrence of prosthetic joint infection has a significant emotional impact on surgeons who report a collective sense of devastation and personal ownership, even though prosthetic joint infection cannot be fully controlled for. Surgeons stressed the importance of openly discussing the management of prosthetic joint infection with a supportive multidisciplinary team and this has implications for the ways in which orthopaedic surgeons may be best supported to manage this complication. This article also acknowledges that surgeons are not alone in experiencing personal impact when patients have infection. PMID- 30485338 TI - Cranial anatomy of the gorgonopsian Cynariops robustus based on CT reconstruction. AB - Gorgonopsia is one of the major clades of non-mammalian synapsids, and includes an array of large-bodied carnivores that were the top terrestrial predators of the late Permian. Most research on the clade has focused on these largest members; small-bodied gorgonopsians are relatively little-studied. Here, we redescribe a small gorgonopsian skull (MB.R.999) from the late Permian (Tropidostoma Assemblage Zone) of South Africa on the basis of neutron and synchrotron CT reconstructions, which yield new data on internal cranial morphology in Gorgonopsia. Because of the largely undistorted nature of MB.R.999, we were also able to reconstruct unossified areas such as the brain endocast and the otic labyrinth. MB.R.999 can be referred to the taxon Cynariops robustus based on its general skull proportions, postcanine tooth count, preparietal morphology, and vomerine morphology. We refer additional small gorgonopsian specimens from the Victoria West area to Cynariops robustus, and consider Cynarioides grimbeeki and Cynarioides laticeps to be synonymous with C. robustus. Inclusion of Cynariops in a phylogenetic analysis of Gorgonopsia recovers it within a large clade of African taxa, more closely related to Lycaenops and rubidgeines than Eriphostoma or Gorgonops. PMID- 30485339 TI - Novel high-throughput myofibroblast assays identify agonists with therapeutic potential in pulmonary fibrosis that act via EP2 and EP4 receptors. AB - Pathological features of pulmonary fibrosis include accumulation of myofibroblasts and increased extracellular matrix (ECM) deposition in lung tissue. Contractile alpha-smooth muscle actin (alpha-SMA)-expressing myofibroblasts that produce and secrete ECM are key effector cells of the disease and therefore represent a viable target for potential novel anti-fibrotic treatments. We used primary normal human lung fibroblasts (NHLF) in two novel high-throughput screening assays to discover molecules that inhibit or revert fibroblast-to-myofibroblast differentiation. A phenotypic high-content assay (HCA) quantified the degree of myofibroblast differentiation, whereas an impedance-based assay, multiplexed with MS / MS quantification of alpha-SMA and collagen 1 alpha 1 (COL1) protein, provided a measure of contractility and ECM formation. The synthetic prostaglandin E1 (PGE1) alprostadil, which very effectively and potently attenuated and even reversed TGF-beta1-induced myofibroblast differentiation, was identified by screening a library of approved drugs. In TGF-beta1-induced myofibroblasts the effect of alprostadil was attributed to activation of prostanoid receptor 2 and 4 (EP2 and EP4, respectively). However, selective activation of the EP2 or the EP4 receptor was already sufficient to prevent or reverse TGF-beta1-induced NHLF myofibroblast transition. Our high-throughput assays identified chemical structures with potent anti-fibrotic properties acting through potentially novel mechanisms. PMID- 30485340 TI - Unprecedented plant species loss after a decade in fragmented subtropical Chaco Serrano forests. AB - Current biodiversity loss is mostly caused by anthropogenic habitat loss and fragmentation, climate change, and resource exploitation. Measuring the balance of species loss and gain in remaining fragmented landscapes throughout time entails a central research challenge. We resurveyed in 2013 plant species richness in the same plots of a previous sampling conducted in 2003 across 18 forest fragments of different sizes of the Chaco Serrano forest in Argentina. While the area of these forest remnants was kept constant, their surrounding forest cover changed over this time period. We compared plant species richness of both sampling years and calculated the proportion of species loss and gain at forest edges and interiors. As in 2003, we found a positive relationship between fragment area and plant richness in 2013 and both years showed a similar slope. However, we detected a net decrease of 24% of species' richness across all forest fragments, implying an unprecedentedly high rate and magnitude of species loss driven mainly by non-woody, short-lived species. There was a higher proportion of lost and gained species at forest edges than in forest interiors. Importantly, fragment area interacted with percent change in surrounding forest cover to explain the proportion of species lost. Small forest fragments showed a relatively constant proportion of species loss regardless of any changes in surrounding forest cover, whereas in larger fragments the proportion of species lost increased when surrounding forest cover decreased. We show that despite preserving fragment area, habitat quality and availability in the surroundings is of fundamental importance in shaping extinction and immigration dynamics of plant species at any given forest remnant. Because the Chaco Serrano forest has already lost 94% of its original cover, we argue that plant extinctions will continue through the coming decades unless active management actions are taken to increase native forest areas. PMID- 30485341 TI - Invasive rat control is an efficient, yet insufficient, method for recovery of the critically endangered Hawaiian plant hau kuahiwi (Hibiscadelphus giffardianus). AB - Biological invasions of rodents and other species have been especially problematic on tropical islands. Invasive Rattus rattus consumption of Hibiscadelphus giffardianus (Malvaceae; common Hawaiian name hau kuahiwi) fruit and seeds has been hypothesized to be the most-limiting factor inhibiting the critically endangered tree, but this has not been experimentally tested, and little is known about other factors affecting seed dispersal, germination, and seedling establishment. Thus, we do not know if rat removal is sufficient to increase hau kuahiwi recruitment. This study aims to evaluate the effect of rat population control on the ability of hau kuahiwi to retain fruit and establish seedlings. We compared hau kuahiwi fruiting and seedling recruitment in a stand treated to reduce rat abundance and a neighbouring control stand. Fruit retention increased following treatment but seedling establishment did not. Although rat control improves the ability of hau kuahiwi to retain fruit, other, presently unknown inhibitors to seed dispersal, germination, and/or seedling development remain. Seed and seedling predation by other species, competition from numerous invasive plant species, unsuitable climate, and/or other factors may be primary inhibitors in the absence of rats, but we emphasize that progressive isolation of these factors at individual hau kuahiwi life stages may be necessary to identify the remaining threats to the conservation of this critically endangered plant. PMID- 30485342 TI - Spatio-temporal epidemiology of anthrax in Hippopotamus amphibious in Queen Elizabeth Protected Area, Uganda. AB - BACKGROUND: Anthrax is a zoonotic disease primarily of herbivores, caused by Bacillus anthracis, a bacterium with diverse geographical and global distribution. Globally, livestock outbreaks have declined but in Africa significant outbreaks continue to occur with most countries still categorized as enzootic, hyper endemic or sporadic. Uganda experiences sporadic human and livestock cases. Severe large-scale outbreaks occur periodically in hippos (Hippopotamus amphibious) at Queen Elizabeth Protected Area, where in 2004/2005 and 2010 anthrax killed 437 hippos. Ecological drivers of these outbreaks and potential of hippos to maintain anthrax in the ecosystem remain unknown. This study aimed to describe spatio-temporal patterns of anthrax among hippos; examine significant trends associated with case distributions; and generate hypotheses for investigation of ecological drivers of anthrax. METHODS: Spatio-temporal patterns of 317 hippo cases in 2004/5 and 137 in 2010 were analyzed. QGIS was used to examine case distributions; Spearman's nonparametric tests to determine correlations between cases and at-risk hippo populations; permutation models of the spatial scan statistics to examine spatio-temporal clustering of cases; directional tests to determine directionality in epidemic movements; and standard epidemic curves to determine patterns of epidemic propagation. KEY FINDINGS: Results showed hippopotamus cases extensively distributed along water shorelines with strong positive correlations (p<0.01) between cases and at-risk populations. Significant (p<0.001) spatio-temporal clustering of cases occurred throughout the epidemics, pointing towards a defined source. Significant directional epidemic spread was detected along water flow gradient (206.6 degrees ) in 2004/5 and against flow gradient (20.4 degrees ) in 2010. Temporal distributions showed clustered pulsed epidemic waves. CONCLUSION: These findings suggest mixed point source propagated pattern of epidemic spread amongst hippos and points to likelihood of indirect spread of anthrax spores between hippos mediated by their social behaviour, forces of water flow, and persistent presence of infectious carcasses amidst schools. This information sheds light on the epidemiology of anthrax in highly social wildlife, can help drive insight into disease control, wildlife conservation, and tourism management, but highlights the need for analytical and longitudinal studies aimed at clarifying the hypotheses. PMID- 30485343 TI - Comparing the capacity of five different dietary treatments to optimise growth and nutritional composition in two scleractinian corals. AB - Developing an optimal heterotrophic feeding regime has the potential to improve captive coral growth and health. This study evaluated the efficacy of three exogenous diets: Artemia nauplii (ART), a commercially available coral diet (Reef Roids) (RR), and a novel, micro-bound diet (ATF), against a comparatively natural, unfiltered seawater treatment (RAW), and an unfed, ultra-filtered seawater treatment (CTL), in adult Acropora millepora and Pocillopora acuta nubbins. After 90 days, both species showed significantly positive weight gain in response to one treatment (A. millepora-RAW, P. acuta-ART), and comparatively low growth in response to another (A. millepora-ATF, P. acuta-RR). The results highlighted substantial differences in the nutritional requirements between species. The nutritional composition of A. millepora in the best performing treatment was dominated by high-energy materials such as storage lipids and saturated and monounsaturated fatty acids. In contrast, the P. acuta nutritional profile in the superior treatment showed a predominance of structural materials, including protein, phospholipids, and polyunsaturated fatty acids. This study demonstrates that Artemia nauplii can successfully replace a natural feeding regime for captive P. acuta, yet highlights the considerable work still required to optimise supplementary feeding regimes for A. millepora. PMID- 30485344 TI - Feasibility and acceptability of the menstrual cup for non-surgical management of vesicovaginal fistula among women at a health facility in Ghana. AB - OBJECTIVE: To assess the feasibility of the menstrual cup for short-term management of urinary leakage among women with vesicovaginal fistula (VVF). METHODS: A repeated measures design compared volume of leakage with and without the cup via a 2-hr pad test among women with VVF seeking surgical repair at a health facility in Ghana. Subsequently a gynecological exam was administered to assess safety outcomes, followed by a questionnaire to assess acceptability and perceived efficacy. A paired t-test was used to analyze reduction of leakage in ml, and percent reduction was reported. Study limitations include observer bias while evaluating adverse outcomes and the possibility of social desirability bias during questionnaire administration that might overestimate the effect of the cup and women's acceptability. RESULTS: Of the 32 patients screened, 11 were eligible (100% consent rate). At baseline, mean (+/-SD) leakage in ml was 63.2 (+/-49.2) (95% CI: 30.2-96.3) over two hours, while the mean leakage over two hours of use of the cup was 16.8 (+/-16.5) (95% CI: 5.7-27.9). The mean difference of 46.4 (+/ 52.1) ml with use of the cup (95% CI: 11.4-81.4) was statistically significant (p = 0.02). With the cup, women experienced an average 61.0% (+/-37.4) (95% CI: 35.9 86.2) leakage reduction, a difference 10/11 users (91.0%) perceived in reduced leakage. One participant, reporting four previous surgical attempts, experienced a 78.7% leakage reduction. Acceptability was high-women could easily insert (8/11), remove (8/11), and comfortably wear (11/11) the cup and most (10/11) would recommend it. No adverse effects attributable to the intervention were observed on exam, although some women perceived difficulties with insertion and removal. Data collection tools were appropriate with slight modification advised. CONCLUSION: A larger trial is warranted for a more robust evaluation of the menstrual cup for management of urinary leakage due to VVF among women who have not yet accessed surgery or for whom surgery was not successful. PMID- 30485345 TI - Delving deeper: Relating the behaviour of a metabolic system to the properties of its components using symbolic metabolic control analysis. AB - High-level behaviour of metabolic systems results from the properties of, and interactions between, numerous molecular components. Reaching a complete understanding of metabolic behaviour based on the system's components is therefore a difficult task. This problem can be tackled by constructing and subsequently analysing kinetic models of metabolic pathways since such models aim to capture all the relevant properties of the system components and their interactions. Symbolic control analysis is a framework for analysing pathway models in order to reach a mechanistic understanding of their behaviour. By providing algebraic expressions for the sensitivities of system properties, such as metabolic flux or steady-state concentrations, in terms of the properties of individual reactions it allows one to trace the high level behaviour back to these low level components. Here we apply this method to a model of pyruvate branch metabolism in Lactococcus lactis in order to explain a previously observed negative flux response towards an increase in substrate concentration. With this method we are able to show, first, that the sensitivity of flux towards changes in reaction rates (represented by flux control coefficients) is determined by the individual metabolic branches of the pathway, and second, how the sensitivities of individual reaction rates towards their substrates (represented by elasticity coefficients) contribute to this flux control. We also quantify the contributions of enzyme binding and mass-action to enzyme elasticity separately, which allows for an even finer-grained understanding of flux control. These analytical tools allow us to analyse the control properties of a metabolic model and to arrive at a mechanistic understanding of the quantitative contributions of each of the enzymes to this control. Our analysis provides an example of the descriptive power of the general principles of symbolic control analysis. PMID- 30485346 TI - The effect of complex intramural microstructure caused by structural remodeling on the stability of atrial fibrillation: Insights from a three-dimensional multi layer modeling study. AB - BACKGROUND: Recent researches have suggested that the complex three-dimensional structures caused by structural remodeling play a key role in atrial fibrillation (AF) substrates. Here we aimed to investigate this hypothesis using a multi-layer model representing intramural microstructural features. METHODS: The proposed multi-layer model was composed of the endocardium, connection wall, and epicardium. In the connection wall, intramural fibrosis was simulated using fibrotic patches randomly scattered in the myocardial tissue of fibrotic layers, while endo-epicardial dissociation was simulated using myocardial patches randomly scattered in the fibrotic tissue of isolation layers. Multiple simulation groups were generated to quantitatively analyze the effects of endo epicardial dissociation and intramural fibrosis on AF stability, including a stochastic group, interrelated groups, fibrosis-degree-controlled groups, and dissociation-degree-controlled groups. RESULTS: 1. Stable intramural re-entries were observed to move along complete re-entrant circuits inside the transmural wall in four of 65 simulations in the stochastic group. 2. About 21 of 23 stable simulations in the stochastic group were distributed in the areas with high endo epicardial dissociation and intramural fibrosis. 3. The difference between fibrosis-degree-controlled groups and dissociation-degree-controlled groups suggested that some distributions of connection areas may affect AF episodes despite low intramural fibrosis and endo-epicardial dissociation. 4. The overview of tracking phase singularities revealed that endo-epicardial dissociation played a visible role in AF substrates. CONCLUSION: The complex intramural microstructure is positively correlated with critical components of AF maintenance mechanisms. The occurrence of intramural re-entry further indicates the complexity of AF wave-dynamics. PMID- 30485347 TI - Social media popularity and election results: A study of the 2016 Taiwanese general election. AB - This paper investigates the relationship between candidates' online popularity and election results, as a step towards creating a model to forecast the results of Taiwanese elections even in the absence of reliable opinion polls on a district-by-district level. 253 of 354 legislative candidates of single-member districts in Taiwan's 2016 general election had active public Facebook pages during the election period. Hypothesizing that the relative popularity of candidates' Facebook posts will be positively related to their election results, I calculated each candidate's Like Ratio (i.e. proportions of all likes on Facebook posts obtained by candidates in their district). In order to have a measure of online interest without the influence of subjective positivity, I similarly calculated the proportion of daily average page views for each candidate's Wikipedia page. I ran a regression analysis, incorporating data on results of previous elections and available opinion poll data. I found the models could describe the result of the election well and reject the null hypothesis. My models successfully predicted 80% of winners in single-member districts and were effective in districts without local opinion polls with a predictive power approaching that of traditional opinion polls. The models also showed good accuracy when run on data for the 2014 Taiwanese municipal mayors election. PMID- 30485348 TI - Copy number variation in the susceptibility to systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic component and etiology characterized by chronic inflammation and autoantibody production. The purpose of this study was to ascertain copy number variation (CNV) in SLE using a case-control design in an admixed Brazilian population. The whole-genome detection of CNV was performed using Cytoscan HD array in SLE patients and healthy controls. The best CNV candidates were then evaluated by quantitative real-time PCR in a larger cohort or validated using droplet digital PCR. Logistic regression models adjusted for sex and ancestry covariates was applied to evaluate the association between CNV with SLE susceptibility. The data showed a synergistic effect between the FCGR3B and ADAM3A loci with the presence of deletions in both loci significantly increasing the risk to SLE (5.9-fold) compared to the deletion in the single FCGR3B locus (3.6-fold). In addition, duplications in these genes were indeed more frequent in healthy subjects, suggesting that high FCGR3B/ADAM3A gene copy numbers are protective factors against to disease development. Overall, 21 rare CNVs were identified in SLE patients using a four-step pipeline created for identification of rare variants. Furthermore, heterozygous deletions overlapping the CFHR4, CFHR5 and HLA-DPB2 genes were described for the first time in SLE patients. Here we present the first genome-wide CNV study of SLE patients in a tri-hybrid population. The results show that novel susceptibility loci to SLE can be found once the distribution of structural variants is analyzed throughout the whole genome. PMID- 30485349 TI - Pro-osteoporotic miR-320a impairs osteoblast function and induces oxidative stress. AB - MicroRNAs (miRNAs) are important regulators of many cellular processes, including the differentiation and activity of osteoblasts, and therefore, of bone turnover. MiR-320a is overexpressed in osteoporotic bone tissue but its role in osteoblast function is unknown. In the present study, functional assays were performed with the aim to elucidate the mechanism of miR-320a action in osteoblastic cells. MiR 320a was either overexpressed or inhibited in human primary osteoblasts (hOB) and gene expression changes were evaluated through microarray analysis. In addition, the effect of miR-320a on cell proliferation, viability, and oxidative stress in hOB was evaluated. Finally, matrix mineralization and alkaline phosphatase activity were assessed in order to evaluate osteoblast functionality. Microarray results showed miR-320a regulation of a number of key osteoblast genes and of genes involved in oxidative stress. Regulation of osteoblast differentiation and ossification appeared as the best significant biological processes (PANTHER P value = 3.74E-05; and P value = 3.06E-04, respectively). The other enriched pathway was that of the cellular response to cadmium and zinc ions, mostly by the overexpression of metallothioneins. In hOBs, overexpression of miR-320a increased cell proliferation and oxidative stress levels whereas mineralization capacity was reduced. In conclusion, overexpression of miR-320a increased stress oxidation levels and was associated with reduced osteoblast differentiation and functionality, which could trigger an osteoporotic phenotype. PMID- 30485350 TI - Performance metrics for an application-driven selection and optimization of psychophysical sampling procedures. AB - When estimating psychometric functions with sampling procedures, psychophysical assessments should be precise and accurate while being as efficient as possible to reduce assessment duration. The estimation performance of sampling procedures is commonly evaluated in computer simulations for single psychometric functions and reported using metrics as a function of number of trials. However, the estimation performance of a sampling procedure may vary for different psychometric functions. Therefore, the results of these type of evaluations may not be generalizable to a heterogeneous population of interest. In addition, the maximum number of trials is often imposed by time restrictions, especially in clinical applications, making trial-based metrics suboptimal. Hence, the benefit of these simulations to select and tune an ideal sampling procedure for a specific application is limited. We suggest to evaluate the estimation performance of sampling procedures in simulations covering the entire range of psychometric functions found in a population of interest, and propose a comprehensive set of performance metrics for a detailed analysis. To illustrate the information gained from these metrics in an application example, six sampling procedures were evaluated in a computer simulation based on prior knowledge on the population distribution and requirements from proprioceptive assessments. The metrics revealed limitations of the sampling procedures, such as inhomogeneous or systematically decreasing performance depending on the psychometric functions, which can inform the tuning process of a sampling procedure. More advanced metrics allowed directly comparing overall performances of different sampling procedures and select the best-suited sampling procedure for the example application. The proposed analysis metrics can be used for any sampling procedure and the estimation of any parameter of a psychometric function, independent of the shape of the psychometric function and of how such a parameter was estimated. This framework should help to accelerate the development process of psychophysical assessments. PMID- 30485351 TI - Accessible mathematics videos for non-disabled students in primary education. AB - Our work applies Universal Design criteria for producing and using Mathematics videos for primary education students, at a time when many countries are shifting towards inclusive education policies. We have focused on how the accessibility criteria used for students with visual impairments might affect non-disabled students. For this, we reviewed applicable Universal Design principles as well as best practices in multimedia learning. We took into account the roles, procedures, tools and standards involved in the multimedia lifecycle. We then undertook an experiment consisting of producing two videos about prime numbers with the same pedagogical contents; one video was accessible for students with visual impairments and the other one was not accessible to them. We conducted a trial in real world school settings with 228 non-disabled children, who were randomly assigned a version, either accessible or not accessible, and were then asked to take a test to measure objective aspects of their learning concerning retention and transfer as well as several subjective aspects, including the attractiveness of the videos. Results indicate that there were no significant differences in the scores obtained by students using either video, although the group who watched the accessible video obtained higher score medians in the retention questions. Moreover, students found the accessible video significantly more attractive (p = 0.042). Our study provides recommendations for different stakeholders and stages within the process of producing multimedia mathematics materials that are accessible to primary students with visual impairments, as well as evidence demonstrating that everybody can benefit from the recommendations for developing good quality, accessible multimedia material. PMID- 30485352 TI - Conservatively managed patients with non-ST-segment elevation acute coronary syndrome are undertreated with indicated medicines. AB - INTRODUCTION AND AIMS: Patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) are often managed conservatively. Clinical practice guidelines recommend treating these patients with the same pharmacological drugs as those who receive invasive treatment. We analyze the use of new antiplatelet drugs (NADs) and other recommended treatments in people discharged following an NSTE ACS according to the treatment strategy used, comparing the medium-term prognosis between groups. METHODS: Prospective observational multicenter registry study in 1717 patients discharged from hospital following an ACS; 1143 patients had experienced an NSTE-ACS. We analyzed groups receiving the following treatment: No cardiac catheterization (NO CATH): n = 134; 11.7%; Cardiac catheterization without revascularization (CATH-NO REVASC): n = 256; 22.4%; percutaneous coronary intervention (PCI): n = 629; 55.0%; and coronary artery bypass graft (CABG): n = 124; 10.8%. We assessed major adverse cardiovascular events (MACE), all-cause mortality, and hemorrhagic complications at one year. RESULTS: NO CATH was the oldest, had the most comorbidities, and was at the highest risk for ischemic and hemorrhagic events. Few patients who were not revascularized with PCI received NADs (NO CATH: 3.7%; CATH-NO REVASC: 10.6%; PCI: 43.2%; CABG: 3.2%; p<0.001). Non revascularized patients also received fewer beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), and statins (p<0.001). At one year, MACE incidence in NO CATH group was three times that of the other groups (30.1%, p<0.001), and all-cause mortality was also much higher (26.3%, p<0.001). There were no significant differences in hemorrhagic events. Belonging to NO CATH group was an independent predictor for MACE at one year in the multivariate analysis (HR 2.72, 95% CI 1.29-5.73; p = 0.008). CONCLUSIONS: Despite current invasive management of NSTE-ACS, patients not receiving catheterization are at very high risk for under treatment with recommended drugs, including NADs. Their medium-term prognosis is poor, with high mortality. Patients treated with PCI receive better pharmacological management, with high use of NADs. PMID- 30485353 TI - Prognostic implications of late gadolinium enhancement at the right ventricular insertion point in patients with non-ischemic dilated cardiomyopathy: A multicenter retrospective cohort study. AB - INTRODUCTION: The presence of late gadolinium enhancement (LGE) at the right ventricular insertion point (RVIP) on cardiac magnetic resonance (CMR) is generally believed to be nonspecific, but the clinical implication of this unique LGE pattern in patients with non-ischemic dilated cardiomyopathy (NICM) has not been elucidated. OBJECTIVES: We investigated the prognostic significance of RVIP LGE in NICM patients. METHODS: A total of 360 consecutive NICM patients referred for CMR (102 with no LGE, 50 with RVIP-LGE, 121 with left ventricular [LV]-LGE, and 87 with both an LV and RVIP-LGE) were studied. The primary endpoint was a composite of the all-cause death, hospitalization due to worsening of heart failure, and major arrhythmic events. RESULTS: During a mean follow-up of 45.2 +/ 36.5 months, 149 (41.4%) patients (22 [21.6%] no LGE vs. 16 [32.0%] RVIP-LGE vs. 62 [51.2%] LV-LGE vs. 49 [56.3%] both LV and RVIP-LGE, P < 0.0001) reached the primary endpoint. A Kaplan Meier curve demonstrated that RVIP-LGE patients had an intermediate trend of an event free survival rate for the composite endpoint (log rank P < 0.0001). In a multivariable Cox regression model, LV-LGE (P = 0.008) and both LV and RVIP-LGE (P = 0.003) were significantly associated with a worse outcome, whereas RVIP-LGE was not (P = 0.101). In addition, RVIP-LGE patients (n = 32) had a more favorable outcome compared to LV-LGE patients (n = 32) even after matching the extent of the LGE (median 3.4% [interquartile range, 3.1-3.8], 8 [25.0%] RVIP-LGE vs. 20 [62.5%] LV-LGE, P = 0.002). CONCLUSIONS: LGE confined to the RVIP among NICM patients did not significantly increase the risk of adverse cardiac events, and also showed a better outcome than the same extent of LGE located in the LV. Identification of this unique LGE distribution may help refine the current risk stratification. PMID- 30485354 TI - Evidence for a role of spindle matrix formation in cell cycle progression by antibody perturbation. AB - In Drosophila it has recently been demonstrated that a spindle matrix in the form of a membrane-less macromolecular assembly embeds the microtubule-based spindle apparatus. In addition, two of its constituents, Megator and Chromator, were shown to function as spatial regulators of spindle checkpoint proteins. However, whether the spindle matrix plays a wider functional role in spatially regulating cell cycle progression factors was unknown. Here using a live imaging approach we provide evidence that a number of key cell cycle proteins such as Cyclin B, Polo, and Ran co-localize with the spindle matrix during mitosis. Furthermore, prevention of spindle matrix formation by injection of a function blocking antibody against the spindle matrix protein Chromator results in cell cycle arrest prior to nuclear envelope breakdown. In such embryos the spatial dynamics of Polo and Cyclin B enrichment at the nuclear rim and kinetochores is abrogated and Polo is not imported into the nucleus. This is in contrast to colchicine arrested embryos where the wild-type dynamics of these proteins are maintained. Taken together these results suggest that spindle matrix formation may be a general requirement for the localization and proper dynamics of cell cycle factors promoting signaling events leading to cell cycle progression. PMID- 30485355 TI - Evaluation of optic nerve subarachnoid space in primary open angle glaucoma using ultrasound examination. AB - OBJECTIVES: To measure Optic Nerve Subarachnoid Space (ONSAS) in patients with primary open-angle glaucoma (POAG) and controls using A-scan ultrasound and to evaluate the measurement of the ONSAS in relation to age patient and OCT parameters. METHODS: This retrospective study included 53 consecutive eyes of 27 patients with POAG and 64 normal eyes of 32 controls. Both glaucomatous and control groups were divided into 2 subgroups according to age: <60 age (glaucomatous and control group 1) and 61-90 age (glaucomatous and control group 2). RESULTS: The ONSAS was significantly lower in all glaucomatous eyes (3.54 +/- 0.38) versus normal eyes (3.87 +/- 0.32) (p = 0.001). Significant reduction of ONSAS was showed in control group 2 (3.63 mm +/- 0.37) compared to control group 1 (3.87 mm +/- 0.32) (p = 0.014) and between glaucoma group 1 (3.54 mm +/- 0.38) and control group 1 (p = 0.001). While no significant differences were observed between glaucomatous group 2 (3.48 mm +/- 0.41) and control group 2 (p = 0.17) and between glaucoma group 1 and glaucoma group 2 (p = 0.609). Lastly, the ONSAS was not significantly associated with GCC and RNFL parameters except for Focal Loss Volume (FLV), Superior RNFL and ONSAS in glaucoma group 1 and for FLV and ONSAS in all glaucomatous group. CONCLUSION: Standardized A-scan ultrasound is a non invasive imaging technique with which it is possible to monitor ONSAS changes in glaucomatous patients. The reduction of ONSAS confirm the importance of the lower orbital CSFP as further risk factor in the progression of glaucoma disease. PMID- 30485356 TI - Information-theoretic models of deception: Modelling cooperation and diffusion in populations exposed to "fake news". AB - The modelling of deceptions in game theory and decision theory has not been well studied, despite the increasing importance of this problem in social media, public discourse, and organisational management. This paper presents an improved formulation of the extant information-theoretic models of deceptions, a framework for incorporating these models of deception into game and decision theoretic models of deception, and applies these models and this framework in an agent based evolutionary simulation that models two very common deception types employed in "fake news" attacks. The simulation results for both deception types modelled show, as observed empirically in many social systems subjected to "fake news" attacks, that even a very small population of deceivers that transiently invades a much larger population of non-deceiving agents can strongly alter the equilibrium behaviour of the population in favour of agents playing an always defect strategy. The results also show that the ability of a population of deceivers to establish itself or remain present in a population is highly sensitive to the cost of the deception, as this cost reduces the fitness of deceiving agents when competing against non-deceiving agents. Diffusion behaviours observed for agents exploiting the deception producing false beliefs are very close to empirically observed behaviours in social media, when fitted to epidemiological models. We thus demonstrate, using the improved formulation of the information-theoretic models of deception, that agent based evolutionary simulations employing the Iterated Prisoner's Dilemma can accurately capture the behaviours of a population subject to deception attacks introducing uncertainty and false perceptions, and show that information-theoretic models of deception have practical applications beyond trivial taxonomical analysis. PMID- 30485357 TI - Impact of an alternating first-line antibiotics strategy in febrile neutropenia. AB - BACKGROUND: Rising antibiotic resistance poses a challenge to the management of febrile neutropenia in patients with haematological malignancies receiving chemotherapy. AIM: We studied an alternating first-line antibiotic strategy to determine its impact on all-cause mortality and bacteremia rates in patients with febrile neutropenia. METHODS: An alternating first-line antibiotic strategy was established in mid-2013. Data for 2012 (before strategy implementation) and 2014 (post-strategy implementation) were compared. Antibiotic Heterogeneity Index (AHI) for each of the two time-periods was also calculated. FINDINGS: There were 2012 admissions (26082 patient-days) in 2012 and 1843 admissions (24331 patient days) in 2014. There was no significant difference in the baseline characteristics of patients in the two groups. The defined daily doses (DDD) of cefepime (CEF) fell while the DDD of piperacillin-tazobactam (PTZ) rose in 2014 compared with 2012. Vancomycin DDD fell in 2014. The AHI was 0.466 in 2012 and 0.582 in 2014. The difference in all-cause mortality was not statistically significant. There was no difference in rates of bacteremia with CEF-resistant, PTZ-resistant and carbapenem-resistant gram-negative organisms in the two groups. Rates of new cases of Methicillin-resistant Staphylococcus aureus (MRSA) were 2.38/1000 and 2.59/1000 patient-days in 2012 and 2014 respectively. Rates of new cases of Vancomycin-resistant Enterococcus (VRE) were 1.84/1000 and 1.81/1000 patient-days in 2012 and 2014 respectively. There was no Carbapenem-resistant Enterobacteriaceae (CRE) bacteremia in 2012 and 1 in 2014. CONCLUSION: An alternating first-line antibiotic strategy resulted in an increase in antibiotic heterogeneity, without increasing mortality. There was also no significant increase in bacteremia rates. PMID- 30485358 TI - Mechanism design of incentive-based reverse auctions with loss-averse 3PLs under incomplete attributes. AB - As a supply chain solution integrator, fourth party logistics (4PL) has become an important focus for improving the operational efficiency of the logistics industry in recent days. This paper addresses the mechanism design problem of the 4PL for selecting a third party logistics (3PL) provider who involves loss-averse behavior to form a longer-term strategic partnership in multi-attribute reverse auctions. Due to fluctuating costs of energy or labor and unintentional delivery failures like traffic jam or technology malfunctions, we consider two incomplete attributes, namely cost uncertainty and delivery risk. Integrating the loss averse behavior of 3PLs, based on the prospect theory, the bid decision model is constructed to obtain 3PLs' bidding strategies. The corresponding efficient and optimal scoring auctions that consist of cost-sharing contract and contingent penalty are developed to maximize the ex ante expected profit of the system or the 4PL depending on whether the 4PL is willing to cooperate or not. Theoretical analysis verified by numerical examples illustrates the advantage of the proposed mechanisms. Impacts of model parameters on the 4PL's decision are also investigated and managerial insights are presented. PMID- 30485359 TI - Associations between questionnaires on lifestyle and atherosclerotic cardiovascular disease in a Japanese general population: A cross-sectional study. AB - OBJECTIVE: We aimed to investigate the association between questionnaires related to lifestyle habits and atherosclerotic cardiovascular diseases (ASCVD). DESIGN: Cross-sectional observational study. SETTINGS: Community-based medical checkups, called specific health checkups started in Japan since 2008. This checkup includes standard medical examinations as well as a specific questionnaire related to lifestyle habits. PARTICIPANTS: Overall, 47,842 subjects (males = 16,913, 35.4%) aged >=40 years who underwent a Japanese specific health checkup in 2014 in Kanazawa city were included. MAIN OUTCOME MEASURES: Association between 12 lifestyle habits-related questionnaires and the presence of ASCVD, including coronary artery disease and stroke. The questionnaire included the following 12 questions on lifestyle habits: 1) weight gain (>10 kg/20 years), 2) exercise (>30 min, twice a week, >1 year), 3) daily walking or equivalent (>1 h), 4) walking faster (than others in the same generation), 5) body weight changes (>3 kg/year), 6) eating faster (than others in the same generation), 7) eating within 2 h before going to bed (more than three times a week), 8) having a snack after dinner (more than three times a week), 9) skipping breakfast (more than three times a week), 10) daily drinking (alcohol), 11) heavy drinking (more than 60 g ethanol/day), and 12) good sleeping. RESULTS: Multivariable logistic regression analyses revealed that walking faster (odds ratio [OR] = 0.74, 95% confidence interval [CI] = 0.69-0.79, p < 0.0003), body weight changes (>3 kg/year, OR = 1.26, 95% CI = 1.16-1.37, p < 0.0003), eating faster (OR = 1.09, 95% CI = 1.03-1.15, p = 0.003), daily drinking (OR = 0.83, 95% CI = 0.76-0.89, p < 0.0003), and good sleeping (OR = 0.86, 95% CI = 0.79-0.93, p < 0.0003) were independently associated with ASCVD. Subjects with a high lifestyle habits risk score (number of bad habits: 7-12) had significantly higher odds for ASCVD than those with a low risk score (number of bad habits: 0-3, OR = 1.78, 95%CI = 1.62 1.95, p < 0.0003). CONCLUSION: Simple questionnaires related to lifestyle habits were associated with self-reported ASCVD. PMID- 30485360 TI - Severe-combined immunodeficient rats can be used to generate a model of perinatal hypoxic-ischemic brain injury to facilitate studies of engrafted human neural stem cells. AB - Cerebral palsy (CP) encompasses a group of non-progressive brain disorders that are often acquired through perinatal hypoxic-ischemic (HI) brain injury. Injury leads to a cascade of cell death events, resulting in lifetime motor and cognitive deficits. There are currently no treatments that can repair the resulting brain damage and improve functional outcomes. To date, preclinical research using neural precursor cell (NPC) transplantation as a therapy for HI brain injury has shown promise. To translate this treatment to the clinic, it is essential that human-derived NPCs also be tested in animal models, however, a major limitation is the high risk of xenograft rejection. A solution is to transplant the cells into immune-deficient rodents, but there are currently no models of HI brain injury established in such a cohort of animals. Here, we demonstrate that a model of HI brain injury can be generated in immune-deficient Prkdc knockout (KO) rats. Long-term deficits in sensorimotor function were similar between KO and wildtype (WT) rats. Interestingly, some aspects of the injury were more severe in KO rats. Additionally, human induced pluripotent stem cell derived (hiPSC)-NPCs had higher survival at 10 weeks post-transplant in KO rats when compared to their WT counterparts. This work establishes a reliable model of neonatal HI brain injury in Prkdc KO rats that will allow for future transplantation, survival, and long-term evaluation of the safety and efficacy of hiPSC-NPCs for neonatal brain damage. This model will enable critical preclinical translational research using human NPCs. PMID- 30485361 TI - Modeling the spatial and seasonal distribution of offshore recreational vessels in the southeast United States. AB - Understanding the distribution and intensity of recreational boating activities is key for managing safety as well as environmental and social impacts. Recreational boating is a very important component of the diverse maritime traffic in the southeastern United States. The seasonal distribution of offshore recreational vessels in waters off the coast of Northeast Florida and Southeast Georgia was modeled using several techniques (Poisson, negative binomial, hurdle and zero inflated modes, generalized additive models, and generalized mixed models) and by combining map-based information provided by recreational boaters with environmental and geographical variables to find the most parsimonious model. Based on model performance, the final model analysis was conducted using a GAM approach with a negative binomial distribution. The best seasonal models explained between 86.1%- 88.6% of the total deviance. For most seasons, a model that included latitude, longitude, interaction between latitude and longitude, chlorophyll a concentration, and abundance of artificial reefs resulted in the best fit. The only exception was the model for the summer season, which did not include chlorophyll a concentration. Given the complexity of the study area, with a number of maritime activities and several marine species co-occurring, these models could provide information to analyze the distribution and overlap of recreational boating trips with other maritime activities (e.g., cargo ships, commercial vessels) and species (e.g., right whales, sea turtles, sharks). These analyses could be used to decrease harmful interactions among these groups and activities. PMID- 30485362 TI - Characterization of the antibacterial activity of Bald's eyesalve against drug resistant Staphylococcus aureus and Pseudomonas aeruginosa. AB - Bald's eyesalve is an Anglo-Saxon medicinal remedy that has been used through ancient times to treat eye sty infections and may represent a source of ancientbiotics. This study assessed the efficacy of Bald's eyesalve against several strains of Staphylococcus aureus and Pseudomonas aeruginosa, including a multi-drug resistant phenotype, and identified the principal compound conveying antibacterial activity. Bald's eyesalve formulations were produced by combining garlic, onion or leek, wine, bovine bile, and brass, with specific ingredient omissions in several formulations, followed by incubation at 4 degrees C for 9 days. Bald's eyesalve formulation ES-GBBr exhibited the greatest antibacterial activity against S. aureus and P. aeruginosa. Fractionation of ES-GBBr using molecular size exclusion and organic solvent partitioning isolated its antibacterial activity to the small molecule nonpolar fraction, and 1D 1H NMR revealed the identity of the antibacterial agent to be allicin. Depletion of allicin from this fraction by addition of exogenous cysteine established that all observable growth inhibition originated from allicin. Quantification of allicin demonstrated that its concentration was significantly greater in ES-GBBr compared to the ES-O formulation; however, this was not due to greater yield. The antibacterial activity of allicin against S. aureus was antagonized by other ingredients within Bald's eyesalve, whereas they were additive or synergistic against P. aeruginosa. These results suggest that neither leek nor onion is necessary for the antibacterial efficacy of Bald's eyesalve against S. aureus or P. aeruginosa, and while allicin was identified as the principal antibacterial agent present, its activity is influenced differentially in the presence of additional Bald's eyesalve ingredients when used against S. aureus compared to P. aeruginosa. Ancientbiotics may provide a source of promising antibacterials; however, identifying the source of activity and assessing distinct formulations for cooperative effects are essential to using ancient remedies, such as Bald's eyesalve, effectively against drug resistant pathogens. PMID- 30485363 TI - NRF2-regulated cell cycle arrest at early stage of oxidative stress response mechanism. AB - Oxidative stress results in activation of several signal transduction pathways controlled by the PERK-substrate NRF2 (nuclear factor erythroid 2-related factor 2); meanwhile the ongoing cell division cycle has to be blocked. It has been recently shown that Cyclin D1 got immediately down-regulated via PERK pathway in response to oxidative stress leading to cell cycle arrest. However, the effect of NRF2 on cell cycle regulation has not been explored yet. We aimed to reveal a crosstalk between PERK-substrate NRF2 and the key elements of cell cycle regulatory network upon oxidative stress using molecular biological techniques- Although Cyclin D1 level remained constant, its activity was blocked by various stoichiometric inhibitors (such as p15, p21 and p27) even at low level of oxidative stress. The activity of these CDK inhibitors completely disappeared, when the addition of oxidative agent was combined with silencing of either PERK or NRF2.This further confirms the important role of NRF2 in blocking Cyclin D1 with stoichiometric inhibitors at early stage of oxidative stress. PMID- 30485364 TI - Peak emission wavelength and fluorescence lifetime are coupled in far-red, GFP like fluorescent proteins. AB - The discovery and use of fluorescent proteins revolutionized cell biology by allowing the visualization of proteins in living cells. Advances in fluorescent proteins, primarily through genetic engineering, have enabled more advanced analyses, including Forster resonance energy transfer (FRET) and fluorescence lifetime imaging microscopy (FLIM) and the development of genetically encoded fluorescent biosensors. These fluorescence protein-based sensors are highly effective in cells grown in monolayer cultures. However, it is often desirable to use more complex models including tissue explants, organoids, xenografts, and whole animals. These types of samples have poor light penetration owing to high scattering and absorption of light by tissue. Far-red light with a wavelength between 650-900nm is less prone to scatter, and absorption by tissues and can thus penetrate more deeply. Unfortunately, there are few fluorescent proteins in this region of the spectrum, and they have sub-optimal fluorescent properties including low brightness and short fluorescence lifetimes. Understanding the relationships between the amino-acid sequences of far-red fluorescence proteins and their photophysical properties including peak emission wavelengths and fluorescence lifetimes would be useful in the design of new fluorescence proteins for this region of the spectrum. We used both site-directed mutagenesis and gene shuffling between mScarlet and mCardinal fluorescence proteins to create new variants and assess their properties systematically. We discovered that for far red, GFP-like proteins the emission maxima and fluorescence lifetime have a strong inverse correlation. PMID- 30485365 TI - Mycoplasmas are no exception to extracellular vesicles release: Revisiting old concepts. AB - Release of extracellular vesicles (EV) by Gram-negative and positive bacteria is being frequently reported. EV are nano-sized, membrane-derived, non-self replicating, spherical structures shed into the extracellular environment that could play a role in bacteria-host interactions. Evidence of EV production in bacteria belonging to the class Mollicutes, which are wall-less, is mainly restricted to the genus Acholeplasma and is scanty for the Mycoplasma genus that comprises major human and animal pathogens. Here EV release by six Mycoplasma (sub)species of clinical importance was investigated. EV were obtained under nutritional stress conditions, purified by ultracentrifugation and observed by electron microscopy. The membrane proteins of EV from three different species were further identified by mass spectrometry as a preliminary approach to determining their potential role in host-pathogen interactions. EV were shown to be released by all six (sub)species although their quantities and sizes (30-220 nm) were very variable. EV purification was complicated by the minute size of viable mycoplasmal cells. The proteins of EV-membranes from three (sub)species included major components of host-pathogen interactions, suggesting that EV could contribute to make the host-pathogen interplay more complex. The process behind EV release has yet to be deciphered, although several observations demonstrated their active release from the plasma membrane of living cells. This work shed new light on old concepts of "elementary bodies" and "not-cell bound antigens". PMID- 30485366 TI - Rumen and plasma metabolomics profiling by UHPLC-QTOF/MS revealed metabolic alterations associated with a high-corn diet in beef steers. AB - High-grain diets are strongly associated with metabolic disorders in beef steers. Metabolomics can be used to explore the relationship between diet and metabolic changes, but no study has reported rumen and plasma metabolomics profiling associated with increasing dietary corn proportions in the diet of beef steers. Therefore, 12 steers paired according to similar body weights and body condition scores were randomly allocated to one of two diets: a low-corn (28.76%) diet (LCD) with a 40:60 ratio of concentrate to roughage and a high-corn (48.76%) diet (HCD) with a 60:40 ratio of concentrate to roughage. Metabolomics profiling by ultra-high-performance liquid tandem chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOF/MS) showed that steers fed the HCD had increased rumen and plasma carbohydrate metabolites and amino acids, which contributed to the growth of the beef steers. However, the rumen acidity and ruminal and plasma lipopolysaccharide (LPS) concentrations significantly increased with the increase amounts of corn in the diet. In total, 717 rumen metabolites and 386 plasma metabolites were identified. By multivariate analysis, 144 rumen and 56 plasma metabolites were further identified that were significantly different between the two groups (P < 0.05 and variable influence on projection > 1). The differential metabolites in the rumen and plasma were associated with different metabolic pathways, and phenylalanine, tyrosine and tryptophan biosynthesis and phenylalanine metabolism were common key metabolic pathways for the two biofluids. In conclusion, the high-corn diet improved the growth performance of beef steers but decreased the ruminal pH and increased the LPS and harmful metabolites in the rumen and blood, which has implications for the incidence of metabolic diseases. The identified differential metabolites in both the rumen and plasma and the related metabolic pathways may contribute to the exploration of potential biomarkers for high-corn diet-based metabolic diseases. PMID- 30485367 TI - Sexual and bladder dysfunction in male ketamine abusers: A large-scale questionnaire study. AB - PURPOSE: To evaluate the prevalence of lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) in the illicit male ketamine abusers (KA). MATERIALS AND METHODS: The male street KAs caught by policemen and patients visiting urologic clinics were invited to answer a structured questionnaire including demographic data, illicit drug use related details (duration, frequency, dosage and abstinence status), international prostate symptoms score (IPSS), interstitial cystitis symptoms and problem index (ICSI and ICPI) and International index of erectile function (IIEF-5). Erectile dysfunction was defined as IIEF-5 ?21. RESULTS: Finally, we included 1056 participants (993 street, 63 hospital KAs) with a mean age of 27.4 +/-6.2 years. ED presented in 30.8% of all KAs. and Hospital KAs were more subject to having ED than street KAs (69.6% vs. 28.0%, p<0.01). Multi-variate analysis revealed that risk factor for male ED were age ?30 years (OR = 1.765). Subgroup analysis on male street KAs disclosed that abstinence ?3 months is a protective factor for ED. Lower urinary tract symptoms (ICSI+ICPI ?12) was prevalent in KAs and multivariate analysis disclosed that significant risk factors for LUTS (ICSI+ICPI ?12) were age ?30 years, duration ?24 months and co-use of other illicit drugs. CONCLUSIONS: Male ED and LUTS were frequently observed in the ketamine abusers. We suggested that street ketamine abuse should be considered in young men presented with ED and LUTS in the clinics. PMID- 30485368 TI - Obesity as an effect modifier of the association between menstrual abnormalities and hypertension in young adult women: Results from Project ELEFANT. AB - BACKGROUND: The menstrual cycle is regulated by reproductive hormones such as estrogen which has been implicated in the pathogenesis of hypertension and is associated with obesity. However, to date there has scant study of hypertension in relation to menstrual characteristics and abnormalities. We hypothesize that adverse menstrual characteristics are associated with an increase the prevalence of hypertension and that this relationship is exacerbated by obesity. METHODS: Our study leverages 178,205 healthy female participants (mean age = 29) in a population-based cross-sectional study in Tianjin, China. Menstrual characteristics including menstrual cycle length and regularity, menstrual bleeding length, menstrual blood loss and dysmenorrhea were assessed by self reported questionnaires, and hypertension was diagnosed by physician. Multiple logistic regression models were used to assess the relationships between menstrual characteristics and hypertension. RESULTS: Normal length menstrual cycle (OR = 1.21, 95% CI: 1.03-1.41), oligomenorrhea (OR = 1.54, 95% CI: 1.12 2.07), irregular cycle (OR = 1.54, 95% CI: 1.22-1.93), and light menstrual blood loss (OR = 1.36, 95% CI: 1.06-1.72) were associated with hypertension among women who are overweight or obese, but not among women who are normal weight. Longer menstrual bleeding duration (OR = 1.44, 95% CI: 1.24-1.67) and dysmenorrhea were associated with increased prevalence of hypertension (OR = 1.20, 95% CI: 1.14 1.41) in all young women. CONCLUSIONS: The prevalence of hypertension is higher among women with menstrual abnormalities, and this association is modified by overweight and obesity. PMID- 30485369 TI - Low rank and sparsity constrained method for identifying overlapping functional brain networks. AB - Analysis of functional magnetic resonance imaging (fMRI) data has revealed that brain regions can be grouped into functional brain networks (fBNs) or communities. A community in fMRI analysis signifies a group of brain regions coupled functionally with one another. In neuroimaging, functional connectivity (FC) measure can be utilized to quantify such functionally connected regions for disease diagnosis and hence, signifies the need of devising novel FC estimation methods. In this paper, we propose a novel method of learning FC by constraining its rank and the sum of non-zero coefficients. The underlying idea is that fBNs are sparse and can be embedded in a relatively lower dimension space. In addition, we propose to extract overlapping networks. In many instances, communities are characterized as combinations of disjoint brain regions, although recent studies indicate that brain regions may participate in more than one community. In this paper, large-scale overlapping fBNs are identified on resting state fMRI data by employing non-negative matrix factorization. Our findings support the existence of overlapping brain networks. PMID- 30485370 TI - Measuring the perceptual grouping of non-adjacent surfaces that are invisibly (amodally) or visibly connected. AB - Classic Gestalt examples of perceptual grouping entail arrays of disconnected surfaces that are grouped on the basis of the surfaces' relative similarity or proximity. However, most natural environments contain multiple objects, each with multiple, connected surfaces. Moreover, an object in a scene is likely to partially occlude other objects in the 2-dimensional retinal projection of the scene. A central question, therefore, is how the visual system forms a 3 dimensional representation of multi-object scenes by determining which surfaces belong to which objects. To this end, a recently developed dynamic grouping methodology determines whether pairs of surfaces are grouped together on the basis of the direction in which motion is perceived across a surface when its luminance is perturbed. It is shown using this method that the visible surfaces of a partially occluded object are perceptually grouped when they are plausibly connected and represented in a depth plane behind the occluding object. Invisible connectivity (amodal completion) as well as connectivity established by a visible surface have a powerful influence on the grouping of surfaces. However, for neither kind of connectivity is grouping affected by the distance between the surfaces. This absence of a distance/proximity effect on grouping is obtained when the space between to-be-grouped surfaces is filled with other surfaces. It contrasts with the strong effect of distance/proximity on the grouping of disconnected surfaces, and on the clarity of illusory contours formed between disconnected contours. It is concluded that distance/proximity is an operative grouping variable only when there is empty space between the to-be-grouped surfaces. PMID- 30485371 TI - Epithelial defects after penetrating keratoplasty in infectious keratitis: An analysis of characteristics and risk factors. AB - To investigate the clinical characteristics, treatment, risk factors of occurrence and graft transparency of corneal epithelial defects after penetrating keratoplasty in patients with infectious keratitis. 594 patients (594 eyes) with infectious keratitis treated by penetrating keratoplasty at Shandong Eye Institute were reviewed retrospectively between January 2008 and January 2018. We investigated the demographic data, diameter and sources of graft, onset time, location, scope, time of healing and treatment of epithelial defects, as well as other postoperative complications and graft clarity. 114 of the 594 grafts (19.2%) that developed epithelial defects were included in the epithelial defects group, while the other 480 patients were classified in the non-defect group. The mean age of patients with epithelial defects was statistically greater than that of patients without epithelial defects (P = 0.006). The epithelial defects group accounted for a larger proportion of male patients (P<0.001). The proportion of patients with a graft diameter >9mm in the epithelial defect group (29.8%) was more than that in the non-defects group (16.3%) (P = 0.001). The incidence of epithelial defects significantly differed among the pathogenic causes of infectious keratitis (P = 0.002). The incidence of graft infection (21.1%, 9.2%, respectively, P<0.001) and graft dysfunction (7.9%, 2.5%, respectively, P = 0.012) in the epithelial defect group was higher than in the non-defects group. Multivariate logistic regression revealed that male sex (P = 0.001), age >= 60 years (P = 0.024), graft diameter >9mm (P = 0.001), bacterial (P = 0.039) and herpes simplex keratitis (P = 0.008), rheumatism (P = 0.031) and cancer treated with chemo- or radiotherapy (P = 0.032) were independent risk factors for epithelial defects. Graft clarity after epithelial defects were significantly differed between fungal and viral infections (P<0.001). We found that being an elderly male patient, a graft diameter >9 mm, bacterial and viral keratitis and systemic diseases (including rheumatism and cancer treated with chemo- or radiotherapy) were independent risk factors for postoperative epithelial defects. PMID- 30485372 TI - Differential detection of tuberculous and non-tuberculous mycobacteria by qPCR in lavage fluids of tuberculosis-suspicious white rhinoceros. AB - Tuberculosis (TB) occurs in a wide range of mammalian species and thus poses a health risk to humans living or working in close proximity with TB infected animals. Despite a high incidence of M. bovis infections in domestic or wildlife species tuberculosis infections in rhinoceros have so far been very limited. Over the past 53 years, tuberculosis of the respiratory tract has been confirmed in just 22 rhinoceros, most of those infected not by M. bovis but M. tuberculosis. However, because of the zoonotic risk TB testing is recommended or becomes even mandatory in endangered species. The dilemma in rhinoceros and many other wildlife species; non-validated tests are highly inconsistent in their ability to identify TB infection. Current lack of TB diagnostics may result in TB positive rhinoceros living with the infection, transmitting it to those around them or in euthanasia of animals found unconfirmed at necropsy. This is an unacceptable diagnostic status considering that some species are critically endangered and therefore should not be euthanized in order to confirm suspicion of disease. To overcome this shortcoming we used bronchoscopy to detect mycobacteria in respiratory fluids of TB suspicious rhinoceros. Fluids from seven, TB suspicious white rhinoceros were harvested during 21 bronchoscopies. Our new approach: In addition to bacterial culture a dual quantitative PCR system tested for the general presence of DNA from NTM and more specifically for DNA from MTC. Both, bacterial culture and qPCR were negative for MTC in respiratory fluids of all rhinoceros (7/7). At the same time, respiratory fluids from six rhinoceros tested positive for the presence of NTM or other closely related bacteria (6/7). M. tuberculosis was found only once in an oesophageal aspirate. The high incidence of mycobacterial DNA in the respiratory tract suggests that white rhinoceros, as strict grazers, are immensely exposed to environmental bacteria of this genus. Presence of NTM in the respiratory or intestinal system could possibly cause false positive results in intradermal tests. A wider use of bronchoalveolar lavage is warranted to further elucidate immunologic response to NTM and exposure to, incidence and prevalence of MTC infections in rhinoceros. PMID- 30485373 TI - Giant panda twin rearing without assistance requires more interactions and less rest of the mother-A case study at Vienna Zoo. AB - The giant pandas' (Ailuropoda melanoleuca) reproductive strategy is unique among mammals. Yet there are characteristics of giant panda behaviour we do not fully understand. Probably one of the least understood is the assumption that in captivity virtually all giant panda females rear only one cub when twins are born and abandon the other if given the chance. So far, only two females have raised twins simultaneously, but just with intensive human assistance. This case-study marks the first successful rearing of giant panda twins in captivity entirely by the mother. Using video data for detailed behavioural observations, we provide the first behavioural assessment of a giant panda female raising two cubs simultaneously without direct human assistance or disturbance. We compared the maternal behaviour during the denning period of twin cubs raised in 2016 with two singleton cubs born 2007 and 2010. YANG YANG, the dam, rested less and interacted more with the twins than with the singletons in the first month postpartum and invested a greater part of her daily time budget on rearing the twins. We discuss potential favourable factors for the autonomous twin-rearing of a female giant panda, which could serve as a model for similar efforts elsewhere. PMID- 30485374 TI - Correction: Effects of pulsed electromagnetic field (PEMF) on the tensile biomechanical properties of diabetic wounds at different phases of healing. AB - [This corrects the article DOI: 10.1371/journal.pone.0191074.]. PMID- 30485375 TI - BOLD fMRI effects of transcutaneous vagus nerve stimulation in patients with chronic tinnitus. AB - OBJECTIVE: Vagus nerve stimulation (VNS) is a neuromodulation method used for treatment of epilepsy and depression. Transcutaneous VNS (tVNS) has been gaining popularity as a noninvasive alternative to VNS. Previous tVNS neuroimaging studies revealed brain (de)activation patterns that involved multiple areas implicated in tinnitus generation and perception. In this study, functional magnetic resonance imaging (fMRI) was used to explore the effects of tVNS on brain activity in patients with tinnitus. METHODS: Thirty-six patients with chronic tinnitus received tVNS to the inner tragus, cymba conchae, and earlobe (sham stimulation). RESULTS: The locus coeruleus and nucleus of the solitary tract in the brainstem were activated in response to stimulation of both locations compared with the sham stimulation. The cochlear nuclei were also activated, which was not observed in healthy subjects with normal hearing. Multiple auditory and limbic structures, as well as other brain areas associated with generation and perception of tinnitus, were deactivated by tVNS, particularly the parahippocampal gyrus, which was recently speculated to cause tinnitus in hearing-impaired patients. CONCLUSIONS: tVNS via the inner tragus or cymba conchae suppressed neural activity in the auditory, limbic, and other tinnitus-related non-auditory areas through auditory and vagal ascending pathways in tinnitus patients. The results from this study are discussed in the context of several existing models of tinnitus. They indicate that the mechanism of action of tVNS might be involved in multiple brain areas responsible for the generation of tinnitus, tinnitus-related emotional annoyance, and their mutual reinforcement. PMID- 30485376 TI - Smoking prevalence and trends among a U.S. national sample of women of reproductive age in rural versus urban settings. AB - U.S. smoking prevalence is declining at a slower rate in rural than urban settings and contributing to regional health disparities. Cigarette smoking among women of reproductive age is particularly concerning due to the potential for serious maternal and infant adverse health effects should a smoker become pregnant. The aim of the present study was to examine whether this rural-urban disparity impacts women of reproductive age (ages 15-44) including pregnant women. Data came from the ten most recent years of the U.S. National Survey on Drug Use and Health (2007-2016). We estimated prevalence of current smoking and nicotine dependence among women categorized by rural-urban residence, pregnancy status, and trends using chi-square testing and multivariable modeling while adjusting for common risk factors for smoking. Despite overall decreasing trends in smoking prevalence, prevalence was higher among rural than urban women of reproductive age overall (chi2(1) = 579.33, p < .0001) and among non-pregnant (chi2(1) = 578.0, p < .0001) and pregnant (chi2(1) = 79.69, p < .0001) women examined separately. An interaction between residence and pregnancy status showed adjusted odds of smoking among urban pregnant compared to non-pregnant women (AOR = .58, [.53 -.63]) were lower than those among rural pregnant compared to non pregnant women (AOR = 0.75, [.62 -.92]), consistent with greater pregnancy related smoking cessation among urban pregnant women. Prevalence of nicotine dependence was also higher in rural than urban smokers overall (chi2(2) = 790.42, p < .0001) and among non-pregnant (chi2(2) = 790.58, p < .0001) and pregnant women examined separately (chi2(2) = 63.69, p < .0001), with no significant changes over time. Associations involving residence and pregnancy status remained significant in models adjusting for covariates (ps < 0.05). Results document greater prevalence of smoking and nicotine dependence and suggest less pregnancy related quitting among rural compared to urban women, disparities that have potential for direct, multi-generational adverse health impacts. PMID- 30485377 TI - Healthcare value of implementing hepatitis C screening in the adult general population in Spain. AB - BACKGROUND: Elimination of hepatitis C virus (HCV) infection requires high diagnostic rates and universal access to treatment. Around 40% of infected individuals are unaware of their infection, which indicates that effective screening strategies are needed. We analyzed the efficiency (incremental cost utility ratio, ICUR) of 3 HCV screening strategies: a) general population of adults, b) high-risk groups, and c) population with the highest anti-HCV prevalence plus high-risk groups. METHODS: An analytical decision model, projecting progression of the disease over a lifetime, was used to establish the candidate population for HCV screening. HCV data were obtained from the literature: anti-HCV prevalence (0.56%-1.54%), viremic patients (31.5%), and percentage of undiagnosed persons among those with viremia (35%). It was assumed that most patients would be treated and have HCV therapy response (98% SVR); transition probabilities, utilities, and disease management annual costs were obtained from the literature. Efficiency over the life of patients under the National Health System perspective was measured as quality-adjusted life years (QALY) and total cost (screening, diagnosis, pharmacological and disease management). A discount rate of 3% was applied to costs and outcomes. RESULTS: Screening of the adult population would identify a larger number of additional chronic hepatitis C cases (N = 52,694) than screening the highest anti-HCV prevalence population plus high-risk groups (N = 42,027) or screening high-risk groups (N = 26,128). ICUR for the general population vs. high-risk groups was ?8914/QALY gained per patient (?18,157 incremental cost and 2.037 QALY). ICUR for the general population vs. population with highest anti-HCV prevalence plus high risk groups was ?7,448/QALY gained per patient (?7,733 incremental cost and 1.038 QALY). These ICUR values are below the accepted efficiency threshold (?22,000 ?30,000). CONCLUSION: HCV screening and treatment of the general adult population is cost-effective compared to screening of high-risk groups or the population with the highest anti-HCV prevalence plus high-risk groups. PMID- 30485378 TI - Correction: A Global Model for Bankruptcy Prediction. AB - [This corrects the article DOI: 10.1371/journal.pone.0166693.]. PMID- 30485379 TI - Health-seeking pathway and factors leading to delays in tuberculosis diagnosis in West Pokot County, Kenya: A grounded theory study. AB - BACKGROUND: Patients' health-seeking behaviour can lead to delays in tuberculosis (TB) diagnosis, however little is known about the experiences and treatment pathways of patients diagnosed with TB in Kenya. The aim of this study is to explore the health seeking practices and factors contributing to delay in TB diagnosis. METHODS: This study was based on explorative qualitative research using a constructivist grounded theory approach. A total of 61 TB patients in the intensive phase of treatment were recruited as informants in the study. Six focus group discussions and 15 in-depth interviews were used to collect data. Data were analysed through three step coding using the grounded theory approach. RESULTS: Participants adopted different treatment pathways as they sought care from a pluralistic health care system involving traditional healers, herbalists, private clinic, drug shops and the public health sector. The study revealed an explanatory model of factors leading to delay illustrated by the participant's expression "I suffered for a long time." The model is comprised of three categories that lead to delays, namely individual, social-cultural and structural factors. CONCLUSION: There is a need to improve timely diagnosis of TB through innovative approaches such as intensive case finding. Similarly, the health-care system should decentralize TB services as much as possible and offer free diagnostic services to increase accessibility. PMID- 30485380 TI - A mouse model of binge alcohol consumption and Burkholderia infection. AB - BACKGROUND: Binge drinking, an increasingly common form of alcohol consumption, is associated with increased mortality and morbidity; yet, its effects on the immune system's ability to defend against infectious agents are poorly understood. Burkholderia pseudomallei, the causative agent of melioidosis can occur in healthy humans, yet binge alcohol use is progressively being recognized as a major risk factor. Although our previous studies demonstrated that binge alcohol exposure results in reduced alveolar macrophage function and increased Burkholderia virulence in vitro, no experimental studies have investigated the outcomes of binge alcohol on Burkholderia spp. infection in vivo. PRINCIPAL FINDINGS: In this study, we used the close genetic relatives of B. pseudomallei, B. thailandensis E264 and B. vietnamiensis, as useful BSL-2 model systems. Eight week-old female C57BL/6 mice were administered alcohol comparable to human binge drinking episodes (4.4 g/kg) or PBS intraperitoneally 30 min before a non-lethal intranasal infection. In an initial B. thailandensis infection (3 x 105), bacteria accumulated in the lungs and disseminated to the spleen in alcohol administered mice only, compared with PBS treated mice at 24 h PI. The greatest bacterial load occurred with B. vietnamiensis (1 x 106) in lungs, spleen, and brain tissue by 72 h PI. Pulmonary cytokine expression (TNF-alpha, GM-CSF) decreased, while splenic cytokine (IL-10) increased in binge drunk mice. Increased lung and brain permeability was observed as early as 2 h post alcohol administration in vivo. Trans-epithelial electrical resistance (TEER) was significantly decreased, while intracellular invasion of non-phagocytic cells increased with 0.2% v/v alcohol exposure in vitro. CONCLUSIONS: Our results indicate that a single binge alcohol dose suppressed innate immune functions and increased the ability of less virulent Burkholderia strains to disseminate through increased barrier permeability and intracellular invasion of non phagocytic cells. PMID- 30485381 TI - A new measure to assess pain in people with haemophilia: The Multidimensional Haemophilia Pain Questionnaire (MHPQ). AB - People with haemophilia (PWH) experience acute pain during joint bleeds and might develop chronic pain due to joint degeneration. However, there is a lack of standardized measures to comprehensively assess pain in PWH. This study aimed to develop a multidimensional questionnaire for haemophilia-related pain, the Multidimensional Haemophilia Pain Questionnaire (MHPQ), and to present initial validation data among adults.The questionnaire distinguishes between acute/chronic pain and queries about pain locations, duration, frequency, triggering factors, intensity, interference, strategies, specialists for pain management and satisfaction with treatment. An initial version was tested with 16 patients to ensure item comprehensibility and face validity. The final version was answered by 104 adults, with 82 (78.8%) reporting haemophilia-related pain in the previous year (mean age = 43.17; SD = 13.00). The non-response analysis revealed good item acceptability. Exploratory and confirmatory factor analysis (EFA/CFA), reliability (internal consistency, test-retest, inter-item and item total correlations) and convergent validity were analysed for the intensity and interference dimensions of the questionnaire. A combined EFA with these two constructs supported a 2-factor structure distinguishing intensity (alpha = 0.88) from interference items (alpha = 0.91). CFA was tested for the interference dimension, demonstrating suitability for this sample. Item-total correlations were >0.30 on both dimensions and most inter-item correlations were <0.70. Test retest reliability (n = 42) was good for intensity (r = 0.88) and interference (r = 0.73), and convergent validity was confirmed for most hypotheses (r>0.30).This questionnaire is a comprehensible tool, achieving a thorough assessment of relevant pain dimensions. The MHPQ can help guide treatment recommendations by highlighting relevant topics and contributing to more effective, integrated treatments. PMID- 30485382 TI - Relationship between hemodynamic parameters and severity of ischemia-induced left ventricular wall thickening during cardiopulmonary resuscitation of consistent quality. AB - Ischemia-induced left ventricular (LV) wall thickening compromises the hemodynamic effectiveness of cardiopulmonary resuscitation (CPR). However, accurate assessment of the severity of ischemia-induced LV wall thickening during CPR is challenging. We investigated, in a swine model, whether hemodynamic parameters, including end-tidal carbon dioxide (ETCO2) level, are linearly associated with the severity of ischemia-induced LV wall thickening during CPR of consistent quality. We retrospectively analyzed 96 datasets for ETCO2 level, arterial pressure, LV wall thickness, and the percent of measured end-diastolic volume (%EDV) relative to EDV at the onset of ventricular fibrillation from eight pigs. Animals underwent advanced cardiovascular life support based on resuscitation guidelines. During CPR, LV wall thickness progressively increased while %EDV progressively decreased. Systolic and diastolic arterial pressure and ETCO2 level were significantly correlated with LV wall thickness and %EDV. Linear mixed effect models revealed that, after adjustment for significant covariates, systolic and diastolic arterial pressure were not associated with LV wall thickness or %EDV. ETCO2 level had a significant linear relationship with %EDV (P = 0.004). However, it could explain only 28.2% of the total variance of %EDV in our model. In conclusion, none of the hemodynamic parameters examined in this study appeared to provide sufficient information on the severity of ischemia induced LV wall thickening. PMID- 30485383 TI - Differential induction of interferon stimulated genes between type I and type III interferons is independent of interferon receptor abundance. AB - It is currently believed that type I and III interferons (IFNs) have redundant functions. However, the preferential distribution of type III IFN receptor on epithelial cells suggests functional differences at epithelial surfaces. Here, using human intestinal epithelial cells we could show that although both type I and type III IFNs confer an antiviral state to the cells, they do so with distinct kinetics. Type I IFN signaling is characterized by an acute strong induction of interferon stimulated genes (ISGs) and confers fast antiviral protection. On the contrary, the slow acting type III IFN mediated antiviral protection is characterized by a weaker induction of ISGs in a delayed manner compared to type I IFN. Moreover, while transcript profiling revealed that both IFNs induced a similar set of ISGs, their temporal expression strictly depended on the IFNs, thereby leading to unique antiviral environments. Using a combination of data-driven mathematical modeling and experimental validation, we addressed the molecular reason for this differential kinetic of ISG expression. We could demonstrate that these kinetic differences are intrinsic to each signaling pathway and not due to different expression levels of the corresponding IFN receptors. We report that type III IFN is specifically tailored to act in specific cell types not only due to the restriction of its receptor but also by providing target cells with a distinct antiviral environment compared to type I IFN. We propose that this specific environment is key at surfaces that are often challenged with the extracellular environment. PMID- 30485384 TI - Unmet home care needs in Canada. AB - BACKGROUND: Unmet home care needs have been linked to poor health, increased use of other health services, admission to nursing homes and reduced emotional well being. DATA AND METHODS: Using data from the 2015/2016 Canadian Community Health Survey, this article describes home care use and unmet home care needs by type (i.e., home health care [HHC] and support services) in community-dwelling adults. Among the population with home care needs, the degree to which needs were met, partially met or unmet is presented, as well as information about the barriers to obtaining home care services and the places services were sought. Multivariate analysis was used to examine factors associated with unmet home care needs by type, while controlling for predisposing, enabling and needs-related factors. RESULTS: In 2015/2016, just over one-third (35.4%) of people with home care needs, an estimated 433,000 people, did not have those needs met. This was more prevalent among those with support needs than those with HHC needs. Availability of services was most often cited as a barrier to obtaining home care services, particularly for those with an unmet need for HHC services. Age group, household type, long-term care insurance and health status factors were associated with perceiving an unmet home care need, with few differences by type of unmet need. DISCUSSION: The degree to which needs were met and the perceived barriers to obtaining home care services varied by type of unmet home care need. The results indicate proportionally higher unmet needs for home care services among adults aged 35 to 49. This suggests a possible service gap. PMID- 30485385 TI - Health Utilities Index Mark 3 scores for major chronic conditions: Population norms for Canada based on the 2013 and 2014 Canadian Community Health Survey. AB - BACKGROUND: Utility scores are frequently used as preference weights when estimating quality-adjusted life years within cost-utility analyses or health adjusted life expectancies. Though previous Canadian estimates for specific chronic conditions have been produced, these may no longer reflect current patient populations. DATA AND METHODS: Data from the 2013 and 2014 Canadian Community Health Survey were used to provide Canadian utility score norms for 17 chronic conditions. Utility scores were estimated using the Health Utilities Index Mark 3 instrument and were reported as weighted average (95% confidence intervals [95% CI]) values. In addition to age- and sex-stratified analyses, results were also stratified according to the number of reported chronic conditions (i.e., "none" to "five or more"). All results were weighted using sampling and bootstrapped weights provided by Statistics Canada. RESULTS: Utility scores were estimated for 123,654 (97.2%) respondents (weighted frequency = 29,337,370 [97.7%]). Of the chronic conditions that were examined, asthma had the least detrimental effect (weighted average utility score = 0.803 [95% CI: 0.795 to 0.811]) on respondents' utility scores, and Alzheimer's disease or any other dementia had the most detrimental effect (weighted average utility score = 0.374 [95% CI: 0.323 to 0.426]). Respondents who reported suffering from no chronic conditions had, on average, the highest utility scores (weighted average utility score = 0.928 [95% CI: 0.926 to 0.930]). Estimates dropped as a function of the number of reported chronic conditions. DISCUSSION: Utility scores differed between various chronic conditions and as a function of the number of reported chronic conditions. Results also highlighted several differences with previously published Canadian utility norms. PMID- 30485387 TI - Talk to Patients About: Whooping Cough. AB - But pertussis has made a resurgence. Anti-vaccine sentiment and other factors allow pertussis to spread, especially in school children. But vaccination still remains the best protection. PMID- 30485386 TI - Understanding future needs of Canadian veterans. AB - BACKGROUND: Planning for the future needs of Canadian veterans requires comprehensive and detailed data on the size of the Canadian veteran population and their health. This article describes current veteran population estimates and examines the health of two eras of veterans compared with the health of Canadians in general. DATA AND METHODS: This study describes the size and age structure of the Canadian veteran population forecasted by Veterans Affairs Canada (VAC). Veteran health was examined for two eras of Regular Force veterans. The health of earlier-era veterans (released between 1954 and 2003) was examined using the 2003 Canadian Community Health Survey. The health of recent-era veterans (released between 1998 and 2012) was examined using the 2013 Life After Service Survey. Health indicators for veterans were compared with the Canadian general population using age- and sex-adjusted rates and confidence intervals. RESULTS: The VAC forecast points to a stable population of about 600,000 veterans for the next decade, but a growing proportion will be older than 70 years old. Regular Force veterans of both eras had a higher prevalence than the Canadian general population of activity limitations and back problems, a lower prevalence of low income, and a similar prevalence of life stress and heavy drinking. Recent-era veterans had a higher prevalence than the Canadian general population of many more indicators-in particular, arthritis, self-rated mental health, depression and anxiety. DISCUSSION: Veterans differed from the Canadian general population in many areas of well-being, and recent-era veterans differed in more areas than earlier-era veterans. These results highlight the need for forecasting and planning, and for policy that is sensitive to these differences and incorporates health status changes as veterans age. Multiple data sources will be required to describe the future health needs of the entire Canadian veteran population. PMID- 30485388 TI - Is Psychiatry Cool Again? More Residents Choosing the Specialty Could Mean Good News for Statewide Shortage. AB - More residents choosing psychiatry could mean good news for the statewide shortage. PMID- 30485390 TI - Evening Out the Scale: TMA Gears Up for Another Legislative Battle Over Surprise Bills. AB - TMA gears up for another legislative battle over surprise bills. PMID- 30485389 TI - Best of Both Worlds: Surgical Resident, Grey's Anatomy Consultant Blends the Arts and Medicine. AB - San Antonio surgical resident Michael Metzner, MD, blends his passions for the arts and medicine as a Grey's Anatomy consultant. PMID- 30485391 TI - On a Medical Mission: New Osteopathic Medical School Changes How Medicine is Taught While Helping San Antonio's Poorest Communities. AB - Incarnate Word's osteopathic medical school is changing how medicine is taught while helping San Antonio's poorest communities. PMID- 30485393 TI - Punching Back: Hospital System Sued Again Over Alleged Peer Review Misconduct. AB - Hospital system sued again over alleged peer review misconduct. PMID- 30485392 TI - Too Big a Step? Medicine Urges CMS to Reverse New Step Therapy Policy. AB - Medicine urges CMS to reverse new policy allowing "fail-first" drug programs known as step therapy. PMID- 30485394 TI - Q&A: Austin Family Physician Quenches Her Patients' Thirst for Improved Health. AB - Austin primary care physician Georgeanne Freeman, DO, aims to improve her patients' overall well-being while increasing and diversifying the clinic's revenue. PMID- 30485395 TI - Front Line: Using Primary Care to Prevent Suicide. AB - Suicide is a growing problem and with a shortage of psychiatrists in Texas and the United States, there's real opportunity for primary care physicians to reach vulnerable patients. PMID- 30485396 TI - Creativity and involvement in art in different types of synaesthesia. AB - The aim of the present study was to test the relationship between different types of synaesthesia and their involvement in art, creative, and visual abilities. We tested 20 grapheme-colour, 18 sound-colour, 19 grapheme-colour-and-sound-colour, 20 sequence-space synaesthetes, and the same number of controls matched by age, gender, and education. We assessed the number of artistic professions, involvement in art, and the performance in psychometric tests of divergent and convergent creativity, as well as visual and visuo-spatial abilities. Results show a higher prevalence of artists among synaesthetes, especially sound-colour synaesthetes. Sound-colour synaesthetes also showed a higher involvement in artistic activities overall while sequence-space synaesthetes showed higher involvement in visual art. Only grapheme-colour-and-sound-colour synaesthetes showed significantly higher divergent creativity compared to matched controls. Additionally, overall, synaesthetes scored higher in visuo-spatial abilities (i.e., mental rotation). For synaesthetes and controls, visuo-spatial abilities correlated with divergent creativity. We discuss that synaesthetes' higher involvement in art is not necessarily reflected in their basic creative abilities. PMID- 30485397 TI - Trends in Hospital Deaths in Denmark from 1980 to 2014, at Ages 50 and Older. AB - OBJECTIVES: To explore temporal trends and individual-level determinants of hospital deaths at ages 50 and older in Denmark from 1980 to 2014. DESIGN: Individual-level register-based retrospective study. SETTING: Denmark, 1980 to 2014. PARTICIPANTS: All deaths that occurred in Denmark from 1980 to 2014 among individuals 50 years or older (N = 1 834 437), extracted from population registers. MEASUREMENTS: A death was defined as a hospital death if the individual was admitted to the hospital as an inpatient and the date of discharge from the hospital is equal to the date of death. RESULTS: The percentage of hospital deaths decreased in both sexes (all ages combined, men: 56% to 44%; women: 49% to 39%) and at ages 50 to 79, remained almost unchanged at ages 80 to 89, and increased in the oldest age group (90+ men: 27% to 32%; women: 18% to 24%). We observed increasing trends of hospital deaths for three groups, people 90 years and older, dying from respiratory diseases, and who had terminal hospitalizations lasting 1 to 3 days. Subanalysis of all hospital deaths according to length of the terminal hospitalizations suggests that the overall reduction of hospital deaths might be driven by a reduction in hospitalizations that were longer than 1 week. Persons who are married, have middle or high income, have a history of hospitalizations in the year before death, or die because of respiratory diseases have higher odds of dying in a hospital. CONCLUSION: Results provide evidence that Danes 50 years and older are increasingly dying outside the hospital context. We find three age-specific patterns in the proportion of hospital deaths. Changes in healthcare and social systems implemented in Denmark during the observation period may underlie the broader reduction in hospital deaths in the country. PMID- 30485398 TI - Novel KIAA1109 variants affecting splicing in a Russian family with ALKURAYA KUCINSKAS syndrome. PMID- 30485399 TI - The cognitive effects of endocrine therapy in survivors of breast cancer: A prospective longitudinal study up to 6 years after treatment. AB - BACKGROUND: After treatment of primary breast cancer, endocrine therapy (ET) is prescribed for patients with hormone receptor-positive cancers. Despite ET recommendations of 5 to 10 years of treatment, to the authors' knowledge there is little prospective study of its impact on cognitive function over an extended period of time. ET has known pharmacologic effects on the brain. Cognitive side effects are a concern for many women, with mixed findings reported in various studies. The current prospective longitudinal study examined the neuropsychological effects of ET over time, up to 6 years after treatment. METHODS: A total of 189 survivors of early-stage breast cancer enrolled in the study prior to initiating ET if prescribed, and were followed at 6 months (175 patients), 12 months (173 patients), and for 3 to 6 years (102 patients) with self-report and neuropsychological assessments. Using linear mixed models, the authors examined whether neuropsychological performance or impairment rates differed over time based on whether or not ET was received. RESULTS: The authors did not find any effect of ET on neuropsychological performance or impairment at any time point among survivors who received it compared with women who did not. However, those who participated in the 3-year to 6-year year visit demonstrated better executive function at baseline. CONCLUSIONS: In the current observational cohort study, no detrimental effect of ET on cognitive function was identified in survivors of early-stage breast cancer receiving treatment with ET compared with those who were not. PMID- 30485400 TI - Safety of guselkumab in patients with moderate-to-severe psoriasis treated through 100 weeks: a pooled analysis from the randomised VOYAGE 1 and VOYAGE 2 studies. AB - BACKGROUND: Long-term evaluation is required to confirm the safety profile of newer biologic agents. Objectives To report on pooled safety data from the on going VOYAGE 1 (NCT02207231) and VOYAGE 2 (NCT02207244) trials through 100 weeks of follow-up. METHODS: Patients were randomized to guselkumab 100 mg at weeks 0 and 4 and every-8-weeks thereafter; placebo at weeks 0, 4, 12 followed by guselkumab 100 mg at weeks 16 and 20 and every-8 weeks thereafter; or adalimumab 80 mg at week 0, 40 mg at week 1, and 40 mg every 2 weeks thereafter. Adalimumab patients crossed over to guselkumab at week 52 (VOYAGE1) and at/after week 28 based on clinical response (VOYAGE2). Open-label extensions, when all patients received guselkumab, started at week 52 (VOYAGE1) and week 76 (VOYAGE2). Rates of adverse events (AEs) per 100 patient-years [PY] are presented through 100 weeks of follow up. RESULTS: Through week 52, observed rates for guselkumab- and adalimumab-treated patients, respectively, were 262.45/100PY and 328.28/100PY for AEs, 6.20/100PY and 7.77/100PY for serious AEs (SAEs), 1.22/100PY and 1.79/100PY for serious infections (SIs), 0.28/100PY and 0.40/100PY for malignancies other than nonmelanoma skin cancers (NMSCs), 0.56/100PY and 0.40/100PY for NMSCs, and 0.47/100PY and 0.40/100PY for MACE. Rates among guselkumab-treated patients through week 52 and week 100, respectively, were (262.45/100PY and 210.41/100PY) for AEs, 6.20 and 6.29/100PY), for SAEs, 1.22/100PY and 1.06/100PY for SIs, 0.28/100PY and 0.38/100PY for malignancies, 0.56/100PY and 0.39/100PY for NMSCs, and 0.47/100PY and 0.38/100PY for MACE. Among adalimumab-treated patients, rates of AEs (328.28/100PY vs 160.15/100PY), SAEs (7.77/100PY vs 4.44/100PY), SIs (1.79/100PY vs 0/100PY), malignancies (0.40/100PY vs 0.40/100PY), NMSCs (0.40/100PY vs 0.81/100PY), and MACE (0.40/100PY vs 0.20/100PY) showed some variability before and after crossover to guselkumab, though no new safety signals were noted after crossover. CONCLUSIONS: The safety profile for guselkumab remains favorable through 100 weeks of treatment in patients with moderate-to-severe psoriasis. This article is protected by copyright. All rights reserved. PMID- 30485401 TI - Therapeutic recommendations for early stage Hodgkin lymphomas. AB - Combined modality treatment has been the standard option for the treatment of early stage Hodgkin lymphoma for several decades. Because of the high success rate and the risk of late toxicities, recent clinical trials have focused on reducing the treatment burden. Field and dose of radiotherapy, and number of cycles of chemotherapy have been successfully reduced, particularly for favourable early stage patients. However, the impact of these treatment reductions on the rate of secondary malignancies remains still unclear. Positron emission tomography-computed tomography (PET-CT) scanning has emerged as a very important tool for disease staging and end of treatment assessment. Interestingly, a PET performed after 2 cycles of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) has been correlated with final outcome and was recently evaluated in a randomized clinical trial to evaluate individualized therapy based on PET response after 2 or 3 cycles of ABVD. These trials aimed to identify good prognosis (early PET-negative) patients who could be spared radiotherapy, but also patients with a bad prognosis (early PET-positive) who need more intensive treatment. More recently, new drugs, such as brentuximab vedotin and checkpoint inhibitors, have shown efficacy in relapsed/refractory patients and are currently under evaluation in early stage patients. PMID- 30485402 TI - Plasma cells in classical Hodgkin lymphoma: a new player in the microenvironment? PMID- 30485403 TI - Ten Things Every Geriatrician Should Know About House Calls. AB - Home-based primary care (HBPC) is experiencing a reemergence to meet the needs of homebound older adults. This brief review based on existing literature and expert opinion discusses 10 key facts about HBPC that every geriatrician should know: (1) the team-based nature of HBPC is key to its success; (2) preparations and after-hour access for house calls are required; (3) home safety for the clinician and patient must be considered; (4) being homebound is an independent mortality risk factor with a high symptom burden; (5) home care medicine presents unique benefits and challenges; (6) a systems-based approach to care is essential; (7) HBPC is a sustainable model within value-based care proven by the Department of Veterans Affairs and the Independence at Home Medicare Demonstration Project; (8) HBPC has an educational mission; (9) national organizations for HBPC include American Academy of Home Care Medicine and Home Centered Care Institute; and (10) practicing HBPC is a privilege. HBPC is a dynamic and unique practice model that will continue to grow in the future. PMID- 30485404 TI - Price of disorder in the lac repressor hinge helix. AB - The Lac system of genes has been pivotal in understanding gene regulation. When the lac repressor protein binds to the correct DNA sequence, the hinge region of the protein goes through a disorder to order transition. The structure of this region of the protein is well understood when it is in this bound conformation, but less so when it is not. Structural studies show that this region is flexible. Our simulations show this region is extremely flexible in solution; however, a high concentration of salt can help kinetically trap the hinge helix. Thermodynamically, disorder is more favorable without the DNA present. PMID- 30485405 TI - Improving surgical outcomes through benchmarking. AB - Benchmarking is a popular quality-improvement tool in economic practice. Its basic principle consists of identifying the best (the benchmark), then comparing with the best, and learning from the best. In healthcare, the concept of benchmarking or establishing benchmarks has been less specific, where comparisons often do not target the best, but the average results. The goal, however, remains improvement in patient outcome. This article outlines the application of benchmarking and proposes a standard approach of benchmark determination in surgery, including the establishment of best achievable real-world postoperative outcomes. Parameters used for this purpose must be reproducible, objective and universal. A systematic approach for determining benchmarks enables self assessment of surgical outcome and facilitates the detection of areas for improvement. The intention of benchmarking is to stimulate surgeons' genuine endeavour for perfection, rather than to judge centre or surgeon performance. PMID- 30485406 TI - Antidiuretic hormone- and interleukin-6-producing angioimmunoblastic T-cell lymphoma associated with syndrome of inappropriate antidiuretic hormone secretion. PMID- 30485407 TI - Long- and short-term responses of Asclepias species differ in respect to fire, grazing, and nutrient addition. AB - PREMISE OF THE STUDY: The tallgrass prairie ecosystem has experienced a dramatic reduction over the past 150 yr. This reduction has impacted the abundance of native grassland species, including milkweeds (Asclepias). METHODS: We used two long-term (27 yr) data sets to examine how fire, grazing, and nutrient addition shape milkweed abundance in tallgrass prairie. We compared these results to those of a greenhouse experiment that varied nutrient levels in the absence of competition, herbivory, and mutualistic relationships. KEY RESULTS: Asclepias species exhibited broad patterns in response to burning regimes that did not include grazing, but experienced more species-specific patterns in other combinations. Asclepias syriaca was the only species to increase in abundance in plots that included burning and nutrient addition. In the greenhouse we found that nitrogen significantly increased biomass, while no effect of phosphorus was detected. CONCLUSIONS: These results indicate that A. syriaca will do best in settings with high nutrient loads, low competition, and no grazers. These characteristics define a small portion of the tallgrass prairie but exemplify modern agricultural settings, which have replaced prairies. However, other milkweeds examined did not share this pattern, which indicates that milkweed species will respond differently when exposed to agricultural settings, with some less able to cope with land conversion to pasture or row-crop agriculture. PMID- 30485408 TI - Modern principles in the management of nodular lymphocyte-predominant Hodgkin lymphoma. AB - Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a unique rare subtype of Hodgkin lymphoma (HL) which differs clinically, pathologically and biologically from classic HL, warranting a nuanced approach to treatment. CD20 expression by malignant lymphocyte-predominant cells, a tendency for late relapses, and the risk of transformation to aggressive large B-cell lymphoma are characteristic features with important implications for treatment and follow-up. Recognition of histopathological variant patterns is also critical, with important implications for prognosis and treatment. The optimal management for NLPHL is unclear and opinions differ as to whether treatment paradigms should be similar to, or differ from, those for classic HL. Therapy differs for early versus advanced stage disease and for frontline versus relapsed or refractory disease. Potential treatment strategies include radiotherapy, combined modality therapy, chemotherapy, rituximab and watchful waiting. Given the excellent overall survival of NLPHL, treatment choices should be geared towards reducing long-term toxicity and optimizing survivorship. In this review, we provide an overview of the current literature and discuss modern principles in the management of NLPHL. PMID- 30485409 TI - Non-Pharmacological Treatment for Primary Headaches Prevention and Lifestyle Changes in a Low-Income Community of Brazil: A Randomized Clinical Trial. AB - BACKGROUND: Primary headaches can be reduced by lifestyle changes, such as stress management and physical activity. However, access to programs focused on behavioral interventions is limited in underserved, poor communities. OBJECTIVES: We performed a randomized open-label clinical trial to test the therapeutic and behavioral effects of aerobic exercise, relaxation, or the combination of both, in individuals with primary headaches of a small, low-income community of the Brazilian Amazon. METHODS: Participants were screened from the riverine/rural population, and individuals with primary headache were included. We assessed clinical characteristics and physical activity levels. Interventions were delivery 3 times/week for 6 months. The primary outcome variable was changes in days with headache, while changes in duration of attacks, pain intensity, and physical activity levels were secondary outcomes variables. RESULTS: Seven hundred and ninety individuals were screened (15.3% of rural/riverine population). Seventy-four participants were randomly assigned to relaxation (n = 25), physical activity orientation program (n = 25), or both (n = 24) interventions. Intention to treat analyses showed all interventions as effective to reduce days with headaches and duration of attacks (both P < .01). Pain intensity was reduced only in relaxation and relaxation + physical activity groups (both P < .01). Physical activity levels increased only in the relaxation + physical activity group (P < .05). CONCLUSIONS: Non-pharmacological interventions such as physical activity and relaxation are effective for reducing headaches, while combining such interventions promote health behavior toward higher physical activity levels in low-income populations with primary headaches. CLINICAL TRIAL REGISTRATION NUMBER: SGPP 1544. PMID- 30485410 TI - Effects of biotic interactions on tropical tree performance depend on abiotic conditions. AB - Predicting biotic responses to environmental change requires understanding the joint effects of abiotic conditions and biotic interactions on community dynamics. One major challenge is to separate the potentially confounding effects of abiotic environmental variation and local biotic interactions on individual performance. The stress gradient hypothesis (SGH) addresses this issue directly by predicting that the effects of biotic interactions on performance become more positive as the abiotic environment becomes more stressful. It is unclear, however, how the predictions of the SGH apply to plants of differing functional strategies in diverse communities. We asked (1) how the effect of crowding on performance (growth and survival) of trees varies across a precipitation gradient, and (2) how functional strategies (as measured by two key traits: wood density and leaf mass per area, LMA) mediate average demographic rates and responses to crowding across the gradient. We built trait-based neighborhood models of growth and survival across a regional precipitation gradient where increasing precipitation is associated with reduced abiotic stress. In total, our dataset comprised ~170,000 individual trees belonging to 252 species. The effect of crowding on tree performance varied across the gradient; crowding negatively affected growth across plots and positively affected survival in the wettest plot. Functional traits mediated average demographic rates across the gradient, but we did not find clear evidence that the strength of these responses depends on species' traits. Our study lends support to the SGH and demonstrates how a trait-based perspective can advance these concepts by linking the diversity of species interactions with functional variation across abiotic gradients. PMID- 30485411 TI - PD-1 expression is upregulated on adapted T cells in experimental autoimmune encephalomyelitis but is not required to maintain a hyporesponsive state. AB - T cell adaptation is an important peripheral tolerogenic process which ensures that the T cell population can respond effectively to pathogens but remains tolerant to self-antigens. We probed the mechanisms of T cell adaptation using an experimental autoimmune encephalomyelitis (EAE) model in which the fate of autopathogenic T cells could be followed. We demonstrated that immunisation with a high dose of myelin basic protein (MBP) peptide and complete Freund's adjuvant failed to effectively initiate EAE, in contrast to low dose MBP peptide immunisation which readily induced disease. The proportion of autopathogenic CD4+ T cells in the central nervous system (CNS) of mice immunised with a high dose of MBP peptide was not significantly different to mice immunised with a low dose. However, autopathogenic T cells in mice immunised with high dose MBP peptide had an unresponsive phenotype in ex vivo recall assays. Importantly, whilst expression of PD-1 was increased on adapted CD4+ T cells within the CNS, loss of PD-1 function did not prevent the development of the unresponsive state. The lack of a role for PD-1 in the acquisition of the adapted state stands in striking contrast to the reported functional importance of PD-1 in T cell unresponsiveness in other disease models. PMID- 30485412 TI - Changes in the incidence and uptake of reproductive surgery versus in vitro fertilisation in Australia between 2001 and 2015: A population-based study. AB - OBJECTIVE: Improvements in success rates of assisted reproduction led to predictions that infertility surgery in both women and men would become extinct in developed countries. We sought to identify the changes in reproductive surgery that occurred between 2001 and 2015 to determine whether these predictions have been accurate. DESIGN: The Australian Institute of Health and Welfare (AIHW) national procedural dataset and the Australian Medicare Benefits Scheme (MBS) claims database were searched for procedure data for male and female reproductive surgery and assisted reproduction from January 2001 to December 2015. The denominators were based on annual point estimates of the total population aged 25 44 years (female) and 25-55 years (male) from the Australian Bureau of Statistics (ABS). This dataset provides procedures undertaken but not their indications. RESULTS: Over the study period the incidence of tubal surgery fell by 66%, vasectomy reversal by 33%, and surgical varicocoelectomy by 50%. In contrast, the rate of hysteroscopic myomectomy increased by 48%, hysteroscopic septoplasty by 125%, and laparoscopy for severe endometriosis increased by 84%. In vitro fertilisation oocyte retrievals increased by 90%. The rate of abdominal myomectomy was unchanged. CONCLUSION: Fertility surgery is not dead but has evolved. PMID- 30485413 TI - Comparison of New-Onset and Persistent Epilepsy in the Elderly. AB - BACKGROUND: Previous studies on elderly epilepsy included only patients with new onset disease, but there are many patients who developed epilepsy earlier and aged. AIM: We compared the characteristics of new-onset and persistence epilepsy in the elderly. METHODS: We performed a 10-year retrospective analysis of elderly patients with epilepsy divided into two groups according to the onset of seizure: new-onset epilepsy (onset age>=65) and persistent epilepsy (onset age<65). RESULTS: Nearly half (78/172, 45.3%) of patients in the new-onset group presented as status epilepticus, and one-fourth of these (19/78, 24.4%) died during the initial treatment for status epilepticus. Patients in the new-onset epilepsy group presented more frequently as status epilepticus (59/153 vs. 12/78, p<0.001) and had a past history of status epilepticus (63/153 vs. 20/78, p=0.02). History of stroke (81/153 vs. 30/78, p=0.04), hypertension (83/153 vs. 29/78, p=0.01), and dyslipidemia (53/153 vs. 17/78, p=0.05) were more common in the new-onset group, but patients in the persistent group used more antiepileptic drugs (AEDs; p=0.036) and total AED drug loads (p=0.028). CONCLUSIONS: Our study shows that new-onset epilepsy has a higher incidence of status epilepticus and more stroke related risk factors but may require fewer AEDs for epilepsy control. This article is protected by copyright. All rights reserved. PMID- 30485414 TI - CD300 receptor family in viral infections. AB - The CD300 molecules constitute an evolutionarily significant family of receptors that are expressed on myeloid and lymphoid cells, but also on other cell types, such as tuft cells. Many of the CD300 receptors have been shown to recognize lipids, e.g. phosphatidylserine and phosphatidylethanolamine. Over the past couple of years, accumulating evidence has shown that this family of receptors is involved in the pathogenesis of many diseases. Specifically, CD300 molecules participate in the mechanisms that viruses employ to develop immune evasion strategies and to infect host cells. The participation of CD300 molecules in viral infection includes both lipid dependent and independent mechanisms, as for example in infections with dengue virus (DENV) and murine norovirus (MNV), respectively. CD300 receptors are also involved in viral escape mechanisms, for instance inhibiting NK cell-mediated cytotoxicity against infected cells. Moreover, it is becoming increasingly recognized that the expression of CD300 receptors is altered during viral diseases. Here we review the involvement of human and murine CD300 molecules in viral binding and entry and in cellular responses to viruses, which highlights the potential of CD300 molecules in the search of new biomarkers for various stages of infection and therapeutic targets for the treatment of viral infections. This article is protected by copyright. All rights reserved. PMID- 30485415 TI - Bacterial expression, purification and biophysical characterization of wheat germ agglutinin and its four hevein-like domains. AB - Wheat germ agglutinin (WGA), a chitin binding lectin, has attracted increasing interest because of its unique characteristics such as conformational stability, binding specificity and transcytosis capacity. To pave the way for the study of the molecular basis of WGA's structural stability and binding capacity, as well as to facilitate its use in biomedical and biotechnological developments, we produced recombinant WGA and its 4 isolated hevein-like domains in a bacterial system. All the proteins were expressed as fusion constructs linked to a thioredoxin domain, which was enzymatically or chemically released. The structural and ligand-binding properties of recombinant WGA were similar to the wild lectin. The 4 isolated domains folded and were ligand-binding competent, indicating that each domain constitutes an independent folding unity. The biophysical characterization of the recombinant domains sheds new light on the intricate folding and binding behavior of this emblematic lectin. PMID- 30485416 TI - Environmental pH and Glu364 to Gln mutation in the chlorophyll-binding CP47 protein affect redox-active TyrD and charge recombination in Photosystem II. AB - In Photosystem II, loop E of the chlorophyll-binding CP47 protein is located near a redox-active tyrosine, YD , forming a symmetrical analog to loop E in CP43, which provides a ligand to the oxygen-evolving complex (OEC). A Glu364 to Gln substitution in CP47, near YD , does not affect growth in the cyanobacterium Synechocystis sp. PCC 6803; however, deletion of the extrinsic protein PsbV in this mutant leads to a strain displaying a pH-sensitive phenotype. Using thermoluminescence, chlorophyll fluorescence, and flash-induced oxygen evolution analyses, we demonstrate that Glu364 influences the stability of YD and the redox state of the OEC, and highlight the effects of external pH on photosynthetic electron transfer in intact cyanobacterial cells. This article is protected by copyright. All rights reserved. PMID- 30485418 TI - Rab5 activation on macropinosomes requires ALS2, and subsequent Rab5 inactivation through ALS2 detachment requires active Rab7. AB - Macropinocytosis is a nonspecific bulk uptake of extracellular fluid. During endosome maturation, the Rab5-to-Rab7 switch machinery executes the conversion from early to late endosomes. However, how the Rab switch works during macropinosome maturation remains unclear. Here, we elucidate the Rab switch machinery in macropinosome maturation using FRET imaging. Rab5 is activated and concurrently recruited to macropinosomes during ruffle closure. ALS2 depletion abolishes transient Rab5 activation on macropinosomes, while ALS2 is recruited to macropinosomes simultaneously with Rab5 activation. Thus, we conclude ALS2 activates Rab5 on macropinosomes. The absence of active Rab7 prolongs ALS2 presence and Rab5 activation on macropinosomes, indicating that active Rab7 is necessary for Rab5 inactivation through ALS2 dissociation and plays key roles in the Rab switch on macropinosomes. This article is protected by copyright. All rights reserved. PMID- 30485419 TI - Research Review: Internalising symptoms in developmental coordination disorder: a systematic review and meta-analysis. AB - BACKGROUND: Developmental coordination disorder (DCD) affects 5%-6% of children. There is growing evidence that DCD is associated with greater levels of internalising symptoms (i.e. depression and anxiety). This is the first systematic review and meta-analysis to explore the magnitude of this effect, the quality of the evidence and potential moderators. METHODS: A systematic search was conducted to identify studies reporting a comparison between individuals with DCD/probable DCD and typically developing (TD) individuals on measures of internalising symptoms. A pooled effect size (Hedges g) was calculated using random-effects meta-analysis. Study quality, publication bias and potential moderators of the effect were explored. RESULTS: Twenty studies, including a total of 23 subsamples, met the inclusion criteria, of which 22 subsamples were included in the meta-analysis (DCD: n = 1123; TD: n = 7346). A significant, moderate effect of DCD on internalising symptoms was found (g = 0.61). This effect remained robust after accounting for publication bias and excluding lower quality studies. The effect was significantly larger in studies utilising a cross sectional design (vs. longitudinal), convenience sampling (vs. population screening) and a majority male sample. CONCLUSIONS: The findings demonstrate that individuals with DCD experience greater levels of internalising symptoms than their peers. This highlights the importance of routine screening for emotional difficulties in DCD, raising awareness of the condition in mental health services and developing psychosocial interventions that extend beyond a focus on motor impairments. However, there is a need for higher quality, longitudinal studies to better understand the causal relationship between DCD and internalising symptoms. PMID- 30485420 TI - Spontaneous remission of residual post-therapy plasma Epstein-Barr virus DNA and its prognostic implication in nasopharyngeal carcinoma: A large-scale, big-data intelligence platform-based analysis. AB - Detectable post-therapy plasma Epstein-Barr virus (EBV) DNA predicts poor survival in non-metastatic nasopharyngeal carcinoma (NPC). However, some patients subsequently experience spontaneous remission of residual EBV DNA during follow up and it was unclear whether these patients were still at high risk of disease failure. Using the NPC database from an established big-data intelligence platform, 3269 NPC patients who had the plasma EBV DNA load measured at the end of therapy (+ 1 week) were identified. In total, 93.0% (3031/3269) and 7.0% (238/3269) of patients had undetectable and detectable (> 0 copy/ml) plasma EBV DNA at the end of therapy (EBV DNAend ), respectively. Detectable EBV DNAend was a prognostic factor for poorer 3-year disease-free survival (DFS), overall survival (OS), distant metastasis-free survival (DMFS), and loco-regional recurrence-free survival (LRRFS) in both univariate and multivariate analyses. Of 238 patients with residual EBV DNAend , 192 underwent EBV DNA assay 3 months after and spontaneous remission occurred in 72.4% (139/192). However, these patients still had poorer 3-year DFS (55.1% vs. 89.8%), OS (79.1% vs. 96.2%), DMFS (68.4% vs. 94.1%) and LRRFS (84.5% vs. 95.0%) than patients with undetectable EBV DNAend (all P < 0.001). And patients with persistent detectable post-therapy EBV DNA had the worst outcomes. These results were confirmed in multivariate analysis. In conclusion, residual EBV DNA post therapy was a robust biomarker for NPC prognosis. Although residual post-therapy EBV DNA could spontaneous remit during follow-up, these patients were still at high risk of disease failure and such patients may benefit from adjuvant therapy. This article is protected by copyright. All rights reserved. PMID- 30485421 TI - Complex Congenital Heart Malformation Including Transposition of the Great Vessels, Presenting as Sudden Unexplained Infant Death. AB - Transposition of the great vessels (TGV) is a common congenital heart defect that is difficult to diagnose before birth. Antenatal diagnosis is associated with increased survival. Unusual features such as anomalous pulmonary artery origin may delay cyanosis, decreasing clinical suspicion. A three-week old female infant who had never been cyanotic presented for forensic autopsy due to onset of unresponsiveness at home. History included risk factors for TGV and signs of heart enlargement that were not recognized during life. Cardiac pathology consultation identified D-type TGV with additional rare anomalies. TGV may present as sudden unexplained infant death (SUID) for forensic autopsy if variant features prevent development of cyanosis. Cardiac pathology consultation is helpful in clarifying these features. PMID- 30485422 TI - Reasons for nonadherence and response to treatment in an adherence intervention trial for relapsing-remitting multiple sclerosis patients. AB - OBJECTIVES: To explore whether patients in an adherence trial who appeared not to take disease modifying therapy (DMT) for avoidance reasons could be reliably identified, by observational coding, for their main reason of not taking DMT. To determine whether reason groups could be distinguished by clinical and self report psychological characteristics and intervention outcomes. METHOD: Participants were multiple sclerosis patients (N = 78, 88.5% female, mean age 45.64) demotivated to take DMT. Audio recordings of the sessions were coded for the main reason of not taking DMT. Reason groups were compared based on patient characteristics and intervention outcomes. RESULTS: Avoidance and three other reasons for not taking DMT (side effects, cost, and mild course) were reliably identified (kappa = 0.88). Patient characteristics failed to distinguish participants in the Avoidance group, which also had poorer outcomes (X2 [2, n = 73] = 6.35, p = 0.036). CONCLUSIONS: Patients not taking DMT for avoidance reasons may need novel methods to identify them and encourage (re-)initiation. PMID- 30485423 TI - Application of patient-derived liver cancer cells for phenotypic characterization and therapeutic target identification. AB - Primary liver cancer (PLC) ranks among the most lethal solid cancers worldwide due to lack of effective biomarkers for early detection and limited treatment options in advanced stages. Development of primary culture models that closely recapitulate phenotypic and molecular diversities of PLC is urgently needed to improve the patient outcome. Long-term cultures of 7 primary liver cancer cell lines of hepatocellular and cholangiocellular origin were established using defined culture conditions. Morphological and histological characteristics of obtained cell lines and xenograft tumors were analyzed and compared to original tumors. Time course analyses of transcriptomic and genomic changes were performed using next-generation sequencing (NGS). Key oncogenic alterations were identified by targeted NGS and cell lines carrying potentially actionable mutations were treated with corresponding specific inhibitors. PDCL fully resembled morphological features of the primary cancers in vitro and in vivo over extended period in culture. Genomic alterations as well as transcriptome profiles showed high similarity with primary tumors and remained stable during long-term culturing. Targeted-NGS confirmed that key oncogenic mutations such as TP53, KRAS, CTNNB1 as well as actionable mutations (e.g. MET, cKIT, KDR) were highly conserved in PDCL and amenable for individualized therapeutic approaches. Integrative genomic and transcriptomic approaches further demonstrated that PDCL more closely resemble molecular and prognostic features of PLC than established cell lines and are valuable tool for direct target evaluation. Our integrative analysis demonstrates that PDCL represents refined model for discovery of relevant molecular subgroups and exploration of precision medicine approaches for the treatment of this deadly disease. This article is protected by copyright. All rights reserved. PMID- 30485424 TI - The connection between social cohesion and personality: A multilevel study in the Kyrgyz Republic. AB - As the discourse around societal cohesion grows and policy makers increasingly turn their attention towards improving cohesion, understanding its role for the lives of individuals becomes ever more important. Our study examines whether the social cohesion of the immediate living context is related to the strength of Big Five personality traits among individuals. Using data from a community survey of 6252 adults living in 30 rural sub-districts in the Kyrgyz Republic, where social cohesion is a sizable policy concern, we conduct a multilevel analysis of the relationship between sub-district cohesion and individual personality. Results indicate that higher levels of cohesion are significantly related to higher individual levels of agreeableness, conscientiousness and openness. However, no relationship is found with extraversion or neuroticism. Thus, where a social entity has higher cohesion, this entity will also have inhabitants with a greater prosocial and communal orientation towards others, greater conscientiousness and more openness to experience. These findings imply that social cohesion may be one geographical social indicator related to variation in personality traits. Moreover, the findings suggest that understanding social cohesion requires both macro- and micro-perspectives and that its connection to these particular personality traits should be taken into consideration. PMID- 30485425 TI - Targeting the arginine metabolic brake enhances immunotherapy for leukaemia. AB - Therapeutic approaches which aim to target Acute Myeloid Leukaemia through enhancement of patients' immune responses have demonstrated limited efficacy to date, despite encouraging preclinical data. Examination of AML patients treated with azacitidine (AZA) and vorinostat (VOR) in a Phase II trial, demonstrated an increase in the expression of Cancer-Testis Antigens (MAGE, RAGE, LAGE, SSX2, and TRAG3) on blasts and that these can be recognised by circulating antigen-specific T cells. Although the T cells have the potential to be activated by these unmasked antigens, the low arginine microenvironment created by AML blast Arginase II activity acts a metabolic brake leading to T cell exhaustion. T cells exhibit impaired proliferation, reduced IFN-gamma release and PD-1 up-regulation in response to antigen stimulation under low arginine conditions. Inhibition of arginine metabolism enhanced the proliferation and cytotoxicity of anti-NYESO T cells against AZA/VOR treated AML blasts, and can boost anti-CD33 Chimeric Antigen Receptor-T cell cytotoxicity. Therefore measurement of plasma arginine concentrations in combination with therapeutic targeting of arginase activity in AML blasts could be a key adjunct to immunotherapy. This article is protected by copyright. All rights reserved. PMID- 30485426 TI - Detection of Cutting Agents in Drug-Positive Seized Exhibits within the United States. AB - The following report summarizes a study performed on seized drug exhibits collected in two U.S. states to evaluate the presence and identification of cutting agents. Aliquots of seized drug materials from Kentucky (n = 200) and Vermont (n = 315) were prepared using a dilute-and-shoot procedure. Initial analysis was performed using gas chromatography-mass spectrometry (GC-MS) followed by analysis using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF). Active compounds detected overall included caffeine (31.0%), quinine/quinidine (24.7%), levamisole (11.6%), acetaminophen, (8.2%) and procaine (8.2%). These compounds were found with several drugs of abuse, such as heroin, fentanyl, methamphetamine, and cocaine. This novel information about cutting agents used to dilute or alter drugs of abuse is important to criminal investigations and in the management of acute intoxications at health centers. However, common methodologies for analysis and standard reporting practices frequently do not include cutting agents, resulting in lacking or inadequate information regarding prevalence of these substances. PMID- 30485427 TI - Regulatory T cells expressing abundant CTLA-4 on the cell surface with a proliferative gene profile are key features of human head and neck cancer. AB - FOXP3+ regulatory T (Treg) cells suppress anti-tumor immunity. The suppression of Treg cells is regulated by cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), whose expression on the cell surface is tightly regulated. Here we found that Treg cells expressing abundant CTLA-4 on the cell surface (surface-CTLA-4+ Treg) were expanded in human head and neck cancer tissues. RNA sequencing of surface CTLA-4+ and surface-CTLA-4- Treg cells infiltrating human head and neck cancer tissues revealed that surface-CTLA-4+ Treg cells have a previously undescribed gene expression profile correlating to cell cycle, cell proliferation, and DNA replication. Moreover, surface-CTLA-4+ Treg cells were PD-1+ , actively proliferated and associated with CD45RA- FOXP3high Treg cells with strong suppressive function. Thus, surface-CTLA-4+ Treg cells with a proliferative gene expression signature and phenotype are key features of head and neck cancer. Targeting surface-CTLA-4+ Treg cells might be new strategies to evoke effective immune responses to head and neck cancer. This article is protected by copyright. All rights reserved. PMID- 30485428 TI - Can unconscious thought detect relational similarities? PMID- 30485429 TI - The novel relationship between Sirt3 and autophagy in myocardial ischemia reperfusion. AB - Class III histone deacetylases (HDACs) belong to the proteasome family, comprising seven family members identified in mammalian cells, identified Sirt1 Sirt7. As an important member of HDACs, Sirt3 is hotly debated for its multiple functions. It was reported that Sirt3 got involved in the alleviation of multiple diseases, including myocardial infarction, neuron ischemia, hypertrophy, and diabetic myopathy. Through regulating many cellular mechanisms, such as apoptosis, autophagy, and clearance of reactive oxygen species (ROS), Sirt3 played an important role in the alleviation of myocardial ischemia-reperfusion injury. Nowadays Sirt3-induced autophagy was indicated to be involved in the process of the development of myocardial ischemia-reperfusion injury. Sirt3 could both activate and inhibit autophagy process by activating different downstream signal pathways, such as Sirt3-AMP-activated protein kinase pathway, Sirt3-Foxo3a pathway, and Sirt3-superoxide dismutase-mitochondrial ROS pathway. Whereas the Sirt3-induced autophagy in different phases of myocardial ischemia-reperfusion has not been systematically illustrated. In this review, we summarized the regulated mechanisms found in these years and listed the updated research about the relationship between Sirt3 and autophagy which are both positive and negative during myocardial ischemia-reperfusion phase. We anticipated that we may controlled the activation of autophagy by regulating the concentration of Sirt3 in myocyte. By maintaining a proper expression of autophagy in different phases of myocardial ischemia-reperfusion, we could reduce the morbidity of patients with myocardial infarction apparently in the future. PMID- 30485430 TI - Predictors of change in cognitive processing therapy for veterans in a residential PTSD treatment program. AB - OBJECTIVE: Cognitive processing therapy is an evidence-based treatment for posttraumatic stress disorder (PTSD); however, questions remain regarding variability in treatment response. METHOD: A total of 123 veterans participated in group-based cognitive processing therapy (CPT) in residential PTSD treatment. Change over time in PTSD symptoms was modeled as a function of selected demographic and clinical variables. RESULTS: PTSD checklist (PCL) scores decreased by an average of 1 point per session (standard deviation [SD] = 0.1). Initial PCL scores were predicted by the Beck Depression Inventory-II (gamma01 = 0.25; standard error [SE] = 0.08), Insomnia Severity Index (gamma02 = 0.53; SE = 0.15), and Infrequency (F) scale of the Minnesota Multiphasic Personality Inventory-2 (gamma03 = 0.09; SE = 0.04). Rate of change was predicted by the Somatic Complaints (RC1) scale (gamma11 = -0.03; SE = 0.01) and the Antisocial Behavior (RC4) scale (gamma12 = 0.02; SE = 0.01). CONCLUSIONS: These results provide insight into characteristics that may influence degree of benefit received from group-based CPT. PMID- 30485431 TI - Microanatomical changes and biomolecular expression at the PDL-entheses during experimental tooth movement. AB - The novel aspect of this study was to contextualize the co-localization of biomolecular expression in widened and narrowed periodontal ligament (PDL)-space within a mechanically activated periodontal complex. The PDL is unique as it is the only ligament with both innervation and vascularization. Maxillary molars in 6-week-old male C57BL/6 mice (N = 5) were experimentally translated for 2 weeks using an elastic spacer. Contralateral teeth were used as controls. Mechanical testing of the periodontal complex of a mouse in situ and imaging using X-ray micro-computed tomography (micro-XCT) illustrated deformations within blood vessels (BV) of the PDL. PDL-bone and PDL-cementum entheses at the widened and narrowed PDL-spaces following experimental tooth movement (ETM) illustrated osterix (OSX), bone sialoprotein (BSP), cluster of differentiation 146 (CD146), and protein gene product 9.5 (PGP9.5), indicating active remodeling at these sites. PGP9.5 positive nerve bundles (NBs) were co-localized with multinucleated cells (MCs), Howship's resorption lacunae, and CD146 positive BVs. Association between nerves and MC was complemented by visualizing the proximity of osmium tetroxide stained NBs with the ultrastructure of MCs by performing scanning transmission electron microscopy. Spatial association of NB with BV, and NB with MC, provided insights into the plausible co-activation of NBs to initiate osteoclastic activity. Resorption of mineral occurred as an attempt to restore PDL-space of the load-bearing complex, specifically at the PDL-entheses. Mapping of anatomy-specific structural elements and their association with regenerative molecules by correlating light and electron micrographs provided insights into the use of these extracellular matrix molecules as plausible targets for pharmacological interventions related to tooth movement. Within the realm of tissue regeneration, modulation of load can reverse naturally occurring mineral formation to experimentally induced resorption, and naturally occurring mineral resorption to experimentally induced formation at the enthesial sites to permit tooth translation. PMID- 30485432 TI - Effectiveness and safety of reduced-dose fluoropyrimidine therapy in patients carrying the DPYD*2A variant: a matched pair analysis. AB - Carriers of the genetic DPYD*2A variant, resulting in dihydropyrimidine dehydrogenase deficiency, are at significantly increased risk of developing severe fluoropyrimidine-associated toxicity. Upfront DPYD*2A genotype-based dose reductions improve patient safety, but uncertainty exists whether this has a negative impact on treatment effectiveness. Therefore, this study investigated effectiveness and safety of DPYD*2A genotype-guided dosing. A cohort of 40 prospectively identified heterozygous DPYD*2A carriers, treated with a ~50% reduced fluoropyrimidine dose, was identified. For effectiveness analysis, a matched pair-analysis was performed where for each DPYD*2A carrier a matched DPYD*2A wild-type patient was identified. Overall survival and progression-free survival were compared between the matched groups. The frequency of severe (grade>=3) treatment-related toxicity was compared to 1] a cohort of 1606 wild type patients treated with full dose and 2] a cohort of historical controls derived from literature, i.e. 86 DPYD*2A variant carriers who received a full fluoropyrimidine dose. For 37 out of 40 DPYD*2A carriers, a matched control could be identified. Compared to matched controls, reduced doses did not negatively affect overall survival (median 27 months versus 24 months, P=0.47) nor progression-free survival (median 14 months versus 10 months, P=0.54). Risk of severe fluoropyrimidine-related toxicity in DPYD*2A carriers treated with reduced dose was 18%, comparable to wild-type patients (23%, P=0.57) and significantly lower than the risk of 77% in DPYD*2A carriers treated with full dose (P<0.001). This study is the first to show that DPYD*2A genotype-guided dosing appears to have no negative effect on effectiveness of fluoropyrimidine-based chemotherapy, while resulting in significantly improved patient safety. This article is protected by copyright. All rights reserved. PMID- 30485433 TI - Laminin gamma2-enriched extracellular vesicles of oral squamous cell carcinoma cells enhance in vitro lymphangiogenesis via intergrin alpha3-dependent uptake by lymphatic endothelial cells. AB - Oral squamous cell carcinoma (OSCC) LN1-l cells previously showed greater capacities for lymphangiogenesis and lymph node metastasis compared to their parental OEC-M1 cells, in addition to an ability to enhance the migration and tube formation of lymphatic endothelial cells (LECs). Purified by a series of differential centrifugations and characterized using electron microscopy, dynamic light scattering, and western blot, LN1-1 cell-derived extracellular vesicles (LN1-1 EVs) were shown to promote LEC migration, tube formation, and uptake by LECs more effectively than did OEC-M1 cell-derived EVs (OEC-M1 EVs). Using stable isotope labeling with amino acids in cell culture/liquid chromatography-tandem mass spectrometry based proteomic platform, the laminin-332 proteins, including laminin alpha3, beta3, and gamma2, were validated as highly expressed proteins in LN1-1 EVs. Clinically, a higher level of laminin-332 was detected in plasma EVs from OSCC patients with lymph node metastasis than in both healthy controls and OSCC patients without lymphatic metastasis, suggesting EV-borne laminin-332 as a novel and non-invasive biomarker for the detection of lymph node metastasis in OSCC. The knockdown of laminin gamma2 and inhibition by anti-laminin-332 neutralizing antibodies impaired LN1-1 EV-mediated LEC migration, tube formation, and uptake by LECs. Importantly, laminin gamma2-deficient EVs showed a reduced ability to drain into lymph nodes in comparison with the control EVs. Additionally, the laminin 332/gamma2-mediated EV uptake was dependent on integrin alpha3 but not beta1, beta4 or alpha6. Collectively, the uptake of laminin gamma2 enriched EVs by LECs enhanced in vitro lymphangiogenesis and EV-borne laminin-332 is thus a viable biomarker for OSCC. This article is protected by copyright. All rights reserved. PMID- 30485434 TI - Interaction between genetic ancestry and common breast cancer susceptibility variants in Colombian women. AB - Latino women show lower incidences of breast cancer (BC) than non-Hispanic whites. Large-scale genetic association studies have identified variants robustly associated with BC risk in European women. We examine here the relevance of these variants to Colombian BC and possible interactions with genetic ancestry. Native American, European and African proportions were estimated for 1,022 Colombian BC cases and 1,023 controls. Logistic regression was applied to assess the association between 78 variants and BC risk and interactions between the variants and ancestry proportions. We constructed a multifactorial risk score combining established BC risk factors, associated risk variants and individual ancestry proportions. Each 1% increase in the Native American proportion translated into a 2.2% lower BC risk (95% CI: 1.4-2.9). Thirteen variants were associated with BC in Colombian women, with allele frequencies and risk effects partially different from European women. Ancestry proportions moderated the risk effects of two variants. The ability of Native American proportions to separate Colombian cases and controls (area-under-the-curve (AUC)=0.61) was similar to the discriminative ability of family history of BC in first-degree female relatives (AUC=0.58) or the combined effect of all 13 associated risk variants (AUC=0.57). Our findings demonstrate ample potential for individualized BC prevention in Hispanic women taking advantage of individual Native American proportions, information on established susceptibility factors and recently identified common risk variants. This article is protected by copyright. All rights reserved. PMID- 30485435 TI - Cover Image, Volume 526, Issue 17. AB - The cover image is based on the Research Article Full: Ontogenesis and development of the nonhuman primate pulvinar by Jihane Homman-Ludiye, William C. Kwan, Mitchell J. de Souza, and James A. Bourne DOI: 10.1002/cne.24534. PMID- 30485436 TI - Identification and functional study of three nAChR regulators, ubiquilin-1, PICK1 and CRELD2, in Locusta migratoria mamilensis dorsal unpaired median neurons. AB - Insect nicotinic acetylcholine receptors (nAChRs) are not only important neuro transmitter receptors but also effective insecticide targets. The regulation of nAChRs has been mainly studied in vertebrates especially in mammals. Here, two types of nAChRs were found present in the locust Locusta migratoria mamilensis dorsal unpaired median (DUM) neurons, alpha-bungarotoxin (alpha-Bgt)-sensitive nAChRs and alpha-Bgt-resistant nAChRs, responding to acetylcholine (ACh) at different concentrations. The homologues to three mammalian nAChR regulators, ubiquilin-1, CRELD2 (Cysteine-rich with EFG-like domain 2) and PICK1 (protein interacting with PRKCA 1), were characterised in L. migratoria and their functions on regulating native nAChRs were investigated via RNAi followed by membrane potential measurement with DiBAC4 (3) and agonist-evoked macroscopic current recording in cultured L. migratoria DUM neurons. Ubiquilin-1 and PICK1 negatively regulated nAChRs because silencing of ubiquilin-1 and PICK1 both resulted in increased membrane potential and increased inward currents in DUM neurons, while CRELD2 positively regulated nAChRs as decreased membrane potential and inward currents were observed in DUM neurons. In addition, ubiquilin-1 regulated both alpha-Bgt-sensitive and alpha-Bgt-resistant types of nAChRs whereas PICK1 and CRELD2 regulated only the alpha-Bgt-resistant nAChRs. The present study broadened our understanding on the regulation of insect nAChRs and will benefit pest management given the important role of nAChRs in insect neurons and insecticide science. This article is protected by copyright. All rights reserved. PMID- 30485437 TI - Clinical Outcomes and Secondary Epidermal Growth Factor Receptor (EGFR) T790M Mutation among First-line Gefitinib, Erlotinib and Afatinib-treated Non-small Cell Lung Cancer Patients with Activating EGFR Mutations. AB - Gefitinib, erlotinib and afatinib are approved for first-line treatment of advanced non-small cell lung cancer (NSCLC) bearing an activating epidermal growth factor receptor (EGFR) mutation. However, the clinical outcomes among the three EGFR tyrosine kinase inhibitors (TKIs) are still controversial. We aimed to evaluate clinical outcomes and secondary EGFR T790M mutation among the three EGFR TKIs. From May 2014 to January 2016, a total of 301 patients received treatment with gefitinib, erlotinib or afatinib, for first-line treatment of advanced NSCLC with an activating EGFR mutation, based on their clinicians' choice. The median overall survival (OS) was 37.0 months. Although the baseline characteristics of patients were unequal, progression free survival and OS did not differ among the 3 groups. Multivariate analysis found that gefitinib (adjusted odds ratio [aOR] 3.29, 95% confidence interval [CI], 1.15 - 9.46, p = 0.027), EGFR TKI treatment duration more than 13 months (aOR 3.16, 95% CI, 1.20 - 8.33, p = 0.020), male (aOR 3.25, 95% CI, 1.10-9.66, p=0.034), initial liver metastasis (aOR 4.97, 95% CI 1.18 - 20.96, p=0.029) and uncommon EGFR mutation (aOR 0.14, 95% CI, 0.02 - 0.97, compared to EGFR deletion 19, p = 0.047) were independent factors for secondary T790M mutation. In real-world practice, choosing first line EGFR TKI based on the patients' clinical characteristics yielded good clinical outcomes. First-line gefitinib, longer EGFR TKI treatment duration, male, initial liver metastasis and uncommon EGFR mutations may be independent factors for secondary EGFR T790M mutation. This article is protected by copyright. All rights reserved. PMID- 30485438 TI - Association of food insecurity with early childhood caries. AB - OBJECTIVES: The aim of this study was to examine the association of food insecurity on the prevalence of dental caries in preschool children. METHODS: Eighty-two children, aged 12-71 months old, from the Marquette University School of Dentistry Community South Clinic and their caregivers participated in this cross-sectional study. Following informed consent, parents completed the validated six-item US Department of Agriculture food insecurity questionnaire and questions regarding demographic information and family structure. Upon clinical examination caries was recorded using the decayed, missing, filled teeth (dmft) index based on the International Caries Detection and Assessment System criteria. RESULTS: The correlation between dmft and food insecurity was found statistically significant (P = 0.002, R2 = 0.115), and children of higher food insecurity demonstrated higher levels of dental caries. Food insecurity was also positively correlated with parental age (P = 0.034), whereby higher levels of food insecurity were associated with the father being less than 25 years of age. Results from the questionnaire revealed that 58.5 percent of the families were fully secure, 11.0 percent had marginal, 24.4 percent had low, and 6.1 percent had very low food security. Results from clinical examination reported dmft 4.09 +/- 4.38, dt 2.20 +/- 2.83, and ft 1.83 +/- 2.95. Most of the children (79.7 percent) were Hispanic, 53.1 percent were female and the median age of the sample was 48 months. CONCLUSIONS: Results of the present study suggest that preschool children with food insecurity have higher levels of dental caries. PMID- 30485439 TI - 3D Culture Models of Malignant Mesothelioma Reveal a Powerful Interplay Between Photodynamic Therapy and Kinase Suppression Offering Hope to Reduce Tumor Recurrence. AB - In this issue, Cramer et al. introduce 3D culture models of metastatic mesothelioma to investigate basic cancer biology and new combination therapies for combating this complex and lethal disease. The results suggest that erlotinib enhanced photodynamic therapy (PDT) could further improve the efficacy of intraoperative light-activation to mop up residual tumor deposits in the clinic following surgical removal of macroscopic mesothelioma metastases. This article is protected by copyright. All rights reserved. PMID- 30485440 TI - Allergic contact dermatitis due to chloramphenicol with prurigo nodularis-like spreading. AB - Topical drugs containing chloramphenicol and clostridiopeptidase A are frequently used for the treatment of cutaneous ulcers and other necrotic lesions. Chloramphenicol is a bacteriostatic broad-spectrum antibiotic widely used in eye and skin ointments to treat bacterial infections and a well-known cause of allergic contact dermatitis (ACD) (1). Clostridiopeptidase A, also called collagenase 1, is a proteolytic enzyme facilitating the tissue granulation with consequent re-epithelization; it has rarely been reported as cause of ACD (2). PMID- 30485441 TI - Discrimination of "hot potato voice" caused by upper airway obstruction utilizing a support vector machine. AB - OBJECTIVES/HYPOTHESIS: "Hot potato voice" (HPV) is a thick, muffled voice caused by pharyngeal or laryngeal diseases characterized by severe upper airway obstruction, including acute epiglottitis and peritonsillitis. To develop a method for determining upper-airway emergency based on this important vocal feature, we investigated the acoustic characteristics of HPV using a physical, articulatory speech synthesis model. The results of the simulation were then applied to design a computerized recognition framework using a mel-frequency cepstral coefficient domain support vector machine (SVM). STUDY DESIGN: Quasi experimental research design. METHODS: Changes in the voice spectral envelope caused by upper airway obstructions were analyzed using a hybrid time-frequency model of articulatory speech synthesis. We evaluated variations in the formant structure and thresholds of critical vocal tract area functions that triggered HPV. The SVMs were trained using a dataset of 2,200 synthetic voice samples generated by an articulatory synthesizer. Voice classification experiments on test datasets of real patient voices were then performed. RESULTS: On phonation of the Japanese vowel /e/, the frequency of the second formant fell and coalesced with that of the first formant as the area function of the oropharynx decreased. Changes in higher-order formants varied according to constriction location. The highest accuracy afforded by the SVM classifier trained with synthetic data was 88.3%. CONCLUSIONS: HPV caused by upper airway obstruction has a highly characteristic spectral envelope. Based on this distinctive voice feature, our SVM classifier, who was trained using synthetic data, was able to diagnose upper airway obstructions with a high degree of accuracy. LEVEL OF EVIDENCE: 2c Laryngoscope, 2018. PMID- 30485442 TI - A Novel Prospective Study Assessing the Combination of Photodynamic Therapy and Proton Radiation Therapy: Safety and Outcomes When Treating Malignant Pleural Mesothelioma. AB - Malignant pleural mesothelioma remains difficult to treat, with high failure rates despite optimal therapy. We present a novel prospective trial combining proton therapy (PT) and photodynamic therapy (PDT) and the largest-ever mesothelioma PT experience (n=10). PDT photosensitizers included porfimer sodium (2mg/kg; 24hr drug-light interval) or 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) (4mg/m2 ;48hr) with wavelengths of 630nm to 60J/cm2 and 665nm to 15-45J/cm2 , respectively. With a median age of 69 years, patients were predominantly male (90%) with epithelioid histology (100%) and stage III-IV disease (100%). PT was delivered to a median of 55.0CGE/1.8-2.0CGE (range 50 75CGE) adjuvantly (n=8) or as salvage therapy (n=2) following extended pleurectomy/decortication (ePD)/PDT. Two-year local control was 90%, with distant and regional failure rates of 50% and 30%, respectively. All patients received chemotherapy, and 4 received immunotherapy. Surgical complications included atrial fibrillation (n=3), pneumonia (n=2), and deep vein thrombosis (n=2). Median survival from PT completion was 19.5 months (30.3 months from diagnosis), and 1- and 2-year survival rates were 58% and 29%. No patient experienced CTCAEv4 grade >=2 acute or late toxicity. Our prolonged survival in very advanced-stage patients compares favorably to survival for PT without PDT and photon therapy with PDT, suggesting possible spatial or systemic cooperativity and immune effect. This article is protected by copyright. All rights reserved. PMID- 30485443 TI - The macroecology and macroevolution of plant species-at-risk. AB - Current rates of extinction are unprecedented in human history. The fossil record and newer molecular phylogenies illuminate historical patterns of speciation and extinction. They reveal both spectacular radiations and the characteristic features of mass extinction events in our geological past. The IUCN Red List provides insight into present-day species declines. There is emerging synthesis that species at risk are nonrandomly distributed across space and phylogeny. This pattern may be explained by geographical variation in driver intensity and species differential sensitivities. However, traits that confer resistance to one global change driver may increase susceptibility to a different driver. A complete understanding of extinction risk requires consideration of the interaction between extinction drivers, ecological traits, and species' evolutionary histories. This article is protected by copyright. All rights reserved. PMID- 30485444 TI - Long-distance pollen dispersal during recent colonization favors a rapid but partial recovery of genetic diversity in Picea sitchensis. AB - Tree species in the northern hemisphere are currently subject to rapid anthropogenic climate change and are shifting their ranges in response. This prompts questions about the mechanisms allowing tree populations to respond quickly to selection pressures when establishing into new areas. Focusing on the northern expanding range edge of Picea sitchensis, a widespread conifer of western North America, we ask how genetic structure and diversity develop during colonization, and assess the role of demographic history in shaping the evolutionary trajectory of an establishing population. We combined 500 years of tree-ring and genotyping-by-sequencing data in 639 trees at the expansion front on the Kodiak Archipelago. We show that alleles accumulated rapidly during an increase in recruitment rate in the early 1700s. A shift from foreign to local pollen flow subsequently homogenized genetic structure at the expansion front. Taking advantage of the exceptional longevity of conifers, we highlight the major role of long-distance pollen dispersal in the rapid but incomplete recovery of genetic diversity during initial stages of colonization. We also warn that slow initial population growth as well as long-lasting dominance of local gene flow by early founders could increase evolutionary load under a rapidly changing climate. This article is protected by copyright. All rights reserved. PMID- 30485445 TI - Cost comparison of treatment for oropharyngeal carcinoma. AB - OBJECTIVES/HYPOTHESIS: Based on current guidelines, surgical and nonsurgical therapies are viable frontline treatment for patients with locoregional oropharyngeal carcinoma (OPC). We sought to compare financial parameters between chemoradiation and transoral robotic surgery (TORS) in this patient population. STUDY DESIGN: Case-control study. METHODS: In this study we identified patients with selected American Joint Committee on Cancer 7th Edition stage II to IVa OPC treated with TORS between January 2013 and December 2014. Fifteen patients who underwent TORS were stage matched with 15 patients treated with chemoradiation. Total charges and cost data for each patient were analyzed at 4-month and 1-year time points; functional and oncologic outcomes were assessed. RESULTS: There were no significant differences in functional and oncologic outcomes. Patients undergoing TORS had a longer inpatient hospital stay, and most required a nasogastric tube for an average of 3.5 days. There were no local or regional recurrences. Across all time points, the TORS group had lower charges and costs compared to the chemoradiation group, with 14% lower costs at 1 year. In the chemoradiation group, nearly two-thirds of costs came from radiation therapy and pharmacy expenses. Chemotherapy accounted for most pharmacy costs. The costs of operating the surgical robot accounted for a about half of surgical costs. CONCLUSIONS: Selected patients with stage II to IVa oropharyngeal carcinoma treated with TORS may incur lower costs than those treated nonsurgically. With rising healthcare spending, the financial impact of treatment might be considered for those patients eligible for treatment regimens with comparable functional and oncologic outcomes. LEVEL OF EVIDENCE: 3b Laryngoscope, 2018. PMID- 30485446 TI - Photolyases and Cryptochromes in UV-resistant Bacteria from High-altitude Andean Lakes. AB - "High-Altitude Andean Lakes" (HAAL) are pristine environments harboring poly extremophilic microbes that show combined adaptations to physical and chemical stress such as large daily ambient thermal amplitude, extreme solar radiation levels, intense dryness, alkalinity, high concentrations of arsenic (up to 200 ppm) and dissolved salts. In this work, we compared the UV resistance profiles, pigment content and photoreactivation abilities of three UV-resistant bacteria isolated from distinct niches from HAAL's: i.e. Acinetobacter sp. Ver3 (water, Lake Verde; 4.400 m), Exiguobacterium sp. S17 (stromatolite, Lake Socompa, 3,570 m) and Nesterenkonia sp. Act20 (soil, Lake Socompa, 3,570 m). UV resistance ability of HAAL's strains indicate a clear adaptation to high radiation exposure encountered in their original habitat, which can be explained by genetic and physiological mechanisms named as the UV-resistome. Thus, the UV-resistome depends on the expression of a diverse set of genes devoted to evading or repairing the damage it provoked direct or indirectly. As pigment extraction and photoreactive assays indicate the presence of photoactive molecules, we characterized more in detail proteins with homology to photolyases/cryptochromes members (CPF). Phylogenetic analyses, sequence comparison and 3D modelling with bonafide CPFs members was used to proof the presence of functional domains and key residues in the novel proteins. This article is protected by copyright. All rights reserved. PMID- 30485447 TI - Cartilage tympanoplasty combined with eustachian tube balloon dilatation in the treatment of adhesive otitis media. AB - OBJECTIVES/HYPOTHESIS: To investigate the simultaneous application of cartilage tympanoplasty combined with eustachian tube (ET) balloon dilatation in the treatment of adhesive otitis media (AdOM). STUDY DESIGN: Multicenter, prospective, double-blind, randomized, controlled clinical trial. METHODS: Patients with AdOM were randomly divided into four groups: control group (conservative treatment), ET balloon dilatation (ETBD) group, cartilage tympanoplasty (CT) group, and cartilage tympanoplasty combined with ET balloon dilatation (ETBD+CT) group. Patients were followed up at 3 months, 6 months, 1 year, and 2 years after treatment, receiving otoendoscopy and pure-tone audiometry, and were evaluated using the Tinnitus Handicap Inventory (THI), visual analogue scale (VAS) for the symptom of ear stuffiness, Chronic Otitis Media Outcome Test (COMOT-15), and eustachian tube scores (ETS). RESULTS: There was no improvement in tympanic membrane (TM) morphology and mean pure-tone air bone gap (ABG) after treatment in the control and ETBD groups. The postoperative TM morphology was improved in the CT group and ETBD+CT group, although retraction pockets reoccurred in two cases of CT group. Reduced ABG and improvements in ETS, THI, VAS, and COMOT-15 were all achieved in these two groups, but the difference was not statistically significant. CONCLUSIONS: Cartilage tympanoplasty combined with ET balloon dilatation could be used as an appropriate surgical technique for AdOM, which could relieve the symptoms of tinnitus and ear stuffiness, and improve postoperative TM morphology, hearing level, ET functions, and quality of life, with low incidence of complications. LEVEL OF EVIDENCE: 2 Laryngoscope, 2018. PMID- 30485448 TI - Phylogenomics of Endogonaceae and evolution of mycorrhizas within Mucoromycota. AB - Endogonales (Mucoromycotina), composed of Endogonaceae and Densosporaceae, is the only known non-Dikarya order with ectomycorrhizal members. They also form mycorrhizal-like association with some non-Spermatophyte plants. It has been recently proposed that Endogonales were among the earliest mycorrhizal partners with land plants. It remains unknown whether Endogonales possess genomes with mycorrhizal-lifestyle signatures and whether Endogonales originated around the same time as land plants did. We sampled sporocarp tissue from four Endogonaceae collections and performed shotgun genome sequencing. After binning the metagenome data, we assembled and annotated the Endogonaceae genomes. We performed comparative analysis on plant-cell-wall-degrading-enzymes (PCWDEs) and small secreted proteins (SSPs). We inferred phylogenetic placement of Endogonaceae and estimated the ages of Endogonaceae and Endogonales with expanded taxon sampling. Endogonaceae have large genomes with high repeat content, low diversity of PCWDEs, but without elevated SSP/secretome ratios. Dating analysis estimated that Endogonaceae originated in the Permian-Triassic boundary and Endogonales originated in the mid-late Silurian. Mycoplasma-related endobacterium sequences were identified in three Endogonaceae genomes. Endogonaceae genomes possess typical signatures of mycorrhizal lifestyle. The early origin of Endogonales suggests that the mycorrhizal association between Endogonales and plants might have played an important role during the colonization of land by plants. This article is protected by copyright. All rights reserved. PMID- 30485449 TI - In Response to To Image or Not to Image? A Cost-effectiveness Analysis of MRI for Patients With Asymmetric Sensorineural Hearing Loss. PMID- 30485450 TI - Inhibitory effects of Sanguisorba officinalis root extract on HYBID (KIAA1199) mediated hyaluronan degradation and skin wrinkling. AB - OBJECTIVES: Hyaluronan (HA), an important constituent of extracellular matrix in the skin, has many biological activities such as hydration that contributes to firmness and bounciness of the skin. We have reported that reduction of HA in the papillary dermis and overexpression of HYBID (HYaluronan Binding protein Involved in hyaluronan Depolymerization, alias KIAA1199 or CEMIP), a key molecule for HA degradation in skin fibroblasts, are implicated in facial skin wrinkling in Japanese and Caucasian women. However, little or no information is available for substances which inhibit the HYBID-mediated HA degradation. METHODS: Inhibition of Sanguisorba officinalis root extract and ziyuglycoside I, one of the components of Sanguisorba officinalis root extract, to the HYBID-mediated HA degradation was assessed by size-exclusion chromatography of HA depolymerized by stable transfectants of HYBID in HEK293 cells (HYBID/HEK293 cells) or normal human skin fibroblasts (Detroit 551 cells and NHDF-Ad cells). The HYBID mRNA and protein expression was examined by quantitative real-time PCR and immunoblotting in the skin fibroblasts treated with Sanguisorba officinalis root extract, and size distribution of newly produced HA was evaluated by preparing metabolically radiolabeled HA. A double-blind, randomized, and placebo-controlled study was carried out in the 21 healthy Japanese women, who were topically treated with the formulation containing Sanguisorba officinalis root extract or the placebo on each side of the face including crow's foot area. RESULTS: Sanguisorba officinalis root extract, but not ziyuglycoside I, abolished HYBID-mediated HA degradation by HYBID/HEK293 cells. Sanguisorba officinalis root extract also inhibited HYBID-mediated HA degradation in skin fibroblasts by down-regulating HYBID mRNA and protein expression. Although control untreated skin fibroblasts produced polydispersed HA, the cells treated with Sanguisorba officinalis root extract produced only high-molecular-weight HA. Treatment with Sanguisorba officinalis root extract-formulated lotion significantly improved skin elasticity, and reduced skin wrinkling scores at the outer eye corner compared with the placebo formulation. CONCLUSION: Sanguisorba officinalis root extract showed an anti-HYBID-mediated HA degradation activity and anti-wrinkle activity on human facial skin, which is accompanied by the improvement in elasticity. Our study provides the possibility of a new strategy to inhibit HYBID-mediated HA degradation for anti-wrinkle care. This article is protected by copyright. All rights reserved. PMID- 30485451 TI - Chromium(III), chromium(VI) and cobalt release from leathers produced in Nicaragua. AB - BACKGROUND: Leather exposure has been associated with chromium (Cr) and cobalt (Co) contact dermatitis. Cr(VI) in leather is now restricted to <3 mg/kg in the EU. Cr(III) is not restricted. OBJECTIVES: To analyse 29 differently coloured Cr tanned leather samples from two Nicaraguan tanneries, and to compare their release of Cr, Cr(VI) and Co with that of leathers produced in Europe. METHODS: Cr, Cr(VI) and Co were extracted in phosphate buffer for 3 hours at 25 degrees C according to EN ISO 17075. Atomic absorption spectroscopy and spectrophotometry were used for detection of the metals in phosphate buffer. RESULTS: There was no difference in total Cr or Cr(VI) release between European and Nicaraguan leathers. There was no association between Cr(VI) and total Cr release. Co was released primarily from leathers of one tannery. Cr(III) was released in significantly higher amounts than Cr(VI). CONCLUSIONS: Future investigations and regulations should focus on Cr(III) and Co as well as on Cr(VI). PMID- 30485452 TI - Determination of the Phosphatidylcholine/Lysophosphatidylcholine Ratio in Intact Serum by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry with Prior Enzymatic Albumin Digestion. AB - Lysophosphatidylcholine (lysoPtdCho) is a well-known biomarker in body fluids for inflammation and oxidative stress and provides a possible clinical screening marker for certain diseases where inflammation is involved. It was shown in our previous article that the measurement of intact serum using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF MS) provides the phosphatidylcholine (PtdCho)/lysoPtdCho ratios faster than the measurements after organic extraction, while the standard deviations of those "intact" measurements are even smaller. Surprisingly, the PtdCho/lysoPtdCho ratio is about two times higher in the intact serum MALDI-TOF MS measurement than in the MALDI-TOF MS analysis of the organic extracts. Albumin binding of lysoPtdCho seems to be a very likely reason for increased PtdCho/lysoPtdCho ratios in the intact serum measurements. In this article, this hypothesis is tested on horse serum as a biological sample. Albumin (equine and bovine) addition to serum shows an increase in the PtdCho/lysoPtdCho ratio detected by MALDI-TOF MS. Further experiments with a comparable lipid model suspension verify that pepsin and trypsin are able to liberate the bound lipids. Under different conditions, the effects of both enzymes on the lipid model suspension are compared. Finally, an improved MALDI-TOF MS measurement of the PtdCho/lysoPtdCho ratio in intact serum after a prior pepsin digestion step was established. As is known that lysoPtdCho is cytotoxic and albumin is capable of decreasing this cytotoxicity by binding lysoPtdCho, this study proposes to consider both PtdCho/lysoPtdCho ratios-with and without albumin-bound lysoPtdCho-that could be superior diagnostic markers for inflammation and oxidative stress. PMID- 30485453 TI - Fear of blood, injections and fainting as barriers to blood donation in Brazil. AB - BACKGROUND AND OBJECTIVES: The objective of the present study was to investigate the fear of blood, injections and fainting as barriers to blood donation in a sample of primary healthcare users in a Brazilian municipality. MATERIALS AND METHODS: This is a cross-sectional survey of primary care patients in 12 randomly selected healthcare facilities in Ribeirao Preto, Brazil in 2015-2016. Key variables were lifetime blood donation history, intentions to donate blood among non-donors and current donation practice. To assess fear of blood in general (FBG), fear of injections in general (FIG) and fear of fainting due to fear of injection (FFI), we used the Blood Injection/Fear Scale (BIFS). We tested associations between variables using regression models and conditional inference trees (CIT). RESULTS: A total of 1055 primary healthcare users participated (79.7% female, mean age 40.6 years [SD = 15.2]), 63.4% never donated blood, 13.3% reported they are unable to donate, 6.1% donated only once, 17.2% donated multiple times. Women had higher scores for FIG and FBG. FFI was associated with middle socioeconomic status. Those who never intended to donate exhibited the highest scores in the three dimension of fear. By CIT analysis, being female and high scores for FBG are associated with decreased blood donation. Among males, blood donation frequency is low among those aged 33 years and under. CONCLUSION: Fear of blood, injections and fainting are barriers to blood donation in Brazil. Efforts to recruit and retain blood donors should convey information on blood donation processes and address misconceptions that may increase fear. PMID- 30485454 TI - Allergic contact dermatitis caused by timolol eyedrops application for infantile hemangioma. AB - Allergic contact dermatitis (ACD) caused by timolol eyedrops is well-known (1, 2) while ACD following its use for infantile hemangiomas has hitherto not been reported. PMID- 30485455 TI - Sequential regiospecific gem-diprenylation of tetrahydroxyxanthone by prenyltransferases from Hypericum sp. AB - Polyprenylated acylphloroglucinol derivatives, such as xanthones, are plant natural products with interesting pharmacological properties. They are difficult to synthesise chemically. Biotechnological production is desirable but requires the understanding of the biosynthetic pathways. cDNAs encoding membrane-bound aromatic prenyltransferase (aPT) enzymes from Hypericum sampsonii seedlings (HsPT8px and HsPTpat) and Hypericum calycinum cell cultures (HcPT8px and HcPTpat) were cloned and expressed in Saccharomyces cerevisiae and Nicotiana benthamiana, respectively. Microsomes and chloroplasts were used for functional analysis. The enzymes catalysed the prenylation of 1,3,6,7-tetrahydroxyxanthone (1367THX) and/or 1,3,6,7-tetrahydroxy-8-prenylxanthone (8PX) and discriminated nine additionally tested acylphloroglucinol derivatives. The transient expression of the two aPT genes preceded the accumulation of the products in elicitor-treated H. calycinum cell cultures. C-terminal YFP fusions of the two enzymes were localised to the envelope of chloroplasts in N. benthamiana leaves. Based on the kinetic properties of HsPT8px and HsPTpat, the enzymes catalyse sequential rather than parallel addition of two prenyl groups to the carbon atom 8 of 1367THX, yielding gem-diprenylated patulone under loss of aromaticity of the gem dialkylated ring. Coexpression in yeast significantly increased product formation. The patulone biosynthetic pathway involves multiple subcellular compartments. The aPTs studied here and related enzymes may be promising tools for plant/microbe metabolic pathway engineering. This article is protected by copyright. All rights reserved. PMID- 30485457 TI - Emanuel Donchin (1935-2018). PMID- 30485456 TI - Der p 1-specific regulatory T cell response during house dust mite allergen immunotherapy. AB - BACKGROUND: Allergen-specific immunotherapy (AIT) is the only available treatment for allergic diseases that can induce specific immune tolerance to allergens. The key mechanisms involved in this process include changes in allergen-specific regulatory T (Treg) cells. METHODS: We studied 25 allergic rhinitis patients undergoing subcutaneous house dust mite-specific immunotherapy. Peripheral blood mononuclear cells were studied before, after 10 weeks, 30 weeks and 3 years of AIT. Der p 1-specific T regulatory cell responses was investigated by characterization of Der p 1-MHC-class II tetramer-positive cells and correlated with nasal symptom score. RESULTS: Twelve of 25 AIT patients matched with their MHC-class II expression to the Der p 1 peptide-MHC-class II tetramers. A significant increase in the numbers of Der p 1-specific FOXP3+ Helios+ CD25+ CD127- Treg cells after 30 weeks was observed, which slightly decreased after 3 years of AIT. In contrast, Der p 1-specific immunoglobulin-like transcript 3 (ILT3)+ CD25+ Treg cells decreased substantially from baseline after 3 years of AIT. ILT3+ Treg cells displayed compromised suppressive function and low FOXP3 expression. In addition, Der p 1-specific IL-10 and IL-22 responses have increased after 30 weeks, but only IL-10+ Der p 1-specific Treg cells remained present at high frequency after 3 years of AIT. Increased number of FOXP3+ Helios+ , IL-10+ and decreased ILT3+ Treg cell responses correlated with improved allergic symptoms. CONCLUSION: The results indicate that AIT involves upregulation of the activated allergen-specific Treg cells and downregulation of dysfunctional allergen-specific Treg cells subset. Correction of dysregulated Treg cells responses during AIT is associated with improved clinical response. This article is protected by copyright. All rights reserved. PMID- 30485458 TI - Associated factors of multiple contact allergies in Thai dermatitis patients: A 10-year retrospective study. AB - BACKGROUND: Multiple contact allergies (MCA) are evidenced by 3 or more positive patch test reactions to unrelated antigens. Factors associated with MCA include female gender, older age, and certain eczema sites. OBJECTIVES: To investigate the prevalence of MCA, risk factors for their development, and patterns of allergen combinations. METHODS: This retrospective, case-control study was conducted on patients suspected of having allergic contact dermatitis who had been patch tested with a baseline series during January 2007 through December 2016. RESULTS: Of the 2 178 included patients, 531 (24.4%) had MCA. A multivariate analysis found that a generalized distribution of dermatitis represented the highest risk factor (OR 3.97), followed by a history of metal allergy (OR 3.18). The other significantly associated factors were, in order of decreasing frequency, the dermatitis sites (hands/feet, extremities, and face); age >= 25 years; and occupationally related dermatitis; their ORs were < 3. CONCLUSIONS: The significantly associated factors of MCA were identified. The ranking of the common contact allergens among the MCA patients was comparable with that of the non-MCA patients. Metal and fragrance allergens were frequently found to cause concurrent positive reactions in the MCA patients. PMID- 30485459 TI - Kinetics of antigen-specific IgM/ IgG/ IgA antibody responses during Zika virus natural infection in two patients. AB - Understanding of kinetics of antibody responses is crucial for developing rapid serological tests and studying the mechanisms of Zika virus (ZIKV) infection. Most of the serological diagnostic assays previously published are based on either IgM or IgG titer, little is known on the level of IgA antibody in saliva and urine. In this study, we investigated the kinetics of IgM/ IgG/ IgA antibody responses in serum, saliva and urine obtained from two ZIKV infected individuals from as early as the 2nd day of onset of symptoms to as long as 2 years post infection. Other than detecting robust early IgM response, long lasting IgG response, we discovered strong early IgA response specific for ZIKV in saliva in both patients. This unique observation provides a novel strategy and scientific basis for the development of non-invasive rapid tests for ZIKV infection. This article is protected by copyright. All rights reserved. PMID- 30485460 TI - Depression in cirrhosis - a prospective evaluation of the prevalence, predictors and development of a screening nomogram. AB - BACKGROUND: Depression is associated with substantial morbidity and mortality in cirrhosis, but is underdiagnosed and undertreated. AIMS: Using the Mini International Neuropsychiatric Interview (MINI) as a gold-standard, to determine prevalence, predictors, and outcomes of depression, and to develop a screening nomogram for use in cirrhosis patients. METHODS: Cirrhotic outpatients 18-80 years of age, not on anti-depressants, were consecutively recruited from liver clinics at three tertiary care hospitals. Baseline health-related quality of life (HRQoL) and frailty were determined by the chronic liver disease questionnaire, EQ-VAS, Clinical Frailty Scale and Fried Frailty Criteria. Depression was identified using the MINI and participants were followed up to 6 months to determine unplanned hospitalization/death. RESULTS: Of 305 patients, 62% were male; mean age 55(10) years; mean MELD 12.5(5), 61% Child Pugh B/C. Prevalence of depression 18% by MINI. Patients with depression had lower baseline HRQoL and higher frailty scores. Five independently predictive factors were used to develop a clinical nomogram for the diagnosis of clinical depression. These included three Hospital Anxiety and Depression Screening tool variables: "I have lost interest in my appearance" (adjusted odds ratio [aOR] 2.2, P = 0.006), "I look forward with enjoyment to things" (aOR 2.0, P = 0.02), "I feel cheerful" (aOR 2.8, P = 0.002), and two demographic variables: younger age (aOR 0.92, P = 0.001) and not being married or in a common-law relationship (aOR 0.30, P = 0.008). CONCLUSIONS: Depression is common in patients with cirrhosis. It has a significant impact on HRQoL and functional status. The developed clinical nomogram is promising for the rapid screening of depression in patients with cirrhosis. PMID- 30485461 TI - Bacteriophages: an overview of the control strategies against multiple bacterial infections in different fields. AB - Bacteriophages (phages/viruses) need host bacteria to replicate and propagate. Primarily, a bacteriophage contains a head/capsid to encapsidate the genetic material. Some phages contain tails. Phages encode endolysins to hydrolyze bacterial cell wall. The two main classes of phages are lytic or virulent and lysogenic or temperate. In comparison with antibiotics, to deal with bacterial infections, phage therapy is thought to be more effective. In 1921, the use of phages against bacterial infections was first demonstrated. Later on, in humans, phage therapy was used to treat skin infections caused by Pseudomonas species. Furthermore, phages were successfully employed against infections in animals - calves, lambs, and pigs infected with Escherichia coli. In agriculture, for instance, phages have successfully been used e.g., Apple blossom infection, caused by Erwinia amylovora, was effectively catered with the use of bacteriophages. Bacteriophages were also used to control E. coli, Salmonella, Listeria, and Campylobacter contamination in food. Comparatively, phage display is a recently discovered technology, whereby, bacteriophages play a significant role. This review is an effort to collect almost recent and relevant information regarding applications and complications associated with the use of bacteriophages. PMID- 30485463 TI - Cell-Cycle-Dependent Regulation of Cell Adhesions: Adhering to the Schedule: Three papers reveal unexpected properties of adhesion structures as cells progress through the cell cycle. AB - Focal adhesions disassemble during mitosis, but surprisingly little is known about how these structures respond to other phases of the cell cycle. Three recent papers reveal unexpected results as they examine adhesions through the cell cycle. A biphasic response is detected where focal adhesions grow during S phase before disassembly begins early in G2. In M phase, activated integrins at the tips of retraction fibers anchor mitotic cells, but these adhesions lack the defining components of focal adhesions, such as talin, paxillin, and zyxin. Re examining cell-matrix adhesion reveals reticular adhesions, a new class of adhesion. These alphaVbeta5 integrin-mediated adhesions also lack conventional focal adhesion components and anchor mitotic cells to the extracellular matrix. As reviewed here, these studies present insight into how adhesion complexes vary through the cell cycle, and how unconventional adhesions maintain attachment during mitosis while providing spatial memory to guide daughter cell re-spreading after cell division. PMID- 30485464 TI - Real World Usability Analysis of two Augmented Reality Headsets in Visceral Surgery. AB - BACKGROUND: Recent developments in the field of augmented reality (AR) have enabled new use cases in surgery. Initial set-up of an appropriate infrastructure for maintaining an AR surgical workflow requires investment in appropriate hardware. METHODS: We compared the usability of the Microsoft HoloLens and Meta 2 head mounted displays (HMDs). Fifteen medicine students tested each device and were questioned with a variant of the System Usability Scale (SUS). Two surgeons independently tested the devices in an intraoperative setting. RESULTS: In our adapted SUS, ergonomics, ease of use and visual clarity of the display did not differ significantly between HMD groups. The field of view (FOV) was smaller in the Microsoft HoloLens than the Meta 2 and significantly more study subjects (80% vs. 13.3%; p < 0.001) felt limited through the FOV. Intraoperatively, decreased mobility due to the necessity of an AC adapter and additional computing device for the Meta 2 proved to be limiting. Object stability was rated superior in the Microsoft HoloLens than the Meta 2 by our surgeons and lead to increased use. CONCLUSIONS: We examined the Meta 2 and the Microsoft HoloLens and found key advantages in the Microsoft HoloLens which provided palpable benefits in a surgical setting. This article is protected by copyright. All rights reserved. PMID- 30485465 TI - To Read More Papers, or to Read Papers Better? A Crucial Point for the Reproducibility Crisis. AB - The overflow of scientific literature stimulates poor reading habits which can aggravate science's reproducibility crisis. Thus, solving the reproducibility crisis demands not only methodological changes, but also changes in our relationship with the scientific literature, especially our reading habits. Importantly, this does not mean reading more, it means reading better. PMID- 30485466 TI - Short-term outcomes of intra-aortic balloon pump combined with venoarterial extracorporeal membrane oxygenation: a systematic review and meta-analysis. AB - OBJECTIVE: The effectiveness of intra-aortic balloon pump (IABP) combined with venoarterial extracorporeal membrane oxygenation (VA-ECMO) in patients with cardiogenic shock or cardiac arrest remains controversial. The aim of this systematic review and meta-analysis was to investigate the short-term clinical outcomes of IABP combined with VA-ECMO versus VA-ECMO alone. METHODS: We searched PubMed, Embase, and the Cochrane Library for English articles published from inception to August 18, 2018. Observational studies comparing IABP combined with VA-ECMO with VA-ECMO were considered eligible for the current study. RESULTS: Twelve observational studies with 3704 patients were included. In the IABP combined with VA-ECMO group mortality was 59.7%, compared with 65.8% in the VA ECMO alone group. The risk ratio (RR) for this comparison was 0.90 (95% confidence interval [CI], 0.80-1.02; P = 0.107; 59.7% vs. 65.8%). In the one-way sensitivity analysis for estimating the effect of each study on mortality, omission of each study did not make a significant difference. Furthermore, the proportion of patients weaned from VA-ECMO was significantly higher in IABP combined VA-ECMO group than in the VA-ECMO alone group (RR, 1.28; 95% CI, 1.21 1.35; P < 0.001; 77.9% vs. 61.2%). CONCLUSIONS: IABP combined with VA-ECMO could improve success rate of weaning from VA-ECMO, but did not reduce in-hospital mortality in patients with cardiogenic shock or cardiac arrest. This article is protected by copyright. All rights reserved. PMID- 30485467 TI - Vaccination for influenza and pneumococcus in patients with gastrointestinal cancer or inflammatory bowel disease: A prospective cohort study of methods for improving coverage. AB - BACKGROUND: Although influenza and pneumococcal vaccinations for high-risk populations are recommended by current guidelines, vaccination coverage is low in patients with gastrointestinal cancer (GC) or inflammatory bowel disease (IBD). AIM: To evaluate the impact of a specialised infectious disease consultation on vaccination coverage rates in these patients. METHODS: Between December 2016 and April 2017, all patients with GC or IBD followed in the outpatient clinic of the Gastroenterology department at the Nancy University Hospital enrolled in a 3 phase vaccination programme. Phase 1: Initial questionnaire (vaccination status, knowledge about vaccines and possible barriers to vaccination); Phase 2: Infectious disease consultation; Phase 3: Subsequent questionnaire (evolution of patients' knowledge about vaccination). RESULTS: A total of 366 patients were included (GC = 99, IBD = 267). Vaccination rate was 34.7% for influenza and 14.5% for pneumococcus. About 43% of the patients feared side effects of vaccines. After the initial questionnaire, 49.3% of the interested patients participated in a specialised vaccination consultation (n = 102). 87.3% (n = 89) received new vaccination, 41.2% changed their mind about vaccination, and 92.2% would recommend this programme to other patients. Among vaccinated patients, 97.8% (n = 87) received pneumococcal vaccine, 40.4% received tetanus-diphtheria-polio vaccine, and 7.9% received influenza vaccine. In GC patients, anti-pneumococcal vaccination rate was 87.5% after the specialised consultation compared with 10.1% before. In IBD patients, corresponding rates were 85.7% and 16.1%. CONCLUSIONS: A specialised infectious disease consultation can improve GC and IBD patients' knowledge about vaccination and vaccination coverage. This approach could be applied to all high-risk populations. PMID- 30485468 TI - Cigarette smoke extract may induce lysosomal storage disease-like adverse health effects. AB - Cigarette smoke is known to be associated with the incidence of a variety of pulmonary diseases, and alveolar macrophages are a key player in the defense mechanism against inhalable toxicants. Herein, we have found that a hydrophilic fraction in smoke extracts from 3R4F reference cigarettes (CSE) contains high concentrations of volatile substances compared to cigarette smoke condensate (amphoteric fraction). We also identified the toxic mechanism of CSE using MH-S, a mouse alveolar macrophage cell line. CSE decreased cell viability accompanying increased lactate dehydrogenase release. Additionally, mitochondrial volume and the potential increased along with enhanced expression of mitochondrial fusion proteins and decreased adenosine triphosphate production. Similarly, CSE clearly induced increase of catalase activity and intracellular calcium concentration and decrease of endoplasmic reticulum and lysosome volume at the highest dose. More interestingly, damaged organelles accumulated in the cytosol, and CSE-containing particles specifically penetrated to mitochondria. Meanwhile, any significant change in autophagy related protein expression was not found in CSE-treated cells. Subsequently, we evaluated the effects of CSE on secretion of inflammatory related cytokines and chemokines, considering the relationship between organelle damage and the disturbed immune response. Very importantly, we found that expression of innate and adaptive immunity related mediators is disrupted following CSE exposure. Taken together, we suggest that CSE may cause the accumulation of damaged organelles in the cytoplasm by impairing selective autophagic function. In addition, this accumulation is responsible for the inadequate ability of immune cells to repair the damage of lung tissue following exposure to CSE. PMID- 30485469 TI - Proteoglycan 4: From Mere Lubricant to Regulator of Tissue Homeostasis and Inflammation: Does proteoglycan 4 have the ability to buffer the inflammatory response? AB - Proteoglycan 4 (PRG4), first identified in synovial fluid, is an extracellular matrix structural protein in the joint implicated in reducing shear at the cartilage surface as well as controlling adhesion-dependent synovial growth and regulating bulk protein deposition onto the cartilage. However, recent evidence suggests that it can bind to and effect downstream signaling of a number of cell surface receptors implicated in regulating the inflammatory response. Therefore, we pose the hypothesis: Does PRG4 regulate the inflammatory response and maintain tissue homeostasis? Based on these novel findings implicating PRG4 as an inflammatory signaling molecule, we will present and discuss several hypotheses regarding potential mechanisms by which PRG4 may be able to regulate inflammation. If future studies can demonstrate that PRG4 is a potent inflammatory mediator, this will change current paradigms in the musculoskeletal and ophthalmological fields regarding the how the inflammatory microenvironment is regulated in these tissues and potentially others. PMID- 30485471 TI - Discontinuation and Nonadherence to Medications for Chronic Conditions after Hematopoietic Cell Transplantation: A Six-Year Propensity Score-Matched Cohort Study. AB - INTRODUCTION: Hematopoietic cell transplantation (HCT) is an established curative option for patients with hematological malignancies and other life-threatening conditions. Evidence on nonpersistence and nonadherence to oral medications for chronic conditions among patients following HCT is lacking. OBJECTIVES: This study aims to examine patterns of oral medication use for chronic conditions following HCT in the United States population. METHODS: Nonpersistence and nonadherence to oral medications for diabetes, hypertension, and dyslipidemia among HCT recipients were assessed in a cohort that included 1382 autologous and 650 allogeneic HCT recipients with hematological malignancies using the Truven Health MarketScan(r) Research Database between 2009 and 2014. Recipients of HCT were compared to propensity score-matched cancer patients receiving chemotherapy without transplantation. Multivariable Cox proportional hazards models and generalized estimating equations were used to determine characteristics associated with nonpersistence and nonadherence to oral chronic medications, respectively. RESULTS: Recipients of HCT had higher risks of discontinuing medication for diabetes mellitus (allogeneic HCT hazard ratio (HR)=1.93, 95% Confidence Incidence (CI) 1.10-3.39; autologous HCT HR=1.49, 95% CI 1.04-2.15); hypertension (allogeneic HCT HR=1.75, 95% CI 1.21-2.53; autologous HCT HR=1.32, 95% CI 1.07-1.62), and dyslipidemia (allogeneic HCT HR=2.02, 95% CI 1.39-2.93; autologous HCT, HR=1.26, 95% CI 0.98-1.61) compared to patients treated with only chemotherapy. Lower odds of adherence to antihypertensive medications (odds ratio (OR)=0.58, 95% CI 0.38-0.89) and to lipid-lowering medications (OR=0.38, 95% CI 0.22-0.65) were observed in allogeneic HCT recipients compared with propensity score-matched patients who underwent chemotherapy. CONCLUSIONS: Poor medication persistence and adherence to chronic disease medications are common post HCT. Further research to improve long-term outcomes following HCT should include management of medication therapy for chronic comorbid conditions. This article is protected by copyright. All rights reserved. PMID- 30485470 TI - Are selection criteria for healthy pregnancies responsible for the gap between fetal growth in the French national Elfe birth cohort and the Intergrowth-21st fetal growth standards? AB - BACKGROUND: The Intergrowth-21st (IG) project proposed prescriptive fetal growth standards for global use based on ultrasound measurements from a multicounty study of low-risk pregnancies selected using strict criteria. We examined whether the IG standards are appropriate for fetal growth monitoring in France and whether potential differences could be due to IG criteria for "healthy" pregnancies. METHOD: We analysed data on femur length and abdominal circumference at the second and/or the third recommended ultrasound examination from 14 607 singleton pregnancies from the Elfe national birth cohort. We compared concordance of centile thresholds using the IG standards and current French references and used restricted cubic splines to plot z-scores by gestational age. A "healthy pregnancy" sub-sample was created based on maternal and pregnancy selection criteria, as specified by IG. RESULTS: Mean gestational age-specific z scores for femur length and abdominal circumference using French references fluctuated around 0 (-0.2 to 0.1), while those based on IG standards were higher (0.3-0.8). Using IG standards, 2.5% and 5.2% of fetuses at the third ultrasound were <10th centile for femur length and abdominal circumference, respectively, and 31.5% and 16.7% were >90th. Only 34% of pregnancies fulfilled IG low-risk criteria, but sub-analyses yielded very similar results. CONCLUSION: Intergrowth standards differed from fetal biometric measures in France, including among low risk pregnancies selected to replicate IG's healthy pregnancy sample. These results challenge the project's assumption that careful constitution of a low risk population makes it possible to describe normative fetal growth across populations. PMID- 30485472 TI - In vitro genotoxicity assessment of an oxidized dextrin-based hydrogel for biomedical applications. AB - Hydrogels are three-dimensional, crosslinked networks of hydrophilic polymers swollen with a large amount of water or biological fluids, without dissolving. Dextrin, a low-molecular-weight carbohydrate composed by glucose residues, has been used to develop an injectable hydrogel for biomedical applications. Dextrin was first oxidized to introduce aldehyde groups, which then reticulate with adipic acid dihydrazide, forming the dextrin-based hydrogel (HG). The HG and its components were tested for cyto- and genotoxicity according to the International Standard ISO 10993-3 on the biological evaluation of medical devices. To assess genotoxicity, a battery of in vitro genotoxicity tests employing both eukaryotic and prokaryotic models was performed: comet assay, cytokinesis-block micronucleus assay and Ames test. Our data revealed that the HG (IC50 = 2.8 mg/mL) and oxidized dextrin by itself (IC50 = 1.2 mg/mL) caused a concentration-dependent decrease in cellular viability of human lymphoblastoid TK6 cells after 24 hours of exposure to the test agents. However, these concentrations are unlikely to be reached in vivo. In addition, no significant increase in the DNA and chromosomal damage of TK6 cells exposed to non-cytotoxic concentrations of the HG and its isolated components was detected. Furthermore, neither the HG nor its metabolites exerted a mutagenic effect in different of Salmonella typhimurium strains and in an Escherichia coli mix. Our data demonstrated the genocompatibility of the HG (up to 3.5 mg/mL) for biomedical applications. To our best acknowledge, this is the first report with a detailed genotoxicity assessment of an aldehyde-modified polysaccharide/adipic acid dihydrazide hydrogel. PMID- 30485473 TI - Fe3 O4 nanoparticles mediated synthesis of novel spirooxindole dihydropyrimidinone molecules as Hsp90 inhibitors. AB - Heat shock protein 90 (Hsp90) is a validated molecular chaperone considered as the new key recipient for cancer intervention. The current study illustrates the synthesis of novel spirooxindole-dihydropyrimidinones (4a-j) by Fe3 O4 nanoparticles intervened synthesis and their Hsp90 ATPase inhibitory activity was investigated by the malachite green assay. All the compounds in the study demonstrated a moderate to potent ATPase inhibitory profile, with IC50 values ranging from 0.18 to 6.80 MUM. Compounds 4j, 4h, 4f, and 4i exhibited maximum inhibitory potential with IC50 values of 0.18, 0.20, 0.35, and 0.55 MUM, respectively. They were found to be better than the standard drug, geldanamycin (Hsp9 ATPase inhibition IC50 = 0.90 MUM). Compounds 4h and 4j with IC50 values of 22.82 +/- 0.532, 20.78 +/- 0.234 and 21.32 +/- 0.765, 28.43 +/- 0.653 uM showed significantly greater potencies against the MCF-7 and HepG2 cell lines, respectively. Compound 4j showed good antioxidant activities in the DPPH test and H2 O2 assay (IC50 = 20.13.23 +/- 0.32 and 23.27 +/- 0.32 MUg/mL) when compared with the standard ascorbic acid (IC50 = 19.16 +/- 0.20 and 20.66 +/- 1.09 MUg/mL). A molecular docking study was performed to observe the binding efficiency and steric interactions of the lead moiety. PMID- 30485474 TI - The influence of relativistic effects on nuclear magnetic resonance spin-spin coupling constant polarizabilities of H2 O2 , H2 S2 , H2 Se2 , and H2 Te2. AB - Relativistic and nonrelativistic calculations have been performed on hydrogen peroxide, dihydrogen disulfide, dihydrogen diselenide, and dihydrogen ditelluride, H2 X2 (X = O, S, Se, Te), to investigate the consequences of relativistic effects on their structures as well as their nuclear magnetic resonance (NMR) spin-spin coupling constants and spin-spin coupling constant polarizabilites. The study has been performed using both one-component nonrelativistic and four-component relativistic calculations at the density functional theory (DFT) level with the B3LYP exchange-correlation functional. The calculation of nuclear spin-spin coupling constant polarizabilities has been performed by evaluating the components of the third order tensor, nuclear spin spin coupling polarizability, using quadratic response theory. From this, the pseudoscalar associated with this tensor has also been calculated. The results show that relativistic corrections become very important for H2 Se2 and H2 Te2 and hint that a new chiral discrimination technique via NMR spectroscopy might be possible for molecules containing elements like Se or Te. (c) 2018 Wiley Periodicals, Inc. PMID- 30485475 TI - CUTANEOUS MANIFESTATIONS OF HEMATOLOGIC MALIGNANCIES. AB - In recent years, dermatologic manifestations in oncohematologic patients have become more common. The aim of our study was to determine the incidence and heterogeneity of skin manifestations in patients followed at our Hematology Department. This observational monocentrical study was conducted on 60 patients. We divided the observed conditions in exanthematous, purpuric, vesicular-bullous, papulo-nodular, urticarial and eczematous manifestations. Moreover, all lesions were classified according to pathogenesis, in: (1) specific skin manifestations, caused by neoplastic skin infiltration; (2) immune-mediated manifestations, based on immunological mechanisms; (3) skin lesions due to immunodeficiency. Altogether, 73 clinical manifestations were reported. Specific manifestations (1) were detected in 15.1% of the cases, mainly with papulo-nodular appearance. Immune-mediated manifestations (2) were found in 37 cases (50.7%), particularly with eczematous or exanthematous appearance, and leukemia was the malignancy most frequently reported in these patients. Eventually, lesions due to immunosuppression (3) were reported in 34.2% of the cases. They were represented by infections and cutaneous malignancies, and usually manifested with papulo nodular lesions. Skin lesions in oncohematologic patients are a common event. A multidisciplinary approach based on the collaboration between the hematologist and the dermatologist is crucial to achieve a proper diagnosis, and correctly manage these manifestations. PMID- 30485476 TI - Pyrazinamide resistance and mutations L19R, R140H, and E144K in Pyrazinamidase of Mycobacterium tuberculosis. AB - Pyrazinamide (PZA) is an important component of first-line antituberculosis drugs activated by Mycobacterium tuberculosis pyrazinamidase (PZase) into its active form pyrazinoic acid. Mutations in the pncA gene have been recognized as the major cause of PZA resistance. We detected some novel mutations, Leucine19Arginine (L19R), Arginine140Histidine (R140H), and Glutamic acid144 Lysine (E144K), in the pncA gene of PZA-resistant isolates in our wet lab PZA drug susceptibility testing and sequencing. As the molecular mechanism of resistance of these variants has not been reported earlier, we have performed multiple analyses to unveil different mechanisms of resistance because of PZase mutations L19R, R140H, and E144K. The mutants and native PZase structures were subjected to comprehensive computational molecular dynamics (MD) simulations at 100 nanoseconds in apo and drug-bound form. Mutants and native PZase binding pocket were compared to observe the consequence of mutations on the binding pocket size. Hydrogen bonding, Gibbs free energy, and natural ligand Fe +2 effect were also analyzed between native and mutants. A significant variation between native and mutant PZase structure activity was observed. The native PZase protein docking score was found to be the maximum, showing strong binding affinity in comparison with mutants. MD simulations explored the effect of the variants on the biological function of PZase. Hydrogen bonding, metal ion Fe +2 deviation, and fluctuation also seemed to be affected because of the mutations L19R, R140H, and E144K. The variants L19R, R140H, and E144K play a significant role in PZA resistance, altering the overall activity of native PZase, including metal ion Fe +2 displacement and free energy. This study offers valuable evidence for better management of drug-resistant tuberculosis. PMID- 30485477 TI - Gold nanoparticle and polyethylene glycol in neural regeneration in the treatment of neurodegenerative diseases. AB - Gold nanoparticles (GNs) have unique characteristics, for example, stability, biocompatibility, small dimensions, and low toxicity. Several clinical applications have been suggested for GNs, such as diagnosis, imaging, and drug delivery. GNs absorb infrared light, indicating their potential value for imaging. There is growing evidence showing the therapeutic application of GN for drug delivery because of their interaction with the blood-brain barrier and DNA, the latter being associated with their genotoxic effects. GN can also be stimulated to produce high local temperatures, indicating their potential value in photodynamic therapy in the treatment of tumors. The aim of the current review is to summarize the potential applications of GNs in the biomedical field, specifically in neurodegenerative diseases. PMID- 30485478 TI - Is the sum of positive neuroendocrine immunohistochemical stains useful for diagnosis of large cell neuroendocrine carcinoma (LCNEC) on biopsy specimen? AB - PURPOSE: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is underdiagnosed on biopsy specimen. We evaluated if routine neuroendocrine immunohistochemical (IHC) stains are helpful in the diagnosis of LCNEC on biopsy specimen. METHODS: Using the Dutch pathology registry (PALGA) surgically resected LCNEC with matching pre-operative biopsy specimen were identified and Haematoxylin and IHC slides (CD56, Chromogranin-A, Synaptophysin) requested. Subsequently, three pathologists assigned 1) the presence or absence of the WHO 2015 criteria and 2) cumulative size of all (biopsy) specimen. For validation, a tissue micro array (TMA) of non-small cell lung cancer (NSCLC) (77) and LCNEC (19) was used. RESULTS: LCNEC was confirmed on the resection specimen in 32/48 re-reviewed cases. In 47% (n=15/32) LCNEC was also confirmed in the paired biopsy specimen. Neuroendocrine morphology was absent in 53% (n=17/32) of paired biopsy specimen, more often when fewer amount of tissue was available for evaluation ((29% <5mm (n=14) versus 67% >=5mm (n=18) P=0.04). Combined with current WHO criteria, positive staining for >=2 out of 3 neuroendocrine IHC markers increased the sensitivity for LCNEC from 47% to 93% on paired biopsy specimen. Further validated using an independent TMA of LCNEC and NSCLC with sensitivity and specificity of 80 and 99%, respectively. CONCLUSIONS: LCNEC is difficult to diagnose because neuroendocrine morphology frequently is absent in biopsy specimen. In NSCLC devoid of obvious morphological squamous or adenocarcinoma features, positive staining in >=2 out of three neuroendocrine IHC stains support the diagnosis of LCNEC. This article is protected by copyright. All rights reserved. PMID- 30485479 TI - A Bayesian approach to Mendelian randomisation with dependent instruments. AB - Mendelian randomisation (MR) is a method for establishing causality between a risk factor and an outcome by using genetic variants as instrumental variables. In practice, the association between individual genetic variants and the risk factor is often weak, which may lead to a lack of precision in the MR and even biased MR estimates. Usually, the most significant variant within a genetic region is selected to represent the association with the risk factor, but there is no guarantee that this variant will be causal or that it will capture all of the genetic association within the region. It may be advantageous to use extra variants selected from the same region in the MR. The problem is to decide which variants to select. Rather than selecting a specific set of variants, we investigate the use of Bayesian model averaging (BMA) to average the MR over all possible combinations of genetic variants. Our simulations demonstrate that the BMA version of MR outperforms classical estimation with many dependent variants and performs much better than an MR based on variants selected by penalised regression. In further simulations, we investigate robustness to violations in the model assumptions and demonstrate sensitivity to the inclusion of invalid instruments. The method is illustrated by applying it to an MR of the effect of body mass index on blood pressure using SNPs in the FTO gene. PMID- 30485481 TI - Call for papers for upcoming themed issue on Maternal Health. PMID- 30485480 TI - Endothelin-1 triggers human peritoneal mesothelial cells' proliferation via ERK1/2-Ets-1 signaling pathway and contributes to endothelial cell angiogenesis. AB - BACKGROUND: Dysfunction of the peritoneum as a dialysis organ may result from progressive membrane injury on peritoneal dialysis (PD). It has been increasingly recognized that the human peritoneal mesothelial cells (HPMCs) play a key role in peritoneal membrane early injury. Recently, it has been reported that bioincompatible PD fluid with high concentrations of glucose and glucose degradation products, low pH, high osmolality, and peritonitis stimulates HPMCs to release endothelin-1 (ET-1). ET-1 causes increased the release of vascular endothelial growth factor, which is important for tumor cell angiogenesis. We hypothesized that activating ET-1 might predict injury of peritoneal membrane. METHODS: HPMCs were isolated from normal omentum. ERK1/2 and Ets-1 phosphorylation were measured by Western blot analysis. HPMC proliferation was detected by the bromodeoxyuridine (BrdU) assay. Capillary networks of tubes formed were photographed under a microscope, and five randomly selected fields from each well were analyzed for total capillary length by using Image J software. RESULTS: MEK-1 blocker significantly abolished the ERK1/2 activation by ET-1, which also triggered phosphorylation, thus activating the transcription factor Ets-1 downstream from ERK1/2. ET-1 was capable to induce HPMC proliferation, which could be attenuated by ET-1 antagonists. Antibody and small interfering RNA mediated blockade of Ets-1 had similar antiproliferative effects. Thus, ET-1 specifically triggered HPMC proliferation via ERK1/2-Ets-1 signaling pathway. VEGF production and endothelial cell angiogenesis were significantly in response to conditioned medium from HPMCs treated with ET-1. CONCLUSIONS: ET-1 triggered HPMC proliferation through the ERK1/2-Ets-1 signaling pathway and contributed to VEGF production and endothelial cell angiogenesis. PMID- 30485482 TI - lncRNA nuclear-enriched abundant transcript 1 promotes cell proliferation and invasion by targeting miR-186-5p/HIF-1alpha in osteosarcoma. AB - Increasing evidence shows that the long noncoding RNA nuclear enriched abundant transcript 1 (NEAT1) plays important roles in tumor progression. However, the function and the underlying mechanism of NEAT1 in osteosarcoma (OS) remain unclear. In the present study, we found that NEAT1 expression was significantly upregulated in OS tissues and cell lines. High NEAT1 expression was closely associated with advanced clinicopathologic features and poor overall survival of patients with OS. Using in vitro function assay, we found that NEAT1 could promote the proliferation, invasion, and epithelial-mesenchymal transition (EMT) process of OS cells. NEAT1 could also promote OS cell growth in vivo. In addition, our studies showed that miR-186-5p was a downstream target of NEAT1 in OS. Functionally, miR-186-5p suppressed the proliferation, invasion, and EMT process of OS cells. Furthermore, our data revealed that HIF-1alpha was a downstream target of miR-186-5p and that NEAT1 could exert its tumor oncogenic roles on OS cells via the miR-186-5p/HIF-1alpha axis. Taking our results together, we elucidated that the NEAT1/miR-186-5p/HIF-1alpha axis might be a therapeutic approach for the treatment of OS. PMID- 30485483 TI - Serum soluble TREM2 as a biomarker for incident dementia: the Hisayama Study. AB - OBJECTIVE: To investigate the association between serum soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a soluble type of an innate immune receptor expressed on the microglia, and the risk of dementia. METHODS: A total of 1,349 Japanese community-residents aged 60 and older without dementia were followed prospectively for 10 years (2002-2012). Serum sTREM2 levels were quantified by using an enzyme-linked immunosorbent assay and divided into quartiles. Cox proportional hazards model was used to estimate the hazard ratios (HRs) of serum sTREM2 levels on the risk of dementia. RESULTS: During the follow up, 300 subjects developed all-cause dementia; 193 had Alzheimer's disease (AD), and 85 had vascular dementia (VaD). The age- and sex-adjusted incidences of all cause dementia, AD, and VaD elevated significantly with higher serum sTREM2 levels (all P for trend <0.012). These associations were not altered after adjustment for confounding factors, including high-sensitive C-reactive protein. Subjects with the highest quartile of serum sTREM2 levels had significantly higher multivariable-adjusted risks of developing all-cause dementia, AD, and VaD than those with the lowest quartile (HR=2.03, 95% CI=1.39-2.97, P<0.001 for all cause dementia; HR=1.62, 95% CI=1.02-2.55, P=0.04 for AD; HR=2.85, 95% CI=1.35 6.02, P=0.006 for VaD). No significant heterogeneity in the association of serum sTREM2 levels with the development of dementia was observed among the other risk factor subgroups (all P for heterogeneity >0.11). INTERPRETATIONS: The present findings suggest a significant association between increased serum sTREM2 levels and the risk of developing all-cause dementia, AD, and VaD in the general elderly Japanese population. This article is protected by copyright. All rights reserved. PMID- 30485484 TI - Knockdown of cathepsin D protects dopaminergic neurons against neuroinflammation mediated neurotoxicity through inhibition of NF-kappaB signaling pathway in Parkinson's disease model. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder pathologically characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Chronic neuroinflammation is one of the hallmarks of PD pathophysiology. Cathepsin D (CathD), a soluble aspartic protease, has been reported to play an important role in neurodegenerative diseases such as PD. This research focused on the role of CathD and the molecular mechanisms involved in the process of neuroinflammation and neurotoxicity. We used 1-methyl-4phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-challenged mice and lipopolysaccharide (LPS)-induced murine microglia BV2 cells as the in vivo and in vitro models, respectively. The effect of CathD on the neuroinflammation, cytotoxicity and the underlying mechanisms associated with NF-kappaB signaling pathway were investigated. Date showed that MPTP induces motor deficit, inflammation and depletion of dopaminergic neurons in PD model mice. Notably, cathD was overexpressed in the SNpc of MPTP-induced PD mice and was highly expressing in LPS-stimulated primary microglial cells and BV-2 cells. Furthermore, knockdown of CathD with lentiviral transduction inhibited LPS induced neuroinflammation through inhibition of NF-kappaB signaling pathway primarily by regulating the NF-kappaB p65 nuclear translocation both in BV-2 and primary microglial cells. Additionally, knockdown of CathD protected the activated-microglia induced dopaminergic neurons MN9D cells from neurotoxicity as well as apoptosis. Our findings bring a new insight into understanding the complex mechanisms underlying the pathogenesis of PD and provide a novel target to attenuate the excessive neuroinflammatory responses in the treatment of PD. This article is protected by copyright. All rights reserved. PMID- 30485485 TI - A C-type CpG ODN accelerates wound healing via regulating fibroblasts and immune response. AB - Abolished or delayed wound healing is a serious problem in clinical surgery, therefore, the new therapy for wound healing is needed. Synthetic oligodeoxynucleotides containing one or more CpG motifs (CpG ODN) has been reported to activate the immune system and improves skin wound healing. The aim of the present study was to evaluate the role of a new C-type CpG ODN in wound healing. We found that the CpG ODN promoted cell proliferation and collagen I production in human skin fibroblasts cells. Besides, we also investigated the effect of CpG ODN on the activation of immune cells. The macrophages and plasmacytoid dendritic cells (pDCs) were incubated with CpG ODN. CpG ODN activated macrophage and pDCs via regulating TLR9/MyD88/NF-kappaB pathway and TLR9/MyD88/IRF7 pathway, respectively. To further evaluate the effect of CpG ODN on wound healing in vivo a wound healing model was established in mice. The results showed that CpG ODN treatment accelerated wound healing in mice. CpG ODN increased cytokines secretion in wound skin and elevated the ratio of CD4 + and CD8 + T cells in the spleen. Our results showed that CpG ODN accelerated wound healing, which was partly due to the regulation of fibroblasts and immune response. The findings suggested that the CpG ODN might be a proper medicament for the treatment of wound healing. PMID- 30485486 TI - Expression of circulating miR-17, miR-25, and miR-133 in breast cancer patients. AB - One of the most lethal cancers among women is breast cancer. MicroRNAs (miRNAs) can be of great importance in the early detection of breast cancer. This study aimed to investigate some miRNAs in the serum of patients with breast cancer compared with the control group. Total RNA was extracted from the serum of patients with breast cancer and healthy volunteers. The expression levels of miRNAs and the genes were assessed using real-time reverse transcriptase polymerase chain reaction with specific primers. Our data showed that miR-25 and miR-133 were downregulated, and miR-17 was upregulated in patients with breast cancer. Upregulation of miR-17 is related to the poor survival time and increased cell proliferation. The reduced expression of miR-133 and miR-25 is significantly associated with clinical stage, metastasis, and survival time of patients with breast cancer. Expressions of miRNAs miR-17, miR-25, and miR-133 are altered in patients with clinical stage, metastasis, poor survival time. PMID- 30485487 TI - Thyrotrophin Receptor Antibody Concentration And Activity, Several Years After Treatment For Graves' Disease. AB - OBJECTIVE: TSH receptor antibodies (TRAb) are responsible for autoimmune hyperthyroid disease (Graves' disease; GD) with TRAb levels tending to decrease following treatment. Measurement of TRAb activity during follow up could prove valuable to better understand treatment effectiveness. STUDY DESIGN: TRAb concentration and stimulating (TSAb) and blocking (TSBAb) activity of patient serum were assessed following different treatment modalities and follow up length. METHODS: Sixty-six subjects were recruited following treatment with carbimazole (n=26), radioiodine (n=27) or surgery (n=13). TRAb, TPO-Ab, Tg-Ab and GAD-Ab were measured at a follow up visit as well as bioassays of TSAb and TSBAb activity. RESULTS: Forty five percent of all patients remained TRAb positive for more than one year and 23% for more than 5 years after diagnosis, irrespective of treatment method. Overall, TRAb concentration fell from a median (IQR) of 6.25 (3.9-12.7) to 0.65 (0.38-3.2) U/L. Surgery conferred the largest fall in TRAb concentration from 11.4 (6.7-29) to 0.58 (0.4-1.4) U/L. Seventy percent of TRAb positive patients were positive for TSAb and 1 patient (3%) was positive for TSBAb. TRAb and TSAb correlated well (r = 0.83). In addition, 38/66 patients were Tg-Ab positive, 47/66 TPO-Ab positive and 6/66 were GADAb positive at follow up. CONCLUSIONS: TRAb levels generally decreased after treatment but persisted for over 5 years in some patients. TRAb activity was predominantly stimulatory, with only one patient demonstrating TSBAb. A large proportion of patients were Tg Ab/TPO-Ab positive at follow up. All treatment modalities reduced TRAb concentrations, however surgery was most effective. This article is protected by copyright. All rights reserved. PMID- 30485488 TI - First-dose effect of the SGLT2 inhibitor ipragliflozin on cardiovascular activity in spontaneously diabetic Torii fatty rats. AB - The first dose of a sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor induces osmotic diuresis, and can thereby affect cardiovascular activity in hyperglycemic patients. We aimed to determine whether the first dose of the selective SGLT2 inhibitor ipragliflozin affects cardiovascular activity in non diabetic Sprague-Dawley (SD) rats and Spontaneously Diabetic Torii (SDT) fatty rats in two studies, a urine collection study and a telemetry study. In the former study, urine was collected for 24 hours after a single oral dose of ipragliflozin. In the latter study, systolic blood pressure (SBP) and heart rate (HR) were continuously monitored for 24 hours under conscious and unrestrained conditions from immediately before the administration of ipragliflozin. The telemetry study was conducted in a cross-over design at successive one-week intervals. Cardiovascular autonomic nerve activity was calculated from the SBP and HR. SDT fatty rats exhibited polyuria, glucosuria and hyperglycemia. In addition, the mean and standard deviation of SBP were higher, while the coefficient of variance of HR was lower than the respective parameters in SD rats. Ipragliflozin increased both urine output and urinary glucose excretion, and the increases were more pronounced in SDT fatty rats than in SD rats. In contrast, ipragliflozin had no effect on SBP, the standard deviation of SBP, HR, and the coefficient of variance of HR, or on autonomic nerve activity in either rat strain. These results suggest that the first dose of the SGLT2 inhibitor ipragliflozin has little impact on cardiovascular activity despite causing glucosuria with osmotic diuresis. This article is protected by copyright. All rights reserved. PMID- 30485489 TI - The beta subunit of soluble guanylyl cyclase GUCY1B3 exerts cardioprotective effects against ischemic injury via the PKCepsilon/Akt pathway. AB - The soluble form of guanylyl cyclase (sGC) is the main receptor for the signaling agent nitric oxide (NO), which regulates cardiomyocyte contractile function and attenuates cardiomyocyte hypertrophy. sGC catalyzes the formation of cyclic guanosine monophosphate (cGMP), a regulator of vascular tone, and cardiac NO-sGC cGMP signaling modulates cardiac stress responses, including ischemia and reperfusion (IR) injury. Here, we investigated the role of GUCY1B3 (the beta subunit of sGC) in cardiomyocyte IR injury and myocardial infarction (MI) in vitro and in vivo. GUCY1B3 was upregulated in neonatal rat ventricular myocytes in response to IR injury, and GUCY1B3 overexpression restored IR-induced cell death and apoptosis. Treatment with specific inhibitors of PKCdelta, PKCepsilon, and Akt suggested that the protective effects of GUCY1B3 were mediated by PKCepsilon/Akt signaling. In a mouse model of coronary artery ligation-induced MI, GUCY1B3 silencing aggravated MI-induced cardiac dysfunction and increased infarct size and exacerbated cardiomyocyte apoptosis in association with the inactivation of PKCepsilon and Akt. Our results suggest that GUCY1B3 exerts cardioprotective effects through the modulation of the PKCepsilon/Akt activity and identify a potential mechanism involved in NO-sGC-cGMP signaling in the heart. PMID- 30485490 TI - LncRNA MALAT1 promotes oxidized low-density lipoprotein-induced autophagy in HUVECs by inhibiting the PI3K/AKT pathway. AB - Emerging evidence suggests that long noncoding RNAs (lncRNAs) are involved in many biological processes, such as cell growth, differentiation, apoptosis, and autophagy. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), highly expressed in endothelial cells, is well conserved and implicated in endothelial cell migration and proliferation. However, whether MALAT1 participates in oxidized low-density lipoprotein (ox-LDL)-induced autophagy regulation in human umbilical vein endothelial cells (HUVECs) remains unknown. In this study, we observed that autophagy was upregulated and MALAT1 expression was markedly increased in HUVECs treated with ox-LDL. The ox-LDL-induced autophagy of HUVECs is significantly associated with the PI3K/AKT pathway. Furthermore, we found that MALAT1 overexpression inhibited PI3K, Akt and p70S6K phosphorylation and downregulated RHEB expression, simultaneously increasing ox-LDL-induced autophagy. MALAT1 silencing caused higher phosphorylated PI3K, Akt and p70S6K levels, upregulated RHEB expression and markedly suppressed autophagy. These results indicated that lncRNA MALAT1 promotes ox-LDL-induced autophagy in HUVECs partly through the PI3K/AKT signaling pathway. PMID- 30485491 TI - USP28 contributes to the proliferation and metastasis of gastric cancer. AB - USP28, a member of the deubiquitinating enzymes family, plays a vital role in the physiological process of cell proliferation, differentiation and apoptosis, DNA repair, immune response, and stress response. USP28 has been reported to be overexpressed in bladder cancer, colon cancer, breast carcinomas, and so on. Nevertheless, the role of USP28 in gastric cancer has not yet been investigated. In our study, we examined the USP28 expression in 87 paired samples of gastric cancer and normal gastric tissues. We found that USP28 was overexpressed in gastric cancer compared with normal gastric tissues (P < 0.01), and its overexpression was related to the degree of differentiation and metastases. Inhibiting USP28 expression in vitro suppressed the proliferation and invasion of gastric cancer cells by downregulating lysine specific demethylase 1. On the basis of our data, it can be concluded that USP28 may be a novel therapeutic target for gastric cancer. PMID- 30485492 TI - The discovery of a novel eight-mRNA-lncRNA signature predicting survival of hepatocellular carcinoma patients. AB - Increasing evidence indicates that the expressions of messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs) undergo a frequent and aberrant change in carcinogenesis and cancer development. But some research was carried out on mRNA lncRNA signatures for prediction of hepatocellular carcinoma (HCC) prognosis. We aimed to establish an mRNA-lncRNA signature to improve the ability to predict HCC patients' survival. The subjects from the cancer genome atlas (TCGA) data set were randomly divided into two parts: training data set (n = 246) and testing data set (n = 124). Using computational methods, we selected eight gene signatures (five mRNAs and three lncRNAs) to generate the risk score model, which were significantly correlated with overall survival of patients with HCC in both training and testing data set. The signature had the ability to classify the patients in training data set into a high-risk group and low-risk group with significantly different overall survival (hazard ratio = 4.157, 95% confidence interval = 2.648-6.526, P < 0.001). The prognostic value was further validated in testing data set and the entire data set. Further analysis revealed that this signature was independent of tumor stage. In addition, Gene Set Enrichment Analysis suggested that high risk score group was associated with cell proliferation and division related pathways. Finally, we developed a well performed nomogram integrating the prognostic signature and other clinical information to predict 3- and 5-year overall survival. In conclusion, the prognostic mRNAs and lncRNAs identified in our study indicate their potential role in HCC biogenesis. The risk score model based on the mRNA-lncRNA may be an efficient classification tool to evaluate the prognosis of patients' with HCC. PMID- 30485493 TI - Identification of potentially critical genes in the development of heart failure after ST-segment elevation myocardial infarction (STEMI). AB - Heart failure (HF) remains a common complication after acute ST-segment elevation myocardial infarction (STEMI). Here, we aim to identify critical genes related to the developed HF in patients with STEMI using bioinformatics analysis. The microarray data of GSE59867, including peripheral blood samples from nine patients with post-infarct HF and eight patients without post-infarct HF, were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between HF and non-HF groups were screened by LIMMA package. Functional enrichment analyses of DEGs were conducted, followed by construction of a protein-protein interaction (PPI) network. The dynamic messenger RNA (mRNA) level of the hub genes during the follow-up was analyzed to further elucidate their role in HF development. A total of 58 upregulated and 75 downregulated DEGs were screen out. They were mainly enriched in biological processes about inflammatory response, extracellular matrix organization, response to cAMP, immune response, and positive regulation of cytosolic calcium ion concentration. Pathway analysis revealed that the DEGs were also involved in hematopoietic cell lineage, pathways in cancer, and extracellular matrix-receptor interaction. In the PPI network consisting of 58 nodes and 72 interactions, CXCL8 (degree = 15), THBS1 (degree = 8), FOS (degree = 7), and ITGA2B (degree = 6) were identified as the hub genes. In the comparison of patients with and without post-infarct HF, the mRNA level of these hub genes were all higher within 30 days but reached similar at 6 months after STEMI. In conclusion, CXCL8, THBS1, FOS, and ITGA2B may play important roles in the development of HF after acute STEMI. PMID- 30485494 TI - Berbamine ameliorates isoproterenol-induced myocardial infarction by inhibiting mitochondrial dysfunction and apoptosis in rats. AB - Berbamine (BBM), a bisbenzylisoquinoline alkaloid from roots, bark, and stem of Berberis plant such as Berberis aristata has a wide range of pharmacological activities. However, the evidence for the cardioprotective effect of BBM is inadequate and the molecular mechanism of BBM remains unclear. This study investigated the underlying molecular mechanism of BBM-mediated cardioprotection on isoproterenol (ISO)-induced mitochondrial dysfunction and apoptosis in rats. The assays of mitochondria antioxidant status, mitochondrial marker enzymes, and electron microscopic analysis of mitochondria revealed BBM significantly prevented the mitochondrial dysfunction induced by ISO. The ISO-induced elevation of mitochondrial oxidative stress was also curbed by BBM. Furthermore, pretreatment with BBM protected the heart tissue from ISO-induced apoptosis as evident from decreased terminal dUTP nickend-labeling positive cells and decreased expression of Bax, cytochrome c, cleaved caspase-9, and caspase-3, and poly (ADP-ribose) polymerase and increased expression of Bcl-2 in ISO-induced rats. These current findings suggest that BBM exerts a significant cardioprotective effect on ISO-induced myocardial infarction in rats. PMID- 30485495 TI - Long noncoding RNA HOXD-AS2 regulates cell cycle to promote glioma progression. AB - Now, numerous exciting findings have been found that long noncoding RNAs (lncRNAs) play a vital role in cancer malignant progression. However, their potential involvement in glioma is not well understood. Here, we performed a high throughput microarray to detect the lncRNA expression profiles between glioma cell lines and normal astrocyte cell lines. HOXD-AS2 was increased in glioma cells and it was associated with glioma grade and poor prognosis. Loss of HOXD AS2 can inhibit glioma cell growth by inducing cell-cycle G1 arrest in vitro. The proliferation of glioma was inhibited followed by knocking down the expression of HOXD-AS2 not only in subcutaneous injection model but also in orthotopic implantation model. These findings indicate that HOXD-AS2 promotes the glioma progression and may serve as a potential target for glioma diagnosis and therapy. PMID- 30485496 TI - Impact of work hours and sleep on well-being and burnout for physicians-in training: the Resident Activity Tracker Evaluation Study. AB - OBJECTIVE: The Resident Activity Tracker Evaluation (RATE) is a prospective observational study evaluating the impact of work hours, sleep and physical activity on resident well-being, burnout and job satisfaction. BACKGROUND: Physician burnout is common and its incidence is increasing. The impact of work hours and sleep on resident well-being and burnout remains elusive. Activity trackers are an innovative tool for measuring sleep and physical activity. METHODS: Residents were recruited from (i) general surgery and orthopaedics (SURG), (ii) internal medicine and neurology (MED) and (iii) anaesthesia and radiology (RCD). Groups 1 and 2 do not enforce restrictions on the duration of being on-call, and group 3 had restricted the duration of being on-call to 12 hours. Participants wore FitBit trackers for 14 days. Total hours worked, daily sleep, sleep on-call and daily steps were recorded. Participants completed validated surveys assessing self-reported well-being (Short-Form Health Survey), burnout (Maslach Burnout Inventory), and satisfaction with medicine. RESULTS: Surgical residents worked the most hours per week, followed by medical and RCD residents (SURG, 84.3 hours, 95% CI, 80.2-88.5; MED, 69.2 hours, 95% CI, 65.3 73.2; RCD, 52.2 hours, 95% CI, 48.2-56.1; p < 0.001). Surgical residents obtained fewer hours of sleep per day (SURG, 5.9 hours, 95% CI, 5.5-6.3; MED, 6.9 hours, 95% CI, 6.5-7.3; RCD, 6.8 hours, 95% CI, 5.6-7.2; p < 0.001). Nearly two-thirds of participants (61%) scored high burnout on the Maslach depersonalisation subscore. Total steps per day and well-being, burnout and job satisfaction were comparable between groups. Total hours worked, daily sleep and steps per day did not predict burnout or well-being. CONCLUSIONS: Work hours and average daily sleep did not affect burnout. Physical activity did not prevent burnout. Work hour restrictions may lead to increased sleep but may not affect resident burnout or well-being. PMID- 30485497 TI - Seminal immunologic discoveries with direct clinical implications: The 2018 Nobel Prize in Physiology or Medicine honours discoveries in cancer immunotherapy. PMID- 30485498 TI - LncRNA OIP5-AS1 predicts poor prognosis and regulates cell proliferation and apoptosis in bladder cancer. AB - Opa-interacting protein 5 antisense RNA 1 (OIP5-AS1) is a long intergenic noncoding RNA, which has been suggested to be dysregulated in human cancers and served as tumor suppressor or promoter depending on tumor types. However, the role of OIP5-AS1 in bladder cancer was still unknown. In our study, OIP5-AS1 was overexpressed in bladder cancer, and associated with clinical progression and short overall survival. The loss-of-function studies suggested downregulation of OIP5-AS1 expression decreased cell viability, induced cell-cycle arrest and promoted cell apoptosis in bladder cancer. There was a positive association between OIP5-AS1 expression and OIP5 expression in bladder cancer tissues. Moreover, downregulation of OIP5-AS1 expression reduced messenger RNA and protein levels of OIP5 in bladder cancer cell lines. In conclusion, OIP5-AS1 is a useful biomarker for predicting clinical progression and poor prognosis and promotes cell proliferation through modulating OIP5 expression. PMID- 30485499 TI - Sedative and antinociceptive effects of different detomidine constant rate infusions, with or without methadone in standing horses. AB - BACKGROUND: Standing surgery avoids the risks of general anaesthesia in horses. OBJECTIVES: To assess sedation, antinociception and gastrointestinal motility in standing horses after a detomidine loading dose and 2-hours constant rate intravenous (i.v.) infusion, with or without methadone. STUDY DESIGN: Blinded, randomised, crossover with seven healthy adult cross-bred horses, three geldings and four females (404 +/- 22 kg). METHODS: Five i.v. treatments were administered to all horses with 1-week washout period: saline (SAL), detomidine low (2.5 MUg/kg bwt + 6.25 MUg/kg bwt/h) (DL) and high doses (5 MUg/kg bwt + 12.5 MUg/kg bwt/h) (DH) alone or combined with methadone (0.2 mg/kg bwt + 0.05 mg/kg bwt/h), (DLM) and (DHM), respectively. Height of head above the ground (HHAG), electrical (ET), thermal (TT) and mechanical (MT) nociceptive thresholds and gastrointestinal motility were evaluated at predetermined times between 5 and 240 minutes. A mixed effect model and Kruskal-Wallis test were used to analyse normally and non-normally distributed data, respectively. RESULTS: Sedation (<50% basal HHAG) was achieved for the duration of the infusion, and for an additional 15 minutes in DH and DHM groups. Nociceptive thresholds were higher than baseline, to the greatest degree and the longest duration, with DHM (ET and TT for 135 minutes and MT for 150 minutes). After DH, TT was significantly higher than baseline from 30 to 120 minutes and MT from 15 to 135 minutes. After DLM, ET was increased at 90 minutes, TT at 30 minutes and MT for 120 minutes. Gastrointestinal motility was reduced for up to 135 minutes after DL, 150 minutes after DLM and 210 minutes after DH and DHM. MAIN LIMITATIONS: Nociceptive thresholds are not equivalent to surgical stimuli. CONCLUSION: Methadone with the highest detomidine dose (DHM) may provide sufficient sedation and analgesia for standing surgical procedures and warrants further investigation. This article is protected by copyright. All rights reserved. PMID- 30485501 TI - Cosyntropin testing does not predict response to glucocorticoids in community acquired pneumonia in a randomized controlled trial. AB - OBJECTIVE: Glucocorticoids have been shown to improve outcome in community acquired pneumonia (CAP). However, glucocorticoids have potential side-effects, and treatment response may vary. It is thus crucial to select patients with high likelihood to respond favorably. In critical illness, cosyntropin testing is recommended to identify patients in need for glucocorticoids. We investigated whether consyntropin testing predicts treatment response to glucocorticoids in CAP. DESIGN: PREDEFINED SECONDARY ANALYSIS OF A RANDOMIZED CONTROLLED TRIAL: PATIENTS: HOSPITALIZED PATIENTS WITH CAP: MEASUREMENTS: We performed 1MUg cosyntropin tests in a randomized trial comparing prednisone 50mg for seven days to placebo. We investigated whether subgroups based on baseline and stimulated cortisol levels responded differently to glucocorticoids with regards to time to clinical stability (TTCS) and other outcomes by inclusion of interaction terms into statistical models. RESULTS: 326 patients in the prednisone and 309 patients in the placebo group were evaluated. Neither basal cortisol nor a Deltacortisol<250nmol/L after stimulation nor the combination of basal cortisol and Deltacortisol predicted treatment response as measured by TTCS (all p for interaction>0.05). Similarly, we found no effect modification with respect to mortality, rehospitalization, antibiotic treatment duration or CAP-related complications (all p for interaction>0.05). However, glucocorticoids had a stronger effect on shortening length of hospital stay in patients with a baseline cortisol of >=938 nmol/L (p for interaction=0.015). CONCLUSIONS: Neither baseline nor stimulated cortisol after low-dose cosyntropin testing at a dose of 1 MUg predicted glucocorticoid responsiveness in mild to moderate CAP. A treatment decision for or against adjunct glucocorticoids in CAP should not be made depending on cortisol values or cosyntropin testing results. This article is protected by copyright. All rights reserved. PMID- 30485500 TI - How hsa-miR-495 performed in the tumorigenesis of pancreatic adenocarcinoma by bioinformatics analysis. AB - INTRODUCTION: Pancreatic adenocarcinoma (PAAD) is one of the most fatal cancers in the world for early metastasis, extensive invasion, and poor prognosis with a 5-year survival rate less than 5%. However, the underlying mechanisms are poorly understood. Therefore, it is urgent to explore molecular markers for early diagnosis or therapy target to improve the outcome of PAAD. METHODS: We retrieved transcriptome data as well as clinical information from patients with PAAD in The Cancer Genome Altas (TCGA) database. Survival time associated microRNAs (miRNAs) and messenger RNAs (mRNAs) were initially identified, followed by enrichment analysis (Gene Ontology [GO] and pathway). The relationship between survival time associated miRNAs-mRNAs was also investigated to discover putative transcriptional control mechanisms of PAAD. Finally, by consulting the literature and retrieving the database, we found that hsa-miR-495 might have played an important role in PAAD. RESULTS: In total, 146 miRNAs from 378 miRNAs and 580 mRNA from 17 100 mRNA, including 328 risk mRNA and 252 protective mRNA, were found to be associated with the survival time of PAAD. Eight hundred eighty-eight mRNA-miRNA pairs were related to the survival time of PAAD, involving in 755 mRNAs and 35 miRNAs. We chose 13 miRNAs predicted by target gene in the miRanda database for further research. Among these 13 miRNAs, hsa-miR-495 was identified as a good biomarker. Through GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, the significantly enriched pathways involved in focal adhesion, Staphylococcus aureus infection, and Intestinal immune network for immunoglobulin A production. And four target genes and 87 pathways of the hsa-miR 495 were enriched in PAAD. Interestingly, we found hsa-miR-495 with a low expression having a poor overall survival and significantly different recurrence rate within 5 years. CONCLUSION: Hsa-miR-495 and its target genes may serve as a prognostic and predictive marker in PAAD. Further research on the function of the hsa-miR-495 and its target genes in the KEGG pathway may provide references for treatment of PAAD. PMID- 30485502 TI - microRNA-145 regulates tumor suppressor candidate 3 and mitogen-activated protein kinase pathway to inhibit the progression of colorectal cancer. AB - BACKGROUND: It has been reported that microRNA-145 (miR-145) is downregulated in various cancers, including colorectal cancer (CRC). However, the role of miR-145 in progress of CRC and its mechanism remains unclear. METHODS: The expressions of miR-145 and tumor suppressor candidate 3 (TUSC3) were determined in CRC tissues and cells by real-time quantitative polymerase chain reaction and Western blot analysis. The effects of miR-145 and TUSC3 on cell viability, migration, and invasion of CRC cells were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl trtrazolium bromide assay and trans-well chamber experiment, respectively. The interaction between miR-145 and TUSC3 was explored by bioinformatics analysis, luciferase reporter assay, and Western blot analysis. The abundances of mitogen activated protein kinase (MAPK) signaling pathway-related proteins were measured by Western blot analysis. RESULTS: miR-145 expression was downregulated in CRC tissues and cell lines, and TUSC3 was upregulated in CRC tissues and correlated inversely with miR-145 abundance. Overexpression of miR-145 and knockdown of TUSC3 suppressed cell viability, migration, and invasion in LS174T and HCT116 cells. Moreover, TUSC3 was indicated as a novel target of miR-145 and its expression was negatively regulated by miR-145. Restoration of TUSC3 can partially reverse the inhibitory effects of miR-145 on phosphorylation of extracellular signal-regulated kinases 1 and 2 in CRC cells. CONCLUSION: miR-145 can inhibit the viability, migration, and invasion through addressing MAPK signaling pathway by targeting TUSC3 in CRC cells, providing a novel biomarker for treatment of CRC. PMID- 30485503 TI - miR-145 is a potential biomarker for predicting clinical outcome in glioblastomas. AB - miR-145 has been found to be significantly downregulated in gliomas, and overexpression of miR-145 increases glioma cell apoptosis and enhances chemosensitivity or herpes simplex virus thymidine kinase gene therapy. However, the correlation between miR-145 and the clinical prognosis of glioblastomas has never been explored. In this study, a retrospective study was conducted in 86 cases of patients with glioblastoma after neurosurgery combined with chemoradiotherapy, and 36 cases with traumatic brain injury. Our results showed that miR-145 was significantly lower in glioblastoma tissues than that in normal brain tissue (P < 0.05). Furthermore, miR-145 was lower in patients with lower Karnofsky Performance Scale (KPS) scores than in patients with higher KPS scores ( P < 0.05). Cox Regression analysis showed that low miR-145 expression was associated with poor patient survival ( P < 0.05). These data suggested that patients with glioblastoma with lower miR-145 expression are prone to shorter overall survival. PMID- 30485504 TI - MicroRNA-373 promotes the development of endometrial cancer by targeting LATS2 and activating the Wnt/beta-Catenin pathway. AB - In the female reproductive tract, endometrial cancer is the most common malignant tumor. Recently, the specific functions of many miRNAs have been identified in endometrial cancer. However, the contradictory effects of microRNA-373 (miR-373) in different human cancers draw our attention. In the present research, upregulation of miR-373 was identified in endometrial cancer which predicted poor prognosis. Moreover, upregulation of miR-373 promoted the migration, invasion, and proliferation of endometrial cancer cells. To further confirm that results, the EMT and Wnt/beta-Catenin pathways were also investigated, which were promoted by overexpression of miR-373. Then, we further investigate the downstream factor, large tumor suppressor kinase 2 (LATS2) which was inhibited by miR-373. LATS2 was verified as a direct target gene of miR-373 through luciferase reporter assay. Especially, the facilitation of miR-373 for cell proliferation, migration and invasion was impaired by LATS2. Taken together, miR-373 promotes the progression of endometrial cancer through targeting LATS2 and promoting EMT and Wnt/beta Catenin pathway. PMID- 30485505 TI - Resveratrol improves ex vivo expansion of CB-CD34+ cells via downregulating intracellular reactive oxygen species level. AB - Intracellular reactive oxygen species (ROS) play important roles in the ex vivo expansion of hematopoietic stem and progenitor cells (HSPCs). In this study, the effects of resveratrol (RES), on the ex vivo expansion of HSPCs were investigated by analyzing CD34+ cells expansion and biological functions, with the objective to optimize ex vivo culture conditions for CD34 + cells. Among the five tested doses (0, 0.1, 1, 10, 20, and 50 MUM), 10 MUM RES was demonstrated to be the most favorable for ex vivo CD34 + cells expansion. In the primary cultures, 10 MUM RES favored higher expansion folds of CD34 + cells, CD34 + CD38 - cells, and colony forming units (CFUs) ( P < 0.05). It was found that the percentages of primitive HSPCs (CD34 + CD38 - CD45R - CD49f + CD90 + cells) in 10 MUM RES cultures were higher than those without RES. Further, in the secondary cultures, expanded CD34 + cells derived from primary cultures with 10 MUM RES exhibited significantly higher total cells and CD34 + cells expansion ( P < 0.05). In the semisolid cultures, the frequency of CFU-GM and total CFUs of 10 MUM RES group were both higher than those of without RES group, demonstrating that CD34 + cells expanded with 10 MUM RES possessed better biological function. Furthermore, the addition of 10 MUM RES downregulated the intracellular ROS level via strengthening the scavenging capability of ROS, and meanwhile reducing the percentages of apoptotic cells in cultures. Collectively, RES could stimulate the ex vivo expansion of CD34 + cells, preserved more primitive HSPCs and maintain better biological function by alleviating intracellular ROS level and cell apoptosis in cultures. PMID- 30485506 TI - Epigenetic and metabolic alterations in human amniotic fluid stem cells induced to cardiomyogenic differentiation by DNA methyltransferases and p53 inhibitors. AB - Human amniotic fluid-derived mesenchymal stem cells (AF-MSCs) may be a valuable source for cell therapy and regenerative medicine. In this study, the potential of DNA methyltransferases (DNMT) inhibitors Decitabine, Zebularine, RG108 alone or combined with Zebularine and p53 inhibitor Pifithrin-alpha to induce cardiomyogenic differentiation of AF-MSCs was investigated. Differentiation into cardiomyocyte-like cells initiation was indicated with all agents by changes in the cell phenotype, upregulation of the relative expression of the main cardiac genes (NKX2-5, TNNT2, MYH6, and DES) as well as of cardiac ion channels genes (sodium, calcium, and potassium) as determined by reverse-transcription quantitative polymerase chain reaction and the increase in Connexin43 levels as detected from Western blot and immunofluorescence data. Cellular energetics and mitochondrial function in induced cells were assessed using Seahorse analyzer and revealed the initiation of AF-MSCs metabolic transformation into cardiomyocyte like cells. All used inducers were nontoxic to AF-MSCs, arrested cell cycle at the G0/G1 phase, and upregulated p53 and p21 expression. The relative expression of miR-34a and miR-145 that are related to cell cycle regulation was also observed. Furthermore, the evaluated levels of chromatin remodeling proteins enhancer of zeste homolog 2, suppressor of zeste 12 protein homolog, DNMT1, histone deacetylase 1 (HDAC1), HDAC2, and heterochromatin protein 1alpha, as well as the rate of activating histone modifications, exhibited rearrangements of chromatin after the induction of cardiomyogenic differentiation. In conclusion, we demonstrated that all explored DNMT and p53 inhibitors initiated cardiomyogenesis-related alterations in AF-MSCs through rather similar mechanisms but to a different extent providing useful insights for the future research and potential applications of AF-MSCs. PMID- 30485507 TI - Long noncoding RNA LINC00968 promotes endothelial cell proliferation and migration via regulating miR-9-3p expression. AB - Long noncoding RNAs (lncRNAs) have been showed to play a crucial role in pathogenesis and development of cardiovascular diseases. Our study aimed to study the expression and functional role of lncRNA LINC00968 in the development of coronary artery disease (CAD). We showed that the LINC00968 expression level was upregulated in the CAD tissues compared with normal arterial tissues. In addition, we showed that the expression level of LINC00968 was upregulated by oxidized low-density lipoprotein (oxLDL) treatment in endothelial cell. Ectopic expression of LINC00968 regulated the proliferation and migration of endothelial cell. Moreover, we showed that overexpression of LINC00968 inhibited miR-9-3p expression in an endothelial cell. Furthermore, we demonstrated that the miR-9-3p expression was downregulated in the CAD samples compared with normal arterial tissues and the expression level of miR-9-3p was downregulated by oxLDL treatment in endothelial cell. Finally, we showed that ectopic expression of LINC00968 promoted endothelial cell proliferation and migration partly through regulating miR-9-3p expression. These results suggested that LINC00968 plays a crucial role in the progression of the CAD. PMID- 30485508 TI - Combined therapy using LHRH-PE40 and anti-CD40 dendritic cells substantially eliminate tumor cells. AB - LHRH-PE40 was used to promote the proliferation of bone marrow derived cell (BMDC) and improve the antigen-presenting ability of BMDC as well as the immune function via the CD40 signal pathway. LHRH-PE40 was also implicated in cancer treatment, targeting a variety of cancer cells that express luteinizing hormone releasing hormone receptor (LHRHR). In the present study, the mechanism and efficacy of LHRH-PE40 were addressed in the following three aspects. Enzyme linked immunosorbent assay was performed to confirm the binding specificity of LHRH-PE40 to LHRHR. The killing effect of LHRH-PE40 on target cells was mediated by LHRHR, which specifically killed LHRHR-positive target cells while the minimal cytotoxicity of LHRHR-negative cells is negligible. Spiegelmers, a molecule mutually exclusive with GnRH and developed by Sven Klussmann and Dr Sven Klussmann of NOXXON Pharmaceuticals in Germany, demonstrated that LHRH-PE40 maintains a combinatory characteristics of LHRH and LHRHR. In the end, the mechanism of LHRH-PE40 underlying induction of apoptosis at low concentration and prolonged conditions was firstly demonstrated by the basic method of detecting apoptosis to induce apoptosis. It provided a scientific basis for clinical application of LHRH-PE40 and laid a foundation for the further study of LHRH-PE40 on inducing apoptosis of target cells. The target cells herein refer to tumor cells that overexpress LHRHR. This study shows that activated DC can more effectively promote the proliferation of CD4+ T cells, and initially proved that DC carrying anti-CD40 antibody promoted the immune treatment of the tumor. Combining LHRH-PE40 with anti-CD40 DCs achieved substantially improved efficacy in killing tumor cells. PMID- 30485509 TI - Expression of DEC2 enhances chemosensitivity by inhibiting STAT5A in gastric cancer. AB - Gastric cancer (GC) is one of the most common cancers. Resistance to 5 fluorouracil (5-Fu)-based chemotherapy is a major cause of treatment failure followed by the poor prognosis of patients. In GC, it was reported that human differentiated embryonic chondrocyte-expressed gene 2 (DEC2), suppressed tumor proliferation and metastasis, but the effect of DEC2 on chemosensitivity of GC cells was unknown. In our study, we found that DEC2 can obviously increase the sensibility of GC cells to 5-Fu by promoting 5-Fu-induced apoptosis. DEC2 overexpression is significantly associated with decreased phosphorylation of STAT5A (P-STAT5A). More importantly, negative correlations between DEC2 with P STAT5A expression were observed in tissue sections from GC patients. GC patients with low expression levels of DEC2 and high expression levels of P-STAT5A showed a poor prognosis. Furthermore, enhanced chemosensitivity mediated by DEC2 can be reversed by STAT5A which confer GC cells resistance to apoptosis induced by 5-Fu. Together, our results suggest that through inhibiting activation of STAT5A, DEC2 enhances 5-Fu-induced apoptosis and suppression of proliferation in GC cells. These findings will provide new insight for identifying potential targets that can be used to sensitize GC cells to chemotherapy. PMID- 30485510 TI - The comparative study of the effects of Fe2 O3 and TiO2 micro- and nanoparticles on oxidative states of lung and bone marrow tissues and colony stimulating factor secretion. AB - Nowadays, increased use of nanomaterials in industry and biomedicine poses potential risks to human health and the environment. Studying their possible toxicological effects is therefore of great significance. The present investigation was designed to examine the status of oxidative stress induced by nanoparticles (NPs) of ferric oxide (Fe2 O 3 ) and titanium oxide (TiO 2 ) with their micro-sized counterpart on mouse lung and bone marrow-derived normal tissue cells. We assessed the induction of oxidative stress by measuring its indicators such as antioxidant scavenging activity of superoxide dismutase and catalase as well as malondialdehyde concentration. Moreover, colony formation of bone marrow cells was assayed following induction with colony stimulating factor (CSF) from lung cells. NPs had a more potent stimulatory effect on the oxidative stress status than their micron-sized counterparts. In addition, the highest level of oxidative stress derived from TiO 2 NPs was observed in both tissue types. Cotreatment with NPs and the antioxidant alpha-tocopherol reduced antioxidant activities and membrane lipid peroxidation (LPO) in the lung cells, but increased CSF-induced colony formation activity of bone marrow cells, suggesting that oxidative stress may be the cause of the cytotoxic effects of NPs. It is concluded that free radicals generated following exposure to NPs resulted in significant oxidative stress in mouse cells, indicated by increased LPO and antioxidant enzyme activity and decreased colony formation. PMID- 30485511 TI - A panel of noncoding RNAs in non-small-cell lung cancer. AB - Non-small-lung cancer (NSCLC) is the leading cause of cancer death. Early detection of NSCLC could pave the way for effective therapies. Analysis of molecular genetic biomarkers in biological fluids has been proposed as a useful tool for cancer diagnosis. Here, we aimed to develop a panel of noncoding RNAs (ncRNAs) in sputum for NSCLC early detection. Expression of 11 ncRNAs were analyzed by real-time polymerase chain reaction in sputum samples of 30 NSCLC patients and 30 sex- and age-matched cancer-free controls. Stability of endogenous microRNAs (miRNAs) in sputum was evaluated after 3 and 6 days at 4 degrees C, 6 months, and 1 year at -80 degrees C. Nine ncRNAs showed significant differences of their expression in sputum between NSCLC patients and controls. A logistic regression model with the best prediction was built based on miR-145, miR-126, and miR-7. The composite of the three miRNAs produced 90% sensitivity and specificity in distinguishing NSCLC patients from the controls. Results indicate that miRNAs could be useful biomarkers based on their stability under various storage conditions and maintain differential changes between cancer and control groups. Moreover, measurement of miRNAs in sputum could be a noninvasive approach for detection of lung cancer. PMID- 30485512 TI - Study of p16 promoter methylation in Egyptian colorectal cancer patients. AB - Many tumor-suppressor genes contain CpG islands in their promoter regions which raised the necessity of investigating the role of methylation in silencing these genes. We examined p16 methylation as a potential biomarker in the peripheral blood of colorectal cancer (CRC) patients. Using methylation-specific polymerase chain reaction method, the methylation status of p16 was investigated in the tumor tissue and blood of 65 CRC patients and blood samples from 70 healthy control individuals. Also, the relationship between p16 methylation level and the clinical-pathological findings in CRC was evaluated. The frequency of blood p16 methylation in CRC cases was significantly higher than in control (P = 0.0001). The sensitivity and specificity of p16 methylation in diagnosing CRC was 55.38% and 98.5%, respectively, with 77.7% diagnostic accuracy. There was significant association between p16 methylation and age, sex, Dukes staging, lymph node involvement, and carcinoembryonic antigen levels. Our study revealed that p16 promoter methylation could be considered as both potential diagnostic and prognostic biomarker of CRC. PMID- 30485513 TI - Long noncoding RNA LINC00339 promotes laryngeal squamous cell carcinoma cell proliferation and invasion via sponging miR-145. AB - Laryngeal squamous cell carcinoma (LSCC) is a very common neoplasm of the head and neck in the world. Long noncoding RNAs play key roles in cell infiltration, fate, apoptosis, and invasion. However, the functional role and expression of LINC00339 remains unclear in LSCC. In this study, we showed that the expression level of LINC00339 was upregulated in LSCC tissues and cell lines. LINC00339 silencing suppressed the proliferation, invasion, and epithelial-mesenchymal transition (EMT) progression of LSCC cells. In addition, we showed that LINC00339 acted as a sponge of miR-145, and LINC00339 silencing promoted the expression of miR-145 in Hep2 cell. Furthermore, the expression of miR-145 was lower in LSCC tissues than in their paired normal samples and the miR-145 expression level was negatively correlated with LINC00339 expression in LSCC tissues. The knockdown of miR-145 promoted the proliferation, invasion, and EMT progression of LSCC cells. Finally, we indicated that LINC00339 silencing inhibited the proliferation, invasion, and EMT progression of LSCC cells by suppressing the miR-145 expression. These data suggested that LINC00339 acted as an oncogene in the development of LSCC, partly by regulating the miR-145 expression. PMID- 30485514 TI - MicroRNA-194 overexpression protects against hypoxia/reperfusion-induced HK-2 cell injury through direct targeting Rheb. AB - Renal ischemia-reperfusion injury, a major cause of renal failure, always leads to acute kidney injury and kidney fibrosis. MicroRNAs (miRs) have been reported to be associated with renal ischemia-reperfusion injury. miR-194 was downregulated following renal ischemia-reperfusion injury; however, the function and mechanism of miR-194 in renal ischemia-reperfusion injury have not yet been fully understood. In the present study, we constructed renal ischemia-reperfusion injury model in vitro through treatment of human kidney proximal tubular epithelial cells HK-2 by hypoxia/reperfusion (H/R). We observed that miR-194 was decreased in H/R-induced HK-2 cells. miR-194 mimic increased H/R-induced HK-2 cell survival, whereas miR-194 inhibitor further strengthened H/R- inhibited HK-2 cell survival. Also, we observed that miR-194 overexpression suppressed oxidative stress markers, including malondialdehyde, glutathione, and secretion of pro inflammatory cytokines, including IL-6, IL-1beta, and TNF-alpha; however, miR-194 inhibitor showed the reverse effects. Results from dual-luciferase analysis confirmed that Ras homology enriched in brain (Rheb) was a direct target of miR 194. Finally, we corroborated that miR-194 affected cell growth, oxidative stress, and inflammation through targeting Rheb in H/R-induced HK-2 cells. In conclusion, our results suggested that miR-194 protect against H/R-induced injury in HK-2 cells through direct targeting Rheb. PMID- 30485516 TI - Two for one? Effects of a couples intervention on partners of persons with Type 2 diabetes: a randomized controlled trial. AB - AIMS: To compare the outcomes of partners who participated in a telephone couples behavioural intervention to improve glycaemic control in persons with Type 2 diabetes with those of untreated partners of participants in an individual intervention or education; to explore 'ripple effects', i.e. positive behaviour changes seen in untreated partners. METHODS: The Diabetes Support Project was a three-arm randomized telephone intervention trial comparing outcomes of couples calls (CC), individual calls (IC) and diabetes education calls (DE). Couples included one partner with Type 2 diabetes and HbA1c >= 58 mmol/mol (7.5%). All arms received self-management education (two calls). CC and IC participated in 10 additional behaviour change calls. CC included partners, emphasizing partner communication, collaboration and support. Blinded assessments were performed at 4, 8 and 12 months. Partner outcomes were psychosocial (diabetes distress, relationship satisfaction, depressive symptoms), medical (BMI, blood pressure) and behavioural (fat intake, activity). RESULTS: Partners' (N = 268) mean age was 55.8 years, 64.6% were female and 29.9% were from minority ethnic groups. CC (vs. IC and DE) partners had greater reductions in diabetes distress, greater increases in marital satisfaction (4 and 8 months), and some improvements in diastolic BP. There were no consistent differences among arms in other outcomes. There was no evidence of a dietary or activity behaviour ripple effect on untreated partners, i.e. comparing partners in the IC and DE arms. CONCLUSIONS: A collaborative couples intervention resulted in significant improvements in partner diabetes distress and relationship satisfaction. There were no consistent effects on behavioural or medical partner outcomes, and no evidence of diet or activity behaviour ripple effects, suggesting that partners should be targeted directly to achieve these changes. This article is protected by copyright. All rights reserved. PMID- 30485515 TI - Acetyl-coenzyme A acyltransferase 2 promote the differentiation of sheep precursor adipocytes into adipocytes. AB - The acetyl CoA acyltransferase 2 (ACAA2) is a key enzyme of the fatty acid oxidation pathway, catalyzing the last step of the mitochondrial beta oxidation, thus playing an important role in the fatty acid metabolism. The purpose of this study was to investigate the effect of knocking out ACAA2 on the expression of genes lipoprteinlipase (LPL), peroxisome proliferator-activated receptor-gamma (PPAR-gamma), fatty acid synthase, fat mass and obesity-associated gene, adipocyte fatty acid-binding protein (AP2) in precursor adipocytes and their differentiation into adipocytes. The knockout vector was constructed using CRISPR Cas RNA-guided nuclease technology with an efficiency of 23.80%, and the vector was transfected into precursor adipocyte cells, while an overexpression vector of the ACAA2 gene was also transfected in another group of preadipocytes. Quantitative polymerase chain reaction showed that the expression of the PPAR gamma, LPL, and AP2 was significantly lower in the knockout compared with the overexpression group, while there was no difference in cell growth. After induction of adipocyte precursor cells into adipocytes using dexamethasone, insulin, and IBMX, oil red staining showed a significantly different number of lipid droplets in the knockout group. These results provide a preliminary indication for a possible involvement of the ACAA2 gene in adipocyte differentiation in vitro. PMID- 30485517 TI - Carvacrol suppresses inflammatory responses in rheumatoid arthritis fibroblast like synoviocytes. AB - BACKGROUND: Fibroblast-like synoviocytes (FLSs) play an essential role in the chronic inflammatory process of rheumatoid arthritis (RA). Carvacrol is a natural monoterpenic phenol that retains significant anti-inflammatory activity. However, the effect of carvacrol on inflammatory response in RA-FLSs has not yet been reported. The present study aimed to investigate the role of carvacrol in lipopolysaccharides (LPS)-induced inflammatory response in human RA-FLSs. METHODS: Cell viability and proliferation were measured by MTT and Cell Counting Kit-8 assays, respectively. The migration was detected by transwell assay. The production of inflammatory cytokines and matrix metalloproteinases (MMPs) were analyzed by enzyme-linked immunosorbent assay. The expressions of toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), NF kappaB, p38, p-p38, ERK1/2, p-ERK1/2, c-Jun N-terminal kinase (JNK), and p-JNK were detected by Western blot analysis. RESULTS: Carvacrol-inhibited LPS-induced cell proliferation and migration of RA-FLSs. The production of inflammatory cytokines, including tumor necrosis factor alpha, interleukin (IL)- 6, and IL-8, was reduced by carvacrol in LPS-induced RA-FLSs. Meanwhile, the induction of MMPs, including MMP-1, MMP-3, and MMP-13, caused by LPS stimulation was inhibited by carvacrol in RA-FLSs. Furthermore, carvacrol prevented LPS-induced activation of the TLR4/MyD88/NF-kappaB, p38, and ERK1/2 pathways in RA-FLSs. CONCLUSIONS: Carvacrol-mitigated LPS-induced cell proliferation, migration, and inflammation in RA-FLSs. The TLR4/MyD88/NF-kappaB, p38 and ERK1/2 pathways might be involved in the protective effect of carvacrol. PMID- 30485518 TI - Fractionated radiotherapy might induce epithelial-mesenchymal transition and radioresistance in a cellular context manner. AB - Despite the fact that radiotherapy is a main therapeutic modality in cancer treatment, recent evidence suggests that fractionated radiotherapy (FR) might confer radioresistance through epithelial-mesenchymal transition (EMT). Nevertheless, the effects of FR on EMT phenotype and the potential link between EMT induction and radioresistance development yet to be clarified. The aim of this study was to assess whether FR could promote EMT, and to elucidate if induction of EMT contributes to the acquisition of radioresistance. To this end, two human cancer cell lines (A549 and HT-29) were irradiated (2 Gy/day) and analyzed using wound healing, transwell migration and invasion assays, real-time polymerase chain reaction (for E-cadherin, N-cadherin, Vimentin, CD44, CD133, Snail, and Twist), clonogenic assay, Annexin V/PI, and 3-[4,5-dimethylthiazol-2 yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. Irradiation of A549 (for 5 or 10 consecutive days) resulted in morphological changes including elongation of cytoplasm and nuclei and pleomorphic nuclei. Also, irradiation-enhanced migratory and invasive potential of A549. These phenotypic changes were in agreement with decreased expression of the epithelial marker (E-cadherin), enhanced expression of mesenchymal markers (N-cadherin, Vimentin, Snail, and Twist) and increased stemness factors (CD44 and CD133). Moreover, induction of EMT phenotype was accompanied with enhanced radioresistance and proliferation of irradiated A549. However, FR (for 5 consecutive days) did not increase HT-29 motility. Furthermore, molecular alterations did not resemble EMT phenotype (downregulation of E-cadherin, Vimentin, ALDH, CD44, CD133, and Snail). Eventually, FR led to enhanced radiosensitivity and decreased proliferation of HT-29. Altogether, our findings suggest that FR might induce EMT and confer radioresistance in a cell context-dependent manner. PMID- 30485519 TI - Silencing of long noncoding RNA MEG3 enhances cerebral protection of dexmedetomidine against hypoxic-ischemic brain damage in neonatal mice by binding to miR-129-5p. AB - Hypoxic-ischemic brain damage (HIBD) is a leading cause of neonatal acute mortality and chronic nervous system injury. Recently, it has been found that long noncoding RNAs (lncRNAs) play a significant role in the neurodevelopment and etiopathogenesis of HIBD. Here, the researchers aimed to determine the role of lncRNA maternally expressed gene (MEG3) in the therapeutic effect of dexmedetomidine (DEX) in neonatal mice with HIBD through the regulation of microRNA-129-5p (miR-129-5p). HIBD models were established in C57/BL6 neonatal mice. Subsequently, the target relationship between MEG3 and miR-129-5p was predicted and verified. The neonatal mice were injected with DEX, ad-shMEG3, and mimics and inhibitors of miR-129-5p to identify roles of MEG3 and miR-129-5p in therapeutic effects of DEX on neuronal apoptosis and injury, cerebral atrophy, and learning and memory ability of neonatal mice with HIBD. MEG3 directly targeted and inhibited the expression of miR-129-5p. Silencing of MEG3 or upregulation of miR-129-5p effectively promoted the therapeutic effect of DEX on neonatal mice with HIBD. Silencing of MEG3 or upregulation of miR-129-5p reduced the neuronal apoptosis rate and degree of cerebral atrophy, and also enhanced the learning and memory ability of HIBD neonatal mice. Collectively, the key findings obtained from the present study support the notion that MEG3 silencing enhances the therapeutic effect of DEX on neonatal mice with HIBD by binding to miR-129 5p. PMID- 30485520 TI - MicroRNA-9 inhibits retinal neovascularization in rats with diabetic retinopathy by targeting vascular endothelial growth factor A. AB - Diabetic retinopathy (DR) is a leading cause of adult visual impairment and loss. This study aims to explore the effects of microRNA-9 (miR-9) on retinal neovascularization during DR by targeting the vascular endothelial growth factor A (VEGFA). DR rat models were successfully established. Retinal microvascular endothelial cells (RMECs) of DR rats were isolated and treated with miR-9 mimic, miR-9 inhibitor or small interfering RNA (siRNA)-VEGFA. The expressions of miR-9, VEGFA, and cluster of differentiation 31 (CD31) of the rats' tissues and cells were examined. The targeting relationship between miR-9 and VEGFA was testified. The tubule formation, the cell proliferation and the periodic distribution and apoptosis were evaluated after transfection. In the retinal tissues of DR rats, miR-9 expression decreased while the expression of VEGFA and CD31 increased. Notably, miR-9 targeted and inhibited VEGFA expression. In response to the treatment of miR-9 mimic and siRNA-VEGFA, a reduction was identified in CD31 expression, tubule formation, and proliferation of RMECs and cell ratio in the S phase, but an increase was observed in apoptosis rate of RMECs. The treatment of miR-9 inhibitor reversed the manifestations. Our study demonstrated that miR-9 could inhibit retinal neovascularization of DR and tubule formation, and promote apoptosis in RMECs by targeting VEGFA. PMID- 30485521 TI - Effects of miR-181a targeting XIAP gene on apoptosis of cardiomyocytes induced by hypoxia/reoxygenation and its mechanism. AB - To investigate the effect of miR-181a targeting XIAP gene on the apoptosis of cardiomyocytes induced by hypoxia/reoxygenation (H/R) and its mechanism. The primary cultured cardiomyocytes were treated with hypoxia for 3 hours and reoxygenation for 4 hours to construct H/R cell model. The expression of miR-181a and XIAP messenger RNA in cardiomyocytes was detected by reverse-transcription polymerase chain reaction, and the expression of XIAP protein in cardiomyocytes was detected by Western blot analysis. H/R cardiomyocytes with low expression of miR-181a and overexpression of XIAP were constructed, and the effects of low expression of miR-181a and upregulation of XIAP on cardiomyocyte apoptosis were detected by flow cytometry. A dual luciferase reporter assay was used to detect the target relationship between miR-181a and XIAP. Further, H/R myocardial cells with low XIAP expression were constructed to observe the effect of downregulation of XIAP expression on apoptosis of myocardial cells with low expression of microarray-181a. The expression of apoptosis-related proteins Bax and Bcl-2 in myocardial cells was detected by Western blot analysis. After H/R treatment, the expression of microRNAs-181a was high but that of XIAP was low. The apoptosis of cardiomyocytes could be inhibited by both the low expression of miR-181a and the upregulation of XIAP. The results of dual luciferase reporter gene showed that XIAP was a potential target gene for miR-181a. The inhibitory effect of low expression of miR-181a on myocardial apoptosis could be reversed and the inhibitory effect of low expression of miR-181a on Bax protein expression and the promotion of Bcl-2 protein expression could be reversed by the downregulation of XIAP. MiR-181a can inhibit the apoptosis of hypoxic-reoxygenated cardiomyocytes by targeting XIAP to downregulate Bax and upregulate Bcl expression. PMID- 30485522 TI - Transcellular traversal of the blood-brain barrier by the pathogenic Propionibacterium acnes. AB - BACKGROUND: Propionibacterium acnes (P. acnes) is an anaerobe commonly stay in the body as part of the commensal microbiota, and a dominant bacterium of the human skin and hair follicles. It has been found that this bacterium could participate in brain inflammation that causes Alzheimer's disease (AD) and Parkinson's disease (PD). But how P. acnes invade the brain remains elusive. METHODS: We established the in vitro blood-brain barrier (BBB) model by culturing the HBMEC/D3 cell line on collagen-coated PFTE membrane. The BBB model was verified by the transepithelial electrical resistance (TEER) and horseradish peroxidase (HRP) permeability rate, and observed by the scanning electron microscope (SEM), transmission electron microscope (TEM), as well as confocal microscope. The P. acnes was then cocultured with the in vitro BBB model and the permeability of P. acnes was measured by counting the bacteria clones collected from the lower chamber of the model. RESULTS: High local concentration of P. acnes invaded the in vitro BBB model through the transcellular traversal pathway. The permeability for P. acnes was increased by the treatment of lipopolysaccharide (LPS), but not mannitol. P. acnes invasion elevated the expression of cell adhesion molecules E-selectin, ICAM-1, and VCAM-1 in HBMEC cells. CONCLUSION: P. acnes has the ability to penetrate the brain though transcellular invasion of the blood-brain barrier. PMID- 30485523 TI - Sulfated hyaluronic acid and dexamethasone possess a synergistic potential in the differentiation of osteoblasts from human bone marrow stromal cells. AB - The development of novel bioactive biomaterials is urgently needed to meet the needs of an aging population. Both sulfated hyaluronic acid and dexamethasone are candidates for the functionalization of bone grafts, as they have been shown to enhance the differentiation of osteoblasts from bone marrow stromal cells in vitro and in vivo. However, the underlying mechanisms are not fully understood. Furthermore, studies combining different approaches to assess synergistic potentials are rare. In this study, we aim to gain insights into the mode of action of both sulfated hyaluronic acid and dexamethasone by a comprehensive analysis of the cellular fraction, released matrix vesicles, and the extracellular matrix, combining classical biochemical assays with mass spectrometry-based proteomics, supported by novel bioinformatical computations. We found elevated differentiation levels for both treatments, which were further enhanced by a combination of sulfated hyaluronic acid and dexamethasone. Single treatments revealed specific effects on osteogenic differentiation. Dexamethasone activates signalling pathways involved in the differentiation of osteoblasts, for example, CXC-motif chemokine receptor type 4 and mitogen-activated protein kinases. The effects of sulfated hyaluronic acid were predominantly linked to an alteration in the composition of the extracellular matrix, affecting the synthesis, secretion, and/or activity of fibrillary (fibronectin and thrombospondin-2) and nonfibrillary (transglutaminase-2, periostin, and lysyloxidase) extracellular matrix components, including proteases and their inhibitors (matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-3). The effects were treatment specific, and less additive or contrary effects were found. Thus, we anticipate that the synergistic action of the treatment-specific effects is the key driver in elevated osteogenesis. PMID- 30485524 TI - Mechanism of miR-137 regulating migration and invasion of melanoma cells by targeting PIK3R3 gene. AB - OBJECTIVE: To investigate the effect of microRNA-137 (miR-137) on the migration and invasion of melanoma cells and its mechanism. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-137 in melanoma tissues and cells. miR-137 mimics, phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) small interfering RNA and corresponding controls were transfected into A375 and WM451 cells by lipofection. The expression of PIK3R3 was examined by qRT-PCR and Western blot analysis. The Trans-well assay was conducted to measure cell migration and invasion. Dual luciferase reporter assay was used to detect the interaction between miR-137 and PIK3R3. RESULTS: Compared with normal pigmented nevus tissue, miR-137 expression was significantly reduced in melanoma tissues. Compared with keratinous HaCaT cells, the level of miR-137 was significantly decreased in melanoma SK-MEL-1, A375, and WM451 cells. Knockdown of miR-137 significantly reduced the migrated and invasive abilities of melanoma A375 and WM451 cells. Moreover, inhibition of PIK3R3 obviously suppressed the migration and invasion abilities of melanoma A375 and WM451 cells. Luciferase activity assay showed that PIK3R3 was a direct target of miR-137. In addition, overexpression of miR-137-inhibited PIK3R3 expression, while knockdown of miR-137-enhanced PIK3R3 abundance. Restoration of PIK3R3 reversed the regulatory effect of miR-137 on cell migration and invasive in melanoma A375 and WM451 cells. CONCLUSION: miR-137 inhibited melanoma cell migration and invasion by targeting PIK3R3 gene. PMID- 30485525 TI - Identification of key biomarkers in diabetic nephropathy via bioinformatic analysis. AB - Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Although intense efforts have been made to elucidate the pathogenesis, the molecular mechanisms of DN remain to be clarified. To identify the candidate genes in the progression of DN, microarray datasets GSE30122, GSE30528, and GSE47183 were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified, and function enrichment analyses were performed. The protein-protein interaction network was constructed and the module analysis was performed using the Search Tool for the Retrieval of Interacting Genes and Cytoscape. A total of 61 DEGs were identified. The enriched functions and pathways of the DEGs included glomerulus development, extracellular exosome, collagen binding, and the PI3K-Akt signaling pathway. Fifteen hub genes were identified and biological process analysis revealed that these genes were mainly enriched in acute inflammatory response, inflammatory response, and blood vessel development. Correlation analysis between unexplored hub genes and clinical features of DN suggested that COL6A3, MS4A6A,PLCE1, TNNC1, TNNI1, TNN2, and VSIG4 may involve in the progression of DN. In conclusion, DEGs and hub genes identified in this study may deepen our understanding of molecular mechanisms underlying the progression of DN, and provide candidate targets for diagnosis and treatment of DN. PMID- 30485526 TI - BMP2/7 heterodimer enhances osteogenic differentiation of rat BMSCs via ERK signaling compared with respective homodimers. AB - Bone morphogenetic protein (BMP)2/7 heterodimer shows greater efficacy in enhancing bone regeneration. However, the precise mechanism and the role of mitogen-activated protein kinase (MAPK) signaling network in BMP2/7-driven osteogenesis remain ambiguous. In this study, we evaluated the effects of BMP2/7 heterodimers on osteoblastic differentiation in rat bone marrow mesenchymal stem cells (BMSCs), with the aim to elaborate how MAPKs might be involved in this cellular process by treatment of rat BMSCs with BMP2/-7 with a special signal pathway inhibitor. We found that BMP2/7 heterodimer induced a much stronger osteogenic response in rat BMSCs compared with either homodimer. Most interestingly, extracellular signal-regulated kinase (ERK) demonstrated a highly sustained phosphorylation and activation in the BMP2/7 heterodimer treatment groups, and inhibition of ERK cascades using U0126 special inhibitor that significantly reduced the activity of ALP and calcium mineralization to a substantial degree in rat BMSCs treated with BMP2/7 heterodimers. Collectively, we demonstrate that BMP2/7 heterodimer shows a potent ability to stimulate osteogenesis in rat BMSCs. The activated ERK signaling pathway involved in this process may contribute partially to an increased osteogenic potency of heterodimeric BMP2/7 growth factors. PMID- 30485527 TI - Association of the study between LncRNA-H19 gene polymorphisms with the risk of breast cancer. AB - BACKGROUND: The H19 is a maternally expressed imprinted gene transcribing a long noncoding RNA (lncRNA), which has previously been reported to be involved in tumorigenesis and cancer progression. The aim of this study was to evaluate the associations between two lncRNA-H19 (rs3741219 T>C and rs217727 C>T) gene polymorphisms with the risk of breast cancer (BC). METHODS: In a case-control investigation, we evaluated 150 BC patients and 100 cancer-free subjects in East Azerbaijan Province of Iran. To assess two gene polymorphisms, the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used. RESULTS: The genotype frequencies of two lncRNA-H19 (rs217727 C>T and rs3741219 T>C) gene polymorphisms TT + TC/CC and CC + CT/TT have not shown a statistically significant association with the risk of BC (P = 0.065; OR = 0.967; 95% CI, 0.938-0.996) and (P = 0.510; OR = 1.583; 95% CI, 0.399-6.726), respectively. In addition, our findings revealed a significant differences in allele frequencies in lncRNA-H19 rs217727 C>T polymorphism between groups (P = 0.033; OR = 1.985; 95% CI, 1.048-3.761). CONCLUSION: Our findings suggested that rs217727 C>T polymorphism may be involved in the pathogenesis of BC, whereas rs3741219 T>C variation may not be involved in the genetic background of BC in Iranian. PMID- 30485528 TI - miR-377-5p inhibits lung cancer cell proliferation, invasion, and cell cycle progression by targeting AKT1 signaling. AB - Lung carcinoma is the most common type of malignant tumors globally, and its molecular mechanisms remained unclear. With the aim to investigate the effects of microRNA (miR)-377-5p on the cell development, invasion, metastasis, and cycle of lung carcinoma, this study was performed. We evaluated miR-377-5p expression levels in lung cancer tissues and cell models. Cell viability, proliferation, migration, invasion abilities, and cell cycle distribution were measured using 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, crystal violet, transwell, and flow cytometry assay. Furthermore, expression levels of protein kinase B alpha subunit (AKT1) and proteins related to cell cycle and epithelial mesenchymal transition (EMT) were assessed using Western blot analysis and quantitative real-time polymerase chain reaction. These results suggested that miR-377-5p was downregulated in vivo and in cell models, and miR-377-5p overexpression inhibited cell viability, proliferation, migration, invasion, and induced cell-cycle arrest. In addition, as a target of miR-377-5p, AKT1 alleviated the decreases of cell viability, proliferation, migration, invasion, the S-phase cells, the expression of cyclin D1, fibronectin, and vimentin, as well as the increases of the G0/G1-phase cells, the expression of Foxo1, p27 kip1 , p21 Cip1 and E-cadherin when miR-377-5p overexpressed. In conclusion, miR-377 5p inhibited cell development and regulated cell cycle distribution and EMT by targeting AKT1, which provided a theoretical basis for further study of lung carcinoma therapeutics. PMID- 30485529 TI - Overexpression of miR-98 attenuates neuropathic pain development via targeting STAT3 in CCI rat models. AB - MicroRNA (miRNA) are significant regulators of neuropathic pain development and neuroinflammation can contribute a lot to the progression of neuropathic pain. Recently, miR-98 has been reported to be involved in various diseases. However, little is known about the role of miR-98 in neuropathic pain development and neuroinflammation. Therefore, our study was aimed to investigate the function of miR-98 in neuropathic pain via establishing a rat model using chronic constriction injury (CCI) of the sciatic nerve. Here, we observed that miR-98 was downregulated in CCI rat models. Overexpression of miR-9 was able to inhibit neuropathic pain progression. Recently, STAT3 has been reported to serve a key role in various processes, including inflammation. Interestingly, our study indicated that STAT3 was dramatically upregulated and activated in CCI rats. By using informatics analysis, STAT3 was predicted as a direct target of miR-98 and the direct correlation was confirmed. Then, miR-98 was overexpressed in CCI rats and it was found that miR-98 was able to repress neuropathic pain development via inhibiting the neuroinflammation. As displayed, interleukin 6 (IL-6), IL-1beta, and tumor necrosis factor-alpha (TNF-alpha) expression was obviously induced in CCI rats, while miR-98 reduced their protein levels. Finally, we found that overexpression of STAT3 reversed the inhibitory effect of miR-98 on neuropathic pain development. Taken these together, we reported that overexpression of miR-98 attenuated neuropathic pain development via targeting STAT3 in CCI rat models. PMID- 30485530 TI - Association study of copy number variation in BMP8A gene with the risk of ankylosing spondylitis in Iranian population. AB - BACKGROUND: Copy number variation (CNV) of DNA segments has been considered as an important component of genetic variation, affecting the quality and quantity of gene expression. Bone morphogenic protein 8A (BMP8A) has been reported to function in bone formation. With respect to the bone and joint complications in ankylosing spondylitis (AS), this investigation aimed to study the role of BMP8A gene CNV in impressing the gene expression as well as the disease risk. METHODS: A total of 900 individuals, including 450 patients with AS and 450 healthy controls were enrolled. The copy numbers of BMP8A gene were detected by TaqMan real-time polymerase chain reaction (PCR) method. BMP8A messenger RNA (mRNA) transcript level in peripheral blood mononuclear cells (PBMCs) was also measured by SYBR Green real-time gene expression PCR method. RESULTS: No significant association of BMP8A copy number was detected with the risk of AS. BMP8A mRNA expression level was significantly downregulated in patients compared with controls. mRNA expression level of BMP8A in both AS patients with and without syndesmophyte was significantly lower than the healthy control group. There was no correlation between the mRNA expression level of BMP8A and both demographic and clinical data of the patients. CONCLUSIONS: Although BMP8A gene expression was downregulated in patients with AS, its copy number could not affect the transcript level of BMP8A gene in PBMCs and was not associated with susceptibility to AS in Iranian population. BMP8a may take into account as an indicator of bone formation process in AS, but it seems that mechanisms other than CNV may regulate this protein. PMID- 30485531 TI - Selenoprotein S protects against high glucose-induced vascular endothelial apoptosis through the PKCbetaII/JNK/Bcl-2 pathway. AB - Vascular endothelial apoptosis is closely associated with the pathogenesis and progression of diabetic macrovascular diseases. Selenoprotein S (SelS) participates in the protection of vascular endothelial and smooth muscle cells from oxidative and endoplasmic reticulum stress-induced injury. However, whether SelS can protect vascular endothelium from high glucose (HG)-induced apoptosis and the underlying mechanism remains unclear. The present study preliminarily analyzed aortic endothelial apoptosis and SelS expression in diabetic rats in vivo and the effects of HG on human umbilical vein endothelial cell (HUVEC) apoptosis and SelS expression in vitro. Subsequently, SelS expression was up- or downregulated in HUVECs using the pcDNA3.1-SelS recombinant plasmid and SelS specific small interfering RNAs, and the effects of high/low SelS expression on HG-induced HUVEC apoptosis and a possible molecular mechanism were analyzed. As expected, HG induced vascular endothelial apoptosis and upregulated endothelial SelS expression in vivo and in vitro. SelS overexpression in HUVECs suppressed HG induced increase in apoptosis and cleaved caspase3 level, accompanied by reduced protein kinase CbetaII (PKCbetaII), c-JUN N-terminal kinase (JNK), and B-cell lymphoma/leukemia-2 (Bcl-2) phosphorylation. In contrast, inhibiting SelS expression in HUVECs further aggravated HG-induced increase in apoptosis and cleaved caspase3 level, which was accompanied by increased PKCbetaII, JNK, and Bcl-2 phosphorylation. Pretreatment with PKC activators blocked the protective effects of SelS and increased the apoptosis and cleaved caspase3 level in HUVECs. In summary, SelS protects vascular endothelium from HG-induced apoptosis, and this was achieved through the inhibition of PKCbetaII/JNK/Bcl-2 pathway to eventually inhibit caspase3 activation. SelS may be a promising target for the prevention and treatment of diabetic macrovascular complications. PMID- 30485532 TI - KDM4B promotes gastric cancer metastasis by regulating miR-125b-mediated activation of Wnt signaling. AB - Emerging evidence has demonstrated that the aberrant expression of histone modifying enzymes such as histone demethylases contributes to gastric carcinogenesis and progression. The role of KDM4B in cancer progression has been gradually revealed. However, the underlying mechanisms regulating gastric cancer metastasis of KDM4B remain unclear. In the present study we determined KDM4B expression in gastric cancer and its biologic function in vitro and in vivo. We found that KDM4B expression was significantly increased in most gastric cancer tissues compared with the adjacent normal tissues. Upregulated expression of KDM4B in human gastric cancer was correlated with poor prognosis. In vitro, KDM4B overexpression in AGS cells promoted cell invasion, whereas knockdown of KDM4B inhibited cell invasion. Furthermore, KDM4B overexpression also promoted tumor metastasis in vivo. Mechanistically, KDM4B upregulated miR-125b expression and activated Wnt signaling pathway. More important, miR-125b partially mediated KDM4B-induced activation of Wnt signaling. Finally, we demonstrated that KDM4B promoted gastric cancer cell invasion in vitro and cancer metastasis in vivo, at least in part, by upregulating miR-125b expression. These data provided novel insights on the role of KDM4B-driven gastric cancer metastasis and indicated that KDM4B may be served as a potential target for gastric cancer. PMID- 30485533 TI - Conservation needs exposed by variability in common-pool governance principles. AB - Common-pool governance principles are becoming increasingly important tools for natural resource management with communities and co-management arrangements. Principle's effectiveness will depend on variability in agreements, trust, and adherence to institutional norms. We evaluated heterogeneity in governance principles by asking 449 people in 30 fishing communities in four East African countries to rate their effectiveness. The influences of individuals, membership, leadership, community, and country were tested. Findings indicate that a person's role was not the main influence and concluding about the effectiveness of specific principles would be difficult independent of the individuals asked. More critical was person's associations with a response-group's perception of each principle's effectiveness and their nationality. Perceptions of effectiveness differed strongly by country and suggest that poorer-nation respondents (Madagascar and Mozambique) were more cohesiveness but had lower between communities conflict resolution mechanisms. Overall, we found that group identity, group autonomy, decision-making process, and conflict resolution principles were perceived to be most effective and likely to be enforced by repeated low-cost intra-group activities. Graduated sanctions, cost-benefit sharing, and monitoring resource users, fisheries, and ecology were the least scaled principles and less affordable via local control. We suggest that these two groups of principles form independently and, as economies develop and natural resource become limiting, sustainable use increasingly depends on the later principles. Therefore, management effectiveness in resource-limited situations will depend on distributing power, skills, and costs beyond fishing communities to insure conservation needs are met. This article is protected by copyright. All rights reserved. PMID- 30485534 TI - Primary motor cortex deactivation as a new mechanism of motor inhibition in conversion paralysis. PMID- 30485535 TI - Safety and tolerability of high intensity statin therapy in heart transplant patients receiving immunosuppression with tacrolimus. AB - BACKGROUND: Following heart transplantation (HT), HMG CoA reductase inhibitors (statins) have been shown to reduce total and low-density lipoprotein (LDL) cholesterol, development of cardiac allograft vasculopathy (CAV), and mortality. Studies in HT patients have demonstrated the safety of low/moderate intensity statins, however little data exists using high intensity (HI) statins. The study aim was to evaluate the safety and efficacy of HI statins in HT recipients receiving tacrolimus. METHODS: This single center, retrospective analysis included adult HT recipients from January 1, 2005 to December 31, 2015 who received HI statin therapy during post-transplant follow-up. The primary outcome, tolerability, was defined as the absence of myalgias, hepatotoxicity, rhabdomyolysis, or HI statin dose reduction/discontinuation. The secondary end point was the mean reduction in total and LDL cholesterol. RESULTS: Among the 24 patients included, one experienced myalgias and therapy discontinuation (4%; p>0.99). No other HI statin dose reduction/discontinuation occurred, and no instances of rhabdomyolysis or hepatotoxicity were observed. The average reduction in total and LDL cholesterol after conversion to HI statin was 35 mg/dL (p=0.02) and 19 mg/dL (p=0.10), respectively. CONCLUSIONS: HI statin therapy appears safe and efficacious in HT recipients receiving tacrolimus and is a reasonable option for treatment of refractory hyperlipidemia. This article is protected by copyright. All rights reserved. PMID- 30485536 TI - Assessment of cardiac-driven liver movements with filtered harmonic phase image representation, optical flow quantification, and motion amplification. AB - PURPOSE: To characterize cardiac-driven liver movements using a harmonic phase image representation (HARP) with an optical flow quantification and motion amplification method. The method was applied to define the cardiac trigger delay providing minimal signal losses in liver DWI images. METHODS: The 16-s breath hold balanced-SSFP time resolved 20 images/s were acquired at 3T in coronal and sagittal orientations. A peripheral pulse unit signal was recorded. Cardiac triggered DWI images were acquired after different peripheral pulse unit delays. A steerable pyramid decomposition with multiple orientations and spatial frequencies was applied. The liver motion field-map was derived from temporal variations of the HARP representation filtered around the cardiac frequency. Liver displacements were quantified with an optical flow method; moreover the right liver motion was amplified. RESULTS: The largest displacements were observed in the left liver (feet-head:3.70 +/- 1.06 mm; anterior-posterior: 2.35 +/- 0.51 mm). Displacements were statistically significantly weaker in the middle right liver (0.47 +/- 0.11 mm; P = 0.0156). The average error was 0.013 +/- 0.022 mm (coronal plane) and 0.021 +/- 0.041 mm (sagittal plane). The velocity field demonstrated opposing movements of the right liver extremities during the cardiac cycle. DWI signal loss was minimized in regions and instants of smallest amplitude of both velocity and velocity gradient. CONCLUSION: Cardiac-driven liver movements were quantified with combined cardiac frequency-filtered HARP and optical flow methods. A motion phase opposition between right liver extremities was demonstrated. Displacement amplitude and velocity were larger in the left liver especially along the vertical direction. Motion amplification visually emphasized cardiac-driven right liver displacements. The optimal cardiac timing minimizing signal loss in liver DWI images was derived. PMID- 30485537 TI - Sensorimotor subthalamic stimulation restores risk-reward trade-off in Parkinson's disease. AB - BACKGROUND: STN-DBS effectively treats motor symptoms of advanced PD. Nonmotor cognitive symptoms, such as impaired impulse control or decision making, may either improve or worsen with DBS. A potential mediating factor of DBS-induced modulation of cognition is the electrode position within the STN with regard to functional subareas of parallel motor, cognitive, and affective basal ganglia loops. However, to date, the volume of tissue activated and weighted stimulation of STN motor versus nonmotor territories are yet to be linked to differential DBS effects on cognition. OBJECTIVES: We aim to investigate whether STN-DBS influences risk-reward trade-off decisions and analyze its dependency on electrode placement. METHODS: Seventeen PD patients ON and OFF STN-DBS and 17 age matched healthy controls conducted a sequential decision-making task with escalating risk and reward. We computed the effect of STN-DBS on risk-reward trade-off decisions, localized patients' bilateral electrodes, and analyzed the predictive value of volume of tissue activated in STN motor and nonmotor territories on behavioral change. RESULTS: We found that STN-DBS not only improves PD motor symptoms, but also normalizes overly risk-averse decision behavior in PD. Intersubject variance in electrode location could explain this behavioral change. Specifically, if STN-DBS activated preferentially STN motor territory, patients' risk-reward trade-off decisions more resembled those of healthy controls. CONCLUSIONS: Our findings support the notion of convergence of different functional circuits within the STN and imply a positive effect of well placed STN-DBS on nonmotor cognitive functioning in PD. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 30485538 TI - Parathyroidectomy decreases serum intact parathyroid hormone and calcium levels and prolongs overall survival in elderly hemodialysis patients with severe secondary hyperparathyroidism. AB - BACKGROUND: The objective of this study was to assess the effect of parathyroidectomy (PTX) treatment on prolonging overall survival (OS) as well as decreasing levels of intact parathyroid hormone (iPTH), calcium (Ca), and phosphorus (P) in elderly hemodialysis patients with severe secondary hyperparathyroidism (SHPT). METHODS: A total of 304 elderly hemodialysis patients with severe SHPT were consecutively enrolled in this cohort study. According to whether PTX operations were applied, patients were classified into PTX group (N = 112) and Control group (N = 192) and were followed up for 3 years. Mortality rate and OS were evaluated, and iPTH, Ca, and P levels were recorded. RESULTS: Compared to control group, increased iPTH (P < 0.001), higher Ca (P = 0.003), elevated AST (P = 0.022), and lower Hb (P = 0.049) concentrations were observed in the PTX group at baseline. The 1-year mortality (P < 0.001), 2-year mortality (P < 0.001), and 3-year mortality (P < 0.001) was reduced in PTX group compared to Control group, and PTX was correlated with prolonged OS (P < 0.001). Multivariate Cox's regression analysis further revealed that PTX treatment (P < 0.001, HR = 0.177) was an independent factor for better OS. Moreover, patients in PTX group had decreased iPTH (P < 0.05) and Ca (P < 0.05) levels compared to Control group at M1-M36, while no difference was found in serum P level between the two groups at M1-M36. CONCLUSION: Parathyroidectomy decreases iPTH and Ca levels, and it associates with favorable survival in elderly hemodialysis patients with severe SHPT. PMID- 30485539 TI - A novel role and mechanism of cystic fibrosis transmembrane conductance regulator in bisphenol A-induced prostate cancer. AB - Bisphenol A (BPA) is a well known environmental endocrine disruptor that may cause human prostate cancer through disturbing cell mitosis, proliferation, and apoptosis. As one of the most important anion channels in organisms, cystic fibrosis transmembrane conductance regulator (CFTR) is proposed as a tumor suppressor in carcinogenesis and development of prostate cancer in recent studies. Whether CFTR plays a role in BPA-induced prostate cancer needs to be further identified. In this study, two prostate cancer cell lines PC-3 and LNCaP were exposed to BPA for detecting the cytotoxic reactions by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and enzyme-linked immunosorbent assays. After the treatment with BPA for 24 hours, the cell viability was decreased significantly with increased cell apoptosis in the two cell lines. Moreover, both PC-3 and LNCaP cells had a reduced expression level of cAMP, CFTR, and adenosine triphosphate upon BPA treatment. In addition, AMPKalpha kinase was found upregulated to promote cell apoptosis through increasing Bax expression and decreasing Bcl-2 expression. Our study suggests a role and mechanism of CFTR in BPA-induced prostate cancer via cell apoptosis for the first time. PMID- 30485540 TI - Defined astrocytic expression of human amyloid precursor protein in Tg2576 mouse brain. AB - Transgenic Tg2576 mice expressing human amyloid precursor protein (hAPP) with the Swedish mutation are among the most frequently used animal models to study the amyloid pathology related to Alzheimer's disease (AD). The transgene expression in this model is considered to be neuron-specific. Using a novel hAPP-specific antibody in combination with cell type-specific markers for double immunofluorescent labelings and laser scanning microscopy, we here report that-in addition to neurons throughout the brain-astrocytes in the corpus callosum and to a lesser extent in neocortex express hAPP. This astrocytic hAPP expression is already detectable in young Tg2576 mice before the onset of amyloid pathology and still present in aged Tg2576 mice with robust amyloid pathology in neocortex, hippocampus, and corpus callosum. Surprisingly, hAPP immunoreactivity in cortex is restricted to resting astrocytes distant from amyloid plaques but absent from reactive astrocytes in close proximity to amyloid plaques. In contrast, neither microglial cells nor oligodendrocytes of young or aged Tg2576 mice display hAPP labeling. The astrocytic expression of hAPP is substantiated by the analyses of hAPP mRNA and protein expression in primary cultures derived from Tg2576 offspring. We conclude that astrocytes, in particular in corpus callosum, may contribute to amyloid pathology in Tg2576 mice and thus mimic this aspect of AD pathology. PMID- 30485541 TI - Use of the Sysmex XT-4000i hematology analyzer in the differentiation of cerebrospinal fluid cells in children. AB - BACKGROUND: Routine analysis of pleocytosis and cellular composition of cerebrospinal fluid (CSF) is carried out with a phase-contrast microscope. The use of hematological analyzers seems to be an alternative to the manual method. The aim of the study was to assess the usefulness of the automated technique for counting and differentiating CSF cells in children. METHODS: The study group consisted of 59 children (28 girls and 31 boys) aged from 4 to 17 years suffering from viral and bacterial meningitis. Children were divided into three subgroups according to CSF cell count: 1st group had a pleocytosis of 6-50 cells/uL, 2nd group-51-100 cells/uL, and 3rd group->100 cells/uL. A reference group involved 32 children (17 girls and 15 boys) aged from 2 to 18 years with a normal range of 0 5 cells/uL. Examination of CSF was performed in parallel by two different method, manual and automated. RESULTS: The analysis of pleocytosis revealed that the values obtained by the manual method were statistically significantly lower in relation to the values obtained by automated technique in subgroups I and II. The number of mononuclear and polymorphonuclear cells in subgroups I, II, and III determined by both manual and automated methods was comparable. CONCLUSION: We conclude that automated method cannot fully replace the previously used manual method and some of the dubious cases, such as samples with low pleocytosis rates or abnormal cells indicated by the analyzer, will still require microscopic examination. PMID- 30485542 TI - Release of astroglial vimentin by extracellular vesicles: Modulation of binding and internalization of C3 transferase in astrocytes and neurons. AB - Clostridium botulinum C3 transferase (C3bot) ADP-ribosylates rho proteins to change cellular functions in a variety of cell types including astrocytes and neurons. The intermediate filament protein vimentin as well as transmembrane integrins are involved in internalization of C3bot into cells. The exact contribution, however, of these proteins to binding of C3bot to the cell surface and subsequent cellular uptake remains to be unraveled. By comparing primary astrocyte cultures derived from wild-type with Vim-/- mice, we demonstrate that astrocytes lacking vimentin exhibited a delayed ADP-ribosylation of rhoA concurrent with a blunted morphological response. This functional impairment was rescued by the extracellular excess of recombinant vimentin. Binding assays using C3bot harboring a mutated integrin-binding RGD motif (C3bot-G89I) revealed the involvement of integrins in astrocyte binding of C3bot. Axonotrophic effects of C3bot are vimentin dependent and postulate an underlying mechanism entertaining a molecular cross-talk between astrocytes and neurons. We present functional evidence for astrocytic release of vimentin by exosomes using an in vitro scratch wound model. Exosomal vimentin+ particles released from wild-type astrocytes promote the interaction of C3bot with neuronal membranes. This effect vanished when culturing Vim-/- astrocytes. Specificity of these findings was confirmed by recombinant vimentin propagating enhanced binding of C3bot to synaptosomes from rat spinal cord and mouse brain. We hypothesize that vimentin+ exosomes released by reactive astrocytes provide a novel molecular mechanism constituting axonotrophic (neuroprotective) and plasticity augmenting effects of C3bot after spinal cord injury. PMID- 30485543 TI - Assessment of rapid diagnostic tests and fourth-generation Enzyme-Linked Immunosorbent Assays in the screening of Human Immunodeficiency and Hepatitis B virus infections among first-time blood donors in Libreville (Gabon). AB - BACKGROUND: Blood transfusion is a pathway for the transmission of blood-borne pathogens such as human immunodeficiency virus (HIV) and hepatitis B virus (HBV) from donors to recipients in most countries in sub-Saharan Africa, including Gabon. The study aimed to compare the performance of four rapid diagnostic tests (RDTs: Alere DETERMINE, BIOSYNEX Exacto Pro HIV, MEDIFF HIV 1&2, and BIOSYNEX IMMUNOQUICK HBsAg) with results of 4th-generation immunoenzymatic assays COBAS 6000 e601 and EVOLIS BioRad for the detection of HIV and hepatitis B surface antigen (HBsAg) in blood donors in Libreville, Gabon. METHODS: Reactive and nonreactive blood samples for HIV and HBsAg were selected using fourth-generation ELISA COBAS 6000 e601 and EVOLIS BioRad. The sensitivities of RDTs were calculated using Epi Info version 6.04dfr (CDC, Atlanta, USA). RESULTS: Sensitivities for the detection of HIV in blood donors were 90.9% for Alere DETERMINE, 81.8% for BIOSYNEX Exacto Pro HIV, and 81.8% for MEDIFF HIV 1&2 Serum/sang Total Cassette compared with COBAS 6000 e601. The sensitivity of Alere DETERMINE compared to the semi-automated ELISA Bio-Rad for HIV detection was 65.6%. The sensitivity of BIOSYNEX IMMUNOQUICK HBsAg compared to ELISA tests for the detection of HBsAg was 78.0%. The specificity of all RDTs for the detection of HIV and HBsAg was 100%. CONCLUSION: Alere DETERMINE HIV-1/2, MEDIFF HIV 1&2 Serum/sang Total Cassette, BIOSYNEX Exacto Pro HIV, and BIOSYNEX IMMUNOQUICK HBsAg are not recommended for determining whether donors qualify to donate blood because of their low sensitivity for the detection of HIV antibodies and HBsAg in blood donors in Gabon. PMID- 30485544 TI - Altered expression of circular RNAs in human placental chorionic plate-derived mesenchymal stem cells pretreated with hypoxia. AB - BACKGROUND: Hypoxic preconditioning alters the biological properties of mesenchymal stem cells (MSCs). It is not known whether this process has an effect on circular RNAs (circRNAs) in MSCs. METHODS: Human placental chorionic plate derived MSCs (hpcpMSCs) isolated from the same placentae were classed into two groups: hypoxic pretreated (hypoxia) group and normally cultured (normoxia) group. The comparative circRNA microarray analysis was used to determine circRNAs expression and verified by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) in the two groups. RESULTS: One hundred and two differentially expressed circRNAs in the hypoxia group were found compared to that in the normoxia group (fold change >1.5-fold and P < 0.05). The expression levels of circRNAs by qRT-PCR were consistent with those evaluated by microarray analysis. Gene ontology (GO) analysis showed that the putative function of their target genes for those differentially expressed circRNAs was primarily involved in cell development and its differentiation and regulation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that transcriptional misregulation in cancer and mitogen-activated protein kinase (MAPK) signaling pathway were the most significant. MAPK signaling pathway was found to be the core regulatory pathway triggered by hypoxia. CONCLUSIONS: The results indicate that the altered expression of specific circRNAs in MSCs is associated with hypoxic preconditioning. This finding provides further exploration of underlying mechanisms of the characteristic changes of MSCs with hypoxic preconditioning. PMID- 30485545 TI - Understanding the role of genetic variability in LRRK2 in Indian population. AB - BACKGROUND: Genetic variability in LRRK2 has been unequivocally established as a major risk factor for familial and sporadic forms of PD in ethnically diverse populations. OBJECTIVES: To resolve the role of LRRK2 in the Indian population. METHODS: We performed targeted resequencing of the LRRK2 locus in 288 cases and 298 controls and resolved the haplotypic structure of LRRK2 in a combined cohort of 800 cases and 402 controls in the Indian population. We assessed the frequency of novel missense variants in the white and East Asian population by leveraging exome sequencing and densely genotype data, respectively. We did computational modeling and biochemical approach to infer the potential role of novel variants impacting the LRRK2 protein function. Finally, we assessed the phosphorylation activity of identified novel coding variants in the LRRK2 gene. RESULTS: We identified four novel missense variants with frequency ranging from 0.0008% to 0.002% specific for the Indian population, encompassing armadillo and kinase domains of the LRRK2 protein. A common genetic variability within LRRK2 may contribute to increased risk, but it was nonsignificant after correcting for multiple testing, because of small cohort size. The computational modeling showed destabilizing effect on the LRRK2 function. In comparison to the wild-type, the kinase domain variant showed 4-fold increase in the kinase activity. CONCLUSIONS: Our study, for the first time, identified novel missense variants for LRRK2, specific for the Indian population, and showed that a novel missense variant in the kinase domain modifies kinase activity in vitro. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 30485546 TI - Transcription factor MafB contributes to the activation of spinal microglia underlying neuropathic pain development. AB - Microglia, which are pathological effectors and amplifiers in the central nervous system, undergo various forms of activation. A well-studied microglial-induced pathological paradigm, spinal microglial activation following peripheral nerve injury (PNI), is a key event for the development of neuropathic pain but the transcription factors contributing to microglial activation are less understood. Herein, we demonstrate that MafB, a dominant transcriptional regulator of mature microglia, is involved in the pathology of a mouse model of neuropathic pain. PNI caused a rapid and marked increase of MafB expression selectively in spinal microglia but not in neurons. We also found that the microRNA mir-152 in the spinal cord which targets MafB expression decreased after PNI, and intrathecal administration of mir-152 mimic suppressed the development of neuropathic pain. Reduced MafB expression using heterozygous Mafb deficient mice and by intrathecal administration of siRNA alleviated the development of PNI-induced mechanical hypersensitivity. Furthermore, we found that intrathecal transfer of Mafb deficient microglia did not induce mechanical hypersensitivity and that conditional Mafb knockout mice did not develop neuropathic pain after PNI. We propose that MafB is a key mediator of the PNI-induced phenotypic alteration of spinal microglia and neuropathic pain development. PMID- 30485547 TI - Serum soluble lymphocyte activation gene-3 as a diagnostic biomarker in Parkinson's disease: A pilot multicenter study. AB - OBJECTIVE: Lymphocyte activation gene-3 (LAG-3) could mediate pathological alpha synuclein transmission in neurodegeneration and may be involved in the pathogenesis of Parkinson's disease (PD). The aim of the present study was to explore soluble LAG-3 (sLAG-3) as a potential diagnostic biomarker for PD. METHODS: Serum sLAG-3 concentrations were measured by a quantitative ELISA for patients with PD, essential tremor (ET) and age- and sex-matched controls. The relationships between sLAG-3 and clinical phenotype were assessed via correlation analysis and logistic regression. RESULTS: Serum sLAG-3 levels in patients with PD were significantly higher than those in ET patients and age- and sex-matched controls. The area under the curve of serum sLAG-3 in differentiating PD from age and sex-matched controls was 0.82. Serum sLAG-3 was associated with non-motor symptoms and excessive daytime sleep. CONCLUSION: sLAG-3 is a candidate novel biomarker for PD. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 30485548 TI - Language Matters-the campaign continues! PMID- 30485549 TI - Dissecting functional phenotypes of microglia and macrophages in the rat brain after transient cerebral ischemia. AB - Ischemic brain injury causes local inflammation, which involves activation of resident microglia, leukocyte, and monocyte infiltration. Involvement of peripheral immune cells in ischemia-induced damage and repair is debatable. Using flow cytometry, gene expression profiling, and immunocytochemistry, we show that microglia predominate in the ischemic brain and express inflammation mediators at Day 1 after transient middle cerebral artery occlusion (MCAo) in rats. At Day 3, both resident microglia and bone marrow (BM)-derived macrophages are detected in the ischemic hemispheres and display unique transcriptomic profiles. Functional groups enriched in BM-macrophages are indicative of the pro-regenerative, immunosuppressive phenotype. Transient depletion of peripheral macrophages with clodronate-filled liposomes reduced the number of Arg1+ Iba1+ expressing cells in the ischemic brain. The analysis of microglia and macrophage signature genes shows that each cell type maintains the expression of their identity genes, even if gene expression is modified in a response to environmental clues. At Day 7, infiltrating BM-macrophages exhibit the reduced expression of Arg1, the elevated expression of iNos and many inflammatory genes, as shown by RNA sequencing. This is consistent with their switch toward a pro-inflammatory phenotype. We propose that BM-macrophages recruited to the injured brain early after ischemia could contribute to functional recovery after stroke, but they switch toward a pro inflammatory phenotype in the ischemic parenchyma. Our results point to the detrimental role of microglia in an ischemic brain and the primarily pro regenerative role of infiltrating BM-macrophages. PMID- 30485550 TI - Cognitive deficits in mice lacking Nsun5, a cytosine-5 RNA methyltransferase, with impairment of oligodendrocyte precursor cells. AB - Williams-Beuren syndrome (WBS) is a microdeletion disorder with cognitive phenotype. NSUN5 gene, which encodes a cytosine-5 RNA methyltransferase, is located in WBS deletion locus. To investigate the influence of NSUN5 deletion on cognitive behaviors, we produced single-gene Nsun5 knockout (Nsun5-KO) mice. Here, we report that adult Nsun5-KO mice showed spatial cognitive deficits. Size of the brain and hippocampal structures and the number of CA1 or CA3 pyramidal cells in Nsun5-KO mice did not differ from WT mice. Basal properties of Schaffer collateral-CA1 synaptic transmission in Nsun5-KO mice were unchanged, but NMDA receptor (NMDAr)-dependent long-term potentiation (LTP) was not induced. The NMDA evoked current in CA1 pyramidal cells was reduced in Nsun5-KO mice without the changes in expression and phosphorylation of NMDAr subunits NR2A and NR2B. Although the protein level of AMPA receptor subunit GluR2 was attenuated in Nsun5 KO mice, the AMPA-evoked current was not altered. Hippocampal immuno-staining showed the selective expression of Nsun5 in NG2 or PDGFRalpha labeled oligodendrocyte precursor cells (OPCs), but not in pyramidal cells or astrocytes. Analysis of RT-PCR determined the Nsun5 expression in purified populations of OPCs rather than neurons or astrocytes. The Nsun5 deficiency led to decreases in the number and neurite outgrowth of OPCs in the hippocampal CA1 and DG, with the decline in NG2 expression and OPCs proliferation. These findings indicate that the Nsun5 deletion suppresses NMDAr activity in neuronal cells probably through the disrupted development and function of OPCs, leading to deficits in NMDAr dependent LTP and spatial cognitive abilities. PMID- 30485551 TI - Episodes of hypovolemia/dehydration in baboons with pig kidney transplants: A new syndrome of clinical importance? PMID- 30485552 TI - ErbB4 point mutation in CU3 inbred rats affects gonadotropin-releasing-hormone neuronal function via compromised neuregulin-stimulated prostaglandin E2 release from astrocytes. AB - Gonadotropin releasing hormone (GnRH)-secretion is not only regulated by neuronal factors but also by astroglia cells via growth factors and ErbB receptors of the epidermal growth factor family. Studies in transgenic mice carrying mutations in the ErbB receptor system experience impaired reproductive capacity. In addition, some of these animals show a typical skin phenotype with wavy hair and curly whiskers. The rat strain SPRD-CU3 (CU3), examined in this study, displays a similar skin phenotype and a significant impairment of the timing of puberty onset and reproductive performance, suggesting a disruption in the astrocytic to GnRH neuronal communication. To address this issue, we analyzed astrocytic prostaglandin E2 (PGE2 ) release from primary hypothalamic astrocytic cell cultures after stimulation with transforming growth factor alpha (TGFalpha), ligand for ErbB1/ErbB2, or Neuregulin 1 beta 2 (NRG1beta2 ), ligand for ErbB4/ErbB2 signaling pathway. Compared to cultures from wild type animals, astrocytic cultures from CU3 rats were unable to respond to NRG stimulation, suggesting a disruption of the ErbB4/ErbB2 signaling pathway. This is confirmed by mutational analysis of ErbB4 that revealed a single point mutation at 3125 bp resulting in an amino acid change from proline to glutamine located at the carboxy-terminal region. As a consequence, substantial conformational changes occur in the transmembrane and intracellular domain of the protein, affecting the ability to form a receptor dimer with a partner and the ability to function as a transcriptional regulator. Thus, astroglia to GnRH neuronal signaling via ErbB4 is essential of timely onset of puberty and reproductive function. PMID- 30485553 TI - Biochemical and magnetic resonance image response in targeted focal cryotherapy to ablate targeted biopsy-proven index lesion of prostate cancer. PMID- 30485554 TI - Is there a need for an emergency card in hypoparathyroidism? AB - BACKGROUND: Patients with hypoparathyroidism are at risk of both hypocalcemic and hypercalcemic crisis. Patients report that health professionals do not always respond adequately in an acute situation. The extent and handling of severe hypo- and hypercalcemia in hypoparathyroidism is unknown. AIMS: To outline the need for a medical emergency card for primary hypoparathyroidism. METHOD: Postal survey among Norwegian and Swedish patients with chronic hypoparathyroidism of all causes. Altogether 455 invitations were sent (333 from Norway and 122 from Sweden). RESULTS: 336 of 455 (74%) patients responded (253 from Norway and 83 from Sweden). The majority was women (79%) and the main cause post-surgical hypoparathyroidism (66%). Overall 44% and 16% had been hospitalized at least once for hypo- or hypercalcemia, respectively. Eighty-seven percent felt that an emergency card would be highly needed or useful. Among those hospitalized for hypocalcemia, 95% felt a card was needed compared to 90% among those hospitalized for hypercalcemia. Five percent believed that a card would not be useful. CONCLUSIONS: The majority answered that an acute card is highly needed or useful. Hospitalization for acute hypocalcemia was more common (44%) than for acute hypercalcemia (16%). As a result of this survey an emergency card will be distributed in three European countries to test its utility. This article is protected by copyright. All rights reserved. PMID- 30485555 TI - Normal and pathological neuronal distribution of the human mesencephalic locomotor region. AB - BACKGROUND: Deep brain stimulation of the pedunculopontine nucleus has been performed to treat dopamine-resistant gait and balance disorders in patients with degenerative diseases. The outcomes, however, are variable, which may be the result of the lack of a well-defined anatomical target. OBJECTIVES: The objectives of this study were to identify the main neuronal populations of the pedunculopontine and the cuneiform nuclei that compose the human mesencephalic locomotor region and to compare their 3-dimensional distribution with those found in patients with Parkinson's disease and progressive supranuclear palsy. METHODS: We used high-field MRI, immunohistochemistry, and in situ hybridization to characterize the distribution of the different cell types, and we developed software to merge all data within a common 3-dimensional space. RESULTS: We found that cholinergic, GABAergic, and glutamatergic neurons comprised the main cell types of the mesencephalic locomotor region, with the peak densities of cholinergic and GABAergic neurons similarly located within the rostral pedunculopontine nucleus. Cholinergic and noncholinergic neuronal losses were homogeneous in the mesencephalic locomotor region of patients, with the peak density of remaining neurons at the same location as in controls. The degree of denervation of the pedunculopontine nucleus was highest in patients with progressive supranuclear palsy, followed by Parkinson's disease patients with falls. CONCLUSIONS: The peak density of cholinergic and GABAergic neurons was located similarly within the rostral pedunculopontine nucleus not only in controls but also in pathological cases. The neuronal loss was homogeneously distributed and highest in the pedunculopontine nucleus of patients with falls, which suggests a potential pathophysiological link. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 30485556 TI - Eye movement disorders and neurological symptoms in late-onset inborn errors of metabolism. AB - Inborn errors of metabolism in adults are still largely unexplored. Despite the fact that adult-onset phenotypes have been known for many years, little attention is given to these disorders in neurological practice. The adult-onset presentation differs from childhood-onset phenotypes, often leading to considerable diagnostic delay. The identification of these patients at the earliest stage of disease is important, given that early treatment may prevent or lessen further brain damage. Neurological and psychiatric symptoms occur more frequently in adult forms. Abnormalities of eye movements are also common and can be the presenting sign. Eye movement disorders can be classified as central or peripheral. Central forms are frequently observed in lysosomal storage disorders, whereas peripheral forms are a key feature of mitochondrial disease. Furthermore, oculogyric crisis is an important feature in disorders affecting dopamine syntheses or transport. Ocular motor disorders are often not reported by the patient, and abnormalities can be easily overlooked in a general examination. In adults with unexplained psychiatric and neurological symptoms, a special focus on examination of eye movements can serve as a relatively simple clinical tool to detect a metabolic disorder. Eye movements can be easily quantified and analyzed with video-oculography, making them a valuable biomarker for following the natural course of disease or the response to therapies. Here, we review, for the first time, eye movement disorders that can occur in inborn errors of metabolism, with a focus on late-onset forms. We provide a step-by-step overview that will help clinicians to examine and interpret eye movement disorders. (c) 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 30485557 TI - Serum markers in the differential diagnosis of Waldenstrom macroglobulinemia and other IgM monoclonal gammopathies. AB - BACKGROUND: IgM monoclonal gammopathy can be present in a broad spectrum of diseases. We evaluated the value of serum markers in the differential diagnosis of Waldenstrom macroglobulinemia (WM) and other types of IgM monoclonal gammopathies. METHODS: We included patients who were first admitted to hospital and identified as having IgM monoclonal gammopathy by serum immunofixation electrophoresis (sIFE). We evaluated basic clinical features, sIFE, diagnosis, and serum markers. Furthermore, we applied the receiver operating characteristic (ROC) curve to analyze the differential diagnosis value of serum markers for WM. Finally, we used logistic regression and ROC curve to analyze the differential diagnosis value of multimarker combinations to identify WM. RESULTS: IgM monoclonal gammopathy was most frequently found in patients with Waldenstrom macroglobulinemia, followed by monoclonal gammopathy of undetermined significance (MGUS), B-cell non-Hodgkin Lymphoma (B-NHL), and multiple myeloma (MM). Serum markers showed significant differences among the four diseases. The diagnostic markers LDH, IgM, IgG, IgA, and serum light chain K had higher diagnostic efficiency. Among these markers, serum IgM provided the highest diagnostic efficiency. Additionally, the combined use of all five serum markers provided the most effective diagnosis. CONCLUSIONS: The five serum markers, LDH, IgM, IgG, IgA, and K, each yielded a specific efficacy in differential diagnosis of WM. The single marker with the highest diagnostic efficiency was the serum IgM level. However, a combination of multiple serum markers was better than the use of a single marker in diagnosing WM. The combined use of all five serum markers provided the most effective diagnosis, with an AUC of .952 and sensitivity and specificity of 87.8% and 86.9%, respectively. PMID- 30485558 TI - Liquid biopsy: A new avenue in pathology. AB - Liquid biopsy is a relatively new entity. This non-invasive technique provides us real-time information of a tumor. The liquid biopsy contains circulating tumor cells, cell-free DNA and exosomes. The main indications for liquid biopsy include the early diagnosis, screening, detection of minimal residual disease, designing personalized treatment and predicting biological behavior of the tumor. In this review, we have discussed various aspects of liquid biopsy and compared it with the conventional biopsy. This article is protected by copyright. All rights reserved. PMID- 30485560 TI - Local validation and calibration of preeclampsia screening algorithms. AB - A recent Practice Guideline issued by the International Society of Ultrasound in Obstetrics and Gynecology recommends a combination of a priori factors and pregnancy-specific makers, determined at 11-13 weeks gestation, as the most efficient method of identifying women at risk of preeclampsia (PE) [1]. This article is protected by copyright. All rights reserved. PMID- 30485559 TI - Superficial-Layer-Enhanced Raman Scattering (SLERS) for Depth Detection of Noncontact Molecules. AB - Although the strength of Raman signals can be increased by many orders of magnitude on noble metal nanoparticles, this enhancement is confined to an extremely short distance from the Raman-active surface. The key to the development of Raman spectroscopy for applications in diagnosis and detection of cancer and inflammatory diseases, and in pharmacology, relies on the capability of detecting analytes that are noninteractive with Raman-active surfaces. Here, a new Raman enhancement system is constructed, superficial-layer-enhanced Raman scattering (SLERS), by covering elongated tetrahexahedral gold nanoparticle arrays with a superficial perovskite (CH3 NH3 PbBr3 ) film. Plasmonic decay is depressed along the vertical direction away from the noble metal surface and the penetration depth is increased in the perovskite media. The vertical penetration of SLERS is verified by the spatial distribution of the analytes via Raman imaging in layer-scanning mode. PMID- 30485561 TI - A multicolor large Stokes shift fluorogen-activating RNA aptamer with cationic chromophores. AB - Large Stokes shift (LSS) fluorescent proteins (FPs) exploit excited state proton transfer pathways to enable fluorescence emission from the phenolate intermediate of their internal 4 hydroxybenzylidene imidazolone (HBI) chromophore. An RNA aptamer named Chili mimics LSS FPs by inducing highly Stokes-shifted emission from several new green and red HBI analogs that are non-fluorescent when free in solution. The ligands are bound by the RNA in their protonated phenol form and feature a cationic aromatic side chain for increased RNA affinity and reduced magnesium dependence. In combination with oxidative functionalization at the C2 position of the imidazolone, this strategy yielded DMHBO+, which binds to the Chili aptamer with a low-nanomolar KD. Because of its highly red-shifted fluorescence emission at 592 nm, the Chili-DMHBO+ complex is an ideal fluorescence donor for Forster resonance energy transfer (FRET) to the rhodamine dye Atto 590 and will therefore find applications in FRET-based analytical RNA systems. PMID- 30485562 TI - Direct oxidation of Csp3-H bonds using in-situ generated trifluoromethylated dioxirane in flow. AB - A fast, scalable and safer Csp3-H oxidation of activated and un-activated aliphatic chain can be enabled by methyl(trifluoromethyl)dioxirane (TFDO). The continuous flow platform allows the in situ generation of TFDO gas and its rapid reactivity toward tertiary and benzylic Csp3-H bonds. The process exhibits a broad scope and good functional group compatibility (28 examples, 8 - 99 %). The scalability of this methodology is demonstrated on 2.5 g scale oxidation of adamantane. PMID- 30485563 TI - Risk factors for infections in newly diagnosed Multiple Myeloma patients: A Danish retrospective nationwide cohort study. AB - OBJECTIVES: Infections pose the greatest risk of early death in patients with Multiple Myeloma. However, few studies have analyzed the risk factors for infections in Multiple Myeloma patients. The aim of this study was to analyze the risk factors infections within a population-based MM cohort. METHODS: Using Danish registries (from 2005 to 2013), we analyzed all ICD-10 codes for infections within the first 6 months of Multiple Myeloma diagnosis in 2557 patients. RESULTS: Pneumonia and sepsis represented 46% of infections. Multivariable regression analysis showed that risk factors for pneumonia were male gender (HR 1.4; P = 0.001), ISS II (HR 1.6; P = 0.0004) and ISSIII (HR 1.8; P = 0.0004) and elevated LDH (HR 2.6; P = 0.0008). Risk factors for sepsis were high bone marrow plasma cell % (HR 1.1; P = 0.038), ISS II (HR 1.7; P = 0.007) ISS III (HR 2.0; P = 0.002) and creatinine (HR 2.1; P = 0.002). Neither immunoparesis (hypogammaglobulinemia) nor comorbidity was significant risk factors. CONCLUSIONS: Our study suggests that tumor burden and renal impairment are risk factors for pneumonia and sepsis in the early phase of Multiple Myeloma. PMID- 30485564 TI - Organization and architecture of AggR-dependent promoters from Enteroaggregative Escherichia coli. AB - Enteroaggregative Escherichia coli (EAEC), is a diarrhoeagenic human pathogen commonly isolated from patients in both developing and industrialized countries. Pathogenic EAEC strains possess many virulence determinants, which are thought to be involved in causing disease, though, the exact mechanism by which EAEC causes diarrhoea is unclear. Typical EAEC strains possess the transcriptional regulator, AggR, which controls the expression of many virulence determinants, including the attachment adherence fimbriae (AAF) that are necessary for adherence to human gut epithelial cells. Here, using RNA-sequencing, we have investigated the AggR regulon from EAEC strain 042 and show that AggR regulates the transcription of genes on both the bacterial chromosome and the large virulence plasmid, pAA2. Due to the importance of fimbriae, we focused on the two AAF/II fimbrial gene clusters in EAEC 042 (afaB-aafCB and aafDA) and identified the promoter elements and AggR-binding sites required for fimbrial expression. In addition, we examined the organization of the fimbrial operon promoters from other important EAEC strains to understand the rules of AggR-dependent activation. Finally, we generated a series of semi-synthetic promoters to define the minimal sequence required for AggR-mediated activation and show that the correct positioning of a single AggR-binding site is sufficient to confer AggR-dependence. This article is protected by copyright. All rights reserved. PMID- 30485565 TI - Vrille is required for larval moulting and metamorphosis of Helicoverpa armigera (Lepidoptera: Noctuidae). AB - Vrille (Vri), a basic leucine zipper (bZIP) transcription factor, plays important roles in insect circadian clock regulation, tracheal development, proliferation, flight, and metamorphosis. Here, Helicoverpa armigera was used as a model to investigate the role of Vri in larval moulting and metamorphosis. Sequence analysis results revealed that Helicoverpa armigera Vri (HaVri) shares a high amino acid identity with other Lepidoptera Vri homologues. Spatial-temporal expression pattern data showed that HaVri expression was highly abundant in larval moulting and metamorphosis stages and was mainly expressed in the midgut and Malpighian tubule during metamorphosis. HaVri knockdown by RNA interference (RNAi) in the 4th-instar larvae prevented larval moulting, and HaVri knockdown in the 5th-instar larvae suppressed midgut remodelling and delayed or blocked metamorphosis. Further studies confirmed that 20-hydroxyecdysone (20E) activated HaVri expression via its heterodimer receptors, ecdysone receptor (EcRB1), and ultraspiracle protein (USP1), whereas methoprene (juvenile hormone analogue [JHA]) promoted HaVri expression via its intracellular receptor methoprene tolerant (Met1). However, 20E and JHA can counteract each other in the activation of HaVri expression. Together, the present results suggested that HaVri was involved in larval moulting and metamorphosis and was regulated by 20E and JHA in H. armigera. This article is protected by copyright. All rights reserved. PMID- 30485566 TI - Flexible Photodetector Arrays Based on Patterned CH3 NH3 PbI3- x Clx Perovskite Film for Real-Time Photosensing and Imaging. AB - The quest for novel deformable image sensors with outstanding optoelectronic properties and large-scale integration becomes a great impetus to exploit more advanced flexible photodetector (PD) arrays. Here, 10 * 10 flexible PD arrays with a resolution of 63.5 dpi are demonstrated based on as-prepared perovskite arrays for photosensing and imaging. Large-scale growth controllable CH3 NH3 PbI3 x Clx arrays are synthesized on a poly(ethylene terephthalate) substrate by using a two-step sequential deposition method with the developed Al2 O3 -assisted hydrophilic-hydrophobic surface treatment process. The flexible PD arrays with high detectivity (9.4 * 1011 Jones), large on/off current ratio (up to 1.2 * 103 ), and broad spectral response exhibit excellent electrical stability under large bending angle (theta = 150 degrees ) and superior folding endurance after hundreds of bending cycles. In addition, the device can execute the functions of capturing a real-time light trajectory and detecting a multipoint light distribution, indicating that it has widespread potential in photosensing and imaging for optical communication, digital display, and artificial electronic skin applications. PMID- 30485567 TI - A MoS2 /PTCDA Hybrid Heterojunction Synapse with Efficient Photoelectric Dual Modulation and Versatility. AB - Just as biological synapses provide basic functions for the nervous system, artificial synaptic devices serve as the fundamental building blocks of neuromorphic networks; thus, developing novel artificial synapses is essential for neuromorphic computing. By exploiting the band alignment between 2D inorganic and organic semiconductors, the first multi-functional synaptic transistor based on a molybdenum disulfide (MoS2 )/perylene-3,4,9,10-tetracarboxylic dianhydride (PTCDA) hybrid heterojunction, with remarkable short-term plasticity (STP) and long-term plasticity (LTP), is reported. Owing to the elaborate design of the energy band structure, both robust electrical and optical modulation are achieved through carriers transfer at the interface of the heterostructure, which is still a challenging task to this day. In electrical modulation, synaptic inhibition and excitation can be achieved simultaneously in the same device by gate voltage tuning. Notably, a minimum inhibition of 3% and maximum facilitation of 500% can be obtained by increasing the electrical number, and the response to different frequency signals indicates a dynamic filtering characteristic. It exhibits flexible tunability of both STP and LTP and synaptic weight changes of up to 60, far superior to previous work in optical modulation. The fully 2D MoS2 /PTCDA hybrid heterojunction artificial synapse opens up a whole new path for the urgent need for neuromorphic computation devices. PMID- 30485568 TI - Effects of L-citrulline supplementation on heat stress physiology, lactation performance and subsequent reproductive performance of sows in summer. AB - Lactating sows are susceptible to heat stress (HS). Part of the thermoregulatory response to HS is to increase peripheral blood flow, which is mediated in part by the vasodilator, nitric oxide (NO). Therefore, the aim of this experiment was to determine the effect of supplementation of L-citrulline, a NO precursor, on symptoms of HS, lactation performance and subsequent reproductive performance of sows in summer. A total of 221 summer farrowing mixed parity sows were fed either a control diet or supplemented with 1% L-citrulline upon entry to the farrowing house (6 +/- 1.8 days for mean +/- standard deviation [SD] before farrowing) until weaning (26 +/- 1.5 days). The average daily minimum and maximum temperature in the farrowing house was 21.0 +/- 1.88 and 29.2 +/- 3.82 degrees C (mean +/- SD). Rectal temperature, respiration rate, and plasma and urinary nitrite and nitrate (NOx) of sows were measured on the 19th day post-farrowing. Supplemental L-citrulline in the diet did not affect the number of piglets born alive, feed intake of sows, body weight or backfat thickness of sows at weaning, or litter weight gain. L-citrulline tended to reduce piglet pre-weaning mortality rate from 18.6% to 15.6% (p = 0.058). L-citrulline reduced the respiration rate of sows compared to the control diet at 17:00 hr (Time * Diet, p < 0.001); however, rectal temperature was not affected. L-citrulline tended to increase urinary NOx concentrations (127 vs. 224 uM, p = 0.057) but not plasma NOx concentrations. L-citrulline did not affect farrowing rate or number of piglets born alive in the subsequent parity. In conclusion, L-citrulline supplementation reduced respiration rate of lactating sows and reduced piglet pre-weaning mortality rate in summer. Whether the effects were due to a NO-dependent mechanism requires further validation. PMID- 30485569 TI - Matrix stiffness regulates arteriovenous differentiation of endothelial progenitor cells during vasculogenesis in nude mice. AB - OBJECTIVES: The aim of the study was to investigate the effect of matrix stiffness on arteriovenous differentiation of endothelial progenitor cells (EPCs) during vasculogenesis in nude mice. MATERIALS AND METHODS: Dextran hydrogels of differing stiffnesses were first prepared by controlling the crosslinking reaction to generate different thioether bonds. Hydrogels with stiffnesses matching those of the arterial extracellular matrix and venous extracellular matrix were separately combined with mouse bone marrow-derived EPCs and subcutaneously implanted on either side of the backs of nude mice. After 14 days, artery-specific marker Efnb2 and vein-specific marker Ephb4 in the neovasculature were detected to determine the effect of matrix stiffness on the arteriovenous differentiation of EPCs in vivo. RESULTS: Fourteen days after the implantation of the EPC-loaded dextran hydrogels, new blood vessels were observed in both types of hydrogels. We further verified that matrix stiffness regulated the arteriovenous differentiation of EPCs during vasculogenesis via the Ras/Mek pathway. CONCLUSIONS: Matrix stiffness regulates the arteriovenous differentiation of EPCs during vasculogenesis in nude mice through the Ras/Mek pathway. PMID- 30485570 TI - MiR-326/Sp1/KLF3: A novel regulatory axis in lung cancer progression. AB - OBJECTIVES: To investigate the function and regulatory mechanism of Kruppel-like factor 3 (KLF3) in lung cancer. MATERIALS AND METHODS: KLF3 expression was analysed by qRT-PCR and Western blot assays. The proliferation, migration, invasion, cycle and apoptosis were measured by CCK-8 and EdU, wound-healing and Transwell, and flow cytometry assays. The tumour growth was detected by nude mouse tumorigenesis assay. In addition, the interaction between KLF3 and Sp1 was accessed by luciferase reporter, EMSA and ChIP assay. JAK2, STAT3, PI3K and p-AKT levels were evaluated by Western blot and IHC assays. RESULTS: The results indicated that KLF3 expression was elevated in lung cancer tissues. Knockdown of KLF3 inhibited lung cancer cell proliferation, migration and invasion, and induced cell cycle arrest and apoptosis. In addition, the downregulation of KLF3 suppressed tumour growth in vivo. KLF3 was transcriptionally activated by Sp1. miR-326 could bind to 3'UTR of Sp1 but not KLF3 and decreased the accumulation of Sp1, which further indirectly reduced KLF3 expression and inactivated JAK2/STAT3 and PI3K/AKT signaling pathways in vitro and in vivo. CONCLUSIONS: Our data demonstrate that miR-326/Sp1/KLF3 regulatory axis is involved in the development of lung cancer, which hints the potential target for the further therapeutic strategy against lung cancer. PMID- 30485571 TI - Prolonged depression of knee-extensor torque complexity following eccentric exercise. AB - NEW FINDINGS: What is the central question of this study? Does eccentric exercise leading to prolonged knee-extensor torque depression also result in a prolonged loss of knee-extensor torque complexity? What is the main finding and its importance? The recovery of the loss of torque complexity after eccentric exercise took 24 h, whereas after acute muscle fatigue it took 10 min. The depression of torque complexity after eccentric exercise was prolonged. ABSTRACT: Neuromuscular fatigue reduces the temporal structure, or complexity, of muscle torque output. Exercise-induced muscle damage reduces muscle torque output for considerably longer than high-intensity fatiguing contractions. We hypothesized that muscle-damaging eccentric exercise would lead to a persistent decrease in torque complexity, whereas fatiguing exercise would not. Ten healthy participants performed five isometric contractions (6 s contraction, 4 s rest) at 50% maximal voluntary contraction (MVC) before, immediately after and 10, 30 and 60 min and 24 h after eccentric (muscle-damaging) and isometric (fatiguing) exercise. These contractions were also repeated 48 h and 1 week after eccentric exercise. Torque and surface EMG signals were sampled throughout each test. Complexity and fractal scaling were quantified using approximate entropy (ApEn) and the detrended fluctuation analysis alpha exponent (DFA alpha). Global, central and peripheral perturbations were quantified using MVCs with femoral nerve stimulation. Complexity decreased after both eccentric [ApEn, mean (SD), from 0.39 (0.10) to 0.20 (0.12), P < 0.001] and isometric exercise [from 0.41 (0.13) to 0.09 (0.04); P < 0.001]. After eccentric exercise, ApEn and DFA alpha required 24 h to recover to baseline levels, but after isometric exercise they required only 10 min. The MVC torque remained reduced [from 233.6 (74.2) to 187.5 (64.7) N m] 48 h after eccentric exercise, with such changes evident only up to 60 min after isometric exercise [MVC torque, from 246.1 (77.2) to 217.9 (71.8) N m]. The prolonged depression in maximal muscle torque output is therefore accompanied by a prolonged reduction in torque complexity. PMID- 30485572 TI - Brain Atrophy in Natalizumab-treated Patients with Multiple Sclerosis: A 5-year Retrospective Study. AB - BACKGROUND AND PURPOSE: Studies demonstrated a higher brain volume loss in the first year after initiation of natalizumab treatment than in the second year, but the experiences beyond 24 months are scarce until now. We investigated the evolution of brain volume changes in multiple sclerosis (MS) patients receiving natalizumab for at least 60 months. METHODS: Using annual 3-dimensional magnetization-prepared rapid acquisition gradient-echo (MPRAGE) sequences acquired on a 3 Tesla magnetic resonance imaging (MRI), we investigated percentage brain volume changes (PBVCs) in 10 MS patients (9 women, mean age at baseline MRI = 29 +/- 9 years; median Expanded Disability Status Scale = 2 +/- 1.5; mean disease duration = 6 +/- 5 years) after 12, 24, 36, 48, and 60 months. RESULTS: PBVCs were statistically higher during the first 12 months (-1.48 +/- 1.05%) when compared to 12-24 months (-.6 +/- .61%; P < .05), but not between 12 24 and 24-36 months (-.43 +/- .54%), 24-36 and 36-48 months (-.28 +/- .49%), and 36-48 and 48-60 months (-.33 +/- .49%; P > .05 for all comparisons). CONCLUSION: Our results contribute to the increasing knowledge of PBVCs in natalizumab treated MS patients. Our data suggests that after a significant PBVC decrease in the first year, brain atrophy rates show a slowdown during long-term follow-up. PMID- 30485573 TI - Performance and intestinal microbiota of chickens receiving probiotic in the feed and submitted to antibiotic therapy. AB - The purpose of this study was to verify the ability of a probiotic in the feed to maintain the stability of the gut microbiota in chickens after antibiotic therapy and its association with growth performance. One thousand six hundred twenty 1 day-old Cobb male were housed in floor pens (36 pens, 45 birds/pen) and were fed corn-/soya bean meal-based diets supplemented with or without probiotic (Bacillus subtilis) during the entire rearing phase. From 21 to 24 days of age (three consecutive days), the chickens were submitted to antibiotic therapy via drinking water (bacitracin and neomycin) in order to mimic a field treatment and induce dysbiosis. Growth performance was monitored until 42 days of age. At 2, 4 and 6 days after antibiotic therapy, three chickens from each pen were euthanized and the contents of the small intestine and caeca were collected and pooled. The trial was conducted with four treatments and nine replicates in a 2 * 2 factorial arrangement for performance characteristics (with and without probiotic * with and without antibiotic therapy); for the intestinal microbiota, it was in a 2 * 2 * 3 factorial arrangement (with and without probiotic * with and without antibiotic therapy * 2, 4 and 6 days after the antibiotic therapy) with three replicates per treatment. Terminal restriction length polymorphism (T-RFLP) analysis showed that the structure of gut bacterial community was shaped by the intestinal segment and by the time after the antibiotic therapy. The number of 16S rDNAs copies in caecum contents decreased with time after the therapeutic treatment. The antibiotic therapy and dietary probiotic supplementation decreased richness and diversity indexes in the caecal contents. The improved performance observed in birds supplemented with probiotic may be related to changes promoted by the feed additive in the structure of the intestinal bacterial communities and phylogenetic groups. Antibiotic therapy modified the bacterial structure, but did not cause loss of broiler performance. PMID- 30485574 TI - CSE1L participates in regulating cell mitosis in human seminoma. AB - OBJECTIVES: CSE1L has been reported to be highly expressed in various tumours. Testicular germ cell tumours are common among young males, and seminoma is the major type. However, whether CSE1L has functions in the seminoma is unclear. MATERIALS AND METHODS: The expression of CSE1L was detected by immunohistochemistry in seminoma tissues and non-tumour normal testis tissues from patients. CSE1L distribution during cell mitosis was determined by immunofluorescent staining with CSE1L, alpha-tubulin and gamma-tubulin antibodies. The effects of Cse1L knockdown on cell proliferation and cell cycle progression were determined by Cell Counting Kit-8 assay, flow cytometry, PH3 staining and bromodeoxyuridine incorporation assay. RESULTS: CSE1L was significantly enriched in the seminoma tissue compared with the non-tumour normal testis tissue. CSE1L also co-localized with alpha-tubulin in the cells with a potential to divide. In the seminoma cell line TCam-2, CSE1L was associated with the spindles and the centrosomes during cell division. The knockdown of CSE1L in TCam-2 cells attenuated the cells' proliferative capacity. Cell cycle assay revealed that the CSE1L-deficient cells were mainly arrested in the G0/G1 phase and moderately delayed in the G2/M phase. The proportion of cells with multipolar spindle and abnormal spindle geometry was obviously increased by CSE1L expression silencing in the TCam-2 cells. CONCLUSIONS: Overall, these findings showed that CSE1L plays a pivotal role in maintaining cell proliferation and cell division in seminomas. PMID- 30485575 TI - Subjectively-defined optimal/non-optimal time of day modulates controlled but not automatic retrieval processes in verbal memory. AB - Performance for controlled, resource-demanding retrieval in episodic memory has been consistently found to be better at an optimal compared with non-optimal time of the day, evidencing a synchrony effect. However, performance in memory tasks in which retrieval is mostly based on automatic processes was inconclusively found either to be better at a non-optimal time of day or independent of synchrony effects. A caveat in most prior studies is that optimal/non-optimal time of day is based on morningness-eveningness composite scores derived from chronotype questionnaires, which might not efficiently predict subjectively defined cognitive efficiency periods. An additional caveat is that separate tasks are used to assess explicit and implicit retrieval in verbal memory. Indeed, no task is process-pure, and both controlled and automatic retrieval processes may potentially contribute to retrieval scores in different types of memory tasks. In the present study, we investigated the impact of individually defined subjective optimal/non-optimal time of day on verbal memory retrieval, using an adaptation of the Process-Dissociation Procedure that allows estimating the respective contributions of automatic and controlled memory retrieval processes within the same memory task. Our results disclose a higher involvement of controlled processes at subjectively optimal compared with non-optimal time of day, but no differences for automatic processes. Synchrony effects and subjectively-defined peaks and troughs of performance for controlled components of memory retrieval should be considered in the evaluation of episodic memory. PMID- 30485576 TI - Authors' reply to the letter-to the-editor by Sabour. AB - We appreciate the response to our article (Foxen-Craft et al., 2018) by Pordanjani, Iranpour, & Sabour for opening the discussion about use of statistical techniques in psychometric validation. Overall, the authors' critiques regarding the limits of the kappa statistic are fair, but there is also justification for its use in this study. This article is protected by copyright. All rights reserved. PMID- 30485577 TI - Behavioural Mechanisms of Sexual Isolation Involving Multiple Modalities and Their Inheritance. AB - Speciation research dissects the genetics and evolution of reproductive barriers between parental species. Hybrids are the 'gatekeepers' of gene flow, so it is also important to understand the behavioural mechanisms and genetics of any potential isolation from their parental species. We tested the role of multiple behavioural barriers in reproductive isolation among closely related field crickets and their hybrids (Teleogryllus oceanicus and T. commodus). These species hybridise in the laboratory, but the behaviour of hybrids is unusual and there is little evidence for gene flow in the wild. We found that heterospecific pairs exhibited reduced rates of courtship behaviour due to discrimination by both sexes, and that this behavioural isolation was symmetrical. However, hybrids were not sexually selected against and exhibited high rates of courtship behaviour even though hybrid females are sterile. Using reciprocal hybrid crosses, we characterized patterns of interspecific divergence and inheritance in key sexual traits that might underlie the mating patterns we found: calling song, courtship song and cuticular hydrocarbons (CHCs). Song traits exhibited both sex linkage and transgressive segregation, whereas CHCs exhibited only the latter. Calculations of the strength of isolation exerted by these sexual traits suggest that close-range signals are as important as long-distance signals in contributing to interspecific sexual isolation. The surprisingly weak mating barriers observed between hybrids and parental species highlights the need to examine reproductive isolating mechanisms and their genetic bases across different potential stages of introgressive hybridisation. This article is protected by copyright. All rights reserved. PMID- 30485578 TI - Genotype-phenotype correlations in focal malformations of cortical development: a pathway to integrated pathological diagnosis in epilepsy surgery. AB - Malformations of cortical development (MCD) comprise a broad spectrum of developmental brain abnormalities. Patients presenting with MCDs often suffer from drug resistant focal epilepsy, and some become candidates for epilepsy surgery. Their likelihood of achieving freedom from seizures, however, remains uncertain, and depends in a major part on the underlying pathology. Tissue samples obtained in epilepsy surgery form the basis of definite histopathological diagnosis; however, new molecular-genetic methods have not yet been implemented in diagnostic process for MCD cases. Furthermore, it has not been completely understood how the underlying pathology affects patients' outcomes in epilepsy surgery. We performed a systematic literature review of studies describing both histopathological and molecular genetic findings in MCD, along with studies on epilepsy surgery outcomes. We aimed to correlate the genetic causes with the underlying morphological abnormalities in focal cortical malformations and to stress the importance of underlying biology for patient management and counselling. From the summarized findings of multiple authors, it is obvious that MCD may have a diverse genetic background despite similar or even identical histopathological picture. Even though most of their molecular genetic findings converge on various levels of the PI3K/AKT/mTOR pathway, the exact mechanisms underlying MCD formation have not yet been completely described or indeed how this pathway generates a diverse range of histological abnormalities. Based on our findings, we therefore propose that all patients diagnosed and operated for drug resistant epilepsy should have an integrated molecular and pathological diagnosis similar to the current practice in brain tumour diagnostic processthat might lead to more accurate diagnosis and effective stratification of patients undergoing epilepsy surgery. This article is protected by copyright. All rights reserved. PMID- 30485579 TI - Embodying compassion; a systematic review of the views of nurses and patients. AB - AIM: To provide a review of empirical research investigating how compassion is expressed by nurses and received by patients in hospital settings. BACKGROUND: Compassion is viewed as an important and fundamental part of a health professional practice. Universally, reports from both media and government agencies have addressed perceived deficits of compassion in healthcare with nurses accused of a lack of compassion. Research into compassion to date has largely focused on the problematic nature of compassion such as burnout, fatigue and other negative personal and work-related outcomes. DESIGN: A systematic literature review of empirical research guided by a meta-ethnographic approach supported the systematic comparison and translation of the included studies. Six online databases were searched from January 2006 to December 2016. METHODS: This review was carried out according to the PRISMA- P reporting guidelines. How compassion in healthcare was defined was extracted alongside findings on how compassion was expressed by nurses and received by patients. Synthesis of the research was completed resulting in new interpretations. RESULTS: Eleven papers met the inclusion criteria and were included in the review. Multiple differing definitions of compassion in healthcare were applied. Nurses embody and enact compassion through behaviours such as spending time with patients and communicating effectively with patients. Patients experience compassion through a sense of togetherness with nurses. CONCLUSION: Existing research demonstrated dissonance between the expression of compassion by nurses and how compassion is experienced by patients. The themes identified in this review should be considered by health professionals providing patient care. RELEVANCE TO CLINICAL PRACTICE: Health providers should acknowledge and account for the time that nurses need with patients to demonstrate compassion in practice. Nursing education relating to the expression of compassion should articulate both the subjectivity and ambiguity of the term and examine the relationship between compassion and suffering. This article is protected by copyright. All rights reserved. PMID- 30485580 TI - pH and Thermo Dual-Responsive Fluorescent Hydrogel Actuator. AB - As one of the most important smart materials, fluorescent hydrogel actuators can produce both color and shape changes under external stimuli. In the present work, an effective approach to develop a novel fluorescent hydrogel actuator with pH and thermo dual responsiveness is proposed. Through incorporating pH-responsive perylene tetracarboxylic acid (PTCA), which is a typical fluorescent moiety with aggregation-caused quenching (ACQ) effect, into an anisotropic poly(N isopropylacrylamide)-polyacrylamide (PNIPAm-PAAm) structure, the obtained hydrogel exhibits stable thermoresponsive shape deformation and switchable fluorescence performance upon a pH trigger. Therefore, fluorescence-quenching based and actuation-based information can be revealed when exposed to UV light and immersed into warm water, respectively. Moreover, the thermoresponsive actuating behavior can be applied to further hide the fluorescence-quenching based images. The present work may provide new insights into the design and preparation of novel stimuli-responsive hydrogel actuators. PMID- 30485582 TI - Extravascular fibrinogen in the white matter of Alzheimer's disease and normal aged brains: implications for fibrinogen as a biomarker for Alzheimer's disease. AB - The blood-brain barrier (BBB) regulates cerebrovascular permeability and leakage of blood-derived fibrinogen has been associated with cerebral arteriolosclerosis small vessel disease (SVD) and subsequent white matter lesions (WML). Furthermore, BBB-dysfunction is associated with the pathogenesis of Alzheimer's disease (AD) with the presence of CSF plasma proteins suggested to be a potential biomarker of AD. We aimed to determine if extravascular fibrinogen in the white matter was associated with the development of AD hallmark pathologies, i.e., hyperphosphorylated tau (HPtau) and amyloid-beta (Abeta), SVD, cerebral amyloid angiopathy (CAA) and measures of white matter damage. Using human post-mortem brains, parietal tissue from 20 AD and 22 non-demented controls was quantitatively assessed for HPtau, Abeta, white matter damage severity, axonal density, demyelination and the burden of extravascular fibrinogen in both WML and normal appearing white matter (NAWM). SVD severity was determined by calculating sclerotic indices. WML- and NAWM fibrinogen burden was not significantly different between AD and controls nor was it associated with the burden of HPtau or Abeta pathology, or any measures of white matter damage. Increasing severity of SVD was associated with and a predictor (both p < 0.05) of both higher WML- and NAWM fibrinogen burden (both P<0.05) in controls only. In cases with minimal SVD NAWM fibrinogen burden was significantly higher in the AD cases (p<0.05). BBB dysfunction was present in both non-demented and AD brains and was not associated with the burden of AD-associated cortical pathologies. BBB dysfunction was strongly associated with SVD but only in the non-demented controls. In cases with minimal SVD, BBB dysfunction was significantly worse in AD cases possibly indicating the influence of CAA. In conclusions, extravascular fibrinogen is not associated with AD hallmark pathologies but indicates SVD, suggesting that the presence of fibrinogen in the CSF is not a surrogate marker for AD pathology. This article is protected by copyright. All rights reserved. PMID- 30485581 TI - FOXM1c promotes oesophageal cancer metastasis by transcriptionally regulating IRF1 expression. AB - OBJECTIVES: We aimed to elucidate the role and molecular mechanisms of FOXM1 in regulating metastasis in oesophageal squamous cell carcinoma (ESCC) as well as its clinical implications. MATERIALS AND METHODS: The expression levels of four isoforms of FOXM1 were analysed by real-time PCR. Next, genetically modification using overexpression and RNAi systems and transwell were employed to examine FOXM1c function in invasion and migration. Dual luciferase and ChIP assays were performed to decipher the underlying mechanism for transcriptional regulation. The expression levels of FOXM1 and IRF1 were determined by immunohistochemistry staining in ESCC specimens. RESULTS: The FOXM1c was predominantly overexpressed in ESCC cell lines compared to the other FOXM1 isoforms. Ectopic expression of FOXM1c promoted invasion and migration of ESCC cells lines, whereas downregulation of FOXM1c inhibited these processes. Moreover, FOXM1c expression was positively correlated with IRF1 expression in ESCC cell lines and tumour specimens. IRF1 is, at least in part, responsible for FOXM1c-mediated invasion and migration. Mechanistically, we identified IRF1 as a transcriptional target of FOXM1c and found a FOXM1c-binding site in the IRF1 promoter region. Furthermore, high expression levels of both FOXM1c and IRF1 were positively associated with low survival rate and predicted a poor prognosis of oesophageal cancer patients. CONCLUSION: FOXM1c promotes the metastasis by transcriptionally targeting IRF1 and may serve as a potential prognostic predictor for oesophageal cancer. PMID- 30485585 TI - Addiction endorses the Open Science badge scheme. PMID- 30485583 TI - TAFA2 induces skeletal (stromal) stem cell migration through activation of Rac1 p38 signaling. AB - Understanding the mechanisms regulating recruitment of human skeletal (stromal or mesenchymal) stem cells (hMSC) to sites of tissue injury is a prerequisite for their successful use in cell replacement therapy. Chemokine-like protein TAFA2 is a recently discovered neurokine involved in neuronal cell migration and neurite outgrowth. Here, we demonstrate a possible role for TAFA2 in regulating recruitment of hMSC to bone fracture sites. TAFA2 increased the in vitro trans well migration and motility of hMSC in a dose-dependent fashion and induced significant morphological changes including formation of lamellipodia as revealed by high content image analysis at single cell level. Mechanistic studies revealed that TAFA2 enhanced hMSC migration through activation of the Rac1-p38 pathway. In addition, TAFA2 enhanced hMSC proliferation, whereas differentiation of hMSC toward osteoblast and adipocyte lineages was not altered. In vivo studies demonstrated transient upregulation of TAFA2 gene expression during the inflammatory phase of fracture healing in a closed femoral fracture model in mice and a similar pattern was observed in serum levels of TAFA2 in patients following hip fracture. Finally, IL-1beta was found as an upstream regulator of TAFA2 expression. Our findings demonstrate that TAFA2 enhances hMSC migration and recruitment and thus is relevant for regenerative medicine applications. (c) AlphaMed Press 2018. PMID- 30485584 TI - Multimorbidity and lifestyle factors among adults with intellectual disabilities: a cross-sectional analysis of a UK cohort. AB - BACKGROUND: Multimorbidity [two or more conditions in addition to intellectual disability (ID)] is known to be more common among people with ID. However, the relationship between multimorbidity and lifestyle factors is currently unknown. The aim of this study was to determine the prevalence of multimorbidity in a population of adults with ID. We also aimed to identify risk factors, including lifestyle factors, for multimorbidity in this population. METHODS: This was a cross-sectional analysis using data from a diabetes screening study of 920 adults aged 18-74 years with ID living in Leicestershire, UK. We described comorbidities and the prevalence of multimorbidity in this population. We explored the relationship between multimorbidity and age, gender, ethnicity, severity of ID, socio-economic status, physical activity, sedentary behaviour, fruit and vegetable consumption and smoking status using multiple logistic regression. RESULTS: The prevalence of multimorbidity was 61.2% (95% CI 57.7-64.7). Multimorbidity was independently associated with being female (P < 0.001) and severe/profound ID (P = 0.004). Increasing age was of borderline significance (P = 0.06). Individuals who were physically inactive or sedentary were more likely to be multimorbid, independent of ability to walk, age, gender, severity of ID, ethnicity and socio-economic status (adjusted OR = 1.91; 95% CI 1.23-2.97; P = 0.004 and OR = 1.98; 95% CI 1.42-2.77; P < 0.001). After excluding probable life long conditions (autism spectrum conditions, attention deficit hyperactivity disorders, epilepsy, cerebral palsy and other paralytic syndromes) as contributing comorbidities, the effect of sedentary behaviour, but not physical activity, remained (P = 0.004). We did not observe a relationship between multimorbidity, fruit and vegetable consumption and smoking status. CONCLUSIONS: Multimorbidity presents a significant burden to people with ID. Individuals who were physically inactive or sedentary were more likely to be multimorbid, but further work is recommended to explore the relationship between multimorbidity and lifestyle factors using standardised objective measures. PMID- 30485586 TI - Robin S. Waples - Recipient of the 2018 Molecular Ecology Prize. AB - Most of us can probably point to one or two individuals who have had a crucial influence on our career development and chosen field of study. For me, one of those instrumental individuals is Robin Waples. I met Robin in 1991 when I was a graduate student at the University of Oregon. Two of my UO mentors, Michael Lynch and Russell Lande, had encouraged me to contact him as I began seeking employment in quantitative conservation biology. This article is protected by copyright. All rights reserved. PMID- 30485587 TI - Development and validation of instrument to measure stress among older adult nursing students: The Student Nurse Stressor-15 Scale (SNS-15). AB - AIMS AND OBJECTIVES: This paper reports the development, testing and validation of an instrument to assess the stressors experienced by student nurses during their older adult clinical placements. BACKGROUND: The world's population of older adults is accelerating rapidly, with associated increased health care demands and a growing need for skilled nursing staff. However, this sector fails to attract adequate numbers of nursing graduates which is leading to a significant gap between nursing supply and demand. Older adult care is considered to be less attractive than other specialties and accompanied by more sources of stress. DESIGN: A QUANTITATIVE DESIGN WAS USED: METHODS: Data was collected from a cohort of Irish student nurses (n=242) completing older adult clinical placements as part of their undergraduate degree. Exploratory and confirmatory factor analysis examined the instrument's underlying latent structure. Discriminant validity was investigated using a confirmatory factor analysis model with covariates. STROBE guidelines for cross-sectional studies informed reporting of this paper's research. RESULTS: Factor analyses identified two factors relating to 'Knowledge and Workload' and 'Resources', which were assessed by nine and six items respectively. Discriminant validity analyses found a significant relationship between age and the workload and knowledge factor, and between year of programme and the resources factor. The new instrument was labelled the Student Nurse Stressor-15 Scale (SNS-15). CONCLUSIONS: The SNS-15 contained some overlap with stressors from extant general student nurse stress instruments and a number of unique stressors encountered in older adult care. Future research directions are discussed. RELEVANCE TO CLINICAL PRACTICE: The SNS-15 may assist stakeholders in nurse education and practice with the development of undergraduate degree programmes and clinical placements, and ultimately, in improving patient care and student retention. This article is protected by copyright. All rights reserved. PMID- 30485588 TI - The species dilemma and its potential impact on enforcing wildlife trade laws. AB - The varied answers to the question "What is a species?" provoke more than lively debates in academic circles. They pose practical problems for law enforcement. Commercial wildlife trade threatens many primate species and is regulated through such laws and international agreements as the U.S. Endangered Species Act and the Convention on International Trade in Endangered Species of Wild Fauna and Flora. Enforcing legislation relies on the ability to identify when violations occur. Species-defining characters may not be preserved in wildlife trade items. For example, pelage patterns and behavioral characters (e.g., vocalizations) are absent from skulls. Accordingly, identifying victims of illegal trade can be difficult, which hinders enforcement. Moreover, identifying new species and "splitting" of currently recognized species can result in enforcement lags and regulatory loopholes. Although such negative consequences should not hinder scientific advancement, we suggest that they be considered by primate taxonomists and provide recommendations to prevent unintended conservation consequences. PMID- 30485589 TI - Upregulated miR-193a-3p is responsible for cisplatin resistance in CD44(+) gastric cancer cells. AB - Cisplatin is a well-known anticancer drug used to treat various cancers. However, development of cisplatin resistance has hindered the efficiency of this drug in cancer treatment. The development of chemoresistance is known to involve many signaling pathways. Recent attention has focused on microRNAs as potentially important upstream regulators in the development of chemoresistance. CD44 is one of the gastric cancer stem cell markers and play a role in regulating self renewal, tumor initiation, metastasis and chemoresistance. The purpose of this study was to examine the mechanism of microRNA mediated chemoresistance to cisplatin in CD44 positive gastric cancer stem cells. We sorted gastric cancer cells according to level of CD44 expression by fluorescence-activated cell sorting (FACS) and analyzed their miRNA expression profiles by microarray analysis. We found that miR-193a-3p was significantly upregulated in CD44(+) cells compared with CD44(-) cells. Moreover, SRSF2 of miR-193a-3p target gene was downregulated in CD44(+) cells. We studied the modulation of Bcl-X and caspase 9 mRNA splicing by SRSF2 and found that more pro-apoptotic variants of these genes were generated. We also found that downstream anti-apoptotic gene such as Bcl-2 was upregulated, whereas pro-apoptotic genes such as Bax and cytochrome C were downregulated in CD44(+) cells compared to CD44(-) cells. In addition, we found that an elevated level of miR-193a-3p triggered the development of cisplatin resistance in CD44(+) cells. Inhibition of miR-193a-3p in CD44(+) cells increased SRSF2 expression and also altered the levels of multiple apoptotic genes. Furthermore, inhibition of miR-193a-3p reduced cell viability and increased the number of apoptotic cells. Therefore, miR-193a-3p may be implicated in the development of cisplatin resistance through regulation of the mitochondrial apoptosis pathway. miR-193a-3p could be a promising target for cancer therapy in cisplatin-resistant gastric cancer. This article is protected by copyright. All rights reserved. PMID- 30485590 TI - Experiences and healthcare preferences of women with ovarian cancer during the diagnosis phase. AB - OBJECTIVE: An ovarian cancer diagnosis presents physical and psychological challenges. Usually identified at an advanced stage, the disease involves invasive treatment and has a high mortality rate. The diagnosis phase is generally a time of heightened distress. Accordingly, the aim of this qualitative study was to explore the healthcare experiences and preferences of women with ovarian cancer during this phase, and identify opportunities to enhance women's experiences and outcomes. METHODS: Thirty-four women diagnosed with ovarian cancer were recruited from across Australia (Median age = 60.5 years, range = 31 74 years). Semi-structured interviews explored participants' experience of healthcare services and preferences during the diagnosis phase. Thematic analysis of interview transcripts followed. RESULTS: Five themes were identified including 'navigating uncertainty' which summarized women's general experiences throughout the diagnosis phase and provided a context for concomitant healthcare preferences. Four other themes highlighted significant areas where healthcare may be better aligned with women's preferences. These included 'responsiveness in healthcare', 'relational communication', 'person-centered information', and 'preparation for living beyond cancer treatment'. CONCLUSIONS: Responsive and prompt healthcare services that employ relational communication, provide patient centered information and prepare women for survivorship could improve the healthcare experiences of women diagnosed with ovarian cancer. PMID- 30485591 TI - Cardiac contractility modulation: mechanisms of action in heart failure with reduced ejection fraction and beyond. AB - Heart failure (HF) is responsible for substantial morbidity and mortality and is increasing in prevalence. Although there has been remarkable progress in the treatment of HF with reduced ejection fraction (HFrEF), morbidity and mortality are still substantial. Cardiac contractility modulation (CCM) signals, consisting of biphasic high-voltage bipolar signals delivered to the right ventricular septum during the absolute refractory period, have been shown to improve symptoms, exercise tolerance and quality of life and reduce the rate of HF hospitalizations in patients with ejection fractions (EF) between 25% and 45%. CCM therapy is currently approved in the European Union, China, India, Australia and Brazil for use in symptomatic HFrEF patients with normal or slightly prolonged QRS duration. CCM is particularly beneficial in patients with baseline EF between 35% and 45%, which includes half the range of HF patients with mid range EFs (HFmrEF). At the cellular level, CCM has been shown in HFrEF patients to improve calcium handling, to reverse the foetal myocyte gene programme associated with HF, and to facilitate reverse remodelling. This review highlights the preclinical and clinical literature related to CCM in HFrEF and HFmrEF and outlines the potential of CCM for HF with preserved EF, concluding that CCM may fill an important unmet need in the therapeutic approach to HF across the range of EFs. PMID- 30485592 TI - Book Review: Molecular Population Genetics. Matthew Hahn. AB - Rapid progress in the field of population genetics, in particular advances in DNA sequencing technology, calls for an up-to-speed textbook that is appropriate for current researchers and students. Molecular Population Genetics, by Matthew Hahn (2018), is an informative and entertaining text that attempts to satisfy this demand. Although it has notable shortcomings and does not replace current texts for undergraduate courses, this book is a worthwhile resource for almost any researcher analyzing population genetic data and is a must-have for graduate student reading lists. This article is protected by copyright. All rights reserved. PMID- 30485593 TI - Potential limits to the benefits of admixture during biological invasion. AB - Species introductions often bring together genetically divergent source populations, resulting in genetic admixture. This geographic reshuffling of diversity has the potential to generate favorable new genetic combinations, facilitating the establishment and invasive spread of introduced populations. Observational support for the superior performance of admixed introductions has been mixed, however, and the broad importance of admixture to invasion questioned. Under most underlying mechanisms, admixture's benefits should be expected to increase with greater divergence among and lower genetic diversity within source populations, though these effects have not been quantified in invaders. We experimentally crossed source populations differing in divergence in the invasive plant Centaurea solstitialis. Crosses resulted in many positive (heterotic) interactions, but fitness benefits declined and were ultimately negative at high source divergence, with patterns suggesting cyto-nuclear epistasis. We explored the literature to assess whether such negative epistatic interactions might be impeding admixture at high source population divergence. Admixed introductions reported for plants came from sources with a wide range of genetic variation, but were disproportionately absent where there was high genetic divergence among native populations. We conclude that while admixture is common in species introductions and often happens under conditions expected to be beneficial to invaders, these conditions may be constrained by predictable negative genetic interactions, potentially explaining conflicting evidence for admixture's benefits to invasion. This article is protected by copyright. All rights reserved. PMID- 30485594 TI - Autophagy induction and antiproliferative effect of a novel curcumin derivative MOMI-1 on the human lung cancer cells A549. AB - To date, there are some chemically synthesized curcumin derivatives which were produced and identified to evade the disadvantages of physiochemical stability and solubility of curcumin. Here, one novel curcumin derivative, (2-(3-{(1E)-{(E) 3-(4-hydroxy-3-methoxybenzylidene)-2-oxocyclohexylidene)methyl)-1H-indol-1 yl)acetic acid}, (abbreviated as MOMI-1) was first used to detect the antiproliferation activity with MTT assays in different cancer cells including A549 lung cancer cells, MCF-7, and HEPG2 cell lines, and exhibited its wide inhibition spectrum. Next, we found that MOMI-1 could induce autophagic genesis of A549 cells by acridine orange or monodansylcadaverine (MDC) staining and green fluorescent protein-light chain 3 (GFP-LC3) recombinant plasmid transfection analysis, respectively. Western blot analysis confirmed the LC3-I/II conversion, beclin-1 increase and p62 reduction of A549 cells after exposure of MOMI-1, which suggested the typical autophagy induction. The following cell cycle test showed that MOMI-1 could block A549 cells in G0/G1 phase. Furthermore, wounding healing experiment and transwell assays demonstrated that MOMI-1 also possessed the antimigration ability of A549 cells. Our current results confirmed that MOMI-1 could inhibit the proliferation and induce autophagy of A549 cells, which provide a new potential chemical candidate of antigrowth of A549 lung cancer cells. Future work needs to focus on the mechanism of autophagy pathway of A549 cells. PMID- 30485595 TI - Clinical and research implications of serum versus plasma potassium measurements. PMID- 30485596 TI - Loneliness as a mediator in the relationship between social engagement and depressive symptoms: Age differences among community-dwelling Korean adults. AB - The purpose of this study was to examine whether loneliness mediates the relationship between social engagement and depressive symptoms and to determine how age moderates the mediation effect. Data for this study came from the survey with community-dwelling adults aged 18 and older in South Korea, from March to April 2017. The total of 1,017 respondents were drawn from three age groups (18 44, 45-64, or 65 and older). The mediating effect of loneliness was tested between each of three social engagement-related variables (family network, friend network, and perceived community support) and depressive symptoms. The results showed age differences in mediation: the effect was most pronounced in the relationship of family network with loneliness for the older group, whereas the size of friend network significantly predicted loneliness for younger adults. Both younger and older groups felt less lonely when they had a higher level of perceived community support; the middle age group remained uninfluenced by the mediation effects. Our findings confirm that loneliness is one of the mechanisms by which social engagement exerts its effect on depressive symptoms. As the Korean society embraces its growing proportions of older adults, the results of the study provide implications for adaptive strategies for changing social engagement need and mental health associated with ageing. PMID- 30485597 TI - Population ageing in a globalized world: Risks and dilemmas? AB - RATIONALE, AIMS, AND OBJECTIVES: This article aims to examine global population ageing and to evaluate the likely risks and dilemmas of demographic ageing within the context of the health and well-being of individuals. METHODS: This paper is based on the author's research in the field of social gerontology, demography, and public health. In addition, a literature review has been carried out focused on the objectives of the research. RESULTS: The study has identified potential risks and dilemmas that the older people may face in the globalized world. There are four main aspects that contribute to an unequal distribution of risks in later life: (a) burden of disease in epidemiological transition, (b) financial security in retirement, (c) familial resources for older peoples' care, and (d) availability of workforce for older peoples' care. Whilst population ageing is a global trend, its impact is not equal across the world, and this is highlighted in this research. There are some important dilemmas which are identified in this paper that may also fuel the potential risks and challenges facing ageing societies. CONCLUSIONS: It is apparent that older people will face numerous risks in later life and those in developing countries are likely to face more challenges than those in developed countries. The findings may be useful to policymakers for formulating future plans and policy implementation. Further research is required to identify the number of health care workers needed to tackle the challenges of an ageing societies across the globe. PMID- 30485598 TI - Benefit finding in renal transplantation and its association with psychological and clinical correlates: A prospective study. AB - OBJECTIVES: The identification of positive psychological changes, including benefit finding (BF), in chronic illness has gained substantial interest. However, less is known about BF in the context of a positive medical intervention. End-stage renal disease (ESRD) can be regarded as a burdensome condition, but transplantation is expected to restore physical and psychological functioning to a large extent after a period of illness. The aim of this study was to examine (1) changes in BF from pre- to 12 months post-transplantation, (2) the concurrent association of disease-related characteristics and optimism to BF, and (3) the potential causal relations between BF and distress. METHODS: In this longitudinal study, 319 patients completed questionnaires before, 3 months, 6 months, and/or 12 months post-transplantation. Multilevel models were used for the analyses. Measures included the Illness Cognitions Questionnaire to measure BF, the Life Orientation Test to measure optimism, and the General Health Questionnaire to measure distress. RESULTS: Benefit finding increased from pre- to post-transplantation. Fewer symptoms and comorbidities, and more optimism, were related to more BF over all time-points. The direction of the relation between BF and distress changed over time. Before transplantation, distress predicted an increase in BF, whereas post-transplantation, distress predicted a decrease in BF. The causal relation between BF and distress post-transplantation appeared to be reciprocal. CONCLUSIONS: A positive medical intervention such as renal transplantation might facilitate the development of BF. This study indicates the need for longitudinal research on the relation between BF and psychological health in the face of positive events. Statement of contribution What is already known on this subject? Benefit finding refers to the identification of positive psychological changes following a negative life event. Individuals can experience benefit finding following chronic illness. The positive event of kidney transplantation is associated with improvements in patients' physical and psychological functioning. What does this study add? Benefit finding increases from pre- to post-kidney transplantation. Fewer symptoms and comorbidities, and higher optimism are related to more benefit finding. Before transplantation, distress predicts an increase in benefit finding. After transplantation, there appears to be a reciprocal relation between distress and benefit finding such that distress predicts a decrease in benefit finding and benefit finding predicts a decrease in distress. PMID- 30485599 TI - Bilingual infants excel at foreign-language talker recognition. AB - Bilingual and monolingual infants differ in how they process linguistic aspects of the speech signal. But do they also differ in how they process non-linguistic aspects of speech, such as who is talking? Here, we addressed this question by testing Canadian monolingual and bilingual 9-month-olds on their ability to learn to identify Spanish talkers in a face-voice matching task. Importantly, neither group was familiar with Spanish prior to participating in the study. In line with our predictions, bilinguals succeeded in learning the face-voice pairings, whereas monolinguals did not. We consider multiple explanations for this finding, including the possibility that simultaneous bilingualism enhances perceptual attentiveness to talker-specific speech cues in infancy (even in unfamiliar languages), and/or that early bilingualism delays perceptual narrowing to language-specific talker recognition cues. This work represents the first evidence that multilingualism in infancy affects the processing of non-linguistic aspects of the speech signal, such as talker identity. This article is protected by copyright. All rights reserved. PMID- 30485600 TI - Working beyond the patient and cancer for adolescents and young adults. PMID- 30485601 TI - Does age matter? A comparison of health-related quality of life issues of adolescents and young adults with cancer. AB - OBJECTIVE: Health-related quality of life (HRQoL) concerns of adolescents and young adults (AYAs) aged 14-25 years were compared with those of older adults (26 60 years) with cancer. METHODS: AYAs and older adults receiving curative intent treatment or supportive palliative care for cancer were recruited from eight research centres across Europe. Participants used a rating scale to score the relevance and importance of a list of 77 issues covering 10 areas of HRQoL concern: symptoms; activity restrictions; social; emotional; body image; self appraisals; outlook on life; lifestyle; treatment-related and life beyond treatment. RESULTS: HRQoL issues were reviewed by 33 AYAs and 25 older adults. Several issues were recognised as relevant and important across all age groups: symptoms, emotional impact, outlook on life, lifestyle and treatment-related. A number of issues were more relevant or important to AYAs including interrupted education, greater motivation to achieve academic goals, increased maturity, boredom, fertility and change in living situation. CONCLUSION: While there is overlap in several of the HRQoL concerns across the age span, it is important that HRQoL measures used with AYAs capture the diverse and unique psychosocial aspects of this developmental stage. PMID- 30485602 TI - Transitioning adolescent and young adult cancer care research out of its adolescence. PMID- 30485603 TI - Is there any association between use of granulocyte colony-stimulating factor and chemotherapy-induced oral mucositis? PMID- 30485604 TI - Issues experienced and support provided to adolescents and young adults at the end of active treatment for cancer: A rapid review of the literature. AB - INTRODUCTION: The end of active treatment is a stressful period for adolescents and young adults (AYA), but little is known about AYA experiences at this time point. The aim was to describe the issues young people experienced and identify interventions to support AYA at the end of treatment. METHODS: We conducted a rapid review of published primary research to identify what is currently known about AYA experiences of the end of treatment, the issues which arise and existing interventions to support AYA at this time. RESULTS: Searches identified 540 papers of which 16 met the inclusion criteria. Five main themes were identified: physical/medical issues; psychological, social and emotional issues; information and support needs; sources of information and support; and difficulties accessing information and support. Within these broader themes, several subthemes were identified and explored further. CONCLUSION: Adolescents and young adults are under prepared for the unpredictable and ongoing nature of the physical, psychological and social issues they face at the end of cancer treatment. Enabling young people's inclusion within their relevant social and educational peer networks should be a priority. Timely, structured and equitable information/support is needed to prepare AYA for treatment ending and subsequent reintegration to "everyday" life. PMID- 30485605 TI - Identifying essential information to support patient decision-making regarding participation in cancer clinical trials: A Delphi study. AB - PURPOSES: This research set out to contribute to ongoing efforts to improve the quality of informed consent information provided to patients by specifically focusing on establishing consensus with regard to essential information to enhance the informed consent process. DESIGN AND METHODS: A Delphi consensus method was used to conduct three rounds of online surveys. Five groups of experts directly or indirectly involved in the informed consent process were invited to participate: patients, family members/friends, physicians, other health professionals and other key informants, including ethicists, contract research staff and pharmaceutical company staff. FINDINGS: Of 156 eligible participants, 101 participants (64.7%) completed all three rounds. In round 1, 994 information items were reported and generated into 74 statements. These were grouped under eight headings essential to the informed consent process. In rounds 2 and 3, the list was reduced to 15 statements representing consensus on essential information to be included in a summarised patient information document to support decision making regarding trial participation. Risks and discomforts, participation requirements and trial governance were identified as important considerations. CONCLUSIONS: The 15 essential statements identified in this study could be used as components of a summarised information sheet given to potential cancer clinical trial participants, as an adjunct to the informed consent process. A robust evaluation of the impact of these statements on the quality of the informed consent process is needed. PMID- 30485606 TI - Toward the development of the true "off-the-shelf" synthetic T cell immunotherapy. AB - Recent outstanding clinical results demonstrated by engineered T cells, including chimeric antigen receptors, have already facilitated further researches that broaden their applicability. One such direction is to explore new T cell sources for allogeneic "off-the-shelf" adoptive immunotherapy. Human pluripotent stem cells may serve as an alternative cell source for this purpose due to its unique features of infinite propagation ability and pluripotency. Here, we describe the current state of engineered T cell transfer with the focus on cell manufacturing processes and the potentials and challenges of induced-pluripotent stem cell derived T cells as a starting material to construct off-the-shelf T cell bank. This article is protected by copyright. All rights reserved. PMID- 30485607 TI - Gratitude - more than just a platitude? The science behind gratitude and health. PMID- 30485608 TI - Designing and evaluating functional laboratory information system requirements integrated to hospital information systems. AB - RATIONALE, AIMS, AND OBJECTIVES: Laboratory information sub-systems play an important role in diagnosis and treatment of patients. This study aimed to determine functional requirements of users and assess the existence of these requirements in the laboratory information system. METHOD: This descriptive cross sectional study was conducted in 2016 in two phases. The first phase was done through three stages. First, based on an unsystematic review of related literature, an outline of functional laboratory information system requirements was identified. In the second stage, these requirements were identified in group meetings in the form of a semi-structured questionnaire and given to experts. Then, modified Delphi technique was used to reach agreement on each item. Then, based on experts' comments, the final version of the questionnaire was presented including 61 closed-ended items using Likert scale and an open-ended item. It was surveyed by 50 experts using Delphi technique. Responses were scored, and the requirements whose mean final score was 3 and above were finally confirmed. In the second phase, based on the confirmed requirements, a checklist comprising 68 requirements was prepared and adopted hospital information systems were evaluated through researcher observation. Data were analysed using descriptive statistics. RESULTS: The final list of functional laboratory information system requirements was prepared with 68 items. The results of the evaluation revealed that confirmed requirements existed in 58.8% of hospital information systems. CONCLUSION: Laboratory information system requirements were designed with 68 items. Evaluation results showed that the systems were moderate in terms of compliance with the requirements. PMID- 30485609 TI - Implementing guideline-checklists: Evaluating health care providers intentional behaviour using an extended model of the theory of planned behaviour. AB - OBJECTIVES: Internationally, clinical guidelines as checklists are increasingly used in acute ward practice to standardize the delivery and raise the quality of care on acute hospital wards. However, when guideline-checklists are implemented repeatedly, health providers' intentions to carry out this type of behaviour are not well understood. Therefore, the objective of this study was to evaluate nurses' and health care assistants' (HCAs) intentions to implement a "care round checklist"; a guideline-intervention repeated hourly on hospital wards. Furthermore, an extended Theory of Planned Behaviour (TPB) model's usefulness in explaining this type of behaviour was also evaluated. METHODS: A theory-informed questionnaire, guided by the TPB, habit, and clinical context variables, was developed to measure the guideline-checklist behaviour. Quantitative questionnaire data were analysed using descriptive and inferential tests to establish differences in nurses' and HCAs' intentions and the predictive value of the model. RESULTS: A sample of 270 nurses and HCAs returned questionnaires from 24 wards in a major hospital in England. The extended TPB model explained 20% of nurses and 24% of HCAs reported intentions to implement a care round checklist, a modest proportion of intent. Attitude and perceived control best predicted nurses' intentions, and attitude and practice habit HCAs' intentions. TPB belief variables helped explain why nurses and HCAs intentions were different. CONCLUSIONS: Statistically, the extended TPB model highlighted that nurses and HCAs intentions to implement this type of guideline are predicted by different variables. This implied professional "role" as an important variable in explaining differences in intentions, which should be evaluated and integrated into the future design of this type of checklist. Further variables could be added to explain and learn more about intentional thinking for this type of behaviour and should help to develop a theoretical understanding of intentions underpinning this type of behaviour and ultimately improve patient care. PMID- 30485610 TI - Pathogenesis investigation of miR-199-5p in oral submucous fibrosis based on bioinformatics analysis. AB - OBJECTIVES: Fibrosis diseases are one of the leading causes of suffering and death. However, no systematic investigation has been carried out on fibrosis related genes. MATERIALS AND METHODS: By querying PubMed using keywords "fibrosis" and "gene" or "protein", we identified fibrosis-related genes in the last decade. Bioinformatics analysis was performed by MAS 3.0 software. Key miRNA was selected to assesse its relationship with oral submucous fibrosis (OSF) and fibroblast functions. RESULTS: 1310 genes related to fibrosis were identified. TGF-beta1, CTGF, MMP9, HSP47 and S1P were found to be associated with mainly fibrotic organs. 244 cellular components terms, 595 molecular function terms, 1816 cellular component terms, 136 KEGG pathway annotations were predicted. MiR 199-5p was selected as the key miRNA, which has higher level in OSF. Upregulated miR-199-5p was significantly related to OSF duration and OSF histological grade (P = 0.028 and 0.012, respectively). Overexpressive miR-199-5p reduced proliferation and induced apoptosis in buccal fibroblasts. Additionally, expression levels of collagen I (COL I) and III (COL III) were promoted by overexpressive miR-199-5p in buccal fibroblasts. CONCLUSION: These results indicate that fibrosis-related genes are related to a series of complex mechanisms. The characteristics of miR-199-5p may supply important clues for developing therapeutic strategy for OSF. This article is protected by copyright. All rights reserved. PMID- 30485611 TI - Translation and psychometric evaluation of the Hebrew version of the Health Care Providers' Pain and Impairment Relationship Scale. AB - BACKGROUND AND PURPOSE: Physiotherapists' different attitudes towards low back pain (LBP) are associated with patients' attitudes towards pain and with patients' disability. The Health Care Providers' Pain and Impairment Relationship Scale (HC-Pairs) is a self-administered instrument that assesses the attitudes and beliefs of health care professionals regarding LBP and the patient's daily function. The aims of this study are to translate, culturally adapt, and asses the psychometric properties of the Hebrew version of the HC-Pairs. METHODS: The English version of the HC-Pairs was forward-backward translated, pretested, and reviewed by a panel of experts. Reliability was determined by computing Cronbach's alpha, and validity by exploring the correlations between the HC Pairs' scores and the Pain Attitudes and Beliefs Scale for Physiotherapists (PABS PT) scores. Confirmatory factor analysis was performed. A convenience sample of 277 physiotherapists was invited to fill the HC-Pairs and PABS-PT questionnaires and a sociodemographic questionnaire. RESULTS: The forward-backward translation process revealed minor discrepancies between the texts. After the pretest, the expert panel agreed on a final version. A sample of 241 physiotherapists completed the questionnaires (response rate of 87%; 241/277); 213 met the inclusion criteria. Factor analysis suggests that the Hebrew version of the scale fits the one-factor model. Cronbach's alpha was 0.81 after deletion of two items and indicated good internal consistency. The scores produced by the instrument showed a substantial correlation with those of the biomedical dimension of the PABS-PT, and poor correlation with the behavioural dimension, in the expected directions. CONCLUSION: The findings of the present study on the psychometric properties of the HC-Pairs are positive. Nevertheless, the Hebrew version of the HC-Pairs is still in a developmental stage. Further psychometric research is needed to assess the attitudes and beliefs of Hebrew-speaking physiotherapists, which have been shown to be associated with treatment orientations and work recommendations. PMID- 30485613 TI - Managing for soil carbon sequestration: Let's get realistic. AB - Improved soil management is increasingly pursued to ensure food security for the world's rising global population, with the ancillary benefit of storing carbon in soils to lower the threat of climate change. While all increments to soil organic matter are laudable, we suggest caution in ascribing large, potential climate change mitigation to enhanced soil management. We find that the most promising techniques, including applications of biochar and enhanced silicate weathering, collectively are not likely to balance more than 5% of annual emissions of CO2 from fossil fuel combustion. PMID- 30485612 TI - Effectiveness of the European Society of Cardiology/Heart Failure Association website 'heartfailurematters.org' and an e-health adjusted care pathway in patients with stable heart failure: results of the 'e-Vita HF' randomized controlled trial. AB - BACKGROUND: Efficient incorporation of e-health in patients with heart failure (HF) may enhance health care efficiency and patient empowerment. We aimed to assess the effect on self-care of (i) the European Society of Cardiology/Heart Failure Association website 'heartfailurematters.org' on top of usual care, and (ii) an e-health adjusted care pathway leaving out 'in person' routine HF nurse consultations in stable HF patients. METHODS AND RESULTS: In a three-group parallel-randomized trial in stable HF patients from nine Dutch outpatient clinics, we compared two interventions ( heartfailurematters.org website and an e health adjusted care pathway) to usual care. The primary outcome was self-care measured with the European Heart Failure Self-care Behaviour Scale. Secondary outcomes were health status, mortality, and hospitalizations. In total, 450 patients were included. The mean age was 66.8 +/- 11.0 years, 74.2% were male, and 78.8% classified themselves as New York Heart Association I or II at baseline. After 3 months of follow-up, the mean score on the self-care scale was significantly higher in the groups using the website and the adjusted care pathway compared to usual care (73.5 vs. 70.8, 95% confidence interval 0.6-6.2; and 78.2 vs. 70.8, 95% confidence interval 3.8- 9.4, respectively). The effect attenuated, until no differences after 1 year between the groups. Quality of life showed a similar pattern. Other secondary outcomes did not clearly differ between the groups. CONCLUSIONS: Both the heartfailurematters.org website and an e-health adjusted care pathway improved self-care in HF patients on the short term, but not on the long term. Continuous updating of e-health facilities could be helpful to sustain effects. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID NCT01755988. PMID- 30485614 TI - Near-Infrared Photoluminescence and Electrochemiluminescence from a Remarkably Simple Boron Difluoride Formazanate Dye. AB - Electrochemiluminescence involves the generation of light via electrochemical reactions and has recently shown utility for single-cell imaging. To further develop this novel imaging platform, it is necessary to produce readily available dyes that photoluminesce and electrochemiluminesce in the near-infrared region to limit absorption by biological tissue. To address this need, we prepared a boron difluoride formazanate dye that exhibits near-infrared photoluminescence and electrochemiluminescence in two straightforward synthetic steps. Examination of its solid-state structure suggests that the N-aryl substituents have significant quinoidal character, which narrows the S1-S0 energy gap and leads to near infrared absorption and photoluminescence. Electrochemical properties were probed using cyclic voltammetry and revealed four electrochemically reversible waves. Electrochemiluminescence properties were examined in the presence of tri-n propylamine, leading to maximum intensity at 910 nm, at least 85 nm (1132 cm-1) red-shifted compared to all other organic dyes. This work sets the stage for the development of future generations of dyes for emerging applications, including single-cell imaging, that require near-infrared photoluminescence and electrochemiluminescence. PMID- 30485615 TI - The eye in AI: artificial intelligence in ophthalmology. PMID- 30485616 TI - Fast response fluorogenic probe for visualizing hypochlorite in living cells and Zebrafishes. AB - A novel fast response and visible fluorogenic probe (D1) for monitoring hypochlorite (ClO-) has been developed based on specific ClO- removal of a C=N bond. The response of the probe to ClO- showed increases linearly, and the fluorescence intensity heighten about 25 times. D1 responses to ClO- were observed with high selectivity and sensitivity within 10 s by naked eyes. D1 can not only detect the level of hypochlorite in vitro such as urine, but also monitoring hypochlorite content in extremely cold condition as low as -78 oC. Meanwhile, the good biocompatibility guaranteed the use of D1 to detect intracellular ClO- under confocal microscopy. Moreover, D1 has been successfully applied to monitor the exogenous and endogenous ClO- in Zebrafishes with fluorescence imaging. PMID- 30485617 TI - National estimates of case-mix, mortality, and economic outcomes among inpatient HIV/AIDS mono-infection and hepatitis C co-infection cases in the US. AB - RATIONALE, AIMS, AND OBJECTIVES: To assess inpatient clinical and economic outcomes for AIDS/HIV and Hepatitis C (HCV) co-infection in the United States from 2003 to 2014. METHOD: This historical cohort study utilized nationally representative hospital discharge data to investigate inpatient mortality, length of stay (LoS), and inflation-adjusted charges among adults (>=18 years). Outcomes were analysed via multivariable generalized linear models according to demographics, hospital and clinical characteristics, and AIDS/HIV or HCV sequelae. RESULTS: Overall, 17.8% of the 2.75 million estimated AIDS/HIV inpatient cases involved HCV from 2003 to 2014, averaging 48.5 +/- 9.0 years of age and 68.0% being male. Advanced sequalae of AIDS and HCV incurred a LoS of 10.3 +/- 11.9 days, charges of $88 789 +/- 131 787, and a 16.9% mortality. Many cases involved noncompliance, tobacco use disorders, and substance abuse. Although mortality decreased over time, multivariable analyses indicated that poorer outcomes were generally associated with more advanced clinical conditions and AIDS-associated sequalae, although mixed results were observed for specific manifestations of HCV. Rural residence was independently associated with a 3.26 times higher adjusted odds of mortality from 2009 to 2014 for HIV/HCV co infection (P < 0.001), although not for AIDS/HCV (OR = 1.38, P = 0.166). CONCLUSION: Given the systemic nature and modifiable risks inherent within coinfection, more proactive screening and intervention appear warranted, particularly within rural areas. PMID- 30485618 TI - Nitridophosphates - A Success Story of Nitride Synthesis. AB - Nitridophosphates and phosphorus nitrides are thoroughly investigated classes of nitrides. Researched for thirty years, their methods of synthesis evolved from condensation of molecular precursors at moderate temperatures and ambient pressures to state-of-the-art high-pressure and high-temperature syntheses. Landmark breakthroughs made in recent years led to a comprehension-based proficiency in nitridophosphate synthesis that is illustrated in the nowadays known large compositional and structural diversity. Here we review the advances made in synthesis with regard to the prevalent problem of nitride synthesis: the susceptibility of nitride ions for oxidation. PMID- 30485619 TI - Unusual case of renal parenchymal urine leak post-transplantation. PMID- 30485620 TI - Corrigendum. PMID- 30485621 TI - What about direct and indirect benefits incurred by the kidney recipients and society? PMID- 30485622 TI - PCSK9 Inhibitor Therapy: A Systematic Review And Meta-Analysis of Metabolic And Cardiovascular Outcomes in Patients With Diabetes. AB - AIM: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors determine a wide reduction of LDL cholesterol, greater than other lipid-lowering agents. Aim of this metanalysis was the assessment of PCSK9 inhibitors effects on glucose metabolism, LDL-cholesterol, cardiovascular morbidity and mortality in patients with and without diabetes. METHODS: A Medline and Clinicaltrials.gov search for eligible studies until December 1st , 2017, was performed. All randomized trials comparing PCSK-9 inhibitors with placebo or active drugs were included. Primary endpoints: a) incident diabetes, fasting glucose and HbA1c; b) LDL-cholesterol at endpoint in patients with diabetes and in the total sample; c) MACE (major cardiovascular events) and mortality in patients with and without diabetes. RESULTS: A total of 38 trials was identified. The risk of incident diabetes was not increased by PCSK-9 inhibitors, either versus placebo or any comparator. The reduction of LDL-cholesterol versus placebo in patients with diabetes was 52.6[41.3;63.8]mg/dl; the corresponding figure for all patients was 66.9[62.4;71.3]mg/dl. Metaregression analysis showed an inverse correlation between proportion of patients with diabetes and drug effect on LDL cholesterol in trials versus ezetimibe, but not in those versus placebo. In studies reporting data on MACE and mortality separately for patients with and without diabetes, the effect of PCSK-9 did not appear to be affected by diabetes. CONCLUSIONS: PCSK-9 inhibitors does not affect glucose metabolism. Their efficacy on LDL-cholesterol and MACE in patients with diabetes does not seem to be very dissimilar from that observed in non-diabetic subjects. This article is protected by copyright. All rights reserved. PMID- 30485623 TI - Interleaved Dual NMR Acquisition of Equivalent Transfer Pathways in TOCSY and HSQC Experiments. AB - A dual NMR data acquisition strategy to handle and detect two active equivalent transfer pathways is presented and discussed. We illustrate the power of this time-efficient approach by collecting two different 2D spectra simultaneously in a single experiment: i) TOCSY or HSQC-TOCSY spectra with different mixing times, ii) F2-13 C-coupled and decoupled HSQC spectra, iii) conventional and pure-shift HSQC spectra, or iv) complementary HSQC and HSQC-TOCSY spectra. PMID- 30485624 TI - Direct Evidence for the Polymeric Nature of Polydopamine. AB - Inspired by the adhesive proteins of mussels, polydopamine (pDA) has emerged as one of the most widely employed methods for functionalizing material surfaces, fueled in part by the versatility, simplicity, and spontaneity of pDA film deposition on most materials upon immersion in an alkaline aqueous solution of dopamine. However, the rapid adoption of pDA for surface modification over the last decade stands in stark contrast to the slow pace in understanding the composition of pDA. Numerous attempts to elucidate the formation mechanism and structure of this fascinating material have resulted in little consensus mainly due to the insoluble nature of pDA; which renders most conventional methods of polymer molecular weight characterization ineffective.[1] Here, we employed the non-traditional approach of single molecule force spectroscopy (SMFS) to characterize pDA films. Retraction of a pDA coated cantilever from an oxide surface shows the characteristic features of a polymer with contour lengths up to 200nm. pDA polymers are generally weakly bound to the surface through much of their contour length, with occasional "sticky" points. Our findings represent the first direct evidence for the polymeric nature of pDA and provide a foundation upon which to understand and tailor its physicochemical properties. PMID- 30485625 TI - Gmelin-Beilstein Memorial Medal for Rene Deplanque / Meyer-Galow Prize for Markus Rarbach / International Prizes from the Real Sociedad Espanola de Quimica. PMID- 30485626 TI - Dynamic nuclear polarization of 13C nuclei in the liquid state over a 10 Tesla field range. AB - Nuclear magnetic resonance (NMR) techniques play an essential role in natural science and medicine. In spite of the tremendous utility associated with the small energies detected, the most severe limitation is the low signal-to-noise ratio. Dynamic nuclear polarization (DNP), a technique based on transfer of polarization from electron to nuclear spins, has emerged as a tool to enhance sensitivity of NMR. However, the approach in liquids is still facing several challenges. Here we report the observation of room temperature, liquid DNP 13C signal enhancements in organic small molecules as high as 600 at 9.4 Tesla and 800 at 1.2 Tesla. A mechanistic investigation of the 13C-DNP field dependence shines light on parameters governing the underlying scalar DNP, indicating that DNP efficiency is raised by proper choice of the polarizing agent (paramagnetic center) and by halogen atoms as mediators of scalar hyperfine interaction. Observation of sizable DNP of 13CH2 and 13CH3 groups in organic molecules at 9.4 T opens up perspective for a broader application of this method . PMID- 30485627 TI - Complete resection of colorectal cancer with ovarian metastases combined with chemotherapy is associated with improved survival. AB - BACKGROUND: Ovarian metastases (OM) from colorectal cancer (CRC) are uncommon, and data about optimal management are lacking. The aim of this study was to examine the management and outcomes of patients with OM from CRC. METHODS: A retrospective review of records of patients with a histopathological diagnosis of OM from CRC who were treated at Christchurch Hospital between 1 January 2000 and 31 December 2016. Data related to presentation, clinicopathological characteristics, treatment and outcomes were recorded. The primary outcomes were overall survival and disease-free survival. RESULTS: Thirty-one patients were identified (median age 55 years, range 28-77), with a median follow-up of 23 months (range 3-84 months). Abdominal pain was the most common presenting symptom (22 patients). Synchronous OM occurred in 22 patients, 14 patients had bilateral ovarian involvement. Twenty-one patients received adjuvant chemotherapy. R0 resection was achieved in 14 patients. For all patients the 5-year disease-free and overall survival were 11% and 12%, respectively, while 5-year overall survival for R0 resections was 30%. Improved median survival was associated with negative colon resection margins (26.7 months versus 7.8 months, P = 0.03), R0 resection (30.5 months versus 23.5 months, P = 0.04), and use of adjuvant chemotherapy (28.8 months versus 8.2 months, P < 0.0001); however, on multivariate analysis adjuvant chemotherapy was the only independent factor associated with improved prognosis (P = 0.01). CONCLUSIONS: OM from CRC are uncommon and carry a poor prognosis. Improved survival was associated with complete surgical resection of the primary tumour and metastatic disease in combination with systemic chemotherapy. PMID- 30485628 TI - One Dimensional CdS Nanotube vs CdS Bulk Structure for Photocatalytic Water Splitting: Role of Dimensionality. AB - Using the state-of-the-art density functional theoretical calculations, we have modelled a facetted CdS nanotube (NT) catalyst for photocatalytic water splitting. The overall photocatalytic activity of the CdS photocatalyst has been predicted based on the electronic structures, band edge alignment, and overpotential study. For comparisons, we have also investigated the water spilitting process over the CdS bulk structure. The band edge alignment along with oxygen evolution reaction/hydrogen evolution reaction (OER/HER) mechanism studies help us to find out the effective overpotential for the overall water splitting on these surfaces. Our study shows that CdS NT has highly stabilized valence band edge compared to that in the CdS bulk due to strong p-d mixing. Such highly stabilized valence band edge is important for the hole-transfer process and reduces the risk of electron-hole recombination. Such nanotube requires less overpotential for water oxidation reaction than the periodic CdS. All these suggest that the efficiency of water oxidation/reduction process further improves in CdS as we reduce its dimensionality. More importantly, we report here that there are two factors, which makes CdS nanotube as a better photocatalyst material compared to its bulk counterpart. Furthermore, the stabilized valence band edge is good for their photostability too as bulk CdS suffers from photostability. PMID- 30485629 TI - Larry Parsons: Researcher, mentor, and friend. PMID- 30485630 TI - Selective Formation of an FeIVO or an FeIIIOOH Intermediate From FeII-H2O2 : Controlled Heterolytic vs Homolytic O-O Bond Cleavage by the Second Coordination Sphere. AB - We demonstrate that the devised incorporation of an alkylamine group into the second coordination sphere of an FeII complex allows to switch its reactivity with H2O2 from the usual formation of FeIII species towards the selective generation of an FeIV-oxo intermediate. The FeIV-oxo was characterized by UV visible absorption and Mossbauer spectroscopy. Variable temperature kinetic analyses point towards a mechanism where the heterolytic cleavage of the O-O bond is triggered by a proton transfer from the proximal to the distal oxygen atom in the FeII-H2O2 complex with the assistance of the pendant amine. DFT studies reveal that this heterolytic cleavage is actually initiated by an homolytic O-O cleavage immediately followed by a proton-coupled electron transfer that leads to the formation of the FeIV-oxo and release of water through a concerted mechanism. PMID- 30485631 TI - Fabrication of Nanofibrous PVA/Alginate-Sulfate Substrates for Growth Factor Delivery. AB - Providing affinity sites on alginate (ALG) matrix enables specific binding of growth factors to the polymer backbone and allows their release in a controlled fashion. In this study, we used a blend of alginate sulfate (ALG-S) and polyvinyl alcohol (PVA) to fabricate electrospun scaffolds capable of delivering a heparin like growth factor, transforming growth factor-beta1 (TGF-beta1). The alginate was sulfated with different degrees of sulfation (DS, from 0.8, 3.4 to 12.4%) by a simple process. The success of sulfation was determined by Fourier-transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (NMR), elemental analysis, ultraviolet (UV) spectroscopy and staining with dimethylmethylene blue. The physical-mechanical properties of nanofibrous mats were characterized by scanning electron microscopy (SEM), FTIR, energy-dispersive X-ray spectroscopy (EDX), tensile strength and mass loss analysis. Additionally, the release kinetics of transforming growth factor-beta1 (TGF-beta1) from PVA/ALG S and PVA/ALG scaffolds were compared. The results showed that the binding and entrapment of TGF-beta1 to the nanofibrous scaffolds are improved by the addition of sulfate group to alginate. In conclusion, our results support that nanofibrous scaffold based on PVA/ALG-S can deliver growth factors in tissue engineering application. (c)2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2018. PMID- 30485632 TI - Superweak Coordinating Anion as Superstrong Enhancer of Cyanine Organic Semiconductor Properties. AB - The superweak tetrakis(nonafluoro-tert-butoxy)aluminate coordinating anion was employed to introduce pseudo-gas-phase conditions to the 2-[5-(1,3-dihydro-1,3,3 trimethyl-2H-indol-2-ylidene)-1,3-pentadien-1-yl]-1,3,3-trimethyl-3H-indolium chromophore. The resulting formation of a photoactive organic-inorganic hybrid salt has led to a highly stabilized excited state of the organic chromophore mainly due to the minimized lattice energy and Coulomb interactions. These highly beneficial features caused by the well dispersed negative charge of the anion have led to an enhanced neat spin-casted film fluorescence intensity, prolonged fluorescence lifetime, smooth thin film surfaces and a record power photovoltaic efficiency of 3.8 % when compared to organic salts of this particular chromophore containing anions with localised negative charge. Clear evidence is given that a superweak coordinating anion is an emerging key parameter in cyanine dye photochemistry. This approach can be seen as a general guideline to prepare highly efficient ionic dyes for organic semiconductor applications. PMID- 30485633 TI - Adherence to prophylactic haemophilic treatment in young patients transitioning to adult care: A qualitative review. AB - Recombinant prophylactic treatment (PTX) has greatly improved morbidity, mortality and health-related quality of life (HRQoL) in patients with severe haemophilia. Yet, treatment adherence appears suboptimal in adolescents and young adults with haemophilia (YWH). Young patients experience major biopsychosocial changes challenging their adherence through the transition from parental to self care, from paediatric to adult care. In clinical practice, a systematic approach to transition is rarely used and there is little evidence on best practices. This qualitative review was based on a systematic literature search including quantitative as well as qualitative research reports to examine all relevant factors influencing adherence to PTX in YWH. We aimed to gain comprehensive insight into main drivers and barriers to adherence by exploring them in the context of YWH's disease perceptions, characteristics, HRQoL and needs. The outcome is an overview of the latest published recommendations to support treatment adherence in YWH during the transition from family-oriented care to self-care and from paediatric to adult care. The literature suggests that adherence to PTX is best supported when individual patient needs and preferences are taken into consideration when planning treatment. Preserving normality is a main priority in young patients making it crucial to support patients from early childhood in considering PTX as enabling rather than hindering a normal social and physically active life. Education in self-management should include psychosocial support of patients as well as caregivers. This requires systematic transition planning including milestone assessments and ongoing multidisciplinary support until full self-management is secured. PMID- 30485634 TI - Update on GM canola crops as novel sources of omega-3 fish oils. AB - There is considerable interest in new sources of omega-3 long-chain (here defined as fatty acids >=C20) polyunsaturated fatty acids (LC-PUFA), specifically eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3), commonly known as omega-3 fish oils, to supplement the limited supplies of oceanic fish oil (Tocher, 2015). These alternative sources include extraction of other diverse marine organisms (e.g. krill, plankton etc.), algal fermentation, and the genetic engineering of microbes such as yeasts. Another approach is the synthesis of omega-3 fish oils in transgenic plants (reviewed in Napier et al., 2015), and this short article will discuss the recent results obtained by two major industry collaborations. This article is protected by copyright. All rights reserved. PMID- 30485635 TI - Mechanical and Biological Evaluation of a Hydroxyapatite-Reinforced Scaffold for Bone Regeneration. AB - With over 500,000 bone grafting procedures performed annually in the United States, the advancement of bone regeneration technology is at the forefront of medical research [1]. Many tissue-engineered approaches have been explored to develop a viable synthetic bone graft substitute, but a major challenge is achieving a load-bearing graft that appropriately mimics the mechanical properties of native bone. In this study, sintered hydroxyapatite (HAp) was used to structurally reinforce a scaffold and yield mechanical properties comparable to native bone. HAp was packed into a cylindrical framework and processed under varying conditions to maximize its mechanical properties. The resulting HAp columns were further tested in a 6-week degradation study to determine their physical and mechanical response. The cellular response of sintered HAp was determined using a murine preosteoblast cell line, MC3T3-E1. Cell viability and morphology were studied over a one-week period and MC3T3-E1 differentiation was determined by measuring the alkaline phosphatase (ALP) levels. Finite Element Analysis (FEA) was used to determine the columns' geometric configuration and arrangement within our previously developed composite bone scaffold. It was determined that incorporating 4 cylindrical HAp columns, fabricated under 44 MPa of pressure and sintered at 1200 degrees C for 5 hours, led to load-bearing properties that match the yield strength of native whole bone. These preliminary results indicate that the incorporation of a mechanically enhanced HAp structural support system is a promising step towards developing one of the first load bearing bone scaffolds that can also support cell proliferation and osteogenic differentiation. This article is protected by copyright. All rights reserved. PMID- 30485636 TI - Wilhelm Keim (1934-2018). AB - Wilhelm "Willi" Keim, professor emeritus at the RWTH Aachen University, passed away on September 30, 2018. Keim was best known for his role in developing the Shell higher olefins process (SHOP), and also made pioneering contributions to the areas of liquid-liquid biphasic catalysis, and green and sustainable chemistry. PMID- 30485637 TI - Effects of intravitreal Bevacizumab in Gram-positive and Gram-negative models of ocular inflammation. AB - BACKGROUND: Exogenous endophthalmitis is a potential complication of intraocular surgery and frequently results in visual impairment. Current treatment involves administration of intravitreal (IVT) antibiotics with or without vitrectomy surgery. Evidence for the use of adjunctive anti-inflammatory agents is conflicting. We set out to determine if bevacizumab, a humanized monoclonal IgG1 antibody targeted against Vascular Endothelial Growth Factor (VEGF), has anti inflammatory properties in experimental models of Gram-positive and Gram-negative inflammation. METHODS: BALB/c mice were subjected to lipopolysaccharide- (LPS) or peptidoglycan- (PGN) induced ocular inflammation and treated with IVT bevacizumab. Iris microvasculature was imaged 6 hours following irritant/treatment using intravital microscopy (IVM) before the mice were euthanized and the eyes were enucleated immediately post-mortem. Following enucleation, levels of VEGF and 23 cytokines and chemokines (IL-1alpha, IL-1beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-17, TNF, KC, G-CSF, GM-CSF, Eotaxin, INF-gamma, MCP-1, MIP-1alpha, MIP-1beta, RANTES) were quantified using a multiplex assay. RESULTS: Levels of VEGF were significantly increased during the inflammatory response, triggered by either PGN or LPS. Both the adherence of leukocytes to the iris vascular endothelium and the levels of pro-inflammatory cytokines and chemokines were significantly increased following administration of either irritant. Treatment with bevacizumab decreased levels of leukocyte adherence in LPS-treated eyes, however, not in PGN-treated eyes. Conversely, bevacizumab treatment decreased levels of cytokines and chemokines (TNF, IL-6, MCP-1, MIP-1alpha, MIP-1beta, RANTES, KC) in PGN-treated eyes, however, not in LPS-treated eyes. CONCLUSIONS: Within a 6-hour window bevacizumab had anti-inflammatory actions that were distinct in both Gram-positive (PIU) and Gram-negative (EIU) models, respectively. Given our findings, this would suggest that bevacizumab may have utility as an adjunctive therapy to IVT antibiotics and vitrectomy in the management of exogenous endophthalmitis. PMID- 30485638 TI - Efficacy and safety of ombitasvir/paritaprevir/ritonavir and ribavirin for chronic hepatitis patients infected with genotype 2a in Japan. AB - AIM: The aim of this study was to evaluate the efficacy and safety of community based ombitasvir/paritaprevir/ritonavir plus ribavirin therapy for non-cirrhotic patients with hepatitis C virus (HCV) genotype 2a infection in a real-world setting. METHODS: Patients with HCV genotype 2a infection were enrolled in this study and received the therapy for 16 weeks at 11 specialized centers between October 2016 and July 2017. Among the 98 patients participating in the study, 4 patients were excluded because of the presence of cirrhosis and/or genotype 2b infection. The remaining 94 patients were subjected to the analysis. RESULTS: The patients consisted of 38 females and 56 males, with a median age of 63 years. The rate of sustained virologic response (SVR) was 97.9%. The SVR rates were similar between patients with and without ribavirin dose reduction (96.0% versus 98.6%, respectively). Of the 2 patients in whom treatment failed, 1 patient completed the treatment but relapse at 4 weeks post-treatment, whereas the other did not show virologic response and therefore discontinued treatment at week 9. At baseline, both patients had NS5A resistance-associated substitution (RAS) L31M but did not have any NS3 RASs. At the time of relapse, the patient had NS5A RAS F28S. At the premature treatment discontinuation, the non-responder had NS3 RAS D168V and NS5A RAS T24S. Ribavirin-induced anemia was the most frequent adverse event. CONCLUSION: Community-based, 16-week, ombitasvir/paritaprevir/ritonavir plus ribavirin therapy was highly efficacious and safe in non-cirrhotic patients with HCV genotype 2a infection in a real-world setting. PMID- 30485640 TI - Use of inotuzumab-ozogamicin in a child with Down syndrome and refractory B-cell precursor acute lymphoblastic leukemia. PMID- 30485639 TI - Effects of family nutrition and physical activity screening for obesity risk in school-age children. AB - PURPOSE: An obesogenic home environment is a major contributor to overeating and sedentariness in school-aged children, as children have less autonomy during this phase of development and are influenced by family environmental cues. The purpose of this study was to implement a screening tool at a low socioeconomic elementary school clinic to identify children at risk of developing obesity and provide standardization for practitioners on educating parents regarding child obesity risk factors. DESIGN AND METHODS: An evidence-based practice design utilizing the Family Nutrition and Physical Activity (FNPA) tool was completed at all visits of patients ages 4 to 11. Parents completed the 20-item screening tool related to 10 factors (family meal patterns, family eating habits, food choices, beverage choices, restriction/reward, screen time behavior and monitoring, healthy environment, family activity involvement, child activity involvement, family routine). The nurse practitioner (NP) provided parents with education regarding healthy home practices based on American Academy of Pediatrics (AAP) recommendations. Level of obesity risk (low, moderate, and high) was determined based on the FNPA score and body mass index (BMI) of the patient. Patients identified as at-risk were scheduled for a 2-month follow-up and rescreened to determine if lifestyle modifications were made. RESULTS: Twenty-seven children were screened using the FNPA tool, with an initial mean FNPA score of 64. Ninety three percent were classified as a moderate or high risk for obesity (BMI percentile 85th or greater and/or moderate-high risk FNPA scores). Seven percent had a healthy BMI and low-risk FNPA scores and did not require follow-up intervention. Sixty-seven percent of patients scores improved at follow-up, with an average FNPA score of 70. Effect size stratified by risk category was low-risk score 0.07 and moderate-risk score 1.49 with a standard deviation of 5.36. PRACTICE IMPLICATIONS: Implementation of the FNPA tool at a school-based clinic is a feasible opportunity to identify children at risk for obesity and allows for anticipatory guidance by the NP to increase awareness of parental influence as role models for healthy lifestyle behaviors. PMID- 30485641 TI - Intraoperative ultrasound for improved 3D tumour reconstruction in robot-assisted surgery: An evaluation of feedback modalities. AB - BACKGROUND: Intraoperative ultrasound scanning induces deformation on the tissue in the absence of a feedback modality, which results in a 3D tumour reconstruction that is not directly representative of real anatomy. METHODS: A biomechanical model with different feedback modalities (haptic, visual, or auditory) was implemented in a simulation environment. A user study with 20 clinicians was performed to assess which modality resulted in the 3D tumour volume reconstruction that most resembled the reference configuration from the respective computed tomography (CT) scans. RESULTS: Integrating a feedback modality significantly improved the scanning performance across all participants and data sets. The optimal feedback modality to adopt varied depending on the evaluation. Nonetheless, using guidance with feedback is always preferred compared with none. CONCLUSIONS: The results demonstrated the urgency to integrate a feedback modality framework into clinical practice, to ensure an improved scanning performance. Furthermore, this framework enabled an evaluation that cannot be performed in vivo. PMID- 30485642 TI - Formation and Reactivity of an Aluminabenzene Ligand at Pentadienyl-Supported Rare-Earth-Metals. AB - The half-open rare-earth metal aluminabenzene complexes [(1-Me-3,5-tBu2-C5H3Al)(u Me)Ln(2,4-dtbp)] (Ln = Y, Lu) are accessible via a salt metathesis reaction employing Ln(AlMe4)3 and K(2,4-dtbp). Treatment of the yttrium complex with B(C6F5)3and tBuCCH gives access to the pentafluorophenylalane complex [{1-(C6F5) 3,5-tBu2-C5H3Al}{u-C6F5}Y{2,4-dtbp}] and the mixed vinyl-acetylide complex [(2,4 dtbp)Y(u-n1:n3-C5H4)(u-CCtBu)AlMe2], respectively. PMID- 30485643 TI - Chemically mediated interactions between Microcystis and Planktothrix: impact on their growth, morphology and metabolic profiles. AB - Freshwater cyanobacteria are known for their ability to produce bioactive compounds, some of which have been described as allelochemicals. Using a combined approach of co-cultures and analyses of metabolic profiles, we investigated chemically mediated interactions between two cyanobacterial strains, Microcystis aeruginosa PCC7806 and Planktothrix agardhii PCC7805. More precisely, we evaluated changes in growth, morphology and metabolite production and release by both interacting species. Co-culture of Microcystis with Planktothrix resulted in a reduction of the growth of Planktothrix together with a decrease of its trichome size and alterations in the morphology of its cells. The production of intracellular compounds by Planktothrix showed a slight decrease between mono and co-culture conditions. Concerning Microcystis, the number of intracellular compounds was higher under co-culture condition than under monoculture. Overall, Microcystis produced a lower number of intracellular compounds under monoculture than Planktothrix, and a higher number of intracellular compounds than Planktothrix under co-culture condition. Our investigation did not allow us to identify specifically the compounds causing the observed physiological and morphological changes of Planktothrix cells. However, altogether, these results suggest that co-culture induces specific compounds as a response by Microcystis to the presence of Planktothrix. Further studies should be undertaken for identification of such potential allelochemicals. This article is protected by copyright. All rights reserved. PMID- 30485644 TI - Anterolateral thigh versus pectoralis major flaps in reconstruction of the lateral temporal bone defect. AB - BACKGROUND: Free tissue reconstruction is reliable in suitable patients but patient selection remains a challenge for the reconstructive surgeon. The anterolateral thigh (ALT) free flap and pedicled pectoralis major myocutaneous flap (PMMF) are two common reconstructive options for a lateral temporal bone resection defect. The threshold at which free tissue reconstruction should be considered over locoregional reconstruction is not defined. We sought to define reconstructive flap choice in the setting of medical comorbidities that may dissuade free tissue transfer. METHODS: A retrospective analysis of lateral temporal bone defects at a single institution was undertaken. The primary outcomes were flap survival, surgical complications and durations of surgery and stay. Data regarding medical comorbidities and potential confounders were examined. RESULTS: Sixty patients with lateral temporal bone defects were identified. Twenty-four (40%) patients underwent PMMF reconstruction and 36 (60%) were reconstructed with ALT. The former were significantly older (73 versus 62 years), though with similar Anesthesiologists Risk Classification System status. Free-flap reconstruction resulted in significantly less flap loss (two versus six) but a longer operating time (790 versus 671 min). CONCLUSION: Patients suffering head and neck cancer with medical comorbidities can make selection of a suitable reconstruction difficult. We found that while patients undergoing ALT reconstruction were typically younger, the comorbidity profile of those patients was similar to patients undergoing PMMF reconstruction. ALT flaps were more reliable than the PMMF, lending credence to the view that free tissue transfer should be the preferred reconstructive option in suitable candidates and defects. PMID- 30485645 TI - Differences in plantar pressure by REBA scores in dental hygienists. AB - OBJECTIVES: The purpose of the present study was to analyze the effects of working posture, physical balance, and work accumulation on shifts in plantar pressure in dental hygienists, by measuring REBA, which evaluates working posture, and plantar pressure, which evaluates physical balance. METHODS: This study was conducted on 24 dental hygienists currently working in dental clinics. The ergonomic assessment method of the Rapid Entire Body Assessment was used to evaluate working posture in the dental hygienists, and a Gait Analyzer was used to measure plantar pressure. RESULTS: The subjects' mean REBA score was 4.96+/ 1.04 points, and 87.5% of the subjects showed poor working posture, with a REBA score of at least 4 points. Among subjects with a REBA score of 4 points or more, 7 of the 8 parts of the sole of the foot showed significant differences in plantar pressure between the right and left feet (p<0.05). When we examined changes in plantar pressure over a week, pressure increase on the left side, and in particular, for subjects with a REBA score of 4 points or higher, pressure increased in the left foot and in the anterior right foot. CONCLUSIONS: Most of the dental hygienists in this study showed poor posture during working. Subjects with poor posture at a level requiring intervention showed differences in plantar pressure between the right and left feet. Inappropriate posture can cause musculoskeletal disorders. Therefore, it will be necessary to prepare internal and external measures to maintain proper working posture in dental hygienists, including education, exercise, improvement of the working environment, and improvement of ergonomic equipment and devices. This article is protected by copyright. All rights reserved. PMID- 30485646 TI - Protease-activated receptor-1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy. AB - End-stage renal disease, the final stage of all chronic kidney disorders, is associated with renal fibrosis and inevitably leads to renal failure and death. Transition of tubular epithelial cells (TECs) into mesenchymal fibroblasts constitutes a proposed mechanism underlying the progression of renal fibrosis and here we assessed whether protease-activated receptor (PAR)-1, which recently emerged as an inducer of epithelial-to-mesenchymal transition (EMT), aggravates renal fibrosis. We show that PAR-1 activation on TECs reduces the expression of epithelial markers and simultaneously induces mesenchymal marker expression reminiscent of EMT. We next show that kidney damage was reduced in PAR-1 deficient mice during unilateral ureter obstruction (UUO) and that PAR-1 deficient mice develop a diminished fibrotic response. Importantly, however, we did hardly observe any signs of mesenchymal transition in both wild-type and PAR 1-deficient mice suggesting that diminished fibrosis in PAR-1-deficient mice is not due to reduced EMT. Instead, the accumulation of macrophages and fibroblasts was significantly reduced in PAR-1-deficient animals which were accompanied by diminished production of MCP-1 and TGF-beta. Overall, we thus show that PAR-1 drives EMT of TECs in vitro and aggravates UUO-induced renal fibrosis although this is likely due to PAR-1-dependent pro-fibrotic cytokine production rather than EMT. PMID- 30485647 TI - Robotic Sigmoidectomy with Intracorporeal Anastomosis using the "Vijan Pop" technique - Video Vignette. AB - Most of the left robotic colectomies require a laparotomy for specimen extraction and anvil placement. This lengthens the procedure obliging the surgeon to leave his robot console and move to the patient's bed. Recently we have adopted a new anastomotic method, which is illustrated in this video, with an intracorporeal insert of the anvil at the beginning of the operation, postponing therefore the abdominal incision only for the specimen extraction after the creation of the anastomosis ("Vijan Pop" technique). This article is protected by copyright. All rights reserved. PMID- 30485648 TI - Association of chorioamnionitis and its duration with adverse maternal outcomes by mode of delivery: a cohort study. AB - OBJECTIVE: To investigate the association of chorioamnionitis and its duration with adverse maternal outcomes by mode of delivery. DESIGN: A retrospective cohort study. SETTING: Data from the Consortium on Safe Labor Study (CSL) in the USA (2002-2008). POPULATION: Singleton deliveries at >=23 weeks of gestation (221,274 assessed deliveries, 62,331 by cesarean). METHODS: The association of chorioamnionitis, and secondarily the duration of chorioamnionitis estimated from intrapartum antibiotic use, with adverse maternal outcomes was analyzed using logistic regression with generalized estimating equations, adjusting for age, parity, race, pre-gestational diabetes, chronic hypertension, gestational age at delivery, study site, and delivery year. Analyses were stratified by vaginal versus cesarean delivery. MAIN OUTCOME MEASURES: The composite adverse maternal outcome included: postpartum transfusion, endometritis, wound/perineal infection/separation, venous thromboembolism, hysterectomy, ICU admission, and/or death. RESULTS: Chorioamnionitis was associated with higher odds of the composite adverse maternal outcome with cesarean delivery (AOR 2.31; 95% CI: 1.97 - 2.71); and the association persisted regardless of whether a patient had a trial of labor, preterm delivery, or maternal group B streptococcus colonization. The most common adverse outcomes after cesarean were postpartum transfusion (56.0%) and wound/perineal infection or endometritis (38.6%). Chorioamnionitis was not associated with adverse maternal outcomes with vaginal delivery. The duration of chorioamnionitis as the exposure did not alter the association between chorioamnionitis and adverse maternal outcomes. CONCLUSIONS: Chorioamnionitis, but not the estimated duration, was associated with increased odds of adverse maternal outcomes with cesarean delivery. This finding has implications for care programs to prevent maternal morbidity after a cesarean complicated by chorioamnionitis. This article is protected by copyright. All rights reserved. PMID- 30485649 TI - Woven collagen biotextiles enable mechanically functional rotator cuff tendon regeneration during repair of segmental tendon defects in vivo. AB - Despite advancements in surgical techniques and materials for rotator cuff repair procedures, primary repair failures remain common. This study examines the use of electrochemically aligned collagen (ELAC) threads woven into biotextile scaffolds as grafts to repair critical infraspinatus tendon defects in New Zealand White rabbits. Three surgical treatment groups were evaluated: rabbits undergoing direct repair as operative controls, rabbits receiving ELAC scaffolds alone, and rabbits treated with mesenchymal stem cell (MSC)-seeded ELAC scaffolds. In each animal, the intact, contralateral infraspinatus served as an internal positive control. Tendon-bone constructs were harvested after 3 months in vivo and outcome measures included biomechanical testing, histological staining, and immunohistochemical staining. Biomechanical testing revealed that maximum load bearing capacity was comparable between all groups, while MSC-seeded scaffold repairs exhibited increased stiffness relative to non-seeded scaffold repairs. Histological staining revealed robust collagen deposition around ELAC fibers and increased cellularity within the continuum of woven scaffolds as compared to native tendon. Immunohistochemical staining revealed presence of collagens I and III in all groups, but procollagen I and the tendon-specific marker tenomodulin were only observed in seeded and non-seeded ELAC scaffold repairs. Findings of this pilot study warrant continued investigation of ELAC biotextile scaffolds for repair of critically-sized rotator cuff tendon defects. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res B Part B, 2018. PMID- 30485650 TI - Spatially resolved covalent functionalization patterns on graphene. AB - Spatially resolved functionalization of 2-D materials is highly demanded but very challenging to achieve. The chemical patterning is typically tackled by preventing contact between the reagent and material, with various accompanying challenges. Photochemical transformation on the other hand inherently provides remote high spatiotemporal resolution using the cleanest reagent - a photon. Here, we combine two competing reactions on a graphene substrate to create functionalization patterns on a micrometre scale via the Mitsunobu reaction. The mild reaction conditions allow introduction of covalently dynamic linkages, which can serve as reversible labels for surface- or graphene-enhanced Raman spectroscopy characterization of the patterns prepared. The proposed methodology thus provides a pathway for local introduction of arbitrary functional groups on graphene. PMID- 30485651 TI - Can youth at high risk of illness progression be identified by measures of rumination and sleep-wake disturbance. AB - AIM: Clinical staging models offer a useful framework for understanding illness trajectories, where individuals are located on a continuum of illness progression from stage 0 (at-risk but asymptomatic) to stage 4 (end-stage disease). Importantly, clinical staging allows investigation of risk factors for illness progression with the potential to target trans-diagnostic mechanisms at an early stage, especially in help-seeking youth who often present with sub-threshold syndromes. While depressive symptoms, rumination and sleep-wake disturbances may worsen syndrome outcomes, the role of these related phenomena has yet to be examined as risk factors for trans-diagnostic illness progression in at-risk youth. METHODS: This study is a prospective follow-up of 248 individuals aged 12 to 25 years presenting to headspace services with sub-threshold syndromes (stage 1) classified under the clinical staging model to determine transition to threshold syndromes (stage 2). Factor analysis of depression, rumination and sleep-wake patterns was used to identify key dimensions and any associations between factors and transition to stage 2 at follow-up. RESULTS: At 1 year, 9% of cases met criteria for stage 2 (n = 22). One of three identified factors, namely the factor reflecting the commonalities shared between rumination and sleep-wake disturbance, significantly differentiated cases that transitioned to stage 2 vs those that did not demonstrate transition. Items loading onto this factor, labelled Anergia, included depression severity and aspects of rumination and sleep-wake disturbance that were characterized as introceptive. CONCLUSIONS: Common dimensions between rumination and sleep-wake disturbance present a detectable trans-diagnostic marker of illness progression in youth, and may represent a target for early intervention. PMID- 30485653 TI - 2018 Asia Pacific Conference on Medical and Health Science, 28-30 November 2018, Nagoya, Japan. PMID- 30485652 TI - Influence of PDLA nanoparticles size on drug release and interaction with cells. AB - Polymeric nanoparticles (NPs) are strong candidates for the development of systemic and targeted drug delivery applications. Their size is a determinant property since it defines the NP-cell interactions, drug loading capacity, and release kinetics. Herein, poly(d,l-lactic acid) (PDLA) NPs were produced by the nanoprecipitation method, in which the influence of type and concentration of surfactant as well as PDLA concentration were assessed. The adjustment of these parameters allowed the successful production of NPs with defined medium sizes, ranging from 80 to 460 nm. The surface charge of the different NPs populations was consistently negative. Prednisolone was effectively entrapped and released from NPs with statistically different medium sizes (i.e., 80 or 120 nm). Release profiles indicate that these systems were able to deliver appropriate amounts of drug with potential applicability in the treatment of inflammatory conditions. Both NPs populations were cytocompatible with human endothelial and fibroblastic cells, in the range of concentrations tested (0.187-0.784 mg/mL). However, confocal microscopy revealed that within the range of sizes tested in our experiments, NPs presenting a medium size of 120 nm were able to be internalized in endothelial cells. In summary, this study demonstrates the optimization of the processing conditions to obtain PDLA NPs with narrow size ranges, and with promising performance for the treatment of inflammatory diseases. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 00A: 1-12, 2018. PMID- 30485654 TI - The use of Sclerotherapy with Polidocanol foam in the treatment of second-degree haemorrhoidal disease - a video vignette. AB - Hemorrhoidal disease (HD) is one of the most common anorectal condition with a prevalence ranging between 4% and 36% of the population. Depending on the severity, HD can be effectively treated with medical treatment and office-based procedures as rubber-band ligation or sclerotherapy [1] or various surgical approaches [2]. Sclerotherapy has been described for treating grade I to III HD [3]. The injection of sclerosing agent such as polidocanol provokes an inflammatory reaction with subsequent necrosis, fibrosis and fixation of the hemorrhoidal tissue. This article is protected by copyright. All rights reserved. PMID- 30485655 TI - Objective and subjective cognitive functioning in relation to psychopathology among women with early psychosis. AB - BACKGROUND: Subjective cognitive impairment (SCI) among early psychosis is under recognized and under-studied. However, SCI is as important as objective impairment to be understood, since it assesses cognitive difficulties in real life situations from a personal perspective and is therefore an essence of individualized medicine. This study aims to explore the associations between the objective and subjective measures of cognitive impairments and to identify factors contributing to SCI among people with early psychosis. METHODS: Participants were 60 females (mean age 24.57 +/- 8.28) who had a diagnosis of psychotic-spectrum disorder within 5 years. They completed a battery of neuropsychological tests assessing a range of cognitive functions including verbal learning, memory, attention, and executive functions. The Subjective Cognitive Impairment Scale (SCIS) was used to assess their perceived cognitive decline. Psychotic symptoms and depression were also assessed. RESULTS: SCIS was not correlated with any of the objective cognitive tests results. It was positively correlated with depression and positive symptoms. A hierarchical multiple regression model revealed that positive symptoms and depression together explained 31.9% of the total variance in SCIS and only depression significantly predicted SCI. Performances on the memory tests were correlated with, and predicted by negative symptoms. CONCLUSIONS: There was no correlation between SCI and objective cognitive performances in patients with early psychosis. Treatments should not only focus on symptomatic remission and performance of cognitive tests, but also place emphasis on improving moods and subjective cognitive functions of individuals with early psychosis. PMID- 30485656 TI - Pediatric dysautonomia: Much-maligned, often overmedicated, but not as complex as you think. AB - Dysautonomia is an increasingly recognized yet still poorly understood disease within the field of pediatrics. Symptoms, including dizziness, headaches, fatigue, joint pain, anxiety, and intolerance of heat or cold, are often significant and difficult to sort, especially in terms of their relation to each other. This often leads to referral to multiple subspecialists, who then proceed to treat seemingly familiar symptoms in kind. In the authors' experience, this leads to more frustration on the part of the patients and their physicians when symptom improvement does not follow (or can even worsen). On the other hand, by understanding the pathophysiology, treatment success is possible by directing therapies toward the root causes and just as importantly, enlisting the patient in a daily treatment plan. In the text that follows, we hope to convey these viewpoints by highlighting an involved case, discussing the pathophysiology, outlining the usual evaluation, and finally describing our approach to treatment. PMID- 30485657 TI - The relationship between serum apelin levels and aortic dilatation in bicuspid aortic valve patients. AB - OBJECTIVE: The bicuspid aortic valve (BAV) is the most common congenital heart disease. The process of aortic dilatation is not completely clear in patients with the BAV. Apelin is a peptide found at high levels in vascular endothelial cells which has a role in vascular regulation and cardiovascular function. The aim of this study was to determine the relationship between serum apelin levels and ascending aortic dilatation in adult patients with BAV. DESIGN: This cross sectional study included 62 patients with isolated BAV and to an age, gender, and body mass index-matched control group of 58 healthy volunteers with tricuspid aortic valve. Transesophageal echocardiography was performed on all patients to determine the type of BAV. Aortic diameters of the aortic root, sinus valsalva, sinotubular junction, and ascending aorta were evaluated with echocardiography. Patients with BAV were divided into two subgroups according to the aortic diameters, as the nondilated BAV group and the dilated BAV group. Serum apelin level was analyzed with ELISA method. RESULTS: The serum apelin levels of the BAV patients were significantly lower than those of the control group (833.5, 25th 75th percentile (713.5-1745) pg/dL vs 1669 (936-2543) pg/dL; P = 0.006). In the subgroup analysis, serum apelin level was significantly different between the nondilated BAV group and the dilated BAV group [977 (790-2433) pg/dL vs 737 (693 870) pg/dL, P < 0.05] and between the dilated BAV group and the control group [737 (693-870) pg/dL vs 1669 (936-2543) pg/dL, P < 0.001]. In multivariate logistic regression analysis apelin [7.27 (95% CI: 1.73-30.42), P = 0.007] and age [1.05 (95% CI: 0.99-1.20), P = 0.049] were determined as independent predictors for ascending aortic dilatation. CONCLUSION: Low serum apelin level was associated with dilatation of ascending aortic in BAV patients. However, apelin was not relevant to BAV without aortic dilatation. PMID- 30485658 TI - From stem cells protection to skin microbiota balance: Orobanche rapum extract, a new natural strategy. AB - BACKGROUND: Healthy skin is a delicate balance between skin renewal and microbiota homeostasis, and its imbalance promotes premature aging and dermatological disorders. Skin stem cells are key actors in this process but their sensitivity to aging and external stressors such as UV reduces the skin renewal power. The skin microbiota has been recently described as active in the healthy skin, and its imbalance could trigger some disorders. AIMS: We hypothesized that reactivation of stem cells and maintenance of microbiota could be a disruptive strategy for younger and healthier skin. We thus developed a new plant extract that restores the entire skin renewal process by sequential activation from stem cells stimulation to microbiota protection. METHODS: We studied stem cells comportment in the presence of Orobanche rapum extract by survivin immunocytochemistry and caspases 3 and 9 dosages. We also analyzed epidermal differentiation markers by immunohistochemistry and lipids organization by GC/MS At the clinical level, we investigated the impact of O. rapum extract on microbiota and on skin aspect. RESULTS: We demonstrated an active protection of skin stem cells through the maintenance of their clone-forming capacity and resistance to UV through the overexpression of survivin coupled to caspases inhibition. Furthermore, we showed the restoration of epidermal differentiation markers and ceramide biosynthesis favorable to orthorhombic organization. Clinical studies, including microbiota analysis, showed an active skin surface renewal coupled with microbiota protection. CONCLUSION: We evidenced that our active ingredient is able to stimulate skin rejuvenation while protecting the cutaneous microbiota, creating healthier skin and thereby beauty. PMID- 30485659 TI - Dysrhythmias in patients with a complete atrioventricular septal defect: From surgery to early adulthood. AB - OBJECTIVE: Outcomes after surgical repair of complete atrioventricular septal defect (cAVSD) have improved. With advancing age, the risk of development of dysrhythmias may increase. The aims of this study were to (1) examine development of sinus node dysfunction (SND), atrial and ventricular tachyarrhythmias, and (2) study progression of atrioventricular conduction abnormalities in young adult patients with repaired cAVSD. STUDY DESIGN: In this retrospective multicenter study, 74 patients (68% female) with a cAVSD repaired in childhood were included. Patients' medical files were evaluated for occurrence of SND, atrioventricular conduction block (AVB), atrial and ventricular tachyarrhythmias. RESULTS: Median age at repair was 6 months (interquartile range 3-10) and median age at last follow-up was 24 years (interquartile range 21-28). SND occurred after a median of 17 years (interquartile range 11-19) after repair in 23% of patients, requiring pacemaker implantation in two patients (12%). Regular supraventricular tachycardia was observed in three patients (4%). Atrial fibrillation and ventricular tachyarrhythmias were not observed. Twenty-seven patients (36%) had first-degree AVB, which was self-limiting in 16 (59%) and persistent in 10 (37%) patients. One patient developed third-degree AVB 7 days after left atrioventricular valve replacement. Spontaneous type II second-degree AVB occurred in a 28-year-old patient. Both patients underwent pacemaker implantation. CONCLUSIONS: Clinically significant dysrhythmias were uncommon in young adult patients after cAVSD repair. However, three patients required pacemaker implantation for either progression of SND or spontaneous type II second-degree AVB. Longer follow-up should point out whether dysrhythmias will progress or become more prevalent with increasing age. PMID- 30485660 TI - Nanofibers for Biomedical and Healthcare Applications. AB - Unique features of nanofibers provide enormous potential in the field of biomedical and healthcare applications. Many studies have proven the extreme potential of nanofibers in front of current challenges in the medical and healthcare field. This review highlights the nanofiber technologies, unique properties, fabrication techniques (i.e., physical, chemical, and biological methods), and emerging applications in biomedical and healthcare fields. It summarizes the recent researches on nanofibers for drug delivery systems and controlled drug release, tissue-engineered scaffolds, dressings for wound healing, biosensors, biomedical devices, medical implants, skin care, as well as air, water, and blood purification systems. Attention is given to different types of fibers (e.g., mesoporous, hollow, core-shell nanofibers) fabricated from various materials and their potential biomedical applications. PMID- 30485662 TI - Environmental DNA metabarcoding studies are critically affected by substrate selection. AB - Effective biomonitoring is critical for driving management outcomes that ensure long-term sustainability of the marine environment. In recent years environmental DNA (eDNA), coupled with metabarcoding methodologies, has emerged as a promising tool for generating biotic surveys of marine ecosystems, including those under anthropogenic pressure. However, more empirical data is needed on how to best implement eDNA field sampling approaches to maximise their utility for each specific application. The effect of the substrate chosen for eDNA sampling on the diversity of marine taxa detected by DNA metabarcoding has not yet been systematically analysed, despite aquatic systems being those most commonly targeted for eDNA studies. We investigated the effect of four commonly used eDNA substrates to explore taxonomic diversity: (i) surface water, (ii) marine sediment, (iii) settlement-plates and (iv) planktonic tows. With a focus on coastal ports, 332 eDNA samples from Australia (Indian and Southern oceans) and Kazakhstan (Caspian Sea) were collected and analysed by multi-assay DNA metabarcoding. Across study locations, between 30-52% of eukaryotic families detected were unique to a particular substrate and less than 6% of families were found in all four substrates. Taxonomic composition varied significantly depending on the substrate sampled implying that the suitability (and bias) of an eDNA substrate will depend on the focal taxa. These findings demonstrate that single substrate eDNA metabarcoding likely underestimates the total eukaryotic diversity. Future eDNA experimental design should consider incorporating multiple substrates or select substrate(s) best suited to the specific detection of target taxa. This article is protected by copyright. All rights reserved. PMID- 30485661 TI - Perioperative outcomes and risk assessment in dialysis patients: current knwoledge and future directions. AB - Perioperative medicine is rapidly emerging as a key discipline to address the specific needs of high-risk surgical groups, such as those on chronic dialysis. Crude hospital separations rates for chronic dialysis patients are considerably higher than patients with normal renal function, with up to 15% of admission being related to surgical intervention. Dialysis dependency carries substantial mortality and morbidity risk compared to patients with normal renal function. This group of patients has a high co-morbid burden and complex medical need making accurate perioperative planning essential. Existing perioperative risk assessment tools are unvalidated in chronic dialysis patients. Furthermore, they fail to incorporate important dialysis treatment-related characteristics that could potentially influence perioperative outcomes. There is a dearth of information on perioperative outcomes of Australasian dialysis patients. Current perioperative outcome estimates stem predominantly from North American literature, however the generalizability of these findings is limited, as the survival of North American dialysis patients is significantly inferior to their Australasian counterparts and potentially confounds reported perioperative outcomes; let alone regional variation in surgical indication and technique. We propose that data-linkage between high-quality national registries will provide more complete data with more detailed patient and procedural information to allow for more informative analyses to develop and validate dialysis specific risk assessment tools. This article is protected by copyright. All rights reserved. PMID- 30485663 TI - Severe conduct problems in adolescence and risk of schizophrenia in early adulthood. AB - AIM: Reform school (RS) is a foster care institution for adolescents with severe conduct problems. Both instability of early rearing environment and severe conduct problems in adolescence may associate with later psychotic disorders. We studied whether the risk of schizophrenia in adulthood is elevated in RS adolescents, and whether it is related to the age at first foster care placement or placement instability. METHODS: Adult age schizophrenia spectrum disorder data from RS subjects (N = 1099) were compared to a comparison group matched by age, sex, and place of birth (N = 5437) in a register based follow-up study, with up to 23 years follow-up time. Schizophrenia was also predicted with chosen placement factors. Cox proportional regression model was used in the analysis. RESULTS: RS subjects had an 8-fold (HR = 7.82, 95% CI 5.63-10.87) risk of schizophrenia compared to the comparison group. RS subjects also had an earlier age of schizophrenia onset. RS cohort, gender, placement instability, or age during the first out-of-home placement did not predict later schizophrenia. CONCLUSIONS: Adolescents with severe conduct problems are a specific high-risk group for later schizophrenia. The risk manifests early, which compromises the pathway to the adult well-being. Specialized screening procedures for psychosis risk should be implemented in the standard clinical procedures when working with adolescents with severe behaviour problems, and early intervention programs should be available. PMID- 30485664 TI - Prognostic factors and outcome of surgically treated patients with brain metastases of non-small cell lung cancer. AB - BACKGROUND: Brain metastases (BM) are a common consequence of lung cancer and surgery is effective; however, the factors affecting survival after surgery are unclear. The aim of this study was to identify the outcomes and prognoses of post metastasectomy patients with BM from non-small cell lung cancer (NSCLC) at a single institution over a 15-year period. METHODS: NSCLC patients who had undergone BM surgery were retrospectively identified. Survival was analyzed using the Kaplan-Meier curve, and univariate and multivariate factors associated with survival were identified using the Cox proportional hazards model. RESULTS: The median overall survival was 9.8 months, 18 (14.8%) patients survived > 24 months, and 6 (4.9%) > 36 months. The one and two-year survival rates were 41% and 18.6%, respectively. Univariate analysis revealed that recursive partitioning analysis (RPA) classification, Karnofsky Performance Scale (KPS) scores, BM number, extracranial metastasis status, different lesion locations, resection extent, postoperative treatment, and salvage therapy after recurrence significantly influenced patient survival. The different treatment modalities for primary lesions also affected postoperative survival. KPS >= 70, RPA class I/II, and postoperative chemotherapy were independent factors that decreased the risk of death from BM. Interestingly, the initial onset of intracranial lesions could increase the risk of death from BM. CONCLUSION: A KPS score >= 70, RPA class I/II, and postoperative chemotherapy could benefit post-metastasectomy patients with BM from NSCLC. Conversely, the initial onset of intracranial lesions is an unfavorable factor that increases the risk of death. These findings support the use of personalized therapy for patients with BM from NSCLC. PMID- 30485665 TI - Omaha System-based discharge guidance improves knowledge and behavior in Mainland Chinese patients with angina who are not receiving interventional treatment: A randomized controlled trial. AB - AIM: To test the effectiveness of discharge guidance based on the theoretical framework of the Omaha System on Mainland Chinese patients with angina without interventional treatment. METHODS: A randomized controlled trial was conducted on 150 Mainland Chinese patients with angina without interventional treatment between December, 2015 and September, 2016. The participants were randomly allocated to discharge guidance based on the Omaha System or usual care. The participants were assessed with the self-designed Problem Rating Survey Scale, including three dimensions and seven items. The Cronbach's alpha coefficient was 0.81. The 7-item-level content validity index was 0.80-1.00 and the scale-level content validity index was 0.94. RESULTS: The scores of the outcome measures differed significantly between the two groups at all three time points (admission day; 3 days before discharge; discharge day) and increased gradually. Improvements in knowledge, behavior , and the total score of the intervention group were significantly higher than those of the control group. An improvement in status did not differ significantly. CONCLUSION: The Omaha System-based discharge guidance is effective at enhancing knowledge and behavior in patients from Mainland China with angina without interventional treatment. PMID- 30485666 TI - Whole-cell biocatalysis platform for gram-scale oxidative dearomatization of phenols. AB - Technologies enabling new enzyme discovery and efficient protein engineering have spurred intense interest in the development of biocatalytic reactions. In recent years, whole-cell biocatalysis has received attention as a simple, efficient, and scalable biocatalytic reaction platform. Inspired by these developments, we have established a whole-cell protocol for oxidative dearomatization of phenols using the flavin-dependent monooxygenase, TropB. This approach provides a scalable biocatalytic platform for accessing gram-scale quantities of chiral synthetic building blocks. PMID- 30485668 TI - ABPI reporting and compression recommendations in global clinical practice guidelines on venous leg ulcer management: A scoping review. AB - Clinical practice guidelines (CPGs) for venous leg ulcer (VLU) management recommend below-knee compression to improve healing outcomes after calculating the ankle-brachial pressure index (ABPI) to rule out significant arterial disease. This systematic scoping review aimed to complete a qualitative and quantitative content analysis of international CPGs for VLU management to determine if consensus existed in relation to recommendations for compression application based on an ABPI reading and clinical assessment. Our review shows that there is a lack of consensus across 13 VLU CPGs and a lack of clear guidance in relation to the specific ABPI range of compression therapy that can be safely applied. An area of uncertainty and disagreement exists in relation to an ABPI between 0.6 and 0.8, with some guidelines advocating that compression is contraindicated and others that there should be reduced compression. This has implications in clinical practice, including when it is safe to apply compression. In addition, the inconsistency in the levels of evidence and the grades of recommendation makes it difficult to compare across various guidelines. PMID- 30485667 TI - Biofunctionalized Electrospun PCL-PIBMD/SF Vascular Grafts with PEG and Cell Adhesive Peptides for Endothelialization. AB - Artificial small-caliber vascular grafts are still limited in clinical application because of thrombosis, restenosis, and occlusion. Herein, a small caliber vascular graft (diameter 2 mm) is fabricated from poly(epsilon caprolactone)-b-poly(isobutyl-morpholine-2,5-dione) (PCL-PIBMD) and silk fibroin (SF) by electrospinning technology and then biofunctionalized with low-fouling poly(ethylene glycol) (PEG) and two cell-adhesive peptide sequences (CREDVW and CAGW) with the purpose of enhancing antithrombogenic activity and endothelialization. The successful grafting of PEG and peptide sequences is confirmed by X-ray photoelectron spectroscopy. The suitable surface wettability of the modified vascular graft is testified by water contact angle analysis. The surface hemocompatibility is verified by platelet adhesion assays and protein adsorption assays, and the results demonstrate that both platelet adhesion and protein adsorption on the biofunctionalized surface are significantly reduced. In vitro studies demonstrate that the biofunctionalized surface with suitable hydrophilicity and cell-adhesive peptides can selectively promote the adhesion, spreading, and proliferation of human umbilical vein endothelial cells. More importantly, compared with control groups, this biofunctionalized small-caliber vascular graft shows high long-term patency and endothelialization after 10 weeks of implantation. The biofunctionalization with PEG and two cell-adhesive peptide sequences is an effective method to improve the endothelialization and long-term performance of synthetic vascular grafts. PMID- 30485669 TI - Stories of the future: manipulating RNA and Intra/Interkingdom communication. PMID- 30485670 TI - Exploratory comparison of auditory verbal hallucinations and other psychotic symptoms among youth with borderline personality disorder or schizophrenia spectrum disorder. AB - OBJECTIVE: This study explored phenomenological aspects of auditory verbal hallucinations (AVH) and other psychotic symptoms among youth with borderline personality disorder (BPD). METHODS: Sixty-eight outpatients, aged 15 to 25 years, were categorized into three groups according to their primary Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis and AVH symptom profile; BPD + AVH (n = 23), schizophrenia spectrum disorder (SZ) + AVH (n = 22) and BPD with no AVH (n = 23). RESULTS: No differences in AVH were found between BPD + AVH and SZ + AVH. Compared with SZ + AVH, BPD + AVH scored lower on delusions and difficulty in abstract thinking and higher on hostility. BPD + AVH reported more severe self-harm, paranoid ideation, dissociation, anxiety and stress than BPD no AVH. CONCLUSIONS: This study replicates, in a sample of youth, the finding from studies of adults that AVH in BPD are indistinguishable from those in SZ, when assessed with the Psychotic Symptom Rating Scales (PSYRATS). Clinicians should specifically enquire about AVH among youth with BPD. When present, AVH appear to be an indicator of a more severe form of BPD. PMID- 30485671 TI - Psychiatrists' opinion towards medication discontinuation in remitted first episode psychosis: A multi-site study of the Asian Network for Early Psychosis. AB - AIM: The study investigated psychiatrists' views towards the issue of medication discontinuation for patients in remission from first-episode psychosis in four countries (Hong Kong, Korea, Singapore and Japan) that are part of the Asian Network for Early Psychosis, focusing on whether the views of these countries differ with one another. METHODS: A questionnaire was distributed to psychiatrists for completion. The questionnaire contained three sections: direct questions probing at views on medication discontinuation, case vignettes to assess applied decision-making and a checklist of criteria psychiatrists may view as necessary for the patient to satisfy before discontinuation. Total of 484 psychiatrists (97 from Hong Kong, 88 from Korea, 64 from Singapore and 233 from Japan) completed the questionnaire. RESULTS: We found that (a) Asian psychiatrists believed that 1% to 19% of remitted patients can discontinue medication, an estimation that was lower than Western psychiatrists; (b) in agreement with clinical guidelines, Asian psychiatrists believed that patients should remain on medication for at least 1 to 2 years following the absence of psychotic symptoms; (c) "Absence of any relapsing episode following first episode" was considered the most important criterion when making a decision; and (d) there were significant differences in clinicians' perceptions across the four countries: for instance, Korean psychiatrists were more conservative with the duration of antipsychotics maintenance, while Singaporean psychiatrists were more open-minded towards clinical trials. CONCLUSIONS: Culture and social norms appear to determine the relative importance of factors that psychiatrists might consider during the decision-making process, thereby producing variations in the views held in different countries. PMID- 30485672 TI - Increasing fluorescence lifetime for resolution improvement in STED nanoscopy. AB - Super-resolution microscopy (SRM) has had a substantial impact on the biological sciences due to its ability to observe tiny objects less than 200 nm in size. Stimulated emission depletion (STED) microscopy represents a major category of these SRM techniques that can achieve diffraction-unlimited resolution based on a purely optical modulation of fluorescence behaviors. Here, we investigated how the laser beams affect fluorescence lifetime in both confocal and STED imaging modes. The results showed that with increasing illumination time, the fluorescence lifetime in two kinds of fluorescent microspheres had an obvious change in STED imaging mode, compared that in confocal imaging mode. As a result, the reduction of saturation intensity induced by the increase of fluorescence lifetime can improve the STED imaging resolution at the same depletion power. The phenomenon was also observed in Star635P labeled human Nup153 in fixed HeLa cells, which can be treated as a reference for the synthesis of fluorescent labels with the sensitivity to the surrounding environment for resolution improvement in STED nanoscopy. The influence of laser beams on the fluorescence lifetime of 40 nm fluorescent microspheres in confocal and STED imaging modes. This article is protected by copyright. All rights reserved. PMID- 30485673 TI - Factors that hindered care seeking among people with a first diagnosis of psychosis. AB - AIM: Evidence-based treatment can improve psychosis outcomes, but service providers need to understand and address the reasons people experiencing first episode psychosis avoid or delay care seeking. The goal of this study was to identify reasons care seeking might be postponed, from the points of view of patients, caregivers and health care professionals in a large health care delivery system, in the United States, without an early psychosis intervention program. METHODS: About 22 patients who had received an initial psychosis diagnosis and 10 of their caregivers were interviewed about their experiences and pathways to care. Additionally, 15 administrator or clinician key informants with responsibility for psychosis services were interviewed and asked to describe ways that they thought early psychosis identification and treatment engagement could be improved. All interviews were transcribed, coded and analysed together using thematic analysis. RESULTS: Some patients did not perceive their early psychotic experiences as concerning because they were familiar. Among those concerned, the desire to make sense of their experiences and avoid detection or stigma caused some to conceal symptoms or isolate themselves. Caregivers who observed withdrawal often attributed it to typical adolescent behaviour, which led to treatment delays. Legal and privacy protections led to delays among young adults. CONCLUSIONS: To attract individuals to early psychosis services, outreach and engagement programs should help individuals and caregivers recognize their experiences as opportunities for care, and design and market services that promote sense-making, offer hope and reduce stigma and system-level privacy related barriers to care engagement. PMID- 30485674 TI - Surveys still teach vital non-technical lessons in General Surgery. AB - In general surgery, observational studies are disregarded and often seen as non noteworthy research. We intend to defend the use of surveys in general surgery and colorectal surgery. This review highlights the historical importance and contemporary utility of surveys internationally and in our region, thus reminding Australasian surgeons and clinicians in numerous disciplines of the usefulness of this research tool. Well-constructed surveys often successfully capture qualitative data otherwise impossible to collect through randomized controlled trial. The results of these surveys may advise national policies and medical registration agencies thus having a direct influence on individuals and their public health. Samples from contemporary survey-based research publications from international and Australasian authors are used to illustrate some of the vital non-technical lessons learned in recent times. PMID- 30485675 TI - Multi-Omics Study on the Impact of Cysteine Feed Level on Cell Viability and mAb Production in a CHO Bioprocess. AB - There is continual demand to maximize CHO cell culture productivity of a biotherapeutic while maintaining product quality. In this study, a comprehensive multi-omics analysis was performed to investigate the cellular response to the level of dosing of the amino acid cysteine (Cys) in the production of a monoclonal antibody (mAb). When Cys feed levels are insufficient, there is a significant decrease in protein titer. Multi-omics (metabolomics and proteomics, with support from RNAseq) was performed over the time course of the CHO bioprocess producing an IgG1 mAb in 5 L bioreactors. Pathway analysis revealed that insufficient levels of Cys in the feed led to Cys depletion in the cell. This depletion negatively impacted antioxidant molecules, such as glutathione (GSH) and taurine, leading to oxidative stress with multiple deleterious cellular effects. In this paper, we consider the resultant ER stress and subsequent apoptosis that affects cell viability and viable cell density. Key metabolic enzymes and metabolites were identified that can be potentially monitored as the process progresses and/or increased in the cell either by nutrient feeding or genetic engineering. This work reinforces the centrality of redox balance to cellular health and success of the bioprocess as well as the power of multi-omics to provide an in-depth understanding of the CHO cell biology during biopharmaceutical production. PMID- 30485676 TI - Selection of the optimum 3D-printed pore and the surface modification techniques for tissue engineering tracheal scaffold in vivo reconstruction. AB - The influences of pore sizes and surface modifications on biomechanical properties and biocompatibility (BC) of porous tracheal scaffolds (PTSs) fabricated by polycaprolactone (PCL) using 3D printing technology. The porous grafts were surface-modified through hydrolysis, amination, and nanocrystallization treatment. The surface properties of the modified grafts were characterized by energy dispersive spectroscopy (EDS) and scanning electron microscopy (SEM). The materials were cocultured with bone marrow mesenchymal stem cells (BMSCs). The effect of different pore sizes and surface modifications on the cell proliferation behavior was evaluated by the cell counting kit-8 (CCK-8). Compared to native tracheas, the PTS has good biomechanical properties. A pore diameter of 200 MUm is the optimum for cell adhesion, and the surface modifications successfully improved the cytotropism of the PTS. Allogeneic implantation confirmed that it largely retains its structural integrity in the host, and the immune rejection reaction of the PTS decreased significantly after the acute phase. Nano-silicon dioxide (NSD)-modified PTS is a promising material for tissue engineering tracheal reconstruction. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A:, 2018. PMID- 30485677 TI - Characteristics of gout patients according to the laterality of nephrolithiasis: A cross-sectional study using helical computed tomography. AB - OBJECTIVE: To clarify the clinical and laboratory characteristics of nephrolithiasis in gout by computed tomography (CT). METHODS: In 350 gout patients, unenhanced CT was performed at the 1st visit to hospital. Calculus density spots exceeding 1 mm in diameter with a CT value >120 Hounsfield units in the kidneys were defined as kidney stones. The association between laterality and the number of stones was investigated in each stone carrier. The 350 patients were classified into three groups (bilateral, unilateral and non-stone carriers). Then serum urate (Sua), renal function, uric acid metabolism, and the prevalence of metabolic syndrome (Mets) were compared among these groups by the Tukey-Kramer test or Fisher's exact test. RESULTS: Kidney stone(s) were detected in 108 (31%) of the 350 patients (bilateral in 58 and unilateral in 50). In 64 of the 108 patients (59%), there was no history of urolithiasis. Sua, serum creatinine and uric acid clearance were significantly higher (P = 0.001, P < 0.001, P = 0.043, respectively), while the estimated glomerular filtration rate was significantly lower (P = 0.039) in bilateral stone carriers than in non-stone carriers. No significant differences of uric acid metabolism or the prevalence of Mets were noted among the three groups. CONCLUSIONS: Approximately one-third of gout patients had kidney stones and more than half of the patients with stones were bilateral and multiple stone carriers. Elevation of Sua might increase the stone burden in gout, leading to more severe renal dysfunction. An association between nephrolithiasis and Mets was not demonstrated in gout patients. PMID- 30485678 TI - Corrigendum. PMID- 30485679 TI - Corrigendum. PMID- 30485680 TI - Rapid discrimination of colon cancer cells with single base mutation in KRAS gene segment using laser tweezers Raman spectroscopy. AB - Laser tweezers Raman spectroscopy (LTRS) as a label-free and non-invasive technology has been proven to be an ideal tool for analysis of single living cells which provides important fingerprint information without interference from surrounding environments. For the first time, LTRS system was successfully employed to examine the colon cancer cells with single base mutation in KRAS gene segment including DKS-8 (KRAS wild-type) and DLD-1 (KRAS mutant-type), HKE-3 (KRAS wild-type) and HCT-116 (KRAS mutant-type). Spectra changes of some vital biomolecules due to the gene mutation state were sensitively recorded by our home made LTRS system. As a result of the comparison between DKS-8 and DLD-1 cells, an index of 97.5% of correct classification was obtained by combining LTRS with PCA LDA statistical analysis, while an index of 97.0% of correct classification was achieved between HKE-3 and HCT-116 cells. Moreover, between wild-type cells (DKS 8 and HKE-3) versus mutant-type cells (DLD-1 and HCT-116), the index of correct classification was 81.2%, which was quite encouraging. Our preliminary results showed that the LTRS system coupled with PCA-LDA analysis will have a great potential for further applications in the rapid and label-free detection of circulating tumor cells in liquid biopsy. This article is protected by copyright. All rights reserved. PMID- 30485681 TI - TMT-Based Quantitative Proteomic Analysis Reveals Proteomic Changes Involved in Longevity. AB - PURPOSE: Individual lifespans vary widely, and longevity is the main concern from ancient to modern times. This study is aimed to identify plasma proteins associated with longevity by proteomics technique. EXPERIMENTAL DESIGN: Tandem mass tags (TMT)-based proteomics analysis is performed for the plasma of Bama longevity group and a control group to analyze the differentially expressed proteins (DEPs). A validation set is used to verify the results of TMT-based proteomics. RESULTS: Between Bama natives and the control individuals, the authors identify 175 DEPs, which are mainly involved in complement and coagulation cascades, metabolism of glyco and lipid, and regulation of actin cytoskeleton. Consistent with the proteomic analysis, plasma levels of MMP2, CCL5, and PF4 are significantly lower in Bama participants than in controls, whereas IGFBP2 and C9 increase in Bama individuals, in the validation set. By ROC analysis, combinations of these five proteins result in a high AUC value (0.991, 95% CI, 0.929-1.000, p < 0.0001) to distinguish longevous participants from controls. CONCLUSIONS AND CLINICAL RELEVANCE: The results highlight the roles of complement and coagulation cascades, metabolism of glyco and lipid, and inflammatory and immune response may play important roles in longevity. And the DEPs may serve as clinically useful biomarkers for healthy aging and predicting longevity. PMID- 30485682 TI - iTRAQ Based Quantitative Proteomics Approach Identifies Novel Diagnostic Biomarkers that were Essential for Glutamine Metabolism and Redox Homeostasis for Gastric Cancer. AB - PURPOSE: To screen the novel biomarkers for gastric cancer and determine the values of glutaminase 1 (GLS1) and gamma-glutamylcyclotransferase (GGCT) for detecting gastric cancer. EXPERIMENTAL DESIGN: A discovery group of four paired gastric cancer tissue samples were labeled with iTRAQ agents and identified with LC-ESI-MS/MS. A validation group of 168 gastric cancer samples and 30 healthy controls were used to validate the expression of GLS1 and GGCT. RESULTS: Four hundred and thirty one proteins were found differentially expressed in gastric cancer tissues. Of these proteins, GLS1 and GGCT were found over expressed in gastric cancer patients, with sensitivity of 75.6% (95%CI: 69%-82.2%) and specificity of 81% (95%CI: 75%-87%) for glutaminase 1, and with sensitivity of 63.1% (95%CI: 55.7%-71.5%) and specificity of 60.7% (95%CI: 53.3%-68.2%) for gamma-glutamylcyclotransferase. The co-expression of GLS1 and GGCT in gastric cancer tissues has sensitivity of 78.1% (95%CI: 70.1%-86.1%) and specificity of 86.5% (95%CI: 79.5-93.4%). Moreover, both GLS1 and GGCT presented higher expression of 82.6% (95%CI: 68.5%-99.4%) and 73.9% (95%CI: 54.5%-93.3%) in lymph node metastasis specimen than those in non lymph node metastasis specimen. The areas under ROC curves were up to 0.734 for the co-expression of GLS1 and GGCT in gastric cancer. The co-expression of GLS1 and GGCT was strongly associated with histological grade, lymph node metastasis and TNM stage III/IV. CONCLUSIONS AND CLINICAL RELEVANCE: The present study provides the quantitative proteomic analysis of gastric cancer tissues to identify prognostic biomarkers of gastric cancer. The co-expression level of GLS1 and GGCT is of great clinical values to serve as diagnostic and therapeutic biomarkers for early gastric cancer. This article is protected by copyright. All rights reserved. PMID- 30485683 TI - Mesenchymal Stem Cells Induced by Microencapsulated Chondrocytes on Repairing of Intervertebral Disc Degeneration. AB - OBJECTIVE: To evaluate the therapeutic effects of mesenchymal stem cells induced by microencapsulated chondrocytes on repairing of intervertebral disc degeneration. METHODS: Rabbit chondrocytes and bone marrow-derived mesenchymal stem cells (MSC) were derived. Chondrocytes were microencapsulated by a microcapsule generator to produce microencapsulated chondrocytes (MEC). MSC were then co-cultured with MEC (MSC-MEC) and the properties and the therapeutic effects on repairing of intervertebral disc degeneration were studied. For the in vitro study, cell proliferation, type II collagen, and glycosaminoglycan (GAG) were studied. The MSC induced by chondrocytes in the Transwell system (MSC-MLC) and pure MSC were used as the control group. For the in vivo studied, MSC-MEC were implanted into the intervertebral disc degenerated (IDD) models, and the radiological images, biomechanical properties, collagen II, and histology of the discs were studied. The IDD, MSC, and MSC-MLC groups were used as the control group. RESULTS: In the in vitro study, no significant differences were found among the three groups, indicating that the microcapsule co-culture system will not affect the proliferation of MSC. The type II collagen quantity secreted by MSC-MEC was 23.57 +/- 2.46 ng/MUL, which was more than for MSC-MLC (15.14 +/- 2.31 ng/MUL) and MSC groups (4.17 +/- 1.23 ng/MUL, all P < 0.025). GAG secreted by MSC-MEC was 0.184 +/- 0.006 mg/well, which was more than for the MSC-MLC (0.151 +/- 0.011 mg/well) and MSC groups (0.023 +/- 0.002 mg/well, all P < 0.025). In the in vivo study, no obvious degenerative or protrusive disc was found in the MSC-MEC group, while protrusive discs could be found in the MSC-MLC group, and both degenerative and protrusive discs were found in MSC and IDD groups, which indicated that the reparative effects of MSC-MEC on degenerated discs were better than for the control groups. Biomechanical properties of discs in the MSC-MEC group were maintained at all four time points (2nd, 4th, 8th, and 16th week after implantation). The compressive strength (CS) and the elastic modulus (EM) of MSC and IDD groups were consistently decreased. The CS of the MSC MLC group was increased in the 4th week but decreased again in the 8th week, while the EM of the MSC-MLC group consistently decreased. Western blot results indicated that discs of the MSC-MEC group had more collagen II, which is an important component of discs. Histology staining showed that the nucleus pulposus of MSC-MEC was complete; no obvious fragment of component loss was found, while those of MSC-MLC, MSC, and IDD groups were widened, broken, and hollow. CONCLUSION: The microencapsulation method for half-contact co-culturing improves the differentiation extent of MSC, and MSC induced by chondrocytes could also be used for treatment of IDD. PMID- 30485684 TI - Comparative Mid-term Follow-up Study of Primary Total Hip Arthroplasty with Metal on-metal and Metal-on-polyethylene Bearings. AB - OBJECTIVE: To compare mid-term clinical results of total hip arthroplasty (THA) with metal-on-metal (MoM) and metal-on-polyethylene (MoP) bearings and to evaluate the biological safety of the two kinds of prostheses. METHODS: Thirty two patients who received a primary THA with an MoM articulation between January 2008 and December 2010 were selected to form the MoM group retrospectively. The MoP group consisted of 32 patients who received a THA with an MoP prosthesis during the same period. Clinical assessments, imaging examinations, laboratory tests, and metal ion concentration detections were conducted on each patient. Another 32 healthy volunteers were recruited as the control group. RESULTS: Twenty-seven patients in the MoM group and 28 patients in the MoP group completed the follow-up, with a mean follow-up time of 74.6 and 75.9 months, respectively. The mean Harris score at the latest follow-up was 91.5 +/- 5.1 in the MoM group versus 88.9 +/- 4.0 in the MoP group (P = 0.22). The MoM group showed a better range of motion in flexion, abduction, and external rotation. Co and Cr levels in the MoM group were 2.5-fold and 2.0-fold of these in the MoP group. A mild change of liver function was observed in both groups, while the values of renal function and humoral immunity stayed static. Elevated proportions of Th1 and Th17 cells and decreased proportion of Th2 cells were observed in the MoM group. The occurrence rate of pseudotumors in the MoM and MoP groups was 40.74% +/- 9.45% and 14.28% +/- 6.61%, respectively (P < 0.05). CONCLUSION: At the mid-term follow up, clinical results were satisfied in both groups. MoM prosthesis could result in elevated serum metal ion levels and there is a higher risk of pseudotumor. Long follow-up is needed to evaluate the safety of MoM prostheses. PMID- 30485685 TI - Role of Parecoxib Sodium in the Multimodal Analgesia after Total Knee Arthroplasty: A Randomized Double-blinded Controlled Trial. AB - OBJECTIVE: Total knee arthroplasty (TKA) is an established surgical technique and is the standard treatment for degenerative knee joint diseases. However, severe pain after TKA makes it difficult for many patients to perform early postoperative rehabilitation and functional exercise, which might result in subsequent unsatisfactory recovery of knee joint function and great reduction in patients' satisfaction and quality of life. Orthopaedic surgeons have tried a large variety of analgesics and analgesic modes to relieve patients' pain after TKA. There are many analgesic regimens available in clinical practice but all have some deficiencies. Parecoxib sodium, a highly selective inhibitor of cyclooxygenase-2 (COX-2), can reduce the synthesis of peripheral prostaglandin to exert the effect of analgesia, and relieve inflammation and prevent central sensitization through inhibition of peripheral and central COX-2 expression. In addition, it can be used as a preemptive analgesic without affecting platelet aggregation. However, there does seem to be conflicting evidence in the current research as to whether parecoxib sodium can be used successfully as a preemptive analgesic; the effect of preemptive analgesia with parecoxib sodium in multimodal analgesia is still controversial. This research investigated the effects of parecoxib sodium in a preemptive multimodal analgesic regimen. METHODS: Eighty eight patients were randomized into two groups. The experimental group received parecoxib (46 patients) and the control group received saline (42 patients), administered 30 min before the initiation of the surgical procedure. A patient controlled analgesia (PCA) pump was applied within 48 h after surgery. The visual analogue scale (VAS), drug consumption through the PCA pump, use of salvaging analgesia, range of motion (ROM) of the knee joints, and postoperative complications were observed. RESULTS: The VAS score in the post-anesthesia care unit (PACU) of the parecoxib group was significantly lower than that of the control group (P = 0.039). There was no significant difference in the demographic profiles, duration of operation, hemorrhage in surgery, postoperative hemorrhage, postoperative drainage, VAS at different time points, function of knee joints, length of hospital stay, use of salvaging analgesia, and postoperative drug consumption through the PCA between the two groups (P > 0.05). CONCLUSION: In preemptive multimodal analgesia regimens, parecoxib sodium can significantly decrease the VAS score in the short term, relieve pain shortly after surgery, and does not increase the incidence of complications. Parecoxib sodium is a safe and effective drug in the perioperative analgesic management for TKA. PMID- 30485686 TI - Recombined humanized endostatin-induced suppression of HMGB1 expression inhibits proliferation of NSCLC cancer cells. AB - BACKGROUND: Recombined humanized endostatin (Rh-endostatin) exhibits a potent anti-cancer effect involving multiple molecular targets and signaling pathways. HMGB1 is a highly conserved DNA-binding protein involved in cancer development. The therapeutic effect of Rh-endostatin on HMGB1 has not been reported, thus we investigate the effect in non-small cell lung cancer (NSCLC) cells. METHODS: Quantitative real-time PCR and Western blot were used to analyze the messenger RNA and protein expression of HMGB1 in A549 cancer cells, while enzyme-linked immunosorbent assay was used to detect the release of HMGB1. Western blot was performed to evaluate HMGB1 expression in SK-MES-1 and H661 NSCLC cells. RESULTS: Rh-endostatin inhibited the proliferation of A549 cancer cells and distinctly downregulated the expression and release of HMGB1 in dose and time dependent manners. Rh-endostatin-induced HMGB1 downregulation was confirmed in different types of NSCLC cells. CONCLUSION: These results demonstrate the general phenomenon that Rh-endostatin can induce HMGB1 suppression in a variety of NSCLC cells. Rh-endostatin may suppress HMGB1 expression and release in A549 cancer cells, thus inhibiting cell proliferation. PMID- 30485687 TI - Lignin valorization by cobalt-catalyzed fractionation of lignocellulose to yield monophenolic compounds. AB - Herein, we present a catalytic reductive fractionation of lignocellulose using a heterogeneous cobalt catalyst and formic acid or formate as a hydrogen donor. The catalytic reductive fractionation of untreated birch wood yield monophenolic compounds in up to 34 wt% yield of total lignin, and this corresponds to 76% of the theoretical maximum yield. By model compound studies, we found that the main role of the cobalt catalyst is to stabilize reactive intermediates formed during the organosolv pulping by transfer hydrogenation and hydrogenolysis reactions. In addition to this, the cobalt catalyst is responsible for depolymerization reactions of fragments of lignin by transfer hydrogenolysis reactions targeting the beta-O-4' bond. We were able to recycle the catalyst three times with only negligible decline in efficiency showing the robustness of this novel system. PMID- 30485688 TI - The evolution of RNA structural probing methods: From gels to next-generation sequencing. AB - RNA molecules are important players in all domains of life and the study of the relationship between their multiple flexible states and the associated biological roles has increased in recent years. For several decades, chemical and enzymatic structural probing experiments have been used to determine RNA structure. During this time, there has been a steady improvement in probing reagents and experimental methods, and today the structural biologist community has a large range of tools at its disposal to probe the secondary structure of RNAs in vitro and in cells. Early experiments used radioactive labeling and polyacrylamide gel electrophoresis as read-out methods. This was superseded by capillary electrophoresis, and more recently by next-generation sequencing. Today, powerful structural probing methods can characterize RNA structure on a genome-wide scale. In this review, we will provide an overview of RNA structural probing methodologies from a historical and technical perspective. This article is categorized under: RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry RNA Methods > RNA Analyses in vitro and In Silico RNA Methods > RNA Analyses in Cells. PMID- 30485689 TI - Enhanced Cycling Performance for Lithium-Sulfur Batteries by a Laminated 2D g-C3 N4 /Graphene Cathode Interlayer. AB - Decay in electrochemical performance resulting from the "shuttle effect" of dissolved lithium polysulfides is one of the biggest obstacles for the realization of practical applications of lithium-sulfur (Li-S) batteries. To meet this challenge, a 2D g-C3 N4 /graphene sheet composite (g-C3 N4 /GS) was fabricated as an interlayer for a sulfur/carbon (S/KB) cathode. It forms a laminated structure of channels to trap polysulfides by physical and chemical interactions. The thin g-C3 N4 /GS interlayer significantly suppresses diffusion of the dissolved polysulfide species (Li2 Sx ; 2 Individual Decision-Making Cognitive Biology > Evolutionary Roots of Cognition Neuroscience > Cognition. PMID- 30485701 TI - The South Region Cancer Registry: an evaluation of its exhaustiveness in a cohort of lung cancer patients. AB - The regional cancer registry for Southern Portugal (ROR-Sul) is a population based registry set up in 1988 to observe and monitor disease incidence, prevalence and survival. Recently, the need to monitor real-life use of early approved and high-priced medicines led to therapeutic effectiveness becoming an emerging area of interest. We aimed to evaluate the exhaustiveness of the ROR-Sul database, covering around 4.8 million inhabitants. We have used a retrospective cohort study comprising 3457 lung cancer cases diagnosed during 2014 and 2015 and extracted from ROR-Sul database. Descriptive analysis of missing data was undertaken using IBM SPSS software, v.24. Exhaustiveness of data registry was classified into high (missing values <1%), medium (missing values {1-15%}) or low (missing values > 15%). High exhaustiveness was found for patients demographic information, date of diagnosis, date of first medical appointment, topography, morphology, cancer differentiation, stage of disease and surgery procedure. Medium exhaustiveness was found for biomarkers (ALK, KRAS, and EGFR) results, and immunotherapy regimens. Low exhaustiveness was found for performance status, chemotherapy regimen, and chemotherapy treatment response. The findings highlight the need to transform treatment variables into compulsory, so that the cancer registry may be used to support effectiveness studies. Education, training and behaviour changes must also be considered to foster the process. PMID- 30485702 TI - Serological Response to Influenza Vaccination Among Adults Hospitalized with Community Acquired Pneumonia. AB - Ninety-five adults enrolled in the Etiology of Pneumonia in the Community study with negative admission influenza polymerase chain reaction (PCR) tests received influenza vaccination during hospitalization. Acute and convalescent influenza serology were performed. After vaccination, seropositive (>=1:40) hemagglutination antibody titers (HAI) were achieved in 55% to influenza A(H1N1)pdm09, 58% to influenza A(H3N2), 77% to influenza B (Victoria), and 74% to influenza B (Yamagata) viruses. Sixty-six (69%) patients seroconverted (>=4-fold HAI rise) to >=1 strain. Failure to seroconvert was associated with diabetes, bacterial detection, baseline seropositive titers for influenza B (Yamagata), and influenza vaccination in the previous season. This article is protected by copyright. All rights reserved. PMID- 30485703 TI - The neurological phenotype of developmental motor patterns during early childhood. AB - INTRODUCTION: During early childhood, typical human motor behavior reveals a gradual transition from automatic motor patterns to acquired motor skills, by the continuous interplay between nature and nurture. During the wiring and shaping of the underlying motor networks, insight into the neurological phenotype of developmental motor patterns is incomplete. In healthy, typically developing children (0-3 years of age), we therefore aimed to investigate the neurological phenotype of developmental motor patterns. METHODS: In 32 healthy, typically developing children (0-3 years), we video-recorded spontaneous motor behavior, general movements (GMs), and standardized motor tasks. We classified the motor patterns by: (a) the traditional neurodevelopmental approach, by Gestalt perception and (b) the classical neurological approach, by the clinical phenotypic determination of movement disorder features. We associated outcomes by Cramer's V. RESULTS: Developmental motor patterns revealed (a) choreatic-like features (<=3 months; associated with fidgety GMs (r = 0.732) and startles (r = 0.687)), (b) myoclonic-like features (<=3 months; associated with fidgety GMs (r = 0.878) and startles (r = 0.808)), (c) dystonic-like features (0-3 years; associated with asymmetrical tonic neck reflex (r = 0.641) and voluntary movements (r = 0.517)), and (d) ataxic-like features (>3 months; associated with voluntary movements (r = 0.928)). CONCLUSIONS: In healthy infants and toddlers (0 3 years), typical developmental motor patterns reveal choreatic-, myoclonic-, dystonic- and ataxic-like features. The transient character of these neurological phenotypes is placed in perspective of the physiological shaping of the underlying motor centers. Neurological phenotypic insight into developmental motor patterns can contribute to adequate discrimination between ontogenetic and initiating pathological movement features and to adequate interpretation of therapeutic interactions. PMID- 30485705 TI - Targeting macrophage scavenger receptor 1 promotes insulin resistance in obese male mice. AB - Immune components can bridge inflammatory triggers to metabolic dysfunction. Scavenger receptors sense lipoproteins, but it is not clear how different scavenger receptors alter carbohydrate metabolism during obesity. Macrophage scavenger receptor 1 (MSR1) and macrophage receptor with collagenous structure (MARCO) are scavenger receptors that have been implicated in lipoprotein metabolism and cardiovascular disease. We assessed glucose control, tissue specific insulin sensitivity, and inflammation in Msr1- and Marco-deficient mice fed with obesogenic diets. Compared to wild-type (WT) mice, Msr1-/- mice had worse blood glucose control that was only revealed after diet-induced obesity, not in lean mice. Obese Msr1-/- mice had worse insulin-stimulated glucose uptake in the adipose tissue, which occurred in the absence of overt differences in adipose inflammation compared to obese WT mice. Msr1 deletion worsened dysglycemia independently from bacterial cell wall insulin sensitizers, such as muramyl dipeptide. MARCO was dispensable for glycemic control in obese mice. Oral administration of the polysaccharide fucoidan worsened glucose control in obese WT mice, but fucoidan had no effect on glycemia in obese Msr1-/- mice. Therefore, MSR1 is a scavenger receptor responsible for changes in glucose control in response to the environmental ligand fucoidan. Given the interest in dietary supplements and natural products reducing inflammation or insulin resistance in metabolic disease during obesity, our results highlight the importance of understanding which ligand-receptor relationships promote versus those that protect against metabolic disease factors. Our results show that ligand or gene targeting of MSR1 exacerbates insulin resistance in obese mice. PMID- 30485704 TI - Endothelial colony-forming cell therapy for heart morphological changes after neonatal high oxygen exposure in rats, a model of complications of prematurity. AB - Very preterm birth is associated with increased cardiovascular diseases and changes in myocardial structure. The current study aimed to investigate the impact of endothelial colony-forming cell (ECFC) treatment on heart morphological changes in the experimental model of neonatal high oxygen (O2 )-induced cardiomyopathy, mimicking prematurity-related conditions. Sprague-Dawley rat pups exposed to 95% O2 or room air (RA) from day 4 (P4) to day 14 (P14) were randomized to receive (jugular vein) exogenous human cord blood ECFC or vehicle at P14 (n = 5 RA-vehicle, n = 8 RA-ECFC, n = 8 O2 -vehicle and n = 7 O2 -ECFC) and the hearts collected at P28. Body and heart weights and heart to body weight ratio did not differ between groups. ECFC treatment prevented the increase in cardiomyocyte surface area in both the left (LV) and right (RV) ventricles of the O2 group (O2 -ECFC vs. O2 -vehicle LV: 121 +/- 13 vs. 179 +/- 21 MUm2 , RV: 118 +/- 12 vs. 169 +/- 21 MUm2 ). In O2 rats, ECFC treatment was also associated with a significant reduction in interstitial fibrosis in both ventricles (O2 -ECFC vs. O2 -vehicle LV: 1.07 +/- 0.47 vs. 1.68 +/- 0.41% of surface area, RV: 1.01 +/- 0.74 vs. 1.77 +/- 0.67%) and in perivascular fibrosis in the LV (2.29 +/- 0.47 vs. 3.85 +/- 1.23%) but in not the RV (1.95 +/- 0.95 vs. 2.74 +/- 1.14), and with increased expression of angiogenesis marker CD31. ECFC treatment had no effect on cardiomyocyte surface area or on tissue fibrosis of RA rats. Human cord blood ECFC treatment prevented cardiomyocyte hypertrophy and myocardial and perivascular fibrosis observed after neonatal high O2 exposure. ECFC could constitute a new regenerative therapy against cardiac sequelae caused by deleterious conditions of prematurity. PMID- 30485706 TI - A Collagen-coated Sponge Silk Scaffold for Functional Meniscus Regeneration. AB - Tissue engineering is a promising solution for meniscal regeneration after meniscectomy. However, in situ reconstruction still poses a formidable challenge due to multifunctional roles of the meniscus in the knee. In this study, we fabricate a silk sponge from 9% (w/v) silk fibroin solution through freeze drying, and then coat its internal space and external surface with collagen sponge. Subsequently, various characteristics of the silk-collagen scaffold are evaluated, and cytocompatibility of the construct is assessed in vitro and subcutaneously. The efficacy of this composite scaffold for meniscal regeneration is evaluated through meniscus reconstruction in a rabbit meniscectomy model. It is found that the internally coated collagen sponge enhances the cytocompatibility of the silk sponge, and the external layer of collagen sponge significantly improves the initial frictional property. Additionally, the silk collagen composite group show more tissue ingrowth and less cartilage wear than the pure silk sponge group at 3 months post-implantation in situ. These findings thus demonstrate that the composite scaffold had less damage to the joint surface than the silk alone through promoting functional meniscal regeneration after meniscectomy, which indicates its clinical potential in meniscus reconstruction. PMID- 30485707 TI - Risk and prognostic factors for endometrial carcinoma after diagnosis of breast or Lynch-associated cancers-A population-based analysis. AB - We hypothesized that endometrial carcinoma (EC) patients with a prior cancer diagnosis, after accounting for EC arising after tamoxifen-treated prior breast carcinoma, are more likely to have an underlying genetic basis. We used information from a population-based study to compare measured risk factors, tumor characteristics, survival, and known mismatch repair (MMR) pathogenic variant status for EC subgroups according to prior diagnosis of cancer (none, breast cancer tamoxifen-treated or not, Lynch Syndrome (LS)-associated cancer). Family history of any cancer was increased for EC cases with prior breast cancer, both tamoxifen treated (P = 0.005) and untreated (P = 0.01). EC cases with prior LS associated cancer more often reported family history of LS-associated cancer (P = 0.04) and breast cancer (P = 0.05). EC patients with a germline pathogenic MMR gene variant were more likely to report a prior cancer than cases with a MMR proficient tumor (P = 0.0001), but more than half (54.5%) of MMR carriers reported no prior cancer. Women developing EC after tamoxifen treatment for breast cancer were significantly more likely to develop EC of malignant mixed mullerian tumor subtype (13.2% vs 2.6%, P = 1.3 * 10-6 ), present with stage IV disease (8.8% vs 1.2%, P = 1.6 * 10-6 ), and have poorer survival (HRadj 1.96; P = 0.001). While report of prior cancer is an indicator of MMR pathogenic variant status, molecular analysis of all ECs at diagnosis is warranted to detect all patients with LS. Results also indicate the importance of longer-term monitoring of women treated with tamoxifen for symptoms of EC, and the need for studies assessing the biological mechanism underlying the poorer prognosis of this subset of EC patients. PMID- 30485708 TI - Protein Corona Liposomes Achieve Efficient Oral Insulin Delivery by Overcoming Mucus and Epithelial Barriers. AB - Oral delivery of peptide/protein drugs has attracted worldwide attention due to its good patient compliance and convenience of administration. Orally administered nanocarriers always encounter the rigorous defenses of the gastrointestinal tract, which mainly consist of mucus and epithelium barriers. However, diametrically opposite surface properties of nanocarriers are required for good mucus penetration and high epithelial uptake. Here, bovine serum albumin (BSA) is adsorbed to cationic liposomes (CLs) to form protein corona liposomes (PcCLs). The aim of using PcCLs is to conquer the mucus and epithelium barriers, eventually improving the oral bioavailability of insulin. Investigations using in vitro and in vivo experiments show that the uptake amounts and transepithelial permeability of PcCLs are 3.24- and 7.91-fold higher than that of free insulin, respectively. Further study of the behavior of PcCLs implies that BSA corona can be shed from PcCLs as they cross the mucus layer, which results in the exposure of CLs to improve the transepithelial transport. Intrajejunal administration of PcCLs in type I diabetic rats produces a remarkable hypoglycemic effect and increases the oral bioavailability up to 11.9%. All of these results imply that PcCLs may provide a new insight into the method for oral insulin delivery by overcoming the multiple barriers. PMID- 30485709 TI - Using the sORFs.Org Database. AB - Ribosome profiling involves sequencing of approximately 30-base-long stretches of ribosome-protected mRNA. The technique enables genome-wide mapping of RNA undergoing active translation. Numerous small open reading frames have been identified by using ribosome profiling, leading researchers to question the assumed non-functional character of sORFs and to the identification of various important sORF translation products. sORFs.org (https://www.sorfs.org) is a public repository of small open reading frames identified by ribosome profiling in a database of over 3 million sORFs across 78 datasets from six species. sORFs.org is a multi-omics endeavor providing tools and metrics to assess the coding potential of the delineated sORFs. A pipeline is also in place to systematically rescan public mass spectrometry datasets to acquire new experimental evidence for sORF-encoded polypeptides. sORFs.org provides two distinct query interfaces, export functionality, and various visualization tools to enable inspection of the available information. (c) 2018 by John Wiley & Sons, Inc. PMID- 30485710 TI - Imprint cytology of strumal carcinoid of the ovary: A case report with immunocytochemical analysis. AB - Strumal carcinoid is a rare ovarian tumor defined as carcinoid associated with struma ovarii. We report here the second cytological case of strumal carcinoid and performed immunocytochemical analysis for the first time. A 68-year-old Japanese female was found to have a solid tumor with small cystic components in the left ovary, and bilateral salpingo-oophorectomy was performed. The Papanicolaou smear of the imprint cytological specimen of the left ovarian tumor revealed presence of two distinct components. The first component included thyroid follicles, which was composed of flat sheets of polygonal epithelial cells without nuclear groove and intranuclear inclusion. The other component was composed of trabecular clusters of columnar cells containing round to slender nuclei with "salt and pepper" chromatin. Immunocytochemical analysis revealed that synaptophysin was expressed in the latter component. Therefore, a cytodiagnosis of strumal carcinoid was made. Histopathological analyses confirmed the diagnosis of strumal carcinoid. Albeit rare, carcinoid tumor occurs in the ovary, and the recognition of characteristic nuclear features and cellular arrangement leads to correct cytodiagnosis. Presence of struma ovarii component suggests an ovarian origin. Moreover, immunocytochemical analysis for neuroendocrine markers aids its differential diagnosis from granulosa cell tumor and carcinoma arising from struma ovarii. PMID- 30485711 TI - Noninvasive exosomal proteomic biosignatures, including cystatin SN, peroxiredoxin-5, and glycoprotein VI, accurately predict chronic rhinosinusitis with nasal polyps. AB - BACKGROUND: Exosomes are secreted epithelial-derived vesicles that contain a conserved protein array representative of their parent cell. Exosomes may be reproducibly and noninvasively purified from nasal mucus. The exosomal proteome can be quantified using SOMAscanTM , a highly multiplexed, aptamer-based proteomic platform. The purpose of this study was to determine whether chronic rhinosinusitis with nasal polyps (CRSwNP) has a unique predictive exosomal proteomic biosignature. METHODS: Exosomes were isolated from whole mucus sampled from control and CRSwNP patients (n = 20 per group) by differential ultracentrifugation. The SOMAscanTM platform was used to simultaneously quantify 1310 biologically relevant human proteins. Matched tissue and whole mucus proteomes were also analyzed. Differential protein expression and discriminatory power were calculated using the unweighted pair group method with arithmetic-mean and principal component analysis, respectively. Bioinformatic analysis was performed using Ingenuity Pathway, MetaCore, and GeneMANIA analyses. RESULTS: The exosomal proteome demonstrated 123 significantly (p < 0.05) differentially regulated proteins in CRSwNP relative to control. Eighty of these proteins overlapped with the matched CRSwNP tissue proteome as compared with only 4 among matched whole mucus samples. Forty-three significantly dysregulated pathway networks overlapped between the exosomal and tissue proteome in CRSwNP as compared with only 3 among matched whole mucus samples. The best-performing protein set (cystatin-SN, peroxiredoxin-5, and glycoprotein VI) achieved an area under the curve (AUC) value of up to 99%. CONCLUSION: Our data contribute a significant advance in the development of a reproducible, noninvasive, serial, and quantitative "liquid biopsy" for rhinosinusitis. The exosomal proteomic approach has revealed a unique biosignature associated with CRSwNP, which outperforms whole mucus sampling, and thus provides a method of noninvasive disease detection and proposes new potential therapeutic targets. PMID- 30485712 TI - Validation of the preoperative controlling nutritional status score as an independent predictor in a large Chinese cohort of patients with upper tract urothelial carcinoma. AB - BACKGROUND: Pretreatment controlling nutritional status (CONUT) score is a novel index which was used to predict outcomes in cancer patients. We aim to explore the prognostic significance of CONUT score in patients with upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). PATIENTS AND METHODS: A total of 662 UTUC patients between 2004 and 2016 were retrospectively analyzed. Patients were categorized into three groups based on CONUT score (Normal: 0-1; Light: 2-4; Moderate/severe: 5-12). Associations of CONUT score with oncological outcomes were analyzed using Logistic and Cox regression analysis. Harrell concordance index was used to assess the predictive accuracy of the multivariate models. Subgroup analyses were conducted according to tumor grade and stage. RESULTS: The median follow-up duration was 41 months. Multivariate Logistic analysis showed that high CONUT score was independently associated with high-grade disease, high pT stage, lymphovascular invasion, sessile carcinoma, variant histology, and positive surgical margins (each P < 0.05). Multivariate analysis demonstrated that CONUT score 5-12 was an independent factor for worse cancer-specific survival (CSS, hazard ratio [HR]:2.39, 95% confidence interval [CI] 1.55-3.68, P < 0.0001), disease recurrence-free-survival (RFS, HR: 1.80, 95% CI 1.24-2.60, P = 0.002), and overall survival (OS, HR: 2.26, 95% CI 1.53-3.34, P < 0.0001). The estimated c index of the multivariate models for CSS, RFS, and OS increased from 0.755, 0.715 and 0.745 to 0.772, 0.723, and 0.756 when CONUT score supplemented. Subgroup analyses showed that especially in patients with high-grade carcinoma and advanced stage (>=pT3), higher CONUT score predicts decreased CSS, RFS, and OS (all P < 0.05). CONCLUSION: Preoperative CONUT score is a negative independent prognostic indicator for both pathologic and survival outcomes in UTUC, especially in those with high-grade carcinoma and advanced stage. Adding this parameter into our clinical prediction model is appropriate so as to improve its predictive accuracy. PMID- 30485713 TI - Short-term Sahaja Yoga meditation training modulates brain structure and spontaneous activity in the executive control network. AB - INTRODUCTION: While cross-sectional studies have shown neural changes in long term meditators, they might be confounded by self-selection and potential baseline differences between meditators and non meditators. Prospective longitudinal studies of the effects of meditation in naive subjects are more conclusive with respect to causal inferences, but related evidence is so far limited. METHODS: Here, we assessed the effects of a 4-week Sahaja Yoga meditation training on gray matter density and spontaneous resting-state brain activity in a group of 12 meditation-naive healthy adults. RESULTS: Compared with 30 control subjects, the participants to meditation training showed increased gray matter density and changes in the coherence of intrinsic brain activity in two adjacent regions of the right inferior frontal gyrus encompassing the anterior component of the executive control network. Both these measures correlated with self-reported well-being scores in the meditation group. CONCLUSIONS: The significant impact of a brief meditation training on brain regions associated with attention, self-control, and self-awareness may reflect the engagement of cognitive control skills in searching for a state of mental silence, a distinctive feature of Sahaja Yoga meditation. The manifold implications of these findings involve both managerial and rehabilitative settings concerned with well-being and emotional state in normal and pathological conditions. PMID- 30485714 TI - Error monitoring in decision-making and timing is disrupted in autism spectrum disorder. AB - Individuals with autism spectrum disorder (ASD) have difficulties in social interactions. The cognitive domains that support these interactions include perceptual decision-making, timing, and error-monitoring, which enable one to appropriately understand and react to the other individual in communicative settings. This study constitutes a comprehensive exploration of decision-making and interval timing in ASD as well as the first investigation of error-monitoring abilities of individuals with ASD regarding their performance in the corresponding domains. We found that children with ASD fared similar to typically developing (TD) children in their first-order task performance in two-alternative forced choice perceptual decision-making and temporal reproduction tasks as well as the secondary tasks (signal detection and free finger tapping tasks). Yet, they had a deficit in error-monitoring in both tasks where their accuracy did not predict their confidence ratings, which was the case for the TD group. The difference between ASD and TD groups was limited to error-monitoring performance. This study attests to a circumscribed impairment in error-monitoring in individuals with ASD, which may partially underlie their social interaction problems. This difficulty in cognitively evaluating one's own performance may also relate to theory of mind deficits reported for individuals with ASD, where they struggle in understanding the mental states and intentions of others. This novel finding holds the potential to inform effective interventions for individuals with ASD that can target this error-monitoring ability to have broad ranging effects in multiple domains involved in communication and social interaction. Autism Res 2018. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Decision-making, timing, and error monitoring are three of many abilities that underlie smooth social interactions. To date, these domains have been only investigated separately, but given their interactive role in social interactions that are impaired in ASD, we conducted the first study to investigate them together. Children with ASD were as successful as typically developing children in their task performances, but unlike them, were unaware of their errors in both decision-making and timing tasks. This deficit that is limited to error-monitoring can contribute to unraveling the unique cognitive signature of ASD and to formulating interventions with positive implications in multiple domains. PMID- 30485715 TI - Autosomal dominant Marfan syndrome caused by a previously reported recessive FBN1 variant. AB - BACKGROUND: Pathogenic variants in FBN1 cause autosomal dominant Marfan syndrome but can also be found in patients presenting with apparently isolated features of Marfan syndrome. Moreover, several families with autosomal recessive Marfan syndrome caused by pathogenic variants in FBN1 have been described. The aim of this report was to underline the clinical variability that can be associated with the pathogenic variant c.1453C>T, p.(Arg485Cys) in FBN1. METHODS: We provide the clinical details of two autosomal dominant families with this specific FBN1 variant, which was previously associated with autosomal recessive Marfan syndrome. RESULTS: Clinical data of 14 individuals carrying this variant from these two families were collected retrospectively. In both families, the diagnosis of autosomal dominant Marfan syndrome was established based on the characteristics of the variant and the phenotype which includes aortic aneurysms and dissections. Of interest, in one of the families, multiple relatives were diagnosed with early onset abdominal aortic aneurysms. CONCLUSION: In conclusion, FBN1 variant c.1453C>T, p.(Arg485Cys) is a pathogenic variant that can cause autosomal dominant Marfan syndrome characterized by a high degree of clinical variability and apparently isolated early onset familial abdominal aortic aneurysms. PMID- 30485716 TI - Impaired eating-related quality of life in chronic rhinosinusitis. AB - BACKGROUND: Despite the tremendous burden of smell and taste dysfunction in patients with chronic rhinosinusitis (CRS), objective measures of smell and taste fail to fully account for eating-related disruptions in CRS patient quality of life (QOL). In this study we sought to investigate the driving force behind impaired eating-related QOL in CRS patients. METHODS: Adult CRS patients were prospectively enrolled and answered a series of surveys relating to smell, taste, overall sinus-specific QOL, and depression. Patients with both smell-related and taste-related eating complaints were considered to have impaired eating-related QOL. Clinical demographics, objective chemosensory scores, and endoscopy scores were collected. RESULTS: Seventy patients were enrolled and 23% showed impaired eating-related QOL. In multivariable analyses, patients with aspirin-exacerbated respiratory disease (AERD) showed 10.7 times higher odds of impaired eating related QOL (odds ratio [OR] 10.72; 95% confidence interval [CI], 1.09 to 105.09; p = 0.042); meanwhile, for every 1-point increase in depression scores, the odds of impaired eating-related QOL increased by 1.3 (OR 1.31; 95% CI, 1.10 to 1.57; p = 0.003). For every 1-point decrease in orthonasal olfactory threshold, the odds of impaired eating-related QOL increased by 1.9 times (OR 1.85; 95% CI, 1.14 to 3.00; p = 0.013). Symptom scores, polyp status, endoscopic scores, and other olfactory measures did not remain significant after adjusting for other variables in forward-selection multivariable modeling. CONCLUSION: Disruptions in eating related QOL cannot be fully explained by objective smell or taste testing alone. We identified AERD and depression as independent risk factors for greater odds of impaired eating-related QOL in CRS. Improved orthonasal threshold scores were independently associated with better eating-related QOL. PMID- 30485717 TI - Mechanistic modeling based process analytical technology implementation for pooling in hydrophobic interaction chromatography. AB - A major challenge in chromatography purification of therapeutic proteins is batch to-batch variability with respect to impurity levels and product concentration in the feed. Mechanistic model can enable process analytical technology (PAT) implementation by predicting impact of such variations and thereby improving the robustness of the resulting process and controls. This paper presents one such application of mechanistic model of hydrophobic interaction chromatography (HIC) as a PAT tool for making robust pooling decisions to enable clearance of aggregates for a monoclonal antibody (mAb) therapeutic. Model predictions were performed prior to the actual chromatography experiments to facilitate feedforward control. The approach has been successfully demonstrated for four different feeds with varying aggregate levels (3.84% to 5.54%) and feed concentration (0.6 mg/mL to 1 mg/mL). The resulting pool consistently yielded a product with 1.32 +/- 0.03% aggregate vs. a target of 1.5%. A comparison of the traditional approach involving column fractionation with the proposed approach indicates that the proposed approach results in achievement of satisfactory product purity (98.68 +/- 0.03% for mechanistic model based PAT controlled pooling vs. 98.64 +/- 0.16% for offline column fractionation based pooling). This article is protected by copyright. All rights reserved. PMID- 30485718 TI - Enhanced Osteogenesis of Bone Marrow-Derived Mesenchymal Stem Cells by a Functionalized Silk Fibroin Hydrogel for Bone Defect Repair. AB - Silk fibroin (SF) from Bombyx mori is a promising natural material for the synthesis of biocompatible and biodegradable hydrogels for use in biomedical applications from tissue engineering to drug delivery. However, weak gelation performance and the lack of biochemical cues to trigger cell proliferation and differentiation currently significantly limit its application in these areas. Herein, a biofunctional hydrogel containing SF (2.0%) and a small peptide gelator (e.g., NapFFRGD = 1.0 wt%) is generated via cooperative molecular self-assembly. The introduction of NapFFRGD to SF is shown to significantly improve its gelation properties by lowering both its threshold gelation concentration to 2.0% and gelation time to 20 min under physiological conditions (pH = 7.4, 37 degrees C), as well as functionalizing the SF hydrogel with cell-adhesive motifs (e.g., RGD). Besides mediating cell adhesion, the RGD ligands incorporated within the SF-RGD gel promote the osteogenic differentiation of bone marrow-derived mesenchymal stem cells encapsulated within the gel matrix, leading to bone regeneration in a mouse calvarial defect model, compared with a blank SF gel (2.0%, pH = 7.4). This work suggests that SF could be easily tailored with bioactive peptide gelators to afford bioactive hydrogels with favorable microenvironments for tissue regeneration applications. PMID- 30485720 TI - The importance of local epidemic conditions in monitoring progress towards HIV epidemic control in Kenya: a modelling study. AB - INTRODUCTION: Setting and monitoring progress towards targets for HIV control is critical in ensuring responsive programmes. Here, we explore how to apply targets for reduction in HIV incidence to local settings and which indicators give the strongest signal of a change in incidence in the population and are therefore most important to monitor. METHODS: We use location-specific HIV transmission models, tailored to the epidemics in the counties and major cities in Kenya, to project a wide range of plausible future epidemic trajectories through varying behaviours, treatment coverage and prevention interventions. We look at the change in incidence across modelled scenarios in each location between 2015 and 2030 to inform local target setting. We also simulate the measurement of a library of potential indicators and assess which are most strongly associated with a change in incidence. RESULTS: Considerable variation was observed in the trajectory of the local epidemics under the plausible scenarios defined (only 10 of 48 locations saw a median reduction in incidence of greater than or equal to an 80% target by 2030). Indicators that provide strong signals in certain epidemic types may not perform consistently well in settings with different epidemiological features. Predicting changes in incidence is more challenging in advanced generalized epidemics compared to concentrated epidemics where changes in high-risk sub-populations track more closely to the population as a whole. Many indicators demonstrate only limited association with incidence (such as "condom use" or "pre-exposure prophylaxis coverage"). This is because many other factors (low effectiveness, impact of other interventions, countervailing changes in risk behaviours, etc.) can confound the relationship between interventions and their ultimate long-term impact, especially for an intervention with low expected coverage. The population prevalence of viral suppression shows the most consistent associations with long-term changes in incidence even in the largest generalized epidemics. CONCLUSIONS: Target setting should be appropriate for the local epidemic and what can feasibly be achieved. There is no one universally reliable indicator to predict future HIV incidence across settings. Thus, the signature of epidemic control must contain indications of success across a wide range of interventions and outcomes. PMID- 30485721 TI - Incidence rate and sex ratio in multiple sclerosis in Lithuania. AB - OBJECTIVES: To determine the temporal changes in incidence rates of multiple sclerosis (MS) over the past 15 years in Lithuania with prediction up to 2020, and to estimate female-to-male sex ratio and its changes among MS patients. MATERIALS AND METHODS: We conducted a descriptive incidence study. The crude incidence rates (CIR) were calculated using 15-year period, sex, age-groups, and the number of newly registered MS patients. Standardized incidence rates (SIR) were calculated using European standard in order to evaluate the influence of resident structure changes on incidence of MS during the last 15 years. The data were processed using Minitab set to estimate a linear trend model for the temporal changes of 16 parameters. RESULTS: The data showed a substantial growth of the incidence rate of MS in Lithuania during the period of 2001-2015. In 2001, MS was diagnosed to 162 new individuals, whereas 343 new cases of MS were diagnosed in 2015. During 2001-2015, the incidence of MS was on average 6.5 (95% CI 5.70-7.30) cases per 100,000 residents, and 4.9 (95% CI 4.46-5.34) and 8.1 (5.86-9.34) for 100,000 male and female, respectively. Female-to-male sex ratio in MS in Lithuania had a tendency to increase over the period. Females were affected from 1.5 to 2 times more often than males. CONCLUSIONS: In 2020, the incidence rate of MS is estimated to reach 13 cases per 100,000 persons and females are expected to be diagnosed with MS two times more often than males. PMID- 30485722 TI - Autism is a prenatal disorder: Evidence from late gestation brain overgrowth. AB - This retrospective study aimed to specify the critical period for atypical brain development in individuals with autism spectrum disorder (ASD) using prenatal and postnatal head growth parameters. The sample consisted of 80 Caucasian, unrelated, idiopathic patients with ASD born after 1995. Fetal ultrasound parameters (head circumference [HC], abdominal circumference, and femur length) were obtained during the second and third trimesters of gestation. HC at birth and postnatal parameters at 12 and 24 months of age were also collected. Head overgrowth, assessed by HC, was highlighted during the second (20-26 weeks of amenorrhea) and third (28-36 weeks of amenorrhea) trimesters. Normal growth of body fetal parameters indicated that head overgrowth was not because of overall body overgrowth. Moreover, postnatal results replicated previously and reported head overgrowth. A critical time window for atypical brain development in autism is hypothesized to begin from the 22nd week of amenorrhea. This period is critical for cortical lamination and glial activation. A pathophysiological cascade is suggested with interactions between candidate genes and environmental factors. Autism Research 2018, 11: 1635-1642. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: It is now widely acknowledged in the scientific community, that autism is a neurodevelopmental disorder. Recent evidence from animal and pathological studies has implicated the in utero period. However, the precise time of onset of abnormal brain development remains unknown. This retrospective study reports novel findings, identifying an atypical head growth trajectory in children with autism, during the in utero period (after the 22nd week of amenorrhea). In the same children, postnatal head overgrowth was also observed. Late gestation is identified as a critical period for atypical brain development underlying autism symptoms. PMID- 30485723 TI - Serological surveillance and factors associated with influenza A virus in backyard pigs in Southern Brazil. AB - Backyard pig populations are not monitored for influenza A virus (IAV) in Brazil and there are limited data about seroprevalence and risk factors in these populations. Our goal was to assess possible factors associated with IAV seroprevalence in backyard pig populations using an indirect ELISA protocol based on a recombinant nucleoprotein. Following the IAV screening using NP-ELISA, subtype-specific serology based on hemagglutination inhibition (HI) assay of the ELISA-positive pigs was conducted. The survey comprised a total of 1,667 sera samples collected in 2012 and 2014 in 479 holdings and the estimated seroprevalence was 5.3% (3.84%-7.33%) and 2.3% (1.34%-3.71%) in the respective years. In both years, H1N1pdm09 was the most prevalent subtype. The multivariable analysis showed main factors such as "age," "sex," "number of suckling pigs" and "neighbours raising pigs" that presented the greatest effect on IAV seroprevalence in these pig populations. These factors may be associated with the low biosecurity measures and management of backyard holdings. In addition, the low IAV seroprevalences found in these backyard pig populations could be related to a low number of animals in each pig holding and low animal movement/replacement that do not favour IAV transmission dynamics. This low frequency of H1N1pdm09 seropositive pigs could also be due to sporadic human-to pig transmission of what is now a human seasonal influenza A virus; however, these factors should be explored in future studies. Herein, these results highlight the importance of IAV continued surveillance in backyard pig holdings, since it is poorly known which IAVs are circulating in these populations and the risk they could pose to public health and virus transmission to commercial farms. PMID- 30485724 TI - Flow cytometry immunophenotyping of vitreous specimens does not contribute to diagnosis of lymphoma without supporting morphologic features. AB - BACKGROUND: Diagnostic vitrectomy with flow cytometry immunophenotyping (FCI) is being increasingly used as part of screening for diagnostically challenging cases. We aim to evaluate the utility of combined cytopathology and FCI in diagnostic pars plana vitrectomy. We also aim to evaluate cytologic features that could potentially predict FCI outcomes. This study provides clearer indications for use of FCI in diagnostic vitrectomy. METHODS: A case series of diagnostic pars plana vitrectomy specimens from 2010 to 2016 from a single institution was retrospectively evaluated. Associations between cytologic features and FCI were analyzed statistically. RESULTS: Ninety-nine vitrectomy specimens (90 patients) were evaluated. Evaluation was diagnostic in 39 of 99 (39.4%) specimens. FCI was performed in 66 of 73 (90.4%) specimens collected for lymphoma indication, and 9 of those 66 FCIs (13.6%) demonstrated abnormal lymphocytes. FCI was performed in 10 of 26 (38.5%) specimens collected for non-lymphomatous indications; all 10 FCIs failed to demonstrate lymphocyte abnormality. The absence of large lymphocytes frequently demonstrated negative FCI (negative predictive value = 97.7%), and was the sole cytologic feature significantly associated with a negative FCI result [OR, 14.0; 95% CI, 1.65-635.6; P = .034]. CONCLUSIONS: Diagnostic vitrectomy with cytopathology evaluation is valuable, and concomitant FCI is useful to confirm intraocular lymphoma. However, the absence of large lymphocytes on cytologic examination is the single significant predictor of a negative FCI, and this finding should preclude the use of FCI. PMID- 30485725 TI - Patterns of olfactory dysfunction in chronic rhinosinusitis identified by hierarchical cluster analysis and machine learning algorithms. AB - BACKGROUND: Olfactory dysfunction is a common symptom of chronic rhinosinusitis (CRS). We previously identified several cytokines potentially linked to smell loss, potentially supporting an inflammatory etiology for CRS-associated olfactory dysfunction. In the current study we sought to validate patterns of olfactory dysfunction in CRS using hierarchical cluster analysis, machine learning algorithms, and multivariate regression. METHODS: CRS patients undergoing functional endoscopic sinus surgery were administered the Smell Identification Test (SIT) preoperatively. Mucus was collected from the middle meatus using an absorbent polyurethane sponge and 17 inflammatory mediators were assessed using a multiplexed flow-cytometric bead assay. Hierarchical cluster analysis was performed to characterize inflammatory patterns and their association with SIT scores. The random forest approach was used to identify cytokines predictive of olfactory function. RESULTS: One hundred ten patients were enrolled in the study. Hierarchical cluster analysis identified 5 distinct CRS clusters with statistically significant differences in SIT scores observed between individual clusters (p < 0.001). A majority of anosmic patients were found in a single cluster, which was additionally characterized by nasal polyposis (100%) and a high incidence of allergic fungal rhinosinusitis (50%) and aspirin-exacerbated respiratory disease (AERD) (33%). A random forest approach identified a strong association between olfaction and the cytokines interleukin (IL)-5 and IL-13. Multivariate modeling identified AERD, computed tomography (CT) score, and IL-2 as the variables most predictive of olfactory function. CONCLUSION: Olfactory dysfunction is associated with specific CRS endotypes characterized by severe nasal polyposis, tissue eosinophilia, and AERD. Mucus IL 2 levels, CT score, and AERD were independently associated with smell loss. PMID- 30485726 TI - A novel, noninvasive assay shows that distal airway oxygen tension is low in cystic fibrosis, but not in primary ciliary dyskinesia. AB - OBJECTIVES: Oxygen tension affects the biology of aerobic and denitrifying organisms. Using a novel, fast-response sensor, we developed a noninvasive procedure to measure pO2 in distal human airways. We hypothesized that distal pO2 would be low in cystic fibrosis (CF) airways. MATERIALS AND METHODS: We measured the fraction of expired oxygen (FEO2 ) in real time using a fast laser diode analyzer in healthy subjects and in patients with CF, asthma, and primary ciliary dyskinesia (PCD). Subjects slowly exhaled to residual volume (RV), where the nadir of FEO2 (NFO) was recorded. Values were compared to peripheral oxygen saturation (Sa O2 ), expired CO2 at RV, FEV1 , FEV1 /FVC, and FEF25-75 . We also measured the effect of supplemental oxygen on FEO2 . RESULTS: Seventy-four subjects completed the study. Seven additional subjects could not perform the maneuver. Mean (+/-SD) NFO values for controls (n = 29), CF patients (n = 23), asthma patients (n = 15), and PCD patients (n = 7) were 13.4 +/- 1.1%, 12.4 +/- 1.2%, 13.3 +/- 1.1%, 14.4 +/- 0.6%, respectively. NFO in CF was lower than in controls (P = 0.0162), and NFO in PCD was higher than in CF (P = 0.0007). Asthma results were heterogeneous. Oxygen caused a dose-dependent increase in NFO (P < 0.0005; n = 3; r2 = 0.91). NFO values were positively associated with FEV1 (P = 0.0009), FEV1 /FVC (P = 0.0019) and FEF25-75 (P = 0.0155), but there was no association with Sa O2 . CONCLUSIONS: Distal airway pO2 is lower in CF than in controls. This may reflect absorption of oxygen in partially plugged acinar units, and/or increased epithelial oxygen consumption. Distal airway pO2 can be precisely titrated to treat infections. PMID- 30485729 TI - Contents, Volume 70, 2018. PMID- 30485730 TI - Incorrect Disclosure Information Added for Author Neogi in the Article by Choi et al (Arthritis Rheumatol, November 2018). PMID- 30485732 TI - Robotic interfaces for cognitive psychology and embodiment research: A research roadmap. AB - Advanced human-machine interfaces render robotic devices applicable to study and enhance human cognition. This turns robots into formidable neuroscientific tools to study processes such as the adaptation between a human operator and the operated robotic device and how this adaptation modulates human embodiment and embodied cognition. We analyze bidirectional human-machine interface (bHMI) technologies for transparent information transfer between a human and a robot via efferent and afferent channels. Even if such interfaces have a tremendous positive impact on feedback loops and embodiment, advanced bHMIs face immense technological challenges. We critically discuss existing technical approaches, mainly focusing on haptics, and suggest extensions thereof, which include other aspects of touch. Moreover, we point out other potential constraints such as limited functionality, semi-autonomy, intent-detection, and feedback methods. From this, we develop a research roadmap to guide understanding and development of bidirectional human-machine interfaces that enable robotic experiments to empirically study the human mind and embodiment. We conclude the integration of dexterous control and multisensory feedback to be a promising roadmap towards future robotic interfaces, especially regarding applications in the cognitive sciences. This article is categorized under: Computer Science > Robotics Psychology > Motor Skill and Performance Neuroscience > Plasticity. PMID- 30485728 TI - Treprostinil treatment decreases circulating platelet microvesicles and their procoagulant activity in pediatric pulmonary hypertension. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) results from pulmonary vascular disease and may eventually lead to right heart failure and death. Vasodilator therapy has greatly improved PAH prognosis. Circulating microvesicles are considered as surrogate markers of endothelial and hematopoietic cell activation. AIM: Thus, our purpose was to determine if MVs are upregulated in pediatric PAH such as reported in adult patients, and to analyze the impact of vasodilator therapies on MV count and function. PATIENTS: Population study consisted of 26 patients of median age 6.09 years, with Congenital Heart Disease (CHD) and elevated pulmonary vascular resistance (CHD-PAH) or idiopathic PAH (iPAH). RESULTS: Compared to healthy controls, all circulating MV subpopulations were found higher in untreated PAH patients. No significant differences of annexin-V+ total MV, endothelial, or leukocyte derived-MV counts were found between untreated patients and those receiving oral vasodilator therapies. Conversely, platelet MVs were significantly lower in the group treated with SC-treprostinil compared with both untreated PAH and oral therapy groups (P = 0.01), and exhibited a significant decrease of phospholipid procoagulant activity. Control samples treated in vitro with treprostinil at therapeutic concentrations showed as expected a significant decrease of platelet aggregation but also a reduced spontaneous MV generation. CONCLUSION: Our results suggest that treprostinil, besides vasodilation, might exert its beneficial effect through an inhibition of platelet activation, resulting in a decreased number and procoagulant activity of circulating MVs. PMID- 30485733 TI - Selective Ablation of Tumorigenic Cells Following Human Induced Pluripotent Stem Cell-Derived Neural Stem/Progenitor Cell Transplantation in Spinal Cord Injury. AB - Tumorigenesis is an important problem that needs to be addressed in the field of human stem/progenitor cell transplantation for the treatment of subacute spinal cord injury (SCI). When certain "tumorigenic" cell lines are transplanted into the spinal cord of SCI mice model, there is initial improvement of motor function, followed by abrupt deterioration secondary to the effect of tumor growth. A significant proportion of the transplanted cells remains undifferentiated after transplantation and is thought to increase the risk of tumorigenesis. In this study, using lentiviral vectors, we introduced the herpes simplex virus type 1 thymidine kinase (HSVtk) gene into a human induced pluripotent stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) line that is known to undergo tumorigenic transformation. Such approach enables selective ablation of the immature proliferating cells and thereby prevents subsequent tumor formation. In vitro, the HSVtk system successfully ablated the immature proliferative neural cells while preserving mature postmitotic neuronal cells. Similar results were observed in vivo following transplantation into the injured spinal cords of immune-deficient (nonobese diabetic-severe combined immune deficient) mice. Ablation of the proliferating cells exerted a protective effect on the motor function which was regained after transplantation, simultaneously defending the spinal cord from the harmful tumor growth. These results suggest a potentially promising role of suicide genes in opposing tumorigenesis during stem cell therapy. This system allows both preventing and treating tumorigenesis following hiPSC-NS/PC transplantation without sacrificing the improved motor function. Stem Cells Translational Medicine 2018; 1-11. PMID- 30485734 TI - Endoscopic Evaluation of the Eustachian Tube: assessment of a novel tool for grading Eustachian tube inflammation. AB - BACKGROUND: Signs of inflammation are commonly encountered during endoscopic examination of the Eustachian tube (ET) region. The clinical applicability of these findings may be enhanced by use of a standardized assessment score. METHODS: Digital video recordings were obtained of 50 nasal endoscopy examinations of the nasopharyngeal portion of the ET. Four fellowship-trained rhinologists independently reviewed the videos with regard to specific physical findings: edema of the ET torus, erythema of the ET torus, exudate at the ET orifice, and presence of tubal tonsil. Scoring of this Endoscopic Evaluation of the Eustachian Tube (3ET) was reported using both 2-point and 3-point scales. Each reviewer repeated the scoring at a 10-day interval. Interrater and intrarater agreement were calculated for each item and the total scores. RESULTS: Interrater and intrarater agreement were greater for the 3-point scale than the 2 point scale. Interrater agreement for overall instrument using the 3-point scale was in the "acceptable" range for Krippendorff's alpha on both the first trial (0.6922) and second trial (0.7238). Intrarater agreement was generally "excellent" for individual items as well as the overall instrument. CONCLUSION: The 3ET comprising these 4 physical findings has acceptable interrater and intrarater reliability, and may be applied to future clinical studies of ET function and disease. PMID- 30485735 TI - Helical multi-detector CT scan as a tool for diagnosing tracheomalacia in children. AB - BACKGROUND/AIMS: Tracheomalacia (TM) is not an unusual diagnosis in pediatric respiratory clinics. The aim of this study was to assess the accuracy of paired static end-inspiratory/end-expiratory helical multi-detector CT scan (MDCT) in detecting TM. METHODS: FB was performed in 28 children suspected of TM on the grounds of presence of recurrent episodes of vibrating cough and a need for more specific diagnostic information. Children diagnosed with flexible bronchoscopy (FB) as having TM were further investigated with MDCT. The cross-sectional area ratio of the trachea during end-expiration and end-inspiration, at the level of maximum end-expiration collapse (CSR), determined the basis for the MDCT diagnosis of TM. FB and MDCT were also performed in five children who suffered from mainly dry-but not honking, barking, or vibrating-cough for more than 3 months, and served as controls. RESULTS: The diagnosis of TM was established bronchoscopically in 26 out of 28 children. CRS was significantly smaller in patients (0.59 +/- 0.14) compared with controls (0.85 +/- 0.11) (P = 0.001). The optimal CSR cut-off point for TM diagnosis, as it was estimated by the ROC curve, was <=0.705 (95%CI: <=0.635-<=0.850) with a sensitivity 84.6% (95%CI: 65.1-95.6), and specificity 100.0% (95%CI: 47.8-100.0). CONCLUSIONS: MDCT can effectively diagnose TM in the majority of children and can be used as an alternative to FB. In children, the established criterion of CSR <=0.5 should be replaced by CSR <=0.7 that seems to be a more appropriate threshold. PMID- 30485736 TI - Synthetic and Spectroscopic Investigations Enabled by Modular Synthesis of Molecular Phosphaalkyne Precursors. AB - A series of dibenzo-7-phosphanorbornadiene compounds, Ph3PC(R)PA (1-R; A = C14H10 , anthracene; R = Me, Et, iPr, sBu), are reported to be capable of thermal fragmentation to generate alkyl-substituted phosphaalkynes (RC=P) concomitant with triphenylphosphine and anthracene. Facile preparation of these molecular precursors proceeds by treatment of ClPA with the appropriate ylide Ph3P=CHR (2 equiv). For methyl, ethyl, and isopropyl substituents, the phosphaalkyne conversions are measured to be 56-73% in solution by quantitative 31P NMR spectroscopy. In the case of compound 1-Me, the kinetic profile of its spontaneous unimolecular fragmentation is investigated by an Eyring analysis. The resulting 1-phosphapropyne is directly detected by solution NMR spectroscopy and gas phase rotational microwave spectroscopy. The latter technique allows for the first time measurement of the phosphorus-31 nuclear spin-rotation coupling tensor. The nuclear spin-rotation coupling provides a link between rotational and NMR spectroscopies, and is contextualized in relation to the chemical shift anisotropy. PMID- 30485737 TI - A pyrazolo[1,5-a]pyridine inhibitor of the respiratory cytochrome bcc complex for the treatment of drug-resistant tuberculosis. AB - Respiration is a promising target for the development of new antimycobacterial agents, with a growing number of compounds in clinical development entering this target space. However, more candidate inhibitors are needed to expand the therapeutic options available for drug-resistant Mycobacterium tuberculosis infection. Here, we characterize a putative respiratory complex III (QcrB) inhibitor, TB47: a pyrazolo[1,5-a]pyridine-3-carboxamide. TB47 is active (MIC between 0.016 - 0.500 ug/mL) against a panel of 56 M. tuberculosis clinical isolates, including 37 multi-drug resistant and 2 extensively-drug resistant strains. Pharmacokinetic and toxicity studies showed promising profiles, including negligible CYP450 interactions, cytotoxicity and hERG channel inhibition. Consistent with other reported QcrB inhibitors, TB47 inhibits oxygen consumption only when the alternative oxidase, cytochrome bd, is deleted. A point mutation in the qcrB cd2-loop (H190Y, M. smegmatis numbering) rescues the inhibitory effects of TB47. Metabolomic profiling of TB47-treated M. tuberculosis H37Rv cultures revealed accumulation of steps in TCA cycle and pentose phosphate pathway that are linked to reducing-equivalents, suggesting that TB47 causes metabolic redox stress. In mouse infection models, a TB47 monotherapy was not bactericidal. However, TB47 was strongly synergistic with pyrazinamide and rifampicin, suggesting a promising role in combination therapies. We propose that TB47 is an effective lead compound for the development of novel Tuberculosis chemotherapies. PMID- 30485738 TI - Forensic DNA Analysis. AB - This review focuses on recent developments in forensic DNA typing. It highlights important recent advances and issues in forensic human identification and identifies representative papers. It is not intended to be comprehensive. The review is divided into several important topic areas. These include developments in forensic serology using RNA, proteomic, and Epigenetic markers, and methods for human identification using short tandem repeats, single nucleotide polymorphisms, and insertion deletions. Sequencing methods for autosomal DNA, sex linked DNA, and mitochondrial DNA are included as well as for the human microbiome. New technologies are also featured, such as real time PCR, microfluidics, integrated rapid PCR systems, and massively parallel sequencing. Expert systems have also been developed to assist with the analysis of data from these complex analytical tools. PMID- 30485739 TI - Nanoscale Surface Structure-Activity in Electrochemistry and Electrocatalysis. AB - Nanostructured electrochemical interfaces (electrodes) are found in diverse applications ranging from electrocatalysis and energy storage to biomedical and environmental sensing. These functional materials, which possess compositional and structural heterogeneity over a wide range of length scales, are usually characterized by classical macroscopic or "bulk" electrochemical techniques, which are not well-suited to analyzing the spatially heterogeneous (non-uniform) fluxes that govern the electrochemical response at complex interfaces. In this Perspective, we highlight new directions to studying fundamental electrochemical and electrocatalytic phenomena, whereby nanoscale-resolved information on activity is related to electrode structure and properties co-located and at a commensurate scale, by using complementary high resolution microscopy techniques. This correlative electrochemical multi-microscopy strategy aims to unambiguously resolve structure and activity by identifying and characterizing the structural features that constitute an active surface, ultimately facilitating the rational design of functional (electro)materials. The discussion begins with high resolution correlative structure-activity investigations at well-defined surfaces such as metal single crystals and layered materials (e.g., graphite and molybdenum disulfide), before building up in complexity to extended structurally/compositionally heterogeneous surfaces such as polycrystalline metals and finally to ensemble-type electrodes exemplified by nanoparticles on an electrode support surface. This Perspective provides a roadmap for next generation studies in electrochemistry and electrocatalysis, advocating that complex electrode surfaces and interfaces are broken down and studied as set of simpler "single entities" (e.g., steps, terraces, defects, crystal facets, grain boundaries, single particles), from which the resulting nanoscale understanding of reactivity can be used to create rational models, underpinned by theory and surface physics, that are self-consistent across broader lengthscales and timescales. PMID- 30485740 TI - Covalent Organic Frameworks: Chemistry beyond the Structure. AB - Covalent organic frameworks (COFs) represent a new field of rapidly growing chemical research which takes direct inspiration from diverse covalent bonds existing between atoms. The success of linking atoms in two and three dimensions to construct extended framework structures moved the chemistry of COFs beyond the structures to methodologies, highlighting the possibility of prospective applications. Although structure to property relation in COFs has led to fascinating properties, chemical stability, processability and scalability were some of the important challenges that needed to be overcome for their successful implementation. In this perspective, we take a closer look at the growth of COFs from mere supramolecular structures to potential industrializable materials. PMID- 30485741 TI - Enhanced photoacoustic and photothermal effect of functionalized polypyrrole nanoparticles for near-infrared theranostic treatment of tumor. AB - Functionalized nanomaterials with near-infrared (NIR) responsive capacity are quite promising for theranostic treatment of tumors, but formation of NIR responsive nanomaterials with enhanced theranostic ability and excellent biocompatibility is still very challenging. Herein, PEGylated indocyanine green (ICG)-loaded polypyrrole nanoparticles (PPI NPs) were designed and successfully formed through selecting polydopamine as the linkage between each component, demonstrating enhanced NIR responsive theranostic ability against tumor. Combining in vitro cell study with in vivo assay, the formed PPI NPs were proved being fantastic biocompatible while effectively internalizing in HeLa cells and retaining in HeLa tumor demonstrated by in vitro flow cytometry/confocal measurement and in vivo photoacoustic imaging assay. With the guidance of photoacoustic imaging, successful photothermal ablation of tumor was achieved when treating with PPI NPs plus laser, which was much more effective than the group treated with NPs free of ICG. The greatly combined enhanced photoacoustic and photothermal effect is mainly ascribed to the functionalized polypyrrole nanoparticles, which could accumulate in tumor site more effectively with a relative longer retention time taking advantage of the nanomaterial-induced endothelial leakiness phenomenon. All these results demonstrate the designed PPI NPs possess enhanced NIR responsive property are to hold a great promise for tumor NIR theranostic applications. PMID- 30485742 TI - Sensing coated iron-oxide nanoparticles with spectral induced polarization (SIP): Experiments in natural sand packed flow-through columns. AB - The development of nanoparticle-based soil remediation techniques is hindered by the lack of accurate in situ nanoparticle (NP) monitoring and characterization methods. Spectral induced polarization (SIP), a non-invasive geophysical technique, offers a promising approach to detect and quantify NPs in porous media. However, its successful implementation as a monitoring tool requires an understanding of the polarization mechanisms, the governing NP-associated SIP responses and their dependence on the stabilizing coatings that are typically used for NPs deployed in environmental applications. Herein, we present SIP responses (0.1-10,000 Hz) measured during injection of a poloxamer-coated super paramagnetic iron-oxide nanoparticle (SPION) suspension in flow-through columns packed with natural sand from the Borden Aquifer. An advective-dispersive transport model is fitted to outflow SPION concentration measurements to compute average concentrations over the SIP spatial response domain (within the columns). The average SPION concentrations are compared with the real and imaginary components of the complex conductivity. Excellent correspondence is found between the average SPION concentrations the columns and the imaginary conductivity values, suggesting that NP-mediated polarization (that is, charge storage) increases proportionally with increasing SPION concentration. Our results support the possibility of SIP monitoring of spatial and temporal NP distributions, which can be immediately deployed in bench-scale studies with the prospect of future real-world field applications. PMID- 30485743 TI - Imaging of Neurite Network with an Anti-L1CAM Aptamer Generated by Neurite-SELEX. AB - Neurite outgrowth is the critical step of nervous development. Molecular probes against neurites are essential for evaluation of the nervous system development, compound neurotoxicity and drug efficacy on nerve regeneration. To obtain neurite probe, we developed a neurite-SELEX strategy, and generated a DNA aptamer, yly12 that strongly binds neurites. The molecular target of yly12 was identified to be neural cell adhesion molecule L1 (L1CAM), a surface antigen expresses in normal nervous system and various cancers. Yly12 was successfully applied to image the 3D network of neurites between live cells, as well as the neurite fibers on normal brain tissue section. This aptamer was also found to have inhibitory effect on neurite outgrowth between cells. Given the advantages of aptamers, yly12 hold great potential as a molecular tool in the neuroscientific research. The high efficiency of neurite-SELEX suggests that SELEX against a subcellular structure instead of the whole cells is more effective to obtain desired aptamers. PMID- 30485744 TI - Discovery and Characterization of Two Classes of Selective Inhibitors of the Suppressor of TCR Signaling Family of Proteins. AB - The Suppressor of T cell receptor Signaling (Sts) proteins, particularly Sts-1, have recently emerged as potential immunostimulatory targets for drug development. Genetic inactivation of the Sts proteins dramatically increases host survival of systemic infection and leads to improved pathogen clearance. The protein tyrosine phosphatase (PTP) activity of these proteins arises from a C terminal 2-histidine phosphatase (HP) domain. To identify new inhibitors of the HP activity of Sts-1 we miniaturized a phosphatase assay to 1,536-well format and conducted a 20,580 compound screen. Among the hits were two classes of structurally related compounds, tetracycline variants and sulfonated azo dyes. These hits had low micromolar to nanomolar IC50 values. Orthogonal screening confirmed the validity of these inhibitors and demonstrated that both act competitively on Sts-1 phosphatase activity. When tested on other PTPs, PTP1B and SHP1, the tetracycline variant, doxycycline, and the sulfonated azo dye, Congo red, are selective inhibitors of Sts-1HP with selectivity indices ranging from 19 to as high as 200. The planar polyaromatic moieties present in both classes of compounds suggested a common binding mode. Mutation of either tryptophan 494 or tyrosine 596, located near the active site of the protein, reduced the Ki of the inhibitors from 3- to 18-fold, indicating that these residues may help promote binding of substrates with aromatic groups. This work provides new insights into substrate selectivity mechanisms and describes two classes of compounds that can serve as probes of function or as a basis for future drug discovery. PMID- 30485745 TI - Generalized Hartree-Fock with a Non-perturbative Treatment of Strong Magnetic Fields: Application to Molecular Spin Phase Transitions. AB - In this work, we present a framework of an ab initio variational approach to effectively explore electronic spin phase transitions in molecular systems inside a homogenous magnetic field. In order to capture this phenomenon, the Complex generalized Hartree-Fock (C-GHF) method is used in the spinor formalism with London orbitals. Recursive algorithms for computing the one- and two-electron integrals of London orbitals are also provided. A Pauli matrix representation of the C-GHF method is introduced to separate spin contributions from the scalar part of the Fock matrix. Next, spin phase transitions in two different molecular systems are investigated in the presence of a strong magnetic field. Non collinear spin configurations are observed during the spin phase transitions in H2and a di-Chromium complex with an increase in magnetic field strength. The competing driving forces of exchange coupling and the spin Zeeman effect have been shown to govern the spin phase transition and its transition rate. Additionally, the energetic contributions of the spin Zeeman, orbital Zeeman, and diamagnetic terms to the potential energy surface are also analyzed. PMID- 30485746 TI - Structure and Dynamics of Biobased Polyester Nanocomposites. AB - The structure and the dynamics of two bio-based polyester polyols are investigated in the bulk and close to surfaces in polymer / layered silicate nanocomposites. The morphology of the neat polymers as well as the structure of the nanohybrids are investigated with X-ray diffraction and their thermal properties are studied by differential scanning calorimetry. One of the investigated polyesters is amorphous whereas the second one is a semi-crystalline polymer with an intriguing thermal behavior. Hybrids have been synthesized over a broad range of compositions and intercalated structures are always obtained. The thermal transitions in the nanocomposites are observed only when the polymers are in excess outside the completely filled galleries. The glass transition, whenever it can be resolved, appears insensitive to the presence of the inorganic material whereas the way the crystallization takes place depends on the composition of the nanohybrid. Dielectric relaxation spectroscopy was utilized to study the polymer dynamics. It revealed multiple relaxation processes for the neat polymers both below and above their glass transition temperatures whereas, in the nanocomposites, similarities and differences are observed depending on the specific mode of dynamic process. PMID- 30485747 TI - Organic carbon amendments affect the chemodiversity of soil dissolved organic matter and its associations with soil microbial communities. AB - The "4 per mil" initiative recognizes the pivotal role of soil in carbon re sequestration. The need for evidence to substantiate the influence of agricultural practices on chemical nature of soil carbon and microbial biodiversity has become a priority. However, owing to the molecular complexity of soil dissolved organic matter (DOM), specific linkages to microbial biodiversity have eluded researchers. Here, we characterized the chemodiversity of soil DOM, assessed the variation of soil bacterial community composition (BCC) and identified specific linkages between DOM traits and BCC. Sustained organic carbon amendment significantly (P < 0.05) increased total organic matter reservoirs, resulted in higher chemodiversity of DOM and emergence of recalcitrant moieties (H/C < 1.5). In the meantime, sustained organic carbon amendment shaped the BCC to a more eutrophic state while long-term chemical fertilization directed the BCC towards an oligotrophic state. Meanwhile, higher connectivity and complexity were observed in organic carbon amendment by DOM-BCC network analysis, indicating that soil microbes tended to have more interaction with DOM molecules after organic matter inputs. These results highlight the potential for organic carbon amendments to not only build soil carbon stocks and increase their resilience but also mediate the functional state of soil bacterial communities. PMID- 30485748 TI - Generalized Unitary Coupled Cluster Wavefunctions for Quantum Computation. AB - We introduce a unitary coupled-cluster (UCC) ansatz termed k-UpCCGSD that is based on a family of sparse generalized doubles operators which provides an affordable and systematically improvable unitary coupled-cluster wavefunction suitable for implementation on a near-term quantum computer. k-UpCCGSD employs k products of the exponential of pair coupled-cluster double excitation operators (pCCD), together with generalized single excitation operators. We compare its performance in both efficiency of implementation and accuracy with that of the generalized UCC ansatz employing the full generalized single and double excitation operators (UCCGSD), as well as with the standard ansatz employing only single and double excitations (UCCCSD). k-UpCCGSD is found to show the best scaling for quantum computing applications, requiring a circuit depth of O(kN), compared with O(N3) for UCCGSD and O((N-eta)2 eta) for UCCSD where N is the number of spin orbitals and ?eta is the number of electrons. We analyzed the accuracy of these three ansatze by making classical benchmark calculations on the ground state and the first excited state of H4 (STO-3G, 6-31G), H2O (STO-3G), and N2 (STO-3G), making additional comparisons to conventional coupled cluster methods. The results for ground states show that k-UpCCGSD offers a good tradeoff between accuracy and cost, achieving chemical accuracy for lower cost of implementation on quantum computers than both UCCGSD and UCCSD. UCCGSD is also found to be more accurate than UCCSD, but at a greater cost for implementation. Excited states are calculated with an orthogonally constrained variational quantum eigensolver approach. This is seen to generally yield less accurate energies than for the corresponding ground states. We demonstrate that using a specialized multi-determinantal reference state constructed from classical linear response calculations allows these excited state energetics to be improved. PMID- 30485750 TI - Semiconducting Langmuir-Blodgett Films of Porphyrin Paddle-Wheel Frameworks for Photoelectric Conversion. AB - Understanding the photocurrent transportation within porphyrin-containing metal organic frameworks (PMOFs) will be a critical step for applying these materials in light-harvesting molecular devices in the future. Two copper porphyrin paddle wheel frameworks (Cu-PPFs) were employed to study the influence of metal ions coordinated into the porphyrin ligands on conductivity and photoelectron transfer capability. To compare the electronic and optical properties of both materials, we prepared an ultra-thin film of each PPF via a Langmuir-Blodgett method. The resulting films exhibited uniform morphology and single-crystalline domains, in addition to photoelectric conversion capabilities. We confirmed both Cu-PPFs have semiconducting properties with an optical bandgap around 2.7 eV. The current density generated by both Cu-PPFs were studied through a mercury drop junction approach. We observed a slightly higher conductivity from the Cu-PPF film consisting of metalloporphyrins than the one without copper doping in the porphyrin centers. In addition, the copper ions coordinated porphyrins were found to be more favorable for facilitating photo-induced electron transfer from the Cu PPF film to a conductive glass substrate. This work presents a new approach of combining thin film fabrication and electro-heterojunction measurement to study electron transfer within an ultra-thin film. PMID- 30485749 TI - Subcellular quantification of uptake in Gram-negative bacteria. AB - Infections by Gram-negative pathogens represent a major health care issue of growing concern due to a striking lack of novel antibacterial agents over the course of the last decades. The main scientific problem behind the rational optimization of novel antibiotics is our limited understanding of small molecule translocation into, and their export from the target compartments of Gram negative species. To address this issue, a versatile, label-free assay to determine the intracellular localization and concentration of a given compound has been developed for Escherichia coli and its efflux-impaired DeltaTolC mutant. The assay applies a fractionation procedure to antibiotic-treated bacterial cells to obtain periplasm, cytoplasm and membrane fractions of high purity, as demonstrated by Western Blots of compartment-specific marker proteins. This is followed by an LC-MS/MS-based quantification of antibiotic content in each compartment. Antibiotic amounts could be converted to antibiotic concentrations by assuming that an E. coli cell is a cylinder flanked by two half spheres and calculating the volumes of bacterial compartments. The quantification of antibiotics from different classes, namely ciprofloxacin, tetracycline, trimethoprim and erythromycin demonstrated pronounced differences in uptake quantities and distribution patterns across the compartments. For example, in the case of ciprofloxacin a higher amount of compound was located was located in the cytoplasm than in the periplasm (592 pg +/-50 pg vs 277 +/-13 pg per 3.9x109 cells), whereas its concentration in the cytoplasm was much lower (37 +/-3 pg/ul vs. 221 +/-10 pg/ul for the periplasm). For erythromycin and tetracycline, differences in MICs between WT and DeltaTolC mutant strains were not reflected by equal differences in uptake, illustrating that additional experimental data are needed to predict antibiotic efficacy. We believe that our assay, providing the antibiotic concentration at the compartment in which the drug target is expressed, constitutes an essential piece of information for a more rational optimization of novel antibiotics against Gram-negative infections. PMID- 30485751 TI - The Platelet Napoleon Complex-Small Cells, but Big Immune Regulatory Functions. AB - Platelets have dual physiologic roles as both cellular mediators of thrombosis and immune modulatory cells. Historically, the thrombotic function of platelets has received significant research and clinical attention, but emerging research indicates that the immune regulatory roles of platelets may be just as important. We now know that in addition to their role in the acute thrombotic event at the time of myocardial infarction, platelets initiate and accelerate inflammatory processes that are part of the pathogenesis of atherosclerosis and myocardial infarction expansion. Furthermore, it is increasingly apparent from recent studies that platelets impact the pathogenesis of many vascular inflammatory processes such as autoimmune diseases, sepsis, viral infections, and growth and metastasis of many types of tumors. Therefore, we must consider platelets as immune cells that affect all phases of immune responses. Expected final online publication date for the Annual Review of Immunology Volume 37 is April 26, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30485752 TI - Maternal separation induces long-term changes in mineralocorticoid receptor in rats subjected to chronic stress and treated with tianeptine. AB - PURPOSE: The aim of this study was to analyze whether early maternal separation would result in long-term, persistent alterations in stress response in adulthood, altering mineralocorticoid receptor immunoreactivity (MR-ir) in the dorsal hippocampal areas [CA1, CA2, CA3 and dentate gyrus (DG)], paraventricular nucleus of the hypothalamus and medial and central nucleus of the amygdala, key structures involved in stress response regulation. We also analyzed whether chronic treatment with the antidepressant tianeptine reverses these possible changes. MATERIAL AND METHODS: Male Wistar rats were subjected to daily maternal separation for 4.5 h during 3 weeks or left undisturbed. As adults, they were exposed to chronic stress during 24 days or left undisturbed, and they were also daily treated with tianeptine (10mg/kg i.p.) or isotonic solution. RESULTS: In the CA2 and DG areas of the dorsal hippocampus, there was an increase in MR-ir in non-maternally separated and chronic stressed groups. Tianeptine raised MR-ir in the CA3. In the DG, control and maternally separated + chronic stress groups treated with tianeptine showed more MR-ir than their respective vehicle groups. In the paraventricular nucleus, tianeptine decreased MR-ir in non-separated groups, but not in maternally separated rats. CONCLUSIONS: Our results support findings that early-life events induce long-term changes in stress response regulation, persistent into adulthood, which are manifested during challenges in later life, and that treatment with tianeptine, which tends to attenuate the hypothalamus-pituitary-adrenal axis dysregulation, depends on the individual experience of each rat. PMID- 30485753 TI - The Rotator Cuff Healing Index: A New Scoring System to Predict Rotator Cuff Healing After Surgical Repair. AB - BACKGROUND:: Scoring systems integrating possible prognostic factors and predicting rotator cuff healing after surgical repair could provide valuable information for clinical practice. PURPOSE:: To determine the prognostic factors predictive of rotator cuff healing after surgical repair and to integrate these factors into a scoring system. STUDY DESIGN:: Case-control study; Level of evidence, 3. METHODS:: The authors reviewed the records of 603 patients who, at least 12 months after primary rotator cuff repair by a single surgeon, had magnetic resonance imaging or computed tomographic arthrography to assess repair integrity. The mean age at the time of surgery was 60 years (range, 39-81 years), and 378 patients were women (62.7%). Previous known or suggested factors affecting cuff integrity were analyzed through univariate and multivariate analyses. Factors identified in the multivariate analysis were integrated in a scoring system based on odds ratios (ORs). RESULTS:: The overall healing failure rate was 24%. The following independent risk factors were identified in the multivariate analysis: age >70 years at the time of surgery ( P = .003, OR = 2.71), size of the tear in anteroposterior dimension ( P = .033, OR = 1.94) and retraction ( P = .000, OR = 4.56), fatty infiltration of infraspinatus exceeding grade 2 ( P = .001, OR = 2.91), low bone mineral density (T score <= -2.5, P = .04, OR = 1.95), and high level of work activity ( P = .036, OR = 2.18). A 15 point scoring system comprised the following: 4 points for retraction; 3 points for fatty infiltration of infraspinatus; and 2 points for anteroposterior tear size, age, bone mineral density, and work activity, weighted according to multivariate analysis ORs. Patients with <=4 points had a 6.0% healing failure rate, and those with >=5 and >=10 points had 55.2% and 86.2% healing failure rates, respectively. CONCLUSION:: A numerical scoring system including significant clinical and radiological factors was designed to predict healing of the rotator cuff after surgical repair. This scoring system helped predict the adequacy of the repair and assist in deciding the appropriate treatment options. PMID- 30485754 TI - Itraconazole-loaded micelles based on linear-dendritic poly (ethylene glycol)-b poly (epsilon-caprolactone). AB - A copolymeric micelle formulation of itraconazole (ITR-M) was prepared using linear-dendritic monoallyloxy poly (ethylene glycol)-b-poly (epsilon caprolactone) (APEG-PCL) as drug carrier materials. DL and EE values of ITR-M were 5.70 +/- 0.12 % and 91.30 +/- 1.90 %, respectively. The micelle formulation enhanced the ITR solubility up to 30.42 MUg/mL. In vitro release of ITR from the ITR-M was mainly drug diffusion process followed by the copolymer's degradation. ITR-M showed similar anti-Candida albicans activity to that of crude ITR although its release of ITR was slow and continuous. The in vivo pharmacokinetic study demonstrated that the ITR-M could improve tissue distribution of ITR. In conclusion, APEG-PCL could be a potential carrier in the development of antifungal drug delivery system. PMID- 30485755 TI - Energy-Coupling Factor-Type ATP-Binding Cassette Transporters. AB - Energy-coupling factor (ECF)-type ATP-binding cassette (ABC) transporters catalyze membrane transport of micronutrients in prokaryotes. Crystal structures and biochemical characterization have revealed that ECF transporters are mechanistically distinct from other ABC transport systems. Notably, ECF transporters make use of small integral membrane subunits (S-components) that are predicted to topple over in the membrane when carrying the bound substrate from the extracellular side of the bilayer to the cytosol. Here, we review the phylogenetic diversity of ECF transporters as well as recent structural and biochemical advancements that have led to the postulation of conceptually different mechanistic models. These models can be described as power stroke and thermal ratchet. Structural data indicate that the lipid composition and bilayer structure are likely to have great impact on the transport function. We argue that study of ECF transporters could lead to generic insight of membrane protein structure, dynamics, and interaction. Expected final online publication date for the Annual Review of Biochemistry Volume 88 is June 20, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30485757 TI - New Approaches for Genome Assembly and Scaffolding. AB - Affordable, high-throughput DNA sequencing has accelerated the pace of genome assembly over the past decade. Genome assemblies from highthroughput, short-read sequencing, however, are often not as contiguous as the first generation of genome assemblies. Whereas early genome assembly projects were often aided by clone maps or other mapping data, many current assembly projects forego these scaffolding data and only assemble genomes into smaller segments. Recently, new technologies have been invented that allow chromosome-scale assembly at a lower cost and faster speed than traditional methods. Here, we give an overview of the problem of chromosome-scale assembly and traditional methods for tackling this problem. We then review new technologies for chromosome-scale assembly and recent genome projects that used these technologies to create highly contiguous genome assemblies at low cost. Expected final online publication date for the Annual Review of Animal Biosciences Volume 7 is February 15, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30485756 TI - Smart Animal Agriculture: Application of Real-Time Sensors to Improve Animal Well Being and Production. AB - Consumption of animal products such as meat, milk, and eggs in first-world countries has leveled off, but it is rising precipitously in developing countries. Agriculture will have to increase its output to meet demand, opening the door to increased automation and technological innovation; intensified, sustainable farming; and precision livestock farming (PLF) applications. Early indicators of medical problems, which use sensors to alert cattle farmers early concerning individual animals that need special care, are proliferating. Wearable technologies dominate the market. In less-value-per-animal systems like sheep, goat, pig, poultry, and fish, one sensor, like a camera or robot per herd/flock/school, rather than one sensor per animal, will become common. PLF sensors generate huge amounts of data, and many actors benefit from PLF data. No standards currently exist for sharing sensor-generated data, limiting the use of commercial sensors. Technologies providing accurate data can enhance a well managed farm. Development of methods to turn the data into actionable solutions is critical. Expected final online publication date for the Annual Review of Animal Biosciences Volume 7 is February 15, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30485758 TI - Multiple Facets of Marine Invertebrate Conservation Genomics. AB - Conservation genomics aims to preserve the viability of populations and the biodiversity of living organisms. Invertebrate organisms represent 95% of animal biodiversity; however, few genomic resources currently exist for the group. The subset of marine invertebrates includes the most ancient metazoan lineages and possesses codes for unique gene products and possible keys to adaptation. The benefits of supporting invertebrate conservation genomics research (e.g., likely discovery of novel genes, protein regulatory mechanisms, genomic innovations, and transposable elements) outweigh the various hurdles (rare, small, or polymorphic starting materials). Here we review best conservation genomics practices in the laboratory and in silico when applied to marine invertebrates and also showcase unique features in several case studies of acroporid corals, crown-of-thorns starfish, apple snails, and abalone. Marine conservation genomics should also address how diversity can lead to unique marine innovations, the impact of deleterious variation, and how genomic monitoring and profiling could positively affect broader conservation goals (e.g., value of baseline data for in situ/ex situ genomic stocks). Expected final online publication date for the Annual Review of Animal Biosciences Volume 7 is February 15, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30485759 TI - Cellular Metabolism in Lung Health and Disease. AB - The lung is often overlooked as a metabolically active organ, yet biochemical studies have long demonstrated that glucose utilization surpasses that of many other organs, including the heart, kidney, and brain. For most cells in the lung, energy consumption is relegated to performing common cellular tasks, like mRNA transcription and protein translation. However, certain lung cell populations engage in more specialized types of energy-consuming behaviors, such as the beating of cilia or the production of surfactant. While many extrapulmonary diseases are now linked to abnormalities in cellular metabolism, the pulmonary community has only recently embraced the concept of metabolic dysfunction as a driver of respiratory pathology. Herein, we provide an overview of the major metabolic pathways in the lung and discuss how cells sense and adapt to low energy states. Moreover, we review some of the emerging evidence that links alterations in cellular metabolism to the pathobiology of several common respiratory diseases. Expected final online publication date for the Annual Review of Physiology Volume 81 is February 10, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30485761 TI - Mitochondrial Iron in Human Health and Disease. AB - Mitochondria are an iconic distinguishing feature of eukaryotic cells. Mitochondria encompass an active organellar network that fuses, divides, and directs a myriad of vital biological functions, including energy metabolism, cell death regulation, and innate immune signaling in different tissues. Another crucial and often underappreciated function of these dynamic organelles is their central role in the metabolism of the most abundant and biologically versatile transition metals in mammalian cells, iron. In recent years, cellular and animal models of mitochondrial iron dysfunction have provided vital information in identifying new proteins that have elucidated the pathways involved in mitochondrial homeostasis and iron metabolism. Specific signatures of mitochondrial iron dysregulation that are associated with disease pathogenesis and/or progression are becoming increasingly important. Understanding the molecular mechanisms regulating mitochondrial iron pathways will help better define the role of this important metal in mitochondrial function and in human health and disease. Expected final online publication date for the Annual Review of Physiology Volume 81 is February 10, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30485760 TI - Branched Chain Amino Acids. AB - Branched chain amino acids (BCAAs) are building blocks for all life forms. We review here the fundamentals of BCAA metabolism in mammalian physiology. Decades of studies have elicited a deep understanding of biochemical reactions involved in BCAA catabolism. In addition, BCAAs and various catabolic products act as signaling molecules, activating programs ranging from protein synthesis to insulin secretion. How these processes are integrated at an organismal level is less clear. Inborn errors of metabolism highlight the importance of organismal regulation of BCAA physiology. More recently, subtle alterations of BCAA metabolism have been suggested to contribute to numerous prevalent diseases, including diabetes, cancer, and heart failure. Understanding the mechanisms underlying altered BCAA metabolism and how they contribute to disease pathophysiology will keep researchers busy for the foreseeable future. Expected final online publication date for the Annual Review of Physiology Volume 81 is February 10, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30485762 TI - Cell Death in the Lung: The Apoptosis-Necroptosis Axis. AB - Regulated cell death is a major mechanism to eliminate damaged, infected, or superfluous cells. Previously, apoptosis was thought to be the only regulated cell death mechanism; however, new modalities of caspase-independent regulated cell death have been identified, including necroptosis, pyroptosis, and autophagic cell death. As an understanding of the cellular mechanisms that mediate regulated cell death continues to grow, there is increasing evidence that these pathways are implicated in the pathogenesis of many pulmonary disorders. This review summarizes our understanding of regulated cell death as it pertains to the pathogenesis of chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, and pulmonary arterial hypertension. Expected final online publication date for the Annual Review of Physiology Volume 81 is February 10, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30485763 TI - Genetic Diversity of Salmonella and Listeria Isolates from Food Facilities. AB - Food production-related facilities (farms, packing houses, etc.) are monitored for foodborne pathogens, and data from these facilities can provide a rich source of information about the population structure and genetic diversity of Salmonella and Listeria. This information is of both academic interest for understanding the evolutionary forces acting on these organisms and of practical interest to those responsible for controlling pathogens in facilities and to those analyzing data from facilities in the context of public health decision making. We have collected information about all positive isolates from facility inspections performed by the U.S. Food and Drug Administration for which whole genome sequencing data are available. The within- and between-facilities observed genetic diversity of isolates was computed and related to the common origin of isolates (as the common collected facility). This relationship provides quantification for assessing the relationship between isolates based on their genetic similarity quantified by single-nucleotide polymorphisms (SNPs). Our results show that if the genetic distance ( D) between two isolates is low, then more likely than not they are from the same facility or have some overlap in their supply chain. For example, if the genetic distance is no more than 20 SNPs, the probability ( P) that two isolates come from the same facility = 0.66 for Salmonella and 0.70 for Listeria. However, if two isolates come from different facilities, their genetic distance is likely large (for Salmonella, P( D > 20 SNPs) = 0.99982; for Listeria, P( D > 20 SNPs) = 0.99949); even if two isolates come from the same facility, their genetic distance is also very likely large (for Salmonella, P( D > 20 SNPs) = 0.794; for Listeria, P( D > 20 SNPs) = 0.692). These results provide insight into what SNP thresholds might be appropriate when determining whether two isolates are from the same facility and thus would be of interest to those investigating foodborne outbreaks and conducting traceback investigations. PMID- 30485764 TI - Visitor Perceptions of Food Safety and Sociodemographic Determinants in Barbados, West Indies. AB - In Barbados, tourism is a significant pillar of the economy; however, there has been no research to document the food safety concerns of tourists. Therefore, the purpose of this study was to survey visitors' perceptions of food safety to understand their concerns, influences, and experiences with foodborne illness. A descriptive cross-sectional quantitative survey was conducted among 398 tourists, using stratified random sampling. Visitors were surveyed at two departure ports, the Grantley Adams International Airport (GAIA) ( n = 240) and the Bridgetown Cruise Terminal (BCT) ( n = 158). Descriptive statistics included frequency distributions. Cross tabulations were performed to determine associations among key variables, and logistic regression analyses were used to report predictor variables at a significance level of P <= 0.05. In both surveys (GAIA and BCT), most respondents had a positive perception of food safety (75.8 and 99.4%) and a low frequency of foodborne illness (6.0 and 0.6%), respectively. Most visitors perceived the likelihood of acquiring food poisoning as a result of eating food from local retailers as "not common," and more visitors were "not concerned" about food hazards than concerned. Significant associations ( P <= 0.05) were found among sociodemographic parameters such as age, gender, ethnicity, and education and three variables of risk perception. The findings in this study can be used to guide risk communication and food safety and risk management within the hospitality industry, and they add to the body of knowledge surrounding consumer risk perceptions. PMID- 30485765 TI - Antibiotic Resistance of Coagulase-Negative Staphylococci and Lactic Acid Bacteria Isolated from Naturally Fermented Chinese Cured Beef. AB - This study provided phenotypic and molecular analysis of the antibiotic resistance within coagulase-negative staphylococci and lactic acid bacteria isolated from naturally fermented Chinese cured beef. A total of 49 strains were isolated by selective medium and identified at the species level by 16S rRNA gene sequencing as follows: Staphylococcus carnosus (37), Lactobacillus plantarum (6), Weissella confusa (4), Lactobacillus sakei (1), and Weissella cibaria (1). All strains were typed by random amplified polymorphic DNA fingerprinting, and their antibiotic resistances profiles to 15 antibiotics were determined as the MIC by using the agar dilution method. All the tested strains were sensitive to ampicillin, and most of them were also sensitive to penicillin, gentamycin, neomycin, norfloxacin, and ciprofloxacin with low MICs. High resistance to streptomycin, vancomycin, erythromycin, roxithromycin, lincomycin, and kanamycin was widely observed, while the resistant levels to tetracycline, oxytetracycline, and chloramphenicol varied. The presence of corresponding resistance genes in resistant isolates was investigated by PCR, with the following genes detected: tet(M) gene in 9 S. carnosus strains and 1 W. confusa strain; erm(F) gene in 10 S. carnosus strains; ere(A) gene in 6 S. carnosus strains; ere(A) gene in 4 S. carnosus strains and 1 L. plantarum strain; and str(A) gene and str(B) gene in 3 S. carnosus strains. The results indicated that multiple antibiotic resistances were common in coagulase-negative staphylococci and lactic acid bacteria strains isolated from naturally fermented Chinese cured beef. Safety analysis and risk assessment should be performed for application in meat products. PMID- 30485766 TI - Prevalence and Characterization of Listeria monocytogenes Isolated from Beef and Sheep Carcasses in Turkey with Characterization of Locally Isolated Listeriophages as a Control Measure. AB - Swab samples from cattle and sheep carcasses (120 of each) were tested for Listeria monocytogenes, and 120 slaughterhouse wastewater samples were tested for listeriophages over 12 months (10 samples per month) to note the seasonal distribution. L. monocytogenes and bacteriophage isolates were characterized, and the biocontrol of L. monocytogenes was investigated in meatballs with a phage cocktail. L. monocytogenes was found in 3.4 and 2.5% of cattle and sheep carcasses, respectively. All the isolates were found to harbor hlyA, actA, inlA, inlB, inlC, inlJ, plcA, plcB, fbpA, and fri genes with varied mRNA expression levels by real-time reverse transcriptase PCR analysis. Five isolates did not harbor the vip gene. According to enterobacterial repetitive intergenic consensus PCR, L. monocytogenes isolates were classified into four different groups based on their DNA patterns. The L. monocytogenes isolates were characterized for antibiotic susceptibility; one strain was found to be resistant to five different antibiotic classes. Of 11 lytic listeriophages, two were selected for the cocktail based on their DNA restriction profiles, efficiency of plating, transmission electron microscopy, and in vitro and in vivo analyses. In the biocontrol study, we used a food model that consisted of a novel bacteriophage cocktail in raw meatballs. The highest reduction of L. monocytogenes was recorded as 2.2 log CFU/g at a multiplicity of cellular infection of 4.7 at the end of 1 h. In conclusion, the new bacteriophage cocktail in this study can be considered an efficient biocontrol agent of L. monocytogenes in meatballs. PMID- 30485767 TI - Disposition of Salmonella and Escherichia coli O157:H7 following Spraying of Contaminated Water on Cucumber Fruit and Flowers in the Field. AB - Cucumbers are frequently consumed raw and have been implicated in several recent foodborne outbreaks. Because this item may become contaminated at the farm, it is vital to explore the fate of attenuated Salmonella Typhimurium or Escherichia coli O157:H7 sprayed onto foliage, flowers, and fruit in fields and determine whether pre- or postcontamination spray interventions could minimize contamination. After spraying cucumber plants with contaminated irrigation water (3.8 log CFU/mL of Salmonella Typhimurium and E. coli O157:H7), 60 to 78% of cucumber fruit were not contaminated because the plant's canopy likely prevented many of the underlying fruit from being exposed to the water. Subsequent exposure of contaminated cucumber plants to a simulated shower event did not appear to dislodge pathogens from contaminated foliage onto the fruit, nor did it appear to consistently wash either pathogen from the fruit. Spraying flowers and attached ovaries directly with a pathogen inoculum (4.6 log CFU/mL) initially led to 100% and 65 to 90% contamination, respectively. Within 3 days, 30 to 40% of the flowers were still contaminated; however, contamination of ovaries was minimal (<=10%), suggesting it was unlikely that internalization occurred through the flower to the ovary with these pathogen strains. In another study, both pathogens were found on a withered flower but not on the fruit to which the flower was attached, suggesting that this contaminated flower could serve as a source of cross-contamination in a storage bin if harvested with the fruit. Because pre- and postcontamination acetic acid-based spray treatments failed to reduce pathogen prevalence, the probability that fruit initially contaminated at 1.3 to 2.8 log CFU of Salmonella Typhimurium or E. coli O157:H7 per cucumber would be positive by enrichment culture decreased by a factor of 1.6 and 1.9 for Salmonella Typhimurium and E. coli O157:H7, respectively, for every day the fruit was held in the field ( P <= 0.0001). Hence, to reduce the prevalence of Salmonella Typhimurium on cucumbers below 5%, more than 1 week would be required. PMID- 30485768 TI - Quality of Care in the United Kingdom after Removal of Financial Incentives. PMID- 30485769 TI - Mutagenesis in Norovirus in Response to Favipiravir Treatment. PMID- 30485770 TI - Sit Back and Listen - The Relevance of Patients' Stories to Trauma-Informed Care. PMID- 30485771 TI - Cast of the Right Bronchial Tree. PMID- 30485772 TI - Circulating Extracellular Vesicles in Human Disease. PMID- 30485773 TI - Nail Pitting in Psoriasis. PMID- 30485774 TI - Case 37-2018: A 23-Year-Old Woman with Vision Loss. PMID- 30485775 TI - Olaparib Desensitization in a Patient with Recurrent Peritoneal Cancer. PMID- 30485776 TI - Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. PMID- 30485777 TI - The FDA Sentinel Initiative - An Evolving National Resource. PMID- 30485778 TI - Of Tragedies and Miracles - Neonatal Organ Donation. PMID- 30485779 TI - Clonal Hematopoiesis Leading to AITL and NPM1-Mutated AML. PMID- 30485780 TI - Attention Deficit-Hyperactivity Disorder and Month of School Enrollment. AB - BACKGROUND: Younger children in a school grade cohort may be more likely to receive a diagnosis of attention deficit-hyperactivity disorder (ADHD) than their older peers because of age-based variation in behavior that may be attributed to ADHD rather than to the younger age of the children. Most U.S. states have arbitrary age cutoffs for entry into public school. Therefore, within the same grade, children with birthdays close to the cutoff date can differ in age by nearly 1 year. METHODS: We used data from 2007 through 2015 from a large insurance database to compare the rate of ADHD diagnosis among children born in August with that among children born in September in states with and states without the requirement that children be 5 years old by September 1 for enrollment in kindergarten. ADHD diagnosis was determined on the basis of diagnosis codes from the International Classification of Diseases, 9th Revision. We also used prescription records to compare ADHD treatment between children born in August and children born in September in states with and states without the cutoff date of September 1. RESULTS: The study population included 407,846 children in all U.S. states who were born in the period from 2007 through 2009 and were followed through December 2015. The rate of claims-based ADHD diagnosis among children in states with a September 1 cutoff was 85.1 per 10,000 children (309 cases among 36,319 children; 95% confidence interval [CI], 75.6 to 94.2) among those born in August and 63.6 per 10,000 children (225 cases among 35,353 children; 95% CI, 55.4 to 71.9) among those born in September, an absolute difference of 21.5 per 10,000 children (95% CI, 8.8 to 34.0); the corresponding difference in states without the September 1 cutoff was 8.9 per 10,000 children (95% CI, -14.9 to 20.8). The rate of ADHD treatment was 52.9 per 10,000 children (192 of 36,319 children; 95% CI, 45.4 to 60.3) among those born in August and 40.4 per 10,000 children (143 of 35,353 children; 95% CI, 33.8 to 47.1) among those born in September, an absolute difference of 12.5 per 10,000 children (95% CI, 2.43 to 22.4). These differences were not observed for other month-to-month comparisons, nor were they observed in states with non-September cutoff dates for starting kindergarten. In addition, in states with a September 1 cutoff, no significant differences between August-born and September-born children were observed in rates of asthma, diabetes, or obesity. CONCLUSIONS: Rates of diagnosis and treatment of ADHD are higher among children born in August than among children born in September in states with a September 1 cutoff for kindergarten entry. (Funded by the National Institutes of Health.). PMID- 30485781 TI - The Role of Deferiprone in Iron Chelation. PMID- 30485782 TI - PCSK9 - A Journey to Cardiovascular Outcomes. PMID- 30485783 TI - More on Anesthesia with a Large Mediastinal Mass. PMID- 30485784 TI - Peripheral Nerve Blocks for Hand Procedures. PMID- 30485785 TI - Erratum. PMID- 30485786 TI - Errata. PMID- 30485787 TI - The factors predicting upgrading of prostate cancer by using International Society for Urological Pathology (ISUP) 2014 Gleason grading system. AB - OBJECTIVE: To investigate the factors to predict Gleason score upgrading (GSU) of patients with prostate cancer who were evaluated by using the International Society for Urological Pathology (ISUP) 2014 Gleason grading system. MATERIAL AND METHODS: Between January 2008 and December 2015, we retrospectively investigated patients who had undergone radical prostatectomy and followed up in the uro oncology outpatient clinic. The pathologic specimens of the patients were evaluated based on the ISUP 2014 classification system. The patients were divided into two groups with or without upgraded Gleason scores. Factors that could be effective in predicting upgrading such as age, prostate-specific antigen (PSA), prostate volume, D'Amico risk classification, PSA density, cancer of the prostate risk assessment (CAPRA) scores, biopsy tumor percentage, body mass index, and clinical stage parameters were compared between both groups. RESULTS: Of the 265 patients who could be evaluated and followed up regularly, Gleason score upgrades were observed in 110 (41.5%) patients. Advanced age (p=0.009), PSA >20 ng/mL (p=0.036), PSA density >0.35 (p=0.005), high CAPRA score (p=0.031), and high biopsy tumor percentage (p=0.009) were discovered to be correlated with Gleason score upgrade in univariate logistic regression analysis. Advanced age alone was a predictor for GSU in multivariate logistic regression analysis (p=0.002). Five year biochemical recurrence-free survival rate was 86% in the non-GSU group and 55% in the GSU group (p<0.001). CONCLUSION: GSU risk should be taken into consideration in making therapeutic decisions for older patients with prostate cancer, and precautions should be taken against development of aggressive disease. PMID- 30485788 TI - Occurrence and Severity of DLI associated Chronic GVHD Influence the Clinical Outcomes in Relapsed Acute Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation. AB - The aim of this study was to investigate the occurrence and severity of chemotherapy plus donor lymphocyte infusion (Chemo-DLI) associated chronic graft versus-host disease (cGVHD) in a consecutive cohort of patients with acute leukemia who experienced relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT; n = 104). The 5-year cumulative incidence of complete remission (CR) after Chemo-DLI was 81.0% (95% CI, 73.3-88.7%) and 84.6% (95% CI, 74.5-94.7%) in the moderate and severe cGVHD groups, respectively, which was significantly higher than that of the mild cGVHD 40.9% (95% CI, 29.3-52.5%) and non-cGVHD groups 29.2% (95% CI 23.1-35.3%). The cumulative incidence of non relapse mortality was comparable between patients with and without cGVHD. The 5 year probabilities of progression-free survival after Chemo-DLI were 42.9% (95% CI, 26.2-70.2%) and 34.6% (95% CI, 15.3-78.2%) in moderate and severe cGVHD groups, respectively, which were both significantly higher than those of mild cGVHD 9.1% (95% CI, 2.4-34.1%) and non-cGVHD groups 8.3% (95% CI 3.3-21.3%). The 5-year probabilities of overall survival after Chemo-DLI were 56.7% (95% CI, 38.9 82.7%) and 43.1% (95% CI, 22.1-84.0%), in moderate and severe cGVHD groups, respectively, which were both significantly higher than those of the mild cGVHD 9.1% (95% CI 1.8-47.1%) and non-cGVHD groups 14.9% (95% CI, 7.3-30.2%). Our observations highlight the close relation between cGVHD and immune-mediated graft versus-leukemia (GVL) effect in patients with relapse receiving Chemo-DLI; however, mild cGVHD may not be associated with a sufficiently strong GVL effect to induce remission and improve survival. PMID- 30485789 TI - Mortality, Resource Utilization And Inpatient Costs Vary Among Pediatric Heart Transplant Indications: A Merged Data Set Analysis From The United Network For Organ Sharing And The Pediatric Health Information Systems (UNOS-PHIS) Databases. AB - BACKGROUND: Merging UNOS and PHIS databases have enabled a more granular analysis of pediatric heart transplant outcomes and resource utilization. We evaluated whether transplant indication at time of transplantation was associated with mortality, resource utilization and inpatient costs during the first year post transplant. METHODS: We analyzed transplant outcomes and resource utilization between 2004 and 2015. Patients were categorized as congenital (CHD), myocarditis or cardiomyopathy based on UNOS-defined primary indication. CHD complexity subgroup analyses (single ventricle, complex, and simple biventricular CHD) were also performed. RESULTS: Of 2251 transplants (49% CHD, 5% myocarditis, 46% cardiomyopathy), CHD recipients were younger (2 [IQR 0-10] vs. 6 [IQR 0-12] vs. 7 [IQR 1-14] years, respectively; p<0.001) and less likely to have ventricular assist device (VAD) at transplant (CHD 3%, myocarditis 27%, cardiomyopathy 13%; p<0.001). Patients with single ventricle CHD had the longest waitlist and were least likely to receive a VAD pre-transplant. After adjusting for patient-level factors, transplant recipients with single ventricle CHD had the greatest mortality during transplant-admission and at 1-year (vs. cardiomyopathy, OR 11.8 [95% CI 5.9-23.6] and OR 6.0 [95% CI 3.6-10.2], respectively). Mortality was similar between patients with myocarditis and cardiomyopathy. Post-transplant length of stay (LOS) was longer in transplant recipients with CHD than myocarditis or cardiomyopathy (25 [IQR 15-45] vs. 21 [IQR 12-35] vs. 16 [IQR 12 25] days; p<0.001), partially related to longer duration of ICU-level care (ICU LOS 8 [IQR 4-20] vs. 6 [IQR 4-13] vs. 5 [IQR 3-8] days; p<0.001). Similarly, patients with CHD had higher median post-transplant costs than myocarditis or cardiomyopathy ($415k [IQR $201-503k] vs. $354k [IQR $179-390k] vs. $284k [IQR $145-319k]; p<0.001) that persisted after adjusting for patient-level factors (CHD vs. cardiomyopathy Adjusted Cost Ratio 1.4 [95% CI 1.4-1.5]) and was primarily driven by longer LOS. Over 50% were readmitted during first year post transplant, although readmission rates were similar across transplant indications (p=0.42). CONCLUSION: Children with CHD, particularly single ventricle patients, require substantially greater hospital resource utilization and have significantly worse outcomes during the first year after heart transplant compared to other indications. Further work is aimed at identifying modifiable pre-transplant risk factors, such as pre-transplant conditioning with VAD support and cardiac rehabilitation, to improve post-transplant outcomes and reduce resource utilization in this complex population. PMID- 30485790 TI - Investigations on the effects of ginsenoside-Rg1 on glucose uptake and metabolism in insulin resistant HepG2 cells. AB - Insulin resistance is a major pathophysiological feature in the development of type 2 diabetes. The liver is an important organ responsible for the development of insulin resistance, and exploring liver glucose metabolism is important to study insulin resistance. We first established the model of insulin resistance in HepG2 cells and then treated them with different concentrations of ginsenoside Rg1. The results showed that ginsenoside-Rg1 is not toxic to HepG2 cells. In addition, ginsenoside-Rg1 relieved the insulin-induced insulin resistance in HepG2 cells. Furthermore, ginsenoside-Rg1 increased the uptake of glucose by reducing reactive oxygen species and down-regulating the phosphorylation level of p38 MAPK. In addition, ginsenoside-Rg1 also decreased the output of glucose by increasing Akt phosphorylation and reducing GSK3beta expression. In conclusion, ginsenoside-Rg1 can alleviate the insulin resistance through increasing the uptake of glucose and decreasing the output of glucose. PMID- 30485791 TI - Non-chromatographic purification of Teriparatide with a pH-responsive CspB tag. AB - Cell surface protein B (CspB) from Corynebacterium glutamicum is used as a pH responsive peptide tag to enable a simple solid-liquid separation method for isolating a CspB fusion protein. Here we demonstrate the first application of a CspB tag for the purification of Teriparatide, which is a biologic drug that is prescribed for osteoporosis. The Teriparatide was constructed as CspB50TEV Teriparatide, comprising 50 amino acid residues of CspB, the cleavage site of TEV protease, and Teriparatide. CspB50TEV-Teriparatide was expressed in a culture supernatant by C. glutamicum secretion system at 3.0 g/L (equivalent to approximately 1.2 g/L Teriparatide). The CspB50TEV-Teriparatide was precipitated by reducing the pH of the culture supernatant, and the precipitate was then dissolved in a neutral buffer. A TEV protease treatment was applied to cleave the Teriparatide from the CspB50TEV-Teriparatide. Then, the remaining digested CspB50TEV, undigested CspB50TEV-Teriparatide, and TEV protease were precipitated in an acidic pH, whereas the soluble Teriparatide remained in the supernatant. The process had a yield of 96.5% and resulted in Teriparatide with a purity of 98.0% and productivity of 1.1 g/L of C. glutamicum culture. Thus, tag-free Teriparatide was successfully purified from the CspB fusion protein using only pH changes, centrifugation, and protease digestion without the need for chromatography. This versatile purification protocol is expected to be applicable to various proteins from laboratory to industrial scales. PMID- 30485792 TI - Ventricular tachycardia prediction in patients with implantable cardioverter defibrillators for primary prevention of sudden cardiac death. PMID- 30485793 TI - Molecular characterization and expression analysis of T cell receptor (TCR) gamma and delta genes in dojo loach (Misgurnus anguillicaudatus) in response to bacterial, parasitic and fungal challenge. AB - In mammalian, T-cell receptors (TCRs) play a key role in recognizing the presented antigen from external to protect organisms against environmental pathogens. To understand the potential roles of TCRgamma and TCRdelta in dojo loach (Misgurnus anguillicaudatus), Ma-TCRgamma and Ma-TCRdelta cDNAs were cloned and their gene expression profiles were investigated after bacterial, parasitic and fungal challenge. The open reading frame (ORF) of Ma-TCRgamma and Ma-TCRdelta cDNAs contained 948 and 867 bp, encoding 316 and 288 amino acid residues, respectively. Structurally, Ma-TCRgamma and Ma-TCRdelta were consisted of a signal peptide, a variable region, a constant region (IgC), a connecting peptide (CPS), a transmembrane region (TM) and a cytoplasmic domain (CYT), which were similar to those of other vertebrates. Multiple sequence alignment and phylogenetic analysis showed Ma-TCRgamma and Ma-TCRdelta were closely related to fish of Cyprinidae family. Ma-TCRgamma and Ma-TCRdelta were widely expressed in all tested organs/tissues, as the highest expressions of Ma-TCRgamma and Ma TCRdelta were detected in kidney and gill, respectively. In addition, three infection models of dojo loach with bacteria (F. columnare G4), parasite (Ichthyophthirius multifiliis) and fungus (Saprolegnia sp.) were constructed. The morphological changes of gills and skin after challenged with F. columnare G4 and Ichthyophthirius multifiliis were investigated. Compared to F. columnare G4 infection, mRNA expression of both TCRgamma and TCRdelta showed higher sensitivity in classical immune organs (kidney and spleen) and mucosal tissues (skin and gill) after challenge with Ichthyophthirius multifiliis and Saprolegnia sp. Our results first indicated that TCRgamma and TCRdelta of dojo loach might function differently in response to challenge with different pathogens. PMID- 30485794 TI - The Musings of Surgeon as Patient. PMID- 30485795 TI - Choosing a meal to increase your appeal: How relationship status, sexual orientation, dining partner sex, and attractiveness impact nutritional choices in social dining scenarios. AB - The impact of social context on dining choices was investigated via an online experiment. Participants were assigned to different hypothetical dining partners of the same or opposite sex and varying levels of attractiveness (or no partner in a control condition) and were then asked to indicate what foods they would order if they were dining with this individual. Following a food selection task, the attractiveness of the hypothetical partner was rated, followed by the measurement of personal characteristics such as current relationship status, participant sex, and sexual orientation. Results revealed that among heterosexual participants, relationship status, partner sex, and partner attractiveness interacted to influence the total number of calories ordered. Heterosexual male and female participants who were not currently in a relationship and had been assigned to an opposite-sex dining partner tended to order fewer calories the more attractive that they perceived their partner to be. The findings of this study build upon previous research on social influences on dining behavior by examining the roles of relationship status and dining partner attractiveness on nutritional decision-making. PMID- 30485796 TI - Repetition priming in amnesia: Distinguishing associative learning at different levels of abstraction. AB - Learned associations between stimuli and responses make important contributions to priming. The current study aimed to determine whether medial temporal lobe (MTL) binding mechanisms mediate this learning. Prior studies implicating the MTL in stimulus-response (S-R) learning have not isolated associative learning at the response level from associative learning at other levels of representation (e.g., task sets or decisions). The current study investigated whether the MTL is specifically involved in associative learning at the response level by testing a group of amnesic patients with MTL damage on a priming paradigm that isolates associative learning at the response level. Patients demonstrated intact priming when associative learning was isolated to the stimulus-response level. In contrast, their priming was reduced when associations between stimuli and more abstract representations (e.g., stimulus-task or stimulus-decision associations) could contribute to performance. These results provide novel neuropsychological evidence that S-R contributions to priming can be supported by regions outside the MTL, and suggest that the MTL may play a critical role in linking stimuli to more abstract tasks or decisions during priming. PMID- 30485797 TI - In vivo stability of supramolecular host-guest complexes monitored by dual isotope multiplexing in a pre-targeting model of experimental liver radioembolization. AB - INTRODUCTION: Cyclodextrin (CD)-based supramolecular interactions have been proposed as nanocarriers for drug delivery. We previously explored the use of these supramolecular interactions to perform targeted hepatic radioembolization. In a two-step procedure the appropriate location of the diagnostic pre-targeting vector can first be confirmed, after which the therapeutic vector will be targeted through multivalent host-guest interactions. Such a procedure would prevent therapeutic errors that come from a mismatch between diagnostic and therapeutic procedures. In the current study we explored the use of dual-isotope imaging to assess the in vivo stability of the formed complex and individual components. METHODS: Dual-isotope imaging of the host and guest vectors was performed after labeling of the pre-targeted guest vector, being adamantane (Ad) functionalized macro-aggregated albumin (MAA) particles, with technetium-99 m (99mTc-MAA-Ad). The host vector, Cy50.5CD9PIBMA39, was labeled with indium-111 (111In-Cy50.5CD9PIBMA39). The in situ stability of both the individual vectors and the resulting [MAA-Ad-111In-Cy50.5CD9PIBMA39] complexes was studied over 44 h at 37 degrees C in a serum protein-containing buffer. In vivo, the host vector 111In-Cy50.5CD9PIBMA39 was administered two hours after local deposition of 99mTc MAA-Ad in mice. Dual-isotope SPECT imaging and quantitative biodistribution studies were performed between 2 and 44 h post intravenous host vector administration. RESULTS: The individual vectors portrayed <5% dissociation of the radioisotope over the course of 20 h. Dissociation of [MAA-Ad-111In Cy50.5CD9PIBMA39] complexes remained within a 10-20% range after incubation in serum. In vivo dual-isotope SPECT imaging of host-guest interactions revealed co localization of the tracer components. Quantitative assessment of the biodistribution revealed that the hepatic accumulation of the host vector nearly doubled between 2 h and 44 h post-injection (from 14.9 +/- 6.1%ID/g to 26.2 +/- 2.1%ID/g). CONCLUSIONS: Assessment of intra-hepatic host-guest complexation was successfully achieved using dual isotope multiplexing, underlining the complex stability that was found in situ (up to 44 h in serum). Overall, the results obtained in this study highlight the potential of supramolecular chemistry as a versatile platform that could advance the field of nanomedicine. PMID- 30485798 TI - Early memory consolidation window enables drug induced state-dependent memory. AB - It is well established that newly acquired information is stabilized over time by processes underlying memory consolidation, these events can be impaired by many drug treatments administered shortly after learning. The consolidation hypothesis has been challenged by a memory integration hypothesis, which suggests that the processes underlying new memories are vulnerable to incorporation of the neurobiological alterations induced by amnesic drugs generating a state-dependent memory. The present experiments investigated the effects of amnesic drugs infused into the insular cortex of male Wistar rats on memory for object recognition training. The findings provide evidence that infusions of several amnesic agents including a protein synthesis inhibitor, an RNA synthesis inhibitor, or an NMDA receptor antagonist administered both after a specific period of time and before retrieval induce state-dependent recognition memory. Additionally, when amnesic drugs were infused outside the early consolidation window, there was amnesia, but the amnesia was not state-dependent. Data suggest that amnesic agents can induce state-dependent memory when administered during the early consolidation window and only if the duration of the drug effect is long enough to become integrated to the memory trace. In consequence, there are boundary conditions in order to induce state-dependent memory. PMID- 30485799 TI - Abnormal response of costal chondrocytes to acidosis in patients with chest wall deformity. AB - Costal cartilage is much understudied compared to the load bearing cartilages. Abnormally grown costal cartilages are associated with the inherited chest wall deformities pectus excavatum and pectus carinatum resulting in sunken or pigeon chest respectively. A lack of understanding of the ultrastructural and molecular biology properties of costal cartilage is a major confounder in predicting causes and outcomes of these disorders. Due to the avascular nature of cartilage, chondrocytes metabolize glycolytically, producing an acidic environment. During physical activity hydrogen ions move within cartilage driven by compressive forces, thus at any one time, chondrocytes experience transient changes in pH. A variety of ion channels on chondrocytes plasma membrane equip them to function in the rapidly changing conditions they experience. In this paper we describe reduced expression of the ASIC2 gene encoding the acid sensing ion channel isoform 2 (previously referred to as ACCN1 or ACCN) in patients with chest wall deformities. We hypothesized that chondrocytes from these patients cannot respond normally to changes in pH that are an integral part of the biology of this tissue. Activation of ASICs indirectly creates a cascade ultimately dependent on intracellular calcium transients. The objective of this paper was to compare internal calcium signaling in response to external pH changes in costal chondrocytes from patients with chest wall deformities and healthy individuals. Although the molecular mechanism through which chondrocytes are regulated by acidosis remains unknown, we observed reduced amplitudes of calcium rise in patient chondrocytes exposed to low pH that become further impaired upon repeat exposure. PMID- 30485800 TI - Early Life Stress Drives Sex-Selective Impairment in Reversal Learning by Affecting Parvalbumin Interneurons in Orbitofrontal Cortex of Mice. AB - Poverty, displacement, and parental stress represent potent sources of early life stress (ELS). Stress disproportionately affects females, who are at increased risk for stress-related pathologies associated with cognitive impairment. Mechanisms underlying stress-associated cognitive impairment and enhanced risk of females remain unknown. Here, ELS is associated with impaired rule-reversal (RR) learning in females, but not males. Impaired performance was associated with decreased expression and density of interneurons expressing parvalbumin (PV+) in orbitofrontal cortex (OFC), but not other interneuron subtypes. Optogenetic silencing of PV+ interneuron activity in OFC of control mice phenocopied RR learning deficits observed in ELS females. Localization of reversal learning deficits to PV+ interneurons in OFC was confirmed by optogenetic studies in which neurons in medial prefrontal cortex (mPFC) were silenced and associated with select deficits in rule-shift learning. Sex-, cell-, and region-specific effects show altered PV+ interneuron development can be a driver of sex differences in cognitive dysfunction. PMID- 30485801 TI - Somatic Mutations Reveal Lineage Relationships and Age-Related Mutagenesis in Human Hematopoiesis. AB - Mutation accumulation during life can contribute to hematopoietic dysfunction; however, the underlying dynamics are unknown. Somatic mutations in blood progenitors can provide insight into the rate and processes underlying this accumulation, as well as the developmental lineage tree and stem cell division numbers. Here, we catalog mutations in the genomes of human-bone-marrow-derived and umbilical-cord-blood-derived hematopoietic stem and progenitor cells (HSPCs). We find that mutations accumulate gradually during life with approximately 14 base substitutions per year. The majority of mutations were acquired after birth and could be explained by the constant activity of various endogenous mutagenic processes, which also explains the mutation load in acute myeloid leukemia (AML). Using these mutations, we construct a developmental lineage tree of human hematopoiesis, revealing a polyclonal architecture and providing evidence that developmental clones exhibit multipotency. Our approach highlights features of human native hematopoiesis and its implications for leukemogenesis. PMID- 30485802 TI - Deletion of APC7 or APC16 Allows Proliferation of Human Cells without the Spindle Assembly Checkpoint. AB - The multisubunit ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome) is essential for mitosis by promoting timely degradation of cyclin B1. APC/C is tightly regulated by the spindle assembly checkpoint (SAC), which involves MPS1 and MAD2-dependent temporal inhibition of APC/C. We analyzed the contribution of the APC/C subunits APC7 and APC16 to APC/C composition and function in human cells. APC16 is required for APC7 assembly into APC/C, whereas APC16 assembles independently of APC7. APC7 and APC16 knockout cells display no major defects in mitotic progression, cyclin B1 degradation, or SAC response, but APC/C lacking these two subunits shows reduced ubiquitylation activity in vitro. Strikingly, deletion of APC7 or APC16 is sufficient to provide synthetic viability to MAD2 deletion. DeltaAPC7DeltaMAD2 cells display accelerated mitosis and require SAC independent MPS1 function for genome stability. These findings reveal that the composition of APC/C critically influences the importance of the SAC in humans. PMID- 30485803 TI - The AMSH3 ESCRT-III-Associated Deubiquitinase Is Essential for Plant Immunity. AB - Plant "nucleotide-binding leucine-rich repeat" receptor proteins (NLRs) detect alterations in host targets of pathogen effectors and trigger immune responses. The Arabidopsis thaliana mutant pen1 syp122 displays autoimmunity, and a mutant screen identified the deubiquitinase "associated molecule with the SH3 domain of STAM3" (AMSH3) to be required for this phenotype. AMSH3 has previously been implicated in ESCRT-mediated vacuolar targeting. Pathology experiments show that AMSH3 activity is required for immunity mediated by the CC-NLRs, RPS2 and RPM1. Co-expressing the autoactive RPM1D505V and the catalytically inactive ESCRT-III protein SKD1E232Q in Nicotiana benthamiana supports the requirement of ESCRT associated functions for this CC-NLR-activated immunity. Meanwhile, loss of ESCRT function in A. thaliana is lethal, and we find that AMSH3 knockout-triggered seedling lethality is "enhanced disease susceptibility 1" (EDS1) dependent. Future studies may reveal whether AMSH3 is monitored by a TIR-NLR immunity receptor. PMID- 30485804 TI - The Mitochondrial Apoptotic Effectors BAX/BAK Activate Caspase-3 and -7 to Trigger NLRP3 Inflammasome and Caspase-8 Driven IL-1beta Activation. AB - Intrinsic apoptosis resulting from BAX/BAK-mediated mitochondrial membrane damage is regarded as immunologically silent. We show here that in macrophages, BAX/BAK activation results in inhibitor of apoptosis (IAP) protein degradation to promote caspase-8-mediated activation of IL-1beta. Furthermore, BAX/BAK signaling induces a parallel pathway to NLRP3 inflammasome-mediated caspase-1-dependent IL-1beta maturation that requires potassium efflux. Remarkably, following BAX/BAK activation, the apoptotic executioner caspases, caspase-3 and -7, act upstream of both caspase-8 and NLRP3-induced IL-1beta maturation and secretion. Conversely, the pyroptotic cell death effectors gasdermin D and gasdermin E are not essential for BAX/BAK-induced IL-1beta release. These findings highlight that innate immune cells undergoing BAX/BAK-mediated apoptosis have the capacity to generate pro inflammatory signals and provide an explanation as to why IL-1beta activation is often associated with cellular stress, such as during chemotherapy. PMID- 30485805 TI - BAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1beta Maturation in Macrophages. AB - IL-1beta is a cytokine of pivotal importance to the orchestration of inflammatory responses. Synthesized as an inactive pro-cytokine, IL-1beta requires proteolytic maturation to gain biological activity. Here, we identify intrinsic apoptosis as a non-canonical trigger of IL-1beta maturation. Guided by the discovery of the immunomodulatory activity of vioprolides, cyclic peptides isolated from myxobacteria, we observe IL-1beta maturation independent of canonical inflammasome pathways, yet dependent on intrinsic apoptosis. Mechanistically, vioprolides inhibit MCL-1 and BCL2, which in turn triggers BAX/BAK-dependent mitochondrial outer membrane permeabilization (MOMP). Induction of MOMP results in the release of pro-apoptotic factors initiating intrinsic apoptosis, as well as the depletion of IAPs (inhibitors of apoptosis proteins). IAP depletion, in turn, operates upstream of ripoptosome complex formation, subsequently resulting in caspase-8-dependent IL-1beta maturation. These results establish the ripoptosome/caspase-8 complex as a pro-inflammatory checkpoint that senses the perturbation of mitochondrial integrity. PMID- 30485806 TI - Identifying and Tracking Low-Frequency Virus-Specific TCR Clonotypes Using High Throughput Sequencing. AB - Tracking antigen-specific T cell responses over time within individuals is difficult because of lack of knowledge of antigen-specific TCR sequences, limitations in sample size, and assay sensitivities. We hypothesized that analyses of high-throughput sequencing of TCR clonotypes could provide functional readouts of individuals' immunological histories. Using high-throughput TCR sequencing, we develop a database of TCRbeta sequences from large cohorts of mice before (naive) and after smallpox vaccination. We computationally identify 315 vaccine-associated TCR sequences (VATS) that are used to train a diagnostic classifier that distinguishes naive from vaccinated samples in mice up to 9 months post-vaccination with >99% accuracy. We determine that the VATS library contains virus-responsive TCRs by in vitro expansion assays and virus-specific tetramer sorting. These data outline a platform for advancing our capabilities to identify pathogen-specific TCR sequences, which can be used to identify and quantitate low-frequency pathogen-specific TCR sequences in circulation over time with exceptional sensitivity. PMID- 30485807 TI - Critical Role of Regulatory T Cells in the Latency and Stress-Induced Reactivation of HSV-1. AB - Herpes simplex virus 1 (HSV-1) spreads in populations through a latency entry and reactivation cycle. The role of host immune-suppressive factor regulatory T cells (Treg cells) in controlling latency establishment and reactivation is not completely understood. Here, using an HSV-1 ocular infection murine model, we observe a positive correlation between the level of Treg cells and viral infectivity and demonstrate the requirement for Treg cells in latency establishment. Furthermore, we show that host stress leads to HSV-1 reactivation via increased Treg cell control of CD8+ T cells, permitting viral replication under diminished immune surveillance. Together, we propose that Treg cell regulation may serve as a key target for controlling HSV infection. PMID- 30485808 TI - Antibiotic-Induced Cell Chaining Triggers Pneumococcal Competence by Reshaping Quorum Sensing to Autocrine-Like Signaling. AB - Streptococcus pneumoniae can acquire antibiotic resistance by activation of competence and subsequent DNA uptake. Here, we demonstrate that aztreonam (ATM) and clavulanic acid (CLA) promote competence. We show that both compounds induce cell chain formation by targeting the d,d-carboxypeptidase PBP3. In support of the hypothesis that chain formation promotes competence, we demonstrate that an autolysin mutant (DeltalytB) is hypercompetent. Since competence is initiated by the binding of a small extracellular peptide (CSP) to a membrane-anchored receptor (ComD), we wondered whether chain formation alters CSP diffusion kinetics. Indeed, ATM or CLA presence affects competence synchronization by shifting from global to local quorum sensing, as CSP is primarily retained to chained cells, rather than shared in a common pool. Importantly, autocrine-like signaling prolongs the time window in which the population is able to take up DNA. Together, these insights demonstrate the versatility of quorum sensing and highlight the importance of an accurate antibiotic prescription. PMID- 30485809 TI - Talin Autoinhibition Regulates Cell-ECM Adhesion Dynamics and Wound Healing In Vivo. AB - Cells in multicellular organisms are arranged in complex three-dimensional patterns. This requires both transient and stable adhesions with the extracellular matrix (ECM). Integrin adhesion receptors bind ECM ligands outside the cell and then, by binding the protein talin inside the cell, assemble an adhesion complex connecting to the cytoskeleton. The activity of talin is controlled by several mechanisms, but these have not been well studied in vivo. By generating mice containing the activating point mutation E1770A in talin (Tln1), which disrupts autoinhibition, we show that talin autoinhibition controls cell-ECM adhesion, cell migration, and wound healing in vivo. In particular, blocking autoinhibition gives rise to more mature, stable focal adhesions that exhibit increased integrin activation. Mutant cells also show stronger attachment to ECM and decreased traction force. Overall, these results demonstrate that modulating talin function via autoinhibition is an important mechanism for regulating multiple aspects of integrin-mediated cell-ECM adhesion in vivo. PMID- 30485810 TI - Esrp1-Regulated Splicing of Arhgef11 Isoforms Is Required for Epithelial Tight Junction Integrity. AB - The epithelial-specific splicing regulators Esrp1 and Esrp2 are required for mammalian development, including establishment of epidermal barrier functions. However, the mechanisms by which Esrp ablation causes defects in epithelial barriers remain undefined. We determined that the ablation of Esrp1 and Esrp2 impairs epithelial tight junction (TJ) integrity through loss of the epithelial isoform of Rho GTP exchange factor Arhgef11. Arhgef11 is required for the maintenance of TJs via RhoA activation and myosin light chain (MLC) phosphorylation. Ablation or depletion of Esrp1/2 or Arhgef11 inhibits MLC phosphorylation and only the epithelial Arhgef11 isoform rescues MLC phosphorylation in Arhgef11 KO epithelial cells. Mesenchymal Arhgef11 transcripts contain a C-terminal exon that binds to PAK4 and inhibits RhoA activation byArhgef11. Deletion of the mesenchymal-specific Arhgef11 exon in Esrp1/2 KO epithelial cells using CRISPR/Cas9 restored TJ function, illustrating how splicing alterations can be mechanistically linked to disease phenotypes that result from impaired functions of splicing regulators. PMID- 30485811 TI - Widespread Accumulation of Ribosome-Associated Isolated 3' UTRs in Neuronal Cell Populations of the Aging Brain. AB - Particular brain regions and cell populations exhibit increased susceptibility to aging-related stresses. Here, we describe the age-specific and brain-region specific accumulation of ribosome-associated 3' UTR RNAs that lack the 5' UTR and open reading frame. Our study reveals that this phenomenon impacts hundreds of genes in aged D1 spiny projection neurons of the mouse striatum and also occurs in the aging human brain. Isolated 3' UTR accumulation is tightly correlated with mitochondrial gene expression and oxidative stress, with full-length mRNA expression that is reduced but not eliminated, and with production of short 3' UTR-encoded peptides. Depletion of the oxidation-sensitive Fe-S cluster ribosome recycling factor ABCE1 induces the accumulation of 3' UTRs, consistent with a model in which ribosome stalling and mRNA cleavage by No-Go decay yields isolated 3' UTR RNAs protected by ribosomes. Isolated 3' UTR accumulation is a hallmark of brain aging, likely reflecting regional differences in metabolism and oxidative stress. PMID- 30485812 TI - Single-Cell Transcriptomics Characterizes Cell Types in the Subventricular Zone and Uncovers Molecular Defects Impairing Adult Neurogenesis. AB - Neural stem cells (NSCs) contribute to plasticity and repair of the adult brain. Niches harboring NSCs regulate stem cell self-renewal and differentiation. We used comprehensive and untargeted single-cell RNA profiling to generate a molecular cell atlas of the largest germinal region of the adult mouse brain, the subventricular zone (SVZ). We characterized >20 neural and non-neural cell types and gained insights into the dynamics of neurogenesis by predicting future cell states based on computational analysis of RNA kinetics. Furthermore, we applied our single-cell approach to document decreased numbers of NSCs, reduced proliferation activity of progenitors, and perturbations in Wnt and BMP signaling pathways in mice lacking LRP2, an endocytic receptor required for SVZ maintenance. Our data provide a valuable resource to study adult neurogenesis and a proof of principle for the power of single-cell RNA sequencing to elucidate neural cell-type-specific alterations in loss-of-function models. PMID- 30485813 TI - PKCepsilon Inhibits Neuronal Dendritic Spine Development through Dual Phosphorylation of Ephexin5. AB - Protein kinase C (PKC)-dependent mechanisms promote synaptic function in the mature brain. However, the roles of PKC signaling during synapse development remain largely unknown. Investigating each brain-enriched PKC isoform in early neuronal development, we show that PKCepsilon acutely and specifically reduces the number of dendritic spines, sites of eventual synapse formation on developing dendrites. This PKCepsilon-mediated spine suppression is temporally restricted to immature neurons and mediated through the phosphorylation and activation of Ephexin5, a RhoA guanine nucleotide exchange factor (GEF) and inhibitor of hippocampal synapse formation. Our data suggest that PKCepsilon acts as an early developmental inhibitor of dendritic spine formation, in contrast to its emerging pro-synaptic roles in mature brain function. Moreover, we identify a substrate of PKCepsilon, Ephexin5, whose early-elevated expression in developing neurons may in part explain the mechanism by which PKCepsilon plays seemingly opposing roles that depend on neuronal maturity. PMID- 30485814 TI - The E3 Ubiquitin Ligases TRIM17 and TRIM41 Modulate alpha-Synuclein Expression by Regulating ZSCAN21. AB - Although accumulating data indicate that increased alpha-synuclein expression is crucial for Parkinson disease (PD), mechanisms regulating the transcription of its gene, SNCA, are largely unknown. Here, we describe a pathway regulating alpha synuclein expression. Our data show that ZSCAN21 stimulates SNCA transcription in neuronal cells and that TRIM41 is an E3 ubiquitin ligase for ZSCAN21. In contrast, TRIM17 decreases the TRIM41-mediated degradation of ZSCAN21. Silencing of ZSCAN21 and TRIM17 consistently reduces SNCA expression, whereas TRIM41 knockdown increases it. The mRNA levels of TRIM17, ZSCAN21, and SNCA are simultaneously increased in the midbrains of mice following MPTP treatment. In addition, rare genetic variants in ZSCAN21, TRIM17, and TRIM41 genes occur in patients with familial forms of PD. Expression of variants in ZSCAN21 and TRIM41 genes results in the stabilization of the ZSCAN21 protein. Our data thus suggest that deregulation of the TRIM17/TRIM41/ZSCAN21 pathway may be involved in the pathogenesis of PD. PMID- 30485815 TI - Sustained Melanopsin Photoresponse Is Supported by Specific Roles of beta Arrestin 1 and 2 in Deactivation and Regeneration of Photopigment. AB - Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) are indispensable for non-image-forming visual responses that sustain under prolonged illumination. For sustained signaling of ipRGCs, the melanopsin photopigment must continuously regenerate. The underlying mechanism is unknown. We discovered that a cluster of Ser/Thr sites within the C-terminal region of mammalian melanopsin is phosphorylated after a light pulse. This forms a binding site for beta-arrestin 1 (betaARR1) and beta-arrestin 2. beta-arrestin 2 primarily regulates the deactivation of melanopsin; accordingly, betaalpharr2-/- mice exhibit prolonged ipRGC responses after cessation of a light pulse. beta arrestin 1 primes melanopsin for regeneration. Therefore, betaalpharr1-/- ipRGCs become desensitized after repeated or prolonged photostimulation. The lack of either beta-arrestin attenuates ipRGC response under prolonged illumination, suggesting that beta-arrestin 2-mediated deactivation and beta-arrestin 1 dependent regeneration of melanopsin function in sequence. In conclusion, we discovered a molecular mechanism by which beta-arrestins regulate different aspects of melanopsin photoresponses and allow ipRGC-sustained responses under prolonged illumination. PMID- 30485816 TI - Six3 and Six6 Are Jointly Required for the Maintenance of Multipotent Retinal Progenitors through Both Positive and Negative Regulation. AB - Gene regulation of multipotent neuroretinal progenitors is partially understood. Through characterizing Six3 and Six6 double knockout retinas (DKOs), we demonstrate Six3 and Six6 are jointly required for the maintenance of multipotent neuroretinal progenitors. Phenotypes in DKOs were not found in either Six3 nulls or Six6 nulls. At the far periphery, ciliary margin (CM) markers Otx1 and Cdon together with Wnt3a and Fzd1 were ectopically upregulated, whereas neuroretinal progenitor markers Sox2, Notch1, and Otx2 were absent or reduced. At the mid periphery, multi-lineage differentiation was defective. The gene set jointly regulated by Six3 and Six6 significantly overlapped with the gene networks regulated by WNT3A, CTNNB1, POU4F2, or SOX2. Stimulation of Wnt/beta-catenin signaling by either Wnt-3a or a GS3Kbeta inhibitor promoted CM progenitors at the cost of neuroretinal identity at the periphery of eyecups. Therefore, Six3 and Six6 together directly or indirectly suppress Wnt/beta-catenin signaling but promote retinogenic factors for the maintenance of multipotent neuroretinal progenitors. PMID- 30485817 TI - Quantitative Proteomics Evaluation of Human Multipotent Stromal Cell for beta Cell Regeneration. AB - Human multipotent stromal cells (hMSCs) are one of the most versatile cell types used in regenerative medicine due to their ability to respond to injury. In the context of diabetes, it has been previously shown that the regenerative capacity of hMSCs is donor specific after transplantation into streptozotocin (STZ) treated immunodeficient mice. However, in vivo transplantation models to determine regenerative potency of hMSCs are lengthy, costly, and low throughput. Therefore, a high-throughput quantitative proteomics assay was developed to screen beta cell regenerative potency of donor-derived hMSC lines. Using proteomics, we identified 16 proteins within hMSC conditioned media that effectively identify beta cell regenerative hMSCs. This protein signature was validated using human islet culture assay, ELISA, and the potency was confirmed by recovery of hyperglycemia in STZ-treated mice. Herein, we demonstrated that quantitative proteomics can determine sample-specific protein signatures that can be used to classify previously uncharacterized hMSC lines for beta cell regenerative clinical applications. PMID- 30485818 TI - Promotion of Myoblast Differentiation by Fkbp5 via Cdk4 Isomerization. AB - Fkbp5 is a widely expressed peptidyl prolyl isomerase that serves as a molecular chaperone through conformational changes of binding partners. Although it regulates diverse protein functions, little is known about its roles in myogenesis. We found here that Fkbp5 plays critical roles in myoblast differentiation through two mechanisms. First, it sequesters Cdk4 within the Hsp90 storage complex and prevents the formation of the cyclin D1-Cdk4 complex, which is a major inhibitor of differentiation. Second, Fkbp5 promotes cis-trans isomerization of the Thr172-Pro173 peptide bond in Cdk4 and inhibits phosphorylation of Thr172, an essential step for Cdk4 activation. Consistent with these in vitro findings, muscle regeneration is delayed in Fkbp5-/- mice. The related protein Fkbp4 also sequesters Cdk4 within the Hsp90 complex but does not isomerize Cdk4 or induce Thr173 phosphorylation despite its highly similar sequence. This study demonstrates protein isomerization as a critical regulatory mechanism of myogenesis by targeting Cdk4. PMID- 30485819 TI - Social Stress Mobilizes Hematopoietic Stem Cells to Establish Persistent Splenic Myelopoiesis. AB - Psychosocial stress accelerates myelopoietic production of monocytes and neutrophils that contributes to a variety of health complications ranging from atherosclerosis to anxiety. Here, we show that social stress in mice mobilizes hematopoietic stem progenitor cells (HSPCs) from the bone marrow that enter circulation, engraft into the spleen, and establish a persistent extramedullary hematopoietic depot. These splenic progenitors actively proliferate and differentiate into multiple cell types, including monocytes, neutrophils, and erythrocytes. Splenic erythropoiesis partially abrogates stress-induced anemia. Repeated injection with isoprenaline induces progenitor mobilization to the spleen, identifying a key role for beta-adrenergic signaling. Moreover, protracted splenic production of CD11b+ cells persists for at least 24 days after the cessation of social stress. Thus, chronic stress establishes a persistent extramedullary hematopoietic depot that can modify a wide range of chronic disease processes and alter homeostasis of the bi-directional regulatory axis between the nervous and immune systems. PMID- 30485821 TI - Cellular and Molecular Responses Unique to Major Injury Are Dispensable for Planarian Regeneration. AB - The fundamental requirements for regeneration are poorly understood. Planarians can robustly regenerate all tissues after injury, involving stem cells, positional information, and a set of cellular and molecular responses collectively called the "missing tissue" or "regenerative" response. follistatin, which encodes an extracellular Activin inhibitor, is required for the missing tissue response after head amputation and for subsequent regeneration. We found that follistatin is required for the missing tissue response regardless of the wound context, but causes regeneration failure only after head amputation. This head regeneration failure involves follistatin-mediated regulation of Wnt signaling at wounds and is not a consequence of a diminished missing tissue response. All tested contexts of regeneration, including head regeneration, could occur with a defective missing tissue response, but at a slower pace. Our findings suggest that major cellular and molecular programs induced specifically by large injuries function to accelerate regeneration but are dispensable for regeneration itself. PMID- 30485820 TI - Improving Cell Survival in Injected Embryos Allows Primed Pluripotent Stem Cells to Generate Chimeric Cynomolgus Monkeys. AB - Monkeys are an optimal model species for developing stem cell therapies. We previously reported generating chimeric cynomolgus monkey fetuses using dome shaped embryonic stem cells (dESCs). However, conventional primed pluripotent stem cells (pPSCs) lack chimera competency. Here, by altering the media in which injected morulae are cultured, we observed increased survival of cynomolgus monkey primed ESCs, induced PSCs, and somatic cell nuclear transfer-derived ESCs, thereby enabling chimeric contributions with 0.1%-4.5% chimerism into the embryonic and placental tissues, including germ cell progenitors in chimeric monkeys. Mechanically, dESCs and pPSCs belong to different cell types and similarly express epiblast ontogenic genes. The host embryonic microenvironment could reprogram injected PSCs to embryonic-like cells. However, the reprogramming level and chimerism were associated with the cell state of injected PSCs. Our findings provide a method to understand pluripotency and broaden the use of embryonic chimeras for basic developmental biology research and regenerative medicine. PMID- 30485822 TI - Microtubule-Based Control of Motor-Clutch System Mechanics in Glioma Cell Migration. AB - Microtubule-targeting agents (MTAs) are widely used chemotherapy drugs capable of disrupting microtubule-dependent cellular functions, such as division and migration. We show that two clinically approved MTAs, paclitaxel and vinblastine, each suppress stiffness-sensitive migration and polarization characteristic of human glioma cells on compliant hydrogels. MTAs influence microtubule dynamics and cell traction forces by nearly opposite mechanisms, the latter of which can be explained by a combination of changes in myosin motor and adhesion clutch number. Our results support a microtubule-dependent signaling-based model for controlling traction forces through a motor-clutch mechanism, rather than microtubules directly relieving tension within F-actin and adhesions. Computational simulations of cell migration suggest that increasing protrusion number also impairs stiffness-sensitive migration, consistent with experimental MTA effects. These results provide a theoretical basis for the role of microtubules and mechanisms of MTAs in controlling cell migration. PMID- 30485823 TI - Dynamic Phosphorylation of the C Terminus of Hsp70 Regulates the Mitochondrial Import of SOD2 and Redox Balance. AB - The import of superoxide dismutase-2 (SOD2) into mitochondria is vital for the survival of eukaryotic cells. SOD2 is encoded within the nuclear genome and translocated into mitochondria for activation after translation in the cytosol. The molecular chaperone Hsp70 modulates SOD2 activity by promoting import of SOD2 into mitochondria. In turn, the activity of Hsp70 is controlled by co-chaperones, particularly CHIP, which directs Hsp70-bound proteins for degradation in the proteasomes. We investigated the mechanisms controlling the activity of SOD2 to signal activation and maintain mitochondrial redox balance. We demonstrate that Akt1 binds to and phosphorylates the C terminus of Hsp70 on Serine631, which inhibits CHIP-mediated SOD2 degradation thereby stabilizing and promoting SOD2 import. Conversely, increased mitochondrial-H2O2 formation disrupts Akt1-mediated phosphorylation of Hsp70, and non-phosphorylatable Hsp70 mutants decrease SOD2 import, resulting in mitochondrial oxidative stress. Our findings identify Hsp70 phosphorylation as a physiological mechanism essential for regulation of mitochondrial redox balance. PMID- 30485824 TI - Integrated Genomic, Epigenomic, and Expression Analyses of Ovarian Cancer Cell Lines. AB - To improve our understanding of ovarian cancer, we performed genome-wide analyses of 45 ovarian cancer cell lines. Given the challenges of genomic analyses of tumors without matched normal samples, we developed approaches for detection of somatic sequence and structural changes and integrated these with epigenetic and expression alterations. Alterations not previously implicated in ovarian cancer included amplification or overexpression of ASXL1 and H3F3B, deletion or underexpression of CDC73 and TGF-beta receptor pathway members, and rearrangements of YAP1-MAML2 and IKZF2-ERBB4. Dose-response analyses to targeted therapies revealed unique molecular dependencies, including increased sensitivity of tumors with PIK3CA and PPP2R1A alterations to PI3K inhibitor GNE-493, MYC amplifications to PARP inhibitor BMN673, and SMAD3/4 alterations to MEK inhibitor MEK162. Genome-wide rearrangements provided an improved measure of sensitivity to PARP inhibition. This study provides a comprehensive and broadly accessible resource of molecular information for the development of therapeutic avenues in ovarian cancer. PMID- 30485825 TI - Exposure to triclosan among the Canadian population: Results of the Canadian Health Measures Survey (2009-2013). AB - Triclosan is a broad-spectrum antimicrobial additive in consumer products that has been detected in human populations globally. The purpose of this study was to assess triclosan exposure among the Canadian population using urinary triclosan as a biomarker. Data from the Canadian Health Measures Survey (CHMS) that reported triclosan concentrations in 8195 urine samples collected from Cycle 2 (2009-2011) and Cycle 3 (2012-2013) were analyzed. Triclosan was detected in 69.8% of samples with the geometric mean concentrations of 16 MUg/L (16 MUg/g creatinine) for the total population, 13 MUg/L (13 MUg/g creatinine) for children (3-19 years of age), and 16 MUg/L (17 MUg/g creatinine) for adults. Triclosan concentrations significantly differed by age, income, education, and employment in healthcare occupations, but not by race/ethnicity, sex, region of residence, or drinking water preferences or sources. Linear regression models were used to identify factors associated with urinary triclosan concentration. Results showed that household income was associated with higher urinary triclosan concentrations in both children and adults. Employed in healthcare occupations were associated with higher urinary triclosan concentrations in adults. Triclosan exposure at the 99th percentile was below the Biomonitoring Equivalents based on reference dose, suggesting that health risks to the Canadian population from triclosan exposure were low. PMID- 30485826 TI - Peptides from rice endosperm protein restrain periodontal bone loss in mouse model of periodontitis. AB - OBJECTIVE: Food-derived peptides have been reported to exhibit antibacterial activity against periodontal pathogenic bacteria. However, no effect has been shown on inflammation and bone resorption in periodontal pathology. The overall objective of the current study was to investigate how rice peptides influence biological defense mechanisms against periodontitis-induced inflammatory bone loss, and identify their novel functions as a potential anti-inflammatory drug. DESIGN: The expression of inflammatory and osteoclast-related molecules was examined in mouse macrophage-derived RAW 264.7 cell cultures using qPCR. Subsequently, the effect of these peptides on inflammatory bone loss in mouse periodontitis was examined using a mouse model of tooth ligation. Briefly, periodontal bone loss was induced for 7 days in mice by ligating the maxillary second molar and leaving the contralateral tooth un-ligated (baseline control). The mice were microinjected daily with the peptide in the gingiva until the day before euthanization. One week after the ligation, TRAP-positive multinucleated cells (MNCs) were enumerated from five random coronal sections of the ligated sites in each mouse. RESULTS: Rice peptides REP9 and REP11 significantly inhibited transcription activity of inflammatory and osteoclast-related molecules. Local treatment with the rice peptides, in mice subjected to ligature induced periodontitis, inhibited inflammatory bone loss, explaining the decreased numbers of osteoclasts in bone tissue sections. CONCLUSION: Therefore, these data suggested that the rice peptides possess a protective effect against periodontitis. PMID- 30485827 TI - Alcohol use severity and age moderate the effects of brief interventions in an emergency department randomized controlled trial. AB - BACKGROUND: The primary aim of this study was to examine the efficacy of two motivational interviewing-based alcohol brief interventions (BIs) among adults presenting to an emergency department (ED). The secondary aim was to evaluate moderators of intervention effects. METHODS: Participants were 750 ED patients reporting recent alcohol misuse. Participants were randomly assigned to: 1) computer-delivered BI (Computer BI), 2) therapist-delivered BI with computer guidance (Therapist BI-CG), or 3) control. The BIs focused on reduction of alcohol use and risk behaviors. The outcome measure was trajectories of alcohol consumption (measured by the AUDIT-C) across baseline, 3-, 6- and 12-month follow up assessments, analyzed using latent growth curve modeling. Moderation of intervention effect by gender, age, and baseline alcohol use disorder severity was examined. RESULTS: Across the full sample (40% males, mean age = 35.8, SD = 12.3), there was an overall reduction in alcohol consumption across 12 months. The main effects of the Therapist and Computer BI were not significant relative to control. Moderation analysis revealed that the impact of Therapist BI-CG, relative to control, was greater on reductions in alcohol consumption in participants with moderate to severe symptoms of alcohol use disorder compared to those with mild symptoms. The effect of the Computer BI on alcohol use, relative to control, was greater among younger participants compared to older participants. CONCLUSIONS: While no overall effect was shown, ED-based Therapist BI-CG with computer guidance may be effective among patients with moderate-severe drinking patterns, whereas Computer BIs may be more effective for younger participants. PMID- 30485828 TI - Microcystin-LR induces angiodysplasia and vascular dysfunction through promoting cell apoptosis by the mitochondrial signaling pathway. AB - The harmful algal blooms are becoming increasingly problematic in the regions that drinking water production depends on surface waters. With a global occurrence, microcystins are toxic peptides produced by multiple cyanobacterial genera in the harmful algal blooms. In this study, we examined the effects of microcystin-LR (MC-LR), a representative toxin of the microcystin family, on vascular development in zebrafish and the apoptosis of human umbilical vein endothelial cells (HUVECs). In zebrafish larvae, MC-LR induced angiodysplasia, damaged vascular structures and reduced lumen size at 0.1 MUM and 1 MUM, leading to the decrease of the blood flow area in the blood vessels and brain hemorrhage, which showed that MC-LR could dose-dependently inhibit vascular development and cause vascular dysfunction. In MC-LR treated HUVECs, the proportion of early apoptosis and late apoptosis cells increased in a concentration-dependent manner. Different concentrations of MC-LR could also activate caspase 3/9 in HUVECs, increase the level of mitochondrial ROS and reduce mitochondrial membrane potential. Additionally, MC-LR could promote the expression of p53 and inhibit the expression of PCNA. The findings showed that MC-LR could promote apoptosis of HUVECs through the mitochondrial signaling pathway. Combined with these results, MC-LR may promote vascular endothelial cell apoptosis through mitochondrial signaling pathway, leading to angiodysplasia and vascular dysfunction. PMID- 30485829 TI - Enhanced Cr(VI) removal from simulated electroplating rinse wastewater by amino functionalized vermiculite-supported nanoscale zero-valent iron. AB - A novel amino-functionalized vermiculite (AVT)-supported nanoscale zero-valent iron (AVT-nZVI) was successfully synthesized for Cr(VI) removal from simulated electroplating rinse wastewater. Since the agglomeration and oxidation of nZVI could be weakened and the reaction rate between Cr(VI) and nZVI could be enhanced for the novel AVT-nZVI, an efficient Cr(VI) removal could be achieved. The experimental results showed that 100% of Cr(VI) removal was obtained with AVT nZVI, whereas only 87.5% was achieved by nZVI after reacting for 60 min with 20.0 mg L-1 Cr(VI) (pH = 5.0). After four cycles, the removal efficiency of Cr(VI) by AVT-nZVI still maintained at above 70%, suggesting that AVT-nZVI exhibited a good performance of reusability. The stability of AVT-nZVI particles was better than nZVI, which was confirmed by the steady-state polarization measurements. Furthermore, the removal of Cr(VI) by AVT-nZVI was proved to be in accordance with the pseudo-second-order adsorption kinetics and Langmuir model. Based on the experiments and characterization, the reaction mechanism of Cr(VI) removal by AVT nZVI was clarified. The protonated amino groups (-NH3+) on the AVT promoted negative Cr(VI) species to be adsorbed on AVT-nZVI surface. Besides, Cr(VI) was reduced by Fe (0) to Cr(III), which was eventually adsorbed on the surface of AVT nZVI particles as the Cr(III)-Fe(III) co-precipitates. PMID- 30485830 TI - Electroautotrophy of Thioalkalivibrio nitratireducens. AB - The electrochemical behavior and electro-autotrophy of a halo-alkaliphilic chemo autotrophic Ectothiorhodospiraceae isolated from a soda lake, Thioalkalivibrio nitratireducens, were investigated using electrochemical methods and confocal fluorescence microscopy. The electrocatalysis of oxygen reduction was observed at -0.25 V/Ag/AgCl (-0.055 V/ SHE) with bioelectrodes polarized at -0.3 V/Ag/AgCl ( 0.105 V/SHE), displaying a maximum catalytic current density of -620 mA m-2 (voltammetry). No catalytic signal toward nitrate reduction was observed under anaerobia. The microscopic observation of the polarized electrodes compared to non-polarized ones, however, revealed a bacterial proliferation both under aerobic and anaerobic conditions, demonstrating the ability of Tv. nitratireducens to grow with the polarized electrode as sole electron source. PMID- 30485831 TI - Differential abundance of proteome associated with intramuscular variation of meat quality in porcine longissimus thoracis et lumborum muscle. AB - Intramuscular variation of meat quality in the porcine longissimus thoracis et lumborum (LTL) muscle was evaluated by assessing the differential abundance of proteome components. Twenty LTL muscles were individually divided into three regions (anterior, medial, and posterior) according to meat color. CIE L* and b* were higher (P < 0.05), but Warner-Bratzler shear force (WBSF) was lower (P < 0.05) in the anterior region, where myosin-1 and -2, TPM2, MLC1f, MLC2, Hsp27, and TPI1 were highly (P < 0.05) abundant. However, CIE a*, drip loss, and WBSF were higher (P < 0.05) in the medial region. Glycolysis enzymes including enolase 3, ALDOA, LDHA, PGM1, and TPI1 were highly abundant in the medial and posterior region, whereas GAPDH and myoglobin were overexpressed in the medial region (P < 0.05). Therefore, intramuscular variations in color, water-holding capacity, and tenderness were associated with differential abundance of the proteome, especially contractile, glycolysis enzymes, and Hsp27. PMID- 30485832 TI - Publication Rates and Characteristics of Registered Randomized Clinical Trials in Digital Health: A Cross Sectional Analysis. AB - BACKGROUND: Clinical trials are key to advancing evidence-based medical research. The medical research literature has identified the impact and risks of publication bias in clinical trials. Selective publication for positive outcomes or non-publication of negative results could lead to misdirection of subsequent research, justify further research, and result in literature reviews leaning towards positive outcomes. Digital health randomized clinical trials face specific challenges, including a high attrition rate, usability issues, and insufficient prior formative research. These challenges may become contributing factors to non-publication of trials' results. To our knowledge, no study exists that has analyzed and reported the characteristics of non-publication rates within the domain of digital health trials. OBJECTIVE: The primary research objective was to examine the prevalence and characteristics of non-published digital health randomized clinical trials, including eHealth, mHealth, and telehealth clinical trials, registered in ClinicalTrials.gov. Our secondary research objective was to determine whether industry funding is a contributing factor to trials non-publication. METHODS: To identify digital health trials, a list of 47 search terms and phrases was developed through an iterative process and applied to the "Title," "Interventions," and "Outcome Measures" fields of registered clinical trials with completion dates between April 1st, 2010 and April 1st, 2013. The search was based on the full dataset exported from the ClinlicalTrials.gov database, with 265,657 registered clinical trials entries downloaded on February 10th, 2018, to allow for up to nearly five years for the publication of the study after trial completion. To identify publications related to the results of the trials, we extracted the registered clinical trials content from the ClinicalTrials.gov website in XML format and identified relevant publications through a comprehensive approach that included an automated as well as a manual publication identification process. RESULTS: In total, 6717 articles matched the a priori search terms and phrases, of which 803 trials matched our latest completion date criteria. 556 randomized trials were included in this study after screening. We found that 150 (27%) of all included trials remain unpublished five years after the completion date of each trial. In bivariate analyses, statistically significant differences in trial characteristics between published and unpublished trials were found for the intervention target condition (cancer having the largest non-publication rate at 45%, while addiction/smoking cessation trials having the lowest non-publication rate at 16%), country (U.S. at 33% and non-U.S. at 18%), trial size (small trials at 52%, larger trials at 30%), clinical trial phases, recruitment and prospective trials registration. In multivariate analyses, differences in trial characteristics between published and unpublished trials remained statistically significant for the intervention target condition, country, trial size, trial phases and recruitment, with the odds of publication for non-U.S.-based trials being significant and 3.3 (CI:1.845-5.964) times more likely to be published compared to the reference group of the U.S. based trials. We observed a trend of 1.5 times higher non-publication rate for industry-funded trials, However, the trend was not statistically significant. CONCLUSIONS: In the domain of digital health, non-publication of registered clinical trials results is prevalent at 27%, which is lower than non-publication rates in other fields. There are substantial differences in publication rates between trials funded by industry and non-industry sponsors. Further research is required to define further determinants and reasons for non-publication, and more importantly to articulate the impact and risk of publication bias in the field of digital health clinical trials. PMID- 30485833 TI - LOC134466 methylation promotes oncogenesis of endometrial carcinoma through LOC134466/hsa-miR-196a-5p/TAC1 axis. AB - To investigate possible mechanism of abnormal methylation of long non-coding RNA (lncRNA) on endometrial carcinoma (EC) progression, we detected the genome methylation profiling of endometrial carcinoma by bioinformatic analysis. Accordingly, gene LOC134466 was chosen for the further research. We also found that TAC1 was the target gene of LOC134466 and miRNA, hsa-miR-196a-5p, might form a connection between LOC134466 and TAC1. The relationship was further proved by dual-luciferase reporter assay. In vitro studies, DNA methylation and expression were determined by MSP and qRT-PCR respectively. Cell proliferation, apoptosis and cell cycle were demonstrated by colony formation assay, Annexin V/PI double staining and flow cytometry. Besides, the function of LOC134466 and TAC1 in EC was further confirmed by Tumor Xenograft. Our results indicated that EC progression was promoted by hypermethylated LOC134466 and TAC1. Moreover, TAC1 transcription was regulated by LOC134466 via hsa-miR-196a-5p binding. LOC134466 and TAC1 demethylation by 5-Aza-2-Deoxycytidine inhibited EC cells proliferation and accelerated cell apoptosis. Furthermore, the expression of TACR1, TACR2 and TACR3 was remarkably decreased through LOC134466 and TAC1 treatments. Our findings establish a novel regulatory axis, LOC134466/hsa-miR-196a-5p/TAC1. Downregulation of the axis promoted EC development through TACR3, which further activated neuroactive ligand-receptor interaction. PMID- 30485834 TI - Beta Adrenergic Receptors Stimulation Attenuates Phosphorylation of NF-kappaB and IkappaBalpha in Hyperglycemic Endothelial Cells. AB - BACKGROUND/AIMS: NF-kappaB induces transcription of a number of genes, associated with inflammation and apoptosis. In this study, we have investigated the effect of beta-adrenergic receptor stimulation on NF-kappaB and IkappaBalpha in HUVECs. METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured in high and low glucose concentrations. All HUVECs were treated with different concentrations of isoproterenol and propranolol for different time periods. The analytical procedures consisted of Western Blot, ELISA, DCFH-DA and TUNEL assays. RESULTS: Isoproterenol (agonist of a beta-adrenergic receptor) significantly reduced phosphorylation at Ser-536 of NF-kappaB; and Ser-32 and Ser-36 of IkappaBalpha in hyperglycemic HUVECs. Isoproterenol also significantly reduced apoptosis and ROS generation. No effect of IkappaBalpha was observed on Tyr-42 phosphorylation. The effect of isoproterenol was reversed by the antagonist propranolol. We also checked if NF-kappaB inhibitor MG132 causes any change at the level of apoptosis. However, we observed an almost similar effect. CONCLUSION: Given data demonstrates that beta-adrenergic receptors stimulation has a protective effect on HUVECs that might be occuring via NF-kappabeta and IkappaBalpha pathway. PMID- 30485835 TI - L-Carnitine Supplementation Increases Trimethylamine-N-Oxide but not Markers of Atherosclerosis in Healthy Aged Women. AB - BACKGROUND: L-carnitine can be metabolized to trimethylamine N-oxide (TMAO), a molecule that promotes atherogenesis through its interaction with macrophages and lipid metabolism. OBJECTIVE: The aim of the present study was to assess whether L carnitine supplementation may promote changes in selected serum biomarkers of atherosclerosis. METHODS: Before the start, in the mid-point and after completing the 24-weeks supplementation protocol, fasting blood samples were taken from the antecubital vein. Plasma free L-carnitine and TMAO were determined by the UPLC/MS/MS method. Serum proteins were determined by the enzyme immunoassay method using commercially available kits. Total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and triglycerides have been determined using standard automatic analyzer. RESULTS: L-carnitine supplementation elevated fasting plasma carnitine in the mid-point of our study and it remained increased until the end of supplementation period. Moreover, it induced tenfold increase in plasma TMAO concentration but did not affect serum C reactive protein, interleukin-6, tumour necrosis factor-alpha, L-selectin, P selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1 or lipid profile markers. CONCLUSION: We demonstrated that -although oral L carnitine supplementation significantly -increased plasma TMAO concentration, no lipid profile changes or other markers of adverse cardiovascular events were detected in healthy aged women over the period of 24 weeks. PMID- 30485836 TI - A multicentre Study of Nutrition Risk Assessment in Adult Patients with Inflammatory Bowel Disease Attending Outpatient Clinics. AB - BACKGROUND: Overnutrition and undernutrition can affect patients with inflammatory bowel disease (IBD). Although all IBD outpatients should be screened for nutrition risk, screening is not routinely performed, potentially leading to reduced identification and treatment. This study aimed to estimate the prevalence of nutrition risk in adult IBD outpatients and the proportion of cases who discussed diet and/or nutrition during their routine clinical appointment. METHODS: Adults with IBD attending outpatient clinics at 4 hospitals in Greece and in UK were recruited. Demographic and anthropometric data were collected using face-to-face patient interviews and clinical records. Patients were classified as high (i.e., body mass index [BMI] < 18.5 or 18.5-20 kg/m2 and weight loss > 5%), moderate (i.e., BMI 20-25 kg/m2 and weight loss > 5%) or low risk of undernutrition and high risk of obesity (i.e., BMI 25-30% and weight gain > 5%). The proportion of patients who discussed diet and/or nutrition during their clinical appointment was calculated. RESULTS: In total, 390 IBD patients participated. Sixteen (4%) patients were underweight, 113 (29%) were overweight and 71 (18%) were obese. Twenty-one (5%) patients were at high risk of undernutrition; of these 4 (19%) were under dietetic care. Of those at high risk of undernutrition, 11 (52%) had discussed diet and/or nutrition during their routine clinical appointment. Fifty-six (14%) patients had gained more than 5% weight since their last recorded/reported weight and 19 (5%) were at high risk of obesity. CONCLUSIONS: Few patients were identified to be at high risk of undernutrition and less than a fifth of these were under dietetic care. Overnutrition is a growing problem in IBD with almost half of adult patients being overweight or obese. Diet and/or nutrition were not routinely discussed in this group of IBD outpatients. PMID- 30485837 TI - The Long Noncoding RNA 150Rik Promotes Mesangial Cell Proliferation via miR 451/IGF1R/p38 MAPK Signaling in Diabetic Nephropathy. AB - BACKGROUND/AIMS: Diabetic nephropathy (DN) as the primary cause of end-stage kidney disease is a common complication of diabetes. However, the initiating molecular events triggering DN are unknown. Recently, long noncoding RNAs (lncRNAs) have been shown to play important roles in DN. METHODS: The expression level of lncRNA 1500026H17Rik (150Rik for short) was measured by qRT-PCR (quantitative real-time PCR). Cell proliferation ability was detected by 5 Ethynyl-2'-deoxyuridine (EdU). The relationship between 150Rik and microRNA 451 (miR-451) was examined by luciferase assay and RNA immunoprecipitation (RIP) assay. Finally, the effect of 150Rik on cell proliferation through the miR 451/insulin-like growth factor 1 receptor (IGF1R)/mitogen-activated protein kinases (p38MAPK) pathway was detected by EdU, flow cytometry analysis, western blot. RESULTS: We found that 150Rik, an evolutionarily conserved lncRNA, was significantly upregulated in renal tissue of db/db DN mice and in mesangial cells (MCs) cultured under a high glucose condition. Further, overexpression or knockdown of 150Rik was found to regulate cell proliferation in MCs. Moreover, 150Rik was found to interact with miR-451 in both a direct and argonaute-2 (Ago2) dependent manner. Results also revealed that overexpression of 150Rik inhibited cell proliferation through the miR-451/IGF1R/p38MAPK pathway in MCs under the high glucose condition, while knockdown of 150Rik increased cell proliferation via the miR-451/IGF1R/p38MAPK pathway. CONCLUSION: Taken together, these results provide new insight into the association between 150Rik and the miR 451/IGF1R/p38MAPK signaling pathway during DN progression. PMID- 30485838 TI - microRNA-29a-3p, Up-Regulated in Human Gastric Cells and Tissues with H.Pylori Infection, Promotes the Migration of GES-1 Cells via A20-Mediated EMT Pathway. AB - BACKGROUND/AIMS: Helicobacter pylori (H. pylori) infection is closely related to human gastric mucosa-associated diseases. Several recent studies on miRNAs have expanded our insights on H.pylori pathogenesis. This study aimed to investigate the biological roles and underlying molecular mechanisms of miR-29a-3p in human gastric cells and tissues with H.pylori infection. METHODS: miR-29a-3p expression was quantified by quantitative RT-PCR (qRT-PCR). A miR-29a-3p target gene was validated by bioinformatics analysis, western blotting and dual luciferase reporter gene assays. Western blotting and immunohistochemistry (IHC) assay were performed to detect the protein expression. Transwell assay was used to determine the cell migration ability. RESULTS: MiR-29a-3p was up-regulated in H.pylori positive gastric mucosa tissues and H.pylori-infected gastric cells. The up regulation of miR-29a-3p was dose-dependent in BGC-823 and GES-1 cells infected with H.pylori. Using gain- and loss-of-function experiments in vitro, we demonstrated that miR-29a-3p promoted the migration of gastric epithelial cells. We further characterized A20 as a direct target of miR-29a-3p. The expression of A20 was decreased in H.pylori-positive gastric mucosa tissues compared with H.pylori-negative gastric mucosa tissues. A20 downregulation was time- and dose dependent in GES-1 and BGC-823 cells infected with H.pylori. In GES-1 and BGC-823 cells infected with H.pylori, the miR-29a-3p mimic significantly blocked A20 expression, which suggests that H.pylori decreased A20 expression through up regulating miR-29a-3p in GES-1 and BGC-823 cells infected with H.pylori. The knockdown of A20 by siRNA enhanced the migration of human gastric epithelial cells and promoted the expression of Snail, Vimentin, and N-cadherin and inhibited the expression of E-cadherin. CONCLUSION: The miR-29a-3p may act as a tumor promotive miRNA by regulating cells migration through directly targeting of A20 gene in human gastric epithelial cells infected with H.pylori. PMID- 30485839 TI - Comprehensive Circular RNA Profiling Reveals the Regulatory Role of the CircRNA 0067835/miR-155 Pathway in Temporal Lobe Epilepsy. AB - BACKGROUND/AIMS: Temporal lobe epilepsy (TLE) is the most common form of adult localization-related epilepsy that is accompanied by progressive etiopathology and high incidences of drug resistance. Circular RNAs (circRNAs) play important roles in fine-tuning gene expression, however, the expression profile and clinical significance of circRNAs in TLE remains unknown. METHODS: Circular RNA microarray was conducted to identify TLE-related circRNAs. CCK8 assays and flow cytometric assays were conducted to clarify the role of circRNA in TLE in vitro. Bioinformatics analysis and in vitro experiments were conducted to clarify the mechanism of circRNA-mediated gene regulation in TLE cell. RESULTS: 586 differentially expressed circRNAs were identified between TLE and the control tissues. The expression of circRNA-0067835 was significantly down-regulated in tissues and plasma from TLE patients. Lower circRNA-0067835 correlated to increased seizure frequency, HS, and higher Engel's score. Overexpression of circRNA-0067835 observably decreased SH-SY5Y cell proliferation by causing G1 arrest and promoting apoptosis. Bioinformatics online programs predicted that circRNA-0067835 acted as miR-155 sponge to regulate FOXO3a expression, which was validated using luciferase reporter assay. CONCLUSION: Our experiments showed that circRNA-0067835 regulated refractory epilepsy progression by acting as a sponge of miR-155 to promote FOXO3a expression, indicating that circRNA-0067835 may serve as a potential therapeutic target for patients with TLE. PMID- 30485840 TI - Risk Factors of Central Venous Catheter-Related Bloodstream Infection for Continuous Renal Replacement Therapy in Kidney Intensive Care Unit Patients. AB - BACKGROUND: The incidence of central venous catheter-related bloodstream infection (CRBSI) for continuous renal replacement therapy (CRRT) in kidney intensive care unit (ICU) patients is worthy of particular attention and recently, we analyzed clinical characteristics and risk factors of CRBSI for CRRT in our kidney ICU patients. METHODS: To be part of this retrospective study, 1,523 patients who had a central venous catheter (CVC) for CRRT during the period April 2010 to May 2015 in our centre were enrolled. The clinical features and pathogens of CRBSI patients were investigated. Patients who also had CRRT of kidney ICU hospitalization without CRBSI were enrolled in a 1: 2 ratio as control. Risk factors of the CRBSI were analyzed. RESULTS: A total of 57 patients had central venous CRBSI. The incidence of the infection was 3.7%. The mean rate of CRBSI was 3.9 per 1,000 catheter days, and the catheter median indwelling time was 14 (7-30) days. The most common pathogens were Gram-positive bacteria, which were noted in 29 cases (50.9%), followed by Gram-negative bacteria (36.8%). The most common pathogens causing CRBSI were Staphylococcus aureus (10 cases) and sewer enterobacteriaceae (10 cases) followed by Staphylococcus epidermidis (9 cases). CVC insertion sites included internal jugular vein (33 cases) and femoral vein (24 cases), accounting for 2.9% of internal jugular vein catheterization (1,140 cases) and 6.3% of femoral vein catheterization (383 cases) respectively. In total, 16, 20, 7 and 14 cases of CRBSI were noted in Spring, Summer, Autumn and Winter, accounting for 28.1, 35.1, 12.3 and 24.6% respectively. The most common infectious manifestations were chills (68.4%), fever (100%), and septic shock (49.1%). Multivariate analysis showed that catheterization of the femoral vein, long catheter indwelling time, low CD4+ lymphocytes and high acute physiology and chronic health evaluation (APACHE) II scores were independent factors associated with CRBSI. CONCLUSIONS: The incidence of CRBSI in our kidney ICU was 3.7%. Central venous CRBSI for CRRT was associated with catheterization of the femoral vein, long catheter indwelling time, compromised immune function and high APACHE II scores. Understanding pathogens and risk factors for central venous CRBSI in kidney ICU can help doctors prevent and treat CRBSI earlier. PMID- 30485841 TI - Long-Term Follow-Up of a Patient with Spondylodiscitis after Laparoscopic Sacrocolpopexy: An Unusual Complication with a Review of the Literature. AB - Sacrocolpopexy is the gold standard treatment for apical compartment prolapse with reported success rates of 78-100%. Spondylodiscitis is a rare complication of sacrocolpopexy and includes a spectrum of spinal infections such as discitis, osteomyelitis, epidural abscess, meningitis, subdural empyema, and spinal cord abscess. Here we report a case of spondylodiscitis following laparoscopic sacrocolpopexy with long-term follow-up and discuss management of spondylodiscitis after abdominal sacrocolpopexy, with a review of the literature. PMID- 30485842 TI - Self-Reported Skin Changes by a Selected Number of Astronauts after Long-Duration Mission on ISS as Part of the Skin B Project. AB - BACKGROUND: One of the most challenging and important factors of manned space missions is to keep astronauts healthy on orbit. In a study on 46 ISS crew members who were on 6-month (average) missions, skin rashes were the most self reported event. Furthermore, among notable events, 40% were classified as skin rashes/hypersensitivities. Thus, especially skin conditions during space travel are of major clinical interest and require further research. AIMS: The aim of the study was to determine skin conditions in space flight among US and European astronauts, especially taking into account the terrestrial skin conditions as well as on-orbit skin care habits. METHODS: A preflight questionnaire was given to the astronauts asking about their terrestrial skin care habits and skin conditions/atopy before launch. In addition, they were asked to fill out a postflight questionnaire asking about their on-orbit skin care routine and whether any special observations regarding the skin were made during flight. RESULTS: A total of 23 skin symptoms were recorded by 8 nonatopic astronauts (mean age: 41 years) during the mission. The symptoms were peeling (21.74%), rash (17.39%), dryness (13.04%), severe dryness (8.70%), reddening (8.70%), itchiness (8.70%), bruising (4.35%), skin sensitivity (4.34%), bumps (4.35%), acne (4.35%) and slow healing of contusions and lacerations (4.35%). Especially the hands and feet were affected by skin problems. As a result of this examination, it was shown that the skin symptoms correlate with poor hygiene on orbit, whereas the factor "environment" on the ISS plays a minor role. Surprisingly, 2 astronauts even experienced positive effects on their skin. CONCLUSION: Based on these preliminary data, it is important to pay more attention to skin hygiene and maintenance in space. PMID- 30485843 TI - Current Data on Effects of Long-Term Missions on the International Space Station on Skin Physiological Parameters. AB - BACKGROUND: Skin reaction to spaceflight has not really been studied yet, although the skin has a very important barrier function to protect the body and can contribute to a more general understanding of physiology. It is proposed here to make a more thorough investigation of the skin during long-term spaceflight, using noninvasive techniques. AIMS: The aim of the present Skin-B study is to investigate the kinetics and range of possible skin modifications during long duration spaceflights and their recovery. METHODS: In order to investigate the effect on skin physiological parameters during spaceflight, measurements were carried out on 6 astronauts with respect to skin hydration, transepidermal water loss/barrier function, and surface evaluation of the living skin in orbit. Additional measured parameters on the ground were skin elasticity, skin density and thickness, as well as microcirculation. RESULTS: Data from the Skin-B subjects (n = 6) contradict the results obtained in the previous pilot study SkinCare (n = 1 subject). In the present study, no deterioration of the skin was found but rather an improvement in skin hydration and skin barrier function, and no changes or improvement in the appearance of the skin surface. Furthermore, the skin density and skin thickness as well as skin elasticity values were unchanged from pre-flight values. CONCLUSION: In conclusion, we found that spaceflight under present conditions has no negative impact on skin physiological parameters. PMID- 30485844 TI - Alpha-Lipoic Acid Preconditioning and Ischaemic Postconditioning Synergistically Protect Rats from Cerebral Injury Induced by Ischemia and Reperfusion Partly via Inhibition TLR4/MyD88/ NF-kappaB Signaling Pathway. AB - BACKGROUND/AIMS: A combination of alpha-lipoic acid preconditioning (ALAP) and ischaemic preconditioning (IPC) has not been tested in an in vivo rat cerebral ischaemia/reperfusion injury (I/RI) model, and the potential protective mechanisms have not been well elucidated. The aim of this study was to investigate the role of the TLR4/ MyD88/ NF-kappaB signaling pathway in the synergistically neuroprotective and anti-inflammatory effects of ALAP and IPC. METHODS: One hundred and fifty male Sprague-Dawley rats, weighing 180-230 g, were randomly divided into the following 5 groups: 1) sham-operated control; 2) I/R; 3) I/R+ALAP; 4) I/R+IPC; 5) I/R+IPC+ALAP. After 2 h of reperfusion, the infarct size, neurological deficit scores, brain oedema, oxidative stress, and inflammatory and apoptotic biomarkers were assessed. In addition, reactive oxygen species (ROS) and cell apoptosis were detected by DHE staining and TUNEL staining, respectively. RESULTS: Both ALAP and IPC treatment attenuated the I/RI induced neuronal injury, reflected by reductions in the infarct size, neurological deficit scores, brain oedema, lactate dehydrogenase (LDH) release and the inflammatory response, as well as decreased HMGB1, TLR4, MyD88, p65, C Caspase 3 and Bax expression and increased IKB-alpha, HO-1, SOD-2 and Bcl-2 expression compared to that in the I/R group. Furthermore, the combination of the two strategies had synergistic anti-inflammatory effects and antioxidant benefits, ultimately limiting neuronal apoptosis. CONCLUSION: The 'cocktail' strategy exhibited a significant neuroprotection against I/RI by attenuating neuroinflammation via inhibition of the TLR4/MyD88/NF-kappaB signaling pathway. PMID- 30485845 TI - Characterization of the Transcriptome of Hair Cell Regeneration in the Neonatal Mouse Utricle. AB - BACKGROUND/AIMS: Hearing and balance deficits are mainly caused by loss of sensory inner ear hair cells. The key signals that control hair cell regeneration are of great interest. However, the molecular events by which the cellular signals mediate hair cell regeneration in the mouse utricle are largely unknown. METHODS: In the present study, we investigated gene expression changes and related molecular pathways using RNA-seq and qRT-PCR in the newborn mouse utricle in response to neomycin-induced damage. RESULTS: There were 302 and 624 genes that were found to be up-regulated and down-regulated in neomycin-treated samples. GO and KEGG pathway analyses of these genes revealed many deregulated cellular components, molecular functions, biological processes and signaling pathways that may be related to hair cell development. More importantly, the differentially expressed genes included 9 transcription factors from the zf-C2H2 family, and eight of them were consistently down-regulated during hair cell damage and subsequent regeneration. CONCLUSION: Our results provide a valuable source for future studies and highlighted some promising genes, pathways or processes that may be useful for therapeutic applications. PMID- 30485846 TI - The Serum microRNA Profile of Intrahepatic Cholestasis of Pregnancy: Identification of Novel Noninvasive Biomarkers. AB - BACKGROUND/AIMS: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy specific disease that significantly increases the risk of fetal complications. Here, we measured serum miRNA levels in ICP patients to identify candidate biomarkers for ICP. METHODS: We used the Agilent miRNA array followed by reverse transcription-polymerase chain reaction assays to identify and validate the serum miRNA profiles of 40 pregnant women with ICP and 40 healthy pregnant controls. We used bioinformatics to identify metabolic processes related to differentially expressed miRNAs. RESULTS: The expression levels of three miRNAs (miR-371a- 5p, miR-6865-5p, and miR-1182) were significantly increased in ICP patients compared to controls; the areas under the receiver operating characteristic (ROC) curves (AUCs) were 0.771, 0.811, and 0.798, respectively. Multiple logistic regression analysis showed that a combination of the levels of the three miRNAs afforded a greater AUC (0.845), thus more reliably diagnosing ICP. The levels of all three miRNAs were positively associated with that of total bile acids. Furthermore, bioinformatics analysis indicated that the three miRNAs principally affected lipid phosphorylation, apoptosis, and the MAPK signaling pathway. CONCLUSION: This preliminary work improves our understanding of serum miRNA changes in pregnant women with ICP. The three miRNAs may serve as novel noninvasive biomarkers of ICP. PMID- 30485847 TI - Dermatonutrigenomics: Past, Present, and Future. PMID- 30485848 TI - Utility of Endoscopic Submucosal Dissection in the Remnant Stomach and Clinical Outcomes for Different Reconstruction Methods. AB - BACKGROUND: The number of patients with remnant gastric tumor during postoperative follow-up is increasing. We evaluated clinical outcomes to determine the feasibility of endoscopic submucosal dissection (ESD) for early gastric neoplasm in the remnant stomach. METHODS: We compared 138 lesions of ESD in the remnant stomach after proximal gastrectomy, distal gastrectomy (DG) or pylorus-preserving DG with 3,237 lesions of ESD in the intact stomach. ESD was performed at our hospital between January 2005 and September 2017. RESULTS: Compared with the intact group, the remnant group had significantly longer mean procedure duration and lower rates of curative resection (all p < 0.01). However, complication rates did not differ significantly between the 2 groups. Among the reconstruction techniques after DG, the rate of lesions at the anastomosis site was significantly higher and the mean procedure duration was significantly longer after Billroth II reconstruction (both p < 0.01). Also, curative resection rate was significantly lower after Billroth II (50.0%) than after Billroth I (p < 0.05). CONCLUSIONS: Although technically demanding, ESD for early gastric tumor in the remnant stomach was a safe and effective therapeutic method. However, because the curative resection rate was lower for the more frequent lesions occurring at the anastomosis site after Billroth II reconstruction, early detection of remnant stomach tumor is desirable after Billroth II reconstruction following DG. PMID- 30485850 TI - Immediate-Type Hypersensitivity Cross-Reactions to Proton Pump Inhibitors: A Descriptive Study of Data from the French National Pharmacovigilance Database. AB - BACKGROUND: Proton pump inhibitors (PPIs) can trigger immediate-type hypersensitivity reactions (HSRs). Three main patterns of cross-reactivity have been identified: reactions to a single PPI, selective cross-reactions, and cross reactions with all PPIs. Several hypotheses have been advanced, but no consensus has been reached. OBJECTIVE: We sought to identify immediate-type hypersensitivity cross-reactions to PPIs using real-world data about hypersensitivity testing from French pharmacovigilance cases. METHODS: Potentially relevant immediate-type HSRs reported from January 1985 to February 2015 were extracted from the French pharmacovigilance database using a standardized MedDRA query (SMQ). Cases describing skin tests or oral provocation tests (OPTs) performed with several PPIs that yielded at least one positive result were included. RESULTS: The SMQ extracted 2,119 cases, 38 of which were included in our study. Data collected from skin tests and OPTs indicated cross reactions with all PPIs (n = 1), reactions to a single PPI (n = 14), or selective cross-reactions (n = 23). Esomeprazole, omeprazole, and pantoprazole concerned 78% of all selective cross-reactions. In more than half of the cases (55.3%), only 2 PPIs were tested. CONCLUSION: To the best of our knowledge, this PPI cross reactivity study is the largest to date in terms of population size, describing 38 immediate-type HSRs to PPIs explored by skin tests or OPTs. This paucity of data belies the lack of standardized procedures for PPI hypersensitivity testing. It is likely that PPI HSR workups in everyday clinical practice are often incomplete. Further research to gain insight into selective cross-reactions between PPIs is needed. In the meantime, thorough workups should be completed when a PPI is suspected to have triggered an HSR, instead of routine contraindication to all PPIs. PMID- 30485849 TI - Impaired Left Ventricular Global Longitudinal Strain among Patients with Chronic Kidney Disease and End-Stage Renal Disease and Renal Transplant Recipients. AB - BACKGROUND: Although heart failure is the most prevalent cardiovascular disease associated with adverse outcome in chronic kidney disease (CKD) and after kidney transplantation, left ventricular (LV) systolic function is often preserved in renal patients. The aim of this study was to evaluate global longitudinal strain (GLS), which is reportedly a more accurate tool for detecting subclinical LV systolic dysfunction, in patients with various degrees of renal function impairment, including kidney transplant recipients (KTRs). METHODS: This prospective study evaluated demographic, clinical, and ultrasound data, including the assessment of LV GLS and mitral E peak velocity and averaged ratio of mitral to myocardial early velocities (E/e'), of 70 consecutive renal patients (20 with stage 2-4 CKD, 25 with end-stage renal disease on hemodialysis [HD], and 25 KTRs). All patients had an LV ejection fraction >=50% and no history of heart failure or coronary artery disease. We used multivariable logistic analysis to assess the risk of compromised GLS. One hundred and twenty control subjects with or without hypertension served as controls. RESULTS: A compromised GLS <-18% was shown in 55% of patients with stage 2-4 CKD, 60% of HD patients, and 28% of KTRs, while it was 32% in hypertensive controls and 12% in non-hypertensive controls (p < 0.0001). Patients with HD had higher systolic pressure and a significantly greater prevalence of increased LV mass and diastolic dysfunction. In renal patients, E/e' (p = 0.025), and LV mass index (p = 0.063) were independent predictors of compromised GLS at logistic regression analysis. E/e', systolic artery pressure, and LV mass also exhibited the greatest areas under the curve on receiver operating characteristic analysis to identify a compromised GLS. CONCLUSIONS: Renal disease proved to be associated with early and subclinical impairment of LV systolic function, which persists after starting dialysis and even in spite of successful kidney transplantation. An increased E/e' resulted to be the most powerful independent predictor of abnormal GLS. PMID- 30485851 TI - Stroke in Patients with Infective Endocarditis: A 15-Year Single-Center Cohort Study. AB - OBJECTIVE: To explore the relationship between infective endocarditis (IE) and stroke. METHODS: The clinical data of patients diagnosed with IE from January 2003 to December 2017 in Beijing Anzhen Hospital Affiliated to Capital Medical University were retrospectively analyzed. RESULTS: A total of 861 patients (mean age: 40.79 +/- 16.27 [SD]) with IE was recruited. Vegetations were confirmed in 97.32% of all the patients, among whom 296 were diagnosed with congenital heart disease and another 53 with rheumatic valvular disease. The most common pathogens were Streptococcus, Staphylococcus, and various types of fungi (13.12, 7.31, and 1.16% respectively). Out of the 138 patients diagnosed with stroke, 101 cases were of ischemic stroke, 23 cases were of hemorrhagic stroke, and 12 cases were of concurrent ischemic and hemorrhagic stroke. There were 31 patients who had infarction lesions in more than 2 vascular systems. The mean age of stroke patients was significantly higher than that of patients without stroke (45.76 +/- 17.88 vs. 39.83 +/- 15.77, p = 0.000). The incidence of mitral valve vegetation (57.24 vs. 43.01%, p = 0.002), atrial fibrillation (4.34 vs. 1.38%, p = 0.018), fungal infection (2.89 vs. 0.83%, p = 0.038) in patients with stroke was significantly higher than those without stroke. Mitral valve vegetation (OR 1.648; 95% CI 1.113-2.442) and age (OR 1.019; 95% CI 1.007-1.032) were independent risk factors for stroke in IE patients. Stroke increased the risk of hospital deaths (OR 7.673 95%CI 3.634-16.202). CONCLUSION: Stroke is a common complication of IE. Mitral valve vegetation and old age may incerease the risk of stroke in patients with IE. PMID- 30485852 TI - Syntaxin 8 and the Endoplasmic Reticulum Processing of DeltaF508-CFTR. AB - BACKGROUND/AIMS: Cystic fibrosis (CF) is a lethal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR). DeltaF508, the most common mutation, is a misfolded protein that is retained in the endoplasmic reticulum and degraded, precluding delivery to the cell surface [1]. METHODS: Here we use a combination of western blotting, immunoprecipitation, and short circuit current techniques combined with confocal microscopy to address whether the SNARE attachment protein, STX8 plays a role in DeltaF508's processing and movement out of the ER. RESULTS: Although the SNARE protein STX8 is thought to be functionally related and primarily localized to early endosomes, we show that silencing of STX8, particularly in the presence of the Vertex corrector molecule C18, rescues DeltaF508-CFTR, allowing it to reach the cell surface and increasing CFTR-dependent chloride currents by approximately 2.5-fold over control values. STX8 silencing reduced the binding of quality control protein, Hsp 27, a protein that targets DeltaF508-CFTR for sumoylation and subsequent degradation, to DeltaF508-CFTR. STX8 silencing increased the levels of Hsp 60 a protein involving in early events in protein folding. CONCLUSION: STX8 knockdown creates an environment favorable for mature DeltaF508 to reach the cell surface. The data also suggest that when present at normal levels, STX8 functions as part of the cell's quality control mechanism. PMID- 30485853 TI - Intensive Statin Therapy for Acute Ischemic Stroke to Reduce the Number of Microemboli: A Preliminary, Randomized Controlled Study. AB - BACKGROUND: To assess whether intensive statin therapy reduces the occurrence of microemboli in patients with acute ischemic stroke. METHODS: Patients with acute ischemic stroke within 72 h of onset were randomized to the intensive statin (atorvastatin 60 mg/day, adjusted to 20 mg/day after 7 days) and control (atorvastatin 20 mg/day) groups. Combined aspirin and clopidogrel were used for antiplatelet therapy. Microemboli were monitored by transcranial Doppler on days 1 (pre-treatment), 3, and 7. Metalloproteinase-9 (MMP-9), high-sensitivity C reactive protein (hs-CRP), and National Institutes of Health Stroke Scale (NIHSS) score were assessed on days 1 and 7. The modified Rankin scale (mRS) was used on day 90. The primary outcome was the proportion of patients with microemboli on day 3. RESULTS: There were 35 (58.3%) and 30 (52.6%) patients with microemboli in the intensive statin (n = 60) and control (n = 57) groups, respectively, on day 1 (p = 0.342). On day 3, there were significantly less microemboli in the intensive statin group (n = 9; 15.0%) compared with controls (n = 16; 28.1%; p = 0.002). No difference was observed in MMP-9 and hs-CRP levels on day 1, but on day 7, MMP-9 (median 79.3 vs. 95.9 MUg/L; p = 0.004) and hs-CRP (median 2.01 vs. 3.60 mg/L; p = 0.020) levels were lower in the intensive statin group compared with controls. There were no differences in NIHSS scores on days 1 and 7. There was no difference in mRS on day 90. CONCLUSION: Intensive atorvastatin therapy in patients with acute ischemic stroke reduces the occurrence of microemboli and inflammation, with no overt adverse events. PMID- 30485855 TI - Chemopreventive Effect of Rebamipide against Gastric Cancer in Patients who undergo Endoscopic Resection for Early Gastric Neoplasms: A Nationwide Claims Study. AB - BACKGROUND/AIMS: Previous studies have shown that rebamipide is potentially protective against gastric cancer; however, no epidemiologic studies of its chemopreventive effects in patients who have a high risk of gastric cancer have been performed. The aim of this study was to investigate whether rebamipide administration reduces the risk of gastric cancer. METHODS: We conducted a population-based cohort study using data retrospectively collected from the Health Insurance Review and Assessment Service database in Korea. Patients who underwent endoscopic submucosal dissection (ESD) for early gastric neoplasms between 2011 and 2014 were included. RESULTS: During 73,416 person-years of follow-up, 711 patients were newly diagnosed with gastric cancer, including 377 low-dose (below median) and 334 high-dose (above median) rebamipide users (37,157.4 and 36,258.3 per 100,000 person-years, respectively; log-rank test, p = 0.052). There were significant differences in gastric cancer incidence rates according to age, sex, and initial diagnosis at the time of index ESD. After adjusting for these clinical factors, high-dose use was associated with a reduced risk of gastric cancer (hazard ratio 0.858; 95% CI 0.739-0.995, p = 0.043). CONCLUSION: High-dose rebamipide is associated with reduced gastric cancer risk in high-risk populations who undergo endoscopic resection for early gastric neoplasms. PMID- 30485854 TI - Nalmefene, Given as Needed, in the Routine Treatment of Patients with Alcohol Dependence: An Interventional, Open-Label Study in Primary Care. AB - AIMS: This 12-week, open-label, primary care study (NCT02195817) evaluated the efficacy and safety of nalmefene, taken as needed, to reduce alcohol consumption in adults with a diagnosis of alcohol dependence and drinking at least at high drinking risk levels (DRL, > 60 g/day for men, > 40 g/day for women). METHODS: Following the Screening Visit, patients recorded their daily alcohol consumption for 2 weeks. Patients were then categorised by their self-reported drinking levels; those who maintained at least a high DRL in the 2-week period were included in Cohort-A, and those who reduced their alcohol consumption below high DRL were included in Cohort-B. Cohort-A received simple psychosocial interventions and were supplied with nalmefene 18 mg to be taken on days when they perceived a risk of drinking alcohol. Patients in Cohort-B received a simple psychosocial intervention and were treated per normal practice. RESULTS: Of the 378 enrolled patients, 330 were included in Cohort-A and 48 in Cohort-B. For patients in Cohort-A, the mean change from screening to Week-12 in the number of heavy drinking days/month was -13.1 days/month (95% CI -14.4 to -11.9, p < 0.0001). Overall, 55% of patients reduced their DRL by >=2 risk levels and 44% of patients reduced to a low DRL. The most common adverse events were nausea (18.3%) and dizziness (17.7%). Patients in Cohort-B maintained their lower level alcohol consumption at the 12-week follow-up. CONCLUSIONS: Patients with alcohol dependence treated in primary care with nalmefene, taken as needed, in conjunction with simple psychosocial support, significantly reduced their alcohol consumption. Treatment was well tolerated. PMID- 30485856 TI - The Human Salivary Antimicrobial Peptide Profile according to the Oral Microbiota in Health, Periodontitis and Smoking. AB - Antimicrobial peptides (AMPs) are a diverse family of peptides that defend the mucosal surfaces of the oral cavity and other locations. Many AMPs have multiple functions and properties that influence aspects of innate defense and colonization by microorganisms. The human oral cavity is home to the second-most diverse microbiome, and the health of the mouth is influenced by the presence of these bacteria as well as by extrinsic factors such as periodontitis and smoking. This study hypothesized that the AMP profile is different in the presence of extrinsic factors and that this would also be reflected in the bacteria present. The AMP profile was analyzed by quantitative selected-reaction-monitoring mass spectrometry analysis and 40 bacterial species were quantified by DNA-DNA hybridization in saliva donated by 41 individuals. Periodontal status was assessed through dental examination and smoking status through medical charting. Periodontal health (in nonsmokers) was associated with a higher abundance of ribonuclease 7, protachykinin 1, beta-defensin 128, lipocalin 1, bactericidal permeability-increasing protein fold-containing family B member 3, and bone marrow proteoglycan. Nonsmoking periodontal disease was associated with an abundance of neutrophil defensin 1 and cathelicidin. However, 7 AMPs were overabundant in periodontal disease in smokers: adrenomedullin, eosinophil peroxidase, 3 different histones, myeloperoxidase, and neutrophil defensin 1. There were no differentially abundant AMPs in smokers versus nonsmokers with periodontal health. Correlation network inference of healthy nonsmokers, healthy smokers, nonsmoking periodontitis, or smoking periodontitis donors demonstrated very different networks growing in complexity with increasing numbers of stressors. The study highlights the importance of the interaction between the oral cavity and its resident microbiota and how this may be influenced by periodontal disease and smoking. PMID- 30485857 TI - The Impact of Late Onset Arterial Hypotension on Respiratory Outcome in Extremely Premature Infants. AB - BACKGROUND: In extremely premature infants, arterial hypotension in the first days after birth has been associated with an increased risk for bronchopulmonary dysplasia (BPD). Some infants present with hypotension at a later postnatal age, but the relationship between late onset hypotension (LOH) and BPD has not been evaluated. OBJECTIVE: To evaluate the association between LOH and BPD and to identify pre- and postnatal factors associated with LOH. METHODS: Prospectively collected data from a cohort of 23-28 weeks gestational age (GA) infants born during years 2005-2015 and alive at day 28 were analyzed. LOH was defined as the receipt of vasopressor treatment during days 8-28. BPD was defined as need for oxygen at 36 weeks postmenstrual age. Late mortality was defined as death after day 28. RESULTS: Of 1,058 infants in the cohort, 90 (9%) had LOH during days 8 28. Infants with LOH had a higher incidence of BPD than normotensive infants (55 vs. 21%, p < 0.001). Multivariate logistic regression analysis (LRA) showed that LOH was associated with an increased risk for BPD (OR 1.87, 95% CI 1.10-3.17). LOH was also associated with an increased risk for late mortality. LRA showed the risk for LOH increased with lower GA, sepsis and patent ductus arteriosus during days 8-28. CONCLUSIONS: In this cohort of extremely premature infants, LOH was associated with an increased the risk for BPD. This association could be secondary to underlying factors that predispose to LOH and BPD or to the deleterious effects of LOH or its treatments on the lung. Further investigation is needed to assess causality. PMID- 30485858 TI - Obstructive Sleep Apnoea in Children and Adolescents with Ehlers-Danlos Syndrome. AB - BACKGROUND: In Ehlers-Danlos syndrome (EDS), a group of monogenic disorders affecting connective tissues, obstructive sleep apnoea (OSA) is highly prevalent in adults. The prevalence of OSA in children with EDS is unknown. OBJECTIVES: This prospective cross-sectional study aimed at determining the prevalence of OSA in paediatric EDS patients. METHODS: Children with EDS (n = 24) were recruited from the Children's Hospital Zurich and matched to healthy controls. Participants completed home respiratory polygraphy and questionnaires (Sleep-Related Breathing Disorder Scale [SRBD], Epworth Sleepiness Scale [ESS], and Child Health Questionnaire [CHQ]). The American Academy of Sleep Medicine criteria were applied for OSA diagnosis (obstructive apnoea-hypopnoea index [oAHI] >=1/h). Conditional logistic regression was used to compare the prevalence of OSA and to adjust for possible confounding. RESULTS: OSA was found in 42% of paediatric EDS patients and in 13% of matched controls (OR = 4.5, 95% CI = 0.97-20.83, p = 0.054). The median oAHI was higher in EDS patients than in controls (0.77/h, IQR = 0.19-1.76, vs. 0.24/h, IQR = 0.0-0.60, p < 0.001 adjusted for age, sex, and BMI z-score). EDS patients had lower scores in most CHQ scales and higher SRBD and ESS scores than controls (0.26, IQR = 0.1-0.35, vs. 0.07, IQR = 0-0.19, p = 0.004); 7 +/- 4 vs. 5 +/- 4, p = 0.033, respectively). CONCLUSION: OSA is a previously underestimated EDS-related complication increasing disease burden. PMID- 30485859 TI - The Difficult Secondary Tracheoesophageal Puncture: A Technique for Safe Insertion. AB - BACKGROUND/AIMS: The tracheoesophageal prothesis (TEP) has become the primary modality for laryngeal communication after total laryngectomy due to high success rates, minimal morbidity, and more natural pulmonary driven speech. Fibrosis, kyphosis, and post-radiation contracture may preclude TEP placement through rigid esophagoscopy, and certain patients may not tolerate an in-office awake procedure. For such patients, a technique for flexible esophageal stenting and TEP placement is necessary. METHODS: We performed a retrospective review of 3 patients who underwent TEP placement through endotracheal-tube esophageal stenting at the Massachusetts Eye and Ear Infirmary. RESULTS: All 3 patients underwent laryngectomy after prior chemoradiotherapy for laryngeal cancer with resulting neck contracture and fibrosis preventing rigid esophagoscopy. All patients underwent successful TEP placement through endotracheal stenting without complication and developed excellent tracheoesophageal speech. Specific technical details are highlighted. CONCLUSIONS: In patients with anatomical constraints preventing traditional TEP placement through rigid esophagoscopy, fiberoptic guidance through an endotracheal tube stent provides a safe and efficient approach for TEP placement. PMID- 30485860 TI - Clinicopathologic profiling of lung carcinoids with a Ki67 index greater than 20. AB -
The clinicopathological features of lung neuroendocrine neoplasms (NEN) with a high proliferative index at the border area between atypical carcinoid and neuroendocrine carcinoma, have not been investigated so far. The aim of this study was, therefore, to search for lung NENs, which are well-differentiated but show Ki67 values that overlap with those of poorly differentiated NENs (PD-NENs). Resected lung NENs from 244 Japanese patients were reviewed and Ki67 index was assessed in all tumors. The data were then correlated to clinicopathological parameters and patient outcome. Among 59 (24%) well-differentiated NENs (WD-NENs) and 185 (76%) lung PD-NENs, seven were defined as WD-NENs with a Ki67 index>20%. The Ki67 index of these tumors (mean 29%, range 24-36) was significantly lower than that of PD-NENs (mean 74%, range 34-99). All WD-NENs with Ki67>20% lacked abnormal p53 and loss of Rb1 expression. In contrast, many PD-NENs expressed p53 (48%) and showed loss of Rb1 (85%). The 2- and 5-year disease free survival rates in WD-NEN Ki67>20% patients were lower than those of WD-NEN Ki67<=20% (p<0.01 for disease free and overall survival). No statistical differences were detected between outcome of patients with WD-NEN Ki67>20% and those of PD-NEN. It is concluded that WD-NENs Ki67>20% share the morphological and immunohistochemical features with WD-NEN Ki67<=20%, but have a worse prognosis, suggesting that this tumor group has to be specifically considered in future classifications and probably need new therapeutic regimes.
. PMID- 30485861 TI - Different PDGF Receptor Dimers Drive Distinct Migration Modes of the Mouse Skin Fibroblast. AB - BACKGROUND/AIMS: The migration of mesenchymal cells is a fundamental cellular process that has been implicated in many pathophysiological conditions and is induced by chemoattractants such as platelet-derived growth factors (PDGFs). However, the regulatory mechanisms shaping this migration remain to be elucidated. METHODS: Here, we prepared mouse skin fibroblasts inactivated for different PDGF receptor genes and systematically measured their chemotactic responses within a gradient of different chemoattractants. RESULTS: We found that PDGFRalphabeta and PDGFRbetabeta dimers were strong inducers of random and directionally-persistent migration, respectively, that was sustained for up to 24 h. MAPK and PI3K were necessary to mediate random and directional migration, respectively. Directional migration was accompanied by abundant ventral stress fiber formation and consistent cell shape with less frequent formation of branch like processes. CONCLUSION: This is the first systematic study that characterized the chemotaxis mediated by three-different types of PDGFR dimers in mesenchymal cell migration. Our data demonstrate that PDGFR dimer formation is the critical step to determine the specific mode of fibroblast chemotaxis, while the accompanying cytoskeletal remodeling might contribute to migration persistence. PMID- 30485862 TI - Misevaluating the Future: Affective Disorder and Decision-Making Capacity for Treatment - A Temporal Understanding. AB - BACKGROUND: Within psychiatric practice and policy there is considerable controversy surrounding the nature and assessment of impairments of decision making capacity (DMC) for treatment in persons diagnosed with affective disorders. We identify the problems of "cognitive bias" and "outcome bias" in assessment of DMC for treatment in affective disorder and aim to help resolve these problems with an analysis of how time is experienced in depression and mania. SAMPLING AND METHODS: We conducted purposeful sampling and a qualitative phenomenological analysis of interview data on patients with depression and mania, exploring temporal experience and decision-making regarding treatment. RESULTS: In both severe depression and mania there is a distinctive experience of the future. Two consequences can follow: a loss of evaluative differentiation concerning future outcomes and, relatedly, inductive failure. This temporal inability can compromise an individual's ability to appreciate or "use or weigh" treatment information. CONCLUSIONS: The decision-making abilities required for self-determination involve an ability to evaluate alternative future outcomes. Our results show that, within severe depression or mania, anticipation of future outcomes is inflexibly fixed at one end of the value spectrum. We therefore propose a temporal model of decision-making abilities, which could be used to improve assessment of DMC in affective disorder. PMID- 30485863 TI - Vascular Remodeling Process of Heparin-Conjugated Poly(epsilon-Caprolactone) Scaffold in a Rat Abdominal Aorta Replacement Model. AB - In the field of vascular graft research, poly-epsilon-caprolactone (PCL) is used owing to its good mechanical strength and biocompatibility. In this study, PCL scaffold was prepared by electrospinning and surface modification with heparin via hexamethylenediamine. Then the scaffolds were implanted into the infrarenal abdominal aorta of Wistar rats and contrast-enhanced micro-ultrasound was used to monitor the patency of grafts after implantation. These grafts were extracted from the rats at 1, 3, and 6 months for histological analysis, immunofluorescence staining, and scanning electron microscopy observation. Although some grafts experienced aneurysmal change, results showed that all implanted grafts were patent during the course of 6 months and these grafts demonstrated well-organized neotissue with endothelium formation, smooth muscle regeneration, and extracellular matrix formation. Such findings confirm feasibility to create heparin-conjugated scaffolds of next-generation vascular grafts. PMID- 30485864 TI - Case mix of patients managed in the resuscitation area of a district-level public hospital in Cape Town. AB - Introduction: At the core of the district health system is the emergency centre, for many the entry point into the healthcare system. Limited data is available on the patient population served by district-level emergency centres in South Africa. The objective of this study is to describe the case mix of adult patients managed in the resuscitation unit of a district-level hospital in the Western Cape. Methods: A six-month prospective observational study was conducted in the resuscitation unit of Khayelitsha Hospital. Data were collected by clinicians in the unit by means of a Smartphone application on their own devices. Variables collected included patient demographics, patient acuity, patient comorbidities, diagnosis made in the unit, interventions received, length of stay, and disposition. Summary statistics were used to describe all variables. Results: A total of 2324 patient admissions were analysed. The mean age was 36.9 years with a male predominance (n = 1367, 58.8%). Most patients were triaged into high acuity categories (n = 1626, 70%). HIV infection was the most common comorbidity (n = 530, 22.8%). Acute medical (n = 1181, 50.8%) and trauma-related patients (n = 928, 39.9%) dominated the cohort. The median length of stay was 195 min and 502 (21.6%) patients were transferred to higher levels of care. There were 74 (3.2%) deaths. Conclusion: This study yields novel epidemiological data of emergency care in a district-level emergency centre. It highlights the burden of trauma and acute medical emergencies at the district level and can be used as a foundation for further research to provide targeted and effective healthcare to all citizens. PMID- 30485865 TI - From the Outgoing Editor in Chief. PMID- 30485866 TI - [Antihormonal therapy of prostate cancer - treatment indication and cardiovascular risk profile - advantage for GnRH antagonists?] AB - INTRODUCTION: Prostate cancer is the most common urological tumour disease in men. In the localized tumour stage in combination with radiotherapy and especially in advanced metastastic disease, classical androgen deprivation remains an essential therapy. During the last 10 years, our knowledge of the cardiovascular risk of this therapy has rapidly increased. MATERIAL AND METHODS: This non-systematic review highlights the current data on cardiovascular risk in the use of androgen deprivation therapy in prostate cancer. RESULTS: Essential publications about the cardiovascular risk of antihormonal therapy are summarised in detail. In particular, the current data on the potential cardiovascular benefit when using GnRH antagonists in androgen deprivation are discussed. The article further highlights the problem of today's antihormonal overtreatment, despite the lack of scientific evidence and points out that patient selection should be improved in the future. CONCLUSION: The multicentre prospective PRONOUNCE study has been designed to answer the question in more detail, as to whether GnRH antagonist therapy provides benefit with respect to the cardiovascular risk as compared to classical LHRH analogue androgen deprivation therapy. PMID- 30485867 TI - The Associations Between CYP2D6 Metabolizer Status and Pharmacokinetics and Clinical Outcomes of Venlafaxine: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The association between CYP2D6 metabolizer status and clinical outcomes of venlafaxine was extensively investigated previously, but no widely accepted conclusion has been reached so far. To obtain a more precise estimation of the association, a systematic review by meta-analysis was conducted in the present study. METHODS: The PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Technology of Chongqing, and Wan Fang Database were searched for eligible studies up to August 2018. RESULTS: Fourteen related studies involving 1035 patients were finally included. Significant associations were found among 3 CYP2D6 phenotypes (NM, IM, and PM) and most pharmacokinetic parameters of venlafaxine. However, CYP2D6 phenotypes were not associated with Hamilton Depression Rating Scale response of venlafaxine. In addition, we also found no significant association between CYP2D6 phenotype and overall rate of adverse events. CONCLUSIONS: CYP2D6 metabolizer status had significant influence on venlafaxine pharmacokinetics, but insufficient evidence demonstrated that CYP2D6 metabolizer status was associated with its therapeutic effects and overall rate of adverse events, which provided further evidence regarding the relationship between CYP2D6 metabolizer status and venlafaxine. PMID- 30485868 TI - [Basic Principles of Optics]. AB - As an ophthalmologist, it is very important to know whether limited vision is caused by refractive problems or whether there is another pathology behind it. That's why refraction plays a key role at the beginning of every eye examination. Therefore, it is important to know the basic principles of optics. When fitting spherical and cylindrical lenses, it is interesting to know which properties the respective lenses have. One should also be aware of the optical paths and refraction laws when fitting spectacle lenses and prisms. In addition, when prescribing spectacle lenses, one should consider changes in the distance between corneal apex and spectacle lens and know conversions for the strength of contact lenses. Only if you have a deeper understanding of refraction and correction of refractive errors you will be able to adjust optimal vision aids for more difficult refraction conditions. PMID- 30485869 TI - [A rare cause of the asymptomatic dissection of the internal carotid artery]. PMID- 30485870 TI - Video Comment on Jae Jun Park et al. PMID- 30485871 TI - Video Comment on Dingguo Zhang et al. PMID- 30485872 TI - Esophageal strictures: in search of the Goldilocks solution. PMID- 30485873 TI - Endoscopic gastroplasty for weight loss: are we finally there? PMID- 30485875 TI - [French comment on article Dilation or biodegradable stent placement for recurrent benign esophageal strictures: a randomized controlled trial]. PMID- 30485874 TI - Resecting a small gastrointestinal stromal tumor: feasible, but are you feeling lucky today? PMID- 30485876 TI - [French comment on article Endoscopic gastric reduction with an endoluminal suturing device: a multicenter prospective trial with 1-year follow-up]. PMID- 30485877 TI - [French comment on article Impact of peritoneal carcinomatosis on clinical outcomes of patients receiving self-expandable metal stents for malignant colorectal obstruction]. PMID- 30485878 TI - Craniovertebral Junction Anomalies in Small Breed Dogs with Atlantoaxial Instability: A Multicentre Case-Control Study. AB - OBJECTIVE: The main purpose of this study was to define criteria to systemically describe craniovertebral junction (CVJ) anomalies and to report the prevalence of CVJ anomalies in small breed dogs with and without atlantoaxial instability (AAI). METHODS: Retrospective multicentre matched case-control study evaluating magnetic resonance imaging and computed tomographic images of small breed dogs with and without AAI for the presence of CVJ anomalies. RESULTS: One hundred and twenty-two dogs were enrolled (61 with and 61 without AAI). Only dogs with AAI had dens axis anomalies such as separation (n = 20) or a short-rounded conformation (n = 35). Patients with AAI were more likely to have atlantooccipital overlapping based on transection of McRae's line by the dorsal arch of the atlas (odds ratio [OR] = 5.62, p < 0.01), a transection of Wackenheim's clivus line (OR = 41.62, p < 0.01) and rostral indentation of the occipital bone (OR = 2.79, p < 0.05). Patients with AAI were less likely to have a larger clivus canal angle (OR = 0.94, p < 0.01) and larger occipital bone lengths (OR = 0.89, p < 0.05). CLINICAL SIGNIFICANCE: Small breed dogs with AAI are more likely to have other CVJ anomalies such as atlantooccipital overlapping or dens anomalies. The grade of brachycephaly does not differ between patients with and without AAI. Certain objective criteria from human literature were found useful for the assessment of both AAI and atlantooccipital overlapping such as McRae's line, Wackenheim's clivus line, and clivus canal angle. The classification criteria used can help to evaluate CVJ anomalies in a more systematic way. PMID- 30485879 TI - Evaluation of Clinical Relevance of Drug-Drug Interaction Alerts Prior to Implementation. AB - INTRODUCTION: Drug-drug interaction (DDI) alerts are often implemented in the hospital computerized provider order entry (CPOE) systems with limited evaluation. This increases the risk of prescribers experiencing too many irrelevant alerts, resulting in alert fatigue. In this study, we aimed to evaluate clinical relevance of alerts prior to implementation in CPOE using two common approaches: compendia and expert panel review. METHODS: After generating a list of hypothetical DDI alerts, that is, alerts that would have been triggered if DDI alerts were operational in the CPOE, we calculated the agreement between multiple drug interaction compendia with regards to the severity of these alerts. A subset of DDI alerts (n = 13), with associated patient information, were presented to an expert panel to reach a consensus on whether each alert should be included in the CPOE. RESULTS: There was poor agreement between compendia in their classifications of DDI severity (Krippendorff's alpha: 0.03; 95% confidence interval: -0.07 to 0.14). Only 10% of DDI alerts were classed as severe by all compendia. On the other hand, the panel reached consensus on 12 of the 13 alerts that were presented to them regarding whether they should be included in the CPOE. CONCLUSION: Using an expert panel and allowing them to discuss their views openly likely resulted in high agreement on what alerts should be included in a CPOE system. Presenting alerts in the context of patient cases allowed panelists to identify the conditions under which alerts were clinically relevant. The poor agreement between compendia suggests that this methodology may not be ideal for the evaluation of DDI alerts. Performing preimplementation review of DDI alerts before they are enabled provides an opportunity to minimize the risk of alert fatigue before prescribers are exposed to false-positive alerts. PMID- 30485880 TI - Social Media in Health Care: Time for Transparent Privacy Policies and Consent for Data Use and Disclosure. PMID- 30485881 TI - Critical Care Considerations in Liver Failure. PMID- 30485882 TI - Acute Liver Failure. AB - Acute liver failure (ALF) is a condition that can rapidly progress to multiorgan failure. This article focuses on the diagnosis and management of ALF. We provide a detailed review of the common etiologies of ALF, including acetaminophen overdose, viral hepatitis, drug-induced liver injury, Wilson's disease, and autoimmune hepatitis. The article then addresses how to recognize ALF and reviews the role of common laboratory and imaging tests in establishing this diagnosis. The remainder of the article details the management of hepatic and extrahepatic organ dysfunctions in ALF. The article concludes with a discussion regarding the prognostication of patients with ALF and the criteria for considering liver transplantation. PMID- 30485883 TI - Neurocritical Care Management of Hepatic Encephalopathy and Coma in Liver Failure. AB - Hepatic encephalopathy (HE) is a severe complication of liver disease, describing a spectrum of neurological and psychiatric abnormalities ranging from subclinical alterations to coma. HE is the leading cause for hospital readmission, intensive care treatment, and mortality in patients with chronic liver disease. The complex and multifaceted pathogenesis is not yet fully understood, but hypotheses focus on ammonia and systemic inflammation, which are the main targets for currently available therapies in clinical practice. Nevertheless, the remaining high clinical relevance and healthcare burden of this syndrome underlines the emergence for further unraveling the full spectrum of pathomechanisms, as this provides the basis for the development of novel, highly targeted therapies. In this review, the most recent literature about current and future therapies for HE, relevant for intensive care management, will be discussed. PMID- 30485884 TI - Shock Etiologies and Fluid Management in Liver Failure. AB - Liver failure can occur in patients with or without underlying chronic liver disease (mainly cirrhosis) and is, respectively, termed acute on chronic liver failure or acute liver failure (ALF). In both cases, it is associated with marked systemic inflammation and profound hemodynamic disturbances, that is, increased cardiac output, peripheral vasodilation, and decreased systemic vascular resistance, on top of several superimposed etiologies of shock. In patients with cirrhosis, sepsis is the main cause of intensive care unit admission but portal hypertension-related gastrointestinal hemorrhage is also common. Septic shock is also particularly frequent in patients with ALF and can complicate the initial hypovolemic shock related to poor oral intake, vomiting, and encephalopathy prior to admission. Given the susceptibility of the liver to hypoxia and also the potential deleterious effects of fluid on liver function, the assessment of hemodynamic status and volume responsiveness is especially important in these patients. However, one should keep in mind that the hyperdynamic state and low systemic vascular resistance in liver failure may bias the accuracy of some hemodynamic monitoring devices. Fluid therapy should use crystalloids, and balanced salt solutions may limit the risk of hyperchloremic acidosis and subsequent adverse kidney events. Nevertheless, the beneficial effects of albumin resuscitation have been demonstrated in patients with cirrhosis and may reflect more than mere volume expansion. PMID- 30485885 TI - Acute Respiratory Failure and Pulmonary Complications in End-Stage Liver Disease. AB - Acute respiratory failure has a high mortality in patients with end-stage liver disease (ESLD). These patients may develop acute respiratory failure for reasons specific to advanced liver disease, including hepatopulmonary syndrome, portopulmonary hypertension, and hepatic hydrothorax. They may also develop respiratory complications due to conditions seen in the general intensive care unit population to which ESLD patients are at higher risk, including infection, volume overload, and the acute respiratory distress syndrome. Management of these patients is complicated and multifaceted, and a comprehensive understanding of the etiologies and treatment of acute respiratory failure is critical in this high-risk patient population. This article reviews current evidence surrounding the prevalence, management, and complications of the various etiologies of acute respiratory failure in ESLD patients. PMID- 30485886 TI - Kidney Injury and Electrolyte Abnormalities in Liver Failure. AB - The liver and kidney are key organs of metabolic homeostasis in the body and display complex interactions. Liver diseases often have direct and immediate effects on renal physiology and function. Conversely, acute kidney injury (AKI) is a common problem in patients with both acute and chronic liver diseases. AKI in patients with acute liver failure is usually multifactorial and involves insults similar to those seen in the general AKI population. Liver cirrhosis affects and is directly affected by aberrations in systemic and renal hemodynamics, inflammatory response, renal handling of sodium and free water excretion, and additional nonvasomotor mechanisms. Subsequent problems, for example, worsening ascites, hyponatremia, and AKI, often complicate management of patients with chronic progressive liver disease and add to their morbidity and mortality. Thus, AKI must be carefully defined and diagnosed in patients with liver disease. The kidney also plays a pivotal role in balancing acid-base disturbances resulting from advanced liver disease, making AKI in the setting of end-stage liver disease very difficult to manage clinically. While renal dysfunction in these patients often resolves following orthotopic liver transplant, dialysis may be required as a bridge to transplantation to mitigate the metabolic disarray found in these critically ill patients. PMID- 30485887 TI - Critical Care Management of Gastrointestinal Bleeding and Ascites in Liver Failure. AB - Gastrointestinal (GI) bleeding and ascites are two significant clinical events that frequently present in critically ill patients with chronic liver failure or decompensated cirrhosis. GI bleeding in patients with cirrhosis, particularly portal hypertensive-associated bleeding, carries a high short-term mortality (15 25%) and requires early initiation of a vasoactive agent and antibiotics as well as timely endoscopic management. Conservative transfusion strategies and adequate airway protection are also imperative to assist in bleeding control. The presence of ascites among hospitalized cirrhotics requires early analysis of ascitic fluid to diagnose spontaneous bacterial peritonitis and initiate appropriate antibiotics and albumin to reduce patients' high associated mortality rates of greater than 25%. Appropriate utilization of portal decompression using transjugular intrahepatic portosystemic shunt placement for selected patients with failure to control bleeding or ascites and early consideration for liver transplantation referral is critical to improve patient survival. This review will aim to elucidate the current strategies for the management of critically ill patients with chronic liver failure presenting with GI bleeding or ascites. PMID- 30485888 TI - Infectious Complications in Critically Ill Liver Failure Patients. AB - Infections remain a leading cause of morbidity and mortality among patients with liver failure. A number of factors, including relative immune dysfunction and systemic inflammation, bacterial translocation, gut dysbiosis, small intestine bacterial overgrowth, altered bile acid pools, and changes in pH due to acid suppression, contribute to the high rates of infection in this population. Though a range of infections can complicate the course of cirrhotic patients, spontaneous bacterial peritonitis (SBP), cholangitis, and cholecystitis in addition to other infections (i.e. pneumonia, urinary tract infection, bacteremia, and Clostridioides difficile colitis) are more common in this population and will be reviewed in this article. Preventative strategies are directed at minimizing the risk of SBP through the use of targeted antimicrobial prophylaxis. Lastly, the critically ill cirrhotic patient may present with an acute need for liver transplantation. Thus, careful assessment for ongoing infection should be performed and treated to optimize outcomes of transplant, if needed. PMID- 30485889 TI - Acute on Chronic Liver Failure and Immune Dysfunction: A Mimic of Sepsis. AB - Both the adaptive and innate arms of immunity are altered in patients with cirrhosis, which have both prognostic and clinical implications. Acute on chronic liver failure (ACLF), defined as decompensated cirrhosis with associated organ failure, carries a high risk of 28-day mortality and is marked by a significant inflammatory response. Patients with decompensated chronic liver disease display a shift from a chronic low-grade inflammatory state to one of intense inflammation, followed by the development of immunoparalysis. Considerable heterogeneity exists depending on the nature of the inciting cause and duration of ACLF. In this review, we will highlight the changes that immune cell populations in the liver undergo during decompensated liver disease, underscoring the immunological paradox between inflammation and increased susceptibility to infection that occurs during ACLF and progressive cirrhosis, as well as provide future perspectives regarding potentially useful biomarkers and possible avenues for treatment. PMID- 30485890 TI - Coagulation Pathways, Hemostasis, and Thrombosis in Liver Failure. AB - Achieving hemostasis, preventing and treating thrombosis, and laboratory measurement of the hemostatic pathways constitute the core elements of managing the critically ill patient with liver failure. Uncontrolled bleeding in acutely decompensated cirrhosis and acute-on-chronic liver failure is probably the most familiar clinical challenge to intensivists. Bleeding in these patients can be broadly divided into pressure-driven (portal hypertension-related) bleeding with only limited dependence on hemostatic pathways and intractable mucosal/wound bleeding, which is much more directly related to a severely disturbed hemostatic system with imbalances in the coagulation cascade and the fibrinolytic system. Both types of bleeding can occur simultaneously and may even coexist with inappropriate thrombosis such as portal vein thrombosis or venous thromboembolism. Due to the fundamental role of the liver in coagulation factor synthesis and its direct and indirect regulation of nearly all aspects of the hemostatic system, laboratory measurements of coagulation pathways also constitute key aspects of all prognostic scores that guide clinical decisions and forecast optimal interventions in both acute and chronic forms of liver failure. PMID- 30485891 TI - Perioperative Considerations in Liver Transplantation. AB - Liver transplantation (LT) has the potential to cure patients with acute and chronic liver failure as well as a number of hepatic and biliary malignancies. Over time, due to the increasing demand for organs as well as improvements in the survival of LT recipients, patients awaiting LT have become sicker, and often undergo the procedure while critically ill. This trend has made the process of preoperative assessment and planning, intraoperative management, and postoperative management even more crucial to the success of LT programs. Multidisciplinary and specialized teams are essential and include anesthesiologists, surgeons, and intensivists. This article focuses on the preoperative evaluation, intraoperative care, and postoperative management of the liver transplant patient. Management relevant to the critically ill patient is discussed, with a focus on the management of postoperative cardiopulmonary conditions including the care of special populations such as those with hepatopulmonary syndrome and portopulmonary hypertension. PMID- 30485892 TI - Emerging Role of Extracorporeal Support in Acute and Acute-on-Chronic Liver Failure: Recent Developments. AB - Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are life threatening illnesses requiring intensive care admission and potentially liver transplantation. Artificial extracorporeal liver support (ECLS) systems remove water-soluble and albumin-bound toxins to maintain normal serum chemistry, prevent further hepatic/organ system damage, and create an environment for potential hepatic regeneration/recovery (ALF) or bridge to liver transplantation (ALF and ACLF). Use of artificial ECLS has been studied in both ALF and ACLF. Artificial ECLS systems have been found to be safe and have demonstrated the following benefits: improvement of biochemistries, hemodynamic status, and hepatic encephalopathy. Despite this, only one prospective randomized controlled trial examining the use of high-volume plasma exchange has demonstrated improvement in transplant-free survival. Bioartificial (cell-based) ECLS systems build on the technology of artificial systems, incorporating living hepatocytes in a bioactive platform to further mimic endogenous hepatic detoxification and synthetic functions. Currently, no bioartificial system has been found to confer a mortality benefit; however, these platforms offer the greatest potential for future development. PMID- 30485893 TI - Evaluation of Strategies in the Management of Infective Aortic Valve Endocarditis at German Cardiac Surgical Departments. AB - BACKGROUND: Surgical treatment of infective aortic valve endocarditis (AVE) remains a therapeutic challenge, necessitating interdisciplinary approach to limit morbidity and mortality in this high-risk cohort. With a considerable spectrum of available laboratory testings, imaging techniques, as well as operative strategies developed in recent years, there is a lack of standardization across cardiac surgical departments in Germany. Thus, the optimal treatment strategy of AVE has yet to be defined. METHODS: A nationwide survey on infective AVE was conducted, including 64 cardiac surgical departments responding to a 41-item questionnaire. The evaluation included common surgical practice, routine diagnostic steps, surgical techniques, perioperative medical treatment, as well as postoperative management. RESULTS: Remarkable differences were observed among the participating institutions, including the following components of the treatment: (1) standardization and extent of the use of imaging techniques and (2) success rate in identification AVE-causing germs, (3) timing of operation in case of cerebral embolization, and (4) choice of valve prosthesis for aortic valve replacement for infective AVE. CONCLUSION: The findings of this survey underline the need for a nationwide registry to further elucidate the nature and course of AVE in Germany, as well as to serve as a solid basis for prospective trials, addressing the most important clinical purposes in the diagnosis and treatment of AVE. PMID- 30485894 TI - Early Prognostic Value of High-Sensitivity Troponin T after Coronary Artery Bypass Grafting. AB - BACKGROUND: Periprocedural myocardial injury after coronary artery bypass grafting (CABG) may affect the patient's prognosis and may be due to a different set of factors beyond the atherosclerotic plaque instability. Considering the challenges in the diagnosis of myocardial injury after CABG, the aim of this study was to determine the association between postoperative early elevation of high-sensitivity troponin T (hsTnT) and all-cause 30-day mortality after CABG. METHODS: We enrolled 600 consecutive patients who underwent CABG. The hsTnT value was measured immediately before surgery and in the morning of the first postoperative day. RESULTS: The baseline hsTnT was 13 ng/L (7-26 ng/L) and 273 patients (45.7%) had baseline hsTnT above the 99th percentile/upper reference limit (URL) (14 ng/L). The median for hsTnT at first postoperative day was 235 ng/L (152-425 ng/L). We calculated the postoperative hsTnT ratio to URL for each patient, representing the number of times exceeding the URL (hsTnT value divided by 14 ng/L). The multivariate analysis by Cox proportional hazard model revealed that age (years) (hazard ratio [HR] = 1.13, 95% confidence interval [CI]: 1.07 1.20; p < 0.001) and postoperative hsTnT ratio to URL (per 10-fold increase) (HR = 1.06, 95% CI: 1.04-1.08; p < 0.001) were independent predictors of all-cause 30 day mortality after CABG. CONCLUSION: In our series, age and higher postoperative hsTnT levels were independent and reliable predictors of all-cause 30-day mortality after CABG. PMID- 30485895 TI - Predictors of Outcome for Aortic Valve Reimplantation Including the Surgeon-A Single-Center Experience. AB - INTRODUCTION: Aortic valve reimplantation is considered technically demanding. We searched for predictors of long-term outcome including the surgeon as risk factor. METHODS: We selected all aortic valve reimplantations performed in our department between December 1999 and January 2017 and obtained a complete follow up. The main indications were combined aortic aneurysm plus aortic valve regurgitation (AR), 69% and aortic dissections (15%). In 14%, valves were bicuspid. Cusp repair was performed in 27% of patients. One-third received additional procedures (coronary artery bypass grafting, mitral, or arch surgery). We performed multivariable analyses for independent risk factors of short- and long-term outcomes, including "surgeon" as variable. Twelve different surgeons operated on 193 patients. We created three groups: surgeons A and B with 84 and 64 procedures, respectively, and surgeon C (10 surgeons for 45 patients). RESULTS: Cardiopulmonary bypass and clamp times were 176 +/- 45 and 130 +/- 24 minutes, respectively. In-hospital mortality was 2%. Postoperatively, 5% had mild and 0.5% had moderate AR. Kaplan-Meier's survival estimates, freedom from reoperation, and freedom from severe AR at 12 years were 97 +/- 1, 93 +/- 2, and 91 +/- 3%, respectively. Age and chronic obstructive pulmonary disease appeared as risk factors for perioperative complications by univariate analysis. Age, coronary artery disease, and duration of cardiopulmonary bypass, but not surgeon, presented as risk factors by multivariable analysis. CONCLUSION: The results suggest that if a David procedure is performed successfully, long-term durability may be excellent. They also suggest that good and durable results are possible even with limited experience of the operating surgeon. PMID- 30485896 TI - Preoperative CHA2DS2-VASc Score Predicts Postoperative Atrial Fibrillation after Lobectomy. AB - BACKGROUND: Postoperative atrial fibrillation (POAF) affects 10 to 20% of noncardiac thoracic surgeries and increases patient morbidity and costs. The purpose of this study is to determine if preoperative CHA2DS2-VASc score can predict POAF after pulmonary lobectomy for nonsmall cell lung cancer. METHODS: Patients with complete CHA2DS2-VASc data who underwent lobectomies from January 2007 to January 2016 at a single institution were analyzed in a retrospective case-control study using a prospective database. An independent samples t-test was used to compare the mean CHA2DS2-VASc scores of POAF and non-POAF groups. A multivariable logistic regression analysis (MVA) evaluated the independent contribution of variables of the CHA2DS2-VASc score in predicting POAF. Chi square test with univariate odds ratios (ORs) was used to determine a statistically significant cutoff score for predicting POAF. RESULTS: Of 525 total patients, 82 (15.6%) developed POAF (mean CHA2DS2-VASc score: 2.7) and 443 (84.4%) did not develop POAF (mean score: 2.3). Mean difference between these groups was significant at 0.43 (p = 0.01; 95% confidence interval [CI]: 0.09 0.76). In the MVA, significant predictors of POAF were age 65 to 74 years (adjusted OR [aOR] = 2.45; 95% CI: 1.31-4.70; p = 0.006) and age >=75 years (aOR = 3.11; 95% CI: 1.62-5.95; p = 0.0006). Patients with CHA2DS2-VASc scores >=5 had significantly increased OR for POAF (OR = 2.59; 95% CI: 1.22-5.50). CONCLUSIONS: Preoperatively calculated CHA2DS2-VASc score can predict POAF in patients undergoing pulmonary lobectomy. Age is the most statistically significant independent predictor, and patients with scores >=5 have significantly increased risk. Trials for POAF prophylaxis should target this population. PMID- 30485897 TI - About the Anti-Mullerian Hormone (AMH) Uses in the Clinical Practice. PMID- 30485898 TI - Methotrexate Therapy for Ectopic Pregnancies: A Tertiary Center Experience. AB - OBJECTIVE: Our aim is to demonstrate the importance of methotrexate (MTX) therapy for the treatment of ectopic pregnancy (EP). METHODS: This retrospective study consisted of 99 patients (72 tubal EPs, 20 pregnancies of unknown location (PUL), 4 cesarean section (CS) scar EPs and 3 cervical EPs) treated with MTX. RESULTS: Methotrexate therapy was successful in 68.5% of EPs. There were statistically significant differences between the MTX success and failure groups based on ultrasonographic findings, patient complaints, gestational week and serum human chorionic gonadotropin (hCG) values. The MTX success rates in PUL and tubal pregnancies were 95% and 61.1%, respectively. The MTX success rates in single-dose, two-dose and multi-dose protocol groups were 86.9%, 28.6% and 40%, respectively. All cervical and CS scar ectopic pregnancies were treated successfully with MTX therapy. CONCLUSION: Methotrexate might be the first-line treatment option for EPs under certain conditions. Physicians must be more cautious in cases with higher hCG values, the presence of abdominal-pelvic pain, the presence of fetal cardiac activity, larger gestational sac (GS) diameters, and more advanced gestational weeks according to the last menstrual period. PMID- 30485899 TI - Do Food Intake and Food Cravings Change during the Menstrual Cycle of Young Women? AB - OBJECTIVE: The aim of the present study was to assess the anthropometric measures, food intake and food cravings during the menstrual cycle of undergraduate students of the faculty of nutrition. METHODS: A cross-sectional study was performed with 27 students from a public university in the state of Mato Grosso do Sul, Brazil, who had their food intake evaluated through a 24-hour food recall, their nutritional status evaluated based on anthropometric measures, and food cravings evaluated using the Food Desire Questionnaire. Data were collected during an evaluation in the follicular phase (between the 5th and the 9th day of the menstrual cycle) and another in the luteal phase (LP) (between the 20th and the 25th day of the menstrual cycle). For food intake variables, the analysis of variance (ANOVA) test was used, followed by the Tukey test. The Mann Whitney test was used for the analysis of food cravings, considering a significance level of 5% (p < 0.05). RESULTS: The desire for foods rich in sugar, salt, and fat, such as chocolate, pastries, snacks and desserts were higher (p < 0.05) during the premenstrual period, although it did not reflect neither a higher energy intake nor an alteration in the distribution of macronutrients. A higher intake of carbohydrates, proteins, fibers, and calcium was observed during the LP; however, without statistical difference between the groups. There were no differences either in the intake of any food group or in the anthropometric measurements (p > 0.05). CONCLUSION: Food cravings of nutrition students differed between the phases of the menstrual cycle; however, with no difference in food intake and in anthropometric measures. PMID- 30485900 TI - Increased Expression Levels of Metalloprotease, Tissue Inhibitor of Metalloprotease, Metallothionein, and p63 in Ectopic Endometrium: An Animal Experimental Study. AB - OBJECTIVE: To characterize the patterns of cell differentiation, proliferation, and tissue invasion in eutopic and ectopic endometrium of rabbits with induced endometriotic lesions via a well- known experimental model, 4 and 8 weeks after the endometrial implantation procedure. METHODS: Twenty-nine female New Zealand rabbits underwent laparotomy for endometriosis induction through the resection of one uterine horn, isolation of the endometrium, and fixation of tissue segment to the pelvic peritoneum. Two groups of animals (one with 14 animals, and the other with15) were sacrificed 4 and 8 weeks after endometriosis induction. The lesion was excised along with the opposite uterine horn for endometrial gland and stroma determination. Immunohistochemical reactions were performed in eutopic and ectopic endometrial tissues for analysis of the following markers: metalloprotease (MMP-9) and tissue inhibitor of metalloprotease (TIMP-2), which are involved in the invasive capacity of the endometrial tissue; and metallothionein (MT) and p63, which are involved in cell differentiation and proliferation. RESULTS: The intensity of the immunostaining for MMP9, TIMP-2, MT, and p63 was higher in ectopic endometria than in eutopic endometria. However, when the ectopic lesions were compared at 4 and 8 weeks, no significant difference was observed, with the exception of the marker p63, which was more evident after 8 weeks of evolution of the ectopic endometrial tissue. CONCLUSION: Ectopic endometrial lesions seem to express greater power for cell differentiation and tissue invasion, compared with eutopic endometria, demonstrating a potentially invasive, progressive, and heterogeneous presentation of endometriosis. PMID- 30485901 TI - The Sensitized Bioluminescence Mechanism of Bacterial Luciferase. AB - After more than one-half century of investigations, the mechanism of bioluminescence from the FMNH2 assisted oxygen oxidation of an aliphatic aldehyde on bacterial luciferase, continues to resist elucidation. There are many types of luciferase from species of bioluminescent bacteria originating from both marine and terrestrial habitats. The luciferases all have close sequence homology and in vitro, a highly efficient light generation is obtained from these natural metabolites as substrates. Sufficient exothermicity equivalent to the energy of a blue photon, is available in the chemical oxidation of the aldehyde to the corresponding carboxylic acid, and a luciferase-bound FMNHOOH is a key player. A high energy species, the source of the exothermicity is unknown except that it is not a luciferin cyclic peroxide, a dioxetanone, as identified in the pathway of the firefly and the marine bioluminescence systems. Besides these natural substrates, variable bioluminescence properties are found using other reactants such as flavin-analogs or aldehydes, but results also depend on the luciferase type. Some rationalization of the mechanism has resulted from spatial structure determination, NMR of intermediates, and dynamic optical spectroscopy. The overall light path appears to fall into the sensitized class of chemiluminescence mechanism, distinct from the dioxetanone types. This article is protected by copyright. All rights reserved. PMID- 30485902 TI - Targeting cytokines secreted by CD4+ CD25high CD127low regulatory T cells inhibits ovarian cancer progression. AB - Epithelial ovarian cancer (EOC) is one of the major malignant cancers with high rates of early metastasis in which regulatory T cells (Tregs) play an important role. Tregs suppress immune responses and promote the development of tumours in patients with EOC. However, the underlying mechanisms remain unclear. In this study, we found higher levels of CD4+ CD25high CD127low Tregs in patients with EOC than in patients with benign ovarian tumours and healthy donors. The immune inhibitory effect of Tregs functions by maintaining high levels of immunosuppressive cytokines in EOC. The high levels of Tregs and related cytokines (TGF-beta1 or IL-10) were associated with lymphatic metastasis and FIGO stages of patients with EOC. Expression of matrix metalloproteinase (MMP)-2 and tissue inhibitors of metalloproteinase (TIMP)-2 in EOC cell lines were significantly regulated in the coculture experiment with CD4+ CD25high CD127low Tregs sorted from EOC patients. Levels of MMP-2 and TIMP-2 conversely changed after blocking IL-10R and TGF-beta1R in EOC cells. The invasion ability of EOC cells was also significantly downregulated in this process. The metastasis of EOC cells was correlated with the levels of TGF-beta1 or IL-10. These findings suggested that immunosuppressive cytokines secreted by CD4+ Tregs could be a novel target for inhibiting EOC progression. This article is protected by copyright. All rights reserved. PMID- 30485903 TI - Effects of formulation composition on the characteristics of mucoadhesive films prepared by hot-melt extrusion technology. AB - OBJECTIVES: To investigate the effects of formulation composition on the physico chemical and drug release properties of mucoadhesive buccal films prepared by melt extrusion technology, using a response surface methodology. METHODS: Salbutamol sulphate, an antiasthmatic drug was used for this study. Klucel hydroxypropylcellulose (HPC) EF (film-forming polymer), Benecel hydroxypropylmethylcellulose (HPMC) K-15M (drug release retardant) and polyethylene glycol (PEG) 4500 (plasticiser) were the three independent factors utilised for the study. The responses were fitted to a full quadratic model and P values for each of the factors were used to determine their significance on the film characteristics. KEY FINDINGS: Films were successfully extruded using the corotating twin-screw extruder. The torque during extrusion was found to be significantly affected by all the three factors and no interaction between factors was observed. A significant interaction was observed between HPC and PEG 4500 for stiffness of films. For disintegration time and swelling index, a significant interaction was found between HPC and HPMC. The in vitro % drug release was directly correlated with HPMC content and not with other factors and varied from 69-89% at 4 h. CONCLUSIONS: The influence of extrusion process and formulation parameters on salbutamol sulphate films was elucidated, indicating the use of melt extrusion as a feasible method for film preparation. PMID- 30485904 TI - Management of abnormal observations in the emergency department: A review. AB - OBJECTIVE: To assess utility and accuracy of general observation modified early warning score charts; and compare sensitivity and specificity of single- and multiple-parameter-based trigger scores on patient outcomes in the ED. METHODS: Retrospective cohort clinical audit of all adult Modified Early Warning Score charts in the ED of a mixed tertiary hospital over 4 weeks. Data extracted included recorded parameters required to calculate Modified Early Warning Score and evidence of response. RESULTS: Of 5901 ED presentations, medical records system identified 2482 Modified Early Warning Score; 347 were missing or blank. Of 2135 Modified Early Warning Score charts, 19.5% contained a calculation error, 51.9% had one or more missing parameters and 36.6% did not have usual/target systolic blood pressure recorded; with 25.1% (95% confidence interval [CI] 23.3 27.0) charts correctly completed. Four hundred and forty-three had a single abnormal parameter of which chart review showed 96.6% (94.5-97.3) were identified as abnormal by nurses with 25.7% (21.9-30.0); only 5.6% (3.9-8.2) had evidence of recognition by medical staff. Modified Early Warning Score sensitivity and specificity for ward admission was 14.7% and 96.1%, respectively. Modelling using the dataset of a single-abnormal parameter suggested sensitivity and specificity of 31.6% and 85.8%, respectively. CONCLUSIONS: This study highlights serious deficiencies in documentation of abnormal parameters and emergency response. It has also shown poor accuracy of both single- and multiple-parameter-based trigger scores in predicting patient outcomes within the ED. However, single-parameter based trigger scores are twice as sensitive as total Modified Early Warning Score for admission and reduces documentation error by 23%. PMID- 30485905 TI - Editorial Comment from Dr Horiguchi to Buccal epithelium Expanded and Encapsulated in Scaffold-Hybrid Approach to Urethral Stricture (BEES-HAUS) procedure: A novel cell therapy-based pilot study. PMID- 30485906 TI - Untangling alpha synuclein fibrils by graphene quantum dots. PMID- 30485907 TI - Spinal cord stimulation for gait dysfunction in Parkinson's disease: Essential questions to discuss. PMID- 30485908 TI - Diverse serotonin actions of vilazodone reduce l-3,4-dihidroxyphenylalanine induced dyskinesia in hemi-parkinsonian rats. AB - BACKGROUND: The serotonergic system is a well-established modulator of l-dopa induced dyskinesia. To date, targeting serotonin transporters or serotonin receptor subtype 1A (5-HT1A ) reduces l-dopa-induced dyskinesia in animal models; however, these strategies have failed to translate clinically. Ideally, a compound acting at both known antidyskinetic sites could optimize serotonin mediated approaches. Vilazodone is a selective serotonin reuptake inhibitor and a partial 5-HT1A agonist approved by the U.S. Food and Drug Administration, situating Vilazodone in a unique position to reduce l-dopa-induced dyskinesia without compromising l-dopa-mediated motor improvements. OBJECTIVES: The goal of the present study was to characterize Vilazodone's effects on l-dopa-induced behaviors, neurochemistry and gene expression in unilateral 6-hydroxydopamine lesioned hemi-parkinsonian rats. METHODS: In experiments 1 and 2, l-dopa-naive and l-dopa-primed animals were coadministered Vilazodone and l-dopa daily for 3 weeks to model subchronic use, and behavioral, neurochemical, and messenger RNA (mRNA) expression changes were measured. In experiment 3, dyskinetic behavior was assessed following 5-HT1A or serotonin receptor subtype 1B blockade prior to Vilazodone-l-dopa coadministration. RESULTS: Vilazodone significantly suppressed developing and established l-dopa-induced dyskinesia without compromising the promotor effects of l-dopa therapy. In the dopamine-depleted striatum, Vilazodone l-dopa cotreatment increased dopamine content, suggesting a normalization of dopamine kinetics in dyskinetic brain, and reduced l-dopa-induced c-Fos and preprodynorphin mRNA overexpression, indicative of attenuated dopamine D1 receptor-mediated direct pathway overactivity. Only 5-HT1A antagonism partially attenuated Vilazodone's antidyskinetic efficacy, suggesting both serotonin transporter-dependent effects and 5-HT1A receptors in Vilazodone's actions. CONCLUSIONS: Our findings show Vilazodone has a serotonin-dependent effect on rodent l-dopa-induced dyskinesia and implicate the potential for repositioning Vilazodone against l-dopa-induced dyskinesia development and expression in Parkinson's disease patients. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 30485909 TI - The treatment of levodopa-induced dyskinesias: Surfing the serotoninergic wave. PMID- 30485910 TI - Reply to: Spinal cord stimulation for gait dysfunction in Parkinson's disease: Essential questions to discuss. PMID- 30485911 TI - A promising orphan target to treat HD. PMID- 30485912 TI - Intact automatic motor inhibition in patients with tourette syndrome. AB - BACKGROUND: Behavioral disinhibition has been proposed as a key mechanism in Tourette syndrome. Yet classic inhibition tasks have yielded inconsistent results, likely reflecting interference by strategies compensating for tic release. METHODS: We examined a core inhibitory function that is immune to such interference because it suppresses movements automatically. We measured automatic motor inhibition behaviorally in 21 adults with Tourette syndrome and 21 healthy controls via the negative compatibility effect. When a motor response is activated, for example, by a subliminal prime stimulus, but execution is delayed, activation turns into inhibition, increasing reaction time and error. Diminished automatic inhibition could underlie tic release. RESULTS: Both controls and patients showed strong automatic motor inhibition with no significant group difference. Bayesian statistics, allowing inference on the absence of effects, favored intact inhibition in patients. Our study was well powered. CONCLUSIONS: Automatic motor inhibition in Tourette syndrome is neither impaired nor harnessed by compensation. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 30485913 TI - Tackling undernutrition in the Asian healthcare setting: a Southeast Asian expert consensus. AB - BACKGROUND AND OBJECTIVES: Malnutrition is under-recognized and under-treated in Asia due to resource constraints, lack of awareness and knowledge among healthcare professionals and patients, and lack of standardized procedures for malnutrition management. While international guidelines for the management of malnutrition are available, they may not be easily applicable to the patient population and healthcare settings within Southeast Asia. This paper provides consensus recommendations, developed by the Regional Nutrition Working Group, to foster evidence-based nutritional care in Southeast Asia to improve patient outcomes. METHODS AND STUDY DESIGN: The group convened and discussed evidence based recommendations and clinical experiences in the management of malnutrition in hospitalized and community-dwelling adults, and the relevance of oral nutritional supplements in clinical practice. Supported by a literature search from January 2007-September 2017, consensus statements on key aspects of malnutrition management were developed. RESULTS: Malnutrition management should be considered as an integral part of patient care and managed by a multidisciplinary team. Hospitalized patients and outpatients should be screened for risk of malnutrition with validated tools. Nutrition intervention, including oral, enteral, or parenteral nutrition, should be accessible and individualized to all patients who are malnourished or at risk of malnutrition. Education on nutrition care is imperative for healthcare professionals, patients and caregivers. CONCLUSION: These consensus recommendations provide practical guidance to improve nutrition practice within healthcare in Southeast Asia. With collaborative efforts from the clinical community, professional societies and policy makers, this regional effort may also facilitate change in the nutrition practice at the institutional and national level. PMID- 30485914 TI - Malnutrition prevalence in adrenal insufficiency among hospitalized elderly patients: limitations of the body mass index in the assessment of malnutrition. AB - BACKGROUND AND OBJECTIVES: This study aimed to evaluate malnutrition prevalence and usefulness of the body mass index (BMI) in the assessment of malnutrition in hospitalized elderly patients with adrenal insufficiency (AI). METHODS AND STUDY DESIGN: 318 hospitalized AI patients were diagnosed by a rapid ACTH stimulation test with a history of steroid treatment and compared with 374 control patients. Nutrition was assessed using the Malnutrition Universal Screening Tool (MUST). Nutritional status was evaluated using the Mini Nutritional Assessment short form (MNA-SF) and BMI. RESULTS: There was no difference in nutritional screening between the AI and control groups. Nutritional assessments indicated that 31.2% of all elderly patients suffered from malnutrition and 33.8% of patients were at risk of malnutrition. Less than half of the patients (34.9%) were identified as well nourished. In this study, 33.6% vs 29.1% of patients were malnourished in the AI and control group, respectively. Overall, prevalence of malnutrition was higher in the AI group than the control group. In the AI group, patients with low basal cortisol had a higher incidence of malnutrition than those with high basal cortisol. The BMI of patients in the AI group was higher than in the control group. According to BMI criteria, 64.3% of malnourished patients were overweight or obese in the AI group. CONCLUSIONS: Elderly AI patients are prone to develop malnutrition despite being overweight or obese. Therefore, more extensive nutritional assessment of elderly patients with AI is required regardless of BMI. PMID- 30485915 TI - Energy requirements for ICU burn patients in whom the total body surface area affected exceeds 50 percent: a practical equation. AB - BACKGROUND AND OBJECTIVES: Energy requirement estimations are crucial for major burn patients' nutrition management. To find a practical equation for patients with burns over >50% of their total body surface area (TBSA)in an intensive care unit (ICU). METHODS AND STUDY DESIGN: We conducted a six-week follow-up study of 21 ICU burn patients aged 17-28 years (second- and third-degree burns, TBSA: 50 90%) who were prescribed enteral nutritional support. The energy consumption ratio (ECR) was calculated by dividing the actual energy intake by the estimated energy requirement. Linear regression was used to evaluate the stability of each equation and the wound healing rate over time. RESULTS: All included patients survived. On the fifth day, among the seven equations used, the ECRs of those dependent on the basal metabolic rate and body weight, namely, 35 kcal/kg BW, BMR * 1.5, and the Toronto formula, reached 74%, 71% and 69%, respectively. The ECRs for the abovementioned formulae achieved nutritional support goal sufficiency (0.9-1.1) from the third week. Additionally, with every 1% increase in the Energy Consumption Increase Rate per week, the wound healing rate increased from 0.35% to 0.80% per week. Both the 28 and 35 kcal/kg BW formulas had the smallest regression coefficients (0.46) over 6 weeks. CONCLUSION: The 35 kcal/kg BW equation was suitable for young patients with burns over >50%TBSA in the ICU because it could be applied without equivocation, in time, and with acceptable wound healing rates. Additionally, it was well tolerated and contributed to stable management with feeding simplicity. PMID- 30485916 TI - The development of a whole-body potassium counter for the measurement of body cell mass in adult humans. AB - BACKGROUND AND OBJECTIVES: Total body potassium (TBK), has a natural radioactive isotope, which can be measured to derive body cell mass (BCM), making it useful in clinical conditions, early growth and pregnancy. The objective was to build a whole-body potassium counter (WBKC), to accurately measure TBK in the body. METHODS AND STUDY DESIGN: A WBKC was designed and constructed using a shadow shield. A cellular four compartment (4C) model of fat free mass (FFM), using estimates of TBK along with total body water (TBW), was compared with a molecular 4C model of the body in twenty healthy adults (10 men and 10 women). The molecular 4C model used measurements of TBW, bone mineral content (BMC), and body volume from deuterium dilution (DD), dual energy x-ray absorptiometry (DXA) and air displacement plethysmography (ADP) respectively. RESULTS: The accuracy and precision of the WBKC were 2.8% and 1.9% with TBK phantoms. The mean estimate of FFM by the molecular 4C model was 40.4+/-6.8 kg, while it was 41.2+/-7.3 kg using the cellular 4C model. CONCLUSIONS: A WBKC constructed from base principles, was relatively low cost, efficient, safe and noninvasive, but requires some design considerations. Its measurement of FFM compared well with the molecular 4C model. Once constructed, it offers a relatively costless, accurate and repeatable method to measure body composition in conditions with uncertain hydration status, at all life stages. PMID- 30485917 TI - A comparison of two malnutrition screening tools in acute medical inpatients and validation of a screening tool among adult Indigenous Australian patients. AB - BACKGROUND AND OBJECTIVES: The objectives of this study were to identify and validate a screening tool to detect malnutrition among Indigenous and non Indigenous Australian patients. METHODS AND STUDY DESIGN: This study included medical patients admitted into three regional hospitals in Australia. A literature review was undertaken of current screening tools before the Malnutrition Screening Tool (MST) and the newly developed Adult Nutrition Tool (ANT) were used to validate a screening tool for use among participants against the Subjective Global Assessment (SGA) tool. The sensitivity and specificity of both the MST and ANT were determined for all study participants as well as according to participants' Indigenous status. RESULTS: A total of 608 participants were enrolled into the study, of whom 271 (44.6%) were Indigenous. The area under the curve (AUC) when utilising ANT was higher in all participants compared to the MST (0.90, 95% CI 0.88-0.92 versus 0.81, 95% CI 0.77-0.84, p<0.001). The AUC was also significantly higher for Indigenous participants when utilising ANT compared to the MST (0.88, 95% CI 0.84-0.92 versus 0.78, 95% CI 0.73-0.83, p<0.001). An ANT >=2 demonstrated superior sensitivity for both Indigenous and non-Indigenous participants (96.0%, 95% CI 92.8-98.7%) than the MST (84.0%, 95% CI 78.9-88.3) but with inferior specificity (59.5%, 95% CI 54.2 64.6) than the MST (70.7%, 95% CI 65.7-75.3). CONCLUSIONS: The ANT is both a valid and accurate tool for Indigenous and non-Indigenous Australian patients. Further research is required to validate ANT to aide in the detection of malnutrition in other clinical settings. PMID- 30485919 TI - Nutrition support in hospitalized cancer patients with malnutrition in China. AB - BACKGROUND AND OBJECTIVES: Malnutrition has adverse impacts on survival of cancer patients. The aim of the present study was to investigate the prevalence of malnutrition, and the nutrition support status in hospitalized patients with cancer in China. METHODS AND STUDY DESIGN: A multi-center, cross-sectional study was conducted in 29 tertiary public hospital wards in 14 Chinese cities. Malnutrition was defined as weight loss (WL) >5% over the past 6 months or body mass index (BMI) <20 kg/m2 with WL >2%. The nutrition risk index (NRI) and performance status (PS) were evaluated. RESULTS: 1138 hospitalized cancer patients (93.4% of the initial sample, 662 men, 60.6+/-14.5 years) were enrolled. Overall, 41.3% of patients were malnourished. The percentage of nutritional disorders as determined by the NRI was 51.4%. PS was 0 in 50.3%, 1 in 15.4%, 2 in 13.9%, and 3 or 4 in 20.4%. Compared with patients with PS of 0-1, patients with PS of 3-4 had a relative risk of malnutrition of 1.275 (95% CI 0.250-0.488, p<0.0001). Only 38.6% of patients received nutrition support, of whom 45.0% of the malnourished and 31.9% of the non-malnourished patients did; 63.2% of patients complained of poor appetite, while merely 14.0% of patients had received nutrition counseling. CONCLUSIONS: The prevalence of malnutrition is high in hospitalized cancer patients, and inappropriate use of nutritional interventions highlights the urgent need to define standard operating procedures and quality control process. PMID- 30485918 TI - Phosphate binders, appetite and nutritional status in maintenance hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: The potential side effects of common phosphate binders are gastrointestinal in practice. We hypothesized that regular use of phosphate binders may be associated with decreased appetite, dietary intake and consequently, poor nutritional status. METHODS AND STUDY DESIGN: This was cross sectional study of 78 patients (mean age 67.5+/-13.0, 34.6% women) undergoing maintenance hemodialysis (MHD) treatment. Participants were divided into three equal groups - sevelamer (n=25), lanthanum (n=24) and the control group (n=29). Eating motivation was assessed using visual analogue scales (VAS) and by a self reported appetite assessment which was graded on a 5-point Likert scale. Main outcome measure was differences in VAS scores for appetite, dietary intake and nutritional status (malnutrition-inflammation score [MIS]) in the study groups. RESULTS: Appetite, dietary intake, biochemical nutritional markers, anthropometric measures and MIS were similar in the three groups. A statistically significant difference was observed in sensation of fullness between the groups: multivariable adjusted ORs in the sevelamer carbonate group was 4.90 (95% CI: 1.12 to 21.43), p=0.04 and in the lanthanum carbonate group was 5.18 (95% CI: 1.15 to 23.30), p=0.03 versus the control group. However, no linear association was observed between MIS scores and VAS scores for appetite in any study group. CONCLUSIONS: Regular use of these phosphate binders was not associated with anorexia, decreased dietary intake and nutritional status in the study population. Therefore, there is no preference in the choice of phosphate binders in MHD patients with hyperphosphatemia, even those who are at nutritional risk. PMID- 30485920 TI - Peripherally inserted central catheter-related complications in infants with intestinal failure. AB - BACKGROUND AND OBJECTIVES: For delivery of parenteral nutrition (PN), long-term central access is often required in infants with intestinal failure (IF). Compared to central venous catheters (CVCs), peripherally inserted central catheters (PICCs) are less invasive, as they are smaller, and they can even be placed without general anesthesia. In this study, we report the complications of long-term use of PICCs, and compare our results with previously published research. METHODS AND STUDY DESIGN: We reviewed the infants in the Xin Hua Hospital to determine the incidence of catheter-related bloodstream infections (CRBSIs) as well as other complication rates. RESULTS: A total of 43 infants diagnosed with intestinal failure and receiving PN through a PICC met the inclusion criteria. There were 66 PICCs accounting for 2563 catheter days, and a total of 29 complications were been recorded. The overall incidence of complications was 11.31 per 1000 catheter days, and the incidence of CRBSI was 5.85 per 1000 catheter days. Gram-positive bacterial species were the most common organisms growing in blood cultures. As for the risk factors, we find that low weight when PICC was inserted was associated with an increased risk of complications as well as low mean weight during the PICC dwelling time. CONCLUSIONS: We did not find an increased incidence rate of CRBSI in using PICC as an alternative to CVC. Also, as PICCs offer an advantage over CVCs in placing and nursing, we recommended PICCs as the first choice in patients with IF. PMID- 30485921 TI - Combined Patient-Generated Subjective Global Assessment and body composition facilitates nutritional support in inflammatory bowel disease: an ambulatory study in Shanghai. AB - BACKGROUND AND OBJECTIVES: Malnutrition is commonly diagnosed in patients with inflammatory bowel disease (IBD). However, only few clinical studies have adequately explored the importance of body composition in the nutritional assessment of Chinese patients with IBD. METHODS AND STUDY DESIGN: A total of 78 IBD patients were enrolled, and Patient-Generated Subjective Global Assessment (PG-SGA) was used to assess malnutrition. Bioelectrical impedance analysis was used to analyze the body composition of IBD patients and their fat free mass indexes (FFMI) were also calculated. FFMI values <17 kg/m2 in men and <15 kg/m2 in women were considered low. Food consumption data were collected using the semi quantitative food frequency questionnaire. RESULTS: Of the 78 patients, 49 (62.8%) had low-FFMI. Among the patients with PG-SGA <4, 12 (41.4%) had altered body composition with low-FFMI. FFMI negatively correlated with the PG-SGA scores and disease activity. No statistically significant differences in fat free mass (FFM) and skeletal muscle mass were observed between patients in the active phase and patients in remission (p>0.05). However, the fat mass and visceral fat area of patients in remission were higher than those of patients in the active phase (p<0.05). The average energy derived from fat, proteins and carbohydrates was 29.6+/-8.45%, 10.4+/-1.97% and 60.3+/-9.33%, respectively. CONCLUSIONS: Our study shows that 41.4% of IBD patients had altered body composition despite being well nourished according to the PG-SGA. Patients in the remission phase presented with fat accumulation and their FFM remained low. The dietary pattern was not adequate among the IBD patients, especially regarding protein intake. PMID- 30485922 TI - Acute effect of soy and soy products on serum uric acid concentration among healthy Chinese men. AB - BACKGROUND AND OBJECTIVES: Soy products are essential to the daily life of the Chinese population. However, the association between soy products and serum uric acid remains unclear. Better understanding of their relationship could provide food choice information for patients with gout. This study assessed the acute effects of soy and soy products on serum uric acid. METHODS AND STUDY DESIGN: Sixty healthy adult male volunteers were recruited and randomly assigned to six groups. Ten participants in each group randomly ingested one of six foods: water, soy, and four different soy products. A blood test was conducted after 3 h to examine uric acid concentration. RESULTS: The serum uric acid concentration significantly increased by 21.4+/-23.4 MUmol/L at 1 h and 16.3+/-19.4 MUmol/L at 2 h following ingestion of whole soybeans. These changes also applied to the soy powder group. The serum uric acid concentration rapidly increased by 38.1+/-20.5 MUmol/L at 1 h, 34.4+/-18.2 MUmol/L at 2 h, and 24.1+/-24.2 MUmol/L at 3 h after the ingestion of soybean milk. The maximum concentration of serum uric acid was observed at 1 h after intake of soybeans and soy products, and then gradually decreased during the subsequent 2-h period. No significant uric acid changes from ingesting bean curd cake and dried bean curd stick were detected. CONCLUSIONS: Ingesting different soy products resulted in different concentrations of serum uric acid, with soybeans, soybean milk, and soy powder considerably increasing serum uric acid. PMID- 30485923 TI - Effect of a cereal and milk meal with or without fruits and nuts on the postprandial glycemic response in Indian men. AB - BACKGROUND AND OBJECTIVES: Some cereals, consumed at breakfast, have shown lower glycemic responses. Limited data exist in the Indian context, where the effect could be modified due to genetic or racial differences. This study aimed to investigate the effect of cereal and milk, with or without fruits/nuts, on the glycemic response in healthy Indian men. METHODS AND STUDY DESIGN: A randomized cross-over study was carried out on 16 men (18 - 45 years), with 3 interventions providing equal amounts of glycemic carbohydrate: a glucose drink (Reference), cereal and milk (CM), and cereal, milk, fruits and nuts (CMO), on separate days. Plasma glucose, serum insulin, C-peptide, ghrelin, energy expenditure (EE), substrate oxidation and appetite/satiety were measured repeatedly over 3 hours post meal. RESULTS: A significant time effect and time x meal interaction between the meals, higher for the Reference meal, was observed for plasma glucose (p<0.001), insulin (p<0.001), C-peptide (p<0.001), and carbohydrate oxidation (p<0.001); while lower for satiety (p<0.001). The plasma glucose concentrations of CM and CMO meals returned to baseline 60 min postprandially, then remained there, unlike the Reference meal, where the plasma glucose values returned to baseline at 120 min and dipped significantly below baseline at 150 and 180 min. A significant effect of time (p<0.001) was observed for EE between meals. Ghrelin levels did not differ significantly between the test meals. CONCLUSIONS: Cereal with milk, along with fruits and nuts at breakfast, has a lower and stable glycemic response, along with increased satiety among healthy male subjects. PMID- 30485924 TI - Oral administration of probiotic Lactobacillus casei Shirota relieves pain after single rib fracture: a randomized double-blind, placebo-controlled clinical trial. AB - BACKGROUND AND OBJECTIVES: Probiotic treatment has proven to increase the density of bone mass, prevent against bone loss, and improve bone formation. We aimed to assess the effect of oral administration of the probiotic Lactobacillus casei Shirota (LcS) on pain relief in patients with single rib fracture. METHODS AND STUDY DESIGN: A total of 283 eligible patients who had a single rib fracture were enrolled and randomly assigned to receive skimmed milk containing either a commercial probiotic LcS or placebo every day through oral administration for 1 month after the fracture. The pain relief effect was assessed during activities that elicited pain; meanwhile, sleep quality and sustained maximal inspiration (SMI) lung volumes were monitored. RESULTS: Patients in the LcS group had more effective pain relief than those in the placebo group during deep breathing, coughing and turning over the body. Between the two groups of patients, increase in SMI lung volume was larger in LcS group patients than that of patients in the placebo group. Sleep quality did not show significant improvements after 1 month LcS treatment. CONCLUSIONS: In patients with a single rib fracture, oral administration of the probiotic LcS could exhibit alleviating effects on pain intensity. PMID- 30485925 TI - The association between blood concentration of 25- hydroxyvitamin D and sarcopenia: a meta-analysis. AB - BACKGROUND AND OBJECTIVES: Associations between blood 25-hydroxyvitamin D (25(OH)D) concentration and sarcopenia remain controversial; thus, this meta analysis was conducted to explore the relationship between blood 25(OH)D concentration and sarcopenia. DESIGN: We searched the PubMed and EMBASE databases for relevant published observational studies that investigated blood 25(OH)D concentration and sarcopenia up to June 2017.We then investigated data from these studies that compared blood 25(OH)D concentrations between the sarcopenia and healthy control groups. A random-effect model was used to calculate the pooled weighted mean difference (WMD) of blood 25(OH)D concentration with a 95% confidence interval (95% CI). RESULTS: Twelve studies (eight cross-sectional, two matched case-control, and two prospective cohort studies) with a total of 22,590 individuals were included. Sarcopenic individuals had lower blood 25(OH)D concentrations than healthy controls (WMD=-2.14, 95% CI: -2.81--1.48; I2=74.6%). Subgroup analysis showed that the methods of assessing both blood 25(OH)D concentrations and sarcopenia might be sources of heterogeneity, and further showed that studies excluding obese individuals and different sarcopenia assessment criteria enhanced the relationship. Sensitivity analysis by one-study removed confirmed the robustness of these results. CONCLUSIONS: Our study shows that sarcopenic adults have lower blood 25(OH)D concentrations. Further high quality large-scale prospective cohort studies are needed to confirm these findings. PMID- 30485926 TI - Association between vitamin C intake and risk of hyperuricemia in US adults. AB - BACKGROUND AND OBJECTIVES: The relationship between vitamin C intake and hyperuricemia among the general US adult population has seldom been reported; thus, the present study examined the associations of total vitamin C (dietary vitamin C plus supplementary vitamin C) and dietary vitamin C intake with the risk of hyperuricemia. METHODS AND STUDY DESIGN: Pooled data from three 2-year cycles (2007-2012) of the cross-sectional National Health and Nutrition Examination Survey were used in the present study. Dietary intake data were extracted from two 24-hour dietary recall interviews. Logistic regression models were used to determine the associations between vitamin C intake and hyperuricemia risk. RESULTS: A total of 14885 adults aged 20 years or older (7269 men and 7616 women) were registered in the present study. The prevalence of hyperuricemia was 19.1%. Based on the lowest quartile of dietary vitamin C intake, multivariate adjusted odds ratios with 95% confidence intervals of hyperuricemia for quartiles 2-4 were 0.84 (0.74-0.95), 0.83 (0.73-0.94), and 0.72 (0.63-0.82), and those for total vitamin C intake were 0.87 (0.77-0.99), 0.85 (0.75-0.96), and 0.66 (0.58-0.76). Inverse associations between vitamin C intake and hyperuricemia were discovered in both men and women, even with or without covariate adjustments. CONCLUSIONS: Total vitamin C and dietary vitamin C intake are inversely associated with hyperuricemia in the general US adult population. PMID- 30485927 TI - Soy product and isoflavone intake associations with allergic diseases in Japanese workers: rhinitis, dermatitis and asthma. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to determine the associations of intake of soy products and isoflavones with allergic diseases. METHODS AND STUDY DESIGN: We conducted a cross-sectional study in 1437 participants (aged 20-64 years) who were living in Tokushima Prefecture, Japan during the period 2010- 2011. We obtained anthropometric data and information on life style characteristics including dietary intake and current medical histories of allergic diseases using a structural self-administered questionnaire. Multiple logistic regression models were used to assess the associations of soy products and isoflavones with allergic diseases after controlling for age, family history of allergic diseases, smoking, drinking, physical activity, energy intake, BMI and dietary factors. RESULTS: Intake of soy products showed significant inverse dose-response relationships with allergic rhinitis. The third quartile for soy products had an adjusted OR of 0.56 (95% CI: 0.35-0.91) compared to the reference group (first quartile), though intake of soy products showed no dose-response relationship with atopic dermatitis. Intake of soy isoflavones showed a significant inverse dose-response relationship with atopic dermatitis, though the association between intake of soy isoflavones and atopic dermatitis was U-shaped after adjustments for potential confounders. On the other hand, the associations between intake of soy isoflavones and other allergic diseases were not significant. CONCLUSIONS: The results indicate that higher intake of soy products is associated with reduced risk of allergic rhinitis in Japanese workers. Furthermore, moderate intake amounts of soy products and soy isoflavones are associated with inverse risk of atopic dermatitis. PMID- 30485929 TI - Longitudinal study of breastfeeding and growth in 0-6 month infants. AB - BACKGROUND AND OBJECTIVES: To explore advantages and challenges for exclusive breastfeeding (EBF), compared to non-exclusive breastfeeding (nEBF). METHODS AND STUDY DESIGN: Mothers from 7 cities in China were visited at 3, 10, 60, 120, and 180 days postpartum. Data about feeding practices, infant growth, and the macronutrient contents of human milk (HM) were collected. RESULTS: 130 lactating mothers attended 5 visits. 59 mothers (45.4%) exclusively breastfed infants for 0 4 month. Frequencies of breastfeeding per day were higher in the EBF group than the nEBF group at day 3, 10, 120 and 180, and were less than 8 times per day in the nEBF group. For Weight-for-age z scores, there were no differences between the two groups. Length-for-age z score was greater in the nEBF group at day 180 (0.74+/-1.05 vs 0.33+/-1.28). Weight-for-length z scores were greater in the EBF group at day 120 and 180 (day 120: 0.88+/-1.08 vs 0.36+/-1.1, day 180: 1.1+/-0.94 vs 0.54+/-1.07). The average protein and lactose contents of HM in the nEBF group were higher than in the EBF group at day 10. CONCLUSIONS: For nEBF infants, intake of formula replaced intake of breastmilk, due to lack of breastfeeding frequency, which did not bring weight gain for nEBF infants. During the introduction of complementary foods, EBF infants needed complementary nutrients to support growth. Therefore, lactating mothers may need to provide appropriate complementary feeding and maternal leave extension to attend to their infant's nutritional requirements. The criteria for linear growth may also need to be more commensurate with breastfeeding and relevant to later health outcomes. PMID- 30485928 TI - The association between lifestyle and maternal vitamin D during pregnancy in West Sumatra, Indonesia. AB - BACKGROUND AND OBJECTIVES: An adequate level of maternal vitamin D is essential for maternal and fetal health during pregnancy. We examined the relationship between lifestyle, maternal vitamin D intake and the vitamin D status of pregnant women. Methods and Study designs: The sample of the cross-sectional study was 203 third trimester pregnant women in September-November 2016 in four different districts of West Sumatra, Indonesia. Questionnaire was used to assess lifestyles, dietary intake, anthropometry, maternal characteristics, demography and socioeconomic data. The Vitamin D serum level was measured by the ELISA method and the data were analyzed using descriptive statistics, chi-squared tests, Pearson's correlation and logistic regression. RESULTS: 160 blood serum samples of pregnant women were collected. The means of 25-hydroxyvitamin D and maternal vitamin D intake were 29.06+/-11.39 ng/mL and 7.92+/-5.26 MUg/day respectively. The prevalence of vitamin D deficiency- insufficiency was 61.25%, and more than 85% of the women had inadequate vitamin D intake. We found that living in mountainous areas (p=0.03) and low physical activity (p=0.02) were significantly associated with maternal vitamin D levels as a prediction factor. In addition, younger who had lower pre-pregnancy weight had a higher prevalence of vitamin D deficiency. CONCLUSIONS: Low levels of vitamin D were common among pregnant women in West Sumatra, Indonesia. Additional intake of vitamin D from supplements may be important to meet the recommended dietary level for pregnant women. PMID- 30485930 TI - Weight status and food habits of preschool children in Abu Dhabi, United Arab Emirates: NOPLAS project. AB - BACKGROUND AND OBJECTIVES: Eating habits established during childhood affect health in later life. The United Arab Emirates (UAE) has a high prevalence of obesity in adolescents and adults; however, data on the health of preschool children are scarce. This study assessed the weight status and dietary habits of Emirati and non-Emirati children attending nurseries in Abu Dhabi, UAE. METHODS AND STUDY DESIGN: Weight and height were measured in children aged 18 months-4 years. Z scores for height-for-age (HAZ), weight-for-age (WAZ), and BMI-for-age (BAZ) were calculated based on WHO protocols. Parents completed a questionnaire regarding demographics and food frequency. RESULTS: A total of 203 children participated. Abnormal anthropometric status (z scores of <-2 or >2) for WAZ was indicated in 12.8% of Emirati children versus 1.4% of non-Emirati children (p=0.008) and for BAZ in 19.9% of Emirati children versus 8.4% of non-Emirati children (p<0.05). Emirati children exhibited higher prevalences of malnutrition (4.3% vs 1.4%), wasting (11.5% vs 2.8%), and overweight (8.5% vs 4.2%) than non Emirati children and consumed discretionary calorie foods and typical components of Emirati cuisine (rice, fish, and pulses) significantly more often than non Emirati children. CONCLUSIONS: Similar to findings in other countries undergoing economic transition, an indication of a double burden of disease was revealed in chil-dren attending nurseries in Abu Dhabi. Malnutrition and overnutrition were represented, especially among Emira-ti children, and were seemingly related to lifestyle rather than genetics. Therefore, policies focusing on child health interventions are required. PMID- 30485931 TI - The relationship between dietary inflammatory index (DII) and muscle mass and strength in Chinese children aged 6-9 years. AB - BACKGROUND AND OBJECTIVES: The dietary inflammatory index (DII(r)) is a measure of the overall inflammatory potential of a person's diet. However, there have been no studies looking at the effect of DII on measures of muscle mass and strength. We aimed to examine the association between DII and skeletal muscle mass and strength in Chinese children. METHODS AND STUDY DESIGN: A total of 466 children aged 6-9 years completed the study. Total body skeletal muscle mass (TSM), appendicular skeletal mass (ASM) and appendicular lean mass (ALM) were determined using Dual-energy X-ray absorptiometry. TSM/Height2, TSM/Weight, ASM/Height2 and ASM/Weight were calculated. The residual method was applied to compute ALM index (ALMI) adjusted for height and body fat. Hand grip strength was measured using hand dynamometer. DII scores were calculated from a 79-item food frequency questionnaire. RESULTS: Fully adjusted linear regression models showed a statistically significant negative relationship between DII and ASM, ASM/Height2, ASM/Weight, ALMI, TSM, TSM/Height2, and TSM/Weight (p: 0.019-0.014). The analysis of covariance indicated that the percentage differences in the extreme quartiles (Q4 vs Q1) of DII for the above-mentioned measures ranged from 1.04% to -4.36% (p-trend: <0.001-0.013). When boys and girls were analyzed separately, similar findings were observed for boys but not for girls. No significant associations were detected between DII and hand grip strength. CONCLUSIONS: DII score was inversely associated with skeletal muscle mass in boys but not in girls aged 6-9 years old. No significant associations were observed between DII and hand grip strength. PMID- 30485932 TI - Dietary and nutrient status of children with attention-deficit/ hyperactivity disorder: a case-control study. AB - BACKGROUND AND OBJECTIVES: Nutritional and dietary habits may affect children's behaviors and learning. The etiology of attention-deficit/hyperactivity disorder (ADHD), a common neurodevelopmental disorder in children, may be associated with unhealthy diets or nutrients deficiencies. The purpose of this study was to examine whether children with ADHD exhibited different dietary habits or nutrient profiles from healthy control subjects. METHODS AND STUDY DESIGN: We recruited 42 patients with ADHD (mean age: 8.1 years) and 36 healthy children as the control group (mean age: 9.8 years). We adopted the ADHD Rating Scale and the Swanson, Nolan, and Pelham Version IV Scale to interview both the ADHD patients and the control subjects and then evaluated participants' dietary intake with a food frequency questionnaire. Logistic regression models were utilized to produce a composite dietary/nutrient score, while receiver operating characteristic (ROC) was adopted to differentiate between the two participant groups. RESULTS: Compared to the control children, children with ADHD demonstrated a higher intake proportion of refined grains (p=0.026) and a lower proportion of dairy (p=0.013), calcium (p=0.043), and vitamin B-2 (p=0.024). We observed that the composite score of dietary and nutrient could significantly distinguish patients with ADHD from healthy controls (p<0.001). The composite dietary/nutrient score demonstrated a significant correlation with the severity of ADHD clinical symptoms (p<0.05). CONCLUSIONS: ADHD children and healthy controls have different dietary patterns and that dietary and nutrient factors may play a role in the pathophysiology of ADHD. Clinicians should consider dietary habits and specific nutrients in the routine assessment of children with ADHD. PMID- 30485933 TI - Association of dietary patterns and dietary diversity with cardiometabolic disease risk factors among adults in South Asia: The CARRS study. AB - BACKGROUND AND OBJECTIVES: To investigate the association of dietary patterns and dietary diversity with cardiometabolic disease risk factors among South Asians. METHODS AND STUDY DESIGN: In a population based study conducted in 2010-11, we recruited 16,287 adults aged >20 years residing in Delhi, Chennai, and Karachi. Diet was assessed using an interviewer-administered 26-item food frequency questionnaire. Principal component analysis identified three dietary patterns: Prudent, Indian, and Non-Vegetarian. We also computed a dietary diversity score. Multinomial and binary logistic regressions were used to calculate adjusted prevalence (95% confidence intervals) of cardio-metabolic disease risk factors across quartiles of dietary pattern and dietary diversity scores. RESULTS: The adjusted prevalence of diagnosed diabetes was lower among participants in the highest versus lowest quartile of the Prudent Pattern (4.7% [3.8-5.6] versus 10.3% [8.5-12.0]), and the Indian Pattern (4.8% [3.7-5.9] versus 8.7% [6.7-10.6] in highest versus lowest quartile, respectively). Participants following the Indian Pattern also had lower adjusted prevalence of diagnosed hypertension (7.0% [5.4-8.5] versus 10.6% [8.6-12.5] in highest versus lowest quartile, respectively). Participants in the highest versus lowest quartile of the dietary diversity score had a lower adjusted prevalence of diagnosed diabetes (4.1% [3.0 5.2] versus 8.2% [7.1-9.3]), diagnosed hypertension (6.7% [5.3-8.1] versus 10.3% [9.1-11.5]), and undiagnosed hypertension (14.2% [12.0-16.4] versus 18.5% [16.9 20.1]). CONCLUSIONS: High dietary diversity appears to be protective against cardio-metabolic disease risk factors in this urban cohort of South Asian adults. Further investigation to understand the underlying mechanism of this observation is warranted. PMID- 30485934 TI - Dietary factors and risk of gout and hyperuricemia: a meta-analysis and systematic review. AB - BACKGROUND AND OBJECTIVES: To evaluate the associations of dietary factors and the risk of gout and hyperuricemia. METHODS AND STUDY DESIGN: PubMed and Embase databases were searched from inception to June 2017 for eligible studies. Nineteen prospective cohort or cross-sectional studies with adequate sample sizes are included, all involving red meat, seafoods, alcohol, fructose, dairy products, soy foods, high-purine vegetables and coffee. RESULTS: Meta-analysis revealed several dietary associations with gout risk: red meat: OR 1.29 (95% CI 1.16-1.44); seafoods: OR 1.31 (95% CI 1.01-1.68); alcohol: OR 2.58 (95% CI 1.81 3.66); fructose: OR 2.14 (95% CI 1.65- 2.78); dairy products: OR 0.56 (95% CI 0.44-0.70); soy foods: OR 0.85 (95% CI 0.76-0.96); high-purine vegetables: OR 0.86 (95% CI 0.75-0.98); coffee: OR 0.47 (95% CI 0.37-0.59).Dietary association with hyperuricemia risk (red meat: OR 1.24 (95% CI 1.04-1.48); seafoods: OR 1.47 (95% CI 1.16-1.86); alcohol: OR 2.06 (95% CI 1.60-2.67); fructose: OR 1.85 (95% CI 1.66-2.07); dairy products: OR 0.50 (95% CI 0.37-0.66); soy foods: OR 0.70 (95% CI 0.56-0.88); high-purine vegetables ingestion: OR 1.10 (95% CI 0.88-1.39), P=0.39; coffee:OR0.76 in men (95% CI 0.55-1.06), OR 1.58 in women (95% CI 1.16 2.16). CONCLUSION: The risk of hyperuricemia and gout is positively correlated with the intake of red meat, seafoods, alcohol or fructose, and negatively with dairy products or soy foods. High-purine vegetables showed no association with hyperuricemia, but negative association with gout. Coffee intake is negatively associated with gout risk, whereas it may be associated with increased hyperuricemia risk in women but decreased risk in men. PMID- 30485935 TI - Availability and price of healthier food choices and association with obesity prevalence in New Zealand Maori. AB - BACKGROUND AND OBJECTIVES: Examine availability and price of healthier foods-vs regular counterparts and their association with obesity. METHODS AND STUDY DESIGN: A cross-sectional survey of weight and height among Maori in 2 urban and 96 rural areas in the Waikato/Lakes Districts-NZ (year 2004-06) was undertaken. Concurrently, availability of 11 'healthier' food in fast-food-outlets was examined by location (urban vs rural) and median income (high-low). In supermarkets, five-specific 'regular' foods were scored against 'healthier' counterparts (white-vs-wholemeal bread, with-skin-vs-skinless chicken, regular-vs trim meat, standard-vs-trim milk, sugarsweetened- beverages vs-water) for in store availability and price according to the Nutrition Environment Measures Survey. RESULTS: Overall, 3,817 Maori (BMI: women: 32.9+/-7.8 kg/m2; men: 33.1+/ 6.7 kg/m2) were included with 451 food-outlets in two urban-clusters and 698 food outlets in 96 rural-clusters. Fast-foods: The availability of healthier food choices was higher for 8/11 items in rural and low-income areas than urban and high-income areas. Multivariate analysis considered location and income as cofactors. No association between number of fast-food-outlets/cluster and healthier foods/cluster with obesity prevalence (General/Maori BMI cutoffs) was observed. Supermarkets: Water was cheaper than sugar-sweetened-beverages and negatively associated with obesity prevalence (General r=-0.53, p=0.03; Maori r= 0.53, p=0.03); high availability scores for trim milk compared to standard milk correlated with higher obesity prevalence (General r=0.49, p=0.04; Maori r=0.57, p=0.01). CONCLUSIONS: Bottled water vs sugar-sweetened-beverages prices were inversely associated with obesity. This supports the argument to regulate the availability and price of sugar-sweetened-beverages in NZ. The positive association of the availability of trim milk with the prevalence of obesity warrants investigation into individual's dietary and food-purchase behaviour. PMID- 30485936 TI - Subclinical thyroid disease and single nucleotide polymorphisms in reproductive age women in areas of Shanxi Province, China, where iodine exposure is excessive. AB - BACKGROUND AND OBJECTIVES: When iodine intake is in excess, a susceptible population that has a genetic predisposition will have an increased risk of hypothyroidism or autoimmune thyroiditis. This study evaluated the vulnerability to iodine excess and subclinical thyroid disease through screening of single nucleotide polymorphisms (SNPs) in reproductive-age women to provide evidence to be used for the prevention of subclinical thyroid disease. METHODS AND STUDY DESIGN: In Shanxi province, four areas where a range of iodine exposures from low to high were chosen in each region, 60 women were anticipated to enrol, including 20 pregnant women, 20 lactating women, and 20 non-pregnant, non-lactating women. Genotyping was performed using whole-blood samples, and the genotypes of 21 SNPs were determined and compared among areas with different water iodine and between controls and patients with subclinical thyroid disease. RESULTS: In total, 241 participants were enrolled. Among the 21 candidate SNPs, no difference was found among areas with various water iodine, whereas, TG (rs2252696), TSHR (rs4903957), CTLA-4 (rs231775), CAPZB (rs1472565), PDE4D (rs27178), and HLA (rs2517532) were significantly associated with various subclinical thyroid diseases; in particular, the PDE4D (rs27178), ad hoc TT allele, was associated with all examined subclinical thyroid diseases. CONCLUSIONS: Vulnerability to subclinical thyroid diseases is influenced by the presence of gene polymorphisms. There is a need for screening of suspected genes to effectively prevent and reduce the occurrence of thyroid diseases. People with the TT allele in PDE4D (rs27178) should be made aware of an increased risk of subclinical thyroid disease. PMID- 30485938 TI - Low Prevalence of Human Papilloma Virus in Patients with Breast Cancer, Kerman; Iran AB - Breast cancer is the first of the most important causes of the deaths of women in the world and in Iran. There arevarious causes and causes of this cancer, one of which has recently been described as a cause of breast cancer, is the humanpapillomavirus (HPV). The HPV is transmitted through sexual contact and skin lesions. There are more than 100 types ofHPV that can influence different parts of the body. Some types of HPV can cause cancer (such as cervical or anal cancer)and others can cause warts (such as genital or plantar warts). To study the risk of HPV infection in Breast Cancer, wemanaged a Case-Control study in Kerman, southeast of Iran. For this purpose, 98 paraffin blocks of breast cancer and40 paraffin blocks of fibrocystic as a control were tested for the presence of HPV DNA using Real-Time PCR, andHPV typing was done using INNo-Lippa assay. HPV DNA was detected in 8 out of 98 patients (8.2%), while it wasnot detected in the control group samples. HPV types 16, 18 were the most common (62.5%) types in positive samples.The prevalence of HPV in patients with breast cancer of Iran is very low and less than other regions of the world,it seems that maybe rout of transmission of HPV in Iran is under control. No one knows exactly why breast canceroccurs. The environment, hormones, Viruses, or your lifestyle could all play a role in the development of breast cancer.Currently, Vaccination is the best way to prevent cancer that's due to HPV. However, additional studies on the largergroup of patients are needed to explain the roles of HPV in Breast cancer. PMID- 30485937 TI - Association between "solute carrier family 30 member 8" (SLC30A8) gene polymorphism and susceptibility to type 2 diabetes mellitus in Chinese Han and minority populations: an updated meta-analysis. AB - BACKGROUND AND OBJECTIVES: In China, some studies have been reported that solute carrier family 30 member 8 (SLC30A8) gene polymorphism might increase the risk of T2DM, but some are not. The aim of this meta-analysis was to systematically investigate the association between the rs13266634 polymorphism of the SLC30A8 gene and T2DM in Chinese Han and ethnic minority populations. METHODS AND STUDY DESIGN: All published electronic articles were retrieved from Pubmed, Web of Knowledge, Chinese National Knowledge Infrastructure (CNKI), Wanfang database, VIP database and Google scholar. Pooled OR and 95% CI were calculated using random- or fixed-effects models. RESULTS: Twenty-five articles involving 62,285 subjects were included in this metaanalysis. Considering the total population, significant associations between the rs13266634 polymorphism and T2DM were observed under the allele model (C vs T: OR=1.23, 95% CI=1.18-1.29), the additive models ( CC vs TT: OR=1.44, 95% CI=1.32-1.56; CC vs CT: OR=1.08, 95% CI=1.02 1.15; CT vs TT: OR=1.25, 95% CI=1.15- 1.37), the dominant model (CC vs CT+TT: OR=1.24, 95% CI=1.17-1.32) and the recessive model (CC+CT vs TT: OR=1.26, 95% CI=1.16-1.35). Based on subgroup analysis, besides the CC vs CT model, these associations were stronger in the ethnic minority groups than in the Han population. Moreover, no association was observed under the CC vs CT model (OR=1.26, 95% CI=0.95-1.66, p=0.105) in ethnic minority groups. CONCLUSIONS: Chinese C allele carriers could have an increased risk of T2DM. Well-designed future studies should be conducted with a larger sample size to better understand this association in ethnic minority groups. PMID- 30485939 TI - Socio-Environmental Patterns Associated with Cancer Mortality: A Study Based on a Quality of Life Approach AB - Background: With 18.6% of total deaths due to malignant tumors in 2016, cancer is the second leading death causein Argentina. While there is a broad consensus on common risk factors at the individual cancer level, those operatingat a contextual level have been poorly studied in developing countries. The objective of our study was to identifysocio-environmental patterns in Argentina (2010), emphasizing quality of life, and to explore their associations with thespatial distribution of cancer mortality in the country. Methods: The study was conducted in 525 geographical divisionsnested into 24 provinces. Sex-specific crude and age standardized mortality rates (ASMR) for cancer (2009-2011 period)were calculated. Empirically derived socio-environmental patterns were identified through principal-component factoranalysis on a selected set of variables: an urban scale and 29 indicators of a quality of life index in Argentina for 2010.Two-level Poisson regression models were used to estimate associations between the ASMR and the continuous factorscores for socio-environmental patterns as covariates. A random intercept was included to account for spatial variabilityin the ASMR distribution using Stata software. Results: Four socio-environmental patterns were identified, termed"Contexts with urban-related resources or cultural capital", "Socioeconomically prosperous contexts", "Environmentswith anthropic exposures" and "Plains region" (cumulative explained variance=57%). High mortality rates were foundin counties characterized by socioeconomically prosperous contexts (RR=1.025 in women; 1.088 in men) and plainlandscapes (RR=1.057 and 1.117, respectively). Counties featuring urban or cultural resources demonstrated increasedmortality in women (RR=1.015, 95%CI=1.005-1.025), whereas rising rates associated with environments havinganthropic exposures (RR=1.008, 95%CI=1.001-1.016) were observed only for men. Conclusion: This study identifiedfour characteristic socio-environmental patterns in Argentina which incorporate features of quality of life, accountingto some extent for the differential burden of cancer mortality in this country. PMID- 30485940 TI - Calculation of Equivalent Square Fields in Radiation Therapy by an Improved Vadash Correction Factor for Collimator Exchange Effects AB - Background and objectives: To determine the head scatter factor, a formalism presented by Vadash and Bjarngardhas been employed to assess collimator exchange effects. The aim of this study was to determine the best Vadashcorrection factor (A) by introducing a new method based on the output factor measured in air for different square andrectangular fields. Materials and Methods: A new simple mathematical method based on selection of the best dosimetricdata was proposed to obtain the A value for Vadash to predict the equivalent square field size. Measurements wereperformed with a Farmer chamber 0.6 cc in SSD 100 cm and build up cap of Plexiglas, 1.5 and 3.5 cm equal to water,for 6 and 18 MV, respectively, with a Perimus Plus linear accelerator. The output factor in air (OFair) was measured forsquare and rectangular fields. MATLAB software (version R2014a) was employed for calculations and curve fitting.Results: A power model with a constant value was applied to the output factor in air as a function of square field size.The output factor in air ranged from 0.983 to 1.038 at 6MV and from 0.731 to 1.05 at 18 MV with the Y collimatorhaving a greater effect. Obtained values for A were 1.42 and 1.55 with respect to sigmamin=0.98 and 2.3 for 6 and 18 MVenergies, respectively. Conclusion: The proposed A values minimize the collimator exchange effect in calculatingequivalent squares, which plays an important role in patient dose calculation and treatment planning. PMID- 30485941 TI - Comparison of Salivary and Serum Soluble CD44 Levels between Patients with Oral SCC and Healthy Controls AB - Background: The most common type of oral cancer is oral squamous cell carcinoma. If it is diagnosed in the earlystages; the success of the treatment can be increased. It seems that ELISA-based techniques as a screening tool forsociety are the most cost-effective methods for early diagnosis. CD44 is a key marker for the detection of SCC stemcells. The aim of this study was to compare the level of soluble CD44 in saliva and serum between patients with oralSCC and healthy controls. Materials and Methods: Saliva and serum were collected from 20 patients with primaryOSCC and 20 healthy persons as control group. The samples were evaluated by an ELISA test kit. Data were analyzedby SPSS software version 22, chi-square, ANOVA, T-test and Spearman correlation test. Results: The mean of solubleCD44 level in serum and saliva of the patient and control groups are 531.51+/-228.95 and 453.3+/-113.74 (for serum)and 48.53+/-59.02 and 17.76+/-39.14 (for saliva) respectively. There was no statistically significant difference in serumand saliva solCD44 level between the patient and control groups (P value = 0.182 and P value = 0.061 respectively).Also, there was no significant correlation between the solCD44 level in each patient and control group in serum (Pvalue = 0.61) and in saliva (P value = 0.445). Conclusions: Determination of solCD44 level in saliva and serum canbe a useful method for diagnosis the person's involvement with cancer cells and the cancer in the early stages. Butaccording to the controversial outcomes of past studies, larger and more accurate studies are needed in groups withmore cases of oral cancer. PMID- 30485942 TI - Tylophorine Abrogates G2/M Arrest Induced by Doxorubicine and Promotes Increased Apoptosis in T47D Breast Cancer Cells AB - Background: The effects of tylophorine, a natural alkaloid found in Tylophora indica, administered as a singlecompound or in combination with doxorubicin on cell cycling and apoptosis were assessed in T47D breast cancer cells,selected as a model system for breast cancer. Methods: Cell cycle distribution and apoptosis were examined by flowcytometry. Caspase 3 and 9 expression was determined by immunocytochemistry.Result: We found that tylophorine didnot significantly influence the cell cycle distribution of T47D cells. However, the alkaloid did prevent accumulation ofcells in the G2/M phase. In addition, tylophorine increased the number of apoptotic cells. Expression of proapoptoticproteins (caspases 3 and 9) was up-regulated upon administration of tyloporine alone or in combination with doxorubicin.Conclusions: Tylophorine alone or in combination with doxorubicin induced apoptosis in T47D breast cancer cellsthrough modulation of the cell cycle and affecting the expression of caspases 3 and 9. PMID- 30485943 TI - Evaluation of Anal Cytology in Women with History of Abnormal Pap Smear, Cervical Intraepithelial Neoplasia, Cervical Cancer and High Risk HPV for Anogenital Dysplasia AB - Background: Anal cancer is uncommon. Although uncommon, the incidence of anal cancer has increased amongthe general population of the United States and other countries over the past 30 years. We evaluated anal cytology inwomen with the history of abnormal pap smear, cervical intraepithelial neoplasia, cervical cancer and high risk HPVfor anogenital dysplasia. Methods: In this cross sectional study, 153 patients over the age of 21 years, referred to ImamHossein Hospital in 1395-1396 who were being monitored due to abnormal pap smear, cervical cancer, CIN and highrisk HPV, were evaluated with anal cytology for anogenital dysplasia. Results: 153 patients were enrolled in fourmain groups. Among those with a history of abnormal pap smear (39 patients), only 25% of the patients with HSILhad abnormal anal pap smear, and the rest of them had negative anal smear. Among those with a history of CIN (61patients), patients with CIN III, 30.8% had abnormal anal smear, while the rest had a negative anal smear. Among thosewith a high risk of HPV (23 patients), 50% of the patients with concurrent positive HPV 16 and 18 had anal abnormalsmear. Patients with a history of cervical cancer (30 patients) who had radiotherapy with or without surgery showed anegative anal smear. The ratio of anal SIL positive of individuals with a sexual partner was only 1.9%, while this ratiowas 27.3% for those with more than one partner and this difference was statistically significant (P <0.0001). 15.4%of smokers had positive anal SIL test result, while, only 2.9% non-smokers had the same result, and this differencewas statistically significant (P = 0.03). 20% of the patients who had anal intercourse showed a positive anal SIL scoreresult, compared to 1% for those who did not. This difference was statistically significant (P <0.0001). Conclusion:Among people with a history of abnormal cervical pap smear, CIN, cervical cancer and high-risk HPV during the last6 months, abnormal anal tests are most commonly seen in patients who had risk factors such as anal sex, cigarette,multi partner etc. with high grade interepithelial squamous cervix such as HSIL, CIN III, HPV 16 and 18; more studiesin larger sample size are needed to have the better conclusion. PMID- 30485944 TI - Sexuality of Moroccan Survivors of Cervical Cancer: A Prospective Data AB - Introduction: This is a prospective study aiming to describe how cervical cancer and its treatment can affectthe sexuality of a specific population of Moroccan women survivors of this disease. Materiels and Methods: It is acomparison of clinical features and Female Sexual Function Index (FSFI) of 3 balanced groups of women, made upof 100 survivors of cervical cancer, 100 survivors of non gynecological cancer and a group of 100 healthy women.Results: 97% of the patients stopped their full sexual activity at the time of treatment; the time interval between treatmentand regular sexual activity was 8 months for the cervical cancer group, and 5.8 months for non-gynecologic cancer (P=0.001). Vaginal length assessed by pelvic examination during follow up visits was estimated at about 6.2 cm, 9.2 cmand 9.5 cm respectively for the cervical cancer group, non-gynecologic cancer group and the control group (p=0.04).On the basis of the FSFI questionnaire, the analysis of the 6 main sexuality parameter scores did attest worse results forthe variables related to sexual function for cervical cancer group, but not in a statistically significant way. Conclusion:In order to preserve an optimal quality of life after cervical cancer, the sexual dimension is a crucial parameter to takeinto consideration throughout treatment phases, especially radiation (by encouraging sexual intercourses, and usingvaginal dilators during the treatment). Moroccan survivors of this disease must be treated according to a multidisciplinaryapproach, that includs the psychological component. PMID- 30485945 TI - Determining Overall Survival and Risk Factors in Esophageal Cancer Using Censored Quantile Regression AB - Background: Esophageal cancer is one of the leading causes of death worldwide. The global increasing rate of thistype of cancer requires more attention. The purpose of this study was to determine the overall survival probability ofesophageal cancer after diagnosis and to assess the potential risk factors in a population of Iranian patients. Materialsand Methods: This retrospective cohort study was conducted on 127 cases with esophageal cancer in the Azarbaijanprovince, East of Iran. Participants in the study were diagnosed during 2009-2010 and were followed up for 5 years. Theevent was considered death due to esophageal cancer and those who survived until the end of the study were assumed asright censored. Censored quntile regression was fitted to find the overall survival of the patients using adjusted effects ofvariables and was compared with Cox regression model. Results: Patients' mean and median survival time were 16.99and 10.06 months respectively and 89% off cases died by the end of the study. The 1, 3, 6, 12 and 36-month survivalprobabilities were 0.95, 0.76, 0.60, 0.43, and 0.18. The median survival time for females and males without surgerywere 21.79 and 14.76 month respectively. The accuracy of predictions were 0.99 and 0.74 for the censored quantileregression and Cox, respectively. Conclusion: We concluded that being male, not having surgery, longer wait timebetween having symptoms and being diagnosed, low socioeconomic status and old age to be significant risk factors inreducing the probability of survival from esophageal cancer. PMID- 30485946 TI - Low Levels of Vitamin D in a Cohort of Women with Impalpable Breast Lesions from Rio de Janeiro/Brazil AB - Background: Low levels of vitamin D have been described as a risk factor for the development of breast cancer.The aim of this study was to evaluate the serum levels of vitamin D (25OHD) in patients with impalpable breast lesionscomparing with a control group. Methods: Vitamin D quantification (25OHD) was assessed in the plasma of 65 patientswith impalpable breast lesions and from 20 health controls using a chemiluminescent microparticle immunoassay.Pearson's chi-square test and nonparametric t-Student were used to evaluate statistical significance between the clinicalvariables and the means of quantification of vitamin D. The receiver operating characteristic (ROC) curve was used toevaluate the correlation between age and vitamin sufficiency for the cases and the controls. Results: The prevalence ofvitamin D deficiency and/or insufficiency in women with malignant lesions was 84% and 60% for the control group.Using the chi-square or Fisher's exact test, the relationship between vitamin D levels and age presented significantassociation only for the control group (P=0.002). Using ROC curve, the plot area (0.778) for the control group defineda cut-off value of 45 years to age, with specificity and sensitivity of 60% and 50%, respectively. Thus, the odds ratiofor vitamin D insufficiency in women over 45 years was 1.37 (P=0.011). For the case group, clinical characteristics,histological grade, and lymph node involvement did not show any significant association. Conclusion: The prevalence ofvitamin D deficiency/insufficiency is high in women with impalpable breast lesions, as well as in the control group,even in a tropical city. According to the results the age advancement may be involved with the decrease in vitamin Dlevels in plasma, but there was no statistical association between low levels of Vitamin D and breast cancer. PMID- 30485947 TI - New taxa and records of Gryllacrididae (Orthoptera, Stenopelmatoidea) from South East Asia and New Guinea with a key to the genera. AB - New records of Gryllacrididae from South East Asia to New Guinea are reported, new taxa are described and type specimens from European collections redescribed. The wing venation of the tegmina and its variation within the family is discussed. A new key to the 50 genera and subgenera of Gryllacrididae occurring in the area from South East Asia to New Guinea is provided. Six genera and two subgenera are introduced as new: Angustogryllacris gen. nov., Minigryllacris gen. nov., Monseremus gen. nov., Siamgryllacris gen. nov., Paraneanias gen. nov., Plexigryllacris gen. nov., Pseudasarca subgen. nov. of Asarcogryllacris Karny, 1937, Xiphilarnaca subgen. nov. of Metriogryllacris Karny, 1937. Two genera Gigantogryllacris Karny, 1937 and Pardogryllacris Karny, 1937 are reduced to subgeneric status under Gryllacris Audinet-Serville, 1831 and one monotypic genus Cyanogryllacris Karny, 1937 is synonymised with Capnogryllacris Karny, 1937. 70 species and nine subspecies are described as new: Eugryllacris gandaki sp. nov., Eugryllacris guomashan sp. nov., Eugryllacris crassicauda sp. nov., Eugryllacris crassicauda cambodiana ssp. nov., Eugryllacris serricauda sp. nov., Eugryllacris trabicauda sp. nov., Eugryllacris vermicauda sp. nov., Eugryllacris sulcata sp. nov., Eugryllacris inversa sp. nov., Gryllacris incornuta sp. nov., Gryllacris sok sp. nov., Gryllacris (Pardogryllacris) ovulicauda sp. nov., Gryllacris (Gigantogryllacris) bilineata sp. nov., Gryllacris (Gigantogryllacris) ligulata sp. nov., Lyperogryllacris forcipata sp. nov., Lyperogryllacris ocellata sp. nov., Lyperogryllacris khuntan sp. nov., Ocellarnaca disjuncta sp. nov., Ocellarnaca fusca sp. nov., Otidiogryllacris lawang sp. nov., Otidiogryllacris bamusbama sp. nov., Prosopogryllacris gamta sp. nov., Prosopogryllacris nigra sp. nov., Prosopogryllacris silacea sp. nov., Xanthogryllacris lineata sp. nov., Xanthogryllacris punctata sp. nov., Xanthogryllacris ralum sp. nov., Xanthogryllacris subrecta sp. nov., Aancistroger inarmatus sp. nov., Angustogryllacris bibulbata sp. nov., Aphanogryllacris sinustylata sp. nov., Aphanogryllacris nigritibiae sp. nov., Asarcogryllacris (Asarcogryllacris) brevis sp. nov., Asarcogryllacris (Asarcogryllacris) parapat sp. nov., Asarcogryllacris (Asarcogryllacris) robusta sp. nov., Asarcogryllacris (Pseudolarnaca) cornualis sp. nov., Asarcogryllacris (Pseudasarca) arborea sp. nov., Australogryllacris guttata sp. nov., Capnogryllacris (C.) erythrocephala fuscifrons ssp. nov., Capnogryllacris (C.) varifrons sp. nov., Capnogryllacris (C.) nigromaculata sp. nov., Capnogryllacris (C.) sakaerat toxica ssp. nov., Celebogryllacris brevitegmina sp. nov., Diaphanogryllacris annamita tenera ssp. nov., Diaphanogryllacris opulenta sp. nov., Diaphanogryllacris recta sp. nov., Diaphanogryllacris sinuata sp. nov., Eremus tigris sp. nov., Furcilarnaca chiangdao sp. nov., Furcilarnaca salit sp. nov., Furcilarnaca trilobata sp. nov., Haplogryllacris bilobulata sp. nov., Homogryllacris armigera sp. nov., Homogryllacris stabilis sp. nov., Larnaca (Larnaca) nigricornis sp. nov., Larnaca (Larnaca) tenuis sp. nov., Larnaca (Larnaca) samkos sp. nov., Larnaca (Larnaca) squamiptera sp. nov., Larnaca (Larnaca) subaptera sp. nov., Melaneremus sikkimensis sp. nov., Minigryllacris perpusilla sp. nov., Monseremus appendiculatus sp. nov., Neanias virens sp. nov., Neolarnaca vera nigrinotum ssp. nov., Phryganogryllacris extensa sp. nov., Phryganogryllacris gialaiensis fovealis ssp. nov., Phryganogryllacris nonangulata sp. nov., Siamgryllacris rufa sp. nov., Ultragryllacris pulchra nan ssp. nov., Ultragryllacris triangula sp. nov., Woznessenskia ampliata sp. nov., Woznessenskia bavi sp. nov., Zalarnaca (Glolarnaca) elegantula sp. nov., Zalarnaca (Glolarnaca) globiceps minor ssp. nov., Zalarnaca (Zalarnaca) maninjau sp. nov., Papuogryllacris diluta baiteta ssp. nov., Papuogryllacris rugifrons sp. nov., Papuogryllacris ligata bundi ssp. nov., Paraneanias striatus sp. nov., Plexigryllacris megastyla sp. nov. The following nomenclatural changes had to be done: Gryllacris bancana Karny, 1930a stat. nov. is raised to full species from subspecies of Gryllacris obscura Brunner von Wattenwyl, 1888; Xanthogryllacris inquinata (Karny, 1928c) comb. stat. nov. is raised to full species from subspecies under Pardogryllacris dyak (Griffini, 1909); Eremus oberthuri Griffini, 1913a stat. nov. is raised to full species from subspecies under Eremus rugosifrons Brunner von Wattenwyl, 1888; Prosopogryllacris nigrovenosa (Karny, 1928b) stat. nov. is raised to full species from subspecies under Prosopogryllacris horvathi (Griffini, 1909); Xanthogryllacris punctipennis aurantiaca (Brunner von Wattenwyl, 1888) stat. reest. and Xanthogryllacris punctipennis dempwolffi (Griffini, 1909b) stat. reest. are treated as valid subspecies under Xanthogryllacris punctipennis (Walker, 1869) instead of being synonyms of the latter; Gryllacris thailandi Gorochov, 2007 and Gryllacris thailandi facemarmiger Gorochov et al., 2015 are downgraded to subspecies of Gryllacris vittata Walker, 1869. Gryllacris kledangensis Karny, 1923 and Gryllacris lombokiana Karny, 1926a become new synonyms of Gryllacris peracca Karny, 1923; Brachyntheisogryllacris abbreviata evolutior (Griffini, 1909a) becomes a new synonym of Brachyntheisogryllacris abbreviata (Brunner von Wattenwyl, 1888), and Haplogryllacris hieroglyphicoides (Chopard, 1924) a new synonym of Haplogryllacris simplex (Walker, 1871). The following new combinations are proposed: Capnogryllacris (C.) basaliatrata (Griffini, 1909c) comb. nov. from Cyanogryllacris Karny, 1937; Haplogryllacris aliena Walker, 1869 comb. nov. and Haplogryllacris durgensis (Gupta Chandra, 2017) comb. nov. from Gryllacris Audinet-Serville, 1831; Homogryllacris artinii (Griffini, 1913b) comb. nov., Homogryllacris buyssoniana (Griffini, 1912c) comb. nov., Homogryllacris kurseonga (Griffini, 1913b) stat. comb. nov. and Homogryllacris ? maindroni (Griffini, 1913a) comb. nov. from Brachyntheisogryllacris Karny, 1937; Larnaca (Larnaca) eugenii (Griffini, 1914b) comb. nov. from Metriogryllacris Karny, 1937; Larnaca (Larnaca) larnacoides (Karny, 1937) comb. nov. and Larnaca (Larnaca) jacobsoni (Griffini, 1913c) comb. nov. from Melaneremus Karny, 1937. PMID- 30485948 TI - Checklist of the Red Sea Fishes with delineation of the Gulf of Suez, Gulf of Aqaba, endemism and Lessepsian migrants. AB - The current checklist provides for each species of the Red Sea its records in the Gulf of Suez, Gulf of Aqaba, Red Sea main basin and its general distribution.This new checklist of Red Sea fishes enumerates 1207 species, representing 164 families. Of these, 797 species were recorded from the Gulf of Aqaba and 339 from the Gulf of Suez. The number of species from the Gulf of Suez is evidently lower than the actual number not including 27 Lessepsian (Red Sea) migrants to the Mediterranean that most likely occur in the Gulf. The current list includes 73 species that were newly described for science since the last checklist of 2010. The most specious Osteichthyes families are: Gobiidae (134 species), Labridae (66), Apogonidae (59), Serranidae (including Anthiadinae) (44), Blenniidae (42), Carangidae (38), Muraenidae (36), Pomacentridae (35), Syngnathidae (34), Scorpaenidae (24) and Lutjanidae (23). Among the families of Chondrichthyes, the most specious families are the Carcharhinidae (18 species) and Dasyatidae (11). The total number of endemic species in the Red Sea is 174 species, of these, 34 species are endemic to the Gulf of Aqaba and 8 to the Gulf of Suez. PMID- 30485949 TI - Revision of the subgenus Stigmatodipogon Ishikawa of the genus Dipogon Fox (Hymenoptera: Pompilidae: Pepsinae). AB - The systematics of the subgenus Stigmatodipogon Ishikawa of the genus Dipogon Fox is revised. Six species are listed. Two new species, Dipogon (Stigmatodipogon) kurokawai Shimizu, sp. nov. (Honshu, Japan) and D. (S.) lao Loktionov Lelej, sp. nov. (Laos) are described and illustrated and other four species from Japan, the Russian Far East and Eastern Siberia are redescribed. A new combination is proposed for D. (S.) budrisi (Loktionov Lelej, 2014), comb. nov. Nesting records of D. (S.) kurokawai and prey records of D. (S.) macrostigmatus Ishikawa, 1959 and D. (S.) petiolatus Lelej, 1986 are presented. These are the first records of biology for this subgenus. A key to species is provided. PMID- 30485950 TI - Some soil-inhabiting mites from Zanzibar (Acari: Laelapidae). AB - This paper reports on six species of soil-inhabiting mites of the family Laelapidae from Zanzibar, Tanzania: Gaeolaelaps praesternalis (Willmann), G. zanzibarensis sp. nov., Hypoaspisella bernhardi sp. nov., Ololaelaps placentula (Berlese), Ololaelaps placidus (Banks) and Pseudoparasitus missouriensis (Ewing). The subgenus Hypoaspis (Hypoaspisella) Bernhard, 1971 is raised to the genus level and its diagnosis is clarified. PMID- 30485952 TI - On the taxonomy and phylogeny of the rare Selangor Mud Snake (Raclitia indica) Gray (Serpentes, Homalopsidae) from Peninsular Malaysia. AB - The taxonomic position of the rare Selangor Mud Snake (Raclitia indica) Gray to other species of homalopsids has remained uncertain due to the scarcity of specimens in collections and the lack of genetic material for comparison. Here we report the first molecular phylogenetic examination of this species based on recently acquired material. The study recovered R. indica nested within the clade of advanced, fanged homalopsids and the sister species to Erpeton tentaculatus Lacepede. We also present notes on variation observed in the new specimens as well as range extensions for the species. PMID- 30485951 TI - A new Raspy Cricket from the northern Australian Rainforests (Orthoptera: Gryllacrididae). AB - An Australian Raspy Cricket, Chauliogryllacris acaropenates Rentz, Su, Bethoux, sp. nov. is described. This cricket was found to harbor a number of mite species of interest to acarologists and the name was needed for them to proceed with their studies. A key to the males of the described species of Chauliogryllacris is provided along with numerous illustrations of the described cricket. Observations and comments on its biology, behavior and ecology are presented. PMID- 30485953 TI - Description of Enterobius (Colobenterobius) emodensis sp. n. (Nematoda: Oxyuridae) collected from Central Himalayan langur, Semnopithecus schistaceus, in Uttarakhand, India. AB - A new pinworm species, Enterobius (Colobenterobius) emodensis sp. n. (Nematoda: Oxyuridae) is described from the Central Himalayan langur, Semnopithecus schistaceus, in Mandal Valley, Chamoli District, Uttarakhand, India, based on mature and immature adults and fourth-stage larvae. This species closely resembles Enterobius (Colobenterobius) zakiri parasitic in Tarai langur, Semnopithecus hector, recorded from Uttarakhand and Uttar Pradesh, India, but is readily distinguished by having a shorter esophagus and a shorter spicule. It is surmised that this pinworm has co-speciated with the host langur. The new species is also characterized in that the posterior 1/3 of the esophageal corpus is much darker. Phylogenetic analysis based on the sequences of partial Cox1 gene of mtDNA suggested a basal position of diversification of Colobenterobius from the Enterobius lineage. PMID- 30485954 TI - A new species of Characidium (Characiformes: Crenuchidae) from the rio Parnaiba basin, northeastern Brazil. AB - Characidium tapuia, a new species apparently endemic to the rio Parnaiba basin, Brazil, is described. The new species is easily distinguished from congeners, except C. lanei, C. nana, and C. samurai, by having a broad and conspicuous dark lateral stripe, extending from the tip of snout to the end of caudal peduncle and by the absence of dark vertical bars on body of specimens larger than 23.0 mm SL. Characidium tapuia differs from the aforementioned species by a series of features, including 12 circumpeduncular scales (vs. 13 or 14 in C. lanei and C. samurai), presence of parietal branch of the supraorbital canal (vs. absence in C. lanei and C. nana), complete lateral line and adipose fin present (vs. lateral line incomplete and adipose fin absent in C. nana), and midlateral stripe with irregular borders (vs. lateral stripe with overall straight borders in C. samurai). PMID- 30485956 TI - The larva of Rhyacophila palmeni McLachlan 1879 (Trichoptera: Rhyacophilidae) from Greece and Kosovo with notes on ecology and zoogeography including a key to the known Greek Rhyacophila larvae. AB - The larva of Rhyacophila palmeni McLachlan 1879 is described, based on material from Greece and Kosovo. The diagnostic features of the species are discussed and illustrated, and some information on its ecology and distribution are included. In addition, diagnostic characters for larvae of the known Greek Rhyacophila species are provided. PMID- 30485955 TI - Moenkhausia goya (Characiformes: Characidae): a new species from the upper rio Tocantins basin, Central Brazil. AB - A new species of Moenkhausia is described from the upper rio Tocantins basin, States of Goias and Tocantins, Brazil. Moenkhausia goya, new species, can be distinguished from its congeners by the shape of the humeral blotch in combination with a uniform dark pigmentation covering the interradial membranes of the dorsal and anal fins. Among congeners, the new species is most similar to M. britskii Azevedo-Santos Benine, M. grandisquamis (Muller Troschel) and M. xinguensis Steindachner by presenting a deep body, a large, round humeral blotch and fins without discrete patches of dark pigmentation (i.e., without well defined blotches or stripes). With the description of M. goya, the number of species endemic to the upper rio Tocantins basin (considered upstream from the mouth of the rio Parana) is raised to 51. Of these, some are widespread in the upper rio Tocantins basin, while others seem to be restricted to one of its sub basins. PMID- 30485957 TI - First record of Polycystididae (Platyhelminthes, Kalyptorhynchia) from Cuba, with the description of a new genus and five new species, and remarks and the description of one new species from Panama. AB - The first records of Polycystididae from Cuba are provided and discussed. In total nine species have been collected, five of which are new to science, one representing a new genus. Polycydora intermedia gen. n. sp. n. shows intermediate features between Polycystis Kolliker, 1845 and Paulodora Marcus, 1948. The ovaries are kidney shaped, with the oocytes arranged in a row, and lack the hard "nozzles" of Paulodora. A female bursa as in Polycystis is present. In P. intermedia gen. n. sp. n. lacks the strong muscle bulb at the male bursa and the accessory glands type I in the male atrium, which are present in Polycystis. The male atrial organs include a prostate stylet type II connected to a free prostate vesicle type II. The four new species (Phonorhynchoides minor sp. n., Phonorhynchopsis capillaris sp. n., Phonorhynchopsis sublinguatus sp. n., Myobulla armenterosi sp. n.) are distinguished from their congeners by the specific shape and length of the male hard copulatory structures. Phonorhynchoides minor sp. n. has the smallest stylets within the genus, and these stylets are more straight than those of the other species of the genus. In Phonorhynchopsis capillaris sp. n. the prostate stylet type IV is only 20% of the length of the accessory stylet type IV, the lowest relative length within the genus. The accessory stylet in this species is extremely thin; it is only 2 um wide. Phonorhynchopsis sublinguatus sp. n. has a prostate stylet widened in the distal half, ending in a rounded tip, not twisted in the middle. Because of its strong resemblance to M. armenterosi sp. n., M. berti sp. n., a new species of Myobulla Artois Schockaert, 2000 collected at the Atlantic coast of Panama is described here too. Both species of Myobulla have a prostate stylet type III that shows a 90 degrees turn at some point, as is the case in some other species of Myobulla. In M. berti sp. n. the stylet is smaller overall and is bent in the middle; in M. armenterosi sp. n. the stylet is larger and it is bent more distally. All of the four known species have a very wide geographical distribution: Phonorhynchopsis haegheni, Alcha evelinae, Paraustrorhynchus elixus, and Gyratrix hermaphroditus. PMID- 30485958 TI - A review of the relationships of Xenochrophis cerasogaster Cantor, 1839 (Serpentes: Colubridae) to its congeners. AB - We sampled snakes of the genus Xenochrophis from across Northeast India. The snakes were evaluated for both morphological and molecular parameters. Phylogenetic relationship was reconstructed using mitochondrial genes (Cytb, 12s rRNA, ND4). The genus Xenochrophis was found to be paraphyletic, X. piscator complex and X. punctulatus form a single clade with Atretium schistosum as their sister taxon. X. cerasogaster forms a distinct lineage. X. vittatus and X. trianguligerus are related to the genus Rhabdophis. Herein it is recommended that X. piscator complex, i.e. X. asperrimus, X. flavipunctatus, X. melanzostus, X. piscator, X. sanctijohannis, X. schnurrenbergeri and X. tytleri, as well as X. punctulatus be reallocated to the genus Fowlea. PMID- 30485959 TI - Final instar larvae of Argia mollis Hagen in Selys, 1865 and Argia smithiana Calvert, 1909 (Odonata: Coenagrionidae) from the Brazilian Cerrado. AB - Recent expeditions to the Serra da Canastra and Chapada dos Guimaraes National Parks in Brazil resulted in the collection of larvae of Argia mollis Hagen in Selys, 1865 and A. smithiana Calvert, 1909. Thus, here we describe the last instar larvae of these two Argia species from the Brazilian Cerrado. PMID- 30485960 TI - A new record of Neoperla obliqua Banks, 1930 (Plecoptera: Perlidae) from Mt. Malindang, Mindanao, Philippines and association of life stages using DNA barcodes. AB - The nymph of the perlid Neoperla obliqua Banks, 1913 from Mt. Malindang, Mindanao Island, the Philippines is described and associated with the male and female adults using DNA barcodes. Using pairwise CO1, the nymph was associated with 99.9 +/- 0.14% interspecific similarity, while comparison between sexes generated a 0.2% intraspecific divergence between males and females of putative conspecifics. Additionally, the mature ova from female adults are described using scanning electron microscopy (SEM). The distinctive chorionic surface is rugose with longitudinal ridge-like pattern with a bare and flat collar. PMID- 30485962 TI - New species and a new record of the mite family Scutacaridae (Acari: Heterostigmata) from alpine New Zealand. AB - Seven new species of the mite family Scutacaridae (Acari: Pygmephoroidea) are described from the alpine zone (1600-1900 m a.s.l.) of the Central Otago region of the South Island of New Zealand: Diversipes laticaudatus sp. nov., Scutacarus isotrichus sp. nov., S. incisus sp. nov., S. spinisetus sp. nov., S. cornutus sp. nov., S. novaezealandicus sp. nov., and S. crassus sp. nov. In addition, Imparipes woodi Mahunka, 1974 is recorded from the New Zealand for the first time and redescribed. PMID- 30485961 TI - A revision of Eastern Palaearctic Anthobium Leach, 1819 (Coleoptera: Staphylinidae: Omaliinae: Anthophagini). II. fusculum group, and two additional species of the nigrum group. AB - The fusculum-group of the genus Anthobium Leach, 1819 is defined and briefly discussed. It contains western-palaearctic A. fusculum (Erichson, 1839), with a new synonym Lathrimaeum mesasiaticum Kirschenblat, 1961 syn.n., and fourteen species from the eastern Palaearctic Region, nine of which are described as new: A. besucheti Shavrin Smetana, sp.n. (central and eastern Nepal), A. capitale Shavrin Smetana, sp.n. (China: Yunnan, Meili-Xue Shan), A. confucii Shavrin Smetana, sp.n. (China: Sichuan, Gongga Shan and Erlang Shan; Hubei, Daba Shan), A. cuccodoroi Shavrin Smetana, sp.n. (India: Uttar Pradesh), A.denticulatum Shavrin Smetana, sp.n. (central Nepal), A. laozii Shavrin Smetana, sp.n. (China: Yunnan, Diancang Shan, Yanmen), A. latissimum Shavrin Smetana, sp.n. (China: Yunnan, Gaoligong Shan), A. liliputense sp.n. (China: Sichuan, Emei Shan) and A. splendidulum Shavrin Smetana, sp.n. (China: Gaoligong Shan, Meili Xue Shan and Baima Shan). A key to the species of the fusculum group is given. Lectotypes are designated for Lathrimaeum cavicrus Champion, 1925 and L. monticola Cameron, 1924. Additionally, two Himalayan species of the nigrum group defined by Shavrin Smetana (2017) are presented: A. alticola Coiffait, 1977 comb.nov. (from Deliphrum) and A. flaveolum Shavrin Smetana, sp.n. (eastern Nepal). The key for the nigrum group was modified. All species are described/redescribed, illustrated and their geographical distribution is mapped. Several members of Anthobium are recorded for the first time from certain area: A. fusculum from Pakistan, A. altivagans (Cameron, 1941), A. cavicrus (Champion, 1925) and A. sociale (Cameron, 1941) from Nepal, and A. monticola (Cameron, 1924) from Pakistan and Nepal. PMID- 30485963 TI - Four new Megaselia species (Diptera: Phoridae) from aanimal carcasses in Bangi, Malaysia. AB - Megaselia bangiensis Disney sp. nov., M. cumpapillarum Disney sp. nov., M. hyplongiseta Disney sp. nov. and M. selangorensis Disney sp. nov. were collected from rabbit carcasses placed in concealed environments in Bangi, Malaysia. PMID- 30485964 TI - The "hairy beast"-Zorotypus hirsutus sp. n., an unusual new species of Zoraptera (Insecta) from Burmese amber. AB - A new species of the order Zoraptera, Zorotypus hirsutus Mashimo sp. n., is described from mid-Cretaceous Burmese amber. The specimen is tentatively assigned to the subgenus Octozoros Engel based on number of antennomeres reduced from nine to eight. It is characterized by an unusually strong setation, appearing much more hirsute than other extant or extinct species of the order. Other unusual autapomorphic features are an elongated head capsule with a concave genal region and very slender, elongate antennomeres. The discovery of this aberrant species suggests that the morphological diversity of Zoraptera was much higher than previously expected. For a reliable placement of Zorotypus hirsutus the discovery of males and a robust species level phylogeny would be required. PMID- 30485965 TI - A new species of highland vampire crab (Crustacea: Brachyura: Sesarmidae: Geosesarma) from Serian, Sarawak. AB - A new species of semiterrestrial highland vampire crab of the family Sesarmidae, Geosesarma larsi n. sp., is described from western Sarawak. This brings the number of Bornean Geosesarma species to 12. Geosesarma larsi n. sp. is distinguished from congeners by the structures of the carapace, third maxilliped exopod and gonopods, as well as the proportions of its ambulatory legs. The colour pattern in life is also strikingly different from allied species. Notes on its ecology are provided and conservation threats briefly discussed. PMID- 30485966 TI - A new name for Dendronephthya kukenthali Gravier, 1908 (Octocorallia, Nephtheidae): Dendronephthya perezi nom. n. AB - The World Register of Marine Species (WoRMS) is an online resource, which provides the most comprehensive database of scientific names of marine organisms (WoRMS, 2018). WoRMS is regularly retrieved by multidisciplinary researchers around the globe, regarded as a source of reliable taxonomic information. The database is continuously improved by taxonomic experts, which frequently have to address issues raised by users and other editors (Costello et al., 2013). This study is a result of one of these exchanges of knowledge stimulated by WoRMS. PMID- 30485967 TI - First record of the alien bamboo leafhopper, Branchana xanthota, in Japan (Hemiptera: Cicadellidae: Deltocephalinae). AB - An alien bamboo leafhopper, Branchana xanthota Li, is recorded from Japan for the first time. Three species of bamboos are recognized as host plants: Phyllostachys bambusoides, Phyllostachys edulis and Pleioblastus simonii. PMID- 30485968 TI - The tadpole of Boana stellae (Anura: Hylidae). AB - Boana stellae (Kwet, 2008) was allocated within the B. pulchella species group and, presumably, is closely related to B. caipora (Antunes, Faivovich, and Haddad, 2008), B. curupi (Garcia, Faivovich, and Haddad, 2007), B. joaquini (Lutz, 1968), and B. semiguttata (Lutz, 1925) due to the similarity of the external morphology of adult specimens (Kwet 2008). Boana stellae is currently only known from adult specimens and embryos from the type locality in Rio Grande do Sul, southeastern Brazil, and from a single locality in Misiones, Argentina (Ferro et al. 2018). Although the embryo morphology has been described in detail (Navarro Acosta et al. 2017; Navarro Acosta Vera Candioti 2017, as Hypsiboas sp. gr. pulchellus), the tadpole of B. stellae has not been yet described. PMID- 30485969 TI - Gonaphodioides zempoaltepetlensis (Coleoptera: Scarabaeidae: Aphodiinae), a new species from Oaxaca, Mexico. AB - The genus Gonaphodioides Dellacasa, Dellacasa, Gordon, 2012 (Coleoptera: Scarabaeidae: Aphodiinae: Aphodiini) was created for seven species distributed in Mesoamerica and South America. Subsequently, G. cartwrighti Dellacasa, Dellacasa, Gordon, 2013 was described from El Salvador (Dellacasa et al. 2013). PMID- 30485971 TI - Ceratophila, a new genus of erotylid beetles (Erotylidae: Pharaxonothinae) inhabiting male cones of the cycad Ceratozamia (Cycadales: Zamiaceae). AB - Ceratophila new genus (Erotylidae: Pharaxonothinae) inhabiting male cones of the Mesoamerican cycad genus Ceratozamia Brongniart (Zamiaceae) is described for seven new species and compared to other genera of the Pharaxonothinae. Ceratophila differs from other genera of the Pharaxonothinae in many characters, most notable of which are: lateral pronotal carina thicker anteriorly in lateral view; head with supraocular and transverse occipital lines; elytra lacking a basal bead; and stridulatory files at base of head narrowly separated. Ceratophila has the male genitalia laterally compressed with a short median lobe and flagellum, similar to other Erotylidae. In comparison, the most superficially similar pharaxonothine genus Pharaxonotha Reitter has: lateral pronotal carina thin along entire length; head lacking supraocular lines, but with transverse occipital lines; elytra with distinct basal bead; stridulatory files at base of head widely separated; and unique male genitalia that are dorsoventrally flattened with a long median lobe and flagellum. Ceratophila contains two subgenera, which differ most notably in external characters and sexual dimorphism. Members of Ceratophila (Ceratophila), the nominal subgenus, have: more cylindrical bodies, pronotum evenly convex dorsally; the pronotum lacking basal longitudinal grooves on disc; metatibiae that are distinctly triangularly dilated toward apex; and no apparent external sexual dimorphism. In comparison, members of Ceratophila (Vovidesa) new subgenus have: dorsoventrally flattened bodies; the pronotum explanate (concave) along lateral margins; the pronotum with basal longitudinal grooves on disc; metatibiae weakly or not dilated toward apex; and with all tibiae in males showing strong sexual dimorphism. Four new species are described within the subgenus Ceratophila: C. (C.) chemnicki, C. (C.) gregoryi, C. (C.) picipennis, C. (C.) sanchezae; and three new species are described within the subgenus Vovidesa: C. (V.) chiapensis, C. (V.) mixeorum, C. (V.) vazquezi. Keys to genera, subgenera and species of known adults based on morphology are provided. PMID- 30485970 TI - A new species of Athaumasta Hampson, 1906 (Lepidoptera, Noctuidae, Bryophilinae) from the Altai Mountains of Mongolia and China. AB - The genus Athaumasta Hampson, 1906 is a small genus of the subfamily Bryophilinae, distributed from Central Asia through mountains of South Siberia to the Korean Peninsula. It is closely related to the genera Victrix Staudinger and Bryophila Treitschke, but differs in forewing pattern, strong pectination of the male antennae, a narrow and dorso-laterally flattened uncus, and distally narrowed and apically pointed male valves. The taxonomy of the genus was discussed by Volynkin Pekarsky (2016). At present the genus includes 10 valid species, some of which were described recently (Volynkin 2012; Volynkin Pekarsky 2016; Pekarsky 2017), and several taxa await description (Kononenko 2016). The present paper describes a new Athaumasta species from southwestern Mongolia and north-western China related to A. pekarskyi Volynkin, 2012. PMID- 30485972 TI - Review of the batfish genus Halicmetus Alcock, 1891 from Australian waters, with descriptions of two new species (Lophiiformes: Ogcocephalidae). AB - A taxonomic review of species of the Indo-Pacific batfish genus Halicmetus occurring in the Australian Exclusive Economic Zone is provided. Treatments of six species in the region, including diagnoses of the widespread Halicmetus niger Ho, Endo Sakamaki, 2008, H. reticulatus Smith Radcliffe, 1912 and H. ruber Alcock 1891, a reclassification of the poorly known H. marmoratus Weber, 1913, and descriptions of two new species, H. westraliensis n. sp. (an Australian endemic) and H. drypus n. sp. (from the northern sector of the Australian Exclusive Economic Zone off Norfolk Island). The Australian species can be distinguished from each other and regional congeners by a combination of morphometrics, meristics and colouration. A key is provided for all known species of the genus. PMID- 30485973 TI - Etmopterus marshae sp. nov, a new lanternshark (Squaliformes: Etmopteridae) from the Philippine Islands, with a revised key to the Etmopterus lucifer clade. AB - A new species of lanternshark, Etmopterus marshae (Squaliformes: Etmopteridae), is described from the Philippine Islands, western North Pacific Ocean. The new species occurs along insular slopes at a depth range of 322-337 m. The new species resembles other members of the "Etmopterus lucifer" clade in having linear rows of dermal denticles, and most closely resembles E. burgessi from Taiwan and E. evansi and E. pycnolepis from the South Pacific. It can be distinguished from all other members of the E. lucifer clade by a combination of characteristics, including length of anterior and posterior flank branches being of relatively equal length, straight vs. curved anterior flank marking, relative lengths of caudal markings, coloration, and relatively small size. A revised key to the revised key to the Etmopterus lucifer clade is provided. PMID- 30485974 TI - Description of Two New Species of the Genus Vorticella (Ciliophora: Peritrichia) Epibionts on Pomacea canaliculata (Mollusca: Ampullariidae: Gastropoda) in Southern Brazil. AB - The peritrich ciliates Vorticella veloxiiforme n.sp. and Vorticella ampullaria n.sp. were found as epibionts on the ampullarid mollusk Pomacea canaliculata collected from Patos Lagoon, Rio Grande do Sul state, Brazil. The detailed morphology of both species was investigated using live and stained specimens, as well as scanning electron microscopy. Zooids of Vorticella veloxiiforme are cup shaped measuring 57 X 41 MUm on average. A J-shaped macronucleus lies in the upper half of the cell. One contractile vacuole was observed in the upper part of the cell. V. ampullaria presents an elongate zooid measuring 70 X 25 um on average. A C-shaped macronucleus lies in the middle of the cell. Two contractile vacuoles are present: one close to the peristome and the other in the lower half of the cell. The pattern of oral polykinetids was typical of the genus, with all infundibular polykinetids composed by three rows of kinetosomes each. SEM revealed a regular pattern of pores present on the zooid membrane of both species. Analyses of the 18s rDNA placed the two new species in the order Vorticellida close to described species of Vorticella. PMID- 30485975 TI - Three new species of Tomocerus from tropical zone of China (Collembola, Tomoceridae). AB - Tomocerids are world-widely distributed, but were seldom reported from tropics. In the present paper, three new species of Tomocerus Nicolet are described from Hainan and Yunnan Provinces, tropical zone of China. All three species have compound-type dental spines and belong to Tomocerus ocreatus species-group. Tomocerus tropicus sp. nov. resembles Tomocerus pseudocreatus Yu, but differs from the latter in mesothoracic macrochaetotaxy, manubrial dorsal scales and denticles on the dental spines. Tomocerus nan sp. nov. resembles Tomocerus virgatus Yu, but differs from the latter in colour pattern, cephalic dorsal macrochaetotaxy, manubrial dorsal scales and denticles on the dental spines. Tomocerus nabanensis sp. nov. resembles T. postantennalis Yu, Zhang Deharveng, Tomocerus dong Yu Li and Tomocerus deharvengi Yu Li, but differs from the three species in PAO, cephalic and tergal dorsal macrochaetotaxy and tenent hairs. Our studies including the present work indicate the importance of future survey on Tomocerinae in and near tropics where diversity of this group was historically underestimated. PMID- 30485976 TI - A review of the genus Afrasura Durante, 2009 from Sao Tome Island with descriptions of a new species and a new subspecies (Lepidoptera: Erebidae: Arctiinae). AB - Present paper contains a review of the lithosiine genus Afrasura Durante, 2009 from Sao Tome Island (Democratic Republic of Sao Tome and Principe). One new species, A. pectinatissima Volynkin Laszlo, sp. nov. and one new subspecies, A. discocellularis saotomensis Volynkin Laszlo, ssp. nov. are described. Asura thomensis Rothschild, 1913 is synonymized with Afrasura hieroglyphica (Bethune Baker, 1911) widely distributed in West Africa. A new combination is established: Afrasura friederikae (Kuhne, 2007), comb. nov. Adults, male and female genitalia of all species mentioned are illustrated. PMID- 30485977 TI - Tolmerus calceatus (Meigen) confirmed as a valid species separate from Tolmerus atricapillus (Fallen) (Diptera: Asilidae). AB - The status of Tolmerus atricapillus calceatus (Meigen) is discussed. Based on morphological, ecological as well as genetic information it is concluded that Tolmerus calceatus stat. rev. should be treated as a valid species separate from T. atricapillus (Fallen). Characters to separate both are provided as well as a key to all Tolmerus species of northwestern Europe. PMID- 30485978 TI - Four new species of the leafhopper genus Riseveinus Li (Hemiptera: Cicadellidae: Evacanthinae) from China and Thailand. AB - The Oriental leafhopper genus Riseveinus Li is recorded from Thailand for the first time. Four new species, R. cervcornutus sp. nov., R. hamatus sp. nov., R. spinatus sp. nov. and R. tenuispinus sp. nov., are described and illustrated. Their diagnostic characteristics are compared with close relatives. A key to all known species of Riseveinus is provided. PMID- 30485979 TI - A review of the genus Smicronyx Schoenherr (Coleoptera, Curculionidae, Curculioninae) in tropical Africa. AB - The genus Smicronyx Schoenherr (Curculionidae, Curculioninae, Smicronychini) contains several species considered as potential biocontrol agents of parasitic and hemi-parasitic plants of crops (Striga spp. (Orobanchaceae) and Cuscuta spp. (Convolvulaceae)). However, the diversity of species occurring in Africa has not been explored in detail. This study reviews the species of Smicronyx occurring in continental tropical Africa. In total, 16 species are recorded for this region: 6 species previously described (S. bisignatus Hoffmann, S. gossypii Marshall, S. guineanus Voss, S. kiboanus Voss, S. pauperculus Wollaston and S. remaudierei Hoffmann), 2 newly recorded for the area (S. albosquamosus Wollaston, S. syriacus Faust), and 8 species are described as new (S. adjamati sp. n., S. crassithorax sp. n., S. kenyanus sp. n., S. namibicus sp. n., S. rufus sp. n., S. buchnerae sp. n., S. zambianus sp. n., S. zonatus sp. n.). A key to the species and photographs of the habitus and male genitalia are provided. PMID- 30485980 TI - On Hydrocanthus Say, 1823 (Coleoptera: Noteridae): description of a new species, two new synonyms and a key to Brazilian species. AB - A new species of Hydrocanthus Say, 1823 is described and illustrated, H. zimmermanni sp. nov. from Peru. A distinct pattern of prosternum and prosternal process setation and aedeagal features differentiate the new species from all other members of Hydrocanthus. Two new synonyms are established: H. rubiginosus Guignot, 1942 as junior synonym of H. debilis Sharp, 1882 (syn. nov.) and H. paludimonstrus Miller, 2001 as junior synonym of H. paraguayensis Zimmermann, 1928 (syn. nov.). In addition, a key to Brazilian species of Hydrocanthus is provided. PMID- 30485981 TI - Two new and potentially highly threatened Megophrys Horned frogs (Amphibia: Megophryidae) from Indochina's highest mountains. AB - Megophrys are a group of morphologically conserved, primarily forest-dependent frogs known to harbour cryptic species diversity. In this study, we examined populations of small-sized Megophrys from mid- and high elevation locations in the Hoang Lien Range, northern Vietnam. On the basis of morphological, molecular and bioacoustic data, individuals of these populations differed from all species of Megophrys known from mainland Southeast Asia north of the Isthmus of Kra and from neighbouring provinces in China. Further, the newly collected specimens formed two distinct species-level groups. We herein describe two new species, Megophrys fansipanensis sp. nov. and Megophrys hoanglienensis sp. nov. Both new species are range restricted and likely to be highly threatened by habitat degradation. These discoveries highlight the importance of the Hoang Lien Range for Vietnam's amphibian diversity. PMID- 30485982 TI - Revision of the genus Theopea Baly (Coleoptera: Chrysomelidae: Galerucinae) of East Asia: species lacking modified clypeus in males and the T. sauteri species group. AB - Theopea Baly, 1864 species lacking a modified clypeus of East Asia are revised. Theopea aureoviridis Chujo, 1935, T. collaris Kimoto, 1989, and T. sauteri Chujo, 1935 are redescribed. Theopea coerulea Gressitt Kimoto, 1963 is removed from synonymy with T. sauteri Chujo, 1935. Hoplosaenidea irregularis (Takizawa 1978) and H. kanmiyai Kimoto, 1984 are transferred to Theopea and redescribed. A lectotype is designated for T. aureoviridis Chujo, 1935. Five new species are described, T. cheni sp. nov. from Taiwan, T. geiseri sp. nov. from Northeast India, T. hainanensis sp. nov. from South China (Hainan Island), T. laosensis sp. nov. from West China, North Laos and Vietnam, and T. sekerkai sp. nov. from Central and South Laos. PMID- 30485983 TI - New species of the genus Amphichroum Kraatz, 1857 (Coleoptera: Staphylinidae: Omaliinae: Anthophagini) from China. AB - Eleven new species of the genus Amphichroum Kraatz, 1857 (Coleoptera: Staphylinidae: Omaliinae: Anthophagini) from China are described and illustrated: A. angustilobatum Shavrin Smetana, sp.n. (Yunnan: Meili Xue Shan), A. assingi Shavrin Smetana, sp.n. (Yunnan: Hengduan Mountains), A. longilobatum Shavrin Smetana, sp.n. (Sichuan: Erlang Shan), A. maculosum Shavrin Smetana, sp.n. (Yunnan: Diancang Shan), A. propinquum Shavrin Smetana, sp.n. (Sichuan: Gongga Shan), A. schuelkei Shavrin Smetana, sp.n. (Yunnan: Gaoligong Shan), A. rotundatum Shavrin Smetana, sp.n. and A. squamosum Shavrin Smetana, sp.n. (Sichuan: Daxue Shan, Gongga Shan), A. subaequale Shavrin Smetana, sp.n. (Shaanxi: Qing Ling Shan), A. subelongatum Shavrin Smetana, sp.n. (Sichuan: Erlang Shan, Daxue Shan), and A.tibetanum Shavrin Smetana, sp.n. (Tibet: Chola Mountains). A key to species known from China and distributional maps of all species are provided. PMID- 30485985 TI - Redescription of Admete sadko Gorbunov, 1946 (Gastropoda: Cancellariidae). AB - Five species of the family Cancellariidae are currently known from Arctic seas: Admete contabulata Friele, 1879, A. clivicola Hoisaeter, 2011, A. solida (Aurivillius, 1885), A. viridula (Fabricius, 1780) and Iphinopsis inflata (Friele, 1879) (Golikov et al. 2001; Kantor Sysoev 2006; Hoisaeter 2011). Admete contabulata, A. clivicola and Iphinopsis inflata are only known from the Atlantic part of the Arctic, i.e. Norwegian and southwestern Barents seas (Hoisaeter 2011; Nekhaev 2014). Admete solida has been rarely reported since its first description from the Bering Strait (Sysoev Kantor 2002), however Nekhaev Krol (2017) recently reported a specimen from the eastern region of the Barents Sea that is similar in morphology to the holotype of this species. Admete viridula is the only representative of Admete reported from Siberian seas (Golikov et al. 2001; Lyubin 2003; Kantor Sysoev, 2006). PMID- 30485984 TI - Groundwater amphipods (Crustacea, Malacostraca) of India, with description of three new cavernicolous species. AB - Stygofaunistic surveys of peninsular India yielded, among others, three new cavernicolous amphipod taxa: Orientogidiella reducta gen. n., sp. n. in the Borra caves of Andhra Pradesh state, Bogidiella hindustanica sp. n. (Bogidiellidae) and Indoniphargus subterraneus sp. n. (Austroniphargidae) in the Kapiladevi caves of Telangana state. The new genus, Orientogidiella gen. n., is proposed to accommodate all the hitherto known species of the Bogidiella indica-group. This paper gives an illustrated description of the three new species together with their taxonomic affinities. A new record of O. indica comb. n., from the Guthikonda caves in Andhra Pradesh is provided as well. The structure of the Indoniphargus mandible is revisited with scanning electron microscopy (SEM) and revealed a poorly known flexible structure on the molar process which could be useful for phylogenetic purposes. The species diversity and geographic distribution of the Indian stygobiotic amphipods are briefly reviewed. PMID- 30485986 TI - A new species of Plaumanniola Costa Lima in French Guiana (Coleoptera: Staphylinidae). AB - The genus Plaumanniola Costa Lima, 1962 was a subject of several taxonomical and morphological studies. It is one of very few scydmaenines originally placed not only in a different beetle family, but even a superfamily. The first species of Plaumanniola, P. sanctaecatharinae Costa Lima, 1962 was confused with myrmecophilous spider beetles and placed in a new subfamily Plaumanniolinae of Ptinidae. Transferred to Scydmaenidae by Lawrence Reichardt (1966), it remained placed as a separate subfamily, and after merging the ant-like stone beetles with Staphylinidae, as a tribe Plaumanniolini of Scydmaenitae (Newton Franz 1998; Grebennikov Newton 2009). Franz (1990) redescribed P. sanctaecatharinae, but Jaloszynski (2013) found his redescription to have been based on a misidentified new species, which he described as P. regina Jaloszynski, 2013. The latter author illustrated previously unknown morphological structures, redefined Plaumanniola and discussed its possible close affinities with Glandulariini (Jaloszynski 2013). The unusually stout and flattened body, with especially flat and broad head (interpreted as possible adaptations towards myrmecophily, e.g., Lenko (1972)), differentiated Plaumanniolini from all other Scydmaeninae, but no other characters were found to support a separate position of this monogeneric tribe. Shortly later, a relatively slender P. simplicissima Jaloszynski, 2014 was described on the basis of material collected in Bolivia. Finally, a discovery made by Jaloszynski (2016) that Euconnus octosetosus Franz, 1994, was in fact a strikingly slender member of Plaumanniola, and that the aedeagus of Plaumanniola highly resembles that of Euconnus (Rhomboconnus Franz, 1986), lead to placing Plaumanniolini as a junior synonym of Glandulariini. It is possible that in future Plaumanniola will be reduced to a subgenus of Euconnus. PMID- 30485987 TI - Description of the first endemic Polistes Latreille, 1802 from Sulawesi (Hymenoptera: Vespidae: Polistinae). AB - A new species of Polistes Latreille, 1802 from Sulawesi, namely Polistes (Polistella) celebensis Selis, sp. nov., is described and figured. This is the first endemic species of this genus from Sulawesi. PMID- 30485988 TI - New record of Hydrozoa Distichopora violacea (Pallas, 1766) (Anthoathecata: Stylasteridae) from Andaman and Nicobar Islands, India. AB - The class Hydrozoa consists of mostly marine and few freshwater organisms classified into 7 orders amongst which the order Anthoathecata consists of 48 families with approximately 1,140 valid species (Cartwright Collins 2007). Stylasteridae is one among the families that comprises the order Anthoathecata, and is characterized by a calcareous exoskeleton which is often brightly pigmented. The members of the family are commonly called lace corals. They are usually small in size and commonly found in crevices and caves in coral reef areas. PMID- 30485989 TI - A new species of the genus Ceracris Walker, 1870 from Hainan of China (Orthoptera: Acridoidea, Arcypteridae). AB - The genus Ceracris Walker, 1870 is a median genus in Arcypteridae, which contains 23 species in the world, among them 10 species distributed in China [Walker, 1870; Bolivar, 1914; Uvarov, 1931; Zheng, 1977; Liu, 1981; Zheng, 1983; Yin, 1984; Liang, 1988; Wang, 1992; Liu et Li, 1995; Ou et al, 1995; Yin et al, 1996; Zheng et Xia, 1998; Zhang et al, 2017; Cigliano, 2018]. A new species of the genus i.e. Ceracris jianfenglingensis sp. nov. is described from Hainan, China in this paper. The new species is similar to Ceracris n. nigrocornis Walker, 1870, but differs from latter by antennae wider, length of middle segment 3.4 times of its width; lateral carinae of pronotum almost parallel; length of interspace 1.2 times minimum width in mesosternum of male; cubital area of tegmen without intercalary vein in male; epiphallus with straight bridge and tegmen of female shorter, reaching the end of hind femur only. Type specimens are deposited in the Natural Museum of Hebei University, Baoding, Hebei, China. PMID- 30485990 TI - On a new species of the spider genus Attacobius Mello-Leitao (Araneae: Corinnidae) from Brazilian Cerrado. AB - At the time the genus Attacobius Mello-Leitao, 1925 was first acknowledged as a member of the subfamily Corinninae, Corinnidae, by Platnick Baptista (1995), only three species were recognized. Since then, that number has increased to 15 currently valid species (Bonaldo Brescovit 1998; 2005; Pereira-Filho et al. 2018). Recently we had the opportunity to discover an additional species of Attacobius, collected in association with fire ants of the genus Solenopsis Westwood in the State of Goias, Midwest Brazil, a region that harbors a large portion of the Brazilian Cerrado, one of the most threatened savannas in the planet. Attacobius lavape n. sp., described below, appears to belong to the same group of species as A. verhaaghi Bonaldo Brescovit, 1998 and A. lamellatus Bonaldo Brescovit, 2005, since these three species share, in the male palp, the presence of an unsclerotized median lobe on the retrolateral tibial apophysis (Figs 9, 11). PMID- 30485991 TI - Re-description of Chinese mitten crab Eriocheir sinensis H. Milne Edwards, 1853 (Crustacea: Brachyura: Grapsoidea: Varunidae) zoeal development using confocal laser scanning microscopy. AB - A number of authors have described the zoeal development of the Chinese mitten crab, Eriocheir sinensis H. Milne Edwards, 1853, while some of these studies only recognised 5 zoeal stages, two of them described six. The present study re examined the zoeal stages of E. sinensis from laboratory-reared material using confocal laser scanning microscopy and visualised the images using the open source software programmes ImageJ and Drishti. From these images 6 zoeal stages were re-described and compared with all previous larval descriptions of the Chinese mitten crab. Comments on the variation of some setal characters are also described in zoeal stages IV-VI. PMID- 30485992 TI - A taxonomic study of Eupolyphaga Chopard, 1929 (Blattodea: Corydiidae: Corydiinae). AB - The cockroach genus Eupolyphaga is revised. Twenty species and two subspecies are recognized, with thirteen species and two subspecies are new to science: E. daweishana sp. nov., E. dongi sp. nov., E. fengi sp. nov., E. hanae sp. nov., E. hupingensis sp. nov., E. maculata sp. nov., E. nigrifera sp. nov., E. nigrinotum sp. nov., E. pilosa sp. nov., E. robusta sp. nov., E. shennongensis sp. nov., E. wooi sp. nov., E. xuorum sp. nov., E. everestiana reni subsp. nov., and E. fengi yongshengensis subsp. nov. Homoeogamia sinensis Saussure is placed as a junior synonym of E. sinensis (Walker) and the replaced name E. limbata (Kirby) for Homoeogamia sinensis is invalid, the status of Eupolyphaga thibetana (Chopard) is recovered. Male genitalia of species in the genus is described and illustrated. Females and oothecae of some species are described and illustrated. Distribution maps and a checklist of Eupolyphaga are provided. A key to males of Eupolyphaga is given. Plenty habitat photographs are shown. PMID- 30485993 TI - Catalogue of Indian Notodontidae Stephens, 1829 (Lepidoptera: Noctuoidea). AB - The present communication consists of the first ever catalogue of Indian Notodontidae Stephens, 1829 comprising systematic accounts of 242 species (including nominotypical subspecies) and 10 subspecies under 116 genera of 10 subfamilies with four new records to India viz. Phalera (Phalera) birmicola Bryk, 1949, Spatalina desiccata stolida Schintlmeister, 2007, Hiradonta hannemanni Schintlmeister, 1989 and Kamalia tattakana (Matsumura, 1927). The account was prepared by compiling findings from both literature survey and field sampling carried out at various Protected Areas in the Indian Himalayas and Chhattisgarh state in the Deccan Peninsular region of India. Zoogeographic analysis of Indian Notodontidae reveals a majority of the assemblage showing Oriental (58.27%) and Palaearctic (40.49%) affinities with maximum species of Sundanian (80.00%), followed by Himalayan (77.65%) origins. In India, the majority of the species are distributed in the Himalayan (35.33%) and North-East (39.40%) biogeographic zones, reflecting maximum endemicity. Extensive surveys in the less explored southern part of the country are expected to enrich the inventory of Indian Notodontidae. The distribution map and detailed illustrations of the four new records are provided. PMID- 30485994 TI - Review of the Brazilian species of Udamopyga Hall, 1938 (Diptera: Sarcophagidae), with the description of a new species and a key to males and females. AB - Udamopyga Hall, 1938 sensu stricto previously comprised 20 species: three from the Nearctic Region and 17 from the Neotropics. A comparative morphological study of the seven species so far recorded from Brazil is presented, including a newly described species from the Brazilian Atlantic Forest, Udamopyga squamata sp. nov., with emphasis on the terminalia and the addition of new diagnostic characters. An identification key to the adults of both sexes of these species is provided. PMID- 30485995 TI - Integrative taxonomy of the Amazonian red-sided opossum Monodelphis glirina (J.A. Wagner, 1842) (Didelphimorphia: Didelphidae). AB - New records for Monodelphis glirina, a short-tailed opossum distributed throughout the Amazon region, from Humaita, Amazonas state, and Confresa, Mato Grosso state, prompted new insights into the geographic distribution and genetic diversity of this species. One of the records extends the species range circa 350 km beyond the previous southeastern limit. Voucher specimens had their identification confirmed by morphological comparison with the holotype and corroborated by molecular data (mitochondrial gene Cytochrome b). Our analyses revealed an east-west geographic structure into two clades that could represent distinct species, M. glirina and M. maraxina. Furthermore, examination of the holotype brought to light that it was never formally linked with the voucher specimen collected by Johann Natterer. PMID- 30485996 TI - Phylogeny and revision of Schraderiellus Rider, 1998 with the description of five new species (Hemiptera, Pentatomidae, Discocephalinae, Ochlerini). AB - A cladistic analysis of Schraderiellus Rider, 1998 is provided in this study. Were used 60 morphological characters for 34 taxa, including the two known species of Schraderiellus and five new species in the ingroup, two species of Discocephalini and 24 species of Ochlerini in the outgroup, and Euschistus hansi Grazia, 1987 as root. The analysis was made using TNT through heuristic searches under implied weighting of characters. The analysis indicates the monophyly of Schraderiellus with seven valid species. Schraderiellus is redescribed, and five new species are described: S. brevicolis sp. nv., S. falcatus sp. nv., S. luridomaculatus sp. nv., S. luteipedis sp. nv. and S. rufilineatus sp. nv., and a key for the species is presented. PMID- 30485997 TI - Fatkullina imitata n. sp., second species of a unique cheilostome bryozoan genus with reversed-polarity zooidal budding, and new family Fatkullinidae. AB - A second species of the unique cheilostome bryozoan genus Fatkullina, with reversed-polarity zooidal budding, has been discovered. Fatkullina imitata n. sp. is described from the western Kamchatka shelf and upper slope of the Sea of Okhotsk. It differs from the type species, F. paradoxa, by the combination of orificial characters, the convex distal third of the frontal shield, and predominantly crimson coloration of dry colonies. A new family, Fatkullinidae, is erected to accommodate Fatkullina (as the type genus) and also Stomacrustula, Pachyegis and Lepralioides. The origin of reversed polarity zooidal budding is considered to arise as a consequence of the unique T-shaped geometry of the ancestrula and transverse daughter zooid followed by spiral budding of periancestrular and succeeding generations of zooids within the zone of astogenetic change. PMID- 30485998 TI - The larvae of Rhyacophila tsurakiana Malicky 1984, Rhyacophila gudrunae Malicky 1972, and Rhyacophila biegelmeieri Malicky 1984, including an update for the larval key to the Greek species of genus Rhyacophila Stephens 1836 (Rhyacophilidae, Trichoptera). AB - Based on adults, mature pupae, and larvae sampled at the same sites on mainland Greece and on the Greek islands of Kerkyra (Corfu) and Crete, the previously unknown larval stages of Rhyacophila tsurakiana Malicky 1984, R. gudrunae Malicky 1972, and R. biegelmeieri Malicky 1984 could be associated and identified. This material enabled us to describe and illustrate the final instar larvae of these three species, and to extract reliable diagnostic characters updating the existing larval key to the Greek species of genus Rhyacophila Stephens 1836 (Karaouzas et.al. 2015). In the context of this key, R. tsurakiana (together with R. tristis Pictet 1834 and R. obtusa Klapalek 1894) lacks abdominal gills; the three species can be separated by the shape of the dorsal sclerite of abdominal segment IX and by anal proleg morphology. Rhyacophila gudrunae is the only Greek species so far where larvae are fitted with one four-filament gill on each body side of the abdomen. Finally, R. biegelmeieri has one tufted multifilament gill on each body side and can be separated from four other species sharing this gill morphology by coloration patterns and head widths; however, separation from R. nubila Zetterstedt 1840 and R. palmeni McLachlan 1879 is not yet possible. Rhyacophila tsurakiana and R. biegelmeieri are large-scale endemic caddisfly species of European Ecoregion 6 (Hellenic Western Balkan), whereas R. gudrunae is a micro-endemic species of this region and restricted to the island of Crete (Malicky 2005b; Graf et al. 2008). PMID- 30485999 TI - A newly recognised species of Cryptes Maskell 1892 (Hemiptera: Coccidae) from Western Australia. AB - Cryptes utzoni Lin, Kondo Cook sp. n. (Hemiptera: Coccidae) is described based on adult female morphology and DNA sequences from mitochondrial and nuclear loci. This Australian endemic species was found on the stem of Acacia aneura (Fabaceae) in Western Australia. All phylogenetic analyses of three independent DNA loci show that C. utzoni is closely related to C. baccatus (Maskell), the type and only species of Cryptes Maskell, 1892. The adult female of C. utzoni is described and illustrated and a table is provided of the characters that differ among adult females of the two species of Cryptes now recognised (C. baccatus and C. utzoni) and a morphologically similar Western Australian species, Austrolichtensia hakearum (Fuller). There is deep genetic divergence in COI among samples of C. baccatus, suggesting the possibility of a species complex in this taxon. PMID- 30486000 TI - A new species of Limnonectes (Amphibia: Anura: Dicroglossidae) from Vietnam. AB - A new species of Limnonectes from central Vietnam is described based on morphological and molecular differences. Morphologically, the new species is distinguishable from its congeners on the basis of a combination of the following diagnostic characters: SVL 47.5-60.9 in males, 42.3-51.1 mm in females; males with moderately enlarged head (HL/SVL 0.48), head longer than wide; vomerine teeth present; external vocal sacs absent; rostral length short (RL/SVL 0.14 in males, 0.15 in females); tympanum invisible; dorsal surface of head, body, and flanks smooth; dorsal surface of tibia and foot distinctly tuberculate, covered with moderately dense, small, low tubercles; supratympanic fold present; dorsolateral fold absent; toes webbed to posterior of terminal phalanx; in life, dorsum with light yellowish brown markings, throat and chest white with brown markings, and ventral surface of abdomen white or white with brown markings. In phylogenetic analyses, the new species is the sister taxon to an undescribed species from Cambodia. PMID- 30486001 TI - Immature stages of Murgantia histrionica (Hemiptera: Pentatomidae). AB - Immature stages of Murgantia histrionica (Hemiptera: Pentatomidae) are described using light and scanning electron microscopy. Specimens of all life stages of M. histrionica were collected on Peritoma arborea (Cleomaceae) in Palm Springs, California. Specimens were observed in light and scanning microscopies, imagens taken and described based on specimens and photographs. We provide images of the eggs and immatures in light microscopy, and SEM of the eggs and first and fifth instars. Eggs of M. histrionica are barrel-shaped, white, with brown band and circular spot; the corium surface carinated, forming hexagonal cells; carinae irregular apically. The nymphal color pattern; the reflexed lateral margins of pro- and mesothorax; and the scattered punctuation of the tegument are a combination of characteristics enabling M. histrionica identification in its nymphal stages. The eggs of M. histrionica are similar in shape, color, and size to other Strachiini genera, such as Bagrada, Eurydema and Stenozygum. Among the Strachiini, the correct identification of M. histrionica based on immatures is possible by the shape of the head and pronotum, overall size of immatures, and coloration patterns. PMID- 30486002 TI - Description of two new species of Paratus Simon, 1898 from southern China (Araneae: Liocranidae). AB - In this paper, two new Paratus species are described from southern China from both sexes: Paratus hamatus sp. n. from Yunnan Province and P. kentingensis sp. n. from Taiwan Province. PMID- 30486004 TI - A new species of Ituglanis Costa Bockmann, 1993 (Siluriformes: Trichomycteridae) from Rio Ribeira de Iguape and upper Rio Tiete basins, southeastern Brazil. AB - Ituglanis amphipotamus, new species, is distinguished from all congeners by the combination of the following characters: anterior cranial fontanel present, i,5 pectoral-fin rays, nasal canal and antorbital segment of infraorbital canal absent, five or six pairs of ribs, 39 post-Weberian vertebrae. It can be further distinguished from the sympatric I. proops by the size of the interopercular patch of odontodes. The new species is described from the Rio Ribeira de Iguape and the upper Rio Tiete basins in the southeastern region of Brazil. Comments on the biogeography of the new taxa and putative relationships with its congeners are presented. [Zoobank: urn:lsid:zoobank.org:act:AC2F3365-92C0-4444-AC89 9546365158EC]. PMID- 30486003 TI - Pupae of the Nearctic species of Culicoides Latreille subgenus Monoculicoides Khalaf (Diptera: Ceratopogonidae). AB - There are 160 valid species of Culicoides Latreille described from the Nearctic Region, but many are unknown as immatures or, although partially described, cannot be readily identified. We provide pupal diagnoses, descriptions, and a key to all seven known species of Culicoides subgenus Monoculicoides Khalaf occurring in the Nearctic biogeographic region. A diagnosis of several characters unique to this subgenus is provided to allow for the recognition of the included species from those of other subgeneric groupings. Microphotography of important morphological characters for both the key and descriptions are provided. This study highlights the usefulness of examining the pupae of Culicoides as a tool for species identification. The pupae of Culicoides grandensis Grogan Phillips, C. occidentalis Wirth Jones, and C. shemanchuki Grogan Lysyk are newly described and those of C. riethi Kieffer, C. stigma (Meigen), and C. variipennis Wirth Jones are redescribed in detail. The seventh species, C. sonorensis, was fully described recently. PMID- 30486006 TI - Rediscovery of Calymmochilus russoi Gibson, 1995 (Hymenoptera, Chalcidoidea, Eupelmidae), and revision of European Calymmochilus Masi, 1919. AB - The European species of Calymmochilus Masi (Hymenoptera, Eupelmidae) are revised. Calymmochilus atratus Masi stat. rev. is removed from synonymy under C. subnubilus (Walker) and treated as a valid species. A lectotype is designated for Calymmochilus atratus. The single extant type specimen of Eupelmus subnubilus Walker is considered as lectotype. Calymmochilus bini Fusu sp. n. is described from a single female collected in Sardinia. A female of Calymmochilus russoi Gibson is reported from Spain as a parasitoid in galls of Parapodia sinaica (Frauenfeld) (Lepidoptera, Gelechiidae) on Tamarix (Tamaricaceae), a new national and host record. The species is redescribed and illustrated, this being the first record of the species after its original description. An illustrated key to females and, when known, males of the now six recognized European species of Calymmochilus is given and available biological and distributional data are reviewed. PMID- 30486005 TI - Synonymy of two important crop pests of burrower bugs, Cyrtomenus mirabilis and C. bergi (Hemiptera: Cydnidae), based in a multi-source approach. AB - Burrower bugs are unique among true bugs, recognized by the morphological adaptations for digging, and include several species of economic importance for causing damages in roots and ground pods. Damage records has been growing in the last two decades in the Neotropics, but taxonomic problems still hampers studies in these group of insects. Cyrtomenus bergi Froeschner and C. mirabilis (Perty), species of economic interest and widely distributed in the Neotropics, have no clear morphological differentiation raising doubts about the correctness of identifications made to date, even validity of these species. Taxonomic problems, as species delimitation and identification, can benefit from different approaches, bringing tools and complementary information for establishing a species status. In this work, we use the different sources (morphology, distribution, linear and geometric morphometric), to access the identity of C. bergi and C. mirabilis and define the recognition of both as separated species. Results shows overlapping of geographical distribution and lack of quantitative and qualitative morphological differences, supporting C. bergi as a junior synonym of C. mirabilis; studies about this important pest species should consider only the latter as valid species. PMID- 30486007 TI - On the genus Systaria (Araneae: Clubionidae) in Southeast Asia: new species from caves and forests. AB - The genus Systaria Simon 1897 is reviewed in Southeast Asia and eight new species are described: S. lannops spec. nov. from Thailand (female), S. longinqua spec. nov. (male, female) and S. luangprabang spec. nov. (female) from Laos, S. procera spec. nov. (male, female) and S. bregibec spec. nov. (male) from Cambodia, S. bifidops spec. nov. from Malaysia (male), S. panay spec. nov. (female) and S. princesa spec. nov. (male, female) from Philippines. S. elberti (Strand 1913) is illustrated and partly re-described. Informal groups of species are proposed for the first time. Distribution ranges and habitat preferences are mapped. PMID- 30486008 TI - The family Hydropsychidae Curtis (Trichoptera) in the Ryukyu Archipelago, southwestern Japan. AB - The caddisfly family Hydropsychidae Curtis is revised for the Ryukyu Archipelago, southwestern Japan. Four new species are described based on adults: Diplectrona uken Ito and Nozaki sp. nov., Homoplectra crassicornea Nozaki and Ito sp. nov., Homoplectra trifurcata Nozaki and Ito sp. nov. and Cheumatopsyche aira Ito and Nozaki sp. nov. Based on examination of type specimens of species described from Taiwan in 1910-1930's: Cheumatopsyche uchidai Kobayashi 1987 and Hydropsyche yaeyamensis Tanida 1986 are synonymized with C. clavalis Martynov 1930 and H. orbiculata Ulmer 1911, respectively. Five East Asian species: Diplectrona burha Schmid 1961, Diplectrona albofasciata (Ulmer 1913), Cheumatopsyche clavalis Martynov 1930, Hydropsyche verrucosa (Ulmer 1911), and Macrostemum formosicolum (Matsumura 1931) are recorded from Japan for the first time and re-described. Adults of two known species, Cheumatopsyche okinawa Olah and Johanson 2008 and Macrostemum okinawanum (Matsumura 1931) are re-described. Females of five species, previously known only as males, are described for the first time. PMID- 30486009 TI - Geometric morphometry of the head in sand flies (Diptera: Psychodidae: Phlebotominae), an alternative approach to taxonomy studies. AB - Almost 30% of female American sand flies are morphologically indistinguishable from one another. These females belong to species-complexes or groups with closely related species, making species-level identification difficult or even impossible. This fact has implications for public health since several of these groups include species which are vectors of human pathogens. Thus, new tools are needed to minimize species-level identification problems. In this context, our research sought to use geometric morphometry in the study of the head of females of closely related species of the genus Psychodopygus, Chagasi series, which includes the following species: P. chagasi, P. complexus, P. squamiventris maripaensis, P. squamiventris squamiventris, and P. wellcomei. We have used ten landmarks distributed on the head of these species. All species were clearly distinguished using the centroid size and shape together. These results highlight the head analysis as an effective tool for future geometric morphometry studies in sand flies. PMID- 30486010 TI - A new species of Hisonotus (Siluriformes: Loricariidae) from Aripuana river, Amazon basin, Brazil. AB - A new species of Hisonotus from rio Juma, located at the right margin of the lower rio Aripuana, rio Madeira basin is described. The new species is distinguished from its congeners mainly by a reddish-tipped premaxillary and dentary teeth, a V-shaped spinelet, three lateral plates in abdominal series, the coloration pattern of caudal fin with three transversal dark bars, and by morphometric characters. PMID- 30486011 TI - Two new species of Aphelochaeta (Annelida: Polychaeta: Cirratulidae) from Korean waters. AB - Two new cirratulid polychaetes of the genus Aphelochaeta collected from Korean waters are reported here along with detailed descriptions and illustrations. Aphelochaeta petila n. sp. is readily distinguished from its congeners by the following characteristics: non-expanded anterior and posterior ends of the body; non-moniliform segments in the abdomen; peristomium with three annulations and an indistinct dorsal crest; both the dorsal tentacles and the first branchiae attached on the peristomium; presence of only a pair of branchiae on chaetiger 1; and the ventrum of the thoracic region with transverse dark blue stripes on the chaetigers 6-16 with methyl green staining. Aphelochaeta intinctoria n. sp. is characterized by a combination of the following features: a rounded prostomium; a peristomium with a dorsal crest; a non-expanded thoracic region; dorsal tentacles on the peristomium and the first pair of branchiae on chaetiger 1; and the thoracic region lacking a distinct methyl green staining pattern. These two new species from Korean waters also differ in details of chaetal ultrastructure. PMID- 30486012 TI - A new species of Agapophyta Guerin-Meneville, 1828 from the Tanimbar Islands, Indonesia (Hemiptera : Heteroptera: Tessaratomidae: Oncomerinae). AB - A new species of Agapophyta Guerin-Meneville, 1831 (Hemiptera: Heteroptera: Tessaratomidae: Oncomerinae), Agapophyta kmenti sp. nov., is described from the Tanimbar Islands, Indonesia, male and female genitalia are illustrated. The new species is close to Agapophyta aurantiaca Blote, 1945 and A. boschmai Blote, 1945. A table of diagnostic characters is given to separate the three species. PMID- 30486013 TI - An illustrated atlas for male genitalia of the New World Polistes Latreille, 1802 (Vespidae: Polistinae). AB - The male genitalia of 58 species of the New World Polistes are described: 29 of Polistes (Aphanilopterus), 12 of Polistes (Epicnemius), 13 of Polistes (Fuscopolistes), one of Polistes (Onerarius) and three of Polistes (Palisotius). Comments and remarks are also provided. PMID- 30486014 TI - Review of the genus Earinus Wesmael (Hymenoptera, Braconidae, Agathidinae) from China. AB - The Chinese species of Earinus Wesmael, 1837 (Braconidae, Agathidinae) are revised and eight species are recognized. Three new species, namely, E. longigena sp. nov., E. pallitarsus sp. nov. and E. protinus sp. nov., are described and illustrated, and two species are recorded from China for the first time, i.e., E. brevistigmus van Achterberg et Long, 2010 and E. elator (Fabricius, 1804). A new synonym is proposed, Earinus albopilosus Chen et Yang, 2006, with Therophilus festivus (Muesebeck, 1953). A key to the Chinese species of the genus Earinus is provided. PMID- 30486015 TI - New species of Trichomycterus (Siluriformes: Trichomycteridae) from the High Andean Plateau of Argentina. AB - Trichomycterus varii new species, is described from a small tributary of the High Andean Plateau Region, Jujuy, Argentina. The new species is distinguished from other species of Trichomycterus by the following characters: the caudal peduncle expanded in the area of procurrent caudal-fin rays, distal tip of pelvic fin not reaching the anus when depressed, the presence of fronto-lachrymal tendon bone without lateral process, the first pectoral-fin ray terminating at the margin of the fin, the distal margin of pectoral-fin rounded, seven pectoral fin rays, 15 19 interopercular odontodes, the supraorbital sensory canal with the presence of pore s3, the infraorbital sensory canal segment with the presence of pores i1 and i3, the laterosensory canal of trunk with three sensory pores, 16 pairs of ribs, 11 precaudal vertebrae, and 25 caudal vertebrae. It closely resembles T. yuska and T. pseudosilvinichthys from northwestern Argentina and western Bolivia, but differs in head canal sensory pattern. PMID- 30486016 TI - Revision of the family Carabodidae (Acari: Oribatida) XVI. Synkrotima tsalakpmenoi sp. nov. from Zimbabwe and Kenya, and Congocepheus thailandae sp. nov. from Thailand, including a complementary study of Cavaecarabodes hauseri (Mahunka 1989). AB - Synkrotima tsalakpmenoi sp. nov. is described from material collected in Zimbabwe and Kenya. This species presents the following characteristics: notogastral integument formed by longitudinally aligned cuticular cords; thick, lanceolate notogastral setae; and genital neotrichy. Synkrotima tsalakpmenoi sp. nov. is compared to S. zimbabwae. Congocepheus thailandae sp. nov. is the first species of this genus described from Thailand, with the following present: large finger like notogastral projection; notogastral setae c1, c2, da, dm, dp, la, lm, lp, h1, h2 situated on promontories; setae c1, c2 located adjacent and parallel. A complementary study of Cavaecarabodes hauseri, making use of Scanning Electron Microscopy (SEM), allows for clarification of particularities regarding complex setae as well as some aspects of the integument, and provides a more detailed diagnosis. PMID- 30486018 TI - Flesh flies (Diptera: Sarcophagidae) from a white-sand habitat in the Brazilian Amazon, with the description of four new species. AB - The white-sand enclaves in the Amazon Basin are small areas scattered through the tropical forest, with sandy and nutrient-poor soils and an unusual vegetation type. The insect fauna of this ecosystem is poorly known, especially in the eastern Amazon. The flesh fly fauna of an area of open herbaceous white-sand vegetation known as "Campo Redondo" in the municipality of Cameta, state of Para, was surveyed, resulting in the discovery of 43 species in 11 genera representing the subfamilies Sarcophaginae and Miltogramminae. Four new species are described: Dexosarcophaga (Dexosarcophaga) campina sp. nov., Helicobia cametaensis sp. nov., Helicobia domquixote sp. nov., and Metopia fofo sp. nov. Lepidodexia (Lepidodexia) grisea Lopes and Lepidodexia (Notochaeta) setifrons (Lopes) are newly recorded from Brazil. Dexosarcophaga (Bezzisca) ampullula (Engel), D. (Dexosarcophaga) transita Townsend and Titanogrypa (Cucullomyia) larvicida (Lopes) are newly recorded from the Brazilian Amazon. PMID- 30486017 TI - Two new species of the Genus Clathria (Demospongiae: Poecilosclerida: Microcionidae) from Jeju Island, Korea. AB - Two new species of sponge, Clathria (Clathria) ramus sp. nov. and Clathria (Clathria) ieoensis sp. nov. are described from Jeju Island of Korea. Clathria (Clathria) ramus sp. nov. is branching with a stalk, yellow in life, with small oscules. Clathria (C.) ieoensis sp. nov. is thickly encrusting, soft and compressible texture, and color is red and dark brown after fixation in ethanol. The new species are compared to other microcionids from the Korean region, and similar species from elsewhere. PMID- 30486019 TI - A new species of Alvinocaris (Crustacea: Decapoda: Caridea: Alvinocarididae) from Costa Rican methane seeps. AB - A new caridean shrimp, Alvinocaris costaricensis, is described from methane seeps in the eastern Pacific off Costa Rica. The new species is the 16th described species of the genus, and by molecular analysis appears closest to Alvinocaris komaii from the Lau Basin, southwestern Pacific, but shares certain morphological characters with A. lusca from the Galapagos Rift and A. muricola from the West Florida Escarpment, as well as with A. kexueae from the Manus Basin in the Southwest Pacific. PMID- 30486020 TI - New species of the genus Polyplectropus Ulmer 1905 (Insecta: Trichoptera: Polycentropodidae) from Indian Himalaya. AB - This paper is another contribution to the Indian caddisfly fauna of genus Polyplectropus Ulmer. Here, we describe and illustrate three new species of the genus from the Indian Himalaya: Polyplectropus sainii sp. nov. and Pol. himachalica sp. nov. (both from Himachal Pradesh) and Pol. kailashchandrai sp. nov. (from Uttarakhand). With these new additions, the genus is now represented by 7 species from India. PMID- 30486021 TI - Chironomus rishii sp. n., an enigmatic non-biting midge (Diptera: Chironomidae: Chironominae) from Neotropical region. AB - A new species of Chironomus Meigen, C. rishii (Diptera: Chironomidae: Chironominae) from Brazil, is described and figured as adults male and female, pupa and larva. Adults of C. rishii sp. n. can be recognized by the prominent scutal tubercle and the hypopygium with narrow, elongated and strongly hooked superior volsella. Pupae of this new species are indistinguishable from most of the described Neotropical species, while larvae may be separated by the mentum with deeply incised trifid median tooth and 7 pairs of lateral teeth and the absence of lateral and ventral tubules. This last feature would place C. rishii sp. n. within the 'salinarius group'. However, this is not a group in the systematic sense, but an artificial grouping equivalent to a morphotype that reflects only the tubule character state. It is suggested that the absence of tubules is an adaptation for tolerating a wide range of salinity levels, however the 'salinarius group' had been also recorded in freshwater environments. Here, larvae without abdominal tubules were found in an environment with low levels of salinity, which indicates that the tubule condition may be result of further abiotic pressures, and configures a rather enigmatic scenario to this feature, particularly when considered the fact that larvae of Chironomus having tubules had also been recorded at the same habitat, living under similar conditions of C. rishi sp. n. PMID- 30486022 TI - A Revised Checklist of the UK Silverfish (Zygentoma: Lepismatidae). AB - With the discovery of Ctenolepisma longicaudata by Goddard et al. (2016) and the record of Ctenolepisma lineata as a possible introduced pest by Notton (2018), as well as the changes to the higher classification reported by Barnard (2011), the current number of UK Lepismatidae (silverfish and firebrats) that an entomologist might encounter has doubled. Therefore, the most recent checklist (Kloet Hicks 1964) is in need of revision. This paper aims to provide an updated check list, guide to keys that can be used to Identify UK Lepismatidae as well as to provide an overview of UK species. PMID- 30486023 TI - Systematic revision of the living African Slender-snouted Crocodiles (Mecistops Gray, 1844). AB - Molecular and morphological evidence has shown that the African slender-snouted, or sharp-nosed, crocodile Mecistops cataphractus (Cuvier, 1824) is comprised of two superficially cryptic species: one endemic to West Africa and the other endemic to Central Africa. Our ability to characterize the two species is compromised by the complicated taxonomic history of the lineage and overlapping ranges of variation in distinguishing morphological features. The name M. cataphractus was evidently originally based on West African material, but the holotype is now lost. Although types exist for other names based on the West African form, the name M. cataphractus is sufficiently entrenched in the literature, and other names sufficiently obscure, to justify retypification. Here, we designate a neotype for M. cataphractus and restrict it to West Africa. We resurrect M. leptorhynchus as a valid species from Central Africa and identify exemplary referred specimens that, collectively, overcome the obscurity and diagnostic limits of the extant holotype. We additionally indicate suitable neotype material in the event the holotype is lost, destroyed, or otherwise needing replacement, and we rectify the previously erroneous type locality designation. We provide a revised diagnosis for crown Mecistops, and revise and update previous descriptions of the two living species, including providing both more complete descriptions and discussion of diagnostic characters. Finally, we provide considerable discussion of the current state of knowledge of these species' ecology, natural history, and distribution. PMID- 30486025 TI - Five new species of the tribe Gyrophaenina Kraatz 1830 (Coleoptera: Staphylinidae: Aleocharinae) from the southern part of the United States. AB - Four new species of Gyrophaena Mannerheim, 1830 and one of Phanerota Casey, 1906 from southern states of the USA are described and illustrated: G. affinifera Enushchenko, sp.n. (Alabama), G. fontanedai Enushchenko, sp.n. (Alabama, Florida), G. marjakata Enushchenko, sp.n. (Arizona), G. velada Enushchenko, sp.n. (Arizona), and Ph. paradissimilis Enushchenko, sp.n. (Florida). A new species group is erected, the nitidula-group, containing G. nitidula (Gyllenhal 1810), G. pseudonitidula Semenov 2015 and G. fontanedai Enushchenko, sp.n., and a key for the species of this group is given. PMID- 30486024 TI - Two new species of the genus Narcotica Sugi, 1982 (Lepidoptera: Noctuidae: Acronictinae). AB - This paper deals with the taxonomy of the genus Narcotica Sugi, 1982, known from China, Japan and the Korean Peninsula. Two species, Narcotica cryptica sp. n. from China and South Korea and Narcotica hoenei sp. n. from China are described as new to science. Images of adults, genitalia and, for the first time, abdominal segments of both sexes are presented. PMID- 30486026 TI - Resolving two Haploembia (Embioptera: Oligotomidae) cryptic species: molecular data confirms parthenogenetic females can be distinguished by their antisocial behavior. AB - The names of two cryptic species of Haploembia found in California are resolved and methods for identification are summarized. Molecular data of the Histone III subunit was used to evaluate color and behavior as species identifiers, confirming that antisocial behavior is a good identifier for the parthenogenetic species (Haploembia tarsalis), whereas the more variable coloration patterns were helpful, but less so. A genome size ratio of 1.44 between the parthenogenetic H. tarsalis and the sexually reproducing H. solieri was observed, along with higher genetic variation within the asexual lineage. This, and the identification of what appears to be a putative hybrid, contributes to current work examining mutation rates and selective pressures on genome size in parthenogenetic populations. PMID- 30486027 TI - A new species of the hermit crab genus Diogenes Dana, 1851 (Decapoda: Anomura: Diogenidae) from southern India. AB - A new species of the hermit crab genus Diogenes Dana, 1851, D. spongicola, is described and illustrated on the basis of material collected from two locations off southern India. It appears close to D. takedai Rahayu, 2012 among about 70 congeners, but easily differentiated from the latter by the spinulose anterolateral margins of the shield, the article 2 of the antennal peduncle armed only with one distal spine, the longer, spinose antennal acicle, the absence of prominent spines on the ventrolateral margin of the cheliped meri, and the different color of the cheliped palm. Specimens of the new species were all collected from cavities of a callyspongiid sponge Callyspongia diffusa (Ridley, 1884), suggesting a possible association between the hermit crab and sponge. PMID- 30486028 TI - A new species of Chimarra from China (Trichoptera, Philopotamidae) with description of its larva. AB - The adult male and larva of a new species in the genus Chimarra Stephens, Chimarra paramonorum n. sp., are described, diagnosed, and illustrated based on the specimens collected in Zhejiang Province, China. The larva and adult male were associated by mtCOI gene sequences. The male can be separated from C. monorum and C. thienemanni mainly by small preanal appendages and by wrinkled, hairless endotheca. The larva of the new species can be separated from other congeners by a combination of characters including the notch on the anterior margin of the frontoclypeus, the teeth of the mandibles, and the length of the seta-bearing process of each forecoxa. The larval description is the first for Chimarra in China. PMID- 30486029 TI - Rhamphothrips genus-group (Thysanoptera, Thripidae) in Japan, with three new species. AB - In Japan, no members of Rhamphothrips genus-group have hitherto been known, but three species of this group are here newly described from Japan: Exothrips yaeyamanus sp. n., Rhamphothrips nemunoki sp. n. and R. ogasawarensis sp. n. Moreover, an uncertain species of Exothrips is recorded from Okinawa on Poaceae. PMID- 30486030 TI - A new species of the genus Isoperla (Plecoptera: Perlodidae) from TIANMU MOUNTAIN NATURE RESERVE, China. AB - A species of the genus Isoperla Banks, 1906, I. oncocauda Huo Du, sp. nov. is described as new to science and is the first record for the family Perlodidae from the Tianmu Mountain Nature Reserve, Zhejiang Province of eastern coastal China. Both sexes of the new species are characterized by tergum 10 with a developed process. The partially extruded aedeagus of the male is membranous without conspicuous larger sclerites and with the ventral surface covered with dense scale-like and nail-shaped spines. PMID- 30486031 TI - Newly recorded leafhoppers of the subfamily Cicadellinae (Hemiptera: Cicadellidae) with description of a new species from Pakistan. AB - Pakistani species of the leafhopper subfamily Cicadellinae are reviewed. One new species, Atkinsoniella fistular sp. nov., is described and illustrated, and three species are newly recorded from Pakistan and illustrated: Atkinsoniella opponens Walker, 1851 n. rec., Atkinsoniella thalia Distant, 1918 n. rec. and Kolla insignis Distant, 1908 n. rec.. A key is given to distinguish all the genera (males) in this subfamily from Pakistan. PMID- 30486032 TI - The larva of Hydropsyche perseus Malicky 2001, endemic to Kerkyra (Corfu) Island, including a key for the known Hydropsyche larvae of the Greek islands. AB - The larva of Hydropsyche perseus Malicky 2001, endemic species of Kerkyra Island (Corfu), Greece, is described for the first time. The diagnostic features of the species are described and illustrated, and some information regarding its ecology is included. In addition, a tabular key for larvae of the known Hydropsyche species of the Greek Islands is provided. PMID- 30486033 TI - A new Lamellibrachia species and confirmed range extension for Lamellibrachia barhami (Siboglinidae, Annelida) from Costa Rica methane seeps. AB - Lamellibrachia Webb, 1969 has eight currently recognized species reported from chemosynthetic environments in the Pacific, Atlantic, and Mediterranean. Of these, Lamellibrachia barhami Webb, 1969 has been reported in the eastern Pacific from Canada to Costa Rica. In this study, phylogenetic analyses of Lamellibrachia tubeworms sampled from the Costa Rica margin confirm the large geographic range of L. barhami and reveal a new Lamellibrachia species from a single methane seep between 999 and 1,040 meters. Lamellibrachia donwalshi sp. nov. differs genetically and morphologically from all congeneric species. Despite its geographic proximity to the eastern Pacific L. barhami, L. donwalshi sp. nov. formed a clade with Atlantic and Mediterranean Lamellibrachia species. This suggests a vicariant event may have occurred after an Atlantic radiation of Lamellibrachia. PMID- 30486034 TI - Contribution to the Trichoptera fauna of the river La Vieja, Bogota, Colombia (Insecta: Trichoptera). AB - Investigation of the Trichoptera fauna from the small river La Vieja on the city border of Bogota yielded a total of 17 species. Nine new species of Trichoptera are described from La Vieja: Atopsyche viejae spec. nov., A. flavoantennata spec. nov., Metrichia trisignata spec. nov., M. longiphallata spec. nov., Smicridea colombosaucia spec. nov., Xiphocentron laviejae spec. nov., Phylloicus monserratensis spec. nov., Marilia bogotaensis spec. nov., and Oecetis chapinera spec. nov. Images of the adults of some species are provided, and the male genitalia are illustrated. The genitalia of three additional species (Hydroptila constricta Bueno-Soria 1984, Polycentropus joergenseni Ulmer 1909, Contulma spec.) are depicted to facilitate their future identifications. PMID- 30486035 TI - An update to the taxonomy of the genus Macroderes Westwood 1842 (Coleoptera: Scarabaeidae: Scarabaeinae) with descriptions of new species from South Africa. AB - The genus Macroderes Westwood, 1842 (Scarabaeidae: Scarabaeinae, tribe incertae sedis) is practically endemic to South Africa with only one species that is found little north in southern Namibia. The ranges of the species are limited to the winter-fall and bimodal biomes of South Africa comprising the regions of Richtersveld as extreme points of its northerly distribution, and extending to the south through Namaqualand to Cape Agulhas. The taxonomy of the genus is revised. Fourteen valid species are recognised and three others are of doubtful validity. Seven new species are described, these are: M. cederbergensis Abdalla Deschodt, new species, M. tortuosus Abdalla Scholtz, new species, M. gifboomi Abdalla Scholtz, new species, M. leipoldti Abdalla Deschodt, new species, M. oreatus Abdalla Deschodt, new species, M. porselinus Abdalla, new species, and M. soleiana Abdalla Deschodt, new species. Macroderes nitidus Harold, 1877 is redescribed and its lectotype is designated. The diagnostic characters as well as an updated geographic distribution of each species are summarised. An updated key of the genus, photographs of habitus, sclerites of internal sac, pronotum, pronotal punctures and elytra also are provided. PMID- 30486036 TI - Hidden gems in museum cabinets: new species and new distributional records of Scolytodes (Coleoptera: Scolytinae). AB - Twenty-one new species of Scolytodes Ferrari are described from Central and South America: Scolytodes cavus Jordal, sp. nov., Scolytodes excavatus Jordal, sp. nov., Scolytodes speculofrons Jordal, sp. nov., Scolytodes potens Jordal, sp. nov., Scolytodes minimus Jordal, sp. nov., Scolytodes setosicauda Jordal, sp. nov., Scolytodes monticola Jordal, sp. nov., Scolytodes aureifrons Jordal, sp. nov., Scolytodes piliscapus Jordal, sp. nov., Scolytodes curvicostatus Jordal, sp. nov., Scolytodes vellus Jordal, sp. nov., Scolytodes granulatus Jordal, sp. nov., Scolytodes bipilosus Jordal, sp. nov., Scolytodes asperatus Jordal, sp. nov., Scolytodes flavifrons Jordal, sp. nov., Scolytodes capillus Jordal, sp. nov., Scolytodes rufus Jordal, sp. nov., Scolytodes johnsoni Jordal, sp. nov., Scolytodes longipilus Jordal, sp. nov., Scolytodes prolatus Jordal, sp. nov., and Scolytodes bicarinatus Jordal, sp. nov. Females of two species were associated with males and described for the first time: Scolytodes pelicipennis (Schedl, 1952) from Mexico, and Scolytodes venustulus Wood, 1967 from Costa Rica. New synonymies were inferred in four species: Scolytodes bolivianus Eggers, 1928 (=Scolytodes aequipunctatus Eggers, 1943 syn. nov.); Scolytodes major Eggers, 1928 (=Scolytodes argentinensis Eggers, 1943 syn. nov.; =Scolytodes boliviensis Eggers, 1928; =Scolytodes similis Eggers, 1928 syn. nov.); Scolytodes ingae (Blackman, 1943), stat. nov. (=Scolytodes trigonus Jordal, 2013 syn. nov.); Scolytodes canalis Wood, 1974 (=Scolytodes amabilis Wood, 1975 syn. nov.). New country records are reported for 13 species: S. alni Wood, 1969 (Panama), S. bolivianus (Brazil), S. canalis Wood, 1974 (Guatemala), S. chapuisi Wood, 1977 (Peru, Brazil), S. costabilis Wood (Costa Rica), S. elongatus Schedl, 1935 (Panama), S. immanis Wood, 1969 (Panama), S. ingae (Blackman, 1943) (Panama), S. irazuensis Wood, 1969 (Panama), S. major (Honduras, Brazil), S. pelicipennis (Schedl, 1952) (Mexico), S. triangulus Jordal, 1998 (Panama), S. unipunctatus (Blandford, 1897) (Panama, Venezuela), S. venustulus Wood, 1967 (Costa Rica). PMID- 30486037 TI - The identity of Osteobrama cotio, and the status of "Osteobrama serrata" (Teleostei: Cyprinidae: Cyprininae). AB - Osteobrama cotio is considered to be a widespread species in India and Bangladesh. Mitochondrial DNA (COI, 16S rRNA) shows that populations from the Meghna River, Karnafuli and Sangu Rivers, Narmada River, and Godavari River are genetically distinct from each other. No morphological differences were found to separate Meghna and Karnafuli+Sangu populations, however. A putative new species, "Osteobrama serrata" has been described from the Barak River basin, stated to be distinguished from O. cotio by the presence of a serrated third dorsal-fin ray. The description of "O. serrata" does not fulfil requirements of the International Code of Zoological Nomenclature, (International Commission on Zoological Nomenclature 1999) and the name is thus unavailable. Published DNA sequences of "Osteobrama serrata" are identical to sequences of O. cotio from Bangladesh. As mentioned already in the original description, O. cotio has a serrated third dorsal-fin ray. PMID- 30486038 TI - One new species and one new record of the species of the family Comesomatidae (Nematoda: Chromadorida) from the South China Sea. AB - One new and one known species of the family Comesomatidae were collected from marine sediments in the South China Sea. Cervonema longispicula sp. nov. has stout cephalic setae, elongated and curved spicules with cephalated proximal end, and gubernaculum with hook-like dorsal apophysis that make the new species easily recognizable from the other 18 recorded Cervonema species. Paracomesoma zhangi Huang Huang, 2018 was redescribed based on more specimens of males and females. These specimens are in accordance with the characteristics of holotype from the East China Sea except having more precloacal supplements (30-39), males slightly smaller (not longer than 1710 um) and with shorter cephalic setae (not longer than 10 MUm). PMID- 30486039 TI - A new species of Cephaloecetes (Bubocorophiina) from the Iranian coasts of the Gulf of Oman and the Hormuz Strait (Crustacea: Amphipoda: Siphonoecetini). AB - The first member of Cephaloecetes in the north-western part of the Indian Ocean, Cephaloecetes ungulatus sp. nov., is described from Chabahar Bay, the Gulf of Oman and Qeshm Island in the western Hormuz Strait, Iran. The new species is characterized from the other two species of genus Cephaloecetes by a unique claw shaped ventral plate on antenna 2 article 2. PMID- 30486040 TI - Description of a new species from the genus Eugoa Walker, 1858 (Lepidoptera: Erebidae: Arctiinae) from the Solomon Islands. AB - The genus Eugoa Walker, 1858 belongs to the tribe Lithosiini and occurs across the Old World, excluding the Western Palearctic Region. Currently, it contains around 120 species, most of them distributed across Asia (Bucsek 2016a, b; Dubatolov Bucsek 2016; Schaus 1922). Ten additional species have been described from Australasia (Bethune-Baker 1904; Rothschild 1915). Since the 19th century, several authors have addressed the taxonomy of the genus Eugoa (Buscek 2008, 2012, 2016a, b; Cerny Bucsek 2014; Hampson 1891, 1898, 1900; Rothschild 1915; Seitz 1914; Van Eecke 1930), but only a few described their habitat preferences (e.g. Holloway 2001). These small to medium sized moths with brown, or brown cream coloured forewings inhabit a wide range of forest types (e.g. alluvial, dipterocarp, heath, kerangas, etc.) from mangroves and lowland-coastal forests (about 300m asl) up to upper montane forests (about 1500 m asl). Unfortunately, life history data for species in the genus Eugoa still remain unavailable. PMID- 30486041 TI - Description and development of the tadpole of Rhacophorus feae (Anura; Rhacophoridae). AB - The genus Rhacophorus Kuhl Van Hasselt is currently known to contain 92 species of frogs (Frost 2018), distributed across south and south-east Asia. Rhacophorus feae Boulenger is a large member of this genus and has a seemingly expansive range been recorded from southern Yunnan in China, the Karen hills in Myanmar, northern Thailand, northern Laos and northern Vietnam (Chanard et al. 1999; Orlov et al. 2002; Nguyen et al. 2005; Stuart 2005; Yang 2008). It is currently included in the intrageneric R. dennysi group (Dubois 1986) along with R. duboisi Ohler, Marquis, Swan Grosjean , R. dennysi Blanford, R. dugritei (David), R. minimus Rao, Wilkinson Liu, R. hungfuensis Liu Hu, R. dorsoviridis Bourret, R. nigropunctatus Liu, Hu Yang, and R. smaragdinus (Blyth). PMID- 30486042 TI - A new synonymy in East Asian Urostylididae (Hemiptera: Heteroptera). AB - Urostylididae is a moderately species-rich family of phytophagous, mainly arboricolous pentatomoid true bugs (Hemiptera: Heteroptera) currently comprising 8 genera and 172 species (Rider et al. 2018). All described species occur in Asia, but undescribed taxa are present in Madagascar (P. Stys, pers. comm.). The present short paper was prompted by a recent contribution by Kim et al. (2018), who reviewed the species of the genus Urostylis Westwood, 1837, occurring in Korea, including the description of a purportedly new species, U. koreana Kim Jung, 2018. The identity of the latter species is clarified below, with proposal of a new subjective synonymy. PMID- 30486043 TI - The genus Leucophenga (Diptera, Drosophilidae), part VIII: twenty-one species from the Oriental region, with morphological and molecular evidence. AB - Twenty-one (six known and 15 new) species of the genus Leucophenga from the Oriental region are described or redescribed: L. jacobsoni Duda, 1926; L. kurahashii Okada, 1987; L. setipalpis Duda, 1923; L. sorii Kang, Lee Bhang, 1965; L. spinifera Okada, 1987; L. varinervis Duda, 1923; L. acantha Huang Chen, sp. nov.; L. alafumosa Huang Chen, sp. nov.; L. brevipenis Huang Chen, sp. nov.; L. brevitabulata Huang Chen, sp. nov.; L. delta Huang Chen, sp. nov.; L. forcipula Huang Chen, sp. nov.; L. fuscipalpula Huang Chen, sp. nov.; L. glabtabulata Huang Chen, sp. nov.; L. helvipecta Huang Chen, sp. nov.; L. hyaloptera Huang Chen, sp. nov.; L. oxyptera Huang Chen, sp. nov.; L. platypyga Huang Chen, sp. nov.; L. serrateiceps Huang Chen, sp. nov.; L. valvata Huang Chen, sp. nov.; L. zebrina Huang Chen, sp. nov. A key and a morphological summary table to all these Leucophenga species are provided. Phylogenetic relationships among these 21 Leucophenga species, another 14 congeneric, known species from seven groups, and two representative outgroup taxa are reconstructed using 169 DNA sequences of the partial mitochondrial cytochrome c oxidase subunit I (mtCOI) gene. In sum, 13 of the 21 Leucophenga species, which possess the only diagnostic character of the proxima species group (abdominal third tergite shortened, anteriorly discolored in males), are not monophyletic. Therefore, all the Leucophenga species described or redescribed in this study are temporarily classified as unplaced species (except for L. sorii, which has been assigned to the sorii species group) to avoid further confusion. PMID- 30486044 TI - An annotated checklist of the marine brachyuran crabs (Crustacea: Decapoda: Brachyura) of India. AB - An annotated checklist of the marine brachyuran crabs occurring in India is compiled from published literature and augmented by collections between 2005 and 2015. A total of 910 species belonging to 361 genera and 62 families are herein listed from Indian waters. Specimens representing 130 species were obtained from Gujarat state during 2005 and 2015, of which 23 are new records to Gujarat state and two species are reported for the first time from the west coast of India. The highest number of species were recorded from the Andaman and Nicobar islands (588 species) while the smallest number were from Goa and Karnataka state (82 species). The records indicate that the east coast of India, with 803 species, is more diverse than the west coast, which has 446 species. PMID- 30486045 TI - Raoiella of the world (Trombidiformes: Tetranychoidea: Tenuipalpidae). AB - We describe 16 new species and redescribe six established species in the genus Raoiella-R. argenta sp. nov. Beard, R. australica Womersley, R. bauchani sp. nov. Beard Ochoa, R. calgoa sp. nov. Beard Ochoa, R. crebra sp. nov. Beard Ochoa, R. davisi sp. nov. Beard, R. didcota sp. nov. Beard, R. eugeniae (Mohanasundaram), R. goyderi sp. nov. Ochoa Beard, R. hallingi sp. nov. Beard, R. illyarrie sp. nov. Beard Ochoa, R. indica Hirst, R. karri sp. nov. Ochoa Beard, R. macfarlanei Pritchard Baker, R. marri sp. nov. Beard Ochoa, R. pandanae Mohanasundaram, R. pooleyi sp. nov. Beard Ochoa, R. shimpana Meyer, R. tallerack sp. nov. Beard Ochoa, R. taronga sp. nov. Beard Ochoa, R. todtiana sp. nov. Beard Ochoa, R. wandoo sp. nov. Beard Ochoa. We discuss molecular evidence of species separation, shared character states among groups of species, and patterns in the additions of leg setae throughout ontogeny that occur in the genus. We provide a key to the known species of Raoiella. PMID- 30486046 TI - Acarine biocontrol agents Neoseiulus californicus sensu Athias-Henriot (1977) and N. barkeri Hughes (Mesostigmata: Phytoseiidae) redescribed, their synonymies assessed, and the identity of N. californicus (McGregor) clarified based on examination of types. AB - In 1954, McGregor described two species of phytoseiids from lemon, in California, USA: Typhlodromus californicus McGregor and T. mungeri McGregor, the former represented by one male, and the latter by two females. Since its description, T. mungeri was synonymised under T. californicus, and the name T. (now Neoseiulus) californicus has been used extensively to represent a species that is now commonly used as a biocontrol agent of crop pests worldwide. However, the true identity of the biocontrol agent is uncertain because the original descriptions of T. californicus and T. mungeri were not adequate enough to allow an irrefutable identification, with each description being based on specimens of a single sex. An examination of the types of N. californicus and N. mungeri revealed that they are morphologically identical to the male and female of N. barkeri Hughes, 1948, respectively, and that they are in fact junior synonyms of N. barkeri-and are therefore distinct from the biocontrol agent globally called N. californicus (sensu Athias-Henriot, 1977; see Griffiths, 2015). This is further supported by a comparison with male and female syntypes of N. barkeri, as well as other specimens of N. barkeri including some collected from the type host in the vicinity of the type location (i.e. lemon in southern California, 1952 1958). We redescribe the male and female of both N. barkeri and N. californicus sensu Athias-Henriot (1977), based on representative specimens from at least 14 and 19 populations, respectively. Based on examination of types, we confirm the synonymy of N. mckenziei (Schuster Pritchard, 1963), N. picketti (Specht, 1968), and N. oahuensis (Prasad, 1968) with N. barkeri, and that the names N. chilenensis (Dosse, 1958b) and N. wearnei (Schicha, 1987) represent the same species as N. californicus sensu Athias-Henriot (1977). We also provide a hypothesis as to why Chant (1959) had erroneously synonymised T. californicus and T. mungeri under T. marinus (Willmann). Finally, we suggest maintaining the prevailing usage of the name N. californicus (McGregor) for the species concept of Athias-Henriot (1977) as followed by subsequent authors, through submission of a separate application to the International Commission of Zoological Nomenclature (ICZN). In the meantime, the current meaning of N. californicus should be maintained until a ruling by the ICZN is made on the application. PMID- 30486047 TI - A new species of the genus Allopsontus Silvestri (Archaeognatha: Machilidae) from the Eastern Kazakhstan. AB - A new bristletail species, Allopsontus ilyai sp. nov., is described from Eastern Kazakhstan. It is most similar to A. smelyanskii Kaplin described from Orenburg Region (Russia). The main differences between these species consist in the color of the eyes, structure of the paired ocelli, legs, urosternites, urocoxites VIII and IX. A key to the subgenera and species of the genus Allopsontus from Kazakhstan is given. PMID- 30486048 TI - Taxonomic revision of four species of the Neotropical land planarian genera Cratera and Geoplana (Platyhelminthes, Tricladida) with a description of two new species and an emendation of Cratera. AB - The Brazilian land planarians Cratera crioula, C. joia, Geoplana hina, and G. taxiarcha (Platyhelminthes, Tricladida, Geoplanidae) are revised taxonomically from type material and additional specimens. Geoplana hina sensu Carbayo et al. (2013) was found to be an undescribed species and therefore is described and named as Cratera picuia sp. n. A new species of the genus is also described and named as Cratera arucuia sp. n. G. hina and G. taxiarcha are transferred to Cratera. The most remarkable morphological feature of Cratera-a dilated terminal portion of the ejaculatory duct-is either absent, inconspicuous, or variable in C. hina, C. joia, C. picuia sp. n., and C. arucuia sp. n. Based on the monophyletic status of Cratera inferred elsewhere, an emendation of the genus is here proposed to encompass the morphological variation observed in the genus. PMID- 30486049 TI - Two new genera of hard ticks, Robertsicus n. gen. and Archaeocroton n. gen., and the solution to the mystery of Hoogstraal's and Kaufman's "primitive" tick from the Carpathian Mountains. AB - We establish two new monotypic genera, Robertsicus n. gen. and Archaeocroton n. gen., based on two enigmatic species of Amblyomma. Robertsicus, with the type species R. elaphensis (Price, 1959) n. comb., is proposed for Amblyomma elaphense, the tick of the Trans-Pecos rat-snake of the Chihuahuan Desert of Mexico and southeastern USA (parts of Arizona, West Texas and New Mexico). Archaeocroton, with the type species Ar. sphenodonti (Dumbleton, 1943) n. comb., is proposed for Amblyomma sphenodonti, the tuatara tick of New Zealand. This is another step in the resolution of the systematic problems concerning the genus Aponomma, a heterogeneous group of eyeless ticks with a predilection for reptiles. By removing R. elaphensis (Price, 1959) and Ar. sphenodonti (Dumbleton, 1943) from the genus Amblyomma we have resolved, for now at least, the polyphyly of the genus Amblyomma. We have also resolved a 50-year old mystery: the identity of Hoogstraal's and Kaufman's "primitive" tick from the Carpathian Mountains that had a "striking resemblance" to Ar. sphenodonti n. comb.; it was an Ar. sphenodonti n. comb. that had travelled to the Carpathian Mountains from New Zealand on a captive tuatara. PMID- 30486051 TI - Morphology and description of infraciliary bands pattern in four Metadinium Awerinzew Mutafowa, 1914 species (Ciliophora, Entodiniomorphida, Ophryoscolecidae) with taxonomic notes on the genus. AB - The genus Metadinium includes ophryoscolecid ciliates, with two retractile ciliary zones in the anterior body portion, two broad skeletal plates, a lobed macronucleus and two contractile vacuoles. Species belonging to this genus were recorded in several geographical locations and in different host species. However, they were mostly described based on a single ciliatological technique, and until now, there is only one description of the infraciliary pattern in Metadinium ciliates (Metadinium medium). The present study performs the morphological and infraciliature characterization of four species belonging to Metadinium: M. esalqum, M. minorum, M. rotundatum and M. ypsilon; and presents taxonomic notes on the genus. The oral infraciliature in these four Metadinium species corresponds to the Diplodinium-type, pattern shared with genera Diplodinium, Diploplastron, Eudiplodinium, Eremoplastron and Polyplastron. A brief review conducted highlights the difficulty of delimiting Metadinium species due to the morphological similarity among them. PMID- 30486050 TI - A new species of Crocodile Newt Tylototriton (Caudata: Salamandridae) from Shan State, Myanmar (Burma). AB - A phylogenetic taxonomic analysis of a monophyletic subgroup of the salamandrid genus Tylototriton revealed that a newly discovered population from Ngar Su Village, 1 km south of Ywangan, Shan State, Myanmar is a new species and most closely related to T. shanorum from approximately 80 km to the west in the vicinity of Taunggyi, Shan State. Tylototriton ngarsuensis sp. nov. differs from other closely related species of Tylototriton on basis of varying combinations of characteristics associated with it shorter head, larger size, rib nodule morphology, and overall drab, very dark, coloration, along with its genetic differentiation. Tylototriton ngarsuensis sp. nov. also appears to breed later in the year than most other species. Unfortunately, this species like many other Asian newts, is being harvested for the pet and medicinal trade and given its restricted distribution, this could pose a serious threat to its long-term survival. PMID- 30486052 TI - Description of Neptosternus haibini sp. nov. from China (Coleoptera: Dytiscidae: Laccophilinae). AB - Neptosternus haibini sp. nov. is described from Guangdong Province, China. The new species is very similar to N. wewalkai Balke, Hendrich Yang, 1997, from which it can be recognised only by the shape of the male genitalia. The habitus and genitalia of both species are illustrated. Neptosternus pocsi Sato, 1972 is recorded from China (Yunnan province), and the Palaearctic region, for the first time. Currently, eight species of Neptosternus are known from China; a key to Chinese Neptosternus is provided. PMID- 30486053 TI - A new species of freshwater crab of the genus Teretamon Yeo Ng, 2007 (Decapoda: Brachyura: Potamidae) from Arunachal Pradesh, northeastern India. AB - A new species of potamid crab of the genus Teretamon Yeo Ng, 2007, is described from Namdapha Tiger Reserve in Changlang district of Arunachal Pradesh, India. The new species, T. kempi n. sp., can be distinguished from its congeners by a distinct combination of carapace and gonopod characters: a relatively high carapace with a bilobed frontal margin; subquadrate sixth abdominal somite with nearly parallel lateral margins; and a relatively small G1 terminal segment with a semicircular to bluntly triangular dorsal flap. All known Teretamon species are compared with the new species, and a key for this genus is provided. PMID- 30486054 TI - Review of Sebadexius Ledoyer, 1984 (Amphipoda, Dexaminidae, Dexamininae) based on new material from The Philippines, with Sebadexius cebuense sp. nov. AB - The amphipod genus Sebadexius Ledoyer, 1984 (New Caledonia) is reviewed, based on new material from Cebu in The Philippines. Some characters are re-interpreted, and a new species, Sebadexius cebuense, is described. PMID- 30486055 TI - Five new Lathys species (Araneae: Dictynidae) from South China and the first description of the male of Lathys spiralis Zhang, Hu Zhang, 2012. AB - Dictynidae spiders were collected from Jinggang Mountain National Nature Reserve, Jiangxi Province, China in the past four years. Five new species are described and illustrated with photographs, SEMs and line drawings: Lathys adunca Liu spec. nov. (male), L. deltoidea Liu spec. nov. (female), L. fibulata Liu spec. nov. (female), L. huangyangjieensis Liu spec. nov. (male, female) and L. zhanfengi Liu spec. nov. (female). Both sexes of the species L. spiralis Zhang, Hu Zhang, 2012 were collected from leaf litter in Jinggangshan University and the male is described for the first time. All specimens are deposited in the Animal Specimen Museum, Life Science College, at the Jinggangshan University (ASM-JGSU). PMID- 30486056 TI - A new genus of Rhaphidophorinae (Orthoptera, Rhaphidophoridae) from China. AB - In this article, a new genus Sinorhaphidophora gen. nov., three new combinations: Sinorhaphidophora hainanensis (Bian Shi, 2016) comb. nov., Neorhaphidophora brevispinula (Bian, Zhu Shi, 2017) comb. nov., Neorhaphidophora longispinula (Bian, Zhu Shi, 2017) comb. nov. and three new species of Rhaphidophora Audinet Serville, 1838: Rhaphidophora quadridentata sp. nov., Rhaphidophora setiformis sp. nov., Rhaphidophora wuzhishanensis sp. nov. are proposed. Keys to all genera of Rhaphidophorinae and all species of Rhaphidophora from China are given. And the female of Rhaphidophora sichuanensis Liu Zhang, 2002 is also added. PMID- 30486058 TI - Scolopsis meridiana, a new species of monocle bream (Perciformes: Nemipteridae) from northern Australia. AB - Scolopsis meridiana n. sp., described from 30 specimens collected from northern Australia, is closely related to S. taenioptera, both species having a dorsal scaled area on the head extending anteriorly to between the anterior margin of the eye and anterior nostril, the upper part of the pectoral-fin base with a reddish blotch when fresh, and lacking a small antrorse spine below the eye. However, the new species is distinguished from the latter by having two bands across the snout dorsum (vs. one band in S. taenioptera), 18-20 diagonal lines on the lateral body surface below the lateral line (diagonal lines absent), the posterior nostril horizontally elongated (vertically elongated), a deep caudal peduncle and short pre-dorsal-fin length. Scolopsis meridiana is distributed in northern Australia, whereas S. taenioptera occurs in Southeast Asia. Two geographic populations of S. taenioptera (Philippines and remaining Southeast Asian region) are recognized following morphological and genetic analyses. PMID- 30486057 TI - Diversity of Armenian mayflies (Ephemeroptera) with the description of a new species of the genus Ecdyonurus (Heptageniidae). AB - We provide the first commented checklist of Armenian mayflies, based on all relevant literature and recent extensive sampling of 72 localities throughout Armenia during 2011, 2014, and 2015. Altogether 46 species are listed, eight of them reported from Armenia for the first time. One new species, Ecdyonurus (Ecdyonurus) eurycephalus sp. nov. is described (larva and male imago) based on morphological and molecular (COI) data. The species is characterized by a unique head shape in male imago and by the presence of tracheal filaments on gill plate VII in the larval stage. PMID- 30486059 TI - A review of the beaded lacewings (Neuroptera: Berothidae) from China. AB - The lacewing family Berothidae (beaded lacewings) of China is a poorly known group. It consists of two genera and 11 previously described species. In this paper, we provide a revision of the beaded lacewings from China. The genus Berotha Walker, 1860, in China contains seven species including one new species: Berotha guangdongana sp. nov. The second genus, Isoscelipteron Costa, 1863, comprises six species from China, including one new species, namely Isoscelipteron acuticaudatum sp. nov. Descriptions and re-descriptions of the species are provided as well as an identification key to the species of Berothidae from China. PMID- 30486060 TI - New species, records, and immature stages of Chimarra Stephens (Trichoptera: Philopotamidae) from Campos Amazonicos National Park, northern Brazil. AB - Campos Amazonicos National Park is a federal conservation unit that contains part of the largest Cerrado refuge in the southern part of Brazilian Amazonia. Recently, during a survey of aquatic insects in the park, specimens of the caddisfly genus Chimarra were collected. The primary objective of this paper, as a result of this effort, is to describe and illustrate the male adult of a new species in Chimarra (Chimarrita), Chimarra singularis sp. nov., and the immature stages of Chimarra usitatissima Flint 1971. Additionally, the distributions of C.(Chimarrita) akantha Blahnik 1997 and C. (Curgia) jugescens Flint 1998 are extended to the southern part of Amazonas state, and C. (Chimarrita) heppneri Blahnik 1997 is recorded for the first time in northern Brazil. PMID- 30486061 TI - Elevation to species level and redescription of Xysticus alpinus Kulczynski, 1887 stat. n. (Araneae, Thomisidae). AB - Xysticus alpinus Kulczynski, 1887 stat. n. from Central-Eastern Alps, previously considered a subspecies of X. lanio C. L. Koch, 1835, is analyzed in detail. Redescription of both sexes and illustrations of habitus and genitalia are provided. A careful comparison with the nominal species is carried out revealing clear differences in morphology and habitat preferences. In light of this evidence, its elevation to species level is proposed. PMID- 30486062 TI - Description of a new genus and two new species of Anacolini (Coleoptera, Cerambycidae, Prioninae) from South America. AB - A new genus, Homoeomyzo gen. nov. and new species H. katsurai sp. nov. are described from Venezuela. A new species Oideterus birai sp. nov. is described from Colombia. The new genus is included in a previously published key and a key to males of Oideterus is provided. PMID- 30486063 TI - Sand fly fauna (Diptera: Psychodidae) from Serra da Mocidade Nacional Park: report of vectors and putative vectors of American cutaneous leishmaniasis and new records for the state of Roraima, Brazil. AB - Phlebotomine sand flies are insects of medical importance, as they are vectors of viruses, bacteria and trypanosomatids of the genus Leishmania Ross, the causative agent of leishmaniasis (Forattini 1973). During the past 20 years approximately 500,000 cases of leishmaniasis have been reported in Brazil. Most of these cases were reported in the North and Northeast regions. In the State of Roraima, almost 2,000 cases, including both cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL), have been reported during the past three years (SINAN 2017). Usually the transmission by infected female sand flies occurs in wild or rural areas, but there have also been recorded cases and vector captures in urban environments. Some sand fly species are known to enter houses in search of resting places and blood meal sources; as a result of this behavior, they are remarkably adaptable to new environments (Carvalhoet al. 2010). PMID- 30486064 TI - New species of genus Mudaria Moore, 1893 and the first record of Mudaria cornifrons Moore, 1893 from Thailand (Lepidoptera, Noctuidae, Noctuinae). AB - The Noctuidae genus Mudaria Moore, 1893, as treated in this paper, comprises 20 species distributed in the Oriental region from India to Fiji, with its centre of diversity in the Sundaland. The biology of the genus is unusual, in that the larvae bore into the fruits or pods of plants in family Bombacaceae (Holloway 1989) and Sterculiaceae (Robinson et al. 2001). Larvae of M. cornifrons have been recorded in the pods of silk-cotton tree (Bombax), in pods of kapok (Ceiba pentandra), in durian fruits (Durio) (Roepke 1916, Holloway 1989, Tan Tan 1991 [1992], Kuroko Lewvanich 1993) and in Pterospermum fruit (Robinson et al. 2001). On Bombax mature larvae emerge from fallen pods and tunnel into the soil to pupate in an earthen cocoon lined with silk (Holloway, 1989). Adult emergence is timed to coincide with the flowering of the host. PMID- 30486065 TI - A checklist of species of Vorticellidae (Ciliophora: Peritrichia) epibionts of crustaceans. AB - The family Vorticellidae includes 21 genera, mainly with species worldwide distributed, as free-living, and attached to diverse organisms as epibionts. The goal of this paper is to provide an updated checklist of the worldwide vorticellids reported attached to the crustaceans. We revised and checked all available records of species of vorticellids including their crustacean hosts. We found 96 vorticellid species belonging to 14 genera with at least a report on the body of 81 species of crustaceans. Four genera of ciliates (Vorticella, Pseudovorticella, Carchesium and Intranstylum) had the major number of species living as epibionts. We provide also the complete list of the species of vorticellids, and conclude the need of a taxonomic revision of the family. PMID- 30486066 TI - New synonymies, new combinations and lectotype designations for weevils in the tribe Naupactini (Coleoptera: Curculionidae: Entiminae). AB - We examined the type material of 15 species of Naupactus Dejean and related genera (Curculionidae: Entiminae), most of them described by Alphonse Hustache (Museum National d'Histoire Naturelle, Paris) and Carl Boheman (Naturhistoriska Riksmuseet, Stockholm). The information associated with the types was compared with the original descriptions, and large series of specimens were examined in order to analyze the variation of each species throughout its range (sexual dimorphism, other kinds of polymorphism or geographic variation). Based on the results of this study we establish seven new combinations, one new placement and nine new synonymies, we make 21 lectotype designations and provide three new country and state records. Alceis curtus (Boh.), Lanterius leucophaeus (Boh.), L. sparsus (Boh.), L. sellatus (Boh.), Parapantomorus carinirostris (Hust.), Symmathetes signatus (Blanchard) and Teratopactus acerbus (Boh.) are new combinations and T. sulphureoviridis Hust. is a new placement. The following names are senior synonyms of those between parentheses: Lanterius inermis (Hust.) (syn. Macrostylus ocellatus Lanteri); Naupactus auricinctus Boh. (syn. N. ruficornis Boh.); N. bridgesii G.R. Waterhouse (syn. N. angulithorax Hust.); N. condecoratus Boh. (syn. N. bosqi Hust.); N. cyphoides (Heller) (syn. N. calamuchitanensis Hust., N. viridinitens Hust, N. viridulus Hust.); N. peregrinus (Buchanan) (syn. N. brevicrinitus Hust.); and Trichonaupactus densior Hust. (syn. T. rexus Hust.). For each species we provide the following information: synonyms, available data on type specimens (sex, body length, geographic location, kind of type, and repository), complete geographic distribution, pictures of types or specimens compared with types, an explanation about the reasons that justify the nomenclatural acts. PMID- 30486067 TI - A new species of long-tailed mouse, genus Oligoryzomys Bangs, 1900 (Rodentia: Cricetidae), from the Bolivian Yungas. AB - Andean long-tailed mice of the genus Oligoryzomys have a complex and instable taxonomic history. Recent studies, in addition to circumscribe O. destructor to populations from southern Peru up to the north, and O. brendae to those from Argentina and southern Bolivia, have identified a candidate species in northern Bolivia. Herein, we assessed the status of the mentioned candidate species by morphologically comparing it with O. brendae, its sister group; with O. destructor, which is morphologically similar and distributed parapatrically; and with O. flavescens occidentalis, which is geographically codistributed. Additionally, we compared it with Oryzomys chaparensis, a poorly known form, currently placed in the synonymy of O. microtis, whose type locality is near the known distribution of the Bolivian candidate species. Results show that the assessed form is morphologically diagnosable. This fact together with its phylogenetic distinction allows us to hypothesize that it represents a new species that is named and described here. PMID- 30486068 TI - Discovery of Lymantini weevils (Coleoptera: Curculionidae: Molytinae) outside the Americas: Devernodes, a new genus for five new species from Southeast Asia. AB - This paper reports a new weevil genus Devernodes gen. n. established for five new species from Southeast Asia: D. alkippe sp. n. (China: Mt. Emei), D. asteria sp. n. (Vietnam: Tam Dao), D. chthonia sp. n. (Vietnam: Tam Dao; the type species), D. drimo sp. n. (Malaysia: Pasoh Forest Reserve) and D. methone sp. n. (Malaysia: Tanah Rata). All Devernodes are wingless and inhabit the forest leaf litter. Adult Devernodes share a combination of two head characters unique among weevils in Asia: antenna with apparently unsegmented club and 6-segmented antennal funicle, as well as strong constriction separating the eye-bearing rostrum from the head capsule. To test monophyly and investigate phylogenetic relationships of Devernodes, Maximum Likelihood phylogenetic analysis was undertaken using parts of mitochondrial (COI) and nuclear ribosomal (28S) genes, as well as the nuclear internal transcribed spacer (ITS2) from 14 Devernodes and 55 outgroup Curculionidae specimens. Results strongly corroborated monophyly of Devernodes and did not suggest its realistic sister-group. The new genus is assigned to the molytine tribe Lymantini (not represented in the DNA analysis) based on two potential synapomorphies: head markedly constricted behind eyes and presence of undivided female hemisternites IX (= "merged coxite and stylus"). Thus interpreted, Devernodes is the twelfth nominal genus of Lymantini and the first record of the tribe outside of the Americas. All original data (localities, DNA sequences, specimen images) are available online in public datasets dx.doi.org/10.5883/DS-DEVERNO1 and dx.doi.org/10.5883/DS-DEVERNO2. PMID- 30486069 TI - Dryophthorinae weevils (Coleoptera: Curculionidae) of the forest floor in Southeast Asia: DNA analysis of two new Nephius from Vietnam and Taiwan suggests non-monophyly of Stromboscerini. AB - The weevil genus Nephius Pascoe is for the first time reported from Vietnam (N. argus sp. nov.) and Taiwan (N. acastus sp. nov.). Until now the genus was attributed to the tribe Stromboscerini and contained nine nominal species and two subspecies known only from the type series. Phylogenetic analysis of one mitochondrial (COI) and two nuclear (ITS2 and 28S) markers strongly rejected monophyly of the tribe by placing the monophyletic Nephius as sister to a clade consisting of reciprocally monophyletic Dryophthorus and the rest of Stromboscerini. All herein used data (localities, DNA sequences, specimen images) are available online in public datasets dx.doi.org/10.5883/DS-NEPHIUS1 and dx.doi.org/10.5883/DS-NEPHIUS2. PMID- 30486070 TI - A new species of Smicridea McLachlan 1871 (Trichoptera: Hydropsychidae) from the Caatinga biome and new distributional records from Brazil. AB - A new species of Smicridea (Smicridea) McLachlan 1871 is described and illustrated based on specimens collected from the Caatinga biome, in Sete Cidades National Park, Piaui state, and Ubajara National Park, Ceara state, northeastern Brazil. Based on phallus morphology, Smicridea (Smicridea) caatinga sp. nov. belongs to the S. nigripennis Group and can be distinguished from other species in this group due to the phallus having two ventral sclerotized projections and, when expanded, two dorsal membranous lobes and one ventrolateral membranous lobe with two spines on the apex. New distributional records of Smicridea species are provided for different Brazilian states: S. (S.) aequalis Banks 1920 for Ceara and Piaui, S. (Rhyacophylax) coronata Flint 1980 for Rio Grande do Sul and Piaui; S. (R.) jundiai Almeida Flint 2002 for Mato Grosso; S. (R.) marlieri Flint 1978 for Roraima; S. (R.) palmar Sganga 2005 for Goias; S. (S.) paranensis Flint 1983 for Ceara and Piaui; and S. (R.) spinulosa Flint 1972 for Rio Grande do Sul. Furthermore, S. (S.) erecta Flint 1974b is recorded for the first time for Brazil, in Amazonas state. [Zoobank: urn:lsid:zoobank.org:act:3C2892F9-D430-492B 98DA-A48569253A63]. PMID- 30486071 TI - Annotated list of the assassin bugs (Heteroptera: Reduviidae) of Belize, with the description of two new species. AB - Fifty-one species of Reduviidae (Hemiptera: Heteroptera) are recorded from Belize; literature citations are provided where relevant, and specimen data are included for examined material. Thirteen previously-described species are reported from Belize for the first time, ten of which represent new generic records: Eupheno histrionicus Stal, 1862 (Cetherinae); Ghinallelia signoreti (Dohrn, 1860) (Emesinae); Rasahus albomaculatus (Mayr, 1865) (Peiratinae); Leogorrus interruptus Champion, 1899; Microlestria laevis Champion, 1899; Nalata quadrituberculata Champion, 1899; Nalata setulosa Stal, 1862; Pseudozelurus superbus (Champion, 1899); Zelurus spinidorsis (Gray, 1832) (all Reduviinae); Oncerotrachelus conformis Uhler, 1894; Saica fuscipes Stal, 1862 (both Saicinae); Gnathobleda litigiosa Stal, 1862; and Stenopoda wygodzinskyi Giacchi, 1969 (both Stenopodainae). Among the ten subfamilies reported, Belizean records for one subfamily, Saicinae, are reported for the first time. Accompanying the checklist are the descriptions of Castolus omega Swanson sp. nov. (Harpactorinae) and Pygolampis aptena Swanson sp. nov. (Stenopodainae). PMID- 30486072 TI - Two new genera and species of flat bugs from the Philippines (Hemiptera: Heteroptera: Aradidae). AB - From the Philippines a new genus of Mezirinae: Cagayanacoris gen.nov. with the species C. menardi sp.nov. and a new genus of Carventinae: Vizcayaptera gen.nov. with the species V. minuta sp.nov. are described and illustrated. PMID- 30486073 TI - A new genus and species of Sophiini Townsend, 1936 (Diptera: Tachinidae) from Brazil, with an updated key to the genera of the tribe. AB - Sophiini is a New World tribe of Tachinidae composed, prior to this study, of 19 species in eight genera. Cryptosophia aurulenta gen. and sp. nov. from Amazonas, Brazil, is described and assigned to that tribe. The new genus can be easily distinguished from the other genera in the tribe, mainly by: head with occiput clearly swollen medially; thorax without a proepisternal seta; and meron with pale yellow setae almost indistinguishable from the yellow integument. It is most similar to members of the genera Neosophia Guimaraes and Sophiella Guimaraes. An updated and illustrated key to the genera of Sophiini is provided, including Cryptosophia gen. nov. Descriptions and illustrations of the female terminalia, spermatheca, and first instar larva are also provided for the new genus and species. PMID- 30486074 TI - New Zealand Austrophthiracarus (Acari, Oribatida, Steganacaridae): two new species from the North Island. AB - Two new species of Austrophthiracarus (Oribatida: Steganacaridae) from national parks on the North Island of New Zealand are described: Austrophthiracarus taranaki sp. nov. from moss along tracks in Wilkies Pools, Egmont National Park, Taranaki and Austrophthiracarus whirinaki sp. nov. from litter in Whirinaki Forest, between Rotorua and Taupo. An updated key to all known species of Austrophthiracarus in New Zealand is presented. PMID- 30486075 TI - Review of the genus Alysia Latreille (Hymenoptera, Braconidae, Alysiinae), with description of six new species from China. AB - Six new species of Alysia Latreille are described and illustrated from China, i.e., Alysia hebeiensis sp. n., A. macularis sp. n., A. melasoma sp. n., A. polita sp. n., A. sparsa sp. n., and A. stenopos sp. n. Also, six species are reported as new to China: Alysia incongrua Nees, 1834, A. lucia Haliday, 1838, A. lucicola Haliday, 1838, A. sirin Belokobylskij, 1998, A. umbrata Stelfox, 1941 and A. vladik Belokobylskij, 1998. A key to the known species of Alysia Latreille from China is provided. PMID- 30486076 TI - Bearing the wrong identity: A case study of an Indo-Pacific common shallow water sponge of the genus Neopetrosia (Haplosclerida; Petrosiidae). AB - Sponges of the order Haplosclerida are often abundant and characteristic components of Indo-Pacific reefs, but are often misidentified, because of the lack of clear distinctive morphological characters. Neopetrosia exigua is an example of a haplosclerid sponge that is very common in Indonesian shallow coral reef environments but bears several different names. In the present study we investigated type material of several Indo-Pacific Neopetrosia species with a similar morphology and examined freshly collected specimen materials including specimens that are deposited at several institutions. In addition, we used molecular phylogenetic methods for assisting the morphological examinations. We conclude that the true identity of Neopetrosia exigua should be Neopetrosia chaliniformis. Likewise, N. exigua and N. pacifica should be considered as junior synonyms of N. chaliniformis. In conclusion, we advocate that molecular barcoding could significantly aid on sponge species' delimitation that possess limited morphological characters. PMID- 30486077 TI - Three new species of Collembola (Arthropoda: Hexapoda) from Central Brazilian shallow caves: side effects of long term application of environmental law on conservation. AB - Three new species of Collembola are described from small shallow caves in Southeastern Brazil: Arrhopalites glabrofasciatus sp. nov., Pseudosinella ambigua sp. nov. and Pseudosinella guanhaensis sp. nov. The species were found in surveys performed as part of the process to accomplish the permits for high impact enterprising. The change in the legislation is discussed and a suggestion is made to improve the process. The long term effects of the law resulted in the discovery of many new species and genera, most of them being (or to be) described. PMID- 30486078 TI - Nemipterus andamanensis, a new nemipterid fish (Perciformes: Nemipteridae) from the Andaman Islands. AB - A new species of threadfin bream, Nemipterus andamanensis n. sp. from the Andaman Islands is described and figured. N. andamanensis resembles N. marginatus (Valenciennes, 1830) in general body form and colour pattern, but differs from the latter by having four yellow stripes on the head region, upper lobe of caudal fin and filament yellow, and lower lobe of caudal fin pinkish. The mitochondrial cytochrome oxidase C subunit I (COI) gene sequence comparison with close species revealed that Nemipterus andamanensis n. sp. has distinct genetic divergence (8.5%) from Nemipterus marginatus and other species of the genus occurring in the area. PMID- 30486079 TI - A new remarkable short-tailed whip-scorpion species of Piaroa (Arachnida, Schizomida, Hubbardiidae) from the Colombian Caribbean region. AB - Herein, we describe a new schizomid species from the genus Piaroa Villarreal, Giuponni Tourinho, 2008, Piaroa turbacoensis sp. nov., based on individuals collected in the Botanical Garden "Guillermo Pineres", Turbaco, Bolivar, Colombian Caribbean region. Piaroa turbacoensis is the sixth species of the genus to be found in Colombia, and the tenth to be found with regards to the genus as a whole. This species is the first Colombian species to be recorded in a Dry Tropical Forest biome. Piaroa turbacoensis is easily distinguishable by the presence of spermathecae lateral lobes with massive circular stalk bases, and male pedipalp with ventroectal truncate process over the femur and ventroectal depression over the patella. Here, we provide an updated distribution map of the genus and comments about the natural history of the new species. PMID- 30486080 TI - New encrusting species of Lanceoporidae (Bryozoa, Cheilostomata) from the southern Great Barrier Reef, Australia. AB - Three new species of lanceoporids from the southern Great Barrier Reef are described. Calyptotheca trimandibulata n. sp. is recorded from inter-reefal sites, Stephanotheca bahloo n. sp. is recorded from a coral reef site, and Stephanotheca kutyeri n. sp. is recorded from inter-reefal sites and also Bass Strait and the Great Australian Bight, and is therefore unusual amongst Australian lanceoporids in occurring in both tropical and temperate locations. The known variation in morphological characters is widened for both genera: C. trimandibulata n. sp. is the only known Calyptotheca species typically having three adventitious avicularia per zooid, S. bahloo n. sp. has the most pronounced orifice dimorphism and the most transversely oval primary orifice for the genus, and S. kutyeri n. sp. is distinguished by long, narrow, slit-like pseudopores in the frontal shield. All three species have occasional dimorphic autozooids, distinguished by larger orifices resembling those of the respective ovicellate zooids, and this is documented for the first time for both genera. PMID- 30486081 TI - Austroectobius invunche: new genus and species of Ectobiidae for Chile (Insecta, Blattaria). AB - We describe a new genus and species of Chilean Blattodea (Ectobiidae), collected on Isla Grande de Chiloe and associated with Fascicularia bicolor (Bromeliaceae). We study the morphology of both sexes with SEM. The new taxon is brachypterous, with tiny ellipsoid tegmina and hind wings absent. The female presents strongly sclerotized genital sclerites and spermathecal plate developed. The male without tergal specializationsand asymmetrical styles. Medium phallomere with modified sclerites, compose a sclerotized complex that includes a long ejaculatory duct. PMID- 30486082 TI - Pterocryptis subrisa, a new silurid catfish (Teleostei: Siluridae) from northeastern India. AB - Pterocryptis subrisa, a new species of silurid catfish from the Kaladan River drainage in northeastern India, is described in this study. It can be distinguished from congeners by the unique combination of the following characters: supralabial fold extending posteriorly beyond vertical through posterior orbital margin; nearly circular eye; head length 17.6-19.6% SL; head depth 10.6-11.9% SL; dorsal-fin height 2.6-4.7% SL; 2 dorsal-fin rays; pectoral fin length 11.8-14.0% SL; body depth at anus 14.4-16.7% SL; caudal peduncle depth 6.8-8.5% SL; 66-75 anal-fin rays; confluent anal and caudal fins separated by deep notch; 17 principal caudal-fin rays; and 57 vertebrae. The generic status of Pterocryptis taytayensis is discussed, with this species being reassigned to Ompok. PMID- 30486083 TI - A new species of Opilioacarus With, 1902 (Acari: Opilioacaridae) from Italy, and a new diagnosis of the genus. AB - No living Opilioacarus species have been described from Europe for more than a century since the first finding and species description in the early twentieth century. Using the material deposited in Museo Civico di Storia Naturale of Verona, Italy, it was possible to identify and describe a new Opilioacarus species and review the genus diagnosis, using the shape of setae d and setation of the preanal segment. The new species is also briefly compared with the other Opilioacarus species; Opilioacarus italicus (With, 1904) is considered a nomen dubium. PMID- 30486084 TI - A new fossil species of Euroleptochromus Jaloszynski (Coleoptera: Staphylinidae: Scydmaeninae) from Eocene Baltic amber. AB - A new species of the extinct scydmaenine genus Euroleptochromus Jaloszynski (Mastigitae: Leptochromini), E. tuberculatus Yin Cai, sp. nov., is described from Eocene Baltic amber. It can be separated from the two previously known congeners by the different proportions of the body parts and spination of the profemur, and more importantly, lack of an elongate postgenal process of the head. Our finding demonstrates for the first time a notable variability of the postgenal structures within Euroleptochromus. PMID- 30486085 TI - Alternative facts: a reconsideration of putatively natural interspecific hybrid specimens in the genus Heliconius (Lepidoptera: Nymphalidae). AB - Mallet et al. (2007 BMC Evolutionary Biology, 7, 28) employed a database of putative interspecific hybrid specimens of the genus Heliconius to advance a hypothesis of "the species boundary as a continuum." Here, each of those specimens, as well as subsequently documented specimens, is individually reassessed regarding its phenotype, potential parentage and chain of custody in collections. Using a quantified scale of reliability, most of the specimens are interpreted differently than Mallet et al.'s identifications, and the actual number of interspecific hybrids is estimated to be much smaller than they proposed. To be specific, of 163 putative hybrid specimens examined, 11% suffered from ambiguous identity, 5% from confounding issues with their data labels, 50% were arguably intraspecific (depending upon alternative species concepts), and 22% were almost certainly reared, commercial specimens. Only eleven of the specimens meet the criteria established here to be legitimate and reliable interspecific hybrids, and all of those are between closely-related species. This result has potentially important implications for current hypotheses of frequent genomic introgression of wing pattern alleles among Heliconius clades. PMID- 30486086 TI - Classification, annotated list and keys for the black flies (Diptera: Simuliidae) of Peninsular Malaysia. AB - The classification, annotated list and keys for the black fly species from Peninsular Malaysia are updated. The number of black fly species increased from 38 in 1995 to 62 (including a new species herein described) in 2018. The 62 species are classified in four subgenera of the genus Simulium: one species in Daviesellum, 35 species in Gomphostilbia, five species in Nevermannia and 21 species in Simulium. Species in the latter three subgenera are further placed in species-groups or subgroups. Keys are provided for females, males, pupae and mature larvae. Simulium (S.) perakense sp. nov. is described and placed in the S. striatum species-group. The males of S. (G.) decuplum, S. (G.) tahanense, S. (S.) malayense, the female of S. (G.) adleri, and the female and larva of S. (G.) varicorne are described for the first time. The female, male, pupa and larva of S. (G.) trangense, the male and pupa of S. (G.) varicorne and the pupa of S. (G.) adleri are redescribed. Simulium (G.) sp. A is identified as S. (G.) pegalanense. Brief notes for each species are given on morphological characteristics, aquatic habitats and geographical distributions. PMID- 30486087 TI - Deep-sea ascidians (Chordata, Tunicata) from the SW Atlantic: species richness with descriptions of two new species. AB - The understudied deep-sea benthic communities from the Southwestern Atlantic continental slope (200 m-3000 m depth) were sampled on August 2012 in an area located around 38 degrees S that included the Mar del Plata submarine canyon. In these samplings we found a total of 16 ascidian species from six different families, of which two corresponded to new species. These were: Aplidium meridianum (Sluiter, 1906); Aplidium variabile (Herdman, 1886); Aplidium marplatensis Maggioni Tatian (sp. nov. present work); Aplidium solitarium Maggioni Tatian (sp. nov. present work); Synoicum georgianum Sluiter, 1932; Synoicum molle (Herdman, 1886); Synoicum sp.; Polysyncraton trivolutum (Millar, 1960); Sycozoa umbellata (Michaelsen, 1898); Ascidia meridionalis Herdman, 1880; Cnemidocarpa drygalskii (Hartmeyer, 1911); Styela squamosa Herdman, 1881; Pyura pilosa Monniot C. Monniot F., 1974; Molgula pyriformis Herdman, 1881; Molgula setigera Arnback-Christie-Linde, 1938 and Asajirus indicus (Oka, 1913). Based on morphological evidence, we propose the new synonymy: Molgula setigera Arnback Christie-Linde, 1938 = Molgula marioni Millar, 1960 = Molgula robini Monniot C. Monniot F., 1983. We also propose to maintain Molgula pyriformis and Molgula malvinensis as separate species. We report: the extension of the distribution range of Aplidium meridianum, Synoicum georgianum, Polysyncraton trivolutum, Sycozoa umbellata, Cnemidocarpa drygalskii, Pyura pilosa and Molgula setigera, being the first time they are collected off La Plata River; the deepest registers for Synoicum georgianum, Poylsyncraton trivolutum, Sycozoa umbellata, Ascidia meridionalis, Pyura pilosa, Molgula pyriformis and Molgula setigera; and the shallowest register for Synoicum molle. PMID- 30486088 TI - Two new species of Plutomurus Yosii (Collembola, Tomoceridae) from the Caucasus. AB - Two new species of Plutomurus, P. pichkhaiai sp. nov. from Garakha and Letsurtsume caves and P. shurubumuensis sp. nov. from Shurubumu Cave (Chkhorotsku district, Western Georgia) are described, and illustrated. The new species are very similar to P. kelasuricus from the Tsebelda karst massif formation in Apkhazeti, Georgia, but differ in having two inner spine-like chaetae on the inner edge of the hind tibiotarsus (only one in P. kelasuricus) and in occupying different, isolated cave formations separated by a geographic distance of nearly a 100 km. A key to the species of Plutomurus with 6 prelabral chaetae is provided. PMID- 30486089 TI - Morphological and molecular analyses confirm the occurrence of two sympatric Lysmata shrimp (Crustacea, Decapoda) in the southwestern Atlantic. AB - An integrative approach was used, combining morphological and molecular analyses, to provide the first report of Lysmata lipkei and L. vittata in Sergipe State, Brazil, and confirm that both species are invasive of the Atlantic Ocean. Lysmata shrimps were sampled in the estuary region of the Vaza-Barris river, Sergipe State, northeastern Brazil, and identified as L. lipkei (n = 8) and L. vittata (n = 20). To molecular phylogenetic analysis was used 16S DNA fragments, comparing 26 species of the Lysmata-Exhippolysmata clade and two species of the genus Merguia (outgroup). Phylogenetic analysis indicated the absence of consistent genetic divergence (p distance < 0.018) between specimens from Atlantic and Indo Pacific oceans. We conclude that L. lipkei and L. vittata have successfully invaded the western Atlantic and are also present in Sergipe State, northeastern Brazil. PMID- 30486090 TI - A new genus of calcareous sponge discovered in the Caribbean Sea: Bidderia gen. nov. (Porifera, Calcarea, Calcinea). AB - Calcareous sponges from the Lesser Antilles were recently inventoried and several specimens morphologically resembling species of the genus Ascoleucetta were collected. Morphological and molecular (C-LSU and ITS) analyses indicated that these specimens from the Lesser Antilles constituted a new genus. They lack the conspicuous and very characteristic ornamentation of the inhalant apertures found in two out of three species of Ascoleucetta, including the type species A. compressa. In the molecular analyses, the specimens clustered as an independent lineage, distant from the clade of A. compressa. Based on these results, we decided to erect a new genus, Bidderia gen. nov., whose type species is Bidderia bicolora gen. nov. sp. nov. Considering this new discovery, we are proposing to transfer the species A. amitsba to the genus Bidderia gen. nov. and to rediagnose Ascoleucetta. PMID- 30486091 TI - Snake eels of the genus Ophichthus (Anguilliformes: Ophichthidae) from Myanmar (Indian Ocean) with the description of two new species. AB - Two new species of ophichthid eels, subfamily Ophichthinae, are described and illustrated from specimens collected from Myanmar by the R/V Dr. Fridtjof Nansen. Included are: Ophichthus nansen sp. nov., from 103-106 m depth, which is unique in its vertebral number (11-53-116), dorsal-fin origin (above mid-pectoral fin), jaw dentition (small, conical and mostly biserial), and coloration (dark gray brown, fins black); and Ophichthus naga sp. nov., from 455-459 m depth, which is unique in its vertebral number (15-65-153), dorsal-fin origin (well behind pectoral fin), dentition (small, conical, biserial in upper jaw and uniserial in lower jaw and on vomer), and dark brown coloration. Also new to Myanmar are Ophichthus cephalozona Bleeker, 1864, and O. lithinus (Jordan Richardson, 1908), which are diagnosed and treated herein. PMID- 30486092 TI - A new species of Terelabrus (Perciformes: Labridae) from the Philippines with a key to species of Terelabrus and new record of Terelabrus dewapyle. AB - A new labrid fish, Terelabrus zonalis sp. nov., the fourth species of the genus, is described on the basis of two specimens collected from the Philippines. The new species is characterized by 44 longitudinal series scale rows, 42 pored lateral-line scales, 11-12 gill rakers (including rudiments), the main supratemporal sensory canal with 8 branches posteriorly, the area bounded by the main supratemporal and postotic sensory canals (dorsal view) with 3 scale rows, the least distance between the orbit anteroventral margin and interopercle 7.0% of standard length and 18 faint silver vertical bands on the body in preserved specimens. An underwater photograph of T. dewapyle is reported as the first record of the species from the Philippines. A key to species of Terelabrus is provided. PMID- 30486093 TI - Lithoseopsis Mockford (Psocodea: Troctomorpha: Amphientomidae): a new species and first record for South America. AB - A species of Lithoseopsis Mockford, from the Brazilian state of Para, is described and illustrated. It is the first species of Lithoseopsis recorded in Brazil, and the first of that genus known in South America. It differs from all the other species in the genus in details of the forewing pigmentation and spermapore sclerite. A map with the distribution of the Lithoseopsis species is included and two species groups of Lithoseopsis are diagnosed. PMID- 30486094 TI - Oleia fieldsi sp. n., a new Orthocladiinae (Diptera: Chironomidae) species from the Brazilian Atlantic rainforest. AB - One new species of the genus Oleia Andersen et Mendes, 2007 (Diptera: Chironomidae: Orthocladiinae), O. fieldsi sp. n. is described and figured as adult male. The specimens were collected in a fragment of secondary forest in the Atlantic Forest, at Iguacu National Park, on the border of Argentina and Brazil. PMID- 30486095 TI - The pliomerid trilobite Ibexaspis and related new genera, with species from the Early Ordovician (Floian; Tulean, Blackhillsian) of the Great Basin, western USA. AB - Field-based revision and phylogenetic analysis demonstrate that the pliomerid trilobite taxon Ibexaspis Pribyl and Vanek (in Pribyl et al., 1985), previously known from a single formally named species (I. brevis [Young, 1973]), belongs to a complex of 14 mostly newly discovered, related species from the Early Ordovician (Floian; Tulean and Blackhillsian) of the northern Laurentian margin. The species are known from silicified samples recovered from sections in eastern Nevada, western Utah, and southeastern Idaho. The stratigraphically early Tuleaspis n. gen. (type species: T. jeneki n. sp.; Tulean; low Protopliomerella contracta Zone) includes its type and two species described in open nomenclature. Tuleaspis is sister to the remainder of the clade. Ibexaspis now includes three additional species: I. coadyi n. sp. (Blackhillsian; Carolinites nevadensis Zone), I. leuppi n. sp. (Blackhillsian; Presbynileus ibexensis Zone), and I. rupauli n. sp. (Blackhillsian; "Pseudocybele nasuta Zone"). Ibexapsis is sister to a clade of Millardaspis n. gen. + Deltapliomera n. gen. Millardaspis (type species M. milsteadi n. sp.; Tulean; Heckethornia hyndeae Zone) also includes M. knoxi n. sp. (Tulean; Panisaspis sevierensis Zone). Deltapliomera (type species D. humphriesi n. sp.; Blackhillsian, Carolinites nevadensis Zone) also includes D. inglei n. sp. (Tulean; Heckethornia bowiei Zone), D. heimbergi (Tulean; Panisaspis sevierensis Zone), D. eppersoni n. sp. (Blackhillsian; Bathyurina plicolabeona Zone), and a species described in open nomenclature. PMID- 30486096 TI - Six new Cyrtodactylus (Squamata: Gekkonidae) from northeast India. AB - We use mitochondrial sequence data to identify divergent lineages within the gekkonid genus Cyrtodactylus in northeast India and use morphological data to describe six new species from within the Indo-Burma clade of Cyrtodactylus. The new species share an irregular colour pattern but differ from described species from the region in morphology and mitochondrial sequence data (>11 % uncorrected pairwise sequence divergence). Three new species are from along the Brahmaputra River and three are from mountains south of the Brahmaputra, including the largest Cyrtodactylus from India and the fifth gecko to be described from a major Indian city, Guwahati. PMID- 30486097 TI - Hitherto unknown and poorly known morphs of Macrosiphoniella davazhamci and M. nikolajevi (Hemiptera: Aphididae)-aphid species new to Iran. AB - We present the first records from Iran of Macrosiphoniella (Asterobium) davazhamci Holman Szelegiewicz, 1974 and M. (Ramitrichophorus) nikolajevi Kadyrbekov, 1999 (Hemiptera: Aphididae: Aphidinae) from samples collected by the late Prof. G. Remaudiere. Previously, Macrosiphoniella davazhamci was known from Kazakhstan, Mongolia and China, whereas M. nikolajevi only from south Kazakhstan. The Iranian material includes hitherto unknown or poorly known morphs of those two species. We describe and illustrate for the first time the alate vivipara of M. nikolajevi and the ovipara and alate male of M. davazhamci. Additionally, we redescribe the poorly known alate vivipara of the latter species. Notes on the distribution and host plants in Iran are also provided. PMID- 30486098 TI - A new species of Polynoncus Burmeister, 1876 from Brazil (Coleoptera: Trogidae). AB - Polynoncus vazdemelloi Huchet Costa-Silva new species (Coleoptera: Trogidae) from Brazil is described and illustrated with data about the natural history and geographic distribution. Comparative data between P. vazdemelloi, P. juglans (Ratcliffe, 1978), and P. gemmingeri (Harold, 1872), species closely related morphologically, are given. Omorgus (Omorgus) triestinae Pittino, 1987 is removed from synonymy with O. (O.) suberosus (Fabricius, 1775) and reinstated as a valid species. PMID- 30486099 TI - Taxonomy of 'Euconnus complex'. Part XVIII. Status of subgenera Palaeoconnus Franz and Heterotetramelus Franz (Coleoptera, Staphylinidae, Scydmaeninae). AB - Based on examination of type species, the subgenera Palaeoconnus Franz and Heterotetramelus Franz are removed from Euconnus Thomson. Adults of Palaeoconnus have the prosternum bearing a subtriangular prosternal process and their metacoxae are contiguous, which exclude this taxon from Euconnus. Palaeoconnus is transferred to Sciacharis Broun as subgenus and redefined. The lectotype is designated for its type species, Scydmaenus brevipes Sharp. Sciacharis andicola (Franz), previously treated as incertae sedis within Sciacharis, is placed in Palaeoconnus. Heterotetramelus is also excluded from Euconnus, on the basis of the mesoventrite lacking the mesoventral intercoxal process and the contiguous metacoxae. Heterotetramelus stat. n. is elevated to genus rank and redefined, and the lectotype is designated for its type species, Euconnus caledonicus Franz. Moreover, the newly defined Heterotetramelus is reclassified to include four subgenera: Heterotetramelus s. str. (with seven species distributed in New Caledonia), Sciacharoides Jaloszynski, stat. n. (reduced from genus; with three Australian species); Australosciacharoides subgen. n. (with only one Australian species transferred from Sciacharoides); and Tamborinus subgen. n. (also with one Australian species transferred from Sciacharoides). PMID- 30486100 TI - Re-description of Grammapsychops lebedevi Martynova, 1954 (Neuroptera: Psychopsidae) with notes on the Late Cretaceous psychopsoids. AB - Grammapsychops lebedevi Martynova, 1954 from the Late Cretaceous (Cenomanian) of Siberia is re-described based on the holotype. The species is represented by a hind wing as its CuA is definitely concave, although the costal space is strongly dilated. This genus together with three other Cretaceous genera (i.e., Embaneura G. Zalessky, 1953, Kagapsychops Fujiyama, 1978, and probably Pulchroptilonia Martins-Neto, 1997) form the Grammapsychops genus-group. The hind wing of Grammapsychops may theoretically be associated with forewings of Kagapsychops or other closely related genera with similar forewing venation. The Late Cretaceous psychopsoids are critically reviewed. All known psychopsoid taxa from this interval are considered as belonging to Psychopsidae. PMID- 30486101 TI - Description of the female of Poecilocampa deqina Saldaitis Pekarsky, 2015 (Lepidoptera, Lasiocampidae), with notes on the biology of the species. AB - The female of lappet moth species Poecilocampa deqina Saldaitis Pekarsky, 2015 recently described from northwestern Yunnan Province, China based on male specimens is reported for the first time. The female, pupa and pupal case of P. deqina are described and illustrated here for the first time. External morphology of the female as well as characters of pupa are discussed and compared with close species. Data on biology of P. deqina is provided. PMID- 30486102 TI - Erratum: OLAVI KURINA, HEIKKI HIPPA DALTON DE SOUZA AMORIM (2018) A contribution to the systematics of the genus Manota Williston (Diptera: Mycetophilidae) in Brazil. Zootaxa, 4472: 001-059. PMID- 30486103 TI - Cribrilinids (Bryozoa, Cheilostomata) associated with deep-water coral habitats at the Great Bahama Bank slope (NW Atlantic), with description of new taxa. AB - Four cribrilinid bryozoans associated with deep-water corals (578-682 m depth) from the Great Bahama Bank slope, are described, two of them are new. The generic allocation of some species prompted us to raise the subgenera Puellina, Cribrilaria, and Glabrilaria to genus rank. The new combination Cribrilaria saginata (Winston, 2005) n. comb. is proposed. Genus Glabrilaria is reported from the NW Atlantic for the first time based on the description of Glabrilaria hirsuta Rosso n. sp. and Glabrilaria polita Rosso n. sp. The new genus Teresaspis Rosso n. gen. is erected, and Teresaspis lineata (Canu Bassler, 1928) n. comb. is proposed as its type species. The new genus Harmelinius Rosso n. gen. is erected for Cribrilina uniserialis (Harmelin, 1978). Both genera have uniserial colonies formed by slightly caudate zooids with extensive gymnocyst and a frontal shield of flattened costae. Teresaspis lineata n. comb., however, has costae with pelmatidia that are connected by few intercostal bridges and separated by intercostal spaces, four orificial costa-like processes with the proximal pair arching above the orifice, hyperstomial acleithral ovicells with a pseudoporous ooecium formed by the distal zooid or a kenozooid, two types of kenozooids (large with costate frontal shield and small with smooth shield and central opesia), and an ancestrula with costate frontal shield. Avicularia are apparently absent in this species. In contrast, the type species of Harmelinius Rosso n. gen. has costae lacking pelmatidia and which are separated by slit-like intercostal spaces. The hyperstomial cleithral ovicells have smooth ooecia with a median suture and without pseudopores, and are formed by a distal kenozooid associated with a small avicularium. Additional paired oral avicularia are occasionally present, as are large kenozooids with a central opesia. Oral spines or spine-like processes are absent. Taxonomy of the above reported cribrilinid genera is discussed in detail together with the geographic distribution of all mentioned taxa. PMID- 30486104 TI - A new species of Notomulciber (Micromulciber) Aurivillius, 1913, from the southern Western Ghats of India (Coleoptera: Cerambycidae: Lamiinae: Homonoeini). AB - Notomulciber (Micromulciber) viraktamathi sp. nov. is described and illustrated from the southern Western Ghats, a hotspot of biodiversity in India. Ecological notes, differential diagnosis of the new species from its close relatives and a key to the species of Notomulciber from India are provided. PMID- 30486105 TI - Review of the genus Paramesius Westwood, 1832 (Hymenoptera: Diapriidae, Spilomicrini) from Russia, with description of four new species. AB - A review of the eight Palaearctic species of the genus Paramesius Westwood is provided, four of which are described and illustrated: P. primorus Chemyreva et Kolyada, sp. nov. (Russia: Primorsky Territory), P. janmaceki Chemyreva et Kolyada, sp. nov. (Russia: Primorsky Territory, Kuril Islands: Kunashir, Shikotan), P. ocampus Chemyreva et Kolyada, sp. nov. (Russia: Primorsky Territory, Sakhalin), and P. spiracularis Chemyreva et Kolyada, sp. nov. (Russia: Primorsky Territory, Khabarovsk Territory, Kuril Islands: Kunashir). New synonyms are proposed (valid name is the first): P. brachypterus Thomson, 1859 = P. spinosus Kieffer, 1911, syn. nov.; P. crassicornis Thomson, 1859 = P. dolosus Kieffer, 1911, syn. nov. = Spilomicrus kaszabi Szabo, 1977, syn. nov.; P. rufipes (Fonscolombe), 1832 = Spilomicrus striatifoveatus Szabo, 1960, syn. nov. All known Palaearctic species of Paramesius are keyed. PMID- 30486106 TI - Review of Indonesian species of the leafhopper genus Drabescus Stal (Hemiptera: Cicadellidae: Deltocephalinae) with description of two new species. AB - Two new species Drabescus stilliformis and D. viraktamathi spp. nov., are described and illustrated from Indonesia. A checklist and key to males from Indonesia are provided. Type specimens of the new species are deposited in the Natural History Museum, London, U.K. (BMNH) and the National Museum of Wales, Cardiff, U.K. (NMW). PMID- 30486107 TI - A new "elfin" butterfly species of Cissatsuma Johnson, 1992 (Lepidoptera, Lycaenidae) from northwestern Sichuan, China. AB - A new species of elfin blue, Cissatsuma berezowskii Krupitsky sp.n., is described from the northwestern Sichuan Province, China, based on two old museum specimens, a male and a female. The new species differs from the most closely related one, C. albilinea (Riley, 1932), in lack of white band of ventral wing surfaces, broadened blue area of dorsal wing surfaces in female, and morphology of the male and female genitalia. The distribution map of the new species and C. albilinea is provided. PMID- 30486108 TI - A new species of black fly with a yellow thorax in the genus Prosimulium (Diptera: Simuliidae) in Japan. AB - A new species of black fly, Prosimulium kazukii, is described based on female, male and pupal specimens collected from central Honshu, Japan. It is placed in the Prosimulium magnum species-group, and is characterized in the female and male by yellow thoraces, and in the pupa by the frons and dorsal surface of the thorax without distinct tubercles. By these characters, it is distinguished from all four related species (P. apoina Ono, P. kalibaense Ono, P. sarurense Ono, and P. yezoense Shiraki) of the same species-group in Japan. The female of this new species was previously known as an aberrant form of P. yezoense. PMID- 30486109 TI - Two new species of Caddisflies (Trichoptera: Insecta) from Lower-Hill Evergreen Forests of Southern Thailand. AB - Two new species of caddisflies, Macrostemum nigralatum n. sp. and Anisocentropus tairomyenensis n. sp., are described and figured from lower-hill evergreen forests in southern Thailand. Wings of M. nigralatum are black, which distinguishes the new species from other related species. Anisocentropus tairomyenensis n. sp. is a member of the subgenus Anisomontropus and is characterized by the obvious basal expansion of the preanal appendages. PMID- 30486110 TI - Taxonomic revision of the Western Palaearctic bees of the subgenus Pseudomegachile (Hymenoptera, Apiformes, Megachilidae, Megachile). AB - The subgenus Pseudomegachile Friese of the large genus Megachile Latreille is revised for the Western Palaearctic region, Iran, and the Arabian Peninsula. Twenty species are recognized, of which five are new: Megachile blepharis Dorchin Praz from Israel, M. plumigera Dorchin Praz from Oman and the United Arab Emirates, M. syriaca Dorchin Praz from Syria and Turkey, M. yezidica Dorchin Praz from Turkey and Iran, and M. maxschwarzi Dorchin Praz from Iran and Central Asia. The following new synonymies are proposed: M. inermis Radoszkowski 1893 (as well as the replacement name M. mitis Cockerell 1899), M. albifasciata Rebmann 1970 and M. transgrediens Rebmann 1970 are placed in synonymy with M. saussurei Radoszkowski 1874; M. tuberculata Radoszkowski 1893 (as well as the replacement name M. tuberculosa Dalla Torre 1896) is placed in synonymy with M. seraxensis Radoszkowski 1893; M. rubripes Morawitz 1875 and M. persica Rebmann 1972 are placed in synonymy with M. flavipes Spinola 1838; M. stolzmanni Radoszkowski 1893 and M. flavidula Rebmann 1970 are placed in synonymy with M. tecta Radoszkowski 1888. Lectotypes are designated for M. cinnamomea Alfken 1926, M. nilotica Perez 1897, M. inermis, M. seraxensis, M. tuberculata, M. farinosa Smith 1853, M. derasa Gerstacker 1869, M. erythrocnemis Alfken 1930 and M. xanthocnemis Alfken 1938. An identification key is provided, a phylogenetic hypothesis including most species in the subgenus is presented, and the biology of the species is briefly summarized. PMID- 30486111 TI - A review of the species of the tribe Chorosomatini of China (Hemiptera: Heteroptera: Rhopalidae). AB - Species of the tribe Chorosomatini (Hemiptera: Heteroptera: Rhopalidae: Rhopalinae) occurring in China are reviewed. Type materials of three species described from China, so far of uncertain identities, are re-examined and documented, and taxonomic changes are accordingly proposed. The following synonymies, suspected but not explicitly proposed by previous authors, are confirmed and explicitly proposed: Agraphopus lethierryi Stal, 1872 = A. yunnanus Hsiao, 1965; Leptoceraea viridis Jakovlev, 1873 = L. granulosa Hsiao, 1965; Chorosoma macilentum Stal, 1858 = Ch. brevicolle Hsiao, 1964. Faunistic records of other species of the tribe are provided, and several misidentifications in the previous literature are corrected; Ch. gracile Josifov, 1968, and Ch. schillingii (Schilling, 1829) are recorded for the first time from China. A checklist of the species and subspecies of Chorosomatini occurring in China, with a review of their distribution, and a key for their identification, are provided. PMID- 30486112 TI - Morphological characterization and genotyping of the marbled crayfish and new evidence on its origin. AB - The obligately parthenogenetic marbled crayfish, Procambarus virginalis, is the first formally described asexual species of the Crustacea Decapoda. It is a triploid descendant of the sexually reproducing slough crayfish, Procambarus fallax. Here we describe the morphology of cultured and wild marbled crayfish of wide size ranges in detail and photodocument all taxonomically relevant characters. Some morphological traits and coloration showed considerable variation within populations despite the monoclonal nature of marbled crayfish. There were also significant differences between wild and laboratory populations with respect to body proportions, coloration and spination. Comparison with Procambarus fallax revealed no qualitative morphological characters that unambiguously identify the marbled crayfish. Analysis of the mitochondrial cytochrome c oxidase subunit I gene (COI) and nuclear microsatellites of marbled crayfish and Procambarus fallax from different sources indicated that the tri allelic microsatellite PclG-02 is better suitable than COI to identify the marbled crayfish. A respective identification key is provided. The COI and microsatellites of Procambarus fallax from different areas of Florida and southern Georgia suggest that the parents of the first marbled crayfish may have come from northern Union County, northern Florida. PMID- 30486113 TI - Five new species of Caddisflies (Trichoptera: Insecta) from Upper Tenasserim Range, Thailand and Myanmar. AB - Five new species of caddisflies are described from the Upper Tenasserim Range, including Chimarra keawpradubi n. sp., Ecnomus niyomwasi n. sp., Psychomyia pinsuwanae n. sp., Leptocerus suwannarati n. sp., and Setodes lertpongsombatae n. sp., based on distinctive characters of male genitalia. Chimarra keawpradubi n. sp. differs from other Chimarra spp. in ventral aspect of inferior appendages, each of which is rectangular with a bulging process apicoventrally and with an acute apex. The basal part of each inferior appendage is square and the apical part is narrow in E. niyomwasi n. sp., differentiating it from other species in the genus. Psychomyia pinsuwanae n. sp. differs from P. amphiaraos Malicky and Chantaramongkol 1997, a closely similar species, by characters of the inferior appendages; the inner branch of each inferior appendage has a long, straight spine on its inner side. Leptocerus suwannarati n. sp. can be distinguished from other Leptocerus spp. by the processes of segment X, which are long, thin, and symmetrical. Setodes lertpongsombatae differs from other Setodes spp. in characters of segment X, which is deeply divided subapically into two very long saber-like blades in lateral view. PMID- 30486114 TI - Taxonomic revision of the genus Monastria Saussure, 1864 (Blattodea: Blaberidae, Blaberinae) from the South American Atlantic forest, with the descriptions of five new species. AB - The genus Monastria Saussure, 1864 includes medium to large sized (40-55 mm) dark brown or black cockroaches found in the understory of the Neotropical Atlantic Forest from the Northeast of Brazil to Paraguay and Argentina. The genus shows evident sexual dimorphism: males are elongated with fully developed wings extending beyond the apex of cerci and females are oval and brachypterous. This study is a revision of the genus with redescription of the three already known species, Monastria biguttata (Thunberg, 1826), Monastria similis (Serville, 1838) and Monastria angulata Saussure, 1864, and description of five new ones, Monastria itubera sp. n. and Monastria itabuna sp. n. from state of Bahia, Monastria cabocla sp. n. from state of Sergipe, Monastria kaingangue sp. n. from state of Sao Paulo and Monastria sagittata sp. n. from state of Minas Gerais. The morphology of the genus and all species is described in details, including male genitalia. Based on this revision, we proposed a new combination for Hiereoblatta papillosa (Thunberg, 1826) comb. n., excluding it from the genus Monastria. For the first time, the juvenile stages of Monastria are characterized and compared to other genera of Blaberinae of the Atlantic forest. Three determination keys are provided. The two first are aimed at identifying the adults and juvenile stages of the five genera of the Blaberinae radiation endemic to the Atlantic forest, respectively. The third concerns the identification of the species of the genus Monastria. A map indicating the localities where species were sampled is also provided. PMID- 30486115 TI - A new species of Eurysthea Thomson, 1861 (Coleoptera: Cerambycidae) from Colombia. AB - Eurysthea Thomson, 1861 is currently composed of 23 species (Botero Santos-Silva 2017; Monne 2018). Its distribution extends from Nicaragua to Argentina, with a certain preference toward the sub-Andean forest areas and the Atlantic forest (Martins 2005; Monne 2018). Currently, six species are recorded for Colombia (Botero Santos-Silva 2017; Monne 2018): E. antonkozlovi Botero Santos-Silva, 2017; E. barsevskisi Botero Santos-Silva, 2017; E. cribripennis Bates, 1885; E. rotundicollis (Martins, 1995); E. sordida (Erichson, 1847); and E. tatianakozlovae Botero Santos-Silva, 2017. PMID- 30486116 TI - Type locality of the Baya Weaver Ploceus philippinus (Passeriformes, Ploceidae). AB - The Baya Weaver Ploceus philippinus (Linnaeus, 1766) was one of the first weaverbirds to be described, and although Linnaeus (1766) provided its specific epithet and the type locality of the Philippines, the Baya Weaver does not occur there. Hartert (1902, p. 577) thus restricted the locality to Ceylon (now Sri Lanka), and this locality has been used in all major references since, in spite of Stresemann (1952) showing that the type was most probably collected by Pierre Poivre in India. This paper draws attention to this error so that avian handbooks and taxonomic works may refer to the correct type locality of the Baya Weaver as Puducherry (previously Pondicherry), Puducherry district, India. PMID- 30486117 TI - Second note on the genus Neacanista Gressitt, 1940 (Coleoptera: Cerambycidae: Lamiinae: Acanthocinini). AB - Huang et al. (2015) treated Hoploranomimus Breuning, 1959 (type species: Acanthocinus harmandi Pic, 1939) and Paracanthocinus Breuning, 1965 (type species: Paracanthocinus laosensis Breuning, 1965) as junior synonyms of Neacanista Gressitt, 1940 (type species: Neacanista tuberculipenne Gressitt, 1940) and commented on the taxonomic status of Neacanista shirakii (Mitono, 1943). PMID- 30486118 TI - Three new species of Seira Lubbock (Collembola, Entomobryidae, Seirinae) from Madagascar with Lepidocyrtus-like habitus. AB - Here three new species of Seira from Madagascar are described and illustrated, all with Lepidocyrtus-like habitus, as short antennae, truncate unguiculus, and overall reduction of dorsal macrochaetae. The new species Seira lepidochaetosa sp. nov., Seira semicaerulea sp. nov. and Seira metafemurata sp. nov. can be distinguished from each other by color patterns and chaetotaxic elements. An identification key for these three species is also provided, including a discussion on truncate unguiculus on Seira species with dense and reduced macrochaetotaxy. PMID- 30486119 TI - Five new species and new records of the spider genus Stemmops Araneae, Theridiidae, Spintharinae) from Brazil. AB - The spider genus Stemmops O. Pickard-Cambridge, 1894, currently comprises 22 described species. Spiders of this genus are mainly known from the Neotropical Region, but are poorly studied in Brazil. In this paper five new species of Brazilian Stemmops are described: Stemmops murici new species; Stemmops carauari new species; Stemmops carajas new species; Stemmops pains new species, and Stemmops guapiacu new species. Additionally, new records from Brazil are provided for Stemmops carius Marques Buckup, 1996 from state of Sao Paulo; Stemmops belavista Marques Buckup, 1996 from Mato Grosso do Sul; and Stemmops vicosa Levi, 1964 from Alagoas. The species Stemmops servus Levi, 1964 (known from Panama) is recorded for the first time in Brazil from states of Amazonas, Paraiba, Alagoas, Minas Gerais, Espirito Santo and Rio de Janeiro. PMID- 30486120 TI - Taxonomic morphology of the genus Adineta (Rotifera: Bdelloidea: Adinetidae) with a new species from a suburban garden. AB - The morphological descriptions of the species of bdelloid rotifers and the associated taxonomic difficulties, primarily resulting from the inadequate original descriptions of many species, are discussed. The genus Adineta, whose members are relatively easy to study and frequently encountered, is proposed as a starting point for taxonomic revisions of the Bdelloidea. The taxonomically significant morphological traits in the genus Adineta are discussed. Some of these have rarely been used: the number of denticles on the rake organ and body proportions. These traits are used to describe Adineta beysunae sp. nov., which was found in a sample from a house garden. The new species is diagnosed by the morphology of its rump, foot and rake organ. The latter has up to 11 denticles, the highest number recorded in an Adineta species. PMID- 30486121 TI - Three new species of Zaischnopsis Ashmead (Hymenoptera: Chalcidoidea: Eupelmidae) from Southern China, with redescription of Zaischnopsis tubatius (Walker). AB - Three new species of Zaischnopsis Ashmead from southern China, Z. candetibia Peng sp. nov., Z. fumosa Peng Xiang sp. nov. and Z. nivalinota Peng Xiang sp. nov., are described and illustrated based on females. The only other species of Zaischnopsis recorded from China, Z. tubatius (Walker) is redescribed and illustrated in detail, and the species are differentiated in a key that includes all Zaischnopsis species recorded from the Oriental region. PMID- 30486122 TI - Illustrated and online catalog of the type specimens of birds (Class: Aves) in the Ornithological Collection at the Instituto de Investigacion de Recursos Biologicos Alexander von Humboldt (IAvH-A), Colombia. AB - The catalog of type specimens of birds deposited in the Bird Collection of Instituto de Investigacion de Recursos Biologicos Alexander von Humboldt (IAvH-A) is presented. The list includes 10 specimens representing two holotypes and eight paratypes of three nominal species and five nominal subspecies. Three specimens also have tissues deposited in the Tissue Collection of the Instituto Humboldt (IAvH-CT). Corrections, additions, and updated information of the original descriptions and geographic locations are included as individual remarks for each catalog number and a gallery of photographs of each specimen is provided. An online version of the catalog is available at: http://colecciones.humboldt.org.co/catalogos/tiposaves. PMID- 30486123 TI - Redescription of Garra turcica from southern Anatolia (Teleostei: Cyprinidae). AB - Garra turcica, from the rivers Kizil, Seyhan, Ceyhan and Arsuz, is re-diagnosed and re-described. The species was treated as a synonym of G. rufa but molecular data strongly suggest that G. turcica represent an own species. It is distinguished from G. rufa by being more slender bodied, having a blunt snout and usually a short rostral cap. Based on COI sequence data, G. turcica is closely related to a group of species from the Persian Gulf basin, all having very small distribution areas nested in or adjacent to the range of G. rufa. The closest relatives of G. turcica are G. elegans, G. mondica and G. amirhosseini from which G. turcica differs by having a free posterior edge of the mental disc, the predorsal back covered by scales and the scales on the chest about as large as on the belly as well as by a minimum K2P distance of 2.2% in its COI barcode region. PMID- 30486124 TI - Giant assassin in the cave: a new species of the genus Myiophanes from Sri Lanka (Hemiptera: Heteroptera: Reduviidae: Emesinae). AB - A new thread-legged assassin bug species, Myiophanes (Myiophanes) wygodzinskyi sp. nov. (Hemiptera: Heteroptera: Reduviidae: Emesinae: Emesini), collected from Ravana Cave in Uva Province of Sri Lanka, is described. It is the largest species of the genus described so far. PMID- 30486125 TI - A new, remarkable erigonine spider genus from eastern Asia (Araneae, Linyphiidae). AB - Erigomicronus new genus is erected for Oreonetides longembolus Wunderlich Li, 1995 (the type species) and Maro lautus Saito, 1984. The genitalia of both species are studied in detail and illustrated. Based to the male palp conformation, the new genus seems to belong to the subfamily Erigoninae, but the epigynum resembles that of some "micronetine" genera, e.g. Maro O. Pickard Cambridge, 1906, Oreonetides Strand, 1901, etc., based on the presence of a scape like projection in the epigynum. All records of M. lautus from Russia are erroneous and actually refer to O. longembolus. PMID- 30486126 TI - Immature stages of the Rubiaceae-feeding metalmark butterflies (Lepidoptera: Riodinidae), and a new function for the tentacle nectary organs. AB - Metalmark butterfly (Riodinidae) diversity is heavily concentrated in the Neotropical lowland forests but despite their prevalence basic information on immature stages is still scarce. Here we describe the life cycle of seven taxa in the Rubiaceae-feeding section of the Mesosemiina, including three Mesosemia Hubner, [1819], three Leucochimona Stichel, 1909, and the first information for Semomesia Westwood, 1851. Immature stage morphology of Mesosemia cippus Hewitson, 1859 is described in detail through scanning electron microscopy. Generally, eggs are laid singly and caterpillars are folivorous with a cryptic green coloration except for M. cippus which has gregarious caterpillars with a bright yellow color pattern. Immature stages of all analyzed species are morphologically similar and characterized by: oblate spheroid eggs with small spines on the rib intersections; nonmyrmecophilous larvae with sparse long setae on chalazae or pinnacles, perforated cupola organs (PCOs) and tentacle nectary organs (TNOs) in all instars; pupae attached longitudinally to the substrate by the cremaster and a silk girdle that crosses over abdominal segments A1 or A2. Functionality of the TNOs is documented for the first time in the "Mesosemia section" of the Mesosemiina, but they are not used to facilitate symbiotic interactions between caterpillars and ants. When molested, caterpillars everted the TNOs secreting a conspicuous drop of opaque and viscous liquid with a defensive function. A summary of the host plants in the "Mesosemia section" is presented, confirming the preponderance of oligophagy in the Rubiaceae. The morphological and behavioral traits here described are discussed in the context of defense against natural enemies and constitute key information to understanding the evolution of ant-organs and myrmecophily in riodinids. PMID- 30486127 TI - New data on the taxonomy, distribution and host plants of Australian Epermeniidae (Lepidoptera: Epermenioidea). AB - During the examination of hitherto undetermined specimens, six new species were found: Gnathifera fuscostriata sp. nov., G. luridicapitella sp. nov., G. montana sp. nov., G. robinsoni sp. nov., Epermenia (Epermeniola) macrodentata sp. nov., Gaedikermenia australica sp. nov. Ochromolopis paropsias Gaedike, 1972 is a new synonym of Gnathifera opsias (Meyrick, 1897). The taxa epispora Meyrick, 1897 and parasitica Meyrick, 1930, previously placed in the genus Epermenia, are transferred to Gaedikermenia Sohn Wu, 2015. The male genitalia of Gnathifera bidentella (Gaedike, 1981) and G. acacivorella (Gaedike, 1968), and the female genitalia of G. pseudaphronesa (Gaedike, 1972) and G. queenslandi (Gaedike, 1968) are described and illustrated for the first time. First records within Australia are established for nine species. New host plants are recorded for Gnathifera eurybias (Meyrick, 1897), G. bipunctata (Gaedike, 1968), G. opsias (Meyrick, 1897), Paraepermenia santaliella Gaedike, 1968 and Gaedikermenia epispora (Meyrick, 1897). Now 25 Epermeniidae species are known from Australia. The systematic and generic affiliation of Epermenia xeranta Meyrick, 1917, is still uncertain. PMID- 30486128 TI - Two new species of Petrobunus from China (Opiliones: Laniatores: Petrobunidae). AB - Two new species of Petrobunus Sharma Giribet, 2011, (Petrobunidae) are described: P. chongqing sp. nov. (??) and P. hebei sp. nov. (??). Petrobunus chongqing sp. nov. is similar to P. spinifer Sharma Giribet, 2011, in having two large spines on the male sternite 7. However, the new species can be distinguished from P. spinifer by the absence of a ventral tubercle on the male femur IV, as well as the presence of three pairs of enlarged tubercles on the lateral margin of area V and free tergites I-II. Petrobunus hebei sp. nov. and P. torosus Sharma Giribet, 2011 closely resemble each other. They are distinguished by the morphology of the ocularium, in that P. torosus has a median tubercle whereas the ocularium of P. hebei sp. nov. is unarmed. The discovery and descriptions of these species greatly expand the known range of the genus Petrobunus. PMID- 30486129 TI - Report of Frank Balfour-Browne's collecting in Gran Canaria and Madeira (1932 1933), with the description of Ochthebius (Cobalius) lanthanus sp. nov. (Coleoptera, Hydraenidae). AB - Ochthebius (Cobalius) lanthanus sp. nov. is described from rockpools in Gran Canaria, based on specimens collected by Professor F. Balfour-Browne in 1932 and newly collected material. The species is morphologically very similar to O. (Cobalius) algicola Wollaston, 1871 from Madeira, but at a genetic distance of ca 10% as measured with the gene cytochrome c oxidase subunit 1. The water beetle collections of Balfour-Browne's trip to Gran Canaria (1932) and Madeira (1933) are also reported. PMID- 30486130 TI - Rediagnosis of the squat lobster genus Gastroptychus Caullery, 1896, with a new genus Sternostylus and a new family Sternostylidae (Crustacea: Decapoda: Anomura: Chirostyloidea). AB - The chirostyloidean squat lobster genus Gastroptychus Caullery, 1896 is revised and is split into two genera: Gastroptychus sensu stricto (type species, Ptychogaster spinifer A. Milne-Edwards, 1880) and Sternostylus new genus (type species, Ptychogaster formosus Filhol, 1884). Gastroptychus sensu stricto, is restricted to nine species with a sternal plastron, at sternite 3, abruptly demarcated from the preceding sternites (excavated sternum) by a distinct step forming a well-defined transverse or concave anterior margin at the articulation with maxillipeds 3, the maxillipeds 3 widely separated, with the distal parts accommodated in the excavated sternum between the left and right maxillipeds 3 when folded, and the P2-4 dactyli with the terminal spine demarcated by a suture. Sternostylus new genus, represented by 12 species, has the sternite 3 anteriorly bluntly produced medially and steeply sloping anterodorsally to the anterior sternite, with a pair of spines directly behind the anterior margin, the left and right maxillipeds 3 adjacent, and the P2-4 dactyli ending in an indistinctly demarcated corneous spine. The above-mentioned characters of Gastroptychus are consistent with Chirostylidae sensu stricto. Published molecular phylogenies indicate, however, that Sternostylus is the sister group to all the other Chirostylidae, and is designated the type genus of a new family, Sternostylidae. PMID- 30486131 TI - Two new species of Dentilabus Heinrich (Hymenoptera: Ichneumonidae: Ichneumoninae) from Japan and Korea, with redefinition of the genus. AB - We discovered Dentilabus Heinrich (Icneumoninae: Platylabini) for the first time from the Eastern Palearctic region. Two new species, D. nigripodus sp. n. [Japan and Korea] and D. iyoensis sp. n. [Japan] are described. Dentilabus nigripodus resembles its Western Palearctic congener, D. variegatus (Wesmael), but they can be easily distinguished by the uniformly black hind femora in D. nigripodus. With the inclusion of D. iyoensis, we also redefine the generic limits of Dentilabus. A key to Palearctic species of the genus is provided. PMID- 30486133 TI - Another unusual new gorgonian (Anthozoa: Octocorallia: Plexauridae) from the Aleutian Islands of Alaska. AB - An unusual new species of plexaurid octocoral, Alaskagorgia splendicitrina, is described from a specimen collected in the far west Aleutian Island Archipelago, Alaska, USA. Unusual features that separate it from its only congener include: the vibrant yellow color of the live colony and an arborescent growth form with numerous coiling and twisting branches, the pale yellow color of the sclerites and the lack of small and densely warted double-headed sclerites. The new species is represented by only a single specimen despite extensive sampling in the region during the past several decades; the speculation is that it radiated from the much less explored region to the west. PMID- 30486132 TI - Morphological characterization of Badis species (Teleostei: Badidae) from Nepal. AB - We characterized morphological variation among 172 specimens of Badis sp. (Teleostei: Badidae), collected from across Nepal and previously identified as Badis badis, to investigate whether any represented an undescribed species. Size corrected principal component analysis (PCA), cluster analysis (CA), and discriminant analysis (DA) revealed four significantly different groups. One group was characterized by shallower body depth and shorter pelvic to anal distance than other groups and lacked a cleithral blotch. It was identified as Badis andrewraoi, previously unknown from Nepal, yet represented in our sample by 19 specimens from small rivers in the southeastern part of the country. Distribution of the remaining groups, all identified as B. badis, did not correspond to a zoogeographic hypothesis relating to major river drainages. Instead, morphological differences among these groups was better explained by allometric shifts. We provide information on the distribution and ecology of B. andrewraoi and B. badis in Nepal. PMID- 30486134 TI - Larvae of Huxelhydrus syntheticus Sharp, 1882 (Coleoptera: Dytiscidae: Bidessini). AB - The three larval instars of Huxelhydrus syntheticus Sharp, 1882, the only species of the New Zealand endemic genus Huxelhydrus Sharp, 1882, are described and illustrated including detailed morphometric and chaetotaxic analyses of the cephalic capsule, head appendages, legs, last abdominal segment and urogomphi. Larvae of this species are characterized by the absence of the primary pore ABc, shared with all other known Bidessini larvae and therefore representing a potential synapomorphy of the tribe. Third instars of Huxelhydrus can be separated from those of all other known Bidessini genera by the following combination of characters: larger size, mandibular pore MNa located in a clearly distal position with respect to pore MNb, and presence of secondary setae on dorsal surface of protarsus, on posteroventral surface of all tarsi, and on urogomphus. First instars, on their part, can be distinguished by the presence of: an occipital suture, the primary pore PAk, a ventroapical spinula on antennomere 3, and an anterotransverse carina on meso- and metathorax. PMID- 30486135 TI - Platiana cechovskyi sp. nov. from Malaysia, a remarkable new member of Dimini (Elateridae: Dendrometrinae) with strongly serrate antennae. AB - Platiana Schimmel, 1993 is a moderately large genus in Dimini endemic to South East Asia. Hitherto only four species of this genus were known from Peninsular Malaysia. Here, we describe and figure Platiana cechovskyi sp. nov. from the Cameron Highlands. This species is characteristic by its relatively small body, dark coloration, and strongly serrate antennae which are rarely encountered in Dimini. An identification key to the Platiana species from Peninsular Malaysia as well as a distribution map for all known species are provided. PMID- 30486136 TI - Caribbean species of Eiconaxius (Decapoda: Axiidea: Axiidae). AB - The type status of specimens of three species of the axiid genus Eiconaxius Bate, 1888 from the Caribbean Sea is clarified. Eiconaxius agassizi Bouvier, 1905, E. borradailei Bouvier, 1905 and E. caribbaeus (Faxon, 1896) are diagnosed and illustrated. Axius (Eiconaxius) communis Bouvier, 1905, Axius (Eiconaxius) rotundifrons Bouvier, 1905, and Axius (Eiconaxius) caribbaeus carinatus Bouvier, 1925, hitherto treated as valid species, are synonymised with E. caribbaeus. Lectotypes are selected for Eiconaxius agassizi Bouvier, 1905 and Eiconaxius borradailei Bouvier, 1905. PMID- 30486137 TI - A new species of Conopsia Strand, 1913 (Lepidoptera: Sesiidae: Tinthiinae) from West Africa. AB - A new species of Sesiidae, discovered during a Lepidoptera survey in the Nimba Mountains, Guinea (West Africa) is described as Conopsia puehringeri sp. nov. The new species is compared to its potential sister species C. bicolor (Le Cerf, 1917), in sense of external morphology and genitalia structure. Male specimens and genitalia of both studied species are depicted. PMID- 30486138 TI - Cryptic diversity within the Megophrys major species group (Amphibia: Megophryidae) of the Asian Horned Frogs: Phylogenetic perspectives and a taxonomic revision of South Asian taxa, with descriptions of four new species. AB - The Megophrys major species group (MMSG) is composed of typically medium to large sized frogs. Within the genus, it is the most geographically widespread clade ranging from the western Himalayas to southern Indochina. In this study, we examined in detail the extent of cryptic diversity within the MMSG-Indian populations based on molecular data (up to ten genes) using multigene concatenation and coalescent-based phylogenetic techniques, species delimitation analyses and extensive morphological data.Molecular evidence suggests a high level of hidden cryptic diversity within the MMSG, particularly within the M. major species complex (MMC), highlighting overlapping distributions, a case of potential mitochondrial transfer between two species, and tree topology discordance between phylogenetic methods and mitochondrial and nuclear data sets. Most analyses indicated distinct eastern and western clades in the MMC, and that the western clade may further divide into a northern and a southern subclade.A detailed taxonomic review of Indian members of the Megophrys major species group is provided. Previously undocumented complex nomenclatural issues involving known species are highlighted and resolved. Megophrys monticola is taxonomically redefined for the first time as a valid species since its synonymy with M. parva in 1893. The taxonomic status of two recently described species, Xenophrys katabhako and X. sanu are discussed in light of increased molecular and morphological sampling, and are synonymised with M. monticola. Megophrys monticola and M. robusta are redescribed based on their original type specimens and recently collected material. Megophrys major is neotypified and M. robusta lectotypified to remove prevailing nomenclatural instability. Four new large sized Indian MMC species are formally described from the Northeast Indian states of Arunachal Pradesh, Meghalaya and Nagaland, and Myanmar. All South Asian MMSG species are morphologically diagnosed from known congeners in the group. The geographic distributions of all taxa discussed are significantly redefined based on the revised taxonomy and extensive literature review. Morphological and molecular evidence suggests that Megophrys major sensu stricto might be endemic to Northeast India; M. glandulosa is formally removed from the Indian and Bhutan species checklists. Numerous misidentifications in literature are highlighted and corrected. In order to reduce future misidentifications of species reported from surrounding regions, high definition images of the holotypes of three Chinese species, M. glandulosa, M. medogensis and M. zhangi are provided for the first time, and a detailed description of Myanmar specimens of M. glandulosa is also given. This study provides the principle foundation for further research into the taxonomic status of the remaining, currently undescribed MMC taxa from Southeast Asia. PMID- 30486139 TI - Mammals of Korea: a review of their taxonomy, distribution and conservation status. AB - The Korean Peninsula and its associated Pacific islands have a distinctive, yet poorly studied mammalian fauna. Korea was a land of invasions and wars for many centuries. The loss of large mammals per unit area that has occurred in Korea may have been greater than in any other country. The peninsula has a depauperate rodent community. The forests are mostly harvested, replaced by intensive agriculture. Unfortunately, the dissemination of information about the mammals of Korea and their taxonomy has been limited because most publications were written in Japanese or Korean. We provide an updated checklist of all the species of Korean mammals, including a review of their taxonomy, distribution, and conservation status based on information extracted from international museum collections, local survey databases (Wildlife Survey and National Nature Environmental Survey, South Korea) and a literature review. We identify 84 species of terrestrial mammals and 43 species of marine mammals that occur, or once occurred, in Korea. Due to previous, erroneous identifications, we delisted three soricids, two vespertilionids, one phocid, one sciurid and one murid. In total, we confirm the presence in Korea of 127 species of mammals distributed in eight Orders and 32 Families. We provide dichotomous keys for the identification of all the Korean species of mammals together with updated distribution maps. PMID- 30486140 TI - The oak gall wasps of Israel (Hymenoptera, Cynipidae, Cynipini)-diversity, distribution and life history. AB - Oak-galling wasps (Hymenoptera: Cynipidae, Cynipini) have been studied in Israel only superficially so far, despite interest in the Israeli fauna given its location at the southern edge of distribution range of the wasps and their oak hosts. We provide the first comprehensive review of the Israeli fauna of oak cynipids based on an extensive survey of the five naturally occurring oak species in Israel. We report 53 cynipid species, 37 of which are reported from Israel for the first time, 10 are currently known only from this country, and 9 are undescribed. With 27 species, Andricus is by far the biggest genus in Israel, followed by Cerroneuroterus, Neuroterus Plagiotrochus, and Pseudoneuroterus with 4 species each. Andricus megalucidus is synonymized under A. cecconii and Cerroneuroterus cerrifloralis is synonymized under C. lanuginosus. The sexual generations of Andricus cecconii, A. coriariformis, A. coriarius, A. miriami, Cerroneuroterus lanuginosus and Pseudoneuroterus macropterus are reported here for the first time. We recorded 65 gall types, with bud galls being the most common and conspicuous, followed by leaf and catkin galls. We provide illustrated keys for all Israeli species based on their galls, as well as information on host associations, life history, phenology and distribution patterns where available. 21 cynipid species are associated with Quercus ithaburensis and 27 species are associated with Q. boissieri, whereas Q. libani, Q. calliprinos and Q. cerris host much fewer species. Most species are currently known from either their sexual or asexual generation while only 24% of them are known from both. Mount Hermon was found to be an important hotspot, hosting about half of the Israeli cynipid fauna, and species richness generally declines from the Golan Heights southwards to the Judean Mountains. Cynipid species that are associated with oaks of sections Cerris and Quercus in Europe are mostly associated with the same sections in Israel.